PMID- 27989116 TI - Elusive Double-Eight-Ring Zeolitic Secondary Building Unit. AB - The double-eight-ring (D8R), an elusive secondary building unit of zeolites, has been stabilized for the first time, both in solution and solid-state. The present study further establishes that any of the three double-ring building blocks of zeolites, viz. D4R, D6R and D8R ([ArPO3Zn(L)]n (n = 4, 6 or 8)), can be preferentially isolated (over the other two) through a careful choice of metal source, aryl phosphate and ancillary ligand, apart from maintaining a meticulous control on the reaction conditions. PMID- 27989117 TI - HPLC Separation of Sulforaphane Enantiomers in Broccoli and Its Sprouts by Transformation into Diastereoisomers Using Derivatization with (S)-Leucine. AB - Racemic sulforaphane, which was derivatized with (S)-leucine (l-leucine), was resolved by reversed phase HPLC with UV detection. The optimum mobile phase conditions were found to be 10 mM citric acid (pH 2.8) containing 22% methanol at 35 degrees C using detection at 254 nm. Sulforaphane enantiomers in florets and stems of five brands of broccoli and leaves and stems of three brands of broccoli sprouts were analyzed by the proposed HPLC method. Both sulforaphane enantiomers were detected in all of the samples. The S/R ratios of sulforaphane in broccoli samples were 1.5-2.6/97.4-98.5% for florets and 5.0-12.1/87.9-95.0% for stems. The S/R ratios in broccoli sprout samples were higher than those in broccoli samples and were found to be 8.3-19.7/80.3-91.7% for leaves and 37.0-41.8/58.2 63.0% for stems. (S)-Sulforaphane detected in the broccoli and its sprout samples was positively identified by separately using an HPLC with a chiral column (Chiralpak AD-RH) and mass spectrometry. PMID- 27989118 TI - High-Speed, Comprehensive, Two Dimensional Separations of Peptides and Small Molecule Biological Amines Using Capillary Electrophoresis Coupled with Micro Free Flow Electrophoresis. AB - Two-dimensional (2D) separations are able to generate significantly higher peak capacities than their one-dimensional counterparts. Unfortunately, current hyphenated 2D separations are limited by the speed of the second dimension separation and the consequent loss of peak capacity due to under sampling of peaks as they elute from the first dimension separation. Continuous micro free flow electrophoresis (MUFFE) separations eliminate under sampling as a limitation when incorporated as the second dimension of a 2D separation. In the current manuscript we describe the first coupling of capillary electrophoresis (CE) with MUFFE to perform 2D CE * MUFFE separations. The CE separation capillary was directly inserted into the MUFFE separation channel using an edge on interface. Analyte peaks streamed directly into the MUFFE separation channel as they migrated off the CE capillary. No complicated injection, valving, or voltage changes were necessary to couple the two separation modes. 2D CE * MUFFE generated an ideal peak capacity of 2 592 in a 9 min separation of fluorescently labeled peptides (7.6 min separation window, 342 peaks/min). Data points were recorded every 250-500 ms (>8 data points/peak), effectively eliminating under sampling as a source of band broadening. CE * MUFFE generated an ideal peak capacity of 1885 in a 2.7 min separation of fluorescently labeled small molecule bioamines (1.8 min separation window, 1053 peaks/min). Peaks in the 2D CE * MUFFE separation of peptides covered 30% of the available separation space, resulting in a corrected peak capacity of 778 (102 peaks/min). The fractional coverage of the 2D CE * MUFFE separation of small molecule bioamines was 20%, resulting in a corrected peak capacity of 377 (209 peaks/min). PMID- 27989120 TI - Tracking Invisible Transformations of Physisorbed Monolayers: LDI-TOF and MALDI TOF Mass Spectrometry as Complements to STM Imaging. AB - Triphenyleneethynylene (TPEE) derivatives bearing one long aliphatic chain on each terminal aryl ring and two short aliphatic chains on the central aryl ring (core chains) self-assemble single component and 1-D patterned, two-component, crystalline monolayers at the solution-graphite interface. The monolayer morphology directs the core chains off the graphite, making them accessible for chemical reactions but invisible to imaging by scanning tunneling microscopy (STM). This precludes using STM to monitor transformations of the core chains, either by reaction or solution-monolayer exchange of TPEE molecules. Laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS) successfully identifies TPEE compounds within physisorbed monolayers. The LDI-TOF spectra of TPEE monolayer-graphite samples exhibit strong molecular ion peaks and minimal fragmentation or background. LDI-TOF and STM techniques are combined to evaluate monolayer composition and morphology, track solution-monolayer exchange, to identify reaction products and to measure kinetics of chemical reactions at the solution-monolayer interface. LDI-TOF MS provides rapid qualitative evaluation of monolayer composition across a graphite substrate. Challenges to quantitative composition evaluation by LDI-TOF include compound-specific light absorption, surface desorption/ionization and fragmentation characteristics. For some, but not all, compounds, applying matrix onto a self-assembled monolayer increases molecular ion intensities and affords more accurate assessment of monolayer composition via matrix assisted laser desorption/ionization (MALDI) MS. Matrix addition precludes subsequent chemical or STM studies of the monolayer, whereas reactions and STM may be performed at nonirradiated regions following LDI-TOF measurements. LDI- and MALDI-TOF MS are useful complements to STM and are easily implemented tools for study of physisorbed monolayers. PMID- 27989122 TI - Optical Fiber-Type Sugar Chip Using Localized Surface Plasmon Resonance. AB - Optical fiber-type Sugar Chips were developed using localized surface plasmon resonance (LSPR) of gold (Au) nanoparticles. The endface of an optical fiber was first aminosilylated and then condensed with alpha-lipoic acid containing a dithiol group. Second, gold nanoparticles were immobilized onto the endface via an Au-S covalent bond. Finally, sugar moieties were attached to the gold nanoparticle using our original sugar chain-ligand conjugates to obtain fiber type Sugar Chips, by which the sugar moiety-protein interaction was analyzed. The specificity, sensitivity, and quantitative binding potency against carbohydrate binding protein were found to be identical to that of a conventional SPR sensor. In this analysis, only a small sample volume (approximately 10 MUL) was required compared with 100 MUL for the conventional SPR sensor, suggesting that the fiber type Sugar Chip and LSPR are applicable for nonpure small masses of proteins. PMID- 27989121 TI - Short Carboxylic Acid-Carboxylate Hydrogen Bonds Can Have Fully Localized Protons. AB - Short hydrogen bonds (H-bonds) have been proposed to play key functional roles in several proteins. The location of the proton in short H-bonds is of central importance, as proton delocalization is a defining feature of low-barrier hydrogen bonds (LBHBs). Experimentally determining proton location in H-bonds is challenging. Here, bond length analysis of atomic (1.15-0.98 A) resolution X-ray crystal structures of the human protein DJ-1 and its bacterial homologue, YajL, was used to determine the protonation states of H-bonded carboxylic acids. DJ-1 contains a buried, dimer-spanning 2.49 A H-bond between Glu15 and Asp24 that satisfies standard donor-acceptor distance criteria for a LBHB. Bond length analysis indicates that the proton is localized on Asp24, excluding a LBHB at this location. However, similar analysis of the Escherichia coli homologue YajL shows both residues may be protonated at the H-bonded oxygen atoms, potentially consistent with a LBHB. A Protein Data Bank-wide screen identifies candidate carboxylic acid H-bonds in approximately 14% of proteins, which are typically short [?dO-O? = 2.542(2) A]. Chemically similar H-bonds between hydroxylated residues (Ser/Thr/Tyr) and carboxylates show a trend of lengthening O-O distance with increasing H-bond donor pKa. This trend suggests that conventional electronic effects provide an adequate explanation for short, charge-assisted carboxylic acid-carboxylate H-bonds in proteins, without the need to invoke LBHBs in general. This study demonstrates that bond length analysis of atomic resolution X-ray crystal structures provides a useful experimental test of certain candidate LBHBs. PMID- 27989123 TI - Standardized Markerless Gene Integration for Pathway Engineering in Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica is a promising microbial host due to its native capacity to produce lipid-based chemicals. Engineering stable production strains requires genomic integration of modified genes, avoiding episomal expression that requires specialized media to maintain selective pressures. Here, we develop a CRISPR-Cas9-based tool for targeted, markerless gene integration into the Y. lipolytica genome. A set of genomic loci was screened to identify sites that were accepting of gene integrations without impacting cell growth. Five sites were found to meet these criteria. Expression levels from a GFP expression cassette were consistent when inserted into AXP, XPR2, A08, and D17, with reduced expression from MFE1. The standardized tool is comprised of five pairs of plasmids (one homologous donor plasmid and a CRISPR-Cas9 expression plasmid), with each pair targeting gene integration into one of the characterized sites. To demonstrate the utility of the tool we rapidly engineered a semisynthetic lycopene biosynthesis pathway by integrating four different genes at different loci. The capability to integrate multiple genes without the need for marker recovery and into sites with known expression levels will enable more rapid and reliable pathway engineering in Y. lipolytica. PMID- 27989124 TI - Vesicle-to-Micelle Transition in Aqueous Solutions of l-Cysteine-Derived Carboxylate Surfactants Containing Both Hydrocarbon and Poly(ethylene glycol) Tails. AB - In our recent reports, we have shown that when a poly(ethylene glycol) (PEG) chain is covalently linked to any ionic group, the resultant molecule behaves like an amphiphile. Depending upon the nature of ionic head groups, they self assemble to form micelles or vesicles, in which the PEG chain constitutes the micellar core or vesicle bilayer. In this study, we intend to examine what happens when both hydrocarbon (HC) and PEG chains are attached to a carboxylate head group. Therefore, we have synthesized two novel amphiphiles in which a PEG and a HC chain is covalently linked to l-cysteine. The surface activities and the solution behavior of the sodium salts of these amphiphiles were investigated at neutral pH. The amphiphiles self-organize to form large unilamellar vesicles in dilute solutions, which transformed into small micelles at higher concentrations. The HC chains of the molecules have been shown to constitute the bilayer membrane of the vesicles and core of micelles. In acidic pH, the amphiphiles were found to form large disklike micelles. The thermodynamic parameters of self-assembly formation were also measured by isothermal titration calorimetry. The vesicle and micelle formation was found to be spontaneous and thermodynamically favorable. The thermal stability of the micelles at neutral and acidic pH was studied. The addition of cholesterol was observed to increase the physical stability of vesicles. PMID- 27989125 TI - Characterization of the Typical Potent Odorants in Chinese Roasted Sesame-like Flavor Type Liquor by Headspace Solid Phase Microextraction-Aroma Extract Dilution Analysis, with Special Emphasis on Sulfur-Containing Odorants. AB - The aroma profile of Chinese roasted sesame-like flavor type liquor was investigated by means of headspace solid phase microextraction-aroma extract dilution analysis (HS-SPME-AEDA). Sixty-three odor-active regions were detected by HS-SPME-AEDA with flavor dilution (FD) factors >5, and 58 of these were further identified. Among them, ethyl hexanoate, 2-furfurylthiol, dimethyl trisulfide, 3-methylbutanal, ethyl butanoate, ethyl 2-methylbutanoate, ethyl pentanoate, and ethyl 4-methylpentanoate appeared with the highest FD factors. In particular, eight sulfur-containing odorants were identified to be potentially important to roasted sesame-like flavor type liquor. The concentration of these odor-active compounds was further quantitated by combination of four different quantitative measurements, and 36 odorants had concentrations higher than their corresponding odor thresholds. On the basis of the odor activity values (OAVs), 2 furfurylthiol (OAV 1182), dimethyl trisulfide (OAV 220), beta-damascenone (OAV 116), and methional (OAV 99) could be responsible for the unique aroma of roasted sesame-like flavor type liquor. An aroma recombination model prepared by mixing 36 aroma compounds with OAVs >1 showed a good similarity to the aroma of the original roasted sesame-like flavor type liquor. For the first time, 2 furfurylthiol was determined to be a typical potent odorant in roasted sesame like flavor type liquor by omission study. PMID- 27989126 TI - Iron Chelation Nanoparticles with Delayed Saturation as an Effective Therapy for Parkinson Disease. AB - Iron accumulation in substantia nigra pars compacta (SNpc) has been proved to be a prominent pathophysiological feature of Parkinson's diseases (PD), which can induce the death of dopaminergic (DA) neurons, up-regulation of reactive oxygen species (ROS), and further loss of motor control. In recent years, iron chelation therapy has been demonstrated to be an effective treatment for PD, which has shown significant improvements in clinical trials. However, the current iron chelators are suboptimal due to their short circulation time, side effects, and lack of proper protection from chelation with ions in blood circulation. In this work, we designed and constructed iron chelation therapeutic nanoparticles protected by a zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) to delay the saturation of iron chelators in blood circulation and prolong the in vivo lifetime, with HIV-1 trans-activating transcriptor (TAT) served as a shuttle to enhance the blood-brain barrier (BBB) permeability. We explored and investigated whether the Parkinsonian neurodegeneration and the corresponding symptoms in behaviors and physiologies could be prevented or reversed both in vitro and in vivo. The results demonstrated that iron chelator loaded therapeutic nanoparticles could reverse functional deficits in Parkinsonian mice not only physiologically but also behaviorally. On the contrary, both untreated PD mice and non-TAT anchored nanoparticle treated PD mice showed similar loss in DA neurons and difficulties in behaviors. Therefore, with protection of zwitterionic polymer and prolonged in vivo lifetime, iron chelator loaded nanoparticles with delayed saturation provide a PD phenotype reversion therapy and significantly improve the living quality of the Parkinsonian mice. PMID- 27989127 TI - Wetting and Dewetting Transitions on Submerged Superhydrophobic Surfaces with Hierarchical Structures. AB - The wetting transition on submersed superhydrophobic surfaces with hierarchical structures and the influence of trapped air on superhydrophobic stability are predicted based on the thermodynamics and mechanical analyses. The dewetting transition on the hierarchically structured surfaces is investigated, and two necessary thermodynamic conditions and a mechanical balance condition for dewetting transition are proposed. The corresponding thermodynamic phase diagram of reversible transition and the critical reversed pressure well explain the experimental results reported previously. Our theory provides a useful guideline for precise controlling of breaking down and recovering of superhydrophobicity by designing superhydrophobic surfaces with hierarchical structures under water. PMID- 27989119 TI - Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future. AB - Serum albumin (Alb) is the most abundant protein in blood plasma. Alb reacts with many carcinogens and/or their electrophilic metabolites. Studies conducted over 20 years ago showed that Alb forms adducts with the human carcinogens aflatoxin B1 and benzene, which were successfully used as biomarkers in molecular epidemiology studies designed to address the role of these chemicals in cancer risk. Alb forms adducts with many therapeutic drugs or their reactive metabolites such as beta-lactam antibiotics, acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, and antiretroviral therapy drugs. The identification and characterization of the adduct structures formed with Alb have served to understand the generation of reactive metabolites and to predict idiosyncratic drug reactions and toxicities. The reaction of candidate drugs with Alb is now exploited as part of the battery of screening tools to assess the potential toxicities of drugs. The use of gas chromatography mass spectrometry, liquid chromatography, or liquid chromatography-mass spectrometry (LC-MS) enabled the identification and quantification of multiple types of Alb xenobiotic adducts in animals and humans during the past three decades. In this perspective, we highlight the history of Alb as a target protein for adduction to environmental and dietary genotoxicants, pesticides, and herbicides, common classes of medicinal drugs, and endogenous electrophiles, and the emerging analytical mass spectrometry technologies to identify Alb-toxicant adducts in humans. PMID- 27989128 TI - [4Fe-4S] Cluster Assembly in Mitochondria and Its Impairment by Copper. AB - The cellular toxicity of copper is usually associated with its ability to generate reactive oxygen species. However, recent studies in bacterial organisms showed that copper toxicity is also strictly connected to iron-sulfur cluster proteins and to their assembly processes. Mitochondria of eukaryotic cells contain a labile copper(I) pool localized in the matrix where also the mitochondrial iron-sulfur (Fe/S) cluster assembly machinery resides to mature mitochondrial Fe/S cluster-containing proteins. Misregulation of copper homeostasis might therefore damage mitochondrial Fe/S protein maturation. To describe, from a molecular perspective, the effects of copper(I) toxicity on such a maturation process, we have here investigated the still unknown mechanism of [4Fe-4S] cluster formation conducted by the mitochondrial ISCA1/ISCA2 and GLRX5 proteins, and defined how copper(I) can impair this process. The molecular model here proposed indicates that the copper(I) and Fe/S protein maturation cellular pathways need to be strictly regulated to avoid copper(I) ion from blocking mitochondrial [4Fe-4S] protein maturation. PMID- 27989129 TI - Dendritic Mesoporous Silica Nanospheres Synthesized by a Novel Dual-Templating Micelle System for the Preparation of Functional Nanomaterials. AB - Highly monodisperse, dendritic, and functionalized mesoporous silica nanospheres (MSNs) with sub-200 nm size were synthesized in a one-pot sol-gel reaction, by a dual-templating micelle system consisting of a partially fluorinated short-chain anionic fluorocarbon surfactant and cetyltrimethylammonium bromide. This kind of anionic fluorocarbon surfactant works simultaneously as a swelling agent to enlarge the pore of the MSNs, an ion-pair agent to the structure-directing silane in the preparation of amine-functionalized MSNs, and a surface tension reducing agent to make the system thermodynamically more stable for producing more uniform MSNs. The particle size and the morphology of the resultant MSNs can be fine tuned by changing the amount of the fluorocarbon surfactant added and the ratio of the functional group containing organosilane to tetraethoxysilane. Subsequently, the as-prepared MSNs were used as base materials for the preparation of drug delivery nanomaterials through the surface grafting of a pH sensitive drug-conjugated polymer and fluorescent nanomaterials through the embedding of europium(III) complex or the immobilization of large molecule fluorescein isothiocyanate-bovine serum albumin. PMID- 27989130 TI - Structural and Biochemical Characterization of Organotin and Organolead Compounds Binding to the Organomercurial Lyase MerB Provide New Insights into Its Mechanism of Carbon-Metal Bond Cleavage. AB - The organomercurial lyase MerB has the unique ability to cleave carbon-Hg bonds, and structural studies indicate that three residues in the active site (C96, D99, and C159 in E. coli MerB) play important roles in the carbon-Hg bond cleavage. However, the role of each residue in carbon-metal bond cleavage has not been well defined. To do so, we have structurally and biophysically characterized the interaction of MerB with a series of organotin and organolead compounds. Studies with two known inhibitors of MerB, dimethyltin (DMT) and triethyltin (TET), reveal that they inhibit by different mechanisms. In both cases the initial binding is to D99, but DMT subsequently binds to C96, which induces a conformation change in the active site. In contrast, diethyltin (DET) is a substrate for MerB and the SnIV product remains bound in the active site in a coordination similar to that of HgII following cleavage of organomercurial compounds. The results with analogous organolead compounds are similar in that trimethyllead (TML) is not cleaved and binds only to D99, whereas diethyllead (DEL) is a substrate and the PbIV product remains bound in the active site. Binding and cleavage is an exothermic reaction, while binding to D99 has negligible net heat flow. These results show that initial binding of organometallic compounds to MerB occurs at D99 followed, in some cases, by cleavage and loss of the organic moieties and binding of the metal ion product to C96, D99, and C159. The N-terminus of MerA is able to extract the bound PbVI but not the bound SnIV. These results suggest that MerB could be utilized for bioremediation applications, but certain organolead and organotin compounds may present an obstacle by inhibiting the enzyme. PMID- 27989131 TI - Integrative "-Omics" Analysis in Primary Human Hepatocytes Unravels Persistent Mechanisms of Cyclosporine A-Induced Cholestasis. AB - Cyclosporine A (CsA) is an undecapeptide with strong immunosuppressant activities and is used a lot after organ transplantation. Furthermore, it may induce cholestasis in the liver. In general, the drug-induced cholestasis (DIC) pathway includes genes involved in the uptake, synthesis, conjugation, and secretion of bile acids. However, whether CsA-induced changes in the cholestasis pathway in vitro are persistent for repeated dose toxicity has not yet been investigated. To explore this, primary human hepatocytes (PHH) were exposed to a subcytotoxic dose of 30 MUM CsA daily for 3 and 5 days. To investigate the persistence of induced changes upon terminating CsA exposure after 5 days, a subset of PHH was subjected to a washout period (WO-period) of 3 days. Multiple -omics analyses, comprising whole genome analysis of DNA methylation, gene expression, and microRNA expression, were performed. The CsA-treatment resulted after 3 and 5 days, respectively, in 476 and 20 differentially methylated genes (DMGs), 1353 and 1481 differentially expressed genes (DEGs), and in 22 and 29 differentially expressed microRNAs (DE-miRs). Cholestasis-related pathways appeared induced during CsA treatment. Interestingly, 828 persistent DEGs and 6 persistent DE-miRs but no persistent DMGs were found after the WO-period. These persistent DEGs and DE-miRs showed concordance for 22 genes. Furthermore, 29 persistent DEGs changed into the same direction as observed in livers from cholestasis patients. None of those 29 DEGs which among others relate to oxidative stress and lipid metabolism are yet present in the DIC pathway or cholestasis adverse outcome pathway (AOP) thus presenting novel findings. In summary, we have demonstrated for the first time a persistent impact of repeated dose administration of CsA on genes and microRNAs related to DIC in the gold standard human liver in vitro model with PHH. PMID- 27989132 TI - Dietary Phytochemicals and Cancer Chemoprevention: A Perspective on Oxidative Stress, Inflammation, and Epigenetics. AB - Oxidative stress occurs when cellular reactive oxygen species levels exceed the self-antioxidant capacity of the body. Oxidative stress induces many pathological changes, including inflammation and cancer. Chronic inflammation is believed to be strongly associated with the major stages of carcinogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating oxidative stress and inflammation by manipulating key antioxidant and detoxification enzyme genes via the antioxidant response element. Many dietary phytochemicals with cancer chemopreventive properties, such as polyphenols, isothiocyanates, and triterpenoids, exert antioxidant and anti-inflammatory functions by activating the Nrf2 pathway. Furthermore, epigenetic changes, including DNA methylation, histone post-translational modifications, and miRNA mediated post-transcriptional alterations, also lead to various carcinogenesis processes by suppressing cancer repressor gene transcription. Using epigenetic research tools, including next-generation sequencing technologies, many dietary phytochemicals are shown to modify and reverse aberrant epigenetic/epigenome changes, potentially leading to cancer prevention/treatment. Thus, the beneficial effects of dietary phytochemicals on cancer development warrant further investigation to provide additional impetus for clinical translational studies. PMID- 27989134 TI - Stability and Application of Reactive Nitrogen and Oxygen Species-Induced Hemoglobin Modifications in Dry Blood Spots As Analyzed by Liquid Chromatography Tandem Mass Spectrometry. AB - Dried blood spot (DBS) is an emerging microsampling technique for the bioanalysis of small molecules, including fatty acids, metabolites, drugs, and toxicants. DBS offers many advantages as a sample format including easy sample collection and cheap sample shipment. Hemoglobin adducts have been recognized as a suitable biomarker for monitoring chemical exposure. We previously reported that certain modified peptides in hemoglobin derived from reactive chlorine, nitrogen, and oxygen species are associated with factors including smoking, diabetes mellitus, and aging. However, the stability of these oxidation-induced modifications of hemoglobin remains unknown and whether they can be formed artifactually during storage of DBS. To answer these questions, globin extracted from the DBS cards was analyzed, and the stability of the modifications was evaluated. After storage of the DBS cards at 4 degrees C or room temperature up to 7 weeks, we isolated globin from a quarter of the spot every week. The extents of 11 sites and types of post-translational modifications (PTMs), including nitration and nitrosylation of tyrosine and oxidation of cysteine and methionine residues, in human hemoglobin were measured in the trypsin digest by nanoflow liquid chromatography nanospray ionization tandem mass spectrometry (nanoLC-NSI/MS/MS) using selected reaction monitoring. The extents of all these PTMs are stable within 14 days when stored on DBS at room temperature and at 4 degrees C, while those from direct extraction of fresh blood are stable for at least 8 weeks when stored as an aqueous solution at -20 degrees C. Extraction of globin from a DBS card is of particular importance for hemolytic blood samples. To our knowledge, this is the first report on the stability of oxidative modifications of hemoglobin on DBSs, which are stable for 14 days under ambient conditions (room temperature, in air). Therefore, it is feasible and convenient to analyze these hemoglobin modifications from DBSs in studies involving large populations. PMID- 27989135 TI - EPR Imaging Spin Probe Trityl Radical OX063: A Method for Its Isolation from Animal Effluent, Redox Chemistry of Its Quinone Methide Oxidation Product, and in Vivo Application in a Mouse. AB - We report herein a method for the recovery, purification, and application of OX063, a costly, commercially available nontoxic spin probe widely used for electron paramagnetic resonance (EPR) imaging, as well as its corresponding quinone methide (QM) form. This precious probe can be successfully recovered after use in animal model experiments (25-47% recovery from crude lyophilizate with 98.5% purity), even from samples that are >2 years old. Significantly, the recovered trityl can be reused in further animal model EPR imaging experiments. The work also describes support for the observed formation of an air-sensitive radical derived from the QM under reducing conditions. PMID- 27989136 TI - Dynamic Phosphorylation of Apoptosis Signal Regulating Kinase 1 (ASK1) in Response to Oxidative and Electrophilic Stress. AB - Apoptosis signal-regulating kinase 1 (ASK1) is a critical cellular stress sensor that senses diverse reactive chemotypes and integrates these chemical signals into a single biological pathway response. It is unknown whether ASK1 senses all stressors in the same way or if unique stress-specific mechanisms detect distinct chemotypes. In order to answer this question, we treated ASK1-expressing cells with two distinct stress activators, H2O2 and 4-hydroxy-2-nonenal (HNE), and monitored the phosphorylation state of ASK1. Phosphorylation is an important regulator for the activity of ASK1, and we hypothesized that these two chemically distinct molecules may produce differences in the phosphorylation state of ASK1. Shotgun mass spectrometry and manual validation identified 12 distinct ASK1 phosphosites. Targeted parallel reaction monitoring assays were used to track the phosphorylation dynamics of each confirmed site in response to treatment. Eleven phosphosites exhibited dynamic response to one or both treatments. Six of these sites were identified in both H2O2- and HNE-treated cells, and four of these exhibited a consistent response between the two molecules. The results confirm that different chemotypes produce distinct phosphorylation patterns in concert with activation of a common MAPK pathway. PMID- 27989138 TI - A History of the Molecular Initiating Event. AB - The adverse outcome pathway (AOP) framework provides an alternative to traditional in vivo experiments for the risk assessment of chemicals. AOPs consist of a number of key events (KEs) linked by key event relationships across a range of biological organization backed by scientific evidence. The first KE in the pathway is the molecular initiating event (MIE)-the initial chemical trigger that starts an AOP. Over the past 3 years the AOP conceptual framework has gained a large amount of momentum in toxicology as an alternative to animal methods, and so the MIE has come into the spotlight. What is an MIE? How can MIEs be measured or predicted? What research is currently contributing to our understanding of MIEs? In this Perspective we outline answers to these key questions. PMID- 27989137 TI - Evaluation of Nitrosamide Formation in the Cytochrome P450-Mediated Metabolism of Tobacco-Specific Nitrosamines. AB - N'-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are carcinogenic tobacco-specific nitrosamines believed to play a vital role in the initiation of tobacco-related cancers. For their carcinogenicities to be exhibited, both NNN and NNK must be metabolically activated by cytochrome P450s, specifically P450 2A6 and P450 2A13, respectively. Prior research has focused on alpha-hydroxylation, which leads to the formation of several DNA adducts that have been identified and quantified in vivo. However, some studies indicate that P450s can retain substrates within their active sites and perform processive oxidation. For nitrosamines, this would oxidize the highly unstable alpha-hydroxynitrosamines to potentially more stable nitrosamides, which could also alkylate DNA. Thus, we hypothesized that both NNN and NNK are processively oxidized in vitro to nitrosamides by P450 2A6 and P450 2A13, respectively. To test this hypothesis, we synthesized the NNN- and NNK-derived nitrosamides, determined their half-lives at pH 7.4 and 37 degrees C, and monitored for nitrosamide formation in an in vitro P450 system with product analysis by LC/NSI+ HRMS/MS. Half-lives of the nitrosamides were determined by HPLC-UV and ranged from 7-35 min, which is more than 40 times longer than the corresponding alpha hydroxynitrosamines. Incubation of NNN in the P450 2A6 system resulted in the formation of the nitrosamide N'-nitrosonorcotinine (NNC) at low levels. Similarly, the nitrosamide 4-(methylnitrosamino)-1-(3-pyridyl)-1,4-butanedione (CH2-oxo-NNK) was detected in low amounts in the incubation of NNK with the P450 2A13 system. The other possible NNK-derived nitrosamide, 4-(nitrosoformamido)-1 (3-pyridyl)-1-butanone (CH3-oxo-NNK), was not observed in the P450 2A13 reactions. CH2-oxo-NNK readily formed O6meGua in reactions with dGuo and calf thymus DNA. These results demonstrate that NNC and CH2-oxo-NNK are novel metabolites of NNN and NNK, respectively. Though low-forming, their increased stability may allow for mutagenic DNA damage in vivo. More broadly, this study provides the first account of a cytochrome P450-mediated conversion of nitrosamines to nitrosamides, which warrants further studies to determine how general this phenomenon is in nitrosamine metabolism. PMID- 27989139 TI - Unpredicted Downregulation of RAD51 Suggests Genome Instability Induced by Tetrachlorobenzoquinone. AB - We previously demonstrated that halogenated quinone induces DNA double strand breaks (DSBs) in a ROS-dependent manner, which coordinates with downstream repair cascade including nonhomologous end joining, base excision repair, and nucleotide excision repair. However, these error-prone processes may cause the potential risk of genome instability, and current has no information on how faithful repair route, such as homologous recombination (HR), was affected. RAD51 is a key protein in the HR pathway of DSBs repair. Here, we found that tetrachlorobenzoquinone (TCBQ) causes a time-dependent reverse U-shape biphasic trend of RAD51 expression. An increase in the early stage and a following decrease of RAD51 expression were found in both 12.5 and 25 MUM TCBQ groups, wherein higher concentration faced a faster response. The upregulated RAD51 in the early phase suggested the attempting to repair TCBQ-induced DNA damage; however, the downregulation of RAD51 in the late phase implicated that the rescue probably be abandoned with severe DNA damage. This phenomenon is a general toxic manner of TCBQ regardless of cell type. Surprisingly, TCBQ showed minimum effect on RAD51 mRNA (or protein) synthesis as well as RAD51 degradation. Specific inhibition of RAD51 by siRNA amplified TCBQ-induced DNA damage and cytotoxicity, while cells with enhanced RAD51 expression resisted TCBQ-induced toxicity. The modulation of RAD51 is correlated with p53 level, which suggests p53 has a role in TCBQ-induced RAD51 clearance. Together, our data suggested that TCBQ increases genome instability and cell death through a unique mechanism of inducing DNA damage and inhibiting DNA repair. PMID- 27989140 TI - Enolate-Forming Compounds as a Novel Approach to Cytoprotection. AB - Evidence from laboratory studies and clinical trials suggests that plant-derived polyphenolic compounds such as curcumin, resveratrol, or phloretin might be useful in the treatment of certain diseases (e.g., Alzheimer's disease) and acute tissue injury states (e.g., spinal cord trauma). However, despite this potential, the corresponding chemical instability, toxic potential, and low bioavailability of these compounds could limit their ultimate clinical relevance. We have shown that pharmacophores of curcumin (e.g., 2-acetylcyclopentanone) and phloretin (e.g., 2',4',6'-trihydroxyacetophenone; THA) can provide cytoprotection in cell culture and animal models of oxidative stress injury. These pharmacophores are 1,3-dicarbonyl and polyphenol derivatives, the enol groups of which can ionize in biological solutions to form an enolate. This carbanionic moiety can chelate metal ions and, as a nucleophile, can scavenge toxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal, and N-acetyl-p-benzoquinone imine) involved in many pathogenic conditions. Aromatic derivatives such as THA can also trap free oxygen and nitrogen radicals and thereby provide another layer of cytoprotection. The multifunctional character of these enolate-forming compounds suggests an ability to block pathogenic processes (e.g., oxidative stress) at several steps. The purpose of this review is to discuss research supporting our theory that enolate formation is a significant cytoprotective property that represents a platform for development of pharmacotherapeutic approaches to a variety of toxic and pathogenic conditions. Our discussion will focus on mechanism and structure activity studies that define enolate chemistry and their corresponding relationships to cytoprotection. PMID- 27989141 TI - No Evidence for Drug-Specific Activation of Circulating T Cells from Patients with HLA-DRB1*07:01-Restricted Lapatinib-Induced Liver Injury. AB - It is hypothesized that lapatinib-induced liver injury is caused by HLA-mediated antigen presentation to CD4 positive T cells. However, analysis of PBMC and cloned T-cells from patients with HLA-DRB1*07:01-restricted lapatinib-induced liver injury revealed no evidence for drug-specific activation. T cells were exposed to lapatinib, the M11 aldehyde, and quinone imine [oxidized form of hydroquinone amine M1] metabolites. Reactivity of the quinone imine was confirmed by mass spectrometry. PMID- 27989143 TI - Introduction: Mass Spectrometry and Emerging Technologies for Biomarker Discovery in the Assessment of Human Health and Disease. PMID- 27989144 TI - Drug-Protein Adducts: Chemistry, Mechanisms of Toxicity, and Methods of Characterization. AB - The formation of drug-protein adducts is considered an important feature in the pharmacological and toxicological profiles of many drugs. Mechanistic insights into the role of specific protein adduct formation in pharmacology and toxicology remain scarce, partly due to the availability of tools to identify and characterize the specific protein adducts, and partly due to the scarcity of relevant in vitro and in vivo predictive models. This review serves to provide a review on the current state of science on the chemistry, toxicology, and methods of detection and characterization of drug-protein adducts and to offer some perspective on the future directions of research into the role of protein adducts in drug effects and toxicity. PMID- 27989145 TI - Cysteine-Based Protein Adduction by Epoxide-Derived Metabolite(s) of Benzbromarone. AB - Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity. PMID- 27989146 TI - Different Reactive Metabolites of Nevirapine Require Distinct Glutathione S Transferase Isoforms for Bioinactivation. AB - Nevirapine (NVP) is a non-nucleoside reverse transcriptase-inhibitor, which is associated with severe idiosyncratic skin rash and hepatotoxicity. These adverse drug reactions are believed to be mediated by the formation of epoxides and/or quinone methide formed by oxidative metabolism by P450s and 12-sulfoxyl-NVP formed by sequential 12-hydroxylation and O-sulfonation. Although different GSH conjugates and corresponding mercapturic acids have been demonstrated previously in vitro and in vivo, the role of the glutathione S-transferases in the inactivation of the different reactive metabolites has not been studied so far. In the present study the activity of 10 recombinant human glutathione S transferases (GSTs) in the detoxification of the different reactive metabolites of NVP was studied. The results show that GSTP1-1 is a highly active catalyst of GSH-conjugation of the oxidative metabolites of NVP, even at high GSH concentration. Experiments with trideuterated NVP suggest involvement of a reactive epoxide rather than quinone methide in the formation of the GSH conjugate formed after oxidative bioactivation. GSH-conjugation of 12-sulfoxyl NVP forming NVP-12-GSH was only catalyzed by GSTM1-1, GSTA1-1, and GSTA3-3. Although the exact expression levels of these enzymes in the skin is unknown, the relatively low activity of this catalysis makes it unlikely that GSTs can provide significant protection against this metabolite. However, since NVP-12-GSH is specifically formed via the 12-sulfoxyl-NVP, its corresponding urinary mercapturic acid can be considered as a biomarker for recent internal exposure to this protein-reactive sulfate. However, it has to be taken into account that 12 sulfoxyl-NVP is not completely trapped by GSH and that rates of bioinactivation will differ between patients due to variability in expression of GSTM1, GSTA1, and GSTA3. PMID- 27989147 TI - 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Is Atropselectively Metabolized to para Hydroxylated Metabolites by Human Liver Microsomes. AB - Exposure to neurotoxic, chiral PCBs has been associated with neurodevelopmental disorders, but their metabolism in humans remains unexplored. We investigated the enantioselective metabolism of PCB 95 by human liver microsomes (HLMs) to potentially neurotoxic, hydroxylated metabolites (OH-PCBs). OH-PCB profiles formed in experiments with HLMs differed from metabolite profiles reported for rodent species. The second eluting atropisomer of 2,2',3,5',6-pentachlorobiphenyl 4'-ol, the major metabolite, was preferentially formed by all HLM preparations investigated. Differences in metabolite formation rates were observed with single donor HLMs. The metabolism of PCBs and its role in PCB-mediated neurodevelopmental disorders need to be further characterized. PMID- 27989148 TI - Chemical Reactivity of Emodin and Its Oxidative Metabolites to Thiols. AB - Polygonum multiflorum is an herbal medicine widely employed in China. Hepatotoxicity of the herbal medicine has been well documented, but the mechanisms of the toxicity remain unknown. Emodin (EM) is a major constituent of the herb and has been reported to be hepatotoxic. The main purpose of this study was to define the metabolic pathways of EM in order to characterize the potential reactive intermediates. EM was incubated with rat liver microsomes or human liver microsomes, followed by LC-MS/MS analysis to investigate the in vitro and in vivo metabolism of EM. As a result, three monohydroxylation metabolites (M1-M3) were detected after exposure to EM: omega-hydroxyemodin, 2-hydroxyemodin, and 5 hydroxyemodin. Urinary M1 and M2 were detected in rats administered EM. Three mercapturic acids (M4-M6) were found in microsomal incubations containing EM, NADPH, and N-acetylcysteine. It appears that M4 originated from parent compound EM, and M5 and M6 originated from M1 and M2, respectively. Two biliary EM-derived GSH conjugates were found in EM-treated rats. One arose from direct adduction of EM with GSH, and the other was derived from M1. Cytochrome P450's 1A2, 2C19, and 3A4 were the predominant P450 enzymes to oxidize EM. The findings helped us to understand the mechanisms of EM-induced hepatotoxicity. PMID- 27989149 TI - Nontrivial Recurrent Intergrowth Structure and Unusual Magnetic Behavior of Intermetallic Compound Fe32+deltaGe33As2. AB - A new phase Fe32+deltaGe33As2 (delta <= 0.136) was obtained by two-step synthesis from the elements. Fe32+deltaGe33As2 crystallizes in its own structure type (space group P6/mmm, Z = 1, a = 11.919(3) A, c = 7.558(4) A) that can be described as a recurrent two-dimensional intergrowth of two intermetallic structure types, MgFe6Ge6 and Co2Al5. Their blocks are represented by infinite columns in the structure. No visible structural changes were observed in the temperature range from 10 to 300 K. At 125 K, Fe32+deltaGe33As2 undergoes an antiferromagnetic-like transition, while above 150 K it shows a typical Curie Weiss paramagnetic behavior. Below the transition temperature, a peculiar field dependent magnetic susceptibility, that shows a significant increase of the susceptibility upon increasing the magnetic field, and a change in transport properties have been observed. Above 140 K, Fe32+deltaGe33As2 reveals a metallic behavior, in agreement with electronic structure calculation, while below this point the resistivity nonmonotonically increases upon cooling. The Seebeck coefficient is positive, indicating that holes are the major charge carriers, and shows a broad maximum around 57 K. PMID- 27989150 TI - Superlong and Color-Tunable Red Persistent Luminescence and Photostimulated Luminescence Properties of NaCa2GeO4F:Mn2+,Yb3+ Phosphor. AB - An excellent persistent luminescence (PersL) phosphor NaCa2GeO4F:Mn2+,Yb3+ has been synthesized by traditional solid-state reaction. By controlling the occupation sites of Mn2+ emitters, the PersL color of this phosphor can be optionally tuned in the red to green-yellow region, and the maximum spectral shift is more than 50 nm. Significantly, the red PersL can be measured for approximately 13 and 3 h (0.32 mcd/m2) and can be observed for more than 20 and 5 h with dark-adapted vision after exposure to ultraviolet irradiation and artificial sunlight, respectively. The crystal/electronic structure and photoluminescence/PersL properties of this phosphor have been investigated in detail. A series of the excitation temperature-dependent thermoluminescence experiments and the initial rising method have been conducted to study the trap properties of this phosphor. It reveals the reasons for the variation of PersL color, excellent red PersL, and degradation of green-yellow PersL. According to the results, the as-prepared NaCa2GeO4F:Mn2+,Yb3+ can be considered as an excellent red PersL phosphor, and it also has potential for application in optical storage. PMID- 27989151 TI - Tunable Self-Assembly and Morphology-Dependent Photoconductivity of a Donor Acceptor-Structured Diruthenium Complex. AB - A donor-acceptor-structured diruthenium complex, 1(PF6)4, that contains an electron-deficient bridging ligand and electron-rich distal diarylamines modified with long aliphatic chains has been synthesized. By varying the solvent environments and assembly conditions, we obtained three different self-assembled nanostructures of 1(PF6)4, including zero-dimensional nanospheres, one dimensional nanofibers, and thin films with interconnected nanowire networks. These structures were investigated by scanning electron microscopy, transmission electron microscopy, dynamic light scattering, X-ray diffraction, and atomic force microscopy (AFM) analysis. Conductive AFM analysis shows that the nanowire networks exhibit a high conductivity of 0.023 S/cm and an enhanced photoconductivity of 0.59 S/cm under visible light irradiation. PMID- 27989142 TI - Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage. AB - A variety of endogenous and exogenous agents can induce DNA damage and lead to genomic instability. Reactive oxygen species (ROS), an important class of DNA damaging agents, are constantly generated in cells as a consequence of endogenous metabolism, infection/inflammation, and/or exposure to environmental toxicants. A wide array of DNA lesions can be induced by ROS directly, including single nucleobase lesions, tandem lesions, and hypochlorous acid (HOCl)/hypobromous acid (HOBr)-derived DNA adducts. ROS can also lead to lipid peroxidation, whose byproducts can also react with DNA to produce exocyclic DNA lesions. A combination of bioanalytical chemistry, synthetic organic chemistry, and molecular biology approaches have provided significant insights into the occurrence, repair, and biological consequences of oxidatively induced DNA lesions. The involvement of these lesions in the etiology of human diseases and aging was also investigated in the past several decades, suggesting that the oxidatively induced DNA adducts, especially bulky DNA lesions, may serve as biomarkers for exploring the role of oxidative stress in human diseases. The continuing development and improvement of LC-MS/MS coupled with the stable isotope-dilution method for DNA adduct quantification will further promote research about the clinical implications and diagnostic applications of oxidatively induced DNA adducts. PMID- 27989152 TI - Metal-Insulator Transition Induced by Spin Reorientation in Fe7Se8 Grain Boundaries. AB - Fe7Se8 exists as a hexagonal NiAs-like crystal structure with a large number of ordered intrinsic vacancies. It is an ideal candidate for studying the effect of defects on properties such as magnetism and electrical transport. In this work, highly crystalline Fe7Se8 with the 3c crystal structure was synthesized by a solid-state reaction. Sharp changes in the magnetization at 100 K confirm a rotation of the spins from the ab plane to the c axis with decreasing temperature. We observe an interesting metal-insulator transition at the same temperature as the spin-direction changes. We propose that locked spins in the grain boundaries induce electron localization and result in the metal-insulator transition. Electron localization is confirmed by X-ray photoelectron spectroscopy of the Fe 2p peaks, which exhibit two characteristic satellite peaks. This mechanism is also verified by comparing it with the properties of the 4c-Fe7Se8 crystal structure. PMID- 27989153 TI - Adsorption of Iodine Based on a Tetrazolate Framework with Microporous Cages and Mesoporous Cages. AB - A three-dimensional tetrazolate framework was synthesized with solvothermal reaction. Single-crystal X-ray diffraction analysis shows that the framework is fabricated by a microporous cage (1.35 nm) and mesoporous cage (2.85 nm) via vertex-sharing packing mode. This compound shows permanent porosity and excellent performance of absorbing iodine. PMID- 27989154 TI - In Situ Generation of NiO Nanoparticles in a Magnetic Metal-Organic Framework Exhibiting Three-Dimensional Magnetic Ordering. AB - NiO nanoparticles were in situ formed in a new metal-organic framework (MOF), [Ni3(pyip)2(HCOO)2(H2O)2]n [1; H2pyip = 5-(pyridine-4-yl)isophthalic acid], which was characterized by Fourier transform infrared spectroscopy, elemental analysis, thermogravimetric analysis, transmission electron microscopy, and powder and single-crystal X-ray diffraction. The MOF 1 shows a 3,6-connected three dimensional rtl topology network with a topological symbol of (4.62)2(42.610.83). Magnetic property studies showed that the combination of NiO nanoparticles within the magnetic MOF leads to the occurrence of long-range magnetic ordering below a critical temperature of 18 K. PMID- 27989155 TI - Selective Carbon Dioxide Adsorption by Two Robust Microporous Coordination Polymers. AB - In the present work we report the design, synthesis, crystal structure determination, and adsorption properties of two new cadmium-based porous coordination polymers, [Cd(pda)0.5(spiro-4-py)0.5(HCOO)].2H2O.DMF (compound 1, pda = p-phenylenediacetate, spiro-4-py = (2,2',7,7'-tetra(pyridin-4-yl)-9,9' spirobi[fluorene], DMF = N,N'-dimethylformamide), and [Cd2(pda)(spiro-4-py) (CH3COO)2].DMA (compound 2, DMA = N,N'-dimethylacetamide) with similar structures. The coordination between cadmium and two organic linkers, pda and spiro-4-py, has yielded two-dimensional frameworks with rhombic openings. Stacking of these two-dimensional networks does not block the openings but rather results in permanent porosity with one-dimensional channels in the final structures. The permanent porosity of these compounds is confirmed by gas adsorption measurements. Compounds 1 and 2 have Brunauer-Emmett-Teller surface areas of 687 and 584 m2/g, respectively. Both compounds show favorable adsorption toward carbon dioxide over other light gases such as nitrogen, oxygen, and carbon monoxide. Ideal adsorbed solution theory is employed to predict the adsorption selectivity of binary gas mixtures. Though compounds 1 and 2 possess similar structures, differences are observed in their gas adsorption behaviors, which can be attributed to their different terminal ligands of formate and acetate, respectively. Strikingly, both compounds show exceptionally high stability in aqueous media with a wide pH range, a characteristic that is highly desirable for gas separation-related applications. The robustness of these structures suggests that the use of hydrophobic spiro-based multipyridine ligands can lead to water stable frameworks built on late-transition metals that are otherwise sensitive to moisture. PMID- 27989156 TI - FA0.8MA0.2SnxPb1-xI3 Hybrid Perovskite Solid Solution: Toward Environmentally Friendly, Stable, and Near-IR Absorbing Materials. AB - We report the first investigation addressing the synthesis and characterization of the FA0.8MA0.2SnxPb1-xI3 solid solution showing a complete solubility of Sn on the Pb-site leading to cubic single-phase materials. The explored composition shows excellent phase stability and absorbance in the near-IR spectral region. PMID- 27989157 TI - Sandwich-Type Polyoxotungstate Consisting of Two Different Trilacunary Keggin Type Units. AB - A unique mixed W/Sb/Mn/Ag sandwich-type metal-O cluster was isolated, in which the six-membered {Ag4O3[Mn(OH2)]2}2+ cationic belt is sandwiched between two different anionic slices: the trilacunary B-beta-[SbW9O33]9- and the central-atom lost A-alpha-{[Mn(OH2)]2W7O32}18-. PMID- 27989158 TI - Step by Step Assembly of Polynuclear Lanthanide Complexes with a Phosphonated Bipyridine Ligand. AB - The synthesis of the octadentate ligand L (LH8 = ((([2,2'-bipyridine]-6,6' diylbis(methylene))bis(azanetriyl))tetrakis(methylene))tetrakis(phosphonic acid)) is reported. The coordination of L with various lanthanide cations was monitored by absorption and luminescence spectrophotometric titration experiments (Ln = Tb, Yb), potentiometry (Ln = La, Eu, Lu), and mass spectrometry (Ln = Tb). It was found that L forms very stable mononuclear (LnL) species in aqueous solutions (log K = 19.80(5), 19.5(2), and 19.56(5) for La, Eu, and Lu, respectively) with no particular trend along the series. Spectroscopic data showed the Ln cations to be enclosed in the cavity formed by the octadentate ligand, thereby shielding the metal from interactions with water molecules in the first coordination sphere. When more than one equivalent of cations is added, the formation of polynuclear [(LnL)2Lnx] complexes (x = 1-3) can be observed, the presence of which could be confirmed by electrospray and MALDI mass spectrometry experiments. DFT modeling of the mononuclear (LnL) complexes indicated that the coordination of the cation in the cavity of the ligand results in a very asymmetric charge distribution, with a region of small negative electrostatic potential on the hemisphere composed of the chromophoric bipyridyl moiety and an electron-rich domain at the opposite hemisphere around the four phosphonate functions. DFT further showed that this polarization is most likely at the origin of the strong interactions between the (LnL) complexes and the incoming additional cations, leading to the formation of the polynuclear species. 1H and 31P NMR were used to probe the possible exchange of the lanthanide complexed in the cavity of the ligand in D2O, revealing no detectable exchange after 4 weeks at 80 degrees C and neutral pD, therefore pointing out an excellent kinetic inertness. PMID- 27989159 TI - Confinement Effects of Metal-Organic Framework on the Formation of Charge Transfer Tetrathiafulvalene Dimers. AB - Three transition metal coordination polymers (CPs) based on the redox-active dimethylthio-tetrathiafulvalene-bicarboxylate (L) and 1,3-bi(4-pyridyl)propane (bpp) ligands, formulated as [MnL(bpp)]n (1), [CdL(bpp)]n (2), and [Cd2L(bpp)2(H2O)(C2O4)0.5]n.n(ClO4).n(H2O) (3), are crystallographically characterized. Complexes 1 and 2 are isostructural 2-D polymers, and 3 features an unusual 3-D metal-organic framework (MOF). The 3-D MOF is constructed from tetranuclear cluster nodes built through the MU2-O bridge of the TTF ligand, which is first found for TTF coordination polymers. It is found that the channel generated by the 3-D MOF exerts a confinement effect on the formation of TTF dimers. The TTF dimers show strong intradimer interaction with partial electron transfer or charge transfer, and hence, the Cd compound 3 has relatively good photocurrent response property in comparison with that of 2-D Cd compound 2. PMID- 27989160 TI - Vacancy Generation and Oxygen Uptake in Cu-Doped Pr-CeO2 Materials using Neutron and in Situ X-ray Diffraction. AB - The oxygen uptake ability of Pr-CeO2-based oxygen carriers, catalysts, and solid oxide fuel cells can be attributed to 3+ cation generation and the presence of vacant oxygen sites. Oxygen occupancies of CeO2, Pr-CeO2, and 5% Cu-doped Pr-CeO2 were investigated using neutron diffraction and related to the oxygen uptake as determined using thermogravimetric analysis (TGA). The presence of vacant tetrahedral oxygen sites at room temperature did not correspond to low temperature oxygen uptake. The materials did not uptake oxygen at 420 degrees C, but oxygen uptake was observed at 600 degrees C, which indicated that a minimum temperature needs to be met to generate sufficient vacancies/3+ cations. Variations in the lattice parameter as a function of temperature were revealed using in situ X-ray diffraction (XRD). With increasing temperature the lattice parameter increased linearly due to thermal expansion and was followed by an exponential increase at ~300-400 degrees C as cations were reduced. Despite segregation of Cu into CuO at high dopant concentration, at 600 degrees C a higher O2 uptake was obtained for Ce0.65Pr0.20Cu0.15O2-delta (120 MUmol g-1), in comparison to Ce0.75Pr0.2Cu0.05O2-delta (92 MUmol g-1), and was higher than that for Ce0.8Pr0.2O2-delta (55 MUmol g-1). Both Pr and Cu introduce vacancies and promote the O2 uptake of CeO2. PMID- 27989162 TI - Alkoxide Migration at a Nickel(II) Center Induced by a pi-Acidic Ligand: Migratory Insertion versus Metal-Ligand Cooperation. AB - Two pathways of alkoxide migration occurring at a nickel(II) center supported by a PPP ligand (PPP- = P[2-PiPr2-C6H4]2-) are presented in this Article. In the first route, the addition of a pi-acidic ligand to a (PPP)Ni alkoxide species reveals the formation of a P-O bond. This reaction occurs via metal-ligand cooperation (MLC) involving a 2-electron reduction at nickel. To demonstrate a P O bond formation, a nickel(II) isopropoxide species (PPP)Ni(OiPr) (4) was prepared. Upon addition of a pi-acidic isocyanide ligand CNtBu, a nickel(0) isocyanide species (PPOiPrP)Ni(CNtBu) (6b) was generated; P-O bond formation occurred via reductive elimination (RE). When CO is present, migratory insertion (MI) occurs instead. The reaction of 4 with CO(g) results in the formation of (PPP)Ni(COOiPr) (5), representing an alternative pathway. The corresponding RE product (PPOiPrP)Ni(CO) (6a) can be independently produced from the substitution reaction of {(PPOiPrP)Ni}2(MU-N2) (3) with CO(g). While two different carbonylation pathways in 4 seem feasible, C-O bond forming migratory insertion singly occurs. Regeneration of a (PPP)Ni moiety via a P-O bond cleavage was demonstrated by treating 3 with CO2(g). The formation of (PPP)Ni(OCOOiPr) (7) clearly shows that an isopropoxide group migrates onto the bound CO2 ligand, and a P-Ni moiety is regenerated. PMID- 27989161 TI - A Bioinspired Dinickel(II) Hydrolase: Solvent Vapor-Induced Hydrolysis of Carboxyesters under Ambient Conditions. AB - From the perspective of synthetic metallohydrolases, a phenoxo-bridged dinickel(II) complex [NiII2(L)(H2O)2(CH3OH)][ClO4].CH3OH (1) (H3L = 2,6-bis[{{(5 bromo-2-hydroxybenzyl)(N',N"-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol) has been synthesized and structurally characterized. The presence of a vacant coordination site and a weakly bound water molecule provides the scope for substrate binding to act as a metallohydrolase model. Ethyl acetate vapor diffusion at 298 K to a CH3CN/CH3OH solution of 1 results in the formation of a pentanuclear acetato-bridged complex [NiII5(H2L)2(MU3-OH)2(MU O2CCH3)4][ClO4]2.CH3CO2C2H5 (2), demonstrating for the first time the metal coordinated water-promoted hydrolysis of a carboxyester at room temperature. When the crystals of 1, moistened with a few drops of ethyl acetate, were kept for ethyl acetate vapor diffusion, it transforms into a monoacetato-bridged complex [NiII2(HL)(MU-O2CCH3)(H2O)2][ClO4].4H2O (3). This kind of solvent (vapor)-induced single-crystal-to-single-crystal structural transformation concomitant with the hydrolysis of external substrate (ethyl acetate) is unprecedented. Reaction of H3L with 2 equiv of NiII(O2CCH3)2.4H2O, followed by the usual workup, and recrystallization from CH2Cl2 led to the isolation of [NiII2(H2L)(MU O2CCH3)2][ClO4].CH2Cl2.2H2O (4). Complex 4 is structurally different from 3, confirming that the reaction of NiII(O2CCH3)2.4H2O with H3L is a different phenomenon from the hydrolysis of ethyl acetate, promoted by NiII-coordinated water in 1. Complex 1 is also capable of hydrolyzing ethyl propionate to a propionato-bridged complex [NiII2(HL)(MU-O2CCH2CH3)(H2O)2][ClO4] (5). For the hydrolytic phenomena mentioned above, the coordinated ligand donor sites (phenolate and tertiary amine) provide a microenvironment around the dinickel(II) center to facilitate efficient stoichiometric hydrolysis of ethyl acetate and ethyl propionate under ambient conditions. Temperature-dependent magnetic studies of dimeric complexes 1, 4, and 5 reveal the presence of moderate antiferromagnetic coupling: J = -25.0(1) cm-1 for 1, J = -20.0(1) cm-1 for 4, and J = -18.80(8) cm-1 for 5. For pentanuclear complex 2, three types of magnetic exchange interactions, two ferromagnetic (Ja = +16.02 cm-1, and Jb = +9.02 cm-1) and an antiferromagnetic (Jc = -49.7 cm-1), have been identified. PMID- 27989163 TI - Two Distinctive Hierarchical Products through the Hydrothermal Process for beta Co(OH)2 Reacting with NaH2PO2 and Their Morphological Effect on Electrochemical Hydrogen Storage. AB - This paper reports a study of the reaction behavior of beta-Co(OH)2 with NaH2PO2 under hydrothermal conditions, depending on the concentration of NaOH (0-9.0 M). Uniform sized beta-Co(OH)2 microplatelets, as the precursor, were prepared by the method of homogeneous precipitation using hydrolysis reaction with hexamethylenetetramine as the base. After the hydrothermal reaction, two distinctive products were obtained: cobalt phosphite [Co11(HPO3)8(OH)6] and hcp Co metal. The XRD analysis reveals that the Co11(HPO3)8(OH)6 appeared in the absence of NaOH. Then, Co11(HPO3)8(OH)6 and the hcp Co metal simultaneously appeared under 1.125 M NaOH. At 2.25-4.5 M NaOH, beta-Co(OH)2 and hcp Co metal appeared concurrently, and only pure hcp Co metal appeared under 9.0 M NaOH. The FE-SEM observations indicated that the obtained particles were dendritic-like Co11(HPO3)8(OH)6 and flower-like Co metal. We found that the solubility of beta Co(OH)2 and the role of the NaH2PO2 were strongly influenced by the concentration of NaOH during this reaction. To investigate the morphological effect of the two obtained products on the electrochemical hydrogen storage performance, materials with the same crystal structures yet with different morphologies were used for comparison. The evaluations of electrochemical performance proved that the two products showed better reversibility, and higher storage capacity and rate dischargeability than the comparative materials. Their relatively good performances can be attributed to their morphology, which resulted in increased surface area, reduced diffusion pathway, and the accommodation of volume change during cycling. PMID- 27989164 TI - Induction and Rationalization of Supramolecular Chirality in the Tweezer-Diamine Complexes: Insights from Experimental and DFT Studies. AB - A series of supramolecular chiral 1:1 sandwich complexes (1M.L and 2M.L) consisting of diphenylether/ethane bridged metallobisporphyrin host (1M and 2M; M: Zn/Mg) and chiral diamine guest (L) have been presented. The host-guest complexes are compared just upon changing the metal ion (Mg vs Zn) or the bridge (highly flexible ethane vs rigid diphenylether) keeping other factors similar. The factors that would influence the chirality induction process along with their contributions toward the sign and intensity of the CD couplet of the overall complex have been analyzed. Larger CD amplitude was observed in the host-guest complex with the more flexible ethane bridge as compared to the rigid diphenylether bridged one, irrespective of the metal ion used. Also, Zn complexes have displayed larger CD amplitude because of their stronger binding with the chiral diamines. A fairly linear dependence between the binding constant (K) and CD amplitude has been observed. Moreover, the amplitude of the CD couplet has been correlated with the relative steric bulk of the substituent at the stereogenic center: with increasing the bulk, CD intensity gradually increases. However, large increase of steric hindrance, after a threshold value, has diminished the intensity. The observation of a weak positive CD couplet between (1R,2R)-DPEA guest and Zn-bisporphyrin hosts indicates that the clockwise-twisted (steric-controlled) conformer is more populated as compared to the anticlockwise (chirality-controlled) one. In contrast, amplitude of the positive CD couplets is larger with Mg-bisporphyrin hosts, suggesting almost exclusive contribution of the clockwise-twisted conformer guided solely by sterics. DFT calculations support the experimental observations and have displayed the possible interconversion between clockwise and anticlockwise twisted conformers just upon changing the bulk of the substituent irrespective of the nature of chirality at the stereogenic center. PMID- 27989165 TI - Rare Neutral Diphosphine Complexes of Scandium(III) and Yttrium(III) Halides. AB - Reaction of Me2PCH2CH2PMe2 or o-C6H4(PMe2)2 (L-L) with a suspension of ScI3 or YI3 in MeCN solution under rigorously anhydrous and oxygen-free conditions produced the highly unusual complexes [ScI3(L-L)2], [YI3(Me2PCH2CH2PMe2)2], and [YI3{o-C6H4(PMe2)2}2MeCN]. X-ray crystal structures reveal that the scandium complexes adopt seven-coordinate, pentagonal-bipyramidal geometries with chelating diphosphines, while the eight-coordinate [YI3{o-C6H4(PMe2)2}2MeCN] is dodecahedral. The complexes were characterized by microanalysis and IR and multinuclear NMR spectroscopy. Solid-state NMR data (45Sc, 89Y, 31P) and variable temperature solution NMR data (1H, 31P{1H}, 45Sc) are presented and compared, leading to the conclusion that the same species are present in both the solid state and CH2Cl2 solution. Attempts to prepare complexes with other scandium halides and with aryl diphosphines and o-C6H4(AsMe2)2 are briefly described. PMID- 27989166 TI - An Electrically Conductive Single-Component Donor-Acceptor-Donor Aggregate with Hydrogen-Bonding Lattice. AB - An electrically conductive D-A-D aggregate composed of a single component was first constructed by use of a protonated bimetal dithiolate (complex 1H2). The crystal structure of complex 1H2 has one-dimensional (1-D) pi-stacking columns where the D and A moieties are placed in a segregated-stacking manner. In addition, these segregated-stacking 1-D columns are stabilized by hydrogen bonds. The result of a theoretical band calculation suggests that a conduction pathway forms along these 1-D columns. The transport property of complex 1H2 is semiconducting (Ea = 0.29 eV, rhort = 9.1 * 104 Omega cm) at ambient pressure; however, the resistivity becomes much lower upon applying high pressure up to 8.8 GPa (Ea = 0.13 eV, rhort = 6.2 * 10 Omega cm at 8.8 GPa). The pressure dependence of structural and optical changes indicates that the enhancement of conductivity is attributed to not only an increase of pi-pi overlapping but also a unique pressure-induced intramolecular charge transfer from D to A moieties in this D-A D aggregate. PMID- 27989167 TI - Effect of Internal Pressure and Temperature on Phase Transitions in Perovskite Oxides: The Case of the Solid Oxide Fuel Cell Cathode Materials of the La2 xSrxCoTiO6 Series. AB - The symmetry of the room-temperature (RT) structure of title compounds La2 xSrxCoTiO6-delta changes with x, from P21/n (0 <= x <= 0.2) to Pnma (0.3 <= x <= 0.5) and to R3c (0.6 <= x <= 1). For x = 1 the three pseudocubic cell parameters become very close suggesting a transition to a cubic structure for higher Sr contents. Similar phase transitions were expected to occur on heating, paralleling the effect of internal pressure induced by substitution of La3+ by Sr2+. However, only some of these aforementioned transitions have been thermally induced. The symmetry-adapted modes formalism is used in the structural refinements and fitting of neutron diffraction data recorded from RT to 1273 K. Thus, for x = 1, the out-of-phase tilting of the BO6 octahedra vanishes progressively on heating, and a cubic structure with Pm3m symmetry is found at 1073 K. For lower Sr contents this transition is predicted to occur far above the temperature limit of common experimental setups. The analysis of the evolution of the perovskite tolerance factor, t-factor, with both Sr content and temperature indicates that temperature has a limited ability to release structural stress and thus to enable transitions to more symmetric phases. This is particularly true when compared to the effect of internal pressure induced by substitution of La by Sr. The existence of phase transitions in materials for solid oxide fuel cells that are usually exposed to heating-cooling cycles may have a detrimental effect. This work suggests strategies to stabilize the high-symmetry high-temperature phase of perovskite oxides through internal-pressure chemically induced. PMID- 27989168 TI - Reactivity of a Molecular Magnesium Hydride Featuring a Terminal Magnesium Hydrogen Bond. AB - The reactivity of the molecular magnesium hydride [Mg(Me3TACD.AliBu3)H] (1) featuring a terminal magnesium-hydrogen bond and an NNNN-type macrocyclic ligand, Me3TACD ((Me3TACD)H = Me3[12]aneN4 = 1,4,7-trimethyl-1,4,7,10 tetraazacyclododecane), can be grouped into protonolysis, oxidation, hydrometalation, (insertion), and hydride abstraction. Protonolysis of 1 with weak Bronsted acids HX such as terminal acetylenes, amines, silanols, and silanes gave the corresponding derivatives [Mg(Me3TACD.AliBu3)X] (X = C=CPh, 3; HN(3,5 Me2-C6H3), 4; OSiMe3, 5; OSiPh3, 6; Cl, 7; Br, 8). Single-crystal X-ray diffraction of anilide 4 showed a square-pyramidal coordination geometry for magnesium. No correlation with the pKa values of the acids was detected. Oxidation of 1 with elemental iodine gave the iodide [Mg(Me3TACD.AliBu3)I] (9), and oxidation with nitrous oxide afforded the MU-oxo-bridged compound [{Mg(Me3TACD.AliBu3)}2(MU-O)] (10) with a linear Mg-O-Mg core, as characterized by single-crystal X-ray diffraction. The Mg-H bond reacted with benzaldehyde, benzophenone, fluorenone, and CO2 under insertion but not with the olefins 1,1,2 triphenylethylene, tert-butylethylene, and cyclopentene. The unstable formate, prepared also by salt metathesis of iodide 9 with potassium formate, revealed kappaO,kappaO' coordination in the solid state. Hydride abstraction with triphenylborane gave the ion pair [Mg(Me3TACD.AliBu3)(thf)][HBPh3] (16), which catalyzed the hydroboration of polar substrates by pinacolborane. PMID- 27989169 TI - Multifunctional Luminescent Eu(III)-Based Metal-Organic Framework for Sensing Methanol and Detection and Adsorption of Fe(III) Ions in Aqueous Solution. AB - A novel lanthanide-organic framework (Eu-HODA), consisting of 2,2',3,3' oxidiphthalic acids as efficient sensitizing units, is assembled and characterized. Eu-HODA features rare chiral helical channels despite the achiral nature of H4ODA. It is found that this MOF shows a unique luminescent response to methanol, in contrast to n-propanol and ethanol. Eu-HODA reveals a turn-off luminescence switching initiated by acetone molecules with an EC50 of 0.03 vol %, which is below the occupational exposure limit of acetone stipulated by the American Conference of Governmental Industrial Hygienists. Furthermore, it also exhibits high sensitivity (Stern-Volmer constant KSV = 2.09 * 104 L/mol) and low detection limit (6.4 ppb) for Fe3+ ions in pure water because of the existence of uncoordinated carboxyl groups within open frameworks. Eu-HODA-based test paper provides a simple and reliable detection method for Fe3+ in practical applications. PMID- 27989170 TI - Significantly Dense Two-Dimensional Hydrogen-Bond Network in a Layered Zirconium Phosphate Leading to High Proton Conductivities in Both Water-Assisted Low Temperature and Anhydrous Intermediate-Temperature Regions. AB - A highly stable layered zirconium phosphate, (NH4)2[ZrF2(HPO4)2] (ZrP-1), was synthesized by an ionothermal method and contains an extremely dense two dimensional hydrogen-bond network that is thermally stable up to 573 K, leading to combined ultrahigh water-assisted proton conductivities of 1.45 * 10-2 S cm-1 at 363 K/95% relative humidity and sustainable anhydrous proton conductivity of 1.1 * 10-5 S cm-1 at 503 K. PMID- 27989171 TI - Cation-Dependent Self-assembly of Vanadium Polyoxoniobates. AB - Reaction of Na7H[Nb6O19].15H2O with NaVO3.2H2O at 220 degrees C in the presence of NaHCO3 gives new bicapped alpha-Keggin vanadododecaniobate [VNb12O40{NbO(CO3)}2]13-, isolated and structurally characterized as Na9H4[VNb12O40{NbO(CO3)}2].37H2O (1). According to 51V NMR and ESI-MS data, this anion equilibrates in solution with [VNb12O40]15- and oligomeric species that result from dissociation of the {NbO(CO3)}+ fragments. In the presence of potassium, the same reaction gives [VxNb24O76]n- (x = 4, n = 12 (2a); x = 3, n = 17 (2b)). The anions with x = 3 and 4 cocrystallize together, but exist as separate entities both in solid and in solution according to 51V MAS NMR and ESI MS data. PMID- 27989172 TI - Density Functional Theory as a Predictive Tool for Cerium Redox Properties in Nonaqueous Solvents. AB - Two methods to correlate and predict experimental redox potentials for cerium complexes were evaluated. Seventeen previously reported cerium complexes were computed using DFT methods in both the CeIII and CeIV oxidation states with a dichloromethane solvent continuum. In the first computational approach, the DeltaGo(CeIV/CeIII) was determined for each of the compounds and these values were correlated with the experimental E1/2 values measured in dichloromethane, referenced to the ferrocene/ferrocenium couple. The second method involved correlating the energies of the CeIV LUMOs (lowest unoccupied molecular orbitals) with the experimental redox potentials, E1/2. The predictive capabilities of these two correlative methods were tested using a new cerium hydroxylamine complex, Ce(ODiNOx)2 (ODiNOx = bis(2-tert-butylhydroxylaminatobenzyl) ether). All 18 complexes studied in this paper were combined with the 15 complexes determined in acetonitrile from a previously published correlation by our group. These sets of data allowed us to develop two methods for predicting the redox potential of cerium complexes regardless of the solvent for the experimental measurement. PMID- 27989173 TI - Iodine-Rich Imidazolium Iodate and Periodate Salts: En Route to Single-Based Biocidal Agents. AB - Two classes of iodine-rich salts that consist of iodine-rich cations and iodate (IO3-) or periodate (IO4-) anions were synthesized. The synthesis of analogous I3O8- salts was more difficult because of poor solubility and hydrolytic instability. All iodine-rich salts were fully characterized by infrared, 1H nuclear magnetic resonance, and 13C nuclear magnetic resonance spectroscopy as well as elemental analyses. The molecular structures of compounds 15 and 24 were elucidated by X-ray single-crystal diffraction. Additionally, the heats of formation were calculated with Gaussian 03. The detonation properties and biocidal efficiency were calculated and evaluated using CHEETAH 7. PMID- 27989174 TI - Chiral Cu(salen)-Based Metal-Organic Framework for Heterogeneously Catalyzed Aziridination and Amination of Olefins. AB - A homochiral 3D porous metal-organic framework was assembled from a chiral dicarboxylic acid-functionalized Cu(salen)-based catalyst and could serve as an efficient heterogeneous catalyst for aziridination and allylic amination of olefins. Besides easy separation and reuse of the catalyst, the chiral framework confinement could impart substrate size selectivity, enhance catalyst activity, and induce product enantioselectivity. PMID- 27989175 TI - Visible-Light-Responsive Chalcogenide Photocatalyst Ba2ZnSe3: Crystal and Electronic Structure, Thermal, Optical, and Photocatalytic Activity. AB - Visible-light-responsive photocatalytic materials have important applications. In this article, through inserting electropositive ion Ba2+ into the three dimensional framework of ZnSe, a one-dimensional chalcogenide Ba2ZnSe3 has been obtained by traditional solid-state reaction. It crystallizes in orthorhombic centrosymmetric space group Pnma with unit cell parameters of a = 9.0744(2) A, b = 4.4229(1) A, c = 17.6308(4) A, and Z = 4. Its structure features [ZnSe3]4- anionic straight chains parallel to the b direction, which are further separated by Ba2+ cations filling in the cavities. On the basis of the UV-vis-NIR diffuse reflectance spectroscopy, Ba2ZnSe3 possesses a typical direct band gap of 2.75 eV, which is in good agreement with the electronic structure calculation. Moreover, Ba2ZnSe3 shows good visible-light-responsive photocatalytic activity and excellent thermal stability and cyclability, which are favorable for its application. PMID- 27989176 TI - Synthesis, Structure, and Electrochemical Properties of Na3MB5O10 (M = Fe, Co) Containing M2+ in Tetrahedral Coordination. AB - In the search for new cathode materials for sodium ion batteries, the exploration of polyanionic compounds has led to attractive candidates in terms of high redox potential and cycling stability. Herein we report the synthesis of the two new sodium transition-metal pentaborates Na3MB5O10 (M = Fe, Co), where Na3FeB5O10 represents the first sodium iron borate reported at present. By means of synchrotron X-ray diffraction, we reveal a layered structure consisting of pentaborate B5O10 groups connected through M2+ in tetrahedral coordination, providing possible three-dimensional Na-ion migration pathways. Inspired by these structural features, we examined the electrochemical performances versus sodium and showed that Na3FeB5O10 is active at an average potential of 2.5 V vs Na+/Na0, correlated to the Fe3+/Fe2+ redox couple as deduced from ex situ Mossbauer measurements. This contrasts with the case for Na3CoB5O10, which is electrochemically inactive. Moreover, we show that their electrochemical performances are kinetically limited, as deduced by complementary ac/dc conductivity measurements, hence confirming once again the complexity in designing high-performance borate-based electrodes. PMID- 27989177 TI - Trifluoromethyl Derivatives of a Monometallic Cyanide Cluster Fullerene, YCN@C82(6)(CF3)16/18. AB - Recently discovered monometallic cyanide cluster fullerenes are a novel family of endohedral molecules, whose chemical reactivity has not yet been probed. High temperature trifluoromethylation of the yttrium cyanide cluster fullerene YCN@C82(6), followed by high-performance liquid chromatography separation and an X-ray diffraction study of the two crystallized fractions, resulted in the structural characterization of YCN@C82(6)(CF3)16/18. In both molecules, exohedrally attached CF3 groups delimit the spherical pi system into localized double bonds, benzenoid rings, larger aromatic assemblies, and a conjugated fragment with the only intact pentagon that is involved in coordination to the interior Y atom. We also present theoretical results on charge distributions in the compounds reported. PMID- 27989178 TI - Theoretical Insights into Halogenated Uranium Cyanide/Isocyanide Compounds. AB - Two kinds of halogenated uranium cyanide/isocyanide compounds, XUCN and XUNC (X = halogen) formed by the insertion of uranium atom into X-C(N) bonds of XCN (or XNC), were investigated by DFT and ab initio methods. Although XNC is less stable thermodynamically than XCN, XUNC is more stable than XUCN and is expected to be prepared and characterized in matrix isolation experiments. The C-N stretching vibration mode (nuC-N) is the primary fingerprint for the identification of these isomers due to its red-shift character with respect to the relevant precursor. Atoms-in-molecule (AIM) analysis illustrates that both X-U and U-C(N) bonds in XUCN and XUNC show closed-shell interaction character, although partial covalent character contributes to them, and can be denoted as X-U2+(CN)- and X-U2+(NC)-, respectively. Charge decomposition analysis (CDA) further reveals that the isocyanide exhibits better donation performance than the cyanide, which should be the root cause of the difference between XUCN and XUNC. PMID- 27989179 TI - Dipicolinate Complexes of Gallium(III) and Lanthanum(III). AB - Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H3dpaa), phosphonate (H4dppa), and bisphosphonate (H7dpbpa), as well as their nonfunctionalized analogue (H2dpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of H2dpa, H3dpaa, and H4dppa, the 1:2 lanthanum(III) complex of H2dpa, and the 1:1 gallium(III) complex of H3dpaa were characterized, including via X-ray crystallography for [La4(dppa)4(H2O)2] and [Ga(dpaa)(H2O)]. H2dpa, H3dpaa, and H4dppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (H3dpaa) or NMR spectrometric (H2dpa and H4dppa) titrations, which showed that the carboxylate (H3dpaa) and phosphonate (H4dppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log betaML and pM values) at physiological pH. In addition, potentiometric titrations with H3dpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log Po/w values using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides 67/68Ga, radiolabeling studies were performed with 67Ga and H3dpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10-5 M, and human serum stability studies were undertaken. PMID- 27989180 TI - Elaboration of a Highly Porous RuII,II Analogue of HKUST-1. AB - When the dinuclear RuII,II precursor [Ru2(OOCCH3)4] is employed under redox-inert conditions, a RuII,II analogue of HKUST-1 was successfully prepared and characterized as a phase-pure microcrystalline powder. X-ray absorption near-edge spectroscopy confirms the oxidation state of the Ru centers of the paddle-wheel nodes in the framework. The porosity of 1371 m2/mmol of RuII,II-HKUST-1 exceeds that of the parent compound HKUST1 (1049 m2/ mmol). PMID- 27989181 TI - Editorial for the ACS Select Virtual Issue on Emerging Investigators in Inorganic Photochemistry and Photophysics. PMID- 27989182 TI - Slow Magnetic Relaxations in Cobalt(II) Tetranitrate Complexes. Studies of Magnetic Anisotropy by Inelastic Neutron Scattering and High-Frequency and High Field EPR Spectroscopy. AB - Three mononuclear cobalt(II) tetranitrate complexes (A)2[Co(NO3)4] with different countercations, Ph4P+ (1), MePh3P+ (2), and Ph4As+ (3), have been synthesized and studied by X-ray single-crystal diffraction, magnetic measurements, inelastic neutron scattering (INS), high-frequency and high-field EPR (HF-EPR) spectroscopy, and theoretical calculations. The X-ray diffraction studies reveal that the structure of the tetranitrate cobalt anion varies with the countercation. 1 and 2 exhibit highly irregular seven-coordinate geometries, while the central Co(II) ion of 3 is in a distorted-dodecahedral configuration. The sole magnetic transition observed in the INS spectroscopy of 1-3 corresponds to the zero-field splitting (2(D2 + 3E2)1/2) from 22.5(2) cm-1 in 1 to 26.6(3) cm 1 in 2 and 11.1(5) cm-1 in 3. The positive sign of the D value, and hence the easy-plane magnetic anisotropy, was demonstrated for 1 by INS studies under magnetic fields and HF-EPR spectroscopy. The combined analyses of INS and HF-EPR data yield the D values as +10.90(3), +12.74(3), and +4.50(3) cm-1 for 1-3, respectively. Frequency- and temperature-dependent alternating-current magnetic susceptibility measurements reveal the slow magnetization relaxation in 1 and 2 at an applied dc field of 600 Oe, which is a characteristic of field-induced single-molecule magnets (SMMs). The electronic structures and the origin of magnetic anisotropy of 1-3 were revealed by calculations at the CASPT2/NEVPT2 level. PMID- 27989183 TI - Manganese Vanadate Chemistry in Hydrothermal BaF2 Brines: Ba3Mn2(V2O7)2F2 and Ba7Mn8O2(VO4)2F23. AB - Manganese vanadate fluorides were synthesized using high-temperature hydrothermal techniques with BaF2 as a mineralizer. Ba3Mn2(V2O7)2F2 crystallizes in space group C2/c and consists of dimers built from edge-sharing MnO4F2 trigonal prisms with linking V2O7 groups. Ba7Mn8O2(VO4)2F23 crystallizes in space group Cmmm, with a manganese oxyfluoride network built from edge- and corner-sharing Mn2+/3+(O,F)6 octahedra. These octahedra form alternating Mn2+ and Mn2+/3+ layers separated by VO4 tetrahedra. This latter compound exhibits a canted antiferromagnetic order below TN = 25 K. PMID- 27989184 TI - The Intersection of NO and H2S: Persulfides Generate NO from Nitrite through Polysulfide Formation. AB - Hydrogen sulfide (H2S) and nitric oxide (NO) are important biosignaling molecules, and their biochemistries are increasingly recognized to be intertwined. Persulfides are an oxidized product of biological H2S and have emerged as important species involved in the biological action of reactive sulfur species. Using isolated persulfides, we employed a combination of experimental and computational methods to investigate the contribution of persulfides to H2S/NO crosstalk. Our studies demonstrate that isolated persulfides react with nitrite to produce NO via polysulfide and perthionitrite intermediates. These results highlight the importance of persulfides, polysulfides, and perthionitrite as intertwined reactive nitrogen and sulfur species. PMID- 27989185 TI - Structural Basis for the Selective Pb(II) Recognition of Metalloregulatory Protein PbrR691. AB - The transcription regulator PbrR691, one of the MerR family proteins, shows extremely high sensitivity and selectivity toward Pb(II) in Ralstonia metallidurans CH34. Here, we present the crystal structure of PbrR691 in complex with Pb(II) at 2.0 A resolution. The Pb(II) coordinates with three conserved cysteines and adopts a unique trigonal-pyramidal (hemidirected) geometry. To our knowledge, the PbrR691-Pb(II) structure provides the first three-dimensional visualization of a functional hemidirected lead(II) thiolate coordinate geometry in a protein. PMID- 27989186 TI - Assembling Dysprosium Dimer Units into a Novel Chain Featuring Slow Magnetic Relaxation via Formate Linker. AB - A dinuclear complex [DyLClCH3OH)]2 (1) and a one-dimensional compound [DyL(HCOO)(CH3OH)]n (2) have been synthesized using an organic ligand of N'-(2 hydroxybenzylidene)picolinohydrazide (H2L). Complex 1 exhibits a symmetric dinuclear structure, in which the Dy3+ centers reside in a pentagonal-bipyramidal coordination environment. In 2, the dinuclear units of 1 are strung into chains by formate anions, in which Dy3+ ions are situated in an octa-coordinated, hula hoop-like coordination geometry. Magnetic studies reveal that ferromagnetic coupling is found between Dy3+ ions in both compounds. Complexes 1 and 2 exhibit slow magnetic relaxation under zero dc field with effective energy barriers of 88.4 and 175.8 K, respectively. Magnetic study combined with ab initio calculations indicates that the better performance of 2 is related to the unique molecular geometry and relatively stronger Dy3+-Dy3+ magnetic interaction within and/or between the dimer units. PMID- 27989187 TI - Cation-Induced Variation of Micromorphology and Luminescence Properties of Tungstate Phosphors by a Hydrothermal Method. AB - Eu3+-doped MWO4 (M = Zn, Cd, Ca, Sr, or Ba) nanorods and rodlike, spherical, dumbbell-like, and double-tapter-like grains have been obtained via a hydrothermal method. The distinct differences in cationic radius lead to a special morphology, which is attributed to the symmetry of the crystal structure and the differences in the growth rates of various crystals, and it further leads to the variation of luminescence. It was found that the charge transfer band of MWO4:0.04Eu3+ exhibits a blue shift with an increasing cationic radius, and the shift is ascribed to less covalency being caused by an increase in the cationic radius. The emission intensity obviously increases with cationic radius, increasing for the samples with a monoclinic phase; however, it is the opposite for the samples with a tetragonal phase, and CaWO4:0.04Eu3+ exhibits an optimal emission intensity. In addition, the possible reasons for the decay lifetime are also discussed in detail. Our results indicate that cations can effectively control the crystal structure, micromorphology, and luminescence in tungstate phosphors, and thus, our approach is effective for obtaining materials with the desired morphology and crystal structure. PMID- 27989188 TI - Structural Channels and Atomic-Cluster Insertion in CsxBi4Te6 (1 <= x <= 1.25) As Observed by Aberration-Corrected Scanning Transmission Electron Microscopy. AB - Microstructural analyses based on aberration-corrected scanning transmission electron microscopy (STEM) observations demonstrate that low-dimensional CsxBi4Te6 materials, known to be a novel thermoelectric and superconducting system, contain notable structural channels that go directly along the b axis, which can be partially filled by atom clusters depending on the thermal treatment process. We successfully prepared two series of CsxBi4Te6 single-crystalline samples using two different sintering processes. The CsxBi4Te6 samples prepared using an air-quenching method show superconductivity at approximately 4 K, while the CsxBi4Te6 with the same nominal compositions prepared by slowly cooling are nonsuperconductors. Moreover, atomic structural investigations of typical samples reveal that the structural channels are often empty in superconducting materials; thus, we can represent the superconducting phase as Cs1-yBi4Te6 with considering the point defects in the Cs layers. In addition, the channels in the nonsuperconducting crystals are commonly partially occupied by triplet Bi clusters. Moreover, the average structures for these two phases are also different in their monoclinic angles (beta), which are estimated to be 102.3 degrees for superconductors and 100.5 degrees for nonsuperconductors. PMID- 27989189 TI - Ruthenium Derivatives of in Situ Generated Redox-Active 1,2-Dinitrosobenzene and 2-Nitrosoanilido. Diverse Structural and Electronic Forms. AB - The article describes one-pot synthesis and structural elucidation of tc [RuII(pap)2(L*-)]ClO4 [1]ClO4 and tc-[RuII(pap)2(L'-)]ClO4 [2]ClO4, which were obtained from tc-[RuII(pap)2(EtOH)2](ClO4)2 and benzofuroxan (L = 1,2 dinitrosobenzene, an intermediate tautomeric form of the biologically active benzofuroxan, L'- = 2-nitrosoanilido, pap = 2-phenylazopyridine, tc = trans and cis corresponding to pyridine and azo nitrogen donors of pap, respectively). The same reaction with the newly synthesized and structurally characterized metal precursor cc-RuII(2,6-dichloropap)2Cl2, however, affords isomeric ct-[RuII(2,6 dichloropap)2(L*-)]+ (3a+) and tc-[RuII(2,6-dichloropap)2(L*-)]+ (3b+) (cc, ct, and tc with respect to pyridine and azo nitrogens of 2,6-dichloropap) with the structural authentication of elusive ct-isomeric form of {Ru(pap)2} family. The impact of trans or cis orientation of the nitroso group of L/L' with respect to the N?N (azo) function of pap in the complexes was reflected in the relative lengthening or shortening of the latter distance, respectively. The redox sensitive bond parameters of 1+ and 3+ reveal the intermediate radical form of L* , while 2+ involves in situ generated L'-. The multiple redox processes of the complexes in CH3CN are analyzed via experimental and density functional theory (DFT) and time-dependent DFT calculations. One-electron oxidation of the electron paramagnetic resonance-active radical species (1+ and 3+) leads to [RuII(pap)2(L)]2+ involving fully oxidized L0 in 12+ and 32+; the same in 2+ results in a radical species [RuII(pap)2(L'*)]2+ (22+). Successive reductions in each case are either associated with pap or L/L'--based orbitals, revealing a competitive scenario relating to their pi-accepting features. The isolated or electrochemically generated radical species either by oxidation or reduction exhibits near-IR transitions in each case, attributing diverse electronic structures of the complexes in accessible redox states. PMID- 27989190 TI - A Potential Wasteform for Cs Immobilization: Synthesis, Structure Determination, and Aqueous Durability of Cs2TiNb6O18. AB - Cs2TiNb6O18 is a potential ceramic wasteform for the long-term immobilization of radioactive cesium. Cs2TiNb6O18 was synthesized using the aqueous precursor method and a solid-state reaction, and its crystal structure was determined from the Rietveld refinement of synchrotron X-ray and neutron powder diffraction data. The structure is a pyrochlore analogue, space group P3m1 with Cs in 9-fold coordination. The calculated bond valence sum from analysis of neutron diffraction data of 0.84 and high coordination number suggest that Cs has a strong bonding environment. The chemical aqueous durability was investigated using the MCC-1 and PCT-B standard test methods. The measured Cs leach rates of 3.8 * 10-3 and 2.1 * 10-3 g m-2 day-1 obtained via the MCC-1 and PCT-B methods, respectively, demonstrate good promise of a safe long-term immobilization material comparable to, if not better than, hollandite-the material in the multiphase titanate ceramics (Synroc) targeted for cesium sequestration. PMID- 27989191 TI - Determinants of Fe2+ over M2+ (M = Mg, Mn, Zn) Selectivity in Non-Heme Iron Proteins. AB - Iron cations are indispensable players in a number of vital biological processes such as respiration, cell division, nitrogen fixation, oxygen transport, nucleotide synthesis, oxidant protection, O2 activation in the metabolism of various organic substrates, gene regulation, and protein structure stabilization. The basic mechanisms and factors governing the competition between Fe2+ and other metal species from the cellular fluids such as Mg2+, Mn2+, and Zn2+ are, however, not well understood, and several outstanding questions remain. (i) How does the Fe2+ binding site select the "right" cation and protect itself from attacks by other biogenic cations present in the surrounding milieu? (ii) Do the iron binding sites employ different selectivity strategies toward metal cations possessing different ligand affinities and cytosolic concentrations? (iii) What are the key determinants of metal selectivity in Fe2+ proteins? In this study, by employing density functional theory calculations combined with polarizable continuum model computations, we endeavor to address these questions by evaluating the thermodynamic outcome of the competition between Fe2+ and Mg2+/Mn2+/Zn2+ in model non-heme mononuclear metal binding sites of various compositions and charge states. The present calculations, which are in line with available experimental data, shed light on the mechanism of Fe2+-Mg2+/Mn2+/Zn2+ competition in non-heme iron proteins and disclose the key factors governing the process. PMID- 27989192 TI - Synthesis and Coordination Chemistry of Hexadentate Picolinic Acid Based Bispidine Ligands. AB - The synthesis and CuII, NiII, ZnII, CoII, and GaIII coordination chemistry of the two isomeric hexadentate N5O ligands 6-[[9-hydroxy-1,5-bis(methoxycarbonyl)-7 methyl-6,8-bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl]methyl]picolinic acid (Hbispa1a) and 6-[[9-hydroxy-1,5-bis(methoxycarbonyl)-7-methyl-2,4 bis(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl]methyl]picolinic acid (Hbispa1b), picolinic acid-appended bispidines, are described. The two ligands are highly preorganized for octahedral coordination geometries and are particularly well suited for tetragonal symmetries, i.e., for Jahn-Teller labile ground states. This is confirmed by all data presented: solid-state structures, solution spectroscopy, electrochemistry, and CuII complex stabilities. Differences in the preorganization of the two isomers for the Jahn-Teller labile CuII centers are thoroughly analyzed on the basis of the crystal structures and an angular-overlap-model-based ligand-field analysis. PMID- 27989193 TI - Synthesis of an Enantipure Tetrazole-Based Homochiral CuI,II-MOF for Enantioselective Separation. AB - An enantipure (1S)-1-(5-tetrazolyl)ethylamine (5-eatz) ligand was first employed to construct a homochiral porous metal-organic framework, {[CuI2CuII(5-eatz)2(CN )(H2O)]+[NO3-]}.[DMF] (1), with unusual ligand-unsupported Cu...Cu interactions. Such a compound shows high stability in water and common organic solvents. Remarkably, it has high enantioselectivity toward (R,S)-1-phenylethanol and (R,S) 1-phenylpropanol with enantiomeric excess values of up to 42% and 48%, respectively. PMID- 27989194 TI - Re(CO)3-Templated Synthesis of Semihemiporphyrazines. AB - Half-hemiporphyrazine macrocycles, which can be called "semihemiporphyrazines", were synthesized using the Re(CO)3 unit as a templating agent. The products of these template reactions are six-coordinate rhenium complexes, with a facial arrangement of carbonyls, a halide, and a bidentate semihemiporphyrazine chelate that tilts out of the plane of coordination. Three types of semihemiporphyrazines can be produced from these reactions, depending on the alternate heterocycle to the isoindoline unit; structures including pyridine, thiazole, and benzimidazole were formed. The electronic structures of these compounds were probed using spectroscopy as well as density functional theory methods. PMID- 27989195 TI - Instability of the Ionic Conductor Li6BaLa2B2O12 (B = Nb, Ta): Barium Exsolution from the Garnet Network Leading to CO2 Capture. AB - The instability of the two garnets Li6BaLa2B2O12 (B = Nb, Ta) has been studied on samples prepared in powder form by solid-state reaction. For this study, we coupled different techniques: powder X-ray diffraction, IR spectrometry, thermal analysis, transmission electron microscopy, and complex impedance spectroscopy. We showed that in ambient air and at low temperature (<150 degrees C), a spontaneous Li+/H+ exchange occurs. At higher temperature (500-700 degrees C), a progressive exsolution of the barium from the garnet framework is observed, leading to the formation of a second garnet, BaCO3, and a 3D cubic perovskite. To conclude this work, we studied the impact of barium exsolution on the ionic conductivity measured by complex impedance spectroscopy. We observed a significant decrease in the starting bulk conductivity (60%) when the pellet is heated at 500 degrees C for 5 h. PMID- 27989196 TI - Structure and Magnetic Properties of KRuO4. AB - The crystal structure of KRuO4 is refined at both 280 and 3.5 K from neutron powder data, and magnetic properties are reported for the first time. The scheelite structure, I41/a, is confirmed at both temperatures. Atomic positions of greater accuracy than the original 1954 X-ray study are reported. The rare Ru7+ ion resides in a site of distorted tetrahedral symmetry with nominal electronic configuration 4d1(e1). Curie-Weiss parameters are near free ion values for the effective moment and theta = -77 K, indicating dominant antiferromagnetic (AF) correlations. A broad susceptibility maximum occurs near 34 K, but long range AF order sets in only below 22.4 K as determined by magnetization and heat capacity data. The entropy loss below 50 K is only 44% of the expected R ln 2, indicating the presence of short-range spin correlations over a wide temperature range. The Ru sublattice consists of centered, corner-sharing tetrahedra which can lead to geometric frustration if both the nearest-neighbor, J1, and the next nearest-neighbor, J2, exchange constants are AF and of similar magnitude. A spin dimer analysis finds J1/J2 ~ 25, indicating weak frustration, and a (dz2)1 ground state. A single, weak magnetic reflection was indexed as (110). The absence of the (002) magnetic reflection places the Ru moments parallel to the c axis. The Ru7+ moment is estimated to be 0.57(7) MUB, reduced from an expected value near 1 MUB. A recent computational study of isostructural, isoelectronic KOsO4 predicts a surprisingly large orbital moment due to spin-orbit coupling (SOC). However, the free ion SOC constant for Ru7+ is only ~30% that of Os7+, so it is unclear that this effect can be implicated in the low ordered moment for KRuO4. The origin of the short-range spin correlations is also not understood. PMID- 27989197 TI - Sol-Gel Synthesis of High-Purity Actinide Oxide ThO2 and Its Solid Solutions with Technologically Important Tin and Zinc Ions. AB - The applicability of epoxide-based sol-gel synthesis for actinide oxide (thoria) starting from air-stable salt, Th(NO3)4, has been examined. The homogeneous gel formed from Th(NO3)4 when calcined at 400 degrees C yielded nanostructured thoria, and with increasing tempeartures (600, 700, and 800 degrees C), the average crystallite size increased. Successful Rietveld refinement of the powder X-ray diffraction pattern of ThO2 in Fm3m space group was carried out with a = 5.6030(35) A. The fingerprint vibrational mode of the fluorite structure of ThO2 was noticed as a sharp band in the Raman spectrum at 457 cm-1. In the SEM image, a near spherical morphology of thoria was noticed. Samples showed blue emission on exciting with lambda = 380 nm in the photoluminescence spectrum indicative of the presence of defects. Following this approach, 50 mol % of Sn4+ could be substituted for Th4+, retaining the fluorite structure as evidenced by the PXRD, Raman spectroscopy, electron microscopy, EDAX, and XPS measurements. Randomization of the lattice was observed for the tin-substituted samples. A significant blue shift in the absorption threshold along with a persistent blue emission in the photoluminesence spectra were evident for the tin-substituted samples. The concentration of Zn2+ ion in thoria was limited to 15 mol % as revealed by PXRD and XPS measurements. The Raman peak shifted to higher values for Zn2+-substituted samples. A change in the optical absorbance characteristics was observed for the zinc-substituted thoria. A 50 mol % Sn4+-substituted thoria degraded aqueous Rhodamine 6G dye solutions in the presence of UV-vis radiation following pseudo-first-order kinetics. PMID- 27989198 TI - Combining 27Al Solid-State NMR and First-Principles Simulations To Explore Crystal Structure in Disordered Aluminum Oxynitride. AB - The nuclear magnetic resonance (NMR) technique gives insight into the local information in a crystal structure, while Rietveld refinement of powder X-ray diffraction (PXRD) sketches out the framework of a crystal lattice. In this work, first-principles calculations were combined with the solid-state NMR technique and Rietveld refinement to explore the crystal structure of a disordered aluminum oxynitride (gamma-alon). The theoretical NMR parameters (chemical shift, deltaiso, quadrupolar coupling constants, CQ, and asymmetry parameter, eta) of Al22.5O28.5N3.5, predicted by the gauge-including projector augmented wave (GIPAW) algorithm, were used to facilitate the analytical investigation of the 27Al magic-angle spinning (MAS) NMR spectra of the as-prepared sample, whose formula was confirmed to be Al2.811O3.565N0.435 by quantitative analysis. The experimental deltaiso, CQ, and eta of 27Al showed a small discrepancy compared with theoretical models. The ratio of aluminum located at the 8a to 16d sites was calculated to be 0.531 from the relative integration of peaks in the 27Al NMR spectra. The occupancies of aluminum at the 8a and 16d positions were determined through NMR investigations to be 0.9755 and 0.9178, respectively, and were used in the Rietveld refinement to obtain the lattice parameter and anion parameter of Al2.811O3.565N0.435. The results from 27Al NMR investigations and PXRD structural refinement complemented each other. This work provides a powerful and accessible strategy to precisely understand the crystal structure of novel oxynitride materials with multiple disorder. PMID- 27989199 TI - Manganese Tricarbonyl Complexes with Asymmetric 2-Iminopyridine Ligands: Toward Decoupling Steric and Electronic Factors in Electrocatalytic CO2 Reduction. AB - Manganese tricarbonyl bromide complexes incorporating IP (2 (phenylimino)pyridine) derivatives, [MnBr(CO)3(IP)], are demonstrated as a new group of catalysts for CO2 reduction, which represent the first example of utilization of (phenylimino)pyridine ligands on manganese centers for this purpose. The key feature is the asymmetric structure of the redox-noninnocent ligand that permits independent tuning of its steric and electronic properties. The alpha-diimine ligands and five new Mn(I) compounds have been synthesized, isolated in high yields, and fully characterized, including X-ray crystallography. Their electrochemical and electrocatalytic behavior was investigated using cyclic voltammetry and UV-vis-IR spectroelectrochemistry within an OTTLE cell. Mechanistic investigations under an inert atmosphere have revealed differences in the nature of the reduction products as a function of steric bulk of the ligand. The direct ECE (electrochemical-chemical electrochemical) formation of a five-coordinate anion [Mn(CO)3(IP)]-, a product of two-electron reduction of the parent complex, is observed in the case of the bulky DIPIMP (2-[((2,6-diisopropylphenyl)imino)methyl]pyridine), TBIMP (2-[((2 tert-butylphenyl)imino)methyl]pyridine), and TBIEP (2-[((2-tert butylphenyl)imino)ethyl]pyridine) derivatives. This process is replaced for the least sterically demanding IP ligand in [MnBr(CO)3(IMP)] (2 [(phenylimino)methyl]pyridine) by the stepwise formation of such a monoanion via an ECEC(E) mechanism involving also the intermediate Mn-Mn dimer [Mn(CO)3(IMP)]2. The complex [MnBr(CO)3(IPIMP)] (2-[((2-diisopropylphenyl)imino)methyl]pyridine), which carries a moderately electron donating, moderately bulky IP ligand, shows an intermediate behavior where both the five-coordinate anion and its dimeric precursor are jointly detected on the time scale of the spectroelectrochemical experiments. Under an atmosphere of CO2 the studied complexes, except for the DIPIMP derivative, rapidly coordinate CO2, forming stable bicarbonate intermediates, with no dimer being observed. Such behavior indicates that the CO2 binding is outcompeting another pathway: viz., the dimerization reaction between the five-coordinate anion and the neutral parent complex. The bicarbonate intermediate species undergo reduction at more negative potentials (ca. -2.2 V vs Fc/Fc+), recovering [Mn(CO)3(IP)]- and triggering the catalytic production of CO. PMID- 27989200 TI - Stacking Faults and Polytypes for Layered Double Hydroxides: What Can We Learn from Simulated and Experimental X-ray Powder Diffraction Data? AB - Layered double hydroxides (LDH) are a broad group of widely studied materials. The layered character of those materials and their high flexibility for accommodating different metals and anions make them technologically interesting. The general formula for the LDH compound is [M1-xIIMxIII(OH)2][An-]x/n.mH2O, where MII is a divalent metal cation which can be substituted by MIII trivalent cation, and An- is a charge compensating anion located between positively charged layers. In this paper we present a comprehensive study on possible structural disorder in LDH. We show how X-ray powder diffraction (XRPD) can be used to reveal important features of the LDH crystal structure such as stacking faults, random interlayer shifts, anion-molecule orientation, crystal water content, distribution of interlayer distances, and also LDH slab thickness. All calculations were performed using the Discus package, which gives a better flexibility in defining stacking fault sequences, simulating and refining XRPD patterns, relative to DIFFaX, DIFFaX+, and FAULTS. Finally, we show how the modeling can be applied to two LDH samples: Ni0.67Cr0.33(OH)2(CO3)0.16.mH2O (3D structure) and Mg0.67Al0.33(OH)2(NO3)0.33 (2D layered structure). PMID- 27989201 TI - Modulation of Eu(III) and Yb(III) Luminescence Using a DTE Photochromic Ligand. AB - In this work, we show that a dithienylethene (DTE) modified dipicolinic amide ligand can be a versatile tool to modulate Eu(III) and Yb(III) luminescence using light as an external stimulus. The nature of the modulation depends on the lanthanide emitter: with the europium ion, the DTE ligand quenches the red luminescence upon ring closure, whereas with the ytterbium ion, ring closure can be used to turn on the luminescence in the NIR range. PMID- 27989202 TI - Unsymmetrical N-Aryl-1-(pyridin-2-yl)methanimine Ligands in Organonickel(II) Complexes: More Than a Blend of 2,2'-Bipyridine and N,N-Diaryl-alpha-diimines? AB - The new organonickel complexes [(R-PyMA)Ni(Mes)X] [R-PyMA = N-aryl-1-(pyridin-2 yl)methanimine; aryl = phenyl, 2,6-Me2-, 3,5-Me2-, 2,4,6-Me3-, 2,6-iPr2-, 3,5 (OMe)2-, 2-NO2-4-Me-, 4-NO2-, 2-CF3-, and 2-CF3-6-F-phenyl; Mes = 2,4,6 trimethylphenyl; X = F, Cl, Br, or I] were obtained as approximate 1/1 cis and trans isomeric mixtures or pure cis isomers depending on the PyMA ligand and X. The [(R-PyMA)Ni(Mes)X] complexes with X = Br or Cl were directly synthesized from the precursors trans-[(PPh3)2Ni(Mes)X], while [(PyMA)Ni(Mes)X] derivatives with X = F or I were obtained from [(PyMA)Ni(Mes)Br] through X exchange reactions. Although density functional theory (DFT) calculations show a preference for the sterically favored cis isomers, both isomers could be observed in many cases; in three cases, even single crystals for X-ray diffraction could be obtained for the trans isomers. Possible intermediates for the isomerization were investigated by DFT calculations. All complexes were studied by multiple spectroscopic means, electrochemistry, and spectroelectrochemistry (for the reduction processes). The long-wavelength metal-to-ligand charge-transfer (MLCT) absorptions vary markedly with the R substituent of the ligand and the cathodic electrochemical potentials to a far smaller degree. Both are almost invariable upon variation of X. All of this is in line with Ni-based and pi*-based lowest unoccupied molecular orbitals (LUMOs). In line with the unsymmetric character of the NPy^Nmethanimine ligand, electrochemistry and MLCT transitions seem to not correspond to the same type of pi* LUMO, making these PyMA ligands more interesting than the symmetric heteroaromatic polypyridine ligands such as 2,2'-bipyridine (bpy; NPy^NPy) and N,N-diaryl-substituted aliphatic alpha-diimines (Nmethanimine^Nmethanimine) such as the diaza-1,3-butadienes (DAB). First attempts to use these complexes in Negishi-type cross-coupling reactions were successful. PMID- 27989203 TI - A Database of the Structural and Electronic Properties of Prussian Blue, Prussian White, and Berlin Green Compounds through Density Functional Theory. AB - Prussian blue and its related compounds are formed by cheap and abundant metals and have shown their importance in the generation of new fuels by renewable sources. To optimize these compounds it is important to understand their electronic structure and thus establish robust structure-activity relationships. To this end, we employed theoretical simulations based on density functional theory, employing functionals of different degree of complexity, including pure generalized gradient approximation (GGA) and GGA+U functionals, which introduce self-interaction correction terms through the Hubbard parameter, and compared those to the hybrid functionals HSE03 and HSE06. With this robust setup, we can identify an appropriate computational scheme that provides the best compromise between computational demand and accuracy. A complete database considering Berlin green and Prussian blue and white for all alkaline cations is presented. PMID- 27989204 TI - Beryllium-Free KBBF Family of Nonlinear-Optical Crystals: AZn2BO3X2 (A = Na, K, Rb; X = Cl, Br). AB - A series of a novel beryllium-free KBBF family of nonlinear-optical materials AZn2BO3X2 (A = K, Rb and X = Cl; A = Na, K, Rb and X = Br) were successfully synthesized through molecular engineering design, and single crystals of AZn2BO3Cl2 (A = K, Rb) were grown by a spontaneous nucleation technique from self flux systems. As a representative for the halogen KBBF family of crystals, KZn2BO3Cl2 features the infinite lattice layer [Zn2BO3Cl2]infinity made up of BO3 and ZnO3Cl anionic groups, and the in-layer BO3 groups are completely coplanar and well-aligned. Besides, KZn2BO3Cl2 exhibits high transmittance in the range of 300-2000 nm with a UV-transmission cutoff of around 200 nm according to transmission spectra. The compounds of AZn2BO3Cl2 (A = K, Rb) are both phase matchable with powder second-harmonic-generation efficiencies of 1.3 and 1.17 times that of KH2PO4 for KZn2BO3Cl2 and RbZn2BO3Cl2, respectively, which are similar to that of KBBF. PMID- 27989205 TI - Bifunctional Chalcogen Linkers for the Stepwise Generation of Multimetallic Assemblies and Functionalized Nanoparticles. AB - The disulfide ligand (SC6H4CO2H-4)2 acts as a simple but versatile linker for a range of group 8 transition metals through reaction of the oxygen donors. This leads to a range of homobimetallic ruthenium and osmium alkenyl compounds, [{M(CH?CHR)(CO)(PPh3)2(O2CC6H4S-4)}2] (M = Ru, Os; R = C6H4Me-4). Additional metal-based functionality can be added through the use of precursors incorporating rhenium bipyridine units (R = (bpy)ReCl(CO)3). The more robust diphosphine ligands in [{Ru(dppm)2(O2CC6H4S-4)}2]2+ (dppm = diphenylphosphinomethane) allow reduction of the disulfide bond with sodium borohydride to yield the thiol complex [Ru(O2CC6H4SH-4)(dppm)2]+. This complex reacts with [AuCl(PPh3)] to afford the bimetallic compound [Ru(dppm)2(O2CC6H4S 4)Au(PPh3)]+. However, an improved route to the same and related heterobimetallic compounds is provided by the reaction of cis-[RuCl2(dppm)2] with [Au(SC6H4CO2H 4)(L)] (L = PPh3, PCy3, PMe3, IDip) in the presence of base and NH4PF6 (IDip = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). The heterotrimetallic compound [Au(SC6H4CO2Ru(dppm)2)2]+ is accessible through the reaction of the homoleptic gold(I) dithiolate [Au(SC6H4CO2H-4)2]PPN (PPN = bis(triphenylphosphine)iminium) with cis-[RuCl2(dppm)2]. Without departure from the same methodology, greater complexity can be incorporated into the system to provide the penta- and heptametallic assemblies [(dppf){AuSC6H4CO2Ru(dppm)2}2]2+ and [(dppf){AuSC6H4CO2Os(CH?CH-bpyReCl(CO)3)(CO)(PPh3)2}2]. The same stepwise approach provides the dinuclear organometallic complexes [(L)Au(SC6H4CO2 4)M(CH?CHC6H4Me-4)(CO)(PPh3)2] (M = Ru, Os; L = PPh3, IDip). Complexes containing three metals from different groups of the periodic table [(L)Au(SC6H4CO2 4)M{CH?CH-bpyReCl(CO)3}(CO)(PPh3)2] (M = Ru, Os) can also be prepared, with one ruthenium example (L = PPh3) being structurally characterized. In order to illustrate the versatility of this approach, the synthesis and characterization (IR and NMR spectroscopy, TEM, EDS, and TGA) of the functionalized gold and palladium nanoparticles Au@[SC6H4CO2Ru(dppm)2]+ and Pd@[SC6H4CO2Ru(dppm)2]+ is reported. PMID- 27989206 TI - Quantum Chemical Investigation of the Transition States and Intermediates for the Reaction of the Nitrosonium Ion with the Pentaammineazidocobalt(III) Ion. AB - The water exchange reaction on Co(NH3)5OH23+ was investigated with various density functionals and basis sets. A Gibbs activation energy (DeltaG?) agreeing with experiment was obtained with the long-range-corrected functionals omegaB97X D3 and LC-BOP-LRD, SMD hydration, and modified Karlsruhe def2-TZVP basis sets. This computational technique was then applied to the reaction of NO+ with Co(NH3)5N32+. All of the possible pathways were investigated, NO+ attack at the terminal N of Co(NH3)5N32+ via the E and the Z isomers of the transition states, and NO+ attack at the bound N of azide, also via both isomers. The most favorable pathway proceeds via the attack at the bound N via the Z isomer. This leads to the intermediate with an oxatetrazole ligand bound to Co(III) at the N in the 3 position, Co(NH3)5(cycl-N4O)3+, which undergoes N2 elimination to yield the Co(NH3)5N2O3+ intermediate. The subsequent substitution of N2O by water follows the Id mechanism with retention of the configuration. No evidence for the existence of the square-pyramidal pentacoordinated intermediate Co(NH3)53+ was found. All of the investigated intermediates, Co(NH3)5N23+, Co(NH3)5[E N(N2)(NO)]3+, Co(NH3)5(E-ON4)3+, Co(NH3)5ON23+, Co(NH3)5(cycl-N4O)3+, and Co(NH3)5N2O3+, exhibit short lifetimes of less than ~60 MUs and react via the Id mechanism. PMID- 27989207 TI - Transformation of One-Dimensional Achiral Structure to Three-Dimensional Chiral Structure: Mechanistic Study and Catalytic Activities of Chiral Structure. AB - We have isolated two copper-based coordination polymers through solvent diffusion and solvothermal methods using copper salt, furan dicarboxylic acid (FDC), 4,4' bipyridine (bpy) in MeOH/ethylene glycol, and water solvents. Compound 1 is adopting P21/c space group and adopts a one-dimensional wirelike structure with a free carboxylate anion. Compound 2 crystallizes in chiral space group P65. This is a three-dimensional structure with helical chains. This helicity might be the reason for chiral generation and symmetry breaking. We have converted compound 1 to compound 2 using grinding, followed by a solvothermal method. The circular dichroism data of 2 showed that it is an enantioenriched compound. We have shown that compound 2 is a very good catalyst for chemo- and regioselective enamination reaction and for azide-alkyne Huisgen cycloaddition, respectively. PMID- 27989208 TI - Electron Paramagnetic Resonance Characterization of Dioxygen-Bridged Cobalt Dimers with Relevance to Water Oxidation. AB - A variety of metal oxides can catalyze the oxidation of water to molecular oxygen when polarized by a sufficiently high electrochemical potential. Minimizing the overpotential and increasing the rate of the oxygen-evolving reaction (OER) are key goals in making such materials a component of viable energy storage devices. However, the structural factors that imbue the metal oxides with their catalytic power are difficult to assess as these solids contain many distinct metal-ion sites, have a varying amount of defect sites within the lattice, and can be composed of multiple phases. In the present study, we determined the magnetic properties for a series of dimeric cobalt complexes in which the two metal centers are bridged by a dioxygen moiety. Our spectroscopically validated electronic structure description indicates that each species is best described as two Co(III) ions that are bound to a MU-eta1eta1 superoxide ligand. Intriguingly, we found evidence that the two compounds that possess oxygen-evolving activity coordinate the superoxide ion in an unusual, nonplanar fashion. It appears as if the intermediately long Co...Co distance of 3.9 A is responsible for the unusual superoxide binding geometry. This structural factor may be an important element in the design of solid-state OER catalysts. PMID- 27989209 TI - Extraction of Water and Speciation of Trivalent Lanthanides and Americium in Organophosphorus Extractants. AB - Complexes of the trivalent lanthanides and Am with di-2-ethylhexylphosphoric acid (HDEHP) dissolved in an aliphatic diluent were probed with UV-vis, X-ray absorption fine structure, and time-resolved fluorescence spectroscopy while the water concentration was determined by Karl Fischer titrations. In particular, our work focuses on the Nd-hypersensitive UV-vis absorbance region to identify the cause of changing absorbance values at 570 and 583 nm in relation to the pseudooctahedral Nd environment when coordinated with three HDEHP dimers. In contrast to recently reported interpretations, we establish that while impurities have an effect on this electronic transition band, a high water content can cause distortion of the pseudooctahedral symmetry of the six-coordinate Nd, resembling the reported spectra of the seven-coordinate Nd compounds. Extended X-ray absorption fine structure analysis of the Nd in high-concentration HDEHP solutions also points to an increase in the coordination number from 6 to 7. The spectral behavior of other lanthanides (Pr, Ho, Sm, and Er) and AmIII as a function of the HDEHP concentration suggests that water coordination with the metal likely depends on the metal's effective charge. Fluorescence data using lifetime studies and excitation and emission spectra support the inclusion of water in the Eu coordination sphere. Further, the role of the effective charge was confirmed by a comparison of the Gibbs free energies of six- and seven coordinate La-HDEHP-H2O and Lu-HDEHP-H2O complexes using density functional theory. In contrast, HEH[EHP], the phosphonic acid analogue of HDEHP, exhibits a smaller capacity for water, and the electronic absorption spectra of Nd or Am appear to be unchanged, although the Pr spectra show a noticeable change in intensity as a function of the water content. Electronic absorption extinction coefficients of AmIII, NdIII, PrIII, SmIII, ErIII, and HoIII as a function of the HDEHP concentration are reported for the first time. PMID- 27989210 TI - Chiral Ruthenium(II) Complexes as Supramolecular Building Blocks for Heterometallic Self-Assembly. AB - A series of enantiopure ruthenium(II) polypyridyl complexes are reported that feature pendant pyridyl groups suitable for building larger self-assembled structures. The complexes are characterized in detail in solution using NMR spectroscopy, cyclic voltammetry, and photophysical methods and in the solid state using single-crystal X-ray crystallography. The complexes are luminescent, displaying long excited-state lifetimes that are quenched when the pendant pyridyl groups are protonated. Reaction with cadmium(II) ions results in the formation of a mixed-metal one-dimensional coordination polymer, which was characterized by single-crystal X-ray crystallography. PMID- 27989211 TI - Electrochemical Oxidation of [1-X-12-I-CB11Me10-] Anions: Formation of Borenium Ylides [12-Dehydro-1-X-CB11Me10] and Iodonium Ylide Anions [{12-(1-X-CB11Me10 )}2I+]. AB - Cyclic voltammograms of 12-iodinated icosahedral carborane anions [1-X-12-I CB11Me10-] (X = H, CH3, C2H5, C3H7, C4H9, C6H13, and COOCH3) show two one electron anodic oxidation peaks at the Pt electrode in liquid SO2. Oddly, the first is irreversible and the second partially reversible. Mass spectrometry of the principal anionic product of preparative anodic oxidation of [1-H-12-I CB11Me11-], identical with the anionic product of its reaction with [Et3Si-H SiEt3]+ and/or Et3Si+, allows it to be identified as the iodonium ylide anion [{12-(1-H-CB11Me10-)}2I+]. Its reversible oxidation to a neutral ylide radical [{12-(1-H-CB11Me10*)}{12-(1-H-CB11Me10-)}I+] is responsible for the second peak. A DFT geometry optimization suggests that both the ylide anion and the ylide radical are very crowded and have an unusually large C-I-C valence angle of ~132 degrees ; they are the first compounds with two bulky highly methylated CB11 cages attached to the same atom. Molecular iodine is another product of the electrolysis. We propose an electrode mechanism in which initial one-electron oxidation of [1-X-12-I-CB11Me10-] is followed by a transfer of an iodine atom from the B-I bond to SO2 to yield a weakly bound radical ISO2* which disproportionates into SO2 and I2. The other product is the borenium ylide [12 dehydro-1-X-CB11Me10], which has a strongly Lewis acidic naked vertex in position 12 that rapidly adds to another [1-X-12-I-CB11Me10-] anion to form the observed stable ylide anion [{12-(1-X-CB11Me10-)}2I+]. In acetonitrile, where it presumably exists as a solvent adduct, [12-dehydro-1-X-CB11Me10] has been trapped with H2O and, to a small extent, with MeOH, but not with several other potential trapping agents. PMID- 27989212 TI - Solid-State Structures of XeO3. AB - The solid-state structure of xenon trioxide, XeO3, was reinvestigated by low temperature single-crystal X-ray diffraction and shown to exhibit polymorphism that is dependent on the crystallization conditions. The previously reported alpha-phase (orthorhombic, P212121) only forms upon evaporation of aqueous HF solutions of XeO3. In contrast, two new phases, beta-XeO3 (rhombohedral, R3) and gamma-XeO3 (rhombohedral, R3c), have been obtained by slow evaporation of aqueous solutions of XeO3. The extended structures of all three phases result from Xe?O-- Xe bridge interactions among XeO3 molecules that arise from the amphoteric donor acceptor nature of XeO3. The Xe atom of the trigonal-pyramidal XeO3 unit has three Xe---O secondary bonding interactions. The orthorhombic alpha-XeO3 displays the greatest degree of variation among the contact distances and has a significantly higher density than the rhombohedral phases. The ambient temperature Raman spectra of solid alpha- and gamma-XeO3 have also been obtained and assigned for the first time. PMID- 27989213 TI - Isolation of Blackberry-Shaped Nanoparticles of a Giant {Mo72Fe30} Cluster and Their Transformation to a Crystalline Nanoferric Molybdate. AB - When an aqueous solution of sodium molybdate is added to an aqueous solution of ferric chloride, acidified with acetic acid, a giant {Mo72Fe30} cluster is instantaneously formed as the amorphous substance Na2[Mo72Fe30O252(CH3COO)4(OH)16(H2O)108].180 H2O (1). Compound 1 consists of aggregated nanovesicles of {Mo72Fe30} clusters, as confirmed by field-emission scanning electron microscopy and transmission electron microscopy images of 1. An aqueous suspension of 1 upon moderate heating results in the formation of crystalline nanoferric molybdate, which gives insight into understanding the formation of a yellow coating mineral, ferrimolybdite, frequently found on the ores of molybdenum. PMID- 27989214 TI - Chemodynamics of Soft Nanoparticulate Metal Complexes: From the Local Particle/Medium Interface to a Macroscopic Sensor Surface. AB - The lability of a complex species between a metal ion M and a binding site S, MS, is conventionally defined with respect to an ongoing process at a reactive interface, for example, the conversion or accumulation of the free metal ion M by a sensor. In the case of soft charged multisite nanoparticulate complexes, the chemodynamic features that are operative within the micro environment of the particle body generally differ substantially from those for dissolved similar single-site complexes in the same medium. Here we develop a conceptual framework for the chemodynamics and the ensuing lability of soft (3D) nanoparticulate metal complexes. The approach considers the dynamic features of MS at the intraparticulate level and their impact on the overall reactivity of free metal ions at the surface of a macroscopic sensing interface. Chemodynamics at the intraparticulate level is shown to involve a local reaction layer at the particle/medium interface, while at the macroscopic sensor level an operational reaction layer is invoked. Under a certain window of conditions, volume exclusion of the nanoparticle body near the medium/sensor interface is substantial and affects the properties of the reaction layer and the overall lability of the nanoparticulate MS complex toward the reactive surface. PMID- 27989215 TI - Bottom-Up Assembly of Molecular Nanostructures by Means of Ferroelectric Lithography. AB - Here, we report on the photochemical deposition of Rhodamine 6G (Rh6G) and Alexa647 molecules from aqueous and methanolic solution along 180 degrees ferroelectric (FE) domain walls (DWs) of z-cut lithium niobate (LNO) single crystals. Molecules and FE domains were investigated by means of dynamic-mode AFM, piezoresponse force microscopy (PFM), and confocal scanning fluorescence microscopy. A high deposition affinity for 180 degrees DWs on the LNO surface is observed, leading to the formation of molecular nanowires. Additionally, a more complex deposition pattern for Rh6G adsorbed to the domain areas of freshly poled samples was equally observed, being associated with the DW dynamics. These results are explained by considering contributions from screening-charge dependent photochemistry as confined to the DWs, UV-induced DW motion, and transient electrostatic fields arising from the metastable defect distribution shortly after poling. Hence, tuning these effects offers the possibility for accurately controlling the complex bottom-up assembly of functional molecular nanostructures through domain-structured ferroelectric templates. PMID- 27989216 TI - The safety of talimogene laherparepvec for the treatment of advanced melanoma. AB - INTRODUCTION: Talimogene laherparepvec (T-VEC, IMLYGIC) is an oncolytic herpes virus type I used as intralesional therapy for the treatment of unresectable metastatic melanoma in a cutaneous, subcutaneous, or nodal location. Talimogene laherparepvec selectively replicates within and lyses tumor cells while producing granulocyte macrophage colony-stimulating factor (GM-CSF), which may promote an immune mediated antitumor response. Areas covered: The US Food and Drug Administration approved Talimogene laherparepvec in late 2015 following the completion of phase I, II and III trials that demonstrated safety and efficacy. Current NCCN practice guidelines have added Talimogene laherparepvec as a primary treatment for stage IIIB/C and stage IVM1a melanoma patients with evidence of good durable response rates, and this article sets out to review the use and safety and efficacy of T-VEC Expert opinion: Treatment options for locally advanced and metastatic melanoma are expanding with new developments in immunotherapy and immune checkpoint inhibitors. The ideal treatment of metastatic melanoma continues to be multimodal, combining systemic treatments, intralesional and regional therapies, surgery and radiotherapy to achieve optimal outcomes. Use of talimogene laherparepvec as intrelsional therapy has demonstrated promising effects in select patients with advanced melanoma. Future directions for Talimogene laherparepvec include combination therapies with other systemic immunotherapies such as anti-CTLA-4 antibody and anti-PD-1 drugs. PMID- 27989217 TI - Long-term safety and tolerability of glatiramer acetate 20 mg/ml in the treatment of relapsing forms of multiple sclerosis. AB - Introduction: Glatiramer acetate (GA) is a first-line therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). It has a well-characterized long-term safety profile and established efficacy, with over 2 million patient years of exposure. Areas covered: To present long-term safety and tolerability findings for GA 20 mg/mL daily in the management of patients with multiple sclerosis (MS). A database analysis of all patients with MS who have ever been exposed to GA 20 mg/mL daily in clinical trials, including patients with up to 20 years of continuous treatment.Total exposure to GA in the clinical trials analyzed was 10,017 patient-years, and treatment duration ranged from 0 to 23.1 years (median 1.8 years). No unexpected adverse events (AEs) were recorded. The most common AEs were injection-site related (ISR), affecting 49% of patients receiving GA in clinical trials. Development of erythema at the injection site was the most common ISR, affecting 29.2% of study patients. Immediate post injection reactions (IPIRs) were experienced by 24.0% of study patients; dyspnea was the most common IPIR, affecting 12.1% of patients. Expert opinion: The results of this analysis are consistent with long-term studies showing GA to be safe and generally well tolerated. PMID- 27989219 TI - Sesquiterpenoids from the twigs and leaves of Fokienia hodginsii. AB - A rare carotane-type sesquiterpenoid, forkienin A (1), a new eudesmane-type sesquiterpenoid, forkienin B (2), and a new natural eudesmane-type sesquiterpenoid, forkienin C (3), were isolated from the twigs and leaves of Fokienia hodginsii, along with eight known sesquiterpenoids. The structures of the new compounds were elucidated on the basis of their spectroscopic analysis, including 1D and 2D NMR methods. All compounds were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines. PMID- 27989220 TI - Mathematical model of LsrR-binding and derepression in Escherichia coli K12. AB - Quorum sensing (QS) enables bacterial communication and collective behavior in response to self-secreted signaling molecules. Unlocking its genetic regulation will provide insight towards understanding its influence on pathogenesis, formation of biofilms, and many other phenotypes. There are few datasets available that link QS-mediated gene expression to its regulatory components and even fewer mathematical models that incorporate known mechanistic detail. By integrating these data with annotated sequence information, mathematical inferences can be pieced together that shed light on regulatory structure. A first principles model, developed here for the E. coli QS system, builds on known mechanistic detail and is used to develop a working model of LuxS-regulated (Lsr) activity. That is, our model is meant to discriminate among hypothetical mechanisms governing lsr transcriptional regulation. Our simulations are in qualitative agreement with experimentally observed data. Importantly, our results point to the importance of transcriptional regulator, LsrR, cycling on genetic control. We also found several experimental observations in E. coli and homologous systems that were not explained by current mechanistic understanding. For example, by comparing simulations with reports of the integrating host factor in Aggrigatibacter actinomycetemcomitans, we conclude that additional transcriptional components are likely involved. An iterative process of simulation and experiment, therefore, is needed to inform new experiments and incorporate new model detail, the benefit of which will more rapidly validate mechanistic understanding. PMID- 27989218 TI - The Safety of available immunotherapy for the treatment of glioblastoma. AB - INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM. Areas covered: Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM. Expert opinion: Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM. PMID- 27989221 TI - Interaction of Prussian blue nanoparticles with bovine serum albumin: a multi spectroscopic approach. AB - Owning to their exceptional properties, Prussian blue nanoparticles (PBNPs) are promising in a variety of biomedical applications. In this scenario, understanding of how PBNPs interact and behave in biological systems is essential. Herein, the interaction of PBNPs with protein was investigated. Specifically, the citric acid stabilized PBNPs with a size of 10 nm were synthesized and characterized. The interactions of these PBNPs with the model protein, bovine serum albumin (BSA), were then probed by spectroscopic methods. It was found that the BSA intrinsic fluorescence was quenched upon addition of PBNPs due to the static interaction, suggesting the binding of PBNPs with BSA. Moreover, the synchronous fluorescence and circular dichroism spectra indicated the conformational change of BSA due to the presence of PBNPs. PMID- 27989222 TI - Pilot Study on the Genetic Background of an Active Matrix Metalloproteinase-8 Test in Finnish Adolescents. AB - BACKGROUND: In periodontitis, genetics and smoking play important roles in host immune system response. The aim of this study is to determine whether the genetic background of initial periodontitis and caries could be detected using an active matrix metalloproteinase (aMMP)-8 chairside test in Finnish adolescents. METHODS: Forty-seven participants gave approval for analysis of both oral fluid collection and DNA. An aMMP-8 chairside test was performed on participants (adolescents aged 15 to 17 years), and full-mouth clinical parameters of oral health were assessed including periodontal, oral mucosal, and caries status in Eastern Finland from 2014 to 2015. DNA was extracted from oral fluid samples and genotyped for 71 polymorphisms in 29 candidate genes for periodontitis. Results were analyzed using a logistic regression model. P values were corrected for multiple testing using false discovery rate (<0.05). RESULTS: aMMP-8 chairside test positivity and three or more >=4 mm pockets were associated with vitamin D receptor (VDR) (rs2228570, P = 0.002, q = 0.04) and MMP3 (rs520540, rs639752, rs679620, P = 0.0009, 0.003, 0.003, q = 0.04, respectively). None of the other single nucleotide polymorphisms studied showed a significant association with the aMMP-8 chairside test and at least one caries lesion positivity. CONCLUSION: Genetic polymorphisms of MMP3 and VDR are linked to initial periodontitis in Finnish adolescents, and the aMMP-8 chairside test can eventually detect initial periodontitis in young patients with predisposing genetic background. PMID- 27989223 TI - Antibacterial Effect of Synthetic Peptide LyeTxI and LyeTxI/beta-Cyclodextrin Association Compound Against Planktonic and Multispecies Biofilms of Periodontal Pathogens. AB - BACKGROUND: Antimicrobial peptides (AMPs) have shown rapid and potent effect against planktonic bacteria. However, control of periodontopathic biofilms is a challenge even for AMPs. Thus, the present study evaluates in vitro antimicrobial activity of synthetic peptide LyeTxI and association compound LyeTxI/beta cyclodextrin (betaCD) against multispecies biofilms. METHODS: Sensibility to LyeTxI and LyeTxI/betaCD was determined for planktonic Gram-negative periodontopathogens. Time-kill kinetic assay was performed at minimum inhibitory concentrations (MICs) in all planktonic strains. Multispecies biofilms were grown on pegs using a biofilm device and studied by scanning electron microscopy at 2, 5, and 10 days. Minimal biofilm eradication concentration (MBEC) was determined for 2- and 4-day multispecies biofilms. Metabolic activity of biofilms was determined by fluorometry study. RESULTS: Biofilms showed reproducible cell density on pegs of the biofilm device. LyeTxI and LyeTxI/betaCD were active against all strains tested at concentrations <=62.5 MUg/mL. Kinetic assays showed rapid bactericidal effect of LyeTxI against all periodontopathogens. MBECs of LyeTxI and LyeTxI/betaCD against multispecies 2-day biofilms were two-fold higher than MICs of cells shed from biofilms. LyeTxI was able to reduce multispecies 2 day metabolic activity by 90%. Multispecies 4-day biofilms were tolerant to all agents tested. CONCLUSIONS: LyeTxI and LyeTxI/betaCD are active against periodontopathic bacteria, showing rapid bactericidal effect and may be used to prevent biofilm development. In the future, AMPs could be therapeutic tools for treatment of periodontitis. PMID- 27989224 TI - Dairy farm wastewater treatment using horizontal subsurface flow wetlands with Typha domingensis and different substrates. AB - The aim of this work was to evaluate the influence of different substrates in the performance of a horizontal flow constructed wetland employed in dairy farm wastewater treatment. Typha domingensis was chosen for this study due to its high productivity and efficiency in nutrient removal. Fifteen microcosm-scale reactors simulating horizontal flow constructed wetlands were disposed in a greenhouse in triplicate. Five substrates (river gravel, gravel, LECA, river gravel + zeolite and gravel + zeolite) were evaluated. Real effluent with previous treatment was used. Dairy farm effluents favoured T. domingensis growth, probably due to their high nutrient concentrations. The treatments with the different substrates studied were efficient in the treatment of the dairy farm effluent obtaining ammonium ([Formula: see text]) and total phosphorus (TP) removals between 88-99% and 86-99%, respectively. Removal efficiencies were significantly higher in treatments using LECA and combined substrate (gravel + zeolite). After treatment, the quality of the final effluent was significantly improved. Outlet effluent complied with regulations and could be discharged into the environment. PMID- 27989225 TI - [Unaffected child born following preimplantation genetic diagnosis with karyomapping]. AB - Preimplantation genetic diagnosis for single gene defects is a well established method in assisted reproductive technologies. Karyomapping is a genome wide parental haplotyping using a high density single nucleotide polymorphism array that allows the diagnosis of any single gene defects. A couple with an affected child with primary congenital glaucoma attended at our clinic. Six oocyte-cumulus complex was retrieved and all three mature oocytes were inseminated. One zygote showed the signs of normal fertilization and was cultured for five days. Trophectoderm biopsy and karyomapping analysis were carried out. Result showed a heterozygous carrier for primary congenital glaucoma. Embryo was thawed and transferred and a healthy girl was delivered at term. Here we report the first live birth following in vitro fertilization combined with preimplantation genetic diagnosis using karyomapping in Hungary. Karyomapping is able to accurately detect single gene disorders from a limited amount of samples without a significant preclinical workup. Orv. Hetil., 2016, 157(51), 2048-2050. PMID- 27989226 TI - [After the epidemic - before the epidemic. Incidence of bronchiolitis at the Pediatric ward of the Bacs-Kiskun County Hospital]. AB - INTRODUCTION: Bronchiolitis may cause severe respiratory insufficiency in infants and toddlers. Respiratory Syncytial Virus (RSV) is its most frequent infective agent. AIM AND METHOD: The authors surveyed the incidence of bronchiolitis during the last 6 seasons, examined the epidemic of the 2014/15 season and compared the groups of RSV positive and negative patients. RSV was tested with a quick essay. Anamnestic data, clinical and laboratory parameters were compared. RESULTS: 72 patients were treated with bronchiolitis. RSV test was performed in 61 cases. There were 36 RSV positive and 25 RSV negative patients. There was a high proportion of prematurely born patients (33% versus 18%, respectively). RSV positive children, who required intensive care therapy, were treated significantly longer at the ICU. No further significant difference was found. CONCLUSIONS: The 2014/15 bronchiolitis season was heavy and may be instructive before the 2016/17 season. Beside supportive care prevention (passive immunization of the risk groups) is important. Orv. Hetil., 2016, 157(51), 2034 2039. PMID- 27989227 TI - [Function, aging and dysfunction of blood-brain barrier. Crossing the barrier]. AB - The blood-brain barrier is an interface between the circulation and brain. It is responsible for the homeostasis of central nervous system, protection and feeding of the brain and for providing the conditions for fine regulation of neurons. The coordinated function of different cell types and the regulated expression of molecular systems make possible the functionality of blood-brain barrier. However, this complex system can be broken due to different insults with a consequence of appearance of elevated levels of unwanted exogenous and endogenous molecules in the brain involved in the pathomechanisms of several disorders. The most important risk factor for the damage of blood-brain barrier is the aging itself, which causes disruption of the barrier through DNA mutation, oxidative stress and release of inflammatory mediators. Although the physiological aging is accompanied by morphological changes, the dysfunction of membrane transporters could also lead to neurodegenerative disorders. Structure, function and breakdown of the blood-brain barrier and the possibilities to cross it, are presented. Orv. Hetil., 2016, 157(51), 2019-2027. PMID- 27989228 TI - [Thermoablation therapy in the treatment of benign lesions]. AB - INTRODUCTION: Depending on their size and location, some benign tumors can cause prolonged discomfort and even rupture and fatal bleeding in severe cases. Hitherto the therapeutic strategies for such lesions were observation, surgery and in selected cases transarterial embolization. AIM: Our aim was to present the possibilities of thermoablation for treating lesions. METHOD: Here we present interventions of four patients in Semmelweis University Department of Transplantation and Surgery. A thyroid adenoma and a kidney angiomyolipoma were treated with radiofrequency ablation. Two patients with a liver haemangioma were treated with microwave thermoablation technique. RESULTS: Complications were not observed in any of the cases. In most cases, the size of the treated lesions decreased. The mean decrease in volume was 32.7%. The contrast enhancement of the lesions also decreased, the mean reduction in contrast enhancing volume was 75.3%. CONCLUSIONS: Thermoablational procedures for the benign tumors presented above are safe. The therapy shows excellent cosmetic results, a shorter hospital stay and quicker recovery. Orv. Hetil., 2016, 157(51), 2040-2047. PMID- 27989229 TI - [Factors influencing early detection of malignant melanoma]. AB - INTRODUCTION AND AIM: Melanoma is a highly aggressive tumour with often unpredictable outcome. Our aim with this study was to determine factors influencing early detection of melanoma. METHOD: We analyzed 139 questionnaires completed by patients diagnosed with melanoma. RESULTS: We found that our patients are health-conscious regarding cardiovascular diseases and attend cancer screenings on recall. However, their knowledge about melanoma is insufficient. Most of them perform skin self-examination, but they do not know what to check. Melanoma is detected mostly by the patients themselves, but it takes more than one year to consult a doctor. Our study confirmed that patients' attitude toward melanoma is an important factor influencing early detection. We found that physical examination and communication about skin cancer prevention is not part of the routine medical care. CONCLUSIONS: It is important to improve knowledge about melanoma among the general population and health care providers and to emphasize that early detection can save lives. Orv. Hetil., 2016, 157(51), 2028 2033. PMID- 27989231 TI - An unexpected way forward: towards a more accurate and rigorous protein-protein binding affinity scoring function by eliminating terms from an already simple scoring function. AB - A fundamental and unsolved problem in biophysical chemistry is the development of a computationally simple, physically intuitive, and generally applicable method for accurately predicting and physically explaining protein-protein binding affinities from protein-protein interaction (PPI) complex coordinates. Here, we propose that the simplification of a previously described six-term PPI scoring function to a four term function results in a simple expression of all physically and statistically meaningful terms that can be used to accurately predict and explain binding affinities for a well-defined subset of PPIs that are characterized by (1) crystallographic coordinates, (2) rigid-body association, (3) normal interface size, and hydrophobicity and hydrophilicity, and (4) high quality experimental binding affinity measurements. We further propose that the four-term scoring function could be regarded as a core expression for future development into a more general PPI scoring function. Our work has clear implications for PPI modeling and structure-based drug design. PMID- 27989232 TI - Subacute Fluoxetine Reduces Signs of Hippocampal Damage Induced by a Single Convulsant Dose of 4-Aminopyridine in Rats. AB - BACKGROUND: Epilepsy is a central disorder associated with neuronal damage and brain hypometabolism. It has been reported that antidepressant drugs show anticonvulsant and neuroprotective effects in different animal models of seizures and epilepsy. AIMS: The purpose of this study was to investigate the eventual short-term brain impairment induced by a single low convulsant dose of the potassium channel blocker 4-aminopyridine (4-AP) and the eventual neuroprotective effects exerted by fluoxetine, a prototypical selective serotonin (5 hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). METHOD: In vivo 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and several histological assessments were carried out in adult male rats after i.p. administration of 3 mg/kg 4-AP for evaluating eventual brain metabolism impairment and signs of hippocampal damage. We also evaluated the effects of a short-term fluoxetine treatment (10 mg/kg, i.p. for 7 days) in this seizure model. RESULTS: [18F]FDG PET analysis revealed no changes in the regional brain metabolism on day 3 after 4-AP injection. The histological assessments revealed signs of damage in the hippocampus, a brain area usually affected by seizures. Thus, reactive gliosis and a significant increase in the expression of caspase-9 were found in the aforementioned brain area. By contrast, we observed no signs of neurodegeneration or neuronal death. Regarding the effects of fluoxetine, this SSRI showed beneficial neurologic effects, since it significantly increased the seizure latency time and reduced the abovementioned 4-AP-induced hippocampal damage markers. CONCLUSION: Overall, our results point to SSRIs and eventually endogenous 5-HT as neuroprotective agents against convulsant-induced hippocampal damage. PMID- 27989233 TI - Fecal microbiota transplantation for multiple organ dysfunction syndrome. PMID- 27989234 TI - Erratum to: Scoring and psychometric validation of the 'Determinants of Intentions to Vaccinate' (DIVA(c)) questionnaire. PMID- 27989235 TI - Rapid detection of carbapenem resistance: targeting a zero level of inadequate empiric antibiotic exposure? PMID- 27989236 TI - Erratum to: The influence of N-acetyl-L-cysteine infusion on cytokine levels and gastric intramucosal pH during severe sepsis. PMID- 27989238 TI - The effects of synbiotic supplementation on markers of insulin metabolism and lipid profiles in gestational diabetes: a randomized, double-blind, placebo controlled trial - CORRIGENDUM. PMID- 27989237 TI - Modernising epidemic science: enabling patient-centred research during epidemics. AB - BACKGROUND: Emerging and epidemic infectious disease outbreaks are a significant public health problem and global health security threat. As an outbreak begins, epidemiological investigations and traditional public health responses are generally mounted very quickly. However, patient-centred research is usually not prioritised when planning and enacting the response. Instead, the clinical research response occurs subsequent to and separate from the public health response, and is inadequate for evidence-based decision-making at the bedside or in the offices of public health policymakers. DISCUSSION: The deficiencies of the clinical research response to severe acute respiratory syndrome, pandemic influenza, Middle East respiratory syndrome coronavirus and Ebola virus demonstrate that current research models do not adequately inform and improve the quality of clinical care or public health response. Three suggestions for improvements are made. First, integrate the data and sample collection needs for clinical and public health decision-making within a unified framework, combined with a risk-based, rather than a discipline-based, approach to ethical review and consent. Second, develop clinical study methods and tools that are specifically designed to meet the epidemiological and contextual challenges of emerging and epidemic infectious diseases. Third, invest in investigator-led clinical research networks that are primed and incentivised to respond to outbreak infections, and which can call on the support and resources of a central centre of excellence. CONCLUSIONS: It is crucial that the field of epidemic science matures to place patients at the heart of the response. This can only be achieved when patient centred research is integrated in the outbreak response from day one and practical steps are taken to reduce the barriers to the generation of reliable and useful evidence. PMID- 27989239 TI - Understanding the Impact of Interventions to Prevent Antimicrobial Resistant Infections in the Long-Term Care Facility: A Review and Practical Guide to Mathematical Modeling. AB - OBJECTIVES (1) To systematically search for all dynamic mathematical models of infectious disease transmission in long-term care facilities (LTCFs); (2) to critically evaluate models of interventions against antimicrobial resistance (AMR) in this setting; and (3) to develop a checklist for hospital epidemiologists and policy makers by which to distinguish good quality models of AMR in LTCFs. METHODS The CINAHL, EMBASE, Global Health, MEDLINE, and Scopus databases were systematically searched for studies of dynamic mathematical models set in LTCFs. Models of interventions targeting methicillin-resistant Staphylococcus aureus in LTCFs were critically assessed. Using this analysis, we developed a checklist for good quality mathematical models of AMR in LTCFs. RESULTS AND DISCUSSION Overall, 18 papers described mathematical models that characterized the spread of infectious diseases in LTCFs, but no models of AMR in gram-negative bacteria in this setting were described. Future models of AMR in LTCFs require a more robust methodology (ie, formal model fitting to data and validation), greater transparency regarding model assumptions, setting-specific data, realistic and current setting-specific parameters, and inclusion of movement dynamics between LTCFs and hospitals. CONCLUSIONS Mathematical models of AMR in gram-negative bacteria in the LTCF setting, where these bacteria are increasingly becoming prevalent, are needed to help guide infection prevention and control. Improvements are required to develop outputs of sufficient quality to help guide interventions and policy in the future. We suggest a checklist of criteria to be used as a practical guide to determine whether a model is robust enough to test policy. Infect Control Hosp Epidemiol 2017;38:216-225. PMID- 27989240 TI - Assessment of an Aggregate-Level Hand Hygiene Monitoring Technology for Measuring Hand Hygiene Performance Among Healthcare Personnel. AB - BACKGROUND Despite significant advances in technological methods for hand hygiene surveillance, a lack of evidence prohibits comparison of systems to one another or against the current gold standard of direct observation. OBJECTIVE To validate a hand hygiene monitoring technology (HHMT) designed to capture hand hygiene behaviors aggregated at the hospital-unit level (GOJO Industries, Akron, OH). METHODS Our team followed a rigorous validation approach to assess the sensitivity and positive predictive value (PPV) of an HHMT. A planned path was first used to measure the accuracy of the system when purposefully activated by investigators. Next, behavioral validation was used to quantify accuracy of the system in capturing real-world behaviors. RESULTS During the planned path phase, investigators performed 4,872 unique events across 3 distinct hospital buildings varying in size and age since construction. Overall sensitivity across the medical center was 88.7% with a PPV of 99.2%. During the behavioral validation phase, trained direct observers recorded 5,539 unique events across 3 distinct hospital buildings. Overall sensitivity across the medical center was 92.7% and PPV was 84.4%. CONCLUSION Objective measures of sensitivity and PPV indicate the promise of the benefit of this and other HHMTs to capture basic behaviors associated with hand hygiene. Infect Control Hosp Epidemiol 2017;38:348-352. PMID- 27989241 TI - Oak in Hospitals, the Worst Enemy of Staphylococcus aureus? PMID- 27989242 TI - Postdischarge Surveillance: Value and Problems Perceived by Infection Control Practitioners in Switzerland. PMID- 27989243 TI - Management of Rabies Prophylaxis for Potential Bat Exposures in a Level III Neonatal Intensive Care Unit. AB - This report describes the unique challenges of managing potential exposure to bats in a neonatal intensive care unit. The outcome demonstrates that rabies post exposure prophylaxis can be safely administered to preterm infants with evidence that preterm infants are able to develop adequate titers post vaccination. Infect Control Hosp Epidemiol 2017;38:483-485. PMID- 27989244 TI - Clinical Risk Score for Prediction of Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae in Bloodstream Isolates. AB - OBJECTIVE To develop a risk score to predict probability of bloodstream infections (BSIs) due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE). DESIGN Retrospective case-control study. SETTING Two large community hospitals. PATIENTS Hospitalized adults with Enterobacteriaceae BSI between January 1, 2010, and June 30, 2015. METHODS Multivariate logistic regression was used to identify independent risk factors for ESBLE BSI. Point allocation in extended-spectrum beta-lactamase prediction score (ESBL-PS) was based on regression coefficients. RESULTS Among 910 patients with Enterobacteriaceae BSI, 42 (4.6%) had ESBLE bloodstream isolates. Most ESBLE BSIs were community onset (33 of 42; 79%), and 25 (60%) were due to Escherichia coli. Independent risk factors for ESBLE BSI and point allocation in ESBL-PS included outpatient procedures within 1 month (adjusted odds ratio [aOR], 8.7; 95% confidence interval [CI], 3.1-22.9; 1 point), prior infections or colonization with ESBLE within 12 months (aOR, 26.8; 95% CI, 7.0-108.2; 4 points), and number of prior courses of beta-lactams and/or fluoroquinolones used within 3 months of BSI: 1 course (aOR, 6.3; 95% CI, 2.7-14.7; 1 point), >=2 courses (aOR, 22.0; 95% CI, 8.6-57.1; 3 points). The area under the receiver operating characteristic curve for the ESBL-PS model was 0.86. Patients with ESBL-PSs of 0, 1, 3, and 4 had estimated probabilities of ESBLE BSI of 0.7%, 5%, 24%, and 44%, respectively. Using ESBL-PS >=3 to indicate high risk provided a negative predictive value of 97%. CONCLUSIONS ESBL-PS estimated patient-specific risk of ESBLE BSI with high discrimination. Incorporation of ESBL-PS with acute severity of illness may improve adequacy of empirical antimicrobial therapy and reduce carbapenem utilization. Infect Control Hosp Epidemiol 2017;38:266-272. PMID- 27989245 TI - The clinical features of mania and their representation in modern diagnostic criteria. AB - This review seeks to determine the degree to which modern operationalized diagnostic criteria for mania reflect the clinical features of mania described historically by expert textbook authors. Clinical descriptions of mania appearing in 18 textbooks published between 1899 and 1956 were reviewed and compared to the criteria for mania from six modern operationalized diagnostic systems. Twenty-two prominent symptoms and signs were reported by five or more authors. Two symptoms (elevated mood and grandiosity) and four signs (hyperactivity, pressured speech, irritability, and new activities with painful consequences) were reported by every author. A strong relationship was seen between the frequency with which the clinical features were reported and the likelihood of their inclusion in modern diagnostic systems. However, many symptoms and signs including impulsivity, hypersexuality, mood lability, altered moral standards, increased humor, hypergraphia, and a vigorous physical appearance were not included in any modern criteria. Indeed, DSM-5 contains only eight of the historically noted clinical features. We conclude that modern operationalized criteria for mania well reflect symptoms and signs frequently reported by historical experts. This suggests that the clinical construct of mania has been relatively stable in western Psychiatry since the turn of the 20th century. However, many useful clinical features of mania described in these textbooks are missing from these criteria thereby illustrating the limitations of clinical evaluations restricted to the assessment of only current diagnostic criteria. The disorders we study and treat are considerably richer clinically than is reflected in the DSM criteria which we use to diagnose them. PMID- 27989246 TI - Cervicofacial emphysema following Harmonic scalpel tonsillectomy: case report and comprehensive review of the literature. AB - BACKGROUND: Tonsillectomy is one of the most common surgical procedures performed worldwide. There are a handful of common complications, with bleeding being the most feared; however, rarer complications can present to a wide range of medical professionals. METHODS: A 12-year-old girl presented with cervicofacial emphysema following tonsillectomy. This paper discusses the case and the management adopted, and presents the findings of a comprehensive literature review. RESULTS: The patient made a full recovery, and was discharged after 3 days following conservative management with intravenous broad-spectrum antibiotics and supplemental low-flow oxygen. CONCLUSION: This paper presents the first reported case of cervicofacial emphysema following Harmonic scalpel tonsillectomy. Although this is an exceptionally rare complication, it is potentially serious and warrants further description to improve awareness. PMID- 27989247 TI - Electronic Syndromic Surveillance for Influenza-Like Illness Across Treatment Settings. AB - OBJECTIVE Syndromic surveillance for influenza-like illness (ILI) is predominantly performed in the outpatient setting. The objective of this study was to compare patterns of ILI activity in outpatient, emergency department (ED), and inpatient settings using an electronic syndromic surveillance algorithm. DESIGN Retrospective cohort study over 7.5 years. SETTING A large community health system comprised of 5 hospitals and >50 clinics. METHODS We applied an electronic syndromic surveillance algorithm for ILI to all primary-care outpatient visits, inpatient encounters, and ED encounters at our health system. Comparisons of ILI activity over time were performed using Spearman's rank correlation coefficient. Cross correlation was used to compare the timing of ILI activity among treatment settings. RESULTS Overall, 4,447,769 patient encounters occurred during the study period; 152,607 of these (3.4%) were consistent with ILI. The correlation coefficient for ILI activity in the outpatient versus ED setting was 0.877, and for the outpatient versus inpatient setting, the correlation coefficient was 0.699. ILI activity among outpatients preceded ILI activity among inpatients by 1 week. ILI activity among children in the outpatient setting preceded ILI activity among adults in all 3 settings by 1 week. CONCLUSIONS Syndromic surveillance for ILI in the outpatient setting yields similar results to surveillance in the ED setting, but it produces less similar results than ILI surveillance in the inpatient setting. ILI activity in the pediatric outpatient population is a potential predictor of future ILI activity in the general population. Infect Control Hosp Epidemiol 2017;38:393-398. PMID- 27989248 TI - Effect of surgical intervention on middle-ear cholesteatoma with associated facial paralysis. AB - OBJECTIVES: To investigate the presenting symptoms, intra-operative findings and long-term facial nerve function in patients treated for cholesteatoma with associated facial paralysis. METHODS: Fifteen patients with facial paralysis due to middle-ear cholesteatoma who underwent tympanomastoidectomy surgery from February 2000 to February 2015 were retrospectively reviewed. After removal of the cholesteatoma, a limited area of the fallopian canal, in which facial nerve oedema or redness was evident, was opened. Incision of the epineural sheath for nerve decompression was not performed. RESULTS: Pre-operative House-Brackmann grade was grade II in two patients, grade III in four, grade IV in seven, grade V in one and grade VI in one. Facial nerve perineurium damage was observed in two patients with poor prognoses. All patients treated within the first 15 days after paralysis onset showed normal facial function at long-term follow up. Post operative House-Brackmann grade was grade I in 11 patients, grade II in 1, grade III in 2 and grade VI in 1. CONCLUSION: Early surgical treatment is more likely to give good results, and poor outcomes are observed in patients with facial nerve perineurium damage. PMID- 27989250 TI - A subtest analysis of The Montreal Cognitive Assessment (MoCA): which subtests can best discriminate between healthy controls, mild cognitive impairment and Alzheimer's disease? AB - The authors would like to apologise for a typographical error in the discussion of the above mentioned article. In the discussion on page 830 of the article, paragraph 'In the present sample, when we tested the accuracy of the MoCA to discriminate between MCI and healthy participants using ROC curves, the best cut off score was 24 points, with good sensitivity and specificity ( 92% and 82%, respectively).' Should read: In the present sample, when we tested the accuracy of the MoCA to discriminate between MCI and healthy participants using ROC curves, the best cut-off score was 24 points, with good sensitivity and specificity (83% and 89%, respectively). PMID- 27989249 TI - Risk Factors for Surgical Site Infections Following Neurosurgical Spinal Fusion Operations: A Case Control Study. AB - OBJECTIVE To determine risk factors for the development of surgical site infections (SSIs) in neurosurgery patients undergoing spinal fusion. DESIGN Retrospective case-control study. SETTING Large, academic, quaternary care center. PATIENTS The study population included all neurosurgery patients who underwent spinal fusion between August 1, 2009, and August 31, 2013. Cases were defined as patients in the study cohort who developed an SSI. Controls were patients in the study cohort who did not develop an SSI. METHODS To achieve 80% power with an ability to detect an odds ratio (OR) of 2, we performed an unmatched case-control study with equal numbers of cases and controls. RESULTS During the study period, 5,473 spinal fusion procedures were performed by neurosurgeons in our hospital. With 161 SSIs recorded during the study period, the incidence of SSIs associated with these procedures was 2.94%. While anterior surgical approach was found to be a protective factor (OR, 0.20; 95% confidence interval [CI], 0.08-0.52), duration of procedure (OR, 1.58; 95% CI, 1.29-1.93), American Society of Anesthesiologists score of 3 or 4 (OR, 1.79; 95% CI, 1.00 3.18), and hospitalization within the prior 30 days (OR, 5.8; 95% CI, 1.37-24.57) were found in multivariate analysis to be independent predictors of SSI following spinal fusion. Prior methicillin-resistant Staphylococcus aureus (MRSA) nares colonization was highly associated with odds 20 times higher of SSI following spinal fusion (OR, 20.30; 95% CI, 4.64-8.78). CONCLUSIONS In additional to nonmodifiable risk factors, prior colonization with MRSA is a modifiable risk factor very strongly associated with development of SSI following spinal fusion. Infect Control Hosp Epidemiol 2017;38:348-352. PMID- 27989251 TI - Priapism as the Presenting Complaint in Fatal Group A Streptococcal Induced Disseminated Intravascular Coagulation. AB - A 60-year-old male presented to an emergency department (ED) with priapism following a sore throat illness. He did not have typical findings of sepsis. The patient then developed severe headache, mental status changes, and hypertension, then suffered a cardiopulmonary arrest. Autopsy showed group A streptococcal (GAS) sepsis, disseminated intravascular coagulation (DIC), and a septic thrombosis to the penile vein. This is the first known case of priapism being the presenting symptom of DIC. PMID- 27989252 TI - Dietary live yeast and mannan-oligosaccharide supplementation attenuate intestinal inflammation and barrier dysfunction induced by Escherichia coli in broilers. AB - The effects of live yeast (LY) and mannan-oligosaccharide (MOS) supplementation on intestinal disruption induced by Escherichia coli in broilers were investigated. The experimental design was a 3*2 factorial arrangement with three dietary treatments (control, 0.5 g/kg LY (Saccharomyces cerevisiae, 1.0*1010 colony-forming units/g), 0.5 g/kg MOS) and two immune treatments (with or without E. coli challenge from 7 to 11 d of age). Samples were collected at 14 d of age. The results showed that E. coli challenge impaired (P<0.05) growth performance during the grower period (1-21 d) and the overall period (1-35 d) of broilers, increased (P<0.05) serum endotoxin and diamine oxidase levels coupled with ileal myeloperoxidase and lysozyme activities, whereas reduced (P<0.05) maltase activity, and compromised the morphological structure of the ileum. Besides, it increased (P<0.05) the mRNA expressions of several inflammatory genes and reduced occludin expression in the ileum. Dietary treatment with both LY and MOS reduced (P<0.05) serum diamine oxidase and ileal myeloperoxidase levels, but elevated villus height (P<0.10) and the ratio of villus height:crypt depth (P<0.05) of the ileum. It also alleviated (P<0.05) E. coli-induced increases (P<0.05) in ileal Toll-like receptor 4, NF-kappa B and IL-1 beta expressions. Moreover, LY supplementation reduced (P<0.05) feed conversion ratio of birds during the grower period and enhanced (P<0.05) the community diversity (Shannon and Simpson indices) of ileal microbiota, whereas MOS addition counteracted (P<0.05) the decreased ileal IL-10 and occludin expressions in challenged birds. In conclusion, both LY and MOS supplementation could attenuate E. coli-induced intestinal disruption by alleviating intestinal inflammation and barrier dysfunction in broilers. Moreover, LY addition could improve intestinal microbial community structure and feed efficiency of broilers. PMID- 27989253 TI - Montmorency Tart cherries (Prunus cerasus L.) modulate vascular function acutely, in the absence of improvement in cognitive performance. AB - Cerebral blood volume and metabolism of oxygen decline as part of human ageing, and this has been previously shown to be related to cognitive decline. There is some evidence to suggest that polyphenol-rich foods can play an important role in delaying the onset or halting the progression of age-related health disorders such as CVD and Alzheimer's disease and to improve cognitive function. In the present study, an acute, placebo-controlled, double-blinded, cross-over, randomised Latin-square design study with a washout period of at least 14 d was conducted on twenty-seven, middle-aged (defined as 45-60 years) volunteers. Participants received either a 60 ml dose of Montmorency tart cherry concentrate (MC), which contained 68.0 (sd 0.26) mg cyanidin-3-glucoside/l, 160.75 (sd 0.55) mean gallic acid equivalent/l and 0.59 (sd 0.02) mean Trolox equivalent/l, respectively, or a placebo. Cerebrovascular responses, cognitive performance and blood pressure were assessed at baseline and 1, 2, 3 and 5 h following consumption. There were significant differences in concentrations of total Hb and oxygenated Hb during the task period 1 h after MC consumption (P<=0.05). Furthermore, MC consumption significantly lowered systolic blood pressure (P<=0.05) over a period of 3 h, with peak reductions of 6+/-2 mmHg at 1 h after MC consumption relative to the placebo. Cognitive function and mood were not affected. These results show that a single dose of MC concentrate can modulate certain variables of vascular function; however, this does not translate to improvements in cognition or mood. PMID- 27989254 TI - Suicidal ideation and subsequent completed suicide in both psychiatric and non psychiatric populations: a meta-analysis. AB - AIMS: Several authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations. METHODS: A meta-analysis of cohort and case control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up. RESULTS: The risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43-3.87) in affective disorder populations to 8.00 (95% CI 5.46-11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74-2.64) than in non psychiatric participants (risk 0.23%, 95% CI 0.10-0.54). Past suicide attempt adjusted risk ratios were not pooled due to large underreporting. CONCLUSIONS: Assessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide. PMID- 27989255 TI - A randomised controlled trial of repeated filmed social contact on reducing mental illness-related stigma in young adults. AB - AIMS: Public stigma alters attitudes towards people with mental illness, and is a particular concern for young people since most mental health problems occur in adolescence and young adulthood. However, little is known about the long-term effects of repeated filmed social contact (FSC) on reducing mental health-related stigma among young adults in the general population, compared with self instructional Internet search (INS) and control interventions. METHODS: This study is a parallel-group randomised controlled trial over 12 months conducted in Tokyo, Japan. A total of 259 university students (male n = 150, mean age = 20.0 years, s.d. = 1.2) were recruited from 20 colleges and universities between November 2013 and July 2014, without being provided information about the mental health-related survey or trial. Participants were assigned to one of three groups before completion of the baseline survey (FSC/INS/control = 89/83/87). The FSC group received a computer-based 30-min social contact film with general mental health education and five follow-up web-based FSCs at 2-month intervals. The INS group undertook a 30-min search for mental health-related information with five follow-up web-based reminders for self-instructional searches at 2-month intervals. The control group played PC games and had no follow-up intervention. The main outcome measures were the future (intended behaviour) domain of the Reported and Intended Behaviour Scale at 12 months after the intervention. Analysis was conducted in September 2015. RESULTS: At the 12-month follow-up, 218 participants completed the survey (84.1%, 75:70:73). The FSC group showed the greatest change at the 12-month follow-up (FSC: mean change 2.11 [95% CI 1.49, 2.73], INS: 1.04 [0.29, 1.80], control: 0.71 [0.09, 1.33]; FSC v. INS p = 0.037, FSC v. controls p = 0.004). No adverse events were reported during the follow-up period. CONCLUSIONS: FSC was more successful in reducing stigma at 12 months after intervention than INS or control interventions. FSC could be used to reduce stigma in educational lectures and anti-stigma campaigns targeted at young people. STUDY REGISTRATION: This study is registered at UMIN-CTR (No. UMIN000012239). PMID- 27989256 TI - Junctional tachycardia in a child with non-rheumatic fever streptococcal pharyngitis. AB - Accelerated junctional rhythm has been reported in children in the setting of acute rheumatic fever; however, we describe a hitherto unreported case of isolated junctional tachycardia in a child with streptococcal pharyngitis, not meeting revised Jones criteria for rheumatic fever. A previously healthy, 9-year old girl presented to the emergency department with complaints of sore throat, low-grade fever, and intermittent chest pain. She was found to have a positive rapid streptococcal antigen test. The initial electrocardiogram showed junctional tachycardia with atrioventricular dissociation in addition to prolonged and aberrant atrioventricular conduction. An echocardiogram revealed normal cardiac anatomy with normal biventricular function. The patient responded to treatment with amoxicillin for streptococcal pharyngitis. The junctional tachycardia and other electrocardiogram abnormalities resolved during follow-up. PMID- 27989257 TI - High-dose adenosine for refractory supraventricular tachycardia: a case report and literature review. AB - Supraventricular tachycardia is the most common significant arrhythmia in children. If prolonged, it may cause heart failure and progress to cardiogenic shock warranting prompt treatment. The recommended interventions following vagal manoeuvres are intravenous adenosine and in the unstable patient electrical cardioversion. We present an infant with an unstable supraventricular tachycardia that was resistant to electrical cardioversion and recommended doses of adenosine. He reverted to sinus rhythm with a higher dose of adenosine, suggesting that such doses may be required in refractory supraventricular tachycardia. PMID- 27989258 TI - Musical hallucinations: a brief review of functional neuroimaging findings. AB - Musical hallucinations are uncommon phenomena characterized by intrusive and frequently distressful auditory musical percepts without an external source, often associated with hypoacusis, psychiatric illness, focal brain lesion, epilepsy, and intoxication/pharmacology. Their physiological basis is thought to involve diverse mechanisms, including "release" from normal sensory or inhibitory inputs as well as stimulation during seizures, or they can be produced by functional or structural disorders in diverse cortical and subcortical areas. The aim of this review is to further explore their pathophysiology, describing the functional neuroimaging findings regarding musical hallucinations. A literature search of the PubMed electronic database was conducted through to 29 December 2015. Search terms included "musical hallucinations" combined with the names of specific functional neuroimaging techniques. A total of 18 articles, all clinical case reports, providing data on 23 patients, comprised the set we reviewed. Diverse pathological processes and patient populations with musical hallucinations were included in the studies. Converging data from multiple studies suggest that the superior temporal sulcus is the most common site and that activation is the most common mechanism. Further neurobiological research is needed to clarify the pathophysiology of musical hallucinations. PMID- 27989259 TI - Buying less and wasting less food. Changes in household food energy purchases, energy intakes and energy density between 2007 and 2012 with and without adjustment for food waste. AB - OBJECTIVE: Consumers in the UK responded to the rapid increases in food prices between 2007 and 2009 partly by reducing the amount of food energy bought. Household food and drink waste has also decreased since 2007. The present study explored the combined effects of reductions in food purchases and waste on estimated food energy intakes and dietary energy density. DESIGN: The amount of food energy purchased per adult equivalent was calculated from Kantar Worldpanel household food and drink purchase data for 2007 and 2012. Food energy intakes were estimated by adjusting purchase data for food and drink waste, using waste factors specific to the two years and scaled for household size. SETTING: Scotland. SUBJECTS: Households in Scotland (n 2657 in 2007; n 2841 in 2012). RESULTS: The amount of food energy purchased decreased between 2007 and 2012, from 8.6 to 8.2 MJ/adult equivalent per d (P<0.001). After accounting for the decrease in food waste, estimated food energy intake was not significantly different (7.3 and 7.2 MJ/adult equivalent per d for 2007 and 2012, respectively; P=0.186). Energy density of foods purchased increased slightly from 700 to 706 kJ/100 g (P=0.010). CONCLUSIONS: While consumers in Scotland reduced the amount of food energy that they purchased between 2007 and 2012, this was balanced by reductions in household food and drink waste over the same time, resulting in no significant change in net estimated energy intake of foods brought into the home. PMID- 27989260 TI - The website-based eaTracker(r) 'My Goals' feature: a qualitative evaluation. AB - OBJECTIVE: In 2011, Dietitians of Canada added 'My Goals' to its website-based nutrition/activity tracking program (eaTracker(r), http://www.eaTracker.ca/); this feature allows users to choose 'ready-made' or 'write-your-own' goals and to self-report progress. The purpose of the present study was to document experiences and perceptions of goal setting and My Goals, and report users' feedback on what is needed in future website-based goal setting/tracking tools. DESIGN: One-on-one semi-structured interviews were conducted with (i) My Goals users and (ii) dietitians providing a public information support service, EatRight Ontario (ERO). SETTING: My Goals users from Ontario and Alberta, Canada were recruited via an eaTracker website pop-up box; ERO dietitians working in Ontario, Canada were recruited via ERO. SUBJECTS: My Goals users (n 23; age 19-70 years; 91 % female; n 5 from Alberta/n 18 from Ontario) and ERO dietitians (n 5). RESULTS: Dietitians and users felt goal setting for nutrition (and activity) behaviour change was both a beneficial and a challenging process. Dietitians were concerned about users setting poor-quality goals and users felt it was difficult to stick to their goals. Both users and dietitians were enthusiastic about the My Goals concept, but felt the current feature had limitations that affected use. Dietitians and users provided suggestions to improve My Goals (e.g. more prominent presence of My Goals in eaTracker; assistance with goal setting; automated personalized feedback). CONCLUSIONS: Dietitians and users shared similar perspectives on the My Goals feature and both felt goal use was challenging. Several suggestions were provided to enhance My Goals that are relevant to website-based goal setting/tracking tool design in general. PMID- 27989261 TI - Task shifting to clinical officer-led echocardiography screening for detecting rheumatic heart disease in Malawi, Africa. AB - BACKGROUND: Echocardiographic screening for rheumatic heart disease in asymptomatic children may result in early diagnosis and prevent progression. Physician-led screening is not feasible in Malawi. Task shifting to mid-level providers such as clinical officers may enable more widespread screening. Hypothesis With short-course training, clinical officers can accurately screen for rheumatic heart disease using focussed echocardiography. METHODS: A total of eight clinical officers completed three half-days of didactics and 2 days of hands-on echocardiography training. Clinical officers were evaluated by performing screening echocardiograms on 20 children with known rheumatic heart disease status. They indicated whether children should be referred for follow-up. Referral was indicated if mitral regurgitation measured more than 1.5 cm or there was any measurable aortic regurgitation. The kappa statistic was calculated to measure referral agreement with a paediatric cardiologist. Sensitivity and specificity were estimated using a generalised linear mixed model, and were calculated on the basis of World Heart Federation diagnostic criteria. RESULTS: The mean kappa statistic comparing clinical officer referrals with the paediatric cardiologist was 0.72 (95% confidence interval: 0.62, 0.82). The kappa value ranged from a minimum of 0.57 to a maximum of 0.90. For rheumatic heart disease diagnosis, sensitivity was 0.91 (95% confidence interval: 0.86, 0.95) and specificity was 0.65 (95% confidence interval: 0.57, 0.72). CONCLUSION: There was substantial agreement between clinical officers and paediatric cardiologists on whether to refer. Clinical officers had a high sensitivity in detecting rheumatic heart disease. With short-course training, clinical officer-led echo screening for rheumatic heart disease is a viable alternative to physician-led screening in resource-limited settings. PMID- 27989262 TI - Sun exposure, UV irradiance and serum 25-hydroxycholecalciferol in pregnant women in rural north India. AB - OBJECTIVE: To document the effect of season and environmental pollution on UVB irradiance; and to estimate cutaneous vitamin D synthesis in village women in different seasons. DESIGN: Radiant UVB energy was measured by a spectroradiometer in different seasons and, in April and May, on successive days in open areas at the city outskirts, at a crowded inner-city area and the villages of our participants. Clothing, outdoor activity pattern and serum 25 hydroxycholecalciferol (25(OH)D) levels were documented. SETTING: Rural north India, latitude 26.8 degrees N. SUBJECTS: Pregnant women (n 139, aged 20-40 years). RESULTS: UVB irradiance ranged from 56 uW/cm2 in January to 470 uW/cm2 in June. Proportion of skin exposed was 18.5 % in summer and 9.5 % in winter. Mean (sd) daily duration of sun exposure was 3.2 (0.2) h during winter and 2.1 (0.4) h during summer. Cutaneous vitamin D synthesis was estimated to be 19.25 ug (770 IU) during winter and 37.25 ug (1490 IU) during summer. Mean (sd) serum 25(OH)D was 28 (15) nmol/l during winter (92 % of participants with 50 nmol/l). Mean (sd) UVB irradiance at peak summer was significantly higher at the open areas and in the villages than at the inner-city location (340 (45) and 310 (60) v. 250 (50) uW/cm2, P=0.03). CONCLUSIONS: In our population, at latitude 26.8 degrees N, poor skin exposure is a limiting factor in all seasons. During winter, low UVB radiation energy also contributes. Particulate pollution limits UVB irradiance. Vitamin D supplementation during winter may be necessary. PMID- 27989263 TI - Comparison of the ability to identify cardiometabolic risk factors between two new body indices and waist-to-height ratio among Chinese adults with normal BMI and waist circumference. AB - OBJECTIVE: Waist-to-height ratio (WHtR) has been reported to be more strongly associated with cardiometabolic risk factors among non-obese individuals than BMI and waist circumference (WC). A body shape index (ABSI) and body roundness index (BRI) have been proposed recently to assess obesity-related disorders or mortalities. Our aim was to compare the ability of ABSI and BRI with that of WHtR to identify cardiometabolic risk factors in Chinese adults with normal BMI and WC. DESIGN: Receiver-operating characteristic curves and areas under the curve (AUC) were employed to evaluate the ability of the indices (WHtR, BRI, ABSI) to identify metabolic risk factors and to determine the indices' optimal cut-off values. The value of each index that resulted in maximization of the Youden index (sensitivity + specificity - 1) was defined as optimal. Differences in the AUC values between the indices were also evaluated. SETTING: Individuals attending a voluntary health check-up in Beijing, China, July-December 2015, were recruited to the study. SUBJECTS: Non-obese adults (n 1596). RESULTS: Among both genders, ABSI exhibited the lowest AUC value for identifying each risk factor among the three indices; the AUC value of BRI for identifying each risk factor was very close to that of WHtR, and no significant differences were observed between the AUC values of the two new indices. CONCLUSIONS: When evaluating cardiometabolic risk factors among non-obese adults, WHtR was a simple and effective index in the assessment of cardiometabolic risk factors, BRI could be used as an alternative body index to WHtR, while ABSI could not. PMID- 27989264 TI - Study sponsorship and the nutrition research agenda: analysis of randomized controlled trials included in systematic reviews of nutrition interventions to address obesity. AB - OBJECTIVE: To categorize the research topics covered by a sample of randomized controlled trials (RCT) included in systematic reviews of nutrition interventions to address obesity; to describe their funding sources; and to explore the association between funding sources and nutrition research topics. DESIGN: Cross sectional study. SUBJECTS: RCT included in Cochrane Reviews of nutrition interventions to address obesity and/or overweight. RESULTS: Two hundred and thirteen RCT from seventeen Cochrane Reviews were included. Funding source and authors' conflicts of interest were disclosed in 82.6 and 29.6 % of the studies, respectively. RCT were more likely to test an intervention to manipulate nutrients in the context of reduced energy intake (44.2 % of studies) than food level (11.3 %) and dietary pattern-level (0.9 %) interventions. Most of the food industry-sponsored studies focused on interventions involving manipulations of specific nutrients (66.7 %). Only 33.1 % of the industry-funded studies addressed dietary behaviours compared with 66.9 % of the non-industry-funded ones (P=0.002). The level of food processing was poorly considered across all funding sources. CONCLUSIONS: The predominance of RCT examining nutrient-specific questions could limit the public health relevance of rigorous evidence available for systematic reviews and dietary guidelines. PMID- 27989265 TI - Posttraumatic stress disorder symptom severity is associated with left hippocampal volume reduction: a meta-analytic study. AB - OBJECTIVE: Many studies have reported hippocampal volume reductions associated with posttraumatic stress disorder (PTSD), while others have not. Here we provide an updated meta-analysis of such reductions associated with PTSD and evaluate the association between symptom severity and hippocampal volume. METHODS: A total of 37 studies met the criteria for inclusion in the meta-analysis. Mean effect sizes (Hedges' g) and 95% confidence intervals (CI 95%) were computed for each study and then averaged to obtain an overall mean effect size across studies. Meta regression was employed to examine the relationship between PTSD symptom severity and hippocampal volume. RESULTS: Results showed that PTSD is associated with significant bilateral reduction of the hippocampus (left hippocampus effect size= 0.400, p<0.001, 5.24% reduction; right hippocampus effect size=-0.462, p<0.001, 5.23% reduction). Symptom severity, as measured by the Clinician-Administered PTSD Scale (CAPS), was significantly associated with decreased left, but not right, hippocampal volume. CONCLUSIONS: PTSD was associated with significant bilateral volume reduction of the hippocampus. Increased symptom severity was significantly associated with reduced left hippocampal volume. This finding is consistent with the hypothesis that PTSD is more neurotoxic to the left hippocampus than to the right. However, whether the association between PTSD and lower hippocampal volume reflects a consequence of or a predisposition to PTSD remains unclear. More prospective studies are needed in this area. PMID- 27989266 TI - The mountainous Cretan dietary patterns and their relationship with cardiovascular risk factors: the Hellenic Isolated Cohorts MANOLIS study. AB - OBJECTIVE: We carried out de novo recruitment of a population-based cohort (MANOLIS study) and describe the specific population, which displays interesting characteristics in terms of diet and health in old age, through deep phenotyping. DESIGN: Cross-sectional study where anthropometric, biochemical and clinical measurements were taken in addition to interview-based completion of an extensive questionnaire on health and lifestyle parameters. Dietary patterns were derived through principal component analysis based on a validated FFQ. SETTING: Geographically isolated Mylopotamos villages on Mount Idi, Crete, Greece. SUBJECTS: Adults (n 1553). RESULTS: Mean age of the participants was 61.6 years and 55.8 % were women. Of the population, 82.7 % were overweight or obese with a significantly different prevalence between overweight men and women (43.4 v. 34.7 %, P=0.002). The majority (70.6 %) of participants were married, while a larger proportion of women were widowed than men (27.8 v. 3.5 %, P<0.001). Smoking was more prevalent in men (38.7 v. 8.2 %, P<0.001), as 88.8% of women had never smoked. Four dietary patterns emerged as characteristic of the population; these were termed 'local', 'high fat and sugar, 'Greek cafe/tavern' and 'olive oil, fruits and vegetables'. Individuals more adherent to the local dietary pattern presented higher blood glucose (beta=4.026, P<0.001). Similarly, individuals with higher compliance with the Greek cafe/tavern pattern had higher waist-to-hip ratio (beta=0.012, P<0.001), blood pressure (beta=1.015, P=0.005) and cholesterol (beta=5.398, P<0.001). CONCLUSIONS: Profiling of the MANOLIS elderly population identifies unique unhealthy dietary patterns that are associated with cardiometabolic indices. PMID- 27989267 TI - Western Australian students' alcohol consumption and expenditure intentions for Schoolies. AB - In Australia, the immediate post-school period (known as 'Schoolies') is associated with heavy drinking and high levels of alcohol-related harm. This study investigated students' intended alcohol consumption during Schoolies to inform interventions to reduce alcohol-related harm among this group. An online survey was administered to students in their senior year of schooling. Included items related to intended daily alcohol consumption during Schoolies, amount of money intended to be spent on alcohol over the Schoolies period, and past drinking behaviour. On average, participants (n=187) anticipated that they would consume eight standard drinks per day, which is substantially higher than the recommended maximum of no more than four drinks on a single occasion. Participants intended to spend an average of A$131 on alcohol over the Schoolies period. Although higher than national guidelines, intended alcohol consumption was considerably lower than has been previously documented during Schoolies events. The substantial amounts of money expected to be spent during Schoolies suggest this group has adequate spending power to constitute an attractive target market for those offering alternative activities that are associated with lower levels of alcohol-related harm. PMID- 27989268 TI - The factor structure of complex posttraumatic stress disorder in traumatized refugees. AB - BACKGROUND: The construct of complex posttraumatic stress disorder (CPTSD) has attracted much research attention in previous years, however it has not been systematically evaluated in individuals exposed to persecution and displacement. Given that CPTSD has been proposed as a diagnostic category in the ICD-11, it is important that it be examined in refugee groups. OBJECTIVE: In the current study, we proposed to test, for the first time, the factor structure of CPTSD proposed for the ICD-11 in a sample of resettled treatment-seeking refugees. METHOD: The study sample consisted of 134 traumatized refugees from a variety of countries of origin, with approximately 93% of the sample having been exposed to torture. We used confirmatory factor analysis to examine the factor structure of CPTSD in this sample and examined the sensitivity, specificity, positive predictive power and negative predictive power of individual items in relation to the CPTSD diagnosis. RESULTS: Findings revealed that a two-factor higher-order model of CPTSD comprising PTSD and Difficulties in Self-Organization (chi2 (47)=57.322, p=0.144, RMSEA=0.041, CFI=0.981, TLI=0.974) evidenced superior fit compared to a one-factor higher-order model of CPTSD (chi2 (48)=65.745, p=0.045, RMSEA=0.053, CFI=0.968, TLI=0.956). Overall, items evidenced strong sensitivity and negative predictive power, moderate positive predictive power, and poor specificity. CONCLUSIONS: Findings provide preliminary evidence for the validity of the CPTSD construct with highly traumatized treatment-seeking refugees. PMID- 27989270 TI - From policy to action: how to operationalize the treatment for all agenda. PMID- 27989269 TI - Dietary tryptophan depletion in humans using a simplified two amino acid formula a pilot study. AB - BACKGROUND: Acute tryptophan depletion (ATD) is a well-established dietary method in translational brain research used to briefly lower central nervous serotonin (5-hydroxytryptamine (5-HT)) synthesis. A simplified two amino acid ATD formula (ATDPHE/LEU) was developed while reducing the overall amount of amino acids (AAs), with the objective of administration especially in children and adolescents in future studies. OBJECTIVE: This study investigated tryptophan (TRP) influx rates across the blood-brain barrier (BBB) after dietary ATDPHE/LEU administration relative to the ATD Moja-De protocol that has been established for use in children and adolescents. DESIGN: Seventy-two healthy adults (50% females) were randomized into four groups and administered ATD Moja-De, its TRP-balanced control condition (BAL), ATDPHE/LEU, or its respective control mixture (BALPHE/LEU) in a counterbalanced, double-blind, between-subjects design. Blood samples were collected at baseline and at hourly intervals for 6 h after AA intake. Questionnaires about mood, taste, and challenge tolerance were completed at fixed time points. RESULTS: Both challenge mixtures significantly reduced central nervous TRP influx as calculated by Michaelis-Menten kinetics relative to baseline and the respective control conditions with only mild and comparable side effects. A greater decline in TRP influx over the BBB after ATDPHE/LEU administration when compared with ATD Moja-De was detected without group effects for taste, challenge tolerance, and mood. There was unintended initial short increase in plasma TRP concentrations observed after ATDPHE/LEU intake, and a possible redistribution between free and protein-bound TRP triggered by protein synthesis stimulated by the ingested AAs may account for this finding. Moreover, a decline in TRP influx after BALPHE/LEU administration over a 6-h period was observed, and the large amount of PHE in the BALPHE/LEU mixture may be a possible explanation for this particular phenomenon, which could have led to an unexpected increase in displacement of TRP at the BBB in this control condition. CONCLUSIONS: This pilot study provides preliminary evidence for the possibility of lowering TRP influx as calculated by Michaelis-Menten kinetics into the brain by using a simplified ATD protocol in humans. The simplified composition of only two AAs, the lower overall AA amount, and the appropriate tolerance are characteristics of the newly developed ATDPHE/LEU protocol. Future studies focusing on the effects of the ATDPHE/LEU protocol and its respective control condition on CSF 5-HIAA concentrations, as well as neurochemical studies in rodents, are needed to further validate this newly developed AA mixture before definite conclusions about its usability in ATD-related research in humans, its specificity, and additional effects can be made. PMID- 27989271 TI - Beyond the 90-90-90: refocusing HIV prevention as part of the global HIV response. AB - INTRODUCTION: The remarkable expansion in availability of antiretroviral therapy (ART) over the past two decades has transformed HIV infection into a manageable chronic condition. People with HIV infection now live long and healthy lives on treatment that is simpler, safer and cheaper. According to UNAIDS estimates, the global coverage of ART reached 46% in 2015, resulting in a 26% decrease in annual HIV-related deaths since 2010. Such success has positioned treatment access at the centre of the global HIV response as a way to prevent mortality, morbidity and HIV transmission through a "Treat All" approach. Continuing expansion of treatment is needed to further reduce HIV-related mortality. This progress with treatment, however, masks a stagnation in the estimated annual number of new HIV infections. Continuing levels of HIV incidence despite treatment scale-up stem from several factors, which should be addressed in order to prevent new infections and decrease the numbers of people requiring treatment in the future. DISCUSSION: ART can only reach those already diagnosed, and although it is unclear what proportion of new infections occur during acute and early infection prior to treatment initiation, phylogenetic studies suggest that it might be substantial. Thus, better testing approaches to reach the 40% of people with undiagnosed HIV infection as early as possible are critical. New approaches to reach men, young people and key populations, where HIV risk is highest and HIV prevention, testing and treatment coverage is lowest, are also needed. Overall coverage of effective prevention interventions remains low, enabling HIV transmission to occur, or time is required to show population-level effects. For example, the full impact of the medical male circumcision intervention will be seen once a larger proportion of men in age cohorts with high incidence are circumcised. Finally, strategically focused pre-exposure prophylaxis interventions have the potential to prevent HIV acquisition among populations at substantial risk, averting treatment costs in coming years. CONCLUSIONS: The United Nations (UN) targets to end AIDS include the "90-90-90" targets for HIV diagnosis, treatment and viral suppression. While 90-90-90 has been widely emphasized and adopted by countries and international funders, the focus thus far has largely been on increasing access to ART - the second "90." A similar emphasis on achieving UN HIV prevention targets and adequate funding for meeting these is essential, alongside treatment, in order to reduce population-level incidence and change the trajectory of the HIV epidemic over the long term. PMID- 27989272 TI - The International Society for Extracellular Vesicles launches the first massive open online course on extracellular vesicles. AB - The International Society for Extracellular Vesicles (ISEV) has organised its first educational online course for students and beginners in the field of extracellular vesicles (EVs). This course, "Basics of Extracellular Vesicles," uses recorded lectures from experts in the field and will be open for an unlimited number of participants. The course is divided into 5 modules and can be accessed at www.coursera.org/learn/extracellular-vesicles. The first module is an introduction to the field covering the nomenclature and history of EVs. Module 2 focuses on the biogenesis and uptake mechanisms of EVs, as well as their RNA, protein and lipid cargo. Module 3 covers the collection and processing of cell culture media and body fluids such as blood, breast milk, cerebrospinal fluid and urine prior to isolation of EVs. Modules 4 and 5 present different isolation methods and characterisation techniques utilised in the EV field. Here, differential ultracentrifugation, size-exclusion chromatography, density gradient centrifugation, kit-based precipitation, electron microscopy, cryo-electron microscopy, flow cytometry, atomic-force microscopy and nanoparticle-tracking analysis are covered. This first massive open online course (MOOC) on EVs was launched on 15 August 2016 at the platform "Coursera" and is free of charge. PMID- 27989273 TI - Beyond 'test and treat' - malaria diagnosis for improved pediatric fever management in sub-Saharan Africa. AB - BACKGROUND: Malaria rapid diagnostic tests (RDTs) have great potential to improve quality care and rational drug use in malaria-endemic settings although studies have shown common RDT non-compliance. Yet, evidence has largely been derived from limited hospital settings in few countries. This article reviews a PhD thesis that analyzed national surveys from multiple sub-Saharan African countries to generate large-scale evidence of malaria diagnosis practices and its determinants across different contexts. DESIGN: A mixed-methods approach was used across four studies that included quantitative analysis of national household and facility surveys conducted in multiple sub-Saharan African countries at the outset of new guidelines (Demographic and Health Surveys and Service Provision Assessments). Qualitative methods were used to explore reasons for quantitative findings in select settings. RESULTS: There was low (17%) and inequitable test uptake across 13 countries in 2009-2011/12, with greater testing at hospitals than at peripheral clinics (odds ratio [OR]: 0.62, 95% confidence interval [CI]: 0.56 0.69) or community health workers (OR: 0.31, 95% CI: 0.23-0.43) (Study I). Significant variation was found in the effect of diagnosis on antimalarial use at the population level across countries (Uganda OR: 0.84, 95% CI: 0.66-1.06; Mozambique OR: 3.54, 95% CI: 2.33-5.39) (Study II). A Malawi national facility census indicated common compliance to malaria treatment guidelines (85% clients with RDT-confirmed malaria prescribed first-line treatment), although other fever assessments were not often conducted and there was poor antibiotic targeting (59% clients inappropriately prescribed antibiotics). RDT-negative patients had 16.8 (95% CI: 8.6-32.7) times higher odds of antibiotic overtreatment than RDT positive patients conditioned by cough or difficult breathing complaints (Study III). In Mbarara (Uganda), health workers reportedly prescribed antimalarials to RDT-negative patients if no other fever cause was identified and non-compliance seemed further driven by RDT perceptions, system constraints, and client interactions (Study IV). CONCLUSIONS: A shift from malaria-focused test and treat strategies toward IMCI with testing is needed to improve quality care and rational use of both antimalarial and antibiotic medicines. Strengthened health systems are also needed to support quality clinical care, including adherence to malaria test results, and RDT deployment should be viewed as a unique opportunity to contribute to these important efforts. PMID- 27989274 TI - The social construction of fibromyalgia as a health problem from the perspective of policies, professionals, and patients. AB - This article is a review of the PhD thesis written by Erica Briones-Vozmediano, entitled, 'The social construction of fibromyalgia as a health problem from the perspective of policies, professionals, and patients'. The findings show that in Spain, the fact that fibromyalgia (FM) lacks recognition still remains: in policies, in the clinical and professional fields, and in the patients' social circle. These three spheres have an influence on how this disease is constructed on a social level. International health policy has not yet taken steps to reflect the emergence of this recently diagnosed disease. The care for patients suffering from FM, who are mainly women, leads to frustration among the healthcare professionals and desperation among the patients themselves, as a resolutive treatment for the disease is not existing. Patients show resistance at assuming the sick role. They want to carry on undertaking their daily activities, both in the public sphere and in the private one. Roles involving the gendered division of labour were found to follow a rigid pattern, both prior to and subsequent to the disease, as the causes that led to frustration for men or women differ according to activities that are socially assigned to them. In practice, FM is conceived exclusively as a women's health problem, which may result in a gender biased patient healthcare attention. It is recommended that the implementation of specific policies for FM which could resolve this evident shortcoming should take place. To draw attention on a social level to certain illnesses considered to be attributed to women, such as FM, is of utmost importance, in order to allow the patients to be socially recognised as suffering a real and disabling disease. PMID- 27989275 TI - Monitoring health determinants with an equity focus: a key role in addressing social determinants, universal health coverage, and advancing the 2030 sustainable development agenda. PMID- 27989276 TI - 'Beyond "test and treat" - malaria diagnosis for improved pediatric fever management in sub-Saharan Africa' by Emily White Johansson. PMID- 27989277 TI - Unnecessary Investigations in Environmental Medicine. AB - BACKGROUND: Patients in environmental medicine often want a thorough diagnostic evaluation of nonspecific symptoms. Unconventional testing, as well as conventional testing for indications other than the established ones, can lead to false diagnoses and, in turn, to substantial emotional, social, and financial harm. The goal of this single-center study was to assess inappropriate diagnostic testing among the patients of a specialized university outpatient clinic for environmental medicine. METHODS: The charts of 653 consecutive outpatients seen in the institute and outpatient clinic of occupational, social, and environmental medicine in Erlangen from 2010 to 2015 were evaluated, and inappropriate diagnostic tests were assessed. RESULTS: 9% of the patients had received at least one inappropriate diagnostic test. The most common one was an inappropriate heavy metal test (26%), followed by an inappropriately ordered hair analysis (15%) and biomonitoring in the blood or urine with an erroneous choice of the testing matrix or an erroneous interpretation of the findings (15%). Biomonitoring performed by us did not confirm the suspected environmental diagnosis in any case. Laboratory values exceeding the normal limits were rarer among these patients than in the patients for whom we considered biomonitoring to be indicated without any pretesting. CONCLUSION: An appreciable number of patients in environmental medicine were subjected to inappropriate diagnostic testing. When this happens, proper testing often needs to be done thereafter in order to confirm or refute the findings. This phenomenon should be more thoroughly assessed and quantified. PMID- 27989278 TI - The Effectiveness of a Stress Reduction and Burnout Prevention Program. AB - BACKGROUND: Chronic psychological distress appears to have increased in recent years, mainly among the working population. The data available indicate that mental and behavioral disorders, including burnout syndrome, represent not only a personal problem for those afflicted, but also a serious public health issue. This study aimed at evaluating the effects of an outpatient burnout prevention program in a mono-center health resort setting. METHODS: Adults experiencing an above-average level of stress and thus being at an increased risk of burnout were randomized either to the intervention group (IG) or the waiting control group (WG). The 3-week program included stress management intervention, relaxation, physical exercise and moor applications. The primary outcome was change in perceived stress (PSQ) at 6 months post-intervention. Secondary outcomes included burnout symptoms, well-being, health status, psychological symptoms, back pain, and number of sick days. Participants were examined at baseline, post intervention (3 weeks) and after 1, 3 and 6 months. RESULTS: Data from 88 adults (IG=43; WG=45) were available for (per protocol) analysis (mean age: 50.85; 76.1% female). Participants in the IG experienced significant immediate improvement in all outcome measures, which declined somewhat during the first three months post intervention and then remained stable for at least another three months. Those in the WG did not experience substantial change across time. For the 109 randomized persons, results for PSQ were confirmed in an intention-to-treat analysis with missing values replaced by last observation carried forward (between-group ANCOVA for PSQScore at 6 months, parameter estimator for the group: -20.57; 95% CI: [ 26.09; -15.04]). Large effect sizes (Cohen's d for PSQ: 1.09-1.72) indicate the superiority of the intervention. CONCLUSION: The program proved to be effective in reducing perceived stress, emotional exhaustion and other targets. Future research should examine the long-term impact of the program and the effect of occasional refresher training. PMID- 27989279 TI - Math Matters: How Misinterpretation of Odds Ratios and Risk Ratios May Influence Conclusions. PMID- 27989280 TI - Preliminary Validation of a Parent-Child Relational Framework for Teaching Developmental Assessment to Pediatric Residents. AB - OBJECTIVE: A parent-child relational framework was used as a method to train pediatric residents in basic knowledge and observation skills for the assessment of child development. Components of the training framework and its preliminary validation as an alternative to milestone-based approaches are described. METHODS: Pediatric residents were trained during a 4-week clinical rotation to use a semistructured interview and observe parent-child behavior during health visits using clinical criteria for historical information and observed behavior that reflect developmental change in the parent-child relationship. Clinical impressions of concern versus no concern for developmental delay were derived from parent-child relational criteria and the physical examination. A chart review yielded 330 preterm infants evaluated using this methodology at 4 and 15 months corrected age who also had standardized developmental testing at 6 and 18 months corrected age. Sensitivities and specificities were computed to examine the validity of the clinical assessment compared with standardized testing. A subset of residents who completed 50 or more assessments during the rotation was timed at the end of 4 weeks. RESULTS: Parent-child behavioral markers elicited from the history and/or observed during the health visit correlated highly with standardized developmental assessment. Sensitivities and specificities were 0.72/0.98 and 0.87/0.96 at 4 to 6 and 15 to 18 months, respectively. Residents completed their assessments <1 minute on average if they had completed at least 50 supervised assessments. CONCLUSIONS: A parent-child relational framework is a potentially efficient and effective approach to training residents in the clinical knowledge and skills of child development assessment. PMID- 27989281 TI - Efficacy and Acceptability of Cognitive Behavioral Therapy for Depression in Children: A Systematic Review and Meta-analysis. AB - BACKGROUND: Few meta-analyses have focused on the effect of cognitive behavioral therapy (CBT) for depression in children. STUDY SELECTION: Randomized controlled trials comparing CBT with control conditions for depression in children (<=13 years old) were included. DATA SOURCES: Seven electronic databases (PubMed, Embase, CENTRAL, Web of Science, PsycINFO, CINAHL, and LiLACS) were searched from inception to September 2015. DATA EXTRACTION AND SYNTHESIS: The primary efficacy was defined as mean change scores in depressive symptoms, and the second efficacy (remission) was a score below the threshold for a diagnosis of depression, both after treatment and at the end of follow-up. We also measured acceptability by the proportion of participants who discontinued treatment up to posttreatment. RESULTS: Nine studies with 306 participants were selected for this analysis. At posttreatment, CBT was significantly more effective than control conditions in terms of primary efficacy (standardized mean difference, -0.41; 95% confidence interval [CI], -0.64 to -0.18) and secondary efficacy (odds ratio [OR], 2.16; 95% CI, 1.24 to 3.78). At follow-up, the results were consistent with those of efficacy outcomes at posttreatment, with a standardized mean difference of -0.34 and an OR of 2.04. CBT had no statistical more all-cause discontinuations than the control group (OR, 0.69; 95% CI, 0.26 to 1.82). However, subgroup analyses found that CBT was only significantly more effective than nontreatment, while it was not better than wait list or psychological placebo. CONCLUSIONS: CBT seems to be more beneficial in the treatment of depression in children than nontreatment; however, this finding is limited by the small size of the trials and low literature quality. PMID- 27989282 TI - Predicting acute kidney injury after hip-fracture surgery: Join the (renal) resistance! PMID- 27989283 TI - Prolonged diaphragmatic dysfunction in continuous interscalene brachial plexus block: Is it clinically relevant? PMID- 27989284 TI - Enhanced recovery after caesarean delivery: Potent analgesia and adequate practice patterns are at the heart of successful management. PMID- 27989285 TI - MY APPROACH to the evaluation of restrictive cardiomyopathy. PMID- 27989286 TI - MY APPROACH to the surgeon's view on degenerative mitral regurgitation. PMID- 27989287 TI - Advancing the Science of Health Disparities Through Research on the Social Determinants of Health. PMID- 27989288 TI - The Social Determinants of Health Core: Taking a Place-Based Approach. AB - INTRODUCTION: There is growing recognition that health disparities research needs to incorporate social determinants in the local environment into explanatory models. In the transdisciplinary setting of the Mid-South Transdisciplinary Collaborative Center (TCC), the Social Determinants of Health (SDH) Core developed an approach to incorporating SDH across a variety of studies. This place-based approach, which is geographically based, transdisciplinary, and inherently multilevel, is discussed. METHODS: From 2014 through 2016, the SDH Core consulted on a variety of Mid-South TCC research studies with the goal of incorporating social determinants into their research designs. The approach used geospatial methods (e.g., geocoding) to link individual data files with measures of the physical and social environment in the SDH Core database. Once linked, the method permitted various types of analysis (e.g., multilevel analysis) to determine if racial disparities could be explained in terms of social determinants in the local environment. RESULTS: The SDH Core consulted on five Mid-South TCC research projects. In resulting analyses for all the studies, a significant portion of the variance in one or more outcomes was partially explained by a social determinant from the SDH Core database. CONCLUSIONS: The SDH Core approach to addressing health disparities by linking neighborhood social and physical environment measures to an individual-level data file proved to be a successful approach across Mid-South TCC research projects. PMID- 27989289 TI - A Reliable, Feasible Method to Observe Neighborhoods at High Spatial Resolution. AB - INTRODUCTION: Systematic social observation (SSO) methods traditionally measure neighborhoods at street level and have been performed reliably using virtual applications to increase feasibility. Research indicates that collection at even higher spatial resolution may better elucidate the health impact of neighborhood factors, but whether virtual applications can reliably capture social determinants of health at the smallest geographic resolution (parcel level) remains uncertain. This paper presents a novel, parcel-level SSO methodology and assesses whether this new method can be collected reliably using Google Street View and is feasible. METHODS: Multiple raters (N=5) observed 42 neighborhoods. In 2016, inter-rater reliability (observed agreement and kappa coefficient) was compared for four SSO methods: (1) street-level in person; (2) street-level virtual; (3) parcel-level in person; and (4) parcel-level virtual. Intra-rater reliability (observed agreement and kappa coefficient) was calculated to determine whether parcel-level methods produce results comparable to traditional street-level observation. RESULTS: Substantial levels of inter-rater agreement were documented across all four methods; all methods had >70% of items with at least substantial agreement. Only physical decay showed higher levels of agreement (83% of items with >75% agreement) for direct versus virtual rating source. Intra-rater agreement comparing street- versus parcel-level methods resulted in observed agreement >75% for all but one item (90%). CONCLUSIONS: Results support the use of Google Street View as a reliable, feasible tool for performing SSO at the smallest geographic resolution. Validation of a new parcel level method collected virtually may improve the assessment of social determinants contributing to disparities in health behaviors and outcomes. PMID- 27989291 TI - Street Connectivity and Obesity Risk: Evidence From Electronic Health Records. AB - INTRODUCTION: This study aimed to determine the feasibility of using electronic health record (EHR) data from a federally qualified health center (FQHC) to assess the association between street connectivity, a measure of walkability for the local environment, and BMI obtained from EHRs. METHODS: The study included patients who visited Daughters of Charity clinics in 2012-2013. A total of 31,297 patients were eligible, of which 28,307 were geocoded. BMI and sociodemographic information were compiled into a de-identified database. The street connectivity measure was intersection density, calculated as the number of three-way or greater intersections per unit area. Multilevel analyses of BMI, measured on 17,946 patients who were aged >=20 years, not pregnant, had complete sociodemographic information, and a BMI value that was not considered an outlier, were conducted using random intercept models. RESULTS: Overall, on average, patients were aged 44.1 years, had a BMI of 30.2, and were mainly non-Hispanic black (59.4%). An inverse association between BMI and intersection density was observed in multilevel models controlling for age, gender, race, and marital status. Tests for multiple interactions were conducted and a significant interaction between race and intersection density indicated the decrease in BMI was strongest for non-Hispanic whites (decreased by 2) compared with blacks or Hispanics (decreased by 0.6) (p=0.0121). CONCLUSIONS: EHRs were successfully used to assess the relationship between street connectivity and BMI in a multilevel framework. Increasing street connectivity levels measured as intersection density were inversely associated with directly measured BMI obtained from EHRs, demonstrating the feasibility of the approach. PMID- 27989290 TI - Sociodemographic Patterns of Chronic Disease: How the Mid-South Region Compares to the Rest of the Country. AB - INTRODUCTION: States in the Mid-South region are among the least healthy in the nation. This descriptive study examines sociodemographic differences in the distribution of chronic diseases and health-related behaviors in the Mid-South versus the rest of the U.S., identifying subgroups at increased risk of chronic disease. METHODS: Data were obtained from the 2013 Behavioral Risk Factor Surveillance System; analyses were completed in January 2016. Twelve chronic health conditions were assessed: obesity, diabetes, high blood pressure, coronary heart disease, myocardial infarction, stroke, chronic kidney disease, cancer, arthritis, asthma, chronic obstructive pulmonary disease, and depression. Evaluated health-related behaviors included smoking, physical activity, and fruit and vegetable consumption. Age-standardized percentages were reported using complex survey design parameters to enhance generalizability. RESULTS: The Mid South population had increased rates of chronic disease and worse health-related behaviors than the rest of the U.S. POPULATION: Mid-South blacks had the highest percentages of obesity, diabetes, high blood pressure, and stroke of all subgroups, along with lower physical activity and fruit and vegetable consumption. In both races and regions, individuals with lower income and education had higher rates of chronic disease and unhealthy behaviors than those with higher income and education. However, black men in both regions had higher obesity and cancer rates in the higher education category. In general, education level disparities were more pronounced in health-related behaviors, whereas income-level disparities were more pronounced in chronic health conditions. CONCLUSIONS: Future studies should test tailored interventions to address the specific needs of population subgroups in order to improve their health. PMID- 27989292 TI - Psychosocial Factors and Behaviors in African Americans: The Jackson Heart Study. AB - INTRODUCTION: There are limited reports on the association of psychosocial factors with unhealthy behaviors, which are key mediators in the psychosocial cardiovascular disease pathway. The Jackson Heart Study was used to examine the associations of multiple psychosocial factors with behaviors among African Americans. METHODS: The Jackson Heart Study is a prospective, cohort study of cardiovascular disease among African Americans recruited from the Jackson, MS, metropolitan area between 2000 and 2004. Between 2015 and 2016, multivariable regression was used to analyze the cross-sectional associations of baseline negative affect (cynicism, anger-in, anger-out, and depressive symptoms) and stressors (global stress, Weekly Stress Inventory-event, Weekly Stress Inventory impact, and major life events) with the odds of current smoking and mean differences in dietary fat intake, physical activity, and hours of sleep. RESULTS: Men were more likely to smoke than women (p<0.001) and had higher physical activity scores (p<0.001). Women reported more hours of sleep (p=0.001). In fully adjusted models, each negative affect and stress measure was significantly associated with an increased odds of current smoking. For example, the odds of smoking increased by 14% for each 1-SD increase in cynical distrust score (OR=1.14, 95% CI=1.01, 1.27) in the fully adjusted model. Further, each negative affect and stress measure (except anger-out) was significantly associated with fewer hours of sleep in fully adjusted models. CONCLUSIONS: Using a large sample of African Americans, this study found that multiple psychosocial risk factors were associated with unhealthy behaviors that are prevalent among this population. PMID- 27989293 TI - The Social Determinants of Chronic Disease. AB - This review article addresses the concept of the social determinants of health (SDH), selected theories, and its application in studies of chronic disease. Once ignored or regarded only as distant or secondary influences on health and disease, social determinants have been increasingly acknowledged as fundamental causes of health afflictions. For the purposes of this discussion, SDH refers to SDH variables directly relevant to chronic diseases and, in some circumstances, obesity, in the research agenda of the Mid-South Transdisciplinary Collaborative Center for Health Disparities Research. The health effects of SDH are initially discussed with respect to smoking and the social gradient in mortality. Next, four leading SDH theories-life course, fundamental cause, social capital, and health lifestyle theory-are reviewed with supporting studies. The article concludes with an examination of neighborhood disadvantage, social networks, and perceived discrimination in SDH research. PMID- 27989294 TI - A Comparison of Black and White Racial Differences in Health Lifestyles and Cardiovascular Disease. AB - INTRODUCTION: This study examines the health lifestyles of a cohort of blacks and whites in relation to cardiovascular disease (CVD). The link between health lifestyles and CVD is well established, but most of the focus has been on SES and more research is needed on racial differences. METHODS: Data were from the Coronary Artery Risk Development in Young Adults study of black (n=2,451) and white (n=2,351) men and women. Data were analyzed from baseline examinations in 1985-1986 when the participants were aged 18-30 years and any fatal or nonfatal CVD event that occurred over approximately the next 28 years (until August 2013). The first stage of the analysis used latent class models to identify distinct health lifestyles on the basis of race. The second stage used multinomial logit regression models to analyze specific characteristics in relation to the health lifestyles classes, followed by the third stage in which Cox proportional hazards models analyzed associations of the lifestyle classes with CVD risk. RESULTS: Four separate health lifestyle patterns for blacks and four for whites were identified, with the "unhealthy" lifestyle among blacks (hazard ratio, 1.60) and "most unhealthy" lifestyle among whites (hazard ratio, 3.12) showing an elevated risk of CVD. An important difference is that, in every lifestyle class, blacks showed a higher probability of excessive energy intake than whites-indicative of the potential for obesity. CONCLUSIONS: Health lifestyles differ by race and support the exploratory hypothesis that distinct classes of healthy-unhealthy lifestyles exist within each racial group. PMID- 27989296 TI - The Role of Perceived Discrimination in Obesity Among African Americans. AB - INTRODUCTION: African Americans, especially those in the South, suffer a disproportionate burden of obesity and are at high risk for perceived discrimination (PD). This study investigates the association between PD and weight status among African Americans and clarifies the role of perceived stress and health behaviors in this relationship. METHODS: Data came from the Jackson Heart Study, Examination 1 (2000-2004; analyses conducted in 2016 using Stata, version 14). African Americans from Jackson, Mississippi, aged 21-95 years were recruited (N=5,301). Weight status was measured using anthropometric data with BMI; waist circumference (in centimeters); and obesity class (I, II, III). Survey instruments were used to measure PD, perceived global stress, and health behaviors. Multivariate regression was used to model weight status outcomes as a function of PD, perceived stress, and health behaviors. RESULTS: After controlling for sociodemographic factors and health status, perceived everyday discrimination was associated with higher BMI (b=0.33, p<0.01); higher waist circumference (b=0.70, p<0.01); and higher relative risk of Class III obesity versus non-obesity (relative risk ratio, 1.18; p<0.001). Global perceived stress was linked to higher BMI (b=0.42, p<0.05) and higher waist circumference (b=1.18; p<0.01) and partially mediated the relationships between PD and these weight status outcomes. Health behaviors led to suppression rather than mediation between PD and weight status and between stress and weight status. CONCLUSIONS: PD and perceived stress are potential risk factors for higher weight status. They should be considered as a part of a comprehensive approach to reduce obesity among African Americans. PMID- 27989295 TI - Systemic Inflammation in Midlife: Race, Socioeconomic Status, and Perceived Discrimination. AB - INTRODUCTION: This study investigates social determinants of systemic inflammation, focusing on race, SES, and perceived discrimination. METHODS: Data on 884 white and 170 black participants were obtained from the Survey of Midlife in the U.S., a cross-sectional observational study combining survey measures, anthropometry, and biomarker assay. Data, collected in 2004-2009, were analyzed in 2016. Main outcome measures were fasting blood concentrations of C-reactive protein, interleukin 6, fibrinogen, and E-selectin. For each biomarker, series of multivariate linear regression models were estimated for the pooled sample and separately for blacks and whites. Full models included social determinants; psychological, lifestyle, and health factors; and demographic covariates. RESULTS: Bivariate analyses indicated higher concentrations of all inflammation markers among blacks compared with whites (p<0.001). In fully adjusted models using the pooled sample, racial differences persisted for interleukin 6 (p<0.001) and fibrinogen (p<0.01). For E-selectin and C-reactive protein, racial differences were explained after adjusting for covariates. Education was linked to lower fibrinogen concentration (p<0.05) in the fully adjusted model and C reactive protein concentration (p<0.01) after adjusting for demographic factors and income. Lifetime perceived discrimination was related to higher concentrations of fibrinogen (p<0.05) in the fully adjusted model, and higher concentrations of E-selectin and interleukin 6 (p<0.05) after adjusting for socioeconomic status (SES) and demographic factors. CONCLUSIONS: This study clarifies the contributions of race, SES, and perceived discrimination to inflammation. It suggests that inflammation-reducing interventions should focus on blacks and individuals facing socioeconomic disadvantages, especially low education. PMID- 27989298 TI - Contribution of Four Comorbid Conditions to Racial/Ethnic Disparities in Mortality Risk. AB - INTRODUCTION: The prevalence of key forms of morbidity such as obesity, diabetes, and chronic kidney disease have increased dramatically in the U.S. and elsewhere for decades. Hypertension is etiologically related but its prevalence has been reduced through improved treatment. These diseases are known to have higher than expected rates of comorbidity, but it is not known whether and how these cluster together differentially by race, nor the degree to which they contribute to racial disparities in mortality. METHODS: Using data from the National Health Interview Survey mortality follow-up (1997-2009, analyzed in 2016), this paper modeled interdependencies between each combination of these four types of morbidity, overall and net of demographic, socioeconomic, and behavioral controls. It then analyzed whether these diseases mediate the relationship between race/ethnicity and mortality risk using discrete time complementary log log survival models. RESULTS: American Indians and blacks had significantly elevated rates of comorbidity compared with whites, and Asians' and Pacific Islanders' rates were often significantly lower than whites'. Controlling for these diseases significantly moderated the mortality risk disparity between African American, Hispanic, and Asian/Pacific Islanders and whites. This remained true when individual health behaviors and neighborhood fixed effects were statistically adjusted for. Notably, the full controls model statistically eliminated the association between African American race and mortality risk. CONCLUSIONS: These diseases contribute significantly to racial/ethnic mortality disparities, particularly between blacks and whites. Future research should consider the mediating role of these diseases for the relationship between social conditions and mortality risks. PMID- 27989297 TI - Perceived Discrimination and Privilege in Health Care: The Role of Socioeconomic Status and Race. AB - INTRODUCTION: This study examined how perceived racial privilege and perceived racial discrimination in health care varied with race and socioeconomic status (SES). METHODS: The sample consisted of white, black, and Native American respondents to the Behavioral Risk Factor Surveillance System (2005-2013) who had sought health care in the past 12 months. Multiple logistic regression models of perceived racial privilege and perceived discrimination were estimated. Analyses were performed in 2016. RESULTS: Perceptions of racial privilege were less common among blacks and Native Americans compared with whites, while perceptions of racial discrimination were more common among these minorities. In whites, higher income and education contributed to increased perceptions of privileged treatment and decreased perceptions of discrimination. The pattern was reversed in blacks, who reported more discrimination and less privilege at higher income and education levels. Across racial groups, respondents who reported foregone medical care due to cost had higher risk of perceived racial discrimination. Health insurance contributed to less perceived racial discrimination and more perceived privilege only among whites. CONCLUSIONS: SES is an important social determinant of perceived privilege and perceived discrimination in health care, but its role varies by indicator and racial group. Whites with low education or no health insurance, well-educated blacks, and individuals who face cost-related barriers to care are at increased risk of perceived discrimination. Policies and interventions to reduce these perceptions should target structural and systemic factors, including society-wide inequalities in income, education, and healthcare access, and should be tailored to account for racially specific healthcare experiences. PMID- 27989299 TI - Corrigendum to "The Importance of Interaction Between Urologists and Pathologists in Incidental Prostate Cancer Management" [Eur Eurol 2011;60;75-7]. PMID- 27989300 TI - Corrigendum to "Re: Kari A.O. Tikkinen, Anssi Auvinen. Does the Imprecise Definition of Overactive Bladder Serve Commercial Rather than Patient Interests? Eur Urol 2012;61:746-8. The Origin of the Term Overactive Bladder, Industry, and Patient Care" [Eur Urol 2012;61:749-50]. PMID- 27989301 TI - Editorial. PMID- 27989302 TI - Corrigendum to "Real-Time Magnetic Resonance Imaging-Guided Focal Laser Therapy in Patients with Low-Risk Prostate Cancer" [Eur Urol 2010;58:173-77]. PMID- 27989303 TI - Corrigendum to "Re: Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort with Localized Prostate Cancer" [Eur Urol 2010;58:179-80]. PMID- 27989304 TI - Corrigendum to "Stress Proteins and Cytokines are Urinary Biomarkers for Diagnosis and Staging of Bladder Cancer" [Eur Urol 2011;59:113-9]. PMID- 27989305 TI - Corrigendum to "Systematic Review of Oncological Outcomes Following Surgical Management of Localised Renal Cancer" [Eur Urol 2012;61:972-93]. PMID- 27989306 TI - Corrigendum to "Validation of the 2009 TNM Version in a Large Multi-Institutional Cohort of Patients Treated for Renal Cell Carcinoma: Are Further Improvements Needed?" [Eur Urol 2010;58:588-95]. PMID- 27989307 TI - From the Editor's desk... PMID- 27989308 TI - RETRACTED: The Virtual Cutting Edge: Adolescent Self-injury and YouTube. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Authors. We wish to retract the abstract "The Virtual Cutting Edge: Adolescent Self-injury and YouTube," published in the October 2015 issue of Annals. The abstract excessively borrowed from the text and methodology of a previous study published elsewhere.1 All authors recognize the seriousness of this issue and apologize to the editors and readers of Annals. Jeffrey S. Jones, MD Chad Garthe, MD Lindsey Ouellette, MS Jason Seamon, DO Department of Emergency Medicine MSU College of Human Medicine Grand Rapids, MI 1. Lewis SP, Heath NL, St. Denis JM, et al. The scope of nonsuicidal self-injury on YouTube. Pediatrics. 2011;1127:e552-e557. PMID- 27989310 TI - Foreword. PMID- 27989309 TI - Comparative Efficacy of Clinical Events Prevention of Five Anticoagulants in Patients With Atrial Fibrillation (A Network Meta-Analysis). AB - Atrial fibrillation (AF) ranks the most prevailing type of cardiac rhythm disorder and AF patients are associated with a significantly increased risk of stroke compared to others. This study is designed to assess the relative efficacy of several clinical events prevention anticoagulants in patients with AF. Conventional pairwise meta-analysis was performed with fixed-effect model initially, then network meta-analysis was performed with random-effects model within results illustrated by cumulative odds ratios (ORs) and corresponding 95% credible interval (CrI). The rank probabilities of each treatment outcomes were summarized by the surface under the cumulative ranking curve (SUCRA). We conducted a systematic review and collected key clinical data from 37 studies with respect to 5 anticoagulant treatments for AF. Patients treated with rivaroxaban and apixaban are associated with a reduced risk of stroke compared to those treated with warfarin (OR 0.72, 95% CrI 0.53 to 0.88; OR 0.68, 95% CrI 0.48 to 0.91). Rivaroxaban (SUCRA = 0.712) appears to be the most preferable one with respect to vascular events, and both apixaban (SUCRA = 0.720) and rivaroxaban (SUCRA = 0.678) are preferable to others with respect to stroke. Dabigatran outperforms others with respect to the outcome of mortality (SUCRA = 0.695), hemorrhage events (SUCRA = 0.747), and myocardial infarction (SUCRA = 0.620). In conclusion, dabigatran has a noticeable and comprehensive advantage compared to others with respect to preventing several complications including hemorrhage events, myocardial infarction, and mortality. In addition, apixaban may be the best choice of preventing stroke, and rivaroxaban is more preferable to others with respect to preventing vascular events. PMID- 27989311 TI - An Update on the Management of Chronic Thromboembolic Pulmonary Hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life threatening form of pulmonary artery hypertension that is defined as a mean arterial pulmonary pressure greater than 25mmHg that persists for more than 6 months following anticoagulation therapy in the setting of pulmonary emboli. CTEPH is categorized by the World Health Organization as group IV pulmonary hypertension and is thought to be due to unresolved thromboemboli in the pulmonary artery circulation. Among the 5 classes of pulmonary hypertension, CTEPH is unique in that it is potentially curable with the use of pulmonary thromboendarterectomy surgery. Despite an increasing array of medical and surgical treatment options for patients with CTEPH over the past 2 decades, patients commonly present with advanced disease and carry a poor prognosis, thus, the need for early diagnosis and appropriate referral to an expert center. This review article first highlights the epidemiology, pathophysiology, and clinical presentation of CTEPH. The article then provides diagnostic and therapeutic algorithms for the management of the patient with suspected CTEPH. PMID- 27989312 TI - Safety of UV Lamps for Cosmetic Use: Regulatory Considerations. PMID- 27989313 TI - An ultrasound elastography method to determine the local stiffness of arteries with guided circumferential waves. AB - Arterial stiffness is highly correlated with the functions of the artery and may serve as an important diagnostic criterion for some cardiovascular diseases. To date, it remains a challenge to quantitatively assess local arterial stiffness in a non-invasive manner. To address this challenge, we investigated the possibility of determining arterial stiffness using the guided circumferential wave (GCW) induced in the arterial wall by a focused acoustic radiation force. The theoretical model for the dispersion analysis of the GCW is presented, and a finite element model has been established to calculate the dispersion curve. Our results show that under described conditions, the dispersion relations of the GCW are basically independent of the curvature of the arterial wall and can be well described using the Lamb wave (LW) model. Based on this conclusion, an inverse method is proposed to characterize the elastic modulus of artery. Both numerical experiments and phantom experiments had been performed to validate the proposed method. We show that our method can be applied to the cases in which the artery has local stenosis and/or the geometry of the artery cross-section is irregular; therefore, this method holds great potential for clinical use. PMID- 27989314 TI - Clinical outcomes after Nellix Endovascular Aneurysm Sealing. AB - The published evidence on clinical outcomes of Nellix Endovascular Aneurysm Sealing for elective abdominal aortic aneurysm repair has confirmed low procedural morbidity and reintervention rate. This early clinical experience with Nellix is encouraging, despite the device and procedural steps being in evolution, and patients being treated outside of the recommended instructions for use. The long-term follow-up of a treated patient cohort is now available and demonstrates low aneurysm-related mortality and morbidity. The initial experience with the commercially available Nellix device was captured in a multicenter report involving 171 patients and two independently monitored, company-sponsored device registries (EVAS Forward Global Trial and Forward US Investigational Device Exemption Trial). All three clinical studies report a 99% procedural technical success, low mortality, and persistent endoleak rate with re intervention rates comparable to conventional EVR device registries. Nellix EVAS is applicable to a range of aneurysm anatomies, including patients with isolated of concomitant iliac artery aneurysms. The post-procedural imaging appearances after Nellix EVAS are unique due to the AAA sac polymer, change with time, but are now well understood. PMID- 27989315 TI - Extended use of endovascular aneurysm sealing for ruptured abdominal aortic aneurysms. AB - Endovascular repair of abdominal aortic aneurysms (EVAR) is now an established treatment modality for suitable patients presenting with aneurysm rupture. EVAR for ruptured aneurysms reduces transfusion, mechanical ventilation, intensive care. and hospital stay when compared with open surgery. In the emergency setting, however, EVAR is limited by low applicability due to adverse clinical or anatomical characteristics and increased need for reintervention. In addition, ongoing bleeding from aortic side branches post-EVAR can cause hemodynamic instability, larger hematomas, and abdominal compartment syndrome. Endovascular aneurysm sealing, based on polymer filling of the aneurysm, has the potential to overcome some of the limitations of EVAR for ruptured aneurysms and to improve outcomes. Recent literature suggests that endovascular aneurysm sealing can be performed with early mortality similar to that of EVAR for ruptured aortic aneurysms, but experience is limited to a few centers and a small number of patients. The addition of chimney grafts can increase the applicability of endovascular aneurysm sealing in order to treat short-neck and juxtarenal aneurysms as an alternative to fenestrated endografts. Further evaluation of the technique, with larger longitudinal studies, is necessary before advocating wider implementation of endovascular aneurysm sealing in the emergency setting. PMID- 27989316 TI - Treating iliac aneurysm using the Nellix Endovascular Sac Sealing System. AB - As endovascular treatment of abdominal aortic aneurysms has become established, there has been growing focus on treatment of the aneurysmal iliac artery. Isolated, large iliac aneurysms >30 mm pose a risk of rupture, but, in addition, 20% to 30% of abdominal aortic aneurysms are associated with iliac aneurysmal dilatation, which can compromise long-term outcomes. Endovascular solutions are evolving and until recently have utilized standard stent graft technology. The endovascular aortic sealing system was introduced as a new, effective method for the treatment of infrarenal aortic aneurysms. In this article, we present our recent extended use of the Nellix system, with or without a combination of adjuvant endovascular techniques, in the treatment of 84 common iliac artery aneurysms. The results support the use of endovascular aortic sealing system in endovascular therapy for aneurysmal iliac pathologies. Different endovascular sealing techniques for the treatment of common iliac artery aneurysms, re interventions, and extended follow-up are also discussed. PMID- 27989317 TI - Extended use of endovascular aneurysm sealing: Chimneys for juxtarenal aneurysms. AB - Hostile infrarenal aortic neck anatomy presents a challenge for the endovascular treatment of abdominal aortic aneurysm. Open surgical repair has been seen as the gold standard treatment for juxtarenal abdominal aortic aneurysm; however, endovascular techniques are now becoming more prevalent, particularly in patients deemed high risk for morbidity and mortality with open repair. The morphology of an aneurysm is a determinant of long-term outcomes, and short aneurysm necks are associated with poorer outcomes and a higher rate of secondary reinterventions. Parallel grafts have been used in combination with endovascular aneurysm repair to elongate the sealing zone into the paravisceral segment of the aorta. This technique is associated with a risk of proximal Type I endoleak due to "guttering." This risk may be decreased when parallel grafts are used in combination with endovascular aneurysm sealing and, as such, this technique may represent an alternative to current techniques for the treatment of juxtarenal abdominal aortic aneurysm, such as the use of conventional bifurcated grafts (with or without parallel grafts) and fenestrated endovascular stent grafts. PMID- 27989318 TI - Appearance of the Nellix endoprosthesis on postoperative imaging: implications for patient and device surveillance. AB - The Nellix stent graft has novel features that influence interpretation of imaging follow-up, in particular, the use of endobags that seal the aneurysm sac. The polymer within the endobags contains a small amount of contrast medium, which causes a predictable temporal change in appearances. Understanding of these features allows correct image evaluation. In this article, we review the appearance of Nellix on computed tomography, ultrasound, magnetic resonance imaging, and plain radiography. We describe the special considerations that are important to consider when reviewing imaging, including endobag position and seal, endobag configuration, endobag and polymer maturation, and endobag gas. Detection of complications is discussed, with suggestion of a follow-up protocol based on the authors' experience. PMID- 27989319 TI - Percutaneous interventions following endovascular aneurysm sac sealing: Endoleak embolization and limb-related adverse events. AB - The Nellix endovascular aneurysm sealing system is a novel alternative to conventional endovascular aneurysm repair for aortic aneurysm management using paired balloon-expandable endografts supported by polymer-filled endobags to achieve sealing and anatomic fixation. Part of the promise of endovascular aneurysm sealing is increased resistance to lateral and longitudinal forces and a potential for reduced rates of device-related failures, particularly endoleaks. Initial efficacy data on this device are encouraging, but our knowledge of its associated complications and their management is limited. Reported adverse events include Type I and II endoleaks, graft stenosis, and occlusion. The aim of this article was to review the early experience of endovascular aneurysm sealing, focusing on the incidence, significance, and management of device-related complications. PMID- 27989320 TI - Introduction: The endovascular aneurysm sealing revolution. PMID- 27989321 TI - Patient selection for endovascular sac sealing of abdominal aortic aneurysm. AB - Endovascular sealing is a developing technique for treatment of abdominal aortic aneurysm that draws on novel concepts utilizing polymer filling of endobags within the aorto-iliac lumen. The morphologic indications and patient selection, while similar to those of endovascular aneurysm repair, differ in some regards. The Instructions for Use for the Nellix sealing device may expand the indications for aneurysm treatment and are closely scrutinized in this article. The authors draw on current evidence and their own experience and opinion in the discussion around appropriate patient selection and its influence on outcomes after endovascular aneurysm sealing. A recommendation for stricter adherence to Instructions for Use in the early phase of clinical experience is made, with acknowledgement that the natural evolution of endovascular aneurysm sealing may involve more challenging cases. PMID- 27989322 TI - Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. AB - In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues. PMID- 27989323 TI - Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors. AB - Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 Finns we identified 27 genome-widely significant loci (p < 1.2 * 10-9) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets. PMID- 27989325 TI - Introduction. PMID- 27989324 TI - Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy. AB - MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children. PMID- 27989327 TI - Pathogenesis of Pain. AB - The pathogenesis of pain sensation includes mechanisms that result in acute or chronic pain. Pain itself is described as an unpleasant sensory and emotional experience beginning with a peripheral stimulus that undergoes a physiological process ultimately resulting in the sensation of pain. Biologists recognize pain to be a common sign of potential tissue damage. Hence, pain sensation is protective in function. However, pathologic states of pain exist secondary to disruption of the nociceptive process both peripherally and centrally or secondary to psychological conditions. It is essential to identify these aberrant states of pain and distinguish them from situations of potential tissue damage. Chronic pain is defined as pain that exceeds 3 or 6 months duration. This article is an overview of the essential neuroanatomy and neurophysiology of normal pain nociception, its clinical implications, and the development of persistent and pathological pain conditions following improperly or poorly treated pain. PMID- 27989326 TI - Pediatric Pain Measurement, Assessment, and Evaluation. AB - Assessment provides the foundation for diagnosis, selection of treatments, and evaluation of treatment effectiveness for pediatric patients with acute, recurrent, and chronic pain. Extensive research has resulted in the availability of a number of valid, reliable, and recommended tools for assessing children's pain. Yet, evidence suggests children's pain is still not optimally measured or treated. In this article, we provide an overview of pain evaluation for premature neonates to adolescents. The difference between pain assessment and measurement is highlighted; and the key steps to follow are identified. Information about self-report and behavioral pain assessment tools appropriate for children are provided; and factors to be considered when choosing a specific one are outlined. Finally, we preview future approaches to personalized pain medicine in pediatrics that include harnessing the use of potential digital health technologies and genomics. PMID- 27989328 TI - Pharmacologic Treatment of Pain. AB - Adolescents and children are frequently affected by chronic pain conditions that can lead to disability and distress. The best approach to evaluation and treatment of these conditions involves use of the biopsychosocial model, which includes use of medication management. Chronic pain conditions are treated pharmacologically with a number of different medication classes via several routes of administration as drug delivery systems have progressed. These include anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics. Most are prescribed without regulatory body approval to treat specific pain syndromes as data to support their use are sparse. Medical decision making is guided by experience, empiric evidence, extrapolation from adult studies, and matching medication classes with the theorized mechanism of the pain condition. It is not recommended that nonpain practitioners prescribe opioid medications for treatment of chronic pain conditions, and pain management practitioners should seek to minimize their use. The appropriate and commonly used medications for pain conditions are presented in this narrative review. PMID- 27989329 TI - Nonpharmacologic Treatment of Pain. AB - Pain is a complex biopsychosocial experience that is influenced by neurological processes and psychosocial factors. Systematic reviews and meta-analyses of randomized controlled trials of psychological interventions have demonstrated evidence for psychological approaches in treating procedural pain and multiple types of chronic pain, including headaches, abdominal pain, and musculoskeletal pain. This article is directed toward clinicians and would provide an overview of cognitive-behavioral therapy, including specific cognitive-behavioral techniques for pediatric pain. A review is provided of preparation and psychoeducation, distraction, exposure and psychological desensitization, relaxation techniques, additional cognitive and behavioral therapy, exercise and alternative options, use of technology, multicomponent approaches, and final considerations in treating acute and chronic pain. It is important to consider multiple characteristics of the child when selecting an intervention for chronic pain, which are reviewed in the article. PMID- 27989330 TI - Pain Amplification Syndrome: A Biopsychosocial Approach. AB - Pediatric neurologists frequently encounter patients who present with significant musculoskeletal pain that cannot be attributed to a specific injury or illness, which can often be defined as pain amplification syndrome (PAS). PAS in children and adolescents is the result of a heightened pain sensitivity pathway, which is intensified by significant biological, psychological, and social contributors. Appropriate assessment and multimodal intervention of PAS are crucial to treatment success, including neurology and behavioral health collaborative treatment plans to restore patient function and reduce pain perception. Pediatric neurologists are imperative in the identification of patients with PAS, providing the family assurance in diagnosis and validation of pain, and directing patients to the appropriate multidisciplinary treatment pathway. PMID- 27989331 TI - Juvenile Fibromyalgia: A Primary Pain, or Pain Processing, Disorder. AB - Juvenile fibromyalgia (JFM), a chronic disorder of widespread musculoskeletal pain in combination with autonomic, sensory, and cognitive dysfunction, is responsible for considerable morbidity and impaired quality of life in affected patients and their families. Historically, fibromyalgia has been incorrectly characterized as a psychosomatic or psychogenic disorder, but new understanding of the science of pain has demonstrated unambiguously that it is an organic disorder of the pain processing system itself. This new science provides a framework for understanding the pathophysiology of fibromyalgia and for developing rational therapeutic interventions. Advances in JFM include the verification of adult criteria for diagnosis in pediatric patients and the publication of effective therapies based on cognitive and physical neuromuscular intervention. Although primarily nonpharmacologic therapy can include adjunctive medications as well. Finally, the recognition that JFM is a disorder of the central and peripheral nervous systems suggests that neurologists can be important in the care of these patients. PMID- 27989332 TI - Neuropathic and Myopathic Pain. AB - The evaluation and management of childhood pain syndromes of neuromuscular origin have distinct challenges, as the patterns of disease presentation and the ability of a child to describe symptoms may differ from that of an adult. Advances in scientific and clinical knowledge are leading to significant progress in the care of affected children. The genetic origins of Fabry disease and the inherited form of erythromelalgia are better understood. The increasing interest in neuroimmunology among pediatric neurologists has led to more sophisticated diagnostic and therapeutic approaches. Treatment protocols for complex regional pain syndrome have become more standardized. In addition, investigations continue into potential new interventions for metabolic muscle diseases such as McArdle disease and carnitine palmitoyl transferase deficiency type II. In the years to come, children with pain of neuromuscular origin will have access to more precise diagnostic tools and novel therapies that would alleviate this particularly distressing category of disease. PMID- 27989333 TI - Inherited Pain Syndromes and Ion Channels. AB - Individuals rely on the perception of pain to avoid injury, to signal disease, and to warn about tissue inflammation and damage. However, the inheritance of inappropriate, extreme, or inadequate pain production is a source of significant human suffering. Substantial progress has been made in our understanding of the genetics and pathophysiology of pain through the study of individuals and families with several specific inherited pain syndromes. These studies have led to the discovery of a number of gene mutations associated with specific ion channel disturbances that produce familial inherited pain sensitivity and insensitivity syndromes. The sodium channel has been identified as the primary determinant of most of these syndromes. This article focuses on the inherited pain syndromes and their corresponding ion channel mutations. There is hope that through continued research into these ion channels and pain syndromes, targeted drug therapy would be fruitful and beneficial to those afflicted. PMID- 27989334 TI - Corrigendum to "A meta-analysis on the impact of disease-specific education programs on health outcomes for patients with chronic obstructive pulmonary disease" [Geriatr Nurs 33 (4) (2012) 280-296]. PMID- 27989335 TI - The Opioid Crisis. PMID- 27989336 TI - A Review of 399 Total Ankle Replacements: Analysis of Ipsilateral Subtalar Joint Arthrodesis and Associated Talar Component Subsidence. AB - Total ankle replacement (TAR) is an accepted treatment for end-stage ankle arthritis. When concurrent subtalar joint pathologic features exist, ipsilateral subtalar joint arthrodesis (STJA) can be performed either simultaneous with TAR or as a staged procedure. Limited data exist on the effect of talar component subsidence and prosthesis survivorship. The present study purpose was to evaluate the effect of STJA on talar component subsidence after primary TAR and its effect on TAR survivorship. All patients, a minimum of 18 years old, from a single institution with modern-generation TAR and 1-year minimum follow-up data available were evaluated. The study group included patients who had also undergone STJA, and the control group (no STJA) was matched 1:1 by age, gender, and prosthesis. The initial postoperative weightbearing and most recent weightbearing radiographs were compared for talar component subsidence. We reviewed 399 primary TARs from 2004 to 2012. A total of 33 patients with ipsilateral STJA met the inclusion criteria and had an appropriate control group match. In the study group, 8 patients required a return to the operating room for 4 revisions and 4 reoperations at a median follow-up point of 24.3 months. Of the controls, 9 patients required a return to the operating room, with 4 revisions and 5 reoperations at a median follow-up point of 38.4 months. No statistically significant radiographic differences were found between the 2 groups. Primary TAR and ipsilateral STJA were infrequently required (41 of 399; 10.3%). TAR did not result in decreased survivorship when performed with ipsilateral STJA at an early follow-up point. Further study is warranted to determine any differences among previous, simultaneous, and subsequent STJA with ipsilateral TAR, and a matched longitudinal analysis is needed to determine longer term survivorship. PMID- 27989337 TI - Review of Drop Hallux: Assessment and Surgical Repair. AB - Peroneal nerve palsy is common. The hallmark clinical manifestation of peroneal nerve palsy is drop foot. In the drop foot condition, the ankle cannot flex, and the foot does not clear the ground during the swing phase of gait. Spontaneous nerve repair can yield complete or incomplete resolution of drop foot. Some patients with incomplete resolution are left with a drop hallux condition, in which the ankle can dorsiflex, but the hallux remains unable to dorsiflex. This has not been thoroughly discussed in the past, regarding surgical repair. In the present report, we have reviewed the drop hallux condition and an effective surgical repair option (extensor hallucis longus to tibialis anterior tendon anastomosis). Our case report presents a healthy 27-year-old male who had persistent drop hallux after drop foot resolution, 3 years after external fixation of a closed, proximal tibia-fibula fracture. PMID- 27989338 TI - Investigation of the Relationship Between Flatfoot and Patellar Subluxation in Adolescents. AB - Patellar subluxation is common in adolescents, and a variety of factors are related to this condition, with valgus of the knee joint an important factor. The results of many studies suggest that flatfoot can cause an abnormality of the lower limb power line. Structural abnormalities of the foot caused by the high stresses exerted by body weight can lead to structural deformity of the knee and can also cause knee valgus. Screening for foot problems can help determine the risk of patellar subluxation, and early intervention can lessen the incidence of this condition. The purpose of the present study was to investigate the effects of flatfoot on the structure and function of the knees and, especially, the risk of patellar subluxation. A total of 72 participants were recruited for this cross sectional study. The mean age at examination was 15.4 +/- 4.0 (range 9 to 22) years. The measured parameters were heel valgus angle, arch index, and quadriceps angle (Q-angle). Overall, the mean values of the heel valgus angle, arch index, and Q-angle were 5.9 degrees +/- 2.4 degrees (range 1 degrees to 11 degrees ), 0.33 +/- 0.07 (range 0.23 to 0.46), and 19.1 degrees +/- 3.5 degrees (range 9 degrees to 26 degrees ), respectively. The Q-angle was directly associated with the heel valgus angle (r = 0.818, p < .001) and arch index (r = 0.655, p < .001). We found that flatfoot can affect the morphology of the knee joint and increase the risk of patellar subluxation. PMID- 27989339 TI - Anatomic Description of the Naviculocuneiform Articulation. AB - The naviculocuneiform articulation is composed of the navicular proximally and the 3 cuneiforms distally. It is not uncommon to perform surgical interventions at this joint for multiple pathologic foot etiologies. To date, no detailed anatomic measurement is available for each cuneiform articulation on the navicular. The purpose of the present study was to present an anatomic description of this complex joint to aid in better surgical understanding and improve surgical outcomes. Ten fresh, frozen, and thawed below-the-knee cadaveric specimens were used for anatomic dissection of the navicular and associated cuneiforms. The height and width were recorded across the largest span of the entire navicular-cuneiform joint complex and each facet. The mean navicular height and width was 19.9 mm and 34.7 mm, respectively. The medial cuneiform facet mean height and width was 19.9 mm and 15.8 mm, respectively. The intermediate cuneiform facet mean height and width was 20.4 mm and 16.9 mm, respectively. The lateral cuneiform facet mean height and width was 17.5 mm and 14.7 mm, respectively. A detailed description of this joint complex will aid foot and ankle surgeons in screw placement and surgical decision-making when performing complex medial column fusions. Advanced 3-dimensional weightbearing computed tomography would give us a better idea of the motion that occurs within this complex joint. PMID- 27989340 TI - Endoscopic Excision of Symptomatic Os Trigonum in Professional Dancers. AB - The present study reports the clinical results of excision of a symptomatic os trigonum using an endoscopic procedure in professional ballet dancers. The hypothesis was that posterior endoscopic excision of the os trigonum would be safe and effective in treating posterior ankle impingement syndrome related to the os trigonum. Twelve professional dancers underwent excision of a symptomatic os trigonum for PAIS using a posterior endoscopic technique after failure of conservative treatment. The patients were evaluated pre- and postoperatively according to the American Orthopaedic Foot and Ankle Society hindfoot scale score, the Tegner activity scale score, and the visual analog scale score. The surgical time, timing of a return to sports, patient satisfaction, and any complications related to the procedure were recorded. The average postoperative follow-up duration was 38.9 +/- 20.6 (range 12 to 72) months. The mean Tegner activity scale score increased from 4.3 +/- 0.8 (range 3 to 5) preoperatively to 9 +/- 0.2 postoperatively (p < .05). The mean American Orthopaedic Foot and Ankle Society scale score increased from 67.8 +/- 6.0 (range 58 to 76) preoperatively to 96 +/- 5.1 (range 87 to 100) postoperatively, with 7 of 12 patients (58.3%) reporting the maximum score of 100 points (p < .05). The return to sports was 8.7 +/- 0.7 (range 8 to 10) weeks. No major complications were recorded. The results of the present study demonstrate that the endoscopic excision of symptomatic os trigonum using a 2-portal technique after failure of conservative treatment is characterized by excellent results with low morbidity. PMID- 27989341 TI - Juvenile Particulate Osteochondral Allograft for Treatment of Osteochondral Lesions of the Talus: Detection of Altered Repair Tissue Biochemical Composition Using 7 Tesla MRI and T2 Mapping. AB - During the previous 2 decades, numerous surgical procedures have become available to treat osteochondral lesions of the talus. The objective of the present study was to use 7 Tesla (7T) magnetic resonance imaging (MRI) to quantify and compare T2 values (a marker of collagen architecture) of native tibiotalar cartilage and cartilage repair tissue in patients treated with a juvenile particulate allograft for osteochondral lesions of the talus. The institutional review board approved the present study, and all subjects provided written informed consent. We scanned the ankles of 7 cartilage repair patients using a 7T MRI scanner with a multi echo spin-echo sequence to measure the cartilage T2 values. We assessed the cartilage T2 values in the talar repair tissue, adjacent native talar cartilage, and overlying tibial cartilage. We compared the differences between groups using the paired t test. The talar cartilage repair tissue demonstrated greater mean T2 relaxation times compared with the native adjacent talar cartilage (64.88 +/- 12.23 ms versus 49.56 +/- 7.82 ms; p = .043). The tibial cartilage regions overlying these talar cartilage regions demonstrated a trend toward greater T2 relaxation times (77.00 +/- 31.29 ms versus 59.52 +/- 7.89 ms; p = .067). 7T MRI can detect differences in T2 values in cartilage repair tissue compared with native cartilage and could be useful for monitoring the status of cartilage health after surgical intervention. PMID- 27989342 TI - Comparison of Suture-Based Anchors and Traditional Bioabsorbable Anchors in Foot and Ankle Surgery. AB - We compared the pullout strength of a suture-based anchor versus a bioabsorbable anchor in the distal fibula and calcaneus and evaluated the relationship between bone mineral density and peak load to failure. Eight paired cadaveric specimens underwent a modified Brostrom procedure and Achilles tendon reattachment. The fibula and calcaneus in the paired specimens received either a suture-based anchor or a bioabsorbable suture anchor. The fibular and calcaneal specimens were loaded to failure, defined as a substantial decrease in the applied load or pullout from the bone. In the fibula, the peak load to failure was significantly greater with the suture-based versus the bioabsorbable anchors (133.3 +/- 41.8 N versus 76.8 +/- 35.3 N; p = .002). No significant difference in load with 5 mm of displacement was found between the 2 groups. In the calcaneus, no difference in the peak load to failure was found between the 2 groups, and the peak load to failure with 5 mm of displacement was significantly lower with the suture-based than with the bioabsorbable anchors (52.2 +/- 9.8 N versus 75.9 +/- 12.4 N; p = .003). Bone mineral density and peak load to failure were significantly correlated in the fibula with the suture-based anchor. An innovative suture-based anchor had a greater peak load to failure compared with a bioabsorbable anchor in the fibula. In the calcaneus, the load at 5 mm of displacement was significantly lower in the suture-based than in the bioabsorbable group. The correlation findings might indicate the need for a cortical bone shelf with the suture-based anchor. Suture-based anchors could be a viable alternative to bioabsorbable anchors for certain foot and ankle procedures. PMID- 27989343 TI - Early Protected Weightbearing After Ankle Fractures in Patients With Diabetes Mellitus. AB - The traditional protocol for treatment after ankle fracture in the diabetic patient involves a period of prolonged non-weightbearing to reduce the incidence of complications. The goal of the present study was to identify the risk factors and complications associated with early protected weightbearing after closed ankle fractures in patients with diabetes. The data from 73 diabetic patients with operatively and nonoperatively treated ankle fractures were retrospectively reviewed. All patients were allowed to begin protected weightbearing in a cast or removable boot at 2 weeks after the index injury or surgery. The mean follow-up period was 51 (range of 26 to 480) weeks. Complications occurred in 25% of the operative cases and 8% of the nonoperative cases. In both categories, the complication rate was less than that from existing reports using prolonged non weightbearing. Wound dehiscence was the most common complication in the operatively treated patients (18.8%). A statistically significant difference was found in the complications rates for the patients aged >60 years (p = .0403). No statistically significant differences were identified according to hemoglobin A1c, the presence of peripheral neuropathy, smoking status, fracture type, or the presence of end-stage renal disease. The results of the present study suggest that early protected weightbearing after closed ankle fractures in diabetic patients is fairly safe, with an acceptable complication rate. However, the patients selected for early weightbearing had low comorbidity profiles, which might have accounted, in part, for the low complication rate. PMID- 27989344 TI - A Proximal Fibularis Brevis Muscle Is Associated with Longitudinal Split Tendons: A Cadaveric Study. AB - The anomalous distal musculotendinous junction of the fibularis brevis muscle has been hypothesized to contribute to the development of longitudinal fibularis brevis tendon tears. Specifically, the mass effect of the low-lying fibularis brevis muscle belly was thought to increase the pressure on the superior peroneal retinaculum and increase the probability of fibularis brevis tendon subluxation. A more recent examination of the fibularis brevis tendon junction found, contrary to this hypothesis, a statistically significant association between an anomalous proximal musculotendinous junction and the prevalence of longitudinal split tears. However, no rationale was offered. The present study examined the relationship between the musculotendinous junction and the prevalence of longitudinal fibularis brevis tendon tears. A total of 24 fibularis brevis tendon lengths were measured bilaterally in 12 human cadaveric specimens. The tendon lengths were assessed as the vertical distance from the most inferior aspect of the lateral malleolus to the most distal fibularis brevis musculotendinous extension. Only full-thickness tears were identified and included. The lengths of tendons with and without longitudinal tears were compared. Of the 24 tendons examined, 7 (29%) presented with full-thickness longitudinal tears from 4 cadavers (33%). The mean length for the tendons with tears was significantly longer (p < .001) than the mean length of those without tears (28.86 +/- 3.02 mm versus 16.29 +/- 7.30 mm). Our research concurs with the most recent findings, identifying a statistically significant association between an anomalous proximal muscle belly extension and longitudinal fibularis brevis tendon tears. Furthermore, we propose the hypothesis that a more proximal musculotendinous junction might predispose individuals to a lesser stabilizing effect of the muscle against the posterior lateral surface of the fibula, increasing the probability of anterolateral subluxation, attrition, and longitudinal tear development. PMID- 27989345 TI - Gravity Equinus Position to Control the Tendon Length of Reversed Free Tendon Flap Reconstruction for Chronic Achilles Tendon Rupture. AB - Repair of chronic Achilles tendon rupture is a surgical challenge. We describe the use of a free turndown tendon flap augmentation raised from the proximal gastrocnemius aponeurosis. To control optimal tension or the reconstructed Achilles tendon length, we used an original method by referring to the gravity planter flexion ankle angle of the contralateral limb. Key aspects of the technique are described. A retrospective analysis of the short-term outcomes achieved in a case series (n = 56) is presented. The postoperative anthropometric findings are also presented to indicate the successful outcomes achieved with this technique. PMID- 27989346 TI - Assessment of Multipotent Mesenchymal Stromal Cells in Bone Marrow Aspirate From Human Calcaneus. AB - Bone marrow aspirates (BMAs), owing to their innate osteogenic potential, are well-documented supplements to osteoconductive and/or osteoinductive materials. The calcaneal body provides foot and ankle surgeons a convenient harvest site with low morbidity and minimal cost. In the present study, we sought to identify and characterize multipotent mesenchymal stromal cells (MSCs) in BMAs harvested from the human calcaneal body. Ten healthy patients aged 18 to 65 years were enrolled in the present study. BMAs were harvested from the patients without any reported postoperative complications related to the harvest. Cells isolated from all the aspirates were adherent to culture plates and expressed positive MSC surface markers (CD105, CD90, and CD73) and a low level of negative MSC markers (CD34 and CD45). The cells maintained the ability to proliferate and differentiate into cells of mesenchymal lineages. The BMAs from the human calcaneal body offer a healthy source of multipotent MSCs. PMID- 27989347 TI - Effect of Combined Fibular Osteotomy on the Pressure of the Tibiotalar and Talofibular Joints in Supramalleolar Osteotomy of the Ankle: A Cadaveric Study. AB - We investigated the effect of combined fibular osteotomy on the pressure of the tibiotalar and talofibular joints in medial opening-wedge supramalleolar osteotomy. Three different tibial osteotomy gaps (6, 8, and 10 mm) were created in 10 cadaveric models, and the pressure in the tibiotalar and talofibular joints was measured under axial load before and after fibular osteotomy. The heel alignment angle and talar translation ratio were evaluated radiographically. An increase in osteotomy gap led to increases in hindfoot valgus (p = .001) and the contact and peak pressures in the talofibular joint (p = .03 and p = .004). In contrast, the contact and peak pressures in the tibiotalar joint were unchanged with an increasing osteotomy gap (p = .52 and p = .76). Fibular osteotomy reduced the contact and peak pressures in the talofibular joint (p < .001 and p = .001, respectively), and it did not influence the contact and peak pressures in the tibiotalar joint (p = .46 and p = .14, respectively). Therefore, fibular osteotomy might be necessary in supramalleolar osteotomy for medial ankle arthritis to minimize the increase in pressure in the talofibular joint, especially when the osteotomy gap is large. PMID- 27989348 TI - Patient Expectations and Satisfaction With Foot and Ankle Surgery in Saudi Arabia: A Retrospective Cohort Study. AB - The success of surgery is associated not only with the quality of the procedure but also with the degree to which it meets the patient's expectations. Limited data are available on patient expectations related to foot and ankle surgery in Saudi Arabia. Our study assessed the preoperative expectations and postoperative satisfaction of patients who had undergone foot and ankle surgery at 1 hospital in Saudi Arabia. A survey-based, retrospective cohort study was conducted among patients who had undergone elective foot or ankle surgery at King Abdul-Aziz Medical City, Riyadh, from January 2010 to December 2015. The participants, who were randomly selected, were interviewed by telephone in April 2016. The average interval between the surgery and the telephone interview was 1 year. We performed stepwise multiple logistic regression analysis to assess the predictors of patient satisfaction with surgery. A total of 383 participants were interviewed (51.7% male). The sample included participants with a wide age range. Most participants had undergone surgery because of pain (74.9%) or movement difficulties (37.1%); only 9.4% had undergone surgery for cosmetic reasons. Most (80%) of the participants reported they were satisfied with the surgical results. Young age, bilateral surgery, efficient pain control, and fulfilled expectations had the greatest positive effects on satisfaction. The findings of the present study will help improve our understanding of the expectations of patients who undergo elective foot and ankle surgery in Saudi Arabia. Additionally, our results can give orthopedic surgeons insight into patients' ideas and concerns regarding their surgery, which might ultimately improve communication between surgeons and patients. PMID- 27989349 TI - Intravascular Papillary Endothelial Hyperplasia at Foot Level: A Case Report and Literature Review. AB - Intravascular papillary endothelial hyperplasia is a benign vascular lesion. Its importance lies in the differential diagnosis of malignant vascular neoplasms, such as angiosarcoma, to avoid unnecessary aggressive treatment. We present a case report on this type of tumor at the dorsal region of the foot to describe the pathogenic and histologic features of this lesion. PMID- 27989350 TI - Iatrogenic Arteriovenous Fistula With Associated Pseudoaneurysm of Posterior Tibial Artery After Revision Total Ankle Arthroplasty: A Case Report. AB - Iatrogenic vascular injuries in elective orthopedic surgery are rare. However, these are important complications to recognize early and treat appropriately because the potential sequelae can be devastating. Arteriovenous fistula of the lower extremity after total ankle arthroplasty has not been previously described in published studies. The proper diagnosis of arteriovenous fistulas can be difficult without a high index of suspicion, and treatment often involves surgical intervention. We present the case of a 62-year-old male who developed an iatrogenic arteriovenous fistula with associated pseudoaneurysm of the posterior tibial artery after revision total ankle arthroplasty that was treated with surgical ligation and excision, followed by reverse saphenous vein grafting. PMID- 27989351 TI - Occult Isolated Articular Branch Cyst of the Lateral Plantar Nerve. AB - We present the first known case of cyst fluid localized to an articular branch without involvement of the larger parent nerve. During a routine tarsal tunnel decompression in a patient with fluctuating plantar foot symptoms and "normal" magnetic resonance imaging findings, we identified cyst fluid within an articular branch of the lateral plantar nerve to the subtalar joint. Our incidental intraoperative discovery was corroborated by retrospective review of the magnetic resonance images. Although we do not know whether this cyst was responsible for the patient's complaints, we believe this finding represents a snapshot into the life cycle of intraneural ganglion cysts: either the "birth" of an ultra-early one or the remnant of a once larger one. Both interpretations are consistent with the unifying articular theory and add further insight into the dynamic phases of the progression of intraneural ganglion cysts. PMID- 27989352 TI - Reliability of Visual Estimation of the First Intermetatarsal Angle. AB - The size of the radiographic first intermetatarsal (IM) angle is one of the main considerations in selecting a surgical procedure for hallux abducto valgus. Instead of directly measuring the IM angle with a goniometer or a virtual measurement system, physicians will often estimate the size of the IM angle by direct visual estimation. The purpose of the present study was to determine the accuracy of visual estimation of the IM angle size compared with direct measurement. A total of 45 respondents, composed of students, residents, and attending physicians, reviewed a series of radiographs with IM angles varying from 6 degrees to 19 degrees . The attending physician visual estimates differed from the measured values by 3.28 degrees +/- 1.56 degrees . The interrater reliability, as determined by the intraclass correlation (ICC), increased with experience by group category: 0.426 (95% confidence interval 0.239 to 0.672) for students, 0.476 (95% confidence interval 0.290 to 0.710) for residents, and 0.656 (95% confidence interval 0.483 to 0.833) for attending physicians. Larger IM angles, defined as >10 degrees were less accurately estimated than were smaller IM angles (3.96 degrees +/- 1.60 degrees [n = 24] for larger IM angles and 3.14 degrees +/- 0.79 degrees [n = 21] for smaller IM angles; p = .0389). These results suggest caution when visually estimating IM angles, especially larger IM angles. Direct angle measurement might be more appropriate for surgical decision making. PMID- 27989353 TI - Nerve Transfer With Entubulated Nerve Allograft Transfers to Treat Recalcitrant Lower Extremity Neuromas. AB - Neuroma formation in the lower extremity can be debilitating to patients, especially when the neuromas are recurrent. The results of an advanced nerve reconstruction technique consisting of nerve transfer combined with nerve allograft and entubulation was evaluated in 4 patients with severe, debilitating, lower extremity neuromas. At a mean follow-up period of 26 months, the mean visual analog scale had improved from 9.5 preoperatively to 1.25 postoperatively (p < .05). These data suggest that techniques using a nerve allograft with a nerve conduit could be of great assistance in successfully managing debilitating neuromas of the lower extremity. Thus, further in-depth evaluation of these techniques is warranted. PMID- 27989355 TI - Knee, Shoulder, and Fundamentals of Arthroscopic Surgery Training: Validation of a Virtual Arthroscopy Simulator. AB - PURPOSE: To validate the knee, shoulder, and virtual Fundamentals of Arthroscopic Training (FAST) modules on a virtual arthroscopy simulator via correlations with arthroscopy case experience and postgraduate year. METHODS: Orthopaedic residents and faculty from one institution performed a standardized sequence of knee, shoulder, and FAST modules to evaluate baseline arthroscopy skills. Total operation time, camera path length, and composite total score (metric derived from multiple simulator measurements) were compared with case experience and postgraduate level. Values reported are Pearson r; alpha = 0.05. RESULTS: 35 orthopaedic residents (6 per postgraduate year), 2 fellows, and 3 faculty members (2 sports, 1 foot and ankle), including 30 male and 5 female residents, were voluntarily enrolled March to June 2015. Knee: training year correlated significantly with year-averaged knee composite score, r = 0.92, P = .004, 95% confidence interval (CI) = 0.84, 0.96; operation time, r = -0.92, P = .004, 95% CI = -0.96, -0.84; and camera path length, r = -0.97, P = .0004, 95% CI = -0.98, 0.93. Knee arthroscopy case experience correlated significantly with composite score, r = 0.58, P = .0008, 95% CI = 0.27, 0.77; operation time, r = -0.54, P = .002, 95% CI = -0.75, -0.22; and camera path length, r = -0.62, P = .0003, 95% CI = -0.8, -0.33. Shoulder: training year correlated strongly with average shoulder composite score, r = 0.90, P = .006, 95% CI = 0.81, 0.95; operation time, r = 0.94, P = .001, 95% CI = -0.97, -0.89; and camera path length, r = -0.89, P = .007, 95% CI = -0.95, -0.80. Shoulder arthroscopy case experience correlated significantly with average composite score, r = 0.52, P = .003, 95% CI = 0.2, 0.74; strongly with operation time, r = -0.62, P = .0002, 95% CI = -0.8, -0.33; and camera path length, r = -0.37, P = .044, 95% CI = -0.64, -0.01, by training year. FAST: training year correlated significantly with 3 combined FAST activity average composite scores, r = 0.81, P = .0279, 95% CI = 0.65, 0.90; operation times, r = -0.86, P = .012, 95% CI = -0.93, -0.74; and camera path lengths, r = 0.85, P = .015, 95% CI = -0.92, -0.72. Total arthroscopy cases performed did not correlate significantly with overall FAST performance. CONCLUSIONS: We found significant correlations between both training year and knee and shoulder arthroscopy experience when compared with performance as measured by composite score, camera path length, and operation time during a simulated diagnostic knee and shoulder arthroscopy, respectively. Three FAST activities demonstrated significant correlations with training year but not arthroscopy case experience as measured by composite score, camera path length, and operation time. CLINICAL RELEVANCE: We attempt to validate an arthroscopy simulator that could be used to supplement arthroscopy skills training for orthopaedic residents. PMID- 27989356 TI - Arthroscopic Revision Surgery for Failure of Open Latarjet Technique. AB - PURPOSE: To evaluate the efficacy in treating pain, limited range of motion, and continued instability of the Latarjet open technique via the use of arthroscopy. METHODS: A retrospective review of patients who underwent arthroscopic capsule plication after failure of an open Latarjet technique was performed. Revision surgery was indicated in cases of recurrent instability and associated pain. Only patients with a glenoid defect <25% were considered. The Constant and Rowe scores were administered, whereas pain was assessed with a visual analog scale before the reoperation and at 24 months after operation. Radiographs, computed tomography, and CT arthrography scans were performed. RESULTS: Twelve patients met the inclusion criteria. All patients had capsular distension and consequently were subjected to a capsuloplasty. Shoulder function, stability, and pain had all improved significantly at 24 months after arthroscopic revision (P < .0001). In particular, the Constant score increased from 44.9 (standard deviation [SD] 7.10) to 89.3 (SD 12.6) points, the Rowe score improved from 49.5 (SD 10.1) to 80.9 (SD 10.9), whereas the visual analog scale pain score decreased from 6.75 (SD 1.17) to 1.38 (SD 1.06). CONCLUSIONS: Primary open Latarjet with a glenoid bone defect <25% that failed due to capsular redundancy is amenable to successful treatment with arthroscopic capsuloplasty. CLINICAL RELEVANCE: Arthroscopic approaches can offer a good solution for treating previously failed open Latarjet procedures. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27989354 TI - Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. AB - BACKGROUND: Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE: To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS: The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died <= 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died <= 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS: Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY: Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age. PMID- 27989357 TI - Trigeminocardiac reflex. PMID- 27989358 TI - Preface. PMID- 27989359 TI - Complications in head and neck surgery. AB - Head and neck anatomy is topographically complex and the region is densely populated by vital nerves and vascular and lymphatic structures. Injury to many of these structures is associated with significant morbidity and may even be fatal. A thorough knowledge of regional anatomy is imperative and complications need to be managed in a thoughtful directed manner. The pediatric surgeon may be called upon to address both congenital and acquired conditions and should be prepared to encounter reoperative fields after failed initial surgery. This review summarizes the current literature on four frequently encountered surgical conditions of the head and neck: branchial cleft anomalies, thyroglossal duct cyst, thyroid disease, and lymphatic malformations, with a focus on the prevention and treatment of complications. PMID- 27989360 TI - Complications in neonatal surgery. AB - Neonatal surgery is recognized as an independent discipline in general surgery, requiring the expertise of pediatric surgeons to optimize outcomes in infants with surgical conditions. Survival following neonatal surgery has improved dramatically in the past 60 years. Improvements in pediatric surgical outcomes are in part attributable to improved understanding of neonatal physiology, specialized pediatric anesthesia, neonatal critical care including sophisticated cardiopulmonary support, utilization of parenteral nutrition and adjustments in fluid management, refinement of surgical technique, and advances in surgical technology including minimally invasive options. Nevertheless, short and long term complications following neonatal surgery continue to have profound and sometimes lasting effects on individual patients, families, and society. PMID- 27989361 TI - Complications in pediatric enteral and vascular access. AB - Obtaining reliable enteral and vascular access constitutes a significant fraction of a pediatric surgeon's job. Multiple approaches are available. Given the complicated nature of this patient population multiple complications can also occur. This article discusses the various techniques and potential complications associated with short- and long-term enteral and vascular access. PMID- 27989362 TI - Complications in colorectal surgery. AB - Colorectal pediatric surgery is a diverse field that encompasses many different procedures. The pullthrough for Hirschsprung disease, the posterior sagittal anorectoplasty for anorectal malformations including complex cloaca reconstructions and the ileal pouch anal anastomosis for ulcerative colitis and familial adenomatous polyposis present some of the most technically challenging procedures pediatric surgeons undertake. Many children prevail successfully following these surgical interventions, however, a small number of patients suffer from complications following these procedures. Anticipated postoperative problems are discussed along with medical and surgical strategies for managing these complications. PMID- 27989363 TI - Complications in pediatric hepatobiliary surgery. AB - This review highlights the complications and their risk factors encountered in pediatric hepatobiliary surgery, specifically in the context of pediatric hepatic resection, excision of choledochal cyst, and the Kasai hepatoportoenterostomy procedure for biliary atresia as well as other procedures potentially affecting the biliary tree. With the understanding that these are relatively rare procedures, case reports and small case series are included in addition to larger series when available. The review focuses on publications in English over the past 15 years. Complications included both surgery-specific pathology, such as biliary stricture after excision of choledochal cyst, and disease-specific entities, such as malnutrition in biliary atresia. This review may be useful when considering a particular procedure or in the discussion thereof with a patient and family. Additionally, it illuminates the need for additional work with larger patient databases to refine and expand our knowledge of these complications and precipitating risk factors. PMID- 27989364 TI - Complications in the surgical management of children with malignant solid tumors. AB - With improvement in the outcomes for children with cancer has come an increasing focus on minimizing the morbidity from therapeutic interventions, including surgical procedures, while continuing to have a high likelihood of cure. Thus, an appreciation for the potential complications of surgery, both acute and long term, is critical when considering the risks and benefits of any procedure performed on a child with cancer. Although not meant to be an exhaustive review, here we discuss the most common and significant surgical complications that may occur when performing diagnostic, therapeutic, or supportive procedures in children with the most common malignant solid tumors. PMID- 27989365 TI - Complications in common general pediatric surgery procedures. AB - Complications related to general pediatric surgery procedures are a major concern for pediatric surgeons and their patients. Although infrequent, when they occur the consequences can lead to significant morbidity and psychosocial stress. The purpose of this article is to discuss the common complications encountered during several common pediatric general surgery procedures including inguinal hernia repair (open and laparoscopic), umbilical hernia repair, laparoscopic pyloromyotomy, and laparoscopic appendectomy. PMID- 27989366 TI - Dental and Temporomandibular Joint Pathology of the American Black Bear (Ursus americanus). AB - Museum specimens (maxillae and/or mandibles) from 371 American black bears (Ursus americanus) acquired between 1889 and 2006 were examined macroscopically according to predefined criteria, and 348 were included in this study. Of the 348 specimens, 126 (36.2%) were from male animals, 106 (30.5%) were from female animals and 116 (33.3%) were from animals of unknown sex. Specimen ages ranged from young adult (n = 63, 18.1%) to adult (n = 285, 81.9%), with juveniles excluded from the study. The number of teeth available for examination was 12,019 (82.2%); 7.0% of teeth were absent artefactually, 0.4% were deemed absent due to acquired tooth loss and 9.7% were absent congenitally. In 43 specimens (12.3%), 82 teeth (0.68%) were small vestigial structures with crowns that were flush with the level of surrounding alveolar bone. The remaining teeth (99.3%) were of normal morphology. Only three supernumerary teeth and three instances of enamel hypoplasia were encountered. Persistent deciduous teeth or teeth with an aberrant number of roots were not encountered in any of the specimens. Approximately one third of the teeth examined (4,543, 37.8%) displayed attrition/abrasion, affecting nearly all of the specimens (n = 338, 97.1%). Incisor and molar teeth accounted for 52.5% and 34.3% of the affected teeth, respectively, with significantly more adults affected than young adults. Dental fractures were noted in 63 bears, affecting 18.1% of specimens and 1.0% of the total number of present teeth. The canine teeth were most often fractured, with adults having significantly more complicated crown fractures of these teeth than young adults. There were 11 specimens (3.2%) that displayed periapical lesions, affecting 12 (0.1%) dental alveoli. There were 179 specimens (51.4%) displaying bony changes indicative of periodontitis, affecting 816 (6.8%) dental alveoli. The proportion of adult bears affected by periodontitis (57.9%) was significantly greater than that of young adults (22.2%). Exactly half of the specimens (n = 174) possessed lesions consistent with mild temporomandibular joint osteoarthritis. The occurrence and severity of the dental pathology encountered in this study may play an important role in the morbidity and mortality of the American black bear. PMID- 27989367 TI - Structural and Computational Study of 4 New Solvatomorphs of Betulin: A Combined X-Ray, Hirshfeld Surface, and Thermal Analysis. AB - Four new solvatomorphs of betulin were reported and characterized by X-ray diffractometry as well as thermal and vibrational spectroscopic analyses. Single crystal X-ray diffraction was used to analyze the X-ray structures of the compounds and confirmed the stoichiometric ratio between the host and guest molecules from thermal data. Results indicated that solvatomorphism occurred in several betulin solvates. Changes in intermolecular arrangements, stoichiometry, and hydrogen-bonding interactions of solvatomorphs were due to solvent incorporation to solvates. Hirshfeld surface analyses, especially dnorm surface and fingerprint plots, were used to determine intermolecular interactions in the crystal network. Solvent molecules played an important role in the construction of a 3D architecture. The stabilities of these solvates were evaluated by thermal analyses. Nonisothermal kinetic analysis was used to explain the kinetics of solid-solid phase transition (desolvation) of betulin solvates. The apparent activation energies were evaluated using Kissinger and Ozawa methods. Moreover, phase transitions were visually investigated by hot-stage microscopic analysis. PMID- 27989368 TI - In Vitro Cellular Gene Delivery Employing a Novel Composite Material of Single Walled Carbon Nanotubes Associated With Designed Peptides With Pegylation. AB - Single-walled carbon nanotubes (SWCNTs) attract great interest in biomedical fields including application for drug delivery system. In this study, we developed a novel gene delivery system employing SWCNTs associated with polycationic and amphiphilic H-(-Lys-Trp-Lys-Gly-)7-OH [(KWKG)7] peptides having pegylation. SWCNTs wrapped with (KWKG)7 formed a complex with plasmid DNA (pDNA) in aqueous solution based on polyionic interaction but later underwent aggregation. On the other hand, a complex of pDNA and SWCNT-(KWKG)7 modified with polyethylene glycol (PEG) chains of 12 units [SWCNT-(KWKG)7-(PEG)12] afforded good dispersion stability for 24 h even in a cell culture medium. The in vitro cellular uptake of SWCNT-(KWKG)7-(PEG)12/pDNA complex prepared with fluorescence labeled pDNA was evaluated with fluorescent microscopic observation and flow cytometry. The uptake by A549 human lung adenocarcinoma epithelial cells increased along with the extent of pegylation, suggesting the importance of dispersion stability in addition to the cationic charge which facilitates ionic cellular interaction. The expression of pDNA encoding the monomeric Kusabira Orange 2 fluorescent protein in the form of the SWCNT-(KWKG)7-(PEG)12/pDNA complex demonstrated remarkable enhancement of transfection depending also on the extent of pegylation and the N/P ratio. The potential of the SWCNT composite wrapped with polycationic and amphiphilic (KWKG)7 with pegylation as a carrier for gene delivery was demonstrated. PMID- 27989369 TI - Study claims midwifery care harms babies: A critique of flawed research. PMID- 27989370 TI - Antiplasmodial dimeric chalcone derivatives from the roots of Uvaria siamensis. AB - Four dimeric chalcone derivatives, 8",9"-dihydrowelwitschin H, uvarins A-C, a naphthalene derivative, 2-hydroxy-3-methoxy-6-(4'- hydroxyphenyl)naphthalene, and the known dimeric chalcones, dependensin and welwitschin E, flavonoids, a cyclohexane oxide derivative, an aromatic aldehyde were isolated from the roots of Uvaria siamensis (Annonaceae). The structures of the compounds were elucidated by spectroscopic analysis, as well as by comparison with literature data. The isolated compounds with a sufficient amount for biological assays were evaluated for their antimalarial, antimycobacterial, and cytotoxic activities. The dimeric chalcones 8",9"-dihydrowelwitschin H, uvarins B and C, dependensin and welwitschin E showed strong antiplasmodial activity with IC50 values of 3.10, 3.02, 3.09, 4.21 and 3.99 MUg/mL, respectively. A possible biosynthesis pathway of the dimeric chalcones is discussed. PMID- 27989371 TI - Effects of high salinity from desalination brine on growth, photosynthesis, water relations and osmolyte concentrations of seagrass Posidonia australis. AB - Highly saline brines from desalination plants expose seagrass communities to salt stress. We examined effects of raised salinity (46 and 54psu) compared with seawater controls (37psu) over 6weeks on the seagrass, Posidonia australis, growing in tanks with the aim of separating effects of salinity from other potentially deleterious components of brine and determining appropriate bioindicators. Plants survived exposures of 2-4weeks at 54psu, the maximum salinity of brine released from a nearby desalination plant. Salinity significantly reduced maximum quantum yield of PSII (chlorophyll a fluorescence emissions). Leaf water potential (Psiw) and osmotic potential (Psipi) were more negative at increased salinity, while turgor pressure (Psip) was unaffected. Leaf concentrations of K+ and Ca2+ decreased, whereas concentrations of sugars (mainly sucrose) and amino acids increased. We recommend leaf osmolarity, ion, sugar and amino acid concentrations as bioindicators for salinity effects, associated with brine released in desalination plant outfalls. PMID- 27989372 TI - A 76-year-old woman with electrolyte abnormalities. PMID- 27989373 TI - Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia. AB - BACKGROUND: In cirrhotics with low circulating platelets (PLT), restoration of normal cell counts has been traditionally recommended before invasive procedures. However, there is neither consensus on the PLT transfusion threshold nor evidence of its clinical efficacy. PATIENTS: In order to fill this gap of knowledge, we prospectively collected and analyzed data on circulating PLT counts [and International Normalized Ratio (INR)] values in a case series of 363 cirrhotics scheduled to undergo invasive investigations. PLT and/or fresh-frozen plasma (FFP) units were infused at the discretion of the attending physician, and the occurrence of post-procedural bleeding was related to pre-and post-infusion results. RESULTS: 852 Procedures were carried out in 363 cirrhotics sub-grouped according to the Child-Pugh-Turcotte (CPT) classification (class A/B/C: 124/154/85). The infusion of PLT and/or FFP improved only marginally circulating PLT counts and INR values. Ten post-procedural bleeds occurred in the whole case series, i.e. 1 episode every 85 procedures or every 36 patients. Post-procedural bleeding was unrelated to the PLT counts, to the degree of INR abnormalities, nor to the CPT classes, but was more frequent in patients who underwent repeated investigations. In the 10 patients with the most profound alterations in PLT and/or INR values, no post-procedural bleeding occurred. CONCLUSIONS: In cirrhotic patients with low PLT and/or abnormal INR values undergoing invasive investigations, post-procedural bleeding was rare and unpredicted by PLT counts or abnormal INR values. In particular, the recommendation to infuse platelets when counts are <50*103/L is not substantiated by this case series of cirrhotic patients. PMID- 27989374 TI - Functional, quality of life, and neurodevelopmental outcomes after congenital cardiac surgery. AB - Throughout the past few decades, advances in cardiology, neonatal intensive care, and surgical techniques have resulted in a growing cohort of thriving school-aged children with previously lethal complex congenital heart diseases. While survival has increased, there remains significant morbidity following repair including neurodevelopmental sequelae. Compared to children with a structurally normal heart, these infants and children have a higher frequency of abnormalities in tone, feeding, and delayed developmental milestones, as well as challenges with speech and learning disabilities, while a higher proportion of adolescents suffer from problems with processing speed, executive function, and a unique set of medical hardships related to exercise intolerance and obesity, medication burden, and mental health comorbidities. Innovative perioperative techniques and early psychosocial intervention in these young survivors has shown that despite the obstacles, the majority of these children can grow to have fulfilling lives with intelligence and social skills in the normal range. Additionally, a comprehensive medical home aids in optimizing the quality of life for these children and their families. PMID- 27989375 TI - Con: Cardiothoracic Anesthesiologists Are Not Necessary for the Management of Patients With Ventricular Assist Devices Undergoing Noncardiac Surgery. PMID- 27989376 TI - Severe Tricuspid Valve Injury During Right Ventricular Lead Extraction. PMID- 27989377 TI - Commentary on: Implementing mechanical thrombectomy for acute ischaemic stroke in the UK. PMID- 27989378 TI - vanA-positive multi-drug-resistant Enterococcus spp. isolated from surfaces of a US hospital laundry facility. AB - BACKGROUND: Enterococcus spp. are a normal part of the gastrointestinal tract of humans and animals. They are also important pathogens, being responsible for 14% of US nosocomial infections from 2007 to 2010. AIM: To examine a laundry facility that processes clinical linens for the presence and seasonality of vancomycin resistant Enterococcus spp. METHODS: Surface samples were collected four times in 2015 from the dirty and clean areas of the laundry facility. Isolates were confirmed using biochemical assays, and antibiotic susceptibility testing was performed. Further investigations included molecular characterization by multi locus sequence typing (MLST), detection of acquired vanA and vanB and/or intrinsic vanC1 genes by polymerase chain reaction, and eBURST analysis. FINDINGS: Seventy-four vanA-positive multi-drug-resistant Enterococcus spp. were identified: 64/120 (53%) in the dirty area and 10/120 (8%) in the clean area. There were 14 ST types among the E. faecium isolates identified (ST16, 17, 18, 117, 186, 280, 324, 412, 584, 664, 665, 736, 750 and 1038). Both E. faecalis isolates were ST109. CONCLUSION: Isolation of vancomycin-resistant enterococci (VRE) isolates was significantly higher (53% vs 8%) in the dirty area of the facility compared with the clean area. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to examine an industrial laundry facility for the presence of VRE, and may be an unrecognized reservoir. PMID- 27989380 TI - Diagnosis and prognosis of acute on chronic liver failure (ACLF) in cirrhosis. PMID- 27989379 TI - Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study. AB - Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently. PMID- 27989381 TI - Dietary patterns at 4 years old: Association with appetite-related eating behaviours in 7 year-old children. AB - BACKGROUND & AIMS: A possible relationship between children's dietary intake and certain aspects of eating behaviours has been documented, but most studies are cross-sectional and do not consider the complexity of the diet. The aim of this study was to quantify the association between dietary patterns established at 4 years old and appetite-related eating behaviours identified at 7 years old. METHODS: Participants are children from the Generation XXI population-based birth cohort. Trained interviewers collected data at birth, 4 and 7 years old on socio demographics, health and lifestyles, and anthropometrics. At 4 years old, diet was assessed by a Food Frequency Questionnaire and three dietary patterns were identified by Latent Class Analysis: 'Healthier', 'Snacking' and 'Energy Dense Foods' (EDF). A Portuguese version of the original Children's Eating Behaviour Questionnaire (CEBQ) was self-completed by mothers at 7 year-old. This version has previously shown good psychometric properties and the 8 CEBQ sub-domains were combined into two wider dimensions: Appetite Restraint and Appetite Disinhibition. Generalized linear models were used to estimate the associations after adjustment for maternal characteristics (n = 4358). Interaction effects were tested. RESULTS: Children belonging to the 'Snacking' (beta = 0.329, 95%CI: 0.265; 0.393) and to the 'EDF' (beta = 0.138, 95%CI: 0.098; 0.179) dietary patterns at 4 years old scored increasingly higher, respectively, on Appetite Restraint and Appetite Disinhibition dimensions at 7 years old, comparatively to children in the 'Healthier' dietary pattern. Maternal BMI before pregnancy modified the 'Snacking' pattern associations; they were stronger in children from underweight/normal weight mothers for Appetite Restraint and present only among overweight/obese mothers for Appetite Disinhibition. CONCLUSIONS: This study suggests that children following less healthy dietary patterns early in life have more often disordered eating behaviours in later childhood. Maternal weight status may influence these associations. PMID- 27989382 TI - Ptosis. PMID- 27989383 TI - Dynamic property changes in stapedial annular ligament associated with acute otitis media in the chinchilla. AB - Located at the end of the ossicular chain, the stapedial annular ligament (SAL) serves as a closed yet mobile boundary between the cochlear fluid and stapes footplate. It is unclear how SAL properties change with acute otitis media (AOM). This paper reports the measurements of SAL dynamic properties in chinchilla AOM model using dynamic mechanical analyzer (DMA) and frequency-temperature superposition (FTS) principle. AOM was analyzed in two infection groups: 4 days (4D) and 8 days (8D) post induction. SAL specimens were measured using DMA at three temperatures: 5, 25, and 37 degrees C. To extend the testing frequencies to higher levels, FTS principle was employed. Then generalized Maxwell model was utilized to define the constitutive equations of the SAL. The complex shear moduli were obtained from seven samples of control, 4D, and 8D groups. Results show that the storage and loss shear moduli of SALs decreased due to AOM. The storage moduli for 4D and 8D ears were similar below 100Hz, and the loss modulus for 4D was significantly larger than 8D across the entire frequency range. This study reports data that contributes to ear biomechanics and improves understanding on the effects of AOM in middle ear tissues. PMID- 27989384 TI - Evaluation of predicted knee function for component malrotation in total knee arthroplasty. AB - Soft-tissue balancing for total knee arthroplasty (TKA) remains subjective and highly dependent on surgical expertise. Pre-operative planning may support the clinician in taking decisions by integrating subject-specific computer models that predict functional outcome. However, validation of these models is essential before they can be applied in clinical practice. The aim of this study was to evaluate a knee modelling workflow by comparing experimental cadaveric measures to model-based kinematics and ligament length changes. Subject-specific models for three cadaveric knees were constructed from medical images. The implanted knees were mounted onto a mechanical rig to perform squatting, measuring kinematics and ligament length changes with optical markers and extensometers. Coronal malrotation was introduced using tibial inserts with a built-in slope. The model output agreed well with the experiment in all alignment conditions. Kinematic behaviour showed an average RMSE of less than 2.7mm and 2.3 degrees for translations and rotations. The average RMSE was below 2.5% for all ligaments. These results show that the presented model can quantitatively predict subject-specific knee behaviour following TKA, allowing evaluation of implant alignment in terms of kinematics and ligament length changes. In future work, the model will be used to evaluate subject-specific implant position based on ligament behaviour. PMID- 27989385 TI - Cannabis and epilepsy: An ancient treatment returns to the fore. AB - Cannabis has been associated with the treatment of epilepsy throughout history, and if ancient Assyrian sources referring to "hand of ghost" are considered credible, this relationship may span four millennia. A tradition of usage continued in Arabic medicine and Ayurvedic practice in India, which led, in turn, to early experiments in Europe and North America with "Indian hemp." Lack of standardization, bioavailability issues, and ultimately prohibition were all factors in cannabis-based medicines failing to maintain mainstream usage in seizure treatment, but investigation was resumed in the 1970s with interesting signals noted in both laboratory and clinical settings. Early case studies showed promise, but lacked sufficient rigor. Resumption of research coupled with mass experimentation by families of epilepsy patients has led to intense interest in cannabis-based medicines for its treatment once more, with greatest focus on cannabidiol, but additional investigation of tetrahydrocannabinol, tetrahydrocannabinolic acid, and other phytocannabinoids. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy". PMID- 27989386 TI - Halogenated flame retardants in bobcats from the midwestern United States. AB - In response to the restrictions of polybrominated diphenyl ether (PBDE) flame retardants in various consumer products, alternative halogenated flame retardants have been subjected to increased use. Compared to aquatic ecosystems, relatively little information is available on the contamination of alternative flame retardants in terrestrial ecosystems, especially with regards to mammalian wildlife. In this study we used a top terrestrial carnivore, the bobcat (Lynx rufus), as a unique biomonitoring species for assessing flame retardant contamination in the Midwestern United States (U.S.) terrestrial ecosystems. Concentrations of ?PBDEs (including all detectable PBDE congeners) ranged from 8.3 to 1920 ng/g lipid weight (median: 50.3 ng/g lw) in livers from 44 bobcats collected during 2013-2014 in Illinois. Among a variety of alternative flame retardants screened, Dechloranes (including anti- and syn-Dechlorane Plus and Dechlorane-602, 603, and 604), tetrabromo-o-chlorotoluene (TBCT), and hexabromocyclododecane (HBCD) were also frequently detected, with median concentrations of 28.7, 5.2, and 11.8 ng/g lw, respectively. Dechlorane analogue compositions in bobcats were different from what has been reported in other studies, suggesting species- or analogue-dependent bioaccumulation, biomagnification, or metabolism of Dechlorane chemicals in different food webs. Our findings, along with previously reported food web models, suggest Dechloranes may possess substantial bioaccumulation and biomagnification potencies in terrestrial mammalian food webs. Thus, attention should be given to these highly bioavailable flame retardants in future environmental biomonitoring and risk assessments in a post-PBDE era. PMID- 27989387 TI - Alteration in successional trajectories of bacterioplankton communities in response to co-exposure of cadmium and phenanthrene in coastal water microcosms. AB - Coexistence of heavy metals and organic contaminants in coastal ecosystems may lead to complicated circumstances in ecotoxicological assessment for biological communities due to potential interactions of contaminants. Consequences of metals and polycyclic aromatic hydrocarbons (PAHs) co-contamination on coastal marine microbes at the community level were paid less attention. We chose cadmium (Cd) and phenanthrene (PHE) as representatives of metals and PAHs, respectively, and mimicked contaminations using coastal water microcosms spiked with Cd (1 mg/L), PHE (1 mg/L), and their mixture over two weeks. 16S rRNA gene amplicon sequencing was used to compare individual and cumulative effects of Cd and PHE on temporal succession of bacterioplankton communities. Although we found dramatic impacts of dimethylsulfoxide (DMSO, used as a carrier solvent for PHE) on bacterial alpha diversity and composition, the individual and cumulative effects of Cd and PHE on bacterial alpha-diversity were temporally variable showing an antagonistic pattern at early stage in the presence of DMSO. Temporal succession of bacterial community composition (BCC) was associated with temporal variability of water physicochemical parameters, each of which explained more variation in BCC than two target contaminants did. However, Cd, PHE, and their mixture distinctly altered the successional trajectories of BCC, while only the effect of Cd was retained at the end of experiment, suggesting certain resilience in BCC after the complete dissipation of PHE along the temporal trajectory. Moreover, bacterial assemblages at the genus level associated with the target contaminants were highly time-dependent and more unpredictable in the co-contamination group, in which some genera possessing hydrocarbon-degrading members might contribute to PHE degradation. These results provide preliminary insights into how co-exposure of Cd and PHE phylogenetically alters successional trajectories of bacterioplankton communities in the manipulated coastal water microcosms. PMID- 27989388 TI - A first overview of textile fibers, including microplastics, in indoor and outdoor environments. AB - Studies about microplastics in various environments highlighted the ubiquity of anthropogenic fibers. As a follow-up of a recent study that emphasized the presence of man-made fibers in atmospheric fallout, this study is the first one to investigate fibers in indoor and outdoor air. Three different indoor sites were considered: two private apartments and one office. In parallel, the outdoor air was sampled in one site. The deposition rate of the fibers and their concentration in settled dust collected from vacuum cleaner bags were also estimated. Overall, indoor concentrations ranged between 1.0 and 60.0 fibers/m3. Outdoor concentrations are significantly lower as they range between 0.3 and 1.5 fibers/m3. The deposition rate of the fibers in indoor environments is between 1586 and 11,130 fibers/day/m2 leading to an accumulation of fibers in settled dust (190-670 fibers/mg). Regarding fiber type, 67% of the analyzed fibers in indoor environments are made of natural material, primarily cellulosic, while the remaining 33% fibers contain petrochemicals with polypropylene being predominant. Such fibers are observed in marine and continental studies dealing with microplastics. The observed fibers are supposedly too large to be inhaled but the exposure may occur through dust ingestion, particularly for young children. PMID- 27989389 TI - An environmental index of noise and light pollution at EU by spatial correlation of quiet and unlit areas. AB - Quietness exists in places without human induced noise sources and could offer multiple benefits to citizens. Unlit areas are sites free of human intense interference at night time. The aim of this research is to develop an integrated environmental index of noise and light pollution. In order to achieve this goal the spatial pattern of quietness and darkness of Europe was identified, as well as their overlap. The environmental index revealed that the spatial patterns of Quiet and Unlit Areas differ to a great extent highlighting the importance of preserving quietness as well as darkness in EU. The spatial overlap of these two environmental characteristics covers 32.06% of EU surface area, which could be considered a feasible threshold for protection. This diurnal and nocturnal metric of environmental quality accompanied with all direct and indirect benefits to human well-being could indicate a target for environmental protection in the EU policy and practices. PMID- 27989390 TI - Blood cell responses and metallothionein in the liver, kidney and muscles of bullfrog tadpoles, Lithobates catesbeianus, following exposure to different metals. AB - The hematological parameters and metallothionein (MT) levels in the liver, kidney and muscles were measured in bullfrog tadpoles, Lithobates catesbeianus, following exposures to 1 MUg L-1 of zinc (Zn), copper (Cu) and cadmium (Cd) alone or in combination (1:1 and 1:1:1) for 2 and 16 days. Metal accumulation occurred in all organs, with the highest values found in the kidney, followed by the muscles and liver. After exposure to isolated metals, the accumulation was in the following order: Cd > Zn > Cu in the liver and muscles and Cd > Cu > Zn in the kidney. Exposure to combined metals (Zn + Cu, Zn + Cd, Cu + Cd and Zn + Cu + Cd) revealed complex responses, such as metal accumulation increased or decreased over the exposure periods, suggesting possible competion at the uptake sites and/or metabolization and elimination processes in each organ. The MT concentration increased in the organs of tadpoles following metal exposure alone, mainly in the liver, for both periods. After the combined exposures, the MT levels were higher in the liver and muscles at 16 days, suggesting that the interaction between metals was additive, and the level was decreased in the kidney after 2 and 16 days of exposure. The whole blood hemoglobin content (Hb), red blood cell count (RBCs) and mean corpuscular hemoglobin (MCH) differed from the control groups after 2 and 16 days of exposure, showing changes in the improvement of oxygen transport. The number of lymphocytes increased, and the levels of neutrophils, eosinophils, basophils and monocytes were reduced after exposure to the metals. The changes in blood cells suggested that tadpoles have a mechanism to improve oxygen transport probably because of the increased oxygen demand and a general reduction in defense cells. The exposure of L. catesbeianus to metals during the larval phase can generate long-term dysfunction to a degree, which could lead to alterations in their health status. PMID- 27989391 TI - [Medical anthropology consultations for refugees: Why are they necessary?] PMID- 27989392 TI - [Cutaneous involvement in plasma cell leukaemia]. PMID- 27989393 TI - Radiotelemetric EEG recordings in mice - Critical role of transmitter bandwidth and nominal sampling rate in frequency analysis. PMID- 27989394 TI - Combined Functional Voice Therapy in Singers With Muscle Tension Dysphonia in Singing. AB - OBJECTIVES: The purpose of this study was to evaluate vocal tract function and the voice quality in singers with muscle tension dysphonia (MTD) after undergoing combined functional voice therapy of the singing voice. DESIGN: This is a prospective, randomized study. METHODS: Forty singers (29 females and 11 males, mean age: 24.6 +/- 8.8 years) with MTD were enrolled in the study. The study group consisted of 20 singers who underwent combined functional voice therapy (10 15 individual sessions, 30-40 minutes each). Singers who did not opt for vocal rehabilitation consisted of the control group. Effects of rehabilitation were assessed with videolaryngostroboscopy, palpation of the vocal tract structures, flexible fiberoptic evaluation of the pharynx and the larynx, perceptual speaking and singing voice assessment, acoustic analysis, maximal phonation time, and the Voice Handicap Index. RESULTS: After combined functional voice therapy in the study group, great improvement was noticed in palpation of the vocal tract structures (P < 0.001), perceptual voice assessment (P < 0.001), phonetograms (P = 0.002), and singing range obtained from acoustic analysis of glissando (P < 0.001). In the control group, no statistically significant differences were found between the first and the second assessments. CONCLUSIONS: Combined functional voice therapy proved to be an efficacious treatment method in singers with MTD in singing. Development of palpation and perceptual singing voice examination protocols enables one to compare results before and after rehabilitation in clinics. PMID- 27989395 TI - Sex Hormone Receptor Expression in the Human Vocal Fold Subunits. AB - OBJECTIVE: The study aimed to evaluate the existence of sex hormone receptors in the subunits of vocal fold. STUDY DESIGN: This is a cadaver study. METHODS: The androgen, estrogen, and progesterone receptors were examined in the epithelium (EP), superficial layer of the lamina propria (SLP), vocal ligament (VL), and macula flava (MF) of the vocal folds from 42 human cadavers (21 male, 21 female) by immunohistochemical methods. Their staining ratios were scored and statistically compared. RESULTS: The androgen receptor score was significantly higher for the MF than for the EP and SLP (P < 0.001 and P = 0.001, respectively). The androgen receptor score was significantly higher for the VL than for the EP and SLP (P < 0.001 and P = 0.001, respectively). No significant difference was noted in the androgen receptor scores between the MF and VL and between the EP and SLP. The estrogen receptor score showed no significant difference between the MF and VL, whereas all other areas showed statistically significant differences (P < 0.001). No significant differences were observed between the EP and SLP in terms of progesterone receptor scores, but statistically significant differences were detected among the other areas. CONCLUSION: Sex hormone receptors exist within several subunits of the vocal fold, mostly in the MF and VLs. PMID- 27989396 TI - Oral Feeding Outcome in Infants with a Tracheostomy. AB - PURPOSE: Currently, there is a lack of evidence-based guidelines on the proper protocol for feeding infants with a tracheostomy in the neonatal intensive care unit (NICU). The purpose of this study was to provide preliminary insight into the outcomes of these infants in one mid-Atlantic pediatric hospital. DESIGN AND METHODS: Retrospective and descriptive. The study team reviewed 114 patient records, 42 of which met the inclusion criteria. Data were organized based on: 1) general demographics and history; b) feeding-related variables at multiple points; c) speech-related variables, including assessments and swallowing studies; d) respiratory variables at multiple points; and, e) discharge data. Other variables included birth-related information, ventilation settings and feeding modifications. RESULTS: Infants were placed into three groups at discharge based on feeding outcomes. Forty-three percent were discharged on full oral feeds, 38% on combined oral and gavage, and 19% of infants were discharged on full gavage feeds. Informal analysis showed that all three categories of infants gained weight during hospitalization, different PEEP pressures and different lengths of hospitalization were observed among the groups, and infant characteristics (e.g., APGAR, gestational ages) were similar across groups. CONCLUSIONS: Overall results provide insight into factors that may be predictive of feeding status at discharge for infants with a tracheostomy in an NICU. PRACTICAL IMPLICATIONS: Results of this study can provide important insight into the feeding outcomes of infants in a NICU with a tracheostomy and can hopefully lead to additional research to help determine the most efficacious procedures for feeding this patient population. PMID- 27989397 TI - Masticatory function parameters in patients with varying degree of mandibular bone resorption. AB - PURPOSE: This cross-sectional study analyzes how bone resorption affects the masticatory function and investigates the relation between perceived and measured masticatory function. METHODS: Thirty complete dentures wearers were divided in two groups according to mandible bone atrophy based on the classification criteria from Cawood & Howell. Retention and stability of the mandibular complete denture, masticatory performance (MP) indexes (X_50 and B) and masticatory efficiency (ME, sieves 4 and 2.8) were evaluated. Geriatric Oral Health Assessment Index (GOHAI) and Dental Impact on Daily Living (DIDL) questionnaires were completed by the patients. RESULTS: A strong correlation between bone atrophy and poor retention was found (P=0.0132). Neither masticatory performance indexes nor GOHAI and DIDL domains showed statistical differences (P>0.05) when patients were compared according to the atrophy criteria. Mandibular length showed a negative correlation with ME4, showing a positive association (R2=0.17, beta=-0.67, P=0.029). Mandibular denture retention was significantly correlated with MPB (P=0.01) and ME2.8 (P=0.01). GOHAI showed a positive association between the physical and the functional domains and ME2.8 (R2=0.17; beta=1.22; P=0.02). DIDL showed a negative association between ME4 and oral comfort domain (R2=0.16; beta=-2.94; P=0.02). CONCLUSION: Mandibular bone height does not directly affect the masticatory function and is inversely correlated with the self-perceived masticatory ability. PMID- 27989398 TI - Generating high quality evidence in palliative and end-of-life care. PMID- 27989400 TI - Heart and lung leadership article. PMID- 27989399 TI - The long term impact of an end-of-life communication intervention among veterans with COPD. AB - OBJECTIVE: To assess if an end-of-life communication intervention with patients with COPD led to higher long-term documentation of advance care planning discussions at the end-of-life. BACKGROUND: We previously demonstrated that providing clinicians a patient-specific feedback form about patients' communication preferences improved the occurrence and quality of clinician communication about end-of-life care. METHODS: Among those individuals enrolled in the intervention study (2004-2007) who had died during the follow-up period (up to 2013), we assessed if patients in the intervention arm had more goals of care discussions and formal advance directives completed as compared to controls. We conducted logistic models accounting for provider level clustering, adjusting for age, FEV1, and race. RESULTS: Among the 376 patients in the study, 157 died (76 in the intervention arm, 81 in the control arm). Over an average duration of 3.6 years (from the time of the first study appointment to death), 115 (73%) patients engaged in 451 unique end-of-life care discussions. The intervention was not associated with a higher percentage of patients with documented end-of-life conversations (I:C 75% vs 72%, p = 0.63) or completion of advance care directives (26% vs 29%, p = 0.55). CONCLUSIONS: Despite initially improving the occurrence of end-of-life conversations, the intervention did not increase the documentation of subsequent conversations about end-of-life care, nor did it improve documentation of advance directives. Future research should focus on testing multi-faceted, longitudinal, system-level interventions to enhance conversations about goals of care that promote goal-concurrent care. PMID- 27989401 TI - CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation. AB - Lysine acetylation is becoming increasingly recognized as a general biological principle in cellular homeostasis, and is subject to abnormal control in different human pathologies. Here, we describe a global effect on amyloid-like protein aggregation in human cells that results from aberrant lysine acetylation. Bromodomain reader proteins are involved in the aggregation process and, using chemical biology and gene silencing, we establish that p300/CBP bromodomains are necessary for aggregation to occur. Moreover, protein aggregation disturbs proteostasis by impairing the ubiquitin proteasome system (UPS) and protein translation, resulting in decreased cell viability. p300/CBP bromodomain inhibitors impede aggregation, which coincides with enhanced UPS function and increased cell viability. Aggregation of a pathologically relevant form of huntingtin protein is similarly affected by p300/CBP inhibition. Our results have implications for understanding the molecular basis of protein aggregation, and highlight the possibility of treating amyloid-like pathologies and related protein folding diseases with bromodomain inhibitor-based strategies. PMID- 27989402 TI - Dynamic CT imaging of volumetric changes in pulmonary nodules correlates with physical measurements of stiffness. AB - BACKGROUND AND PURPOSE: A major challenge in CT screening for lung cancer is limited specificity when distinguishing between malignant and non-malignant pulmonary nodules (PN). Malignant nodules have different mechanical properties and tissue characteristics ('stiffness') from non-malignant nodules. This study seeks to improve CT specificity by demonstrating in rats that measurements of volumetric ratios in PNs with varying composition can be determined by respiratory-gated dynamic CT imaging and that these ratios correlate with direct physical measurements of PN stiffness. METHODS AND MATERIALS: Respiratory-gated MicroCT images acquired at extreme tidal volumes of 9 rats with PNs from talc, matrigel and A549 human lung carcinoma were analyzed and their volumetric ratios (delta) derived. PN stiffness was determined by measuring the Young's modulus using atomic force microscopy (AFM) for each nodule excised immediately after MicroCT imaging. RESULTS: There was significant correlation (p=0.0002) between PN volumetric ratios determined by respiratory-gated CT imaging and the physical stiffness of the PNs determined from AFM measurements. CONCLUSION: We demonstrated proof of concept that PN volume changes measured non-invasively correlate with direct physical measurements of stiffness. These results may translate clinically into a means of improving the specificity of CT screening for lung cancer and/or improving individual prognostic assessments based on lung tumor stiffness. PMID- 27989403 TI - [Speaking about life and death in neonatology: How can communication with families be optimized?] AB - Technological progress and improved clinical knowledge have increased survival of neonates who would previously have died. Survival is sometimes accompanied by a risk of short- or long-term adverse outcomes, which may lead to complex decisions about withholding or withdrawing life-sustaining interventions. These decisions are among the most difficult decisions in pediatric practice. They also involve communicating with parents and are emotionally charged. Many articles examining end-of-life decisions in neonatology state the need for healthcare providers to be caring, compassionate, and human without offering clear, practical advice. In this article, the way in which neonates die and the ethical decision-making surrounding these decisions will be reviewed. Guidelines to reflect on the life trajectories of neonates will be offered, as well as recommendations to optimize communication with families during these difficult moments. PMID- 27989404 TI - Nailfold capillaroscopic parameters and skin telangiectasia patterns in patients with systemic sclerosis. AB - OBJECTIVE: To correlate nailfold capillaroscopic parameters with the presence of skin telangiectases (TAs) in systemic sclerosis patients (SSc). METHODS: Thirty three consecutive patients (28 women and 5 men, mean age 59+/-21years) affected by SSc according to the ACR/EULAR criteria, 30 with limited (lcSSc) and 3 with diffuse (dcSSc) skin disease, displaying the presence of skin TAs on face, hands, forearms, neck, and decollete were recruited. Nailfold videocapillaroscopy (NVC) was performed to classify the patients into one of the three main patterns of SSc microangiopathy ("early", "active", "late"), and to calculate the microangiopathy evolution score (MES). SSc patients underwent also dermoscopy (DS) for the analysis of the TA score and patterns (spot or reticular). Possible correlations between clinical findings, serum autoantibodies, TA patterns and both NVC patterns and MES were investigated. RESULTS: The "late" NVC pattern was found associated with a highest total number of TAs (p=0.005): in particular both "spot" and "reticular" TA patterns were found equally distributed in SSc patients with the "late" pattern. High MES values were found associated with the highest total number of TAs (p=0.003), with the "reticular" but not with the "spot" DS pattern (p=0.003) and with the "late" pattern of microangiopathy (p=0.001). CONCLUSIONS: The severity of nailfold microangiopathy seems to correlate in SSc patients with both progressive cutaneous microvascular abnormalities and Medsger's severity score, as evaluated by NVC analysis and DS. The assessment of the microvascular damage may be useful not only during the onset of SSc for the early diagnosis, but also to monitor its evolution. PMID- 27989405 TI - Aberrant default mode network homogeneity in patients with first-episode treatment-naive melancholic depression. AB - BACKGROUND: Melancholic depression is a relatively homogenous subtype of major depressive disorders (MDD). The condition has several endogenous symptoms and represents strong biological components. However, its specific neurobiological mechanisms remain unknown. Previous neuroimaging findings indicated that default mode network (DMN) is closely related to MDD. The present study examined the network homogeneity (NH) of the DMN in patients with melancholic MDD. METHODS: A total of 33 first-episode, treatment-naive melancholic MDD patients and 32 healthy controls underwent a resting-state functional magnetic resonance imaging scan. The data were analyzed using the NH method. RESULTS: Compared with healthy controls, patients with melancholic MDD showed low NH values in the right middle temporal gyrus and temporal pole (MTG/TP). The abnormal NH of this region and clinical characteristics were not correlated. CONCLUSION: Abnormal NH pattern of DMN exists in patients with melancholic MDD. This feature may be part of the pathophysiological basis of this disorder. PMID- 27989406 TI - Features of Heart Rate Variability Capture Regulatory Changes During Kangaroo Care in Preterm Infants. AB - OBJECTIVE: To determine whether heart rate variability (HRV) can serve as a surrogate measure to track regulatory changes during kangaroo care, a period of parental coregulation distinct from regulation within the incubator. STUDY DESIGN: Nurses annotated the starting and ending times of kangaroo care for 3 months. The pre-kangaroo care, during-kangaroo care, and post-kangaroo care data were retrieved in infants with at least 10 accurately annotated kangaroo care sessions. Eight HRV features (5 in the time domain and 3 in the frequency domain) were used to visually and statistically compare the pre-kangaroo care and during kangaroo care periods. Two of these features, capturing the percentage of heart rate decelerations and the extent of heart rate decelerations, were newly developed for preterm infants. RESULTS: A total of 191 kangaroo care sessions were investigated in 11 preterm infants. Despite clinically irrelevant changes in vital signs, 6 of the 8 HRV features (SD of normal-to-normal intervals, root mean square of the SD, percentage of consecutive normal-to-normal intervals that differ by >50 ms, SD of heart rate decelerations, high-frequency power, and low frequency/high-frequency ratio) showed a visible and statistically significant difference (P <.01) between stable periods of kangaroo care and pre-kangaroo care. HRV was reduced during kangaroo care owing to a decrease in the extent of transient heart rate decelerations. CONCLUSION: HRV-based features may be clinically useful for capturing the dynamic changes in autonomic regulation in response to kangaroo care and other changes in environment and state. PMID- 27989407 TI - Family-Based Smoking Cessation Intervention for Smoking Fathers and Nonsmoking Mothers with a Child: A Randomized Controlled Trial. AB - OBJECTIVE: To examine whether a family-based intervention targeting both smoking fathers and nonsmoking mothers in well-child health clinics is effective in increasing fathers' abstinence from cigarette smoking. STUDY DESIGN: This parallel 2-arm randomized controlled trial recruited a total of 1158 families with a daily-smoking father, a nonsmoking mother, and a child aged 0-18 months from the 22 maternal and child health centers in Hong Kong. The intervention group received the family-based intervention, including 6 nurse-led individual face-to-face and telephone counseling sessions within 1 month after recruitment and a voluntary face-to-face family counseling session (FCS). The control group received a leaflet, a self-help booklet, and brief quitting advice only. Father reported 7-day and 6-month abstinence, smoking reduction, quit attempts, mother reported help and support, and child salivary cotinine level were assessed at 12 months. Generalized estimating equation models were used to compare these outcomes between the 2 study groups. RESULTS: Compared with the control group, the intervention group reported a greater prevalence of 7-day (13.7% vs 8.0%; OR, 1.92; 95% CI, 1.16-3.17; P < .01) and 6-month self-reported abstinence (13.4% vs. 7.5%; OR, 2.10; 95% CI, 1.30-3.40; P < .01). Within the intervention group, compared with receipt of individual counseling only, participation in the FCS was associated with increases in fathers' self-reported abstinence (20.2% vs 12.3%; P = .02), mothers' help (66.1% vs 43.8%; P < .01), and support to the fathers (55.0% vs 45.4%; P < .01). CONCLUSIONS: The family-based smoking cessation intervention for the families in the well-child healthcare setting was effective in increasing the fathers' self-reported abstinence. Additional participation in the FCS increased mothers' help and support to the fathers. TRIAL REGISTRATION: Controlled-trials.com: ISRCTN99111655; Hkuctr.com: HKUCTR-465. PMID- 27989408 TI - Estimating Premium and Out-of-Pocket Outlays Under All Child Dental Coverage Options in the Federally Facilitated Marketplace. AB - OBJECTIVE: To estimate premium and out-of-pocket costs for child dental care services under various dental coverage options offered within the federally facilitated marketplace. STUDY DESIGN: We estimated premium and out-of-pocket costs for child dental care services for 12 patient profiles, which vary by dental care use and spending. We did this for 1039 medical plans that include child dental coverage, 2703 medical plans that do not include child dental coverage, and 583 stand-alone dental plans for the 2015 plan year. Our analysis is based on plan data from the Center for Consumer Information and Insurance Oversight and Data.HealthCare.Gov. RESULTS: On average, expected total financial outlays for child dental care services were lower when dental coverage was embedded within a medical plan compared with the alternative of a stand-alone dental plan. The difference, however, in average expected out-of-pocket spending varied significantly for our 12 patient profiles. Older children who are very high users of dental care, for example, have lower expected out-of-pocket costs under a stand-alone dental plan. For the vast majority of other age groups and dental care use profiles, the reverse holds. CONCLUSIONS: Our results show that embedding dental coverage within medical plans, on average, results in lower total financial outlays for child beneficiaries. Although our results are specific to the federally facilitated marketplace, they hold lessons for both state-based marketplaces and the general private health insurance and dental benefits market, as well. PMID- 27989410 TI - Reply. PMID- 27989409 TI - The Burden of Ionizing Radiation Studies in Children with Ventricular Shunts. AB - OBJECTIVES: To quantify the number of shunt-related imaging studies that patients with ventricular shunts undergo and to calculate the proportion of computed tomography (CT) scans associated with a surgical intervention. STUDY DESIGN: Retrospective longitudinal cohort analysis of patients up to age 22 years with a shunt placed January 2002 through December 2003 at a pediatric hospital. Primary outcome was the number of head CT scans, shunt series radiograph, skull radiographs, nuclear medicine, and brain magnetic resonance imaging studies for 10 years following shunt placement. Secondary outcome was surgical interventions performed within 7 days of a head CT. Descriptive statistics were used for analysis. RESULTS: Patients (n = 130) followed over 10 years comprised the study cohort. The most common reasons for shunt placement were congenital hydrocephalus (30%), obstructive hydrocephalus (19%), and atraumatic hemorrhage (18%), and 97% of shunts were ventriculoperitoneal. Patients underwent a median of 8.5 head CTs, 3.0 shunt series radiographs, 1.0 skull radiographs, 0 nuclear medicine studies, and 1.0 brain magnetic resonance imaging scans over the 10 years following shunt placement. The frequency of head CT scans was greatest in the first year after shunt placement (median 2.0 CTs). Of 1411 head CTs in the cohort, 237 resulted in surgical intervention within 7 days (17%, 95% CI 15%-19%). CONCLUSIONS: Children with ventricular shunts have been exposed to large numbers of imaging studies that deliver radiation and most do not result in a surgical procedure. This suggests a need to improve the process of evaluating for ventricular shunt malfunction and minimize radiation exposure. PMID- 27989411 TI - Changes in Gustatory Function and Taste Preference Following Weight Loss. AB - OBJECTIVE: To investigate taste changes of obese children during an inpatient weight reduction treatment in comparison with normal weight children. STUDY DESIGN: Obese (n = 60) and normal weight (n = 27) children aged 9-17 years were assessed for gustatory functions using taste strips (taste identification test for the taste qualities sour, salty, sweet, and bitter), taste preferences, and experienced taste sensitivity. Obese children were examined upon admission (T1) and before discharge (T2). Normal weight children served as the control group. RESULTS: Irrespective of taste quality, obese children exhibited a lower ability to identify taste (total taste score) than normal weight children (P < .01); this overall score remained stable during inpatient treatment in obese children. Group and treatment effects were seen when evaluating individual taste qualities. In comparison with normal weight children, obese children exhibited poorer sour taste identification performance (P < .01). Obese children showed improvement in sour taste identification (P < .001) and deterioration in sweet taste identification (P < .001) following treatment. Subjective reports revealed a lower preference for sour taste in obese children compared with normal weight children (P < .05). The sweet and bitter taste ability at T1 predicted the body mass index z score at T2 (R2 = .23, P < .01). CONCLUSIONS: We identified differences in the ability to discriminate tastes and in subjective taste perception between groups. Our findings of increased sour and reduced sweet taste discrimination after the intervention in obese children are indicative of an exposure-related effect on taste performance, possibly mediated by increased acid and reduced sugar consumption during the intervention. Because the sweet and bitter taste ability at T1 predicted weight loss, addressing gustatory function could be relevant in individualized obesity treatment approaches. TRIAL REGISTRATION: Germanctr.de: DRKS00005122. PMID- 27989412 TI - A Retrospective Analysis of the Utility of Head Computed Tomography and/or Magnetic Resonance Imaging in the Management of Benign Macrocrania. AB - OBJECTIVE: To assess whether computed tomography (CT), magnetic resonance imaging (MRI), and neurosurgical evaluations altered the diagnosis or management of children diagnosed with benign macrocrania of infancy by ultrasonography (US). STUDY DESIGN: We queried our radiology database to identify patients diagnosed with benign macrocrania of infancy by US between 2006 and 2013. Medical records of those with follow-up CT/MRI were reviewed to determine clinical/neurologic status and whether or not CT/MRI imaging resulted in diagnosis of communicating hydrocephalus or required neurosurgical intervention. RESULTS: Patients with benign macrocrania of infancy (n = 466) were identified (mean age at diagnosis: 6.5 months). Eighty-four patients (18.0%) received subsequent head CT/MRI; of these, 10 patients had neurologic abnormalities before 2 years of age, of which 3 had significant findings on MRI (temporal lobe white matter changes, dysmorphic ventricles, thinned corpus callosum). One patient without neurologic abnormalities had nonspecific white matter signal abnormality (stable over 6 months) but no change in management. None required neurosurgical intervention. Another 9/84 patients had incidental findings including Chiari I (3), small subdural bleeds (2), arachnoid cyst (1), small cavernous malformation (1), frontal bone dermoid (1), and a linear parietal bone fracture after a fall (1). CONCLUSIONS: Children diagnosed with benign macrocrania of infancy on US without focal neurologic findings do not require subsequent brain CT/MRI or neurosurgical evaluation. Decreasing unnecessary imaging would decrease costs, minimize radiation and sedation exposures, and increase clinic availability of neurology and neurosurgery specialists. PMID- 27989413 TI - A Noninvasive Surfactant Adsorption Test Predicting the Need for Surfactant Therapy in Preterm Infants Treated with Continuous Positive Airway Pressure. AB - OBJECTIVE: To determine the diagnostic accuracy of the surfactant adsorption test (SAT) as a predictor for the need for surfactant replacement therapy in neonates with respiratory distress syndrome (RDS). STUDY DESIGN: Amniotic fluid samples were collected from 41 preterm neonates with RDS treated with continuous positive airway pressure (CPAP) and 15 healthy control term neonates. Purified porcine surfactant served as a further control. Lamellar bodies and lung ultrasound score were also measured in a subset of the neonates treated with CPAP. Surfactant was administered according to the European guidelines, and clinical data were collected prospectively. Surfactant activity was measured as adsorption at the air/liquid interface and given in relative fluorescent units (RFU). RESULTS: Surfactant activity differed among native porcine surfactant (median, 4863 RFU; IQR, 4405-5081 RFU), healthy term neonates (median, 2680 RFU; IQR, 2069-3050 RFU), and preterm neonates with RDS (median, 442 RFU; IQR, 92-920 RFU; P <.0001). The neonates who failed CPAP had lower surfactant activity compared with those who did not fail CPAP (median, 92 RFU; IQR, 0-315 RFU vs 749 RFU; IQR, 360-974 RFU; P = .0002). Differences between groups were more evident beyond 20-30 minutes of fluorescence; the 30-minute time point showed the highest area under the curve (0.84; P <.001) and the best cutoff level (170 RFU; specificity, 72%; sensitivity, 96%) for the prediction of CPAP failure. Surfactant activity at 30 minutes was significantly correlated with lamellar bodies (r = 0.51, P = .006) and lung ultrasound score (r = -0.39, P = .013). CONCLUSION: This technique has the potential to be developed into a fast, simple-to-interpret clinical test. The SAT can reliably identify preterm infants with subsequent CPAP failure and shows promise as a screening test for surfactant replacement in preterm neonates. PMID- 27989414 TI - Conceptual Design of Future Children's Hospitals in Europe: Planning, Building, Merging, and Closing Hospitals. PMID- 27989415 TI - Feasibility of voxel-based Dose Painting for recurrent Glioblastoma guided by ADC values of Diffusion-Weighted MR imaging. AB - PURPOSE: Glioblastoma Multiforme (GBM) is the most common malignant brain tumor and frequently recurs in the same location after radiotherapy. Intensive treatment targeting localized lesion is required to improve GBM outcome, but dose escalation using conventional methods is limited by healthy tissue tolerance. Helical Tomotherapy (HT) Dose Painting (DP) treatments were simulated to safely deliver high doses in the recurrent regions. MATERIALS AND METHODS: Apparent Diffusion Coefficient (ADC) data from five recurrent GBM were retrospectively considered for planning. Hypo-fractionated (25-50Gy, 5 fractions) voxel-based prescriptions were opportunely converted to personalized structured-based dose maps to create DP plans with a commercial Treatment Planning System. Optimized plans were generated and analyzed in terms of plan conformity to dose prescription (Q0.90-1.10), tolerance of the healthy tissues (DMAX), and dosimetry accuracy of the deliverable plans (gamma-index). RESULTS: Only three of the five cases could receive a safe retreatment without violating the maximum critical organs dose constraints. The conformity of the simulated plans was between 40.9% and 79.9% (Q0.90-1.10), their delivery time was in the range of 38.3-63.6min, while the dosimetry showed gamma-index of 82.4-92.4%. CONCLUSIONS: This study proved the ability of our method to simulate personalized, deliverable and dosimetrically accurate DPBN plans. HT hypo-fractionated treatments guided by ADC maps can be realized and applied to deliver high doses in the GBM recurrent regions, although there are some critical issues related to low Q0.90-1.10 values, to exceeding of healthy-tissue dose constraints for some patients and long delivery times. PMID- 27989417 TI - 1-Heteroarylpropan-2-ones as inhibitors of fatty acid amide hydrolase: Studies on structure-activity relationships and metabolic stability. AB - The serine hydrolase fatty acid amide hydrolase (FAAH) catalyzes the degradation of the endocannabinoid anandamide, which possesses analgesic and anti inflammatory effects. A new series of 1-heteroarylpropan-2-ones was synthesized and evaluated for FAAH inhibition. Structure-activity relationship studies revealed that 1H-benzotriazol-1-yl, 1H-7-azabenzotriazol-1-yl, 1H-tetrazol-1-yl and 2H-tetrazol-2-yl substituents have the highest impact on inhibitory potency. Furthermore, attempts were made to increase the limited metabolic stability of the ketone functionality of these compounds towards metabolic reduction by introduction of shielding alkyl substituents in proximity of this serine reactive group. PMID- 27989416 TI - Towards the development of activity-based probes for detection of lysine-specific demethylase-1 activity. AB - The implications of lysine-specific demethylase-1 (LSD1) in tumorigenesis have urged scientists to develop diagnostic tools in order to explore the function of this enzyme. In this work, we present our efforts on the development of tranylcypromine (TCP)-based functionalized probes for activity-based protein profiling (ABPP) of LSD1 activity. Biotinylated forms of selected compounds enabled dose-dependent enzyme labeling of recombinant LSD1. However, treatment with LSD1 inhibitors did not clearly reduce the LSD1 labeling efficiency thus indicating that labeling using these probes is not activity dependent. This calls for alternative strategies to develop probes for ABPP of the enzyme LSD1. PMID- 27989418 TI - The Value of Scatter Plots. PMID- 27989419 TI - Re: "Dry Needling Alters Trigger Points in the Upper Trapezius Muscle and Reduces Pain in Subjects with Chronic Myofascial Pain". PMID- 27989420 TI - Reply. PMID- 27989421 TI - Persistence of foveal capillary plexi in a case of fovea plana evident on OCT angiography. AB - We report the case of a 12-year-old boy with fovea plana discovered on a systematic work-up. His best-corrected visual acuity was limited to 20/25 in both eyes. Anterior segment examination showed no evidence of iris transillumination or aniridia. Macular OCT revealed persistence of the inner nuclear layers in the foveolar area and an absence of foveal pits, suggesting a diagnosis of fovea plana. Fluorescein angiography revealed that the foveal avascular zone (FAZ) was absent. OCT angiography revealed persistence of the superficial and deep capillary plexi. Our case confirms that OCT angiography affords additional insights into macular exploration and the diagnosis of fovea plana by revealing absence of the foveal pit associated with persistence of both superficial and deep capillary plexi in the foveal area. PMID- 27989422 TI - [A typical case of Susac's syndrome]. PMID- 27989423 TI - [Diagnostic and therapeutic contribution of microbiological analysis in severe microbial keratitis at Reims University Hospital between 2012 and 2014]. AB - PURPOSE: To investigate the contribution of microbial analysis in the diagnosis and management of severe microbial keratitis. MATERIAL AND METHOD: This is a monocentric retrospective study at the University Hospital of Reims from January 2012 to December 2014. Corneal scrapings with infectious keratitis were subjected to routine bacterial and fungal culture. PCR was also performed to detect various viral DNA (VZV, CMV, EBV, HSV 1 & 2, adenovirus) and Acanthamoeba sp. DNA. All contact lens cases were analyzed if available. RESULTS: One hundred and six patients were hospitalized, including 30 contact lens wearers (28.3%). Sixty-four bacterial cultures were positive (68%). Twenty-five different bacterial species were identified with a majority of gram-positive bacteria (67.92%). Among contact lens wearers, the initial VA was better than non-wearers (P=0.0004) and 37% of bacteria identified (a plurality) were gram positive. Of 11 contact lens case analyzed, in only one case (3.3%) did the result correlate with the corneal culture. Only 9 samples from the 323 viral DNA extractions and real time PCR were positive (2.8%); 7 were HSV1. No prior antiviral therapy had been started. Fungal culture was positive in 2 of the 97 corneal samples taken and 63.6% of the contact lens cases (7/11 cases). Only one of the 40 Acanthamoeba sp. PCR's was positive. CONCLUSION: The systematic performance of microbiological investigations is a good diagnostic approach given the polymorphism of clinical presentations of corneal ulcers, which can sometimes be extremely misleading. Culture of contact lens cases appears ineffective for the detection and determination of the causative microorganism. The high incidence of Staphylococcus in bacterial keratitis and the prevalence of infections with gram positive bacteria in contact lens wearers were noted. PMID- 27989424 TI - WITHDRAWN: Designing and computational validation of microarray probe sets for the diagnosis of viruses of non-human vertebrates. PMID- 27989425 TI - Curdlan induces selective mast cell degranulation without concomitant release of LTC4, IL-6 or CCL2. AB - Mast cells are sentinel cells with a tissue-specific localization in the interface between the host and the external environment. Their quick and selective response upon encountering pathogens is part of the innate host response and typically initiates the following adaptive immune response. Among several pattern recognition receptors (PRRs) involved in the recognition of pathogens by mast cells, the C-type lectin receptor Dectin-1 has been associated with the recognition of fungi. Our previous studies have shown that mast cells are the predominant cell type expressing Dectin-1 in human skin, and they also recognize and respond to Malassezia sympodialis by producing cytokines connected to the innate host response and upregulating the expression of Dectin-1. In the present study, we investigated mast cell responses to Curdlan, a beta-glucan that acts as an agonist for the fungi receptor Dectin-1, and found a unique response pattern with induced degranulation, but surprisingly without synthesis of Leukotriene C4, IL-6 or CCL2. Since mast cells are the predominant Dectin-1 expressing cell in the human skin, this study suggests that mast cell degranulation in response to fungi is an important part of the first line of defense against these pathogens. PMID- 27989426 TI - Surgical Management of Complicated Necrotizing Pneumonia in Children. AB - BACKGROUND: There are no well-established indications for the surgical management of acute necrotizing pneumonitis in children. This study presents our experience regarding this challenging topic. METHODS: Between 2002 and 2009, 56 necrotizing pneumonitis patients with empyema were treated surgically. The outcomes were analyzed retrospectively. Computed tomography findings of massive lung necrosis or large cavities involving more than 50% of the involved lobe were deemed to be complicated necrotizing pneumonitis. Patients without the above indications were considered uncomplicated. RESULTS: Thirty-one cases were uncomplicated and 25 were complicated. Operative procedures included 38 decortications (31 uncomplicated and seven complicated), 14 wedge resections, and four lobectomies (complicated only). Preoperatively, patients with complicated necrotizing pneumonia had a higher incidence of pneumothorax (32% vs. 14.3%; p = 0.001), endotracheal intubation (44% vs. 9.7%; p = 0.008), and hemolytic uremic syndrome (20% vs. 3.2%; p = 0.01). These patients also had higher incidences of intraoperative transfusion (68% vs. 9.7%; p = 0.03), major postoperative complications (16% vs. 0%; p = 0.02), reoperations (16% vs. 0%; p = 0.02), and longer postoperative stay (19.8 +/- 24.2 days vs. 11.2 +/- 5.8 days; p = 0.03). Four complicated patients, who initially had decortications and limited resections, underwent reoperations. Compared with uncomplicated patients, those who underwent decortications and wedge resection required longer postoperative stays (23.6 +/- 9.9 days, p < 0.01 and 21.1 +/- 30.7 days, p = 0.04, respectively), whereas patients who had lobectomy had a similar duration of recovery (9.0 +/- 2.1 days, p = 0.23). All patients improved significantly at follow-up. CONCLUSION: Children with complicated necrotizing pneumonitis have more preoperative morbidities, more major postoperative complications, and require longer postoperative stays. Aggressive surgical treatment results in significant clinical improvement. Lobectomy in patients with complicated necrotizing pneumonitis may shorten the postoperative course and avoid subsequent surgery. PMID- 27989427 TI - Exome sequencing is a valuable approach in critically ill patients with suspected monogenic disease: Diagnosis of X-linked centronuclear myopathy in preterm twins. PMID- 27989428 TI - San Antonio Breast Cancer Symposium 2016. PMID- 27989429 TI - Duloxetine lessens joint pain in early-stage breast cancer. PMID- 27989430 TI - Osimertinib effective in EGFR T790M-positive lung cancer. PMID- 27989431 TI - Personalised vaccine against acute myeloid leukaemia. PMID- 27989432 TI - Assisted dying legislation in Victoria, Australia. PMID- 27989433 TI - Complement-mediated inflammation and injury in brain dead organ donors. AB - The importance of the complement system in renal ischemia-reperfusion injury and acute rejection is widely recognized, however its contribution to the pathogenesis of tissue damage in the donor remains underexposed. Brain-dead (BD) organ donors are still the primary source of organs for transplantation. Brain death is characterized by hemodynamic changes, hormonal dysregulation, and immunological activation. Recently, the complement system has been shown to be involved. In BD organ donors, complement is activated systemically and locally and is an important mediator of inflammation and graft injury. Furthermore, complement activation can be used as a clinical marker for the prediction of graft function after transplantation. Experimental models of BD have shown that inhibition of the complement cascade is a successful method to reduce inflammation and injury of donor grafts, thereby improving graft function and survival after transplantation. Consequently, complement-targeted therapeutics in BD organ donors form a new opportunity to improve organ quality for transplantation. Future studies should further elucidate the mechanism responsible for complement activation in BD organ donors. PMID- 27989434 TI - Corrigendum to "Reactive oxygen species generated in different compartments induce cell death, survival, or senescence". [Free Radic. Biol. Med. 2013 Apr; 57:176-187.]. PMID- 27989435 TI - Testosterone and progesterone concentrations in blow samples are biologically relevant in belugas (Delphinapterus leucas). AB - Steroid hormone analysis in blow (respiratory vapor) may provide a minimally invasive way to assess the reproductive status of wild cetaceans. Biological validation of the method is needed to allow for the interpretation of hormone measurements in blow samples. Utilizing samples collected from trained belugas (Delphinapterus leucas, n=20), enzyme immunoassays for testosterone and progesterone were validated for use with beluga blow samples. Testosterone concentrations in 40 matched blood and blow samples collected from 4 male belugas demonstrated a positive correlation (R2=0.52, p<0.0001). Progesterone concentrations in 64 matching blood and blow samples from 11 females were also positively correlated (R2=0.60, p<0.0001). Testosterone concentrations (mean+/ SD) in blow samples collected from adult males (119.3+/-14.2pg/ml) were higher (p<0.01) than that of a juvenile male (<8years) (59.4+/-6.5pg/ml) or female belugas (54.1+/-25.7pg/ml). Among adult males, testosterone concentrations in blow demonstrated a seasonal pattern of secretion, with peak secretion occurring during the breeding season (February-April, 136.95+/-33.8pg/ml). Progesterone concentrations in blow varied by reproductive status; pregnant females (410.6+/ 87.8pg/ml) and females in the luteal phase of the estrous cycle (339.5+/ 51.0pg/ml) had higher (p<0.0001) blow progesterone concentrations than non pregnant females without a corpus luteum (242.5+/-27.3pg/ml). Results indicate that blow sample analysis can be used to detect variation in reproductive states associated with large differences in circulating testosterone or progesterone in belugas. PMID- 27989436 TI - Gene Architectures that Minimize Cost of Gene Expression. AB - Gene expression burdens cells by consuming resources and energy. While numerous studies have investigated regulation of expression level, little is known about gene design elements that govern expression costs. Here, we ask how cells minimize production costs while maintaining a given protein expression level and whether there are gene architectures that optimize this process. We measured fitness of ~14,000 E. coli strains, each expressing a reporter gene with a unique 5' architecture. By comparing cost-effective and ineffective architectures, we found that cost per protein molecule could be minimized by lowering transcription levels, regulating translation speeds, and utilizing amino acids that are cheap to synthesize and that are less hydrophobic. We then examined natural E. coli genes and found that highly expressed genes have evolved more forcefully to minimize costs associated with their expression. Our study thus elucidates gene design elements that improve the economy of protein expression in natural and heterologous systems. PMID- 27989437 TI - Chromatin Constrains the Initiation and Elongation of DNA Replication. AB - Eukaryotic chromosomal DNA is faithfully replicated in a complex series of cell cycle-regulated events that are incompletely understood. Here we report the reconstitution of DNA replication free in solution with purified proteins from the budding yeast Saccharomyces cerevisiae. The system recapitulates regulated bidirectional origin activation; synthesis of leading and lagging strands by the three replicative DNA polymerases Pol alpha, Pol delta, and Pol epsilon; and canonical maturation of Okazaki fragments into continuous daughter strands. We uncover a dual regulatory role for chromatin during DNA replication: promoting origin dependence and determining Okazaki fragment length by restricting Pol delta progression. This system thus provides a functional platform for the detailed mechanistic analysis of eukaryotic chromosome replication. PMID- 27989438 TI - Chromatin Controls DNA Replication Origin Selection, Lagging-Strand Synthesis, and Replication Fork Rates. AB - The integrity of eukaryotic genomes requires rapid and regulated chromatin replication. How this is accomplished is still poorly understood. Using purified yeast replication proteins and fully chromatinized templates, we have reconstituted this process in vitro. We show that chromatin enforces DNA replication origin specificity by preventing non-specific MCM helicase loading. Helicase activation occurs efficiently in the context of chromatin, but subsequent replisome progression requires the histone chaperone FACT (facilitates chromatin transcription). The FACT-associated Nhp6 protein, the nucleosome remodelers INO80 or ISW1A, and the lysine acetyltransferases Gcn5 and Esa1 each contribute separately to maximum DNA synthesis rates. Chromatin promotes the regular priming of lagging-strand DNA synthesis by facilitating DNA polymerase alpha function at replication forks. Finally, nucleosomes disrupted during replication are efficiently re-assembled into regular arrays on nascent DNA. Our work defines the minimum requirements for chromatin replication in vitro and shows how multiple chromatin factors might modulate replication fork rates in vivo. PMID- 27989439 TI - C2c1-sgRNA Complex Structure Reveals RNA-Guided DNA Cleavage Mechanism. AB - C2c1 is a type V-B CRISPR-Cas system dual-RNA-guided DNA endonuclease. Here, we report the crystal structure of Alicyclobacillus acidoterrestris C2c1 in complex with a chimeric single-molecule guide RNA (sgRNA). AacC2c1 exhibits a bi-lobed architecture consisting of a REC and NUC lobe. The sgRNA scaffold forms a tetra helical structure, distinct from previous predictions. The crRNA is located in the central channel of C2c1, and the tracrRNA resides in an external surface groove. Although AacC2c1 lacks a PAM-interacting domain, our analysis revealed that the PAM duplex has a similar binding position found in Cpf1. Importantly, C2c1-sgRNA system is highly sensitive to single-nucleotide mismatches between guide RNA and target DNA. The resulting reduction in off-target cleavage renders C2c1 a valuable addition to the current arsenal of genome-editing tools. Together, our findings indicate that sgRNA assembly is achieved through a mechanism distinct from that reported previously for Cas9 or Cpf1 endonucleases. PMID- 27989441 TI - Autonomous Metabolic Oscillations Robustly Gate the Early and Late Cell Cycle. AB - Eukaryotic cell division is known to be controlled by the cyclin/cyclin dependent kinase (CDK) machinery. However, eukaryotes have evolved prior to CDKs, and cells can divide in the absence of major cyclin/CDK components. We hypothesized that an autonomous metabolic oscillator provides dynamic triggers for cell-cycle initiation and progression. Using microfluidics, cell-cycle reporters, and single cell metabolite measurements, we found that metabolism of budding yeast is a CDK independent oscillator that oscillates across different growth conditions, both in synchrony with and also in the absence of the cell cycle. Using environmental perturbations and dynamic single-protein depletion experiments, we found that the metabolic oscillator and the cell cycle form a system of coupled oscillators, with the metabolic oscillator separately gating and maintaining synchrony with the early and late cell cycle. Establishing metabolism as a dynamic component within the cell-cycle network opens new avenues for cell-cycle research and therapeutic interventions for proliferative disorders. PMID- 27989443 TI - Rating perceived exertion using facial expressions. PMID- 27989440 TI - Metabolism of Free Guanidine in Bacteria Is Regulated by a Widespread Riboswitch Class. AB - The guanidyl moiety is a component of fundamental metabolites, including the amino acid arginine, the energy carrier creatine, and the nucleobase guanine. Curiously, reports regarding the importance of free guanidine in biology are sparse, and no biological receptors that specifically recognize this compound have been previously identified. We report that many members of the ykkC motif RNA, the longest unresolved riboswitch candidate, naturally sense and respond to guanidine. This RNA is found throughout much of the bacterial domain of life, where it commonly controls the expression of proteins annotated as urea carboxylases and multidrug efflux pumps. Our analyses reveal that these proteins likely function as guanidine carboxylases and guanidine transporters, respectively. Furthermore, we demonstrate that bacteria are capable of endogenously producing guanidine. These and related findings demonstrate that free guanidine is a biologically relevant compound, and several gene families that can alleviate guanidine toxicity exist. PMID- 27989442 TI - How the Eukaryotic Replisome Achieves Rapid and Efficient DNA Replication. AB - The eukaryotic replisome is a molecular machine that coordinates the Cdc45-MCM GINS (CMG) replicative DNA helicase with DNA polymerases alpha, delta, and epsilon and other proteins to copy the leading- and lagging-strand templates at rates between 1 and 2 kb min-1. We have now reconstituted this sophisticated machine with purified proteins, beginning with regulated CMG assembly and activation. We show that replisome-associated factors Mrc1 and Csm3/Tof1 are crucial for in vivo rates of replisome progression. Additionally, maximal rates only occur when DNA polymerase epsilon catalyzes leading-strand synthesis together with its processivity factor PCNA. DNA polymerase delta can support leading-strand synthesis, but at slower rates. DNA polymerase delta is required for lagging-strand synthesis, but surprisingly also plays a role in establishing leading-strand synthesis, before DNA polymerase epsilon engagement. We propose that switching between these DNA polymerases also contributes to leading-strand synthesis under conditions of replicative stress. PMID- 27989444 TI - Analog Method for Radiographic Assessment of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva. AB - RATIONALE AND OBJECTIVES: Severe progressive multifocal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate owing to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in patients with FOP. MATERIALS AND METHODS: Institutional review board approval was obtained from the University of Pennsylvania, and all data comply with Health Insurance Portability and Accountability Act regulations. The University of Pennsylvania Institutional Animal Care and Use Committee approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semiquantitative analog scale for estimating relative heterotopic bone volume. Second, we used this validated scale to estimate the relative amount of HO from a retrospective analysis of plain radiographs from 63 patients with classic FOP. Finally, the scale was applied to a retrospective analysis of computed tomographic images from three patients with FOP. RESULTS: In the FOP-mouse model, the observed rating on the analog scale is highly correlated to heterotopic bone volumes measured by microcomputed tomography (R2 = 0.89). The scoring system that was applied to radiographs of patients with FOP captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of computed tomographic scans of patients with FOP found that observed radiograph ratings were highly correlated with HO volume (R2 = 0.80). CONCLUSIONS: The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. The development of the six-point analog scale described here provides and validates a much-needed, reproducible, and quantifiable method for describing and assessing HO in patients with FOP. This scale has the potential to be a key descriptor that can inform patients with FOP and clinicians about disease progression and response of HO lesions to interventions and treatments. PMID- 27989445 TI - The Objective Identification and Quantification of Interstitial Lung Abnormalities in Smokers. AB - RATIONALE AND OBJECTIVES: Previous investigation suggests that visually detected interstitial changes in the lung parenchyma of smokers are highly clinically relevant and predict outcomes, including death. Visual subjective analysis to detect these changes is time-consuming, insensitive to subtle changes, and requires training to enhance reproducibility. Objective detection of such changes could provide a method of disease identification without these limitations. The goal of this study was to develop and test a fully automated image processing tool to objectively identify radiographic features associated with interstitial abnormalities in the computed tomography scans of a large cohort of smokers. MATERIALS AND METHODS: An automated tool that uses local histogram analysis combined with distance from the pleural surface was used to detect radiographic features consistent with interstitial lung abnormalities in computed tomography scans from 2257 individuals from the Genetic Epidemiology of COPD study, a longitudinal observational study of smokers. The sensitivity and specificity of this tool was determined based on its ability to detect the visually identified presence of these abnormalities. RESULTS: The tool had a sensitivity of 87.8% and a specificity of 57.5% for the detection of interstitial lung abnormalities, with a c-statistic of 0.82, and was 100% sensitive and 56.7% specific for the detection of the visual subtype of interstitial abnormalities called fibrotic parenchymal abnormalities, with a c-statistic of 0.89. CONCLUSIONS: In smokers, a fully automated image processing tool is able to identify those individuals who have interstitial lung abnormalities with moderate sensitivity and specificity. PMID- 27989446 TI - Time-Resolved Quantitative Analysis of the Diaphragms During Tidal Breathing in a Standing Position Using Dynamic Chest Radiography with a Flat Panel Detector System ("Dynamic X-Ray Phrenicography"): Initial Experience in 172 Volunteers. AB - RATIONALE AND OBJECTIVES: Diaphragmatic motion in a standing position during tidal breathing remains unclear. The purpose of this observational study was to evaluate diaphragmatic motion during tidal breathing in a standing position in a health screening center cohort using dynamic chest radiography in association with participants' demographic characteristics. MATERIALS AND METHODS: One hundred seventy-two subjects (103 men; aged 56.3 +/- 9.8 years) underwent sequential chest radiographs during tidal breathing using dynamic chest radiography with a flat panel detector system. We evaluated the excursions of and peak motion speeds of the diaphragms. Associations between the excursions and participants' demographics (gender, height, weight, body mass index [BMI], smoking history, tidal volume, vital capacity, and forced expiratory volume) were investigated. RESULTS: The average excursion of the left diaphragm (14.9 +/- 4.6 mm, 95% CI 14.2-15.5 mm) was significantly larger than that of the right (11.0 +/ 4.0 mm, 95% CI 10.4-11.6 mm) (P <0.001). The peak motion speed of the left diaphragm (inspiratory, 16.6 +/- 4.2 mm/s; expiratory, 13.7 +/- 4.2 mm/s) was significantly faster than that of the right (inspiratory, 12.4 +/- 4.4 mm/s; expiratory, 9.4 +/- 3.8 mm/s) (both P <0.001). Both simple and multiple regression models demonstrated that higher BMI and higher tidal volume were associated with increased excursions of the bilateral diaphragm (all P <0.05). CONCLUSIONS: The average excursions of the diaphragms are 11.0 mm (right) and 14.9 mm (left) during tidal breathing in a standing position. The diaphragmatic motion of the left is significantly larger and faster than that of the right. Higher BMI and tidal volume are associated with increased excursions of the bilateral diaphragm. PMID- 27989448 TI - Spanish Food Vocabulary: Improving Communication with Mexican Immigrants. PMID- 27989447 TI - No Time for Family Meals? Parenting Practices Associated with Adolescent Fruit and Vegetable Intake When Family Meals Are Not an Option. AB - BACKGROUND: Despite research linking family meals to healthier diets, some families are unable to have regular meals together. These families need guidance about other ways to promote healthy eating among adolescents. OBJECTIVE: Our aim was to examine the association between various parenting practices and adolescent fruit and vegetable (F/V) intake at different levels of family meal frequency. DESIGN: We conducted a cross-sectional, population-based survey of influences on adolescent weight-related behaviors using Project EAT (Eating and Activity in Teens) 2010. PARTICIPANTS/SETTING: Participants were 2,491 adolescents recruited from middle/high schools in Minneapolis/St Paul, MN. MEASURES: Adolescent F/V intake was ascertained with a food frequency questionnaire. Survey items assessed frequency of family meals and F/V parenting practices (availability, accessibility, parent modeling, parent encouragement, and family communication). STATISTICAL ANALYSES: Linear regression models were used to examine associations with and interactions among family meals and parenting practices. Models were adjusted for age, sex, socioeconomic status, race/ethnicity, and energy intake (kilocalories per day). RESULTS: Family meals, F/V availability, F/V accessibility, F/V modeling, and encouragement to eat healthy foods were independently associated with higher F/V intake. Of the 949 (34%) adolescents who reported infrequent family meals (<=2 days/wk), mean F/V intake was 3.6 servings/day for those with high home F/V availability vs 3.0 servings/day for those with low home F/V availability. Similar differences in mean F/V intake (0.3 to 0.6 servings/day) were found for high vs low F/V accessibility, parental modeling, and parent encouragement for healthy eating. Frequent family meals in addition to more favorable parenting practices were associated with the highest F/V intakes. CONCLUSIONS: Food parenting practices and family meals are associated with greater adolescent F/V intake. Longitudinal and intervention studies are needed to determine which combination of parenting practices will lead to improvements in adolescent diets. PMID- 27989449 TI - Dental Disparities and Psychological Distress Among Mobility-Impaired Adults. AB - INTRODUCTION: More than one in five American adults has a disability, the most common being mobility impairment (MI). People with MI face significant barriers to healthcare access and are more likely to experience psychological distress. This study examined disparities in access to medical and dental care among people with MI and examine the mediational role of psychological distress on this relationship. METHODS: Analyses were conducted on 36,697 adults (aged >=18 years) responding to the 2014 National Health Interview Survey (analyzed in 2015). MI was defined as needing special equipment and having difficulty walking a quarter mile without equipment. Outcomes included having lost all natural teeth (edentulous), unmet dental needs, annual dental visit, and annual medical visit. Psychological distress was measured using the Kessler psychological distress (K6) scale. RESULTS: Compared with adults without MI, adults with MI had greater odds of being edentulous (OR=2.10, 95% CI=1.82, 2.43), having unmet dental needs (OR=1.99, 95% CI=1.66, 2.40), and lower odds of having annual dental visits (OR=0.62, 95% CI=0.54, 0.71). However, adults with MI were significantly more likely to have annual medical visits (OR=2.31, 95% CI=1.90, 2.81) than adults without MI. Psychological distress partially, yet significantly, mediated the relationship between MI and outcomes. CONCLUSIONS: People with MI have significant oral health needs and poor access to dental care, which are partially mediated by psychological distress. Results suggest that mental health services should be considered for inclusion in interventions and medical visits can be leveraged to improve oral health outcomes in this population. PMID- 27989450 TI - Correlates of Hookah Pipe Awareness and Perceived Harmfulness Among U.S. Adults. AB - INTRODUCTION: Hookah smoking has recently become a common form of smoking, and its prevalence has increased worldwide. This study determined the prevalence and correlates of hookah awareness and perceived harmfulness among U.S. adults. METHODS: Weighted multivariable logistic regression analyses were performed on 6,711 adults aged >=18 years collected from the 2013-2014 Health Information National Trends Survey (Cycles 3 and 4). Analysis was conducted in 2016. RESULTS: Overall, 74.3% were aware of hookah. Of these, 73.4% believed hookah pipes were equally harmful as cigarettes whereas 15.7% believed otherwise. Older (OR=0.13, 95% CI=0.09, 0.18), black (OR=0.51, 95% CI=0.38, 0.71), Hispanic (OR=0.52, 95% CI=0.37, 0.71), and less-educated (OR=0.42, 95% CI=0.27, 0.65) respondents had lower odds of being aware of hookah. Compared with non-smokers, former smokers had 83% (95% CI=1.44, 2.33) higher odds of hookah awareness. Among those aware of hookah, older (OR=0.44, 95% CI=0.31, 0.62), black (OR=0.64, 95% CI=0.43, 0.96), and less-educated (OR=0.55, 95% CI=0.33, 0.92) respondents had lower odds of perceiving hookah as less harmful than cigarettes. CONCLUSIONS: Most adults in U.S. are aware of hookah, but only 15.7% believe it is less harmful than cigarettes. This small proportion are mostly young, white, and college graduates. Targeted behavioral interventions will be necessary to increase individuals' perceived risk, knowledge, and perceived harmfulness of hookah smoking. PMID- 27989451 TI - Diabetes Prevention in U.S. Hispanic Adults: A Systematic Review of Culturally Tailored Interventions. AB - CONTEXT: Type 2 diabetes, prediabetes, and metabolic syndrome are highly prevalent in Hispanic individuals in the U.S. Cultural adaptations of traditional lifestyle interventions have been recommended to better reach this high-risk population. This systematic review examined the effectiveness of diabetes prevention programs for Hispanics in lowering risk for Type 2 diabetes, as evidenced by a reduction in weight or improvement in glucose regulation. EVIDENCE ACQUISITION: PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and PsycINFO were searched from database inception to June 2016 for studies that evaluated diabetes prevention trials targeting U.S. Hispanic populations. Twelve publications met criteria for inclusion. EVIDENCE SYNTHESIS: Interventions varied substantially in length, rigor, and tailoring strategies. Five of 12 studies were RCTs. Eight studies included entirely or largely (>70%) female samples. All studies were delivered in Spanish and took place in community settings. Nine studies reported significant reductions in weight, and two in glucose regulation, post-intervention or when compared with controls. Effect sizes were small to moderate, study quality was moderate, and attrition was high in most trials. Interventions with the largest effect sizes included one or more of the following adaptations: literacy modification, Hispanic foods/recipes, cultural diabetes beliefs, family/friend participation, structured community input, and innovative experiential learning. CONCLUSIONS: Culturally tailored lifestyle interventions for diabetes prevention appear to be modestly effective in reducing risk for diabetes in Hispanics in the U.S. More studies are needed that utilize randomized controlled designs, recruit Hispanic men, report intervention content and tailoring strategies systematically, and publish participant evaluation and feedback. PMID- 27989452 TI - Long-term Quit Rates in Fax-Referred as Compared to Self-Referred Tobacco Quitline Registrants. AB - INTRODUCTION: To increase the use of quitlines for treating tobacco use and dependence, quitline referral interventions are recommended for healthcare systems and providers. Research is limited as to whether fax-referred smokers have quit outcomes similar to those of traditional self-callers to quitlines. METHODS: Oklahoma Tobacco Helpline registration data from March 2013 to October 2014 and 7-month follow-up data were used to compare hospital- and clinic-based fax-referred registrants (n=537) to self-callers (n=2,577). Contingency table chi square tests and relative risks were used to identify differences in 30-day point prevalence abstinence at 7-month follow-up. Two-sided p-values <0.05 were considered statistically significant. Analyses were conducted in 2015. RESULTS: Fax-referred registrants versus self-callers were significantly more likely to be older (49.4 vs 47.6 years), white (70.6% vs 59.1%), non-Hispanic (96.8% vs 94.2%), and to have smoked fewer than one pack of cigarettes per day (54.0% vs 44.9%). Self-callers versus fax-referred registrants were significantly more likely to be uninsured (36.5% vs 29.4%) and have received nicotine-replacement therapy from the Helpline (92.3% vs 79.9%). At 7-month follow-up, a similar proportion of fax-referred registrants reported not using tobacco in the past 30 days as compared to self-callers (29.3% vs 31.8%, p=0.2945). CONCLUSIONS: Although differences in sociodemographics, tobacco use behavior, and Helpline services were observed between fax-referred registrants and self-callers, quit outcomes at follow-up did not differ. This observational study has important implications for tobacco control initiatives as it shows patients fax-referred by hospitals and clinics to quitlines may be as successful as self-callers in quitting smoking. PMID- 27989453 TI - The Transition From Thinness-Oriented to Muscularity-Oriented Disordered Eating in Adolescent Males: A Clinical Observation. AB - PURPOSE: Robust empirical evidence has illustrated a rising prevalence of body dissatisfaction and disordered eating among males, noting that both may be oriented more toward muscularity-as opposed to thinness-oriented concerns. While an elevated prevalence of premorbid anorexia nervosa (AN) has been noted among those with muscle dysmorphia, little evidence has examined the process of this transition from thinness-oriented to muscularity-oriented disordered eating. METHODS: This clinical observation presents a case of AN in an adolescent male, whose symptom presentation transitioned during the course of treatment for AN, into more muscularity-oriented disordered eating. RESULTS: Despite the core body image disturbance and disordered eating behaviors being retained, the behavioral expression of muscularity-oriented disordered eating was difficult to detect during treatment for AN, and he was discharged from treatment as his muscularity oriented disordered eating escalated. CONCLUSIONS: Transdiagnostic crossover between thinness-oriented and muscularity-oriented disordered eating represents an important clinical concern, which may be challenging to measure and assess. Implications for treatment are discussed, and the early detection of muscularity oriented disordered eating. PMID- 27989454 TI - Documentation of Gender Identity in an Adolescent and Young Adult Clinic. AB - PURPOSE: To determine if changing electronic health record (EHR) note templates can increase documentation of gender identity in an adolescent and young adult clinic. METHODS: A two-step gender question was added to EHR note templates for physicals in February 2016. A retrospective chart review was performed 3 months before and after this addition. The primary measure was whether answers to the two-step question were documented. Gender identity/birth-assigned sex discordance, age, and use of the appropriate note template post-template change were also measured. RESULTS: One hundred twenty-five pretemplate change and 106 post-template change physicals were reviewed with an inter-rater reliability of 97%. Documentation of answers to the two-step gender identity question increased from 11% to 84% (p < .001). CONCLUSIONS: This study suggests that incorporating a standardized question into EHR note templates is effective at improving the documentation of gender identity in youth presenting for annual physicals. PMID- 27989455 TI - Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines. AB - Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling. PMID- 27989456 TI - Laminar Organization of Attentional Modulation in Macaque Visual Area V4. AB - Attention is critical to perception, serving to select behaviorally relevant information for privileged processing. To understand the neural mechanisms of attention, we must discern how attentional modulation varies by cell type and across cortical layers. Here, we test whether attention acts non-selectively across cortical layers or whether it engages the laminar circuit in specific and selective ways. We find layer- and cell-class-specific differences in several different forms of attentional modulation in area V4. Broad-spiking neurons in the superficial layers exhibit attention-mediated increases in firing rate and decreases in variability. Spike count correlations are highest in the input layer and attention serves to reduce these correlations. Superficial and input layer neurons exhibit attention-dependent decreases in low-frequency (<10 Hz) coherence, but deep layer neurons exhibit increases in coherence in the beta and gamma frequency ranges. Our study provides a template for attention-mediated laminar information processing that might be applicable across sensory modalities. PMID- 27989457 TI - BK Channels Are Required for Multisensory Plasticity in the Oculomotor System. AB - Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits. PMID- 27989458 TI - Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c. AB - Development of proper cortical circuits requires an interaction of sensory experience and genetic programs. Little is known of how experience and specific transcription factors interact to determine the development of specific neocortical circuits. Here, we demonstrate that the activity-dependent transcription factor, Myocyte enhancer factor-2C (Mef2c), differentially regulates development of local versus long-range excitatory synaptic inputs onto layer 2/3 neurons in the somatosensory neocortex in vivo. Postnatal, postsynaptic deletion of Mef2c in a sparse population of L2/3 neurons suppressed development of excitatory synaptic connections from all local input pathways tested. In the same cell population, Mef2c deletion promoted the strength of excitatory inputs originating from contralateral neocortex. Both the synapse promoting and synapse suppressing effects of Mef2c deletion required normal whisking experience. These results reveal a role of Mef2c in experience-dependent development of specific sensory neocortical circuits. PMID- 27989459 TI - AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input Defined Neural Pathways for Defense Behaviors. AB - To decipher neural circuits underlying brain functions, viral tracers are widely applied to map input and output connectivity of neuronal populations. Despite the successful application of retrograde transsynaptic viruses for identifying presynaptic neurons of transduced neurons, analogous anterograde transsynaptic tools for tagging postsynaptically targeted neurons remain under development. Here, we discovered that adeno-associated viruses (AAV1 and AAV9) exhibit anterograde transsynaptic spread properties. AAV1-Cre from transduced presynaptic neurons effectively and specifically drives Cre-dependent transgene expression in selected postsynaptic neuronal targets, thus allowing axonal tracing and functional manipulations of the latter input-defined neuronal population. Its application in superior colliculus (SC) reveals that SC neuron subpopulations receiving corticocollicular projections from auditory and visual cortex specifically drive flight and freezing, two different types of defense behavior, respectively. Together with an intersectional approach, AAV-mediated anterograde transsynaptic tagging can categorize neurons by their inputs and molecular identity, and allow forward screening of distinct functional neural pathways embedded in complex brain circuits. PMID- 27989460 TI - Touch Receptor-Derived Sensory Information Alleviates Acute Pain Signaling and Fine-Tunes Nociceptive Reflex Coordination. AB - Painful mechanical stimuli activate multiple peripheral sensory afferent subtypes simultaneously, including nociceptors and low-threshold mechanoreceptors (LTMRs). Using an optogenetic approach, we demonstrate that LTMRs do not solely serve as touch receptors but also play an important role in acute pain signaling. We show that selective activation of neuropeptide Y receptor-2-expressing (Npy2r) myelinated A-fiber nociceptors evokes abnormally exacerbated pain, which is alleviated by concurrent activation of LTMRs in a frequency-dependent manner. We further show that spatial summation of single action potentials from multiple NPY2R-positive afferents is sufficient to trigger nocifensive paw withdrawal, but additional simultaneous sensory input from LTMRs is required for normal well coordinated execution of this reflex. Thus, our results show that combinatorial coding of noxious and tactile sensory input is required for normal acute mechanical pain signaling. Additionally, we established a causal link between precisely defined neural activity in functionally identified sensory neuron subpopulations and nocifensive behavior and pain. PMID- 27989461 TI - Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons. AB - Ingestion of water and food are major hypo- and hyperosmotic challenges. To protect the body from osmotic stress, posterior pituitary-projecting, vasopressin secreting neurons (VPpp neurons) counter osmotic perturbations by altering their release of vasopressin, which controls renal water excretion. Vasopressin levels begin to fall within minutes of water consumption, even prior to changes in blood osmolality. To ascertain the precise temporal dynamics by which water or food ingestion affect VPpp neuron activity, we directly recorded the spiking and calcium activity of genetically defined VPpp neurons. In states of elevated osmolality, water availability rapidly decreased VPpp neuron activity within seconds, beginning prior to water ingestion, upon presentation of water predicting cues. In contrast, food availability following food restriction rapidly increased VPpp neuron activity within seconds, but only following feeding onset. These rapid and distinct changes in activity during drinking and feeding suggest diverse neural mechanisms underlying anticipatory regulation of VPpp neurons. PMID- 27989462 TI - Bidirectional Control of Generalized Epilepsy Networks via Rapid Real-Time Switching of Firing Mode. AB - Thalamic relay neurons have well-characterized dual firing modes: bursting and tonic spiking. Studies in brain slices have led to a model in which rhythmic synchronized spiking (phasic firing) in a population of relay neurons leads to hyper-synchronous oscillatory cortico-thalamo-cortical rhythms that result in absence seizures. This model suggests that blocking thalamocortical phasic firing would treat absence seizures. However, recent in vivo studies in anesthetized animals have questioned this simple model. Here we resolve this issue by developing a real-time, mode-switching approach to drive thalamocortical neurons into or out of a phasic firing mode in two freely behaving genetic rodent models of absence epilepsy. Toggling between phasic and tonic firing in thalamocortical neurons launched and aborted absence seizures, respectively. Thus, a synchronous thalamocortical phasic firing state is required for absence seizures, and switching to tonic firing rapidly halts absences. This approach should be useful for modulating other networks that have mode-dependent behaviors. PMID- 27989463 TI - Coupling between One-Dimensional Networks Reconciles Conflicting Dynamics in LIP and Reveals Its Recurrent Circuitry. AB - Little is known about the internal circuitry of the primate lateral intraparietal area (LIP). During two versions of a delayed-saccade task, we found radically different network dynamics beneath similar population average firing patterns. When neurons are not influenced by stimuli outside their receptive fields (RFs), dynamics of the high-dimensional LIP network during slowly varying activity lie predominantly in one multi-neuronal dimension, as described previously. However, when activity is suppressed by stimuli outside the RF, slow LIP dynamics markedly deviate from a single dimension. The conflicting results can be reconciled if two LIP local networks, each underlying an RF location and dominated by a single multi-neuronal activity pattern, are suppressively coupled to each other. These results demonstrate the low dimensionality of slow LIP local dynamics, and suggest that LIP local networks encoding the attentional and movement priority of competing visual locations actively suppress one another. PMID- 27989464 TI - Bisalbuminemia in a patient with metastatic lung cancer. PMID- 27989465 TI - Neuroprotective effect of sevoflurane in general anaesthesia. AB - INTRODUCTION AND OBJECTIVE: The aim of this study was to evaluate the brain damage caused by inhaled sevoflurane, by determining the concentration of serum S100B protein before and after the exposure to this drug as the only anaesthetic agent. PATIENTS AND METHOD: Paediatric patients undergoing general anaesthesia for the conduct of a nuclear magnetic resonance were included in the study. A venous blood sample was taken from each patient before (basal sample) and after (post-exposure sample) administering the general anaesthesia. The concentration of serum S100B protein was determined in the basal (S100Bb) and post-exposure sample (S100Bp). RESULTS: A total of 72 patients were included in the study, with a mean patient age of 2 to 13 years (median=6), 28 males and 44 females. S100Bp values (median=66.5ng/L) were significantly lower (P=.0059) than those of S100Bb (median=84.0ng/L). The median of the difference between S100Bp and S100Bb was 11.0ng/L. CONCLUSIONS: Inhaled sevoflurane at low doses causes a decrease of serum S100B protein levels, hence, this drug could have a neuroprotective effect in the central nervous system. PMID- 27989466 TI - Overdiagnosis: Realities and perspectives. PMID- 27989467 TI - Metabolite fingerprinting of Punica granatum L. (pomegranate) polyphenols by means of high-performance liquid chromatography with diode array and electrospray ionization-mass spectrometry detection. AB - The present study was aimed at the development of a new analytical method for the comprehensive multi-component analysis of polyphenols in Punica granatum L. (pomegranate) juice and peel. While pomegranate juice was directly analysed after simple centrifugation, different extraction techniques, including maceration, heat reflux extraction, ultrasound-assisted extraction and microwave-assisted extraction, were compared in order to obtain a high yield of the target analytes from pomegranate peel. Dynamic maceration with a mixture of water and ethanol 80:20 (v/v) with 0.1% of hydrochloric acid as the extraction solvent provided the best result in terms of recovery of pomegranate secondary metabolites. The quali- and quantitative analysis of pomegranate polyphenols was performed by high performance liquid chromatography with diode array and electrospray ionization mass spectrometry detection. The application of fused-core column technology allowed us to obtain an improvement of the chromatographic performance in comparison with that of conventional particulate stationary phases, thus enabling a good separation of all constituents in a shorter time and with low solvent usage. The analytical method was completely validated to show compliance with the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use guidelines and successfully applied to the characterisation of commercial and experimental pomegranate samples, thus demonstrating its efficiency as a tool for the fingerprinting of this plant material. The quantitative data collected were submitted to principal component analysis, in order to highlight the possible presence of pomegranate samples with high content of secondary metabolites. From the statistical analysis, four experimental samples showed a notable content of bioactive compounds in the peels, while commercial ones still represent the best source of healthy juice. PMID- 27989468 TI - Validation of an analytical method for simultaneous high-precision measurements of greenhouse gas emissions from wastewater treatment plants using a gas chromatography-barrier discharge detector system. AB - Wastewater treatment plants (WWTPs) emit CO2 and N2O, which may lead to climate change and global warming. Over the last few years, awareness of greenhouse gas (GHG) emissions from WWTPs has increased. Moreover, the development of valid, reliable, and high-throughput analytical methods for simultaneous gas analysis is an essential requirement for environmental applications. In the present study, an analytical method based on a gas chromatograph (GC) equipped with a barrier ionization discharge (BID) detector was developed for the first time. This new method simultaneously analyses CO2 and N2O and has a precision, measured in terms of relative standard of variation RSD%, equal to or less than 6.6% and 5.1%, respectively. The method's detection limits are 5.3ppmv for CO2 and 62.0ppbv for N2O. The method's selectivity, linearity, accuracy, repeatability, intermediate precision, limit of detection and limit of quantification were good at trace concentration levels. After validation, the method was applied to a real case of N2O and CO2 emissions from a WWTP, confirming its suitability as a standard procedure for simultaneous GHG analysis in environmental samples containing CO2 levels less than 12,000mg/L. PMID- 27989469 TI - Targeted and untargeted characterisation of free and glycosylated simple phenols in cocoa beans using high resolution-tandem mass spectrometry (Q-Orbitrap). AB - Free simple phenols have positive effects on health and influence the organoleptic profile of cocoa products, contributing towards defining their aroma and nutritional properties. Glycosidically bound simple phenols can be hydrolysed during the production phase to the corresponding free forms, and thus potentially contribute to the final sensory profile. In this work, 60 samples of Forastero cocoa beans from all over the world were analysed, combining on-line solid phase extraction (SPE) clean-up with ultra-high performance liquid chromatography (UHPLC), coupled with high resolution mass spectrometry. Operating in negative ion mode and with a heated electrospray, 62 simple phenols were measured, of which four were glucosidic precursors, with quantification limits ranging from 0.04 to 40mgkg-1, calibration R2 of 0.99 for over 93% of compounds, and precision (R.S.D.%) always lower than 12%. On the basis of accurate mass, isotope pattern and MS/MS spectrum, 32 monoglycosylated simple phenols such as hexoside and pentoside precursors, and 14 diglycosylated simple phenols such as hexoside hexoside, hexoside-pentoside and pentoside-hexoside precursors, were tentatively identified. The untargeted approach was validated using 3 glucosidic precursors synthesized by an external supplier. Honestly Significant Difference Tukey's test (p<0.05) and Discriminant Analysis showed it was possible to distinguish the geographical origin of cocoa beans. In particular, the absolute free phenol profile made it possible to characterise 4 out of 5 production macro-areas well, while an untargeted approach based on the ionisation profiles of glycosylated forms allowed complete characterisation of all the 5 macro-areas. PMID- 27989470 TI - Differences between WHO AND CDC early growth measurements in the assessment of Cystic Fibrosis clinical outcomes. AB - BACKGROUND: Early childhood growth status has been used to predict long-term clinical outcomes in Cystic Fibrosis (CF) patients. Adulthood CF outcomes based on early weight-for-length (WFL) measurements, using either World Health Organization (WHO) or Centers for Disease Control (CDC) scales, have not been compared. METHODS: Cystic Fibrosis Foundation registry patients were studied (n=3014). Participants were categorized at age two years as WFL <50th percentile on both WHO and CDC scales, >=50th percentile on WHO but not CDC, or >=50th percentile on both. Pulmonary function and overall survival were assessed at age 18years. RESULTS: Stepwise gains in pulmonary function and lung transplant-free survival were noted across the three increasing WFL categories. CONCLUSIONS: Children with CF who achieve higher WFL at age two years have improved pulmonary and survival outcomes into adulthood. CF providers should continue to utilize current early growth recommendations, with goal WFL >=50th percentile on CDC growth charts before age two. PMID- 27989471 TI - Diverse toxicological risks of PAHs in surface water with an impounding level of 175m in the Three Gorges Reservoir Area, China. AB - The impounding level of 175m for the Three Gorges Reservoir (TGR) is of vital importance for efficient flood control, power generation and convenient navigation in China. However, little is known about the spatial distribution and toxicological risks of major pollutants in the Three Gorges Reservoir Area (TGRA) at that stage. The aim of this study is to probe the ubiquitous polycyclic aromatic hydrocarbons (PAHs) contamination and toxicological impacts in the surface water of the TGRA at the highest water impoundment level of 175m. Our results showed that the ?PAHs levels ranged from 83 to 1631ng/L in the upper reaches, 354 to 1159ng/L in the middle reaches, and 23 to 747ng/L in the lower reaches of the TGRA. Source apportionment of PAHs indicated that coal combustion, industrial emissions, heavy traffic, agriculture and shipping activities were the primary sources. Compositional pattern highlighted >85% dominancy of low molecular weight (LMW) PAHs in the reservoir. Risk assessment based on risk quotients (RQs) implied moderate to high ecological risks: the upper reaches>the middle reaches>the lower reaches. However, gene expression profiles portrayed contrary scenario because of the presence of relatively higher footprints of high molecular weight (HMW) PAHs in the middle and the lower reaches, which was confirmed by Cox hazard proportional model. Moreover, the transgenic zebrafish Tg(cyp1a:gfp) induced by PAHs also expressed stronger fluorescent signals in the middle and lower reaches. Taken together, different approaches were employed to firstly reveal the real status of ecological toxicity of PAHs and explore the underlying mechanisms at the highest impounding level of 175m in the TGRA. PMID- 27989472 TI - Monitoring sanitation and hygiene in the 2030 Agenda for Sustainable Development: A review through the lens of human rights. AB - International monitoring of drinking water and sanitation has been jointly carried out by WHO and UNICEF through their Joint Monitoring Programme (JMP). With the end of the Millennium Development Goals (MDGs) era in 2015, the JMP has proposed a post-2015 framework for integrated monitoring of water and sanitation targets included in the Sustainable Development Goal no. 6. This article discusses how each element of the proposed sanitation target and corresponding indicators can be understood from a human rights perspective. Building on the MDGs, and although some of the weaknesses and gaps persist, the discussion suggests that the post-2015 proposal is a step forward towards a monitoring framework where human rights elements related to sanitation are effectively promoted. In addition, to support the interpretation and implementation of the normative content of human rights obligations related to sanitation, the study proposes a reduced set of easy-to-assess indicators to measure the normative criteria of this right, which are then grouped in a multidimensional framework to describe increasing levels of sanitation service. To do this, the study combines literature review and specific local experience from three case studies. It is shown that the proposed monitoring tools, namely the indicators and the multidimensional indicator framework, provide guidance on monitoring the human right to sanitation. In doing so, they might ultimately help sector stakeholders in the realization of this right. PMID- 27989473 TI - Highly time-resolved characterization of water-soluble inorganic ions in PM2.5 in a humid and acidic mega city in Sichuan Basin, China. AB - To investigate the characteristics of water-soluble inorganic ions (WSIIs) in Chongqing, a well-known foggy and acid region in southwestern China, hourly real time concentrations of five cations (Na+, K+, NH4+, Ca2+, and Mg2+) and six anions (F-, Cl-, NO2-, NO3-, PO43-, and SO42-) in PM2.5 during winter (from Dec. 18, 2015 to Mar. 20, 2016) in Chongqing were collected by applying In-situ Gas and Aerosol Compositions Monitor. The hourly total concentration of WSIIs was 38.5MUg/m3 on average, accounting for 57% of PM2.5 mass concentration. Secondary inorganic aerosols (NH4+, NO3-, and SO42-) were dominant WSIIs, accounting for 91% of WSIIs mass. Compared to ten years ago, SO42- concentrations were decreased by 31% but NO3- levels were doubled, likely indicative of sharply enhanced contribution to fine particle pollution from mobile sources over stationary sources. NO3- originated from the current fluxes of NH3 and HNO3 onto sulfate particles and/or from in-cloud processes were critical pathways under humid conditions in the study area. Water content and/or RH might be important factors controlling nitrate formation. Trajectory analysis manifested that aerosol pollutions in Chongqing were mostly caused by local emissions. PMID- 27989474 TI - Assessing the recharge of a coastal aquifer using physical observations, tritium, groundwater chemistry and modelling. AB - Assessing recharge is critical to understanding groundwater and preventing pollution. Here, we investigate recharge in an Australian coastal aquifer using a combination of physical, modelling and geochemical techniques. We assess whether recharge may occur through a pervasive layer of floodplain muds that was initially hypothesized to be impermeable. At least 59% of the precipitation volume could be accounted for in the shallow aquifer using the water table fluctuation method during four significant recharge events. Precipitation events <20mm did not produce detectable aquifer recharge. The highest recharge rates were estimated in the area underneath the floodplain clay layer rather than in the sandy area. A steady-state chloride method implied recharge rates of at least 200mm/year (>14% of annual precipitation). Tritium dating revealed long term net vertical recharge rates ranging from 27 to 114mm/year (average 58mm/year) which were interpreted as minimum net long term recharge. Borehole experiments revealed more permeable conditions and heterogeneous infiltration rates when the floodplain soils were dry. Wet conditions apparently expand floodplain clays, closing macropores and cracks that act as conduits for groundwater recharge. Modelled groundwater flow paths were consistent with tritium dating and provided independent evidence that the clay layer does not prevent local recharge. Overall, all lines of evidence demonstrated that the coastal floodplain muds do not prevent the infiltration of rainwater into the underlying sand aquifer, and that local recharge across the muds was widespread. Therefore, assuming fine grained floodplain soils prevent recharge and protect underlying aquifers from pollution may not be reasonable. PMID- 27989475 TI - Rapid decolorization of dye Orange G by microwave enhanced Fenton-like reaction with delafossite-type CuFeO2. AB - Bimetallic oxide CuFeO2 as a new heterogeneous catalyst has shown much higher catalytic ability for activating peroxide than single-metal oxides. The present work demonstrated a synergistic microwave (MW) enhanced Fenton-like process with CuFeO2 for rapid decolorization of azo dye Orange G (OG). The MW irradiation dramatically enhanced the OG degradation efficiency, achieving 99.9% decolorization within 15min at pH5. The XRD analysis of reused CuFeO2, together with metal leaching tests, indicated merits of recycling for CuFeO2. The subsequent surface element analysis by XPS for fresh and used CuFeO2 showed a complex network for reactions between copper-iron redox pairs and surface hydroxyl groups, leading to a synergistic Fenton-like system accelerated by MW irradiation. In the CuFeO2 initiated Fenton-like reactions, several oxidant species (i.e., OH, O2-, electron hole, and FeIVO) responsible to the OG oxidation were identified by quenching experiments, showing the MW generated high temperature and "hot spots" enhanced the yield of OH by generation of electron hole pairs. Further, the 26 detected degradation products confirmed the OH dominant oxidation of OG. This study shows that the MW-enhanced Fenton-like reaction using CuFeO2 has potential applications for rapid decolorization of dye effluent. PMID- 27989476 TI - A novel hybrid model for air quality index forecasting based on two-phase decomposition technique and modified extreme learning machine. AB - The randomness, non-stationarity and irregularity of air quality index (AQI) series bring the difficulty of AQI forecasting. To enhance forecast accuracy, a novel hybrid forecasting model combining two-phase decomposition technique and extreme learning machine (ELM) optimized by differential evolution (DE) algorithm is developed for AQI forecasting in this paper. In phase I, the complementary ensemble empirical mode decomposition (CEEMD) is utilized to decompose the AQI series into a set of intrinsic mode functions (IMFs) with different frequencies; in phase II, in order to further handle the high frequency IMFs which will increase the forecast difficulty, variational mode decomposition (VMD) is employed to decompose the high frequency IMFs into a number of variational modes (VMs). Then, the ELM model optimized by DE algorithm is applied to forecast all the IMFs and VMs. Finally, the forecast value of each high frequency IMF is obtained through adding up the forecast results of all corresponding VMs, and the forecast series of AQI is obtained by aggregating the forecast results of all IMFs. To verify and validate the proposed model, two daily AQI series from July 1, 2014 to June 30, 2016 collected from Beijing and Shanghai located in China are taken as the test cases to conduct the empirical study. The experimental results show that the proposed hybrid model based on two-phase decomposition technique is remarkably superior to all other considered models for its higher forecast accuracy. PMID- 27989477 TI - Monoterpene emissions in response to long-term night-time warming, elevated CO2 and extended summer drought in a temperate heath ecosystem. AB - Monoterpenes emitted from plants have an important role in atmospheric chemistry through changing atmospheric oxidative capacity, forming new particles and secondary organic aerosols. The emission rates and patterns can be affected by changing climate. In this study, emission responses to six years of climatic manipulations (elevated CO2, extended summer drought and night-time warming) were investigated in a temperate semi-natural heath ecosystem. Samples for monoterpene analysis were collected in seven campaigns during an entire growing season (April November, 2011). The results showed that the temperate heath ecosystem was a considerable source of monoterpenes to the atmosphere, with the emission averaged over the 8month measurement period of 21.7+/-6.8MUgm-2groundareah-1 for the untreated heath. Altogether, 16 monoterpenes were detected, of which the most abundant were alpha-pinene, delta-3-carene and limonene. The emissions of these three compounds were positively correlated with light, chamber temperature and litter abundance, but negatively correlated with soil temperature. Elevated CO2 tended to decrease the average monoterpene emissions by 40% over the whole growing season, and significantly reduced emissions in August. Extended summer drought significantly decreased the emission right after the drought treatment period, but also in the late growing season. Night-time warming significantly increased the total emissions (mainly alpha-pinene) in April, and tended to mitigate the decrease caused by drought. The inhibition effects of elevated CO2 on emissions were diminished when the treatment was combined with drought or warming. The emission responses to different treatments were not explained by vegetation changes, and the monoterpene emission profile was only moderately related to plant species coverage. The emission responses to these long-term climate manipulations varied over the growing season (with strong correlation with litter abundance) and the observed antagonistic effects in the combined treatments underlie the importance of long-term studies with multiple factors acting in concert. PMID- 27989478 TI - Environmental and socio-economic methodologies and solutions towards integrated water resources management. AB - Semi-arid regions are facing the challenge of managing water resources under conditions of increasing scarcity and drought. These are recently pressured by the impact of climate change favoring the shifting from using surface water to groundwater without taking sustainability issues into account. Likewise, water scarcity raises the competition for water among users, increasing the risk of social conflicts, as the availability of fresh water in sufficient quality and quantity is already one of the major factors limiting socio-economic development. In terms of hydrology, semi-arid regions are characterized by very complex hydro- and hydrogeological systems. The complexity of the water cycle contrasts strongly with the poor data availability, (1) which limits the number of analysis techniques and methods available to researchers, (2) limits the accuracy of models and predictions, and (3) consequently challenges the capabilities to develop appropriate management measures to mitigate or adapt the environment to scarcity and drought conditions. Integrated water resources management is a holistic approach to focus on both environmental as well as on socio-economic factors influencing water availability and supply. The management approaches and solutions adopted, e.g. in form of decision support for specific water resources systems, are often highly specific for individual case studies. PMID- 27989479 TI - Aqueous-phase aerosols on the air-water interface: Response of fatty acid Langmuir monolayers to atmospheric inorganic ions. AB - Atmospheric aerosol particles composed of a mixture of organic and inorganic compounds are common and constitute an important fraction of air pollutants. In this study, the activities of common atmospheric inorganic ions (Ag+, Zn2+, Fe3+, Fe2+, Ca2+ and Al3+) and fatty acid molecules (stearic acid and arachidic acid) at air-aqueous interface were investigated by Langmuir methods and infrared reflection-absorption spectroscopy (IRRAS). In the presence of different inorganic ions, surface pressure-area isotherms of the Langmuir films showed compressed or expanded characteristics. IRRAS spectra confirmed that the existence of inorganic ions in the fatty acid monolayer changes the surface properties of aqueous-phase aerosols. Formation of different coordination types of carboxylates at the air-water interface alters the dissolution and partitioning behavior, which has significant influence of Raoult effect on nucleating cloud droplets. Our work displays the relationship between structure and surface properties for aqueous-phase aerosols and implies an efficient method for further understanding of their formation mechanism and potential atmospheric implications. PMID- 27989480 TI - Atmospheric occurrence and health risks of PCDD/Fs, polychlorinated biphenyls, and polychlorinated naphthalenes by air inhalation in metallurgical plants. AB - Metallurgical plants are important sources of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polychlorinated naphthalenes (PCNs). It is significant to evaluate the air levels and human risks of PCDD/Fs, PCBs and PCNs in metallurgical plants considering their adverse effects on human health and thousands of metallurgical plants being in operation in China. The estimated inhalation intakes of PCDD/Fs, PCBs, and PCNs together in eight iron ore sintering plants, three secondary copper plants, four secondary aluminum plants, and one secondary lead plant were 4.9-213.4, 21.4-4026.4, 28.7 630, and 11.7fgTEQkg-1day-1, respectively, and the corresponding cancer risks were estimated to be 8.7*10-7 to 3.8*10-5, 5.1*10-6 to 1.1*10-4, 3.8*10-6 to 7.1*10-4, and 2.1*10-6, respectively. The estimated cancer risk were higher than 100 per million people for three secondary aluminum and copper smelters among the sixteen metallurgical plants, indicating high cancer risks. Stack gas samples from metallurgical plants were also collected and analyzed for comparing their emission profiles with that of air samples. The comparison of PCDD/F, PCB and PCN profiles between air samples and stack gas samples by similarity calculation and principal component analysis suggested the influence of stack gas emissions from metallurgical plants on surrounding air. These results are helpful for understanding the exposure risk to PCDD/Fs, PCBs and PCNs in numerous metallurgical plants being operation in China. PMID- 27989481 TI - Trace metals in the dissolved fraction (<0.45MUm) of the lower Athabasca River: Analytical challenges and environmental implications. AB - Water samples were collected on the Athabasca River (AR), upstream and downstream from bitumen mines and upgrading facilities, to identify changes in water quality due to industrial activities in this region of northern Alberta, Canada. Starting upstream of Fort McMurray and proceeding downstream ca. 100km, waters were collected in duplicate at 13 locations on the main stem of the river, as well as 5 tributary streams, using ultraclean sampling protocols developed for polar snow and ice. To estimate potential bioaccessibility, trace elements of concern (Ag, Cd, Pb, Sb, Tl) were determined in the dissolved fraction (<0.45MUm) along with metals known for their enrichments in bitumen (V, Ni, Mo, Re) and those found mainly in ionic (Li, Sr) or colloidal forms (Al, Co, Cr, Fe, Ga, Mn, Th, Y). Analyses were performed in the metal-free, ultraclean SWAMP lab using quadrupole and sector-field ICP-MS. Concentrations of Ag, Cd, Pb, Sb and Tl were extremely low, not significantly more abundant downstream of industry and probably reflect "background" values. In contrast, V, Ni, Mo and Re concentrations were all significantly (p<0.05) greater downstream of industry. However, chloride also increased downstream, due to natural inputs of saline groundwaters and it is unclear whether the increases in V, Ni, Mo and Re are due to natural or anthropogenic inputs to the river. Although it had been claimed that the industrial development of the Athabasca Bituminous Sands (ABS) is a significant source of Ag, Cd, Pb, Sb and Tl to the river, our study failed to find any evidence to support this. Here we provide a first, robust (accurate and precise) description of baseline values for these trace elements in the AR, and suggest that V, Ni, Mo and Re are more valuable tracers for environmental monitoring and source assessment. PMID- 27989482 TI - Improvement of chitinase Pachi with nematicidal activities by random mutagenesis. AB - Chitinase, an enzyme that can degrade the main compositions of insect intestine and cuticle, has been used in the bio-control field. Our previous work has reported the chitinase Pachi with nematicidal activity (Caenorhabditis elegans). In the present study, to improve the chitinolytic and nematicidal activities of Pachi, a random mutant library was constructed by error-prone PCR and screened by bacteriophage T7-based high-throughput screening system. One mutant, PachiN35D was obtained from about 10, 000 clones. The kinetics analysis revealed that PachiN35D exhibited a 63% decrease in Km value against chitosan, a 2.1-fold enhancement in kcat/Km value and a 1.2-fold increase in specific activity over the wild-type Pachi. Moreover, the mortality analysis against Caenorhabditis elegans showed that the 50% lethal concentration (LC50) of PachiN35D is 309.6+/ 1.1MUg/ml and a 20% increase in nematicidal activity over the wild-type Pachi (with a LC50 value of 387.3+/-31.7MUg/ml). The structure modeling and superimposition indicated that the substitution N35D reduced the distance between substrate and substrate-binding site Asp141, finally resulting in an increase in substrate affinity, catalytic efficiency and specific activity. These results provide useful information for the study of structure-function relationship of Pachi and lay a foundation for its potential applications in agro-biotechnology. PMID- 27989483 TI - Clinical Study of Seven Patients with Infarction in Territories of the Anterior Inferior Cerebellar Artery. AB - BACKGROUND: The prominent features of anterior inferior cerebellar artery (AICA) infarction are vertigo, cerebellar ataxia, and impaired hearing. The present study investigated neurological characteristics associated with AICA infarction. MATERIALS AND METHODS: The locations of infarcts in 7 patients (age, 32-72 years) with AICA infarction were divided into the lower lateral pons, the middle cerebellar peduncle (MCP), and the cerebellum. RESULTS: Ischemic lesions were located in the MCP in 6 patients, spread to the lower lateral pons in 3, and involved the cerebellum in 4 patients. Standing posture and gait were impaired in all patients. Five and 4 patients had impaired hearing and vertigo, respectively. Two patients had only symptoms of labyrinthine disease, and 1 had these symptoms accompanied by impaired hearing. The symptoms in 2 patients with the lesion in the lateral pons were consistent with those in Gasperini syndrome. Two of 3 patients without vertigo had ataxia of the extremities. Stenosis of the vertebral artery or basilar artery in 5 patients indicated that the etiology was branch atheromatous disease. CONCLUSIONS: The most prominent symptom of truncal and gait ataxia and the frequent association between vertigo and impaired hearing were consistent with the characteristics of AICA infarction. Two patients without vertigo had ataxia of the trunk and extremities that might have been due to involvement of the dorsal spinocerebellar tract in the inferior cerebellar peduncle. PMID- 27989485 TI - Acute Oxaliplatin-induced Hemolytic Anemia, Thrombocytopenia, and Renal Failure: Case Report and a Literature Review. PMID- 27989484 TI - Significant impact of divalent metal ions on the fidelity, sugar selectivity, and drug incorporation efficiency of human PrimPol. AB - Human PrimPol is a recently discovered bifunctional enzyme that displays DNA template-directed primase and polymerase activities. PrimPol has been implicated in nuclear and mitochondrial DNA replication fork progression and restart as well as DNA lesion bypass. Published evidence suggests that PrimPol is a Mn2+ dependent enzyme as it shows significantly improved primase and polymerase activities when binding Mn2+, rather than Mg2+, as a divalent metal ion cofactor. Consistently, our fluorescence anisotropy assays determined that PrimPol binds to a primer/template DNA substrate with affinities of 29 and 979nM in the presence of Mn2+ and Mg2+, respectively. Our pre-steady-state kinetic analysis revealed that PrimPol incorporates correct dNTPs with 100-fold higher efficiency with Mn2+ than with Mg2+. Notably, the substitution fidelity of PrimPol in the presence of Mn2+ was determined to be in the range of 3.4*10-2 to 3.8*10-1, indicating that PrimPol is an error-prone polymerase. Furthermore, we kinetically determined the sugar selectivity of PrimPol to be 57-1800 with Mn2+ and 150-4500 with Mg2+, and found that PrimPol was able to incorporate the triphosphates of two anticancer drugs (cytarabine and gemcitabine), but not two antiviral drugs (emtricitabine and lamivudine). PMID- 27989486 TI - Littered Cans-Death Trap of Snakes. PMID- 27989487 TI - Effect of BKCa Channel Opener LDD175 on Erectile Function in an In Vivo Diabetic Rat Model. AB - INTRODUCTION: The development of novel therapeutic options is imperative in patients with erectile dysfunction, especially those non-responsive to phosphodiesterase type 5 inhibitors. LDD175, a potent BKCa channel opener, has a relaxation effect on the in vitro cavernosal smooth muscle strip. AIM: To investigate the effect of LDD175 on erectile function using in vivo animal disease model. METHODS: Male Sprague-Dawley rats were assigned to a normal control group and seven diabetic groups: diabetic control, sildenafil (1 and 5 mg/kg), LDD175 (5 and 10 mg/kg), LDD175 5 mg/kg plus sildenafil 1 mg/kg, and LDD175 10 mg/kg plus tetraethylammonium. MAIN OUTCOME MEASURES: Intracavernosal pressure (ICP), ratio of ICP to mean arterial pressure (MAP), and the area under curve of ICP/MAP of eight groups were compared using in vivo pelvic nerve stimulation. RESULTS: The ICP, ICP/MAP ratio, and area under curve of the ICP/MAP ratio of the normal control rats increased with an increase in electrical field stimulation voltage. All parameters in the diabetic control group were significantly lower than those in the normal control rats, with an electrical field stimulation ranging from 1 to 5 V (P < .05). LDD175 improved the erectile response in diabetic rats in a dose-dependent manner. The combination of sildenafil (1 mg/kg) and LDD175 (5 mg/kg) showed a significant additive effect (P < .05) on the improvement of erectile function compared with sildenafil (1 mg/kg) alone. The enhancement of erectile function by LDD175 was completely blocked by tetraethylammonium. CONCLUSION: The results showed that the BKCa channel opener LDD175 improved erectile function in an in vivo diabetic rat model. Furthermore, combination therapy of LDD175 and sildenafil had an additive effect on the improvement of erectile function in diabetic rats. LDD175 could be a new candidate for the treatment of erectile dysfunction. PMID- 27989488 TI - Considering Attachment and Partner Perceptions in the Prediction of Physical and Emotional Sexual Satisfaction. AB - INTRODUCTION: Attachment theory provides a framework for understanding sexual satisfaction; in general, research suggests that attachment anxiety and avoidance are associated with decreased sexual satisfaction. Given their different working models of self and other, perceptions of the partner's level of satisfaction might differentially influence people's own perceptions of satisfaction based on their attachment avoidance and anxiety. AIM: To examine the predictive value of attachment anxiety and avoidance and perceptions of partner satisfaction in predicting physical and emotional satisfaction after sexual interactions in two studies. METHODS: Participants (study 1, n = 52; study 2, n = 144) completed a one-time survey containing a measurement of attachment and then reported on their physical and emotional sexual satisfaction after each sexual interaction over the course of 2 to 3 weeks. MAIN OUTCOME MEASURES: The Experiences in Close Relationships Scale-Revised was completed during the one-time survey, and ratings of personal physical and emotional sexual satisfaction (studies 1 and 2) and perceptions of partner's physical and emotional satisfaction were completed after sexual interactions (study 2). RESULTS: Greater attachment avoidance was associated with lesser physical and emotional satisfaction. Moreover, when perceiving the partner to be emotionally satisfied, people with more attachment avoidance reported less emotional satisfaction for themselves. For greater attachment anxiety, greater perceived partner satisfaction (physical and emotional) predicted greater personal satisfaction of the two types. CONCLUSION: The findings support attachment theory as a valuable lens through which to study sexual satisfaction. Moreover, the results suggest that it is important to consider perceptions of partner sexual satisfaction in understanding the sexual satisfaction of people who demonstrate attachment anxiety and avoidance. PMID- 27989489 TI - Testosterone Pellet Implantation Practices: A Sexual Medicine Society of North America (SMSNA) Member Questionnaire. AB - INTRODUCTION: There has been renewed interest in the use of subcutaneous testosterone pellets for the treatment of hypogonadism since the introduction of Testopel in 2008 by Slate Pharmaceuticals (Durham, NC, USA). Manufacturer guidelines recommend using two to six pellets; however, in the clinical setting, this is deemed insufficient. This has produced a wide variety of testosterone pellet usage that is not fully understood. AIM: To better understand subcutaneous testosterone pellet implantation practices among members of the Sexual Medicine Society of North America (SMSNA). METHODS: A 19-item questionnaire was emailed to the 687 members of the SMSNA. Of the 19 questions, 17 were multiple choice and two required write-in responses. Usage patterns, satisfaction rates, and complication rates were investigated. MAIN OUTCOME MEASURES: Data regarding indications for initiating treatment with Testopel, initial dosage, follow-up of testosterone levels and dose titration, patient tolerance and satisfaction, technique of implantation, and procedural complications were collected. RESULTS: Eighty-seven survey responses were received (12.9%). At initiation of Testopel therapy, 80.5% of respondents would implant at least 10 pellets, whereas only 4.6% would place six to seven pellets and 3.4% would implant fewer than six pellets. Many respondents would determine the starting dose based on some combination of baseline testosterone level and weight, although 24.1% described using a standard starting dose for all patients. All respondents would check testosterone levels within 3 months of initiating therapy, with the vast majority (72.4%) doing so at 1 month. Subsequent dosing of Testopel was not changed in most patients, with 41.4% and 26.4% of respondents reporting that 60% to 80% and 80% to 100% of patients, respectively, remained on their initial dose. Most respondents would re-implant pellets at a 3-month (21.8%) or 4-month (43.7%) interval. High patient satisfaction was described by respondents, with 56.3% finding patients to be satisfied "most times" and 34.5% "almost always." CONCLUSION: This study provides insight into the usage of Testopel among members of the SMSNA. We found that the vast majority of specialists use at least 10 pellets at initial implantation, with limited need for subsequent dose adjustments, good durability of response, and high patient satisfaction and tolerability. PMID- 27989490 TI - Paraphilic Sexual Offenders Do Not Differ From Control Subjects With Respect to Dopamine- and Serotonin-Related Genetic Polymorphisms. AB - INTRODUCTION: Rape and pedophilic child molestation are the most commonly convicted sexual offenses in Poland. Recent studies have suggested a possible genetic contribution toward pathologic sexual interests and behaviors. AIM: To analyze and compare functional polymorphisms of genes associated with the activity of the serotonin and dopamine systems in a group of paraphilic sexual offenders and control subjects. METHODS: The study sample (n = 97) consisted of two groups: paraphilic sexual offenders (65 pedophilic child molesters and 32 rapists) and controls (n = 76). Genetic polymorphisms previously associated with behavioral control, addictive behaviors, and sexual functions were chosen for analyses. Specifically, functional polymorphisms in dopamine receptors genes (DRD1, DRD2, DRD4), catechol-O-methyltransferase gene (COMT), dopamine transporter gene (DAT), serotonin transporter gene (SLC6A4), serotonin type 2A receptor gene (5HTR2A), tryptophan hydroxylase 2 gene (TPH2), monoamine oxidase A gene (MAOA), and brain-derived neurotrophic factor gene (BDNF) were analyzed. MAIN OUTCOME MEASURES: An association between a history of sexual offense and the distribution of genotypes and alleles in the analyzed polymorphisms. RESULTS: Our results found no association between a history of sexual offense and the distribution of genotypes or alleles in the analyzed polymorphisms. CONCLUSION: Although these results are limited by the small sample and are exploratory, they highlight a novel approach to sample selection in a population that is difficult to access and study. Future research should include larger samples and other relevant polymorphisms to advance this field of study. PMID- 27989491 TI - Reference intervals for C-peptide and insulin derived from a general adult Danish population. AB - BACKGROUND: Despite international efforts to standardize C-peptide and insulin calibrators and immunoassays, platform dependent differences still exist, and platform specific reference intervals are hence needed for correct interpretation. We therefore wanted to establish traceable reference intervals for C-peptide and insulin. METHODS: In 623 consecutively recruited participants, insulin and C-peptide were measured using the Cobas e411 (Roche Diagnostics, Switzerland). Participants with diabetes were excluded (fasting Glucose >=7.0mmol/L or HbA1c>=6.5%/>=48mmol/L) and reference intervals were calculated with and without the inclusion of persons who were prediabetic, according to two definitions (The World Health Organization (WHO) and American Diabetes Association (ADA)). To ensure the correctness of calibration, the control pools were analyzed by a reference laboratory. The reference intervals were calculated according to the IFCC guidelines, using the RefVal software (Solberg, Oslo, Norway). RESULTS: Comparison of our results with those from the reference laboratory revealed equivalence for C-peptide results whereas the insulin determined on the Cobas e411 assay were 15-20% higher. The difference is attributed to an incorrect conversion factor for converting from activity to metric units. The Cobas e411 assay uses the factor 6.945 for converting from U/mL to pmol/L. This is in disagreement with the biological activity of insulin which is 166.8*106IU/mol or 6.00nmol/IU. CONCLUSION: We successfully established reference intervals for C-peptide and insulin for non-diabetic and prediabetic participants. The reference intervals for fasting C-peptide and fasting insulin are ready for implementation. A recertification of the insulin standards is needed. PMID- 27989492 TI - A statistical method to calculate blood contamination in the measurement of salivary hormones in healthy women. AB - OBJECTIVES: Previous studies have reported that salivary concentrations of certain hormones correlate with their respective serum levels. However, most of these studies did not control for potential blood contamination in saliva. In the present study we developed a statistical method to test the amount of blood contamination that needs to be avoided in saliva samples for the following hormones: cortisol, estradiol, progesterone, testosterone and oxytocin. DESIGN & METHODS: Saliva and serum samples were collected from 38 healthy, medication-free women (mean age=33.8+/-7.3yr.; range=19-45). Serum and salivary hormonal levels and the amount of transferrin in saliva samples were determined using enzyme immunoassays. RESULTS: Salivary transferrin levels did not correlate with salivary cortisol or estradiol (up to 3mg/dl), but they were positively correlated with salivary testosterone, progesterone and oxytocin (p<0.05). After controlling for blood contamination, only cortisol (r=0.65, P<0.001) and progesterone levels (r=0.57, P=0.002) displayed a positive correlation between saliva and serum. Our analyses suggest that transferrin levels higher than 0.80, 0.92 and 0.64mg/dl should be avoided for testosterone, progesterone and oxytocin salivary analyses, respectively. CONCLUSIONS: We recommend that salivary transferrin is measured in research involving salivary hormones in order to determine the level of blood contamination that might affect specific hormonal salivary concentrations. PMID- 27989493 TI - Consequences of the presence and absence of empathy during consultations in primary care: A focus group study with patients. AB - OBJECTIVE: There is general consensus that explicit expression of empathy in patient-GP communication is highly valued. Yet, little is known so far about patients' personal experiences with and expectations of empathy. Insight into these experiences and expectations can help to achieve more person-centeredness in GP practice care. METHODS: Participants were recruited by a press report in local newspapers. INCLUSION CRITERIA: adults, a visit to the GP in the previous year. Exclusion criterion: a formal complaint procedure. Five focus groups were conducted. The discussions were analyzed using constant comparative analysis. RESULTS: In total 28 participants took part in the focus group interviews. Three themes were identified: (1) Personalized care and enablement when empathy is present; (2) Frustrations when empathy is absent; (3) Potential pitfalls of empathy. Participants indicated that empathy helps build a more personal relationship and makes them feel welcome and at ease. Furthermore, empathy makes them feel supported and enabled. A lack of empathy can result in avoiding a visit to the GP. CONCLUSION: Empathy is perceived as an important attribute of patient GP communication. Its presence results in feelings of satisfaction, relief and trust. Furthermore, it supports patients, resulting in new coping strategies. A lack of empathy causes feelings of frustration and disappointment and can lead to patients avoiding visiting their GP. PRACTICE IMPLICATIONS: More explicit attention should be given to empathy during medical education in general and during vocational GP-training. PMID- 27989494 TI - Self-Monitoring of Blood Glucose: Impact of Quantity Limits in Public Drug Formularies on Provincial Costs Across Canada. AB - OBJECTIVES: For most patients with diabetes, routine use of blood glucose test strips (BGTS) has not been shown to be beneficial, yet the economic implications of broad publicly funded reimbursement for BGTS are substantial. We assessed the potential impact of BGTS quantity limits on utilization and costs for 6 publicly funded drug plans across Canada. METHODS: A cross-sectional analysis was conducted in 6 provinces (Alberta, Saskatchewan, Manitoba, Nova Scotia, Newfoundland and Labrador and Prince Edward Island) for patients who received at least 1 prescription for BGTS in 2014 through the public drug program. We determined the number of BGTS that would have exceeded the quantity limits and the associated costs to the provincial drug program. RESULTS: A total of $38,051,026 was spent on BGTS reimbursed through public drug programs among the 6 provinces. In provinces where BGTS use is largely restricted to patients using insulin, the potential annual savings were minimal, ranging from 0.4% to 2.3%, whereas in provinces with more liberal listings, potential savings ranged from 12.4% to 19.8%. Combining these results with data from a previous analysis in Ontario and British Columbia, the cost savings associated with BGTS quantity limits for 8 provinces across Canada (capturing approximately three-quarters of the Canadian population) is estimated to be $30.3 million annually. CONCLUSIONS: The national implementation of a quantity limit policy for BGTS that aligns with evidence of efficacy, optimal prescribing and patient safety can lead to considerable savings for most public drug plans across Canada. PMID- 27989495 TI - Assessing Whether the Association Between Sleep Apnea and Diabetes is Bidirectional. AB - OBJECTIVES: To determine whether there is a bidirectional association between sleep apnea and diabetes mellitus. METHODS: We conducted longitudinal analyses of a population-based cohort over 12 years using Taiwan's national universal health insurance database. In analysis I, we included 102 355 individuals without type 2 diabetes mellitus at baseline and estimated the hazard ratio of incident diagnosis of type 2 diabetes mellitus for patients with and those without sleep apnea. In analysis II, we included 258 053 participants without sleep apnea at baseline and calculated the hazard ratio of developing sleep apnea for patients with and those without type 2 diabetes. RESULTS: In analysis I, the incidence rates of type 2 diabetes were 17.7 and 11.1 per 1000 person-years for patients with and those without sleep apnea, respectively. Patients with sleep apnea had an increased risk for diabetes (adjusted hazard ratio [aHR] = 1.33; 95% confidence interval [CI], 1.22 to 1.46). In analysis II, the risk for sleep apnea with diabetes was not statistically significant (aHR = 1.06; 95% CI, 0.98 to 1.16). These associations in both analyses did not substantively change after accounting for various latent periods. CONCLUSIONS: Baseline sleep apnea is associated with incident type 2 diabetes; however, the presence of type 2 diabetes cannot predict the development of sleep apnea. PMID- 27989496 TI - Effects of first exogenous nutrients on the mRNA levels of atrogin-1/MAFbx and GLUT1 in the skeletal muscles of newly hatched chicks. AB - The aim of this study was to examine the effects of first exogenous nutrients on the mRNA levels of muscle atrophy F-box (atrogin-1/MAFbx) and glucose transporters (GLUTs) in the skeletal muscles of newly hatched chicks with no feed experience. In experiment 1, newly hatched chicks had free access to feed or were fasted for the first 24h. The chicks having free access to feed for the first 24h increased their body weight and had decreased atrogin-1/MAFbx mRNA levels in their sartorius and pectoralis major muscles compared with the fasted chicks. In experiment 2, newly hatched chicks received a single feed via intubation into the crop. Three hours after intubation, levels of atrogin-1/MAFbx mRNA in the sartorius muscle were decreased whereas the plasma insulin concentration and phosphorylated AKT levels in the sartorius muscle were increased. In addition, the mRNA levels of GLUT1 and GLUT8 were increased in the sartorius muscle after the intubation. However, in the pectoralis major muscle, AKT phosphorylation and levels of atrogin-1/MAFbx, GLUT1 and GLUT8 mRNA were not affected 3h after intubation. The first exogenous nutrients increased the level of phosphorylated AKT in the sartorius muscle of newly hatched chicks, possibly because of the decrease in atrogin-1/MAFbx mRNA levels. Furthermore, the sartorius muscle in newly hatched chicks appeared to be more susceptible to the first feed compared with the pectoralis major muscle. PMID- 27989497 TI - Dacryoadenitis associated with IgG4-related disease in an Afro-Colombian adolescent. AB - IgG4-related disease (IgG4-RD) is a recently recognized clinical condition with multiple aspects not yet elucidated. It is characterized by a fibrous inflammatory process that involves multiple organs and clinical, serological and histopathological findings, which represent a major challenge for the clinician. Classically described as an expansive tumor lesion with storiform fibrosis, lymphoplasmacytic infiltration (IgG4-positive) and elevated serum IgG4. Clinical features are variable, and pancreatic as well as extrapancreatic involvement has been reported, more frequently in Asian men over 50 years and rarely described in black people. We report the case of an Afro-Colombian teenage woman, who had a unilateral ocular protrusion of unknown cause, with histopathologic findings that revealed infiltration of lymphocyte and plasma cells into the lacrimal gland. It was positive for IgG4, ruling out other conditions, and confirming IgG4-related dacryoadenitis. PMID- 27989498 TI - Recent advancements in the molecular genetics of left ventricular noncompaction cardiomyopathy. AB - Left ventricular noncompaction cardiomyopathy (LVNC) is a myocardial disorder characterized by prominent and excessive trabeculations with deep recesses in the ventricular wall. Clinical manifestations of LVNC are highly variable, ranging from no symptoms to arrhythmias, heart failure, thromboembolism, or even sudden cardiac death. It is a heterogenetic disease which can be presented as an autosomal, X-linked or mitochondrial disorder. A series of candidate mutations have been identified in LVNC patients or murine models. It is generally believed that these gene mutations may share a final common pathway in the pathogenesis of LVNC, but the underlying molecular mechanisms are unknown. In this review, we discuss the gene mutations identified in LVNC patients and summarize recent advancements in the molecular genetic analysis of LVNC. PMID- 27989499 TI - Biological agents in polyarticular juvenile idiopathic arthritis: A meta-analysis of randomized withdrawal trials. AB - BACKGROUND AND OBJECTIVE: Although various biological agents are in use for polyarticular juvenile idiopathic arthritis (pJIA), head-to-head trials comparing the efficacy and safety among them are lacking. We aimed to compare the efficacy and safety of biological agents in pJIA using all currently available randomized withdrawal trials (wRCTs). METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov was performed. Eligible wRCTs: patients with pJIA where a biological agent was compared with another biological agent or placebo. Efficacy was evaluated using disease flare as a measure. Adverse events (AEs) and serious AEs were evaluated. Network meta-analysis compared biological agents based on a (empirical Bayes) mixed-effects logistic regression model that combines statistical inference from both direct and indirect comparisons of the treatment effects between biological agents. RESULTS: Of 496 references identified, five wRCTs were included-abatacept, adalimumab, anakinra, etanercept, and tocilizumab, one trial each, all vs. placebo. There were no differences in efficacy among biological agents and most showed statistically significant efficacy compared with placebo (nearly all exceptions were in agreement with the original study data). Serious AEs occurred very infrequently (0-8%) and an analysis was not possible. There were no differences for AEs when compared among biological agents or to placebo. CONCLUSION: There were no statistical differences among biological agents for efficacy or safety. Overall, biological agents were effective and safe when compared to placebo. Based on these data, other considerations such as price and availability may need to be used to decide among biological agents when treating pJIA patients. PMID- 27989500 TI - Gray matter abnormalities associated with fibromyalgia: A meta-analysis of voxel based morphometric studies. AB - OBJECTIVES: Studies employing voxel-based morphometry (VBM) have reported inconsistent findings on the association of gray matter (GM) abnormalities with fibromyalgia. The aim of the present study is to identify the most prominent and replicable GM areas that involved in fibromyalgia. METHODS: A systematic search of the PubMed database from January 2000 to September 2015 was performed to identify eligible whole-brain VBM studies. Comprehensive meta-analyses to investigate regional GM abnormalities in fibromyalgia were conducted with the Seed-based d Mapping software package. RESULTS: Seven studies, reporting nine comparisons and including a grand total of 180 fibromyalgia patients and 126 healthy controls, were included in the meta-analyses. In fibromyalgia patients compared with healthy controls, regional GM decreases were consistently found in the bilateral anterior cingulate/paracingulate cortex/medial prefrontal cortex, the bilateral posterior cingulate/paracingulate cortex, the left parahippocampal gyrus/fusiform cortex, and the right parahippocampal gyrus/hippocampus. Regional GM increases were consistently found in the left cerebellum. Meta-regression demonstrated that age was correlated with GM anomalies in fibromyalgia patients. CONCLUSIONS: The current meta-analysis identified a characteristic pattern of GM alterations within the medial pain system, default mode network, and cerebro cerebellar circuits, which further supports the concept that fibromyalgia is a symptom complex involving brain areas beyond those implicated in chronic pain. PMID- 27989501 TI - A randomized, blinded, multicenter trial of a gentamicin vancomycin gel (DFA-02) in patients undergoing abdominal surgery. AB - BACKGROUND: SI is a significant medical problem. DFA-02 is an investigational bioresorbable modified release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL). A Phase 2a study, where the drug was applied during surgical incision closure, suggested safety and tolerability but was not designed to assess its efficacy. STUDY DESIGN: In a Phase 2b randomized, blinded trial patients undergoing abdominal, primarily colorectal, surgery were randomized (4:1:1) to one of three study arms: DFA-02, matching placebo gel, or standard of care (SOC) involving irrigation of the wound with normal saline. The DFA-02 and placebo gel groups received up to 20 mL of study drug inserted above the fascia during wound closure, and were treated in a double-blind manner; the SOC group was treated in a single-blind manner. The primary endpoint was SSI (adjudicated centrally by a blinded committee) through postoperative day 30. RESULTS: Overall, 445 subjects (intention-to-treat) were randomized at 35 centers with 425 subjects completing the study and being evaluable. There were 67 SSIs (15.8%): 64.2% superficial, 7.5% deep, and 28.4% organ space. The incidence of SSI was not statistically significantly different between the DFA-02 and the placebo gel/SOC arms combined, 42/287 = 14.6% vs 25/138 = 18.1% (p = 0.36), respectively. Rehospitalization within 30 days was also similar between study groups (DFA-02 28.6%, placebo gel 21.4%, SOC 27.3%). CONCLUSION: In this multicenter, blinded, randomized trial with central adjudication, the gentamicin/vancomycin gel was not associated with a significant reduction in SSI. SUMMARY: Patients undergoing abdominal surgery were randomized to one of three study arms: DFA-02 gel consisting of both gentamicin and vancomycin, matching placebo gel, or standard of care (SOC). Of 425 patients completing the study at 35 sites the gentamicin/vancomycin gel was not associated with a significant reduction in SSI. PMID- 27989502 TI - Profiles of serum cytokine levels in Takayasu arteritis patients: Potential utility as biomarkers for monitoring disease activity. AB - BACKGROUND: Takayasu arteritis (TA) is an autoimmune arteritis of unknown etiology. Currently, the erythrocyte sedimentation rate (ESR) and serum C reactive protein (CRP) levels are widely used to monitor disease activity of TA. However, sometimes it is difficult to reflect inflammatory symptoms in either CRP or ESR values, especially in TA patients with immunosuppressive therapies. Therefore, higher-accuracy biomarkers for evaluating disease activity need to be explored. METHODS AND RESULTS: We examined 21 Japanese patients diagnosed with TA; 17 TA patients were treated with prednisone with or without additional immunosuppressive therapies and the remaining 4 patients were treated with infliximab, a human monoclonal anti-tumor necrosis factor (TNF)-alpha antibody. In active phase, the serum levels of both TNF-alpha and interleukin (IL)-6 were significantly higher than in healthy subjects, as is the case with both the levels of CRP and ESR. In contrast, the levels of both IL-12 and IL-23 remained in the normal range. Both TNF-alpha and IL-6 levels were markedly decreased in response to therapies, on equality with both CRP and ESR levels. Regarding the TA patients treated with infliximab, both CRP and IL-6 levels tended to be decreased after infliximab therapy. Conversely, TNF-alpha level after infliximab therapy was higher than before therapy. CONCLUSION: Both TNF-alpha and IL-6 levels, but not IL-12 or IL-23 levels, in the serum could be potent biomarkers that can reflect the activity of TA. PMID- 27989503 TI - A Purinergic Trail for Metastases. AB - Nucleotides and nucleosides have emerged as important modulators of tumor biology. Recently acquired evidence shows that, when these molecules are released by cancer cells or surrounding tissues, they act as potent prometastatic factors, favoring tumor cell migration and tissue colonization. Therefore, nucleotides and nucleosides should be considered as a new class of prometastatic factors. In this review, we focus on the prometastatic roles of nucleotides and discuss future applications of purinergic signaling modulation in view of antimetastatic therapies. PMID- 27989504 TI - Morin and Esculetin supplementation modulates c-myc induced energy metabolism and attenuates neoplastic changes in rats challenged with the procarcinogen 1,2 - dimethylhydrazine. AB - Targeting tumor metabolism by natural products is a novel approach and provides rationale for anti-cancer drug discovery. The present study aims to explore the impact of morin and/or esculetin on c-myc induced energy metabolism in 1,2 dimethylhydrazine (DMH) induced colon cancer in rats. In order to achieve this aim we analyzed the expression of glucose and glutamine transporters and the key enzymes of glycolytic pathway besides the markers of neoplastic changes viz., mucin depleted foci (MDF), beta catenin accumulated crypts (BCAC), and markers of cell proliferation viz., proliferating cell nuclear antigen (PCNA), argyrophilic nucleolar antigen (AgNOR), c-myc, c-jun and c-fos. All the parameters tested in the present study are highly influenced by the phytochemicals morin and/or esculetin in a way to prevent colon carcinogenesis. Morin and/or esculetin supplementation effectively targets tumor metabolism via beta-cateinin/c-myc signaling and affects glycolysis and glutaminolysis to abrogate colon cancer in rats. The anti-cancer effect of morin is more pronounced than esculetin. The effect obtained through the combined treatment of morin and esculetin is comparable to that of individual supplementation of morin and there is no synergistic effect. Overall individual supplementation of morin scores well as a potential anticancer agent targeting glycolysis and glutaminolysis in colon cancer. PMID- 27989505 TI - Endothelial miRNAs as Cellular Messengers in Cardiometabolic Diseases. AB - Metabolic syndrome is a clustering of risk factors that increases susceptibility to serious cardiometabolic complications, including type 2 diabetes (T2D) and myocardial infarction. Understanding the underlying mechanisms will advance the development of diagnostic and therapeutic approaches. A prominent feature of cardiometabolic diseases is endothelial dysfunction. Endothelial cell (EC) homeostasis and response to pathological stimuli are controlled by gene regulatory networks in which miRNAs play a critical role. Recently, miRNAs have been implicated as cell-cell messengers that can influence cellular function. This review investigates the known and potential roles for miRNA-based cell-cell communication in the control of cardiovascular health and explores the value of identifying miRNA biomarkers and developing therapeutics that harness or antagonize miRNA-based communication. PMID- 27989506 TI - Novel androgen-induced activity of an antimicrobial beta-defensin: Regulation of Wolffian duct morphogenesis. AB - The Wolffian duct (WD) undergoes morphological changes induced by androgens to form the epididymis, which is an organ essential for sperm maturation. Androgen action in WD epithelium involves paracrine factors of mesenchymal origin that function by still poorly understood mechanisms. Here we studied the antimicrobial beta-defensin SPAG11C as a new player in duct morphogenesis, localized prenatally in the WD mesenchyme. Organotypic culture of rat WDs and tissues from Androgen Receptor (AR) knockout mice (ARKO) were used. Our results show that androgen/AR signaling differentially regulated SPAG11C expression at mRNA and protein levels in the developing WD. WDs incubated with recombinant human SPAG11C were shorter and less coiled as a result of reduced epithelial cell proliferation, but not increased apoptosis. Our results suggested beta-defensin SPAG11C as an androgen target required for WD morphogenesis. This highlights the multifunctional repertoire of the beta-defensin protein family and their potential contribution to the in utero environment that determines male reproductive success. PMID- 27989507 TI - Corrigendum to "Profile of Silodosin" [Eur Urol Suppl 2010;9:491-5]. PMID- 27989508 TI - A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease. AB - Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD. PMID- 27989509 TI - Anti-inflammatory effect of the six compounds isolated from Nauclea officinalis Pierrc ex Pitard, and molecular mechanism of strictosamide via suppressing the NF kappaB and MAPK signaling pathway in LPS-induced RAW 264.7 macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nauclea officinalis Pierrc ex Pitard. is a Chinese medicinal herb that contains high level of alkaloids which is the most abundant and active constituent. Strictosamide isolated from Nauclea officinalis Pierrc ex Pitard. showed significant effects on inflammatory response, compared with pumiloside, 3-epi-pumiloside, vincosamide, 3alpha,5alpha tetrahydrodeoxycordifoline lactam and naucleamide A-10-O-beta-D-glucopyranoside of this plant. AIM OF STUDY: we investigated the biological activities of the six compounds mentioned-above, and the underlying molecular mechanism exerted by the most potent one, strictosamide. MATERIALS AND METHODS: The effects of strictosamide and other five compounds on the inhibitory activity of nitric oxide (NO) were screened by Griess test. The contents of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in media were detected by using Enzyme-linked immunosorbent (ELISA) kits. The effects on the mRNA expression of nitric oxide synthase (iNOS), TNF-alpha and IL-1beta of strictosamide were further investigated by RT-qPCR. Western blot assay was conducted to illustrate the effects of strictosamide on iNOS and phosphorylation of p65, inhibitor of NF kappaB (IkappaB)-alpha, IkappaB-kinase (IKK)-alpha as well as p-extracellular signal-regulated kinase (ERK), p-c-jun N-terminal kinase (JNK) and p-p38 in the protein levels. RESULTS: Strictosamide potently suppressed the productions of NO, TNF-alpha and IL-1beta in LPS-induced RAW 264.7 macrophages, and it dose dependently alleviated the LPS-simulated protein level of iNOS as well as the mRNA expressions of iNOS, TNF-alpha and IL-1beta. In addition, molecular data revealed that strictosamide markedly decreased the expressions of p-p65, p IkappaBalpha and p-IKKalpha. Furthermore, strictosamide significantly attenuated LPS-induced the phosphorylation of p38, ERK and JNK. CONCLUSIONS: At present study, the results indicated that the anti-inflammatory activity of strictosamide was associated with the restraint of NO, TNF-alpha and IL-1beta via negative regulation of both NF-kappaB and mitogen-activated protein kinases (MAPKs) in LPS induced RAW 264.7 cells. PMID- 27989510 TI - Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal kappa-opioid receptors. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A. AIM OF THE STUDY: To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naive mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine. RESULTS: Single subcutaneous injection of bullatine A or dynorphin A(1-17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naive mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective kappa-opioid receptor antagonist GNTI. CONCLUSION: These results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide pharmacological basis for concurrent bullatine A and morphine treatment for chronic pain and morphine analgesic tolerance. PMID- 27989511 TI - Increment of serum bilirubin as an independent marker predicting new-onset type 2 diabetes mellitus in a Korean population. AB - BACKGROUND AND AIMS: Several cross-sectional studies reported that serum bilirubin concentrations had an inverse association with type 2 diabetes mellitus (T2DM) prevalence. The aim of the current study was to investigate the relationship between percentage change in bilirubin levels (PCB) and incident risk of T2DM using a longitudinal model. METHODS AND RESULTS: 22,084 participants who received regular health check-ups between 2006 and 2012 were enrolled. Multivariable-adjusted Cox regression models were used to determine the hazard ratio (HR) of incident T2DM based on PCB. PCB was determined by subtracting baseline serum bilirubin level (BB) from the bilirubin level at the end of follow up or a year before the last date of diagnosis, dividing by BB and multiplying by 100. Compared to non-diabetics, BB was lower in the diabetic group at the initial visit. There were 20,098 participants without T2DM at the initial visit; 1253 new cases occurred during follow-up. As PCB increased, T2DM incidence also increased (P < 0.001). After adjusting for confounders, the HR of incident T2DM in the highest PCB quartile was 2.08 (95% confidence interval [CI] 1.76-2.46). This trend remained significant when PCB was analyzed as a continuous variable (HR for 1-SD increment, 1.25; 95% CI 1.19-1.31). Additional analysis comparing the rate of PCB during the follow-up period revealed that the serum bilirubin level of the Incident T2DM group increased before T2DM development and decreased rapidly thereafter compared to others (P < 0.001). CONCLUSIONS: Bilirubin level increment over time is associated with T2DM development. PMID- 27989512 TI - Increased cost sharing and changes in noncompliance with specialty referrals in The Netherlands. AB - INTRODUCTION: The compulsory deductible, a form of patient cost-sharing in the Netherlands, has more than doubled during the past years. There are indications that as a result, refraining from medical care has increased. We studied the relation between patient cost-sharing and refraining from medical care by evaluating noncompliance with referrals to medical specialists over several years. METHODS: Noncompliance with specialty referrals was assessed in the Netherlands from 2008 until 2013, using routinely recorded referrals from general practitioners to medical specialists and claims from medical specialists to health insurers. Associations with patient characteristics were estimated using multilevel logistic regression analyses. RESULTS: Noncompliance rates were approximately stable from 2008 to 2010 and increased from 18% in 2010 to 27% in 2013. Noncompliance was highest in adults aged 25-39 years. The increase was highest in children and patients with chronic diseases. No significantly higher increase among patients from urban deprived areas was found. DISCUSSION/CONCLUSION: Noncompliance increased during the rise of the compulsory deductible. Our results do not suggest a one-to-one relationship between increased patient cost-sharing and noncompliance with specialty referrals. In order to develop effective policy for reducing noncompliance, it is advisable to focus on the mechanisms for noncompliance in the groups with the highest noncompliance rates (young adults) and with the highest increase in noncompliance (children and patients with chronic diseases). PMID- 27989513 TI - Category-specific features and valence in action-effect prediction: An EEG study. AB - Despite extensive research on action-effect anticipation, little attention has been paid to the anticipation of different attributes of an event. An action effect is not only a sensory event; it is often also an event of emotional value which can be pleasant or aversive. This latter attribute of action-effect prediction is similar to anticipation of reward versus punishment. To date the neural systems controlling sensory and reward anticipation have not been systematically compared. To this end, we designed an experiment to manipulate the sensory content and the emotional valence of the stimuli in an orthogonal fashion. We recorded and compared event-related potentials (ERPs) to the presentation of stimuli instantiating expected or unexpected features. Our results suggest (1) that both features are processed altogether and (2) that the prediction error resulting from the manipulation is reflected in an enhanced N400 component. PMID- 27989514 TI - The effect of cortisol on autobiographical memory retrieval depends on remoteness and valence of memories. AB - There is evidence that specificity of autobiographical memory (AM) retrieval is impaired by cortisol. However, it is unknown whether glucocorticoids differentially influence the retrieval of recent versus remote AMs. Therefore, the aim of the current study was to investigate the effects of cortisol on AM retrieval, in terms of memory specificity, with respect to remoteness of the retrieved memories. A placebo controlled, double blind study was conducted. Thirty female and 24 male healthy participants (mean age 24.5, SD=3.7) received either placebo or 10mg hydrocortisone before completing an autobiographical memory test. Participants showed higher memory specificity for recent memories compared to remote ones. There was no main effect of cortisol on AM retrieval. However, interaction effects suggest that cortisol affects remote, but not recent memories, which seems to depend upon valence. PMID- 27989515 TI - Cytokine ratios in chronic periodontitis and type 2 diabetes mellitus. AB - AIM: Chronic periodontitis may influence systemic cytokines in type 2 diabetes. This study aimed to evaluate the cytokine ratios in type 2 diabetes with, and without chronic periodontitis. MATERIALS & METHODS: Gingival status, periodontal, glycemic parameters and serum cytokines were evaluated in participants grouped as healthy, chronic periodontitis, and type 2 diabetes with, and without chronic periodontitis. RESULTS AND CONCLUSIONS: Cytokine ratios showed significant differences in type 2 diabetes and chronic periodontitis, were highest in participants having both type 2 diabetes and chronic periodontitis, with a statistically significant cut-off point and area under curve by receiver operating characteristic. PMID- 27989516 TI - Analysis of relationship of high fat mass and low muscle mass with lipid profile in Brazilians aged 80 years or over. AB - AIM: To analyze the lipid profile of older people aged >=80 years according to body composition (high fat mass, low muscle mass and both). MATERIAL AND METHOD: The sample consisted of 113 older people aged >=80 years. The assessment of body composition was made using Dual Energy X-ray Absorptiometry (DXA) and the lipid profile analysis using an enzymatic colorimetric kit. We used Analysis of Variance (ANOVA) test to compare the mean of lipid profile according to body composition and were constructed logistic regression models to verify the association between these two variables. RESULTS: It was found that older people with high fat had higher mean values of TG compared to normal and low muscle mass group. Older people with low muscle mass showed mean values of LDL-c lower than other groups. It was observed that older people with high fat is more likely to have (OR 2.70; 95%CI 1.14-6.37) high blood concentration of TG. CONCLUSION: Thus, it appears that high fat is related to the high blood concentration of TG in older people aged >=80 years, especially those with Asian origin and diabetes besides those with low muscle mass shows lower mean values of LDL-c. PMID- 27989517 TI - Significant disparities in risks of diabetes mellitus and metabolic syndrome among chronic hepatitis C virus patients in the U.S. AB - AIM: Diabetes mellitus (DM) and metabolic syndrome (MetSyn) among chronic hepatitis C virus (HCV) patients increases risks for nonalcoholic fatty liver disease (NAFLD) and more rapid progression to hepatocellular carcinoma (HCC). We aim to evaluate the prevalence of DM and MetSyn among HCV patients, focusing on age-specific and race/ethnicity-specific disparities. METHODS: We retrospectively evaluated 2003-2012 National Health and Nutrition Examination Survey (NHANES) data for age and race disparities in concurrent DM and MetSyn among HCV patients. Multivariate logistic regression models evaluated for independent predictors of DM and MetSyn among HCV patients. RESULTS: Overall U.S. prevalence of HCV was 1.29% from 2003 to 2012 and prevalence of DM and MetSyn among HCV patients was 17.5% and 35.0%, respectively. Higher rates of DM (36.9% vs. 3.3%, p<0.001) and MetSyn (50.5% vs. 11.7%, p<0.001) were seen among HCV patients >=60 compared to <40years. The highest rates of DM and MetSyn were seen among African Americans (AA) (DM: 39.1%, MetSyn: 29.2%) and the lowest in non-Hispanic whites (DM: 9.4%, MetSyn: 33.0%). On multivariate regression, patients >=60 were significantly more likely to have DM compared to patients <40 years (OR 11.90, 95% CI 2.73-52.60, p=0.001); AA were significantly more likely to have DM compared to non-Hispanic whites (OR 2.82, 95% CI 1.53-5.20, p=0.001). CONCLUSION: Among chronic HCV patients, the highest risk of DM and MetSyn was seen among older patients, African Americans, and women. These groups are at higher risk of cirrhosis and HCC due to concurrent NAFLD. PMID- 27989518 TI - Obesity and diabetes as prognostic factors in patients with colorectal cancer. AB - Colorectal carcinoma is one of the most prevalent cancer types for both men and women. Prognosis of the disease is mostly defined by the stage. Localized disease has a better prognosis especially in earlier stages I and II. In addition most patients with more advanced localized stage III disease are expected to survive with a combination of surgery and adjuvant treatments. Progress in treatment of metastatic disease has led to median survivals exceeding 2 years and a minority of oligometastatic patients may survive even longer or be cured with multimodality therapy. Besides stage of the disease few prognostic factors are available to guide informative discussions with patients or guide therapeutic decisions. One area of research that may provide information in this direction is comorbidity conditions of the metabolic syndrome spectrum. Despite a significant body of literature investigating elements of the metabolic syndrome such as obesity and diabetes in isolation as risk and prognostic factors in colorectal cancer, a more restricted amount of research is dealing with the combination of these two factors as prognosticators of colorectal cancer. This paper will discuss published data on these factors and specifically their combination in the prognosis of colorectal cancer and will address some of their pathogenesis and therapy implications. PMID- 27989519 TI - The function of appendage patterning genes in mandible development of the sexually dimorphic stag beetle. AB - One of the defining features of the evolutionary success of insects is the morphological diversification of their appendages, especially mouthparts. Although most insects share a common mouthpart ground plan, there is remarkable diversity in the relative size and shapes of these appendages among different insect lineages. One of the most prominent examples of mouthpart modification can be found in the enlargement of mandibles in stag beetles (Coleoptera, Insecta). In order to understand the proximate mechanisms of mouthpart modification, we investigated the function of appendage-patterning genes in mandibular enlargement during extreme growth of the sexually dimorphic mandibles of the stag beetle Cyclommatus metallifer. Based on knowledge from Drosophila and Tribolium studies, we focused on seven appendage patterning genes (Distal-less (Dll), aristaless (al), dachshund (dac), homothorax (hth), Epidermal growth factor receptor (Egfr), escargot (esg), and Keren (Krn). In order to characterize the developmental function of these genes, we performed functional analyses by using RNA interference (RNAi). Importantly, we found that RNAi knockdown of dac resulted in a significant mandible size reduction in males but not in female mandibles. In addition to reducing the size of mandibles, dac knockdown also resulted in a loss of the serrate teeth structures on the mandibles of males and females. We found that al and hth play a significant role during morphogenesis of the large male specific inner mandibular tooth. On the other hand, knockdown of the distal selector gene Dll did not affect mandible development, supporting the hypothesis that mandibles likely do not contain the distal-most region of the ancestral appendage and therefore co-option of Dll expression is unlikely to be involved in mandible enlargement in stag beetles. In addition to mandible development, we explored possible roles of these genes in controlling the divergent antennal morphology of Coleoptera. PMID- 27989521 TI - Predictors of weight regain in patients who underwent Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for obesity and results in long-term weight loss and resolution of co-morbidities. However, weight regain may occur as soon as 1-2 years after surgery. OBJECTIVES: This retrospective study aimed to investigate the prevalence of weight regain and possible preoperative predictors of this phenomenon after RYGB. SETTING: An academic medical center in the United States. METHODS: A total of 1426 obese patients (15.8% male) who underwent RYGB during January 2000 to 2012 and had at least a 2-year follow-up were reviewed. We included only patients who were initially successful, having achieved at least 50% excess weight loss at 1 year postoperatively. Patients were then categorized into either the weight regain group (WR) or sustained weight loss (SWL) group based upon whether they gained>=15% of their 1-year postoperative weight. RESULTS: Weight regain was observed in 244 patients (17.1%). Preoperative body mass index was similar between groups. Body mass index was significantly higher and percent excess weight loss was significantly lower in the WR group (P<.001). Average weight regain was 19.5+/-9.3 kg and-.8+/-8.5 in the WR and SWL groups, respectively (P<.001). Time elapsed since RYGB was significantly longer in the WR group (WR 6.0+/-2.4 years versus SWL 3.3+/-1.8 years; P<.001; range 2-12 yr). Patients in the WR group were significantly younger (WR 42.3+/-9.8 yr versus SWL 45.7+/-10.8 years; P<.001), had fewer co-morbidities, and were less likely to have type 2 diabetes with insulin dependence preoperatively. Univariate analysis found that older age, male gender, having hypertension, dyslipidemia, and insulin-treated type 2 diabetes were all factors associated with sustained weight loss. Moreover, a longer duration after RYGB was associated with weight regain. Multivariate analysis revealed that younger age was a significant predictor of weight regain even after adjusting for time since RYGB. CONCLUSION: The present study confirmed that a longer interval after RYGB was associated with weight regain. Younger age was a significant predictor of weight regain even after adjusting for time since RYGB. The findings of this study underscore the complexity of the mechanisms underlying weight loss and regain after RYGB. Future prospective studies are needed to further explore the prevalence, predictors, and mechanisms of weight regain after RYGB. PMID- 27989520 TI - Differences in brain networks during consecutive swallows detected using an optimized vertex-frequency algorithm. AB - Patients with dysphagia can have higher risks of aspiration after repetitive swallowing activity due to the "fatigue effect". However, it is still unknown how consecutive swallows affect brain activity. Therefore, we sought to investigate differences in swallowing brain networks formed during consecutive swallows using a signal processing on graph approach. Data were collected from 55 healthy people using electroencephalography (EEG) signals. Participants performed dry swallows (i.e., saliva swallows) and wet swallows (i.e., water, nectar-thick, and honey thick swallows). After standard pre-processing of the EEG time series, brain networks were formed using the time-frequency-based synchrony measure, while signals on graphs were formed as a line graph of the brain networks. For calculating the vertex frequency information from the signals on graphs, the proposed algorithm was based on the optimized window size for calculating the windowed graph Fourier transform and the graph S-transform. The proposed algorithms were tested using synthetic signals and showed improved energy concentration in comparison to the original algorithm. When applied to EEG swallowing data, the optimized windowed graph Fourier transform and the optimized graph S-transform showed that differences exist in brain activity between consecutive swallows. In addition, the results showed higher differences between consecutive swallows for thicker liquids. PMID- 27989522 TI - A randomized trial comparing reflux symptoms in sleeve gastrectomy patients with or without hiatal hernia repair. AB - BACKGROUND: The effect of laparoscopic sleeve gastrectomy (SG) on reflux symptoms is unclear. Many surgeons offer SG only to patients with minor or no reflux symptoms, fearing that patients with severe reflux symptoms will experience worsening of their condition after SG. Many also advocate crural repair at the time of SG to prevent de novo or worsening reflux symptoms. These decisions are made without suitable data to form such conclusions. OBJECTIVE: To determine the effect of SG with or without hiatal hernia repair on reflux symptoms. SETTING: University of Texas Health Sciences Center in Houston. METHODS: The Gastrointestinal Symptom Rating Scale (GSRS) was administered to 100 consecutive, preoperative SG patients who were then randomly assigned into a crural repair group or nonrepair group in a parallel design. The patients were subsequently followed-up every 3 months for 1 year. We compared reflux symptoms of the 2 groups on the basis of demographic characteristics, body mass index, weight loss, presence and size of hiatal hernia, and GSRS for 12 months. RESULTS: At 1 year, with 78% follow-up, the data demonstrated a significant decrease in the GSRS for both groups (P<.001); however, there was no difference between the groups (P = .35). Age, starting body mass index, percent excessive weight loss, and hiatal hernia size did not correlate with change in the GSRS score. The only variable that affected outcome was the preoperative GSRS. At 12 months, 38% of patients with a preoperative GSRS score less than the median score of the study population experienced worsening of their symptoms compared with only 2% of patients who had a preoperative GSRS score greater than the median. Overall, 19% experienced worsening reflux (5% de novo), 14% had no change, and 66% reported an improvement in symptoms. CONCLUSION: These data suggest that a crural repair at the time of SG does not significantly reduce reflux symptoms compared with SG alone. Preoperative patients with significant reflux symptoms experienced a more significant improvement in symptoms after surgery compared with those who did not report significant reflux symptoms before surgery. The high incidence of reflux after SG observed in the current literature may be a result of a specific patient subpopulation who undergoes SG because of surgeon bias rather than an inherent property of SG itself or the presence of a hiatal hernia. PMID- 27989523 TI - Gastrointestinal phytobezoar following bariatric surgery: Systematic review. AB - Bezoars are collections of undigested foreign material that accumulate in the gastrointestinal tract. The most common are phytobezoars, which are formed from plant fibers, especially those related to the ingestion of persimmon. Patients who undergo abdominal surgery, including bariatric surgery for obesity, and particularly gastrectomy, are prone to bezoar formation due to reduced gastric motility, loss of pyloric function, and hypoacidity. Bezoars can form months to years postoperatively. Our objective was to review the published literature regarding phytobezoar formation after bariatric surgery. We investigated the entire scientific literature on phytobezoars as a complication after bariatric surgery using PubMed and Embase searches of all reports published to date. We used the following keywords: "phytobezoars" or "bezoars" and "bariatric surgery" or "laparoscopic adjustable gastric band" or "laparoscopic sleeve gastrectomy" or "Roux-en-Y gastric bypass" or "single anastomosis gastric bypass" or "biliopancreatic diversion." Seventeen eligible articles were included in the study. We provide an overview of the incidence, classification, and manifestations of bezoar formation as a rare, late morbidity of bariatric surgery. Treatment options include chemical enzyme therapy, endoscopic dissolution and removal, or surgery. Nutritional counseling regarding bezoar formation and prevention of recurrence after bariatric surgery should emphasize changing eating habits, including sufficient drinking and chewing and avoiding the overindulgence of foods with high-fiber content, especially citrus pith and persimmons. Clinicians should be aware of this potential rare complication. Additional studies are needed to examine the eating habits and food choices of bariatric patients with bezoar complications and to elucidate more clearly the risk factors for this pathologic condition. PMID- 27989524 TI - Gastric necrosis due to adhesive band formed by lap-band fixation suture managed by laparoscopy-assisted LES preserving proximal gastrectomy. PMID- 27989525 TI - Acute thrombotic thrombocytopenic purpura after sleeve gastrectomy: a case report and review of the literature. PMID- 27989526 TI - Improving the prediction of environmental fate of engineered nanomaterials by fractal modelling. AB - A critical analysis of the available engineered nanomaterials (ENMs) environmental fate modelling approaches indicates that existing tools do not satisfactorily account for the complexities of nanoscale phenomena. Fractal modelling (FM) can complement existing kinetic fate models by including more accurate interpretations of shape and structure, density and collision efficiency parameters to better describe homo- and heteroaggregation. Pathways to including hierarchical symmetry concepts and a route to establishing a structural classification of nanomaterials based on FM are proposed. PMID- 27989527 TI - The Landscape of Cutaneous Lymphomas in 2016, An Introduction. PMID- 27989528 TI - Adaptive nonlinear robust relative pose control of spacecraft autonomous rendezvous and proximity operations. AB - This paper studies relative pose control for a rigid spacecraft with parametric uncertainties approaching to an unknown tumbling target in disturbed space environment. State feedback controllers for relative translation and relative rotation are designed in an adaptive nonlinear robust control framework. The element-wise and norm-wise adaptive laws are utilized to compensate the parametric uncertainties of chaser and target spacecraft, respectively. External disturbances acting on two spacecraft are treated as a lumped and bounded perturbation input for system. To achieve the prescribed disturbance attenuation performance index, feedback gains of controllers are designed by solving linear matrix inequality problems so that lumped disturbance attenuation with respect to the controlled output is ensured in the L2-gain sense. Moreover, in the absence of lumped disturbance input, asymptotical convergence of relative pose are proved by using the Lyapunov method. Numerical simulations are performed to show that position tracking and attitude synchronization are accomplished in spite of the presence of couplings and uncertainties. PMID- 27989529 TI - A fast iterative recursive least squares algorithm for Wiener model identification of highly nonlinear systems. AB - In this paper, an online identification algorithm is presented for nonlinear systems in the presence of output colored noise. The proposed method is based on extended recursive least squares (ERLS) algorithm, where the identified system is in polynomial Wiener form. To this end, an unknown intermediate signal is estimated by using an inner iterative algorithm. The iterative recursive algorithm adaptively modifies the vector of parameters of the presented Wiener model when the system parameters vary. In addition, to increase the robustness of the proposed method against variations, a robust RLS algorithm is applied to the model. Simulation results are provided to show the effectiveness of the proposed approach. Results confirm that the proposed method has fast convergence rate with robust characteristics, which increases the efficiency of the proposed model and identification approach. For instance, the FIT criterion will be achieved 92% in CSTR process where about 400 data is used. PMID- 27989530 TI - Corrigendum to "Prevention of Recurrent Urinary Tract Infections by Intravesical Administration of Hyaluronic Acid and Chondroitin Sulphate: A Placebo-Controlled Randomised Trial [Eur Urol 2011;59:645-51]. PMID- 27989531 TI - Corrigendum to "Reply to Ruth E. Langley, Patricia Price and Paul D. Abel's Letter to the Editor re: Claude C. Schulman, Jacques Irani, Juan Morote, et al. Androgen-Deprivation Therapy in Prostate Cancer: A European Expert Panel Review. Eur Urol Suppl 2010;9:675-91" [Eur Urol 2011;59:e26]. PMID- 27989532 TI - Comparative detection and recovery of Pseudomonas aeruginosa by membrane filtration and a Most Probable Number technique. AB - Two reference membrane filtration methods (Standard Methods: SM 9213E and U.S.EPA), the Most Probable Number method (Pseudalert(r)) and a membrane filtration method currently used by the Ontario Ministry of the Environment and Climate Change (MOECC) Laboratory Services Branch Etobicoke, Canada (Method E3371) were compared for the detection and recovery of Pseudomonas aeruginosa (P. aeruginosa) in sterile phosphate buffered dilution water (PBDW), un-spiked and spiked environmental water samples. The confirmation of presumptive-positive P. aeruginosa colonies was performed by API(r)20NE and on Milk Agar. Detection and recoveries were compared by determining the sensitivity and specificity of the methods and the performance of the methods was evaluated for statistical differences using ANOVA. The recovery of P. aeruginosa from PBDW spiked at a level of 100CFU/100mL was significantly higher (p<0.05) with Pseudalert(r) compared to the other methods. However, there were no significant differences (p>0.5) between all four methods when spiked at 5 and 40CFU/100mL. In the analysis of 61 environmental surface water samples, the MPN method (Pseudalert(r)) demonstrated the highest sensitivity (100%) while the Standard Method-SM9213E had the lowest sensitivity (3%). The U.S.EPA method and SM9213E demonstrated the highest specificity (100%) while Pseudalert(r) had the lowest (71.0%). Pseudalert(r) was able to detect P. aeruginosa in samples with higher amount of suspended solids as compared to other MF methods. Analysis of 24 environmental surface water samples (previously found to be negative for P. aeruginosa), which were spiked with P. aeruginosa at 5CFU/100mL, showed different sensitivities in recovery including Pseudalert(r) (100%), MOECC E3371 (92%), U.S.EPA (33%) and SM 9213E (33%). The highest mean recovery was observed with Pseudalert(r) (5.3 MPN/100mL) and the least with the U.S.EPA method (0.4CFU/100mL). Pseudalert(r) demonstrated improved performance in the detection and recovery of P. aeruginosa over SM9213E, U.S.EPA and MOECC E3371 in terms of sensitivity. However, Pseudalert(r) reported the highest amount of false positive results compared to the other three MF methods. The addition of a confirmation step with Milk Agar eliminated the false positive results. Therefore, this confirmatory step is recommended in order to increase the specificity of the Pseudalert(r) method. PMID- 27989534 TI - Corrigendum to "The Epidemiology of Renal Cell Carcinoma" [Eur Urol 2011;60:615 21]. PMID- 27989533 TI - The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome. AB - INTRODUCTION: Antiphospholipid syndrome (APS) is a common acquired thrombophilia associated with a high thrombotic risk, in which vitamin K antagonists (VKA) represent the mainstay of therapy. Case series involving up to 35 patients with APS suggested limited efficacy and safety of direct oral anticoagulants (DOACs). MATERIAL AND METHODS: In the prospective case series we followed 56 consecutive patients with APS (44 women and 12 men, aged from 22 to 64years), including 33 (60%) associated with systemic lupus erythematosus (SLE) and 16 (28.6%) with triple APS who were treated with DOACs due to their preferences or unstable anticoagulation with VKA. DOACs were started at least 3months since the thromboembolic event in patients with D-dimer below 500ng/ml. RESULTS: Forty-nine (87.5%) patients were treated with rivaroxaban, 4 (7.3%) with dabigatran and 3 (5.4%) with apixaban. During follow-up of 2 to 43 (mean 22) months, 6 (10.7%, 5.8 per 100 patient-years) patients (4 women and 2 men, 4 with triple positive APS) experienced recurrent thrombosis, including deep vein thrombosis (n=4, including 2 episodes preceded by nonadherence), superficial vein thrombosis (n=1) and non ST elevation myocardial infarction (n=1). The recurrence rate of VTE on DOACs was 5.8 per 100 patient-years. Two patients (3.6%) experienced severe bleeding. CONCLUSIONS: This case-series suggests that DOACs are safe in patients with APS. These findings need to be confirmed in larger studies. PMID- 27989535 TI - History of hypospadias: Lost in translation. AB - : The evolution of hypospadias surgery can be classified under 3 periods that were closely related to advances in surgical instruments, introduction of anesthesia, and newer suture materials. Stretching dominated the early period, tunneling during the Middle Ages, and flaps during the modern period. Suture materials have included at various time silver wires, horsehair, and stainless steel. Examination and translation of the original manuscripts showed that Galen recommended stretching and suturing of glanular hypospadias and not amputation or partial penectomy as has been currently reported. The term chordee was first introduced in the 18th century in relation to gonorrhea and was defined as "painful imperfect erection of the penis during gonorrhea, with downward incurvation." This was a common complication of gonorrhea before the introduction of antibiotics. Mettauer, Duplay, Mayo, and others used the terms incurvation, ventral deformity, ventral curvature, and others. Clinton Smith in 1938 was the first surgeon to use the term congenital chordee in direct relation to hypospadias. The use of prepuce for urethroplasty, popular now, was first reported by Liston in 1838, Rochet in 1899, Russell in 1900, and Mayo in 1901. The two stage repair performed in the early 20th century differed from that in the early 21st century in that urethroplasty was performed in the first stage and only anastomosis to the original meatus was performed in the second stage. The two-stage repair, currently known as Bracka's two-stage repair, was first described in 1962 by Cloutier. The use of the urethral plate in epispadias was first described by Liston in 1838, Thiersch in 1869 and by Anger & Duplay in hypospadias in 1874. Partially epithelialized urethroplasty using the urethral plate was described by Duplay in 1880, Russell 1915, Denis Browne 1940, Reddy 1975, Orkiszewski 1987, Rich 1989, and Snodgrass in 1994. LEVEL OF EVIDENCE: V. PMID- 27989536 TI - Complications of bladder closure in cloacal exstrophy: Do osteotomy and reoperative closure factor in? AB - BACKGROUND/PURPOSE: The aims of surgical management in cloacal exstrophy (CE) have shifted to optimizing outcomes and quality of life while minimizing morbidity. This report reviews the single-institution experience of complications of bladder closure in CE. METHODS: Patients with CE were identified from a prospectively-maintained bladder exstrophy-epispadias complex database. Operative and follow-up data were analyzed to compare complications and failure rates of bladder closure between closures performed with and without osteotomy and primary versus reoperative closures. RESULTS: Of 134 patients followed with CE, 112 met inclusion criteria. Median follow-up time was 3.05years. The failure rate among 112 primary closures (mean age 8.4months) was 31.3% versus 51.9% in reoperative closures (mean age 19.7months) (p=0.044). Complication rate among primary and reoperative closures was 17.9% and 33.3%, respectively (p=0.076). For closures with pelvic osteotomy, failure rate was 24.0% versus 45.9% without osteotomy (p=0.018). Among primary closures with osteotomy, the complication rate was 21.3% versus 10.8% without osteotomy (p=0.171). CONCLUSIONS: Complications of bladder closure are common in CE. Pelvic osteotomy reduces failure rates without a significant rise in complications, which are often minor. There was no statistically significant difference in complication rates between reoperative and primary closures. However, reoperative closures were more likely to fail, emphasizing the importance of a successful primary closure. LEVEL OF EVIDENCE: II: retrospective study. PMID- 27989537 TI - Delayed cardiac tamponade: A rare but life-threatening complication of catheter ablation. AB - Delayed cardiac tamponade (DCT) is a rare and life-threatening complication of catheter ablation performed as a treatment of atrial fibrillation, with few cases described in the medical literature. We present the case of a 57year-old man presenting with DCT 61days following a catheter ablation procedure. To the best of our knowledge, this is the most delayed case of cardiac tamponade (CT) following catheter ablation described in the literature. We also discuss the importance of point of care ultrasound (POCUS) in the diagnosis and treatment of CT. Emergency physicians must maintain a high index of suspicion in making the diagnosis of CT as patients may present with vague symptoms such as neck or back pain, shortness of breath, fatigue, dizziness, or altered mental status, often without chest pain. Common risk factors for CT include cancer, renal failure, pericarditis, cardiac surgery, myocardial rupture, trauma, and retrograde aortic dissection. In addition, although rare, both catheter ablation and use of anticoagulation carry risks of developing CT. A worldwide survey of medical centers performing catheter ablation found CT as a complication in less than 2% of cases [1]. Some proposed mechanisms of DCT include small pericardial hemorrhages following post-procedural anticoagulation or rupture of the sealed ablation-induced left atrial wall [2]. Clinical examination and electrocardiography may be helpful. However, the criterion standard for diagnosing CT is echocardiography [3]. PMID- 27989538 TI - Clinical profile of patients of acute aortic dissection presenting to the ED without chest pain. PMID- 27989539 TI - Comments: Ultrasound measurement of inferior vena cava collapse predicts propofol induced hypotension. PMID- 27989540 TI - Assessing postoperative acute kidney injury in high-risk patients undergoing major abdominal surgery: Author's reply. PMID- 27989541 TI - Editorial Conundrums. PMID- 27989542 TI - Chromatin Is Stretched but Intact When the Nucleus Is Squeezed through Constrictions. PMID- 27989544 TI - Use of dual energy X-ray absorptiometry in pediatric patients. AB - Dual Energy X-ray Absorptiometry (DXA) is a vital tool for assessing bone health in patients at risk for fragility fractures. In pediatric patients, this technology is used in conjunction with clinical fracture history to diagnosis osteoporosis and monitor treatment response. Childhood and adolescence is characterized by linear growth and bone mass accrual; thus there are important differences in the interpretation of bone measurements obtained by DXA in these young patients. This review aims to explore the current indications for DXA use and interpretation of DXA in the pediatric age group using currently available reference databases. Limitations of DXA in pediatric patients, specifically in children with short stature, will be explored. We will review several pathophysiologic mechanisms that may lead to low bone density in children, discussing representative diseases and the recommendations for monitoring bone health with DXA in these conditions. Finally, we will highlight new methods by which DXA imaging can gather additional information on bone health in children and may improve our ability to predict fractures and osteoporosis. PMID- 27989543 TI - Role of endoplasmic reticulum stress in disuse osteoporosis. AB - Osteoporosis is a major skeletal disease with low bone mineral density, which leads to an increased risk of bone fracture. Salubrinal is a synthetic chemical that inhibits dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) in response to endoplasmic reticulum (ER) stress. To understand possible linkage of osteoporosis to ER stress, we employed an unloading mouse model and examined the effects of salubrinal in the pathogenesis of disuse osteoporosis. The results presented several lines of evidence that osteoclastogenesis in the development of osteoporosis was associated with ER stress, and salubrinal suppressed unloading-induced bone loss. Compared to the age-matched control, unloaded mice reduced the trabecular bone area/total area (B.Ar/T.Ar) as well as the number of osteoblasts, and they increased the osteoclasts number on the trabecular bone surface in a time-dependent way. Unloading-induced disuse osteoporosis significantly increased the expression of Bip, p-eIF2alpha and ATF4 in short-term within 6h of tail suspension, but time dependent decreased in HU2d to HU14d. Furthermore, a significant correlation of ER stress with the differentiation of osteoblasts and osteoclasts was observed. Administration of salubrinal suppressed the unloading-induced decrease in bone mineral density, B.Ar/T.Ar and mature osteoclast formation. Salubrinal also increased the colony-forming unit-fibroblasts and colony-forming unit osteoblasts. It reduced the formation of mature osteoclasts, suppressed their migration and adhesion, and increased the expression of Bip, p-eIF2alpha and ATF4. Electron microscopy showed that rough endoplasmic reticulum expansion and a decreased number of ribosomes on ER membrane were observed in osteoblast of unloading mice, and the abnormal ER expansion was significantly improved by salubrinal treatment. A TUNEL assay together with CCAAT/enhancer binding protein homologous protein (CHOP) expression indicated that ER stress-induced osteoblast apoptosis was rescued by salubrinal. Collectively, the results support the notion that ER stress plays a key role in the pathogenesis of disuse osteoporosis, and salubrinal attenuates unloading-induced bone loss by altering proliferation and differentiation of osteoblasts and osteoclasts via eIF2alpha signaling. PMID- 27989545 TI - Physical activity and sedentary behavior levels in children and adolescents with type 1 diabetes using insulin pump or injection therapy - The importance of parental activity profile. AB - In children and adolescents, treatments for type 1 diabetes (T1D) have recently evolved with the introduction of the insulin pump. However, little is known about how a pump is associated with physical activity (PA) patterns. The goal of the study was to examine the activity profile of Canadian children and adolescents with T1D according to their insulin treatment (pump vs. injections), as well as barriers to exercise and parental lifestyle habits. A self-administered questionnaire was completed by 188 subjects with T1D aged 6 to 17 and their parents at the endocrinology clinic of Sainte-Justine's University Hospital Center (Montreal, Canada). Sixty percent of patients used an insulin pump. There were no significant differences in any components of the PA profile, sedentary habits, and exercise barriers between subjects using injections and those using a pump. Fear of hypoglycemia was the main PA barrier in both treatment groups. A more diverse PA practice by parents was associated with more moderate-to-vigorous PA and less screen time in adolescents. In conclusion, type of treatment was not associated with more activity in pediatric patients with T1D and a varied parental PA profile was the main factor of interest for healthier habits in adolescents with T1D. PMID- 27989546 TI - Superoxide anion generation and oxidative stress in methylmercury-induced endothelial toxicity in vitro. AB - Emerging evidence has pointed to mercury exposure as a risk factor for hypertension, atherosclerosis, myocardial infarction and coronary heart disease. However, the underlying mechanisms are not well understood. This study investigated potential toxic effects of low concentrations of methylmercury (MeHg) in cultured bovine aortic endothelial cells (BAECs) and the possible involvement of reactive species, particularly superoxide anion, in mediating such toxicity. MeHg treatment increased the oxidation of 2',7' dichlorodihydrofluorescein diacetate (a general probe for reactive species) and dihydroethidium, a specific probe for superoxide anion. MeHg-induced 2',7' dichlorodihydrofluorescein diacetate and dihydroethidium oxidations were significantly decreased by apocynin, an inhibitor of the enzyme NADPH oxidase, which represents a main source of superoxide anion in endothelial cells. MeHg treatment significantly disrupted mitochondrial membrane potential and this event was also reversed by apocynin. MeHg treatment also decreased glutathione levels and this event preceded glutathione peroxidase inhibition, which was observed only at 24h after treatment. These results indicate that MeHg induces oxidative stress in cultured BAECs and that this event is related to the production of superoxide anion. Moreover, the observed protective effects of apocynin in BAECs suggest the potential involvement of NADPH-oxidase in MeHg-induced endothelial dysfunction, which represents a pivotal event in most cardiovascular diseases. PMID- 27989547 TI - Graft inflow modulation in adult-to-adult living donor liver transplantation: A systematic review. AB - INTRODUCTION: Small-for-size syndrome (SFSS) has an incidence between 0 and 43% in small-for-size graft (SFSG) adult living donor liver transplantation (LDLT). Portal hypertension following reperfusion and the hyperdynamic splanchnic state are reported as the major triggering factors of SFSS. Intra- and postoperative strategies to prevent or to reduce its onset are still under debate. We analyzed graft inflow modulation (GIM) during adult LDLT considering the indications, efficacy of the available techniques, changes in hemodynamics and outcomes. MATERIALS AND METHODS: A systematic literature search was performed using PubMed, EMBASE, Scopus and the Cochrane Library Central. Treatment outcomes including in hospital mortality and morbidity, re-transplantation rate, 1-, 3-, and 5-year patient overall survival and 1-, 3-, and 5-year graft survival rates, hepatic artery and portal vein flows and pressures before and after inflow modulation were analyzed. RESULTS: From 563 articles, 12 studies dated between 2003 and 2014 fulfilled the selection criteria and were therefore included in the study. These comprised a total of 449 adult patients who underwent inflow modulation during adult-to-adult LDLT. Types of GIM described were splenic artery ligation, splenectomy, meso-caval shunt, spleno-renal shunt, portocaval shunt, and splenic artery embolization. Mortality and morbidity ranged between 0 and 33% and 17% and 70%, respectively. Re-transplantation rates ranged between 0% and 25%. GIM was associated with good survival for both graft and recipients, reaching an 84% actuarial rate at 5 years. Through the use of GIM, irrespective of the technique, a statistically significant reduction of PVF and PVP was obtained. CONCLUSIONS: GIM is a safe and efficient technique to avoid or limit portal hyperperfusion, especially in cases of SFSG, decreasing overall morbidity and improving outcomes. PMID- 27989548 TI - DNA replication and inter-strand crosslink repair: Symmetric activation of dimeric nanomachines? AB - Eukaryotic DNA replication initiation and the Fanconi anemia pathway of interstrand crosslink repair both revolve around the recruitment of a set of DNA processing factors onto a dimeric protein complex, which functions as a loading platform (MCM and FANCI-FANCD2 respectively). Here we compare and contrast the two systems, identifying a set of unresolved mechanistic questions. How is the dimeric loading platform assembled on the DNA? How can equivalent covalent modification of both factors in a dimer be achieved? Are multicomponent DNA interacting machines built symmetrically around their dimeric loading platform? Recent biochemical reconstitution studies are starting to shed light on these issues. PMID- 27989549 TI - Hemorrhagic pheochromocytoma presenting as severe hypertension with myocardial infarction. PMID- 27989550 TI - PET imaging for thyroid cancers: Current status and future directions. AB - Positron emission tomography-computed tomography (PET/CT) combines both functional and anatomic information and provides in vivo molecular information on biological processes that can be useful at different steps of evolution of thyroid cancers. 18Fluorodeoxyglucose being highly trapped in rapidly dividing cells makes 18F-FDG-PET recommended in the staging, prognostic evaluation and follow-up of metastatic and/or of poorly differentiated thyroid carcinomas. 18F FDG PET/CT can help in the localization of persistent/recurrent disease. However, its sensitivity depends widely on tumor burden and histology. Iodine 124 (124I) is currently under evaluation for diagnosis and pretherapeutic dosimetry planning. PET/CT using 18F-FDOPA is the most sensitive radiopharmaceutical for localizing persistent/recurrent medullary thyroid carcinoma (MTC). However, its sensitivity depends on calcitonin levels, with a threshold value of around 150pg/mL. 18F-FDG PET/CT can also be used in MTC with short calcitonin or CEA doubling time. PMID- 27989551 TI - Uncertainty quantification of environmental performance metrics in heterogeneous aquifers with long-range correlations. AB - We investigate how the uncertainty stemming from disordered porous media that display long-range correlation in the hydraulic conductivity (K) field propagates to predictions of environmental performance metrics (EPMs). In this study, the EPMs are quantities that are of relevance to risk analysis and remediation, such as peak flux-averaged concentration, early and late arrival times among others. By using stochastic simulations, we quantify the uncertainty associated with the EPMs for a given disordered spatial structure of the K-field and identify the probability distribution function (PDF) model that best captures the statistics of the EPMs of interest. Results indicate that the probabilistic distribution of the EPMs considered in this study follows lognormal PDF. Finally, through the use of information theory, we reveal how the persistent/anti-persistent correlation structure of the K-field influences the EPMs and corresponding uncertainties. PMID- 27989552 TI - Defining early CAA: insights from a rare monogenic disorder. PMID- 27989553 TI - Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study. AB - BACKGROUND: Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D) is a genetic form of CAA that can be diagnosed before the onset of clinical symptoms by DNA testing. We aimed to investigate whether haemodynamic measures are decreased in presymptomatic and symptomatic HCHWA-D mutation carriers compared with healthy controls. METHODS: In this case-control study, we included presymptomatic and symptomatic HCHWA-D mutation carriers diagnosed through genetic testing and recruited through the HCHWA-D patient association (Katwijk, Netherlands) and the outpatient clinic of the Department of Neurology of the Leiden University Medical Center (Leiden, Netherlands), and healthy controls. We measured regional cerebral blood flow (rCBF) using pseudo-continuous arterial spin labelling. Quantitative flow was measured by phase-contrast magnetic resonance angiography of the cerebropetal vessels. Vascular reactivity was established by measuring changes in blood-oxygen-level-dependent (BOLD) signal after visual stimulation. Data from presymptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis. FINDINGS: Between May 15, 2012, and December 22, 2015, we investigated cross sectional imaging data from 27 HCHWA-D mutation carriers (12 presymptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical grey matter rCBF in the occipital lobe (mean difference -11.1 mL/100 g per min, 95% CI -2.8 to -19.3; uncorrected p=0.010) and decreased flux in the basilar artery (mean difference 0.9 mL/s, 95% CI -1.5 to -0.2; uncorrected p=0.019). However, we noted no changes in rCBF and flux in presymptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both presymptomatic (mean BOLD change 1.1% [SD 0.5], mean difference -0.4% change, 95% CI -0.7 to -0.2; p=0.001; mean time to baseline 10.1 s [SD 7.6], mean difference 4.6 s, 95% CI 0.4 to 8.8; p=0.032) and symptomatic carriers (mean BOLD change 0.4% [SD 0.1], mean difference -0.9%, 95% CI -1.1 to -0.6; p<0.0001; mean time to baseline 20.3 s [SD 8.4], mean difference 13.1 s, 95% CI 9.4 to 16.9; p<0.0001) compared with controls; however, the difference in mean time to peak was only significant for symptomatic carriers (mean difference 12.2 s, 95% CI 8.6 to 15.9; p<0.0001). INTERPRETATION: Our findings suggest that determination of vascular reactivity might be a useful biomarker for early detection of vascular amyloid pathology in sporadic CAA, and a biomarker of efficacy in future intervention trials. Our data indicate that vascular reactivity measurements might be useful for differential diagnosis in dementia to determine the vascular component. FUNDING: USA National Institutes of Health. PMID- 27989557 TI - The invisible child: childhood heart disease in global health. PMID- 27989559 TI - Expanding GBD collaboration-call for experts in health financing and health systems. PMID- 27989560 TI - India's demonetisation drive is affecting access to medical care. PMID- 27989554 TI - Hypertranscription in Development, Stem Cells, and Regeneration. AB - Cells can globally upregulate their transcriptome during specific transitions, a phenomenon called hypertranscription. Evidence for hypertranscription dates back over 70 years but has gone largely ignored in the genomics era until recently. We discuss data supporting the notion that hypertranscription is a unifying theme in embryonic development, stem cell biology, regeneration, and cell competition. We review the history, methods for analysis, underlying mechanisms, and biological significance of hypertranscription. PMID- 27989558 TI - New metrics for the Lancet Standing Commission on Liver Disease in the UK. PMID- 27989561 TI - Cell penetrating SERPINA5 (ProteinC inhibitor, PCI): More questions than answers. AB - SERPINA5 (proteinC inhibitor, plasminogen activator inhibitor-3) is a secreted, extracellular clade A serpin. Its main characteristics are broad protease reactivity and wide tissue distribution (in man). SERPINA5 has originally been described as an inhibitor of activated protein C and independently as an inhibitor of the plasminogen activator urokinase. SERPINA5 binds glycosaminoglycans, phospholipids, and retinoic acid. Glycosaminoglycans and certain phospholipids can modulate its inhibitory activity and specificity. Studies suggest that SERPINA5 may play a role in hemostasis, in male reproduction, in host defense, and as a tumor suppressor. However, its biological role has not yet been defined. So far SERPINA5 deficiency has not been described in man. Mouse models are of limited value, since in mice serpinA5 is almost exclusively expressed in the reproductive tract. Consistently the only obvious phenotype of serpinA5-knockout mice is infertility of homozygous males. SERPINA5 can be internalized by cells and translocated to the nucleus. The internalization is dependent on the phospholipid phosphatidylethanolamine and on the intact N terminus of SERPINA5, which functions as a cell penetrating peptide. Further functional analysis of intracellular SERPINA5 will contribute to our understanding of the biological role of this molecule. PMID- 27989562 TI - Changing shape and shaping change: Inducing the inner ear. AB - The inner ear arises from non-neural ectoderm as a result of instructions sent by surrounding tissues. These interactions progressively restrict the potential of the ectoderm, resulting in the formation of the otic placode, a disk of thickened ectoderm that will give rise to all of the inner ear derivatives and its neurons. While otic placode is a surface structure, the inner ear is internalised, embedded within the cranial mesenchyme. Here, the cellular and molecular interactions that restrict the lineage of non-neural ectoderm in its transition to otic placode are reviewed, and how these interactions impinge on the coordination of otic placodal cell shape that drive the dramatic morphogenesis of the placode, as it becomes the otocyst. PMID- 27989563 TI - Preclinical evidence for the addiction potential of highly palatable foods: Current developments related to maternal influence. AB - It is well established that obesity has reached pandemic proportions. Over the last four decades the prevalence of obesity and morbid obesity have risen substantially in both men and women worldwide. Although there are many causative factors leading to excessive weight gain including genetics and sedentary lifestyle, the transformation of the food environment has undoubtedly contributed to the dangerously high rates of obesity. The current food landscape is inundated with food engineered to contain artificially high levels of sugar and fat. Overconsumption of these types of food overrides the homeostatic mechanisms, which under normal circumstances regulate appetite and body mass, leading to hedonic eating. Evidence from the animal literature has illustrated nutrition influenced perturbations that occur within the mesolimbic dopamine pathway, as well as maladaptive behavioral responses that result from chronic ingestion of highly palatable foods. These neurobehavioral adaptations are similar to what is observed in drugs of abuse. Recent evidence also supports that maternal exposure to these foods is capable of provoking neurobehavioral alterations in offspring. Therefore the purpose of this review is to summarize the current developments on the addictive potential of highly palatable foods, as well as illuminate the impact of maternal hyperphagia and obesity on the reward-related neurocircuitry and addiction-like behaviors in the offspring. PMID- 27989564 TI - Behavioral evidence of emotion dysregulation in binge eaters. AB - Binge eating is the most common disordered eating symptom and can lead to the development of obesity. Previous self-report research has supported the hypothesis that individuals who binge eat report greater levels of general emotion dysregulation, which may facilitate binge-eating behavior. However, to date, no study has experimentally tested the relation between binge eating history and in-vivo emotion dysregulation. To do this, a sample of female college students who either endorsed binge eating (n = 40) or denied the presence of any eating pathology (n = 47) completed the Difficulties with Emotion Regulation Scale (DERS) and a behavioral distress tolerance task (the Paced Auditory Serial Addition Task-Computer: PASAT-C) known to induce negative affect and distress. The binge eating group was 2.96 times more likely to quit the PASAT-C early (chi2 = 5.04, p = 0.025) and reported greater irritability (F(1,84) = 7.09 p = 0.009) and frustration (F(1,84) = 5.00, p = 0.028) after completing the PASAT-C than controls, controlling for initial levels of these emotions. Furthermore, across the entire sample, quitting early was associated with greater emotion dysregulation on the DERS (rpb = 0.342, p < 0.01). This study is the first to demonstrate that individuals who binge eat show in-vivo emotional dysregulation on a laboratory task. Future studies should examine the PASAT-C to determine its potential clinical utility for individuals with or at risk of developing binge eating. PMID- 27989565 TI - Tracking food intake as bites: Effects on cognitive resources, eating enjoyment, and self-control. AB - While monitoring food intake is critical for controlling eating, traditional tools designed for this purpose can be impractical when one desires real-time feedback. Further, the act of monitoring can deplete valuable cognitive resources. In response to these concerns, technologies have been developed to aid those wanting to control their food intake. Of note, devices can now track eating in number of bites taken as opposed to more traditional units such as pieces or volume. Through two studies, the current research investigates the effects of tracking food portions at the bite level on cognitive resources, enjoyment of the eating experience, and objective and subjective self-control. Results indicate that using wearable technology to track bite portions, as compared to doing so mentally, (1) reduces cognitive resource depletion, (2) is equally as effective for allowing users to successfully achieve eating goals, and (3) does not reduce enjoyment of the eating experience. These results support the viability of tracking food intake at the bite level, which holds a number of potential implications for eating and weight management. PMID- 27989566 TI - Gender differences in eating behavior and eating pathology: The mediating role of rumination. AB - OBJECTIVE: Rumination is a maladaptive emotion regulation strategy which contributes to psychopathology and is more frequently used by women than men. It has been found to mediate the relationship between gender and the occurrence of anxiety disorders or depression. Since gender differences also appear in dysfunctional eating, the aim of the study is to test, whether rumination mediates the association between gender and several facets of eating pathology. METHOD: A total of 295 participants (205 women) completed an online-questionnaire including the assessment of different facets of dysfunctional eating and rumination. Mediation analyses were conducted with PROCESS. RESULTS: Women reported significantly higher levels in both, rumination and eating pathology. Moreover, rumination mediated the relationship between gender and all assessed aspects of dysfunctional eating. DISCUSSION: The present study extends findings on the mediating role of rumination accounting for gender differences in psychopathology to eating pathology in a community sample. Results suggest that cognitive factors play a substantial role in explaining gender differences in eating pathology which tend to be reduced to biologicals factors and beauty ideals. PMID- 27989567 TI - Corrigendum to "Impaired eye blink classical conditioning distinguishes dystonic patients with and without tremor" [Park. Relat. Disord. 31 (2016) 23-27]. PMID- 27989568 TI - Child abuse and neglect profiles and their psychosocial consequences in a large sample of incarcerated males. AB - Research examining child abuse and neglect (CAN) profiles among adult offender populations is lacking. Therefore, the primary aim of the present study was to address this limitation by using latent class analysis (LCA) to identify meaningful classes of individuals who have experienced physical abuse, emotional abuse, sexual abuse, as well as neglect. Another aim was to estimate the association between CAN class membership and external criteria (psychopathy factors, self-esteem, attitudes towards male sexual violence in dating relationships, child sexual abuse myth acceptance, violent offending, and age). Data were collected among a large systematically selected sample of adult male inmates (N=1261). Based on LCA, three unique classes of CAN were distinguished, including a 'low abuse' group (43.4% of the sample), a 'high physical and emotional abuse' group (51.3%), and a 'poly-victimized' group (5.3%). The analysis revealed that the CAN classes were differentially associated with affective responsiveness, cognitive responsiveness, personal self-esteem, prison self-esteem, attitudes towards male sexual violence in dating relationships, and violent offending. Findings highlight the unique nature of CAN constellations among criminal justice involved participants. The significance of the present results is discussed in relation to past and future research. Potential contributions to treatment strategies are also presented. PMID- 27989569 TI - Comparison of the effects of various lubricant eye drops on the in vitro rabbit corneal healing and toxicity. AB - Ingredients of lubricant eye drops are potentially harmful to the ocular surface. The products Optive, Optive Fusion, Neopt were tested regarding corneal irritability versus Vismed Multi and 0.01% benzalkonium chloride as negative and positive control, respectively. Formulas (30-40MUl per hour) were applied hourly in-vitro for six days on rabbit corneas (n=5, per product) cultured in artificial anterior chambers (EVEIT system). Initially, four corneal abrasions (2.4-4.6mm2) were induced. All defects were monitored during drop application by fluorescein stains and photographs. To ensure corneal vitality, glucose and lactate concentrations in artificial anterior chamber fluids were determined photometrically. All products showed a complete corneal healing on day 2. Thereafter, all five Optive-treated corneas developed progressive fluorescein positive epithelial lesions until day six (24.96MUm, +/-21.45MUm, p<0.01). For Optive Fusion three corneas showed corneal erosions on day six (23.11MUm, +/ 37.02MUm, p>0.5) while Vismed Multi did not adversely affect the corneal integrity. Glucose/lactate concentrations remained unchanged while lubricants were applied. Histology revealed epithelial loss and severe alterations of the superficial stroma for Optive. Optive Fusion displayed a comparable pathology. Neopt did not significantly affect the corneal healing and integrity. This study suggested a cumulative corneal toxicity of Optive and, to a lesser extent, Optive Fusion most likely caused by its oxidative preservative, SOC. Clinical data are needed to clarify the application frequency at which corneal toxicity might occur. Neopt and Vismed Multi did not affect the corneal integrity. PMID- 27989570 TI - The effect of tannic acid on the bone tissue of adult male Wistar rats exposed to cadmium and lead. AB - Toxic elements such as cadmium (Cd) and lead (Pb) accumulate to the largest extent in bones. Rats at the age of 12 weeks were used to check whether tannic acid (TA) at the concentration of 0.5%, 1.0%, 1.5%. 2.0% or 2.5% would have a protective effect on the structure and properties of bones in the case of exposure to Cd and Pb (diet: 7mg Cd/kg and 50mg Pb/kg) for 12 weeks. The effects of administration of TA in Cd- and Pb-poisoned rats on bone mechanical and geometric properties, trabecular histomorphometry as well as the morphology of articular and growth cartilages were determined. All the rats co-exposured to Cd and Pb had enhanced heavy metals concentration in blood plasma and bone and reduced bone Ca content irrespective of the tannic acid administration. Heave metals given to adult rats did not influence the morphology and geometry of the femur, but reduced the mechanical endurance and histomorphometric parameters of trabecular bone irrespective of the treatment. A diet rich in TA improved articular cartilage and growth plate constituents in heavy metal-poisoned rats, as indicated by the measurement of the thickness of particular zones. It seems that a use of alimentary TA supplementation in adult rats can counteract, in a dose-dependent manner, only some of the destructive changes evoked by Cd and Pb excess. PMID- 27989571 TI - Mapping the convergent temporal epileptic network in left and right temporal lobe epilepsy. AB - Left and right mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis (HS) exhibits similar functional and clinical dysfunctions, such as depressive mood and emotional dysregulation, implying that the left and right mTLE may share a common network substrate. However, the convergent anatomical network disruption between the left and right HS remains largely uncharacterized. This study aimed to investigate whether the left and right mTLE share a similar anatomical network. We examined 43 (22 left, 21 right) mTLE patients with HS and 39 healthy controls using diffusion tensor imaging. Machine learning approaches were applied to extract the abnormal anatomical connectivity patterns in both the left and right mTLE. The left and right mTLE showed that 28 discriminating connections were exactly the same when compared to the controls. The same 28 connections showed high discriminating power in comparisons of the left mTLE versus controls (91.7%) and the right mTLE versus controls (90.0%); however, these connections failed to discriminate the left from the right mTLE. These discriminating connections, which were diminished both in the left and right mTLE, were primarily located in the limbic-frontal network, partially agreeing with the limbic-frontal dysregulation model of depression. These findings suggest that left and right mTLE share a convergent circuit, which may account for the mood and emotional deficits in mTLE and may suggest the neuropathological mechanisms underlying the comorbidity of depression and mTLE. PMID- 27989572 TI - The role of cAMP and its downstream targets in neurite growth in the adult nervous system. AB - Injured neurons in the adult mammalian central nervous system (CNS) have a very limited capacity for axonal regeneration and neurite outgrowth. This inability to grow new axons or to regrow injured axons is due to the presence of molecules that inhibit axonal growth, and age related changes in the neuron's innate growth capabilities. Available levels of cAMP are thought to have an important role in linking both of these factors. Elevated levels of cAMP in the developing nervous system are important for the guidance and stability of growth cones. As the nervous system matures, cAMP levels decline and the growth promoting effects of cAMP diminish. It has frequently been demonstrated that increasing neuronal cAMP can enhance neurite growth and regeneration. Some methods used to increase cAMP include administration of cAMP agonists, conditioning lesions, or electrical stimulation. Furthermore, it has been proposed that multiple stages of cAMP induced growth exist, one directly caused by its downstream effector Protein Kinase A (PKA) and one caused by the eventual upregulation of gene transcription. Although the role cAMP in promoting axon growth is well accepted, the downstream pathways that mediate cAMP-mediated axonal growth are less clear. This is partly because various key studies that explored the link between PKA and axonal outgrowth relied on the PKA inhibitors KT5720 and H89. More recent studies have shown that both of these drugs are less specific than initially thought and can inhibit a number of other signalling molecules including the Exchange Protein Activated by cAMP (EPAC). Consequently, it has recently been shown that a number of intracellular signalling pathways previously attributed to PKA can now be attributed solely to activation of EPAC specific pathways, or the simultaneous co activation of PKA and EPAC specific pathways. These new studies open the door to new potential treatments for repairing the injured spinal cord. PMID- 27989573 TI - Prenatal morphine exposure during late embryonic stage enhances the rewarding effects of morphine and induces the loss of membrane-bound protein kinase C-alpha in intermediate medial mesopallium in the chick. AB - The susceptibility to drug abuse may be associated with the structural and/or functional changes in the reward-related brain regions induced by drug exposure during sensitive periods of embryonic development. Previously, we have found that prenatal morphine exposure during embryonic days 17-20 may be crucial for developing the susceptibility to morphine reward after hatching. However, the underlying structure and cellular mechanisms need further investigation. In the present study, the chicks of a few days old, which were prenatally exposed to morphine during E17-20, obviously showed higher preference for the morphine paired chamber and hyperactivity during the expression of morphine conditioned place preference (CPP), and the reduction in membrane-bound of PKCalpha of the bilateral intermediate medial mesopallium (IMM) assayed immunologically. These results indicate that the decreased expression of PKCalpha in IMM may participate in the development of the susceptibility to the rewarding effects of morphine in chicks prenatally exposed to morphine, and provide further support for the cross species evolutionary concordance among amniotes. PMID- 27989574 TI - Corrigendum to "T0070907 inhibits repair of radiation-induced DNA damage by targeting RAD51" [Toxicol. Vitro 37C (2016) 1-8]. PMID- 27989575 TI - The holy grail of HIV programme effectiveness. PMID- 27989577 TI - Autophagy may be impelled by collected fatty acids in Type 2 diabetic myocardial cells. PMID- 27989576 TI - Population levels and geographical distribution of HIV RNA in rural Ugandan and Kenyan communities, including serodiscordant couples: a cross-sectional analysis. AB - BACKGROUND: As sub-Saharan Africa transitions to a new era of universal antiretroviral therapy (ART), up-to-date assessments of population-level HIV RNA suppression are needed to inform interventions to optimise ART delivery. We sought to measure population viral load metrics to assess viral suppression and characterise demographic groups and geographical locations with high-level detectable viraemia in east Africa. METHODS: The Sustainable East Africa Research in Community Health (SEARCH) study is a cluster-randomised controlled trial of an HIV test-and-treat strategy in 32 rural communities in Uganda and Kenya, selected on the basis of rural setting, having an approximate population of 10 000 people, and being within the catchment area of a President's Emergency Plan for AIDS Relief-supported HIV clinic. During the baseline population assessment in the SEARCH study, we did baseline HIV testing and HIV RNA measurement. We analysed stable adult (aged >=15 years) community residents. We defined viral suppression as a viral load of less than 500 copies per mL. To assess geographical sources of transmission risk, we established the proportion of all adults (both HIV positive and HIV negative) with a detectable viral load (local prevalence of viraemia). We defined transmission risk hotspots as geopolitical subunits within communities with an at least 5% local prevalence of viraemia. We also assessed serodiscordant couples, measuring the proportion of HIV-positive partners with detectable viraemia. The SEARCH study is registered with ClinicalTrials.gov, number NCT01864603. FINDINGS: Between April 2, 2013, and June 8, 2014, of 303 461 stable residents, we enumerated 274 040 (90.3%), of whom 132 030 (48.2%) were adults. Of these, 117 711 (89.2%) had their HIV status established, of whom 11 964 (10.2%) were HIV positive. Of these, we measured viral load in 8828 (73.8%) people. Viral suppression occurred in 3427 (81.6%) of 4202 HIV-positive adults on ART and 4490 (50.9%) of 8828 HIV-positive adults. Regional viral suppression among HIV positive adults occurred in 881 (48.2%) of 1827 people in west Uganda, 516 (45.0%) of 1147 in east Uganda, and 3093 (52.8%) of 5854 in Kenya. Transmission risk hotspots occurred in three of 21 parishes in west Uganda and none in east Uganda and in 24 of 26 Kenya geopolitical subunits. In Uganda, 492 (2.9%) of 16 874 couples were serodiscordant: in 287 (58.3%) of these couples, the HIV positive partner was viraemic (and in 69 [14.0%], viral load was >100 000 copies per mL). In Kenya, 859 (10.0%) of 8616 couples were serodiscordant: in 445 (53.0%) of these couples, the HIV-positive partner was viraemic (and in 129 [15%], viral load was >100 000 copies per mL). INTERPRETATION: Before the start of the SEARCH trial, 51% of east African HIV-positive adults had viral suppression, reflecting ART scale-up efforts to date. Geographical hotspots of potential HIV transmission risk and detectable viraemia among serodiscordant couples warrant intensified interventions. FUNDING: National Institute of Allergy and Infectious Diseases (National Institutes of Health) and the President's Emergency Plan for AIDS Relief. PMID- 27989578 TI - Reply to: Diabetes mellitus and Takotsubo syndrome: Dissecting the paradox. PMID- 27989579 TI - Plasma palmitoylethanolamide (PEA) as a potential biomarker for impaired coronary function. AB - BACKGROUND: Among endocannabinoid (EC)-related mediators, Oleoyl-ethanolamide (OEA) and Palmitoyl-ethanolamide (PEA), two endogenous PPARalpha agonists with lipolytic and anti-inflammatory action, respectively, are being actively investigated. Here, we assessed the potential association between plasma levels of PEA and OEA and coronary function in a cohort including normal, overweight, obese, and morbidly obese (MOB) individuals. METHODS: Myocardial perfusion and endothelium-related myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with 13N-ammonia positron emission tomography/computed tomography. OEA and PEA were extracted from human plasma by liquid-liquid extraction, separated by liquid chromatography and quantified by mass spectrometry. Serum levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1) were measured by colorimetric enzyme-linked immunosorbent assay. RESULTS: Circulating levels of PEA and VCAM-1 were increased in MOB as compared to normal weight subjects. Circulating levels of OEA and PEA were associated with body mass index, but not with adhesion molecules. Increases of PEA levels were associated with and predictive of worsened coronary function in MOB and the overall cohort studied. CONCLUSION: Plasma levels of PEA are increased in MOB patients and associated with coronary dysfunction as a functional precursor of CAD process. Larger trials are needed to confirm PEA as a potential circulating biomarker of coronary dysfunction in both MOB patients and the general population. PMID- 27989580 TI - The promises and challenges of exome sequencing in familial, non-syndromic congenital heart disease. AB - BACKGROUND: Exome sequencing is an established strategy to identify causal variants in families with two or more members affected by congenital heart disease (CHD). This unbiased approach, in which both rare and common variants are identified, makes it suitable to research complex, heterogeneous diseases such as CHD. METHODS AND RESULTS: Exome sequencing was performed on two affected members of a three generation family with atrial septal defects (ASD), suggesting a dominant inheritance pattern. Variants were filtered using two bioinformatics pipelines and prioritised according to in silico prediction programs. Segregation studies and functional analyses were used to assess co-segregation with disease and effects on protein function, respectively. Following the data and in silico analyses, ten candidate variants were prioritised. Of these, SRPK2 (c.2044C>T[p.Arg682Trp]) and NOTCH1 (c.3835C>T[p.Arg1279Cys]), co-segregated with disease in the family; however, previous functional analyses on SRPK2 make this an unlikely candidate. Functional analyses in the variant (c.3835C>T[p.Arg1279Cys]) of the known CHD gene NOTCH1 demonstrated a non significant decrease in signalling activity. CONCLUSION: This study demonstrates both the potential, as well as the challenges, of applying exome sequencing to complex diseases such as CHD. While in silico evidence and segregation analyses in the NOTCH1 p.Arg1279Cys variant are highly suggestive of pathogenicity, the minimal change in signalling capacity suggests that other variants may be required for CHD development. This study highlights the difficulties of applying exome sequencing in familial, non-syndromic CHD in the clinical environment and a cautionary note in the interpretation of apparently causal abnormalities in silico without supportive functional data. PMID- 27989581 TI - Influence of Temperature on Cyclic Fatigue Resistance of ProTaper Gold and ProTaper Universal Rotary Files. AB - INTRODUCTION: The aim of this study was to evaluate the cyclic fatigue resistance of ProTaper Universal (PTU; Dentsply Maillefer, Baillagues, Switzerland) and ProTaper Gold (PTG, Dentsply Maillefer) nickel-titanium rotary files at room and intracanal temperatures. METHODS: A total of 120 files were used to test the cyclic fatigue resistance of PTU (S1 and F2) and PTG (S1 and F2) in an artificial canal at room temperature (20 degrees C) and at intracanal temperature (35 degrees C). The number of cycles to failure and the fracture length of the fragment were recorded, and data were subjected to statistical analysis. RESULTS: PTG registered no differences in fatigue life between the 2 temperatures tested (P > .05), whereas PTU showed a statistically significant reduction in fatigue life at intracanal temperature compared with room temperature (P < .05). PTG instruments exhibited a statistically higher resistance to cyclic fatigue than PTU instruments both at room and intracanal temperatures (P < .05). There were no statistically significant differences among the fracture length of separated instruments (P > .05). CONCLUSIONS: Intracanal temperature influenced the cyclic fatigue resistance of instruments produced with traditional nickel-titanium, whereas it did not influence the fatigue life of instruments produced with gold heat treatment. Gold heating treatment enhances the resistance to cyclic fatigue of ProTaper instruments. PMID- 27989582 TI - Expression of Cannabinoid Type 1 Receptors in Human Odontoblast Cells. AB - INTRODUCTION: The aim of this study was to investigate the functional expression of cannabinoid type 1 (CB1) receptors in human odontoblasts (HODs) and the possible internal mechanism. METHODS: In the present study, we examined the molecular and functional expression of the CB1 receptors in cultured HOD-like cells and native HODs obtained from healthy wisdom teeth. RESULTS: Immunohistochemistry and immunofluorescence revealed that CB1 receptors localize to native HODs and HOD-like cells, respectively. Both reverse-transcription polymerase chain reaction and Western blot analysis confirmed gene and protein expression of CB1 receptors. The ultrastructural distribution by immunoelectron microscopy also found that CB1 receptors labeled by colloidal gold particles distribute sparsely in the cytoplasm and odontoblastic processes. In functional assays, 2-arachidonyl glycerol, as an agonist of CB receptors, elicited the increase of intracellular fluorescence intensity that could be inhibited by a CB1 specific receptor antagonist rather than a selective CB2 receptor antagonist with fluo-3AM Ca2+ fluorescence. The source of the increase of intracellular fluorescence intensity elicited by CB1 receptors was from extracellular Ca2+ but not intracellular Ca2+ stores. The process of 2-arachidonyl glycerol activating CB1 receptors modulated transient receptor potential vanilloid 1-mediated Ca2+ entry via the cyclic adenosine monophosphate signaling pathway. CONCLUSIONS: We conclude that HODs can express functional CB1 receptors that may play an important role in mediating the physiological function in tooth pulp. PMID- 27989583 TI - Collaborative Management of Combined Periodontal-endodontic Lesions with a Palatogingival Groove: A Case Series. AB - INTRODUCTION: This article reports 3 representative cases of interdisciplinary management of a palatogingival groove in maxillary lateral incisors. The development, pathology, and effectiveness of management approaches in cases involving a combined periodontal-endodontic lesion with a palatogingival groove are discussed. METHODS: We describe 3 patients with a noncontributory medical history presenting with a chief complaint related to a maxillary incisor and diagnosed with a combined periodontal-endodontic lesion with a palatogingival groove at Seoul National University Dental Hospital, Seoul, Korea. RESULTS: Palatogingival grooves were mostly associated with deep periodontal pockets connected to a periapical lesion. Optional collaborative treatments were performed according to the condition as follows: case 1, root canal treatment (RCT), open flap debridement, odontoplasty, and guided tissue regeneration; case 2, RCT, apicoectomy, open flap debridement, and odontoplasty; and case 3, RCT, crown restoration, root planning, and odontoplasty. After clinical examination and radiographic assessments, the periapical lesion and periodontal deep pocket were successfully resolved with periodontal-endodontic collaborative treatment involving both periodontal surgical procedures (cases 1 and 2) and a nonsurgical procedure (case 3). CONCLUSIONS: Within the limitations of this study, these case reports show that accurate diagnosis of developmental anomalies and elimination of inflammatory irritants are key factors for favorable long-term outcomes. PMID- 27989584 TI - Comparative Effectiveness of New Mechanical Irrigant Agitating Devices for Debris Removal from the Canal and Isthmus of Mesial Roots of Mandibular Molars. AB - INTRODUCTION: The aim of this study was to compare the effectiveness of Easy Clean (Easy Dental Equipment, Belo Horizonte, MG, Brazil) in continuous and reciprocating motion, passive ultrasonic irrigation (PUI), Endoactivator systems (Dentsply Maillefer, Ballaigues, Switzerland), and conventional irrigation for debris removal from root canals and isthmus. METHODS: Fifty mesial roots of mandibular molars were embedded in epoxy resin using a metal muffle; afterward, the blocks containing the roots were sectioned at 2, 4, and 6 mm from the apex. After instrumentation, the roots were divided into 5 groups (n = 10) for application of the final irrigation protocol using Easy Clean in continuous rotation, Easy Clean in reciprocating motion, PUI, Endoactivator, and conventional irrigation. Scanning electron microscopic images were taken after instrumentation and after the first, second, and third activation of irrigating solution to evaluate the area of remaining debris with image J software (National Institutes of Health, Bethesda, MD). RESULTS: The protocol of 3 irrigating solution activations for 20 seconds provided better cleaning of the canal and isthmus. On conclusion of all procedures, analysis of the canals showed a statistical difference only at 2 mm; the Easy Clean in continuous rotation was more efficient than conventional irrigation (P < .05). On conclusion of all steps, the largest difference was observed in the isthmus in which the Easy Clean in continuous rotation was more effective than conventional irrigation at the 3 levels analyzed and the Endoactivator at 4 mm (P < .05). The PUI promoted greater cleaning than conventional irrigation at 6 mm (P < .05). There was no statistical difference between Easy Clean in continuous rotation, Easy Clean in reciprocating motion, and PUI (P > .05). CONCLUSIONS: Irrigating solution activation methods provided better cleaning of the canal and isthmus, especially the Easy Clean used in continuous rotation. The protocol of 3 irrigating solution activations for 20 seconds favored better cleaning. PMID- 27989585 TI - The importance of accurately correcting for the natural abundance of stable isotopes. AB - The use of isotopically labeled tracer substrates is an experimental approach for measuring in vivo and in vitro intracellular metabolic dynamics. Stable isotopes that alter the mass but not the chemical behavior of a molecule are commonly used in isotope tracer studies. Because stable isotopes of some atoms naturally occur at non-negligible abundances, it is important to account for the natural abundance of these isotopes when analyzing data from isotope labeling experiments. Specifically, a distinction must be made between isotopes introduced experimentally via an isotopically labeled tracer and the isotopes naturally present at the start of an experiment. In this tutorial review, we explain the underlying theory of natural abundance correction of stable isotopes, a concept not always understood by metabolic researchers. We also provide a comparison of distinct methods for performing this correction and discuss natural abundance correction in the context of steady state 13C metabolic flux, a method increasingly used to infer intracellular metabolic flux from isotope experiments. PMID- 27989586 TI - An emerging evidence base for the management of neonatal hypoglycaemia. AB - Neonatal hypoglycaemia is common, and screening and treatment of babies considered at risk is widespread, despite there being little reliable evidence upon which to base management decisions. Although there is now evidence about which babies are at greatest risk, the threshold for diagnosis, best approach to treatment and later outcomes all remain uncertain. Recent studies suggest that treatment with dextrose gel is safe and effective and may help support breast feeding. Thresholds for intervention require a wide margin of safety in light of information that babies with glycaemic instability and with low glucose concentrations may be associated with a higher risk of later higher order cognitive and learning problems. Randomised trials are urgently needed to inform optimal thresholds for intervention and appropriate treatment strategies. PMID- 27989587 TI - Cellular and humoral biomarkers of Bronchopulmonary Dysplasia. AB - The pathogenesis of Bronchopulmonary Dysplasia (BPD) is multifactorial and the clinical phenotype of BPD is extremely variable. Predicting BPD is difficult, as it is a disease with a clinical operational definition but many clinical phenotypes and endotypes. Most biomarkers studied over the years have low predictive accuracy, and none are currently used in routine clinical care or shown to be useful for predicting longer-term respiratory outcome. Targeted cellular and humoral biomarkers and novel systems biology 'omic' based approaches including genomic and microbiomic analyses are described in this review. PMID- 27989588 TI - Acute phospholipid microspherule associated arthritis: Is it rare? AB - Joint fluid analysis must be performed as part of the diagnostic workup for acute arthritis, most notably to rule out septic arthritis and to allow the identification of crystal-induced arthritis (gout or calcium pyrophosphate deposition disease), which is one of the most common causes. However, the detection of monosodium urate or calcium pyrophosphate microcrystals is not the only goal of the polarized light microscopy examination of joint fluid. Other, less common microcrystals may be found. Among them are phospholipid microspherules, which are easily recognized microscopically based on their Maltese cross-like appearance. Phospholipid microspherules are a cause of acute arthritis that is often missed by rheumatologists and may therefore be more common than generally believed. PMID- 27989589 TI - Efficacy of triple association methotrexate, sulfasalazine and hydroxychloroquine in early treatment of rheumatoid arthritis with insufficient response to methotrexate: Meta-analysis of randomized controlled trials. AB - OBJECTIVES: To evaluate the efficacy of the triple synthetic Disease Modifying Anti-Rheumatic Drugs (sDMARD) combination methotrexate, sulfasalazine and hydroxychloroquine versus a biologic DMARD (bDMARD) in the treatment of early rheumatoid arthritis. METHODS: A systematic literature search was performed using the PubMed and Cochrane databases, and abstracts presented at rheumatology scientific meetings until December 2013. Randomized controlled trials comparing the efficacy and the safety of biologic DMARD with the triple combination were included. Outcome measures were Van der Heijde modified Sharp score (SHS), remission rate, ACR criteria response, adverse events. RESULTS: A total of 1225 abstracts were screened. We extracted data from 5 trials including patients (515 in the triple combination group and 710 in the bDMARD group). We showed higher ACR70 response (OR=1.79, 95% CI [1.17, 2.72]) in patients treated with bDMARDs, whereas radiological progression was not different from patient with triple combination (OR=1.10, 95% CI [-0.04, 0.28]). At year 2, ACR70 response and remission rate, the results were similar in both groups with respectively OR=1.44 (95% CI [0.86, 2.43]) and SMD=0.45 (95% CI [0.17, 0.72]). The proportion of serious adverse events was similar in both groups OR=1.02 (95% CI [0.68, 1.52], P=0.92, I2=0%). Gastro-intestinal adverse events were higher in the triple combination group (OR=1.75, 95% CI [0.73, 4.21], P=0.21, I2=75%). Infectious adverse events were more frequent in the bDMARD group (OR=0.50, 95% CI [0.35, 0.70], P<0.0001, I2=36%). CONCLUSION: Biological treatment seems to be more efficient than triple combination in terms of radiological progression in RA with inadequate response to methotrexate. PMID- 27989590 TI - Effect of the short-course regimen on the global epidemic of multidrug-resistant tuberculosis. PMID- 27989591 TI - Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis. AB - BACKGROUND: In May, 2016, WHO endorsed a 9 month regimen for multidrug-resistant tuberculosis that is cheaper and potentially more effective than the conventional, longer (20-24 month) therapy. We aimed to investigate the population-level implications of scaling up this new regimen. METHODS: In this population modelling analysis, we developed a dynamic transmission model to simulate the introduction of this short-course regimen as an instantaneous switch in 2016. We projected the corresponding percentage reduction in the incidence of multidrug-resistant tuberculosis by 2024 compared with continued use of longer therapy. In the primary analysis in a representative southeast Asian setting, we assumed that the short-course regimen would double treatment access (through savings in resources or capacity) and achieve long-term efficacy at levels seen in preliminary cohort studies. We then did extensive sensitivity analyses to explore a range of alternative scenarios. FINDINGS: Under the optimistic assumptions in the primary analysis, the incidence of multidrug-resistant tuberculosis in 2024 would be 3.3 (95% uncertainty range 2.2-5.6) per 100 000 population with the short-course regimen and 4.3 (2.9-7.6) per 100 000 population with continued use of longer therapy-ie, the short-course regimen could reduce incidence by 23% (10-38). Incidence would be reduced by 14% (4-28) if the new regimen affected only treatment effectiveness and by 11% (3-24) if it affected only treatment availability. Under more pessimistic assumptions, the short-course regimen would have minimal effect and even potential for harm-eg, when 30% of patients are ineligible for the new regimen because of second-line drug resistance, we projected a change in incidence of -2% (-20 to +28). The new regimen's effect was greater in settings with more ongoing transmission of multidrug-resistant tuberculosis, but results were otherwise similar across settings with different levels of tuberculosis incidence and prevalence of multidrug resistance. INTERPRETATION: The short-course regimen has potential to substantially lessen the multidrug-resistant tuberculosis epidemic, but this effect depends on its long-term efficacy, its ability to expand treatment access, and the role of second-line drug resistance. FUNDING: US National Institutes of Health and Bill & Melinda Gates Foundation. PMID- 27989592 TI - COMETS2: An advanced MATLAB toolbox for the numerical analysis of electric fields generated by transcranial direct current stimulation. AB - BACKGROUND: Since there is no way to measure electric current generated by transcranial direct current stimulation (tDCS) inside the human head through in vivo experiments, numerical analysis based on the finite element method has been widely used to estimate the electric field inside the head. In 2013, we released a MATLAB toolbox named COMETS, which has been used by a number of groups and has helped researchers to gain insight into the electric field distribution during stimulation. The aim of this study was to develop an advanced MATLAB toolbox, named COMETS2, for the numerical analysis of the electric field generated by tDCS. NEW METHOD: COMETS2 can generate any sizes of rectangular pad electrodes on any positions on the scalp surface. To reduce the large computational burden when repeatedly testing multiple electrode locations and sizes, a new technique to decompose the global stiffness matrix was proposed. RESULTS: As examples of potential applications, we observed the effects of sizes and displacements of electrodes on the results of electric field analysis. The proposed mesh decomposition method significantly enhanced the overall computational efficiency. COMPARISON WITH EXISTING METHODS: We implemented an automatic electrode modeler for the first time, and proposed a new technique to enhance the computational efficiency. CONCLUSIONS: In this paper, an efficient toolbox for tDCS analysis is introduced (freely available at http://www.cometstool.com). It is expected that COMETS2 will be a useful toolbox for researchers who want to benefit from the numerical analysis of electric fields generated by tDCS. PMID- 27989593 TI - Differences in the responses of three plasma selenium-containing proteins in relation to methylmercury-exposure through consumption of fish/whales. AB - Putative protective effects of selenium (Se) against methylmercury (MeHg) toxicity have been examined but no conclusion has been reached. We recently reported the lack of serious neurological symptoms in a Japanese fish-eating population with high intakes of MeHg and suggested a potential protective role for Se. Here, relationships between levels of Hg and Se in the blood and plasma samples, with a quantitative evaluation of Se-containing proteins, obtained from this population were examined. While levels of the whole-blood Hg (WB-Hg) and plasma Se (P-Se) showed a positive correlation, stratified analysis revealed that they correlated only in samples with higher (greater than the median) levels of MeHg. A food frequency questionnaire showed that consumption of fish/whales correlated with WB-Hg, but not with P-Se, suggesting that the positive correlation between WB-Hg and P-Se might not be the result of co-intake of these elements from seafood. Speciation of plasma Se revealed the differences in the responses of two plasma selenoproteins, glutathione peroxidase (GPx) and selenoprotein P (SePP), in relation to Hg exposure. In the high-Hg group, SePP showed a positive correlation with WB-Hg, but GPx did not. In the low-Hg group, neither SePP nor GPx showed any correlation with WB-Hg. These observations suggest that the increase in P-Se in the high-Hg group might be associated with an increase in SePP, which may, in turn, suggest an increased demand for one or more selenoproteins in various organs, for which SePP supplies the element. PMID- 27989594 TI - Salvianolic acid B protects against chronic alcoholic liver injury via SIRT1 mediated inhibition of CRP and ChREBP in rats. AB - Salvianolic acid B (SalB), a water-soluble polyphenol extracted from Radix Salvia miltiorrhiza, has been reported to possess many pharmacological activities. This study investigated the hepatoprotective effects of SalB in chronic alcoholic liver disease (ALD) and explored the related signaling mechanisms. In vivo, SalB treatment significantly attenuated ethanol-induced liver injury by blocking the elevation of serum aminotransferase activities and markedly decreased hepatic lipid accumulation by reducing serum and liver triglyceride (TG) and total cholesterol (TC) levels. Moreover, SalB treatment ameliorated ethanol-induced hepatic inflammation by decreasing the levels of hepatotoxic cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Importantly, SalB pretreatment significantly increased the expression of SIRT1 and downregulated the expression of inflammatory mediator C-reactive protein (CRP) and lipoprotein carbohydrate response element-binding protein (ChREBP). In vitro, SalB significantly reversed ethanol-induced down-regulation of SIRT1 and increased CRP and ChREBP expression. Interestingly, the effects of SalB on SIRT1, CRP and ChREBP were mostly abolished by treatment with either SIRT1 siRNA or EX527, a specific inhibitor of SIRT1, indicating that SalB decreased CRP and ChREBP expression by activating SIRT1. SalB exerted anti-steatotic and anti inflammatory effects against alcoholic liver injury by inducing SIRT1-mediated inhibition of CRP and ChREBP expression. PMID- 27989595 TI - Analysis of genomic responses in a rat lung model treated with a humidifier sterilizer containing polyhexamethyleneguanidine phosphate. AB - The antimicrobial biocide polyhexamethyleneguanidine (PHMG) phosphate is the main ingredient in the commercially available humidifier disinfectant. PHMG phosphate based humidifier disinfectants can cause pulmonary fibrosis and induce inflammatory and fibrotic responses both in vivo and in vitro. However, toxicological mechanisms including genomic alterations induced by inhalation exposure to PHMG phosphate have not been elucidated. Therefore, this study evaluated the toxicological effects of the PHMG phosphate-containing humidifier disinfectant. We used DNA microarray to identify global gene expression changes in rats treated with PHMG phosphate-containing humidifier disinfectant for 4 weeks and 10 weeks. Functional significance of differentially expressed genes (DEGs) was estimated by gene ontology (GO) analysis. Four weeks post-exposure, 320 and 392 DEGs were identified in female and male rats, respectively (>2-fold, p<0.05). Ten weeks post-exposure, 1290 and 995 DEGs were identified in females and males, respectively. Of these, 119 and 556 genes overlapped between females and males at 4 weeks and 10 weeks, respectively, post-PHMG phosphate exposure. In addition, 21 genes were upregulated and 4 genes were downregulated in response to PHMG phosphate in a time-dependent manner. Thus, we predict that changes in genomic responses could be a significant molecular mechanism underlying PHMG phosphate toxicity. Further studies are required to determine the detailed mechanism of PHMG phosphate-induced pulmonary toxicity. PMID- 27989596 TI - Fascin2 regulates cisplatin-induced apoptosis in NRK-52E cells. AB - Previous studies have shown that the aging kidney has a marked loss of alpha(E) catenin in proximal tubular epithelium. alpha-Catenin, a key regulator of the actin cytoskeleton, interacts with a variety of actin-binding proteins. Cisplatin induced loss of fascin2, an actin bundling protein, was observed in cells with a stable knockdown of alpha(E)-catenin (C2 cells), as well as in aging (24 mon), but not young (4 mon), kidney. Fascin2 co-localized with alpha-catenin and the actin cytoskeleton in NRK-52E cells. Knockdown of fascin2 increased the susceptibility of tubular epithelial cells to cisplatin-induced injury. Overexpression of fascin2 in C2 cells restored actin stress fibers and attenuated the increased sensitivity of C2 cells to cisplatin-induced apoptosis. Interestingly, fascin2 overexpression attenuated cisplatin-induced mitochondrial dysfunction and oxidative stress in C2 cells. These data demonstrate that fascin2, a putative target of alpha(E)-catenin, may play important role in preventing cisplatin-induced acute kidney injury. PMID- 27989597 TI - Comparative and evolutionary studies of ALDH18A1 genes and proteins. AB - Vertebrate ALDH18A1 genes encode a bifunctional mitochondrial enzyme, catalyzing a 2-step conversion of glutamate to glutamyl semialdehyde, subsequently converted into proline, ornithine and arginine. Bioinformatic analyses of vertebrate and invertebrate genomes were undertaken using known ALDH18A1 amino acid sequences. G5K (glutamyl kinase) and GPR (glutamyl phosphate reductase) domain sequences were identified for all vertebrate and invertebrate genomes examined, whereas bacterial sequences encoded separate enzymes. Vertebrate ALDH18A1 (also called P5CS) sequences were highly conserved throughout vertebrate evolution. A mechanism for generating two major vertebrate ALDH18A1 isoforms is proposed with 'a' isoform containing Asn239-Val240 with wide tissue expression, whereas the 'b' isoform lacking the dipeptide has been reported in gut tissues. Phylogenetic analyses describe the relationships and potential origins of the ALDH18A1 gene during vertebrate and invertebrate evolution and a proposal for generating the bifunctional vertebrate and invertebrate ALDH18A1 gene from a bacterial operon (proBA) encoding G5K and GPR. A more recent Aldh18a1 gene duplication event has apparently occurred with a primordial rat genome. PMID- 27989598 TI - Effect of trans-anethole, limonene and your combination in nutritional components and their reflection on reproductive parameters and testicular apoptosis in Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - Spodoptera frugiperda is a major pest in several crops due to its polyphagous habit. Studies on the use of essential oils for pest control have been increasing over the years, presenting itself as a promising alternative with less environmental impact. Chemical profile evaluations of essential oils enable the knowledge and use of major compounds, providing a better understanding of their actions in the life history of insects. Thus, the study evaluated the effects of the major compounds limonene, trans-anethole and the combined effects upon nutrition, reproduction and testicular apoptosis in S. frugiperda. Larvae of third instar were submitted to the LD50 of the compounds by topical contact and 48 h later the amounts of lipids, proteins, total sugar and glycogen were evaluated. The testicular apoptosis was evaluated in the treated larvae after 48 h and the reproductive parameters were evaluated after adult emergence. All treatments reduced the amounts of lipid, protein, total sugar and glycogen when compared to control. The most significant results were obtained by the association of compounds. All treatments reduced the number of eggs, oviposition period and adult longevity when compared to control. There were no changes in the pre-oviposition and post-oviposition periods. Testicular apoptosis was observed in the limonene and in the combined treatments. It is concluded that limonene and trans-anethole, especially in association, cause adverse effects upon nutrition and reproduction in S. frugiperda, altering essential parameters for its survival and establishment on crops. PMID- 27989599 TI - Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice. AB - Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo. PMID- 27989600 TI - Novel ferrocenyl pyrazoles inhibit breast cancer cell viability via induction of apoptosis and inhibition of PI3K/Akt and ERK1/2 signaling. AB - Despite the advances in early detection and targeted therapies, chemotherapy is still of vital importance in breast cancer treatment. However, development of drug resistance and serious side effects limits their usage. Thus, there is an urgent need for safer and more effective agents against breast cancer. We have previously described the synthesis of a number of pyrazole derivatives, and in the current study, we have investigated the effects of two different ferrocenyl pyrazole (FP) derivates, 5-ferrocenyl-1-phenyl-1H-pyrazole (FP-Ph) and 5 ferrocenyl-1H-pyrazole (FP-H), on breast cancer cells. First, we investigated the effects of both FPs on cell viability and induction of cell death in breast cancer cells and benign MCF-10A cells by XTT and DNA fragmentation assays, respectively. Morphological changes in human breast cancer cells after FPs treatment were detected by both phase contrast microscope and atomic force microscopy (AFM). Then, we tested whether FPs exert their cytotoxic effect through inhibiting PI3K/Akt and/or ERK1/2 signaling pathways by using specific inhibitors. Both FPs induced cytotoxicity in a time and concentration-dependent manner in breast cancer cells; however, MCF-10A benign breast epithelial cells were much less susceptible to the cytotoxic effect of both FPs. FPs inhibited both PI3K/Akt and ERK 1/2 signaling pathways in breast cancer cells. The ultra structure images of MCF-7 cells by AFM showed that the cell surface was smooth in untreated cells, but it was rough with protrusions in treated cells. Both FPs induced apoptotic cell death in MDA-MB-231 cells; however, necrotic cell death was induced in caspase-3 lack MCF-7 cells, which implies that the synthesized FPs may induce apoptosis through caspase-3 dependent mechanism. In summary, these results suggest that FPs might be promising agents for the breast cancer therapy. PMID- 27989601 TI - Epileptic spasms - 175 years on: Trying to teach an old dog new tricks. AB - PURPOSE: This text provides an overview of how the condition "infantile spasms" has evolved in the last 175 years. METHOD: Key references are summarised to assimilate this review. RESULTS: Infantile spasms, first described by Dr West in 1841, has undergone extensive investigation to understand the pathogenesis, aetiologies, optimal intervention and most likely prognosis for the affected child. The terminology has recently evolved such that the preferred term for the condition is now "epileptic spasms" in recognition of the fact that cases can present outside infancy. The aetiologies are diverse and can be structural, genetic, metabolic or acquired. Increasing numbers of presumed causative genetic mutations are now being identified. The condition is an epileptic encephalopathy such that without adequate control of the clinical seizures and correction of the abnormal EEG, ongoing neurological damage occurs. In some cases neuroregression is inevitable despite intervention. First-line treatments are either hormonal therapies, adrenocortcotrophic hormone or prednisolone, or vigabatrin. In the sub group of patients with tuberous sclerosis complex, vigabatrin is the preferred treatment. High dose prednisolone may be a more viable option in resource limited settings. Recent research has suggested that combining hormonal therapies with vigabatrin will result in more patients achieving spasm cessation. CONCLUSIONS: Despite extensive study, the pathogenic mechanisms remain an area of debate and in need of further exploration. The enigma, however, may be explained as the role of resting state and dysfunctional brain networks are elucidated further. PMID- 27989602 TI - Lung inflation with hydrogen sulfide during the warm ischemia phase ameliorates injury in rat donor lungs via metabolic inhibition after cardiac death. AB - BACKGROUND: Hydrogen sulfide attenuates lung ischemia-reperfusion injury when inhaled or administered intraperitoneally. This study investigated the effects of lung inflation with H2S during the warm ischemia phase on lung grafts from rat donors after cardiac death. METHODS: One hour after cardiac death, donor lungs were inflated in situ for 2 h with either O2 or H2S (O2 or H2S group) during the warm ischemia phase or were deflated as a control procedure (n = 8). After 3 h of cold preservation, lung transplantation was performed. During the warm ischemia phase, the metabolism and mitochondrial structures of donor lungs were analyzed. Arterial blood gas analysis was performed on the recipients. Protein expression in the graft of nuclear factor E2-related factor (Nrf)2 and nuclear factor kappa B (NF-kappaB) was analyzed by Western blotting, and static compliance, inflammation, oxidative stress, and cell apoptosis were assessed after 3 h of reperfusion. RESULTS: When the O2 and H2S groups were compared with the control group, the mitochondrial structures were improved, and lactic acid levels, inflammation, oxidative stress, and cell apoptosis were significantly decreased; and glucose levels, as well as graft oxygenation and static compliance were increased. Simultaneously, the above indices showed further improvements, and the Nrf2 protein expression was significantly greater, and NF-kappaB protein expression was less in the H2S group than the O2 group. CONCLUSION: Lung inflation with H2S during the warm ischemia phase inhibited metabolism in donor lungs via mitochondrial protection, attenuated graft ischemic-reperfusion injury, and improved graft function through NF-kappaB-dependent anti-inflammatory and Nrf2-dependent antioxidative and antiapoptotic effects. PMID- 27989603 TI - Electro-operative adjuncts for hemostasis in thyroidectomy. PMID- 27989604 TI - Why I think the robot will be the future for laparoscopic cholecystectomies. PMID- 27989605 TI - Effectiveness of repeat hepatic resection for patients with recurrent intrahepatic cholangiocarcinoma: Factors associated with long-term outcomes. AB - BACKGROUND: Tumor recurrence after liver resection for intrahepatic cholangiocarcinoma is common. The effective treatment for recurrent intrahepatic cholangiocarcinoma remains to be established. This study evaluated the short- and long-term prognoses of patients after repeat hepatic resection for recurrent intrahepatic cholangiocarcinoma. METHODS: Data for 72 patients who underwent R0 repeat hepatic resection for recurrent intrahepatic cholangiocarcinoma at the Eastern Hepatobiliary Surgery Hospital between 2005 and 2013 were analyzed. Tumor re-recurrence, recurrence-to-death survival, and overall survival were calculated and compared using the Kaplan-Meier method and the log-rank test. Independent risk factors were identified by Cox regression analysis. RESULTS: Operative morbidity and mortality rates were 18.1% and 1.4%, respectively. The 1-, 2-, and 3-year re-recurrence rates were 53.2%, 80.2%, and 92.6%, respectively, and the corresponding recurrence-to-death survival was 82.9%, 53.0%, and 35.3%, respectively. The 1-, 3-, and 5-year overall survival was 97.2%, 67.0%, and 41.9%, respectively. Patients with a time to recurrence of >1 year from the initial hepatectomy achieved higher 1-, 2-, and 3-year recurrence-to-death survival than patients with a time to recurrence of <=1 year (92.5%, 61.7%. and 46.6% vs 70.4%, 42.2%, and 23.0%, P = .022). Multivariate analysis identified that recurrent tumor >3 cm (hazard ratio: 2.346; 95% confidence interval: 1.288 4.274), multiple recurrent nodules (2.304; 1.049-5.059), cirrhosis (3.165; 1.543 6.491), and a time to recurrence of <=1 year (1.872; 1.055-3.324) were independent risk factors of recurrence-to-death survival. CONCLUSION: Repeat hepatic resection for recurrent intrahepatic cholangiocarcinoma was safe and produced long-term survival outcomes in selected patients based on prognostic stratification with the presence of the independent risk factors of recurrence-to death survival. PMID- 27989607 TI - Papillary thyroid microcarcinoma in a developing country scenario with endemic iodine deficiency. PMID- 27989606 TI - Improving diagnostic recognition of primary hyperparathyroidism with machine learning. AB - BACKGROUND: Parathyroidectomy offers the only cure for primary hyperparathyroidism, but today only 50% of primary hyperparathyroidism patients are referred for operation, in large part, because the condition is widely under recognized. The diagnosis of primary hyperparathyroidism can be especially challenging with mild biochemical indices. Machine learning is a collection of methods in which computers build predictive algorithms based on labeled examples. With the aim of facilitating diagnosis, we tested the ability of machine learning to distinguish primary hyperparathyroidism from normal physiology using clinical and laboratory data. METHODS: This retrospective cohort study used a labeled training set and 10-fold cross-validation to evaluate accuracy of the algorithm. Measures of accuracy included area under the receiver operating characteristic curve, precision (sensitivity), and positive and negative predictive value. Several different algorithms and ensembles of algorithms were tested using the Weka platform. Among 11,830 patients managed operatively at 3 high-volume endocrine surgery programs from March 2001 to August 2013, 6,777 underwent parathyroidectomy for confirmed primary hyperparathyroidism, and 5,053 control patients without primary hyperparathyroidism underwent thyroidectomy. Test-set accuracies for machine learning models were determined using 10-fold cross validation. Age, sex, and serum levels of preoperative calcium, phosphate, parathyroid hormone, vitamin D, and creatinine were defined as potential predictors of primary hyperparathyroidism. Mild primary hyperparathyroidism was defined as primary hyperparathyroidism with normal preoperative calcium or parathyroid hormone levels. RESULTS: After testing a variety of machine learning algorithms, Bayesian network models proved most accurate, classifying correctly 95.2% of all primary hyperparathyroidism patients (area under receiver operating characteristic = 0.989). Omitting parathyroid hormone from the model did not decrease the accuracy significantly (area under receiver operating characteristic = 0.985). In mild disease cases, however, the Bayesian network model classified correctly 71.1% of patients with normal calcium and 92.1% with normal parathyroid hormone levels preoperatively. Bayesian networking and AdaBoost improved the accuracy of all parathyroid hormone patients to 97.2% cases (area under receiver operating characteristic = 0.994), and 91.9% of primary hyperparathyroidism patients with mild disease. This was significantly improved relative to Bayesian networking alone (P < .0001). CONCLUSION: Machine learning can diagnose accurately primary hyperparathyroidism without human input even in mild disease. Incorporation of this tool into electronic medical record systems may aid in recognition of this under-diagnosed disorder. PMID- 27989608 TI - Is intraoperative neural monitoring necessary for exploration of the superior laryngeal nerve? AB - BACKGROUND: We aimed to evaluate the contribution of intraoperative neuromonitoring to the visual and functional identification of the external branch of the superior laryngeal nerve and the effect on postoperative voice changes. METHODS: The prospective data of 221 patients (183 women, 38 men) who underwent thyroid operation with intraoperative neuromonitoring for exploration of the external branch of the superior laryngeal nerve were evaluated retrospectively. The surface endotracheal tube-based Medtronic NIM3 (Medtronic, Jacksonville, FL) intraoperative neuromonitoring device was used. The function of the external branch of the superior laryngeal nerve was evaluated by cricothyroid muscle twitch. Additionally, the contribution of the external branch of the superior laryngeal nerve to vocal cord adduction was evaluated using electromyographic records. RESULTS: A total of 374 (95.2%) of 393 external branch of the superior laryngeal nerves were identified; 145 (36.9%) external branch of the superior laryngeal nerves were identified visually before being stimulated with a probe, and 130 (33.1%) external branch of the superior laryngeal nerves were identified visually after being identified with a probe. Although 99 (25.2%) external branch of the superior laryngeal nerves were identified with a probe, they were not visualized. Intraoperative neuromonitoring provided meaningful contributions to visual (P = .001) and functional (P = .001) identification of the external branch of the superior laryngeal nerve. Positive electromyographic responses were recorded from 257 external branch of the superior laryngeal nerves (68.7%). After the patients with recurrent laryngeal nerve palsy were excluded, voice changes were detected in 6 (3.3%) of 184 patients with identified external branch of the superior laryngeal nerves and 3 (20%) of 15 patients in whom at least 1 external branch of the superior laryngeal nerve could not be identified with intraoperative neuromonitoring. CONCLUSION: Intraoperative neuromonitoring provided an important contribution to the visual and functional identification of the external branch of the superior laryngeal nerve. Intraoperative neuromonitoring is a helpful adjunct for identifying the external branch of the superior laryngeal nerve. PMID- 27989610 TI - Microbiological quality of honey from the Pampas Region (Argentina) throughout the extraction process. AB - The microbiological quality of honey obtained from different processing points and the environmental quality within honey houses were assessed in the Pampas Region (Argentina). Mold and yeast (MY), culturable heterotrophic mesophilic bacteria (CHMB), the number of spore-forming bacteria as well as the presence of Shigella spp., Salmonella spp. and fecal coliforms were evaluated in 163 samples. These samples were taken from eight honey houses. Results showed that 89 samples had <=10CFU of MY/g honey, 69 ranged from 10 to 50CFU/g and two reached 65.5CFU/g. Eighty one percent of the samples showed <=30CFU of CHMB/g honey and only seven samples had between 50 and 54.25CFU/g. Thirty six honey samples were obtained from drums: in 25 samples (69.4%) CHMB counts were less than <=30CFU/g of honey; in 20 samples (55.5%) the values of MY were between 10 and 50CFU/g honey and total coliforms were only detected in 20 samples. Fecal coliforms, spores of clostridia as well as Salmonella spp. and Shigella spp were not detected and less than 50 spores of Bacillus spp. per g were observed in the honey from drums. Therefore, the microbiological honey quality within the honey houses did not show any sanitary risks. Our results were reported to honey house owners to help them understand the need to reinforce proper honey handling and sanitation practices. PMID- 27989609 TI - Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus. AB - Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force sustaining alcohol use/abuse and contributing to relapse in alcoholics. Although no animal model exactly duplicates alcoholism, models for specific factors, including the withdrawal syndrome, are useful for identifying potential genetic and neural determinants of liability in humans. We previously identified highly significant quantitative trait loci (QTLs) with large effects on predisposition to withdrawal after chronic and acute alcohol exposure in mice and mapped these loci to the same region of chromosome 1 (Alcdp1 and Alcw1, respectively). The present studies utilize a novel Alcdp1/Alcw1 congenic model (in which an interval spanning Alcdp1 and Alcw1 from the C57BL/6J donor strain [build GRCm38 150.3-174.6 Mb] has been introgressed onto a uniform inbred DBA/2J genetic background) known to demonstrate significantly less severe chronic and acute withdrawal compared to appropriate background strain animals. Here, using c-Fos induction as a high-resolution marker of neuronal activation, we report that male Alcdp1/Alcw1 congenic animals demonstrate significantly less alcohol withdrawal-associated neural activation compared to appropriate background strain animals in the prelimbic and cingulate cortices of the prefrontal cortex as well as discrete regions of the extended amygdala (i.e., basolateral) and extended basal ganglia (i.e., dorsolateral striatum, and caudal substantia nigra pars reticulata). These studies are the first to begin to elucidate circuitry by which this confirmed addiction-relevant QTL could influence behavior. This circuitry overlaps limbic circuitry involved in stress, providing additional mechanistic information. Alcdp1/Alcw1 maps to a region syntenic with human chromosome 1q, where multiple studies find significant associations with risk for alcoholism. PMID- 27989611 TI - Phoenixin is negatively associated with anxiety in obese men. AB - Phoenixin was recently identified in the rat hypothalamus and initially implicated in reproductive functions. A subsequent study described an anxiolytic effect of the peptide. The aim of the study was to investigate a possible association of circulating phoenixin with anxiety in humans. We therefore enrolled 68 inpatients with a broad spectrum of psychometrically measured anxiety (GAD-7). We investigated men since a menstrual cycle dependency of phoenixin has been assumed. Obese subjects were enrolled since they often report psychological comorbidities. In addition, we also assessed depressiveness (PHQ-9) and perceived stress (PSQ-20). Plasma phoenixin levels were measured using a commercial ELISA. First, we validated the ELISA kit performing a spike-and-recovery experiment showing a variance of 6.7+/-8.8% compared to the expected concentrations over the whole range of concentrations assessed, while a lower variation of 1.6+/-0.8% was observed in the linear range of the assay (0.07-2.1ng/ml). We detected phoenixin in the circulation of obese men at levels of 0.68+/-0.50ng/ml. These levels showed a negative association with anxiety scores (r=-0.259, p=0.043), while no additional associations with other psychometric parameters were observed. In summary, phoenixin is present in the human circulation and negatively associated with anxiety in obese men, a population often to report comorbid anxiety. PMID- 27989613 TI - Rebuttal From Dr Bach. PMID- 27989612 TI - Psychological stress in geriatric patients with genito-urinary cancers. AB - BACKGROUND: Two-thirds of all cancer cases affect patients who are older than 65years, yet the specific conditions of the treatment and supportive care in this age group are poorly studied. There are limited data on the specific psycho oncological problems in elderly patients with genito-urinary cancers. The aim of this study was to investigate the psychosocial needs of elderly patients with genito-urinary tumors using screening questionnaires and to use such screening questionnaires for an in-patient psychosocial treatment program. METHODS: Patients (>=65years, n=319) who underwent surgical (n=295) or medical treatment (n=24) for genito-urinary malignancies between 06/2014 and 11/2015 in our institution were included for prospective stress assessment. This was done with standardized questionnaires for stress screening and for the identification of need for care (NCCN Distress Thermometer and Hornheider Screening Instrument, HSI). RESULTS: The patients scored an average of 4.4 on the Distress Thermometer. According to the survey evaluation, 28% of patients had need for psychosocial care. However, only a minority of patients (4%) did actually communicate any need for psychosocial care. We also assessed the actual utilization of inpatient psychosocial support which is offered to all patients. CONCLUSION: There is a significant number of elderly patients with genito-urinary cancer with increased psychological stress and a consecutive need of psychosocial care. This is underreported and underused by the patients. Therefore, an easy low-threshold access system with an interdisciplinary and inter-professional collaborative support system would be desirable. Measuring psychological distress systematically can be helpful in treating older patients with malignant diseases. PMID- 27989614 TI - POINT: Is Noninvasive Ventilation Always the Most Appropriate Manner of Long-term Ventilation for Infants With Spinal Muscular Atrophy Type 1? Yes, Almost Always. PMID- 27989615 TI - Rebuttal From Dr Panitch. PMID- 27989616 TI - COUNTERPOINT: Is Noninvasive Ventilation Always the Most Appropriate Manner of Long-term Ventilation for Infants With Spinal Muscular Atrophy Type 1? No. PMID- 27989617 TI - The application of PBPK models in estimating human brain tissue manganese concentrations. AB - Mn is an essential element that causes neurotoxicity in humans when inhaled at high concentrations. This metal has well-recognized route-dependent differences in absorption, with greater proportionate uptake for inhalation versus dietary exposure. Physiologically-based pharmacokinetic (PBPK) models for Mn have included these route specific differences in uptake and their effect on delivery of Mn to target tissues via systemic circulation. These PBPK models include components describing ingestion and inhalation, homeostatic control (concentration dependent biliary elimination and gastrointestinal absorption), and delivery to target sites within the brain. The objective of this study was to combine PBPK modeling of target tissue Mn concentration and categorical regression analysis to identify Mn intake levels (both by food and air) that are expected to cause minimal toxicity. We first used the human PBPK model to describe blood Mn data from three occupational exposure studies, demonstrating consistency between model predictions and measured data. The PBPK model was then used to predict concentrations of Mn in the globus pallidus (the presumed target tissue for motor function disruption in humans) for various epidemiological studies. With the predicted globus pallidus concentration of Mn, we conducted categorical regression modeling between globus pallidus Mn and severity-scored neurological outcome data from the human cohorts. This structured tissue dose - response analysis led to an estimated 10% extra risk concentration (ERC10) of 0.55MUg/g Mn in the globus pallidus, which is comparable to similar values estimated by the Agency of Toxic Substances and Disease Registry and Health Canada (after translation from external exposure to tissue dose). The steep dose response curve below this ERC10 value may be used to inform the choice of adjustment factor to translate the ERC10 as a point of departure to a reference concentration for occupational or environmental exposure to Mn. Because these results are based on human epidemiological data and a human PBPK model, adjustment or translation of results from animals to humans is not required. PMID- 27989618 TI - Pharmacokinetic Interactions Between Pelubiprofen and Eperisone Hydrochloride: A Randomized, Open-label, Crossover Study of Healthy Korean Men. AB - PURPOSE: Pelubiprofen is a novel nonsteroidal anti-inflammatory, analgesic, and antipyretic drug with at least similar efficacy and better tolerability compared with other nonsteroidal anti-inflammatory, analgesic, and antipyretic drugs such as naproxen and aceclofenac. Eperisone hydrochloride is a centrally acting muscle relaxant that performs by blocking calcium channels. The combined use of pelubiprofen and eperisone hydrochloride is increasingly anticipated to promote the clinical effectiveness of pelubiprofen in relieving musculoskeletal symptoms of osteoarthritis, rheumatoid arthritis, and low back pain. No published data are yet available, however, regarding the pharmacokinetic interactions between these 2 drugs when administered concurrently. The objective of this study was to evaluate any pharmacokinetic interactions between pelubiprofen and eperisone hydrochloride in healthy Korean male volunteers. METHODS: This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and orally received either 45-mg sustained-release pelubiprofen, 75-mg sustained-release eperisone hydrochloride, or both as a single dose in each treatment period, with a 7-day washout period between each treatment. Serial blood samples were collected over 24 hours after dosing, and plasma concentrations of each drug and the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen) were determined by using a validated HPLC-MS/MS system. Pharmacokinetic analyses were conducted by using noncompartmental methods. FINDINGS: A total of 24 men (mean +/- standard deviation of: age, 29 +/- 4 years; weight, 72.5 +/- 7.8 kg; body mass index, 23.4 +/- 1.9 kg/m2) were enrolled, and 23 participants completed the study. For pelubiprofen, the geometric mean ratios (90% CIs) of Cmax and AUC0-infinity were 1.02 (0.87-1.19) and 0.97 (0.88-1.07), respectively. For the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), the geometric mean ratios (90% CIs) of Cmax and AUC0-infinity were 1.05 (0.98-1.13) and 1.04 (1.01 1.07). For eperisone, the geometric mean ratios (90% CIs) of Cmax and AUC0 infinity were 0.87 (0.67-1.15) and 1.05 (0.85-1.30). None of the study participants experienced serious adverse events during the study. IMPLICATIONS: No clinically significant changes were noted in the pharmacokinetic interactions of pelubiprofen, the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), and eperisone hydrochloride between monotherapy and combination therapy with 45-mg sustained-release pelubiprofen and 75-mg sustained-release eperisone hydrochloride. PMID- 27989619 TI - Determinants of Treatment Eligibility in Veterans With Hepatitis C Viral Infection. AB - PURPOSES: The objective of this study was to determine the percentage of veterans with active hepatitis C virus (HCV) infection who were deemed to be candidates for treatment and to identify factors associated with treatment ineligibility. METHODS: This was a multisite, retrospective cohort analysis of veterans with HCV infection within the Veteran Integrated Service Network 21. Patients evaluated between August and November 2015 who were viremic and not receiving HCV treatment were included in the analysis. Reasons for treatment exclusion were determined by an experienced clinician and recorded into a regional population management dashboard. Descriptive statistics were used to describe the population. The t test for normally distributed data, the Mann-Whitney rank sum test for data that failed normality testing, or the chi2 test were used to examine differences between the treatment eligible and ineligible cohorts. Generalized linear mixed effects models were conducted to estimate patient outcomes relevant to various disease states and characteristics while controlling for interfacility variability. FINDINGS: The cohort included 1,003 veterans within 5 medical centers; 988 (98.5%) were male, and 625 (62%) had a fibrosis 4 score >3.25, indicating the presence of ALD. According to clinician classification, 478 (48%) were considered HCV treatment candidates, whereas 525 (52%) were determined to be treatment ineligible. The most common reasons documented by clinicians for treatment ineligibility included unstable or uncontrolled comorbidities (n = 118 [22.4%]), excessive alcohol use (n = 116 [22.1%]), and treatment refusal by the patient (n = 69 [13%]). On the basis of statistical modeling and reporting odds ratios (ORs) and 95% CIs, diagnoses of active alcohol use disorder (OR = 0.68; 95% CI, 0.47-0.98; P = 0.038), hepatocellular carcinoma (OR = 0.24; 95% CI, 0.13 0.47; P < 0.001), and palliative care status (OR = 0.21; 95% CI, 0.05-0.99; P = 0.049) were statistically associated with treatment ineligibility, whereas posttraumatic stress disorder (OR = 1.48; 95% CI, 1.01-2.18; P = 0.046) was associated with treatment eligibility. There were no statistically significant differences found for other psychiatric diagnoses or an encounter for homelessness. IMPLICATIONS: Results of this study indicate that a high percentage of patients may not be considered treatment eligible at initial clinical review. Within this veteran population, the presence of uncontrolled comorbidities and excessive alcohol use were the most commonly reported reasons for treatment ineligibility. On the basis of this analysis, processes could be established to address modifiable barriers to treatment, thus expanding the number of individuals receiving potentially curative therapy for HCV infection. PMID- 27989620 TI - Flexibility in the Periplasmic Domain of BamA Is Important for Function. AB - The beta-barrel assembly machine (BAM) mediates the biogenesis of outer membrane proteins (OMPs) in Gram-negative bacteria. BamA, the central BAM subunit composed of a transmembrane beta-barrel domain linked to five polypeptide transport associated (POTRA) periplasmic domains, is thought to bind nascent OMPs and undergo conformational cycling to catalyze OMP folding and insertion. One model is that conformational flexibility between POTRA domains is part of this conformational cycling. Nuclear magnetic resonance (NMR) spectroscopy was used here to study the flexibility of the POTRA domains 1-5 in solution. NMR relaxation studies defined effective rotational correlational times and together with residual dipolar coupling data showed that POTRA1-2 is flexibly linked to POTRA3-5. Mutants of BamA that restrict flexibility between POTRA2 and POTRA3 by disulfide crosslinking displayed impaired function in vivo. Together these data strongly support a model in which conformational cycling of hinge motions between POTRA2 and POTRA3 in BamA is required for biological function. PMID- 27989622 TI - The Molecular Basis of Aichi Virus 3A Protein Activation of Phosphatidylinositol 4 Kinase IIIbeta, PI4KB, through ACBD3. AB - Phosphatidylinositol 4-kinase III beta (PI4KIIIbeta) is an essential enzyme in mediating membrane transport, and plays key roles in facilitating viral infection. Many pathogenic positive-sense single-stranded RNA viruses activate PI4KIIIbeta to generate phosphatidylinositol 4-phosphate (PI4P)-enriched organelles for viral replication. The molecular basis for PI4KIIIbeta activation during viral infection has remained largely unclear. We describe the biochemical reconstitution and characterization of the complex of PI4KIIIbeta with the Golgi protein Acyl-coenzyme A binding domain containing protein 3 (ACBD3) and Aichi virus 3A protein on membranes. We find that 3A directly activates PI4KIIIbeta, and this activation is sensitized by ACBD3. The interfaces between PI4KIIIbeta ACBD3 and ACBD3-3A were mapped with hydrogen-deuterium exchange mass spectrometry (HDX-MS). Determination of the crystal structure of the ACBD3 GOLD domain revealed a unique N terminus that mediates the interaction with 3A. Rationally designed complex-disrupting mutations in both ACBD3 and PI4KIIIbeta completely abrogated the sensitization of 3A activation by ACBD3. PMID- 27989621 TI - Binding of Myomesin to Obscurin-Like-1 at the Muscle M-Band Provides a Strategy for Isoform-Specific Mechanical Protection. AB - The sarcomeric cytoskeleton is a network of modular proteins that integrate mechanical and signaling roles. Obscurin, or its homolog obscurin-like-1, bridges the giant ruler titin and the myosin crosslinker myomesin at the M-band. Yet, the molecular mechanisms underlying the physical obscurin(-like-1):myomesin connection, important for mechanical integrity of the M-band, remained elusive. Here, using a combination of structural, cellular, and single-molecule force spectroscopy techniques, we decode the architectural and functional determinants defining the obscurin(-like-1):myomesin complex. The crystal structure reveals a trans-complementation mechanism whereby an incomplete immunoglobulin-like domain assimilates an isoform-specific myomesin interdomain sequence. Crucially, this unconventional architecture provides mechanical stability up to forces of ~135 pN. A cellular competition assay in neonatal rat cardiomyocytes validates the complex and provides the rationale for the isoform specificity of the interaction. Altogether, our results reveal a novel binding strategy in sarcomere assembly, which might have implications on muscle nanomechanics and overall M band organization. PMID- 27989624 TI - Reprint of: A new definition for oral health supported by FDI opens the door to a universal definition of oral health. PMID- 27989623 TI - Full-Length Anion Exchanger 1 Structure and Interactions with Ankyrin-1 Determined by Zero Length Crosslinking of Erythrocyte Membranes. AB - Anion exchanger 1 (AE1) is a critical transporter and the primary structural scaffold for large macromolecular complexes responsible for erythrocyte membrane flexibility and integrity. We used zero-length crosslinking and mass spectrometry to probe AE1 structures and interactions in intact erythrocyte membranes. An experimentally verified full-length model of AE1 dimers was developed by combining crosslink-defined distance constraints with homology modeling. Previously unresolved cytoplasmic loops in the AE1 C-terminal domain are packed at the domain-domain interface on the cytoplasmic face of the membrane where they anchor the N-terminal domain's location and prevent it from occluding the ion channel. Crosslinks between AE1 dimers and ankyrin-1 indicate the likely topology for AE1 tetramers and suggest that ankyrin-1 wraps around AE1 tetramers, which may stabilize this oligomer state. This interaction and interactions of AE1 with other major erythrocyte membrane proteins show that protein-protein contacts are often substantially more extensive than previously reported. PMID- 27989625 TI - Pneumonia prevention: Cost-effectiveness analyses of two vaccines among refugee children aged under two years, Haemophilus influenzae type b-containing and pneumococcal conjugate vaccines, during a humanitarian emergency, Yida camp, South Sudan. AB - By September 2013, war between Sudan and South Sudan resulted in >70,000 Sudanese refugees and high pneumonia incidence among the 20,000 refugees in Yida camp, South Sudan. Using Medecins Sans Frontieres (MSF)-provided data and modifying our decision-tree models, we estimated if administering Haemophilus influenzae type b (Hib)-containing (pentavalent vaccine, also with diphtheria pertussis and tetanus [DPT] and hepatitis B) and pneumococcal conjugate (PCV) vaccines were cost effective against hospitalized pneumonia. Among children <2years old, compared with no vaccination, one- and two-doses of combined Hib-containing and PCV would avert an estimated 118 and 125 pneumonia cases, and 8.5 and 9.1 deaths, respectively. The cost per Disability-Adjusted-Life-Year averted for administering combined one- and two-doses was US$125 and US$209, respectively. MSF demonstrated that it was possible to administer these vaccines during an emergency and our analysis found it was highly cost-effective, even with just one dose of either vaccine. Despite unknown etiology, there is strong field and now economic rationale for administering Hib and PCV during at least one humanitarian emergency. PMID- 27989626 TI - Novel immunological insights in accelerating RSV vaccine development. PMID- 27989627 TI - Development of bioluminescence imaging of respiratory syncytial virus (RSV) in virus-infected live mice and its use for evaluation of therapeutics and vaccines. AB - Respiratory Syncytial virus (RSV) is one of the leading causes of pneumonia among infants with no human vaccine or efficient curative treatments. Efforts are underway to develop new RSV vaccines and therapeutics. There is a dire need for animal models for preclinical evaluation and selection of products against RSV. Herein, we developed a whole body bioluminescence imaging to follow replication of RSV A2 virus strain expressing firefly luciferase (RSVA2-line19-FFL) in live BALB/c mice that can be used as an extremely sensitive readout for studying effects of antiviral and vaccines in living mice. Strong bioluminescence signal was detected in the nasal cavity and in the lungs following intranasal infection of mice with RSVA2-line19-FFL. The kinetics of viral replication in lungs quantified by daily live imaging strongly correlated with viral titers measured by ex-vivo plaque assay and by assessing viral RNA by qRT-PCR. Vaccination of mice with a pre-fusion F protein elicited high neutralizing antibody titers conferring strong protective immunity against virus replication in the nasal cavity and lungs. In contrast, post-challenge treatment of mice with the monoclonal antibody Palivizumab two days after infection reduced viral replication in the nasal cavity at day 4, but only modestly reduced virus loads in the lungs by day 5. In contrast to RSV bioluminescence, plaque assay did not detect viral titers in lungs on day 5 in Palivizumab-treated animals. This difference between viral loads measured by the two assays was found to be due to coating of virions with the Palivizumab that blocked infection of target cells in vitro and shows importance of live imaging in evaluation of RSV therapeutics. This recombinant RSV based live imaging animal model is convenient and valuable tool that can be used to study host dissemination of RSV and evaluation of antiviral compounds and vaccines against RSV. PMID- 27989628 TI - [Care of Merkel cell carcinoma and role of the radiotherapy]. AB - Merkel cell carcinoma is a rare neuro-endocrine tumor of skin with a poor prognosis. Data available in literature are scarce. Current treatment for locoregional disease is based on combined treatment by surgery and radiotherapy. However these treatments are controversial. The aim of the present review is to sum up the different available studies and to compare national and international guidelines. PMID- 27989629 TI - [50th anniversary of cisplatin]. AB - We have just celebrated the 50th anniversary of cisplatin cytotoxic potential discovery. It is time to take stock... and it seems mainly positive. This drug, that revolutionized the treatment of many cancer types, continues to be the most widely prescribed chemotherapy. Despite significant toxicities, resistance mechanisms associated with treatment failures, and unresolved questions about its mechanism of action, the use of this cytotoxic agent remains unwavering. The interest concerning this "old" invincible drug has not yet abated. Indeed many research axes are in the news. New platinum salts agents are tested, new cisplatin formulations are developed to target tumor cells more efficiently, and new combinations are established to increase the cytotoxic potency of cisplatin or overcome the resistance mechanisms. PMID- 27989630 TI - [Specificities of carcinomas in adolescents and young adults]. AB - Carcinomas are rare tumors of the adolescent-young adult (AYA) with a different spectrum from those of adults. The most common sites outside of the thyroid is the nasopharynx, salivary gland, colon-rectum and ovaries. If nasopharyngeal carcinoma or salivary gland tumors are good prognosis, others are more reserved prognosis, such as digestive carcinomas, gynecological or midline. The revelation modes are non-specific and depend on the location: mass, tumor syndrome, pain, impaired general condition. The unusual of pediatric carcinomas led to propose a systematic oncogenetic exploration. The medical history of the family, the symptoms and the type of the carcinoma should guide the analysis. In the absence of guidance, analysis of TP53 gene and, for carcinomas of the expanded spectrum of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, the search for mutation of MMR genes (mismatch repair) seems essential. Because of the rarity of these diseases and the absence of homogeneous recommendations, members of the rare tumors committee of the SFCE recommended for the management of these AJA, an histological review by a pathologist familiar with carcinomas of the adult, a double discussion between pediatric and adult oncologists, analysis of adult standards with adaptation to pediatric data, especially in terms of risk of side effects. An advice to a national opinion (by a member of FRACTURE group) or European (group EXPERT) is sometimes necessary in the most complex situations. PMID- 27989631 TI - Molecular phylogeny, character evolution and historical biogeography of Cryptanthus Otto & A. Dietr. (Bromeliaceae). AB - Cryptanthus comprises 72 species endemic to eastern Brazil with a center of diversity in the Atlantic Forest. The majority of the species are threatened due to habitat loss. We reconstructed phylogenetic relationships in Cryptanthus based on amplified fragment length polymorphisms (AFLP) including 48 species and 109 accessions. The Bayesian phylogenetic analysis revealed four major lineages in Cryptanthus and provided further evidence for the paraphyly of subgen. Hoplocryptanthus, while subgenus Cryptanthus was resolved as monophyletic. Monophyly of previously recognized morphological species groups at sectional level could not be confirmed. Based on the phylogenetic reconstruction we inferred the evolution of the sex system in Cryptanthus via maximum likelihood (ML) ancestral character reconstruction. Homoecy, the possession of hermaphrodite flowers only, was reconstructed as the ancestral state in the genus and characterizes three of the four main lineages within Cryptanthus. Andromonoecy, the possession of male and hermaphrodite flowers on the same plant, evolved only once and represents a synapomorphy of the fourth main lineage, C. subgen. Cryptanthus. The ancestral biome analysis reconstructed Cerrado (semiarid scrublands and forests) and campos rupestres (rock fields) as the most likely ancestral biomes for the genus. A shift to the Atlantic Forest biome was reconstructed to have occurred twice, in the ancestor of the first diverging lineage within the genus and in the ancestor of the C. subgen. Cryptanthus clade. A shift to the Caatinga (tropical dryland savanna) and one reversal to Cerrado (campos rupestres - rock fields) was reconstructed to have occurred once, in C. bahianus and C. arelii, respectively. The ancestral biome reconstruction indicates a high degree of niche conservatism within Cryptanthus with rare biome shifts throughout the evolution of the genus. Further, our results imply that the current infrageneric taxonomy of Cryptanthus is problematic and requires revision. PMID- 27989632 TI - Molecular phylogeny and patterns of diversification in syngnathid fishes. AB - The family Syngnathidae is a large and diverse clade of morphologically unique bony fishes, with 57 genera and 300 described species of seahorses, pipefishes, pipehorses, and seadragons. They primarily inhabit shallow coastal waters in temperate and tropical oceans, and are characterized by a fused jaw, male brooding, and extraordinary crypsis. Phylogenetic relationships within the Syngnathidae remain poorly resolved due to lack of generic taxon sampling, few diagnostic morphological characters, and limited molecular data. The phylogenetic placement of the threatened, commercially exploited seahorses remains a topic of intense interest, with conflicting topologies based on morphology and predominantly mitochondrial genetic data. In this study, we integrate eight nuclear and mitochondrial markers and 17 morphological characters to investigate the phylogenetic structure of the family Syngnathidae at the generic level. We include 91 syngnathid species representing 48 of the 57 recognized genera, all major ocean basins, and a broad array of temperate and tropical habitats including rocky and coral reefs, sand and silt, mangroves, seagrass beds, estuaries, and rivers. Maximum likelihood and Bayesian analyses of 5160bp from eight loci produced high congruence among alternate topologies, defining well supported and sometimes novel clades. We present a hypothesis that confirms a deep phylogenetic split between lineages with trunk- or tail-brood pouch placement, and provides significant new insights into the morphological evolution and biogeography of this highly derived fish clade. Based on the fundamental division between lineages - the tail brooding "Urophori" and the trunk brooding "Gastrophori" - we propose a revision of Syngnathidae classification into only two subfamilies: the Nerophinae and the Syngnathinae. We find support for distinct principal clades within the trunk-brooders and tail-brooders, the latter of which include seahorses, seadragons, independent lineages of pipehorses, and clades that originated in southern Australia and the Western Atlantic. We suggest the seahorse genus Hippocampus is of Indo-Pacific origin and its sister clade is an unexpected grouping of several morphologically disparate Indo-Pacific genera, including the Pacific pygmy pipehorses. Taxonomic revision is required for multiple genera, particularly to reflect deep evolutionary splits in nominal lineages from the Atlantic versus the Indo-Pacific. PMID- 27989633 TI - The microsporidium Nosema disstriae (Thomson 1959): Fine structure and phylogenetic position within the N. bombycis clade. AB - A microsporidium Nosema disstriae (Thomson) is a parasite of the forest tent caterpillar Malacasoma disstria (Lepidoptera: Lasiocampidae), a notable defoliator of deciduous trees in North America. The goal of this paper was to demonstrate the ultrastructure of N. disstriae and to determine the position of this microsporidium within the N. bombycis clade (NBC) using comparative morphology and multiple molecular phylogenetic markers: RPB1, LSU-, ITS- and SSU rDNA. As a part of this goal, the revision of the described members of the NBC has been performed. The ultrastructure of proliferating stages and spores of N. disstriae were similar to previously described Nosema spp. parasitizing lepidopteran species. Meronts produced tubular-like structures on their surfaces and exhibited a tight association with host mitochondria. All stages were diplokaryotic and developed without interfacial envelopes. Disporoblastic sporogony produced typical Nosema-type spores with 9-12 polar filament coils. A vesicle with immature spores was once recognized on sections, concordant with the previous record of octosporous sporogony in the N. disstriae life cycle. Rarely, spores with thinner envelopes and large posterior vacuoles were seen in the midgut. Tracheae were most heavily infected. Midgut, surrounding muscles, haemocytes and fat body also contained microsporidia. SSUrRNA-inferred phylogenies were consistent with previously published articles and did not resolve the relation within the NBC clade. The RPB1-inferred trees and concatenated RPB1 and LSU-ITS-SSUrDNA-based trees demonstrated clustering of N. disstriae with N. antheraeae as early divergent species within the NBC. PMID- 27989634 TI - Heterologous expression of Paranosema (Antonospora) locustae hexokinase in lepidopteran, Sf9, cells is followed by accumulation of the microsporidian protein in insect cell nuclei. AB - Paranosema (Nosema, Antonospora) locustae is the only microsporidium produced as a commercial product for biological control. Molecular mechanisms of the effects of this pathogen and other invertebrate microsporidia on host cells remain uncharacterized. Previously, we immunolocalized P. locustae hexokinase in nuclei of Locusta migratoria infected adipocytes. Here, the microsporidian protein was expressed in the yeast Pichia pastoris and in lepidopteran Sf9 cells. During heterologous expression, P. locustae hexokinase was accumulated in the nuclei of insect cells but not in yeast cell nuclei. This confirms nuclear localization of hexokinase secreted by microsporidia into infected host cells and suggests convenient model for its further study. PMID- 27989635 TI - Reply to the Letter to the Editor concerning 'High levels of the soluble programmed death-ligand identify hepatocellular carcinoma patients with a poor prognosis'. PMID- 27989638 TI - Interfacial Au nanoparticle decoration of a disulfide modified G-wire. AB - BACKGROUND: The guanine-rich oligonucleotide (GRO), dGGGGTTGGGG (G4T2G4), has the capacity to form a linear supramolecular polymer known as a G-wire. Individual nucleotides of the component GROs can be functionally modified to serve as site specific attachment points in the G-wire while not interfering with its self assembling properties. An amine linker modification to an internal thymine base of the GRO, denoted G4TT*G4, serves as a chemically versatile attachment site. METHODS: In this work, addition of an alkyl disulfide to G4TT*G4 produces the GRO G4TTdG4 enabling binding to gold nanoparticles via place exchange chemistry. G wires assembled by combining G4T2G4 and G4TTdG4 were stably maintained in an aqueous environment. Disulfide modified G-wires (DS_G-wire) were then covered with dodecanethiol capped gold nanoparticles in an organic solvent via an interfacial place exchange reaction. Tapping Mode AFM and TEM were used to image G-wires decorated with gold nanoparticles. The specificity of the interfacial place exchange reaction was measured using a fluorometric dye displacement from the gold nanoparticles. RESULTS: The results show that a two component DS_G-wire with an amphipathic tether readily self-assemble as shown by PAGE and TM-AFM. The amphipathic disulfide moiety of DS_G-wires facilitates place exchange chemistry with alkylthiol protected Au nanoparticles across an aqueous-organic interface. CONCLUSION: Interfacial place exchange is an effective strategy for decorating DS_G-wires with Au nanoparticles. GENERAL SIGNIFICANCE: The use of modified G wire self-assembly combined with a high degree of nanoparticle binding specificity presents another strategy for the use of G-wires as a rigid one dimensional molecular scaffold with potential applications in nanoscale device construction. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 27989640 TI - Commentary to 'Bleeding after circumcision is more likely in children with Lichen sclerosus: "Facts are stubborn, but statistics are more pliable" '. PMID- 27989639 TI - The Swedish Infant High-grade Reflux Trial - Bladder function. AB - INTRODUCTION: It has been suggested that infants with high-grade vesicoureteral reflux (VUR) have lower urinary tract dysfunction (LUTD) that is characterised by large bladder capacity (BC) and increased post-void residual (PVR). However, most of these infants have normal or small BC in early infancy and develop large capacity during the first year of life. OBJECTIVE: This study aimed to see whether LUTD development during the infant years in children with high-grade VUR could be prevented by early reflux resolution. MATERIALS AND METHODS: For early VUR intervention, endoscopic treatment (ET) was used in a randomised trial comprising 77 infants (55 boys) aged <8 months with VUR grade 4-5 (n = 30/n = 47); 39 were randomised to antibiotic prophylaxis and 38 to ET. Voiding cystourethrogram, free voiding observation (FVO) and renal scintigraphy were performed at baseline and after 1 year. Bladder capacity and PVR were obtained from FVO. LUTD was defined as a BC of >=150% of expected and a PVR of >=20 ml. RESULTS: There were no differences in bladder function variables seen between the treatment groups, despite significant differences in VUR resolution. Analysing bladder function related to VUR outcome (VUR grade <=2 vs grade >2), independent of treatment, showed that VUR grade <=2 was associated with a smaller BC at 1 year (P = 0.050) (a tendency already seen at baseline) and a lower PVR at baseline (P = 0.010). PVR increased from baseline to 1 year (P = 0.037) in children with grade <=2 VUR (Summary Table). The group with persistent bilateral grade 5 VUR at 1 year had more abnormal bladder variables compared with other study subjects, with a tendency of larger BC (P = 0.057), higher PVR (P = 0.0073) and more LUTD (P = 0.029) at baseline and a larger BC at 1 year (P = 0.016). In explanatory analyses, using logistic regression, a high PVR at baseline was identified as a predictor of VUR grade >2 (P = 0.046), persistent bilateral grade 5 VUR (P = 0.022), recurrent urinary tract infection (P = 0.034), and only a tendency was seen regarding new renal damage (P = 0.053). CONCLUSION: There was no between-group difference seen in bladder function. In children with VUR resolution at follow-up, independent of treatment, BC decreased, whereas PVR increased. High PVR at baseline was a predictive factor for both non-resolution of high-grade VUR and recurrent urinary tract infection. The results suggest that LUTD cannot be prevented by early VUR resolution, but rather is an important prognostic factor for VUR outcome in both endoscopic and prophylactic treatment. PMID- 27989641 TI - Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) describes a group of conditions with a common hemodynamic phenotype of increased pulmonary artery pressure, driven by progressive remodeling of small pulmonary arteries, leading to right heart failure and death. Vascular remodeling is the key pathological feature of PAH, but treatments targeting this process are lacking. In this review, we summarize important advances in our understanding of PAH pathogenesis from novel genetic and epigenetic factors, to cell metabolism and DNA damage. We show how these processes may integrate and highlight exploitable targets that could alter the relentless vascular remodeling in PAH. PMID- 27989643 TI - SerpinI2 (pancpin) is an inhibitory serpin targeting pancreatic elastase and chymotrypsin. AB - SerpinI2/Pancpin/MEPI is a 46kDa member of the serpin (serine protease inhibitor) superfamily. It is downregulated in pancreatic and breast cancer, and associated with acinar cell apoptosis and pancreatic insufficiency when absent in mice. However, the target protease and protein properties of serpinI2 are previously uncharacterised. We have expressed and purified recombinant serpin I2 in E. coli. The protein exhibited thermal instability typical of inhibitory serpins, which was lost following RCL cleavage. SerpinI2 did not inhibit trypsin, but was found to inhibit pancreatic chymotrypsin and elastase with Kass values >105M-1s-1, and with stoichiometry of inhibition of 1.4 and 1.7 respectively. Mutagenesis of the predicted critical hinge region residue Ser344 abolished inhibitory activity, and a cleavage site C-terminal to Met358 was identified. The protein is also prone to polymerisation/aggregation at 45 degrees C, a characteristic of serpins associated with disease. This study therefore reveals a function for serpinI2 and supports the hypothesis that this protein can protect pancreatic cells from prematurely activated zymogens. PMID- 27989644 TI - Activity-regulated cytoskeleton-associated protein predicts response to cognitive remediation among individuals with first-episode psychosis. PMID- 27989642 TI - MicroRNA Regulation of RNA Virus Replication and Pathogenesis. AB - microRNAs (miRNAs) are non-coding RNAs that regulate many processes within a cell by manipulating protein levels through direct binding to mRNA and influencing translation efficiency, or mRNA abundance. Recent evidence demonstrates that miRNAs can also affect RNA virus replication and pathogenesis through direct binding to the RNA virus genome or through virus-mediated changes in the host transcriptome. Here, we review the current knowledge on the interaction between RNA viruses and cellular miRNAs. We also discuss how cell and tissue-specific expression of miRNAs can directly affect viral pathogenesis. Understanding the role of cellular miRNAs during viral infection may lead to the identification of novel mechanisms to block RNA virus replication or cell-specific regulation of viral vector targeting. PMID- 27989645 TI - Effects of environmental risks and polygenic loading for schizophrenia on cortical thickness. AB - There are established differences in cortical thickness (CT) in schizophrenia (SCZ) and bipolar (BD) patients when compared to healthy controls (HC). However, it is unknown to what extent environmental or genetic risk factors impact on CT in these populations. We have investigated the effect of Environmental Risk Scores (ERS) and Polygenic Risk Scores for SCZ (PGRS-SCZ) on CT. Structural MRI scans were acquired at 3T for patients with SCZ or BD (n=57) and controls (n=41). Cortical reconstructions were generated in FreeSurfer (v5.3). The ERS was created by determining exposure to cannabis use, childhood adverse events, migration, urbanicity and obstetric complications. The PGRS-SCZ were generated, for a subset of the sample (Patients=43, HC=32), based on the latest PGC GWAS findings. ANCOVAs were used to test the hypotheses that ERS and PGRS-SCZ relate to CT globally, and in frontal and temporal lobes. An increase in ERS was negatively associated with CT within temporal lobe for patients. A higher PGRS-SCZ was also related to global cortical thinning for patients. ERS effects remained significant when including PGRS-SCZ as a fixed effect. No relationship which survived FDR correction was found for ERS and PGRS-SCZ in controls. Environmental risk for SCZ was related to localised cortical thinning in patients with SCZ and BD, while increased PGRS-SCZ was associated with global cortical thinning. Genetic and environmental risk factors for SCZ appear therefore to have differential effects. This provides a mechanistic means by which different risk factors may contribute to the development of SCZ and BD. PMID- 27989646 TI - Methods for monitoring signaling molecules in cellular compartments. AB - Cells, irrespective of whether they are from multicellular or single-celled organisms, must communicate with the external environment through dynamic regulation of their internal metabolism, which are critical for their survival. Fluorescent and bioluminescent proteins, and related genetic engineering technologies, have provided new opportunities to investigate the molecular dynamics of cells and their internal compartments, with high spatio-temporal resolution. In this review article, since there is a sufficient number of previous reviews summarizing the history of their development and the techniques behind them, here we will focus on molecular features or technologies that have the potential to further open novel investigations of cellular and subcellular dynamics. PMID- 27989647 TI - Costs of promoting cancer screening: Evidence from CDC's Colorectal Cancer Control Program (CRCCP). AB - The Colorectal Cancer Control Program (CRCCP) provided funding to 29 grantees to increase colorectal cancer screening. We describe the screening promotion costs of CRCCP grantees to evaluate the extent to which the program model resulted in the use of funding to support interventions recommended by the Guide to Community Preventive Services (Community Guide). We analyzed expenditures for screening promotion for the first three years of the CRCCP to assess cost per promotion strategy, and estimated the cost per person screened at the state level based on various projected increases in screening rates. All grantees engaged in small media activities and more than 90% used either client reminders, provider assessment and feedback, or patient navigation. Based on all expenditures, projected cost per eligible person screened for a 1%, 5%, and 10% increase in state-level screening proportions are $172, $34, and $17, respectively. CRCCP grantees expended the majority of their funding on Community Guide recommended screening promotion strategies but about a third was spent on other interventions. Based on this finding, future CRC programs should be provided with targeted education and information on evidence-based strategies, rather than broad based recommendations, to ensure that program funds are expended mainly on evidence-based interventions. PMID- 27989648 TI - A serum metabolomics-based profile in low bone mineral density postmenopausal women. AB - Osteoporosis is characterized as a metabolic disorder of bone tissue, and various metabolic markers are now available to support its diagnosis and evaluate treatment effects. Substances produced as end products of metabolomic activities are the correlated factors to the biological or metabolic status, and thus, metabolites are considered highly sensitive markers of particular pathological states, including osteoporosis. Here we undertook comprehensive serum metabolomics analysis in postmenopausal women with or without low bone mineral density (low BMD vs controls) for the first time using capillary electrophoresis/mass spectrometry. Among the metabolites tested, 57 were detected in sera. Levels of hydroxyproline, Gly-Gly and cystine, differed significantly between groups, with Gly-Gly and cystine significantly lower in the low BMD group and hydroxyproline, a reported marker of osteoporosis, significantly higher. Levels of TRACP5b, a bone resorption marker, were significantly higher in the low BMD group, supporting the study's validity. Taken together, our findings represent novel metabolomic profiling in low BMD in postmenopausal women. PMID- 27989649 TI - Muscle mass is associated with incident fracture in postmenopausal women: The OFELY study. AB - The relationships between body composition and bone mineral density are well established but the contribution of body composition to the risk of fracture (Fx) has rarely been evaluated prospectively. We analyzed the risk of Fx by body composition in 595 postmenopausal women (mean age 66+/-8years) from a longitudinal cohort study (Os des Femmes de Lyon). We assessed the risk of the first incident fragility Fx according to body composition obtained from whole body DXA: abdominal visceral (VFAT) and subcutaneous fat mass (SFAT), total body fat mass (FM), lean mass index (LMI) and appendicular skeletal muscle mass index (ASMI). During a median [IQ] follow-up of 13.1years [1.9], 138 women sustained a first incident Fx, including 85 women with a major osteoporotic Fx (MOP Fx: hip, clinical spine, humerus or wrist). After adjustment for age, women who sustained Fx had lower BMI (-4%, p=0.01), LMI (-6%, p=0.002) and ASMI (-3%, p=0.003), compared with women without Fx. After adjustment for age, prevalent Fx, physical activity, incident falls and FN BMD, each SD increase of baseline values of LMI and ASMI was associated with decreased Fx risk with adjusted hazard ratios of 0.76 for both of p<=0.02. Those associations were similar after accounting for the competing risk of death. VFAT and SFAT were associated with Fx risk in the multivariate model only for MOP Fx and the association did not persist after consideration of competing mortality. We conclude that lean mass and appendicular muscle mass indexes are associated with the risk of fracture in postmenopausal women independently of BMD and clinical risk factors. PMID- 27989650 TI - Phenotypic characterization of Grm1crv4 mice reveals a functional role for the type 1 metabotropic glutamate receptor in bone mineralization. AB - Recent increasing evidence supports a role for neuronal type signaling in bone. Specifically glutamate receptors have been found in cells responsible for bone remodeling, namely the osteoblasts and the osteoclasts. While most studies have focused on ionotropic glutamate receptors, the relevance of the metabotropic glutamate signaling in bone is poorly understood. Specifically type 1 metabotropic glutamate (mGlu1) receptors are expressed in bone, but the effect of its ablation on skeletal development has never been investigated. Here we report that Grm1crv4/crv4 mice, homozygous for an inactivating mutation of the mGlu1 receptor, and mainly characterized by ataxia and renal dysfunction, exhibit decreased body weight, bone length and bone mineral density compared to wild type (WT) animals. Blood analyses of the affected mice demonstrate the absence of changes in circulating factors, such as vitamin D and PTH, suggesting renal damage is not the main culprit of the skeletal phenotype. Cultures of osteoblasts lacking functional mGlu1 receptors exhibit less homogeneous collagen deposition than WT cells, and present increased expression of osteocalcin, a marker of osteoblast maturation. These data suggest that the skeletal damage is directly linked to the absence of the receptor, which in turn leads to osteoblasts dysfunction and earlier maturation. Accordingly, skeletal histomorphology suggests that Grm1crv4/crv4 mice exhibit enhanced bone maturation, resulting in premature fusion of the growth plate and shortened long bones, and further slowdown of bone apposition rate compared to the WT animals. In summary, this work reveals novel functions of mGlu1 receptors in the bone and indicates that in osteoblasts mGlu1 receptors are necessary for production of normal bone matrix, longitudinal bone growth, and normal skeletal development. PMID- 27989652 TI - AVP1: One Protein, Many Roles. AB - Constitutive expression of the Arabidopsis vacuolar proton-pumping pyrophosphatase (H+-PPase) gene (AVP1) increases plant growth under various abiotic stress conditions and, importantly, under nonstressed conditions. Many interpretations have been proposed to explain these phenotypes, including greater vacuolar ion sequestration, increased auxin transport, enhanced heterotrophic growth, and increased transport of sucrose from source to sink tissues. In this review, we evaluate all the roles proposed for AVP1, using findings published to date from mutant plants lacking functional AVP1 and transgenic plants expressing AVP1. It is clear that AVP1 is one protein with many roles, and that one or more of these roles act to enhance plant growth. The complexity suggests that a systems biology approach to evaluate biological networks is required to investigate these intertwined roles. PMID- 27989651 TI - The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes. AB - Skeletal co-morbidities in type 1 diabetes include an increased risk for fracture and delayed fracture healing, which are intertwined with disease duration and the presence of other diabetic complications. As such, chronic hyperglycemia is undoubtedly a major contributor to these outcomes, despite standard insulin replacement therapy. Therefore, using the streptozotocin (STZ)-induced model of hypoinsulinemic hyperglycemia in DBA/2J male mice, we compared the effects of two glucose lowering therapies on the fracture resistance of bone and markers of bone turnover. Twelve week-old diabetic (DM) mice were treated for 9weeks with: 1) oral canagliflozin (CANA, dose range ~10-16mg/kg/day), an inhibitor of the renal sodium-dependent glucose co-transporter type 2 (SGLT2); 2) subcutaneous insulin, via minipump (INS, 0.125units/day); 3) co-therapy (CANA+INS); or 4) no treatment (STZ, without therapy). These groups were also compared to non-diabetic control groups. Untreated diabetic mice experienced increased bone resorption and significant deficits in cortical and trabecular bone that contributed to structural weakness of the femur mid-shaft and the lumbar vertebra, as determined by three-point bending and compression tests, respectively. Treatment with either canagliflozin or insulin alone only partially rectified hyperglycemia and the diabetic bone phenotype. However, when used in combination, normalization of glycemic control was achieved, and a prevention of the DM-related deterioration in bone microarchitecture and bone strength occurred, due to additive effects of canagliflozin and insulin. Nevertheless, CANA-treated mice, whether diabetic or non-diabetic, demonstrated an increase in urinary calcium loss; FGF23 was also increased in CANA-treated DM mice. These findings could herald ongoing bone mineral losses following CANA exposure, suggesting that certain CANA-induced skeletal consequences might detract from therapeutic improvements in glycemic control, as they relate to diabetic bone disease. PMID- 27989653 TI - Co-adaptation of electric organ discharges and chirps in South American ghost knifefishes (Apteronotidae). AB - Animal communication signals that simultaneously share the same sensory channel are likely to co-evolve to maximize the transmission of each signal component. Weakly electric fish continuously produce a weak electric field that functions in communication. Fish modulate the electric organ discharge (EOD) on short timescales to produce context-specific signals called chirps. EODs and chirps are simultaneously detected by electroreceptors and processed in the electrosensory system. We analyzed these signals, first to explore whether EOD waveform is encoded in the signal received by electroreceptors and then to examine how EODs and chirps interact to influence conspicuousness. Our findings show that gross discrimination of sinusoidal from complex EOD waveforms is feasible for all species, but fine discrimination of waveform may be possible only for species with waveforms of intermediate complexity. The degree of chirp frequency modulation and chirp relative decay strongly influenced chirp conspicuousness, but other chirp parameters were less influential. The frequency difference between the interacting EODs also strongly impacted chirp conspicuousness. Finally, we developed a method for creating hybrid chirp/EOD combinations to independently analyze the impact of chirp species, EOD species, and EOD difference frequency on chirp conspicuousness. All three components and their interactions strongly influenced chirp conspicuousness, which suggests that evolutionary changes in parameters of either chirps or EODs are likely to influence chirp detection. Examining other environmental factors such as noise created by fish movement and species-typical patterns of sociality may enrich our understanding of how interacting EODs affect the detection and discrimination of chirps across species. PMID- 27989656 TI - Pathways of Unconventional Protein Secretion. AB - Secretory proteins are conventionally transported through the endoplasmic reticulum to the Golgi and then to the plasma membrane where they are released into the extracellular space. However, numerous substrates also reach these destinations using unconventional pathways. Unconventional protein secretion (UPS) is complex and comprises cargos without a signal peptide or a transmembrane domain that can translocate across the plasma membrane, and cargos that reach the plasma membrane by bypassing the Golgi despite entering the endoplasmic reticulum (ER). With a few exceptions, unconventional secretion is largely triggered by stress. Here I review new results and concepts that are beginning to define these pathways. PMID- 27989654 TI - Endocytosis, Metastasis and Beyond: Multiple Facets of SNX9. AB - Sorting nexin (SNX)9 was first discovered as an endocytic accessory protein involved in clathrin-mediated endocytosis. However, recent data suggest that SNX9 is a multifunctional scaffold that coordinates membrane trafficking and remodeling with changes in actin dynamics to affect diverse cellular processes. Here, we review the accumulated knowledge on SNX9 with an emphasis on its recently identified roles in clathrin-independent endocytic pathways, cell invasion, and cell division, which have implications for SNX9 function in human disease, including cancer. PMID- 27989655 TI - Actomyosin Pulsing in Tissue Integrity Maintenance during Morphogenesis. AB - The actomyosin cytoskeleton is responsible for many changes in cell and tissue shape. For a long time, the actomyosin cytoskeleton has been known to exhibit dynamic contractile behavior. Recently, discrete actomyosin assembly/disassembly cycles have also been observed in cells. These so-called actomyosin pulses have been observed in a variety of contexts, including cell polarization and division, and in epithelia, where they occur during tissue contraction, folding, and extension. In epithelia, evidence suggests that actomyosin pulsing, and more generally, actomyosin turnover, is required to maintain tissue integrity during contractile processes. This review explores possible functions for pulsing in the many instances during which pulsing has been observed, and also highlights proposed molecular mechanisms that drive pulsing. PMID- 27989657 TI - Evaluating landfill aftercare strategies: A life cycle assessment approach. AB - This study investigates the potential impacts caused by the loss of active environmental control measures during the aftercare period of landfill management. A combined mechanistic solute flow model and life cycle assessment (LCA) approach was used to evaluate the potential impacts of leachate emissions over a 10,000year time horizon. A continuum of control loss possibilities occurring at different times and for different durations were investigated for four different basic aftercare scenarios, including a typical aftercare scenario involving a low permeability cap and three accelerated aftercare scenarios involving higher initial infiltration rates. Assuming a 'best case' where control is never lost, the largest potential impacts resulted from the typical aftercare scenario. The maximum difference between potential impacts from the 'best case' and the 'worst case', where control fails at the earliest possible point and is never reinstated, was only a fourfold increase. This highlights potential deficiencies in standard life cycle impact assessment practice, which are discussed. Nevertheless, the results show how the influence of active control loss on the potential impacts of landfilling varies considerably depending on the aftercare strategy used and highlight the importance that leachate treatment efficiencies have upon impacts. PMID- 27989659 TI - [Skeletal muscle ischemia-reperfusion and ischemic conditioning pathophysiology clinical applications for the vascular surgeon]. AB - Ischemia-reperfusion, which is characterized by deficient oxygen supply and subsequent restoration of blood flow, can cause irreversible damage to tissue. The vascular surgeon is daily faced with ischemia-reperfusion situations. Indeed, arterial clamping induces ischemia, followed by reperfusion when declamping. Mechanisms underlying ischemia-reperfusion injury are complex and multifactorial. Increases in cellular calcium and reactive oxygen species, initiated during ischemia and then amplified upon reperfusion are thought to be the main mediators of reperfusion injury. Mitochondrial dysfunction also plays an important role. Extensive research has focused on increasing skeletal muscle tolerance to ischemia-reperfusion injury, especially through the use of ischemic conditioning strategies. The purpose of this review is to focus on the cellular responses associated with ischemia-reperfusion, as well as to discuss the effects of ischemic conditioning strategies. This would help the vascular surgeon in daily practice, in order to try to improve surgical outcome in the setting of ischemia reperfusion. PMID- 27989660 TI - Adaptation and Validation of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) for Use in Spain. AB - INTRODUCTION AND OBJECTIVES: The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is a patient-reported outcome measure of health-related quality of life and quality of life specific to individuals with pulmonary hypertension (PH). This questionnaire has demonstrated superiority over other instruments assessing similar domains. The objective of the present study was to adapt and validate the Spanish version of the questionnaire. METHODS: The adaptation consisted of 3 stages: translation from English to Spanish using bilingual and lay panels, cognitive debriefing interviews with patients, and assessment of psychometric properties by means of a postal validation survey. RESULTS: The translation panels produced a version of the CAMPHOR that was considered suitable for use by Spanish PH patients. The relevance, comprehensiveness, and acceptability of this version were confirmed in interviews with PH patients. Finally, the validation survey (n = 70) revealed that the 3 CAMPHOR scales (Symptoms, Activities, and Quality of life) showed strong psychometric properties. The internal consistency (Cronbach alpha) coefficients of the scales were above 0.89, and the test-retest reliability was above 0.87. The convergent and known group validity of the CAMPHOR scales was also demonstrated. CONCLUSIONS: The Spanish version of the CAMPHOR is a valid and reliable instrument for the assessment of health-related quality of life and quality of life in Spanish PH patients. Therefore, it is recommended for use in future research and clinical practice in the Spanish population of PH patients. PMID- 27989661 TI - Measles re-emergence in Northern Italy: Pathways of measles virus genotype D8, 2013-2014. AB - Molecular surveillance and advanced phylogenetic methods are important tools to track the pathways of Measles virus (MV) genotypes, provide evidence for the interruption of endemic transmission and verify the elimination of the disease. The aims of this study were to describe the genetic profile of MV genotype D8 (D8 MV) strains circulating in Northern Italy (Lombardy Region) during the 2013-2014 period and to analyze the transmission chains and estimate the introduction time points using a phylogenetic approach. Forty-four strains of D8-MV identified from 12 outbreaks and 28 cases reported as sporadic were analyzed. Molecular analysis was performed by sequencing the highly variable 450nt region of the N gene of MV genome (N-450), as recommended by the WHO. Phylogenetic analyses and tree time scaled reconstruction were performed with BEAST software. We could trace back the transmission pathways that resulted in three chains of transmission, two introductions with limited spread (two familiar outbreaks), and two single introductions (true sporadic cases). The D8-Taunton transmission chain, which was involved in 7 outbreaks and 13 sporadic cases, was endemic during the studied period. Furthermore, two novel local variants emerged independently in March 2014 and caused two transmission chains linked to at least 3 outbreaks. Overall, viral diversity was high and strains belonging to 5 different variants were identified. The results of this study clearly demonstrate that multiple lineages of D8-MV co circulated in Northern Italy. Measles can be considered a re-emerging disease in Italy and additional efforts are necessary to achieve measles elimination goal. PMID- 27989663 TI - Integration of Telemedicine Into Clinical Gastroenterology and Hepatology Practice. PMID- 27989662 TI - Immunoinformatics analysis and in silico designing of a novel multi-epitope peptide vaccine against Staphylococcus aureus. AB - Staphylococcus aureus is a pathogen that causes a variety of infections in humans. Methicillin-resistant S. aureus, which is an antibiotic-resistant form, is responsible for nosocomial staphylococcal infections, whose frequency is increasing in healthy people. Thereby, the development of novel techniques is required to overcome this bacterial infection. In this context, the use of vaccines to control infections is an appropriate alternative. In this study, immunoinformatics analysis is used on three antigenic determinants as vaccine candidates, and a novel multi-epitope vaccine is designed to induce cellular, humoral, and innate immune responses against S. aureus. Alpha-enolase, clumping factor A, and iron surface determinant B were selected as the protective antigens; and phenol-soluble modulin alpha 4was applied as the adjuvant. Epitopes identification was done for each antigen using various immunoinformatics servers. Moreover, the tertiary structure of our protein vaccine was predicted and validated. Subsequently, the best-modeled protein structure was used for the refinement process. There fined model was then applied for docking studies with Toll-like receptor 2 (TLR2).In the next step, molecular dynamics (MD) simulation was used to evaluate the stability of vaccine molecule and TLR2-vaccine complex. The high ranked epitopes were selected from the mentioned antigens. The selected epitopes and the adjuvant were fused together by proper linkers. Then, the modeled protein structure was selected and validated. Validation results indicated that the initial model needs refinement. After a refinement process, the final model was generated. Finally, the best-docked model of vaccine and TLR2 complex was selected. In this research, we attempted to design an efficient subunit vaccine, which could stimulate humoral and cellular immune responses. Therefore, we expect that our designed vaccine could defeat antibiotic-resistant staphylococcal infections. PMID- 27989664 TI - Effective Interprofessional Perioperative Training Requires not Only Multi Professional and Multi-Department, but also Multi-Hospital Participation. PMID- 27989665 TI - The cell wall precursor lipid II acts as a molecular signal for the Ser/Thr kinase PknB of Staphylococcus aureus. AB - The assembly of the bacterial cell wall requires synchronization of a multitude of biosynthetic machineries and regulatory networks. The eukaryotic-like serine/threonine kinase PknB has been implicated in coordinating cross-wall formation, autolysis and cell division in Staphylococcus aureus. However, the signal molecule sensed by this kinase remained elusive so far. Here, we provide compelling biochemical evidence that PknB interacts with the ultimate cell wall precursor lipid II, triggering kinase activity. Moreover, we observed crosstalk of PknB with the two component system WalKR and identified the early cell division protein FtsZ as another PknB phosphorylation substrate in S. aureus. In agreement with the implied role in regulation of cell envelope metabolism, we found PknB to preferentially localize to the septum of S. aureus and the PASTA domains to be crucial for recruitment to this site. The data provide a model for the contribution of PknB to control cell wall metabolism and cell division. PMID- 27989666 TI - Structure-activity relationships of benzothiazole GPR35 antagonists. AB - The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound. PMID- 27989667 TI - Ser422 phosphorylation blocks human Tau cleavage by caspase-3: Biochemical implications to Alzheimer's Disease. AB - Proteolytic truncation of microtubule associated human (h) Tau protein by caspase 3 at the carboxy (C) terminus has been linked to the pathogenesis of Alzheimer's Disease (AD). This cleavage likely occurs between Asp421?Ser422 leading to the formation of 421-mer truncated Tau protein which has been found to be present as aggregate in high level after phosphorylation in mortal AD brain tissue compared to normal. At least 50 phosphorylation sites involving Ser, Thr and Tyr residues have been identified or proposed in hTau and a selected number of them have been implicated in hTau aggregation following latter's proteolytic truncation. Interestingly, it is further noted that Ser422 residue present in the P1' position of hTau caspase-3 cleavage region is a potential phosphorylation site. So we became interested to examine in vitro the effect of phospho-Ser422 residue on hTau cleavage by caspase-3 which is a crucial upstream event associated with hTau self-assembly leading to AD pathogenesis. The goal of this project is to study in vitro the caspase-3 cleavage site of hTau protein and to examine the kinetics of this cleavage following Ser422 phosphorylation and treatment with caspase-3 inhibitors. This is achieved by designing peptides from the sequence of hTau protein containing the proposed caspase-3 cleavage region. Peptides were designed from 441-mer major human Tau protein sequence that encompasses the proposed caspase-3 cleavage site [Asp421?Ser422]. Corresponding phospho-, dextro Ser422 and dextro-Asp421 analogs were also designed. Peptides were synthesized by solid phase chemistry, purified and fully characterized by mass spectrometry. These were then incubated with recombinant caspase-3 enzyme under identical condition for digestion and analyzed for cleavage by mass spectrometry and RP HPLC chromatograms. Our results indicated that while the control peptide is efficiently cleaved by caspase-3 at Asp421?Ser422 site producing the expected N- and C-terminal fragment peptides, the corresponding phospho-Ser422 peptide remained completely resistant to the cleavage. Substitution of Asp421 by its dextro isoform also blocks peptide cleavage by caspase-3. However substitution of Ser422 by its dextro isoform in the peptide did not affect the cleavage significantly. The above results were further confirmed by caspase-3 digestion experiment in the presence of varying amounts of caspase-3 inhibitor (Ac-DQVD aldehyde) which was found to block this cleavage in a highly effective manner. Our results highlighted the crucial significance of Ser422 phosphorylation and suggest that the kinase associated with this Ser-phosphorylation may protect Tau from aggregation. Thus specific promoters/activators of this kinase may find useful therapeutic benefits in arresting Tau truncation by caspase-3 and the progression of AD. In addition our data demonstrated that Tau-peptides where Ser422 or Asp421 are substituted by their respective dextro isomers, exhibit different cleavage kinetics by caspase-3 and this may have important implications in therapeutic intervention of Tau aggregation and associated AD. PMID- 27989668 TI - Natural NO inhibitors from the leaves of Callicarpa kwangtungensis: Structures, activities, and interactions with iNOS. AB - A phytochemical investigation to obtain new NO inhibitors resulted in the isolation of a new diterpenoid with a rare 9,10-seco-abietane skeleton (1) and twelve known terpenoids (2-13) from Callicarpa kwangtungensis. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses, and the absolute configuration of compound 1 was established by comparison of the calculated and experimental electronic circular dichroism (ECD) spectra. The inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells of these terpenoids were evaluated, and all of the compounds showed inhibitory effects. The following molecular docking studies showed interactions of the bioactive compounds with the iNOS protein. PMID- 27989669 TI - Editorial: Why are guidelines not followed in clinical practice? PMID- 27989671 TI - Marine Dispersal Scales Are Congruent over Evolutionary and Ecological Time. AB - The degree to which offspring remain near their parents or disperse widely is critical for understanding population dynamics, evolution, and biogeography, and for designing conservation actions. In the ocean, most estimates suggesting short distance dispersal are based on direct ecological observations of dispersing individuals, while indirect evolutionary estimates often suggest substantially greater homogeneity among populations. Reconciling these two approaches and their seemingly competing perspectives on dispersal has been a major challenge. Here we show for the first time that evolutionary and ecological measures of larval dispersal can closely agree by using both to estimate the distribution of dispersal distances. In orange clownfish (Amphiprion percula) populations in Kimbe Bay, Papua New Guinea, we found that evolutionary dispersal kernels were 17 km (95% confidence interval: 12-24 km) wide, while an exhaustive set of direct larval dispersal observations suggested kernel widths of 27 km (19-36 km) or 19 km (15-27 km) across two years. The similarity between these two approaches suggests that ecological and evolutionary dispersal kernels can be equivalent, and that the apparent disagreement between direct and indirect measurements can be overcome. Our results suggest that carefully applied evolutionary methods, which are often less expensive, can be broadly relevant for understanding ecological dispersal across the tree of life. PMID- 27989670 TI - UV-B Perceived by the UVR8 Photoreceptor Inhibits Plant Thermomorphogenesis. AB - Small increases in ambient temperature can elicit striking effects on plant architecture, collectively termed thermomorphogenesis [1]. In Arabidopsis thaliana, these include marked stem elongation and leaf elevation, responses that have been predicted to enhance leaf cooling [2-5]. Thermomorphogenesis requires increased auxin biosynthesis, mediated by the bHLH transcription factor PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) [6-8], and enhanced stability of the auxin co-receptor TIR1, involving HEAT SHOCK PROTEIN 90 (HSP90) [9]. High temperature-mediated hypocotyl elongation additionally involves localized changes in auxin metabolism, mediated by the indole-3-acetic acid (IAA)-amido synthetase Gretchen Hagen 3 (GH3).17 [10]. Here we show that ultraviolet-B light (UV-B) perceived by the photoreceptor UV RESISTANCE LOCUS 8 (UVR8) [11] strongly attenuates thermomorphogenesis via multiple mechanisms inhibiting PIF4 activity. Suppression of thermomorphogenesis involves UVR8 and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1)-mediated repression of PIF4 transcript accumulation, reducing PIF4 abundance. UV-B also stabilizes the bHLH protein LONG HYPOCOTYL IN FAR RED (HFR1), which can bind to and inhibit PIF4 function. Collectively, our results demonstrate complex crosstalk between UV-B and high-temperature signaling. As plants grown in sunlight would most likely experience concomitant elevations in UV-B and ambient temperature, elucidating how these pathways are integrated is of key importance to the understanding of plant development in natural environments. PMID- 27989672 TI - Bloom Syndrome Helicase Promotes Meiotic Crossover Patterning and Homolog Disjunction. AB - In most sexually reproducing organisms, crossover formation between homologous chromosomes is necessary for proper chromosome disjunction during meiosis I. During meiotic recombination, a subset of programmed DNA double-strand breaks (DSBs) are repaired as crossovers, with the remainder becoming noncrossovers [1]. Whether a repair intermediate is designated to become a crossover is a highly regulated decision that integrates several crossover patterning processes, both along chromosome arms (interference and the centromere effect) and between chromosomes (crossover assurance) [2]. Because the mechanisms that generate crossover patterning have remained elusive for over a century, it has been difficult to assess the relationship between crossover patterning and meiotic chromosome behavior. We show here that meiotic crossover patterning is lost in Drosophila melanogaster mutants that lack the Bloom syndrome helicase. In the absence of interference and the centromere effect, crossovers are distributed more uniformly along chromosomes. Crossovers even occur on the small chromosome 4, which normally never has meiotic crossovers [3]. Regulated distribution of crossovers between chromosome pairs is also lost, resulting in an elevated frequency of homologs that do not receive a crossover, which in turn leads to elevated nondisjunction. PMID- 27989673 TI - Phylogenomics and Morphology of Extinct Paleognaths Reveal the Origin and Evolution of the Ratites. AB - The Palaeognathae comprise the flightless ratites and the volant tinamous, and together with the Neognathae constitute the extant members of class Aves. It is commonly believed that Palaeognathae originated in Gondwana since most of the living species are found in the Southern Hemisphere [1-3]. However, this hypothesis has been questioned because the fossil paleognaths are mostly from the Northern Hemisphere in their earliest time (Paleocene) and possessed many putative ancestral characters [4]. Uncertainties regarding the origin and evolution of Palaeognathae stem from the difficulty in estimating their divergence times [1, 2] and their remarkable morphological convergence. Here, we recovered nuclear genome fragments from extinct elephant birds, which enabled us to reconstruct a reliable phylogenomic time tree for the Palaeognathae. Based on the tree, we identified homoplasies in morphological traits of paleognaths and reconstructed their morphology-based phylogeny including fossil species without molecular data. In contrast to the prevailing theories, the fossil paleognaths from the Northern Hemisphere were placed as the basal lineages. Combined with our stable divergence time estimates that enabled a valid argument regarding the correlation with geological events, we propose a new evolutionary scenario that contradicts the traditional view. The ancestral Palaeognathae were volant, as estimated from their molecular evolutionary rates, and originated during the Late Cretaceous in the Northern Hemisphere. They migrated to the Southern Hemisphere and speciated explosively around the Cretaceous-Paleogene boundary. They then extended their distribution to the Gondwana-derived landmasses, such as New Zealand and Madagascar, by overseas dispersal. Gigantism subsequently occurred independently on each landmass. PMID- 27989674 TI - Non-junctional E-Cadherin Clusters Regulate the Actomyosin Cortex in the C. elegans Zygote. AB - Classical cadherins are well known for their essential function in mediating cell cell adhesion via their extra-cellular cadherin domains and intra-cellular connections to the actin cytoskeleton [1-3]. There is evidence, however, of adhesion-independent cadherin clusters existing outside of cell-cell junctions [4 6]. What function, if any, these clusters have is not known. HMR-1, the sole classical cadherin in Caenorhabditis elegans, plays essential roles during gastrulation, blastomere polarity establishment, and epidermal morphogenesis [7 11]. To elucidate the physiological roles of non-junctional cadherin, we analyzed HMR-1 in the C. elegans zygote, which is devoid of neighbors. We show that non junctional clusters of HMR-1 form during the one-cell polarization stage and associate with F-actin at the cortex during episodes of cortical flow. Non junctional HMR-1 clusters downregulate RHO-1 activity and inhibit accumulation of non-muscle myosin II (NMY-2) at the anterior cortex. We found that HMR-1 clusters impede cortical flows and play a role in preserving the integrity of the actomyosin cortex, preventing it from splitting in two. Importantly, we uncovered an inverse relationship between the amount of HMR-1 at the cell surface and the rate of cytokinesis. The effect of HMR-1 clusters on cytokinesis is independent of their effect on NMY-2 levels, and is also independent of their extra-cellular domains. Thus, in addition to their canonical role in inter-cellular adhesion, HMR-1 clusters regulate RHO-1 activity and NMY-2 level at the cell surface, reinforce the stability of the actomyosin cortex, and resist its movement to influence cell-shape dynamics. PMID- 27989675 TI - Optogenetic Stimulation of Frontal D1 Neurons Compensates for Impaired Temporal Control of Action in Dopamine-Depleted Mice. AB - Disrupted mesocortical dopamine contributes to cognitive symptoms of Parkinson's disease (PD). Past work has implicated medial frontal neurons expressing D1 dopamine receptors (D1DRs) in temporal processing. Here, we investigated whether these neurons can compensate for behavioral deficits resulting from midbrain dopamine dysfunction. We report three main results. First, both PD patients and mice with ventral tegmental area (VTA) dopamine depletion had attenuated delta activity (1-4 Hz) in the medial frontal cortex (MFC) during interval timing. Second, we found that optogenetically stimulating MFC D1DR neurons could increase ramping activity among MFC neurons. Finally, stimulating MFC D1DR neurons specifically at delta frequencies (2 Hz) compensated for deficits in temporal control of action caused by VTA dopamine depletion. Our results suggest that cortical networks can be targeted by frequency-specific brain stimulation to improve dopamine-dependent cognitive processing. PMID- 27989677 TI - Salt controls feeding decisions in a blood-sucking insect. AB - Salts are necessary for maintaining homeostatic conditions within the body of all living organisms. Like with all essential nutrients, deficient or excessive ingestion of salts can result in adverse health effects. The taste system is a primary sensory modality that helps animals to make adequate feeding decisions in terms of salt consumption. In this work we show that sodium and potassium chloride salts modulate the feeding behavior of Rhodnius prolixus in a concentration-dependent manner. Feeding is only triggered by an optimal concentration of any of these salts (0.1-0.15M) and in presence of the phagostimulant ATP. Conversely, feeding solutions that do not contain salts or have a high-salt concentration (>0.3M) are not ingested by insects. Notably, we show that feeding decisions of insects cannot be explained as an osmotic effect, because they still feed over hyperosmotic solutions bearing the optimal salt concentration. Insects perceive optimal-salt, no-salt and high-salt solutions as different gustatory information, as revealed the electromyogram recordings of the cibarial pump. Moreover, because insects do a continuous gustatory monitoring of the incoming food during feeding, sudden changes beyond the optimal sodium concentration decrease and even inhibit feeding. The administration of amiloride, a sodium channel blocker, noticeably reduces the ingestion of the optimal sodium solution but not of the optimal potassium solution. Salt detection seems to occur at least through two salt receptors, one amiloride-sensitive and another amiloride-insensitive. Our results confirm the importance of the gustatory system in R. prolixus, showing the relevant role that salts play on their feeding decisions. PMID- 27989678 TI - Introduction: A New Renaissance in Pericardial Diseases. PMID- 27989676 TI - DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration. AB - Migration through micron-size constrictions has been seen to rupture the nucleus, release nuclear-localized GFP, and cause localized accumulations of ectopic 53BP1 a DNA repair protein. Here, constricted migration of two human cancer cell types and primary mesenchymal stem cells (MSCs) increases DNA breaks throughout the nucleoplasm as assessed by endogenous damage markers and by electrophoretic "comet" measurements. Migration also causes multiple DNA repair proteins to segregate away from DNA, with cytoplasmic mis-localization sustained for many hours as is relevant to delayed repair. Partial knockdown of repair factors that also regulate chromosome copy numbers is seen to increase DNA breaks in U2OS osteosarcoma cells without affecting migration and with nucleoplasmic patterns of damage similar to constricted migration. Such depletion also causes aberrant levels of DNA. Migration-induced nuclear damage is nonetheless reversible for wild-type and sub-cloned U2OS cells, except for lasting genomic differences between stable clones as revealed by DNA arrays and sequencing. Gains and losses of hundreds of megabases in many chromosomes are typical of the changes and heterogeneity in bone cancer. Phenotypic differences that arise from constricted migration of U2OS clones are further illustrated by a clone with a highly elongated and stable MSC-like shape that depends on microtubule assembly downstream of the transcription factor GATA4. Such changes are consistent with reversion to a more stem-like state upstream of cancerous osteoblastic cells. Migration-induced genomic instability can thus associate with heritable changes. PMID- 27989679 TI - Three Years as Editor-in-Chief. PMID- 27989680 TI - Prokineticin system modulation as a new target to counteract the amyloid beta toxicity induced by glutamatergic alterations in an in vitro model of Alzheimer's disease. AB - The accumulation of beta-amyloid (Abeta) is one of the hallmarks of Alzheimer disease (AD). Beyond the inflammatory reactions promoted by Abeta, it has been demonstrated that the prokineticin (PK) system, composed of the chemokine prokineticin 2 (PK2) and its receptors, is involved in Abeta toxicity. In this study we have analyzed how the Abeta chronic treatment affects the glutamatergic transmission on neurons from primary cortical cultures, clearly demonstrating the PK system involvement on its action mechanism. In fact, we have observed a significant increase of the ionic current through the AMPA receptors in primary cortical neurons and an up-regulation of the PK system in cultures chronically treated with Abeta. All effects were nullified by the prokineticin antagonist PC 1. Moreover, we have herein firstly demonstrated that the incubation of primary cortical culture with Bv8, the amphibian homologue of PK2, was able to increase in neurons the AMPA currents at specific doses and exposure times, measured both as evoked and as spontaneous currents. This effect was not due to a modification of the AMPA receptor subunit expression. In contrast, the up-modulation of AMPA currents were blocked by PC-1 and were mediated by the activation of the intracellular protein kinase C (PKC) transduction pathways because Go6983, the PKC inhibitor added in the medium, nullified the effect. Finally, cellular death induced by kainate was also reduced following treatment with PC1. In conclusion, our results show that the prokineticin system may be a key mediator in the Abeta induced neuronal damage, suggesting PK antagonists as new therapeutic compounds to ameliorate the AD progression. PMID- 27989681 TI - Twelve-year follow-up of catheter ablation for atrial fibrillation: A prospective, multicenter, randomized study. AB - BACKGROUND: Randomized and controlled studies have reported the effect of catheter ablation (CA) for atrial fibrillation (AF) over a follow-up of 12-24 months. OBJECTIVE: We report on the effect of CA plus antiarrhythmic drugs in comparison with antiarrhythmic drugs alone on the maintenance of sinus rhythm over 12-year follow-up. METHODS: We extended the follow-up duration of the 137 patients who were enrolled in the Catheter Ablation for the Cure of Atrial Fibrillation Study between February 1, 2002, and June 30, 2003, and randomized to antiarrhythmic drugs (control group) or antiarrhythmic drugs plus CA (ablation group). The primary end point was time to first symptomatic or asymptomatic recurrence of atrial arrhythmia lasting >30 seconds during follow-up. RESULTS: During follow-up, 19 of 68 (27.9%; 95% confidence interval [CI] 18.7%-39.6%) ablation group patients and 3 of 69 (4.3%; 95% CI 1.49%-12.0%) control group patients did not experience any relapse of atrial tachyarrhythmia (P < .001). The Kaplan-Meier analysis performed to determine the probability of survival free from atrial arrhythmias showed a statistical difference in favor of the ablation group (log-rank, P < .001). The effect of CA was consistent in both patients with paroxysmal AF and those with persistent AF. In the multivariate Cox regression analysis, belonging to the control group (hazard ratio 2.95; 95% CI 1.896-4.726; P < .001) and longer time since first AF episode (hazard ratio 1.004; 95% CI 1.002-1.084; P = .041) were predictors of atrial tachyarrhythmia recurrence. CONCLUSION: In patients with paroxysmal and persistent AF, CA significantly increased time to first recurrence of atrial arrhythmias during 12-year follow up. PMID- 27989682 TI - Catheter ablation of supraventricular tachycardia in d-transposition of the great arteries after corrective surgery. PMID- 27989683 TI - Reply to the Editor-On misuse of null hypothesis testing: Analysis of biophysical model simulations. PMID- 27989684 TI - Pacing requirement after valvular heart surgery: "It ain't over 'til it's over". PMID- 27989685 TI - Calcitriol (1,25-dihydroxyvitamin D3) increases L-type calcium current via protein kinase A signaling and modulates calcium cycling and contractility in isolated mouse ventricular myocytes. AB - BACKGROUND: Calcitriol, the bioactive metabolite of vitamin D, exerts its effects through interaction with the nuclear vitamin D receptor (VDR) to induce genomic responses. Calcitriol may also induce rapid responses via plasma membrane associated VDR, involving the activation of second messengers and modulation of voltage-dependent channels. VDR is expressed in cardiomyocytes, but the molecular and cellular mechanisms involved in the rapid responses of calcitriol in the heart are poorly understood. OBJECTIVE: The aim of the present study was to analyze the rapid nongenomic effect of calcitriol on L-type calcium channels, intracellular Ca2+ ([Ca2+]i) transients, and cell contractility in ventricular myocytes. METHODS: We used the whole-cell patch-clamp technique to record L-type calcium current (ICaL) and confocal microscopy to study global [Ca2+]i transients evoked by electrical stimulation and cell shortening in adult mouse ventricular myocytes treated with vehicle or with calcitriol. In some experiments, ICaL was recorded using the perforated patch-clamp technique. RESULTS: Calcitriol treatment of cardiomyocytes induced a concentration-dependent increase in ICaL density (Half maximal effective concentration (EC50) = 0.23 nM) and a significant increase in peak [Ca2+]i transients and cell contraction. The effect of calcitriol on ICaL was prevented by pretreatment of cardiomyocytes with the protein kinase A (PKA) inhibitor KT-5720 but not with the beta-adrenergic blocker propranolol. The effect of calcitriol on ICaL was absent in myocytes isolated from VDR knockout mice. CONCLUSION: Calcitriol induces a rapid response in mouse ventricular myocytes that involves a VDR-PKA-dependent increase in ICaL density, enhancing [Ca2+]i transients and contraction. PMID- 27989686 TI - Balloon-assisted rescue of four consecutive patients with vascular lacerations inflicted during lead extraction. PMID- 27989688 TI - Can a pacemaker improve our ability to manage sleep apnea? PMID- 27989687 TI - Role of protein kinase C in metabolic regulation of the cardiac Na+ channel. AB - BACKGROUND: The reduced form of nicotinamide adenine dinucleotide (NADH) increases in cardiomyopathy, activates protein kinase C (PKC), up-regulates mitochondrial reactive oxygen species (mitoROS), and down-regulates the cardiac Na+ channel (NaV1.5). OBJECTIVE: The purpose of this study was to determine how NADH signals down-regulation of NaV1.5. METHODS: Isolated mouse cardiomyocytes were used for patch-clamp recording and for monitoring mitoROS with MitoSOX Red. HEK293 cells were used for transient transfections. HEK293 cells stably expressing human NaV1.5 were used for single channel recording, whole-cell patch clamp recording, activity measurements of phospholipase C and phospholipase D (PLD), channel protein purification, and co-immunoprecipitation with PKC isoforms. HL-1 cells were used for mitochondria isolation. RESULTS: NADH enhanced PLD activity (1.6- +/- 0.1-fold, P <.01) and activated PKCdelta. Activated PKCdelta translocated to mitochondria and up-regulated mitoROS (2.8- +/- 0.3 fold, P <.01) by enhancing the activities of mitochondrial complexes I, II, and IV (1.1- to 1.5-fold, P <.01). PKCdelta also interacted with NaV1.5 to down regulate Na+ current (INa). Reduction in INa by activated PKCdelta was prevented by antioxidants and by mutating the known PKC phosphorylation site S1503. At the single channel level, the mechanism of current reduction by PKC and recovery by protein kinase A was a change in single channel conductance. CONCLUSION: NADH activated PKCdelta by enhancing PLD activity. PKCdelta modulated both mitoROS and NaV1.5. PKCdelta elevated mitoROS by enhancing mitochondrial oxidative phosphorylation complex activities. PKCdelta-mediated channel phosphorylation and mitoROS were both required to down-regulate NaV1.5 and alter single channel conductance. PMID- 27989689 TI - CD40 signaling and hepatic steatosis: Unanticipated links. AB - Obesity predisposes to an increased risk of nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis is the key pathological feature of NAFLD and has emerged as a metabolic disorder in which innate and adaptive arms of the immune response play a central role in disease pathogenesis. Recent studies have revealed unexpected relationships between CD40 signaling and hepatic steatosis in high fat diet rodent models. CD154, the ligand of CD40, is a mediator of inflammation and controls several critical events of innate and adaptive immune responses. In the light of these reports, we discuss potential links between CD40 signaling and hepatic steatosis in NAFLD. PMID- 27989690 TI - Comparing the Efficacy of Tadalafil Versus Placebo on Pulmonary Artery Systolic Pressure and Right Ventricular Function in Patients with Beta-Thalassaemia Intermedia. AB - BACKGROUND: Conventional oral therapies in the management of pulmonary hypertension in people without haemoglobinopathies are of limited value in thalassaemia patients because of toxicity and poor effectiveness. This study was conducted to assess the effect of tadalafil on pulmonary artery pressure and right ventricular systolic function in patients with beta-thalassaemia intermedia. METHODS: Forty-four patients with beta-thalassaemia intermedia with pulmonary hypertension based on transthoracic echocardiography (TTE) were entered in the study. Patients with hepatic or renal insufficiency and also patients who were treated with organic nitrates or alpha-blockers were excluded. The patients were randomly divided into two groups (n=22) and they were treated for six weeks with tadalafil (40mg daily) or placebo. The pulmonary artery systolic pressure (PASP), tricuspid regurgitation velocity (TRV) and parameters related to systolic function of the right ventricle were measured by the TTE before and after treatment. RESULTS: Significant improvement in TRV (3.02+/-0.02 m/s-2.52+/-0.06 m/s), PASP (45.31+/-0.66 mmHg-34.26+/-1.15mmHg) and parameters related to systolic function of the right ventricle were observed in the group who received tadalafil compared to placebo (p< 0.05). CONCLUSIONS: Tadalafil significantly decreased PASP and TRV in patients with beta-thalassaemia intermedia. Likewise, tadalafil improved right ventricular systolic function in the patients. PMID- 27989691 TI - Aquatic Exercise Training is Effective in Maintaining Exercise Performance in Trained Heart Failure Patients: A Randomised Crossover Pilot Trial. AB - BACKGROUND: Providing flexible models and a variety of exercise options are fundamental to supporting long-term exercise participation for patients with heart failure (HF). The aim of this pilot study was to determine the feasibility and efficacy of aquatic exercise training during a maintenance phase for a clinical heart failure population. METHODS: In this 2 x 2 crossover design trial, individuals who had previously completed HF rehabilitation were randomised into either a land-based or aquatic training program once per week for six weeks, after which time they changed to the alternate exercise training protocol for an additional six weeks. Six-minute walk test (6MWT), grip strength, walk speed, and measures of balance were compared for the two training protocols. RESULTS: Fifty one participants (43 males, mean age 69.2 yrs) contributed data for the analysis. Both groups maintained function during the follow-up period, however improvements in 6MWT were greater in the land-based training group (95% CI: 0.7, 22.5; p=0.038), by a mean difference of 10.8 metres. No significant difference was observed for other parameters when the two training protocols were compared. CONCLUSION: Attending an aquatic exercise program once per week is feasible for patients with stable HF and may provide a suitable option to maintain functional performance in select patients. PMID- 27989692 TI - Multivessel spontaneous coronary artery dissection in a puerperal young woman. PMID- 27989694 TI - Developmental cannabinoid exposure: New perspectives on outcomes and mechanisms. PMID- 27989693 TI - Comparison of the clinical efficacy of preserved and preservative-free hydroxypropyl methylcellulose-dextran-containing eyedrops. AB - PURPOSE: This study aimed to compare the efficacy of two sustained-release formulation of artificial tear drops. PATIENTS AND METHODS: This is a randomized patient-masked clinical trial, a total 88 patients into two group A (n=41; with single dose of artificial tear, containing dextran 70, 1mg/ml and hypromellose, 3mg/ml hydroxypropyl methylcellulose (HPMC) and group B (n=47; with multidose of artificial tear, containing 0.3g HPMC and 0.1g of dextran 70, with 0.01% benzalkonium chloride (BAK) as preservative) were completed the study. The ocular surface disease index (OSDI) questionnaire, tear break up time (TBUT), corneal and conjunctival staining and Schirmer test, were performed. Repeated measures ANOVA was used to assess the differences among the two products. A p-value less than 0.05 was considered significant. RESULTS: The mean of age of the participants in the Group A and B was 44.08+/-6.29 (range, 33-58 years) years and 45.83+/-8.42 (31-60 years), respectively. In comparing two groups before the intervention, the OSDI scores, the TBUT scores, the conjunctival and corneal staining scores and the Schirmer scores did not show statistically significant differences (p=0.339, p=0.640, p=0.334, p=0.807 and p=0.676, respectively). After 4 weeks, the OSDI scores, conjunctival and corneal staining scores showed improvement in compare to those before the intervention (p<0.001). But, the differences for the Schirmer test score and TBUT score was not significant (p=0.115, p=0.013, respectively). CONCLUSION: Our outcomes indicated that improvement occurred with use of both products but there was no statistically significant difference between them. PMID- 27989695 TI - The genetics of isoflurane-induced developmental neurotoxicity. AB - INTRODUCTION: Neurotoxicity induced by early developmental exposure to volatile anesthetics is a characteristic of organisms across a wide range of species, extending from the nematode C. elegans to mammals. Prevention of anesthetic induced neurotoxicity (AIN) will rely upon an understanding of its underlying mechanisms. However, no forward genetic screens have been undertaken to identify the critical pathways affected in AIN. By characterizing such pathways, we may identify mechanisms to eliminate isoflurane induced AIN in mammals. METHODS: Chemotaxis in adult C. elegans after larval exposure to isoflurane was used to measure AIN. We initially compared changes in chemotaxis indices between classical mutants known to affect nervous system development adding mutants in response to data. Activation of specific genes was visualized using fluorescent markers. Animals were then treated with rapamycin or preconditioned with isoflurane to test effects on AIN. RESULTS: Forty-four mutations, as well as pharmacologic manipulations, identified two pathways, highly conserved from invertebrates to humans, that regulate AIN in C. elegans. Activation of one stress-protective pathway (DAF-2 dependent) eliminates AIN, while activation of a second stress-responsive pathway (endoplasmic reticulum (ER) associated stress) causes AIN. Pharmacologic inhibition of the mechanistic Target of Rapamycin (mTOR) blocks ER-stress and AIN. Preconditioning with isoflurane prior to larval exposure also inhibited AIN. DISCUSSION: Our data are best explained by a model in which isoflurane acutely inhibits mitochondrial function causing activation of responses that ultimately lead to ER-stress. The neurotoxic effect of isoflurane can be completely prevented by manipulations at multiple points in the pathways that control this response. Endogenous signaling pathways can be recruited to protect organisms from the neurotoxic effects of isoflurane. PMID- 27989696 TI - Methyl mercury exposure and neurodevelopmental outcomes in the Seychelles Child Development Study Main cohort at age 22 and 24years. AB - BACKGROUND: All fish contain methyl mercury (MeHg), a known neurotoxicant at adequate dosage. There is still substantial scientific uncertainty about the consequences, if any, of mothers consuming fish with naturally-acquired levels of MeHg contamination. In 1989-1990, we recruited the Main Cohort of the Seychelles Child Development Study to assess the potential developmental effects of prenatal MeHg exposure. We report here on associations with neurodevelopmental outcomes obtained at 22 and 24years of age. METHODS: Neurodevelopmental tests at 22years included the Boston Naming Test, Cambridge Neuropsychological Test Automated Battery (CANTAB), and the Profile of Mood States. At 24years, we administered the Stroop Word-Color Test, the Barkley Adult ADHD Rating Scale, the Test of Variables of Attention, and the Finger Tapping test. We also administered a healthy behaviors survey at both ages. Primary analyses examined covariate adjusted associations in multiple linear regression models with prenatal MeHg exposure. In secondary analyses we also examined associations with recent postnatal MeHg exposure. RESULTS: We did not observe adverse associations between prenatal MeHg exposure and any of the measured endpoints. Some measures of attention, executive function, and delayed recall showed improved performance with increasing exposure. Secondary analysis did not show consistent patterns of association with postnatal exposure. CONCLUSIONS: Our cohort has been examined at ten different ages over 24years of follow-up. Findings suggest that prenatal and recent postnatal MeHg exposure from ocean fish consumption is not adversely associated with neurobehavioral development at levels that are about ten times higher than typical U.S. exposures. PMID- 27989697 TI - Developmental benzo[a]pyrene (B[a]P) exposure impacts larval behavior and impairs adult learning in zebrafish. AB - Polycyclic aromatic hydrocarbons (PAHs) are produced from incomplete combustion of organic materials or fossil fuels, and are present in crude oil and coal; therefore, they are ubiquitous environmental contaminants present in urban air, dust, soil, and water. It is widely recognized that PAHs pose risks to human health, especially for the developing fetus and infant where PAH exposures have been linked to in-utero mortality, cardiovascular effects, and lower intelligence. Using the zebrafish model, we evaluated the developmental toxicity of benzo[a]pyrene (B[a]P). Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 0.4 and 4MUM B[a]P. The Viewpoint Zebrabox systems were used to evaluate larval photomotor response (LPR) activity and we identified that exposure to 4MUM B[a]P resulted in a hyperactive LPR phenotype. To evaluate the role of aryl hydrocarbon receptor (AHR) in this larval phenotype, we exposed ahr2hu2334 null larvae to 4MUM B[a]P. Though ahr2hu2334 larvae did not display hyperactive swimming, these larvae had a decrease in LPR activity, suggesting that AHR2 plays a role in B[a]P induced larval hyperactivity. To determine if developmental B[a]P exposures would produce adult behavioral deficits, a subset of exposed animals was raised to adulthood and tested in a conditioned stimulus test using shuttleboxes. Developmentally exposed B[a]P zebrafish exhibited decreased learning and memory. Together this data demonstrates that developmental B[a]P exposure adversely impacts larval behavior, and learning in adult zebrafish. PMID- 27989698 TI - Tumor suppressor RYBP harbors three nuclear localization signals and its cytoplasm-located mutant exerts more potent anti-cancer activities than corresponding wild type. AB - Ectopically expressed Ring1 and YY1 binding protein (RYBP) induces tumor cell apoptosis through promoting the formation of the death-inducing signaling complex (DISC) in the cytoplasm. However, transiently overexpressed as well as endogenous RYBP in tumor tissues were observed to be mainly located in the nucleus while that in adjacent non-tumor tissues distributed majorly in the cytoplasm. Currently, we do not know the nuclear localization signals and biological function of different subcellular location of RYBP. In this study, we employed bioinformatic analysis, deletion, point mutation, enhanced green fluorescence protein (EGFP) fusion and others, to investigate the elements responsible for RYBP nuclear import and to explore the anti-tumor activities of cytoplasm- and nuclear-located RYBP. Herein, we identified three functional monopartite nuclear localization signals (NLSs), all of which located at the N-terminus of RYBP. Through four basic amino acid replacements within the NLSs, we obtained a cytoplasm-located RYBP mutant (RYBPmut). Compared with wild-type counterpart, RYBPmut exhibited more potent abilities to bind to caspase 8, to prevent MDM2 mediated polyubiquitination and degradation of p53, thereby leading to its stabilization. Further investigation revealed that, in contrast to its wild type, RYBPmut showed more potentials to inhibit tumor cell proliferation and to induce apoptosis, in both p53-dependent and -independent manner. Collectively, our current study revealed the molecular mechanism responsible for RYBP nuclear translocation, and provided evidences to support that RYBPmut could be a more promising candidate agent for cancer treatment. PMID- 27989699 TI - Kalirin, a GEF for Rac1, plays an important role in FSTL-1-mediated glucose uptake in skeletal muscle cells. AB - Follistatin-like 1 (FSTL-1) is a novel myokine; however, little is known about its metabolic role. Here, FSTL-1 stimulated glucose uptake in an AMP-activated protein kinase (AMPK)-dependent manner in L6 rat skeletal muscle cells. FSTL-1 increased intracellular calcium concentration. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) inhibition blocked FSTL-1-induced AMPK phosphorylation and glucose uptake. In addition, FSTL-1 stimulated the phosphorylation of p21-activated kinase 1 (PAK1), a small GTPase Rac1 downstream protein. PAK1 knockdown or inhibition of Rac1 blocked FSTL-1-induced glucose uptake; moreover, kalirin, a Rac1 guanine nucleotide exchange factor (GEF), was induced by FSTL-1. Kalirin knockdown with siRNA blocked FSTL-1-induced PAK1 phosphorylation and glucose uptake. Consistent with the induction of Rac1 GEF kalirin, the GTP-bound form of Rac1 was increased by FSTL-1. FSTL-1 increased the production of glucose transporter type 4 (GLUT4) protein and also stimulated the translocation of GLUT4 to the plasma membrane. Translocation of GLUT4 was not observed in cells pre-treated with AMPK inhibitor, Rac1 inhibitor, or kalirin siRNA. In primary myoblast cell culture, FSTL-1 increased glucose uptake in an AMPK-dependent manner. A CaMKK inhibitor or kalirin knockdown blocked FSTL-1 induced glucose uptake. These results suggest that kalirin and Rac1 GEF play important roles in FSTL-1-mediated glucose regulation in skeletal muscle cells. PMID- 27989700 TI - Cathepsin L is involved in X-ray-induced invasion and migration of human glioma U251 cells. AB - An important therapeutic method of glioblastoma, the most common primary brain tumor, is radiotherapy. However, several studies reported recently that radiation could also promote the invasion and migration of malignant tumor. Herein, we have identified that a significant increase of migration and invasiveness of human glioma U251 cells undergoing X-ray was observed compared to controls, accompanied by the increase of cathepsin L (CTSL), which is a lysosomal cysteine protease overexpressed and secreted by tumor cells. To verify if there was a relationship between CTSL and the X-ray-induced glioma invasion, a CTSL specific inhibitor Z FY-CHO or a short hairpin RNA interference was used to pretreat U251 cells. As a result, the cell invasion and migration was impaired via down-regulation of CTSL. Additionally, a marked reduction of the cell-signaling molecules Rho kinase was also detected compared with controls. We also found that CTSL is involved in EMT progress: both in vitro and in clinical specimens. Overall, our findings show that CTSL is an important protein which mediates cell invasion and migration of human glioma U251 cells induced by X-ray, and the inhibition of CTSL expression might diminish the invasion of U251 cells by reducing the activity of RhoA and CDC42 as well as EMT positive markers. PMID- 27989701 TI - Inhibition of SLC drug transporter activities by environmental bisphenols. AB - The plastic component bisphenol A (BPA) is suspected to exert deleterious effects towards human health and targets various cellular and molecular pathways, including activity of ATP-binding cassette drug transporters. The present study was designed to determine whether BPA and some derivatives, like its substitutes bisphenol F (BPF) and bisphenol S (BPS) and the flame retardant tetrabromobisphenol A (TBBPA), may additionally interact with solute carrier (SLC) drug transporters. Activities of the various following SLC transporters were inhibited in a major way (by >60%) by 100MUM bisphenols: OCT1 and MATE1 (by BPA and TBBPA), OATP1B1 (by BPA, BPF and TBBPA), OATP1B3 and NTCP (by TBBPA) and OAT3 (by BPA, BPF, BPS and TBBPA); by contrast, activities of other transporters were not impacted (MATE2-K) or were stimulated (notably OCT1 by BPS and OCT2 by BPF). Transporter inhibitions due to bisphenols were concentrations-dependent, with half maximal inhibitory concentrations (IC50) ranging from 0.5MUM to 73.5MUM. BPA was finally shown to be not transported by OAT3, although inhibiting this transporter in a competitive manner. Taken together, these data indicate that bisphenols interact with SLC transporters, at concentration levels however rather higher than those occurring in humans in response to environmental exposure. PMID- 27989702 TI - Development of novel self-assembled ES-PLGA hybrid nanoparticles for improving oral absorption of doxorubicin hydrochloride by P-gp inhibition: In vitro and in vivo evaluation. AB - To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X-ray diffraction (XRD) results revealed that the DOX ES complex was in an amorphous form. An in vitro release (pH6.8 PBS) study showed the excellent sustained-release characteristics of DOX-loaded EPNs (DOX-EPNs). In addition, in situ intestinal perfusion and intestinal biodistribution experiments demonstrated the improved membrane permeability and intestinal wall bioadhesion of DOX-EPNs, and caveolin- and clathrin-mediated endocytosis pathways were the main mechanisms responsible. The cytotoxicity of DOX was significantly increased by EPNs in Caco-2 cells, compared with DOX-Sol. Confocal laser scanning microscope (CLSM) images confirmed that the amount of DOX-EPNs internalized by Caco-2 cells was higher than that of DOX-Sol showing that P-glycoprotein-mediated drug efflux was reduced by the introduction of EPNs. The qualitative detection of transcytosis demonstrated the ability of the nanoparticles (NPs) to cross Caco-2 cell monolayers. An in vivo toxicity experiment demonstrated that DOX-EPNs reduced cardiac and renal toxic effects and were biocompatible. An in vivo pharmacokinetics study showed that the AUC(0-t) and t1/2 of DOX-EPNs were increased to 3.63-fold and 2.47-fold in comparison with DOX solution (DOX-Sol), respectively. All these results indicated that the novel EPNs were an excellent platform to improve the encapsulation efficiency of an aqueous solution of this antitumor drug and its oral bioavailability. PMID- 27989703 TI - Usefulness of MRI-CBCT image registration in the evaluation of temporomandibular joint internal derangement by novice examiners. AB - OBJECTIVE: To assess whether novice examiners can more reliably determine temporomandibular joint (TMJ) disk derangements with the use of fused images of magnetic resonance imaging and cone beam computed tomography (MRI-CBCT) compared with MRI images alone. STUDY DESIGN: Thirty dental students with minimal exposure to TMJ imaging received a 30-minute calibration session in which TMJ diagnostic imaging and the normal anatomy of the TMJ internal derangement were explained. The students evaluated the disk positions of 16 TMJs in two sets of images (MRI images alone and MRI-CBCT images) randomly and independently. The disk positions evaluated by two experienced radiologists were used for comparison. RESULTS: The internal consistency among all students improved from an unacceptable consistency (alpha = 0.40) with MRI images alone to a good consistency (alpha = 0.84) with MRI-CBCT images. The agreement in evaluation between the students and the radiologists improved from a poor agreement with MRI images alone (k mean = 0.07 +/- 0.12) to a moderate agreement with MRI-CBCT images (k mean = 0.55 +/- 0.25). This improvement in the agreement was significant (P < .001). CONCLUSIONS: The use of fused MRI and CBCT images to visualize the TMJ in a single display significantly improved the examiners' reliability and accuracy of assessment of disk positions. The improvement of novice readers in assessing the disk positions highlights the potential use of MRI-CBCT image fusion as an educational tool. PMID- 27989704 TI - The tooth as a monitor of cholestatic liver disease in rats. AB - OBJECTIVE: Measure, noninvasively, the deposition of bilirubin in the tooth by using DIAGNOdent and correlate it to liver dysfunction. STUDY DESIGN: After confirming the capacity of DIAGNOdent to measure varying bile concentrations in plaster blocks, a cholestatic liver disease model was studied to detect increasing bilirubin impregnation in the teeth of rats. Wistar-EPM rats (n = 50) were divided into three groups: (1) BDL: rats submitted to bile duct ligation (BDL); (2) Naive: rats without procedure; and (3) Sham: rats submitted to laparotomy without BDL (n = 10/period/group). The rats' teeth were monitored with the use of DIAGNOdent before the procedure and at days 10 and 50 following surgery. Serum bilirubin was also monitored. RESULTS: Tests in vitro showed that DIAGNOdent detected bile in plaster blocks according to its concentration. BDL promoted progressive liver dysfunction, with death occurring approximately 50 days later. DIAGNOdent values obtained on teeth showed correlation with the progression of serum hyperbilirubinemia. CONCLUSIONS: The tooth was found to be a good tissue for noninvasively monitoring the progression of bilirubinemia in cholestatic liver disease in rats by using DIAGNOdent. PMID- 27989705 TI - Histochemical observation of bony reversal lines in bisphosphonate-related osteonecrosis of the jaw. AB - OBJECTIVE: To contrast the pattern of bony reversal linesin bisphosphonate osteonecrosis of the jaw with infected osteomyelitis derived acute osteonecrosis of the jaw. STUDY DESIGN: This study investigated the histochemical characteristics of reversal lines in 50 cases of BP-related osteonecrosis of the jaw (BRONJ) compared with non-BP-involved bones in 20 cases of chronic osteomyelitis of the jaws. Necrotic bones were stained by using the toluidine blue, Safranin O, Giemsa, van Gieson, and Masson's trichrome staining methods. RESULTS: All BP-involved bones in BRONJ were distinguishable from non-BP-involved bones in chronic osteomyelitis of the jaws by multiple thick, irregular, reversal lines, which were strongly stained with toluidine blue, Safranin O, and Giemsa solution. The reversal lines of BP-involved bones (average 31.2 +/- 10.85 MUm) were thicker than those of osteomyelitic bones (average 11.1 +/- 3.76 MUm), and they were closely associated with immature bony matrices containing collagenous materials positive for van Gieson and Masson's trichrome staining with statistical significance (P = .0212 in t test statistics). The immature reversal lines of BP-involved bones continuously appeared as thick non-birefringence lines between lamellate structures as observed under a polarizing microscope, whereas the reversal lines of non-BP-involved bones were gradually thinned as their mineralization advanced. CONCLUSIONS: BP-involved bones had immature bony matrices outlined by thick reversal lines, which might be crucial to rapid osteonecrosis of BRONJ and also could be hallmarks for the differential diagnosis of BRONJ from chronic osteomyelitis of the jaws. PMID- 27989706 TI - Osseous osteoarthritic-like changes and joint mobility of the temporomandibular joints and upper cervical spine: is there a relation? AB - OBJECTIVES: To compare 1) temporomandibular joint (TMJ) mobility between patients with and without reduced upper cervical spine (UCS) mobility and with and without TMJ osseous osteoarthritic-like changes, and 2) UCS osseous changes between patients with and without TMJ osseous osteoarthritic-like changes and with and without reduced UCS mobility. STUDY DESIGN: The study comprised 39 patients without pain from TMJ or UCS and with obstructive sleep apnea, 15 women (age range 26-72 years, mean 56.0) and 24 men (age range 27-71 years, mean 49.8). The range of motion (ROM) of the mandible and UCS was assessed clinically. Osseous changes of the TMJ and UCS were assessed by cone beam computed tomography. Differences were tested and adjusted for age and gender by multiple linear and logistic regression analyses. RESULTS: The mandibular ROM was within normal range (45-64 mm) but the UCS ROM was reduced in 15 patients. Osseous TMJ and UCS changes were both found in 38.5% of the patients. Osseous UCS changes were found more frequently in patients with than without TMJ changes (P = .0003; odds ratio 21.9). No other significant results were found. CONCLUSIONS: The present findings of comorbid osseous changes in patients with obstructive sleep apnea support a possible biomechanical relationship between the TMJ and the UCS. PMID- 27989707 TI - N-RAS expression in patients with salivary adenoid cystic carcinoma: association with clinicopathologic features and prognosis. AB - OBJECTIVE: The aim of this study was to investigate N-RAS expression in patients with salivary adenoid cystic carcinoma (SACC) and to analyze its association with clinicopathologic features and prognosis. STUDY DESIGN: We determined N-RAS expression in SACC tumors via immunohistochemistry and evaluated the association between N-RAS expression and clinicopathologic variables. The disease-free survival (DFS) curves were plotted by using the Kaplan-Meier method. The parameters of prognostic significance found by univariate analysis were tested by a multivariate Cox regression model. RESULTS: N-RAS expression was detected in 61 of 72 SACC tumor samples (84.7%). In univariate analyses, N-RAS expression was associated with clinical stage, tumor size, adjacent tissue invasion, and distant metastasis. N-RAS expression was associated with DFS in univariate analysis; however, in multivariate analysis, N-RAS was not an independent prognostic indicator, but clinical stage (0.04) and histologic subtype (0.02) were statistically significant. CONCLUSIONS: Our data suggest that N-RAS was overexpressed in SACC tissues, but was not an independent prognostic indicator of DFS. Only clinical stage and histologic subtype were prognostic indicators of DFS. PMID- 27989708 TI - The emerging role of long noncoding RNAs in oral cancer. AB - Although less than 3% of the genome encodes proteins, at least 75% of the genome is transcribed into RNAs with no protein-coding potential (noncoding RNAs [ncRNAs]). On the basis of their size and the arbitrary 200 nucleotides cutoff, ncRNAs are classified into long ncRNAs (lncRNAs) or small ncRNAs (including microRNAs). Over the last few years, the role of microRNAs in oral squamous cells carcinoma (OSCC) has been extensively addressed, but the possible role of lncRNAs in OSCC remains unclear. We aimed to explore and discuss the potential role of lncRNAs in OSCC. The detection of lncRNAs in saliva holds promise not only as a noninvasive diagnostic tool in OSCC but also in the early detection of oral cancer recurrence. lncRNAs are promising future therapeutic targets in the OSCC scenario, and research in this field may expand greatly in the next decade. PMID- 27989709 TI - Head and neck nonmelanoma cutaneous malignancy treatment in a skin cancer referral center. AB - OBJECTIVE: The purpose of our study was to determine the level of accuracy provided by clinical diagnosis in head and neck cutaneous malignancy as confirmed by histopathologic examination of the specimen in a skin cancer referral center. Positive predictive value was selected as a reliable measure of diagnostic accuracy. We also aimed to audit our surgical outcomes and record and present the completeness of excision, the rates of recurrence and metastasis, and the reconstructive method. STUDY DESIGN: We reviewed the electronic charts of 867 consecutive patients with skin tumors and calculated the positive and negative predictive values of clinical diagnosis. RESULTS: The positive predictive value was 91% for basal cell carcinoma and 78.8% for squamous cell carcinoma. Of the 178 histologically diagnosed squamous cell carcinomas, 15 were metastatic. CONCLUSIONS: In a skin cancer referral center, expert clinical diagnosis may safely overcome the need for preoperative biopsy. Relying on clinical diagnosis to formalize a treatment plan for head and neck nonmelanoma skin cancer is safe and efficient. This is more reliable in cases of basal cell carcinoma compared with suspected squamous cell carcinomas. PMID- 27989710 TI - Death related to dental treatment: a systematic review. AB - OBJECTIVE: The aim of this study was to identify factors associated with death in relation to dental care. STUDY DESIGN: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. PubMed, Dental and Oral Sciences Source, Web of Science, and the Cochrane database were searched, and the references of all retrieved articles were analyzed. Studies were included if death had occurred within 90 days of the dental appointment, and if the patient's age, procedure, and information regarding cause or time of death were provided. Factors associated with death were assessed by multivariate analyses and logistic regression. RESULTS: Fifty six publications, including retrospective studies and case reports/series that reported 148 fatalities, were analyzed. On average, 2.6 deaths were reported per year. The leading cause of deaths was anesthesia/sedation/medication-related complications (n = 70). Other causes were cardiovascular events (n = 31), infection (n = 19), airway-respiratory complications (n = 18), bleeding (n = 5), and others (n = 5). Age (P < .0001), disease severity (P < .02), disease stability (P < .006), dental provider characteristics (P < .05), level of consciousness/sedation (P < .02), and drug effects (P < .03) had significant associations with death. CONCLUSIONS: Reports of death were rare; however, specific risk factors associated with dentistry were identified. A better understanding of these factors is important for the development of guidelines that help prevent fatalities in dentistry. PMID- 27989711 TI - Oral health status in patients with acquired brain injury: a systematic review. AB - OBJECTIVE: To undertake a systematic review of the current knowledge and future perspectives regarding the status of various oral health factors, including social and behavioral aspects, in patients with acquired brain injury (ABI). STUDY DESIGN: A structured search strategy was applied to PubMed, Embase, and Scopus electronic databases until January 2016 to identify studies presenting assessments of the oral health status of patients afflicted with any kind of ABI. The search strategy was restricted to English-language publications that enrolled patients aged more than 18 years. Studies on the association of oral health conditions and brain injury were excluded. No study was excluded based on its qualitative analysis. RESULTS: A total of 27 studies were reviewed. Stroke was the most commonly studied ABI. Stroke patients had a higher number of missing teeth, poorer plaque and gingival index scores, and higher colonization of Candida albicans in saliva, all of which were significantly reduced after intervention. Oral health-related quality of life was poorer in patients compared to the general population. CONCLUSION: Stroke was the most predominant brain injury condition studied in the literature, with few publications focusing on other forms of brain injury. Overall, oral health has been noted to be poor in patients with ABI, but oral hygiene and oral health-related quality of life have been found to improve when oral hygiene interventions are provided to patients. PMID- 27989712 TI - Assessment of zygomatic bone using cone beam computed tomography in a Turkish population. AB - OBJECTIVE: To provide linear and volumetric measurements of zygomatic bone using cone beam computed tomography (CBCT) images. STUDY DESIGN: CBCT images were assessed for 198 patients. Posterior and anterior zygomatic bone widths (M1 and M2), zygomatic bone projection (M3), zygomatic bone height (M4), combined zygomatic arch diameter (M5), maximum cortical thickness (M6), gray value obtained from maximum cortical thickness region (M7), minimum cortical thickness (M8), and gray value obtained from minimum cortical thickness region (M9) were measured. Volume and surface area measurements of the zygomatic bone were also conducted. Sex, age, and side were recorded for each patient. General linear model analysis of variance (ANOVA) was performed (P < .05). RESULTS: Age (P < .001) and gender (P = .001) significantly affected M1. Gender significantly affected M3 (P = .003) and M4 (P = .000), with higher values for men. Gender (P = .000) and age (P = .000) significantly affected M5 variation. Only age had a significant effect on M6 variation, with an increase with age (P < .015). Only gender had a significant effect on M7 (P = .005), M8 (P = .000), and M9 (P = .004), with higher values for men. All the factors significantly affected zygomatic bone volume variation (gender, P = .000; age, P = .000; and side, P < .004). CONCLUSION: Detailed examination of the zygomatic bone region can be performed with CBCT images. PMID- 27989713 TI - Castleman's Disease Presenting in the Pelvis. AB - Castleman's disease (CD) is a rare benign lymphoid disorder with unknown etiology. There are 2 major forms of this disease, unicentric (ie, localized CD) and multicentric, which play a major role in determining therapy. The mediastinum is the most common localization for the localized CD, whereas its occurrence in the pelvis is even rarer. We report the case of a 22-year-old woman who had a pelvic mass located in the region of the left iliac fossa. The patient subsequently underwent a robotic-assisted laparoscopic tumorectomy. Pathological examination revealed pelvic localized CD of the hyaline-vascular type. CD should be included in the differential diagnosis of pelvic masses that are noted in the pelvic cavity. PMID- 27989714 TI - IFNy+ and IFNy- Treg subsets with stable and unstable Foxp3 expression in kidney transplant recipients with good long-term graft function. AB - BACKGROUND: Treg are a heterogenous cell population. In the present study we attempted to identify Treg subsets that might contribute to stable and good long term graft function. METHOD: Lymphocyte and Treg subsets were studied in 136 kidney transplant recipients with good long-term graft function and in 52 healthy control individuals using eight-color-fluorescence flow cytometry. Foxp3 TSDR methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations using high resolution melt analysis. RESULTS: Compared with healthy controls, patients showed strong associations of IFNy secreting Helios+ and Helios- Treg with Treg that co-expressed perforin and/or CTLA4 (CD152; p<0.01). Moreover they showed associations of IFNy-Helios+ Treg with Treg that produced TGFbeta and/or perforin and of IFNy-Helios- Treg with TGFbeta production (all p<0.01). Only in patients, but not in healthy controls, were IFNy- Helios+ and Helios- Treg associated with higher CD45+, CD3+, (CD4+), CD19+ lymphocyte counts (p<0.001). In addition IFNy-Helios+ Treg were associated with CD16+56+ lymphocytes (p<0.001). Enriched IFNy- Treg from female but not male patients showed an association of Foxp3 methylation with higher total Treg and higher Helios+IFNy-, CXCR3+Lselectin+ (CD183+CD62L+), CXCR3-Lselectin+ and CD28+HLADR+ Treg subsets (p<0.01). Enriched IFNy+ Treg from male patients showed an association of demethylated Foxp3 with total Treg and IL10-TFGbeta+ Treg counts, and in enriched IFNy- Treg an association of methylated Foxp3 with APO1/FasR+FasL+ (CD95+CD178+) Treg (p<0.01). CONCLUSIONS: Kidney recipients with good long-term graft function possess IFNy+ and IFNy- Treg with stable and unstable Foxp3 expression in the blood. They co-express CD28, HLADR, CTLA4, CXCR3, Lselectin, TGFbeta, perforin and FasL and might contribute to the establishment and maintenance of good long term graft function. PMID- 27989716 TI - The influence of coping strategies and behavior on the physiological response to social stress in women: The role of age and menstrual cycle phase. AB - There is information indicating that the variations induced by the menstrual cycle may influence the capacity of young women to respond to stress. The physiological response to stress changes across the stages of the lifespan; however, in spite of the great increase in life expectancy, the way women react after menopause, a period characterized by a dramatic decline in sex hormones, has not been sufficiently studied. The main objective of the study was to examine the capacity to respond to and recover from an acute social stressor in post menopausal women compared to young women. The second objective was to investigate the consequences of behavior on the self-regulatory systems. We measured behavior, cortisol, and heart rate during a speaking task in front of a committee in sixty-seven women: 36 post-menopausal and 31 pre-menopausal (follicular group n=14; luteal group n=17). No differences in heart rate reactivity between three groups were found. Post-menopausal women showed less cortisol reactivity to stress; they also displayed a higher percentage of Gestures during the speaking task, reflecting a clearer pattern of active coping compared to the young women. In post-menopausal women, behaviors that reflect active coping strategies were related to better autonomic regulation. By contrast, in pre-menopausal women, cortisol changes seemed to be modulated by passive and reactive behaviors such as Submission and Assertion. These results emphasize the importance of considering age and Hormonal Status in coping processes, including reactivity and recovery from stressful situations. PMID- 27989715 TI - Human Embryonic Stem Cells Do Not Change Their X Inactivation Status during Differentiation. AB - Applications of embryonic stem cells (ESCs) require faithful chromatin changes during differentiation, but the fate of the X chromosome state in differentiating ESCs is unclear. Female human ESC lines either carry two active X chromosomes (XaXa), an Xa and inactive X chromosome with or without XIST RNA coating (XiXIST+Xa;XiXa), or an Xa and an eroded Xi (XeXa) where the Xi no longer expresses XIST RNA and has partially reactivated. Here, we established XiXa, XeXa, and XaXa ESC lines and followed their X chromosome state during differentiation. Surprisingly, we found that the X state pre-existing in primed ESCs is maintained in differentiated cells. Consequently, differentiated XeXa and XaXa cells lacked XIST, did not induce X inactivation, and displayed higher X linked gene expression than XiXa cells. These results demonstrate that X chromosome dosage compensation is not required for ESC differentiation. Our data imply that XiXIST+Xa ESCs are most suited for downstream applications and show that all other X states are abnormal byproducts of our ESC derivation and propagation method. PMID- 27989717 TI - Psychophysiological effects of music on acute recovery from high-intensity interval training. AB - Numerous studies have examined the multifarious effects of music applied during exercise but few have assessed the efficacy of music as an aid to recovery. Music might facilitate physiological recovery via the entrainment of respiratory rhythms with music tempo. High-intensity exercise training is not typically associated with positive affective responses, and thus ways of assuaging negative affect warrant further exploration. This study assessed the psychophysiological effects of music on acute recovery and prevalence of entrainment in between bouts of high-intensity exercise. Thirteen male runners (Mage=20.2+/-1.9years; BMI=21.7+/-1.7; VO2 max=61.6+/-6.1mL.kg.min-1) completed three exercise sessions comprising 5*5-min bouts of high-intensity intervals interspersed with 3-min periods of passive recovery. During recovery, participants were administered positively-valenced music of a slow-tempo (55-65bpm), fast-tempo (125-135bpm), or a no-music control. A range of measures including affective responses, RPE, cardiorespiratory indices (gas exchange and pulmonary ventilation), and music tempo-respiratory entrainment were recorded during exercise and recovery. Fast tempo, positively-valenced music resulted in higher Feeling Scale scores throughout recovery periods (p<0.01, etap2=0.38). There were significant differences in HR during initial recovery periods (p<0.05, etap2=0.16), but no other music-moderated differences in cardiorespiratory responses. In conclusion, fast-tempo, positively-valenced music applied during recovery periods engenders a more pleasant experience. However, there is limited evidence that music expedites cardiorespiratory recovery in between bouts of high-intensity exercise. These findings have implications for athletic training strategies and individuals seeking to make high-intensity exercise sessions more pleasant. PMID- 27989718 TI - Interobserver and intraobserver variability of glenoid track measurements. AB - BACKGROUND: A method of assessing combined glenoid and humeral bone loss in traumatic shoulder instability with an associated treatment protocol was recently published. The aim of this study was to investigate its reliability and reproducibility. METHODS: Seventy-one patients with unilateral anteroinferior shoulder instability underwent computed tomography scans, from which 3 dimensional images were derived. En face views of both glenoid fossae and with 3 views of the humeral head were provided to 4 assessors to determine interobserver reliability. From these measurements, the shoulder was assigned a treatment classification. Two observers repeated their assessments 1 month later to determine intraobserver reliability. For each measurement, the mean coefficient of variability was calculated. RESULTS: Assessment of glenoid bone loss showed good interobserver (4 observers agreeing in 90.1% of cases) and also good intraobserver agreement (94% and 96%). There was a poor level of interobserver reliability regarding the on-track or off-track classification (72%). Intraobserver reliability for this measurement was less variable (90% and 80%). There was a poor level of agreement between observers (65%) regarding treatment classification. The coefficient of variability for the Hill-Sachs lesion measured 19.2%, indicating a high level of variability for this measurement compared with <4% for all other measures. CONCLUSION: Linear bone loss on the glenoid can be measured reliably and reproducibly; however, evaluation of Hill-Sachs lesions demonstrates a high level of variability, and poor interobserver reliability. PMID- 27989719 TI - Coracoid bypass procedure: surgical technique for coracoclavicular reconstruction with coracoid insufficiency. AB - BACKGROUND: Failed acromioclavicular (AC) joint reconstruction secondary to a coracoid fracture or insufficiency of the coracoid is an uncommon but challenging clinical situation. We describe a surgical technique of revision coracoclavicular (CC) reconstruction, the coracoid bypass procedure, and report short-term results with this technique in 3 patients. METHODS: In the coracoid bypass procedure, reconstruction of the CC ligaments is performed by passing a tendon graft through a surgically created bone tunnel in the scapular body (inferior to the base of the coracoid) and then fixing the graft around the clavicle or through bone tunnels in the clavicle. Three patients treated with this technique were retrospectively reviewed. RESULTS: AC joint reconstruction performed for a traumatic AC joint separation failed in the 3 patients reported in this series. The previous procedures were an anatomic CC reconstruction in 2 patients and a modified Weaver-Dunn procedure in 1 patient. The coracoid fractures were detected postoperatively, and the mean interval from the index surgery to the coracoid bypass procedure was 8 months. The patients were a mean age of 44 years, and average follow-up was 21 months. At the last follow-up, all 3 patients were pain free, with full range of shoulder motion, preserved CC distance, and a stable AC joint. CONCLUSION: The coracoid bypass procedure is a treatment option for CC joint reconstruction during revision AC joint surgery in the setting of a coracoid fracture or coracoid insufficiency. PMID- 27989720 TI - Prevention of Propionibacterium acnes biofilm formation in prosthetic infections in vitro. AB - BACKGROUND: The role of Propionibacterium acnes in shoulder arthroplasty and broadly in orthopedic prosthetic infections has historically been underestimated, with biofilm formation identified as a key virulence factor attributed to invasive isolates. With an often indolent clinical course, P acnes infection can be difficult to detect and treat. This study investigates absorbable cements loaded with a broad-spectrum antibiotic combination as an effective preventive strategy to combat P acnes biofilms. METHODS: P acnes biofilm formation on an unloaded synthetic calcium sulfate (CaSO4) bone void filler cement bead was evaluated by scanning electron microscopy over a period of 14 days. Beads loaded with tobramycin alone or vancomycin alone (as comparative controls) and beads loaded with a vancomycin-tobramycin dual treatment were assessed for their ability to eradicate planktonic P acnes, prevent biofilm formation, and eradicate preformed biofilms using a combination of viable-cell counts, confocal microscopy, and scanning electron microscopy. RESULTS: P acnes surface colonization and biofilm formation on unloaded CaSO4 beads was slow. Beads loaded with antibiotics were able to kill planktonic cultures of 106 colony-forming units/mL, prevent bacterial colonization, and significantly reduce biofilm formation over periods of weeks. Complete eradication of established biofilms was achieved with a contact time of 1 week. CONCLUSIONS: This study demonstrates that antibiotic-loaded CaSO4 beads may represent an effective antibacterial and antibiofilm strategy to combat prosthetic infections in which P acnes is involved. PMID- 27989721 TI - Rejecting the Alzheimer's disease vaccine development for the wrong reasons. AB - The development of amyloid beta (Abeta) vaccines for Alzheimer's disease (AD) has consistently failed clinically, an outcome that is assumed to result from flaws in the proposed role of Abeta as the crucial causative agent of this disease. This opinion resulted in this research approach being disregarded, yet, review of the development of these vaccines indicates that they are more suited to transgenic mice, which is unsurprising given that these animal models were used to determine the efficacy of these vaccines, and that the approach overlooked research findings relevant to AD vaccines. Hence, new strategies using new immunogens and anti-inflammatory adjuvants mimicking the natural protective immunity against AD should be implemented to develop effective preventive vaccines. PMID- 27989722 TI - Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations. AB - Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and non-governmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathways-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this. PMID- 27989723 TI - Does educational attainment increase the risk of low back pain when genetics are considered? A population-based study of Spanish twins. AB - BACKGROUND CONTEXT: There is limited research investigating educational attainment as a risk factor for low back pain (LBP), with the influence of gender commonly being neglected. Furthermore, genetics and early shared environment explain a substantial proportion of LBP cases and need to be controlled for when investigating risk factors for LBP. PURPOSE: To investigate whether educational attainment affects the prevalence and risk of LBP differently in men and women while controlling for the influence of genetics and early shared environment. STUDY DESIGN: This is a cross-sectional and prospective twin case-control study. PATIENT SAMPLE: Adult monozygotic (MZ) and dizygotic (DZ) twins from the Murcia Twin Registry, with available data on educational attainment, formed the base sample for this study. The prevalence analysis considered twins with available data on LBP in 2013 (n=1,580). The longitudinal analysis considered twins free of LBP at baseline (2009-2011), with available data on LBP at follow-up (2013) (n=1,077). OUTCOME MEASURES: Data on the lifetime prevalence of activity limiting LBP (outcome) and educational attainment (risk factor) were self-reported. METHODS: The prevalence analysis investigated the cross-sectional association between educational attainment and LBP, whereas the longitudinal analysis investigated whether educational attainment increased the risk of developing LBP. Both analyses were performed in the following sequence. First, a total sample analysis was performed on all twins (considering them as individuals), adjusting for confounding variables selected by the data. Second, to control for the influence of genetics and early shared environment, a within-pair case-control analysis (stratified by zygosity) was performed on complete twin pairs discordant for LBP (ie, one twin had LBP, whereas the co-twin did not). All analyses were stratified for gender where possible, with an interaction term determining whether gender was a significant moderator of the association between educational attainment and LBP. RESULTS: Women with either general secondary or university education were less likely to experience (prevalence analysis) or to develop LBP (longitudinal analysis). Educational attainment did not affect the risk of LBP in men. When controlling for the effects of genetics and early shared environment, the relationship between educational status and LBP in women was no longer statistically significant. CONCLUSIONS: Educational attainment affects LBP differently in men and women, with higher levels of education only decreasing the risk of developing LBP in women. After adjusting for genetics and early shared environment, the relationship between educational attainment and LBP in women disappears. This suggests that genetics and early shared environment are confounding the relationship between educational attainment and LBP in women. PMID- 27989724 TI - Frailty is associated with morbidity in adults undergoing elective anterior lumbar interbody fusion (ALIF) surgery. AB - BACKGROUND CONTEXT: Prior studies have suggested no significant differences in functional status and postoperative complications of elderly versus nonelderly patients undergoing posterior lumbar interbody fusion; however, similar studies have not been comprehensively investigated in the setting of anterior lumbar interbody fusion (ALIF). PURPOSE: The objective was to quantify the ability of the modified Frailty Index (mFI) to predict postoperative events in patients undergoing ALIF. STUDY DESIGN: Secondary analysis of prospectively collected data. PATIENT SAMPLE: Patients undergoing ALIF in the National Surgical Quality Improvement Program (NSQIP) participant files for the period 2010 through 2014. OUTCOMES MEASURES: Outcome measures included any postoperative complication, return to operating room (OR), and length of stay >5 days. METHODS: NSQIP participant files from 2010 to 2014 were used to identify patients undergoing ALIF. The mFI used in the present study is an 11-variable assessment that maps 16 NSQIP variables to 11 variables in the Canadian Study of Health and Ageing Frailty Index. Univariate analysis and multivariable logistic regression models were used to compare the relative strength of association between mFI with outcome variables of interest. RESULTS: In total, 3,920 ALIF cases were identified and grouped according to their mFI score: 0 (n=2,025), 0.09 (n=1,382), 0.18 (n=464), or >=0.27 (n=49). As the mFI increased from 0 (no frailty associated variables) to 0.27 (4 of 11) or higher, there was a significant stepwise increase in any complication from 10.8% to 32.7%. After multivariable regression analysis, no significant association was found between higher mFI scores with urinary tract infections and venous thromboembolism. High frailty scores were significant predictors of any complication (mFI of >=0.27 [reference: 0]; OR 2.4; p=.040) and pulmonary complications (mFI score >=0.27; OR 7.5; p=.001). CONCLUSIONS: In summary, high mFI scores were found to be independently associated with any complication and pulmonary complications in patients who underwent ALIF. The use of mFI together with traditional risk factors may help better identify high-surgical risk patients, which may be useful for preoperative and postoperative care optimization. PMID- 27989725 TI - Creation of an injectable in situ gelling native extracellular matrix for nucleus pulposus tissue engineering. AB - BACKGROUND CONTEXT: Disc degeneration is the leading cause of low back pain and is often characterized by a loss of disc height, resulting from cleavage of chondroitin sulfate proteoglycans (CSPGs) present in the nucleus pulposus. Intact CSPGs are critical to water retention and maintenance of the nucleus osmotic pressure. Decellularization of healthy nucleus pulposus tissue has the potential to serve as an ideal matrix for tissue engineering of the disc because of the presence of native disc proteins and CSPGs. Injectable in situ gelling matrices are the most viable therapeutic option to prevent damage to the anulus fibrosus and future disc degeneration. PURPOSE: The purpose of this research was to create a gentle decellularization method for use on healthy nucleus pulposus tissue explants and to develop an injectable formulation of this matrix to enable therapeutic use without substantial tissue disruption. STUDY DESIGN: Porcine nuclei pulposi were isolated, decellularized, and solubilized. Samples were assessed to determine the degree of cell removal, matrix maintenance, gelation ability, cytotoxic residuals, and native cell viability. METHODS: Nuclei pulposi were decellularized using serial detergent, buffer, and enzyme treatments. Decellularized nuclei pulposi were solubilized, neutralized, and buffered. The efficacy of decellularization was assessed by quantifying DNA removal and matrix preservation. An elution study was performed to confirm removal of cytotoxic residuals. Gelation kinetics and injectability were quantified. Long-term in vitro experiments were performed with nucleus pulposus cells to ensure cell viability and native matrix production within the injectable decellularized nucleus pulposus matrices. RESULTS: This work resulted in the creation of a robust acellular matrix (>96% DNA removal) with highly preserved sulfated glycosaminoglycans (>47%), and collagen content and microstructure similar to native nucleus pulposus, indicating preservation of disc components. Furthermore, it was possible to create an injectable formulation that gelled in situ within 45 minutes and formed fibrillar collagen with similar diameters to native nucleus pulposus. The processing did not result in any remaining cytotoxic residuals. Solubilized decellularized nucleus pulposus samples seeded with nucleus pulposus cells maintained robust viability (>89%) up to 21 days of culture in vitro, with morphology similar to native nucleus pulposus cells, and exhibited significantly enhanced sulfated glycosaminoglycans production over 21 days. CONCLUSIONS: A gentle decellularization of porcine nucleus pulposus followed by solubilization enabled the creation of an injectable tissue-specific matrix that is well tolerated in vitro by nucleus pulposus cells. These matrices have the potential to be used as a minimally invasive nucleus pulposus therapeutic to restore disc height. PMID- 27989727 TI - Dilating Venous Diseases: Varicocele and Varicose Vein. PMID- 27989728 TI - Mayaro virus: a forest virus primed for a trip to the city? AB - Mayaro virus (MAYV) is an emerging arthropod-borne virus (arbovirus). Infection by MAYV can produce Mayaro virus disease (MAYVD) which is usually a clinically diagnosed, acute, febrile illness associated with prolonged and painful joint inflammation and swelling. MAYVD may be clinically indistinguishable from dengue, chikungunya fever, malaria, rabies, measles or other arboviral diseases. The full spectrum of disease, sequelae, routes of infection, virus shedding and any rarer means of transmission remain undefined. MAYVD cases in humans have so far been localised to Central and South America, particularly regions in and around the Amazon basin. MAYV usually circulates in a sylvan cycle of forest mosquitoes and vertebrates, however it has also been found in more urban locations alongside anthropophilic (preferring humans) insect vectors. If transmission via anthropophilic mosquitoes becomes more efficient following viral change, or existing vectors change their habitat and biting habits, the risk of urban establishment and further spread into non-forested areas will grow. Surveillance, testing and vector control remain key to monitoring and preventing global spread and establishment. The possibility of MAYV becoming further urbanized is worthy of note, consideration and action to ensure MAYV does not spread beyond the forests and establish in the world's cities. PMID- 27989729 TI - Physiotherapy management of intensive care unit-acquired weakness. AB - [Hodgson CL, Tipping CJ (2016) Physiotherapy management of intensive care unit acquired weakness.Journal of Physiotherapy63: 4-10]. PMID- 27989730 TI - Behaviour change intervention increases physical activity, spinal mobility and quality of life in adults with ankylosing spondylitis: a randomised trial. AB - QUESTIONS: Does a 3-month behaviour change intervention targeting physical activity (PA) increase habitual physical activity in adults with ankylosing spondylitis (AS)? Does the intervention improve health-related physical fitness, AS-related features, and attitude to exercise? Are any gains maintained over a 3 month follow-up? DESIGN: Parallel-group, randomised, controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. PARTICIPANTS: Forty adults with a diagnosis of AS, on stable medication, and without PA-limiting comorbidities. INTERVENTION: Over a 3-month period, the experimental group engaged in individually-tailored, semi-structured consultations aiming to motivate and support individuals in participating in PA. The control group continued with usual care. OUTCOME MEASURES: The primary outcome was PA measured by accelerometry over 1 week. Secondary outcomes included clinical questionnaires and measures of health-related physical fitness. Measures were taken at baseline, post-intervention, and after a 3-month follow-up period. RESULTS: Baseline characteristics were similar across groups, except age and body composition. There were statistically significant, moderate-to-large time-by group effects in health-enhancing PA (mixed-design ANOVA for overall effect F(2, 76)=14.826, p<0.001), spinal mobility (F(2, 76)=5.691, p<0.005) and quality of life (chi2(2)=8.400, p<0.015) favouring the intervention group; post-intervention improvements were sustained 3 months later. No significant effects were seen in other physical fitness outcomes or on clinical questionnaires. No adverse effects were reported during the study. CONCLUSION: Health-enhancing PA, spinal mobility and quality of life were significantly improved after the intervention, and improvements were maintained at 3-month follow-up. TRIAL REGISTRATION: NCT02374502. [O'Dwyer T, Monaghan A, Moran J, O'Shea F, Wilson F (2016) Behaviour change intervention increases physical activity, spinal mobility and quality of life in adults with ankylosing spondylitis: a randomised trial.Journal of PhysiotherapyXX: XX-XX]. PMID- 27989731 TI - Biofeedback improves performance in lower limb activities more than usual therapy in people following stroke: a systematic review. AB - QUESTION: Is biofeedback during the practice of lower limb activities after stroke more effective than usual therapy in improving those activities, and are any benefits maintained beyond the intervention? DESIGN: Systematic review with meta-analysis of randomised trials with a PEDro score > 4. PARTICIPANTS: People who have had a stroke. INTERVENTION: Biofeedback (any type delivered by any signal or sense) delivered concurrently during practice of sitting, standing up, standing or walking compared with the same amount of practice without biofeedback. OUTCOME MEASURES: Measures of activity congruent with the activity trained. RESULTS: Eighteen trials including 429 participants met the inclusion criteria. The quality of the included trials was moderately high, with a mean PEDro score of 6.2 out of 10. The pooled effect size was calculated as a standardised mean difference (SMD) because different outcome measures were used. Biofeedback improved performance of activities more than usual therapy (SMD 0.50, 95% CI 0.30 to 0.70). CONCLUSION: Biofeedback is more effective than usual therapy in improving performance of activities. Further research is required to determine the long-term effect on learning. Given that many biofeedback machines are relatively inexpensive, biofeedback could be utilised widely in clinical practice. [Stanton R, Ada L, Dean CM, Preston E (2016) Biofeedback improves performance in lower limb activities more than usual therapy in people following stroke: a systematic review.Journal of Physiotherapy63: 11-16]. PMID- 27989732 TI - Exercise, especially combined stretching and strengthening exercise, reduces myofascial pain: a systematic review. AB - QUESTION: Among people with myofascial pain, does exercise reduce the intensity of the pain and disability? DESIGN: Systematic review of randomised and quasi randomised controlled trials. PARTICIPANTS: People with myofascial pain of any duration. INTERVENTION: Exercise versus minimal or no intervention and exercise versus other intervention. OUTCOME MEASURES: Pain intensity and disability. RESULTS: Eight studies involving 255 participants were included. Pooled estimates from six studies showed statistically significant effects of exercise when compared with minimal or no intervention (support and encouragement or no treatment) on pain intensity at short-term follow-up. The weighted mean difference in pain intensity due to exercise was -1.2 points (95% CI -2.3 to 0.1) on a 0 to 10 scale. Pooled estimates from two studies showed a non significant effect of exercise when compared with other interventions (electrotherapy or dry needling) on pain intensity at short-term follow-up. The weighted mean difference in pain intensity due to exercise instead of other therapies was 0.4 points (95% CI -0.3 to 1.1) on a 0 to 10 scale. Individual studies reported no significant effects of exercise on disability compared with minimal intervention (-0.4, 95% CI -1.3 to 0.5) and other interventions (0.0, 95% CI -0.8 to 0.8) at short-term follow-up. Sensitivity analysis suggested that combining stretching and strengthening achieves greater short-term effects on pain intensity compared with minimal or no intervention (-2.3, 95% CI -4.1 to 0.5). CONCLUSION: Evidence from a limited number of trials indicates that exercise has positive small-to-moderate effects on pain intensity at short-term follow-up in people with myofascial pain. A combination of stretching and strengthening exercises seems to achieve greater effects. These estimates may change with future high-quality studies. [Mata Diz JB, de Souza JRLM, Leopoldino AAO, Oliveira VC (2016) Exercise, especially combined stretching and strengthening exercise, reduces myofascial pain: a systematic review.Journal of Physiotherapy63: 17-22]. PMID- 27989733 TI - Immunomagnetic separation of human myeloperoxidase using an antibody-mimicking peptide identified by phage display. AB - Phage display biopanning is a powerful in vitro selection process for screening and identifying peptides that bind to a target protein of interest. With the aim of replacing antibodies in immuno-diagnostic applications, we identified peptides whose binding characteristics mimicked those of anti-human myeloperoxidase (hMPO), a biomarker for acute cardiac diseases. Based on ELISA results from four phage clones, we selected and chemically synthesized a 12-mer peptide (SYIEPPERHRHR). Quartz crystal microbalance and surface plasmon resonance analyses revealed that the molar binding equilibrium ratio of the synthesized peptide was 0.023, approximately 43-fold lower than that of the anti-hMPO antibody. The dissociation constant (Kd) was 57nM, which was comparable to that of the native antibody (83nM). Next, we biotinylated the peptide at its N terminus and attached the biotinylated peptide to the surface of streptavidin coated magnetic particles to assess its ability to selectively capture hMPO. The binding equilibrium data were similar to the previous analyses; specifically, around 0.021mol peptide bound to 1mol of hMPO. Antigen capture was found to be selective and to be relatively little influenced by the presence of human serum albumin (HSA), an abundant constituent of serum. Our work demonstrates the potential of immunomagnetic isolation to achieve selective capture of a low concentration antigen from complex solutions such as serum. PMID- 27989734 TI - Systemic application of AAV vectors targeting GFAP-expressing astrocytes in Z Q175-KI Huntington's disease mice. AB - Huntington's disease (HD) affects both neurons and astrocytes. To target the latter and to ensure brain-wide transgene expression, adeno-associated viral (AAV) vectors can be administered intravenously, as AAV vectors cross the blood brain barrier (BBB) and enable preferential transduction of astrocytes due to their close association with blood vessels. However, there is a possibility that the subclass of GFAP-expressing astrocytes performs a distinct role in HD and reacts differently to therapeutic measures than the rest of the astrocytes. The gfaABC1D promoter allows specific targeting of the GFAP-expressing astrocytes (~25% of S100beta-expressing astrocytes). We have examined the expression of three different transgenes (GCaMP6f, Kir4.1 and GLT1) and tested the effects of the AAV serotypes 9 and rh8. The AAV vectors were injected into the tail vein of 1-year-old homozygous Z-Q175-KI HD mice and their wild-type (WT) littermates. At this age, HD mice exhibit motor symptoms, including pronounced hypokinesia and circling behaviour. The expression times ranged from 3 to 6weeks. The target cell population was defined as the cells expressing S100beta in addition to GFAP. Viewfields in the dorsal striatum and the overlaying cortex were evaluated and the transduction rate was defined as the percentage of target cells that expressed the reporter transgene (enhanced green fluorescent protein, EGFP, or Tomato). In all cases, the transduction rate was higher in the cortex than in the striatum. AAV9 was more efficient than AAVrh8. One of the injected constructs (AAV9-gfaABC1D-GLT1-Tomato) was tested for the first time. GLT1, the principal astrocytic glutamate transporter, is deficient in HD and therefore considered as a potential target for gene therapy. At a dose of 1.86*1011 vector genome (vg) per animal, the fraction of GLT1-Tomato+ cells in the striatum and the cortex amounted to 30% and 49%, respectively. In individual Tomato+ HD astrocytes, treatment with the GLT1 vector increased the level of GLT1 immunofluorescence by 21% compared to the HD control. The described approach offers new and interesting opportunities to examine the pathophysiological consequences of brain-wide transgene expression in a specific astrocyte subpopulation. PMID- 27989735 TI - Neuregulin1 alpha activates migration of neuronal progenitors expressing ErbB4. AB - Deficits in neuronal migration during development in the central nervous system may contribute to psychiatric diseases. The ligand neuregulin1 (NRG1) and its receptor ErbB4 are genes conferring susceptibility to schizophrenia, playing a key role in the control of neuronal migration both during development and adulthood. Several NRG1 and ErbB4 isoforms were identified, which deeply differ in their characteristics. Here we focused on the four ErbB4 isoforms and the two NRG1 isoforms differing in their EGF-like domain, namely alpha and beta. We hypothesized that these isoforms, which are differently regulated in schizophrenic patients, could play different roles in neuronal migration. Our hypothesis was strengthened by the observation that both NRG1alpha and NRG1beta and the four ErbB4 isoforms are expressed in the medial and lateral ganglionic eminences and in the cortex during development in rat. We analysed in vitro the signal transduction pathways activated by the different ErbB4 isoforms following the treatment with soluble recombinant NRG1alpha or NRG1beta and the ability to stimulate migration. Our data show that two ErbB4 isoforms, namely JMa-cyt2 and JMb-cyt1, following NRG1alpha and NRG1beta treatment, strongly activate AKT phosphorylation, conferring high migratory activity to neuronal progenitors, thus demonstrating that both NRG1alpha and NRG1beta can play a role in neuronal migration. PMID- 27989736 TI - Construction of pDUO: A bicistronic shuttle vector series for dual expression of recombinant proteins. AB - Our ability to genetically manipulate microbial systems is often hampered by the availability of genetic tools. Thus, there is a need for the continued expansion of our molecular tool box. In support of this expansion, this study reports the design, construction, and validation of a new bicistronic shuttle vector series, pDUO, for the dual expression of genes in different hosts. Each vector was designed and constructed to contain two araC-pBAD inducible promoter systems for tight control over gene expression. Each araC-pBAD promoter precedes a ribosomal binding site and a multicloning site (MCS). The 5' end of MCS1 contains a sequence encoding an affinity HIS-tag N-terminus and MCS2 terminates with a sequence encoding an affinity S-tag C-terminus for one-step purification of recombinant proteins encoded by the inserted genes. Both MCS are followed by an rrnBT1 and T2 transcriptional terminator sequence. Each vector in this series also contains a PBR322 and pRO1600-derived replicon to support replication in different host bacteria along with one of four different selectable markers. The functionality of the pDUO vector series was validated through the dual expression of oxalate biosynthetic component (obc) 1 and mrfp in Escherichia coli and Pseudomonas fluorescens. It is anticipated that this new vector series will facilitate functional studies as well as the engineering of bacterial strains for biotechnological purposes. PMID- 27989743 TI - High resolution mass spectrometry characterization of the oxidation pattern of methionine and cysteine residues in rat liver mitochondria voltage-dependent anion selective channel 3 (VDAC3). AB - Voltage-dependent anion selective channels (VDACs) are integral membrane proteins found in the mitochondrial outer membrane. In comparison with the most abundant isoform VDAC1, there is little knowledge about the functional role of VDAC3. Unlikely VDAC1, cysteine residues are particularly abundant in VDAC3. Since the mitochondrial intermembrane space (IMS) has an oxidative potential we questioned whether the redox state of VDAC3 can be modified. By means of SDS-PAGE separation, tryptic and chymotryptic proteolysis and UHPLC/High Resolution ESI MS/MS analysis we investigated the oxidation state of cysteine and methionine residues of rat liver VDAC3. Our results demonstrate that the mitochondrial VDAC3, in physiological state, contains methionines oxidized to methionine sulfoxide. Furthermore, cysteine residues 36, 65, and 165 are oxidized to a remarkable extend to sulfonic acid. Cysteines 2 and 8 are observed exclusively in the carboxyamidomethylated form. Cys229 is detected exclusively in the oxidized form of sulfonic acid, whereas the oxidation state of Cys122 could not be determined because peptides containing this residue were not detected. Control experiments ruled out the possibility that over-oxidation of cysteines might be due to artefactual reasons. The peculiar behavior of Met and Cys residues of VDAC3 may be related with the accessibility of the protein to a strongly oxidizing environment and may be connected with the regulation of the activity of this trans-membrane pore protein. PMID- 27989744 TI - Characterization of extracellular vesicles by IR spectroscopy: Fast and simple classification based on amide and CH stretching vibrations. AB - Extracellular vesicles isolated by differential centrifugation from Jurkat T-cell line were investigated by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR). Amide and CH stretching band intensity ratios calculated from IR bands, characteristic of protein and lipid components, proved to be distinctive for the different extracellular vesicle subpopulations. This proposed 'spectroscopic protein-to-lipid ratio', combined with the outlined spectrum analysis protocol is valid also for low sample concentrations (0.15-0.05mg/ml total protein content) and can carry information about the presence of other non vesicular formations such as aggregated proteins, lipoproteins and immune complexes. Detailed analysis of IR data reveals compositional changes of extracellular vesicles subpopulations: second derivative spectra suggest changes in protein composition from parent cell towards exosomes favoring proteins with beta-turns and unordered motifs at the expense of intermolecular beta-sheet structures. The IR-based protein-to-lipid assessment protocol was tested also for red blood cell derived microvesicles for which similar values were obtained. The potential applicability of this technique for fast and efficient characterization of vesicular components is high as the investigated samples require no further preparations and all the different molecular species can be determined in the same sample. The results indicate that ATR-FTIR measurements provide a simple and reproducible method for the screening of extracellular vesicle preparations. It is hoped that this sophisticated technique will have further impact in extracellular vesicle research. PMID- 27989745 TI - Interaction of different statins with model membranes by NMR data. AB - Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins reduce the amount of low-density lipoprotein (LDL) cholesterol, which is known as a well-established risk factor for atherosclerosis. Despite the fact that statins have a common pharmacologic target essential to sterol biosynthesis, their efficacy, safety, and potential non-LDL actions vary significantly for different statins. There is a hypothesis that pharmacological features of statins depend on their location in cell membrane, but to the present day there is a lack of information in literature on interactions of statins with the surface of the cell membrane in liquid media. The results of NMR experiments showed that all studied statins form intermolecular complexes with models of cell membranes (dodecylphosphocholine micelles) in water solution. Locations of pravastatin, simvastatin, fluvastatin and cerivastatin on model membranes were established by NOESY NMR data. Distinctions in their positions can explain differences in pharmacological properties of studied compounds. PMID- 27989746 TI - Tension (re)builds: Biophysical mechanisms of embryonic wound repair. AB - Embryonic tissues display an outstanding ability to rapidly repair wounds. Epithelia, in particular, serve as protective layers that line internal organs and form the skin. Thus, maintenance of epithelial integrity is of utmost importance for animal survival, particularly at embryonic stages, when an immune system has not yet fully developed. Rapid embryonic repair of epithelial tissues is conserved across species, and involves the collective migration of the cells around the wound. The migratory cell behaviours associated with wound repair require the generation and transmission of mechanical forces, not only for the cells to move, but also to coordinate their movements. Here, we review the forces involved in embryonic wound repair. We discuss how different force-generating structures are assembled at the molecular level, and the mechanisms that maintain the balance between force-generating structures as wounds close. Finally, we describe the mechanisms that cells use to coordinate the generation of mechanical forces around the wound. Collective cell movements and their misregulation have been associated with defective tissue repair, developmental abnormalities and cancer metastasis. Thus, we propose that understanding the role of mechanical forces during embryonic wound closure will be crucial to develop therapeutic interventions that promote or prevent collective cell movements under pathological conditions. PMID- 27989747 TI - Chronic postnatal monoamine oxidase inhibition affects affiliative behavior in rat pupso. AB - Monoamine neurotransmitters serotonin (5-HT), dopamine (DA), and noradrenaline (NA) act as important modulators of mammalian brain development and represent neurobiological substrates of affiliative behavior reflected in rat pups as a tendency to huddle or produce ultrasonic vocalizations (USV) when separated from the nest. Monoamines are metabolized through oxidative deamination catalyzed by the mitochondrial enzyme monoamine oxidase (MAO). In this study, we examined the consequences of postnatal MAO inhibition on affiliative behavior in rat pups. Pups received daily injections of either an irreversible non-selective MAO inhibitor tranylcypromine (TCP) or saline, from post-natal day (PND) 1 to PND 22. Quantitative and qualitative components of USV were analyzed on PNDs 10, 13 and 16 in order to determine the level of separation-induced anxiety and the modality of vocal communication. In comparison to control pups, TCP-treated pups displayed higher cortical 5-HT, DA and NA levels, higher peripheral 5-HT concentration, lower body mass throughout the pre-weaning period, higher isolation-induced drop in body temperature, and reduced total number of calls. Furthermore, they produced lower pitched calls of longer average duration without a preferable waveform. Our results demonstrate that chronic MAO inhibition by TCP primarily affects 5-HT concentrations, but also raises central catecholamine levels. They further indicate that disturbed monoaminergic homeostasis during early postnatal development leads to decreased weight-gain, compromised thermoregulation, and altered affiliative behavior in pre-weaning pups as reflected in reduced separation anxiety and inadequate vocal communication. Finally, they suggest a need for thorough examination of the potential effects of TCP and other monoamine inhibitors on the developing human brain. PMID- 27989748 TI - NOX4 supports glycolysis and promotes glutamine metabolism in non-small cell lung cancer cells. AB - Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and contributes to cancer progression. Nevertheless, the comprehensive mechanisms for NOX4-mediated malignant progression and oxidative resistance of cancer cells remain largely unknown. This study found that NOX4 directed glucose metabolism not only to the glycolysis but also to pentose phosphate pathway (PPP) pathway for production of NADPH in NSCLC cell lines. Besides, we also found that NOX4 promoted glutaminolysis into total GSH synthesis. Specifically, the data showed that ectopic NOX4 expression did not induce apoptosis of NSCLC cells; however, inhibition of GSH production resulted in obvious apoptotic death of NOX4 overexpressed NSCLC cells. Furthermore, we demonstrated that NOX4-induced glycolysis probably via ROS/PI3K/Akt signaling-dependent c-Myc upregulation. The selective NOX4 inhibitor, GKT137831, significantly inhibited glucose and glutamine metabolic phenotypes both in vitro and in vivo, and itself or combination with 2-DG, a synthetic glycolytic inhibitor, suppressed cancer cell growth both in vivo and in vitro. Elimination of NOX4-derived H2O2 effectively reversed NOX4 overexpression-mediated metabolic effects in NSCLC cells. NOX4 levels were significantly correlated with increased glucose and glutamine metabolism-related genes, as well as Akt phosphorylation and c-Myc expression in primary NSCLC specimens. In conclusion, these results reveal that NOX4 promotes glycolysis, contributing to NSCLC growth, and supports glutaminolysis for oxidative resistance. Therefore, NOX4 may be a promising target to reverse malignant progression of NSCLC. PMID- 27989749 TI - ROS-JNK1/2-dependent activation of autophagy is required for the induction of anti-inflammatory effect of dihydroartemisinin in liver fibrosis. AB - Accumulating evidence identifies autophagy as an inflammation-related defensive mechanism against diseases including liver fibrosis. Therefore, autophagy may represent a new pharmacologic target for drug development to treat liver fibrosis. In this study, we sought to investigate the effect of dihydroartemisinin (DHA) on autophagy, and to further examine the molecular mechanisms of DHA-induced anti-inflammatory effects. We found that DHA appeared to play an essential role in controlling excessive inflammation. DHA suppressed inflammation in rat liver fibrosis model and inhibited the expression of proinflammatory cytokines in activated hepatic stellate cells (HSCs). Interestingly, DHA increased the autophagosome generation and autophagic flux in activated HSCs, which is underlying mechanism for the anti-inflammatory activity of DHA. Autophagy depletion impaired the induction of anti-inflammatory effect of DHA, while autophagy induction showed a synergistic effect with DHA. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of DHA-induced autophagy. Antioxidants, such as glutathione and N acetyl cysteine, significantly abrogated ROS production, and in turn, prevented DHA-induced autophagosome generation and autophagic flux. Besides, we found that c-Jun N-terminal kinase1/2 (JNK1/2) was a downstream signaling molecule of ROS that mediated the induction of autophagy by DHA. Down-regulation of JNK1/2 activity, using selective JNK1/2 inhibitor (SP600125) or siJNK1/2, led to an inhibition of DHA-induced autophagy. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced anti-inflammatory effects, by which points to the possibility of using DHA based proautophagic drugs for the treatment of inflammatory diseases. PMID- 27989750 TI - The antioxidant uncoupling protein 2 stimulates hnRNPA2/B1, GLUT1 and PKM2 expression and sensitizes pancreas cancer cells to glycolysis inhibition. AB - Several evidence indicate that metabolic alterations play a pivotal role in cancer development. Here, we report that the mitochondrial uncoupling protein 2 (UCP2) sustains the metabolic shift from mitochondrial oxidative phosphorylation (mtOXPHOS) to glycolysis in pancreas cancer cells. Indeed, we show that UCP2 sensitizes pancreas cancer cells to the treatment with the glycolytic inhibitor 2 deoxy-D-glucose. Through a bidimensional electrophoresis analysis, we identify 19 protein species differentially expressed after treatment with the UCP2 inhibitor genipin and, by bioinformatic analyses, we show that these proteins are mainly involved in metabolic processes. In particular, we demonstrate that the antioxidant UCP2 induces the expression of hnRNPA2/B1, which is involved in the regulation of both GLUT1 and PKM2 mRNAs, and of lactate dehydrogenase (LDH) increasing the secretion of L-lactic acid. We further demonstrate that the radical scavenger N-acetyl-L-cysteine reverts hnRNPA2/B1 and PKM2 inhibition by genipin indicating a role for reactive oxygen species in the metabolic reprogramming of cancer cells mediated by UCP2. We also observe an UCP2-dependent decrease in mtOXPHOS complex I (NADH dehydrogenase), complex IV (cytochrome c oxidase), complex V (ATPase) and in mitochondrial oxygen consumption, suggesting a role for UCP2 in the counteraction of pancreatic cancer cellular respiration. All these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation with the concomitant metabolic shift from mtOXPHOS to the glycolytic pathway. PMID- 27989751 TI - Regular treadmill exercise inhibits mitochondrial accumulation of cholesterol and oxysterols during myocardial ischemia-reperfusion in wild-type and ob/ob mice. AB - Mitochondria play a central role in the irreversible damages induced to the heart by a prolonged period of ischemia followed by reperfusion. We previously demonstrated that (1) myocardial ischemia-reperfusion induces mitochondrial accumulation of cholesterol and oxysterols that are deleterious for the organelle; (2) inhibition of cholesterol and oxysterol accumulation prevents mitochondrial injury at reperfusion; (3) exercise is cardioprotective and remains efficient in the presence of co-morbidities such as obesity. The aim of this study was to investigate whether regular exercise limits mitochondrial cholesterol and oxysterol accumulation in wild-type and obese mice. Wild-type C57BL/6J and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise and submitted to 30min of coronary artery occlusion followed by 15min of reperfusion. Regular exercise improved oxidative phosphorylation, restored the antioxidant capacity of the heart by increasing the expression of SOD1 and catalase and reduced the mitochondrial generation of oxysterols in wild type as well as in ob/ob mice. In wild-type animals, exercise limited the production of oxysterols. In ob/ob mice, despite hypercholesterolemia, chronic exercise abolished the mitochondrial accumulation of cholesterol and concomitantly reduced the generation of 7alpha-hydroxycholesterol, 7 ketocholesterol and cholesterol-5alpha,6alpha-epoxide. In conclusion, regular exercise prevents the mitochondrial accumulation of cholesterol and oxysterols which occurs during early reperfusion of an ischemic myocardium in mice. This effect is observed in normo and hypercholesterolemic animals. It may be partly responsible for the antioxidant properties of regular exercise and contribute to its cardioprotective effect in obese conditions. PMID- 27989752 TI - Comprehensive analysis of the formation and stability of peroxynitrite-derived 8 nitroguanine by LC-MS/MS: Strategy for the quantitative analysis of cellular 8 nitroguanine. AB - Peroxynitrite is a major oxidizing and nitrating biological agent formed at sites of inflammation. Peroxynitrite can cause DNA damage and is thought to contribute to inflammation-related carcinogenesis. This study describes a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the direct determination of peroxynitrite-derived 8-nitroguanine (8-nitroGua) in DNA hydrolysates. This method exhibited a sensitive detection limit of 3 fmol and inter- and intraday imprecision of <10% and was applied to systemically examine the formation and stability of peroxynitrite-derived 8-nitroGua in different DNA substrates under various conditions. The 8-nitroGua formation was maximal at pH 8. The formation rate of 8-nitroGua in different DNA substrates decreased in the order of monodeoxynucleoside>single-stranded DNA>double-stranded DNA. A stability test revealed that the half-life for the depurination of 8-nitroGua from DNA was short and affected by both the temperature and DNA structure. When present in monodeoxynucleoside, the half-life of 8-nitroGua was estimated to be ~6min at 25 degrees C and 2.3h at ~0 degrees C. In single-stranded DNA, the half-life varied from 1.6h at 37 degrees C to 533h at -20 degrees C, whereas the half-life increased from 2.4h at 37 degrees C to 1115h at -20 degrees C in double-stranded DNA. We demonstrated that the measurement of 8-nitroGua in isolated DNA is not practicable because 8-nitroGua is unstable and lost during DNA extraction from cell. Therefore, we suggest that directly detecting cellular 8-nitroGua following nuclear membrane lysis is an alternative measure of the nitrative damage of nucleic acids, accounting for both DNA and RNA lesions within cells. PMID- 27989753 TI - The tetrahydrobiopterin radical interacting with high- and low-spin heme in neuronal nitric oxide synthase - A new indicator of the extent of NOS coupling. AB - Reaction intermediates trapped during the single-turnover reaction of the neuronal ferrous nitric oxide synthase oxygenase domain (Fe(II)nNOSOX) show four EPR spectra of free radicals. Fully-coupled nNOSOX with cofactor (tetrahydrobiopterin, BH4) and substrate (l-arginine) forms the typical BH4 cation radical with an EPR spectrum ~4.0mT wide and hyperfine tensors similar to reports for a biopterin cation radical in inducible NOSOX (iNOSOX). With excess thiol, nNOSox lacking BH4 and l-arg is known to produce superoxide. In contrast, we find that nNOSOX with BH4 but no l-arg forms two radicals with rather different, fast (~250MUs at 5K) and slower (~500MUs at 20K), electron spin relaxation rates and a combined ~7.0mT wide EPR spectrum. Rapid freeze-quench CW- and pulsed-EPR measurements are used to identify these radicals and their origin. These two species are the same radical with identical nuclear hyperfine couplings, but with spin-spin couplings to high-spin (4.0mT component) or low spin (7.0mT component) Fe(III) heme. Uncoupled reactions of nNOS leave the enzyme in states that can be chemically reduced to sustain unregulated production of NO and reactive oxygen species in ischemia-reperfusion injury. The broad EPR signal is a convenient indicator of uncoupled nNOS reactions producing low-spin Fe(III) heme. PMID- 27989754 TI - Vam3 ameliorates total body irradiation-induced hematopoietic system injury partly by regulating the expression of Nrf2-targeted genes. AB - Vam3, a resveratrol dimer, has been implicated in the regulation of chronic obstructive pulmonary disease. However, the effect of Vam3 on total body irradiation (TBI)-induced hematopoietic progenitor cells (HPCs), and hematopoietic stem cells (HSCs) injury is unknown. In this study, we examined whether Vam3could ameliorate hematopoietic system injury induced by TBI. Our results indicated that Vam3 alleviated TBI-induced injury by improving the self renewal and differentiation of HPCs, and HSCs. Vam3 decreased the intracellular ROS levels in irradiated mice HPCs/HSCs or c-kit positive cells and inhibited apoptosis and DNA damage in LSKs and HPCs after TBI. Vam3 up-regulated the expression of Nrf2 and related genes and proteins in irradiated c-kit positive cells in vitro. However, Vam3 did not increase the cell viability or the number of CFU-GM c-kit positive cells in irradiated Nrf2-/- mice but decreased the cellular ROS level. The above data showed that Vam3 ameliorates total body irradiation-induced hematopoietic system injury and that Nrf2 is essential in mediating Vam3's protective effect on the proliferation of c-kit positive cells after irradiation but not its ability to scavenge for free radicals. PMID- 27989756 TI - Redox signaling mediated by the gut microbiota. AB - The microbiota that inhabits the mammalian intestine can influence a range of physiological functions, including the modulation of immune responses, enhancement epithelial barrier function, and the stimulation of cell proliferation. While the mechanisms by which commensal prokaryotes stimulate immune signaling networks are well-characterized, less is known about the mechanistic control over homeostatic pathways within tissues. Recent reports by our research group have demonstrated that contact between the gut epithelia and some groups of enteric commensal bacteria prompts the rapid generation of reactive oxygen species (ROS) within host cells. Whereas the bacterial-induced production of ROS in phagocytes in response to ligand binding to Formyl Peptide Receptors (FPRs) and ensuing activation of NADPH oxidase 2 (Nox2) is a well defined mechanism, ROS generated by other cell types such as intestinal epithelia in response to microbial signals via FPRs and the NADPH oxidase 1 (Nox1) is less appreciated. Importantly, enzymatically generated ROS have been shown to function as second messengers in many signal transduction pathways via the transient oxidative activity on sensor proteins bearing oxidant-sensitive thiol groups. Examples of redox sensitive proteins include tyrosine phosphatases that serve as regulators of MAPK pathways, focal adhesion kinase, as well as components involved NF-kB activation. Here, we review the leading edge discoveries gleaned from investigations that focus on microbial-induced generation of ROS and their functional effects on host physiology. These studies identify the functional molecular elements and mechanistic events that mediate the established effects of the normal microbiota on intestinal physiology. PMID- 27989755 TI - Oxidatively-generated damage to DNA and proteins mediated by photosensitized UVA. AB - UVA accounts for about 95% of the solar ultraviolet (UV) radiation that reaches Earth and most likely contributes to human skin cancer risk. In contrast to UVB, which comprises the remaining 5% and is absorbed by DNA nucleobases to cause direct photodamage, UVA damages DNA indirectly. It does this largely through its interactions with cellular chromophores that act as photosensitisers to generate reactive oxygen species. Exogenously supplied chemicals, including some widely prescribed medicines, may also act as photosensitisers and these drugs are associated with an increased risk of sun-related cancer. Because they amplify the effects of UVA on cells, they provide a means to investigate the mechanisms and effects of UVA-induced photodamage. Here, we describe some of the major lesions induced by two groups of UVA photosensitisers, the DNA thionucleotides and the fluoroquinolone antibiotics. In thionucleotides, replacement of the oxygen atoms of canonical nucleobases by sulfur converts them into strong UVA chromophores that can be incorporated into DNA. The fluoroquinolones are also UVA chromophores. They are not incorporated into DNA and induce a different range of DNA damages. We also draw attention to the potentially important contribution of photochemical protein damage to the cellular effects of photosensitised UVA. Proteins targeted for oxidation damage include DNA repair factors and we suggest that UVA-mediated protein damage may contribute to sunlight-induced cancer risk. PMID- 27989758 TI - Low level of mono(2-ethylhexyl) phthalate reduces oocyte developmental competence in association with impaired gene expression. AB - Di-(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono-(2-ethylhexyl) phthalate (MEHP), are reproductive toxicants. However, disruptive effects of MEHP at low concentrations on the oocyte and developing blastocyst are unknown. Previously, we detected low levels of MEHP in follicular fluid aspirated from DEHP-treated cows associated with reduced estradiol levels. Moreover, the MEHP concentrations found were similar to those reported for follicular fluid aspirated from women who have undergone IVF cycles. In the current study, we used an in vitro embryo production model to examine the effect of MEHP at low levels on oocyte developmental competence. We set up several experiments to mimic the follicular fluid content, i.e., low MEHP level and low estradiol. For all experiments, cumulus oocyte complexes (COCs) were aspirated from bovine ovaries, then matured in vitro in standard oocyte maturation medium (OMM) supplemented with: MEHP at a range levels (20-1000nM) or with estradiol at a range levels (0 2000ng/ml). Then, oocytes were fertilized and cultured for an additional 7days to allow blastocyst development. Findings revealed that MEHP at low levels impairs oocyte developmental competence in a dose-dependent manner (P<0.05) and that estradiol by itself does not impair it. Accordingly, in another set of experiments, COCs were matured in vitro with MEHP at two choosen concentrations (20 or 1000nM) with or without estradiol, fertilized and cultured for 7days. Samples of mature oocytes and their derived blastocysts were subjected to quantitative real-time PCR to examine the profiles of selected genes (CYC1, MT CO1, ATP5B, POU5F1, SOX2 and DNMT3b). Maturation of COCs with MEHP (20 or 1000nM) affected gene expression in the mature oocyte. Maturation of COCs with MEHP (20 or 1000nM) in the absence of estradiol reduced oocyte developmental competence (P<0.05). A differential carryover effect on transcript abundance was recorded in blastocysts developed from MEHP-treated oocytes. In the presence of estradiol, increased expression was recorded for CYC1, ATP5B, SOX2 and DNMT3b. In the absence of estradiol, decreased expression was recorded, with a significant effect for 1000nM MEHP (P<0.05). Taken together, the findings suggest that low levels of phthalate must be taken into consideration in risk assessments. PMID- 27989759 TI - A new set of assays for the discovery of aminoacyl-tRNA synthetase inhibitors. AB - Current biochemical methods available to monitor the activity of aminoacyl-tRNA synthetases (ARS) are ill-suited to high-throughput screening approaches for the identification of small-molecule inhibitors of these enzymes. In an attempt to improve the limitations of current assays we have developed a suite of new methods designed to streamline the discovery of new ARS antagonists. This set of assays includes approaches to monitor ARS activity in vitro, in human cells, and in bacteria. They are applicable to several ARSs from any given organism, can be easily adapted to very high-throughput set-ups, and allow for a multi-factorial selection of drug candidates. PMID- 27989761 TI - Anti-endothelial cell antibodies in vasculitis: A systematic review. AB - Anti-endothelial cell antibodies (AECAs) are those that can bind to endothelial cells (ECs) via variable region-specific interactions. The identification and quantification of AECAs varies depending on the technique used. The best approach would be to combine at least two different methods. Thus, AECA measurement cannot be considered a diagnostic tool, but the detection and titers of AECAs are associated with disease activity in various systemic vasculitis diseases. AECAs have been described in almost all primary systemic vasculitis diseases but also in many secondary vasculitis diseases, with the identification of various antigens. AECAs may play a pathogenic role in vasculitis, both in vitro and in vivo, mainly via EC activation and induction of apoptosis. We used a systematic review of the literature to better define the prevalence, clinical association, targeted antigens, possible pathophysiologic role and clinical usefulness of AECAs in various types of vasculitis. PMID- 27989757 TI - Retinal pigment epithelium and microglia express the CD5 antigen-like protein, a novel autoantigen in age-related macular degeneration. AB - We report on a novel autoantigen expressed in human macular tissues, identified following an initial Western blot (WB)-based screening of sera from subjects with age-related macular degeneration (AMD) for circulating auto-antibodies (AAbs) recognizing macular antigens. Immunoprecipitation, 2D-gel electrophoresis (2D-GE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), direct enzyme linked immunosorbent assays (ELISA), WBs, immunohistochemistry (IHC), human primary and ARPE-19 immortalized cell cultures were used to characterize this novel antigen. An approximately 40-kDa autoantigen in AMD was identified as the scavenger receptor CD5 antigen-like protein (CD5L), also known as apoptosis inhibitor of macrophage (AIM). CD5L/AIM was localized to human RPE by IHC and WB methods and to retinal microglial cells by IHC. ELISAs with recombinant CD5L/AIM on a subset of AMD sera showed a nearly 2-fold higher anti-CD5L/AIM reactivity in AMD vs. Control sera (p = 0.000007). Reactivity >=0.4 was associated with 18-fold higher odds of having AMD (chi2 = 21.42, p = 0.00063). Circulating CD5L/AIM levels were also nearly 2-fold higher in AMD sera compared to controls (p = 0.0052). The discovery of CD5L/AIM expression in the RPE and in retinal microglial cells adds to the known immunomodulatory roles of these cells in the retina. The discovery of AAbs recognizing CD5L/AIM identifies a possible novel disease biomarker and suggest a potential role for CD5L/AIM in the pathogenesis of AMD in situ. The possible mechanisms via which anti-CD5L/AIM AAbs may contribute to AMD pathogenesis are discussed. In particular, since CD5L is known to stimulate autophagy and to participate in oxidized LDL uptake in macrophages, we propose that anti-CD5L/AIM auto-antibodies may play a role in drusen biogenesis and inflammatory RPE damage in AMD. PMID- 27989762 TI - Thiol-induced nitric oxide donation mechanisms in substituted dinitrobenzofuroxans. AB - The goal of present work is the quantum chemical study of NO donation mechanism in dinitrobenzofuroxan aryl derivative. Mechanisms of its structural non-rigidity (1,3-N-oxidic and Boulton-Katritzky rearrangements) and minimum energy pathways of NO donation under the action of sulfanyl radical SH. were considered in details. DFT calculations were performed using B3LYP and UB3LYP functionals in the 6-311++G(d,p) basis set. Obtained results showed that a high experimentally proven NO-donor activity of dinitrobenzofuroxan aryl derivative is connected with its existence in the form of mixture of 1-N-oxide and 3-N-oxide, where the 3-N oxide is more reactive towards SH.. The thiol-induced low-barrier mechanism of NO donation is a result of para-aminophenyl substituent availability in position 7 of dinitrobenzofuroxan. PMID- 27989763 TI - The multifaceted roles of Leptospira enolase. AB - A previous study had demonstrated that Leptospira enolase is secreted extracellularly by a yet unknown mechanism and reassociates with the bacterial membrane. Surface-anchored leptospiral enolase displays plasminogen binding activity. In this work, we explored the consequences of this interaction and also assessed whether Leptospira enolase might display additional moonlighting functions by interacting with other host effector proteins. We first demonstrated that enolase-bound plasminogen is converted to its active form, plasmin. The protease plasmin targets human fibrinogen and vitronectin, but not the complement proteins C3b and C5. Leptospira enolase also acts as an immune evasion protein by interacting with the negative complement regulators C4b binding protein and factor H. Once bound to enolase, both regulators remain functional as cofactors of factor I, mediating cleavage of C4b and C3b. In conclusion, enolase may facilitate leptospiral survival and dissemination, thus contributing to bacterial virulence. The identification and characterization of moonlighting proteins is a growing field of bacterial pathogenesis, as these multifaceted proteins may represent potential future therapeutic targets to fight bacterial infections. PMID- 27989764 TI - Spore-forming bacteria responsible for food spoilage. AB - This review explores the main spore-forming bacteria involved in the spoilage of various processed foods. Bakery products are specifically spoiled by Bacillus species, the dominant one being Bacillus amyloliquefaciens, while different Clostridium species classically contaminate refrigerated vacuum-packed meats. These two genera have also been isolated from milk products, even when milk is pasteurized, sterilized, dehydrated or fermented, according to heat treatment and storage temperature. Finally, the most heat-resistant microorganisms are isolated in low-acid canned foods, the three predominant species being Geobacillus stearothermophilus, Moorella thermoacetica and Thermoanaerobacterium spp. PMID- 27989765 TI - Chitosan-coupled solid lipid nanoparticles: Tuning nanostructure and mucoadhesion. AB - Solid Lipid Nanoparticles (SLNs) composed of biodegradable physiological lipids have been widely proposed as efficient drug delivery systems, also for ophthalmic administration. Recently, chitosan-associated-SLNs have been developed to further improve the residence time of these colloidal systems in the precorneal area by means of mucoadhesive interaction. In the present study, a one-step preparation protocol was used aiming both at scale-up ease and at stronger coupling between chitosan and SLNs. The resulting particles were chitosan associated-SLNs (CS SLNs). These nanoparticles were characterized, as compared to both the chitosan free and the usual chitosan-coated ones, by applying a multi-technique approach: light, neutron and X-ray scattering, Zeta-potential, AFM, calorimetry. It was assessed that, while keeping the features of nano-size and surface-charge required for an efficient vector, these new nanoparticles display a strong and intimate interaction between chitosan and SLNs, far more settled than the usual simple coverage. Moreover, this one-step preparation method allows to obtain a strong and intimate interaction between chitosan and SLNs, firmer than the usual simple coating. This confers to the CS-SLNs an improved mucoadhesion, opening the way for a high-performing ophthalmic formulation. PMID- 27989766 TI - Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles - Composition dependent skin penetration enhancement of a dye probe and biocompatibility. AB - Nanoparticles can improve topical drug delivery: size, surface properties and flexibility of polymer nanoparticles are defining its interaction with the skin. Only few studies have explored skin penetration for one series of structurally related polymer particles with systematic alteration of material composition. Here, a series of rigid poly[acrylonitrile-co-(N-vinyl pyrrolidone)] model nanoparticles stably loaded with Nile Red or Rhodamin B, respectively, was comprehensively studied for biocompatibility and functionality. Surface properties were altered by varying the molar content of hydrophilic NVP from 0 to 24.1% and particle size ranged from 35 to 244nm. Whereas irritancy and genotoxicity were not revealed, lipophilic and hydrophilic nanoparticles taken up by keratinocytes affected cell viability. Skin absorption of the particles into viable skin ex vivo was studied using Nile Red as fluorescent probe. Whilst an intact stratum corneum efficiently prevented penetration, almost complete removal of the horny layer allowed nanoparticles of smaller size and hydrophilic particles to penetrate into viable epidermis and dermis. Hence, systematic variations of nanoparticle properties allows gaining insights into critical criteria for biocompatibility and functionality of novel nanocarriers for topical drug delivery and risks associated with environmental exposure. PMID- 27989767 TI - Carpal tunnel syndrome after chikungunya infection. PMID- 27989768 TI - XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development. AB - Sex chromosome dosage compensation is essential in most metazoans, but the developmental timing and underlying mechanisms vary significantly, even among placental mammals. Here we identify human-specific mechanisms regulating X chromosome activity in early embryonic development. Single-cell RNA sequencing and imaging revealed co-activation and accumulation of the long noncoding RNAs (lncRNAs) XACT and XIST on active X chromosomes in both early human pre implantation embryos and naive human embryonic stem cells. In these contexts, the XIST RNA adopts an unusual, highly dispersed organization, which may explain why it does not trigger X chromosome inactivation at this stage. Functional studies in transgenic mouse cells show that XACT influences XIST accumulation in cis. Our findings therefore suggest a mechanism involving antagonistic activity of XIST and XACT in controlling X chromosome activity in early human embryos, and they highlight the contribution of rapidly evolving lncRNAs to species-specific developmental mechanisms. PMID- 27989771 TI - Relationship between RSUME and HIF-1alpha/VEGF-A with invasion of pituitary adenoma. AB - The RWD-containing sumoylation enhancer (RSUME) can stabilize hypoxia-inducible factor-1alpha (HIF-1alpha) which promotes vascular endothelial growth factor-A (VEGF-A) expression. RSUME plays an important role in promoting the invasion of pituitary adenoma. In this study, we compared the mRNA and protein levels of RSUME, HIF-1alpha, and VEGF-A in pituitary adenoma tissue and analyzed the correlation. We found that the expression levels of RSUME, HIF-1alpha, and VEGF-A in invasive pituitary adenoma were significantly higher than in noninvasive pituitary adenoma. Moreover, a positive correlation was found between RSUME and HIF-1alpha/VEGF pathways. RSUME and HIF-1alpha were treated with hypoxia mimicking CoCl2 and transfected into AtT-20 and GT1.1 cell lines to determine the relationship between them. It was found that RSUME effects post-transcriptional expression of HIF-1alpha regulated VEGF-A secretion. Reducing RSUME expression using siRNA transfection resulted in a decrease of the invasion inhibition rate of AtT-20 cells, as determined using Transwell and MTT assays. Together, we found that RSUME silencing can inhibit the invasion of pituitary adenoma cells. PMID- 27989770 TI - Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation. AB - Naive human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X chromosome state has remained unresolved. Here, we show that the inactive X chromosome (Xi) of primed hESCs was reactivated in naive culture conditions. Like cells of the blastocyst, the resulting naive cells contained two active X chromosomes with XIST expression and chromosome-wide transcriptional dampening and initiated XIST-mediated X inactivation upon differentiation. Both establishment of and exit from the naive state (differentiation) happened via an XIST-negative XaXa intermediate. Together, these findings identify a cell culture system for functionally exploring the two X chromosome dosage compensation processes in early human development: X dampening and X inactivation. However, remaining differences between naive hESCs and embryonic cells related to mono-allelic XIST expression and non-random X inactivation highlight the need for further culture improvement. As the naive state resets Xi abnormalities seen in primed hESCs, it may provide cells better suited for downstream applications. PMID- 27989769 TI - Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. AB - Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways. PMID- 27989772 TI - Cell cycle and growth stimuli regulate different steps of RNA polymerase I transcription. AB - Transcription of the ribosomal RNA genes (rDNA) by RNA polymerase I (Pol I) is a major control step for ribosome synthesis and is tightly linked to cellular growth. However, the question of whether this process is modulated primarily at the level of transcription initiation or elongation is controversial. Studies in markedly different cell types have identified either initiation or elongation as the major control point. In this study, we have re-examined this question in NIH3T3 fibroblasts using a combination of metabolic labeling of the 47S rRNA, chromatin immunoprecipitation analysis of Pol I and overexpression of the transcription initiation factor Rrn3. Acute manipulation of growth factor levels altered rRNA synthesis rates over 8-fold without changing Pol I loading onto the rDNA. In fact, robust changes in Pol I loading were only observed under conditions where inhibition of rDNA transcription was associated with chronic serum starvation or cell cycle arrest. Overexpression of the transcription initiation factor Rrn3 increased loading of Pol I on the rDNA but failed to enhance rRNA synthesis in either serum starved, serum treated or G0/G1 arrested cells. Together these data suggest that transcription elongation is rate limiting for rRNA synthesis. We propose that transcription initiation is required for rDNA transcription in response to cell cycle cues, whereas elongation controls the dynamic range of rRNA synthesis output in response to acute growth factor modulation. PMID- 27989774 TI - Failure to retreat: Blunted sensitivity to negative feedback supports risky behavior in adolescents. AB - Decision-making processes rarely occur in isolation. Rather, representations are updated constantly based on feedback to past decisions and actions. However, previous research has focused on the reaction to feedback receipt itself, instead of examining how feedback information is integrated into future decisions. In the current study, we examined differential neural sensitivity during risk decisions following positive versus negative feedback in a risk-taking context, and how this differential sensitivity is linked to adolescent risk behavior. Fifty-eight adolescents (ages 13-17 years) completed the Balloon Analogue Risk Task (BART) during an fMRI session and reported on their levels of risk-taking behavior. Results show that reduced medial PFC (mPFC) response following negative versus positive feedback is associated with fewer reductions in task-based risky decisions following negative feedback, as well as increased self-reported risk taking behavior. These results suggest that reduced neural integration of negative feedback into during future decisions supports risky behavior, perhaps by discounting negative relative to positive feedback information when making subsequent risky decisions. PMID- 27989775 TI - Intranasal oxytocin reduces social perception in women: Neural activation and individual variation. AB - Most intranasal oxytocin research to date has been carried out in men, but recent studies indicate that females' responses can differ substantially from males'. This randomized, double-blind, placebo-controlled study involved an all-female sample of 28 women not using hormonal contraception. Participants viewed animations of geometric shapes depicting either random movement or social interactions such as playing, chasing, or fighting. Probe questions asked whether any shapes were "friends" or "not friends." Social videos were preceded by cues to attend to either social relationships or physical size changes. All subjects received intranasal placebo spray at scan 1. While the experimenter was not blinded to nasal spray contents at Scan 1, the participants were. Scan 2 followed a randomized, double-blind design. At scan 2, half received a second placebo dose while the other half received 24 IU of intranasal oxytocin. We measured neural responses to these animations at baseline, as well as the change in neural activity induced by oxytocin. Oxytocin reduced activation in early visual cortex and dorsal-stream motion processing regions for the social > size contrast, indicating reduced activity related to social attention. Oxytocin also reduced endorsements that shapes were "friends" or "not friends," and this significantly correlated with reduction in neural activation. Furthermore, participants who perceived fewer social relationships at baseline were more likely to show oxytocin-induced increases in a broad network of regions involved in social perception and social cognition, suggesting that lower social processing at baseline may predict more positive neural responses to oxytocin. PMID- 27989773 TI - In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging. AB - BACKGROUND: Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals. METHODS: Our approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain-tissue-specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure. Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR=0; n=23) or with mild AD dementia (CDR=0.5 or 1; n=11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (Abeta) biomarker Abeta42. A subset of 19 participants also underwent PET PiB studies to assess their brain Abeta burden. According to the Abeta status, cognitively normal participants were divided into normal (Abeta negative; n=13) and preclinical (Abeta positive; n=10) groups. RESULTS: GEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI-determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy. Our studies also uncovered strong correlations between GEPCI brain tissue metrics and beta-amyloid (Abeta) burden defined by positron emission tomography (PET) - the current in vivo gold standard for detection of cortical Abeta, thus supporting GEPCI as a potential surrogate marker for Abeta imaging - a known biomarker of early AD. Remarkably, the data show significant correlations not only in the areas of high Abeta accumulation (e.g. precuneus) but also in some areas of medial temporal lobe (e.g. parahippocampal cortex), where Abeta accumulation is relatively low. CONCLUSION: We have demonstrated that GEPCI provides a new approach for the in vivo evaluation of AD-related tissue pathology in the preclinical and early symptomatic stages of AD. Since MRI is a widely available technology, the GEPCI surrogate markers of AD pathology have a potential for improving the quality of AD diagnostic, and the evaluation of new disease-modifying therapies. PMID- 27989776 TI - Language in context: Characterizing the comprehension of referential expressions with MEG. AB - A critical component of comprehending language in context is identifying the entities that individual linguistic expressions refer to. While previous research has shown that language comprehenders resolve reference quickly and incrementally, little is currently known about the neural basis of successful reference resolution. Using source localized MEG, we provide evidence across 3 experiments and 2 languages that successful reference resolution in simple visual displays is associated with increased activation in the medial parietal lobe. In each trial, participants saw a simple visual display containing three objects which constituted the referential domain. Target referential expressions were embedded in questions about the displays. By varying the displays, we manipulated referential status while keeping the linguistic expressions constant. Follow-up experiments addressed potential interactions of reference resolution with linguistic predictiveness and pragmatic plausibility. Notably, we replicated the effect in Arabic, a language that differs in a structurally informative way from English while keeping referential aspects parallel to our two English studies. Distributed minimum norm estimates of MEG data consistently indicated that reference resolution is associated with increased activity in the medial parietal lobe. With one exception, the timing of the onset of the medial parietal response fell into a mid-latency time-window at 350-500ms after the onset of the resolving word. Through concurrent EEG recordings on a subset of subjects we also describe the EEG topography of the effect of reference resolution, which makes the result available for comparison with a larger existing literature. Our results extend previous reports that medial parietal lobe is involved in referential language processing, indicating that it is relevant for reference resolution to individual referents, and suggests avenues for future research. PMID- 27989777 TI - Hand classification of fMRI ICA noise components. AB - We present a practical "how-to" guide to help determine whether single-subject fMRI independent components (ICs) characterise structured noise or not. Manual identification of signal and noise after ICA decomposition is required for efficient data denoising: to train supervised algorithms, to check the results of unsupervised ones or to manually clean the data. In this paper we describe the main spatial and temporal features of ICs and provide general guidelines on how to evaluate these. Examples of signal and noise components are provided from a wide range of datasets (3T data, including examples from the UK Biobank and the Human Connectome Project, and 7T data), together with practical guidelines for their identification. Finally, we discuss how the data quality, data type and preprocessing can influence the characteristics of the ICs and present examples of particularly challenging datasets. PMID- 27989779 TI - Tracking thoughts: Exploring the neural architecture of mental time travel during mind-wandering. AB - The capacity to imagine situations that have already happened or fictitious events that may take place in the future is known as mental time travel (MTT). Studies have shown that MTT is an important aspect of spontaneous thought, yet we lack a clear understanding of how the neurocognitive architecture of the brain constrains this element of human cognition. Previous functional magnetic resonance imaging (MRI) studies have shown that MTT involves the coordination between multiple regions that include mesiotemporal structures such as the hippocampus, as well as prefrontal and parietal regions commonly associated with the default mode network (DMN). The current study used a multimodal neuroimaging approach to identify the structural and functional brain organisation that underlies individual differences in the capacity to spontaneously engage in MTT. Using regionally unconstrained diffusion tractography analysis, we found increased diffusion anisotropy in right lateralised temporo-limbic, corticospinal, inferior fronto-occipital tracts in participants who reported greater MTT. Probabilistic connectivity mapping revealed a significantly higher connection probability of the right hippocampus with these tracts. Resting-state functional MRI connectivity analysis using the right hippocampus as a seed region revealed greater functional coupling to the anterior regions of the DMN with increasing levels of MTT. These findings demonstrate that the interactions between the hippocampus and regions of the cortex underlie the capacity to engage in MTT, and support contemporary theoretical accounts that suggest that the integration of the hippocampus with the DMN provides the neurocognitive landscape that allows us to imagine distant times and places. PMID- 27989778 TI - Modulation of ventral striatal activity by cognitive effort. AB - Effort discounting theory suggests that the value of a reward should be lower if it was effortful to obtain, whereas contrast theory suggests that the contrast between the costly effort and the reward makes the reward seem more valuable. To test these alternative hypotheses, we used functional magnetic resonance imaging (fMRI) as participants engaged in feedback-based learning that required low or high cognitive effort to obtain positive feedback, while the objective amount of information provided by feedback remained constant. In the low effort condition, a single image was presented with four response options. In the high effort condition, two images were presented, each with two response options, and correct feedback was presented only when participants responded correctly to both of the images. Accuracy was significantly lower for the high effort condition, and all participants reported that the high effort condition was more difficult. A region of the ventral striatum selected for sensitivity to feedback value also showed increased activation to feedback presentation associated with the high effort condition relative to the low effort condition, when controlling for activation from corresponding control conditions where feedback was random. These results suggest that increased cognitive effort produces corresponding increases in positive feedback-related ventral striatum activity, in line with the predictions made by contrast theory. The accomplishment of obtaining a hard-earned intrinsic reward, such as positive feedback, may be particularly likely to promote reward related brain activity. PMID- 27989780 TI - Shifting visual perspective during retrieval shapes autobiographical memories. AB - The dynamic and flexible nature of memories is evident in our ability to adopt multiple visual perspectives. Although autobiographical memories are typically encoded from the visual perspective of our own eyes they can be retrieved from the perspective of an observer looking at our self. Here, we examined the neural mechanisms of shifting visual perspective during long-term memory retrieval and its influence on online and subsequent memories using functional magnetic resonance imaging (fMRI). Participants generated specific autobiographical memories from the last five years and rated their visual perspective. In a separate fMRI session, they were asked to retrieve the memories across three repetitions while maintaining the same visual perspective as their initial rating or by shifting to an alternative perspective. Visual perspective shifting during autobiographical memory retrieval was supported by a linear decrease in neural recruitment across repetitions in the posterior parietal cortices. Additional analyses revealed that the precuneus, in particular, contributed to both online and subsequent changes in the phenomenology of memories. Our findings show that flexibly shifting egocentric perspective during autobiographical memory retrieval is supported by the precuneus, and suggest that this manipulation of mental imagery during retrieval has consequences for how memories are retrieved and later remembered. PMID- 27989781 TI - The Present and Future of Human Sexuality: Impact of Faulty Perinatal Hormonal Imprinting. AB - INTRODUCTION: Hormonal imprinting occurs perinatally, when the developing hormone receptors connect to their target hormones. This is required for the normal development of the receptor-hormone connection. At this time, the selectivity of receptors is weak and can be misdirected to related endogenous or exogenous molecules, such as other members of the same hormone family, synthetic hormones, drugs, hormone-like environmental pollutants, and endocrine disruptors. In this situation, faulty hormonal imprinting develops with lifelong consequences, which are manifested by altered receptor binding capacity, hormone production, changed bone formation, and brain neurotransmitter content. The effect of faulty imprinting is epigenetically inherited and manifested in progeny. AIM: To evaluate the effects of hormonal imprinting on sexuality based on published results. METHODS: Review of perinatal (mainly single) treatment of experimental animals with hormones or hormone-like materials and the study of their effects in adulthood and in progeny. MAIN OUTCOME MEASURE: Consistency of experimental results with the previous information and expectations. RESULTS: In each published experiment, perinatal treatments with hormones acting on members of a steroid receptor superfamily or endocrine disruptors (eg, bisphenol A, vinclozolin, benzpyrene or soybean genistein) caused faulty imprinting with altered sexual hormone receptor binding and sexual function. Indices of sexual activity showed the strong influence of these treatments. CONCLUSION: Sexuality is influenced by perinatal faulty hormonal imprinting at the receptor and behavioral levels. Because faulty imprinting is an epigenetic process, it is transmitted to the members of cell line and to progeny. In the modern age, the amount of artificial (industrial, communal, and medical) imprinters and their effects on the human organism are increasing enormously. This is likely to change human sexuality now and in the future. Csaba G. The Present and Future of Human Sexuality: Impact of Faulty Perinatal Hormonal Imprinting. Sex Med Rev 2017;5:163 169. PMID- 27989782 TI - The Conception and Evaluation of Sexual Health Literature. AB - INTRODUCTION: Understanding the appropriate evaluation and development methods for studying the literature as it pertains to sexual health is important for those practicing within the subspecialty. AIM: To further understand the methodology that is necessary to evaluate and design optimal studies in sexual health. METHODS: A PubMed search was performed using the terms urologic study design, urologic validated questionnaires, clinical trials, and study bias. Articles with current and relevant topics in sexual health were selected for evaluation. MAIN OUTCOME MEASURE: Summary of the current state of sexual medicine literature with insights into the evaluation and development of this literature. RESULTS: Most of the urologic and sexual medicine literature consists of retrospective studies that have resulted in low levels of evidence. Case series, case-control studies, cohort studies, and experimental studies are designs commonly used in sexual health. There are numerous types of bias that decrease the validity of the results within the literature. There are multiple validated questionnaires that can decrease bias when collecting data. These instruments are preferred over non-validated questionnaires and can help discern whether an intervention improves a patient's quality of life. The quality of the literature varies and often reflects the incidence of the condition being studied. CONCLUSION: Those caring for patients with sexual dysfunction need to recognize the quality of the literature they read and understand the means of developing the highest quality studies, recommendations, and published literature. DeLay KJ, Voznesensky I, Hellstrom WJG. The Conception and Evaluation of Sexual Health Literature. Sex Med Rev 2017;5:135-145. PMID- 27989784 TI - Emodin suppresses TGF-beta1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway. AB - Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-beta1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration dependent manner; reduces the expression of Collagen I, alpha-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-beta1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-beta1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. PMID- 27989783 TI - The binding effectiveness of anti-r-disintegrin polyclonal antibodies against disintegrins and PII and PIII metalloproteases: An immunological survey of type A, B and A+B venoms from Mohave rattlesnakes. AB - Snake venoms are known to have different venom compositions and toxicity, but differences can also be found within populations of the same species contributing to the complexity of treatment of envenomated victims. One of the first well documented intraspecies venom variations comes from the Mohave rattlesnake (Crotalus scutulatus scutulatus). Initially, three types of venoms were described; type A venom is the most toxic as a result of ~45% Mojave toxin in the venom composition, type B lacks the Mojave toxin but contains over 50% of snake venom metalloproteases (SVMPs). Also, type A+B venom contains a combination of Mojave toxin and SVMP. The use of an anti-disintegrin antibody in a simple Enzyme Linked Immunosorbent Assay (ELISA) can be used to identify the difference between the venoms of the type A, B, and A+B Mohave rattlesnakes. This study implements the use of an anti-recombinant disintegrin polyclonal antibody (ARDPA) for the detection of disintegrins and ADAMs (a disintegrin and metalloproteases) in individual crude snake venoms of Mohave rattlesnakes (Crotalus scutulatus scutulatus) of varying geographical locations. After correlation with Western blots, coagulation activity and LD50 data, it was determined that the antibody allows for a quick and cost-efficient identification of venom types. PMID- 27989785 TI - Prognostic value of vascular endothelial growth factor (VEGF), VEGF receptor 2, platelet-derived growth factor-beta (PDGF-beta), and PDGF-beta receptor expression in papillary renal cell carcinoma. AB - The prognostic value of the expression of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), platelet-derived growth factor (PDGF)-beta, and PDGF receptor (PDGFR)-beta in papillary renal cell carcinoma (pRCC) is unknown. A total of 145 patients, who were confirmed to have pRCC, were analyzed. Expression levels of molecular markers were assessed via immunohistochemistry. The median follow-up period for all patients was 52.0 (interquartile range, 34.5-90.5) months. Among the cohort of 145 patients, high VEGF expression was observed in 100 (69.0%) patients, whereas high expression of VEGFR2, PDGF-beta, and PDGFR beta was observed in 64 (44.1%), 42 (29.0%), and 30 (20.7%) patients, respectively. Only patients with high VEGFR2 expression exhibited improved 10 year recurrence-free survival (85.3% versus 58.1%; P=.005) and cancer-specific survival (86.4% versus 70.1%; P=.014) rates compared with individuals who exhibited low expression. Multivariate analysis revealed that high VEGFR2 expression was an independent prognostic factor for recurrence (hazard ratio, 0.326; P=.006) and cancer-specific mortality (hazard ratio, 0.334; P=.046). During follow-up, 17 patients received targeted drug therapy. Patients with high VEGFR2 expression showed a better initial response (partial response, 40%; stable disease, 20%; progressive disease, 40%) than patients with low expression did (partial response, 0%; stable disease, 58.3%; progressive disease, 41.7%; P=.052). pRCC with high VEGFR2 expression seems to be associated with a better initial response to targeted drug therapy and a better prognostic outcome. PMID- 27989786 TI - Malignant tenosynovial giant cell tumor with CDKN2A/B genomic alteration: a histological, immunohistochemical, and molecular study. AB - Diffuse-type tenosynovial giant cell tumor (D-T TSGCT) is regarded as a benign but locally aggressive neoplasm with significant recurrent potential. We report a case of malignant D-T TSGCT with pleural metastases arising in the left knee in a 57-year-old man. The tumor demonstrated atypical features, including a solid infiltrative pattern with spindling of the tumor cells, nuclear pleomorphism with prominent nucleoli, and markedly increased mitotic activity (>20 mitoses/10 high power fields). The immunoprofile demonstrated clusterin+, D2-40+, CD68+, p63+, MDM2+, and p16+ tumor. The next-generation sequencing-based assay demonstrated loss of the CDKN2A/B gene. Pleural metastases with identical histologic and immunohistochemical features were identified 2 years later after primary tumor resection. To the best of our knowledge, this is the first reported case of D-T TSGCT with CDKN2A/B genomic alteration, MDM2 expression, and p16 loss. Clinicians and pathologists should be aware of the morphologic variability and the metastatic propensity of this entity. PMID- 27989787 TI - Prognostic significance of centromere 17 copy number gain in breast cancer depends on breast cancer subtype. AB - Increased copy number of chromosome enumeration probe (CEP) targeting centromere 17 is frequently encountered during HER2 in situ hybridization (ISH) in breast cancer. The aim of this study was to clarify the clinicopathologic significance of CEP17 copy number gain in a relatively large series of breast cancer patients. We analyzed 945 cases of invasive breast cancers whose HER2 fluorescence ISH reports were available from 2004 to 2011 at a single institution and evaluated the association of CEP17 copy number gain with clinicopathologic features of tumors and patient survival. We detected 186 (19.7%) cases of CEP17 copy number gain (CEP17>=3.0) among 945 invasive breast cancers. In survival analysis, CEP17 copy number gain was not associated with disease-free survival of the patients in the whole group. Nonetheless, it was found to be an independent adverse prognostic factor in the HER2-negative group but not in the HER2-positive group. In further subgroup analyses, CEP17 copy number gain was revealed as an independent poor prognostic factor in HER2-negative and hormone receptor-positive breast cancers, and it was associated with aggressive histologic variables including high T stage, high histologic grade, lymphovascular invasion, p53 overexpression, and high Ki-67 proliferative index. In conclusion, we found that elevated CEP17 count can serve as a prognostic marker in luminal/HER2-negative subtype of invasive breast cancer. We advocate the use of the dual-colored fluorescence ISH using CEP17 rather than the single-colored one because it gives additional valuable information on CEP17 copy number alterations. PMID- 27989788 TI - Distinction between inflammatory hepatocellular adenoma and mass effect on liver sampling. AB - Inflammatory hepatocellular adenoma (IHA) is characterized by sinusoidal dilation, inflammation, and bile ductular reaction. However, these changes can also be seen in nonneoplastic liver tissue adjacent to a mass lesion. This differential may arise in biopsy tissue attempting to sample a liver mass. Serum amyloid A (SAA) immunostaining is useful for the diagnosis of IHA but is not entirely specific. In addition, the histologic pattern of mass effect (ME) has received little formal scrutiny. We compared the clinical, morphologic, and immunohistochemical findings in 18 IHA and 36 livers with ME. Several histologic findings were evaluated in all cases. SAA and CD34 staining were also performed. Patients with IHA were younger (P<.0001) and more often female (P=.0044) than patients with specimens showing ME, but lesions were multifocal on imaging in two thirds of patients in each category. Unpaired arteries were only seen in IHA (P<.0001), whereas ductular reaction was more common in ME (P=.012). Strong SAA immunostaining was observed in 100% of IHAs and 56% of ME cases (P=.0004), and CD34 staining was seen in 95% of IHAs and 6% of ME cases (P<.0001). Unpaired arteries and staining for SAA and CD34 best distinguish IHA from ME. However, unpaired arteries may be absent because of sampling, and SAA is not available in all laboratories. Ductular reaction can occur in IHA but is more common in ME. PMID- 27989790 TI - Using wall thickness to understand both sides of the substrate story: Can we predict electrograms with imaging? PMID- 27989789 TI - Very high rate programming in primary prevention patients with reduced ejection fraction implanted with a defibrillator: Results from a large multicenter controlled study. AB - BACKGROUND: Programming implantable cardioverter-defibrillators (ICDs) with a high-rate therapy strategy has proven to be effective in reducing shocks and is associated with a reduced mortality. OBJECTIVE: We sought to determine the impact of a very high rate cutoff programming strategy on outcomes in patients with a primary indication for an ICD due to reduced left ventricular ejection fraction. METHODS: Using data from the multicenter French DAI-PP registry, this cohort controlled study compared outcomes in 500 patients programmed with a very high rate cutoff (VH-RATE group: monitor zone 170-219 beats/min; ventricular fibrillation zone >=220 beats/min with 13 +/- 4 detection intervals) with 1500 matched control patients programmed with 1 or 2 therapy zone. All ICDs were implanted for primary prevention in patients with systolic dysfunction. Risks of events were compared after propensity score matching of sex, age, ejection fraction, New York Heart Association class, cardiomyopathy, atrial fibrillation, and type of device. RESULTS: After a mean follow-up of 3.6 +/- 2.3 years, VH-RATE programming was associated with a reduction of appropriate therapy risk (hazard ratio [HR] 0.40; 95% confidence interval [CI] 0.31-0.51; P < .0001) and inappropriate shock (HR 0.42; 95% CI 0.27-0.63; P < .0001). It was also associated with a decreased risk of sudden cardiac death (HR 0.43; 95% CI 0.17 0.99; P = .04) as compared with patients programmed with 2 therapy zones. There was no significant difference in overall survival between the groups. CONCLUSION: In patients implanted with an ICD in primary prevention with left ventricular dysfunction, very high rate cutoff programming (single therapy zone >=220 beats/min) was associated with a 60% reduction of appropriate therapies as well as inappropriate shocks, without affecting mortality. PMID- 27989791 TI - Coronary sinus activation patterns in patients with and without left bundle branch block undergoing electroanatomic mapping system-guided cardiac resynchronization therapy device implantation. AB - BACKGROUND: Implantation of the left ventricular (LV) lead in segments with delayed electrical activation may improve response to cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to evaluate the amount and regional distribution of LV electrical delay (LVED) in patients with or without left bundle branch block (LBBB). METHODS: We enrolled 60 patients who underwent electroanatomic mapping system-guided CRT device implantation. Activation mapping of the coronary sinus (CS) branches was performed using an insulated guidewire. LVED was defined as the interval between the beginning of the QRS complex on the surface electrocardiogram (ECG) and the local electrogram and expressed in milliseconds or as percentage of the total QRS duration (LVED%). RESULTS: Forty-three patients showed a LBBB and 17 a non-LBBB electrocardiographic pattern. A total of 148 CS branches (mean 2.5 per patient; range 2-4 per patient) were mapped. Patients with LBBB showed higher maximum LVED (135 ms [108-150 ms] vs 100 ms [103-110 ms]; P < .001) and LVED% (86% [79%-89%] vs 72% [54%-80%]; P < .001) than did patients without LBBB. The maximum LVED was recorded in mid-basal anterolateral or inferolateral LV segments (traditional CRT targets), significantly more often in patients with LBBB than in patients without LBBB (85% vs 59%; P = .02). The number of CS branches showing LVED >50% of the total QRS duration, >75% of the total QRS duration, and >85 ms was significantly higher in patients with LBBB than in patients without LBBB. CONCLUSION: Patients without LBBB showed lower LVED and more heterogeneous electrical activation of the CS than did patients with LBBB. This finding may contribute to a lower rate of response to CRT of patients without LBBB and suggests the use of activation mapping to guide LV lead placement. PMID- 27989794 TI - Synchronous disruption of anisotropic arrangement of the osteocyte network and collagen/apatite in melanoma bone metastasis. AB - Cancer metastasis to bones increases the risk of fragility fracture by altering bone metabolism and disrupting bone structure. Osteocytes, which organize a dense network that is closely linked with the circumambient matrix, play a key role in regulation of bone microstructure and material properties. The aim of this study was to elucidate the influence of cancer metastasis on the organization of the osteocyte network and collagen/biological apatite (BAp) microstructure in the context of osteocyte/matrix coupling. Using a mouse model intracardially injected with B16F10 melanoma cells or vehicle, the geometric and metabolic changes to osteocytes were analyzed by nano-computed tomography (nano-CT) and histology, and the alignment of collagen fibrils and BAp was analyzed by birefringence measurement and microbeam-X-ray diffraction, respectively. The material properties of bones were further analyzed with nanoindentation method. These experiments revealed that the osteocyte network was markedly disorganized in cancer-bearing bone tissues. The osteocytes showed a variety of residing states in the lacunae; some lacunae were osteolytic while some were replete with immature matrix, suggesting significant disruption in osteocyte/matrix coupling. Collagen/BAp microstructure was also disorganized in cancer-bearing bones as observed by significant decreases in the preferential alignment of both collagen fibrils and BAp; the latter was further shown to be significantly correlated with Young's modulus. The present study revealed that the disruption in the arrangement of the osteocyte network and collagen/BAp microstructure and the deterioration of mechanical function occurred synchronously during cancer bone metastasis. PMID- 27989795 TI - A stable epoxide of estrone: Evidence for formation of a 'new' estrogen metabolite. AB - Oxidative metabolism of estrogens is an important feature in liver and some non hepatic tissues. In initial studies on estrogen metabolism in tissues from the reproductive tract of the stallion, where testicular estrogen secretion is remarkably high, a prominent radiolabeled product from [3H]-estrone (E1) was noted on chromatography; it had a retention time (Rt) between 17beta-estradiol (E2) and E1. Unexpectedly, when non-radiolabeled E1 was the substrate no UV absorption at 280nm was seen at the Rt for the [3H]-labeled product-suggesting a non-aromatic ring A. The following efforts were made to reveal more about the nature of the "unknown" compound. Reduction and acetylation showed, separately, the presence of a single keto and hydroxyl group. Exposure to acid gave a single radiolabeled peak with Rt of 6alpha-hydroxy-E1-suggesting the presence of a third molecule of oxygen. Mass spectrometry with limited material was inconclusive but supportive for a formula of C18H22O3. Thus, an epoxide involving the aromatic ring of E1 is suggested as a labile intermediate in the formation of the "unknown" metabolite. Estrogen epoxides as labile, reactive intermediates have been considered as potential precursors of the 2- and 4-hydroxy catechol estrogens with implications in breast cancer [Soloway, 2007]. Because of the association of the "unknown" metabolite with 6alpha-hydroxy-E1, the structural form proposed for the stable epoxide is that for 5alpha,6alpha-epoxy-estrone. This represents an alternative to the production of the 2- and 4-hydroxy-catechol estrogens. The broad range in normal tissues where the "unknown" compound was shown to be a persistent metabolite (e.g. mouse mammary glands, ovary, uterus, brain, muscle, equine conceptus, stallion and domestic boar reproductive tracts) suggests more general biological implications. PMID- 27989793 TI - Community metabolic modeling approaches to understanding the gut microbiome: Bridging biochemistry and ecology. AB - Interest in the human microbiome is at an all time high. The number of human microbiome studies is growing exponentially, as are reported associations between microbial communities and disease. However, we have not been able to translate the ever-growing amount of microbiome sequence data into better health. To do this, we need a practical means of transforming a disease-associated microbiome into a health-associated microbiome. This will require a framework that can be used to generate predictions about community dynamics within the microbiome under different conditions, predictions that can be tested and validated. In this review, using the gut microbiome to illustrate, we describe two classes of model that are currently being used to generate predictions about microbial community dynamics: ecological models and metabolic models. We outline the strengths and weaknesses of each approach and discuss the insights into the gut microbiome that have emerged from modeling thus far. We then argue that the two approaches can be combined to yield a community metabolic model, which will supply the framework needed to move from high-throughput omics data to testable predictions about how prebiotic, probiotic, and nutritional interventions affect the microbiome. We are confident that with a suitable model, researchers and clinicians will be able to harness the stream of sequence data and begin designing strategies to make targeted alterations to the microbiome and improve health. PMID- 27989796 TI - Altered SOX9 genital tubercle enhancer region in hypospadias. AB - Human mutations in the SOX9 gene or its regulatory region can disrupt testicular development, leading to disorders of sex development (DSDs). Our previous work involving the genomic analysis of isolated DSD patients revealed a 78kb minimal sex determining region (RevSex) far upstream of SOX9 that was duplicated in 46,XX and deleted in 46,XY DSDs. It was postulated that RevSex contains a gonadal enhancer. However, the most highly conserved sub-region within RevSex, called SR4, was neither responsive to sex determining factors in vitro nor active in the gonads of transgenic mice, suggesting that SR4 may not be functioning as a testicular enhancer. Interestingly, SR4 transgenic mice showed reporter activity in the genital tubercle, the primordium of the penis and clitoris, a previously unreported domain of Sox9 expression. SOX9 protein was detected in the genital tubercle, notably in the urethral plate epithelium, preputial glands, ventral surface ectoderm and corpus cavernosa. SR4 may therefore function as a Sox9 genital tubercle enhancer, mutations of which could possibly lead to hypospadias, a birth defect seen in the DSD patients in the RevSex study. SR4 activity and the observed SOX9 expression pattern suggest that SR4 may function as a Sox9 genital tubercle enhancer. However, conditional ablation of Sox9 in the genital tubercle using Shh-Cre/+;Sox9flox/flox mice revealed no genital tubercle abnormalities, possibly due to compensation by similar Sox factors. To conclude, we have identified a novel regulatory enhancer driving Sox9 expression during external genitalia development. PMID- 27989799 TI - Quantum-like model of partially directed evolution. AB - The background of this study is that models of the evolution of living systems are based mainly on the evolution of replicators and cannot explain many of the properties of biological systems such as the existence of the sexes, molecular exaptation and others. The purpose of this study is to build a complete model of the evolution of organisms based on a combination of quantum-like models and models based on partial directivity of evolution. We also used optimal control theory for evolution modeling. We found that partial directivity of evolution is necessary for the explanation of the properties of an evolving system such as the stability of evolutionary strategies, aging and death, the presence of the sexes. The proposed model represents a systems approach to the evolution of species and will facilitate the understanding of the evolution and biology as a whole. PMID- 27989797 TI - Vitamin D receptor agonist VS-105 directly modulates parathyroid hormone expression in human parathyroid cells and in 5/6 nephrectomized rats. AB - Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to treat secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD). Current VDRA therapy often causes hypercalcemia, which is a critical risk for vascular calcification. Previously we have shown that a novel VDRA, VS-105, effectively suppresses serum parathyroid hormone (PTH) without affecting serum calcium levels in 5/6 nephrectomized (NX) uremic rats. However, it is not known whether VS-105 directly regulates PTH gene expression. To study the direct effect of VS-105 on modulating PTH, we tested VS-105 and paricalcitol in the spheroid culture of parathyroid cells from human SHPT patients, and examined the time-dependent effect of the compounds on regulating serum PTH in 5/6 NX uremic rats (i.p. 3x/week for 14days). In human parathyroid cells, VS-105 (100nM) down-regulated PTH mRNA expression (to 3.6% of control) and reduced secreted PTH (to 43.9% of control); paricalcitol was less effective. VS-105 effectively up-regulated the expression of VDR (1.9-fold of control) and CaSR (1.8-fold of control) in spheroids; paricalcitol was also less effective. In 5/6 NX rats, one single dose of 0.05-0.2MUg/kg of VS-105 or 0.02-0.04MUg/kg of paricalcitol effectively reduced serum PTH by >40% on Day 2. Serum PTH remained suppressed during the dosing period, but tended to rebound in the paricalcitol groups. These data indicate that VS-105 exerts a rapid effect on suppressing serum PTH, directly down-regulates the PTH gene, and modulates PTH, VDR and CaSR gene expression more effectively than paricalcitol. PMID- 27989798 TI - Development of immunoaffinity chromatographic method for Ara h 2 isolation. AB - Ara h 2 is considered a major allergen in peanut. Due to the difficulty of separation, Ara h 2 had not been fully studied. Immunoaffinity chromatography (IAC) column can separate target protein with high selectivity, which made it possible to purify Ara h 2 from different samples. In this study, IAC method was developed to purify Ara h 2 and its effect was evaluated. By coupling polyclonal antibody (pAb) on CNBr-activated Sepharose 4B, the column for specific extraction was constructed. The coupling efficiency of the IAC column was higher than 90%, which made the capacity of column reached 0.56 mg per 0.15 g medium (dry weight). The recovery of Ara h 2 ranged from 93% to 100% for different concentrations of pure Ara h 2 solutions in 15 min. After using a column 10 times, about 88% of the column capacity remained. When applied to extract Ara h 2 from raw peanut protein extract and boiled peanut protein extract, the IAC column could recovery 94% and 88% target protein from the mixture. SDS-PAGE and Western blotting analysis confirmed the purified protein was Ara h 2, its purity reached about 90%. Significantly, the IAC column could capture dimer of Ara h 2, which made it feasible to prepared derivative of protein after processing. PMID- 27989800 TI - Next generation sequencing identifies abnormal Y chromosome and candidate causal variants in premature ovarian failure patients. AB - Premature ovarian failure (POF) is characterized by heterogeneous genetic causes such as chromosomal abnormalities and variants in causal genes. Recently, development of techniques made next generation sequencing (NGS) possible to detect genome wide variants including chromosomal abnormalities. Among 37 Korean POF patients, XY karyotype with distal part deletions of Y chromosome, Yp11.32-31 and Yp12 end part, was observed in two patients through NGS. Six deleterious variants in POF genes were also detected which might explain the pathogenesis of POF with abnormalities in the sex chromosomes. Additionally, the two POF patients had no mutation in SRY but three non-synonymous variants were detected in genes regarding sex reversal. These findings suggest candidate causes of POF and sex reversal and show the propriety of NGS to approach the heterogeneous pathogenesis of POF. PMID- 27989801 TI - Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells. AB - Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the core mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used in vivo murine and human tumor models to identify the tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 blocks IGF1 and inhibits expansion and aggresiveness of tumor stem-like cells (TSCs) expressing IGF1 receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R+ TSCs to express FGF4, inducing a feedforward FGFR1-ETS2 angiocrine cascade that obviates TEC IGFBP7. Thus, loss of IGFBP7 and upregulation of IGF1 activates the FGF4-FGFR1-ETS2 pathway in TECs and converts naive tumor cells to chemoresistant TSCs, thereby facilitating their invasiveness and progression. PMID- 27989803 TI - Folic Acid Production by Engineered Ashbya gossypii. AB - Folic acid (vitamin B9) is the common name of a number of chemically related compounds (folates), which play a central role as cofactors in one-carbon transfer reactions. Folates are involved in the biosynthesis and metabolism of nucleotides and amino acids, as well as supplying methyl groups to a broad range of substrates, such as hormones, DNA, proteins, and lipids, as part of the methyl cycle. Humans and animals cannot synthesize folic acid and, therefore, need them in the diet. Folic acid deficiency is an important and underestimated problem of micronutrient malnutrition affecting billions of people worldwide. Therefore, the addition of folic acid as food additive has become mandatory in many countries thus contributing to a growing demand of the vitamin. At present, folic acid is exclusively produced by chemical synthesis despite its associated environmental burdens. In this work, we have metabolically engineered the industrial fungus Ashbya gossypii in order to explore its potential as a natural producer of folic acid. Overexpression of FOL genes greatly enhanced the synthesis of folates and identified GTP cyclohydrolase I as the limiting step. Metabolic flux redirection from competing pathways also stimulated folic acid production. Finally, combinatorial engineering synergistically increased the production of different bioactive forms of the folic vitamin. Overall, strains were constructed which produce 146-fold (6595ug/L) more vitamin than the wild-type and by far represents the highest yield reported. PMID- 27989792 TI - Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. AB - Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre clinical models of PH, while traditional high-nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate- and nitrite-based therapeutics for PH, CVD and their risk factors. PMID- 27989804 TI - Metabolic engineering of cyanobacteria for the photosynthetic production of succinate. AB - Succinate is an important commodity chemical currently used in the food, pharmaceutical, and polymer industries. It can also be chemically converted into other major industrial chemicals such as 1,4-butanediol, butadiene, and tetrahydrofuran. Here we metabolically engineered a model cyanobacterium Synechococcus elongatus PCC 7942 to photosynthetically produce succinate. We expressed the genes encoding for alpha-ketoglutarate decarboxylase and succinate semialdehyde dehydrogenase in S. elongatus PCC 7942, resulting in a strain capable of producing 120mg/L of succinate. However, this recombinant strain exhibited severe growth retardation upon induction of the genes encoding for the succinate producing pathway, potentially due to the depletion of alpha ketoglutarate. To replenish alpha-ketoglutarate, we expressed the genes encoding for phosphoenolpyruvate carboxylase and citrate synthase from Corynebacterium glutamicum into the succinate producing strain. The resulting strain successfully restored the growth phenotype and produced succinate with a titer of 430mg/L in 8 days. These results demonstrated the possibility of photoautotrophic succinate production. PMID- 27989802 TI - Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. AB - Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention. PMID- 27989806 TI - Engineering electron metabolism to increase ethanol production in Clostridium thermocellum. AB - The NfnAB (NADH-dependent reduced ferredoxin: NADP+ oxidoreductase) and Rnf (ion translocating reduced ferredoxin: NAD+ oxidoreductase) complexes are thought to catalyze electron transfer between reduced ferredoxin and NAD(P)+. Efficient electron flux is critical for engineering fuel production pathways, but little is known about the relative importance of these enzymes in vivo. In this study we investigate the importance of the NfnAB and Rnf complexes in Clostridium thermocellum for growth on cellobiose and Avicel using gene deletion, enzyme assays, and fermentation product analysis. The NfnAB complex does not seem to play a major role in metabolism, since deletion of nfnAB genes had little effect on the distribution of fermentation products. By contrast, the Rnf complex appears to play an important role in ethanol formation. Deletion of rnf genes resulted in a decrease in ethanol formation. Overexpression of rnf genes resulted in an increase in ethanol production of about 30%, but only in strains where the hydG hydrogenase maturation gene was also deleted. PMID- 27989805 TI - Engineering a functional 1-deoxy-D-xylulose 5-phosphate (DXP) pathway in Saccharomyces cerevisiae. AB - Isoprenoids are used in many commercial applications and much work has gone into engineering microbial hosts for their production. Isoprenoids are produced either from acetyl-CoA via the mevalonate pathway or from pyruvate and glyceraldehyde 3 phosphate via the 1-deoxy-D-xylulose 5-phosphate (DXP) pathway. Saccharomyces cerevisiae exclusively utilizes the mevalonate pathway to synthesize native isoprenoids and in fact the alternative DXP pathway has never been found or successfully reconstructed in the eukaryotic cytosol. There are, however, several advantages to isoprenoid synthesis via the DXP pathway, such as a higher theoretical yield, and it has long been a goal to transplant the pathway into yeast. In this work, we investigate and address barriers to DXP pathway functionality in S. cerevisiae using a combination of synthetic biology, biochemistry and metabolomics. We report, for the first time, functional expression of the DXP pathway in S. cerevisiae. Under low aeration conditions, an engineered strain relying solely on the DXP pathway for isoprenoid biosynthesis achieved an endpoint biomass 80% of that of the same strain using the mevalonate pathway. PMID- 27989807 TI - Overcoming the membrane barrier: Recruitment of gamma-glutamyl transferase for intracellular release of metabolic cargo from peptide vectors. AB - Semipermeable membranes of cells frequently pose an obstacle in metabolic engineering by limiting uptake of substrates, intermediates, or xenobiotics. Previous attempts to overcome this barrier relied on the promiscuous nature of peptide transport systems, but often suffered from low versatility or chemical instability. Here, we present an alternative strategy to transport cargo molecules across the inner membrane of Escherichia coli based on chemical synthesis of a stable cargo-peptide vector construct, transport through the peptide import system, and efficient intracellular release of the cargo by the promiscuous enzyme gamma-glutamyl transferase (GGT). Retaining the otherwise periplasmic GGT in the cytoplasm was critical for the functionality of the system, as was fine-tuning its expression in order to minimize toxic effects associated to cytoplasmic GGT expression. Given the established protocols of peptide synthesis and the flexibility of peptide transport and GGT, the system is expected to be suitable for a broad range of cargoes. PMID- 27989808 TI - Assessment of Synthetic Glue for Mesh Attachment in Laparoscopic Sacrocolpopexy: A Prospective Multicenter Pilot Study. AB - STUDY OBJECTIVE: To assess the anatomic efficacy and safety of synthetic glue to fix prosthetic material in laparoscopic sacrocolpopexy. DESIGN: A 1-year follow up in a prospective multicenter pilot study between November 2013 and November 2014 (Canadian Task Force Classification II-2). SETTING: An academic urogynecology research hospital. PATIENTS: Seventy consecutive patients with Pelvic Organ Prolapse Quantification stage >=3 anterior and/or medial prolapse underwent laparoscopic sacrocolpopexy. INTERVENTIONS: All women underwent laparoscopic sacrocolpopexy with the same standardized technique using a synthetic surgical glue to fix anterior and posterior meshes. MEASUREMENTS AND MAIN RESULTS: Patients were followed up at 1 month and 1 year, with anatomic and functional assessment (Pelvic Floor Distress Inventory-20, Pelvic Floor Impact Questionnaire-7, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12). Anatomic success was defined as 1-year Pelvic Organ Prolapse Quantification stage <=1. Sixty-six patients were included; the mean age was 56.7 +/- 1.2 years. The mean operative time was 145 +/- 5 minutes. The mean glue fixation time was less than 2 minutes for both anterior and posterior meshes. The 1-year anatomic success rate was 87.5% in the anterior compartment (Ba at -2.3 cm, p < .0001) and 95.3% in the medial compartment (point C at -6.1 cm, p < .0001). There were no intra- or postoperative complications and no cases of mesh exposure; 5 cases of mesh shrinkage (7.8%) were observed at 1 year. The postoperative urinary stress incontinence rate was 29.7% at 1 year. Eight patients (12.1%) underwent revision surgery with transobturator tape. All quality of life scores showed significant improvement (p < .0001) at 1 year. CONCLUSION: Synthetic glue attachment of prosthetic material in laparoscopic sacrocolpopexy proved straightforward, safe, time-saving, and effective at 1 year. Prospective randomized studies will be needed to confirm the long-term benefit. PMID- 27989809 TI - Molecular Innovations in Sentinel Lymph Node Evaluation: Moving Beyond Radiotracers and Colored Dyes. PMID- 27989810 TI - Needleoscopic Conservative Staging of Borderline Ovarian Tumor. AB - STUDY OBJECTIVE: To investigate the safety and technical feasibility of needleoscopic fertility-sparing staging of borderline ovarian tumors. DESIGN: Video article and review of the literature (Canadian Task Force classification Level III). SETTING: This 29-year-old woman had a right ovarian cyst suspicious for borderline ovarian tumor on preoperative magnetic resonance imaging and ultrasound showing the presence of a right unilocular ovarian cyst with a papillary projection. Informed consent for abdominal or laparoscopic approach was obtained from the patient in accordance with the local legislation. The patient also provided informed consent to use images and videos of the procedure. Institutional Review Board approval was not required for this kind of procedure. INTERVENTIONS: Treatment involved conservative staging with right ovarian cystectomy, peritoneal biopsies, infracolic omental biopsy, and peritoneal cytology. Instrumentation included two 2.4-mm needleoscopic instruments. The total operative time was 62 minutes, and estimated blood loss was <10 mL. No intraoperative complications were recorded. At the end of the surgical procedure, the outer diameter of the incision was increased by only up to 3 mm. The patient was discharged the day after the procedure. Histopathological analysis confirmed a serous borderline ovarian tumor. A 30 days postoperative follow-up, a satisfactory cosmetic result was reported by both the patient (score of 10 of out of a possible 10) and the surgeon (10 of 10). CONCLUSION: To the best of our knowledge, there are no previously published reports of needleoscopic treatment of borderline ovarian tumor, which represents a great challenge for ultra minimally invasive approaches [1-3]. Based on our initial experience, the needleoscopic instruments could prove to be a beneficial tool in adnexal benign or borderline disease. At present, only a hybrid operative setting should be considered to overcome the lack of bipolar energy [4-6]. Further studies are needed to define the benefits, advantages, and costs of this novel approach. PMID- 27989816 TI - Extractive text summarization system to aid data extraction from full text in systematic review development. AB - OBJECTIVES: Extracting data from publication reports is a standard process in systematic review (SR) development. However, the data extraction process still relies too much on manual effort which is slow, costly, and subject to human error. In this study, we developed a text summarization system aimed at enhancing productivity and reducing errors in the traditional data extraction process. METHODS: We developed a computer system that used machine learning and natural language processing approaches to automatically generate summaries of full-text scientific publications. The summaries at the sentence and fragment levels were evaluated in finding common clinical SR data elements such as sample size, group size, and PICO values. We compared the computer-generated summaries with human written summaries (title and abstract) in terms of the presence of necessary information for the data extraction as presented in the Cochrane review's study characteristics tables. RESULTS: At the sentence level, the computer-generated summaries covered more information than humans do for systematic reviews (recall 91.2% vs. 83.8%, p<0.001). They also had a better density of relevant sentences (precision 59% vs. 39%, p<0.001). At the fragment level, the ensemble approach combining rule-based, concept mapping, and dictionary-based methods performed better than individual methods alone, achieving an 84.7% F-measure. CONCLUSION: Computer-generated summaries are potential alternative information sources for data extraction in systematic review development. Machine learning and natural language processing are promising approaches to the development of such an extractive summarization system. PMID- 27989817 TI - Evaluating common data models for use with a longitudinal community registry. AB - OBJECTIVE: To evaluate common data models (CDMs) to determine which is best suited for sharing data from a large, longitudinal, electronic health record (EHR)-based community registry. MATERIALS AND METHODS: Four CDMs were chosen from models in use for clinical research data: Sentinel v5.0 (referred to as the Mini Sentinel CDM in previous versions), PCORnet v3.0 (an extension of the Mini Sentinel CDM), OMOP v5.0, and CDISC SDTM v1.4. Each model was evaluated against 11 criteria adapted from previous research. The criteria fell into six categories: content coverage, integrity, flexibility, ease of querying, standards compatibility, and ease and extent of implementation. RESULTS: The OMOP CDM accommodated the highest percentage of our data elements (76%), fared well on other requirements, and had broader terminology coverage than the other models. Sentinel and PCORnet fell short in content coverage with 37% and 48% matches respectively. Although SDTM accommodated a significant percentage of data elements (55% true matches), 45% of the data elements mapped to SDTM's extension mechanism, known as Supplemental Qualifiers, increasing the number of joins required to query the data. CONCLUSION: The OMOP CDM best met the criteria for supporting data sharing from longitudinal EHR-based studies. Conclusions may differ for other uses and associated data element sets, but the methodology reported here is easily adaptable to common data model evaluation for other uses. PMID- 27989818 TI - The binuclear form of dinitrosyl iron complexes with thiol-containing ligands in animal tissues. AB - It has been established that treatment of mice with sodium nitrite, S nitrosoglutathione and the water-soluble nitroglycerine derivative isosorbide dinitrate (ISDN) as NO donors initiates in vivo synthesis of significant amounts of EPR-silent binuclear dinitrosyl iron complexes (B-DNIC) with thiol-containing ligands in the liver and other tissues of experimental mice. This effect is especially apparent if NO donors are administered to mice simultaneously with the Fe2+-citrate complex. Similar results were obtained in experiments on isolated liver and other mouse tissues treated with gaseous NO in vitro and during stimulation of endogenous NO synthesis in the presence of inducible NO synthase. B-DNIC appeared in mouse tissues after in vitro treatment of tissue samples with an aqueous solution of diethyldithiocarbamate (DETC), which resulted in the transfer of iron-mononitrosyl fragments from B-DNIC to the thiocarbonyl group of DETC and the formation of EPR-detectable mononitrosyl iron complexes (MNIC) with DETC. EPR-Active MNIC with N-methyl-d-glucamine dithiocarbamate (MGD) were synthesized in a similar way. MNIC-MGD were also formed in the reaction of water soluble MGD-Fe2+ complexes with sodium nitrite, S-nitrosoglutathione and ISDN. PMID- 27989819 TI - Detachment of the fucoxanthin chlorophyll a/c binding protein (FCP) antenna is not involved in the acclimative regulation of photoprotection in the pennate diatom Phaeodactylum tricornutum. AB - When grown under intermittent light (IL), the pennate diatom Phaeodactylum tricornutum forms 'super' non-photochemical fluorescence quenching (NPQ) in response to excess light. The current model of diatom NPQ mechanism involves two quenching sites, one of which detaches from photosystem II reaction centres (RCIIs) and aggregates into oligomeric complexes. Here we addressed how antenna reorganisation controls NPQ kinetics in P. tricornutum cells grown under continuous light (CL) and IL. Overall, IL acclimation induced: (i) reorganisation of chloroplasts, containing greater pigment pools without a strongly enhanced operation of the xanthophyll cycle, and (ii) 'super NPQ' causing a remarkable reduction of the chlorophyll excited state lifetime at Fm'. Regardless of different levels of NPQ formed in both culture conditions, its dark recovery was rapid and similar fractions of their antenna uncoupled (~50%). Although antenna detachment relieved excitation pressure, it provided a minor protective contribution equivalent to NPQ~1, while the largest NPQ was 4.4+/-0.2 (CL) and 13+/-0.8 (IL). The PSII cross-section decrease took place only at relatively low NPQ values, beyond which the cross-section remained constant whilst NPQ continued to rise. This finding suggests that the energy trapping efficiency of diatom antenna quenchers cannot over-compete that of RCIIs, similarly to what has been observed on higher plants. We conclude that such 'economic photoprotection' operates to flexibly adjust the overall efficiency of diatom light harvesting. PMID- 27989820 TI - In-situ single pass intestinal permeability and pharmacokinetic study of developed Lumefantrine loaded solid lipid nanoparticles. AB - The present investigation aims to develop lumefantrine loaded binary solid lipid nanoparticles (LF-SLNs) to improve its poor and variable oral bioavailability. The oral bioavailability of LF is poor and variable due to its limited aqueous solubility and P-gp mediated efflux occurring in small intestine. LF-SLNs were prepared using binary lipid mixture of stearic acid and caprylic acid stabilized with TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate) and Poloxamer 188. Developed LF-SLNs were characterized for particle size distribution, zeta potential, entrapment efficiency, solid state properties and biopharmaceutical properties including in situ intestinal permeability and oral bioavailability. The particle size distribution, zeta potential and entrapment efficiency of optimized batch (LF-SLN7) was found to be 357.7+/-43.27nm, 25.29+/-1.15mV and 97.35+/-0.30%, respectively. DSC thermographs showed loss of crystalline nature of lumefantrine in LF-SLNs. In situ single pass intestinal permeability study (SPIP) study indicated significant enhancement in the effective intestinal permeability of LF from LF-SLN7 as compared to that of control. Pharmacokinetic study also showed significant increase in Cmax and area under curve (AUC0 infinity) from LF-SLN7 (3860+/-521ng/mL and 43181+/-2557h*ng/mL, respectively) as compared to that of LF-control suspension (1425+/-563ng/mL and 19586+/ 1537h*ng/mL, respectively). Thus, developed LF-SLNs can be promising to overcome P-gp efflux pump and enhance the oral bioavailability of lumefantrine. PMID- 27989821 TI - Biocompatibility and drug release behavior of curcumin conjugated gold nanoparticles from aminosilane-functionalized electrospun poly(N-vinyl-2 pyrrolidone) fibers. AB - Curcumin (CUR) has a wide spectrum of biological and pharmacological activities, yet problems of its bioavailability remained a major challenge in preclinical studies. Thus, the design of the delivery systems with CUR as a model drug featuring dual release process - an initial burst followed by sustained release - to provide the optimal drug pharmacokinetics in the therapeutic region has been actively pursued. In this study, the 3-aminopropyltriethoxysilane (APTES) functionalized electrospun poly(N-vinyl-2-pyrrolidone) fibers (NH2-PVP) were utilized as a free-standing substrate for the immobilization of CUR-PVP capped gold nanoparticles (CUR-PGNPs) conjugates. The conjugate was synthesized by sonication and the drug entrapment percentage was determined to be 54.2 +/-1.8. CUR-PGNPs immobilized on NH2-PVP fibers showed a moderate burst release during the first few hours, followed by a sustained release lasting for 2days. The drug release was found pH-dependent (pH 5.0>6.0>7.4). The two-stage release profiles of CUR-PGNPs@NH2-PVP fibers were fitted well to Korsmeyer-Peppas model, indicating a non-Fickian diffusion mechanism for initial burst release and Fickian diffusion-controlled mechanism for the sustained release. Initial biocompatibility assessments based on lactate dehydrogenase (LDH) assay and morphological examination by SEM with L-929 mouse fibroblasts revealed that CUR PGNPs@NH2-PVP nanofibrous scaffold was capable of supporting cell growth over a culture period of 3days. PMID- 27989822 TI - gamma-Cyclodextrin. AB - gamma-Cyclodextrin (gammaCD) is a cyclic oligosaccharide formed by bacterial digestion of starch and used as solubilizing agent and stabilizer in a variety of pharmaceutical and food products. gammaCD is a large (molecular weight 1297Da) hydrophilic molecule that does not readily permeate biological membranes and is rapidly digested by bacteria in the gastrointestinal tract. In humans gammaCD is metabolized by alpha-amylase that is found in, for example, saliva, bile fluid and tears. Thus, bioavailability of gammaCD is negligible. Also, gammaCD is readily excreted unchanged in the urine after parenteral administration. Like other cyclodextrins, gammaCD can form water-soluble inclusion complexes with many poorly-soluble compounds. In comparison with the natural alphaCD and betaCD, gammaCD has the largest hydrophobic cavity, highest water solubility and the most favorable toxicological profile. The focus of this review is production, physiochemical properties, pharmacokinetics, toxicity and applications of gammaCD and its derivatives. Also, the aggregation behavior of gammaCD in aqueous media is discussed. PMID- 27989823 TI - Porous microscaffolds for 3D culture of dental pulp mesenchymal stem cells. AB - The collective power of stem cells due to their evident advantages is incessantly investigated in regenerative medicine to be the next generation exceptional remedy for tissue regeneration and treatment of diseases. Stem cells are highly sensitive and a 3D culture environment is a requisite for its successful transplantation and integration with tissues. Porous microscaffolds can create a 3D microenvironment for growing stems cells, controlling their fate both in vitro and in vivo. In the present study, interconnected porous PLGA microscaffolds were fabricated, characterized and employed to propagate human dental pulp mesenchymal stem cells (DPMSCs) in vitro. The porous topography was investigated by scanning electron microscopy and the pore size was controlled by fabrication conditions such as the concentration of porogen. DPMSCs were cultured on microscaffolds and were evaluated for their morphology, attachment, proliferation, cell viability via MTT and molecular expression (RT-PCR). DPMSCs were adequately proliferated and adhered over the microscaffolds forming a 3D cell-microscaffold construct. The average number of DPMSCs grown on PLGA microscaffolds was significantly higher than monolayer 2D culture during 5th and 7th day. Moreover, cell viability and gene expression results together corroborated that microscaffolds maintained the viability, stemness and plasticity of the cultured dental pulp mesenchymal stem cells. The novel porous microscaffold developed acts as promising scaffold for 3D culture and survival and transplantation of stem cells for tissue engineering. PMID- 27989824 TI - Rapid and cost-effective xenograft hepatocellular carcinoma model in Zebrafish for drug testing. AB - We developed a novel, rapid and cost-effective Zebrafish xenograft model of hepatocellular carcinoma (HCC) for drug screening in the disease. Following injection into the yolk sack of Zebrafish larvae of the human HCC cell line JHH6 stained by a vital dye, tumor mass growth was followed by fluorescence microscopy and by human Ki67 quantification. Tumor induced neo-angiogenesis was evaluated by alkaline phosphatase staining of the vessels, by using the Tg(fli1:EGFP)y1 strain of Zebrafish and by the quantification of the zebrafish vascular endothelial growth factor and of its receptor. We show that it is feasible to micro-inject JHH6 in Zebrafish larvae, that injected cells can grow for different days and that this induces a marked neo-angiogenesis. Finally, we show that our model allows testing the effects of anti-HCC drugs such as Bortezomib. Compared to more complex HCC mouse models, our model is far less expensive, faster to set up and does not need immunosuppressant treatment. Finally, the model makes use of JHH6, an aggressive form of HCC cell line never tested before in Zebrafish. In conclusion, the possibility to test anti HCC/neo-angiogenesis drugs makes our JHH6 model useful to select therapeutic molecules for a highly vascularized tumor such as HCC. PMID- 27989826 TI - Development and optimization of self-assembling nanosystem for intra-articular delivery of indomethacin. AB - Osteoarthritis is a propagated debilitating condition affecting patients' quality of life. Intra-articular injection approach was investigated as a localized treatment strategy providing: site-specific delivery, decreased side effects and, increased patient compliance. A 32 full factorial experimental design was employed to prepare the indomethacin-loaded self-assembling nanosystems (SANS). The surfactant (Poloxamer 407/Tetronic 90R4) ratio and the poly(lactic-co glycolic acid) (PLGA) concentration significantly affected encapsulation efficiency and drug release (p<0.05). The optimized formula was subjected to modification by addition of different proteoglycans, as a compensatory treatment, to improve its pharmacological properties. The modified SANS, containing glucosamine (150mg), was selected for in-vivo studies as it had a sustained drug release profile and a small particle size (173.90nm). The effect of the optimized SANS, with or without PLGA, was compared with the modified formula containing glucosamine and, with the drug suspension on the arthritic knee joints of rats. It was found that the formulation containing PLGA and glucosamine showed significantly higher reduction in both, knee diameter and TNF-alpha levels, compared to other groups. Furthermore, all SANS showed histological improvement in the cellularity of the synovial membranes and joints. Our results indicate that SANS containing PLGA and glucosamine is capable of treating arthritic joints. PMID- 27989825 TI - Specific targeting delivery to MUC1 overexpressing tumors by albumin-chitosan nanoparticles conjugated to DNA aptamer. AB - Chitosan-coated human serum albumin nanoparticles were functionalized by MUC1 aptamer to obtain a selective drug carrier toward cancers overexpressing MUC1. The negative charges of albumin nanoparticles were shifted to positive charges by surface modification with chitosan, and MUC1 was conjugated through an acrylate spacer. The cytotoxicity of targeted nanoparticles was significantly more than non-aptamer nanoparticles, and also the chitosan-coated nanoparticles had more cytotoxic effects than the negatively charged albumin nanoparticles. The IC50 of targeted nanoparticles was 28 and 26% of free paclitaxel in MCF7 and T47D cells at 48h, respectively. Confocal laser scanning electron microscopy showed that aptamer conjugation and positive charge increase the cellular uptake. 66% of paclitaxel was released within 32h, but 100% of drug was released at pH=5.5 (similar cancer cells). The paclitaxel plasma amount was at a good level of 17.6% at 2h for increasing the chance of cellular uptake. PMID- 27989827 TI - Induction of a balanced Th1/Th2 immune responses by co-delivery of PLGA/ovalbumin nanospheres and CpG ODNs/PEI-SWCNT nanoparticles as TLR9 agonist in BALB/c mice. AB - To develop effective and safe vaccines with reduced dose of antigen and adjuvant, intelligent delivery systems are required. Many delivery systems have been developed to enhance the biological activity of cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODN) as both immunotherapeutic agents and vaccine adjuvants. In this study we designed a novel CpG ODN delivery system based on single-walled carbon nanotube (SWCNT) functionalized with polyethylenimine (PEI) and alkylcarboxylated PEI (AL-PEI). The physicochemical characteristics, cytotoxicity and cellular uptake studies of these carriers were performed. All carriers were conjugated with CpG ODN followed by co-delivery with ovalbumin (OVA) encapsulated into poly (lactic-co-glycolic acid) nanospheres (PLGA NSs) to enhance the induction of immune responses. The effect of these formulations on antibody (IgG1, IgG2a) and cytokine (IL-1beta, IFN-gamma, IL-4) production was evaluated in an in vivo experiment. The results showed that all nano-adjuvant formulations had a strong influence in up-regulation of IFN-gamma and IL-4 in parallel with high IgG1-IgG2a isotype antibody titers in mice. In particular, SWCNT-AL-PEI nano-adjuvant formulation generated a balanced Th1 and Th2 immune response with more biased toward Th1 response without exhibiting any inflammatory and toxic effects. Therefore this nano-adjuvant formulation could be used as an efficient prophylactic immune responses agent. PMID- 27989828 TI - Where does hydrolysis of nandrolone decanoate occur in the human body after release from an oil depot? AB - Long-term therapy of nandrolone (N) is recommended to increase mineral density and muscle strength. Using a parenteral sustained release drug formulation with nandrolone decanoate (ND), therapeutic N levels can be achieved and maintained. Until now, it is unknown if hydrolysis of ND into N occurs in tissue at the injection site or after systemic absorption. Therefore, hydrolysis studies were conducted to investigate the location and rate of ND hydrolysis after its release from the oil depot. ND hydrolysis was studied in porcine tissues, to mimic the human muscular and subcutaneous tissues. Additionally, the ND hydrolysis was studied in human whole blood, plasma and serum at a concentration range of 23.3 233.3MUM. ND hydrolysis only occurred in human whole blood. The hydrolysis did not start immediately, but after a lag time. The mean lag time for all studied concentrations was 34.9+/-2.5min. Because of a slow penetration into tissue, hydrolysis of ND is found to be very low in surrounding tissue. Therefore the local generation of the active compound is clinically irrelevant. It is argued that after injection of the oil depot, ND molecules will be transported via the lymphatic system towards lymph nodes. From here, it will enter the central circulation and within half an hour it will hydrolyse to the active N compound. PMID- 27989829 TI - Osmolality of antisense oligonucleotide parenteral formulations: Implications on counterion dissociation and recommended osmometry techniques. AB - The intrinsic osmolality of aqueous solutions of sodium salt antisense oligonucleotides (ASOs) has been studied to inform formulation practices, understand the molecular basis underlying the difference between theoretical and empirical results, and determine suitable measurement methods. It was found that regardless of nucleotide sequence, ASO concentration of ~140mg/mL has isotonic osmolality of ~290mOsm/kg water (SI unit: mmol osmotically-active particles/kg water), such that lower concentration formulations require excipients for tonicity adjustment. The range of osmolality values at a given active ingredient concentration can be ascribed to drug substance lot-to-lot purity differences impacting total oligonucleotide content (i.e., including oligonucleotide-related impurities). Empirical osmolality measurements were found to be ~70% of theoretical values, which corresponds to an osmotic coefficient value of ~0.7, thus inferring incomplete counterion dissociation. When comparing theoretical (ideal) osmolality of multiple sequences with various nucleotide compositions and chemistries at the same w/v concentration, the "average osmolar mass" (molar mass of the oligonucleotide, including the sodium counterions, divided by the ideal Van't Hoff factor, iid) appears to be the strongest factor governing theoretical osmolality values. Other factors examined were the sequence length, backbone chemistry, 2' sugar chemistry, and nucleotide composition. A head-to-head comparison between two osmolality techniques showed that vapor pressure osmometry is generally more suitable than freezing point osmometry for oligonucleotide solutions greater than ~150mg/mL due to viscosity effects, but the two techniques are comparable otherwise. PMID- 27989830 TI - Hydrogel based approaches for cardiac tissue engineering. AB - Heart failure still represents the leading cause of death worldwide. Novel strategies using stem cells and growth factors have been investigated for effective cardiac tissue regeneration and heart function recovery. However, some major challenges limit their translation to the clinic. Recently, biomaterials have emerged as a promising approach to improve delivery and viability of therapeutic cells and proteins for the regeneration of the damaged heart. In particular, hydrogels are considered one of the most promising vehicles. They can be administered through minimally invasive techniques while maintaining all the desirable characteristics of drug delivery systems. This review discusses recent advances made in the field of hydrogels for cardiac tissue regeneration in detail, focusing on the type of hydrogel (conventional, injectable, smart or nano and micro-gel), the biomaterials used for its manufacture (natural, synthetic or hybrid) and the therapeutic agent encapsulated (stem cells or proteins). We expect that these novel hydrogel-based approaches will open up new possibilities in drug delivery and cell therapies. PMID- 27989831 TI - Subtype distribution of Blastocystis spp. isolated from children in Eskisehir, Turkey. AB - Blastocystis spp. is the most common enteric protist found in human feces. The pathogenic role of Blastocystis remains controversial and it has been suggested that the symptomatology of Blastocystis is associated with its subtypes (ST). However, only few studies have investigated the relationship between the symptomatology and subtypes of Blastocystis in children. This study aimed to investigate the prevalence of Blastocystis in children aged 3 to 13years with or without gastrointestinal complaints and determine the distribution of the subtypes of Blastocystis. A total of 303 stool samples obtained from symptomatic (n=84) and asymptomatic (n=219) children were included in the study. The presence of Blastocystis was investigated using native-lugol examination, trichrome staining and real-time PCR method. Using the real-time PCR method, 115 samples were found positive for Blastocystis. Subtyping was successfully performed on 46 samples using sequenced-tagged site (STS) primers and PCR. The remaining 69 samples could not be subtyped. The most frequently detected subtype was ST3 (43.4%) followed by ST1 (26.1%), ST4 (10.9%) and ST2 (8.7%). The mixed subtypes were identified in five samples (10.9%) as; ST1+ST3 (n=3), ST1+ST2 (n=1) and ST2+ST3 (n=1). None of the samples had ST5, ST6 or ST7. No statistically significant difference was found between the symptomatic and asymptomatic groups in terms of the Blastocystis positivity and the distribution of subtypes (p>0.05). To our knowledge, this is the first study to investigate the subtype distribution of Blastocystis in children in Turkey and the results are in agreement with the related data available in Turkey. PMID- 27989833 TI - Identification and characterization of protein 14-3-3 in carcinogenic liver fluke Opisthorchis viverrini. AB - Protein 14-3-3s are abundant phospho-serine/threonine binding proteins, which are highly conserved among eukaryotes. Members of this protein family mediate metabolism and signal transduction networks through binding to hundreds of other protein partners. Protein 14-3-3s have been studied in other species of parasitic helminthes, but little is known about this protein in the carcinogenic liver fluke Opisthorchis viverrini. In this study, we identified and characterized protein 14-3-3s of O. viverrini. Seven protein 14-3-3 encoded sequences were retrieved from the O. viverrini genome database. Multiple alignment and phylogenetic analysis were performed. Two isoforms (protein 14-3-3 zeta and protein 14-3-3 epsilon) that have been previously found in the excretory secretory (ES) products of O. viverrini were produced as recombinant protein in E. coli and the proteins were then used to immunize mice to obtain specific antibodies. Western blot analysis showed that both proteins were detected in all obtainable developmental stages of O. viverrini and the ES products. Immunolocalization revealed that both isoforms were expressed throughout tissues and organs except the gut epithelium. The highest expression was observed in testes especially in developing spermatocytes, suggesting their role in spermatogenesis. Prominent expression was also detected on tegumental surface of the parasite and on epical surface of bile duct epithelium indicates their additional role in host-parasite interaction. These findings indicate that protein 14-3-3s play important role in the life cycle of the parasite and might be involved in the pathogenesis of O. viverrini infection. PMID- 27989834 TI - miR-276 and miR-3016-modulated expression of acetyl-CoA carboxylase accounts for spirotetramat resistance in Aphis gossypii Glover. AB - Acetyl-coenzyme A carboxylase (acetyl-CoA carboxylase, ACC) catalyses the carboxylation of acetyl-CoA to produce malonyl-CoA during de novo fatty acid synthesis. A laboratory-selected spirotetramat-resistant strain (SR) of cotton aphid was used in this study. RT-qPCR results demonstrated significant increases in the levels of ACC transcript in the resistant strain compared to the susceptible strain. Depletion of overexpressed ACC transcripts by RNAi also significantly enhanced the sensitivity of the resistant aphid to spirotetramat. We hypothesized that ACC gene expression is subject to post-transcriptional regulation. To investigate the underlying mechanism, the 66 known miRNAs of Aphis gossypii were used for target prediction, eight of which were predicted to target ACC. Validation identified two miRNAs, miR-276 and miR-3016, with abundance levels that were highly inversely correlated with ACC transcript levels. This result suggests that the miRNAs miR-276 and miR-3016 may play major roles in the post-transcriptional regulation of the ACC gene. Modulation of the abundance of miR-276 and miR-3016 through addition of inhibitors/mimics of miR-276 or miR-3016 to the artificial diet significantly altered both ACC transcript levels and the tolerance of A. gossypii to spirotetramat, thus confirming the roles of these two miRNAs in the regulation of spirotetramat resistance. PMID- 27989837 TI - Prophenoloxidase activation and antimicrobial peptide expression induced by the recombinant microbe binding protein of Manduca sexta. AB - Manduca sexta microbe binding protein (MBP) is a member of the beta-1,3-glucanase related protein superfamily that includes Gram-negative bacteria-binding proteins (GNBPs), beta-1,3-glucan recognition proteins (betaGRPs), and beta-1,3 glucanases. Our previous and current studies showed that the purified MBP from baculovirus-infected insect cells had stimulated prophenoloxidase (proPO) activation in the hemolymph of naive and immune challenged larvae and that supplementation of the exogenous MBP and peptidoglycans (PGs) had caused synergistic increases in PO activity. To explore the underlying mechanism, we separated by SDS-PAGE naive and induced larval plasma treated with buffer or MBP and detected on immunoblots changes in intensity and/or mobility of hemolymph (serine) proteases [HP14, HP21, HP6, HP8, proPO-activating proteases (PAPs) 1-3] and their homologs (SPH1, SPH2). In a nickel pull-down assay, we observed association of MBP with proHP14 (slightly), betaGRP2, PG recognition protein-1 (PGRP1, indirectly), SPH1, SPH2, and proPO2. Further experiments indicated that diaminopimelic acid (DAP) or Lys PG, MBP, PGRP1, and proHP14 together trigger the proPO activation system in a Ca2+-dependent manner. Injection of the recombinant MBP into the 5th instar naive larvae significantly induced the expression of several antimicrobial peptide genes, revealing a possible link between HP14 and immune signal transduction. Together, these results suggest that the recognition of Gram-negative or -positive bacteria via their PGs induces the melanization and Toll pathways in M. sexta. PMID- 27989838 TI - Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4 methylenedioxy-methamphetamine (MDMA) exposure. AB - The recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has been shown to produce neurotoxic damage and long-lasting changes in several brain areas. In addition to the involvement of serotoninergic and dopaminergic systems, little information exists about the contribution of nociceptin/orphaninFQ (N/OFQ) NOP and dynorphin (DYN)-KOP systems in neuronal adaptations evoked by MDMA. Here we investigated the behavioral and molecular effects induced by acute (8mg/kg) or repeated (8mg/kg twice daily for seven days) MDMA exposure. MDMA exposure affected body weight gain and induced hyperlocomotion; this latter effect progressively decreased after repeated administration. Gene expression analysis indicated a down-regulation of the N/OFQ system and an up-regulation of the DYN system in the nucleus accumbens (NAc), highlighting an opposite systems regulation in response to MDMA exposure. Since histone modifications have been strongly associated to the addiction-related maladaptive changes, we examined two permissive (acH3K9 and me3H3K4) and two repressive transcription marks (me3H3K27 and me2H3K9) at the pertinent opioid gene promoter regions. Chromatin immunoprecipitation assays revealed that acute MDMA increased me3H3K4 at the pN/OFQ, pDYN and NOP promoters. Following acute and repeated treatment a significant decrease of acH3K9 at the pN/OFQ promoter was observed, which correlated with gene expression results. Acute treatment caused an acH3K9 increase and a me2H3K9 decrease at the pDYN promoter which matched its mRNA up regulation. Our data indicate that the activation of the DYNergic stress system together with the inactivation of the N/OFQergic anti-stress system contribute to the neuroadaptive actions of MDMA and offer novel epigenetic information associated with MDMA abuse. PMID- 27989839 TI - Cilostazol and enzymatically modified isoquercitrin attenuate experimental colitis and colon cancer in mice by inhibiting cell proliferation and inflammation. AB - We previously reported the anti-inflammatory effects of cilostazol, a selective inhibitor of phosphodiesterase 3, and two antioxidants, enzymatically modified isoquercitrin and alpha-lipoic acid in a dextran sodium sulphate-induced colitis mouse model. We further examined the chemopreventive effects of these substances in a murine azoxymethane/dextran sodium sulphate -induced colorectal carcinoma model and compared the effects with those of the well-known anticancer natural plant pigment, anthocyanin. In addition, the effects on cell proliferation activity were evaluated in colon cancer cell lines and mucosal epithelial cells in a model of acute dextran sodium sulphate-induced colitis. Cilostazol and enzymatically modified isoquercitrin improved the outcome of azoxymethane/dextran sodium sulphate-induced colorectal cancer along with anthocyanin though inhibiting inflammation and cell proliferation, but the effect of alpha-lipoic acid was minimal. Inhibition of cell proliferation by cilostazol was confirmed in vitro. In the acute dextran sodium sulphate-induced colitis model, cilostazol and enzymatically modified isoquercitrin prevented the decrease in epithelial proliferative cells. These results indicate that cilostazol and enzymatically modified isoquercitrin first exhibited an anti-dextran sodium sulphate effect at the initial stage of colitis and then showed antitumour effects throughout subsequent inflammation-related cancer developmental stages. PMID- 27989840 TI - TMS of supplementary motor area (SMA) facilitates mental rotation performance: Evidence for sequence processing in SMA. AB - In the present study we applied online transcranial magnetic stimulation (TMS) bursts at 10Hz to the supplementary motor area (SMA) and primary motor cortex to test whether these regions are causally involved in mental rotation. Furthermore, in order to investigate what is the specific role played by SMA and primary motor cortex, two mental rotation tasks were used, which included pictures of hands and abstract objects, respectively. While primary motor cortex stimulation did not affect mental rotation performance, SMA stimulation improved the performance in the task with object stimuli, and only for the pairs of stimuli that had higher angular disparity between each other (i.e., 100 degrees and 150 degrees ). The finding that the effect of SMA stimulation was modulated by the amount of spatial orientation information indicates that SMA is causally involved in the very act of mental rotation. More specifically, we propose that SMA mediates domain general sequence processes, likely required to accumulate and integrate information that are, in this context, spatial. The possible physiological mechanisms underlying the facilitation of performance due to SMA stimulation are discussed. PMID- 27989842 TI - Recognizing approaching walkers: Neural decoding of person familiarity in cortical areas responsive to faces, bodies, and biological motion. AB - In natural viewing environments, we recognize other people as they move through the world. Behavioral studies indicate that the face, body, and gait all contribute to recognition. We examined the neural basis of person recognition using a decoding approach aimed at discriminating the patterns of neural activity elicited in response to seeing visually familiar versus unfamiliar people in motion. Participants learned 30 identities by viewing multiple videos of the people in action. Recognition was tested inside a functional magnetic resonance imaging (fMRI) scanner using 8-s videos of 60 people (30 learned and 30 novel) approaching from a distance (~13m). Full brain images were taken while participants watched the approach. These images captured neural activity at four time points (TRs) corresponding to progressively closer views of the walker. We used pattern classification techniques to examine familiarity decoding in lateralized ROIs and the combination of left and right (bilateral) regions. Results showed accurate decoding of familiarity at the farthest distance in the bilateral posterior superior temporal sulcus (bpSTS). At a closer distance, familiarity was decoded in the bilateral extrastriate body area (bEBA) and left fusiform body area (lFBA). The most robust decoding was found in the time window during which the average behavioral recognition decision was made - and when the face came into clearer view. Multiple regions, including the right occipital face area (rOFA), bOFA, bFBA, bpSTS, and broadly distributed face- and body-selective voxels in the ventral temporal cortex decoded walker familiarity in this time window. At the closest distance, the lFBA decoded familiarity. These results reveal a broad system of ventral and dorsal visual areas that support person recognition from face, body, and gait. Although the face has been the focus of most person recognition studies, these findings remind us of the evolutionary advantage of being able to differentiate the people we know from strangers at a safe distance. PMID- 27989841 TI - Cardiorespiratory fitness is differentially associated with cortical thickness in young and older adults. AB - Aging is associated with reductions in gray matter volume and cortical thickness. One factor that may play a role in mitigating age-associated brain decline is cardiorespiratory fitness (CRF). Although previous work has identified a positive association between CRF and gray matter volume, the relationship between CRF and cortical thickness, which serves as a more sensitive indicator of gray matter integrity, has yet to be assessed in healthy young and older adults. To address this gap in the literature, 32 young and 29 older adults completed treadmill based progressive maximal exercise testing to assess CRF (peak VO2), and structural magnetic resonance imaging (MRI) to determine vertex-wise surface based cortical thickness metrics. Results indicated a significant CRF by age group interaction such that Peak VO2 was associated with thicker cortex in older adults but with thinner cortex in young adults. Notably, the majority of regions demonstrating a positive association between peak VO2 and cortical thickness in older adults overlapped with brain regions showing significant age-related cortical thinning. Further, when older adults were categorized as high or low fit based on normative data, we observed a stepwise pattern whereby cortex was thickest in young adults, intermediate in high fit older adults and thinnest in low fit older adults. Overall, these results support the notion that CRF-related neuroplasticity may reduce although not eliminate age-related cortical atrophy. PMID- 27989843 TI - Cortical rich club regions can organize state-dependent functional network formation by engaging in oscillatory behavior. AB - Cognition is hypothesized to require the globally coordinated, functionally relevant integration of otherwise segregated information processing carried out by specialized brain regions. Studies of the macroscopic connectome as well as recent neuroimaging and neuromodeling research have suggested a densely connected collective of cortical hubs, termed the rich club, to provide a central workspace for such integration. In order for rich club regions to fulfill this role they must dispose of a dynamic mechanism by which they can actively shape networks of brain regions whose information processing needs to be integrated. A potential candidate for such a mechanism comes in the form of oscillations which might be employed to establish communication channels among relevant brain regions. We explore this possibility using an integrative approach combining whole-brain computational modeling with neuroimaging, wherein we investigate the local dynamics model brain regions need to exhibit in order to fit (dynamic) network behavior empirically observed for resting as well as a range of task states. We find that rich club regions largely exhibit oscillations during task performance but not during rest. Furthermore, oscillations exhibited by rich club regions can harmonize a set of asynchronous brain regions thus supporting functional coupling among them. These findings are in line with the hypothesis that the rich club can actively shape integration using oscillations. PMID- 27989844 TI - In need of constraint: Understanding the role of the cingulate cortex in the impulsive mind. AB - Impulsive behavior often occurs without forethought and can be driven by strong emotions or sudden impulses, leading to problems in cognition and behavior across a wide range of situations. Although neuroimaging studies have explored the neurocognitive indicators of impulsivity, the large-scale functional networks that contribute to different aspects of impulsive cognition remain unclear. In particular, we lack a coherent account of why impulsivity is associated with such a broad range of different psychological features. Here, we use resting state functional connectivity, acquired in two independent samples, to investigate the neural substrates underlying different aspects of self-reported impulsivity. Based on the involvement of the anterior cingulate cortex (ACC) in cognitive but also affective processes, five seed regions were placed along the caudal to rostral gradient of the ACC. We found that positive urgency was related to functional connectivity between subgenual ACC and bilateral parietal regions such as retrosplenial cortex potentially highlighting this connection as being important in the modulation of the non-prospective, hastiness - related aspects of impulsivity. Further, two impulsivity dimensions were associated with significant alterations in functional connectivity of the supragenual ACC: (i) lack of perseverance was positively correlated to connectivity with the bilateral dorsolateral prefrontal cortex and right inferior frontal gyrus and (ii) lack of premeditation was inversely associated with functional connectivity with clusters within bilateral occipital cortex. Further analysis revealed that these connectivity patterns overlapped with bilateral dorsolateral prefrontal and bilateral occipital regions of the multiple demand network, a large-scale neural system implicated in the general control of thought and action. Together these results demonstrate that different forms of impulsivity have different neural correlates, which are linked to the functional connectivity of a region of anterior cingulate cortex. This suggests that poor perseveration and premeditation might be linked to dysfunctions in how the rostral zone of the ACC interacts with the multiple demand network that allows cognition to proceed in a controlled way. PMID- 27989845 TI - Convexity-constrained and nonnegativity-constrained spherical factorization in diffusion-weighted imaging. AB - Diffusion-weighted imaging (DWI) facilitates probing neural tissue structure non invasively by measuring its hindrance to water diffusion. Analysis of DWI is typically based on generative signal models for given tissue geometry and microstructural properties. In this work, we generalize multi-tissue spherical deconvolution to a blind source separation problem under convexity and nonnegativity constraints. This spherical factorization approach decomposes multi shell DWI data, represented in the basis of spherical harmonics, into tissue specific orientation distribution functions and corresponding response functions, without assuming the latter as known thus fully unsupervised. In healthy human brain data, the resulting components are associated with white matter fibres, grey matter, and cerebrospinal fluid. The factorization results are on par with state-of-the-art supervised methods, as demonstrated also in Monte-Carlo simulations evaluating accuracy and precision of the estimated response functions and orientation distribution functions of each component. In animal data and in the presence of oedema, the proposed factorization is able to recover unseen tissue structure, solely relying on DWI. As such, our method broadens the applicability of spherical deconvolution techniques to exploratory analysis of tissue structure in data where priors are uncertain or hard to define. PMID- 27989846 TI - Cortical areas involved in behavioral expression of external pallidum dysfunctions: A PET imaging study in non-human primates. AB - The external pallidum (GPe) is a component of the indirect pathway centrally placed in the basal ganglia. Studies already demonstrated that the pharmacological disinhibition of the sensorimotor, associative, and limbic GPe produced dyskinesia, hyperactivity, and compulsive behaviors, respectively. The aim of this study was to investigate the cortical regions altered by the disinhibition of each GPe functional territory. Thus, 5 macaques were injected with bicuculline in sensorimotor, associative, and limbic sites of the GPe producing dyskinesia, hyperactivity, and compulsive behaviors, and underwent in vivo positron tomography with 18F-2-fluoro-2-deoxy-D-glucose to identify cortical dysfunctions related to GPe disinhibition. Blood cortisol levels were also quantified as a biomarker of anxiety for each condition. Our results showed that pallidal bicuculline injections in anesthetized animals reproducibly modified the activity of specific ipsilateral and contralateral cortical areas depending on the pallidal territory targeted. Bicuculline injections in the limbic GPe led to increased ipsilateral activations in limbic cortical regions (anterior insula, amygdala, and hippocampus). Injections in the associative vs. sensorimotor GPe increased the activity in the ipsilateral midcingulate vs. somatosensory and parietal cortices. Moreover, bicuculline injections increased blood cortisol levels only in animals injected in their limbic GPe. These are the first functional results supporting the model of opened cortico-striato-thalamo cortical loops where modifications in a functional pallidal territory can impact cortical activities of the same functional territory but also cortical activities of other functional territories. This highlights the importance of the GPe as a crucial node in the top-down control of the cortico-striato-thalamo-cortical circuits from the frontal cortex to influence the perception, attention, and emotional processes at downstream (or non-frontal) cortical levels. Finally, we showed the implication of the ventral pallidum with the amygdala and the insular cortex in a circuit related to aversive processing that should be crucial for the production of anxious disorders. PMID- 27989847 TI - Assessing and tuning brain decoders: Cross-validation, caveats, and guidelines. AB - Decoding, i.e. prediction from brain images or signals, calls for empirical evaluation of its predictive power. Such evaluation is achieved via cross validation, a method also used to tune decoders' hyper-parameters. This paper is a review on cross-validation procedures for decoding in neuroimaging. It includes a didactic overview of the relevant theoretical considerations. Practical aspects are highlighted with an extensive empirical study of the common decoders in within- and across-subject predictions, on multiple datasets -anatomical and functional MRI and MEG- and simulations. Theory and experiments outline that the popular "leave-one-out" strategy leads to unstable and biased estimates, and a repeated random splits method should be preferred. Experiments outline the large error bars of cross-validation in neuroimaging settings: typical confidence intervals of 10%. Nested cross-validation can tune decoders' parameters while avoiding circularity bias. However we find that it can be favorable to use sane defaults, in particular for non-sparse decoders. PMID- 27989848 TI - Effectiveness and Tolerability of Direct Acting Antiviral Therapy for Hepatitis C in a Real World Elderly Cohort. PMID- 27989849 TI - Colonic Polyp in a Human Immunodeficiency Virus-Positive Patient: An Unexpected Diagnosis. PMID- 27989850 TI - Long-Standing Diarrhea Associated With Sevelamer Crystalopathy in Colonic Mucosa. PMID- 27989851 TI - Endoscopic Bariatric and Metabolic Therapies: Surgical Analogues and Mechanisms of Action. AB - Obesity is a worsening pandemic with numerous related comorbid illnesses. Conservative management including lifestyle modification and medications have limited efficacy. In contradistinction, bariatric surgery is effective, however, with substantial cost and non-negligible morbidity and mortality. As such, a small percentage of eligible patients undergo surgery. Over the past decade, endoscopic bariatric and metabolic therapies have been introduced as a less invasive option for the treatment of obesity and its related comorbid illnesses. This article reviews major endoscopic bariatric and metabolic therapies, their surgical analogues, and proposed mechanisms of action. Clinical trial data for each device also are discussed. PMID- 27989852 TI - Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex. AB - BACKGROUND: Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. METHODS: The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants. Each participant received 30mg morphine or placebo as oral solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty subjects was included in the data analysis. There was no change in the activity in resting EEG (P>0.05) after morphine administration as compared to placebo. During cold pressor stimulation, morphine significantly lowered the relative activity in the delta (1-4Hz) band (P=0.03) and increased the activity in the alpha (8-12Hz) band (P=0.001) as compared to placebo. The reflex amplitudes significantly decreased after morphine administration (P=0.047) as compared to placebo. There was no correlation between individual EEG changes during cold pressor stimulation and the decrease in the reflex amplitude after morphine administration (P>0.05). CONCLUSIONS: Cold pressor EEG and the nociceptive reflex were more sensitive to morphine analgesia than resting EEG and can be used as standardized objective methods to assess opioid effects. However, no correlation between the analgesic effect of morphine on the spinal and cortical assessments could be demonstrated. PMID- 27989853 TI - Analyzing the miRNA content of extracellular vesicles by fluorescence nanoparticle tracking. AB - We present a method that takes advantage of the fluorophore loading dependence of fluorescence nanoparticle tracking (fNTA) to determine the content of specific miRNA targets in extracellular vesicles (EVs) and their stoichiometry across the entire EV population. The method is based on an assay for detecting EV miRNA by hybridization to fluorescently labeled, miRNA-specific molecular beacons encapsulated in cationic lipoplex nanoparticles that fuse non-specifically with negatively charged EVs. To demonstrate the method, we carry out a stoichiometric analysis of miR-21 in EVs released from A549 lung cancer cells. We find approximately 2.3% of the A549 EVs have an average copy number of ~44 miR-21/A549 EV and contain at least a threshold number of 33 miR-21 copies/A549 EV required for fluorescence tracking. Potential applications of sizing, enumerating, and phenotyping EVs using this method include specifying dosages for therapeutic applications and identifying specific EV subpopulations in patient samples for diagnostic applications. PMID- 27989854 TI - RECOPE: How to succeed in bringing ideas from academia to market without compromising ingenuity. AB - Translation of biomedical technology originated in academia to the market is hindered by lack of consideration of market needs and commercialization pathways that leads academic research away from the market, leaving the public without long-awaited cures. Here we describe Reverse Conceptual Product Engineering (RECOPE), an approach applied in academic setting early in the course of the research project to facilitate biomedical research translation from bench to bedside. By using expertise of diverse set of biomedical professionals and trainees to solve a problem, RECOPE helps to make research goals more relevant to the society needs and translatable in a long-term perspective. Through the use of RECOPE one can critically reassess research design and translational potential and identify new market opportunities. RECOPE also provides for considerable educational opportunities to pre- and post-doctoral trainees. Adoption of RECOPE as a basic to for research design education will have a noticeable impact on academic research. PMID- 27989855 TI - Formulation and evaluation of chitosan/polyethylene oxide nanofibers loaded with metronidazole for local infections. AB - Nanofibers combined with an antimicrobial represent a powerful strategy for treatment of various infections. Local infections usually have a low fluid volume available for drug release, whereas pharmacopoeian dissolution tests include a much larger receptor volume. Therefore, the development of novel drug-release methods that more closely resemble the in-vivo conditions is necessary. We first developed novel biocompatible and biodegradable chitosan/polyethylene oxide nanofibers using environmentally friendly electrospinning of aqueous polymer solutions, with the inclusion of the antimicrobial metronidazole. Here, the focus is on the characterization of these nanofibers, which have high potential for bioadhesion and retention at the site of application. These can be used where prolonged retention of the delivery system at an infected target site is needed. Drug release was studied using three in-vitro methods: a dissolution apparatus (Apparatus 1 of the European Pharmacopoeia), vials, and a Franz diffusion cell. In contrast to other studies, here the Franz diffusion cell method was modified to introduce a small volume of medium with the nanofibers in the donor compartment, where the nanofibers swelled, eroded, and released the metronidazole, which then diffused into the receptor compartment. This set-up with nanofibers in a limited amount of medium released the drug more slowly compared to the other two in-vitro methods that included larger volumes of medium. These findings show that drug release from nanofibers strongly depends on the release method used. Therefore, in-vitro test methods should closely resemble the in-vivo conditions for more accurate prediction of drug release at a therapeutic site. PMID- 27989856 TI - Development of oral site-specific pellets containing flavonoid extract with antioxidant activity. AB - Herbal medicines are recognized as an effective treatment of common diseases, mainly associated with oxidative stress. Therefore developing drug delivery systems of these biological active ingredients are gaining interest. Parsley (Petroselinum crispum L.) is a well-known culinary herb and its leaf contains high amount of apigenin, therefore it is suitable as a natural source of this flavonoid. Apigenin possess many health effects such as antioxidant, anti inflammatory and anticancer activities. Unfortunately, these benefits are limited due to the low water solubility and bioavailability, it was recently classified as BCS II group compound. Therefore the aim of this study was to develop a carrier system for Petroselinum crispum extract, containing high amount of apigenin. Microcrystalline cellulose inert pellet cores were chosen and enteric coatings were applied. The produced multiparticulates had spherical shape, narrow size distribution and low moisture content. 10% (w/w) Eudragit(r) L 30 D-55 and 15% (w/w) Eudragit(r) FS 30 D coating was adequate for the modified release in vitro. The layered pellets demonstrated antioxidant activity. It was concluded that development of oral site-specific pellets containing flavonoid extract successful and the therapeutic effectiveness could be hypothesized. PMID- 27989857 TI - Evaluation of PLGA containing anti-CTLA4 inhibited endometriosis progression by regulating CD4+CD25+Treg cells in peritoneal fluid of mouse endometriosis model. AB - Our study investigated poly(lactic-co-glycolic acid) (PLGA) as protein delivery vehicles encapsulate CTLA-4-antibody (anti-CTLA-4) which is essential for CD4+CD25+Treg cells suppressive function exposing superior potential for inhibiting endometriosis progress in mouse model than single anti-CTLA-4. Anti CTLA-4 loaded PLGA combined to ligands CTLA-4 in surface of CD4+CD25+Treg cells which distributed in peritoneal fluid of mouse endometriosis model. The particle size, zeta potential of the anti-CTLA-4 loaded nanoparticles was detected by dynamic light scattering. Morphology of nanoparticles was evaluated by transmission electron microscopy (TEM). Confocal laser scanning microscopy (CLSM) indicated distribution of anti-CTLA-4 with PLGA or without in peritoneal fluid. Cumulative anti-CTLA-4 release from nanoparticles was evaluated by Micro BCA assay. The percentage of CD4+CD25+Treg cells in peritoneal fluid was demonstrated by flow cytometer. In vitro experiment we co-culture ectopic endometrial cells (EEC) with isolated CD4+CD25+Treg cells in peritoneal fluid (PF), proliferation and invasion of ectopic endometrial cells (EEC) was measured by BrdU ELISA assay and Matrigel invasion assay. In comparison with anti-CTLA-4 without nanoparticles, the bioconjugates PLGA/anti-CTLA-4 were tolerated in peritoneal fluid with a controlled release of anti-CTLA-4 in 3, 7, 14days. Moreover, PLGA/anti-CTLA-4 had superior protective regulation ability to reduce level of CD4+CD25+Treg cells in peritoneal fluid. Most strikingly, in vitro experiment, PLGA/anti-CTLA-4 exhibited better ability in inhibiting proliferation and invasion of ectopic endometrial cells in co-culture system compared with anti CTLA-4. Progressively, PLGA/anti-CTLA-4 had better suppressive activity to inhibited IL-10 and TGF-beta secreted by CD4+CD25+Treg cells which indicating that PLGA/anti-CTLA-4 suppressed cells proliferation and invasion through reduced IL-10 and TGF-beta production. Thus, PLGA/anti-CTLA-4 may be a potential strategy for endometriosis therapy. PMID- 27989858 TI - Aerosolizable modified-release particles of montelukast improve retention and availability of the drug in the lungs. AB - Montelukast, a cysteinyl leukotriene receptor antagonist available as oral tablets, is used as a second-line therapy in asthma. In this study, we sought to enhance the availability of montelukast in the lungs by encapsulating the drug in poly (lactide-co-glycolic acid)-based (PLGA) respirable large porous particles. We determined the oral and lung specific availability of montelukast by assessing metabolic stability of the drug in the lung and liver homogenates, respectively. We similarly measured the oral and inhalational bioavailability by monitoring the pharmacokinetics and disposition of the drug in live animals. After preparing montelukast-loaded particles with various polymers, in the absence or presence of polyethylenimine (PEI-1), we characterized the particles for physical-chemical properties, entrapment efficiency, in vitro release, uptake by alveolar macrophages, deposition in the lungs, and safety after pulmonary administration. When incubated in lung or liver homogenates, the amount of intact drug in the lung homogenates was greater than that in the liver homogenates. Likewise, the extent of montelukast absorption via the lungs was greater than that via the oral route. Compared with smaller non-porous particles, large porous particles (PEI-1) were taken up by the alveolar macrophages at a lesser extent but deposited in the lungs at a greater extent. The levels of injury markers in the bronchoalveolar lavage fluid (BALF), collected from rat lungs treated with PEI-1, were no different from that in BALF collected from saline treated rats. Overall, the retention time and concentration of montelukast in the lungs can be increased by formulating the drug in large porous particles of PLGA. PMID- 27989860 TI - Immunometabolic dysregulation is associated with reduced cortical thickness of the anterior cingulate cortex. AB - BACKGROUND: Immunometabolic dysregulation (low-grade inflammation and metabolic dysregulation) has been associated with the onset and more severe course of multiple psychiatric disorders, partly due to neuroanatomical changes and impaired neuroplasticity. We examined the effect of multiple markers of immunometabolic dysregulation on hippocampal and amygdala volume and anterior cingulate cortex thickness in a large sample of patients with depression and/or anxiety and healthy subjects (N=283). METHODS: Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), c-reactive protein (CRP), triglyceride levels and HDL-cholesterol and genomic profile risk scores (GPRS) for immunometabolic dysregulation were determined in peripheral blood and T1 MRI scans were acquired at 3T. Regional brain volume and cortical thickness was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed to examine the relationship between immunometabolic dysregulation and brain volume/thickness across all subjects. RESULTS: Multiple immunometabolic dysregulation markers (i.e. triglyceride levels and inflammation) were associated with lower rostral ACC thickness across all subjects. IL-6 was inversely associated with hippocampal and amygdala volume in healthy subjects only. GPRS for immunometabolic dysregulation were not associated with brain volume or cortical thickness. CONCLUSIONS: Multiple serum, but not genetic immunometabolic dysregulation markers were found to relate to rostral ACC structure, suggesting that inflammation and metabolic dysregulation may impact the ACC through similar mechanisms. PMID- 27989859 TI - Development and mechanistic insight into enhanced cytotoxic potential of hyaluronic acid conjugated nanoparticles in CD44 overexpressing cancer cells. AB - The overexpression of CD44 in cancer cells reroutes number of oncogenic pathways including the central Pi3K/Akt/NF-kB pathway leading to cancer progression and malignancy. Herein, we developed hyaluronic acid-modified poly(dl-lactic-co glycolic acid)-poly (ethylene glycol) nanoparticles (PLGA-PEG-HA NPs) for targeted delivery of TTQ (thio-tetrazolyl analog of a clinical candidate, IC87114) to CD44 overexpressing cancer cells. The PLGA-PEG co-polymer was synthesized and characterized by NMR and FTIR. The co-polymer based nanoparticles were prepared by solvent evaporation method and hyaluronic acid (HA) was conjugated on to the nanoparticle surface via EDC/NHS chemistry. The PLGA-PEG-HA NPs had a desirable particle size (<200nm) with reduced polydispersibility and exhibited spherical shape under atomic force microscope (AFM). In vitro cytotoxicity and cellular uptake studies demonstrated higher cytotoxicity and enhanced intracellular accumulation of PLGA-PEG-HA NPs compared to PLGA-PEG NPs in high CD44 expressing MiaPaca-2 cells compared to MDA-MB-231 and MCF7 cells. At the molecular level, the PLGA-PEG-HA NPs were found to be inducing premature senescence with increase in senescence associated beta-galactosidase activity and senescence specific marker p21 expression through modulation of Pi3K/Akt/NF-kB signaling pathway in MiaPaca-2 cells. These findings collectively indicated that HA-modified nanoparticles might serve as a promising nanocarrier for site specific drug delivery, and can be explored further to increase the therapeutic efficacy of anticancer drugs via targeting to CD44 over-expressing cancer cells. PMID- 27989861 TI - Identification and activity of a paralog of cathepsin S from yellow catfish (Pelteobagrus fulvidraco) involved in immune response. AB - Cathepsin S, a papain-like cysteine peptidase, is an important regulator and signaling molecule with diverse biological actions in addition to immune presentation. However, our understanding of its structure and properties remains limited. Herein, a full-length cathepsin Sa from yellow catfish was cloned and named PfCTSSa. It contained 1366 bp, including a 981 bp ORF flanked by a 123 bp 5'-untranslated region (UTR) and a 262 bp 3'-UTR. This ORF encoded a 36.5 kD cysteine protease with the deduced amino acid sequence having a 76% sequence identity with Ictalurus punctatus ctssa. Additionally, PfCTSSa was found to be a paralog of cathepsin S since it generated a new cluster with cathepsin Sa in the phylogenic tree. Furthermore, PfCTSSa was found to contain more N-glycosylation sites than cathepsin S. The recombinant PfCTSSa was overexpressed in E. coli BL21 (DE3) and appeared to have the strongest activity at pH 8.5 and 35 degrees C in a concentration-dependent manner, with activity further affected by metal ions and detergents. Moreover, PfCTSSa mRNA was highly expressed in classic and mucosal immune tissues, although constitutively distributed in all of the examined tissues. Yellow catfish were then challenged with inactivated Aeromonas hydrophila and PfCTSSa was remarkably increased in the head kidney, liver and spleen when compared to the PBS control. Collectively, these results indicate that PfCTSSa is a paralog of cathepsin S and functions in the yellow catfish immune response. PMID- 27989862 TI - Characterization of a novel disease resistance gene rtp3 and its association with VNN disease resistance in Asian seabass. AB - Asian seabass, an important food fish in Southeast Asia, has suffered from nervous necrosis virus (NNV) infection, resulting in massive mortality of Asian seabass larvae and enormous economic losses. Identification and characterization of disease resistance genes is important. Previous transcriptome analysis of Asians seabass epithelial cells after NNV infection revealed a highly inducible gene, receptor-transporting protein 3 (rtp3), indicating it could play an important role in Asian seabass - NNV interaction. To characterize this gene, we determined its expression pattern and subcellular localization. The rtp3 was highly induced in most examined tissues and organs of Asian seabass after NNV infection, and protein Rtp3 was localized in cytoplasm. Further association study in multiple families revealed that a microsatellite marker, (GT)ntt(GT)n, in the 3' UTR of rtp3 was significantly associated with VNN disease resistance in Asian seabass. Our results imply that rtp3 may be a novel disease resistance gene in Asian seabass. This data could improve our understanding of molecular interaction between Asian seabass and NNV, and has the potential to be applied in marker assisted selection for disease resistance breeding in Asian seabass. PMID- 27989863 TI - Cloning and functional characterization of IRAK4 in large yellow croaker (Larimichthys crocea) that associates with MyD88 but impairs NF-kappaB activation. AB - As crucial signaling transducer in Toll-like receptor (TLR) and interleukin (IL) 1 receptor (IL-1R) signaling pathway, IL-1R-associated kinase 4 (IRAK4) mediates downstream signaling cascades and plays important roles in innate and adaptive immune responses. In the present study, an IRAK4 orthologue was characterized from large yellow croaker (Larimichthys crocea), named Lc-IRAK4, with a conservative N-terminal death domain and a C-terminal protein kinase domain. The genome of Lc-IRAK4 is structured into eleven exons and ten introns. Expression analysis indicated that Lc-IRAK4 was widely expressed in tested tissues, with the highest level in liver and weakest in muscle. Additionally, in the spleen, liver tissues and blood, it could be induced by poly I:C and LPS stimulation, but not be induced by Vibrio parahemolyticus infection. Fluorescence microscopy assays revealed that Lc-IRAK4 localized in the cytoplasm in HEK 293T cells. It was also determined that Lc-IRAK4 could interact with MyD88, whereas MyD88-mediated NF kappaB activation was significantly impaired when co-transfected the two in HEK 293T cells. These findings collectively indicated that although Lc-IRAK4 was evolutionarily conserved in vertebrates, the exact function especially the signaling transduction mediated by IRAK4 in fish immune response was different from that in mammals, which impaired MyD88-mediated NF-kappaB activation. PMID- 27989864 TI - Fluorescence visualization efficacy for detecting oral lesions more prone to be dysplastic and potentially malignant disorders: a pilot study. AB - BACKGROUND: To analyze the efficacy of fluorescence visualization in early detection of oral early neoplastic processes when used by an inexperienced and an adept oral examiner. METHODS: A dental student and an expert professional in oral diagnosis examined 15 randomly selected patients using conventional oral examination and fluorescence visualization searching for early signs of epithelial dysplasia and oral potentially malignant disorders. Patients detected with oral lesions in any of examinations were submitted to incisional biopsy for definitive diagnosis. RESULTS: Taking histopathologic analysis as Gold Standard, sensitivity, specificity, positive and negative predictive values and accuracy of inexperienced examiner for detecting both epithelium dysplasia and oral potentially malignant disorders increased when using fluorescence visualization compared to conventional white light examination, matching the same values found for expert professional in oral diagnosis. Furthermore, it was possible to observe discrete increase in the efficacy of expert professional's examination when using fluorescence visualization. CONCLUSION: This study indicates fluorescence visualization is capable of improve inexperienced professionals' efficacy for early detecting oral lesions more prone to be dysplastic and oral potentially malignant disorders. PMID- 27989865 TI - Effect of mechanical debridement with and without adjunct antimicrobial photodynamic therapy in the treatment of peri-implant diseases in prediabetic patients. AB - OBJECTIVE: There are no studies that have assessed the efficacy of mechanical debridement (MD) with and without adjunct antimicrobial photodynamic therapy (aPDT) in the treatment of periimplant diseases in patients with prediabetes. The aim of the present 6-month follow-up study was to assess the effect of MD with and without adjunct aPDT in the treatment of periimplant diseases in patients with prediabetes. METHODS: Treatment: wise, patients were divided into 2 groups: (a) test-group (n=30): patients underwent MD+aPDT; and (b) control group (n=30): patients underwent MD alone. Hemoglobin A1c (HbA1c) levels and periimplant bleeding on probing (BOP) and probing depth (PD) >=4mm were measured at baseline and after 3 and 6 months in both groups. Group comparisons were performed using the Kruskall-Wallis test and for multiple comparisons Bonferroni post hoc test was used. Level of significance was set at P<0.05. RESULTS: Sixty individuals (30 in the test-group and 30 in the control-group) were included. At 3-months follow up, BOP and PD >=4mm were statistically significantly higher in the control-group compared with the test-group. At-6-months follow-up, there was no statistically significant difference in BOP and PD >=4mm between the test and control-groups. At 6-months follow-up, BOP and PD >=4mm in the test- and control-groups were comparable to their respective values at 3-months follow-up. HbA1c levels were comparable in all groups at all time intervals. CONCLUSION: In the short-term, MD with adjunct aPDT is more effective in the treatment of periimplant inflammation compared to MD alone in prediabetic patients. PMID- 27989866 TI - Localization and expression of molt-inhibiting hormone and nitric oxide synthase in the central nervous system of the green shore crab, Carcinus maenas, and the blackback land crab, Gecarcinus lateralis. AB - In decapod crustaceans, molting is controlled by the pulsatile release of molt inhibiting hormone (MIH) from neurosecretory cells in the X-organ/sinus gland (XO/SG) complex in the eyestalk ganglia (ESG). A drop in MIH release triggers molting by activating the molting gland or Y-organ (YO). Post-transcriptional mechanisms ultimately control MIH levels in the hemolymph. Neurotransmitter mediated electrical activity controls Ca2+-dependent vesicular release of MIH from the SG axon terminals, which may be modulated by nitric oxide (NO). In green shore crab, Carcinus maenas, nitric oxide synthase (NOS) protein and NO are present in the SG. Moreover, C. maenas are refractory to eyestalk ablation (ESA), suggesting other regions of the nervous system secrete sufficient amounts of MIH to prevent molting. By contrast, ESA induces molting in the blackback land crab, Gecarcinus lateralis. Double-label immunofluorescence microscopy and quantitative polymerase chain reaction were used to localize and quantify MIH and NOS proteins and transcripts, respectively, in the ESG, brain, and thoracic ganglion (TG) of C. maenas and G. lateralis. In ESG, MIH- and NOS-immunopositive cells were closely associated in the SG of both species; confocal microscopy showed that NOS was localized in cells adjacent to MIH-positive axon terminals. In brain, MIH positive cells were located in a small number of cells in the olfactory lobe; no NOS immunofluorescence was detected. In TG, MIH and NOS were localized in cell clusters between the segmental nerves. In G. lateralis, Gl-MIH and Gl-crustacean hyperglycemic hormone (CHH) mRNA levels were ~105-fold higher in ESG than in brain or TG of intermolt animals, indicating that the ESG is the primary source of these neuropeptides. Gl-NOS and Gl-elongation factor (EF2) mRNA levels were also higher in the ESG. Molt stage had little or no effect on CHH, NOS, NOS interacting protein (NOS-IP), membrane Guanylyl Cyclase-II (GC-II), and NO independent GC-III expression in the ESG of both species. By contrast, MIH and NO receptor GC-I beta subunit (GC-Ibeta) transcripts were increased during premolt and postmolt stages in G. lateralis, but not in C. maenas. MIH immunopositive cells in the brain and TG may be a secondary source of MIH; the release of MIH from these sources may contribute to the difference between the two species in response to ESA. The MIH-immunopositive cells in the TG may be the source of an MIH-like factor that mediates molt inhibition by limb bud autotomy. The association of MIH- and NOS-labeled cells in the ESG and TG suggests that NO may modulate MIH release. A model is proposed in which NO-dependent activation of GC I inhibits Ca2+-dependent fusion of MIH vesicles with the nerve terminal membrane; the resulting decrease in MIH activates the YO and the animal enters premolt. PMID- 27989868 TI - Extracorporeal Life Support: Physiological Concepts and Clinical Outcomes. AB - Extracorporeal life support (ECLS) describes a system that involves drainage from the venous circulation and return via an oxygenator into the arterial circulation (veno-arterial extracorporeal membrane oxygenation). ECLS provides effective cardiopulmonary support, but the parallel circulation has complex effects on the systemic and pulmonary circulatory physiology. An understanding of the physiological changes is fundamental to the management of ECLS. In this review, the key physiological concepts and the implications on the clinical management of ECLS are discussed. In addition, the clinical outcomes associated with ECLS in cardiogenic shock are systematically reviewed. The paucity of clinical trials on ECLS highlights the need for randomized trials to guide the selection of patients. PMID- 27989867 TI - Identification and functional characterization of a novel antistasin/WAP-like serine protease inhibitor from the tropical sea cucumber, Stichopus monotuberculatus. AB - A novel antistasin/WAP-like serine protease inhibitor, named as StmAW-SPI, was identified from sea cucumber (Stichopus monotuberculatus) and functionally characterized in this study. The full-length cDNA of StmAW-SPI is 1917 bp in length with a 72 bp 5'-untranslated region (UTR), a 294 bp 3'-UTR and a 1551 bp open reading frame (ORF) encoding a protein of 516 amino acids with a deduced molecular weight of 54.56 kDa. The StmAW-SPI protein has 5-fold internal repeats (IRs) of antistasin domain and 6-fold IRs of WAP domain. For the gene structure, StmAW-SPI contains 10 exons separated by 9 introns. The StmAW-SPI mRNA expression pattern was determined using quantitative real-time PCR. The highest level of StmAW-SPI was found in the intestine, followed by coelomocytes, gonad, body wall and respiratory tree. The StmAW-SPI expressions were significantly up-regulated after polyriboinosinic polyribocytidylic acid [Poly (I:C)] or lipopolysaccharides (LPS) challenge in in vitro experiments performed in primary coelomocytes. In addition, the serine protease inhibitory activity and bacterial protease inhibitory activity of StmAW-SPI were examined, and the antibacterial activity was also demonstrated in this study. Our study, as a whole, suggested that StmAW SPI might play a critical role in the innate immune defense of sea cucumber against microbial infections, by not only inactivating the serine protease but also inhibiting the growth of pathogens. PMID- 27989869 TI - The Physiology of Continuous-Flow Left Ventricular Assist Devices. AB - The use of left ventricular assist devices (LVADs) has increased significantly over the past few years, in part because heart transplant activity has plateaued, but also because of the improving clinical outcomes with contemporary continuous flow LVAD. As such, there is now a growing population of patients with continuous flow LVADs. Management of these patients is complicated by the altered circulatory physiology, because continuous-flow LVADs provide a parallel circulation from the heart to the aorta, which interacts with the native left heart (systemic) circulation with consequent effects on the right heart circulation. In addition, the displayed pump parameters can mislead the unwary clinician. An understanding of LVAD physiology can guide clinicians in the management of patients with LVADs. This review describes the basic design of axial and centrifugal continuous-flow LVADs, the functional anatomy and physiology of continuous-flow LVADs, and the interaction between the heart and the LVAD. leading to a discussion about the interpretation of the pump parameters in clinical practice. PMID- 27989870 TI - Time Course of Electrical Remodeling of Native Conduction After Cardiac Resynchronization Therapy and Its Impact on Clinical Outcome. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) induces structural and electrical remodeling (ER) in heart failure (HF) patients. Our aim was to assess time course of ER of native conduction and mechanical remodeling after CRT and impact of CRT-induced ER on clinical outcome. METHODS AND RESULTS: We prospectively included 62 patients (aged 66 +/- 10 years). Echocardiographic and ECG parameters were measured at baseline and 1, 3, 6, 9, and 12 months after implantation. Biventricular pacing was temporary inhibited during each follow-up to record intrinsic ECG. ER was defined as a decrease in native pre-implantation QRS duration >=10 ms. During follow-up HF hospitalizations, cardiovascular death and transplantation (combined end point) were recorded. There were significant changes in intrinsic ECG parameters during follow-up; the narrowing of QRS duration was already observed after 1 month (median 185 ms [interquartile range (IQR) 175-194] vs 180 ms [170-194]; P < .001). Left ventricular (LV) volumes decreased only after 3 months of CRT (median end-systolic volume 167 mL [137-206] vs 140 mL [112-196]; P < .001). Only patients with ER (n = 24) exhibited significant mechanical remodeling and showed superior survival free from the combined end point compared with patients without ER (log-rank P = .028). CONCLUSIONS: Electrical remodeling of native conduction precedes detectable left ventricular structural changes after CRT. ER of native conduction is associated with better clinical outcome following CRT. PMID- 27989871 TI - State of Research on Palliative Care in Heart Failure as Evidenced by Published Literature, Conference Proceedings, and NIH Funding. AB - BACKGROUND: Heart failure (HF) is the most common diagnosis in hospitalized patients older than 65 years of age. Although these patients often need specialist-directed palliative care, <10% ever receive these services. This may be due to a lack of evidence examining the benefits of palliative care for these patients. To understand the current state of research on the interface of palliative care and HF, we examined trends in publications, presentations at national meetings, and National Institutes of Health (NIH) funding. METHODS: Using key terms, we identified items about palliative care and HF in the following sources: (1) the tables of contents of nine leading cardiology journals, (2) abstracts of conference proceedings from four cardiology societies, and (3) all NIH grants from 2009 to 2013. RESULTS: Of the journals reviewed, fewer than 1% of their publications related to palliative care. Less than 2% of HF-related sessions in conference proceedings mentioned palliative care. Of the NIH's $45 billion directed to HF research, only $14 million (0.03%) was spent on palliative care research. CONCLUSIONS: Despite calls for improving palliative care for patients with advanced HF, a lack of sufficient attention persists in research abstracts, concurrent sessions at national meetings, and NIH funding to increase the evidence base. Without these improvements, the ability to deliver high-quality specialist palliative care to patients with HF and their families will remain severely limited. PMID- 27989872 TI - Chondrogenic progenitor cells promote vascular endothelial growth factor expression through stromal-derived factor-1. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) is elevated in joint fluids from patients diagnosed with osteoarthritis (OA). VEGF is known to contribute to vascular tidemark invasion and osteophyte formation, which are classic features of advanced OA. Among the factors that may drive VEGF accumulation in diseased joints, stromal cell-derived factor-1alpha (SDF-1alpha) is a likely culprit, as it is enriched in synovial fluids from osteoarthritic joints and is a potent inducer of VEGF expression. Chondrogenic progenitor cells (CPCs) that overexpress SDF-1alpha are abundant in osteoarthritic cartilage, implicating them in elevating synovial SDF-1alpha levels. Here we conducted a series of experiments to determine the potential for CPCs to stimulate VEGF expression via autocrine and paracrine mechanisms. DESIGN: Immunohistochemistry, immunoblotting, and PCR were used to evaluate the effects of SDF-1alpha on VEGF expression in CPCs and chondrocytes, and the effects of CPC-conditioned medium on chondrocytes. An SDF 1alpha receptor antagonist and inhibitors of mitogen-activated protein kinases (MAPKs) were used to probe the pathway linking SDF-1 with VEGF expression in CPCs. RESULTS: SDF-1alpha and CPC-conditioned medium stimulated VEGF expression in chondrocytes. In both chondrocytes and CPCs, SDF-1alpha stimulated increased VEGF expression via C-X-C chemokine receptor type 4 (CXCR4), a cell-surface SDF 1alpha receptor. This response in CPCs is dependent on p38 MAPK activation, but not on ERK or c-Jun N-terminal kinase (JNK) activation. CONCLUSIONS: By secreting SDF-1alpha, CPCs stimulate VEGF expression in nearby cells. The co-expression of SDF-1 and its receptor by CPCs indicates they are capable of self-sustained VEGF expression via an autocrine mechanism. PMID- 27989873 TI - A platycoside-rich fraction from the root of Platycodon grandiflorum enhances cell death in A549 human lung carcinoma cells via mainly AMPK/mTOR/AKT signal mediated autophagy induction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Platycodon grandiflorum (PG), commonly known as Kilkyong in Korea, Jiegeng in China, and Kikyo in Japan, has been extensively used as a traditional anti-inflammatory medicine in Asia for the treatment of respiratory conditions, such as bronchitis, asthma, and tonsillitis. Platycosides isolated from PG are especially well-known for their anti-cancer effects. AIM OF THE STUDY: We investigated the involvement of autophagic cell death and other potential molecular mechanisms induced by the platycoside containing butanol fraction of PG (PGB) in human lung carcinoma cells. MATERIALS AND METHODS: PGB-induced growth inhibition and cell death were measured using a 5 diphenyl-tetrazolium bromide (MTT) assay. The effects of PGB on autophagy were determined by observing microtubule-associated protein 1 light chain 3 (LC3) redistribution with confocal microscopy. The PGB-mediated regulation of autophagy associated proteins was investigated using Western blotting analysis. Furthermore, the anti-cancer mechanism of PGB was confirmed using chemical inhibitors. A high-performance liquid chromatography (HPLC)-DAD system was used to analyze the platycosides in PGB. RESULTS: In A549 cells, PGB induced significant autophagic cell death. Specifically, PGB upregulated LC3-II in a time and dose-dependent manner, and it redistributed LC3 via autophagosome formation in the cytoplasm. PGB treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and subsequently suppressed the AKT/mammalian target of the rapamycin (mTOR) pathway. Furthermore, PGB inhibited cell proliferation by regulating the mitogen-activated protein kinase (MAPK) pathways. In this study, six types of platycosides were identified in the PGB using HPLC. CONCLUSIONS: PGB efficiently induced cancer cell death via autophagy and the modulation of the AMPK/mTOR/AKT and MAPK signaling pathways in A549 cells. Therefore, PGB may be an efficacious herbal anti-cancer therapy. PMID- 27989874 TI - Effect of Diabetea tea TM consumption on inflammatory cytokines and metabolic biomarkers in type 2 diabetes patients. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Diabetea teaTM (DT) is an anti-diabetic alternative medicine in some Asian countries. The main constituent of DT is black tea originating from Camellia sinensis that is supplemented by 12 other medicinal plants. Black tea contains a large amount of the flavonoids catechins especially epigallocatechin gallate (EGCG) which has anti-inflammatory and antioxidative capacity. This study was undertaken to evaluate the possible effects of DT intake on inflammatory cytokines, regulatory T cells (Tregs) and metabolic biomarkers in T2DM. MATERIALS AND METHODS: The study included 50 patients with T2DM. The patients had received 3 cups (600ml) of DT extract or placebo (PL) extract per day during a period of 12 weeks. Intracellular cytokine expression in peripheral blood mononuclear cell (PBMC) as well as the glycemic and lipid profiles were measured at baseline and after the treatment period. The active constituents of the medicinal plants included in DT were investigated by gas chromatography-mass spectrometry (GC/MS). RESULTS: Ingestion of DT suppressed CD4+ T cell expression of IL-1beta and Il-8 (p<0.05) and up-regulated the expression of IL-10 and the Treg/IL-17 ratio (p<0.05) which was not shown in PL. A significant decrease in HbA1c and LDL was observed at the end of the study period (p<0.05) in DT. The GC/MS analyses of DT indicated the presence of lupeol, beta-Amyrin and beta sitosterol. Also analyses of individual herbs showed the presence of higher levels of lupeol and beta-Amyrin in Nuga Ficus bengalensis and beta-sitosterol in the Attikka Ficus racemosa, indicating that the active ingredients of DT are concentrated in these two herbs. CONCLUSION: The present study provides evidence that DT has hypoglycemic and antihyperlipidemic properties. Interestingly, DT has anti-inflammatory effects. These properties are attributed to the flavonoids, triterpenes and phytosterol contents of the tea. We suggest that DT protects against diabetes complications in the long term. PMID- 27989875 TI - Ethnobotany, phytochemistry, toxicology and pharmacological properties of Terminalia sericea Burch. ex DC. (Combretaceae) - A review. AB - ETHNOPHARMACOLOGICAL REFERENCE: The use of medicinal plants in the treatment of infections is ancient. A wide variety of ethnotherapeutic properties and pharmacological actions has been attributed to Terminalia sericea. Studies by various groups of investigators reveal that it is a multipurpose medicinal plant used mostly in the treatment of diarrhoea, sexually transmitted infections, skin rashes, tuberculosis and other infections. The current paper is aimed at providing an overview of the ethnomedicinal uses, toxicology, pharmacology and the phytochemistry of Terminalia sericea. MATERIALS AND METHODS: Information was retrieved using various search engines, including Pubmed, Science Direct, Google Scholar, Scielo, SciFinder and Scopus. The key words used included Terminalia sericea, secondary metabolites, phytochemistry, biological activity, pharmacology, ethnobotanical survey, medicinal uses, safety, toxicology and other related words. RESULTS: Terminalia sericea is an important medicinal plant which possesses anti-HIV, anti-fungal, anti-bacterial, anticancer, lipolytic, wound healing, antiparasitic, anti-inflammatory and anti-oxidant activity, as the most valuable biological activities, thus lending pharmacological support to the plant's folkloric uses in indigenous medicine. Toxicologically, the extracts and isolated compounds from the plant species may have mild toxic effects. Phytochemically, the plant species possesses valuable compounds including triterpenes, alkaloids and flavonoids which may well contribute to its biological activity. CONCLUSIONS: Terminalia sericea contains secondary metabolites which are valuable in the treatment of a variety of human infections, including community acquired infections which may be prevalent in developing countries. The degree of toxicity reported in various extracts warrants further exploration of the cytotoxicity of the plant species, both against normal human cell lines and in vivo. Moreover, the acetylcholinesterase inhibitory and anti-inflammatory effects also need to be further investigated as there are only a few reports from the literature on these aspects. There is also a need to further understand the mode of action of the extracts against various enzymes relating to inflammation. Antioxidant activity of the plant extracts against various forms of free radicals needs to be investigated. Although T. sericea is reported to be used for ethnoveterinary infections, there are no scientific reports on the anti-parasitic activity of the plant species against common animal parasites. PMID- 27989876 TI - Iridoid glycoside from Cornus officinalis ameliorated diabetes mellitus-induced testicular damage in male rats: Involvement of suppression of the AGEs/RAGE/p38 MAPK signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis (CO) has been widely used as a traditional Chinese medicine for treating diabetes mellitus (DM) and its complications. Iridoid glycoside from C. officinalis (IGCO) can resist apoptosis, hyperglycemia, oxidation and so on. The aim of this study was to investigate the therapeutic effects of IGCO on DM-induced testicular damage through inhibition of the AGEs/RAGE/p38 MAPK signaling pathway. MATERIALS AND METHODS: A DM model of male Wistar rats was induced with streptozotocin injection (30mg/kg, i.p.) and high-fat diet. The DM rats were administrated with IGCO at low and high doses (15 and 30mg/kg, p.o.) for 12 weeks. Testicular damage was evaluated by estimating relative testicular weights, testicular pathohistology, sperm count, live sperm rate, endogenous sex hormone level and activity of testicular marker enzymes. Besides, general diabetic symptoms, renal function, oxidative stress parameters and testicular apoptosis marker were also determined. Finally, the mechanism was explored based on the AGEs/RAGE/p38 MAPK pathway. RESULTS: IGCO effectively mitigated the general symptoms of DM rats including weight loss, polydipsia, polyphagia, polyuria, elevated blood glucose level and low serum insulin level. Nourishing the kidney evidently, IGCO reduced serum creatinine, urea nitrogen and urine protein excretion, and also markedly protected against DM-induced testicular damage by increasing testis/body weight ratio and live sperm rate, improving the histomorphology of testes, upregulating testosterone, LH, FSH and GnRH levels and preventing the decrease of testicular marker enzymes LDH, ACP and gamma-GT. Moreover, IGCO showed considerable anti-oxidative and anti-apoptotic effects, which downregulated the increase of ROS and MDA levels, restored SOD and CAT activities, and decreased spermatogenic cell apoptosis and Bax/Bcl-2 ratio. In the end, the increased AGEs, RAGE and p-p38 MAPK protein levels in DM rats were also reversed by IGCO significantly. CONCLUSIONS: The kidney tonic IGCO well protected DM rats from testicular damage, which may be related to suppression of the AGEs-RAGE-p38 MAPK pathway. PMID- 27989877 TI - Chinese herbal medicine Fuzheng Kang-Ai decoction sensitized the effect of gefitinib on inhibition of human lung cancer cells through inactivating PI3-K/Akt -mediated suppressing MUC1 expression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) Fuzheng Kang-Ai (FZKA for short) decoction has been used as adjuvant treatment strategies in lung cancer patients for decades. However, the molecular mechanism underlying the therapeutic potential especially in sensitizing the effect of EGFR-TKI gefitinib has not been well elucidated. MATERIALS AND METHODS: Cell viability was detected by MTT assay. Cell cycle distribution was detected by flow cytometry. Western blot were used to examine phosphorylation and protein levels of Akt, p65, p50 and MUC1. The mRNA level of MUC1 was measured by qRT-PCR. Transient transfection experiments were used to overexpression of Akt, p65 and MUC1. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the in vitro findings. RESULTS: Cell viability was inhibited by FZKA treatment and showed more significant when treated with FZKA and gefitinib in combine in lung cancer cells. FZKA induced the cell arrest at G0/G1 phase. Mechanistically, we showed that the phosphorylation of Akt, protein expressions of p65 and MUC1 were suppressed by FZKA and even more responses were observed in the FZKA and gefitinib combining. Overexpressed Akt overcame the effect of FZKA on p65 protein, and exogenously expressed p65 resisted the inhibitory effect of MUC1 protein expression by FZKA. On the contrary, while overexpressed MUC1 had no effect on p65 expression, it feedback increased phosphorylation of Akt, and more importantly, reversed the cell growth inhibition affected by FZKA. In line with the above, our results confirmed the synergistic effects of FZKA and gefitinib combination on tumor growth, the phosphorylation of Akt, and protein expression of p65 and MUC1 in vivo. CONCLUSION: This study shows that FZKA decoction inhibits the growth of NSCLC cells through Akt-mediated inhibition of p65, followed by reducing the expression of MUC1. More importantly, there is a synergistic effect of FZKA decoction and gefitinib combination with greater suppression. The positive feedback regulatory loop of MUC1 to Akt signaling pathway further added the important role of MUC1 in mediating the overall responses of FZKA decoction in this process. The in vitro and in vivo study provides an additional and a novel mechanism by which the FZKA decoction enhances the growth inhibition of gefitinib in gefitinib-resistant NSCLC cells. PMID- 27989878 TI - Aphrodisiac and spermatogenic potential of alkaloidal fraction of Hygrophila spinosa T. Ander in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Seeds of Hygrophila spinosa T. Ander (Acanthaceae) are traditionally used as aphrodisiac and spermatogenic in Indian System of medicine. AIM OF THE STUDY: Preliminary phytochemical screening of plant revealed the presence of alkaloids in seeds. As, alkaloidal fractions of several plants showed aphrodisiac and spermatogenic potential, set of experiments were designed to assess alkaloid enriched fraction of seeds of the plant for spermatogenic and aphrodisiac activity using in vitro and in vivo methods. MATERIALS AND METHODS: Alkaloid enriched fraction was prepared and assessed for spermatogenic activity using isolated rat Leydig cells in vitro. The fraction was further evaluated in vivo for spermatogenic and aphrodisiac potential using rat as an experimental animal. Increase in weight of reproductive organs, biochemical evaluation of selected parameters, histological studies of testes and sexual behavioral studies were selected as evaluation parameters for in vivo studies. RESULTS: Isolated rat Leydig cells treated with the fraction showed increased amount of testosterone present in culture media (14.7ug/ml) as compared to that of control (0.8ug/ml). Results of in vivo studies showed increase in serum testosterone level in treated animals (50mg/kg) by (115%), increase in weight of testes (8.0%) as compared to control. Marked improvement in testis histo architecture of rats evident preliminarily by observing overcrowding of spermatozoa in enlarged lumen of seminiferous tubules in animals treated with testosterone and test fraction. Sertoli cells in treated animals were enlarged with highly granulated cytoplasm. Leydig cells also showed enlarged nucleus and darkly stained cytoplasm as compared to control. Mounting behavior of test animals improved, while latency period was decreased, as observed in behavioral studies. CONCLUSION: The set studies confirmed the ability of the fraction to stimulate Leydig cells and increased serum testosterone level. Increased testosterone level might be responsible for higher number of spermatozoa in testicular lumen as seen in testicular histology as well as increased libido as observed in behavioral studies. PMID- 27989879 TI - Bioassay-guided isolation of cytotoxic flavonoids from aerial parts of Coronopus didymus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Coronopus didymus Linn. (Brassicaceae) is a medicinal plant used traditionally as antipyretic, expectorant, to purify blood and for alleviating symptoms of pain, inflammations, malaria, wounds and cancer. AIM OF THE STUDY: The present study was designed to isolate and identify the cytotoxic compounds responsible for anticancer activity from this traditionally useful medicinal plant. MATERIALS AND METHODS: Bioassay-guided fractionation of the ethanolic extract of aerial parts of C. didymus allowed the isolation of compounds responsible for anticancer activity. Their structures were elucidated by UV Spectroscopy (with shift reagents), ESI-MS and NMR spectral data. Preliminary anticancer activity of ethanolic extract, different fractions and isolated compounds was assessed through MTT in vitro cytotoxicity assay in a dose dependent manner against human cancer cell lines (HeLa and LN18) and normal 293T cells. RESULTS: Three flavonoids namely 5,7,4'-trihydroxy-3'-methoxyflavone-4'-O beta-D-glucoside (1), 5,7,4'-trihydroxy-3'-methoxyflavone-4'-O-(6''-acetyl)-beta D-glucoside (2) and 5,7,4'-trihydroxy-3'-methoxy flavone (3), were isolated from aerial parts. Compound 1 was identified for the first time from the genus Coronopus. All the compounds 1-3 showed promising activity against HeLa cells with IC50 values of 43.50, 0.63 and 3.67 uM, respectively. Significant result was also obtained with compound 3 against LN18 cells with IC50 value of 46.63 uM. CONCLUSION: The cytotoxic activity of the crude extract and fractions which may largely be due to its major isolated constituents, flavonoids 1-3, against both HeLa and LN18 cells provides a scientific basis for the ethnopharmacological use of C. didymus as anticancer agent. PMID- 27989880 TI - Spatholobi Caulis extracts promote angiogenesis in HUVECs in vitro and in zebrafish embryos in vivo via up-regulation of VEGFRs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Spatholobi Caulis is a traditional blood activating and stasis-dispelling herb medicine, which has been used to treat diseases related to blood stasis syndrome (BSS) by inhibiting platelet aggregation, stimulate hematopoiesis, etc. It has been demonstrated that pro angiogenesis could improve BSS. However, the pro-angiogenic activity of Spatholobi Caulis was not well elucidated AIM OF STUDY: To determine the potential pro-angiogenic activity of Spatholobi Caulis and elucidate its underlying mechanism. The active fractions of Spatholobi Caulis were further screened. MATERIAL AND METHODS: Gelatin precipitation and reversed-phase liquid chromatography (RPLC) were used to purify the methanol extracts of Spatholobi Caulis, respectively. The RPLC was also used to prepare fractions. Total flavonoids of purified methanol extracts of Spatholobi Caulis (PSC) were determined using ultraviolet spectrophotometry. The morphological observation of subintestinal vessel plexus (SIVs) and tyrosine kinase inhibitor II (VRI)-induced intersegmental blood vessels (ISVs) loss in transgenic zebrafish Tg(fli-1a: EGFP)y1 were selected to evaluate the pro-angiogenic activity of PSC in vivo. Cell proliferation by MTT assay and cell migration assay were used to evaluate the pro-angiogenesis effect of PSC in human umbilical vein endothelial cells (HUVECs) in vitro. Both zebrafish and HUVECs were used in screening active fractions of PSC. The mechanism of PSC promoting angiogenesis were studied by real-time PCR in zebrafish and western blotting in HUVECs. RESULTS: Co-treatment PSC dramatically rescued VRI-induced ISVs loss in zebrafish embryos in a dose dependent manner and 80% of the defective vascular recovered at the concentration of 30MUg/ml compared with VRI-only group. PSC also concentration-dependently increased average sprouting number and diameter of SIVs in zebrafish embryo. Real time PCR assay proved that PSC significantly restored the down regulation of VEGFRs including Flt-1, Kdr and Kdrl induced by VRI in zebrafish (P<0.001). Furthermore, PSC not only promoted proliferation and migration of normal HUVECs but also ameliorated VRI-induced HUVECs cytotoxicity. Western blotting assay showed that co-treatment of PSC increased the expression of VEGFRs and phosphorylation of MAPKs which decreased by VRI treatment. In addition, quality evaluation experiments showed that the content of total flavonoids of PSC reached 56.36% and the main pro-angiogenic fractions of PSC were F3, F4 and F5 both in zebrafish and HUVECs. CONCLUSIONS: Our data demonstrated that PSC presented pro angiogenic activity both in zebrafish and HUVECs, and principal pro-angiogenic active components were likely flavonoids. Thus, the current study provided evidence for the clinical usage of Spatholobi Caulis in promoting blood circulation and removing stasis in traditional Chinese medicine (TCM). PMID- 27989881 TI - Malaria: Massive open online courses MOOC. PMID- 27989882 TI - Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome. AB - Mitochondrial impairment is hypothesized to be involved in chronic fatigue syndrome (CFS) and schizophrenia. We performed a clinical, genetic and functional mitochondrial study in a family consisting of a female presenting schizophrenia in addition to CFS symptoms and her mother and older sister, both presenting with CFS. The three family members showed higher blood lactate levels, higher mitochondrial mass, lower mtDNA content and overall lower mitochondrial enzymatic activities and lower oxygen consumption capacities than healthy women. This family presented mtDNA depletion; however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied. PMID- 27989883 TI - Whole mitochondrial genome analysis in South Indian patients with Leber's hereditary optic neuropathy. AB - Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) associated neurodegenerative disorder of retinal ganglion cells. In this study, whole mitochondrial genome sequencing of 75 LHON patients and 40 controls was performed to identify the mutation frequency and haplogroup background of South Indian population. Analysis of mtDNA revealed 559 different variants in LHON patients, including 7 pathogenic mutations, 30 private, and 22 other disease associated variants. A significantly higher (p=0.0008) overall variation load per individual was noted among LHON patients versus controls. We reported for the first time, the association of M haplogroup (p=0.028) with LHON in this cohort. PMID- 27989884 TI - Association between titanium and silver concentrations in maternal hair and risk of neural tube defects in offspring: A case-control study in north China. AB - Increasing uses of titanium and silver in various products raise concerns for their potential adverse effects on pregnancy outcomes. We aimed to examine the associations between titanium and silver concentrations in maternal hair growing during the periconception period and the risk of neural tube defects (NTDs) in offspring. Our case-control study recruited 191 women with NTD-affected pregnancies and 261 women delivering healthy infants. Metal concentrations in maternal hair were measured by inductively coupled plasma-mass spectrometry. The adjusted odds ratios (AOR) of titanium concentration above the median were 1.46 (95% confidence interval (CI), 0.99-2.13) for total NTDs and 2.10 (95% CI, 1.12 3.94) for anencephaly, while OR of silver wasn't statistically significant. Titanium concentration was positively correlated with consumptions of vegetables and fruits. Maternal exposure to titanium during the periconception period was associated with an increased NTD risk in offspring, which may be partly mediated through maternal dietary habits. PMID- 27989885 TI - Transcaval Access and Closure for Transcatheter Aortic Valve Replacement: A Prospective Investigation. AB - BACKGROUND: Transcaval access may enable fully percutaneous transcatheter aortic valve replacement (TAVR) without the hazards and discomfort of transthoracic (transapical or transaortic) access. OBJECTIVES: The authors performed a prospective, independently adjudicated, multicenter, single-arm trial of transcaval access for TAVR in patients who were ineligible for femoral artery access and had high or prohibitive risk of complications from transthoracic access. METHODS: A total of 100 patients underwent attempted percutaneous transcaval access to the abdominal aorta by electrifying a caval guidewire and advancing it into a pre-positioned aortic snare. After exchanging for a rigid guidewire, conventional TAVR was performed through transcaval introducer sheaths. Transcaval access ports were closed with nitinol cardiac occluders. A core laboratory analyzed pre-discharge and 30-day abdominal computed tomograms. The Society of Thoracic Surgeons predicted risk of mortality was 9.6 +/- 6.3%. RESULTS: Transcaval access was successful in 99 of 100 patients. Device success (access and closure with a nitinol cardiac occluder without death or emergency surgical rescue) occurred 98 of 99 patients; 1 subject had closure with a covered stent. Inpatient survival was 96%, and 30-day survival was 92%. Second Valve Academic Research Consortium (VARC-2) life-threatening bleeding and modified VARC 2 major vascular complications possibly related to transcaval access were 7% and 13%, respectively. Median length of stay was 4 days (range 2 to 6 days). There were no vascular complications after discharge. CONCLUSIONS: Transcaval access enabled TAVR in patients who were not good candidates for transthoracic access. Bleeding and vascular complications, using permeable nitinol cardiac occluders to close the access ports, were common but acceptable in this high-risk cohort. Transcaval access should be investigated in patients who are eligible for transthoracic access. Purpose-built closure devices are in development that may simplify the procedure and reduce bleeding. (Transcaval Access for Transcatheter Aortic Valve Replacement in People With No Good Options for Aortic Access; NCT02280824). PMID- 27989886 TI - Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment: The YELLOW II Study. AB - BACKGROUND: Despite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive. OBJECTIVES: This study assessed changes in plaque morphology using intravascular imaging, with a comprehensive evaluation of cholesterol efflux capacity (CEC) and peripheral blood mononuclear cell (PBMC) transcriptomics in patients receiving high-dose statin therapy. METHODS: In a prospective study, 85 patients with stable coronary artery disease underwent percutaneous coronary intervention for a culprit lesion, followed by intracoronary multimodality imaging, including optical coherence tomography (OCT) of an obstructive nonculprit lesion. All subjects received 40 mg of rosuvastatin daily for 8 to 12 weeks, when the nonculprit lesion was reimaged and intervention performed. Blood samples were drawn at both times to assess CEC and transcriptomic profile in PBMC. RESULTS: Baseline OCT minimal fibrous cap thickness (FCT) was 100.9 +/- 41.7 MUm, which increased to 108.6 +/- 39.6 MUm at follow-up, and baseline CEC was 0.81 +/- 0.14, which increased at follow-up to 0.84 +/- 0.14 (p = 0.003). Thin-cap fibroatheroma prevalence decreased from 20.0% to 7.1% (p = 0.003). Changes in FCT were independently associated with CEC increase by multivariate analysis (beta: 0.30; p = 0.01). PBMC microarray analysis detected 117 genes that were differentially expressed at follow-up compared to baseline, including genes playing key roles in cholesterol synthesis (SQLE), regulation of fatty acids unsaturation (FADS1), cellular cholesterol uptake (LDLR), efflux (ABCA1 and ABCG1), and inflammation (DHCR24). Weighted coexpression network analysis revealed unique clusters of genes associated with favorable FCT and CEC changes. CONCLUSIONS: The study demonstrated an independent association between fibrous cap thickening and improved CEC that may contribute to morphological changes suggesting plaque stabilization among patients taking intensive statin therapy. Furthermore, the significant perturbations in PBMC transcriptome may help determine the beneficial effects of statin on plaque stabilization. (Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering [YELLOW II]; NCT01837823). PMID- 27989887 TI - Fibrous Cap Thickness by Optical Coherence Tomography In Vivo. AB - BACKGROUND: Optical coherence tomography (OCT) imaging is considered to be the only imaging modality with sufficient resolution to measure fibrous cap thickness (FCT) in vivo. However, reproducibility of the measurements in vivo has been unsatisfactory. OBJECTIVES: The authors aimed to investigate whether satisfactory reproducibility of FCT measurements by OCT in vivo can be achieved between independent observers. METHODS: One hundred seventy OCT pullbacks were analyzed by 2 independent observers with intravascular imaging expertise in accordance with current guidelines to assess the interobserver variability of FCT measurement by intraclass correlation coefficient (ICC). The main sources of the variability were analyzed and incorporated in lesion assessment criteria. The same 170 OCT pullbacks were reanalyzed by the same observers using the developed criteria, and the interobserver reproducibility of the measurements was reassessed. On the basis of the developed criteria, a third independent observer interpreted all 170 OCT images. Assessment of the maximal lipid arc was also undertaken similarly before and after the development of interpretation criteria. RESULTS: The original ICC of the FC thickness was 0.56 (95% confidence interval [CI]: 0.38 to 0.69). The poor definition of necrotic core facing border of FC and the neointimal presence of macrophages and calcification contributed to the high interobserver variability of FCT measurement. The ICC of FCT measurements by OCT in vivo was 0.88 (95% CI: 0.80 to 0.93) after we developed lesion assessment criteria. The ICC for the maximal lipid arc assessment before and after was 0.76 and 0.82 respectively. The third independent observer was extensively coached and returned the ICC of 0.82 (95% CI: 0.74 to 0.87) with observer 1 and 0.90 (95% CI: 0.86 to 0.94) with observer 2. CONCLUSIONS: Careful consideration of OCT features mimicking fibroatheroma lesions and imaging artifacts contributed to significantly higher levels of interobserver agreement. Interobserver variation can be partially resolved by development of standard interpretation algorithms. PMID- 27989888 TI - TRPV4 antagonist GSK2193874 does not modulate cough response to osmotic stimuli. AB - Osmolarity changes of airway superficial fluid are associated with cough and are used in research. TRPV4 is calcium channel initially described as osmosensor. In the airways, it can play role in increasing cough reflex sensitivity. The aim of our study was to test whether cough to osmotic stimuli is mediated via TRPV4 channel. Cough response was measured in 12 male guinea pigs by inhalation of saline, distilled water, hypertonic solution and citric acid for 10min in whole body plethysmograph. Data were obtained in naive animals and after pre-treatment with selective TRPV4 antagonist GSK2193874 in doses 300MUg/kg (GSK300) and 900MUg/kg (GSK900). Cough response to all tested aerosols was significantly higher than to saline. Pre-treatment with GSK300 did not influence response to osmotic stimuli - only reduced cough to citric acid. GSK900 reduced cough response to hypotonic stimuli and citric acid. TRPV4 mediated activation of airway afferents does not seem to be the exclusive mechanism responsible for cough to osmotic stimuli. PMID- 27989889 TI - Oxytocin's role on the cardiorespiratory activity of endotoxemic rats. AB - BACKGROUND: Recent findings concerning oxytocin indicate its anti-inflammatory, cardioprotective and parasympathetic modulating properties. In this study, we investigated the effects of systemically applied oxytocin on the cardiorespiratory activity in a rodent model of moderate endotoxemia. METHODS: Telemetrically recorded electrocardiogram (ECGs) from animals which received lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide+oxytocin (LPS+Ox), or vehicle (V) were analyzed using the ECG-derived respiration (EDR) technique to estimate the respiratory rate. The mean R-R interval and the spectral parameters of heart rate variability (HRV), such as the natural logarithm of the high frequency (lnHF) and low frequency (lnLF) components were also estimated up to 24h after treatment. RESULTS: The endotoxemic animals (LPS) showed an elevated respiratory rate as well as a reduced mean R-R interval, lnHF and lnLF components compared to controls (V) from +5 to +12h after the treatment. The administration of oxytocin significantly attenuated the hyperventilation produced by the LPS induced endotoxemia (LPS+Ox) and restored the values of the mean R-R interval and such spectral parameters at different time points. CONCLUSIONS: Our results support the existence of a link among the respiratory, cardiovascular, and immune systems in which oxytocin seems to act as a potential cardioprotective peptide by favoring cardiac cholinergic autonomic coupling. As a result, oxytocin diminished animal's endotoxemic tachypnea and restored the cardiorespiratory interactions, which was indicated by the spectral components of HRV. PMID- 27989890 TI - Impact of sleep disordered breathing on carotid body size. AB - We tested the hypotheses that: (1) carotid body size can be measured by computed tomographic angiography (CTA) with high inter-observer agreement, and (2) patients with sleep apnea exhibit larger carotid bodies than those without sleep apnea. A chart review was conducted from patients who underwent neck CTA and polysomnography at the Mayo Clinic between January 2000 and February 2015. Widest axial measurements of the carotid bodies, performed independently by two radiologists, were possible in 81% of patients. Intra-class correlation coefficients ranged from 0.93 to 0.95 (Right carotid body: 0.93; Left: 0.94; Average: 0.95). Widest axial measurements of the carotid bodies were greater in patients with sleep apnea (n=32) compared to controls (n=46, P-value range 0.02 0.04). After adjusting for age, no differences in carotid body size were observed between the patient groups (P-value range 0.45-0.59). We conclude carotid body size can be detected by CTA with high inter-observer agreement; however, carotid body size is not increased in patients with sleep apnea. PMID- 27989891 TI - Ventilatory acclimatization to hypoxia in mice: Methodological considerations. AB - We examined ventilatory acclimatization to hypoxia (VAH) in CD1 mice, and contrasted results obtained using the barometric method on unrestrained mice with pneumotachography and pulse oximetry on restrained mice. Responses to progressive step reductions in O2 fraction (21%-8%) were assessed in mice acclimated to normoxia and hypobaric hypoxia (barometric pressure of 60kPa for 6-8 weeks). Hypoxia acclimation increased the hypoxic ventilatory response (primarily by increasing breathing frequency rather than tidal volume), arterial O2 saturation (SaO2) and heart rate in deep hypoxia, hypoxic chemosensitivity (ventilatory O2/CO2 equivalents versus SaO2), and respiratory water loss, and it blunted the hypoxic depression of metabolism and body temperature. Although some effects of hypoxia acclimation were qualitatively similar between methods, the effects were often greater in magnitude when assessed using pneumotachography. Furthermore, whereas hypoxia acclimation reduced ventilatory O2 equivalent and increased pulmonary O2 extraction in barometric experiments, it had the opposite effects in pneumotachography experiments. Our findings highlight the importance of considering the impact of how breathing is measured on the apparent responses to hypoxia. PMID- 27989894 TI - Efficacy of the switch to oral antibiotics in the treatment of non-Staphylococcus aureus infective endocarditis in non-severely ill patients. PMID- 27989896 TI - An overview of the necessary thymic contributions to tolerance in transplantation. AB - The thymus is important for the development of the immune system. However, aging leads to predictable involution of the thymus and immunodeficiency. These immunodeficiencies may be rectified with thymic rejuvenation. Atrophy of the thymus is governed by a complex interplay of molecular, cytokine and hormonal factors. Herein we review the interaction of these factors across age and how they may be targeted for thymic rejuvenation. We further discuss the growing pre clinical evidence defining the necessary and sufficient contributions of the thymus to successful tolerance induction in transplantation. PMID- 27989897 TI - Phenotypic changes of peripheral blood mononuclear cells upon corticosteroid treatment in idiopathic intermediate uveitis. AB - We analyzed phenotype and function of peripheral blood mononuclear cells in 9 patients with active idiopathic intermediate uveitis (IIU) before and after 6 and 12weeks of systemic corticosteroid (CS) treatment and compared to 28 healthy individuals. Monocytes from IIU patients showed increased MHCII expression compared with controls (p=0.09). Treatment reduced expression of MHCII, CD86, CD39 and CD124 (all p<0.05), whereas the percentage of CD121b-expressing monocytes was increased by week 6 (p=0.039). Patients showed alterations in T cell polarization (Th1/Th2 ratio: patients 5.2 versus controls 3.1, p=0.054; Th17/Treg ratio: 3.0 versus 1.7, p=0.027). S100A12 serum levels were higher in active IIU (p=0.057). Phagocytosis, oxidative burst and serum cytokine levels did not differ between patients and controls, and were not altered by treatment. In conclusion, monocytes from patients with active IIU show increased co-stimulatory capacities, which are modulated by systemic CS treatment, whereas innate immune cell functions are not altered. PMID- 27989895 TI - Intraperitoneal injection of IDO-expressing dermal fibroblasts improves the allograft survival. AB - Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme with tolerogenic effects on different immune cells. Our group has previously shown that co transplantation of IDO-expressing fibroblasts with donor tissues can delay immune rejection by inducing local immunosuppression. In this study, we have employed a systemic approach to improve allograft survival without using any immunosuppressive medication. To achieve this, 10 million lentiviral transduced IDO-expressing donor derived fibroblasts were injected into the peritoneal cavity of allograft recipients. We showed that IDO-fibroblast therapy increases the survival of both islets and skin allografts and decreases the infiltration of immune cells in subcutaneous transplanted skins. Indirect pathway of allo reactive T cell activation was suppressed more than the direct pathway. Injected IDO-fibroblasts were found in peritoneal cavity and mesenteric lymph nodes of the recipient mice. In conclusion, IDO-expressing fibroblast therapy proved to be a novel approach in improving the allogeneic graft survival. PMID- 27989898 TI - Inflammation elevated IL-33 originating from the lung mediates inflammation in acute lung injury. AB - Excessive inflammatory reactions occur with acute respiratory distress syndrome (ARDS), however, the underlying mechanisms of ARDS remain incompletely understood. Here we investigated whether interleukin (IL)-33 was elevated in ARDS patients. Serum samples were obtained from 14 ARDS patients and 24 control healthy volunteers. ELISA was used to measure the concentrations of IL-33. Besides, we established pulmonary ARDS and extrapulmonary ARDS models in mice, and serum and lung tissue samples were collected for analyses. The results showed that serum IL-33 concentrations were significantly higher in pulmonary ARDS patients compared to controls. Also, the levels of IFN-gamma and IL-2 were positively correlated with IL-33 levels. We also showed that there were increased IL-33 levels in both the serum and lungs in the pulmonary ARDS model. This was not the case, however, in the extrapulmonary ARDS model. Pulmonary inflammation and injury in the pulmonary ARDS model was reduced with IL-33 neutralizing antibody treatment. PMID- 27989901 TI - Flow versus permeability weighting in estimating the forward volumetric transfer constant (Ktrans) obtained by DCE-MRI with contrast agents of differing molecular sizes. AB - PURPOSE: To quantify the differential plasma flow- (Fp-) and permeability surface area product per unit mass of tissue- (PS-) weighting in forward volumetric transfer constant (Ktrans) estimates by using a low molecular (Gd-DTPA) versus high molecular (Gadomer) weight contrast agent in dynamic contrast enhanced (DCE) MRI. MATERIALS AND METHODS: DCE MRI was performed using a 7T animal scanner in 14 C57BL/6J mice syngeneic for TRAMP tumors, by administering Gd-DTPA (0.9kD) in eight mice and Gadomer (35kD) in the remainder. The acquisition time was 10min with a sampling rate of one image every 2s. Pharmacokinetic modeling was performed to obtain Ktrans by using Extended Tofts model (ETM). In addition, the adiabatic approximation to the tissue homogeneity (AATH) model was employed to obtain the relative contributions of Fp and PS. RESULTS: The Ktrans values derived from DCE-MRI with Gd-DTPA showed significant correlations with both PS (r2=0.64, p=0.009) and Fp (r2=0.57, p=0.016), whereas those with Gadomer were found only significantly correlated with PS (r2=0.96, p=0.0003) but not with Fp (r2=0.34, p=0.111). A voxel-based analysis showed that Ktrans approximated PS (<30% difference) in 78.3% of perfused tumor volume for Gadomer, but only 37.3% for Gd-DTPA. CONCLUSIONS: The differential contributions of Fp and PS in estimating Ktrans values vary with the molecular weight of the contrast agent used. The macromolecular contrast agent resulted in Ktrans values that were much less dependent on flow. These findings support the use of macromolecular contrast agents for estimating tumor vessel permeability with DCE-MRI. PMID- 27989899 TI - Estrogen receptor alpha promotes lupus in (NZB*NZW)F1 mice in a B cell intrinsic manner. AB - Lupus is a systemic autoimmune disease characterized by the production of autoreactive antibodies against nuclear antigens. Women are disproportionately affected by lupus, and this sex bias is thought to be due, in large part, to the ability of estrogens to promote lupus pathogenesis. Previously, we have shown that global deletion of estrogen receptor alpha (ERalpha) significantly attenuated loss of tolerance, immune cell activation, autoantibody production, and the development of lupus nephritis. Here we show that targeted deletion of ERalpha specifically in B cells retards production of pathogenic autoantibodies and the development of nephritis in lupus-prone (NZB*NZW)F1 mice. Furthermore, we observed that ERalpha deletion in B cells was associated with decreased B cell activation in young, pre-autoimmune (NZB*NZW)F1 females. Altogether, these data suggest that ERalpha acts in a B cell-intrinsic manner to control B cell activation, autoantibody production, and lupus nephritis. PMID- 27989902 TI - Alternate update of shifted extended keyholes (AUSEK): A new accelerating strategy for interventional MRI. AB - Real-time or near-real-time acquisition plays a key role in providing immediate image guidance for interventional magnetic resonance imaging (iMRI). However, the requirement of accurate needle tip localization has made several accelerating techniques, like Keyhole imaging or sliding window reconstruction, difficult to be applied to iMRI. The purpose of this work was to further explore the possible ways of applying view sharing techniques to iMRI. Inspired by Keyhole imaging, we present an easy-to-implement accelerating strategy called "Alternate update of shifted extended keyholes (AUSEK)". In this method, the keyhole views are not only extended but also shifted towards either high-frequency edge to form two divisions in k-space. The divisions which are mirrored to each other along the center are alternately updated following a reference scan. By using simulations and experiments, we demonstrate that AUSEK could effectively preserve the spatial resolution of the image, especially of the needle, at a temporal acceleration rate of about 2.5. AUSEK was implemented online in an open-configuration low field MR imaging system. PMID- 27989903 TI - De-aliasing for signal restoration in Propeller MR imaging. AB - PURPOSE: Objects falling outside of the true elliptical field-of-view (FOV) in Propeller imaging show unique aliasing artifacts. This study proposes a de aliasing approach to restore the signal intensities in Propeller images without extra data acquisition. MATERIALS AND METHODS: Computer simulation was performed on the Shepp-Logan head phantom deliberately placed obliquely to examine the signal aliasing. In addition, phantom and human imaging experiments were performed using Propeller imaging with various readouts on a 3.0 Tesla MR scanner. De-aliasing using the proposed method was then performed, with the first low-resolution single-blade image used to find out the aliasing patterns in all the single-blade images, followed by standard Propeller reconstruction. The Propeller images without and with de-aliasing were compared. RESULTS: Computer simulations showed signal loss at the image corners along with aliasing artifacts distributed along directions corresponding to the rotational blades, consistent with clinical observations. The proposed de-aliasing operation successfully restored the correct images in both phantom and human experiments. CONCLUSION: The de-aliasing operation is an effective adjunct to Propeller MR image reconstruction for retrospective restoration of aliased signals. PMID- 27989905 TI - Mapping of left ventricle wall thickness in mice using 11.7-T magnetic resonance imaging. AB - BACKGROUND: The left ventricle (LV) wall thickness is an important and routinely measured cardiologic parameter. Here we introduce three-dimensional (3D) mapping of LV wall thickness and function using a self-gated magnetic resonance (MR) sequence for ultra-high-field 11.7-T MR cine imaging of mouse hearts. METHODS AND RESULTS: Six male C57BL/6-j mice were subjected to 11.7-T MR imaging (MRI). Three standard views-short axis, long axis four-chamber, and long axis two-chamber-and eight consecutive short axis scans from the apex to base were performed for each mouse. The resulting 11 self-gated cine images were used for fast low-angle shot analysis with a navigator echo over an observation period of approximately 35min. The right ventricle (RV) and LV were identified in the short axis and four chamber views. On 3D color-coded maps, the interventricular septum wall (diastole: 0.94+/-0.05mm, systole: 1.20+/-0.09mm) and LV free wall (diastole: 1.07+/-0.15mm, systole: 1.79+/-0.11mm) thicknesses were measured. CONCLUSION: This 3D wall thickness mapping technique can be used to observe regional wall thickness at the end-diastole and end-systole. Self-gated cine imaging based on ultra-high-field MRI can be used to accurately and easily measure cardiac function and wall thickness in normal mouse hearts. As in the preclinical study, this versatile and simple method will be clinically useful for the high-field-MRI evaluation of cardiac function and wall thickness. PMID- 27989904 TI - Dependence on b-value of the direction-averaged diffusion-weighted imaging signal in brain. AB - PURPOSE: The dependence of the direction-averaged diffusion-weighted imaging (DWI) signal in brain was studied as a function of b-value in order to help elucidate the relationship between diffusion weighting and brain microstructure. METHODS: High angular resolution diffusion imaging (HARDI) data were acquired from two human volunteers with 128 diffusion-encoding directions and six b-value shells ranging from 1000 to 6000s/mm2 in increments of 1000s/mm2. The direction averaged signal was calculated for each shell by averaging over all diffusion encoding directions, and the signal was plotted as a function of b-value for selected regions of interest. As a supplementary analysis, similar methods were also applied to retrospective DWI data obtained from the human connectome project (HCP), which includes b-values up to 10,000s/mm2. RESULTS: For all regions of interest, a simple power law relationship accurately described the observed dependence of the direction-averaged signal as a function of the diffusion weighting. In white matter, the characteristic exponent was 0.56+/-0.05, while in gray matter it was 0.88+/-0.11. Comparable results were found with the HCP data. CONCLUSION: The direction-averaged DWI signal varies, to a good approximation, as a power of the b-value, for b-values between 1000 and 6000s/mm2. The exponents characterizing this power law behavior were markedly different for white and gray matter, indicative of sharply contrasting microstructural environments. These results may inform the construction of microstructural models used to interpret the DWI signal. PMID- 27989906 TI - Advanced diffusion models in head and neck squamous cell carcinoma patients: Goodness of fit, relationships among diffusion parameters and comparison with dynamic contrast-enhanced perfusion. AB - PURPOSE: We assessed advanced fitting models of diffusion weighted imaging (DWI) in head/neck squamous cell carcinoma (HNSCC) patients to determine the best goodness of fit and correlations among diffusion parameters. We compared these results with those of dynamic contrast-enhanced (DCE) perfusion parameters. MATERIALS AND METHODS: We retrospectively evaluated 32 HNSCC patients (12 sinonasal, 20 pharynx/oral cavity). The DWI acquisition used single-shot spin echo echo-planar imaging (EPI) with 12 b-values (0-2000). We calculated 14 DWI parameters using mono-exponential, bi-exponential, and tri-exponential models, stretched exponential model (SEM) and diffusion kurtosis imaging (DKI) models. We compared each model's goodness of fit using the residual sum of squares (RSS), Akaike Information Criterion (AIC) and Bayesian information criterion (BIC) value. We determined the correlation between each pair of DWI parameters and between each DWI parameter and DCE perfusion parameter. RESULTS: The tri exponential fit's RSS, AIC and BIC values were significantly smaller than those for bi-exponential fit. The RSS, AIC and BIC values of the SEM fit and DKI fit were significantly smaller than mono-exponential model. Significant correlations were observed in 30 pairs (sinonasal cavity) and 31 (sinonasal cavity group) among 91 DWI parameter combinations. Significant correlations were also observed in nine pairs (both sinonasal cavity and pharynx/oral cavity group) among 64 DWI/DCE perfusion parameter pairs, in particular, high positive correlations between the tri-exponential model's intermediate diffusion fraction (f2) and the volume of the extracellular extravascular space per unit volume of tissue (ve) were observed in both patient groups. CONCLUSION: We identified several correlations between DWI parameters by advanced fitting models and correlations between DWI and DCE parameters. These will help determine HNSCC patients' detailed tissue structures. PMID- 27989907 TI - Traveling Internal Plane-wave Synthesis (TIPS) for uniform B1 in high field MRI. AB - A new target-field approach to generating uniform radio frequency (RF) fields within the human body for high field MRI is described. The method involves producing a set of external fields which, after interaction with a dielectric object, superimpose to produce a traveling plane wave, exposing all spins to the same RF amplitude (B1) over a cycle of the harmonic field. Conceptually this is similar to conventional RF shimming, but uses a different RF source design, input data, and objective function. The method requires a detailed knowledge of the coupling between exterior field modes, produced by an array of RF sources, and field modes within the body. Given an estimate of the coupling matrix, the linear superposition of external modes that produces a desired internal target field can be determined. The new method is termed Traveling Internal Plane-wave Synthesis (TIPS). A simple design of a coil array is described that can, in principle, generate the required field modes. Simulations demonstrate that radio frequency magnetic fields of nearly uniform (<1% variation) magnitude can be produced within dielectric objects larger than a wavelength in size. If the dielectric medium has non-zero conductivity, traveling waves are attenuated as they traverse the object, but field uniformity within planar slices is preserved. For general 3D imaging, a superposition of plane waves can provide field focusing to balance conductive losses, thereby achieving nearly uniform-magnitude B1+ magnetic fields over a volume of interest. PMID- 27989908 TI - Fast T1 mapping of the brain at high field using Look-Locker and fast imaging. AB - This study aims to develop and evaluate a new method for fast high resolution T1 mapping of the brain based on the Look-Locker technique. Single-shot turboflash sequence with high temporal acceleration is used to sample the recovery of inverted magnetization. Multi-slice interleaved acquisition within one inversion slab is used to reduce the number of inversion pulses and hence SAR. Accuracy of the proposed method was studied using simulation and validated in phantoms. It was then evaluated in healthy volunteers and stroke patients. In-vivo results were compared to values obtained by inversion recovery fast spin echo (IR-FSE) and literatures. With the new method, T1 values in phantom experiments agreed with reference values with median error <3%. For in-vivo experiments, a T1 map was acquired in 3.35s and the T1 maps of the whole brain were acquired in 2min with two-slice interleaving, with a spatial resolution of 1.1*1.1*4mm3. The T1 values obtained were comparable to those measured with IR-FSE and those reported in literatures. These results demonstrated the feasibility of the proposed method for fast T1 mapping of the brain in both healthy volunteers and stroke patients at 3T. PMID- 27989909 TI - Altered regional homogeneity of brain spontaneous signals in SIV infected rhesus macaque model. AB - BACKGROUND: Regional homogeneity (ReHo), a measurement from resting-state functional magnetic imaging (rs-fMRI) to reflect local synchronization of brain activities, has been widely explored in previous studies of neurological diseases. SIV infected model for detecting the neurological changes with progression was studied. METHODS: In the study, six rhesus macaques infected by simian immunodeficiency virus (SIV) were scanned by resting-state fMRI at the following time points: before SIV inoculation (baseline), 12weeks and 24weeks post inoculation (12wpi, 24wpi). Meanwhile, the immunological parameters including serum percentage of CD4+ T cell, CD4/CD8 ratio and absolute CD4+ T cell number were measured and analyzed. RESULTS: In comparison of baseline, significant decreased ReHo was found in the left superior frontal gyrus, left superior temporal gyrus, left hippocampus, right precuneus, left angular gyrus, and bilateral occipital gyrus; in contrast increased ReHo in putamen at 12wpi. Moreover, at the time of 24wpi, decreased ReHo was observed in the right postcentral gyrus, left precentral gyrus, posterior cingulated gyrus and thalamus, while ReHo was increased in the left putamen, hippocampus, left anterior cingulated cortex and precentral cortex. The correlation analysis revealed that ReHo in the superior frontal gyrus showed negative association with CD4/CD8 ratio and positive with absolute CD4+ T cell number. The correlation analysis showed that percentage of CD4+ was correlated with the ReHo values in right middle frontal gyrus, bilateral thalamus and amygdala positively; negative relationship with left putamen, left superior frontal gyrus, left superior and middle temporal gyrus. CONCLUSION: The study first indicates that hippocampus, putamen, frontal and occipital lobe were impaired by using rs-fMRI and correlated with immunological parameters. Thus, ReHo value can be utilized as a noninvasive biomarker of spontaneous brain activity changes caused by the progression of neurological impairments. PMID- 27989910 TI - A 32-channel coil system for MR vessel wall imaging of intracranial and extracranial arteries at 3T. AB - PURPOSE: To develop a RF coil system for joint imaging of intracranial and extracranial arterial vessel wall at 3T. MATERIALS AND METHOD: The coil system consists of a 24-channel head coil combined with an 8-channel carotid coil. It is compared with a standard coil configuration (12-channel head coil+4-channel neck coil+8-channel carotid coil) for SNR and g-factors in phantoms and healthy volunteers. The clinical relevance of the proposed coil system is also evaluated in patients. RESULTS: In phantom experiments, the SNR of the proposed coil system is 53% higher than the maximum SNR of the standard coil configuration at the center of the phantom which usually corresponds to the intracranial region of the head. The g-factors of the proposed coil system in the sagittal plane are lower than the standard coil configuration (by 10.8% and 26.6% for R=2 and 4 respectively) in the same experiment. In healthy volunteer experiments, 55% of the pixels have SNR above 100 for the proposed coil system, which is 33% more than that of the standard coil configuration. The maximum g-factors in the standard configuration are higher than those from the new coil design by 12% at R=2 and up to 36% at R=4 in the sagittal plane. In patients, in-vivo intracranial and extracranial arterial wall images at an isotropic spatial resolution of 0.6mm can be acquired using the proposed coil system. Plaques are well depicted from the images. CONCLUSIONS: The performance of the proposed coil set is superior to the standard coil configuration, providing high SNR, low g-factor and good spatial coverage needed for simultaneous high resolution imaging of intracranial and extracranial arterial walls. Images acquired in 7.6min using the proposed coil system can achieve an isotropic spatial resolution of 0.6mm and can be used to depict plaques on the intracranial and extracranial arterial walls in patients. PMID- 27989911 TI - Accelerated electron paramagnetic resonance imaging using partial Fourier compressed sensing reconstruction. AB - PURPOSE: Electron paramagnetic resonance (EPR) imaging has evolved as a promising tool to provide non-invasive assessment of tissue oxygenation levels. Due to the extremely short T2 relaxation time of electrons, single point imaging (SPI) is used in EPRI, limiting achievable spatial and temporal resolution. This presents a problem when attempting to measure changes in hypoxic state. In order to capture oxygen variation in hypoxic tissues and localize cycling hypoxia regions, an accelerated EPRI imaging method with minimal loss of information is needed. METHODS: We present an image acceleration technique, partial Fourier compressed sensing (PFCS), that combines compressed sensing (CS) and partial Fourier reconstruction. PFCS augments the original CS equation using conjugate symmetry information for missing measurements. To further improve image quality in order to reconstruct low-resolution EPRI images, a projection onto convex sets (POCS) based phase map and a spherical-sampling mask are used in the reconstruction process. The PFCS technique was used in phantoms and in vivo SCC7 tumor mice to evaluate image quality and accuracy in estimating O2 concentration. RESULTS: In both phantom and in vivo experiments, PFCS demonstrated the ability to reconstruct images more accurately with at least a 4-fold acceleration compared to traditional CS. Meanwhile, PFCS is able to better preserve the distinct spatial pattern in a phantom with a spatial resolution of 0.6mm. On phantoms containing Oxo63 solution with different oxygen concentrations, PFCS reconstructed linewidth maps that were discriminative of different O2 concentrations. Moreover, PFCS reconstruction of partially sampled data provided a better discrimination of hypoxic and oxygenated regions in a leg tumor compared to traditional CS reconstructed images. CONCLUSIONS: EPR images with an acceleration factor of four are feasible using PFCS with reasonable assessment of tissue oxygenation. The technique can greatly enhance EPR applications and improve our understanding cycling hypoxia. Moreover this technique can be easily extended to various MRI applications. PMID- 27989913 TI - Quantitative Dixon MRI sequences to relate muscle atrophy and fatty degeneration with range of motion and muscle force in brachial plexus injury. AB - BACKGROUND: Assessment of muscle atrophy and fatty degeneration in brachial plexus injury (BPI) could yield valuable insight into pathophysiology and could be used to predict clinical outcome. The objective of this study was to quantify and relate fat percentage and cross-sectional area (CSA) of the biceps to range of motion and muscle force of traumatic brachial plexus injury (BPI) patients. METHODS: T1-weighted TSE sequence and three-point Dixon images of the affected and non-affected biceps brachii were acquired on a 3 Tesla magnetic resonance scanner to determine the fat percentage, total and contractile CSA of 20 adult BPI patients. Regions of interest were drawn by two independent investigators to determine the inter-observer reliability. Paired Students' t-test and multivariate analysis were used to relate fat percentage, total and contractile CSA to active flexion and biceps muscle force. RESULTS: The mean fat percentage 12+/-5.1% of affected biceps was higher than 6+/-1.0% of the non-affected biceps (p<0.001). The mean contractile CSA 8.1+/-5.1cm2 of the affected biceps was lower than 19.4+/-4.9cm2 of the non-affected biceps (p<0.001). The inter-observer reliability was excellent (ICC 0.82 to 0.96). The contractile CSA contributed most to the reduction in active flexion and muscle force. CONCLUSION: Quantitative measurement of fat percentage, total and contractile CSA using three point Dixon sequences provides an excellent reliability and relates with active flexion and muscle force in BPI. PMID- 27989912 TI - Sex differences in sodium deposition in human muscle and skin. AB - The aim of this work was to investigate possible sex differences in the patterns of sodium deposition between muscle and skin using sodium MRI. A total of 38 subjects were examined for comparisons: 20 males, aged 25-79years with a median age of 51; 18 females, aged 38-66years, median age 53. All subjects underwent sodium MRI scans of the calf muscles together with cross sections through four calibration standards containing known sodium contents (10mM, 20mM, 30mM, and 40mM). Tissue sodium concentrations (TSC) in muscle and skin were then calculated by comparing signal intensities between tissues and reference standards using a linear analysis. A Wilcoxon rank sum test was applied to the DeltaTSC (=TSCmuscle TSCskin) series of males and females to examine if they were significantly different. Finally, a multiple linear regression was utilized to account for the effects from two potential confounders, age and body mass index (BMI). We found that sodium content appears to be higher in skin than in muscle for men, however women tend to have higher muscle sodium than skin sodium. This sex-relevant sodium deposition is statistically significant (P=3.10*10-5) by the Wilcoxon rank sum test, and this difference in distribution seems to be more reliable with increasing age. In the multiple linear regression, gender still has a statistically significant effect (P<1.0*10-4) on the difference between sodium deposition in muscle and skin, while taking the effects of age and BMI into account. PMID- 27989914 TI - A fast screening protocol for carotid plaques imaging using 3D multi-contrast MRI without contrast agent. AB - PURPOSE: To implement a fast (~15min) MRI protocol for carotid plaque screening using 3D multi-contrast MRI sequences without contrast agent on a 3Tesla MRI scanner. MATERIALS AND METHODS: 7 healthy volunteers and 25 patients with clinically confirmed transient ischemic attack or suspected cerebrovascular ischemia were included in this study. The proposed protocol, including 3D T1 weighted and T2-weighted SPACE (variable-flip-angle 3D turbo spin echo), and T1 weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) was performed first and was followed by 2D T1-weighted and T2-weighted turbo spin echo, and post-contrast T1-weighted SPACE sequences. Image quality, number of plaques, and vessel wall thicknesses measured at the intersection of the plaques were evaluated and compared between sequences. RESULTS: Average examination time of the proposed protocol was 14.6min. The average image quality scores of 3D T1 weighted, T2-weighted SPACE, and T1-weighted magnetization prepared rapid acquisition gradient echo were 3.69, 3.75, and 3.48, respectively. There was no significant difference in detecting the number of plaques and vulnerable plaques using pre-contrast 3D images with or without post-contrast T1-weighted SPACE. The 3D SPACE and 2D turbo spin echo sequences had excellent agreement (R=0.96 for T1 weighted and 0.98 for T2-weighted, p<0.001) regarding vessel wall thickness measurements. CONCLUSION: The proposed protocol demonstrated the feasibility of attaining carotid plaque screening within a 15-minute scan, which provided sufficient anatomical coverage and critical diagnostic information. This protocol offers the potential for rapid and reliable screening for carotid plaques without contrast agent. PMID- 27989915 TI - Application of carbon nanoparticles accelerates the rapid recovery of parathyroid function during thyroid carcinoma surgery with central lymph node dissection: A retrospective cohort study. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of carbon nanoparticles in identifying lymph nodes and promoting parathyroid gland function recovery after thyroid carcinoma surgery along with central lymph node dissection. METHODS: A total of 231 patients who underwent thyroid carcinoma surgery combined with central lymph node dissection were divided into two groups: the CN group (intraoperative carbon nanoparticles injections) and the control group (no injection). Datas were collected respectively on the pre-operative, 1st, 7th and 30th postoperative days and monthly thereafter. While the pathological results (e.g. amount of incidental removed parathyroid glands and lymph nodes dissected), complications (e.g. rates of vocal cord paralysis, the neuromuscular symptoms, hypocalcemia and hypoparathyroidism), as well as follow up outcomes of the serum Ca2+ and PTH levels were gathered and measured to be included in. RESULTS: In regard to the results of the pathological tests, the control group had a relatively higher incidence of incidental parathyroidectomy when compared to the CN group (P < 0.05). The mean number of central lymph nodes dissected was rather higher in the CN group than that of the control group (P < 0.05).With respect to the follow-up results, the CN group had an earlier and faster recovery of serum PTH levels as compared to the control group (P < 0.05). The serum PTH levels of the CN group were apparently higher than that of the control group at the first week and month postoperatively (P < 0.05). No significant differences were found in rates of long-term postoperative complications between the two groups (P > 0.05). CONCLUSION: Carbon nanoparticles play a key role in accurately identifying lymph nodes, reducing mistaken excision of parathyroid glands, accelerating rapid recovery of parathyroid function during thyroid carcinoma surgery with central lymph node dissection, without increasing the probability of postoperative complications. PMID- 27989916 TI - Robot-assisted radical prostatectomy in the setting of previous abdominal surgery: Perioperative results, oncological and functional outcomes, and complications in a single surgeon's series. AB - BACKGROUND: Data on safety and efficacy of robot-assisted radical prostatectomy (RARP) after previous abdominal surgery are scarce. Hence, we assessed perioperative, oncological and functional outcomes, and complications of RARP in patients with previous abdominal surgery after 1-year minimum follow-up. MATERIALS AND METHODS: Prospectively collected data from 339 consecutive patients undergoing transperitoneal RARP by a single surgeon (AM) between November 2008 and May 2014 were analysed. Complications were classified according to Modified Clavien System. Biochemical recurrence (BCR) was defined as two consecutive PSA values >= 0.2 ng/ml. Functional outcomes were assessed using validated, self administered questionnaires. In particular, only patients undergoing nerve sparing RARP with no erectile dysfunction (baseline IIEF-5 score >21) and no use of phosphodiesterase-5 inhibitors preoperatively who were interested in erections and required no adjuvant therapy (radiation, orchiectomy and androgen-deprivation therapy) were evaluated concerning potency recovery. Patients without and with previous abdominal surgery were compared using Mann-Whitney and chi-square tests (or Fisher exact test). RESULTS: On 339 patients, 247 (71.6%) had not undergone previous abdominal surgery (Group 1) and 92 (28.4%) were pre-operated (Group 2). There were no statistically significant differences between Groups 1 and 2 regarding mean operative time (260 vs. 257 min; p = 0.597), median number of resected nodes (16 vs. 17; p = 0.484), mean length of stay (7.2 vs. 7.1 d; p = 0.151), positive surgical margin (12.5% vs. 16.3%; p = 0.233) and complication rates (26.7% vs. 31.5%; p = 0.187). Median (IQR) follow-up was 36 (12-48) months. For Groups 1 and 2, BCR-free survival rates were 78.5% and 79.8% (p = 0.467); continence rates were 97.9% and 100% (p = 0.329), whereas a potency recovery was achieved in 69.5% and 62.2% of patients (p = 0.460), respectively. CONCLUSIONS: Transperitoneal RARP is a safe and efficient treatment for clinically localised prostate cancer even in patients with previous abdominal surgery. However, further studies with higher number of patients are warranted. PMID- 27989917 TI - Minimally invasive surgery for the treatment of pilonidal disease. The Gips procedure on 2347 patients. AB - BACKGROUND: Pilonidal disease is a quite common chronic inflammatory disease that causes discomfort, embarrassment and absence from work or school. In line with its acquired pathogenesis, a number of surgical alternatives to conventional en bloc excision have been proposed over the last decades, yielding encouraging results. We reviewed our experience with minimally invasive sinusectomy to evaluate its safety and efficacy. METHODS: this study was a review of a prospectively maintained database of consecutive patients over a 7-year period. From November 2009 to December 2015, 2347 patients with pilonidal disease were operated on using the Gips procedure. Patients received surgery as a day-case procedure under local anesthesia. Operative and perioperative data were examined. RESULTS: there were 1714 men (73%) and 633 women (27%) in the study; the median age was 19 years. Recurrent diseases in patients who had previously undergone surgery elsewhere composed 61% of cases. Globally, 102 cases of clinically relevant postoperative complication occurred (4.3%). At a median follow up of 16 months, the recurrence rate was 5.8%. The treatment of recurrent disease did not correlate to increased recurrence rate following sinusectomy. Recurrent patients were more likely to be male and have delayed wound healing. CONCLUSIONS: the Gips procedure for the treatment of pilonidal disease is safe and feasible. It has a low complication and recurrence rate, early return to daily activities and offers a good cosmetic result. PMID- 27989918 TI - HPV Update. PMID- 27989919 TI - Electrically conductive graphene/polyacrylamide hydrogels produced by mild chemical reduction for enhanced myoblast growth and differentiation. AB - : Graphene and graphene derivatives, such as graphene oxide (GO) and reduced GO (rGO), have been extensively employed as novel components of biomaterials because of their unique electrical and mechanical properties. These materials have also been used to fabricate electrically conductive biomaterials that can effectively deliver electrical signals to biological systems. Recently, increasing attention has been paid to electrically conductive hydrogels that have both electrical activity and a tissue-like softness. In this study, we synthesized conductive graphene hydrogels by mild chemical reduction of graphene oxide/polyacrylamide (GO/PAAm) composite hydrogels to obtain conductive hydrogels. The reduced hydrogel, r(GO/PAAm), exhibited muscle tissue-like stiffness with a Young's modulus of approximately 50kPa. The electrochemical impedance of r(GO/PAAm) could be decreased by more than ten times compared to that of PAAm and unreduced GO/PAAm. In vitro studies with C2C12 myoblasts revealed that r(GO/PAAm) significantly enhanced proliferation and myogenic differentiation compared with unreduced GO/PAAm and PAAm. Moreover, electrical stimulation of myoblasts growing on r(GO/PAAm) graphene hydrogels for 7days significantly enhanced the myogenic gene expression compared to unstimulated controls. As results, our graphene-based conductive and soft hydrogels will be useful as skeletal muscle tissue scaffolds and can serve as a multifunctional platform that can simultaneously deliver electrical and mechanical cues to biological systems. STATEMENT OF SIGNIFICANCE: Graphene-based conductive hydrogels presenting electrical conductance and a soft tissue-like modulus were successfully fabricated via mild reduction of graphene oxide/polyacrylamide composite hydrogels to study their potential to skeletal tissue scaffold applications. Significantly promoted myoblast proliferation and differentiation were obtained on our hydrogels. Additionally, electrical stimulation of myoblasts via the graphene hydrogels could further upregulate myogenic gene expressions. Our graphene-incorporated conductive hydrogels will impact on the development of new materials for skeletal muscle tissue engineering scaffolds and bioelectronics devices, and also serve as novel platforms to study cellular interactions with electrical and mechanical signals. PMID- 27989920 TI - Mechanical characterization of human brain tissue. AB - : Mechanics are increasingly recognized to play an important role in modulating brain form and function. Computational simulations are a powerful tool to predict the mechanical behavior of the human brain in health and disease. The success of these simulations depends critically on the underlying constitutive model and on the reliable identification of its material parameters. Thus, there is an urgent need to thoroughly characterize the mechanical behavior of brain tissue and to identify mathematical models that capture the tissue response under arbitrary loading conditions. However, most constitutive models have only been calibrated for a single loading mode. Here, we perform a sequence of multiple loading modes on the same human brain specimen - simple shear in two orthogonal directions, compression, and tension - and characterize the loading-mode specific regional and directional behavior. We complement these three individual tests by combined multiaxial compression/tension-shear tests and discuss effects of conditioning and hysteresis. To explore to which extent the macrostructural response is a result of the underlying microstructural architecture, we supplement our biomechanical tests with diffusion tensor imaging and histology. We show that the heterogeneous microstructure leads to a regional but not directional dependence of the mechanical properties. Our experiments confirm that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry. Using our measurements, we compare the performance of five common constitutive models, neo-Hookean, Mooney-Rivlin, Demiray, Gent, and Ogden, and show that only the isotropic modified one-term Ogden model is capable of representing the hyperelastic behavior under combined shear, compression, and tension loadings: with a shear modulus of 0.4-1.4kPa and a negative nonlinearity parameter it captures the compression-tension asymmetry and the increase in shear stress under superimposed compression but not tension. Our results demonstrate that material parameters identified for a single loading mode fail to predict the response under arbitrary loading conditions. Our systematic characterization of human brain tissue will lead to more accurate computational simulations, which will allow us to determine criteria for injury, to develop smart protection systems, and to predict brain development and disease progression. STATEMENT OF SIGNIFICANCE: There is a pressing need to characterize the mechanical behavior of human brain tissue under multiple loading conditions, and to identify constitutive models that are able to capture the tissue response under these conditions. We perform a sequence of experimental tests on the same brain specimen to characterize the regional and directional behavior, and we supplement our tests with DTI and histology to explore to which extent the macrostructural response is a result of the underlying microstructure. Results demonstrate that human brain tissue is nonlinear and viscoelastic, with a pronounced compression tension asymmetry, and we show that the multiaxial data can best be captured by a modified version of the one-term Ogden model. PMID- 27989921 TI - A model system for developing a tissue engineered meniscal enthesis. AB - : The meniscus acts as a stabilizer, lubricator, and load distributer in the knee joint. The mechanical stability of the meniscus depends on its connection to the underlying bone by a fibrocartilage to bone transition zone called the meniscal enthesis. Tissue engineered menisci hold great promise as a treatment alternative however lack a means of integrated fixation to the underlying bone needed in order for a tissue engineered meniscal replacement to be successful. Tissue engineering the meniscal enthesis is a difficult task given the complex gradients of cell type, mineral, and extracellular matrix molecules. Therefore, there is a need for a simplified and high throughput enthesis model to test experimental parameters. The goal of this study was to develop a simplified enthesis model to test collagen integration with decellularized bone. We found that injection molding collagen into tubing loaded with decellularized bone plugs resulted in a scaffold with three regions: bone, bone-collagen, and collagen. Furthermore, collagen formation was directed in the axial direction by using mechanical fixation at the bony ends. The results of this study showed that this technique can be used to mimic the native enthesis morphology and serves as ideal test platform to generate a model tissue engineered enthesis. STATEMENT OF SIGNIFICANCE: The meniscal enthesis is a complex structure that is essential to mechanical stability of the meniscus and the knee joint. Several studies document the development of anatomically shaped tissue engineered meniscus constructs, but none have focused on how to integrate such tissues with underlying bone. This study establishes a simplified construct to model the meniscal enthesis composed of a collagen gel seeded with meniscal fibrochondrocytes integrated with decellularized cancellous bone. Mechanical fixation at the bony ends induced tissue integration of fibers into the bony tissue, which is critical for mechanical performance and has yet to be shown in enthesis literature. Our test platform is amenable to targeted experiments investigating mineralization gradients, collagen fiber alignment, cell population phenotype, and media conditioning with experimental impact on enthesis studies for meniscus, tendon, and ligament. PMID- 27989922 TI - Well-defined star polymers for co-delivery of plasmid DNA and imiquimod to dendritic cells. AB - Co-delivery of antigen-encoding plasmid DNA (pDNA) and immune-modulatory molecules has importance in advancing gene-based immunotherapy and vaccines. Here novel star polymer nanocarriers were synthesized for co-delivery of pDNA and imiquimod (IMQ), a poorly soluble small-molecule adjuvant, to dendritic cells. Computational modeling and experimental results revealed that the polymers formed either multimolecular or unimolecular core-shell-type micelles in water, depending on the nature of the outer hydrophilic shell. Micelles loaded with both IMQ and pDNA were able to release IMQ in response to intracellular pH of the endo lysosome and transfect mouse dendritic cells (DC2.4 line) in vitro. Importantly, IMQ-loaded micelle/pDNA complexes displayed much enhanced transfection efficiency than IMQ-free complexes. These results demonstrate the feasibility of co-delivery of pDNA and IMQ to antigen-presenting cells by multifunctional polymer nanocarriers with potential use in gene-based vaccine approaches. PMID- 27989924 TI - The need for re-defining cut-off values in heart failure: From obesity to iron deficiency. AB - The health status of older people is frequently complicated by one or more chronic diseases. Some conditions might have a different meaning in certain groups of elderly subjects, like in frail people or older patients with heart failure. Cut-off values defining these conditions may require adjustment in such groups. Indeed, several such conditions (e.g. obesity and hypercholesterolemia) have been discussed recently in light of so-called paradoxical situations, which are - counter-intuitively - associated with better outcome instead of a negative impact on survival in the general population. Therefore, different cut-off values may be needed in some groups of older subjects. The pathophysiological mechanisms for these paradoxical situations need to be understood in at least two different ways, causal and non-causal. The aim of this review is to provide an overview of a variety of conditions (obesity, dyslipidaemia, hypertension, and diabetes) in which new cut-offs may have diagnostic, clinical, or prognostic value, focusing on heart failure as a chronic disease, which is frequently observed in older patients. Haemoglobin concentration may need a different cut-off in heart failure for a reason other than paradox. Namely, underlying iron deficiency itself, both in those with or without anaemia, can have effects on symptoms and quality of life. Further studies will be needed for re-defining cut-off values in heart failure and maybe in the other chronic illnesses. PMID- 27989925 TI - Cholesterol regulates DAF-16 nuclear localization and fasting-induced longevity in C. elegans. AB - Cholesterol has attracted significant attention as a possible lifespan regulator. It has been reported that serum cholesterol levels have an impact on mortality due to age-related disorders such as cardiovascular disease. Diet is also known to be an important lifespan regulator. Dietary restriction retards the onset of age-related diseases and extends lifespan in various organisms. Although cholesterol and dietary restriction are known to be lifespan regulators, it remains to be established whether cholesterol is involved in dietary restriction induced longevity. Here, we show that cholesterol deprivation suppresses longevity induced by intermittent fasting, which is one of the dietary restriction regimens that effectively extend lifespan. We also found that cholesterol is required for the fasting-induced upregulation of transcriptional target genes such as the insulin/IGF-1 pathway effector DAF-16 and that cholesterol deprivation suppresses the long lifespan of the insulin/IGF-1 receptor daf-2 mutant. Remarkably, we found that cholesterol plays an important role in the fasting-induced nuclear accumulation of DAF-16. Moreover, knockdown of the cholesterol-binding protein NSBP-1, which has been shown to bind to DAF-16 in a cholesterol-dependent manner and to regulate DAF-16 activity, suppresses both fasting-induced longevity and DAF-16 nuclear accumulation. Furthermore, this suppression was not additive to the cholesterol deprivation-induced suppression, which suggests that NSBP-1 mediates, at least in part, the action of cholesterol to promote fasting-induced longevity and DAF-16 nuclear accumulation. These findings identify a novel role for cholesterol in the regulation of lifespan. PMID- 27989923 TI - A robust vitronectin-derived peptide for the scalable long-term expansion and neuronal differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (hNPCs). AB - Despite therapeutic advances, neurodegenerative diseases and disorders remain some of the leading causes of mortality and morbidity in the United States. Therefore, cell-based therapies to replace lost or damaged neurons and supporting cells of the central nervous system (CNS) are of great therapeutic interest. To that end, human pluripotent stem cell (hPSC) derived neural progenitor cells (hNPCs) and their neuronal derivatives could provide the cellular 'raw material' needed for regenerative medicine therapies for a variety of CNS disorders. In addition, hNPCs derived from patient-specific hPSCs could be used to elucidate the underlying mechanisms of neurodegenerative diseases and identify potential drug candidates. However, the scientific and clinical application of hNPCs requires the development of robust, defined, and scalable substrates for their long-term expansion and neuronal differentiation. In this study, we rationally designed a vitronectin-derived peptide (VDP) that served as an adhesive growth substrate for the long-term expansion of several hNPC lines. Moreover, VDP-coated surfaces allowed for the directed neuronal differentiation of hNPC at levels similar to cells differentiated on traditional extracellular matrix protein-based substrates. Overall, the ability of VDP to support the long-term expansion and directed neuronal differentiation of hNPCs will significantly advance the future translational application of these cells in treating injuries, disorders, and diseases of the CNS. PMID- 27989927 TI - Major Depressive Disorder Among Preadolescent Canadian Children: Rare Disorder or Rarely Detected? AB - OBJECTIVE: Despite agreement that preadult onset of depression is associated with greater illness severity, and that children can meet the diagnostic criteria for major depressive disorder (MDD), few studies have examined the presentation of MDD among young children. This is the first nationwide study of MDD among preadolescent children in Canada. METHODS: Pediatrician members (2500) of a Canadian pediatric surveillance network were surveyed monthly over 3 years to report new cases of MDD among 5- to 12-year-olds. Survey response and questionnaire completion rates were 80% and 85%, respectively. Symptom presentation and duration, impairment, medical and psychiatric history, and management were reported. RESULTS: Twenty-nine new cases of MDD were identified by pediatricians. Of these, 23 (79%) experienced symptoms for >6 months before presentation with global functional impairment. Parental depression or anxiety, commonly maternal, was present in 21 cases (72%). Twenty-two children (76%) reported suicidal ideation; 6 (21%) had attempted suicide. Twenty-three children (79%) were treated with medication. Thirteen children (45%) were treated with 2 or more medications. CONCLUSIONS: Children with MDD frequently had a parental history of mood disorders, experienced long-standing symptom presence, high symptom burden and functional impairment prior to presentation; and commonly treatment with polypharmacy. PMID- 27989926 TI - Age differences in dynamic fatigability and variability of arm and leg muscles: Associations with physical function. AB - INTRODUCTION: It is not known whether the age-related increase in fatigability of fast dynamic contractions in lower limb muscles also occurs in upper limb muscles. We compared age-related fatigability and variability of maximal-effort repeated dynamic contractions in the knee extensor and elbow flexor muscles; and determined associations between fatigability, variability of velocity between contractions and functional performance. METHODS: 35 young (16 males; 21.0+/ 2.6years) and 32 old (18 males; 71.3+/-6.2years) adults performed a dynamic fatiguing task involving 90 maximal-effort, fast, concentric, isotonic contractions (1 contraction/3s) with a load equivalent to 20% maximal voluntary isometric contraction (MVIC) torque with the elbow flexor and knee extensor muscles on separate days. Old adults also performed tests of balance and walking endurance. RESULTS: Old adults had greater fatigue-related reductions in peak velocity compared with young adults for both the elbow flexor and knee extensor muscles (P<0.05) with no sex differences (P>0.05). Old adults had greater variability of peak velocity during the knee extensor, but not during the elbow flexor fatiguing task. The age difference in fatigability was greater for the knee extensor muscles (35.9%) compared with elbow flexor muscles (9.7%, P<0.05). Less fatigability of the knee extensor muscles was associated with greater walking endurance (r=-0.34, P=0.048) and balance (r=-0.41, P=0.014) among old adults. CONCLUSIONS: An age-related increase in fatigability of a dynamic fatiguing task was greater for the knee extensor compared with the elbow flexor muscles in males and females, and greater fatigability was associated with lesser walking endurance and balance. PMID- 27989928 TI - Anti-botulism single-shot vaccine using chitosan for protein encapsulation by simple coacervation. AB - The aim of the present study was to compare the potency and safety of vaccines against Clostridium botulinum (C. botulinum) type C and D formulated with chitosan as controlled release matrix and vaccines formulated in conventional manner using aluminum hydroxide. Parameters were established for the development of chitosan microspheres, using simple coacervation to standardize the use of this polymer in protein encapsulation for vaccine formulation. To formulate a single shot vaccine inactivated antigens of C. botulinum type C and D were used with original toxin titles equal to 5.2 and 6.2 log LD50/ml, respectively. For each antigen a chitosan based solution of 50 mL was prepared. Control vaccines were formulated by mixing toxoid type C and D with aluminum hydroxide [25% Al(OH)3, pH 6.3]. The toxoid sterility, innocuity and potency of vaccines were evaluated as stipulated by MAPA-BRASIL according to ministerial directive no. 23. Encapsulation efficiency of BSA in chitosan was 32.5-40.37%, while that the encapsulation efficiency to toxoid type C was 41,03% (1.94 mg/mL) and of the toxoid type D was 32.30% (1.82 mg/mL). The single shot vaccine formulated using chitosan for protein encapsulation through simple coacervation showed potency and safety similar to conventional vaccine currently used in Brazilian livestock (10 and 2 IU/mL against C. botulinum type C and D, respectively). The present work suggests that our single shot vaccine would be a good option as a cattle vaccine against these C. botulinum type C and D. PMID- 27989929 TI - Matching at Human Leukocyte Antigen-C Improved the Outcomes after Double Umbilical Cord Blood Transplantation for Recipients of Two to Four of Six Human Leukocyte Antigen-Matched Grafts. AB - We studied the effect of HLA-C matching in 515 patients after double umbilical cord blood (UCB) transplantation. After HLA matching HLA-A, -B, and -DRB1 at the allele level, we scored patients according to number of donor-recipient HLA-C matches at 4 possible loci: 2 from each donor unit, at the allele level. Given a direct interaction between HLA-A, -B, and -DRB1 matching and HLA-C score, we analyzed HLA-C matching in those receiving at least 1 2/6 to 4/6 HLA-matched unit (n = 389) versus those receiving only 5/6 or 6/6-matched units (n = 126). In those with at least 1 2/6 to 4/6 HLA-matched unit, a better HLA-C matching score was associated with significantly lower risk of death of any cause and nonrelapse mortality and better disease-free survival. There was no association with the risk of relapse, acute and chronic graft-versus-host disease, and hematopoietic recovery. In contrast, among patients receiving only allele-level 5/6 or 6/6 HLA matched UCB units, HLA-C match had no demonstrable effect on any outcome. For patients receiving at least 1 allele-level 2/6 to 4/6 HLA-matched UCB unit, matching at HLA-C reduces nonrelapse mortality and improves survival. PMID- 27989930 TI - Identification of DPB1 Permissive Unrelated Donors Is Highly Likely. AB - HLA-DPB1 permissive matching based on T cell epitope (TCE) groups should be considered when selecting among equally matched HLA-A, -B, -C, -DRB1 unrelated hematopoietic stem cell donors to improve patient survival. Previous studies have defined 3 TCE groups based on functional assays of alloreactivity. Combinations of donor and recipient DPB1 alleles with low immunogenic potential identify permissive donors, who provide no increased risk of mortality compared with DPB1 matched donors. To determine the likelihood of identifying a DPB1 permissive matched (includes both allele-matched and DPB1-permissive mismatched) unrelated donor for patients with high-resolution matches at 10/10 HLA-A, -B,- C, -DRB1, and -DQB1 in the Be The Match Registry, preliminary search requests from United States' transplant centers for 595 DPB1-typed patients were evaluated for existence of a DPB1 permissive-matched donor, identified either among already typed donors or by prospective DPB1 typing. The baseline DPB1 permissive match rate was 69% and improved to 80% after additional donor DPB1 typing (median, 4 donors per patient). When seeking a 10/10-matched, young (18- to 32-year-old) donor in the registry, the probability of finding a DPB1 permissive-matched donor started lower at 59% and improved to 70% after additional DPB1 testing. Our results show that most patients with a 10/10 match can find a DPB1 permissive matched donor. PMID- 27989931 TI - National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: Developing Recommendations to Improve Survivorship and Long-Term Outcomes. AB - Continual advances in hematopoietic cell transplantation (HCT) have greatly improved early transplantation-related mortality and broadened the applicability of this intense but curative therapy. With growing success there is increasing awareness of late complications, occurring >=1 year after treatment, and their associated morbidity and mortality in HCT survivors. These late effects occur with a wide spectrum in terms of latency, intensity, reversibility, and lethality. There is a need to understand the biology, surveillance, management, and patient experience of HCT-related effects, as well as the health care and research infrastructure to manage this growing population. To address these needs, the National Cancer Institute and National Heart, Lung and Blood Institute cosponsored a 12-month initiative to identify barriers and knowledge gaps and to formulate research and practice recommendations. Six major areas of interest were identified: research methodology and study design, subsequent neoplasms, patient centered outcomes, immune dysregulation and pathobiology, cardiovascular disease and associated risk factors, and health care delivery. These findings were presented during the 2016 workshop and revised based on public response. This report provides an overview of the National Institutes of Health HCT Late Effects Initiative process and recommendations. PMID- 27989932 TI - Allele-Level HLA Matching Impacts Key Outcomes Following Umbilical Cord Blood Transplantation for Inherited Metabolic Disorders. AB - Allogeneic hematopoietic stem cell transplantation has demonstrated efficacy for numerous inherited metabolic disorders (IMDs). Umbilical cord blood transplant (UCBT) is increasingly used as a graft source in IMDs, but little is known of the impact of cord blood unit (CBU)/recipient HLA allelic disparity on key outcomes following UCBT for IMD. We reviewed outcomes of 106 consecutive first, single UCBTs for IMD at the University of Minnesota with regard to CBU/recipient HLA allelic matching (HLA-A, -B, -C, and -DRB1). The median age at UCBT was 1 year, and 87 patients (82%) received myeloablative conditioning. Primary diagnoses were Hurler syndrome (41%), cerebral adrenoleukodystrophy (35%), metachromatic leukodystrophy/globoid cell leukodystrophy (9%), and other (16%). The 5-year overall survival (OS) for the entire cohort was 70% (95% confidence interval, 59% to 79%). Rates of severe acute and chronic graft-versus-host disease were low (6% for each). CBU/recipient HLA conventional matching was based on antigen-level matching at HLA-A and -B, and on allele-level matching at HLA-DRB1. Of 46 conventional matched UCBTs, 20 (43%) were mismatched at 1 or more alleles. Of 49 conventional 5/6 UCBTs, 30 (61%) were mismatched at >=2 alleles and 19 (39%) were mismatched at >=3 alleles. Within the 6/6 conventional match stratum, comparisons of key outcomes between allele-matched and allele-mismatched UCBT were as follows: 5-year OS, 88% versus 42% (P < .01); 1-year engrafted survival (ES) with >=90% donor chimerism, 73% versus 60% (P = .33); graft failure, 8% versus 30% (P = .05); and transplantation-related mortality (TRM), 8% versus 30% (P = .04). For patients undergoing conventional 5/6 HLA-matched UCBT, better allelic matching was associated with similar outcomes: 5-year OS, 77% versus 74% (P = .72); 1-year ES, 73% versus 47% (P = .06); graft failure, 17% versus 42% (P = .05); and TRM, 10% versus 16% (P = .54). On multivariable analyses, fewer allele-level mismatches within each conventional match stratum continued to predict more favorable outcomes following UCBT. These data provide evidence that allele-level HLA matching considerations within a conventional HLA match stratum may better predict outcomes of interest after UCBT for IMD. Larger studies are warranted to confirm these findings and explore other allele-level HLA match dynamics. PMID- 27989934 TI - NF-Y and the immune response: Dissecting the complex regulation of MHC genes. AB - Nuclear Factor Y (NF-Y) was first described as one of the CCAAT binding factors. Although CCAAT motifs were found to be present in various genes, NF-Y attracted a lot of interest early on, due to its role in Major Histocompatibility Complex (MHC) gene regulation. MHC genes are crucial in immune response and show peculiar expression patterns. Among other conserved elements on MHC promoters, an NF-Y binding CCAAT box was found to contribute to MHC transcriptional regulation. NF-Y along with other DNA binding factors assembles in a stereospecific manner to form a multiprotein scaffold, the MHC enhanceosome, which is necessary but not sufficient to drive transcription. Transcriptional activation is achieved by the recruitment of yet another factor, the class II transcriptional activator (CIITA). In this review, we briefly discuss basic findings on MHCII transcription regulation and we highlight NF-Y different modes of function in MHCII gene activation. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani. PMID- 27989935 TI - The multifaceted roles of NUCLEAR FACTOR-Y in Arabidopsis thaliana development and stress responses. AB - NUCLEAR FACTOR-Y (NF-Y) is a heterotrimeric transcription factor (TF) consisting of evolutionarily distinct NF-YA, NF-YB and NF-YC subunits. The functional NF-Y heterotrimer binds to CCAAT elements in eukaryotic gene promoters and influences their expression. The genome of the model organism Arabidopsis thaliana encodes 10 distinct NF-YA, NF-YB, and NF-YC proteins, allowing for enormous combinatorial and functional diversity. Two decades of research have elucidated the importance of NF-Ys in plant growth, development and stress responses; however, the molecular mechanisms of action remain largely unexplored. Intriguingly, recent evidence suggests that NF-Ys are frequently associated with other groups of TFs, expanding the potential NF-Y combinatorial complexity. Further, information regarding the regulation of individual NF-Y subunits at the transcriptional and post-transcriptional level is beginning to emerge. In this review, we will identify developing trends within the NF-Y field and discuss recent progress towards a better understanding of NF-Y function, molecular action, and regulation in the context of Arabidopsis. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani. PMID- 27989936 TI - Thirty years of the HAP2/3/4/5 complex. PMID- 27989937 TI - Unearthing Bulgakov's trace proteome from the Master i Margarita manuscript. AB - : Ten pages, selected from a total of 127, of the last manuscript of Master i Margarita, written by Bulgakov in the last four years of his life, have been analysed in order to harvest and identify any trace proteome left on the margin by the novelist, in the hope of finding biomarkers of his fatal nephrotic syndrome. To that aim, we prepared a special ethyl-vinyl acetate film as binder of ground AG 501 Bio-Rad mix-bed strong cation/strong anion exchange resins for adsorbing any protein left on the margins of the pages via saliva and/or sweat. After eluting, digesting and interrogating the peptides by LC-MS/MS, we could identify three proteins, periostin, N-acetyl-beta-glucosaminidase and nephrin, reported as biomarkers of renal pathologies. Additionally a further 29 unique gene products, of saliva and skin origin, have been identified, together with two bacterial proteins. The novel method here reported could be safely applied to any other research on manuscripts stored in public libraries and repositories of the World Cultural Heritage. SIGNIFICANCE: The present manuscript aims at finding proteomics traces in a 75-year old manuscript in order to confirm the health state of the author. In the case of Bulgakov it was known that he died of renal disease, possibly leaving traces and/or biomarkers of this pathology on the margins of the pages analysed. Three proteins, stated to be biomarkers of nephrotic syndrome, could be identified. In order not to contaminate the manuscript pages with resin particles, we have devised a novel harvesting film, by which strong cation and anion exchangers are embedded in ethyl-vinyl acetate foils. It is felt that this technology could be safely applied to other specimens belonging to the Word Heritage. PMID- 27989938 TI - Proteomic analysis provides insights into the molecular bases of hydrogen gas induced cadmium resistance in Medicago sativa. AB - : Recently, molecular hydrogen (H2) has emerged as a bio-regulator both in animals and plants. Normally, functions of endogenous generated H2 could be mimicked by exogenously applied hydrogen-rich water (HRW) or hydrogen-rich saline (particularly in animals). Although alfalfa seedlings showed more cadmium (Cd) resistance after the administration with HRW, corresponding molecular mechanism is still elusive. To address this gap, iTRAQ-based quantitative proteomics was used. The results showed that a total of 2377 proteins were identified with <1% FDR, and 1254 protein abundance perturbations were confidently assessed. Total of 248 significant differential proteins were identified in Cd- and/or HRW-treated samples. Furthermore, 92 proteins from the 248 proteins were selected for further bioinformatics analysis. Interestingly, results indicated that they were classified into seven categories: defense and response to stress, sulfur compound metabolic process, amino acid and protein metabolic process, carbohydrate and energy metabolic process, secondary metabolic process, oxidation-reduction process, and metal ion homeostasis. In addition, the protein expression patterns were consistent with the results of decreased lipid peroxidation, increased non protein thiols abundance, as well as iron and zinc content. These suggest that HRW alleviates Cd toxicity mainly by decreasing oxidative damage, enhancing sulfur compound metabolic process, and maintaining nutrient element homeostasis. BIOLOGICAL SIGNIFICANCE: Contamination of soils by Cd has become a potential concern to crops. Medicago sativa is a widely used forage around the world. Recently, hydrogen gas (H2) was suggested as a candidate of signal molecule, and found to effectively attenuate Cd-induced damage in alfalfa seedlings. However, the underlying molecular mechanism still needs to be further elucidated. In the present work, an iTRAQ-based quantitative proteomics was firstly carried out, and the results revealed the main molecular targets and metabolic processes associated with Cd resistance conferred by H2. This study may expand our understanding of hydrogen gas-medicated heavy metal tolerance in plants. PMID- 27989933 TI - Transcription factors that influence RNA polymerases I and II: To what extent is mechanism of action conserved? AB - In eukaryotic cells, nuclear RNA synthesis is accomplished by at least three unique, multisubunit RNA polymerases. The roles of these enzymes are generally partitioned into the synthesis of the three major classes of RNA: rRNA, mRNA, and tRNA for RNA polymerases I, II, and III respectively. Consistent with their unique cellular roles, each enzyme has a complement of specialized transcription factors and enzymatic properties. However, not all transcription factors have evolved to affect only one eukaryotic RNA polymerase. In fact, many factors have been shown to influence the activities of multiple nuclear RNA polymerases. This review focuses on a subset of these factors, specifically addressing the mechanisms by which these proteins influence RNA polymerases I and II. PMID- 27989939 TI - High-resolution mass spectrometry-based global proteomic analysis of probiotic strains Lactobacillus fermentum NCDC 400 and RS2. AB - Lactobacillus fermentum strains NCDC 400 and RS2, previously isolated from dairy sources, exhibited excellent probiotic properties were studied for the global proteomic profile. A total of 1125 proteins were identified by a high-resolution mass spectrometer, ESI-qTOF (nano-LC-MS/MS) in the strains of L. fermentum. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis resulted in 60.9% and 59.2% of the total proteins were functionally annotated for NCDC 400 and RS2 respectively. Simultaneously, a cluster of orthologous groups (COGs) and KEGG together revealed the presence of a significant number of proteins involved in transcription, translation, chaperones, peptidoglycan biosynthesis, nucleotide, amino acid and carbohydrate metabolism. Most of the proteins that play a vital role in the formation of RNA polymerase, ribosomal subunits, and aminoacyl-tRNA biosynthesis were fully mapped. Further analysis by bioinformatics tools revealed that 13.83% of the proteins were hydrophobic while 86.17% were hydrophilic in nature. The present findings represent the first draft proteome map of L. fermentum strains and demonstrate the involvement of important proteins in normal physiology and growth of potential probiotic strain. PMID- 27989940 TI - The Aotus nancymaae erythrocyte proteome and its importance for biomedical research. AB - : The Aotus nancymaae species has been of great importance in researching the biology and pathogenesis of malaria, particularly for studying Plasmodium molecules for including them in effective vaccines against such microorganism. In spite of the forgoing, there has been no report to date describing the biology of parasite target cells in primates or their biomedical importance. This study was thus designed to analyse A. nancymaae erythrocyte protein composition using MS data collected during a previous study aimed at characterising the Plasmodium vivax proteome and published in the pertinent literature. Most peptides identified were similar to those belonging to 1189 Homo sapiens molecules; >95% of them had orthologues in New World primates. GO terms revealed a correlation between categories having the greatest amount of proteins and vital cell function. Integral membrane molecules were also identified which could be possible receptors facilitating interaction with Plasmodium species. The A. nancymaae erythrocyte proteome is described here for the first time, as a starting point for more in-depth/extensive studies. The data reported represents a source of invaluable information for laboratories interested in carrying out basic and applied biomedical investigation studies which involve using this primate. SIGNIFICANCE: An understanding of the proteomics characteristics of A. nancymaae erythrocytes represents a fascinating area for research regarding the study of the pathogenesis of malaria since these are the main target for Plasmodium invasion. However, and even though Aotus is one of the non-human primate models considered most appropriate for biomedical research, knowledge of its proteome, particularly its erythrocytes, remains unknown. According to the above and bearing in mind the lack of information about the A. nancymaae species genome and transcriptome, this study involved a search for primate proteins for comparing their MS/MS spectra with the available information for Homo sapiens. The great similarity found between the primate's molecules and those for humans supported the use of the monkeys or their cells for continuing assays involved in studying malaria. Integral membrane receptors used by Plasmodium for invading cells were also found; this required timely characterisation for evaluating their therapeutic role. The list of erythrocyte protein composition reported here represents a useful source of basic knowledge for advancing biomedical investigation in this field. PMID- 27989942 TI - MALDI-TOF mass spectrometry for rapid diagnosis of postoperative endophthalmitis. AB - This study describes an innovative strategy for rapid detection and identification of bacteria causing endophthalmitis, combining the use of an automated blood culture system with MALDI-TOF mass spectrometry methodology. Using this protocol, we could identify 96% of 45 bacterial strains isolated from vitreous samples collected in acute post-operative endophthalmitis patients. PMID- 27989941 TI - A multicentric study to evaluate the use of relative retention times in targeted proteomics. AB - : Despite the maturity reached by targeted proteomic strategies, reliable and standardized protocols are urgently needed to enhance reproducibility among different laboratories and analytical platforms, facilitating a more widespread use in biomedical research. To achieve this goal, the use of dimensionless relative retention times (iRT), defined on the basis of peptide standard retention times (RT), has lately emerged as a powerful tool. The robustness, reproducibility and utility of this strategy were examined for the first time in a multicentric setting, involving 28 laboratories that included 24 of the Spanish network of proteomics laboratories (ProteoRed-ISCIII). According to the results obtained in this study, dimensionless retention time values (iRTs) demonstrated to be a useful tool for transferring and sharing peptide retention times across different chromatographic set-ups both intra- and inter-laboratories. iRT values also showed very low variability over long time periods. Furthermore, parallel quantitative analyses showed a high reproducibility despite the variety of experimental strategies used, either MRM (multiple reaction monitoring) or pseudoMRM, and the diversity of analytical platforms employed. BIOLOGICAL SIGNIFICANCE: From the very beginning of proteomics as an analytical science there has been a growing interest in developing standardized methods and experimental procedures in order to ensure the highest quality and reproducibility of the results. In this regard, the recent (2012) introduction of the dimensionless retention time concept has been a significant advance. In our multicentric (28 laboratories) study we explore the usefulness of this concept in the context of a targeted proteomics experiment, demonstrating that dimensionless retention time values is a useful tool for transferring and sharing peptide retention times across different chromatographic set-ups. PMID- 27989943 TI - Identification of actin beta-like 2 (ACTBL2) as novel, upregulated protein in colorectal cancer. AB - : Early diagnosis of colorectal cancer (CRC) can be of value for increasing the survival rate of patients. Recently, proteomic strategies to identify markers for the diagnosis of cancer at an early stage have been employed with noteworthy results. To extend these studies, we utilized two dimensional gel electrophoresis and mass spectrometry for expression profiling of proteins extracted from the freshly frozen human colorectal cancer tissue specimens and the comparable regions of adjacent normal mucosa (serving as controls). Four gel spots were determined to be differentially stained between the tumor and the control samples on a consistent basis. Following mass spectrometric analysis of these spots, six proteins were identified; five of these had previously been reported to be associated with colorectal cancer. One protein actin beta-like 2 (ACTBL2), not linked with colorectal cancer in the earlier reports, was however found to be at higher abundance in colorectal tumor samples both by proteomics and immunohistochemistry analysis. Thus ACTBL2 association and differential upregulation in colorectal cancer is novel, and as such may contribute to our understanding of the colorectal carcinogenesis and potentially serve a function in developing markers for colorectal cancer. BIOLOGICAL SIGNIFICANCE: Colorectal cancer (CRC) is a major cause of death world-wide and good markers for early detection are lacking. In this study we conducted a proteomic analysis of tumor vs. normal tissue. We corroborated the finding of a number of previously identified proteins associated with CRC and more importantly identified a novel protein, ACTBL2, which we demonstrated to be upregulated in CRC. As additional proteins associated with CRC are identified the potential for developing panels of markers may be realized with better outcomes in early cancer detection. PMID- 27989944 TI - Top-down protein identification using isotopic envelope fingerprinting. AB - : For top-down protein database search and identification from tandem mass spectra, our isotopic envelope fingerprinting search algorithm and ProteinGoggle search engine have demonstrated their strength of efficiently resolving heavily overlapping data as well separating non-ideal data with non-ideal isotopic envelopes from ideal ones with ideal isotopic envelopes. Here we report our updated ProteinGoggle 2.0 for intact protein database search with full-capacity. The indispensable updates include users' optional definition of dynamic post translational modifications and static chemical labeling during database creation, comprehensive dissociation methods and ion series, as well as a Proteoform Score for each proteoform. ProteinGoggle has previously been benchmarked with both collision-based dissociation (CID, HCD) and electron-based dissociation (ETD) data of either intact proteins or intact proteomes. Here we report our further benchmarking of the new version of ProteinGoggle with publically available photon-based dissociation (UVPD) data (http://hdl.handle.net/2022/17316) of intact E. coli ribosomal proteins. BIOLOGICAL SIGNIFICANCE: Protein species (aka proteoforms) function at their molecular level, and diverse structures and biological roles of every proteoform come from often co-occurring proteolysis, amino acid variation and post translational modifications. Complete and high-throughput capture of this combinatorial information of proteoforms has become possible in evolving top-down proteomics; yet, various methods and technologies, especially database search and bioinformatics identification tools, in the top-down pipeline are still in their infancy stages and demand intensive research and development. PMID- 27989945 TI - Specific adjustments in grapevine leaf proteome discriminating resistant and susceptible grapevine genotypes to Plasmopara viticola. AB - : Grapevine downy mildew is an important disease affecting crop production leading to severe yield losses. This study aims to identify the grapevine cultivar-specific adjustments of leaf proteome that allow the discrimination between resistance and susceptibility towards P. viticola (constitutive (0h) and in after inoculation (6, 12 and 24h). Leaf proteome analysis was performed using 2D difference gel electrophoresis followed by protein identification via mass spectrometry. In addition, we analysed ROS production, antioxidant capacity, lipid peroxidation and gene expression. Proteins related to photosynthesis and metabolism allowed the discrimination of resistant and susceptible grapevine cultivars prior to P. viticola inoculation. Following inoculation increase of hydrogen peroxide levels, cellular redox regulation, establishment of ROS signalling and plant cell death seem to be key points differentiating the resistant genotype. Lipid associated signalling events, particularly related to jasmonates appear also to play a major role in the establishment of resistance. The findings from this study contribute to a better understanding of genotype specific differences that account for a successful establishment of a defence response to the downy mildew pathogen. BIOLOGICAL SIGNIFICANCE: Here, we present for the first time grapevine cultivar-specific adjustments of leaf proteome that allow the discrimination between resistance and susceptibility towards P. viticola (constitutive (0h) and in after inoculation (6, 12 and 24h). We have highlighted that, following inoculation, the major factors differentiating the resistant from the susceptible grapevine cultivars are the establishment of effective ROS signalling together with lipid-associated signalling events, particularly related to jasmonates. It is believed that plants infected with biotrophic pathogens suppress JA-mediated responses, however recent evidences shown that jasmonic acid signalling pathway in grapevine resistance against Plasmopara viticola. Our results corroborate those evidences and highlight the importance of lipid- signalling for an effective resistance response against the downy mildew pathogen. PMID- 27989946 TI - iTRAQ analysis of the tobacco leaf proteome reveals that RNA-directed DNA methylation (RdDM) has important roles in defense against geminivirus betasatellite infection. AB - : Geminiviruses have caused serious losses in crop production. To investigate the mechanisms underlying host defenses against geminiviruses, an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic approach was used to explore the expression profiles of proteins in Nicotiana benthamiana (N. benthamiana) leaves in response to tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB) at an early phase. In total, 4155 proteins were identified and 272 proteins were changed differentially in response to TYLCCNV/TYLCCNB infection. Bioinformatics analysis indicated that S adenosyl-l-methionine cycle II was the most significantly up-regulated biochemical process during TYLCCNV/TYLCCNB infection. The mRNA levels of three proteins in S-adenosyl-l-methionine cycle II were further analyzed by qPCR, each was found significantly up-regulated in TYLCCNV/TYLCCNB-infected N. benthamiana. This result suggested a strong promotion of the biosynthesis of available methyl groups during geminivirus infections. We further tested the potential role of RdDM in N. benthamiana by virus-induced gene silencing (VIGS) and found that a disruption in RdDM resulted in more severe infectious symptoms and higher accumulation of viral DNA after TYLCCNV/TYLCCNB infection. Although the precise functions of these proteins still need to be determined, our proteomic results enhance the understanding of plant antiviral mechanisms. BIOLOGICAL SIGNIFICANCE: One of the major limitations to crop growth in the worldwide is the prevalence of geminiviruses. They are able to infect food and cash crops and cause serious crop failures and economic losses worldwide, especially in Africa and Asia. Tomato yellow leaf curl China virus (TYLCCNV), which causes severe viral diseases in China, is a monopartite geminivirus associated with the betasatellite (TYLCCNB). However, the mechanisms underlying the TYLCCNV/TYLCCNB defense in plants are still not fully understood at the molecular level. In this study, the combined proteomic, bioinformatic and VIGS analyses revealed that TYLCCNV/TYLCCNB invasion caused complex proteomic alterations in the leaves of N. benthamiana involving the processes of stress and defense, energy production, photosynthesis, protein homeostasis, metabolism, cell structure, signal transduction, transcription, transportation, and cell growth/division. Promotion of available methyl groups via the S-adenosyl-l-methionine cycle II pathway in N. benthamiana appeared crucial for antiviral responses. These findings enhance our understanding in the proteomic aspects of host antiviral defenses against geminiviruses, and also demonstrate that the combination of proteomics with bioinformatics and VIGS analysis is an effective approach to investigate systemic plant responses to geminiviruses and to shed light on plant-virus interactions. PMID- 27989947 TI - Otoacoustic emission estimates of human basilar membrane impulse response duration and cochlear filter tuning. AB - This study describes a method based on temporal suppression of click-evoked otoacoustic emissions (CEOAEs) to estimate the time course and duration of human basilar membrane impulse responses (BM IRs). This was achieved by tracing the suppression of dominant peaks in the CEOAE spectrum as a function of the temporal separation between two equal-level stimulus clicks. The relationship between the suppression pattern and underlying BM IR duration near the generation site of the CEOAE frequency was established using model simulations. To relate BM IR duration estimates to cochlear filter tuning (QERB), a tuning ratio was derived from available BM IR measurements in animals. Results for 11 normal-hearing subjects yielded BM IR duration estimates of 37.4/F ms at 65 dB peSPL and 36.4/F ms at 71 dB peSPL, with F in kHz. Corresponding QERB estimates were 14.2F[in kHz]0.22 at 65 dB peSPL and 13.8F[in kHz]0.22 at 71 dB peSPL. Because the proposed temporal suppression method relies on cochlear nonlinearity, the method is applicable for stimulus levels above 30-40 dB SPL and complements existing OAE methods to assess human cochlear filter tuning. PMID- 27989948 TI - Impulsive noise: A brief review. PMID- 27989949 TI - The effect of sensorineural hearing loss and tinnitus on speech recognition over air and bone conduction military communications headsets. AB - Military personnel are at risk for hearing loss due to noise exposure during deployment (USACHPPM, 2008). Despite mandated use of hearing protection, hearing loss and tinnitus are prevalent due to reluctance to use hearing protection. Bone conduction headsets can offer good speech intelligibility for normal hearing (NH) listeners while allowing the ears to remain open in quiet environments and the use of hearing protection when needed. Those who suffer from tinnitus, the experience of perceiving a sound not produced by an external source, often show degraded speech recognition; however, it is unclear whether this is a result of decreased hearing sensitivity or increased distractibility (Moon et al., 2015). It has been suggested that the vibratory stimulation of a bone conduction headset might ameliorate the effects of tinnitus on speech perception; however, there is currently no research to support or refute this claim (Hoare et al., 2014). Speech recognition of words presented over air conduction and bone conduction headsets was measured for three groups of listeners: NH, sensorineural hearing impaired, and/or tinnitus sufferers. Three levels of speech-to-noise (SNR = 0, 6, -12 dB) were created by embedding speech items in pink noise. Better speech recognition performance was observed with the bone conduction headset regardless of hearing profile, and speech intelligibility was a function of SNR. Discussion will include study limitations and the implications of these findings for those serving in the military. PMID- 27989951 TI - Published diagnostic models safely excluded colorectal cancer in an independent primary care validation study. AB - OBJECTIVE: To validate published diagnostic models for their ability to safely reduce unnecessary endoscopy referrals in primary care patients suspected of significant colorectal disease. STUDY DESIGN AND SETTING: Following a systematic literature search, we independently validated the identified diagnostic models in a cross-sectional study of 810 Dutch primary care patients with persistent lower abdominal complaints referred for endoscopy. We estimated diagnostic accuracy measures for colorectal cancer (N = 37) and significant colorectal disease (N = 141; including colorectal cancer, inflammatory bowel disease, diverticulitis, or >1-cm adenomas). RESULTS: We evaluated 18 models-12 specific for colorectal cancer-, of which most were able to safely rule out colorectal cancer: the best model (National Institute for Health and Care Excellence-1) prevented 59% of referrals (95% confidence interval [CI]: 56-63%), with 96% sensitivity (95% CI: 83-100%), 100% negative predictive value (NPV; 95% CI: 99-100%), and an area under the receiver operating characteristics curve (AUC) of 0.86 (95% CI: 0.80 0.92). The models performed less for significant colorectal disease: the best model (Brazer) prevented 23% of referrals (95% CI: 20-26%), with 95% sensitivity (95% CI: 90-98%), 96% NPV (95% CI: 92-98%), and an AUC of 0.73 (95% CI: 0.69 0.78). CONCLUSION: Most models safely excluded colorectal cancer in many primary care patients with lower gastrointestinal complaints referred for endoscopy. Models performed less well for significant colorectal disease. PMID- 27989950 TI - Plastic changes along auditory pathway during salicylate-induced ototoxicity: Hyperactivity and CF shifts. AB - High dose of salicylate, the active ingredient in aspirin, has long been known to induce transient hearing loss, tinnitus and hyperacusis making it a powerful experimental tool. These salicylate-induced perceptual disturbances are associated with a massive reduction in the neural output of the cochlea. Paradoxically, the diminished neural output of the cochlea is accompanied by a dramatic increase in sound-evoked activity in the auditory cortex (AC) and several other parts of the central nervous system. Exactly where the increase in neural activity begins and builds up along the central auditory pathway are not fully understood. To address this issue, we measured sound-evoked neural activity in the cochlea, cochlear nucleus (CN), inferior colliculus (IC), and AC before and after administering a high dose of sodium salicylate (SS, 300 mg/kg). The SS treatment abolished low-level sound-evoked responses along the auditory pathway resulting in a 20-30 dB threshold shift. While the neural output of the cochlea was substantially reduced at high intensities, the neural responses in the CN were only slightly reduced; those in the IC were nearly normal or slightly enhanced while those in the AC considerably enhanced, indicative of a progress increase in central gain. The SS-induced increase in central response in the IC and AC was frequency-dependent with the greatest increase occurring in the mid frequency range the putative pitch of SS-induced tinnitus. This frequency dependent hyperactivity appeared to result from shifts in the frequency receptive fields (FRF) such that the response areas of many FRF shifted/expanded toward the mid-frequencies. Our results suggest that the SS-induced threshold shift originates in the cochlea. In contrast, enhanced central gain is not localized to one region, but progressively builds up at successively higher stage of the auditory pathway either through a loss of inhibition and/or increased excitation. PMID- 27989952 TI - Latin American Clinical Epidemiology Network Series - Paper 4: Economic evaluation of Kangaroo Mother Care: cost utility analysis of results from a randomized controlled trial conducted in Bogota. AB - BACKGROUND AND OBJECTIVE: Although kangaroo mother care (KMC) has been shown to be safe and effective in randomized controlled trials (RCTs), there are no published complete economic evaluations including the three components of the full intervention. METHODS: A cost utility analysis performed on the results of an RCT conducted in Bogota, Colombia between 1993 and 1996. Hospital and ambulatory costs were estimated by microcosting in a sample of preterm infants from a University Hospital in Bogota in 2011 and at a KMC clinic in the same period. Utility scores were assigned by experts by means of (1) direct ordering and scoring discrete health states and (2) constructing a multi-attribute utility function. Ninety-five percent confidence intervals (CIs) for the incremental cost utility ratios (ICURs) were computed by the Fiellers theorem method. One-way sensitivity analysis on price estimates for valuing costs was performed. RESULTS: ICUR at 1 year of corrected age was $ -1,546 per extra quality-adjusted life year gained using the KMC method (95% CI $ -7,963 to $ 4,910). CONCLUSION: In Bogota, the use of KMC is dominant: more effective and cost-saving. Although results from an economic analysis should not be extrapolated to different systems and communities, this dominant result suggests that KMC could be cost-effective in similar low and middle income countries settings. PMID- 27989953 TI - Latin American Clinical Epidemiology Network Series - Paper 8: Ticagrelor was cost-effective vs. clopidogrel in acute coronary syndrome in Chile. AB - OBJECTIVE: To evaluate the incremental cost-effectiveness ratio (ICER) of the use of ticagrelor as a substitute for clopidogrel for secondary prevention of acute coronary syndrome in Chile. STUDY DESIGN AND SETTING: Cost-effectiveness analysis based on a Markov model: Safety and effectiveness data of ticagrelor were obtained from a systematic review of the literature. Costs are expressed in Chilean pesos (CLP) as of 2013. The evaluation was conducted from the payer standpoint. A probabilistic sensitivity analysis comprising discount rates and national cost variability was done. A budget impact analysis estimated for 2015 was conducted to calculate the total cost for both treatments. RESULTS: The ICER with a discount rate of 6% for ticagrelor vs. clopidogrel was CLP 4,893,126 per quality-adjusted life-year (QALY) gained (=9,689 US$). In the budget impact analysis for the baseline scenario, considering 100% of treatment, coverage, and adherence, ticagrelor represented an additional cost of CLP 5,233,854,272, for 979 QALYs gained compared with clopidogrel. CONCLUSIONS: Ticagrelor is cost effective in comparison with clopidogrel for the secondary prevention of acute coronary syndrome. These findings are similar to those reported in other international cost-effectiveness studies. PMID- 27989954 TI - Finding the Evidence in Real-World Evidence: Moving from Data to Information to Knowledge. PMID- 27989955 TI - Selective Venous Occlusions for Reducing Blood Loss During Right Anterior Sectionectomy of the Liver for Hepatocellular Carcinoma. PMID- 27989956 TI - Pseudoalteromonas haloplanktis produces methylamine, a volatile compound active against Burkholderia cepacia complex strains. AB - The Antarctic marine bacterium Pseudoalteromonas haloplanktis TAC125 has been reported to produce several Volatile Organic Compounds (VOCs), which are able to inhibit the growth of Burkholderia cepacia complex (Bcc) strains, opportunistic pathogens responsible for the infection of immune-compromised patients. However, no specific antibacterial VOCs have been identified to date. The purpose of the present study was to identify specific VOCs that contribute to Bcc inhibition by the Antarctic strain. When grown on defined medium containing D-gluconate and L glutamate as carbon, nitrogen and energy sources, P. haloplanktis TAC125 is unable to inhibit the growth of Bcc strains. However, single addition of several amino acids to the defined medium restores the P. haloplanktis TAC125 inhibition ability. With the aim of identifying specific volatile compound/s responsible for Bcc inhibition, we set up an apparatus for VOC capture, accumulation, and storage. P. haloplanktis TAC125 was grown in an automatic fermenter which was connected to a cooling system to condense VOCs present in the exhaust air outlet. Upon addition of methionine to the growth medium, the VOC methylamine was produced by P. haloplanktis TAC125. Methylamine was found to inhibit the growth of several Bcc strains in a dose-dependent way. Although it was reported that P. haloplanktis TAC125 produces VOCs endowed with antimicrobial activity, this is the first demonstration that methylamine probably contributes to the anti-Bcc activity of P. haloplanktis TAC125 VOCs. PMID- 27989957 TI - Renewable feedstocks for biobutanol production by fermentation. AB - This paper reports a study of potential feedstock for butanol production via the biotechnological route. Several waste(water) streams rich in sugars and lignocellulosic biomass were studied: cheese-whey, leftovers of high sugar content beverages, food lost or wasted, agriculture residues. The maximum butanol production rate from each type of feedstock was assessed according to the parameters indicated in the literature: feedstock availability rate, feedstock average composition and butanol yield. In Europe the potential biotechnological production of butanol from the feedstock studied was assessed to be about 39 Mt yr-1, which would be enough to meet the current European demand of biofuels. The potential butanol production at local level was also assessed taking into account the concentration of feedstock suppliers in the Campania region. PMID- 27989958 TI - Functional significance of exosomes applied in sepsis: A novel approach to therapy. AB - The nanoparticles referred as exosomes play an active role in intercellular communication. Their potential positive therapeutic effect in bacterial inflammation and sepsis has been the subject of several studies that have examined the feasibility of exosomes as drug-delivery vehicles. The underlying mechanism of interest involves the selective transport of cellular cargo. Most attention has been focused on the exosome-mediated transport of microRNA and protein. Thus, exosomes are expected to be an important tool in the treatment of inflammatory disease. This review covers the relevant literature, focusing on the relationship between exosomes and sepsis and therapeutic use of exosomes in bacterially mediated inflammation or sepsis. We evaluate exosomes as drug vehicles, including their therapeutic cargo, potential mechanisms of action, choice of donor cells, and routes of administration. PMID- 27989959 TI - Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury. AB - BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is characterized by hepatocellular damage, sterile inflammation, and compromised postoperative liver function. Generally used mouse I/R models are too severe and poorly reflect the clinical injury profile. The aim was to establish a mouse I/R model with better translatability using hepatocellular injury, liver function, and innate immune parameters as endpoints. METHODS: Mice (C57Bl/6J) were subjected to sham surgery, 30min, or 60min of partial hepatic ischemia. Liver function was measured after 24h using intravital microscopy and spectroscopy. Innate immune activity was assessed at 6 and 24h of reperfusion using mRNA and cytokine arrays. Liver inflammation and function were profiled in two patient cohorts subjected to I/R during liver resection to validate the preclinical results. RESULTS: In mice, plasma ALT levels and the degree of hepatic necrosis were strongly correlated. Liver function was bound by a narrow damage threshold and was severely impaired following 60min of ischemia. Severe ischemia (60min) evoked a neutrophil-dominant immune response, whereas mild ischemia (30min) triggered a monocyte-driven response. Clinical liver I/R did not compromise liver function and displayed a cytokine profile similar to the mild I/R injury model. CONCLUSIONS: Mouse models using <=30min of ischemia best reflect the clinical liver I/R injury profile in terms of liver function dynamics and type of immune response. GENERAL SIGNIFICANCE: This short duration of ischemia therefore has most translational value and should be used to increase the prospects of developing effective interventions for hepatic I/R. PMID- 27989960 TI - A type VII collagen subdomain mutant is thermolabile and shows enhanced proteolytic degradability - Implications for the pathogenesis of recessive dystrophic epidermolysis bullosa? AB - Type VII collagen is the major constituent of anchoring fibrils. It has a central collagenous domain that is surrounded by a small C-terminal non-collagenous domain (NC2) and a large N-terminal non-collagenous (NC1) domain. Mutations in type VII collagen can lead to hereditary skin blistering disease dystrophic epidermolysis bullosa (DEB). Most of the pathogenic missense mutations are within the collagenous domain. NC1 domain mediates interactions with other extracellular matrix molecules and only very few missense mutations within NC1 causing DEB have been reported. Interestingly, fibronectin III like (FNIII) domain 8 in the human protein can harbour different mutations at position 886 with one (R886P) leading to recessive DEB, whereas the others do not. We characterized subdomains of murine NC1, the FNIII domains 7-8, and the individual domains FNIII7 and FNIII8 by NMR- and CD-spectroscopy. We analysed the influence on stability for a mutation causing DEB and a non-pathogenic mutation. Whereas the silent mutation behaves as the wild type, the pathogenic mutation leads to a dramatic decrease in thermal stability of the FNIII8 domain. The melting temperature lowered from 77 degrees C to 40 degrees C compared to the wild type protein. This renders the domain susceptible to protease cleavage which could be shown by degradation tests with cathepsin G, cathepsin K, and MMP9. Our data show partial unfolding of type VII collagen due to the mutation causes an increased degradation. This could lead to skin blistering and opens new concomitant treatment options in some types of type VII collagen related skin blistering diseases. PMID- 27989962 TI - Cryptic epitopes and functional diversity in extracellular proteins. AB - The functional diversity of proteins is a major factor determining the complexity of cells and tissues. Both translational and post-translational modifications contribute to this diversity. Recently, protein unfolding and refolding has been recognised as another mechanism for diversity by unmasking buried or cryptic sequences (epitopes) that possess physiological functions. In the current review, we focus on extracellular proteins where folding dynamics can be influenced by mechanical forces, protein-protein interactions and denaturation. Many cryptic epitopes in these proteins are exposed following proteolytic cleavage, but recent data indicate that unfolding/refolding play an important role in regulating the physiological behaviour of extracellular proteins. By understanding how and when hidden sequences are exposed, novel techniques for manipulating the function of these proteins may be uncovered. PMID- 27989963 TI - Tuning constitutive and pathological inflammation in the gut via the interaction of dietary nitrate and polyphenols with host microbiome. AB - Chronic inflammation is currently recognized as a critical process in modern-era epidemics such as diabetes, obesity and neurodegeneration. However, little attention is paid to the constitutive inflammatory pathways that operate in the gut and that are mandatory for local welfare and the prevention of such multi organic diseases. Hence, the digestive system, while posing as a barrier between the external environment and the host, is crucial for the balance between constitutive and pathological inflammatory events. Gut microbiome, a recently discovered organ, is now known to govern the interaction between exogenous agents and the host with ensued impact on local and systemic homeostasis. Whereas gut microbiota may be modulated by a myriad of factors, diet constitutes one of its major determinants. Thus, dietary compounds that influence microbial flora may thereby impact on inflammatory pathways. One such example is the redox environment in the gut lumen which is highly dependent on the local generation of nitric oxide along the nitrate-nitrite-nitric oxide pathway and that is further enhanced by simultaneous consumption of polyphenols. In this paper, different pathways encompassing the interaction of dietary nitrate and polyphenols with gut microbiota will be presented and discussed in connection with local and systemic inflammatory events. Furthermore, it will be discussed how these interactive cycles (nitrate-polyphenols-microbiome) may pose as novel strategies to tackle inflammatory diseases. PMID- 27989961 TI - Role of mineralocorticoid receptor activation in cardiac diastolic dysfunction. AB - The prevalence of cardiac diastolic dysfunction and heart failure with preserved ejection, a major cause of morbidity and mortality in the western world, is increasing due, in part, to increases in obesity and type 2 diabetes. Characteristics of cardiac diastolic dysfunction include increased myocardial stiffness and impaired left ventricular (LV) relaxation that is characterized by prolonged isovolumic LV relaxation and slow LV filling. Obesity, insulin resistance and type 2 diabetes, especially in females promote activation of mineralocorticoid receptor (MR) signaling with resultant increases in oxidative stress, maladaptive immune responses, inflammation, and impairment of coronary blood flow and cardiac interstitial fibrosis. This review highlights findings from the recent surge in cardiac diastolic dysfunction research. To this end it highlights our contemporary understanding of molecular mechanisms of MR regulation by genetic, epigenetic and posttranslational modifications and resultant cardiac diastolic dysfunction associated with insulin resistance, obesity and type 2 diabetes. This review also explores potential preventative and therapeutic strategies directed in the prevention of cardiac diastolic dysfunction and heart failure with preserved ejection. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure edited by Dr. Jun Ren & Yingmei Zhang. PMID- 27989964 TI - Histone acetylation of glucose-induced thioredoxin-interacting protein gene expression in pancreatic islets. AB - Thioredoxin-interacting protein (TXNIP) has been shown to be associated with glucose-induced deterioration of pancreatic beta cell function in diabetes. However, whether epigenetic mechanisms contribute to the regulation of TXNIP gene expression by glucose is not clear. Here we studied how glucose exerts its effect on TXNIP gene expression via modulation of histone acetylation marks. To achieve this, we applied clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) to knock out histone acetyltransferase (HAT) p300 in a rat pancreatic beta cell line INS1 832/13. We also treated the cells and human islets with chemical inhibitors of HAT p300 and histone deacetylase (HDAC). In human islets, diabetes and high glucose resulted in elevated TXNIP and EP300 expression, and glucose-induced TXNIP expression could be reversed by p300 inhibitor C646. In INS1 832/13 cells, Ep300 knock-out by CRISPR/Cas9 elevated glucose-induced insulin secretion and greatly reduced glucose-stimulated Txnip expression and cell apoptosis. This effect could be ascribed to decrease in histone marks H3K9ac and H4ac at the promoter and first coding region of the Txnip gene. Histone marks H3K9ac and H4ac in the Txnip gene in the wild-type cells was inhibited by HDAC inhibitor at high glucose, which most likely was due to enhanced acetylation levels of p300 after HDAC inhibition; and thereby reduced p300 binding to the Txnip gene promoter region. Such inhibition was absent in the Ep300 knock-out cells. Our study provides evidence that histone acetylation serves as a key regulator of glucose-induced increase in TXNIP gene expression and thereby glucotoxicity-induced apoptosis. PMID- 27989966 TI - Origin and evolution of the panarthropod head - A palaeobiological and developmental perspective. AB - The panarthropod head represents a complex body region that has evolved through the integration and functional specialization of the anterior appendage-bearing segments. Advances in the developmental biology of diverse extant organisms have led to a substantial clarity regarding the relationships of segmental homology between Onychophora (velvet worms), Tardigrada (water bears), and Euarthropoda (e.g. arachnids, myriapods, crustaceans, hexapods). The improved understanding of the segmental organization in panarthropods offers a novel perspective for interpreting the ubiquitous Cambrian fossil record of these successful animals. A combined palaeobiological and developmental approach to the study of the panarthropod head through deep time leads us to propose a consensus hypothesis for the intricate evolutionary history of this important tagma. The contribution of exceptionally preserved brains in Cambrian fossils - together with the recognition of segmentally informative morphological characters - illuminate the polarity for major anatomical features. The euarthropod stem-lineage provides a detailed view of the step-wise acquisition of critical characters, including the origin of a multiappendicular head formed by the fusion of several segments, and the transformation of the ancestral protocerebral limb pair into the labrum, following the postero-ventral migration of the mouth opening. Stem-group onychophorans demonstrate an independent ventral migration of the mouth and development of a multisegmented head, as well as the differentiation of the deutocerebral limbs as expressed in extant representatives. The anterior organization of crown-group Tardigrada retains several ancestral features, such as an anterior-facing mouth and one-segmented head. The proposed model aims to clarify contentious issues on the evolution of the panarthropod head, and lays the foundation from which to further address this complex subject in the future. PMID- 27989967 TI - Modified Interscalene Approach for Resection of Symptomatic Cervical Rib: Anatomic Review and Clinical Study. AB - BACKGROUND: Cervical ribs have been reported to be present in about 0.5% of the general population, 10% of patients with cervical rib who are symptomatic usually have neurogenic symptoms, but some have arterial symptoms. In 1861, Coote was the first to excise a cervical rib through a supraclavicular approach and relieved the symptoms of thoracic outlet syndrome. OBJECTIVE: In this study, we address the efficacy and safety of a modification to the supraclavicular approach for resection of symptomatic cervical ribs. PATIENTS AND METHODS: The surgical team in collaboration with an anatomist performed cadaveric dissections of the posterior triangle of the neck in the Department of Anatomy, Ain Shams University. A prospective study was performed of 25 patients with moderate to severe neck or upper limb pain; this pain was resistant to medical treatment for at least 6 months. Preoperative cervical radiography showed cervical ribs. Pain was assessed by using the visual analog scale. Electrophysiologic tests were performed to confirm the diagnosis. In this study, we performed a modified supraclavicular interscalene approach with resection of the symptomatic rib and without resecting either of the scalene muscles or the first thoracic rib. RESULTS: A total of 25 patients were included in this study; the mean age was 36 years (+/- 12 standard deviation), and the mean follow-up period was 12.3 months. All patients had moderate (28%) to severe (72%) preoperative pain. Motor deficits were present in 6 cases (24%); Sensory manifestations were present in 80%. All patients had a relief of severe pain at the first postoperative visit in the first week. There were improvements in the motor power in 5 of the 6 patients who had preoperative motor deficit. CONCLUSIONS: A modified supraclavicular interscalene approach for resection of symptomatic cervical ribs has been shown to be effective in the treatment of neuralgic pain. Compared with other approaches, it proved to be less invasive, with small transverse incision and without resection of scalenus anterior muscle. PMID- 27989968 TI - Superior Cluneal Nerve Entrapment Neuropathy and Gluteus Medius Muscle Pain: Their Effect on Very Old Patients with Low Back Pain. AB - OBJECTIVE: In the very elderly, their general condition and poor compliance with drug regimens can render the treatment of low back pain (LBP) difficult. We report the effectiveness of a less-invasive treatment for intractable LBP from superior cluneal nerve entrapment neuropathy (SCN-EN) and gluteus medius muscle (GMeM) pain. PATIENTS AND METHODS: Between April 2013 and March 2015, we treated 17 consecutive elders with LBP, buttock pain, and leg pain. They were 4 men and 13 women ranging in age from 85 to 91 years (mean 86.6 years). We carefully ascertained that their symptoms were attributable to SCN-EN and GMeM pain. The median follow-up period was 21.5 +/- 12.2 months (range 2-35 months). RESULTS: SCN-EN was diagnosed in 15 patients (28 sites) and GMeM pain in 14 (27 sites). In 5 patients, we obtained symptom control by local block (Numerical Rating Scale for LBP: declined from 7.8 to 0.8 [P < 0.05], Roland-Morris Disability Questionnaire score: declined from 16.5 to 5.2). The other 12 were operated under local anesthesia (SCN neurolysis, GMeM decompression). As 3 patients reported the persistence of leg pain postoperatively, they subsequently underwent peroneal nerve neurolysis and surgery for tarsal tunnel syndrome. These treatments resulted in significantly symptom abatement (Numerical Rating Scale: from 8.2 to 1.7, Roland-Morris Disability Questionnaire score: from 12.8 to 8.6; P < 0.05). CONCLUSIONS: Even very old patients with intractable LBP, buttock pain, and leg pain due to SCN-EN or GMeM pain can be treated successfully by peripheral block and less-invasive surgery under local anesthesia. PMID- 27989969 TI - Does the Simultaneous Use of a Neuroendoscope Influence the Incidence of Ventriculoperitoneal Shunt Infection? AB - BACKGROUND: The relationship between the use of an endoscope during ventriculoperitoneal shunt (VPS) procedures and infection remains poorly defined. In this study, we sought to analyze whether the simultaneous use of an endoscope could in fact increase the infection rate associated with VPS procedures. METHODS: This study included 438 VPS procedures, 49 in which an endoscope was used (11.2%) and 389 in which an endoscope was not used (88.8%). The infection rates in these 2 main groups were calculated and compared. Subsequently, 4 new groups were created, composed of patients with a shunt inserted for the first time (groups 1A and 1B) and patients with a shunt reviewed or inserted for a second time (groups 2A and 2B). Groups 1A and 2A comprised patients in whom an endoscope was used simultaneously with VPS surgery, and groups 1B and 2B comprised patients in whom an endoscope was not used. These groups were compared to determine the infection rate. RESULTS: The overall infection rate was 18.5%, including 22.4% in the groups in which an endoscope was used and 18% in those in which an endoscope was not used (P = 0.449). Groups 1A and 1B and groups 2A and 2B were matched for possible intervening risk factors. The infection rate was 28.6% in group 1A and 16.2% in group 1B (P = 0.27), and 20% in group 2A and 19.8% in group 2B (P = 0.977). CONCLUSIONS: In the present study, the use of an endoscope during VPS procedures did not increase the risk of surgical infection. PMID- 27989970 TI - Neurocognitive Function Surrounding the Resection of Frontal WHO Grade I Meningiomas: A Prospective Matched-Control Study. AB - OBJECTIVE: Patients with intracranial meningiomas can experience neurocognitive dysfunctions in specific cognitive domains depending on tumor location and size. The literature regarding cognitive function surrounding the resection of frontal meningiomas is sparse. METHODS: We performed a prospective matched-control study to investigate the cognitive performance of frontal meningioma patients undergoing resection. The neurocognitive status 1 week and 2 months after resection was compared with the preoperative status and matched-controls. Matching was performed for age, sex, handedness, education, and profession. An extensive test battery was used to assess perceptual speed, executive function, visual-spatial and verbal working memory, short- and long-term memory, verbal fluency, fluid intelligence, anxiety, and depression. RESULTS: Twelve patients with frontal World Health Organization grade I meningioma and 12 matched-controls underwent cognitive testing. Macroscopically, complete removal was achieved in all cases. Comparison of patients and controls revealed significant cognitive impairments in perceptual speed, executive function, short-term memory, and verbal fluency preoperatively and postoperatively. At 2 months' follow-up, perceptual speed and verbal fluency were still significantly impaired, whereas executive function and short-term memory were equal to that in the control group. None of the patients experienced cognitive deterioration after surgical therapy. CONCLUSION: Patients with frontal meningiomas display preoperative and postoperative deficits in perceptual speed, executive function, short-term memory, and verbal fluency. The risk for cognitive deterioration owing to surgical resection is low. Within the first two months after surgery, executive function and short-term memory appear to recover. PMID- 27989971 TI - Neurophysiological Identification of Cranial Nerves During Endoscopic Endonasal Surgery of Skull Base Tumors: Pilot Study Technical Report. AB - INTRODUCTION: Intraoperative identification of cranial nerves is crucial for safe surgery of skull base tumors. Currently, only a small number of published papers describe the technique of trigger electromyography (t-EMG) in endoscopic endonasal removal of such tumors. OBJECTIVE: To assess the effectiveness of t-EMG in preventing intraoperative cranial nerve damage in endoscopic endonasal surgery of skull base tumors. MATERIALS AND METHODS: Nine patients were operated on using the endoscopic endonasal approach within a 1-year period. The tumors included large skull base chordomas and trigeminal neurinomas localized in the cavernous sinus. During the surgical process, cranial nerve identification was carried out using monopolar and bipolar t-EMG methods. Assessment of cranial nerve functional activity was conducted both before and after tumor removal. RESULTS: We mapped 17 nerves in 9 patients. Third, fifth, and sixth cranial nerves were identified intraoperatively. There were no cases of postoperative functional impairment of the mapped cranial nerves. In one case we were unable to get an intraoperative response from the fourth cranial nerve and observed its postoperative transient plegia (the function was normal before surgery). CONCLUSION: t-EMG allows surgeons to control the safety of cranial nerves both during and after skull base tumor removal. PMID- 27989972 TI - Frontal Lobe Decortication (Frontal Lobectomy with Ventricular Preservation) in Epilepsy-Part 1: Anatomic Landmarks and Surgical Technique. AB - BACKGROUND: An extensive frontal resection is a frequently performed neurosurgical procedure, especially for treating brain tumor and refractory epilepsy. However, there is a paucity of reports available regarding its surgical anatomy and technique. OBJECTIVES: We sought to present the anatomic landmarks and surgical technique of the frontal lobe decortication (FLD) in epilepsy. The goals were to maximize the gray matter removal, spare primary and supplementary motor areas, and preserve the frontal horn. MATERIAL AND METHODS: The anatomic study was based on dissections performed in 15 formalin-fixed adult cadaveric heads. The clinical experience with 15 patients is summarized. RESULT: FLD consists of 5 steps: 1) coagulation and section of arterial branches of lateral surface; 2) paramedian subpial resection 3 cm ahead of the precentral sulcus to reach the genu of corpus callosum; 3) resection of gray matter of lateral surface, preserving the frontal horn; 4) removal of gray matter of basal surface preserving olfactory tract; 5) removal of gray matter of the medial surface under the rostrum of corpus callosum. The frontal horn was preserved in all 15 patients; 12 patients (80%) had no complications; 2 patients presented temporary hemiparesis; and 1 Rasmussen syndrome patient developed postoperative fever. The best seizure control was in cases with focal magnetic resonance imaging abnormalities limited to the frontal lobe. CONCLUSION: FLD is an anatomy-based surgical technique for extensive frontal lobe resection. It presents reliable anatomic landmarks, selective gray matter removal, preservation of frontal horn, and low complication rate in our series. It can be an alternative option to the classical frontal lobectomy. PMID- 27989973 TI - Management of Pyogenic Cerebral Ventriculitis by Neuroendoscopic Surgery. AB - BACKGROUND: Pyogenic cerebral ventriculitis is a debilitating form of intracranial infection with an unfavorable outcome as a result of lack of experience in surgical management. OBJECTIVE: To study retrospectively a group of pyogenic cerebral ventriculitis patients managed by neuroendoscopic surgery (NES). METHODS: The standard intraventricular protocols of NES to treat this disease included 1 or more of the following: 1) obliteration of debris, 2) evidence of microbial infection, 3) septomy, 4) incision of the septation, or 5) monitoring catheter insertion. Modified external ventricular drainage EVD (mEVD) was combined with NES when intraventricular debris and bacterial plaques could not be evacuated completely. Subsequent surgical treatment strategies depended on the clinical manifestation, cerebrospinal fluid analysis, and mEVD blockage tests approximately 3 weeks after the last NES. RESULTS: Forty-one patients, who were distributed in 7 hospitals and underwent NES, were included. Five patients received 1 NES, 18 received 2, 16 received 3, and 2 received 4. mEVD was performed in all patients, and mean mEVD duration in the hospital was 27.6 days. At discharge, 15 patients were cured, 15 were cured but ventriculoperitoneal shunt dependent, 9 were mEVD dependent, and 2 died (mean modified Rankin Scale score was 2.48). Two mEVD-dependent patients died, and no other outcomes changed during postoperative follow-up (mean modified Rankin Scale score, 2.67). CONCLUSIONS: The results suggest a relatively favorable outcome for management of pyogenic cerebral ventriculitis by NES. The techniques and strategies are practical and should be applied more extensively. PMID- 27989974 TI - Volumetric Analysis Using Low-Field Intraoperative Magnetic Resonance Imaging for 168 Newly Diagnosed Supratentorial Glioblastomas: Effects of Extent of Resection and Residual Tumor Volume on Survival and Recurrence. AB - BACKGROUND: Extent of resection (EOR) remains controversial in therapy for glioblastoma (GBM). However, an increasing number of studies favor maximum EOR as being associated with longer patient survival. Residual tumor volume (RTV) has also recently emerged as a prognostic factor. Low-field intraoperative magnetic resonance imaging (iMRI) has contributed to improve the EOR of GBM. The purpose of this study was to analyze the relationships between EOR/RTV and overall survival (OS)/progression-free survival (PFS) in patients with newly diagnosed GBM using low-field iMRI. METHODS: Adult patients who underwent surgery for newly diagnosed supratentorial GBM between 2000 and 2012 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate analysis was used to evaluate the relationships between EOR/RTV and OS/PFS. RESULTS: Of 168 patients, 126 (75%) died and 154 (91%) showed tumor recurrence. Median OS and PFS for patients with iMRI were 19.3 months (95% confidence interval, 15.4-23.7 months) and 9.5 months (95% confidence interval, 7.8-10.8 months). Median preoperative tumor volume was 37.0 cm3 (interquartile range [IQR], 19.9-59.8 cm3). Median RTV was 0 cm3 (IQR, 0-1.6 cm3). Median EOR was 100% (IQR, 96.2% 100%). In multivariate analysis, after controlling for age and Karnofsky Performance Status, EOR and RTV remained significantly associated with survival (hazard ratio, 1.56; P = 0.018) and recurrence (hazard ratio, 1.53; P = 0.013). Maximum RTV for survival was 3 cm3. CONCLUSIONS: This volumetric analysis for low field iMRI showed that both EOR and RTV were significantly associated with survival and recurrence. We determined a threshold RTV of 3 cm3 as the maximum RTV associated with survival. PMID- 27989976 TI - Ultrasonography Monitoring with Superb Microvascular Imaging Technique in Brain Tumor Surgery. AB - BACKGROUND: Neuronavigation based on preoperative magnetic resonance imaging has been developed as a useful tool to improve visibility of the surgical site in the operative field. Ultrasonography (US) monitoring has also been used as a reliable imaging technique, providing real-time information during neurosurgical operations. We combined the latest innovative imaging technique for detecting very low-flow components, Superb Microvascular Imaging (SMI), with US monitoring during brain tumor surgery. CASE DESCRIPTION: Fifteen patients diagnosed with brain tumor (8 malignant and 7 benign) underwent neurosurgery with US monitoring using an Aplio 400/500 US system with the new SMI technique (imaging frequency, 10-12 MHz; frame rate, 28-31 Hz). Features of the SMI images in the gray scale mode include 1) visualization of low-velocity flow with minimal motion artifact, 2) high resolution of images, and 3) high frame rates. The tumors, tumor vessels, compressed and shifted healthy vessels, and cistern were clearly visualized on the SMI images in the gray scale mode, detailing the characteristics of healthy brain tissue (vertically penetrating, fine, straight vessels), glioblastoma (rounding, dilating, and bending vessels), low-grade glioma (fine and straight vessels), meningioma (many large and branching vessels), and lymphoma (less vascular, low echoic tumor) and demonstrating the tumor-defined border. We also performed biopsies under US monitoring with SMI. CONCLUSIONS: We combined SMI technique with US monitoring during brain tumor surgery and observed healthy and tumor vessels. Further research is important for the development of a more precise and reliable neurosurgery. PMID- 27989975 TI - Is There a Magnetic Resonance Imaging-Discernible Cause for Trigeminal Neuralgia? A Structured Review. AB - BACKGROUND: Trigeminal neuralgia (TN) is a chronic brain condition involving the trigeminal nerve and characterized by severe and recurrent facial pain. Although the cause of TN has been researched extensively, there is a lack of convergence on the physiologic processes leading to pain symptoms. This review seeks to better elucidate the underlying pathophysiology of TN by analyzing the outcomes of studies that use magnetic resonance structural imaging and diffusion-weighted imaging to examine nerve damage in patients with TN. METHODS: Performing a structured review of the literature, the authors included human magnetic resonance anatomic and diffusion-weighted imaging studies aimed at visualizing the trigeminal nerve or measuring neural damage pertaining to TN. Studies that measured and compared nerve damage in the affected and unaffected sides in patients or patients and controls were analyzed for neural changes associated with TN. RESULTS: Twenty-five studies met inclusion criteria. Overall, the data from the anatomic and diffusion studies showed decreased volume and cross sectional area, decreased fractional anisotropy, and increased apparent diffusion coefficient and diffusivity associated with the affected side of patients compared with the unaffected side as well as in patients compared with controls. CONCLUSIONS: A review of the studies included indicates that neural differences exist between the affected and unaffected sides in patients as well as between patients and controls in both structural and diffusion metrics. The amalgamated data suggest that damage of the trigeminal nerve tissue is commonly found in patients with TN and could be a primary factor in TN pathophysiology. PMID- 27989977 TI - A Review of the Literature on the Transciliary Supraorbital Keyhole Approach. AB - BACKGROUND: Conventional craniotomy approaches involve substantial soft tissue manipulation that can cause complications. The transciliary supraorbital keyhole approach was developed to avoid these complications. The aim of this review is to evaluate the safety and the effectiveness of the transciliary supraorbital keyhole approach. METHODS: We searched the PubMed/Medline database for full-text publications from 1996 onward containing data on 100 or more cases of aneurysm clipping or tumor resection by the transciliary supraorbital keyhole approach. The primary outcome was the incidence of approach-related complications. The secondary outcomes were the aneurysm occlusion rate and the extent of tumor resection. RESULTS: Eight publications met the eligibility criteria. All publications were of the retrospective case-series or case-cohort type without any independent assessment of outcomes. The risk of bias at the individual study level may thus have influenced any conclusions drawn from the overall study population, which included 2783 patients with 3085 lesions (2508 aneurysms and 577 tumors). Approach-related complications included 3.3% cerebrospinal fluid collection or leak, 4.3% permanent and 1.6% temporary supraorbital hypesthesia, 2.9% permanent and 1% temporary facial nerve palsy, and 1% wound healing disturbance or wound infection. Complete aneurysm clipping was achieved in 97% of cases. Complete tumor resection in 90% of cases. The overall surgical revision rate was 2.5%. The esthetic outcome was typically reported as highly acceptable. CONCLUSIONS: This approach may represent a safe, effective, and less invasive alternative to conventional craniotomies in experienced hands and for a well selected subset of patients. However, higher-level evidence is needed to confirm this hypothesis. PMID- 27989978 TI - Simultaneous Occurrence of a Pituitary Adenoma and a Foramen Magnum Meningioma: Case Report. AB - The coexistence of a pituitary adenoma and a meningioma is a rare event. In all previously reported cases, only 1 of these 2 tumors was symptomatic. We present the case of 61-year-old woman with no significant medical history who was treated for a simultaneously symptomatic pituitary nonfunctioning adenoma and foramen magnum meningioma. Such an association has not been reported previously. PMID- 27989979 TI - Conservative Management for Odontoid Cervical Fractures: Halo or Rigid Cervical Collar? PMID- 27989980 TI - Spinal Dural Arteriovenous Fistulas with Segmental Arterial Supply Also Giving Rise to a Radiculomedullary Artery: A Case Report and Review of the Literature. AB - BACKGROUND: During the past 3 decades, a handful of spinal dural arteriovenous fistula cases have been reported in which the segmental artery giving rise to the fistulous connection also supplies a radiculomedullary artery that contributes to the anterior spinal artery. CASE DESCRIPTION: Here, we describe the case of a 62 year-old woman who developed spinal cord and conus medullaris dysfunction over the course of a year attributable to a spinal dural arteriovenous fistula supplied by an L1 radicular artery that also contributed to the anterior spinal artery. Despite rapid deterioration in the weeks leading up to presentation, microsurgical disconnection led to a notable improvement in motor symptoms. We present the details of our case and review the literature regarding this anatomic variant. CONCLUSIONS: Recognizing this likely rare anatomical variant is critical in optimizing functional outcome. PMID- 27989981 TI - Heterotopic Intracranial Skin Presenting as Chronic Draining Sinus After Remote Craniotomy. AB - BACKGROUND: Craniotomies for trauma are associated with a significant risk of wound complications. We report a case in which a chronic nonhealing draining sinus was caused by an ectopic epidermal lining deep to the craniotomy bone flap, adherent to the underlying dura. CASE DESCRIPTION: A 61-year-old man was examined for a 3-year-old, nonhealing scalp wound resulting after a traumatic brain injury. His initial surgery consisted of an intracranial hematoma evacuation through a temporoparietal craniotomy; this was complicated by wound dehiscence and a chronic sinus draining clear fluid that did not resolve with antimicrobial therapy. Intraoperatively, a layer of hair-bearing skin adherent to the dura was found deep to the entirety of the previous bone flap. There was no dura tear or overt cerebrospinal fluid leak. This necessitated removal of the skin over the dura as well as the overlying bone flap. The resultant defect was reconstructed with a titanium mesh and hydroxyapatite cranioplasty, with a scalp rotation flap for coverage of the cutaneous defect. Pathology confirmed skin with intact adnexal structures. CONCLUSION: This case demonstrates that it is possible for hair-bearing skin to grow directly on dura, deep to an intact craniotomy bone flap. With a chronic draining sinus in the absence of computed tomography and magnetic resonance imaging findings, this should be part of the differential diagnosis. PMID- 27989982 TI - Meta-Analysis of Microarray-Based Expression Profiles to Identify Differentially Expressed Genes in Intracranial Aneurysms. AB - OBJECTIVE: To gain comprehensive insight into the molecular mechanism of formation and rupture of intracranial aneurysms (IAs). METHODS: All publicly accessible microarray-based whole-genome gene expression profiles on IAs were retrieved. The significance analysis of microarrays method was applied to identify differentially expressed genes (DEGs). Functional annotation was performed using gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Expression of DEGs was examined using quantitative polymerase chain reaction. RESULTS: Six data sets of 3 microarray platforms were qualified and analyzed. Comparing expression profiles between aneurysmal wall and control vessels, 5232 significant DEGs were identified among 3 platforms, and MMP12 was shown to have the largest fold change of upregulation. In all 3 platforms, 46 DEGs were shared, and 1297 DEGs were commonly resolved in at least 2 microarray platforms. Among these 1297 concordant DEGs, the 512 upregulated genes were mainly enriched in inflammatory and immune response processes, whereas the 785 downregulated genes were primarily concentrated in smooth muscle cell contraction and development pathways. Comparison between expression profiles of ruptured and unruptured IAs revealed that a few angiogenic factors, including HIF1A, VEGFA, and ANGPTL4, were upregulated in ruptured aneurysms. Subsequently, the upregulation of MMP12, HIF1A, and VEGFA was partially confirmed using quantitative polymerase chain reaction among independent samples. CONCLUSIONS: Inflammation, immune response, and loss of contractile vascular smooth muscle cells could potentially contribute to the formation of IAs, whereas the role of angiogenesis and vascular remodeling in IA formation and rupture needs further exploration. PMID- 27989983 TI - Optical Neuronavigation without Rigid Head Fixation During Awake Surgery. AB - OBJECTIVE: Optical neuronavigation without rigid pin fixation of the head may lead to inaccurate results because of the patient's movements during awake surgery. In this study, we report our results using a skull-mounted reference array for optical tracking in patients undergoing awake craniotomy for eloquent gliomas. METHODS: Between March 2013 and December 2014, 18 consecutive patients (10 men, 8 women) with frontotemporal (n = 16) or frontoparietal (perirolandic; n = 2) lesions underwent awake craniotomy without rigid pin fixation. All patients had a skull-mounted reference array for optical tracking placed on the forehead. Accuracy of navigation was determined with pointer tip deviation measurements on superficial and bony anatomic structures. Good accuracy was defined as a tip deviation <2 mm. RESULTS: Gross total resection (>98%) was achieved in 7 patients (38%); >90% of tumor was resected in 8 patients (44%). In 3 patients, only subtotal resection or biopsy was performed secondary to stimulation results. In all patients, good accuracy of the optical neuronavigation system could be demonstrated without intraoperative peculiarities or complications. The reference array had to be repositioned because of loosening in 1 patient. Neuronavigation could be reliably applied to support stimulation-based resection. CONCLUSIONS: A skull-mounted reference array is a simple and safe method for optical neuronavigation tracking without rigid pin fixation of the patient's head. PMID- 27989984 TI - Anterior Cervical Discectomy and Fusion: Comparison of Fusion, Dysphagia, and Complication Rates Between Recombinant Human Bone Morphogenetic Protein-2 and Beta-Tricalcium Phosphate. AB - INTRODUCTION: Anterior cervical discectomy and fusion (ACDF) is one of the most common spinal procedures performed. A direct comparison of the fusion and complication rates between recombinant human bone morphogenetic protein-2 (rhBMP2) and beta-tricalcium phosphate (bTCP) has not been reported. METHODS: A retrospective study of 191 consecutive patients who underwent ACDF with polyetheretherketone plastic fusion spacers during a 2-year period with either rhBMP2 (n = 84, 46%) or bTCP (n = 107, 56%) was performed. Patients underwent 1- (35%), 2- (41%), 3- (20%), and 4- (4%) level operations. The primary outcome measure was mature arthrodesis, with secondary measures including clinical outcomes and complication occurrence. Fusion was graded on plain lateral radiographs, with median length of follow-up of 12 months. RESULTS: Rates of cervical fusion were significantly greater for patients treated with rhBMP2 than bTCP at both 6 months (70% vs. 26%, P = 0.000) and 12 months (99% vs. 85%, P = 0.000). Postoperative dysphagia was reported in 35 patients (18%), with no difference in dysphagia incidence between rhBMP2 and bTCP (20% vs. 17%, P = 0.5); however, dysphagia was more severe in the rhBMP2 group, with greater rates of readmission and steroid use (both P < 0.05). A multivariable sensitivity analyses to control for patient characteristics and number of spinal fusion levels showed no differences in dysphagia rate between rhBMP2 and bTCP. CONCLUSIONS: In our cohort, the rate of mature arthrodesis after ACDF was greater with rhBMP2 compared with bTCP with no increased incidence of postoperative dysphagia; however, dysphagia severity was greater in the rhBMP2 cohort. PMID- 27989986 TI - Emergence of Candida auris: An International Call to Arms. PMID- 27989985 TI - Mild Carotid Stenosis with Recurrent Symptoms Triggered by Eating. AB - BACKGROUND: Carotid atherosclerosis is a known risk factor for acute ischemic stroke. Although severe luminal narrowing is a well-established risk factor for future ischemic events, 10% of patients with acute ischemic stroke or transient ischemic attacks are thought to have ischemic events secondary to vulnerable carotid plaques in the setting of mild to moderate carotid artery stenosis. CASE DESCRIPTION: A 78-year-old man presented with multiple recurrent strokes and transient ischemic attacks that consistently occurred with eating. Based on the anatomic relationships of the proximal internal carotid artery harboring the plaque, we hypothesized that multiple recurrent emboli occurred secondary to the mechanical effect of the esophagus "squeezing" the vulnerable plaque against the surrounding fixed tissues despite a mild degree of stenosis (approximately 20% stenosis on magnetic resonance angiography and angiography). Despite the mild stenosis, a carotid endarterectomy was performed, which resulted in immediate resolution of the ischemic events. CONCLUSIONS: We postulate that the likely mechanical "squeeze" of the vulnerable plaque involving the retropharyngeal proximal internal carotid artery was responsible for the multiple recurrent transient ischemic attacks, which characteristically occurred only while eating. Resolution of the episodes after carotid endarterectomy supports this hypothesis. PMID- 27989987 TI - Overcoming Outpatient Loss to Follow-up as a Barrier to Efficiently Instituting Hepatitis B Liver-related Care. PMID- 27989988 TI - Novel mutations and structural deletions in TUBB8: expanding mutational and phenotypic spectrum of patients with arrest in oocyte maturation, fertilization or early embryonic development. AB - STUDY QUESTION: Are there any new type of mutations and novel phenotypes in patients with arrest in oocyte maturation, fertilization or early embryonic development having tubulin beta eight class VIII (TUBB8) mutations? SUMMARY ANSWER: We identified new types of mutations in TUBB8 associated with maturation, fertilization and developmental arrest. WHAT IS KNOWN ALREADY: We previously found heterozygous mutations and a homozygous frameshift/internal seven amino acid deletion in TUBB8 that are responsible for oocyte maturation arrest. STUDY DESIGN, SIZE, DURATION: We recruited 10 new primary infertility patients from 9 families from December 2015 to May 2016, most of which exhibited failures in oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ten primary infertility patients were recruited from the reproduction centers in local hospitals. Genomic DNA samples from the affected individuals, their family members and healthy controls were extracted from peripheral blood. TUBB8 in the DNA samples were sequenced by Sanger sequencing. TUBB8 sequence was then aligned by CodonCode software to identify rare variants. ExAC database was used to search frequency of corresponding mutations. In silico analysis of mutations was used by Polyphen and PROVEAN. Phenotypes of oocytes and embryos were evaluated by light microscopy, polarization microscopy or immunolabeling. MAIN RESULTS AND THE ROLE OF CHANCE: Besides several novel heterozygous missense mutations, we also identified other new types of genetic variants, including homozygous mutations and a de novo compound heterozygous mutation. We also found a patient with a homozygous deletion of the whole TUBB8 gene, which is the first reported case of a large structural variation in this gene. In addition, we found different mutations in TUBB8 that could result in variability in oocyte/embryo phenotypes, including oocyte maturation arrest, first polar body (PB1) oocytes that cannot be fertilized, and PB1 oocytes that can be fertilized but arrest at an early embryonic stage. LIMITATIONS, REASONS FOR CAUTION: The exact molecular mechanism has not been analyzed and should be further investigated in the future. In addition, immunostaining of more oocytes with mutations and checking spindle status of oocytes with mutations non-invasively by polarization microscopy needs to be done in order to determine exact stage of PB1 oocytes and the functional differences of these mutations. WIDER IMPLICATIONS OF THE FINDINGS: The results not only emphasize the important role of TUBB8 in oocyte maturation, fertilization and early embryonic development but they also provide a basis for determining the genetic variations in TUBB8 as a potential additional criterion for evaluating the quality of patients' functional PB1 oocytes. STUDY FUNDING/COMPETING INTERESTS: National Key R&D Program of China (2016YFC1000600); Basic Research Program of China (2015CB943300); National Natural Science Foundation of China (81270747 and 81571501). No competing interests declared. PMID- 27989989 TI - Total circulating microparticle levels are increased in patients with deep infiltrating endometriosis. AB - STUDY QUESTION: Are the levels of total circulating cell-derived microparticles (cMPs) and circulating tissue factor-containing microparticles (cMP-TF) increased in patients with endometriosis? SUMMARY ANSWER: The levels of total cMP, but not cMP-TF, were higher in patients with endometriosis, and these were attributed to higher levels in patients with deep infiltrating endometriosis (DIE). WHAT IS KNOWN ALREADY: Previous studies have reported elevated levels of total cMP in inflammatory conditions as well as higher levels of other inflammatory biomarkers in endometriosis. Increased expression of tissue factor (a transmembrane receptor for Factor VII/VIIa) in eutopic and ectopic endometrium from patients with endometriosis has been described. There is no previous data regarding total cMP and cMP-TF levels in patients with endometriosis. STUDY DESIGN, SIZE, DURATION: A prospective case-control study including two groups of patients was carried out. The E group included 65 patients with surgically confirmed endometriosis (37 with DIE lesions) and the C group comprises 33 women without surgical findings of any form of endometriosis. Patients and controls were recruited during the same 10 month period. Controls were the next patient without endometriosis undergoing surgery, after including two patients with endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Venous blood samples for total cMP and cMP-TF determinations were obtained at the time of surgery, before anesthesia at a tertiary care center. To assess total cMP, an ELISA functional assay was used and cMP-TF activity in plasma was measured using an ELISA kit. MAIN RESULTS AND THE ROLE OF CHANCE: Total cMP levels in plasma were higher in the E group compared with the C group (P < 0.0001). The subanalysis of endometriosis patients with DIE or with ovarian endometriomas without DIE showed that total cMP levels were higher in the DIE group (P = 0.001). There were no statistically significant differences in cMP TF levels among the groups analyzed. LIMITATIONS, REASONS FOR CAUTION: This is a preliminary study in which the sample size was arbitrarily decided, albeit in keeping with previous studies analyzing cMP in other inflammatory diseases and other biomarkers in endometriosis. The control group included patients with other pathologies as well as healthy controls, and blood samples were taken at different phases of the cycle. WIDER IMPLICATIONS OF THE FINDINGS: Elevated total cMP levels in DIE patients may reflect an inflammatory and/or procoagulant systemic status in these patients. Further studies are warranted to confirm our findings and to assess the role of cMP levels in the pathophysiology of DIE. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by a grant from FIS-PI11/01560 and FIS-PI11/00977 within the 'Plan Nacional de I + D + I' and co-funded by the 'ISCIII-Subdireccion General de Evaluacion' and 'Fondo Europeo de Desarrollo Regional (FEDER)' and by the grant 'Premi Fi de Residencia Emili Letang 2015' from the Hospital Clinic of Barcelona. The authors have no competing interests to disclose. PMID- 27989990 TI - Effectiveness of lifestyle intervention in subgroups of obese infertile women: a subgroup analysis of a RCT. PMID- 27989991 TI - Age-related references in national public health, technology appraisal and clinical guidelines and guidance: documentary analysis. AB - Background: older people may be less likely to receive interventions than younger people. Age bias in national guidance may influence entire public health and health care systems. We examined how English National Institute for Health & Care Excellence (NICE) guidance and guidelines consider age. Methods: we undertook a documentary analysis of NICE public health (n = 33) and clinical (n = 114) guidelines and technology appraisals (n = 212). We systematically searched for age-related terms, and conducted thematic analysis of the paragraphs in which these occurred ('age-extracts'). Quantitative analysis explored frequency of age extracts between and within document types. Illustrative quotes were used to elaborate and explain quantitative findings. Results: 2,314 age-extracts were identified within three themes: age documented as an a-priori consideration at scope-setting (518 age-extracts, 22.4%); documentation of differential effectiveness, cost-effectiveness or other outcomes by age (937 age-extracts, 40.5%); and documentation of age-specific recommendations (859 age-extracts, 37.1%). Public health guidelines considered age most comprehensively. There were clear examples of older-age being considered in both evidence searching and in making recommendations, suggesting that this can be achieved within current processes. Conclusions: we found inconsistencies in how age is considered in NICE guidance and guidelines. More effort may be required to ensure age is consistently considered. Future NICE committees should search for and document evidence of age-related differences in receipt of interventions. Where evidence relating to effectiveness and cost-effectiveness in older populations is available, more explicit age-related recommendations should be made. Where there is a lack of evidence, it should be stated what new research is needed. PMID- 27989992 TI - Adverse outcomes in older adults attending emergency departments: a systematic review and meta-analysis of the Identification of Seniors At Risk (ISAR) screening tool. AB - Background: older adults are frequent users of emergency services and demonstrate high rates of adverse outcomes following emergency care. Objective: to perform a systematic review and meta-analysis of the Identification of Seniors At Risk (ISAR) screening tool, to determine its predictive value in identifying adults >=65 years at risk of functional decline, unplanned emergency department (ED) readmission, emergency hospitalisation or death within 180 days after index ED visit/hospitalisation. Methods: a systematic literature search was conducted in PubMed, EMBASE, CINAHL, EBSCO and the Cochrane Library to identify validation and impact analysis studies of the ISAR tool. A pre-specified ISAR score of >=2 (maximum score 6 points) was used to identify patients at high risk of adverse outcomes. A bivariate random effects model generated pooled estimates of sensitivity and specificity. Statistical heterogeneity was explored and methodological quality was assessed using validated criteria. Results: thirty-two validation studies (n = 12,939) are included. At >=2, the pooled sensitivity of the ISAR for predicting ED return, emergency hospitalisation and mortality at 6 months is 0.80 (95% confidence interval (CI) 0.70-0.87), 0.82 (95% CI 0.74-0.88) and 0.87 (95% CI 0.75-0.94), respectively, with a pooled specificity of 0.31 (95% CI 0.24-0.38), 0.32 (95% CI 0.24-0.41) and 0.35 (95% CI 0.26-0.44). Similar values are demonstrated at 30 and 90 days. Three heterogeneous impact analysis studies examined the clinical implementation of the ISAR and reported mixed findings across patient and process outcomes. Conclusion: the ISAR has modest predictive accuracy and may serve as a decision-making adjunct when determining which older adults can be safely discharged. PMID- 27989995 TI - The cancer risk related to meat and meat products. AB - Introduction: Meat has been classified by International Agency for Research on Cancer (IARC) as carcinogenic to humans. The evidence and the implications for health are reviewed. Sources of data: Evidence was obtained from published reports and systematic reviews published before and since the IARC decision. Areas of agreement: Epidemiology indicates that processed meat products are associated with increased risk of colorectal cancer. Evidence for red meat and for other cancers remains tentative. Areas of controversy: Several mechanisms for mutagenic effects of meat consumption have been identified but it is not clear which cause cancer in humans. The extent to which complete abstention from meat protects against cancer is also uncertain. Growing points: Prospective studies on meat consumption in western populations will continue to illuminate the details of carcinogenesis, and effective strategies for reducing risk. Areas timely for developing research: Further studies on the precise mechanisms of carcinogenesis in human populations would assist both food manufacturers and the general public to minimize risk. PMID- 27989996 TI - Editorial. PMID- 27989994 TI - Functional assessment of thoracic aortic aneurysms - the future of risk prediction? AB - Introduction: Treatment guidelines for the thoracic aorta concentrate on size, yet acute aortic dissection or rupture can occur when aortic size is below intervention criteria. Functional imaging and computational techniques are a means of assessing haemodynamic parameters involved in aortic pathology. Sources of data: Original articles, reviews, international guidelines. Areas of agreement: Computational fluid dynamics and 4D flow MRI allow non-invasive assessment of blood flow parameters and aortic wall biomechanics. Areas of controversy: Aortic valve morphology (particularly bicuspid aortic valve) is associated with aneurysm of the ascending aorta, although the exact mechanism of aneurysm formation is not yet established. Growing points: Haemodynamic assessment of the thoracic aorta has highlighted parameters which are linked with both clinical outcome and protein changes in the aortic wall. Wall shear stress, flow displacement and helicity are elevated in patients with bicuspid aortic valve, particularly at locations of aneurysm formation. Areas timely for developing research: With further validation, functional assessment of the aorta may help identify patients at risk of aortic complications, and introduce new haemodynamic indices into management guidelines. PMID- 27989997 TI - Angiosarcoma following radiation therapy for breast cancer Case report. AB - : More and better accessibility to screening and increasing women's knowledge about the main symptomatic breast cancer signs result in detection of this neoplasm at an early stage, allowing a conservative surgical treatment. Breast conserving therapy (BCT) due to breast carcinoma involves the use of adjuvant radiotherapy which carries a risk the secondary radiation-induced malignancy. Angiosarcoma of the breast is an extremely rare radiation-induced malignant tumor following breast conserving therapy (BCT), first described by Schmidt in 1887. In this article the authors presented the case of a 56-year-old woman who was admitted to the hospital because of diagnosed angiosarcoma of the right breast after breast conserving therapy (BCT) with the Sentinel Node Biopsy (SNB) and adjuvant radiotherapy of her breast carcinoma 5 years earlier. The patient had a simple mastectomy performed and on the second day after surgery was discharged home. KEY WORDS: Angiosarcoma, Breast cancer, Radiation therapy, Surgery, Treatment. PMID- 27989998 TI - Phylogenetic analysis reveals the taxonomically diverse distribution of the Pseudomonas putida group. AB - Pseudomonas putida is well-known for degradation activities for a variety of compounds and its infections have been reported. Thus, P. putida includes both clinical and nonclinical isolates. To date, no reports have examined the phylogenetic relationship between clinical and nonclinical isolates of the P. putida group. In this study, fifty-nine strains of P. putida group containing twenty-six clinical, and thirty-three nonclinical, isolates, were subjected to phylogenetic and taxonomic analyses based on 16S rRNA gene sequences and nine housekeeping gene sequences, including argS, dnaN, dnaQ, era, gltA, gyrB, ppnK, rpoB, and rpoD, to obtain insights into the diversity of species in this group. More than 97.6% similarity was observed among the 16S rRNA gene sequences of all the strains examined, indicating that the resolution of 16S rRNA gene sequences is inadequate. Phylogenetic analysis based on the individual housekeeping genes listed above improved the resolution of the phylogenetic trees, which are different from each other. Multilocus sequence analysis (MLSA) based on the concatenated sequences of the nine genes significantly improved the resolution of the phylogenetic tree, and yielded approximately the same results as average nucleotide identity (ANI) analysis, suggesting its high reliability. ANI analysis classified the fifty-nine strains into twenty-six species containing seventeen singletons and nine strain clusters based on the 95% threshold. It also indicated the mixed distribution of clinical and nonclinical isolates in the six clusters, suggesting that the genomic difference between clinical and nonclinical isolates of the P. putida group is subtle. The P. putida type strain NBRC 14164T is a singleton that is independently located from the P. putida strains distributed among the six clusters, suggesting that the classification of these strains and the differentiation of species in the P. putida group should be re-examined. This study greatly expands insights into the phylogenetic diversity of the P. putida group. PMID- 27989999 TI - Candidate nematicidal proteins in a new Pseudomonas veronii isolate identified by its antagonistic properties against Xiphinema index. AB - The nematode Xiphinema index affects grape vines and transmits important viruses associated with fanleaf degeneration. Pseudomonas spp. are an extensive bacterial group in which important biodegradation and/or biocontrol properties can occur for several strains in the group. The aim of this study was to identify new Pseudomonas isolates with antagonist activity against X. index. Forty bacterial isolates were obtained from soil and root samples from Chilean vineyards. Thirteen new fluorescent pseudomonads were found and assessed for their antagonistic capability. The nematicide Pseudomonas protegens CHA0 was used as a control. Challenges of nematode individuals in King's B semi-solid agar Petri dishes facilitated the identification of the Pseudomonas veronii isolate R4, as determined by a 16S rRNA sequence comparison. This isolate was as effective as CHA0 as an antagonist of X. index, although it had a different lethality kinetic. Milk-induced R4 cultures exhibited protease and lipase activities in cell supernatants using both gelatin/tributyrin Petri dish assays and zymograms. Three proteins with these activities were isolated and subjected to mass spectrometry. Amino acid partial sequences enabled the identification of a 49-kDa protease similar to metalloprotease AprA and two lipases of 50 kDa and 69 kDa similar to LipA and ExoU, respectively. Electron microscopy analyses of challenged nematodes revealed degraded cuticle after R4 supernatant treatment. These results represent a new and unexplored property in this species associated with the presence of secretable lipases and protease, similar to characterized enzymes present in biocontrol pseudomonads. PMID- 27990000 TI - Phenotypic difference between Delta(srl-recA)306 and DeltarecA::Km elucidated by next-generation sequencing combined with a long-PCR system. AB - Many significant gene mutations in E. coli have contributed to the development of genetics. Among these, a commonly used recA mutation, Delta(srl-recA)306 has been sequenced by a next-generation sequencer combined with a long PCR. An original report described that Delta(srl-recA)306 cells were deleted from srlR to recA genes in their genome. The next-generation sequencer enables more accurate details to be determined. We ask whether both surrounding genes from hypF to norV for srlR and alaS for recA is there first. The long PCR was carried out with primers, norR and alaS, and amplified DNA fragments differed in length from wild to Delta(srl-recA)306 cells, suggesting that an entire Delta(srl-recA)306 mutation was included. Sequences of those DNA fragments indicated that 9147 bp, from srlR to recA including 10 genes, were replaced by a Tn10 DNA sequence. Junction points at both srlR-Tn10 and Tn10-recA were determined precisely. The results indicate that the first 97% of recA gene sequences were lost with a downstream recX gene remaining intact. The phenotypic difference between Delta(srl-recA)306 and DeltarecA::Km is discussed. PMID- 27990001 TI - Archaeal histone distribution is associated with archaeal genome base composition. AB - A subpopulation of Archaea possesses histones, which are similar to eukaryotic histones H3 and H4. However, archaeal histones are smaller than H3 and H4, and are not post-translationally modified. In addition, the fundamental unit of archaeal histones might be a dimer. The organization of archaeal nucleosomes, therefore, differs from that of eukaryotic nucleosomes. The base compositions of archaeal genome are much more diversified than those of eukaryote and the archaeal histones have more diversified amino acid sequences, which are reflected by their varied isoelectric points. We hypothesized that the highly diversified archaeal genomic DNA base composition may cause the archaeal histone variation. Phylogenetic analysis revealed that the distribution of archaeal histones is associated with their genomic DNA base composition. This result strongly suggests that archaeal histones have evolved concomitantly with their genomic DNA base composition. Eukaryotic histones are one of the most evolutionarily conserved proteins and would limit the diversification of genomic DNA base composition. In contrast, archaeal histones have diversified and would permit the great diversification of genomic DNA base composition. PMID- 27990003 TI - Current status of genome editing in vector mosquitoes: A review. AB - Mosquitoes pose a major threat to human health as they spread many deadly diseases like malaria, dengue, chikungunya, filariasis, Japanese encephalitis and Zika. Identification and use of novel molecular tools are essential to combat the spread of vector borne diseases. Genome editing tools have been used for the precise alterations of the gene of interest for producing the desirable trait in mosquitoes. Deletion of functional genes or insertion of toxic genes in vector mosquitoes will produce either knock-out or knock-in mutants that will check the spread of vector-borne diseases. Presently, three types of genome editing tools viz., zinc finger nuclease (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats (CRISPR) and CRISPR associated protein 9 (Cas9) are widely used for the editing of the genomes of diverse organisms. These tools are also applied in vector mosquitoes to control the spread of vector-borne diseases. A few studies have been carried out on genome editing to control the diseases spread by vector mosquitoes and more studies need to be performed with the utilization of more recently invented tools like CRISPR/Cas9 to combat the spread of deadly diseases by vector mosquitoes. The high specificity and flexibility of CRISPR/Cas9 system may offer possibilities for novel genome editing for the control of important diseases spread by vector mosquitoes. In this review, we present the current status of genome editing research on vector mosquitoes and also discuss the future applications of vector mosquito genome editing to control the spread of vectorborne diseases. PMID- 27990002 TI - Cinepazide Maleate Improves Cognitive Function and Protects Hippocampal Neurons in Diabetic Rats with Chronic Cerebral Hypoperfusion. AB - To determine the combined effect of type 2 diabetes (T2D) and chronic cerebral hypoperfusion (CCH) on learning and spatial memory, we developed a rat model of CCH by permanent occlusion of bilateral common carotid arteries (2-vessel occlusion (2VO)) in high-fat diet (HFD)-fed rats injected with low-dose streptozotocin (STZ). Furthermore, we examined the effect of cinepazide maleate (CM) on cognitive deficits and brain damage in this rat model. Rats were maintained on HFD for 6 weeks and then injected with 35 mg/kg STZ to induce T2D. Sham or 2VO surgery was performed in non-diabetic or diabetic (DM) rats to obtain four groups: blank, DM, CCH, and DM-CCH groups. Cognitive function was tested by the Morris water maze (MWM) test. To determine the effects of the vasodilator cinepazide maleate (CM) on cognitive deficits and brain damage, DM-CCH rats were administered with 10 mg/kg CM or saline daily for 14 d. Neuronal damage in DM-CCH rats was associated with increased expression of glial fibrillary acidic protein (GFAP) and beta-secretase 1 (BACE1), but decreased expression of choline acetyltransferase (ChAT). Moreover, the levels of all these proteins were significantly alleviated by CM treatment. These results suggest that T2D exacerbated CCH-induced brain damage and cognitive impairment, and CM ameliorated these effects. PMID- 27990004 TI - Endoscopic and surgical ampullectomy for non-invasive ampullary tumors: Short term outcomes. AB - Non-invasive ampullary tumors, may be treated with endoscopic (EA) or surgical ampullectomy (SA). However, evidence on the morbidity of these techniques remains limited. This pilot study aimed to assess and compare morbidity of EA and SA. Patients undergoing EA or SA for non-invasive ampullary tumors were retrospectively analyzed and compared. Outcomes were postoperative complications graded with Clavien Classification and Comprehensive Complication Index (CCI), and length of stay (LoS). A review of the literature was performed to propose an evidence-based algorithm to treat ampullary tumors. A total of 11 EA and 19 SA were identified and analyzed. EA was associated with shorter intervention (51 vs. 191 min, p < 0.001) and decreased blood loss (0 vs. 100 mL, p < 0.001). Postoperative complications were more frequent after surgery compared to endoscopy (9% vs. 68%, p = 0.002). Surgical patients showed a higher CCI (0 vs. 8.7, p < 0.001). LoS was reduced in patients undergoing endoscopy (0 vs. 14 days, p < 0.001), with comparable readmissions rates (p = 0.126). Necessity of subsequent treatment was more frequent after endoscopic, compared to SA (5 vs. 1, p = 0.016). EA was associated with lower morbidity than SA and appeared as an appropriate first-line treatment for non-invasive ampullary tumors. SA remains a valuable alternative after EA failure. PMID- 27990005 TI - Ledipasvir and sofosbuvir for recurrent hepatitis C after liver transplantation. AB - Management of recurrent hepatitis C following liver transplantation still remains a challenge. Here, we report five patients who achieved viral responses following combined treatment with ledipasvir and sofosbuvir. All the patients received tacrolimus for immunosuppression. No dose adjustment was made before the ledipasvir and sofosbuvir therapy. All completed the intended 12-week treatment course with the full dose of ledipasvir and sofosbuvir. There were no significant adverse events greater than grade 2. During the study period, no acute rejection episodes were detected. The trough levels of tacrolimus were maintained stably. Hepatitis C virus RNA was not detected at week 12 in any of the patients. Based on the findings from this pilot study, combined ledipasvir and sofosbuvir therapy for 12 weeks is effective and safe for living - donor liver transplantation recipients with recurrence of hepatitis C virus. PMID- 27990006 TI - Nitric oxide donor hybrid compounds as promising anticancer agents. AB - Nitric oxide (NO) plays important roles in cardiovascular regulation, nerve transmission delivery and immune responses. In the last semicenturry, it has been proved that though low concentration of NO is tumor-promoting, high concentration of NO could exhibit multiple antitumor effects, which led to the research and development of kinds of NO donors and NO donor hybrid compounds as antitumor agents. Herein, the recent development of NO donor hybrid compounds is briefly reviewed. PMID- 27990007 TI - A newborn with hemorrhagic meningoencephalitis due to Proteus mirabilis. AB - Neonatal meningoencephalitis is a severe condition for the developing brain of a newborn. Radiologic findings of necrosis and liquefaction due to hemorrhagic meningoencephalitis may be confused with brain abcess. In this article, we report a neonate having liquefaction necrosis due to hemorrhagic meningoencephalitis mimicing intracranial abscess due to Proteus mirabilis. We would like to describe the clinical course and evolution of brain imaging and emphasize the importance of the serial MR imaging (MRI). PMID- 27990008 TI - Anemia Treatment by Erythropoiesis-stimulating Agents during the 6 Months before the Initiation of Hemodialysis: Comparison of Darbepoetin Alfa and Continuous Erythropoietin Receptor Activator. AB - Anemia in chronic kidney disease (CKD) is a risk factor for cardiovascular diseases and is treated by long-acting erythropoiesis-stimulating agents (ESAs). Although the results of previous studies have shown that hemoglobin levels could not be maintained at the initiation of dialysis in CKD patients treated with recombinant human erythropoietin, it remains undetermined whether long-acting ESAs are effective in preventing the progression of anemia at the initiation of dialysis. In the present study, hemoglobin levels in 40 CKD patients treated with darbepoetin alfa (DA) and 15 CKD patients treated with a continuous erythropoietin receptor activator (CERA) were retrospectively compared during the 6 months period before the initiation of dialysis. Results showed that DA and CERA both maintained hemoglobin levels at around 10 g/dL from 6 months to 1 month before dialysis. However, hemoglobin levels at the initiation of dialysis significantly decreased to 9.1 +/- 1.2 g/dL in the DA group and to 9.0 +/- 1.0 g/dL in the CERA group. Although the total doses of ESAs used during the 6-month period were similar between the two groups, DA-treated CKD patients received subcutaneous injections more frequently than did patients treated with CERA. These results suggest that CKD patients require more intense ESA therapy to prevent a decline in hemoglobin levels at the initiation of dialysis, including those treated with long-acting ESAs. The results also raise the possibility that CERA is more useful than DA for reducing the number of injections during the pre dialysis period. PMID- 27990009 TI - Distribution of methicillin-resistant coagulase-positive staphylococci (MRCoPS) in a surgical unit and cystotomy operation sites in a veterinary teaching hospital. AB - This study aimed to investigate the spread of methicillin-resistant coagulase positive staphylococci (MRCoPS) among veterinary staff, hand-touch sites and surgical tissue during cystotomy operations on cats and dogs that were patients, and to analyze the genetic relatedness and antimicrobial resistance profiles of the isolates. Human and environmental samples were obtained from the nasal passageways of 12 surgeons and veterinary assistants and from 29 hand-touch sites of instruments in operative units and subjected to bacterial isolation and enumeration. Swab samples were collected in triplicate from 29 dogs and three cats at the site of incision, from the incision area, from the peritoneum during surgery and from the peritoneum before suture. MRCoPS were identified by mecA gene detection and characterized by their antibiogram profile, SCCmec type and pulsed-field gel electrophoresis. Twenty-four staphylococci were isolated, derived from one veterinary assistant, 12 operating room floor areas and hand touch sites, three dogs and one cat. Methicillin-resistant S. pseudintermedius (MRSP) was found on an electric clipper and rebreathing circuits in the operating room. Three dogs were positive for MRSP during surgery, and one methicillin resistant S. aureus (MRSA) was detected in a cat. All MRCoPS were resistant to doxycycline, erythromycin, clindamycin and enrofloxacin, but no patients developed surgical site infections. According to their genotypic patterns, the clones obtained from the environment and human sources differed from the animal clones. Despite intensive hygienic management, a variety of MRCoPS clones were present within the surgical unit and during surgery. PMID- 27990010 TI - A Case of endoscopic retrieval of a long bamboo stick from a Humboldt penguin (Spheniscus humboldti). AB - An eighteen-month-old female Humboldt penguin (Spheniscus humboldti) that was 50 cm in length and 4.5 kg in weight was presented with anorexia and vomiting. The hematological and blood biochemical profiles revealed no remarkable findings, and no Salmonella, Shigella or Vibrio spp. were isolated from the fecal culture. However, radiographic imaging revealed a long linear foreign body presenting from the lower esophagus to the stomach. To retrieve this foreign body, flexible endoscopic extraction was performed using flexible rat tooth grasping forceps. A long bamboo stick (29 * 1 cm) was removed from the stomach, and the penguin fully recovered. PMID- 27990011 TI - Retrospective analysis of canine gallbladder contents in biliary sludge and gallbladder mucoceles. AB - The pathophysiology of canine gallbladder diseases, including biliary sludge, gallbladder mucoceles and gallstones, is poorly understood. This study aimed to evaluate the component of gallbladder contents and bacterial infection of the gallbladder in order to elucidate the pathophysiology of biliary sludge and gallbladder mucoceles. A total of 43 samples of canine gallbladder contents (biliary sludge, 21 and gallbladder mucoceles, 22) were subjected to component analysis by infrared spectroscopy, and the resultant infrared spectra were compared with that of swine mucin. Of the 43 samples, 41 were also evaluated by aerobic and anaerobic bacterial culture. The contents of 20 (95.2%) biliary sludge and 22 (100%) gallbladder mucocele samples exhibited similar infrared spectra as swine mucin. Although biliary sludge and gallbladder mucocele contents exhibited similar infrared spectra, one sample of biliary sludge (4.8%) was determined to be composed of proteins. The rate of bacterial infection of the gallbladder was 10.0% for biliary sludge and 14.3% for gallbladder mucoceles. Almost all of the identified bacterial species were intestinal flora. These results indicate that the principal components of gallbladder contents in both gallbladder mucoceles and biliary sludge are mucins and that both pathophysiologies exhibit low rates of bacterial infection of the gallbladder. Therefore, it is possible that gallbladder mucoceles and biliary sludge have the same pathophysiology, and, rather than being independent diseases, they could possibly represent a continuous disease. Thus, biliary sludge could be considered as the stage preceding the appearance of gallbladder mucoceles. PMID- 27990012 TI - Characterization of the TRAF3IP1 gene in Yesso scallop (Patinopecten yessoensis) and its expression in response to bacterial challenge. AB - Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an important adaptor that transmits upstream activation signals to induce innate immune responses. TRAF3 interacting protein 1 (TRAF3IP1) interacts specifically with TRAF3, but its function in innate immunity remains unclear, especially in marine invertebrates. In this study, to better understand the functions of TRAFs in innate immune responses, we identified and characterized the first bivalve TRAF3IP1 gene, PyTRAF3IP1, from Yesso scallop (Patinopecten yessoensis), one of the most important mollusk species for aquaculture. The PyTRAF3IP1 cDNA is 2,367 bp, with an open reading frame of 1,629 bp encoding 542 amino acids. Phylogenetic and protein structural analysis confirmed the gene's identity and revealed that PyTRAF3IP1 was more similar to vertebrate TRAF3IP1s than to those of invertebrates. PyTRAF3IP1 was expressed in all the adult tissues and developmental stages sampled, implying that it plays versatile roles in many biological processes. Furthermore, PyTRAF3IP1 expression was dramatically induced in the acute phase (3-6 h) after infection with both Gram-positive (Micrococcus luteus) and Gram-negative (Vibrio anguillarum) bacteria, even stronger induction being observed after V. anguillarum challenge. This is the first report of the characterization and immune response involvement of TRAF3IP1 in marine invertebrates, and suggests that TRAF3IP1 contributes to innate immunity in bivalves. PMID- 27990013 TI - Intraoperative Gastric Intramural Hematoma: A Rare Complication of Percutaneous Endoscopic Gastrostomy. AB - BACKGROUND Intramural hematomas primarily present in the esophagus or duodenum. We report a case of intramural hematoma in the gastric wall (GIH) secondary to percutaneous endoscopic gastrostomy (PEG) tube placement in a setting of platelet dysfunction. CASE REPORT This case study reviews the hospitalization of a 73-year old male with a history of chronic kidney disease who was admitted for coronary artery bypass graft surgery and mitral valve repair. During his complicated hospital course, he inadvertently required the placement of a PEG tube. His coagulation profile prior to this procedure was within normal limits. The patient had no history of coagulopathy and was taking aspirin 81 mg per day. PEG tube placement was withheld due to an expanding hematoma that was noted at the site of needle insertion in the gastric wall. A single dose of intravenous desmopressin (0.3 microgram/kilogram) was administered under the suspicion of uremic bleeding. No further gastrointestinal bleeding events were observed. A platelet function assay (PFA) and collagen/epinephrine closure time indicated platelet dysfunction. Three days later, we again attempted a PEG tube placement. His PFA prior to this procedure had normalized due to aspirin discontinuation and improvement of renal function. Esophagogastroduodenoscopy (EGD) showed an area of flat bluish gastric submucosal bruising at the site of the previous hematoma. The PEG tube was placed successfully at an adjacent site. Over the course of the following month, the patient underwent uneventful feeding through the PEG tube. CONCLUSIONS To our knowledge, cases of GIH are rarely documented in literature. Multidisciplinary vigilance is required to maintain a high index of suspicion for this complication in patients with uremia or other coagulopathies to aid in prompt diagnosis. PMID- 27990014 TI - Prognostic Value of the Combination of Preoperative Hemoglobin, Lymphocyte, Albumin, and Neutrophil in Patients with Locally Advanced Colorectal Cancer. AB - BACKGROUND Systemic inflammatory response and nutritional status are important to the prognosis of patients with colorectal cancer (CRC). This study aimed to investigate the prognostic value of the combination of preoperative hemoglobin, lymphocyte, albumin, and neutrophil (HLAN) in patients with locally advanced CRC (LACRC). MATERIAL AND METHODS We performed a retrospective analysis in 536 LACRC patients undergoing radical surgery. The value of HLAN was defined as follow: HLAN=Hemoglobin (g/L)*Lymphocyte (/L)*Albumin (g/L)/Neutrophil (/L)/100. The X tile program was used to determine the optimal cut-point of HLAN, and the prognostic value of HLAN for overall survival (OS) was evaluated with the Cox proportional hazard model. RESULTS The cut-point of HLAN was set at 19.5. Compared with the high-HLAN group, the low-HLAN group had a 1.50-fold (95% confidence interval 1.09-2.05) increased risk of death and a significantly lower OS rate (P<0.001). Furthermore, the risk stratification model based on HLAN (AUC=0.72) displayed better accuracy in OS prediction than the TNM system (AUC=0.61). CONCLUSIONS HLAN is a valuable prognostic marker for patients with LACRC. PMID- 27990016 TI - Thrombotic microangiopathies: VEGF-complement interactions. PMID- 27990017 TI - Glomerular disease: Role of tonsillar B cells in IgAN. PMID- 27990015 TI - The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. AB - Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell mediated kidney protection. PMID- 27990020 TI - Genetic engineering: CREATE-ing genome-wide designed mutations. PMID- 27990018 TI - Chlamydial protease-like activity factor mediated protection against C. trachomatis in guinea pigs. AB - We have comprehensively demonstrated using the mouse model that intranasal immunization with recombinant chlamydial protease-like activity factor (rCPAF) leads to a significant reduction in bacterial burden, genital tract pathology and preserves fertility following intravaginal genital chlamydial challenge. In the present report, we evaluated the protective efficacy of rCPAF immunization in guinea pigs, a second animal model for genital chlamydial infection. Using a vaccination strategy similar to the mouse model, we intranasally immunized female guinea pigs with rCPAF plus CpG deoxynucleotides (CpG; as an adjuvant), and challenged intravaginally with C. trachomatis serovar D (CT-D). Immunization with rCPAF/CpG significantly reduced vaginal CT-D shedding and induced resolution of infection by day 24, compared with day 33 in CpG alone treated and challenged animals. Immunization induced robust anti-rCPAF serum IgG 2 weeks following the last immunization, and was sustained at a high-level 4 weeks post challenge. Upregulation of antigen-specific IFN-gamma gene expression was observed in rCPAF/CpG-vaccinated splenocytes. Importantly, a significant reduction in inflammation in the genital tissue in rCPAF/CpG-immunized guinea pigs compared with CpG-immunized animals was observed. Taken together, this study provides evidence of the protective efficacy of rCPAF as a vaccine candidate in a second animal model of genital chlamydial infection. PMID- 27990021 TI - Microbiome: Rhythm and bacteria. PMID- 27990023 TI - The Bio Bay Game: Three-Dimensional Learning of Biomagnification. AB - Pressing concerns about sustainability and the state of the environment amplify the need to teach students about the connections between ecosystem health, toxicology, and human health. Additionally, the Next Generation Science Standards call for three-dimensional science learning, which integrates disciplinary core ideas, scientific practices, and crosscutting concepts. The Bio Bay Game is a way to teach students about the biomagnification of toxicants across trophic levels while engaging them in three-dimensional learning. In the game, the class models the biomagnification of mercury in a simple aquatic food chain as they play the roles of anchovies, tuna, and humans. While playing, the class generates data, which they analyze after the game to graphically visualize the buildup of toxicants. Students also read and discuss two articles that draw connections to a real-world case. The activity ends with students applying their understanding to evaluate the game as a model of biomagnification. Throughout the activity, students practice modeling and data analysis and engage with the crosscutting concepts of patterns and cause and effect to develop an understanding of core ideas about the connections between humans and the environment. PMID- 27990019 TI - Transcriptional architecture of the mammalian circadian clock. AB - Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology. PMID- 27990024 TI - Integrating the Dimensions of NGSS within a Collaborative Board Game about Honey Bees. AB - The current reform in U.S. science education calls for the integration of three dimensions of science learning in classroom teaching and learning: Science and Engineering Practices, Crosscutting Concepts, and Disciplinary Core Ideas. While the Next Generation Science Standards provide flexibility in how curriculum and instruction are structured to meet learning goals, there are few examples of existing curricula that portray the integration of these dimensions as "three dimensional learning." Here, we describe a collaborative board game about honey bees that incorporates scientific evidence on how genetic and environmental factors influence variations of traits and social behavior and requires students to collaboratively examine and use a system model. Furthermore, we show how students used and evaluated the game as a model in authentic classroom settings. PMID- 27990022 TI - RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins. AB - Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis. PMID- 27990026 TI - Assessment of bioavailable organic phosphorus in tropical forest soils by organic acid extraction and phosphatase hydrolysis. AB - Soil organic phosphorus contributes to the nutrition of tropical trees, but is not accounted for in standard soil phosphorus tests. Plants and microbes can release organic anions to solubilize organic phosphorus from soil surfaces, and synthesize phosphatases to release inorganic phosphate from the solubilized compounds. We developed a procedure to estimate bioavailable organic phosphorus in tropical forest soils by simulating the secretion processes of organic acids and phosphatases. Five lowland tropical forest soils with contrasting properties (pH 4.4-6.1, total P 86-429 mg P kg- 1) were extracted with 2 mM citric acid (i.e., 10 MUmol g- 1, approximating rhizosphere concentrations) adjusted to soil pH in a 4:1 solution to soil ratio for 1 h. Three phosphatase enzymes were then added to the soil extract to determine the forms of hydrolysable organic phosphorus. Total phosphorus extracted by the procedure ranged between 3.22 and 8.06 mg P kg- 1 (mean 5.55 +/- 0.42 mg P kg- 1), of which on average three quarters was unreactive phosphorus (i.e., organic phosphorus plus inorganic polyphosphate). Of the enzyme-hydrolysable unreactive phosphorus, 28% was simple phosphomonoesters hydrolyzed by phosphomonoesterase from bovine intestinal mucosa, a further 18% was phosphodiesters hydrolyzed by a combination of nuclease from Penicillium citrinum and phosphomonoesterase, and the remaining 51% was hydrolyzed by a broad-spectrum phytase from wheat. We conclude that soil organic phosphorus can be solubilized and hydrolyzed by a combination of organic acids and phosphatase enzymes in lowland tropical forest soils, indicating that this pathway could make a significant contribution to biological phosphorus acquisition in tropical forests. Furthermore, we have developed a method that can be used to assess the bioavailability of this soil organic phosphorus. PMID- 27990027 TI - Identified research directions for using manufacturing knowledge earlier in the product lifecycle. AB - Design for Manufacturing (DFM), especially the use of manufacturing knowledge to support design decisions, has received attention in the academic domain. However, industry practice has not been studied enough to provide solutions that are mature for industry. The current state of the art for DFM is often rule-based functionality within Computer-Aided Design (CAD) systems that enforce specific design requirements. That rule-based functionality may or may not dynamically affect geometry definition. And, if rule-based functionality exists in the CAD system, it is typically a customization on a case-by-case basis. Manufacturing knowledge is a phrase with vast meanings, which may include knowledge on the effects of material properties decisions, machine and process capabilities, or understanding the unintended consequences of design decisions on manufacturing. One of the DFM questions to answer is how can manufacturing knowledge, depending on its definition, be used earlier in the product lifecycle to enable a more collaborative development environment? This paper will discuss the results of a workshop on manufacturing knowledge that highlights several research questions needing more study. This paper proposes recommendations for investigating the relationship of manufacturing knowledge with shape, behavior, and context characteristics of product to produce a better understanding of what knowledge is most important. In addition, the proposal includes recommendations for investigating the system-level barriers to reusing manufacturing knowledge and how model-based manufacturing may ease the burden of knowledge sharing. Lastly, the proposal addresses the direction of future research for holistic solutions of using manufacturing knowledge earlier in the product lifecycle. PMID- 27990028 TI - Optimal decay rates for the compressible viscoelastic flows. AB - In this paper, we study the compressible viscoelastic flows in three-dimensional whole space. Under the assumption of small initial data, we establish the unique global solution by the energy method. Furthermore, we obtain the time decay rates of the higher-order spatial derivatives of the solution if the initial data belong to L1(R3) additionally. PMID- 27990025 TI - The Fracture of Relational Space in Depression: Predicaments in Primary Care Help Seeking. AB - Primary care clinicians treat the majority of cases of depression in the United States. The primary care clinic is also a site for enactment of a disease oriented concept of depression that locates disorder within an individual body. Drawing on theories of the self and stigma, this article highlights problematics of primary care depression treatment by examining the lived experience of depression. The data come from individuals who screened positive for depressive symptoms in primary care settings and were followed over ten years. After iterative mixed-methodological exploration of a large dataset, we analyzed interviews from a purposive sample of 46 individuals using grounded and phenomenological approaches. We describe two major results. First, we note that depression is experienced as located within and inextricable from relational space and that the self is experienced as relational, rather than autonomous, in depression. Second, we describe the ways in which the experience of depression contradicts a disease-oriented concept such that help-seeking intensifies rather than alleviates the relational problem of depression. We conclude by highlighting that an understanding of illness experience may be essential to improving primary care depression treatment and by questioning the bracketing of relational concerns in depression within the construct of stigma. PMID- 27990029 TI - Seeking exposure: conversions of scientific knowledge in an African city. AB - Transnational medical research has become a common feature in many parts of Africa. This paper explores the contribution such activity makes to the social and economic lives of those involved, including both trial subjects and local staff. By considering the value of the 'exposure' that involvement brings to staff and research participants, we reflect on the conversion of scientific knowledge into practical knowledge and its value to sustaining precarious livelihoods in an economically fragile city. We consider the interplay between science and sociality and argue for a need to take seriously the circulation of scientific knowledge beyond the confines of expert spaces. PMID- 27990030 TI - Triple bag hermetic technology for controlling a bruchid (Spermophagus sp.) (Coleoptera, Chrysomelidae) in stored Hibiscus sabdariffa grain. AB - We assessed the performance of hermetic triple layer Purdue Improved Crop Storage (PICS) bags for protecting Hibiscus sabdariffa grain against storage insects. The major storage pest in the grain was a bruchid, Spermophagus sp.. When we stored infested H. sabdariffa grain for six months in the woven polypropylene bags typically used by farmers, the Spermophagus population increased 33-fold over that initially present. The mean number of emergence holes per 100 seeds increased from 3.3 holes to 35.4 holes during this time period, while grain held for the same length of time in PICS bags experienced no increase in the numbers of holes. Grain weight loss in the woven control bags was 8.6% while no weight loss was observed in the PICS bags. Seed germination rates of grain held in woven bags for six months dropped significantly while germination of grain held in PICS bags did not change from the initial value. PICS bags can be used to safely store Hibiscus grain after harvest to protect against a major insect pest. PMID- 27990031 TI - Grain size and grain depth restrict oxygen movement in leaky hermetic containers and contribute to protective effect. AB - Postharvest insect pests threaten the nutritional and financial security of smallholder farmers in the developing world. Hermetic storage, a technology that protects grain against insects by blocking their supply of oxygen, alleviates the problem of insect-caused losses. PICS (Purdue Improved Crop Storage) bags represent one hermetic technology that improves food availability and incomes of farmers. The polyethylene liners of PICS bags are sometime damaged during use, acquiring small holes or tears. Observations in the laboratory and field suggest that insect development remains localized around the point where the bag is damaged. We hypothesized that the grain within a hermetic container that has minimal localized damage (such as an insect hole), helps retard leakage of oxygen into the bag and contributes to limiting insect damage and to the overall protective effect. To test this hypothesis, we filled 4 cm dia. by 10 cm long PVC pipes with Callosobruchus maculatus (F.) infested cowpeas and sealed them with caps having a single, insect-sized hole in its center. A vertical tube positioned above the cowpea-filled PVC pipe was filled with one of three different grains (sesame, sorghum, and maize) to different depths (0, 5, 15, 30, 50 cm). Seed size and grain barrier depth significantly reduced the level of bruchid damage to the stored cowpea in the PVC container. Smaller sized grains used for the barriers retarded insect development more effectively than larger sized grains, while deeper grain depth was more effective than shallower barriers. The grain held in a hermetic container contributes in a small, but significant, way to the effectiveness of the containers. PMID- 27990032 TI - Impact of opening hermetic storage bags on grain quality, fungal growth and aflatoxin accumulation. AB - Purdue Improved Crop Storage (PICS) bags are used by farmers in Sub-Saharan Africa for pest management of stored grains and products, including maize. These bags hermetically seal the products, preventing exchange with external moisture and gases. Biological respiration within the bags create an environment that is unsuitable for insect development and fungal growth. This study was conducted to determine the impact of routine opening of the storage bags for maize consumption on fungal growth and aflatoxin contamination. Maize with moisture contents (MC) high enough to support fungal growth (15%, 16%, 18% and 20%) was stored in PICS bags, which were opened weekly and exposed to humid conditions (85% RH) for 30 min over a period of 8 weeks and 24 weeks. Monitors indicated that oxygen defused into the open bags but did not reach equilibrium with the bottom layers of grain during the 30-min exposure period. Fungal colony forming units obtained from the grain surface increased 3-fold (at 15% MC) to 10,000-fold (at 20% MC) after 8 weeks. At both 8 weeks and 24 weeks, aflatoxin was detected in at least one bag at each grain moisture, suggesting that aflatoxin contamination spread from a planted source of A. flavus-colonized grain to non-inoculated grain. The results indicate that repeatedly breaking the hermetic seal of the PICS bags will increase fungal growth and the risk of aflatoxin contamination, especially in maize stored at high moisture content. This work also further demonstrates that maize should be properly dried prior to storage in PICS bags. PMID- 27990033 TI - PTSD-Related Cardiovascular Disease and Accelerated Cellular Aging. AB - We reviewed the literature from 2010 to 2016 on the relationship between posttraumatic stress disorder (PTSD) and cardiometabolic health conditions, including metabolic syndrome, coronary artery disease, stroke, and myocardial infarction, among others. Collectively, PTSD was associated with increased risk of cardiometabolic health problems, with pre-clinical and clinical studies offering evidence of behavioral (e.g., poor sleep, cigarette use, poor diet and insufficient exercise) and biological (e.g., autonomic reactivity, inflammation) mediators of these associations. We discuss the possibility that these behavioral and biological mechanisms lead to accelerated cellular aging, as regulated in the epigenome, which contributes to premature cardiometabolic health decline. This has implications for the assessment, prevention, and treatment of cardiometabolic conditions among those with PTSD. It also highlights the need to better understand the mechanisms linking PTSD to accelerated aging and to develop interventions to attenuate or reverse this phenomenon. PMID- 27990034 TI - A Dynamic Bayesian Model for Characterizing Cross-Neuronal Interactions During Decision-Making. AB - The goal of this paper is to develop a novel statistical model for studying cross neuronal spike train interactions during decision making. For an individual to successfully complete the task of decision-making, a number of temporally organized events must occur: stimuli must be detected, potential outcomes must be evaluated, behaviors must be executed or inhibited, and outcomes (such as reward or no-reward) must be experienced. Due to the complexity of this process, it is likely the case that decision-making is encoded by the temporally-precise interactions between large populations of neurons. Most existing statistical models, however, are inadequate for analyzing such a phenomenon because they provide only an aggregated measure of interactions over time. To address this considerable limitation, we propose a dynamic Bayesian model which captures the time-varying nature of neuronal activity (such as the time-varying strength of the interactions between neurons). The proposed method yielded results that reveal new insight into the dynamic nature of population coding in the prefrontal cortex during decision making. In our analysis, we note that while some neurons in the prefrontal cortex do not synchronize their firing activity until the presence of a reward, a different set of neurons synchronize their activity shortly after stimulus onset. These differentially synchronizing sub-populations of neurons suggests a continuum of population representation of the reward seeking task. Secondly, our analyses also suggest that the degree of synchronization differs between the rewarded and non-rewarded conditions. Moreover, the proposed model is scalable to handle data on many simultaneously recorded neurons and is applicable to analyzing other types of multivariate time series data with latent structure. Supplementary materials (including computer codes) for our paper are available online. PMID- 27990035 TI - Efficient Estimation of the Cox Model With Auxiliary Subgroup Survival Information. AB - With the rapidly increasing availability of data in the public domain, combining information from different sources to infer about associations or differences of interest has become an emerging challenge to researchers. This paper presents a novel approach to improve efficiency in estimating the survival time distribution by synthesizing information from the individual-level data with t-year survival probabilities from external sources such as disease registries. While disease registries provide accurate and reliable overall survival statistics for the disease population, critical pieces of information that influence both choice of treatment and clinical outcomes usually are not available in the registry database. To combine with the published information, we propose to summarize the external survival information via a system of nonlinear population moments and estimate the survival time model using empirical likelihood methods. The proposed approach is more flexible than the conventional meta-analysis in the sense that it can automatically combine survival information for different subgroups and the information may be derived from different studies. Moreover, an extended estimator that allows for a different baseline risk in the aggregate data is also studied. Empirical likelihood ratio tests are proposed to examine whether the auxiliary survival information is consistent with the individual-level data. Simulation studies show that the proposed estimators yield a substantial gain in efficiency over the conventional partial likelihood approach. Two sets of data analysis are conducted to illustrate the methods and theory. PMID- 27990036 TI - Probabilistic Cause-of-death Assignment using Verbal Autopsies. AB - In regions without complete-coverage civil registration and vital statistics systems there is uncertainty about even the most basic demographic indicators. In such regions the majority of deaths occur outside hospitals and are not recorded. Worldwide, fewer than one-third of deaths are assigned a cause, with the least information available from the most impoverished nations. In populations like this, verbal autopsy (VA) is a commonly used tool to assess cause of death and estimate cause-specific mortality rates and the distribution of deaths by cause. VA uses an interview with caregivers of the decedent to elicit data describing the signs and symptoms leading up to the death. This paper develops a new statistical tool known as InSilicoVA to classify cause of death using information acquired through VA. InSilicoVA shares uncertainty between cause of death assignments for specific individuals and the distribution of deaths by cause across the population. Using side-by-side comparisons with both observed and simulated data, we demonstrate that InSilicoVA has distinct advantages compared to currently available methods. PMID- 27990037 TI - Dynamic 3-D computer graphics for designing a diagnostic tool for patients with schizophrenia. AB - We introduce a novel procedure that uses dynamic 3-D computer graphics as a diagnostic tool for assessing disease severity in schizophrenia patients, based on their reduced influence of top-down cognitive processes in interpreting bottom up sensory input. Our procedure uses the hollow-mask illusion, in which the concave side of the mask is misperceived as convex, because familiarity with convex faces dominates sensory cues signaling a concave mask. It is known that schizophrenia patients resist this illusion and their resistance increases with illness severity. Our method uses virtual masks rendered with two competing textures: (a) realistic features that enhance the illusion; (b) random-dot visual noise that reduces the illusion. We control the relative weights of the two textures to obtain psychometric functions for controls and patients and assess illness severity. The primary novelty is the use of a rotating mask that is easy to implement on a wide variety of portable devices and avoids the use of elaborate stereoscopic devices that have been used in the past. Thus our method, which can also be used to assess the efficacy of treatments, provides clinicians the advantage to bring the test to the patient's own environment, instead of having to bring patients to the clinic. PMID- 27990038 TI - Morbid Obesity and Use of Second Generation Antipsychotics among Adolescents in Foster Care: Evidence from Medicaid. AB - BACKGROUND: Many adolescents enter foster care with high body mass index (BMI), and patterns of treatment further exacerbate the risk of morbid obesity. A principal risk factor for such exacerbation is the use of second generation antipsychotics (SGAs). We examine the association between receiving a morbid obesity diagnosis and SGA prescriptions among adolescents in foster care. METHODS: We analyzed claims from 36 states' Medicaid Analytic Extract (MAX) files for 2000 through 2003. Obesity diagnoses were ascertained through a primary or secondary diagnosis claim of morbid obesity. Covariates included gender, race/ethnicity. age, insurance status, state obesity rate, and state fixed effects. We calculated relative risks of a diagnosis based upon four SGAs (clozapine, olanzapine, quetiapine, and risperidone) associated with obesity and a polypharmacy indicator. RESULTS: Of the 1,261,806 foster care adolescent-years in the MAX files, 6,517 were diagnosed with morbid obesity, an annual prevalence of 0.5%. The risk of a morbid obesity diagnosis is much higher for female and non white adolescents. The risk increases with age. Quetiapine and clozapine increased the risk of a morbid obesity diagnosis more than 2.5 times, and two or more psychotropic drugs (polypharmacy) increased the risk fivefold. CONCLUSIONS: Adolescents in foster care are much more likely to be on SGA medications, and therefore may be more susceptible to weight gain and obesity. Given that SGA prescribing for younger populations has only expanded since these data were released, our study may actually understate the magnitude of the problem. Care is needed when prescribing SGAs for foster care adolescents. PMID- 27990039 TI - Foster care placement change: The role of family dynamics and household composition. AB - Sibling co-placement and kinship care have each been shown to protect against the occurrence of placement change for youth in substitute care. However, little is known about the effects of different combinations of sibling placement and relative caregiver status on placement change. Nor does the field fully understand how family dynamics may differ in these households. Utilizing data from the Supporting Siblings in Foster Care study, this paper examines family dynamics across four typologies of living composition, and tests the effects of living composition membership on the odds of experiencing a placement change over an 18-month period of time. Findings suggest that across living composition typologies, children who were placed separately from their siblings in non relative care were more likely to be older, have more extensive placement histories, and experience more placement changes both prior to and during the study than were children in other living composition groups. Family living composition was found to influence the occurrence of placement change. Specifically, children co-placed in kinship care were least likely to experience movement; however, sibling co-placement in non-relative care was also protective. Results reveal the need to conduct additional research into the experiences of children in different family living arrangements, and tailor case management services and supports to children in substitute care accordingly. Implications and future directions are discussed. PMID- 27990040 TI - Measuring Cultural Socialization Attitudes and Behaviors of Mexican-Origin Mothers With Young Children: A Longitudinal Investigation. AB - We describe the development and psychometric testing of the Cultural Socialization Behaviors Measure (CSBM) and the Cultural Socialization Attitudes Measure (CSAM). The CSBM assesses cultural socialization behaviors that parents use with young children, and the CSAM assesses the attitudes that parents have regarding the importance of socializing their young children about their culture. Both measures demonstrated strong reliability, validity, and cross-language equivalence (i.e., Spanish and English) among a sample of 204 Mexican-origin young mothers (Mage = 20.94 years, SD = 1.01) with 4-year-old children. In addition, the measures demonstrated longitudinal equivalence when children were 4 and 5 years of age. PMID- 27990041 TI - Supplying trees in an era of environmental uncertainty: Identifying challenges faced by the forest nursery sector in Great Britain. AB - In recent years, numerous articles have addressed management strategies aimed at assisting forests to adapt to climate change. However, these seldom take into account the practical and economic implications of implementing these strategies, notably, supply of forest plants and seed. Using semi-structured interviews with practitioners involved in the plant and seed supply chain in Great Britain, we highlight a series of practical and economic bottlenecks commonly encountered in the supply of locally sourced seed and domestically produced planting stock for native woodland and hedging markets. We find that adoption of alternative seed sourcing strategies, designed specifically to account for directional climate warming, is likely to exacerbate existing problems by adding further complexity to decisions nurseries make about tree species and seed origins to produce. The lack of long-term market predictability brought about by the current configuration of forestry grants and regulations and, in particular, the administrative systems for processing grant applications is identified as a major impediment to having a sustainable and competitive supply of home-grown and currently adapted planting stock. Finally, the time and effort it takes to supply healthy plants for native woodland creation projects deserves much wider recognition throughout the industry and will be crucial if planting objectives are to be met sustainably. PMID- 27990042 TI - Safety considerations of biosimilars. PMID- 27990043 TI - Treating osteoporosis. PMID- 27990044 TI - Acute sinusitis. PMID- 27990045 TI - New drug for allergic rhinitis. PMID- 27990046 TI - Correcting iron deficiency. PMID- 27990047 TI - Long-term prescribing of new oral anticoagulants. PMID- 27990048 TI - Paediatric pharmacokinetics and drug doses. PMID- 27990049 TI - The practice pharmacist: a natural fit in the general practice team. PMID- 27990050 TI - Midwifery prescribing in Australia. PMID- 27990052 TI - Top 10 drugs 2015-16. PMID- 27990051 TI - Medicines Australia Code of Conduct: breaches. PMID- 27990053 TI - Blinatumomab for lymphoblastic leukaemia. PMID- 27990054 TI - Ocriplasmin for vitreomacular traction. PMID- 27990055 TI - Sacubitril/valsartan for chronic heart failure. PMID- 27990056 TI - Ulipristal acetate for emergency contraception. PMID- 27990057 TI - Ulipristal acetate for fibroids. PMID- 27990058 TI - An assessment of efficient water heating options for an all-electric single family residence in a mixed-humid climate. AB - An evaluation of a variety of efficient water heating strategies for an all electric single family home located in a mixed-humid climate is conducted using numerical modeling. The strategies considered include various combinations of solar thermal, heat pump, and electric resistance water heaters. The numerical model used in the study is first validated against a year of field data obtained on a dual-tank system with a solar thermal preheat tank feeding a heat pump water heater that serves as a backup. Modeling results show that this configuration is the most efficient of the systems studied over the course of a year, with a system coefficient of performance (COPsys) of 2.87. The heat pump water heater alone results in a COPsys of 1.9, while the baseline resistance water heater has a COPsys of 0.95. Impacts on space conditioning are also investigated by considering the extra energy consumption required of the air source heat pump to remove or add heat from the conditioned space by the water heating system. A modified COPsys that incorporates the heat pump energy consumption shows a significant drop in efficiency for the dual tank configuration since the heat pump water heater draws the most heat from the space in the heating season while the high temperatures in the solar storage tank during the cooling season result in an added heat load to the space. Despite this degradation in the COPsys, the combination of the solar thermal preheat tank and the heat pump water heater is the most efficient option even when considering the impacts on space conditioning. PMID- 27990059 TI - Decentralized Feedback Controllers for Exponential Stabilization of Hybrid Periodic Orbits: Application to Robotic Walking. AB - This paper presents a systematic algorithm to design time-invariant decentralized feedback controllers to exponentially stabilize periodic orbits for a class of hybrid dynamical systems arising from bipedal walking. The algorithm assumes a class of parameterized and nonlinear decentralized feedback controllers which coordinate lower-dimensional hybrid subsystems based on a common phasing variable. The exponential stabilization problem is translated into an iterative sequence of optimization problems involving bilinear and linear matrix inequalities, which can be easily solved with available software packages. A set of sufficient conditions for the convergence of the iterative algorithm to a stabilizing decentralized feedback control solution is presented. The power of the algorithm is demonstrated by designing a set of local nonlinear controllers that cooperatively produce stable walking for a 3D autonomous biped with 9 degrees of freedom, 3 degrees of underactuation, and a decentralization scheme motivated by amputee locomotion with a transpelvic prosthetic leg. PMID- 27990060 TI - The Structure of Working Memory in Young Children and Its Relation to Intelligence. AB - This study investigated the structure of working memory in young school-age children by testing the fit of three competing theoretical models using a wide variety of tasks. The best fitting models were then used to assess the relationship between working memory and nonverbal measures of fluid reasoning (Gf) and visual processing (Gv) intelligence. One hundred sixty-eight English speaking 7-9 year olds with typical development, from three states, participated. Results showed that Cowan's three-factor embedded processes model fit the data slightly better than Baddeley and Hitch's (1974) three-factor model (specified according to Baddeley, 1986) and decisively better than Baddeley's (2000) four factor model that included an episodic buffer. The focus of attention factor in Cowan's model was a significant predictor of Gf and Gv. The results suggest that the focus of attention, rather than storage, drives the relationship between working memory, Gf, and Gv in young school-age children. Our results do not rule out the Baddeley and Hitch model, but they place constraints on both it and Cowan's model. A common attentional component is needed for feature binding, running digit span, and visual short-term memory tasks; phonological storage is separate, as is a component of central executive processing involved in task manipulation. The results contribute to a zeitgeist in which working memory models are coming together on common ground (cf. Cowan, Saults, & Blume, 2014; Hu, Allen, Baddeley, & Hitch, 2016). PMID- 27990062 TI - Electrical Activity of the Cerebral Cortex during the Low-Frequency Acoustic Stimulation in Women with Different Characteristics of Alpha Rhythm. AB - BACKGROUND: Human functional capabilities, to a certain extent, depend on an individual's nervous system. The recording of the spontaneous electroencephalogram (EEG) makes it possible to estimate specific features of the nervous system, and in particular the activity of the human brain. PURPOSE: This study is aimed at investigating the brain in women with a high or a low individual alpha-frequency (IalphaF), determined in a quiescent state during low frequency acoustic stimulation. METHODS: The study group consisted of 113 right handed healthy women in the age group 19-21 years. The study group was divided into 2 categories in terms of the average magnitude of IalphaF - groups with high (n = 59, IalphaF >=10.25 Hz) and low (n = 54, IalphaF <=10.25 Hz) values of IalphaF. The power and coherence of electrical activity of the cerebral cortex as well as the differences between the groups were evaluated in a quiescent state during low-frequency acoustic stimulation. RESULTS: In case of low-frequency acoustic stimulation, a high rate of EEG theta-, beta2-power, gamma-waves in the cortex, alpha1-oscillations - in frontal areas were registered in women with a high alpha-frequency, while the power alpha2-, alpha3- and beta1-activity became lower in the cortex. Women with a low alpha-frequency had a decrease of the cerebral cortex alpha-theta-, alpha- and beta-activity. This was recorded as more generalized, and the expression of gamma-waves was more localized. All the participants had increased values of coherence of the EEG frequency components in the cortex. Some overexertion on the right side was detected in the right hemisphere posterior structures. Some local reduction of the coherence of theta-, alpha1-, alpha3-oscillations was found in women with a high alpha-frequency and alpha1-activity among the study group members with a low alpha-frequency in the frontal and anterior temporal areas. CONCLUSION: The establishment of common factors in the study group is an important step towards defining clear prognostic criteria for the physiological capabilities of people based on the congenital features of brain function. PMID- 27990061 TI - Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects. AB - The cytokine erythropoietin (EPO) stimulates proliferation and differentiation of erythroid progenitor cells. Moreover, EPO has neuroprotective, anti-inflammatory, and antioxidative effects, but the use of EPO as a neuroprotective agent is hampered by its erythropoietic activity. We have recently designed the synthetic, dendrimeric peptide, Epobis, derived from the sequence of human EPO. This peptide binds the EPO receptor and promotes neuritogenesis and neuronal cell survival. Here we demonstrate that Epobis in vitro promotes neuritogenesis in primary motoneurons and has anti-inflammatory effects as demonstrated by its ability to decrease TNF release from activated AMJ2-C8 macrophages and rat primary microglia. When administered systemically Epobis is detectable in both plasma and cerebrospinal fluid, demonstrating that the peptide crosses the blood-brain barrier. Importantly, Epobis is not erythropoietic, but systemic administration of Epobis in rats delays the clinical signs of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the peptide has long-term, but not short-term, effects on working memory, detected as an improved social memory 3 days after administration. These data reveal Epobis to be a nonerythropoietic and neuroprotective EPO receptor agonist with anti-inflammatory and memory enhancing properties. PMID- 27990063 TI - Optical Coherence Tomography in Glaucoma. AB - The optic disk and the RNFL are the principal sites of apparent glaucomatous damage which precedes glaucomatous visual field alterations. RNFL defects are known to precede detection of visual field defects by approximately 6 years. Accurate early detection and monitoring of ONH and RNFL defects has become the prime focus of effective management of glaucoma. Optical coherence tomography employs low-coherence interferometry to obtain cross-sectional images of the ocular tissues. This review attempts to critically analyse the applications of both, anterior and posterior segment OCT in glaucoma management. PMID- 27990064 TI - Drug-induced Angle-Closure Glaucoma. AB - Drug-induced angle-closure glaucoma is an important entity for the ophthalmologist as well as the general physician as it represents a preventable cause of potential blindness. This brief review highlights the fact that a high index of suspicion, in a susceptible individual followed by confirmation on appropriate imaging modality (UBM, ultrasound or anterior segment OCT) can alleviate the threat to sight and also help to institute appropriate therapy. PMID- 27990065 TI - Perspectives on Quality of Life in Glaucoma. AB - Chronic diseases are invariably associated with decreased functioning ability of the individual in one form or the other depending upon the system/organ involved. Disability consequent to the disease is the major factor affecting the patient's physical and psychosocial well-being; in other words, the 'Quality of Life (QOL)'. Besides the disease itself, the treatment and its consequences are also major determinants of QOL of the patients. Globally, glaucoma, which is emerging as one of the leading causes of blindness, is one such chronic ophthalmic disease characterized by a progressive loss of visual function and a potential to cause irreversible blindness, if not treated at an early stage. Patients of glaucoma need to take lifelong medications in order to keep their intraocular pressure within limits. It's impact on the daily life of patients cannot be overexpressed and compounded by the fact that it remains asymptomatic for a considerable time after the disease has set in; has led to new imperatives in diagnosis, treatment and epidemiological and outcome studies. Assessment of the debilitating effect of glaucoma and side effects of its treatment on the emotional and physical QOL of the patient is therefore an important criterion for arriving at the treatment regimen. An extensive literature search was done on Pubmed Central, Pubmed and Google Scholar using the keywords 'glaucoma', 'quality of life in glaucoma', 'management in POAG' and 'QOL assessment tools'. Various tools available for the assessment of QOL, and their advantages and limitations have been reviewed in this article. PMID- 27990066 TI - The Surgical Treatment of Neovascular Glaucoma with Ex-PRESS P-50 Miniature Glaucoma Shunt. AB - Surgical treatment for neovascular glaucoma has evolved from cyclodestructive procedures to full-thickness filtration surgery, to trabeculectomy with antifibrosis drugs and glaucoma drainage implant surgery. The choice of a surgical approach may be influenced by several factors, including the stage of the disease. Many surgeons favor drainage implants when the disease is more advanced or when severe inflammation is present, which would be associated with a poorer prognosis if trabeculectomy were chosen. New devices are being developed to allow surgeons increased control with more predictable postoperative results. One such device, the Ex-PRESSTM mini glaucoma shunt, has undergone changes in design and method of insertion making it more appealing for use in patients requiring IOP-lowering surgery. This report highlights the use of Ex-PRESS mini glaucoma shunt in neovascular glaucoma, surgical technique and summarize pertinent literature on the role of this device in glaucoma surgery. PMID- 27990067 TI - Ocular Response Analyzer. AB - Until recently, corneal biomechanical properties could not be measured in vivo. The ocular response analyzer is a new, noninvasive device that analyses corneal biomechanical properties simply and rapidly. The ORA allows cornea compensated IOP measurements and can estimate corneal hysteresis (CH) and corneal resistance factor (CRF). It is designed to improve the accuracy of IOP measurement by using corneal biomechanical data to calculate a biomechanically adjusted estimate of intraocular pressure. This review critically evaluates the technology and its implications in current day glaucoma management. PMID- 27990068 TI - Low Vision Aids in Glaucoma. AB - A large number of glaucoma patients suffer from vision impairments that qualify as low vision. Additional difficulties associated with low vision include problems with glare, lighting, and contrast, which can make daily activities extremely challenging. This article elaborates on how low vision aids can help with various tasks that visually impaired glaucoma patients need to do each day, to take care of themselves and to lead an independent life. PMID- 27990070 TI - Editorial. PMID- 27990069 TI - Overview of Ultrasound Biomicroscopy. AB - Ultrasound biomicroscopy (UBM) is a high-resolution ultrasound technique that allows noninvasive in vivo imaging of structural details of the anterior ocular segment at near light microscopic resolution and provides detailed assessment of anterior segment structures, including those obscured by normal anatomic and pathologic relations. This review gives an overview regarding the instrument, technique and its applications. PMID- 27990072 TI - Fatal PCA Adverse Events Continue To Happen: Better Patient Monitoring Is Essential to Prevent Harm. AB - Preventing fatal PCA adverse events. PMID- 27990073 TI - Medicare Names Six Plans for Part D MTM Demo Starting in January. AB - Medicare names plans for Part D MTM demo. PMID- 27990071 TI - Risk and Protective Factors for Early Substance Use Initiation: A Longitudinal Study of Mexican-Origin Youth. AB - Substance use initiation in adolescence is a critical issue, given its association with substance dependency and associated problems in adulthood. However, due to the dearth of fine-grained, longitudinal studies, the factors associated with early initiation are poorly understood, especially in minority youth. The present study examined substance use initiation in a sample of Mexican origin youth (N=674) assessed annually from age 10 to 16. Using discrete-time survival analyses, we found that initiation escalated rapidly from late childhood to adolescence, and we identified a wide range of factors, from the individual to the cultural level of analysis, that significantly increased or decreased risk for early initiation. These findings have important implications for programs aimed at preventing early substance use by Mexican-origin youth. PMID- 27990074 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 27990075 TI - Pharmaceutical Approval Update. AB - Lisinopril oral solution (Qbrelis) for the treatment of hypertension, heart failure, and acute myocardial infarction; etanercept-szzs (Erelzi) for multiple autoimmune disorders; and lumacaftor/ivacaftor (Orkambi) for cystic fibrosis. PMID- 27990076 TI - Daclatasvir (Daklinza): A Treatment Option for Chronic Hepatitis C Infection. AB - Daclatasvir (Daklinza) for chronic hepatitis C infection. PMID- 27990077 TI - Medicare Adds New Long-Term-Care Pharmacy Rules: Agency Passes Again on Pharmacist Independence Requirements. AB - A final rule from the Centers for Medicare and Medicaid Services has added pharmacy requirements for long-term-care facilities that put more responsibility on pharmacists but don't address conflict-of-interest concerns. PMID- 27990079 TI - Research Briefs. PMID- 27990078 TI - Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-Onset Neutropenia. AB - Rituximab can cause late-onset neutropenia that may result in serious life threatening complications. The author describes the pathophysiology, incidence, and management of this adverse reaction and presents two case histories. PMID- 27990080 TI - Systemic Thrombolysis for Pulmonary Embolism: A Review. AB - The authors review the evidence behind the use of thrombolytic therapy in patients with massive or submassive pulmonary embolism. Concurrent heparin therapy and the management of bleeding episodes are also discussed. PMID- 27990081 TI - Zika in America: The Year in Review. AB - Short on funds and with no therapeutics or vaccines in sight, U.S. health officials are scrambling to prepare for a protracted fight with Zika virus and the mosquitoes that carry it. In this article, the author focuses on the arrival of Zika in the U.S. PMID- 27990082 TI - European Society for Medical Oncology 2016 Congress. AB - We review several key sessions from the European Society for Medical Oncology's annual congress, including those on emerging immunotherapies for melanoma and non small-cell lung cancer and on treatments for renal, ovarian, and breast cancer. PMID- 27990084 TI - Salvage intraperitoneal chemotherapy for relapsed type II endometrial cancer: A pilot case-control study. AB - OBJECTIVE: Epithelial ovarian cancer and relapsed type II endometrial cancer share common characteristics. Although the role of intraperitoneal (IP) chemotherapy in the treatment of epithelial ovarian cancer has been well established, its role in the treatment of relapsed type II endometrial cancer remains to be elucidated. MATERIAL AND METHODS: From January 2000 to December 2012, patients who were diagnosed with relapsed type II endometrial cancer and underwent secondary cytoreductive surgery, patients with residual tumors less than 1 cm in diameter were initially screened for this study. Of the screened patients, consecutive patients who received salvage IP chemotherapy (IP platinum plus intravenous paclitaxel) were considered the case group. The case study group was matched to a control group that was composed of patients who received salvage systemic chemotherapy (intravenous platinum plus intravenous paclitaxel) in a 1:2 ratio. The overall survival was compared between the case group and the control group, and the IP treatment-related toxicities were reported. RESULTS: In total, 11 patients were assigned into the case group and 22 patients were assigned into the control group. The median overall survival (95% confidence interval) was 40.5 (25.5-56.2) months for the case group versus 28.0 (18.0-37.0) for the control group (hazard ratio=0.37 (95% confidence interval, 0.15-0.95); p=0.032, by the log-rank test). The most commonly observed toxicity was of gastrointestinal origin (81.8%). Toxicities that stemmed from hematological, cardiovascular, neurological, and catheter-related complications were similar to results published in other studies on IP chemotherapy for ovarian cancer. CONCLUSION: Salvage IP chemotherapy may potentially confer a longer overall survival than conventional systemic chemotherapy in the treatment of relapsed type II endometrial cancer. PMID- 27990085 TI - The association between level of maternal serum leptin in the third trimester and the occurrence of moderate preterm labor. AB - OBJECTIVE: We aimed to investigate the relationship between the level of maternal serum leptin and the occurrence of moderate preterm labor. MATERIAL AND METHODS: This was a case control study conducted on pregnant women referred to Al-Zahra Hospital in Rasht, north of Iran in 2013. Cases included 30 moderate preterm delivering women and 30 control pregnant women with the same gestational age. The maternal serum leptin was measured for each mother at the time of entering the study. RESULTS: The mean serum leptin in the control group (56.66+/-34.18) was significantly higher than the preterm (33.65+/-16.70) group. There were no significant differences between the groups in terms of body mass index and age. Logistic regression revealed that age and body mass index did not have a significant relationship to moderate preterm birth. However, an increased leptin level as low as 1 microgram per liter was associated with the risk of moderate preterm birth incidence (OR: 0.973, CI: 0.948-0.997). CONCLUSION: Higher levels of leptin in pregnant women are associated with a decreased risk of moderate preterm birth. Further investigations are recommended with a larger sample size. PMID- 27990086 TI - Are adipokines associated with gestational diabetes mellitus? AB - OBJECTIVE: To investigate the association of maternal serum levels of chemerin, retinol binding protein-4 (RBP-4), and visfatin with gestational diabetes mellitus (GDM). MATERIAL AND METHODS: 158 pregnant women were screened between 24 and 28 weeks of gestation. They were divided into two groups: GDM group (n=76) and control group (n=82). Maternal serum concentrations of chemerin, RBP-4, visfatin, insulin, and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed. RESULTS: There were no differences in age and gestational age between the GDM group and the control group (p=0.058 and p=0.820, respectively). Body mass index (BMI) at 24 to 28 weeks of gestation was higher in the GDM group (p<0.001). The serum concentrations of RBP-4, chemerin, and visfatin did not demonstrate significant differences between the GDM and control groups (p=0.871, p=0.100, and p=0.886, respectively). Significant differences in serum level of insulin and HOMA-IR were found between the GDM and control groups (14.94 vs 9.87, p<0.001 and 3.73 vs 1.77, p<0.001, respectively). Correlation analyses of chemerin, RBP-4, visfatin, insulin, and HOMA-IR in both groups revealed a weak degree of positive correlation between RBP-4 and chemerin (Spearman r=0.251, p=0.026) and a strong positive correlation between maternal insulin and HOMA (Spearman r=0.868, p<0.001). CONCLUSION: No differences were found in serum chemerin, RBP-4, and visfatin between pregnant women with GDM and healthy pregnant women. Further prospective studies will be essential to elucidate the contribution of adipokines to GDM and the positive correlation between maternal RBP-4 and chemerin. PMID- 27990087 TI - Furan toxicity on testes and protective role of lycopene in diabetic rats. AB - OBJECTIVE: Furan (C4H4O) is a heat-induced food contaminant that is utilized as an industrial chemical agent. Lycopene is a natural substance that is produced by plants and tomatoes. We aimed to evaluate the toxicity of furan on testes and the protective effect of lycopene in diabetic rats. MATERIAL AND METHODS: Male Wistar albino rats were divided into five groups: Group 1 (control group) received 1 mL/kg corn oil. Group 2 (diabetic control group) received 55 mg/kg STZ and 1 mL/kg corn oil. Group 3 (diabetic lycopene group) received 55 mg/kg STZ and 4 mg/kg lycopene. Group 4 (diabetic furan group) received 55 mg/kg STZ and 40 mg/kg furan. Group 5 (diabetic furan + lycopene group) received 55 mg/kg STZ, 40 mg/kg furan, and 4 mg/kg lycopene. After 28 days, the testes were extirpated in all groups. In the testicular tissue samples, the level of malondialdehyde (MDA) and the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and reducted glutathione (GST) were studied. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were measured. Histopathologic examination was performed by light microscope. RESULTS: The MDA level and the activities of CAT, GPx, SOD, and GST were found to be higher in the furan group than in the control and diabetic control groups (p<0.05). The MDA level and the activities of CAT, GPx, SOD, and GST were significantly lower in the furan + lycopene group than in the furan group (p<0.05). CONCLUSION: The low blood testosterone level in the rats who received furan suggested the presence of endocrinological defects and cellular degenerative changes. Lycopene may be effective to reverse furan toxicity in diabetic rat testes. PMID- 27990088 TI - Impact of office hysteroscopy in repeated implantation failure: Experience of a single center. AB - OBJECTIVE: Repeated implantation failure (RIF) is a clinical entity affecting many couples undergoing assisted reproductive technology (ART). Various intrauterine pathologies contribute to RIF. Nevertheless, vaginal sonography and hysterosalpingography, which are the common diagnostic tools for the initial follow-up, have limited sensitivities. In this context, we aimed to evaluate the impact of office hysteroscopy (oHS) on live birth rates (LBRs) when performed prior to subsequent ART cycles in women with a history of RIF. MATERIAL AND METHODS: The database of an assisted reproduction center was retrospectively reviewed to detect eligible cases. A total of 363 women out of 2875 admissions were consecutively included in the analysis, of which 119 formed the oHS group and 244 formed the non-oHS group prior to a new ART cycle. Women in the oHS arm were examined during their early follicular phase via a vaginoscopic approach 1-6 months before the beginning of a new cycle. The standard in-vitro fertilization intracytoplasmic sperm injection (IVF/ICSI) cycle was applied to all the women. RESULTS: In the oHS group (n=119), 61 patients had intrauterine abnormalities, with an overall abnormality rate of 51.2%. Implantation, pregnancy, and LBRs of the groups were statistically similar. LBRs of the women with abnormal oHS findings (15/61, 24.5%), with normal oHS findings (14/58, 24.1%), and without oHS (39/244, 16%) were statistically similar (p=0.41). CONCLUSION: Unrecognized intrauterine pathologies can be easily detected and concurrently treated during oHS with high success rate. However, a beneficial impact depends on the extent of the pathology and thus, routine application to enhance reproductive outcomes is still not warranted. PMID- 27990090 TI - Why do multiparous women with a history of vaginal delivery give birth by cesarean section? AB - OBJECTIVE: A cesarean section (C-section) is performed to deliver a baby through the mother's abdomen. In recent years, the rate of incidences requiring a C section is steadily increasing all over the world. Advanced maternal age, chronic health problems, multiple pregnancies as a result of the development of assisted reproductive technologies, and an insufficient supplementary health network can be considered as the reasons why mothers and obstetricians prefer a C-section. Our study aimed to identify the risk factors for the need of C-section in women with a history of vaginal delivery. MATERIAL AND METHODS: 238 multiparous women with a history of vaginal birth at 37-42 gestational weeks were enrolled in our study. 110 women had underwent C-section. Control group was chosen randomly from women giving birth by vaginal route. RESULTS: Overall, 238 multiparous women with a history of vaginal delivery at 37-42 gestational weeks were enrolled in our study. The history of operative delivery, that of labor induction and presence of meconium and the indication of admission to the delivery room were different between groups. A lower Bishop score and biophysical profile, smaller gestational period, and lower birth weight were associated with the group requiring a C section, whereas older age and a long time interval from the previous birth were associated with the group not requiring a C-section. CONCLUSION: A strategy involving either labor induction or not could be individualized for each patient to eliminate the risk factors for adverse outcomes. To identify criteria for the standardization of labor management, further studies are needed. PMID- 27990089 TI - Metabolic and carbohydrate characteristics of different phenotypes of polycystic ovary syndrome. AB - OBJECTIVE: To compare the prevalence of various metabolic and cardiovascular risk factors and insulin resistance between polycystic ovary syndrome (PCOS) patients with or without hyperandrogenism. MATERIAL AND METHODS: This is a retrospective cross-sectional study involving women with PCOS as diagnosed according to the Androgen Excess (AE) Society definition (n=504) and women with normoandrogenemic PCOS (n=183). Anthropometrics, lipid profile, glucose, insulin, oral glucose tolerance test (OGTT), and reproductive hormone levels were evaluated. RESULTS: Women with PCOS diagnosed according to the AE Society had a significantly higher prevalence of metabolic syndrome compared with the normoandrogenemic PCOS phenotype: odds ratio (OR) 2.95 [95% confidence interval (CI) 1.21-7.21]. There was no significant difference in the prevalence glucose intolerance test between the groups [OR: 2.15, 95% CI 0.71-6.56]. The prevalence of low high density lipoprotein (HDL)-cholesterol in the group under the AE-PCOS Society criteria was higher than that of the normoandrogenemic PCOS group [OR: 2.82, 95%CI 1.29-3.36]. CONCLUSION: The risks of metabolic syndrome and cardiovascular disease may vary among the phenotypes of PCOS based on the Rotterdam criteria. This new data may be of reference in informing women with PCOS, although further prospective studies are needed to validate this proposition. PMID- 27990091 TI - Novel applications of COX-2 inhibitors, metformin, and statins for the primary chemoprevention of breast cancer. AB - Recent evidence shows that commonly prescribed drugs, such as non-steroidal anti inflammatory drugs (NSAIDs), metformin, and statins, may have beneficial roles in the primary chemoprevention of breast cancer. Therefore, these drugs could potentially be used in addition to the hormonal drugs currently used for this purpose (namely, selective estrogen receptor modulators and aromatase inhibitors) due to their alternative mechanisms of action. PMID- 27990093 TI - Two successful pregnancies achieved by converting an in vitro fertilization cycle to an intrauterine insemination cycle in five cases with documented premature ovulation. AB - We here report two successful pregnancies obtained by converting an in vitro fertilization (IVF) cycle to an intrauterine insemination (IUI) cycle in five poor responder patients whose oocyte pick-up (OPU) procedures were canceled due to documented premature ovulation immediately before OPU. To our knowledge, this is the first article that demonstrates that switching an IVF cycle to an IUI cycle when premature ovulation occurs on the day of OPU can produce successful pregnancies, even in poor responder patients. PMID- 27990092 TI - Robotic surgery in gynecology. AB - Robotic surgery is the most dynamic development in the sector of minimally invasive operations currently. It should not be viewed as an alternative to laparoscopy, but as the next step in a process of technological evolution. The advancement of robotic surgery, in terms of the introduction of the Da Vinci Xi, permits the variable use of optical devices in all four trocars. Due to the new geometry of the "patient cart," an operation can be performed in all spatial directions without re-docking. Longer instruments and the markedly narrower mechanical elements of the "patient cart" provide greater flexibility as well as access similar to those of traditional laparoscopy. Currently, robotic surgery is used for a variety of indications in the treatment of benign gynecological diseases as well as malignant ones. Interdisciplinary cooperation and cooperation over large geographical distances have been rendered possible by telemedicine, and will ensure comprehensive patient care in the future by highly specialized surgery teams. In addition, the second operation console and the operation simulator constitute a new dimension in advanced surgical training. The disadvantages of robotic surgery remain the high costs of acquisition and maintenance as well as the laborious training of medical personnel before they are confident with using the technology. PMID- 27990094 TI - What is your diagnosis? PMID- 27990096 TI - miR-125b and miR-100 Are Predictive Biomarkers of Response to Induction Chemotherapy in Osteosarcoma. AB - Osteosarcoma is the most common primary malignancy in bone. Patients who respond poorly to induction chemotherapy are at higher risk of adverse prognosis. The molecular basis for such poor prognosis remains unclear. We investigated miRNA expression in eight open biopsy samples to identify miRNAs predictive of response to induction chemotherapy and thus maybe used for risk stratification therapy. The samples were obtained from four patients with inferior necrosis (Huvos I/II) and four patients with superior necrosis (Huvos III/IV) following induction chemotherapy. We found six miRNAs, including miR-125b and miR-100, that were differentially expressed > 2-fold (p < 0.05) in patients who respond poorly to treatment. The association between poor prognosis and the abundance of miR-125b and miR-100 was confirmed by quantitative reverse transcriptase-polymerase chain reaction in 20 additional osteosarcoma patients. Accordingly, overexpression of miR-125b and miR-100 in three osteosarcoma cell lines enhanced cell proliferation, invasiveness, and resistance to chemotherapeutic drugs such as methotrexate, doxorubicin, and cisplatin. In addition, overexpression of miR-125b blocked the ability of these chemotherapy agents to induce apoptosis. As open biopsy is routinely performed to diagnose osteosarcoma, levels of miR-125b and miR-100 in these samples may be used as basis for risk stratification therapy. PMID- 27990097 TI - Propensity score weighting for a continuous exposure with multilevel data. AB - Propensity score methods (e.g., matching, weighting, subclassification) provide a statistical approach for balancing dissimilar exposure groups on baseline covariates. These methods were developed in the context of data with no hierarchical structure or clustering. Yet in many applications the data have a clustered structure that is of substantive importance, such as when individuals are nested within healthcare providers or within schools. Recent work has extended propensity score methods to a multilevel setting, primarily focusing on binary exposures. In this paper, we focus on propensity score weighting for a continuous, rather than binary, exposure in a multilevel setting. Using simulations, we compare several specifications of the propensity score: a random effects model, a fixed effects model, and a single-level model. Additionally, our simulations compare the performance of marginal versus cluster-mean stabilized propensity score weights. In our results, regression specifications that accounted for the multilevel structure reduced bias, particularly when cluster level confounders were omitted. Furthermore, cluster mean weights outperformed marginal weights. PMID- 27990098 TI - Formation of hybrid guanidine-stabilized bis(MU-oxo)dicopper cores in solution: Electronic and steric perturbations. AB - A series of new hybrid peralkylated-amine-guanidine ligands based on a 1,3 propanediamine backbone and their Cu-O2 chemistry is reported. The copper(I) complexes react readily with O2 at low temperatures in aprotic solvents with weakly coordinating anions to form exclusively bis(MU-oxo) dicopper species (O). Variation of the substituents on each side of the hybrid bidentate ligand highlights that less sterically demanding amine and guanidine substituents increase not only the thermal stability of the formed O cores but enhance inner sphere phenolate hydroxylation pathways. TD-DFT analysis on selected guanidine amine O species suggest that the additional visible feature observed is a guanidine pi*-> Cu2O2 LMCT, which appears along with the classic oxo-zetau* >Cu(III) and pizeta*-> Cu(III) LMCT transitions. PMID- 27990100 TI - II-VI Quantum Cascade emitters in the 6-8MUm range. AB - We present the growth and characterization of ZnCdSe/ZnCdMgSe quantum cascade (QC) heterostructures grown by molecular beam epitaxy (MBE) and designed to operate at 6-8MUm. These structures utilize the better-understood ZnCdMgSe with InP lattice matched compositions yielding a bandgap of 2.80 eV as compared to previous work which used ZnCdMgSe compositions with bandgaps at 3.00 eV. Grown structures posses good structural and optical properties evidenced in X-ray diffraction and photoluminescence studies. Fabricated mesa devices show temperature dependent I-V measurements with differential resistance of 3.6 Omega, and a turn on voltage of 11V consistent with design specifications. Electroluminescence was observed in these devices up to room temperature with emission centered at 7.1 MUm and line widths of ~16%(DeltaE/E) at 80K. The results show that these are well-behaved electroluminescent structures. Addition of waveguide layers and further improvements in well barrier interfaces are being pursued in efforts to demonstrate lasing. PMID- 27990099 TI - Cardiovascular diseases-related GNB3 C825T polymorphism has a significant sex specific effect on serum soluble E-selectin levels. AB - BACKGROUND: The C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit beta3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. Its association with inflammatory mediators such as cell adhesion molecules has not been studied, although they are heavily involved in cardiovascular diseases' (CVDs) processes. The aim of our study was then to investigate a possible sex-specific effect of the GNB3 C825T polymorphism on serum soluble cell adhesion molecules such as E, P and L-selectins (sE, sP and sL-selectins). RESULTS: Participants were from the STANISLAS Family Study and were free of chronic disease as CVDs or cancer. We included in total 771 subjects aged 6 to 58 years (391 males (50.71%) and 380 females (49.29%)). No significant association of rs5443 was observed in the whole population with serum sE, sP and sL-selectins after adjusting for age, sex, body mass index, systolic blood pressure, anti-inflammatory drugs and hormonal drugs consumption. A significant interaction of rs5443 was observed with sex for sE-selectin (p < 0.001), but not for sP and sL-selectins. After adjusting for covariables, the T allele was significantly associated with an additive increase effect on serum sE-selectin levels in males (beta = 5.03 +/- 2.18; p = 0.020), while a significant additive decrease effect was observed in females (beta =-4.46 +/- 2.06; p = 0.030). These associations stayed significant after correction for multiple tests (p = 0.045 in males and in females). The additive phenotypic variance was 21.54% in males versus 1.91% in females. CONCLUSIONS: In our Caucasian population, the GNB3 C825T polymorphism showed a significant sex-specific effect on serum sE-selectin levels, with a disadvantage for males, as increased sE-selectin levels has been associated with CVDs outcomes. The T allele has been previously associated with the same CVDs as increased sE-selectin, but more often in males. The link we observed between this polymorphism and E-selectin is then consistent with previous findings, and helps to better understand the deleterious effect of the GNB3 825 T allele on CVDs outcomes in males. We revealed in this study an important pathway through which the GNB3 gene induces CVDs' outcomes. PMID- 27990101 TI - Reconstruction of Gene Regulatory Networks based on Repairing Sparse Low-rank Matrices. AB - With the growth of high-throughput proteomic data, in particular time series gene expression data from various perturbations, a general question that has arisen is how to organize inherently heterogenous data into meaningful structures. Since biological systems such as breast cancer tumors respond differently to various treatments, little is known about exactly how these gene regulatory networks (GRNs) operate under different stimuli. Challenges due to the lack of knowledge not only occur in modeling the dynamics of a GRN but also cause bias or uncertainties in identifying parameters or inferring the GRN structure. This paper describes a new algorithm which enables us to estimate bias error due to the effect of perturbations and correctly identify the common graph structure among biased inferred graph structures. To do this, we retrieve common dynamics of the GRN subject to various perturbations. We refer to the task as "repairing" inspired by "image repairing" in computer vision. The method can automatically correctly repair the common graph structure across perturbed GRNs, even without precise information about the effect of the perturbations. We evaluate the method on synthetic data sets and demonstrate an application to the DREAM data sets and discuss its implications to experiment design. PMID- 27990102 TI - A neglected opportunity for China's tobacco control? Shift in smoking behavior during and after wives' pregnancy. AB - BACKGROUND: Although observational data suggest that men's attempts and behavior at quitting smoking are often stimulated during their spouses' pregnancy, few studies have systematically examined this phenomenon. METHODS: This was a cross sectional study which examined Chinese men's smoking behaviors during and after their wives' pregnancy. Women who visited community health centers for routine immunization of their children were approached. Information was mainly collected on men's tobacco use before, during and after pregnancy in July to August 2011. Individual and socio-environmental factors were examined by non-conditional logistical regression analysis to find potential reasons behind men's quitting during pregnancy and maintained this change till the post-partum period. RESULTS: Totally 765 of 811 eligible women (94.3%) completed the interview. Prior to pregnancy, 42.9% of husbands smoked; this decreased to 36.34% during pregnancy, a reduction of 6.53%. Although the rate increased to a higher level (43.79%) after delivery, positive changes in men's smoking behavior were detected. One-third (29.88%) reduced the daily number of cigarettes smoked, and nearly half (45.12%) relocated themselves to smoke when their pregnant wives were nearby. Noticeably, those who quit were most likely occasional smokers (Odds Ratio(OR) = 4.83, 95%CI [2.22, 10.48]), smoking less than ten years (OR = 2.80, 95%CI [1.19, 6.58]), not smoking at home (OR = 4.48, 95%CI [1.94, 10.39]), not smoking for social use (OR = 4.05, 95%CI [1.74, 9.41]), under lower financial pressure after the birth of child (OR = 5.28, 95%CI [2.14, 13.02]) and influenced by family members (OR = 2.82, 95%CI [1.25, 6.38]). However, only 22% of spontaneous cessation was maintained postpartum. Most relapses occurred within 6 months after delivery. CONCLUSIONS: Pregnancy offers an opportunity to decrease smoking amongst Chinese males. Intervention programs involving expectant fathers may be effective to further reduce prevalence of smoking among men in China. PMID- 27990103 TI - Two Cases of Rectal Neuroendocrine Tumor Resection Combined with Dissection of the Circular Muscle Layer Using the Endoscopic Submucosal Dissection Technique. AB - Generally, lesions of rectal neuroendocrine tumors (NETs) 10 mm or smaller are less malignant and are indicated for endoscopic therapy. However, the vertical margin may remain positive after conventional endoscopic mucosal resection (EMR) because NETs develop in a way similar to submucosal tumors (SMTs). The usefulness of EMR with a ligation device, which is modified EMR, and endoscopic submucosal dissection (ESD) was reported, but no standard treatment has been established. We encountered 2 patients in whom rectal NETs were completely resected by combined dissection and resection of the circular muscle layer using the ESD technique. Case 1 was an 8-mm NET of the lower rectum. Case 2 was NET of the lower rectum treated with additional resection for a positive vertical margin after EMR. In both cases, the circular muscle layer was dissected applying the conventional ESD technique, followed by en bloc resection while conserving the longitudinal muscle layer. No problems occurred in the postoperative course in either case. Rectal NETs are observed in the lower rectum in many cases, and it is less likely that intestinal perforation by endoscopic therapy causes peritonitis. The method employed in these cases, namely combined dissection and resection of the circular muscle layer using the ESD technique, can be performed relatively safely, and it is possible to ensure negativity of the vertical margin. In addition, it may also be useful for additional treatment of cases with a positive vertical margin after EMR. PMID- 27990104 TI - Hepatic Encephalopathy due to Congenital Multiple Intrahepatic Portosystemic Venous Shunts Successfully Treated by Percutaneous Transhepatic Obliteration. AB - Hepatic encephalopathy due to intrahepatic portosystemic venous shunts (IPSVS) in a non-cirrhotic condition is rare. Here we report a rare case of a patient with congenital multiple IPSVS successfully treated by percutaneous transhepatic obliteration. The patient was a 67-year-old woman who presented to our hospital with progressive episodes of consciousness disorder and vomiting. Laboratory tests revealed hyperammonemia (192.0 MUg/dL), and computed tomography revealed multiple IPSVS in both lobes. There was no evidence of underlying liver disease or hepatic trauma. Transcatheter embolization for IPSVS was performed because conservative therapy was not sufficiently effective. After endovascular shunt closure, hepatic encephalopathy improved. The serum ammonia level normalized during the 5-year follow-up period. Thus, transcatheter embolization may be an effective therapy for patients with symptomatic and refractory IPSVS. Careful follow-up is necessary for portal hypertension-related complications after transcatheter embolization for IPSVS. PMID- 27990105 TI - Novel Methodology for Creating Macaque Retinas with Sortable Photoreceptors and Ganglion Cells. AB - Purpose: The ability to generate macaque retinas with sortable cell populations would be of great benefit to both basic and translational studies of the primate retina. The purpose of our study was therefore to develop methods to achieve this goal by selectively labeling, in life, photoreceptors (PRs) and retinal ganglion cells (RGCs) with separate fluorescent markers. Methods: Labeling of macaque (Macaca fascicularis) PRs and RGCs was accomplished by subretinal delivery of AAV5-hGRK1-GFP, and retrograde transport of micro-rubyTM from the lateral geniculate nucleus, respectively. Retinas were anatomically separated into different regions. Dissociation conditions were optimized, and cells from each region underwent fluorescent activated cell sorting (FACS). Expression of retinal cell type- specific genes was assessed by quantitative real-time PCR to characterize isolated cell populations. Results: We show that macaque PRs and RGCs can be simultaneously labeled in-life and enriched populations isolated by FACS. Recovery from different retinal regions indicated efficient isolation/enrichment for PRs and RGCs, with the macula being particularly amendable to this technique. Conclusions: The methods and materials presented here allow for the identification of novel reagents designed to target RGCs and/or photoreceptors in a species that is phylogenetically and anatomically similar to human. These techniques will enable screening of intravitreally delivered AAV capsid libraries for variants with increased tropism for PRs and/or RGCs and the evaluation of vector tropism and/or cellular promoter activity of gene therapy vectors in a clinically relevant species. PMID- 27990106 TI - Localization of Neuropeptide Gene Expression in Larvae of an Echinoderm, the Starfish Asterias rubens. AB - Neuropeptides are an ancient class of neuronal signaling molecules that regulate a variety of physiological and behavioral processes in animals. The life cycle of many animals includes a larval stage(s) that precedes metamorphic transition to a reproductively active adult stage but, with the exception of Drosophila melanogaster and other insects, research on neuropeptide signaling has hitherto largely focused on adult animals. However, recent advances in genome/transcriptome sequencing have facilitated investigation of neuropeptide expression/function in the larvae of protostomian (e.g., the annelid Platynereis dumerilii) and deuterostomian (e.g., the urochordate Ciona intestinalis) invertebrates. Accordingly, here we report the first multi-gene investigation of larval neuropeptide precursor expression in a species belonging to the phylum Echinodermata-the starfish Asterias rubens. Whole-mount mRNA in situ hybridization was used to visualize in bipinnaria and brachiolaria stage larvae the expression of eight neuropeptide precursors: L-type SALMFamide (S1), F-type SALMFamide (S2), vasopressin/oxytocin-type, NGFFYamide, thyrotropin-releasing hormone-type, gonadotropin-releasing hormone-type, calcitonin-type and corticotropin-releasing hormone-type. Expression of only three of the precursors (S1, S2, NGFFYamide) was observed in bipinnaria larvae but by the brachiolaria stage expression of all eight precursors was detected. An evolutionarily conserved feature of larval nervous systems is the apical organ and in starfish larvae this comprises the bilaterally symmetrical lateral ganglia, but only the S1 and S2 precursors were found to be expressed in these ganglia. A prominent feature of brachiolaria larvae is the attachment complex, comprising the brachia and adhesive disk, which mediates larval attachment to a substratum prior to metamorphosis. Interestingly, all of the neuropeptide precursors examined here are expressed in the attachment complex, with distinctive patterns of expression suggesting potential roles for neuropeptides in the attachment process. Lastly, expression of several neuropeptide precursors is associated with ciliary bands, suggesting potential roles for the neuropeptides derived from these precursors in control of larval locomotion and/or feeding. In conclusion, our findings provide novel perspectives on the evolution and development of neuropeptide signaling systems and neuroanatomical insights into neuropeptide function in echinoderm larvae. PMID- 27990107 TI - A Novel Striated Muscle-Specific Myosin-Blocking Drug for the Study of Neuromuscular Physiology. AB - The failure to transmit neural action potentials (APs) into muscle APs is referred to as neuromuscular transmission failure (NTF). Although synaptic dysfunction occurs in a variety of neuromuscular diseases and impaired neurotransmission contributes to muscle fatigue, direct evaluation of neurotransmission by measurement of successfully transduced muscle APs is difficult due to the subsequent movements produced by muscle. Moreover, the voltage-gated sodium channel inhibitor used to study neurotransmitter release at the adult neuromuscular junction is ineffective in embryonic tissue, making it nearly impossible to precisely measure any aspect of neurotransmission in embryonic lethal mouse mutants. In this study we utilized 3-(N-butylethanimidoyl) 4-hydroxy-2H-chromen-2-one (BHC), previously identified in a small-molecule screen of skeletal muscle myosin inhibitors, to suppress movements without affecting membrane currents. In contrast to previously characterized drugs from this screen such as N-benzyl-p-toluene sulphonamide (BTS), which inhibit skeletal muscle myosin ATPase activity but also block neurotransmission, BHC selectively blocked nerve-evoked muscle contraction without affecting neurotransmitter release. This feature allowed a detailed characterization of neurotransmission in both embryonic and adult mice. In the presence of BHC, neural APs produced by tonic stimulation of the phrenic nerve at rates up to 20 Hz were successfully transmitted into muscle APs. At higher rates of phrenic nerve stimulation, NTF was observed. NTF was intermittent and characterized by successful muscle APs following failed ones, with the percentage of successfully transmitted muscle APs diminishing over time. Nerve stimulation rates that failed to produce NTF in the presence of BHC similarly failed to produce a loss of peak muscle fiber shortening, which was examined using a novel optical method of muscle fatigue, or a loss of peak cytosolic calcium transient intensity, examined in whole populations of muscle cells expressing the genetically-encoded calcium indicator GCaMP3. Most importantly, BHC allowed for the first time a detailed analysis of synaptic transmission, calcium signaling and fatigue in embryonic mice, such as in Vamp2 mutants reported here, that die before or at birth. Together, these studies illustrate the wide utility of BHC in allowing stable measurements of neuromuscular function. PMID- 27990108 TI - The Time-Course of Acute Changes in Corticospinal Excitability, Intra-Cortical Inhibition and Facilitation Following a Single-Session Heavy Strength Training of the Biceps Brachii. AB - Objective: The current understanding of acute neurophysiological responses to resistance training remains unclear. Therefore, we aimed to compare the time course of acute corticospinal responses following a single-session heavy strength training (HST) of the biceps brachii (BB) muscle and provide quantifiable evidence based on the super-compensation model in an applied setting. Methods: Fourteen participants completed a counter-balanced, cross-over study that consisted of a single HST session (5 sets * 3 repetition maximum [RM]) of the BB and a control session (CON). Single- and paired-pulse transcranial magnetic stimulation (TMS) was used to measure changes in motor-evoked potential (MEP) amplitude, intra-cortical facilitation (ICF), short-interval intra-cortical inhibition (SICI) and long-interval intra-cortical inhibition (LICI). Additionally, maximal muscle compound wave (MMAX) and maximal voluntary isometric contraction (MVIC) of the BB were taken. All measures were taken at baseline, immediately post and at 10, 20, 30 min and 1, 2, 6, 24, 48 and 72 h post training. Results: A significant reduction in MEP amplitude was observed immediately post training (P = 0.001), while MVIC (P < 0.001) and MMAX (P = 0.047) were reduced for up to 30 min post-training. An increase in MVIC (p < 0.001) and MMAX (p = 0.047) was observed at 6 h, while an increase in MEP amplitude (p = 0.014) was only observed at 48 and 72 h. No changes in SICI, ICF and LICI were observed. Conclusion: Our results suggest that: (1) acute changes in corticospinal measures returned to baseline in a shorter timeframe than the current super-compensation model (24-48 h) and (2) changes in corticospinal excitability post-HST may be modulated "downstream" of the primary motor cortex (M1). PMID- 27990109 TI - Timing Intervals Using Population Synchrony and Spike Timing Dependent Plasticity. AB - We present a computational model by which ensembles of regularly spiking neurons can encode different time intervals through synchronous firing. We show that a neuron responding to a large population of convergent inputs has the potential to learn to produce an appropriately-timed output via spike-time dependent plasticity. We explain why temporal variability of this population synchrony increases with increasing time intervals. We also show that the scalar property of timing and its violation at short intervals can be explained by the spike-wise accumulation of jitter in the inter-spike intervals of timing neurons. We explore how the challenge of encoding longer time intervals can be overcome and conclude that this may involve a switch to a different population of neurons with lower firing rate, with the added effect of producing an earlier bias in response. Experimental data on human timing performance show features in agreement with the model's output. PMID- 27990110 TI - Scleromyxedema without Paraproteinemia: Treatment with Thalidomide and Prednisolone. AB - Scleromyxedema is a rare and distinctive variant of cutaneous mucinoses of unknown etiology. It is presenting with generalized papular eruption and sclerodermoid induration. Numerous treatment modalities have been reported to produce partial or permanent responses. This study reports on a case of scleromyxedema without paraproteinemia in a subject who experienced a partial response to thalidomide and prednisolone. PMID- 27990111 TI - TTF-1 Expression in Rectal Adenocarcinoma: A Case Report and Review of the Literature. AB - Thyroid transcription factor 1 (TTF-1) is considered a highly sensitive and specific marker for primary lung adenocarcinoma. However, in recent years retrospective studies of tumor samples have confirmed that, although rare, TTF-1 can also be expressed in colorectal adenocarcinoma. There are a few case reports of patients with TTF-1-positive colon adenocarcinoma in the medical literature but none of TTF-1-positive rectal adenocarcinoma. Here, we present a case of rectal adenocarcinoma with lung metastasis found to be TTF-1 positive on immunohistochemistry. A review and discussion of the available literature is also included. PMID- 27990112 TI - Synchronous and Metachronous Colon Cancers in Patients with Gastric Cancer: Report of 2 Cases. AB - Colorectal cancer is the most common synchronous or metachronous cancer in patients with gastric cancer. I report two cases of synchronous and metachronous colon cancer with gastric cancer. Case 1: A 70-year-old man was admitted to our hospital for the treatment of gastric cancer, which had been diagnosed during esophagogastroduodenoscopy (EGD) screening. The recommended preoperative testing was colonofiberscopy (CFS). The CFS revealed a 3-cm ulcerofungating mass, located 20 cm from the anal verge. The pathological report showed a well-differentiated adenocarcinoma. Consequently, we performed radical total gastrectomy and low anterior resection simultaneously. There was no recurrence during the 40-month follow-up of this individual on an out-patient basis. Case 2: A 71-year-old man who was treated with laparoscopically assisted distal gastrectomy (LADG) due to early gastric cancer underwent regular follow-up examination with EGD and abdominopelvic computed tomography. A CFS performed 5 years after the LADG revealed a polypoid mass in the sigmoid colon. The pathological report showed a villous adenoma with adenocarcinoma in situ. The patient underwent a colonofiberscopic mucosectomy. At 36 months after the endoscopic mucosectomy, the patient remained free of recurrence. PMID- 27990113 TI - Iliofemoral Venous Thrombosis Mainly Related to Iliofemoral Venous Obstruction by External Tumor Compression in Cancer Patients. AB - BACKGROUND: To study iliofemoral venous thrombosis related to iliofemoral venous obstruction in cancer patients. METHODS: In this case series study, 829 cancer patients were surveyed for iliofemoral obstruction/thrombosis within 10 years. The criteria for inclusion were: (1) presence of unilateral lower-extremity swelling; (2) computed tomography (CT) scans showing a tumor with external compression of the iliac or femoral vein, and (3) duplex ultrasound scans showing venous thrombosis or venous flow insufficiency over a femoral vein or saphenous vein. RESULTS: Sixty-three patients (8%) developed an iliofemoral venous obstruction. The presence of iliofemoral venous thrombosis was detected in 21 of these patients (33%). The rate of iliofemoral venous thrombosis was significantly higher in patients with an invasion of the inguinal region, D-dimer levels >3,000 ng/ml, gastrointestinal cancer, or invasion of the inguinal lymph nodes. However, none of our patients with iliofemoral venous thrombosis had a detection of iliofemoral venous obstruction. Improved lower-extremity swelling was reported in 84% of the patients following combination therapy involving low-molecular-weight heparin (LMWH) and systemic therapy. CONCLUSION: Patients with an iliofemoral venous thrombosis mainly had iliofemoral venous obstruction by external tumor compression. Combination therapy with LMWH and systemic therapy were mandatory for these patients. PMID- 27990114 TI - Sparing Surgery for the Successful Treatment of Thyroid Papillary Carcinoma Invading the Trachea: A Case Report. AB - Published reports on salvage treatment for trachea reconstruction after total thyroidectomy or partial tracheotomy are available, some of them using structures of the trachea itself, auricular cartilage, a musculocutaneous flap, or other methods. In our report, we emphasize the importance of a search for a new material and approach for sparing surgery. The purpose of this article is to describe a case of a successful sparing surgery in a patient with advanced thyroid papillary carcinoma invading the trachea. After total thyroidectomy in 2012, partial resection of the trachea was performed in 2014. The lesion defect was 5.5 * 2.3 cm in size, located between 4 (2nd-6th) tracheal cartilaginous rings and involving about a semicircumference. It was reconstructed with the aid of the knitted TiNi-based mesh endograft, which has been prefabricated in the sternocleidomastoid muscle and further covered with the skin draped over the wound. The tracheostoma was fully closed 6 weeks after the surgery. There were neither side effects nor complications. This kind of tracheal surgery for extensive lesions demonstrates good functional and cosmetic outcomes. PMID- 27990115 TI - Urgent Coronary Artery Bypass Surgery in a Patient with Postinfarction Angina and Active Myelomonocytic Leukaemia. AB - Chronic myelomonocytic leukaemia (CMML) is a myelodysplastic/myeloproliferative neoplasm affecting the production and differentiation of the monocyte cell lineage. Cardiac surgery in the context of CMML poses challenges that are not routinely encountered. This is the first reported case in the literature of a patient with active CMML undergoing urgent on-pump coronary artery bypass grafting. A 68-year-old Caucasian man with a history of hypertension, hyperlipidaemia, hypothyroidism, and hypercholesterolaemia, who had been diagnosed by the haematologists with CMML a few months earlier but had remained untreated, underwent urgent surgical coronary revascularisation because of postinfarction angina following a non-ST elevation myocardial infarction associated with troponin I rise. The patient had fulminant postoperative myelomonocytic leukaemoid reaction, with a clinical picture of severe systemic inflammatory response syndrome and multiple organ dysfunction syndrome. This led to extensive vasodilation and heart failure that resulted in the death of the patient. Various authors have suggested different techniques and treatment options, each attempting to mitigate the effect of the postoperative inflammatory response. However, this is a high-risk endeavour with a myriad of inflammatory signals mobilised into action because of the surgical insult. Off-pump surgery or preoperative pharmacological attenuation of CMML activity might have dampened this response and resulted in a positive outcome for the patient. PMID- 27990116 TI - Combined Acute Haemolytic and Secondary Angle Closure Glaucoma following Spontaneous Intraocular Haemorrhages in a Patient on Warfarin. AB - BACKGROUND: To report the first described case of combined haemolytic and acute angle closure glaucoma secondary to spontaneous intraocular haemorrhages in a patient on excessive anticoagulation. To the best of our knowledge, this is the first case reported in the literature presenting with raised intraocular pressure due to both mechanisms. CASE DESCRIPTION: A 90-year-old woman presented with acute pain and reduction in vision in the left eye. Her intraocular pressure (IOP) was 55 mm Hg. There were red tinted blood cells in the anterior chamber giving it a reddish hue. The patient was known to have advanced wet macular degeneration. She was taking oral warfarin for atrial fibrillation. Her international normalised ratio (INR) was 7.7. B-scan ultrasound of posterior segment showed vitreous and suprachoroidal haemorrhages. An ultrabiomicroscopic examination confirmed open angles. A diagnosis of haemolytic glaucoma secondary to intraocular haemorrhages was made. The IOP was controlled medically. Warfarin was withdrawn and oral vitamin K therapy was initiated leading to a rapid INR reduction. Three days later, her anterior chamber became progressively shallower causing a secondary acute angle closure which was managed medically. After 2 months, the left IOP was well-controlled without any medications and the eye was not inflamed. Her vision in that eye remained perception of light. CONCLUSION: Patients with suprachoroidal haemorrhages should be closely monitored as they might subsequently develop acute angle closure despite an initially open angle and well-controlled INR and IOP. Excessive anticoagulation needs to be prevented to minimise the risk of sight-threatening complications. PMID- 27990117 TI - A Case of Proliferative Diabetic Retinopathy with HIV Infection in Which HAART Possibly Influenced the Prognosis of Visual Function. AB - BACKGROUND: We report on a patient with proliferative diabetic retinopathy (PDR) and human immunodeficiency virus (HIV) infection who exhibited extremely active PDR followed by a rapid onset of blindness in the right eye. The progression of visual disturbance in the patient's left eye was slowed after starting highly active anti-retroviral therapy (HAART), and vision in that eye was rescued after vitrectomy. CASE REPORT: A 72-year-old male developed pneumocystis carinii pneumonia stemming from an HIV infection and began HAART at the Department of Hematology, Osaka Medical College, Takatsuki City, Japan. Prior to HAART, the patient had shown rapidly progressing retinopathy in the right eye accompanied by vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma, ultimately leading to early-onset blindness. After starting HAART, the progression of the retinopathy in the left eye became slower compared to the right eye, with corrected visual acuity improving to 0.6 after vitrectomy, despite being accompanied by vitreous hemorrhage. The patient's overall condition has remained stable following the operation, and the condition of the ocular fundus in the left eye has also settled. CONCLUSION: Significant differences were found in the progression rate of PDR with HIV infection between before and after starting HAART. Our findings suggest that early administration of HAART to HIV patients with diabetic retinopathy is crucial for maintaining visual function. PMID- 27990119 TI - Oral Administration of Sitagliptin Activates CREB and Is Neuroprotective in Murine Model of Brain Trauma. AB - Introduction: Traumatic brain injury is a major cause of mortality and morbidity. We have previously shown that the injectable glucagon-like peptide-1 (GLP-1) analog, liraglutide, significantly improved the outcome in mice after severe traumatic brain injury (TBI). In this study we are interested in the effects of oral treatment of a different class of GLP-1 based therapy, dipeptidyl peptidase IV (DPP-IV) inhibition on mice after TBI. DPP-IV inhibitors reduce the degradation of endogenous GLP-1 and extend circulation of this protective peptide in the bloodstream. This class has yet to be investigated as a potential therapy for TBI. Methods: Mice were administrated once-daily 50 mg/kg of sitagliptin in a Nutella(r) ball or Nutella(r) alone throughout the study, beginning 2 days before severe trauma was induced with a stereotactic cryo-lesion. At 2 days post trauma, lesion size was determined. Brains were isolated for immunoblotting for assessment of selected biomarkers for pathology and protection. Results: Sitagliptin treatment reduced lesion size at day 2 post-injury by ~28% (p < 0.05). Calpain-driven necrotic tone was reduced ~2-fold in sitagliptin-treated brains (p < 0.001) and activation of the protective cAMP-response element binding protein (CREB) system was significantly more pronounced (~1.5-fold, p < 0.05). The CREB-regulated, mitochondrial antioxidant protein manganese superoxide dismutase (MnSOD) was increased in sitagliptin-treated mice (p < 0.05). Conversely, apoptotic tone (alpha-spectrin fragmentation, Bcl-2 levels) and the neuroinflammatory markers IL-6, and Iba-1 were not affected by treatment. Conclusions: This study shows, for the first time, that DPP-IV inhibition ameliorates both anatomical and biochemical consequences of TBI and activates CREB in the brain. Moreover, this work supports previous studies suggesting that the effect of GLP-1 analogs in models of brain damage relates to GLP-1 receptor stimulation in a dose-dependent manner. PMID- 27990118 TI - Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies. AB - Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1 binding motif within the promotor region of the ALOX5 gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the LTC4S gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the CYSLTR2 gene, encoding the Met201Val CYSLTR2 receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ~2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. In vitro work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca2+ flux and inositol phosphate generation. In addition, the CYSLTR1 gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma. PMID- 27990120 TI - Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer. AB - Polyunsaturated fatty acids (PUFAs) are bioactive lipids which modulate inflammation and immunity. They gained recognition in nutritional therapy and are recommended dietary supplements. There is a growing body of evidence suggesting the usefulness of PUFAs in active therapy of various gastrointestinal (GI) diseases. In this review we briefly cover the systematics of PUFAs and their metabolites, and elaborate on their possible use in inflammatory bowel disease (IBD), functional gastrointestinal disorders (FGIDs) with focus on irritable bowel syndrome (IBS), and colorectal cancer (CRC). Each section describes the latest findings from in vitro and in vivo studies, with reports of clinical interventions when available. PMID- 27990121 TI - Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis. AB - Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation. Despite the significant progress in our understanding of liver fibrosis, the molecular mechanisms through which the extracellular matrix promotes HSC activation are not well understood and no effective therapies have been approved to date that can target this early, reversible, stage in liver fibrosis. Several new lines of investigation now provide important insight into this area of study and identify two nuclear targets whose inhibition has the potential of reversing liver fibrosis by interfering with HSC activation: Yes associated protein (YAP), a transcriptional co-activator and effector of the mechanosensitive Hippo pathway, and bromodomain-containing protein 4 (BRD4), an epigenetic regulator of gene expression. YAP and BRD4 activity is induced in response to mechanical stimulation of HSCs and each protein independently controls waves of early gene expression necessary for HSC activation. Significantly, inhibition of either protein can revert the chronic activation of HSCs and impede pathological progression of liver fibrosis in clinically relevant model systems. In this review we will discuss the roles of these nuclear co activators in HSC activation, their mechanism of action in the fibrotic process in the liver and other organs, and the potential of targeting their activity with small molecule drugs for fibrosis reversal. PMID- 27990122 TI - Chinese Herbal Medicine on Cardiovascular Diseases and the Mechanisms of Action. AB - Cardiovascular diseases are the principal cause of death worldwide. The potentially serious adverse effects of therapeutic drugs lead to growing awareness of the role of Chinese herbal medicine in the treatment of cardiovascular diseases. Chinese herbal medicine has been widely used in many countries especially in China from antiquity; however, the mechanisms by which herbal medicine acts in the prevention and treatment of cardiovascular diseases are far from clear. In this review, we briefly describe the characteristics of Chinese herbal medicine by comparing with western medicine. Then we summarize the formulae and herbs/natural products applied in the clinic and animal studies being sorted according to the specific cardiovascular diseases. Most importantly, we elaborate the existing investigations into mechanisms by which herbal compounds act at the cellular levels, including vascular smooth muscle cells, endothelial cells, cardiomyocytes and immune cells. Future research should focus on well-designed clinic trial, in-depth mechanic study, investigations on side effects of herbs and drug interactions. Studies on developing new agents with effectiveness and safety from traditional Chinese medicine is a promising way for prevention and treatment of patients with cardiovascular diseases. PMID- 27990123 TI - Brief Rewarming Blunts Hypothermia-Induced Alterations in Sensation, Motor Drive and Cognition. AB - Background: It is well known that cold exposure experienced during occupational or recreational activities may adversely affect motor, cognitive performance, and health. Most research has used prolonged passive external rewarming modalities and focused on the direct effects on the kinetics of physiological and psychological responses in hypothermic subjects. However, the brief whole body rewarming effects on physiological and psychological responses in parallel with functional consequences on cognitive and neurophysiological functions have not been investigated. This study explores these effects in 12 healthy young men. Methods: Subjects (20 +/- 1 years) participated in 4 randomized trials, which were designed to compare the effects of whole-body brief (5-min) rewarming in 37 degrees C water with rewarming for the same duration in 24 degrees C (air) thermoneutral environment in mildly hypothermic subjects. After each rewarming, indicators of neuromuscular function (reflexes, central activation ratio, electromyography of exercising muscle, and contractile properties of calf muscles) and cognitive function (attention, simple motor speed, and information processing speed) were assessed. Results: Compared to rewarming in thermoneutral environment, after brief rewarming in 37 degrees C water, significantly lower metabolic heat production (MHP) (206 +/- 33.4 vs. 121.9 +/- 24.3 W.m2, P < 0.01), heart rate (76 +/- 16 vs. 60 +/- 12 b.min-1, P < 0.01), cold strain (6.4 +/- 3.1 vs. 5.3 +/- 2.7, P < 0.01), improved thermal comfort and induced cessation of shivering were found. Electrically induced maximum torque amplitudes increased (P100, 102.8 +/- 21.3 vs. 109.2 +/- 17.5 Nm and PTT100, 83.1 +/- 17.1 vs. 92.7 +/ 16.0 Nm, P < 0.05), contraction half-relaxation time decreased (599.0 +/- 53.8 vs. 589.0 +/- 56.3 ms, P < 0.05), and Mmax-wave latency shortened (17.5 +/- 2.2 vs. 15.6 +/- 2.0 ms, P < 0.05) after 37 degrees C water rewarming. Unlike rewarming in thermoneutral environment, 37 degrees C water rewarming blunted the hypothermia-induced alterations in neural drive transmission (4.3 +/- 0.5 vs. 3.4 +/- 0.8 mV H-reflex and 4.9 +/- 0.2 vs. 4.4 +/- 0.4 mV V-wave, P < 0.05), which increased central fatigue during a 2-min maximum load (P < 0.05). Furthermore, only in brief warm water rewarming cerebral alterations were restored to the control level and it was indicated by shortened reaction times (P < 0.05). Conclusions: Brief rewarming in warm water rather than the same duration rewarming in thermoneutral environment blunted the hypothermia-induced alterations for sensation, motor drive, and cognition, despite the fact that rectal and deep muscle temperature remained lowered. PMID- 27990126 TI - Editorial: Using Stress-Based Animal Models to Understand the Mechanisms Underlying Psychiatric and Somatic Disorders. PMID- 27990125 TI - Promises, Pitfalls, and Basic Guidelines for Applying Machine Learning Classifiers to Psychiatric Imaging Data, with Autism as an Example. AB - Most psychiatric disorders are associated with subtle alterations in brain function and are subject to large interindividual differences. Typically, the diagnosis of these disorders requires time-consuming behavioral assessments administered by a multidisciplinary team with extensive experience. While the application of Machine Learning classification methods (ML classifiers) to neuroimaging data has the potential to speed and simplify diagnosis of psychiatric disorders, the methods, assumptions, and analytical steps are currently opaque and not accessible to researchers and clinicians outside the field. In this paper, we describe potential classification pipelines for autism spectrum disorder, as an example of a psychiatric disorder. The analyses are based on resting-state fMRI data derived from a multisite data repository (ABIDE). We compare several popular ML classifiers such as support vector machines, neural networks, and regression approaches, among others. In a tutorial style, written to be equally accessible for researchers and clinicians, we explain the rationale of each classification approach, clarify the underlying assumptions, and discuss possible pitfalls and challenges. We also provide the data as well as the MATLAB code we used to achieve our results. We show that out of-the-box ML classifiers can yield classification accuracies of about 60-70%. Finally, we discuss how classification accuracy can be further improved, and we mention methodological developments that are needed to pave the way for the use of ML classifiers in clinical practice. PMID- 27990127 TI - The Timing of Utterance Planning in Task-Oriented Dialogue: Evidence from a Novel List-Completion Paradigm. AB - In conversation, interlocutors rarely leave long gaps between turns, suggesting that next speakers begin to plan their turns while listening to the previous speaker. The present experiment used analyses of speech onset latencies and eye movements in a task-oriented dialogue paradigm to investigate when speakers start planning their responses. German speakers heard a confederate describe sets of objects in utterances that either ended in a noun [e.g., Ich habe eine Tur und ein Fahrrad ("I have a door and a bicycle")] or a verb form [e.g., Ich habe eine Tur und ein Fahrrad besorgt ("I have gotten a door and a bicycle")], while the presence or absence of the final verb either was or was not predictable from the preceding sentence structure. In response, participants had to name any unnamed objects they could see in their own displays with utterances such as Ich habe ein Ei ("I have an egg"). The results show that speakers begin to plan their turns as soon as sufficient information is available to do so, irrespective of further incoming words. PMID- 27990124 TI - Endothelial Progenitor Cells Physiology and Metabolic Plasticity in Brain Angiogenesis and Blood-Brain Barrier Modeling. AB - Currently, there is a considerable interest to the assessment of blood-brain barrier (BBB) development as a part of cerebral angiogenesis developmental program. Embryonic and adult angiogenesis in the brain is governed by the coordinated activity of endothelial progenitor cells, brain microvascular endothelial cells, and non-endothelial cells contributing to the establishment of the BBB (pericytes, astrocytes, neurons). Metabolic and functional plasticity of endothelial progenitor cells controls their timely recruitment, precise homing to the brain microvessels, and efficient support of brain angiogenesis. Deciphering endothelial progenitor cells physiology would provide novel engineering approaches to establish adequate microfluidically-supported BBB models and brain microphysiological systems for translational studies. PMID- 27990128 TI - Commentary: The Experience of Depression during the Careers of Elite Male Athletes. PMID- 27990130 TI - Acquiring Complex Focus-Marking: Finnish 4- to 5-Year-Olds Use Prosody and Word Order in Interaction. AB - Using a language game to elicit short sentences in various information structural conditions, we found that Finnish 4- to 5-year-olds already exhibit a characteristic interaction between prosody and word order in marking information structure. Providing insights into the acquisition of this complex system of interactions, the production data showed interesting parallels to adult speakers of Finnish on the one hand and to children acquiring other languages on the other hand. Analyzing a total of 571 sentences produced by 16 children, we found that children rarely adjusted input word order, but did systematically avoid marked OVS order in contrastive object focus condition. Focus condition also significantly affected four prosodic parameters, f0, duration, pauses and voice quality. Differing slightly from effects displayed in adult Finnish speech, the children produced larger f0 ranges for words in contrastive focus and smaller ones for unfocused words, varied only the duration of object constituents to be longer in focus and shorter in unfocused condition, inserted more pauses before and after focused constituents and systematically modified their use of non-modal voice quality only in utterances with narrow focus. Crucially, these effects were modulated by word order. In contrast to comparable data from children acquiring Germanic languages, the present findings reflect the more central role of word order and of interactions between word order and prosody in marking information structure in Finnish. Thus, the study highlights the role of the target language in determining linguistic development. PMID- 27990131 TI - The Spanish General Knowledge Norms. PMID- 27990129 TI - Developmental Trajectories of Sleep Problems from Childhood to Adolescence Both Predict and Are Predicted by Emotional and Behavioral Problems. AB - Although the prevalence rates of sleep disorders at different stages of childhood and adolescence have been well established, little is known about the developmental course of general sleep problems. This also holds true for the bidirectional relationship between sleep problems and emotional as well as behavioral difficulties. This longitudinal study investigated the general pattern and the latent trajectory classes of general sleep problems from a large community sample aged 5-14 years. In addition, this study examined the predictive value of emotional/behavioral difficulties (i.e., anxiety/depression, attention problems, and aggressive behavior) on sleep problems latent trajectory classes, and vice-versa. Participants (N = 1993) were drawn from a birth cohort of Western Australian children born between 1989 and 1991 who were followed until 14 years of age. Sleep problems were assessed at ages 5, 8, 10, and 14, respectively, whereas anxiety/depression, attention problems, and aggressive behavior were assessed at ages 5 and 17 years. Latent growth curve modeling revealed a decline in an overall pattern of sleep problems during the observed 10-year period. Anxiety/depression was the only baseline factor that predicted the longitudinal course of sleep problems from ages 5 to 14 years, with anxious and depressed participants showing faster decreasing patterns of sleep problems over time than those without anxiety or depression. Growth mixture modeling identified two classes of sleep problem trajectories: Normal Sleepers (89.4%) and Troubled Sleepers (10.6%). Gender was randomly distributed between these groups. Childhood attention problems, aggressive behavior, and the interaction between gender and anxiety/depression were significantly predictive of membership in the group of Troubled Sleepers. Group membership in Troubled Sleepers was associated with higher probability of having attention problems and aggressive behavior in mid adolescence. Boys and girls with behavioral difficulties, and girls with emotional difficulties were at increased risk of having sleep problems during later childhood and adolescence. Developmental trajectories of sleep problems were also predictive of behavioral difficulties in later life. Findings from this study provide empirical evidence for the heterogeneity of sleep problems and their development, and emphasize the importance of understanding sleep problems and their relationship to children and adolescents' mental health. PMID- 27990132 TI - Judgments of Learning for Words in Vertical Space. AB - Close relationship between physical space and internal knowledge representations has received ample support in the literature. For example, location of visually perceived information in vertical space has been shown to affect different numerical judgments. In addition, physical dimensions, such as weight or font size, were shown to affect judgments of learning (JOLs, an estimation of the likelihood that an item will be remembered later, or its perceived memorability). In two experiments we tested the hypothesis that differences in positioning words in vertical space may affect their perceived memorability, i.e., JOLs. In both Experiments, the words were presented in lower or in upper screen locations. In Experiment 1, JOLs were collected in the centre of the screen following word presentation. In Experiment 2, JOLs were collected at the point of word presentation and in the same location. In both experiments participants completed a free recall test. JOLs were compared between different vertically displaced presentation locations. In general, Bayesian analyses showed evidence in support for the null effect of vertical location on JOLs. We interpret our results as indicating that the effects of physical dimensions on JOLs are mediated by subjective importance, information that vertical location alone fails to convey. PMID- 27990133 TI - Editorial: Interoception, Contemplative Practice, and Health. PMID- 27990134 TI - Allocentric Spatial Memory Testing Predicts Conversion from Mild Cognitive Impairment to Dementia: An Initial Proof-of-Concept Study. AB - The hippocampus is one of the first regions to exhibit neurodegeneration in Alzheimer's disease (AD), and knowledge of its role in allocentric spatial memory may therefore aid early diagnosis of AD. The 4 Mountains Test (4MT) is a short and easily administered test of spatial memory based on the cognitive map theory of hippocampal function as derived from rodent single cell and behavioral studies. The 4MT has been shown in previous cross-sectional studies to be sensitive and specific for mild cognitive impairment (MCI) due to AD. This report describes the initial results of a longitudinal study testing the hypothesis that allocentric spatial memory is predictive of conversion from MCI to dementia. Fifteen patients with MCI underwent baseline testing on the 4MT in addition to CSF amyloid/tau biomarker studies, volumetric MRI and neuropsychological assessment including the Rey Auditory Verbal Learning Test (RAVLT) and Trail Making Test "B" (TMT-B). At 24 months, 9/15 patients had converted to AD dementia. The 4MT predicted conversion to AD with 93% accuracy (Cohen's d = 2.52). The predictive accuracies of the comparator measures were as follows: CSF tau/beta-amyloid1-42 ratio 92% (d = 1.81), RAVLT 64% (d = 0.41), TMT-B 78% (d = 1.56), and hippocampal volume 77% (d = 0.65). CSF tau levels were strongly negatively correlated with 4MT scores (r = -0.71). This proof-of-concept study provides initial support for the hypothesis that allocentric spatial memory testing is a predictive cognitive marker of hippocampal neurodegeneration in pre dementia AD. The 4MT is a brief, non-invasive, straightforward spatial memory test and is therefore ideally suited for use in routine clinical diagnostic practice. This is of particular importance given the current unmet need for simple accurate diagnostic tests for early AD and the ongoing development of potential disease-modifying therapeutic agents, which may be more efficacious when given earlier in the disease course. By applying a test based on studies of hippocampal function in rodents to patient populations, this work represents the first step in the development of translatable biomarkers of hippocampal involvement in early AD for use in both animal models and human subjects. PMID- 27990135 TI - Predominance of CTX-M-15 among ESBL Producers from Environment and Fish Gut from the Shores of Lake Victoria in Mwanza, Tanzania. AB - Extended-Spectrum Beta-Lactamase (ESBL)-producing bacteria are a common cause of healthcare and community-associated infections worldwide. The distribution of such isolates in the environment and their presence in fish as a result of sewage contamination is not well-studied. Here we examined fish and environmental samples from Mwanza city for the presence of ESBL-producing bacteria. From 196 fish sampled from local markets, 26 (13.3%) contained lactose-fermenting ESBL producing bacteria, while 39/73 (53.4%) environmental samples from the same area were ESBL producers. Antibiotic resistance genes, multi locus sequence types (MLST) and plasmid replicon types in 24 selected isolates from both populations were identified with whole genome sequencing using Illumina MiSeq. Nine of eleven sequenced fish isolates had the blaCTX-M-15 gene whereas 12/13 from environment carried blaCTX-M-15. Antibiotic resistance genes encoding resistance to sulfonamides (sul1/sul2), tetracyclines [tet(A)/tet(B)] fluoroquinolones [e.g., aac(6')-Ib-cr, qnrS1], aminoglycosides [e.g., aac(3)-lld, strB, strA,] and trimethoprim (e.g., dfrA14) were detected. E. coli sequence type ST-38 (2) and ST 5173 (2) were detected in isolates both from the environment and fish. IncY plasmids carrying blaCTX-M-15, qnrS1, strA, and strB were detected in five environmental E. coli isolates and in one E. coli isolate from fish. Our data indicate spillage of resistant environmental isolates into Lake Victoria through the sewage system. Persistence of blaCTX-M-15 in the Mwanza city environment is complex, and involves both clonal spread of resistant strains as well as dissemination by commonly occurring IncY plasmids circulating in isolates present in humans, the environment as well as in the food chain. PMID- 27990136 TI - Non-selective Separation of Bacterial Cells with Magnetic Nanoparticles Facilitated by Varying Surface Charge. AB - Recovering microorganisms from environmental samples is a crucial primary step for understanding microbial communities using molecular ecological approaches. It is often challenging to harvest microorganisms both efficiently and unselectively, guaranteeing a similar microbial composition between original and separated biomasses. A magnetic nanoparticles (MNPs) based method was developed to effectively separate microbial biomass from glass fiber pulp entrapped bacteria. Buffering pH and nanoparticle silica encapsulation significantly affected both biomass recovery and microbial selectivity. Under optimized conditions (using citric acid coated Fe3O4, buffering pH = 2.2), the method was applied in the pretreatment of total suspended particle sampler collected bioaerosols, the effective volume for DNA extraction was increased 10-folds, and the overall method detection limit of microbial contaminants in bioaerosols significantly decreased. A consistent recovery of the majority of airborne bacterial populations was demonstrated by in-depth comparison of microbial composition using 16S rRNA gene high-throughput sequencing. Surface charge was shown as the deciding factor for the interaction between MNPs and microorganisms, which helps developing materials with high microbial selectivity. To our knowledge, this study is the first report using MNPs to separate diverse microbial community unselectively from a complex environmental matrix. The technique is convenient and sensitive, as well as feasible to apply in monitoring of microbial transport and other related fields. PMID- 27990137 TI - Immuno Affinity SELEX for Simple, Rapid, and Cost-Effective Aptamer Enrichment and Identification against Aflatoxin B1. AB - Aflatoxins are naturally occurring mycotoxins that contaminate food and agro commodities, leading to acute and chronic health conditions in human and animals. In the present work, an attempt was made to generate high-affinity single stranded DNA aptamers that specifically bind to Aflatoxin B1 (AFB1) by a modified Systemic Evolution of Ligands by Exponential Enrichment (SELEX) procedure with the aid of Immunoaffinity columns. Ten rounds of SELEX and alternating three counter SELEX rounds with a cocktail of related and other mycotoxins were performed to enhance the specificity. Resultant 105 aptamers were clustered into 12 groups according to their primary sequence homology. Candidates with lowest Gibbs free energy (dG value) and unique stem loop structures were selected for further characterization. Aptamers, AFLA5, AFLA53, and AFLA71 exhibiting lower Kd values (50.45 +/- 11.06, 48.29 +/- 9.45, and 85.02 +/- 25.74 nM) were chosen for development of ELONA and determination of purification ability of toxin. The detection limit (LOD) of AFLA5 and AFLA71 was 20 and 40 ng/ml, respectively. HPLC analysis implied that selected aptamers were able to recover and quantify 82.2 to 96.21% (LOQ - 53.74 ng) and 78.3 to 94.22% (LOQ - 66.75 ng) of AFB1 from spiked corn samples, respectively. These findings indicate, immunoaffinity based SELEX can pave an alternative approach to screen aptamers against mycotoxin detection and purification. PMID- 27990138 TI - Purification of Antilisterial Peptide (Subtilosin A) from Novel Bacillus tequilensis FR9 and Demonstrate Their Pathogen Invasion Protection Ability Using Human Carcinoma Cell Line. AB - This study focuses on isolation, screening, and characterization of novel probiotics from gastrointestinal tract of free-range chicken (Gallus gallus domesticus). Fifty seven colonies were isolated and three isolates (FR4, FR9, and FR12) were selected and identified as Lactobacillus gasseri FR4, Bacillus tequilensis FR9, and L. animalis FR12 by 16S rRNA sequencing. Three strains were able to survive in stimulated acidic and bile conditions and inhibit the growth of pathogens. Especially, FR9 exhibited maximum inhibition against Listeria monocytogenes and none of them exhibited hemolytic activity. Native-PAGE revealed the presence of low molecular weight (3.4-5.0 KDa) antimicrobial peptide. The peptide was further purified by Sephadex G-50 column and RP-HPLC using C18 column. N-terminal amino acid sequencing of antimicrobial peptide showed 100% consensus to antilisterial peptide Subtilosin A and SboA gene was amplified from FR9 genome. FR9 showed maximum aggregation activity, exopolysaccharide production (85.46 mg/L) and cholesterol assimilation (63.12 +/- 0.05 MUg/mL). Strong adhesion property (12.6%) and pathogen invasion protection ability was revealed by B. tequilensis FR9 towards HCT-116 human colon carcinoma cell line. This is the first study to demonstrate antilisterial Subtilosin A production of B. tequilensis. Our results indicate that B. tequilensis FR9 strain furnish the essential characteristics of a potential probiotics and might be incorporated into human and animal food supplements. PMID- 27990139 TI - Cysteine-Mediated Gene Expression and Characterization of the CmbR Regulon in Streptococcus pneumoniae. AB - In this study, we investigated the transcriptomic response of Streptococcus pneumoniae D39 to cysteine. Transcriptome comparison of the D39 wild-type grown at a restricted concentration of cysteine (0.03 mM) to one grown at a high concentration of cysteine (50 mM) in chemically-defined medium (CDM) revealed elevated expression of various genes/operons, i.e., spd-0150, metQ, spd-0431, metEF, gshT, spd-0618, fhs, tcyB, metB-csd, metA, spd-1898, yvdE, and cysK, likely to be involved in the transport and utilization of cysteine and/or methionine. Microarray-based data were further confirmed by quantitative RT-PCR. Promoter lacZ-fusion studies and quantitative RT-PCR data showed that the transcriptional regulator CmbR acts as a transcriptional repressor of spd-0150, metEF, gshT, spd-0618, tcyB, metA, and yvdE, putatively involved in cysteine uptake and utilization. The operator site of CmbR in the promoter regions of CmbR regulated genes is predicted and confirmed by mutating or deleting CmbR operator sites from the promoter regions of these genes. PMID- 27990140 TI - Insight into the ERVK Integrase - Propensity for DNA Damage. AB - Retroviruses create permanently integrated proviruses that exist in the host genome. Retroviral genomes encode for functionally conserved gag, pro, pol, and env regions, as well as integrase (IN), which is required for retroviral integration. IN mediates viral genome insertion through 3' end processing of the viral DNA and the strand transfer reaction. This process requires the formation of a pre-integration complex, comprised of IN, viral DNA, and cellular proteins. Viral insertion causes DNA damage, leading to the requirement of host DNA repair mechanisms. Therefore, a failure of DNA repair pathways may result in genomic instability and potentially cause host cell death. Considering the numerous human diseases associated with genomic instability, the endogenous retrovirus-K (ERVK) IN should be considered as a putative contributor to DNA damage in human cells. Future research and drug discovery should focus on ERVK IN activity and its role in human conditions, such as neurological disease and cancers. PMID- 27990141 TI - The Ecological Coherence of Temperature and Salinity Tolerance Interaction and Pigmentation in a Non-marine Vibrio Isolated from Salar de Atacama. AB - The occurrence of microorganisms from the Vibrio genus in saline lakes from northern Chile had been evidenced using Numerical Taxonomy decades before and, more recently, by phylogenetic analyses of environmental samples and isolates. Most of the knowledge about this genus came from marine isolates and showed temperature and salinity to be integral agents in shaping the niche of the Vibrio populations. The stress tolerance phenotypes of Vibrio sp. Teb5a1 isolated from Salar de Atacama was investigated. It was able to grow without NaCl and tolerated up to 100 g/L of the salt. Furthermore, it grew between 17 degrees and 49 degrees C (optimum 30 degrees C) in the absence of NaCl, and the range was expanded into cold temperature (4-49 degrees C) in the presence of the salt. Other additional adaptive strategies were observed in response to the osmotic stress: pigment production, identified as the known antibacterial prodigiosin, swimming and swarming motility and synthesis of a polar flagellum. It is possible to infer that environmental congruence might explain the cellular phenotypes observed in Vibrio sp. considering that coupling between temperature and salinity tolerance, the production of antibacterial agents at higher temperatures, flagellation and motility increase the chance of Vibrio sp. to survive in salty environments with high daily temperature swings and UV radiation. PMID- 27990143 TI - Corrigendum: Cell division in Corynebacterineae. AB - [This corrects the article on p. 132 in vol. 5, PMID: 24782835.]. PMID- 27990142 TI - Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation. AB - Homeostatic proliferation (HSP) is a major mechanism by which long-lived naive and memory CD4+ T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4+ T cells that were initially differentiated via T-cell receptor (TCR) stimulation into memory/effector cells, latent infection of naive resting CD4+ T cells maintained under HSP conditions has not been fully addressed. Here, we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naive resting CD4+ T cells. CD4+ T cells isolated from several healthy donors were infected with HIV pseudotypes expressing GFP and cultured under HSP conditions or TCR conditions as control. Cell proliferation, phenotype, and GFP expression were analyzed by flow cytometry. RNA expression was quantified by qRT-PCR. Under HSP culture conditions, latently HIV-1 infected naive cells are in part maintained in the non dividing (= resting) state. Although a few HIV-1 provirus+ cells were present in these resting GFP negative cells, the estimated level of GFP transcripts per infected cell seems to indicate a block at the post-transcriptional level. Interestingly, neither TCR nor the prototypic HDAC inhibitor SAHA were able to reactivate HIV-1 provirus from these cells. This lack of reactivation was not due to methylation of the HIV LTR. These results point to a mechanism of HIV control in HSP-cultured resting naive CD4+ T cells that may be distinct from that in TCR stimulated memory/effector T cells. PMID- 27990144 TI - Glucose-Regulated Protein 78-Induced Myeloid Antigen-Presenting Cells Maintained Tolerogenic Signature upon LPS Stimulation. AB - The 78-kDa glucose-regulated protein (Grp78) is stress-inducible chaperone that mostly reside in the endoplasmic reticulum. Grp78 has been described to be released at times of cellular stress and as having extracellular properties that are anti-inflammatory or favor the resolution of inflammation. As antigen presenting cells (APCs) play a critical role in both the priming of adaptive immune responses and the induction of self-tolerance, herein, we investigated the effect of Grp78 on the maturation of murine myeloid APCs (CD11c+ cells). Results showed that CD11c+ cells could be bound by AF488-labeled Grp78 and that Grp78 treatment induced a tolerogenic phenotype comparable to immature cells. Furthermore, when exposed to lipopolysaccharide, Grp78-treated CD11c+ cells (DCGrp78) did not adopt a mature dendritic cell phenotype. DCGrp78-primed T cells exhibited reduced proliferation along with a concomitant expansion of CD4+CD25+FoxP3+ cells in pancreaticoduodenal lymph nodes and induction of T cell apoptosis in vitro and ex vivo. The above work suggests that Grp78 is an immunomodulatory molecule that could aid resolution of inflammation. It may thus contribute to induce durable tolerance to be of potential therapeutic benefit in transplanted allogeneic grafts and autoimmune diseases such as type I diabetes. PMID- 27990145 TI - Oxidative Burst-Dependent NETosis Is Implicated in the Resolution of Necrosis Associated Sterile Inflammation. AB - Necrosis is associated with a profound inflammatory response. The regulation of necrosis-associated inflammation, particularly the mechanisms responsible for resolution of inflammation is incompletely characterized. Nanoparticles are known to induce plasma membrane damage and necrosis followed by sterile inflammation. We observed that injection of metabolically inert nanodiamonds resulted in paw edema in WT and Ncf1** mice. However, while inflammation quickly resolved in WT mice, it persisted over several weeks in Ncf1** mice indicating failure of resolution of inflammation. Mechanistically, NOX2-dependent reactive oxygen species (ROS) production and formation of neutrophil extracellular traps were essential for the resolution of necrosis-induced inflammation: hence, by evaluating the fate of the particles at the site of inflammation, we observed that Ncf1** mice deficient in NADPH-dependent ROS failed to generate granulation tissue therefore being unable to trap the nanodiamonds. These data suggest that NOX2-dependent NETosis is crucial for preventing the chronification of the inflammatory response to tissue necrosis by forming NETosis-dependent barriers between the necrotic and healthy surrounding tissue. PMID- 27990146 TI - Comparative Transcriptomic Analysis of Virulence Factors in Leptosphaeria maculans during Compatible and Incompatible Interactions with Canola. AB - Leptosphaeria maculans is a hemibiotrophic fungus that causes blackleg of canola (Brassica napus), one of the most devastating diseases of this crop. In the present study, transcriptome profiling of L. maculans was performed in an effort to understand and define the pathogenicity genes that govern both the biotrophic and the necrotrophic phase of the fungus, as well as those that separate a compatible from an incompatible interaction. For this purpose, comparative RNA seq analyses were performed on L. maculans isolate D5 at four different time points following inoculation on susceptible cultivar Topas-DH16516 or resistant introgression line Topas-Rlm2. Analysis of 1.6 billion Illumina reads readily identified differentially expressed genes that were over represented by candidate secretory effector proteins, CAZymes, and other pathogenicity genes. Comparisons between the compatible and incompatible interactions led to the identification of 28 effector proteins whose chronology and level of expression suggested a role in the establishment and maintenance of biotrophy with the plant. These included all known Avr genes of isolate D5 along with eight newly characterized effectors. In addition, another 15 effector proteins were found to be exclusively expressed during the necrotrophic phase of the fungus, which supports the concept that L. maculans has a separate and distinct arsenal contributing to each phase. As for CAZymes, they were often highly expressed at 3 dpi but with no difference in expression between the compatible and incompatible interactions, indicating that other factors were necessary to determine the outcome of the interaction. However, their significantly higher expression at 11 dpi in the compatible interaction confirmed that they contributed to the necrotrophic phase of the fungus. A notable exception was LysM genes whose high expression was singularly observed on the susceptible host at 7 dpi. In the case of TFs, their higher expression at 7 and 11 dpi on susceptible Topas support an important role in regulating the genes involved in the different pathogenic phases of L. maculans. In conclusion, comparison of the transcriptome of L. maculans during compatible and incompatible interactions has led to the identification of key pathogenicity genes that regulate not only the fate of the interaction but also lifestyle transitions of the fungus. PMID- 27990147 TI - Molecular Characterization of Rice OsLCB2a1 Gene and Functional Analysis of its Role in Insect Resistance. AB - In plants, sphingolipids, such as long-chain bases (LCBs), act as bioactive molecules in stress responses. Until now, it is still not clear if these lipids are involved in biotic stress responses to herbivore. Herein we report that a rice LCB gene, OsLCB2a1 encoding a subunit of serine palmitoyltransferase (SPT), a key enzyme responsible for the de novo biosynthesis of sphingolipids, plays a critical role in plant defense response to the brown planthopper (BPH) attack and that its up-regulation protects plants from herbivore infestation. Transcripts of OsLCB2a1 gene in rice seedlings were increased at 4 h, but decreased at 8-24 h after BPH attack. Sphingolipid measurement profiling revealed that overexpression of OsLCB2a1 in Arabidopsis thaliana increased trihydroxylated LCB phytosphingosine (t18:0) and phytoceramide by 1.7 and 1.3-fold, respectively, compared with that of wild type (WT) plants. Transgenic Arabidopsis plants also showed higher callose and wax deposition in leaves than that of WT. Overexpression of OsLCB2a1 gene in A. thaliana reduced the population size of green peach aphid (Myzus persicae). Moreover, the electrical penetration graph (EPG) results indicated that the aphids encounter resistance factors while reaching for the phloem on the transgenic plants. The defense response genes related to salicylic acid signaling pathway, remained uplgulated in the OsLCB2a1 overexpressing transgenic plants. Our data highlight the key functions of OsLCB2a1 in biotic stress response in plants. PMID- 27990148 TI - ROS Production and Scavenging under Anoxia and Re-Oxygenation in Arabidopsis Cells: A Balance between Redox Signaling and Impairment. AB - Plants can frequently experience low oxygen concentrations due to environmental factors such as flooding or waterlogging. It has been reported that both anoxia and the transition from anoxia to re-oxygenation determine a strong imbalance in the cellular redox state involving the production of reactive oxygen species (ROS) and nitric oxide (NO). Plant cell cultures can be a suitable system to study the response to oxygen deprivation stress since a close control of physicochemical parameters is available when using bioreactors. For this purpose, Arabidopsis cell suspension cultures grown in a stirred bioreactor were subjected to a severe anoxic stress and analyzed during anoxia and re-oxygenation for alteration in ROS and NO as well as in antioxidant enzymes and metabolites. The results obtained by confocal microscopy showed the dramatic increase of ROS, H2O2, and NO during the anoxic shock. All the ascorbate-glutathione related parameters were altered during anoxia but restored during re-oxygenation. Anoxia also induced a slight but significant increase of alpha-tocopherol levels measured at the end of the treatment. Overall, the evaluation of cell defenses during anoxia and re-oxygenation in Arabidopsis cell cultures revealed that the immediate response involving the overproduction of reactive species activated the antioxidant machinery including ascorbate-glutathione system, alpha-tocopherol and the ROS-scavenging enzymes ascorbate peroxidase, catalase, and peroxidase making cells able to counteract the stress toward cell survival. PMID- 27990149 TI - Genistein: A Novel Anthocyanin Synthesis Promoter that Directly Regulates Biosynthetic Genes in Red Cabbage in a Light-Dependent Way. AB - Genistein (GNT), an isoflavone, is used in the clinical treatment of various health disorders. GNT is found in primary food source plants and some medical plants. However, studies on the functions of GNT in plants are rarely reported. In this study, we demonstrated that GNT plays an important role in promoting anthocyanin accumulation in red cabbage. GNT solutions (10, 20, 30, 40, and 50 mg/L) as foliar fertilizers were applied to red cabbage. Consequently, anthocyanin accumulation in red cabbage increased in a light-dependent manner. GNT solution at 30 mg/L exhibited the optimal effect on anthocyanin accumulation, which was twice that of the control. Quantitative real-time PCR analysis indicated that GNT application upregulated the expression of all structural genes, contributing to anthocyanin biosynthesis under light conditions. Under dark conditions, GNT exerted no significant promotive effect on anthocyanin accumulation; only early biosynthetic genes of anthocyanin biosynthesis responded to GNT. The promotive effect of GNT on anthocyanin biosynthesis is directly attributable to the regulation of structural gene expression. Transcription factors exhibited no response to GNT. The levels of anthocyanin in red cabbage positively correlated with the enzyme activities of antioxidant systems. This finding correlation suggested that the promotive effect of GNT on anthocyanin levels was correlated with improved antioxidant activity in the red cabbage. PMID- 27990150 TI - Transcriptional Regulation of Tetrapyrrole Biosynthesis in Arabidopsis thaliana. AB - Biosynthesis of chlorophyll (Chl) involves many enzymatic reactions that share several first steps for biosynthesis of other tetrapyrroles such as heme, siroheme, and phycobilins. Chl allows photosynthetic organisms to capture light energy for photosynthesis but with simultaneous threat of photooxidative damage to cells. To prevent photodamage by Chl and its highly photoreactive intermediates, photosynthetic organisms have developed multiple levels of regulatory mechanisms to coordinate tetrapyrrole biosynthesis (TPB) with the formation of photosynthetic and photoprotective systems and to fine-tune the metabolic flow with the varying needs of Chl and other tetrapyrroles under various developmental and environmental conditions. Among a wide range of regulatory mechanisms of TPB, this review summarizes transcriptional regulation of TPB genes during plant development, with focusing on several transcription factors characterized in Arabidopsis thaliana. Key TPB genes are tightly coexpressed with other photosynthesis-associated nuclear genes and are induced by light, oscillate in a diurnal and circadian manner, are coordinated with developmental and nutritional status, and are strongly downregulated in response to arrested chloroplast biogenesis. LONG HYPOCOTYL 5 and PHYTOCHROME-INTERACTING FACTORs, which are positive and negative transcription factors with a wide range of light signaling, respectively, target many TPB genes for light and circadian regulation. GOLDEN2-LIKE transcription factors directly regulate key TPB genes to fine-tune the formation of the photosynthetic apparatus with chloroplast functionality. Some transcription factors such as FAR-RED ELONGATED HYPOCOTYL3, REVEILLE1, and scarecrow-like transcription factors may directly regulate some specific TPB genes, whereas other factors such as GATA transcription factors are likely to regulate TPB genes in an indirect manner. Comprehensive transcriptional analyses of TPB genes and detailed characterization of key transcriptional regulators help us obtain a whole picture of transcriptional control of TPB in response to environmental and endogenous cues. PMID- 27990151 TI - Genome-Editing Technologies for Enhancing Plant Disease Resistance. AB - One of the greatest challenges for agricultural science in the 21st century is to improve yield stability through the progressive development of superior cultivars. The increasing numbers of infectious plant diseases that are caused by plant-pathogens make it ever more necessary to develop new strategies for plant disease resistance breeding. Targeted genome engineering allows the introduction of precise modifications directly into a commercial variety, offering a viable alternative to traditional breeding methods. Genome editing is a powerful tool for modifying crucial players in the plant immunity system. In this work, we propose and discuss genome-editing strategies and targets for improving resistance to phytopathogens. First of all, we present the opportunities to rewrite the effector-target sequence for avoiding effector-target molecular interaction and also to modify effector-target promoters for increasing the expression of target genes involved in the resistance process. In addition, we describe potential approaches for obtaining synthetic R-genes through genome editing technologies (GETs). Finally, we illustrate a genome editing flowchart to modify the pathogen recognition sites and engineer an R-gene that mounts resistance to some phylogenetically divergent pathogens. GETs potentially mark the beginning of a new era, in which synthetic biology affords a basis for obtaining a reinforced plant defense system. Nowadays it is conceivable that by modulating the function of the major plant immunity players, we will be able to improve crop performance for a sustainable agriculture. PMID- 27990152 TI - Transcriptional Profiling of Rice Treated with MoHrip1 Reveal the Function of Protein Elicitor in Enhancement of Disease Resistance and Plant Growth. AB - MoHrip1 is a protein elicitor isolated from Magnaporthe oryzae and was found to induce blast-resistance in rice. To investigate the comprehensive functions of MoHrip1, next-generation sequencing (NGS)-based digital gene expression (DGE) profiling was performed to collect the transcriptional data of differentially expressed genes (DEGs) induced by MoHrip1. A total of 308 genes were identified with differential expression, and 80 genes were predicted to be induced specifically by MoHrip1. Among these 308 genes, a series of genes associated with the salicylic acid (SA) pathway, phytoalexin, transcription factors, and pathogen related proteins were identified. Both the SA signaling pathway and the gibberellin (GA) pathway were activated, while the jasmonic acid (JA) signaling pathway was repressed. The contents of endogenous SA and GA and the morphological characteristics of the rice after treatment were measured to provide evidence supporting the predictions made based on the DGE data. The 80 genes mentioned above might be candidate genes for studying interactions with MoHrip1. The transcriptional data provided global effect information in rice induced by MoHrip1, and all the results demonstrated that MoHrip1 could induce pathogen resistance and promote plant growth by regulating the contents of SA and GA directly or indirectly. PMID- 27990153 TI - Characterization and Functional Analysis of Calmodulin and Calmodulin-Like Genes in Fragaria vesca. AB - Calcium is a universal messenger that is involved in the modulation of diverse developmental and adaptive processes in response to various stimuli. Calmodulin (CaM) and calmodulin-like (CML) proteins are major calcium sensors in all eukaryotes, and they have been extensively investigated for many years in plants and animals. However, little is known about CaMs and CMLs in woodland strawberry (Fragaria vesca). In this study, we performed a genome-wide analysis of the strawberry genome and identified 4 CaM and 36 CML genes. Bioinformatics analyses, including gene structure, phylogenetic tree, synteny and three-dimensional model assessments, revealed the conservation and divergence of FvCaMs and FvCMLs, thus providing insight regarding their functions. In addition, the transcript abundance of four FvCaM genes and the four most related FvCML genes were examined in different tissues and in response to multiple stress and hormone treatments. Moreover, we investigated the subcellular localization of several FvCaMs and FvCMLs, revealing their potential interactions based on the localizations and potential functions. Furthermore, overexpression of five FvCaM and FvCML genes could not induce a hypersensitive response, but four of the five genes could increase resistance to Agrobacterium tumefaciens in Nicotiana benthamiana leaves. This study provides evidence for the biological roles of FvCaM and CML genes, and the results lay the foundation for future functional studies of these genes. PMID- 27990154 TI - NSP-Dependent Simple Nitrile Formation Dominates upon Breakdown of Major Aliphatic Glucosinolates in Roots, Seeds, and Seedlings of Arabidopsis thaliana Columbia-0. AB - One of the best-studied plant defense systems, the glucosinolate-myrosinase system of the Brassicales, is composed of thioglucosides known as glucosinolates and their hydrolytic enzymes, the myrosinases. Tissue disruption brings these components together, and bioactive products are formed as a consequence of myrosinase-catalyzed glucosinolate hydrolysis. Among these products, isothiocyanates have attracted most interest as chemical plant defenses against herbivores and pathogens and health-promoting compounds in the human diet. Previous research has identified specifier proteins whose presence results in the formation of alternative product types, e.g., nitriles, at the expense of isothiocyanates. The biological roles of specifier proteins and alternative breakdown products are poorly understood. Here, we assessed glucosinolate breakdown product profiles obtained upon maceration of roots, seedlings and seeds of Arabidopsis thaliana Columbia-0. We identified simple nitriles as the predominant breakdown products of the major endogenous aliphatic glucosinolates in root, seed, and seedling homogenates. In agreement with this finding, genes encoding nitrile-specifier proteins (NSPs) are expressed in roots, seeds, and seedlings. Analysis of glucosinolate breakdown in mutants with T-DNA insertions in any of the five NSP genes demonstrated, that simple nitrile formation upon tissue disruption depended almost entirely on NSP2 in seeds and mainly on NSP1 in seedlings. In roots, about 70-80% of the nitrile-forming activity was due to NSP1 and NSP3. Thus, glucosinolate breakdown product profiles are organ-specifically regulated in A. thaliana Col-0, and high proportions of simple nitriles are formed in some parts of the plant. This should be considered in future studies on biological roles of the glucosinolate-myrosinase system. PMID- 27990155 TI - Dietary supplement comprised of beta-carotene, vitamin C, vitamin E, and magnesium: failure to prevent music-induced temporary threshold shift. AB - This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of beta carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose consumed approximately 30-min pre-exposure. There were no group differences in post-exposure TTS or music-induced decreases in distortion product otoacoustic emission (DPOAE) amplitude. Transient tinnitus was more likely to be reported by the treatment group, but there were no group differences in perceived loudness or bothersomeness. All subjects were monitored until auditory function returned to pre-exposure levels. Taken together, this supplement had no effect on noise-induced changes in hearing. Recommendations for future clinical trials are discussed. PMID- 27990156 TI - Classifying Aging As a Disease: The Role of Microbes. PMID- 27990157 TI - Palliative Gastrectomy Prolongs Survival of Metastatic Gastric Cancer Patients with Normal Preoperative CEA or CA19-9 Values: A Retrospective Cohort Study. AB - Background. Palliative gastrectomy has been suggested to improve survival of patients with metastatic gastric cancer, but limitations in study design and availability of robust prognostic factors have cast doubt on the overall merit of this procedure. Methods. The characteristics and clinical outcomes of 173 patients diagnosed between 2008 and 2012 were analyzed to determine the value of palliative gastrectomy and to identify potential prognostic factors. Results. Median overall patient survival was 6.5 months. To attenuate potential selection bias, patients with adequate performance and survival time of >= 2 months since diagnosis were included for risk factor analysis (n = 137). The median overall survival was longer for patients who were younger than 60 years, had better performance status (8.7 versus 6.4 months, P = 0.015), received systemic chemotherapy, or had palliative gastrectomy in univariate analyses. Gastrectomy (P = 0.002) remained statistically significant in multivariate analyses. Subgroup analysis showed that patients aged < 60 years, CEA < 5 ng/mL or CA19-9 < 35 U/mL, obtained a survival advantage from palliative gastrectomy. In fact, palliative gastrectomy doubled overall survival for patients who had normal CEA and/or normal CA19-9. Conclusions. Palliative gastrectomy prolongs the survival of metastatic gastric cancer patients with normal CEA and/or CA19-9 level at the time of diagnosis. PMID- 27990158 TI - Chronic Functional Constipation and Encopresis in Children in Relationship with the Psychosocial Environment. AB - Functional constipation is an issue for both the patient and his/her family, affecting the patient's psychoemotional balance, social relations, and their harmonious integration in the school environment. We aimed to highlight the connection between chronic constipation and encopresis and the patient's psychosocial and family-related situation. Material and Method. 57 patients with ages spanning from 6 to 15 were assessed within the pediatric gastroenterology ward. Sociodemographic, medical, and psychological data was recorded. The collected data was processed using the SPSS 20 software. Results. The study group consisted of 57 children diagnosed with encopresis (43 boys (75.44%) and 14 girls (24.56%)), M = 10.82 years. It was determined that most of the children came from urban families with a poor socioeducational status. We identified a level of studies of 11.23 +/- 5.56 years in mothers, while fathers had an average number of 9.35 +/- 4.53 years of study. We also found a complex relationship between encopretic episodes and school performances (F = 7.968, p = 0.001, 95% Cl). Children with encopresis were found to have more anxiety/depression symptoms, greater social problems, more disruptive behavior, and poorer school performance. Conclusions. The study highlights the importance of the family environment and socioeconomic factors in manifestations of chronic constipation and encopresis. PMID- 27990159 TI - Changes in IL-2 and IL-10 during Chronic Administration of Isoniazid, Nevirapine, and Paracetamol in Rats. AB - The aim of this study was to illustrate the initial subclinical drug-induced liver injury and the associated adaptive immune response by monitoring for the changes in plasma IL-2, IL-10, and some cytochrome P450 activity during chronic administration of nevirapine (NVP), isoniazid (INH), and paracetamol (PAR) in rats without clinical hepatotoxicity. Male Sprague-Dawley (SD) rats were divided into four groups (saline (S), NVP, INH, and PAR) of 25 animals each. The drugs were administered daily for 42 days at therapeutic doses (NVP 200 mg/kg, PAR 500 mg/kg, and INH 20 mg/kg) to the respective groups by oral gavage and five rats per group were sacrificed weekly. All the three drugs induced a subclinical liver injury in the first 2-3 weeks followed by healing, indicating adaption. The liver injury was pathologically similar and was associated with immune stimulation and increased cytochrome P450 activity. NVP- and PAR-induced liver injury lasted up to 14 days while that for INH lasted for 28 days. NVP-induced liver injury was associated with increased IL-2, CD4 count, and CYP3A2 activity, followed by increased IL-10 during the healing phase. In conclusion, the initial drug-induced subclinical liver injury, its spontaneous healing, and the associated adaptive immune response have been demonstrated. PMID- 27990160 TI - The Roles of PI3K/AKT/mTOR and MAPK/ERK Signaling Pathways in Human Pheochromocytomas. AB - Objectives. The roles of PI3K/AKT/mTOR and MAPK/ERK pathways involved in the pathogenesis of pheochromocytoma and paraganglioma (PPGL) were demonstrated mostly by in vitro studies with rat or mouse cells and were mainly studied at transcriptional level. This study aimed to investigate the effect of these pathways on the proliferation of human PPGL cells and the activation of these pathways in PPGLs. Methods. Human PPGL cells were treated with sunitinib and inhibitors of PI3K (LY294002), MEK1/2 (U0126), and mTORC1/2 (AZD8055). Cell proliferation was detected by MTT assay. Protein phosphorylation was detected by Western blotting. Results. In most PPGLs, AKT, ERK1/2, and mTOR were activated. LY294002 (10 MUM), U0126 (10 MUM), AZD8055 (1 MUM), and sunitinib (1 MUM) inhibited PPGL cell proliferation in ten primary cultures of tissues, including four from patients with gene mutations. MEK1/2 inhibitor decreased mTOR phosphorylation. Inhibition of mTOR reduced phosphorylation of AKT and ERK1/2. Sunitinib inhibited phospho-ERK1/2 and phospho-mTOR. Conclusion. Our study suggested that PI3K/AKT/mTOR and MAPK/ERK signaling pathways play vital roles in human PPGL and are activated in most PPGLs. Inhibiting multiple pathways might be a novel therapeutic approach for PPGLs. PMID- 27990161 TI - Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells. AB - Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease. PMID- 27990162 TI - The Changes of Serum Leptin and Kisspeptin Levels in Chinese Children and Adolescents in Different Pubertal Stages. AB - The aim of the study is to investigate the changes of serum leptin and kisspeptin levels in children and adolescents with different pubertal stages and nutritional states. A total of 647 Chinese children and adolescents were recruited, and serum estradiol, testosterone, pituitary gonadotropins, leptin, and kisspeptin levels were measured. The results showed that serum leptin levels of boys in T2 stage were the highest among the five stages, while they showed a gradual increase from T1 to T5 stage in girls and reached the highest in T5 stage (P < 0.05). Conversely, serum kisspeptin levels of boys were higher in T4 and T5 stages than those in T1 stage, while its levels of girls were the highest in T2 stage, 21.4% higher than those in T1 stage (P < 0.05). Both leptin and kisspeptin levels were positively correlated with BMI, WC, and weight in all boys and girls (all P < 0.05). In conclusion, kisspeptin levels were firstly found to be notably changed in pubertal stages and nutritional status in Chinese children and adolescents with a significant sexual dimorphism. Obese/overweight girls had higher kisspeptin levels, and there was a positive correlation between kisspeptin and FSH and LH and obesity-related parameters in all boys and girls. PMID- 27990163 TI - The Effect of Epidural Analgesia on the Delivery Outcome of Induced Labour: A Retrospective Case Series. AB - Objective. To investigate whether the use of epidural analgesia during induced labour was a risk factor for instrumental vaginal delivery and caesarean section (CS) delivery. Study Design. This was a retrospective case series of primigravidae women being induced at term for all indications with a normal body mass index (BMI) at booking and under the age of 40 years. Results. We identified 1,046 women who fulfilled the inclusion criteria of which 31.2% had an epidural analgesia. Those with an epidural analgesia had significantly greater maternal age, higher BMI, greater percentage of oxytocin usage, and a longer first and second stage of labour. Women with an epidural analgesia had a higher instrumental delivery (37.9% versus 16.4%; p < 0.001) and CS delivery rate (26% versus 10.1%; p < 0.001). Multivariable analysis indicated that the use of an epidural was not a risk factor for a CS delivery but was a risk factor for an instrument-assisted delivery (adjusted OR = 3.63; 95% CI: 2.51-5.24; p < 0.001). Conclusion. Our study supports the literature evidence that the use of an epidural increases the instrumental delivery rates. It has also added that there is no effect on CS delivery and the observed increase is due to the presence of confounding factors. PMID- 27990164 TI - Phase I/II Trial of Autologous Bone Marrow Stem Cell Transplantation with a Three Dimensional Woven-Fabric Scaffold for Periodontitis. AB - Regenerative medicine is emerging as a promising option, but the potential of autologous stem cells has not been investigated well in clinical settings of periodontal treatment. In this clinical study, we evaluated the safety and efficacy of a new regenerative therapy based on the surgical implantation of autologous mesenchymal stem cells (MSCs) with a biodegradable three-dimensional (3D) woven-fabric composite scaffold and platelet-rich plasma (PRP). Ten patients with periodontitis, who required a surgical procedure for intrabony defects, were enrolled in phase I/II trial. Once MSCs were implanted in each periodontal intrabony defect, the patients were monitored during 36 months for a medical exam including laboratory tests of blood and urine samples, changes in clinical attachment level, pocket depth, and linear bone growth (LBG). All three parameters improved significantly during the entire follow-up period (p < 0.0001), leading to an average LBG of 4.7 mm after 36 months. Clinical mobility measured by Periotest showed a decreasing trend after the surgery. No clinical safety problems attributable to the investigational MSCs were identified. This clinical trial suggests that the stem cell therapy using MSCs-PRP/3D woven-fabric composite scaffold may constitute a novel safe and effective regenerative treatment option for periodontitis. PMID- 27990165 TI - Factors Associated with Successful Mentoring of Parents Addressing Childhood Obesity: A Mixed Methods Approach. AB - Objective. Parents mentoring other parents as a behavioral intervention for child obesity is novel with limited data describing the experience and dynamics of this approach. This study aimed to describe the experiences of parent mentors and the self-efficacy and attitudes of their mentees in the context of a clinical trial for childhood obesity. Methods. The context for this study was a randomized clinical trial using either parent mentors or a community health worker engaging parents of obese children in behavioral change over six months. Parent mentors were interviewed at the mid-point of the intervention using a semistructured questionnaire to elicit their perceptions and experiences during the process of mentoring. Parent mentees completed a survey assessing their self-efficacy, perception of the parent mentor, and attitudes and beliefs related to their child's weight. Results. The qualitative analysis of parent mentor interviews indicated high commitment despite their nonprofessional status, facing challenges of engagement with fellow parents and attitudes of persistence and being nonjudgmental. The parent mentee ratings of parent mentors were overall very high and similar to the ratings of a community health worker (paraprofessional). Conclusion. The data suggest that a parent mentor model of intervention for child obesity is an acceptable mode of approaching behavior change in the Hispanic population around childhood obesity with potential for scalability if proven effective. PMID- 27990166 TI - Morbidity and Mortality in Preterm Infants following Antacid Use: A Retrospective Audit. AB - Background and Objectives. Antacids are often prescribed to preterm infants due to misdiagnosis of gastro-oesophageal reflux. This suppresses gastric acidity, a major defence mechanism against infection. This study aims to determine if ranitidine and omeprazole use in very low birth weight (VLBW) neonates, <1500 grams, is associated with increased risk of late onset sepsis, necrotising enterocolitis (NEC), and mortality. Methods. Retrospective analysis was conducted on neonates, <1500 grams, born and admitted into the Neonatal Intensive Care Unit at The Canberra Hospital during the period from January 2008 to December 2012. Information regarding late onset sepsis, NEC, mortality, ranitidine/omeprazole use, and other neonatal/hospital factors was collected for each neonate. Results. 360 neonates were evaluated, 64 received ranitidine and/or omeprazole, and 296 had not. There were no statistically significant differences in incidence of late onset sepsis (OR = 0.52, CI = 0.24-1.1, and p = 0.117), NEC Stage 2 and above (OR = 0.4, CI = 0.05-3.2, and p = 0.7), or mortality (OR = 0.35, CI = 0.08-1.5, and p = 0.19) between the two groups. After adjusting significant differences in neonatal and hospital factors, risk of late onset sepsis was significantly lower in those that received ranitidine/omeprazole (OR = 0.28, CI = 0.13-0.65, and p = 0.003). Conclusions. Ranitidine and omeprazole use in VLBW preterm infants may not be associated with an increased risk of infection, NEC, and mortality. PMID- 27990167 TI - Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer. AB - OBJECTIVE: Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor beta (TGFbeta) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations. METHODS: Patients with advanced or metastatic cancer were enrolled into this single-center, 3 period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. RESULTS: Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-infinity) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. CONCLUSIONS: In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation. PMID- 27990168 TI - Traditional Chinese Mind and Body Exercises for Promoting Balance Ability of Old Adults: A Systematic Review and Meta-Analysis. AB - The purpose of this study was to provide a quantitative evaluation of the effectiveness of traditional Chinese mind and body exercises in promoting balance ability for old adults. The eligible studies were extensively searched from electronic databases (Medline, CINAHL, SportDicus, and Web of Science) until 10 May 2016. Reference lists of relevant publications were screened for future hits. The trials used randomized controlled approaches to compare the effects of traditional Chinese mind and body exercise (TCMBE) on balance ability of old adults that were included. The synthesized results of Berg Balance Scale (BBS), Timed Up and Go Test (TUG), and static balance with 95% confidence intervals were counted under a random-effects model. Ten studies were selected based on the inclusion criteria, and a total of 1,798 participants were involved in this review. The results of the meta-analysis showed that TCMBE had no significant improvement on BBS and TUG, but the BBS and TUG could be obviously improved by prolonging the intervention time. In addition, the results showed that TCMBE could significantly improve the static balance compared to control group. In conclusion, old adults who practiced TCMBE with the time not less than 150 minutes per week for more than 15 weeks could promote the balance ability. PMID- 27990169 TI - A Correlation Study between Two Adjacent Same-Meridian Acupoints after Laser Needle Acupuncture with Optical Coherence Tomography and Diffuse Reflectance Spectra. AB - This study is to investigate the correlations among Sanjian (LI3), Hegu (LI4), and Yangxi (LI5) acupoints and their corresponding nonacupoints on the Yangming Large Intestine Meridian of Hand before and after laser irradiation using optical coherence tomography (OCT) and diffuse reflectance spectra. The experiment was conducted on 10 healthy people. A 658 nm laser with 50 mW output power was used for irradiating LI4, LI5 acupoints and their corresponding nonacupoints. As to LI4 acupoint with laser irradiation for duration of 15 or 45 minutes, the OCT backscattered light intensities of LI4 and LI5 acupoints increased significantly, and the reflectance intensities (RIs) of the LI3, LI4, and LI5 acupoints decreased significantly. As to LI5 acupoint with laser irradiation for duration of 15 or 45 minutes, the changes of OCT backscattered light intensities of the corresponding irradiated acupoint and LI4 acupoint increased significantly, and the RIs decreased significantly. However, the OCT backscattered light intensities and RIs for their nonacupoints were almost not changed. The results show that an association exists between two adjacent same-meridian acupoints on the same meridian after laser-needle acupuncture to some extent. PMID- 27990170 TI - Evaluation of Wound Healing Properties of Grape Seed, Sesame, and Fenugreek Oils. AB - Background. Medicinal plants have proved at all times to be a powerful remedy for health care. Accordingly, grape seed, sesame, and fenugreek extracted oils with pharmacological properties are investigated as wound treatments. This study assesses the potential of our oils for healing wounds induced on rats. Methods. Phytochemical analyses of oils have involved: quality value, polyphenol, chlorophylls, carotene, and fatty acids. Antibacterial activity was carried out. Antioxidant activity was evaluated: the scavenging effect on DPPH radicals, the reducing power, and beta-carotene discoloration. Uniform wound excision was induced on rats dorsum randomly divided into five groups: groups treated with "CICAFLORA(r)" and tested oils and untreated one. The posthealing biopsies were histologically assessed. Results. Wound biopsies treated with oils showed the best tissue regeneration compared to control groups. Groups treated with our oils and "CICAFLORA" had higher wound contraction percentage. Polyunsaturated fatty acids in oils act as inflammatory mediators increasing neovascularization, extracellular remodeling, migration, and cell differentiation. Wound healing effect was attributed to antibacterial and antioxidant synergy. Conclusion. According to findings, oils showed better activity in wound healing compared to "CICAFLORA" due to a phytoconstituents synergy. However, clinical trials on humans are necessary to confirm efficacy on human pathology. PMID- 27990171 TI - Challenge of Innovative Technology: How to Improve Efficiency of Korean Medicine? PMID- 27990173 TI - Working and Environmental Factors on Job Burnout: A Cross-sectional Study Among Nurses. AB - BACKGROUND: Burnout is a problem that impacts on the staff management costs and on the patient care quality. OBJECTIVE: This work aimed to investigate some psychosocial factors related to burnout. Specifically, we explored the sample characteristics for moderate/high emotional exhaustion, cynicism and professional inefficacy, as well as the relationship between both working and environmental variables and burnout. METHOD: A cross-sectional study involving 307 nurses from one Italian hospital was carried out. A self-reported questionnaire was used to collect data. Data analysis was performed by using SPSS 19.0. RESULTS: The results showed that there was a significant difference between nurses with low and moderate/high burnout in all the three components in almost all the examined organizational variables. In addition, we found that the aspects of working life had a significant impact on the three dimensions of burnout. CONCLUSIONS: The findings of this study not only can provide useful basis for future research in the field, but also can offer practical suggestions for improving nursing practice and promote effective workplace, thus reducing the risk burnout among nurses. PMID- 27990174 TI - Determinants of exclusive breastfeeding practice to infants aged less than six months in Offa district, Southern Ethiopia: a cross-sectional study. AB - BACKGROUND: World Health Organization (WHO) recommends timely initiation of breastfeeding after birth and only feeding breast milk to infants during the first 6 months of life. It was estimated that exclusive breastfeeding can reduce infant deaths by 13%. The practice of exclusive breastfeeding is suboptimal in many parts of Ethiopia to a varied extent. Factors associated with exclusive breastfeeding practice and the proportion of its practice was not well documented in Offa district. Therefore, this study was aimed to assess the determinants of exclusive breastfeeding in the first 6 months of life in Offa district, Southern Ethiopia. METHODS: A community-based cross-sectional study was carried out in 396 mothers of infants younger than 6 months using random sampling. Data were collected from mothers of the infants by trained interviewers. Exclusive breastfeeding was measured by the history of infant feeding in the prior 24 h. Pretested and structured questionnaires adopted from standard questionnaires and Ethiopia linkages modules were used. Multivariate logistic regression was used to identify factors significantly influencing exclusive breastfeeding practice. RESULTS: Based on findings of this study of 396 participants, the proportion of exclusive breastfeeding was 78.0% and awareness of exclusive breastfeeding and bottle feeding were 85.6 and 6.1% respectively. About 6% of infants were given prelacteal feeds. The number of infants fed cow milk was 12.9%, formula 7.8%, water 8.5%, fruits and semisolids 1.5%, over 24 h prior to the survey. The initiation of breastfeeding within one h (AOR 2.2; 95% CI 1.1, 4.27), attending formal education (AOR 4; 95% CI 2.20, 7.25), having an awareness on the benefits of exclusive breastfeeding (AOR 6; 95% CI 3.10, 11.70) and knowledge of colostrum feeding (AOR 2.1; 95% CI 1.11, 4.27) had a statistically significant association with exclusive breastfeeding in the study area. CONCLUSIONS: The practice of exclusive breastfeeding as well as awareness was worthy in Offa district. Additionally the proportion of bottle feeding use was small. However, feeding other than breast milk was associated with the perception that breast milk alone was insufficient for their child. Strategies on promoting exclusive breastfeeding practice must focus on strengthening women's education and awareness creation activities further. PMID- 27990172 TI - Nutritional modulation of endogenous glucagon-like peptide-1 secretion: a review. AB - BACKGROUND: The positive influences of glucagon-like peptide-1 (GLP-1) on blood glucose homeostasis, appetite sensations, and food intake provide a strong rationale for its therapeutic potential in the nutritional management of obesity and type 2 diabetes. AIM: To summarize GLP-1 physiology and the nutritional modulation of its secretion in the context of obesity and type 2 diabetes management. FINDINGS: GLP-1 is mainly synthesized and secreted by enteroendocrine L-cells of the gastrointestinal tract. Its secretion is partly mediated by the direct nutrient sensing by G-protein coupled receptors which specifically bind to monosaccharides, peptides and amino-acids, monounsaturated and polyunsaturated fatty acids as well as to short chain fatty acids. Foods rich in these nutrients, such as high-fiber grain products, nuts, avocados and eggs also seem to influence GLP-1 secretion and may thus promote associated beneficial outcomes in healthy individuals as well as individuals with type 2 diabetes or with other metabolic disturbances. CONCLUSION: The stimulation of endogenous GLP-1 secretion by manipulating the composition of the diet may be a relevant strategy for obesity and type 2 diabetes management. A better understanding of the dose-dependent effects as well as the synergistic effects of nutrients and whole foods is needed in order to develop recommendations to appropriately modify the diet to enhance GLP-1 beneficial effects. PMID- 27990175 TI - The development of non-coding RNA ontology. AB - Identification of non-coding RNAs (ncRNAs) has been significantly improved over the past decade. On the other hand, semantic annotation of ncRNA data is facing critical challenges due to the lack of a comprehensive ontology to serve as common data elements and data exchange standards in the field. We developed the Non-Coding RNA Ontology (NCRO) to handle this situation. By providing a formally defined ncRNA controlled vocabulary, the NCRO aims to fill a specific and highly needed niche in semantic annotation of large amounts of ncRNA biological and clinical data. PMID- 27990176 TI - Enhanced production of 2,3-butanediol by engineered Saccharomyces cerevisiae through fine-tuning of pyruvate decarboxylase and NADH oxidase activities. AB - BACKGROUND: 2,3-Butanediol (2,3-BD) is a promising compound for various applications in chemical, cosmetic, and agricultural industries. Pyruvate decarboxylase (Pdc)-deficient Saccharomyces cerevisiae is an attractive host strain for producing 2,3-BD because a large amount of pyruvate could be shunted to 2,3-BD production instead of ethanol synthesis. However, 2,3-BD yield, productivity, and titer by engineered yeast were inferior to native bacterial producers because of the following metabolic limitations. First, the Pdc deficient yeast showed growth defect due to a shortage of C2-compounds. Second, redox imbalance during the 2,3-BD production led to glycerol formation that lowered the yield. RESULTS: To overcome these problems, the expression levels of Pdc from a Crabtree-negative yeast were optimized in S. cerevisiae. Specifically, Candida tropicalis PDC1 (CtPDC1) was used to minimize the production of ethanol but maximize cell growth and 2,3-BD productivity. As a result, productivity of the BD5_G1CtPDC1 strain expressing an optimal level of Pdc was 2.3 folds higher than that of the control strain in flask cultivation. Through a fed-batch fermentation, 121.8 g/L 2,3-BD was produced in 80 h. NADH oxidase from Lactococcus lactis (noxE) was additionally expressed in the engineered yeast with an optimal activity of Pdc. The fed-batch fermentation with the optimized 2-stage aeration control led to production of 154.3 g/L 2,3-BD in 78 h. The overall yield of 2,3-BD was 0.404 g 2,3-BD/g glucose which corresponds to 80.7% of theoretical yield. CONCLUSIONS: A massive metabolic shift in the engineered S. cerevisiae (BD5_G1CtPDC1_nox) expressing NADH oxidase was observed, suggesting that redox imbalance was a major bottleneck for efficient production of 2,3-BD by engineered yeast. Maximum 2,3-BD titer in this study was close to the highest among the reported microbial production studies. The results demonstrate that resolving both C2-compound limitation and redox imbalance is critical to increase 2,3-BD production in the Pdc-deficient S. cerevisiae. Our strategy to express fine-tuned PDC and noxE could be applicable not only to 2,3-BD production, but also other chemical production systems using Pdc-deficient S. cerevisiae. PMID- 27990177 TI - matK-QR classifier: a patterns based approach for plant species identification. AB - BACKGROUND: DNA barcoding is widely used and most efficient approach that facilitates rapid and accurate identification of plant species based on the short standardized segment of the genome. The nucleotide sequences of maturaseK (matK) and ribulose-1, 5-bisphosphate carboxylase (rbcL) marker loci are commonly used in plant species identification. Here, we present a new and highly efficient approach for identifying a unique set of discriminating nucleotide patterns to generate a signature (i.e. regular expression) for plant species identification. METHODS: In order to generate molecular signatures, we used matK and rbcL loci datasets, which encompass 125 plant species in 52 genera reported by the CBOL plant working group. Initially, we performed Multiple Sequence Alignment (MSA) of all species followed by Position Specific Scoring Matrix (PSSM) for both loci to achieve a percentage of discrimination among species. Further, we detected Discriminating Patterns (DP) at genus and species level using PSSM for the matK dataset. Combining DP and consecutive pattern distances, we generated molecular signatures for each species. Finally, we performed a comparative assessment of these signatures with the existing methods including BLASTn, Support Vector Machines (SVM), Jrip-RIPPER, J48 (C4.5 algorithm), and the Naive Bayes (NB) methods against NCBI-GenBank matK dataset. RESULTS: Due to the higher discrimination success obtained with the matK as compared to the rbcL, we selected matK gene for signature generation. We generated signatures for 60 species based on identified discriminating patterns at genus and species level. Our comparative assessment results suggest that a total of 46 out of 60 species could be correctly identified using generated signatures, followed by BLASTn (34 species), SVM (18 species), C4.5 (7 species), NB (4 species) and RIPPER (3 species) methods As a final outcome of this study, we converted signatures into QR codes and developed a software matK-QR Classifier (http://www.neeri.res.in/matk_classifier/index.htm), which search signatures in the query matK gene sequences and predict corresponding plant species. CONCLUSIONS: This novel approach of employing pattern-based signatures opens new avenues for the classification of species. In addition to existing methods, we believe that matK-QR Classifier would be a valuable tool for molecular taxonomists enabling precise identification of plant species. PMID- 27990178 TI - Non-canonical Helitrons in Fusarium oxysporum. AB - BACKGROUND: Helitrons are eukaryotic rolling circle transposable elements that can have a large impact on host genomes due to their copy-number and their ability to capture and copy genes and regulatory elements. They occur widely in plants and animals, and have thus far been relatively little investigated in fungi. RESULTS: Here, we comprehensively survey Helitrons in several completely sequenced genomes representing the F. oxysporum species complex (FOSC). We thoroughly characterize 5 different Helitron subgroups and determine their impact on genome evolution and assembly in this species complex. FOSC Helitrons resemble members of the Helitron2 variant that includes Helentrons and DINEs. The fact that some Helitrons appeared to be still active in FOSC provided the opportunity to determine whether Helitrons occur as a circular intermediate in FOSC. We present experimental evidence suggesting that at least one Helitron subgroup occurs with joined ends, suggesting a circular intermediate. We extend our analyses to other Pezizomycotina and find that most fungal Helitrons we identified group phylogenetically with Helitron2 and probably have similar characteristics. CONCLUSIONS: FOSC genomes harbour non-canonical Helitrons that are characterized by asymmetric terminal inverted repeats, show hallmarks of recent activity and likely transpose via a circular intermediate. Bioinformatic analyses indicate that they are representative of a large reservoir of fungal Helitrons that thus far has not been characterized. PMID- 27990179 TI - Analysis of Urine, Oral fluid and Fingerprints by Liquid Extraction Surface Analysis Coupled to High Resolution MS and MS/MS - Opportunities for Forensic and Biomedical Science. AB - Liquid Extraction Surface Analysis (LESA) is a new, high throughput tool for ambient mass spectrometry. A solvent droplet is deposited from a pipette tip onto a surface and maintains contact with both the surface and the pipette tip for a few seconds before being re-aspirated. The technique is particularly suited to the analysis of trace materials on surfaces due to its high sensitivity and low volume of sample removal. In this work, we assess the suitability of LESA for obtaining detailed chemical profiles of fingerprints, oral fluid and urine, which may be used in future for rapid medical diagnostics or metabolomics studies. We further show how LESA can be used to detect illicit drugs and their metabolites in urine, oral fluid and fingerprints. This makes LESA a potentially useful tool in the growing field of fingerprint chemical analysis, which is relevant not only to forensics but also to medical diagnostics. Finally, we show how LESA can be used to detect the explosive material RDX in contaminated artificial fingermarks. PMID- 27990180 TI - The effect of RGD peptide on 2D and miniaturized 3D culture of HEPM cells, MSCs, and ADSCs with alginate hydrogel. AB - Advancements in tissue engineering require the development of new technologies to study cell behavior in vitro. This study focuses on stem cell behavior within various miniaturized three-dimensional (3D) culture conditions of alginate biomaterials modified with the Arg-Gly-Asp (RGD) peptide known for its role in cell adhesion/attachment. Human embryonic palatal mesenchyme (HEPM) cells, bone marrow derived mesenchymal stem cells (MSCs), and human adipose derived stem cells (ADSCs) were cultured on a flat hydrogel of different concentrations of alginate-RGD, and in the miniaturized 3D core of microcapsules with either a 2% alginate or 2% alginate-RGD shell. The core was made of 0%, 0.5%, or 2% alginate RGD. Cell spreading was observed in all systems containing the RGD peptide, and the cell morphology was quantified by measuring the cell surface area and circularity. In all types of stem cells, there was a significant increase in the cell surface area (p < 0.05) and a significant decrease in cell circularity (p < 0.01) in alginate-RGD conditions, indicating that cells spread much more readily in environments containing the peptide. This control over the cell spreading within a 3D microenvironment can help to create the ideal biomimetic condition in which to conduct further studies on cell behavior. PMID- 27990181 TI - Risk of Cerebral Embolization with Caseous Calcification of the Mitral Annulus: Review Article. AB - BACKGROUND: Caseous calcification of the mitral annulus (CCMA) is believed to have a benign prognosis. Several authors have recommended conservative management in asymptomatic patients. However, the prevalence of cerebrovascular events (CVE) in patients with CCMA has never been evaluated before. The aims of this study are to investigate whether patients with CCMA are at increased risk of cerebral embolization, and to determine whether elective surgical resection of CCMA should be considered to prevent a cardioembolic stroke. METHODS: A comprehensive literature search was obtained from MEDLINE via PubMed.gov, ScienceDirect.com, and Google Scholar using the following search queries: caseous calcification of the mitral annulus, intracardiac pseudotumor, mitral annular calcification, and cardioembolic stroke. RESULTS: From our initial search that yielded 1,502 articles, we identified a total of 130 patients with CCMA reported in 86 publications. Literature review revealed that the prevalence of CVE associated with CCMA is 19.2% (25 of 130) which is significantly higher than the prevalence of CVE reported with mitral annular calcification (MAC), 11.8% (214 of 1818) (range 4.8% to 24.1%) (P = 0.01796) (odds ratio = 1.78; 0.95 confidence interval = 1.1278 - 2.8239). Only four of 25 (16.0%) patients with CCMA who suffered a CVE had history of atrial fibrillation (AF). CONCLUSION: Based on our review, it would be reasonable to consider elective surgical resection of CCMA in asymptomatic patients who are good surgical candidates, because patients with CCMA may be at increased risk of embolic strokes, which are unrelated to AF. PMID- 27990182 TI - Effect of ATP-binding Cassette Transporter A1 (ABCA1) Gene Polymorphisms on Plasma Lipid Variables and Common Demographic Parameters in Greek Nurses. AB - OBJECTIVE: The present study is on line with our previous studies evaluating the influence of ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms on the lipid variables of Greek student-nurses. The current study was undertaken to (1) estimate the influence of variant(s) such as rs2066715 (V825I), R219K, R1587K, I883M of ABCA1 gene on lipid variables and (2) evaluate the effect of all four ABCA1 polymorphisms on common demographic parameters. METHODS: The study population involved 432 unrelated nurses (86 men) who were genotyped for ABCA1 polymorphisms and correlated according to lipid variables [total cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) A] and demographic parameters (age, gender, BMI, waist circumference). RESULTS: According to lipid variables concentration there was no difference between genotypes and alleles of V825I, R219K and I883M polymorphisms. The LDL-C concentration was 13% lower in RR compared with RK genotype (100.7 vs. 113.9 mg/dl, p=0.013) of R1587K gene polymorphism. In regression analysis the effects of age, gender and only R1587K gene polymorphism on LDL-C concentrations were proved significant. Additionally, LDL-C was increased (by 1.29 mg/dl on average) by every year of increase of age. Moreover, females had lower LDL-C concentrations as compared with males. CONCLUSION: Findings suggested that only R1587K polymorphism of ABCA1 gene was associated with lipid variables, age, and gender of Greek nurses. These findings may be helpful in assessing the risk factors for premature coronary heart disease and distinct individuals with lower/higher atherosclerotic burden. PMID- 27990183 TI - Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders. AB - BACKGROUND: In recent years, a large number of studies around the world have led to the identification of causal genes for hereditary types of common and rare neurological and psychiatric disorders. OBJECTIVE: To explore the functional and genomic features of known human genes mutated in neuropsychiatric disorders. METHODS: A systematic search was used to develop a comprehensive catalog of genes mutated in neuropsychiatric disorders (NPD). Functional enrichment and protein protein interaction analyses were carried out. A false discovery rate approach was used for correction for multiple testing. RESULTS: We found several functional categories that are enriched among NPD genes, such as gene ontologies, protein domains, tissue expression, signaling pathways and regulation by brain expressed miRNAs and transcription factors. Sixty six of those NPD genes are known to be druggable. Several topographic parameters of protein-protein interaction networks and the degree of conservation between orthologous genes were identified as significant among NPD genes. CONCLUSION: These results represent one of the first analyses of enrichment of functional categories of genes known to harbor mutations for NPD. These findings could be useful for a future creation of computational tools for prioritization of novel candidate genes for NPD. PMID- 27990184 TI - The Role of Occlusion in the Dental Implant and Peri-implant Condition: A Review. AB - Dental implants have become a widely used dental treatment approach. It is important to identify factors that can be detrimental to dental implants and the peri-implant complex. There is controversy regarding whether occlusion plays a role in the implant and peri-implant condition. The present study aims to review the scientific literature regarding this topic. Animal and human studies, and previous reviews on the topic are included and presented. There is a wide heterogeneity among study designs. Several articles demonstrated that occlusion and occlusion overload could detrimentally affect the peri-implant condition, while other articles did not support these results. More studies are needed to help understand the mechanisms by which occlusion might play a role in the peri implant condition. PMID- 27990185 TI - Long-term Stability of Soft Tissue Esthetic Outcomes Following Conventional Single Implant Treatment in the Anterior Maxilla: 10-12 Year Results. AB - PURPOSE: The present study aimed to evaluate the long-term stability of esthetic outcomes of soft tissue around maxillary anterior single-tooth implants after 10 to-12 years of loading. METHODS: Patients who had been treated for single-tooth implants in the anterior maxilla between February 2000 and July 2002 were invited to participate in the study. All implants had been placed according to delayed implant placement and conventional loading protocols without any connective tissue graft or papilla preservation flaps. Pink Esthetic Score (PES) was rated using standardized clinical photographs to assess the esthetic outcomes of the implant treatment at the time of crown placement and at time of follow-up examination which was at least 10 years after the crown placement. RESULTS: A total of 19 patients were included. The mean score of PES was 11.63 (SD 1.61; range 7-14) at baseline. After 10-to-12 years of function, a mean PES score of 11.05 (SD 2.09; range 6-14) was recorded. No significant differences were found in the esthetic outcomes, categorized based on clinically relevant levels, between the baseline and follow-up session (p>0.05). CONCLUSION: Within limitation of the present study, it can be concluded that the esthetic outcomes of soft tissue around the maxillary anterior single-tooth implants placed using conventional implant placement technique remained stable in the long-term. PMID- 27990186 TI - An Optical System to Monitor the Displacement Field of Glass-fibre Posts Subjected to Thermal Loading. AB - Endocanalar posts are necessary to build up and retain coronal restorations but they do not reinforce dental roots. It was observed that the dislodgement of post retained restorations commonly occurs after several years of function and long term retention may be influenced by various factors such as temperature changes. Temperature changes, in fact, produce micrometric deformations of post and surrounding tissues/materials that may generate high stress concentrations at the interface thus leading to failure. In this study we present an optical system based on the projection moire technique that has been utilized to monitor the displacement field of endocanalar glass-fibre posts subjected to temperature changes. Measurements were performed on forty samples and the average displacement values registered at the apical and middle region were determined for six different temperature levels. A total of 480 displacement measurements was hence performed. The values of the standard deviation computed for each of the tested temperatures over the forty samples appear reasonably small which proves the robustness and the reliability of the proposed optical technique. The possible implications for the use of the system in the applicative context were discussed. PMID- 27990187 TI - Diagnosis of Lingual Atrophic Conditions: Associations with Local and Systemic Factors. A Descriptive Review. AB - Atrophic glossitis is a condition characterised by absence of filiform or fungiform papillae on the dorsal surface of the tongue. Consequently, the ordinary texture and appearance of the dorsal tongue, determined by papillary protrusion, turns into a soft and smooth aspect. Throughout the years, many factors, both local and systemic, have been associated with atrophic glossitis as the tongue is currently considered to be a mirror of general health. Moreover, various tongue conditions were wrongly diagnosed as atrophic glossitis. Oral involvement can conceal underlying systemic conditions and, in this perspective, the role of clinicians is fundamental. Early recognition of oral signs and symptoms, through a careful examination of oral anatomical structures, plays a crucial role in providing patients with a better prognosis. PMID- 27990189 TI - Effects of Modification of Pain Protocol on Incidence of Post Operative Nausea and Vomiting. AB - BACKGROUND: A Perioperative Surgical Home (PSH) care model applies a standardized multidisciplinary approach to patient care using evidence-based medicine to modify and improve protocols. Analysis of patient outcome measures, such as postoperative nausea and vomiting (PONV), allows for refinement of existing protocols to improve patient care. We aim to compare the incidence of PONV in patients who underwent primary total joint arthroplasty before and after modification of our PSH pain protocol. METHODS: All total joint replacement PSH (TJR-PSH) patients who underwent primary THA (n=149) or TKA (n=212) in the study period were included. The modified protocol added a single dose of intravenous (IV) ketorolac given in the operating room and oxycodone immediate release orally instead of IV Hydromorphone in the Post Anesthesia Care Unit (PACU). The outcomes were (1) incidence of PONV and (2) average pain score in the PACU. We also examined the effect of primary anesthetic (spinal vs. GA) on these outcomes. The groups were compared using chi-square tests of proportions. RESULTS: The incidence of post-operative nausea in the PACU decreased significantly with the modified protocol (27.4% vs. 38.1%, p=0.0442). There was no difference in PONV based on choice of anesthetic or procedure. Average PACU pain scores did not differ significantly between the two protocols. CONCLUSION: Simple modifications to TJR-PSH multimodal pain management protocol, with decrease in IV narcotic use, resulted in a lower incidence of postoperative nausea, without compromising average PACU pain scores. This report demonstrates the need for continuous monitoring of PSH pathways and implementation of revisions as needed. PMID- 27990188 TI - Application of Laser Irradiation for Restorative Treatments. AB - Nowadays, lasers are widely used in many fields of medicine. Also, they can be applied at many branches of dental practice such as diagnosis, preventive procedures, restorative treatments, and endodontic therapies. Procedures like caries removal, re-mineralization, and vital pulp therapy are the most noticeable effects of laser irradiation which has gained much attention among clinicians. With controlled and appropriate wavelength, they can help stimulating dentinogenesis, controlling pulpal hemorrhage, sterilization, healing of collagenic proteins, formation of a fibrous matrix, and inducing hard tissue barrier. Nevertheless, there are many controversies in literatures regarding their effects on the quality of bonded restorations. It hampered a wide application of lasers in some aspects of restorative dentistry and requirements to identify the best way to use this technology. The aim of this mini review is to explain special characteristics of laser therapy and to introduce the possible applications of laser devices for dental purposes. PMID- 27990190 TI - Spontaneous Osteonecrosis of the Knee: A Retrospective Analysis by Using MRI and DEXA. AB - OBJECTIVE: Although there are many etiology and prediction for prognosis of spontaneous osteonecrosis of the knee (SONK) by using radiological examinations, these issue have not been clarified yet. Furthermore, most of the studies evaluated them by only radiological examination such as magnetic resonance imaging (MRI), bone mineral density (BMD) in dual-energy X-ray abosorptiometry (DEXA) or plain X-ray. Therefore, we focused our investigation on the measurements of the affected area in MRI and BMD in DEXA, and whether these results were conected with the cause and prognosis of SONK or not. METHOD: A consecutive case series of two groups composed of ten osteoporotic patients who were suffering from SONK was considered. Based on the severity or duration of pain, one group was treated with surgical procedure which was unicompartmental knee arthroplasty (UKA), the other received conservative treatment. Both groups underwent DEXA in their distal femur and proximal tibia and all patients who took MRI measured the affected lesion in low and high intensity area on T2 weighted images. This data was analyzed from these areas and units. RESULTS: Significant decrease in regional bone density of the affected femoral condyle compared to the unaffected side was observed. However, the bone mineral density in the affected side was similar in the non-operative and surgical group. The area of the lesion which showed in both low and high intensity indicated that the operation group was significantly larger than the conservative group on T2 weighted images. CONCLUSION: The cause and prognosis of SONK have a close relationship with the size of the affected lesion and decreased bone mineral density. PMID- 27990191 TI - Relief of Lower Back and Leg Pain after Myelography. AB - INTRODUCTION: It is well-known that many patients will have adverse reactions such as headache and nausea after undergoing myelography, but we have often seen cases where symptoms such as lower back pain and leg pain were alleviated following myelography. To the best of our knowledge, such clinical cases of post myelographic alleviation have not been reported. MATERIALS AND METHODS: A total of 325 patients with a degenerative lumbar spinal disorder who underwent myelography were prospectively investigated at four hospitals from April 2012 to March 2014 to survey the post-myelographic alleviation of lower back and leg pain prospectively. The severities of lower back pain, leg pain and numbness of the lower extremities were evaluated and intermittent claudication distance was measured before myelography. The magnetic resonance imaging (MRI) findings and myelographic findings were also evaluated for the patients that their symptoms were improved. RESULTS: Thirty-five of 325 cases (10.8%) of these patients had their symptoms alleviated after undergoing myelography; 26 cases of lower back pain, two cases of leg pain, two cases of numbness of the lower extremity, and five cases of intermittent claudication. CONCLUSION: In the patients of a degenerative lumbar spinal disorder, about 10% cases with lower back pain or intermittent claudication had post-myelographic alleviation. Intradural injection therapy might be a therapeutic method to alleviate these symptoms. PMID- 27990192 TI - Long Term Results of Innovative Procedure in Surgical Management of Chronic Lymphedema. AB - BACKGROUND: Lymphedema is the result of impaired lymphatic drainage by the affected organ. This abnormality can be primary or secondary. Different operative approaches have been introduced to treat chronic lymphedema. MATERIALS AND METHODS: This retrospective study included 816 patients who were diagnosed with chronic lower extremity lymphedema and did not respond to non-operative management for at least six months. Data was collected over 25 years, between March 1987 and March 2013. Doppler ultrasonography of the deep venous system was routinely undertaken in all patients to confirm patency. The patients underwent surgery and their progress was followed for at least one year postoperatively. RESULTS: All patients were operated by the suggested technique and long term fallow-up which is a modified form of the Homan's technique. The outcome was excellent, and 89.2% of patients were free of complication and 2% had poor results. The most common complication was wound seroma and wound infection. CONCLUSION: The long term results and considering the difficulties associated with the treatment of chronic lymphedema and the variety of surgical options, our method achieved excellent results, and may be proposed for the standard operative procedure for treating intractable forms of this disease. PMID- 27990193 TI - Does Weather Matter? The Effect of Weather Patterns and Temporal Factors on Pediatric Orthopedic Trauma Volume. AB - OBJECTIVES: Orthopaedists often speculate how weather and school schedule may influence pediatric orthopedic trauma volume, but few studies have examined this. This study aims to determine: how do weather patterns, day, month, season and public school schedule influence the daily frequency of pediatric orthopedic trauma consults and admissions? METHODS: With IRB approval, orthopedic trauma data from a level 1 pediatric trauma center, including number of daily orthopedic trauma consults and admissions, were collected from July 2009 to March 2012. Historical weather data (high temperatures, precipitation and hours of daylight), along with local public school schedule data were collected for the same time period. Univariate and multivariate regression models were used to show the average number of orthopedic trauma consults and admissions as a function of weather and temporal variables. RESULTS: High temperature, precipitation, month and day of the week significantly affected the number of daily consults and admissions. The number of consults and admissions increased by 1% for each degree increase in temperature (p=0.001 and p<0.001, respectively), and decreased by 21% for each inch of precipitation (p<0.001, p=0.006). Daily consults on snowy days decreased by an additional 16% compared to days with no precipitation. November had the lowest daily consult and admission rate, while September had the highest. Daily consult rate was lowest on Wednesdays and highest on Saturdays. Holiday schedule was not independently significant. CONCLUSION: Pediatric orthopedic trauma consultations and admissions are highly linked to temperature and precipitation, as well as day of the week and time of year. PMID- 27990194 TI - Predictors of Bone Status by Quantitative Ultrasound Measurements in a Mountain Village in Japan. AB - BACKGROUND: It seems to be important to recognize predictors of bone health condition in Japanese super-aged society. The purpose of this study was to investigate predictors of the speed of sound (SOS) of calcaneus by quantitative ultrasound measurements of mountain village residents. MATERIALS AND METHODS: Medical examinations were conducted on 214 participants (69 men, 145 women; average age of 63.6 years). Each had completed a self-administered questionnaire including items such as gender, dominant hand, occupation, and history of smoking and drinking alcohol, experience of falls, and the EuroQol-5-dimensions-3-level Japanese version and a 25-question geriatric locomotive function scale proposed by the Japanese Orthopaedic Association. Bilateral grip and key pinch strength were measured. The SOS of calcaneus was assessed using ultrasound bone densitometry. Body composition was measured using a multi-frequency segmental body composition analyzer. Spearman's rank correlation coefficient was calculated to elucidate the relation between SOS and evaluation items. Stepwise logistic regression was used to identify predictors of SOS using the investigated factors as explanatory variables. P values of < .05 were regarded as statistically significant. RESULTS: Significant positive correlation was found between the SOS and dominant and non-dominant grip and key pinch strength and Euro index and QOL VAS in all participants. In stepwise logistic regression, non-dominant key pinch (beta coefficient= 0.27, p= .022) and Euro QOL VAS (beta coefficient= 0.24, p= .0001) were predictors of calcaneal SOS for all participants. CONCLUSION: Key pinch strength and Euro QOL VAS assessment might be useful to predict calcaneal SOS in the general population. PMID- 27990195 TI - Resilience and Life Expectations of Perinatally HIV-1 Infected Adolescents in France. AB - BACKGROUND: Resilience of perinatally HIV-infected youth in European countries is poorly studied. Life satisfaction and expectations for adulthood are rarely examined. OBJECTIVE: This cross-sectional, descriptive study of a French cohort of 54 perinatally HIV-infected adolescents raised in France (age 14-20 years) aimed to (1) evaluate their psychosocial adjustment, (2) identify their expectations for adulthood and (3) delineate risk and protective factors associated with mental health, life satisfaction, and HIV-1 viral load level. METHOD: Medical evaluation, psychological semi-structured interview, and self report questionnaires were used. RESULTS: All the adolescents had been receiving Highly Active Anti-Retroviral Therapy (HAART) for 9 to 11 years and 2/3 were healthy with controlled viral load (<50 copies/mL). The majority had medium to high levels of life satisfaction. They viewed HIV as having only minor impact on their current daily life and had positive expectations for adulthood. However, 46% exhibited psychiatric symptomatology. Multivariable analysis showed that having a deceased parent and current worries about HIV were substantial risk factors for psychiatric symptoms. Having two living parents and being satisfied with life were protective factors for mental health. Good quality of caregiver adolescent relationships and high life satisfaction were significant protective factors for controlled viral load. CONCLUSION: These data indicate psychosocial resilience among perinatally HIV-1 infected adolescents with 10 years of HAART treatment. These findings demonstrate the influence of life satisfaction, parent's life status and quality of caregiver-adolescent relationships on resilience and health outcomes in these patients. We conclude that healthcare providers should attend to these factors. PMID- 27990197 TI - Transcatheter Aortic Valve Implantation for Treatment of Aortic Valve Stenosis: A Health Technology Assessment. AB - BACKGROUND: Surgical aortic valve replacement (SAVR) is the gold standard for treating aortic valve stenosis. It is a major operation that requires sternotomy and the use of a heart-lung bypass machine, but in appropriately selected patients with symptomatic, severe aortic valve stenosis, the benefits of SAVR usually outweigh the harms. Transcatheter aortic valve implantation (TAVI) is a less invasive procedure that allows an artificial valve to be implanted over the poorly functioning valve. METHODS: We identified and analyzed randomized controlled trials that evaluated the effectiveness and safety of TAVI compared with SAVR or balloon aortic valvuloplasty and were published before September 2015. The quality of the body of evidence for each outcome was examined according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. The overall quality was determined to be high, moderate, low, or very low using a step-wise, structural methodology. We also developed a Markov decision-analytic model to assess the cost-effectiveness of TAVI compared with SAVR over a 5-year time horizon, and we conducted a 5-year budget impact analysis. RESULTS: Rates of cardiovascular and all-cause mortality were similar for the TAVI and SAVR groups in all studies except one, which reported significantly lower all-cause mortality in the TAVI group and a higher rate of stroke in the SAVR group. Trials of high-risk patients who were not suitable candidates for SAVR showed significantly better survival with TAVI than with balloon aortic valvuloplasty. Median survival in the TAVI group was 31 months, compared with 11.7 months in the balloon aortic valvuloplasty group. Compared with SAVR, TAVI was associated with a significantly higher risk of stroke, major vascular complications, paravalvular aortic regurgitation, and the need for a permanent pacemaker. SAVR was associated with a higher risk of bleeding. Transapical TAVI was associated with higher rates of mortality and stroke than transfemoral TAVI in high-risk patients. TAVI and SAVR both improved patients' quality of life during the first year. However, because of a large amount of missing data and the lack of published data beyond 1 year, it was difficult to evaluate the impact of critical adverse outcomes on patients' longer-term health status. In the base-case analysis, when TAVI was compared with SAVR, the incremental cost-effectiveness ratio was $51,988 per quality-adjusted life-year. The 5-year budget impact of funding TAVI ranged from $7.6 to $8.3 million per year. CONCLUSIONS: Moderate quality evidence showed that TAVI and SAVR had similar mortality rates in patients who were eligible for surgery. Information about quality of life showed similar results for TAVI and SAVR in the first year, but was based on low quality evidence. Moderate quality evidence also showed that TAVI was associated with higher rates of adverse events than SAVR. In patients who were not suitable candidates for surgery, moderate quality evidence showed that TAVI improved survival compared with balloon aortic valvuloplasty. When TAVI was compared with SAVR, the incremental cost-effectiveness ratio was $51,988 per quality-adjusted life-year. PMID- 27990196 TI - Levonorgestrel-Releasing Intrauterine System (52 mg) for Idiopathic Heavy Menstrual Bleeding: A Health Technology Assessment. AB - BACKGROUND: Heavy menstrual bleeding affects as many as one in three women and has negative physical, economic, and psychosocial impacts including activity limitations and reduced quality of life. The goal of treatment is to make menstruation manageable, and options include medical therapy or surgery such as endometrial ablation or hysterectomy. This review examined the evidence of effectiveness and cost-effectiveness of the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) as a treatment alternative for idiopathic heavy menstrual bleeding. METHODS: We conducted a systematic review of the clinical and economic evidence comparing LNG-IUS with usual medical therapy, endometrial ablation, or hysterectomy. Medline, EMBASE, Cochrane, and the Centres for Reviews and Dissemination were searched from inception to August 2015. The quality of the evidence was assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We also completed an economic evaluation to determine the cost-effectiveness and budget impact of the LNG-IUS compared with endometrial ablation and with hysterectomy. The economic evaluation was conducted from the perspective the Ontario Ministry of Health and Long-Term Care. RESULTS: Relevant systematic reviews (n = 18) returned from the literature search were used to identify eligible randomized controlled trials, and 16 trials were included. The LNG-IUS improved quality of life and reduced menstrual blood loss better than usual medical therapy. There was no evidence of a significant difference in these outcomes compared with the improvements offered by endometrial ablation or hysterectomy. Mild hormonal side effects were the most commonly reported. The quality of the evidence varied from very low to moderate across outcomes. Results from the economic evaluation showed the LNG-IUS was less costly (incremental saving of $372 per person) and more effective providing higher quality-adjusted life years (incremental value of 0.05) compared with endometrial ablation. Similarly, the LNG-IUS costs less (incremental saving of $3,138 per person) and yields higher quality-adjusted life-years (incremental value of 0.04) compared with hysterectomy. Publicly funding LNG-IUS as an alternative to endometrial ablation and hysterectomy would result in annual cost savings of $3 million to $9 million and $0.1 million to $23 million, respectively, over the first 5 years. CONCLUSIONS: The 52-mg LNG-IUS is an effective and cost-effective treatment option for idiopathic heavy menstrual bleeding. It improves quality of life and menstrual blood loss, and is well tolerated compared with endometrial ablation, hysterectomy, or usual medical therapies. PMID- 27990198 TI - Magnetic Resonance Imaging as an Adjunct to Mammography for Breast Cancer Screening in Women at Less Than High Risk for Breast Cancer: A Health Technology Assessment. AB - BACKGROUND: Screening with mammography can detect breast cancer early, before clinical symptoms appear. Some cancers, however, are not captured with mammography screening alone. Among women at high risk for breast cancer, magnetic resonance imaging (MRI) has been suggested as a safe adjunct (supplemental) screening tool that can detect breast cancers missed on screening mammography, potentially reducing the number of deaths associated with the disease. However, the use of adjunct screening tests may also increase the number of false-positive test results, which may lead to unnecessary follow-up testing, as well as patient stress and anxiety. We investigated the benefits and harms of MRI as an adjunct to mammography compared with mammography alone for screening women at less than high risk (average or higher than average risk) for breast cancer. METHODS: We searched Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Centre for Reviews and Dissemination (CRD) Health Technology Assessment Database, and National Health Service (NHS) Economic Evaluation Database, from January 2002 to January 2016, for evidence of effectiveness, harms, and diagnostic accuracy. Only studies evaluating the use of screening breast MRI as an adjunct to mammography in the specified populations were included. RESULTS: No studies in women at less than high risk for breast cancer met our inclusion criteria. CONCLUSIONS: It remains uncertain if the use of adjunct screening breast MRI in women at less than high risk (average or higher than average risk) for breast cancer will reduce breast cancer-related mortality without significant increases in unnecessary follow-up testing and treatment. PMID- 27990199 TI - No Association of Obesity and Type 2 Diabetes Mellitus Related Genetic Variants With Colon Cancer. AB - BACKGROUND: Obesity and type 2 diabetes mellitus (T2D) are known risk factors for colon cancer. Recent reports from a number of genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with obesity and T2D. Here we tested the hypothesis that these SNPs may also be associated with risk of colon cancer. METHODS: We genotyped nine SNPs reported in GWAS of obesity and/or T2D, including SNPs in HHEX, KCNJ11, SLC30A8, FTO, CDKN2, CDKAL1, TCF2, and the rs9300039 SNP in an intergenic region, in 561 colon cancer cases and 721 population controls. RESULTS: None of these SNPs were statistically significantly associated with colon cancer in our sample. CONCLUSIONS: Overall, these results suggest that these obesity and T2D genetic susceptibility loci are unlikely to influence the risk of colon cancer. PMID- 27990200 TI - Prognostic Factors of Patients With Transmural Advanced Gastric Carcinoma. AB - BACKGROUND: The purpose of this study is to evaluate perioperative morbidity, mortality and the prognostic factors that influence survival of the patients with transmural advanced gastric carcinoma after curative surgical therapy. METHODS: Fifty patients with transmural advanced gastric adenocarcinoma underwent curative resection in our clinic. The records of the patients were reviewed and the prognostic factors such as age, gender, location and size of the tumor, type of surgery, blood transfusion, depth of tumor invasion, lymph node metastases, stage of the disease, grading, vascular invasion, lymph vessel invasion, characteristics of the tumor according to Lauren's classification, and lymph node ratio were evaluated by using statistical methods. RESULTS: In a total of 12 patients (24%) major morbidities developed, and five patients (10%) died. The overall survival rate was 48% at 1 year, 31% at 3 years, and 19% at 5 years. Lymph node metastases (P = 0.03), lymph vessel invasion (P = 0.001), blood transfusion (P = 0.021), and lymph node ratio (P = 0.006) were the prognostic features identified by univariate analysis. Among the multiple significant prognostic factors in the univariate analysis only one factor, lymph node ratio, proved to be independently significant in the multivariate analysis (RR: 4.47). CONCLUSIONS: Our data showed that we can expect a good survival for patients with a lymph node ratio less than 0.2. PMID- 27990202 TI - The Value of Survivin Gene and Proliferation of Hepatocytes in Screening for Hepatocellular Carcinoma. AB - BACKGROUND: The prospective surveillance programs on patients with liver diseases based on repeat ultrasound examinations of liver and serum alpha-fetoprotein (AFP) detection were reported having the probability of finding hepatocellular carcinoma (HCC) at its early stage, but it is time-consuming and not cost effective. To improve the effectiveness and cost-effective of HCC surveillance program, close monitoring has been focused on patients with liver cirrhosis who have particularly high risk of HCC development. It has been found that high liver cell proliferation is a reliable predictor of HCC development, and survivin is a new gene with the role of suppressing apoptosis which has been studied mostly over the past few years. This study aimed to evaluate the usefulness of proliferation cell nuclear antigen (PCNA) and survivin detection in the process of screening cirrhotic patients with high risk of HCC development. METHODS: Total RNA was extracted from fresh specimens of HCC and liver cirrhosis. Survivin mRNA amplification was performed by reverse transcription polymerase chain reaction (RT-PCR). Immunostaining for PCNA was employed to assess liver cell proliferation activity in formalin-fixed, paraffin embedded liver specimens. Five liver specimens obtained from patients operated for hemangioma were used as normal control. The PCNA labeling index was determined as the mean value of positive cells in ten different microscopic fields. RESULTS: RT-PCR was performed in 17 HCC and 10 liver cirrhosis specimens, 11 HCC specimens showed 344bps molecular survivin DNA band in 1% agarose electrophoresis, but none of liver cirrhosis specimens showed positive band. The survivin positive rate in HCC specimens was 64.7% (11/17); The PCNA labeling index was 2.38 +/- 2.11 in 30 liver cirrhosis specimens, while 10.08 +/- 12.28 in 30 HCC specimens, the latter was significantly higher than the former, P = 0.003. The median PCNA labeling index of 11 survivin positive HCC specimens was 6.8 (from 0.5 to 40), which is significantly higher than that of 6 survivin negative HCC specimens (2.15). CONCLUSIONS: Survivin expressed in HCC tissues but not in liver cirrhosis tissues, this phenomenon indicates that the gene expression may occur at the late phase of liver cell cancer transformation. Compared with survivin detection, the PCNA detection on liver cells of cirrhosis patients is better to differentiate high-risk HCC transformation among liver cirrhosis patients. PMID- 27990201 TI - Role of Rosiglitazone as a Gastroprotective Agent Against Indomethacin-Induced Gastric Mucosal Injury in Rats. AB - BACKGROUND: Rosiglitazone, an insulin sensitizing agent, has been recently implicated in the control of inflammatory processes and modulation of expression of various cytokines such as tumor necrosis factor (TNF-alpha). However, its mechanistic effect of gastric mucosal integrity remains to be elucidated. METHODS: The present study was designed to determine effect of rosiglitazone on gastric mucosal lesions induced by indomethacin (IND) in rats. Pyloric ligation was performed for the collection of gastric juice, and gastric ulceration was induced by a single intraperitoneal injection of IND (30 mg/kg). RESULTS: IND administration caused a significant decrease in the volume of gastric juice mucin and gastric mucosal nitrite and prostaglandin E2 (PGE2) levels. This was accompanied by a significant increase in gastric juice free and total acidity and pepsin activity. In addition, an elevation in the gastric mucosal lipid peroxide and serum TNF-alpha level was observed. Pretreatment with rosiglitazone (10 mg/kg, orally, for 1 weeks) resulted in a significant reduction in the elevated gastric mucosal lesions and lipid peroxides levels. This was associated with a marked increase in gastric juice mucin and a reduction in TNF-alpha level. Moreover, rosiglitazone significantly increased the gastric mucosal total nitrite and PGE2 levels. CONCLUSIONS: Rosiglitazone exerts a gastroprotective effect against IND-induced gastric mucosal lesions and its anti-ulcer effect is mediated via scavenging free radicals, increasing NO, PGE2 and mucus production in addition to its anti-inflammatory mechanisms. Thus, rosiglitazone could be a relevant drug for patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and at high risk of developing gastric ulceration. PMID- 27990203 TI - Study of Chronic Hepatopathy in Patients With Sickle Cell Disease. AB - BACKGROUND: Hepatic lesions in sickle cell disease were studied essentially in autopsy specimens. We investigated chronic hepatopathy in living adults with sickle cell disease and report the clinical, biochemical, and hepatic histological findings in these patients. METHODS: A total of 170 adult patients with sickle cell syndrome were prospectively investigated. Clinical and laboratory investigation including liver function tests, serological tests for viral hepatitis, autoimmune hepatitis, and abdominal ultrasonography were performed in all of the patients. Liver biopsies were studied from 27 patients. RESULTS: There was clinical evidence of jaundice in 123 (72.4%) patients, 118 (69.4%) patients had palpable liver, and 69% percent of the patients had elevated enzymes. Serological tests demonstrated the presence of hepatitis B infection in 18 (10.6%) patients and hepatitis C infection in 39 (23%) patients, serological markers for autoimmune hepatitis were positive in two female patients, one diagnosed chronic intrahepatic cholestasis. All 27 biopsies presented some degree of sickling hepatopathy. Moderate or marked liver siderosis was associated with the number of transfusions. CONCLUSIONS: The clinical spectrum of sickle cell disease ranges from mild liver function test abnormalities to significant hepatic abnormalities with marked hyperbilirubinemia. Multiple factors may contribute to the etiology of the liver disease, including ischemia, transfusion related viral hepatitis, iron overload, and gallstones. PMID- 27990204 TI - Quantitative Platelet Abnormalities in Patients With Hepatitis B Virus-Related Liver Disease. AB - BACKGROUND: Platelets play a central role in primary hemostasis. Quantitative abnormalities of platelets are known to occur in chronic liver disease. The study was carried out to determine the abnormalities of platelet count in various forms of Hepatitis B virus-related liver disease. METHODS: Platelet count was carried out on consecutive chronic liver disease patients seen at the gastroenterology unit of the University of Nigeria Teaching Hospital Ituku/Ozalla who tested positive for Hepatitis B surface antigen (HBsAg) from January 2007 to June 2009. Dyspeptic patients undergoing upper gastrointestinal endoscopy who were HBsAg negative were used as controls. RESULTS: There were 142 patients with various forms of HBV-related liver disease (asymptomatic infection 29.6%, chronic hepatitis 8.4%, cirrhosis 27.5%, and hepatocellular carcinoma 34.5%). There was no statistically significant difference between the mean platelet count in the patients with Hepatitis B virus (HBV) related liver disease as a whole and control subjects (p = 0.4655). However patients with cirrhosis had a statistically significant lower platelet count than control subjects (p < 0.0001). Conversely, patients with hepatocellular carcinoma (HCC) had a higher platelet count than control subjects (p < 0.0001), and cirrhotic patients (p < 0.0001). CONCLUSIONS: Abnormalities of platelet count occur in HBV-related liver disease. Patients with liver cirrhosis tend to have lower platelet count while patients with HCC tend to have higher counts. Thrombocytosis may be a paraneoplastic manifestation of HCC. PMID- 27990205 TI - Penetration of Gastric Ulcer into the Splenic Artery: A Rare Complication. AB - Gastric ulcer and its complications are commonly encountered by physicians. Penetration is only noted in about 20% of the cases. Penetration into the splenic artery is a very rare occurrence. Making the diagnosis early on is important in order to prevent morbidity and mortality due to the brisk bleeding that can follow. In our report we describe the case, the imaging and the interventional radiological findings which helped with management. We review the literature published including radiological findings in such cases and describe the proposed pathogenesis. Definitive treatment usually involves controlling the bleeding either by means of embolization using coils or ligating the bleeding vessel. PMID- 27990206 TI - Endometriosis of the Vermiform Appendix Presenting as a Tumor. AB - Endometriosis of the vermiform appendix is a rare condition. Most patients with this disease are asymptomatic or present as acute or chronic appendicitis. The author herein reports a case of appendiceal endometriosis presenting as a tumor at the appendiceal oriffice. A 41-year-old woman complained of chronic abdominal pain. A colon endoscopy showed a tumor in the appendiceal orifice. Two biopsies of the tumor showed no remarkable changes. Imaging modalities including CT and MRI also revealed an appendiceal tumor. Resection of appendix, cecum, ascending colon, terminal ileum, and 16 lymph nodes were performed under the clinical diagnosis of gastrointestinal stromal tumor. Grossly, a tumor measuring 3 x 3 x 3 cm was recognized in the appendiceral orifice. Histologically, the tumor was endometriosis consisting of islands of endometrial glands and stroma. Immunohistochemically, the lesion was positive for estrogen receptor and progesterone receptor, but it was negative for p53 protein and Ki-67 labeling was very low (0.5%). Similar endometriosis-like glands or Mullerian duct remnants were recognized in six out of 16 regional lymph nodes. The present case suggests that appendiceal endometriosis may present as a tumor. PMID- 27990207 TI - Recurrent Multiple Cervical Esophageal Webs: An Unusual Presentation of Celiac Disease. AB - Although the association of celiac disease with esophageal web has been reported earlier, in this case patient presented with persistent dysphagia. Upper gastrointestinal endoscopy revealed multiple esophageal webs which were recurring despite endoscopic dilatation. Diagnosis and treatment of underlying celiac disease led to long term improvement. PMID- 27990208 TI - A Case of O1 Vibrio Cholera Bacteremia and Primary Peritonitis in a Patient With Liver Cirrhosis. AB - Vibrio cholerae are Gram-negative bacteria that are differentiated into O1/O139 and non-O1/non-O139 serogroups depending on their ability to agglutinate with specific antiserum. In contrast to non-O1/non-0139 Vibrio cholerae, which are more prone to invade the bloodstream, Vibrio cholerae O1 is rarely the cause of bacteremia. We report a case of O1 Vibrio cholera bacteremia and primary peritonitis in a patient with liver cirrhosis. The literature on the subject is also reviewed. PMID- 27990209 TI - Spontaneously Ruptured Gastrointestinal Stromal Tumor With Pelvic Abscess: A Case Report and Review. AB - Gastrointestinal stromal tumors (GISTs) originate from interstitial Cajal cells on intestinal pacemaker cells that arise from the muscularis propria of the gastrointestinal tract wall. GISTs are characterized by the expression of c-KIT protein (CD 117, stem cell factor receptor) and are the most common mesenchymal tumors of the digestive tract. That protein, which is detected via immunohistochemical analysis, is the primary diagnostic criterion for a GIST. The rupture of a gastrointestinal stromal tumor of the peritoneal cavity is critical complication, although it is infrequently described in the literature. We describe the computed tomographic findings of a ruptured gastrointestinal stromal tumor of the jejunal wall with an accompanying abscess. We also review the clinical features, radiologic and pathologic findings, and treatment of similar previously reported cases. PMID- 27990210 TI - Non-functioning Well Differentiated Endocrine Carcinoma of the Pancreas. AB - The author reports a typical but rare case of non-functioning well differentiated endocrine carcinoma of the pancreas. A 67-year-old man was admitted to our hospital because of abdominal pain. No hormone-related symptoms were recognized. He has no familiar history of pancreatic neoplasms. Various imaging modalities including US, CT and MRI revealed a tumor of the pancreatic body. Distal pancreatectomy and splenectomy were performed. A solid well demarcated tumor was present in the pancreatic body. Peripancreatic lymph nodes showed marked swelling suggestive of metastases. Immunohistyochemically, tumor cells were positive for cytokeratin, synaptophysin, neuron-specific enolase, and CD56; they were negative for chromogranin, gastrin, glucagon, somatostatin, pancreatic polypeptide, and vasoactive intestinal polypeptide. The pathological diagnosis was non-functioning well differentiated endocrine carcinoma of the pancreas. PMID- 27990211 TI - Automated electrorotation shows electrokinetic separation of pancreatic cancer cells is robust to acquired chemotherapy resistance, serum starvation, and EMT. AB - We used automated electrorotation to measure the cytoplasmic permittivity, cytoplasmic conductivity, and specific membrane capacitance of pancreatic cancer cells under environmental perturbation to evaluate the effects of serum starvation, epithelial-to-mesenchymal transition, and evolution of chemotherapy resistance which may be associated with the development and dissemination of cancer. First, we compared gemcitabine-resistant BxPC3 subclones with gemcitabine naive parental cells. Second, we serum-starved BxPC3 and PANC-1 cells and compared them to untreated counterparts. Third, we induced the epithelial-to mesenchymal transition in PANC-1 cells and compared them to untreated PANC-1 cells. We also measured the electrorotation spectra of white blood cells isolated from a healthy donor. The properties from fit electrorotation spectra were used to compute dielectrophoresis (DEP) spectra and crossover frequencies. For all three experiments, the median crossover frequency for both treated and untreated pancreatic cancer cells remained significantly lower than the median crossover frequency for white blood cells. The robustness of the crossover frequency to these treatments indicates that DEP is a promising technique for enhancing capture of circulating cancer cells. PMID- 27990212 TI - Drop-on-demand inkjet-based cell printing with 30-MUm nozzle diameter for cell level accuracy. AB - We present drop-on-demand inkjet-based mammalian cell printing with a 30-MUm nozzle diameter for cell-level accuracy. High-speed imaging techniques have been used to analyze the go-and-stop movement of cells inside the nozzle under a pulsed pressure generated by a piezo-actuator and the jet formation after ejection. Patterning of an array of 20 * 20 dots on a glass substrate reveals that each printed drop contains 1.30 cells on average at the cell concentration of 5.0 * 106 cells ml-1 for the very small nozzle, whereas larger nozzles with the diameter of 50 and 80 MUm deliver 2.57 and 2.88 cells per drop, respectively. The effects of the size and concentration of printed cells on the number of cells have also been investigated. Furthermore, the effect of the nozzle diameter on printed cells has been evaluated through an examination of viability, proliferation, and morphology of cells by using a live/dead assay kit, CCK-8 assay, and cellular morphology imaging, respectively. We believe that the 30-MUm inkjet nozzle can be used for precise cell deposition without any damages to the printed mammalian cells. PMID- 27990213 TI - A hybrid microfluidic device for on-demand orientation and multidirectional imaging of C. elegans organs and neurons. AB - C. elegans is a well-known model organism in biology and neuroscience with a simple cellular (959 cells) and nervous (302 neurons) system and a relatively homologous (40%) genome to humans. Lateral and longitudinal manipulation of C. elegans to a favorable orientation is important in many applications such as neural and cellular imaging, laser ablation, microinjection, and electrophysiology. In this paper, we describe a micro-electro-fluidic device for on-demand manipulation of C. elegans and demonstrate its application in imaging of organs and neurons that cannot be visualized efficiently under natural orientation. To achieve this, we have used the electrotaxis technique to longitudinally orient the worm in a microchannel and then insert it into an orientation and imaging channel in which we integrated a rotatable glass capillary for orientation of the worm in any desired direction. The success rates of longitudinal and lateral orientations were 76% and 100%, respectively. We have demonstrated the application of our device in optical and fluorescent imaging of vulva, uterine-vulval cell (uv1), vulB1?2 (adult vulval toroid cells), and ventral nerve cord of wild-type and mutant worms. In comparison to existing methods, the developed technique is capable of orienting the worm at any desired angle and maintaining the orientation while providing access to the worm for potential post-manipulation assays. This versatile tool can be potentially used in various applications such as neurobehavioral imaging, neuronal ablation, microinjection, and electrophysiology. PMID- 27990214 TI - Shape induced acid responsive heat triggered highly facilitated drug release by cube shaped magnetite nanoparticles. AB - This paper reports a very simple yet better method for synthesis of cube shaped magnetite nanoparticles (MNPs) and their application in the drug delivery system (DDS). Structural analysis was done by XRD measurements to confirm the phase of the material, and morphological information was obtained through TEM analysis to confirm the shape and size of the particles. It has been shown that these particles can be decomposed in acid medium. These acid-decomposable magnetite nano-particles have been used for heat triggered, remote-controlled, on demand delivery and release of a cancer drug doxorubicin for research and therapeutic purposes. Here, we have shown that the pH stimulated and heat-triggered release of drug from our MNPs significantly enhances the release efficiency. In this case, we observe that pH induced release is far better in comparison to heat triggered release. From these inspiring results, it may be expected that this methodology may become a significant step towards the development of a pH sensitive heat triggered drug delivery system minimizing drug toxicity. PMID- 27990215 TI - Label-free discrimination of membrane-translocating peptides on porous silicon microfluidic biosensors. AB - A label-free optical sensor was constructed by integrating electrochemically etched porous silicon (pSi) and supported phospholipid bilayers in a microfluidic chip. The translocation of peptides through the phospholipid bilayers could induce a red shift in effective optical thickness of the pSi layer, which could be monitored by reflective interferometric Fourier transform spectroscopy. By measuring the kinetic data of membrane translocating on the phospholipid bilayers/pSi chip, the relationship between the behavior of membrane translocating peptides (MTPs) and translocating mechanism was established. With these optical data, MTPs with different action modes on the cell membrane can be correctly discriminated. The bio-functionalized microfluidic sensor will provide a reliable and cost-effective platform to study the transmembrane behavior of peptides, which is of great importance in the MTP screening and peptide function study. PMID- 27990216 TI - In-flow real-time detection of spectrally encoded microgels for miRNA absolute quantification. AB - We present an in-flow ultrasensitive fluorescence detection of microRNAs (miRNAs) using spectrally encoded microgels. We researched and employed a viscoelastic fluid to achieve an optimal alignment of microgels in a straight measurement channel and applied a simple and inexpensive microfluidic layout, allowing continuous fluorescence signal acquisitions with several emission wavelengths. In particular, we chose microgels endowed with fluorescent emitting molecules designed for multiplex spectral analysis of specific miRNA types. We analysed in a quasi-real-time manner circa 80 microgel particles a minute at sample volumes down to a few microliters, achieving a miRNA detection limit of 202 fM in microfluidic flow conditions. Such performance opens up new routes for biosensing applications of particles within microfluidic devices. PMID- 27990217 TI - Flexible control of cellular encapsulation, permeability, and release in a droplet-templated bifunctional copolymer scaffold. AB - Designing cell-compatible, bio-degradable, and stimuli-responsive hydrogels is very important for biomedical applications in cellular delivery and micro-scale tissue engineering. Here, we report achieving flexible control of cellular microencapsulation, permeability, and release by rationally designing a diblock copolymer, alginate-conjugated poly(N-isopropylacrylamide) (Alg-co-PNiPAM). We use the microfluidic technique to fabricate the bifunctional copolymers into thousands of mono-disperse droplet-templated hydrogel microparticles for controlled encapsulation and triggered release of mammalian cells. In particular, the grafting PNiPAM groups in the synthetic cell-laden microgels produce lots of nano-aggregates into hydrogel networks at elevated temperature, thereafter enhancing the permeability of microparticle scaffolds. Importantly, the hydrogel scaffolds are readily fabricated via on-chip quick gelation by triggered release of Ca2+ from the Ca-EDTA complex; it is also quite exciting that very mild release of microencapsulated cells is achieved via controlled degradation of hydrogel scaffolds through a simple strategy of competitive affinity of Ca2+ from the Ca-Alginate complex. This finding suggests that we are able to control cellular encapsulation and release through ion-induced gelation and degradation of the hydrogel scaffolds. Subsequently, we demonstrate a high viability of microencapsulated cells in the microgel scaffolds. PMID- 27990218 TI - Carbohydrate Mouth Rinse Improves 1.5 h Run Performance: Is There A Dose-Effect? AB - There is a substantial body of recent evidence showing ergogenic effects of carbohydrate (CHO) mouth rinsing on endurance performance. However, there is a lack of research on the dose-effect and the aim of this study was to investigate the effect of two different concentrations (6% and 12% weight/volume, w/v) on 90 minute treadmill running performance. Seven active males took part in one familiarization trial and three experimental trials (90-minute self-paced performance trials). Solutions (placebo, 6% or 12% CHO-electrolyte solution, CHO E) were rinsed in the mouth at the beginning, and at 15, 30 and 45 minutes during the run. The total distance covered was greater during the CHO-E trials (6%, 14.6 +/- 1.7 km; 12%, 14.9 +/- 1.6 km) compared to the placebo trial (13.9 +/- 1.7 km, P < 0.05). There was no significant difference between the 6% and 12% trials (P > 0.05). There were no between trial differences (P > 0.05) in ratings of perceived exertion (RPE) and feeling or arousal ratings suggesting that the same subjective ratings were associated with higher speeds in the CHO-E trials. Enhanced performance in the CHO-E trials was due to higher speeds in the last 30 minutes even though rinses were not provided during the final 45 minutes, suggesting the effects persist for at least 20-45 minutes after rinsing. In conclusion, mouth rinsing with a CHO-E solution enhanced endurance running performance but there does not appear to be a dose-response effect with the higher concentration (12%) compared to a standard 6% solution. PMID- 27990219 TI - Acute effects of walking with Nordic poles in persons with mild to moderate low back pain. AB - Regular walking with or without Nordic poles is effective over time at reducing discomfort in individuals with chronic low back pain (LBP). Nordic pole use increases balance and stability, distributes weight through the arms and torso, and decreases loading of the spine and lower limbs. The purpose of this study was to determine if Nordic poles would reduce perceived acute discomfort while self paced walking in individuals with LBP. We also examined whether walking with or without poles increased heart rate (HR) and ratings of perceived exertion (RPE) or speed of movement. Subjects included 20 adults (12 males, 8 females; mean age of 45.1+/-16.3) who were experiencing LBP of at least six months' duration (Oswestry Disability Index (ODI): mean 17 +/- 8%, range 6-36% indicating minimal to moderate disability) with no current active flare-up. Participants walked a predetermined dirt-path course (805 m or 0.5 mi) with and without poles in randomized order. Data were analyzed using a 2 X 2 repeated measures ANOVA (Condition X Time), where Condition was poles vs no poles and Time was pre- and post-walk. HR and RPE increased significantly from walking the course, whereas pain did not change. There were also no differences between walking with or without poles for pain (ODI Sec #1: 0.2 points, p=0.324), HR (4 bpm, p=0.522) and RPE (0 points, p=0.759). The mean course time (sec) was slower with poles: 617+/ 87 vs 566+/-65 (p<0.001). Unexpectedly, there was a noticeable drop in pain following the warm up which was done using poles (0.9 points, p<0.001). Nordic pole use is well tolerated in those with current back pain and can be encouraged, however it cannot be recommended as a superior method of addressing acute symptoms when walking. PMID- 27990220 TI - Effect of Music Tempo on Attentional Focus and Perceived Exertion during Self selected Paced Walking. AB - This study investigated the influence of music on the rating of perceived exertion (RPE) and attentional focus during walking at a self-selected pace. Fifteen overweight and obese women volunteered to participate in the study. They underwent four sessions: the first for incremental maximal test and anthropometric measurement followed by three experimental sessions. After the first session, they were exposed to three 30-minute walking sessions at a self selected pace in a counterbalanced order: fast-tempo music (FT), medium-tempo music (MT) and no-music control (NM). Borg's RPE Scale and an Attentional Focus Questionnaire were used to measure the perceptual response and attentional focus, respectively. Results showed that the RPE was higher in the no-music control than in the medium-tempo music (12.05 +/- 0.6 vs. 10.5 +/- 0.5). Furthermore, dissociative attentional focus was greater for both conditions with music in comparison with the no-music control (NM= 39.0 +/- 4.1; MT= 48.4 +/- 4.1 and FT= 47.9 +/- 4.5). The results indicated that the use of music during walking can modulate attentional focus, increasing dissociative thought, and medium-tempo music can reduce the RPE. PMID- 27990221 TI - Polycystic Ovary Syndrome Presents Higher Sympathetic Cardiac Autonomic Modulation that is not altered by Strength Training. AB - Polycystic ovary syndrome (PCOS) may present important comorbidities, such as cardiovascular and metabolic diseases, which are often preceded by changes in cardiac autonomic modulation. Different types of physical exercises are frequently indicated for the prevention and treatment of PCOS. However, little is known about the effects of strength training on the metabolic, hormonal, and cardiac autonomic parameters. Therefore, our aim was to investigate the effects of strength training on the autonomic modulation of heart rate variability (HRV) and its relation to endocrine-metabolic parameters in women with PCOS. Fifty three women were divided into two groups: CONTROL (n=26) and PCOS (n=27). The strength training lasted 4 months, which was divided into mesocycles of 4 weeks each. The training load started with 70% of one repetition maximum (1RM). Blood samples were collected before and after intervention for analysis of fasting insulin and glucose, HOMA-IR, testosterone, androstenedione and testosterone/androstenedione (T/A) ratio. Spectral analysis of HRV was performed to assess cardiac autonomic modulation indexes. The PCOS group presented higher insulin and testosterone levels, T/A ratio, along with increased sympathetic cardiac autonomic modulation before intervention. The training protocol used did not cause any change of endocrine-metabolic parameters in the CONTROL group. Interestingly, in the PCOS group, reduced testosterone levels and T/A ratio. Additionally, strength training did not have an effect on the spectral parameter values of HRV obtained in both groups. Strength training was not able to alter HRV autonomic modulation in women with PCOS, however may reduce testosterone levels and T/A ratio. PMID- 27990222 TI - Spatial Awareness is Related to Moderate Intensity Running during a Collegiate Rugby Match. AB - The purpose of the present study was to evaluate the relationship between spatial awareness, agility, and distance covered in global positioning system (GPS) derived velocity zone classifications during a collegiate rugby match. Twelve American collegiate rugby union players (mean+/-SD; age: 21.2+/-1.4 y; weight: 85.0+/-16.0 kg; 7 forwards & 5 backs) on a single team volunteered to participate in this investigation. The distances travelled at low (walking/jogging; <2.7m/s), moderate (cruising/striding; 2.7-5.0 m/s), and high intensities (running/sprinting; >5.0 m/s) were measured for each player using GPS sensors and normalized according to playing time during an official USA Rugby match. Spatial awareness was measured as visual tracking speed from one core session of a 3 dimensional multiple-object-tracking speed (3DMOTS) test (1.35+/-0.59 cm.sec-1). Agility was assessed utilizing the pro agility (5.05+/-0.28 sec) and t drill (10.62+/-0.39 sec). Analysis of variance revealed that athletes travelled the greatest distance during walking/jogging (39.5+/-4.5 m.min-1) and least distance during running/sprinting (4.9+/-3.5 m.min-1). Pearson product moment correlations revealed that only distance covered while cruising/striding (20.9+/-6.5 m.min-1) was correlated to spatial awareness (r=0.798, p=0.002). Agility did not correlate to distance covered at any velocity zone or spatial awareness. Spatial awareness, as determined by 3DMOTS, appears to be related to the moderate intensity movement patterns of rugby union athletes. PMID- 27990223 TI - Effects of Acute Vaporized Nicotine in Non-Tobacco Users at Rest and during Exercise. AB - Smokers, and even non-smokers, may utilize vaporized nicotine delivered by electronic cigarette (EC) due to the perception that EC are "healthier" than traditional tobacco cigarettes. The effects of vaporized nicotine delivered by EC on resting blood pressure (BP) and resting metabolic rate (RMR), or BP and aerobic power during exercise have not been studied. This investigation tested the effects of acute vaporized nicotine inhalation by EC on resting BP and RMR and cycle exercise BP, metabolic responses, and aerobic power in young, normotensive non-smokers. Using a double-blind design, 20 subjects (10 female) participated in two randomized trials: placebo (0 mg nicotine) or nicotine (18 mg nicotine). Participants inhaled from EC once every 30 s for 10 min (20 inhalations total). RMR was assessed 40 min later by indirect calorimetry followed by an incremental cycle test. RMR was not different between trials (p=0.79). Compared to the placebo, resting diastolic pressure (DBP) was 3 mmHg higher with nicotine (p=0.04). VO2peak was not different between the nicotine trial (2.3+/-0.8 L*min-1) and placebo (2.3+/-0.7 L*min-1) trials (p=0.77), and Wmax was also similar between nicotine (201.0+/-53.8 W) and the placebo (204.8+/ 57.8 W) (p=0.29). During the cycle exercise test, average DBP was higher following nicotine use compared with placebo trial (p=0.05), and exercise DBPpeak after nicotine (79.4+/-7.6) was significantly higher than placebo (74.9+/-8.3 mmHg) (p=0.02). Resting systolic blood pressure (SBP) was 3.7 mmHg lower for nicotine trial (p=0.04) but no SBP treatment effect was observed during exercise (p=0.14). Our results show that acute vaporized nicotine inhalation via EC increases resting and exercise DBP but does not affect RMR or cycle aerobic power in young, normotensive non-smokers. PMID- 27990224 TI - The Relationship Between Aerobic and Anaerobic Performance in Recreational Runners. AB - Research has indicated that combined aerobic and anaerobic training (concurrent training) may improve aerobic performance greater than aerobic training alone. The purpose of this investigation was to establish any associations between aerobic and anaerobic performance. Eleven participants (n = 11, age = 34.1 +/- 13 years, VO2max = 58.4 +/- 7.8) volunteered for this study. Participants were asked for endurance training experience (4.7 +/- 3.7 years) and resistance training experience (4.1 +/- 4.6 years). To meet training status, participants were to have a VO2max in the 80th percentile as per ACSM guidelines. The Bruce treadmill test was used to measure aerobic performance. In order to measure anaerobic performance, several tests were completed utilizing a force platform. A Pearson Product R Correlation Coefficient was calculated to determine correlations between variables. The results show significant correlation between VO2max and RFD (r = 0.68). Further analyses utilizing Cohen's effect size indicated a strong association between VO2max and peak force, as well as running efficiency and peak power, relative peak power, and power endurance. These results indicate an existing possibility that anaerobic performance measures such as RFD may have a positive relationship with aerobic performance measures such as VO2max. Therefore, it may be beneficial to integrate specific training components which focus on improving RFD as a method of improving running performance. PMID- 27990225 TI - Quantifying Inter-Segmental Coordination during the Instep Soccer Kicks. AB - In order to generate a high ball speed in soccer, the inter-segmental coordination of the kicking leg is critical. The purpose of this study was to quantify the coordination between the thigh and shank movement in the sagittal plane during instep kicks. Eleven female soccer players were video recorded using a high-speed (80 Hz) video camera during penalty kicks. Hip, knee and ankle joint centers of the right leg were digitized, and the movement was analyzed using Dartfish TeamPro (6.0). The thigh and shank segment angles were generated, and the coordination was quantified using the cross-correlation and the vector coding method. Four coordination patterns were defined based on coupling angles: in phase, anti-phase, thigh-phase and shank-phase. The time spent in each coordination pattern was analyzed. The cross-correlation coefficient was positive for all the participants, indicating that the two segments rotated with similar patterns. Based on the vector coding method, we observed dominant coordination patterns of shank-phase and in-phase during the backswing and forward swing phase, respectively. We hope the outcomes of our study could provide a better understanding of soccer kicking coordination and benefit training young soccer players. Future studies may use the methodology and outcomes in the present study to investigate the coordination of different levels of players to better understand the process of skill acquisition. PMID- 27990226 TI - The Effects of Eccentric, Velocity-Based Training on Strength and Power in Collegiate Athletes. AB - The purpose of this study was to determine if combining velocity-based training with eccentric focus (VEB) and velocity-based training (VBT) results in power and strength gains. Nineteen men and women collegiate track and field athletes participated in this study. The subjects completed a 12-week intervention with either a VEB program or a VBT program. To determine the effectiveness of each program, the subjects completed four exercise tests before and after the training period: vertical jump, medicine ball put test, 1RM projected bench press and 1RM projected squat. There were no significant differences between the VBT results and the VEB results. However, there were significant improvements between the pre test and post-test measures for each group. There were increases in 1RM projected squat for VEB men, VBT men, and VBT women. There were also significant improvements in the VEB male vertical jump and medicine ball put test pre- to post-intervention. For track and field athletes, both programs may result in strength and power gains, however, the results cannot be used to conclude that one resistance training program is superior. PMID- 27990227 TI - Effects of a Pre-workout Energy Drink Supplement on Upper Body Muscular Endurance Performance. AB - The use of pre-workout beverages is becoming an increasingly common method of improving performance during exercise in athletic and recreationally active populations. Therefore, the purpose of this study was to investigate the effects of a commercially available energy drink on exercise performance. Thirty-one healthy males (n=23) and females (n=8) participated in this study and were separated into two groups: supplement (SU; n=16) or placebo (PL; n=15). Subjects visited the laboratory on 2 occasions separated by no more than 7 days. The first visit consisted of completing a push up to fatigue protocol (PUFP) without ingesting the pre-workout energy drink supplement (PWEDS). The second visit consisted of ingesting either a placebo or the PWEDS 30 minutes prior to completing the PUFP. Rate of perceived exertion (RPE) was recorded following each set of pushups on both testing days. Also, participant's height, weight, and body composition were collected. There was no significant differences at baseline in any variable between groups (p = >.05). After the second testing session, both groups significantly improved total push-ups (PL Pre: 133.3 +/-39.4, PL Post: 155.3 +/- 54.1; SU Pre: 139.3 +/- 58.5, SU Post: 161.3 +/- 79.4; p=<.001), and push-ups completed in each of the 3 sets (p=<.001), when compared to baseline. Post-testing revealed no significant difference between groups in total push-ups completed or RPE at any time point, when compared to baseline. In conclusion, the commercially available PWEDS offered no additional ergogenic effects when compared to the placebo. PMID- 27990228 TI - 90 Minutes of Moderate-Intensity Exercise does not Attenuate Postprandial Triglycerides in Older Adults. AB - To determine whether 90 minutes of moderate-intensity exercise, prior to a high fat meal, attenuates postprandial triglycerides (PPT) in older adults. Eight sedentary older adult volunteers (mean +/- SD age = 58 +/- 8 years, BMI 26.5 +/- 4.2); completed two trials consisting of exercise and a no-exercise control. Exercise trials involved 90 minutes of moderate-intensity exercise 60% heart rate reserve (HRR). Following exercise, an overnight fast of 12-16 hours was performed. Participants were given a high fat meal that consisted of 146 grams of CHO, and 92 grams of fat and instructed to rest. Lipid levels were collected at pre-feeding, 1, 2, 3, and 4 hours post feeding. The control trial involved no exercise, performed an overnight fast of 12-16 hours, and was given the high fat meal followed by four hours of rest and data collection. There was no difference in PPT between the control and exercise trials (p < 0.05). Triglycerides (TG) increased in both trials over pre-feeding values (pre-feeding 123.13 +/- 65.03 con. 111 +/- 53.9 ex., 1hr 161.50 +/- 83.77 con. 149 +/- 71.03 ex., 2hrs 208.25 +/- 120.69 con. 177 +/- 97.29 ex., 3hrs 228 +/- 146.99 con. 147.25 +/- 87.64 ex., 4hrs 211.75 +/- 140.15 con. 169.5 +/- 68.14 ex). No difference in triglycerides over time was observed among older adults between the exercise and control trials. PMID- 27990230 TI - In Vivo Photonic Stimulation of Sciatic Nerve with a 1470 nm Laser. AB - Photonic stimulation is a new modality of nerve stimulation, which could overcome some of the electrical stimulation limitations. In this paper, we present the results of photonic stimulation of rodent sciatic nerve with a 1470 nm laser. Muscle activation was observed with radiant exposure of 0.084 J/cm2. PMID- 27990231 TI - Fast Simulation and Optimization Tool to Explore Selective Neural Stimulation. AB - In functional electrical stimulation, selective stimulation of axons is desirable to activate a specific target, in particular muscular function. This implies to simulate a fascicule without activating neighboring ones i.e. to be spatially selective. Spatial selectivity is achieved by the use of multicontact cuff electrodes over which the stimulation current is distributed. Because of the large number of parameters involved, numerical simulations provide a way to find and optimize electrode configuration. The present work offers a computation effective scheme and associated tool chain capable of simulating electrode-nerve interface and find the best spread of current to achieve spatial selectivity. PMID- 27990229 TI - Effects of Allicin on Hypertension and Cardiac Function in Chronic Kidney Disease. AB - This work was performed to study the effect of allicin on hypertension and cardiac function in a rat model of CKD. The groups were control, CKD (5/6 nephrectomy), and CKD-allicin treated (CKDA) (40 mg/kg day/p.o.). Blood pressure was monitored (weekly/6 weeks). The cardiac function, vascular response to angiotensin II, oxidative stress, and heart morphometric parameters were determined. The CKD group showed hypertension and proteinuria. The coronary perfusion and left ventricular pressures were decreased in CKD group. In contrast, the vascular response to angiotensin II and expression of angiotensin II type 1 receptor (AT1R) were increased. These data were associated with the increment in morphometric parameters (weight of heart and left ventricle, heart/BW and left ventricular mass index, and wall thickness). Concurrently, the oxidative stress was increased and correlated inversely with the expression of Nrf2, Keap1, and antioxidant enzymes Nrf2-regulated. Allicin treatment attenuated hypertension and improved the renal and the cardiac dysfunctions; furthermore, it decreased the vascular reactivity to angiotensin II, AT1R overexpression, and preserved morphometric parameters. Allicin also downregulated Keap1 and increased Nrf2 expression, upregulated the antioxidant enzymes, and reduced oxidative stress. In conclusion, allicin showed an antihypertensive, nephroprotective, cardioprotective, and antioxidant effects, likely through downregulation of AT1R and Keap1 expression. PMID- 27990232 TI - Power Strategy in DC/DC Converters to Increase Efficiency of Electrical Stimulators. AB - Power efficiency is critical for electrical stimulators. Battery life of wearable stimulators and wireless power transmission in implanted systems are common limiting factors. Boost DC/DC converters are typically needed to increase the supply voltage of the output stage. Traditionally, boost DC/DC converters are used with fast control to regulate the supply voltage of the output. However, since stimulators are acting as current sources, such voltage regulation is not needed. Banking on this, this paper presents a DC/DC conversion strategy aiming to increase power efficiency. It compares, in terms of efficiency, the traditional use of boost converters to two alternatives that could be implemented in future hardware designs. PMID- 27990233 TI - Laser-Induced Carbon Pyrolysis of Electrodes for Neural Interface Systems. AB - The objective of this work is to produce a laser- fabricated polymer-metal polymer electrode with the merit of a carbon-based coating as the active site. A 10 um-thick layer of parylene-C is used serving as the insulation layer in which the active site is locally laser-pyrolyzed. Our preliminary results show that the proposed method is promising in terms of fabrication feasibility and desired electrochemical capabilities. PMID- 27990234 TI - Can FES-Augmented Active Cycling Training Improve Locomotion in Post-Acute Elderly Stroke Patients? AB - Recent studies advocated the use of active cycling coupled with functional electrical stimulation to induce neuroplasticity and enhance functional improvements in stroke adult patients. The aim of this work was to evaluate whether the benefits induced by such a treatment are superior to standard physiotherapy. A single-blinded randomized controlled trial has been performed on post-acute elderly stroke patients. Patients underwent FES-augmented cycling training combined with voluntary pedaling or standard physiotherapy. The intervention consisted of fifteen 30-minutes sessions carried out within 3 weeks. Patients were evaluated before and after training, through functional scales, gait analysis and a voluntary pedaling test. Results were compared with an age matched healthy group. Sixteen patients completed the training. After treatment, a general improvement of all clinical scales was obtained for both groups. Only the mechanical efficiency highlighted a group effect in favor of the experimental group. Although a group effect was not found for any other cycling or gait parameters, the experimental group showed a higher percentage of change with respect to the control group (e.g. the gait velocity was improved of 35.4% and 25.4% respectively, and its variation over time was higher than minimal clinical difference for the experimental group only). This trend suggests that differences in terms of motor recovery between the two groups may be achieved increasing the training dose. In conclusion, this study, although preliminary, showed that FES augmented active cycling training seems to be effective in improving cycling and walking ability in post-acute elderly stroke patients. A higher sample size is required to confirm results. PMID- 27990235 TI - A Hybrid Functional Electrical Stimulation for Real-Time Estimation of Joint Torque and Closed-Loop Control of Muscle Activation. AB - As a neuroprosthetic technique, functional electrical stimulation (FES) can restore lost motor performance of impaired patients. Through delivering electrical pulses to target muscles, the joint movement can be eventually elicited. This work presents a real-time FES system which is able to deal with two neuroprosthetic missions: one is estimating FES-induced joint torque with evoked electromyograph (eEMG), and the other is artificially controlling muscle activation with such eEMG feedback. The clinical experiment results on spinal cord injured (SCI) patients and healthy subjects show promising performance of the proposed FES system. PMID- 27990236 TI - Electrotactile Feedback Improves Performance and Facilitates Learning in the Routine Grasping Task. AB - Aim of this study was to investigate the feasibility of electrotactile feedback in closed loop training of force control during the routine grasping task. The feedback was provided using an array electrode and a simple six-level spatial coding, and the experiment was conducted in three amputee subjects. The psychometric tests confirmed that the subjects could perceive and interpret the electrotactile feedback with a high success rate. The subjects performed the routine grasping task comprising 4 blocks of 60 grasping trials. In each trial, the subjects employed feedforward control to close the hand and produce the desired grasping force (four levels). First (baseline) and the last (validation) session were performed in open loop, while the second and the third session (training) included electrotactile feedback. The obtained results confirmed that using the feedback improved the accuracy and precision of the force control. In addition, the subjects performed significantly better in the validation vs. baseline session, therefore suggesting that electrotactile feedback can be used for learning and training of myoelectric control. PMID- 27990237 TI - RehaMovePro: A Versatile Mobile Stimulation System for Transcutaneous FES Applications. AB - Functional Electrical Stimulation is a commonly used method in clinical rehabilitation and research to trigger useful muscle contractions by electrical stimuli. In this work, we present a stimulation system for transcutaneous electrical stimulation that gives extensive control over the stimulation waveform and the stimulation timing. The system supports electrode arrays, which have been suggested to achieve better selectivity and to simplify electrode placement. Electromyography (EMG) measurements are obtained from the active stimulation electrodes (between the stimulation pulses) or from separate surface EMG electrodes. The modular design enables the implementation of sophisticated stimulation control systems including external triggers or wireless sensors. This is demonstrated by the standalone implementation of a feedback-controlled drop foot neuroprosthesis, which uses a wireless inertial sensor for realtime gait phase detection and foot orientation measurement. PMID- 27990238 TI - A Study on Cross-Talk Nerve Stimulation: Electrode Placement and Current Leakage Lid. AB - Cross-talk phenomena should be avoided when stimulating nerves. One option to limit the current spread is to use tripolar electrodes, but at the cost of increasing the number of wires connection. This should be avoided since cables must be thin and compliant. We investigated the impact of the central electrode position and of current spread due to a gap between book and lid on cross-talk, in a set of tripolar or quasi-tripolar configurations.. PMID- 27990240 TI - Paired Associative Stimulation Using Brain-Computer Interfaces for Stroke Rehabilitation: A Pilot Study. AB - Conventional therapies do not provide paralyzed patients with closed-loop sensorimotor integration for motor rehabilitation. Paired associative stimulation (PAS) uses brain-computer interface (BCI) technology to monitor patients' movement imagery in real-time, and utilizes the information to control functional electrical stimulation (FES) and bar feedback for complete sensorimotor closed loop. To realize this approach, we introduce the recoveriX system, a hardware and software platform for PAS. After 10 sessions of recoveriX training, one stroke patient partially regained control of dorsiflexion in her paretic wrist. A controlled group study is planned with a new version of the recoveriX system, which will use a new FES system and an avatar instead of bar feedback. PMID- 27990241 TI - Android Platform for Realtime Gait Tracking Using Inertial Measurement Units. AB - One of the most important movements performed by the humans is gait. Biomechanical Gait analysis is usually by optical capture systems. However, such systems are expensive and sensitive to light and obstacles. In order to reduce those costs a system based on Inertial Measurements Units (IMU) is proposed. IMU are a good option to make movement analisys indoor with a low post-processing data, allowing to connect those systems to an Android platform. The design is based on two elements: a) The IMU sensors and the b) Android device. The IMU sensor is simple, small (35 x 35 mm), portable and autonomous (7.8 hrs). A resolution of 0.01 degrees in their measurements is obtained, and sends data via Bluetooth link. The Android application works for Android 4.2 or higher, and it is compatible with Bluetooth devices 2.0 or higher. Three IMU sensors send data to a Tablet wirelessly, in order to evaluate the angles evolution for each joint of the leg (hip, knee and ankle). This information is used to calculate gait index and evaluate the gait quality online during the physical therapist is working with the patient. PMID- 27990239 TI - Towards Parameters and Protocols to Recommend FES-Cycling in Cases of Paraplegia: A Preliminary Report. AB - Functional Electrical Stimulation assisted cycling (FES-Cycling) is increasingly becoming an alternative option recommended to people with spinal cord injury struggling with paraplegia and interested in practicing sports. In order to propose preconditions to guide FES-Cycling recommendation, we aimed to investigate some features and their potential relationships with responsiveness to Neuromuscular Electrical Stimulation (NMES). Fourteen volunteers attended a public recruitment forum to be assessed about their responsiveness through the 16 sessions of NMES. Volunteers were separated in two groups (responsive and non responsive to NMES) which were investigated in the light of some personal, clinical, structural and functional features. Fifty seven percent of the initial sample responded to electrical stimulation with a visual contraction. This responsive group was predominantly composed by subjects presenting traumatic spinal cord injuries above T12 vertebral level. Only two subjects became responsive at the 3rd and 16th sessions. Among the observed features, the etiology and level of injuries seems to be more associated to responsiveness. Our observations seem to indicate that subjects with traumatic spinal cord injury above T12 level were the best potential candidates for FES-cycling. PMID- 27990242 TI - Effect of Stochastic Modulation of Inter-Pulse Interval During Stimulated Isokinetic Leg Extension. AB - Recumbent cycling exercise achieved by functional electrical stimulation (FES) of the paralyzed leg muscles is effective for cardiopulmonary and musculoskeletal conditioning after spinal cord injury, but its full potential has not yet been realized. Mechanical power output and efficiency is very low and endurance is limited due to early onset of muscle fatigue. The aim of this work was to compare stochastic modulation of the inter-pulse interval (IPI) to constant-frequency stimulation during an isokinetic leg extension task similar to FES-cycling. Seven able-bodied subjects participated: both quadriceps muscles were stimulated (n = 14) with two activation patterns (P1-constant frequency, P2-stochastic IPI). There was significantly higher power output with P2 during the first 30 s (p = 0.0092), the last 30 s (p = 0.018) and overall (p = 0.0057), but there was no overall effect on fatiguability when stimulation frequency was randomly modulated. PMID- 27990243 TI - Human-FES Cooperative Control for Wrist Movement: A Preliminary Study. AB - Functional electrical stimulation (FES) sometimes applies to patients with partial paralysis, so human voluntary control and FES control both exist. Our study aims to build a cooperative controller to achieve human-FES cooperation. This cooperative controller is formed by a classical FES controller and an impedance controller. The FES controller consists of a back propagation (BP) neural network-based feedforward controller and a PID-based feedback controller. The function of impedance controller is to convert volitional force/torque, which is estimated from a three-stage filter based on EMG, into additional angle. The additional angle can reduce the FES intensity in our cooperative controller, comparing to that in classical FES controller. Some assessment experiments are designed to test the performance of the cooperative controller. PMID- 27990244 TI - Electrically and Hybrid-Induced Muscle Activations: Effects of Muscle Size and Fiber Type. AB - The effect of three electrical stimulation (ES) frequencies (10, 35, and 50 Hz) on two muscle groups with different proportions of fast and slow twitch fibers (abductor pollicis brevis (APB) and vastus lateralis (VL)) was explored. We evaluated the acute muscles' responses individually and during hybrid activations (ES superimposed by voluntary activations). Surface electromyography (sEMG) and force measurements were evaluated as outcomes. Ten healthy adults (mean age: 24.4 +/- 2.5 years) participated after signing an informed consent form approved by the university Institutional Review Board. Protocols were developed to: 1) compare EMG activities during each frequency for each muscle when generating 25% Maximum Voluntary Contraction (MVC) force, and 2) compare EMG activities during each frequency when additional voluntary activation was superimposed over ES induced 25% MVC to reach 50% and 75% MVC. Empirical mode decomposition (EMD) was utilized to separate ES artifacts from voluntary muscle activation. For both muscles, higher stimulation frequency (35 and 50Hz) induced higher electrical output detected at 25% of MVC, suggesting more recruitment with higher frequencies. Hybrid activation generated proportionally less electrical activity than ES alone. ES and voluntary activations appear to generate two different modes of muscle recruitment. ES may provoke muscle strength by activating more fatiguing fast acting fibers, but voluntary activation elicits more muscle coordination. Therefore, during the hybrid activation, less electrical activity may be detected due to recruitment of more fatigue-resistant deeper muscle fibers, not reachable by surface EMG. PMID- 27990246 TI - Feasibility of Using Lokomat Combined with Functional Electrical Stimulation for the Rehabilitation of Foot Drop. AB - This study investigated the clinical feasibility of combining the electromechanical gait trainer Lokomat with functional electrical therapy (LokoFET), stimulating the common peroneal nerve during the swing phase of the gait cycle to correct foot drop as an integrated part of gait therapy. Five patients with different acquired brain injuries trained with LokoFET 2-3 times a week for 3-4 weeks. Pre- and post-intervention evaluations were performed to quantify neurophysiological changes related to the patients' foot drop impairment during the swing phase of the gait cycle. A semi-structured interview was used to investigate the therapists' acceptance of LokoFET in clinical practice. The patients showed a significant increase in the level of activation of the tibialis anterior muscle and the maximal dorsiflexion during the swing phase, when comparing the pre- and post-intervention evaluations. This showed an improvement of function related to the foot drop impairment. The interview revealed that the therapists perceived the combined system as a useful tool in the rehabilitation of gait. However, lack of muscle selectivity relating to the FES element of LokoFET was assessed to be critical for acceptance in clinical practice. PMID- 27990245 TI - Feedback Error Learning Controller for Functional Electrical Stimulation Assistance in a Hybrid Robotic System for Reaching Rehabilitation. AB - Hybrid robotic systems represent a novel research field, where functional electrical stimulation (FES) is combined with a robotic device for rehabilitation of motor impairment. Under this approach, the design of robust FES controllers still remains an open challenge. In this work, we aimed at developing a learning FES controller to assist in the performance of reaching movements in a simple hybrid robotic system setting. We implemented a Feedback Error Learning (FEL) control strategy consisting of a feedback PID controller and a feedforward controller based on a neural network. A passive exoskeleton complemented the FES controller by compensating the effects of gravity. We carried out experiments with healthy subjects to validate the performance of the system. Results show that the FEL control strategy is able to adjust the FES intensity to track the desired trajectory accurately without the need of a previous mathematical model. PMID- 27990247 TI - BCI-Triggered Functional Electrical Stimulation Therapy for Upper Limb. AB - We present here the integration of brain-computer interfacing (BCI) technology with functional electrical stimulation therapy to restore voluntary function. The system was tested with a single man with chronic (6 years) severe left hemiplegia resulting from a stroke. The BCI, implemented as a simple "brain-switch" activated by power decreases in the 18 Hz - 28 Hz frequency range of the participant's electroencephalograpic signals, triggered a neuroprosthesis designed to facilitate forward reaching, reaching to the mouth, and lateral reaching movements. After 40 90-minute sessions in which the participant attempted the reaching tasks repeatedly, with the movements assisted by the BCI triggered neuroprosthesis, the participant's arm function showed a clinically significant six point increase in the Fugl-Meyer Asessment Upper Extermity Sub Score. These initial results suggest that the combined use of BCI and functional electrical stimulation therapy may restore voluntary reaching function in individuals with chronic severe hemiplegia for whom the rehabilitation alternatives are very limited. PMID- 27990248 TI - Asymmetric addition of alpha-branched cyclic ketones to allenamides catalyzed by a chiral phosphoric acid. AB - We describe the asymmetric addition of unactivated alpha-branched cyclic ketones to allenamides catalyzed by a chiral phosphoric acid, generating an all-carbon quaternary stereocenter with broad substrate scope and high enantioselectivity. The products are easily transformed into their corresponding 1,5- and 1,4 ketoaldehyde derivatives, which are both important building blocks in organic synthesis. PMID- 27990250 TI - Abundance of ADAM9 transcripts increases in the blood in response to tissue damage. AB - Background: Members of the ADAM (a disintegrin and metalloprotease domain) family have emerged as critical regulators of cell-cell signaling during development and homeostasis. ADAM9 is consistently overexpressed in various human cancers, and has been shown to play an important role in tumorigenesis. However, little is known about the involvement of ADAM9 during immune-mediated processes. Results: Mining of an extensive compendium of transcriptomic datasets led to the discovery of gaps in knowledge for ADAM9 that reveal its role in immunological homeostasis and pathogenesis. The abundance of ADAM9 transcripts in the blood was increased in patients with acute infection but changed very little after in vitro exposure to a wide range of pathogen-associated molecular patterns (PAMPs). Furthermore it was found to increase significantly in subjects as a result of tissue injury or tissue remodeling, in absence of infectious processes. Conclusions: Our findings indicate that ADAM9 may constitute a valuable biomarker for the assessment of tissue damage, especially in clinical situations where other inflammatory markers are confounded by infectious processes. PMID- 27990249 TI - Sex differences in sympathetic innervation and browning of white adipose tissue of mice. AB - BACKGROUND: The higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in beta3-adrenergic remodeling of WAT in mice. METHODS: Effects of the beta3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days. RESULTS: We found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate. CONCLUSIONS: Collectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen dependent sympathetic innervation. PMID- 27990251 TI - Plant adaptation to cold climates. AB - In this short review, I will first summarize criteria by which environments can be considered "cold", with plant stature (size, height above ground) playing a central role for the climate actually experienced. Plants adapted to such environments have to cope with both extremes and with gradual influences of low temperature. The first requires freezing resistance, which is tightly coupled to developmental state (phenology) and prehistory (acclimation). Gradual low temperature constraints affect the growth process (meristems) long before they affect photosynthetic carbon gain. Hence, plants growing in cold climates are commonly not carbon limited. PMID- 27990252 TI - Cluster analysis of Plasmodium RNA-seq time-course data identifies stage-specific co-regulated biological processes and regulatory elements. AB - In this study, we interpreted RNA-seq time-course data of three developmental stages of Plasmodium species by clustering genes based on similarities in their expression profile without prior knowledge of the gene function. Functional enrichment of clusters of upregulated genes at specific time-points reveals potential targetable biological processes with information on their timings. We identified common consensus sequences that these clusters shared as potential points of coordinated transcriptional control. Five cluster groups showed upregulated profile patterns of biological interest. This included two clusters from the Intraerythrocytic Developmental Cycle (cluster 4 = 16 genes, and cluster 9 = 32 genes), one from the sexual development stage (cluster 2 = 851 genes), and two from the gamete-fertilization stage in the mosquito host (cluster 4 = 153 genes, and cluster 9 = 258 genes). The IDC expressed the least numbers of genes with only 1448 genes showing any significant activity of the 5020 genes (~29%) in the experiment. Gene ontology (GO) enrichment analysis of these clusters revealed a total of 671 uncharacterized genes implicated in 14 biological processes and components associated with these stages, some of which are currently being investigated as drug targets in on-going research. Five putative transcription regulatory binding motifs shared by members of each cluster were also identified, one of which was also identified in a previous study by separate researchers. Our study shows stage-specific genes and biological processes that may be important in antimalarial drug research efforts. In addition, timed-coordinated control of separate processes may explain the paucity of factors in parasites. PMID- 27018240 TI - From simple to supercomplex: mitochondrial genomes of euglenozoan protists. AB - Mitochondria are double membrane organelles of endosymbiotic origin, best known for constituting the centre of energetics of a eukaryotic cell. They contain their own mitochondrial genome, which as a consequence of gradual reduction during evolution typically contains less than two dozens of genes. In this review, we highlight the extremely diverse architecture of mitochondrial genomes and mechanisms of gene expression between the three sister groups constituting the phylum Euglenozoa - Euglenida, Diplonemea and Kinetoplastea. The earliest diverging euglenids possess a simplified mitochondrial genome and a conventional gene expression, whereas both are highly complex in the two other groups. The expression of their mitochondrial-encoded proteins requires extensive post transcriptional modifications guided by complex protein machineries and multiple small RNA molecules. Moreover, the least studied diplonemids, which have been recently discovered as a highly abundant component of the world ocean plankton, possess one of the most complicated mitochondrial genome organisations known to date. PMID- 27990254 TI - Analysis of red autofluorescence (650-670nm) in epidermal cell populations and its potential for distinguishing contributors to 'touch' biological samples. AB - Interpretation of touch DNA mixtures poses a significant challenge for forensic caseworking laboratories. Front end techniques that facilitate separation of contributor cell populations before DNA extraction are a way to circumvent this problem. The goal of this study was to survey intrinsic fluorescence of epidermal cells collected from touch surfaces and investigate whether this property could potentially be used to discriminate between contributor cell populations in a biological mixture. Analysis of red autofluorescence (650-670nm) showed that some contributors could be distinguished on this basis. Variation was also observed between autofluorescence profiles of epidermal cell populations from a single contributor sampled on different days. This dataset suggests that red autofluorescence may be a useful marker for identifying distinct cell populations in some mixtures. Future efforts should continue to investigate the extrinsic or intrinsic factors contributing to this signature, and to identify additional biomarkers that could complement this system. PMID- 27990255 TI - Reproductive success is predicted by social dynamics and kinship in managed animal populations. AB - Kin and group interactions are important determinants of reproductive success in many species. Their optimization could, therefore, potentially improve the productivity and breeding success of managed populations used for agricultural and conservation purposes. Here we demonstrate this potential using a novel approach to measure and predict the effect of kin and group dynamics on reproductive output in a well-known species, the meerkat Suricata suricatta. Variation in social dynamics predicts 30% of the individual variation in reproductive success of this species in managed populations, and accurately forecasts reproductive output at least two years into the future. Optimization of social dynamics in captive meerkat populations doubles their projected reproductive output. These results demonstrate the utility of a quantitative approach to breeding programs informed by social and kinship dynamics. They suggest that this approach has great potential for improvements in the management of social endangered and agricultural species. PMID- 27990256 TI - DNA barcoding of Clarias gariepinus, Coptodon zillii and Sarotherodon melanotheron from Southwestern Nigeria. AB - DNA barcoding has been adopted as a gold standard rapid, precise and unifying identification system for animal species and provides a database of genetic sequences that can be used as a tool for universal species identification. In this study, we employed mitochondrial genes 16S rRNA (16S) and cytochrome oxidase subunit I (COI) for the identification of some Nigerian freshwater catfish and Tilapia species. Approximately 655 bp were amplified from the 5' region of the mitochondrial cytochrome C oxidase subunit I (COI) gene whereas 570 bp were amplified for the 16S rRNA gene. Nucleotide divergences among sequences were estimated based on Kimura 2-parameter distances and the genetic relationships were assessed by constructing phylogenetic trees using the neighbour-joining (NJ) and maximum likelihood (ML) methods. Analyses of consensus barcode sequences for each species, and alignment of individual sequences from within a given species revealed highly consistent barcodes (99% similarity on average), which could be compared with deposited sequences in public databases. The nucleotide distance between species belonging to different genera based on COI ranged from 0.17% between Sarotherodonmelanotheron and Coptodon zillii to 0.49% between Clarias gariepinus and C. zillii, indicating that S. melanotheron and C. zillii are closely related. Based on the data obtained, the utility of COI gene was confirmed in accurate identification of three fish species from Southwest Nigeria. PMID- 27441086 TI - RNA-seq analysis is easy as 1-2-3 with limma, Glimma and edgeR. AB - The ability to easily and efficiently analyse RNA-sequencing data is a key strength of the Bioconductor project. Starting with counts summarised at the gene level, a typical analysis involves pre-processing, exploratory data analysis, differential expression testing and pathway analysis with the results obtained informing future experiments and validation studies. In this workflow article, we analyse RNA-sequencing data from the mouse mammary gland, demonstrating use of the popular edgeR package to import, organise, filter and normalise the data, followed by the limma package with its voom method, linear modelling and empirical Bayes moderation to assess differential expression and perform gene set testing. This pipeline is further enhanced by the Glimma package which enables interactive exploration of the results so that individual samples and genes can be examined by the user. The complete analysis offered by these three packages highlights the ease with which researchers can turn the raw counts from an RNA sequencing experiment into biological insights using Bioconductor. PMID- 27990258 TI - Case Report: 84 year-old woman with alien hand syndrome. AB - Background: Alien hand syndrome [AHS] is a rare and ill-defined neurological disorder. It produces complex, goal-directed motion of one hand that is involuntarily instigated. This syndrome characteristically arises after brain trauma, brain surgery, stroke or encephalitis. We describe a case of AHS in a patient who had a previous episode of subarachnoid hemorrhage affecting the left frontal lobe and corpus callosum. Case presentation: An 84-year-old woman presented to the emergency department complaining of headaches and several episodes of her left arm moving as if it was groping around trying to grab at her own body. A computed tomography scan of the head demonstrated an acute left superior frontal hemorrhage with compression of the corpus callosum. Transcranial Doppler report showed no significant abnormality in the insonated vessels. After being stabilized for the acute bleed, she was treated with clonazepam 0.5 mgat night for the uncontrolled hand movements. Her movements resolved by her next month follow up. The diagnosis of AHS was made based on her clinical presentation, characterization of the movement and localization correlating with findings in neuroimaging. Conclusion: We document a rare neurologic disorder seen in patients presenting with a history of previous strokes and a typical description of involuntary and unintentional, uncontrolled unilateral arm movements with repetitive grasping. The present case has a combination of frontal and callosal lesions. These findings appear to support a potential destruction leading to the rare syndrome. PMID- 27990259 TI - Anterior single odontoid screw placement for type II odontoid fractures: our modified surgical technique and initial results in a cohort study of 15 patients. AB - Objective: Anterior odontoid screw fixation for type II odontoid fracture is the ideal management option. However in the context of unavailability of an O-arm or neuro-navigation and poor images from the available C-arm may be an obstacle to ideal trajectory and placement of the odontoid screw. We herein detail our surgical technique so as to ensure a correct trajectory and subsequent good fusion in Type II odontoid fractures. This may be advantageous in clinical set ups lacking state of the art facilities. Methods and Results: In this cohort study we included 15 consecutive patients who underwent anterior odontoid screw placement. We routinely dissect the longus colli to completely visualize the entire width of C3 body. We then perform a median C2-C3 disectomy followed by creating a gutter in the superior end of C3 body. We then guide the Kirchsner (K) wire purchasing adequate anterior cortex of C2. Rest of the procedure follows the similar steps as described for odontoid screw placement. We achieved 100% correct trajectory and screw placement in our study. There were no instances of screw break out, pull out or nonunion. There was one patient mortality following myocardial infarction in our study. Conclusion: Preoperative imaging details, proper patient positioning, meticulous dissection, thorough anatomical knowledge and few added surgical nuances are the cornerstones in ideal odontoid screw placement. This may be pivotal in managing patients in developing nations having rudimentary neurosurgical set up. PMID- 27990260 TI - Genomic variant annotation workflow for clinical applications. AB - Annotation and interpretation of DNA aberrations identified through next generation sequencing is becoming an increasingly important task. Even more so in the context of data analysis pipelines for medical applications, where genomic aberrations are associated with phenotypic and clinical features. Here we describe a workflow to identify potential gene targets in aberrated genes or pathways and their corresponding drugs. To this end, we provide the R/Bioconductor package rDGIdb, an R wrapper to query the drug-gene interaction database (DGIdb). DGIdb accumulates drug-gene interaction data from 15 different source databases and allows filtering on different levels. The rDGIdb package makes these resources and tools available to R users. Moreover, DGIdb queries can be automated through incorporation of the rDGIdb package into NGS sequencing pipelines. PMID- 27928497 TI - The invariances of power law size distributions. AB - Size varies. Small things are typically more frequent than large things. The logarithm of frequency often declines linearly with the logarithm of size. That power law relation forms one of the common patterns of nature. Why does the complexity of nature reduce to such a simple pattern? Why do things as different as tree size and enzyme rate follow similarly simple patterns? Here I analyze such patterns by their invariant properties. For example, a common pattern should not change when adding a constant value to all observations. That shift is essentially the renumbering of the points on a ruler without changing the metric information provided by the ruler. A ruler is shift invariant only when its scale is properly calibrated to the pattern being measured. Stretch invariance corresponds to the conservation of the total amount of something, such as the total biomass and consequently the average size. Rotational invariance corresponds to pattern that does not depend on the order in which underlying processes occur, for example, a scale that additively combines the component processes leading to observed values. I use tree size as an example to illustrate how the key invariances shape pattern. A simple interpretation of common pattern follows. That simple interpretation connects the normal distribution to a wide variety of other common patterns through the transformations of scale set by the fundamental invariances. PMID- 27990263 TI - Lies, irony, and contradiction - an annotation of semantic conflict in the movie "Forrest Gump". AB - Here we extend the information on the structure of the core stimulus of the studyforrest project (http://studyforrest.org) with a description of semantic conflict in the "Forrest Gump" movie. Three observers annotated the movie independently regarding episodes with portrayal of lies, irony or sarcasm. We present frequency statistics, and inter-observer reliability measures that qualify and quantify semantic conflict in the stimulus. While the number of identified events is limited, this annotation nevertheless enriches the knowledge about the complex high-level structure of this stimulus, and can help to evaluate its utility for future studies, and the usability of the existing brain imaging data regarding this aspect of cognition. PMID- 27990264 TI - Creating a driving profile for older adults using GPS devices and naturalistic driving methodology. AB - Background/Objectives: Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. We adapted an existing, commercial, off-the-shelf, in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers. Design: The Azuga G2 Tracking Device TM was installed in each participant's vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven. Setting: The Knight Alzheimer's Disease Research Center at Washington University School of Medicine. Participants: Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance. Participants were aged 65+ years and had normal cognition. Measurements: Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations. Temporal components included number of trips taken during different times of the day. Behavioral components included number of hard braking, speeding and sudden acceleration events. Methods: Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS. Results: Primary locations were confirmed to be 100% accurate when compared to known addresses. Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns. Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night. Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period. Conclusions: This pilot study indicated that Driving Profiles for older adults can be created and compared month-to-month or year-to-year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions. PMID- 27703668 TI - Protein domain architectures provide a fast, efficient and scalable alternative to sequence-based methods for comparative functional genomics. AB - A functional comparative genome analysis is essential to understand the mechanisms underlying bacterial evolution and adaptation. Detection of functional orthologs using standard global sequence similarity methods faces several problems; the need for defining arbitrary acceptance thresholds for similarity and alignment length, lateral gene acquisition and the high computational cost for finding bi-directional best matches at a large scale. We investigated the use of protein domain architectures for large scale functional comparative analysis as an alternative method. The performance of both approaches was assessed through functional comparison of 446 bacterial genomes sampled at different taxonomic levels. We show that protein domain architectures provide a fast and efficient alternative to methods based on sequence similarity to identify groups of functionally equivalent proteins within and across taxonomic boundaries. As the computational cost scales linearly, and not quadratically with the number of genomes, it is suitable for large scale comparative analysis. Running both methods in parallel pinpoints potential functional adaptations that may add to bacterial fitness. PMID- 27990265 TI - Building pathway graphs from BioPAX data in R. AB - Biological pathways are increasingly available in the BioPAX format which uses an RDF model for data storage. We can retrieve the information in this data model in the scripting language R using the package rBiopaxParser, which converts the BioPAX format to one readable in R. It also has a function to build a regulatory network from the pathway information, here we describe an extension of this function. The new function will also include non-regulatory interactions in the pathway and thus allow extraction of maximum information. This function will be available as part of the rBiopaxParser distribution from Bioconductor. PMID- 27990267 TI - Two-step feature selection for predicting survival time of patients with metastatic castrate resistant prostate cancer. AB - Metastatic castrate resistant prostate cancer (mCRPC) is the major cause of death in prostate cancer patients. Even though some options for treatment of mCRPC have been developed, the most effective therapies remain unclear. Thus finding key patient clinical variables related with mCRPC is an important issue for understanding the disease progression mechanism of mCRPC and clinical decision making for these patients. The Prostate Cancer DREAM Challenge is a crowd-based competition to tackle this essential challenge using new large clinical datasets. This paper proposes an effective procedure for predicting global risks and survival times of these patients, aimed at sub-challenge 1a and 1b of the Prostate Cancer DREAM challenge. The procedure implements a two-step feature selection procedure, which first implements sparse feature selection for numerical clinical variables and statistical hypothesis testing of differences between survival curves caused by categorical clinical variables, and then implements a forward feature selection to narrow the list of informative features. Using Cox's proportional hazards model with these selected features, this method predicted global risk and survival time of patients using a linear model whose input is a median time computed from the hazard model. The challenge results demonstrated that the proposed procedure outperforms the state of the art model by correctly selecting more informative features on both the global risk prediction and the survival time prediction. PMID- 27990266 TI - Breeding novel solutions in the brain: a model of Darwinian neurodynamics. AB - Background: The fact that surplus connections and neurons are pruned during development is well established. We complement this selectionist picture by a proof-of-principle model of evolutionary search in the brain, that accounts for new variations in theory space. We present a model for Darwinian evolutionary search for candidate solutions in the brain. Methods: We combine known components of the brain - recurrent neural networks (acting as attractors), the action selection loop and implicit working memory - to provide the appropriate Darwinian architecture. We employ a population of attractor networks with palimpsest memory. The action selection loop is employed with winners-share-all dynamics to select for candidate solutions that are transiently stored in implicit working memory. Results: We document two processes: selection of stored solutions and evolutionary search for novel solutions. During the replication of candidate solutions attractor networks occasionally produce recombinant patterns, increasing variation on which selection can act. Combinatorial search acts on multiplying units (activity patterns) with hereditary variation and novel variants appear due to (i) noisy recall of patterns from the attractor networks, (ii) noise during transmission of candidate solutions as messages between networks, and, (iii) spontaneously generated, untrained patterns in spurious attractors. Conclusions: Attractor dynamics of recurrent neural networks can be used to model Darwinian search. The proposed architecture can be used for fast search among stored solutions (by selection) and for evolutionary search when novel candidate solutions are generated in successive iterations. Since all the suggested components are present in advanced nervous systems, we hypothesize that the brain could implement a truly evolutionary combinatorial search system, capable of generating novel variants. PMID- 27990268 TI - Monitoring the compliance of the academic enterprise with the Fair Labor Standards Act. AB - Background: On December 1 2016, the Fair Labor Standards Act (FLSA) will be updated by the U.S. Department of Labor. The key changes are an increase in the salary threshold for exemption from overtime for working more than 40 hours per week, and indexing the salary level so that it is updated automatically every 3 years. This update is predicted to have a profound effect on the academic enterprise as a large proportion of the postdoctoral researcher population is currently paid at a salary below the new threshold for exemption. Here we review the key changes to the FLSA, how they came about, and how the postdoctoral population is affected by the ruling. Methods: We describe recent data collection efforts (checking university websites and contacting HR departments) to uncover what institutions in the 2014 NSF Survey of Graduate Students and Postdoctorates in Science and Engineering are doing to comply with the FLSA ruling for postdocs. Results: Our data show that 41% of the estimated postdoctoral workforce in STEM and 57% of institutions checked have not decided or have no public decision yet available one month prior to implementation, and only 35.5% of institutions are planning to raise salaries to the new minimum. Conclusions: Our data show the uncertainty of postdoc salaries in the U.S. one month prior to implementation of the FLSA ruling. This implementation also gives rise to various issues that have arisen in an already strained research enterprise, including short-, medium- and long-term effects on academe. PMID- 27990269 TI - Disambiguate: An open-source application for disambiguating two species in next generation sequencing data from grafted samples. AB - Grafting of cell lines and primary tumours is a crucial step in the drug development process between cell line studies and clinical trials. Disambiguate is a program for computationally separating the sequencing reads of two species derived from grafted samples. Disambiguate operates on alignments to the two species and separates the components at very high sensitivity and specificity as illustrated in artificially mixed human-mouse samples. This allows for maximum recovery of data from target tumours for more accurate variant calling and gene expression quantification. Given that no general use open source algorithm accessible to the bioinformatics community exists for the purposes of separating the two species data, the proposed Disambiguate tool presents a novel approach and improvement to performing sequence analysis of grafted samples. Both Python and C++ implementations are available and they are integrated into several open and closed source pipelines. Disambiguate is open source and is freely available at https://github.com/AstraZeneca-NGS/disambiguate. PMID- 27990271 TI - Recent advances in understanding & managing male infertility. AB - Male infertility remains a struggle to definitively diagnose and treat with many men labelled as "idiopathic infertility" and eventually requiring assisted reproductive techniques. Along those lines, research groups are continuing to explore current social and environmental factors, including the obesity epidemic, and their effects on male fertility potential. Novel biomarkers of natural fertility status and azoospermia etiology have additionally seen recent attention with ACRV1 and TEX101/ECM1 assays either currently or soon to be commercially available. Despite these advancements, however, medical treatment options have seen little progress. Though surgical therapies have similarly seen little transformation, groups are exploring the use of testicular sperm for couples with elevated sperm DNA fragmentation and either planned or previously failed IVF/ICSI. Concerted collaborative efforts will be needed as we move forward to better understand the challenges men face when struggling to conceive. PMID- 27990270 TI - Recent advances in the management of pulmonary arterial hypertension. AB - Over the past 20 years, there has been an explosion in the development of therapeutics to treat pulmonary arterial hypertension (PAH), a rare but life threatening disorder associated with progressive elevation of pulmonary pressures and severe right heart failure. Recently, the field has seen the introduction of riociguat, a soluble guanylate cyclase stimulator, a new endothelin receptor antagonist (macitentan), and oral prostanoids (treprostinil and selexipag). Besides new drugs, there have been significant advances in defining the role of upfront combination therapy in treatment-naive patients as well as proposed methods to deliver systemic prostanoids by use of implantable pumps. In this review, we will touch upon the most important developments in PAH therapeutics over the last three years and how these have changed the guidelines for the treatment of PAH. These exciting developments herald a new era in the treatment of PAH which will be punctuated by the use of more clinically relevant endpoints in clinical research trials and a novel treatment paradigm that may involve upfront double- or triple-combination therapy. We anticipate that the future will make use of these strategies to test the efficacy of upcoming new drugs that aspire to reduce disease progression and improve survival in patients afflicted with this devastating disease. PMID- 27990272 TI - Evaluation of recombinant monoclonal antibody SVmab1 binding to Na V1.7 target sequences and block of human Na V1.7 currents. AB - Identification of small and large molecule pain therapeutics that target the genetically validated voltage-gated sodium channel Na V1.7 is a challenging endeavor under vigorous pursuit. The monoclonal antibody SVmab1 was recently published to bind the Na V1.7 DII voltage sensor domain and block human Na V1.7 sodium currents in heterologous cells. We produced purified SVmab1 protein based on publically available sequence information, and evaluated its activity in a battery of binding and functional assays. Herein, we report that our recombinant SVmAb1 does not bind peptide immunogen or purified Na V1.7 DII voltage sensor domain via ELISA, and does not bind Na V1.7 in live HEK293, U-2 OS, and CHO-K1 cells via FACS. Whole cell manual patch clamp electrophysiology protocols interrogating diverse Na V1.7 gating states in HEK293 cells, revealed that recombinant SVmab1 does not block Na V1.7 currents to an extent greater than observed with an isotype matched control antibody. Collectively, our results show that recombinant SVmab1 monoclonal antibody does not bind Na V1.7 target sequences or specifically inhibit Na V1.7 current. PMID- 27990273 TI - Advances in the management of osteosarcoma. AB - Osteosarcoma, a bone cancer most commonly seen in adolescents and young adults, is usually a high-grade malignancy characterized by a very high risk for the development of pulmonary metastases. High-grade osteosarcomas are usually treated by preoperative and postoperative chemotherapy and surgery, with a very limited number of active agents available. Rarer lower-grade variants such as parosteal and periosteal osteosarcoma or low-grade central osteosarcoma are treated by surgery only. Imaging to search for possible metastases focuses on the lung. Computed tomography is the most sensitive method but cannot reliably distinguish small metastases from benign lesions. Advances of local imaging and surgical reconstruction now allow the use of limb-salvage in an ever-increasing proportion of patients. While still troubled by complications, non-invasive endoprosthesis lengthening mechanisms have led to an increased uptake of limb-salvage, even for young, skeletally immature patients. Radiotherapy is employed when osteosarcomas cannot be removed with clear margins, but very high doses are required, and both proton and carbon-ion radiotherapy are under investigation. Unfortunately, the past 30 years have witnessed few, if any, survival improvements. Novel agents have not led to universally accepted changes of treatment standards. In patients with operable high-grade osteosarcomas, the extent of histological response to preoperative chemotherapy is a significant predictive factor for both local and systemic control. Attempts to improve prognosis by adapting postoperative treatment to response, recently tested in a randomized, prospective setting by the European and American Osteosarcoma Study Group, have not been proven to be beneficial. Many agree that only increased knowledge about osteosarcoma biology will lead to novel, effective treatment approaches and will be able to move the field forward. PMID- 27990274 TI - Bacteriophage-based tools: recent advances and novel applications. AB - Bacteriophages (phages) are viruses that infect bacterial hosts, and since their discovery over a century ago they have been primarily exploited to control bacterial populations and to serve as tools in molecular biology. In this commentary, we highlight recent diverse advances in the field of phage research, going beyond bacterial control using whole phage, to areas including biocontrol using phage-derived enzybiotics, diagnostics, drug discovery, novel drug delivery systems and bionanotechnology. PMID- 27990275 TI - Recent advances in the medical treatment of breast cancer. AB - Over the past few decades, the systemic therapy of breast cancer (early and advanced) has changed considerably. For the past 40-50 years, and since the discovery and further therapeutic use of tamoxifen, a selective estrogen receptor modulator, breast cancer treatment has become the model for the development and success of tailored medical treatment. Much still needs to be done in improving outcomes for all patients with breast cancer, and especially for those who have advanced breast cancer, a challenging area for medical oncologists. Ongoing international clinical trials are currently evaluating new therapeutic approaches and identifying specific biological subsets that could determine a patient's ability to respond to particular chemotherapeutic drugs. PMID- 27990277 TI - Biting the hand that feeds: current opinion on the interpersonal causes, correlates, and consequences of borderline personality disorder. AB - Borderline personality disorder (BPD) is a complex psychiatric diagnosis characterized by dysregulated behaviors, emotions, cognitions, and interpersonal relationships. In recent years, developmental psychopathologists have sought to identify early origins of BPD, with the ultimate goal of developing and providing effective preventative interventions for those at highest risk. In addition to heritable biological sensitivities, many scholars assert that environmental and interpersonal risk factors contribute to the emergence and maintenance of key borderline traits. Nonetheless, many BPD researchers examine only affected individuals, neglecting the family, peer, couple, and other dynamic contextual forces that impinge upon individual-level behavior. In the past decade, however, theoretical and empirical research has increasingly explored the interpersonal causes, correlates, and consequences of BPD. Such work has resulted in novel research and clinical theories intended to better understand and improve interpersonal dynamics among those with borderline traits. A major objective for the field is to better characterize how interpersonal dynamics affect (and are affected by) the behaviors, emotions, and thoughts of vulnerable individuals to either reduce or heighten risk for BPD. PMID- 27990276 TI - Recent advances in understanding Streptomyces. AB - About 2,500 papers dated 2014-2016 were recovered by searching the PubMed database for Streptomyces, which are the richest known source of antibiotics. This review integrates around 100 of these papers in sections dealing with evolution, ecology, pathogenicity, growth and development, stress responses and secondary metabolism, gene expression, and technical advances. Genomic approaches have greatly accelerated progress. For example, it has been definitively shown that interspecies recombination of conserved genes has occurred during evolution, in addition to exchanges of some of the tens of thousands of non-conserved accessory genes. The closeness of the association of Streptomyces with plants, fungi, and insects has become clear and is reflected in the importance of regulators of cellulose and chitin utilisation in overall Streptomyces biology. Interestingly, endogenous cellulose-like glycans are also proving important in hyphal growth and in the clumping that affects industrial fermentations. Nucleotide secondary messengers, including cyclic di-GMP, have been shown to provide key input into developmental processes such as germination and reproductive growth, while late morphological changes during sporulation involve control by phosphorylation. The discovery that nitric oxide is produced endogenously puts a new face on speculative models in which regulatory Wbl proteins (peculiar to actinobacteria) respond to nitric oxide produced in stressful physiological transitions. Some dramatic insights have come from a new model system for Streptomyces developmental biology, Streptomyces venezuelae, including molecular evidence of very close interplay in each of two pairs of regulatory proteins. An extra dimension has been added to the many complexities of the regulation of secondary metabolism by findings of regulatory crosstalk within and between pathways, and even between species, mediated by end products. Among many outcomes from the application of chromosome immunoprecipitation sequencing (ChIP-seq) analysis and other methods based on "next-generation sequencing" has been the finding that 21% of Streptomyces mRNA species lack leader sequences and conventional ribosome binding sites. Further technical advances now emerging should lead to continued acceleration of knowledge, and more effective exploitation, of these astonishing and critically important organisms. PMID- 27990279 TI - Genetic factors influencing risk to orofacial clefts: today's challenges and tomorrow's opportunities. AB - Orofacial clefts include cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), which combined represent the largest group of craniofacial malformations in humans with an overall prevalence of one per 1,000 live births. Each of these birth defects shows strong familial aggregation, suggesting a major genetic component to their etiology. Genetic studies of orofacial clefts extend back centuries, but it has proven difficult to define any single etiologic mechanism because many genes appear to influence risk. Both linkage and association studies have identified several genes influencing risk, but these differ across families and across populations. Genome-wide association studies have identified almost two dozen different genes achieving genome-wide significance, and there are broad classes of 'causal genes' for orofacial clefts: a few genes strongly associated with risk and possibly directly responsible for Mendelian syndromes which include orofacial clefts as a key phenotypic feature of the syndrome, and multiple genes with modest individual effects on risk but capable of disrupting normal craniofacial development under the right circumstances (which may include exposure to environmental risk factors). Genomic sequencing studies are now underway which will no doubt reveal additional genes/regions where variants (sequence and structural) can play a role in controlling risk to orofacial clefts. The real challenge to medicine and public health is twofold: to identify specific genes and other etiologic factors in families with affected members and then to devise effective interventions for these different biological mechanisms controlling risk to complex and heterogeneous birth defects such as orofacial clefts. PMID- 27990278 TI - Understanding nontuberculous mycobacterial lung disease: it's been a long time coming. AB - With a surprising predictability, most studies and reviews addressing therapy for nontuberculous mycobacterial (NTM) lung disease either start or end by mentioning the paucity of data from randomized and controlled trials. That is a legitimate criticism for NTM lung disease therapy, but it also somehow seems to influence attitudes toward all aspects of NTM investigation. Certainly the study of NTM diseases in general and NTM lung disease in particular is a recent development. Previously, NTM were viewed as minor, if inconvenient, pathogens similar to Mycobacterium tuberculosis. However, over the last three decades, NTM have emerged as increasingly important pathogens that are clearly different compared with tuberculosis. Although there has been frustratingly slow progress in the treatment of NTM diseases, in contrast there has unquestionably been impressive progress in almost every other realm of investigation into NTM disease. Our understanding of NTM lung disease a) pathophysiology, including mechanisms of organism acquisition, b) epidemiology, including estimates of disease prevalence, c) mycobacteriology, including application of molecular laboratory techniques and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, and d) even treatment strategies, including the recognition of innate drug resistance mechanisms, has immeasurably and permanently changed and advanced the landscape for NTM lung disease. It is no longer necessary to apologize for the state of NTM lung disease knowledge and understanding, but rather it is time to recognize the great distance we have travelled over the last 30 years. PMID- 27990280 TI - Hyphal ontogeny in Neurospora crassa: a model organism for all seasons. AB - Filamentous fungi have proven to be a better-suited model system than unicellular yeasts in analyses of cellular processes such as polarized growth, exocytosis, endocytosis, and cytoskeleton-based organelle traffic. For example, the filamentous fungus Neurospora crassa develops a variety of cellular forms. Studying the molecular basis of these forms has led to a better, yet incipient, understanding of polarized growth. Polarity factors as well as Rho GTPases, septins, and a localized delivery of vesicles are the central elements described so far that participate in the shift from isotropic to polarized growth. The growth of the cell wall by apical biosynthesis and remodeling of polysaccharide components is a key process in hyphal morphogenesis. The coordinated action of motor proteins and Rab GTPases mediates the vesicular journey along the hyphae toward the apex, where the exocyst mediates vesicle fusion with the plasma membrane. Cytoplasmic microtubules and actin microfilaments serve as tracks for the transport of vesicular carriers as well as organelles in the tubular cell, contributing to polarization. In addition to exocytosis, endocytosis is required to set and maintain the apical polarity of the cell. Here, we summarize some of the most recent breakthroughs in hyphal morphogenesis and apical growth in N. crassa and the emerging questions that we believe should be addressed. PMID- 27990282 TI - The complement system: an evolution in progress. AB - The complement system, which consists of three independent but interacting pathways, constitutes a powerful arm of innate immunity. Its major function is to recognize and destroy pathogenic microorganisms as well as eliminate modified self-antigens. Although it is a fine-tuned system with innate capacity to discriminate self from non-self as well as danger from non-danger signals, an unwarranted activation can nonetheless occur and cause tissue destruction. To prevent such activation, specific regulators present both in plasma and on the cell surface tightly control it. Data accumulated over the past four decades have also shown that the complement system is capable of not only cross-talk with the activation cascades of plasma--i.e. blood coagulation, contact activation, and the kinin/kallikrein system--but also serving as a bridge between innate and adaptive immunity. It is for these reasons that the various activation steps of the complement system have been recently targeted for therapy to treat diseases in which the role of complement is beyond doubt. This trend will certainly continue for years to come, especially as novel concepts guiding the field into areas never contemplated before are continuing to be discovered. PMID- 27990283 TI - The gut microbiota and immune-regulation: the fate of health and disease. PMID- 27990281 TI - Mitochondrial apoptosis and BH3 mimetics. AB - The BCL2-selective BH3 mimetic venetoclax was recently approved for the treatment of relapsed, chromosome 17p-deleted chronic lymphocytic leukemia (CLL) and is undergoing extensive testing, alone and in combination, in lymphomas, acute leukemias, and solid tumors. Here we summarize recent advances in understanding of the biology of BCL2 family members that shed light on the action of BH3 mimetics, review preclinical and clinical studies leading to the regulatory approval of venetoclax, and discuss future investigation of this new class of antineoplastic agent. PMID- 27990284 TI - A structure-function approach to optimizing TLR4 ligands for human vaccines. AB - Adjuvants are combined with vaccine antigens to enhance and modify immune responses, and have historically been primarily crude, undefined entities. Introducing toll-like receptor (TLR) ligands has led to a new generation of adjuvants, with TLR4 ligands being the most extensively used in human vaccines. The TLR4 crystal structures demonstrate extensive contact with their ligands and provide clues as to how they discriminate a broad array of molecules and activate or attenuate innate, as well as adaptive, responses resulting from these interactions. Leveraging this discerning ability, we made subtle chemical alterations to the structure of a synthetic monophosphoryl lipid-A molecule to produce SLA, a designer TLR4 ligand that had a number of desirable adjuvant effects. The SLA molecule stimulated human TLR4 and induced Th1 biasing cytokines and chemokines. On human cells, the activity of SLA plateaued at lower concentrations than the lipid A comparator, and induced cytokine profiles distinct from other known TLR4 agonists, indicating the potential for superior adjuvant performance. SLA was formulated in an oil-in-water emulsion, producing an adjuvant that elicited potent Th1-biased adaptive responses. This was verified using a recombinant Leishmania vaccine antigen, first in mice, then in a clinical study in which the antigen-specific Th1-biased responses observed in mice were recapitulated in humans. These results demonstrated that using structure-based approaches one can predictably design and produce modern adjuvant formulations for safe and effective human vaccines. PMID- 27990285 TI - Non-small cell lung cancer is characterised by a distinct inflammatory signature in serum compared with chronic obstructive pulmonary disease. AB - Development of lung cancer is closely related to smoking in a majority of patients. Most smokers, however, do not develop lung cancer in spite of a high mutational load accumulating in the lung tissue. Here we investigate whether a cancer-specific footprint can be revealed by investigating circulating inflammatory markers in patients with non-small cell lung cancer (NSCLC) compared with patients with chronic obstructive pulmonary disease (COPD), both cohorts characterised by similar smoking history. Serum concentrations of 57 cytokines and matrix metalloproteinases (MMPs) from 43 patients with advanced NSCLC were evaluated by multiplex immunoassays and compared with serum samples from 35 patients with COPD. Unsupervised hierarchical clustering and non-parametric analyses were performed. False discovery rate was used to adjust for multiple testing. Clustering of cytokine and MMP concentrations in the serum revealed a distinct separation of the NSCLC patients from the COPD group. Individual concentrations of thymus and activation-regulated cytokine (C-C motif chemokine ligand 17), Gro-b (C-X-C motif chemokine ligand 2 (CXCL2)), CXCL13, interleukin (IL)-1ra, IL-6, IL-8 (CXCL8), IL-16, IL-17A, macrophage migration inhibitory factor (MIF), granulocyte colony-stimulating factor, platelet-derived growth factor subunit B, MMP-2, MMP-8 and MMP-12 were significantly different in serum from NSCLC and COPD patients. Moreover, the interferon-gamma/IL-10 ratio was lower in cancer patients compared with COPD patients, consistent with a cytokine milieu favouring tumour tolerance. Our results suggest that NSCLC is characterised by a distinct inflammatory signature in serum. The different cytokine profiles in NSCLC and COPD patients may represent tumour-promoting and tumour-suppressing immune responses developing in response to mucosal inflammation and mutations induced by smoking. PMID- 27990286 TI - Guanylate-binding protein 5 is a marker of interferon-gamma-induced classically activated macrophages. AB - Macrophage activation is the main immunological process occurring during the development of several diseases, and the heterogeneity of macrophage activation or differentiation has been suggested to be involved in disease progression. In the present study, we attempted to identify molecules specifically expressed on human classically activated macrophages (M1) to investigate the significance of the M1-like phenotype in human diseases. Human monocyte-derived macrophages were differentiated into M1, M2a, M2b and M2c phenotypes, and also M1(-) (the M1 phenotype differentiated with interferon-gamma) to eliminate the strong effects of lipopolysaccharides (LPS) on the gene expression profile. The gene expression profiles of those macrophage phenotypes were analyzed by a cDNA microarray analysis and were used for a bioinformatics examination to identify the markers of the M1 phenotype that are expressed in both M1 and M1(-). The gene expression profiles of murine macrophages were also evaluated. We identified guanylate binding protein 5 (GBP5), which is associated nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) mediated inflammasome assembly in the M1 macrophages of both humans and mice. Notably, the expression of GBP5 protein was detected in cultured M1(-) as well as in M1 macrophages by western blotting, which means that GBP5 is a more generalized marker of the M1 phenotype compared with the M1 markers that can be induced by LPS stimulation. GBP5 is a useful candidate marker of the M1 phenotype. PMID- 27990287 TI - Coeliac disease: a unique model for investigating broken tolerance in autoimmunity. AB - Coeliac disease, a prevalent immune-mediated enteropathy driven by dietary gluten, provides an exceptional human model to dissect the genetic, environmental and immunologic factors operating in autoimmunity. Despite the causative antigen being an exogenous food protein, coeliac disease has many features in common with autoimmune disease including a strong HLA class II association and the presence of pathogenic CD4+ T cells and autoantibodies. CD8+ intraepithelial lymphocytes specifically target and destroy intestinal epithelium in response to stress signals and not a specific antigen. A unique feature of coeliac disease is the ability to remove gluten to induce disease remission and reintroduce it to trigger a memory response. This provides an unparalleled opportunity to study disease-relevant CD4+ T cells that have been expanded in vivo. As a result, the causative peptides have been characterised at a level unprecedented for any autoimmune disease. Despite the complexity of the gluten proteome, resistance to gastrointestinal proteolysis and susceptibility to post-translational modification by transglutaminase help shape a restricted repertoire of immunogenic gluten peptides that have high affinity for disease-associated HLA. The critical steps in coeliac disease pathogenesis have been broadly elucidated and provide the basis for experimental therapies in pre-clinical or clinical development. However, little is known about how and why tolerance to gluten sometimes breaks or fails to develop. Understanding the interactions between genes, the environment, gluten immunity and the microbiome may provide novel approaches for the prevention and treatment of disease. PMID- 27990289 TI - Physiological reactions to capture in hibernating brown bears. AB - Human disturbance can affect animal life history and even population dynamics. However, the consequences of these disturbances are difficult to measure. This is especially true for hibernating animals, which are highly vulnerable to disturbance, because hibernation is a process of major physiological changes, involving conservation of energy during a resource-depleted time of year. During the winters of 2011-15, we captured 15 subadult brown bears (Ursus arctos) and recorded their body temperatures (n = 11) and heart rates (n = 10) before, during and after capture using biologgers. We estimated the time for body temperature and heart rate to normalize after the capture event. We then evaluated the effect of the captures on the pattern and depth of hibernation and the day of den emergence by comparing the body temperature of captured bears with that of undisturbed subadult bears (n = 11). Both body temperature and heart rate increased during capture and returned to hibernation levels after 15-20 days. We showed that bears required 2-3 weeks to return to hibernation levels after winter captures, suggesting high metabolic costs during this period. There were also indications that the winter captures resulted in delayed den emergence. PMID- 27990288 TI - Infiltrating monocytes in liver injury and repair. AB - Noninfectious liver injury causes many acute and chronic liver diseases around the globe, and particularly in developed nations. Bone marrow-derived monocytes infiltrate the damaged liver tissue and are a critical component of the innate immune response that may drive injury resolution or host death in the short term or chronic inflammation, fibrosis and hepatocellular carcinoma in the long term. Monocytes often play dual roles in liver injury-both perpetuating inflammation and promoting resolution of inflammation and fibrosis. Thus, we will address the role that monocytes play in different experimental forms of noninfectious liver injury; considering in particular the importance of the transition from inflammatory Ly6Chi monocytes to pro-resolution Ly6Clo monocyte-derived macrophages and the consequences of this transition for disease progression and resolution. PMID- 27990290 TI - Tropical fish in a warming world: thermal tolerance of Nile perch Lates niloticus (L.) in Lake Nabugabo, Uganda. AB - Key to predicting the response of fishes to climate change is quantifying how close fish are to their critical thermal limits in nature and their ability to adjust their thermal sensitivity to maintain performance. Here, we evaluated the effects of body size and habitat on aerobic scope (AS) and thermal tolerance of Nile perch Lates niloticus (L.), a fish of great economic and food security importance in East Africa, using respirometry and critical thermal maximum (CTmax) trials. Juvenile Nile perch from distinct habitats (high or low dissolved oxygen concentrations) of Lake Nabugabo, Uganda were exposed for 4.6 +/- 0.55 days to a temperature treatment (25.5, 27.5, 29.5 or 31.5 degrees C) prior to experimentation, with the lowest temperature corresponding to the mean annual daytime temperature in Lake Nabugabo and the highest temperature being 3 degrees C higher than the maximal monthly average. As expected, metabolic rates increased with body mass. Although resting metabolic rate increased with temperature, maximal metabolic rate showed no change. Likewise, AS did not vary across treatments. The CTmax increased with acclimation temperature. There was no effect of habitat on maximal metabolic rate, AS or CTmax; however, there was a trend towards a lower resting metabolic rate for Nile perch captured in the low dissolved oxygen habitat than in well-oxygenated waters. This study shows that juvenile Nile perch maintain a large AS at temperatures near the upper limit of their natural thermal range and provides evidence that Nile perch have physiological mechanisms to deal with acute exposure to thermal stress. PMID- 27990291 TI - Limited variability in upper thermal tolerance among pure and hybrid populations of a cold-water fish. AB - As climate warming threatens the persistence of many species and populations, it is important to forecast their responses to warming thermal regimes. Climate warming often traps populations in smaller habitat fragments, not only changing biotic parameters, but potentially decreasing adaptive potential by decreasing genetic variability. We examined the ability of six genetically distinct and different-sized populations of a cold-water fish (brook trout, Salvelinus fontinalis) to tolerate acute thermal warming and whether this tolerance could be altered by hybridizing populations. Critical thermal maximum (CTmax) assays were conducted on juveniles from each population to assess thermal tolerance, and the agitation temperature was recorded for assessing behavioural changes to elevated temperatures. An additional metric, which we have called the 'CTmax-agitation window' (CTmax minus agitation temperature), was also assessed. The CTmax differed between five out of 15 population pairs, although the maximal CTmax difference was only 0.68 degrees C (29.11-29.79 degrees C). Hybridization between one large population and two small populations yielded no obvious heterosis in mean CTmax, and no differences in agitation temperature or CTmax-agitation window were detected among pure populations or hybrids. Summer variation in temperature within each stream was negatively correlated with mean CTmax and mean CTmax agitation window, although the maximal difference was small. Despite being one of the most phenotypically divergent and plastic north temperate freshwater fishes, our results suggest that limited variability exists in CTmax among populations of brook trout, regardless of their population size, standing genetic variation and differing natural thermal regimes (temperature variation, minimum and maximum). This study highlights the level to which thermal tolerance is conserved between isolated populations of a vertebrate species, in the face of climate warming. PMID- 27990292 TI - Lionfish misidentification circumvents an optimized escape response by prey. AB - Invasive lionfish represent an unprecedented problem in the Caribbean basin, where they are causing major changes to foodwebs and habitats through their generalized predation on fishes and invertebrates. To ascertain what makes the red lionfish (Pterois volitans) such a formidable predator, we examined the reaction of a native damselfish prey, the whitetail damsel (Pomacentrus chrysurus), to a repeatable startle stimulus once they had been forewarned of the sight or smell of lionfish. Fast-start responses were compared with prey forewarned of a predatory rockcod (Cephalopholis microprion), a corallivorous butterflyfish (Chaetodon trifasctiatus) and experimental controls. Forewarning of the sight, smell or a combination of the two cues from a rockcod led to reduced escape latencies and higher response distances, speed and maximal speed compared with controls, suggesting that forewarning primed the prey and enabled a more effective escape response. In contrast, forewarning of lionfish did not affect the fast-start kinematics measured, which were the same as in the control and non predatory butterflyfish treatments. Lionfish appear to be able to circumvent mechanisms commonly used by prey to identify predators and were misclassified as non-predatory, and this is likely to contribute to their success as predators. PMID- 27990293 TI - Vitamin levels in adults with ADHD. AB - BACKGROUND: Micronutrients containing vitamins are reported to reduce symptom levels in persons with attention-deficit hyperactivity disorder (ADHD), but data on vitamin levels in ADHD are sparse. AIMS: To examine the relationship between vitamin concentrations, ADHD diagnosis and psychiatric symptoms in young adult ADHD patients and controls. METHOD: Eight vitamins and the nicotine metabolite cotinine were analysed in serum samples from 133 ADHD patients and 131 controls aged between 18 and 40, who also reported ADHD symptoms and comorbid conditions. RESULTS: Lower concentrations of vitamins B2, B6 and B9 were associated with the ADHD diagnosis, and B2 and B6 also with symptom severity. Smokers had lower levels of vitamins B2 and B9. CONCLUSIONS: ADHD patients were overrepresented in the group with low levels of some vitamins, possibly indicative of inadequate dietary intake of these micronutrients in a subgroup of patients. It is important to identify these patients in dietary intervention trials of ADHD. DECLARATION OF INTEREST: J.H. has received lecture honoraria as part of continuing medical education programmes sponsored by Novartis, Eli Lilly and Company, and Janssen Cilag. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 27990294 TI - Prevalence and associated factors for suicidal ideation in the Lagos State Mental Health Survey, Nigeria. AB - BACKGROUND: To combat the increasing rate of suicide, basic data on suicidal behaviours reflecting the uniqueness of the locality are needed in sub-Saharan Africa. AIMS: To assess the prevalence of suicidal ideation and associated factors. METHOD: Adults (n=11 246) from the five administrative divisions of Lagos State completed questionnaires detailing suicidal ideation, socio demographic details, common mental disorders (depression, anxiety and somatic symptoms), alcohol and psychoactive substance use disorders and disability. RESULTS: The weighted prevalence of current suicidal ideation was 7.28% (s.e. 0.27). Independently associated factors were older age, being female, not married, low occupational group, depression, anxiety, somatic symptoms and disability. CONCLUSIONS: Despite the validity of cross-national surveys, there is need for individual countries to generate complementary local data to explain variability in rates and risk factors in order to plan for suicide prevention or develop timely and effective response. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 27990295 TI - A retrospective analysis of personality disorder presentations in a Canadian university-affiliated hospital's emergency department. AB - BACKGROUND: Individuals with personality disorders often have extensive involvement with healthcare services including frequent utilisation of emergency departments. AIMS: The aim of this study was to identify factors associated with emergency department presentations by individuals with personality disorders. METHOD: A 12-month retrospective data analysis of all mental-health-related emergency department visits was performed. Age, gender, time and season of presentation, length of stay, mode of arrival and discharge arrangements for individuals with personality disorders were compared to individuals with other psychiatric diagnoses. RESULTS: There were 336 visits by individuals with personality disorders and 5290 visits by individuals with other psychiatric diagnoses. Individuals with personality disorders were significantly more likely to be female, young adults, brought in by police, arrive in the evening, discharged home and have a longer median length of stay. CONCLUSION: Knowing what factors are associated with emergency department presentations by individuals with personality disorders can help ensure that appropriately trained support staff are available. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC ND) license. PMID- 27990298 TI - Suppression of CRTC2-mediated hepatic gluconeogenesis by TRAF6 contributes to hypoglycemia in septic shock. AB - Although hypoglycemia has been documented as a major cause of high mortality in the setting of septic shock, the mechanism of hypoglycemia in infection has not been clearly determined. Hepatic gluconeogenesis serves as an important mechanism to maintain glucose levels under physiological conditions and CREB coactivator CRTC2 plays an important role in regulating gluconeogenic gene expression. Here, we show that triggering of the Toll-like receptor 4 pathway in response to endotoxin lipopolysaccharide (LPS) inhibits gluconeogenic gene expression and hepatic glucose output by blocking CRTC2 activation. Interleukin-1beta (IL-1beta) is found to disrupt gluconeogenic gene expression via the activation of the E3 ubiquitin ligase TRAF6, a key component of the Toll-like receptor 4 signaling pathway that associates with and ubiquitinates CRTC2. TRAF6 promotes the K63 linked ubiquitination of CRTC2, a modification that blocks binding of calcineurin at an adjacent calcineurin-binding site, thereby disrupting CRTC2 dephosphorylation in response to glucagon signals. Mutation of TRAF6-binding sites or ubiquitination site in CRTC2 rescues hepatic gluconeogenesis in LPS challenged mice. These results suggest that pro-inflammatory signals intersect with the CRTC2 pathway in liver, thus contributing to hypoglycemia caused by infection. PMID- 27990297 TI - HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress induced nuclear gene expression. AB - Reduced mitochondrial DNA copy number, mitochondrial DNA mutations or disruption of electron transfer chain complexes induce mitochondria-to-nucleus retrograde signaling, which induces global change in nuclear gene expression ultimately contributing to various human pathologies including cancer. Recent studies suggest that these mitochondrial changes cause transcriptional reprogramming of nuclear genes although the mechanism of this cross talk remains unclear. Here, we provide evidence that mitochondria-to-nucleus retrograde signaling regulates chromatin acetylation and alters nuclear gene expression through the heterogeneous ribonucleoprotein A2 (hnRNAP2). These processes are reversed when mitochondrial DNA content is restored to near normal cell levels. We show that the mitochondrial stress-induced transcription coactivator hnRNAP2 acetylates Lys 8 of H4 through an intrinsic histone lysine acetyltransferase (KAT) activity with Arg 48 and Arg 50 of hnRNAP2 being essential for acetyl-CoA binding and acetyltransferase activity. H4K8 acetylation at the mitochondrial stress responsive promoters by hnRNAP2 is essential for transcriptional activation. We found that the previously described mitochondria-to-nucleus retrograde signaling mediated transformation of C2C12 cells caused an increased expression of genes involved in various oncogenic processes, which is retarded in hnRNAP2 silenced or hnRNAP2 KAT mutant cells. Taken together, these data show that altered gene expression by mitochondria-to-nucleus retrograde signaling involves a novel hnRNAP2-dependent epigenetic mechanism that may have a role in cancer and other pathologies. PMID- 27990299 TI - Sharing health-related data: a privacy test? AB - Greater sharing of potentially sensitive data raises important ethical, legal and social issues (ELSI), which risk hindering and even preventing useful data sharing if not properly addressed. One such important issue is respecting the privacy-related interests of individuals whose data are used in genomic research and clinical care. As part of the Global Alliance for Genomics and Health (GA4GH), we examined the ELSI status of health-related data that are typically considered 'sensitive' in international policy and data protection laws. We propose that 'tiered protection' of such data could be implemented in contexts such as that of the GA4GH Beacon Project to facilitate responsible data sharing. To this end, we discuss a Data Sharing Privacy Test developed to distinguish degrees of sensitivity within categories of data recognised as 'sensitive'. Based on this, we propose guidance for determining the level of protection when sharing genomic and health-related data for the Beacon Project and in other international data sharing initiatives. PMID- 27990296 TI - A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation. AB - Acetyl-CoA carboxylases (ACCs) are crucial metabolic enzymes and attractive targets for drug discovery. Eukaryotic acetyl-CoA carboxylases are 250 kDa single chain, multi-domain enzymes and function as dimers and higher oligomers. Their catalytic activity is tightly regulated by phosphorylation and other means. Here we show that yeast ACC is directly phosphorylated by the protein kinase SNF1 at residue Ser1157, which potently inhibits the enzyme. Crystal structure of three ACC central domains (AC3-AC5) shows that the phosphorylated Ser1157 is recognized by Arg1173, Arg1260, Tyr1113 and Ser1159. The R1173A/R1260A double mutant is insensitive to SNF1, confirming that this binding site is crucial for regulation. Electron microscopic studies reveal dramatic conformational changes in the holoenzyme upon phosphorylation, likely owing to the dissociation of the biotin carboxylase domain dimer. The observations support a unified molecular mechanism for the regulation of ACC by phosphorylation as well as by the natural product soraphen A, a potent inhibitor of eukaryotic ACC. These molecular insights enhance our understanding of acetyl-CoA carboxylase regulation and provide a basis for drug discovery. PMID- 27990300 TI - Agreement between Gonioscopic Examination and Swept Source Fourier Domain Anterior Segment Optical Coherence Tomography Imaging. AB - Purpose. To evaluate interobserver, intervisit, and interinstrument agreements for gonioscopy and Fourier domain anterior segment optical coherence tomography (FD ASOCT) for classifying open and narrow angle eyes. Methods. Eighty-six eyes with open or narrow anterior chamber angles were included. The superior angle was classified open or narrow by 2 of 5 glaucoma specialists using gonioscopy and imaged by FD ASOCT in the dark. The superior angle of each FD ASOCT image was graded as open or narrow by 2 masked readers. The same procedures were repeated within 6 months. Kappas for interobserver and intervisit agreements for each instrument and interinstrument agreements were calculated. Results. The mean age was 50.9 (+/-18.4) years. Interobserver agreements were moderate to good for both gonioscopy (0.57 and 0.69) and FD ASOCT (0.58 and 0.75). Intervisit agreements were moderate to excellent for both gonioscopy (0.53 to 0.86) and FD ASOCT (0.57 and 0.85). Interinstrument agreements were fair to good (0.34 to 0.63), with FD ASOCT classifying more angles as narrow than gonioscopy. Conclusions. Both gonioscopy and FD ASOCT examiners were internally consistent with similar interobserver and intervisit agreements for angle classification. Agreement between instruments was fair to good, with FD ASOCT classifying more angles as narrow than gonioscopy. PMID- 27990301 TI - Robotic Seals as Therapeutic Tools in an Aged Care Facility: A Qualitative Study. AB - Robots, including robotic seals, have been used as an alternative to therapies such as animal assisted therapy in the promotion of health and social wellbeing of older people in aged care facilities. There is limited research available that evaluates the effectiveness of robot therapies in these settings. The aim of this study was to identify, explore, and describe the impact of the use of Paro robotic seals in an aged care facility in a regional Australian city. A qualitative, descriptive, exploratory design was employed. Data were gathered through interviews with the three recreational therapists employed at the facility who were also asked to maintain logs of their interactions with the Paro and residents. Data were transcribed and thematically analysed. Three major themes were identified from the analyses of these data: "a therapeutic tool that's not for everybody," "every interaction is powerful," and "keeping the momentum." Findings support the use of Paro as a therapeutic tool, revealing improvement in emotional state, reduction of challenging behaviours, and improvement in social interactions of residents. The potential benefits justify the investment in Paro, with clear evidence that these tools can have a positive impact that warrants further exploration. PMID- 27990302 TI - Does Deep Cervical Flexor Muscle Training Affect Pain Pressure Thresholds of Myofascial Trigger Points in Patients with Chronic Neck Pain? A Prospective Randomized Controlled Trial. AB - Background. We need to understand more about how DNF performs in different contexts and whether it affects the pain threshold over myofascial trigger points (MTrPs). Purpose. The objectives were to investigate the effect of neck muscles training on disability and pain and on pain threshold over MTrPs in people with chronic neck pain. Methods. Patients with chronic neck pain were eligible for participation with a Neck Disability Index (NDI) score of over 5/50 and having at least one MTrP on either levator scapulae, upper trapezoid, or splenius capitis muscle. Patients were randomly assigned into either DNF training, superficial neck muscle exercise, or advice group. Generalized linear model (GLM) was used to detect differences in treatment groups over time. Results. Out of 67 participants, 60 (47 females, mean age: 39.45 +/- 12.67) completed the study. Neck disability and neck pain were improved over time between and within groups (p < 0.05). However, no differences were found within and between the therapeutic groups (p < 0.05) in the tested muscles' PPTs and in cervicothoracic angle over a 7-week period. Conclusion. All three groups improved over time. This infers that the pain pathways involved in the neck pain relief are not those involved in pain threshold. PMID- 27990304 TI - Nonneoplastic Tongue Swellings of Lymphatic and Lymphocytic Origin: Three Case Reports. AB - Tongue is formed of a mass of muscles and salivary gland embedded in anterior highly vascular and posterior lymphoid stroma and covered by specialized surface epithelium. Growths from all of these heterogonous components may occur resulting in a wide variation in clinical features and behavior, ranging from self-limiting to aggressive lesions. Therefore, surgical excision is the treatment of choice. The aim of the current study is to report three different lesions that came to the Oral Surgery Department in the Faculty of Oral and Dental Medicine, Cairo University. Following clinical and histopathological examination, the diagnosis of reactive lymphoproliferative lesion, cystic lymphoepithelial lesion, and developmental lymphatic vessel malformation was reached. PMID- 27990303 TI - Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery. AB - Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG) extracted from exudates of Anacardium occidentale L. and khaya gum (KYG) extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG). The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG < CSG < ACG. Calcium was the predominant ion in CSG while potassium was predominant in KYG. The FTIR spectra of CSG and KYG were similar and slightly different from that of ACG. Acacia and khaya gums exhibited the same thermal behaviour which is different from that of CSG. X-ray diffraction revealed that the three gums are the same type of polymer, the major difference being the concentration of metal ions. This work suggests the application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs. PMID- 27990305 TI - A 66-Year-Old Woman with a Progressive, Longitudinally Extensive, Tract Specific, Myelopathy. AB - A 66-year-old woman presented with progressive lancinating pain and sensory deficits attributable to a myelopathy of unclear etiology. Spinal cord magnetic resonance imaging showed a longitudinally extensive T2-hyperintense lesion of the dorsal columns. Comprehensive serum, urine, and cerebrospinal fluid analyses failed to identify an etiology. Empiric intravenous methylprednisolone and intravenous immunoglobulin were of no benefit and serial screens for an occult malignancy were negative. She developed dysesthesias and allodynia affecting her entire body and lost the use of her arms and legs due to severe sensory ataxia that was steadily progressive from onset. She opted against additional aggressive medical management of her condition and passed away on hospice eleven months after symptom onset. Autopsy revealed findings most consistent with polyphasic spinal cord ischemia affecting the dorsal and lateral white matter tracts and, to a lesser extent, adjacent gray matter. The underlying etiology for the progressive vasculopathy remains unknown. Spinal cord ischemia affecting the posterior spinal cord is rare and to our knowledge this case represents the only instance of a progressive spinal cord tractopathy attributable to chronic spinal cord ischemia. PMID- 27990306 TI - Primary Pericardial Sarcoma with Right Atrial Invasion and Multiple Bilateral Pulmonary Metastases in a Patient with Hereditary Nonpolyposis Colorectal Cancer. AB - Primary tumours originating from the pericardium are extremely rare. Previous studies have reported that these tumours account for only 6.7-12.8% of all mediastinal tumours with an overall prevalence of 0.001% to 0.007%. The majority of these tumours are benign lipomas or pericardial cysts. The most common pericardial malignancy is mesothelioma. Sarcomas are soft-tissue mesenchymal malignancies originating from various parts of the body but are extremely rare in this area. We report a case of a 52-year-old female who was diagnosed with a primary sarcoma with rhabdoid differentiation originating from the pericardium. The patient presented to her GP with a four-week history of progressive dyspnea and chest pain on exertion. Chest X-Ray demonstrated a prominent pericardial effusion and suspicious chest and pericardial lesions. Biopsies of the effusion and primary tumour identified on FDG/PET scans revealed the diagnosis of primary undifferentiated sarcoma. On thoracotomy, it was noted that the tumour had invaded the right atrium; therefore, pericardial window was aborted and a drain inserted instead. The patient was then started on chemotherapy; however, progression soon occurred and the patient died within 4 months, suggesting there is urgent need for efficacious treatments for sarcomatous lesions. PMID- 27990307 TI - Endogenous Fusarium Endophthalmitis in Diabetes Mellitus. AB - Endogenous endophthalmitis accounts for 2% to 8% of cases of endophthalmitis. Immunocompromised state and intravenous drug use are the 2 most common causes of endogenous endophthalmitis due to molds fungi. Aspergillus, Fusarium, and Scedosporium are the common organisms in mold endophthalmitis. We report a case of Fusarium endophthalmitis in a patient with uncontrolled diabetes. While diabetes mellitus is a well-known risk factor for endogenous endophthalmitis, we did not find any reported case of Fusarium endophthalmitis in a case of diabetes mellitus. The patient presented with granulomatous uveitis masquerading as noninfectious uveitis with a very good response to steroids. The characteristic clinical features were established late in the clinical course associated with poor outcome. This case highlights the significance of uncontrolled diabetes as a risk factor for Fusarium endophthalmitis and also the presentation of endophthalmitis as a masquerade syndrome. The clinician should have high index of suspicion as these cases have poor outcomes. PMID- 27990308 TI - Delayed Reconstruction by Total Calcaneal Allograft following Calcanectomy: Is It an Option? AB - Many options are available in literature for the management of delayed reconstruction following calcanectomy. In cases of low-grade tumor lesions, conservative surgery can be considered. We describe a case of delayed reconstruction by calcaneal allograft after calcanectomy for low-grade chondrosarcoma. At 12-month follow-up, the patient had no pain; MSTS score and AOFAS score were satisfactory. Subtalar nonunion was observed with no secondary displacement or graft necrosis. The aim of conservative treatment for this patient was to restore normal gait with plantigrade locomotion and function of the Achilles tendon. Calcaneal reconstruction by total allograft is an alternative approach following calcanectomy for calcaneal tumors. We also discussed other options of calcaneal reconstruction. PMID- 27990309 TI - A Case of Periodontal Necrosis following Embolization of Maxillary Artery for Epistaxis. AB - Embolization of the maxillary artery (MA) is a common treatment modality for refractory epistaxis. Tissue necrosis after embolization of the MA is a rare complication. Here, we reported the first case of the development of necrosis of soft tissue and alveolar bone in the periodontium after embolization. A 48-year old man with poor oral hygiene and a heavy smoking habit was referred to our clinic due to intractable epistaxis. After treatment with anterior-posterior nasal packing (AP nasal packing), the epistaxis relapsed. Therefore, he underwent embolization of the MA. Although he did not experience epistaxis after embolization, periodontal necrosis developed gradually. The wound healed with necrotomy, administration of antibiotics and prostaglandin, and hyperbaric oxygen therapy. We speculated that the periodontal necrosis was provoked by reduction of blood supply due to embolization and AP nasal packing based on this preexisting morbid state in the periodontium. Poor condition of the oral cavity and smoking may increase the risk of periodontal necrosis after embolization. PMID- 27990310 TI - Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C>T mutation in CLCN7. AB - Type II autosomal dominant osteopetrosis (ADO2), which is the most common form of osteopetrosis, is caused by heterozygous mutations in the chloride channel 7 (CLCN7) gene. The osteopetrosis of ADO2 has been attributed to hypofunctional osteoclasts. The mechanism underlying the abnormality in osteoclast function remains largely unknown. This study was designed to investigate gene mutations and osteoclast function in a case that was clinically diagnosed as ADO2. Genomic DNA was extracted from blood samples of this patient, and the 25 exons of CLCN7 were amplified. Peripheral blood from the ADO2 subject and a healthy age- and sex matched control was used to evaluate osteoclastogenesis, osteoclast morphology, and bone resorption. Analysis of DNA from the patient showed a germline heterozygous missense mutation, c.1856C>T (p.P619L), in exon 20 of CLCN7. A similar homozygous mutation at this site was previously reported in a patient with autosomal recessive osteopetrosis. When cultured, the peripheral blood mononuclear cells (PBMCs) from the ADO2 patient spontaneously differentiated into mature osteoclasts in vitro. The ADO2 patient's PBMCs formed enhanced, but heterogeneous, osteoclasts in both the presence and absence of macrophage-colony stimulating factor, and nuclear factor-KB ligand. Bone resorption was reduced in the ADO2 patient's osteoclasts, which exhibited aberrant morphology and abnormal distribution of integrin avbeta3. Gene analysis found increased c-fos expression and reduced RhoA and integrin beta 3 expression in ADO2 cells. In conclusion, our data suggest that enhanced, heterogeneous osteoclast induction may be an intrinsic characteristic of ADO2. PMID- 27990311 TI - Rescue pallidotomy for dystonia through implanted deep brain stimulation electrode. AB - BACKGROUND: Some patients with deep brain stimulation (DBS), where removal of implants is indicated due to hardware related infections, are not candidates for later re-implantation. In these patients a rescue lesion through the DBS electrode has been suggested as an option. In this case report we present a patient where a pallidotomy was performed using the DBS electrode. CASE DESCRIPTION: An elderly woman with bilateral Gpi DBS suffered an infection around the left burr hole involving the DBS electrode. A unilateral lesion was performed through the DBS electrode before it was removed. No side effects were encountered. Burke-Fahn-Marsden (BFM) dystonia movement scale score was 39 before DBS. With DBS before lesioning BFM score was 2.5 points. The replacement of the left sided stimulation with a pallidotomy resulted in only a minor deterioration of the score to 5 points. CONCLUSIONS: In the case presented here a small pallidotomy performed with the DBS electrode provided a satisfactory effect on the patient's dystonic symptoms. Thus, rescue lesions through the DBS electrodes, although off-label, might be considered in patients with Gpi DBS for dystonia when indicated. PMID- 27990312 TI - Ultra-extended euthermic pulsed radiofrequency for the treatment of ophthalmic neuralgia: A case report with elaboration of a new technique. AB - BACKGROUND: Pulsed radiofrequency although present for many years has been used little compared to ablative procedures for pain relief. Its use in trigeminal neuralgia is sparse and unreported in the ophthalmic division, where the possibility of sensory loss can lead to high morbidity. We wished to explore the potential of this reportedly safe modality for a prolonged duration in a highly sensitive anatomic neural location, however, in a very secure, structured, and staged manner. CASE DESCRIPTION: A patient suffering from ophthalmic division (V1) medically uncontrolled neuralgia with a preoperative visual analog scale (VAS) score of 9/10 was subjected to a percutaneous pain relief procedure. The patient was treated with prolonged duration pulsed radiofrequency (PRF) for 40 min, with corneal sensation monitoring under conscious sedation keeping a low voltage (7 V) and tip temperature at 37 degrees C. The patient obtained immediate relief, which was verified on the operation table itself. Postoperative VAS score of 0/10 was recorded. More than 6 months after the procedure, the patient is completely free from neuralgic pain and continues to have a VAS score of 0/10. CONCLUSION: As opposed to conventional PRF where mostly a tip temperature of 42 degrees C and high voltage have been used for 2 to a maximum of 8 min, PRF with a tip temperature of 37 degrees C and a safe voltage of 7 V over an ultra-extended duration of 40 min can give a more distinct and effective but equally safe result. Although our case verified the safety and efficacy of prolonged duration PRF in sensitive anatomic locations, more studies are warranted for establishing this as a standard line of treatment. The specific use of PRF in ophthalmic division neuralgia in the manner described in our case report has hitherto not been reported in medical literature and will open a new vista in the minimally invasive treatment of this disease. PMID- 27990313 TI - Deep brain stimulation of a patient with psychogenic movement disorder. AB - BACKGROUND: The long-term safety of deep brain stimulation (DBS) is an important issue because new applications are being investigated for a variety of disorders. Studying instances where DBS was inadvertently implanted in patients without a movement disorder may provide information about the safety of the therapy. We report the case of a patient with a psychogenic movement disorder treated with deep brain stimulation (DBS). CASE DESCRIPTION: The patient presented at our clinic after 5 years of chronic DBS of the subthalamic nucleus (STN) for presumed Parkinson's disease. A dopamine transporter (DAT) scan (DaTscan) showed normal DAT distribution in the striatum. A positron emission tomography (PET) scan showed no abnormal metabolic patterns. Further psychiatric and neurological evaluations revealed that the patient was suffering from a psychogenic movement disorder. The patient displayed no sign or symptom from the stimulation, and DBS did not lead to any benefits or side effects for this patient. CONCLUSION: We argue that the absence of side effects, the normal DaTscan, and PET scan after 5 years of chronic stimulation illustrate the safety of DBS on neural tissue. PMID- 27990314 TI - Deep brain stimulation for Parkinson's disease prior to L-dopa treatment: A case report. AB - BACKGROUND: Leva-dopa (L-dopa) is the gold-standard treatment for Parkinson's disease (PD). Deep brain stimulation is generally reserved for patients who become refractory to l-dopa treatment. CASE DESCRIPTION: We present a male patient with a 9-year course of PD who at 53 years of age preferred deep brain stimulation (DBS) of the subthalamic nucleus over initial l-dopa treatment. The patient argued that he wanted to avoid the serious adverse effects of l-dopa, which would have presented within his time of full professional activity. DBS resulted in significant motor improvement lasting for 6 years without l-dopa treatment. CONCLUSION: Large multicentre-based international trials with long follow-ups are needed to answer the effectiveness of early DBS in PD. PMID- 27990315 TI - Pretreatment clinical prognostic factors for brain metastases from breast cancer treated with Gamma Knife radiosurgery. AB - BACKGROUND: Brain metastases significantly affect morbidity and mortality rates for patients with metastatic breast cancer. Treatment for brain metastases lengthens survival, and options such as stereotactic radiosurgery (SRS) can increase survival to 12 months or longer. This study retrospectively analyzes the prognostic factors for overall survival (OS) for patients with one or multiple brain metastases from breast cancer treated with SRS. METHODS: Between December 2001 and May 2015, 111 patients with brain metastases from breast cancer were grouped by potential prognostic factors including age at diagnosis, Karnofsky Performance Status (KPS) score, number of brain metastases, and whether or not they received adjuvant treatments such as whole brain radiotherapy (WBRT) or surgical resection. Survival rates were determined for all groups, and hazard ratios were calculated using univariate and multivariate analyses to compare differences in OS. RESULTS: Median OS was 16.8 +/- 4.22 months. Univariate analysis of patients with a KPS <=60 and multivariate analysis of KPS 70-80 showed significantly shorter survival than those with KPS 90-100 (5.9 +/- 1.22 months, 21.3 +/- 11.69 months, and 22.00 +/- 12.56 months, P = 0.024 and < 0.001). Other results such as age >=65 years and higher number of brain metastases trended toward shorter survival but were not statistically significant. No difference in survival was found for patients who had received WBRT in addition to SRS (P = 0.779). CONCLUSION: SRS has been shown to be safe and effective in treating brain metastases from breast cancer. We found our median survival to be 16.8 +/- 4.22 months, an increase from other clinical reports. In addition, 38.4% of our population was alive at 2 years and 15.6% survived 5 years. Significant prognostic factors can help inform clinical treatment decisions. This study found that KPS was a significant prognostic indicator of OS in these patients. PMID- 27990316 TI - Subthalamus stimulation in Parkinson disease: Accounting for the bilaterality of contacts. AB - BACKGROUND: Deep brain stimulation (DBS) in Parkinson's disease uses bi hemispheric high-frequency stimulation within the subthalamus, however, the specific impacts of bilaterality of DBS are still not clear. Thus, we aimed to study the individual-level clinical impact of locations of right-left contact pair-up accounting for each subthalamic nucleus (STN) anatomy. METHODS: Contact locations and effects at 1 year were studied retrospectively in an unselected series of 53 patients operated between 2004 and 2010. Location of contacts was defined relatively to the main axis of STN used to map longitudinal and transversal positions, and STN membership (out meaning out-of-STN). Contact pairings were described via three methods: (i) Unified contact location (UCL) collapsing DBS into an all-in-one contact; (ii) balance of contact pair-up (BCPU), defined as symmetric or asymmetric regardless of laterality; (iii) hemisphere-wise most frequent contact pair-up (MFCP) regardless of BCPU. Clinical data were: mean levodopa equivalent dose, Unified Parkinson's Disease Rating Scale (UPDRS) motor score III without medication, UPDRS II and III speech sub scores, UPDRS II freezing sub-score, 1 year versus preoperative values, with and without levodopa. Ad-hoc two-sided tests were used for statistical analysis. RESULTS: Worsening speech, was more frequent for UCL_out patients and when the left MFCP contact was rear and/or superolateral, however, it less frequent for BCPU-asymmetric patients. Worsening freezing was more frequent when the right MFCP contact was rear and superolateral. CONCLUSIONS: These results point to strategies for minimizing dysarthria and freezing as adverse effects of DBS. PMID- 27990317 TI - Synergy and Anti-Synergy between Palladium and Gold in Nanoparticles Dispersed on a Reducible Support. AB - Highly active and stable bimetallic Au-Pd catalysts have been extensively studied for several liquid-phase oxidation reactions in recent years, but there are far fewer reports on the use of these catalysts for low-temperature gas-phase reactions. Here we initially established the presence of a synergistic effect in a range of bimetallic Au-Pd/CeZrO4 catalysts, by measuring their activity for selective oxidation of benzyl alcohol. The catalysts were then evaluated for low temperature WGS, CO oxidation, and formic acid decomposition, all of which are believed to be mechanistically related. A strong anti-synergy between Au and Pd was observed for these reactions, whereby the introduction of Pd to a monometallic Au catalyst resulted in a significant decrease in catalytic activity. Furthermore, monometallic Pd was more active than Pd-rich bimetallic catalysts. The nature of the anti-synergy was probed by several ex situ techniques, which all indicated a growth in metal nanoparticle size with Pd addition. However, the most definitive information was provided by in situ CO DRIFTS, in which CO adsorption associated with interfacial sites was found to vary with the molar ratio of the metals and could be correlated with the catalytic activity of each reaction. As a similar correlation was observed between activity and the presence of Au0* (as detected by XPS), it is proposed that peripheral Au0* species form part of the active centers in the most active catalysts for the three gas-phase reactions. In contrast, the active sites for the selective oxidation of benzyl alcohol are generally thought to be electronically modified gold atoms at the surface of the nanoparticles. PMID- 27990318 TI - 1,4-Dihydropyridines as Alkyl Radical Precursors: Introducing the Aldehyde Feedstock to Nickel/Photoredox Dual Catalysis. AB - A Ni/photoredox dual catalytic cross-coupling is disclosed in which a diverse range of (hetero)aryl bromides are used as electrophiles, with 1,4 dihydropyridines serving as precursors to Csp3-centered alkyl radical coupling partners. The reported method is characterized by its extremely mild reaction conditions, enabling access to underexplored cores. PMID- 27990319 TI - Direct Synthesis of Symmetrical Azines from Alcohols and Hydrazine Catalyzed by a Ruthenium Pincer Complex: Effect of Hydrogen Bonding. AB - Azines (2,3-diazabuta-1,3-dienes) are a widely used class of compounds with conjugated C=N double bonds. Herein, we present a direct synthesis of azines from alcohols and hydrazine hydrate. The reaction, catalyzed by a ruthenium pincer complex, evolves dihydrogen and can be run in a base-free version. The dehydrogenative coupling of benzylic and aliphatic alcohols led to good conversions and yields. Spectroscopic evidence for a hydrazine-coordinated dearomatized ruthenium pincer complex was obtained. Isolation of a supramolecular crystalline compound provided evidence for the important role of hydrogen bonding networks under the reaction conditions. PMID- 27990320 TI - High-Throughput Diagnostic Assay for a Highly Prevalent Cardiomyopathy-Associated MYBPC3 Variant. AB - A 25-basepair deletion variant of MYBPC3 occurs at high frequency in individuals of South Asian descent and is estimated to affect 55 million people worldwide, carrying an increased likelihood of cardiomyopathy. Since this variant is prevalent and severe in this subpopulation, quick and affordable screening to provide risk-assessment to guide treatment for these patients is critical. An RNaseH qPCR assay was developed to quickly and specifically diagnose the presence of the 25-basepair deletion variant in MYBPC3. RNAseH-blocked nucleotide primers were designed to identify the presence or absence of the wild type MYBPC3 allele or the genomic sequence containing the 25-basepair deletion. Using this assay, three blinded operators were able to accurately determine the genotype from human genomic DNA samples from blood and saliva using a qPCR thermocycler. Furthermore, positive variant subjects were examined by both electrocardiography and echocardiography for the presence of cardiomyopathy. A simple, robust assay was established, verified and validated that can be automated to detect the presence of the highly prevalent 25-basepair deletion MYBPC3 variant using both blood and saliva samples. The assay will provide quick and accurate prescreening of individuals at high risk for cardiomyopathies and allow for better clinical identification of 25-basepair deletion MYBPC3 carriers in large cohort epidemiological studies. PMID- 27990321 TI - Travel Volume to the United States from Countries and U.S. Territories with Local Zika Virus Transmission. AB - INTRODUCTION: Air, land, and sea transportation can facilitate rapid spread of infectious diseases. In May 2015 the Pan American Health Organization (PAHO) issued an alert regarding the first confirmed Zika virus infection in Brazil. As of March 8, 2016, the U.S. Centers for Disease Control and Prevention (CDC) had issued travel notices for 33 countries and 3 U.S. territories with local Zika virus transmission. METHODS: Using data from five separate datasets from 2014 and 2015, we estimated the annual number of passenger journeys by air and land border crossings to the United States from the 33 countries and 3 U.S. territories listed in the CDC's Zika travel notices as of March 8, 2016. We also estimated the annual number of passenger journeys originating in and returning to the United States (primarily on cruises) with visits to seaports in areas with local Zika virus transmission. Because of the adverse pregnancy and birth outcomes that have been associated with Zika virus disease, the number of passenger journeys completed by women of childbearing age and pregnant women was also estimated. RESULTS: An estimated 216.3 million passenger journeys by air, land, and sea are made annually to the United States from areas with local Zika virus transmission (as of March 8). The destination states with the largest numbers of arrivals were Texas (by land) and Florida (by air and sea). An estimated 51.7 million passenger journeys were made by women of childbearing age and an estimated 2.3 million were made by pregnant women. CONCLUSION: Travel volume analyses provide important information that can be used to effectively target public health interventions as well as direct public health resources and efforts at local, regional, and country-specific levels. PMID- 27990322 TI - Recent Advances and Controversies in Peripartum Depression. AB - PURPOSE OF REVIEW: The purpose of this review is to update readers on recent controversies and findings on the underlying biology and clinical management of peripartum depression. RECENT FINDINGS: Topics discussed include the discovery and replication of two epigenetic biomarkers of peripartum depression, two well controlled studies that do NOT find associations between in utero antidepressant exposure and cardiac defects and persistent pulmonary hypertension of the newborn and ongoing controversy on whether antidepressant use during pregnancy prevents peripartum depression and whether or not hormonal treatments have a place in the management of postpartum depression. SUMMARY: Peripartum depression, or depression during and/or immediately following pregnancy is a unique psychiatric illness that not only may have unique biological underpinnings but demands unique and thoughtful approaches to management due to the developing neonate. A number of controversies exist in this area ranging from the recent terminology change in psychiatry's Diagnostic and Statistical Manual from "postpartum" to "peripartum" depression, to the safety of antidepressant use during pregnancy, to whether or not antidepressants prevent or decrease peripartum depression. Research in this area is growing and a number of exciting developments have occurred including the identification of two epigenetic biomarkers of peripartum depression that may eventually lead to early identification and intervention, the potential for hormonal treatments and the recommendation for and early institution of universal screening for peripartum depression. These topics are explored and put into context from a clinical management perspective. PMID- 27990324 TI - Correction: Chronic Pulmonary Histoplasmosis and its Clinical Significance: an Under-reported Systemic Fungal Disease. AB - [This corrects the article DOI: 10.7759/cureus.751.]. PMID- 27990323 TI - Impaired functional responses in follicular lymphoma CD8+TIM-3+ T lymphocytes following TCR engagement. AB - Upregulation of T cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore, CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+T cells was observed by phospho-flow analysis. Finally, short relapse-free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R chemotherapy. PMID- 27990325 TI - Enhancing disease surveillance with novel data streams: challenges and opportunities. AB - Novel data streams (NDS), such as web search data or social media updates, hold promise for enhancing the capabilities of public health surveillance. In this paper, we outline a conceptual framework for integrating NDS into current public health surveillance. Our approach focuses on two key questions: What are the opportunities for using NDS and what are the minimal tests of validity and utility that must be applied when using NDS? Identifying these opportunities will necessitate the involvement of public health authorities and an appreciation of the diversity of objectives and scales across agencies at different levels (local, state, national, international). We present the case that clearly articulating surveillance objectives and systematically evaluating NDS and comparing the performance of NDS to existing surveillance data and alternative NDS data is critical and has not sufficiently been addressed in many applications of NDS currently in the literature. PMID- 27990327 TI - Circadian-Based Therapies for Circadian Rhythm Sleep-Wake Disorders. AB - This review summarizes recent developments relevant to the treatment of circadian rhythm sleep-wake disorders. The clinical practice guidelines for the treatment of intrinsic circadian rhythm sleep-wake disorders is described, followed by recent treatment studies for delayed sleep-wake phase disorder, non-24 hour sleep wake disorder, irregular sleep-wake disorder and shift work. New methods to estimate circadian phase, including home saliva collection to estimate the dim light melatonin onset, circadian questionnaires and general rules to guide light and exogenous melatonin treatments are described. New developments in light treatment are detailed, including light flashes during sleep and wearable light devices. Substances such as caffeine and alcohol, and devices such as electronic tablets are also considered for their potential to shift circadian timing. Finally, an update on melatonin supplements in the US is discussed, along with the controversy surrounding the use of melatonin supplements in patients with prediabetes or diabetes. PMID- 27990328 TI - Bioluminescence in the ghost fungus Omphalotus nidiformis does not attract potential spore dispersing insects. AB - Bioluminescence has been known from fungi since ancient times, but little work has been done to establish its potential role. There is evidence that some bioluminescent fungi differentially attract potential spore-dispersing insects, and we aimed to establish if this was the case for the ghost fungus, Omphalotus nidiformis (Agaricales,Marasmiaceae), a widespread Australian temperate zone species. We examined three corroborative lines of evidence: circadian rhythmicity of bioluminescence; field-recorded insect abundance at the time of basidiome production; and attractiveness of glowing fungi to flying insects. Basidiomes glowed continuously day and night, and were present in winter (June-July) when insect abundance was low. To assess attractiveness, we deployed sticky-traps in open woodland in the absence of light pollution, in Treatment (baited with fresh bioluminescent O. nidiformis) and Control pairs, for 480 trap-hours on moonless nights. There was no statistical difference in mean insect abundance between Treatment and Control traps (mean 0.33 and 0.54 individuals per trap night, respectively). To interpret these results, we provide a brief review of competing hypotheses for fungal bioluminescence, and conclude that for some fungi, bioluminescence may be an incidental by-product of metabolism rather than conferring any selective advantage. It is possible that the role of bioluminescence differs among evolutionary lineages of fungi and/or with attributes of their growth environments that could affect spore dispersal, such as wind and insect abundance. PMID- 27990326 TI - Brain mechanisms of Change in Addictions Treatment: Models, Methods, and Emerging Findings. AB - Increased understanding of "how" and "for whom" treatment works at the level of the brain has potential to transform addictions treatment through the development of innovative neuroscience-informed interventions. The 2015 Science of Change meeting bridged the fields of neuroscience and psychotherapy research to identify brain mechanisms of behavior change that are "common" across therapies, and "specific" to distinct behavioral interventions. Conceptual models of brain mechanisms underlying effects of Cognitive Behavioral Therapy, mindfulness interventions, and Motivational Interviewing were discussed. Presentations covered methods for integrating neuroimaging into psychotherapy research, and novel analytic approaches. Effects of heavy substance use on the brain, and recovery of brain functioning with sustained abstinence, which may be facilitated by cognitive training, were reviewed. Neuroimaging provides powerful tools for determining brain mechanisms underlying psychotherapy and medication effects, predicting and monitoring outcomes, developing novel interventions that target specific brain circuits, and identifying for whom an intervention will be effective. PMID- 27990329 TI - Two new Aroramyces species (Hysterangiaceae, Hysterangiales) from Mexico. AB - Little is known of the truffle-like fungi of northern Mexico. Few mycologists have collected truffle-like specimens in this area. The wide diversity of habitat and potential mycorrhizal partners portend a unique and varied truffle-like mycota. In the conduct of recent field studies in this region we collected many interesting truffle-like specimens. We present two taxa that have unique characteristics, brownish spores with spines embedded within a distinctly inflated utricle surrounding each spore. Aroramyces balanosporus and A. herrerae are described as new species. This is the first record of the genus Aroramyces from North America. PMID- 27990330 TI - Kombocles bakaiana gen. sp. nov. (Boletaceae), a new sequestrate fungus from Cameroon. AB - Kombocles bakaiana gen. sp. nov. is described as new to science. This sequestrate, partially hypogeous fungus was collected around and within the stilt root system of an ectomycorrhizal (ECM) tree of the genus Uapaca (Phyllanthaceae) in a Guineo-Congolian mixed tropical rainforest in Cameroon. Molecular data place this fungus in Boletaceae (Boletales, Agaricomycetes, Basidiomycota) with no clear relationship to previously described taxa within the family. Macro- and micromorphological characters, habitat, and DNA sequence data are provided. Unique morphological features and a molecular phylogenetic analysis of 304 sequences across the Boletales justify the recognition of the new taxa. Kombocles bakaiana is the fourth sequestrate Boletaceae described from the greater African tropics, and the first to be described from Cameroon. PMID- 27990332 TI - New cryptic species of Teratosphaeria on Eucalyptus in Australia. AB - Teratosphaeria destructans and T. viscida are serious pathogens causing leaf, bud and shoot blight diseases of Eucalyptus plantations in the subtropics and tropics of South-East Asia (T. destructans) and North Queensland, Australia (T. viscida). During disease surveys in northern Western Australia and the Northern Territory of Australia, symptoms resembling those of T. destructans were observed on young and adult leaves of native and plantation Eucalyptus spp. and its hybrids. Phylogenetic studies revealed Teratosphaeria species associated with these symptoms are new taxonomic novelties described here as T. novaehollandiae and T. tiwiana spp. nov. Isolates from previous records of T. destructans recorded in Australia were re-examined and based upon the phylogenetic evidence are reassigned to these new taxa. We conclude that T. destructans is absent from Australia. PMID- 27990331 TI - Wongia gen. nov. (Papulosaceae, Sordariomycetes), a new generic name for two root infecting fungi from Australia. AB - The classification of two root-infecting fungi, Magnaporthe garrettii and M. griffinii, was examined by phylogenetic analysis of multiple gene sequences. This analysis demonstrated that M. garrettii and M. griffinii were sister species that formed a well-supported separate clade in Papulosaceae (Diaporthomycetidae, Sordariomycetes), which clusters outside of the Magnaporthales. Wongia gen. nov, is established to accommodate these two species which are not closely related to other species classified in Magnaporthe nor to other genera, including Nakataea, Magnaporthiopsis and Pyricularia, which all now contain other species once classified in Magnaporthe. PMID- 27990333 TI - New Raffaelea species (Ophiostomatales) from the USA and Taiwan associated with ambrosia beetles and plant hosts. AB - Raffaelea (Ophiostomatales) is a genus of more than 20 ophiostomatoid fungi commonly occurring in symbioses with wood-boring ambrosia beetles. We examined ambrosia beetles and plant hosts in the USA and Taiwan for the presence of these mycosymbionts and found 22 isolates representing known and undescribed lineages in Raffaelea. From 28S rDNA and beta-tubulin sequences, we generated a molecular phylogeny of Ophiostomatales and observed morphological features of seven cultures representing undescribed lineages in Raffaelea s. lat. From these analyses, we describe five new species in Raffaelea s. lat.: R. aguacate, R. campbellii, R. crossotarsa, R. cyclorhipidia, and R. xyleborina spp. nov. Our analyses also identified two plant-pathogenic species of Raffaelea associated with previously undocumented beetle hosts: (1) R. quercivora, the causative agent of Japanese oak wilt, from Cyclorhipidion ohnoi and Crossotarsus emancipatus in Taiwan, and (2) R. lauricola, the pathogen responsible for laurel wilt, from Ambrosiodmus lecontei in Florida. The results of this study show that Raffaelea and associated ophiostomatoid fungi have been poorly sampled and that future investigations on ambrosia beetle mycosymbionts should reveal a substantially increased diversity. PMID- 27990334 TI - Peering into the Mediterranean black box: Lactifluus rugatus ectomycorrhizas on Cistus. AB - We describe the morpho-anatomical features of the ectomycorrhizas (ECMs) formed by Lactifluus rugatus on Cistus, a genus of about 20 species of woody shrubs typical of the Mediterranean maquis. The description of L. rugatus mycorrhizas on Cistus is the first ECM description of a species belonging to Lactifluus subgen. Pseudogymnocarpi. The ECM identity was verified through molecular tools. Anatomically, the characteristic of L. rugatus mycorrhiza is the presence of abundant, long "bottle-shaped" cystidia on mantle surface. Indeed, the overwhelming majority of milkcap mycorrhizas are acystidiate. This is the third Lactarius/Lactifluus mycorrhiza to have been described associated with Cistus, the others being Lactarius cistophilus and L. tesquorum. The phylogenetic distance between all these taxa is reflected by the diversity of the principal features of their ECMs, which share host-depending ECM features known for Cistus, but are otherwise distinguishable on the host roots. Comparison of Lactifluus rugatus ECM with those formed by L. vellereus and L. piperatus on Fagus reveals elevated intrageneric diversity of mycorrhizal structures. Such a diversity is supported by analysis of ITS sequences of relevant species within European Lactifluus species. Our study extends knowledge of Cistus mycorrhizal biology and confirms the informative value of mycorrhizal structures in understanding phylogenetic relationships in ECM fungi. PMID- 27990335 TI - Competing sexual-asexual generic names of Pezizomycetes and recommendations for use. AB - Following the change that eliminated dual naming of sexual and asexual morphs of fungi, generic names of Pezizomycetes have been evaluated to determine which of the competing names should be recommended for use. Evaluation is based on congruence of type species to determine if the names are congeneric and which name is most commonly cited as well as priority. In the Pezizomycetes six pairs of generic names were determined to compete. In all cases the older name, representing the sexual morph, is recommended for use, specifically Caloscypha rather than Geniculodendron, Desmazierella rather than Verticicladium, Miladina rather than Actinosporella, Morchella rather than Costantinella, Sarcoscypha rather than Molliardiomyces, and Trichophaea rather than Dichobotrys. PMID- 27990337 TI - Mycosarcoma (Ustilaginaceae), a resurrected generic name for corn smut (Ustilago maydis) and its close relatives with hypertrophied, tubular sori. AB - Ustilago is a polyphyletic genus of smut fungi found mainly on Poaceae. The development of a taxonomy that reflects phylogeny requires subdivision of Ustilago into smaller monophyletic genera. Several separate systematic analyses have determined that Macalpinomyces mackinlayi, M. tubiformis, Tolyposporella pachycarpa, Ustilago bouriquetii and U. maydis, occupy a unique phylogenetic position within the Ustilaginaceae. A previously introduced monotypic generic name typified by U. maydis, Mycosarcoma, is available to accommodate these species, which resolves one component of polyphyly for Ustilagos.lat. in Ustilaginaceae. An emended description of Mycosarcoma is provided to reflect the morphological synapomorphies of this monophyletic group. A specimen of Ustilago maydis that has had its genome sequenced is designated as a neotype for this species. Taxonomic stability will further be provided by a forthcoming proposal to conserve the name Uredo maydis over Lycoperdon zeae, which has priority by date, in order to preserve the well-known epithet maydis. PMID- 27990338 TI - IMA Genome-F 7: Draft genome sequences for Ceratocystis fagacearum, C. harringtonii, Grosmannia penicillata, and Huntiella bhutanensis. AB - Draft genomes for the fungi Ceratocystis fagacearum, C. harringtonii, Grosmannia penicillata, and Huntiella bhutanensis are presented. Ceratocystis fagacearum is a major causal agent of vascular wilt of oaks and other trees in the family Fagaceae. Ceratocystis harringtonii, previously known as C. populicola, causes disease in Populus species in the USA and Canada. Grosmannia penicillata is the causal agent of bluestain of sapwood on various conifers, including Picea spp. and Pinus spp. in Europe. Huntiella bhutanensis is a fungus in Ceratocystidaceae and known only in association with the bark beetle Ips schmutzenhorferi that infests Picea spinulosa in Bhutan. The availability of these genomes will facilitate further studies on these fungi. PMID- 27990339 TI - Variety of fruit and vegetables is related to preschoolers' overall diet quality. AB - Children are encouraged to eat a specific amount of fruits and vegetables to optimize health. The purpose of this study was to assess whether consumption of a variety of fruits and vegetables, respectively, was associated with a greater diet quality among preschool-aged children. Analyses were performed using a cross sectional, nationally representative sample of US children. Dietary intakes from 24-h dietary recalls of two-five year old children (n = 2595) in 2005-2010 NHANES were examined. Diet quality was evaluated using MyPlate equivalents and the Healthy Eating Index 2010 (HEI-2010). Variety categories were determined based on children's fruit, fruit juice, and vegetable consumption on the recalled day. Differences in diet quality were examined using t-tests. Variety of fruits and vegetables was linked to higher overall diet quality. Children who consumed whole fruit had better diet quality scores for total fruit, whole fruit, whole grains, dairy, seafood, refined grains, sodium, and empty calories (P <= 0.018). Significantly higher HEI-2010 scores for total fruit, whole fruit, fatty acids, sodium, and empty calories, but a lower dairy HEI-2010 score, were identified in children who drank fruit juice (P <= 0.038). Vegetable consumption was significantly associated with higher total vegetables, greens/beans, and empty calories, but a lower sodium score (P <= 0.027). Children who consumed whole fruit, fruit juice and non-starchy vegetables (P <= 0.017), but not white potatoes, had significantly higher total HEI-2010 scores. Reinforcing fruit and 100% fruit juice consumption may indirectly support healthier diets among children. However, underlying associations between fruit and vegetable intakes and overall diet quality should be examined further. PMID- 27990336 TI - Overlooked competing asexual and sexually typified generic names of Ascomycota with recommendations for their use or protection. AB - With the change to one scientific name for fungal species, numerous papers have been published with recommendations for use or protection of competing generic names in major groups of ascomycetes. Although genera in each group of fungi were carefully considered, some competing generic names were overlooked. This paper makes recommendations for additional competing genera not considered in previous papers. Chairs of relevant Working Groups of the ICTF were consulted in the development of these recommendations. A number of generic names need protection, specifically Amarenographium over Amarenomyces, Amniculicola over Anguillospora, Balansia over Ephelis, Claviceps over Sphacelia, Drepanopeziza over Gloeosporidiella and Gloeosporium, Golovinomyces over Euoidium, Holwaya over Crinium, Hypocrella over Aschersonia, Labridella over Griphosphaerioma, Metacapnodium over Antennularia, and Neonectria over Cylindrocarpon and Heliscus. The following new combinations are made: Amniculicola longissima, Atichia maunauluana, Diaporthe columnaris, D. liquidambaris, D. longiparaphysata, D. palmicola, D. tersa, Elsinoe bucidae, E.caricae, E. choisyae, E. paeoniae, E. psidii, E. zorniae, Eupelte shoemakeri, Godronia myrtilli, G. raduloides, Sarcinella mirabilis, S. pulchra, Schizothyrium jamaicense, and Trichothallus niger. Finally, one new species name, Diaporthe azadirachte, is introduced to validate an earlier name, and the conservation of Discula with a new type, D. destructiva, is recommended. PMID- 27990340 TI - Implementation of a food insecurity screening and referral program in student-run free clinics in San Diego, California. AB - Food insecurity is associated with many poor health outcomes yet is not routinely addressed in clinical settings. The purpose of this study was to implement a food insecurity screening and referral program in Student-run Free Clinics (SRFC) and to document the prevalence of food insecurity screening in this low-income patient population. All patients seen in three SRFC sites affiliated with one institution in San Diego, California were screened for food insecurity using the 6-item United States Department of Agriculture (USDA) Food Security Survey between January and July 2015 and referred to appropriate resources. The percentage of patients who were food insecure was calculated. The screening rate was 92.5% (430/463 patients), 74.0% (318/430) were food insecure, including 30.7% (132/430) with very low food security. A food insecurity registry and referral tracking system revealed that by January 2016, 201 participants were receiving monthly boxes of food onsite, 66 used an off-site food pantry, and 64 were enrolled in the Supplemental Nutrition Assistance Program (SNAP). It is possible to implement a food insecurity screening and referral program into SRFCs. The prevalence of food insecurity in this population was remarkably high yet remained largely unknown until this program was implemented. Other health care settings, particularly those with underserved patient populations, should consider implementing food insecurity screening and referral programs. PMID- 27990341 TI - Smokers' BMI and perceived health: Does the order of questions matter? AB - We surveyed 431 daily smokers between November 2014 and March 2015 to examine the impact of the order of questions on the response to a self-reported health question as part of a larger experimental study. We randomized the question order, with some respondents providing their weight prior to self-reporting their health, while others did the opposite. We found that self-reported health outcomes are worse when smokers are first asked to report their weight. However, the order of questions only seems to impact those who are overweight as we did not find evidence that the order of questions affected responses for those with a BMI below 25. These findings suggest that the order of asking self-rated health and weight questions appears to matter, at least for overweight current smokers. PMID- 27990342 TI - Digital PCR, a technique for the future PMID- 27990343 TI - Homogeneous and digital proximity ligation assays for the detection of Clostridium difficile toxins A and B. AB - BACKGROUND: The proximity ligation assay (PLA) detects proteins via their interaction with pairs of proximity probes, which are antibodies coupled to noncomplementary DNA oligonucleotides. The binding of both proximity probes to their epitopes on the target protein brings the oligonucleotides together, allowing them to be bridged by a third oligonucleotide with complementarity to the other two. This enables their ligation and the detection of the resulting amplicon by real-time quantitative PCR (qPCR), which acts as a surrogate marker for the protein of interest. Hence PLA has potential as a clinically relevant diagnostic tool for the detection of pathogens where nucleic acid based tests are inconclusive proof of infection. METHODS: We prepared monoclonal and polyclonal proximity probes targeting Clostridium difficile toxins A (TcdA) and B (TcdB) and used hydrolysis probe-based qPCR and digital PCR (dPCR) assays to detect antibody/antigen interactions. RESULTS: The performance of the PLA assays was antibody-dependent but both TcdA and TcdB assays were more sensitive than comparable ELISAs in either single- or dualplex formats. Both PLAs could be performed using single monoclonal antibodies coupled to different oligonucleotides. Finally, we used dPCR to demonstrate its potential for accurate and reliable quantification of TcdA. CONCLUSIONS: PLA with either qPCR or dPCR readout have potential as new diagnostic applications for the detection of pathogens where nucleic acid based tests do not indicate viability or expression of toxins. Importantly, since it is not always necessary to use two different antibodies, the pool of potential antibodies useful for PLA diagnostic assays is usefully enhanced. PMID- 27990344 TI - Applicability of digital PCR to the investigation of pediatric-onset genetic disorders. AB - Early-onset rare diseases have a strong impact on child healthcare even though the incidence of each of these diseases is relatively low. In order to better manage the care of these children, it is imperative to quickly diagnose the molecular bases for these disorders as well as to develop technologies with prognostic potential. Digital PCR (dPCR) is well suited for this role by providing an absolute quantification of the target DNA within a sample. This review illustrates how dPCR can be used to identify genes associated with pediatric-onset disorders, to identify copy number status of important disease causing genes and variants and to quantify modifier genes. It is also a powerful technology to track changes in genomic biomarkers with disease progression. Based on its capability to accurately and reliably detect genomic alterations with high sensitivity and a large dynamic detection range, dPCR has the potential to become the tool of choice for the verification of pediatric disease-associated mutations identified by next generation sequencing, copy number determination and noninvasive prenatal screening. PMID- 27990345 TI - Fundamentals of multiplexing with digital PCR. AB - Over the past decade numerous publications have demonstrated how digital PCR (dPCR) enables precise and sensitive quantification of nucleic acids in a wide range of applications in both healthcare and environmental analysis. This has occurred in parallel with the advances in partitioning fluidics that enable a reaction to be subdivided into an increasing number of partitions. As the majority of dPCR systems are based on detection in two discrete optical channels, most research to date has focused on quantification of one or two targets within a single reaction. Here we describe 'higher order multiplexing' that is the unique ability of dPCR to precisely measure more than two targets in the same reaction. Using examples, we describe the different types of duplex and multiplex reactions that can be achieved. We also describe essential experimental considerations to ensure accurate quantification of multiple targets. PMID- 27990346 TI - Designing and interpretation of digital assays: Concentration of target in the sample and in the source of sample. AB - We explain how to design classic digital assays, comprising identical partitions, in order to obtain the required precision of the estimate within a defined range of concentrations. The design, including the number and volume of partitions, depends significantly on whether the assay is to assess the concentration of the target analyte in the sample or in the source of the sample (e.g. a patient body) with a given precision. We also show how to translate the result referring to the concentration in the sample into the concentration in the source of the sample, including the significant change in the breath of the confidence intervals. PMID- 27990347 TI - Digital PCR dynamic range is approaching that of real-time quantitative PCR. AB - Digital PCR (dPCR) has been reported to be more precise and sensitive than real time quantitative PCR (qPCR) in a variety of models and applications. However, in the majority of commercially available dPCR platforms, the dynamic range is dependent on the number of partitions analysed and so is typically limited to four orders of magnitude; reduced compared with the typical seven orders achievable by qPCR. Using two different biological models (HIV DNA analysis and KRAS genotyping), we have demonstrated that the RainDrop Digital PCR System (RainDance Technologies) is capable of performing accurate and precise quantification over six orders of magnitude thereby approaching that achievable by qPCR. PMID- 27990349 TI - Digital polymerase chain reaction for characterisation of DNA reference materials. AB - Accurate, reliable and reproducible quantification of nucleic acids (DNA/RNA) is important for many diagnostic applications and in routine laboratory testing, for example, for pathogen detection and detection of genetically modified organisms in food. To ensure reliable nucleic acid measurement, reference materials (RM) that are accurately characterised for quantity of target nucleic acid sequences (in copy number or copy number concentration) with a known measurement uncertainty are needed. Recently developed digital polymerase chain reaction (dPCR) technology allows absolute and accurate quantification of nucleic acid target sequences without need for a reference standard. Due to these properties, this technique has the potential to not only improve routine quantitative nucleic acid analysis, but also to be used as a reference method for certification of nucleic acid RM. The article focuses on the use and application of both dPCR and RMs for accurate quantification. PMID- 27990348 TI - Three-color crystal digital PCR. AB - Digital PCR is an exciting new field for molecular analysis, allowing unprecedented precision in the quantification of nucleic acids, as well as the fine discrimination of rare molecular events in complex samples. We here present a novel technology for digital PCR, Crystal Digital PCRTM, which relies on the use of a single chip to partition samples into 2D droplet arrays, which are then subjected to thermal cycling and finally read using a three-color fluorescence scanning device. This novel technology thus allows three-color multiplexing, which entails a different approach to data analysis. In the present publication, we present this innovative workflow, which is both fast and user-friendly, and discuss associated data analysis issue, such as fluorescence spillover compensation and data representation. Lastly, we also present proof-of-concept of this three-color detection system, using a quadriplex assay for the detection of EGFR mutations L858R, L861Q and T790M. PMID- 27990350 TI - Supporting Parents of Premature Infants Transitioning from the NICU to Home: A Pilot Randomized Control Trial of a Smartphone Application. AB - OBJECTIVE: To determine whether parents of Very Low Birth Weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU) transitioning home with the NICU-2 Home smartphone application have greater parenting self-efficacy, are better prepared for discharge and have shorter length of stay (LOS) than control parents. METHODS: A four-week pilot randomized controlled trial during the transition home with 90 VLBW parents randomized to usual care (n=44) or usual care plus NICU-2-Home (n=46), a smartphone application designed for VLBW parents. Parenting Sense of Competence Scale (PSOC) was assessed at baseline, day after discharge, and two weeks post-discharge. Preparedness for discharge and length of stay (LOS) were secondary outcomes. Analyses by usage were also included. RESULTS: While parents of VLBW infants in the intervention group did not show an improvement in PSOC during the transition when compared directly to controls, after accounting for actual mean app usage, PSOC improved 7% (2.71 points/time greater; 95%CI = 1.45, 6.27) for intervention versus controls. Compared to controls, above-average users increased their PSOC score by 14% (6.84 points/time; 95%CL = 5.02, 8.67), average users by 11% (4.58 points/time; 95%CL = 2.89, 6.27) and below-average users by 6% (2.41 points/time; 95%CL = 0.04, 4.79). Moderate evidence showed LOS was shorter for above-average users compared to the control group (beta = 12.2. SE = 6.9, p = 0.085). CONCLUSION: A smartphone application used by parents of VLBW infants during the transition home from the NICU can improve parenting self-efficacy, discharge preparedness, and LOS with improved benefits based on usage. PMID- 27990351 TI - Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo. AB - Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve axon growth in other cell types, including combinatorial overexpression of AP1 factors, overexpression of histone acetyltransferases, and pharmacological inhibitors of histone deacetylases. This insensitivity could be due to intermediate chromatin closure at the time of culture, and highlights important differences in cell culture models used to test potential pro-regenerative interventions. PMID- 27990352 TI - PARANOID INDIVIDUALS WITH SCHIZOPHRENIA SHOW GREATER SOCIAL COGNITIVE BIAS AND WORSE SOCIAL FUNCTIONING THAN NON-PARANOID INDIVIDUALS WITH SCHIZOPHRENIA. AB - Paranoia is a common symptom of schizophrenia that may be related to how individuals process and respond to social stimuli. Previous investigations support a link between increased paranoia and greater social cognitive impairments, but these studies have been limited to single domains of social cognition, and no studies have examined how paranoia may influence functional outcome. Data from 147 individuals with schizophrenia were used to examine whether actively paranoid and non-paranoid individuals with schizophrenia differ in social cognition and functional outcomes. On measures assessing social cognitive bias, paranoid individuals endorsed more hostile and blaming attributions and identified more faces as untrustworthy; however, paranoid and non-paranoid individuals did not differ on emotion recognition and theory of mind tasks assessing social cognitive ability. Likewise, paranoid individuals showed greater impairments in real-world interpersonal relationships and social acceptability as compared to non-paranoid patients, but these differences did not extend to performance based tasks assessing functional capacity and social competence. These findings isolate specific social cognitive disparities between paranoid and non-paranoid subgroups and suggest that paranoia may exacerbate the social dysfunction that is commonly experienced by individuals with schizophrenia. PMID- 27990353 TI - Effect of dihydrotestosterone on the expression of mucin 1 and the activity of Wnt signaling in mouse corneal epithelial cells. AB - AIM: To explore the effects of the androgen dihydrotestosterone on the expression of mucin 1 (MUC1) and the activity of Wnt signaling in mouse corneal epithelial cells. METHODS: Primary mouse corneal epithelial cells were isolated from the corneas of BALB/c mice. Quantitative real-time polymerase chain reaction, immunofluorescence and Western blot analysis were used to quantify the differential expression of selected genes. The androgen receptor was silenced by transfecting cells with androgen receptor shRNAs. TOP-Flash and FOP-flash reporter plasmids were used to measure beta-catenin-driven transcription. RESULTS: Dihydrotestosterone treatment increased MUC1 expression and activated the Wnt signaling pathway and led to the translocation of beta-catenin and upregulation of the Wnt downstream target gene TATA box binding protein and urokinase plasminogen activator. These effects were prevented by downregulating the androgen receptor. CONCLUSION: Androgens may protect against dry eye by regulating the expression of MUC1 which is stimulated by the activation of Wnt signaling via the androgen receptor. An understanding of the mechanisms associated with androgen-mediated protection against dry eye is an important step in developing new therapies for this disease. PMID- 27990354 TI - Effect of trapping vascular endothelial growth factor-A in a murine model of dry eye with inflammatory neovascularization. AB - AIM: To evaluate whether trapping vascular endothelial growth factor A (VEGF-A) would suppress angiogenesis and inflammation in dry eye corneas in a murine corneal suture model. METHODS: We established two groups of animals, one with non dry eyes and the other with induced dry eyes. In both groups, a corneal suture model was used to induce inflammation and neovascularization. Each of two groups was again divided into three subgroups according to the treatment; subgroup I (aflibercept), subgroup II (dexamethasone) and subgroup III (phosphate buffered saline, PBS). Corneas were harvested and immunohistochemical staining was performed to compare the extents of neovascularization and CD11b+ cell infiltration. Real-time polymerase chain reaction was performed to quantify the expression of inflammatory cytokines and VEGF-A in the corneas. RESULTS: Trapping VEGF-A with aflibercept resulted in significantly decreased angiogenesis and inflammation compared with the dexamethasone and PBS treatments in the dry eye corneas (all P<0.05), but with no such effects in non-dry eyes. The anti inflammatory and anti-angiogenic effects of VEGF-A trapping were stronger than those of dexamethasone in both dry eye and non-dry eye corneas (all P<0.05). The levels of RNA expression of VEGF-A, TNF-alpha, and IL-6 in the aflibercept subgroup were significantly decreased compared with those in the PBS subgroup in the dry eye group. CONCLUSION: Compared with non-dry eye corneas, dry eye corneas have greater amounts of inflammation and neovascularization and also have a more robust response to anti-inflammatory and anti-angiogenic agents after ocular surface surgery. Trapping VEGF-A is effective in decreasing both angiogenesis and inflammation in dry eye corneas after ocular surface surgery. PMID- 27990356 TI - MicroRNA-34a promoting apoptosis of human lens epithelial cells through down regulation of B-cell lymphoma-2 and silent information regulator. AB - AIM: To investigate the role of microRNA-34a (miR-34a) in the induction of apoptosis of human lens epithelial (HLE-B3) cells. METHODS: The apoptosis of HLE B3 cells was detected by Annexin V-PE apoptosis detection kit after the treatment with 200 umol/L H2O2 for 24h and lentiviral miR-34a vector transfection. The expression of miR-34a in the cells was quantified by quantitative real time polymerase chain reaction (qRT-PCR) in response to H2O2 exposure and the vector transfection. The effects of overexpression of miR-34a on the expression of B cell lymphoma-2 (Bcl-2) and silent information regulator 1 (SIRT1) was determined by qRT-PCR and Western blot. RESULTS: The expression of miR-34a was up-regulated by the treatment of H2O2 in HLE-B3 cells. The increased expression of miR-34a is accompanied with the cell apoptosis. Consistence with the H2O2 exposure, ectopic overexpression of miR-34a in HLE-B3 cells promoted cells apoptosis. Importantly the anti-apoptosis factors Bcl-2 and SIRT1 were reduced significantly by up regulation of miR-34a in HLE-B3 cells. CONCLUSION: MiR-34a promotes the apoptosis of HLE-B3 cells by down-regulating Bcl-2 and SIRT1, suggesting that miR-34a may involve in the pathogenesis of cataract formation and targeting miR-34a may be a potentially therapeutic approach for treatment of cataract. PMID- 27990355 TI - Corneal collagen cross-linking and liposomal amphotericin B combination therapy for fungal keratitis in rabbits. AB - AIM: To observe the therapeutic effect of corneal collagen cross-linking (CXL) in combination with liposomal amphotericin B in fungal corneal ulcers. METHODS: New Zealand rabbits were induced fungal corneal ulcers by scratching and randomly divided into 3 groups, i.e. control, treated with CXL, and combined therapy of CXL with 0.25% liposomal amphotericin B (n=5 each). The corneal lesions were documented with slit-lamp and confocal microscopy on 3, 7, 14, 21 and 28d after treatment. The corneas were examined with transmission electron microscopy (TEM) at 4wk. RESULTS: A rabbit corneal ulcer model of Fusarium was successfully established. The corneal epithelium defect areas in the two treatment groups were smaller than that in the control group on 3, 7, 14 and 21d (P<0.05). The corneal epithelium defect areas of the combined group was smaller than that of the CXL group (P<0.05) on 7 and 14d, but there were no statistical differences on 3, 21 and 28d. The corneal epithelium defects of the two treatment groups have been healed by day 21. The corneal epithelium defects of the control group were healed on 28d. The diameters of the corneal collagen fiber bundles (42.960+/-7.383 nm in the CXL group and 37.040+/-4.160 nm in the combined group) were thicker than that of the control group (24.900+/-1.868 nm), but there was no difference between the two treatment groups. Some corneal collagen fiber bundles were distorted and with irregular arrangement, a large number of fibroblasts could be seen among them but no inflammatory cells in both treatment groups. CONCLUSION: CXL combined with liposomal amphotericin B have beneficial effects on fungal corneal ulcers. The combined therapy could alleviate corneal inflammattions, accelerate corneal repair, and shorten the course of disease. PMID- 27990357 TI - A novel mutation of p.F32I in GJA8 in human dominant congenital cataracts. AB - AIM: To identify a causative mutation in a three-generation family with autosomal dominant congenital total cataract and dissect the molecular consequence of the identified mutation. METHODS: Clinical and ophthalmological examinations were performed on the affected and unaffected family members. Mutation were screened in recruited family members by polymerase chain reaction (PCR) of the two reported genes (CRYAA and GJA8) which were linked to human total cataracts and direct sequencing of the PCR product. The molecular consequences of the identified mutation was dissected. The plasmids carrying wild-type and mutant mouse ORF of Gja8, coding for connexin 50 (Cx50), were generated and ectopic expressed in 293 cells. Recombinant protein expression and cellular localization of recombinated Cx50 were assessed by confocal microscopy. RESULTS: Clinical and ophthalmological examinations were performed on the affected and unaffected family members. Mutation were screened in recruited family members by PCR of the two reported genes (CRYAA and GJA8) which were linked to human total cataracts and direct sequencing of the PCR product. The molecular consequences of the identified mutation was dissected. The plasmids carrying wild-type and mutant mouse ORF of Gja8, coding for Cx50, were generated and ectopic expressed in 293 cells. Recombinant protein expression and cellular localization of recombinated Cx50 were assessed by confocal microscopy. CONCLUSION: This study has identified a novel cataract mutation in GJA8, which adds a novel mutation to the existing spectrum of Cx50 mutations with cataract. The molecular consequences of p.F32I mutation in GJA8 exclude instability and the mislocalization of mutant Cx50 protein. PMID- 27990358 TI - Neuropathy optic glaucomatosa induced by systemic hypertension through activation endothelin-1 signaling pathway in central retinal artery in rats. AB - AIM: To evaluate effect of hypertension on retinal ganglion cell (RGC) apoptosis, intraocular pressure (IOP), and the activation of endothelin-1 (ET-1) signaling pathway in central retinal artery (CRA) in rats. METHODS: The experimental study was performed on 20 male Sprague Dawley rats that were divided into control group, and hypertension groups. The hypertension was induced by subcutaneous deoxycorticoacetate (DOCA) 10 mg/kg twice a week and administered 0.9% NaCl solution daily for 2, 6, and 10wk. Blood pressure (BP) was measured using animal BP analyzer. IOP was measured by handheld tonometry. Retinal tissue preparations by paraffin blocks were made after enucleation. The expression of ET-1, eNOS, ET 1 receptor A (ETRA), ET-1 receptor B (ETRB), and phosphorylated myosin light chain kinase (MLCK), and caldesmon (CaD) in CRA and RGC apoptosis were evaluated through immunofluorescent staining method then observed using laser scanning confocal microscopy. RESULTS: BP significantly increased in all of the hypertension groups compared to control (P=0.001). Peak IOP elevation (7.78+/ 4.14 mm Hg) and RGC apoptosis (576.15+/-33.28 Au) occurred on 2wk of hypertension. ET-1 expression (1238.6+/-55.1 Au) and eNOS expression (2814.2+/ 70.7 Au) were found highest in 2wk of hypertension, although the ratio of ET 1/eNOS decreased since 2wk. ETRA reached peak expression in 10wk of hypertension (1219.4+/-6.3 Au), while ETRB significantly increased only in 2 weeks group (1069.2+/-9.6 Au). The highest MLCK expression (1190.09+/-58.32 Au), CaD (1670.28+/-18.36 Au) were also found in 2wk of hypertension. CONCLUSION: Hypertension effects to activation of ET-1 signaling pathway significantly in CRA, elevation of IOP, and RGC apoptosis. The highest value was achieved at 2wk, which is the development phase of hypertension. PMID- 27990359 TI - Effect of endothelial progenitor cells derived from human umbilical cord blood on oxygen-induced retinopathy in mice by intravitreal transplantation. AB - AIM: To investigate the effect of endothelial progenitor cells (EPCs) labeled by carboxy fluorescein diacetate succinimidyl ester (CFSE) on murine oxygen-induced retinopathy (OIR) by intravitreal transplantation. METHODS: After isolated from human umbilical cord blood mononuclear cells, EPCs were cultivated and then labeled with CFSE in vitro. C57BL/6J mice were placed to 75% hyperoxia chamber from P7 to P12 to establish OIR model. At P12, OIR mice were intravitreally injected with 1 uL suspension contained 2*105 EPCs (EPCs group) or isometric phosphate buffered saline (PBS group). The contralateral eye of each mice received no injection (OIR group). Evans blue angiography and frozen section were examined to track the labeled cells in OIR group at P15 and P19. Using retina paraffin sections and adenosinediphos phatase staining at P12 and P19, the effect of EPCs on OIR mice was evaluated quantitatively and qualitatively. RESULTS: The retinas from EPCs group with less non-perfusion area and fewer peripheral tufts were observed at P19, comparing with that from PBS or OIR group. The retinopathy in EPCs group receded earlier with less non-ganglion cells and neovascular nuclei, together with relatively regular distribution. The counts of the neovascular nuclei at P19 were reduced by 44% or 45%, compared with those of OIR group or PBS group respectively. Three days after EPCs injection, a large number of EPCs appeared in the vitreous cavity and adhered to the retinal surface. While at one week, the cells gathered between the internal plexiform layer and the inner limiting membrane, and some EPCs appeared in retinal vessels. CONCLUSION: EPCs transplantation can participate in the reparative procedure of the neovascularization in OIR. PMID- 27990360 TI - Suppressive effect of microRNA-143 in retinoblastoma. AB - AIM: To investigate microRNA-143 expression and effect on suppression of retinoblastoma (RB) cells. METHODS: The expression of microRNA-143 was investigated and compared in normal human retina tissue samples and in RB cell lines of Y79 and Weri1. The microRNA-143 mimics were transfected into the RB cell lines separately, and its effect on RB cell lines was detected using reverse transcription quantitative polymerase chain reaction and Western blotting methods. RESULTS: The microRNA-143 expression was significantly suppressed in RB cell lines. Overexpression of microRNA-143 significantly lowered cell viability and invasion of the RB cell lines, and increased the number of apoptotic cells. Meanwhile, the Bax expression was up-regulated and much higher in the microRNA 143 mimics transfected group than that in the negative control and the microRNA 143 inhibitor groups. CONCLUSION: MicroRNA-143 exhibits suppressive effects in RB. The current study provides the perspective of a potential therapeutic treatment for RB. PMID- 27990361 TI - Upregulated inflammatory associated factors and blood-retinal barrier changes in the retina of type 2 diabetes mellitus model. AB - AIM: To examine the expression of high mobility group box-1 (HMGB-1) and intercellular adhesion molecule-1 (ICAM-1) in the retina and the hippocampal tissues; and further to evaluate the association of these two molecules with the alterations of blood-retinal barrier (BRB) and blood-brain barrier (BBB) in a rat model of type 2 diabetes. METHODS: The type-2 diabetes mellitus (DM) model was established with a high-fat and high-glucose diet combined with streptozotocin (STZ). Sixteen weeks after DM induction, morphological changes of retina and hippocampus were observed with hematoxylin-eosin staining, and alternations of BRB and BBB permeability were measured using Evans blue method. Levels of HMGB-1 and ICAM-1 in retina and hippocampus were detected by Western blot. Serum HMGB-1 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: A significantly higher serum fasting blood glucose level in DM rats was observed 2wk after STZ injection (P<0.01). The serum levels of fasting insulin, Insulin resistance homeostatic model assessment (IRHOMA), total cholesterol (TC), total triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) in the DM rats significantly higher than those in the controls (all P<0.01). HMGB-1 (0.96+/ 0.03, P<0.01) and ICAM-1 (0.76+/-0.12, P<0.05) levels in the retina in the DM rats were significantly higher than those in the controls. HMGB-1 (0.83+/-0.13, P<0.01) and ICAM-1 (1.15+/-0.08, P<0.01) levels in the hippocampal tissues in the DM rats were also significantly higher than those in the controls. Sixteen weeks after induction of DM, the BRB permeability to albumin-bound Evans blue dye in the DM rats was significantly higher than that in the controls (P<0.01). However, there was no difference of BBB permeability between the DM rats and controls. When compared to the controls, hematoxylin and eosin staining showed obvious irregularities in the DM rats. CONCLUSION: BRB permeability increases significantly in rats with type-2 DM, which may be associated with the up regulated retinal expression of HMGB-1 and ICAM-1. PMID- 27990362 TI - Corneal sensitivity, ocular surface health and tear film stability after punctal plug therapy of aqueous deficient dry eye. AB - AIM: To evaluate the effect of punctal occlusion using thermosensitive (smart plug) versus silicone plug for management of aqueous deficient dry eye on corneal sensitivity, ocular surface health and tear film stability. METHODS: A comparative prospective interventional case study included 45 patients with bilateral severe form of aqueous deficient dry eye. In each patient, the smart plug was inserted in the lower punctum of the right eye which was considered as study group 1 and silicone plug was inserted in the lower punctum of the left eye of the same patient which was considered as study group 2. All patients were subjected to careful history taking and questionnaire for subjective assessment of severity of symptoms. Corneal sensitivity, corneal fluorescein, rose bengal staining, Schirmer's I test, tear film break up time and conjunctival impression cytology were performed pre and 1, 3 and 6mo post plug insertion. RESULTS: A statistically significant improvement in subjective and objective manifestations occurred following treatment with both types of plugs (P<0.01). The thermosensitive plug caused significant overall improvement, decrease in frequency of application of tear substitutes and improvement of conjunctival impression cytology parameters in the inserted side (P<0.01). Canaliculitis was reported in two eyes (4.4%) following punctal occlusion using thermosensitive plug (study group 1). Spontaneous plug loss occurred in 21 eyes (46.6%) in the silicone plug group (study group 2). CONCLUSION: Improvement of subjective and objective manifestations of aqueous deficient dry eye occurs following punctal plug occlusion. Thermosensitive plug has good patient's compliance with fewer complications and lower rates of loss compared to the silicone plug. PMID- 27990363 TI - Comparison of iris-fixated foldable lens and scleral-fixated foldable lens implantation in eyes with insufficient capsular support. AB - AIM: To compare the outcomes of vision using two different intraocular lens (IOL) replacement techniques, iris-fixated foldable intraocular lens (IF-IOL) and scleral-fixated foldable intraocular lens (SF-IOL) in patients with insufficient capsular support. METHODS: Total 63 eyes (62 patients) with insufficient posterior capsule support underwent replacement of IF-IOL or SF-IOL between January 2008 and August 2011. Outcome measures included changes in visual acuity, slit lamp examination, refractive indices and corneal curvatures. RESULTS: The mean improvement of uncorrected visual acuity (UCVA) was greater in IF-IOL group compared to the SF-IOL group (0.43 D+/-0.19 D vs 0.35 D+/-0.18 D, P<0.05). Moreover, 12 (38.71%) eyes in IF-IOL group and 4 (12.50%) in SF-IOL group had a higher postoperative UCVA than preoperative best corrected visual acuity (BCVA) while 9 (29.03%) eyes in IF-IOL group and 18 (56.25%) in SF-IOL group had a lower postoperative UCVA than preoperative BCVA. The myopic mean manifest sphere and mean cylinder magnitude were lower in the IF-IOL group than that in the SF-IOL group (-0.47 D+/-0.58 D vs 0.50 D+/-0.43 D, P<0.01; 0.84 D+/-0.53 D vs 1.23 D+/ 0.70 D, P<0.05). No difference of corneal astigmatism and surgically induced astigmatism was found between the two groups. In addition, fewer complications were observed in IF-IOL eyes. CONCLUSION: IF-IOL implantation can give a significant improvement in vision with fewer complications than SF-IOL in patients with insufficient capsular support. PMID- 27990365 TI - Comparison of the anti-inflammatory effects of fluorometholone 0.1% combined with levofloxacin 0.5% and tobramycin/dexamethasone eye drops after cataract surgery. AB - AIM: To compare the combination of fluorometholone 0.1% and levofloxacin 0.5% to tobramycin/dexamethasone eye drops in controlling inflammation and preventing infection after phacoemulsification with an intraocular lens implantation. METHODS: Sixty eyes from 60 patients undergoing cataract phacoemulsification were randomized into two groups; half of the patients were treated with fluorometholone (6 times/d) combined with levofloxacin (4 times/d), while the other half were treated with tobramycin/dexamethasone (4 times/d) eye drops for one week. Preoperative and postoperative intraocular pressure, aqueous flare, corneal thickness, and signs and symptoms were recorded before the operation and 1wk following treatments. RESULTS: There were no statistically significant differences between the two groups in corneal thickness (P>=0.629), aqueous flare (P>=0.398), and signs and symptoms scores (P>=0.350) at each time point. Ocular hypertension was only observed in two eyes in the tobramycin/dexamethasone group. CONCLUSION: Fluorometholone combined with levofloxacin treatment shows comparable efficacy but without the tendency to increase intraocular pressure; thus, it might be a better regimen for postoperative use. PMID- 27990364 TI - Blood pressure change during phacoemulsification and femtosecond laser-assisted cataract surgery. AB - AIM: To evaluate blood pressure (BP) changes during phacoemulsification (PC) and femtosecond laser (FSL)-assisted cataract surgery. METHODS: A retrospective chart review was performed for all patients who received traditional phacoemulsification surgery (PC group) and FSL-assisted cataract surgery (FS group) from July 2013 to December 2014. Totally 206 eyes from 133 patients receiving the two types of procedures were included. Patient characteristics (age, gender, and hypertension history), pre- and post-operative BPs were collected. RESULTS: The pro-operative systolic and diastolic BPs (mm Hg) were 124.89+/-20.48 vs 126.98+/-16.85, and 71.88+/-9.81 vs 73.56+/-10.03, in PC and FS groups, respectively. While the post-operative systolic and diastolic BPs (mm Hg) were 130.13+/-22.59 vs 134.77+/-17.52, and 73.41+/-11.62 vs 78.89+/-12.2, in PC and FS groups, respectively. Paired-sample t-tests showed obvious systolic and diastolic BP elevations in FS group after surgery (P=0.001 and 0.007) and no reliability in PC group (P=0.094 and 0.359). A linear regression model revealed systolic and diastolic BP elevations, which were related to longer surgical times for FS group (P=0.008 and 0.021). Age, gender, and hypertension history were not correlated with blood pressure elevation in either group. CONCLUSION: BP increases but at a limited level after FSL-assisted cataract surgery compared to traditional phacoemulsification. PMID- 27990366 TI - Comparison of ICare and IOPen vs Goldmann applanation tonometry according to international standards 8612 in glaucoma patients. AB - AIM: To compare IOPen and ICare rebound tonometry to Goldmann applanation tonometry (GAT) according to International Standards Organization (ISO) 8612 criteria. METHODS: Totally 191 eyes (n=107 individuals) were included. Criteria of ISO 8612 were fulfilled: 3 clusters of IOP, measured by GAT, were formed. The GAT results were given as mean+/-standard deviation. RESULTS: GAT (19.7+/-0.5 mm Hg) showed a significant correlation to ICare (19.8+/-0.5 mm Hg) (r=0.547, P<0.001) and IOPen (19.5+/-0.5 mm Hg) (r=0.526, P<0.001). According to ISO 8612 criteria in all 3 IOP groups the number of outliers (of the 95% limits of agreement) exceeded 5% for ICare and IOPen vs GAT: No.1 (n=68) 29.4% and 22.1%, No.2 (n=62) 35.5% and 37.1%, No.3 (n=61) 26.2% and 42.6%, respectively. CONCLUSION: The strict requirements of the ISO 8612 are not fulfilled in a glaucoma collective by ICare and IOPen at present. As long as the Goldmann tonometry is applicable it should be used first of all for reproducible IOP readings. ICare and IOPen tonometry should be considered as an alternative tool, if application of Goldmann tonometry is not possible. PMID- 27990367 TI - Missed retinal breaks in rhegmatogenous retinal detachment. AB - AIM: To evaluate the causes and associations of missed retinal breaks (MRBs) and posterior vitreous detachment (PVD) in patients with rhegmatogenous retinal detachment (RRD). METHODS: Case sheets of patients undergoing vitreo retinal surgery for RRD at a tertiary eye care centre were evaluated retrospectively. Out of the 378 records screened, 253 were included for analysis of MRBs and 191 patients were included for analysis of PVD, depending on the inclusion criteria. Features of RRD and retinal breaks noted on examination were compared to the status of MRBs and PVD detected during surgery for possible associations. RESULTS: Overall, 27% patients had MRBs. Retinal holes were commonly missed in patients with lattice degeneration while missed retinal tears were associated with presence of complete PVD. Patients operated for cataract surgery were significantly associated with MRBs (P=0.033) with the odds of missing a retinal break being 1.91 as compared to patients with natural lens. Advanced proliferative vitreo retinopathy (PVR) and retinal bullae were the most common reasons for missing a retinal break during examination. PVD was present in 52% of the cases and was wrongly assessed in 16%. Retinal bullae, pseudophakia/aphakia, myopia, and horse shoe retinal tears were strongly associated with presence of PVD. Traumatic RRDs were rarely associated with PVD. CONCLUSION: Pseudophakic patients, and patients with retinal bullae or advanced PVR should be carefully screened for MRBs. Though Weiss ring is a good indicator of PVD, it may still be over diagnosed in some cases. PVD is associated with retinal bullae and pseudophakia, and inversely with traumatic RRD. PMID- 27990368 TI - Evaluation of retinal nerve fiber layer thickness profile in thyroid ophthalmopathy without optic nerve dysfunction. AB - AIM: To evaluate retinal nerve fiber layer (RNFL) thickness profile in patients of thyroid ophthalmopathy with no clinical signs of optic nerve dysfunction. METHODS: A prospective, case-control, observational study conducted at a tertiary care centre. Inclusion criteria consisted of patients with eyelid retraction in association with any one of: biochemical thyroid dysfunction, exophthalmos, or extraocular muscle involvement; or thyroid dysfunction in association with either exophthalmos or extra-ocular muscle involvement; or a clinical activity score (CAS)>3/7. Two measurements of RNFL thickness were done for each eye, by Cirrus HD-optical coherence tomography 6mo apart. RESULTS: Mean age of the sample was 38.75y (range 13-70y) with 18 males and 22 females. Average RNFL thickness at first visit was 92.06+/-12.44 um, significantly lower than control group (101.28+/-6.64 um) (P=0.0001). Thickness of inferior quadrant decreased from 118.2+/-21.27 um to 115.0+/-22.27 um after 6mo (P=0.02). There was no correlation between the change in CAS and RNFL thickness. CONCLUSION: Decreased RNFL thickness is an important feature of thyroid orbitopathy, which is an inherent outcome of compressive optic neuropathy of any etiology. Subclinical RNFL damage continues in the absence of clinical activity of the disease. RNFL evaluation is essential in Grave's disease and active intervention may be warranted in the presence of significant damage. PMID- 27990369 TI - Macular changes of neuromyelitis optica through spectral-domain optical coherence tomography. AB - AIM: To evaluate the thickness of the retinal layers in the macula using spectral domain optical coherence tomography (SD-OCT) in patients with neuromyelitis optica (NMO). METHODS: Spectralis SD-OCT, utilizing automated macular layer segmentation, was performed in 26 NMO patients and 26 healthy controls. Visual function including visual field tests and pattern visual evoked potential were recorded in study subjects. RESULTS: Forty-one eyes from 26 NMO patients and 52 eyes from 26 age- and sex-matched healthy controls were included. Besides total macular volume, peri-paipillary retinal nerve fiber layer (RNFL) thickness, the thickness of macular RNFL, ganglion cell layer (GCL) and inner plexiform layer (IPL) were also significantly reduced in NMO patients compared to those inhealthy controls (P<0.000). No differences were found in the thickness of macular inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) between the two groups. Reversely, the outer retinal layer (ORL) was shown to be thicker in NMO than controls (P<0.05). Compared with the peri-papillary RNFL thickness, the GCL thickness was demonstrated to correlate with visual function better. CONCLUSION: The study provides in vivo evidence of retinal neural loss in NMO patients and demonstrates a better structure-function correlation between retinal ganglion cell and visual function than peri-papillary RNFL does. In addition, no evidence of primary neural damage is found. Besides, the photoreceptor cells and retinal pigments epithelial (RPE) cells presumably proliferated in compensation in NMO after retinal neural loss. PMID- 27990370 TI - Adult reference values of the computerized diplopia test. AB - AIM: To estimate the adult reference values for measured deviations by a computerized diplopia test and testify the validity. METHODS: Totally 391 participants were recruited and taken the computerized diplopia test. The plots and amplitude of deviations were recorded. The differences in different gender, age and visual acuity groups were analyzed respectively. Of 30 subjects were enrolled to testify the interobserver reliability. Another 46 subjects (including 26 normal subjects and 20 patients) were taken the test and theirs deviations were recorded to testify the validity of the reference value. RESULTS: The max horizontal and vertical deviations were 2.55 degrees and 0.76 degrees with normal corrected visual acuity while 3.88 degrees and 1.46 degrees for subjects with poor corrected vision. The differences between age groups was insignificant (Z=3.615, 4.758; P=0.461, 0.313 for horizontal and vertical respectively). The max horizontal deviation of female was smaller than male (Z=-2.177; P=0.029), but the difference in max vertical deviation was insignificant (Z=-1.296; P=0.195). The mean difference between observers were both -0.1 degrees , with 95% confidence limits (CI) of -1.4 degrees and 1.6 degrees in max horizontal deviations while -2.1 degrees and 1.8 degrees in max vertical deviation. The mean deviation of 26 normal subjects was 1.02 degrees +/-0.84 degrees for horizontal and 0.47 degrees +/-0.30 degrees for vertical which both within the range of reference values. The mean deviation of 20 patients was 13.51 degrees +/ 11.69 degrees for horizontal and 8.34 degrees +/-8.58 degrees for vertical which both beyond the reference range. CONCLUSION: The max amplitude of horizontal and vertical deviation is pointed as the numerical parameters of computerized diplopia test. The reference values are different between normal corrected visual acuity and poor corrected vision. These values may useful for evaluating patients with diplopia in veriety conditions during clinical practice. PMID- 27990372 TI - Main visual symptoms associated to refractive errors and spectacle need in a Brazilian population. AB - AIM: To determine the main visual symptoms in a Brazilian population sample, associated to refractive errors (REs) and spectacle need to suggest priorities in preventive programs. METHODS: A cross-sectional study was conducted in nine counties of the southeast region of Brazil, using a systematic sampling of households, between March 2004 and July 2005. The population was defined as individuals aged between 1 and 96y, inhabitants of 3600 residences to be evaluated and 3012 households were included, corresponding to 8010 subjects considered for participation in the survey, of whom 7654 underwent ophthalmic examinations. The individuals were evaluated according their demographic data, eye complaints and eye examination including the RE and the need to prescribe spectacles according to age. Statistical analysis was performed using SPSS software package and descriptive analysis using 95% confidence intervals (P<0.05). RESULTS: The main symptom detected was asthenopia, most frequent in the 2nd and 3rd decades of life, with a significant decline after the 4th decade. Astigmatism was the RE most associated with asthenopia. Reduced near vision sight was more frequent in those >=40y with a progressive decline thereafter. Spectacles were most frequently required in subjects of >=40 years of age. CONCLUSION: The main symptom related to the vision was asthenopia and was associated to astigmatism. The greatest need for spectacles prescription occurred after 40's, mainly to correct near vision. Subjects of >=40 years old were determined to be at high risk of uncorrected REs. These observations can guide intervention programs for the Brazilian population. PMID- 27990373 TI - A bibliometric analysis of academic publication on diabetic retinopathy disease trends during 1980-2014: a global and medical view. AB - AIM: To investigate diabetic retinopathy (DR) literature using the Institute for Scientific Information (ISI) Web of Science (WoS) database and to analyse the correlation results between socio-economic development datas and number of DR publications. METHODS: The statistical analysis of the documents published during 1980-2014 was analysed. The data of this study were based on the database of WoS. "Diabetic retinopathy" was used as the keywords to search the WoS database. RESULTS: The United States ranked first in the DR research with 1840 publications and 24.38% of the world production followed by England and Japan. Besides, the most productive country was Iceland. A high correlation was found between number of publications and 2014 gross domestic product (GDP) values of 81 countries (r=0.800, P<0.001). We found a significant correlation between number of publications and Human Development Index (HDI) (r=0.645, P=0.001). There is a moderate correlation between people with diabetes and number of DR publications for 81 countries (r=0.514, P<0.01). It could be analysed that estimated publication number with DR title will be 445 according to the regression curve constituted with cubic model in 2015 (R2=1.000). CONCLUSION: More DR studies have been published in developed countries, DR and other complications of diabetes have gradually increased in developing countries over recent decades. It can be expected that the number of DR studies will gradually increase in developing countries. PMID- 27990371 TI - Retinal nerve fiber layer thickness changes in obstructive sleep apnea syndrome: a systematic review and Meta-analysis. AB - AIM: To evaluate the retinal nerve fiber layer (RNFL) thickness changes in patients with obstructive sleep apnoea syndrome (OSAS), and detect possible prevalence of glaucoma in this population. METHODS: Comprehensive studies were conducted on the Cochrane Library, PubMed and Embase through March, 2015. Only studies that fit the selection criteria about RNFL and OSAS would be included. For the measures, we calculated the 95% confidence interval (CI) and weighted mean differences (WMD). The systematic review and Meta-analysis was performed by RevMan 5.2 software. RESULTS: Nine case-control studies were analyzed containing a total of 1086 cases and 580 controls. Average RNFL thickness in OSAS was reduced significantly compared with healthy controls in random effects model (WMD=-2.56, 95% CI: -4.82 to -0.31, P =0.003, I2=57%). A significant RNFL thickness reduction were found between the two groups in inferior quadrant (WMD= 3.11, 95% CI: -5.53 to -0.69, P=0.01), superior quadrant (WMD=-2.37, 95%CI: -4.7 to 0.04, P=0.05). In nasal quadrant (WMD=-2.54, 95% CI: -6.53 to 1.45, P=0.21) and temporal quadrant (WMD=-1.26, 95% CI: -2.19 to 0.47, P=0.15) there was no difference of RNFL thickness between the two groups. CONCLUSION: The results show that RNFL thickness is lower in patients with moderate or severe OSAS than in normal subjects or patients with mild OSAS according to the nine homogeneity studies. PMID- 27990374 TI - Trends in ophthalmology journals: a five-year bibliometric analysis (2009-2013). AB - AIM: To explore the trends in the ophthalmic literature over a 5-year period in relation to country, research expenditure and demographics. METHODS: Articles published between 2009 and 2013 by the 20highest-contributing countries in the 20 top-ranked ophthalmology journals were identified by their country of affiliation. The number of articles published and mean impact factor were measured per country for each year and trends explored using regression analysis with 5-year and 10-year forecasts calculated. Data on research expenditure was collected and tested for correlation with the number of articles and mean impact factor. RESULTS: The analysis included 19 338 articles. The USA, UK and Europe accounted for 60.2% of articles published, with the USA contributing 7388 articles (34.0%). The USA also demonstrated the highest mean impact factor (3.5). Research expenditure was significantly correlated with both research output (r=0.86, P<0.001) and scholarly impact (r=0.42, P<0.001). China (P<0.01), Korea (P<0.01) and India (P<0.02) demonstrated a significant growth in research output over the study period. The research contribution of these three countries combined is forecasted to overtake that of Europe within ten years, with China expected to be the second-largest contributor within five years. These countries were also among those demonstrating the greatest growth in research expenditure. CONCLUSION: While the USA and European countries are major contributors of ophthalmic research, the productivity of some Asian countries is growing impressively. The contribution of China, Korea and India is forecasted to outweigh that of Europe by 2023. Research expenditure is highly correlated with research productivity and these trends reflect the differing economic priorities across the world. PMID- 27990376 TI - Management of glaucoma in pregnancy: risks or choices, a dilemma? AB - The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother as against the potential harm to the fetus or newborn. Most anti-glaucoma drugs (i.e. beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors topical and systemic, cholinergics, anticholinesterases, and apraclonidine) are considered category C agents and ophthalmologists are usually limited to treating patients with the category B drugs of brimonidine and dipivefrin. Brimonidine is generally the preferred first line drug in the first, second and early third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns wherein topical carbonic anhydrase inhibitors may be the optimal choice. Glaucoma surgery can be performed with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetics, sedative agents, and antimetabolites still have potential risk for the fetus. Argon laser trabeculoplasty (ALT) or selective laser trabeculoplasty (SLT) is an alternative treatment that can be performed in all trimesters. Carbonic anhydrase inhibitors and beta-blockers are certified by the American Academy of Pediatrics for use during nursing. However, low doses of these medications should be considered when used in the breast feeding period. Optimum treatment for glaucoma in pregnancy must not be withheld so as to prevent any further deterioration in progressive vision loss and quality of life. PMID- 27990377 TI - Caruncle excision to treat epiphora caused by caruncle swelling in patients with active Graves' ophthalmopathy: case series. PMID- 27990375 TI - Review of clinical and basic approaches of fungal keratitis. AB - Fungal keratitis (FK) is a serious disease which can cause blindness. This review has current information about the pathogenesis, limitations of traditional diagnosis and therapeutic strategies, immune recognition and the diagnosis and therapy of FK. The information of this summary was reviewed regularly and updated as what we need in the diagnosis and therapy of FK nowadays. PMID- 27990378 TI - A sutureless subconjunctival M-shaped limbus incision for hard cataracts. PMID- 27990379 TI - Analysis and management of intraoperative complications during small-incision lenticule extraction. PMID- 27990380 TI - Kawasaki disease for dermatologists. AB - Kawasaki disease (KD) is a systemic vasculitis that mostly affects children below the age of 5. The vasculitis involves arteries of medium size, especially the coronaries. Various etiologies have been proposed including association with micro-organisms, bacterial superantigens, and genetic factors, however, the exact cause remains unknown. There is no specific laboratory test for KD. Diagnosis is clinical and depends upon the presence of fever for >=5 days and 4 or more of five principal features, viz. polymorphous exanthem, extremity changes, mucosal changes involving the lips and oral cavity, bilateral bulbar conjunctival injection, and unilateral cervical lymphadenopathy. The term "incomplete KD" refers to the presence of fever and less than four principal clinical features. Recognition of this group of patients is important because it is usually seen in infants and risk of coronary abnormalities is increased probably because of delays in diagnosis. However, what appears to be "incomplete" at a given point of time may not actually be so because some of the features may have already subsided and others may evolve over time. Hence, a detailed dermatological examination is warranted in all cases, especially in incomplete KD, to ensure timely diagnosis. Although KD is a self-limiting disease in most patients, coronary artery abnormalities (CAAs) including coronary dilatations and aneurysms may develop in up to 25% of untreated patients. CAAs are the most common cause of morbidity and mortality in patients with KD. Treatment is aimed at reducing inflammation and consists of intravenous immunoglobulin (IVIG) along with aspirin. Despite treatment, some patients may still develop CAAs, and hence, long term follow up is of utmost importance. PMID- 27990381 TI - Psoriasis: Epidemiology, clinical features, co-morbidities, and clinical scoring. AB - On the basis of current evidence derived from hospital-based studies, mostly from North India, the prevalence of psoriasis in adults varies from 0.44 to 2.8%, with a much lower prevalence in children. The peak age at onset in adults is in the third and fourth decade of life, with a slight male preponderance. It is recommended that population-based large epidemiologic studies should be undertaken in different parts of the country for estimating the correct prevalence of psoriasis in general population. Chronic plaque-type psoriasis is the most common morphologic presentation of psoriasis, accounting for more than 90% of all cases. Other morphologic variants that deserve special mention include palmoplantar psoriasis, pustular psoriasis, and recalcitrant psoriasis. For epidemiologic purposes, psoriasis can be classified into early and late onset psoriasis. Psoriasis can be classified on the basis of morphology and extent of involvement into localized and widespread disease. For the purpose of clinical trials, psoriasis may be classified as mild psoriasis, moderate psoriasis, and severe psoriasis. The literature shows that there is a significant risk of psoriatic arthritis (7-48%) in patients with plaque-type psoriasis. Hence, it is recommended to evaluate for its presence by detailed history taking and clinical examination, and if necessary, by appropriate radiological investigations. Evidence on the association between plaque-type psoriasis and cardiovascular disease risk factors and ischemic heart disease isinconsistent. On the basis ofavailable evidence, it is prudent to proactively look for metabolic syndrome, dyslipidemia, and obesity, especially in patientswith severe psoriasis (Level 1+ evidence based on systematic reviews and meta-analysis). Based on the current evidence, the psoriasis area severity index appears to be the most valid and reproducible clinical severity score in the management of adult patients with plaque-type psoriasis. PMID- 27990383 TI - Biologics use in Indian psoriasis patients. AB - The biologics currently in use for psoriasis in India are etanercept, infliximab and recently introduced itolizumab and secukinumab. Biosimilars, expected to play a significant role in psoriasis management in future, have also been available for the last few years. Patients with psoriasis may be considered eligible to receive treatment with any of the licensed biologic interventions when they fulfill the eligibility criteria. The decision to proceed with treatment must be made in collaboration with the patient and include a careful assessment of the associated risks and benefits. Etanercept is indicated in moderate to severe psoriasis and moderate to severe psoriatic arthritis with a dose of 25 mg or 50 mg twice weekly. Methotrexate may be recommended as co-medication in certain clinical circumstances, e.g., where it is required for associated arthropathy, or to improve efficacy. Infliximab is indicated in severe psoriasis and moderate to severe psoriatic arthritis. Infliximab therapy should be initiated at a dose of 5 mg/kg at weeks 0, 2 and 6 and disease response assessed at 3 months. In patients who respond, subsequent infusions (5 mg/kg) should be given at 8-week intervals to maintain disease control although long-term data are available only up to 1 year. Interrupted therapy should be avoided given the associated increased risk of infusion reactions and poorer disease control. Itolizumab is indicated in moderate to severe plaque psoriasis. It is given in a dose of 1.6mg/kg iv infusions every 2 weeks for 12 weeks initially and then 1.6mg/kg every 4 weeks up to 24 weeks. Long term data are unavailable. Secukinumab is indicated in moderate to severe plaque psoriasis and psoriatic arthritis. An initial loading dosing regimen of 300 mg secukinumab should be given by subcutaneous injection at weeks 0, 1, 2 and 3 followed by maintenance dose of 300 mg every 4 weeks starting at week 4. To exclude tuberculosis (TB) before anti TNF alfa therapy and therapy with itolizumab, pretreatment chest X-ray and Mantoux skin test currently remain the preferred screening tests in patients not on immunosuppression. During treatment, and for 6 months following discontinuation, a high index of suspicion for TB should be maintained. The effect of secukinumab on TB reactivation is as yet poorly understood, hence, in the Indian scenario, it is better to follow the same guidelines for ruling out latent TB. PMID- 27990382 TI - General measures and quality of life issues in psoriasis. AB - Psoriasis generally does not affect survival but has significant detrimental effect on quality of life (QOL), which may be comparable to that of ischemic heart disease, diabetes, depression, and cancer. The foremost important thing in the management of psoriasis is counseling of the patient. The clinician needs to be empathetic and spend adequate time with the patient and educating the patient about psoriasis. Clinicians should make it clear to the patient that the primary goal of treatment is control of the disease rather than cure. Eating a balanced and low glycemic diet could be an important adjuvant factor in the prevention and treatment of moderate nonpustular psoriasis. Obese people are more likely to have severe psoriasis and psoriatic arthritis than people with an average body mass index. Dietary supplementation with oily fish, rich in n-3 fatty acids, in psoriasis had shown mixed results in trials. Promising results have been documented for parenteral application of n-3 fatty acid, but not with oral supplementation. Increased smoking or alcohol abuse increases the risk of developing psoriasis and may influence disease severity, and hence must be avoided. Soaking in warm water with bath oil can be done in extensive psoriasis for hydration and emollient effect, and bland soaps or soap substitutes should be used; antiseptics should be avoided as they may irritate the skin. Relatively small, localized patches of psoriasis may improve with occlusion, i.e., waterproof adhesive dressings. The use of emollients is an internationally accepted standard adjunctive to the treatment of psoriasis. Dermatology Life Quality Index is a psychometrically sound and responsive measure of psoriasis specific outcomes and most comprehensively captures the impact of clinical signs and symptoms on patient's well-being. PMID- 27990384 TI - A descriptive study of facial acanthosis nigricans and its association with body mass index, waist circumference and insulin resistance using HOMA2 IR. AB - INTRODUCTION: The term facial acanthosis nigricans (FAN) lacks definition of precise clinical and histopathological features. We present a descriptive study of patients with FAN to define pigmentary patterns and estimate the prevalence of obesity and insulin resistance in these cases. MATERIALS AND METHODS: It is a prospective study that included all patients with classical AN of the neck and/or other areas with facial acanthosis nigricans described as brown-to-black macular pigmentation with blurred ill-defined margins, found on the zygomatic and malar areas. The body mass index (BMI) and waist circumference (WC) of the included patients were used as parameters of obesity. Homeostatic Model of Assessment of Insulin Resistance (HOMA2 IR) was used as a parameter to evaluate insulin resistance. Histopathological features of the 6 skin biopsies that were possible were reviewed. RESULTS: Among the 102 included individuals, the patterns of facial pigmentation seen in addition to the classic pattern involving zygomatic and malar areas were a hyperpigmented band on the forehead in 59.80%, periorbital darkening in 17.64%, perioral darkening in 12.74%, and generalized darkening in 9.8% of cases. 85.29% of the males and 100% of the females were found to be obese. Varying degrees of insulin resistance was noted in 82.34% of the individuals. Six biopsies available for evaluation showed changes such as mild epidermal hyperplasia with prominent basal melanin, however, without the typical papillomatosis seen in AN of the flexures. CONCLUSION: We document an increased prevalence of obesity and insulin resistance in patients presenting with FAN and its presentations in addition to the classical description. We propose that FAN can be considered a cutaneous marker of insulin resistance and that HOMA2 IR can serve as a parameter of insulin resistance in such cases. PMID- 27990385 TI - Segmental neurofibromatosis with deep schwannoma. AB - An elderly patient presented with two clusters of asymptomatic fleshy and pedunculated papules. Biopsy of the papules was consistent with neurofibromas. Decades prior she had undergone a surgery for the excision of a large schwannoma. Given her lack of other neurofibromatosis findings, the patient was diagnosed with multisegmental neurofibromatosis (multi-SN) with deep schwannoma, a possible new phenotype of SN. Because this entity may be associated with internal malignancy, it is important to screen and educate these patients as well as to provide regular follow-up. PMID- 27990386 TI - Griscelli syndrome type-3. AB - Griscelli syndrome (GS) is a rare autosomal recessive multisystem disorder of pigmentary dilution of skin, silver gray hair, variable immunodeficiency, neurological impairment, and abnormal accumulation of melanosomes in melanocytes. GS type 3 is characterized by hypomelanosis with no immunological and neurological manifestation. Prognosis is very good in type 3 GS and usually require no active intervention, as opposed to type 1 and 2 where early diagnosis and treatment plays a crucial role in patient's survival. The characteristic phenotypic appearance, especially the pigment dilution of the patient's hair, is emphasized here. PMID- 27990387 TI - Late-onset acute graft-versus-host disease mimicking hand, foot, and mouth disease. AB - Acute skin graft-versus-host disease (GVHD) classically presents as a pruritic erythematous maculopapular rash. We describe a patient who underwent allogeneic hematopoietic stem cell transplantation and presented with a hand foot and mouth disease like clinical presentation. Histopathology was suggestive of acute GVHD. This case is being reported to make dermatologists aware of this unusual presentation of GVHD. PMID- 27990389 TI - Laryngeal involvement with fatal outcome in progressive nodular histiocytosis: A rare case report. AB - Progressive nodular histiocytosis (PNH) represents a very rare type of non Langerhans cell histiocytosis. It is characterized by progressive appearance of papules and nodules without spontaneous resolution. We report a 60-year-old patient with novel clinical features in the form of extensive noduloulcerative lesions, ichthyotic patches, and laryngeal involvement culminating in fatal outcome prior to therapeutic intervention. Although the presenting features were baffling, histopathology and immunohistochemistry clinched the diagnosis of PNH. PMID- 27990388 TI - Mucocutaneous manifestations of Cowden's syndrome. AB - Cowden's syndrome is an autosomal dominant genodermatosis with variable orofacial and systemic manifestations. Here we present one such classical case of Cowden's syndrome in a 45-year-old female patient with features such as multiple cutaneous papillomatosis, oral fibromas, and fibromas involving multiple organs such as gastrointestinal tract (multiple polyps), thyroid disorders, and breast cancer. PMID- 27990390 TI - Nekam's disease. AB - Keratosis lichenoides chronica also known as Nekam's disease is a rare mucocutaneous disorder, characterized clinically by asymptomatic violaceous keratotic papules arranged in linear, reticular, or plaque form usually on the trunk and extremities and histologically by interface dermatitis. The disease is considered rare with only 128 cases being reported in the literature till date and very few from India. We report a case of a 40-year-old man who presented with constellation of features of lichen planus, seborrheic dermatitis, and apthous ulcers, which upon workup was found to be Nekam's disease. PMID- 27990391 TI - Encephalocraniocutaneous lipomatosis (Haberland syndrome): A rare case report. AB - Haberland syndrome or Fishman syndrome also known as encephalocraniocutaneous lipomatosis (ECCL) is a rare, congenital neurocutaneous disorder. It is characterized by unilateral involvement of skin, eyes and central nervous system. We report the case of a 28-year-old woman who presented with soft lipomatous swelling over right temporal area with nonscarring alopecia of part of frontal and parietal region. The patient had a history of seizures and ipsilateral scleral dermoid. Computed tomography scan findings were suggestive of lipomas and calcification of falx. Magnetic resonance imaging showed right-sided hemi atrophy and two intracranial cysts. We report this case because of its rarity. PMID- 27990392 TI - Primary cutaneous anaplastic large cell lymphoma masquerading as large pyogenic granuloma. AB - Primary cutaneous anaplastic large cell lymphoma (pcALCL) forms 9% of the cutaneous T-cell lymphomas. It usually presents as solitary reddish brown ulcerating nodule or indurated plaque. Sometimes, it mimics other dermatological diseases such as eczema, pyoderma gangrenosum, pyogenic granuloma, morphea, and squamous cell carcinoma. Our case presented with large pyogenic granuloma like lesion with regional lymphadenopathy. Since pcALCL is rare, one can misdiagnose such cases and therefore high index of suspicion is necessary. PMID- 27990393 TI - Subcutaneous panniculitis-like T-cell lymphoma with macrophage activation syndrome treated by cyclosporine and prednisolone. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL; alpha/beta T-cell subtype) is a distinct variantof cutaneous T-cell lymphomas, which presents as inflammatory subcutaneous nodules. A 17-year-old male presented with recurrent fever with concomitant facial swelling, pedal edema, hepatosplenomegaly, and mildly tender subcutaneous plaques in generalized distribution along with patches of scarring alopecia on scalp. There were features of macrophage activation syndrome in the form of hemophagocytosis in the bone marrow, pancytopenia, high serum lactate dehydrogenase levels, low fibrinogen clotting activity, prolonged activated prothrombine time (aPTT), increased serum ferritin, hypoalbuminemia, and hypertriglyceridemia. Histopathology showed lobular panniculitis-like infiltration by atypical lymphocytes rimming the adipocytes. Immunohistochemistry revealed positive CD3 and CD8 markers, whereas CD4, CD56, and CD20 were negative, consistent with the diagnosis of alpha/beta type of SPTCL. Treatment with oral prednisolone (1mg/kg/day) and cyclosporine (2mg/kg/day; 100 mg) led to rapid subsidence of fever, plaques, and abnormal hematological parameters within a few weeks. PMID- 27990394 TI - Great saphenous vein dilatation with reflux at the saphenofemoral junction: A rare underlying association of eccrine angiomatous hamartoma. AB - Eccrine angiomatous hamartoma (EAH) is an exceedingly rare benign tumor-like lesion prevalent in childhood, which can produce pain and marked sweating. Histological features include proliferation of eccrine sweat glands and angiomatous capillary channels. It may be rarely associated with underlying pathological conditions. A 15-year-old female patient presented with multiple tender reddish papules and nodules coalescing to form plaques of 10 * 8 cm over the anterior aspect of the right lower thigh since birth. It was associated with hypertrichosis, hyperhidrosis, pain, and occasional bleeding on trauma. Histopathological examination of the lesion showed increased proliferation of both eccrine and angiomatous channels. Ultrasonography and Color Doppler of the right thigh showed dilatation of the great saphenous vein (GSV) above the right knee, with evidence of grade 3 reflux at saphenofemoral junction. Magnetic resonance imaging revealed large dilated GSV with slow flow and venous malformation in the anterior part of the right knee. PMID- 27990395 TI - Dermatopathology quiz: Keratotic papules of the palms. PMID- 27990396 TI - Clinical study of cutaneous leishmaniasis in the Kashmir Valley. PMID- 27990398 TI - Coexistence of psoriasis and primary high-grade subcutaneous leiomyosarcoma. PMID- 27990399 TI - Salute sign: A nonambiguous histopathological sign in pityriasis rosea. PMID- 27990397 TI - Unilateral zosteriform lichen planus involving multiple noncontiguous dermatomes with oral involvement. PMID- 27990400 TI - Implementation of enhanced gonococcal antimicrobial surveillance program in Thailand. PMID- 27990401 TI - An uncommon presentation of eccrine poroma. PMID- 27990402 TI - Broad based giant fibroepithelial polyp over an unusual location: A report. PMID- 27990403 TI - Nevirapine-induced toxic epidermal necrolysis and psychosis in a human immunodeficiency virus-positive patient. PMID- 27990405 TI - Camouflage in xeroderma pigmentosum. PMID- 27990404 TI - Kangri: A boon or bane for Kashmiris. PMID- 27990406 TI - SkIndia Quiz 30: A cystic nodule in the periorbital region. PMID- 27990407 TI - SkIndia Quiz 31: Erythematous plaque over the chin. PMID- 27990408 TI - Cheilitis granulomatosa. PMID- 27990409 TI - Dermoscopic pattern in a case of suction purpura over the face. PMID- 27990410 TI - The Phosphatidylinositol 3-kinase/Akt Signaling Pathway in Neuroendocrine Tumors. AB - The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is often aberrantly activated in neuroendocrine-derived cancers. Therefore, selectively targeting this pathway using small-molecule inhibitors may reduce neuroendocrine tumor burden, potentiate adjunct therapies, and achieve symptomatic control for patients with hormonally active and inoperable disease. Here, we discuss the role of the PI3K-Akt pathway in the malignant transformation of neuroendocrine tumors, specifically carcinoids and small cell lung cancers. The collective findings presented in this review propose that selective targeting of the PI3K-Akt pathway may mitigate neuroendocrine tumor progression, thus offering a viable therapeutic approach for managing systemic disease. PMID- 27990411 TI - Identification of Human Cathelicidin Peptide LL-37 as a Ligand for Macrophage Integrin alphaMbeta2 (Mac-1, CD11b/CD18) that Promotes Phagocytosis by Opsonizing Bacteria. AB - LL-37, a cationic antimicrobial peptide, has numerous immune-modulating effects. However, the identity of a receptor(s) mediating the responses in immune cells remains uncertain. We have recently demonstrated that LL-37 interacts with the alphaMI-domain of integrin alphaMbeta2 (Mac-1), a major receptor on the surface of myeloid cells, and induces a migratory response in Mac-1-expressing monocyte/macrophages as well as activation of Mac-1 on neutrophils. Here, we show that LL-37 and its C-terminal derivative supported strong adhesion of various Mac 1-expressing cells, including HEK293 cells stably transfected with Mac-1, human U937 monocytic cells and murine IC-21 macrophages. The cell adhesion to LL-37 was partially inhibited by specific Mac-1 antagonists, including mAb against the alphaM integrin subunit and neutrophil inhibitory factor, and completely blocked when anti-Mac-1 antibodies were combined with heparin, suggesting that cell surface heparan sulfate proteoglycans act cooperatively with integrin Mac-1. Coating both Gram-negative and Gram-positive bacteria with LL-37 significantly potentiated their phagocytosis by macrophages, and this process was blocked by a combination of anti-Mac-1 mAb and heparin. Furthermore, phagocytosis by wild-type murine peritoneal macrophages of LL-37-coated latex beads, a model of foreign surfaces, was several fold higher than that of untreated beads. By contrast, LL 37 failed to augment phagocytosis of beads by Mac-1-deficient macrophages. These results identify LL-37 as a novel ligand for integrin Mac-1 and demonstrate that the interaction between Mac-1 on macrophages and bacteria-bound LL-37 promotes phagocytosis. PMID- 27990413 TI - Corrigendum to "Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy". AB - [This corrects the article DOI: 10.1155/2016/7181685.]. PMID- 27990412 TI - Potential Role of Circulating Tumor Cell Detection and Monitoring in Breast Cancer: A Review of Current Evidence. AB - The phenomenon of hematogenous tumor cell dissemination in patients with solid tumors has been extensively explored over the last decades. Breast cancer research investigated at first disseminated tumor cells in the bone marrow; however, the focus soon moved to circulating tumor cells (CTCs) in the peripheral blood as blood is easily accessible without an invasive procedure. The prognostic significance of CTC presence has been shown in large studies both in adjuvant and metastatic setting and commercially available detection assays have been evaluated for monitoring in clinical trials. Beyond detection and enumeration of CTCs, the characterization of single tumor cells may enhance our knowledge on disease progression and thus optimize treatment choices. PMID- 27990414 TI - What Is New in Genetics of Congenital Heart Defects? AB - Epidemiological studies, clinical observations, and advances in molecular genetics are contributing to the understanding of the etiology of congenital heart defects (CHDs). Several phenotype-genotype correlation studies have suggested that specific morphogenetic mechanisms put in motion by genes can result in a specific cardiac phenotype. The use of new technologies has increased the possibility of identification of new genes and chromosomal loci in syndromic and non-syndromic CHDs. There are a number of methods available for genetic research studies of CHDs, including cytogenetic analysis, linkage and association studies, copy number variation (CNV) and DNA micro-array analysis, and whole exome sequencing. The altered dosage of contiguous genes included inside CNVs can produce new syndromic CHDs, so that several different new genomic conditions have been identified. These include duplication 22q11.2 syndrome, distal 22q11.2 deletion syndrome, deletion and duplication 1q21.1, and deletion 1p36 syndrome. Molecular techniques such as whole exome sequencing have lead to the identification of new genes for monogenic syndromes with CHD, as for example in Adams-Oliver, Noonan, and Kabuki syndrome. The variable expressivity and reduced penetrance of CHDs in genetic syndromes is likely influenced by genetic factors, and several studies have been performed showing the involvement of modifier genes. It is not easy to define precisely the genetic defects underlying non syndromic CHDs, due to the genetic and clinical heterogeneity of these malformations. Recent experimental studies have identified multiple CNVs contributing to non-syndromic CHD. The number of identified genes for non syndromic CHDs is at this time limited, and each of the identified genes has been shown to be implicated only in a small proportion of CHD. The application of new technologies to specific cases of CHD and pedigrees with familial recurrence and filtering genes mapping in CNV regions can probably in the future add knowledge about new genes for non-syndromic CHDs. PMID- 27990415 TI - The Problem with Big Data: Operating on Smaller Datasets to Bridge the Implementation Gap. AB - Big datasets have the potential to revolutionize public health. However, there is a mismatch between the political and scientific optimism surrounding big data and the public's perception of its benefit. We suggest a systematic and concerted emphasis on developing models derived from smaller datasets to illustrate to the public how big data can produce tangible benefits in the long term. In order to highlight the immediate value of a small data approach, we produced a proof-of concept model predicting hospital length of stay. The results demonstrate that existing small datasets can be used to create models that generate a reasonable prediction, facilitating health-care delivery. We propose that greater attention (and funding) needs to be directed toward the utilization of existing information resources in parallel with current efforts to create and exploit "big data." PMID- 27990416 TI - Coordinating Care for Falls via Emergency Responders: A Feasibility Study of a Brief At-Scene Intervention. AB - Falls account for a substantial portion of 9-1-1 calls, but few studies have examined the potential for an emergency medical system role in fall prevention. We tested the feasibility and effectiveness of an emergency medical technician (EMT)-delivered, at-scene intervention to link elders calling 9-1-1 for a fall with a multifactorial fall prevention program in their community. The intervention was conducted in a single fire department in King County, Washington and consisted of a brief public health message about the preventability of falls and written fall prevention program information left at scene. Data sources included 9-1-1 reports, telephone interviews with intervention department fallers and sociodemographically comparable fallers from three other fire departments in the same county, and in-person discussions with intervention department EMTs. Interviews elicited faller recall and perceptions of the intervention, EMT perceptions of intervention feasibility, and resultant referrals. Sixteen percent of all 9-1-1 calls during the intervention period were for falls. The intervention was delivered to 49% of fallers, the majority of whom (75%) were left at scene. Their mean age (N = 92) was 80 +/- 8 years; 78% were women, 39% had annual incomes under $20K, and 34% lived alone. Thirty-five percent reported that an EMT had discussed falls and fall prevention (vs. 8% of comparison group, P < 0.01); 84% reported that the information was useful. Six percent reported having made an appointment with a fall prevention program (vs. 3% of comparison group). EMTs reported that the intervention was worthwhile and did not add substantially to their workload. A brief, at-scene intervention is feasible and acceptable to fallers and EMTs. Although it activates only a small percent to seek out fall prevention programs, the public health impact of this low-cost strategy may be substantial. PMID- 27990417 TI - Multiple Eruptive Sebaceous Hyperplasia Secondary to Cyclosporin in a Patient with Bone Marrow Transplantation. AB - Many cutaneous complications have been described in patients treated with cyclosporin. Alterations of the pilosebaceous unit such as hypertrichosis are particularly frequent. However, the occurrence of sebaceous hyperplasia is exceptional. These lesions seem to be specific to cyclosporin rather than secondary to immunosuppression. Here, we report an exceptional case of eruptive and disseminated sebaceous hyperplasia arising in a bone marrow transplant recipient only a few months after starting immunosuppressive treatment with cyclosporin. PMID- 27990418 TI - Finite Element Study of a Lumbar Intervertebral Disc Nucleus Replacement Device. AB - Nucleus replacement technologies are a minimally invasive alternative to spinal fusion and total disc replacement that have the potential to reduce pain and restore motion for patients with degenerative disc disease. Finite element modeling can be used to determine the biomechanics associated with nucleus replacement technologies. The current study focuses on a new nucleus replacement device designed as a conforming silicone implant with an internal void. A validated finite element model of the human lumbar L3-L4 motion segment was developed and used to investigate the influence of the nucleus replacement device on spine biomechanics. In addition, the effect of device design changes on biomechanics was determined. A 3D, L3-L4 finite element model was constructed from medical imaging data. Models were created with the normal intact nucleus, the nucleus replacement device, and a solid silicone implant. Probabilistic analysis was performed on the normal model to provide quantitative validation metrics. Sensitivity analysis was performed on the silicone Shore A durometer of the device. Models were loaded under axial compression followed by flexion/extension, lateral bending, or axial rotation. Compressive displacement, endplate stresses, reaction moment, and annulus stresses were determined and compared between the different models. The novel nucleus replacement device resulted in similar compressive displacement, endplate stress, and annulus stress and slightly higher reaction moment compared with the normal nucleus. The solid implant resulted in decreased displacement, increased endplate stress, decreased annulus stress, and decreased reaction moment compared with the novel device. With increasing silicone durometer, compressive displacement decreased, endplate stress increased, reaction moment increased, and annulus stress decreased. Finite element analysis was used to show that the novel nucleus replacement device results in similar biomechanics compared with the normal intact nucleus. PMID- 27990421 TI - Effect on Soil Properties of BcWRKY1 Transgenic Maize with Enhanced Salinity Tolerance. AB - Maize (Zea mays L.) is the most important cereal crop in the world. However, soil salinity has become a major problem affecting plant productivity due to arable field degradation. Thus, transgenic maize transformed with a salinity tolerance gene has been developed to further evaluate its salt tolerance and effects on agronomic traits. It is necessary to analyze the potential environmental risk of transgenic maize before further commercialization. Enzyme activities, physicochemical properties, and microbial populations were evaluated in saline and nonsaline rhizosphere soils from a transgenic maize line (WL-73) overexpressing BcWRKY1 and from wild-type (WT) maize LH1037. Measurements were taken at four growth stages (V3, V9, R1, and R6) and repeated in three consecutive years (2012-2014). There was no change in the rhizosphere soils of either WL-73 or WT plants in the four soil enzyme activities, seven soil physicochemical properties, and the populations of three soil organisms. The results of this study suggested that salinity tolerant transgenic maize had no adverse impact on soil properties in soil rhizosphere during three consecutive years at two different locations and provided a theoretical basis for environmental impact monitoring of salinity tolerant transgenic maize. PMID- 27990419 TI - Mutations in the Human AAA+ Chaperone p97 and Related Diseases. AB - A number of neurodegenerative diseases have been linked to mutations in the human protein p97, an abundant cytosolic AAA+ (ATPase associated with various cellular activities) ATPase, that functions in a large number of cellular pathways. With the assistance of a variety of cofactors and adaptor proteins, p97 couples the energy of ATP hydrolysis to conformational changes that are necessary for its function. Disease-linked mutations, which are found at the interface between two main domains of p97, have been shown to alter the function of the protein, although the pathogenic mutations do not appear to alter the structure of individual subunit of p97 or the formation of the hexameric biological unit. While exactly how pathogenic mutations alter the cellular function of p97 remains unknown, functional, biochemical and structural differences between wild-type and pathogenic mutants of p97 are being identified. Here, we summarize recent progress in the study of p97 pathogenic mutants. PMID- 27990420 TI - Prevalence and Factors Associated with Undernutrition among Adults with Major Depressive Disorder in Northwest Ethiopia. AB - Background. Undernutrition and major depressive disorder are frequently co occurring. Patients with impaired mental health are strongly vulnerable to the risks of having involuntary weight loss or deficiency of essential nutrients. However, there is no study which assesses undernutrition among major depressive patients in Ethiopia. Method. A total of 422 clients were included in the study. Structured questionnaires and anthropometric measurements were used for collecting the data. Bivariate and multivariate logistic regression model was fitted to identify factors associated with undernutrition. Odds ratio with 95% confidence interval was computed to determine the level of significance. Results. The prevalence of undernutrition was 31.4% [95% CI: 27.2-36.0]. Being in a rural residence [AOR = 1.84, 95% CI (1.18-2.85)], taking multiple medication [AOR = 1.77, 95% CI (1.03-3.05)], taking prescribed diet [AOR = 1.90, 95% CI (1.06 3.41)], and current use of alcohol [AOR = 2.96, 95% CI (1.34-6.55)] were factors significantly associated with undernutrition among depressive patients. Conclusion. The prevalence of undernutrition among adults with major depressive disorder was found to be higher than the general population. Appropriate nutritional education and nutritional assessment are recommended during the course of major depressive disorder. PMID- 27990422 TI - Premature Destruction of Microbubbles during Voiding Urosonography in Children and Possible Underlying Mechanisms: Post Hoc Analysis from the Prospective Study. AB - The aim of this study is to describe premature microbubbles destruction with contrast-enhanced voiding urosonography (ce-VUS) in children using 2nd-generation ultrasound contrast agents (UCA) and to hypothesize about the reason. 141 children (61 females and 80 males) were included in the study, with mean age of 3.3 years (range 4 weeks-16.0 years), who underwent ce-VUS examination between 2011 and 2014. Premature destruction of the microbubbles in the urinary bladder during ce-VUS was observed in 11 children (7.8%). In all these cases the voiding phase of ce-VUS examination could not be performed because of destroyed UCA microbubbles. This was noted in anxious, crying infants and children with restricted voiding. The premature destruction of ultrasound contrast agent during ce-VUS is an underreported, important limitation of ce-VUS, which prevents evaluation of the voiding phase and the establishment of vesicoureteric reflux (VUR). This was particularly noted in crying infants and children. PMID- 27990423 TI - Size Does Not Make the Difference: 3D/4D Transperineal Sonographic Measurements of the Female Urethra in the Assessment of Urinary Incontinence Subtypes. AB - Purpose. The objective was to evaluate the usefulness of transperineal ultrasound in the assessment of the urethral length and urethral lumen by 3D/4D transperineal sonography to discriminate between female patients with subtypes of urinary incontinence. Methods. A total of 150 female patients underwent an examination because of urinary incontinence. 41 patients were diagnosed with urgency urinary incontinence (OAB), 67 patients were diagnosed with stress urinary incontinence (SUI), and 42 patients were in the control group (CTRL). Three diameters of the urethral lumen (proximal (U1), medial (U2), and distal (U3)) and the urethral length were measured. By the assessment of the urethral lumen, the presence of the urethral funneling was evaluated. Results. We found a significant difference in the urethral length and urethral lumen U2 of OAB and SUI versus CTRL. The urethral length was significantly greater (P < 0.05) and the urethral lumen was significantly wider (P < 0.05) in the patients with urinary incontinence. The incidence of the urethral funneling was significantly higher (P < 0.05) in the study groups with urinary incontinence than in the control group. Conclusions. Our results have shown the urethral changes obtained by ultrasound in patients with urinary incontinence, but they are still insufficient to distinguish between subtypes of urinary incontinence. PMID- 27990424 TI - Diagnostic Accuracy of Robot-Guided, Software Based Transperineal MRI/TRUS Fusion Biopsy of the Prostate in a High Risk Population of Previously Biopsy Negative Men. AB - Objective. In this study, we compared prostate cancer detection rates between MRI TRUS fusion targeted and systematic biopsies using a robot-guided, software based transperineal approach. Methods and Patients. 52 patients received a MRIT/TRUS fusion followed by a systematic volume adapted biopsy using the same robot-guided transperineal approach. The primary outcome was the detection rate of clinically significant disease (Gleason grade >= 4). Secondary outcomes were detection rate of all cancers, sampling efficiency and utility, and serious adverse event rate. Patients received no antibiotic prophylaxis. Results. From 52 patients, 519 targeted biopsies from 135 lesions and 1561 random biopsies were generated (total n = 2080). Overall detection rate of clinically significant PCa was 44.2% (23/52) and 50.0% (26/52) for target and random biopsy, respectively. Sampling efficiency as the median number of cores needed to detect clinically significant prostate cancer was 9 for target (IQR: 6-14.0) and 32 (IQR: 24-32) for random biopsy. The utility as the number of additionally detected clinically significant PCa cases by either strategy was 0% (0/52) for target and 3.9% (2/52) for random biopsy. Conclusions. MRI/TRUS fusion based target biopsy did not show an advantage in the overall detection rate of clinically significant prostate cancer. PMID- 27990425 TI - Comparative Evaluation of Anthelmintic Activity of Edible and Ornamental Pomegranate Ethanolic Extracts against Schistosoma mansoni. AB - Due to the development of praziquantel (PZQ) schistosomes resistant strains, the discovery of new antischistosomal agents is of high priority in research. This work reported the in vitro and in vivo effects of the edible and ornamental pomegranate extracts against Schistosoma mansoni. Leaves and stem bark ethanolic extracts of both dried pomegranates were prepared at 100, 300, and 500 MUg/mL for in vitro and 600 and 800 mg/kg for in vivo. Adult worms Schistosoma mansoni in RPMI-1640 medium for in vitro and S. mansoni infected mice for in vivo tests were obtained from Theodor Bilharz Research Institute, Cairo, Egypt. In vitro activity was manifested by significant coupled worms separation, reduction of motor activity, lethality, and ultrastructural tegumental alterations in adult worms. In vivo activity was manifested revealed by significant reduction of hepatic granulomas number and diameter, decreased number of bilharzial eggs in liver tissues, lowered liver inflammatory infiltration, decreased hepatic fibrosis, and inducible nitric oxide synthase (iNOS) expression. Ethanolic stem bark extract of edible pomegranate exhibited highest antischistosomal activities both in vitro and in vivo. Therefore, pomegranate showed a good potential to be used as a promising new candidate for the development of new schistosomicidal agents. PMID- 27990426 TI - Instructors' Perceptions of Mostly Seated Exercise Classes: Exploring the Concept of Chair Based Exercise. AB - Chair based exercise (CBE) can be used to engage older adults unable to take part in standing exercise programmes. Defining and understanding the context of CBE have been acknowledged as a challenge. We explore instructor experiences of delivering mostly seated exercise classes for older people and how this helps us to further understand the concept of CBE. We extracted qualitative data from a cross-sectional survey with 731 exercise instructors. 378 delivered mostly seated classes and 223 of those instructors provided qualitative data. There were 155 instructors who did not provide any qualitative comments. Framework analysis was used and informed by a Delphi consensus study on CBE. Instructors perceived mostly seated classes as predominantly CBE; they defined it as an introductory class that should be offered as part of a continuum of exercise. It was considered suitable for those with limitations and older adults in long-term care and with dementia. Instructors reported CBE used inappropriately for more active older people. Instructors reported observing improvements in mood and cognition and broader social benefits. Instructors' perspectives largely support expert consensus that CBE has an important role in a continuum of exercise. Providers of CBE need to ensure that more challenging exercises are introduced where appropriate. Further research is needed to explore older adults' perceptions of CBE. PMID- 27990427 TI - Positive Expression of Human Cytomegalovirus Phosphoprotein 65 in Atherosclerosis. AB - Previous studies showed that human cytomegalovirus (HCMV) is associated with atherosclerosis. However, local vascular atherosclerosis related HCMV infection and protein expression remain unclear. This study aimed to assess the relationship between HCMV infection and atherosclerosis. Formalin-fixed, paraffin embedded peripheral artery specimens were obtained from 15 patients with atherosclerosis undergoing vascular surgery from 2008 to 2010 at Zhongnan Hospital, Wuhan University. Pathological analyses were carried out after hematoxylin and eosin (H&E) and Masson trichrome staining. In situ hybridization and immunohistochemistry with two different monoclonal antibodies were employed to detect HCMV nucleic acids and proteins, respectively. H&E and Masson trichrome staining showed homogeneous extracellular matrix in femoral artery, while smooth muscle fibers were interlaced with collagen fibers; in carotid artery, inflammatory cell infiltration, foam cell vascular change, cholesterol crystals, and layered collagen fibers were observed. In situ hybridization showed no expression of HCMV nucleic acids in all 15 cases. Immunohistochemical staining for protein immediate-early protein (IE1 72) was negative in all cases, while phosphoprotein 65 (pp65) expression was detected in 14 cases. A high rate of positive pp65 signals was found in patients with atherosclerosis, suggesting that local HCMV infection may be associated with the pathogenesis of atherosclerosis. Further studies on this relationship are warranted. PMID- 27990428 TI - Laryngeal High-Speed Videoendoscopy: Sensitivity of Objective Parameters towards Recording Frame Rate. AB - The current use of laryngeal high-speed videoendoscopy in clinic settings involves subjective visual assessment of vocal fold vibratory characteristics. However, objective quantification of vocal fold vibrations for evidence-based diagnosis and therapy is desired, and objective parameters assessing laryngeal dynamics have therefore been suggested. This study investigated the sensitivity of the objective parameters and their dependence on recording frame rate. A total of 300 endoscopic high-speed videos with recording frame rates between 1000 and 15 000 fps were analyzed for a vocally healthy female subject during sustained phonation. Twenty parameters, representing laryngeal dynamics, were computed. Four different parameter characteristics were found: parameters showing no change with increasing frame rate; parameters changing up to a certain frame rate, but then remaining constant; parameters remaining constant within a particular range of recording frame rates; and parameters changing with nearly every frame rate. The results suggest that (1) parameter values are influenced by recording frame rates and different parameters have varying sensitivities to recording frame rate; (2) normative values should be determined based on recording frame rates; and (3) the typically used recording frame rate of 4000 fps seems to be too low to distinguish accurately certain characteristics of the human phonation process in detail. PMID- 27990429 TI - Atypical Complete Femoral Fractures Associated with Bisphosphonate Use or Not Associated with Bisphosphonate Use: Is There a Difference? AB - The purpose of this study is to compare clinical characteristics and surgical outcome of atypical complete femoral fractures associated with bisphosphonates (BPs) use and those of fractures not associated with BPs use. Seventy-six consecutive patients (81 fractures) who had been operatively treated for a complete atypical femoral fracture were recruited. Of the 81 fractures, 73 occurred after BPs medication of at least 3 years (BP group) while 8 occurred without a history of BP medication (non-BP group). There were no differences in demographic data and fracture- and surgery-associated factors between the two groups. Of 76 patients (81 fractures), 54 (66.7%) fractures showed bony union within 6 months after the index surgery and 23 (28.4%) showed delayed union at a mean of 11.2 months (range, 8-18 months). The remaining 4 fractures were not healed, even 18 months after the index surgery. There was no difference in healing rate between the BP group and the non-BP group. There were strong correlations between the fracture height and the degree of bowing regardless of BPs medication. All fractures except 1 occurred at the diaphyseal region of the femur when not associated with BP medication. PMID- 27990430 TI - Metformin Prevents Nonunion after Three-Cannulated-Screw Fixation in Displaced Femoral Neck Fractures: A Retrospective Study. AB - Patients aged from 40 to 60 with displaced fractures of the femoral neck (Garden III or IV) who received fixation with three cannulated screws from January 2005 to December 2012 were evaluated retrospectively for the development of nonunion. Plasma HbA1C, a marker for long-term plasma glucose level, anti-T2DM medication, and other potential risk factors were recorded for the purpose of this study. There were no differences between the union and nonunion groups with respect to age, gender, Garden classification, Pauwel's angle, reduction quality, and T2DM presence. There were significant differences in reduction quality and preoperative plasma HbA1C level between patients with and those without union. The odds ratio (OR) for fracture nonunion was 2.659 (95% confidence interval [CI], 1.530-4.620) in subjects with anatomical reduction compared with those without anatomical reduction, 4.797 (95% CI, 1.371-16.778), in subjects with poor blood glucose control (HbA1C > 10%). The metformin usage showed a preventive effect on nonunion development (OR: 0.193 and CI: 0.060-0.616). The nonunion rate of metformin group (6.7%, 6/89) was even much lower than that of patients without T2DM (17.4%, 80/460). PMID- 27990431 TI - Spatiotemporal Changes of Calcitonin Gene-Related Peptide Innervation in Spinal Fusion. AB - Few studies have investigated the role calcitonin gene-related peptide (CGRP) plays in the process of spinal fusion. The aim of the present study is to observe the temporal and spatial changes of CGRP induced by experimental fusion surgery in rats and elucidate the role of CGRP in spinal fusion. Male Sprague-Dawley rats were used in the study and the specimens were collected on the 7th, 14th, 21st, and 28th day, respectively. Then, histological and immunohistochemical analysis were applied to evaluate the fusion mass and spatiotemporal changes of CGRP chronologically. The results demonstrated that density of CGRP reached peak on the 21st day after surgery and most of the CGRP expression located surrounding the interface of allograft and fibrous tissue where the cells differentiate into osteoblasts, indicating that CGRP might be involved in the process of bone formation and absorption. PMID- 27990432 TI - Kinetics of Cardiac Output at the Onset of Exercise in Precapillary Pulmonary Hypertension. AB - Purpose. Cardiac output (CO) is a cornerstone parameter in precapillary pulmonary hypertension (PH). The Modelflow (MF) method offers a reliable noninvasive determination of its beat-by-beat changes. So MF allows exploration of CO adjustment with the best temporal resolution. Methods. Fifteen subjects (5 PH patients, 10 healthy controls) performed a submaximal supine exercise on a cycle ergometer after 5 min of rest. CO was continuously determined by MF (COMF). Kinetics of heart rate (HR), stroke volume (SV), and CO were determined with 3 monoexponential models. Results. In PH patients, we observed a sudden and transitory drop of SV upon exercise onset. This implied a transitory drop of CO whose adjustment to a new steady state depended on HR increase. The kinetics of HR and CO for PH patients was slower than that of controls for all models and for SV in model 1. SV kinetics was faster for PH patients in models 2 and 3. Conclusion. This is the first description of beat-by-beat cardiovascular adjustments upon exercise onset in PH. The kinetics of HR and CO appeared slower than those of healthy controls and there was a transitory drop of CO upon exercise onset in PH due to a sudden drop of SV. PMID- 27990433 TI - Evaluating the Primary Prevention of Ischemic Stroke of Oral Antithrombotic Therapy in Head and Neck Cancer Patients with Radiation Therapy. AB - Although previous studies demonstrated the risk of ischemic stroke (IS) in patients with head and neck cancer (HNC), the impact of oral antithrombotic therapy (OAT) on this risk has not yet been assessed. We aimed to evaluate the effectiveness and safety of OAT in patients with HNC treated with RT. This retrospective cohort study was performed using the National Health Insurance Research Database of Taiwan. A total of 37,638 patients diagnosed with HNC included in the study were classified as users and nonusers of OAT. Primary outcome was IS or transient ischemic attack (TIA), and secondary outcomes were death and major bleeding. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). There was no significant difference in the risk of IS or TIA between patients on continuous OAT and nonusers (adjusted HR, 0.812; 95% CI, 0.199-3.309). The risk of major bleeding was not significantly different between the groups. From a national population database, we did not find an association between OAT and decreasing risk of ischemic stroke/TIA or increasing hazard of major bleeding. PMID- 27990434 TI - Cornel Iridoid Glycoside Improves Locomotor Impairment and Decreases Spinal Cord Damage in Rats. AB - Purpose. This study was to investigate the effects of cornel iridoid glycoside (CIG) on spinal cord injury (SCI) in rats. Methods. The thoracic cord (at T9) of rats was injured by clip compression for 30 sec. Locomotor function was assessed using the Basso, Beattie, and Bresnahan (BBB) rating scale. Neuroanatomic stereological parameters as well as Nogo-A, p75 neurotrophin receptor (p75NTR), and ROCKII expression were measured by histological processing, immunohistochemistry, and stereological analyses. The axons passing through the lesion site were detected by BDA tracing. Results. Intragastric administration of CIG (60 and 180 mg/kg) improved the locomotor impairment at 10, 17, 24, and 31 days post-injury (dpi) compared with untreated SCI model rats. CIG treatment decreased the volume of the lesion epicenter (LEp) and increased the volume of spared tissue and the number of surviving neurons in the injured spinal cord at 31 dpi. CIG promoted the growth of BDA-positive axons and their passage through the lesion site and decreased the expression of Nogo-A, p75NTR, and ROCKII both in and around the LEp. Conclusion. CIG improved the locomotor impairment, decreased tissue damage, and downregulated the myelin-associated inhibition signaling pathway in SCI rats. The results suggest that CIG may be beneficial for SCI therapy. PMID- 27990435 TI - Low-Volume Brachial Plexus Block Providing Surgical Anesthesia for Distal Arm Surgery Comparing Supraclavicular, Infraclavicular, and Axillary Approach: A Randomized Observer Blind Trial. AB - Background. Distal arm surgery is widely performed under regional anesthesia with brachial plexus block. The preponderance of evidence for the efficacy relies upon injection of local anesthetic in excess of 30 mL. We aimed to compare three different ultrasound-guided brachial plexus block techniques restricting the total volume to 20 mL. Methods. 120 patients were prospectively randomized to ultrasound-guided brachial plexus block with 20 mL ropivacaine 0.75% at either the supraclavicular, infraclavicular, or axillary level. Multiinjection technique was performed with all three approaches. Primary outcome measure was performance time. Results. Performance time and procedural pain were similar between groups. Needle passes and injection numbers were significantly reduced in the infraclavicular group (P < 0.01). Nerve visibility was significantly reduced in the axillary group (P = 0.01). Success-rate was significantly increased in the supraclavicular versus the axillary group (P < 0.025). Total anesthesia-related time was significantly reduced in the supraclavicular compared to the infraclavicular group (P < 0.01). Block duration was significantly increased in the infraclavicular group (P < 0.05). No early adverse effects occurred. Conclusion. Supraclavicular and infraclavicular blocks exhibited favorable characteristics compared to the axillary block. Supraclavicular brachial plexus block with the multiinjection intracluster technique exhibited significantly reduced total anesthesia-related time and higher success rate without any early adverse events. PMID- 27990436 TI - Human Bocavirus in Korean Children with Gastroenteritis and Respiratory Tract Infections. AB - Human bocaviruses (HBoVs) are suggested to be etiologic agents of childhood respiratory and gastrointestinal infections. There are four main recognized genotypes of HBoVs (HBoV1-4); the HBoV-1 genotype is considered to be the primary etiologic agent in respiratory infections, whereas the HBoV2-4 genotypes have been mainly associated with gastrointestinal infections. The aim of the present study was to determine the distribution of HBoV genotypes in children with respiratory or gastrointestinal infections in a hospital in Korea. A total of 662 nasopharyngeal swabs (NPSs) and 155 fecal specimens were collected from children aged 5 years or less. Polymerase chain reaction (PCR) was conducted to detect the NS1 HBoV gene. The VP1 gene of HBoV was further amplified in samples that were positive for the NS1 gene. The PCR products of VP1 gene amplification were genotyped by sequence analysis. HBoV was detected in 69 (14.5%) of 662 NPSs and in 10 (6.5%) of 155 fecal specimens. Thirty-three isolates from NPSs and five isolates from fecal specimens were genotyped, and all 38 sequenced isolates were identified as the HBoV-1 genotype. HBoV-1 is the most prevalent genotype in children with respiratory or gastrointestinal HBoV infections in a hospital in Korea. PMID- 27990438 TI - The Experience of Older People in the Shared Decision-Making Process in Advanced Kidney Care. AB - Introduction. This qualitative descriptive study was designed to understand the experiences of older people (>70 years) when making a decision about renal replacement therapy. This was a coproduced study, whereby patients and carers were involved in all aspects of the research process. Methods. A Patient and Carer Group undertook volunteer and research training. The group developed the interview questions and interviewed 29 people who had commenced dialysis or made a decision not to have dialysis. Interview data were transcribed and analysed, and common themes were identified. Results. 22 men and 7 women (mean age 77.4 yrs) from two hospitals were interviewed. 18 had chosen haemodialysis, 6 peritoneal dialysis, and 5 supportive care. The majority of patients were involved in the dialysis decision. Most were satisfied with the amount of information that they received, although some identified that the quality of the information could be improved, especially how daily living can be affected by dialysis. Conclusion. Our findings show that overall older patients were involved in the dialysis decision along with their families. Our approach is innovative because it is the first time that patients and carers have been involved in a coproduced study about shared decision-making. PMID- 27990437 TI - Enhanced Performance and Mode of Action of a Novel Antibiofilm Hydrofiber(r) Wound Dressing. AB - Biofilm development in wounds is now acknowledged to be a precursor to infection and a cause of delayed healing. A next-generation antibiofilm carboxymethylcellulose silver-containing wound dressing (NGAD) has been developed to disrupt and kill biofilm microorganisms. This in vitro study aimed to compare its effectiveness against various existing wound dressings and examine its mode of action. A number of biofilm models of increasing complexity were used to culture biofilms of wound-relevant pathogens, before exposure to test dressings. Confocal microscopy, staining, and imaging of biofilm constituents, total viable counting, and elemental analysis were conducted to assess dressing antibiofilm performance. Live/dead staining and viable counting of biofilms demonstrated that the NGAD was more effective at killing biofilm bacteria than two other standard silver dressings. Staining of biofilm polysaccharides showed that the NGAD was also more effective at reducing this protective biofilm component than standard silver dressings, and image analyses confirmed the superior biofilm killing and removal performance of the NGAD. The biofilm-disruptive and silver-enhancing modes of action of the NGAD were supported by significant differences (p < 0.05) in biofilm elemental markers and silver donation. This in vitro study improves our understanding of how antibiofilm dressing technology can be effective against the challenge of biofilm. PMID- 27990440 TI - Corrigendum to "Effect of Short-Term Stimulation with Interleukin-1beta and Differentiation Medium on Human Mesenchymal Stromal Cell Paracrine Activity in Coculture with Osteoblasts". AB - [This corrects the article DOI: 10.1155/2015/714230.]. PMID- 27990439 TI - Effect of Exogenous Fetuin-A on TGF-beta/Smad Signaling in Hepatic Stellate Cells. AB - Objective. To explore the effects of low concentration of exogenous fetuin-A intervention on TGF-beta1 induced LX2 cells through detection of the expression of mRNA and protein of Smad2, Smad3, and Smad7. Methods. MTT assay was used to detect the LX2 cells proliferation and the regression equation calculating software was applied to determine IC50 of fetuin-A. RT-PCR was used to determine the relative content of Smad2, Smad3, and Smad7 mRNA in LX2 cells. Western blot was used to detect the LX2 cells relative content of Smad2, Smad3, Smad7 protein expression, respectively. Results. The analysis from RT-PCR and western blot showed that when compared with the other groups TGF-beta1 + fetuin-A group increased the expression of Smad2 and Smad3 while decreased the expression of Smad7 (P < 0.05). Conclusion. Fetuin-A may improve the excessive activation of hepatic stellate cells which is caused by an enhanced positive regulation of Smad2 and Smad3 protein and the deficiency in negative regulation of Smad7 protein. This is through inhibiting the expression of Smad2 and Smad3 gene and promoting the expression of Smad7 gene. As a result, the development of liver fibrosis will be reduced. PMID- 27990441 TI - Diabetic Retinopathy in Italy: Epidemiology Data and Telemedicine Screening Programs. AB - In Italy, the number of people living with diabetes is about 3.5 million (5.5% of the population), with an increase by about 60% in the last 20 years and with 1 person out of 3 older than 65 years. The Italian Health Service system estimates that 10 billion euros is spent annually on caring for patients with diabetes, a figure that increases yearly. No national data on prevalence and incidence of legal blindness in patients with diabetes and no national registry of patients with diabetic retinopathy (DR) are currently available. However, the available epidemiological data (in several locations throughout the country) are consistent with those reported in other European countries. The use of telemedicine for the screening of DR in Italy is confined to geographically limited locations. The available data in the literature on implementation and use of telematic screening proved to be successful from patient, caregiver, and authorities point of view. This review addresses the available epidemiological data on DR and telematic screening realities in Italy and thus may help in establishing a national screening program. PMID- 27990442 TI - Comment on "Incidence of Type 1 Diabetes among Children and Adolescents in Italy between 2009 and 2013: The Role of a Regional Childhood Diabetes Registry". PMID- 27990443 TI - Glucose Tolerance, MTHFR C677T and NOS3 G894T Polymorphisms, and Global DNA Methylation in Mixed Ancestry African Individuals. AB - The aim of this study is to quantify global DNA methylation and investigate the relationship with diabetes status and polymorphisms in MTHFR C677T and NOS3 G894T genes in mixed ancestry subjects from South Africa. Global DNA methylation was measured, and MTHFR rs1801133 and NOS3 rs1799983 polymorphisms were genotyped using high throughput real-time polymerase chain reaction and direct DNA sequencing. Of the 564 participants, 158 (28%) individuals had T2DM of which 97 (17.2%) were screen-detected cases. Another 119 (21.1%) had prediabetes, that is, impaired fasting glucose, impaired glucose tolerance, or the combination of both, and the remainder 287 (50.9%) had normal glucose tolerance. Global DNA methylation was significantly higher in prediabetes and screen-detected diabetes than in normal glucose tolerance (both p <= 0.033) and in screen-detected diabetes compared to known diabetes on treatment (p = 0.019). There was no difference in global DNA methylation between known diabetes on treatment and normal glucose tolerance (p > 0.999). In multivariable linear regression analysis, only NOS3 was associated with increasing global DNA methylation (beta = 0.943; 95% CI: 0.286 to 1.560). The association of global DNA methylation with screen-detected diabetes but not treated diabetes suggests that glucose control agents to some extent may be reversing DNA methylation. The association between NOS3 rs1799983 polymorphisms and DNA methylation suggests gene-epigenetic mechanisms through which vascular diabetes complications develop despite adequate metabolic control. PMID- 27990444 TI - Association of Serum CXCL13 with Intrarenal Ectopic Lymphoid Tissue Formation in Lupus Nephritis. AB - Aims. To assess the concentrations of serum CXCL13 and intrarenal ectopic lymphoid tissue (ELT) profiles and their correlation in the patients with lupus nephritis (LN). Methods. Serum CXCL13 levels were measured using enzyme-linked immunosorbent assays (ELISA). The expression of CD3, CD20, and CD21 in renal biopsy specimens was tested using immunohistochemical methods. Results. Serum CXCL13 levels were significantly higher in the LN group than those in the SLE group without LN and also in the type III and IV LN patients than in type V LN patients. LN patients with positive CD20 expression (CD20+ LN) had a longer disease course and poorer response to combination therapy and higher serum CXCL13 levels than CD20- LN patients. Moreover, the serum CXCL13 level was positively correlated with the number of B cells/HP in the renal tissue of LN patients. The coexpression patterns of CD3, CD20, and CD21 in the renal tissue of LN patients with different WHO pathological types were significantly different. Serum CXCL13 levels were significantly higher in ELT-2 type LN patients than in 0 or 1 type LN patients. Conclusions. This study suggested that increased serum levels of CXCL13 might be involved in renal ELT formation and renal impairment process in LN. PMID- 27990445 TI - Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports. AB - BACKGROUND: Voriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis. AIM: Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. CASE PRESENTATION: Voriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes. CONCLUSIONS: Voriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase, voriconazole trough and fluoride levels as well as a bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes. PMID- 27990447 TI - Clinical development of gene- and cell-based therapies: overview of the European landscape. AB - In the last decade, many clinical trials with gene- and cell-based therapies were performed and increasing interest in the development was established by (national) authorities, academic developers, and commercial companies. However, until now only eight products have received marketing authorization (MA) approval. In this study, a comprehensive overview of the clinical development of gene- and cell-based therapies in Europe is presented, with a strong focus on product-technical aspects. Public data regarding clinical trials with gene- and cell-based therapies, obtained from the European Union (EU) clinical trial database (EudraCT) between 2004 and 2014 were analyzed, including product technical variables as potential determinants affecting development. 198 unique gene and cell therapy products were identified, which were studied in 278 clinical trials, mostly in phase 1/2 trials and with cell therapies as major group. Furthermore, most products were manufactured from autologous starting material mostly manufactured from stem cells. The majority of the trials were sponsored by academia, whereas phase 3 trials mostly by large companies. Academia dominated early-stage development by mainly using bone marrow derived products and stem cells. Conversely, commercial sponsors were more actively pursuing in vivo gene therapy medicinal product development, and cell therapies derived from differentiated tissue in later-stage development. PMID- 27990446 TI - The superior regenerative potential of muscle-derived stem cells for articular cartilage repair is attributed to high cell survival and chondrogenic potential. AB - Three populations of muscle-derived cells (PP1, PP3, and PP6) were isolated from mouse skeletal muscle using modified preplate technique and retrovirally transduced with BMP4/GFP. In vitro, the PP1 cells (fibroblasts) proliferated significantly slower than the PP3 (myoblasts) and PP6 cells (muscle-derived stem cells); the PP1 and PP6 cells showed a superior rate of survival compared with PP3 cells under oxidative stress; and the PP6 cells showed significantly superior chondrogenic capabilities than PP1 and PP3 cells. In vivo, the PP6 cells promoted superior cartilage regeneration compared with the other muscle-derived cell populations. The cartilage defects in the PP6 group had significantly higher histological scores than those of the other muscle-derived cell groups, and GFP detection revealed that the transplanted PP6 cells showed superior in vivo cell survival and chondrogenic capabilities compared with the PP1 and PP3 cells. PP6 cells (muscle-derived stem cells) are superior to other primary muscle-derived cells for use as a cellular vehicle for BMP4-based ex vivo gene therapy to heal full-thickness osteo-chondral defects. The superiority of the PP6/muscle-derived stem cells appears to be attributable to a combination of increased rate of in vivo survival and superior chondrogenic differentiation capacity. PMID- 27990448 TI - Transcriptional activity of novel ALDH1L1 promoters in the rat brain following AAV vector-mediated gene transfer. AB - Aldehyde dehydrogenase family 1, member L1 (ALDH1L1) is a recently characterized pan-astrocytic marker that is more homogenously expressed throughout the brain than the classic astrocytic marker, glial fibrillary acidic protein. We generated putative promoter sequence variants of the rat ALDH1L1 gene for use in adeno associated viral vector-mediated gene transfer, with an aim to achieve selective regulation of transgene expression in astrocytes in the rat brain. Unexpectedly, ALDH1L1 promoter variants mediated transcriptional activity exclusively in neurons in the substantia nigra pars compacta as assessed by luciferase reporter expression at 3 weeks postvector infusion. This selectivity for neurons in the substantia nigra pars compacta also persisted in the context of adeno-associated viral serotype 5, 8 or 9 vector-mediated gene delivery. An in vivo promoter comparison showed the highest performing ALDH1L1 promoter variant mediated higher transgene expression than the neuronal-specific synapsin 1 and tyrosine hydroxylase promoters. The ALDH1L1 promoter was also transcriptionally active in dentate granule neurons following intrahippocampal adeno-associated viral vector infusion, whereas transgene expression was detected in both striatal neurons and astrocytes following vector infusion into the striatum. Our results demonstrate the potential suitability of the ALDH1L1 promoter as a new tool in the development of gene therapy and disease modelling applications. PMID- 27990449 TI - Elimination of proliferating cells from CNS grafts using a Ki67 promoter-driven thymidine kinase. AB - Pluripotent stem cell (PSC)-based cell therapy is an attractive concept for neurodegenerative diseases, but can lead to tumor formation. This is particularly relevant as proliferating neural precursors rather than postmitotic mature neurons need to be transplanted. Thus, safety mechanisms to eliminate proliferating cells are needed. Here, we propose a suicide gene approach, based on cell cycle-dependent promoter Ki67-driven expression of herpes simplex virus thymidine kinase (HSV-TK). We generated a PSC line expressing this construct and induced neural differentiation. In vitro, proliferating PSC and early neural precursor cells (NPC) were killed by exposure to ganciclovir. In vivo, transplantation of PSC led to tumor formation, which was prevented by early ganciclovir treatment. Transplanted NPC did not lead to tumor formation and their survival and neural maturation were not affected by ganciclovir. In conclusion, the cell cycle promoter-driven suicide gene approach described in this study allows killing of proliferating undifferentiated precursor cells without expression of the suicide gene in mature neurons. This approach could also be of use for other stem cell-based therapies where the final target consists of postmitotic cells. PMID- 27990450 TI - Action potential block in neurons by infrared light. AB - Short infrared laser pulses (SILP) have many physiological effects on cells, including the ability to stimulate action potentials (APs) in neurons. Here, we show that SILPs can also reversibly block APs. Reversible AP block in hippocampal neurons was observed following SILP (0.26 to [Formula: see text]; 1.37 to 5.01 ms; 1869 nm) with the block persisting for more than 1 s with exposures greater than [Formula: see text]. AP block was sustained for 30 s with SILPs pulsed at 1 to 7 Hz. Full recovery of neuronal activity was observed 5 to 30 s post SILP exposure. These results indicate that SILP can be used for noncontact, reversible AP block. Due to the high spatial precision and noncontact manner of infrared light delivery, AP block by SILP (infrared neural inhibition) has the potential to transform medical care for sustained pain inhibition and suppression of unwanted nerve activity. PMID- 27990451 TI - Patterned photostimulation via visible-wavelength photonic probes for deep brain optogenetics. AB - Optogenetic methods developed over the past decade enable unprecedented optical activation and silencing of specific neuronal cell types. However, light scattering in neural tissue precludes illuminating areas deep within the brain via free-space optics; this has impeded employing optogenetics universally. Here, we report an approach surmounting this significant limitation. We realize implantable, ultranarrow, silicon-based photonic probes enabling the delivery of complex illumination patterns deep within brain tissue. Our approach combines methods from integrated nanophotonics and microelectromechanical systems, to yield photonic probes that are robust, scalable, and readily producible en masse. Their minute cross sections minimize tissue displacement upon probe implantation. We functionally validate one probe design in vivo with mice expressing channelrhodopsin-2. Highly local optogenetic neural activation is demonstrated by recording the induced response-both by extracellular electrical recordings in the hippocampus and by two-photon functional imaging in the cortex of mice coexpressing GCaMP6. PMID- 27990454 TI - Pseudononlinear ultrasound simulation approach for reverberation clutter. AB - Multipath scattering, or reverberation, takes a substantial toll on image quality in many clinical exams. We have suggested a model-based solution to this problem, which we refer to as aperture domain model image reconstruction (ADMIRE). For ADMIRE to work well, it must be trained with precisely characterized data. To solve this specific problem and the general problem of efficiently simulating reverberation, we propose an approach to simulate reverberation with linear simulation tools. Our simulation method defines total propagation time, first scattering site, and a final scattering site. We use a linear simulation package, such as Field II, to simulate scattering from the final site and then shift the simulated wavefront later in time based on the total propagation time and the geometry of the first scattering site. We validate our simulations using theoretical descriptions of clutter in the literature and data acquired from ex vivo tissue. We found that ex vivo tissue clutter had a mean speckle SNR of [Formula: see text], which we could simulate with about 2 scatterers per resolution cell. Axial clutter distributions drawn from an exponential distribution with a mean of 5 mm and at least 0.5 scatters per resolution cell resulted in clutter that was statistically indistinguishable from the van Cittert Zernike behavior predicted by literature. PMID- 27990452 TI - Review of mesoscopic optical tomography for depth-resolved imaging of hemodynamic changes and neural activities. AB - Understanding the functional wiring of neural circuits and their patterns of activation following sensory stimulations is a fundamental task in the field of neuroscience. Furthermore, charting the activity patterns is undoubtedly important to elucidate how neural networks operate in the living brain. However, optical imaging must overcome the effects of light scattering in the tissue, which limit the light penetration depth and affect both the imaging quantitation and sensitivity. Laminar optical tomography (LOT) is a three-dimensional (3-D) in vivo optical imaging technique that can be used for functional imaging. LOT can achieve both a resolution of 100 to [Formula: see text] and a penetration depth of 2 to 3 mm based either on absorption or fluorescence contrast, as well as large field-of-view and high acquisition speed. These advantages make LOT suitable for 3-D depth-resolved functional imaging of the neural functions in the brain and spinal cords. We review the basic principles and instrumentations of representative LOT systems, followed by recent applications of LOT on 3-D imaging of neural activities in the rat forepaw stimulation model and mouse whisker barrel system. PMID- 27990455 TI - A versatile setup for ultrafast broadband optical spectroscopy of coherent collective modes in strongly correlated quantum systems. AB - A femtosecond pump-probe setup is described that is optimised for broadband transient reflectivity experiments on solid samples over a wide temperature range. By combining high temporal resolution and a broad detection window, this apparatus can investigate the interplay between coherent collective modes and high-energy electronic excitations, which is a distinctive characteristic of correlated electron systems. Using a single-shot readout array detector at frame rates of 10 kHz allows resolving coherent oscillations with amplitudes <10-4. We demonstrate its operation on the charge-transfer insulator La2CuO4, revealing coherent phonons with frequencies up to 13 THz and providing access into their Raman matrix elements. PMID- 27990456 TI - An unexpected digital papillary adenocarcinoma of the thumb. AB - Digital papillary adenocarcinoma (DPAca) is an aggressive lesion with high metastatic potential, which is easily misdiagnosed. We present a 55-year-old male with a cystic lesion on his right thumb. Above all else, lesions of the digits should be sent for histopathology routinely, regardless of their history or appearance. PMID- 27990453 TI - Lung nodule malignancy classification using only radiologist-quantified image features as inputs to statistical learning algorithms: probing the Lung Image Database Consortium dataset with two statistical learning methods. AB - In the assessment of nodules in CT scans of the lungs, a number of image-derived features are diagnostically relevant. Currently, many of these features are defined only qualitatively, so they are difficult to quantify from first principles. Nevertheless, these features (through their qualitative definitions and interpretations thereof) are often quantified via a variety of mathematical methods for the purpose of computer-aided diagnosis (CAD). To determine the potential usefulness of quantified diagnostic image features as inputs to a CAD system, we investigate the predictive capability of statistical learning methods for classifying nodule malignancy. We utilize the Lung Image Database Consortium dataset and only employ the radiologist-assigned diagnostic feature values for the lung nodules therein, as well as our derived estimates of the diameter and volume of the nodules from the radiologists' annotations. We calculate theoretical upper bounds on the classification accuracy that are achievable by an ideal classifier that only uses the radiologist-assigned feature values, and we obtain an accuracy of 85.74 [Formula: see text], which is, on average, 4.43% below the theoretical maximum of 90.17%. The corresponding area-under-the-curve (AUC) score is 0.932 ([Formula: see text]), which increases to 0.949 ([Formula: see text]) when diameter and volume features are included and has an accuracy of 88.08 [Formula: see text]. Our results are comparable to those in the literature that use algorithmically derived image-based features, which supports our hypothesis that lung nodules can be classified as malignant or benign using only quantified, diagnostic image features, and indicates the competitiveness of this approach. We also analyze how the classification accuracy depends on specific features and feature subsets, and we rank the features according to their predictive power, statistically demonstrating the top four to be spiculation, lobulation, subtlety, and calcification. PMID- 27990457 TI - Septic arthritis of the wrist caused by Mycobacterium intracellulare: a case report. AB - Septic arthritis of the wrist is rare entity, especially; atypical mycobacterial infection of the wrist is extremely rare. We report a case of septic arthritis of the wrist caused by Mycobacterium intracellulare, which was successfully treated by radical debridement followed by wrist arthrodesis using vascularised fibular grafting. PMID- 27990458 TI - Osteochondritis dissecans of the fourth proximal interphalangeal joint in a Japanese drummer. AB - We report a rare case of osteochondritis dissecans involving the fourth proximal interphalangeal joint in a young Japanese drummer. We treated it successfully with the removal of loose body and drilling of the donor site. PMID- 27990459 TI - Paraneoplastic cerebellar ataxia with central hypoventilation. PMID- 27990461 TI - Adolescent Light Cigarette Smoking Patterns and Adult Cigarette Smoking. AB - PURPOSE: Light cigarette smoking has had limited research. The purpose of this study was to examine the relationship between light smoking in adolescence with smoking in adulthood. METHODS: National Longitudinal Study of Adolescent Health data, Waves I and IV, were analyzed. Previous month adolescent smoking of 1-5 cigarettes/day (cpd) (light smoking); 6-16 cpd (average smoking); 17 or more cpd (heavy smoking); and nonsmoking were compared with the outcome of adult smoking. RESULTS: At baseline, 15.9% of adolescents were light smokers, 6.8% were average smokers, and 3.6% were heavy smokers. The smoking patterns were significantly related to adult smoking. In logistic regression analyses, adolescent light smokers had an adjusted odds ratio (AOR) of 2.45 (95% CI: 2.00, 3.00) of adult smoking; adolescent average or heavy smokers had AOR of 5.57 (95% CI: 4.17, 7.43) and 5.23 (95% CI: 3.29, 8.31), respectively. CONCLUSION: Individuals who initiate light cigarette smoking during adolescence are more likely to smoke as young adults. PRACTICAL IMPLICATIONS: When screening for tobacco use by adolescents, there is a need to verify that the adolescents understand that light smoking constitutes smoking. There is a need for healthcare providers to initiate interventions for adolescent light smoking. PMID- 27990460 TI - The Development of Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) During Gastric Repair Is Absent in the Aged Stomach. AB - BACKGROUND & AIMS: During aging, physiological changes in the stomach result in more tenuous gastric tissue that is less capable of repairing injury, leading to increased susceptibility to chronic ulceration. Spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) is known to emerge after parietal cell loss and during Helicobacter pylori infection, however, its role in gastric ulcer repair is unknown. Therefore, we sought to investigate if SPEM plays a role in epithelial regeneration. METHODS: Acetic acid ulcers were induced in young (2-3 mo) and aged (18-24 mo) C57BL/6 mice to determine the quality of ulcer repair with advancing age. Yellow chameleon 3.0 mice were used to generate yellow fluorescent protein-expressing organoids for transplantation. Yellow fluorescent protein-positive gastric organoids were transplanted into the submucosa and lumen of the stomach immediately after ulcer induction. Gastric tissue was collected and analyzed to determine the engraftment of organoid-derived cells within the regenerating epithelium. RESULTS: Wound healing in young mice coincided with the emergence of SPEM within the ulcerated region, a response that was absent in the aged stomach. Although aged mice showed less metaplasia surrounding the ulcerated tissue, organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Organoid transplantation in the aged mice led to the emergence of SPEM and gastric regeneration. CONCLUSIONS: These data show the development of SPEM during gastric repair in response to injury that is absent in the aged stomach. In addition, gastric organoids in an injury/transplantation mouse model promoted gastric regeneration. PMID- 27990462 TI - The Biological Metallic versus Metallic Solution in Treating Periprosthetic Femoral Fractures: Outcome Assessment. AB - Introduction. The periprosthetic fracture of the femur is, in order of frequency, the fourth leading cause (5.9%) of surgical revision. Our study aims to demonstrate how the grafting of bone splint betters the outcomes. Materials. We treated 15 periprosthetic femoral fractures divided into two groups: PS composed of 8 patients treated with plates and splints and PSS involving 7 patients treated only with plates. The evaluation criteria for the two groups during the clinical and radiological follow-up were the quality of life measured by the Short Form (36) Health Survey (SF-36), Harris Hip Score (HHS), Modified Cincinnati Rating System Questionnaire (MCRSQ), bone healing measured by the Radiographic Union Score (RUS), postoperative complications, and mortality. The evaluation endpoint was set at 24 months for both groups (p < 0.05). Results. The surgery lasted an average of 124.5 minutes for the PS group and 112.6 minutes for the PSS. At 24 months all clinical and radiographic scores were p < 0.05 for the PS group. During follow-up 4 patients (2 in each group) died of causes not related to surgery. Conclusions. The use of the metal plate as opposed to cortical allogenic splint should be taken into consideration as a noteworthy point for periprosthetic femoral fractures. PMID- 27990463 TI - Occurrence of Ticks in Cattle in the New Pastoral Farming Areas in Rufiji District, Tanzania. AB - Ticks and tick-borne diseases plus trypanosomosis are a constraint to cattle rearing in Tanzania. Rufiji district was not known for important ticks infesting cattle because inhabitants were not engaged in keeping livestock. Not only has settlement of pastoralists and cattle in Rufiji increased the number of cattle but also cattle have been the source of bringing in and spreading of ticks. This study investigated tick species that have been introduced and managed to establish themselves in the new livestock farming areas in cattle in Rufiji. Tick distribution study was undertaken in three villages of Chumbi ward seasonally in 2009, 2011, and 2012. The identified ticks were Amblyomma variegatum (56.10%), Rhipicephalus evertsi (10.25%), R. microplus (27.40%), and R. appendiculatus (6.19%) out of 12940 ticks. Results indicate that ticks are present in the new livestock settlement areas. The occurrence of ticks is correlated with the recent settlement of cattle in the district. PMID- 27990464 TI - Human Dissection in Medical Education: More than Just Anatomy. AB - The dissection course is an essential component of the medical curriculum. Nonetheless, the time expenditure and intensity of supervising the students in this course has been diminishing since the 1970s. That endangers not only the transmission of fundamental knowledge of anatomy. It also concerns key concepts such as establishing values, the concept of humans, and physician competencies, because medical education must be seen not merely as fact-directed instruction but instead should be connected with a mission for professional acculturation. PMID- 27990465 TI - Training of practical skills - implementation in the D-A-CH-Region. PMID- 27990466 TI - Workplace-based assessment of communication skills: A pilot project addressing feasibility, acceptance and reliability. AB - Background: Imparting communication skills has been given great importance in medical curricula. In addition to standardized assessments, students should communicate with real patients in actual clinical situations during workplace based assessments and receive structured feedback on their performance. The aim of this project was to pilot a formative testing method for workplace-based assessment. Our investigation centered in particular on whether or not physicians view the method as feasible and how high acceptance is among students. In addition, we assessed the reliability of the method. Method: As part of the project, 16 students held two consultations each with chronically ill patients at the medical practice where they were completing GP training. These consultations were video-recorded. The trained mentoring physician rated the student's performance and provided feedback immediately following the consultations using the Berlin Global Rating scale (BGR). Two impartial, trained raters also evaluated the videos using BGR. For qualitative and quantitative analysis, information on how physicians and students viewed feasibility and their levels of acceptance was collected in written form in a partially standardized manner. To test for reliability, the test-retest reliability was calculated for both of the overall evaluations given by each rater. The inter-rater reliability was determined for the three evaluations of each individual consultation. Results: The formative assessment method was rated positively by both physicians and students. It is relatively easy to integrate into daily routines. Its significant value lies in the personal, structured and recurring feedback. The two overall scores for each patient consultation given by the two impartial raters correlate moderately. The degree of uniformity among the three raters in respect to the individual consultations is low. Discussion: Within the scope of this pilot project, only a small sample of physicians and students could be surveyed to a limited extent. There are indications that the assessment can be improved by integrating more information on medical context and student self-assessments. Despite the current limitations regarding test criteria, it is clear that workplace-based assessment of communication skills in the clinical setting is a valuable addition to the communication curricula of medical schools. PMID- 27990467 TI - Analysis of educational research at a medical faculty in Germany and suggestions for strategic development - a case study. AB - Background: Evidence-based medical education is playing an increasingly important role in the choice of didactic methods and the development of medical curricula and assessments. In Germany, a growing number of educational research projects has accompanied an ongoing change in the medical education process. The aim of this project was to assess medical education research activities at one medical faculty to develop procedural recommendations for the support and development of best evidence medical education. Methods: Using a newly developed online questionnaire, the 65 institutes and departments of the medical faculty of Hamburg University at Hamburg University Medical-Center (UKE) were asked to report their medical education research and service projects, medical education publications, medical education theses, financial support for educational projects, and supportive structures that they would consider helpful in the future. The data were grouped, and a SWOT analysis was performed. Results: In total, 60 scientists who were involved in 112 medical education research publications between 1998 and 2014 were identified at the UKE. Twenty-five of them had published at least one manuscript as first or last author. Thirty-three UKE institutions were involved in educational service or research projects at the time of the study, and 75.8% of them received internal or external funding. Regular educational research meetings and the acquisition of co-operation partners were mentioned most frequently as beneficial supportive structures for the future. Conclusion: An analysis to define the status quo of medical education research at a medical faculty seems to be a helpful first step for the development of a strategy and structure to further support researchers in medical education. PMID- 27990468 TI - Prevention and health promotion from theory to practice: The interprofessional MeMPE Summer University for students of Medicine, Master of Public Health and Epidemiology. AB - Objective: During the 2015 summer semester of Munich's Ludwig Maximilian University (LMU) medical school, the pilot project "MeMPE Summer University - An Interprofessional Seminar on Prevention and Health Promotion" was implemented as a compulsory elective subject. In 90 teaching units of 45 minutes each, 20 students from the degree programs of Medicine, Master of Public Health and Master of Science Epidemiology (MeMPE) completed modules in theoretical introduction, scientific project work as well as practical assignments and conference attendance. Methods: The project was evaluated by students using pre- and post project questionnaires (26 and 57 items, evaluated on a Five-level Likert scale of 1="fully agree" to 5="fully disagree"). The evaluation interviews of the instruction participants were recorded, transcribed and analyzed according to Mayring's qualitative content analysis. Results: Questionnaire response rate was 100 %. In pre/post comparison, the students reported an improvement in factual knowledge (pre median=3.0; post median=2.0; p<0.0001), in scientific work (pre median=3.0; post median=1.0; p<0.0001) and in interprofessional work (pre median=2.0; post median=1.0; p=0.024). In 18 interviews, the instructors largely expressed their motivation to participate in the project again. Conclusion: The MeMPE Summer University can serve as an example of best practice for interprofessional communication of prevention and health-promotion topics in theory and practice. The evaluation results show that the project enjoyed a high level of acceptance among students and instructors, and that it should be conducted in a revised version again in 2016. PMID- 27990469 TI - Attitude towards and Readiness for Interprofessional Education in Medical and Nursing Students of Bern. AB - Objectives: Interprofessional collaboration is becoming increasingly important in health care for various reasons. Interprofessional Education (IPE) can provide a basis for this. The aim of our study was to find out how medical (MS) and nursing students (NS) think about their own and other professions, what they know about each other, how strong their willingness to embrace IPE is, and what forms of IPE they deem useful. Methodology: Seven IPE experts rated the two measuring instruments, Readiness for Interprofessional Learning Scale RIPLS, and Interdisciplinary Education Perception Scale IEPS in terms of relevance of the items, and the quality of translation into German. Nine RIPLS items and 13 IEPS items were considered content-valid. All MS of the University of Bern and NS of the two Bernese educational institutions for nursing were invited to the online survey in the fall of 2014 by email. Results: 498 (254 MS, 244 NS) of the 2374 invited students completely filled in the questionnaire (21%). The results of the reduced RIPLS allowed no conclusive statements. When assessing their own occupational group in the IEPS, the MS attributed "competence and autonomy" to themselves significantly more frequently, while to the NS, the same was true for the item, "actual cooperation". MS know significantly less about the training of other health professionals. NS show a significantly higher willingness to embrace IPE. Teaching ethics, communication, team training, and clinical skills are deemed suitable for IPE by both groups. From the comments it appears that in both groups a majority welcomes IPE; however, the various arguments had different prevalence in both groups. Both groups fear that IPE leads to heightened stress during the study. A subgroup of MS fears a lowering of academic level. Conclusion: The results of this survey of Bernese MS and NS concerning IPE provide important information for the planning and implementation of IPE. Important steps in the introduction of IPE will be a clear justification and the definition of its objectives. These must be explicitly communicated to all students. PMID- 27990471 TI - Are the results of questionnaires measuring non-cognitive characteristics during the selection procedure for medical school application biased by social desirability? AB - Introduction: A stronger consideration of non-cognitive characteristics in Medical School application procedures is desirable. Psychometric tests could be used as an economic supplement to face-to-face interviews which are frequently conducted during university internal procedures for Medical School applications (AdH, Auswahlverfahren der Hochschulen). This study investigates whether the results of psychometric questionnaires measuring non-cognitive characteristics such as personality traits, empathy, and resilience towards stress are vulnerable to distortions of social desirability when used in the context of selection procedures at Medical Schools. Methods: This study took place during the AdH of Lubeck University in August 2015. The following questionnaires have been included: NEO-FFI, SPF, and AVEM. In a 2x1 between-subject experiment we compared the answers from an alleged application condition and a control condition. In the alleged application condition we told applicants that these questionnaires were part of the application procedure. In the control condition applicants were informed about the study prior to completing the questionnaires. Results: All included questionnaires showed differences which can be regarded as social desirability effects. These differences did not affect the entire scales but, rather, single subscales. Conclusion: These results challenge the informative value of these questionnaires when used for Medical School application procedures. Future studies may investigate the extent to which the differences influence the actual selection of applicants and what implications can be drawn from them for the use of psychometric questionnaires as part of study-place allocation procedures at Medical Schools. PMID- 27990472 TI - The Effort and Reward of Teaching Medical Psychology in Germany: an Online Survey. AB - Background: The increasing significance of university teaching also leads to higher demands for academic teachers. Against this background this study inquires how teachers in the field of medical pychology experience and evaluate their various activities and how their efforts on the one hand and gratifications on the other hand relate to each other (as conceptualized by the effort-reward imbalance, ERI). Methods: A cross-sectional online survey was conducted in 2012 among the academic staff of departments of medical psychology in Germany. The questionnaire was answered by 188 participants (return rate: 39.2%), of whom 62% were women. Work stress was measured according to Siegrist's effort-reward imbalance (ERI) model. Further questions referred to the distribution of academic activities and meaningfulness. Results: Among all participants, 67.3% were satisfied with the portion of their workload devoted to teaching, while 63% wanted more time for research. The ERI-coefficient was on average M=0.76 (SD=0.45), thus indicating a shift towards reward. There were no associations with gender, age, or fixed-term work contracts. Meaningfulness was associated negatively with the ERI (r=-.21, p=.012), and positively with overcommitment (r=.52, p<.001) and the desire for less administrative tasks (r=.24, p=.017). Conclusions: Teaching medical psychology is evaluated as positive and meaningful by a majority of respondents. In general, the rewarding aspects seem to outweigh the stressful factors. Thus, teaching might be a protective factor with regard to coping with work related burden. PMID- 27990470 TI - Medical Students' Development of Ethical Judgment - Exploring the Learners' Perspectives using a mixed methods approach. AB - Objective: Contemporary healthcare requires physicians to have well developed ethical judgment skills in addition to excellent clinical skills. However, no consensus has been reached on how to best teach ethical judgment skills during medical training. Previous studies revealed inconclusive results and applied varying theoretical frameworks. To date, the students' perspectives on their development in ethical judgment has received less attention. Better insights in the learners' experiences can help to improve educational interventions in medical ethics. Methods: A vignette featuring a challenging case with opposing views between a patient's parents and a physician followed by a questionnaire was presented to a cohort of medical students at a German medical school at three points in time during their medical training (Year 1, 2 and 5). The questionnaire included closed and open-ended questions addressing the participant's preferred, hypothetical actions, their reasoning as well as the resources informing their reasoning. Content analysis was used for qualitative data; frequencies and percentages were used to describe quantitative findings. Results: The response rate remained stable (28%) over the study period. Participants' responses changed overtime. Accepting parents' autonomy in the decision-making process was the majority standpoint of students in year 1 and 2 and became less often cited in year 5 (Year 1/2/5: 68/67/48%). On the contrary, not readily following the parents' decision for medical reasons was a minority standpoint in year 1 and became more prevalent over time (year 1/2/5: 12/17/42%). Judgments were only partly based on ethics training. Instead, participants drew on experiences from their clinical clerkships and their personal lives. Throughout the study, participants did not feel well-prepared to make a judgment in the case (Average 2.7 on a Likert-Scale; 1=very well prepared, 4=very poor). Conclusions: Over the course of their medical training, the participants seemed to increasingly frame the presented vignette as a medical problem. To optimize the development of ethical judgment teaching of ethics should be more integrated in clinical teaching. In addition to the analysis of rare and extreme cases, teaching ethics should also expand on challenges students and junior doctors commonly encounter themselves to promote ethical sensitivity and confidence in students. PMID- 27990473 TI - A station-based concept for teaching the neurological examination: A prospective quasi-experimental study. AB - Background: The neurological examination is considered to be complex and contributes to the phenomenon of "neurophobia". It is traditionally taught in small groups by residents ("traditional concept"), making the learning success partially dependent on the resident's level of clinical training, didactic education and personal motivation. Aim of this study was to examine the effects of a newly developed concept ("station concept") for teaching the neurological examination on achieving an improved and more equal transfer of knowledge and practical skills. Methods: A prospective quasi-experimental design was used to compare the traditional concept with the newly developed station concept, in which the teaching content was divided in eight subdivisions (stations) with one resident being assigned to one station. The primary endpoints of the study were the differences in students' self-assessments of learning success in the different subdomains of the neurological examination, and secondary analyses focused on evaluation results of students and residents. Results: 144 students and 28 residents participated in the traditional concept (summer semester 2012) and 151 students and 28 residents in the station concept (winter semester 2012/13). In the station-concept students' self-assessment significantly improved in the domains "Motor System", "Coordination" and "Mental Status" compared to the traditional concept. Students' evaluation showed significant improvement in five out of eight points. Fifty percent of residents rated the new approach superior to the traditional approach, ten percent as inferior. Conclusion: The station concept improved students' self-assessed learning success as well as evaluation results while simultaneously achieving high acceptance in residents. PMID- 27990474 TI - Clinican Scientists? Medical Scientists? Clinician and Medical Science Educators! PMID- 27990475 TI - Evolving data access policy: The Canadian context. AB - In setting up a data access policy to share controlled access data from the McGill Epigenomics Mapping Centre (EMC), an International Human Epigenome Consortium (IHEC) partner project, we encountered ethical and legal challenges that are likely to be relevant to other researchers sharing data, especially from Canadian projects. We discuss our solutions to the following data-sharing challenges, based on comparative legal and policy analysis: (1) providing access to data to a growing number of researchers; (2) maintaining Canadian privacy standards while sharing controlled access data internationally; (3) freedom of information requests; and (4) providing more incentives for researchers to share pre-publication data. PMID- 27990476 TI - Next frontiers in CAR T-cell therapy. PMID- 27990478 TI - Editorial: Letter of Recommendation. PMID- 27990477 TI - The effect of D-cycloserine on social anxiety treatment using a behavioral outcome measure and a post-session administration strategy. AB - BACKGROUND: The drug D-Cycloserine (DCS) has been used as an adjunct to increase the pace of symptom reductions during exposure therapy for anxiety disorders. This procedure has met with mixed results andmany questions remain. Aims: The findings from two investigations are reported here, highlighting important domains for furthering our understanding of DCS effects. METHOD: Study 1 (n = 16) treated social anxiety among a sample of emerging adults, and in addition to self report utilized a behavioral measure of symptom improvement to evaluate outcomes. Study 2 (n = 16), utilizing a similar design, introduced an algorithm based post session administration strategy following sessions where anxiety reductions were evident. Both investigations were double-blind, placebo controlled, randomized trials with participants diagnosed with social anxiety. Treatment was an exposure based CBT-protocol adopted in other investigations that tested DCS. RESULTS: Findings of Study 1 yielded an interaction effect in favor of DCS for self reported distress ratings (p=.02) and on a behavioral measure of anxiety (p=.01). Findings from Study 2 revealed a significant effect for self-reported subjective distress ratings (p=.002). CONCLUSIONS: Although limitations of small sample size constrain generalization and limit power, results illustrate some beneficial effects of DCS within the context of exposure-based intervention for social anxiety, yet are discussed in the context of statistical vs. clinical significance and the DCS literature as a whole. Present findings highlight the potential usefulness of a post-session administration strategy and the behavioral measure for future efforts with an eye towards preventing bias through more nuanced and powered studies. PMID- 27990479 TI - Prevalence of Donor-Specific Antibodies After Pediatric Liver Transplantation: A Meta-Analysis. PMID- 27990480 TI - Efficacy of Acute Cellular Rejection Treatment According to Banff Score in Kidney Transplant Recipients: A Systematic Review. AB - BACKGROUND: The poor prognosis classically associated with Banff grade 2 acute cell-mediated rejection (CMR) may be due to unrecognized antibody-mediated damage. We thus performed a systematic review of the literature to determine the rate of response to treatment in kidney transplant recipients with pure CMR, stratified by Banff class. METHODS: In addition to a manual search, databases interrogated included Excerpta Medica Database (EMBASE), Medical Literature Analysis and Retrieval System Online (MEDLINE), Evidence-Based Medicine (EBM) databases, Central, PubMed and CINAHL. Studies providing functional and/or histological response rates to the treatment of CMR rejection by Banff class (1997 or more recent) were included. RESULTS: Among the 746 articles identified, 5 articles were included in the final review. Two studies excluded some, and 2 excluded all features of antibody-mediated rejection, while providing data on functional recovery. The absence of functional recovery was reported in 4% of borderline, 15% for Banff grade 1A and IB pooled, 0% to 25% of Banff grade 1B alone, 11% to 20% of Banff grade 2A, and 38% of Banff grade 2B rejections. CONCLUSIONS: The rate of functional recovery of pure Banff IIA CMR overlapped with that of Banff grade 1 CMR, whereas Banff grade 2B showed worse prognosis. There was important heterogeneity in the definition of response to treatment and paucity of data describing the histological response to treatment stratified by Banff class. There is a pressing need to standardize outcome metrics for the reversibility of rejection in kidney transplant recipients in order to design high-quality trials for novel therapeutic alternatives. PMID- 27990482 TI - The World's Youngest Cadaveric Kidney Transplant: Medical, Surgical and Ethical Issues. AB - BACKGROUND: We report here the first successful transplant from a preterm cadaveric donor. This was performed in November 1994. The donor, who had been born at about 33 weeks of gestation, was diagnosed as having agenesis of the corpus callosum. The transplant was carried out 10 days after the donor's birth. The recipient was a 17-month-old boy with a diagnosis of Denys-Drash syndrome (WT1 mutation). METHOD: We describe and analyze the ethical, social, cultural, medical and surgical issues encountered and how these were addressed. The major issue of determining death in a beating heart, very young donor was dealt with in the absence of worldwide experience and guidelines. RESULTS: The transplanted recipient has lived with the grafted pair of kidneys for more then 22 years. He has led a relatively normal life. CONCLUSIONS: It is possible for immature preterm deceased donor kidneys to be transplanted into a 17-month-old recipient and for the grafted kidneys to grow with the recipient and function for 22 years. There were challenges in ethically determining the death of the donor, in surgical techniques to obviate potential surgical complications, and in postoperative care of the recipient, but these were managed successfully. PMID- 27990481 TI - Increased Telomere Attrition After Renal Transplantation-Impact of Antimetabolite Therapy. AB - BACKGROUND: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied. METHODS: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls. RESULTS: Non-CKD patients had significantly (P <= 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003). CONCLUSIONS: The associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention. PMID- 27990483 TI - Identification of Novel and Noninvasive Biomarkers of Acute Cellular Rejection After Liver Transplantation by Protein Microarray. AB - BACKGROUND: Acute cellular rejection (ACR) is one of the main factors in transplanted organ failure in liver transplantation. A precise marker for diagnosing or predicting rejection is not currently available; therefore, invasive liver biopsy is standard procedure. To develop a noninvasive method for precise diagnosis of ACR, we evaluated autoantibodies from patient sera as potential biomarkers using protein microarrays (seromics). METHODS: Sera from hepatitis C virus-positive ACR patients were compared to three hepatitis C virus cirrhosis control groups and healthy volunteers. The control groups consisted of 2 no-ACR groups obtained on postoperative day 28 and 1 year after transplantation and a preoperative group obtained 1 day before transplantation. For validation, we evaluated whether the candidate antibodies can distinguish ACR from other types of liver dysfunction after liver transplantation using enzyme-linked immunosorbent assay. RESULTS: Seromic analysis by weighted average difference (WAD) ranking and Mann-Whitney U test revealed a significant increase of 57 autoantibodies in the sera of ACR patients with liver dysfunction. Among the 57 candidates, autoantibodies to charged multivesicular body protein 2B, potassium channel tetramerization domain containing 14, voltage gated subfamily A regulatory beta subunit 3, and triosephosphate isomerase 1 were regarded as potential biomarkers of ACR after liver transplantation. Using 20 ACR patients with variable backgrounds for validation, the autoantibodies to charged multivesicular body protein 2B and triosephosphate isomerase 1 were significantly increased in ACR patients compared to other control groups. CONCLUSIONS: A panel of autoantibodies identified by seromics as potential noninvasive biomarkers was clinically useful for diagnosing ACR after liver transplantation. PMID- 27990484 TI - Initial Experience of Video Capsule Endoscopy After Intestinal Transplantation. AB - BACKGROUND: Intestinal transplantation is a procedure which inflicts immunological and infectious complications that affect the transplanted graft, posing both diagnostic and therapeutic challenges. Video capsule endoscopy (VCE) offers easy access to the entire small intestine and presents itself as an interesting option. However, at present, no studies evaluating the usefulness of video capsule endoscopies in this setting have been published. Our aim was to evaluate the usefulness of VCE in detecting complications that arise after intestinal transplantation. METHODS: We included 7 adult patients with either isolated intestine (n = 1) or multivisceral grafts (n = 6). These patients underwent 12 VCE between 2004 and 2015 at the Sahlgrenska University Hospital. The median age was 42 (21-67) years (4 women/3 men). VCE was used in clinical situations where the conventional diagnostic methods failed to provide answers to the clinical question. RESULTS: Indications for the procedure were: suspicion of rejection (n = 4 examinations), gastrointestinal dysmotility (n = 4 examinations), high stomal output (n = 2 examinations), suspicion of lymphoproliferative disease in the transplanted graft (n = 1 examination), and clinical surveillance (n = 1 examination). The median time after transplantation for performing an examination was 740 (26-3059) days. VCE was useful in 83% of the examinations and the results influenced the planned management. The overall agreement between VCE findings and biopsies was moderate (kappa = 0.54, P = 0.05) but increased when comparing the presence of inflammation/rejection (kappa = 0.79, P < 0.001). CONCLUSIONS: VCE is a promising diagnostic method after intestinal transplantation. However, larger studies are needed to evaluate its potential risks and gains. PMID- 27990485 TI - The Association Between Broad Antigen HLA Mismatches, Eplet HLA Mismatches and Acute Rejection After Kidney Transplantation. AB - BACKGROUND: Epitope matching, which evaluates mismatched amino acids within antigen-antibody interaction sites (eplets), may better predict acute rejection than broad antigen matching alone. We aimed to determine the association between eplet mismatches and acute rejection in kidney transplant recipients. METHODS: The association between eplet mismatches, broad antigen mismatches and acute rejection was assessed using adjusted Cox proportional hazard regression. Model discrimination for acute rejection was evaluated using the area under receiver operating characteristic curves. RESULTS: Of the 3,499 kidney transplant recipients from 2006 to 2011, the average (SD) number of broad antigen and eplet mismatches were 3.4 (1.7) and 22.8 (12.2), respectively. Compared with 0 to 2 eplet mismatches, the adjusted hazard ratio (HR) for acute rejection among those with 20 or greater eplet mismatches was 2.16 (95% confidence interval [CI], 1.33 3.52; P = 0.001). The adjusted area under the curve for broad antigen mismatches was 0.58 (95% CI, 0.56-0.61), similar to that for eplet mismatches (HR, 0.59; 95% CI, 0.56-0.61; P = 0.365). In recipients who were considered as low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with 20 or greater eplet mismatches experienced an increased risk of rejection compared to those with less than 20 mismatches (adjusted HR, 1.85; 95% CI, 1.11-3.08; P = 0.019). CONCLUSIONS: Increasing number of eplet mismatches is associated with acute rejection in kidney transplant recipients. Consideration of eplet HLA mismatches may improve risk stratification for acute rejection in a selected group of kidney transplant candidates. PMID- 27990486 TI - Successful Simultaneous Liver-Kidney Transplantation in the Presence of Multiple High-Titered Class I and II Antidonor HLA Antibodies. AB - The results of simultaneous liver-kidney transplants in highly sensitized recipients have been controversial in terms of antibody-mediated rejection and kidney allograft outcomes. This case report provides a detailed and sophisticated documentation of histocompatibility and pathologic data in a simultaneous liver kidney transplant performed in a recipient with multiple high-titered class I and II antidonor HLA antibodies and a strongly positive cytotoxic crossmatch. Patient received induction with steroids, rituximab, and eculizumab without lymphocyte depleting agents. The kidney transplant was delayed by 6 hours after the liver transplant to allow more time to the liver allograft to "absorb" donor-specific antibodies (DSA). Interestingly, the liver allograft did not prevent immediate antibody-mediated injury to the kidney allograft in this highly sensitized recipient. Anti-HLA single antigen bead analysis of liver and kidney allograft biopsy eluates revealed deposition of both class I and II DSA in both liver and kidney transplants during the first 2 weeks after transplant. Afterward, both liver and kidney allograft functions improved and remained normal after a year with progressive reduction in serum DSA values. PMID- 27990488 TI - Enhanced Human-Induced Pluripotent Stem Cell Derived Cardiomyocyte Maturation Using a Dual Microgradient Substrate. AB - Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) raise many possibilities for cardiac research but they exhibit an immature phenotype, which influences experimental outcomes. The aim of our research is to investigate the effects of a topographical gradient substrate on the morphology and function of commercially available hiPSC-CM. The lateral dimensions the microgrooves on the substrate varied from 8 to 100 MUm space between the 8 MUm grooves on one axis and from ~5 nm to ~1 MUm in depth on the other axis. Cells were seeded homogeneously across the substrate and according to the manufacturers protocols. At days 4 and 10, measures of eccentricity, elongation, orientation, sarcomere length (SL), and contractility of the hiPSC-CM were taken. Only the deepest and widest region (8-30 MUm wide and 0.85-1 MUm deep) showed a significantly higher percentage of hiPSC-CM with an increased eccentricity (31.3 +/- 6.4%), elongation (10.4 +/- 4.3%), and orientation (<10 degrees ) (32.1 +/- 2.7%) when compared with the control (flat substrate) (15.8 +/- 5.0%, 3.4 +/- 2.7%, and 10.6 +/- 1.1%, respectively). Additionally, during stimulus-induced contraction, the relaxation phase of the twitch was prolonged (400 ms) compared to nonelongated cells (200 ms). These findings support the potential use of dual microgradient substrates to investigate substrate topographies that stimulate migration and/or maturation of hiPSC-CM. PMID- 27990489 TI - Designing and defining dynamic protein cage nanoassemblies in solution. AB - Central challenges in the design of large and dynamic macromolecular assemblies for synthetic biology lie in developing effective methods for testing design strategies and their outcomes, including comprehensive assessments of solution behavior. We created and validated an advanced design of a 600-kDa protein homododecamer that self-assembles into a symmetric tetrahedral cage. The monomeric unit is composed of a trimerizing apex-forming domain genetically linked to an edge-forming dimerizing domain. Enhancing the crystallographic results, high-throughput small-angle x-ray scattering (SAXS) comprehensively contrasted our modifications under diverse solution conditions. To generate a phase diagram associating structure and assembly, we developed force plots that measure dissimilarity among multiple SAXS data sets. These new tools, which provided effective feedback on experimental constructs relative to design, have general applicability in analyzing the solution behavior of heterogeneous nanosystems and have been made available as a web-based application. Specifically, our results probed the influence of solution conditions and symmetry on stability and structural adaptability, identifying the dimeric interface as the weak point in the assembly. Force plots comparing SAXS data sets further reveal more complex and controllable behavior in solution than captured by our crystal structures. These methods for objectively and comprehensively comparing SAXS profiles for systems critically affected by solvent conditions and structural heterogeneity provide an enabling technology for advancing the design and bioengineering of nanoscale biological materials. PMID- 27990487 TI - Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D. AB - Current treatments for chronic xerostomia, or "dry mouth", do not offer long-term therapeutic benefits for head and neck cancer survivors previously treated with curative radiation. Towards the goal of creating tissue-engineered constructs for the restoration of salivary gland functions, we developed new hyaluronic acid (HA)-based hydrogels using thiolated HA (HA-SH) and acrylated HA (HA-AES) with a significant molecular weight mismatch. Four hydrogel formulations with varying HA concentration, (1-2.4 wt%) and thiol/acrylate ratios (2/1 to 36/1) and elastic moduli (G': 35 to 1897 Pa, 2 h post-mixing) were investigated. In our system, thiol/acrylate reaction was initiated rapidly upon mixing of HA-SH/HA-AES to establish thioether crosslinks with neighboring ester groups, and spontaneous sulfhydryl oxidation occurred slowly over several days to install a secondary network. The concurrent reactions cooperatively create a cell-permissive network to allow for cell expansion and aggregation. Multicellular spheroids formed readily from a robust ductal epithelial cell line (Madin-Darby Canine Kidney, MDCK cells) in all hydrogel formulations investigated. Primary salivary human stem/progenitor cells (hS/PCs), on the other hand, are sensitive to the synthetic extracellular environment, and organized acini-like structures with an average diameter of 50 um were obtained only in gels with G' <= 216 Pa and a thiol/acrylate ratio >=18. The spheroid size and size distribution were dependent on the HA content in the hydrogel. Cells in hS/PC spheroids formed tight junctions (occludin), remained viable and proliferative, secreted structural proteins (collagen IV and laminin) found in the basement membrane and maintained key stem/progenitor markers. We conclude that incorporation of time-dependent, dynamic features into a covalently crosslinked HA network produces an adaptable hydrogel framework that promotes hS/PC assembly and supports early aspects of salivary morphogenesis, key to reconstitution of a fully functional implantable salivary gland. PMID- 27990490 TI - Long photoperiods sustain high pH in Arctic kelp forests. AB - Concern on the impacts of ocean acidification on calcifiers, such as bivalves, sea urchins, and foraminifers, has led to efforts to understand the controls on pH in their habitats, which include kelp forests and seagrass meadows. The metabolism of these habitats can lead to diel fluctuation in pH with increases during the day and declines at night, suggesting no net effect on pH at time scales longer than daily. We examined the capacity of subarctic and Arctic kelps to up-regulate pH in situ and experimentally tested the role of photoperiod in determining the capacity of Arctic macrophytes to up-regulate pH. Field observations at photoperiods of 15 and 24 hours in Greenland combined with experimental manipulations of photoperiod show that photoperiods longer than 21 hours, characteristic of Arctic summers, are conducive to sustained up-regulation of pH by kelp photosynthesis. We report a gradual increase in pH of 0.15 units and a parallel decline in pCO2 of 100 parts per million over a 10-day period in an Arctic kelp forest over midsummer, with ample scope for continued pH increase during the months of continuous daylight. Experimental increase in CO2 concentration further stimulated the capacity of macrophytes to deplete CO2 and increase pH. We conclude that long photoperiods in Arctic summers support sustained up-regulation of pH in kelp forests, with potential benefits for calcifiers, and propose that this mechanism may increase with the projected expansion of Arctic vegetation in response to warming and loss of sea ice. PMID- 27990491 TI - Livestock vaccinations translate into increased human capital and school attendance by girls. AB - To fulfill the United Nation's Sustainable Development Goals (SDGs), it is useful to understand whether and how specific agricultural interventions improve human health, educational opportunity, and food security. In sub-Saharan Africa, 75% of the population is engaged in small-scale farming, and 80% of these households keep livestock, which represent a critical asset and provide protection against economic shock. For the 50 million pastoralists, livestock play an even greater role. Livestock productivity for pastoralist households is constrained by multiple factors, including infectious disease. East Coast fever, a tick-borne protozoal disease, is the leading cause of calf mortality in large regions of eastern and Southern Africa. We examined pastoralist decisions to adopt vaccination against East Coast fever and the economic outcomes of adoption. Our estimation strategy provides an integrated model of adoption and impact that includes direct effects of vaccination on livestock health and productivity outcomes, as well as indirect effects on household expenditures, such as child education, food, and health care. On the basis of a cross-sectional study of Kenyan pastoralist households, we found that vaccination provides significant net income benefits from reduction in livestock mortality, increased milk production, and savings by reducing antibiotic and acaricide treatments. Households directed the increased income resulting from East Coast fever vaccination into childhood education and food purchase. These indirect effects of livestock vaccination provide a positive impact on rural, livestock-dependent families, contributing to poverty alleviation at the household level and more broadly to achieving SDGs. PMID- 27990492 TI - The Orphan C2orf40 Gene is a Neuroimmune Factor in Alzheimer's Disease. AB - Expression of the orphan C2orf40 gene is associated with the aggregation of the neurofibrillary tangle-protein tau in transgenic mice, tumor suppression, the induction of senescence in CNS, and the activation of microglia and peripheral mononuclear leukocytes. This gene also encodes several secreted pro- and anti inflammatory neuropeptide-like cytokines, suggesting they might be implicated in the inflammatory component(s) of Alzheimer's disease (AD). Accordingly, we evaluated human AD and control brains for expression changes by RT-qPCR, Western blot, and histological changes by immunolabeling. RT-qPCR demonstrated increased cortical gene expression in AD. The molecular form of Ecrg4 detected in cortex was 8-10 kDa, which was shown previously to interact with the innate immunity receptor complex. Immunocytochemical studies showed intensely stained microglia and intravascular blood-borne monocytes within cerebral cortical white matter of AD patients. Staining was diminished within cortical neurons, except for prominent staining in neurofibrillary tangles. Choroid plexuses showed a decreasing trend. These findings support our hypothesis that c2orf40 participates in the neuroimmune response in AD. PMID- 27990493 TI - THE CHALLENGES OF SCHOOL-BASED YOUTH SUICIDE PREVENTION: EXPERIENCES AND PERCEPTIONS OF MENTAL HEALTH PROFESSIONALS IN SOUTH AFRICAN SCHOOLS. AB - Youth suicidal behaviour poses a significant public health concern. Mental health care professionals working in schools have an important role to play in youth suicide prevention initiatives, although little is known of the experiences of this group of professionals in the developing world. The aim of this study was to explore the experiences of mental health professionals working in South African schools and document their insights, attitudes and beliefs regarding youth suicidal behaviour. In-depth semi-structured interviews were conducted with seven school-based mental health care professionals and data were analysed using Thematic Analysis. Participants reported that they relied on a reactive strategy by responding to youths who were in crisis. They were challenged by a lack of support from faculty staff, lack of access to resources, and heavy caseloads. Findings highlight the need for a proactive and collaborative approach to suicide prevention among mental health care professionals, teachers and parents in South African schools and improved training and supervision. PMID- 27990494 TI - Relationships Between Altered Functional Magnetic Resonance Imaging Activation and Cortical Thickness in Patients With Euthymic Bipolar I Disorder. AB - BACKGROUND: Performance during cognitive control functional magnetic resonance imaging (fMRI) tasks are associated with frontal lobe hypoactivation in patients with bipolar disorder, even while euthymic. Here, we study the structural underpinnings for this functional abnormality simultaneously with brain activation data. METHODS: In a sample of ninety adults (45 with inter-episode Bipolar I disorder and 45 healthy controls), we explored whether abnormal functional activation patterns in bipolar euthymic subjects during a Go-NoGo fMRI task are associated with regional deficits in cortical gray matter thickness in the same regions. Cross-sectional differences in fMRI activation were used to form a-priori hypotheses for region-of-interest cortical gray matter thickness analyses. fMRI BOLD to structural magnetic resonance imaging (sMRI) thickness correlations were conducted across the sample and within patients and controls separately. RESULTS: During response inhibition (NoGo minus Go), bipolar subjects showed significant hypoactivation and reduced thickness in the inferior frontal cortex (IFC), superior frontal gyrus and cingulate compared to controls. Cingulate hypoactivation corresponded with reduced regional thickness. A significant activation by disease state interaction was observed with thickness in left prefrontal areas. CONCLUSIONS: Reduced cingulate fMRI activation is associated with reduced cortical thickness. In the left frontal lobe, a thinner cortex was associated with increased fMRI activation in patients, but showed a reverse trend in controls. These findings suggest that reduced activation in the IFC and cingulate during a response inhibition task may have an underlying structural etiology, which may explain task-related functional hypoactivation that persists even when patients are euthymic. PMID- 27990497 TI - activeNotes: Computer-Assisted Creation of Patient Progress Notes. AB - We present activeNotes, a prototype application that supports the creation of Critical Care Notes by physicians in a hospital intensive care unit. activeNotes integrates automated, context-sensitive patient data retrieval and user control of automated data updates and alerts into the note-creation process. In a user study at New York Presbyterian Hospital, we gathered qualitative feedback on the prototype from 15 physicians. The physicians found activeNotes to be valuable and said they would use it to create both formal notes for medical records and informal notes. One surprising finding is that while physicians have rejected template-based clinical documentation systems in the past, they expressed a desire to use activeNotes to create personalized, physician-specific note templates to be reused with a given patient, or for a given condition. PMID- 27990495 TI - Optical coherence tomography angiography in pediatric choroidal neovascularization. AB - PURPOSE: To report two cases of pediatric choroidal neovascularization (CNV) and the associated neo-vascular and retinal findings identified on Optical Coherence Tomography Angiography (OCTA) imaging. METHODS: A 14-year-old boy with handheld laser-induced maculopathy-related CNV and a 13-year-old boy with idiopathic CNV were evaluated with visual acuity testing, slit-lamp exam, fundus photography, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and OCTA. RESULTS: Macular CNV were identified in both pediatric patients using OCTA imaging. The first case demonstrated a classic pediatric type II CNV with a "tree-like" pattern and a single vessel in-growth site, while the second case demonstrated a type I CNV with a "glomerular" pattern. CONCLUSION: Distinct choroidal neovascular patterns were visualized in these two cases of pediatric CNV when compared to adult subtypes. OCTA is a noninvasive imaging modality capable of evaluating and characterizing pediatric CNV and their associated vascular patterns. PMID- 27990496 TI - Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy. AB - Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies. PMID- 27990498 TI - Big-Data Based Decision-Support Systems to Improve Clinicians' Cognition. AB - Complex clinical decision-making could be facilitated by using population health data to inform clinicians. In two previous studies, we interviewed 16 infectious disease experts to understand complex clinical reasoning. For this study, we focused on answers from the experts on how clinical reasoning can be supported by population-based Big-Data. We found cognitive strategies such as trajectory tracking, perspective taking, and metacognition has the potential to improve clinicians' cognition to deal with complex problems. These cognitive strategies could be supported by population health data, and all have important implications for the design of Big-Data based decision-support tools that could be embedded in electronic health records. Our findings provide directions for task allocation and design of decision-support applications for health care industry development of Big data based decision-support systems. PMID- 27990500 TI - Determinants of Employment among Well-Educated Refugees before and After the 2007 U.S. Economic Recession. AB - Little is known about how the overall employment conditions in a country impact the likelihood of employment of newly arrived refugees. In the current study, we compare employment and determinant of employment of highly educated Middle Eastern refugees to Michigan that arrived before and after the 2007 recession. We also look at self-reported barriers to employment. Results show that the general downturn of the economy made it substantially more difficult to secure employment, even for well-educated refugees. Thus, before the economic downturn, 22.9 % of refugees were unemployed as compared to 55.1 % once the recession had set in (p < 0.01). There were also substantially more self-reported barriers to employment after the economic downturn. The study points to the importance of understanding both individual characteristics and the general employment conditions in the new host country when studying variation in refugee employment success. PMID- 27990499 TI - Obesity and Multiple Sclerosis Susceptibility: A Review. AB - Several studies conducted around the world over the last decade have demonstrated that early childhood and adolescent obesity are significant risk factors for MS susceptibility. This association has been largely confirmed in females, while evidence supporting a strong role for obesity and risk of MS in males has been mixed. Further, interaction between increased body mass index and genetic as well as environmental factors in MS susceptibility has been proposed, and evidence of a causal relationship has recently been established. In this review, we discuss findings supporting the significant association between obesity and MS, as well as identify areas for future investigation. PMID- 27990501 TI - mCrave: Continuous Estimation of Craving During Smoking Cessation. AB - Craving usually precedes a lapse for impulsive behaviors such as overeating, drinking, smoking, and drug use. Passive estimation of craving from sensor data in the natural environment can be used to assist users in coping with craving. In this paper, we take the first steps towards developing a computational model to estimate cigarette craving (during smoking abstinence) at the minute-level using mobile sensor data. We use 2,012 hours of sensor data and 1,812 craving self reports from 61 participants in a smoking cessation study. To estimate craving, we first obtain a continuous measure of stress from sensor data. We find that during hours of day when craving is high, stress associated with self-reported high craving is greater than stress associated with low craving. We use this and other insights to develop feature functions, and encode them as pattern detectors in a Conditional Random Field (CRF) based model to infer craving probabilities. PMID- 27990502 TI - Designing Patient-Centric Information Displays for Hospitals. AB - Electronic medical records are increasingly comprehensive, and this vast repository of information has already contributed to medical efficiency and hospital procedure. However, this information is not typically accessible to patients, who are frequently under-informed and unclear about their own hospital courses. In this paper, we propose a design for in-room, patient-centric information displays, based on iterative design with physicians. We use this as the basis for a Wizard-of-Oz study in an emergency department, to assess patient and provider responses to in-room information displays. 18 patients were presented with real-time information displays based on their medical records. Semi-structured interviews with patients, family members, and hospital staff reveal that subjective response to in-room displays was overwhelmingly positive, and through these interviews we elicited guidelines regarding specific information types, privacy, use cases, and information presentation techniques. We describe these findings, and we discuss the feasibility of a fully-automatic implementation of our design. PMID- 27990503 TI - Editorial: Is new necessarily better than old? ... and the story of the chameleon that behaved like an ostrich. PMID- 27990504 TI - The clinical value of membranes in bone augmentation procedures in oral implantology: ?A systematic review of randomised controlled trials. AB - PURPOSE: To determine the clinical value of membranes in bone augmentation procedures such as ridge augmentation with simultaneous (one-stage) and delayed (two-stage) implant placement, sinus augmentation surgery, ridge preservation and immediate implant placement. MATERIALS AND METHODS: In April 2016, Embase, Medline (Ovid-SP), Cochrane Central, Web of Science and PubMed (as supplied by the publisher) were searched. There were no restrictions regarding language or publication date. Randomised controlled trials that reported membranes in bone augmentation procedures with a minimum follow-up period of 6 months after implant loading or that described geometrical changes of the bone graft at re-entry were included. Membrane placement had to be the only variable in the procedure. Outcomes were implant failure, complications, horizontal bone gain and resorption, graft resorption, defect height reduction, marginal bone loss around implants, aesthetic results and patient satisfaction. The results were pooled using fixed-effect models with mean differences (MDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes. RESULTS: After screening the titles and abstracts of 1843 papers, 32 potentially eligible articles were selected. Seventeen articles involving 10 trials were included in this review. These studies presented outcome data for 355 patients. Seven trials were considered to be at a high risk of bias, two at a low risk of bias and one at an unclear risk of bias. Insufficient evidence was found to determine whether there were differences in implant failure rates, marginal bone level changes, aesthetic results or patient satisfaction. For one-stage ridge augmentation (two trials; n = 52), there was evidence of more horizontal bone gain (MD: 0.84 mm, 95% CI: 0.46 to 1.21, P < 0.00001; two trials), defect height reduction (MD: 18.36%, 95% CI: 10.23 to 26.50, P < 0.00001; two trials), and prevention of graft resorption (P = 0.004; one trial) in favour of the membrane-covered group, although substantial heterogeneity was found for horizontal bone gain (Chi2; P = 0.05, I2=74%). There was insufficient evidence to determine whether any differences exist in two-stage ridge augmentation (three trials; n = 81), sinus augmentation (one trial; n = 104) and ridge preservation (one trial; n = 20). For immediate implant placement (three trials; n = 98), there was evidence of an increased defect height reduction in favour of the membrane-covered groups (MD: 6.25%, 95% CI: 1.67 to 10.82, P = 0.007; two trials), although with substantial heterogeneity (Chi2; P = 0.03, I2 = 79%). More complications were observed when a membrane was used (OR: 2.52, 95% CI: 1.07 to 5.93, P = 0.03; three trials). CONCLUSIONS: There is insufficient evidence regarding the effects of membranes on bone augmentation procedures to support any definitive conclusions. Only 10 studies were included; they had limited sample sizes and short follow-up periods, and the majority were at a high risk of bias. However, no difference in implant failure was found, and the possible clinical value is still unknown, as long-term clinical parameters such as marginal bone loss, aesthetic results and patient satisfaction have been insufficiently studied. Conflict-of-interest and source-of-funding statement: The authors declare that they have no possible conflicts of interest. No funding for this review was received. PMID- 27990505 TI - Clinical evaluation of a novel dental implant system as single implants under immediate loading conditions - 4-month post-loading results from a multicentre randomised controlled trial. AB - PURPOSE: To evaluate the safety and clinical effectiveness of a novel dental implant system (GENESIS Implant System, Keystone Dental, Massachusetts, USA) using another dental implant system by the same manufacturer as a control (PRIMA Implant System, Keystone Dental). MATERIALS AND METHODS: A total of 53 patients requiring at least two single crowns had their sites randomised according to a split-mouth design to receive both implant systems at six centres. If implants could be placed with a torque superior to 40 Ncm they were to be loaded immediately with provisional crowns, otherwise after 3 months of submerged healing. Provisional crowns were replaced by definitive crowns 4 months after initial loading, when the follow-up period for the initial part of this study was completed. Outcome measures were crown/implant failures, complications, pink esthetic score (PES), peri-implant marginal bone level changes, plaque score, marginal bleeding, patients and preference of the clinician. RESULTS: In total 53 PRIMA and 53 GENESIS implants were placed. Three patients dropped out but all of the remaining patients were followed up to 4-months post-loading. No PRIMA implant failed whereas four GENESIS implants failed. Only two complications were reported for PRIMA implants. There were no statistically significant differences for crown/implant failures (difference in proportions = 0.080; P (McNemar test) = 0.125) and complications (difference in proportions = -0.04; P (McNemar test) = 0.500) between the implant systems. There were no differences at 4-months post loading for plaque (difference = -0.54, 95% CI: -3.01 to 1.93; P (Paired t-test) = 0.660), marginal bleeding (difference = -3.8, 95% CI: -7.63 to 0.019; P (Paired t-test) = 0.051), PES (difference = 0.47, 95% CI: -0.56 to 1.50; P (Paired t test) = 0.365) and marginal bone level changes (difference in mm = -0.04, 95% CI: -0.33 to 0.26; P (Paired t-test) = 0.795). The majority of the patients (46) had no preference regarding the two implant systems evaluated. Three operators preferred GENESIS implants, two had no preference and one preferred GENESIS in medium and soft bone and PRIMA in hard bone. CONCLUSIONS: No statistically significant differences were observed between the systems' implant types, although four GENESIS implants failed versus none of the PRIMA type. Longer follow-ups of wider patient populations are needed to better understand whether there is an effective advantage with one of the two implant designs. Conflict-of interest statement: This research project was originally funded by Keystone Italia, Dental spa (Verona, Italy), the manufacturer of the implants evaluated in this investigation. ? ?However, when Keystone Italia received the data of the present manuscript, they refused to honour the financial agreement for the present publication. Therefore, no further follow-ups of this trial will be considered. A legal action was initiated against Keystone Italia. The data belonged to the authors and by no means was the manufacturer allowed to interfere with the conduct of the trial or the publication of the results. PMID- 27990506 TI - Platform switching versus regular platform implants: 3-year post-loading results from a randomised controlled trial. AB - PURPOSE: To test the hypothesis that platform switching and regular platform implants would have different outcomes in single-tooth replacement against the alternative hypothesis of no difference. MATERIAL AND METHODS: This study was designed as a randomised controlled split-mouth trial. Eighteen patients with bilaterally missing single premolars or molars to be restored with implant supported single crowns, were consecutively enrolled. Implant sites were randomly assigned to be treated according to the platform switching concept (PS group), or with matching implant-abutment diameters (RP group). A total of 36 Nobel Replace Tapered Groovy implants were installed. All the implants were inserted in healed bone, with an insertion torque between 35 and 45 Ncm, according to a one-stage protocol. Both implant types were loaded with a screw-retained temporary crown 3 months after implant insertion. Definitive screw-retained single crowns were delivered 2 months later. Outcome measures were implant and prosthetic survival rates, biological and prosthetic complications, radiographic marginal bone level (MBL) changes, pocket probing depth (PPD) and bleeding on probing (BOP). Clinical data was collected at implant placement (baseline), and at 3, 9 and 36 months after loading. RESULTS: No patients dropped out and no implant failed. No prosthetic complications were recorded. One patient experienced mucosal inflammation with positive BOP (RP group) after 3 months, three patients had bilateral peri-implant mucosal inflammation with positive BOP at 6, 24 and 30 months after loading, respectively. There were no statistically significant differences between groups for complications (3/18 versus 4/18; P = 1.0; Odds Ratio = 1.333; 95% CI: 0.3467 to 5.1272). Nine months after loading, the mean MBL was 0.93 +/- 0.26 mm in the RP group and 0.84 +/- 0.23 mm in the PS group, with no statistically significant differences between groups (mean difference = 0.09 mm, 95% CI: -0.22 to 0.04, P = 0.18). Three years after loading, mean MBL was 1.09 +/- 0.31 mm in the RP group and 1.06 +/- 0.24 mm in the PS group, with no statistically significant differences between groups (mean difference = 0.02 mm, 95% CI: -0.06 to 0.10, P = 0.70). Marginal bone level changes between 3 years and baseline were 0.72 +/- 0.28 mm in the RP group and 0.71 +/- 0.27 mm in the PS group, with no statistically significant differences between the groups (mean difference = -0.00 mm, 95% CI: -0.07 to 0.07, P = 0.89). Mean PPD was 2.70 +/- 0.52 mm in the RP group and 2.46 +/- 0.69 mm in the PS group at 36 months after loading, with no statistically significant differences between the groups (mean difference = 0.23 mm, 95% CI: -0.05 to 0.35, P = 0.43). Mean BOP was 0.83 +/- 0.96 mm in the RP group and 0.89 +/- 0.99 mm in the PS group at 36 months after loading, with no statistically significant differences between the groups (mean difference = 0.07 mm, 95% CI: -0.03 to 0.17, P = 0.77).? Conclusions: The clinical and radiographic outcomes of implants restored according to the platform switching concept versus implants restored with the matching implant-abutment diameters are comparable, 3 years after loading. Conflict of interest statement: This study was not supported by any company. All authors declare no conflict of interest. PMID- 27990507 TI - Four mm-long versus longer implants in augmented bone in atrophic posterior jaws: 4-month post-loading results from a multicentre randomised controlled trial. AB - PURPOSE: To evaluate whether 4-mm long dental implants could be an alternative to augmentation with equine bone blocks and the placement of at least 10-mm long implants in atrophic posterior jaws. MATERIALS AND METHODS: Forty patients with atrophic posterior (premolar and molar areas) mandibles having 5 to 6 mm bone height above the mandibular canal and 40 patients with atrophic maxillae having 4 to 5 mm below the maxillary sinus, were randomised according to a parallel group design to receive one to three 4.0 mm-long implants or one to three implants, which were at least 10 mm long, in augmented bone at two centres. All implants had a diameter of 4.0 or 4.5 mm. Mandibles were vertically augmented with interpositional equine bone blocks and resorbable barriers. Implants were placed 4 months after interpositional grafting. Maxillary sinuses were augmented with particulated porcine bone via a lateral window covered with resorbable barriers, and implants were placed simultaneously. Implants were not submerged and were loaded after 4 months with provisional prostheses. Four months later, screw retained reinforced acrylic restorations were delivered, and then replaced after 4 months by definitive screw-retained metal-composite prostheses. Patients were followed up to 4-months post-loading. Outcome measures included prosthesis and implant failures, any complication and peri-implant marginal bone level changes. RESULTS: No patient dropped out. In six augmented mandibles (30%), it was not possible to place implants which were at least 10.0-mm long, therefore shorter implants had to be placed instead. In particular, one mandible fractured and the patient did not want to go ahead with the treatment. One implant of the patient with the mandible fracture from the augmented group failed versus two 4.0 mm implants in two patients from the short implant group. In the maxillae, three short implants failed in two patients versus five long implants in three patients (two long implants and one short implant dropped into the maxillary sinus). Two prostheses on short implants (one mandibular and one maxillary) were placed at a later stage because of implant failures versus four prostheses (one mandibular and three maxillary) at augmented sites. In particular, three patients of the augmented group (one mandible and two maxillary) were not prosthetically rehabilitated. There were no statistically significant differences in implant failures (P (chi-square test) = 1.000; difference in proportion = 0; 95% Cl: 0.13 to 0.13 or prostheses failures (P (chi-square test) = 0.399; difference in proportion = 0.05; 95% Cl: -0.06 to 0.16). At mandibular sites, nine augmented patients were affected by complications versus one patient treated with short implants (P (chi-square test) = 0.003; difference in proportion = 0.40; 95% Cl: 0.16 to 0.64), with the difference being statistically significant. No significant differences were found for the maxillae: eight sinus lift patients versus three patients rehabilitated with maxillary short implants were affected by complications (P (chi-square test) = 0.077; difference in proportion = 0.25; 95% Cl: -0.02 to 0.52). Patients with mandibular short implants lost on average 0.40 mm of peri-implant bone at 4 months and patients with 10 mm or longer mandibular implants lost 0.52 mm. Patients with short maxillary implants lost on average 0.48 mm peri-implant bone at 4 months and patients with 10 mm or longer maxillary implants lost 0.50 mm. The difference was statistically significant in the mandibles (mean difference: -0.12 mm, 95% CI: -0.20 to -0.04, P (ANCOVA) = 0.006), but not in the maxillae (mean difference: -0.02 mm, 95% CI: -0.10 to 0.07, P (ANCOVA) = 0.711). CONCLUSIONS: Four months after loading 4.0 mm-long implants achieved similar results, if not better, than longer implants in augmented jaws, but were affected by fewer complications. Short implants might be a preferable choice to bone augmentation, especially in mandibles, since the treatment is less invasive, faster, cheaper, and associated with less morbidity; however, 5- to 10-year post-loading data is necessary before making reliable recommendations. Conflict-of-interest statement: Global-D (Brignais, France) partially supported this trial and donated the implants and prosthetic components; however, data property belonged to the authors and by no means did Global-D interfere with the conduct of the trial or the publication of the results. PMID- 27990508 TI - Quantification of bone quality using different cone beam computed tomography devices: Accuracy assessment for edentulous human mandibles. AB - PURPOSE: To determine the accuracy of the latest cone beam computed tomography (CBCT) machines in comparison to multi-slice computer tomography (MSCT) and micro computed tomography (micro-CT) for objectively assessing trabecular and cortical bone quality prior to implant placement. MATERIALS AND METHODS: Eight edentulous human mandibular bone samples were scanned with seven CBCT scanners (3D Accuitomo 170, i-CAT Next Generation, ProMax 3D Max, Scanora 3D, Cranex 3D, Newtom GiANO and Carestream 9300) and one MSCT system (Somatom Definition Flash) using the clinical exposure protocol with the highest resolution. Micro-CT (SkyScan 1174) images served as a gold standard. A volume of interest (VOI) comprising trabecular and cortical bone only was delineated on the micro-CT. After spatial alignment of all scan types, micro-CT VOIs were overlaid on the CBCT and MSCT images. Segmentation was applied and morphometric parameters were calculated for each scanner. CBCT and MSCT morphometric parameters were compared with micro-CT using mixed-effect models. Intraclass correlation analysis was used to grade the accuracy of each scanner in assessing trabecular and cortical quality in comparison with the gold standard. Bone structure patterns of each scanner were compared with micro-CT in 2D and 3D to facilitate the interpretation of the morphometric analysis. RESULTS: Morphometric analysis showed an overestimation of the cortical and trabecular bone quantity during CBCT and MSCT evaluation compared to the gold standard micro-CT. The trabecular thickness (Tb.Th) was found to be significantly (P < 0.05) different and the smallest overestimation was found for the ProMax 3D Max (180 um), followed by the 3D Accuitomo 170 (200 um), Carestream 9300 (220 um), Newtom GiANO (240 um), Cranex 3D (280 um), Scanora 3D (300 um), high resolution MSCT (310 um), i-CAT Next Generation (430 um) and standard resolution MSCT (510 um). The underestimation of the cortical thickness (Ct.Th) in ProMax 3D Max (-10 um), the overestimation in Newtom GiANO (10 um) and the high resolution MSCT (10 um) were neglible. However, a significant overestimation (P < 0.05) was found for 3D Accuitomo 170 (110 um), Scanora 3D (140 um), standard resolution MSCT (150 um), Carestream 9300 (190 um), Cranex 3D (190 um) and i-CAT Next Generation (230 um). Comparison of the 2D network and 3D surface distance confirmed the overestimation in bone quantity, but only demonstrated a deviant trabecular network for the i-CAT Next Generation and the standard resolution MSCT. Intraclass correlation coefficients (ICCs) showed a significant (P < 0.05) high intra-observer reliability (ICC > 0.70) in morphometric evaluation between micro-CT and commercially available CBCT scanners (3D Accuitomo 170, Newtom GiANO and ProMax 3D Max). The ICC for Tb.Th and Ct.Th were 0.72 and 0.98 (3D Accuitomo 170), 0.71 and 0.96 (Newtom GiANO), and 0.87 and 0.92 (ProMax 3D Max), respectively. CONCLUSIONS: High resolution CBCT offers a clinical alternative to MSCT to objectively determine the bone quality prior to implant placement. However, not all tested CBCT machines have sufficient resolution to accurately depict the trabecular network or cortical bone. Conflict of-interest statement: There is no conflict of interest to declare. FUNDING: Fellowship support came from Research Foundation Flanders (FWO) from the Belgian government, and Coordination for the Improvement of Higher Education Personnel (CAPES) program and Science without borders from the Brazilian government. PMID- 27990509 TI - Removal of dental implants displaced into the maxillary sinus: A case series. AB - PURPOSE: To present a retrospective case series of displaced dental implants in the maxillary sinus. MATERIALS AND METHODS: Patients with unintentional displacement of dental implants in the maxillary sinus over a 5-year period who underwent or were candidates for surgical implant removal were included. The patients' characteristics, medical history, clinical and imaging results, and post-removal outcome were retrospectively assessed. RESULTS: Out of 14 patients, 13 underwent surgical removal. In one case the implant spontaneously exiled into the nose before surgery. The timespan between dental implantation and presentation ranged from 3 months to 9 years. Imaging evaluation showed a displaced implant (100%), oroantral fistula (65%), complete opacification of the maxillary sinus (28%), circumferential opacification (21%), isolated maxillary sinus outflow obstruction (7%) and a sinus which appeared normal (43%). Symptoms and signs included nasal obstruction (36%), purulent secretions (36%), facial pain (21%), tenderness on percussion (21%) and foul smell (14%). Two patients (14%) were asymptomatic. Intraoperative inspection of nine sinuses revealed mucosal changes and purulent secretions in 55% of patients. In all cases the implant had migrated from the maxillary sinus floor towards the natural ostium. Endoscopic removal was carried out successfully in all operated cases. All sinuses eventually healed. CONCLUSIONS: Migration of displaced implants and mucosal changes may occur over a short period, eventually causing secondary sinusitis. We therefore favour surgical removal. Surgery should be as close as possible to displacement in order to minimise mucosal inflammation and to prevent unnecessary manipulation during surgical removal. Conflict of interest statement: None of the authors report any financial interests or potential conflict of interests. PMID- 27990511 TI - Research in focus. AB - This section presents a brief review of articles on dental implants considered to be of special interest to the reader in order to encourage the development of research, the interest in data analysis, and the attention to scientific publications. Your comments are welcome. Please contact Dr Michele Nieri at: michelenieri@gmail.com. PMID- 27990510 TI - Mandibular osteomyelitis associated with dental implants. A case series. AB - PURPOSE: To present a series of rare and serious complications associated with endosseous implant therapy. MATERIALS AND METHODS: Five cases of mandibular osteomyelitis emerging in dental implant insertion sites are presented. In three cases, the clinical signs and symptoms of osteomyelitis occurred almost immediately following implant insertion. All cases occurred in patients with stable pre-existing medical conditions. Three of the patients were females and two were males, all of whom were in their sixth and seventh decades of life. RESULTS: Clinical symptoms such as pain and local infection were observed in all cases, despite long-term antibiotic treatment. All cases underwent progressive surgical treatment including corticotomy, saucerization, sequestrectomy and drainage. Two cases exhibited spreading of bone infection in the mandible which required segmental mandibulectomy and fixation using reconstruction plates. The symptom-free state was only achieved following surgical intervention and antibiotic treatment in four patients. A minimal follow-up of 1 year revealed complete resolution of the infection and symptoms in four out of five patients. The outcome of the fifth patient is unknown. CONCLUSIONS: Osteomyelitis related to dental implants is a rare and serious complication. Prolonged antibiotics at high dosage together with aggressive surgical treatment is required. Increasing the awareness among dental surgeons and maintaining correct surgical principles are essential in order to reduce the risk of osteomyelitis. Conflict of interest statement: We have no conflict of interests to report. PMID- 27990512 TI - Warfarin genotyping with hybridization-induced aggregation on a poly(ethylene terephthalate) microdevice. AB - Warfarin, a commonly prescribed oral anticoagulant, is burdened by a narrow therapeutic index and high inter-individual variability in response, making it the second leading cause of drug-related emergency room visits. Since genetic factors contribute significantly to warfarin sensitivity, a genotype-guided dosing strategy may reduce the occurrence of adverse events. While numerous methods have been demonstrated for warfarin genotyping, the specifications of most assays with respect to turnaround time and cost are not ideal for routine testing. Here, we present a unique method for warfarin genotyping based on multiplex PCR coupled with Hybridization-induced Aggregation (HIA), a bead-based technique for sequence-specific detection. A multiplex allele-specific PCR reaction was used to generate products corresponding to 3 genetic variants associated with warfarin sensitivity [CYP2C9 *2, CYP2C9 *3, and VKORC1 (1173C>T)] and an internal control product. The products were detected simultaneously on a poly(ethylene terephthalate) (PeT) microdevice using HIA, which provided genotyping results in approximately 15 minutes following PCR. The genotyping results of 23 patient DNA samples using this approach were in 100% concordance with the results of a validated test (WARFGENO test, ARUP laboratories). Additionally, the PCR reaction was successfully transferred to a PeT chip, which provided accurate genotyping results from patient DNA samples in under an hour. This work demonstrates a simple, rapid, and affordable approach to warfarin genotyping based on multiplex allele-specific PCR coupled with HIA detection. By demonstrating both chemistries on PeT microdevices, we show the potential for integration on a single device for sample-to-answer genotyping. PMID- 27990513 TI - Lowering water oxidation overpotentials using the ionisable imidazole of copper(2 (2'-pyridyl)imidazole). AB - Rapid and low overpotential oxidation of water to dioxygen remains a key hurdle for storage of solar energy. Here, we address this issue by demonstrating that deprotonation of 2-(2'-pyridyl)-imidazole (pimH)-ligated copper complexes promotes water oxidation at low overpotential and low catalyst loading. This improves upon other work on homogeneous copper-based water oxidation catalysts, which are highly active, but limited by high overpotentials. EPR and UV-vis spectroscopic evaluation of catalyst speciation shows that at pH >= 12 coordinated pimH is deprotonated and a bis(hydroxide) Cu2+ active catalyst forms. Rapid electrochemical water oxidation (35 s-1, 0.85 V onset potential) was observed with 150 MUM catalyst. These results demonstrate that catalytic water oxidation potentials can be shifted by hundreds of mV in homogeneous metal catalysts bearing an ionisable imidazole ligand. PMID- 27990514 TI - Mixed-linker UiO-66: structure-property relationships revealed by a combination of high-resolution powder X-ray diffraction and density functional theory calculations. AB - The use of mixed-linker metal-organic frameworks (MIXMOFs) is one of the most effective strategies to modulate the physical-chemical properties of MOFs without affecting the overall crystal structure. In many instances, MIXMOFs have been recognized as solid solutions, with random distribution of ligands, in agreement with the empirical rule known as Vegard's law. In this work, we have undertaken a study combining high-resolution powder X-ray diffraction (HR-PXRD) and density functional theory (DFT) calculations with the aim of understanding the reasons why UiO-66-based amino- and bromo-functionalized MIXMOFs (MIXUiO-66) undergo cell expansion obeying Vegard's law and how this behaviour is related to their physical-chemical properties. DFT calculations predict that the unit cell in amino-functionalized UiO-66 experiences only minor expansion as a result of steric effects, whereas major modification to the electronic features of the framework leads to weaker metal-linker interaction and consequently to the loss of stability at higher degrees of functionalization. For bromo-functionalized UiO 66, steric repulsion due to the size of bromine yields a large cell expansion, but the electronic features remain very similar to pristine UiO-66, preserving the stability of the framework upon functionalization. MIXUiO-66 obtained by either direct synthesis or by post-synthetic exchange shows Vegard-like behaviour, suggesting that both preparation methods yield solid solutions, but the thermal stability and the textural properties of the post-synthetic exchanged materials do not display a clear dependence on the chemical composition, as observed for the MOFs obtained by direct synthesis. PMID- 27990515 TI - Cationic gemini surfactant as a dual linker for a cholic acid-modified polysaccharide in aqueous solution: thermodynamics of interaction and phase behavior. AB - Understanding the thermodynamics of formation of biocompatible aggregates is a key factor in the bottom up approach to the development of novel types of drug carriers and their structural tuning using small amphiphilic molecules. We chose an anionic amphiphilic and biocompatible polymer that consists of a dextran and grafted cholic acid pendants, randomly distributed along the dextran backbone, with a degree of substitution (DS) of 15 mol% (designated Dex-15CACOONa). The thermodynamics of interaction and phase behavior of mixtures of this polyelectrolyte and a cationic gemini surfactant hexanediyl-alpha,omega bis(dodecyldimethylammonium bromide) (C12C6C12Br2) or its monomer surfactant dodecyltrimethylammonium bromide (DTAB) in aqueous solution were characterized by isothermal titration calorimetry (ITC) and turbidity, together with cryogenic transmission electron microscopy (Cryo-TEM). The various critical concentrations and the enthalpy changes of the corresponding phase transitions for the oppositely charged system were obtained from the plots of the observed enthalpy change (DeltaHobs) and turbidity measurements as a function of gemini concentration. The morphologies of the aggregates in various phases were observed by Cryo-TEM. Altogether these results suggest the critical role of gemini as a dual linker. At the concentrations where the crosslink between the pendant aggregates happens, the free gemini concentration is proximately zero and the aggregate retains its negative charge. The analysis of various factors involved in the interaction allowed a rationalization of the driving forces for mixed aggregate formation, which will contribute to a subsequent rational design of drug delivery systems based on this polymer/surfactant system. PMID- 27990516 TI - Surface chemistry and density distribution influence on visible luminescence of silicon quantum dots: an experimental and theoretical approach. AB - The impact of the surface reconstruction of the density distribution and photoluminescence of silicon quantum dots (QDs) embedded in a silicon oxide matrix (SiOx) has been studied. Annealing treatments carried out on the as deposited samples provoked the effusion of hydrogen species. Moreover, depending on the surrounding density and coalescence of QDs, they resulted in a change in the average size of the particles depending on the initial local environment. The shift in the luminescence spectra all over the visible region (blue, green and red) shows a strong dependence on the resultant change in the size and/or the passivation environment of QDs. Density functional theoretical (DFT) calculations support this fact and explain the possible electronic transitions (HOMO-LUMO gap) involved. Passivation in the presence of oxygen species lowers the band gap of Si29 and Si35 nanoclusters up to 1.7 eV, whereas, surface passivation in the environment of hydrogen species increases the band gap up to 4.4 eV. These results show a good agreement with the quantum confinement model described in this work and explain the shift in the luminescence all over the visible region. The results reported here offer vital insight into the mechanism of emission from silicon quantum dots which has been one of the most debated topics in the last two decades. QDs with multiple size distribution in different local environments (band gap) observed in this work could be used for the fabrication of light emission diodes (LEDs) or shift-conversion thin films in third generation efficient tandem solar cells for the maximum absorption of the solar spectrum in different wavelength regions. PMID- 27990517 TI - Copper-promoted methylene C-H oxidation to a ketone derivative by O2. AB - The methylene group of the ligand 1,2-di(pyridin-2-yl)-ethanone oxime (dpeo) is slowly oxygenated by the O2 in air under ambient conditions when [Cu(dpeo)2](ClO4)2 is dissolved in ethanol or acetonitrile. An initial transient ketone product, 2-(hydroxyimino)-1,2-di(pyridine-2-yl)ethanone, (hidpe) was characterized in the heteroleptic copper(ii) complex [Cu(bpca)(hidpe)](ClO4). The co-ligand in this complex, N-(2'-pyridylcarbonyl)pyridine-2-carboximidate (bpca ), is derived from a copper-promoted Beckmann rearrangement of hidpe. In the presence of bromide only [Cu(bpca)Br] is isolated. When significant water is present in reaction mixtures copper complexes of dpeo, hidpe and bpca- are not recovered and [Cu(pic)2H2O] is isolated. This occurs since two equivalents of picolinate are ultimately generated from one equivalent of oxidized and hydrolysed dpeo. The copper-dependent O2 activation and consequent stoichiometric dpeo C-H oxidation is reminiscent of the previously observed catalysis of dpeo oxidation by Mn(ii) [C. Deville, S. K. Padamati, J. Sundberg, V. McKee, W. R. Browne, C. J. McKenzie, Angew. Chem., Int. Ed., 2016, 55, 545-549]. By contrast dpeo oxidation is not observed during complexation reactions with other late transition metal(ii) ions (M = Fe, Co, Ni, Zn) under aerobic conditions. In these cases bis and tris complexes of bidentate dpeo are isolated in good yields. It is interesting to note that dpeo is not oxidised by H2O2 in the absence of Cu or Mn, suggesting that metal-based oxidants capable of C-H activation are produced from the dpeo-Cu/Mn systems and specifically O2. The metastable copper complexes [Cu(dpeo)2](ClO4)2 and [Cu(bpca)(hidpe)](ClO4), along with [NiX2(dpeo)2] (X = Cl, Br), [Ni(dpeo)3](ClO4)2, [Co(dpeo)3](ClO4)3 and the mixed valence complex [FeIIIFe(dpeo-H)3(dpeo)3](PF6)4, have been structurally characterized. PMID- 27990518 TI - Adsorption/desorption process of formaldehyde onto iron doped graphene: a theoretical exploration from density functional theory calculations. AB - The interaction of formaldehyde (H2CO) onto Fe-doped graphene (FeG) was studied in detail from density functional theory calculations and electronic structure analyses. Our aim was to obtain insights into the adsorption, desorption and sensing properties of FeG towards H2CO, a hazardous organic compound. The adsorption of H2CO was shown to be energetically stable onto FeG, with adsorption energies of up to 1.45 eV and favored in different conformations. This interaction was determined to be mostly electrostatic in nature, where the oxygen plays an important role in this contribution; besides, our quantum molecular dynamics results showed the high stability of the FeG-H2CO interaction at ambient temperature (300 K). All the interactions were determined to be accompanied by an increase in the HOMO-LUMO energy gap with respect to the isolated adsorbent, indicating that FeG is highly sensitive to H2CO with respect to pristine graphene. Finally, it was found that external electric fields of 0.04-0.05 a.u. were able to induce the pollutant desorption from the adsorbent, allowing the adsorbent reactivation for repetitive applications. These results indicate that FeG could be a promising candidate for adsorption/sensing platforms of H2CO. PMID- 27990519 TI - Roles of the methyl and methylene groups of mercapto acids in the photoluminescence efficiency and carrier trapping dynamics of CdTe QDs. AB - Surface protection using an appropriate ligand is essential for controlling the size, stability and luminescence properties of the quantum dots (QDs). Though 3 mercaptopropanoic acid (3-MPA) is regarded as the most suitable protecting ligand among the mercapto acids for water soluble CdTe QDs, one receives a different picture from recent studies, which report a much higher luminescence efficiency of 3-mercaptobutyric acid (3-MBA) capped QDs compared with those capped by 3-MPA and attribute the observation to the influence of the side methyl group of mercapto acids. Herein we report the luminescence properties and carrier trapping dynamics of four different, but structurally related mercapto acid capped CdTe QDs prepared using a different method. The results show that these QDs are much more fluorescent than those prepared directly in an aqueous environment and surprisingly, no enhanced luminescence for the QDs capped by mercapto acids containing a side methyl group is observed. Ultrafast pump-probe measurements confirm these results in addition to providing insight into the carrier trapping dynamics of these systems. It is shown that our findings, which appear to be in conflict with the recent literature, can be rationalized and the exact role of the side methyl group of the mercapto acids can be understood by careful analysis of the results taking into consideration the difference in the methods of preparation of the QDs in the two cases. PMID- 27990520 TI - Slow magnetic relaxation in a dimeric Mn2Ca2 complex enabled by the large Mn(iii) rhombicity. AB - In this paper we present the characterization of a complex with the formula [Mn2Ca2(hmp)6(H2O)4(CH3CN)2](ClO4)4 (1), where hmp-H = 2-(hydroxymethyl)pyridine. Compound 1 crystallizes in the monoclinic space group C2/c with the cation lying on an inversion centre. Static magnetic susceptibility, magnetization and heat capacity measurements reflect a unique Mn(iii) valence state, and single-ion ligand field parameters with remarkable large rhombic distortion (D/kB = -6.4 K, E/kB = -2.1 K), in good agreement with the high-field electron paramagnetic resonance experiments. At low temperature Mn2Ca2 cluster behaves as a system of ferromagnetically coupled (J/kB = 1.1 K) Mn dimers with a ST = 4 and mT = +/-4 ground state doublet. Frequency dependent ac susceptibility measurements reveal the slow magnetic relaxation characteristic of a single molecule magnet (SMM) below T = 4 K. At zero magnetic field, an Orbach-type spin relaxation process (tau ~ 10-5 s) with an activation energy Ea = 5.6 K is observed, enabled by the large E/D rhombicity of the Mn(iii) ions. Upon the application of a magnetic field, a second, very slow process (tau ~ 0.2 s) is observed, attributed to a direct relaxation mechanism with enhanced relaxation time owing to the phonon bottleneck effect. PMID- 27990522 TI - Homoleptic organolanthanide compounds supported by the bis(dimethylsilyl)benzyl ligand. AB - A beta-SiH functionalized benzyl anion [C(SiHMe2)2Ph]- is obtained by deprotonation of HC(SiHMe2)2Ph with KCH2Ph or by reaction of KOtBu and (Me2HSi)3CPh; LnI3(THF)n and three equivalents of this carbanion combine to provide homoleptic tris(alkyl)lanthanide compounds Ln{C(SiHMe2)2Ph}3 (Ln = La, Ce, Pr, Nd) containing secondary metal-ligand interactions. PMID- 27990521 TI - QCT dynamics study of OH/OD + GeH4 reactions. The problem of water bending excitation. AB - Using a full-dimensional analytical potential energy surface describing the OH/OD + GeH4 hydrogen abstraction reactions (J. Espinosa-Garcia, C. Rangel and J. C. Corchado, Phys. Chem. Chem. Phys., 2016, 18, 16941), quasi-classical trajectory calculations were performed at 298 K to simulate the scarce experimental data at this temperature. This system presents wells in the entrance and exit channels, influencing product angular distribution, which is practically isotropic. Moreover, isotopic effects were not observed. It was found that the GeH3 co product presents little internal energy (11% of the total available energy), although not negligible, and that the water product receives the major part of the available energy, mainly in the newly formed OH bond, while the initial OH/OD reactant bond acts as a spectator mode. These results reproduce the experimental evidence, the larger discrepancy being in the water bending vibrational distribution, which is broader in the experiment. Several factors were analyzed to account for this discrepancy, and it was concluded that the zero-point energy violation per mode is the main, but not the only, cause. PMID- 27990523 TI - Teichoic acids: synthesis and applications. AB - This review describes the developments in the synthesis of teichoic acids (TA) - glycosylated poly(alditolphosphates) - and the application of these fragments in immunological studies. These structurally diverse biopolymers are omnipresent constituents of the Gram-positive bacterial cell wall where they fulfill a variety of vital functions. They have been and continue to be attractive synthetic targets because of their challenging structures and the fact that their microheterogeneity precludes their isolation in single and pure enough form from natural sources. Progress in glycosylation chemistry and the development of effective phosphorylation chemistry has driven TA synthesis over the years, and highly complex and large TA structures can now reliably be targeted. Starting from the first TA synthesis in 1981, this review highlights the progress made in the field over the years. The synthesized TA fragments have been used to unravel their role in immunology and it is described how focused libraries of TAs have been used to discover the active principles of the TA polymers that interact with the innate immune system. Recently, synthetic TA fragments have also found applications as well-defined synthetic antigens for the generation of novel vaccine modalities to combat Gram-positive bacterial infections. It is foreseen that synthetic TA fragments will be valuable tools in the future to unravel the mode of action of these biomolecules at the molecular level. They will be instrumental in discovering and characterizing their designated biological binding partners, be it pattern recognition receptors or carbohydrate binding lectins or biomachinery enzymes. This review thus serves to showcase the potential of organic synthesis for (chemical) biology and immunology. PMID- 27990525 TI - Insights into the electrochemical performances of Bi anodes for Mg ion batteries using 25Mg solid state NMR spectroscopy. AB - Bi nanowires as anode materials for Mg ion batteries exhibit excellent electrochemical behaviour, forming Mg3Bi2; this is in part ascribed to the rapid Mg mobility between the two Mg sites of Mg3Bi2, as revealed by the 25Mg NMR spectra of Mg3Bi2 formed electrochemically and via ball-milling. A mechanism involving hops into vacant Mg sites is proposed. PMID- 27990524 TI - Gold(i)-catalyzed 6-endo-dig azide-yne cyclization: efficient access to 2H-1,3 oxazines. AB - Denitrogenative 6-endo-dig azide-yne cyclization of alpha-propargyloxy-beta haloalkylazides was enabled by gold catalysis, thus providing 2H-1,3-oxazines. This rare cyclization mode in gold-catalyzed reactions of azide-yne substrates was demonstrated to be facilitated and controlled by electronic and resonance effects of the alkyne substituents. Molecular transformations of the as-prepared 2H-1,3-oxazines were also investigated. PMID- 27990527 TI - Acetylene adsorption on delta-MoC(001), TiC(001) and ZrC(001) surfaces: a comprehensive periodic DFT study. AB - A comprehensive study of acetylene adsorption on delta-MoC(001), TiC(001) and ZrC(001) surfaces was carried out by means of calculations based on periodic density functional theory, using the Perdew-Burke-Ernzerhof exchange-correlation functional. It was found that the bonding of acetylene was significantly affected by the electronic and structural properties of the carbide surfaces. The adsorbate interacted with metal and/or carbon sites of the carbide. The interaction of acetylene with the TiC(001) and ZrC(001) surfaces was strong (binding energies higher than -3.5 eV), while moderate acetylene adsorption energies were observed on delta-MoC(001) (-1.78 eV to -0.66 eV). Adsorption energies, charge density difference plots and Mulliken charges suggested that the binding of the hydrocarbon to the surface had both ionic and covalent contributions. According to the C-C bond lengths obtained, the adsorbed molecule was modified from acetylene-like into ethylene-like on the delta-MoC(001) surface (desired behavior for hydrogenation reactions) but into ethane-like on TiC(001) and ZrC(001). The obtained results suggest that the delta-MoC(001) surface is expected to have the best performance in selective hydrogenation reactions to convert alkynes into alkenes. Another advantage of delta-MoC(001) is that, after C2H2 adsorption, surface carbon sites remain available, which are necessary for H2 dissociation. However, these sites were occupied when C2H2 was adsorbed on TiC(001) and ZrC(001), limiting their application in the hydrogenation of alkynes. PMID- 27990528 TI - An efficient parts-per-million alpha-Fe2O3 nanocluster/graphene oxide catalyst for Suzuki-Miyaura coupling reactions and 4-nitrophenol reduction in aqueous solution. AB - A new alpha-Fe2O3 nanocluster/graphene oxide catalyst is found to be efficient in parts-per-million for Suzuki-Miyaura coupling and 4-nitrophenol reduction in aqueous solution, and this catalyst is recycled at least 4 times in good yields. PMID- 27990532 TI - Porous nanopeapod Pd catalyst with excellent stability and efficiency. AB - Porous Pd@m-C/SiO2 nanopeapods are prepared by a nanoconfinement method. The Pd nanoparticles show high efficiency and stability in chemical reactions such as reduction of nitrobenzene by H2 and reduction of NO by NH3. The high catalytic activity is attributed to the unique peapod structure, mesoporous wall, and large specific surface area on Pd@m-C/SiO2 rendering the Pd nanoparticles highly active in chemical reactions. PMID- 27990530 TI - Strongly enhanced Raman scattering of Cu-phthalocyanine sandwiched between graphene and Au(111). AB - Graphene and flat gold have both been argued to enhance Raman scattering of molecular adsorbates through a chemical mechanism. Here we show that these two effects can add to each other. For Cu-phthalocyanine in between graphene and Au(111) on mica a Raman enhancement up to 68-fold has been observed. PMID- 27990533 TI - A new way to do an old reaction: highly efficient reduction of organic azides by sodium iodide in the presence of acidic ion exchange resin. AB - Organic azides are readily reduced to the corresponding amines by treatment with sodium iodide in the presence of acidic ion exchange resin. The process, optimal when performed at 40 degrees C and 200 mbar pressure on a rotatory evaporator, is extremely efficient, clean, and tolerant of a variety of functional groups. PMID- 27990534 TI - Noninvasive photothermal cancer therapy nanoplatforms via integrating nanomaterials and functional polymers. AB - In the cutting-edge field of cancer therapy, noninvasive photothermal therapy (PTT) has received great attention because it is considered to overcome the drawbacks of conventional surgery, radiotherapy and chemotherapy of severe body injuries and side effects on the immune system. The construction of PTT therapeutic and theranostic nanoplatforms is the key issue in achieving tumor targeting, imaging and therapy in a synergetic manner. In this review, we focus on the recent advances in constructing PTT therapeutic and theranostic nanoplatforms by integrating nanomaterials and functional polymers. The noninvasive photothermal cancer therapy mechanism and achievement strategies of PTT therapeutic and theranostic nanoplatforms are presented as well as the innovative construction strategies and perspectives for the future. Owing to their high tumor ablation efficiency, biological availability and low- or non toxicity, PTT therapeutic and theranostic nanoplatforms are promising and emerging in medicine and clinical applications. PMID- 27990535 TI - Switchable long-range double layer force observed in a protic ionic liquid. AB - A repulsive double layer force has been measured for ethylammonium nitrate (EAN) at 373 K and 393 K, which is absent at lower temperatures. This temperature tuneable change in behaviour is the opposite of recent observations which challenge traditional views of ionicity. This finding thus widens the debate about the very nature of ionic liquids. PMID- 27990536 TI - Facile synthesis of cyanofurans via Michael-addition/cyclization of ene-yne ketones with trimethylsilyl cyanide. AB - We have developed a Michael-addition/cyclization procedure between ene-yne ketones and TMSCN under metal-free conditions. A wide range of cyanofurans was delivered in high yields, which could be further transformed to a series of furo furanimines, furo-pyridazines or carboxamido-furans. In addition, deuterium labeling experiments have been conducted to clarify the reaction pathway. PMID- 27990538 TI - Online sensing of palladium in flowing streams. AB - Rapid palladium (Pd) catalyzed deallylation of an uncoloured reagent within a flowing stream affords a dose dependent colour formation that can be used for convenient online analysis of trace levels of Pd contamination using a modified HPLC instrument. An application to the online sensing of Pd breakthrough from a flow through Pd adsorption cartridge is described. An alternative configuration of the instrumentation allows the rapid (<1 min) and accurate measurement of Pd levels within samples injected via a conventional HPLC autosampler. PMID- 27990537 TI - Engineering the surface chemistry of lead chalcogenide nanocrystal solids to enhance carrier mobility and lifetime in optoelectronic devices. AB - We introduce a stepwise, hybrid ligand-exchange method for lead chalcogenide nanocrystal (NC) thin films using the compact-inorganic ligand thiocyanate and the short organic ligand benzenediothiolate. Spectroscopic and device measurements show that hybrid exchange enhances both carrier mobility and lifetime in NC thin films. The increased mobility-lifetime product achieved by this method enables demonstration of optoelectronic devices with enhanced power conversion and quantum efficiency. PMID- 27990539 TI - Reversible formylborane/SO2 coupling at a frustrated Lewis pair framework. AB - Carbon monoxide is reduced by HB(C6F5)2 at the Mes2PCH2CH2B(C6F5)2 P/B FLP template to give the respective FLP stabilized (eta2-formyl)borane product 2. This adds sulfur dioxide by insertion of a SO bond into the three-membered ring to give the P/B FLP coordinated SO2 adduct 9. PMID- 27990540 TI - Plasma free reversible and irreversible microfluidic bonding. AB - We demonstrate a facile, plasma free process to fabricate both reversibly and irreversibly sealed microfluidic chips using a PDMS-based adhesive polymer mixture. This is a versatile method that is compatible with current PDMS microfluidics processes. It allows for easier fabrication of multilayer microfluidic devices and is compatible with micropatterning of proteins for cell culturing. When combined with our Shrinky-Dink microfluidic prototyping, complete microfluidic device fabrication can be performed without the need for any capital equipment, making microfluidics accessible to the classroom. PMID- 27990543 TI - The Castanea sativa bur as a new potential ingredient for nutraceutical and cosmetic outcomes: preliminary studies. AB - Chestnuts are a common food product in Mediterranean countries, being recognized also for their beneficial effects on human health. Nevertheless, during processing, these fruits generate a large amount of food by-products, such as shells and burs. In the present work, the macronutrient composition, vitamin E profile and amino acid content of the burs were determined in samples from three different Portuguese regions (Minho, Tras-os-Montes and Beira-Alta). The nutritional composition was similar for all samples, being characterised by a high moisture content and low fat amounts. All essential amino acids were present in considerable amounts. Concerning vitamin E, the predominant vitamer was alpha tocopherol for the Minho and Beira-Alta samples. The total phenolic compounds were quantified, and the antioxidant activity evaluated in different extracts using two biochemical assays (DPPH and FRAP). All bur extracts showed a high total phenolic content, the highest obtained being that for the Beira-Alta samples. The chestnut bur from Minho showed the highest antioxidant activity in both assays. This study aims to demonstrate the potential of the Castanea sativa bur as a cosmetic and nutraceutical ingredient. PMID- 27990544 TI - Anomalous dispersion X-ray diffraction study of Pb/Bi ordering/disordering states in PbTiO3-based perovskite oxides. AB - Synchrotron radiation-based anomalous dispersion X-ray powder diffraction (ADSPD) was carried out to reveal the Pb/Bi ordering/disordering states in a series of PbTiO3-based negative thermal expansion materials (1 - x)PbTiO3 - xBiFeO3 (x = 0.1, 0.3, 0.5) and (1 - x)PbTiO3 - xBi(Zn1/2Ti1/2)O3 (x = 0.1, 0.2, 0.3). It gives strong evidence of the disordered Pb/Bi distributions in these compositions, which is consistent with electron diffraction studies. Combined with binding energy calculation, we show that the disordered nature of Pb/Bi distributions is likely to be attributed to the similar electron configurations of Pb2+ and Bi3+ as well as their comparable coordinate environments in perovskite structures. The results of this study may be helpful to better understand the structure-property relationship in Pb/Bi-containing perovskites and are useful for further developing underlying physics in relevant materials. PMID- 27990542 TI - 3D-templated, fully automated microfluidic input/output multiplexer for endocrine tissue culture and secretion sampling. AB - A fully automated, 16-channel microfluidic input/output multiplexer (MUMUX) has been developed for interfacing to primary cells and to improve understanding of the dynamics of endocrine tissue function. The device utilizes pressure driven push-up valves for precise manipulation of nutrient input and hormone output dynamics, allowing time resolved interrogation of the cells. The ability to alternate any of the 16 channels from input to output, and vice versa, provides for high experimental flexibility without the need to alter microchannel designs. 3D-printed interface templates were custom designed to sculpt the above-channel polydimethylsiloxane (PDMS) in microdevices, creating millimeter scale reservoirs and confinement chambers to interface primary murine islets and adipose tissue explants to the MUMUX sampling channels. This MUMUX device and control system was first programmed for dynamic studies of pancreatic islet function to collect ~90 minute insulin secretion profiles from groups of ~10 islets. The automated system was also operated in temporal stimulation and cell imaging mode. Adipose tissue explants were exposed to a temporal mimic of post-prandial insulin and glucose levels, while simultaneous switching between labeled and unlabeled free fatty acid permitted fluorescent imaging of fatty acid uptake dynamics in real time over a ~2.5 hour period. Application with varying stimulation and sampling modes on multiple murine tissue types highlights the inherent flexibility of this novel, 3D-templated MUMUX device. The tissue culture reservoirs and MUMUX control components presented herein should be adaptable as individual modules in other microfluidic systems, such as organ-on-a-chip devices, and should be translatable to different tissues such as liver, heart, skeletal muscle, and others. PMID- 27990545 TI - Unsymmetrical NCN-pincer mononuclear and dinuclear nickel(ii) complexes of N heterocyclic carbene (NHC): synthesis, structure and catalysis for Suzuki-Miyaura cross-coupling. AB - This report describes the synthesis and characterization of a family of unsymmetrical NCN pincer Ni(ii) complexes 2-8 with NHC-triazole arms. All of these complexes have been fully characterized by X-ray single crystal analysis, NMR spectroscopy, and elemental analysis. Complexes 2 and 4-6 were square planar with a chloride trans to the carbene carbon atoms. Complex 3 was a paramagnetic octahedral complex with its central metal surrounded by two NCN pincer ligands. Complexes 7 and 8 contain [(NHC)2Ni2-OH] moieties bearing a OH bridge. Both the [(NHC)2Ni2-OH] complexes 7 and 8 and [(NCNHCN)Ni-Cl] complexes 2 and 4-6 were synthesized similarly via the reactions of the in situ formed Ag-NHCs from the corresponding imidazolium salts with [NiCl2(PPh3)2]. The catalytic activities of all complexes for Suzuki-Miyaura cross-coupling were examined. Under the optimized conditions, complex 4 was active in the Suzuki-Miyaura cross-coupling reactions of aryl iodides and aryl bromides at 110 degrees C. Aryl chlorides were successfully coupled in the presence of triphenylphosphine as an additive. PMID- 27990546 TI - Protonation of aqueous alanine by photoionization of water. AB - Hydronium ions produced by photolysis of water are used to study the protonation dynamics of alanine zwitterions in water. The measurements are done by UV-VIS and UV-IR femtosecond transient absorption spectroscopy on alanine in H2O and D2O. It is estimated that the reaction rate constant for the deuteration of alanine zwitterions is 4 * 1010 M-1 s-1, while the reverse process has a rate constant of 2 * 108 s-1. In addition to hydronium ions the photolysis of water yields hydrogen atoms and hydrated electrons together with hydroxyl radicals and hydroxyl ions. However, no other products resulting from reactions between aqueous alanine and the photolysis products of water are positively identified during the first 530 ps after the photolysis. Potential secondary reactions that are not observed experimentally are discussed and an upper limit is set for their yield where possible. PMID- 27990547 TI - Copper(i)-catalysed transfer hydrogenations with ammonia borane. AB - Highly Z-selective alkyne transfer semihydrogenations and conjugate transfer hydrogenations of enoates can be effected by employing a readily available and air-stable copper(i)/N-heterocyclic carbene (NHC) complex, [IPrCuOH]. As an easy to handle and potentially recyclable H2 source, ammonia borane (H3NBH3) is used. PMID- 27990548 TI - Simulation of selective thermodynamic deposition in nanoholes. AB - The deposition of particles in nanoholes is analyzed, taking into account the curvature of their inner walls. Different lattice-gas models of the nanoholes are considered. The heterogeneous surface are shaped from a (100)-surface where a nanohollow are incorporated with parallelepiped or polyhedral geometry. Several deposition stages are identified as a function of the degree of curvature of the inner walls of the nanoholes. The Monte Carlo technique in the grand canonical ensemble is used to calculate isotherms, isosteric heats, energies per site and other thermodynamic properties. This study is based on different magnitudes of the interaction energies between the particles being deposited and those surrounding the nanohole. PMID- 27990549 TI - Improving thermoelectric performance of TiNiSn by mixing MnNiSb in the half Heusler structure. AB - The thermoelectric properties of the n-type semiconductor TiNiSn were optimized by partial substitution with metallic MnNiSb in the half Heusler structure. Herein, we study the transport properties and intrinsic phase separation in the Ti1-xMnxNiSn1-xSbx system. The alloys were prepared by arc-melting and annealed at temperatures obtained from differential thermal analysis and differential scanning calorimetry results. The phases were characterized using powder X-ray diffraction patterns, energy-dispersive X-ray spectroscopy, and differential scanning calorimetry. After annealing, the majority phase was TiNiSn with some Ni rich sites, and the minority phases were primarily Ti6Sn5, Sn and MnSn2. The Ni rich sites were caused by Frenkel defects; this led to metal-like behavior in the semiconductor specimens at low temperature. For x <= 0.05 the samples showed an activated conduction, whereas for x > 0.05 they showed metallic character. The figure of merit for x = 0.05 was increased by 61% (zT = 0.45) in comparison with the pure TiNiSn. PMID- 27990550 TI - Guest-induced SC-SC transformation within the first K/Cd heterodimetallic triazole complex: a luminescent sensor for high-explosives and cyano molecules. AB - The first K/Cd heterodimetallic complex {[Cd1.5(TTPE)1.5Cl3K(H2O)3].3H2O}n (1b) based on triazole has been generated from {[Cd(TTPE)(HCOO)](NO3).3DMAC.H2O}n (1) during the ion- and solvent-exchange experiment in an irreversible SC-SC transformation. Based on its luminescence properties, we have, for the first time, demonstrated that 1b is a heterodimetallic sensor for detection of high explosives and cyano molecules. PMID- 27990551 TI - Solvent effects on the triplet-triplet annihilation upconversion of diiodo-Bodipy and perylene. AB - Solvent effects play a very important role in photochemical reactions and energy transfer processes in solution; however, these effects are rarely mentioned in the triplet-triplet annihilation (TTA) upconversion fluorescence experiments. In a typical TTA upconversion system of a photosensitizer of diiodo-Bodipy (I2 Bodipy) and a triplet acceptor of perylene, five common inert solvents, hexane, heptane, toluene, 1,4-dioxane, and dimethyl sulfoxide (DMSO), were used to investigate the solvent effects on the overall quantum yield of upconversion fluorescence. Femtosecond and nanosecond time-resolved transient difference absorption spectra were obtained to study the efficiencies of intersystem crossing (ISC) and triplet-triplet energy transfer (TTET). From the obtained upconversion fluorescence emission spectra, the overall TTA upconversion fluorescence quantum yield was derived. Among the five solvents, the upconversion quantum yield in dioxane is the highest at 19.16%, more than twice that that in toluene (8.75%). For the solvents hexane, heptane, toluene, and dioxane, the yields generally follow the sequences of polarity and viscosity. However, a very low upconversion quantum yield (1.51%) was observed in DMSO although the TTET process and fluorescence quantum yield of perylene in DMSO were almost as efficient as in dioxane. Based on density functional theory calculations, a reasonable explanation for these solvent effects was proposed. PMID- 27990552 TI - Supramolecular assembly of a thermoresponsive steroidal surfactant with an oppositely charged thermoresponsive block copolymer. AB - Supramolecular rearrangements are crucial in determining the response of stimuli sensitive soft matter systems such as those formed by mixtures of oppositely charged amphiphiles. Here mixtures of this kind were prepared by mixing the cationic block copolymer pAMPTMA30-b-pNIPAAM120 and an anionic surfactant obtained by the modification of the bile salt sodium cholate. As pure components, the two compounds presented a thermoresponsive self-assembly at around 30-35 degrees C; a micelle formation in the case of the copolymer and a transition from fibers to tubes in the case of the bile salt derivative. When both were present in the same solution they associated into mixed aggregates that showed complex thermoresponsive features. At room temperature, the core of the aggregate was comprised of a supramolecular twisted ribbon of the bile salt derivative. The block copolymers were anchored on the surface of this ribbon through electrostatic interactions between their charged blocks and the oppositely charged heads of the bile salt molecules. The whole structure was stabilized by a corona of the uncharged blocks that protruded into the surrounding solvent. By increasing the temperature to 30-34 degrees C the mixed aggregates transformed into rods with smooth edges that associated into bundles and clusters, which in turn induced clouding of the solution. Circular dichroism allowed us to follow progressive rearrangements of the supramolecular organization within the complex, occurring in the range of temperature of 20-70 degrees C. PMID- 27990553 TI - Imaging the electronic structure of on-surface generated hexacene. AB - Surface-assisted reduction of specially designed air-stable precursors allows us to study single hexacene molecules on Au(111) by scanning tunneling microscopy and spectroscopy, mapping with intramolecular resolution their extended electronic eigenstates. PMID- 27990554 TI - GNA11-mutated and BAP1-negative Melanomas Ex Blue Naevi: A Particularly Aggressive Entity. PMID- 27990555 TI - Root-associated bacterial diversities of Oryza rufipogon and Oryza sativa and their influencing environmental factors. AB - Oryza rufipogon is the ancestor of human-cultivated Oryza sativa. However, little is known about the difference between the root-associated microorganisms of O. rufipogon and O. sativa. In this study, the root-associated bacteria of O. rufipogon, Leersia hexandra, and O. sativa from different latitudes in China were studied by DGGE analysis. Their bacterial community structures were compared by principal component analysis. The relationship between root-associated bacteria and soil properties was explored by canonical correspondence analysis. The relationships of glomalin-related soil protein (GRSP) content, soluble sugar content, proline content of the plant, and bacterial diversity indices of their root-associated microorganisms were also investigated. We found both broad spectrum and host-specific bacteria, and the similarity, diversity and abundance indices of O. rufipogon and L. hexandra were higher than O. sativa root associated bacteria. However, even living in the same habitat, O. rufipogon and L. hexandra selected different root-associated bacteria. Microbial composition was primarily correlated with available N, P, and K and the annual precipitation. We also found a positive correlation between the soluble sugar content of the plant and GRSP content of the root soil. The above results indicated that the community structure of root-associated bacteria differs between wild rice and cultivated rice. Human activity and the natural selection of the host plants shaped the differences, consistent with our hypothesis. PMID- 27990556 TI - Impact of depressive/anxiety symptoms on the quality of life of adolescents with ADHD: a community-based 1-year prospective follow-up study. AB - Adolescents with attention-deficit/hyperactivity disorder (ADHD) often exhibit functional impairment even those having less visible symptoms. Therefore, it is of great clinical importance to identify ADHD symptoms among adolescents in the community. Furthermore, little is known regarding the role of internalizing symptoms in their quality of life. Thus, this study aimed to screen ADHD in a sample of high school students using the Adult ADHD Self-report Scale (ASRS) and to investigate the impact of internalizing symptoms on their well-being. In the first year, adolescents aged 15-17 years old from a senior high school (N = 1947) completed the Adult ADHD Self-rating Scale (ASRS), Wender Utah Rating Scale, Impulsiveness Scale, Beck's Depression Inventory and Beck's Anxiety Inventory. In the second year, the World Health Organization Quality of Life-BREF was applied for the measurement of their psychosocial outcomes. Results showed that adolescents with higher ASRS scores manifested more severe concurrent depressive and anxiety symptoms. ADHD symptoms among these adolescents were significantly associated with poorer quality of life 1 year later (p < 0.001). And both depressive and anxiety symptoms were mediators in the relationship between ADHD symptoms and quality of life. The finding of this study supports that the concurrent internalizing symptoms may underlie the negative relations between ADHD symptoms and quality of life in adolescents in the community. The application of ASRS in adolescents may help clinicians in early intervention for their ADHD problems as well as emotional symptoms. PMID- 27990557 TI - Intracerebral evidence of rhythm transform in the human auditory cortex. AB - Musical entrainment is shared by all human cultures and the perception of a periodic beat is a cornerstone of this entrainment behavior. Here, we investigated whether beat perception might have its roots in the earliest stages of auditory cortical processing. Local field potentials were recorded from 8 patients implanted with depth-electrodes in Heschl's gyrus and the planum temporale (55 recording sites in total), usually considered as human primary and secondary auditory cortices. Using a frequency-tagging approach, we show that both low-frequency (<30 Hz) and high-frequency (>30 Hz) neural activities in these structures faithfully track auditory rhythms through frequency-locking to the rhythm envelope. A selective gain in amplitude of the response frequency locked to the beat frequency was observed for the low-frequency activities but not for the high-frequency activities, and was sharper in the planum temporale, especially for the more challenging syncopated rhythm. Hence, this gain process is not systematic in all activities produced in these areas and depends on the complexity of the rhythmic input. Moreover, this gain was disrupted when the rhythm was presented at fast speed, revealing low-pass response properties which could account for the propensity to perceive a beat only within the musical tempo range. Together, these observations show that, even though part of these neural transforms of rhythms could already take place in subcortical auditory processes, the earliest auditory cortical processes shape the neural representation of rhythmic inputs in favor of the emergence of a periodic beat. PMID- 27990558 TI - Comparative proteomic analysis of hemolymph from uninfected and Candidatus Liberibacter asiaticus-infected Diaphorina citri. AB - Hemolymph was characterized from Diaphorina citri adults infected with the phytopathogen, Candidatus Liberibacter asiaticus (CLas), and compared with that from uninfected psyllids. This study identified 5531 and 3220 peptides within infected and uninfected hemolymph using nano-LC-MS/MS. A reduced number of proteins were detected for D. citri and all known endosymbionts within infected hemolymph as compared to uninfected hemolymph. A large number of immune defense proteins were absent from D. citri hemolymph; however, a single recognition protein (PGRP), two serine protease inhibitors, three prophenoloxidase (proPO) enzymes, and a single serine protease in an uninfected D. citri were detected. The hemolymph is nearly devoid of nutrient storage proteins. This is the first proteomic analysis of D. citri hemolymph that also analyses the components contributed by all the endosymbionts. By comparing the contribution of each endosymbiont (CCR, CPA, and WB) in the presence and absence of CLas infection, this study offers initial insights regarding the hemolymph response to microbial community shifts associated with D. citri infection status. Our data also present potential protein targets for analysis and disruption of CLas transmission that may facilitate management of huanglongbing (HLB) caused by CLas in citrus. PMID- 27990559 TI - Prevention of hypoglycemia-induced hippocampal neuronal death by N-acetyl-L cysteine (NAC). AB - Type 1 and type 2 diabetic patients who are treated with insulin or other blood glucose reducing agents for tight control of blood glucose levels are frequently at risk of experiencing severe hypoglycemia which can lead to seizures, loss of consciousness and death. Hypoglycemic neuronal cell death is not a simple result of low glucose supply to the brain, but, instead, results from a cell death signaling pathway that is started by the re-administration of glucose after glucose deprivation. Zinc is a biologically important element for physiological function of central nervous system. However, excessive zinc release from the presynaptic terminals and subsequent translocation into the postsynaptic neurons may contribute to neuronal death following hypoglycemia. N-acetyl-L-cysteine (NAC) acts as a zinc chelator that alleviates zinc-induced neuronal death processes. In addition, NAC restores levels of neuronal glutathione (GSH), a potent antioxidant, by providing a cell-permeable source of cysteine. Thus, we hypothesized that NAC treatment can reduce neuronal cell death, not only by increasing GSH concentration but also by zinc chelation. As a result, we found that NAC decreased the oxidative stress, zinc release and translocation, and improved the level of glutathione. Therefore, NAC administration alleviated hippocampal neuron death in hypoglycemia-induced rats. PMID- 27990560 TI - Diagnostic value of tumor markers for lung adenocarcinoma-associated malignant pleural effusion: a validation study and meta-analysis. AB - BACKGROUND: Pleural effusion is one of the most common complications of lung adenocarcinoma and is diagnostically challenging. This study aimed to investigate the diagnostic performance of carcinoembryonic antigen (CEA), cytokeratin fragment (CYFRA) 21-1, and cancer antigen (CA) 19-9 for lung adenocarcinoma associated malignant pleural effusion (MPE) through a validation study and meta analysis. METHODS: Pleural effusion samples were collected from 81 lung adenocarcinoma-associated MPEs and 96 benign pleural effusions. CEA, CYFRA 21-1, and CA19-9 were measured by electrochemiluminescence immunoassay. The capacity of tumor markers was assessed with receiver operating characteristic curve analyses and the area under the curve (AUC) was calculated. Standard methods for meta analysis of diagnostic studies were used to summarize the diagnostic performance of CEA, CYFRA 21-1, and CA19-9 for lung adenocarcinoma-associated MPE. RESULTS: The pleural levels of CEA, CYFRA 21-1, and CA19-9 were significantly increased in lung adenocarcinoma-associated MPE compared to benign pleural effusion. The cut off points for CEA, CYFRA 21-1, and CA19-9 were optimally set at 4.55 ng/ml, 43.10 MUg/ml, and 12.89 U/ml, and corresponding AUCs were 0.93, 0.85, and 0.81, respectively. The combination of CEA, CYFRA 21-1, and CA19-9 increased the sensitivity to 95.06%, with an AUC of 0.95. Eight studies were included in this meta-analysis. CEA showed the best diagnostic performance with pooled sensitivity, specificity, positive/negative likelihood ratio, and diagnostic odds ratio of 0.75, 0.96, 16.01, 0.23, and 81.49, respectively. The AUC was 0.93. CONCLUSIONS: CEA, CYFRA 21-1, and CA19-9 play a role in the diagnosis of lung adenocarcinoma-associated MPE. The combination of these tumor markers increases the diagnostic accuracy. PMID- 27990562 TI - Bioethanol production from Gracilaria verrucosa using Saccharomyces cerevisiae adapted to NaCl or galactose. AB - This study examined the pretreatment, enzymatic saccharification, and fermentation of the red macroalgae Gracilaria verrucosa using adapted saccharomyces cerevisiae to galactose or NaCl for the increase of bioethanol yield. Pretreatment with thermal acid hydrolysis to obtain galactose was carried out with 11.7% (w/v) seaweed slurry and 373 mM H2SO4 at 121 degrees C for 59 min. Glucose was obtained from enzymatic hydrolysis. Enzymatic saccharification was performed with a mixture of 16 U/mL Celluclast 1.5L and Viscozyme L at 45 degrees C for 48 h. Ethanol fermentation in 11.7% (w/v) seaweed hydrolysate was carried out using Saccharomyces cerevisiae KCTC 1126 adapted or non-adapted to high concentrations of galactose or NaCl. When non-adapted S. cerevisiae KCTC 1126 was used, the ethanol productivity was 0.09 g/(Lh) with an ethanol yield of 0.25. Ethanol productivity of 0.16 and 0.19 g/(Lh) with ethanol yields of 0.43 and 0.48 was obtained using S. cerevisiae KCTC 1126 adapted to high concentrations of galactose and NaCl, respectively. Adaptation of S. cerevisiae KCTC 1126 to galactose or NaCl increased the ethanol yield via adaptive evolution of the yeast. PMID- 27990563 TI - Selective reaching in macaques: evidence for action-centred attention. AB - When a monkey selects a piece of food lying on the ground from among other viable objects in the near vicinity, only the desired item governs the particular pattern and direction of the animal's reaching action. It would seem then that selection is an important component controlling the animal's action. But, we may ask, is the selection process in such cases impervious to the presence of other objects that could constitute potential obstacles to or constraints on movement execution? And if it is, in fact, pervious to other objects, do they have a direct influence on the organization of the response? The kinematics of macaques' reaching movements were examined by the current study that analysed some exemplars as they selectively reached to grasp a food item in the absence as well as in the presence of potential obstacles (i.e., stones) that could affect the arm trajectory. Changes in movement parameterization were noted in temporal measures, such as movement time, as well as in spatial ones, such as paths of trajectory. Generally speaking, the presence of stones in the vicinity of the acting hand stalled the reaching movement and affected the arm trajectory as the hand veered away from the stone even when it was not a physical obstacle. We concluded that nearby objects evoke a motor response in macaques, and the attentional mechanisms that allow for a successful action selection are revealed in the reaching path. The data outlined here concur with human studies indicating that potential obstacles are internally represented, a finding implying basic cognitive operations allowing for action selection in macaques. PMID- 27990561 TI - Dopaminergic medication unrelated myoclonus is less related to tremor in idiopathic Parkinson's disease. AB - Myoclonus in Parkinson's disease (PD) may be related or unrelated to dopaminergic medication and may share some features of cortical myoclonus. The aim of this study was to analyze clinical and electrophysiological correlates of the dopaminergic treatment unrelated myoclonus in PD patients. We included 17 PD patients with the end-of-dose myoclonus and 16 PD patients without myoclonus between January 2010 and June 2011. Surface electromyography of upper extremity muscles and long latency reflexes (LLRs) were performed. Positive or negative myoclonus with a duration of 35-100 ms was observed. Rest tremor was less frequent in the group with myoclonus. Only one PD patient with myoclonus had C reflex. Mean LLR amplitude was significantly high in PD with myoclonus compared to the group without myoclonus (p = 0.024). Dopaminergic treatment unrelated myoclonus is less related to rest tremor in PD, may be positive or negative, and exhibits similar features to cortical myoclonus. PMID- 27990564 TI - Planarian cholinesterase: in vitro characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity and reactivation. AB - The freshwater planarian Dugesia japonica has recently emerged as an animal model for developmental neurotoxicology and found to be sensitive to organophosphorus (OP) pesticides. While previous activity staining of D. japonica, which possess a discrete cholinergic nervous system, has shown acylthiocholine catalysis, it is unknown whether this is accomplished through an acetylcholinesterase (AChE), butyrylcholinesterase (BChE), or a hybrid esterase and how OP exposure affects esterase activity. Here, we show that the majority of D. japonica cholinesterase (DjChE) activity departs from conventional AChE and BChE classifications. Inhibition by classic protonable amine and quaternary reversible inhibitors (ethopropazine, donepezil, tacrine, edrophonium, BW284c51, propidium) shows that DjChE is far less sensitive to these inhibitors than human AChE, suggesting discrete differences in active center and peripheral site recognition and structures. Additionally, we find that different OPs (chlorpyrifos oxon, paraoxon, dichlorvos, diazinon oxon, malaoxon) and carbamylating agents (carbaryl, neostigmine, physostigmine, pyridostigmine) differentially inhibit DjChE activity in vitro. DjChE was most sensitive to diazinon oxon and neostigmine and least sensitive to malaoxon and carbaryl. Diazinon oxon-inhibited DjChE could be reactivated by the quaternary oxime, pralidoxime (2-PAM), and the zwitterionic oxime, RS194B, with RS194B being significantly more potent. Sodium fluoride (NaF) reactivates OP-DjChE faster than 2-PAM. As one of the most ancient true cholinesterases, DjChE provides insight into the evolution of a hybrid enzyme before the separation into distinct AChE and BChE enzymes found in higher vertebrates. The sensitivity of DjChE to OPs and capacity for reactivation validate the use of planarians for OP toxicology studies. PMID- 27990565 TI - Characterization of apple stem grooving virus and apple chlorotic leaf spot virus identified in a crab apple tree. AB - Apple stem grooving virus (ASGV), apple chlorotic leaf spot virus (ACLSV), and prunus necrotic ringspot virus (PNRSV) were identified in a crab apple tree by small RNA deep sequencing. The complete genome sequence of ACLSV isolate BJ (ACLSV-BJ) was 7554 nucleotides and shared 67.0%-83.0% nucleotide sequence identity with other ACLSV isolates. A phylogenetic tree based on the complete genome sequence of all available ACLSV isolates showed that ACLSV-BJ clustered with the isolates SY01 from hawthorn, MO5 from apple, and JB, KMS and YH from pear. The complete nucleotide sequence of ASGV-BJ was 6509 nucleotides (nt) long and shared 78.2%-80.7% nucleotide sequence identity with other isolates. ASGV-BJ and the isolate ASGV_kfp clustered together in the phylogenetic tree as an independent clade. Recombination analysis showed that isolate ASGV-BJ was a naturally occurring recombinant. PMID- 27990566 TI - Genetic characterization of H9N2 avian influenza virus in plateau pikas in the Qinghai Lake region of China. AB - Qinghai Lake is a major migratory-bird breeding site that has experienced several highly pathogenic avian influenza virus (AIV) epizootics. Plateau pikas (Ochotona curzoniae) have previously been implicated in the ecology of avian influenza virus in this region. We first isolated an H9N2 AIV (A/Pika/Menyuan/01/2008) from plateau pikas between November 2008 and October 2009. Sequence analysis showed that the A/Pika/Menyuan/01/2008 AIV was closely related to the H9N2 AIV strain (A/Turkey/Wisconsin/ 1/1966). Our findings suggested that plateau pikas may contribute to AIV epidemiology in the Qinghai Lake region. PMID- 27990567 TI - Identification and characterization of multiple porcine astrovirus genotypes in Hunan province, China. AB - Astroviruses (AstVs) can infect a variety of hosts, including mammalian and avian species, and are commonly associated with enteric infections. Recently, mammalian AstVs have been linked to extra-intestinal manifestations, including neurologic disorders in humans, cattle and minks, demonstrating zoonotic potential. So far, five porcine AstV (PAstV) genotypes have been identified, with PAstV1, PAstV2, PAstV3 and PAstV5 implicated in cross-species transmission. Our knowledge about PAstV epidemiology in China is still limited. In this study, two duplex differential RT-PCR assays were developed to investigate the distribution and prevalence of PAstV1, PAstV2, PAstV4 and PAstV5. Two hundred eighteen samples were collected from 33 farms and pigs with known diarrhea status in nine regions of Hunan province in China. Specifically, 126 small intestines, 51 fecal swabs, 20 lungs, 19 spleens and two kidneys were obtained. PAstVs were detected in all nine regions and in 81.8% (27/33) of the pig farms investigated. The overall prevalence of PAstV was 46.3% (101/218), with PAstV5 as the predominant type, with a positive rate of 24.8% (54/218). The prevalence of PAstV4, PAstV1 and PAstV2 was 16.1% (35/218), 14.7% (32/218) and 10.1% (22/218), respectively. Besides being present in intestines and fecal swabs, PAstV RNA was also detected in lungs, spleens and kidneys. Sequencing revealed a high level of genetic divergence within each genotype, and a higher positive rate of PAstV5 was associated with pigs with diarrhea compared to pigs without diarrhea. This study revealed for the first time that PAstV4 is circulating in China, and that PAstV5 is the dominant genotype in pig herds in Hunan province in China. PMID- 27990568 TI - Evaluation of in vitro antioxidant and anticancer activity of Allophylus cobbe leaf extracts on DU-145 and PC-3 human prostate cancer cell lines. AB - Allophylus cobbe (L.) Raeusch. belonging to the family Sapindaceae, is a commonly distributed small shrub in Western Ghats of India previously reported for its traditional medicinal properties. It is used for the treatment of various ailments. The present study is aimed at investigating preliminary phytochemicals, inducing the determination of the total phenolic contents, antioxidant assays and anticancer activity of A. cobbe leaf extracts on (DU-145) and (PC-3) cell lines. Preliminary phytochemical screening showed a broad spectrum of secondary metabolites. Highest amount of phenolic content was present in aqueous extract (91.96 +/- 0.61 mg/g GAE) and it also proved to have the most potent antioxidant activity at a concentration of 100 mg/ml (64.71 +/- 0.15%). IC50 value was (431.10 +/- 15.05 ug/mL) for DU-145 and (362.08 +/- 24.17 ug/mL) for PC-3 cell lines while the standard drug paclitaxel showed an IC50 value of 0.3 uM/mL. Morphological changes was observed in cancerous cells undergoing apoptosis in human prostate cancer cell lines (DU-145 and PC-3) while the extract showed no cytotoxicity towards normal cells (MEF-L929). It can be concluded that the tested extracts holds significant antioxidant and anticancer activities. However further investigation on lead compounds of A. cobbe will enable its therapeutic use. PMID- 27990569 TI - Icariin-treated human umbilical cord mesenchymal stem cells decrease chronic liver injury in mice. AB - Human umbilical cord mesenchymal stem cells (hUMSCs) have been shown to have multiple differentiation potentials. However, a key problem is that only a small number of hUMSCs can migrate to damaged tissue after transplantation. According to "The Theory of Kidney Essence" in Traditional Chinese Medicine, some traditional Chinese medicines used for tonifying the kidneys can be applied in promoting the differentiation and migration of stem cells in vivo. Our previous study demonstrated that icariin (ICA) could up-regulate the pluripotent genes of hUMSCs in vitro and induce cell migration in mice in an acute kidney injury model in vivo. The aim of this study was to investigate the effects of ICA-induced hUMSCs in chronic liver injury (CLI) caused by carbon tetrachloride (CCl4). CLI was induced by intraperitoneal injection of CCl4. ICA-treated hUMSCs were transplanted via intra-venous injection. The animals were followed for survival, biochemistry analysis and pathology. The results show that ICA-treated hUMSCs accelerate the recovery of liver function in mice with CLI. In addition, ICA treated hUMSCs increase the anti-oxidant activities in liver and prevent the progression to hepatic fibrosis. Moreover, ICA induces the migration of hUMSCs to the injured liver tissue. In conclusion, these data demonstrate that ICA-treated hUMSCs exhibit recovery and protective properties in the mice model of CCl4 induced CLI. PMID- 27990570 TI - Four mononuclear platinum(II) complexes: synthesis, DNA/BSA binding, DNA cleavage and cytotoxicity. AB - Four new platinum(II) complexes: PtII L1.H2O (C1, H2 L1 = C20H16N2O2), PtII L2Cl2 (C2, L2 = C22H16N2O2), PtII L3Cl2.H2O (C3, L3 = C20H16N2), PtII L4Cl2.0.4H2O (C4, L4 = C18H14N4) have been synthesized and characterized by using various physico chemical techniques. The binding interaction of the four platinum(II) complexes C1-C4 with calf thymus (CT)-DNA has been investigated by UV-Vis and fluorescence emission spectrometry. The apparent binding constant (K app) values follow the order: C3 > C1 > C2 > C4. In addition, fluorescence spectrometry of bovine serum albumin (BSA) with the four platinum(II) complexes C1-C4 showed that the quenching mechanism might be a static quenching procedure. For C1-C4, the number of binding sites was about one for BSA and the binding constants follow the order: C3 (7.08 * 105M-1) > C1 (2.82 * 105M-1) > C2 (0.85 * 105M-1) > C4 (0.15 * 105M-1). With the single condition change such as absence of an external agent, the DNA cleavage abilities of C3 exhibit remarkable changes. In addition, the cytotoxicity of C3 in vitro on tumor cells lines (MCF-7, HepG2 and HT29) were examined by MTT and showed better antitumor effects on the tested cells. PMID- 27990572 TI - Creation of a novel risk score for surgical site infection and occurrence after ventral hernia repair. AB - BACKGROUND: Complex ventral hernia repair (VHR) is a common surgical operation but carries a risk of complications from surgical site infections (SSI) and occurrences (SSO). We aimed to create a predictive risk score to identify patients at increased risk for SSO or SSI within 30 days of surgery. METHODS: Data were prospectively collected on all patients undergoing VHR between January 2008 and February 2015 by a single surgeon. Multivariable logistic regression was used to identify independent factors predictive of SSO and SSI. Significant predictors of SSO and SSI were assigned point values based on their odds ratios to create a novel risk score, the Hopkins ventral hernia repair SSO/SSI risk score; predicted and actual rates of outcomes were then compared using weighted regression. RESULTS: During the study period, 362 patients underwent open VHR. Thirty-day SSO and SSI occurred in 18.5 and 10% of patients, respectively. After risk adjustment, ASA class >=3 (1 point), operative time >=4 h (2 points), and the absence of a postoperative wound vacuum dressing (1 point) were predictive of 30-day SSO. Predicted risk of SSO utilizing this scoring system was 9.7, 19.4, 29.1, and 38.8% for 1, 2, 3, and 4 points (AUC = 0.73). For SSI, operative time >=4 h (1 point) and the lack of a wound vacuum dressing (1 point) were predictive. Predicted risk of SSI based on this scoring system was 12.5% for 1 point and 25% for 2 points (AUC = 0.71). Actual vs. predicted rates of SSO and SSI correlated strongly for risk model with a coefficient of determination (R 2) of 0.92 and 0.91, respectively. CONCLUSION: The novel Hopkins ventral hernia repair risk score accurately predicts risk of SSO and SSI after complex VHR. Further studies using a prospective randomized controlled trial will be needed to further validate our findings. PMID- 27990573 TI - De novo post-illumination monoterpene burst in Quercus ilex (holm oak). AB - MAIN CONCLUSION: Explicit proof for de novo origin of a rare post-illumination monoterpene burst and its consistency under low O 2 , shows interaction of photorespiration, photosynthesis, and isoprenoid biosynthesis during light-dark transitions. Quercus ilex L (holm oak) constitutively emits foliar monoterpenes in an isoprene-like fashion via the methyl erythritol phosphate (MEP) pathway located in chloroplasts. Isoprene-emitting plants are known to exhibit post illumination isoprene burst, a transient emission of isoprene in darkness. An analogous post-illumination monoterpene burst (PiMB) had remained elusive and is reported here for the first time in Q. ilex. Using 13CO2 labelling, we show that PiMB is made from freshly fixed carbon. PiMB is rare at ambient (20%) O2, absent at high (50%) O2, and becomes consistent in leaves exposed to low (2%) O2. PiMB is stronger and occurs earlier at higher temperatures. We also show that primary and secondary post-illumination CO 2 bursts (PiCO2B) are sensitive to O2 in Q. ilex. The primary photorespiratory PiCO2B is absent under both ambient and low O2, but is induced under high (>50%) O2, while the secondary PiCO2B (of unknown origin) is absent under ambient, but present at low and high O2. We propose that post-illumination recycling of photorespired CO2 competes with the MEP pathway for photosynthetic carbon and energy, making PiMB rare under ambient O2 and absent at high O2. PiMB becomes consistent when photorespiration is suppressed in Q. ilex. PMID- 27990571 TI - Strategic analysis of tuberculosis prevention and control actions in Brazil and Ethiopia: one size fits all? AB - OBJECTIVES: This study aimed at conducting a strategic analysis of Tuberculosis prevention and control actions in Brazil and Ethiopia, looking at the potential of directly observed treatment short-course strategy (DOTS) and community DOTS in both countries. METHODS: Literature review was conducted using PubMed, Medline Ovid, EMBASE, and SCIELO databases. The reviewed terms were Tuberculosis, prevention and control and Brazil (or Brasil) or Ethiopia (or Etiopia). Study's eligibility included article's title or abstract in English or Portuguese and comprised the following Tuberculosis policy components: management; care; communication, and social mobilization; training and professional development; epidemiological surveillance, and monitoring and evaluation. The study identified, compared, and analyzed the challenges and recommendations reported in the literature. RESULTS: Although DOTS was not able to address all the difficulties regarding Tuberculosis control and prevention, it contributes to overcome challenges identified in the literature review. Decentralizing DOTS in Ethiopia and implementing DOTS in Brazil were key recommendations to overcome problems of access and treatment default. CONCLUSIONS: DOTS and Community DOTS cannot solve every identified Tuberculosis challenge, but together they complement each other. Both strategies need to be tailored to site's challenges. PMID- 27990574 TI - Differences in photosynthetic responses of NADP-ME type C4 species to high light. AB - MAIN CONCLUSION: Three species chosen as representatives of NADP-ME C4 subtype exhibit different sensitivity toward photoinhibition, and great photochemical differences were found to exist between the species. These characteristics might be due to the imbalance in the excitation energy between the photosystems present in M and BS cells, and also due to that between species caused by the penetration of light inside the leaves. Such regulation in the distribution of light intensity between M and BS cells shows that co-operation between both the metabolic systems determines effective photosynthesis and reduces the harmful effects of high light on the degradation of PSII through the production of reactive oxygen species (ROS). We have investigated several physiological parameters of NADP-ME-type C4 species (e.g., Zea mays, Echinochloa crus-galli, and Digitaria sanguinalis) grown under moderate light intensity (200 umol photons m-2 s-1) and, subsequently, exposed to excess light intensity (HL, 1600 umol photons m-2 s-1). Our main interest was to understand why these species, grown under identical conditions, differ in their responses toward high light, and what is the physiological significance of these differences. Among the investigated species, Echinochloa crus-galli is best adapted to HL treatment. High resistance of the photosynthetic apparatus of E. crus-galli to HL was accompanied by an elevated level of phosphorylation of PSII proteins, and higher values of photochemical quenching, ATP/ADP ratio, activity of PSI and PSII complexes, as well as integrity of the thylakoid membranes. It was also shown that the non radiative dissipation of energy in the studied plants was not dependent on carotenoid contents and, thus, other photoprotective mechanisms might have been engaged under HL stress conditions. The activity of the enzymes superoxide dismutase and ascorbate peroxidase as well as the content of malondialdehyde and H2O2 suggests that antioxidant defense is not responsible for the differences observed in the tolerance of NADP-ME species toward HL stress. We concluded that the chloroplasts of the examined NADP-ME species showed different sensitivity to short-term high light irradiance, suggesting a role of other factors excluding light factors, thus influencing the response of thylakoid proteins. We also observed that HL affects the mesophyll chloroplasts first hand and, subsequently, the bundle sheath chloroplasts. PMID- 27990575 TI - Dynamic landscape of alternative polyadenylation during retinal development. AB - The development of the central nervous system (CNS) is a complex process that must be exquisitely controlled at multiple levels to ensure the production of appropriate types and quantity of neurons. RNA alternative polyadenylation (APA) contributes to transcriptome diversity and gene regulation, and has recently been shown to be widespread in the CNS. However, the previous studies have been primarily focused on the tissue specificity of APA and developmental APA change of whole model organisms; a systematic survey of APA usage is lacking during CNS development. Here, we conducted global analysis of APA during mouse retinal development, and identified stage-specific polyadenylation (pA) sites that are enriched for genes critical for retinal development and visual perception. Moreover, we demonstrated 3'UTR (untranslated region) lengthening and increased usage of intronic pA sites over development that would result in gaining many different RBP (RNA-binding protein) and miRNA target sites. Furthermore, we showed that a considerable number of polyadenylated lncRNAs are co-expressed with protein-coding genes involved in retinal development and functions. Together, our data indicate that APA is highly and dynamically regulated during retinal development and maturation, suggesting that APA may serve as a crucial mechanism of gene regulation underlying the delicate process of CNS development. PMID- 27990576 TI - Coordinated shift of olfactory amino acid responses and V2R expression to an amphibian water nose during metamorphosis. AB - All olfactory receptors identified in teleost fish are expressed in a single sensory surface, whereas mammalian olfactory receptor gene families segregate into different olfactory organs, chief among them the main olfactory epithelium expressing ORs and TAARs, and the vomeronasal organ expressing V1Rs and V2Rs. A transitional stage is embodied by amphibians, with their vomeronasal organ expressing more 'modern', later diverging V2Rs, whereas more 'ancient', earlier diverging V2Rs are expressed in the main olfactory epithelium. During metamorphosis, the main olfactory epithelium of Xenopus tadpoles transforms into an air-filled cavity (principal cavity, air nose), whereas a newly formed cavity (middle cavity) takes over the function of a water nose. We report here that larval expression of ancient V2Rs is gradually lost from the main olfactory epithelium as it transforms into the air nose. Concomitantly, ancient v2r gene expression begins to appear in the basal layers of the newly forming water nose. We observe the same transition for responses to amino acid odorants, consistent with the hypothesis that amino acid responses may be mediated by V2R receptors. PMID- 27990577 TI - Relationships Among Adherence and Physical and Mental Health Among Women Living with HIV in Rural India. AB - We conducted a cross-sectional examination of the physical and psychological factors related to ART adherence among a sample of 400 women living with HIV/AIDS in rural India. Interviewer-administered measures assessed adherence, internalized stigma, depressive symptoms, quality of life, food insecurity, health history and sociodemographic information. CD4 counts were measured using blood collected at screening. Findings revealed that adherence to ART was generally low, with 94% of women taking 50% or less of prescribed medication in past month. Multivariate analyses showed a non-linear association between numbers of self-reported opportunistic infections (OIs) in past 6 months (p = 0.016) and adherence, with adherence decreasing with each additional OI for 0-5 OIs. For those reporting more than 5 OIs, the association reversed direction, with increasing OIs beyond 5 associated with greater adherence. PMID- 27990578 TI - Unsafe Sexual Behavior Among Gay/Bisexual Men in the Era of Combination Antiretroviral Therapy (cART). AB - The aim of this study was to determine the association between psychosocial determinants of unprotected receptive anal intercourse (URAI) and unprotected insertive anal intercourse (UIAI). Data from 417 HIV positive men who have sex with men (MSM) in the Multicenter AIDS Cohort Study from April 1999 to March 2012 were analyzed and adjusted odds were calculated. It was found that 66% (n = 277) and 72% (n = 299) reported any UIAI or URAI over follow-up, respectively. Cumulative cART-years (median = 5.30 years) was associated with 33 and 47% increases in UIAI and URAI, respectively. Not having reduced concern about HIV transmission (UIAI: OR 0.37, p-value = 0.0004; URAI: OR 0.57, p-value = 0.04), increased safe sex fatigue (UIAI: OR 2.32, 95% p-value = 0.0002; URAI: OR 1.94, p value = 0.003), and sexual sensation seeking (UIAI: OR 1.76, p-value = 0.002; URAI: OR 1.56, p-value = 0.02) were associated with UIAI and URAI. Serosorting was associated with UIAI (OR 6.11, p-value < 0.0001) and URAI (OR 6.80, p-value < 0.0001). Findings suggest that negative attitudes about HIV transmission are sustained among older men who have sex with men. PMID- 27990579 TI - Predictors of HIV Care Engagement, Antiretroviral Medication Adherence, and Viral Suppression Among People Living with HIV Infection in St. Petersburg, Russia. AB - Over 1 million HIV infections have been diagnosed in Russia, and HIV care uptake and viral suppression are very low. 241 HIV-positive individuals in St. Petersburg were enrolled through social networks, provided blood for viral load testing, and completed measures of medication-taking adherence, readiness, and self-efficacy; psychosocial well-being; and substance use. Outcomes included attending an HIV care appointment in the past 6 months, >90% ART adherence, and undetectable viral load. 26% of participants had no recent care appointment, 18% had suboptimal adherence, and 56% had detectable viral load. Alcohol use consistently predicted all adverse health outcomes. Having no recent care visit was additionally associated with being single and greater past-month drug injection frequency. Poor adherence was additionally predicted by lower medication-taking self-efficacy and lower anxiety. Detectable viral load was additionally related to younger age. Comprehensive interventions to improve HIV care in Russia must address substance abuse, anxiety, and medication-taking self efficacy. PMID- 27990581 TI - Reproducibility of Respondent-Driven Sampling (RDS) in Repeat Surveys of Men Who have Sex with Men, Unguja, Zanzibar. AB - To assess the reproducibility of respondent-driven sampling (RDS) in obtaining comparable samples across two survey rounds, we conducted integrated bio behavioral surveillance surveys (IBBSS) using RDS in 2007 and 2011 among men who have sex with men (MSM) on Unguja island in Zanzibar. Differences in the two rounds were assessed by comparing RDS-adjusted population estimates, stratified estimates, and bottleneck plots. Participants in the 2011 survey round were younger (31.4 vs. 9.9% under 19 years old, p < 0.001), more likely to have tested for HIV in the last year (53.7 vs. 10.6%, p < 0.001), and less likely to have injected drugs in the last 3 months (1.0 vs. 23.2%, p < 0.001) compared to participants in the 2007 round. HIV prevalence was 12.3% in 2007 compared to 2.6% in 2011 (p < 0.001). The difference in HIV prevalence persisted after stratifying and adjusting for known differences in the two surveys rounds. Bottleneck plots suggest that recruitment chains were "trapped" in the social networks of MSM who injected drugs to a greater extent in 2007 than in 2011. We conclude that the two rounds of RDS sampled different subsets of the MSM population on Unguja, particularly with respect to inclusion of MSM within the social networks of people who inject drugs. Findings underscore the need to evaluate the reproducibility of RDS in repeated rounds of IBBSS and to develop new sampling methods for key populations at high risk for HIV in order to track the epidemic, develop evidence-based prevention and care programs, and assess their impact. PMID- 27990580 TI - A Longitudinal Analysis of the Impact of Physical Activity on Neurocognitive Functioning Among HIV-Infected Adults. AB - Higher levels of physical activity (PA) have been linked to better neurocognitive functioning in many populations. The current study examines the longitudinal association between PA and neurocognitive functioning among HIV-infected and HIV uninfected persons. Community-dwelling adults (N = 291) self-reported level of PA and completed a comprehensive neuropsychological battery at two to four study visits (Mean follow-up time = 2.6 years). Participants were divided into three PA groups: "No PA" (no PA at any visit), "consistent PA" (PA at >=50% of visits), and "inconsistent PA" (PA < 50% of visits). A mixed effect model, adjusting for significant covariates showed that all PA groups had statistically significant, yet modest, neurocognitive decline over time; and, the consistent PA group began with, and maintained, significantly better neurocognitive function compared to the other two PA groups. This effect was evident among both HIV-uninfected and HIV-infected persons, despite the fact that HIV-infected persons showed lower baseline neurocognitive function. PA is a modifiable lifestyle behavior that may help to protect against neurocognitive impairment regardless of HIV status, however, given the proportion of HIV-infected individuals who evidence neurocognitive difficulties, a focus on increasing PA seems warranted. PMID- 27990583 TI - The Role of Internalized Stigma in the Disclosure of Injecting Drug Use Among People Who Inject Drugs and Self-Report as HIV-Positive in Kohtla-Jarve, Estonia. AB - Disclosure of injecting drug use and its associations with stigma have received very little research attention. This cross-sectional study examined the role of internalized HIV and drug stigma (i.e., self-stigmatization) in the disclosure of injecting drug use among people who inject drugs (PWID) self-reporting as HIV positive (n = 312) in Kohtla-Jarve, Estonia. The internalization of both stigmas was relatively high. On average, PWID disclosed to three disclosure targets out of seven. Disclosure was highest to close friends and health care workers and lowest to employers and casual sex partners. Internalized drug stigma was negatively associated with disclosure to other family members (AOR = 0.48; 95% CI 0.30-0.77) and health care workers (AOR = 0.46; 95% CI 0.25-0.87). Internalized HIV stigma was positively associated with disclosure to health care workers (AOR = 2.26; 95% CI 1.27-4.00). No interaction effect of internalized stigmas on disclosures emerged. We concluded that effects of internalized stigmas on disclosures are few and not uniform. PMID- 27990582 TI - Predictors of Adult Retention in HIV Care: A Systematic Review. AB - A systematic literature review was conducted to identify predictors of poor adult retention in HIV medical care in developed and developing countries. An electronic search was conducted with MEDLINE (OVID), PubMED, EBSCO, SCOPUS, and Cochrane databases, as well as manual searches. Original, quantitative, adult studies in English, published between 1995 and 2015 were included. Only those with a focus on predictors of retention in care were reported on. Of the 345 articles identified, thirty were included following an independent assessment by two raters. In developed countries, the most frequently cited predictors of poor retention were active substance use and demographic factors. In developing countries, physical health factors were most frequently associated with poor retention in care. The results from this review suggests primary concerns for poor retention include substance use and physical health factors. Other psychosocial factors, such as psychiatric illness and social/welfare factors, were also found to be relevant. PMID- 27990584 TI - Post-traumatic Stress Disorder Symptoms Among People Living with HIV/AIDS in Rural China. AB - Among people living with HIV/AIDS (PLHA), the occurrence of post-traumatic stress disorder (PTSD) symptoms associated with HIV diagnosis is a common problem. This study examined HIV diagnosis-related PTSD symptoms and its associated factors among PLHA in rural China. We used baseline data from a randomized controlled trial conducted in Anhui Province, China. Surveys of 522 PLHA were conducted via computer-assisted personal interview method. PTSD symptoms were measured based on re-experiencing, avoidance and arousal of the day of HIV diagnosis. Association between PTSD symptoms and demographic characteristics, physical and social functioning were assessed by multiple regression analysis and structural equation modeling. Social functioning exhibited a direct association with HIV diagnosis related PTSD symptoms, and also mediated the association between PTSD symptoms and age, family income, and physical functioning. The study findings underscore the importance of developing interventions that alleviate PTSD symptoms and improve social functioning among PLHA in rural China. PMID- 27990585 TI - Vengeance, Condomless Sex and HIV Disclosure Among Men Who Have Sex with Men Living with HIV. AB - Vengeance has been shown to be a risk factor for HIV nondisclosure. Research examining the associations between vengeance, condomless sex, and HIV nondisclosure is lacking. The aim of the current study was to explore the association between vengeance, condomless sex and disclosure (behavior, attitude and intention) among men who have sex with men (MSM) living with HIV. Participants included 266 MSM who were a part of a disclosure intervention study. Men were recruited from local and state AIDS service organizations (ASOs), HIV related venues and forums, and at local eating and drinking establishments in Tampa, Florida, and Columbus and Dayton, Ohio metropolitan statistical areas (MSAs). Advertisements were also placed in local daily newspapers. Vengeance was operationalized into three groups based on percentiles (least, more, and most vengeful) and as a continuous variable. Crude and multivariable logistic regression models were used to examine the association between vengeance and condomless sex in the past 30 days. Simple and multiple linear regression models were used to determine the association between vengeance and HIV disclosure. After adjusting for demographic and geographic characteristics, participants who were "most vengeful" had, on average, an approximate six-point decrease (beta: 5.46; 95% CI -9.55, -1.36) in disclosure intention compared to MSM who were "least vengeful." Prevention and intervention programs geared towards improving disclosure among MSM should address vengeance. PMID- 27990586 TI - HIV Disclosure and Unprotected Sex Among Vietnamese Men with a History of Drug Use. AB - Additional barriers to self-disclosure of HIV status exist for people living with HIV (PLH) with a history of drug use. The objectives of this study were to explore the extent of HIV disclosure, sexual practice patterns and the relationships between HIV disclosure and unprotected sex among Vietnamese male PLH with a history of drug use. We used cross-sectional data of a sample of 133 PLH collected from a randomized controlled intervention trial in Vietnam. More than one-quarter of the participants reported not disclosing their HIV status to any sexual partners. Self-reported rates of condom use were 67.8, 51.1 and 32.6% with regular, casual, and commercial partners, respectively. Unprotected sex, testing positive for heroin, and fewer years since HIV diagnosis were significantly associated with lower level of HIV disclosure. Future intervention programs should focus on the complex interplay among HIV disclosure, drug use, and unprotected sexual practices in this vulnerable population. PMID- 27990588 TI - No Longer Home Alone? Home Care and the Canada Health Act. AB - In this paper, I argue that addressing the medical needs of older persons warrants expanding the array of insured services as described by the Canada Health Act (CHA) to include home care. The growing importance of chronic care supports my call for federally regulated home care services as the nature of disease management has changed significantly in the last decades. In addition, if the values of equity, fairness and solidarity, which are the keystone values of the CHA, are to be upheld within the current social and demographic context, then Canada's health care system should adapt accordingly. I focus my argument on the services provided to older persons for two main reasons. First, the changing nature of disease management is best seen in this population. If it is to be successfully argued that the transformations in medicine warrant an expansion of insured services covered by the CHA, it will be best illustrated by looking at the needs of older persons. Second, with the demographic shift looming large in the policy agenda, an exploration of this issue is not only crucial but timely. PMID- 27990587 TI - Willingness to Use Pre-Exposure Prophylaxis (PrEP): An Empirical Test of the Information-Motivation-Behavioral Skills (IMB) Model among High-Risk Drug Users in Treatment. AB - Evidence from recent pre-exposure prophylaxis (PrEP) trials has demonstrated its safety and efficacy in significantly reducing the risk of HIV acquisition for those who are at considerable risk of acquiring HIV infection. With a rapid increase in the amount of research on the efficacy of PrEP for HIV prevention, complementary research on the willingness to use PrEP has grown, especially among MSM, but limited research has been focused among people who use drugs (PWUD). As part of the formative process, we utilized the information-motivation-behavioral skills (IMB) model of health behavior change to characterize and guide intervention development for promoting willingness to use PrEP among high-risk PWUD. The analysis included 400 HIV-negative high-risk PWUD enrolled in a community-based methadone maintenance treatment who reported drug- and/or sex related HIV risk behaviors in the past 6-months. Analyses revealed support for the IMB model as PrEP-related behavioral skills were found to mediate the influence of PrEP-related information and motivation on willingness to use PrEP. The results provide evidence as to the utility of the IMB model to increase willingness to use PrEP among high-risk PWUD. It therefore makes an important contribution to our understanding of the applicability of theoretically-grounded models of willingness to use PrEP among high-risk PWUD, who are one of the key risk populations who could benefit from the use of PrEP. PMID- 27990590 TI - Angiopoietins as serum biomarkers for lymphatic anomalies. AB - Vascular anomalies can cause significant morbidity and mortality. Advances in diagnosis will be improved if noninvasive biomarkers can be identified, as obtaining a tissue biopsy can worsen the disease and precipitate complications. The goal of this study was to identify biomarkers for vascular anomaly patients to aid diagnosis and potentially give insights into pathogenesis. Blood was collected at baseline and then 6 and 12 months after treatment with the mTOR inhibitor sirolimus. Patients groups included generalized lymphatic anomaly (GLA), kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE) with or without the Kasabach-Merritt phenomenon (KMP) coagulopathy. Serum was obtained from healthy controls selected to match the age and sex of the patients (21 days-28.5 years; 42% males; 58% females). Angiogenic and lymphangiogenic factors (VEGF-A, C, D, Ang-1 and Ang-2) were measured in serum using ELISA. In lymphatic anomaly patients, baseline levels of VEGF-A and VEGF-D were not different compared to controls. Angiopoietin-2 (Ang-2) levels were near controls levels in GLA patients but 10-fold greater in KLA patients and 14-fold greater in KHE patients when the KMP coagulopathy was present but not when it was absent. VEGF-C and angiopoietin-1 (Ang-1) levels were lower in KHE patients with KMP. Our analyses suggest that Ang-2 and Ang-1 can be used as biomarkers to help identify KLA and KHE patients with KMP coagulopathy with high sensitivity and specificity. After 12 months of sirolimus treatment, Ang-2 levels were lower in KLA and KHE with KMP patients compared to baseline levels and with most patients showing a clinical response. Hence, serum Ang-2 and Ang-1 levels may help in the diagnosis of patients with lymphatic anomalies and are concordant to sirolimus response. PMID- 27990591 TI - On the Role of Imitation on Adolescence Methamphetamine Abuse Dynamics. AB - Adolescence methamphetamine use is an issue of considerable concern due to its correlation with later delinquency, divorce, unemployment and health problems. Understanding how adolescents initiate methamphetamine abuse is important in developing effective prevention programs. We formulate a mathematical model for the spread of methamphetamine abuse using nonlinear ordinary differential equations. It is assumed that susceptibles are recruited into methamphetamine use through imitation. An epidemic threshold value, [Formula: see text], termed the abuse reproduction number, is proposed and defined herein in the drug-using context. The model is shown to exhibit the phenomenon of backward bifurcation. This means that methamphetamine problems may persist in the population even if [Formula: see text] is less than one. Sensitivity analysis of [Formula: see text] was performed to determine the relative importance of different parameters in methamphetamine abuse initiation. The model is then fitted to data on methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse in the treatment centres of Cape Town and parameter values that give the best fit are chosen. Results show that the proportion of methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse will continue to decrease in Cape Town of South Africa. The results suggest that intervention programs targeted at reducing adolescence methamphetamine abuse, are positively impacting methamphetamine abuse. PMID- 27990592 TI - Combined NOTES total mesorectal excision and single-incision laparoscopy principles for conservative proctectomy: a single-centre study. AB - BACKGROUND: Surgery for low rectal cancer remains a challenge when a standard laparoscopic approach is used. Transanal endoscopic total mesorectal excision (TME) has been shown to be feasible and to be associated with a low conversion rate. Combining the transanal and transabdominal single-port approaches (with an abdominal single port implanted in the future stoma and extraction site) could allow TME with minimal wound trauma, low morbidity, and faster recovery. The aim of the current study was to assess the short- and mid-term results of this technique. METHODS: We conducted a prospective single-centre study of consecutive patients presenting with low rectal cancer requiring a conservative proctectomy with a manual coloanal anastomosis between January 2012 and April 2015. RESULTS: During the study period, 41 patients were recruited. Conversion to open surgery was required in only one patient (2.4%). The median operating time was 358.5 min (range 300-600 min). Partial intersphincteric resection was necessary for 15 patients (36.6%). The specimens were mostly extracted via the abdominal access (n = 34) without wound complications. The mean number of lymph nodes harvested was 12.7 (range 6-24 lymph nodes). Specimens were graded as complete (n = 31) or nearly complete (n = 10) in all of the patients, and the circumferential resection margin positivity was 4.9%. Intraoperative morbidity rate was 4.9%, and the 30-day morbidity rate was 24.4% (n = 10). Sixty per cent (n = 6) of the patients with 30-day morbidity were Dindo I-II. At a median follow-up of 29 months, overall and disease-free survival rates were 97.5 and 80.5%, respectively. The stoma-free survival rate was 95.1%. CONCLUSIONS: Combining an endoscopic transanal TME and a single laparoscopic ileostomy-site proctectomy is a promising minimally invasive approach for the treatment of low rectal cancer. PMID- 27990589 TI - Approach to Lynch Syndrome for the Gastroenterologist. AB - Lynch syndrome is an autosomal-dominant hereditary cancer syndrome. Mutations in mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2, are implicated in the pathogenesis of the syndrome through microsatellite instability (MSI) and a rapid adenoma-carcinoma sequence. The primary methodologies for diagnosis include clinical criteria (Amsterdam I/II, Revised Bethesda Guidelines), computational models, and genetic testing (MSI, immunohistochemistry, germline testing). Universal genetic testing of colorectal cancers has gained popularity as a method to identify high-risk individuals and to offer appropriate cancer surveillance, psychological reassurance, and family planning. Management includes short interval surveillance with colonoscopy in those without colorectal cancer and colectomy for those with cancer. Long-term chemoprevention with aspirin may improve mortality. PMID- 27990593 TI - Is the unaffected eye really unaffected? Color Doppler ultrasound findings in unilaterally active central serous chorioretinopathy. AB - PURPOSE: To evaluate ocular hemodynamic changes using color Doppler ultrasonography imaging (CDI) with an emphasis on unaffected eyes of patients with central serous chorioretinopathy (CSC). METHODS: Twenty-seven patients with active CSC and 25 controls were analyzed using spectral domain-optical coherence tomography (SD-OCT) and CDI for choroidal imaging and evaluation of retrobulbar vessels, respectively. RESULTS: Resistive index (RI), pulsatility index (PI), and peak systolic velocity (PSV) of the ophthalmic artery (OA) and PSV, end-diastolic velocity (EDV), and mean velocity (Vmean) of the central retinal artery (CRA) in the patient group were less than those in the control group. RI and PI of the CRA were greater in the patient group compared to the control group. RI, PI, PSV, and Vmean of the OA and PSV, EDV, and Vmean of the CRA in the patients' unaffected eyes were less than those in the control group. OCT measurements of central choroidal thickness (CCT) of the affected eyes in the patient group were significantly greater than those of the unaffected eyes in the patient and control groups; that of the unaffected eyes was greater than that in the control group. CONCLUSIONS: Hemodynamic changes in OA reflect choroidal hyperperfusion. Hemodynamic and OCT changes in the unaffected eyes of the patient group suggest CSC as a bilateral disorder and the systemic nature of the disease. Further investigations may aid in the evaluation of treatment response and the follow-up of disease, providing a new insight into management strategies. PMID- 27990594 TI - Health care costs of borderline personality disorder and matched controls with major depressive disorder: a comparative study based on anonymized claims data. AB - BACKGROUND: Borderline personality disorder (BPD) and major depressive disorder (MDD) pose a significant burden to the German health care system in terms of direct and indirect costs. The aim of this study was to determine the incremental costs that arise due to the treatment of patients with BPD, in relation to MDD patients adjusted for gender and age. METHODS: Insured persons who suffered from BPD (F60.3; N = 6599) or MDD (F32, F33; N = 26,396) in the year 2010 were identified from the German Health Risk Institute research database. To estimate the costs resulting from disorder-specific health care service utilization and the mean total costs per patient for the health care system, we analyzed anonymized claims data of individuals with BPD and matched individuals with MDD. RESULTS: The costs resulting from disorder-specific health care service utilization 1 year after index diagnosis amounted to 8508 EUR for BPD and 8281 EUR for MDD per patient utilizing services. With mean total annual costs per patient of 4636 EUR versus 2020 EUR 1 year preceding index diagnosis, 7478 EUR versus 3638 EUR in the year after index diagnosis, and 11,817 EUR versus 6058 EUR 2 years after index diagnosis, BPD patients incurred markedly higher costs. CONCLUSIONS: Since the treatment of BPD causes incremental costs for the German health care system compared to the treatment of MDD, and since both conditions are associated with a high level of suffering, there is a need for establishing adequate and early treatment of these mental disorders. PMID- 27990596 TI - Ten concerns about blood pressure measurement and targets in paediatric sepsis. PMID- 27990597 TI - Ultrasound-guided core needle biopsy in the diagnosis of neuroblastic tumors in children: a retrospective study on 83 cases. AB - AIM: Ultrasound-guided biopsy technique with the large-core needle has widely been applied in the diagnosis of adult abdominopelvic cavity, thyroid, and neck tumors. There are few reports on ultrasound-guided biopsy using large-core needle in pediatric abdominopelvic cavity tumors. This study was to evaluate the ultrasound features and the diagnostic value of ultrasound-guided core needle biopsy for pediatric neuroblastic tumors. METHODS: The pediatric patients with neuroblastic tumor that underwent ultrasound examination and ultrasound-guided core needle biopsy from January 2009 to November 2015 were reviewed. A minimum of two cores in each case was obtained. The biopsy results were confirmed by subsequent surgical histopathology. The ultrasound features and the diagnostic accuracy of ultrasound-guided core needle biopsy were evaluated. RESULTS: Eighty three patients were enrolled into the study. Conventional ultrasound examination showed irregular hypoechoic or mixed echo masses and calcification and liquefied necrosis. The diagnostic accuracy of ultrasound-guided core needle biopsy was 96.4% (80/83). Three cases were misdiagnosed because of inadequate tissue sample. No serious complication, infection, or needle track seeding occurred. CONCLUSIONS: Ultrasound-guided core needle biopsy seems to be an accurate, minimally invasive, and safe diagnostic method of pediatric neuroblastic tumor. PMID- 27990595 TI - Distribution of TERT promoter mutations in primary and metastatic melanomas in Austrian patients. AB - BACKGROUND: TERT promoter mutations were detected at high frequencies in several cancer types including melanoma. Previous reports showed that these recurrent mutations increase TERT gene expression and the use of TERT mutation status as prognostic factor was suggested. OBJECTIVES: Here we screen a panel of 115 melanoma tumor samples from Austrian patients to evaluate the prevalence and distribution of TERT promoter mutations. The association with clinical and tumor characteristics and the effect on overall survival was analyzed. METHODS: Genomic DNA from formalin-fixed paraffin-embedded tumor samples was isolated followed by PCR amplification, Sanger sequencing and statistical analysis. RESULTS: We identified TERT promoter mutations in 63 of 115 (54.8%) tumor samples. No statistical significant difference in mutation frequency between primary (22/40 [55%]) and metastatic lesions (41/75 [54.7%]) was detected. BRAF-/NRAS-mutated tumors showed a higher frequency of TERT mutations (pT OR 2.24, 95% CI 0.56-9.02, p = 0.3) (met OR 2.74, 95% CI 0.98-7.66, p = 0.05). In primary melanoma, the presence of alterations in TERT was associated with the carrier status of a common single-nucleotide polymorphism rs2853669 (OR 4.55, CI 1.18-17.52, p = 0.03). In this patient cohort, TERT promoter mutations were not associated with clinical characteristics such as the presence of ulceration or Breslow thickness or showed an effect on overall survival. CONCLUSION: Alterations in the TERT promoter region are one of the most frequent mutations in melanoma. Based on this analysis and preliminary evidence, prospective studies will be needed to evaluate the reliability of TERT promoter mutations as prognostic factors in melanoma. PMID- 27990598 TI - Disorders of sex development (DSD): not only babies with ambiguous genitalia. A practical guide for surgeons. AB - INTRODUCTION AND METHODS: In this review, we describe the common clinical scenarios that may be present to a paediatric surgeon when a patient has a disorder of sex development (DSD). Our aim was to prepare surgeons so that they can respond with correct approaches to diagnose and manage the given situations. RESULTS: DSD present in three distinct clinical situations: in the neonate with some abnormality of the external genitalia; in the child undergoing surgical treatment for inguinal hernia or during open or laparoscopic orchidopexy or during hypospadias correction; and at or after puberty, which may be precocious or delayed or in an adolescent girl with masculinisation at puberty. We describe the clinical features, likely diagnoses and the recommended management pathway in these scenarios. PMID- 27990599 TI - The effect of sodium fluoride, formaldehyde, and storage temperature on the stability of methamidophos in post-mortem blood and liver. AB - Poisoning by organophosphorus insecticides such as methamidophos makes up a significant portion of forensic identification cases in China. Stability of methamidophos during specimen storage remains largely unknown. This study aimed to examine the long-term stability of methamidophos in postmortem specimens. Three experimental dogs after oral administration of methamidophos were sacrificed, and blood and liver specimens were collected and stored at various conditions. Gas chromatography-mass spectrometry (GC/MS) was used to measure the methamidophos concentrations after 0, 4, 7, 12, 16, 60, and 180 days of storage. The results showed that methamidophos was not stable and followed first-order degradation kinetics at all storage conditions investigated. The degradation half life in blood was 12.2, 16.9, 11.0, and 1.0 days when the samples were stored at room temperature (RT, 20 degrees C), 4 degrees C, -20 degrees C, and at RT with 1 % sodium fluoride (NaF), respectively. The degradation half-life in liver was 4.1, 9.8, 17.8, and 2.0 days when the samples were stored at RT, 4 degrees C, -20 degrees C, and at RT with liver fixed in 10 % formaldehyde solution, respectively. These findings are significant in guiding sample storage and data interpretation. Specimens containing methamidophos should be stored at -20 degrees C and analyzed as early as possible. Addition of NaF in blood and fixation of liver in formaldehyde should be avoided due to the accelerated degradation of methamidophos under these conditions. The preliminary study suggests that it might be possible to calculate methamidophos concentration at the time of death based on its first-order degradation kinetic under specific storage conditions. PMID- 27990600 TI - Once upon a time.... Dual mobility: history. AB - INTRODUCTION: Since 1962, the low friction arthroplasty developed by Sir John Charnley has given us very good long terms results at more than 40 years follow up, but dislocation remains a major complication. The dislocation rate is a permanent risk during the life of the patient and the prosthesis, defined by J. Caton and D. Berry in 2004 as a cumulative risk. History and concept development: The concept of dual mobility was thought up by G. Bousquet, A. Rambert and J. Rieu in the 1970s (1974-1979). The first one in 1979 was called NOVAE and combined two articulations: one large and one smaller by a recruitement phenomenon increasing the jumps distance and so decreasing dislocation forces. In 2003, D. Noyer published the first paper about the "third articulation": a true metal/PE bearing. Since 1996, twenty years after the first patent, many dual mobility cups have been developed with various fixation ways and various designs. CONCLUSION: Today with the same principles there are many differences for the "third generation" with excellent results at more than ten years FU with less than 1% to 2% dislocation rate in primary, revision, recurrent THA dislocation and THA after femoral neck fractures. PMID- 27990601 TI - Comparative Analysis of Proteome Patterns of Francisella tularensis Isolates from Patients and the Environment. AB - Francisella tularensis is the causative agent of tularemia. Although major contributors and the main mechanism of the virulence are well known, some of the molecular details are still missing. Proteomics studies regarding F. tularensis have provided snapshot pictures of the organism grown under different culture conditions to understand the mechanism of virulence. In general, such studies were carried out with standard strains e.g., LVS and did not involve comparisons of F. tularensis isolates from either clinical or environmental sources. In this study, we performed two-dimensional gel electrophoresis (2DE)-based proteomic analysis and compared the protein profiles of the F. tularensis subsp. holarctica strains isolated from the clinical and the environmental samples. Regulations were detected in 14 spots when twofold regulation criteria were applied. The regulated protein spots were subjected to MALDI-TOF/TOF analysis and identified. Classification of the identified proteins based on metabolic functions revealed that the translation machinery was the most varying metabolic processes among the isolates. Using normalized protein spot intensities, PCA analysis was also performed. The results indicated that the strain isolated from water source was different then the strains isolated from the patients. Most interestingly, the isolates were strikingly distinguishable from the standard NCTC 10857 strain. PMID- 27990602 TI - Endoscopic tympanoplasty: learning curve for a surgeon already trained in microscopic tympanoplasty. AB - The aim of this study was to evaluate the learning curve of endoscopic tympanoplasty for a surgeon already trained in microscopic tympanoplasty. We analyzed the clinical records of 81 patients who underwent transcanal endoscopic type 1 tympanoplasty and 30 control patients who underwent microscopic tympanoplasty between 2013 and 2015 in a tertiary hospital. All operations were performed by a single surgeon already trained in microscopic tympanoplasty. Patients were divided into four groups according to the date of surgery chronologically (group 1 early stage, group 2 intermediate stage, group 3 advanced stage and group 4 control). We evaluated the four groups according to surgery duration, audiometric results, and graft intake success. The operation duration shortened in accordance with the surgeon's experience and there were two subsequent steps during the learning curve: first, after 30 procedures; and second, after 60 procedures. The mean operation duration was 88.60 +/- 21.10 min in group 1, and 62.00 +/- 12.48 min in group 2. After 60 procedures, the mean operation duration was 43.81 +/- 8.34 min in group 3. In the control group, the microscopic tympanoplasty duration was 69.93 +/- 12.56 min. When we compared audiologic results (air conduction, bone conduction, and air-bone gap) and graft intake success rates, there were no significant differences between groups. Endoscopic tympanoplasty is a minimally invasive and effective technique. Mastering endoscopic tympanoplasty takes approximately 60 operations for a surgeon already trained in microscopic tympanoplasty. Graft intake success rates and hearing results are stable during the learning curve. PMID- 27990603 TI - Sinonasal characteristics and quality of life by SNOT-22 in adult patients with cystic fibrosis. AB - : The prevalence of chronic sinus disease in cystic fibrosis (CF) has gradually increased. Sinonasal involvement may have influence on pulmonary exacerbations and can have a negative impact on the quality of life. To evaluate nasal characteristics and quality of life in adult patients with CF; to establish an association and determine the predictors in SNOT-22 questionnaire. Cross- sectional study with prospective data collection was performed to evaluate adult CF patients. Patients underwent clinical evaluation, lung function tests, nasal endoscopy, and paranasal sinuses CT scan. All the patients answered the SNOT-22 questionnaire. RESULTS: A total of 91 patients were allocated, of which, 45.1% were male. Patients were divided into three groups by SNOT-22. A high average age, late age of diagnosis, rhinitis symptoms, and clinical criteria for rhinosinusitis were observed more frequently in patients with high SNOT-22 scores (p < 0.05). Overall, 84.6% patients had abnormal CT findings, with aplasia/hypoplasia of the sphenoid sinus being the most common finding. In multiple regression model, age, female gender, and Pseudomonas aeruginosa in the sputum were associated with high SNOT-22 scores in the nasal domain. Hyposmia and lack of medial bulging of lateral nasal wall were variables associated with high SNOT-22 scores in the quality of life domain. In total score, there was a positive association with age and the presence of P. aeruginosa in sputum. Despite high prevalence of abnormal tomographic findings, patients reported mild intensity of sinonasal symptoms. Advanced age and the presence of P. aeruginosa were associated with higher SNOT-22 scores. PMID- 27990604 TI - A novel environmental exposure index and its interaction with familial susceptibility on oral cancer in non-smokers and non-drinkers: a case-control study. AB - The objective of this study was to explore the collective effect of environmental factors and its interaction with familial susceptibility on oral cancer among non smokers and non-drinkers (NSND). A hospital-based case-control study, including 319 oral cancer patients and 994 frequency-matched controls, was conducted in Fujian, China. We raised a weighed environmental exposure index according to nine significant environmental factors obtained from multivariable logistic regression model. And then, the index was classified into three categories according to the tertiles of controls (<1.34, 1.34-2.43, and >2.43). Multiplicative and additive interactions were evaluated between environmental exposure index and family cancer history. Our results showed that environmental exposure index was associated with an increased risk of oral cancer especially for those with family cancer history. Compared to subjects with low environmental exposure index and without family cancer history, those with high index and family cancer history showed the highest magnitude of OR in oral cancer risk (OR 10.40, 95% CI 5.46 19.80). Moreover, there was a multiplicative interaction between environmental exposure index and family cancer history for the risk of oral cancer (P < 0.001). This study puts forward a novel environmental exposure index, which enables a comprehensive evaluation on the overall effect of environmental risk factors on oral cancer among NSND and may interact with family cancer history. Further studies are warranted to explore the underlying mechanisms. PMID- 27990606 TI - Geochemical Assessment of Trace Element Pollution in Surface Sediments from the Georges River, Southern Sydney, Australia. AB - Measurement of elevated trace elements is an important component of environmental assessment and management of estuarine marine sediments in systems adjacent to concentrated human activity. The present study surveys the estuarine sediments in selected tributary bays, creeks, and the upper segments of the Georges River system, NSW, Australia, which flows into the Tasman Sea through Botany Bay. A total of 146 surface sediment samples were analysed by X-ray fluorescence. Potential pollution of sediments was evaluated using potential load index, modified degree of contamination, and potential ecological risk index. The spatial distribution of trace elements varies between sites. Variable sources of contamination, including runoff from catchment areas, and emissions from watercraft and boatyards are contributing sources. Bay morphologies and their interactions with catchment and tidal flows play significant roles in the distribution of trace elements. The greatest concentration of trace elements occurs around discharge points and in the inner parts of bays that have high percentages of mud particles and organic matter. The lowest contamination by trace elements was found in sandy sediments along the shoreline and edges of the bays. Trace element distributions decline in concentration in residential-free areas and reach background levels in deeper sediment cores. The concentrations of trace elements were controlled by discharge points from the catchment area, marine boat activities, bay morphology, and sediment types (sand, silt, and clay). The highest pollutant concentrations are the result of past legal, but uncontrolled, discharge of waste from manufacturing into Salt Pan Creek. PMID- 27990605 TI - Profiling of Selected Functional Metabolites in the Central Nervous System of Marine Medaka (Oryzias melastigma) for Environmental Neurotoxicological Assessments. AB - The simultaneous profiling of 43 functional metabolites in the brain of the small model vertebrate organism, marine medaka (Oryzais melastigma), has been accomplished via dansyl chloride derivatization and LC-MS/MS quantification. This technique was applied to examine effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), one of the most abundant polybrominated diphenyl ether flame retardants in the natural environment, on the central nervous system (CNS) of vertebrates. The model teleosts were fed with bioencapsulated Artemia nauplii for up to 21 days. Multivariate statistical analysis has demonstrated that levels of numerous classical neurotransmitters and their metabolites in the CNS of the fish were perturbed even at the early phase of dietary exposure. Subsequent metabolic pathway analysis further implied potential impairment of the arginine and proline metabolism; glycine, serine and threonine metabolism; D-glutamine and D-glutamate metabolism; alanine, aspartate, and glutamate metabolism; valine, leucine, and isoleucine biosynthesis, and the cysteine and methionine metabolism in the brain of the test organism. Our results demonstrate that targeted profiling of functional metabolites in the CNS may shed light on how the various neurological pathways of vertebrates, including humans, are affected by toxicant/stress exposure. PMID- 27990607 TI - Family history of venous thromboembolism and mortality after venous thromboembolism: a Swedish population-based cohort study. AB - Studies on whether family history (FH) of venous thromboembolism (VTE) affects long-term mortality after VTE are missing. The aim of this study was to determine whether FH of VTE affects long-term mortality after a first episode of VTE. Using Swedish medical databases, we conducted a 30-year nationwide cohort study of 49,159 adult Swedish born patients included in the multi-generation register (born 1932 or later) with a first-time VTE (1981-2010). Using Cox regression, we assessed mortality Hazard ratios (HRs) with 95% confidence intervals (CIs). Totally 10,093 (20.5%) patients with VTE had a first-degree FH of VTE (parent/sibling). Patients without FH of VTE had significantly more VTE provoking risk factors and comorbidities than those with FH. The mortality HR the first 10 years after first time VTE was decreased for those with FH of VTE compared to for those without FH: crude HR 0.807, 95% CI 0.771-0.845 and adjusted HR 0.864, 95% CI 0.826-0.905. After 10-years of follow-up there was no significant effect of FH of VTE on mortality: crude HR = 1.018, 95% CI 0.905-1.145 and adjusted HR = 0.995, 95% CI 0.884-1.119. Cancer-associated mortality was more common in those without FH the first 10 years (56.9 vs. 53.4%, p = 0.002). After 10 years there were no difference in cancer-associated mortality (4.9 vs. 5.6%, p = 0.604). The results suggest that patients with FH of VTE have lower thrombotic threshold and need less provoking factors and comorbidities. They have also slightly lower total and cancer mortality the first 10 years after VTE. PMID- 27990608 TI - Development and validation of a new questionnaire measuring treatment satisfaction in patients with non-valvular atrial fibrillation: SAFUCA(r). AB - OBJECTIVE: To develop a new questionnaire with good psychometric properties to measure satisfaction with medical care in patients with non-valvular atrial fibrillation. METHOD: The initial instrument was composed of 37 items, arranged in 6 dimensions: efficacy, ease and convenience, impact on daily activities, satisfaction with medical care, undesired effects of medication, and overall satisfaction. Items and dimensions were extracted from reviewing existing instruments, 3 focus groups with chronic patients, and a panel of 8 experts. Additionally, 3 visual analog scales measuring quality of life, effectiveness, and overall satisfaction were administered. A convenience sample of 119 patients was used for item reduction. Classic psychometric theory and item analysis techniques were used (exploratory factor and confirmatory factor analysis, test retest, and correlation with visual scales). A validation sample of 230 patients was used to assess convergent validity, and an additional 220 patients sample was used to discriminate between treatment and compliance groups. RESULTS: The questionnaire was reduced in length to 25 items, but the impact dimension had split in treatment inconvenience and treatment control. Overall reliability was high (alpha = 0.861) with acceptable dimensional reliabilities (alpha = 0.764 0.908). Individual dimensions correlated to varying degrees. Test-retest correlations were high (r = 0.784-0.965), and correlations with visual and already validated scales were substantial. Differences were detected between antivitamin K and new-oral-anticoagulant treatments in several dimensions (p < 0.05). Treatment satisfaction was related with compliance. CONCLUSION: This new 25-item questionnaire has good psychometric properties for measuring satisfaction with medical care in patients with this condition. It is capable of detecting differences between different treatments. PMID- 27990610 TI - Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? AB - The cancer stem cell (CSC) hypothesis has been disproved in many cancers. CSCs may exist in blood cancer, while many epithelial cancers may not have CSCs but tumor-initiating cells (TICs). Several independent studies have provided strong evidence for existence of CSCs in brain, skin, and colon cancers (Mani et al. in Cell 133:704-715, 2008, Joseph et al. in Cancer Cell 13:129-140, 2008, Reya et al. in Nature 414:105-111, 2001), while the CSC hypothesis remains controversial (Magee et al. in Cancer Cell 21:283-296, 2012). Liver TICs have bipotential to give rise to two different lineage types: hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). In the liver cancer field, the origin of HCC and CC is extensively debated. Several groups have validated that TICs gave rise to HCC and CC. Hepatocytes gave rise to HCC. Several groups have demonstrated that oval cells (or liver progenitor cells) give rise to TICs. However, CSCs may be a myth in gastrointestinal cancer, while many groups have validated liver TICs. The definition of CSCs includes pluripotency, while TICs do not have to have pluripotency and only need to have bi- or multipotential to give rise to diverse tumor types and tumor initiation potential in mouse models. The CSC hypothesis therefore controversial (Magee et al. in Cancer Cell 21:283-296, 2012). Cancer tissues contain subpopulations of cells known as tumor-initiating stem-like cells (TICs, so-called CSCs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells proliferate via self renewing division in which the two daughter cells differ in proliferative potential, with one displaying differentiated phenotype and the other retaining self-renewing activity. PMID- 27990609 TI - Effect of exercise on the quality of life in type 2 diabetes mellitus: a systematic review. AB - PURPOSE: Diabetic patients tend to have a poor quality of life. A sedentary lifestyle is considered to be a modifiable risk factor for type 2 diabetes and an independent predictor of poor quality of life. Exercise is a key treatment for people living with diabetes. The purpose of this study was to conduct a systematic review to assess the effect of exercise on the quality of life of people with type 2 diabetes. METHODS: We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Web of Science, Embase, Cochrane Library, CINAHL and three Chinese databases were searched for studies published until January 2016. The review included all clinical trials that evaluated the effect of exercise on quality of life compared with that of usual care for people with type 2 diabetes. Two reviewers independently assessed the quality of all the included studies, by using the Downs and Black Quality Index (QI). RESULTS: Thirty studies met inclusion criteria, with 2785 participants. We divided the exercise into four modes: aerobic, resistance, a combination of aerobic and resistance and yoga. Aerobic exercise showed a significant effect between groups. Resistance and combined exercise showed mixed results. Yoga also showed good intervention effects on quality of life. CONCLUSIONS: The effect of aerobic exercise on the quality of life in people with type 2 diabetes was safe and effective. Then, most of the studies on aerobic exercise were of good methodological quality. The effects of resistance exercise and combined exercise on the quality of life in people with type 2 diabetes were mixed, and the effect of yoga on quality of life still need more research. PMID- 27990612 TI - 1H, 13C and 15N NMR assignments of an unusual Ca2+-binding protein from Entamoeba histolytica in its apo form. AB - We report almost complete sequence specific 1H, 13C and 15N NMR assignments of an unusual Ca2+-binding protein from Entamoeba histolytica (EhCaBP6) in its apo form as a prelude to its structural and functional characterization. PMID- 27990613 TI - Site-Specific Acetyl Lysine Antibodies Reveal Differential Regulation of Histone Acetylation upon Kinase Inhibition. AB - Lysine acetylation regulates diverse biological functions for the modified proteins. Mass spectrometry-based proteomic approaches have identified thousands of lysine acetylation sites in cells and tissues. However, functional studies of these acetylation sites were limited by the lack of antibodies recognizing the specific modification sites. Here, we generated 55 site-specific acetyl lysine antibodies for the detection of this modification in cell lysates and evaluated the quality of these antibodies. Based on the immunoblotting analyses, we found that the nature of amino acid sequences adjacent to the modification sites affected the specificity of the site-specific acetyl lysine antibodies. Amino acids with charged, hydrophilic, small, or flexible side chains adjacent to the modification sites increase the likelihood of obtaining high quality site specific acetyl lysine antibodies. This result may provide valuable insights in fine-tuning the amino acid sequences of the epitopes for the generation of site specific acetyl lysine antibodies. Using the site-specific acetyl lysine antibodies, we further discovered that acetylation of histone 3 at four lysine residues was differentially regulated by kinase inhibitors. This result demonstrates the potential application of these antibodies in the study of new signaling pathways that lysine acetylation may participate in. PMID- 27990614 TI - Anatomical variation in the anterolateral ligament of the knee and a new dissection technique for embalmed cadaveric specimens. AB - Claes et al. recently documented and described the anterolateral ligament (ALL) of the knee, demonstrating its existence in 97% of their samples. Here, we further examined the anatomy of this ligament, documented its morphological variation, and assessed the feasibility of its dissection in preserved cadaveric specimens. To achieve this, we dissected 53 preserved cadaveric knees and documented their morphological variation in the anterolateral ligament. The originally described dissection technique for identifying and following the ALL requires flexion of the knee, a state which is often not possible in stiff, preserved cadavers. Here, we describe and confirm the feasibility of an alternate dissection technique in which the quadriceps femoris tendon is incised, for use on specimens in which flexion of the undissected knee is not possible. We also identify a novel technique for assessing whether the anterolateral ligament is absent from a specimen or has simply been obliterated or overlooked, using the lateral inferior genicular vasculature. These dissection techniques have great potential for the dissection of preserved cadavers used in gross anatomy laboratories, and we discuss the applications of such an approach in student-led dissections. Our dissections also uncovered noticeable variation in the anterolateral ligament course and position. Most notably, it often inserts significantly more laterally than the classical presentation (30.2%), or originates more proximally with superficial fibers extending superiorly and laterally over the distal femur (7.5%). PMID- 27990611 TI - Coronary risk score for mineral bone disease in chronic non-diabetic hemodialysis patients: results from a prospective pilot study. AB - INTRODUCTION: Chronic kidney disease-mineral bone disorder enhances coronary artery impairment (often occult and difficult to diagnose) in hemodialysis (HD) patients. The aim of the study was to correlate biochemical and imagistic parameters of MBD with the degree of documented coronary artery disease (CAD) in non-diabetic HD patients, in order to obtain a MBD-coronary risk score as a screening algorithm. METHODS: A 3-year prospective study was conducted on 168 non diabetic HD patients, evaluating MBD biochemical parameters along with pulse wave velocity (PWV) determination and valve/coronary calcification assessment; coronary angiography was performed in symptomatic patients. Correlations between noninvasive parameters and the degree of coronary obstruction were assessed using IBM SPSS Statistics 20 software, Chi-square test and the determination of odds ratio. RESULTS: Significant differences in serum calcium (p < 0.001), phosphates (p = 0.03), bicarbonate (p < 0.001), albumin and iPTH (p = 0.002), percentage of deviations from PWV normal values (p = 0.004), average doses of phosphate binders and vitamin D and the number of vascular/valve calcifications were noted between the study group (angina, n = 17) and control group (asymptomatic, n = 151). After applying MBD-coronary risk score in control group, coronary angiography was performed in high-score patients. CONCLUSION: A noninvasive screening algorithm for early diagnosis of CAD in asymptomatic HD patients with altered MBD parameters is necessary. Applying MBD-coronary risk score might be an important step in the prevention of major coronary episodes by extending the indication for further investigations, early diagnosis and treatment management. PMID- 27990615 TI - Sodium fluoride does not affect the working memory and number of pyramidal cells in rat medial prefrontal cortex. AB - Fluoride is a chemical compound known to bring about fluorosis. It is thought to disrupt the central nervous system because of its ability to induce excitotoxicity and oxidative stress. Any damage of pyramidal cells in the prefrontal cortex would result in cognitive function and working memory regulation disorders. The present study aimed at investigating the effects of sodium fluoride (NaF) on the working memory and estimated total number of medial prefrontal cortex pyramidal cells of adult male rats. Thirty-two male Wistar rats were assigned into four groups, namely control and three treated groups receiving 5, 10 and 20 mg/kg BW, respectively, of oral NaF solution for 30 days. The working memory test was carried out using a Y-maze. The number of pyramidal cells in the medial prefrontal cortex was estimated using an unbiased stereological method. There was no significant difference among groups in the working memory and number of pyramidal neurons in the medial prefrontal cortex cells. PMID- 27990616 TI - The Relationship Between Religion and Risky Behaviors Among Iranian University Students. AB - One factor that protects an individual from risky behavior is religiosity, which is referred to as a shield against risky behaviors. Belief in God and religion plays an important role in young people's lives, and in comparison with their non religious peers. They engage less frequently in risky behaviors, such as violence and sexual relations. The present study investigated the relationship between religiosity and engagement in risky behaviors among students from the Pishva branch of the Islamic Azad University, Tehran Province in Iran. This is a descriptive, analytic cross-sectional study. The sample was comprised of 448 students from different degree majors attending the University. Participants completed two questionnaires, including the Risk-Taking Scale and Duke University Religion Index. The data analyses used one-way ANOVAs and Pearson's correlations. This study found that students who engaged more often in organized religious activities and had higher intrinsic religiosity were less likely to engage in risky behaviors such as sexual risk taking, careless driving, violence, smoking, along with alcohol and drug abuse. Participants with higher involvement in private religious activities reported lower tendencies for the above-mentioned risky behaviors, except sexual risk taking. The findings of this study indicate that the different dimensions of religiousness are related to students' tendency to avoid risky behavior. Thus, it appears that religion may have a role to play in preventing risky taking behavior in Iran. PMID- 27990617 TI - Stroke: Temporal Trends and Association with Atmospheric Variables and Air Pollutants in Northern Spain. AB - Stroke, the second cause of death and the most frequent cause of severe disability among adults in developed countries, is related to a large variety of risk factors. This paper assesses the temporal patterns in stroke episodes in a city in Northern Spain during a 12-year period and analyzes the possible effects that atmospheric pollutants and meteorological variables may have on stroke on a daily scale. Our results show that there is an increase in stroke admissions (r = 0.818, p = 0.001) especially in patients over 85 years old. On a weekly scale, the number of hospital admissions due to stroke remains stable from Monday to Friday, whereas it abruptly decreases during the weekends, reaching its minimum values on Sunday (p < 0.005); however, mortality in patients admitted to the hospital is higher on Sundays than on other days of the week. Finally, a statistically significant positive correlation between the number of stroke hospital admissions and NO2 levels (p = 0.012) and an inverse correlation with relative humidity (p = 0.032) were found. The analysis of the relationship between ischemic strokes and atmospheric circulation shows a higher frequency of the former in Santander with enhanced negative air pressure anomalies over western Spain; the fact that under these conditions the region studied registers very low values of relative humidity is in line with the aforementioned inverse correlation, which has not been described elsewhere in the literature. This study could be a first step for implementing stroke alert protocols depending on air pollution levels and circulation patterns forecasts. PMID- 27990618 TI - Lipid Emulsion Inhibits Apoptosis Induced by a Toxic Dose of Verapamil via the Delta-Opioid Receptor in H9c2 Rat Cardiomyoblasts. AB - The goals of this study were to investigate the effects of lipid emulsion (LE) on apoptosis induced by a toxic dose of verapamil in H9c2 cells and to elucidate the associated cellular mechanism. The effects of LE alone and combined with an inhibitor on the decreases in cell counts and viability induced by verapamil and diltiazem were examined using the MTT assay. The effects of verapamil alone, combined LE and verapamil treatment, and combined inhibitor, LE and verapamil treatment on cleaved caspase-3, caspase-8 and Bax expression, were examined using Western blotting. The effects of verapamil alone and combined with LE on the number of TUNEL-positive H9c2 cells were also examined. LE attenuated the decreases in cell counts and viability induced by verapamil and diltiazem. However, the magnitude of the LE-mediated attenuation of decreased cell viability was enhanced by verapamil compared with diltiazem treatment. Naloxone, naltrindole hydrochloride, LY294002 and MK-2206 inhibited the LE-mediated attenuation of increased cleaved caspase-3 and caspase-8 expression induced by verapamil. LE attenuated the increase in the number of TUNEL-positive cell induced by verapamil. These results suggest that LE attenuates apoptosis induced by verapamil via activation of the delta-opioid receptor, phosphoinositide 3 kinase and Akt. PMID- 27990619 TI - Doxorubicin and Liposomal Doxorubicin Differentially Affect Expression of miR 208a and let-7g in Rat Ventricles and Atria. AB - Anthracyclines use is limited by profound cardiotoxicity. Involvement of miRNAs in anthracycline-induced cardiotoxicity (AIC) is still not completely understood. Thus, the expression of AIC-related microRNAs was determined in rat atria and ventricles after doxorubicin (DOX) and liposomal doxorubicin (L-DOX) administration. Vehiculum, DOX or L-DOX were applied intraperitoneally in a single dose to male Wistar rats (3 groups: control, DOX and L-DOX, respectively). Rats were sacrificed after 24 h, and samples from left atrium (LA)/ventricle (LV) and right atrium (RA)/ventricle (RV) were obtained. Expressions of miR-208a, let 7g and snU6 were determined using qRT-PCR. In the control group, miR-208a was highly abundant in the atria compared to the ventricles and in the left-sided structures compared to the right-sided structures, while let-7g showed only atrio ventricular gradient with predominant expression in the atria. Administration of both DOX and L-DOX resulted in 38.87 and 23.57% reduction in miR-208a expression in the LV (p = 0.028) and in 13.79 and 14.70% reduction in let-7g expression in the LA (p = 0.015), respectively. Acute administration of DOX/L-DOX alters expression of miR-208a in LV and of let-7g in LA. These changes may partly contribute to the development of AIC. PMID- 27990620 TI - Role of Peroxynitrite-Induced Activation of Poly(ADP-Ribose) Polymerase (PARP) in Circulatory Shock and Related Pathological Conditions. AB - Peroxynitrite is a powerful oxidant, formed from the reaction of nitric oxide and superoxide. It is known to interact and modify different biological molecules such as DNA, lipids and proteins leading to alterations in their structure and functions. These events elicit various cellular responses, including cell signaling, causing oxidative damage and committing cells to apoptosis or necrosis. This review discusses nitrosative stress-induced modification in the DNA molecule that results in the formation of 8-nitroguanine and 8-oxoguanine, and its role in disease conditions. Different approaches of cell death, such as necrosis and apoptosis, are modulated by cellular high-energy species, such as ATP and NAD+. High concentrations of peroxynitrite are known to cause necrosis, whereas low concentrations lead to apoptosis. Any damage to DNA activates cellular DNA repair machinery, like poly(ADP-ribose) polymerase (PARP). PARP-1, an isoform of PARP, is a DNA nick-sensing enzyme that becomes activated upon sensing DNA breakage and triggers the cleavage of NAD+ into nicotinamide and ADP ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite induced hyperactivation of PARP causes depletion of NAD+ and ATP culminating cell dysfunction, necrosis or apoptosis. This mechanistic pathway is implicated in the pathogenesis of a variety of diseases, including circulatory shock (which is characterized by cellular hypoxia triggered by systemic altered perfusion and tissue oxygen utilization leading end-organ dysfunction), sepsis and inflammation, injuries of the lung and the intestine. The cytotoxic effects of peroxynitrite centering on the participation of PARP-1 and ADP-ribose in previously stated diseases have also been discussed in this review. PMID- 27990621 TI - High-definition dacryoendoscopic features of a canalicular squamous papilloma. PMID- 27990622 TI - Refractive outcome of combined phacoemulsification and endoscopic cyclophotocoagulation. AB - PURPOSE: To compare the refractive outcome of eyes that underwent phacoemulsification combined with endoscopic cyclophotocoagulation (phaco-ECP) with the eyes that underwent phacoemulsification alone. METHODS: A retrospective case series review of 103 consecutive eyes that underwent phaco-ECP and 62 eyes that underwent phacoemulsification between January 2006 and August 2012 was conducted. Post-operative refractive outcomes were obtained by subjective refraction or autorefraction. Demographic data, best corrected visual acuity, intraocular pressure, number of glaucoma agents and mean deviation of the Humphrey visual field test (MD) were also analysed. RESULTS: The total number of eyes included in the study was 62 eyes for the phaco-ECP group and 62 eyes for the control group who underwent phacoemulsification alone. More than 90% of eyes (n = 56) in phaco-ECP group achieved post-operative refraction within +/-1 dioptre (D) of the target refraction. In the control group, 100% of eyes achieved post-operative refraction within +/-1D of the target refraction. When comparing the difference between the target and the actual refractive outcome between the phaco-ECP and the control group, there was no statistically significant difference. CONCLUSIONS: Refractive outcome after phaco-ECP is comparable to phacoemulsification alone. This study suggests that the intraocular lens power can be selected for cataract surgery alone and that ECP does not change the effective lens position significantly; therefore, no modification of biometry formulae is required. Phaco-ECP should be considered as an effective, safe and predictable surgical treatment option for glaucoma patients with co-existing cataract. PMID- 27990623 TI - The Effect of Time-to-Surgery on Outcome in Patients with Neurological Deficits Caused by Spinal Tuberculosis. AB - AIM: To compare and analyze the influence of the duration of neurological symptoms and degree of neurological deficits on the postoperative neurological recovery of patients with neurological deficits caused by spinal tuberculosis (TB). MATERIAL AND METHODS: We retrospectively reviewed the data of 47 adult patients with neurological deficits caused by spinal TB. They were divided into three and four groups according to the duration of neurological symptoms and degree of neurological deficits, respectively. Differences in the mean rank within groups were statistically evaluated, and logistic regression of the two factors was performed to evaluate how these factors influence the recovery of neurological function. RESULTS: Non-parametric tests indicated a significant difference among improvement grades in the three groups based on the duration of neurological symptoms (p < 0.05). No significant difference was found among improvement grades of the patients preoperatively in the four groups based on the grade of neurological deficits (p > 0.05). Logistic regression showed that the preoperative grade of neurological deficits significantly influenced the improvement grade of neurological deficits (p < 0.05), but the correlation was not close (R2=0.28). CONCLUSION: The duration of neurological symptoms, but not the grade of neurological involvement, is correlated with postoperative neurological recovery of patients with neurological deficits caused by spinal TB. However, reducing preoperative chemotherapy does not significantly yield improved outcomes; therefore, undergoing four weeks of preoperative chemotherapy is acceptable. PMID- 27990625 TI - In vitro fertilization healthcare professionals generally underestimate patients' satisfaction with quality of care. AB - INTRODUCTION: Previous studies have mainly compared professionals' and patients' ratings of the importance of different care aspects, finding poor agreement between the groups concerning patient-centered quality of care. There is still little known about professionals' knowledge of how patients experience the quality of care they receive during in vitro fertilization (IVF) treatments. The aim of this study was to investigate how IVF healthcare professionals estimate patients' experience of patient-centered quality of care and if certain factors influenced the IVF professionals' perceptions and IVF patients' experience of quality of care. MATERIAL AND METHODS: All 16 IVF public and private clinics in Sweden participated in this cross-sectional study. A total of 268 IVF healthcare professionals and 3298 patients (women and men) undergoing IVF treatment between January and May 2015 participated by answering the validated questionnaire "Quality from the patients' perspective of in vitro fertilization treatment" (QPP IVF). RESULTS: Healthcare professionals significantly underestimated patients' satisfaction with the patient-centered quality of care they received in all aspects measured. Both patients and professionals rated the most deficient factors to be "responsibility/continuity", "participation" and "availability". Healthcare professionals and patients belonging to private clinics evaluated patient-centered care as significantly better than professionals and patients at public clinics in almost all aspects measured. CONCLUSION: The results of this study will increase the professionals' understanding of the patients' experiences during IVF treatment and provide additional knowledge when identifying areas to prioritize to improve quality of care. PMID- 27990624 TI - Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies. AB - Glioblastoma (GBM) is one hypervascular and hypoxic tumor known among solid tumors. Antiangiogenic therapeutics (AATs) have been tested as an adjuvant to normalize blood vessels and control abnormal vasculature. Evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance to AATs. Here, we identified that GBM following AAT (Vatalanib) acquired an alternate mechanism to support tumor growth, called vascular mimicry (VM). We observed that Vatalanib induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer-side. The PAS+ matrix is positive for basal laminae (laminin) indicating vascular structures. Vatalanib treated GBM displayed various stages of VM such as initiation (mosaic), sustenance, and full-blown VM. Mature VM structures contain red blood cells (RBC) and bear semblance to the functional blood vessel-like structures, which provide all growth factors to favor tumor growth. Vatalanib treatment significantly increased VM especially in the core of the tumor, where HIF-1alpha was highly expressed in tumor cells. VM vessels correlate with hypoxia and are characterized by co-localized MHC-1+ tumor and HIF-1alpha expression. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at periphery of the tumors. In summary, AAT induced resistance characterized by VM is an alternative mechanism adopted by tumors to make functional vessels by transdifferentiation of tumor cells into endothelial-like cells to supply nutrients in the event of hypoxia. AAT induced VM is a potential therapeutic target of the novel formulation of HET0016. Our present study suggests that HET0016 has a potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials. PMID- 27990626 TI - Changing Teacher-Child Dyadic Interactions to Improve Preschool Children's Externalizing Behaviors. AB - A randomized controlled trial was used to examine the impact of an attachment based, teacher-child, dyadic intervention (Banking Time) to improve children's externalizing behavior. Participants included 183 teachers and 470 preschool children (3-4 years of age). Classrooms were randomly assigned to Banking Time, child time, or business as usual (BAU). Sparse evidence was found for main effects on child behavior. Teachers in Banking Time demonstrated lower negativity and fewer positive interactions with children compared to BAU teachers at post assessment. The impacts of Banking Time and child time on reductions of parent- and teacher-reported externalizing behavior were greater when teachers evidenced higher-quality, classroom-level, teacher-child interactions at baseline. An opposite moderating effect was found for children's positive engagement with teachers. PMID- 27990627 TI - The Fertility Assessment and Counseling Clinic - does the concept work? A prospective 2-year follow-up study of 519 women. AB - INTRODUCTION: The Fertility Assessment and Counseling (FAC) Clinic was initiated to provide women with information about their current fertility status to prevent infertility and smaller families than desired. The aim was to study the predictive value of a risk assessment score based on known fertility risk factors in terms of time to pregnancy. MATERIAL AND METHODS: Prospective cohort study of the first 570 women attending the FAC Clinic from 2011 to 2013 at Rigshospitalet, Denmark. A consultation included: risk assessment score sheet with items on infertility risk factors, anti-Mullerian hormone and ultrasound. The risk score was categorized as low, medium or high. After 2 years an email-based questionnaire was distributed regarding subsequent pregnancies. RESULTS: The follow-up questionnaire was answered by 519 women (91.1%). The mean age was 35 years and 38% were single at inclusion. The majority (67.8%, 352/519) tried to conceive within 2 years after attending the FAC Clinic. At follow up, 73.6% (259/352) had achieved a pregnancy, 21% (74/352) were still trying and 5.4% (19/352) had given up. Two-thirds (65%) with only low risk scores conceived spontaneously within 12 months, although this figure was only 32% for women with at least one high risk score (n = 82). Accordingly, presence of at least one high risk score reduced the odds of achieving a pregnancy within 12 months by 75% (OR 0.25, 95% CI 0.12-0.52). CONCLUSION: The new FAC Clinic concept seems usable and offers a tool for fertility experts to guide women on how to fulfill their reproductive life-plan. PMID- 27990628 TI - Action plans with brief patient education for exacerbations in chronic obstructive pulmonary disease. AB - BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major driver of decline in health status and impose high costs on healthcare systems. Action plans offer a form of self-management that can be delivered in the outpatient setting to help individuals recognise and initiate early treatment for exacerbations, thereby reducing their impact. OBJECTIVES: To compare effects of an action plan for COPD exacerbations provided with a single short patient education component and without a comprehensive self-management programme versus usual care. Primary outcomes were healthcare utilisation, mortality and medication use. Secondary outcomes were health-related quality of life, psychological morbidity, lung function and cost-effectiveness. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register along with CENTRAL, MEDLINE, Embase and clinical trials registers. Searches are current to November 2015. We handsearched bibliographic lists and contacted study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCT) and quasi-RCTs comparing use of an action plan versus usual care for patients with a clinical diagnosis of COPD. We permitted inclusion of a single short education component that would allow individualisation of action plans according to management needs and symptoms of people with COPD, as well as ongoing support directed at use of the action plan. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. For meta analyses, we subgrouped studies via phone call follow-up directed at facilitating use of the action plan. MAIN RESULTS: This updated review includes two additional studies (and 976 additional participants), for a total of seven parallel-group RCTs and 1550 participants, 66% of whom were male. Participants' mean age was 68 years and was similar among studies. Airflow obstruction was moderately severe in three studies and severe in four studies; mean post bronchodilator forced expiratory volume in one second (FEV1) was 54% predicted, and 27% of participants were current smokers. Four studies prepared individualised action plans, one study an oral plan and two studies standard written action plans. All studies provided short educational input on COPD, and two studies supplied ongoing support for action plan use. Follow-up was 12 months in four studies and six months in three studies.When compared with usual care, an action plan with phone call follow-up significantly reduced the combined rate of hospitalisations and emergency department (ED) visits for COPD over 12 months in one study with 743 participants (rate ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.79; high-quality evidence), but the rate of hospitalisations alone in this study failed to achieve statistical significance (RR 0.69, 95% CI 0.47 to 1.01; moderate-quality evidence). Over 12 months, action plans significantly decreased the likelihood of hospital admission (odds ratio (OR) 0.69, 95% CI 0.49 to 0.97; n = 897; two RCTs; moderate-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) 19 (11 to 201)) and the likelihood of an ED visit (OR 0.55, 95% CI 0.38 to 0.78; n = 897; two RCTs; moderate-quality evidence; NNTB over 12 months 12 (9 to 26)) compared with usual care.Results showed no significant difference in all-cause mortality during 12 months (OR 0.88, 95% CI 0.59 to 1.31; n = 1134; four RCTs; moderate-quality evidence due to wide confidence interval). Over 12 months, use of oral corticosteroids was increased with action plans compared with usual care (mean difference (MD) 0.74 courses, 95% CI 0.12 to 1.35; n = 200; two RCTs; moderate-quality evidence), and the cumulative prednisolone dose was significantly higher (MD 779.0 mg, 95% CI 533.2 to 10248; n = 743; one RCT; high-quality evidence). Use of antibiotics was greater in the intervention group than in the usual care group (subgrouped by phone call follow-up) over 12 months (MD 2.3 courses, 95% CI 1.8 to 2.7; n = 943; three RCTs; moderate-quality evidence).Subgroup analysis by ongoing support for action plan use was limited; review authors noted no subgroup differences in the likelihood of hospital admission or ED visits or all-cause mortality over 12 months. Antibiotic use over 12 months showed a significant difference between subgroups in studies without and with ongoing support.Overall quality of life score on St George's Respiratory Questionnaire (SGRQ) showed a small improvement with action plans compared with usual care over 12 months (MD -2.8, 95% CI -0.8 to -4.8; n = 1009; three RCTs; moderate-quality evidence). Low-quality evidence showed no benefit for psychological morbidity as measured with the Hospital Anxiety and Depression Scale (HADS). AUTHORS' CONCLUSIONS: Use of COPD exacerbation action plans with a single short educational component along with ongoing support directed at use of the action plan, but without a comprehensive self-management programme, reduces in-hospital healthcare utilisation and increases treatment of COPD exacerbations with corticosteroids and antibiotics. Use of COPD action plans in this context is unlikely to increase or decrease mortality. Whether additional benefit is derived from periodic ongoing support directed at use of an action plan cannot be determined from the results of this review. PMID- 27990630 TI - Functional and structural characterisation of a bacterial O-methyltransferase and factors determining regioselectivity. AB - Mg2+ -dependent catechol-O-methyltransferases occur in animals as well as in bacteria, fungi and plants, often with a pronounced selectivity towards one of the substrate's hydroxyl groups. Here, we show that the bacterial MxSafC exhibits excellent regioselectivity for para as well as for meta methylation, depending on the substrate's characteristics. The crystal structure of MxSafC was solved in apo and in holo form. The structure complexed with a full set of substrates clearly illustrates the plasticity of the active site region. The awareness that a wide range of factors influences the regioselectivity will aid the further development of catechol-O-methyltransferases as well as other methyltransferases as selective and efficient biocatalysts for chemical synthesis. PMID- 27990629 TI - Immigrant Chinese Mothers' Socialization of Achievement in Children: A Strategic Adaptation to the Host Society. AB - Academic socialization by low-income immigrant mothers from Mainland China was investigated in two studies. Immigrant Chinese mothers of first graders (n = 52; Mage = 38.69) in the United States (Study 1) and kindergartners (n = 86; Mage = 36.81) in Hong Kong (Study 2) tell stories that emphasized achieving the best grade through effort more than did African American (n = 39; Mage = 31.44) and native Hong Kong (n = 76; Mage = 36.64) mothers, respectively. The emphasis on achievement was associated with mothers' heightened discussion on discrimination (Study 1) and beliefs that education promotes upward mobility (Study 2), as well as children's expectations that a story protagonist would receive maternal criticism for being nonpersistent in learning (Study 2). PMID- 27990631 TI - Holliday junction-resolving enzymes-structures and mechanisms. AB - Holliday junction-resolving enzymes are nucleases that are highly specific for the structure of the junction, to which they bind in dimeric form. Two symmetrically disposed cleavages are made. These are not simultaneous, but the second cleavage is accelerated relative to the first, so ensuring that bilateral cleavage occurs during the lifetime of the DNA-protein complex. In eukaryotic cells there are two known junction-resolving activities. GEN1 is similar to enzymes from lower organisms. A crystallographic structure of a fungal GEN1 bound to the product of resolution has been determined. These complexes are dimerized within the crystal lattice such that the strands of the products may be simply reconnected to form a junction. These structures suggest a trajectory for the resolution process. PMID- 27990632 TI - RNPS1 is modulated by ubiquitin-specific protease 4. AB - RNA-binding protein with serine-rich domain 1 (RNPS1) is a component of pre splicing and post-splicing multiprotein complexes, which activates constitutive and alternative splicing. RNPS1 participates in the formation of the spliceosome and activates the pre-mRNA splicing process. In the present study, we found that ubiquitin-specific protease 4 (USP4) is a binding partner of RNPS1. Although RNPS1 is polyubiquitinated by both K48- and K63-linkages, USP4 exclusively deubiquitinates K63-linked polyubiquitin chains of RNPS1. We also demonstrate that the catalytic activity of USP4 on ubiquitinated RNPS1 is elevated by squamous cell carcinoma antigen recognized by T cells 3 (Sart3). PMID- 27990633 TI - A Ferris Wheel Accident at a Movable Amusement Park. AB - This study presented a Ferris wheel accident case. A Ferris wheel is composed of many parts, and the outmost ring of it is assembled using a lock pin. This accident occurred because the lock pin caught the door of a gondola and the gondola overturned. Five of the seven passengers in the gondola fell to the ground, along with the gondola's viewing window. The investigation revealed that the gondola became stuck when its door was caught by a lock pin at the Ferris wheel's three o'clock position. The contact between the door and the lock pin was due to a structural problem: There was not enough space allotted between the door and the lock pin. Therefore, if a passenger pushed on the gondola's door, the potential existed for contact between the door and the lock pin. PMID- 27990634 TI - Out-group threats and distress as antecedents of common in-group identity among majority and minority group members in the aftermath of a natural disaster. AB - The aim of the present study was to examine the role of out-group threats in fostering one-group perceptions directly and indirectly via post-traumatic stress symptoms in the aftermath of a natural disaster. We also tested whether these relationships differ depending on the ethnic group of belonging (majority vs. minority). Participants were 589 Italians and 122 immigrants from a region strongly affected by the earthquakes that struck Northern Italy in 2012. Results revealed that among Italians threat stemming from negative out-group behaviour was associated positively with post-traumatic stress symptoms and negatively with perceptions of being a common group with immigrant survivors. Among immigrants, threat posed by the out-group for economic resources was positively associated with post-traumatic stress symptoms and, indirectly, with higher one-group perceptions. PMID- 27990635 TI - A flexible cofactor-binding loop in the novel arginine methyltransferase Sfm1. AB - Arginine methylation is a common post-translational modification and is critical for many cellular processes. Sfm1 is a novel arginine methyltransferase that contains a SpoU-TrmD (SPOUT) domain, a typical fold known for RNA methylation, but acts on a ribosomal protein. The underlying mechanism is poorly understood. Here, we report cocrystal structures of Sfm1 in complex with various ligands. We found that a critical loop responsible for S-adenosyl-l-methionine (SAM) binding adopts a different conformation from previous reports, and SAM appears to exhibit double conformations. Deletion of this loop greatly reduces the affinity of Sfm1 to SAM. Additionally, by comparison to closely related tRNA-methyltransferase Trm10, our structural analyses offer a good explanation why the two enzymes utilize distinct substrates, providing insights into the molecular mechanism. PMID- 27990636 TI - Factitious Disorder in a Patient Claiming to be a Sexually Sadistic Serial Killer. AB - Factitious disorder involves the conscious simulation of psychological or physiological symptoms of illness, for the purpose of fulfilling the unconscious desire to be taken care of or to assume the "sick role." Typically patients with factitious disorder simulate conditions that are designed to arouse feelings of empathy in care providers with the intention to engage them in caretaking. However, patients might also simulate conditions that arouse revulsion or rejection and still meet full diagnostic criteria for factitious disorder. In this case report, we present a patient who fabricated an elaborate history of being a sexually sadistic serial killer with homicidal ideation with the intention of obtaining personal attention, nurturance, and empathy from his psychotherapist. However, given the nature of his feigned condition, the patient frightened the very person whom he sought to engage in caretaking. PMID- 27990637 TI - Gastrointestinal symptoms and food intolerance 2 years after laparoscopic Roux-en Y gastric bypass for morbid obesity. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective treatment for morbid obesity, but might aggravate gastrointestinal complaints and food intolerance. The long-term prevalence of these symptoms has not been well studied. METHODS: In a cross-sectional study, all patients who underwent primary LRYGB from May to October 2012 were approached 2 years after surgery to complete a general health questionnaire, the Gastrointestinal Symptom Rating Scale (GSRS), and a food intolerance questionnaire. The results were compared with those for a control group of morbidly obese patients. RESULTS: A total of 249 patients were included for analysis, representing a response rate of 93.9 per cent. Mean(s.d.) total weight loss was 30.8(8.7) per cent. The total mean GSRS score was higher in patients who had LRYGB (median 2.19 versus 1.75 in unoperated patients; P < 0.001); the difference in symptoms of indigestion was most notable (P < 0.001). Food intolerance for specific products was reported by 70.7 (95 per cent c.i. 64.8 to 76.0) per cent of the postoperative patients, for a median of 4 foods. There was a positive correlation between food intolerance and score on the GSRS. There was no correlation between either food intolerance or the total mean GSRS score and weight loss, but there was a correlation between weight loss and abdominal pain. CONCLUSION: At 2 years after surgery, patients undergoing LRYGB for morbid obesity have more gastrointestinal complaints than obese controls. Food intolerance is a common side-effect of LRYGB independent of degree of weight loss or the presence of other abdominal symptoms. PMID- 27990639 TI - Reconstructing larval growth and habitat use in an amphidromous goby using otolith increments and microchemistry. AB - High-resolution analysis of growth increments, trace element chemistry and oxygen isotope ratios (delta18 O) in otoliths were combined to assess larval and post larval habitat use and growth of Awaous stamineus, an amphidromous goby native to Hawai'i. Otolith increment widths indicate that all individuals experience a brief period of rapid growth during early life as larvae and that the duration of this growth anomaly is negatively correlated with larval duration. A protracted high-growth period early in larval life is associated with a lower ratio of Sr:Ca, which may reflect low salinity conditions in nearshore habitats. A distinct shift in delta18 O (range: 4-50/00) is closely associated with the metamorphic mark in otoliths, indicating that larval metamorphosis occurs promptly upon return to fresh water. Strontium and other trace elements are not as tightly coupled to the metamorphosis mark, but confirm the marine-to freshwater transition. Integration of microstructural and microchemical approaches reveals that larvae vary substantially in growth rate, possibly in association with habitat differences. Although time and financial costs make it difficult to achieve large sample sizes, present results show that examining even a small number of individuals can lead to novel inferences about early life history in diadromous fishes and illustrates the value of integrating analyses. PMID- 27990638 TI - Calretinin Immunoreactivity in the Human Testis Throughout Fetal Life. AB - The main functions of the testis are sex hormone and sperm cell production. Steroidogenesis occurs in the Leydig interstitial cells and spermatogenesis in the seminiferous tubules. Male gonad morphogenesis is a finely orchestrated process, mainly coordinated by hormones, whose actions can significantly affect post-pubertal testicular function. Calcium is a key intracellular messenger, which regulates many signal transduction pathways, and is also implicated in steroidogenesis. Calcium homeostasis and signaling rely on many calcium-binding proteins including calretinin, of the "EF-hand" protein family. Calretinin is a highly conserved protein mainly expressed in the nervous system but also detected in rat and human adult and fetal testis as well as in pathological conditions. Calretinin expression in the fetal testis, however, has not been thoroughly analyzed probably owing to limited availability and paucity of tissues. Here, we examined by immunocytochemistry the expression of calretinin in human fetal testis specimens, obtained from natural and therapeutic abortions, at various developmental ages. We found that calretinin-immunoreactive Leydig cells were visible throughout the timeframe studied (14th-27th week). Immunoreactivity was also observed in Sertoli cells and in the germ cells of the immature seminiferous tubules. Overall our data indicate that calretinin expression parallels the decline in Leydig cell number, suggesting that its presence is indeed correlated to their steroidogenic activity. They also suggest that the intratubular positivity of calretinin could be linked to the ability of Sertoli cells to produce locally acting hormones contributing to the histodifferentiation of the male genital tract. J. Cell. Physiol. 232: 1872-1878, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990640 TI - The mechanism of folding robustness revealed by the crystal structure of extra superfolder GFP. AB - Stability of green fluorescent protein (GFP) is sometimes important for a proper practical application of this protein. Random mutagenesis and targeted mutagenesis have been used to create better-folded variants of GFP, including recently reported extra-superfolder GFP. Our aim was to determine the crystal structure of extra-superfolder GFP, which is more robustly folded and stable than GFP and superfolder GFP. The structural and structure-based mutagenesis analyses revealed that some of the mutations that created extra-superfolder GFP (F46L, E126K, N149K, and S208L) contribute to folding robustness by stabilizing extra superfolder GFP with various noncovalent bonds. PMID- 27990641 TI - Cytoplasmic Localization of RUNX3 via Histone Deacetylase-Mediated SRC Expression in Oxidative-Stressed Colon Cancer Cells. AB - Runt domain transcription factor 3 (RUNX3) is a transcription factor that functions as a tumor suppressor. RUNX3 is frequently inactivated by epigenetic silencing or its protein mislocalization (cytoplasmic localization) in many cancer types. This study investigated whether oxidative stress induces redistribution of RUNX3 from the nucleus to the cytoplasm. The cytoplasmic localization of RUNX3 was associated with oxidative stress-induced RUNX3 phosphorylation at tyrosine residues via SRC activation. Moreover, oxidative stress increased expression of histone deacetylases (HDACs). RUNX3 phosphorylation and SRC expression induced by oxidative stress were inhibited by knockdown of HDAC1, restoring the nuclear localization of RUNX3 under oxidative stress. In conclusion, these results demonstrate that HDAC1- and SRC-mediated phosphorylation of RUNX3 induced by oxidative stress is associated with the cytoplasmic localization of RUNX3 and can lead to RUNX3 inactivation and carcinogenesis. J. Cell. Physiol. 232: 1914-1921, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990642 TI - Anemia tolerance during normo-, hypo-, and hypervolemia. AB - BACKGROUND: Restrictive intraoperative fluid management has been demonstrated to improve outcome of visceral and lung surgery in several studies. However, subsequent hypovolemia (HOV) may be accompanied by a decrease of anemia tolerance, resulting in increased transfusion needs. We therefore investigated the effect of volume status on anemia tolerance. STUDY DESIGN AND METHODS: Eighteen domestic pigs of either sex (mean weight, 23.5 +/- 4.8 kg) were anesthetized, ventilated, and randomized into three experimental groups: normovolemia (no intervention), HOV (blood loss of 40% of blood volume), and hypervolemia (HEV; volume infusion of 40% of blood volume). The animals were then hemodiluted until their individual critical hemoglobin concentrations (Hbcrit ) were reached by the exchange of whole blood for hydroxyethyl starch (HES; 130:0.4). Subsequently, organ-specific hypoxia was assessed using pimonidazole tissue staining in relevant organs. Hemodynamic and metabolic variables were also investigated. RESULTS: Despite significant differences in exchangeable blood volume, Hbcrit was the same in all groups (2.3 g/dL, NS). During HOV, tissue hypoxia was aggravated in the myocardium, brain, and kidneys, whereas tissue oxygenation of the liver and intestine was not influenced by volume status. HEV increased tissue hypoxia in the lungs, but did not impact tissue oxygenation of other organs. CONCLUSIONS: The combination of hemorrhagic HOV with subsequent anemia leads to accentuated tissue hypoxia, revealed by a significant increase in pimonidazole binding at Hbcrit , in heart, lungs, brain, and kidney. The lungs were the only organ that showed increased tissue hypoxia after pretreatment of HES infusion and subsequent anemia by normovolemic hemodilution. PMID- 27990644 TI - Authors' reply - Re: Wang et al. Controversial role of the possible oxyntic stem cell marker ASPM in gastric cancer. PMID- 27990643 TI - Phase 1 Randomized, Double-Blind, Placebo-Controlled Study to Determine the Safety, Tolerability, and Pharmacokinetics of a Single Escalating Dose and Repeated Doses of CN-105 in Healthy Adult Subjects. AB - Spontaneous intracranial hemorrhage (ICH) remains a devastating stroke subtype, affecting as many as 80,000 people annually in the United States and associated with extremely high mortality. In the absence of any pharmacological interventions demonstrated to improve outcome, care for patients with ICH remains largely supportive. Thus, despite advances in the understanding of ICH and brain injury, there remains an unmet need for interventions that improve neurologic recovery and outcomes. Recent research suggesting inflammation and APOE genotype play a role in modifying neurologic outcome after brain injury has led to the development of an APOE-derived peptide agent (CN-105). Preclinical studies have demonstrated that CN-105 effectively downregulates the inflammatory response in acute brain injury, including ICH. Following Investigational New Drug (IND) enabling studies in murine models, this first-in-human single escalating dose and multiple dose placebo-controlled clinical trial was performed to define the safety and pharmacokinetics (PK) of CN-105. A total of 48 subjects (12 control, 36 active) were randomized in this study; all subjects completed the study. No significant safety issues were identified with both dosing regimens, and PK analysis revealed linearity without significant drug accumulation. The median half-life in the terminal elimination phase of CN-105 following a single or repeated dosing regimen did not change (approximately 3.6 hours). With the PK and preliminary safety of CN-105 established, the drug is now poised to begin first in-disease phase 2 clinical trials in patients with ICH who urgently need new therapeutic options. PMID- 27990645 TI - Evaluation of a Unique Defibrillation Unit with Dual-Vector Biphasic Waveform Capabilities: Towards a Miniaturized Defibrillator. AB - BACKGROUND: Automated external defibrillators can provide life-saving therapies to treat ventricular fibrillation. We developed a prototype unit that can deliver a unique shock waveform produced by four independent capacitors that is delivered through two shock vectors, with the rationale of providing more robust shock pathways during emergent defibrillation. We describe the initial testing and feasibility of this unique defibrillation unit, features of which may enable downsizing of current defibrillator devices. METHODS: We tested our defibrillation unit in four large animal models (two canine and two swine) under general anesthesia. Experimental defibrillation thresholds (DFT) were obtained by delivery of a unique waveform shock pulse via a dual-vector pathway with four defibrillation pads (placed across the chest). DFTs were measured and compared with those of a commercially available biphasic defibrillator (Zoll M series, Zoll Medical, Chelmsford, MA, USA) tested in two different vectors. Shocks were delivered after 10 seconds of stable ventricular fibrillation and the output characteristics and shock outcome recorded. Each defibrillation series used a step-down to failure protocol to define the defibrillation threshold. RESULTS: A total of 96 shocks were delivered during ventricular fibrillation in four large animals. In comparison to the Zoll M series, which delivered a single-vector, biphasic shock, the energy required for successful defibrillation using the unique dual-vector biphasic waveform did not differ significantly (P = 0.65). CONCLUSIONS: Our early findings support the feasibility of a unique external defibrillation unit using a dual-vector biphasic waveform approach. This warrants further study to leverage this unique concept and work toward a miniaturized, portable shock delivery system. PMID- 27990647 TI - Discharge of a Pistol Out a Car Window with the Breech Within the Interior of the Car: Analysis of Gunshot Residue on a Car's Interior Surfaces. AB - The defendant, the driver of the questioned car, allegedly extended his right arm over the passenger seat and fired a single shot from a 380 pistol out the passenger window with the pistol's breech within the car. A simulation of this shooting scenario using the same model car, but different year, was conducted to quantitate gunshot residue (GSR) contamination of interior surfaces within the car. The test car's dash and headliner/window frame above the pistol had the heaviest GSR contamination. The dash GSR from airborne deposition documents a firearm discharge within the vehicle. Transfer from GSR-contaminated hands or clothing to the dash is unlikely. The heavy GSR contamination of the headliner/window frame above the pistol likely documents the window from which the pistol was fired, but additional experiments are needed to verify. PMID- 27990646 TI - Controversial role of the possible oxyntic stem cell marker ASPM in gastric cancer. PMID- 27990649 TI - Quantification of surgical margin length changes after excision of feline injection site sarcomas-A pilot study. AB - OBJECTIVE: To evaluate degree length change of lateral surgical margins at various stages of processing for histological examination and quantify the length change between grossly normal surgical margins (GNSM) and pathologist-reported histologic tumor-free margin (HTFM) in widely resected feline injection site sarcoma (FISS) specimens. STUDY DESIGN: Prospective clinical study. ANIMALS: Five client-owned cats with injection site sarcomas. METHODS: All cats underwent wide surgical excision (35-55 mm gross lateral margins, 2 fascial planes deep). Gross normal lateral margin measurements from tumor edge were recorded in 4 directions (cranial, caudal, dorsal, ventral) at 5 time points: intra-op (in vivo GNSM); immediately following excision (ex vivo GNSM); following formalin fixation (post fixation GNSM); after trimming and mounting on glass slides (on-slide GNSM); and HTFM at the narrowest point from the HTFM from the same slides used for on-slide GNSM. Percent change in lateral margin length from in vivo measurements was quantified at each time point and compared using 1-way repeated measures ANOVA. RESULTS: The largest mean decrease in percent GNSM length occurred immediately after excision (in vivo to ex vivo GNSM = 29%; P = .016). Formalin fixation, trimming, and mounting on slides did not result in additional significant changes in length. Mean HTFM length was significantly decreased compared to both in vivo GNSM (33%; P = .014) and on-slide GNSM (7%; P = .024). CONCLUSION: Significant decreases in surgical margin length in FISS specimens occur immediately following excision (prior to formalin fixation). Subgross evaluation of tumor-free margins from on-slide GNSM to HTFM overestimates the actual (histologic) tumor-free margins. PMID- 27990648 TI - Total laparoscopic gastropexy using 1 simple continuous barbed suture line in 63 dogs. AB - OBJECTIVE: To describe the use and outcome of a single, simple continuous, barbed suture line for prophylactic, total laparoscopic gastropexy in dogs. STUDY DESIGN: Multi-center, retrospective case series. ANIMALS: Sixty-three client owned dogs. METHODS: Medical records of dogs undergoing total laparoscopic gastropexy using a barbed suture at 4 academic veterinary hospitals from 2011 2015 were reviewed. Data collected included signalment, procedure time, procedure associated complications, short-term complications, and long-term outcome. All procedures were performed under general anesthesia in dorsal to dorsal-left oblique recumbency. Laparoscopic ports were placed on ventral midline in 1 of 3 port configurations, and 5 mm laparoscopic needle drivers were used for intracorporeal sutured gastropexy with unidirectional barbed suture. The gastropexy was positioned just caudal to the 13th rib, 2-4 cm lateral to the rectus abdominis muscle. RESULTS: Sixty-three dogs underwent total laparoscopic gastropexy with a single, simple continuous, barbed suture line. Median gastropexy surgery time was 70 minutes (interquartile range [IQR] 60-90 minutes). One dog sustained splenic laceration from Veress needle penetration during initial abdominal insufflation. Short term (>24 hours to 6 months postoperative) complications included incisional seroma formation (n = 2) and suture reaction (n = 1). Long term (>6 months postoperative) complications included intermittent regurgitation and chronic diarrhea in 1 dog. Fifteen dogs had postoperative ultrasound and all had intact gastropexy sites. CONCLUSION: Total laparoscopic barbed gastropexy using a single, simple continuous, barbed suture line in dogs is safe and results in an intact gastropexy long term. PMID- 27990650 TI - Phenotypic characterization of qualitative parameters and antioxidant contents in peach and nectarine fruit and changes after jam preparation. AB - BACKGROUND: Sugars and antioxidants in peaches contribute to fresh fruit quality and nutrition; however, information on widely grown cultivars and changes induced after peach jam preparation is limited. In the present study, colour, sugars and antioxidant parameters were determined in fruit and jam from 45 peach and nectarine cultivars. RESULTS: Pronounced varietal differences were found in sorbitol (42-fold range), total phenolics (TPs) and antioxidant capacities (10- to 19-fold range). Sorbitol levels were greater in non-melting peach, followed by nectarine, and lower values were found in melting peach cultivars. Late-harvested peach and nectarine cultivars tended to have a higher soluble solid content and antioxidant potential. Cultivars with relatively high antioxidant contents produced darker and redder jams, containing more antioxidants, than the jam or the fruit from the other cultivars. Jam-TPs were reduced by 48% compared to fruit TPs, with greater reduction being noted in high antioxidant cultivars. The most favorable jam organoleptic characteristics were found in 'Morsiani 90', 'Amiga', 'Romea' and 'Alirosada', as well as in non-melting compared to melting peach cultivars. CONCLUSION: The best cultivars for each fruit flesh type and jam were identified. Peach jam could be an alternative substitute when fresh fruit is not available and when it is prepared with high antioxidant cultivars. (c) 2016 Society of Chemical Industry. PMID- 27990651 TI - Laparoscopic kidney biopsy in dogs: Comparison of cup forceps and core needle biopsy. AB - OBJECTIVE: To investigate the feasibility of laparoscopic kidney biopsy with cup biopsy forceps in dogs (CupBF), and to compare to the use of a core biopsy needle (CoreBN). STUDY DESIGN: Experimental; randomized, controlled design. ANIMALS: Eight healthy, adult Beagle dogs. METHODS: Dogs were randomized to undergo laparoscopic biopsy of the right kidney using either 5 mm CupBF or a 16 gauge CoreBN. Intraoperative hemorrhage of the biopsy site was monitored. Biopsy quality was evaluated for tissue fragmentation and crushing, presence of renal cortex with or without medulla, and number of glomeruli. Postoperative packed cell volume, urinalysis, and ultrasonographic appearance of the biopsy site were evaluated. RESULTS: Biopsy specimens were obtained by both techniques and reliable hemostasis was achieved with direct compression in all dogs. The histologic score for CupBF biopsies was not significantly different from CoreBN biopsies. One CoreBN biopsy contained both renal cortex and medullar, while all CupBF biopsies contained cortex only. The mean (SD) number of glomeruli was significantly higher in CupBF biopsies [60 (9.1)] than CoreBN biopsies [26 (4.3)]. There was no gross hematuria, perirenal hematoma, or hydronephrosis in any dog postoperative. CONCLUSION: Laparoscopic kidney biopsy in dogs using 5 mm cup biopsy forceps is feasible with minimal risk and more glomeruli obtained compared to laparoscopic kidney biopsy using 16 gauge core biopsy needles. PMID- 27990653 TI - Population Pharmacokinetic and Pharmacodynamic Modeling of Epacadostat in Patients With Advanced Solid Malignancies. AB - Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration-time profiles were adequately described by a population PK model comprised of the first-order kinetics of oral absorption with 2-compartment distribution and constant clearance from the central compartment. Body weight was the only significant covariant to influence EPA PK. Determination of EPA's on-target potency, ie, its half-maximal inhibitory concentration (IC50 ) against IDO1, is important for dose selection but complicated by the bioconversion of tryptophan (TRP) to kynurenine (KYN) catalyzed by both IDO1 and TRP 2,3-dioxygenase (TDO). In vitro and ex vivo, the IC50 was estimated following the selective induction of IDO1, rendering the TDO activity relatively insignificant; however, it was desirable to determine the in vivo IC50 without inducing an IDO1 abundance. A mechanistic population PD model was developed based on time-matched EPA, TRP, and KYN plasma concentrations in 44 oncology patients, and EPA in vivo IC50 was estimated to be ~70 nM, consistent with the ex vivo value independently determined. The model suggests that ~60% and 40% of TRP->KYN bioconversion was mediated by IDO1 and TDO, respectively, in the cancer patients at baseline. For this study population of limited numbers of subjects, neither age nor sex was a significant covariate for EPA PK or PD. PMID- 27990652 TI - Two ovine mitochondrial DNAs harboring a fifth 75/76 bp repeat motif without altered gene expression in Northern Spain. AB - The Basque Country is home to the Latxa sheep breed, which is divided in several varieties such as Latxa Black Face (LBKF) and Latxa Blonde Face (LBLF). Mitochondrial DNA control region analysis of 174 male sheep (97 LBKF and 77 LBLF) was performed with the objective of characterizing the maternal lineages of these two varieties that are the basis to produce the cheese with Idiazabal quality label. The percentage of unique haplotypes was 77.32% in LBKF and 67.53% in LBLF. Most of the individuals were classified into B haplogroup (98.85%), while A haplogroup was much less frequent. Two Latxa individuals (one LBKF and one LBLF), both belonging to B haplogroup, displayed an additional 75/76 bp tandem repeat motif. Only 33 other sequences with this repeat motif were found among 11 061 sheep sequences included in the GenBank database. Gene expression was analyzed in peripheral blood leukocytes since the additional 75/76 bp repeat motif falls within ETAS1, a domain with a possible function in regulation of replication and transcription. The mRNA expression from four mitochondrial genes (COI, cyt b, ND1, and ND2) was analyzed in the two individuals of this study with a fifth repeat motif and in four without it. Although lower transcription was observed when the additional 75/76 bp repeat motif was present, no statistically significant differences were observed. Therefore, the variation in the number of the 75/76 repeat motif does not seem to modify the gene expression rate in mitochondrial genes. PMID- 27990654 TI - Measurement of electroosmotic and electrophoretic velocities using pulsed and sinusoidal electric fields. AB - In this work, we explore two methods to simultaneously measure the electroosmotic mobility in microchannels and the electrophoretic mobility of micron-sized tracer particles. The first method is based on imposing a pulsed electric field, which allows to isolate electrophoresis and electroosmosis at the startup and shutdown of the pulse, respectively. In the second method, a sinusoidal electric field is generated and the mobilities are found by minimizing the difference between the measured velocity of tracer particles and the velocity computed from an analytical expression. Both methods produced consistent results using polydimethylsiloxane microchannels and polystyrene micro-particles, provided that the temporal resolution of the particle tracking velocimetry technique used to compute the velocity of the tracer particles is fast enough to resolve the diffusion time-scale based on the characteristic channel length scale. Additionally, we present results with the pulse method for viscoelastic fluids, which show a more complex transient response with significant velocity overshoots and undershoots after the start and the end of the applied electric pulse, respectively. PMID- 27990655 TI - Transcutaneous drug delivery by liposomes using fractional laser technology. AB - OBJECTIVE: Transdermal delivery of hydrophilic peptides remains a challenge due to their poor cellular uptake and transdermal penetration. We hypothesize that combination of a CO2 fractional laser to enhance percutaneous absorption and liposomes as transdermal carriers would improve skin penetration of hydrophilic drugs. STUDY DESIGN: NA. METHODS: Liposomes were prepared using membrane fusion lipid dioleoylphosphatidylethanolamine, and used to deliver 5-carboxyfluorescein (CF) and fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC) as model hydrophilic peptide drugs. Liposome size was estimated by dynamic light scattering. Liposome uptake into murine macrophage cells and penetration or permeation into Yucatan micropig skin after irradiation by CO2 fractional laser at varying energy levels (laser power and exposure duration) were investigated using Franz cell and fluorescence microscopy. Oxidative damage to the irradiated mouse skin was assessed by electron spin resonance. RESULTS: Size of CF and OVA FITC encapsulated liposomes was 324 +/- 75 nm. Cellular uptake of OVA-FITC delivered by liposomes was 10-fold higher (1,370 relative fluorescence units, RFU) than delivered in solution form (130 RFU). Fractional laser irradiation increased skin permeation rate of CF liposomes (0-10%) and OVA-FITC liposomes (4 40%) in a dose-dependent manner. Although peeling off the stratum corneum facilitated CF liposome penetration at low energy levels (2.69-3.29 J/cm2 ; 10-20 W for 500 MUs), drug permeation was similar (7-8%) in peeled or untreated skin at higher laser energy levels (6.06 J/cm2 ; 20 W for 1,500 MUs). FITC penetrated deeper in the skin after laser irradiation. However, OH, O2-, and VC reactive oxygen species were generated upon irradiation of the skin with a fractional CO2 laser. CONCLUSIONS: Increasing laser power and irradiation, time increased liposome uptake by cells and penetration of peptide drugs across the skin in a dose-dependent manner. High-energy CO2 fractional laser overcomes the rate limiting barrier function of the stratum corneum. Further investigations are required to establish the safety and efficacy of fractional laser-irradiation assisted delivery of liposome-encapsulated drugs as a transcutaneous drug delivery system. Lasers Surg. Med. 49:525-532, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990656 TI - Exosomal and Non-Exosomal Urinary miRNAs in Prostate Cancer Detection and Prognosis. AB - BACKGROUND: MicroRNAs (miRNAs) are non-coding small RNAs, involved in post transcriptional regulation of many target genes. METHODS: Five miRNAs that have been consistently found deregulated in PCa (miR-21, miR-141, miR-214, miR-375, and let-7c) were analyzed in urinary pellets from 60 prostate cancer (PCa) patients and 10 healthy subjects by qRT-PCR. Besides, urinary exosomes were isolated by differential centrifugation and analyzed for those miRNAs. RESULTS: Significant upregulation of miR-21, miR-141, and miR-375 was found comparing PCa patients with healthy subjects in urinary pellets, while miR-214 was found significantly downregulated. Regarding urinary exosomes, miR-21 and miR-375 were also significantly upregulated in PCa but no differences were found for miR-141. Significant differences were found for let-7c in PCa in urinary exosomes while no differences were observed in urinary pellets. A panel combining miR-21 and miR 375 is suggested as the best combination to distinguish PCa patients and healthy subjects, with an AUC of 0.872. Furthermore, the association of miRNAs with clinicopathological characteristics was investigated. MiR-141 resulted significantly correlated with Gleason score in urinary pellets and let-7c with clinical stage in urinary exosomes. Additionally, miR-21, miR-141, and miR-214 were found significantly deregulated in intermediate/high-risk PCa versus low risk/healthy subjects in urinary pellets. Significant differences between both groups were found in urinary exosomes for miR-21, miR-375, and let-7c. CONCLUSIONS: These findings suggest that the analysis of miRNAs-especially miRNA 21 and miR-375- in urine could be useful as biomarkers in PCa. Prostate 77: 573 583, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990657 TI - Interpersonal emotion regulation in Asperger's syndrome and borderline personality disorder. AB - OBJECTIVES: Interpersonal emotion regulation (ER) plays a significant role in how individuals meet others' emotional needs and shape social interactions, as it is key to initiating and maintaining high-quality social relationships. Given that individuals with borderline personality disorder (BPD) or Asperger's syndrome (AS) exhibit problems in social interactions, the aim of this study was to examine their use of different interpersonal ER strategies compared to normative control participants. METHODS: Thirty individuals with AS, 30 with BPD, and 60 age-, gender-, and education-matched control participants completed a battery of measures to assess interpersonal ER, which assessed to what extent participants tended to engage in interpersonal affect improvement and worsening and to what extent they used different strategies. Before completing those measures, all groups were screened for disorders of Axis I and Axis II with the Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders. RESULTS: Compared to controls, individuals with AS and with BPD engaged less in affect improvement. No differences were found for affect worsening. Individuals with AS reported to use less adaptive (attention deployment, cognitive change) and more maladaptive (expressive suppression) interpersonal ER strategies, compared to individuals with BPD and control participants who did not differ from each other. CONCLUSIONS: The obtained results suggest the need to develop tailored ER interventions for each of the clinical groups studied. Furthermore, they highlight the need to study further potential differences in intrapersonal and interpersonal ER in clinical populations. PRACTITIONER POINTS: Individuals with Asperger's syndrome (AS) and borderline personality disorder (BPD) engaged significantly less than healthy controls in interpersonal affect improvement. Individuals with BPD did not differ from healthy controls in the use of interpersonal strategies. Individuals with AS reported to use more maladaptive and less adaptive strategies than BPD individuals and healthy controls. Understanding differences in interpersonal emotion regulation in individuals with AS and with BPD and normative controls might help practitioners develop better interventions. PMID- 27990659 TI - Oxidative stability of sesame and flaxseed oils and their effects on morphometric and biochemical parameters in an animal model. AB - BACKGROUND: Sesame and flaxseed oils, which are rich in essential n-6 and n-3 polyunsaturated fatty acids, are widely consumed. We have determined the optical behavior with respect to the quality and identity of cold-pressed sesame and flaxseed oils. The effects of these oils and their combinations on metabolic parameters in animal models were also measured. RESULTS: Flaxseed oil emitted carotenoid fluorescence (500-650 nm), although it was more unstable than sesame oil, which had a larger induction period by the Rancimat method. The greater stability of sesame may be a result of the lower quantity of linolenic fatty acids. These oils were added to the feed of 56 rats, whereas animal fat was used for the control group. The sesame oil, flaxseed oil and sesame + flaxseed oils groups showed a significantly reduced adiposity index and blood glucose compared to the control group, whereas total cholesterol, high-density lipoprotein and triglycerides were lower in flaxseed oil and sesame + flaxseed oils (P < 0.05). Sesame + flaxseed oils had reduced levels of low-density lipoprotein and non-high density lipoprotein (P < 0.05), indicating an anti-atherogenic effect in this group. CONCLUSION: Sesame oil was more stable than flaxseed oil. In an animal model, the diets with polyunsaturated fat sources proportions of 1:1 n-6:n-3 polyunsaturated fatty acids, improved the metabolic parameters, implying cardioprotective effects. (c) 2016 Society of Chemical Industry. PMID- 27990660 TI - Competition for attentional resources between low spatial frequency content of emotional images and a foreground task in early visual cortex. AB - Low spatial frequency (LSF) image content has been proposed to play a superior functional role in emotional content extraction via the magnocellular pathway biasing attentional resources toward emotional content in visual cortex. We investigated whether emotionally unpleasant complex images that were presented either unfiltered or with LSF content only in the background while subjects performed a foreground task will withdraw more attentional resources from the task compared to unemotional, neutral images (distraction paradigm). We measured steady-state visual evoked potentials (SSVEPs) driven by flickering stimuli of a foreground task. Unfiltered unpleasant images resulted in a significant reduction of SSVEP amplitude compared to neutral images. No statistically significant differences were found with LSF background images. In a behavioral control experiment, we found no significant differences for complexity ratings between unfiltered and LSF pictures. Content identification was possible for unfiltered and LSF picture (correct responses > 74%). An additional EEG study examined typical emotion-related components for complex images presented either as unfiltered, LSF, or high spatial frequency (HSF, as an additional control) filtered, unpleasant, and neutral images. We found a significant main effect of emotional valence in the early posterior negativity. Late positive potential differences were only found for unfiltered and HSF images. Results suggest that, while LSF content is sufficient to allow for content and emotional cue extraction when images were presented alone, LSF content is not salient enough to serve as emotional distractor that withdraws attentional resources from a foreground task in early visual cortex. PMID- 27990658 TI - Identification of liver metastases with probe-based confocal laser endomicroscopy at two excitation wavelengths. AB - BACKGROUND: Metastasis of colorectal cancer to the liver is the most common indication for hepatic resection in a western population. Incomplete excision of malignancy due to residual microscopic disease normally results in worse patient outcome. Therefore, a method aiding in the real time discrimination of normal and malignant tissue on a microscopic level would be of benefit. MATERIAL AND METHODS: The ability of fluorescent probe-based confocal laser endomicroscopy (pCLE) to identify normal and malignant liver tissue was evaluated in an orthotopic murine model of colorectal cancer liver metastasis (CRLM). To maximise information yield, two clinical fluorophores, fluorescein and indocyanine green (ICG) were injected and imaged in a dual wavelength approach (488 and 660 nm, respectively). Visual tissue characteristics on pCLE examination were compared with histological features. Fluorescence intensity in both tissues was statistically analysed to elucidate if this can be used to differentiate between normal and malignant tissue. RESULTS: Fluorescein (488 nm) enabled good visualisation of normal and CRLM tissue, whereas ICG (660 nm) visualisation was limited to normal liver tissue only. Fluorescence intensity in areas of CRLM was typically 53-100% lower than normal hepatic parenchyma. Using general linear mixed modelling and receiver operating characteristic analysis, high fluorescence intensity was found to be statistically more likely in normal hepatic tissue. CONCLUSION: Real time discrimination between normal liver parenchyma and metastatic tissue with pCLE examination of fluorescein and ICG is feasible. Employing two (rather than a single) fluorophores allows a combination of qualitative and quantitative characteristics to be used to distinguish between hepatic parenchyma and CRLM. Lasers Surg. Med. 49:280-292, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990661 TI - Association of Obesity-Related Hemodilution of Prostate-Specific Antigen, Dihydrotestosterone, and Testosterone. AB - BACKGROUND: Prostate-specific antigen (PSA) hemodilution is the leading theory for lower PSA values in obese men. However, testosterone and dihydrotestosterone (DHT), which are necessary for PSA production, are reduced in obese men. We assessed the relationship of body mass index (BMI) and PSA, taking into consideration the effect of testosterone and DHT. METHODS: Among 8,122 participants in Reduction by Dutasteride of Prostate Cancer Events (REDUCE), complete data were available for 7,275. BMI was categorized as normal (<25 kg/m2 ), overweight (25-29.9 kg/m2 ), obese (30-34.9 kg/m2 ), or moderate + severely obese (>=35 kg/m2 ). Associations between BMI, testosterone, and DHT and the outcome variable of PSA were examined using linear regression. RESULTS: There were 1,964 (27.0%) normal weight, 3,826 (52.6%) overweight, 1,200 (16.5%) obese, and 285 (3.9%) moderately + severely obese patients. With increasing BMI, there was a progressive decrease in PSA (P = 0.02), increase in prostate volume (P < 0.001), and decrease in both testosterone (P < 0.001) and DHT (P < 0.001). Using linear regression, increasing BMI was associated with decreasing serum PSA values. Furthermore, BMI remained inversely associated with PSA after individually adjusting for testosterone and DHT, as well as when adjusting for testosterone and DHT in the same model. Decreased androgen levels accounted for only 19% of the lower PSA in men with higher BMI. CONCLUSIONS: Only a fraction of lower PSA in obese men could be attributed to testosterone and DHT levels. The remaining factors explaining lower PSA are unaccounted for, presumably secondary to hemodilution associated with increased plasma volume in obese men. Prostate 77:466-470, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990662 TI - Derivatizing assay for the determination of aldehydes using micellar electrokinetic chromatography. AB - In this work, the use of a novel derivatization agent for the determination of aldehydes (in this particular case: formaldehyde, acetaldehyde, propionaldehyde, and valeraldehyde) using micellar electrokinetic chromatography is reported. The derivatization reaction is based on the reaction of aldehydes with benzhydrazide to form the corresponding derivates with maximum absorbance at 250 nm. The experimental conditions of the derivatization reaction as well of the separation were optimized. The adducts were separated with a +22 kV voltage at a temperature of 29 degrees C. The adducts' separation was performed in less than 14 min using as the running buffer a mixture containing 110 mmol/L of sodium dodecyl sulfate and 27 mmol/L of sodium tetraborate at pH 9.45. Samples were injected using hydrodynamic mode (50 mbar * 5 s). The calibration curves were linear up to 15.0 mg/L with r2 above 0.99. Intra and inter-day precisions were in average 3 and 4%, respectively, and recoveries were in average of 95%. Limits of detection and quantification were around 0.5 and 1.5 mg/L, respectively. The developed method was successfully applied in the analysis of low molar weight aldehydes in yogurt and vinegar samples. PMID- 27990663 TI - alphavbeta3 integrins negatively regulate cellular forces by phosphorylation of its distal NPXY site. AB - BACKGROUND INFORMATION: Integrins are key receptors that allow cells to sense and respond to their mechanical environment. Although they bind the same ligand, beta1 and beta3 integrins have distinct and cooperative roles in mechanotransduction. RESULTS: Using traction force microscopy on unconstrained cells, we show that deleting beta3 causes traction forces to increase, whereas the deletion of beta1 integrin results in a strong decrease of contractile forces. Consistently, loss of beta3 integrin also induces an increase in beta1 integrin activation. Using a genetic approach, we identified the phosphorylation of the distal NPXY domain as an essential process for beta3 integrin to be able to modulate traction forces. Loss of beta3 integrins also impacted cell shape and the spatial distribution of traction forces, by causing forces to be generated closer to the cell edge, and the cell shape. CONCLUSIONS: Our results emphasize the role of beta3 integrin in spatial distribution of cellular forces. We speculate that, by modulating its affinity with kindlin, beta3 integrins may be able to locate near the cell edge where it can control beta1 integrin activation and clustering. SIGNIFICANCE: Tensional homeostasis at the single cell level is performed by the ability of beta3 adhesions to negatively regulate the activation degree and spatial localization of beta1 integrins. By combining genetic approaches and new tools to analyze traction distribution and cell morphology on a population of cells we were able to identify the molecular partners involved in cellular forces regulation. PMID- 27990664 TI - Storage stability of packaged baby formula in poly(lactide)-whey protein isolate laminated pouch. AB - BACKGROUND: The use of biodegradable polymeric materials has been proposed as an environmentally-friendly alternative to petroleum-based packaging. To extend the shelf life of food products, these bioplastics must possess appropriate barrier properties and food-package stability. In the present study, shelf life analysis of packaged baby formula in biopolymeric, multilayer film, fabricated from poly(lactide) (PLA) and whey protein isolate (WPI), PLA/WPI/PLA and PLA pouches was performed at 4-35 o C and 50-59% relative humidity. RESULTS: Despite the possible sorption of food components into contact PLA surfaces, the results demonstated that the transparency and barrier properties of PLA-based pouches were insignificantly changed over time (P > 0.05), although the films showed a slow rate of color change. The baby formula packaged in PLA/WPI/PLA had a delayed lipid oxidation compared to the sample in the PLA pouch, especially at a higher temperature. The application of WPI in the multilayer structure shifted the shelf life determination factor from lipid oxidation to moisture gain. CONCLUSION: The results indicate that the PLA/WPI/PLA pouch has good storage stability. The film could be used to package dry food properly at 4-35 o C and 50-59% relative humidity for an extended period of time. (c) 2016 Society of Chemical Industry. PMID- 27990665 TI - Clinical assessment of a new 755 nm diode laser for hair removal: Efficacy, safety and practicality in 56 patients. AB - BACKGROUND AND OBJECTIVE: Recently, the first diode laser with a wavelength of 755 nm for in-motion hair removal came on the market. The objective of this study was to check its efficacy, safety, and practicality under different options for its use. METHODS: A prospective study in a heterogeneous group of 56 patients who had hair removed from various areas of their bodies using three different treatment methods. Four sessions were scheduled in all cases, with a gap of 3 months between each session. Efficacy was assessed by counting of hairs per cm2 and the adverse effects in each session were recorded in detail in the patients' clinical histories. RESULTS: The three tested options achieved a significant reduction in the number of hairs (P < 0.0001). The average clearances achieved using the conventional method (HR), the in-motion method (SHR) and the stacking method were 75.5%, 70.1%, and 41.9%, respectively. The degree of satisfaction of the participants on a scale of 0-10 was 7.7, 8.1 and 6.8, respectively. Erythema and perifollicular edema, which are characteristic responses in laser hair removal, were observed. The incidence of burns was 1.33%. CONCLUSION: The 755-nm diode laser performed efficiently and safely in all the tested areas, using high total accumulated energy per surface unit. Based on our prior experience with other equipment, the results are promising. Lasers Surg. Med. 49:355-360, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990666 TI - Increased Intracellular Reactive Oxygen Species Mediates the Anti-Cancer Effects of WZ35 via Activating Mitochondrial Apoptosis Pathway in Prostate Cancer Cells. AB - BACKGROUND: The limited treatment option for recurrent prostate cancer and eventual resistant to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents. WZ35, a chemical analog of curcumin, had been demonstrated to have high chemical stability and potential anticancer effects in gastric cancer cells. The present study aimed to investigate the anti-prostate cancer effects of WZ35 in vitro and in vivo as well as the underlying mechanism. METHODS: Two prostate cancer cell lines RM-1 and DU145 were utilized to test the anti-cancer effects of WZ35 and the underlying mechanism. MTT assay was used to assess the cytotoxic effect of WZ35. Cell cycle distribution, apoptosis, alteration of ROS, and [Ca2+ ]i level were evaluated using flow cytometry. Western blotting assay was applied to measure the levels of proteins associated with apoptosis and cell cycle. Immunofluorescence staining and Electron micrographs were used to evaluate activation of mitochondrial apoptosis pathway. Tumor models in nude mice were induced by injection of RM-1 prostate cancer cells to test the in vivo anticancer action of WZ35. RESULTS: Our results showed that WZ35 treatment induced loss of cell viability, cell apoptosis, and G2/M cycle arrest in both RM-1 and DU145 cells, coupled with ROS overproduction, intracellular calcium surge, and activation of mitochondrial apoptosis pathway in RM-1 cells. Interestingly, all above changes induced by WZ35 were completely reversed by ROS blockage. In addition, prevention of [Ca2+ ]i elevation by BAPTA/AM also inhibited activation of mitochondrial apoptosis pathway induced by WZ35. In vivo studies, WZ35 treatment significantly inhibited RM-1 homograft tumor growth along with increased ROS accumulation, mitochondrial disruption, and cell apoptosis in tumor tissues. CONCLUSIONS: In conclusion, this work provides a novel anticancer candidate for the treatment of prostate cancer and demonstrated that increased ROS mediate the anti-cancer effects of WZ35 via activating mitochondrial apoptosis pathway. Importantly, this work also reveals that targeting ROS generation might be an effective strategy in human androgen resistant prostate cancer treatment. Prostate 77:489-504, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990667 TI - Clinical Correlates of Benefit From Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer. AB - BACKGROUND: We sought to identify potential clinical variables associated with outcomes after radium-223 therapy in routine practice. METHODS: Consecutive non trial mCRPC patients who received >=1 dose of radium dichloride-223 at four academic and one community urology-specific cancer centers from May 2013 to June 2014 were retrospectively identified. Association of baseline and on-therapy clinical variables with number of radium doses received and clinical outcomes including overall survival were analyzed using chi-square statistics, cox proportional hazards, and Kaplan-Meier methods. Bone Scan Index (BSI) was derived from available bone scans using EXINI software. RESULTS: One hundred and forty five patients were included. Radium-223 was administered for six cycles in 74 patients (51%). One-year survival in this heavily pre-treated population was 64% (95%CI: 54-73%). In univariate and multivariate analysis, survival was highly associated with receiving all six doses of Radium-223. Receipt of six doses was associated with ECOG PS of 0-1, lower baseline PSA & pain level, no prior abiraterone/enzalutamide, <5 BSI value, and normal alkaline phosphatase. In patients who reported baseline pain (n = 72), pain declined in 51% after one dose and increased in 7%. PSA declined >=50% in 16% (18/110). Alkaline phosphatase declined >=25% in 48% (33/69) and >=50% in 16/69 patients. BSI declined in 17 (68%) of the 25 patients who had bone scan available at treatment follow-up. Grade >=3 neutropenia, anemia, and thrombocytopenia occurred in 4% (n = 114), 4% (n = 125), and 5% (n = 123), respectively. CONCLUSIONS: Patients earlier in their disease course with <5 BSI, low pain score, and good ECOG performance status are optimal candidates for radium-223. Radium-223 therapy is well tolerated with most patients reporting declines in pain scores and BSI. Prostate 77:479-488, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27990668 TI - Femoral head ostectomy for the treatment of acetabular fracture and coxofemoral joint luxation in a Potbelly pig. AB - OBJECTIVE: To report the successful surgical treatment of a comminuted left acetabular fracture, a dorsally luxated left femoral head, and avulsion of the ligament of the femoral head by femoral head ostectomy (FHO) and physical therapy in a companion Potbelly pig. STUDY DESIGN: Case report. ANIMALS: A 1-year-old, 13 kg, castrated male, companion Potbelly pig. METHODS: The pig presented with a nonweight bearing left pelvic limb lameness of 3 weeks' duration that was noticed shortly after the pig got caught under a fence. Under general anesthesia a lateral approach was made to the fractured limb. A FHO was performed as described for dogs. Following surgery, a period of physical therapy was initiated based on protocols described for dogs. RESULTS: The canine surgical procedure with the approach modified for pigs was successfully performed in our pig. Following surgery, the pig was comfortable and weight bearing. A physical therapy regimen of supervised activity, stairs, and water therapy was used to rehabilitate the leg, as well as a weight management protocol to maintain ideal body condition. The owner was highly satisfied with the outcome. Telephone follow-up with the owner at 12 months after surgery revealed no impairment to movement, and the pig was maintaining normal ambulation without lameness. No complications were observed with this case. CONCLUSION: FHO, as described for dogs, provided a favorable outcome for hip luxation caused by acetabular fracture, luxation, and avulsion of the femoral head ligament in this small size Potbelly pig. PMID- 27990669 TI - Cutaneous Merkel cell carcinoma: multiple asynchronous primary lesions in a patient on immunosuppressive therapy. PMID- 27990670 TI - Magnetic Resonance Imaging Study of Adipose Tissues in the Head of a Common Dolphin (Delphinus delphis): Structure Identification and Influence of a Freezing Thawing Cycle. AB - Magnetic resonance imaging (MRI) was used to scan the head of a common dolphin (Delphinus delphis) in order to visualize the different adipose tissues involved in echolocation functioning and to precisely delineate their anatomical topology. MRI scans were performed on the head taken from a freshly stranded carcass and repeated after a 2-week freezing time followed by thawing. The main fatty organs of the head, that is the melon, the mandibula bulba, the bursae cantantes, and their different connections with surrounding tissues were identified and labelled. The nasal sacs, other organs of echolocation, were also identified and labelled thanks to different MRI acquisitions. The shape, the location, the type of MRI signal of each organ and of their different connections were successfully analysed on all images, and then, the images of the head fresh or after thawing were compared. No impacts of the freezing/thawing cycle on the fatty tissues of the head were identified. Different parts were distinguished in the melon on the basis of the MRI signal emitted, corresponding most likely to the internal and external melon already identified by other analytical approaches, and linked to differences in lipid composition. MRI is shown here to be a useful tool to study the functional anatomy of the organs responsible for echolocation in odontocetes, with a particularly high level of precision. PMID- 27990671 TI - Synthesis of carbon-13 labeled oxalates exhibiting extended nuclear singlet state lifetimes. AB - Unsymmetrical perdeuterated doubly 13 C labelled oxalates exhibit extended lifetimes in the nuclear singlet state. Synthesis of 1,2 13 C2 oxalates from commercially available precursors is described, facilitating preparation of unsymmetrical oxalates in a controlled manner. PMID- 27990673 TI - Trichodysplasia Spinulosa in a 7-Year-Old Boy Managed Using Physical Extraction of Keratin Spicules. AB - Trichodysplasia spinulosa (TS) is an uncommon skin disease characterized by a folliculocentric papular eruption and keratin spine formation, classically appearing on the central face and ears. It occurs in immunosuppressed patients and is linked to a viral etiology. Diagnostic tests including polymerase chain reaction (PCR) are available for detection of the TS-associated polyomavirus. Effective treatment options include topical cidofovir and oral valganciclovir. We present a case diagnosed using PCR with skin scrapings and treated using physical extraction of the keratin spicules. Significant improvement was noted, suggesting a safe, cost-effective treatment alternative. PMID- 27990674 TI - Nationwide Survey of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children in the United States. AB - Although Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious, life-threatening reactions to drug therapies, no efforts have been made to investigate the comprehensive change in epidemiology with respect to age, sex, and race and ethnicity in children. The risk of death was 0.3% to 1.5%, and the highest hospitalization rates were in children 15 to 19 years of age, boys, and black children. The highest proportions of hospitalizations were children with very low household income, those with private insurance, and those treated at large urban teaching hospitals in the West. A significant winter-autumn predominance was observed. PMID- 27990675 TI - The Tongue Dorsal Surface in Fish: A Comparison Among Three Farmed Species. AB - The oral cavity of vertebrates has a very important role in many functions strictly related to the food processing. Two species, sea bass Dicentrarchus labrax and seabream Sparus aurata, are mainly involved in the aquaculture industry in the mediterranean area; moreover, the white seabream Diplodus sargus sargus was recently chosen as the best candidate for the diversification of species of commercial interest. This investigation was carried out, using the standard procedures for light and scanning electron microscopy, to analyse the morphology of the tongue dorsal surface in order to show whether relationships are present between the tongue morphology and the nutritional choices of these species. In all the three investigated species, three different areas were observed on the dorsal lingual surface: an apex, a body and a root. In the sea bass D. labrax, numerous caninelike teeth, organized in pads, were present along the dorsal surface. The presence of numerous taste buds, scattered on the tongue, was shown. In the seabream S. aurata, the apical part of the tongue is inserted in a pouch with a characteristic medial ridge on the body surface. Numerous taste buds were scattered on the whole surface. In the white seabream D. sargus sargus, a pouch partially covering the apex was clearly observed. In the pouch, filiform like and foliate-like papillae can be distinguished. The results show the important role of the fish tongue in the food ingestion process, demonstrating the interaction of food processing, taste and morphological characteristics. PMID- 27990676 TI - Updated competencies for the dental public health specialist: using the past and present to frame the future. AB - OBJECTIVE: A new set of competencies for entry-level specialists in dental public health (DPH) developed in 2016 updates the 1998 version. Our objective is to provide some context and perspective on this update. METHODS: We discuss the evolution of this dental specialty, how it differs from other dental specialties, and its importance for the public's oral health. Some societal trends that provide the rationale for this update are summarized. The ways in which this set of competencies differs from the last version are described. RESULTS: The first set of behavioral objectives was established in 1974 and updated at workshops in 1988 and 1997. Advanced population-based knowledge and public health perspectives beyond that obtained in predoctoral dental education continue to be essential for the nation's oral health. Since 1998, the impact of the digital age, advances in science and technology, changes in population demographics, health status and increasing inequalities, treatment needs, prevention and treatment modalities, healthcare delivery systems, financing, personnel, legislation, and regulations have all influenced DPH practice. The updated competencies include guiding principles for the specialty, a new focus on social determinants of health, and more flexibility to address the increasing complexity and interdisciplinary nature of public health problems and the expanding knowledge and skills needed to address them. The rapid expansion of public health education might serve as an important pipeline for future DPH specialists. CONCLUSION: The updated competencies can guide the educational preparation of DPH specialists and are aligned with the rapidly changing environment. PMID- 27990672 TI - Fast indirect fluorine-18 labeling of protein/peptide using the useful 6 fluoronicotinic acid-2,3,5,6-tetrafluorophenyl prosthetic group: A method comparable to direct fluorination. AB - Fluorine-18 labeling of biomolecules is mostly performed by an indirect labeling method using a prosthetic group. Fluorine-18 labeled 6-fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester is a useful prosthetic group to radiolabel a protein. Recently, we reported an improved preparation of this prosthetic group. To test the conjugation efficiency of the labeled ester prepared by this method, we have performed conjugation reactions with a peptide, a protein, and a small molecule. Prostate-specific membrane antigen targeting small molecule [18 F]DCFPyL, alphavbeta3 integrin receptors targeting peptide [18 F]c(RGDfK) and [18 F]albumin were prepared in good radiochemical yields. The conjugation reactions were completed at 40 degrees C to 50 degrees C in 10 minutes. The overall radiochemical yield was 25% to 43% in 30 to 45 minutes. PMID- 27990677 TI - A survey of dental public health specialists on current dental public health competencies. AB - In preparation to update the Dental Public Health specialty competencies, the Expert Panel determined that a needs assessment be conducted. A nine item open and close ended survey developed by the Expert Panel was used to collect data on the Diplomates current work environment, the utility of the current set of Dental Public Health competencies, and to identify any gaps in the current competencies. In 2015, the survey was administered to all active Diplomates of the American Board of Dental Public Health. One hundred and nine Diplomates responded. Diplomates overwhelmingly reported that each of the ten current competencies were still relevant for Dental Public Health specialists in the 21st Century, but needed to be updated to be more contemporary. Domains suggested to achieve this were interprofessional care, cultural competency, health literacy, and evidence based dentistry. PMID- 27990678 TI - Competencies in graduate dental public health education. PMID- 27990679 TI - New competencies for the 21st century dental public health specialist. AB - The American Board of Dental Public Health (ABDPH) currently recognizes 10 core competencies, which identify the skills, knowledge and understanding expected of all dental public health specialists. The last update to the competencies was 1998. The American Board of Dental Public Health, along with the American Association of Public Health Dentistry and its many partners, initiated a process to revise the competencies. This report presents the process and the new competencies for the dental public health specialist of the 21st century. Each of the developed competencies is supported by a "statement of intent". These competencies take effect immediately. The new competencies will be used in testing candidates for specialty status beginning with the 2018 ABDPH examination. PMID- 27990680 TI - Retrospective Study of Rocky Mountain Spotted Fever in Children. AB - BACKGROUND/OBJECTIVES: Rocky Mountain spotted fever (RMSF), a lethal tick-borne illness, is prevalent in the south central United States. Children younger than 10 years old have the greatest risk of fatal outcome from RMSF. The objective of the current study was to review pediatric cases of RMSF seen in the dermatology consult service and to evaluate dermatology's role in the diagnosis and management of this disease. METHODS: A retrospective review was performed of inpatient dermatology consultations at a tertiary care center in North Carolina from 2001 to 2011. Data collected included patient demographic characteristics, symptoms, pre- and postconsultation diagnoses, diagnostic procedures, length of hospital stay, and outcome. RESULTS: A total of 3,912 consultations were conducted in the dermatology service over 10 years. Six patients with RMSF, ranging in age from 22 months to 10 years (mean 5.1 years), were evaluated during April, May, and June. All preconsultation diagnoses included RMSF in the differential diagnosis. All patients underwent skin biopsies, and a culture was obtained in one case. Fifty percent of patients died within 4 days of hospitalization. CONCLUSIONS: Variables associated with mortality from RMSF are delayed diagnosis and initiation of antirickettsial therapy. Physicians should consider RMSF in children presenting with fever and rash during the summer months. Dermatology consultation is useful in evaluating patients with suspicious clinical features of RMSF with skin findings. PMID- 27990681 TI - Factors influencing eye-care seeking behaviour of parents for their children in Nigeria. AB - BACKGROUND: The eye-care seeking behaviour of parents for their children has a role to play in increasing or reducing the prevalence of childhood blindness. In Nigeria, little or no work has been done in this area. Hence, this study was carried out with a view to assisting eye-care professionals plan better program regimens and also to help them identify various elements that either facilitate or hinder eye-care seeking behaviour of parents for their school age children. METHODS: This was a qualitative narrative study. Data were collected using in depth interviews (IDIs) and focus group discussions (FGDs). Thirty-five parents and 10 eye-care practitioners were selected by random sampling and homogenous sampling methods, respectively. Parents were selected, based on those who sought care and those who did not seek care for their children after a school screening exercise. Collected data were analysed qualitatively by transcribing the voice recordings of interview sessions into textual data and themes were raised. RESULTS: Four FGDs and 13 IDIs were conducted. Parents were more likely to seek care for manifest conditions than for conditions they could not perceive. A family history of ocular disease and repetitiveness of complaints facilitated parents to seek eye care for their children. The cost of eye-care services was a major barrier. Logistics such as fixing a doctor's appointment, getting time off work and long waiting periods at the clinic were also reported as barriers. Fear of treatment options and family interferences were also mentioned. CONCLUSION: Parents have some concerns and challenges in seeking eye care for their children. This study recommends that more work be done through planned awareness programs to educate parents and help them overcome the concerns and barriers that hinder them from seeking eye care for their children. PMID- 27990683 TI - Association of heart rate variability with diabetes and vitamin D levels. PMID- 27990682 TI - Is there potential for therapeutic drug monitoring of biologic agents in rheumatoid arthritis? AB - The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration-effect relationship and the use of pharmacokinetic-pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost-effectiveness. PMID- 27990684 TI - Transjugular closure of secundum atrial septal defects. AB - OBJECTIVE: This study reports the results of a steerable delivery system under the guidance of transesophageal echocardiography (TEE) for the treatment of transjugular closure of secundum atrial septal defects (ASD). METHODS: From July 2015 to May 2016, 33 patients underwent transjugular closure of a secundum ASD under general anesthesia with TEE guidance. The right internal jugular vein was punctured and a FuStarTM steerable sheath was implanted into the right atrium and aligned vertically with the septum, and a closure device was deployed to close the defect. RESULTS: Thirty-two patients with an ASD were successfully occluded; one patient required ASD closure on cardiopulmonary bypass. Procedure time ranged from 5 to 15 (8.2 +/- 3.8) min. The length of stay was three to five days after the operation. The follow-up time ranged from 1.1 to 11.0 (5.5 +/- 1.5) months. There was no valve regurgitation, no malignant arrhythmias, no device dislocation, or other serious complications. CONCLUSIONS: A steerable delivery system under the guidance of TEE is a safe, effective, and cosmetic method for the transjugular closure of secundum ASDs. PMID- 27990686 TI - Validation of the Composite Autonomic Symptom Score 31 (COMPASS 31) for the assessment of symptoms of autonomic neuropathy in people with diabetes. AB - AIM: To validate the Composite Autonomic Symptom Score (COMPASS) 31, in its Italian version, for the diagnosis of diabetic cardiovascular autonomic neuropathy in a clinic-based, single-centre study. METHODS: A total of 73 participants with diabetes (age 55 +/- 14 years) completed the COMPASS 31 questionnaire before undergoing cardiovascular autonomic neuropathy and diabetic polyneuropathy assessment according to cardiovascular reflex tests, neuropathic symptoms and signs, and vibration and thermal thresholds. RESULTS: The COMPASS 31 total weighted score differed between participants with and without cardiovascular autonomic neuropathy (29.9 +/- 19.5 vs 16.1 +/- 14.7; P = 0.003) and with and without diabetic polyneuropathy (28.9 +/- 19.1 vs 12.7 +/- 11.3; P < 0.0001). It was related to cardiovascular reflex tests score (rho = 0.38, P = 0.0013) as well as diabetic polyneuropathy symptoms (rho=0.61, P < 0.0001) and signs scores (rho = 0.49, P < 0.0001). Receiver-operating curve analysis showed a fair diagnostic accuracy of total score for cardiovascular autonomic neuropathy (area under the curve 0.748 +/- 0.068, 95% CI 0.599-0.861) and diabetic polyneuropathy (area under the curve 0.742 +/- 0.061, 95% CI 0.611-0.845). The best score thresholds were 16 for early cardiovascular autonomic neuropathy (sensitivity 75.0%, specificity 64.9%, positive predictive value 37.5% and negative predictive value 90.2%), and 17 for both confirmed cardiovascular autonomic neuropathy and diabetic polyneuropathy (sensitivity 70.0% and 65.5%, respectively; specificity 66.7% and 79.5%, respectively; positive predictive value 25.0% and 67.9%, respectively; and negative predictive value 93.0% and 77.8%, respectively). COMPASS 31 had a good internal consistency according to Cronbach's alpha coefficient of 0.73. CONCLUSIONS: COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms in diabetic neuropathy, with a fair diagnostic accuracy for both cardiovascular autonomic neuropathy and diabetic polyneuropathy. PMID- 27990687 TI - Reply to Kurtoglu: Association of heart rate variability with diabetes and vitamin D levels. PMID- 27990685 TI - Statistical assessment of treatment response in a cancer patient based on pre therapy and post-therapy FDG-PET scans. AB - This work arises from consideration of sarcoma patients in which fluorodeoxyglucose positron emission tomography (FDG-PET) imaging pre-therapy and post-chemotherapy is used to assess treatment response. Our focus is on methods for evaluation of the statistical uncertainty in the measured response for an individual patient. The gamma distribution is often used to describe data with constant coefficient of variation, but it can be adapted to describe the pseudo Poisson character of PET measurements. We propose co-registering the pre-therapy and post- therapy images and modeling the approximately paired voxel-level data using the gamma statistics. Expressions for the estimation of the treatment effect and its variability are provided. Simulation studies explore the performance in the context of testing for a treatment effect. The impact of misregistration errors and how test power is affected by estimation of variability using simplified sampling assumptions, as might be produced by direct bootstrapping, is also clarified. The results illustrate a marked benefit in using a properly constructed paired approach. Remarkably, the power of the paired analysis is maintained even if the pre-image and post- image data are poorly registered. A theoretical explanation for this is indicated. The methodology is further illustrated in the context of a series of fluorodeoxyglucose-PET sarcoma patient studies. These data demonstrate the additional prognostic value of the proposed treatment effect test statistic. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27990688 TI - Effect of 12-month weekly professional oral hygiene care on the composition of the oral flora in dentate, dependent elderly residents: A prospective study. AB - OBJECTIVE: To study the effect of weekly professional oral hygiene care on the proportion of micro-organisms associated with good oral health, caries, and periodontal and soft tissue diseases in oral biofilms in dentate, dependent elderly residents. BACKGROUND: Assisted oral hygiene care reduces the plaque score and number of micro-organisms in the oral biofilms in elderly residents. Less is known about the effect on the quality/composition of the remaining oral flora. MATERIALS AND METHODS: Participants comprised 33 residents in the study and 35 in the control group. Dental status (>=10 natural teeth and no removable dentures to be included), plaque score, salivary secretion rate and prescription medicines were recorded. Duplicate samples, collected from supragingival plaque and tongue, were analysed using cultivation technique. Differences between and within groups were analysed using one-way and two-way ANOVA, respectively. RESULTS: At the baseline, the number of teeth in the participants (mean age, 83.7 +/- 7.4 years) was 22.0 +/- 4.5. The number of prescription medicines was 9.4 +/- 4.5. Seventy-six per cent had low salivary secretion rate. Fifty per cent had "visible thick" supragingival plaque. At the 12-month registration, "no visible" or "visible but thin" plaque was recorded in 92% in the study group. The proportions of bacteria associated with good oral health and periodontal diseases were decreased over time, while the frequency and proportions of micro-organisms associated with caries and soft tissue infection were unaffected or increased. CONCLUSION: The results indicate that assisted oral hygiene care alone is not sufficient to regain an oral microbial flora associated with good oral health in dentate, dependent elderly residents. PMID- 27990689 TI - Resetting the bar: Statistical significance in whole-genome sequencing-based association studies of global populations. AB - Genome-wide association studies (GWAS) of common disease have been hugely successful in implicating loci that modify disease risk. The bulk of these associations have proven robust and reproducible, in part due to community adoption of statistical criteria for claiming significant genotype-phenotype associations. As the cost of sequencing continues to drop, assembling large samples in global populations is becoming increasingly feasible. Sequencing studies interrogate not only common variants, as was true for genotyping-based GWAS, but variation across the full allele frequency spectrum, yielding many more (independent) statistical tests. We sought to empirically determine genome-wide significance thresholds for various analysis scenarios. Using whole-genome sequence data, we simulated sequencing-based disease studies of varying sample size and ancestry. We determined that future sequencing efforts in >2,000 samples of European, Asian, or admixed ancestry should set genome-wide significance at approximately P = 5 * 10-9 , and studies of African samples should apply a more stringent genome-wide significance threshold of P = 1 * 10-9 . Adoption of a revised multiple test correction will be crucial in avoiding irreproducible claims of association. PMID- 27990690 TI - Hamlyn R Brier (1911-2001). PMID- 27990691 TI - Synthesis and Evaluation of New Naphthalene and Naphthoquinone Derivatives as Anticancer Agents. AB - DNA topoisomerase I inhibitors, both synthetic and of natural origin, are receiving increasing consideration primarily as drugs against refractory tumors. Alkannin and shikonin, two enantiomeric dyes from Alkanna tinctoria and Lithospermum erythrorhizon, have been known over many centuries as dyestuff, wound healing, anti-inflammatory, antibacterial and antitumor substances. Although multiple mechanisms appear to be implicated, their potency is associated with the inhibition of topoisomerase I and with the redox properties of the naphthazarin scaffold. Here, the synthesis of new naphthalene and naphthoquinone derivatives inspired by alkannin and shikonin is described and their structural and biological properties were examined. Different oxidation states of the naphthalene nucleus were examined to observe the effect of this parameter on cytotoxicity. Antiproliferative activities against a panel of human cancer cell lines were evaluated and the implication of topoisomerase I was assessed. PMID- 27990693 TI - Redox-Responsive Molecular Systems and Materials. AB - Redox reactions can alter the electronic, optical, and magnetic properties of molecules and their ensembles by adding or removing electrons. Here, the developments made over the past 10 years using molecular events are discussed, such as assembly/disassembly, transformation of ensembles, geometric changes, and molecular motions that are designed to be redox-responsive. Considerable progress has occurred in the application of these events to the realization of electronic memory, color displays, actuators, adhesives, and drug delivery. In these cases, systems behave in either a highly or a poorly correlated manner depending on the number of redox-active units involved, based on the method of integration. One of the great advantages of redox-responsive devices and materials is that they have the potential to be readily integrated into existing electronic technologies. PMID- 27990694 TI - Blood donation by persons with diabetes. PMID- 27990692 TI - A multicenter randomized controlled clinical trial using a new resorbable non cross-linked collagen membrane for guided bone regeneration at dehisced single implant sites: interim results of a bone augmentation procedure. AB - OBJECTIVE: To compare clinical performance of a new resorbable non-cross-linked collagen membrane, creos xenoprotect (CXP), with a reference membrane (BG) for guided bone regeneration at dehisced implant sites. MATERIALS AND METHODS: This randomized controlled clinical trial enrolled patients with expected dehiscence defects following implant placement to restore single teeth in the maxillary and mandibular esthetic zone and premolar area. Implants were placed using a two stage surgical protocol with delayed loading. Bone augmentation material placed at the implant surface was immobilized with CXP or BG membrane. Soft tissue health was followed during the healing period, and the defect size was measured at reentry and 6 months after implant placement. RESULTS: Of the 49 included patients, 24 were treated with CXP and 25 with BG. Patient characteristics did not differ between the two arms. In the CXP arm, the defect height at implant insertion was (mean +/- SD) 5.1 +/- 2.1 mm (n = 24) and reduced at reentry by 81% to 1.0 +/- 1.3 mm (n = 23). In the BG arm, the defect height at implant insertion was 4.9 +/- 1.9 mm (n = 25) and reduced at reentry by 62% to 1.7 +/- 2.1 mm (n = 24). Assuming a margin of non-inferiority of 1 mm, CXP was non-inferior to BG. Membrane exposure rate was highest at week 3 in both arms, reaching 16.7% for BG and 8.7% for CXP. CONCLUSIONS: The new resorbable non-cross-linked collagen membrane facilitates bone gain to support implant placement in expected dehiscence defects. The observed trend toward higher mean bone gain and lower exposure rate with CXP compared to BG should be further investigated. PMID- 27990695 TI - Photovoltaic Devices: Opto-Electro-Thermal Physics and Modeling. AB - An opto-electro-thermal simulation of solar cells (SCs) is presented by addressing optoelectronic and thermodynamic responses simultaneously. The photocurrent losses due to carrier recombinations and the intrinsic heat generation (thermalization/Joule/Peltier/recombination heat) and dissipation (convective/radiative cooling) processes in the SCs are investigated quantitatively. PMID- 27990696 TI - Comparison of Bailout and Planned Rotational Atherectomy for Heavily Calcified Coronary Lesions: A Single-Center Experience. AB - OBJECTIVES: The aim of this study was to compare outcomes of bailout and planned rotational atherectomy (RA) in the treatment of calcified coronary lesions. BACKGROUND: Current guidelines recommend RA as a bailout procedure for calcified or fibrotic lesions that cannot be adequately dilated before stenting. Nonetheless, planned RA is sometimes performed in certain challenging anatomies. METHODS: Data of patients treated with RA between 2002 and 2014 at a single center registry were retrospectively analyzed. The bailout RA group included patients where RA was employed after failure of balloon dilatation or stent delivery. Planned RA included patients where RA was employed electively without previous device failure. RESULTS: The study comprised 204 patients (221 lesions) and 308 patients (338 lesions) treated with bailout or planned RA, respectively. Angiographic success was achieved in the majority of cases, but was lower in the bailout RA group (93.7% vs. 97.6%, P = 0.02). Coronary dissections occurred more frequently in the bailout RA group (8.6% vs. 4.4%, P = 0.04), mean contrast amount was higher (279 +/- 135 mL vs. 202 +/- 92 mL, P < 0.001), and fluoroscopy time and procedural duration were longer in that group (32 min [IQR 21-51] vs. 18 min [IQR 14-28], P < 0.001 and 111 +/- 50 min vs. 76 +/- 35 min, P < 0.001, respectively). In-hospital death and myocardial infarction were not significantly different between the groups (2.9% vs. 1.3%, P = 0.21 and 6.9% vs. 4.2%, P = 0.19). In-hospital major adverse cardiac events (MACE) were higher in the bailout RA group (10.3% vs. 5.5%, P = 0.04). The 2-year estimated rates of MACE (25.2% vs. 28.7%, log rank P = 0.52) and its components death, myocardial infarction, and target vessel revascularization were not significantly different between the groups. Equivalence of 2-year MACE rates was also seen in all examined subgroups. CONCLUSION: Shortened procedural duration and reduction of coronary dissections were observed with planned RA for selected lesions. However, this strategy does not affect long-term clinical outcomes. PMID- 27990697 TI - Improving production efficiency in the presence of genotype by environment interactions in pig genomic selection breeding programmes. AB - We simulated a genomic selection pig breeding schemes containing nucleus and production herds to improve feed efficiency of production pigs that were cross breed. Elite nucleus herds had access to high-quality feed, and production herds were fed low-quality feed. Feed efficiency in the nucleus herds had a heritability of 0.3 and 0.25 in the production herds. It was assumed the genetic relationships between feed efficiency in the nucleus and production were low (rg = 0.2), medium (rg = 0.5) and high (rg = 0.8). In our alternative breeding schemes, different proportion of production animals were recorded for feed efficiency and genotyped with high-density panel of genetic markers. Genomic breeding value of the selection candidates for feed efficiency was estimated based on three different approaches. In one approach, genomic breeding value was estimated including nucleus animals in the reference population. In the second approach, the reference population was containing a mixture of nucleus and production animals. In the third approach, the reference population was only consisting of production herds. Using a mixture reference population, we generated 40-115% more genetic gain in the production environment as compared to only using nucleus reference population that were fed high-quality feed sources when the production animals were offspring of the nucleus animals. When the production animals were grand offspring of the nucleus animals, 43-104% more genetic gain was generated. Similarly, a higher genetic gain generated in the production environment when mixed reference population was used as compared to only using production animals. This was up to 19 and 14% when the production animals were offspring and grand offspring of nucleus animals, respectively. Therefore, in genomic selection pig breeding programmes, feed efficiency traits could be improved by properly designing the reference population. PMID- 27990698 TI - Dietary strategies for achieving adequate vitamin D and iron intakes in young children in Ireland. AB - BACKGROUND: Inadequate intakes of vitamin D and iron have been reported in young children in Ireland. The present study aimed to identify the main foods determining vitamin D and iron intakes and to model the impact of dietary strategies to improve adequacy of these micronutrients in young children. METHODS: The present study is based on the Irish National Pre-School Nutrition Survey (NPNS), which estimated food and nutrient intakes in a representative sample (n = 500) of children (aged 1-4 years) using a 4-day weighed food record. Dietary strategies were modelled using DaDiet(c) software (Dazult Ltd, Co. Kildare, Republic of Ireland) and the usual intake distribution, prevalence of inadequate intakes and risk of excessive intakes were estimated using the National Cancer Institute method. RESULTS: Fortified foods and nutritional supplements were the key foods influencing the intakes of vitamin D and iron. Adding a 5 MUg day-1 vitamin D supplement, fortifying cow's milk (CM) with vitamin D or replacing CM with growing-up milk (GUM) would modestly increase intakes of vitamin D. A combined strategy of fortifying CM with vitamin D or replacing CM with GUM plus a 5 MUg day-1 vitamin D supplement would increase mean intakes of vitamin D (from 3.5 MUg day-1 at baseline to >=11 MUg day-1 ) and substantially reduce the prevalence of inadequate intakes (from >95% to 12-36%). Fortifying CM with iron or replacing CM with GUM would increase mean intakes of iron (from 7.3 mg day-1 to >10 mg day-1 ), achieving adequate intakes across all ages. CONCLUSIONS: Based on real food consumption data in a representative sample of Irish children, we have shown that through targeted dietary strategies adequate intakes of iron are achievable and intakes of vitamin D could be greatly improved. PMID- 27990701 TI - Maintained right ventricular pressure overload induces ventricular-arterial decoupling in mice. AB - NEW FINDINGS: What is the central question of this study? The aim was to investigate whether complementary assessment of non-invasive ultrasound imaging together with closed chest-derived intracardiac pressure-volume catheterization is applicable to mice for an in-depth characterization of right ventricular (RV) function even upon maintained pressure overload. What is the main finding and its importance? Characterization of RV function by the complementary use of echocardiographic imaging together with pressure-volume catheterization reveals ventricular-arterial decoupling upon maintained pressure overload, where RV systolic function correlates with ventricular-arterial coupling rather than contractility, whereas diastolic function correlates well with RV diastolic pressure. This combined approach allows us to phenotype RV function and dysfunction better in genetically modified and/or pharmacologically treated mice. Assessment of right ventricular (RV) function in rodents is a challenge because of the complex RV anatomy and structure. To date, the best characterization of RV function has been achieved by accurate cardiovascular phenotyping, involving a combination of non-invasive imaging and intracardiac pressure-volume measurements. We sought to investigate the feasibility of two complementary phenotyping techniques for the evaluation of RV function in an experimental mouse model of sustained RV pressure overload. Mice underwent either sham surgery (n = 5) or pulmonary artery banding (n = 8) to induce isolated RV pressure overload. After 3 weeks, indices of RV function were assessed by echocardiography (Vevo2100) and closed chest-derived invasive pressure-volume measurements (PVR 1030). Pulmonary artery banding resulted in RV hypertrophy and dilatation accompanied by systolic and diastolic dysfunction. Invasive RV haemodynamic measurements demonstrated an increased end-systolic elastance and arterial elastance after pulmonary artery banding compared with sham operation, resulting in ventricular-arterial decoupling. Regression analysis revealed that tricuspid annular plane systolic excursion is correlated with ventricular-arterial coupling (r2 = 0.77, P = 0.002) rather than with RV contractility (r2 = -0.61, P = 0.07). Furthermore, the isovolumic relaxation time to ECG-derived R-R interval and the ratio of the early diastolic peak velocity measured by pulsed wave Doppler to the early diastolic peak obtained during tissue Doppler imaging correlate well with RV end-diastolic pressure (r2 = 0.87, P = 0.0001 and r2 = 0.82, P = 0.0009, respectively). Commonly used indices of systolic RV function are associated with RV-arterial coupling rather than contractility, whereas diastolic indices well correlate with end-diastolic pressure when there is maintained pressure overload. PMID- 27990700 TI - Biomass fuel smoke exposure was associated with adverse cardiac remodeling and left ventricular dysfunction in Peru. AB - While household air pollution from biomass fuel combustion has been linked to cardiovascular disease, the effects on cardiac structure and function have not been well described. We sought to determine the association between biomass fuel smoke exposure and cardiac structure and function by transthoracic echocardiography. We identified a random sample of urban and rural residents living in the high-altitude region of Puno, Peru. Daily biomass fuel use was self reported. Participants underwent transthoracic echocardiography. Multivariable linear regression was used to examine the relationship of biomass fuel use with echocardiographic measures of cardiac structure and function, adjusting for age, sex, height, body mass index, diabetes, physical activity, and tobacco use. One hundred and eighty-seven participants (80 biomass fuel users and 107 non-users) were included in this analysis (mean age 59 years, 58% women). After adjustment, daily exposure to biomass fuel smoke was associated with increased left ventricular internal diastolic diameter (P=.004), left atrial diameter (P=.03), left atrial area (four-chamber) (P=.004) and (two-chamber) (P=.03), septal E' (P=.006), and lateral E' (P=.04). Exposure to biomass fuel smoke was also associated with worse global longitudinal strain in the two-chamber view (P=.01). Daily biomass fuel use was associated with increased left ventricular size and decreased left ventricular systolic function by global longitudinal strain. PMID- 27990702 TI - Synthesis of Highly Anisotropic Semiconducting GaTe Nanomaterials and Emerging Properties Enabled by Epitaxy. AB - A new member of the layered pseudo-1D material family-monoclinic gallium telluride (GaTe)-is synthesized by physical vapor transport on a variety of substrates. The [010] atomic chains and the resulting anisotropic behavior are clearly revealed. The GaTe flakes display multiple sharp photoluminescence emissions in the forbidden gap, which are related to defects localized around selected edges and grain boundaries. PMID- 27990703 TI - 'You never come back the same': the challenge of spiritual care in a deployed military nursing context. AB - AIMS AND OBJECTIVES: To explore the experience of spirituality and spiritual care by military nurses on deployed operations. BACKGROUND: Despite an increasing body of research addressing spirituality in nursing care in a variety of clinical settings, the deployed military nursing context remains poorly understood. DESIGN: A qualitative, philosophical hermeneutic design. METHOD: Ten Australian military nurses were interviewed about their experiences of spirituality and spiritual care while on deployed operations. Analyses were performed using a phenomenological method informed by philosophical hermeneutics. RESULTS: The participants perceived that they had an important role in the provision of spiritual care in the absence of family on deployed operations. However, the nurse also needed to care for their own spiritual needs. The results suggested that spirituality and spiritual care may provide positive benefits in protecting against the long-term psychological, emotional and spiritual impacts of military service on deployed operations. CONCLUSIONS: Military nurses need to understand the factors that influence spiritual care delivery in their practice setting. Nurses need to be cognizant of the importance of spiritual care in the deployed military context, not only for their patients and colleagues, but also for themselves. Spirituality is argued as a protective factor against the challenges and consequences often associated with deployment. Well-developed spiritual resilience may assist in ensuring that military personnel return home emotionally, psychologically and spiritually 'fit'. RELEVANCE FOR CLINICAL PRACTICE: To provide effective spiritual nursing care to deployed military populations, the nurse needs to understand the complex military practice environment, the personal and individual nature of spiritual expressions and their own spiritual care requirements. Meaningful spiritual care aids resilience against the psychological, emotional and spiritual dangers of deployment. PMID- 27990704 TI - Differentiation of bone marrow-derived stage-specific embryonic antigen 1 positive pluripotent stem cells into male germ cells. AB - Studies published in recent years have changed the outlook on sterility and germ cell development by producing gametes from stem cells. In present study, a novel approach on differentiation of bone marrow-derived stage-specific embryonic antigen 1 positive (SSEA-1+ ) pluripotent stem cells into male germ cells has been addressed. SSEA-1+ stem cells were separated from murine bone marrow using magnetic-activated cell sorting (MACS) system and propagated on a feeder layer cells. To evaluate the pluripotency characteristic of the purified cells, they were differentiated toward cells of three germ layers. Later the SSEA-1+ stem cells were induced to differentiate along male germ cell lineage with retinoic acid. Flowcytometric analysis of SSEA-1+ stem cells revealed purity of about 62% which increased to 91% after cultivation over feeder cells. Expression of specific transcripts of Oct4, SSEA-1, Nanog, Dppa3, fragilis, Rex-1, SOX-2, and alkaline-phosphatase and immunofluorescence evaluation of Oct4 and SSEA-1 expression showed the differentiation of purified stem cells toward the cells of three germ layers. Differentiation potential of purified cells was positively evidenced by expression markers specific for primordial germ cells, spermatogonial stem cells and spermatogonia including Mvh, fragilis, Dppa3, Stra8, DAZL, Piwil2, beta1, and alpha6-integrins as well as meiotic-specific marker SYCP3. Our results showed that SSEA-1+ pluripotent stem cells are able to differentiate into male germ cells. The results of the present study are encouraging enough to merit further investigation, provide a new hope for those suffering from infertility and introduce a novel platform for research on germ cell development. PMID- 27990706 TI - The symptom experiences of Puerto Rican children undergoing cancer treatments and alleviation practices as reported by their mothers. AB - Although symptoms during cancer treatments are prevalent and are important clinical outcomes of childhood cancer, the symptom experiences of Puerto Rican children along with the symptom alleviation/care practices that parents provide during cancer treatments have received limited attention. To examine the occurrence/severity of symptoms on the Therapy-Related Symptom Checklist-Children (TRSC-C), reported by mothers of Puerto Rican children undergoing cancer treatments and identifying mothers' symptom alleviation/management strategies. Descriptive study conducted between January and May 2012. Mothers of 65 Puerto Rican children/adolescents undergoing cancer treatments responded to the Spanish versions of the TRSC-C, Symptom Alleviation: Self-Care Methods, and a Demographic and Health form. The children/adolescents' mean age was 9.2 (1-17) years; 62% were boys; 56 had chemotherapy; 9 had chemoradiotherapy. Children diagnoses were 35.4% leukemia, 24.6% solid tumors, 24.6% nervous system tumors, and 15.4% other. On the TRSC-C, the symptoms experienced by 70% or more of the children were: irritability (77%), nausea (75%), and hair loss (72%). On the Symptom Alleviation: Self-Care Methods, the most commonly reported symptom alleviation category was "taking prescribed medicines." Puerto Rican mothers reported the use of alleviation practices to treat their children experiencing symptoms during pediatric cancer treatments. Patients and caregivers need to be educated about treatment-induced side effects, and the life-threatening consequences of underreporting and undermanagement. Symptoms should always be addressed at the time of initiation of primary or adjuvant cancer therapy because pretreatment symptoms may persist or get worse across the trajectory of treatment. A continuous assessment and management of symptoms during the childhood cancer trajectory can optimize clinical care and improve quality of life of patients and families. PMID- 27990707 TI - Acute Kidney Injury and mortality prognosis in Acute Coronary Syndrome patients: A meta-analysis. AB - AIM: The aim of this study is to provide a robust estimate of mortality risk in acute coronary syndrome (ACS)-associated acute kidney injury (AKI) to inform clinical practice and policy. METHODS: A meta-analysis of cohort studies evaluating outcomes of ACS and which reported AKI and AKI-associated mortality. Studies were excluded if they incorporated patients not admitted through the emergency department (i.e. for elective procedures), were limited to cardiogenic shock or cardiac arrest, or relied on registry data for outcomes without further adjudication. The predictor was ACS-associated AKI and outcomes early (30 day or in-hospital) mortality and late-mortality (post-hospital discharge). RESULTS: Thirty-six studies with 37 unique cohorts comprising 100 476 patients were included. The pooled rate of ACS-associated AKI was 15.8%. In 32 cohorts reporting early mortality, the crude early mortality rate was 15.0% amongst those with AKI compared with 2.0% amongst those without AKI. The pooled estimate of the relative risk of AKI-associated early mortality was 4.1 (95% confidence interval: 3.3 to 5.0) with high heterogeneity between studies (I 2 = 84% (61% to 88%)). When heterogeneity was accounted for mathematically using credibility ceilings, the risk of mortality was lower, but still clinically significant (3.1 (2.6 to 3.6)). In 19 cohorts reporting late mortality (1 to 10 years), the relative risk of AKI-associated mortality was 2.6 (2.0 to 3.3) with moderate heterogeneity (I 2 = 65 % [35% to 88%]). Following application of credibility ceiling relative risk estimate dropped to 2.2 (1.9 to 2.6). CONCLUSIONS: Acute coronary syndrome associated AKI is associated with more than a three-fold increase in early mortality and more than two-fold in long-term mortality. PMID- 27990709 TI - The importance of TH22 and TC22 cells in the pathogenesis of Helicobacter pylori associated gastric diseases. AB - BACKGROUND: An association exists between Helicobacter pylori (H. pylori), peptic ulcers, gastritis, and sometimes gastric carcinomas. Th22 cells have protective and inflammatory roles in defense against microbes. AIM: We investigated the frequencies of Th22, Tc22, Th22/17, and Tc22/17 cells in addition to the changes in levels of cytokines IL-22, IL-6, IL-23, TNF-alpha, IL-1beta, and TGF-beta in sera from patients with H. pylori-associated gastritis, and peptic ulcer, and in uninfected patients. METHODS: A total of 76 patients with H. pylori-associated disorders formed the studied group. Frequencies of T-cell subsets were determined by flow cytometry. Levels of cytokines IL-22, IL-6, IL-23, TNF-alpha, IL-1beta, and TGF-beta in the sera and supernatants of patients were measured by ELISA and flow cytometry. RESULTS: The study participants included 32 males and 44 females with a mean age of 38.5+/-15.3 years. We divided the infected group into peptic ulcer and gastritis (mild, moderate, active chronic, and chronic). The frequencies of Th22, Tc22, and Tc22/17 increased significantly in the peptic ulcer, moderate, active chronic, and chronic gastritis groups compared to the uninfected group. Th22/17 only increased significantly in the chronic gastritis group. We observed significant increases in IL-22 in the moderate and active chronic gastritis, IL-23 in the active chronic and chronic gastritis, and TNF alpha in the peptic ulcer and moderate gastritis groups. Following in vitro antigenic stimulation, we observed significantly higher levels of IL-1beta, IL 23, and IL-6 in the active chronic gastritis group, as well as IL-6 and IL-1beta in the chronic gastritis group compared to the uninfected group. CONCLUSION: Increased Th22, Tc22, and Tc22/17 cells and IL-22 levels appear to be influential in progression and severity of H. pylori infection. Th22/17 can be an interesting therapeutic target for chronic H. pylori infections where eradication is more difficult. PMID- 27990708 TI - Temporal accumulation and localization of isoflurane in the C57BL/6 mouse and assessment of its potential contamination in 19 F MRI with perfluoro-crown-ether labeled cardiac progenitor cells at 9.4 Tesla. AB - PURPOSE: To assess the uptake, accumulation, temporal stability, and spatial localization of isoflurane (ISO) in the C57BL/6 mouse, and to identify its potential interference with the detection of labeled cardiac progenitor cells using 19 F MRI/MR spectroscopy (MRS). MATERIALS AND METHODS: Objectives are demonstrated using (a) in vitro ISO tests, (b) in vivo temporal accumulation/spatial localization C57BL/6 studies (n = 3), and (c) through injections of perfluoro-crown-ether (PFCE) labeled cardiac progenitor cells into femoral muscle areas of the murine hindlimb post-mortem (n = 1) using 1 H/19 F MRI/MRS at 9.4 Tesla. Data were acquired using double-gated spoiled gradient echo images and pulse-acquire spectra. For the in vivo study, the temporal stability of ISO resonances was quantified using coefficient of variability (CV) (5 min) estimates. RESULTS: Two ISO resonances were observed in vivo that correspond to the -CF3 and -OCHF2 moieties. CV values ranged between 3.2 and 6.4% (-CF3 ) and 6.4 and 11.2% (-OCHF2 ). Reductions of the ISO dose (2.0 to 1.7%) at 80 min postinduction had insignificant effects on ISO signals (P = 0.23; P = 0.71). PFCE labeled cells exhibited a resonance at -16.25 ppm in vitro that did not overlap with the ISO resonances, a finding that is confirmed with MRS post-mortem using injected, labeled cells. Based on 19 F MRI, similar in vivo/post-mortem ISO compartmentalization was also confirmed in peripheral and thoracic skeletal muscles. CONCLUSION: Significant ISO accumulation was observed by 19 F MRS in vivo with temporally stable signals over 90 min postinduction. ISO effects on PFCE labels are anticipated to be minimal but may be more prominent for perfluoropolyether or perfluorooctyl bromide labels. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;45:1659-1667. PMID- 27990711 TI - A novel functional variant in Wilms' Tumor 1 (WT1) is associated with idiopathic non-obstructive azoospermia. AB - Idiopathic nonobstructive azoospermia (INOA) is one of the most severe forms of male infertility, yet its pathophysiology remains unclear. WT1 (Wilms' tumor 1) regulates the polarity of Sertoli cells, thereby playing a critical, indirect role in spermatogenesis. Here, we evaluated WT1 gene variation associates with INOA by assessing its promoter and coding regions in 200 patients diagnosed with INOA and 200 proven-fertile men. Three novel variants in the WT1 coding region were detected only in INOA patients, including two synonymous variants and one missense variant, p.Phe435Leu (p.F435L), which was predicted to be deleterious to protein function. The results of dual luciferase reporter showed that the WT1 p.F435L variant decreases transcription of COL4A1 and WNT4 promoters through a dominant-negative effect. Furthermore, chromatin immunoprecipitation assays revealed that COL4A1 and WNT4 promoter is directly bound by wild-type WT1 protein, but not the p.F435L WT1 variant. Thus, we identified a novel functional variant of WT1 functionally associated with INOA. Mol. Reprod. Dev. 84: 222-228, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27990710 TI - Efficacy of early sivelestat administration on acute lung injury and acute respiratory distress syndrome. AB - BACKGROUND AND OBJECTIVE: The efficacy of sivelestat, a neutrophil elastase inhibitor, for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remains controversial. We investigated the role of sivelestat in ALI/ARDS patients on mortality as an end point between the sivelestat group and the non sivelestat group within 7 days of admission. METHODS: This study was performed using the Japanese nationwide administrative database (Diagnostic Procedure Combination; DPC) in 2012. We employed the propensity score weighting method with a Cox proportional hazards model to compare the mortality between the sivelestat group and the non-sivelestat group. RESULTS: A total of 4276 patients were eligible for this study; 1997 patients were treated with sivelestat and 2279 patients did not receive sivelestat within 7 days of admission. After adjusting for confounds, the mortality within 3 months was significantly lower in the sivelestat group compared with the non-sivelestat group (weighted hazard ratio: 0.83; 95% CI: 0.75-0.93; P < 0.002). Multiple regression analysis revealed that younger age, absence of cancer, no need for haemodialysis and no use of high-dose methylprednisolone were significantly correlated with treatment success (survive). CONCLUSION: These results of this retrospective and observational study suggest that administration of sivelestat within 7 days of admission may improve the prognosis of patients with ALI/ARDS. To our knowledge, this is the largest study to evaluate the efficacy of sivelestat on ALI/ARDS. PMID- 27990712 TI - The genesis and development of the Endodontic Study Club of Brisbane (1964-1970). AB - This narrative delineates the International, Australian and Queensland settings, between 1940 and 1970 that impeded the development of endodontology and evidence based endodontic practice. It explores the genesis of the Endodontic Study Club of Brisbane between 1964 and 1970. Pioneers' contributions to endodontology in Australia, together with contemporaneous problems, are identified. The author used literature review and historic method. The historical and constitutional backgrounds contributed to the disjointed origins of the Australian Society of Endodontology, which were networked but autonomous study clubs that appeared in capital cities between 1960 and 1965. This was an era when dental education in Queensland was emerging from serious problems. Brown and Simpson liaised with Ehrmann and established the Endodontic Study Club of Brisbane. Members of the Endodontic Study Club of Brisbane were collegiate, disciplined, few, innovative, insular, isolated and visionary. Membership demanded a commitment to self education, collective learning and peer review. PMID- 27990713 TI - Letter to the Editor: In response to 'Nurse administrators' intentions and considerations in recruiting inactive nurses'. PMID- 27990715 TI - Peptide hydrogel in vitro non-inflammatory potential. AB - Peptide-based hydrogels have attracted significant interest in recent years as these soft, highly hydrated materials can be engineered to mimic the cell niche with significant potential applications in the biomedical field. Their potential use in vivo in particular is dependent on their biocompatibility, including their potential to cause an inflammatory response. In this work, we investigated in vitro the inflammatory potential of a beta-sheet forming peptide (FEFEFKFK; F: phenylalanine, E: glutamic acid; K: lysine) hydrogel by encapsulating murine monocytes within it (3D culture) and using the production of cytokines, IL-beta, IL-6 and TNFalpha, as markers of inflammatory response. No statistically significant release of cytokines in our test sample (media + gel + cells) was observed after 48 or 72 h of culture showing that our hydrogels do not incite a pro-inflammatory response in vitro. These results show the potential biocompatibility of these hydrogels and therefore their potential for in vivo use. The work also highlighted the difference in monocyte behaviour, proliferation and morphology changes when cultured in 2D vs. 3D. (c) 2016 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID- 27990716 TI - Quantitative Measurement of Communication Ability in Children with Angelman Syndrome. AB - BACKGROUND: Angelman syndrome is a rare disorder in which most individuals do not develop speech. Testing of communication ability using traditional neuropsychological measures reveals a performance level at or near the floor of the instrument resulting in an inability to detect change when experimental therapeutics are applied. METHODS: Nine individuals, with molecularly confirmed AS, ranging in age from 34 to 126 months, and a single healthy control child (age 16 months) were audio and video-recorded while interacting with a licensed speech language pathologist in an attempt to elicit vocalization and non-verbal communication. Thirty-minute audio recordings were transcribed and categorized per the Stark Assessment of Early Vocal Development-Revised and a phonetic inventory was created. Using video recordings, gestures were classified by function, either behavioral regulation or social interaction and further categorized as deictic or representational (i.e., behavioral regulation) and joint attention or shared engagement (i.e., social interaction). RESULTS: The range of vocalizations produced by the children with AS was characteristic of children between 0-6 months and none of the children with AS used advanced forms of vocalizations. The mean frequency of reflexive vocalizations, control of phonation and expansion far exceeded the number of uses of canonical syllables, consistant with the characteristics of children around 12 months of age. Most vocalizations were either laughter or isolated vowels, only three children with AS produced consonant-vowel combinations. Children with AS tended to use central and low vowels with few producing high vowels, suggesting the presence of childhood apraxia of speech. CONCLUSION: Our results show the utilization of video-recorded behavioral observations provides a feasible and reliable alternative for quantification of communication ability in this patient population and may be employed during future clinical studies of potential therapeutics. PMID- 27990717 TI - The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. AB - AIMS: The third isotype of beta adrenergic receptors (beta3 ARs) has distinctly different effects on cardiomyocytes compared with beta1 and beta2 ARs. Stimulation of beta3 ARs may reduce cardiomyocyte Na+ overload and reduce oxidative stress in heart failure (HF). We examined if treatment with the beta3 AR agonist mirabegron increases LVEF in patients with HF. METHODS AND RESULTS: In a double-blind trial we randomly assigned 70 patients with NYHA class II-III HF and LVEF <40% at screening-echocardiography to receive mirabegron or placebo for 6 months as add-on to optimized standard therapy. The primary endpoint was an increase in LVEF after 6 months as measured by computed tomography (CT). Changes in LVEF after 6 months between treatment groups were not significantly different (0.4%, -3.5 to 3.8%, P = 0.82). In an exploratory analysis, based on an expectation that the pathophysiological substrate targeted with treatment is dependent on the baseline LVEF, patients with LVEF <40% by CT given mirabegron had a significant increase in LVEF while no increase was seen in patients given placebo. The changes were significantly different between groups (5.5%, 0.6 10.4%, P < 0.03). Additionally, there was interaction between baseline LVEF and change in LVEF in the entire group of patients treated with mirabegron (R2 = 0.40, beta = -0.63, P < 0.001), but not in the placebo group (R2 = 0.00, beta = -0.01, P = 0.95). Treatment was generally well tolerated. Three patients in each group had fatal or life-threatening events. CONCLUSIONS: The primary endpoint was not reached. Exploratory analysis indicated that beta3 AR stimulation by mirabegron increased LVEF in patients with severe HF. Treatment appeared safe. Additional studies in severe HF are needed. TRIAL REGISTRATION: NCT01876433. PMID- 27990718 TI - Determinants of morbidity associated with infant male circumcision: community level population-based study in rural Ghana. AB - OBJECTIVE: Male circumcision services have expanded throughout Africa as part of a long-term HIV prevention strategy. We assessed the effect of type of service provider (formal and informal) and hygiene practices on circumcision-related morbidities in rural Ghana. METHODS: Population-based, cross-sectional study conducted between May and December 2012 involving 2850 circumcised infant males aged under 12 weeks. Multivariable logistic regression models were adjusted for maternal age, maternal education, income, birthweight and site of circumcision. RESULTS: A total of 2850 (90.7%) infant males were circumcised. Overall, the risk of experiencing a morbidity (defined as complications occurring during or after the circumcision procedure as reported by the primary caregiver) was 8.1% (230). Risk was not significantly increased if the circumcision was performed by informal providers (121, 7.2%) vs. formal health service providers (109, 9.8%) [adjusted odds ratio (aOR) 1.11, 95% CI 0.80-1.47, P = 0.456]. Poor hygiene practices were associated with significantly increased risk of morbidity: no handwashing [148 (11.7%)] (aOR 1.78, 95% CI 1.27-2.52, P = 0.001); not cleaning circumcision instruments [174 (10.6%)] (aOR 1.80, 95% CI 1.27-2.54, P = 0.001); and uncleaned penile area [190 (10.0%)] (aOR 1.84, 95% CI 1.25-2.70, P = 0.002). CONCLUSION: The risk of morbidity after infant male circumcision in rural Ghana is high, chiefly due to poor hygiene practices. Governmental and non-governmental organisations need to improve training of circumcision providers in hygiene practices in sub-Saharan Africa. PMID- 27990719 TI - Interpersonal movement synchrony facilitates pro-social behavior in children's peer-play. AB - The emergence of pro-social behaviors and social interaction skills is a major focus of research on children's development. Here, we consider one important feature of human social interactions, interpersonal movement synchrony, and explore its effects on pro-sociality among young children. Coordinated movements are a crucial part of mother-infant interactions, with important social effects extending well into childhood. Musical interactions are also known to facilitate bonding between infants and caretakers and pro-sociality among peers. We specifically examine the pro-social effects of interpersonal movement synchrony in a naturalistic peer-play context among 4- to 6-year-old children. We assessed the amount of helping behavior between pairs of children following an activity that they performed synchronously or non-synchronously. Children who engaged in synchronous play, as compared with non-synchronous play, showed significantly more subsequent spontaneous helping behavior. Further, more mutual smiling and eye contact were observed in the synchronous condition and amounts of mutual smiling and eye contact during the movement task correlated with amount of helping behavior observed. Neither measure mediated the condition-wise effects on helping, however. These results are discussed in terms of their contribution to existing literature and their broader implications for the development of pro sociality and coordinated movements in early childhood. PMID- 27990721 TI - When Like Charged Ions Attract in Ionic Liquids: Controlling the Formation of Cationic Clusters by the Interaction Strength of the Counterions. AB - The properties of ionic liquids are described by a subtle balance between Coulomb interaction, hydrogen bonding, and dispersion forces. We show that lowering the attractive Coulomb interaction by choosing weakly coordinating anions leads to the formation of cationic clusters. These clusters of like-charged ions are stabilized by cooperative hydrogen bonding and controlled by the interaction potential of the anion. IR and NMR spectroscopy combined with computational methods are used to detect and characterize these unusual, counter-intuitively formed clusters. They can be only observed for weakly coordinating anions. When cationic clusters are formed, cyclic tetramers are particularly stable. Therein, cooperative hydrogen-bond attraction can compete with like-charge repulsion. We present a simple but effective spectroscopic scale for the possibility of like charge attraction in ionic liquids, based on IR and NMR signatures. PMID- 27990720 TI - A functional variant of the neuropeptide S receptor-1 gene modulates clinical outcomes and healthcare utilization in patients with systolic heart failure: results from the Interdisciplinary Network Heart Failure (INH) Study. AB - AIMS: Psychopathologies may occur in heart failure (HF) and can be associated with adverse outcomes. Amongst neuropeptide S receptor gene functional sequence variants, the T-allele [asparagine(107)isoleucine, NPSR1 rs324981] has been identified as a risk factor for increased anxiety/overinterpretation of bodily symptoms. We investigated all-cause death and re-hospitalization (composite primary endpoint, CPEP) and healthcare utilization in patients hospitalized for decompensated systolic HF with the TT vs. the AT/AA genotype. METHODS AND RESULTS: Participants in the Interdisciplinary Network Heart Failure programme were eligible if consenting to genetic testing (n = 924) and randomization to usual care (UC, n = 464) or nurse-co-ordinated disease management (DM, n = 460). Follow-up was 180 days (100% complete). Compared with AT/AA carriers (n = 726), TT genotype carriers (n = 198) had more CPEP events [47% vs. 39%, hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.01-1.61, P = 0.044] and were more frequently re-hospitalized (43% vs. 35%, HR 1.31, 95% CI 1.02-1.67, P = 0.033); mortality rate was similar in both groups (HR 1.11, 95% CI 0.68-1.81, P = 0.664). In subjects undergoing DM, CPEP and re-hospitalization occurred more often in TT (51% and 47%) than in AT/AA carriers (36% and 33%; HR 2.14, 95% CI 1.44-3.19, and HR 2.29, 95% CI 1.52-3.44, genotype/treatment interaction both P = 0.007). Furthermore, TT genotype carriers undergoing DM visited cardiologists and other specialists more often than AT/AA carriers (P = 0.009 and P = 0.005). With UC, event rates did not differ between genotype subgroups. CONCLUSION: We identified a psychogenetic determinant of clinical outcomes and healthcare utilization after acute HF, which was modulated by the type of care. Future investigations need to clarify whether NPSR1 genotyping might further enhance the concept of 'personalized' medicine in HF. TRIAL REGISTRATION: ISRCTN23325295. PMID- 27990723 TI - Presence of Clostridium difficile in pig faecal samples and wild animal species associated with pig farms. AB - AIMS: To determine the presence of Clostridium difficile on fattening pig farms in north-eastern Spain. METHODS AND RESULTS: Twenty-seven farms were sampled. Pools of pig faecal samples (n = 210), samples of intestinal content from common farm pest species (n = 95) and environment-related samples (n = 93) were collected. Isolates were tested for toxin genes of C. difficile, and typed by PCR ribotyping and toxinotyping. The minimal inhibitory concentrations of six antimicrobial agents were determined using Etest. Thirty-four isolates were obtained from 12 farms, and 30 (88.2%) had toxin genes. Seven ribotypes were identified. Ribotype 078 and its variant 126 were predominant (52.9%). The same ribotypes were isolated from different animal species on the same farm. None of the isolates were resistant to metronidazole or vancomycin. CONCLUSIONS: Clostridium difficile was common within the pig farm environment. Most of the positive samples came from pest species or were pest-related environmental samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Pest species were colonized with toxigenic and antimicrobial-resistant C. difficile strains of the same ribotypes that are found in humans and pigs. Rodents and pigeons may transmit toxigenic and antimicrobial-resistant C. difficile strains that are of the same ribotypes as those occuring in humans. PMID- 27990724 TI - Audio-visual speech in noise perception in dyslexia. AB - Individuals with developmental dyslexia (DD) may experience, besides reading problems, other speech-related processing deficits. Here, we examined the influence of visual articulatory information (lip-read speech) at various levels of background noise on auditory word recognition in children and adults with DD. We found that children with a documented history of DD have deficits in their ability to gain benefit from lip-read information that disambiguates noise-masked speech. We show with another group of adult individuals with DD that these deficits persist into adulthood. These deficits could not be attributed to impairments in unisensory auditory word recognition. Rather, the results indicate a specific deficit in audio-visual speech processing and suggest that impaired multisensory integration might be an important aspect of DD. PMID- 27990722 TI - Radiomic features for prostate cancer detection on MRI differ between the transition and peripheral zones: Preliminary findings from a multi-institutional study. AB - PURPOSE: To evaluate in a multi-institutional study whether radiomic features useful for prostate cancer (PCa) detection from 3 Tesla (T) multi-parametric MRI (mpMRI) in the transition zone (TZ) differ from those in the peripheral zone (PZ). MATERIALS AND METHODS: 3T mpMRI, including T2-weighted (T2w), apparent diffusion coefficient (ADC) maps, and dynamic contrast-enhanced MRI (DCE-MRI), were retrospectively obtained from 80 patients at three institutions. This study was approved by the institutional review board of each participating institution. First-order statistical, co-occurrence, and wavelet features were extracted from T2w MRI and ADC maps, and contrast kinetic features were extracted from DCE-MRI. Feature selection was performed to identify 10 features for PCa detection in the TZ and PZ, respectively. Two logistic regression classifiers used these features to detect PCa and were evaluated by area under the receiver-operating characteristic curve (AUC). Classifier performance was compared with a zone ignorant classifier. RESULTS: Radiomic features that were identified as useful for PCa detection differed between TZ and PZ. When classification was performed on a per-voxel basis, a PZ-specific classifier detected PZ tumors on an independent test set with significantly higher accuracy (AUC = 0.61-0.71) than a zone-ignorant classifier trained to detect cancer throughout the entire prostate (P < 0.05). When classifiers were evaluated on MRI data from multiple institutions, statistically similar AUC values (P > 0.14) were obtained for all institutions. CONCLUSION: A zone-aware classifier significantly improves the accuracy of cancer detection in the PZ. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:184-193. PMID- 27990725 TI - Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules. AB - Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics. PMID- 27990726 TI - Photocatalytic Dehydrogenative Cross-Coupling of Alkenes with Alcohols or Azoles without External Oxidant. AB - Direct cross-coupling between alkenes/R-H or alkenes/RXH is a dream reaction, especially without external oxidants. Inputting energy by photocatalysis and employing a cobalt catalyst as a two-electron acceptor, a direct C-H/X-H cross coupling with H2 evolution has been achieved for C-O and C-N bond formation. A new radical alkenylation using alkene as the redox compound is presented. A wide range of aliphatic alcohols-even long chain alcohols-are tolerated well in this system, providing a new route to multi-substituted enol ether derivatives using simple alkenes. Additionally, this protocol can also be used for N-vinylazole synthesis. Mechanistic insights reveal that the cobalt catalyst oxidizes the photocatalyst to revive the photocatalytic cycle. PMID- 27990727 TI - Coupling Sensitive Nucleic Acid Amplification with Commercial Pregnancy Test Strips. AB - The detection of nucleic acid biomarkers for point-of-care (POC) diagnostics is currently limited by technical complexity, cost, and time constraints. To overcome these shortcomings, we have combined loop-mediated isothermal amplification (LAMP), programmable toehold-mediated strand-exchange signal transduction, and standard pregnancy test strips. The incorporation of an engineered hCG-SNAP fusion reporter protein (human chorionic gonadotropin-O6 alkylguanine-DNA alkyltransferase) led to LAMP-to-hCG signal transduction on low cost, commercially available pregnancy test strips. Our assay reliably detected as few as 20 copies of Ebola virus templates in both human serum and saliva and could be adapted to distinguish a common melanoma-associated SNP allele (BRAF V600E) from the wild-type sequence. The methods described are completely generalizable to many nucleic acid biomarkers, and could be adapted to provide POC diagnostics for a range of pathogens. PMID- 27990728 TI - Photoarylation of Iodocarboranes with Unactivated (Hetero)Arenes: Facile Synthesis of 1,2-[(Hetero)Aryl]n -o-Carboranes (n=1,2) and o-Carborane-Fused Cyclics. AB - Photoarylation of iodocarboranes with unactivated arenes/heteroarenes at room temperature has been achieved, for the first time, thus leading to the facile synthesis of a large variety of cage carbon mono(hetero)arylated and di(hetero)arylated o-carboranes. This work represents a clean, efficient, transition-metal-free, and cheap synthesis of functionalized carboranes, which has significant advantages over the known methods. PMID- 27990729 TI - Protein Structural Ensembles Visualized by Solvent Paramagnetic Relaxation Enhancement. AB - A protein can be in different conformations when fulfilling its function. Yet depiction of protein structural ensembles remains difficult. Here we show that the accurate measurement of solvent paramagnetic relaxation enhancement (sPRE) in the presence of an inert paramagnetic cosolute allows the assessment of protein dynamics. Demonstrated with two multi-domain proteins, we present a method to characterize protein microsecond-millisecond dynamics based on the analysis of the sPRE. Provided with the known structures of a protein, our method uncovers an ensemble of structures that fully accounts for the observed sPRE. In conjunction with molecular dynamics simulations, our method can identify protein alternative conformation that has only been theorized before. Together, our method expands the application of sPRE beyond structural characterization of rigid proteins and complements the established PRE NMR technique. PMID- 27990730 TI - Total Synthesis of (-)-Histrionicotoxin through a Stereoselective Radical Translocation-Cyclization Reaction. AB - Stereoselective total syntheses of (-)-histrionicotoxin and (-)-histrionicotoxin 235A are described. The 1-azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation-cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (-) histrionicotoxin 235A through a one-pot partial-reduction-allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3-amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (-)-histrionicotoxin. PMID- 27990731 TI - 'Shutting the World Out': An Interpretative Phenomenological Analysis Exploring the Paternal Experience of Parenting a Young Adult with a Developmental Disability. AB - BACKGROUND: An in-depth exploration of the experience of midlife fathers of developmentally disabled young adults (aged 19-32 years) was motivated by a dearth of research in this area (McKnight, PsyPAG Quarterly, 94, 2015, 10). METHOD: Five fathers participated in semi-structured interviews which were subjected to interpretative phenomenological analysis (Smith, Flowers and Larkin, 2009, Interpretative Phenomenological Analysis: Theory, Method, and Research. London: Sage). RESULTS: The final thematic structure comprises four inter-related themes. They demonstrate a high degree of concern for children's well-being; the joy adult children confers on their father's lives as well as the difficulties men experience in response to the limited opportunities available to their offspring. Importantly findings also illustrate the way in which men struggle to contend with painful emotions. CONCLUSIONS: Societal conceptions of masculinity, fatherhood and disability necessarily influence the way fathers experience the world (Yarwood, Fathering, 9, 2011, 150). It is imperative that service providers recognize the particular challenges faced by fathers, seeking ways to better engage and support them. PMID- 27990732 TI - Symptoms among patients receiving in-center hemodialysis: A qualitative study. AB - INTRODUCTION: Assessment of dialysis-related symptoms is not currently a requirement for hemodialysis (HD) providers in the United States. The purpose of this study was to describe patients' perspectives on symptoms associated with end stage chronic kidney disease treated with thrice-weekly, in-center HD. METHODS: We performed a qualitative study using interpretive description. Interview questions were based on a KDIGO (Kidney Disease Improving Global Outcomes) controversies conference and a literature review. Semi-structured interviews were analyzed for characterizations of symptoms. FINDINGS: Fifty participants (48% female; 42% Hispanic; 30% American Indian; 14% Black; 12% non-Hispanic White) were recruited from six outpatient dialysis centers (four urban, two rural) in the southwestern United States. Median HD duration was 4 years. Of 13 symptoms assessed, nearly all participants reported difficulties with muscle cramping, fatigue, or both. Negotiating fluid removal with dialysis personnel helped to manage cramping. Some participants tried to adjust dialysis days and shift to mitigate fatigue. Most participants reported having experienced depression early in the course of dialysis; for some, it was a persistent or recurrent problem. Relatively few participants reported using antidepressants or counseling to cope with depression. Itching was highly distressing for those who experienced it frequently. Topical treatments, antihistamines, dietary modifications, and phosphate binders were identified as potentially helpful by some participants. DISCUSSION: The major symptoms attributed to HD treatment by participants were cramping, fatigue, depression, and itching. Greater attention by health care providers to the most common and bothersome symptoms could positively impact daily life for HD patients. PMID- 27990733 TI - Facile Reductive Silylation of UO22+ to Uranium(IV) Chloride. AB - General reductive silylation of the UO22+ cation occurs readily in a one-pot, two step stoichiometric reaction at room temperature to form uranium(IV) siloxides. Addition of two equivalents of an alkylating reagent to UO2 X2 (L)2 (X=Cl, Br, I, OTf; L=triphenylphosphine oxide, 2,2'-bipyridyl) followed by two equivalents of a silyl (pseudo)halide, R3 Si-X (R=aryl, alkyl, H; X=Cl, Br, I, OTf, SPh), cleanly affords (R3 SiO)2 UX2 (L)2 in high yields. Support is included for the key step in the process, reduction of UVI to UV . This procedure is applicable to a wide range of commercially available uranyl salts, silyl halides, and alkylating reagents. Under this protocol, one equivalent of SiCl4 or two equivalents of Me2 SiCl2 results in direct conversion of the uranyl to uranium(IV) tetrachloride. Full spectroscopic and structural characterization of the siloxide products is reported. PMID- 27990735 TI - Societe Chimique de France Prizes 2016. PMID- 27990734 TI - Enantioselective Synthesis and Racemization of (-)-Sinoracutine. AB - Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers of sinoracutine have been independently isolated from the same plant, yet the molecule does not appear to occur as a racemate. Here, we present a short synthesis of (-)-sinoracutine that relies on a highly diastereoselective Pauson-Khand reaction and a Mandai-Claisen reaction to install the quaternary stereocenter. Our work establishes the absolute configuration of the levorotatory isomer and suggests that the optical purity of sinoracutine varies in nature due to its gradual racemization. Experimental evidence supports this proposal, and a plausible mechanism for the racemization is provided. PMID- 27990736 TI - Construction of Chiral Tetraorganosilicons by Tandem Desymmetrization of Silacyclobutanes/Intermolecular Dehydrogenative Silylation. AB - We report a method to construct chiral tetraorganosilicons by tandem silacyclobutane (SCB) desymmetrization-dehydrogenative silylations. A wide array of dibenzosiloles with stereogenic quaternary silicon centers were obtained in good yields and enantioselectivities up to 93 % ee. Chiral TMS-segphos was found to be a superior ligand in terms of reactivity and enantioselectivity. PMID- 27990738 TI - Beneficial Coercion in Psychiatric Care: Insights from African Ethico-Cultural System. AB - There is a 'catch 22' situation about applying coercion in psychiatric care. Autonomous choices undeniably are rights of patients. However, emphasizing rights for a mentally-ill patient could jeopardize the chances of the patient receiving care or endanger the public. Conversely, the beneficial effects of coercion are difficult to predict. Thus, applying coercion in psychiatric care requires delicate balancing of individual-rights, individual well-being and public safety, which has not been achieved by current frameworks. Two current frameworks may be distinguished: the civil liberty approach and the Stone model. Both frameworks are restrictive, and not respectful of human dignity. In a civil liberty approach, individuals who are severely mentally-ill but not dangerous would be denied care because they do not meet the dangerousness threshold or because the use of coercion will not lead to rebirthing of autonomy. This is unsatisfactory. Albeit involuntary interventions such as talk therapies, peer-support etc., may not always lead to rebirthing of autonomy or free patients from mental illness; they can however help to maintain the dignity of each mentally ill patient. In place of these frameworks, this study proposes a new ethical framework for applying coercion in psychiatric care that is respectful of human dignity. Specifically, it draws on insights from the African ethico-cultural system by using the Yoruba concept Omo-olu-iwabi to develop this new framework. This way, the study shows that only a more respectful approach for applying coercion in psychiatric care can lead to the careful balancing of the competing interests of individual's rights, individual's well-being and public safety. PMID- 27990737 TI - Tailoring the composition of novel wax esters in the seeds of transgenic Camelina sativa through systematic metabolic engineering. AB - The functional characterization of wax biosynthetic enzymes in transgenic plants has opened the possibility of producing tailored wax esters (WEs) in the seeds of a suitable host crop. In this study, in addition to systematically evaluating a panel of WE biosynthetic activities, we have also modulated the acyl-CoA substrate pool, through the co-expression of acyl-ACP thioesterases, to direct the accumulation of medium-chain fatty acids. Using this combinatorial approach, we determined the additive contribution of both the varied acyl-CoA pool and biosynthetic enzyme substrate specificity to the accumulation of non-native WEs in the seeds of transgenic Camelina plants. A total of fourteen constructs were prepared containing selected FAR and WS genes in combination with an acyl-ACP thioesterase. All enzyme combinations led to the successful production of wax esters, of differing compositions. The impact of acyl-CoA thioesterase expression on wax ester accumulation varied depending on the substrate specificity of the WS. Hence, co-expression of acyl-ACP thioesterases with Marinobacter hydrocarbonoclasticus WS and Marinobacter aquaeolei FAR resulted in the production of WEs with reduced chain lengths, whereas the co-expression of the same acyl-ACP thioesterases in combination with Mus musculus WS and M. aquaeolei FAR had little impact on the overall final wax composition. This was despite substantial remodelling of the acyl-CoA pool, suggesting that these substrates were not efficiently incorporated into WEs. These results indicate that modification of the substrate pool requires careful selection of the WS and FAR activities for the successful high accumulation of these novel wax ester species in Camelina seeds. PMID- 27990740 TI - Hypertensive eye disease: a review. AB - Hypertension is a risk factor for a number of vision-threatening eye conditions including retinal vascular occlusion, retinal macroaneurysm and non arteritic anterior ischaemic optic neuropathy. In addition, hypertension may exacerbate the vision-threatening effects of diabetic retinopathy and has been implicated in the pathogenesis of age-related macular degeneration. The effects of sustained hypertension are directly visible in the eye as hypertensive retinopathy and choroidopathy, reflecting a pathological process occurring throughout the body. Close collaboration between ophthalmologists and general practitioners/physicians is needed to ensure that hypertensive patients are identified and treated. Timely intervention in these patients may reduce the risk of both vision-threatening and systemic complications. PMID- 27990739 TI - Acute alcohol effects on set-shifting and its moderation by baseline individual differences: a latent variable analysis. AB - AIMS: To compare the acute effects of alcohol on set-shifting task performance (relative to sober baseline performance) during ascending and descending limb breath alcohol concentration (BrAC), as well as possible moderation of these effects by baseline individual differences. DESIGN: Shifting performance was tested during an initial baseline and a subsequent drinking session, during which participants were assigned randomly to one of three beverage conditions (alcohol, placebo or control) and one of two BrAC limb conditions [ascending and descending (A/D) or descending-only (D-only)]. SETTING: A human experimental laboratory on the University of Missouri campus in Columbia, MO, USA. PARTICIPANTS: A total of 222 moderate-drinking adults (ages 21-30 years) recruited from Columbia, MO and tested between 2010 and 2013. MEASUREMENTS: The outcome measure was performance on set-shifting tasks under the different beverage and limb conditions. Shifting performance assessed at baseline was a key moderator. FINDINGS: Although performance improved across sessions, this improvement was reduced in the alcohol compared with no-alcohol groups (post-drink latent mean comparison across groups, all Ps <= 0.05), and this effect was more pronounced in individuals with lower pre-drink performance (comparison of pre- to post-drink path coefficients across groups, all Ps <= 0.05). In the alcohol group, performance was better on descending compared with ascending limb (P <= 0.001), but descending limb performance did not differ across the A/D and D-only groups. CONCLUSIONS: Practising tasks before drinking moderates the acute effects of alcohol on the ability to switch between tasks. Greater impairment in shifting ability on descending compared with ascending breath alcohol concentration is not related to task practice. PMID- 27990741 TI - Water-Rich Fluid Material Containing Orderly Condensed Proteins. AB - A fluid material with high protein content (120-310 mg mL-1 ) was formed through the ordered self-assembly of native proteins segregated from water. This material is instantly prepared by the simple mixing of a protein solution with anionic and cationic surfactants. By changing the ratio of the surfactants based on the electrostatic characteristics of the target protein, we observed that the surfactants could function as a versatile molecular glue for protein assembly. Moreover, these protein assemblies could be disassembled back into an aqueous solution depending on the salt conditions. Owing to the water-retaining properties of the hydrophilic part of surfactants, the proteins in this material are in a water-rich environment, which maintains their native structure and function. The inclusion of water also provides functional extensibility to this material, as demonstrated by the preparation of an enzymatically active gel. We anticipate that the unique features of this material will permit the use of proteins not only in solution but also as elements of integrated functionalized materials. PMID- 27990742 TI - In memoriam David Grimwade (1962-2016). PMID- 27990743 TI - Punishment of Minor Female Genital Ritual Procedures: Is the Perfect the Enemy of the Good? AB - Female genital alteration (FGA) is any cutting, removal or destruction of any part of the external female genitalia. Various FGA practices are common throughout the world. While most frequent in Africa and Asia, transglobal migration has brought ritual FGA to Western nations. All forms of FGA are generally considered undesirable for medical and ethical reasons when performed on minors. One ritual FGA procedure is the vulvar nick (VN). This is a small laceration to the vulva that does not cause morphological changes. Besides being performed as a primary ritual procedure it has been proposed as a substitute for more extensive forms of FGA. Measures advocated or taken to reduce the burden of FGA can be punitive or non-punitive. Even if it is unethical to perform VN, we argue that it also is unethical to attempt to suppress it through punishment. First, punishment of VN is likely to cause more harm than good overall, even to those ostensibly being protected. Second, punishment is likely to exceed legitimate retributive ends. We do not argue in favor of performing VN. Rather, we argue that non-punitive strategies such as education and harm reduction should be employed. PMID- 27990745 TI - Letter from the Editors. PMID- 27990744 TI - 'En face' ex vivo reflectance confocal microscopy to help the surgery of basal cell carcinoma of the eyelid. AB - BACKGROUND: Ex vivo confocal microscopy is a recent imaging technique for the perioperative control of skin tumour margins. Up to date, it has been used in the fluorescence mode and with vertical sections of the specimen margins. The aim of this study was to evaluate its use in the reflectance mode and with a horizontal ('en face') scanning of the surgical specimen in a series of basal cell carcinoma of the eyelid. DESIGN: Prospective consecutive cohort study was performed at the University Hospital of Saint-Etienne, France. PARTICIPANTS: Forty-one patients with 42 basal cell carcinoma of the eyelid participated in this study. METHODS: Basal cell carcinomas were excised with a 2-mm-wide clinically safe margin. The surgical specimens were analysed under ex vivo confocal microscopy in the reflectance mode and with an en face scanning in order to control at a microscopic level if the margins were free from tumour invasion. Histopathogical examination was later performed in order to compare the results. MAIN OUTCOME MEASURES: Sensitivity and specificity of ex vivo confocal microscopy for the presence of tumour-free margins. RESULTS: Ex vivo confocal microscopy results were consistent with histopathology in all cases (tumour-free margins in 40 out of 42 samples; sensitivity and specificity of 100%). CONCLUSIONS: Ex vivo confocal microscopy in the reflectance mode with an 'en face' scanning can control tumour margins of eyelid basal cell carcinomas and optimize their surgical management. This procedure has the advantage on the fluorescent mode of not needing any contrast agent to examine the samples. PMID- 27990746 TI - Parents' Opinions about an Intervention to Manage Repetitive Behaviours in Young Children with Autism Spectrum Disorder: A Qualitative Study. AB - BACKGROUND: Early intervention for autism spectrum disorder (ASD) tends to focus on enhancing social communication skills. We report data collected via focus group discussions as part of a feasibility and acceptability pilot randomized controlled trial (RCT) about a new parent group intervention to manage restricted and repetitive behaviours (RRB) in young children with ASD. METHODS: The focus groups were led by two independent facilitators and followed a semi-structured topic guide with the aim of considering three key topics: experiences of participating in a RCT, opinions about the intervention and the impact of the intervention on the participants, their children and the family. RESULTS: Fourteen participants attended the focus groups. Most participants reported that they had little knowledge of RRB before attending the intervention and that it had had a positive impact on them, their children and their family. CONCLUSION: The findings support the view that there is an unmet need for a parent-mediated intervention focusing on RRB. PMID- 27990747 TI - Corrigendum: 3-Hz Subthreshold Oscillations of CA2 Neurons In Vivo. PMID- 27990748 TI - How the use of nitrogen fertiliser may switch plant suitability for aphids: the case of Miscanthus, a promising biomass crop, and the aphid pest Rhopalosiphum maidis. AB - BACKGROUND: The use of nitrogen fertiliser in agrosystems can alter plant nitrogen and consequently improve nutrient availability for herbivores, potentially leading to better performance for herbivores and higher pest pressure in the field. We compared, in laboratory conditions, the effects of nitrogen fertilisation on a promising biomass crop, Miscanthus * giganteus, and its parents M. sinensis and M. sacchariflorus. The plant-mediated effects were compared on the second trophic level, the green corn leaf aphid Rhopalosiphum maidis. RESULTS: Results showed that the biomass and leaf C:N ratio of M. sinensis plants treated with nitrogen fertiliser were significantly greater than those of non-treated plants. As regards M. * giganteus and M. sacchariflorus, the only reported change was a significantly smaller leaf C:N ratio for treated M. sacchariflorus compared with non-treated plants. Surprisingly, nitrogen fertilisation had opposite effects on plant-herbivore interactions. Following nitrogen treatments, M. sinensis was less suitable in terms of intrinsic rate of increase for R. maidis, the feeding behaviour of which was negatively affected, while M. sacchariflorus and M. * giganteus exhibited greater suitability in terms of aphid weight. CONCLUSION: Nitrogen fertilisation had contrasting effects on the three species of Miscanthus plants. These effects cascaded up to the second trophic level, R. maidis aphid pests, either through a modification of their weight or demographic parameters. The implications of these results were discussed in the context of agricultural sustainability and intensive production practices. (c) 2016 Society of Chemical Industry. PMID- 27990749 TI - Winter flooding of California rice fields reduces immature populations of Lissorhoptrus oryzophilus (Coleoptera: Curculionidae) in the spring. AB - BACKGROUND: In California, rice fields are flooded over the winter months (November to March) to facilitate degradation of post-harvest rice straw and to provide temporary habitat for migratory waterfowl. Prior research showed that winter flood rice fields had fewer rice water weevil (Lissorhoptrus oryzophilus), larvae and pupae during the rice production season than fields that were left unflooded in the winter. A series of experiments were conducted to provide further support for these trends under controlled conditions and to find a mechanism for this phenomenon. RESULTS: Under winter flooded conditions there was a 50% reduction in populations of weevil immatures compared with the untreated control (no straw or winter flood). These same conditions corresponded to a 20% increase in the amount of silicon found in plant tissues in 2014 and a 39 to 90% decrease in methane production in the soil from 2013 to 2014, respectively. CONCLUSION: Evidence from previous field research and these controlled studies supports winter flooding as an appropriate tactic for controlling L. oryzophilus populations in the spring. However, the mechanism that would explain why winter flooding adversely affects L. oryzophilus immatures remains unclear. (c) 2016 Society of Chemical Industry. PMID- 27990750 TI - Buttressing Salicylaldehydes: A Multipurpose Directing Group for C(sp3 )-H Bond Activation. AB - A palladium-catalyzed reaction of primary amines with iodoarenes produces gamma arylated primary amines. A bulky salicylaldehyde, which is marked as easily available, installable, removable, and recoverable, plays a key role in directing palladium to site-selectively activate the C-H bond located gamma to the amino group. PMID- 27990751 TI - Curcumin improves glucose tolerance via stimulation of glucagon-like peptide-1 secretion. AB - SCOPE: Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted from enteroendocrine L-cells. Our previous studies demonstrated that curcumin (a yellow pigment of turmeric) significantly increases the secretion of GLP-1 in enteroendocrine L cell line (GLUTag cells). However, it is not clear whether its action in vivo directly enhances GLP-1 secretion, which then leads to a reduction in blood glucose levels via the stimulation of insulin secretion. In addition, the molecular target of curcumin-induced GLP-1 secretion has not been clarified. METHODS AND RESULTS: Glucose tolerance was significantly improved in rats after pre-administered curcumin (1.5 mg/kg) followed by intraperitoneal glucose injections via the stimulation of GLP-1 secretion and the induction of insulin secretion. In GLUTag cells, curcumin-induced GLP-1 secretion was associated with G protein-coupled receptor (GPR) 40/120. Furthermore, the glucose-lowering effect induced by curcumin was significantly reduced after the administration of a GPR40/120 antagonist in rats. CONCLUSION: These findings demonstrate the biological function of curcumin as a GLP-1 secretagogue and the possible molecular target that mediates GLP-1 secretion. Increases in the secretion of endogenous GLP-1 induced by curcumin may allow the dosages of other diabetic medicines to be reduced and aid in the prevention of diabetes. PMID- 27990752 TI - Risk for Hip Fracture due to Alpha Blocker Treatment in Korean Women: National Health Insurance Database Study. AB - OBJECTIVE: The aim of this study is to evaluate the risk for hip fracture associated with adverse drug reactions caused by alpha1-adrenergic (alpha) blockers to treat female voiding dysfunction. METHODS: Information from the Health Insurance Review and Assessment Service database from January 1, 2008 to December 31, 2012 was used. Hip fracture women patients who received a prescription for an alpha blocker due to voiding dysfunction were the cases. A 30 day hazard period after administration of an alpha blocker was set. The 30-day control period was defined as 360 days before administration. The standardized incidence ratio and hazard ratio for the risk of hip bone fracture as related to alpha blocker use were analyzed. RESULTS: The study cohort included 287 383 subjects having a mean age of 65.1 +/- 9.7 years in the study cohort. A total of 170 and 79 hip fracture cases were diagnosed in the hazard period and control period, respectively. The incidence of newly diagnosed hip fractures per 100 000 person-years was 763.4 in the hazard period and 348.5 in the control period. The hazard ratio for hip fracture after use of an alpha blocker was 2.19 (95% confidence interval, 1.74-2.77). CONCLUSIONS: Alpha blockers to treat voiding dysfunction may have association with the risk for hip fracture in elderly women. PMID- 27990753 TI - Triangle of Marcille: the anatomical gateway to lateral pelvic exenteration. AB - BACKGROUND: To perform more radical surgery for complex pelvic malignancies and recurrent colorectal cancer, the surgeon must increasingly operate outside the conventional anatomical planes. Published in 1963 the 'Triangle of Marcille' (lumbosacral triangle) remained primarily of intellectual interest being found lateral to the traditional operating field. However, with the advancement of complex colorectal and gynaecological surgery it now provides a schema to assist surgeons in becoming acquainted with a complex and poorly understood anatomical region. Additionally, it prepares the surgeon for the extent of lateral dissection required to achieve the 'holy grail' for oncological surgery in pelvic malignancy, the complete resection (R0). METHODS: To prosect a preserved cadaver in order to demonstrate, in vivo, the contents and borders of the Triangle of Marcille for the purposes of teaching surgeons and future surgeons. RESULTS: The Triangle of Marcille is both described and demonstrated in vivo, illustrated with diagrams and photographs. The importance of this region to the surgical management of complex colorectal and gynaecological surgery is discussed. CONCLUSION: The Triangle of Marcille is a vital anatomical region for advanced pelvic surgery, particularly in the current era of pelvic exenteration, and especially for those that include the lateral pelvic compartment. PMID- 27990754 TI - Tetra-primer ARMS PCR for rapid detection and characterisation of Plasmopara viticola phenotypes resistant to carboxylic acid amide fungicides. AB - BACKGROUND: The occurrence of Plasmopara viticola populations resistant to carboxylic acid amide (CAA) fungicides is becoming a serious problem in the control of grapevine downy mildew worldwide. The resistance is caused by point mutations in the PvCesA3 gene. These isolates with this mutation have been detected mainly by determining the minimum inhibitory concentration of fungicides, which is always time consuming and inefficient. RESULTS: To establish a suitable method for rapid detection of the G1105S mutation in P. viticola, an efficient and simple molecular method was developed, based on tetra-primer ARMS PCR. A set of four primers were designed and optimised to distinguish the different genotypes within one step. Only 2 h was required from the sampling of symptoms to the phenotyping of fungicide resistance. Using this method, CAA resistant P. viticola were identified for the first time in China. Also, the finding of sensitive heterozygotes indicated that the resistant allele is spreading in the population in Ziyuan. CONCLUSION: This new method proved to be useful as an early warning system for resistance outbreaks of P. viticola to CAA fungicides in the field and may be helpful in decisions concerning rotation of different fungicide groups. (c) 2016 Society of Chemical Industry. PMID- 27990755 TI - Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant. AB - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory disease caused by TNFRSF1A mutations. Patients with TRAPS suffer from recurrent, long episodes with fever, arthralgia/arthritis, migratory myalgias, abdominal pain, serositis, conjunctivitis and migratory erythematous skin rash. More than 70 different TNFRSF1A mutations have been reported to date, and as consequence of its genetic heterogeneity, TRAPS shows a variable phenotypic expression. Among TNFRSF1A variants, the low-penetrance p.Arg92Gln variant represents the most commonly detected, and is typically associated with mild and short episodes, with a higher tendency to spontaneous resolution, and less familial association than the structural TNFRSF1A mutations. Pericardial involvement is rare but a well-known clinical feature of TRAPS, with a significant increased rate in those adult patients in whom the onset of the disease occurred during adulthood. Moreover, idiopathic recurrent acute pericarditis has also been occasionally described as a clinical presentation of TRAPS. However, cardiac tamponade is an unusual initial manifestation of the disease. Herein, we present a brief review based on the description of the exceptional case of a 35-year-old female patient who presented with recurrent pericardial effusions and cardiac tamponade. TNFRSF1A analyses showed a heterozygous genotype for the low-penetrance p.Arg92Gln variant. Due to disease severity, the patient was treated with the anti-interleukin-1 drug anakinra, showing a prompt resolution of her clinical manifestations. PMID- 27990757 TI - Gastroscopy: Advancing further into the horizontal part of the duodenum. PMID- 27990756 TI - Dental Implant Survival and Complication Rate over 2 Years for Individuals with Poorly Controlled Type 2 Diabetes Mellitus. AB - BACKGROUND: Emerging evidence suggests that implant therapy may be a viable option for diabetic individuals with elevated glycemic levels. PURPOSE: The purpose of this 2 year observational study was to evaluate survival and clinical complications of dental implants following placement in type 2 diabetes individuals having poor glycemic control. MATERIALS AND METHODS: Adult participants (n = 24) with poorly controlled type 2 diabetes (8.0% <= HbA1c <= 12.0%) received two or more transgingival dental implants. Survival was evaluated after 1 (23 participants, 72 implants) and 2 (20 participants, 59 implants) years. Clinical complications were evaluated in 18 participants (52 implants) after 21-34 months. Relationships between complications and stratified HbA1c levels were assessed using Pearson's correlation test. RESULTS: Survival rates were 98.6% (71/72 implants) after 1 year and 96.6% (57/59 implants) after 2 years. Complications were identified in 29% of participants with peri-implant mucositis, the most common event. Complications correlated directly with number of implants across HbA1c strata (0.42, R2 = 0.66). There was no correlation between HbA1c and the occurrences of complications or mucositis. CONCLUSIONS: This 2-year evaluation supports the broader application of implant therapy in type 2 diabetes individuals with poor glycemic control in demonstrating high survival rates with limited complications. PMID- 27990758 TI - Factor analysis of recurrent biliary events in long-term follow up of gallstone pancreatitis. AB - OBJECTIVE: Recurrent attacks after acute gallstone pancreatitis (GSP) are substantial problems, together with associated morbidity and mortality. The recommended therapies for recurrent attacks are cholecystectomy and endoscopic sphincterotomy (EST). This study aimed to evaluate the long-term results of cholecystectomy and EST after clinical improvement of GSP. METHODS: A consecutive series of patients who were admitted with GSP from January 2003 to December 2014 were analyzed. Patients were categorized into three treatment subgroups: cholecystectomy (n = 53), EST (n = 51) and conservative care (n = 67). RESULTS: A total of 171 patients were enrolled. The mean follow-up period was 58 months (range 6-125 months). The pancreatitis-induced in-hospital mortality rate was 1.5%. The cholecystectomy and EST groups had a significantly lower frequency of recurrent pancreatitis than the conservative care group (P < 0.01). For recurrent pancreatitis, there was no significant difference between the cholecystectomy with and without EST subgroups. With respect to total recurrent biliary events, the cholecystectomy group was superior to the EST only group (P < 0.01). In patients receiving definitive treatment (cholecystectomy with or without EST), the presence of common bile duct (CBD) stone was an independent risk factor for recurrent biliary events (P < 0.01). CONCLUSIONS: In the long-term follow up of GSP, cholecystectomy can offer better protection against recurrent biliary events than EST only. The presence of CBD stones at time of definitive therapy might be a risk factor for recurrent biliary events. PMID- 27990759 TI - The toxicity of flonicamid to cotton leafhopper, Amrasca biguttula (Ishida), is by disruption of ingestion: an electropenetrography study. AB - BACKGROUND: The cotton leafhopper, Amrasca biguttula, is one of the most destructive pests of cotton in Asia. This species is thought to cause damage by injecting enzymatic saliva into various, presently unknown, cotton tissues and ingesting the resulting macerate. Flonicamid is a novel systemic insecticide used to control the cotton leafhopper; however, its mode of action is unknown. RESULTS: The mechanism of action of flonicamid on cotton leafhopper was investigated using electropenetrography (EPG). EPG recordings revealed six waveforms, i.e. Np (non-probing), A1 (channel cutting), A2, A3, A4, A5 and A6. Waveforms A2 and A3 probably represent active ingestion with (A2) and without (A3) simultaneous watery salivation. The meanings of A4, A5 and A6 are presently unknown, but minor in duration. Flonicamid significantly increased the mean duration of non-probing events and strongly inhibited ingestion by treated insects, which resulted in the slow death of leafhoppers. Inhibition of ingestion was dose dependent, and near-complete suppression was observed when the flonicamid concentration was increased to 10 000 mg L-1 . CONCLUSIONS: We propose that starvation caused by inhibition of active ingestion is the mechanism of toxicity for flonicamid. This knowledge could aid in applicability and use of this new insecticide for field management of leafhopper populations. (c) 2016 Society of Chemical Industry. PMID- 27990760 TI - COR27 and COR28 encode nighttime repressors integrating Arabidopsis circadian clock and cold response. AB - It was noted that circadian components function in plant adaptation to diurnal temperature cycles and freezing tolerance. Our genome-wide transcriptome analysis revealed that evening-phased COR27 and COR28 mainly repress the transcription of clock-associated evening genes PRR5, ELF4 and cold-responsive genes. Chromatin immunoprecipitation indicated that CCA1 is recruited to the site containing EE elements of COR27 and COR28 promoters in a temperature-dependent way. Further genetic analysis shows COR28 is essential for the circadian function of PRR9 and PRR7. Together, our results support a role of COR27 and COR28 as nighttime repressors integrating circadian clock and plant cold stress responses. PMID- 27990761 TI - Hollow fiber stir bar sorptive extraction for determination of phthalic acid esters in environmental and biological matrices. AB - The purpose of this paper is to introduce a novel hollow fiber stir bar sorptive extraction for collecting and determining of phthalic acid esters in environmental and biological matrices. Shell-core ZrO2 /SiO2 composite microspheres and porous C18 silica microspheres were compared as the sorbents, which were loaded in the lumen of a microporous hollow fiber membrane. A thin stainless-steel wire was also inside of the hollow fiber membrane acting as the magnetic stirrer, thus affording the procedures like stir bar sorptive extraction to perform the active trapping of the analytes. Variables affecting the extraction (salt addition and pH of samples, extraction temperature, and time) and desorption (microwave time and eluted solvents) have been optimized. Under the optimal conditions, good linearity (r > 0.9968) of all calibration curves was obtained in validation experiments. And the limits of quantification ranged from 0.01 to 1000 ng/mL. The recoveries in different matrices were in the range of 64.90-112.60% with relative standard deviations less than 8.60%. The present work demonstrated the applicability of the developed method for the determination of phthalic acid esters in environmental and biological sample, allowing the selective extraction of phthalate esters in complex samples with low consumption of organic solvents and no sample clean-up. PMID- 27990762 TI - Arthroscopic guided synovial biopsy in rheumatology: current perspectives. AB - Synovial membrane (SM) pathology has provided valuable insights into our current understanding of immunopathological processes and treatment responses in the inflammatory arthritides. Amongst various methods of synovial biopsy, arthroscopic techniques remain the 'gold standard' owing to better sampling from sites of interest, particularly in patients with partially treated disease and from areas within joints that may be difficult to access using other techniques. Newer sophisticated techniques of SM membrane analyses allow assessment of differentially regulated pathways, the knowledge of which may help elucidate diagnostic and therapeutic targets in an attempt towards developing strategies for personalised medicine in the current era of targeted biologic therapies. PMID- 27990763 TI - Circulating fibroblast activation protein and dipeptidyl peptidase 4 in rheumatoid arthritis and systemic sclerosis. AB - AIM: To quantify circulating fibroblast activation protein (cFAP) and dipeptidyl peptidase 4 (cDPP4) protease activities in patients with rheumatoid arthritis (RA), systemic sclerosis (SSc), and a control group with mechanical back pain and to correlate plasma levels with disease characteristics. METHODS: Plasma was collected from patients with RA (n = 73), SSc (n = 37) and control subjects (n = 26). DPP4 and FAP were quantified using specific enzyme activity assays. RESULTS: Median cDPP4 was significantly lower in the RA group (P = 0.02), and SSc group (P = 0.002) compared with controls. There were no significant differences in median cFAP between the three groups. DPP4 and FAP demonstrated a negative correlation with inflammatory markers and duration of disease. There were no associations with disease subtypes in RA, including seropositive and erosive disease. Decreased cDPP4 was found in SSc patients with myositis. Plasma FAP was lower in RA patients receiving prednisone (P = 0.001) or leflunomide (P = 0.04), but higher with biologic agents (P = 0.01). RA patients receiving leflunomide also had decreased cDPP4 (P = 0.014). SSc patients receiving prednisone (P = 0.02) had lower cDPP4 but there was no association with cFAP. CONCLUSIONS: No association was found between cFAP and RA or SSc. Plasma DPP4 was decreased in RA and SSc when compared with controls. cDPP4 and cFAP correlated negatively with inflammatory markers and there were no significant correlations with disease characteristics in this RA cohort. PMID- 27990764 TI - Predicting Institutional Aggression in Offenders with Intellectual Disabilities Using the Violence Risk Appraisal Guide. AB - BACKGROUND: One of the most extensively tested risk assessment instruments in offenders with an intellectual disability (OIDs) is the Violence Risk Appraisal Guide (VRAG). The purpose of this prospective study was to test the ability of this instrument to predict institutional aggression in OIDs. METHOD: VRAG scores were collected for 52 OIDs, and staff registered aggressive incidents during a period of 6 months. Predictive accuracy was analysed using several performance indicators. RESULTS: The VRAG was not able to significantly predict aggressive behaviour, although a trend towards significance was found for interpersonal physical aggression. Furthermore, the VRAG was only accurate in prospectively identifying low-risk individuals. CONCLUSION: Compared to other studies, demonstrating good predictive validity for institutional aggression in OIDs, the VRAG performed poorly in this study. The usefulness of this instrument in identifying high-risk offenders is questioned. Until further evidence is available from studies using multiple performance indicators, clinicians have to be very careful in relying on the results of a risk assessment tool. PMID- 27990765 TI - An Independent Investigation of the Utility of the Learning Disability Screening Questionnaire (LDSQ) within a Community Learning Disability Team. AB - BACKGROUND: The Learning Disability Screening Questionnaire (LDSQ) has been shown to have high sensitivity and specificity to identify those who are likely to meet intellectual disability diagnostic criteria (McKenzie, et al. ). However, there is no independent research to date to support these findings. MATERIALS AND METHODS: An archival research design was used, utilizing data from diagnostic tools including the LDSQ, Wechsler Adult Intelligence assessments and Adaptive Behavior Assessment System Second Edition (ABAS-II) scores. RESULTS: Sensitivity and specificity values derived here were lower than those reported by (McKenzie, et al. ). Only IQ, not adaptive/social functioning, was found to be an accurate predictor of the LDSQ score. CONCLUSIONS: Results indicate limited validity in using (McKenzie, et al. ) proposed cut-off scores. The authors have expressed caution around using the LDSQ in isolation to identify those with an intellectual disability. PMID- 27990766 TI - Characteristics and sequelae of erupted supernumerary teeth: A study of 218 cases among Sri Lankan children. AB - AIM: In the present study, we investigated the characteristics and sequelae of erupted supernumerary teeth (ST) in a sample of Sri Lankan children. METHODS: Data were recorded from patients' clinical records, radiographs, models, and extracted teeth. RESULTS: The sample consisted of 239 ST from 218 patients. The mean age of the sample was 9.08 +/- 2.47 years. The male-to-female ratio was 2.8:1. The majority (42.66%) of patients with ST were in aged 8-10 years. Many (94.94%) of the ST were located in the premaxilla (incisor), followed by the canine (4.22%), premolar (0.42%), and molar (0.42%) regions. The most common shape of ST teeth was conical. Malocclusion (59.83%) was the major problem associated with ST, and the clinical impact was highest on the 8-10-year age group. A strong association was observed between patients' age and clinical impact to the dentition (chi2 =42.09, P=.000). CONCLUSION: Because the majority of ST can lead to malocclusion, especially in mixed dentition, awareness, early detection, and timely clinical intervention of ST are recommended. PMID- 27990767 TI - Contribution of serum adipocyte fatty acid-binding protein levels to the presence of microalbuminuria in a Chinese hyperglycemic population. AB - AIMS/INTRODUCTION: Individuals with type 2 diabetes mellitus are vulnerable to micro- and macrovascular complications in the presence of microalbuminuria. Adipocyte fatty acid-binding protein (A-FABP) was proposed as an indicator for albuminuria in patients with diabetes. The present study aimed to explore the associations between serum A-FABP levels and microalbuminuria in the hyperglycemic population. MATERIALS AND METHODS: Serum A-FABP levels were detected using sandwich enzyme-linked immunosorbent assay. Microalbuminuria was identified by urinary albumin-to-creatinine ratio (UACR), when the value was between 30-300 mg/g. The participants were divided into the subgroups based on sex and the status of impaired glucose regulation or newly diagnosed type 2 diabetes mellitus. RESULTS: A total of 939 participants, consisting of 436 men and 503 women, were enrolled. Serum levels of A-FABP were much higher in participants with microalbuminuria than those without microalbuminuria. This result held true for all subgroups (all P < 0.05). For Spearman's correlation analyses, serum A-FABP levels showed a positive relationship with the UACR in men and women (both P < 0.01). Multiple stepwise regression analysis showed that serum A-FABP levels were independently and positively correlated with UACR in both sexes (men: standardized beta = 0.256, P < 0.001; women: standardized beta = 0.155, P = 0.001). This relationship remained significant in every subgroup (all P < 0.01). CONCLUSIONS: For hyperglycemic individuals, serum A-FABP levels increased in the presence of microalbuminuria. Serum A-FABP levels were identified as an independent factor positively associated with the UACR. PMID- 27990768 TI - A Bone Glue with Sustained Adhesion under Wet Conditions. AB - Bone glues often suffer from low adhesion to bone under wet conditions. This study aims to improve wet adhesiveness of a bone glue based on a photocurable poly(ethylene glycol) dimethacrylate matrix through in situ interpenetrating network formation by addition of six-armed isocyanate functional star-shaped prepolymers (NCO-sP(EO-stat-PO)). Biodegradable ceramic fillers are added to adjust the paste workability. The 3-point bending strength of the bone glues is in the range of 3.5-5.5 MPa and not significantly affected by the addition of NCO sP(EO-stat-PO). Storage in phosphate buffered saline (PBS) decreases the bending strength of all formulations to approximately 1 MPa but the adhesion to cortical bone increases from 0.15-0.2 to 0.3-0.5 MPa after adding 20-40 wt% NCO-sP(EO-stat PO) to the matrix. Bone glues without the NCO-sP(EO-stat-PO) additive lose their adhesiveness to bone after aging in PBS for 7 days, whereas modified glues maintain a shear strength of 0.18-0.25 MPa demonstrating the efficacy of the approach. Scanning electron microscopy and energy-dispersive X-ray spectroscopy investigations of the fracture surfaces prove a high amount of residual adhesive on the bone surface indicating that adhesion to the bone under wet conditions is stronger than cohesion. PMID- 27990769 TI - A specific brushing sequence and plaque removal efficacy: a randomized split mouth design. AB - AIM: It has been propagated by the dental care professionals to start toothbrushing the lingual aspect of teeth first. In general, it is assumed that these surfaces of teeth are more difficult to clean. The evidence to support this recommendation is sparse. METHOD: In this randomized controlled clinical trial using a split-mouth design, 46 students were included. Before the visit, the participants were requested to refrain from any oral hygiene procedure for 48 h. First, the plaque index (PI) score was assessed full mouth. Two randomly chosen contra-lateral quadrants were used to start brushing from the lingual aspect first. The opposing two quadrants were used to start brushing from the buccal aspect. After the brushing exercise was completed, full-mouth PI was scored again. Subanalyses were performed for the buccal, lingual and approximal surfaces. RESULTS: At baseline, there was no statistically significant difference between the two sets of contra-lateral quadrants (P = 0.770). Starting at the lingual aspect of the lower jaw resulted in a 55% reduction of plaque scores in comparison with 58% when the brushing exercise was started buccally. [Correction added on 16 January 2017, after first online publication: In the preceding sentence, the percentage reduction of plaque scores when the brushing exercise was started buccally, was previously wrong and has been corrected to 58% throughout this article.] The difference in mean plaque scores between brushing orders was 0.04, which was not significant (P = 0.219). None of the subanalyses revealed any significant differences for the isolated surfaces. CONCLUSION: Using a manual toothbrush reduced the plaque scores between 55 and 58% with no difference between brushing from either the lingual or buccal aspect first. Within the limitations of this study, a recommendation to start toothbrushing the lingual aspect is not supported by the outcome in this young student population. PMID- 27990771 TI - Rapid Visual Screening and Programmable Subtype Classification of Ebola Virus Biomarkers. AB - The massive outbreaks of the highly transmissible and lethal Ebola virus disease were caused by infection with one of the Ebolavirus species. It is vital to develop cost-effective, highly sensitive and selective multitarget biosensing platforms that allow for both the detection and phenotyping. Here, a highly programmable, cost-efficient and multianalyte sensing approach is reported that enables visual detection and differentiation of conserved oligonucleotide regions of all Ebolavirus subtypes known to infect human primates. This approach enables the detection of as little as 400 amols (24 * 106 molecules) of target sequences with the naked eye. Furthermore, the detection assay can be used to classify four virus biomarkers using a single nanoprobe template. This can be achieved by using different combinations of short single stranded initiator molecules, referred to as programming units, which also enable the simultaneous and rapid identification of the four biomarkers in 16 different combinations. The results of 16 * 5 array studies illustrate that the system is extremely selective with no false-positive or false-negative. Finally, the target strands in liquid biopsy mimics prepared from urine specimens are also able to be identified and classified. PMID- 27990770 TI - Bioactive secondary metabolites with multiple activities from a fungal endophyte. AB - In order to replace particularly biohazardous nematocides, there is a strong drive to finding natural product-based alternatives with the aim of containing nematode pests in agriculture. The metabolites produced by the fungal endophyte Fusarium oxysporum 162 when cultivated on rice media were isolated and their structures elucidated. Eleven compounds were obtained, of which six were isolated from a Fusarium spp. for the first time. The three most potent nematode antagonistic compounds, 4-hydroxybenzoic acid, indole-3-acetic acid (IAA) and gibepyrone D had LC50 values of 104, 117 and 134 MUg ml-1 , respectively, after 72 h. IAA is a well-known phytohormone that plays a role in triggering plant resistance, thus suggesting a dual activity, either directly, by killing or compromising nematodes, or indirectly, by inducing defence mechanisms against pathogens (nematodes) in plants. Such compounds may serve as important leads in the development of novel, environmental friendly, nematocides. PMID- 27990772 TI - Poor methodological quality and reporting standards of systematic reviews in burn care management. AB - The methodological and reporting quality of burn-specific systematic reviews has not been established. The aim of this study was to evaluate the methodological quality of systematic reviews in burn care management. Computerised searches were performed in Ovid MEDLINE, Ovid EMBASE and The Cochrane Library through to February 2016 for systematic reviews relevant to burn care using medical subject and free-text terms such as 'burn', 'systematic review' or 'meta-analysis'. Additional studies were identified by hand-searching five discipline-specific journals. Two authors independently screened papers, extracted and evaluated methodological quality using the 11-item A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool and reporting quality using the 27-item Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Characteristics of systematic reviews associated with methodological and reporting quality were identified. Descriptive statistics and linear regression identified features associated with improved methodological quality. A total of 60 systematic reviews met the inclusion criteria. Six of the 11 AMSTAR items reporting on 'a priori' design, duplicate study selection, grey literature, included/excluded studies, publication bias and conflict of interest were reported in less than 50% of the systematic reviews. Of the 27 items listed for PRISMA, 13 items reporting on introduction, methods, results and the discussion were addressed in less than 50% of systematic reviews. Multivariable analyses showed that systematic reviews associated with higher methodological or reporting quality incorporated a meta-analysis (AMSTAR regression coefficient 2.1; 95% CI: 1.1, 3.1; PRISMA regression coefficient 6.3; 95% CI: 3.8, 8.7) were published in the Cochrane library (AMSTAR regression coefficient 2.9; 95% CI: 1.6, 4.2; PRISMA regression coefficient 6.1; 95% CI: 3.1, 9.2) and included a randomised control trial (AMSTAR regression coefficient 1.4; 95%CI: 0.4, 2.4; PRISMA regression coefficient 3.4; 95% CI: 0.9, 5.8). The methodological and reporting quality of systematic reviews in burn care requires further improvement with stricter adherence by authors to the PRISMA checklist and AMSTAR tool. PMID- 27990773 TI - Long noncoding RNAs in the p53 network. AB - The tumor-suppressor protein p53 is activated in response to numerous cellular stresses including DNA damage. p53 functions primarily as a sequence-specific transcription factor that controls the expression of hundreds of protein-coding genes and noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). While the role of protein-coding genes and miRNAs in mediating the effects of p53 has been extensively studied, the physiological function and molecular mechanisms by which p53-regulated lncRNAs act is beginning to be understood. In this review, we discuss recent studies on lncRNAs that are directly or indirectly regulated by p53 and how they contribute to the biological outcomes of p53 activation. WIREs RNA 2017, 8:e1410. doi: 10.1002/wrna.1410 For further resources related to this article, please visit the WIREs website. PMID- 27990774 TI - Appendiceal adenocarcinoma masquerading as a primary rectal tumour. PMID- 27990775 TI - The CD44-Mediated Uptake of Hyaluronic Acid-Based Carriers in Macrophages. AB - CD44 is a potentially rewarding target in cancer therapy, although its mechanisms of ligand binding and internalization are still poorly understood. In this study, we have established quantitative relationships between CD44 expression in differently polarized macrophages (M0, M1, and M2-polarized THP-1 human macrophages) and the uptake of hyaluronic acid (HA)-based materials, which are potentially usable for CD44 targeting. We have validated a robust method for macrophage polarization, which sequentially uses differentiating and polarizing factors, and allows to show that CD44 expression depends on polarization (M1 > M0 >= M2). It is noteworthy that THP-1 M2 expressed CD44v6, suggesting their suitability as a model of tumor-associated macrophages. In the uptake of HA, both as a soluble polymer and in the form of (siRNA-loaded) nanoparticles, CD44 expression correlated positively with binding, but negatively with internalization. Counterintuitively, it appears that a higher presence of CD44 (in M1) allows a more efficient capture of HA materials, but a lower expression (in M2) is conducive to better internalization. Although possibly cell-specific, this unexpected relationship indicates that the common paradigm "higher CD44 expression = better targetability" is too simplistic; mechanistic details of both receptor presentation and association still need to be elucidated for a predictable targeting behavior. PMID- 27990776 TI - Sodium-glucose co-transporter-2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: A randomized, open-label, 3-arm parallel comparative, exploratory study. AB - This study investigated the safety and efficacy of the sodium-glucose co transporter-2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate-adjusted meals for 14 days (days 1-14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8-14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5-8 and days 12-15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC-HGI group compared with the HC-HGI and HC-LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor-associated diabetic ketoacidosis. PMID- 27990778 TI - A simple method for measuring excess adsorption isotherms of organic eluent components on reversed-phase packing materials. AB - A simple frontal analysis method has been developed for the reliable measurement of excess adsorption isotherms of an organic component on reversed-phase adsorbents in a series of programmed concentration steps. In the present method, a peak, which is produced by refractive index change in column eluate, is detected at 589 nm; it represents the elution volume of the boundary. The method is applied to the measurement of the excess adsorption isotherms of organic eluent components from water on commercially available reversed-phase stationary phases. The results are in good agreement with the previously reported isotherms. We also measure the excess adsorption isotherms of organic eluent components from solutions containing electrolytes. There are not any interference peaks on the elution traces. The method is thus reliably applicable to the evaluation of the excess adsorption of organic eluent components in practical systems. PMID- 27990777 TI - Polyarteritis nodosa in north India: clinical manifestations and outcomes. AB - OBJECTIVE: There has been a significant decrease in the number of published reports of classical polyarteritis nodosa (PAN) in the post-Chapel Hill consensus conference (CHCC) nomenclature era with only two series published from Asia. We report a case series of PAN from north India. PATIENTS AND METHODS: A retrospective study of all patients diagnosed to have PAN according to American College of Rheumatology criteria/CHCC nomenclature. The details of clinical presentation, investigation findings, treatment details and outcomes were noted from the records. These findings between the hepatitis B positive and negative groups were compared. RESULTS: Twenty-seven patients (20 male, seven female) were diagnosed as having PAN, out of which seven (25.9%) were hepatitis B surface antigen positive. Nervous system involvement was most common with 24 patients (88.9%) having mononeuritis multiplex. Weight loss was present in 20 (74%), fever in 14 (51.9%), renal involvement in 16 (59.3%), cutaneous in nine (33.3%), peripheral gangrene in eight (29.6%), gastrointestinal (GI) involvement in eight (29.6%), testicular pain in 6/20 (30%) and cardiac involvement in four (14.8%). Twenty-three (85.2%) patients recovered, three died (11.1%) and one was lost to follow-up. Median follow-up duration was 37 (interquartile range 22.00-69.75) months. The cumulative survival was 114.16 months (95% CI: 98.27-129.95). There was no significant difference in five factor score (FFS) or revised FFS between those patients who died and those who survived (P = 0.248, 0.894, respectively). Hepatitis B-related PAN had a lower FFS compared to non-hepatitis B-related PAN (P = 0.039). No other significant differences were noted between the two groups. CONCLUSION: In comparison to classic PAN in other populations, classic PAN in north India is associated with higher neurological involvement and lower GI involvement. PMID- 27990780 TI - Sleep research in the near future: a passing outlook. PMID- 27990779 TI - Current issues involved with the identification and nutritional value of wood grubs consumed by Australian Aborigines. AB - The so called witchetty grub is a publicized food source for Australian Aborigines. Despite heavy use, the identities and number of species consumed is still not known because of the lack of identified voucher specimens. Taxonomy based on adults makes identification of larval forms difficult. Dwelling in the root, trunks, and stems of woody plants, grubs are a reliable and highly valued food source that may be in decline. Much information on edible insects may already be lost in parts of Australia heavily settled by Europeans. However, there are many parts of Australia where information on edible insects is still strong and needs to be recorded accurately for long-term use. Recent identification of "witchetty grubs" from the witchetty bush at Barrow Creek has revealed that those there, based on their DNA, are not Endoxyla leucomochla. As grubs are collected and eaten before they mature and scientific taxonomy is based on adults, there are many unanswered questions on the grub identification and biology, host plants, and plant and grub distributions. PMID- 27990781 TI - Sex differences, endogenous sex-hormone hormones, sex-hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes. AB - In assessing clinical and pathophysiological development of type 2 diabetes (T2D), the critical role of the sex steroids axis is underappreciated, particularly concerning the sex-specific relationships with many relevant cardiometabolic outcomes. In this issue of the Journal of Diabetes, we provide a comprehensive overview of these significant associations of germline variants in the genes governing the sex steroid pathways, plasma levels of steroid hormones, and sex hormone-binding globulin (SHBG) with T2D risk that have been observed in many clinical and high-quality large prospective cohorts of men and women across ethnic populations. Together, this body of evidence indicates that sex steroids and SHBG should be routinely incorporated into clinical characterization of T2D patients, particularly in screening prediabetic patients, such as those with metabolic syndrome, using plasma levels of SHBG. Given that several germline mutations in the SHBG gene have also been directly related to both plasma concentrations of SHBG and clinical manifestation of T2D, targeting signals in the sex steroid axis, particularly SHBG, may have significant utility in the prediction and treatment of T2D. Further, many of the environmental endocrine disrupting chemicals may exert their potential adverse effects on cardiometabolic outcomes via either estrogenic or androgenic signaling pathways, highlighting the importance of using the sex steroids and SHBG as important biochemical markers in both clinical and population studies in studying sex-specific mechanisms in the pathogenesis of T2D and its complications, as well as the need to equitably allocate resources in studying both men and women. PMID- 27990782 TI - Developing a patient-led electronic feedback system for quality and safety within Renal PatientView. AB - BACKGROUND: It is increasingly acknowledged that patients can provide direct feedback about the quality and safety of their care through patient reporting systems. The aim of this study was to explore the feasibility of patients, healthcare professionals and researchers working in partnership to develop a patient-led quality and safety feedback system within an existing electronic health record (EHR), known as Renal PatientView (RPV). METHODS: Phase 1 (inception) involved focus groups (n = 9) and phase 2 (requirements) involved cognitive walkthroughs (n = 34) and 1:1 qualitative interviews (n = 34) with patients and healthcare professionals. A Joint Services Expert Panel (JSP) was convened to review the findings from phase 1 and agree the core principles and components of the system prototype. Phase 1 data were analysed using a thematic approach. Data from phase 1 were used to inform the design of the initial system prototype. Phase 2 data were analysed using the components of heuristic evaluation, resulting in a list of core principles and components for the final system prototype. RESULTS: Phase 1 identified four main barriers and facilitators to patients feeding back on quality and safety concerns. In phase 2, the JSP agreed that the system should be based on seven core principles and components. DISCUSSION: Stakeholders were able to work together to identify core principles and components for an electronic patient quality and safety feedback system in renal services. Tensions arose due to competing priorities, particularly around anonymity and feedback. Careful consideration should be given to the feasibility of integrating a novel element with differing priorities into an established system with existing functions and objectives. PMID- 27990783 TI - Radiation Exposure During Videourodynamics: Establishing Risk Factors. AB - OBJECTIVES: The use of fluoroscopy during urodynamics can be helpful in the evaluation of patients with lower urinary tract dysfunction. However, fluoroscopy introduces the potential hazards of ionizing radiation, including malignancy. In this study we analyzed the data for radiation exposure during videourodynamic study (VUDS) at our center; we have also tried to establish the factors associated with increased exposure to radiation during VUDS. METHODS: We reviewed all VUDS from August 2010 to May 2011. Patients were included if they were >=18 years old and had data recorded on total radiation exposure (radcm2 ). Age, sex, body mass index, fluoroscopy time, diagnosis, and urodynamic findings were recorded. Multivariate linear regression analysis was used to identify independent risk factors that influenced increased radiation exposure. RESULTS: A total of 203 videourodynamic studies were assessed in 106 female and 97 male patients with a mean age of 64.3 and body mass index of 26.8. The average fluoroscopy time was 100.2 sec and exposure was 560.9 radcm2 . The most common indication for videourodynamics was incontinence, 40.9%. On multivariate linear regression analysis body mass index, vesico-ureteral reflux, sex, number of fill cycles, and larger capacity were independent predictors of increased radiation exposure. CONCLUSIONS: We have shown that increased radiation exposure as measure with Dose Area Product during VUDS was significantly associated with larger BMI, female gender, larger bladder capacity, presence of VUR, junior operator, and higher number of fill cycles. Further studies are now underway to attempt to reduce exposure based on these findings. PMID- 27990785 TI - Inhibitor development in haemophilia. PMID- 27990784 TI - New findings on inhibitor development: from registries to clinical studies. AB - The high incidence of inhibitors against factor VIII (FVIII) concentrates in patients with haemophilia A has encouraged debate as to whether product-type plays a role. There is debate in the literature as to whether rFVIII concentrates are associated with a higher incidence of inhibitors compared to pdFVIII products. The management of haemophilia in patients with inhibitors includes on demand/prophylaxis treatment with bypassing agents, and/or immune tolerance induction (ITI). However, these options create an economic and emotional burden on patients, their families and healthcare practitioners. Although ITI eliminates inhibitors successfully in 60-80% of cases, it is costly. Despite high costs, preliminary data from a decision analytical model have indicated that ITI is economically advantageous compared with on-demand/prophylactic treatment with bypassing agents. In patients with persistent inhibitors and those who are not candidates for ITI or have failed ITI, bleeding-related mortality and morbidity increase and quality of life decreases, compared with non-inhibitor patients. This article provides an update on the risk of inhibitor development and discusses best management approaches for patients with high-risk factors for inhibitor development. PMID- 27990786 TI - Rectal adenocarcinoma perforation following palliative colorectal stenting. PMID- 27990787 TI - Metabolic Surgery for Type 2 Diabetes Mellitus: Experience from Asia. AB - Type 2 diabetes mellitus (T2DM) is a current global health priority and Asia is the epicenter of this epidemic disease. Unlike in the west, where older population is most affected, the burden of diabetes in Asian countries is disproportionately high in young to middle-age adults. The incidence of diabetic nephropathy is alarmingly high in patients with early onset T2DM, especially in those with poor glycemic control. How to control this chronic and debilitating disease is currently a very important health issue in Asia. Bariatric surgery has proven successful in treating not just obesity but also T2DM in morbid obese patients (body mass index [BMI] >35 kg/m2). Gastrointestinal metabolic surgery recently has been proposed as a new treatment modality for obesity related T2DM for patients with BMI <35 kg/m2. Many studies from Asia reported promising results of metabolic surgery to treat obese patients with T2DM which is not well controlled. It has been demonstrated that changes in gastrointestinal hormone secretion after gastrointestinal surgery would favor an early improvement of T2DM in Asians. New procedures have also been designed and proposed specifically for the treatment of diabetes in Asia. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of metabolic surgery for the treatment of T2DM in the Asia. We propose a systematic approach to surgical treatment, addressing current evidences, patient selection, procedure of choice, and timing and guideline for new procedures. PMID- 27990788 TI - Determinants of the Risk of Diabetic Kidney Disease and Diabetic Retinopathy Independent of Glucose Exposure. PMID- 27990789 TI - Letter: Investigating Susceptibility to Diabetes Using Features of the Adipose Tissue in Response to In Utero Polycyclic Aromatic Hydrocarbons Exposure (Diabetes Metab J 2016;40:494-508). PMID- 27990790 TI - Response: Investigating Susceptibility to Diabetes Using Features of the Adipose Tissue in Response to In Utero Polycyclic Aromatic Hydrocarbons Exposure (Diabetes Metab J 2016;40:494-508). PMID- 27990792 TI - Diabetes mellitus and non-alcoholic fatty liver disease: the thread of Ariadne. AB - Non alcoholic fatty liver disease (NAFLD, the hepatic fat accumulation) and non alcoholic steatohepatitis (NASH, the aggressive form of liver steatosis plus inflammation and hepatocyte necrosis) are reaching epidemic dimensions in subjects with diabetes mellitus (DM). Taking into account that the incidence of DM increases worldwide, these entities represent major health problems. There is accumulating evidence that diabetic subjects with NASH are at increased risk not only for cardiovascular disease compications but also for cirrhosis and hepatocellular cancer. On the other hand, the presence of NAFLD correlates with an increased risk for the development of DM. The most-widely accepted pathophysiological mechanisms relating DM and NAFLD include central obesity and insulin resistanc, but new insights are under scrutiny. Therapeutic modalities used for the management of diabetes have been studied for their impact on NAFLD/NASH and both neutral and beneficial effects have been reported. In this review, we discuss issues regarding the epidemiology, the pathophysiological pathways relating NAFLD with DM and consider strategies that may be useful in the management of NAFLD in the diabetic population. PMID- 27990791 TI - The role of carbon adsorbent in the conservative management of chronic kidney disease. AB - Indoxyl sulfate is a uremic toxin, and cannot be removed efficiently by hemodialysis due to its protein-binding. Indoxyl sulfate induces cellular dysfunction by producing reactive oxygen species (ROS) such as superoxide by activating nicotinamide adenine dinucleotide phosphate oxidase, and by activating aryl hydrocarbon receptor through its uptake via organic anion transporters (OAT1 and OAT3). Indoxyl sulfate shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts, osteoclasts, and myocytes. Indoxyl sulfate stimulates the progression of chronic kidney disease (CKD), cardiovascular disease (CVD), osteodystrophy, and sarcopenia. The carbon adsorbent AST-120 might be useful to delay the progression of not only CKD but also CVD, osteodystrophy, and sarcopenia by adsorbing its precursor, indole, in the intestines, and consequently reducing the serum levels of indoxyl sulfate. In this review, the author provides an overview on the current status of knowledge on the effects of AST-120 on uremic toxins, CKD animals, CKD patients, and CKD patients with CVD, and safety of AST-120. A large clinical study (EPPIC-1 and EPPIC-2) has failed to demonstrate the efficacy of AST-120 on the progression of CKD. However, the post hoc subgroup analysis suggested that AST-120 might delay the progression of CKD patients. Further clinical studies are required to demonstrate the clinical efficacy of AST-120 on the progression of CKD by administering AST-120 only to those patients with progressive CKD and good compliance. PMID- 27990794 TI - The impact of semen processing on sperm parameters and pregnancy rates after intrauterine insemination. AB - BACKGROUND: The objective of this retrospective study was to evaluate the effect of semen processing on computer analyzed semen parameters and pregnancy rates after intrauterine insemination (IUI). METHODS: Over a two-year period, a total of 981 couples undergoing 2231 IUI cycles were evaluated and the freshly collected non-donor semen was analyzed before and after density gradient centrifugation (DGC). RESULTS: DGC led to significant increases in sperm concentration by 66+/-74 *106/mL (P=0.0001), percentage of motile sperm by 24+/ 22% (P=0.0001), concentration motile by 27+/-58 *106/mL (P=0.0001), and forward sperm progression by 18+/-14 u/s (P=0.0001). In 95% of cases, there was a decrease in the total motile sperm count (TMSC), with an average decrease of 50+/ 124% compared to pre-processed samples (P=0.0001). Importantly, the decrease in TMSC did not negatively affect pregnancy rates (P=0.45). CONCLUSIONS: This study proves that DGC leads to significant increases in most sperm parameters, with the exception of TMSC. Remarkably, the decrease in TMSC did not affect the pregnancy rate. This should reassure clinicians when the TMSC is negatively affected by processing. PMID- 27990793 TI - Therapeutic management of acute uncomplicated diverticulitis. AB - Acute diverticulitis is a painful disease of the colon characterized by peridiverticular inflammation and/or infection. The spectrum of acute diverticulitis ranges from isolated peridiverticular inflammation all the way to free perforation with purulent or feculent peritonitis. Among gastrointestinal disorders, acute diverticulitis is one of the most common diagnoses in the ambulatory setting and principal hospital discharge diagnoses. Acute diverticulitis accounts for substantial utilization of healthcare resources and is a detriment to patients' quality of life. In the last decade, several cohort studies and trials have significantly improved our understanding of acute diverticulitis. This paper will review the current literature on acute uncomplicated diverticulitis with a focus on therapeutic management. PMID- 27990795 TI - Thrombus aspiration in STEMI patients: an updated systematic review and meta analysis. AB - INTRODUCTION: Clinical efficacy and safety of adjunctive thrombus aspiration (TA) in patients with ST-segment elevation myocardial infarction (STEMI) during percutaneous coronary intervention (PCI) remain controversial. EVIDENCE ACQUISITION: Twenty-five eligible randomized controlled trials were included to compare the use of TA with PCI and PCI-only for STEMI. The primary endpoint was major adverse cardiac events (MACE) according to study definitions. The secondary endpoints were all-cause mortality, recurrent myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and stroke. EVIDENCE SYNTHESIS: In comparison with conventional PCI, TA followed by PCI was associated with a lower risk for MACE with statistical significance [relative risk (RR): 0.91; 95% confidence interval (CI): 0.83-0.99; P=0.04). Regarding secondary endpoints, there was a significant increase in the risk for stroke (RR: 1.56; 95% CI: 1.09-2.24; P=0.015); there were no differences in the risk of all-cause mortality (RR: 0.88; 95% CI: 0.78-1.01; P=0.06), myocardial infarction (RR: 0.94; 95% CI: 0.79-1.13; P=0.537), target vessel revascularization (RR: 0.92; 95% CI: 0.82-1.04; P=0.177), and definite or probable stent thrombosis (RR: 0.84; 95% CI: 0.66-1.07; P=0.151). CONCLUSIONS: Updated data about routine TA-assisted PCI in STEMI showed reduced risk of subsequent MACE in comparison with conventional primary PCI, but get limited benefits related to the clinical endpoints, and may be associated with an increase in the risk of stroke. As a routine strategy, TA in patients with STEMI cannot be supported. PMID- 27990796 TI - Highly Stretchable and Highly Conductive PEDOT:PSS/Ionic Liquid Composite Transparent Electrodes for Solution-Processed Stretchable Electronics. AB - Stretchable conductive materials have received great attention owing to their potential for realizing next-generation stretchable electronics. However, the simultaneous achievement of excellent mechanical stretchability and high electrical conductivity as well as cost-effective fabrication has been a significant challenge. Here, we report a highly stretchable and highly conducting polymer that was obtained by incorporating an ionic liquid. When 1-ethyl-3 methylimidazolium tetracyanoborate (EMIM TCB) was added to an aqueous conducting polymer solution of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), it was found that EMIM TCB acts not only as a secondary dopant but also as a plasticizer for PEDOT:PSS, resulting in a high conductivity of >1000 S cm-1 with stable performance at tensile strains up to 50% and even up to 180% in combination with the prestrained substrate technique. Consequently, by exploiting the additional benefits of high transparency and solution-processability of PEDOT:PSS, we were able to fabricate a highly stretchable, semitransparent, and wholly solution-processed alternating current electroluminescent device with unimpaired performance at 50% strain by using PEDOT:PSS/EMIM TCB composite films as both bottom and top electrodes. PMID- 27990797 TI - Flexible Overoxidized Polypyrrole Films with Orderly Structure as High Performance Anodes for Li- and Na-Ion Batteries. AB - Flexible polypyrrole (PPy) films with highly ordered structures were fabricated by a novel vapor phase polymerization (VPP) process and used as the anode material in lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs). The PPy films demonstrate excellent rate performance and cycling stability. At a charge/discharge rate of 1 C, the reversible capacities of the PPy film anode reach 284.9 and 177.4 mAh g-1 in LIBs and SIBs, respectively. Even at a charge/discharge rate of 20 C, the reversible capacity of the PPy film anode retains 54.0% and 52.9% of the capacity of 1 C in LIBs and SIBs, respectively. After 1000 electrochemical cycles at a rate of 10 C, there is no obvious capacity fading. The molecular structure and electrochemical behaviors of Li- and Na-ion doping and dedoping in the PPy films are investigated by XPS and ex situ XRD. It is believed that the PPy film electrodes in the overoxidized state can be reversibly charged and discharged through the doping and dedoping of lithium or sodium ions. Because of the self-adaptation of the doped ions, the ordered pyrrolic chain structure can realize a fast charge/discharge process. This result may substantially contribute to the progress of research into flexible polymer electrodes in various types of batteries. PMID- 27990798 TI - Poly(ethylene glycol) Crowding as Critical Factor To Determine pDNA Packaging Scheme into Polyplex Micelles for Enhanced Gene Expression. AB - A critical role of polyethylene glycol (PEG) crowding in the packaging of plasmid DNA (pDNA) into polyplex micelles (PMs) was investigated using a series of PEG-b poly(l-lysine) (PEG-PLys) block copolymers with varying molecular weights of both PEG and PLys segments. Rod-shaped PMs preferentially formed when the tethered PEG chains covering pDNA in a precondensed state were dense enough to overlap one another (reduced tethering density (RTD) > 1), whereas globular PMs were obtained when they were not overlapped (RTD < 1). These results submitted a scheme that steric repulsive effect of PEG regulated packaging pathways of pDNA either through folding into rod-shape or collapsing into globular depending on whether the PEG chains are overlapped or not. The rod-shaped PMs gave significantly higher gene expression efficacies in a cell-free system compared to the globular PMs, demonstrating the practical relevance of regulating packaging structure of pDNA for developing efficient gene delivery systems. PMID- 27990799 TI - Development of a Method for the Determination of Acyl-CoA Compounds by Liquid Chromatography Mass Spectrometry to Probe the Metabolism of Fatty Acids. AB - Acyl-Coenzyme As (acyl-CoAs) are a group of activated fatty acid molecules participating in multiple cellular processes including lipid synthesis, oxidative metabolism of fatty acids to produce ATP, transcriptional regulation, and protein post-translational modification. Quantification of cellular acyl-CoAs is challenging due to their instability in aqueous solutions and lack of blank matrices. Here we demonstrate an LC-MS/MS analytical method which allows for absolute quantitation with broad coverage of cellular acyl-CoAs. This assay was applied to profile endogenous acyl-CoAs under the challenge of a variety of dietary fatty acids in prostate and hepatic cells. Additionally, this approach allowed for detection of multiple fatty acid metabolic processes including the biogenesis of acyl-CoAs, and their elongation, degradation, and desaturation. Hierarchical clustering in the remodeling of acyl-CoA profiles revealed a fatty acid-specific pattern across all tested cell lines, which provides a valuable reference for making predictions in other cell models. Individual acyl-CoAs were identified which were altered differentially by exogenous fatty acids in divergent tumorigenicity states of cells. These findings demonstrate the power of acyl-CoA profiling toward understanding the mechanisms for the progression of tumors or other diseases in response to fatty acids. PMID- 27990800 TI - Bacteriophage-Based Bioconjugates as a Flow Cytometry Probe for Fast Bacteria Detection. AB - Robust detection of bacteria can significantly reduce risks of nosocomial infections, which are a serious problem even in developed countries (4.1 million cases each year in Europe). Here we demonstrate utilization of novel multifunctional bioconjugates as specific probes for bacteria detection. Bifunctional magnetic-fluorescent microparticles are coupled with bacteriophages. The T4 bacteriophage, due to its natural affinity to bacterial receptors, namely, OmpC and LPS, enables specific and efficient detection of Escherichia coli bacteria. Prepared probes are cheap, accessible (even in nonbiological laboratories), as well as versatile and easily tunable for different bacteria species. The magnetic properties of the bioconjugates facilitate the separation of captured target bacteria from other components of complex samples and other bacteria strains. Fluorescence enables simple analysis. We chose flow cytometry as the detection method as it is fast and widely used for biotests. The capture efficiency of the prepared bioconjugates is close to 100% in the range of bacteria concentrations from tens to around 105 CFU/mL. The limit of detection is restricted by flow cytometry capabilities and in our case was around 104 CFU/mL. PMID- 27990801 TI - Tryptophan-Rich Sensory Protein/Translocator Protein (TSPO) from Cyanobacterium Fremyella diplosiphon Binds a Broad Range of Functionally Relevant Tetrapyrroles. AB - Tryptophan-rich sensory protein/translocator protein (TSPO) is a membrane protein involved in stress adaptation in the cyanobacterium Fremyella diplosiphon. Characterized mammalian and proteobacterial TSPO homologues bind tetrapyrroles and cholesterol ligands. We investigated the ligand binding properties of TSPO from F. diplosiphon (FdTSPO1), which was functionally characterized in prior genetic studies. Two additional TSPO proteins (FdTSPO2 and FdTSPO3) are present in F. diplosiphon; they are similar in size to reported bacterial TSPOs and smaller than FdTSPO1. The longer cyanobacterial TSPO1 is found almost exclusively in filamentous cyanobacteria and has a relatively low degree of homology to bacterial and mammalian TSPO homologues with confirmed tetrapyrrole binding. To probe distinctions of long-form TSPOs, we tested the binding of porphyrin and bilin to FdTSPO1 and measured binding affinities in the low micromolar range, with the highest binding affinity detected for heme. Although tetrapyrrole ligands bound FdTSPO1 with affinities similar to those previously reported for proteobacterial TSPO, binding of cholesterol to FdTSPO1 was particularly poor and was not improved by introducing an amino acid motif known to enhance cholesterol binding in other bacterial TSPO homologues. Additionally, we detected limited binding of bacterial hopanoids to FdTSPO1. Cyanobacterial TSPO1 from the oxygenic photosynthetic F. diplosiphon, thus, binds a range of tetrapyrroles of functional relevance with efficiencies similar to those of mammalian and proteobacterial homologues, but the level of cholesterol binding is greatly reduced compared to that of mammalian TSPO. Furthermore, the DeltaFdTSPO1 mutant exhibits altered growth in the presence of biliverdin compared to that of wild-type cells under green light. Together, these results suggest that TSPO molecules may play roles in bilin homeostasis or trafficking in cyanobacteria. PMID- 27990802 TI - Indirect Nitrous Oxide Emission Factors for Agricultural Field Drains and Headwater Streams. AB - Agriculture is a major source of nitrous oxide (N2O) emissions, a potent greenhouse gas. While direct N2O emissions from soils have been widely investigated, indirect N2O emissions from nitrogen (N) enriched surface water and groundwater bodies are poorly understood. In this contribution, indirect N2O emissions from subsurface agricultural field drains and headwater streams were monitored over a two-year period (2013-2015) in an intensive arable catchment in eastern England. Indirect N2O emission factors for groundwater (EF5g) and surface runoff (EF5r) were calculated for both field drain and streamwater samples, respectively, using two approaches: the N2O-N/NO3-N ratio and the IPCC (2006) methodology. Mean EF5g values derived from the N2O-N/NO3-N ratio were 0.0012 for field drains and 0.0003 for streamwater. Using the IPCC (2006) methodology, the mean EF5g values were 0.0011 for field drains and 0.0001 for streamwater. Thus, EF values derived from both methods were below the current IPCC (2006) default value of 0.0025 and a downward revision to 0.0012 for EF5g and 0.0002 for EF5r is recommended. Such revision would halve current estimates of N2O emissions associated with nitrogen leaching and runoff from agriculture for both the UK and globally. PMID- 27990803 TI - Correction to "Computational Study of the Thermochemistry of N2O5 and the Kinetics of the Reaction N2O5 + H2O -> 2 HNO3". PMID- 27990804 TI - Interfacial Multiferroics of TiO2/PbTiO3 Heterostructure Driven by Ferroelectric Polarization Discontinuity. AB - Novel phenomena appear when two different oxide materials are combined together to form an interface. For example, at the interface of LaAlO3/SrTiO3, two dimensional conductive states form to avoid the polar discontinuity, and magnetic properties are found at such an interface. In this work, we propose a new type of interface between two nonmagnetic and nonpolar oxides that could host a magnetic state, where it is the ferroelectric polarization discontinuity instead of the polar discontinuity that leads to the charge transfer, forming the interfacial magnetic state. As a concrete example, we investigate by first-principles calculations the heterostructures made of ferroelectric perovskite oxide PbTiO3 and nonferroelectric polarized oxide TiO2. We show that charge is transferred to the interfacial layer forming an interfacial ferromagnetic ordering that may persist up to room temperature. Especially, the strong coupling between bulk ferroelectric polarization and interface ferromagnetism represents a new type of magnetoelectric effect, which provides an ideal platform for exploring the intriguing interfacial multiferroics. The findings here are important not only for fundamental science but also for promising applications in nanoscale electronics and spintronics. PMID- 27990805 TI - Unraveling Mixed Hydrate Formation: Microscopic Insights into Early Stage Behavior. AB - The molecular-level details of mixed hydrate nucleation remain unclear despite the broad implications of this process for a variety of scientific domains. Through analysis of mixed hydrate nucleation in a prototypical CH4/H2S/H2O system, we demonstrate that high-level kinetic similarities between mixed hydrate systems and corresponding pure hydrate systems are not a reliable basis for estimating the composition of early stage mixed hydrate nuclei. Moreover, we show that solution compositions prior to and during nucleation are not necessarily effective proxies for the composition of early stage mixed hydrate nuclei. Rather, microscopic details, (e.g., guest-host interactions and previously neglected cage types) apparently play key roles in determining early stage behavior of mixed hydrates. This work thus provides key foundational concepts and insights for understanding mixed hydrate nucleation. PMID- 27990807 TI - Molecular Precision and Enzymatic Degradation: From Readily to Undegradable Polymeric Micelles by Minor Structural Changes. AB - Studying the enzymatic degradation of synthetic polymers is crucial for the design of suitable materials for biomedical applications ranging from advanced drug delivery systems to tissue engineering. One of the key parameters that governs enzymatic activity is the limited accessibility of the enzyme to its substrates that may be collapsed inside hydrophobic domains. PEG-dendron amphiphiles can serve as powerful tools for the study of enzymatic hydrolysis of polymeric amphiphiles due to the monodispersity and symmetry of the hydrophobic dendritic block, which significantly simplifies kinetic analyses. Using these hybrids, we demonstrate how precise, minor changes in the hydrophobic block are manifested into tremendous changes in the stability of the assembled micelles toward enzymatic degradation. The obtained results emphasize the extreme sensitivity of self-assembly and its great importance in regulating the accessibility of enzymes to their substrates. Furthermore, the demonstration that the structural differences between readily degradable and undegradable micelles are rather minor, points to the critical roles that self-assembly and polydispersity play in designing biodegradable materials. PMID- 27990808 TI - Self-Assembly of Thermoreversible Hydrogels via Molecular Recognition toward a Spatially Organized Coculture System. AB - In this study, we present the spontaneous adhesion of two thermoreversible physically cross-linked hydrogels via molecular recognition under a physiological condition. We successfully prepared two types of hydrogels generated using two kinds of well-defined ABA type triblock copolymers: CAT-ABA and PBA-ABA, which contain catechol and phenylboronic acid groups as functional side chains, respectively. Both types of ABA triblock copolymers were able to undergo sol-to gel transition with the increase in temperature resulting from the formation of physical cross-links at a physiological temperature, which enables easy cell encapsulation in the hydrogel. It was determined that the cell encapsulating hydrogels exhibited spontaneous macroscopic adhesion through the formation of boronic esters between phenylboronic acid and catechol at the hydrogel interface. This novel system likely represents a promising method to construct a precisely organized, three-dimensional coculture system to enable the reconstruction of complicated tissues such as the liver in vitro. PMID- 27990806 TI - Fabricating Pt/Sn-In2O3 Nanoflower with Advanced Oxygen Reduction Reaction Performance for High-Sensitivity MicroRNA Electrochemical Detection. AB - Herein, an efficient electrochemical tracer with advanced oxygen reduction reaction (ORR) performance was designed by controllably decorating platinum (Pt) (diameter, 1 nm) on the surface of compositionally tunable tin-doped indium oxide nanoparticle (Sn-In2O3) (diameter, 25 nm), and using the Pt/Sn-In2O3 as electrochemical tracer and interfacial term hairpin capture probe, a facile and ultrasensitive microRNA (miRNA) detection strategy was developed. The morphology and composition of the generated Pt/Sn-In2O3 NPs were comprehensively characterized by spectroscopic and microscopic measurements, indicating numerous Pt uniformly anchored on the surface of Sn-In2O3. The interaction between Pt and surface Sn as well as high Pt(111) exposure resulted in the excellent electrochemical catalytic ability and stability of the Pt/Sn-In2O3 ORR. As proof of-principle, using streptavidin (SA) functionalized Pt/Sn-In2O3 (SA/Pt/Sn-In2O3) as electrochemical tracer to amplify the detectable signal and a interfacial term hairpin probe for target capture probe, a miRNA biosensor with a linear range from 5 pM to 0.5 fM and limit of detection (LOD) down to 1.92 fM was developed. Meanwhile, the inherent selectivity of the term hairpin capture probe endowed the biosensor with good base discrimination ability. The good feasibility for real sample detection was also demonstrated. The work paves a new avenue to fabricate and design high-effective electrocatalytic tracer, which have great promise in new bioanalytical applications. PMID- 27990809 TI - Molybdenum-Doped PdPt@Pt Core-Shell Octahedra Supported by Ionic Block Copolymer Functionalized Graphene as a Highly Active and Durable Oxygen Reduction Electrocatalyst. AB - Development of highly active and durable electrocatalysts that can effectively electrocatalyze oxygen reduction reactions (ORR) still remains one important challenge for high-performance electrochemical conversion and storage applications such as fuel cells and metal-air batteries. Herein, we propose the combination of molybdenum-doped PdPt@Pt core-shell octahedra and the pyrene functionalized poly(dimethylaminoethyl methacrylate)-b-poly[(ethylene glycol) methyl ether methacrylate] ionic block copolymer-functionalized reduced graphene oxide (Mo-PdPt@Pt/IG) to effectively augment the interfacial cohesion of both components using a tunable ex situ mixing strategy. The rationally designed Mo PdPt@Pt core-shell octahedra have unique compositional benefits, including segregation of Mo atoms on the vertexes and edges of the octahedron and 2-3 shell layers of Pt atoms on a PdPt alloy core, which can provide highly active sites to the catalyst for ORR along with enhanced electrochemical stability. In addition, the ionic block copolymer functionalized graphene can facilitate intermolecular charge transfer and good stability of metal NPs, which arises from the ionic block copolymer interfacial layer. When the beneficial features of the Mo-PdPt@Pt and IG are combined, the Mo-PdPt@Pt/IG exhibits substantially enhanced activity and durability for ORR relative to those of commercial Pt/C. Notably, the Mo PdPt@Pt/IG shows mass activity 31-fold higher than that of Pt/C and substantially maintains high activities after 10 000 cycles of intensive durability testing. The current study highlights the crucial strategies in designing the highly active and durable Pt-based octahedra and effective combination with functional graphene supports toward the synergetic effects on ORR. PMID- 27990811 TI - Effect of Sodium Oxide Modifier on Structural and Elastic Properties of Silicate Glass. AB - Molecular dynamics (MD) simulations and Brillouin light scattering (BLS) spectroscopy experiments have been carried to study the structure of sodium silicate glasses (SiO2)(100-X)(Na2O)X, where X ranges from 0 to 45 at room temperature. The MD-obtained glass structures have been subjected to energy minimization at zero temperature to extract the elastic constants also obtained by BLS spectroscopy. The structures obtained are in good agreement with the structural experimental data realized by different techniques. The simulations show that the values of the elastic constants as a function of X (i.e., Na2O mol %) agree well with those measured by BLS spectroscopy. The variations of elastic constants C11 and C44 as a function of Na2O mol % are discussed and correlated to structural results and potential energies of oxygen atoms. PMID- 27990810 TI - Human Exposure to Short- and Medium-Chain Chlorinated Paraffins via Mothers' Milk in Chinese Urban Population. AB - Chlorinated paraffins (CPs) are high production volume synthetic chemicals, found ubiquitously in various environmental matrices. However, little information is available on CP contamination in mothers' milk. In this study, 1370 urban mothers' milk samples were collected from 12 Chinese provinces in 2007 and 16 provinces in 2011. CP geographical distribution and congener group profiles were studied to assess the CP levels and figure out the source of exposure in humans. Twenty-eight pooled samples were analyzed for 48 short-chain CP (SCCP) and medium chain CP (MCCP) congener groups using the GC * GC-ECNI-HRTOFMS method. The median concentrations of SCCPs were 681 and 733 ng/g lipid in 2007 and 2011, respectively; median concentrations of MCCPs were 60.4 and 64.3 ng/g lipid in 2007 and 2011, respectively. Variations of more than 2 orders of magnitude in CP exposure levels were found between different provinces. The levels of CPs increased from 2007 to 2011, which indicates that CP production and use may be an important exposure source. This is the first global comprehensive and large-scale investigation of CPs in mothers' milk, and it lays foundations for improving our understanding of the metabolism of CPs in humans. The high CP concentrations found in Chinese mothers' milk should raise concern about potential toxic effects in both mothers and breastfeeding infants. PMID- 27990812 TI - Nonlinear Kinetic Behavior in Constitutional Dynamic Reaction Networks. AB - Creating synthetic chemical systems which emulate the complexity observed in cells relies on exploiting chemical networks exhibiting nonlinear kinetic behavior. While control over reaction complexity using synthetic gene regulatory networks and DNA nanotechnology has developed greatly, little control exists over small molecule reaction networks. Toward this goal, we demonstrate a general framework for inducing nonlinear kinetic behavior in dynamic chemical networks based on molecules containing reversible chemical bonds. Specifically, this strategy relies on constituent species with differing thermodynamic stabilities that readily exchange components at rates that are faster than their formation rates. Such nonlinear networks (NLN) readily lead to sigmoidal kinetic profiles as a function of the relative thermodynamic stabilities of the constituent species. Furthermore, this behavior could be readily extended to more complex mixtures while maintaining nonlinearity. The generality of this method opens the possibility to generate nonlinear networks using a broad range of small molecule structures. PMID- 27990814 TI - Correction to Variational Optimization of an All-Atom Implicit Solvent Force Field To Match Explicit Solvent Simulation Data. PMID- 27990815 TI - Influence of Functional Groups on the Viscosity of Organic Aerosol. AB - Organic aerosols can exist in highly viscous or glassy phase states. A viscosity database for organic compounds with atmospherically relevant functional groups is compiled and analyzed to quantify the influence of number and location of functional groups on viscosity. For weakly functionalized compounds the trend in viscosity sensitivity to functional group addition is carboxylic acid (COOH) ~ hydroxyl (OH) > nitrate (ONO2) > carbonyl (CO) ~ ester (COO) > methylene (CH2). Sensitivities to group addition increase with greater levels of prior functionalization and decreasing temperature. For carboxylic acids a sharp increase in sensitivity is likely present already at the second addition at room temperature. Ring structures increase viscosity relative to linear structures. Sensitivities are correlated with analogously derived sensitivities of vapor pressure reduction. This may be exploited in the future to predict viscosity in numerical models by piggybacking on schemes that track the evolution of organic aerosol volatility with age. PMID- 27990813 TI - Cytochrome c Can Form a Well-Defined Binding Pocket for Hydrocarbons. AB - Cytochrome c can acquire peroxidase activity when it binds to cardiolipin in mitochondrial membranes. The resulting oxygenation of cardiolipin by cytochrome c provides an early signal for the onset of apoptosis. The structure of this enzyme substrate complex is a matter of considerable debate. We present three structures at 1.7-2.0 A resolution of a domain-swapped dimer of yeast iso-1-cytochrome c with the detergents, CYMAL-5, CYMAL-6, and omega-undecylenyl-beta-d maltopyranoside, bound in a channel that places the hydrocarbon moieties of these detergents next to the heme. The heme is poised for peroxidase activity with water bound in place of Met80, which serves as the axial heme ligand when cytochrome c functions as an electron carrier. The hydroxyl group of Tyr67 sits 3.6-4.0 A from the nearest carbon of the detergents, positioned to act as a relay in radical abstraction during peroxidase activity. Docking studies with linoleic acid, the most common fatty acid component of cardiolipin, show that C11 of linoleic acid can sit adjacent to Tyr67 and the heme, consistent with the oxygenation pattern observed in lipidomics studies. The well-defined hydrocarbon binding pocket provides atomic resolution evidence for the extended lipid anchorage model for cytochrome c/cardiolipin binding. Dimer dissociation/association kinetics for yeast versus equine cytochrome c indicate that formation of mammalian cytochrome c dimers in vivo would require catalysis. However, the dimer structure shows that only a modest deformation of monomeric cytochrome c would suffice to form the hydrocarbon binding site occupied by these detergents. PMID- 27990816 TI - Glass-Based Transparent Conductive Electrode: Its Application to Visible-to Ultraviolet Light-Emitting Diodes. AB - Nitride-based ultraviolet light-emitting diodes (UV LEDs) are promising replacements for conventional UV lamps. However, the external quantum efficiency of UV LEDs is much lower than for visible LEDs due to light absorption in the p GaN contact and electrode layers, along with p-AlGaN growth and doping issues. To minimize such absorption, we should obtain direct ohmic contact to p-AlGaN using UV-transparent ohmic electrodes and not use p-GaN as a contact layer. Here, we propose a glass-based transparent conductive electrode (TCE) produced using electrical breakdown (EBD) of an AlN thin film, and we apply the thin film to four (Al)GaN-based visible and UV LEDs with thin buffer layers for current spreading and damage protection. Compared to LEDs with optimal ITO contacts, our LEDs with AlN TCEs exhibit a lower forward voltage, higher light output power, and brighter light emission for all samples. The ohmic transport mechanism for current injection and spreading from the metal electrode to p-(Al)GaN layer via AlN TCE is also investigated by analyzing the p-(Al)GaN surface before and after EBD. PMID- 27990819 TI - Nanoionics-Based Three-Terminal Synaptic Device Using Zinc Oxide. AB - Artificial synaptic thin film transistors (TFTs) capable of simultaneously manifesting signal transmission and self-learning are demonstrated using transparent zinc oxide (ZnO) in combination with high kappa tantalum oxide as gate insulator. The devices exhibit pronounced memory retention with a memory window in excess of 4 V realized using an operating voltage less than 6 V. Gate polarity induced motion of oxygen vacancies in the gate insulator is proposed to play a vital role in emulating synaptic behavior, directly measured as the transmission of a signal between the source and drain (S/D) terminals, but with the added benefit of independent control of synaptic weight. Unlike in two terminal memristor/resistive switching devices, multistate memory levels are demonstrated using the gate terminal without hampering the signal transmission across the S/D electrodes. Synaptic functions in the devices can be emulated using a low programming voltage of 200 mV, an order of magnitude smaller than in conventional resistive random access memory and other field effect transistor based synaptic technologies. Robust synaptic properties demonstrated using fully transparent, ecofriendly inorganic materials chosen here show greater promise in realizing scalable synaptic devices compared to organic synaptic and other liquid electrolyte gated device technologies. Most importantly, the strong coupling between the in-plane gate and semiconductor channel through ionic charge in the gate insulator shown by these devices, can lead to an artificial neural network with multiple presynaptic terminals for complex synaptic learning processes. This provides opportunities to alleviate the extreme requirements of component and interconnect density in realizing brainlike systems. PMID- 27990818 TI - The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design. AB - Halogen bonds (XBs) have been attracting increasing attention in biological systems, especially in drug discovery and design, for their advantages of both improving drug-target binding affinity and tuning ADME/T properties. After a comprehensive literature survey in drug discovery and design, we found that most of the studies on XBs between ligands and proteins have focused on the protein backbone. Meanwhile, we also noticed that the proportion of side-chain XBs to overall XBs decreases as structural resolution becomes lower and lower. We postulated that protein side chains are more flexible in comparison with backbone structures, leading to more unclear electron density and lower resolution of the side chains. As the classic force field used to refine protein structures from diffraction data cannot handle XBs correctly, some of the interactions are lost during the refinement. On the contrary, there is no change in the corresponding ratio of hydrogen bonds (HBs) during structural resolution because HBs can be handled well with the classic force field. Further analysis revealed that Thr and Gln account for a large part of the decreasing XB trend, which could be partly attributed to the misidentified N, C, or O atoms. In addition, the lost XBs might be recovered after the atoms are reassigned, e.g., by flipping Thr side chains. In summary, formation of XBs with protein side chains is underestimated, and more attention should be paid to the potential formation of XBs between organohalogens and protein side chains during X-ray crystallography studies. PMID- 27990817 TI - Applications of Systematic Molecular Scaffold Enumeration to Enrich Structure Activity Relationship Information. AB - Establishing structure-activity relationships (SARs) in hit identification during early stage drug discovery is important in accelerating hit confirmation and expansion. We describe the development of EnCore, a systematic molecular scaffold enumeration protocol using single atom mutations, to enhance the application of objective scaffold definitions and to enrich SAR information from analysis of high-throughput screening output. A list of 43 literature medicinal chemistry compound series, each containing a minimum of 100 compounds, published in the Journal of Medicinal Chemistry was collated to validate the protocol. Analysis using the top representative Level 1 scaffolds this list of literature compound series demonstrated that EnCore could mimic the scaffold exploration conducted when establishing SAR. When EnCore was applied to analyze an HTS library containing over 200 000 compounds, we observed that over 70% of the molecular scaffolds matched extant scaffolds within the library after enumeration. In particular, over 60% of the singleton scaffolds with only one representative compound were found to have structurally related compounds after enumeration. These results illustrate the potential of EnCore to enrich SAR information. A case study using literature cyclooxygenase-2 inhibitors further demonstrates the advantage of EnCore application in establishing SAR from structurally related scaffolds. EnCore complements literature enumeration methods in enabling changes to the physicochemical properties of molecular scaffolds and structural modifications to aliphatic rings and linkers. The enumerated scaffold clusters generated would constitute a comprehensive collection of scaffolds for scaffold morphing and hopping. PMID- 27990820 TI - Exploiting Polydopamine Nanospheres to DNA Computing: A Simple, Enzyme-Free and G Quadruplex-Free DNA Parity Generator/Checker for Error Detection during Data Transmission. AB - Molecular logic devices with various functions play an indispensable role in molecular data transmission/processing. However, during any kinds of data transmission, a constant and unavoidable circumstance is the appearance of bit errors, which have serious effects on the regular logic computation. Fortunately, these errors can be detected via plugging a parity generator (pG) at the transmitting terminal and a parity checker (pC) at the receiving terminal. Herein, taking advantage of the efficient adsorption/quenching ability of polydopamine nanospheres toward fluorophore-labeled single-stranded DNA, we explored this biocompatible nanomaterial to DNA logic computation and constructed the first simple, enzyme-free, and G-quadruplex-free DNA pG/pC for error detection through data transmission. Besides, graphene oxide (GO) was innovatively introduced as the "corrective element" to perform the output correction function of pC. All the erroneous outputs were corrected to normal conditions completely, ensuring the regular operation of later logic computing. The total operation of this non-G4 pG/pC system (error checking/output correction) could be completed within 1 h (about 1/3 of previous G4 platform) in a simpler and more efficient way. Notably, the odd pG/pC with analogous functions was also achieved through negative logic conversion to the fabricated even one. Furthermore, the same system could also perform three-input concatenated logic computation (XOR-INHIBIT), enriching the complexity of PDs-based logic computation. PMID- 27990822 TI - Unusual C-I...O Halogen Bonding in Triazole Derivatives: Gelation Solvents at Two Extremes of Polarity and Formation of Superorganogels. AB - To investigate the influence of halogen bond (XB) on the gelation of a one component organogel system, a new family of 5-iodo-1H-1,2,3-triazole and 1H-1,2,3 triazole gelators was designed and synthesized. The iodo gelators (1I, 3I) gelled various solvents at low concentrations and formed many superorganogels, whereas the hydrogenous gelators (1H, 3H) showed much poorer gelling performance. An X ray analysis of the single crystals of two reference compounds (16I, 16H) reveals that the unusual C-I...O XB interaction is responsible for this difference. The results of spectroscopic examinations (XRD, SEM, 1H NMR, and UV) are well consistent with those of single-crystal analyses. Under the guidance of the XB interaction and the weak pi-pi interaction, 1I and 3I self-assemble to hexagonal columnar aggregations in the gel state, whereas 1H and 3H, driven by CH-pi interactions, feature the formation of gels with a lamellar structure. The mechanical property of iodo gels is much better than that of hydrogenous gels under the same concentration. Gels from 1I respond to the stimuli of Hg2+, Cu2+, Zn2+, and Mg2+ as perchlorate salts, and gels from 1H are selectively responsive to Hg2+ solely. PMID- 27990821 TI - Dual microRNAs-Fueled DNA Nanogears: A Case of Regenerated Strategy for Multiple Electrochemiluminescence Detection of microRNAs with Single Luminophore. AB - The determination of multiple biomarkers from cancer cells features a considerable step toward early diagnosis of cancers. However, realizing different biomarkers detection with single electrochemiluminescence (ECL) luminophore and regenerating the sensing platform remain a compelling goal. Herein, dual miRNAs fueled DNA nanogears were designed for an enzyme-free ECL biosensor construction to perform the multiple sensitive detection of the microRNA (miRNA) biomarkers with single luminophore. The nanogears were assembled on CdS quantum dots (QDs) modified sensing surface. Using miRNA-21 as motive power, Au nanoparticles (AuNPs)-labeled nanogears B could be activated to roll against nanogear A, increasing the distance between AuNPs and CdS QDs. Thus, the significant ECL enhancement of CdS QDs was obtained owing to the ECL energy transfer between AuNPs and CdS QDs, simultaneously realizing the detection of miRNA-21. After the incubation of miRNA-155, nanogear B revolved against nanogear A continuously and realized the close-range of AuNPs and CdS QDs, resulting in the quenching of ECL intensity due to the Forster energy transfer and realizing the analysis of miRNA 155. The successive locomotion of the nanogears led to a significant ECL increasing for analysis of miRNA-21 down to 0.16 fM and a remarkable ECL suppression for determination of miRNA-155 down to 0.33 fM. Impressively, the proposed biosensor was able to be regenerated along with the gears roll against each other. In general, this enzyme-free strategy initiates a new thought to realize the multiple ECL detection with single luminophore, paving the way for applications of nanomachines in biosensing and clinical diagnosis. PMID- 27990824 TI - Surface Tension of Acid Solutions: Fluctuations beyond the Nonlinear Poisson Boltzmann Theory. AB - We extend our previous study of surface tension of ionic solutions and apply it to acids (and salts) with strong ion-surface interactions, as described by a single adhesivity parameter for the ionic species interacting with the interface. We derive the appropriate nonlinear boundary condition with an effective surface charge due to the adsorption of ions from the bulk onto the interface. The calculation is done using the loop-expansion technique, where the zero loop (mean field) corresponds of the full nonlinear Poisson-Boltzmann equation. The surface tension is obtained analytically to one-loop order, where the mean-field contribution is a modification of the Poisson-Boltzmann surface tension and the one-loop contribution gives a generalization of the Onsager-Samaras result. Adhesivity significantly affects both contributions to the surface tension, as can be seen from the dependence of surface tension on salt concentration for strongly absorbing ions. Comparison with available experimental data on a wide range of different acids and salts allows the fitting of the adhesivity parameter. In addition, it identifies the regime(s) where the hypotheses on which the theory is based are outside their range of validity. PMID- 27990823 TI - ABRF Proteome Informatics Research Group (iPRG) 2015 Study: Detection of Differentially Abundant Proteins in Label-Free Quantitative LC-MS/MS Experiments. AB - Detection of differentially abundant proteins in label-free quantitative shotgun liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments requires a series of computational steps that identify and quantify LC-MS features. It also requires statistical analyses that distinguish systematic changes in abundance between conditions from artifacts of biological and technical variation. The 2015 study of the Proteome Informatics Research Group (iPRG) of the Association of Biomolecular Resource Facilities (ABRF) aimed to evaluate the effects of the statistical analysis on the accuracy of the results. The study used LC-tandem mass spectra acquired from a controlled mixture, and made the data available to anonymous volunteer participants. The participants used methods of their choice to detect differentially abundant proteins, estimate the associated fold changes, and characterize the uncertainty of the results. The study found that multiple strategies (including the use of spectral counts versus peak intensities, and various software tools) could lead to accurate results, and that the performance was primarily determined by the analysts' expertise. This manuscript summarizes the outcome of the study, and provides representative examples of good computational and statistical practice. The data set generated as part of this study is publicly available. PMID- 27990825 TI - Effect of Polyvinyl Alcohol on Ice Formation in the Presence of a Liquid/Solid Interface. AB - Tuning ice formation is of great importance in biological systems and some technological applications. Many synthetic polymers have been shown to affect ice formation, in particular, polyvinyl alcohol (PVA). However, the experimental observations of the effect of PVA on ice formation are still conflicting. Here, we introduced colloidal silica (CS) as the model liquid/solid interface and studied the effect of PVA on ice formation in detail. The results showed that either PVA or CS promoted ice formation, whereas the mixture of these two (CS PVA) prevented ice formation (antifreezing). Using quantitative analysis based on classical nucleation theory, we revealed that the main contribution came from the kinetic factor J0 rather than the energy barrier factor Gamma. Combined with the PVA adsorption behavior on CS particles, it is strongly suggested that the adsorption of PVA at the interface has significantly reduced ice nucleation, which thus may provide new ideas for developing antifreezing agents. PMID- 27990826 TI - X!TandemPipeline: A Tool to Manage Sequence Redundancy for Protein Inference and Phosphosite Identification. AB - X!TandemPipeline is a software designed to perform protein inference and to manage redundancy in the results of phosphosite identification by database search. It provides the minimal list of proteins or phosphosites that are present in a set of samples using grouping algorithms based on the principle of parsimony. Regarding proteins, a two-level classification is performed, where groups gather proteins sharing at least one peptide and subgroups gather proteins that are not distinguishable according to the identified peptides. Regarding phosphosites, an innovative approach based on the concept of phosphoisland is used to gather overlapping phosphopeptides. The graphical interface of X!TandemPipeline allows the users to launch X!tandem identification, to inspect spectra and to manually validate their assignment to peptides, to launch the grouping program, and to visualize elementary data as well as grouping and redundancy information. Identification results obtained from other search engines can also be processed. X!TandemPipeline results can be exported as ready-to-use tabulated files or as XML files that can be directly used by the PROTICdb database or by the MassChroQ quantification software. X!TandemPipeline runs fast, is easy to use, and can process hundreds of samples simultaneously. It is freely available under the GNU General Public License v3.0 at http://pappso.inra.fr/bioinfo/xtandempipeline/ . PMID- 27990827 TI - Coordination between Intra- and Extracellular Forces Regulates Focal Adhesion Dynamics. AB - Focal adhesions (FAs) are important mediators of cell-substrate interactions. One of their key functions is the transmission of forces between the intracellular acto-myosin network and the substrate. However, the relationships between cell traction forces, FA architecture, and molecular forces within FAs are poorly understood. Here, by combining Forster resonance energy transfer (FRET)-based molecular force biosensors with micropillar-based traction force sensors and high resolution fluorescence microscopy, we simultaneously map molecular tension across vinculin, a key protein in FAs, and traction forces at FAs. Our results reveal strong spatiotemporal correlations between vinculin tension and cell traction forces at FAs throughout a wide range of substrate stiffnesses. Furthermore, we find that molecular tension within individual FAs follows a biphasic distribution from the proximal (toward the cell nucleus) to distal end (toward the cell edge). Using super-resolution imaging, we show that such a distribution relates to that of FA proteins. On the basis of our experimental data, we propose a model in which FA dynamics results from tension changes along the FAs. PMID- 27990828 TI - [Osteoporosis in men]. AB - The health burden of osteoporosis in men is expected to increase with an aging population and increasing life expectancy. Both hip and vertebral fractures are associated with increased morbidity and mortality in men. The clinical evaluation, measurement of bone mineral density using dual-energy X-ray absorptiometry, laboratory tests and fracture risk assessment is now recognized as the standard for diagnosis of osteoporosis in males, and a preferred approach to guide treatment decisions. Clinical trials have demonstrated efficacy of several treatment options available for men with osteoporosis. Moreover, clinical interventions to improve physical performance could also reduce the risk of future fractures. PMID- 27990829 TI - [Islet transplantation as a treatment for hypoglycemia unawareness syndrome. Evaluation of the pilot program and comparison with pancreas transplantation]. AB - Islet transplantation (ITx) started in 2005 in IKEM as a potentially safer alternative to pancreas transplantation (PTx), which so far had represented the method of choice in type-1 diabetic patients with conservatively intractable hypoglycemia unawareness syndrome. The aim of the study was to compare these two methods with regard to severe hypoglycemia elimination and to frequency of complications.Up to November 2015 a total number of 48 patients underwent ITx. The results from 22 patients with hypoglycemia unawareness were statistically analyzed. The mean number of transplanted islet equivalents was 12,096 (6,93316,705) IEQ/kg administered percutaneously in local anesthesia under radiological control to the portal vein. 44 patients underwent PTx from 1996. We evaluated glycated hemoglobin(HbA1c), insulin dose, fasting and stimulated C peptide, frequency of severe hypoglycemia and complications. Medians (interquartile range) were analyzed using the Wilcoxon signed-rank test.One and two years after ITx, HbA1c decreased, C-peptide became significantly positive, insulin dose and frequency of severe hypoglycemia decreased and 18 % of ITx recipients were temporarily insulin-independent. Bleeding was present in 41 % of patients. One year after PTx, 73 % of patients were insulin and hypoglycemia free, after two years 68 % of patients were insulin and hypoglycemia-free; graftectomy occurred in 20 % of recipients.Both methods led to restoration of insulin secretion and severe hypoglycemia elimination. PTx made more recipients insulin-independent at the cost of serious complications. PMID- 27990830 TI - [The secular trend in body height and weight in the adult population in the Czech republic]. AB - Secular changes in anthropometric parameters reflect the effect of socio-economic conditions in interaction with other factors on individuals in the course of 100 200 years. The main aim of the research was to determine the average body height and weight for the current adult population of men 19 to 94 years old and women 19 to 86 years old in the Czech Republic, and to compare the average values of body height and weight of the monitored group with the reference values for the adult population observed in our country from 1895 to 2001.Body height and weight were measured with standard anthropometry in 973 men aged 19-94 years and 2,606 women aged 19-86 years. The research was carried out from 2013 to 2015. Statistical tests: t-test, one-way analysis of variance (ANOVA). The average body weight and height of the current adult male is 178.58 cm and 80.86 kg, and of adult female 165.99 cm and 65.67 kg. When compared to men, women show significantly lower average height by 12.59 cm and lower weight by 15.19 kg. The results show that men today are about 10.61 cm higher and weigh 9.01 kilograms more than men in 1895. Todays women are about 9.43 centimeters taller, but weigh 0,58 kg less than women of the same age in 1895.Comparison of results from 1895 to 2015 shows that at present there is likely stagnation or decline in the positive secular trend in body height among men and women. The weight of men is increasing while there is stagnation in the body weight of women. PMID- 27990831 TI - [Clinical evaluation of acid-base status: Henderson-Hasselbalch, or Stewart-Fencl approach?] AB - Two approaches have been used in clinical evaluation the acid-base status: traditional (bicarbonate-centered) is based on the Henderson-Hasselbalch equation complemented by calculation of the anion gap, and more recent quantitative approach proposed by Stewart and Fencl. The latter method defines the three independent variables, which regulate pH. These include: the difference between the sum of charges carried by strong plasma cations and anions termed the strong ion difference - SID (decrease causes acidosis, and vice versa); the total concentration of the weak non-volatile acids [Atot] (inorganic phosphate and albumin, decrease causes alkalosis and vice versa), and pCO2. According to this approach, pH and bicarbonate are dependent variables. Their concentrations change if and only if one or more independent variables are altered.The main advantage of the Stewart-Fencl approach is the calculation of the concentration of plasma acids, which are not routinely measured. In the traditional approach, their presence is inferred from the anion gap. The correction of the value of anion gap according to the serum albumin level increases the specificity. This correction brings traditional approach closer to the Stewart-Fencl method that precisely calculates unmeasured strong anions by further adjustment of the corrected anion gap according to the serum phosphate, calcium and magnesium levels. The precise calculation of unmeasured anions is important in critically ill patients with the metabolic breakdown, where the traditional approach may overlook the presence of unmeasured anions. Consideration of the sodium-chloride difference draws the attention to acid-base disturbance caused by change of the strong ion difference. PMID- 27990832 TI - [Non-coding RNA - from useless to essential]. AB - Whole-genome sequencing analyses revealed that the majority of the human genome is transcribed and identified thousands of protein non-coding transcripts. Non coding RNAs (ncRNAs) are divided into two main groups: small and long ncRNAs. This review is focused on the regulatory ncRNAs mainly on microRNAs and long ncRNAs. These ncRNAs regulate gene expression at the transcriptional and post transcriptional levels. In this context, ncRNAs are involved in the regulation of most cellular processes and their deregulation has serious impacts on the phenotype. Hundreds of studies have implicated ncRNAs in the pathogenesis of many diseases ranging from metabolic disorders to diseases of organ systems as well as various types of cancers.Clinically, ncRNAs belong to a new generation of diagnostic and prognostic biomarkers with a great potential. Due to high tissue specificity and ability to regulate multiple genes often within one signaling pathway, ncRNAs represent attractive therapeutic targets. Increasing knowledge about a wide spectrum of ncRNA actions demonstrate a pivotal role of these transcripts in expression regulation. Many aspects of the ncRNA biology are still unclear and their understanding will provide us a new perspective on the complexity of the regulatory network. PMID- 27990833 TI - [Correct indications and performing of autopsies in the Czech republic]. AB - Since July 1st 2016 Czech law, after more than two years after the new Civil code came into force, in turn, permits performing the clinician indicated pathological anatomical autopsies with regard to their basic purpose, which is to identify the cause of death, other diseases, complications of diseases and to verify the clinical diagnosis and medical treatment of patient.For physicians requesting an autopsy it is important to know the rules for their indication and implementation. These rules respect the public interest in performing the autopsies as well as the possibility to decide about post-mortem treatment of the own body and bodies of close relatives.Clinical autopsies can be divided into three groups: absolutely obligatory (carried always), relatively obligatory for professional reasons (with possibility of cancellation after additional professional assessment by a provider performing the autopsy) and relatively mandatory after the disapproval of the autopsy (by the deceased during his life or on the request of close relatives after death).The paper presents a review of medical practice regarding autopsies indicated by clinicians according to generally binding legal regulations in the Czech Republic. PMID- 27990834 TI - [The challenges of diagnostic reasoning or "how doctors think"]. AB - Basic overview of diagnostic errors with particular focus on cognitive biases and strategies to minimize or avoid them. PMID- 27990835 TI - Influence of sustained viral response on the regression of fibrosis and portal hypertension in cirrhotic HCV patients treated with antiviral triple therapy. AB - BACKGROUND AND AIMS: The regression of liver fibrosis and portal hypertension (PH) and their influence on the natural history of compensated hepatitis C virus (HCV)-related cirrhosis has not been studied previously. Our objective was to evaluate the influence of sustained virologic response (SVR) on the portal pressure gradient (HVPG) and non-invasive parameters of PH and prognostic factors of response. METHODS: Sixteen patients with compensated HCV genotype 1-related cirrhosis with PH (HVPG > 6 mmHg) without beta-blocker therapy were considered as candidates for PEGalpha2a + RBV + BOC (48 weeks; lead-in and accepted stopping rules). A hemodynamic study and Fibroscan(r) were performed at baseline, at eight weeks and, in the case of SVR, 24 weeks after treatment. In each hemodynamic study, serum samples were analyzed for inflammatory biomarkers associated with PH. RESULTS: In eight cases, SVR was obtained; five patients relapsed, and treatment was stopped early for non-response to lead in (one case) and a decrease of < 3 log at week 8 (two patients). Compared to baseline, there was a significant decrease in HVPG and Fibroscan(r) at weeks 8 and 72 (10.31 +/- 4.3 vs 9.4 +/- 5.04 vs 6.1 +/- 3.61 mmHg, p < 0.0001 and 21.3 +/- 14.5 vs 16.2 +/- 9.5 vs 6.4 +/- 4.5 kPa, p < 0.0001, respectively). The average HVPG decrease in SVR was 40.8 +/- 17.53%, achieving an HVPG < 6 mmHg in five patients (62.5%) and a Fibroscan(r) < 7.1 kPa in three patients (37.5%). CONCLUSIONS: Complete hemodynamic response (HVPG < 6 mmHg) and fibrosis regression (Fibroscan(r) < 7.1 kPa) occur in more than half and one-third of patients achieving SVR, respectively, and must be another target in cirrhotic patients with SVR. PMID- 27990837 TI - Unusual presentation of infection by Helicobacter pylori: gastritis associated with Russell bodies, infrequent and poorly understood pathology. AB - Russell bodies gastritis is a very rare disease, with few cases reported in literature, and characterized by the finding of plasma cells with eosinophilic intracytoplasmic inclusions in the gastric mucosa, called Mott cells. Although it has been partnered since its first description to Helicobacter pylori infection, it is important to considered differential diagnoses such as lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, plasmacytoma and signet ring cell carcinom. In this case report, we address a patient with histologic confirmation and her follow up. PMID- 27990836 TI - Practical aspects of high resolution esophageal manometry. AB - High resolution esophageal manometry (HRM) is currently under development as can be seen in the various Chicago classifications. In order to standardize criteria in certain practical aspects with limited scientific evidence, the First National Meeting for Consensus in High Resolution Manometry of the Spanish Digestive Motility Group took place, bringing together a wide group of experts. The proposals were based on a prior survey composed of 47 questions, an exhaustive review of the available literature and the experience of the participants. Methodological aspects relating to the poorly defined analysis criteria of certain new high resolution parameters were discussed, as well as other issues previously overlooked such as spontaneous activity or secondary waves. Final conclusions were drawn with practical applications. PMID- 27990838 TI - Multiple perforation of small-intestine diverticula in a patient with Ehlers Danlos syndrome. AB - Ehlers-Danlos syndrome represents a group of hereditary connective tissue disorders characterized by ligamentous hyperlaxity, fragile skin and joint hypermobility. Gastrointestinal complications in this syndrome are less well known. PMID- 27990839 TI - Alopecia areata as a paraneoplastic syndrome of gastric cancer. AB - Alopecia areata produces hair loss in circular patches by an immune mechanism. The association with hematologic malignancies and with digestive tumors has been described. We report the case of a man who presented alopecia areata and two months later he was diagnosed with gastric adenocarcinoma. PMID- 27990840 TI - Novel strategies for assessing platelet reactivity. AB - There are many approaches to assessing platelet reactivity and many uses for such measurements. Initially, measurements were based on the ability of platelets separated from other blood cells to aggregate together following activation with an appropriate 'aggregating agent'. Later, measurements of platelet aggregation in blood itself were performed, and this led to a point-of-care approach to platelet function testing. Measurement of secretory activity through the appearance of the activation marker P-selectin on platelets now provides an alternative approach, which enables remote testing. Measurement of vasodilator stimulated phosphoprotein phosphorylation is also moving toward application in situations remote from the testing laboratory. Here we provide an overview of the various approaches that are now available, assess their advantages and disadvantages, and describe some of the clinical situations in which they are being used. PMID- 27990841 TI - Management of pregnancy in cardiomyopathies and heart failure. AB - Pregnancy exposes women with inherited cardiomyopathies to increased risk for arrhythmias and heart failure. In asymptomatic patients with inherited cardiomyopathies, pregnancy is generally well tolerated. Preconception evaluation, risk assessment and proper counseling by a team of experienced physicians are mandatory in managing women with inherited cardiomyopathies planning pregnancy. In this paper, we reviewed the clinical course, risk assessment and management during pregnancy of women with cardiomyopathies. PMID- 27990843 TI - Impact of QT interval prolongation following antiarrhythmic drug therapy on left ventricular function. AB - AIM: We assessed whether antiarrhythmic drug-induced QT interval prolongation affects left ventricular function. METHODS: Study population included 54 patients with symptomatic recent onset atrial fibrillation spontaneously cardioverted to sinus rhythm. Electrocardiographic and echocardiographic studies were done before initiating and after achieving drug's steady state. RESULTS: Significantly prolonged corrected QT interval (QTc) was noticed following only sotalol and amiodarone. The corrected precontraction time increased after sotalol (p = 0.005) and amiodarone (p = 0.017), not propafenone (p = 0.139). Analysis results between DeltaEF and DeltaQTc, DeltaEF and DeltaQTc(p), DeltaE/e' and DeltaQTc, DeltaE/e' and DeltaQTc(p) for amiodarone group were (p = 0.66, p = 0.20, p = 0.66, p = 0.33), for sotalol (p = 0.36, p = 0.51, p = 0.44, p = 0.33) and for propafenone (p = 0.38, p = 0.12, p = 0.89, p = 0.61), respectively. CONCLUSION: QT interval prolongation following antiarrhythmic therapy does not affect significantly left ventricular function. PMID- 27990844 TI - Artificial heart pumps: bridging the gap between science, technology and personalized medicine by relational medicine. AB - In the US population of 300 million, 3 million have heart failure with reduced ejection fraction and 300,000 have advanced heart failure. Long-term mechanical circulatory support will, within the next decade, be recommended to 30,000 patients annually in the USA, 3000 undergo heart transplantation annually. What do these advances mean for persons suffering from advanced heart failure and their loved ones/caregivers? In this perspective article, we discuss - by exemplifying a case report of a 27-year-old man receiving a Total Artificial Heart - a practice concept of modern medicine that fully incorporates the patient's personhood perspective which we have termed Relational MedicineTM. From this case study, it becomes apparent that the successful practice of modern cardiovascular medicine requires the person-person encounter as a core practice element. PMID- 27990845 TI - The effect of obstructive sleep apnea treatment on cardiovascular outcomes. PMID- 27990846 TI - Are different imaging methods affecting the treatment decision of extractions of mandibular third molars? AB - OBJECTIVES: To find the differences between treatment decisions of lower impacted third molars among experts of oral and maxillofacial surgery according to panoramic radiographic and CBCT findings. METHODS: A retrospective analysis of 62 panoramic radiographs and CBCT of lower third molars evaluated for treatment decisions by 9 independent experts of oral and maxillofacial surgery. RESULTS: Differences in interpretation of the panoramic radiography were found between surgeons. The absence of radiological signs suspected for risk to the inferior alveolar nerve lead to the decision of extraction according to panoramic radiography without CBCT (p < 0.01). The presence of those signs lead to referral to CBCT by surgeons before treatment but did not change their decision. CONCLUSIONS: Treatment decision for surgical treatment of the lower third molar can be accepted without CBCT findings. The use of CBCT is popular before extraction of lower third molars. We found that it has a little effect on the treatment decision of the surgical intervention in comparison to panoramic radiography. PMID- 27990847 TI - A developmental approach to induced pluripotent stem cells-based tissue engineered heart valves. PMID- 27990848 TI - A psychometric evaluation of the University of Auckland General Practice Report of Educational Environment: UAGREE. AB - PURPOSE: The aim of this study was to develop an instrument (University of Auckland General Practice Report of Educational Environment: UAGREE) with robust psychometric properties that measured the educational environment of undergraduate primary care. The questions were designed to incorporate measurements of the teaching of cultural competence. METHODS: Following a structured consensus process and an initial pilot, a list of 55 questions was developed. All Year 5 and 6 students completing a primary care attachment at Auckland University were invited to complete the questionnaire. The results were analysed using exploratory factor analysis and confirmatory factor analysis resulting in a 16-item instrument. RESULTS: Three factors were identified explaining 53% of the variance. The items' reliability within the factors were high (Learning: 0.894; Teaching: 0.871; Cultural competence: 0.857). Multiple groups analysis by gender; and separately across ethnic groups did not find significant differences between groups. CONCLUSION: UAGREE is a specific instrument measuring the undergraduate primary care educational environment. Its questions fit within established theoretical educational environment frameworks and the incorporation of cultural competence questions reflects the importance of teaching cultural competence within medicine. The psychometric properties of UAGREE suggest that it is a reliable and valid measure of the primary care education environment. PMID- 27990849 TI - Investigation of T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) polymorphisms in essential thrombocythaemia (ET). AB - OBJECTIVES: T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) is preferentially expressed on terminally differentiated Th1 cells and inhibits their IFN-gamma production. It has been reported that chronic inflammation may be an important driving force for myeloproliferative neoplasms (MPNs). Therefore, we hypothesized that as an important inflammation regulator, TIM-3 may be involved in essential thrombocythaemia (ET). The goal of this study was to investigate whether the -1516G > T, -574G > T and +4259T > G single-nucleotide polymorphisms (SNPs) within the TIM-3 gene contribute to the genetic susceptibility of individuals to ET. METHODS: Genotyping of the TIM-3 -1516G > T, -574G > T and + 4259T > G SNPs was performed in 175 patients with ET and in 151 controls via a polymerase chain reaction-restriction fragment length polymorphism assay. We also investigated the relationships between the genotypes of each SNP and the risk factors of ET such as routine blood indexes, age and JAK2 V617F mutation. RESULTS: The genotype and allele frequencies of the -1516G > T SNP (p = 0.016 and 0.019, respectively), the -574G > T SNP (p = 0.035 and 0.038, respectively) and the +4259T > G SNP (p = 0.036 and 0.038, respectively) of the ET patients and the controls were significantly different. A haplotype analysis found that the GGT and TGT haplotypes had significantly different distributions between ET and controls (p = 0.041 and 0.041, respectively). However, no significant differences were detected between the genotypes of all SNPs and routine blood indexes, age and JAK2V617F mutation. CONCLUSION: The -1516G > T, -574G > T and +4259T > G SNPs within TIM-3 gene might play an important role as a genetic risk factor in the pathogenesis of ET. PMID- 27991016 TI - [Retrospective analysis of carcinomas of the rectum operated by TEM during one year at our institute]. AB - INTRODUCTION: The very first TEM (transanal endoscopyc microsurgery) in Hungary was performed in our department by professor Attila Nagy in 1992. Up to August 2016, 1385 operation in total was performed with an average number of 60 per year., 992 operations were carried out for benign reasons and 393 cases for malignancies. We analyze the malignant cases operated by TEM in 2013. SUBJECTS AND METHODS: In 2013 we performed 121 TEM on 118 patients (in 3 cases twice). 70 patients had benign, 48 patients had malignant pathology. The average follow-up was 32 (12-39) month.We analyzed the cases retrospectively, presenting the history of each patient in detail. The pathological stages were the following: 8 in situ carcinomas, 14 T1, 12 T2, 9 T3 and 5 Tx. 17 patients received preoperative RCT, (4 ypT0, 2 ypT1, 3 ypT2, 8 ypT3). RESULTS: In the pTis group one patient was lost to follow up. Local recurrence was noted in 2 cases (14.28%), from which one was malignant. No distant metastasis was observed; DFS: 85.71%, OS: 100%. From the pT1 group one patient was lost to follow up after 4 month. Local recurrence was found in 2/13 cases (15.38%), distant metastases in 1 out of 13 (7.69%); DFS: 84.61%, OS: 84.61%. In the pT2 group 3 local recurrences was observed (27.2%). Distant metastases occurred in one patient (9.09%); DFS: 81.81%, OS: 81.81%. In the pT3 group 2/8 local recurrence (25%), and 3/8 (37.5%) distant metastasis was found, DFS: 62.5%,OS: 75%. 4 patient out of the 5 pTx cases showed complete pathological response after neoadjuvant RCT and one patient's histology turned out to be carcinoid. Downstaging was observed in 10 patients who received neoadjuvant RCT. CONCLUSIONS: By a thorough discussion of each individual patient's history we would like to draw attention on the complexity of treatment of rectal malignancies with TEM and the need of personalized care. Firm conclusions cannot be drawn from our series because of the small number of the patients and the heterogeneity of the therapies. The establishment of a precise preoperative diagnostic algorithm and accurate histopathological staging is inevitable for the effective use of the TEM and TEM like techniques. The number of the patients eligible for TEM after neoadjuvant RCT does not depends only on bowel screening programme, but also on finding an accurate way to determine the responder-non-responder status for neoadjuvant treatment. PMID- 27991017 TI - [Proctocolectomy with J pouch. Ileo-anal anastomosis performed with PPH stapler. Our experiences after 88 cases]. AB - AIM: Ulcerative colitis (CU) or Familiar Polyposis (FAP) can be the indication for proctocolectomy reconstructed with J pouch. The complete removal of the colon mucosa is essential regarding the late complications and at the same time the atraumatic surgical technique is very important concerning on the long term functional results. Both aspects seems to be answered by the stapled ileo-anal anastomosis using a "procedure for prolaps and haemorrhoids (PPH)" stapler applied by us since 2000. PATIENTS AND METHODS: 117 proctocolectomies reconstructed with J pouch and ileo-anal anastomosis were performed in our department between March 1990 and September 2016 indicated by CU or by FAP. In the first time period the ileo-anal anastomosis was sutured by hand (29 cases) and since 2000 the PPH stapler was applied as a routine (88 patients). Deviating ileostomy was performed in most cases of us. The data of the 117 patients were collected from the database of our hospital, 45 of them were interviewed personally and another 31 patients were contacted by phone, so 76 patients (65%) were eligible for follow-up. Frequency of stool, use of loperamid, level of incontinence (Wexner score) and perianal dermatitis were detected. The mean follow-up time was 18.6 years in the hand-sewn anastomosis group and 7.6 years in the PPH group. RESULTS: In the hand-sewn anastomosis group in 4/29 cases (13.8%) the removal of the pouch with definite ileostomy were necessary (2 pouchitis, 1 pouch necrosis, 1 recidiv rectum cancer); the mean stool frequency was 4.3 per day; the Wexner incontinence score was 8.5 and 2/15 patients (13.3%) live with ileostomy caused by incontinence. In the PPH stapled ileo-anal anastomosis group in 4/88 cases (4.5%) were the pouch removed (caused by pouchitis), the mean stool frequency was 4.0 per day; the Wexner score was 7.6 and 4/61 patients (6.6%) live with ileostomy caused by incontinence. CONCLUSIONS: Based on our experience the ileo-anal anastomosis performed by PPH stapler is technically feasible, seems to be effective concerning on the complete removal of the rectal mucosa and we observed better functional results compared with the hand-sewn anastomosis. Our data should be confirmed because of the low patients' volume. PMID- 27991019 TI - ? PMID- 27991018 TI - [Our experiences with the use of 3-dimensional meshes to prevent and to repair parastomal hernias]. AB - INTRODUCTION: Albeit there is decreasing tendency nowadays for stoma construction, if it still happens, parastomal herniation might occur in up to 50% of cases afterwards. One third of the cases requires surgical correction, not rarely as an emergency. The different methods of repair can be quite demanding and the complication rates are high. From 2003 we have started to use specially designed 3-dimensional meshes for the prevention and repair of parastomal hernias. METHODS: From 1st of January 2012 to 1st of June 2016 we have used these devices within the framework of a prospective, controlled, randomized study enrolling the patients in preventive and repair arms. Until now mesh was implanted for prevention at the time of the index operation in 38 cases, (control group: 46 cases), and for repair in 14 cases (control group: 18 cases). Recruitment of the patients will end in 2017. The operations were performed by laparoscopic approach in 22 cases and by open approach in 62 cases in the preventive arm, and 6/26 cases in the repair arm respectively. Mean follow up period is 19.2 months in the mesh group and 22.6 months in the non mesh group in the preventive arm, and 25.9/20.4 months in the repair arm respectively. RESULTS: No statistical analysis was used to interpret these interim results in this paper, we intend to analyze our results at the end of the study. At this stage apparently there is no difference between the group of patients in terms of complications in both arms. Parastomal herniation was found in 18 cases (39.1%) in the non mesh group and in 3 cases (7.8%) in the mesh group in the preventive arm. Recurrency was noted in 8 cases (44%) in the non mesh group, and in 1 case (7.1%) in the mesh group in the repair arm. CONCLUSIONS: Our results correlate with other studies where mesh insertion was used to prevent and/or repair parastomal hernias. We attribute these results mainly to the special, 3 dimensional design of the meshes used by us. This construction was developed based on understanding the patomechanism of parastomal hernia formation. PMID- 27991020 TI - [Examination of liver mitochondria with respirometry]. AB - Due to their diverse physiological functions, mitochondria can cause various acute and chronic liver diseases, thus being potential targets for therapies and diagnostics as well. In this study, the advantages of high-resolution respirometry are presented for the assessment of liver mitochondrial functions. During respitometry, the mitochondrial electron transport, the oxydative phosphorilation and the efficacy of the ADP synthesis can be calculated on the basis of oxygen consumption of freshly-taken tissue samples. Respirometry is a robust tool for the pre- or intraoperative analysis of liver mitochondrial functions and may increase the effectiveness of surgical interventions. PMID- 27991022 TI - [Minimal invasive esophageal resection with anastomosis on the neck [McKeown]. Our experiences after 20 cases]. AB - OBJECTIVE: Esophageal resection is a traumatic intervention usually performed on patients with poor condition, resulting high mortality and morbidity. To improve the high incidence of complications, minimal invasive interventions were introduced. The results of the thoracoscopically and laparoscopically performed esophageal resection (McKeown) was investigated after 20 cases and the technical details of the surgical intervention are presented. PATIENTS AND METHOD: 20 thoracoscopic esophageal resection with laparoscopic gastric tube formation (sec. Akiyama) preparing the esophago-gastric anastomosis on the neck were performed in our department in the last four years. 1 patient with stricture and the other 19 patients with esophageal cancer were operated on, among them11 had T4 stage. 17 patient received neoadjuvant chemo-radiotherapy because of advanced disease. Regular follow up examinations were performed in the oncological outpatient department. RESULTS: 8 patients are alive after a mean follow up period of 25 months, 2 of them are treated oncologically because of recurrent disease. 19 patients were extubated within 12 hours after the intervention and the time spent in the intensive care unit were reduced to 1 or 2 days. The mean duration of the intervention was 320 minutes. Thoracoscopic dissection was performed in 8 patients without ventilation of the right lung using double lumen tracheal tube, among them 3 patients developed pneumonia in the postoperative period. The remaining 12 patients were operated with ventilated right lung, among them one patient developed pneumonia. One patient was converted because of injury of the thoracic aorta, after urgent thoracotomy we managed to suture the aortic wall. 1 patient died in 30 days after the operation, caused by leakage of the anastomosis, resulting mediastinitis and esophago-tracheal fistula. In two patients re-thoracoscopy and ligation of the thoracic duct was performed because of chylothorax refractory for conservative treatment. CONCLUSIONS: According to our observation the minimal invasive esophageal resection resulted in comparable oncological results with relevant reduction of mortality and morbidity compared to the open procedure. After procedures performed with ventilated lung further reduction of pulmonary complication was found. In case of tumors infiltrating the tracheal or the aortic wall, thoracotomy should be considered to explore the thoracic cavity and to carry out the dissection, if it is possible. Our results should be reinforced because of low number of patients. PMID- 27991021 TI - [Our metabolic surgical activity, 2010-2016]. AB - INTRODUCTION: The prevalence of morbid obesity and its co-morbidities - first of all diabetes type 2 - increased dramatically in the last decades. As the conservative ways of treatment (diet, training, etc.) in most cases does not lead to effective and long term weight loss, there is an increasing need for the metabolic surgical interventions. METHOD: During the last 6 and half years 514 laparoscopic RouxY gastric bypass (LRYGB) and 54 laparoscopic gastric sleeve resection (LGSR) were performed in our department. The data of random selected 40 patients after primary LRYGB and 15 patients after sleeve resection were collected. The applied criteria of the indication for surgery, the routine examinations and treatments before and after the intervention, the results and the type and the rate of the complications will be presented. RESULTS: According to our experience both procedures are long term effective for weight loss and for the resolution of co-morbidities, and can be performed with low risk of complications. After LRYGB more effective weight loss (extra weight loss 88% vs. 68%) and higher rate of resolution of diabetes type 2, hypertension and gastro esophageal reflux were found compared to sleeve resection. CONCLUSION: Based on our results we prefer LRYGB. Gastric sleeve resection is indicated by us, when there is no way - or only with high risk - to perform gastric bypass, taking into consideration of course the individual requirements of the patients. PMID- 27991023 TI - [Heart transplantation and long-term lvad support cost-effectiveness model]. AB - Heart transplantation is a high priority project at Semmelweis University. In accordance with this, the funding of heart transplantation and mechanical circulatory support also constitutes an important issue. In this report, the authors discuss the creation of a framework with the purpose of comparing the cost-effectiveness of heart transplantation and artificial heart implantation. Our created framework includes the calculation of cost, using the direct allocation method, calculating the incremental cost-effectiveness ratio and creating a cost-effectiveness plane. Using our model, it is possible to compare the initial, perioperative and postoperative expenses of both the transplanted and the artificial heart groups. Our framework can possibly be used for the purposes of long term follow-up and with the inclusion of a sufficient number of patients, the creation of cost-effectiveness analyses and supporting strategic decision-making. PMID- 27991024 TI - [Cooperation between the plastic surgery and the head & neck surgery departments in the treatment of unusual cases, Veszprem, Hungary, 2010-2015]. AB - INTRODUCTION: Handling problems in the head and neck region often requires a close cooperation between allied professions, just as in the challenging cases presented by us. Cases and methodology: With the first patient, we performed a radical surgery on the left side of the face due to recidivious basal cell carcinoma, followed by reconstruction using a Type I chimeric anterolateral thigh flap (ALT), while in the case of the second patient, we carried out a radical surgery on the right side of the face due to epithelial carcinoma and reconstruction with a Type I chimeric thoracodorsal flap. With our third patient, a reconstructive operation was performed due to left-sided congenital hemifacial microsomia, using a profunda artery perforator (PAP) flap. The fourth patient, due to the loss of the right hemi mandible as a result of an injury, went through a reconstructive procedure designed with Computer-Aided Design and Computer-Aided Manufacturing (CAD-CAM) technology, using a fibula free flap. RESULTS: All chosen reconstructive methods proved to be efficient and safe solutions in handling the problems. CONCLUSION: Through the cases presented, we intend to raise awareness of the importance of cooperation between maxillofacial and plastic surgery as well as of the ever-growing range of reconstructive opportunities through the flaps used. PMID- 27991025 TI - ? PMID- 27991026 TI - ? PMID- 27991027 TI - [News of the Society]. PMID- 27991028 TI - ? PMID- 27991029 TI - The Electrophysiological Signature of Remember-Know Is Confounded with Memory Strength and Cannot Be Interpreted as Evidence for Dual-process Theory of Recognition. AB - The quantity and nature of the processes underlying recognition memory remains an open question. A majority of behavioral, neuropsychological, and brain studies have suggested that recognition memory is supported by two dissociable processes: recollection and familiarity. It has been conversely argued, however, that recollection and familiarity map onto a single continuum of mnemonic strength and hence that recognition memory is mediated by a single process. Previous electrophysiological studies found marked dissociations between recollection and familiarity, which have been widely held as corroborating the dual-process account. However, it remains unknown whether a strength interpretation can likewise apply for these findings. Here we describe an ERP study, using a modified remember-know (RK) procedure, which allowed us to control for mnemonic strength. We find that ERPs of high and low mnemonic strength mimicked the electrophysiological distinction between R and K responses, in a lateral positive component (LPC), 500-1000 msec poststimulus onset. Critically, when contrasting strength with RK experience, by comparing weak R to strong K responses, the electrophysiological signal mapped onto strength, not onto subjective RK experience. Invoking the LPC as support for dual-process accounts may, therefore, be amiss. PMID- 27991030 TI - Network Connectivity of the Right STS in Three Social Perception Localizers. AB - The posterior STS (pSTS) is an important brain region for perceptual analysis of social cognitive cues. This study seeks to characterize the pattern of network connectivity emerging from the pSTS in three core social perception localizers: biological motion perception, gaze recognition, and the interpretation of moving geometric shapes as animate. We identified brain regions associated with all three of these localizers and computed the functional connectivity pattern between them and the pSTS using a partial correlations metric that characterizes network connectivity. We find a core pattern of cortical connectivity that supports the hypothesis that the pSTS serves as a hub of the social brain network. The right pSTS was the most highly connected of the brain regions measured, with many long-range connections to pFC. Unlike other highly connected regions, connectivity to the pSTS was distinctly lateralized. We conclude that the functional importance of right pSTS is revealed when considering its role in the large-scale network of brain regions involved in various aspects of social cognition. PMID- 27991181 TI - The Pivotal Role of the Right Parietal Lobe in Temporal Attention. AB - The visual system is extremely efficient at detecting events across time even at very fast presentation rates; however, discriminating the identity of those events is much slower and requires attention over time, a mechanism with a much coarser resolution [Cavanagh, P., Battelli, L., & Holcombe, A. O. Dynamic attention. In A. C. Nobre & S. Kastner (Eds.), The Oxford handbook of attention (pp. 652-675). Oxford: Oxford University Press, 2013]. Patients affected by right parietal lesion, including the TPJ, are severely impaired in discriminating events across time in both visual fields [Battelli, L., Cavanagh, P., & Thornton, I. M. Perception of biological motion in parietal patients. Neuropsychologia, 41, 1808-1816, 2003]. One way to test this ability is to use a simultaneity judgment task, whereby participants are asked to indicate whether two events occurred simultaneously or not. We psychophysically varied the frequency rate of four flickering disks, and on most of the trials, one disk (either in the left or right visual field) was flickering out-of-phase relative to the others. We asked participants to report whether two left-or-right-presented disks were simultaneous or not. We tested a total of 23 right and left parietal lesion patients in Experiment 1, and only right parietal patients showed impairment in both visual fields while their low-level visual functions were normal. Importantly, to causally link the right TPJ to the relative timing processing, we ran a TMS experiment on healthy participants. Participants underwent three stimulation sessions and performed the same simultaneity judgment task before and after 20 min of low-frequency inhibitory TMS over right TPJ, left TPJ, or early visual area as a control. rTMS over the right TPJ caused a bilateral impairment in the simultaneity judgment task, whereas rTMS over left TPJ or over early visual area did not affect performance. Altogether, our results directly link the right TPJ to the processing of relative time. PMID- 27991183 TI - The Ventromedial Frontal Lobe Contributes to Forming Effective Solutions to Real world Problems. AB - Although the ventromedial frontal lobe (VMF) has been implicated in several complex cognitive tasks such as decision-making and problem solving, the processes for which this region is critical remain unclear. Laboratory studies have largely focused on how the VMF contributes to decision-making when outcomes or options are provided, but in the real world generating appropriate options is likely a crucial and rate-limiting initial step. Here, we determined how VMF damage affected the option generation phase of naturalistic problem solving. A group of patients with VMF damage and two controls groups-age-matched healthy participants and patients with frontal damage sparing VMF-were asked to generate as many options as possible to five scenarios depicting open-ended, real-world problems (e.g., having lunch at a restaurant and forgetting your wallet at home). Both the number of options and the effectiveness of each option generated were examined. Damage to VMF led to a significant reduction in both the number of options produced across all problem-solving scenarios and the ability to generate effective options, most notably for scenarios that were social in nature. We discuss these findings in terms of the mechanisms by which the VMF may contribute to option generation, focusing on proposals suggesting this region is important for integrating subjective value and retrieving schematic representations. PMID- 27991184 TI - Parahippocampal and Entorhinal Resection Extent Predicts Verbal Memory Decline in an Epilepsy Surgery Cohort. AB - The differential contribution of medial-temporal lobe regions to verbal declarative memory is debated within the neuroscience, neuropsychology, and cognitive psychology communities. We evaluate whether the extent of surgical resection within medial-temporal regions predicts longitudinal verbal learning and memory outcomes. This single-center retrospective observational study involved patients with refractory temporal lobe epilepsy undergoing unilateral anterior temporal lobe resection from 2007 to 2015. Thirty-two participants with Engel Class 1 and 2 outcomes were included (14 left, 18 right) and followed for a mean of 2.3 years after surgery (+/-1.5 years). Participants had baseline and postsurgical neuropsychological testing and high-resolution T1-weighted MRI scans. Postsurgical lesions were manually traced and coregistered to presurgical scans to precisely quantify resection extent of medial-temporal regions. Verbal learning and memory change scores were regressed on hippocampal, entorhinal, and parahippocampal resection volume after accounting for baseline performance. Overall, there were no significant differences in learning and memory change between patients who received left and right anterior temporal lobe resection. After controlling for baseline performance, the extent of left parahippocampal resection accounted for 27% (p = .021) of the variance in verbal short delay free recall. The extent of left entorhinal resection accounted for 37% (p = .004) of the variance in verbal short delay free recall. Our findings highlight the critical role that the left parahippocampal and entorhinal regions play in recall for verbal material. PMID- 27991185 TI - Neural Correlates of the False Consensus Effect: Evidence for Motivated Projection and Regulatory Restraint. AB - The false consensus effect (FCE), the tendency to project our attitudes and opinions on to others, is a pervasive bias in social reasoning with a range of ramifications for individuals and society. Research in social psychology has suggested that numerous factors (anchoring and adjustment, accessibility, motivated projection, etc.) may contribute to the FCE. In this study, we examine the neural correlates of the FCE and provide evidence that motivated projection plays a significant role. Activity in reward regions (ventromedial pFC and bilateral nucleus accumbens) during consensus estimation was positively associated with bias, whereas activity in right ventrolateral pFC (implicated in emotion regulation) was inversely associated with bias. Activity in reward and regulatory regions accounted for half of the total variation in consensus bias across participants (R2 = .503). This research complements models of the FCE in social psychology, providing a glimpse into the neural mechanisms underlying this important phenomenon. PMID- 27991182 TI - Salience Network Connectivity Modulates Skin Conductance Responses in Predicting Arousal Experience. AB - Individual differences in arousal experience have been linked to differences in resting-state salience network connectivity strength. In this study, we investigated how adding task-related skin conductance responses (SCR), a measure of sympathetic autonomic nervous system activity, can predict additional variance in arousal experience. Thirty-nine young adults rated their subjective experience of arousal to emotionally evocative images while SCRs were measured. They also underwent a separate resting-state fMRI scan. Greater SCR reactivity (an increased number of task-related SCRs) to emotional images and stronger intrinsic salience network connectivity independently predicted more intense experiences of arousal. Salience network connectivity further moderated the effect of SCR reactivity: In individuals with weak salience network connectivity, SCR reactivity more significantly predicted arousal experience, whereas in those with strong salience network connectivity, SCR reactivity played little role in predicting arousal experience. This interaction illustrates the degeneracy in neural mechanisms driving individual differences in arousal experience and highlights the intricate interplay between connectivity in central visceromotor neural circuitry and peripherally expressed autonomic responses in shaping arousal experience. PMID- 27991186 TI - Timing in Predictive Coding: The Roles of Task Relevance and Global Probability. AB - Predictive coding models of attention propose that attention and prediction operate synergistically to optimize perception, as reflected in interactive effects on early sensory neural responses. It is yet unclear whether attention and prediction based on the temporal attributes of expected events operate in a similar fashion. We investigated how attention and prediction based on timing interact by manipulating the task relevance and a priori probability of auditory stimulus onset timing within a go/no-go task while recording EEG. Preparatory activity, as indexed via the contingent negative variation, reflected temporally specific anticipation as a function of both attention and prediction. Higher stimulus probability led to significant predictive N1 suppression; however, we failed to find an effect of task relevance on N1 amplitude and an interaction of task relevance with prediction. We suggest the predictability of sensory timing is the predominant influence on early sensory responses where a priori probabilities allow for strong prior beliefs. When this is the case, we find that the effects of temporal prediction on early sensory responses are independent of the task relevance of sensory stimuli. Our findings contribute to the expansion of predictive coding frameworks to include the role of timing in sensory processing. PMID- 27991399 TI - Editorial: High Performance Computing in Drug Discovery. PMID- 27991400 TI - Isolation of Chemical Constituents of Centaurea virgata Lam. and Xanthine Oxidase Inhibitory Activity of the Plant Extract and Compounds. AB - BACKGROUND: Centaurea virgata Lam. is a species widely used in the traditional medicine in Turkey for the treatment of diabetes, allergy and gastric ulcers. The rationale of its use in the therapy has not been studied previously, therefore the present work aimed at the chemicalpharmacological evaluation of the plant. OBJECTIVE: The xanthine oxidase (XO) inhibitory activity of the MeOH extract and its subextracts (n-hexane, CHCl3 and remaining MeOH-H2O) prepared from C. virgata was investigated in vitro. Moderate activity was exerted in case of the CHCl3 extract (98.9 +/- 15.8 MUg/mL), therefore constituents of this extract were analysed. METHOD: Different purification steps, such as VLC, CPC, PLC and crystallization were used for the isolation, and ESIMS, NMR, LC-MS and authentic standards were applied for identification of the compounds. XO inhibitory and DPPH assays were used for evaluation of the bioactivities. RESULTS: Sesquiterpenes [8alpha-hydroxysonchucarpolide, 8alpha-(3,4-dihydroxy-2 methylenebutanoyloxy)- dehydromelitensine, and cnicin], flavones (apigenin, hispidulin, salvigenin, eupatorin, 3'-methyleupatorin), and the flavonol isokaempferide were isolated from the active extract. The XO-inhibitory activity of these compounds was analyzed using allopurinol as a positive control (IC50 7.49 +/- 0.29 MUM). It was found that sesquiterpenes and flavonoids, containing 7 OMe group, are inactive. CONCLUSION: 7-Hydroxyflavones (apigenin and hispidulin) exerted significant XO inhibitory effect with IC50 values of 0.99 +/- 0.33 MUM and 4.88 +/- 1.21 MUM, respectively. Therefore, these compounds are responsible for the XO-inhibitory effect of the extract. The free radical scavenging activity of the isolated flavonoids was determined by DPPH assay, and it was stated that none of the compounds have substantial antioxidant activity, therefore the reduced generation of reactive oxygen species may be the consequence only of XO inhibition. PMID- 27991401 TI - Editorial (Thematic Issue: Common Receptor Signalling in Glial & Immune Cells). PMID- 27991402 TI - Editorial (Thematic Issue: New Approaches in Stem Cell Technology and Innovative Biomaterials for Tissue Engineering and Regenerative Medicine). PMID- 27991403 TI - Editorial: Future Directions for Stem Cell Banking and Therapy. PMID- 27991404 TI - Editorial (Thematic Issue: The Predictive Pathology in the Target Therapy Era). PMID- 27991405 TI - Assessment of multiple factors is necessary when evaluating the success rate of myringoplasty. PMID- 27991406 TI - Oropharyngeal carcinoma, incidental findings on magnetic resonance imaging scans for audiovestibular symptoms, penetrating neck trauma and myringoplasty. PMID- 27991407 TI - Palliative care is treatment for Muslims who wish to be faithful. PMID- 27991408 TI - Do dermatomyositis and polymyositis affect similar thigh muscles? A comparative MRI-based study. AB - OBJECTIVES: Dermatomyositis (DM) and polymyositis (PM) commonly cause weakness of the thigh muscles. However, it is debated whether DM and PM affect similar thigh muscles. Muscle oedema on fat-suppressed MRI sequences is thought to represent active inflammation. In this study, we aimed to assess which thigh muscle groups are preferentially inflamed in DM and PM, respectively, using short-tau inversion recovery MRI sequences. METHODS: We analysed 71 patients from 2 Rheumatology centres, 31 with DM and 40 with PM diagnosed according to the Bohan and Peter criteria. MRI oedema (1=present, 0=absent) was assessed bilaterally on fat suppressed sequences in 17 pelvic floor and thigh muscles. An MRI oedema score (range 0-17) was calculated by adding the separate scores bilaterally and dividing them by two. Inter-rater variability was assessed by intraclass correlation coefficient. Fisher's exact test was used to compare binomial data. RESULTS: Age and gender ratio were similar in patients with DM and PM. Disease duration (months, mean+/-SD) was shorter (20+/-31) in DM than in PM (53+/-69) (p=0.02). The intraclass correlation coefficient between the radiologists involved was 0.78. Muscle oedema was more common in DM than in PM except in the posterior thigh muscles. In particular, 68% of patients with DM had involvement of at least one anterior thigh muscle versus 38% of patients with PM (p=0.02). CONCLUSIONS: Compared with PM, DM affects more thigh muscles, except those of the posterior compartment, which are equally involved in both disorders. These findings may be useful to target physiotherapy at the more frequently affected muscles. PMID- 27991409 TI - Can we currently and confidently assess the true burden of illness due to non radiographic axial spondyloarthritis? PMID- 27991410 TI - Reply to the editorial: Can we currently and confidently assess the true burden of illness due to non-radiographic axial spondyloarthritis? by S. van der Linden and M.A. Khan. PMID- 27991411 TI - One year in review 2016: idiopathic inflammatory myopathies. AB - Idiopathic inflammatory myopathies (IIM) are a group of rare, acquired, clinically heterogeneous autoimmune inflammatory muscle disorders characterised by muscle weakness and multisystem involvement. Recently, new concepts about pathogenesis, diagnosis and treatment of these complex diseases have been provided. The purpose of this manuscript is to summarise the most relevant literature contributions published over the last year. PMID- 27991412 TI - Erratum Corrige. PMID- 27991413 TI - Erratum Corrige. PMID- 27991414 TI - A description of Echinorhynchus baeri Kostylew, 1928 (Acanthocephala: Echinorhynchidae) from Salmo trutta in Turkey, with notes on synonymy, geographical origins, geological history, molecular profile, and X-ray microanalysis. AB - A population of Echinorhynchus baeri Kostylew, 1928 with 18-24 rows of 8-10 proboscis hooks each and long fusiform eggs measuring 95-110 * 18-22 MUm collected from Salmo trutta (Salmonidae) in a branch of the Murat River in Turkey is described and specimens are designated as neotype. Specimens of two similar populations of E. baeri (E. baeri Kostylew, 1928 and E. sevani Dinnik, 1932) were previously described from Salmo ischchan in Lake Sevan, Armenia. Waters of Lake Sevan and the Murat River were previously joined during the Middle Miocene Pliocene. The two populations from Lake Sevan and ours from Turkey had identical morphology and size eggs. The proboscis armature and eggs, among other features of our Turkish specimens, proved intermediate between E. baeri and E. sevani, thus eliminating the significance of the described differences between these two species and confirming their synonymy with priority to Echinorhynchus baeri (junior synonym: Echinorhynchus sevani Dinnik, 1932). Echinorhynchus baeri is apparently a highly variable species. The two descriptions from Lake Sevan did not include features or illustrations of females, except for references to trunk and egg size but the eggs were illustrated. Complete morphometric comparisons are made and females of the Turkish material are described for the first time. DNA sequencing (mitochondrial cytochrome oxidase subunit I gene; nuclear 18S rRNA gene) results from two available E. baeri individuals were equivocal. New features to the Acanthocephala include the presence of rootless uncalcified apical proboscis hooks studied with X-ray microanalysis. PMID- 27991415 TI - Assessment of the efficacy of a topical combination of fipronil-permethrin (Frontline Tri-Act(r)/Frontect(r)) against egg laying and adult emergence of the cat flea (Ctenocephalides felis) in dogs. AB - This study was conducted to assess the prevention of egg laying and the inhibition of the emergence of the cat flea (Ctenocephalides felis) resulting from the application of a combination of fipronil and permethrin (Frontline Tri Act(r)/Frontect(r), Merial) on dogs. Sixteen healthy dogs were included after pre treatment live flea counts and randomly allocated to two groups. Eight dogs served as untreated controls and 8 dogs were treated on Day 0 and Day 30 with topical application of fipronil/permethrin at the minimum dose of 6.76 mg/kg fipronil and 50.48 mg/kg permethrin. On days -2, 7, 21, 28, 42 and 56, each dog was infested with 100 fleas. Flea eggs were collected from each dog in individual trays from 12 to 36 h after treatment or each flea re-infestation. All fleas were removed by combing and counted 36 h after treatment or infestations. The collected eggs were counted and incubated for 28 days for larval development and adult emergence assessment. The curative efficacy of Frontline Tri Act(r)/Frontect(r) against adult fleas 36 h after treatment was 95.3% and the efficacy remained 100% after subsequent flea infestations for 8 weeks. Compared to the control group, the treatment reduced egg laying by 84.5% within 36 h after first treatment and was 99.9%, 100%, 100%, 100%, 100% on collection days 7, 21, 29, 43 and 57, respectively. Frontline Tri-Act(r)/Frontect(r) reduced by 28.7% the emergence of new adult fleas from eggs laid during the 48 h of pre-treatment infestation. The inhibition of adult emergence from incubated flea eggs could not be assessed after flea re-infestation in the treated group as no eggs were collected. PMID- 27991416 TI - Small-Cell Carcinoma of the Bladder: 20-Year Single-Institution Retrospective Review. AB - INTRODUCTION: Small-cell carcinoma of the bladder is a poorly differentiated neoplasm with aggressive behavior. We analyzed clinical outcomes of patients who were treated at our institution to identify an optimal treatment strategy. MATERIALS AND METHODS: Retrospective chart analysis was performed for patients who were treated for small-cell carcinoma of the bladder at Fox Chase Cancer Center between 1995 and 2015. Survival was compared between different treatment periods (before January 2010 vs. after January 2010) and different treatment modalities (surgery vs. neoadjuvant chemotherapy vs. radiation). RESULTS: Thirty eight patients were treated for small-cell carcinoma of the bladder at our institution during the 20-year study period. Median survival was 11.8 months and overall survival rates after 1, 3, and 5 years were 46.6%, 26.2%, and 14%, respectively. Survival analysis adjusted for age, histology, and stage showed that no single treatment strategy was significantly superior (95% confidence interval [CI], 0.26-3.03; P = .860 for surgery; 95% CI, 0.31-2.87; P = .928 for neoadjuvant chemotherapy; 95% CI, 0.65-5.49; P = .238 for radiation). In separate analyses of long-term survivors, we found that most received platinum-based neoadjuvant chemotherapy followed by radical cystectomy. Among the 20 patients who received neoadjuvant chemotherapy, downstaging occurred in 9 (45%). CONCLUSION: Although none of the treatment options were found to be significantly superior with respect to survival, neoadjuvant chemotherapy might halt the progression of the disease until cystectomy and lead to downstaging. At our institution, the best outcomes were observed in patients who received neoadjuvant platinum-based chemotherapy combined with radical cystectomy. PMID- 27991417 TI - The Economic Burden of Chronic Psychotic Disorders in Ontario. AB - BACKGROUND: Chronic psychotic disorders are severe and disabling mental disorders associated with poor psychiatric and medical outcomes. These disorders are considered one of the most costly mental disorders due young age at onset and the need for intensive health care over the life course. AIMS OF THE STUDY: The purpose of this study was to estimate the direct health care costs of chronic psychotic disorders in Ontario in 2012 from the perspective of the third-party payer (i.e., the ministry of health), using a prevalence-based cost-of-illness approach. METHODS: We selected all patients eligible for public health insurance over the age of 15 with a diagnosis of chronic psychotic disorder, using a validated algorithm. Using linked administrative health care databases, we estimated net costs associated with chronic psychotic disorders (i.e., the difference in cost for patients with psychosis and control subjects), using a case-control design. Mean net prevalence costs were estimated for the full sample and disaggregated by sex, age group (16-24; 25-44; 45-64; 65 and over) and health service. RESULTS: In 2012, there were 142,821 patients with a chronic psychotic disorder in Ontario. They had a mean age of 49, were made up of slightly more males (53%) and were mostly from low-income, urban neighbourhoods. Roughly 17% of patients had a psychiatric hospitalization, with an average of 2 hospitalizations and average length of stay of 49 days. The total direct cost of patients with chronic psychotic disorders to the ministry of health was just under 2.1 billion CAD. Total net costs were around 1.5 billion CAD. The main cost drivers were psychiatric hospitalizations (48%), followed by long-term care (14%). Mean net costs were slightly higher for females than males (CAD 10,653 vs. CAD 10,647, respectively). Mean net costs were highest for patients 65 and over, and lowest for patients 25-44 (CAD 15,230 vs. CAD 8,585, respectively). The main cost drivers also varied with age. For younger patients, three-quarters of the net cost were due to psychiatric hospitalizations (74%), while for older patients net costs were mainly due long-term care (38%), followed by psychiatric (24%) and non psychiatric (14%) hospitalizations. DISCUSSION AND LIMITATIONS: The direct net costs of treating patients with chronic psychotic disorders are substantial and represent a sizeable portion of the Ontario health care budget (3%). Previous research has found similar findings in other jurisdictions. These estimates do not account for costs of addiction services. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Our results suggest there are important utilization/cost differences between age groups. As patients with chronic psychotic disorders become older chronic disease and disability become more prominent, as reflected in higher costs with long-term care and non-psychiatric hospitalizations. IMPLICATIONS FOR HEALTH POLICIES: These findings highlight the need for health care systems to address both physical and mental illness simultaneously, especially for older patients with chronic psychotic disorders. IMPLICATIONS FOR FURTHER RESEARCH: Future research should focus on the predictors of care over the life course of patients with chronic psychotic disorders. In addition, further work should examine how the interplay between mental and physical health contribute to increased costs among patients with psychosis. PMID- 27991418 TI - Medical Resource Utilization by Taiwanese Psychiatric Inpatients under the National Health Insurance System. AB - BACKGROUND: The length of stay in Taiwan's psychiatric facilities is unusually long compared with that of other countries. AIMS OF THE STUDY: To identify factors associated with the high length of stay in the acute and chronic psychiatric wards of a public psychiatric hospital. METHODS: The present study consisted of 912 inpatients discharged from a public psychiatric hospital in Northern Taiwan in 2005. Demographic characteristics, discharge diagnoses, and medical resource utilization were retrieved from the inpatient claim data of the National Health Insurance Database. Multivariate logistic regression models were performed to identify significant predictors for a long length of stay (LOS). Covariate adjusted odds ratios and a 95% confidence interval (CI) were applied to explore the effects of financial barriers, demographic, and diagnostic characteristics, and readmission for medical care. RESULTS: A median LOS of 35.0 days and median medical charge of USD 3,271.50 were reported. A greater likelihood of a high degree of medical care was found among patients who were exempt from copayments, were diagnosed with schizophrenia, had a co-morbidity factor, and were admitted from emergency visits. The results showed that patients in the 45--60 year age group had a higher risk of long LOS than those in the 18- 30 year age group. DISCUSSION AND LIMITATIONS: A longer LOS in Taiwan might reflect more free access to hospitals and further extensive utilization of medical facilities under the National Health Insurance system. It was noted that age, sex, disease characteristics, and insurance policies were associated with a high medical utilization. However, the lack of a copayment may partially explain the long LOS in our study. Other causes, such as inadequate supplies of resources for psychiatric services, may also deserve closer study. A failure to adjust for potentially confounding factors might limit interpretation of the observed relationship between such potential factors and medical resource utilization. These findings support the future planning of specific care policies in mental health services in Taiwan. IMPLICATIONS FOR HEALTH POLICIES: While an exemption in copayment aims to remove financial barriers for indigent people, it contributed to the extended LOS. To make psychiatric care more efficient, facilities in the community must be strengthened, patients must be directed to appropriate care to avoid emergency check-ins, and the reimbursement policy must be geared to facilitate the efficient delivery of care. IMPLICATIONS FOR FURTHER RESEARCH: Our study calls for further research on the role of resource allocation, incentives for efficient delivery of care, and the frequency of hospitalization, in particular, on the long LOS of psychiatric patients in Taiwan. PMID- 27991419 TI - Cost-Effectiveness of Four Parenting Programs and Bibliotherapy for Parents of Children with Conduct Problems. AB - BACKGROUND: Parenting programs and self-help parenting interventions employing written materials are effective in reducing child conduct problems (CP) in the short-term compared to control groups, however evidence on the cost-effectiveness of such interventions is insufficient. Few studies have looked at the differences in effects between interventions in the same study design. AIM: This study aimed to determine the cost-effectiveness of four parenting programs: Comet, Incredible Years (IY), Cope and Connect, and bibliotherapy, compared to a waitlist control (WC), with a time horizon of 4 months, targeting CP in children aged 3-12 years. METHODS: This economic evaluation was conducted alongside an RCT of the four parenting interventions and bibliotherapy compared to a WC. The study sample consisted of 961 parents of 3-12 year-old children with CP. CP was measured by the Eyberg Child Behavior Inventory. Effectiveness was expressed as the proportion of "recovered" cases of CP. The time horizon of the study was four months with a limited health sector perspective, including parents' time costs. We performed an initial comparative cost analysis for interventions whose outcomes differed significantly from the WC, and later a cost-effectiveness analysis of interventions whose outcomes differed significantly from both the WC and each other. Secondary analyses were performed: (i) joint outcome "recovered and improved", (ii) intervention completers, (iii) exclusion of parents' time costs, (iv) exclusion of training costs. RESULTS: All interventions apart from Connect significantly reduced CP compared to the WC. Of the other interventions Comet resulted in a significantly higher proportion of recovered cases compared to bibliotherapy. A comparative cost analysis of the effective interventions rendered an average cost per recovered case for bibliotherapy of USD 483, Cope USD 1972, Comet USD 3741, and IY USD 6668. Furthermore, Comet had an ICER of USD 8375 compared to bibliotherapy. Secondary analyses of "recovered and improved" and of intervention completers held Cope as the cheapest alternative. Exclusion of parents' time and training costs did not change the cost-effectiveness results. DISCUSSION: The time horizon for this evaluation is very short. This study also had a limited costing perspective. Results may be interpreted with caution when considering decision-making about value for money. The inclusion of a multi-attribute utility instrument sensitive to domains of quality-of-life impacted by CP in children would be valuable so that pragmatic value for money estimations can be made. IMPLICATIONS FOR FUTURE RESEARCH: Further studies are needed with longer follow-up periods to ascertain on the sustainability of the effects, and fuller economic evaluations and economic modeling to provide insights on longer-term cost-effectiveness. These results also raise the need to investigate the cost-effectiveness of the provision of these interventions as a "stepped care" approach. CONCLUSIONS: The results suggest the delivery of different programs according to budget constraints and the outcome desired. In the absence of a WTP threshold, bibliotherapy could be a cheap and effective option to initially target CP within a limited budget, whereas Comet could be offered to achieve greater effects based on decision-makers' willingness to make larger investments. In its turn, Cope could be offered when targeting broader outcomes, such as symptom improvement, rather than clinical caseness. PMID- 27991420 TI - Accurate radiation temperature and chemical potential from quantitative photoluminescence analysis of hot carrier populations. AB - In order to characterize hot carrier populations in semiconductors, photoluminescence measurement is a convenient tool, enabling us to probe the carrier thermodynamical properties in a contactless way. However, the analysis of the photoluminescence spectra is based on some assumptions which will be discussed in this work. We especially emphasize the importance of the variation of the material absorptivity that should be considered to access accurate thermodynamical properties of the carriers, especially by varying the excitation power. The proposed method enables us to obtain more accurate results of thermodynamical properties by taking into account a rigorous physical description and finds direct application in investigating hot carrier solar cells, which are an adequate concept for achieving high conversion efficiencies with a relatively simple device architecture. PMID- 27991421 TI - A first-principles model of copper-boron interactions in Si: implications for the light-induced degradation of solar Si. AB - The recent discovery that Cu contamination of Si combined with light exposure has a significant detrimental impact on carrier life-time has drawn much concern within the solar-Si community. The effect, known as the copper-related light induced degradation (Cu-LID) of Si solar cells, has been connected to the release of Cu interstitials within the bulk (2016 Sol. Energy Mater. Sol. Cells 147 115 26). In this paper, we describe a comprehensive analysis of the formation/dissociation process of the CuB pair in Si by means of first-principles modelling, as well as the interaction of CuB defects with photo-excited minority carriers. We confirm that the long-range interaction between the [Formula: see text] cation and the [Formula: see text] anion has a Coulomb-like behaviour, in line with the trapping-limited diffusivity of Cu observed by transient ion drift measurements. On the other hand, the short-range interaction between the d electrons of Cu and the excess of negative charge on [Formula: see text] produces a repulsive effect, thereby decreasing the binding energy of the pair when compared to the ideal point-charge Coulomb model. We also find that metastable CuB pairs produce acceptor states just below the conduction band minimum, which arise from the Cu level emptied by the B acceptor. Based on these results, we argue that photo-generated minority carriers trapped by the metastable pairs can switch off the Coulomb interaction that holds the pairs together, enhancing the release of Cu interstitials, and acting as a catalyst for Cu-LID. PMID- 27991422 TI - Volumetric capnography in the exclusion of pulmonary embolism at the emergency department: a pilot study. AB - The analysis of the [Formula: see text] in expired air as a function of the exhaled volume (volumetric capnography) might result in a more specific exclusion tool for pulmonary embolism (PE) in addition to the Wells-score and D-dimer. A novel combination of volumetric capnography parameters ([Formula: see text]) should be decreased in PE and could possibly be used to decrease the number of requested computed tomography pulmonary angiograms (CTPA). Volumetric capnography measurements were performed on consecutive patients seen in the emergency department for which, due to suspected PE (due to increased D-dimer level or Wells-score), a CTPA was ordered. A total of 30 subjects were included, of which in 13 PE was seen on CTPA. Median [Formula: see text] was 4.36 kPa (IQR 3.92 4.88) in the no PE group versus 4.07 kPa (IQR 3.37-4.39) in the PE group (p = 0.086). Median of the novel parameter [Formula: see text] was 1.85 min.kPa dl-1 (IQR 1.21-3.00) in the no PE group versus 1.18 min.kPa dl-1 (IQR 0.61-1.38) in the PE group (p = 0.006). Using a threshold for the new parameter of 1.90 min.kPa dl-1 or higher to exclude PE resulted in a negative predictive value of 100% (95% CI: 77%-100%) and would have potentially excluded PE in 47% (95% CI: 26%-69%) of the no PE group without the need for CTPA. This pilot study introduces a novel parameter [Formula: see text] which is significantly decreased in PE subjects. Future studies regarding validation and addressing aspects such as reproducibility and normalization after treatment are needed to confirm its usability in excluding PE in the emergency department. PMID- 27991423 TI - Experimental method for the determination of adsorption-induced changes of pressure and surface stress in nanopores. AB - The change of surface stress is an important quantity characterising the behaviour of nanoporous systems, however, it is difficult to assess experimentally. In this letter we develop and demonstrate an experimental method for the determination of adsorption-induced changes of the surface stress in nanoporous materials. With the aid of ultrasonic measurements we determine the dependence of the adsorbate's longitudinal modulus [Formula: see text] on the adsorption-induced normal pressure, [Formula: see text], which is exerted by the adsorbate on the porous matrix. From this dependence we deduce the normal pressure at saturation, [Formula: see text], and thereby changes of the surface stress [Formula: see text] at the interface between the solid matrix and the liquid adsorbate. For the model system of argon in nanoporous glass (pore radius [Formula: see text] nm) the ultrasonic method reveals a value for [Formula: see text] that is in very good agreement with the theoretical value known for the argon-silica interface. The disclosure of this experimental method and its application on other systems will enable a better understanding of the behaviour of adsorbates in nanoporous materials. PMID- 27991424 TI - Porphyrin molecules boost the sensitivity of epitaxial graphene for NH3 detection. AB - The sensitivity of quasi-free standing epitaxial graphene for NH3 detection is strongly enhanced by chemical functionalization with cobalt porphyrins resulting in a detection limit well below 100 ppb. Hybridization between NH3 and cobalt porphyrins induces a charge transfer to graphene and results in a shift of the graphene Fermi-level as detected by Hall measurements and theoretically explained by electronic structure calculations. PMID- 27991425 TI - High-pressure single-crystal synchrotron diffraction study of MnGe and related compounds. AB - Single crystal synchrotron diffraction for pressures up to 50 GPa has revealed an essential difference in structural properties and compressibility of MnGe compared with Mn$_{1-x}$Co$_x$Ge and Mn$_{1-x}$Fe$_x$Ge solid solutions. A negative thermal expansion has been observed for MnGe at low-temperatures and high-pressures. The single crystal refinement has shown a discontinuous change of the atomic coordinates and Mn-Ge interatomic distances of MnGe in contrast to Mn$_{0.1}$Co$_{0.9}$Ge. These peculiarities of MnGe are likely to be associated with high-spin - low-spin transition. The relation between anisotropy of the coordination of Mn-atom and its magnetic moment is discussed. PMID- 27991426 TI - Psychophysical correspondence between vibrotactile intensity and intracortical microstimulation for tactile neuroprostheses in rats. AB - OBJECTIVE: Recent studies showed that intracortical microstimulation (ICMS) generates artificial sensations which can be utilized as somatosensory feedback in cortical neuroprostheses. To mimic the natural psychophysical response, ICMS parameters are modulated according to psychometric equivalence functions (PEFs). PEFs match the intensity levels of ICMS and mechanical stimuli, which elicit equal detection probabilities, but they typically do not include the frequency as a control variable. We aimed to establish frequency-dependent PEFs for vibrotactile stimulation of the glabrous skin and ICMS in the primary somatosensory cortex of awake freely behaving rats. APPROACH: We collected psychometric data for vibrotactile and ICMS detection at three stimulation frequencies (40, 60 and 80 Hz). The psychometric data were fitted with a model equation of two independent variables (stimulus intensity and frequency) and four subject-dependent parameters. For each rat, we constructed a separate PEF which was used to estimate the ICMS current amplitude for a given displacement amplitude and frequency. The ICMS frequency was set equal to the vibrotactile frequency. We validated the PEFs in a modified task which included randomly selected probe trials presented either with a vibrotactile or an ICMS stimulus, and also at frequencies and intensity levels not tested before. MAIN RESULTS: The PEFs were generally successful in estimating the ICMS current intensities (no significant differences between vibrotactile and ICMS trials in Kolmogorov Smirnov tests). Specifically, hit rates from both trial conditions were significantly correlated in 86% of the cases, and 52% of all data had perfect match in linear regression. SIGNIFICANCE: The psychometric correspondence model presented in this study was constructed based on surface functions which define psychophysical detection probability as a function of stimulus intensity and frequency. Therefore, it may be used for the real-time modulation of the frequency and intensity of ICMS pulses in somatosensory neuroprostheses. PMID- 27991427 TI - Hot carrier relaxation in CdTe via phonon-plasmon modes. AB - Carrier and lattice dynamics of laser excited CdTe was studied by time-resolved reflectivity for excitation fluences spanning about three orders of magnitude, from 0.064 to 6.14 mJ cm-2. At fluences below 1 mJ cm-2 the transient reflectivity is dominated by the dynamics of hybrid phonon-plasmon modes. At fluences above 1 mJ cm-2 the time-dependent reflectivity curves show a complex interplay between band-gap renormalization, band filling, carrier dynamics and recombination. A framework that accounts for such complex dynamics is presented and used to model the time-dependent reflectivity data. This model suggests that the excess energy of the laser-excited hot carriers is reduced much more efficiently by emitting hybrid phonon-plasmon modes rather than bare longitudinal optical phonons. PMID- 27991428 TI - Observation of the weak electronic correlations in KFeCoAs2 (3d 6): an isoelectronic to the parent compounds of 122 series of iron pnictides BaFe2As2. AB - Using the angle-resolved photoemission spectroscopy and band structure calculations we study the electronic structure of KFeCoAs2, which is isoelectronic to the parent material of 122 series of iron-based superconductors BaFe2As2. Although band structure calculations predict nearly identical dispersions of the electronic states in both compounds, experiment reveals drastic differences in both the global renormalization and Fermi surfaces. On the basis of the comparison of electronic structures of these two isoelectronic compounds, we demonstrate local magnetic correlations as a vital role for the peculiar low-energy electron dynamics of iron-based superconductors. PMID- 27991429 TI - Phonon spectral functions of photo-generated hot carrier plasmas: effects of carrier screening and plasmon-phonon coupling. AB - We investigate spectral behavior of phonon spectral functions in an interacting multi-component hot carrier plasma. Spectral analysis of various phonon spectral functions is performed considering carrier-phonon channels of polar and nonpolar optical phonons, acoustic deformation-potential, and piezoelectric Coulomb couplings. Effects of phonon self-energy corrections are examined at finite temperature within a random phase approximation extended to include the effects of dynamic screening, plasmon-phonon coupling, and local-field corrections of the plasma species. We provide numerical data for the case of a photo-generated electron-hole plasma formed in a wurtzite GaN. Our result shows the clear significance of the multiplicity of the plasma species in the phonon spectral functions of a multi-component plasma giving rise to a variety of spectral behaviors of carrier-phonon coupled collective modes. A useful sum rule on the plasma-species-resolved dielectric functions is also found. PMID- 27991430 TI - Bacteria in the airways of patients with cystic fibrosis are genetically capable of producing VOCs in breath. AB - Breath contains hundreds of volatile organic compounds (VOCs), the composition of which is altered in a wide variety of diseases. Bacteria are implicated in the formation of VOCs, but the biochemical mechanisms that lead to the formation of breath VOCs remain largely hypothetical. We hypothesized that bacterial DNA fragments in sputum of CF patients could be sequenced to identify whether the bacteria present were capable of producing VOCs found in the breath of these patients. Breath from seven patients with cystic fibrosis was sampled and analyzed by gas-chromatography and mass-spectrometry. Sputum samples were also collected and microbial DNA was isolated. Metagenomic sequencing was performed and the DNA fragments were compared to a reference database with genes that are linked to the metabolism of acetaldehyde, ethanol and methanol in the KEGG database. Bacteria in the genera Escherichia, Lactococcus, Pseudomonas, Rothia and Streptococcus were found to have the genetic potential to produce acetaldehyde and ethanol. Only DNA sequences from Lactococcus were implicated in the formation of acetaldehyde from acetate through aldehyde dehydrogenase family 9 member A1 (K00149). Escherichia was found to be genetically capable of producing ethanol in all patients, whilst there was considerable heterogeneity between patients for the other genera. The ethanol concentration in breath positively correlated with the amount of Escherichia found in sputum (Spearman rho = 0.85, P = 0.015). Rothia showed the most versatile genetic potential for producing methanol. To conclude, bacterial DNA fragments in sputum of CF patients can be linked to enzymes implicated in the production of ethanol, acetaldehyde and methanol, which are VOCs that are predictive of respiratory tract colonization and/or infection. This supports that the lung microbiome can produce VOCs directly. PMID- 27991431 TI - Bio-inspired energy-harvesting mechanisms and patterns of dynamic soaring. AB - Albatrosses can make use of the dynamic soaring technique extracting energy from the wind field to achieve large-scale movement without a flap, which stimulates interest in effortless flight with small unmanned aerial vehicles (UAVs). However, mechanisms of energy harvesting in terms of the energy transfer from the wind to the flyer (albatross or UAV) are still indeterminate and controversial when using different reference frames in previous studies. In this paper, the classical four-phase Rayleigh cycle, includes sequentially upwind climb, downwind turn, downwind dive and upwind turn, is introduced in analyses of energy gain with the albatross's equation of motions and the simulated trajectory in dynamic soaring. Analytical and numerical results indicate that the energy gain in the air-relative frame mostly originates from large wind gradients at lower part of the climb and dive, while the energy gain in the inertial frame comes from the lift vector inclined to the wind speed direction during the climb, dive and downwind turn at higher altitude. These two energy-gain mechanisms are not equivalent in terms of energy sources and reference frames but have to be simultaneously satisfied in terms of the energy-neutral dynamic soaring cycle. For each reference frame, energy-loss phases are necessary to connect energy-gain ones. Based on these four essential phases in dynamic soaring and the albatrosses' flight trajectory, different dynamic soaring patterns are schematically depicted and corresponding optimal trajectories are computed. The optimal dynamic soaring trajectories are classified into two closed patterns including 'O' shape and '8' shape, and four travelling patterns including 'Omega' shape, 'alpha' shape, 'C' shape and 'S' shape. The correlation among these patterns are analysed and discussed. The completeness of the classification for different patterns is confirmed by listing and summarising dynamic soaring trajectories shown in studies over the past decades. PMID- 27991432 TI - The effect of proton pump inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-13C breath test in GERD patients: clinical relevance for personalized medicine. AB - Patients with gastroesophageal reflux disease (GERD) are routinely prescribed one of the six FDA approved proton pump inhibitors (PPI). All of these PPI are inhibitors of CYP2C19 enzyme to varying degrees. The phenotype pantoprazole-13C breath test (Ptz-BT) was used to identify patients who are poor metabolizers (PM) and the extent of phenoconversion of CYP2C19 enzyme activity caused by four PPI (omeprazole, esomprazole pantoprazole and rabeprazole) in 54 newly diagnosed GERD patients prior to initiating randomly selected PPI therapy and 30 d after PPI therapy. The phenoconversion after 30 d of PPI therapy in GERD patients was statistically significant (p =0.001) with omeprazole/esomeprazole (n = 27) strong CYP2C19 inhibitors, while there was no change in CYP2C19 enzyme activity (p = 0.8) with pantoprazole/ rabeprazole (n = 27), weak CYP2C19 inhibitors. The concommitant use of omeprazole/esomeprazole, therefore, could have critical clinical relevance in individualizing medications metabolized primarily by CYP2C19 such as PPI, clopidogrel, phenytoin, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, proguanil, tivantinib etc. The rapid (30 min), in vivo, and non-invasive phenotype Ptz-BT can evaluate CYP2C19 enzyme activity. More importantly, it can identify GERD patients with low CYP2C19 enzyme activity (PM), caused by PPI or other concomitant medications, who would benefit from dose adjustments to maintain efficacy and avoid toxicity. The existing CYP2C19 genotype tests cannot predict the phenotype nor can it detect phenoconversion due to non genetic factors. PMID- 27991433 TI - Recent advances in liquid mixtures in electric fields. AB - When immiscible liquids are subject to electric fields interfacial forces arise due to a difference in the permittivity or the conductance of the liquids, and these forces lead to shape change in droplets or to interfacial instabilities. In this topical review we discuss recent advances in the theory and experiments of liquids in electric fields with an emphasis on liquids which are initially miscible and demix under the influence of an external field. In purely dielectric liquids demixing occurs if the electrode geometry leads to sufficiently large field gradients. In polar liquids field gradients are prevalent due to screening by dissociated ions irrespective of the electrode geometry. We examine the conditions for these 'electro prewetting' transitions and highlight few possible systems where they might be important, such as in stabilization of colloids and in gating of pores in membranes. PMID- 27991434 TI - Functional theories of thermoelectric phenomena. AB - We review the progress that has been recently made in the application of time dependent density functional theory to thermoelectric phenomena. As the field is very young, we emphasize open problems and fundamental issues. We begin by introducing the formal structure of thermal density functional theory, a density functional theory with two basic variables-the density and the energy density-and two conjugate fields-the ordinary scalar potential and Luttinger's thermomechanical potential. The static version of this theory is contrasted with the familiar finite-temperature density functional theory, in which only the density is a variable. We then proceed to constructing the full time-dependent non equilibrium theory, including the practically important Kohn-Sham equations that go with it. The theory is shown to recover standard results of the Landauer theory for thermal transport in the steady state, while showing greater flexibility by allowing a description of fast thermal response, temperature oscillations and related phenomena. Several results are presented here for the first time, i.e. the proof of invertibility of the thermal response function in the linear regime, the full expression of the thermal currents in the presence of Luttinger's thermomechanical potential, an explicit prescription for the evaluation of the Kohn-Sham potentials in the adiabatic local density approximation, a detailed discussion of the leading dissipative corrections to the adiabatic local density approximation and the thermal corrections to the resistivity that follow from it. PMID- 27991435 TI - A combined cICA-EEMD analysis of EEG recordings from depressed or schizophrenic patients during olfactory stimulation. AB - OBJECTIVE: We propose a combination of a constrained independent component analysis (cICA) with an ensemble empirical mode decomposition (EEMD) to analyze electroencephalographic recordings from depressed or schizophrenic subjects during olfactory stimulation. APPROACH: EEMD serves to extract intrinsic modes (IMFs) underlying the recorded EEG time. The latter then serve as reference signals to extract the most similar underlying independent component within a constrained ICA. The extracted modes are further analyzed considering their power spectra. MAIN RESULTS: The analysis of the extracted modes reveals clear differences in the related power spectra between the disease characteristics of depressed and schizophrenic patients. Such differences appear in the high frequency gamma-band in the intrinsic modes, but also in much more detail in the low frequency range in the alpha-, theta- and delta-bands. SIGNIFICANCE: The proposed method provides various means to discriminate both disease pictures in a clinical environment. PMID- 27991436 TI - Ultraclean suspended monolayer graphene achieved by in situ current annealing. AB - Ultraclean graphene is essential for studying its intrinsic transport properties or fabricating high-performance electronic devices. Unfortunately, the contamination on graphene is unavoidable after microelectromechanical system processing. Here, we report an in situ current-annealing method for achieving ultraclean suspended monolayer graphene. The charge mobility of cleaned graphene reached a surprising 3.8 * 105 cm2 V-1 s-1, one of the highest values ever reported. For the first time, the process of current annealing was recorded under a high-resolution electron scanning microscope. It was demonstrated that temperature was the only dominant factor of the current-annealing process. Meanwhile, the mobility of suspended graphene was found to be highly sensitive to structural defects. The mobility decreased by a factor of over 100 after ion irradiation on graphene. The results revealed the underlying mechanism of current annealing on graphene and provided an effective means of preparing ultraclean graphene membranes. PMID- 27991437 TI - Time-over-threshold for pulse shape discrimination in a time-of-flight phoswich PET detector. AB - It is well known that a PET detector capable of measuring both photon time-of flight (TOF) and depth-of-interaction (DOI) improves the image quality and accuracy. Phoswich designs have been realized in PET detectors to measure DOI for more than a decade. However, PET detectors based on phoswich designs put great demand on the readout circuits, which have to differentiate the pulse shape produced by different crystal layers. A simple pulse shape discrimination approach is required to realize the phoswich designs in a clinical PET scanner, which consists of thousands of scintillation crystal elements. In this work, we studied time-over-threshold (ToT) as a pulse shape parameter for DOI. The energy, timing and DOI performance were evaluated for a phoswich detector design comprising [Formula: see text] mm LYSO:Ce crystal optically coupled to [Formula: see text] mm calcium co-doped LSO:Ce,Ca(0.4%) crystal read out by a silicon photomultiplier (SiPM). A DOI accuracy of 97.2% has been achieved for photopeak events using the proposed time-over-threshold (ToT) processing. The energy resolution without correction for SiPM non-linearity was [Formula: see text]% and [Formula: see text]% FWHM at 511 keV for LYSO and LSO crystal layers, respectively. The coincidence time resolution for photopeak events ranges from 164.6 ps to 183.1 ps FWHM, depending on the layer combinations. The coincidence time resolution for inter-crystal scatter events ranges from 214.6 ps to 418.3 ps FWHM, depending on the energy windows applied. These results show great promises of using ToT for pulse shape discrimination in a TOF phoswich detector since a ToT measurement can be easily implemented in readout electronics. PMID- 27991438 TI - Limitations of analytical dose calculations for small field proton radiosurgery. AB - The purpose of the work was to evaluate the dosimetric uncertainties of an analytical dose calculation engine and the impact on treatment plans using small fields in intracranial proton stereotactic radiosurgery (PSRS) for a gantry based double scattering system. 50 patients were evaluated including 10 patients for each of 5 diagnostic indications of: arteriovenous malformation (AVM), acoustic neuroma (AN), meningioma (MGM), metastasis (METS), and pituitary adenoma (PIT). Treatment plans followed standard prescription and optimization procedures for PSRS. We performed comparisons between delivered dose distributions, determined by Monte Carlo (MC) simulations, and those calculated with the analytical dose calculation algorithm (ADC) used in our current treatment planning system in terms of dose volume histogram parameters and beam range distributions. Results show that the difference in the dose to 95% of the target (D95) is within 6% when applying measured field size output corrections for AN, MGM, and PIT. However, for AVM and METS, the differences can be as great as 10% and 12%, respectively. Normalizing the MC dose to the ADC dose based on the dose of voxels in a central area of the target reduces the difference of the D95 to within 6% for all sites. The generally applied margin to cover uncertainties in range (3.5% of the prescribed range + 1 mm) is not sufficient to cover the range uncertainty for ADC in all cases, especially for patients with high tissue heterogeneity. The root mean square of the R90 difference, the difference in the position of distal falloff to 90% of the prescribed dose, is affected by several factors, especially the patient geometry heterogeneity, modulation and field diameter. In conclusion, implementation of Monte Carlo dose calculation techniques into the clinic can reduce the uncertainty of the target dose for proton stereotactic radiosurgery. If MC is not available for treatment planning, using MC dose distributions to adjust the delivered doses level can also reduce uncertainties below 3% for mean target dose and 6% for the D95. PMID- 27991440 TI - Simulating charge transport in organic semiconductors and devices: a review. AB - Charge transport simulation can be a valuable tool to better understand, optimise and design organic transistors (OTFTs), photovoltaics (OPVs), and light-emitting diodes (OLEDs). This review presents an overview of common charge transport and device models; namely drift-diffusion, master equation, mesoscale kinetic Monte Carlo and quantum chemical Monte Carlo, and a discussion of the relative merits of each. This is followed by a review of the application of these models as applied to charge transport in organic semiconductors and devices, highlighting in particular the insights made possible by modelling. The review concludes with an outlook for charge transport modelling in organic electronics. PMID- 27991439 TI - Augmenting atlas-based liver segmentation for radiotherapy treatment planning by incorporating image features proximal to the atlas contours. AB - Atlas-based segmentation utilizes a library of previously delineated contours of similar cases to facilitate automatic segmentation. The problem, however, remains challenging because of limited information carried by the contours in the library. In this studying, we developed a narrow-shell strategy to enhance the information of each contour in the library and to improve the accuracy of the exiting atlas-based approach. This study presented a new concept of atlas based segmentation method. Instead of using the complete volume of the target organs, only information along the organ contours from the atlas images was used for guiding segmentation of the new image. In setting up an atlas-based library, we included not only the coordinates of contour points, but also the image features adjacent to the contour. In this work, 139 CT images with normal appearing livers collected for radiotherapy treatment planning were used to construct the library. The CT images within the library were first registered to each other using affine registration. The nonlinear narrow shell was generated alongside the object contours of registered images. Matching voxels were selected inside common narrow shell image features of a library case and a new case using a speed-up robust features (SURF) strategy. A deformable registration was then performed using a thin plate splines (TPS) technique. The contour associated with the library case was propagated automatically onto the new image by exploiting the deformation field vectors. The liver contour was finally obtained by employing level set based energy optimization within the narrow shell. The performance of the proposed method was evaluated by comparing quantitatively the auto-segmentation results with that delineated by physicians. A novel atlas-based segmentation technique with inclusion of neighborhood image features through the introduction of a narrow-shell surrounding the target objects was established. Application of the technique to 30 liver cases suggested that the technique was capable to reliably segment liver cases from CT, 4D-CT, and CBCT images with little human interaction. The accuracy and speed of the proposed method are quantitatively validated by comparing automatic segmentation results with the manual delineation results. The Jaccard similarity metric between the automatically generated liver contours obtained by the proposed method and the physician delineated results are on an average 90%-96% for planning images. Incorporation of image features into the library contours improves the currently available atlas-based auto-contouring techniques and provides a clinically practical solution for auto-segmentation. The proposed mountainous narrow shell atlas based method can achieve efficient automatic liver propagation for CT, 4D-CT and CBCT images with following treatment planning and should find widespread application in future treatment planning systems. PMID- 27991441 TI - Evidence of contact epitaxy in the self-assembly of HgSe nanocrystals formed at a liquid-liquid interface. AB - The grazing incidence x-ray scattering results presented here show that the self assembly process of HgSe nanocrystals formed at a liquid-liquid interface is quite different along the in-plane direction and across the interface. In situ x ray reflectivity and ex situ microscopy measurements suggest quantized out-of plane growth for HgSe nanoparticles of a size of about [Formula: see text] nm initially. Grazing incidence small-angle x-ray scattering measurements for films transferred from the water-toluene interface at various stages of reaction show that these nanoparticles first form random clusters with an average radius of 2.2 nm, giving rise to equally spaced rings of several orders. Finally, these clusters self-organize into face-centered cubic superstructures, giving sharp x ray diffraction peaks oriented normal to the liquid-liquid interface with more than 100 nm-coherent domains. We also observed the x-ray diffraction pattern of the HgSe crystalline phase, with the superlattice peaks in these grazing incidence measurements of the transferred films. The electron microscopy and atomic force microscopy results support the x-ray observation of the self organization of HgSe nanocrystals into close-packed superlattices. These results show that capillary wave fluctuation promotes the oriented attachment of clusters at the liquid-liquid interface, giving direct experimental evidence of contact epitaxy. PMID- 27991442 TI - Milestones of general relativity. AB - We present a summary for non-specialists of the special issue of the journal Classical and Quantum Gravity on 'Milestones of general relativity', commemorating the 100th anniversary of the theory. PMID- 27991443 TI - Hydrostatic-pressure-induced changes of magnetic anisotropy in (Ga, Mn)As thin films. AB - The impact of hydrostatic pressure on magnetic anisotropy energies in (Ga, Mn)As thin films with in-plane and out-of-plane magnetic easy axes predefined by epitaxial strain was investigated. In both types of sample we observed a clear increase in both in-plane and out-of-plane anisotropy parameters with pressure. The out-of-plane anisotropy constant is well reproduced by the mean-field p-d Zener model; however, the changes in uniaxial anisotropy are much larger than expected in the Mn-Mn dimer scenario. PMID- 27991444 TI - Toward a new microscopic framework for Kondo lattice materials. AB - Understanding the emergence and subsequent behavior of heavy electrons in Kondo lattice materials is one of the grand challenges in condensed matter physics. From this perspective we review the progress that has been made during the past decade and suggest some directions for future research. Our focus will be on developing a new microscopic framework that incorporates the basic concepts that emerge from a phenomenological description of the key experimental findings. PMID- 27991445 TI - Enhancement of magnetic ordering and magnetodielectric coupling by hole doping in a multiferroic DyFe0.5Cr0.5O3. AB - We report the results of our investigations of magnetic, thermodynamic and dielectric properties of Ca substituted half-doped orthochromite, Dy0.6Ca0.4Fe0.5Cr0.5O3. Magnetic susceptibility and heat capacity data bring out that this compound undergoes two magnetic transitions, one at ~ 132 and the other at ~22 K. These values are higher than that those of DyFe0.5Cr0.5O3. This finding highlights that non-magnetic hole doping of Ca+2 in the place of magnetic Dy+3 tends to enhance magnetic transition temperatures in this half-doped orthochromite. We attribute it to possible change in the valence state of Cr/Fe ion ions due to hole doping. Dielectric anomalies are also seen near the magnetic ordering temperatures indicating magnetodielectric coupling, which is confirmed by magnetic field dependent dielectric studies. The most notable observation is that magnetodielectric coupling strength gets significantly enhanced as compared to DyFe0.5Cr0.5O3. The results reveal that it is possible to tune magnetoelectric coupling by hole doping in this system. PMID- 27991446 TI - A self-consistent determination of the RVB and SC gaps in the YRZ ansatz. AB - A correct understanding of the origin of the pseudogap in high temperature (high T c) cuprate superconductors is considered to be a peripheral breakthrough in the understanding of the microscopic mechanism of the high-T c superconductivity. Yang-Rice-Zhang (YRZ) ansatz is an important phenomenological theory to describe the phenomenon of pseudogap. However, in the framework of YRZ, the pseudogap (resonant valence bond (RVB) gap) and the superconducting (SC) gap are unable to have a self-consistent determination at different doping concentrations, and this severely limits the application of the YRZ ansatz. Based on the YRZ ansatz, this study develops a technical method to determine the RVB and SC gaps in a self consistent manner. It is revealed that the self-consistent calculations of the doping dependence of RVB, SC gaps and spectral function are not only consistent with the empirical gap formula in the YRZ framework, but also consistent with the doping evolution of the Fermi surface observed in the angle-resolved photoemission spectroscopy (ARPES) experiments. Our method will greatly extend the applications of the YRZ ansatz, and will deepen our understanding of the origin of pseudogap as well as the mechanism of high-T c superconductivity. PMID- 27991447 TI - Temperature-dependent transport and hysteretic behaviors induced by interfacial states in MoS2 field-effect transistors with lead-zirconate-titanate ferroelectric gating. AB - We report the temperature and gate-voltage-dependent electrical properties of lead-zirconate-titanate-gated MoS2 field-effect transistors (MoS2-PZT FETs) within a temperature range of 300 to 380 K. The MoS2 transistors with PZT gating exhibit large reproducible clockwise hysteresis, which is induced by the dynamic charge-trapping/de-trapping process of interfacial states between PZT films and MoS2 channels under the modulation of ferroelectric polarization of PZT films. In this way, the modulation of the gate effect on the hysteresis behavior has been achieved by activating the dynamic charge-trapping/de-trapping process in the interfacial states under different V gs . Moreover, the temperature dependence of the current in the range of 300 to 380 K indicates thermally activated hysteretic behaviors. The hysteresis in the transfer characteristics of MoS2-PZT FETs shows a simultaneous enlargement with increasing temperature, which can be attributed to the thermally sensitive dynamic trapping/de-trapping process of interfacial states. PMID- 27991448 TI - Monte Carlo simulations of nanoscale Ne+ ion beam sputtering: investigating the influence of surface effects, interstitial formation, and the nanostructural evolution. AB - We present an updated version of our Monte-Carlo based code for the simulation of ion beam sputtering. This code simulates the interaction of energetic ions with a target, and tracks the cumulative damage, enabling it to simulate the dynamic evolution of nanostructures as material is removed. The updated code described in this paper is significantly faster, permitting the inclusion of new features, namely routines to handle interstitial atoms, and to reduce the surface energy as the structure would otherwise develop energetically unfavorable surface porosity. We validate our code against the popular Monte-Carlo code SRIM-TRIM, and study the development of nanostructures from Ne+ ion beam milling in a copper target. PMID- 27991449 TI - Accelerated magnetic resonance thermometry in the presence of uncertainties. AB - A model-based information theoretic approach is presented to perform the task of magnetic resonance (MR) thermal image reconstruction from a limited number of observed samples on k-space. The key idea of the proposed approach is to optimally detect samples of k-space that are information-rich with respect to a model of the thermal data acquisition. These highly informative k-space samples can then be used to refine the mathematical model and efficiently reconstruct the image. The information theoretic reconstruction was demonstrated retrospectively in data acquired during MR-guided laser induced thermal therapy (MRgLITT) procedures. The approach demonstrates that locations with high-information content with respect to a model-based reconstruction of MR thermometry may be quantitatively identified. These information-rich k-space locations are demonstrated to be useful as a guide for k-space undersampling techniques. The effect of interactively increasing the predicted number of data points used in the subsampled model-based reconstruction was quantified using the L2-norm of the distance between the subsampled and fully sampled reconstruction. Performance of the proposed approach was also compared with uniform rectilinear subsampling and variable-density Poisson disk subsampling techniques. The proposed subsampling scheme resulted in accurate reconstructions using a small fraction of k-space points, suggesting that the reconstruction technique may be useful in improving the efficiency of thermometry data temporal resolution. PMID- 27991450 TI - Self-assembling Ni(OH)2/alpha-Fe2O3 composites for pseudocapacitors with excellent electrochemical performance. AB - Novel two-dimensional (2D) nanostructured Ni(OH)2 nanosheet/alpha-Fe2O3 nanoplate composites (NFCs) were successfully synthesized by a simple two-step solvothermal method where the proportion of alpha-Fe2O3 nanoplates was found to be controllable. These composites achieved excellent performance in aqueous electrolyte due to the synergistic effect between Ni(OH)2 nanosheets and alpha Fe2O3 nanoplates, such as high specific capacitance and long-term cycle stability. The obtained NFC8 possessed a maximum mass specific capacitance of 1745.33F g-1 at a current density of 2 A g-1, and with 84.28% retention after 3000 cycles galvanostatic charge/discharge at a high current density of 20 A g-1. The above results show that these novel 2D nanostructured Ni(OH)2/alpha-Fe2O3 composites are promising electrode materials for pseudocapacitors. PMID- 27991451 TI - A Monte Carlo study of monoenergetic and polyenergetic normalized glandular dose (DgN) coefficients in mammography. AB - We investigated the influence of model assumptions in GEANT4 Monte Carlo (MC) simulations for the calculation of monoenergetic and polyenergetic normalized glandular dose coefficients (DgN) in mammography, focussing on the effect of the skin thickness and composition, of the role of compression paddles and of the bremsstrahlung processes. We showed that selecting a skin thickness of 4 mm instead of 1.45 mm produced DgN values with deviations from 9% to 32% for x-ray spectra routinely adopted in mammography. Consideration of the bremsstrahlung radiation had a weak influence on monoenergetic DgN. Simulations (in the range 8 40 kVp) which included consideration of bremsstrahlung radiation, a skin thickness of 1.45 mm and a 2 mm thick compression paddles produced polyenergetic DgN coefficients up to 19% higher than corresponding literature data. Adding a 2 mm thick adipose layer between the skin layer and the radiosensitive portion of the breast produces polyenergetic DgN values up to 15% higher than those routinely adopted. These findings provide a quantitative estimate of the influence of model parameters on the calculation of the mean glandular dose in mammography. PMID- 27991452 TI - Formation of an indium tin oxide nanodot/Ag nanowire electrode as a current spreader for near ultraviolet AlGaN-based light-emitting diodes. AB - Indium tin oxide (ITO) nanodots (NDs) were combined with Ag nanowires (Ag NWs) as a p-type electrode in near ultraviolet AlGaN-based light-emitting diodes (LEDs) to increase light output power. The Ag NWs were 30 +/- 5 nm in diameter and 25 +/ 5 MUm in length. The transmittance of 10 nm-thick ITO-only was 98% at 385 nm, while the values for ITO ND/Ag NW were 83%-88%. ITO ND/Ag NW films showed lower sheet resistances (32-51 Omega sq-1) than the ITO-only film (950 Omega sq-1). LEDs (chip size: 300 * 800 MUm2) fabricated using the ITO NDs/Ag NW electrodes exhibited higher forward-bias voltages (3.52-3.75 V at 20 mA) than the LEDs with the 10 nm-thick ITO-only electrode (3.5 V). The LEDs with ITO ND/Ag NW electrodes yielded a 24%-62% higher light output power (at 20 mA) than those with the 10 nm thick ITO-only electrode. Furthermore, finite-difference time-domain (FDTD) simulations were performed to investigate the extraction efficiency. Based on the emission images and FDTD simulations, the enhanced light output with the ITO ND/Ag NW electrodes is attributed to improved current spreading and better extraction efficiency. PMID- 27991453 TI - Low-dose lung cancer screening with photon-counting CT: a feasibility study. AB - To evaluate the feasibility of using a whole-body photon-counting detector (PCD) CT scanner for low-dose lung cancer screening compared to a conventional energy integrating detector (EID) system. Radiation dose-matched EID and PCD scans of the COPDGene 2 phantom were acquired at different radiation dose levels (CTDIvol: 3.0, 1.5, and 0.75 mGy) and different tube voltages (120, 100, and 80 kVp). EID and PCD images were compared for quantitative Hounsfield unit (HU) accuracy, noise levels, and contrast-to-noise ratios (CNR) for detection of ground-glass nodules (GGN) and emphysema. The PCD HU accuracy was better than EID for water at all scan parameters. PCD HU stability for lung, GGN and emphysema regions were superior to EID and PCD attenuation values were more reproducible than EID for all scan parameters (all P < 0.01), while HUs for lung, GGN and emphysema ROIs changed significantly for EID with decreasing dose (all P < 0.001). PCD showed lower noise levels at the lowest dose setting at 120, 100 and 80 kVp (15.2 +/- 0.3 HU versus 15.8 +/- 0.2 HU, P = 0.03; 16.1 +/- 0.3 HU versus 18.0 +/- 0.4 HU, P = 0.003; and 16.1 +/- 0.3 HU versus 17.9 +/- 0.3 HU, P = 0.001, respectively), resulting in superior CNR for evaluation of GGNs and emphysema at 100 and 80 kVp. PCD provided better HU stability for lung, ground-glass, and emphysema-equivalent foams at lower radiation dose settings with better reproducibility than EID. Additionally, PCD showed up to 10% less noise, and 11% higher CNR at 0.75 mGy for both 100 and 80 kVp. PCD technology may help reduce radiation exposure in lung cancer screening while maintaining diagnostic quality. PMID- 27991454 TI - A novel method for interactive multi-objective dose-guided patient positioning. AB - In intensity-modulated radiation therapy (IMRT), 3D in-room imaging data is typically utilized for accurate patient alignment on the basis of anatomical landmarks. In the presence of non-rigid anatomical changes, it is often not obvious which patient position is most suitable. Thus, dose-guided patient alignment is an interesting approach to use available in-room imaging data for up to-date dose calculation, aimed at finding the position that yields the optimal dose distribution. This contribution presents the first implementation of dose guided patient alignment as multi-criteria optimization problem. User-defined clinical objectives are employed for setting up a multi-objective problem. Using pre-calculated dose distributions at a limited number of patient shifts and dose interpolation, a continuous space of Pareto-efficient patient shifts becomes accessible. Pareto sliders facilitate interactive browsing of the possible shifts with real-time dose display to the user. Dose interpolation accuracy is validated and the potential of multi-objective dose-guided positioning demonstrated for three head and neck (H&N) and three prostate cancer patients. Dose-guided positioning is compared to replanning for all cases. A delineated replanning CT served as surrogate for in-room imaging data. Dose interpolation accuracy was high. Using a [Formula: see text] dose difference criterion, a median pass-rate of 95.7% for H&N and 99.6% for prostate cases was determined in a comparison to exact dose calculations. For all patients, dose-guided positioning allowed to find a clinically preferable dose distribution compared to bony anatomy based alignment. For all H&N cases, mean dose to the spared parotid glands was below [Formula: see text] (up to [Formula: see text] with bony alignment) and clinical target volume (CTV) [Formula: see text] above 99.1% (compared to 95.1%). For all prostate patients, CTV [Formula: see text] was above 98.9% (compared to 88.5%) and [Formula: see text] to the rectum below [Formula: see text] (compared to 56.1%). Replanning yielded improved results for the H&N cases. For the prostate cases, differences to dose-guided positioning were minor. PMID- 27991455 TI - Collision-kerma conversion between dose-to-tissue and dose-to-water by photon energy-fluence corrections in low-energy brachytherapy. AB - The AAPM TG-43 brachytherapy dosimetry formalism, introduced in 1995, has become a standard for brachytherapy dosimetry worldwide; it implicitly assumes that charged-particle equilibrium (CPE) exists for the determination of absorbed dose to water at different locations, except in the vicinity of the source capsule. Subsequent dosimetry developments, based on Monte Carlo calculations or analytical solutions of transport equations, do not rely on the CPE assumption and determine directly the dose to different tissues. At the time of relating dose to tissue and dose to water, or vice versa, it is usually assumed that the photon fluence in water and in tissues are practically identical, so that the absorbed dose in the two media can be related by their ratio of mass energy absorption coefficients. In this work, an efficient way to correlate absorbed dose to water and absorbed dose to tissue in brachytherapy calculations at clinically relevant distances for low-energy photon emitting seeds is proposed. A correction is introduced that is based on the ratio of the water-to-tissue photon energy-fluences. State-of-the art Monte Carlo calculations are used to score photon fluence differential in energy in water and in various human tissues (muscle, adipose and bone), which in all cases include a realistic modelling of low-energy brachytherapy sources in order to benchmark the formalism proposed. The energy-fluence based corrections given in this work are able to correlate absorbed dose to tissue and absorbed dose to water with an accuracy better than 0.5% in the most critical cases (e.g. bone tissue). PMID- 27991456 TI - A new approach to integrate GPU-based Monte Carlo simulation into inverse treatment plan optimization for proton therapy. AB - Monte Carlo (MC)-based spot dose calculation is highly desired for inverse treatment planning in proton therapy because of its accuracy. Recent studies on biological optimization have also indicated the use of MC methods to compute relevant quantities of interest, e.g. linear energy transfer. Although GPU-based MC engines have been developed to address inverse optimization problems, their efficiency still needs to be improved. Also, the use of a large number of GPUs in MC calculation is not favorable for clinical applications. The previously proposed adaptive particle sampling (APS) method can improve the efficiency of MC based inverse optimization by using the computationally expensive MC simulation more effectively. This method is more efficient than the conventional approach that performs spot dose calculation and optimization in two sequential steps. In this paper, we propose a computational library to perform MC-based spot dose calculation on GPU with the APS scheme. The implemented APS method performs a non uniform sampling of the particles from pencil beam spots during the optimization process, favoring those from the high intensity spots. The library also conducts two computationally intensive matrix-vector operations frequently used when solving an optimization problem. This library design allows a streamlined integration of the MC-based spot dose calculation into an existing proton therapy inverse planning process. We tested the developed library in a typical inverse optimization system with four patient cases. The library achieved the targeted functions by supporting inverse planning in various proton therapy schemes, e.g. single field uniform dose, 3D intensity modulated proton therapy, and distal edge tracking. The efficiency was 41.6 +/- 15.3% higher than the use of a GPU-based MC package in a conventional calculation scheme. The total computation time ranged between 2 and 50 min on a single GPU card depending on the problem size. PMID- 27991457 TI - Real-time auto-adaptive margin generation for MLC-tracked radiotherapy. AB - In radiotherapy, abdominal and thoracic sites are candidates for performing motion tracking. With real-time control it is possible to adjust the multileaf collimator (MLC) position to the target position. However, positions are not perfectly matched and position errors arise from system delays and complicated response of the electromechanic MLC system. Although, it is possible to compensate parts of these errors by using predictors, residual errors remain and need to be compensated to retain target coverage. This work presents a method to statistically describe tracking errors and to automatically derive a patient specific, per-segment margin to compensate the arising underdosage on-line, i.e. during plan delivery. The statistics of the geometric error between intended and actual machine position are derived using kernel density estimators. Subsequently a margin is calculated on-line according to a selected coverage parameter, which determines the amount of accepted underdosage. The margin is then applied onto the actual segment to accommodate the positioning errors in the enlarged segment. The proof-of-concept was tested in an on-line tracking experiment and showed the ability to recover underdosages for two test cases, increasing [Formula: see text] in the underdosed area about [Formula: see text] and [Formula: see text], respectively. The used dose model was able to predict the loss of dose due to tracking errors and could be used to infer the necessary margins. The implementation had a running time of 23 ms which is compatible with real-time requirements of MLC tracking systems. The auto-adaptivity to machine and patient characteristics makes the technique a generic yet intuitive candidate to avoid underdosages due to MLC tracking errors. PMID- 27991458 TI - Detection of auditory signals in quiet and noisy backgrounds while performing a visuo-spatial task. AB - CONTEXT: The ability to detect important auditory signals while performing visual tasks may be further compounded by background chatter. Thus, it is important to know how task performance may interact with background chatter to hinder signal detection. AIM: To examine any interactive effects of speech spectrum noise and task performance on the ability to detect signals. SETTINGS AND DESIGN: The setting was a sound-treated booth. A repeated measures design was used. MATERIALS AND METHODS: Auditory thresholds of 20 normal adults were determined at 0.5, 1, 2 and 4 kHz in the following conditions presented in a random order: (1) quiet with attention; (2) quiet with a visuo-spatial task or puzzle (distraction); (3) noise with attention and (4) noise with task. STATISTICAL ANALYSIS: Multivariate analyses of variance (MANOVA) with three repeated factors (quiet versus noise, visuo-spatial task versus no task, signal frequency). RESULTS: MANOVA revealed significant main effects for noise and signal frequency and significant noise frequency and task-frequency interactions. Distraction caused by performing the task worsened the thresholds for tones presented at the beginning of the experiment and had no effect on tones presented in the middle. At the end of the experiment, thresholds (4 kHz) were better while performing the task than those obtained without performing the task. These effects were similar across the quiet and noise conditions. CONCLUSION: Detection of auditory signals is difficult at the beginning of a distracting visuo-spatial task but over time, task learning and auditory training effects can nullify the effect of distraction and may improve detection of high frequency sounds. PMID- 27991459 TI - Early indication of noise-induced hearing loss from PMP use in adolescents: A cross-sectional analysis. AB - CONTEXT: Distortion product otoacoustic emissions (DPOAEs) may indicate preclinical noise-induced hearing loss (NIHL) in adolescents from unsafe personal music player (PMP) use. AIMS: The objective, therefore, was to observe preclinical signs of NIHL in 9th grade adolescents with clinically normal hearing by comparing DPOAE signals between different levels of A-weighted equivalent PMP exposure. SETTINGS AND DESIGN: Subjects were recruited from all secondary-level schools located in the city of Regensburg, Germany during two academic years 2009/2010 and 2010/2011. SUBJECTS AND METHODS: A-weighted equivalent sound pressure levels (SPLs) for a 40-hour work week (LAeq,40h) were estimated from questionnaire responses on output and duration of PMP use of the previous week. Subjects were then categorized into four levels of exposure: <80, 80-85, >85 to <90, and >=90 A-weighted Decibel [dB(A)]. DPOAE signals were collected by trained audiological staff, applying a standard optimized protocol, at the Department of Otorhinolaryngology of the University Hospital Regensburg. STATISTICAL ANALYSIS USED: Mean DPOAE signals were compared between levels by unpaired t test. Novel linear regression models adjusting for other leisure noise exposures and with outcome variables DPoutcome and 4 kilo Hertz (kHz) DPOAEs estimated effects between levels. RESULTS: A total of 1468 subjects (56% female, mostly aged 15 or 16 years) were available for analysis. Comparison of DPOAE means by PMP exposure typically showed no greater than 1 dB difference between groups. In fact, comparisons between >=90 dB(A) and <80 dB(A) presented the least differences in magnitude. Both DPoutcome and 4 kHz linear regression models presented a weak association with the 4-level PMP exposure variable. An expected dose-response to PMP exposure was not observed in any analyses. CONCLUSIONS: DPOAE signal strength alone cannot indicate preclinical NIHL in adolescents. PMID- 27991460 TI - Acute acoustic trauma in the French armed forces during 2007-2014. AB - CONTEXT: Despite existing preventive measures, the number of acute acoustic trauma (AAT) cases reported to the French Military Epidemiological Surveillance System (MESS) remains high. AIMS: The objective of this study was to describe AAT and the preventive measures already implemented. SUBJECTS AND METHODS: We conducted a descriptive cross-sectional analysis of AAT using data from the MESS for the period 2007-2014. In addition, we reviewed the current prevention measures that exist in the French armed forces. STATISTICAL ANALYSIS USED: Comparisons between different incidence rates were made by Poisson and quasi Poisson regression. RESULTS: Between 2007 and 2014, 10,487 AAT cases were reported to the MESS, with a significant decrease in 2013 (P < 0.001). AAT incidence rates were the highest among those aged <25 years - 14.3 per 1000 person-years (PYs) (P < 0.001), and those in the army; with 8.1 per 1000 PYs (P < 0.001), and men had almost twice the risk of women (P < 0.001). AAT mainly occurred in training schools or at camps during exercises. The main prevention actions identified were the following: official regulations, education, making hearing protection devices (HPDs) available for all service members, and regular hearing monitoring. A working group has been set up and has proposed an informative chapter in the weapon handling instruction book, an AAT simulator, and a new HPD, the 3M(r) earplug, with an information brochure. CONCLUSIONS: AAT rates decreased from 2007 to 2014 in the French armed forces. Further analysis is needed to identify the underlying factors involved to improve the prevention actions proposed. The MESS and targeted surveys will assess the impact of the different prevention measures implemented. PMID- 27991461 TI - The viability of hearing protection device fit-testing at navy and marine corps accession points. AB - INTRODUCTION: The viability of hearing protection device (HPD) verification (i.e., fit-testing) on a large scale was investigated to address this gap in a military accession environment. MATERIALS AND METHODS: Personal Attenuation Ratings (PARs) following self-fitted (SELF-Fit) HPDs were acquired from 320 US Marine Corps training recruits (87.5% male, 12.5% female) across four test protocols (1-, 3-, 5-, and 7- frequency). SELF-Fit failures received follow-up to assess potential causes. Follow-up PARs were acquired (Experimenter fit [EXP Fit], followed by Subject re-fit [SUB Re-Fit]). EXP-Fit was intended to provide a perception (dubbed "ear canal muscle memory") of what a correctly fitted HPD should feel like. SUB Re-Fit was completed following EXP-Fit to determine whether a training recruit could duplicate EXP-Fit on her/his own without assistance. RESULTS: A one-way analysis of variance (ANOVA) (N = 320) showed that SELF-Fit means differed significantly between protocols (P < 0.001). Post-hoc analyses showed that the 1-freq SELF-Fit mean was significantly lower than all other protocols (P < 0.03) by 5.6 dB or more. No difference was found between the multi frequency protocols. For recruits who were followed up with EXP-Fit (n = 79), across all protocols, a significant (P < 0.001) mean improvement of 25.68 dB (10.99) was found, but PARs did not differ (P = 0.99) between EXP-Fit protocols. For recruits in the 3-freq and 5-freq protocol groups who experienced all three PAR test methods (n = 33), PAR methods differed (P < 0.001) but no method by protocol interaction was found (P = 0.46). Post hoc tests showed that both EXP Fit and SUB Re-Fit had significantly better attenuation than SELF-Fit (P < 0.001), but no difference was found between EXPFit and SUB Re-Fit (P = 0.59). For SELF-Fit, the 1-freq protocol resulted in a 35% pass rate, whereas the 3-, 5-, and 7-freq protocols resulted in >60% pass rates. Results showed that once recruits experienced how HPDs should feel when inserted correctly, they were able to properly replicate the procedure with similar results to the expert fit suggesting "ear canal muscle memory" may be a viable training strategy concomitant with HPD verification. Fit-test duration was also measured to examine the tradeoff between results accuracy and time required to complete each protocol. DISCUSSION: Results from this study showed the critical importance of initial selection and fitting of HPDs followed by verification (i.e., fit testing) at Navy and Marine Corps accession points. Achieving adequate protection from an HPD is fundamentally dependent on obtaining proper fit of the issued HPD as well as the quality of training recruits receive regarding HPD use. PMID- 27991462 TI - Application of the online hearing screening test "Earcheck": Speech intelligibility in noise in teenagers and young adults. AB - OBJECTIVE: The objective was to describe the speech intelligibility in noise test results among Dutch teenagers and young adults aged 12-24 years, using a national online speech reception threshold (SRT) test, the Earcheck. A secondary objective was to assess the effect of age and gender on speech intelligibility in noise. DESIGN: Cross-sectional SRT data were collected over a 5-year period (2010-2014), from participants of Earcheck. Regression analyses were performed, with SRT as the dependent variable, and age and gender as explaining variables. To cross validate the model, data from 12- to 24-year olds from the same test distributed by a hearing aid dispenser (Hoorscan) were used. RESULTS: In total, 96,803 valid test results were analyzed. The mean SRT score was -18.3 dB signal-to-noise ratio (SNR) (standard deviation (SD) = 3.7). Twenty-five percent of the scores was rated as insufficient or poor. SRT performance significantly improved with increasing age for teenagers aged 12-18 years by 0.49 dB SNR per age-year. A smaller age-effect (0.09 dB SNR per age-year) was found for young adults aged 19 24 years. Small differences between male and female users were found. CONCLUSION: Earcheck generated large quantities of national SRT data. The data implied that a substantial number of users of Earcheck may have some difficulty in understanding speech in noise. Furthermore, the results of this study showed an effect of gender and age on SRT performance, suggesting an ongoing maturation of speech-in noise performance into late adolescence. This suggests the use of age-dependent reference values, but for this purpose, more research is required. PMID- 27991463 TI - Parametric method for the noise risk assessment of professional orchestral musicians. AB - BACKGROUND: The Occupational Health and Safety (OH&S) literature shows that noise could represent a risk factor for professional orchestral musicians. The continuative exposition to elevated noise levels and the particular nature of the activity make necessary an "atypical" OH&S approach, which was identified to be necessarily organizational. MATERIALS AND METHODS: In this study, a parametric based method for orchestral exposure assessment and management was developed. The goal was to achieve a predictive tool to involve safety in the decision making of concert season program. After setting the parameters, the project's hypothesis was defined and then validated through a yearly-scale monitoring on an important European symphonic orchestra. Moreover, workers' exposure was assessed from the parametric study by a wide measurement campaign. RESULTS: A general validation of the method was obtained by the verification of the main parameters' (repertoire, headcount, and disposition) significant influence on the sound pressure levels produced by the orchestra. Exposure levels comparable to the trends in literature for symphonic orchestras were observed, with criticalities among brass musicians, which was the only group exceeding the upper exposure action values. CONCLUSION: This research has emphasized that the exposure condition of musicians can be critical and requires the implementation of improvement plans. The study has shown that the predictive analysis can be performed on parameters describing the concert's emissive characteristics. The future development of research currently under study will focus on the concert's pieces and the use of parameters as indicators of the exposure context. PMID- 27991464 TI - Tram squealing noise and its impact on human health. AB - INTRODUCTION: Tramway has become a serious urban noise source in densely populated areas. The disturbance from squealing noise is significant. Curve squeal is the very loud, tonal noise emitted by tram operation in tight radius curves. Studies had reported a relationship between noise levels and health effects, such as annoyance, sleep disturbance, and elevated systolic and diastolic blood pressure. MATERIALS AND METHODS: This study aimed to analyze the wheel squeal noise along the tramway line in Kosice, Slovakia, review the effects on human health, and discuss its inclusion in the design method. To observe the influence of a track curve on noise emission, several measurement points were selected, and the noise emission was measured both in the curve and in the straight lines employing the same type of permanent way. RESULTS: The results in the sections with the radius below 50 m were greatly affected by the presence of a squeal noise, while the resulting noise level in the sections with the radius above 50 m depended on their radius. The difference between the average values of LAeq with and without the squeal in the measurement points with the radius below 50 m was 9 dB. The difference between the measurements in the curve sections with the radius below 50 m and those in the straight line was 2.7 dB. CONCLUSION: The resulting noise level in general was influenced by the car velocity and the technical shape of the permanent way. These results can be used in noise prognoses and in the health effect predictions. PMID- 27991465 TI - Specific and combined subjective responses to noise and their association with cardiovascular diseases. AB - INTRODUCTION: Noise is one of the most extensive environmental factors affecting the general population. The present study is focused on the association between discomfort caused by noise and the incidence of certain diseases (ischaemic heart disease, stroke and hypertension). MATERIALS AND METHODS: This cross-sectional questionnaire study, conducted in 10 cities in the Czech Republic, comprises two stages with 3592 obtained questionnaires in the first phase and 762 in the second phase. Twelve variables describe subjective responses to noise from different sources at different times of day. The intensity of the associations between variables was measured by correlation coefficient. Logistic regression was used for fitting models of morbidity, and confounders such as age and socio-economic status were included. The hypotheses from the first phase were independently validated using data from the second phase. RESULTS: The general rates of noise annoyance/sleep disturbance had greater correlation with traffic noise variables than with neighbourhood noise variables. Factors significantly associated with diseases are: for hypertension - annoyance by traffic noise (the elderly, odds ratio (OR) 1.4) and sleep disturbance by traffic and neighbourhood noise (the elderly, OR 1.6); for ischaemic heart disease - the general rate of noise annoyance (all respondents, OR 1.5 and the adults 30-60 years, OR 1.8) and the general rate of annoyance and sleep disturbance (all respondents, OR 1.3); for stroke - annoyance and sleep disturbance by traffic and neighbourhood noise (all respondents, OR 1.8). CONCLUSION: Factors that include multiple sources of noise or non-specific noise are associated with the studied diseases more frequently than the source-specific factors. PMID- 27991466 TI - Prevalence of tinnitus and noise-induced hearing loss in dentists. AB - INTRODUCTION: The purpose of this study was to evaluate noise levels in dental offices and to estimate the risk and prevalence of tinnitus and noise-induced hearing loss (NIHL) in practicing dentists. MATERIALS AND METHODS: First, measures were collected of sound pressure levels produced by dental handpieces and dental suction in the University of Oklahoma Health Sciences Center (OUHSC) College of Dentistry. Second, a survey was distributed to members of the Oklahoma Dental Association (ODA). RESULTS: Measurements made in the dental operatory revealed dangerous levels when high-volume suction was in use alone and in conjunction with a dental handpiece. Questionnaire results suggested that practicing dentists report sensorineural hearing loss at a rate broadly in line with national averages. However, dentists reported a higher prevalence of tinnitus symptoms than would be expected based on sample demographics. CONCLUSION: Results from sound level measurements and questionnaire responses indicate that dentists are a population that could be placing their hearing health at risk in a typical daily work environment. PMID- 27991467 TI - The risk of occupational injury increased according to severity of noise exposure after controlling for occupational environment status in Korea. AB - OBJECTIVES: The aim of this study was to examine the relationship between noise exposure and risk of occupational injury. MATERIALS AND METHODS: Korean National Health and Nutrition Examination Survey was used for the current study. Self report questionnaires were used to investigate occupational injury and exposure to noise, chemicals, and machines and equipments. RESULTS: In separate analyses for occupation and occupational hazard, the proportion of occupational injuries increased according to severity of noise exposure (all P < 0.05). Compared to the non-exposure group, the respective odds ratio (95% confidence intervals) for occupational injury was 1.39 (1.07-1.80) and 1.67 (1.13-2.46) in the mild and severe noise exposure groups, after controlling for age, gender, sleep hours, work schedule (shift work), and exposure status to hazardous chemicals and hazardous machines and equipments. CONCLUSIONS: The current study highlights the association between noise exposure and risk of occupational injury. Furthermore, risk of occupational injury increased according to severity of noise exposure. PMID- 27991468 TI - Arterial indices and serum cystatin C level in individuals with occupational wide band noise exposure. AB - BACKGROUND: Chronic exposure to noise is known to cause a wide range of health problems including extracellular matrix (ECM) proliferation and involvement of cardiovascular system. There are a few studies to investigate noise-induced vascular changes using noninvasive methods. In this study we used carotid artery intima-media thickness (CIMT) and aortic augmentation as indices of arterial properties and cystatin C as a serum biomarker relating to ECM metabolism. MATERIALS AND METHODS: Ninety-three male participants were included in this study from aeronautic technicians: 39 with and 54 without a history of wide band noise (WBN) exposure. For better discrimination, the participants were divided into the two age groups: <40 and >40 years old. Adjusted aortic augmentation index (AI) for a heart rate equal to 75 beats per minute (AIx@HR75) were calculated using pulse wave analysis (PWA). CIMT was measured in 54 participants who accepted to undergo Doppler ultrasonography. Serum cystatin C was also measured. RESULTS: Among younger individuals the mean CIMT was 0.85 +/- 0.09 mm and 0.75 +/- 0.22 mm in the in the exposed and the control groups respectively. Among older individuals CIMT had a mean of 1.04 +/- 0.22 mm vs. 1.00 +/- 0.25 mm for the exposed vs. the control group. However, in both age groups the difference was not significant at the 0.05 level. A comparison of AIx@HR75 between exposure group and control group both in younger age group (5.46 +/- 11.22 vs. 8.56 +/- 8.66) and older age group (17.55 +/- 10.07 vs. 16.61 +/- 5.77) revealed no significant difference. We did not find any significant correlation between CIMT and AIx@HR75 in exposed group (r = 0.314, P value = 0.145) but the correlation was significant in control group (r = 0.455, P value = 0.019). Serum cystatin C level was significantly lower in individuals with WBN exposure compared to controls (441.10 +/- 104.70 ng/L vs. 616.89 +/- 136.14, P value < 0.001) both in younger and older groups. CONCLUSION: We could not find any evidence for the association of WBN exposure with arterial properties, but cystatin C was significantly lower in the exposed group. PMID- 27991470 TI - Air traffic controllers' long-term speech-in-noise training effects: A control group study. AB - INTRODUCTION: Speech perception in noise relies on the capacity of the auditory system to process complex sounds using sensory and cognitive skills. The possibility that these can be trained during adulthood is of special interest in auditory disorders, where speech in noise perception becomes compromised. Air traffic controllers (ATC) are constantly exposed to radio communication, a situation that seems to produce auditory learning. The objective of this study has been to quantify this effect. SUBJECTS AND METHODS: 19 ATC and 19 normal hearing individuals underwent a speech in noise test with three signal to noise ratios: 5, 0 and -5 dB. Noise and speech were presented through two different loudspeakers in azimuth position. Speech tokes were presented at 65 dB SPL, while white noise files were at 60, 65 and 70 dB respectively. RESULTS: Air traffic controllers outperform the control group in all conditions [P<0.05 in ANOVA and Mann-Whitney U tests]. Group differences were largest in the most difficult condition, SNR=-5 dB. However, no correlation between experience and performance were found for any of the conditions tested. The reason might be that ceiling performance is achieved much faster than the minimum experience time recorded, 5 years, although intrinsic cognitive abilities cannot be disregarded. DISCUSSION: ATC demonstrated enhanced ability to hear speech in challenging listening environments. This study provides evidence that long-term auditory training is indeed useful in achieving better speech-in-noise understanding even in adverse conditions, although good cognitive qualities are likely to be a basic requirement for this training to be effective. CONCLUSION: Our results show that ATC outperform the control group in all conditions. Thus, this study provides evidence that long-term auditory training is indeed useful in achieving better speech-in-noise understanding even in adverse conditions. PMID- 27991469 TI - Gender differences in use of hearing protection devices among farm operators. AB - PURPOSE: Although farm operators have frequent exposure to hazardous noise and high rates of noise-induced hearing loss, they have low use of hearing protection devices (HPDs). Women represent about one-third of farm operators, and their numbers are climbing. However, among published studies examining use of HPDs in this worker group, none have examined gender-related differences. The purpose of this study was to examine gender-related differences in use of hearing protection and related predictors among farm operators. MATERIALS AND METHODS: Data previously collected at farm shows and by telephone were analyzed using t-tests and generalized linear model with zero inflated negative binomial (ZINB) distribution. FINDINGS: The difference in rate of hearing protector use between men and women farm operators was not significant. There was no difference between men and women in most hearing protector-related attitudes and beliefs. CONCLUSION: Although men and women farm operators had similar rates of use of hearing protectors when working in high-noise environments, attitudes about HPD use differed. Specifically, interpersonal role modeling was a predictor of HPD use among women, but not for men. This difference suggests that while farm operators of both genders may benefit from interventions designed to reduce barriers to HPD use (e.g., difficulty communicating with co-workers and hearing warning sounds), farm women have unique needs in relation to cognitive-perceptual factors that predict HPD use. Women farm operators may lack role models for use of HPDs (e.g., in peers and advertising), contributing to their less frequent use of protection. PMID- 27991471 TI - Cigarette- and snus-modified association between unprotected exposure to noise from hunting rifle caliber weapons and high frequency hearing loss. A cross sectional study among swedish hunters. AB - AIM: To investigate in this cross-sectional study among Swedish hunters if tobacco use modifies the previously observed association, expressed as prevalence ratio (PR), between unprotected exposure to impulse noise from hunting rifle caliber (HRC) weapons and high-frequency hearing impairment (HFHI). SETTINGS AND DESIGN: A nationwide cross-sectional epidemiologic study was conducted among Swedish sport hunters in 2012. MATERIALS AND METHODS: The study was Internet based and consisted of a questionnaire and an Internet-based audiometry test. RESULTS: In all, 202 hunters completed a questionnaire regarding the hearing test. Associations were modeled using Poisson regression. Current, daily use of tobacco was reported by 61 hunters (19 used cigarettes, 47 moist snuff, and 5 both). Tobacco users tended to be younger, fire more shots with HRC weapons, and report more hunting days. Their adjusted PR (1-6 unprotected HRC shots versus 0) was 3.2 (1.4-6.7), P < 0.01. Among the nonusers of tobacco, the corresponding PR was 1.3 (0.9-1.8), P = 0.18. P value for the interaction was 0.01. The importance of ear protection could not be quantified among hunters with HRC weapons because our data suggested that the HFHI outcome had led to changes in the use of such protection. Among hunters using weapons with less sound energy, however, no or sporadic use of hearing protection was linked to a 60% higher prevalence of HFHI, relative to habitual use. CONCLUSION: Tobacco use modifies the association between exposure to unprotected impulse noise from HRC weapons and the probability of having HFHI among susceptible hunters. The mechanisms remain to be clarified, but because the effect modification was apparent also among the users of smokeless tobacco, combustion products may not be critical for this effect. PMID- 27991472 TI - Modeling signal-to-noise ratio of otoacoustic emissions in workers exposed to different industrial noise levels. AB - INTRODUCTION: Noise is considered as the most common cause of harmful physical effects in the workplace. A sound that is generated from within the inner ear is known as an otoacoustic emission (OAE). Distortion-product otoacoustic emissions (DPOAEs) assess evoked emission and hearing capacity. The aim of this study was to assess the signal-to-noise ratio in different frequencies and at different times of the shift work in workers exposed to various levels of noise. It was also aimed to provide a statistical model for signal-to-noise ratio (SNR) of OAEs in different frequencies based on the two variables of sound pressure level (SPL) and exposure time. MATERIALS AND METHODS: This case-control study was conducted on 45 workers during autumn 2014. The workers were divided into three groups based on the level of noise exposure. The SNR was measured in frequencies of 1000, 2000, 3000, 4000, and 6000 Hz in both ears, and in three different time intervals during the shift work. According to the inclusion criterion, SNR of 6 dB or greater was included in the study. The analysis was performed using repeated measurements of analysis of variance, spearman correlation coefficient, and paired samples t-test. RESULTS: The results showed that there was no statistically significant difference between the three exposed groups in terms of the mean values of SNR (P > 0.05). Only in signal pressure levels of 88 dBA with an interval time of 10:30-11:00 AM, there was a statistically significant difference between the right and left ears with the mean SNR values of 3000 frequency (P = 0.038). The SPL had a significant effect on the SNR in both the right and left ears (P = 0.023, P = 0.041). The effect of the duration of measurement on the SNR was statistically significant in both the right and left ears (P = 0.027, P < 0.001). CONCLUSION: The findings of this study demonstrated that after noise exposure during the shift, SNR of OAEs reduced from the beginning to the end of the shift. PMID- 27991473 TI - Response to McCunney et al.: Wind turbines and health: An examination of a proposed case definition. PMID- 27991474 TI - The dialysis outcomes and practice patterns study phase 5 in the Gulf Cooperation Council countries: Design and study methods. AB - The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international prospective cohort study of the relationships between hemodialysis (HD) care practices and HD patient outcomes. The DOPPS began in 1996, in the United States, and has since expanded to 21 countries, collecting detailed data from >75,000 HD patients, with >200 scientific publications, focused on describing HD practices associated with improved HD patient outcomes. The goal of DOPPS is to help HD patients "live better and live longer." Starting in 2012, the DOPPS was able to expand to all six of the Gulf Cooperation Council (GCC) countries, namely, Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. The DOPPS study design consists of selecting HD facilities for study participation in each country to represent the different types of HD facilities and geographic regions within each GCC country. Within each study site, HD patients were randomly selected for detailed data collection to represent the HD practices within each participating HD facility. Altogether, 41 HD facilities have participated in the GCC-DOPPS Phase 5 study including 20 facilities from Saudi Arabia, nine from the United Arab Emirates, four each from Kuwait and Oman, two from Qatar, and one from Bahrain. Herein, we provide a detailed description of the study design and methods, data collection, study management, scientific investigator oversight and guidance, and study governance and support for the GCCDOPPS Phase 5 study. PMID- 27991475 TI - Demographics and key clinical characteristics of hemodialysis patients from the Gulf Cooperation Council countries enrolled in the dialysis outcomes and practice patterns study phase 5 (2012-2015). PMID- 27991476 TI - Cardiovascular and cerebrovascular comorbidities in hemodialysis patients from the Gulf Cooperation Council countries enrolled in the dialysis outcome and practice pattern study phase 5 (2012-2015). AB - To determine the prevalence of cardiovascular comorbidities and their active risk factors in the selected hemodialysis centers in the Gulf Cooperation Council (GCC) countries, the Dialysis Outcome and Practice Pattern Study (DOPPS) was performed on 40 dialysis centers in the six GCC countries from June 2012 to May 2015. There were 21 dialysis centers from Saudi Arabia, nine from the United Arab Emirates (UAE), four from Kuwait, four from Oman, two from Qatar, and one from Bahrain. There were 922 patients participating in the study; 419 patients from Saudi Arabia, 144 from the UAE, 164 from Kuwait, 89 from Oman, 58 from Qatar, and 25 from Bahrain. Baseline data and laboratory investigations were obtained from every study patient, and the patients with any new events, change of dialysis prescription, or death were reported to the DOPPS main center during follow-up. The median age of the patients in the GCC centers was 55 years (range 32- 80 years), and the median percentage of males was 57%. The most common cause of chronic kidney disease among the study patients was diabetes mellitus (median: 43%) followed by hypertension (median: 29%) and glomerulonephritis (median: 9%). Hypertension (median 90%) and diabetes mellitus (median 52%) were the most common predisposing comorbidities to cardiovascular events in the study patients. The median ratios of patients with coronary artery disease, peripheral vascular disease, and congestive heart failure were 34%, 23%, and 24%, respectively. The median ratio for cerebrovascular comorbidities was 9%. The median prevalence of the factors that may predispose to the cardiovascular and cerebrovascular comorbidities such as gender of the patients, adequacy of dialysis, diabetes, hypertension, hypercholesterolemia, levels of anemia, parathormone levels, and calcium and phosphorus levels in the GCC countries were comparable with those in the previous DOPPS in other countries. PMID- 27991477 TI - Nutritional status and outcomes in hemodialysis patients from the Gulf Cooperation Council countries enrolled in the dialysis outcome and practice patterns study phase 5 (2012-2015). AB - Nutrition is an important factor in maintaining good health of hemodialysis (HD) patients, affecting their morbidity and mortality. The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international observational study assessing differences in dialysis practices and outcomes across >20 countries. Here, we present the results for the Gulf Cooperation Council (GCC) countries regarding nutrition data and its relationship with outcomes as a part of the DOPPS Phase 5 study (2012-2015). Data were from Phase 5 of the DOPPS. Main analyses were based on 927 adult chronic HD patients enrolled at the start of the GCC-DOPPS Phase 5 study from each of the 40 randomly selected GCC HD facilities from Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. Within each participating facility, 20-30 patients were randomly selected, depending on facility size. Analysis showed minor differences across GCC countries in age, albumin levels, nutrition supplement use, and being bothered by the lack of appetite. Elderly (>60 years old) and diabetic HD patients displayed poorer nutritional parameters than young and nondiabetic patients. A low albumin level (<3.2 g/dL) was associated with the highest risk of mortality with a hazard ratio (HR) of 2.47 (P <0.0001) followed by diabetes with HR 1.57 (P <0.04) and older age [HR= 1.27/10 years older (P <0.01)]. Quality of life measures physical component summary and mental component summary correlated negatively with albumin <3.2 g/dL (-2.18 and -5.5, respectively, P <0.05 for each), and with serum creatinine level <7.5 mg/dL (-2.29 and -2.1 respectively, P <0.05 for each. We are presenting the first study of the nutrition status and outcomes for HD patients in the GCC countries in DOPPS. Our results were mostly comparable to findings in previous trials in other countries. Although the data are observational, our study provides good insight into aspects of nutrition in the GCC countries and can be compared to the rest of the world to better understand trends and practice differences. PMID- 27991478 TI - Hemodialysis delivery, dialysis dose achievement, and vascular access types in hemodialysis patients from the Gulf Cooperation Council countries enrolled in the dialysis outcomes and practice patterns study phase 5 (2012-2015). AB - The prospective observational Dialysis Outcomes and Practice Patterns Study (DOPPS) was initiated in late 2012 in national samples of hemodialysis (HD) units (n = 41 study sites) in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates). For many years, guidelines have recommended single pool Kt/V >=1.2 as the minimum adequate dose for chronic HD patients. Here, we report initial DOPPS results regarding HD practices related to dialysis dose achievement in the GCC. A total of 928 adult HD patients were included in this analysis from 41 centers representing all six GCC countries. Baseline descriptive statistics (e.g., mean, standard deviation, median, interquartile range, or percentage) were calculated for the study sample. Results were weighted according to the fraction of HD patients sampled within each participating study site. Mean age varied between 51 years in Bahrain, Oman, and Saudi Arabia, 55 years in the United Arab Emirates (UAE) and Kuwait, and 62 years in Qatar. Mean body mass index (BMI) was the lowest in Oman patients (23.9 kg/m 2 , but the remaining GCC countries had mean BMIs of 25.7-28.9 kg/m 2 and substantial fractions of overweight patients. Median dialysis vintage ranged from 1.52 years in Kuwait to 3.52 years in Oman. Mean treatment time per session varied from 202 min in Saudi Arabia to 230 min in Qatar while mean blood flow rate (BFR) ranged between 267 mL/min in Oman and 310 mL/min in Saudi Arabia. Interdialytic weight gain varied considerably among GCC countries between 3.1 and 4.0 kg. Central venous catheter use was high among GCC countries, ranging from 29% in Oman to 56% in Kuwait, with other countries averaging 30-40% catheter use. Data were available only for 50-76% of patients in four GCC countries (Kuwait, Qatar, Saudi Arabia, and UAE) for calculating single pool Kt/V to indicate dialysis adequacy. When calculated for patients with vintage >1 year and dialyzing three times per week, mean single pool Kt/V was highest in Qatar and the UAE (1.50-1.51), intermediate in Kuwait (1.35), and lowest in Saudi Arabia (1.29). A higher risk of mortality was observed for patients having a single pool Kt/V <1.2 (vs. >=1.2) [hazard ratio (HR) = 1.71, 95% confidence interval [CI]: 1.01-2.92]. Achievement of Kt/V in the GCC, although lower than in other DOPPS regions such as Europe/ANZ and North America, was similar to that in Japan. Japan and the GCC also share the practice of having a lower blood volume filtered per HD session per kg body weight. These findings suggest that increasing mean BFR and treatment time in the GCC, along with reducing catheter use, would substantially increase overall achievement of Kt/V >1.2 in the GCC, and hence, may improve survival. These mortality findings will need to be confirmed with up-coming GCC-DOPPS 6 analysis. PMID- 27991479 TI - Gulf Cooperation Council-dialysis outcomes and practice patterns study: An overview of anemia management trends at the regional and country specific levels in the Gulf Cooperation Council countries. AB - The Gulf Cooperation Council-Dialysis Outcomes and Practice Patterns Study (GCC DOPPS) marks the joining of the six Gulf region countries including Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates to the main DOPPS study in 2012. The current review is a descriptive reporting on results related to the management of anemia from these countries. Our data demonstrate consistent anemia management patterns across the GCC countries allowing the achievement of international treatment levels. Overall, the majority of hemodialysis patients were prescribed appropriate erythropoiesis-stimulating agents (ESAs) and supplemental iron, enabling the attainment of mean hemoglobin (Hb) level of 10.9 g/dL. Comparisons of the individual country profiles reveal individual differences in the choice and mode of ESA and iron administration. However, all countries displayed good compliance with guideline recommendations. The same challenges as elsewhere are faced in the GCC, with respect to optimizing Hb levels and judiciously using ESA and iron supplements. Some opportunities exist for focused efforts to fine tune inter-facility variability in anemia management based on continued data tracking. The latter is vital in enabling adopting new trends to further improve not only anemia management but also the wholesome care of dialysis patients. PMID- 27991480 TI - Mineral bone disorder and its management among hemodialysis patients in the Gulf Cooperation Council: Initial findings from the dialysis outcomes and practice patterns study (2012-2015). AB - The prospective cohort Dialysis Outcomes and Practice Patterns Study (DOPPS) initiated data collection in national samples of hemodialysis (HD) units (total of 41 study sites) in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates) in late 2012. Here, we report initial results regarding mineral bone disorders (MBDs) and its management in the GCC countries. Forty-one randomly selected HD facilities, treating >23 HD patients each, were sampled and represent care for >95% of GCC HD patients. Descriptive results for the GCC countries based on a random sample of 20-30 HD patients in each study facility. Initial results for the GCC are from 931 HD patients treated at 41 dialysis units (ranging from 1 unit in Bahrain to 21 in Saudi Arabia). Results are presented as weighted estimates, accounting for the sampling fraction in each unit. Baseline descriptive statistics (e.g., mean, median, or percentage), weighted by facility sampling fraction were calculated for the study sample. For analyses examining the percent of facility patients having (a) serum phosphorus >6.0 mg/dL or (b) parathyroid hormone (PTH) >600 pg/mL, analyses were restricted to facilities having at least 10 HD patients with a reported serum phosphorus or PTH measurement, respectively. Logistic regression analyses of the indicated binary outcomes were based on the use of generalized estimating equations and were adjusted for GCC country, patient age category (<45 years, 45-65 years, and >65 years old), sex, and whether the patient was diagnosed with diabetes mellitus. Logistic models accounted for clustering of patients within facilities, assuming an exchangeable working correlation matrix. Mean age of HD patients in the GCC countries was 53 years vs. 61-64 years in the three other DOPPS regions. MBD markers showed slightly lower mean serum Calcium in the GCC countries, similar mean serum phosphorus, and intermediate median PTH levels compared with the three other DOPPS regions. Among GCC countries, the country mean value of MBD markers ranged from 8.6-9.0 mg/dL for serum calcium, 4.4-5.4 mg/dL for serum phosphorus, whereas median PTH ranged from 163-389 pg/mL. Similar to other DOPPS regions, PTH was higher among patients who were younger or without diabetes, and serum phosphorus was lower with older age (P <0.001 for each). History of parathyroidectomy was lower in the GCC countries versus other regions but did not differ when adjusted for age and dialysis vintage. Among treatments used for managing MBD, the GCC countries showed one of the highest uses of cinacalcet (24%) and phosphorus binder use (81%), whereas intravenous Vitamin D use (24%) was slightly higher than that in EURANZ. A much larger fraction of HD patients in the GCC countries had a dialysate calcium bath >=3.5 mEq/L (43%) versus 0-4% in the three other DOPPS regions. Although many aspects of MBD management and MBD marker achievement are similar in the GCC countries to that seen in other DOPPS study regions, large variability was seen across countries and facilities in the GCC. Mean serum calcium was lower in the GCC despite the much greater use of dialysate Ca of ~3.5 mEq/L which may be due to the relatively low use of vitamin D and higher cinacalcet use, meriting further study. Future work will focus on GCC facility HD practices and patient characteristics most strongly related to the achievement of MBD target levels and associated outcomes. PMID- 27991482 TI - The effects of unstable surface balance training on postural sway, stability, functional ability and flexibility in women. AB - BACKGROUND: This study examined the effects of balance training routine, using both sides utilized balance trainer (BOSU) and aerobic step (STEP) on postural sway and functional ability in middle-aged women. METHODS: Twenty-seven females participated in the study, age 40.6+/-12.0 years, body mass 72.0+/-14.0 kg, height 164.0+/-7.7 cm, BMI 26.5+/-4.5 kg/m2, and relative body fat 33.1+/-7.4%. Participants were divided into two groups and performed progressive exercise routine on either STEP or BOSU for three weeks. Pre- and post-test consisted of Postural Sway Test performed on the Biodex Balance System, Functional Ability Test, Sit and Reach Test and Plank. RESULTS: A significant time effect was observed for both groups for sway index(P=0.029) and center of pressure antero posterior (AP) displacement (P=0.038) but not for sway area or medio-lateral (ML) displacement (P>0.05). In addition, BOSU group had significantly lower Sway Index(P=0.048) and ML range (P=0.035) scores when vision and surface was altered compared to STEP group. A significant time effect was observed in walking-up the stairs (P=0.020), sit and reach test (P=0.035), and plank (P<0.001), but not for walking down the stairs. However, no other significant interactions were observed. CONCLUSIONS: Programs that incorporate multisensory balance training have a potential to induce adaptive responses in neuromuscular system that enhances postural control, balance and functional ability of women. The training using BOSU may help improve static balance and functional ability in women. PMID- 27991481 TI - Circulating MicroRNA-21, MicroRNA-23a, and MicroRNA-125b as Biomarkers for Diagnosis and Prognosis of Burkitt Lymphoma in Children. AB - BACKGROUND The aim of this study was to investigate the diagnostic and prognostic value of microRNA (miRNA)-21, miRNA-23a, and miRNA-125b in Burkitt lymphoma (BL) in children. MATERIAL AND METHODS We recruited 41 children with BL for the case group, 56 children with lymph node inflammation for the positive control group, and 60 healthy children for the negative control group. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was conducted for detection of circulating miRNA-21, miRNA-23a, and miRNA-125b. A receiver operating characteristic (ROC) curve was drawn to compare the diagnostic value of miRNA-21, miRNA-23a, and miRNA-125b. Kaplan-Meier method and log-rank test were used for prognostic analyses. RESULTS MiRNA-21 and miRNA-23a had significantly higher expression in cases than in positive and negative controls (all P<0.05). Overexpression of miRNA-21 and miRNA-23a were associated with staging, WBC, upregulated serum lactate dehydrogenase (LDH) level, presence of lymphoma size >=6 cm, and cluster of differentiation 10 (CD10) expression, while miRNA-125b expression had an association with staging and upregulated serum LDH level (both P<0.05). ROC curves of miRNA-21, miRNA-23a, and miRNA-125b presented an area under curve (AUC) of 0.759, 0.853 and 0.615, respectively. MiRNA-21 and miRNA-23a in combination had an AUC of 0.869. After treatment, both miRNA-21 and miRNA-23a expression were significantly decreased (both P<0.05). Advanced clinical stage, upregulated LDH, and lymphoma size of 36 cm were related to low complete remission rate (all P<0.05). CONCLUSIONS Patients with high expression of miRNA 21 and miRNA-23a had significantly lower complete remission rates and survival rates than those with low expression. Expression of miRNA-21 and miRNA-23a may serve as useful diagnostic and prognostic biomarkers in children with BL. PMID- 27991483 TI - Differing six minute pacing strategies affect anaerobic contribution, oxygen uptake, muscle deoxygenation and cycle performance. AB - BACKGROUND: This study compared an all-out start (AO) to a constant power start strategy (CON) during a 6 min cycle performance on utilization of W' (energy above critical power [CP]), muscle deoxygenation (HHb), oxygen uptake (VO2) and performance in recreationally active individuals. The AO strategy was similar to that employed by rowers. METHODS: Eight healthy males (age =24+/-3 y) completed a ramp test to fatigue (VO2peak =4.42+/-0.54 L?min-1; peak power =385+/-35 W) and a 3-min all-out test to determine CP and the CON work rate. The AO strategy began with a 12 s sprint, followed by 258 s at 5%= 7.30), mild/moderate (7.1 <= pH < 7.30) and severe (pH < 7.1). Two multiple logistic regression models were used to evaluate the time trend of DKA frequency considered as present versus absent and severe versus absent, adjusted for gender, age group and geographical area of residence at diagnosis. Overall, 9,040 cases were ascertained. DKA frequency was 40.3% (95%CI: 39.3-41.4%), with 29.1% and 11.2% for mild/moderate and severe DKA, respectively. Severe DKA increased significantly during the period (OR = 1.03, 95%CI: 1.003-1.05). Younger-age children and children living in Southern Italy compared to Central Italy were at significantly higher risk of DKA and severe DKA. Family history of type 1 diabetes and residence in Sardinia compared to Central Italy were significantly associated with a lower probability of DKA and severe DKA. The high frequency of ketoacidosis in Italy over time and high variability among age groups and geographical area of residence, strongly suggests a continuing need for nationwide healthcare strategies to increase awareness of early detection of diabetes. PMID- 27991503 TI - Tumour homing and therapeutic effect of colloidal nanoparticles depend on the number of attached antibodies. AB - Active targeting of nanoparticles to tumours can be achieved by conjugation with specific antibodies. Specific active targeting of the HER2 receptor is demonstrated in vitro and in vivo with a subcutaneous MCF-7 breast cancer mouse model with trastuzumab-functionalized gold nanoparticles. The number of attached antibodies per nanoparticle was precisely controlled in a way that each nanoparticle was conjugated with either exactly one or exactly two antibodies. As expected, in vitro we found a moderate increase in targeting efficiency of nanoparticles with two instead of just one antibody attached per nanoparticle. However, the in vivo data demonstrate that best effect is obtained for nanoparticles with only exactly one antibody. There is indication that this is based on a size-related effect. These results highlight the importance of precisely controlling the ligand density on the nanoparticle surface for optimizing active targeting, and that less antibodies can exhibit more effect. PMID- 27991504 TI - The origin of ultrahigh piezoelectricity in relaxor-ferroelectric solid solution crystals. AB - The discovery of ultrahigh piezoelectricity in relaxor-ferroelectric solid solution single crystals is a breakthrough in ferroelectric materials. A key signature of relaxor-ferroelectric solid solutions is the existence of polar nanoregions, a nanoscale inhomogeneity, that coexist with normal ferroelectric domains. Despite two decades of extensive studies, the contribution of polar nanoregions to the underlying piezoelectric properties of relaxor ferroelectrics has yet to be established. Here we quantitatively characterize the contribution of polar nanoregions to the dielectric/piezoelectric responses of relaxor ferroelectric crystals using a combination of cryogenic experiments and phase field simulations. The contribution of polar nanoregions to the room-temperature dielectric and piezoelectric properties is in the range of 50-80%. A mesoscale mechanism is proposed to reveal the origin of the high piezoelectricity in relaxor ferroelectrics, where the polar nanoregions aligned in a ferroelectric matrix can facilitate polarization rotation. This mechanism emphasizes the critical role of local structure on the macroscopic properties of ferroelectric materials. PMID- 27991506 TI - Genome engineering: NHEJ and CRISPR-Cas9 improve gene therapy. PMID- 27991507 TI - Organelle dynamics: Controlling phase separation of P granules. PMID- 27991508 TI - Cellular senescence: Senescence and reprogramming go hand-in-hand. PMID- 27991505 TI - Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53 mediated apoptosis. AB - Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53 dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner. PMID- 27991510 TI - RNA decay: NoBody binds to mRNA decapping proteins. PMID- 27991509 TI - Protein translocation: The third route to the ER. PMID- 27991511 TI - Chromatin: The chemical brothers: nucleosomes and transcription. PMID- 27991512 TI - Complementarity of PALM and SOFI for super-resolution live-cell imaging of focal adhesions. AB - Live-cell imaging of focal adhesions requires a sufficiently high temporal resolution, which remains a challenge for super-resolution microscopy. Here we address this important issue by combining photoactivated localization microscopy (PALM) with super-resolution optical fluctuation imaging (SOFI). Using simulations and fixed-cell focal adhesion images, we investigate the complementarity between PALM and SOFI in terms of spatial and temporal resolution. This PALM-SOFI framework is used to image focal adhesions in living cells, while obtaining a temporal resolution below 10 s. We visualize the dynamics of focal adhesions, and reveal local mean velocities around 190 nm min 1. The complementarity of PALM and SOFI is assessed in detail with a methodology that integrates a resolution and signal-to-noise metric. This PALM and SOFI concept provides an enlarged quantitative imaging framework, allowing unprecedented functional exploration of focal adhesions through the estimation of molecular parameters such as fluorophore densities and photoactivation or photoswitching kinetics. PMID- 27991513 TI - Real-time measurements of spontaneous breathers and rogue wave events in optical fibre modulation instability. AB - Modulation instability is a fundamental process of nonlinear science, leading to the unstable breakup of a constant amplitude solution of a physical system. There has been particular interest in studying modulation instability in the cubic nonlinear Schrodinger equation, a generic model for a host of nonlinear systems including superfluids, fibre optics, plasmas and Bose-Einstein condensates. Modulation instability is also a significant area of study in the context of understanding the emergence of high amplitude events that satisfy rogue wave statistical criteria. Here, exploiting advances in ultrafast optical metrology, we perform real-time measurements in an optical fibre system of the unstable breakup of a continuous wave field, simultaneously characterizing emergent modulation instability breather pulses and their associated statistics. Our results allow quantitative comparison between experiment, modelling and theory, and are expected to open new perspectives on studies of instability dynamics in physics. PMID- 27991514 TI - A Mott insulator continuously connected to iron pnictide superconductors. AB - Iron-based superconductivity develops near an antiferromagnetic order and out of a bad-metal normal state, which has been interpreted as originating from a proximate Mott transition. Whether an actual Mott insulator can be realized in the phase diagram of the iron pnictides remains an open question. Here we use transport, transmission electron microscopy, X-ray absorption spectroscopy, resonant inelastic X-ray scattering and neutron scattering to demonstrate that NaFe1-xCuxAs near x~0.5 exhibits real space Fe and Cu ordering, and are antiferromagnetic insulators with the insulating behaviour persisting above the Neel temperature, indicative of a Mott insulator. On decreasing x from 0.5, the antiferromagnetic-ordered moment continuously decreases, yielding to superconductivity ~x=0.05. Our discovery of a Mott-insulating state in NaFe1 xCuxAs thus makes it the only known Fe-based material, in which superconductivity can be smoothly connected to the Mott-insulating state, highlighting the important role of electron correlations in the high-Tc superconductivity. PMID- 27991515 TI - A Large Ornithurine Bird (Tingmiatornis arctica) from the Turonian High Arctic: Climatic and Evolutionary Implications. AB - Bird fossils from Turonian (ca. 90 Ma) sediments of Axel Heiberg Island (High Canadian Arctic) are among the earliest North American records. The morphology of a large well-preserved humerus supports identification of a new volant, possibly diving, ornithurine species (Tingmiatornis arctica). The new bird fossils are part of a freshwater vertebrate fossil assemblage that documents a period of extreme climatic warmth without seasonal ice, with minimum mean annual temperatures of 14 degrees C. The extreme warmth allowed species expansion and establishment of an ecosystem more easily able to support large birds, especially in fresh water bodies such as those present in the Turonian High Arctic. Review of the high latitude distribution of Northern Hemisphere Mesozoic birds shows only ornithurine birds are known to have occupied these regions. We propose physiological differences in ornithurines such as growth rate may explain their latitudinal distribution especially as temperatures decline later in the Cretaceous. Distribution and physiology merit consideration as factors in their preferential survival of parts of one ornithurine lineage, Aves, through the K/Pg boundary. PMID- 27991517 TI - An antireflection transparent conductor with ultralow optical loss (<2 %) and electrical resistance (<6 Omega sq-1). AB - Transparent conductors are essential in many optoelectronic devices, such as displays, smart windows, light-emitting diodes and solar cells. Here we demonstrate a transparent conductor with optical loss of ~1.6%, that is, even lower than that of single-layer graphene (2.3%), and transmission higher than 98% over the visible wavelength range. This was possible by an optimized antireflection design consisting in applying Al-doped ZnO and TiO2 layers with precise thicknesses to a highly conductive Ag ultrathin film. The proposed multilayer structure also possesses a low electrical resistance (5.75 Omega sq 1), a figure of merit four times larger than that of indium tin oxide, the most widely used transparent conductor today, and, contrary to it, is mechanically flexible and room temperature deposited. To assess the application potentials, transparent shielding of radiofrequency and microwave interference signals with ~30 dB attenuation up to 18 GHz was achieved. PMID- 27991516 TI - Metagenomic mining for thermostable esterolytic enzymes uncovers a new family of bacterial esterases. AB - Biocatalysts exerting activity against ester bonds have a broad range of applications in modern biotechnology. Here, we have identified a new esterolytic enzyme by screening a metagenomic sample collected from a hot spring in Kamchatka, Russia. Biochemical characterization of the new esterase, termed EstDZ2, revealed that it is highly active against medium chain fatty acid esters at temperatures between 25 and 60 degrees C and at pH values 7-8. The new enzyme is moderately thermostable with a half-life of more than six hours at 60 degrees C, but exhibits exquisite stability against high concentrations of organic solvents. Phylogenetic analysis indicated that EstDZ2 is likely an Acetothermia enzyme that belongs to a new family of bacterial esterases, for which we propose the index XV. One distinctive feature of this new family, is the presence of a conserved GHSAG catalytic motif. Multiple sequence alignment, coupled with computational modelling of the three-dimensional structure of EstDZ2, revealed that the enzyme lacks the largest part of the "cap" domain, whose extended structure is characteristic for the closely related Family IV esterases. Thus, EstDZ2 appears to be distinct from known related esterolytic enzymes, both in terms of sequence characteristics, as well as in terms of three-dimensional structure. PMID- 27991518 TI - Greenland subglacial drainage evolution regulated by weakly connected regions of the bed. AB - Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology. PMID- 27991519 TI - Corrigendum: Efficacy of PIVKA-II in prediction and early detection of hepatocellular carcinoma: a nested case-control study in Chinese patients. PMID- 27991520 TI - The Safety Limits Of An Extended Fast: Lessons from a Non-Model Organism. AB - While safety of fasting therapy is debated in humans, extended fasting occurs routinely and safely in wild animals. To do so, food deprived animals like breeding penguins anticipate the critical limit of fasting by resuming feeding. To date, however, no molecular indices of the physiological state that links spontaneous refeeding behaviour with fasting limits had been identified. Blood proteomics and physiological data reveal here that fasting-induced body protein depletion is not unsafe "per se". Indeed, incubating penguins only abandon their chick/egg to refeed when this state is associated with metabolic defects in glucose homeostasis/fatty acid utilization, insulin production and action, and possible renal dysfunctions. Our data illustrate how the field investigation of "exotic" models can be a unique source of information, with possible biomedical interest. PMID- 27991521 TI - Sub-cycle ionization dynamics revealed by trajectory resolved, elliptically driven high-order harmonic generation. AB - The sub-cycle dynamics of electrons driven by strong laser fields is central to the emerging field of attosecond science. We demonstrate how the dynamics can be probed through high-order harmonic generation, where different trajectories leading to the same harmonic order are initiated at different times, thereby probing different field strengths. We find large differences between the trajectories with respect to both their sensitivity to driving field ellipticity and resonant enhancement. To accurately describe the ellipticity dependence of the long trajectory harmonics we must include a sub-cycle change of the initial velocity distribution of the electron and its excursion time. The resonant enhancement is observed only for the long trajectory contribution of a particular harmonic when a window resonance in argon, which is off-resonant in the field free case, is shifted into resonance due to a large dynamic Stark shift. PMID- 27991523 TI - Non-binary Colour Modulation for Display Device Based on Phase Change Materials. AB - A reflective-type display device based on phase change materials is attractive because of its ultrafast response time and high resolution compared with a conventional display device. This paper proposes and demonstrates a unique display device in which multicolour changing can be achieved on a single device by the selective crystallization of double layer phase change materials. The optical contrast is optimized by the availability of a variety of film thicknesses of two phase change layers. The device exhibits a low sensitivity to the angle of incidence, which is important for display and colour consistency. The non-binary colour rendering on a single device is demonstrated for the first time using optical excitation. The device shows the potential for ultrafast display applications. PMID- 27991522 TI - Quantitative assessment of the regenerative and mineralogenic performances of the zebrafish caudal fin. AB - The ability of zebrafish to fully regenerate its caudal fin has been explored to better understand the mechanisms underlying de novo bone formation and to develop screening methods towards the discovery of compounds with therapeutic potential. Quantifying caudal fin regeneration largely depends on successfully measuring new tissue formation through methods that require optimization and standardization. Here, we present an improved methodology to characterize and analyse overall caudal fin and bone regeneration in adult zebrafish. First, regenerated and mineralized areas are evaluated through broad, rapid and specific chronological and morphometric analysis in alizarin red stained fins. Then, following a more refined strategy, the intensity of the staining within a 2D longitudinal plane is determined through pixel intensity analysis, as an indicator of density or thickness/volume. The applicability of this methodology on live specimens, to reduce animal experimentation and provide a tool for in vivo tracking of the regenerative process, was successfully demonstrated. Finally, the methodology was validated on retinoic acid- and warfarin-treated specimens, and further confirmed by micro-computed tomography. Because it is easily implementable, accurate and does not require sophisticated equipment, the present methodology will certainly provide valuable technical standardization for research in tissue engineering, regenerative medicine and skeletal biology. PMID- 27991524 TI - Macrophages Enhance Migration in Inflammatory Breast Cancer Cells via RhoC GTPase Signaling. AB - Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. All IBC patients have lymph node involvement and one-third of patients already have distant metastasis at diagnosis. This propensity for metastasis is a hallmark of IBC distinguishing it from less lethal non-inflammatory breast cancers (nIBC). Genetic profiling studies have been conducted to differentiate IBC from nIBC, but no IBC cancer-cell-specific gene signature has been identified. We hypothesized that a tumor-extrinsic factor, notably tumor-associated macrophages, promotes and contributes to IBC's extreme metastatic phenotype. To this end, we studied the effect of macrophage-conditioned media (MCM) on IBC. We show that two IBC cell lines are hyper-responsive to MCM as compared to normal-like breast and aggressive nIBC cell lines. We further interrogated IBC's hyper-responsiveness to MCM using a microfluidic migration device, which permits individual cell migration path tracing. We found the MCM "primes" the IBC cells' cellular machinery to become extremely migratory in response to a chemoattractant. We determined that interleukins -6, -8, and -10 within the MCM are sufficient to stimulate this enhanced IBC migration effect, and that the known metastatic oncogene, RhoC GTPase, is necessary for the enhanced migration response. PMID- 27991525 TI - Bacterial cytosolic proteins with a high capacity for Cu(I) that protect against copper toxicity. AB - Bacteria are thought to avoid using the essential metal ion copper in their cytosol due to its toxicity. Herein we characterize Csp3, the cytosolic member of a new family of bacterial copper storage proteins from Methylosinus trichosporium OB3b and Bacillus subtilis. These tetrameric proteins possess a large number of Cys residues that point into the cores of their four-helix bundle monomers. The Csp3 tetramers can bind a maximum of approximately 80 Cu(I) ions, mainly via thiolate groups, with average affinities in the (1-2) * 1017 M-1 range. Cu(I) removal from these Csp3s by higher affinity potential physiological partners and small-molecule ligands is very slow, which is unexpected for a metal-storage protein. In vivo data demonstrate that Csp3s prevent toxicity caused by the presence of excess copper. Furthermore, bacteria expressing Csp3 accumulate copper and are able to safely maintain large quantities of this metal ion in their cytosol. This suggests a requirement for storing copper in this compartment of Csp3-producing bacteria. PMID- 27991526 TI - Putative WRKYs associated with regulation of fruit ripening revealed by detailed expression analysis of the WRKY gene family in pepper. AB - WRKY transcription factors play important roles in plant development and stress responses. Here, global expression patterns of pepper CaWRKYs in various tissues as well as response to environmental stresses and plant hormones were systematically analyzed, with an emphasis on fruit ripening. The results showed that most CaWRKYs were expressed in at least two of the tissues tested. Group I, a subfamily of the entire CaWRKY gene family, had a higher expression level in vegetative tissues, whereas groups IIa and III showed relatively lower expression levels. Comparative analysis showed that the constitutively highly expressed WRKY genes were conserved in tomato and pepper, suggesting potential functional similarities. Among the identified 61 CaWRKYs, almost 60% were expressed during pepper fruit maturation, and the group I genes were in higher proportion during the ripening process, indicating an as-yet unknown function of group I in the fruit maturation process. Further analysis suggested that many CaWRKYs expressed during fruit ripening were also regulated by abiotic stresses or plant hormones, indicating that these CaWRKYs play roles in the stress-related signaling pathways during fruit ripening. This study provides new insights to the current research on CaWRKY and contributes to our knowledge about the global regulatory network in pepper fruit ripening. PMID- 27991527 TI - Strain tunable magnetism in SnX2 (X = S, Se) monolayers by hole doping. AB - By first-principles calculations, the magnetism of hole doped tin dichalcogenides SnX2 (X = S, Se) monolayers is systematically studied. It is found that a phase transition from nonmagnetic to ferromagnetic ground state appears once above the critical hole density (~1014 cm-2). The spin magnetic moment can maintain a magnitude of 1.0 MUB/hole with excellent stability of ferromagnetic state. Furthermore, we demonstrate that strain is very useful to modulate the DOS near the valence band, resulting in the reduction of the critical hole density to ~1013 cm-2 when the strain reaches 4% (6%) in SnS2 (SnSe2), which can be realized in common field effect transistors. Moreover, the phonon dispersion calculations for the strained SnX2 monolayers indicate that they can keep the dynamical stability under the hole doping. Therefore, the strain tunable magnetic transition in hole doped tin dichalcogenides indicates their potential promising applications in spintronic devices. PMID- 27991528 TI - Prognostic Value of Bone Mineral Density on Curve Progression: A Longitudinal Cohort Study of 513 Girls with Adolescent Idiopathic Scoliosis. AB - Osteopenia has been found to occur in about 30% of Adolescent Idiopathic Scoliosis (AIS) patients. This study aimed to investigate its prognostic value on the risk of curve progression to surgical threshold. Newly diagnosed AIS girls (N = 513) with Cobb angle 10 degrees -40 degrees were recruited with follow-up till maturity. Bilateral hips were assessed with dual-energy x-ray absorptiometry (DXA). Distal radius of a subgroup of 90 subjects was further assessed with high resolution peripheral quantitative computed tomography (HR-pQCT). 55 patients progressed to surgical threshold or underwent spine surgery at the end of follow up. Cox model with osteopenia status performed significantly better than the model without (p = 0.010). Osteopenic patients had significantly higher risk of surgery (HR2.25, p = 0.011), even after adjustment for menarche status, age and initial Cobb angle. The incremental predictive value of osteopenia was, however, not statistically significant. In the subgroup analysis, cortical bone density was identified as a better marker to improve the sensitivity of the prediction, but requires further larger study to validate this finding. These consistent results of bone density measured at different sites suggest a systemic effect, rather than local effect to the deformed spine, and support to the link of abnormal bone density to the etiopathogenesis in AIS patients. PMID- 27991529 TI - The biosynthetic pathway of 2-azahypoxanthine in fairy-ring forming fungus. AB - "Fairy rings" resulting from fungus-stimulated plant growth occur all over the world. In 2010, 2-azahypoxanthine (AHX) from a fungus Lepista sordida was identified as the "fairy" that stimulates plant growth. Furthermore, 2-aza-8 oxohypoxanthine (AOH) was isolated as a common metabolite of AHX in plants, and the endogenous existence of AHX and AOH in plants was proved. The structure of AHX allowed us to hypothesize that AHX was derived from 5-aminoimidazole-4 carboxamide ribonucleotide (AICAR). Thus, we performed a feeding experiment that supplied AICAR to L. sordida. Consumption of AICAR and accumulation of AHX were observed after feeding. The mycelia extract had enzymatic activity of adenine/5 aminoimidazole-4-carboxamide phosphoribosyltransferase (APRT). APRT gene of L. sordida revealed its structural characteristics in homology modeling and showed transcriptional enhancement after feeding. These results support that AHX was synthesized from AICAR and AHX biosynthesis was transcriptionally controlled by AICAR, indicating the presence of novel purine metabolic pathway in L. sordida. PMID- 27991530 TI - Comparative metagenomics reveals taxonomically idiosyncratic yet functionally congruent communities in periodontitis. AB - The phylogenetic characteristics of microbial communities associated with periodontitis have been well studied, however, little is known about the functional endowments of this ecosystem. The present study examined 73 microbial assemblages from 25 individuals with generalized chronic periodontitis and 25 periodontally healthy individuals using whole genome shotgun sequencing. Core metabolic networks were computed from taxa and genes identified in at least 80% of individuals in each group. 50% of genes and species identified in health formed part of the core microbiome, while the disease-associated core microbiome contained 33% of genes and only 1% of taxa. Clinically healthy sites in individuals with periodontitis were more aligned with sites with disease than with health. 68% of the health-associated metagenome was dedicated to energy utilization through oxidative pathways, while in disease; fermentation and methanogenesis were predominant energy transfer mechanisms. Expanded functionality was observed in periodontitis, with unique- or over-representation of genes encoding for fermentation, antibiotic resistance, detoxification stress, adhesion, invasion and intracellular resistance, proteolysis, quorum sensing, Type III/IV secretion systems, phages and toxins in the disease-associated core microbiome. However, different species or consortia contributed to these functions in each individual. Several genes, but not species, demonstrated robust discriminating power between health and disease. PMID- 27991531 TI - Redox properties of extracellular polymeric substances (EPS) from electroactive bacteria. AB - Although the capacity for electroactive bacteria to convert environmental metallic minerals and organic pollutants is well known, the role of the redox properties of microbial extracellular polymeric substances (EPS) in this process is poorly understood. In this work, the redox properties of EPS from two widely present electroactive bacterial strains (Shewanella oneidensis and Pseudomonas putida) were explored. Electrochemical analysis demonstrates that the EPS extracted from the two strains exhibited redox properties. Spectroelectrochemical and protein electrophoresis analyses indicate that the extracted EPS from S. oneidensis and P. putida contained heme-binding proteins, which were identified as the possible redox components in the EPS. The results of heme-mediated behavior of EPS may provide an insight into the important roles of EPS in electroactive bacteria to maximize their redox capability for biogeochemical cycling, environmental bioremediation and wastewater treatment. PMID- 27991532 TI - Possible Source Populations of the White-backed Planthopper in the Greater Mekong Subregion Revealed by Mitochondrial DNA Analysis. AB - The white-backed planthopper, Sogatella furcifera (Horvath) (Hemiptera: Delphacidae), is a serious pest of rice in Asia. However, little is known regarding the migration of this pest insect from the Greater Mekong Subregion (GMS) including Cambodia, Laos, Myanmar (Burma), Thailand, and Vietnam, into China's Yunnan Province. To determine the migration patterns of S. furcifera in the GMS and putative secondary immigration inside China's Yunnan Province, we investigated the population genetic diversity, genetic structure, and gene flow of 42 S. furcifera populations across the six countries in the GMS by intensive sampling using mitochondrial genes. Our study revealed the potential emigration of S. furcifera from the GMS consists primarily of three major sources: 1) the S. furcifera from Laos and Vietnam migrate into south and southeast Yunnan, where they proceed to further migrate into northeast and central Yunnan; 2) the S. furcifera from Myanmar migrate into west Yunnan, and/or central Yunnan, and/or northeast Yunnan; 3) the S. furcifera from Cambodia migrate into southwest Yunnan, where the populations can migrate further into central Yunnan. The new data will not only be helpful in predicting population dynamics of the planthopper, but will also aid in regional control programs for this economically important pest insect. PMID- 27991533 TI - Distinct urine metabolome after Asian ginseng and American ginseng intervention based on GC-MS metabolomics approach. AB - Ginseng occupies a prominent position in the list of best-selling natural products worldwide. Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius) show different properties and medicinal applications in pharmacology, even though the main active constituents of them are both thought to be ginsenosides. Metabolomics is a promising method to profile entire endogenous metabolites and monitor their fluctuations related to exogenous stimulus. Herein, an untargeted metabolomics approach was applied to study the overall urine metabolic differences between Asian ginseng and American ginseng in mice. Metabolomics analyses were performed using gas chromatography-mass spectrometry (GC-MS) together with multivariate statistical data analysis. A total of 21 metabolites related to D-glutamine and D-glutamate metabolism, glutathione metabolism, TCA cycle and glyoxylate and dicarboxylate metabolism, differed significantly under the Asian ginseng treatment; 34 metabolites mainly associated with glyoxylate and dicarboxylate metabolism, TCA cycle and taurine and hypotaurine metabolism, were significantly altered after American ginseng treatment. Urinary metabolomics reveal that Asian ginseng and American ginseng can benefit organism physiological and biological functions via regulating multiple metabolic pathways. The important pathways identified from Asian ginseng and American ginseng can also help to explore new therapeutic effects or action targets so as to broad application of these two ginsengs. PMID- 27991534 TI - Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: A systematic review and meta-analysis. AB - Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and impaired platelet production. In this study, we conducted a systematic review and meta-analysis to determine the efficacy and safety of thrombopoietin receptor agonists (TPO-RAs) in primary ITP patients. Thirteen randomized controlled trials were included in this study, the pooled results of which demonstrated that TPO-RAs significantly increased platelet response (R) and durable response (DR) rates [risk ratio (RR): 2.77, 95% confidence interval (CI): 2.01-3.82, P = 5.9 * 10-10; RR: 7.52, 95% CI: 3.94 14.35, P = 9.2 * 10-10; respectively] and that TPO-RAs significantly reduced the incidences of any or severe bleeding events (RR: 0.80, 95% CI: 0.67-0.95, P = 0.013; RR: 0.52, 95% CI: 0.27-0.99, P = 0.048; respectively). Moreover, our results indicated that there was a significant reduction in the proportion of patients needing rescue medications in the TPO-RA groups compared with the control groups (RR: 0.50, 95% CI: 0.42-0.59, P = 2.0 * 10-15) and that the rates of any or severe adverse events were similar between the TPO-RA and control regimens (RR: 1.01, 95% CI: 0.92-1.10; RR: 0.74, 95% CI: 0.54-1.01; respectively). These findings demonstrate that TPO-RAs are an effective and safe second-line treatment option for primary ITP patients. PMID- 27991535 TI - Implications for management and conservation of the population genetic structure of the wedge clam Donax trunculus across two biogeographic boundaries. AB - In a resource management perspective, the understanding of the relative influence of the physical factors on species connectivity remains a major challenge and is also of great ecological and conservation biology interest. Despite the overfishing threat on the wedge clam Donax trunculus in Europe, relatively little information is known about its population genetic structure and connectivity and their consequences on conservation policies. We employed 16 microsatellite loci to characterise the genetic diversity and population structure of D. trunculus. A total of 514 samples from seven different localities along the Atlantic Mediterranean transition, from the Atlantic (Gulf of Cadiz) to the north-western Mediterranean were genotyped. The analysis of the population genetic structure displayed a clear distinction along the Atlantic-Mediterranean transition with different clusters in the Atlantic Ocean, the Alboran Sea and the northwestern Mediterranean. Consequently, we recommend that these three areas should be considered as different management units. We showed that all populations seem to be at high long-term risk of extinction with the exception of the protected Donana National Park population which still seems to have evolutionary potential. Therefore, our results emphasized the necessity of protection of this economic resource and the validity of molecular tools to evaluate the population dynamics. PMID- 27991536 TI - Genes encoding norcoclaurine synthase occur as tandem fusions in the Papaveraceae. AB - Norcoclaurine synthase (NCS) catalyzes the enantioselective Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde as the first step in benzylisoquinoline alkaloid (BIA) biosynthesis. NCS orthologs in available transcriptome databases were screened for variants that might improve the low yield of BIAs in engineered microorganisms. Databases for 21 BIA-producing species from four plant families yielded 33 assembled contigs with homology to characterized NCS genes. Predicted translation products generated from nine contigs consisted of two to five sequential repeats, each containing most of the sequence found in single-domain enzymes. Assembled contigs containing tandem domain repeats were detected only in members of the Papaveraceae family, including opium poppy (Papaver somniferum). Fourteen cDNAs were generated from 10 species, five of which encoded NCS orthologs with repeated domains. Functional analysis of corresponding recombinant proteins yielded six active NCS enzymes, including four containing either two, three or four repeated catalytic domains. Truncation of the first 25 N-terminal amino acids from the remaining polypeptides revealed two additional enzymes. Multiple catalytic domains correlated with a proportional increase in catalytic efficiency. Expression of NCS genes in Saccharomyces cereviseae also produced active enzymes. The metabolic conversion capacity of engineered yeast positively correlated with the number of repeated domains. PMID- 27991538 TI - How mobile are dye adsorbates and acetonitrile molecules on the surface of TiO2 nanoparticles? A quasi-elastic neutron scattering study. AB - Motions of molecules adsorbed to surfaces may control the rate of charge transport within monolayers in systems such as dye sensitized solar cells. We used quasi-elastic neutron scattering (QENS) to evaluate the possible dynamics of two small dye moieties, isonicotinic acid (INA) and bis-isonicotinic acid (BINA), attached to TiO2 nanoparticles via carboxylate groups. The scattering data indicate that moieties are immobile and do not rotate around the anchoring groups on timescales between around 10 ps and a few ns (corresponding to the instrumental range). This gives an upper limit for the rate at which conformational fluctuations can assist charge transport between anchored molecules. Our observations suggest that if the conformation of larger dye molecules varies with time, it does so on longer timescales and/or in parts of the molecule which are not directly connected to the anchoring group. The QENS measurements also indicate that several layers of acetonitrile solvent molecules are immobilized at the interface with the TiO2 on the measurement time scale, in reasonable agreement with recent classical molecular dynamics results. PMID- 27991537 TI - The Identification and Characterization of Two Novel Epitopes on the Nucleocapsid Protein of the Porcine Epidemic Diarrhea Virus. AB - Porcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that causes severe diarrhea and death, particularly in neonatal piglets. The nucleocapsid protein (N protein) of PEDV presents strong immunogenicity and contributes to the cross-reactivity between PEDV and TGEV. However, the characterization of epitopes on the PEDV N protein remains largely unknown. Here, two monoclonal antibodies (MAbs) specific to the N protein of a PEDV strain, FJzz1/2011, were generated and screened against a partially overlapping library of 24 GST-fusion N protein-truncated constructs. We confirmed that residues 18 133 (designated NEP-D4) and residues 252-262 (designated NEP-D6) were the epitopes targeted by MAbs PN-D4 and PN-D6, respectively. Sequence analysis revealed that these two epitopes were highly conserved among PEDV strains but were significantly different from other members of the Coronavirinae subfamily. Western blot analysis showed that they could be specifically recognized by PEDV antisera but could not be recognized by TGEV hyperimmune antisera. Indirect immunofluorescence (IFA) assays confirmed no cross-reaction between these two MAbs and TGEV. In addition, the freeze-thaw cycle and protease treatment results indicated that NEP-D4 was intrinsically disordered. All these results suggest that these two novel epitopes and their cognate MAbs could serve as the basis for the development of precise diagnostic assays for PEDV. PMID- 27991539 TI - Detection of Extremely Low Concentrations of Biological Substances Using Near Field Illumination. AB - An external force-assisted near-field illumination biosensor (EFA-NI biosensor) detects a target substance that is propelled through an evanescent field by an external force. The target substance is sandwiched between an antibody coupled to a magnetic bead and an antibody coupled to a polystyrene bead. The external force is supplied by a magnetic field. The magnetic bead propels the target substance and the polystyrene bead emits an optical signal. The detection protocol includes only two steps; mixing the sample solution with a detection reagent containing the antibody-coated beads and injecting the sample mixture into a liquid cell. Because the system detects the motion of the beads, the sensor allows detection of trace amounts of target substances without a washing step. The detection capability of the sensor was demonstrated by the detection of norovirus virus like particles at a concentration of ~40 particles per 100 MUl in contaminated water. PMID- 27991540 TI - Bursty properties revealed in large-scale brain networks with a point-based method for dynamic functional connectivity. AB - The brain is organized into large scale spatial networks that can be detected during periods of rest using fMRI. The brain is also a dynamic organ with activity that changes over time. We developed a method and investigated properties where the connections as a function of time are derived and quantified. The point based method (PBM) presented here derives covariance matrices after clustering individual time points based upon their global spatial pattern. This method achieved increased temporal sensitivity, together with temporal network theory, allowed us to study functional integration between resting-state networks. Our results show that functional integrations between two resting-state networks predominately occurs in bursts of activity. This is followed by varying intermittent periods of less connectivity. The described point-based method of dynamic resting-state functional connectivity allows for a detailed and expanded view on the temporal dynamics of resting-state connectivity that provides novel insights into how neuronal information processing is integrated in the human brain at the level of large-scale networks. PMID- 27991541 TI - Disorder-induced topological phase transitions in two-dimensional spin-orbit coupled superconductors. AB - Normal superconductors with Rashba spin-orbit coupling have been explored as candidate systems of topological superconductors. Here we present a comparative theoretical study of the effects of different types of disorder on the topological phases of two-dimensional Rashba spin-orbit coupled superconductors. First, we show that a topologically trivial superconductor can be driven into a chiral topological superconductor upon diluted doping of isolated magnetic disorder, which close and reopen the quasiparticle gap of the paired electrons in a nontrivial manner. Secondly, the superconducting nature of a topological superconductor is found to be robust against Anderson disorder, but the topological nature is not, converting the system into a topologically trivial state even in the weak scattering limit. These topological phase transitions are distinctly characterized by variations in the topological invariant. We discuss the central findings in connection with existing experiments, and provide new schemes towards eventual realization of topological superconductors. PMID- 27991543 TI - Ultrashort pulse laser ablation of dielectrics: Thresholds, mechanisms, role of breakdown. AB - In this paper, we establish connections between the thresholds and mechanisms of the damage and white-light generation upon femtosecond laser irradiation of wide bandgap transparent materials. On the example of Corning Willow glass, evolution of ablation craters, their quality, and white-light emission were studied experimentally for 130-fs, 800-nm laser pulses. The experimental results indicate co-existence of several ablation mechanisms which can be separated in time. Suppression of the phase explosion mechanism of ablation was revealed at the middle of the irradiation spots. At high laser fluences, air ionization was found to strongly influence ablation rate and quality and the main mechanisms of the influence are analysed. To gain insight into the processes triggered by laser radiation in glass, numerical simulations have been performed with accounting for the balance of laser energy absorption and its distribution/redistribution in the sample, including bremsstrahlung emission from excited free-electron plasma. The simulations have shown an insignificant role of avalanche ionization at such short durations of laser pulses while pointing to high average energy of electrons up to several dozens of eV. At multi-pulse ablation regimes, improvement of crater quality was found as compared to single/few pulses. PMID- 27991542 TI - Adjunctive treatment of brexpiprazole with fluoxetine shows a rapid antidepressant effect in social defeat stress model: Role of BDNF-TrkB signaling. AB - Addition of low doses of the atypical antipsychotic drug brexpiprazole with selective serotonin reuptake inhibitors (SSRIs) could promote antidepressant effect in patients with major depressive disorder although the precise mechanisms underlying the action of the combination are unknown. Combination of low dose of brexpiprazole (0.1 mg/kg) and SSRI fluoxetine (10 mg/kg) could promote a rapid antidepressant effect in social defeat stress model although brexpiprazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling and dendritic spine density in the prefrontal cortex, hippocampus, and nucleus accumbens in the susceptible mice after social defeat stress. Interestingly, TrkB antagonist ANA-12 significantly blocked beneficial effects of combination of brexpiprazole and fluoxetine on depression-like phenotype. These results suggest that BDNF-TrkB signaling plays a role in the rapid antidepressant action of the combination of brexpiprazole and fluoxetine. PMID- 27991545 TI - Enhancing mung bean hydration using the ultrasound technology: description of mechanisms and impact on its germination and main components. AB - The ultrasound technology was successfully used to improve the mass transfer processes on food. However, the study of this technology on the grain hydration and on its main components properties was still not appropriately described. This work studied the application of the ultrasound technology on the hydration process of mung beans (Vigna radiata). This grain showed sigmoidal hydration behavior with a specific water entrance pathway. The ultrasound reduced ~25% of the hydration process time. In addition, this technology caused acceleration of the seed germination - and some hypothesis for this enhancement were proposed. Moreover, it was demonstrated that the ultrasound did not change both structure and pasting properties of the bean starch. Finally, the flour rheological properties proved that the ultrasound increased its apparent viscosity, and as the starch was not modified, this alteration was attributed to the proteins. All these results are very desirable for industry since the ultrasound technology improves the hydration process without altering the starch properties, accelerates the germination process (that is important for the malting and sprouting process) and increases the flour apparent viscosity, which is desirable to produce bean-based products that need higher consistency. PMID- 27991544 TI - Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria. AB - Cerebral malaria is a pathology involving inflammation in the brain. There are many immune cell types activated during this process, but there is little information on the response of microglia, in this severe complication. We examined microglia by genome wide transcriptomic analysis in a model of experimental cerebral malaria (ECM), in which C57BL/6 mice are infected with Plasmodium berghei ANKA. Thousands of transcripts were differentially expressed in microglia at two different time points during infection. Proliferation of microglia was a dominant feature before the onset of ECM, and supporting this, we observed an increase in numbers of these cells in the brain. When cerebral malaria symptoms were manifest, genes involved in immune responses and chemokine production were upregulated, which were possibly driven by Type I Interferon. Consistent with this hypothesis, in vitro culture of a microglial cell line with Interferon-beta, but not infected red blood cells, resulted in production of several of the chemokines shown to be upregulated in the gene expression analysis. It appears that these responses are associated with ECM, as microglia from mice infected with a mutant P. berghei parasite (DeltaDPAP3), which does not cause ECM, did not show the same level of activation or proliferation. PMID- 27991546 TI - APC/CCDC20 and APC/C play pivotal roles in the process of embryonic development in Artemia sinica. AB - Anaphase Promoting Complex or Cyclosome (APC/C) is a representative E3 ubiquitin ligase, triggering the transition of metaphase to anaphase by regulating degradation and ensures the exit from mitosis. Cell division cycle 20 (CDC20) and Cell division cycle 20 related protein 1 (CDH1), as co-activators of APC/C, play significant roles in the spindle assembly checkpoint, guiding ubiquitin-mediated degradation, together with CDC23. During the embryonic development of the brine shrimp, Artemia sinica, CDC20, CDH1 and CDC23 participate in cell cycle regulation, but the specific mechanisms of their activities remain unknown. Herein, the full-length cDNAs of cdc20 and cdc23 from A. sinica were cloned. Real time PCR analyzed the expression levels of As-cdc20 and As-cdc23. The locations of CDH1, CDC20 and CDC23 showed no tissue or organ specificity. Furthermore, western blotting showed that the levels of As-CDC20, securin, cyclin B, CDK1, CDH1, CDC14B, CDC23 and geminin proteins conformed to their complicated degradation relationships during different embryo stages. Our research revealed that As-CDC20, As-CDH1 and APC mediate the mitotic progression, downstream proteins degradation and cellular differentiation in the process of embryonic development in A. sinica. PMID- 27991547 TI - Angiopoietin-2, Angiopoietin-1 and subclinical cardiovascular disease in Chronic Kidney Disease. AB - Angiopoietins (Angpt) and vascular endothelial growth factor (VEGF) have been associated with cardiovascular disease. The study enrolled 270 pre-dialysis stage 3-5 CKD patients to assess the link between circulating Angpt2, Angpt1 and VEGF-A and subclinical measures of cardiovascular structure and function. Serum markers of angiogenesis were measured using commercial enzyme-linked immunosorbent assays. Cardiac structure and function were examined by echocardiography. Brachial-ankle pulse wave velocity (baPWV) was measured by the ankle-brachial index. The adjusted mean of left ventricular mass index (LVMI) was 2.05 in patients of Angpt2 quartile 4 and 1.99 in those of Angpt2 quartile 1 (P = 0.04). Angpt2 was significantly associated with LV hypertrophy (LVH) (Angpt2 quartile 4 compared with Angpt2 quartile 1: adjusted OR: 2.68, 95% CI: 1.15-6.20). Angpt1 was negatively correlated with left atrial diameter (adjusted mean of LAD: 3.59 in Angpt1 quartile 4, 3.92 in Angpt1 quartile 1, P = 0.03). A positive and significant correlation was found between Angpt2 level and baPWV in spearman's correlation, but not in adjusted model. In conclusion, high Angpt2 and low Angpt1 levels were positively associated with abnormal cardiac structure in stages 3-5 CKD patients, which is compatible with the viewpoint that angiopoietins participates in cardiovascular burdens. PMID- 27991549 TI - Synthesis of single-crystal low-loss LiB3O5 nanowire and its optical properties. AB - Optical-quality single-crystal LiB3O5 (LBO) nanowires are synthesized for the first time using a sol-gel method. The LBO nanowires possess diameters ranging from 200 to 800 nm and lengths of up to 200 MUm, and exhibit excellent uniformity, smooth surfaces, and good mechanical properties. A typical propagating loss of 0.038 dB/MUm at 532 nm is obtained for a 620 nm-diameter nanowire. This is a decrease of one order of magnitude compared with that of a beta-BaB2O4 (BBO) nanowire with similar diameter, which makes the LBO nanowire a promising candidate to construct miniaturized nonlinear photonic devices. PMID- 27991548 TI - Non-Thermal Atmospheric Pressure Plasma Efficiently Promotes the Proliferation of Adipose Tissue-Derived Stem Cells by Activating NO-Response Pathways. AB - Non-thermal atmospheric pressure plasma (NTAPP) is defined as a partially ionized gas with electrically charged particles at atmospheric pressure. Our study showed that exposure to NTAPP generated in a helium-based dielectric barrier discharge (DBD) device increased the proliferation of adipose tissue-derived stem cells (ASCs) by 1.57-fold on an average, compared with untreated cells at 72 h after initial NTAPP exposure. NTAPP-exposed ASCs maintained their stemness, capability to differentiate into adipocytes but did not show cellular senescence. Therefore, we suggested that NTAPP can be used to increase the proliferation of ASCs without affecting their stem cell properties. When ASCs were exposed to NTAPP in the presence of a nitric oxide (NO) scavenger, the proliferation-enhancing effect of NTAPP was not obvious. Meanwhile, the proliferation of NTAPP-exposed ASCs was not much changed in the presence of scavengers for reactive oxygen species (ROS). Also, Akt, ERK1/2, and NF-kappaB were activated in ASCs after NTAPP exposure. These results demonstrated that NO rather than ROS is responsible for the enhanced proliferation of ASCs following NTAPP exposure. Taken together, this study suggests that NTAPP would be an efficient tool for use in the medical application of ASCs both in vitro and in vivo. PMID- 27991550 TI - Proteomic Analysis Reveals That Metabolic Flows Affect the Susceptibility of Aeromonas hydrophila to Antibiotics. AB - The overuse of antibiotics results in the development of antibiotic resistance and limits the useful life of these drugs in fighting bacteria, including Aeromonas hydrophila, a well-known opportunistic pathogen that causes serious infections in fish and other animals. In this study, we investigated the adaptive resistance mechanism in A. hydrophila by multiple proteomic methods. Dimethyl labeling and label-free methods were performed to compare the differential expression of proteins in response to various doses of oxytetracycline (OXY). The results point to the conclusions that, in response to OXY stress, translational processes increase the abundance of these proteins whereas largely central metabolic pathways decrease their abundance. To confirm our hypothesis, various exogenous metabolites were compounded with OXY, and the resulting survival capabilities were measured. Results show that 7 metabolites (malic acid, serine, methionine, etc.) significantly decreased the survival capabilities of A. hydrophila in the presence of OXY, whereas 4 metabolites (arginine, lysine, tyrosine, etc.) did the opposite. Further investigation suggests that a compound comprising exogenous metabolites in combination with various antibiotics could have a significant bactericidal effect and might come into widespread use, especially together with tetracycline antibiotics. These findings may provide new clues to the antimicrobial treatment of A. hydrophila infection. PMID- 27991551 TI - Brain tissue banking for stem cells for our future. AB - In our lab we study neurogenesis and the development of brain tumors. We work towards treatment strategies for glioblastoma and towards using autologous neural stem cells for tissue regeneration strategies for brain damage and neurodegenerative disorders. It has been our policy to try to establish living cell cultures from all human biopsy material that we obtain. We hypothesized that small pieces of brain tissue could be cryopreserved and that live neural stem cells could be recovered at a later time. DMSO has been shown to possess a remarkable ability to diffuse through cell membranes and pass into cell interiors. Its chemical properties prevent the formation of damaging ice crystals thus allowing cell storage at or below -180 C. We report here a protocol for successful freezing of small pieces of tissue derived from human brain and human brain tumours. Virtually all specimens could be successfully revived. Assays of phenotype and behaviour show that the cell cultures derived were equivalent to those cultures previously derived from fresh tissue. PMID- 27991552 TI - Triggering of spin-flipping-modulated exchange bias in FeCo nanoparticles by electronic excitation. AB - The exchange coupling between ferromagnetic (FM)-antiferromagnetic (AF) interfaces is a key element of modern spintronic devices. We here introduce a new way of triggering exchange bias (EB) in swift heavy ion (SHI) irradiated FeCo SiO2 films, which is a manifestation of spin-flipping at high irradiation fluence. The elongation of FeCo nanoparticles (NPs) in SiO2 matrix gives rise to perpendicular magnetic anisotropy at intermediate fluence. However, a clear shift in hysteresis loop is evident at the highest fluence. This reveals the existence of an AF exchange pinning domain in the NPs, which is identified not to be oxide shell from XANES analysis. Thermal spike calculations along with first-principles based simulations under the framework of density functional theory (DFT) demonstrate that spin flipping of 3d valence electrons is responsible for formation of these AF domains inside the FM NPs. EXAFS experiments at Fe and Co K edges further unravel that spin-flipping in highest fluence irradiated film results in reduced bond lengths. The results highlight the possibility of miniaturization of magnetic storage devices by using irradiated NPs instead of conventionally used FM-AF multilayers. PMID- 27991553 TI - Deconstructing the Cognitive Estimation Task: A Developmental Examination and Intra-Task Contrast. AB - The cognitive estimation task (CET) requires participants to answer estimation questions that lack definitive answers. Few studies examine CET performance in healthy populations, and even fewer in children. Previous research has not considered differences between categories within the CET. The categories differ in their reliance on units of measurement, which is significant when examining CET performance in children due to educational factors. The goal of the study was to examine CET performance in 10 and 12 year-old children and contrast the CET categories. We found a developmental effect in overall CET performance: children's performance was more extreme than adults but no differences were found between the groups of children. Examination of the CET categories revealed differential developmental trajectories: the children's scores were more extreme in weight and time, while comparable to adults in quantity. We conclude that CET questions that require application of units of measurement are more difficult for childern due to higher involvement of executive functions, and children have less experience applying them in daily life. The CET is not a unified construct and has the potential to shed light on how children acquire an understanding of magnitudes and units of measurement. PMID- 27991554 TI - Water soluble organic aerosols in the Colorado Rocky Mountains, USA: composition, sources and optical properties. AB - Atmospheric aerosols have been shown to be an important input of organic carbon and nutrients to alpine watersheds and influence biogeochemical processes in these remote settings. For many remote, high elevation watersheds, direct evidence of the sources of water soluble organic aerosols and their chemical and optical characteristics is lacking. Here, we show that the concentration of water soluble organic carbon (WSOC) in the total suspended particulate (TSP) load at a high elevation site in the Colorado Rocky Mountains was strongly correlated with UV absorbance at 254 nm (Abs254, r = 0.88 p < 0.01) and organic carbon (OC, r = 0.95 p < 0.01), accounting for >90% of OC on average. According to source apportionment analysis, biomass burning had the highest contribution (50.3%) to average WSOC concentration; SOA formation and motor vehicle emissions dominated the contribution to WSOC in the summer. The source apportionment and backward trajectory analysis results supported the notion that both wildfire and Colorado Front Range pollution sources contribute to the summertime OC peaks observed in wet deposition at high elevation sites in the Colorado Rocky Mountains. These findings have important implications for water quality in remote, high-elevation, mountain catchments considered to be our pristine reference sites. PMID- 27991555 TI - Simple reverse genetics systems for Asian and African Zika viruses. AB - Zika virus (ZIKV), a typical example of a re-emerging pathogen, recently caused large outbreaks in Pacific islands and the Americas, associated with congenital diseases and neurological complications. Deciphering the natural history, ecology and pathophysiology of this mosquito-borne pathogen requires effective reverse genetics tools. In the current study, using the bacterium-free 'Infectious Subgenomic Amplicons' (ISA) method, we generated and made available to the scientific community via the non-profit European Virus Archive collection, two simple and performing reverse genetics systems for ZIKV. One is based on an Asian ZIKV strain belonging to the outbreak lineage (French Polynesia 2013). The second was designed from the sequence of a low-passaged ZIKV African strain (Dakar 1984). Using the ISA procedure, we derived wild-type and a variety of specifically engineered ZIKVs in days (intra- and inter-lineage chimeras). Since they are based on low-passaged ZIKV strains, these engineered viruses provide ideal tools to study the effect of genetic changes observed in different evolutionary time-scales of ZIKV as well as pathophysiology of ZIKV infections. PMID- 27991557 TI - Ferromagnetic glass-coated microwires with good heating properties for magnetic hyperthermia. AB - The heating properties of Fe71.7Si11B13.4Nb3Ni0.9 amorphous glass-coated microwires are explored for prospective applications in magnetic hyperthermia. We show that a single 5 mm long wire is able to produce a sufficient amount of heat, with the specific loss power (SLP) reaching a value as high as 521 W/g for an AC field of 700 Oe and a frequency of 310 kHz. The large SLP is attributed to the rectangular hysteresis loop resulting from a peculiar domain structure of the microwire. For an array of parallel microwires, we have observed an SLP improvement by one order of magnitude; 950 W/g for an AC field of 700 Oe. The magnetostatic interaction strength essential in the array of wires can be manipulated by varying the distance between the wires, showing a decreasing trend in SLP with increasing wire separation. The largest SLP is obtained when the wires are aligned along the direction of the AC field. The origin of the large SLP and relevant heating mechanisms are discussed. PMID- 27991556 TI - KIF2A regulates the spindle assembly and the metaphase I-anaphase I transition in mouse oocyte. AB - KIF2A, a member of the kinesin-13 family, has been reported to play a role in spindle assembly in mitosis. However, its function in mammalian meiosis remains unknown. In this research, we examined the expression, localization and function of KIF2A during mouse oocyte meiosis. KIF2A was expressed in some key stages in mouse oocyte meiosis. Immunofluorescent staining showed that KIF2A distributed in the germinal vesicle at the germinal vesicle stage and as the spindle assembling after meiosis resumption, KIF2A gradually accumulated to the entire spindle. The treatment of oocytes with taxol and nocodazole demonstrated that KIF2A was co localized with alpha-tubulin. Depletion of KIF2A by specific short interfering (si) RNA injection resulted in abnormal spindle assembly, failure of spindle migration, misaligned chromosomes and asymmetric cell division. Meanwhile, SKA1 expression level was decreased and the TACC3 localization was disrupted. Moreover, depletion of KIF2A disrupted the actin cap formation, arrested oocytes at metaphase I with spindle assembly checkpoint protein BubR1 activated and finally reduced the rate of the first polar body extrusion. Our data indicate that KIF2A regulates the spindle assembly, asymmetric cytokinesis and the metaphase I-anaphase I transition in mouse oocyte. PMID- 27991558 TI - Senescence marker protein 30 (SMP30) serves as a potential prognostic indicator in hepatocellular carcinoma. AB - Senescence marker protein 30 (SMP30) has been identified as a tumor-related molecule of hepatocellular carcinoma (HCC). Its clinical significance and underlying mechanisms in HCC tissues, however, remain largely unexplored. We have demonstrated a preferentially expressed SMP30 in normal liver using a tissue microarray. By employing real-time quantitative PCR, two tissue microarrays and Oncomine database analysis, we have also shown that the SMP30 in HCC tissues has significantly reduced when compared with that in paired adjacent non-tumor tissues (P = 0.0037). The reduced expression of SMP30 is very noticeably related to larger tumor size (P = 0.012), enhanced TNM (P = 0.009) and worse survival (P < 0.0001) in HCC patients. The analyses using Cox regression have indicated that the decreased SMP30 expression is an independent risk to the reduced overall survival rate of HCC patients (P = 0.001), and the down-regulation of SMP30 in HCC might be mediated by DNA methylation. Moreover, genes co-expressed with SMP30 may affect the prognosis through apoptotic process, biological adhesion and blood coagulation by PANTHER analyses. Our studies have indicated that the SMP30 may serve as a candidate of HCC clinical prognostic marker and a potential therapeutic target. PMID- 27991559 TI - Shedding of neurexin 3beta ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons. AB - Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3beta is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease gamma-secretase, producing secreted neurexin3beta (sNrxn3beta) and a single intracellular domain (Nrxn3beta-ICD). We further completed the full characterization of the sites at which Nrxn3beta is processed by these proteases. Supporting the physiological relevance of the Nrxn3beta processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3beta on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3beta produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3beta produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3beta in plasticity and network remodeling during neuronal development. PMID- 27991560 TI - TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. AB - Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3 mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) beta stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation. PMID- 27991561 TI - Genome-wide Analysis of WD40 Protein Family in Human. AB - The WD40 proteins, often acting as scaffolds to form functional complexes in fundamental cellular processes, are one of the largest families encoded by the eukaryotic genomes. Systematic studies of this family on genome scale are highly required for understanding their detailed functions, but are currently lacking in the animal lineage. Here we present a comprehensive in silico study of the human WD40 family. We have identified 262 non-redundant WD40 proteins, and grouped them into 21 classes according to their domain architectures. Among them, 11 animal specific domain architectures have been recognized. Sequence alignment indicates the complicated duplication and recombination events in the evolution of this family. Through further phylogenetic analysis, we have revealed that the WD40 family underwent more expansion than the overall average in the evolutionary early stage, and the early emerged WD40 proteins are prone to domain architectures with fundamental cellular roles and more interactions. While most widely and highly expressed human WD40 genes originated early, the tissue specific ones often have late origin. These results provide a landscape of the human WD40 family concerning their classification, evolution, and expression, serving as a valuable complement to the previous studies in the plant lineage. PMID- 27991562 TI - Local recording of biological magnetic fields using Giant Magneto Resistance based micro-probes. AB - The electrical activity of brain, heart and skeletal muscles generates magnetic fields but these are recordable only macroscopically, such as in magnetoencephalography, which is used to map neuronal activity at the brain scale. At the local scale, magnetic fields recordings are still pending because of the lack of tools that can come in contact with living tissues. Here we present bio-compatible sensors based on Giant Magneto-Resistance (GMR) spin electronics. We show on a mouse muscle in vitro, using electrophysiology and computational modeling, that this technology permits simultaneous local recordings of the magnetic fields from action potentials. The sensitivity of this type of sensor is almost size independent, allowing the miniaturization and shaping required for in vivo/vitro magnetophysiology. GMR-based technology can constitute the magnetic counterpart of microelectrodes in electrophysiology, and might represent a new fundamental tool to investigate the local sources of neuronal magnetic activity. PMID- 27991563 TI - Reversible Self-Actuated Thermo-Responsive Pore Membrane. AB - Smart membranes, which can selectively control the transfer of light, air, humidity and temperature, are important to achieve indoor climate regulation. Even though reversible self-actuation of smart membranes is desirable in large scale, reversible self-regulation remains challenging. Specifically, reversible 100% opening/closing of pore actuation showing accurate responsiveness, reproducibility and structural flexibility, including uniform structure assembly, is currently very difficult. Here, we report a reversible, thermo-responsive self activated pore membrane that achieves opening and closing of pores. The reversible, self-actuated thermo-responsive pore membrane was fabricated with hybrid materials of poly (N-isopropylacrylamide), (PNIPAM) within polytetrafluoroethylene (PTFE) to form a multi-dimensional pore array. Using Multiphysics simulation of heat transfer and structural mechanics based on finite element analysis, we demonstrated that pore opening and closing dynamics can be self-activated at environmentally relevant temperatures. Temperature cycle characterizations of the pore structure revealed 100% opening ratio at T = 40 degrees C and 0% opening ratio at T = 20 degrees C. The flexibility of the membrane showed an accurate temperature-responsive function at a maximum bending angle of 45 degrees . Addressing the importance of self-regulation, this reversible self-actuated thermo-responsive pore membrane will advance the development of future large-scale smart membranes needed for sustainable indoor climate control. PMID- 27991564 TI - Statistical Characterization of the Medical Ultrasound Echo Signals. AB - Medical ultrasound echo signals provide the basic information for obtaining the ultrasonic image in medical ultrasound technology. The statistics of the ultrasound echo signals reveals the systematic structure of the medical ultrasonic image via analyzing the corresponding statistical distributions. A novel statistical distribution, the ascending order K distribution, was proposed here to model the medical ultrasound echo signals. The ascending order K distribution was developed in light of the statistical analysis of the sequential waveforms in the echo signals. Comparison with the previous statistical distributions was made to verify the superiority of the ascending order K distribution. Further discussion showed the determination of the statistical principles for the ultrasound signals can enhance our understanding of the statistical principles of the ultrasound imaging, and thus, facilitate the optimization of the ultrasound image and the tissue identification in the ultrasound diagnosis. PMID- 27991565 TI - Wide-angle Spectrally Selective Perfect Absorber by Utilizing Dispersionless Tamm Plasmon Polaritons. AB - We theoretically investigate wide-angle spectrally selective absorber by utilizing dispersionless Tamm plasmon polaritons (TPPs) under TM polarization. TPPs are resonant tunneling effects occurring on the interface between one dimensional photonic crystals (1DPCs) and metal slab, and their dispersion properties are essentially determined by that of 1DPCs. Our investigations show that dispersionless TPPs can be excited in 1DPCs containing hyperbolic metamaterials (HMMs) on metal substrate. Based on dispersionless TPPs, electromagnetic waves penetrate into metal substrate and are absorbed entirely by lossy metal, exhibiting a narrow-band and wide-angle perfect absorption for TM polarization. Our results exhibit nearly perfect absorption with a value over 98% in the angle of incidence region of 0-80 degree. PMID- 27991566 TI - Corrigendum: Dual-species transcriptional profiling during systemic candidiasis reveals organ-specific host-pathogen interactions. PMID- 27991567 TI - Anti-melanoma activity of Forsythiae Fructus aqueous extract in mice involves regulation of glycerophospholipid metabolisms by UPLC/Q-TOF MS-based metabolomics study. AB - Metabolomics is a comprehensive assessment of endogenous metabolites of a biological system in a holistic context. In this study, we evaluated the in vivo anti-melanoma activity of aqueous extract of Forsythiae Fructus (FAE) and globally explored the serum metabolome characteristics of B16-F10 melanoma bearing mice. UPLC/Q-TOF MS combined with pattern recognition approaches were employed to examine the comprehensive metabolic signatures and differentiating metabolites. The results demonstrated that FAE exhibited remarkable antitumor activity against B16-F10 melanoma in C57BL/6 mice and restored the disturbed metabolic profile by tumor insult. We identified 17 metabolites which were correlated with the antitumor effect of FAE. Most of these metabolites are involved in glycerophospholipid metabolisms. Notably, several lysophosphatidylcholines (LysoPCs) significantly decreased in tumor model group, while FAE treatment restored the changes of these phospholipids to about normal condition. Moreover, we found that lysophosphatidylcholine acyltransferase 1 (LPCAT1) and autotaxin (ATX) were highly expressed in melanoma, and FAE markedly down-regulated their expression. These findings indicated that modulation of glycerophospholipid metabolisms may play a pivotal role in the growth of melanoma and the antitumor activity of FAE. Besides, our results suggested that serum LysoPCs could be potential biomarkers for the diagnosis and prognosis of melanoma and other malignant tumors. PMID- 27991568 TI - Identification of cancer risk lncRNAs and cancer risk pathways regulated by cancer risk lncRNAs based on genome sequencing data in human cancers. AB - Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. The complexity of cancer can be reduced to a small number of underlying principles like cancer hallmarks which could govern the transformation of normal cells to cancer. Besides, the growth and metastasis of cancer often relate to combined effects of long non-coding RNAs (lncRNAs). Here, we performed comprehensive analysis for lncRNA expression profiles and clinical data of six types of human cancer patients from The Cancer Genome Atlas (TCGA), and identified six risk pathways and twenty three lncRNAs. In addition, twenty three cancer risk lncRNAs which were closely related to the occurrence or development of cancer had a good classification performance for samples of testing datasets of six cancer datasets. More important, these lncRNAs were able to separate samples in the entire cancer dataset into high-risk group and low-risk group with significantly different overall survival (OS), which was further validated in ten validation datasets. In our study, the robust and effective cancer biomarkers were obtained from cancer datasets which had information of normal-tumor samples. Overall, our research can provide a new perspective for the further study of clinical diagnosis and treatment of cancer. PMID- 27991571 TI - Tuning apparent friction coefficient by controlled patterning bulk metallic glasses surfaces. AB - Micro-honeycomb structures with various pitches between adjacent cells were hot embossed on Zr35Ti30Cu8.25Be26.75 bulk metallic glass surface. The effect of pitch geometry on the frictional behavior of metallic glass surface was systematically investigated. The results revealed that all textured metallic glass surfaces show a reduction in friction coefficient compared to smooth surface. More intriguingly, the friction coefficient first decreased and then increased gradually with increasing pitches. Such unique behavior can be understood fundamentally from the perspective of competing effects between contact area and local stress level with increasing pitches. This finding not only enhance the in-depth understanding of the mechanism of the significant role of surface topography on the frictional behavior of metallic glass surface, but also opens a new route towards other functional applications for bulk metallic glasses. PMID- 27991570 TI - Establishment of a highly sensitive sandwich ELISA for the N-terminal fragment of titin in urine. AB - Muscle damage and loss of muscle mass are triggered by immobilization, loss of appetite, dystrophies and chronic wasting diseases. In addition, physical exercise causes muscle damage. In damaged muscle, the N-terminal and C-terminal regions of titin, a giant sarcomere protein, are cleaved by calpain-3, and the resulting fragments are excreted into the urine via glomerular filtration. Therefore, we considered titin fragments as promising candidates for reliable and non-invasive biomarkers of muscle injury. Here, we established a sandwich ELISA that can measure the titin N-terminal fragment over a biologically relevant range of concentrations, including those in urine samples from older, non-ambulatory Duchenne muscular dystrophy patients and from healthy donors under everyday life conditions and after exercise. Our results indicate that the established ELISA could be a useful tool for the screening of muscular dystrophies and also for monitoring the progression of muscle disease, evaluating the efficacy of therapeutic approaches, and investigating exercise-related sarcomeric disruption and repair processes. PMID- 27991569 TI - Identification and Characterization of Roseltide, a Knottin-type Neutrophil Elastase Inhibitor Derived from Hibiscus sabdariffa. AB - Plant knottins are of therapeutic interest due to their high metabolic stability and inhibitory activity against proteinases involved in human diseases. The only knottin-type proteinase inhibitor against porcine pancreatic elastase was first identified from the squash family in 1989. Here, we report the identification and characterization of a knottin-type human neutrophil elastase inhibitor from Hibiscus sabdariffa of the Malvaceae family. Combining proteomic and transcriptomic methods, we identified a panel of novel cysteine-rich peptides, roseltides (rT1-rT8), which range from 27 to 39 residues with six conserved cysteine residues. The 27-residue roseltide rT1 contains a cysteine spacing and amino acid sequence that is different from the squash knottin-type elastase inhibitor. NMR analysis demonstrated that roseltide rT1 adopts a cystine-knot fold. Transcriptome analyses suggested that roseltides are bioprocessed by asparagine endopeptidases from a three-domain precursor. The cystine-knot structure of roseltide rT1 confers its high resistance against degradation by endopeptidases, 0.2 N HCl, and human serum. Roseltide rT1 was shown to inhibit human neutrophil elastase using enzymatic and pull-down assays. Additionally, roseltide rT1 ameliorates neutrophil elastase-stimulated cAMP accumulation in vitro. Taken together, our findings demonstrate that roseltide rT1 is a novel knottin-type neutrophil elastase inhibitor with therapeutic potential for neutrophil elastase associated diseases. PMID- 27991572 TI - Topographic relationship between root apex of mesially and horizontally impacted mandibular third molar and lingual plate: cross-sectional analysis using CBCT. AB - The present study was aimed to determine the topographic relationship between root apex of the mesially and horizontally impacted mandibular third molar and lingual plate of mandible. The original cone beam computed tomography (CBCT) data of 364 teeth from 223 patients were retrospectively collected and analyzed. The topographic relationship between root apex and lingual plate on cross-sectional CBCT images was classified as non-contact (99), contact (145) and perforation (120). The cross-sectional morphology of lingual plate at the level of root apex was defined as parallel (28), undercut (38), slanted (29) and round (4). The distribution of topographic relationship between root apex and lingual plate significantly associated with gender, impaction depth, root number and lingual plate morphology. Moreover, the average bone thickness of lingual cortex and distance between root apex and the outer surface of lingual plate were 1.02 and 1.39 mm, respectively. Furthermore, multivariate regression analyses identified impaction depth and lingual plate morphology as the risk factors for the contact and perforation subtypes between root apex and lingual plate. Collectively, our findings reveal the topographic proximity of root apex of impacted mandibular third molar to the lingual plate, which might be associated with intraoperative and postoperative complications during tooth extraction. PMID- 27991573 TI - Porcine circovirus type 2 (PCV2) evolution before and after the vaccination introduction: A large scale epidemiological study. AB - Since their commercialization, vaccines against Porcine circovirus type 2 (PCV2) have been the cornerstone control strategy. Nevertheless, the periodic emergence of new genotype waves and the recent reports of vaccine failure outbreaks have raised the question if widespread vaccination strategies could have driven viral evolution and affected different genotype fitness. To investigate this issue an in-deep analysis, based on a bioinformatics and biostatistics approach, has been implemented. ORF2 sequences from vaccinated and non-vaccinated populations (i.e. domestic pigs before and after vaccine introduction and wild boars) were considered. The action of selective forces on PCV2 strains has been analyzed and compared among groups. Remarkable differences were found in the selective forces acting on viral populations circulating in different "immune environments". Particularly for PCV2a, a directional selection promoting a change in the viral capsid away from the vaccine specific antigenic determinants has been detected after vaccine introduction. Involved amino acids were previously reported to be part of viral epitopes whose variability is responsible of immune escape. Our findings support a change in PCV2 evolutionary pattern after widespread vaccination introduction and stress once more the compulsoriness of a continuous monitoring of PCV2 epidemiology to promptly act in response to the emergence of possible vaccine-escaping mutants. PMID- 27991574 TI - Artificial Neuron Based on Integrated Semiconductor Quantum Dot Mode-Locked Lasers. AB - Neuro-inspired implementations have attracted strong interest as a power efficient and robust alternative to the digital model of computation with a broad range of applications. Especially, neuro-mimetic systems able to produce and process spike-encoding schemes can offer merits like high noise-resiliency and increased computational efficiency. Towards this direction, integrated photonics can be an auspicious platform due to its multi-GHz bandwidth, its high wall-plug efficiency and the strong similarity of its dynamics under excitation with biological spiking neurons. Here, we propose an integrated all-optical neuron based on an InAs/InGaAs semiconductor quantum-dot passively mode-locked laser. The multi-band emission capabilities of these lasers allows, through waveband switching, the emulation of the excitation and inhibition modes of operation. Frequency-response effects, similar to biological neural circuits, are observed just as in a typical two-section excitable laser. The demonstrated optical building block can pave the way for high-speed photonic integrated systems able to address tasks ranging from pattern recognition to cognitive spectrum management and multi-sensory data processing. PMID- 27991576 TI - Periodic fluctuation of reference evapotranspiration during the past five decades: Does Evaporation Paradox really exist in China? AB - Evidence that the pan evaporation or reference evapotranspiration (ET0) as the indicator of atmospheric evaporation capability have decreased along with the continuous increase in temperature over the past decades (coined as "evaporation paradox") has been reported worldwide. Here, we provide a nationwide investigation of spatiotemporal change of ET0 using meteorological data from 602 stations with the updated data (1961-2011). In addition, we explore the trigger mechanism by quantitative assessment on the contribution of climatic factors to ET0 change based on a differential equation method. In despite of different shift points regionally, our results suggest that the ET0 generally present decadal variations rather than monotonic response to climate change reported in previous studies. The significant decrease in net radiation dominate the decrease in ET0 before early 1990s in southern regions, while observed near-surface wind speed is the primary contributor to the variations of ET0 for the rest regions during the same periods. The enhancements of atmospheric evaporation capability after early 1990s are driven primarily by recent relative humidity limitation in China. From a continental scale view, as highly correlating with to Pacific Decadal Oscillation, the shift behaviors of ET0 is likely an episodic phenomenon of the ocean-atmosphere interaction in earth. PMID- 27991575 TI - Efficient derivation of extraembryonic endoderm stem cell lines from mouse postimplantation embryos. AB - Various types of stem cell lines have been derived from preimplantation or postimplantation mouse embryos: embryonic stem cell lines, epiblast stem cell lines, and trophoblast stem cell lines. It is not known if extraembryonic endoderm stem (XEN) cell lines can be derived from postimplantation mouse embryos. Here, we report the derivation of 77 XEN cell lines from 85 postimplantation embryos at embryonic day E5.5 or E6.5, in parallel to the derivation of 41 XEN lines from 69 preimplantation embryos at the blastocyst stage. We attain a success rate of 100% of XEN cell line derivation with our E5.5 whole-embryo and E6.5 disaggregated-embryo methods. Immunofluorescence and NanoString gene expression analyses indicate that the XEN cell lines that we derived from postimplantation embryos (post-XEN) are very similar to the XEN cell lines that we derived from preimplantation embryos (pre-XEN) using a conventional method. After injection into blastocysts, post-XEN cells contribute to extraembryonic endoderm in chimeras at E6.5 and E7.5. PMID- 27991577 TI - A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression. AB - Diabetic retinopathy (DR) is a major complication of diabetes mellitus, and is the leading cause of blindness in working-age people. Usually, DR progresses from the asymptomatic non-proliferative DR that does not significantly alter vision, to proliferative DR (PDR), which can result in aberrant retinal neovessel formation and blindness. The High-Mobility-Group A1 (HMGA1) protein is a transcriptional master regulator of numerous genes, including metabolic and inflammatory genes, which, by modulating the expression of angiogenic factors, may induce retinal neovascularization, a hallmark of PDR. Herein, we examined the relationship between HMGA1 rs139876191 variant and DR. Results revealed that patients with type 2 diabetes, who were carriers of the HMGA1 rs139876191 variant had a significantly lower risk of developing PDR, compared to non-carrier diabetic patients. From a mechanistic point of view, our findings indicated that, by adversely affecting HMGA1 protein expression and function, the HMGA1 rs139876191 variant played a key role in this protective mechanism by downregulating the expression of vascular endothelial growth factor A (VEGFA), a major activator of neovascularization in DR. These data provide new insights into the pathogenesis and progression of DR, and may offer opportunities for discovering novel biomarkers and therapeutic targets for diagnosis, prevention and treatment of PDR. PMID- 27991578 TI - Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators. AB - Targeting bacterial virulence mechanisms without compromising bacterial growth is a promising strategy to prevent drug resistance. LysR-type transcriptional regulators (LTTRs) possess structural conservation across bacterial species and regulate virulence in numerous pathogens, making them attractive targets for antimicrobial agents. We targeted AphB, a Vibrio cholerae LTTR, which regulates the expression of genes encoding cholera toxin and toxin-co-regulated pilus for inhibitor designing. Since AphB ligand is unknown, we followed a molecular fragment-based approach for ligand designing using FDA-approved drugs and subsequent screen to identify molecules that exhibited high-affinity binding to AphB ligand-binding pocket. Among the identified compounds, ribavirin, an anti viral drug, antagonized AphB functions. Ribavirin perturbed Vibrio cholerae pathogenesis in animal models. The inhibitory effects of the drug was limited to the bacteria expressing wild type AphB, but not its constitutively active mutant (AphBN100E), which represents the ligand-bound state, suggesting that ribavirin binds to the active site of AphB to exert its inhibitory role and there exists no AphB-independent mechanism of its action. Similarly, ribavirin suppressed the functions of Salmonella Typhi LTTR Hrg, indicating its broad spectrum efficacy. Moreover, ribavirin did not affect the bacterial viability in culture. This study cites an example of drug repurposing for anti-infective therapy. PMID- 27991579 TI - Serum soluble urokinase-type plasminogen activator receptor as a biological marker of bacterial infection in adults: a systematic review and meta-analysis. AB - The serum concentration of soluble urokinase-type plasminogen activator receptor (suPAR) reflects immune activation. We performed a meta-analysis to evaluate the usefulness of suPAR for the diagnosis and prognosis of bacterial infections. PubMed, Embase and Cochrane Library databases were searched for studies reporting the detection of suPAR in adult patients with bacterial infections. Seventeen studies were selected from 671 studies. The pooled sensitivity and specificity of suPAR for diagnosing infection were 0.73 and 0.79, respectively, and the area under the summary receiver operating characteristic curve (AUC) was 0.82. Subgroup analyses revealed suPAR showed similar AUC values for diagnosing sepsis and bacteremia, but the AUC for differentiating sepsis from systemic inflammatory response syndrome (SIRS) was only 0.68. Elevated suPAR levels were significantly associated with a high risk of death, with a pooled risk ratio of 3.37 (95% confidence interval, 2.60-4.38). The pooled sensitivity and specificity for predicting mortality were 0.70 and 0.72, respectivfely, with an AUC of 0.77. Serum suPAR could be a biomarker for the diagnosis and prognosis of bacterial infection, but it is relatively ineffective for differentiating sepsis from SIRS. Further investigation is required to evaluate whether using of suPAR in combination with other biomarkers can improve diagnostic efficacy. PMID- 27991580 TI - Anatomically correct visualization of the human upper airway using a high-speed long range optical coherence tomography system with an integrated positioning sensor. AB - The upper airway is a complex tissue structure that is prone to collapse. Current methods for studying airway obstruction are inadequate in safety, cost, or availability, such as CT or MRI, or only provide localized qualitative information such as flexible endoscopy. Long range optical coherence tomography (OCT) has been used to visualize the human airway in vivo, however the limited imaging range has prevented full delineation of the various shapes and sizes of the lumen. We present a new long range OCT system that integrates high speed imaging with a real-time position tracker to allow for the acquisition of an accurate 3D anatomical structure in vivo. The new system can achieve an imaging range of 30 mm at a frame rate of 200 Hz. The system is capable of generating a rapid and complete visualization and quantification of the airway, which can then be used in computational simulations to determine obstruction sites. PMID- 27991581 TI - The "Intermediate" CD14++CD16+ monocyte subset increases in severe peripheral artery disease in humans. AB - Monocytes are key players in atherosclerotic. Human monocytes display a considerable heterogeneity and at least three subsets can be distinguished. While the role of monocyte subset heterogeneity has already been well investigated in coronary artery disease (CAD), the knowledge about monocytes and their heterogeneity in peripheral artery occlusive disease (PAOD) still is limited. Therefore, we aimed to investigate monocyte subset heterogeneity in patients with PAOD. Peripheral blood was obtained from 143 patients suffering from PAOD (Rutherford stage I to VI) and three monocyte subsets were identified by flow cytometry: CD14++CD16- classical monocytes, CD14+CD16++ non-classical monocytes and CD14++CD16+ intermediate monocytes. Additionally the expression of distinct surface markers (CD106, CD162 and myeloperoxidase MPO) was analyzed. Proportions of CD14++CD16+ intermediate monocyte levels were significantly increased in advanced stages of PAOD, while classical and non-classical monocytes displayed no such trend. Moreover, CD162 and MPO expression increased significantly in intermediate monocyte subsets in advanced disease stages. Likewise, increased CD162 and MPO expression was noted in CD14++CD16- classical monocytes. These data suggest substantial dynamics in monocyte subset distributions and phenotypes in different stages of PAOD, which can either serve as biomarkers or as potential therapeutic targets to decrease the inflammatory burden in advanced stages of atherosclerosis. PMID- 27991582 TI - Ubiquitylation Directly Induces Fold Destabilization of Proteins. AB - Ubiquitin is a common post-translational modifier and its conjugation is a key signal for proteolysis by the proteasome. Because the molecular mass of ubiquitin is larger than that of other modifiers such as phosphate, acetyl, or methyl groups, ubiquitylation not only influences biochemical signaling, but also may exert physical effects on its substrate proteins by increasing molecular volume and altering shape anisotropy. Here we show that ubiquitylation destabilizes the fold of two proteins, FKBP12 and FABP4, and that elongation of the conjugated ubiquitin chains further enhances this destabilization effect. Moreover, NMR relaxation analysis shows that ubiquitylation induces characteristic structural fluctuations in the backbone of both proteins. These results suggest that the ubiquitylation-driven structural fluctuations lead to fold destabilization of its substrate proteins. Thus, physical destabilization by ubiquitylation may facilitate protein degradation by the proteasome. PMID- 27991583 TI - Identification of disease comorbidity through hidden molecular mechanisms. AB - Despite multiple diseases co-occur, their underlying common molecular mechanisms remain elusive. Identification of comorbid diseases by considering the interactions between molecular components is a key to understand the underlying disease mechanisms. Here, we developed a novel approach utilizing both common disease-causing genes and underlying molecular pathways to identify comorbid diseases. Our approach enables the analysis of common pathologies shared by comorbid diseases through molecular interaction networks. We found that the integration of direct genetic sharing and indirect high-level molecular associations revealed significantly strong consistency with known comorbid diseases. In addition, neoplasm-related diseases showed high comorbidity patterns within themselves as well as with other diseases, indicating severe complications. This study demonstrated that molecular pathway information could be used to discover disease comorbidity and hidden biological mechanism to understand pathogenesis and provide new insight on disease pathology. PMID- 27991584 TI - Chemically modulated graphene quantum dot for tuning the photoluminescence as novel sensory probe. AB - A band gap tuning of environmental-friendly graphene quantum dot (GQD) becomes a keen interest for novel applications such as photoluminescence (PL) sensor. Here, for tuning the band gap of GQD, a hexafluorohydroxypropanyl benzene (HFHPB) group acted as a receptor of a chemical warfare agent was chemically attached on the GQD via the diazonium coupling reaction of HFHPB diazonium salt, providing new HFHPB-GQD material. With a help of the electron withdrawing HFHPB group, the energy band gap of the HFHPB-GQD was widened and its PL decay life time decreased. As designed, after addition of dimethyl methyl phosphonate (DMMP), the PL intensity of HFHPB-GQD sensor sharply increased up to approximately 200% through a hydrogen bond with DMMP. The fast response and short recovery time was proven by quartz crystal microbalance (QCM) analysis. This HFHPB-GQD sensor shows highly sensitive to DMMP in comparison with GQD sensor without HFHPB and graphene. In addition, the HFHPB-GQD sensor showed high selectivity only to the phosphonate functional group among many other analytes and also stable enough for real device applications. Thus, the tuning of the band gap of the photoluminescent GQDs may open up new promising strategies for the molecular detection of target substrates. PMID- 27991586 TI - Corrigendum: Self-Assembly of Amphiphilic Block Copolypeptoids - Micelles, Worms and Polymersomes. PMID- 27991585 TI - Hephaestin and ceruloplasmin facilitate iron metabolism in the mouse kidney. AB - Multicopper ferroxidases (MCFs) play an important role in cellular iron homeostasis. However, the role of MCFs in renal metabolism remains unclear. We used Hephaestin (Heph) and Ceruloplasmin (Cp) single or double (Heph/Cp) knockout (KO) mice to study the roles of MCFs in the kidney. Renal iron levels and the expression of iron metabolism genes were examined. The non-heme iron content both in the renal cortex and medulla of Heph/Cp KO mice was significantly increased. Perls' Prussian blue staining showed iron accumulation on the apical side of renal tubular cells in Heph/Cp KO mice. A significant increase in ferritin protein expression was also observed in the renal medulla and cortex of Heph/Cp KO mice. Both DMT1 and TfR1 protein expression were significantly decreased in the renal medulla of Heph/Cp KO mice, while the expression of DMT1 protein was significantly increased in the renal cortex of these animals. Significant increase in proteinuria and total urinary iron was observed in the double knockout mice, and this was associated with compromised structural integrity. These results suggest that KO of both the HEPH and CP genes leads to kidney iron deposition and toxicity, MCFs could protect kidney against a damage from iron excess. PMID- 27991588 TI - Tremor activity inhibited by well-drained conditions above a megathrust. AB - Tremor occurs on megathrusts under conditions of near-lithostatic pore-fluid pressures and extremely weakened shear strengths. Although metamorphic reactions in the slab liberate large amounts of fluids, the mechanism for enhancing pore fluid pressures along the megathrust to near-lithostatic values remains poorly understood. Here we show anti-correlation between low-frequency earthquake (LFE) activity and properties that are markers of the degree of metamorphism above the megathrust, whereby LFEs occur beneath the unmetamorphosed overlying plate but are rare or limited below portions that are metamorphosed. The extent of metamorphism in the overlying plate is likely controlled by along-strike contrasts in permeability. Undrained conditions are required for pore-fluid pressures to be enhanced to near-lithostatic values and for shear strength to reduce sufficiently for LFE generation, whereas well-drained conditions reduce pore-fluid pressures at the megathrust and LFEs no longer occur at the somewhat strengthened megathrust. Our observations suggest that undrained conditions are a key factor for the genesis of LFEs. PMID- 27991587 TI - A bromodomain-DNA interaction facilitates acetylation-dependent bivalent nucleosome recognition by the BET protein BRDT. AB - Bromodomains are critical components of many chromatin modifying/remodelling proteins and are emerging therapeutic targets, yet how they interact with nucleosomes, rather than acetylated peptides, remains unclear. Using BRDT as a model, we characterized how the BET family of bromodomains interacts with site specifically acetylated nucleosomes. Here we report that BRDT interacts with nucleosomes through its first (BD1), but not second (BD2) bromodomain, and that acetylated histone recognition by BD1 is complemented by a bromodomain-DNA interaction. Simultaneous DNA and histone recognition enhances BRDT's nucleosome binding affinity and specificity, and its ability to localize to acetylated chromatin in cells. Conservation of DNA binding in bromodomains of BRD2, BRD3 and BRD4, indicates that bivalent nucleosome recognition is a key feature of these bromodomains and possibly others. Our results elucidate the molecular mechanism of BRDT association with nucleosomes and identify structural features of the BET bromodomains that may be targeted for therapeutic inhibition. PMID- 27991590 TI - Polarization-independent split bull's eye antennas for infrared nano photodetectors. AB - Split bull's eye (SBE) antennas exhibit much larger extraordinary optical transmission and strong polarization dependence rather than bull's eye (BE) antennas in the infrared range due to the introduced sub-wavelength slit. Here, we demonstrate a dual-split bull's eye (DSBE) antenna, which consists of two sub wavelength slits crossing through the center of the BE antenna with an intersection angle theta. The polarization dependence in transmission can be flexibly tailored by adjusting the intersection angle, following a cos2 (Phi + theta/2) angular dependence on polarization angle Phi. When theta = 90 degrees , the DSBE antenna yields high and polarization-independent transmission enhancement over the entire infrared spectrum. It presents highly promising applications for polarization-insensitive photodetectors and other optoelectronic devices. PMID- 27991589 TI - An integrated multi-omics analysis of the NK603 Roundup-tolerant GM maize reveals metabolism disturbances caused by the transformation process. AB - Glyphosate tolerant genetically modified (GM) maize NK603 was assessed as 'substantially equivalent' to its isogenic counterpart by a nutrient composition analysis in order to be granted market approval. We have applied contemporary in depth molecular profiling methods of NK603 maize kernels (sprayed or unsprayed with Roundup) and the isogenic corn to reassess its substantial equivalence status. Proteome profiles of the maize kernels revealed alterations in the levels of enzymes of glycolysis and TCA cycle pathways, which were reflective of an imbalance in energy metabolism. Changes in proteins and metabolites of glutathione metabolism were indicative of increased oxidative stress. The most pronounced metabolome differences between NK603 and its isogenic counterpart consisted of an increase in polyamines including N-acetyl-cadaverine (2.9-fold), N-acetylputrescine (1.8-fold), putrescine (2.7-fold) and cadaverine (28-fold), which depending on context can be either protective or a cause of toxicity. Our molecular profiling results show that NK603 and its isogenic control are not substantially equivalent. PMID- 27991591 TI - Anode potential influences the structure and function of anodic electrode and electrolyte-associated microbiomes. AB - Three bioelectrochemical systems were operated with set anode potentials of +300 mV, +550 mV and +800 mV vs. Standard Hydrogen Electrode (SHE) to test the hypothesis that anode potential influences microbial diversity and is positively associated with microbial biomass and activity. Bacterial and archaeal diversity was characterized using 16 S rRNA gene amplicon sequencing, and biofilm thickness was measured as a proxy for biomass. Current production and substrate utilization patterns were used as measures of microbial activity and the mid-point potentials of putative terminal oxidases were assessed using cyclic voltammetry. All measurements were performed after 4, 16, 23, 30 and 38 days. Microbial biomass and activity differed significantly between anode potentials and were lower at the highest potential. Anodic electrode and electrolyte associated community composition was also significantly influenced by anode potential. While biofilms at +800 mV were thinner, transferred less charge and oxidized less substrate than those at lower potentials, they were also associated with putative terminal oxidases with higher mid-point potentials and generated more biomass per unit charge. This indicates that microbes at +800 mV were unable to capitalize on the potential for additional energy gain due to a lack of adaptive traits to high potential solid electron acceptors and/or sensitivity to oxidative stress. PMID- 27991593 TI - Room temperature synthesis of biodiesel using sulfonated graphitic carbon nitride. AB - Sulfonation of graphitic carbon nitride (g-CN) affords a polar and strongly acidic catalyst, Sg-CN, which displays unprecedented reactivity and selectivity in biodiesel synthesis and esterification reactions at room temperature. PMID- 27991592 TI - Brain networks for visual creativity: a functional connectivity study of planning a visual artwork. AB - Throughout recorded history, and across cultures, humans have made visual art. In recent years, the neural bases of creativity, including artistic creativity, have become a topic of interest. In this study we investigated the neural bases of the visual creative process with both professional artists and a group of control participants. We tested the idea that creativity (planning an artwork) would influence the functional connectivity between regions involved in the default mode network (DMN), implicated in divergent thinking and generating novel ideas, and the executive control network (EN), implicated in evaluating and selecting ideas. We measured functional connectivity with functional Magnetic Resonance Imaging (fMRI) during three different conditions: rest, visual imagery of the alphabet and planning an artwork to be executed immediately after the scanning session. Consistent with our hypothesis, we found stronger connectivity between areas of the DMN and EN during the creative task, and this difference was enhanced in professional artists. These findings suggest that creativity involves an expert balance of two brain networks typically viewed as being in opposition. PMID- 27991594 TI - Demonstration of Complementary Ternary Graphene Field-Effect Transistors. AB - Strong demand for power reduction in state-of-the-art semiconductor devices calls for novel devices and architectures. Since ternary logic architecture can perform the same function as binary logic architecture with a much lower device density and higher information density, a switch device suitable for the ternary logic has been pursued for several decades. However, a single device that satisfies all the requirements for ternary logic architecture has not been demonstrated. We demonstrated a ternary graphene field-effect transistor (TGFET), showing three discrete current states in one device. The ternary function was achieved by introducing a metal strip to the middle of graphene channel, which created an N-P N or P-N-P doping pattern depending on the work function of the metal. In addition, a standard ternary inverter working at room temperature has been achieved by modulating the work function of the metal in a graphene channel. The feasibility of a ternary inverter indicates that a general ternary logic architecture can be realized using complementary TGFETs. This breakthrough will provide a key stepping-stone for an extreme-low-power computing technology. PMID- 27991595 TI - PGRP negatively regulates NOD-mediated cytokine production in rainbow trout liver cells. AB - Pattern-recognition receptors (PRRs) initiate innate immunity via pathogen recognition. Recent studies suggest that signalling pathways downstream of different PRRs and their crosstalk effectively control immune responses. However, the cross-regulation among PRRs and its effects have yet to be fully described in fish. Here, we examined the crosstalk between OmPGRP-L1, a long form of PGRP in rainbow trout, and other PRRs during pathogenic infections. OmPGRP-L1 expression was increased in RTH-149 cells by iE-DAP and MDP, which are agonists of NOD1 and NOD2, respectively. The silencing of NOD1 and NOD2 specifically inhibited the upregulation of OmPGRP-L1 expression induced by their cognate ligands. Suppression of RIP2 and NF-kappaB activation prevented the induction of OmPGRP-L1 expression. An in silico analysis and electrophoretic mobility shift assay revealed that the promoter of OmPGRP-L1 has NF-kappaB binding sites, suggesting that OmPGRP-L1 is produced through the NOD-RIP2-NF-kappaB signalling pathway. Loss-of-function and gain-of-function experiments indicated that OmPGRP-L1 downregulates the induction of NOD-mediated pro-inflammatory cytokine expression. Mechanistically, secreted OmPGRP-L1 inhibited the activation of the NOD-induced NF-kappaB pathway via downregulation of TAK1 and IkappaBalpha phosphorylation through A20 expression. Our data demonstrate that OmPGRP-L1 and NODs might play interdependent roles in the inflammatory response to bacterial infections in rainbow trout. PMID- 27991596 TI - Predisposing factors for poor outcome of surgery for cervical spondylotic amyotrophy: a multivariate analysis. AB - The purpose of this study was to characterize risk factors for poor surgical outcome in patients with cervical spondylotic amyotrophy (CSA). We retrospectively reviewed 88 cases of CSA surgery and investigated age, sex, duration of symptoms, atrophy type, preoperative muscle power, signal changes on MRI, anterior horn (AH) or ventral nerve root (VNR) compression, compression levels, surgical approach and postoperative recovery. Fifty (56.8%) patients had good surgical outcome. Logistic regression, with poor outcome as dependent variable, showed independent risks associated with duration of symptoms (OR; 1 for symptom duration less than 3 months versus 3.961 [95% CI; 1.203-13.039, p = 0.024] for symptom duration of 3-6 months versus 18.724 [95% CI; 3.967-88.367, p < 0.001] for symptom duration greater than 6 months), compression type (OR; 1 for VNR versus 4.931 [95% CI; 1.457-16.685, p = 0.010] for AH versus 5.538 [95% CI; 1.170-26.218, p = 0.031] for VNR + AH), and atrophy type (OR; 1 for proximal type versus 6.456 [95% CI; 1.938-21.508, p = 0.002] for distal type). These findings suggest that a long duration of symptoms, AH or both AH and VNR compression, and distal type are risk factors for poor surgical outcome in patients with CSA. PMID- 27991597 TI - Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury. AB - Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1alpha activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI. PMID- 27991598 TI - Using anti-poly(ethylene glycol) bioparticles for the quantitation of PEGylated nanoparticles. AB - Attachment of polyethylene glycol (PEG) molecules to nanoparticles (PEGylation) is a widely-used method to improve the stability, biocompatibility and half-life of nanomedicines. However, the evaluation of the PEGylated nanomedicine pharmacokinetics (PK) requires the decomposition of particles and purification of lead compounds before analysis by high performance liquid chromatography (HPLC), mass spectrometry, etc. Therefore, a method to directly quantify un-decomposed PEGylated nanoparticles is needed. In this study, we developed anti-PEG bioparticles and combined them with anti-PEG antibodies to generate a quantitative enzyme-linked immunosorbent assay (ELISA) for direct measurement of PEGylated nanoparticles without compound purification. The anti-PEG bioparticles quantitative ELISA directly quantify PEG-quantum dots (PEG-QD), PEG-stabilizing super-paramagnetic iron oxide (PEG-SPIO), Lipo-Dox and PEGASYS and the detection limits were 0.01 nM, 0.1 nM, 15.63 ng/mL and 0.48 ng/mL, respectively. Furthermore, this anti-PEG bioparticle-based ELISA tolerated samples containing up to 10% mouse or human serum. There was no significant difference in pharmacokinetic studies of radiolabeled PEG-nanoparticles (Nano-X-111In) through anti-PEG bioparticle-based ELISA and a traditional gamma counter. These results suggest that the anti-PEG bioparticle-based ELISA may provide a direct and effective method for the quantitation of any whole PEGylated nanoparticles without sample preparation. PMID- 27991599 TI - Nucleation of mercury sulfide by dealkylation. AB - Metal sulfide minerals are assumed to form naturally at ambient conditions via reaction of a metallic element with (poly)sulfide ions, usually produced by microbes in oxygen-depleted environments. Recently, the formation of mercury sulfide (beta-HgS) directly from linear Hg(II)-thiolate complexes (Hg(SR)2) in natural organic matter and in cysteine solutions was demonstrated under aerated conditions. Here, a detailed description of this non-sulfidic reaction is provided by computations at a high level of molecular-orbital theory. The HgS stoichiometry is obtained through the cleavage of the S-C bond in one thiolate, transfer of the resulting alkyl group (R') to another thiolate, and subsequent elimination of a sulfur atom from the second thiolate as a thioether (RSR'). Repetition of this mechanism leads to the formation of RS-(HgS)n-R chains which may self-assemble in parallel arrays to form cinnabar (alpha-HgS), or more commonly, quickly condense to four-coordinate metacinnabar (beta-HgS). The mechanistic pathway is thermodynamically favorable and its predicted kinetics agrees with experiment. The results provide robust theoretical support for the abiotic natural formation of nanoparticulate HgS under oxic conditions and in the absence of a catalyst, and suggest a new route for the (bio)synthesis of HgS nanoparticles with improved technological properties. PMID- 27991601 TI - On the Road Less Traveled: Journey of an Oncology Palliative Care Researcher. AB - In 2001, as the Trish Greene Quality of Life lecturer, I described coming to a career crossroads and cited a metaphor from Robert Frost's poem "The Road Not Taken," realizing that, as I chose to leave the path of bone marrow transplantation clinician and go to that of palliative care nurse, there was no turning back. In this article based on my 2016 Oncology Nursing Society Congress Distinguished Nurse Researcher Award lecture, I would like to continue the Frost metaphor as I describe what has transpired since taking "the one less traveled by"-that of palliative care nurse scientist. PMID- 27991600 TI - Cervical Cancer Screening Among Arab Women in the United States: An Integrative Review. AB - PROBLEM IDENTIFICATION: Arab American women are an ethnic minority and immigrant population in the United States with unique and nuanced sociocultural factors that influence preventive health behaviors. The aims of this article are to evaluate and synthesize the existing evidence on cervical cancer screening behaviors, as well as determine factors that influence these behaviors, among Arab American women.?. LITERATURE SEARCH: Extensive literature searches were performed using PubMed, CINAHL(r), Scopus, Embase, and Cochrane databases; articles published through October 2015 were sought. ?. DATA EVALUATION: Of 17 articles, 14 explicitly identified Arab and/or Muslim women and cervical cancer screening in either the title or the abstract; the remaining three focused on cancer attitudes and behaviors in Arab Americans in general but measured cervical cancer screening. Eleven articles reported different aspects of one intervention. Because of methodologic heterogeneity, the current authors synthesized results narratively.?. SYNTHESIS: Key factors influencing cervical cancer screening were identified as the following. CONCLUSIONS: Cervical cancer screening rates among Arab American women are comparable to other ethnic minorities and lower than non Hispanic White women. Findings are inconsistent regarding factors influencing cervical cancer screening behaviors in this underrepresented group. ?. IMPLICATIONS FOR RESEARCH: Significant need exists for more research to better understand cervical cancer prevention behaviors in this group to inform culturally relevant interventions. Healthcare providers play a crucial role in increasing cervical cancer screening awareness and recommendations for Arab American women. PMID- 27991602 TI - Perceptions of Hematopoietic Stem Cell Transplantation and Coping Predict Emotional Distress During the Acute Phase After Transplantation. AB - PURPOSE/OBJECTIVES: To test whether a widely used model of adjustment to illness, the self-regulatory model, explains the patterns of distress during acute hematopoietic stem cell transplantation (HSCT). According to the model, perceptions of HSCT, coping, and coping appraisals are associated with distress.?. DESIGN: Longitudinal, correlational.?. SETTING: The Centre for Clinical Haematology at Nottingham City Hospital and the Department of Haematology at Royal Hallamshire Hospital in Sheffield, both in the United Kingdom.?. SAMPLE: 45 patients receiving mostly autologous transplantations for a hematologic malignancy.?. METHODS: Patients were assessed at baseline, on transplantation day, and two and four weeks after transplantation using three questionnaires. MAIN RESEARCH VARIABLES: Psychological distress, including depression, anxiety, stress, and overall distress (DASS-21); use of different coping styles (Brief COPE); and perceptions of HSCT and coping appraisals (Brief IPQ).?. FINDINGS: As suggested by the self-regulatory model, greater distress was associated with negative perceptions of HSCT, controlling for the effects of confounding variables. Mixed support was found for the model's predictions about the impact of coping styles on distress. Use of active and avoidant coping styles was associated with more distress during the acute phase after HSCT.?. CONCLUSIONS: Negative perceptions of HSCT and coping contribute to psychological distress during the acute phase after HSCT and suggest the basis for intervention.?. IMPLICATIONS FOR NURSING: Eliciting and discussing patients' negative perceptions of HSCT beforehand and supporting helpful coping may be important ways to reduce distress during HSCT. PMID- 27991603 TI - Relationship Between Depressive Symptoms and Social Cognitive Processing in Partners of Long-Term Breast Cancer Survivors. AB - PURPOSE/OBJECTIVES: To determine (a) if depressive symptoms in partners of long term breast cancer survivors (BCSs) could be predicted by social cognitive processing theory and (b) if partners of younger and older BCSs were differentially affected by the cancer experience.?. DESIGN: A cross-sectional, descriptive study using self-report questionnaires.?. SETTING: Indiana University in Bloomington and 97 ECOG-ACRIN Cancer Research Group sites in the United States.?. SAMPLE: 508 partners of BCSs diagnosed three to eight years prior to the study. ?. METHODS: Secondary data mediation analyses were conducted to determine if cognitive processing mediated the relationship between social constraints and depressive symptoms. Age-related differences on all scales were tested.?. MAIN RESEARCH VARIABLES: Depressive symptoms; secondary variables included social constraints, cognitive processing (avoidance and intrusive thoughts), and potentially confounding variables.?. FINDINGS: Cognitive processing mediated the relationship between social constraints and depressive symptoms for partners. Partners of younger BCSs reported worse outcomes on all measures than partners of older BCSs.?. CONCLUSIONS: As predicted by the social cognitive processing theory, cognitive processing mediated the relationship between social constraints and depressive symptoms. In addition, partners of younger BCSs fared worse on social constraints, intrusive thoughts, and depressive symptoms than partners of older BCSs. ?. IMPLICATIONS FOR NURSING: Results provide support for using the social cognitive processing theory in an intervention design with partners of long-term BCSs to decrease depressive symptoms. PMID- 27991605 TI - Some Things Must Not Change. AB - The past three months have been a season of tremendous change, and many of us have been surprised by the political events that have taken place. January heralds a change in administration for the United States, and the future seems uncertain. I sense that change is going to be the new normal, and we have to be able to cope with it-and with each other-for a long time. What I want to talk about is those things that do not change and how we, as nurses and scientists, must remain true to our roots.?. PMID- 27991604 TI - A Pilot Randomized, Controlled Trial of a Wall Climbing Intervention for Gynecologic Cancer Survivors. AB - PURPOSE/OBJECTIVES: To examine the feasibility and preliminary efficacy of an eight-week supervised climbing intervention for gynecologic cancer survivors (GCSs).?. DESIGN: A pilot randomized, controlled trial.?. SETTING: The Wilson Climbing Center in Edmonton, Alberta, Canada.?. SAMPLE: 35 GCSs who had completed cancer therapy.?. METHODS: GCSs were randomized to an eight-week (16 session) supervised wall climbing intervention (WCI) (n = 24) or usual care (UC) (n = 11).?. MAIN RESEARCH VARIABLES: Feasibility outcomes included recruitment rate, adherence rate, skill performance, and safety. Preliminary efficacy outcomes were objective health-related and functional fitness assessed before and after the eight-week intervention using the Senior Fitness Test.?. FINDINGS: Median adherence to the WCI was 13.5 of 16 sessions. Most GCSs were proficient on 16 of 24 skill assessment items. No serious adverse events were reported. Based on intention-to-treat analyses, the WCI group was superior to the UC group for the 6 minute walk, 30-second chair stand, 30-second arm curls, sit and reach, 8-foot up and-go, grip strength-right, and grip strength-left assessments.?. CONCLUSIONS: The Gynecologic Cancer Survivors Wall Climbing for Total Health (GROWTH) Trial demonstrated that an eight-week supervised WCI was safe, feasible, and improved functional fitness in GCSs. Phase II and III trials are warranted to further establish the safety, feasibility, and efficacy of WCIs in cancer survivors.?. IMPLICATIONS FOR NURSING: Oncology nurses may consider a climbing wall as an alternative type of physical activity for improving functional fitness in GCSs. PMID- 27991606 TI - Patients' Experiences of Preparation for Radiation Therapy: A Qualitative Study. AB - PURPOSE/OBJECTIVES: To explore patients' experiences of and preferences for preparation for radiation therapy.?. RESEARCH APPROACH: Qualitative study. ?. PARTICIPANTS: 26 individuals who recently received radiation therapy for cancer. ?. SETTING: One Australian radiation oncology clinic located within a tertiary referral hospital in New South Wales.?. METHODOLOGIC APPROACH: Semistructured interviews were conducted and analyzed based on a qualitative descriptive approach and content analysis of the transcribed interviews.?. FINDINGS: Four main themes related to preparation techniques were identified. CONCLUSIONS: The information gained in this study indicates what strategies may best prepare patients for radiation therapy. ?. INTERPRETATION: Providing patients with information that creates a realistic expectation of what radiation therapy involves both before and after treatment seems particularly important in helping them feel prepared. PMID- 27991607 TI - A Multiorganization Approach to Improving Palliative Care in Honduras. AB - Since 2011, oncology nurses and physicians in the United States have been volunteering in Honduras with the International Cancer Corps (ICC), organized by the American Society of Clinical Oncology (ASCO), in partnership with Health Volunteers Overseas (HVO). In this article, the authors will summarize the work of the ASCO/HVO ICC teams that developed educational programs with local partners to improve cancer and palliative care in Honduras. PMID- 27991608 TI - Testing an Intervention to Decrease Healthcare Workers' Exposure to Antineoplastic Agents. AB - PURPOSE/OBJECTIVES: To develop and test a worksite intervention that protects healthcare workers who handle antineoplastic drugs from work-related exposures. ?. DESIGN: Intervention study. ?. SETTING: A university hospital in a large midwestern metropolitan area and its outpatient chemotherapy infusion clinic.?. SAMPLE: 163 staff (nurses, pharmacists, and pharmacy technicians) who work with antineoplastic agents.?. METHODS: A self-report survey measured workplace and individual factors to assess use of personal protective equipment (PPE). Wipe samples were tested for surface contamination. An intervention incorporating study findings and worker input was developed.?. MAIN RESEARCH VARIABLES: PPE use was the dependent variable, and the independent variables included knowledge of the hazard, perceived risk, perceived barriers, interpersonal influence, self efficacy, conflict of interest, and workplace safety climate. ?. FINDINGS: PPE use was lower than recommended and improved slightly postintervention. Self efficacy and perceived risk increased on the post-test survey. Chemical residue was found in several areas. Awareness of safe-handling precautions improved postintervention. The unit where nurses worked was an important predictor of safety climate and PPE use on the pretest but less so following the intervention. ?. CONCLUSIONS: Involving staff in developing an intervention for safety ensures that changes made will be feasible. Units that implemented workflow changes had decreased contamination. ?. IMPLICATIONS FOR NURSING: Worksite analysis identifies specific targets for interventions to improve antineoplastic drug handling safety. PMID- 27991610 TI - Response to "Nursing Care at the Time of Death: A Bathing and Honoring Practice"?. AB - I am a nurse in a bone marrow transplantation unit at the University of Florida Health Shands Hospital in Gainesville. We are a high-risk center in the sense that we care for transplant patients who have been denied at other centers. Our patients are very sick with resistant disease and often with multiple comorbidities as well. These sad facts translate into long, torturous, brave battles that end in death. The nursing staff, patients, and families become very close over many months of fighting together. We witness waves of death of these people we have grown to love. The staff has struggled with sadness and an inability to process so much grief.?. PMID- 27991609 TI - Oncology Nurses' Attitudes Toward the Edmonton Symptom Assessment System: Results From a Large Cancer Care Ontario Study. AB - PURPOSE/OBJECTIVES: To examine oncology nurses' attitudes toward and reported use of the Edmonton Symptom Assessment System (ESAS) and to determine whether the length of work experience and presence of oncology certification are associated with their attitudes and reported usage.?. DESIGN: Exploratory, mixed-methods study employing a questionnaire approach.?. SETTING: 14 regional cancer centers (RCCs) in Ontario, Canada.?. SAMPLE: Oncology nurses who took part in a larger province-wide study that surveyed 960 interdisciplinary providers in oncology care settings at all of Ontario's 14 RCCs.?. METHODS: Oncology nurses' attitudes and use of ESAS were measured using a 21-item investigator-developed questionnaire. Descriptive statistics and Kendall's tau-b or tau-c test were used for data analyses. Qualitative responses were analyzed using content analysis.?. MAIN RESEARCH VARIABLES: Attitudes toward and self-reported use of standardized symptom screening and ESAS.?. FINDINGS: More than half of the participants agreed that ESAS improves symptom screening, most said they would encourage their patients to complete ESAS, and most felt that managing symptoms is within their scope of practice and clinical responsibilities. Qualitative comments provided additional information elucidating the quantitative responses. Statistical analyses revealed that oncology nurses who have 10 years or less of work experience were more likely to agree that the use of standardized, valid instruments to screen for and assess symptoms should be considered best practice, ESAS improves symptom screening, and ESAS enables them to better manage patients' symptoms. No statistically significant difference was found between oncology certified RNs and noncertified RNs on attitudes or reported use of ESAS.?. CONCLUSIONS: Implementing a population-based symptom screening approach is a major undertaking. The current study found that oncology nurses recognize the value of standardized screening, as demonstrated by their attitudes toward ESAS.?. IMPLICATIONS FOR NURSING: Oncology nurses are integral to providing high quality person-centered care. Using standardized approaches that enable patients to self-report symptoms and understanding barriers and enablers to optimal use of patient-reported outcome tools can improve the quality of patient care. PMID- 27991611 TI - Dyadic Perceptions of the Decision Process in Families Living With Lung Cancer. AB - PURPOSE/OBJECTIVES: To use dyadic analyses to identify determinants of patients' and family members' perceptions of the positive and negative aspects of the decision-making process in families living with lung cancer. ?. DESIGN: Cross sectional study. ?. SETTING: Community setting in Greater Portland, Oregon.?. SAMPLE: 109 family care dyads (patient and family member) recruited from a statewide cancer registry. ?. METHODS: Surveys were completed in-person, separately, and privately by each member of the family care dyad. Secondary analysis was completed using multilevel modeling. ?. MAIN RESEARCH VARIABLES: Negative and positive aspects of the decision process. ?. FINDINGS: Level 1 data revealed significant variability across care dyads' positive or negative perceptions of the decision-making process. Level 2 results for negative perceptions of decision making indicated that patient and family member perceptions were significantly associated with their own depressive symptoms and feelings of not being listened to by others. Level 2 results for positive perceptions of decision making indicated that patient and family member perceptions were significantly inversely associated with their own feelings of not being listened to and being in nonspousal relationships. In addition, family members' perceptions were more positive when the patients were older. ?. CONCLUSIONS: This study highlighted the complexity of the decision-making process in families with lung cancer, and underscored the importance of the care dyad feeling listened to by family members in the context of life-threatening illnesses. ?. IMPLICATIONS FOR NURSING: Nurses assisting families with decisions about lung cancer should be aware of the dynamics of the care dyad and how the decision process is perceived by patients and their family members. PMID- 27991612 TI - Patient-Reported Self-Efficacy, Anxiety, and Health-Related Quality of Life During Chemotherapy: Results From a Longitudinal Study. AB - PURPOSE/OBJECTIVES: To explore changes over time in self-efficacy and the predictive ability of changes in state anxiety and health-related quality of life during chemotherapy.?. DESIGN: Secondary analysis of a longitudinal dataset derived from a larger, multicenter study.?. SETTING: Outpatient oncology clinics across eight general hospitals in England, Scotland, and Northern Ireland.?. SAMPLE: 137 patients scheduled to receive adjuvant chemotherapy for breast or colorectal cancer.?. METHODS: At the beginning of each of six chemotherapy cycles, participants completed the Strategies Used by People to Promote Health questionnaire, the State-Trait Anxiety Inventory, and the Functional Assessment of Cancer Therapy-Breast or -Colorectal questionnaire. Multilevel model analysis was used to analyze longitudinal data, adjusted for demographic and clinical variables.?. MAIN RESEARCH VARIABLES: Self-efficacy, anxiety, and health-related quality of life.?. FINDINGS: No significant time effects were found for patients' overall perceived self-efficacy or self-efficacy parameters. A trend toward greater self-efficacy was evident as chemotherapy progressed. Self-efficacy was significantly associated with decreased state anxiety throughout chemotherapy. Increases in overall self-efficacy and perceived ability to maintain a positive attitude were significantly associated with over-time increases in physical, emotional, and functional well-being, as well as with fewer cancer-related concerns.?. CONCLUSIONS: Findings highlight the importance of clinical assessments throughout treatment that focus on patients' perceived self-efficacy as a positive regulator of mood and well-being. ?. IMPLICATIONS FOR NURSING: The current study suggests self-efficacy enhancement should be a key component of psycho-behavioral programs designed to support patients with cancer throughout chemotherapy. PMID- 27991614 TI - Evaluation of the WinROP system for identifying retinopathy of prematurity in Czech preterm infants. AB - AIMS: Retinopathy of Prematurity (ROP) is a potentially serious condition that can afflict preterm infants. Timely and correct identification of individuals at risk of developing a serious form of ROP is therefore of paramount importance. WinROP is an online system for predicting ROP based on birth weight and weight increments. However, the results vary significantly for various populations. It has not been evaluated in the Czech population. This study evaluates the test characteristics (specificity, sensitivity, positive and negative predictive values) of the WinROP system in Czech preterm infants. METHODS: Data on 445 prematurely born infants included in the ROP screening program at the University Hospital Ostrava, Czech Republic, were retrospectively entered into the WinROP system and the outcomes of the WinROP and regular screening were compared. RESULTS: All 24 infants who developed high-risk (Type 1 or Type 2) ROP were correctly identified by the system. The sensitivity and negative predictive values for this group were 100%. However, the specificity and positive predictive values were substantially lower, resulting in a large number of false positives. Extending the analysis to low risk ROP, the system did not provide such reliable results. CONCLUSIONS: The system is a valuable tool for identifying infants who are not likely to develop high-risk ROP and this could help to substantially reduce the number of preterm infants in need of regular ROP screening. It is not suitable for predicting the development of less serious forms of ROP which is however in accordance with the declared aims of the WinROP system. PMID- 27991613 TI - Healthcare Factors for Obtaining a Mammogram in Latinas With a Variable Mammography History. AB - PURPOSE/OBJECTIVES: To understand the relationship between mammography history and current thoughts about obtaining a mammogram among Latinas and examine the mediation effects of several healthcare factors.?. DESIGN: Cross-sectional survey.?. SETTING: Federally qualified health centers (Sea Mar Community Health Centers) in western Washington.?. SAMPLE: 641 Latinas nonadherent and adherent with screening mammography.?. METHODS: Baseline survey data from Latinas with a mammography history of never, not recent (more than two years), or recent (less than two years) were analyzed. Preacher and Hayes methods were used to estimate the mediation effect of healthcare factors.?. MAIN RESEARCH VARIABLES: The survey assessed mammography history, sociodemographic and healthcare factors, and current thoughts about obtaining a mammogram.?. FINDINGS: Latinas' thoughts about obtaining a mammogram were associated with mammography history. Having had a clinical breast examination mediated 70% of differences between Latinas with a never and recent mammography history. Receipt of a provider recommendation mediated 54% of differences between Latinas with and without a recent mammography history.?. CONCLUSIONS: These findings emphasize the importance of the patient provider relationship during a clinic visit and help inform how nurses may be incorporated into subsequent screening mammography interventions tailored to Latinas.?. IMPLICATIONS FOR NURSING: As providers, health educators, and researchers, nurses have critical roles in encouraging adherence to screening mammography guidelines among Latinas. PMID- 27991615 TI - Impact of foot progression angle modification on plantar loading in individuals with diabetes mellitus and peripheral neuropathy. AB - AIMS: To determine if participants can reduce foot progression angle (FPA), and if FPA reduction decreases regional plantar stresses and forces in individuals with diabetes. METHODS: Design: Three-group cross-sectional design with repeated measures. subjects: twenty-eight participants either with diabetes mellitus (DM), diabetes and peripheral neuropathy with (DMPN+NPU) or without a prior history of ulceration (DMPN-NPU) were studied. Intervention: Participants were first instructed to walk over a 3.6 m walkway at their preferred FPA, and then to walk with their foot aligned parallel with the line of gait progression at their self selected speed. Dynamic plantar kinetics in six masked regions were collected using an EMED-st-P-2 pedobarograph. Main measures: Primary outcome measures were FPA, peak plantar pressure (PPP), and force-time integral (FTI). A repeated measures ANOVA was conducted to determine group differences in FPA for both walking conditions. Regional differences in PPPs and FTIs between preferred and corrected walking conditions were analyzed using repeated measures ANCOVA. RESULTS: Participants showed a reduction in FPA magnitude on the 'Involved' foot between the preferred and corrected walking conditions (p<0.01). There were no differences in PPPs or FTIs in any mask between walking conditions (p>0.05). CONCLUSION: Results from this investigation offer important evidence that people with diabetes can modify their FPA with a simple intervention of visual and verbal cueing. Future research should examine if gait retraining strategies in regular footwear more effectively offload areas of elevated regional plantar stresses and forces in adults with diabetes mellitus and peripheral neuropathy. PMID- 27991616 TI - ATB0,+ transporter-mediated targeting delivery to human lung cancer cells via aspartate-modified docetaxel-loading stealth liposomes. AB - Tumor cells have an increased demand for amino acids to support their rapid growth and malignant metastasis. Transfer of amino acids across plasma membranes depends on several amino acid transporters that are highly upregulated in tumor cells and are promising targets for tumor cell-selective therapy. In this study, stealth liposomal systems functionalized with aspartate-polyoxyethylene stearate conjugate (APS) were developed for transporter-mediated targeted delivery to ATB0,+, which is overexpressed human lung cells. The resultant ATB0,+-targeting liposomes (APS-Lips) consisted of a liposome core and the surface coverage of the APS modifier had an optimized density of 10%. APS-Lips had a uniform particle size distribution and high encapsulation efficiency of docetaxel (DTX, >80%). APS modification had a negligible effect on the DTX release from liposomes. Compared with Taxotere and unmodified liposomes, APS-Lips showed increased intracellular delivery and antitumor potency against human lung cells. Furthermore, competitive endocytosis studies showed that the cellular uptake of APS-Lips was notably decreased in the presence of glycine, a typical substrate of ATB0,+, and was increased through adhesion to the cell membrane via transporter-substrate interactions. Finally, in vitro hemolysis and in vivo vascular irritation studies in rabbits confirmed the good blood compatibility and minimal vascular stimulation of the synthetic ATB0,+-targeting material APS. These results demonstrated that the aspartate-modified liposomes could be a promising nanocarrier for ATB0,+ transporter-mediated targeted drug delivery to treat lung cancer. PMID- 27991618 TI - Correction: Design and development of photoanodes for water-splitting dye sensitized photoelectrochemical cells. AB - Correction for 'Design and development of photoanodes for water-splitting dye sensitized photoelectrochemical cells' by John R. Swierk et al., Chem. Soc. Rev., 2013, 42, 2357-2387. PMID- 27991617 TI - Pursuing the active species in an aluminium-based Lewis acid system for catalytic Diels-Alder cycloadditions. AB - Several Al-based complexes supported by a bis(imino)aryl NCN pincer ligand have been prepared. Systematic structural and experimental evidence identified a cationic species, supported by a THF molecule, as the best Lewis acid precatalyst for a range of Diels-Alder cycloadditions. This highlighted the importance of fully isolating and characterizing the active species in any catalytic process especially when Lewis acids are used due to the presence of hidden Bronsted acids (HBAs). Finally, the control experiments conducted in order to eliminate HBA activity that involve a bulky pyridine base should be performed with caution as the corresponding protonated pyridinium salt could also serve as a proton source. PMID- 27991619 TI - Synthesis and characterization of phosphorescent two-coordinate copper(i) complexes bearing diamidocarbene ligands. AB - The photophysical properties of four, two-coordinate, linear diamidocarbene copper(i) complexes, [(DAC)2Cu][BF4] (1), (DAC)CuOSiPh3 (2), (DAC)CuC6F5 (3) and (DAC)Cu(2,4,6-Me3C6H2) (4) (DAC = 1,3-bis(2,4,6-trimethylphenyl)-5,5-dimethyl-4,6 diketopyrimidinyl-2-ylidene) have been investigated. Complex 1 shows a high photoluminescence quantum efficiency (PhiPL) in both the solid state (PhiPL = 0.85) and in CH2Cl2 solution (PhiPL = 0.65). The emission band of 1, both as a crystalline solid and in solution, is narrow (fwhm = 2300 cm-1) relative to the emission bands of 2 (fwhm = 2900 cm-1) and 3 (fwhm = 3700 cm-1). Complexes 2 and 3 are each brightly luminescent in the solid state (PhiPL = 0.62 and 0.18, respectively), but markedly less so in CH2Cl2 solution (PhiPL = 0.03 and <0.01, respectively). Complex 4 is not emissive in either the solid state or in solution. Phosphorescence of 1 in CH2Cl2 solution shows negligible quenching by oxygen in CH2Cl2 solution. This insensitivity to quenching is attributed to the excited state redox potential being insufficient for electron transfer to oxygen. PMID- 27991620 TI - Computational study of An-X bonding (An = Th, U; X = p-block-based ligands) in pyrrolic macrocycle-supported complexes from the quantum theory of atoms in molecules and bond energy decomposition analysis. AB - A systematic computational study of organoactinide complexes of the form [LAnX]n+ has been carried out using density functional theory, the quantum theory of atoms in molecules (QTAIM) and Ziegler-Rauk energy decomposition analysis (EDA) methods. The systems studied feature L = trans-calix[2]benzene[2]pyrrolide, An = Th(iv), Th(iii), U(iii) and X = BH4, BO2C2H4, Me, N(SiH3)2, OPh, CH3, NH2, OH, F, SiH3, PH2, SH, Cl, CH2Ph, NHPh, OPh, SiH2Ph, PHPh2, SPh, CPh3, NPh2, OPh, SiPh3 PPh2, SPh. The PBE0 hybrid functional proved most suitable for geometry optimisations based on comparisons with available experimental data. An-X bond critical point electron densities, energy densities and An-X delocalisation indices, calculated with the PBE functional at the PBE0 geometries, are correlated with An-X bond energies, enthalpies and with the terms in the EDA. Good correlations are found between energies and QTAIM metrics, particularly for the orbital interaction term, provided the X ligand is part of an isoelectronic series and the number of open shell electrons is low (i.e. for the present Th(iv) and Th(iii) systems). PMID- 27991621 TI - Transitions of two magnetic interaction states in dinuclear Dy(iii) complexes via subtle structural variations. AB - Herein we explored the transitions of two magnetic interaction states (antiferromagnetic or ferromagnetic) upon structural variations in two dinuclear Dy(iii) complexes. PMID- 27991622 TI - Slow relaxation dynamics of a mononuclear Er(iii) complex surrounded by a ligand environment with anisotropic charge density. AB - Two sets of isostructural mononuclear compounds, [Ln(LOMe)2(H2O)2](PF6) [1, Ln = Er; 3, Ln = Gd; LOMe = CpCo{P(O)(O(CH3))2}3] and Ln(LOMe)2(NO3) (2, Ln = Er and 4, Ln = Gd), are synthesized by self-assembly of the respective lanthanide ions and tripodal chelate ligands. The Ln ions are encircled by two LOMe ligands, and two water molecules or one nitrate anion. Each octacoordinated Ln center adopts a distorted square antiprism geometry. The Er complex (2) chelated by a nitrate anion shows slow dynamics in magnetic relaxation, diagnostic of a single-ion magnet. Quantum tunneling in 2 is effectively blocked by application of an external field. Weak intermolecular magnetic interactions occur in 2, and are supported by the magnetic behavior of 4. Chemical dilution of Er with the diamagnetic Y ion can nullify magnetic interactions and suppress quantum tunneling. Generation of slow relaxation dynamics in the Er system is related to the anisotropic charge distribution supplied by the coordination of ligands with different charge densities, as observed in the Dy analogue. This suggests that magnetic anisotropy arises in a coordination system when an anisotropic lanthanide ion (Dy and Er) is surrounded by a ligand environment with anisotropic charge density, resulting in slow magnetic relaxation. PMID- 27991623 TI - Real-time analysis of Pd2(dba)3 activation by phosphine ligands. AB - A combination of UV-Vis spectroscopy and electrospray ionization mass spectrometry is used for real-time monitoring of Pd2(dba)3 activation with sulfonated versions of PPh3 and Buchwald-type ligands. This provides insight into the effect of ligand and preparation conditions on activation and allows for establishment of rational activation protocols. PMID- 27991624 TI - Fundamental organometallic chemistry under bimetallic influence: driving beta hydride elimination and diverting migratory insertion at Cu and Ni. AB - Bimetallic effects on stoichiometric beta-hydride elimination and migratory insertion reactions were examined. Bimetallic reaction conditions drove beta hydride elimination at Cu, while bimetallic C-B elimination occurred in the absence of beta-hydrogens. The inherent migratory insertion chemistry of alkynes at Ni was diverted under bimetallic reaction conditions to favor C-H deprotonation. PMID- 27991625 TI - A rapid and highly enantioselective C-11C bond formation of l-[11C]phenylalanine via chiral phase-transfer catalysis. AB - A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [11C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [11C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [11C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d [11C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq MUmol-1 of the enantiomerically pure [11C]phenylalanine, showing that the process is robust and amenable to broad use in PET. PMID- 27991626 TI - Impact of distributions on the archetypes and prototypes in heterogeneous nanoparticle ensembles. AB - The magnitude and complexity of the structural and functional data available on nanomaterials requires data analytics, statistical analysis and information technology to drive discovery. We demonstrate that multivariate statistical analysis can recognise the sets of truly significant nanostructures and their most relevant properties in heterogeneous ensembles with different probability distributions. The prototypical and archetypal nanostructures of five virtual ensembles of Si quantum dots (SiQDs) with Boltzmann, frequency, normal, Poisson and random distributions are identified using clustering and archetypal analysis, where we find that their diversity is defined by size and shape, regardless of the type of distribution. At the complex hull of the SiQD ensembles, simple configuration archetypes can efficiently describe a large number of SiQDs, whereas more complex shapes are needed to represent the average ordering of the ensembles. This approach provides a route towards the characterisation of computationally intractable virtual nanomaterial spaces, which can convert big data into smart data, and significantly reduce the workload to simulate experimentally relevant virtual samples. PMID- 27991627 TI - Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2 a][1,10]phenanthrolines via an intramolecular C-H amination reaction. AB - In the present study a series of N-phenyl-1,10-phenanthroline-2-amine derivatives were obtained by heating 2-chlorophenanthroline with aniline derivatives under solvent free conditions in good to excellent yields. The N-phenyl-1,10 phenanthroline-2-amines were employed as substrates in a copper(ii)-catalyzed C-H amination reaction to give derivatives of the novel heterocyclic system benzo[4,5]imidazo[1,2-a][1,10]phenanthroline. The structure of these compounds was predicted to be helical by DFT calculations and single crystal X-ray diffraction of an example of this system confirmed the non-planar helical structure. The luminescence properties of the parent heterocyclic system were characterized. PMID- 27991628 TI - Rapid access to N-(indol-2-yl)amides and N-(indol-3-yl)amides as unexplored pharmacophores. AB - Preparation of N-(indol-2-yl)amides and N-(indol-3-yl)amides are scarce in the scientific literature due to unstable intermediates impeding current reported syntheses. We have employed cheap and readily available substrates in the Curtius rearrangement of indole-3-carboxazide to afford N-(indol-3-yl)amides. The reaction is observed for alkyl and aryl carboxylic acids and both N-substituted or 1H-indole derivatives are tolerated. This approach was extended to the preparation of N-(indol-2-yl)amides from the corresponding indole-2-carboxazides. PMID- 27991629 TI - Controllable synthesis of functional nanoparticles by microfluidic platforms for biomedical applications - a review. AB - Nanoparticles have drawn significant attention in biomedicine due to their unique optical, thermal, magnetic and electrical properties which are highly related to their size and morphologies. Recently, microfluidic systems have shown promising potential to modulate critical stages in nanosynthesis, such as nucleation, growth and reaction conditions so that the size, size distribution, morphology, and reproducibility of nanoparticles are optimized in a high throughput manner. In this review, we put an emphasis on a decade of developments of microfluidic systems for engineering nanoparticles in various applications including imaging, biosensing, drug delivery, and theranostic applications. PMID- 27991630 TI - Zinc-catalyzed chemoselective alkylation of alpha-keto amides with 2 alkylazaarenes. AB - A zinc-catalyzed C(sp3)-H addition of 2-alkylazaarenes to alpha-keto amides to furnish azaarene incorporated alpha-hydroxy amides has been developed with a wide range of substrates in moderate to excellent yields, respectively. Chemoselective alkylation of the keto functionality of the alpha-keto amides in the presence of simple ketones is the key advantage of this Zn-catalyzed transformation. This approach has been demonstrated to one gram-scale synthesis. 1H NMR and D2O exchange experimental studies reveal that the reaction proceeds through a Zn enamide intermediate. PMID- 27991631 TI - Positive variation of the MRI signal via intramolecular inclusion complexation of a C-2 functionalized beta-cyclodextrin. AB - The synthesis of a new contrast agent based on a beta-cyclodextrin scaffold and bearing a flexible lipophilic spacer arm on its secondary face is reported. Intermolecular host-guest inclusion complexes were known to undergo an enhancement of the contrast imaging. We extend this concept to intramolecular complexation. Inter- and intramolecular interactions are compared by NMR spectroscopy, circular dichroism and magnetic resonance imaging using hydrocinnamic acid and adamantane carboxylic acid as external guests. This positive variation of the observed relaxivity is a key element of new strategies aiming at developing smart molecular MRI probes. PMID- 27991633 TI - The ionic strength dependent zeta potential at the surface of hexadecane droplets in water and the corresponding interfacial adsorption of surfactants. AB - An anomalous maximum in the ionic strength dependent electrophoretic mobility curves has been observed in previous reports from particles dispersed in colloids. This maximum has been considered anomalous because it is contradictory with the Gouy-Chapman model. The existence of such a maximum has been attributed to specific ionic adsorption, a hairy layer at the surface, or the effect of the anomalous change of surface conductivity in different studies. It was also pointed out that the O'Brien-White approach based on the Gouy-Chapman model could be used to understand this maximum in electrophoretic mobility curves and lead to understandable zeta potential curves. This implied that the observed maximum was actually not "anomalous". In this work we report our simulation of ionic strength dependent zeta potential curves based on the O'Brien-White approach and experimental studies of the ionic strength dependent electrophoretic mobility of the hexadecane droplets in the hexadecane-water emulsions at different pH or in the presence of sodium dodecyl sulphate at varied concentrations. In some cases, the simulation shows that the calculation with the O'Brien-White approach does change the trend in the concerned ionic strength dependent curves. However, the simulation in some other cases also leads to similar trends in the ionic strength dependent electrophoretic mobility curves and zeta potential curves. In the experiments, both the existence and non-existence of such a maximum were observed and demonstrated to be system dependent. The corresponding molecular structure of the oil-water interface was then discussed with the analyses of the zeta potential curves and second harmonic generation signals recorded at the hexadecane-water interface. PMID- 27991632 TI - Tissue factor-specific ultra-bright SERRS nanostars for Raman detection of pulmonary micrometastases. AB - Here we demonstrate a novel application of 'surface enhanced resonance Raman scattering nanoparticles' (SERRS NPs) for imaging breast cancer lung metastases with much higher precision than currently feasible. A breast cancer lung metastasis mouse model was established by intravenous injection of LM2 cells. These mice were intravenously administered SERRS NPs conjugated with ALT-836, an anti-tissue factor (TF) monoclonal antibody, and subjected to Raman imaging to visualize the expression of TF both in vivo and ex vivo. Raman imaging indicated marked uptake of alphaTF-SERRS-NPs by the lung metastases compared to isotype and blocking controls. Conversely, little uptake of alphaTF-SERRS-NPs was observed in the lungs of healthy mice. Successful detection and delineation of pulmonary micrometastatic lesions as small as 200 MUm, corroborated by histology, immunohistochemistry, and bioluminescence imaging confirmed the suitability of both TF as a target and alphaTF-SERRS-NPs as an effective contrast agent for imaging breast cancer lung metastases. Further advancements of this technique in the form of Raman endoscopes coupled with ultrabright SERRS NPs developed in this work could lead to minimally invasive detection and resection of lung metastases. PMID- 27991634 TI - Interfacial properties and emulsification performance of thylakoid membrane fragments. AB - Thylakoids membranes are sophisticated, dynamic structures found in plant leaves, composed of protein complexes in a dynamic lipid matrix. The interfacial absorption dynamics and viscoelasticity of thylakoid membranes fragments were measured to assess the properties of the interfacial layer and to elucidate an emulsifying mechanism that includes the role of thylakoid's composition and 3D structure. Thylakoid membranes were extracted from sugar beet leaves by a series of buffer washing, filtration and centrifugation. The extract containing the intact thylakoid membranes was suspended in water through high-pressure homogenisation, which disrupted the structure into membrane fragments. Thylakoid fragments showed surface and interfacial behaviour similar to soft particles or Pickering stabilizers with slow adsorption kinetics. After adsorption, an elastic and stable thin film was formed, indicating formation of new interactions between adjacent thylakoid fragments. In an emulsion, thylakoid fragments stabilised oil droplets against coalescence, despite droplet aggregation occurring already during emulsification. Droplet aggregation occurred by steric and electrostatic bridging, which in turn forms a 3D network where the oil droplets are immobilised, preventing further droplet coalescence or aggregation. It was concluded that both composition and structure of thylakoid fragments determine their emulsifying properties, conferring potential for encapsulation systems, where the search for natural materials is gaining more attention. PMID- 27991635 TI - Mesoscale simulation of phoretically osmotic boundary conditions. AB - Boundary walls can drive the tangential flow of fluids by phoretic osmosis when exposed to a gradient field, including chemical, thermal or electric potential gradient. At the microscale, such boundary driving mechanisms become quite pronounced. Here, we propose a mesoscale strategy to simulate the phoretically osmotic boundaries, in which the microscopic fluid-wall interactions are coarse grained into the bounce-back or specular reflection, and the phoretically osmotic force is generated by selectively reversing the tangential velocity of specific fluid particles near the boundary wall. With this scheme, the phoretically osmotic boundary can be realized with a minimal modification to the widely used mesoscopic no-slip/slip hydrodynamic boundary condition. Its implementation is quite efficient and the resulting phoretically osmotic flow is flexibly tunable. Its validity is verified by performing extensive mesoscale simulations for both the diffusioosmotic and thermoosmotic boundaries. In particular, we use the proposed scheme to investigate fluid transport driven by the phoretic osmosis in microfluidic systems and the effects of the diffusioosmosis on the dynamics of active catalytic colloidal particles. Our work thus offers new possibilities to study the phoretically osmotic effect in active complex fluids and microfluidic systems by simulation, where the gradient fields are ubiquitous. PMID- 27991636 TI - Suppressed weak antilocalization in the topological insulator Bi2Se3 proximity coupled to antiferromagnetic NiO. AB - Time-reversal symmetry (TRS) breaking of the topological insulators (TIs) is a prerequisite to observe the quantum anomalous Hall effect (QAHE) and topological magnetoelectric effect (TME). Although antiferromagnetism as well as ferromagnetism could break the TRS and generate massive Dirac surface states in the TIs, no attention has been paid to the antiferromagnet-TI heterostructures. Herein, we report the magnetotransport measurements of Bi2Se3 proximately coupled to antiferromagnetic NiO. Thin films of Bi2Se3 were successfully grown on the NiO (001) single crystalline substrates by molecular beam epitaxy. Unexpectedly, we observed a strong suppression of the weak antilocalization effect, which is similar to the case of TIs coupled to the ferromagnetic materials. For the 5 nm thick Bi2Se3 sample on NiO, we even observed a crossover to weak localization at 2 K. These behaviors are attributed to the strong magnetic exchange field from the Ni 3d electrons. Our results show the effectiveness of the antiferromagnetic materials in breaking the TRS of TIs by the proximity effect and their possible applications for QAHE and TME observations. PMID- 27991637 TI - Ultrafast imaging of photochemical dynamics: roadmap to a new conceptual basis for chemistry. PMID- 27991639 TI - delta-Phosphorene: a two dimensional material with a highly negative Poisson's ratio. AB - As a basic mechanical parameter, Poisson's ratio (nu) measures the mechanical responses of solids against external loads. In rare cases, materials have a negative Poisson's ratio (NPR), and present an interesting auxetic effect. That is, when a material is stretched in one direction, it will expand in the perpendicular direction. To design modern nanoscale electromechanical devices with special functions, two dimensional (2D) auxetic materials are highly desirable. In this work, based on first principles calculations, we rediscover the previously proposed delta-phosphorene (delta-P) nanosheets [Jie Guan, et al., Phys. Rev. Lett., 2014, 113, 046804] which are good auxetic materials with a high NPR. The results show that the Young's modulus and Poisson's ratio of delta-P are all anisotropic. The NPR value along the grooved direction is up to -0.267, which is much higher than the recently reported 2D auxetic materials. The auxetic effect of delta-P originating from its puckered structure is robust and insensitive to the number of layers due to weak interlayer interactions. Moreover, delta-P possesses good flexibility because of its relatively small Young's modulus and high critical crack strain. If delta-P can be synthesized, these extraordinary properties would endow it with great potential in designing low dimensional electromechanical devices. PMID- 27991638 TI - Modulation of phase separation at the micron scale and nanoscale in giant polymer/lipid hybrid unilamellar vesicles (GHUVs). AB - Phase separation in giant polymer/lipid hybrid unilamellar vesicles (GHUVs) has been described over the last few years. However there is still a lack of understanding on the physical and molecular factors governing the phase separation in such systems. Among these parameters it has been suggested that in analogy to multicomponent lipid vesicles hydrophobic mismatches as well as lipid fluidity play a role. In this work, we aim to map a global picture of phase separation and domain formation in the membrane of GHUVs by using various copolymers based on poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEO) with different architectures (grafted, triblock) and molar masses, combined with phospholipids in the fluid (POPC) or gel state (DPPC) at room temperature. From confocal imaging and fluorescence lifetime imaging microscopy (FLIM) techniques, the phase separation into either micro- or nano-domains within GHUVs was studied. In particular, our systematic studies demonstrate that in addition to the lipid/polymer fraction or the lipid physical state, important factors such as line tension at lipid polymer/lipid boundaries can be finely modulated by the molar mass and the architecture of the copolymer and lead to the formation of stable lipid domains with different sizes and morphologies in such GHUVs. PMID- 27991640 TI - A string of nickel hexacyanoferrate nanocubes coaxially grown on a CNT@bipolar conducting polymer as a high-performance cathode material for sodium-ion batteries. AB - The development of suitable cathode materials for sodium-ion batteries is the key issue to realize their large-scale applications owing to the lack of appropriate materials with adequate electrochemical capacity and reversibility for Na-ion insertion reaction. Here, a string of nickel hexacyanoferrate (NiHCF) nanocubes is coaxially grown on a CNT@bipolar conducting polymer (BCP) by a facile electrochemical route, and used as a high-performance cathode material for sodium ion batteries. The obtained cathode shows a surprisingly high specific capacity of 194 mA h g-1 upon the initial discharge, a good cycling performance and excellent rate performance. It is considered that the unique nanostructure not only effectively facilitates the electrode/electrolyte interaction and the electronic and ionic transportation but also exerts a synergistic effect between the BCP and NiHCF nanocubes to trigger the kinetics of the electron and ion transport. It is expected that such a promising environmentally friendly alternative cathode material can be widely applied for sodium-ion batteries (SIBs). PMID- 27991642 TI - Dry writing of highly conductive electrodes on papers by using silver nanoparticle-graphene hybrid pencils. AB - The development of paper electronics would enable realization of extremely cheap devices for portable, disposable, and environmentally-benign electronics. Here, we propose a simple dry-writing tool similar to a pencil, which can be used to draw electrically conducting lines on paper for use in paper-based electronic devices. The fabricated pencil is composed of silver nanoparticles decorated on graphene layers to construct layered hybrid nanostructures. This pencil can draw highly conductive lines that are flexible and foldable on conventional papers. Electrodes drawn using this pencil on conventional copy paper are stable during repetitive mechanical folding and highly resistant to moisture/chemicals. This pencil can draw a conductive line where its resistance can be tuned by changing the amount of nanoparticles. A nonvolatile memory device is realized on papers by hand written lines with different resistance. All memory elements are composed of carbons on papers, so complete data security can be achieved by burning the memory papers. This work will provide a new opportunity to fabricate electronic devices on real papers with good conductivity as well as robust mechanical/chemical stability. PMID- 27991641 TI - Acoustic actuation of bioinspired microswimmers. AB - Acoustic actuation of bioinspired microswimmers is experimentally demonstrated. Microswimmers are fabricated in situ in a microchannel. Upon acoustic excitation, the flagellum of the microswimmer oscillates, which in turn generates linear or rotary movement depending on the swimmer design. The speed of these bioinspired microswimmers is tuned by adjusting the voltage amplitude applied to the acoustic transducer. Simple microfabrication and remote actuation are promising for biomedical applications. PMID- 27991643 TI - Dimension-controlled formation of crease patterns on soft solids. AB - Soft solids such as PDMS or silicone are widely needed in many advanced applications such as flexible electronics and medical engineering. The ability to control the structure and properties of the surface of soft solids provides new opportunities in these applications. In particular, mechanical loading induced elastic instability is a convenient method to control the surface morphology. The critical strain at which the crease nucleates is experimentally measured under plane strain conditions, and is found to be consistent with that predicted by nonlinear large deformation theory of creases. Under compressive loading, we find that silicone undergoes a transition of creasing pattern from a single channeling or double channeling crease to an unchanneling crease, depending on the specimen's width and height. Finite element simulations are performed to better understand the underlying mechanism of creasing, wherein a relationship between the depth and spacing of the creases is established. It is found to be in good agreement with the experimental data obtained. PMID- 27991645 TI - A new appearance and new approaches of JRM! AB - is missing (Editorial). PMID- 27991644 TI - Pulmonary surfactant protein SP-D opsonises carbon nanotubes and augments their phagocytosis and subsequent pro-inflammatory immune response. AB - Carbon nanotubes (CNTs) are increasingly being developed for use in biomedical applications, including drug delivery. One of the most promising applications under evaluation is in treating pulmonary diseases such as tuberculosis. Once inhaled or administered, the nanoparticles are likely to be recognised by innate immune molecules in the lungs such as hydrophilic pulmonary surfactant proteins. Here, we set out to examine the interaction between surfactant protein D (SP-D), a key lung pattern recognition molecule and CNTs, and possible downstream effects on the immune response via macrophages. We show here that a recombinant form of human SP-D (rhSP-D) bound to oxidised and carboxymethyl cellulose (CMC) coated CNTs via its C-type lectin domain and enhanced phagocytosis by U937 and THP-1 macrophages/monocytic cell lines, together with an increased pro-inflammatory response, suggesting that sequestration of SP-D by CNTs in the lungs can trigger an unwanted and damaging immune response. We also observed that functionalised CNTs, opsonised with rhSP-D, continued to activate complement via the classical pathway, suggesting that C1q, which is the recognition sub-component of the classical pathway, and SP-D have distinct pattern recognition sites on the CNTs. Consistent with our earlier reports, complement deposition on the rhSP-D opsonised CNTs led to dampening of the pro-inflammatory immune response by THP-1 macrophages, as evident from qPCR, cytokine array and NF-kappaB nuclear translocation analyses. This study highlights the importance of understanding the interplay between innate immune humoral factors including complement in devising nanoparticle based drug delivery strategies. PMID- 27991646 TI - Materials for retrograde filling in root canal therapy. AB - BACKGROUND: Root canal therapy is a sequence of treatments involving root canal cleaning, shaping, decontamination and obturation. It is conventionally performed through a hole drilled into the crown of the affected tooth, namely orthograde root canal therapy. For teeth that cannot be treated with orthograde root canal therapy, or for which it has failed, retrograde root filling, which seals the root canal from the root apex, is a good alternative. Many materials, such as amalgam, zinc oxide eugenol and mineral trioxide aggregate (MTA), are generally used. Since none meets all the criteria an ideal material should possess, selecting the most efficacious material is of utmost importance. OBJECTIVES: To determine the effects of different materials used for retrograde filling in children and adults for whom retrograde filling is necessary in order to save the tooth. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 13 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 13 September 2016); MEDLINE Ovid (1946 to 13 September 2016); Embase Ovid (1980 to 13 September 2016); LILACS BIREME Virtual Health Library (1982 to 13 September 2016); and OpenSIGLE (1980 to 2005). ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. We also searched Chinese BioMedical Literature Database (in Chinese, 1978 to 20 September 2016); VIP (in Chinese, 1989 to 20 September 2016); China National Knowledge Infrastructure (in Chinese, 1994 to 20 September 2016); and Sciencepaper Online (in Chinese, to 20 September 2016). No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) only that compared different retrograde filling materials, with reported success rate that was assessed by clinical or radiological methods for which the follow-up period was at least 12 months. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently and in duplicate. Original trial authors were contacted for any missing information. Two review authors independently carried out risk of bias assessments for each eligible study following Cochrane methodological guidelines. MAIN RESULTS: We included six studies (916 participants with 988 teeth) reported in English. All the studies had high risk of bias. The six studies examined five different comparisons, including MTA versus intermediate restorative material (IRM), MTA versus super ethoxybenzoic acid cement (Super EBA), Super-EBA versus IRM, dentine-bonded resin composite versus glass ionomer cement and glass ionomer cement versus amalgam. There was therefore little pooling of data and very little evidence for each comparison.There is weak evidence of little or no difference between MTA and IRM at the first year of follow-up (risk ratio (RR) 1.09; 95% confidence interval (CI): 0.97 to 1.22; 222 teeth; quality of evidence: low). Insufficient evidence of a difference between MTA and IRM on success rate at the second year of follow-up (RR 1.06; 95% CI: 0.89 to 1.25; 86 teeth, 86 participants; quality of evidence: very low). All the other outcomes were based on a single study. There is insufficient evidence of any difference between MTA and Super-EBA at the one-year follow-up (RR 1.03; 95% CI: 0.96 to 1.10; 192 teeth, 192 participants; quality of evidence: very low), and only weak evidence indicating there might be a small increase in success rate at the one-year follow-up in favour of IRM compared to Super-EBA (RR 0.90; 95% CI: 0.80 to 1.01; 194 teeth; quality of evidence: very low). There was also insufficient and weak evidence to show that dentine-bonded resin composite might be a better choice for increasing retrograde filling success rate compared to glass ionomer cement at the one-year follow-up (RR 2.39; 95% CI: 1.60 to 3.59; 122 teeth, 122 participants; quality of evidence: very low). And there was insufficient evidence of a difference between glass ionomer cement and amalgam at both the one-year (RR 0.98; 95% CI: 0.86 to 1.12; 105 teeth; quality of evidence: very low) and five-year follow-ups (RR 1.00; 95% CI: 0.84 to 1.20; 82 teeth; quality of evidence: very low).None of these studies reported an adverse event. AUTHORS' CONCLUSIONS: Based on the present limited evidence, there is insufficient evidence to draw any conclusion as to the benefits of any one material over another. We conclude that more high-quality RCTs are required. PMID- 27991647 TI - I'm So Glad You're Here: Positive Aspects of Informal Caregiving. PMID- 27991648 TI - Quality of Life, Perceptions, and Health Satisfaction of Older Adults with End Stage Renal Disease: A Systematic Review. AB - OBJECTIVES: To explore the quality of life (QOL), perceptions, and health satisfaction of older adults with end-stage renal disease (ESRD) undergoing renal replacement therapy (RRT). DESIGN: Systematic review of literature. PARTICIPANTS: Individuals with ESRD undergoing RRT aged 65 and older. MEASUREMENTS: Articles identified from PubMed database search from January 1994 to December 2014. The methodological quality of each of the selected articles was assessed using eight standards adapted from well-established research quality review criteria. RESULTS: Of the initial 1,401 articles identified, 23 met the inclusion criteria. The age range of study participants examined was 65 to 90. Seventy-eight percent of the studies met six or more of the methodological standards; 47% found overall health-related and mental component summary QOL scores in elderly adults with ESRD to be similar to or higher than those of age-matched controls or younger individuals, although the physical component summary QOL scores tended to be lower in older adults. Only six studies addressed health satisfaction and perceptions of elderly adults with ESRD, with widely variable findings. CONCLUSION: Few studies specifically examine QOL in elderly adults with ESRD undergoing RRT and even fewer address issues of perceptions and health satisfaction. However, the limited data from the QOL studies looks promising with a significant proportion showing similar or higher overall health-related and mental component summary QOL scores in elderly adults with ESRD. The very limited data on perceptions and health satisfaction of elderly adults with ESRD undergoing RRT makes it difficult to make any generalizable conclusions. Overall, more research is needed to examine these factors in elderly adults with ESRD. PMID- 27991649 TI - Preoperative Psoas Muscle Size Predicts Postoperative Delirium in Older Adults Undergoing Surgery: A Pilot Cohort Study. PMID- 27991651 TI - Oxygen therapy for acute myocardial infarction. AB - BACKGROUND: Oxygen (O2) is widely used in people with acute myocardial infarction (AMI). Previous systematic reviews concluded that there was insufficient evidence to know whether oxygen reduced, increased or had no effect on heart ischaemia or infarct size. Our first Cochrane review in 2010 also concluded there was insufficient evidence to know whether oxygen should be used. Since 2010, the lack of evidence to support this widely used intervention has attracted considerable attention, prompting further trials of oxygen therapy in myocardial infarction patients. It is thus important to update this Cochrane review. OBJECTIVES: To assess the effects of routine use of inhaled oxygen for acute myocardial infarction (AMI). SEARCH METHODS: We searched the following bibliographic databases on 6 June 2015: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (OVID), Embase (OVID), CINAHL (EBSCO) and Web of Science (Thomson Reuters). LILACS (Latin American and Caribbean Health Sciences Literature) was last searched in September 2016. We also contacted experts to identify eligible studies. We applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials in people with suspected or proven AMI (ST-segment elevation myocardial infarction (STEMI) or non-STEMI) within 24 hours after onset, in which the intervention was inhaled oxygen (at normal pressure) compared to air, regardless of co-therapies provided to participants in both arms of the trial. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the titles and abstracts of identified studies to see if they met the inclusion criteria and independently undertook the data extraction. We assessed the quality of studies and the risk of bias according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was death. The measure of effect used was the risk ratio (RR) with a 95% confidence interval (CI). We used the GRADE approach to evaluate the quality of the evidence and the GRADE profiler (GRADEpro) to import data from Review Manager 5 and create 'Summary of findings' tables. MAIN RESULTS: The updated search yielded one new trial, for a total of five included studies involving 1173 participants, 32 of whom died. The pooled risk ratio (RR) of all-cause mortality in the intention-to-treat analysis was 0.99 (95% CI 0.50 to 1.95; 4 studies, N = 1123; I2 = 46%; quality of evidence: very low) and 1.02 (95% CI 0.52 to 1.98; 4 studies, N = 871; I2 = 49%; quality of evidence: very low) when only analysing participants with confirmed AMI. One trial measured pain directly, and two others measured it by opiate usage. The trial showed no effect, with a pooled RR of 0.97 for the use of opiates (95% CI 0.78 to 1.20; 2 studies, N = 250). The result on mortality and pain are inconclusive. There is no clear effect for oxygen on infarct size (the evidence is inconsistent and low quality). AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials to support the routine use of inhaled oxygen in people with AMI, and we cannot rule out a harmful effect. Given the uncertainty surrounding the effect of oxygen therapy on all-cause mortality and on other outcomes critical for clinical decision, well conducted, high quality randomised controlled trials are urgently required to inform guidelines in order to give definitive recommendations about the routine use of oxygen in AMI. PMID- 27991650 TI - Mortality in Incident Cognitive Impairment: Results of the Prospective AgeCoDe Study. AB - OBJECTIVES: To investigate mortality risk and survival time in new-incident cases of cognitive impairment (CI) in old age. DESIGN: Prospective cohort study in six German cities. SETTING: German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe). PARTICIPANTS: Two thousand eighty-nine nondemented GP patients aged 75+. MEASUREMENTS: Every 18 months, trained psychologists and physicians conducted structured clinical interviews at the participants' homes. Dates of death were obtained from relatives, general practitioner (GP), or the local registry offices. We used the Kaplan-Meier survival method to estimate survival times of individuals with and without incident CI and multivariable Cox proportional hazards regressions to assess the association between CI and mortality risk, controlled for covariates. RESULTS: Out of the 2,089 included patients at follow-up I, 859 (41.1%) died during the subsequent mean observation period of 8.0 years. Patients with incident CI at follow-up I showed a significantly higher case-fatality rate per 1,000 person years (74.2, 95% CI = 64.2-84.2 vs 47.8, 95% CI = 44.6-51.0) and a significantly shorter mean survival time in the observation period than those without (7.8 vs 9.1 years; P < .001). The association between incident CI and mortality remained significant in the multivariable Cox analyses-incident CI was associated with a 42% increased, incident severe CI with a 75% increased mortality risk. CONCLUSION: Our findings suggest an elevated mortality risk in newly acquired cognitive deficits in old age. Even though further studies are required to analyze potential underlying mechanisms, our findings support the notion that such cognitive deficits should be taken seriously in clinical practice not only for an increased risk of developing dementia but also for a broader range of possible adverse health outcomes. PMID- 27991653 TI - Clinical Outcomes Associated with Medication Regimen Complexity in Older People: A Systematic Review. AB - OBJECTIVES: To systematically review clinical outcomes associated with medication regimen complexity in older people. DESIGN: Systematic review of EMBASE, MEDLINE, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane library. SETTING: Hospitals, home, and long term care. PARTICIPANTS: English-language peer-reviewed original research published before June 2016 was eligible if regimen complexity was quantified using a metric that considered number of medications and at least one other parameter, regimen complexity was calculated for participants' overall regimen, at least 80% of participants were aged 60 and older, and the study investigated a clinical outcome associated with regimen complexity. MEASUREMENTS: Quality assessment was conducted using an adapted version of the Joanna Briggs Institute critical appraisal tool. RESULTS: Sixteen observational studies met the inclusion criteria. Regimen complexity was associated with medication nonadherence (2/6 studies) and higher rates of hospitalization (2/4 studies). One study found that participants with less-complex medication administration were more likely to stop medications when feeling worse. One study each identified an association between regimen complexity and higher ability to administer medications as directed, medication self-administration errors, caregiver medication administration hassles, hospital discharge to non-home settings, postdischarge potential adverse drug events, all-cause mortality, and lower patient knowledge of their medication. Regimen complexity had no association with postdischarge medication modification, change in medication- and health-related problems, emergency department visits, or quality of life as rated by nursing staff. CONCLUSION: Research into whether medication regimen complexity is associated with nonadherence and hospitalization has produced inconsistent results. Moderate quality evidence from four studies (two each for nonadherence and hospitalization) suggests that medication regimen complexity is associated with nonadherence and higher rates of hospitalization. PMID- 27991652 TI - Trends in Prevalence of Dementia in French Farmers from Two Epidemiological Cohorts. AB - OBJECTIVES: To determine the prevalence of dementia and cognitive impairment in older people across generations. DESIGN: Two prospective cohort studies (Personnes Agees QUID (PAQUID), Aging Multidisciplinary Investigation (AMI)). SETTING: Baseline data from two subsamples of older farmers in southwestern France. PARTICIPANTS: PAQUID (n = 595) and AMI (n = 906) participants aged 65 and older living at home at baseline (1988 PAQUID, 2008 AMI). MEASUREMENTS: Two methods were used to diagnose dementia: a clinical consensus diagnosis and a computer-assisted taxonomy approach (cognitive impairment with disability (CIWD)) using Mini-Mental State Examination and instrumental activity of daily living scores. Crude and standardized prevalences (using PAQUID age-sex structure) and 95% confidence intervals were calculated, and logistic regression was used to explore confounding. RESULTS: The prevalence of consensus diagnosis of dementia was higher in AMI in 2008 than in PAQUID in 1988 (12.0% vs 5.7%, P < .001), whereas the reverse was observed for CIWD (14.8% vs 23.8%, P < .001), confirmed by logistic regressions (odds ratio (OR)AMIvsPAQUID = 2.50, 95% confidence interval (CI) = 1.52-4.12; ORAMIvs.PAQUID = 0.60, 95% CI = 0.42-0.87, respectively). Educational level increased and management of vascular risk factors improved over the study period, and health and living conditions improved globally. CONCLUSION: These findings suggest global cognitive and functional improvement in old farmers (the prevalence of CIWD decreased by 40% over 20 years) and simultaneously a marked change in the subjective boundary between dementia and nondementia according to clinicians. PMID- 27991654 TI - Weight Trajectory over 20 Years and Likelihood of Mild Cognitive Impairment or Dementia Among Older Women. AB - OBJECTIVES: The association between weight change and cognition is controversial. We examined the association between 20-year weight change and cognitive function in late life. DESIGN: Cohort study. SETTING: Study of Osteoporotic Fractures (SOF). PARTICIPANTS: One thousand two hundred eighty-nine older, community dwelling women (mean baseline age 68 (65-81) and 88 (82-102) at cognitive testing). MEASUREMENTS: Study of Osteoporotic Fractures participants had body weight measured repeatedly over 20 years (mean 8 weights). Adjudicated cognitive status was classified as normal (n = 775) or mild cognitive impairment (MCI)/dementia (n = 514) at Year 20. Logistic models were used to evaluate whether absolute weight change, rate of weight loss per year, presence of abrupt, unrecovered weight loss, and weight variability were associated with MCI or dementia. RESULTS: Women with greater rate of weight loss over 20 years had increased chance of developing MCI or dementia. In age/education/clinic-adjusted "base" models, each 0.5 kg/yr decrease resulted in 30% increased odds of MCI/dementia (OR = 1.30 [95% CI: 1.14, 1.49]). After adjustment for age, education, clinic, depression, and walking speed, there was 17% (OR = 1.17 [95% CI: 1.02, 1.35]) increased odds of MCI/dementia for each 0.5 kg/yr decrease in weight. In base models, variability in weight was significant. Each 1% average deviation from each woman's predicted weight curve was associated with 11% increased odds of MCI/dementia (OR = 1.11 [95% CI: 1.04, 1.18]). The estimate was attenuated after full adjustment (OR = 1.06 [95% CI: 0.99, 1.14]). The presence of an abrupt weight decline was not associated with MCI/dementia. CONCLUSIONS: Rate of weight loss over 20 years was associated with development of MCI or dementia in women surviving past 80 years, suggesting that nutritional status, social-environmental factors, and/or adipose tissue function and structure may affect cognitive function with aging. PMID- 27991656 TI - The neuropsychological profile of children with basal ganglia encephalitis: a case series. AB - Inflammatory basal ganglia encephalitis (BGE) is a rare but distinct entity of putative autoimmune aetiology, with specific basal ganglia inflammation and acute movement disorders. Unlike most brain injuries, BGE is a radiologically pure basal ganglia syndrome. The current study systematically describes the neuropsychological outcomes of four paediatric cases of BGE, and thus the neuropsychological outcomes of focal basal ganglia insult in childhood. Although all patients made significant motor recoveries, all four cases displayed executive dysfunction, fine motor difficulties, and anxiety. Three out of four cases displayed attention deficits. The case who received intravenous immunoglobulin (IVIg) treatment and steroids during the acute phase of the disease had the best cognitive outcome. These findings highlight the need for detailed neuropsychological assessment and long-term follow-up. PMID- 27991655 TI - Anger-irritability as a mediator of attention deficit hyperactivity disorder risk for adolescent alcohol use and the contribution of coping skills. AB - BACKGROUND: Research on susceptibility to alcohol use disorder within the attention deficit/hyperactivity disorder (ADHD) population has begun to expand examination of putative moderators and mediators in order to develop effective treatments. Specific dysregulated emotions have been separately associated with ADHD and with alcohol use difficulties. The current study is the first to conjointly study these variables by testing anger-irritability as a mediator of ADHD risk for adolescent alcohol use. METHODS: Frequency of binge drinking, drunkenness, and alcohol problems were examined for 142 children with ADHD followed into adolescence and compared to 100 demographically similar youth without ADHD. Parent-rated anger-irritability was tested as a mediator. Behavioral and cognitive coping skills, which are key clinical treatment targets, were studied as moderators of these associations. RESULTS: Childhood ADHD was positively associated with anger-irritability and the drinking outcomes in adolescence. Anger-irritability mediated the association between ADHD and alcohol use problems, but not binge drinking or drunkenness. Behavioral and cognitive, but not avoidant, coping played a moderating role, but only of the association between childhood ADHD and anger-irritability. CONCLUSIONS: Active coping strategies by adolescents with ADHD may reduce the vulnerability to alcohol problems through a reduction of negative emotions. Future research on additional mediators and treatments that target these skills is encouraged. PMID- 27991657 TI - Molecular typing for blood group antigens within 40 min by direct polymerase chain reaction from plasma or serum. AB - Determining blood group antigens by serological methods may be unreliable in certain situations, such as in patients after chronic or massive transfusion. Red cell genotyping offers a complementary approach, but current methods may take much longer than conventional serological typing, limiting their utility in urgent situations. To narrow this gap, we devised a rapid method using direct polymerase chain reaction (PCR) amplification while avoiding the DNA extraction step. DNA was amplified by PCR directly from plasma or serum of blood donors followed by a melting curve analysis in a capillary rapid-cycle PCR assay. We evaluated the single nucleotide polymorphisms underlying the clinically relevant Fya , Fyb , Jka and Jkb antigens, with our analysis being completed within 40 min of receiving a plasma or serum sample. The positive predictive value was 100% and the negative predictive value at least 84%. Direct PCR with melting point analysis allowed faster red cell genotyping to predict blood group antigens than any previous molecular method. Our assay may be used as a screening tool with subsequent confirmatory testing, within the limitations of the false-negative rate. With fast turnaround times, the rapid-cycle PCR assay may eventually be developed and applied to red cell genotyping in the hospital setting. PMID- 27991658 TI - Untangling the Association Between Migraine, Pain, and Anxiety: Examining Migraine and Generalized Anxiety Disorders in a Canadian Population Based Study. AB - OBJECTIVE: The aims of this study were to investigate: (1) the prevalence and unadjusted and adjusted odds of 12-month generalized anxiety disorder (GAD) among adults with migraine in comparison to those without migraine; (2) If debilitating pain and/or limitations in instrumental activities of daily living (IADLs) are mediators of the migraine-GAD association; and (3) Factors associated with past year GAD among adults with migraine. METHODS: Secondary data analysis of the nationally representative 2012 Canadian Community Health Survey-Mental Health (CCHS-MS), a population-based survey of community dwellers with a response rate of 68.9%. The first subsample included those with (n = 2232) and without migraine (n = 19,270), and the second subsample was restricted to those with migraine (n = 2232). GAD was based on the WHO-CIDI scale. RESULTS: Fully, 6% of those with migraines had past year GAD in comparison of 2.1% of those without migraine (P < .001). The socio-demographically adjusted odds of past year GAD were two and a half times higher among those with migraine than those without (OR= 2.46; 95% CI = 2.00, 3.02). A path analysis indicated that debilitating pain and limitations in IADLs were mediators in the relationship between migraine and GAD. In the sample restricted to migraineurs, the factors associated with higher odds of 12 month GAD included having a university degree, having low income, being without a confidant, and being male. CONCLUSIONS: Generalized anxiety disorder is robustly associated with migraine and targeted outreach and interventions are warranted. PMID- 27991660 TI - Expansion of inverted repeat does not decrease substitution rates in Pelargonium plastid genomes. AB - For species with minor inverted repeat (IR) boundary changes in the plastid genome (plastome), nucleotide substitution rates were previously shown to be lower in the IR than the single copy regions (SC). However, the impact of large scale IR expansion/contraction on plastid nucleotide substitution rates among closely related species remains unclear. We included plastomes from 22 Pelargonium species, including eight newly sequenced genomes, and used both pairwise and model-based comparisons to investigate the impact of the IR on sequence evolution in plastids. Ten types of plastome organization with different inversions or IR boundary changes were identified in Pelargonium. Inclusion in the IR was not sufficient to explain the variation of nucleotide substitution rates. Instead, the rate heterogeneity in Pelargonium plastomes was a mixture of locus-specific, lineage-specific and IR-dependent effects. Our study of Pelargonium plastomes that vary in IR length and gene content demonstrates that the evolutionary consequences of retaining these repeats are more complicated than previously suggested. PMID- 27991659 TI - Sexual selection modulates genetic conflicts and patterns of genomic imprinting. AB - Recent years have seen a surge of interest in linking the theories of kin selection and sexual selection. In particular, there is a growing appreciation that kin selection, arising through demographic factors such as sex-biased dispersal, may modulate sexual conflicts, including in the context of male-female arms races characterized by coevolutionary cycles. However, evolutionary conflicts of interest need not only occur between individuals, but may also occur within individuals, and sex-specific demography is known to foment such intragenomic conflict in relation to social behavior. Whether and how this logic holds in the context of sexual conflict-and, in particular, in relation to coevolutionary cycles-remains obscure. We develop a kin-selection model to investigate the interests of different genes involved in sexual and intragenomic conflict, and we show that consideration of these conflicting interests yields novel predictions concerning parent-of-origin specific patterns of gene expression and the detrimental effects of different classes of mutation and epimutation at loci underpinning sexually selected phenotypes. PMID- 27991661 TI - Myotonic dystrophy type 1: role of CCG, CTC and CGG interruptions within DMPK alleles in the pathogenesis and molecular diagnosis. AB - Myotonic dystrophy type 1 (DM1) is a multisystem neuromuscular disease caused by a CTG triplet expansion in the 3'-untranslated region (3'-UTR) of DMPK gene. This CTG array is usually uninterrupted in both healthy and DM1 patients, but recent studies identified pathological variant expansions containing unstable CCG, CTC and CGG interruptions with a prevalence of 3-5% of cases. In this review, we will describe the clinical, molecular and genetic issues related to the occurrence of variant expansions associated with DM1. Indeed, the identification of these complex DMPK alleles leads to practical consequences in DM1 genetic counseling and testing, because these exams can give false negative results. Moreover, DM1 patients carrying interrupted alleles can manifest either additional atypical neurological symptoms or, conversely, mild, late-onset forms. Therefore, the prognosis of the disease in these patients is difficult to determine because of the great uncertainty about the genotype-phenotype correlations. We will discuss the putative effects of the variant DM1 alleles on the pathogenic disease mechanisms, including mitotic and meiotic repeats instability and splicing alteration typical of DM1 tissues. Interruptions within the DMPK expanded alleles could also interfere with the chromatin structure, the transcriptional activity of the DM1 locus and the interaction with RNA CUG-binding proteins. PMID- 27991662 TI - Balance and Mobility in Community-Dwelling Older Adults: Effect of Daytime Sleepiness. AB - OBJECTIVES: To examine the effect of self-reported daytime sleepiness on performance-based balance measures and self-reported balance confidence in community-dwelling older adults. DESIGN: Cross-sectional secondary analysis of an observational cohort study designed to develop and refine measures of balance and mobility in community-dwelling older adults. SETTING: Community. PARTICIPANTS: Older adults (aged 78.2 +/- 5.9) (n = 120). MEASUREMENTS: The performance-based gait and balance measures included gait speed, double support time, and step width. Narrow walk, obstacle walk, and timed standing balance were also assessed. The Activities-Specific Balance Confidence Scale was included as a self-reported measure. Daytime sleepiness was defined as an Epworth Sleepiness Scale score of 9 or greater. Body mass index, fall-related comorbidities, and use of central nervous system (CNS) medications were considered as covariates. RESULTS: Forty five percent of participants reported daytime sleepiness. Participants reporting daytime sleepiness differed significantly from those without in gait speed (adjusted difference (standard error (SE)) -0.09 (0.04) m/s, P = .03), step width (adjusted difference (SE) 0.02 (0.01), P = .03), and self-reported balance confidence (adjusted difference (SE) -1.02 (0.38), P = .01) even after adjusting for covariates. Two-way analysis of variance of CNS medication use and daytime sleepiness showed no significant interaction effects. CONCLUSION: Self-reported daytime sleepiness is associated with slower gait speed and poor balance confidence in community-dwelling older adults. Subjective sleep assessment should be considered when assessing balance and implementing interventions for improving balance in older adults. Further study is needed to examine the role of CNS medication use. PMID- 27991663 TI - Is the ice bath finally melting? Cold water immersion is no greater than active recovery upon local and systemic inflammatory cellular stress in humans. PMID- 27991664 TI - Elasticity of population growth with respect to the intensity of biotic or abiotic driving factors. AB - Demographic analysis can elucidate how driving factors, such as climate or species interactions, affect populations. One important question is how growth would respond to future changes in the mean intensity of a driving factor or in its variability, such as might be expected in a fluctuating and shifting climate. Here I develop an approach to computing new stochastic elasticities to address this question. The linchpin of this novel approach is the multidimensional demographic difference that expresses how a population responds to change in the driving factor between two discrete levels of intensity. I use this difference to design a perturbation matrix that links data from common empirical sampling schemes with rigorous theory for stochastic elasticities. Although the starting point is a difference, the products of this synthesis are true derivatives: they are elasticity with respect to the mean intensity of a driving factor, and elasticity with respect to variability in a driving factor. Applying the methods to published data, I demonstrate how these new elasticities can shed light on growth rate response within and at the boundary of the previously observed range of the driving factor, thus helpfully indicating nonlinearity in the observed and in the potential future response. The stochastic approach simplifies in a fixed environment, yielding a compact formula for deterministic elasticity to a driving factor. PMID- 27991665 TI - The Development of Preschoolers' Living Kinds Concept: A Longitudinal Study. AB - Given limitations in the integrative scope of past research, basic questions about the organization and development of preschoolers' living kinds concept remain open to debate. This study was designed to address past limitations through use of a longitudinal design, extensive stimulus set, and alternate indices of understanding. Thirty-five English-speaking 3-year-olds from middle class families in Albuquerque, NM participated in four testing sessions over 1 year. Indices of understanding included statements that preschoolers generated about various living and nonliving objects, biological properties they attributed to the objects, and their characterization of objects as "alive" or not. Results reveal a multifaceted picture of developmental change in preschoolers' living kinds concept involving both the construction and elaboration of a core biological understanding. PMID- 27991666 TI - Plant grafting: how genetic exchange promotes vascular reconnection. AB - Grafting has been widely used to improve horticultural traits. It has also served increasingly as a tool to investigate the long-distance transport of molecules that is an essential part for key biological processes. Many studies have revealed the molecular mechanisms of graft-induced phenotypic variation in anatomy, morphology and production. Here, we review the phenomena and their underlying mechanisms by which macromolecules, including RNA, protein, and even DNA, are transported between scions and rootstocks via vascular tissues. We further propose a conceptual framework that characterizes and quantifies the driving mechanisms of scion-rootstock interactions toward vascular reconnection and regeneration. PMID- 27991667 TI - Balance Impairments in Different Subgroups of Patients With Migraine. AB - BACKGROUND: Patients with migraine often experience balance impairments. However, the relationship between clinical features - like aura and chronicity - and the severity of balance impairments is not well established. The objective of this study was to assess balance impairments in different subgroups of migraine patients. METHOD: One hundred five subjects diagnosed according to the ICHD-III were recruited in the study. They were uniformly distributed among three groups: migraine with aura, migraine without aura, and chronic migraine. Thirty-five controls were also recruited in the study. Balance impairments were assessed in all subjects via the modified Sensory Organization test and the Limits of Stability test. The results in the four groups were compared using ANCOVA tests with age, BMI, presence of dizziness, level of physical activity, time of migraine onset, and medication intake as covariates. RESULTS: Subjects in the migraine with aura and the chronic migraine groups showed poorer balance control than control subjects in three of the four conditions tested using the modified Sensory Organization test: FirmCE: CG: 1.5 cm2 , 95%CI 1.3 to 1.7; M: 2.1 cm2 , 95%CI 1.6 to 2.6; MA: 4.5 cm2 , 95%CI 3.2 to 5.8; CM: 4.5 cm2 , 95%CI 3.0 to 6.0; P < .027; FoamOE: CG: 5.1 cm2 , 95%CI 4.6 to 5.6; M: 5.6 cm2 , 95%CI 5.0 to 6.1; MA: 8.8 cm2 , 95%CI 7.3 to 10.2; CM: 8.8 cm2 , 95%CI 7.7 to 10.0; P < .018; FoamCE: CG: 14.8 cm2 , 95%CI 13.7 to 15.9 cm2; M: 17.3 cm2 , 95%CI 15.4 to 19.1; MA: 21.9 cm2 , 95%CI 19.1 to 24.7; CM: 22.4 cm2 , 95%CI 19.9 to 24.9; P < .0001. In the FoamOE and FoamCE conditions, both groups also showed poorer postural control than subjects in the migraine without aura group (P < .01). Differences between control subjects and subjects in all the migraine groups were found in the reaction time, movement velocity, endpoint excursion, and maximal excursion parameters (P < .04) in all the directions tested during the Limits of Stability test. None of the covariates appeared to affect the balance parameters (P > .05). CONCLUSION: There is evidence of balance control impairments in subjects with all subtypes of migraine compared to control subjects. The presence of aura and frequent migraine attacks reflect negatively in the postural control performance and may have a significant clinical impact in patients with migraine that should be addressed with appropriate clinical interventions. PMID- 27991668 TI - Silicon in 'pure gold'? Theoretical contributions and observations on teleanalysis by videoconference. AB - Ideas about psychoanalysis via videoconference-videoconference teleanalysis (VT) are presented with the general understanding that these settings produce a twofold split between various degrees of recognition/negativisation of the absence of the other, on one hand, and the expectation of physical co-presence, on the other. This split has been put forward as dismantling the here, now, with me pre-reflexive unity of the analytic experience. This article suggests that both members of the analytic dyad will seek to reappropriate the experience through a forced ego integration that interferes with accessing states of unintegration in the analytic treatment and produces subtle alterations to symbolisation work. The effort to overcome this condition is illustrated with clinical vignettes and therapists' comments about feelings of inauthenticity and discontent when trying to sustain evenly-suspended attention, as well as in the perception of a form of flattening of the alive nature of speech. However, this is not a constant for all VT, and mutual understanding can be an important mitigating feature. The focus of the discussion should be on the capacity of the analytic dyad to overcome such a split and not on a direct extrapolation of the perceptual limitations of VT to possible effects on transference / countertransference. PMID- 27991669 TI - Characteristics of Headache After an Intracranial Endovascular Procedure: A Prospective Observational Study. AB - BACKGROUND: Two editions of the International Classification of Headache Disorders (ICHD) diagnostic criteria for "Headache attributed to an intracranial endovascular procedure" have been published, in 2004 and 2013.1,2 Despite studies that have suggested that the former is not very practical, the ICHD-3 beta did not contain major changes. Moreover, so far no consensus exists regarding characteristics of headache after intracranial endovascular procedure. Thus, there is a need for sound suggestions to improve the ICHD-3 beta diagnostic criteria. METHODS: Using a prospective design, we identified consecutive patients with unruptured intracranial aneurysms (UIAs) with neuroendovascular treatment from January 2014 to December 2014. RESULTS: In total, 73 patients were enrolled, and 58 patients ultimately completed the 6-month follow-up. After the procedure, five of the 29 patients (17.2%) with pre-existing headache experienced marked worsening after the procedure, while seven of the 29 patients without prior headache developed new-onset headache post-procedurally. The headaches started within 24 hours, with a mean duration of 24-72 hours. The headaches were moderate to severe. The eligibility of these events to be considered headaches caused by neuroendovascular procedures according to the ICHD-3 beta diagnostic criteria for designation was far from ideal. CONCLUSIONS: Most cases of markedly worsening headaches and new-onset headaches started within 24 hours and persisted longer than that specified in the ICHD-3 beta diagnostic criteria. Moreover, considering that some items are not very practical, the ICHD-3 beta diagnostic criteria should be revised in the light of recent literature reports. PMID- 27991670 TI - The fascinating facets of plant selenium accumulation - biochemistry, physiology, evolution and ecology. AB - Contents 1582 I. 1582 II. 1583 III. 1588 IV. 1590 V. 1592 1592 References 1592 SUMMARY: The importance of selenium (Se) for medicine, industry and the environment is increasingly apparent. Se is essential for many species, including humans, but toxic at elevated concentrations. Plant Se accumulation and volatilization may be applied in crop biofortification and phytoremediation. Topics covered here include beneficial and toxic effects of Se on plants, mechanisms of Se accumulation and tolerance in plants and algae, Se hyperaccumulation, and ecological and evolutionary aspects of these processes. Plant species differ in the concentration and forms of Se accumulated, Se partitioning at the whole-plant and tissue levels, and the capacity to distinguish Se from sulfur. Mechanisms of Se hyperaccumulation and its adaptive significance appear to involve constitutive up-regulation of sulfate/selenate uptake and assimilation, associated with elevated concentrations of defense related hormones. Hyperaccumulation has evolved independently in at least three plant families, probably as an elemental defense mechanism and perhaps mediating elemental allelopathy. Elevated plant Se protects plants from generalist herbivores and pathogens, but also gives rise to the evolution of Se-resistant specialists. Plant Se accumulation affects ecological interactions with herbivores, pollinators, neighboring plants, and microbes. Hyperaccumulation tends to negatively affect Se-sensitive ecological partners while facilitating Se resistant partners, potentially affecting species composition and Se cycling in seleniferous ecosystems. PMID- 27991671 TI - The mitochondrial calcium uniporter in the heart: energetics and beyond. AB - Ca2+ and mitochondria are inextricably linked to cardiac function and dysfunction. Ca2+ is central to cardiac excitation-contraction coupling and stimulates mitochondrial energy production to fuel contraction. Under pathological conditions of dysregulated Ca2+ cycling, mitochondrial Ca2+ overload activates cellular death pathways. Thus, in the cardiomyocyte, the mitochondrial Ca2+ microdomain is where contraction, energy and death collide. A key component of mitochondrial Ca2+ signalling is the mitochondrial Ca2+ uniporter complex (uniplex), an inner membrane Ca2+ transporter and major pathway of mitochondrial Ca2+ entry. Once known only as the unidentified target for ruthenium red and related compounds, in recent years, the uniplex has evolved into a complex multiprotein assembly. The identification of the molecular constituents of the uniplex has made possible the generation of targeted genetic models to interrogate uniplex function in vivo. This review will summarize our current understanding of the molecular structure of the uniplex, its impact on mitochondrial energetics and cardiac physiology, its contribution to cardiomyocyte death, and its expanding roles in cardiac biology. PMID- 27991673 TI - Cryoballoon ablation of atrial fibrillation: a practical and effective approach. AB - Medical management of atrial fibrillation (AF), the most common arrhythmia in the general population, has had modest efficacy in controlling symptoms and restoring and maintaining sinus rhythm. Since the seminal observation in 1998 that pulmonary veins host the triggers of AF in the majority of cases, electrical isolation of all pulmonary veins constitutes the cornerstone of ablation in patients with symptomatic AF. However, due to the elaborate and tedious technique of the conventional point-by-point method with radiofrequency ablation guided by electroanatomical mapping, newer, more versatile single-shot techniques, such as cryoballoon ablation, have been sought and developed over recent years and are progressively prevailing. Cryoballoon ablation appears to be the most promising practical and effective approach, and we review it here by presenting all available relevant data from the literature as well as from our own experience in an attempt to apprise colleagues of the significant progress made over the last several years in this important field of electrophysiology. PMID- 27991672 TI - Self-Reported Hearing Impairment and Incident Frailty in English Community Dwelling Older Adults: A 4-Year Follow-Up Study. AB - OBJECTIVES: To examine the association between hearing impairment and incident frailty in older adults. DESIGN: Cross-sectional and longitudinal analyses with 4 year follow-up using data from the English Longitudinal Study of Ageing. SETTING: Community. PARTICIPANTS: Community-dwelling individuals aged 60 and older with data on hearing and frailty status (N = 2,836). MEASUREMENTS: Hearing impairment was defined as poor self-reported hearing. Having none of the five Fried frailty phenotype components (slow walking, weak grip, self-reported exhaustion, weight loss and low physical activity) was defined as not frail, having one or two as prefrail, and having three or more as frail. Participants who were not frail at baseline were followed for incident prefrailty and frailty. Participants who were prefrail at baseline were followed for incident frailty. RESULTS: One thousand three hundred ninety six (49%) participants were not frail, 1,178 (42%) were prefrail, and 262 (9%) were frail according to the Fried phenotype. At follow-up, there were 367 new cases of prefrailty and frailty among those who were not frail at baseline (n = 1,396) and 133 new cases of frailty among those who were prefrail at baseline (n = 1,178). Cross-sectional analysis showed an association between hearing impairment and frailty (age- and sex-adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.37-2.01), which remained after further adjustments for wealth, education, cardiovascular disease, cognition, and depression. In longitudinal analyses, nonfrail participants with hearing impairment were at greater risk of becoming prefrail and frail at follow-up (OR = 1.43, 95% CI = 1.05-1.95), but the association was attenuated after further adjustment. Prefrail participants with hearing impairment had a greater risk of becoming frail at follow-up (OR = 1.64, 95% CI = 1.07-2.51) even after further adjustment. CONCLUSION: Hearing impairment in prefrail older adults was associated with greater risk of becoming frail, independent of covariates, suggesting that hearing impairment may hasten the progression of frailty. PMID- 27991675 TI - A supervoxel-based segmentation method for prostate MR images. AB - PURPOSE: Segmentation of the prostate on MR images has many applications in prostate cancer management. In this work, we propose a supervoxel-based segmentation method for prostate MR images. METHODS: A supervoxel is a set of pixels that have similar intensities, locations, and textures in a 3D image volume. The prostate segmentation problem is considered as assigning a binary label to each supervoxel, which is either the prostate or background. A supervoxel-based energy function with data and smoothness terms is used to model the label. The data term estimates the likelihood of a supervoxel belonging to the prostate by using a supervoxel-based shape feature. The geometric relationship between two neighboring supervoxels is used to build the smoothness term. The 3D graph cut is used to minimize the energy function to get the labels of the supervoxels, which yields the prostate segmentation. A 3D active contour model is then used to get a smooth surface by using the output of the graph cut as an initialization. The performance of the proposed algorithm was evaluated on 30 in-house MR image data and PROMISE12 dataset. RESULTS: The mean Dice similarity coefficients are 87.2 +/- 2.3% and 88.2 +/- 2.8% for our 30 in-house MR volumes and the PROMISE12 dataset, respectively. The proposed segmentation method yields a satisfactory result for prostate MR images. CONCLUSION: The proposed supervoxel-based method can accurately segment prostate MR images and can have a variety of application in prostate cancer diagnosis and therapy. PMID- 27991674 TI - Photolyase: Dynamics and Mechanisms of Repair of Sun-Induced DNA Damage. AB - Photolyase, a photomachine discovered half a century ago for repair of sun induced DNA damage of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), has been characterized extensively in biochemistry (function), structure and dynamics since 1980s. The molecular mechanism and repair photocycle have been revealed at the most fundamental level. Using femtosecond spectroscopy, we have mapped out the entire dynamical evolution and determined all actual timescales of the catalytic processes. Here, we review our recent efforts in studies of the dynamics of DNA repair by photolyases. The repair of CPDs in three life kingdoms includes seven electron transfer (ET) reactions among 10 elementary steps through initial bifurcating ET pathways, a direct tunneling route and a two-step hopping path both through an intervening adenine from the cofactor to CPD, with a conserved folded structure at the active site. The repair of 6-4PPs is challenging and requires similar ET reactions and a new cyclic proton transfer with a conserved histidine residue at the active site of (6-4) photolyases. Finally, we also summarize our efforts on multiple intraprotein ET of photolyases in different redox states and such mechanistic studies are critical to the functional mechanism of homologous cryptochromes of blue-light photoreceptors. PMID- 27991677 TI - A longitudinal four-dimensional computed tomography and cone beam computed tomography dataset for image-guided radiation therapy research in lung cancer. AB - PURPOSE: To describe in detail a dataset consisting of serial four-dimensional computed tomography (4DCT) and 4D cone beam CT (4DCBCT) images acquired during chemoradiotherapy of 20 locally advanced, nonsmall cell lung cancer patients we have collected at our institution and shared publicly with the research community. ACQUISITION AND VALIDATION METHODS: As part of an NCI-sponsored research study 82 4DCT and 507 4DCBCT images were acquired in a population of 20 locally advanced nonsmall cell lung cancer patients undergoing radiation therapy. All subjects underwent concurrent radiochemotherapy to a total dose of 59.4-70.2 Gy using daily 1.8 or 2 Gy fractions. Audio-visual biofeedback was used to minimize breathing irregularity during all fractions, including acquisition of all 4DCT and 4DCBCT acquisitions in all subjects. Target, organs at risk, and implanted fiducial markers were delineated by a physician in the 4DCT images. Image coordinate system origins between 4DCT and 4DCBCT were manipulated in such a way that the images can be used to simulate initial patient setup in the treatment position. 4DCT images were acquired on a 16-slice helical CT simulator with 10 breathing phases and 3 mm slice thickness during simulation. In 13 of the 20 subjects, 4DCTs were also acquired on the same scanner weekly during therapy. Every day, 4DCBCT images were acquired on a commercial onboard CBCT scanner. An optically tracked external surrogate was synchronized with CBCT acquisition so that each CBCT projection was time stamped with the surrogate respiratory signal through in-house software and hardware tools. Approximately 2500 projections were acquired over a period of 8-10 minutes in half-fan mode with the half bow-tie filter. Using the external surrogate, the CBCT projections were sorted into 10 breathing phases and reconstructed with an in-house FDK reconstruction algorithm. Errors in respiration sorting, reconstruction, and acquisition were carefully identified and corrected. DATA FORMAT AND USAGE NOTES: 4DCT and 4DCBCT images are available in DICOM format and structures through DICOM-RT RTSTRUCT format. All data are stored in the Cancer Imaging Archive (TCIA, http://www.cancerimagingarchive.net/) as collection 4D-Lung and are publicly available. DISCUSSION: Due to high temporal frequency sampling, redundant (4DCT and 4DCBCT) data at similar timepoints, oversampled 4DCBCT, and fiducial markers, this dataset can support studies in image-guided and image-guided adaptive radiotherapy, assessment of 4D voxel trajectory variability, and development and validation of new tools for image registration and motion management. PMID- 27991678 TI - Complex beryllium amidoboranes: Structures, stability, and evaluation of their potential as hydrogen storage materials. AB - Complex beryllium amidoboranes Mx [Be(NH2 BH3 )x+2 ] (M = Li-Cs, x = 1,2) have been computationally studied at M06-2X/def2-TZVPPD//B3LYP/def2-TZVPPD level of theory. Compounds are predicted to be stable at room temperature but release H2 on heating. Agostic Be...H?B bonds play an important role in stabilization of oligomeric beryllium imidoboranes. Polymeric imidoborane, hydrogen, and ammonia are expected as major thermal decomposition products of complex beryllium amidoboranes. Ammonia evolution is predicted to proceed at slightly higher temperatures than hydrogen evolution. Based on thermodynamic analysis, Li[Be(NH2 BH3 )3 ] and Li2 [Be(NH2 BH3 )4 ] are the most perspective synthetic targets. Synthetic approaches to these potentially efficient hydrogen storage materials have been proposed. (c) 2016 Wiley Periodicals, Inc. PMID- 27991676 TI - The Impact of Peer Substance Use and Polygenic Risk on Trajectories of Heavy Episodic Drinking Across Adolescence and Emerging Adulthood. AB - BACKGROUND: Heavy episodic drinking is developmentally normative among adolescents and young adults, but is linked to adverse consequences in later life, such as drug and alcohol dependence. Genetic and peer influences are robust predictors of heavy episodic drinking in youth, but little is known about the interplay between polygenic risk and peer influences as they impact developmental patterns of heavy episodic drinking. METHODS: Data were from a multisite prospective study of alcohol use among adolescents and young adults with genome wide association data (n = 412). Generalized linear mixed models were used to characterize the initial status and slopes of heavy episodic drinking between age 15 and 28. Polygenic risk scores (PRS) were derived from a separate genome-wide association study for alcohol dependence and examined for their interaction with substance use among the adolescents' closest friends in predicting the initial status and slopes of heavy episodic drinking. RESULTS: Close friend substance use was a robust predictor of adolescent heavy episodic drinking, even after controlling for parental knowledge and peer substance use in the school. PRS were predictive of the initial status and early patterns of heavy episodic drinking in males, but not in females. No interaction was detected between PRS and close friend substance use for heavy episodic drinking trajectories in either males or females. CONCLUSIONS: Although substance use among close friends and genetic influences play an important role in predicting heavy episodic drinking trajectories, particularly during the late adolescent to early adult years, we found no evidence of interaction between these influences after controlling for other social processes, such as parental knowledge and broader substance use among other peers outside of close friends. The use of longitudinal models and accounting for multiple social influences may be crucial for future studies focused on uncovering gene-environment interplay. Clinical implications are also discussed. PMID- 27991679 TI - Acantholytic invasive squamous cell carcinoma: tumor diameter, invasion depth, grade of differentiation, surgical margins, perineural invasion, recurrence and death rate. AB - BACKGROUND: Squamous cell carcinoma (SCC) may present with or without the feature of acantholysis. METHODS: Investigate invasive acantholytic SCC by microscopic maximum tumor surface diameter, depth of invasion, grade of differentiation, perineural invasion (PNI) and percentage of acantholysis. Assess recurrence following excision. RESULTS: A total of 1658 consecutive invasive SCC cases were examined, comprising 4.9% acantholytic SCC. Median tumor microscopic maximum diameter was 8 mm for acantholytic SCC and 7.3 mm for non-acantholytic SCC. Median tumor invasion depth was 1.0 mm for acantholytic SCC and 1.5 mm for non acantholytic SCC. Well, moderate and poor differentiation were not significantly different between acantholytic SCC and non-acantholytic SCC. One PNI case was found in 82 acantholytic SCC cases. A total of 77 acantholytic SCC cases were followed up over a median 25 months finding histologic proven recurrence at three acantholytic SCC excision sites. CONCLUSIONS: Acantholytic SCC were more likely to be located on head sites with less median depth than non-acantholytic SCC. Increasing percentage of acantholysis within acantholytic SCC was not associated with a shift towards poor differentiation. Histologic margins of 1.2 mm may adequately excise small acantholytic SCC. No recorded deaths, low PNI and low recurrence rates suggests acantholytic SCC is low-risk. PMID- 27991680 TI - Toward amino acid typing for proteins in FFLUX. AB - Continuing the development of the FFLUX, a multipolar polarizable force field driven by machine learning, we present a modern approach to atom-typing and building transferable models for predicting atomic properties in proteins. Amino acid atomic charges in a peptide chain respond to the substitution of a neighboring residue and this response can be categorized in a manner similar to atom-typing. Using a machine learning method called kriging, we are able to build predictive models for an atom that is defined, not only by its local environment, but also by its neighboring residues, for a minimal additional computational cost. We found that prediction errors were up to 11 times lower when using a model specific to the correct group of neighboring residues, with a mean prediction of ~0.0015 au. This finding suggests that atoms in a force field should be defined by more than just their immediate atomic neighbors. When comparing an atom in a single alanine to an analogous atom in a deca-alanine helix, the mean difference in charge is 0.026 au. Meanwhile, the same difference between a trialanine and a deca-alanine helix is only 0.012 au. When compared to deca-alanine models, the transferable models are up to 20 times faster to train, and require significantly less ab initio calculation, providing a practical route to modeling large biological systems. (c) 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 27991681 TI - Assessing the shelf life of cost-efficient conservation plans for species at risk across gradients of agricultural land use. AB - High costs of land in agricultural regions warrant spatial prioritization approaches to conservation that explicitly consider land prices to produce protected-area networks that accomplish targets efficiently. However, land-use changes in such regions and delays between plan design and implementation may render optimized plans obsolete before implementation occurs. To measure the shelf life of cost-efficient conservation plans, we simulated a land-acquisition and restoration initiative aimed at conserving species at risk in Canada's farmlands. We accounted for observed changes in land-acquisition costs and in agricultural intensity based on censuses of agriculture taken from 1986 to 2011. For each year of data, we mapped costs and areas of conservation priority designated using Marxan. We compared plans to test for changes through time in the arrangement of high-priority sites and in the total cost of each plan. For acquisition costs, we measured the savings from accounting for prices during site selection. Land-acquisition costs and land-use intensity generally rose over time independent of inflation (24-78%), although rates of change were heterogeneous through space and decreased in some areas. Accounting for spatial variation in land price lowered the cost of conservation plans by 1.73-13.9%, decreased the range of costs by 19-82%, and created unique solutions from which to choose. Despite the rise in plan costs over time, the high conservation priority of particular areas remained consistent. Delaying conservation in these critical areas may compromise what optimized conservation plans can achieve. In the case of Canadian farmland, rapid conservation action is cost-effective, even with moderate levels of uncertainty in how to implement restoration goals. PMID- 27991684 TI - Carbon-Based Microbial-Fuel-Cell Electrodes: From Conductive Supports to Active Catalysts. AB - Microbial fuel cells (MFCs) have attracted considerable interest due to their potential in renewable electrical power generation using the broad diversity of biomass and organic substrates. However, the difficulties in achieving high power densities and commercially affordable electrode materials have limited their industrial applications to date. Carbon materials, which can exhibit a wide range of different morphologies and structures, usually possess physiological activity to interact with microorganisms and are therefore fast-emerging electrode materials. As the anode, carbon materials can significantly promote interfacial microbial colonization and accelerate the formation of extracellular biofilms, which eventually promotes the electrical power density by providing a conductive microenvironment for extracellular electron transfer. As the cathode, carbon based materials can function as catalysts for the oxygen-reduction reaction, showing satisfying activities and efficiencies nowadays even reaching the performance of Pt catalysts. Here, first, recent advancements on the design of carbon materials for anodes in MFCs are summarized, and the influence of structure and surface functionalization of different types of carbon materials on microorganism immobilization and electrochemical performance is elucidated. Then, synthetic strategies and structures of typical carbon-based cathodes in MFCs are briefly presented. Furthermore, future applications of carbon-electrode-based MFC devices in the energy, environmental, and biological fields are discussed, and the emerging challenges in transferring them from laboratory to industrial scale are described. PMID- 27991682 TI - The role of metastasis-associated in colon cancer 1 (MACC1) in endometrial carcinoma tumorigenesis and progression. AB - Metastasis-associated in colon cancer-1 (MACC1), has recently been identified as a key regulator in the progression of many cancers. However, its role in endometrial carcinoma (EC) remains unknown. MACC1 expression was determined in EC and normal endometrial tissues by immunohistochemistry. EC cell phenotypes and related molecules were examined after MACC1 downregulation by Small interfering RNA (siRNA) or microRNA (miRNA) transfection. We found that MACC1 was highly expressed in EC tissues than normal samples, and was significantly different in FIGO staging (I and II vs. III and IV), the depth of myometrial infiltration (<1/2 vs. >=1/2), lymph nodes metastasis (negative vs. positive), besides, MACC1 overexpression was correlated with lower cumulative and relapse-free survival rate. MACC1 downregulation by siRNA transfection significantly induced G1 phrase arrest, suppressed EC cell proliferation, migration, and invasion. In addition, MACC1 downregulation also reduced expression of Cyclin D1 and Cyclin-dependent Kinase 2 (CDK2), N-cadherin (N-Ca), alpha-SMA, matrix metalloproteinase 2 (MMP2), and MMP9, but increased expression of E-cadherin (E-Ca). Bioinformatic predictions and dual-luciferase reporter assays indicate that MACC1 is a possible target of miR-23b. MiR-23b overexpression reduced MACC1 expression in vitro and induced G1 phrase arrest, suppressed cell proliferation, migration, and invasion. MiR-23b transfection also reduced Cyclin D1 and CDK2, N-Ca, alpha-SMA, MMP2, MMP9 expression, but increased E-Ca expression. Furthermore, the nude mouse xenograft assay showed that miR-23b overexpression suppressed tumour growth through downregulating MACC1 expression. Taken together, our results demonstrate for the first time that MACC1 may be a new and important diagnosis and therapeutic target of endometrial carcinoma. PMID- 27991683 TI - Platelet Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men. AB - BACKGROUND: Thrombocytopenia during intoxication, rebound thrombocytosis during 1 to 3 weeks of abstinence, and subsequent normalization of the platelet count are common in alcoholics. METHODS: We evaluated 989 Japanese alcoholic men to identify the effects of genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) on platelet counts during an 8-week in-hospital abstinence period. RESULTS: Thrombocytopenia (<15 * 104 /MUl) was observed in 25.9% of the subjects upon admission. The platelet counts increased from 21.4 +/- 0.3 * 104 /MUl (mean +/- SE) to 27.6 +/- 0.3 * 104 /MUl, and a rebound platelet increase of >=10 * 104 /MUl was observed in 28.6% of the patients during the first 2 weeks after admission. By 4 weeks, the mean platelet counts had returned to intermediate levels and remained stable thereafter. The reversible suppression and rebound increase in the platelet counts were more prominent in the slow-metabolizing ADH1B*1/*1 group than in the fast-metabolizing ADH1B*2 group. Throughout the 8 weeks, the mean platelet counts of the active ALDH2*1/*1 group were consistently lower than those in the inactive ALDH2*1/*2 group. Cirrhosis was a strong determinant of a lower platelet count. After adjustments for nongenetic factors including cirrhosis, multiple linear regression analyses showed that the ADH1B*1/*1 genotype was associated with a lower platelet count (partial regression coefficient = -1.3 * 104 /MUl) on the admission day, but subsequently had a positive effect on the platelet count at 1 and 2 weeks after admission (+1.5 and +3.8 * 104 /MUl, respectively). The ALDH2*1/*1 genotype was associated with a lower platelet count (-2.1 to -3.9 * 104 /MUl) consistently throughout the 8 weeks. Multiple logistic regression analyses showed that the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission (odds ratio [95% confidence interval] = 1.61 [1.14 to 2.27]) and of a rebound platelet increase during the first 2 weeks (3.86 [2.79 to 5.34]). The ALDH2*1/*1 genotype increased the risk of thrombocytopenia upon admission (1.73 [1.06 to 2.82]). CONCLUSIONS: In alcoholics, the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission and of a rebound platelet increase 2 weeks thereafter, while the ALDH2*1/*1 genotype was associated with lower platelet counts throughout the 8-week hospital stay. PMID- 27991687 TI - Graphite-to-Graphene: Total Conversion. AB - The rush to develop graphene applications mandates mass production of graphene sheets. However, the currently available complex and expensive production technologies are limiting the graphene commercialization. The addition of a protective diluent to graphite during ball-milling is demonstrated to result in a game-changer yield (>90%) of defect-free graphene, whose size is controlled by the milling energy and the diluent type. PMID- 27991686 TI - Co-expression changes of lncRNAs and mRNAs in the cervical sympathetic ganglia in diabetic cardiac autonomic neuropathic rats. AB - Cardiac autonomic neuropathy in Type 2 diabetes (T2D) is often a devastating complication. Long non-coding RNAs (lncRNAs) have important effects on both normal development and disease pathogenesis. In this study, we explored the expression profiles of some lncRNAs involved in inflammation which may be co expressed with messenger RNA (mRNA) in superior cervical and stellate ganglia after type 2 diabetic injuries. Total RNA isolated from 10 pairs of superior cervical and stellate ganglia in diabetic and normal male rats was hybridized to lncRNA arrays for detections. Pathway analysis indicated that the most significant gene ontology (GO) processes that were upregulated in diabetes were associated with immune response, cell migration, defense response, taxis, and chemotaxis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that most of the target genes of the lncRNAs were located in cytokine-cytokine receptor interactions, the chemokine signaling pathway and cell adhesion molecules, which were involved in T2D. Gene co-expression network construction showed that the co-expression network in the experimental rats consisted of 268 regulation edges among 105 lncRNAs and 11 mRNAs. Our studies demonstrated the co expression profile of lncRNAs and mRNAs in diabetic cardiac autonomic ganglia, suggesting possible roles for multiple lncRNAs as potential targets for the development of therapeutic strategies or biomarkers for diabetic cardiac autonomic neuropathy. (c) 2016 Wiley Periodicals, Inc. PMID- 27991685 TI - Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases. AB - AIMS: Massive gastric polyposis is a rare entity that is often associated with juvenile polyposis syndrome (JPS). The aim of this study was to evaluate the clinicopathological features of 22 patients with abundant gastric juvenile-type or hyperplastic-like polyps. METHODS AND RESULTS: The study included 12 males and 10 females with a median age of 48 years (range: 13-79 years). Fourteen (64%) patients carried a diagnosis of JPS, and three had prior gastrointestinal adenocarcinomas. Patients without known JPS presented at an older median age (60 years versus 40 years; P = 0.0068). Clinical symptoms included nausea, vomiting, and abdominal pain; 23% of patients were asymptomatic. Eighteen cases showed complete or near-complete carpeting of the gastric mucosa by innumerable polyps, ranging from a few millimetres to ~100 mm. Most polyps formed long, bulbous projections and had characteristic histological features, including a smooth outer contour, prominent stromal oedema, and widely spaced, often cystically dilated glands lined by foveolar epithelium; some polyps had less stroma and more hyperplastic foveolar epithelium. All had normal underlying or adjacent mucosa. Four (18%) cases harboured adenocarcinoma, and seven (32%) others showed dysplasia. SMAD4 immunohistochemical staining showed patchy loss in polyps from 19 of 20 cases tested. Five of six (84%) patients tested had a germline SMAD4 mutation. CONCLUSIONS: Massive gastric juvenile-type polyposis can occur in patients with and without known JPS, and may mimic different conditions, such as other polyposis syndromes and Menetrier disease. Pathologists play an important role in disease classification, as some patients lack a family or personal history of JPS, have few if any colonic polyps, and may not harbour diagnostic germline mutations. PMID- 27991688 TI - Translating research into clinical practice across the developmental spectrum: Examining the clinical utility of the short treatment allocation tool for eating disorders. PMID- 27991690 TI - Associations between mothers' active engagement with infants at 6 months and children's adjustment to school life at ages 5.5 and 11 years. AB - BACKGROUND: In Japan, students' poor adjustment to school life such as school refusals has been recognized as a nation-wide problem. In this study, we examined the link between the absence of mothers' active engagement with their infants at 6 months and children's risks of poor adjustment toward elementary school life at the ages of 5.5 and 11. METHODS: We used a Japanese national longitudinal survey (n = 43 132) with 11 years of follow-up. Because of social patterning in how mothers engage with their infants, we employed propensity score matching analyses to control for confounding by socio-economic and other factors. We matched mothers with active engagement and those without on various social and parental characteristics such as educational attainment and household income. RESULTS AND CONCLUSIONS: Among matched pairs, we observed higher risks of poor adjustment to school life at both 5.5 and 11 years among Japanese children who lacked mothers' active engagement at 6 months. For example, the relative risk was 1.46 [95% confidence interval: 1.10, 1.94] for inability to get along with others in a group setting at the age of 5.5 years and 1.29 [1.10, 1.51] for inability to get along with teachers at the age of 11 years. Our findings corroborate previous findings, which emphasize the importance of providing an enriched environment for infants' social development and may indicate the need for an intervention for caregivers who lack appropriate nurturing skills. PMID- 27991689 TI - Incorporating Pyrrolic and Pyridinic Nitrogen into a Porous Carbon made from C60 Molecules to Obtain Superior Energy Storage. AB - Nitrogen-doped porous carbon is obtained by KOH activation of C60 in an ammonia atmosphere. As an anode for Li-ion batteries, it shows a reversible capacity of up to ~1900 mA h g-1 at 100 mA g-1 . Simulations suggest that the superior Li-ion storage may be related to the curvature of the graphenes and the presence of pyrrolic/pyridinic group dopants. PMID- 27991691 TI - Morphology of rare exogenous materials in dermatopathology. AB - Dermatopathologists are occasionally challenged by exogenous materials found in their biopsies. Recognition of most of the structures and morphological parts of foreign materials is not always easy because most of the literature thus far has focused on the study of the histological and histopathological aspects of human tissues, as well as on the granulomatous response elicited by such foreign bodies. However, there are some cases of rare exogenous material in biopsies, mainly published as case reports; and dermatopathologists often lose precious time searching for information about such cases. In this article, we examine the morphology of the following elements: alimentary detritus, cacti barbs, cotton fibers, silica particles, nail polish, maggots, sea urchin spines and honey bee stings. PMID- 27991692 TI - Inhibition of lung cancer in diethylnitrosamine-induced mice by Rhizoma paridis saponins. AB - Lung cancer is the foremost cause of cancer mortality and a growing economic burden worldwide. Rhizoma paridis saponins (RPS) have been reported to exhibit potential anti-tumor effects on many kinds of tumor models. The present study was designed to investigate the mechanism-based chemopreventive nature of RPS against DEN-induced lung carcinogenesis in Kunming mice. As a result, the treatment with RPS reduced the severity of pulmonary histopathology. The mechanism of its antitumor effect involved in (a) reducing oxidative stress injury through up regulating activities of CAT and SOD; (b) down-regulating the levels of inflammatory factors, like TNF-alpha, IL6, COX-2, and PGE2; (c) activation of caspase-3 and up-regulating the pro-apoptotic protein Bax; (d) decreasing the expression of PCNA; (e) depressing the expression of cancer stem cells marker CD133; (f) suppressing aberrant expression of cytokeratin 8 and 18; and (g) inhibiting EGFR/ PI3 K/Akt, EGFR/Ras/Erk and NF-kappaB pathways. Taken together, RPS would be a potent agent inhibiting lung tumor in the future. PMID- 27991693 TI - Achieving the Trade-Off between Selectivity and Activity in Semihydrogenation of Alkynes by Fabrication of (Asymmetrical Pd@Ag Core)@(CeO2 Shell) Nanocatalysts via Autoredox Reaction. AB - (Asymmetrical Pd@Ag core)@(CeO2 shell) nanostructures are successfully fabricated via a clean and facile modified autoredox reaction by the preaddition of Pd seeds in the growth solution. In a subsequent catalytic test, it is found that the as obtained bimetallic core@shell nanoparticles exhibit excellent catalytic performance in semihydrogenation of alkynes. The trade-off between selectivity and activity is well realized. PMID- 27991694 TI - Characterizing severe and enduring anorexia nervosa: An empirical approach. AB - Targeted approaches for the treatment of severe and enduring anorexia nervosa (SE AN) have been recommended, but there is no consensus definition of SE-AN to inform research and clinical practice. This study aimed to take initial steps toward developing an empirically based definition of SE-AN by characterizing associations among putative indicators of severity and chronicity in eating disorders. Patients with AN (N = 355) completed interviews and questionnaires at treatment admission and discharge; height and weight were assessed to calculate body mass index (BMI). Structural equation mixture modeling was used to test whether associations among potential indicators of SE-AN (illness duration, treatment history, BMI, binge eating, purging, quality-of-life) formed distinct subgroups, a single group with one or more dimensions, or a combination of subgroups and dimensions. A three-factor (dimensional), two-profile (categorical) mixture model provided the best fit to the data. Factor 1 included eating disorder behaviors; Factor 2 comprised quality-of-life domains; Factor 3 was characterized by illness duration, number of hospitalizations, and admission BMI. Profiles differed on eating disorder behaviors and quality-of-life, but not on indicators of chronicity or BMI. Factor scores, but not profile membership, predicted outcome at discharge from treatment. Data suggest that patients with AN can be classified on the basis of eating disorder behaviors and quality-of-life, but there was no evidence for a chronic subgroup of AN. Rather, indices of chronicity varied dimensionally within each class. Given that current definitions of SE-AN rely on illness duration, these findings have implications for research and clinical practice. PMID- 27991695 TI - Application of extended bi-pedicle anterolateral thigh free flaps for reconstruction of large defects: A case series. AB - BACKGROUND: The anterolateral thigh flap is a workforce flap in reconstructive surgery, however, variations in it is vascular anatomy are not uncommon. These variations may affect flap design and survival, especially when large flaps are required. In some anatomical variants the anterolateral thigh flap is supplied by two separate dominant pedicles, and in these cases a bi-pedicle modification may be necessary to ensure complete flap viability. The aim of this report is to evaluate the outcomes, and present our approach in using bi-pedicle anterolateral thigh flaps as a method to reduce the risk of partial flap necrosis when reconstructing sizeable soft tissue defects. PATIENTS AND METHODS: From October of 2013 to November of 2015, seventeen patients were treated with extended bi pedicled ALT flaps for reconstruction of large defects (16 to 25 * 8 to 13 cm). Following doppler mapping of the lateral thigh perforators, an anterior incision was made. When a distinct oblique branch (OB) was present and the perforators of the descending branch of the lateral circumflex femoral artery (d-LCFA) were small, the large bi-pedicle ALT flaps were harvested based on both the oblique branch and the d-LCFA pedicle. We evaluated the perfusion of the flap using only one pedicle by clamping alternately the OB and the d-LCFA. After flap harvest, we performed two end-to-end venous anastomosis between the lateral circumflex femoral vein and a recipient vein, and the oblique branch vein with a second recipient vein. End to end arterial anastomosis were performed between the two pedicles and two recipient arteries. Y-shaped interposition vein graft (YVG) was applied when single recipient artery was available for revascularization. The flaps were used for scar contracture, chest wall, lower and upper extremity soft tissue defects, breast, scalp, oral cancer, and esophageal reconstruction. RESULTS: The flaps size were 18 to 26 * 10 to 14 cm. For all seventeen patients the reconstructive goals were achieved with complete survival of the large ALT flaps with no events of partial necrosis or failure. We reported one case of re exploration of a congested flap due to venous thrombosis, which was successfully salvaged. CONCLUSION: Bi-pedicled ALT flaps could be a considered as a valuable option when a second pedicle is encountered and large flaps are required. PMID- 27991697 TI - Materials Chemistry of Nanoultrasonic Biomedicine. AB - As a special cross-disciplinary research frontier, nanoultrasonic biomedicine refers to the design and synthesis of nanomaterials to solve some critical issues of ultrasound (US)-based biomedicine. The concept of nanoultrasonic biomedicine can also overcome the drawbacks of traditional microbubbles and promote the generation of novel US-based contrast agents or synergistic agents for US theranostics. Here, we discuss the recent developments of material chemistry in advancing the nanoultrasonic biomedicine for diverse US-based bio-applications. We initially introduce the design principles of novel nanoplatforms for serving the nanoultrasonic biomedicine, from the viewpoint of synthetic material chemistry. Based on these principles and diverse US-based bio-application backgrounds, the representative proof-of-concept paradigms on this topic are clarified in detail, including nanodroplet vaporization for intelligent/responsive US imaging, multifunctional nano-contrast agents for US based multi-modality imaging, activatable synergistic agents for US-based therapy, US-triggered on-demand drug releasing, US-enhanced gene transfection, US based synergistic therapy on combating the cancer and potential toxicity issue of screening various nanosystems suitable for nanoultrasonic biomedicine. It is highly expected that this novel nanoultrasonic biomedicine and corresponding high performance in US imaging and therapy can significantly promote the generation of new sub-discipline of US-based biomedicine by rationally integrating material chemistry and theranostic nanomedicine with clinical US-based biomedicine. PMID- 27991696 TI - Linking the Transcriptional Landscape of Bone Induction to Biomaterial Design Parameters. AB - New engineering possibilities allow biomaterials to serve as active orchestrators of the molecular and cellular events of tissue regeneration. Here, the molecular control of tissue regeneration for calcium phosphate (CaP)-based materials is established by defining the parameters critical for tissue induction and those are linked to the molecular circuitry controlling cell physiology. The material properties (microporosity, ion composition, protein adsorption) of a set of synthesized osteoinductive and noninductive CaP ceramics are parameterized and these properties are correlated to a transcriptomics profile of osteogenic cells grown on the materials in vitro. Using these data, a genetic network controlling biomaterial-induced bone formation is built. By isolating the complex material properties into single-parameter test conditions, it is verified that a subset of these genes is indeed controlled by surface topography and ions released from the ceramics, respectively. The gene network points to a decisive role for extracellular matrix deposition in osteoinduction by genes such as tenascin C and hyaluronic acid synthase 2, which are controlled by calcium and phosphate ions as well as surface topography. This work provides insight into the biomaterial composition and material engineering aspects of bone void filling and can be used as a strategy to explore the interface between biomaterials and tissue regeneration. PMID- 27991698 TI - A CD13-targeting peptide integrated protein inhibits human liver cancer growth by killing cancer stem cells and suppressing angiogenesis. AB - CD13 is a marker of angiogenic endothelial cells, and recently it is proved to be a biomarker of human liver cancer stem cells (CSCs). Herein, the therapeutic effects of NGR-LDP-AE, a fusion protein composed of CD13-targeting peptide NGR and antitumor antibiotic lidamycin, on human liver cancer and its mechanism were studied. Western blot and immunofluorescence assay demonstrated that CD13 (WM15 epitope) was expressed in both human liver cancer cell lines and vascular endothelial cells, while absent in normal liver cells. MTT assay showed that NGR LDP-AE displayed potent cytotoxicity to cultured tumor cell lines with IC50 values at low nanomolar level. NGR-LDP-AE inhibited tumorsphere formation of liver cancer cells, and the IC50 values were much lower than that in MTT assay, indicating selectively killing of CSCs. In endothelial tube formation assay, NGR LDP-AE at low cytotoxic dose significantly inhibited the formation of intact tube networks. Animal experiment demonstrated that NGR-LDP-AE inhibited the growth of human liver cancer xenograft. Immunohistochemical analysis showed that NGR-LDP-AE induced the down-regulation of CD13. In vitro experiment using cultured tumor cells also confirmed this result. NGR-LDP-AE activated both apoptotic and autophagic pathways in cultured tumor cells, while the induced autophagy protected cells from death. Conclusively, NGR-LDP-AE exerts its antitumor activity via killing liver CSCs and inhibiting angiogenesis. With one targeting motif, NGR-LDP-AE acts on both liver CSCs and angiogenic endothelial cells. It is a promising dual targeting fusion protein for liver cancer therapy, especially for advanced or relapsed cancers. PMID- 27991699 TI - A Supercritical Lens Optical Label-Free Microscopy: Sub-Diffraction Resolution and Ultra-Long Working Distance. AB - A planar metalens for achieving super-resolution imaging in far-field is proposed. This metalens, which has a non-sub-wavelength feature size, can be fabricated by conventional laser pattern generator. The imaging process is purely physical and captured in real time, without any pre- and post-processing. PMID- 27991700 TI - Metal-Organic Framework Supported on Processable Polymer Matrix by In Situ Copolymerization for Enhanced Iron(III) Detection. AB - Metal-organic frameworks (MOFs) represent a promising class of porous materials. However, MOFs show poor processability that impedes their full potential in applications. This work develops a composite strategy to skillfully load MOFs on a polymer plate to afford processability for these powder materials. A predesigned mesoporous MOF with active -NH2 groups around the pore walls was prepared and its copolymerization with the -NCO groups of macromonomers (polyurethane acrylate) could be facilely induced by an initiator under mild conditions. Notably, the target MOF-polymer composite is transparent, elastic, and shows enhanced Fe3+ detection compared with that of the individual MOF functional component. This result can be ascribed to the synergistic effect of the composite with newly formed chemical bonds between the MOF particle and polymer matrix. PMID- 27991701 TI - Elongated Dihydrogen versus Compressed Dihydride in Osmium Complexes. AB - Small modifications on the co-ligands of complexes containing two coordinated hydrogen atoms can determine the elongated dihydrogen versus compressed dihydride nature of these species and therefore their chemical behavior. 2,6 diphenylpyridine favors the formation of the osmium(IV) cation [OsH2 (C6 H4 pyPh)(PiPr3 )2 ]+ , whereas 2-phenoxy-6-phenylpyridine, which contains an oxygen atom between the heterocycle and one of the phenyl groups, stabilizes the osmium(II) elongated dihydrogen species [Os(C6 H4 pyOPh)(eta2 -H2 )(PiPr3 )2 ]+ . In contrast to the latter, the former shows a marked tendency to undergo reductive elimination of the heterocycle. PMID- 27991702 TI - Effective Photo- and Triboluminescent Europium(III) Coordination Polymers with Rigid Triangular Spacer Ligands. AB - Luminescent EuIII coordination polymers with rigid triangular spacer ligands are reported. The EuIII coordination polymer, [Eu3 (hfa)9 (tppb)2 ]n (hfa: hexafluoroacetylacetonate, tppb: tris(4-diphenylphosphorylphenyl)benzene), shows high thermo-stability (decomposition temperature=354 degrees C) and photoluminescence quantum yield (Phi4f-4f =82 %, photosensitized energy transfer efficiency=78 %). The triboluminescence efficiency of EuIII coordination polymer with triangular spacers under laser pulse irradiation (Nd:YAG, lambda=1064 nm, pulse width=5 ns, pulse energy=0.1 mJ) is calculated to be 49 %. Characteristic triangular structure, high emission quantum yield, effective photosensitized energy transfer, and remarkable triboluminescence properties of EuIII coordination polymers are demonstrated for the first time. PMID- 27991703 TI - Risk Assessment via Metabolism and Cell Growth Inhibition in a HepG2/C3A Cell Line Upon Treatment with Arpadol and its Active Component Harpagoside. AB - Harpagophytum procumbens (Hp) has been used as antiinflammatory and analgesic agent for the treatment of rheumatic diseases. The principal active component of Hp is harpagoside (HA). We tested the toxicity of this new therapeutic agent in a hepatic cell line (HepG2/C3A). Hp was found to be cytotoxic, and HA was found to decrease the number of cells in S phase, increase the number of cells in G2/M phase and induce apoptosis. Neither Hp nor HA was genotoxic. The expression of CDK6 and CTP3A4 was reduced by Hp, and both HA and Hp caused a significant reduction of CYP1A2 and CYP3A4 expression. It is possible that the cytotoxicity caused by HA and Hp does not involve transcriptional regulation of the cyclins and CDKs tested but is instead related to the inhibition of metabolism. This is evidenced by the results of an MTT assay and changes in the expression of genes related to drug metabolism, leading to cell death. Indeed, the cells exhibited decreased proliferation upon exposure to Hp and HA. The data show that treatment with either Hp or HA can be cytotoxic, and this should be taken into consideration when balancing the risks and benefits of treatments for rheumatic diseases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27991704 TI - Patient navigation and activation interventions for elderly patients with cancer: A systematic review. AB - Patient navigation (PN) and patient activation (PA) interventions are widely used to help patients with cancer to manage the disease and the care trajectory. However, the usability and impact of these interventions on older patients and their well-being are unclear. This study aims to show which PN and PA interventions are being used and what impact they have. After systematically searching the literature, we assessed the quality of the publications we found. The publications had to involve at least a subgroup of older people with minimally one abnormal oncologic test result each, and they had to focus on PN or PA interventions. Six PA publications examined the interventions exclusively for elderly patients. Each of the 11 PN and PA publications contained at least one comment about the impact on older patients. The types of impact varied substantially, but there was scant attention to the quality of life. The type of intervention, the outcome measures and the quality of publications also varied considerably. Generally, age is not an important factor in PN and PA studies. To facilitate adjustment of navigation and activation interventions to the individual patient, more rigorous research into the impact of PN and PA interventions on older patients is necessary. PMID- 27991705 TI - Binocular function during unequal monocular input. AB - The fine task of stereoscopic depth discrimination in human subjects requires a functional binocular system. Behavioral investigations show that relatively small binocular abnormalities can diminish stereoscopic acuity. Clinical evaluations are consistent with this observation. Neurons in visual cortex represent the first stage of processing of the binocular system. Cells at this level are generally acutely sensitive to differences in relative depth. However, an apparent paradox in previous work demonstrates that tuning for binocular disparities remains relatively constant even when large contrast differences are imposed between left and right eye stimuli. This implies a range of neural binocular function that is at odds with behavioral findings. To explore this inconsistency, we have conducted psychophysical tests by which human subjects view vertical sinusoidal gratings drifting in opposite directions to left and right eyes. If the opposite drifting gratings are integrated in visual cortex, as wave theory and neurophysiological data predict, the subjects should perceive a fused stationary grating that is counter-phasing in place. However, this behavioral combination may not occur if there are differences in contrast and therefore signal strength between left and right eye stimuli. As expected for the control condition, our results show fused counter-phase perception for equal inter-ocular grating contrasts. Our experimental tests show a striking retention of counter-phase perception even for relatively large differences in inter-ocular contrast. This finding demonstrates that binocular integration, although relatively coarse, can occur during substantial differences in left and right eye signal strength. PMID- 27991706 TI - On the benefits of living in clumps: a case study on Polytrichastrum formosum. AB - The study concerns the mechanics and water relationships of clumps of a species of endohydric moss, Polytrichastrum formosum. Anatomical and morphological studies were done using optical and scanning electron microscopy. Experiments on waterdrop capture and their distribution to adjacent shoots within a moss clump were performed with the experimental set-up for the droplet collision phenomena and ultra-high speed camera. The mechanical strength of the moss clump was tested on an electromechanical testing machine. During the process of moss clump wetting, the falling water drops were captured by the apical stem part or leaves, then flowed down while adhering to the gametophore and never lost their surface continuity. In places of contact with another leaf, the water drop stops there and joins the leaves, enabling their hydration. Mathematical analysis of anatomical images showed that moss stems have different zones with varying cell lumen and cell wall/cell radius ratios, suggesting the occurrence of a periodic component structure. Our study provides evidence that the reaction of mosses to mechanical forces depends on the size of the clump, and that small groups are clearly stronger than larger groups. The clump structure of mosses acts as a net for falling rain droplets. Clumps of Polytrichastrum having overlapping leaves, at the time of loading formed a structure similar to a lattice. The observed reaction of mosses to mechanical forces indicates that this phenomenon appears to be analogous to the 'size effect on structural strength' that is of great importance for various fields of engineering. PMID- 27991707 TI - Guillain-Barre syndrome in France: a nationwide epidemiological analysis based on hospital discharge data (2008-2013). AB - Guillain-Barre syndrome (GBS) is potentially life threatening and typically occurs after an infection. No detailed information is available concerning the epidemiological characteristics of GBS in France. We estimated age- and sex specific incidence rates (IRs) based on a French nationwide hospital discharge database. All patients hospitalized for GBS between 2008 and 2013 were identified by International Classification of Diseases-10 code G61.0 as principal diagnosis. Patients previously hospitalized for GBS in 2006 and 2007 were excluded. Sensitivity analyses were performed by considering alternative case definitions, based on more restrictive sets of codes. A total of 9,391 patients were identified, leading to an overall crude IR of 2.42 per 100,000 person-years (world standardized IR = 2.00). IRs increased with age, reaching a peak in the 70 79-year age group. IR was 46% higher in men than in women, and 44% higher in winter than in summer. In children, the highest IR was observed at the age of 2 years. These patterns were not modified by the use of alternative case definitions. This French nationwide study showed similar GBS epidemiological patterns in adults to those reported in other countries. We also report a childhood incidence peak around the age of 2 years, as previously observed in Latin American and Chinese populations. PMID- 27991708 TI - Mortality, fecundity and development among bed bugs (Cimex lectularius) exposed to prolonged, intermediate cold stress. AB - BACKGROUND: Bed bugs (Cimex lectularius L.) have returned as a nuisance pest worldwide. Their ability to withstand different types of environmental stress should be explored in order potentially to increase the efficiency of control methods. RESULTS: Immediate and long-term effects of exposure to temperatures from 0 to -10 degrees C for 1, 2 and 3 weeks are reported. Fifth-instar nymphs and adults were exposed to constant or fluctuating temperatures. Increased cold and extended time yielded higher mortality; nymphs were more resilient than adults at the shorter durations of exposure. At intermediate temperatures, mortality was higher at constant compared with fluctuating temperatures, whereas all individuals died after 3 weeks of exposure to -7 degrees C. The success among survivors after cold treatment was also affected in terms of reduced egg production, hatching success and the ability of fifth-instar nymphs to advance into the adult stage; however, nymphs produced after cold treatment developed normally. CONCLUSIONS: Detrimental effects of prolonged exposure to low temperatures were seen in bed bugs both during and after cold treatment. The results suggest that temperatures below -7 degrees C can be applied by laymen to control this pest in small items if available treatment time is of less concern. (c) 2016 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 27991709 TI - RNA interference unveils the importance of Pseudotrichonympha grassii cellobiohydrolase, a protozoan exoglucanase, in termite cellulose degradation. AB - Based on prior work, a cellulase from glycosyl hydrolase family 7 (GHF7) was identified and found to be expressed at a high level in Coptotermes formosanus. To determine the function of GHF7 family members in vivo, we used RNA interference (RNAi) to functionally analyse the exoglucanase gene Pseudotrichonympha grassii cellobiohydrolase gene (PgCBH), which was highly expressed in Pseudotrichonympha grassii, a flagellate found in the hindgut of C. formosanus. In this study, the expression level of PgCBH was down-regulated by RNAi, causing the death of P. grassii, but no effect was observed for other flagellates found in C. formosanus. RNAi also resulted in significantly reduced exoglucanase activity, and no effect was observed for endoglucanase and beta glucosidase activities. This result demonstrated that the PgCBH gene plays a role in the protist lignocellulolytic process and is also important for host survival. PgCBH can be used as a target gene and has potential as a bioinsecticide for use against termites. PMID- 27991710 TI - RNA interference in mosquito: understanding immune responses, double-stranded RNA delivery systems and potential applications in vector control. AB - RNA interference (RNAi) refers to the process of post-transcriptional silencing of cellular mRNA by the application of double-stranded RNA (dsRNA). RNAi strategies have been widely employed to regulate gene expression in plants and animals including insects. With the availability of the full genome sequences of major vector mosquitoes, RNAi has been increasingly used to conduct genetic studies of human pathogens in mosquito vectors and to study the evolution of insecticide resistance in mosquitoes. This review summarizes the recent progress in our understanding of mosquito-pathogen interactions using RNAi and various methods of dsRNA delivery in mosquitoes at different stages. We also discuss potential applications of this technology to develop novel tools for vector control. PMID- 27991711 TI - A computational model of the effect of capillary density variability on oxygen transport, glucose uptake, and insulin sensitivity in prediabetes. AB - OBJECTIVES: The purpose of this study was to model how CD variability affects tissue oxygenation under resting and exercise conditions. Additionally, we examine how CD impacts glucose and insulin transport in skeletal muscle. METHODS: We applied an established 3D finite difference model of oxygen transport to predict tissue oxygenation using FCD, hemodynamics, and SO2 measurements from a previous study. A 2D finite element model of glucose transport was applied to predict glucose and insulin uptake in PP and fasting conditions using the same range of CD. RESULTS: Control simulations used CD ranging from 562.5 to 781.3 capillaries/mm2 , whereas prediabetic densities ranged from 375.0 to 593.8 capillaries/mm2 . Mean tissue PO2 was 30.6+/-4.6 to 40.5+/-3.6 mm Hg for rest and 19.6+/-6.7 to 33.27+/-4.7 mm Hg for control and prediabetic simulations, respectively. Mean PP glucose concentrations were 5.85+/-1.13 mmol/L in the control group and 5.11+/-1.28 in the prediabetic simulations. Glucose uptake rates were 35% lower in the lowest capillary CD case compared to the high CD simulation. CONCLUSIONS: Our simulations predict that CD decreases can have a substantial effect on oxygen delivery and glucose disposal across the observed physiological ranges of capillarization. PMID- 27991713 TI - Roles of the gut in the metabolic syndrome: an overview. AB - The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and arterial hypertension), indicating an increased risk of diabetes, cardiovascular disease and premature mortality. The gastrointestinal tract is seldom discussed as an organ system of principal importance for metabolic diseases. The present overview connects various metabolic research lines into an integrative physiological context in which the gastrointestinal tract is included. Strong evidence for the involvement of the gut in the metabolic syndrome derives from the powerful effects of weight reducing (bariatric) gastrointestinal surgery. In fact, gastrointestinal surgery is now recommended as a standard treatment option for type 2 diabetes in obesity. Several gut-related mechanisms that potentially contribute to the metabolic syndrome will be presented. Obesity can be caused by hampered release of satiety signalling gut hormones, reduced meal-associated energy expenditure and microbiota-assisted harvest of energy from nondigestible food ingredients. Adiposity per se is a well-established risk factor for hyperglycaemia. In addition, a leaky gut mucosa can trigger systemic inflammation mediating peripheral insulin resistance that together with a blunted incretin response aggravates the hyperglycaemic state. The intestinal microbiota is strongly associated with obesity and the related metabolic disease states, although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be involved in the pathophysiology of hypertension and postprandial triglyceride rich chylomicrons; in addition, intestinal cholesterol metabolism probably contributes to atherosclerosis. It is likely that in the future, the metabolic syndrome will be treated according to novel pharmacological principles interfering with gastrointestinal functionality. PMID- 27991714 TI - How should ambulatory blood pressure measurement be used in general practice? PMID- 27991712 TI - Targeting of tail-anchored membrane proteins to subcellular organelles in Toxoplasma gondii. AB - Proper protein localization is essential for critical cellular processes, including vesicle-mediated transport and protein translocation. Tail-anchored (TA) proteins are integrated into organellar membranes via the C-terminus, orienting the N-terminus towards the cytosol. Localization of TA proteins occurs posttranslationally and is governed by the C-terminus, which contains the integral transmembrane domain (TMD) and targeting sequence. Targeting of TA proteins is dependent on the hydrophobicity of the TMD as well as the length and composition of flanking amino acid sequences. We previously identified an unusual homologue of elongator protein, Elp3, in the apicomplexan parasite Toxoplasma gondii as a TA protein targeting the outer mitochondrial membrane. We sought to gain further insight into TA proteins and their targeting mechanisms using this early-branching eukaryote as a model. Our bioinformatics analysis uncovered 59 predicted TA proteins in Toxoplasma, 9 of which were selected for follow-up analyses based on representative features. We identified novel TA proteins that traffic to specific organelles in Toxoplasma, including the parasite endoplasmic reticulum, mitochondrion, and Golgi apparatus. Domain swap experiments elucidated that targeting of TA proteins to these specific organelles was strongly influenced by the TMD sequence, including charge of the flanking C-terminal sequence. PMID- 27991715 TI - Impact of glyphosate-resistant sugar beet. AB - Glyphosate-resistant (GR) sugar beet became commercially available to US sugar beet growers in 2008 and was rapidly adopted. Prior to the availability of GR sugar beet, growers would commonly make 3-5 herbicide applications. This often resulted in some crop injury, but was accepted to reduce the impact of weeds. In addition, non-GR sugar beet was cultivated 1-3 times and often followed by hand weeding. The introduction of GR sugar beet drastically reduced the complexity of weed management. Concerns about GR weeds in the United States also apply to sugar beet growers. Changes in weed management strategies will be required to keep this technology. Sugar beet is arguably one of the most suitable crops for GR technology because: (1) none of the herbicides registered for use in this crop was very effective without risking crop injury; (2) sugar beet cannot be grown in the same field year after year owing to disease concerns and thus requires a 3-4 year rotation; (3) pollen-mediated gene flow is negligible from the sugar beet crop because it is a biennial and harvested before it flowers; (4) the processing of harvested roots to extract the sucrose rapidly degrades the DNA in the extracted raw juice and subsequent refining so that no DNA is present in the finished sugar; (5) studies have shown that processed GR beet sugar is identical to non-GR beet sugar, as well as cane sugar. (c) 2016 Society of Chemical Industry. PMID- 27991716 TI - Absorption, distribution, metabolism, and excretion of [14 C]sesamin in rats. AB - SCOPE: Sesamin is a major lignan in sesame seeds and has various physiological effects. Although metabolism of sesamin by cytochrome P450 or intestinal microflora has been reported, little is known concerning the mass balance, pharmacokinetics, and tissue distribution of sesamin. METHODS AND RESULTS: Absorption, distribution, metabolism, and excretion of [14 C]sesamin were investigated after a single oral dose of 5 mg/kg in rats. Sesamin was absorbed with peak plasma radioactivity at 1.0 h and declined with a terminal half-life 4.7 h. The cumulative excretion of radioactivity was 37.5 +/- 3.1% in urine and 58.7 +/- 4.8% in feces. In bile duct-cannulated rats, the cumulative excretion of radioactivity was 66.3 +/- 8.4% in bile and 27.8 +/- 10.2% in urine. Tissue distribution was investigated using quantitative whole-body autoradiography. Radioactivity was widely distributed over the whole body and was highly detected in the liver and kidney. The metabolites profile was examined using radiochromatography. Sesamin was mainly distributed in the form of conjugate metabolites. CONCLUSIONS: Sesamin was absorbed efficiently and distributed over the whole body. In particular, sesamin was highly distributed in the form of the metabolites in the liver and kidney. The results of this study are useful in elucidating the action mechanism of sesamin. PMID- 27991719 TI - Electrofishing method improves evaluation of amphibian larvae abundance: a case of "beaver rivers". AB - There are many locations in Russia where Eurasian beaver (Castor fiber) populations have been restored. As a keystone species, beavers provide wide ranging direct and indirect impacts on aquatic ecosystems. In particular, beaver created ponds are sites for spawning and nursery places for tadpoles of the brown frogs (genus Rana). Because of such impacts, study techniques for assessing aquatic organism abundance are being developed. We compared two methods for estimating tadpole abundance: traditional catches by dipnet and electrofishing. Our results show that the dipnet catch data for the shallower ponds with larger water surface area were five times lower than that obtained by electrofishing. Therefore, we conclude that dipnet catches are not suitable for comparing the relative abundance of tadpoles in the two beaver ponds that were studied. PMID- 27991718 TI - Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. SURVIVAL AND LEUKEMIC/FIBROTIC TRANSFORMATION: Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. THROMBOSIS RISK STRATIFICATION: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age <=60 years, no thrombosis history, JAK2/MPL un mutated), low risk (age <=60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 * 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. RISK-ADAPTED THERAPY: The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high risk ET patients but it is not mandatory for intermediate-risk patients. First line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-alpha and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27991720 TI - A Metal-Organic Framework Approach toward Highly Nitrogen-Doped Graphitic Carbon as a Metal-Free Photocatalyst for Hydrogen Evolution. AB - Zeolitic imidazolate framework-8 (ZIF-8)-derived N-doped graphene analogous polyhedrons (ZNGs) obtained via the direct carbonation of ZIF-8 are applied to photocatalytic hydrogen evolution for the first time. The contents of different types of nitrogen atoms in ZNGs can be fine-tuned via the calcination temperature, which significantly influences the hydrogen evolution rate of the ZNGs. PMID- 27991717 TI - Lack of beta, beta-carotene-9', 10'-oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice. AB - SCOPE: beta,beta-Carotene-9',10'-dioxygenase 2 (BCO2) is a carotenoid cleavage enzyme localized to the inner mitochondrial membrane in mammals. This study was aimed to assess the impact of genetic ablation of BCO2 on hepatic oxidative stress through mitochondrial function in mice. METHODS AND RESULTS: Liver samples from 6-wk-old male BCO2-/- knockout (KO) and isogenic wild-type (WT) mice were subjected to proteomics and functional activity assays. Compared to the WT, KO mice consumed more food (by 18%) yet displayed significantly lower body weight (by 12%). Mitochondrial proteomic results demonstrated that loss of BCO2 was associated with quantitative changes of the mitochondrial proteome mainly shown by suppressed expression of enzymes and/or proteins involved in fatty acid beta oxidation, the tricarboxylic acid cycle, and the electron transport chain. The mitochondrial basal respiratory rate, proton leak, and electron transport chain complex II capacity were significantly elevated in the livers of KO compared to WT mice. Moreover, elevated reactive oxygen species and increased mitochondrial protein carbonylation were also demonstrated in liver of KO mice. CONCLUSIONS: Loss of BCO2 induces mitochondrial hyperactivation, mitochondrial stress, and changes of the mitochondrial proteome, leading to mitochondrial energy insufficiency. BCO2 appears to be critical for proper hepatic mitochondrial function. PMID- 27991721 TI - An optimized high quality male DNA extraction from spermatophores in open thelycum shrimp species. AB - The crucial step of most of the current genetic studies is the extraction of DNA of sufficient quantity and quality. Several genomic DNA isolation methods have been described to successfully obtain male DNA from shrimp species. However, all current protocols require invasive handling methods with males for DNA isolation. Using Aristeus antennatus as a model we tested a reliable non-invasive differential DNA extraction method to male DNA isolation from spermatophores attached to female thelycum. The present protocol provides high quality and quantity DNA for polymerase chain reaction amplification and male genotyping. This new approach could be useful to experimental shrimp culture to select sires with relevant genetic patterns for selective breeding programs. More importantly, it can be applied to identify the mating pairs and male structure in wild populations of species as A. antennatus, where males are often difficult to capture. Our method could be also valuable for biological studies on other spermatophore-using species, such as myriapods, arachnids and insects. PMID- 27991722 TI - Twelve-month course and outcome of methamphetamine-induced psychosis compared with first episode primary psychotic disorders. AB - BACKGROUND: To assess the clinical course and outcome of patients with methamphetamine-induced psychosis in comparison with patients with primary psychotic disorders. METHODS: This prospective study was conducted on patients with methamphetamine-induced psychosis, and 2 groups of primary psychotic disorders: affective psychosis and non-affective psychosis admitted to 2 psychiatric hospitals in Tehran, Iran, with a first episode of a psychotic illness. A total of 165 subjects (55 in each group) were selected using convenience sampling. They were assessed at the time of admission, discharge and 6 and 12 months after discharge using the Positive and Negative Syndrome Scale, the Young Mania Rating Scale and the Global Assessment of Functioning Scale. The frequency of readmissions and suicide attempts were also assessed. RESULTS: Significant differences were found in the trend of changes of symptoms and functioning among the 3 groups. At all-time points, the severity of negative psychotic symptoms and dysfunction in the non-affective psychosis group were greater than those in affective or methamphetamine-induced psychosis groups, with latter 2 having similar profiles. However, the course of positive symptoms in methamphetamine-induced psychosis was more similar to non-affective psychosis. Number of suicide attempts and readmissions were non-significantly higher in methamphetamine-induced psychosis than in the other groups. CONCLUSION: Methamphetamine-induced psychosis does not have a satisfactory course and in some cases symptoms may remain even after many months of follow-up. Rate of certain outcomes such as re-hospitalization is also considerably high. It is a challenge for the health-care system that requires evidence-based interventions. PMID- 27991724 TI - Effects of acute cold exposure on oxidative balance and total antioxidant capacity in juvenile Chinese soft-shelled turtle, Pelodiscus sinensis. AB - Acute cold exposure may disturb the physiological homeostasis of the body in ectotherms. To date, there has been no information on the effects of cold exposure on homeostasis of reactive oxygen species (ROS) or antioxidant defense response in the Chinese soft-shelled turtle, Pelodiscus sinensis. In this study, P. sinensis juveniles were acclimated at 28 degrees C, transferred to 8 degrees C as cold exposure for 12 h, then moved back to 28 degrees C rewarming for 24 h. We measured the ROS level and total antioxidant capacity (TAC) in the brain, liver, kidney and spleen at 2 and 12 h cold exposure, and at the end of the rewarming period. Malonaldehyde (MDA) and carbonyl protein were used as markers of oxidative damage. Turtles being maintained simultaneously at 28 degrees C were used as the control group. Cold exposure did not disturb the ROS balance in all 4 tissues, while rewarming raised the ROS level in the brain and kidney of P. sinensis. Cold exposure and rewarming decreased the TAC in the brain, liver and spleen but did not change the TAC in the kidney. MDA and carbonyl protein levels did not increase during the treatment, indicating no oxidative damage in all 4 tissues of P. sinensis. Our results indicated that extreme cold exposure did not impact the inner oxidative balance of P. sinensis, but more ROS was produced during rewarming. P. sinensis showed good tolerance to the harsh temperature change through effective protection of its antioxidant defense system to oxidative damage. This study provides basic data on the stress biology of P. sinensis. PMID- 27991723 TI - Comparative proteomics analyses for 139A and ME7 scrapie infected mice brains in the middle and terminal stages. AB - PURPOSE: To analyze the proteomics patterns in the cortex regions of scrapie strains 139A- and ME7-infected mice collected in the middle and terminal stages. EXPERIMENTAL DESIGN: Western Blot and immunohistochemistry methods are used to analyze the pathological changes in mice collected in the middle and terminal stages. The technique of iTRAQ and multidimensional LC and MS are used to analyze the proteomics patterns of mice in different stages. RESULTS: In total, 2891 with 95% confidence interval are identified. The study here also demonstrates a similar protein expressions in the CNS tissues of two scrapie strains infected mice at the terminal stages, but markedly different one between the middle and terminal samples, not only in the numbers of differentially expressed proteins and involved gene ontologies and pathways but also in the relevant functional constitutions. CONCLUSIONS: It may provide useful clue in exploring the abnormalities of biological functions at different time points of prion infections and in searching for potential therapeutic and diagnostic biomarkers for prion diseases. PMID- 27991725 TI - A blind climber: The first evidence of ultrasonic echolocation in arboreal mammals. AB - The means of orientation is studied in the Vietnamese pygmy dormouse Typhlomys chapensis, a poorly known enigmatic semi-fossorial semi-arboreal rodent. Data on eye structure are presented, which prove that Typhlomys (translated as "the blind mouse") is incapable of object vision: the retina is folded and retains no more than 2500 ganglion cells in the focal plane, and the optic nerve is subject to gliosis. Hence, Typhlomys has no other means for rapid long-range orientation among tree branches other than echolocation. Ultrasonic vocalization recordings at the frequency range of 50-100 kHz support this hypothesis. The vocalizations are represented by bouts of up to 7 more or less evenly-spaced and uniform frequency-modulated sweep-like pulses in rapid succession. Structurally, these sweeps are similar to frequency-modulated ultrasonic echolocation calls of some bat species, but they are too faint to be revealed with a common bat detector. When recording video simultaneously with the ultrasonic audio, a significantly greater pulse rate during locomotion compared to that of resting animals has been demonstrated. Our findings of locomotion-associated ultrasonic vocalization in a fast-climbing but weakly-sighted small mammal ecotype add support to the "echolocation-first theory" of pre-flight origin of echolocation in bats. PMID- 27991726 TI - An optimised version of the secretome protein enrichment with click sugars (SPECS) method leads to enhanced coverage of the secretome. AB - The secretome, the entirety of all soluble proteins either being secreted or proteolytically released by a cell, plays a key role in inter-cellular communication of multi-cellular organisms. Pathological alterations contribute to diseases such as hypertension, cancer, autoimmune disorders or neurodegenerative diseases. Hence, studying disease-related perturbations of the secretome and the secretome itself covers an important aspect of cellular physiology. We recently developed the secretome protein enrichment with click sugars (SPECS) method that enables the analysis of secretomes of in vitro cell cultures even in the presence of FCS with MS. So far, SPECS facilitated the identification of protease substrates of BACE1, SPPL3 and ADAM10. Though, the SPECS method has already enabled deep insights into secretome biology, we aimed to improve the SPECS protocol to obtain even more information from MS-based secretome analysis and reduce the amount of input material. Here, we optimised the reaction buffer, the pH and replaced Dibenzocyclooctyne (DBCO) PEG12-biotin with the more water soluble variant DBCO-sulpho-biotin to finally provide an optimised protocol of the recently published SPECS protocol. Overall, the number of quantified glycoproteins and their average sequence coverage was increased by 1.6- and 2.4 fold, respectively. Thus, the opzimised SPECS protocol allows reducing the input material by half without losing information. These improvements make the SPECS method more sensitive and more universal applicable to cell types with limited availability. PMID- 27991728 TI - Two-dimensional solid-phase extraction strategy for the selective enrichment of aminoglycosides in milk. AB - An orthogonal two-dimensional solid-phase extraction strategy was established for the selective enrichment of three aminoglycosides including spectinomycin, streptomycin, and dihydrostreptomycin in milk. A reversed-phase liquid chromatography material (C18 ) and a weak cation-exchange material (TGA) were integrated in a single solid-phase extraction cartridge. The feasibility of two dimensional clean-up procedure that experienced two-step adsorption, two-step rinsing, and two-step elution was systematically investigated. Based on the orthogonality of reversed-phase and weak cation-exchange procedures, the two dimensional solid-phase extraction strategy could minimize the interference from the hydrophobic matrix existing in traditional reversed-phase solid-phase extraction. In addition, high ionic strength in the extracts could be effectively removed before the second dimension of weak cation-exchange solid-phase extraction. Combined with liquid chromatography and tandem mass spectrometry, the optimized procedure was validated according to the European Union Commission directive 2002/657/EC. A good performance was achieved in terms of linearity, recovery, precision, decision limit, and detection capability in milk. Finally, the optimized two-dimensional clean-up procedure incorporated with liquid chromatography and tandem mass spectrometry was successfully applied to the rapid monitoring of aminoglycoside residues in milk. PMID- 27991727 TI - Strategies for Enhancing the Catalytic Performance of Metal-Organic Frameworks in the Fixation of CO2 into Cyclic Carbonates. AB - Metal-organic frameworks (MOFs) with accessible Lewis acid sites are finding increasing application in the field of heterogeneous catalysis. However, the structural instability of MOFs when they are exposed to high temperature and/or high pressure often limits their applicability. In this study, two strategies were applied to achieve a MOF catalyst with high stability, activity and selectivity in the reaction of CO2 with styrene oxide to produce styrene carbonate. In the first approach, a MOF with linkers with high connectivity as MIL-100(Cr) was studied, leading to promising activity and recyclability in consecutive catalytic runs without loss of activity. In the second strategy, a MOF with linkers with lower connectivity but with encapsulated Keggin phosphotungstic acid (MIL-101(Cr)[PTA]) was prepared. However, the activity of this catalyst decreased upon reuse as a consequence of deterioration of the MOF. Further investigations were dedicated to the enhancement of the catalytic performance of MIL-100 and included the variation of the metal centre as well as the type and loading of organic salt acting as nucleophile source. This allowed tuning the nature of the organic halide to the specific porous structure of MIL 100(Cr) to prevent diffusion limitations. The best catalytic performance was obtained for MIL-100(Cr) in combination with EMIMBr ionic liquid, which gave very high styrene carbonate yield (94 %) with complete selectivity after 18 h of reaction at mild temperature (60 degrees C). PMID- 27991729 TI - Inhibiting the Migration of M1 Microglia at Hyperacute Period Could Improve Outcome of tMCAO Rats. AB - AIM: To study whether inhibiting microglia migration to the ischemic boundary zone (IBZ) at the early phase could improve neurological outcomes after stroke. METHODS: The transient middle cerebral artery occlusion (tMCAO) was induced in adult male Sprague-Dawley rats. AMD3100, a highly selective CXC-chemokine receptor 4 (CXCR4) antagonist, was used to inhibit microglia migration. Microglia was evaluated by immunofluorescence in vivo, and their migration was tested by transwell assay in vitro. Expressions of cytokines were detected by real-time PCR. Infarct volume was determined by triphenyltetrazolium chloride (TTC) staining. Functional recovery of tMCAO rats was evaluated by behavior tests. RESULTS: M1 microglia in the IBZ was rapidly increased within 3 days after tMCAO, accompanied with enhanced expression of CXCR4. Chemokine CXC motif chemokine ligand 12 (CXCL12) was also increased in the IBZ. And AMD3100 could obviously decline M1 microglia migration induced by CXCL12 and secretion of related inflammatory cytokines in the IBZ after stroke. This was accompanied by significant attenuated infarct volume and improved neurological outcomes. CONCLUSION: This study confirms the protective efficacy of inhibiting microglia migration at the hyperacute phase as a therapeutic strategy for ischemic stroke in tMCAO model of rats, and its therapeutic time window could last for 24 h after cerebral ischemia reperfusion. PMID- 27991730 TI - European Pain Federation position paper on appropriate opioid use in chronic pain management. AB - : Poorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi-faceted treatment programme in circumstances where more simple measures have failed. Throughout, all patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to yield the desired results and/or the patient is additionally burdened by an unacceptable level of adverse effects, the overall management strategy must be reviewed and revised. No responsible clinician will wish to pursue a failed treatment strategy or persist with an ineffective and burdensome treatment. In a considered attempt to empower and inform non-specialist opioid prescribers, EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper on appropriate opioid use in chronic pain. The expert panel reviewed the available literature and harnessed the experience of many years of clinical practice to produce these series of recommendations. Its success will be judged on the extent to which it contributes to an improved pain management experience for chronic pain patients across Europe. SIGNIFICANCE: This position paper provides expert recommendations for primary care physicians and other non- specialist healthcare professionals in Europe, particularly those who do not have ready access to specialists in pain medicine, on the safe and appropriate use of opioid medications as part of a multi-faceted approach to pain management, in properly selected and supervised patients. PMID- 27991731 TI - Novel treatment concepts in Hodgkin lymphoma. AB - Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid-1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long-term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18- to 65-year-old patients diagnosed during the period 1992 2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high-dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life-prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first- or second-line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long-term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors. PMID- 27991733 TI - Geneticists, health professionals suggest recasting requests to test children for adult-onset diseases: New study explores parents' reasons for seeking predictive genetic testing. PMID- 27991732 TI - Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. AB - DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown-Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML. (c) 2016 Wiley Periodicals, Inc. PMID- 27991734 TI - Advocates call for long-term extension of the FDA's rare pediatric disease priority review program: Federal voucher program considered instrumental in shortening drug review, approval period. PMID- 27991736 TI - KMT2D p.Gln3575His segregating in a family with autosomal dominant choanal atresia strengthens the Kabuki/CHARGE connection. AB - Choanal atresia is rarely reported in Kabuki syndrome, but is a common feature of CHARGE syndrome. Otherwise, the two conditions have a number of overlapping features, and the molecular links between them have recently been elucidated. Here, we report a case of a mother and her two children who presented with congenital choanal atresia. We performed whole exome sequencing on DNA from the mother and her two unaffected parents, and identified a de novo, novel variant in KMT2D. KMT2D p.Gln3575His segregated with disease status in the family, and is associated with a unique and conserved phenotype in the affected family members, with features overlapping with Kabuki and CHARGE syndromes. Our findings further support the potential etiological link between these two classically distinct conditions. (c) 2016 Wiley Periodicals, Inc. PMID- 27991739 TI - Paediatric HUS Cases Related to the Consumption of Raw Milk Sold by Vending Machines in Italy: Quantitative Risk Assessment Based on Escherichia coli O157 Official Controls over 7 years. AB - A quantitative risk assessment (RA) was developed to estimate haemolytic-uremic syndrome (HUS) cases in paediatric population associated with the consumption of raw milk sold in vending machines in Italy. The historical national evolution of raw milk consumption phenomenon since 2008, when consumer interest started to grow, and after 7 years of marketing adjustment, is outlined. Exposure assessment was based on the official Shiga toxin-producing Escherichia coli O157:H7 (STEC) microbiological records of raw milk samples from vending machines monitored by the regional Veterinary Authorities from 2008 to 2014, microbial growth during storage, consumption frequency of raw milk, serving size, consumption preference and age of consumers. The differential risk considered milk handled under regulation conditions (4 degrees C throughout all phases) and the worst time temperature field handling conditions detected. In case of boiling milk before consumption, we assumed that the risk of HUS is fixed at zero. The model estimates clearly show that the public health significance of HUS cases due to raw milk STEC contamination depends on the current variability surrounding the risk profile of the food and the consumer behaviour has more impact than milk storage scenario. The estimated HUS cases predicted by our model are roughly in line with the effective STEC O157-associated HUS cases notified in Italy only when the proportion of consumers not boiling milk before consumption is assumed to be 1%. Raw milk consumption remains a source of E. coli O157:H7 for humans, but its overall relevance is likely to have subsided and significant caution should be exerted for temporal, geographical and consumers behaviour analysis. Health education programmes and regulatory actions are required to educate people, primarily children, on other STEC sources. PMID- 27991738 TI - Down syndrome in diverse populations. AB - Down syndrome is the most common cause of cognitive impairment and presents clinically with universally recognizable signs and symptoms. In this study, we focus on exam findings and digital facial analysis technology in individuals with Down syndrome in diverse populations. Photos and clinical information were collected on 65 individuals from 13 countries, 56.9% were male and the average age was 6.6 years (range 1 month to 26 years; SD = 6.6 years). Subjective findings showed that clinical features were different across ethnicities (Africans, Asians, and Latin Americans), including brachycephaly, ear anomalies, clinodactyly, sandal gap, and abundant neck skin, which were all significantly less frequent in Africans (P < 0.001, P < 0.001, P < 0.001, P < 0.05, and P < 0.05, respectively). Evaluation using a digital facial analysis technology of a larger diverse cohort of newborns to adults (n = 129 cases; n = 132 controls) was able to diagnose Down syndrome with a sensitivity of 0.961, specificity of 0.924, and accuracy of 0.943. Only the angles at medial canthus and ala of the nose were common significant findings amongst different ethnicities (Caucasians, Africans, and Asians) when compared to ethnically matched controls. The Asian group had the least number of significant digital facial biometrics at 4, compared to Caucasians at 8 and Africans at 7. In conclusion, this study displays the wide variety of findings across different geographic populations in Down syndrome and demonstrates the accuracy and promise of digital facial analysis technology in the diagnosis of Down syndrome internationally. (c) 2016 Wiley Periodicals, Inc. PMID- 27991740 TI - Determination of rabeprazole enantiomers in dog plasma by supercritical fluid chromatography tandem mass spectrometry and its application to a pharmacokinetic study. AB - Rabeprazole is a novel benzimidazole proton pump inhibitor used for the treatment of gastrointestinal disorders. It is a chiral molecule that gives rise to the possibility of stereoselective pharmacokinetics. To investigate this phenomenon, a rapid and sensitive chiral assay based on supercritical fluid chromatography tandem mass spectrometry was developed and applied to the determination of (R) rabeprazole and (S)-rabeprazole in dog plasma. Sample preparation involved protein precipitation with acetonitrile after the addition of (R)-lansoprazole as internal standard. Baseline separation of enantiomers in 4.5 min was achieved on an Acquity UPC2 system using an ACQUITY UPC2 Trefoil CEL2 column maintained at 60 degrees C and a mobile phase consisting of methanol/CO2 (30:70, v/v) delivered at 2.5 mL/min. Detection was achieved by multiple reaction monitoring of the transitions at m/z 360.0->242.2 (rabeprazole) and 370.3->252.0 (internal standard) in the positive ion mode. The assay was linear in the range of 1-1000 ng/mL and free of matrix effects. Intra- and interday precisions were less than 10.0% with accuracy in the range of -2.6 to 3.1%. The method was successfully applied to a pharmacokinetic study of rabeprazole enantiomers after administration of a single oral dose of 10 mg racemate to beagle dogs. PMID- 27991741 TI - 4beta-Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State. AB - Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4beta-hydroxycholesterol (4betaOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs). The 4betaOHC was compared in 41 patients before and 2-5 months after initiating TNFalpha inhibitors (n = 31), IL-6 inhibitors (n = 5), or B-cell inhibitors (n = 5). Correlations between 4betaOHC and inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs. 4betaOHC did not differ following bDMARD treatment (P = 0.6), nor in patients who started with IL-6 inhibitors (median 51.6 vs. 50.6 nmol/L). The 4betaOHC and CRP/ESR did not correlate before treatment (P > 0.5), but correlated significantly after bDMARDs (CRP = Spearman r -0.40; P < 0.01; ESR = r -0.34; P = 0.028) suggesting that mainly non-CYP3A4-suppressive cytokines were reduced during treatment. Thus, this study does not support a generally regained CYP3A4 phenotype in patients with RA following initiation of bDMARDs. PMID- 27991744 TI - Erratum. PMID- 27991743 TI - Vector synthesis high-resolution electrocardiography, atrial natriuretic peptide and N-terminal prohormone brain natriuretic peptide for estimation of cardiac load in pregnancy. AB - AIM: We analyzed atrial natriuretic peptide (ANP), N-terminal pro-brain natriuretic natriuretic peptide (NT-proBNP) and vector synthesis high-resolution electrocardiography (ECG), to estimate cardiac load with circulatory dynamic change from pregnancy through the post-partum period. METHODS: The subjects were singleton pregnant women (n = 19), who were divided into three stages: stage 1, 34-36 weeks of gestation; stage 2, 2-6 post-partum days; and stage 3, 1-3 months after delivery. Vector synthesis high-resolution ECG, ANP and NT-proBNP were analyzed for all subjects. RESULTS: A pregnant woman with massive uterin liomyoma expressed largest the corrected recover time (RTc) dispersion in I + II of tow Dimensional (2D) color distribution map ANP and NT-proBNP were significantly higher in stage 2 than in stages 1 and 3. CONCLUSIONS: ANP, NT-proBNP and vector synthesis high-resolution ECG there might be able to evaluate cardiac load of normal pregnancy. PMID- 27991742 TI - Novel approach to uterine artery pseudoaneurysm embolization for delayed post partum hemorrhage. AB - Uterine artery pseudoaneurysms (UAP) are a rare cause of post-partum hemorrhage. Conservative management is discouraged due to the risk of spontaneous hemorrhage. Intra-arterial embolization is highly successful (>90%) and offers definitive treatment. We present the case of a 27-year-old woman with significant delayed post-partum hemorrhage after cesarean section who was found to have a UAP on imaging. Her tortuous vascular anatomy and spasmodic aneurysmal neck presented technical challenges to embolization with traditional material, such as gel foam and coils. Intra-arterial thrombin was then employed with good technical and clinical outcome. To our knowledge, this is the first case describing the use of intra-arterial thrombin in the treatment of UAP. Given its success in this case, we argue that intra-arterial thrombin should be considered a viable alternative for embolization of UAP when more traditional techniques fail. PMID- 27991745 TI - Ovarian transmigration of intrauterine device. AB - Extrauterine translocation of intrauterine device (IUD) to peritoneal cavity is an uncommon event, moreover the ovarian embedding of a transmigrated IUD is very rare, and only two previous cases have been reported in the literature. We present a single case treated with laparoscopy. The aims of this study were to focus attention on the utility of preoperative computed tomography in planning the best surgical approach and to describe the two-port technique. PMID- 27991746 TI - Rural Medicare Advantage Market Dynamics and Quality: Historical Context and Current Implications. AB - Purpose. In this policy brief, we assess variation in Medicare's star quality ratings of Medicare Advantage (MA) plans that are available to rural beneficiaries. Evidence from the recent Centers for Medicare & Medicaid Services (CMS) quality demonstration suggests that market dynamics, i.e., firms entering and exiting the MA marketplace, play a role in quality improvement. Therefore, we also discuss how market dynamics may impact the smaller and less wealthy populations that are characteristic of rural places. Key Data Findings. (1) Highly rated MA plans serving rural Medicare beneficiaries are more likely to be health maintenance organizations (HMOs) and local preferred provider organizations (PPOs), as opposed to regional PPOs. HMOs and local PPOs may be better able to improve their quality scores strategically in response to the bonus payment incentive due to existing internal monitoring mechanisms. (2) On average, the rural enrollment rate is lower in plans with higher quality scores (59 percent) than the corresponding urban rate (71 percent). This differential is likely due, in part, to lack of availability of highly rated plans in rural areas: 17.8 percent of rural counties lacked access to a plan with four or more (out of five) stars, while just 3.7 percent of urban counties lacked such access. (3) MA plans with high quality scores have been operating longer, on average, and have a lower percentage of rural counties within their contract service areas than plans with lower quality scores. PMID- 27991747 TI - Medicare Advantage Enrollment Update 2016. AB - Purpose. The RUPRI Center for Rural Health Policy Analysis reports annually on rural beneficiary enrollment in Medicare Advantage (MA) plans, noting any trends or new developments evident in the data. These reports are based on data through March of each year, capturing results of open enrollment periods. Key Findings. (1)The number of non-metropolitan beneficiaries enrolled in MA and other prepaid plans increased to 2,189,300 as of March 2016, representing 21.8 percent of all non-metropolitan Medicare beneficiaries compared with 31.5 percent of beneficiaries enrolled in MA and other prepaid plans nationally. (2) While non metropolitan enrollment continued to increase through March 2016, the annual growth rate slowed to 5.5 percent, compared to 6.8 percent between March 2014 and March 2015. (3) Enrollment in private fee-for-service MA plans continued to decline, both nationally and in non-metropolitan counties, while enrollment in other types of MA plans increased. (4) The states with the highest percentage of non-metropolitan beneficiaries enrolled in MA plans continued to be Minnesota, Hawaii, Pennsylvania, Wisconsin, and New York, ranging from a high of 53.4 percent in Minnesota to 32.6 percent in New York. (5) Non-metropolitan beneficiary enrollment (counts) in MA plans declined in five states: Hawaii, Idaho, Ohio, Washington, and Wyoming. PMID- 27991748 TI - Spread of Accountable Care Organizations in Rural America. AB - Purpose. The RUPRI Center for Rural Health Policy Analysis continues to monitor the spread of Medicare accountable care organizations (ACOs) into rural U.S. counties to determine whether this model appeals to rural providers and health systems. The RUPRI Center's periodic reports reveal trends in rural ACO activity; this brief follows one released in July 2013, with data through December 2015. Key Findings. The following findings are based on activity through 2015: (1) Medicare ACOs operate in 41.8 percent of all nonmetropolitan counties. (2) Non metropolitan provider participation in ACOs has increased considerably since 2013, especially in the South, West, and Northeast census regions. (3) The 101 new ACO entrants in 2016 included at least 43 ACOs with providers in non metropolitan areas. PMID- 27991749 TI - Medicare Accountable Care Organizations: Quality Performance by Geographic Categories. AB - Purpose. This policy brief continues the work of the RUPRI Center analyzing the performance of Medicare Accountable Care Organizations (ACOs) serving rural areas. In this brief, we examine the differences in performance on four domains of quality measures and the overall quality score among Medicare Shared Savings ACOs with different levels of rural presence. Key Findings. (1) ACOs located in rural counties performed better than those in urban counties on Care Coordination/Patient Safety, Preventive Health, and At-Risk Population domain scores and the overall quality score in 2014. (2) Urban ACOs performed better than ACOs in other geographic categories on the Patient/Caregiver Experience score in 2014. (3) ACOs in all geographic categories improved their quality performance between 2014 and 2015. PMID- 27991750 TI - Fabrication of Patterned Thermoresponsive Microgel Strips on Cell-Adherent Background and Their Application for Cell Sheet Recovery. AB - Interfaces between materials and cells play a critical role in cell biomedical applications. Here, a simple, robust, and cost-effective method is developed to fabricate patterned thermoresponsive poly(N-isopropylacrylamide-co-styrene) microgel strips on a polyethyleneimine-precoated, non-thermoresponsive cell adherent glass coverslip. The aim is to investigate whether cell sheets could be harvested from these cell-adherent surfaces patterned with thermoresponsive strips comprised of the microgels. We hypothesize that if the cell-to-cell interaction is strong enough to retain the whole cell sheet from disintegration, the cell segments growing on the thermoresponsive strips may drag the cell segments growing on the cell-adherent gaps to detach, ending with a whole freestanding and transferable cell sheet. Critical value concerning the width of the thermoresponsive strip and its ratio to the non-thermoresponsive gap may exist for cell sheet recovery from this type of surface pattern. To obtain this critical value, a series of strip patterns with various widths of thermoresponsive strip and non-thermoresponsive gap were prepared using negative microcontact printing technology, with COS7 fibroblast cells being used to test the growth and detachment. The results unraveled that COS7 cells preferentially attached and proliferated on the cell-adherent, non-thermoresponsive gaps to form patterned cell layers and that they subsequently proliferated to cover the microgel strips to form a confluent cell layer. Intact COS7 cell sheets could be recovered when the width of the thermoresponsive strip is no smaller than that of the non-thermoresponsive gap. Other cells such as HeLa, NIH3T3, 293E, and L929 could grow similarly; that is, they showed initial preference to the non thermoresponsive gaps and then migrated to cover the entire patterned surface. However, it was difficult to detach them as cell sheets due to the weak interactions within the cell layers formed. In contrast, when COS7 and HeLa cells were cultured successively, they formed the cocultured cell layer that could be detached together. These freestanding patterned cell sheets could lead to the development of more elaborate tumor models for drug targeting and interrogation. PMID- 27991751 TI - Regulating the Catalytic Function of Reduced Graphene Oxides Using Capping Agents for Metal-Free Catalysis. AB - Reduced graphene oxide (rGO) functionalized with organic capping agents has gained increasing attention as a promising metal-free catalyst. To optimize the properties of rGO for target applications, comprehending the link between the catalytic function of rGO and the chemical and structural characteristics of capping agents is critical. Herein, we report a systematic study on the effect of capping agents on the catalytic function of rGO for redox reactions using nitrogen-containing surface modifiers with distinctly different chemical structures, such as poly(diallyldimethylammonium chloride), cetyltrimethylammonium chloride, and poly(allylamine hydrochloride), which have the capability to endow rGO with improved suspension stability, enhanced reactant adsorption, and modified electronic properties. Functionalized rGOs were facilely prepared by the reduction of graphene oxide with hydrazine in the presence of the capping agents. The results of model redox reactions, that is, 4-nitrophenol and ferricyanide reduction reactions, catalyzed by the functionalized rGOs corroborated that the way the capping agents functionalize rGO, which is highly correlated with their chemical structure, drastically influences the overall reaction kinetics, including induction time, reduction rate, total reaction time, and reaction order. This strongly suggests that the judicious selection of capping agents is crucial to fully harness the catalytic function of rGO and thus to design novel rGO-based non-metallic catalysts with controllable reaction kinetics. PMID- 27991752 TI - Encapsulation of Perovskite Nanocrystals into Macroscale Polymer Matrices: Enhanced Stability and Polarization. AB - Lead halide perovskites hold promise for photonic devices, due to their superior optoelectronic properties. However, their use is limited by poor stability and toxicity. We demonstrate enhanced water and light stability of high-surface-area colloidal perovskite nanocrystals by encapsulation of colloidal CsPbBr3 quantum dots into matched hydrophobic macroscale polymeric matrices. This is achieved by mixing the quantum dots with presynthesized high-molecular-weight polymers. We monitor the photoluminescence quantum yield of the perovskite-polymer nanocomposite films under water-soaking for the first time, finding no change even after >4 months of continuous immersion in water. Furthermore, photostability is greatly enhanced in the macroscale polymer-encapsulated nanocrystal perovskites, which sustain >1010 absorption events per quantum dot prior to photodegradation, a significant threshold for potential device use. Control of the quantum dot shape in these thin-film polymer composite enables color tunability via strong quantum-confinement in nanoplates and significant room temperature polarized emission from perovskite nanowires. Not only does the high-molecular-weight polymer protect the perovskites from the environment but also no escaped lead was detected in water that was in contact with the encapsulated perovskites for months. Our ligand-passivated perovskite-macroscale polymer composites provide a robust platform for diverse photonic applications. PMID- 27991753 TI - Three-Dimensional Hierarchical NixCo1-xO/NiyCo2-yP@C Hybrids on Nickel Foam for Excellent Supercapacitors. AB - Active materials and special structures of the electrode have decisive influence on the electrochemical properties of supercapacitors. Herein, three-dimensional (3D) hierarchical NixCo1-xO/NiyCo2-yP@C (denoted as NiCoOP@C) hybrids have been successfully prepared by a phosphorization treatment of hierarchical NixCo1-xO@C grown on nickel foam. The resulting NiCoOP@C hybrids exhibit an outstanding specific capacitance and cycle performance because they couple the merits of the superior cycling stability of NixCo1-xO, the high specific capacitance of NiyCo2 yP, the mechanical stability of carbon layer, and the 3D hierarchical structure. The specific capacitance of 2638 F g-1 can be obtained at the current density of 1 A g-1, and even at the current density of 20 A g-1, the NiCoOP@C electrode still possesses a specific capacitance of 1144 F g-1. After 3000 cycles at 10 A g 1, 84% of the initial specific capacitance is still remained. In addition, an asymmetric ultracapacitor (ASC) is assembled through using NiCoOP@C hybrids as anode and activated carbon as cathode. The as-prepared ASC obtains a maximum energy density of 39.4 Wh kg-1 at a power density of 394 W kg-1 and still holds 21 Wh kg-1 at 7500 W kg-1. PMID- 27991754 TI - Ultrafine Co-based Nanoparticle@Mesoporous Carbon Nanospheres toward High Performance Supercapacitors. AB - A general synthetic methodology is reported to grow ultrafine cobalt-based nanoparticles (NPs, 2-7 nm) within high-surface-area mesoporous carbon (MC) frameworks. Our design strategy is based on colloidal amphiphile (CAM) templated oxidative self-polymerization of dopamine. The CAM templates consisting of a hydrophobic silica-like core and a hydrophilic PEO shell can coassemble with dopamine and template its self-polymerization to form polydopamine (PDA) nanospheres. Given that PDA has rich binding sites such as catechol and amine to coordinate metal ions (e.g., Co2+), PDA nanospheres containing Co2+ ions can be converted into hierarchical porous carbon frameworks containing ultrafine metallic Co NPs (Co@MC) using high-temperature pyrolysis. The CAM templates offer strong "nanoconfinements" to prevent the overgrowth of Co NPs within carbon frameworks. The yielded ultrafine Co NPs have an average size of <7 nm even at a very high loading of 65 wt %. Co@MC can be further converted into various oxides and sulfides, e.g., CoO, Co3O4, CoS2 and transition-metal doped bimetallic CoxM1 xS2, without significantly changing the size of NPs. As a proof-of-concept application, the porous Co-based NPs@MC hybrids were used as electrode materials for supercapacitors, which exhibit excellent supercapacitive performance with outstanding long-term cycling stability, due to the features such as ultrafine size, controllable chemical compositions, hierarchical porous structures, and full coverage of conductive carbons. PMID- 27991755 TI - Thiol-ol Chemistry for Grafting of Natural Polymers to Form Highly Stable and Efficacious Antibacterial Coatings. AB - Bacterial contamination of surfaces and the associated infection risk is a significant threat to human health. Some natural antibacterial polymers with low toxicity are promising coating materials for alleviating pathogenic colonization on surfaces. However, widespread application of these polymers as antibacterial coatings is constrained by coating techniques which are not easily scalable due to stringent reaction conditions. Herein, thiol-ol reaction involving oxidative conjugation between thiol and hydroxyl groups is demonstrated as a facile technique to graft two natural polymer derivatives, agarose (AG) and quaternized chitosan (QCS), as antibacterial coatings on polymer and metal substrates. The substrate surfaces are first treated with oxygen plasma followed by UV-induced grafting of the polymers under atmospheric conditions. Dimercaprol, a FDA approved drug, is used as both surface anchor and cross-linker of the polymer chains during grafting. The AG coating achieves >2 log reduction in Pseudomonas aeruginosa and Staphylococcus aureus biofilm formation, while the QCS coating reduces bacterial count from contaminated droplets on its surface by >95%. The coatings are noncytotoxic and exhibits a high degree of stability under conditions expected in their potential applications as antibacterial coating for biomedical devices (for AG), and for preventing pathogen transmission in the environment (for QCS). PMID- 27991756 TI - High-Performance Field-Emission Properties of Boron Nitride Nanotube Field Emitters. AB - Boron nitride nanotubes (BNNTs) have attracted considerable attention as a field emission material because of their high mechanical strength, high negative electron affinity, and high oxidation resistance. Nevertheless, the obtained field-emission properties of BNNTs have indicated poor emission performance, which is a very high turn-on electric field with a low emission current. We fabricated BNNT field emitters and investigated their field-emission properties. The field-emission properties of the BNNT field emitters were considerably enhanced compared to those of other BN nanomaterial-based field emitters. The turn-on and the threshold electric fields of the BNNT field emitter were 3.1 and 5.4 V/MUm at the gap distance of 750 MUm, respectively. Both the turn-on and the threshold electric fields of the BNNT field emitters were decreased by increasing the gap distance between the emitter tip and the anode electrode. Degradation of the emission current during field emission operation for 20 h showed no significant difference according to the gap distance. Emission current fluctuation of the BNNT field emitters showed that the smaller gap was more unstable than the larger gap. The enhanced emission properties are mainly attributed to the small diameter, high-quality, and straight structure of BNNTs as well as the stable network formation of the BNNT film with good mechanical and electrical contact between the BNNTs and the cathode electrode. The remarkable emission performance of the BNNT field emitters might have promising applications for various field-emission devices. PMID- 27991757 TI - Conformal Coating of a Phase Change Material on Ordered Plasmonic Nanorod Arrays for Broadband All-Optical Switching. AB - Actively tunable optical transmission through artificial metamaterials holds great promise for next-generation nanophotonic devices and metasurfaces. Plasmonic nanostructures and phase change materials have been extensively studied to this end due to their respective strong interactions with light and tunable dielectric constants under external stimuli. Seamlessly integrating plasmonic components with phase change materials, as demonstrated in the present work, can facilitate phase change by plasmonically enabled light confinement and meanwhile make use of the high sensitivity of plasmon resonances to the variation of dielectric constant associated with the phase change. The hybrid platform here is composed of plasmonic indium-tin-oxide nanorod arrays (ITO-NRAs) conformally coated with an ultrathin layer of a prototypical phase change material, vanadium dioxide (VO2), which enables all-optical modulation of the infrared as well as the visible spectral ranges. The interplay between the intrinsic plasmonic nonlinearity of ITO-NRAs and the phase transition induced permittivity change of VO2 gives rise to spectral and temporal responses that cannot be achieved with individual material components alone. PMID- 27991758 TI - Simple and Cost-Effective Glucose Detection Based on Carbon Nanodots Supported on Silver Nanoparticles. AB - We present a new glucose oxidase (GOx)-mediated strategy for detecting glucose based on carbon nanodots supported on silver nanoparticles (C-dots/AgNPs) as nanocomplexes. The strategy involves three processes: quenching of C-dots' fluorescence by AgNPs, production of H2O2 from GOx-catalyzed oxidation of glucose, and H2O2-induced etching of AgNPs. In the C-dots/AgNPs complex, AgNPs act as a "nanoquencher" to decrease C-dots fluorescence by surface plasmon enhanced energy transfer (SPEET) from C-dots (donor) to AgNPs (acceptor). The H2O2 formed by GOx-catalyzed oxidation of glucose etches the AgNPs to silver ions, thus freeing the C-dots from the AgNPs surfaces and restoring the C-dots' fluorescence. Therefore, the increase in fluorescence depends directly on the concentration of H2O2, which, in turn, depends on the concentration of glucose. The strategy allows the quantitative analysis of glucose with a detection limit of 1.39 MUM. The method based on C-dots/AgNPs offers the following advantages: simplicity of design and facile preparation of nanomaterials, as well as low experimental cost, because chemical modification and separation procedures are not needed. PMID- 27991759 TI - Photoelectrochemical Properties and Behavior of alpha-SnWO4 Photoanodes Synthesized by Hydrothermal Conversion of WO3 Films. AB - Metal oxides with moderate band gaps are desired for efficient production of hydrogen from sunlight and water via photoelectrochemical (PEC) water splitting. Here, we report an alpha-SnWO4 photoanode synthesized by hydrothermal conversion of WO3 films that achieves photon to current conversion at wavelengths up to 700 nm (1.78 eV). This photoanode is promising for overall PEC water-splitting because the flat-band potential and voltage of photocurrent onset are more negative than the potential of hydrogen evolution. Furthermore, the photoanode utilizes a large portion of the solar spectrum. However, the photocurrent density reaches only a small fraction of that which is theoretically possible. Density functional theory based thermodynamic and electronic structure calculations were performed to elucidate the nature and impact of defects in alpha-SnWO4 prepared by this synthetic route, from which hole localization at Sn-at-W antisite defects was determined to be a likely cause for the poor photocurrent. Measurements further showed that the photocurrent decreases over time due to surface oxidation, which was suppressed by improving the kinetics of hole transfer at the semiconductor/electrolyte interface. Alternative synthetic methods and the addition of protective coatings and/or oxygen evolution catalysts are suggested to improve the PEC performance and stability of this promising alpha-SnWO4 material. PMID- 27991760 TI - Detection of Reactive Oxygen Species by a Carbon-Dot-Ascorbic Acid Hydrogel. AB - Detection of reactive oxygen species (ROS) is important in varied biological processes, disease diagnostics, and chemotherapeutic drug screening. We constructed a ROS sensor comprising an ascorbic-acid-based hydrogel encapsulating luminescent amphiphilic carbon-dots (C-dots). The sensing mechanism is based upon ROS-induced oxidation of the ascorbic acid units within the hydrogel scaffold; as a consequence, the hydrogel framework collapses resulting in aggregation of the C dots and quenching of their luminescence. The C-dot-hydrogel platform exhibits high sensitivity and detected ROS generated chemically in solution and in actual cell environments. We demonstrate application of the C-dot-hydrogel for evaluating the efficacy of a chemotherapeutic substance, underscoring the potential of the system for drug screening applications. PMID- 27991761 TI - Visualizing and Calculating Tip-Substrate Distance in Nanoscale Scanning Electrochemical Microscopy Using 3-Dimensional Super-Resolution Optical Imaging. AB - We report a strategy for the optical determination of tip-substrate distance in nanoscale scanning electrochemical microscopy (SECM) using three-dimensional super-resolution fluorescence imaging. A phase mask is placed in the emission path of our dual SECM/optical microscope, generating a double helix point spread function at the image plane, which allows us to measure the height of emitting objects relative to the focus of the microscope. By exciting both a fluorogenic reaction at the nanoscale electrode tip as well as fluorescent nanoparticles at the substrate, we are able to calculate the tip-substrate distance as the tip approaches the surface with precision better than 25 nm. Attachment of a fluorescent particle to the insulating sheath of the SECM tip extends this technique to nonfluorogenic electrochemical reactions. Correlated electrochemical and optical determination of tip-substrate distance yielded excellent agreement between the two techniques. Not only does super-resolution imaging offer a secondary feedback mechanism for measuring the tip-sample gap during SECM experiments, it also enables facile tip alignment and a strategy for accounting for electrode tilt relative to the substrate. PMID- 27991763 TI - The "PepSAVI-MS" Pipeline for Natural Product Bioactive Peptide Discovery. AB - The recent increase in extensively drug-resistant bacterial pathogens and the associated increase of morbidity and mortality demonstrate the immediate need for new antibiotic backbones with novel mechanisms of action. Here, we report the development of the PepSAVI-MS pipeline for bioactive peptide discovery. This highly versatile platform employs mass spectrometry and statistics to identify bioactive peptide targets from complex biological samples. We validate the use of this platform through the successful identification of known bioactive peptides from a botanical species, Viola odorata. Using this pipeline, we have widened the known antimicrobial spectrum for V. odorata cyclotides, including antibacterial activity of cycloviolacin O2 against A. baumannii. We further demonstrate the broad applicability of the platform through the identification of novel anticancer activities for cycloviolacins by their cytotoxicity against ovarian, breast, and prostate cancer cell lines. PMID- 27991764 TI - High-Throughput Lipidomic and Transcriptomic Analysis To Compare SP2/0, CHO, and HEK-293 Mammalian Cell Lines. AB - A combined lipidomics and transcriptomics analysis was performed on mouse myeloma SP2/0, Chinese hamster ovary (CHO), and human embryonic kidney (HEK) cells in order to compare widely used mammalian expression systems. Initial thin layer chromatography (TLC) analysis indicated that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) were the major lipid components in all cell lines with lower amounts of sphingomyelin (SM) in SP2/0 compared to CHO and HEK, which was subsequently confirmed and expanded upon following mass spectrometry (MS) analysis. HEK contained 4-10-fold higher amounts of lyso phosphatidylethanolamine (LPE) and 2-4-fold higher amounts of lyso phosphatidylcholine (LPC) compared to SP2/0 and CHO cell lines. C18:1 followed by C16:1 were the main contributors to the difference in both LPE and LPC levels. Alternatively, the SP2/0 cell line exhibited 30-65-fold lower amounts of SM principally in the amount of 16:0. By mapping the transcriptomics data to KEGG pathways, we found expression levels of secretory phospholipase A2 (sPLA2), lysophospholipid acyltransferase (LPEAT), lysophosphatidylcholine acyltransferase (LPCAT), and lysophospholipase (LYPLA) can contribute to the differences in LPE and LPC. Sphingomyelin synthases (SMS) and sphingomyelin phosphodiesterase (SMase) enzymes may play roles in SM differences across the three cell lines. The results of this study provide insights that will aid the understanding of the physiological and secretory differences across recombinant protein production systems. PMID- 27991762 TI - Tailoring the Edge Structure of Molybdenum Disulfide toward Electrocatalytic Reduction of Carbon Dioxide. AB - Electrocatalytic conversion of carbon dioxide (CO2) into energy-rich fuels is considered to be the most efficient approach to achieve a carbon neutral cycle. Transition-metal dichalcogenides (TMDCs) have recently shown a very promising catalytic performance for CO2 reduction reaction in an ionic liquid electrolyte. Here, we report that the catalytic performance of molybdenum disulfide (MoS2), a member of TMDCs, can be significantly improved by using an appropriate dopant. Our electrochemical results indicate that 5% niobium (Nb)-doped vertically aligned MoS2 in ionic liquid exhibits 1 order of magnitude higher CO formation turnover frequency (TOF) than pristine MoS2 at an overpotential range of 50-150 mV. The TOF of this catalyst is also 2 orders of magnitude higher than that of Ag nanoparticles over the entire range of studied overpotentials (100-650 mV). Moreover, the in situ differential electrochemical mass spectrometry experiment shows the onset overpotential of 31 mV for this catalyst, which is the lowest onset potential for CO2 reduction reaction reported so far. Our density functional theory calculations reveal that low concentrations of Nb near the Mo edge atoms can enhance the TOF of CO formation by modifying the binding energies of intermediates to MoS2 edge atoms. PMID- 27991765 TI - Cation Mixing Properties toward Co Diffusion at the LiCoO2 Cathode/Sulfide Electrolyte Interface in a Solid-State Battery. AB - All-solid-state Li-ion batteries (ASS-LIBs) are expected to be the next generation battery, however, their large interfacial resistance hinders their widespread application. To understand and resolve the possible causes of this resistance, we examined mutual diffusion properties of the cation elements at LiCoO2 (LCO) cathode/beta-Li3PS4 (LPS) solid electrolyte interface as a representative system as well as the effect of a LiNbO3 buffer layer by first principles calculations. Evaluating energies of exchanging ions between the cathode and the electrolyte, we found that the mixing of Co and P is energetically preferable to the unmixed states at the LCO/LPS interface. We also demonstrated that the interposition of the buffer layer suppresses such mixing because the exchange of Co and Nb is energetically unfavorable. Detailed analyses of the defect levels and the exchange energies by using the individual bulk crystals as well as the interfaces suggest that the lower interfacial states in the energy gap can make a major contribution to the stabilization of the Co <-> P exchange, although the anion bonding preference of Co and P as well as the electrostatic interactions may have effects as well. Finally, the Co <-> P exchanges induce interfacial Li sites with low chemical potentials, which enhance the growth of the Li depletion layer. These atomistic understandings can be meaningful for the development of ASS-LIBs with smaller interfacial resistances. PMID- 27991766 TI - Magnetically Actuated Droplet Manipulation and Its Potential Biomedical Applications. AB - Droplet manipulation has found broad applications in various engineering and biomedical fields, such as biochemistry, microfluidic systems, drug delivery, and tissue engineering. Many methods have been developed to enhance the ability for manipulating droplets, among which magnetically actuated droplet manipulation has attracted widespread interests due to its remote, noninvasive manipulation ability and biocompatibility. This review summarizes the approaches and their principles that enable actuating the droplet magnetically. The potential biomedical applications of such a technique in bioassay, cell assembly, and tissue engineering are given. PMID- 27991767 TI - Exploring the Gas Phase Synthesis of the Elusive Class of Boronyls and the Mechanism of Boronyl Radical Reactions under Single Collision Conditions. AB - Until recently, the chemistry of boronyl (BO), a diatomic radical isolectronic with the cyano (CN) species, has remained unknown. The boronyl group is characterized by a boron-oxygen multiple bond, and because of the inherent electron deficiency of the boron atom, boronyls (RBO) are highly reactive and typically only exist in their cyclotrimeric form (RBO)3. Due to their invaluable role as reactants, the isolation of the monomers in gas phase experiments has been extensively sought after by the organic synthesis and physical organic chemistry communities but never achieved. Besides the interests from a physical organic and synthetic point of view, boronyls also play a role as reaction intermediates in boron-assisted rocket propulsion systems. In this Account, we review recent experimental work in which gas phase organo boronyl monomers (RBO) are formed via bimolecular reactions of the boronyl radical (BO) with C2-C6 unsaturated hydrocarbons. The investigated hydrocarbons are widely exploited as fuels, and their reactions with boronyl radicals under single collision conditions lead to the formation of organo boronyls. Our studies also elucidate the mechanisms of their formation reactions thus furnishing a comprehension at the molecular level of this reaction class. The variety of the employed hydrocarbon substrates has allowed us to systematically classify the chemical behavior of the boronyl radicals. With the exception of the case of the dimethylacetylene reaction, the boron monoxide radical versus atomic hydrogen exchange mechanisms were always open leading to the formation of highly unsaturated organo boronyl monomers (RBO), which could be easily identified because they cannot trimerize under single collision conditions. Besides the hydrogen displacement pathway, methylacetylene, dimethylacetylene, and propylene, carrying one or two methyl groups, were also found to eliminate a methyl group. In all systems, the reactions were barrierless, indirect, and initiated by addition of the boron monoxide radical to the pi electron density of the hydrocarbon molecule, with the radical center located at the boron atom of the BO radical, thus leading to doublet radical intermediates. These intermediates either decompose via hydrogen or methyl loss or isomerize prior to their decomposition via atomic hydrogen or migration of the BO moiety. A consistent trend suggests that all exit transition states are rather tight with those involved in the hydrogen atom loss depicting exit barriers of typically 25 to 35 kJ mol-1, whereas the methyl loss pathways are associated with tighter exit transition states located about 30-50 kJ mol-1 above the separated products. Further, the overall energetics suggest that those bimolecular reactions are exoergic by 40-90 kJ mol-1. These findings confirm that this reaction class leads to the formation of highly unsaturated organo boronyl molecules. PMID- 27991768 TI - Surface-Plasmon-Coupled Fluorescence Enhancement Based on Ordered Gold Nanorod Array Biochip for Ultrasensitive DNA Analysis. AB - An innovative gold nanorod (GNR) array biochip was developed to systematically investigate the localized surface plasmon resonance (LSPR)-coupled fluorescence enhancement for signal amplification in molecular beacon detection. An ordered GNR assembly in vertical standing array on a glass surface was fabricated as plasmonic substrates, resulting in dramatically intensified LSPR between adjacent nanoparticles as compared to that from an ensemble of random nanorods. We have shown that the plasmonic response of the nanoarray can be tuned by the proper choice of GNR size to overlap the fluorophore excitation and emission wavelengths greater than 600 nm. Plasmon-induced fluorescence enhancement was found to be distance-dependent with the competition between quenching and enhancement by the metal nanostructures. The augmented fluorescence enhancement by the GNR array can efficiently overcome the quenching effect of the gold nanoparticle even at close proximity. The enhancement correlates with the spectral overlap between the fluorophore excitation/emission and the plasmonic resonance of the GNR array, indicating a surface-plasmon-enhanced excitation and radiative mechanism for the amplification. From these results, the applicability of the ordered GNR array chip was extended to molecular fluorescence enhancement for practical use as a highly functional and ultrasensitive plasmonic DNA biochip in molecular beacon fashion. PMID- 27991769 TI - Efficient Recovery of Neodymium in Acidic System by Free-Standing Dual-Template Docking Oriented Ionic Imprinted Mesoporous Films. AB - Neodymium (Nd) is critical component of sintered neodymium magnets. Separation of Nd from consumer magnets has attracted a widespread attention. In this paper, we presented free-standing ionic imprinted mesoporous film materials for facile and highly efficient targeted separation of Nd from permanent magnets by dual template docking oriented ionic imprinting (DTD-OII) method. DTD-OII is based on dual-template docking oriented molecular imprinting. Compared with conventional imprinting, this novel strategy does not need extra steps, but significantly advance imprinted efficiency. With optimization of functional monomer, our free standing dual-template docking oriented ionic imprinted mesoporous films exhibit excellent adsorption of Nd by solid-liquid extraction. The Nd adsorption capacity for optimized films was 34.98 mg g-1 under pH = 3.0. The distribution coefficient of Nd was 636 mL g-1, which indicates films possess significantly selectivity of Nd. In addition, efficient dual-template docking oriented ionic imprinting makes films demonstrating an outstanding of reusability by cycle test, which appreciating their potential for industrial application. PMID- 27991770 TI - Discrimination of Metalloproteins by a Mini Sensor Array Based on Bispyrene Fluorophore/Surfactant Aggregate Ensembles. AB - Fluorescent sensor arrays with pattern recognition ability have been widely used to detect and identify multiple chemically similar analytes. In the present work, two particular bispyrene fluorophores containing hydrophilic oligo(oxyethylene) spacer, 6 and 4, were synthesized, but one is with and the other is without cholesterol unit. Their ensembles with cationic surfactant (CTAB) assemblies realize multiple fluorescence responses to different metalloproteins, including hemoglobin, myoglobin, ferritin, cytochrome c, and alcohol dehydrogenase. The combination of fluorescence variation at monomer and excimer emission of the two binary sensor ensembles enables the mini sensor array to provide a specific fingerprint pattern to each metalloprotein. Linear discriminant analysis shows that the two-ensemble-sensor-based array could well discriminate the five tested metalloproteins. The present work realizes using a mini sensor array to accomplish discrimination of complex analytes like proteins. They also display a very high sensitivity to the tested metalloproteins with detection limits in the range of picomolar concentration. PMID- 27991771 TI - Hydrothermally Driven Transformation of Oxygen Functional Groups at Multiwall Carbon Nanotubes for Improved Electrocatalytic Applications. AB - The role of carbon nanotubes in the advancement of energy conversion and storage technologies is undeniable. In particular, carbon nanotubes have attracted significant applications for electrocatalysis. However, one central issue related to the use of carbon nanotubes is the required oxidative pretreatment that often leads to significant damage of graphitic structures which deteriorates their electrochemical properties. Traditionally, the oxidized carbon nanomaterials are treated at high temperature under an inert atmosphere to repair the oxidation induced defect sites, which simultaneously removes a significant number of oxygen functional groups. Nevertheless, recent studies have shown that oxygen functional groups on the surface of MWCNT are the essential active centers for a number of important electrocatalytic reactions such as hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR). Herein we first show that hydrothermal treatment as a mild method to improve the electrochemical properties and activities of surface-oxidized MWCNT for OER, HER, and ORR without significantly altering the oxygen content. The results indicate that hydrothermal treatment could potentially repair the defects without significantly reducing the pre-existing oxygen content, which has never been achieved before with conventional high-temperature annealing treatment. PMID- 27991772 TI - Reversibly Actuating Solid Janus Polymeric Fibers. AB - It is commonly assumed that the substantial element of reversibly actuating soft polymeric materials is chemical cross-linking, which is needed to provide elasticity required for the reversible actuation. On the example of melt spun and three-dimensional printed Janus fibers, we demonstrate here for the first time that cross-linking is not an obligatory prerequisite for reversible actuation of solid entangled polymers, since the entanglement network itself can build elasticity during crystallization. Indeed, we show that not-cross-linked polymers, which typically demonstrate plastic deformation in melt, possess enough elastic behavior to actuate reversibly. The Janus polymeric structure bends because of contraction of the polymer and due to entanglements and formation of nanocrystallites upon cooling. Actuation upon melting is simply due to relaxation of the stressed nonfusible component. This approach opens perspectives for design of solid active materials and actuator for robotics, biotechnology, and smart textile applications. The great advantage of our principle is that it allows design of non-cross-linked self-moving materials, which are able to actuate in both water and air, which are not cross-linked. We demonstrate application of actuating fibers for design of walkers, structures with switchable length, width, and thickness, which can be used for smart textile applications. PMID- 27991773 TI - All-Solution-Based Aggregation Control in Solid-State Photon Upconverting Organic Model Composites. AB - Hitherto, great strides have been made in the development of organic systems that exhibit triplet-triplet annihilation-induced photon-energy upconversion (TTA-UC). Yet, the exact role of intermolecular states in solid-state TTA-UC composites remains elusive. Here we perform a comprehensive spectroscopic study in a series of solution-processable solid-state TTA-UC organic composites with increasing segregated phase content for elucidating the impact of aggregate formation in their TTA-UC properties. Six different states of aggregation are reached in composites of the 9,10-diphenylanthracene (DPA) blue emitter mixed with the (2,3,7,8,12,13,17,18-octaethylporphyrinato)platinum(II) sensitizer (PtOEP) in a fixed nominal ratio (2 wt % PtOEP). Fine-tuning of the PtOEP and DPA phase segregation in these composites is achieved with a low-temperature solution processing protocol when three different solvents of increasing boiling point are alternatively used and when the binary DPA:PtOEP system is dispersed in the optically inert polystyrene (PS) matrix (PS:DPA:PtOEP). Time-gated (in the nanosecond and microsecond time scales) photoluminescence measurements identify the upper level of PtOEP segregation at which the PtOEP aggregate-based networks favor PtOEP triplet exciton migration toward the PtOEP:DPA interfaces and triplet energy transfer to the DPA triplet manifold. The maximum DPA TTA-UC luminescence intensity is ensured when the bimolecular annihilation constant of PtOEP remains close to gammaTTA-PtOEP = 1.1 * 10-13 cm3 s-1. Beyond this PtOEP segregation level, the DPA TTA-UC luminescence intensity decreases because of losses caused by the generation of PtOEP delayed fluorescence and DPA phosphorescence in the nanosecond and microsecond time scales, respectively. PMID- 27991774 TI - Abatement of Polychoro-1,3-butadienes in Aqueous Solution by Ozone, UV Photolysis, and Advanced Oxidation Processes (O3/H2O2 and UV/H2O2). AB - The abatement of 9 polychloro-1,3-butadienes (CBDs) in aqueous solution by ozone, UV-C(254 nm) photolysis, and the corresponding advanced oxidation processes (AOPs) (i.e., O3/H2O2 and UV/H2O2) was investigated. The following parameters were determined for 9 CBDs: second-order rate constants for the reactions of CBDs with ozone (kO3) (<0.1-7.9 * 103 M-1 s-1) or with hydroxyl radicals (k*OH) (0.9 * 109 - 6.5 * 109 M-1 s-1), photon fluence-based rate constants (k') (210-2730 m2 einstein-1), and quantum yields (Phi) (0.03-0.95 mol einstein-1). During ozonation of CBDs in a natural groundwater, appreciable abatements (>50% at specific ozone doses of 0.5 gO3/gDOC to ~100% at >=1.0 gO3/gDOC) were achieved for tetra-CBDs followed by (Z)-1,1,2,3,4-penta-CBD and hexa-CBD. This is consistent with the magnitude of the determined kO3 and k*OH. The formation of bromate, a potentially carcinogenic ozonation byproduct, could be significantly reduced by addition of H2O2. For a typical UV disinfection dose (400 J/m2), various extents of phototransformations (10-90%) could be achieved. However, the efficient formation of photoisomers from CBDs with E/Z configuration must be taken into account because of their potential residual toxicity. Under UV-C(254 nm) photolysis conditions, no significant effect of H2O2 addition on CBDs abatement was observed due to an efficient direct phototransformation of CBDs. PMID- 27991775 TI - A New Approach to Sampling Intact Fe Plaque Reveals Si-Induced Changes in Fe Mineral Composition and Shoot As in Rice. AB - The Fe (oxyhydr)oxide rind, or Fe plaque, that forms on aquatic plant roots is an important sorbent of metal(loid)s and plays a role in the attenuation of metal(loid) uptake into higher plants. However, the mineral composition of Fe plaque and thus its potential to sorb metal(loid)s is affected by solution chemistry. The predominant strategy to characterize Fe plaque using dithionite citrate-bicarbonate (DCB) extraction and elemental analysis reveals total Fe quantity but misses the mineral structure of the Fe (oxyhydr)oxide. Here, we developed a new technique using gentle sonication to sample intact Fe plaque from the root system and concentrate it for subsequent mineralogical characterization using synchrotron-based X-ray diffraction and X-ray absorption spectroscopy. We then coupled that data with conventional DCB extraction. The sample preparation method was effective at concentrating As-bound Fe plaque minerals in a uniform coating onto membranes that could easily be analyzed with X-ray techniques. Using these methods, we show that the percentage of poorly ordered Fe minerals in Fe plaque increases with increasing pore-water Si in flooded rice paddy soils. These findings have implications for understanding mineral controls on As cycling in the soil-rice nexus, and the sampling approach can be adopted for other aquatic plant systems. PMID- 27991776 TI - Capsaicin Inhibits Dimethylnitrosamine-Induced Hepatic Fibrosis by Inhibiting the TGF-beta1/Smad Pathway via Peroxisome Proliferator-Activated Receptor Gamma Activation. AB - Capsaicin (CPS) exerts many pharmacological effects, but any possible influence on liver fibrosis remains unclear. Therefore, we evaluated the inhibitory effects of CPS on dimethylnitrosamine (DMN) and TGF-beta1-induced liver fibrosis in rats and hepatic stellate cells (HSCs). CPS inhibited DMN-induced hepatotoxicity, NF kappaB activation, and collagen accumulation. CPS also suppressed the DMN-induced increases in alpha-SMA, collagen type I, MMP-2, and TNF-alpha. In addition, CPS inhibited DMN-induced TGF-beta1 expression (from 2.3 +/- 0.1 to 1.0 +/- 0.1) and Smad2/3 phosphorylation (from 1.5 +/- 0.1 to 1.1 +/- 0.1 and from 1.6 +/- 0.1 to 1.1 +/- 0.1, respectively) by activating Smad7 expression (from 0.1 +/- 0.0 to 0.9 +/- 0.1) via PPAR-gamma induction (from 0.2 +/- 0.0 to 0.8 +/- 0.0) (p < 0.05). Furthermore, in HSCs, CPS inhibited the TGF-beta1-induced increases in alpha-SMA and collagen type I expression, via PPAR-gamma activation. These results indicate that CPS can ameliorate hepatic fibrosis by inhibiting the TGF beta1/Smad pathway via PPAR-gamma activation. PMID- 27991777 TI - Facile Conversion of Ni(II) Cyclopropylchlorins into Novel beta-Substituted Porphyrins through Acid-Catalyzed Ring-Opening Reaction. AB - The conversion of cyclopropylchlorins into porphyrins represents a key step in the synthetic manipulation of macrocycles with tunable physical and chemical properties. Herein, we report a facile method for the synthesis of novel beta substituted porphyrins from cyclopropylchlorins. A series of Ni(II) cyclopropylchlorins was converted into the corresponding Ni(II) and free base porphyrins using TFA and H2SO4 under mild reaction conditions in good yields (75 86%). The new chlorins and porphyrins were characterized by various spectroscopic techniques and the single-crystal X-ray diffraction method. The reaction proceeds very fast (<5 min.) with complete conversion of chlorin into porphyrin with distinct color change. Facile conversion, shorter reaction time scale, and good yield (75-86%) without any side products are the significant features of this new protocol. These porphyrinoids exhibited red-shifted electronic spectral features with varying degrees nonplanar conformation, tunable redox properties, and porphyrin core basicity. PMID- 27991778 TI - Emission Enhancement and Color Tuning for GdVO4:Ln3+ (Ln = Dy, Eu) by Surface Modification at Single Wavelength Excitation. AB - The surface modification can realize systematically the emission enhancement of GdVO4:Ln3+ (Ln = Dy, Eu) microstructures and multicolor emission at single component. The structure, morphology, composition, and the surface ligands modification of as-prepared samples were studied in detail. It is found that the surface-modified ligands can act as sensitizer to improve the emission of the Eu3+ and Dy3+ ions via the energy transfer besides the VO43--Eu3+/Dy3+ process. More importantly, under a single wavelength excitation, the emission color can be effectively tuned by manipulating the doping ratio of the Eu3+ ions in the internal crystal lattice and the Tb3+ ions in the external surface ligands, simultaneously. And further, multicolor emissions are obtained under single wavelength excitation due to the high overlapping between the VO43- absorption and the pi-pi* electron transition of the ligands. These findings may open new avenues to design and develop new highly efficient luminescent materials. PMID- 27991779 TI - Rotational Dynamics of Diazabicyclo[2.2.2]octane in Isomorphous Halogen-Bonded Co crystals: Entropic and Enthalpic Effects. AB - Based on rotational dynamics measurements carried out with isomorphic co-crystals formed by halogen-bonding (XB) between tritylacetylene halides (TrX) and diazabicyclo[2.2.2]octane (dabco), we were able to distinguish the sources of the enthalpic and entropic components in the rotational free energy barrier. We describe the formation of the 1:1 co-crystals (TrX...N(R)3N) obtained from 1 equiv of dabco and 1 equiv of either TrI or TrBr, respectively, to give 4a and 4b instead of the potential 2:1 complexes. The co-crystals were prepared by solvent evaporation and mechanochemical synthesis. No co-crystal with TrCl was obtained, reflecting the weaker nature of the TrCl...NR3 interaction. Single-crystal X-ray diffraction confirmed structures that resemble a spinning top on a tripod and revealed that the two XB co-crystals are isomorphous, with slightly different C X...NR3 (X = I, Br) distances and packing interactions. Quadrupolar-echo 2H NMR experiments with 2H-labeled samples showed that fast rotation of dabco in these co-crystals follows a six-fold potential energy surface with three lowest energy minima. Variable-temperature 1H NMR spin-lattice relaxation (VT 1H T1) data revealed rotational dynamics with indistinguishable pre-exponential factors and small but distinguishable activation energies. The activation energy of 4b (Ea = 0.71 kcal mol-1) is the lowest reported in the field of amphidynamic crystals. Using the Eyring equation, we established that their activation entropy for rotation is small but negative (DeltaS? = -3.0 cal mol-1 K-1), while there is almost a 2-fold difference in activation enthalpies, with 4a having a higher barrier (DeltaH? = 0.95 kcal mol-1) than 4b (DeltaH? = 0.54 kcal mol-1). Analysis of the rotator cavity in the two co-crystals revealed subtle differences in steric interactions that account for their different activation energies. PMID- 27991780 TI - Graded Structural Polymorphism in a Bacterial Thermosensor Protein. AB - Thermosensing is critical for the expression of virulence genes in pathogenic bacteria that infect warm-blooded hosts. Proteins of the Hha-family, conserved among enterobacteriaceae, have been implicated in dynamically regulating the expression of a large number of genes upon temperature shifts. However, there is little mechanistic evidence at the molecular level as to how changes in temperature are transduced into structural changes and hence the functional outcome. In this study, we delineate the conformational behavior of Cnu, a putative molecular thermosensor, employing diverse spectroscopic, calorimetric and hydrodynamic measurements. We find that Cnu displays probe-dependent unfolding in equilibrium, graded increase in structural fluctuations and temperature-dependent swelling of the dimensions of its native ensemble within the physiological range of temperatures, features that are indicative of a highly malleable native ensemble. Site-specific fluorescence and NMR experiments in combination with multiple computational approaches-statistical mechanical model, coarse-grained and all-atom MD simulations-reveal that the fourth helix of Cnu acts as a unique thermosensing module displaying varying degrees of order and orientation in response to temperature modulations while undergoing a continuous unfolding transition. Our combined experimental-computational study unravels the folding-functional landscape of a natural thermosensor protein, the molecular origins of its unfolding complexity, highlights the role of functional constraints in determining folding-mechanistic behaviors, and the design principles orchestrating the signal transduction roles of the Hha protein family. PMID- 27991781 TI - Dehydration of Octacyanido-Bridged NiII-WIV Framework toward Negative Thermal Expansion and Magneto-Colorimetric Switching. AB - An inorganic three-dimensional [NiII(H2O)2]2[WIV(CN)8].4H2O (1) framework undergoes a single-crystal-to-single-crystal transformation upon thermal dehydration, producing a fully anhydrous phase NiII2[WIV(CN)8] (1d). The dehydration process induces changes in optical, magnetic, and thermal expansion properties. While 1 reveals typical positive thermal expansion of the crystal lattice, greenish-yellow color, and paramagnetic behavior, 1d is the first ever reported octacyanido-based solid revealing negative thermal expansion, also exhibiting a deep red color and diamagnetism. Such drastic shift in the physical properties is explained by the removal of water molecules, leaving the exclusively cyanido-bridged bimetallic network, which is accompanied by the transformation of the octahedral paramagnetic [NiII(H2O)2(NC)4]2- to the square planar diamagnetic [NiII(NC)4]2- moieties. PMID- 27991782 TI - Inversion Boundaries and Phonon Scattering in Ga:ZnO Thermoelectric Compounds. AB - We investigated the high-temperature thermoelectric properties of Ga:ZnO bulk compounds, synthesized using a simple and scalable solid-state process. The effects of a low gallium content (x <= 0.04 in Zn1-xGaxO1+x/2) on the structural features and electrical/thermal properties are reviewed. Transmission electron microscopy analyses showed that 2D, nonperiodic defects had formed from a doping content as low as x = 0.01 Ga. The structural description of these nanoscale interfaces is, for the first time, carefully investigated in such low-Ga-content samples by HAADF-STEM analyses combined with structural modeling. It was found that the formation of head-to-head inversion twin (h-IT) boundaries and tail-to tail inversion boundaries (t-IB) in the bulk compounds is responsible for strong phonon scattering, while maintaining relatively good electrical conductivity and thereby enhancing the thermoelectric properties. The absolute value of the Seebeck coefficient decreases abruptly from 475 MUV/K for x = 0 down to 60 MUV/K for x = 0.005 at 350 K. At the same time, the electrical resistivity drops from 1 ohm cm for x = 0 to 1.7 * 10-3 ohm cm for x = 0.005. For higher Ga additions (x > 0.01), the increase in electrical resistivity is likely linked to the formation of interface defects at a larger extent in the wurtzite structure. The thermal conductivity also drops sharply with the increase in the Ga content from ~33 W/m K for x = 0 to ~8 for x = 0.04 at 350 K. This study is progress toward the synthesis of other thermoelectric materials where nanoscale interfaces in bulk compounds provide tremendous opportunities for further enhancing both the phonon scattering and the overall figure of merit. PMID- 27991783 TI - Correction to "Theoretical Study on the Effects of Hydrogen-Bonding and Molecule Cation Interactions on the Sensitivity of HMX". PMID- 27991784 TI - Canted Antiferromagnetism in Two-Dimensional Silver(II) Bis[pentafluoridooxidotungstate(VI)]. AB - By slow reaction between colorless AgIW2O2F9 and elemental F2 in liquid anhydrous HF, violet platelike single crystals of Ag(WOF5)2 were grown. The crystal structure of Ag(WOF5)2 consists of layers built from Ag2+ cations bridged by [WOF5]- anions and not, as previously assumed, from infinite [AgII-F]+infinity chains and [W2O2F9]- anions. A majority (97%) of the disordered AgII cations are found with square-planar coordination of F/O ligands within the same layer, and they form additional long contacts with O/F atoms originating from the neighboring layers. The remaining 3% the of Ag(II) ions are coordinated only by F atoms in a square-planar fashion. The magnetic moments of Ag2+ from the same layer are almost perfectly antiferromagnetically aligned. Weak ferromagnetic interlayer interactions cause a small tilt (~1.5 degrees ) of the magnetic moments, resulting in canted antiferromagnetism. Because of the lowering of the symmetry of [WOF5]- in the solid state, the vibrational spectra show more bands than expected for regular C4v symmetry. The electronic spectrum of Ag(WOF5)2 is reported and analyzed. PMID- 27991785 TI - Absolute Configuration Assignment of Chiral Resorcin[4]arenes from ECD Spectra. AB - Racemates of five chiral resorcin[4]arenes, four tetra-O-substituted and one hepta-O-substituted, have been resolved by enantioselective HPLC, and their ECD spectra have been recorded online by stopped-flow measurements. The absolute configuration has been assigned by comparison of the experimental ECD spectra with DFT and semiempirical calculations. For the four tetra-O-substituted resorcin[4]arenes, the ECD exciton couplet at longer wavelength depends on the chirality induced in the arene scaffold by the substituents rather than on the precise nature of the substituents themselves. Accordingly, the exciton chirality model with excitons localized on the arene scaffold, here generalized to Cn symmetry, accurately describes the relationship between stereochemistry and chiroptical properties for this couplet, while its application at shorter wavelengths is unsafe. For the significantly larger hepta-O-substituted system the assignment particularly benefits from the use of the semiempirical ZINDO method. PMID- 27991786 TI - Chemical Equilibria and Kinetics in Aqueous Solutions of Zymonic Acid. AB - The chemistry of pyruvic acid is of great interest due to its essential role in metabolism for all life and its role in atmospheric chemistry. Pyruvic acid under a wide range of conditions, including normal storage conditions, will spontaneously dimerize to form zymonic acid. We isolated zymonic acid and, using a variety of 1D and 2D NMR techniques, identified it as a single structure as a solid or dissolved in DMSO. When in aqueous solution, however, we identified a mixture of five different tautomers and hydrates in equilibrium with each other with no single dominant form. The kinetics of this conversion were studied in situ via NMR. The reactivity of the tautomers and hydrates in aqueous solution is investigated and discussed in terms of aqueous reaction mechanisms. There is strong evidence for a direct, reversible conversion from an enol to a geminal diol without passing through a ketone intermediate, which implies the reversible addition of water across a double bond under ambient conditions. Additionally, there is evidence for a base catalyzed lactone ring formation, which is in essence a base catalyzed esterification reaction. The equilibrium between pyruvic acid and its oligomers in aqueous solution is of consequence in the natural environment. PMID- 27991787 TI - Excited-State Hydroxide Ion Release From a Series of Acridinol Photobases. AB - The excited-state heterolysis of acridinol-based derivatives leads to the release of the OH- ion and the formation of the corresponding acridinium cations. To evaluate the parameters that control the reaction barriers, the kinetics of excited-state OH- release from a series of acridinol photobases were studied using transient absorption spectroscopy. The rate constants were obtained in three solvents (methanol, butanol, and isobutanol), and the data were modeled using Marcus theory. The intrinsic reorganization energies obtained from these fits were found to correlate well with the solvent reorganization energies calculated using dielectric continuum model, suggesting that the excited-state OH release occurs along the solvent reaction coordinate. Furthermore, the ability of acridinol photobases to photoinitiate chemical reactions was demonstrated using the Michael reaction between dimethylmalonate and nitrostyrene. PMID- 27991788 TI - Surfactant-Mediated Crystallization-Driven Self-Assembly of Crystalline/Ionic Complexed Block Copolymers in Aqueous Solution. AB - A series of crystalline/ionic complexed block copolymers (BCPs) with various compositions have been prepared by sequential reactions. The BCPs with different hydrophilic fractions can self-assemble into various morphologies, such as spindlelike, rodlike, and spherical micelles with different crystallinity of the core. Bis(2-ethylhexyl) sulfosuccinate sodium salt (AOT) is added as a surfactant to induce the morphological transition of BCPs in aqueous media. The introduced AOT can be tightly bound to the cationic units, and a water-insoluble unit in the corona forms, leading to a reduced tethering density. Consequently, morphological variety changing from rods to platelets to fibril to dendrite-like micelles can be observed. PMID- 27991789 TI - Uptake of Pyrene onto Fatty Acid Coated NaCl Aerosol Particles. AB - Photoelectric charging experiments monitor the uptake of pyrene onto NaCl aerosol particles coated with either oleic acid or myristic acid. In both cases, thin coatings produce a small net decrease in pyrene uptake. In the larger coverage limit, the uptake of the myristic acid coated particles remains nearly constant whereas the oleic acid coated particles exhibit greater uptake rates than the bare NaCl particles. Fitting the results with a multilayer kinetic model yields uptake rate coefficients as well as parameters that describe the distribution of organic molecules on the aerosol particle surface. The model accounts for the decrease in uptake associated with thin coatings of oleic acid through a concomitant reduction in surface area. The adsorption rate constants for the myristic and oleic acid coated surfaces are 50 and 80 times faster, respectively, than for NaCl. The desorption rates for pyrene on the fatty acid surfaces are faster, as well. For myristic acid coatings, the fast desorption (over 400 times the rate of desorption from NaCl) results in slower net adsorption, whereas for oleic acid (approximately 12 times the desorption rate from NaCl), the net uptake rate increases with coverage. The results also suggest that both myristic acid and oleic acid spread incompletely on the aerosol surfaces under the conditions of these experiments. In the optimized kinetic model, the fatty acids cover approximately 50% of the surface when the nominal coating thickness is approximately 6 nm. The surface is over 90% covered with a nominal coating thickness of 20 nm, which is approximately 10% of particle diameter in these experiments. Very thin oleic acid coatings reduce the surface area of particles consistent with the preferential coverage of highly corrugated or porous regions. PMID- 27991790 TI - Electron Interference in Hall Effect Measurements on GaAs/InAs Core/Shell Nanowires. AB - We present low-temperature magnetotransport measurements on GaAs/InAs core/shell nanowires contacted by regular source-drain leads as well as laterally attached Hall contacts, which only touch parts of the nanowire sidewalls. Low-temperature measurements between source and drain contacts show typical phase coherent effects, such as universal conductance fluctuations in a magnetic field aligned perpendicularly to the nanowire axis as well as Aharonov-Bohm-type oscillations in a parallel aligned magnetic field. However, the signal between the Hall contacts shows a Hall voltage buildup, when the magnetic field is turned perpendicular to the nanowire axis while current is driven through the wire using the source-drain contacts. At low temperatures, the phase coherent effects measured between source and drain leads are superimposed on the Hall voltage, which can be explained by nonlocal probing of large segments of the nanowire. In addition, the Aharonov-Bohm-type oscillations are also observed in the magnetoconductance at magnetic fields aligned parallel to the nanowire axis, using the laterally contacted leads. This measurement geometry hereby directly corresponds to classical Aharonov-Bohm experiments using planar quantum rings. In addition, the Hall voltage is used to characterize the nanowires in terms of charge carrier concentration and mobility, using temperature- and gate-dependent measurements as well as measurements in tilted magnetic fields. The GaAs/InAs core/shell nanowire used in combination with laterally attached contacts is therefore the ideal system to three-dimensionally combine quantum ring experiments using the cross-sectional plane and Hall experiments using the axial nanowire plane. PMID- 27991791 TI - Following the Assembly of Iron Oxide Nanocubes by Video Microscopy and Quartz Crystal Microbalance with Dissipation Monitoring. AB - We have studied the growth of ordered arrays by evaporation-induced self-assembly of iron oxide nanocubes with edge lengths of 6.8 and 10.1 nm using video microscopy (VM) and quartz crystal microbalance with dissipation monitoring (QCM D). Ex situ electron diffraction of the ordered arrays demonstrates that the crystal axes of the nanocubes are coaligned and confirms that the ordered arrays are mesocrystals. Time-resolved video microscopy shows that growth of the highly ordered arrays at slow solvent evaporation is controlled by particle diffusion and can be described by a simple growth model. The growth of each mesocrystal depends only on the number of nanoparticles within the accessible region irrespective of the relative time of formation. The mass of the dried mesocrystals estimated from the analysis of the bandwidth-shift-to-frequency shift ratio correlates well with the total mass of the oleate-coated nanoparticles in the deposited dispersion drop. PMID- 27991792 TI - Phosphine-Catalyzed Enantioselective [2+4] Cycloaddition to Synthesize Pyrrolidin 2-one Fused Dihydropyrans Using alpha-Substituted Allenoates as C2 Synthons. AB - A bifunctional phosphine-catalyzed highly enantioselective [2+4] cycloaddition of alpha-substituted allenoates with (E)-1-benzyl-4-olefinicpyrrolidine-2,3-diones has been achieved, giving pyrrolidin-2-one fused dihydropyran derivatives in moderate to good yields with excellent enantioselectivities (up to 98% ee). This reaction provides a useful catalytic asymmetric access to dihydropyran structural motifs. PMID- 27991793 TI - Femtosecond Raman-Induced Kerr Effect Study of Temperature-Dependent Intermolecular Dynamics in Imidazolium-Based Ionic Liquids: Effects of Anion Species and Cation Alkyl Groups. AB - The temperature dependence of the intermolecular vibrational dynamics in imidazolium-based ionic liquids (ILs) with 10 different anions was studied by femtosecond Raman-induced Kerr effect spectroscopy. For all ILs investigated in this study, the intensity in the low-frequency region below 50 cm-1 increases, and the spectral density in the high-frequency region above 80 cm-1 decreases (and shows a redshift) with increasing temperature. The first phenomenon would be attributed to the activation of the translational vibrational motions, whereas the second one is ascribed to the slowing librational motion of the imidazolium ring with increasing temperature. Calculated spectra of the density of states for the intermolecular vibrations of 1-butyl-3-methylimidazolium hexafluorophosphate, which is one of the experiment samples studied here, obtained by molecular dynamics simulation agreed well with the experimental results and confirmed the spectral assignments. When we compared the difference spectra between spectra measured at various temperatures and the spectrum measured at 293 K, a clear difference was found in the ~50 cm-1 region of the Kerr spectra of 1-butyl-3 methylimidazolium thiocyanate and 1-butyl-3-methylimidazolium dicyanamide from those of the other ILs. The difference might have originated from the librational motions of the corresponding anions. We also compared the temperature-dependent Kerr spectra of hexafluorophosphate salts of 1-butyl-3-methylimidazolium, 1-hexyl 3-methylimidazolium, and 1-heptyl-3-methylimidazolium cations. These ILs showed a similar temperature dependence, which was not affected by the alkyl group length. The temperature-dependent viscosities and glass transition temperatures of the ILs were also estimated to determine their fragilities. PMID- 27991794 TI - Surface Localization of Defects in Black TiO2: Enhancing Photoactivity or Reactivity. AB - In the past several years, surface-disordered TiO2, which is referred to as black TiO2 and can absorb both visible and near-infrared solar light, has triggered an explosion of interest for many important applications. Despite the excellent optical and electrical features of black TiO2 for various photoelectrochemical (PEC) and photochemical reactions, the current understanding of the photocatalytic mechanism is unsatisfactory and incomplete. On the basis of previous studies, we present new insight into the surface localization of defects and perspectives on the liquid/solid interface. The future prospects for understanding black TiO2 from this perspective suggest that defect engineering at the liquid/solid interface is a potential method of guiding nanomaterial design. PMID- 27991795 TI - Correction to Langmuir Cover Art Credit for Volume 32, Issue 43. PMID- 27991796 TI - Thermoactivated Electrical Conductivity in Perylene Diimide Nanofiber Materials. AB - Thermoactivated electrical conductivity has been studied on nanofibers fabricated from the derivatives of perylene tetracarboxylic diimide (PTCDI) both in the dark and under visible light illumination. The activation energy obtained for the nanofibers fabricated from donor-acceptor (D-A) PTCDIs are higher than that for symmetric n-dodecyl substituted PTCDI. Such difference originates from the strong dependence of thermoactivated charge hopping on material disorder, which herein is dominated by the D-A charge-transfer and dipole-dipole interactions between stacked molecules. When the nanofibers were heated above the first phase transition temperature (around 85 degrees C), the activation energy was significantly increased because of the thermally enhanced polaronic effect. Moreover, charge carrier density can be increased in the D-A nanofibers under visible light illumination. Consistent with the theoretical models in the literature, the increased charge carrier density did cause decrease in the activation energy due to the up-shifting of Fermi level closer to the conduction band edge. PMID- 27991797 TI - Trends in Two- and Three-Body Effects in Multiscale Clusters of Ionic Liquids. AB - Applications of higher correlated levels of ab initio theory to condensed systems require a significant amount of computational resources. The recent development of the fragment molecular orbital (FMO) approach alleviates this issue by splitting the system into individual fragments and achieves the accuracy of the method by accounting for all possible two-body and three-body interactions. In this work a comprehensive application of the FMO approach in combination with a second order of Moller-Plesset perturbation theory method, MP2, is presented for multiscale clusters of ionic liquids such as [C1mim]X, [C1mpyr]X, [C2py]X, and [NMe4]X, where X = chloride and tetrafluoroborates, BF4-, with the clusters varying in size from 4, 8, 16, to 32 ion pairs. Reliable cutoff criteria for the inclusion of two-body and three-body interactions are identified for both HF energy and MP2 correlation energy to achieve the desired accuracy of 1 kJ mol-1. The importance of two-body and three-body interactions in ionic liquids is also discussed. PMID- 27991799 TI - Mechanical Stability of a High-Affinity Toxin Anchor from the Pathogen Clostridium perfringens. AB - The opportunistic pathogen Clostridium perfringens assembles its toxins and carbohydrate-active enzymes by the high-affinity cohesin-dockerin (Coh-Doc) interaction. Coh-Doc interactions characterized previously have shown considerable resilience toward mechanical stress. Here, we aimed to determine the mechanics of this interaction from C. perfringens in the context of a pathogen. Using atomic force microscopy based single-molecule force spectroscopy (AFM-SMFS) we probed the mechanical properties of the interaction of a dockerin from the MU toxin with the GH84C X82 cohesin domain of C. perfringens. Most probable complex rupture forces were found to be approximately 60 pN and an estimate of the binding potential width was performed. The dockerin was expressed with its adjacent FIVAR (found in various architectures) domain, whose mechanostability we determined to be very similar to the complex. Additionally, fast refolding of this domain was observed. The Coh-Doc interaction from C. perfringens is the mechanically weakest observed to date. Our results establish the relevant force range of toxin assembly mechanics in pathogenic Clostridia. PMID- 27991800 TI - The role of facial appearance on CEO selection after firm misconduct. AB - [Correction Notice: An Erratum for this article was reported in Vol 102(4) of Journal of Applied Psychology (see record 2017-10684-001). The wrong figure files were used. All versions of this article have been corrected.] We investigate a particular aspect of CEO successor trustworthiness that may be critically important after a firm has engaged in financial misconduct. Specifically, drawing on prior research that suggests that facial appearance is one critical way in which trustworthiness is signaled, we argue that leaders who convey integrity, a component of trustworthiness, will be more likely to be selected as successors after financial restatement. We predict that such appointments garner more positive reactions by external observers such as investment analysts and the media because these CEOs are perceived as having greater integrity. In an archival study of firms that have announced financial restatements, we find support for our predictions. These findings have implications for research on CEO succession, leadership selection, facial appearance, and firm misconduct. (PsycINFO Database Record PMID- 27991798 TI - Comfortably Numb and Back: Plasma Metabolomics Reveals Biochemical Adaptations in the Hibernating 13-Lined Ground Squirrel. AB - Hibernation is an evolutionary adaptation that affords some mammals the ability to exploit the cold to achieve extreme metabolic depression (torpor) while avoiding ischemia/reperfusion or hemorrhagic shock injuries. Hibernators cycle periodically out of torpor, restoring high metabolic activity. If understood at the molecular level, the adaptations underlying torpor-arousal cycles may be leveraged for translational applications in critical fields such as intensive care medicine. Here, we monitored 266 metabolites to investigate the metabolic adaptations to hibernation in plasma from 13-lined ground squirrels (57 animals, 9 time points). Results indicate that the periodic arousals foster the removal of potentially toxic oxidative stress-related metabolites, which accumulate in plasma during torpor while replenishing reservoirs of circulating catabolic substrates (free fatty acids and amino acids). Specifically, we identified metabolic fluctuations of basic amino acids lysine and arginine, one-carbon metabolism intermediates, and sulfur-containing metabolites methionine, cysteine, and cystathionine. Conversely, reperfusion injury markers such as succinate/fumarate remained relatively stable across cycles. Considering the cycles of these metabolites with the hibernator's cycling metabolic activity together with their well-established role as substrates for the production of hydrogen sulfide (H2S), we hypothesize that these metabolic fluctuations function as a biological clock regulating torpor to arousal transitions and resistance to reperfusion during arousal. PMID- 27991801 TI - The dark side of transparency: How and when pay administration practices affect employee helping. AB - This study examines a long-standing contention of practitioners and scholars alike, namely that pay transparency may adversely affect employees' tendency to offer assistance to coworkers. Drawing from research on social comparison, information vividness, and envy, we develop and test a moderated-mediation model positing that transparency adversely affects the amount of help individuals afford to peers who, based on pay for performance, are paid more than them. Testing our hypotheses in the context of a multiround simulation-based laboratory experiment, we find that this adverse effect of pay transparency on helping is largely explained by transparency's positive association with episodic envy, but only when individual differences grounded in differential social value orientations, specifically those regarding individualism beliefs and prosocial motivation, are taken into consideration. Implications for theory and practice are discussed. (PsycINFO Database Record PMID- 27991802 TI - A computational model of self-efficacy's various effects on performance: Moving the debate forward. AB - Self-efficacy, which is one's belief in one's capacity, has been found to both positively and negatively influence effort and performance. The reasons for these different effects have been a major topic of debate among social-cognitive and perceptual control theorists. In particular, the findings of various self efficacy effects has been motivated by a perceptual control theory view of self regulation that social-cognitive theorists' question. To provide more clarity to the theoretical arguments, a computational model of the multiple processes presumed to create the positive, negative, and null effects for self-efficacy is presented. Building on an existing computational model of goal choice that produces a positive effect for self-efficacy, the current article adds a symbolic processing structure used during goal striving that explains the negative self efficacy effect observed in recent studies. Moreover, the multiple processes, operating together, allow the model to recreate the various effects found in a published study of feedback ambiguity's moderating role on the self-efficacy to performance relationship (Schmidt & DeShon, 2010). Discussion focuses on the implications of the model for the self-efficacy debate, alternative computational models, the overlap between control theory and social-cognitive theory explanations, the value of using computational models for resolving theoretical disputes, and future research and directions the model inspires. (PsycINFO Database Record PMID- 27991803 TI - Should you switch off or stay engaged? The consequences of thinking about work on the trajectory of psychological well-being over time. AB - This study examined how 2 different ways of being mentally engaged with work related issues during evenings (affective rumination and problem-solving pondering) cause changes in psychological well-being over a 1-year period. We conducted a 3-wave longitudinal study with a time lag of 6 months between each wave. At the first measurement moment, participants filled out a survey over 5 consecutive working days assessing work-related affective rumination and problem solving pondering during evenings. Exhaustion and health complaints were assessed at the first measurement moment as well as after 6 and 12 months. The 3 waves of data obtained from a total of 123 participants with full-time and primarily mentally demanding jobs were analyzed using latent growth curve modeling (LGM). The results showed that affective rumination is a significant predictor of increase in exhaustion over time. Problem-solving pondering was not found to be a significant predictor of change in psychological well-being over time. These findings demonstrate that work-related rumination during evenings may lead to health problems over time depending on the type of rumination. It suggests that unlike affective rumination, problem-solving pondering during evenings has no influence on psychological well-being over time. (PsycINFO Database Record PMID- 27991804 TI - What to expect when you're exercising: An experimental test of the anticipated affect-exercise relationship. AB - OBJECTIVE: Anticipated affect may influence exercise behavior via experienced affective responses and intentions. Cognitive manipulations of anticipated affect may inform exercise intervention design. The purpose of this study was to experimentally test the effects of an expectation-based manipulation of affective responses to exercise on anticipated, experienced, and remembered affect and adherence to a 7-day exercise prescription. METHOD: Participants (N = 98) were randomly assigned to a positive anticipated affect manipulation, a negative anticipated affect manipulation, or a no affect manipulation control. They reported anticipated, experienced, and remembered affect during and after a standardized 30-min bout of treadmill exercise at an intensity just below ventilatory threshold. Participants were asked to try to complete the prescribed exercise daily for 1 week. Differences in affect and exercise behavior were examined across conditions, as were relationships between affect measures, intentions and behavior. RESULTS: The manipulation influenced anticipated and experienced affective responses, but not behavior. Participants generally expected exercise to be less pleasant and more fatiguing that it actually was. Anticipated, experienced, and remembered affect were associated with intentions to exercise. Intentions and remembered affect were both directly associated with exercise behavior. CONCLUSIONS: Moderate-to-vigorous exercise can be more pleasant than people expect it to be. Additionally, encouraging exercisers to focus on the positive affective outcomes of exercise can yield a more positive affective experience than those who focus on negative affective outcomes or do not focus on affective outcomes at all. The role of affect in both reflective and automatic motivation to exercise is discussed. (PsycINFO Database Record PMID- 27991805 TI - Understanding the neural basis of cognitive bias modification as a clinical treatment for depression. AB - : [Correction Notice: An Erratum for this article was reported in Vol 85(3) of Journal of Consulting and Clinical Psychology (see record 2017-07144-002). In the article, there was an error in the Discussion section's first paragraph for Implications and Future Work. The in-text reference citation for Penton-Voak et al. (2013) was incorrectly listed as "Blumenfeld, Preminger, Sagi, and Tsodyks (2006)". All versions of this article have been corrected.] Objective: Cognitive bias modification (CBM) eliminates cognitive biases toward negative information and is efficacious in reducing depression recurrence, but the mechanisms behind the bias elimination are not fully understood. The present study investigated, through computer simulation of neural network models, the neural dynamics underlying the use of CBM in eliminating the negative biases in the way that depressed patients evaluate facial expressions. METHOD: We investigated 2 new CBM methodologies using biologically plausible synaptic learning mechanisms continuous transformation learning and trace learning-which guide learning by exploiting either the spatial or temporal continuity between visual stimuli presented during training. We first describe simulations with a simplified 1 layer neural network, and then we describe simulations in a biologically detailed multilayer neural network model of the ventral visual pathway. RESULTS: After training with either the continuous transformation learning rule or the trace learning rule, the 1-layer neural network eliminated biases in interpreting neutral stimuli as sad. The multilayer neural network trained with realistic face stimuli was also shown to be able to use continuous transformation learning or trace learning to reduce biases in the interpretation of neutral stimuli. CONCLUSIONS: The simulation results suggest 2 biologically plausible synaptic learning mechanisms, continuous transformation learning and trace learning, that may subserve CBM. The results are highly informative for the development of experimental protocols to produce optimal CBM training methodologies with human participants. (PsycINFO Database Record PMID- 27991806 TI - Are reductions in pain intensity and pain-related distress necessary? An analysis of within-treatment change trajectories in relation to improved functioning following interdisciplinary acceptance and commitment therapy for adults with chronic pain. AB - OBJECTIVE: A key issue in chronic pain treatment concerns the changes necessary for improved physical and emotional functioning. Traditionally, reducing pain intensity and pain-related distress have been viewed as a prerequisite for these improvements. Alternatively, acceptance and commitment therapy, a behavior change approach, theorizes that pain and distress reduction are not necessary for improvement, rather responses must change, such that functioning improves in clearly specified areas (e.g., engagement in valued activities, decreased disability in social activity) even when pain and distress persist. METHOD: This study sought to directly examine aspects of change in pain and distress over the course of an interdisciplinary program of acceptance and commitment therapy in relation to functioning at treatment's conclusion and a 3-month follow-up in 174 treated patients. Latent change trajectories of pain intensity and pain-related distress were assessed weekly over 4 weeks of treatment and analyzed via latent growth curve and growth mixture modeling. RESULTS: A single latent trajectory with a decreasing quadratic slope was indicated for pain, while 2 separate trajectories were identified for pain-related distress 1 of linear decrease and the other an early increase followed by a decrease to initial level. Overall, and with only 3 exceptions across multiple tests, results indicated that trajectories of pain and distress during treatment were not significantly associated with improvements in functioning at treatment's conclusion and follow-up. CONCLUSIONS: This pattern of findings suggests that significant improvements in functioning may not require decreases in pain intensity and pain-related distress during treatment for chronic pain. (PsycINFO Database Record PMID- 27991807 TI - Practice makes it better: A psychophysical study of visual perceptual learning and its transfer effects on aging. AB - Previous studies on perceptual learning, acquiring a new skill through practice, appear to stimulate brain plasticity and enhance performance (Fiorentini & Berardi, 1981). The present study aimed to determine (a) whether perceptual learning can be used to compensate for age-related declines in perceptual abilities, and (b) whether the effect of perceptual learning can be transferred to untrained stimuli and subsequently improve capacity of visual working memory (VWM). We tested both healthy younger and older adults in a 3-day training session using an orientation discrimination task. A matching-to-sample psychophysical method was used to measure improvements in orientation discrimination thresholds and reaction times (RTs). Results showed that both younger and older adults improved discrimination thresholds and RTs with similar learning rates and magnitudes. Furthermore, older adults exhibited a generalization of improvements to 3 untrained orientations that were close to the training orientation and benefited more compared with younger adults from the perceptual learning as they transferred learning effects to the VWM performance. We conclude that through perceptual learning, older adults can partially counteract age-related perceptual declines, generalize the learning effect to other stimulus conditions, and further overcome the limitation of using VWM capacity to perform a perceptual task. (PsycINFO Database Record PMID- 27991808 TI - Suicide and self-injury-related implicit cognition: A large-scale examination and replication. AB - Suicide and self-injury are difficult to predict because at-risk individuals are often unable or unwilling to report their intentions. Therefore, tools to reliably assess risk without reliance on self-report are critically needed. Prior research suggests that people who engage in suicidal and nonsuicidal self-injury (NSSI) often implicitly (i.e., outside conscious control) associate themselves with self-harm and death, indicating that self-harm-related implicit cognition may serve as a useful behavioral marker for suicide risk. However, earlier studies left several critical questions about the robustness, sensitivity, and specificity of self-harm-related implicit associations unaddressed. We recruited a large sample of participants (N = 7,015) via a public web-based platform called Project Implicit Mental Health (PIMH) to test several hypotheses about self-harm related implicit associations using the Implicit Association Test (IAT). Participants were randomly assigned to complete 1 of 3 self-harm IATs (Self + Cutting using picture stimuli, Self + Suicide using word stimuli, Self + Death using word stimuli). Results replicated prior studies demonstrating that self harm-related implicit associations were stronger among individuals with (vs. without) a history of suicide attempt and NSSI. Results also suggested that self harm-related implicit associations are robust (based on internal replication), are sensitive to recency and severity of self-harm history (e.g., stronger associations for more recent and more lethal prior suicide attempts), and correlate with specific types of self-harm behaviors. These findings clarify the nature of self-harm-related implicit cognition and highlight the IAT's potential to track current risk for specific types of self-harm in ways that more fixed risk factors cannot. (PsycINFO Database Record PMID- 27991809 TI - The psychophysiology of parenting: Individual differences in autonomic reactivity to positive and negative mood inductions and observed parental affect during dyadic interactions with children. AB - Parenting is a complex activity driven, in part, by parental emotional and physiological responses. However, work examining the physiological underpinnings of parenting behavior is still in its infancy, and very few studies have examined such processes beyond early childhood. The current study examines associations between Autonomic Nervous System (ANS) indices of parents' physiological reactivity to positive and negative mood states and observed parental affect during a series of discussion tasks with their adolescent child. Respiratory Sinus Arrhythmia (RSA) was measured as an index of parasympathetic nervous system (PNS) activation while viewing film clips designed to induce neutral, sad, and amused mood states. Parental positive affect, anger, and distress were observed during a series of parent-child discussion tasks, which included an ambiguous discussion regarding adolescent growth, a conflict discussion, and a fun-activity planning discussion. Results supported the association between aspects of parental physiological reactivity and observed affect during dyadic interactions. Further, RSA interacted with maternal depression to predict observed positive affect, anger, and distress, although differences across tasks and specific emotions were found regarding the nature of the interaction effects. Overall, results suggest that such neurobiological processes may be particularly important predictors of parental behavior, particularly in at-risk populations. (PsycINFO Database Record PMID- 27991810 TI - Couple relationship education: A randomized controlled trial of professional contact and self-directed tools. AB - The aim of this randomized controlled trial was to examine the efficacy of an evidence-based relationship distress prevention program, the Couples Coping Enhancement Training (CCET), in dual well-earning couples and to investigate whether effects vary by (a) hours of professional contact and (b) mode of delivery (face to face vs. self-learning DVD). N = 159 couples were randomly assigned to 1 of 4 intervention conditions: (1) standard CCET (15 hours face to face), (2) compact CCET (12 hr face to face), (3) short CCET (self-learning DVD + 8 hr face to face), or (4) wait-list control group. Relationship satisfaction and dyadic coping skills were assessed by means of questionnaires completed prior to and 2 weeks after completion of the treatment, at 3-month follow-up, and at 6 month follow-up. Baseline latent change models for 2 factors showed that the CCET enhanced relationship satisfaction and dyadic coping skills in couples relative to the wait-list control group, albeit effects were small. The standard format of the CCET was not more effective than the compact or the short format indicating that reduced amount of professional contact did not decrease the treatment's efficacy and that the self-learning DVD successfully replaced the psycho educational part of the program. Since dual earner couples usually face multiple stressors, it is a promising finding that they can strengthen their relationship with a relatively short time investment. (PsycINFO Database Record PMID- 27991811 TI - When stress gets into your head: Socioeconomic risk, executive functions, and maternal sensitivity across childrearing contexts. AB - Socioeconomic adversity has been targeted as a key upstream mechanism with robust pathogenic effects on maternal caregiving. Although research has demonstrated the negative repercussions of socioeconomic difficulties, little research has documented potential mechanisms underlying this association. Toward increasing understanding, the present study examined how maternal working memory capacity and inhibitory control may mediate associations between socioeconomic risk and change in maternal sensitivity across free-play and discipline caregiving contexts. This study used a longitudinal design, and utilized a socioeconomically diverse sample of 185 mothers and their 3.5-year-old toddlers. Multi-informants and methods were used to assess constructs. Findings revealed that maternal EF mediated associations between socioeconomic risk and parenting sensitivity with specific effects for working memory and baseline sensitivity and inhibitory control and change in sensitivity as childrearing demands increased. Results are interpreted within emerging conceptual frameworks regarding the role of parental neurocognitive functioning and caregiving. (PsycINFO Database Record PMID- 27991813 TI - Therapist effects on outcome and alliance in inpatient psychotherapy: The contribution of patients' symptom severity. AB - Therapists differ in their effectiveness regarding their patients' symptomatic improvement as well as their therapeutic alliances, but little is known about influencing factors. The current study aimed to investigate therapist effects on outcome and alliance in inpatient psychotherapy and to estimate the influence of patient severity on the magnitude of therapist effects in this specific setting. We examined differences between individual psychotherapists in their patients' early alliance and outcome at discharge in a psychotherapy setting of a psychiatric hospital. The sample included 33 therapists and 3,051 patients, and minimum caseload was 30 patients. Outcome was measured as patient-rated symptoms and interpersonal problems as well as therapist-rated impairment. Similarly, alliance was assessed from the patients' and the therapists' perspective. First, we estimated the amount of variance that was owing to therapists for patients with average symptom severity. Next, we examined whether the therapist effect was influenced by initial patient severity. Therapist effects on patient-rated symptomatic outcome and alliance were not significantly different from zero. Therapist differences were considerably larger for therapist-rated measures. Patient severity did not significantly influence the therapist effect for patient rated outcome or alliance. However, there was a u-shaped association for therapist-rated severity and the therapist effect in therapist-rated alliance. Here, therapist differences were larger for patients with either very low or very high initial severity. The magnitude of the therapist outcome effect was smaller in inpatient therapy compared with outpatient settings. (PsycINFO Database Record PMID- 27991814 TI - Examining the incremental contribution of metacognitive beliefs beyond content specific beliefs in relation to posttraumatic stress in a community sample. AB - OBJECTIVE: Cognitive-behavioral models of posttraumatic stress disorder (PTSD) propose that the content of one's thoughts, including negative beliefs about the self, others, and world, play a fundamental role in our understanding and treatment of PTSD. Metacognitive theory suggests that metacognitive beliefs (i.e., beliefs about thinking), rather than content-specific beliefs, underlie PTSD. The present study provided the first known examination of the incremental contribution of metacognitive beliefs and trauma-related cognitions in relation to posttraumatic stress. METHOD: Community adults recruited through an online crowdsourcing website who reported experiencing a criterion A traumatic event (N = 299) completed self-report measures of the study variables. RESULTS: Results from multiple linear regression analyses indicated that metacognitive beliefs of the uncontrollability and danger of thinking shared associations with each posttraumatic stress symptom cluster after accounting for the effects of content specific beliefs and other covariates. The individual content-specific beliefs did not consistently share associations with posttraumatic stress symptoms in the regression analyses. The contribution of the individual content-specific beliefs to posttraumatic stress symptoms was consistently attenuated or rendered nonsignificant after accounting for metacognitive beliefs. CONCLUSIONS: These results are consistent with metacognitive theory in suggesting that metacognitive beliefs may be more important than trauma-related thought content in relation to posttraumatic stress. (PsycINFO Database Record PMID- 27991815 TI - Effects of learning context on the acquisition and processing of emotional words in bilinguals. AB - Although bilinguals respond differently to emotionally valenced words in their first language (L1) relative to emotionally neutral words, similar effects of emotional valence are hard to come by in second language (L2) processing. We examine the extent to which these differences in first and second language processing are due to the context in which the 2 languages are acquired: L1 is typically acquired in more naturalistic settings (e.g., family) than L2 (e.g., at school). Fifty German-English bilinguals learned unfamiliar German and English negative and neutral words in 2 different learning conditions: One group (emotion video context) watched videos of a person providing definitions of the words with facial and gestural cues, whereas another group (neutral video context) received the same definitions without gestural and emotional cues. Subsequently, participants carried out an emotional Stroop task, a sentence completion task, and a recall task on the words they had just learned. We found that the effect of learning context on the influence of emotional valence on responding was modulated by a) language status, L1 versus L2, and b) task requirement. We suggest that a more nuanced approach is required to capture the differences in emotion effects in the speed versus accuracy of access to words across different learning contexts and different languages, in particular with regard to our finding that bilinguals respond to L2 words in a similar manner as L1 words provided that the learning context is naturalistic and incorporates emotional and prosodic cues. (PsycINFO Database Record PMID- 27991812 TI - Self- and partner-reported psychopathic traits' relations with couples' communication, marital satisfaction trajectories, and divorce in a longitudinal sample. AB - Given that psychopathy is composed in large part by an antagonistic relational approach and is associated with many troubling interpersonally relevant outcomes, its role in romantic functioning warrants greater attention. The current study used data from a community sample of 172 newlywed couples to examine spouses' psychopathic traits in relation to their partners' psychopathic traits, observed communication, 4-year marital satisfaction trajectories, and 10-year divorce rates. Spouses reporting greater levels of psychopathic traits were married to partners reporting greater levels of psychopathic traits. Psychopathic traits were correlated cross-sectionally with more negative affect and less positive affect during conversations regarding sources of tension in the relationship. Longitudinally, hierarchical linear modeling of spouses' 4-year marital trajectories indicated that psychopathic traits generally predicted lower initial and sustained marital satisfaction for spouses and their partners over time. In addition, wives' ratings of husbands' psychopathic traits predicted declines in husbands' satisfaction over time and elevated 10-year divorce rates. These findings highlight the relationship impairment associated with psychopathic traits, indicate that this impairment is present from the beginning of couples' marital trajectories, and show that psychopathic traits predict divorce. Findings also suggest that partner-ratings of psychopathic traits provide substantial incremental validity in the prediction of marital functioning outcomes relative to self-ratings. Future research on the pathways by which psychopathic traits undermine relationship functioning over time would be valuable. (PsycINFO Database Record PMID- 27991816 TI - Instrumental motives in negative emotion regulation in daily life: Frequency, consistency, and predictors. AB - People regulate their emotions not only for hedonic reasons but also for instrumental reasons, to attain the potential benefits of emotions beyond pleasure and pain. However, such instrumental motives have rarely been examined outside the laboratory as they naturally unfold in daily life. To assess whether and how instrumental motives operate outside the laboratory, it is necessary to examine them in response to real and personally relevant stimuli in ecologically valid contexts. In this research, we assessed the frequency, consistency, and predictors of instrumental motives in negative emotion regulation in daily life. Participants (N = 114) recalled the most negative event of their day each evening for 7 days and reported their instrumental motives and negative emotion goals in that event. Participants endorsed performance motives in approximately 1 in 3 events and social, eudaimonic, and epistemic motives in approximately 1 in 10 events. Instrumental motives had substantially higher within- than between-person variance, indicating that they were context-dependent. Indeed, although we found few associations between instrumental motives and personality traits, relationships between instrumental motives and contextual variables were more extensive. Performance, social, and epistemic motives were each predicted by a unique pattern of contextual appraisals. Our data demonstrate that instrumental motives play a role in daily negative emotion regulation as people encounter situations that pose unique regulatory demands. (PsycINFO Database Record PMID- 27991817 TI - Working memory regulates trait anxiety-related threat processing biases. AB - High trait anxious individuals tend to show biased processing of threat. Correlational evidence suggests that executive control could be used to regulate such threat-processing. On this basis, we hypothesized that trait anxiety-related cognitive biases regarding threat should be exaggerated when executive control is experimentally impaired by loading working memory. In Study 1, 68 undergraduates read ambiguous vignettes under high and low working memory load; later, their interpretations of these vignettes were assessed via a recognition test. Trait anxiety predicted biased interpretation of social threat vignettes under high working memory load, but not under low working memory load. In Study 2, 53 undergraduates completed a dot probe task with fear-conditioned Japanese characters serving as threat stimuli. Trait anxiety predicted attentional bias to the threat stimuli but, again, this only occurred under high working memory load. Interestingly however, actual eye movements toward the threat stimuli were only associated with state anxiety, and this was not moderated by working memory load, suggesting that executive control regulates biased threat-processing downstream of initial input processes such as orienting. These results suggest that cognitive loads can exacerbate trait anxiety-related cognitive biases, and therefore represent a useful tool for assessing cognitive biases in future research. More importantly, since biased threat-processing has been implicated in the etiology and maintenance of anxiety, poor executive control may be a risk factor for anxiety disorders. (PsycINFO Database Record PMID- 27991818 TI - Don't look at my teeth when I smile: Teeth visibility in smiling faces affects emotionality ratings and gaze patterns. AB - Research on facial emotion processing has offered inconclusive results on whether certain emotional expressions, like happiness, are detected faster over others. A source of discrepancy among studies could stem from differences in physically salient features (e.g., teeth visibility), which are often left uncontrolled in this field of research. In Study 1, happy faces from the Karolinska Database Emotional Databse with visible, normal teeth unexpectedly obtained lower scores on intensity and prototypicality than the same faces with covered teeth. In Study 2, an eye-tracking methodology revealed that although faces with normal teeth drew participants' initial attention, participants spent more time looking at the eye region in faces with covered teeth, a region that previous research had found to be more informative of emotion than the mouth region. Overall, these results suggest that advantages often associated with certain emotional faces might be partially due to artifacts that should be systematically controlled for in future studies. (PsycINFO Database Record PMID- 27991819 TI - Autonomic reactivity and vulnerability to depression: A multi-wave study. AB - The ability of the autonomic nervous system to flexibly adapt to environmental changes is thought to indicate efficient use of self-regulatory resources. Deficits in autonomic reactivity appear to characterize current depression; however, whether autonomic reactivity confers vulnerability to future depression when individuals encounter environmental stressors is unknown. Fluctuations in respiratory sinus arrhythmia (RSA) and heart rate (HR) were evaluated in response to emotion-eliciting films among 134 undergraduates. Negative events and depressive symptoms were assessed 5 times across 12 weeks. Multilevel modeling demonstrated that smaller decreases in RSA in response to sadness, greater increases in HR following sadness, and smaller increases in HR to amusement were prospectively associated with greater depressive symptoms when individuals encountered high levels of idiographically assessed negative events. These results demonstrate that the lack of contextually appropriate autonomic reactivity may confer vulnerability to depression under conditions of environmental stress, perhaps due to attenuated capacity for effective self regulation. (PsycINFO Database Record PMID- 27991820 TI - Stressful life events and perceived parental control in formerly homeless families: Impact on child-internalizing symptoms. AB - Research has neglected the potential role of perceived parental control as a moderator between stressful life events (SLEs) and child-internalizing symptoms. Using secondary data from the Early Risers "Skills for Success" Program (August, Realmuto, Hektner, & Bloomquist, 2001), this study examined the impact of perceived parental control on the association between SLEs and child internalizing symptoms in formerly homeless families. The sample consisted of 137 families with 223 children between 4 and 12 years of age (M = 8.1, SD = 2.3) living in supportive housing sites in Minneapolis, Minnesota. Participants completed measures assessing the number of SLEs experienced (e.g., unemployment of parent, death of loved one, serious illness, homelessness), perceived parental control, and child-internalizing symptoms. In this sample, 65% of children (n = 144) experienced at least 1 SLE with an average experience of 2 SLEs (M = 2.0, SD = 1.9, range = 0-7). A regression analysis found that experiencing more SLEs and a perceived absence of parental control over child behavior were positively associated with child-internalizing symptoms. A significant interaction between SLEs and perceived absence of parental control over child behavior in predicting child internalizing symptoms was also found. These findings suggest that children of parents who model appropriate control are more likely to experience fewer internalizing symptoms in response to SLEs. (PsycINFO Database Record PMID- 27991821 TI - Youth-serving institutional resources and neighborhood safety: Ties with positive youth development. AB - Neighborhoods are critical contexts for adolescent development, but little attention has been paid to how neighborhood characteristics play a role in positive youth development (PYD), notably among predominantly African American youth. This study examined distinct features of the neighborhood, including youth serving institutional resources (YSI) and safety, as they relate to PYD among adolescents from low-income neighborhoods in an urban setting (n = 491, 68.6% African American). Because neighborhood experiences during adolescence often differ based on gender, we also examined moderation by gender. Results from cross sectional, multilevel data suggest that neighborhood safety, YSIs, and gender are differentially associated with indicators of PYD (i.e., hope, mastery, friend support). The pattern of results suggested that when associated with mastery, YSIs may compensate for low-safety neighborhoods for adolescent females but not males. In terms of associations with friend support, YSIs may foster the development of PYD in low-safety neighborhoods for males but not females. Limitations of the current study and implications for future research are discussed. (PsycINFO Database Record PMID- 27991822 TI - Quick Delay Questionnaire: Reliability, validity, and relations to functional impairments in adults with attention-deficit/hyperactivity disorder (ADHD). AB - The Quick Delay Questionnaire (QDQ) is a self-report measure of delay-related behaviors in adults, and the present study aimed at investigating the psychometric properties of QDQ scores, how well they can discriminate between ADHD adults and both clinical and nonclinical controls, as well as their relations to measures of functional impairments. In the present study, QDQ ratings, a laboratory measure of delay discounting, and ratings of functional impairments were collected from adults diagnosed with attention deficit/hyperactivity disorder (ADHD; n = 51), a clinical control group with other psychiatric disorders (n = 46), and a nonclinical control group (n = 105). Results showed that the QDQ scores showed adequate reliability. Adults with ADHD had higher scores compared with normal controls on both QDQ subscales, and they also reported higher levels of delay aversion than the clinical controls. Logistic regression analyses showed high specificity but low sensitivity when trying to discriminate between adults with ADHD and nonclinical controls. QDQ scores were not associated with a laboratory measure of delay discounting, but with functional impairments such as substance use, criminality, and money management. Our findings indicate that QDQ scores are reliable, but this instrument should be regarded as a complement rather than as a replacement for laboratory measures. The relatively low sensitivity of QDQ scores is in line with current models of heterogeneity stating that only a subgroup of individuals with ADHD has high levels of delay-related behaviors. Our findings further indicate that this subgroup may be at particularly high risk for problems in everyday life. (PsycINFO Database Record PMID- 27991823 TI - Examining the ethnoracial invariance of a bifactor model of anxiety sensitivity and the incremental validity of the physical domain-specific factor in a primary care patient sample. AB - There is growing support for a bifactor conceptualization of the Anxiety Sensitivity Index-3 (ASI-3; Taylor et al., 2007), consisting of a General factor and 3 domain-specific factors (i.e., Physical, Cognitive, Social). Earlier studies supporting a bifactor model of the ASI-3 used samples that consisted of predominantly White respondents. In addition, extant research has yet to support the incremental validity of the Physical domain-specific factor while controlling for the General factor. The present study is an examination of a bifactor model of the ASI-3 and the measurement invariance of that model among an ethnoracially diverse sample of primary-care patients (N = 533). Results from multiple-group confirmatory factor analysis supported the configural and metric/scalar invariance of the bifactor model of the ASI-3 across self-identifying Black, Latino, and White respondents. The Physical domain-specific factor accounted for unique variance in an index of health anxiety beyond the General factor. These results provide support for the generalizability of a bifactor model of the ASI-3 across 3 ethnoracial groups, as well as indication of the incremental explanatory power of the Physical domain-specific factor. Study implications are discussed. (PsycINFO Database Record PMID- 27991824 TI - Symbolic meanings of sex in relationships: Developing the Meanings of Sexual Behavior Inventory. AB - Consistent with symbolic interactionism and motivation research, the study explored the meanings of sexual behavior in romantic relationships in a sample of 3,003 online respondents. Starting with a pool of 104 respondent-generated items, Exploratory and Confirmatory Factor analyses in separate sample halves revealed a stable set of 9 dimensions within that item pool that formed 2 higher-order factors representing positive (to share pleasure, to bond, to de-stress, to energize the relationship, to learn more about each other) and negative (to manage conflict, as an incentive, to express anger, and to control partner) meanings of sexual behavior within relationships. Item Response Theory analyses helped select the 4-5 most effective items of each dimension for inclusion in the Meanings of Sexual Behavior Inventory (MoSBI). Generalizability analyses suggested that the MoSBI subscale scores continued to show high levels of internal consistency across a broad range of demographic subgroups (e.g., racial/ethnic groups, gay and lesbian respondents, and various levels of education). The MoSBI subscales demonstrated moderate and distinct patterns of association with a range of conceptual boundary scales (e.g., relationship and sexual satisfaction, emotional support, negative conflict behavior, and frequency of sexual behavior) suggesting that these scales represent novel relationship processes. Consistent with this, analyses in the 862 respondents completing a 2 month follow-up assessment suggested that the meanings of sexual behavior predicted residual change in relationship satisfaction, even after controlling for frequency of sexual behavior within the relationships. Implications are discussed. (PsycINFO Database Record PMID- 27991825 TI - Is dietary restraint a unitary or multi-faceted construct? AB - Given that approximately two-thirds of adults are overweight or obese, there is substantial interest in dieting (dietary restraint) to promote weight loss. However, research on the associations between dietary restraint and binge eating is inconsistent. One possible explanation for contradictory findings is that measures of dietary restraint assess heterogeneous constructs. Nonclinical samples of university student (n = 433; 62.6% female) and community-recruited (n = 407; 47.4% female) adults completed self-report measures of dietary restraint. Exploratory structural equation modeling and exploratory and confirmatory factor analyses were used to identify latent dietary restraint factor(s). Structural equation modeling and multiple regression were used to test associations among latent dietary restraint factor(s), body mass index (BMI), eating-disorder risk, binge eating, and psychopathological and personality variables. Three latent dietary restraint factors emerged: (a) Calorie Counting; (b) Preoccupation With Dieting; and (c) Weight-Focused Restraint. The model demonstrated a good fit to the data. Eating-disorder risk was significantly and positively associated with all restraint factors, whereas higher levels of BMI and binge eating were significantly associated with greater Preoccupation with Dieting and Weight Focused Restraint only. Our findings indicated that dietary restraint is a heterogeneous construct and that measures of restraint assess different aspects of dieting. Our results have important implications for eating and weight disorders treatment, and suggest that weight-loss interventions that do not simultaneously increase negative attitudes toward one's body may be useful for treating weight disorders, without promoting disordered eating. (PsycINFO Database Record PMID- 27991826 TI - Relationship Between Breastfeeding and Early Childhood Obesity: Results of a Prospective Longitudinal Study from Birth to 4 Years. AB - AIM: To study a potential link between breastfeeding in infancy and obesity at age 4. MATERIALS AND METHODS: A total of 30,508 infants born during 2002-2007 from the databases of the Preventive Child Health Services in two Swedish counties and from national registers were studied. The outcome variable was obesity at age 4. Analyses were conducted by logistic regression models using the methodology of generalized estimating equations. Analyses were adjusted for child sex and maternal anthropometric and sociodemographic variables. RESULTS: In unadjusted analyses, any breastfeeding up to 9 months was linked to successively decreasing odds ratios (ORs) for obesity at age 4 (ORs 0.78-0.33), however, not significantly for 1 week and 2 months of breastfeeding. In adjusted analyses, the same pattern remained statistically significant for breastfeeding for 4 (OR 0.51), 6 (OR 0.55), and 9 (OR 0.47) months. Child sex, maternal education, maternal body mass index, and maternal smoking additionally influenced child obesity. CONCLUSION: Breastfeeding duration for at least 4 months may contribute independently to a reduced risk for childhood obesity at 4 years. PMID- 27991827 TI - Bragging on Facebook: The Interaction of Content Source and Focus in Online Impression Formation. AB - Warranting Theory proposes that third-party testimonials are more influential in online impression formation than target-authored statements. Individuals posting content on social media accurately convey their offline personality while endeavoring to present themselves in a positive light. In doing so, they may misjudge the psychological distance of the majority of viewers, who could view this positive self-presentation as bragging and form resultant negative impressions. In this study, we asked 136 participants to view the Facebook timelines of four female targets. Timeline content varied by source (owner- vs. friend-authored) and focus (generally positive vs. personally positive). Participants were tasked with forming impressions of targets and rating them based on attractiveness, confidence, modesty, and popularity. We found that source and focus played distinct roles in impression formation. More positive impressions were formed when owner-authored content was general, and when friend authored content was personal. This highlights the role played by content focus in impression formation, and the potentially damaging effect of perceived bragging. These results are discussed in relation to the application of the Warranting Theory of impression formation online, and discrepancies between these results and those from related articles are examined. PMID- 27991828 TI - Enterococcus species diversity in fecal samples of wild marine species as determined by real-time PCR. AB - Analyses using culture-independent molecular techniques have improved our understanding of microbial composition. The aim of this work was to identify and quantify enterococci in fecal samples of wild marine species using real-time quantitative PCR. Seven Enterococcus species were examined in fecal DNA of South American fur seals (Arctocephalus australis), Subantarctic fur seals (Arctocephalus tropicalis), green turtles (Chelonia mydas), Magellanic penguins (Spheniscus magellanicus), snowy-crowned tern (Sterna trudeaui), white-backed stilt (Himantopus melanurus), white-chinned petrels (Procellaria aequinoctialis), red knot (Calidris canutus), and black-browed albatross (Thalassarche melanophris). All Enterococcus species evaluated were detected in all fecal samples of wild marine species, with a concentration ranging between 106 and 1012 copies/ng of total DNA. Differences in the enterococci distribution were observed. Enterococcus faecalis and Enterococcus mundtii were most abundant in marine mammals. Enterococcus faecalis was frequent in green turtle, Magellanic penguin, snowy-crowned tern, red knot, and black-browed albatross. Enterococcus hirae and Enterococcus gallinarum showed elevated occurrence in white-backed stilt, and Enterococcus faecium in white-chinned petrel. This study showed highest diversity of enterococci in feces of wild marine species than currently available data, and reinforced the use of culture-independent analysis to help us to enhance our understanding of enterococci in gastrointestinal tracts of wild marine species. PMID- 27991829 TI - Understanding E-Book Continuance Intention: Empirical Evidence from E-Book Users in a Developing Country. AB - The book publishing industry is going through radical transformations that are driven by recent developments in information systems (IS). E-books are merely one of these developments. Notwithstanding the projections in the growth of e-book use, producers of these products contend with the issue of building user retention and loyalty through continued use. Extending the technology acceptance model (TAM), this study examined the impact of factors of perceived usefulness, perceived ease of use, social influence, and facilitating conditions on e-book continuance intention among users. The subjects of this study were 317 students from five higher institutions of learning in South Africa. Empirical testing of the research model was carried out using structural equation modeling. The results indicate that 42 percent of the variance in e-book users' continuance intention is explained by perceived usefulness, perceived ease of use, and social influence. Interestingly, facilitating conditions have an influence, although indirectly, through perceived usefulness, perceived ease of use, and social influence. The study not only contributes to the existing IS literature by extending the TAM to explain continuance intention in the e-book IS domain in a developing country but also makes recommendations to practitioners who attempt to foster continuous use of this technology. PMID- 27991830 TI - Goshajinkigan for Low Back Pain: An Observational Study. AB - OBJECTIVES: Low back pain (LBP) is a chronic condition. Although Western treatments are available, Kampo (traditional Japanese) medicine is widely prescribed and covered by health insurance in Japan. Goshajinkigan (GJG), a Kampo formula, is commonly used to treat LBP. However, cases we have occasionally been encountered in which GJG did not show the expected effects. Hence, the purpose of this retrospective study was to investigate patient factors important in developing the effects of GJG. METHODS: This was a retrospective observational study based at the Center for Kampo Medicine, Keio University Hospital. Data were retrieved from the medical records of 28 patients who visited our hospital between May 2008 and March 2013 and who received GJG for LBP. The patients were divided into responders and non-responders based on whether their LBP improved post treatment. The groups were compared with respect to daily GJG dose, incidence of spine disease, and side effects. RESULTS: Ten patients (responders) reported an improvement in LBP within 6 months. One patient experienced decreased appetite as a side effect. Nine patients reported no improvement (non responders). The number of patients prescribed the usual daily dose of GJG (7.5 g) was significantly higher among responders than it was among non-responders (p = 0.023), and the number of patients with spine disease was significantly greater among non-responders than it was among responders (p = 0.020). The number of patients with spinal stenosis was significantly higher among non-responders than it was among responders (p = 0.011). Therefore, the usual daily dose of GJG provided significant relief of LBP, particularly in patients without any spine disease. CONCLUSIONS: Routine daily administration of GJG in patients without spine disease seems to lead to the effects of the product. However, further investigations using the above-mentioned parameters are needed to confirm these findings. PMID- 27991831 TI - Federal Powers to Control Communicable Conditions: Call for Reforms to Assure National Preparedness and Promote Global Security. PMID- 27991833 TI - Federated Biobanking with Corporate Service Unit: The Munich Biobank Alliance Blueprint. PMID- 27991832 TI - MgF3- and AlF4- transition state analogue complexes of yeast phosphoglycerate kinase. AB - The phospho-transfer mechanism of yeast phosphoglycerate kinase (PGK) has been probed through formation of trifluoromagnesate (MgF3-) and tetrafluoroaluminate (AlF4-) transition state analogue complexes and analyzed using 19F, 1H waterLOGSY and 1H chemical shift perturbation NMR spectroscopy. We observed the first 19F NMR spectroscopic evidence for the formation of metal fluoride transition state analogues of yeast PGK and also observed significant changes to proton chemical shifts of PGK in the presence, but not in the absence, of fluoride upon titration of ligands, providing indirect evidence of the formation of a closed ternary transition state. WaterLOGSY NMR spectroscopy experiments using an uncompetitive model were used in an attempt to measure ligand binding affinities within the transition state analogue complexes. PMID- 27991834 TI - Caregiver Treatment Preferences for Children with a New Versus Existing Attention Deficit/Hyperactivity Disorder Diagnosis. AB - OBJECTIVES: Parental experiences with managing their child's attention deficit/hyperactivity disorder (ADHD) can influence priorities for treatment. This study aimed to identify the ADHD management options caregivers most prefer and to determine if preferences differ by time since initial ADHD diagnosis. METHODS: Primary caregivers (n = 184) of a child aged 4-14 years old in care for ADHD were recruited from January 2013 through March 2015 from community-based pediatric and mental health clinics and family support organizations across the state of Maryland. Participants completed a survey that included child/family demographics, child clinical treatment, and a Best-Worst Scaling (BWS) experiment to elicit ADHD management preferences. The BWS comprised 18 ADHD management profiles showing seven treatment attributes, where the best and worst attribute levels were selected from each profile. A conditional logit model using effect coded variables was used to estimate preference weights stratified by time since ADHD diagnosis. RESULTS: Participants were primarily the mother (84%) and had a college or postgraduate education (76%) with 75% of the children on stimulant medications. One-on-one caregiver behavior training, medication use seven days a week, therapy in a clinic, and an individualized education program were most preferred for managing ADHD. Aside from caregiver training and monthly out-of pocket costs, caregivers of children diagnosed with ADHD for less than two years prioritized medication use lower than other care management attributes and caregivers of children diagnosed with ADHD for two or more years preferred school accommodations, medication, and provider specialty. CONCLUSIONS: Preferences for ADHD treatment differ based on the duration of the child's ADHD. Acknowledging that preferences change over the course of care could facilitate patient/family centered care planning across a range of resources and a multidisciplinary team of professionals. PMID- 27991835 TI - Parent-Reported Improvements in Family Functioning in a Randomized Controlled Trial of Lisdexamfetamine for Treatment of Parental Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: This study examines the effects of parental stimulant medication treatment on parent ratings of parent-child functioning. Ratings of parent-child functioning in the home setting and immediately following a laboratory-based parent-child interaction were collected. METHOD: Participants were 20 parents who along with their children (ages 5-12 years) were diagnosed with Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) attention deficit/hyperactivity disorder (ADHD). Parents completed an open-label titration to determine their optimal dose of lisdexamfetamine (30, 50, or 70 mg/day) and then completed a month-long double-blind randomized pharmacological intervention for parental ADHD. Effects of parental stimulant medication administered for an extended duration were assessed by parent ratings of parent-child functioning in the home setting and immediately following a laboratory parent-child interaction task conducted at an academic mental health center. Data were collected from September 2010 to June 2013. RESULTS: Stimulant medication versus placebo was associated with larger reductions in parental ADHD (d = 1.01-1.09), impairment (d = 0.67-0.82), and executive dysfunction (d = 0.74-0.94) in the home setting. No significant benefits of stimulant medication emerged in measures of parenting or child behavior at home. In the laboratory setting, parents treated with stimulant medication versus placebo reported fewer ADHD symptoms (d = 1.01-1.05) and their interaction was more successful (d = 0.83) and pleasant (d = 0.92). Several additional trends emerged showing beneficial effects of stimulant medication on parent-child functioning. CONCLUSION: Parents treated with stimulant medication evidenced some improvements in parent-child functioning, which support the use of pharmacological intervention to improve functioning in families with parent-child ADHD. CLINICAL TRIALS REGISTRATION: NCT01127607. PMID- 27991836 TI - Correlations Between COL2A and Aggrecan Genetic Polymorphisms and the Risk and Clinicopathological Features of Intervertebral Disc Degeneration in a Chinese Han Population: A Case-Control Study. AB - OBJECTIVES: This case-control study was designed to evaluate the association of three COL2A1 single nucleotide polymorphism (SNPs) (rs1793953, rs2276454, and rs1793937) and Aggrecan variable number of tandem repeat (VNTR) polymorphisms with the risk and clinicopathological features of intervertebral disc degeneration (IVDD) in a Chinese Han population. MATERIALS AND METHODS: Data from 295 IVDD patients (case group) and 324 healthy volunteers (control group) were collected between January 2012 and December 2014. Magnetic resonance examinations were conducted on all included subjects. The frequency distributions of the COL2A1 and Aggrecan polymorphisms were detected using direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, respectively. RESULTS: The genotype and allele frequencies of the COL2A1 genetic polymorphisms (rs1793953 and rs2276454) and the Aggrecan VNTR polymorphisms differed significantly between the case group and the control group (all p < 0.05). The haplotype analysis indicated that the frequencies of ACGL (L, long) and GTCL haplotypes were lower in the case group than in the control group (both p < 0.05). In the case group, the genotype and allele frequencies of the COL2A1 genes, rs1793953 and rs2276454, and Aggrecan VNTR significantly differed in terms of Pfirrmann grades III, IV, and V (all p < 0.05). Personal history of spine sprain or crush injury, history of IVDD in a first-degree relative, and COL2A1 rs2276454 and Aggrecan VNTR presence may be independent risk factors of IVDD (all p < 0.05, odds ratio [OR] >1), whereas tea drinking habit, part-time sports participation, and COL2A1 rs1793953 presence may be protective factors of IVDD (all p < 0.05, OR <1). CONCLUSION: Our study provides evidence that COL2A1 and Aggrecan genetic polymorphisms may be correlated with the risk and clinicopathological features of IVDD in a Chinese Han population, and ACGL and GTCL haplotypes may be protective factors of IVDD. PMID- 27991837 TI - Vision Preservation in Eyes of Polypoidal Choroidal Vasculopathy with Low-Dose Intravitreal Triamcinolone Acetonide. AB - PURPOSE: To evaluate the efficacy and adverse effects of using low-dose intravitreal triamcinolone acetonide (IVTA) to preserve vision in polypoidal choroidal vasculopathy (PCV) eyes. METHODS: This retrospective chart review study examined 8 eyes of 7 PCV patients, for whom verteporfin photodynamic therapy (vPDT) or antivascular endothelial growth factor (VEGF) therapy was not affordable/available and also with intolerable risk because of underlying cardiovascular and/or cerebrovascular ischemia. Low-dose IVTA (1 mg/0.025 mL) monotherapy was administered and repeated every 4 weeks if intraretinal edema or subretinal fluid persisted. RESULTS: The median follow-up time was 26.4 months. Three eyes (3/8) maintained their initial best-corrected visual acuity and 4 eyes (4/8) exhibited improvement, whereas 1 eye (1/8) sustained some loss. The mean injection number per month was 0.7 for the first 6 months, after which it decreased to 0.4. In regard to adverse effects, intraocular pressure (IOP) of more than 21 mmHg was noted as persisting for a few weeks in 4 eyes and that of more than 30 mmHg was noted once in 1 eye. The increased IOP was adequately controlled by using IOP-lowering agents. Two initially phakic eyes each underwent cataract surgery in the 12th and 14th months after treatment. CONCLUSIONS: Low dose IVTA therapy may be valuable for preserving the vision of PCV patients, while vPDT or anti-VEGF is not affordable/available or of those with underlying diseases for whom anti-VEGF therapy is with intolerable risk. PMID- 27991838 TI - Evaluation of a Powered Stapler System with Gripping Surface Technology on Surgical Interventions Required During Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Transection of gastric tissue during laparoscopic sleeve gastrectomy (LSG) can be challenging. Reinforcing the staple line may decrease the incidence of issues requiring intervention. METHODS: The objective of this study was to compare the number of intraoperative surgical interventions for a surgical stapler and reload system with Gripping Surface Technology (GST) to standard reloads in patients who underwent LSG. Patients who underwent elective LSG were enrolled. The study was conducted in two stages. For Stage 1, procedures were performed using a powered stapler and standard reloads. For Stage 2, a reload system with GST was used. The primary endpoint was surgical interventions for bleeding and/or staple line issues during transection of the greater curvature of the stomach. Propensity score matching was applied to create two groups similar in baseline characteristics and risk factors. RESULTS: A total of 111 subjects were enrolled across four centers. Propensity-matched procedures were completed with the standard (n = 38) or GST reloads (n = 38). The mean number of interventions in the standard group was 1.9 (1.29) versus 1.1 (1.45) in the GST group. Nonparametric comparisons were statistically significant, indicating a reduction in the distribution of interventions for GST subjects (P = .0036 for matched pair data). Tissue slippage during transection was low for both groups. Intraoperative leak testing was negative in all procedures, and no procedures were converted to open. CONCLUSIONS: Use of the GST stapling system reduces the need for staple line interventions in LSG. Both stapling systems had an acceptable safety profile. PMID- 27991839 TI - Hypernatremic Dehydration in Breastfed Term Infants: Retrospective Evaluation of 159 Cases. AB - OBJECTIVES: The aim of this study was to reveal the frequency, presenting complaints, risk factors, complications, and ways for prevention of hypernatremic dehydration (HD) among term breastfed infants. METHODS: The files of 159 breastfed term infants hospitalized because of HD between the years 2009 and 2014 were examined retrospectively in the Neonatal Intensive Care Unit of Sivas State Hospital, Turkey. The patients were classified according to serum sodium (Na) levels, group 1 (Na: 146-149 mEq/L, n = 68) and group 2 (Na >=150 mEq/L, n = 91). RESULTS: The most common complaint was fever (67.9%), and the most common physical finding was oral mucosal dryness (76%). There were positive correlations between serum Na levels and weight loss, hospital stay, admission age, admission to neonatal unit after discharge, serum urea levels, and body temperature (p < 0.05). The normalization period of Na levels was significantly longer (21.7 +/- 8.8 versus 29.3 +/- 17.8 hours, p = 0.03), and Na reduction rate was faster in group 2 (0.41 +/- 0.3 versus 0.50 +/- 0.3 mEq/L/hour, p = 0.02). Bradycardia was seen more commonly in group 2 (1.5% versus 16.5%, p = 0.002). CONCLUSIONS: HD is a significant condition that should be treated appropriately to avoid serious complications. PMID- 27991840 TI - How to Train an Injured Brain? A Pilot Feasibility Study of Home-Based Computerized Cognitive Training. AB - OBJECTIVE: Computerized cognitive training programs have previously shown to be effective in improving cognitive abilities in patients suffering from traumatic brain injury (TBI). These studies often focused on a single cognitive function or required expensive hardware, making it difficult to be used in a home-based environment. This pilot feasibility study aimed to evaluate the feasibility of a newly developed, home-based, computerized cognitive training program for adolescents who suffered from TBI. Additionally, feasibility of study design, procedures, and measurements were examined. DESIGN: Case series, longitudinal, pilot, feasibility intervention study with one baseline and two follow-up assessments. MATERIALS AND METHODS: Nine feasibility outcome measures and criteria for success were defined, including accessibility, training motivation/user experience, technical smoothness, training compliance, participation willingness, participation rates, loss to follow-up, assessment timescale, and assessment procedures. Five adolescent patients (four boys, mean age = 16 years 7 months, standard deviation = 9 months) with moderate to severe TBI in the chronic stage were recruited and received 8 weeks of cognitive training with BrainGames. Effect sizes (Cohen's d) were calculated to determine possible training-related effects. RESULTS: The new cognitive training intervention, BrainGames, and study design and procedures proved to be feasible; all nine feasibility outcome criteria were met during this pilot feasibility study. Estimates of effect sizes showed small to very large effects on cognitive measures and questionnaires, which were retained after 6 months. CONCLUSION: Our pilot study shows that a longitudinal intervention study comprising our novel, computerized cognitive training program and two follow-up assessments is feasible in adolescents suffering from TBI in the chronic stage. Future studies with larger sample sizes will evaluate training-related effects on cognitive functions and underlying brain structures. PMID- 27991842 TI - 20 Years: From Outcasts to the O-Zone. PMID- 27991843 TI - Rates and Correlates of Syphilis Reinfection in Men Who Have Sex with Men. AB - PURPOSE: This study examined rates and correlates of syphilis reinfection in men who have sex with men (MSM). METHODS: From 2012 to 2015, time to reinfection was assessed in 323 MSM receiving initial treatment for syphilis in San Francisco. RESULTS: One in five men was reinfected (71/323; 22%). The rate of syphilis reinfection was greater among HIV-infected men (adjusted hazard ratio [aHR] = 1.96; 95% confidence interval [95% CI] = 1.16-3.31) and ketamine users (aHR = 2.76; 95% CI = 1.09-7.00). CONCLUSION: Expanded prevention efforts are needed with HIV-infected and substance-using MSM to reduce the burden of reinfection in this population. PMID- 27991844 TI - External Validation of a Decision Tool To Guide Post-Operative Management of Patients with Secondary Peritonitis. AB - BACKGROUND: Timely identification of patients in need of an intervention for abdominal sepsis after initial surgical management of secondary peritonitis is vital but complex. The aim of this study was to validate a decision tool for this purpose and to evaluate its potential to guide post-operative management. METHODS: A prospective cohort study was conducted on consecutive adult patients undergoing surgery for secondary peritonitis in a single hospital. Assessments using the decision tool, based on one intra-operative and five post-operative variables, were performed on the second and third post-operative days and when the patients' clinical status deteriorated. Scores were compared with the clinical reference standard of persistent sepsis based on the clinical course or findings at imaging or surgery. Additionally, the potential of the decision tool to guide management in terms of diagnostic imaging in three previously defined score categories (low, intermediate, and high) was evaluated. RESULTS: A total of 161 assessments were performed in 69 patients. The majority of cases of secondary peritonitis (68%) were caused by perforation of the gastrointestinal tract. Post operative persistent sepsis occurred in 28 patients. The discriminative capacity of the decision tool score was fair (area under the curve of the receiver operating characteristic = 0.79). The incidence rate differed significantly between the three score categories (p < 0.001). The negative predictive value of a decision tool score categorized as low probability was 89% (95% confidence interval [CI] 82-94) and 65% (95% CI 47-79) for an intermediate score. Diagnostic imaging was performed more frequently when there was an intermediate score than when the score was categorized as low (46% vs. 24%; p < 0.001). CONCLUSION: In patients operated on for secondary peritonitis, the decision tool score predicts with fair accuracy whether persistent sepsis is present. PMID- 27991846 TI - Onward: Markers and Signs Pointing the Way. PMID- 27991847 TI - Different Vancomycin-Intermediate Staphylococcus aureus Phenotypes Selected from the Same ST100-hVISA Parental Strain. AB - The aim of this study is to characterize the factors related to peptidoglycan metabolism in isogenic hVISA/VISA ST100 strains. Recently, we reported the increase in IS256 transposition in invasive hVISA ST100 clinical strains isolated from the same patient (D1 and D2) before and after vancomycin treatment and two laboratory VISA mutants (D23C9 and D2P11) selected from D2 in independent experiments. High performance liquid chromatography-mass spectrometry (HPLC-MS) analysis of peptidoglycan muropeptides showed increased proportion of monomeric muropeptides and a concomitant decrease in the proportion of tetrameric muropeptide in D2 and derived mutants when compared to the original strain D1. In addition, strain D2 and its derived mutants showed an increase in cell wall thickness with increased pbp2 gene expression. The VISA phenotype was not stable in D2P11 and showed a reduced autolysis profile. On the other hand, the mutant D23C9 differentiates from D2 and D2P11 in the autolysis profile, and pbp4 transcription profile. D2-derived mutants exhibited differences in the susceptibility to other antimicrobials. Our results highlight the possibility of selection of different VISA phenotypes from a single hVISA-ST100 genetic background. PMID- 27991848 TI - Molecular Characteristics of Erythromycin-Resistant Streptococcus pyogenes Strains Isolated from Children Patients in Tunis, Tunisia. AB - AIM: The aims of our study were to characterize phenotypically and genotypically erythromycin-resistant Streptococcus pyogenes or group A streptococci (ERGAS) isolates, to evaluate macrolide resistance and to analyze the association between emm types and virulence factors. Included in this study were all ERGAS strains isolated from 2000 to 2013 at the Children's hospital of Tunis. Antimicrobial susceptibility was performed according to the CA-SFM guidelines. Macrolide resistance genes were revealed by polymerase chain reaction (PCR) method. Virulence factor genes (pyrogenic exotoxin genes and superantigen gene) were detected by PCR, and the emm types were defined by the sequencing of the variable 5' end of the emm gene. RESULTS: Among the 289 GAS isolates collected, 15 (5.2%) were resistant to erythromycin; 7 of the strains were assigned to the cMLSB phenotype (46.6%); 5 harbored ermB gene alone (33.3%); and 2 strains coharbored ermB and mefA (13.3%). The remaining (53.4%) were assigned to the M phenotype and harbored the mefA gene. The frequency of detection of each toxin gene among ERGAS was 13.4% for speA (2 strains), 53.4% for speC (8 strains), and 13.4% for ssa (2 strains). Emm types 1, 58, 11, and 78 were the most frequent among ERGAS strains. The distribution of the cMLSB and M phenotypes changed over the period of investigation with a decrement of cMLSB phenotype and ermB gene that predominated between 2000 and 2006 and an increase of M phenotype and mefA gene between 2007 and 2013, but this difference was nonstatistically significant because of the low number of resistant strains. Emm types 1, 58, and 4 were only present among strains assigned to the M phenotype. However strains assigned to the cMLSB phenotype were associated to emm11, emm22, emm28, emm78, or emm76. There was diversity in emm distribution in ERGAS between the two study periods. There was diversity in emm distribution among ERGAS particularly in 2000-2006. Indeed, from 2000 to 2006, the 6 ERGAS belonged to 5 different emm types (22, 28, 76, 11, and 4), while between 2007 and 2013, seven among the nine ERGAS belonged to only 2 emm types 58 and 1. The speA gene was present only among emm1 isolates, and the ssa gene was associated with emm4 and emm78 types. All emm78, emm28, and emm11 strains harbored speC gene. CONCLUSIONS: Our study revealed a low frequency of ERGAS and few emm types were associated with these strains. PMID- 27991849 TI - Trough concentration and ABCG2 polymorphism are better to predict imatinib response in chronic myeloid leukemia: a meta-analysis. AB - AIM: The present study aimed to conduct a series of meta-analyses to investigate the influence of imatinib trough concentration (C0), as well as ABCB1 and ABCG2 polymorphisms, on the clinical response in patients with chronic myeloid leukemia (CML). METHODS: A literature search was conducted using the PubMed and Cochrane electronic databases to locate relevant papers from 2003 onward. Then, an initial meta-analysis of 14 studies involving 2184 patients was conducted to understand the effect of imatinib mesylate (IM) C0 on clinical outcome in CML patients. Subsequently, a series of meta-analyses were performed, including up to 23 studies with 2577 patients, on the effect of genetic polymorphisms of ABCB1 and ABCG2 on the clinical response to IM. RESULTS: Meta-analysis revealed that patients who achieved a major molecular response (MMR) have a significantly higher IM C0 than those who failed to achieve an MMR. We also found that the patients who achieved a complete cytogenic response (CCyR) have a significantly higher IM C0 than those who did not achieve a CCyR. However, no significant difference in IM C0 was found between the complete molecular response and non complete molecular response groups. Additional analysis showed that ABCG2 421 variant A allele was significantly associated with a higher rate of MMR and overall response, especially in Asian patients. Meta-analysis did not reveal a correlation between ABCB1 C3435T and C1236T polymorphisms with any clinical response to IM. However, the G2677T/A polymorphism could play a role in IM response in the recessive model. CONCLUSION: This meta-analysis demonstrates that there was a significant correlation between the IM trough concentration and clinical responses, especially MMR and CCyR, in CML patients. Furthermore, we found that the probability of successful treatment was correlated with the ABCG2 C421A polymorphism, at least within the Asian population. We failed to determine an association between ABCB1 polymorphisms and IM response, although the G2677T/A polymorphism might be involved. However, further large-scale investigations using more sensitive genotyping methods would be required to confirm this. PMID- 27991850 TI - Mitochondrial support of persistent presynaptic vesicle mobilization with age dependent synaptic growth after LTP. AB - Mitochondria support synaptic transmission through production of ATP, sequestration of calcium, synthesis of glutamate, and other vital functions. Surprisingly, less than 50% of hippocampal CA1 presynaptic boutons contain mitochondria, raising the question of whether synapses without mitochondria can sustain changes in efficacy. To address this question, we analyzed synapses from postnatal day 15 (P15) and adult rat hippocampus that had undergone theta-burst stimulation to produce long-term potentiation (TBS-LTP) and compared them to control or no stimulation. At 30 and 120 min after TBS-LTP, vesicles were decreased only in presynaptic boutons that contained mitochondria at P15, and vesicle decrement was greatest in adult boutons containing mitochondria. Presynaptic mitochondrial cristae were widened, suggesting a sustained energy demand. Thus, mitochondrial proximity reflected enhanced vesicle mobilization well after potentiation reached asymptote, in parallel with the apparently silent addition of new dendritic spines at P15 or the silent enlargement of synapses in adults. PMID- 27991851 TI - Semi-intact ex vivo approach to investigate spinal somatosensory circuits. AB - The somatosensory input that gives rise to the perceptions of pain, itch, cold and heat are initially integrated in the superficial dorsal horn of the spinal cord. Here, we describe a new approach to investigate these neural circuits in mouse. This semi-intact somatosensory preparation enables recording from spinal output neurons, while precisely controlling somatosensory input, and simultaneously manipulating specific populations of spinal interneurons. Our findings suggest that spinal interneurons show distinct temporal and spatial tuning properties. We also show that modality selectivity - mechanical, heat and cold - can be assessed in both retrogradely labeled spinoparabrachial projection neurons and genetically labeled spinal interneurons. Finally, we demonstrate that interneuron connectivity can be determined via optogenetic activation of specific interneuron subtypes. This new approach may facilitate key conceptual advances in our understanding of the spinal somatosensory circuits in health and disease. PMID- 27991853 TI - Influences of proton pump inhibitor on Helicobacter pylori adherence to the gastrointestinal cell lines. AB - BACKGROUND/AIMS: Helicobacter pylori is a carcinogenic bacterium that could induce P-glycoprotein expression in the human gastrointestinal tract. Bacterial adherence to the gastrointestinal cell lines could be influenced by the level of P-glycoprotein. This study aimed to determine the influence of proton pump inhibitors that exhibit an inhibitory effect on P-glycoprotein in gastrointestinal carcinoma cell lines, namely Caco-2 and LS174T, in relation to H. pylori adherence. MATERIALS AND METHODS: Caco-2 and LS174T cells lines treated with omeprazole and esomeprazole were used in this study to assess the bacterial attachment of H. pylori within certain incubation periods. RESULTS: The presence of proton pump inhibitors increased the H. pylori adherence in a time-dependent manner in both Caco-2 and LS174T cell lines. The double inhibition of P glycoprotein using proton pump inhibitor and P-glycoprotein inhibitor caused low P-glycoprotein expression in the cell lines, resulting in higher H. pylori adherence compared to the control cell lines. CONCLUSION: Proton pump inhibitors may alter P-glycoprotein expression in the gastrointestinal tract, and subsequently H. pylori adherence on the cell lines, and may contribute to resistance to drug therapy. PMID- 27991854 TI - Mean arterial pressure drop is an independent risk factor of death in patients with HBV-related cirrhosis ascites. AB - BACKGROUND/AIMS: In patients with cirrhosis ascites, mean arterial pressure (MAP) is a credible sign of circulatory dysfunction. There are no studies on the relationship between MAP and long-term prognosis in hepatitis B virus (HBV) related liver cirrhosis ascites. Therefore, we assessed the association between MAP and prognosis in patients with liver cirrhosis ascites. MATERIALS AND METHODS: In total, 110 patients of HBV-related liver cirrhosis ascites were prospectively followed for 5 years. After their admission, the patients underwent laboratory tests and MAP measurements. Multivariate analysis was conducted using backward stepwise Cox proportional hazards regression. Receiver operator characteristic (ROC) curves were used to confirm the best cutoff value of several baseline parameters, including MAP, for predicting death in patients with liver cirrhosis ascites. RESULTS: In a follow-up period of 5 years, 60 (54.5%) patients survived. MAP (OR 1.176, 95% CI 1.045 to 1.326, p=0.003) was an independent risk factor of death, together with Child-Pugh score (OR 1.204, 95% CI 1.068 to 1.357, p=0.002) and model for end-stage liver disease score (OR 1.297, 95% CI 1.198 to 1.405, p=0.000). The area under the ROC curve of MAP was 0.819 at baseline (95% CI 0.741 to 0.897, p=0.000). A baseline MAP value of <=83.5 mmHg was an independent risk factor of death. CONCLUSION: A decrease in MAP was a valuable predictor of death in patients with HBV-related liver cirrhosis ascites. MAP may be used for determining the prognosis and exploring new treatment measures directed at optimizing the treatment of liver cirrhosis ascites. PMID- 27991855 TI - Promotional effect of nonalcoholic fatty liver disease on Gallstone disease: A systematic review and meta-analysis. AB - BACKGROUND/AIMS: Growing evidence indicates that nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) share the same risk factors, and that NAFLD may be associated with the occurrence of GD. However, overall results remain controversial. The aim of this study is to perform a meta-analysis to assess the relationship between GD and NAFLD. MATERIALS AND METHODS: Five databases (PubMed, Medline, Embase, Web of Science, and Cochrane Library) were queried, and observational studies that assessed the association between GD and NAFLD were selected. We pooled the prevalence of GD in participants with NAFLD, and compared the prevalence of GD in NAFLD and non-NAFLD groups in four trials. RESULTS: Twelve studies met our inclusion criteria. The pooled prevalence of GD in cases with NAFLD was 17% (95% CI: 0.12-0.23). Compared with the non-NAFLD group, NAFLD was significantly correlated with GD (OR: 1.40, 95% CI: 1.23-1.59). Additional analyses reveal that participants in the GD group included more females (OR: 1.95, 95% CI: 1.36-2.79), were older (WMD: 6.61, 95% CI: 3.80-9.42), and had higher BMIs (WMD: 1.63, 95% CI: 0.62-2.65) in the population with NAFLD, compared to the non-GD group. CONCLUSION: GD prevalence in NAFLD patients is higher than that in the general population. Furthermore, the occurrence of GD is significantly associated with the female sex, age and BMI in NAFLD patients. PMID- 27991856 TI - Results of 12-month rescue treatment with Teduglutide in severely active and parenteral nutrition-dependent Crohn's disease. PMID- 27991852 TI - Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival. AB - Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood. PMID- 27991857 TI - A rare cause of severe gastrointestinal bleeding in a thrombocytopenic patient with acute myeloid leukemia. PMID- 27991859 TI - Breath mass ion biomarkers of breast cancer. AB - BACKGROUND: Breath volatile organic compounds (VOCs) contain biomarkers of breast cancer that are detectable with gas chromatography mass spectrometry (GC MS). However, chemical identification of breath VOC biomarkers may be erroneous because spectral matching can misidentify their structure. Breath mass ions detected with GC MS have been proposed as intrinsically robust biomarkers because they can be identified without spectral matching. We investigated whether breath mass ion biomarkers could identify breast cancer. METHODS: We re-analyzed data from a previous study of breath VOCs in 54 women with biopsy-proven breast cancer and in 204 healthy controls. Subjects were randomly assigned to a training set (2/3) and a test set (1/3). Chromatograms were processed with metabolomic analysis software (XCMS in R) in order to generate a table listing retention times with their associated ion masses and intensities, and binned into a series of 5 sec retention time segments. In the training set, mass ions in each time segment were ranked according to their diagnostic accuracy i.e. the area under curve (AUC) of the receiver operating characteristic (ROC) curve. We employed multiple Monte Carlo simulations to select the biomarker mass ions in each time segment that identified breast cancer with greater than random accuracy and combined those with the highest diagnostic accuracy in a predictive algorithm using multivariate weighted digital analysis (WDA). We then employed this algorithm to predict the diagnosis in the test set. RESULTS: The training set WDA algorithm employing 21 mass ion biomarkers identified breast cancer with ROC curve AUC = 0.79. In the test set, this algorithm predicted breast cancer with ROC curve AUC = 0.77. CONCLUSION: Breath mass ions biomarkers accurately identified women with breast cancer and could potentially be used in early diagnosis and treatment monitoring. PMID- 27991858 TI - EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis. AB - BACKGROUND: During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience. METHODS: The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics. RESULTS: The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration >=60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined. CONCLUSIONS: A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established. PMID- 27991861 TI - Astrocytic calcium release mediates peri-infarct depolarizations in a rodent stroke model. AB - Stroke is one of the most common diseases and a leading cause of death and disability. Cessation of cerebral blood flow (CBF) leads to cell death in the infarct core, but tissue surrounding the core has the potential to recover if local reductions in CBF are restored. In these areas, detrimental peri-infarct depolarizations (PIDs) contribute to secondary infarct growth and negatively affect stroke outcome. However, the cellular pathways underlying PIDs have remained unclear. Here, we have used in vivo multiphoton microscopy, laser speckle imaging of CBF, and electrophysiological recordings in a mouse model of focal ischemia to demonstrate that PIDs are associated with a strong increase of intracellular calcium in astrocytes and neurons. We found that astroglial calcium elevations during PIDs are mediated by inositol triphosphate receptor type 2 dependent (IP3R2-dependent) release from internal stores. Importantly, Ip3r2 deficient mice displayed a reduction of PID frequency and overall PID burden and showed increased neuronal survival after stroke. These effects were not related to local CBF changes in response to PIDs. However, we showed that the release and extracellular accumulation of glutamate during PIDs is strongly curtailed in Ip3r2-deficient mice, resulting in ameliorated calcium overload in neurons and astrocytes. Together, these data implicate astroglial calcium pathways as potential targets for stroke therapy. PMID- 27991860 TI - M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. AB - The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD. PMID- 27991862 TI - Fluorescent aminoglycosides reveal intracellular trafficking routes in mechanosensory hair cells. AB - Aminoglycosides (AGs) are broad-spectrum antibiotics that are associated with kidney damage, balance disorders, and permanent hearing loss. This damage occurs primarily by killing of proximal tubule kidney cells and mechanosensory hair cells, though the mechanisms underlying cell death are not clear. Imaging molecules of interest in living cells can elucidate how molecules enter cells, traverse intracellular compartments, and interact with sites of activity. Here, we have imaged fluorescently labeled AGs in live zebrafish mechanosensory hair cells. We determined that AGs enter hair cells via both nonendocytic and endocytic pathways. Both routes deliver AGs from the extracellular space to lysosomes, and structural differences between AGs alter the efficiency of this delivery. AGs with slower delivery to lysosomes were immediately toxic to hair cells, and impeding lysosome delivery increased AG-induced death. Therefore, pro death cascades induced at early time points of AG exposure do not appear to derive from the lysosome. Our findings help clarify how AGs induce hair cell death and reveal properties that predict toxicity. Establishing signatures for AG toxicity may enable more efficient evaluation of AG treatment paradigms and structural modifications to reduce hair cell damage. Further, this work demonstrates how following fluorescently labeled drugs at high resolution in living cells can reveal important details about how drugs of interest behave. PMID- 27991865 TI - Fruits of Education: E-technology and applications in lab animal training. PMID- 27991866 TI - Models matter in metastasis. PMID- 27991863 TI - Carbohydrate-binding protein CLEC14A regulates VEGFR-2- and VEGFR-3-dependent signals during angiogenesis and lymphangiogenesis. AB - Controlled angiogenesis and lymphangiogenesis are essential for tissue development, function, and repair. However, aberrant neovascularization is an essential pathogenic mechanism in many human diseases, including diseases involving tumor growth and survival. Here, we have demonstrated that mice deficient in C-type lectin family 14 member A (CLEC14A) display enhanced angiogenic sprouting and hemorrhage as well as enlarged jugular lymph sacs and lymphatic vessels. CLEC14A formed a complex with VEGFR-3 in endothelial cells (ECs), and CLEC14A KO resulted in a marked reduction in VEGFR-3 that was concomitant with increases in VEGFR-2 expression and downstream signaling. Implanted tumor growth was profoundly reduced in CLEC14A-KO mice compared with that seen in WT littermates, but tumor-bearing CLEC14A-KO mice died sooner. Tumors in CLEC14A-KO mice had increased numbers of nonfunctional blood vessels and severe hemorrhaging. Blockade of VEGFR-2 signaling suppressed these vascular abnormalities and enhanced the survival of tumor-bearing CLEC14A-KO mice. We conclude that CLEC14A acts in vascular homeostasis by fine-tuning VEGFR-2 and VEGFR-3 signaling in ECs, suggesting its relevance in the pathogenesis of angiogenesis-related human disorders. PMID- 27991864 TI - Gsalpha deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsalpha mutations. AB - Gsalpha, encoded by Gnas, mediates hormone and neurotransmitter receptor stimulated cAMP generation. Heterozygous Gsalpha-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gsalpha imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gsalpha expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia. Although maternal Gnas deletion impaired activation of brown adipose tissue (BAT) in mice, their responses to cold environment remained intact. Similar findings were observed in mice with DMH-specific deficiency of melanocortin MC4R receptors, which are known to activate Gsalpha. Our results show that Gsalpha imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from Gsalpha mutations and that DMH MC4R/Gsalpha signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold. PMID- 27991867 TI - Response to Protocol Review Scenario: The spirit of the law. PMID- 27991868 TI - A blood boost for NAD. PMID- 27991869 TI - Terminal procedures: Should an IACUC require a literature review for less painful alternatives? PMID- 27991870 TI - A cost-effective software solution for vivarium management. PMID- 27991871 TI - Automation: robots in the vivarium. AB - Automation technologies are improving efficiency in the vivarium and helping institutions keep up with the growing number of mutant rodents in their colonies. PMID- 27991872 TI - Turning up the heat on thermoregulation research. PMID- 27991873 TI - Waking up with dopamine. PMID- 27991874 TI - Response to Protocol Review Scenario: Training and education. PMID- 27991875 TI - Response to Protocol Review Scenario: Gotcha! PMID- 27991877 TI - Viruses and circadian rhythms. PMID- 27991880 TI - Earliest direct evidence of plant processing in prehistoric Saharan pottery. AB - The invention of thermally resistant ceramic cooking vessels around 15,000 years ago was a major advance in human diet and nutrition1-3, opening up new food groups and preparation techniques. Previous investigations of lipid biomarkers contained in food residues have routinely demonstrated the importance of prehistoric cooking pots for the processing of animal products across the world4. Remarkably, however, direct evidence for plant processing in prehistoric pottery has not been forthcoming, despite the potential to cook otherwise unpalatable or even toxic plants2,5. In North Africa, archaeobotanical evidence of charred and desiccated plant organs denotes that Early Holocene hunter-gatherers routinely exploited a wide range of plant resources6. Here, we reveal the earliest direct evidence for plant processing in pottery globally, from the sites of Takarkori and Uan Afuda in the Libyan Sahara, dated to 8200-6400 bc. Characteristic carbon number distributions and delta13C values for plant wax-derived n-alkanes and alkanoic acids indicate sustained and systematic processing of C3/C4 grasses and aquatic plants, gathered from the savannahs and lakes in the Early to Middle Holocene green Sahara. PMID- 27991881 TI - Relic DNA is abundant in soil and obscures estimates of soil microbial diversity. AB - Extracellular DNA from dead microorganisms can persist in soil for weeks to years1-3. Although it is implicitly assumed that the microbial DNA recovered from soil predominantly represents intact cells, it is unclear how extracellular DNA affects molecular analyses of microbial diversity. We examined a wide range of soils using viability PCR based on the photoreactive DNA-intercalating dye propidium monoazide4. We found that, on average, 40% of both prokaryotic and fungal DNA was extracellular or from cells that were no longer intact. Extracellular DNA inflated the observed prokaryotic and fungal richness by up to 55% and caused significant misestimation of taxon relative abundances, including the relative abundances of taxa integral to key ecosystem processes. Extracellular DNA was not found in measurable amounts in all soils; it was more likely to be present in soils with low exchangeable base cation concentrations, and the effect of its removal on microbial community structure was more profound in high-pH soils. Together, these findings imply that this 'relic DNA' remaining in soil after cell death can obscure treatment effects, spatiotemporal patterns and relationships between microbial taxa and environmental conditions. PMID- 27991882 TI - Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture. AB - With a single exception, all isolates of hepatitis C virus (HCV) require adaptive mutations to replicate efficiently in cell culture. Here, we show that a major class of adaptive mutations regulates the activity of a cellular lipid kinase, phosphatidylinositol 4-kinase IIIalpha (PI4KA). HCV needs to stimulate PI4KA to create a permissive phosphatidylinositol 4-phosphate-enriched membrane microenvironment in the liver and in primary human hepatocytes (PHHs). In contrast, in Huh7 hepatoma cells, the virus must acquire loss-of-function mutations that prevent PI4KA overactivation. This adaptive mechanism is necessitated by increased PI4KA levels in Huh7 cells compared with PHHs, and is conserved across HCV genotypes. PI4KA-specific inhibitors promote replication of unadapted viral isolates and allow efficient replication of patient-derived virus in cell culture. In summary, this study has uncovered a long-sought mechanism of HCV cell-culture adaptation and demonstrates how a virus can adapt to changes in a cellular environment associated with tumorigenesis. PMID- 27991883 TI - Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes. AB - Microbial stimuli such as lipopolysaccharide (LPS) induce robust metabolic rewiring in immune cells known as the Warburg effect. It is unknown whether this increase in glycolysis and decrease in oxidative phosphorylation (OXPHOS) is a general characteristic of monocytes that have encountered a pathogen. Using CD14+ monocytes from healthy donors, we demonstrated that most microbial stimuli increased glycolysis, but that only stimulation of Toll-like receptor (TLR) 4 with LPS led to a decrease in OXPHOS. Instead, activation of other TLRs, such as TLR2 activation by Pam3CysSK4 (P3C), increased oxygen consumption and mitochondrial enzyme activity. Transcriptome and metabolome analysis of monocytes stimulated with P3C versus LPS confirmed the divergent metabolic responses between both stimuli, and revealed significant differences in the tricarboxylic acid cycle, OXPHOS and lipid metabolism pathways following stimulation of monocytes with P3C versus LPS. At a functional level, pharmacological inhibition of complex I of the mitochondrial electron transport chain diminished cytokine production and phagocytosis in P3C- but not LPS-stimulated monocytes. Thus, unlike LPS, complex microbial stimuli and the TLR2 ligand P3C induce a specific pattern of metabolic rewiring that involves upregulation of both glycolysis and OXPHOS, which enables activation of host defence mechanisms such as cytokine production and phagocytosis. PMID- 27991884 TI - Global leaf trait estimates biased due to plasticity in the shade. AB - The study of leaf functional trait relationships, the so-called leaf economics spectrum1,2, is based on the assumption of high-light conditions (as experienced by sunlit leaves). Owing to the exponential decrease of light availability through canopies, however, the vast majority of the world's vegetation exists in at least partial shade. Plant functional traits vary in direct dependence of light availability3, with different traits varying to different degrees, sometimes in conflict with expectations from the economic spectrum3. This means that the derived trait relationships of the global leaf economic spectrum are probably dependent on the extent to which observed data in existing large-scale plant databases represent high-light conditions. Here, using an extensive worldwide database of within-canopy gradients of key physiological, structural and chemical traits3, along with three different global trait databases4,5, we show that: (1) accounting for light-driven trait plasticity can reveal novel trait relationships, particularly for highly plastic traits (for example, the relationship between net assimilation rate per area (Aa) and leaf mass per area (LMA)); and (2) a large proportion of leaf traits in current global plant databases reported as measured in full sun were probably measured in the shade. The results show that even though the majority of leaves exist in the shade, along with a large proportion of observations, our current understanding is too focused on conditions in the sun. PMID- 27991885 TI - Origins of pandemic Vibrio cholerae from environmental gene pools. AB - Some microorganisms can transition from an environmental lifestyle to a pathogenic one1-3. This ecological switch typically occurs through the acquisition of horizontally acquired virulence genes4,5. However, the genomic features that must be present in a population before the acquisition of virulence genes and emergence of pathogenic clones remain unknown. We hypothesized that virulence adaptive polymorphisms (VAPs) circulate in environmental populations and are required for this transition. We developed a comparative genomic framework for identifying VAPs, using Vibrio cholerae as a model. We then characterized several environmental VAP alleles to show that while some of them reduced the ability of clinical strains to colonize a mammalian host, other alleles conferred efficient host colonization. These results show that VAPs are present in environmental bacterial populations before the emergence of virulent clones. We propose a scenario in which VAPs circulate in the environment and become selected and enriched under certain ecological conditions, and finally a genomic background containing several VAPs acquires virulence factors that allow for its emergence as a pathogenic clone. PMID- 27991886 TI - Hepatitis E virus infection and hepatic GvHD in allogeneic hematopoietic stem cell transplantation recipients. PMID- 27991888 TI - Recipient and donor age impact the risk of developing chronic GvHD in children after allogeneic hematopoietic transplant. PMID- 27991889 TI - Cord blood transplantation, a cost-effective alternative: a health-economic analysis of the National Swedish Cord Blood Bank. PMID- 27991887 TI - Autologous hematopoietic stem cell transplantation for intravascular large B-cell lymphoma: the European Society for Blood and Marrow Transplantation experience. PMID- 27991890 TI - Pericardial effusion requiring surgical intervention after stem cell transplantation: a case series. PMID- 27991891 TI - Diffusing capacity impairment is prevalent in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation. PMID- 27991892 TI - Tissue-based chimerism analysis enhances detection of donor-derived neoplasia in allogeneic stem cell transplant patients. PMID- 27991893 TI - Cord blood transplantation: rewind to fast forward. AB - The utilization of cord blood as a source of stem cells for transplantation has decreased in recent years. Although cord blood transplantation (CBT) is an established practice for the treatment of adult and pediatric patients with hematological malignancies, the high acquisition cost of CB units along with high transplant-related mortality due to delayed hematopoietic recovery and immune reconstitution have contributed to the slowing in widespread adoption of CBT. Strategies aimed to enhance speed of engraftment and ongoing clinical trials are investigating ways to make CBT more widely available. Meanwhile, the recent clinical data suggest that the choice of CBT might be preferable for patients with pre-transplant minimal residual disease. We review here the background data on the utilization of CB for the treatment of hematological malignancies, and discuss the current challenges and future directions in the field of CBT. PMID- 27991894 TI - Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. AB - We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6000 MUM min (N=111), stratified for remission status and allo grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD. PMID- 27991896 TI - Visilizumab with tacrolimus and methotrexate for GvHD prevention after allogeneic hematopoietic cell transplantation from mismatched unrelated donors. PMID- 27991895 TI - Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study. AB - Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre transplant IFI does not appear to be a contraindication to allogeneic HSCT. PMID- 27991898 TI - An independent, landmark-dominated head-direction signal in dysgranular retrosplenial cortex. AB - We investigated how landmarks influence the brain's computation of head direction and found that in a bidirectionally symmetrical environment, some neurons in dysgranular retrosplenial cortex showed bidirectional firing patterns. This indicates dominance of neural activity by local environmental cues even when these conflicted with the global head direction signal. It suggests a mechanism for associating landmarks to or dissociating them from the head direction signal, according to their directional stability and/or utility. PMID- 27991897 TI - Pregnancy leads to long-lasting changes in human brain structure. AB - Pregnancy involves radical hormone surges and biological adaptations. However, the effects of pregnancy on the human brain are virtually unknown. Here we show, using a prospective ('pre'-'post' pregnancy) study involving first-time mothers and fathers and nulliparous control groups, that pregnancy renders substantial changes in brain structure, primarily reductions in gray matter (GM) volume in regions subserving social cognition. The changes were selective for the mothers and highly consistent, correctly classifying all women as having undergone pregnancy or not in-between sessions. Interestingly, the volume reductions showed a substantial overlap with brain regions responding to the women's babies postpartum. Furthermore, the GM volume changes of pregnancy predicted measures of postpartum maternal attachment, suggestive of an adaptive process serving the transition into motherhood. Another follow-up session showed that the GM reductions endured for at least 2 years post-pregnancy. Our data provide the first evidence that pregnancy confers long-lasting changes in a woman's brain. PMID- 27991899 TI - Subiculum neurons map the current axis of travel. AB - Flexible navigation demands knowledge of boundaries, routes and their relationships. Within a multi-path environment, a subpopulation of subiculum neurons robustly encoded the axis of travel. The firing of axis-tuned neurons peaked bimodally, at head orientations 180 degrees apart. Environmental manipulations showed these neurons to be anchored to environmental boundaries but to lack axis tuning in an open arena. Axis-tuned neurons thus provide a powerful mechanism for mapping relationships between routes and the larger environmental context. PMID- 27991901 TI - Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ. AB - Body fluid conditions are continuously monitored in the brain to regulate thirst and salt-appetite sensations. Angiotensin II drives both thirst and salt appetite; however, the neural mechanisms underlying selective water- and/or salt intake behaviors remain unknown. Using optogenetics, we show that thirst and salt appetite are driven by distinct groups of angiotensin II receptor type 1a positive excitatory neurons in the subfornical organ. Neurons projecting to the organum vasculosum lamina terminalis control water intake, while those projecting to the ventral part of the bed nucleus of the stria terminalis control salt intake. Thirst-driving neurons are suppressed under sodium-depleted conditions through cholecystokinin-mediated activation of GABAergic neurons. In contrast, the salt appetite-driving neurons were suppressed under dehydrated conditions through activation of another population of GABAergic neurons by Nax signals. These distinct mechanisms in the subfornical organ may underlie the selective intakes of water and/or salt and may contribute to body fluid homeostasis. PMID- 27991902 TI - Crystal structures of human glycine receptor alpha3 bound to a novel class of analgesic potentiators. AB - Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM 1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRalpha3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-A resolution. AM 3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain. PMID- 27991900 TI - Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. AB - The hypothalamus contains the highest diversity of neurons in the brain. Many of these neurons can co-release neurotransmitters and neuropeptides in a use dependent manner. Investigators have hitherto relied on candidate protein-based tools to correlate behavioral, endocrine and gender traits with hypothalamic neuron identity. Here we map neuronal identities in the hypothalamus by single cell RNA sequencing. We distinguished 62 neuronal subtypes producing glutamatergic, dopaminergic or GABAergic markers for synaptic neurotransmission and harboring the ability to engage in task-dependent neurotransmitter switching. We identified dopamine neurons that uniquely coexpress the Onecut3 and Nmur2 genes, and placed these in the periventricular nucleus with many synaptic afferents arising from neuromedin S+ neurons of the suprachiasmatic nucleus. These neuroendocrine dopamine cells may contribute to the dopaminergic inhibition of prolactin secretion diurnally, as their neuromedin S+ inputs originate from neurons expressing Per2 and Per3 and their tyrosine hydroxylase phosphorylation is regulated in a circadian fashion. Overall, our catalog of neuronal subclasses provides new understanding of hypothalamic organization and function. PMID- 27991904 TI - Pif1-family helicases cooperatively suppress widespread replication-fork arrest at tRNA genes. AB - Saccharomyces cerevisiae expresses two Pif1-family helicases-Pif1 and Rrm3-which have been reported to play distinct roles in numerous nuclear processes. Here, we systematically characterized the roles of Pif1 helicases in replisome progression and lagging-strand synthesis in S. cerevisiae. We demonstrate that either Pif1 or Rrm3 redundantly stimulates strand displacement by DNA polymerase delta during lagging-strand synthesis. By analyzing replisome mobility in pif1 and rrm3 mutants, we show that Rrm3, with a partially redundant contribution from Pif1, suppresses widespread terminal arrest of the replisome at tRNA genes. Although both head-on and codirectional collisions induce replication-fork arrest at tRNA genes, head-on collisions arrest a higher proportion of replisomes. In agreement with this observation, we found that head-on collisions between tRNA transcription and replication are under-represented in the S. cerevisiae genome. We demonstrate that tRNA-mediated arrest is R-loop independent and propose that replisome arrest and DNA damage are mechanistically separable. PMID- 27991903 TI - Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. AB - APOBEC-catalyzed cytosine-to-uracil deamination of single-stranded DNA (ssDNA) has beneficial functions in immunity and detrimental effects in cancer. APOBEC enzymes have intrinsic dinucleotide specificities that impart hallmark mutation signatures. Although numerous structures have been solved, mechanisms for global ssDNA recognition and local target-sequence selection remain unclear. Here we report crystal structures of human APOBEC3A and a chimera of human APOBEC3B and APOBEC3A bound to ssDNA at 3.1-A and 1.7-A resolution, respectively. These structures reveal a U-shaped DNA conformation, with the specificity-conferring -1 thymine flipped out and the target cytosine inserted deep into the zinc coordinating active site pocket. The -1 thymine base fits into a groove between flexible loops and makes direct hydrogen bonds with the protein, accounting for the strong 5'-TC preference. These findings explain both conserved and unique properties among APOBEC family members, and they provide a basis for the rational design of inhibitors to impede the evolvability of viruses and tumors. PMID- 27991906 TI - Hepatic stimulator substance inhibits calcium overflow through the mitochondria associated membrane compartment during nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease is considered a disorder of the endoplasmic reticulum (ER) and mitochondria. Recent studies have shown that the ER and mitochondrial membranes overlap by 15-20%, a region referred to as the 'mitochondria-associated ER membrane' (MAM). Some proteins, including sarco/ER calcium ATPase (SERCA), are located in the MAM and have an important role in Ca2+ signaling and homeostasis between the ER and the mitochondria. Our previous study showed that hepatic stimulator substance (HSS) inhibits the ER stress induced by reactive oxygen species, thus reducing mitochondrial damage. However, the mechanism underlying the protective effect of HSS on the ER and ER-mitochondrial interaction remains unclear. In this study, we confirmed that the exogenous expression of HSS protected the liver from steatosis in mice with nonalcoholic steatohepatitis. More importantly, the protection provided by HSS allowed SERCA in the MAM compartment to function well, preventing the extensive influx of cytosolic free Ca2+ to the mitochondria, thus preserving the mitochondrial functions from calcium overload and relieving palmitic-acid-induced hepatocyte steatosis. Our results suggest that the protective effect of HSS on SERCA expression is associated with the maintenance of calcium homeostasis within the MAM, thus ameliorating the disordered Ca2+ communication between the ER and mitochondria. PMID- 27991905 TI - Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). AB - Mutations in either polycystin-1 (PC1 or PKD1) or polycystin-2 (PC2, PKD2 or TRPP1) cause autosomal-dominant polycystic kidney disease (ADPKD) through unknown mechanisms. Here we present the structure of human PC2 in a closed conformation, solved by electron cryomicroscopy at 4.2-A resolution. The structure reveals a novel polycystin-specific 'tetragonal opening for polycystins' (TOP) domain tightly bound to the top of a classic transient receptor potential (TRP) channel structure. The TOP domain is formed from two extensions to the voltage-sensor like domain (VSLD); it covers the channel's endoplasmic reticulum lumen or extracellular surface and encloses an upper vestibule, above the pore filter, without blocking the ion-conduction pathway. The TOP-domain fold is conserved among the polycystins, including the homologous channel-like region of PC1, and is the site of a cluster of ADPKD-associated missense variants. Extensive contacts among the TOP-domain subunits, the pore and the VSLD provide ample scope for regulation through physical and chemical stimuli. PMID- 27991908 TI - Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration. AB - The effects of paracrine action from early activated hepatic stellate cells (HSCs) on resident liver epithelium cells are not clear. Here, we investigated whether a systemic infusion of early activated HSC-derived paracrine factors (HSC CM) would evoke an enhanced liver protective response in acetaminophen (APAP) induced acute liver injury (ALI) in mice and explored the possible underlying mechanisms. The survival rate, liver injury, and liver regeneration were analyzed in mice with or without HSC-CM treatment in vivo. A systemic infusion of HSC-CM provided a significant survival benefit in APAP-induced ALI. HSC-CM therapy resulted in a reduction of hepatocellular death and increased numbers of both proliferating hepatocytes and adult hepatic progenitor cells (AHPCs) with up regulation of liver regeneration relevant genes. The HSC-CM treatment reduced leukocyte infiltration and down-regulated systemic inflammation with decreases in IFN-gamma, IL-1ra, IL-1beta, TNF-alpha, and increases in IL-10. The direct anti death and pro-regeneration effects of HSC-CM on AHPCs were demonstrated using in vitro assays. Treatment with HSC-CM promoted AHPCs proliferation and resulted in increased pAkt expression in vitro, and this effect was abolished by the PI3K/Akt inhibitor LY294002. These data provide evidence that early activated HSC-CM therapy offered trophic support to the acutely injured liver by inhibiting liver cell death and stimulating regeneration, potentially creating a new method for the treatment of ALI. PMID- 27991907 TI - Immunomodulating property of MAPK inhibitors: from translational knowledge to clinical implementation. AB - Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2. Furthermore, the presence of oncogenic BRAF leads to an immune suppressive phenotype characterized by the presence of inhibitory immune cells such as regulatory T cells, myeloid-derived suppressor cells, or tumor-associated macrophages, which can in turn inhibit the function of tumor-infiltrating T cells. Growing evidence suggests that, in addition to their established molecular mechanism of action, the therapeutic efficacy of BRAF inhibitors and MEK inhibitors relies on additional factors that affect the tumor-host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells. Focus of the present review is to summarize the off target mechanisms of response to BRAF inhibitors and MEK inhibitors and the synergy between targeted therapy and immunotherapy as the biological source to open a window of strategic opportunities for the design of new exciting clinical trials. PMID- 27991910 TI - Establishment and characterization of BHD-F59RSVT, an immortalized cell line derived from a renal cell carcinoma in a patient with Birt-Hogg-Dube syndrome. AB - Hereditary renal cell carcinomas (RCCs) are life-threatening disorders not only for the patients but also for their relatives. Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). The protein product, FLCN, functions as a tumor suppressor, and the affected patients have high risks of developing multiple RCCs. The carcinogenic mechanisms stemming from FLCN dysfunction have been investigated using rodent models and human RCC tissues. However, very limited information has been available about in vitro signaling of human renal cells with genetically mutant FLCN. Herein, we established a new cell line, BHD-F59RSVT, from a BHD patient's chromophobe RCC by transfecting SV40 large T antigen. We investigated FLCN mutations, chromosome profiles, and cytopathologic characteristics of the cell line. BHD-F59RSVT reflected the patient's FLCN germline mutation, a 3-nt deletion in exon 13 (c.1528_1530delGAG). Neither somatic mutation nor loss of heterozygosity of FLCN was detectable. Chromosome 17p11.2 of the FLCN proximal region demonstrated a trimodal pattern. Genome-wide chromosomal analysis revealed a loss of chromosome 16 and mosaic segmental gains in chromosome 7. BHD-F59RSVT cells were positive when immunostained for cytokeratin 7, supporting their origin from distal convoluted tubules. Western blotting analysis demonstrated severely suppressed FLCN expression at the protein level. The collective findings indicate that the established cell line will be suitable for functional analysis of the typical phenotype of BHD-associated RCC with suppressed FLCN expression. PMID- 27991909 TI - Lymphatic invasion and angiotropism in primary cutaneous melanoma. AB - Access of melanoma cells to the cutaneous vasculature either via lymphatic invasion or angiotropism is a proposed mechanism for metastasis. Lymphatic invasion is believed to be a mechanism by which melanoma cells can disseminate to regional lymph nodes and to distant sites and may be predictive of adverse outcomes. Although it can be detected on hematoxylin- and eosin-stained sections, sensitivity is markedly improved by immunohistochemistry for lymphatic endothelial cells. Multiple studies have reported a significant association between the presence of lymphatic invasion and sentinel lymph node metastasis and survival. More recently, extravascular migratory metastasis has been suggested as another means by which melanoma cells can spread. Angiotropism, the histopathologic correlate of extravascular migratory metastasis, has also been associated with melanoma metastasis and disease recurrence. Although lymphatic invasion and angiotropism are not currently part of routine melanoma reporting, the detection of these attributes using ancillary immunohistochemical stains may be useful in therapeutic planning for patients with melanoma. PMID- 27991911 TI - Inhibition of infarction-induced sympathetic innervation with endothelin receptor antagonism via a PI3K/GSK-3beta-dependent pathway. AB - Although endothelin (ET)-1 has been shown to upregulate nerve growth factor (NGF) expression, the molecular mechanisms are largely unknown. Phosphatidylinositol 3 kinase (PI3K)/Akt/glycogen synthase kinase (GSK)-3beta signal has been implicated in the regulation of NGF. We investigated whether selective ET receptor blockers attenuated cardiac sympathetic reinnervation through restoring PI3K/Akt/GSK-3beta activity. After ligation of the left anterior descending artery, male Wistar rats were randomized to either vehicle, atrasentan (an ETA receptor antagonist) or A 192621 (an ETB receptor antagonist) for 4 weeks. Sympathetic hyperinnervation after infarction was confirmed by myocardial norepinephrine measurement and immunofluorescent analysis. Post infarction was associated with increased reactive oxygen species (ROS), as measured by myocardial superoxide levels and dihydroethidine fluorescence staining. This was paralleled by a significant upregulation of NGF expression on mRNA and protein levels in the vehicle-treated rats, which reduced after administering atrasentan, not A-192621. Arrhythmic scores in the vehicle-treated rats were significantly higher than those treated with atrasentan. In an in vivo study atrasentan-induced decreased NGF was associated with activation of PI3K/Akt signaling pathway, which was further confirmed by the ex vivo study showing the restoration of NGF levels after coadministration of PI3K inhibitors (wortmannin and LY294002). Lithium chloride, an inhibitor of GSK-3beta, did not provide additional attenuated NGF levels compared with atrasentan alone. Finally, atrasentan-attenuated NGF levels were reversed in the presence of peroxynitrite generator. ETA receptor antagonism is a mediator to attenuate sympathetic hyperinnervation probably through restoration of PI3K/Akt/GSK-3beta/ROS signaling pathway, a potential pharmacological target for arrhythmias after infarction. PMID- 27991912 TI - Plausible rice yield losses under future climate warming. AB - Rice is the staple food for more than 50% of the world's population1-3. Reliable prediction of changes in rice yield is thus central for maintaining global food security. This is an extraordinary challenge. Here, we compare the sensitivity of rice yield to temperature increase derived from field warming experiments and three modelling approaches: statistical models, local crop models and global gridded crop models. Field warming experiments produce a substantial rice yield loss under warming, with an average temperature sensitivity of -5.2 +/- 1.4% K-1. Local crop models give a similar sensitivity (-6.3 +/- 0.4% K-1), but statistical and global gridded crop models both suggest less negative impacts of warming on yields (-0.8 +/- 0.3% and -2.4 +/- 3.7% K-1, respectively). Using data from field warming experiments, we further propose a conditional probability approach to constrain the large range of global gridded crop model results for the future yield changes in response to warming by the end of the century (from -1.3% to 9.3% K-1). The constraint implies a more negative response to warming (-8.3 +/- 1.4% K-1) and reduces the spread of the model ensemble by 33%. This yield reduction exceeds that estimated by the International Food Policy Research Institute assessment (-4.2 to -6.4% K-1) (ref. 4). Our study suggests that without CO2 fertilization, effective adaptation and genetic improvement, severe rice yield losses are plausible under intensive climate warming scenarios. PMID- 27991913 TI - Linking genomic reorganization to tumor initiation via the giant cell cycle. AB - To investigate the mechanisms underlying our recent paradoxical finding that mitotically incapacitated and genomically unstable polyploid giant cancer cells (PGCCs) are capable of tumor initiation, we labeled ovarian cancer cells with alpha-tubulin fused to green fluorescent protein, histone-2B fused to red fluorescent protein and FUCCI (fluorescent ubiquitination cell cycle indicator), and tracked the spatial and time-dependent change in spindle and chromosomal dynamics of PGCCs using live-cell fluorescence time-lapse recording. We found that single-dose (500 nm) treatment with paclitaxel paradoxically initiated endoreplication to form PGCCs after massive cell death. The resulting PGCCs continued self-renewal via endoreplication and further divided by nuclear budding or fragmentation; the small daughter nuclei then acquired cytoplasm, split off from the giant mother cells and acquired competency in mitosis. FUCCI showed that PGCCs divided via truncated endoreplication cell cycle (endocycle or endomitosis). Confocal microscopy showed that PGCCs had pronounced nuclear fragmentation and lacked expression of key mitotic proteins. PGCC-derived daughter cells were capable of long-term proliferation and acquired numerous new genome/chromosome alterations demonstrated by spectral karyotyping. These data prompt us to conceptualize a giant cell cycle composed of four distinct but overlapping phases, initiation, self-renewal, termination and stability. The giant cell cycle may represent a fundamental cellular mechanism to initiate genomic reorganization to generate new tumor-initiating cells in response to chemotherapy-induced stress and contributes to disease relapse. PMID- 27991914 TI - The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair factors and R-loop processing. AB - Recent whole-exome sequencing of malignancies have detected recurrent somatic mutations in U2 small nuclear ribonucleoprotein complex (snRNP) components of the spliceosome. These factors have also been identified as novel players in the DNA damage response (DDR) in several genome-wide screens and proteomic analysis. Although accumulating evidence implies that the spliceosome has an important role in genome stability and is an emerging hallmark of cancer, its precise role in DNA repair still remains elusive. Here we identify two distinct mechanisms of how spliceosome U2 snRNP factors contribute to genome stability. We show that the spliceosome maintains protein levels of essential repair factors, thus contributing to homologous recombination repair. In addition, real-time laser microirradiation analysis identified rapid recruitment of the U2 snRNP factor SNRPA1 to DNA-damage sites. Functional analysis of SNRPA1 revealed a more immediate and direct role in preventing R-loop-induced DNA damage. Our present study implies a complex interrelation between transcription, mRNA splicing and the DDR. Cells require rapid spatio-temporal coordination of these chromatin transactions to cope with various forms of genotoxic stress. PMID- 27991915 TI - KLF4 functions as an activator of the androgen receptor through reciprocal feedback. AB - In prostate cancer, Kruppel-like factor 4 (KLF4) depletion occurs frequently, suggesting a role as suppressor tumor. KLF4 is a transcription factor associated with androgen receptor (AR) expression; however, its cellular functions and signaling regulation mechanism remain largely unknown. In this study, we demonstrated that activated AR binds to the KLF4 promoter and enhances KLF4 expression, which reciprocally targets the AR promoter, thus sustaining KLF4 activity. Ectopic KLF4 expression in androgen-independent prostate cancer cells induced AR expression and decreased cell proliferation, invasion and bone metastasis. We previously showed that increased microRNA (miR)-1 expression is associated with reduced bone metastasis of prostate cancer cells. Here we observed that KLF4 targets the primary miR-1-2 stem-loop promoter and stimulates miR-1 expression. In clinical prostate cancer specimens, KLF4 levels were positively correlated with miR-1 and AR levels. These data suggest that the loss of KLF4 expression is one mechanistic link between aggressive prostate cancer progression and low canonical AR output through miR-1 inactivation. PMID- 27991916 TI - The HIF/PHF8/AR axis promotes prostate cancer progression. AB - Recent studies provide strong evidence that the androgen receptor (AR) signaling pathway remains active in castration-resistant prostate cancer (CRPC). However, the underlying mechanisms are not well understood. In this study, we demonstrate that plant homeo domain finger protein 8 (PHF8 )interacts with and functions as an essential histone demethylase activity-dependent AR coactivator. Furthermore, we demonstrate that the expression of PHF8 is induced by hypoxia in various prostate cancer cell lines. Knockdown of either hypoxia-inducible factor HIF2alpha or HIF1alpha almost completely abolished hypoxia-induced PHF8 expression. Importantly, we observed that PHF8 is highly expressed in clinical androgen deprived prostate cancer samples and expression of PHF8 correlates with increased levels of HIF1alpha and HIF2alpha. Moreover, elevated PHF8 is associated with higher grade prostate cancers and unfavorable outcomes. Our findings support a working model in which hypoxia in castrated prostate cancer activates HIF transcription factors which then induces PHF8 expression. The elevated PHF8 in turn promotes the AR signaling pathway and prostate cancer progression. Therefore, the HIF/PHF8/AR axis could serve as a potential biomarker for CRPC and is also a promising therapeutic target in combating CRPC. PMID- 27991917 TI - A chikungunya fever vaccine utilizing an insect-specific virus platform. AB - Traditionally, vaccine development involves tradeoffs between immunogenicity and safety. Live-attenuated vaccines typically offer rapid and durable immunity but have reduced safety when compared to inactivated vaccines. In contrast, the inability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, often necessitating multiple doses and boosters. To overcome these tradeoffs, we developed the insect-specific alphavirus, Eilat virus (EILV), as a vaccine platform. To address the chikungunya fever (CHIKF) pandemic, we used an EILV cDNA clone to design a chimeric virus containing the chikungunya virus (CHIKV) structural proteins. The recombinant EILV/CHIKV was structurally identical at 10 A to wild-type CHIKV, as determined by single-particle cryo electron microscopy, and it mimicked the early stages of CHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery. Yet the recombinant virus remained completely defective for productive replication, providing a high degree of safety. A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 d) and long-lasting (>290 d) neutralizing antibodies that provided complete protection in two different mouse models. In nonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia and telemetrically monitored fever. Our EILV platform represents the first structurally native application of an insect-specific virus in preclinical vaccine development and highlights the potential application of such viruses in vaccinology. PMID- 27991918 TI - Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. AB - Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance. PMID- 27991919 TI - SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. AB - The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML. PMID- 27991920 TI - TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-kappaB activation and tumor progression. AB - Epidermal growth factor receptor (EGFR) family members play pivotal roles in cell proliferation, differentiation and survival. Overexpression and mutations of EGFRs, or aberrant EGFR signaling are commonly associated with the development of various cancers, where constitutive NF-kappaB activation is often found to promote the expression of various proteins involved in the proliferation, survival, migration and epithelial-to-mesenchymal transition of cancer cells. However, the mechanism of EGFR-induced NF-kappaB activation is not fully defined. Here, we used a Bimolecular Fluorescence Complementation-based functional genomics method to perform a high throughput screening and identified TMEM43/LUMA as a critical component in EGFR signaling network, mediating EGFR-induced NF kappaB activation. Our data show that EGFR recruits TMEM43 following EGF stimulation. TMEM43 interacts with the scaffold protein CARMA3 and its associating complex to induce downstream NF-kappaB activation, and plays a critical role in controlling cell survival. TMEM43 deficiency significantly affects colony formation, survival of anoikis-induced cell death, migration and invasion of cancer cells in vitro, as well as tumor progression in vivo. Importantly, higher expression of TMEM43 closely correlates with brain tumor malignancy, and suppression of TMEM43 expression in brain tumor cells inhibited their growth both in vitro and in vivo. Altogether, our studies reveal a crucial link of EGF receptor to NF-kappaB activation and tumor progression. PMID- 27991921 TI - ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF kappaB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-kappaB mediated progression. AB - To study ROCK2 activation in carcinogenesis, mice expressing 4-hydroxytamoxifen (4HT)-activated ROCK2 (K14.ROCKer) were crossed with mice expressing epidermal activated rasHa (HK1.ras1205). At 8 weeks, 4HT-treated K14.ROCKer/HK1.ras1205 cohorts exhibited papillomas similar to HK1.ras1205 controls; however, K14.ROCKer/HK1.ras1205 histotypes comprised a mixed papilloma/well-differentiated squamous cell carcinoma (wdSCC), exhibiting p53 loss, increased proliferation and novel NF-kappaB expression. By 12 weeks, K14.ROCKer/HK1.ras1205 wdSCCs exhibited increased NF-kappaB and novel tenascin C, indicative of elevated rigidity; yet despite continued ROCK2 activities/p-Mypt1 inactivation, progression to SCC required loss of compensatory p21 expression. K14.ROCKer/HK1.ras1205 papillomatogenesis also required a wound promotion stimulus, confirmed by breeding K14.ROCKer into promotion-insensitive HK1.ras1276 mice, suggesting a permissive K14.ROCKer/HK1.ras1205 papilloma context (wound-promoted/NF kappaB+/p53-/p21+) preceded K14.ROCKer-mediated (p-Mypt1/tenascin C/rigidity) malignant conversion. Malignancy depended on ROCKer/p-Mypt1 expression, as cessation of 4HT treatment induced disorganized tissue architecture and p21 associated differentiation in wdSCCs; yet tenascin C retention in connective tissue extracellular matrix suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal layer p21 that confined endogenous ROCK2/p-Mypt1/NF-kappaB to supra-basal layers, and was paralleled by restored basal layer p53. In later SCCs, 4HT cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-kappaB expression and tenascin C-associated rigidity, with p Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and rasHa/ROCK2/NF-kappaB signalling in skin carcinogenesis. Collectively, these data show that ROCK2 activation induces malignancy in rasHa-initiated/promoted papillomas in the context of p53 loss and novel NF-kappaB expression, whereas increased tissue rigidity and cell motility/contractility help mediate tumour progression. PMID- 27991923 TI - A platform for interrogating cancer-associated p53 alleles. PMID- 27991922 TI - Phosphoglycerate mutase 1 promotes cancer cell migration independent of its metabolic activity. AB - Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that coordinates glycolysis and biosynthesis to promote cancer growth via its metabolic activity. Here, we report the discovery of a non-metabolic function of PGAM1 in promoting cancer metastasis. A proteomic study identified alpha-smooth muscle actin (ACTA2) as a PGAM1-associated protein. PGAM1 modulated actin filaments assembly, cell motility and cancer cell migration via directly interacting with ACTA2, which was independent of its metabolic activity. The enzymatically inactive H186R mutant retained its association with ACTA2, whereas 201-210 amino acids deleted PGAM1 mutant lost the interaction with ACTA2 regardless of intact metabolic activity. Importantly, PGAM1 knockdown decreased metastatic potential of breast cancer cells in vivo and PGAM1 and ACTA2 were jointly associated with the prognosis of breast cancer patients. Together, this study provided the first evidence revealing a non-metabolic function of PGAM1 in promoting cell migration, and gained new insights into the role of PGAM1 in cancer progression. PMID- 27991924 TI - Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche. AB - The growth of disseminated tumor cells into metastatic lesions depends on the establishment of a favorable microenvironment in the stroma of the target organs. Here we show that mice treated with anakinra, an antagonist of the interleukin (IL)-1beta receptor (IL-1R), or harboring a targeted deletion of IL-1R are significantly less prone to develop bone tumors when inoculated in the arterial circulation with human prostate cancer (PCa) cells expressing IL-1beta. Interestingly, human mesenchymal stem cells exposed in vitro to medium conditioned by IL-1beta-expressing cancer cells responded by upregulating S100A4, a marker of cancer-associated fibroblasts (CAFs), and this effect was blocked by anakinra. Analogously, the stroma adjacent to skeletal metastases generated in mice by IL-1beta-expressing cancer cells showed a dramatic increase in S100A4, COX-2 and the alteration of 30 tumor-related genes as measured by Nanostring analysis. These effects were not observed in the stroma associated with the rare and much smaller metastases generated by the same cells in IL-1R knockout animals, confirming that tumor-secreted IL-1beta generates skeletal CAFs and conditions the surrounding bone microenvironment. In skeletal lesions from patients with metastatic PCa, histological and molecular analyses revealed that IL-1beta is highly expressed in cancer cells in which the androgen receptor (AR) is not detected (AR-), whereas this cytokine is uniformly absent in the AR positive (AR+) metastatic cells. The stroma conditioned by IL-1beta-expressing cancer cells served as a supportive niche also for coexisting IL-1beta-lacking cancer cells, which are otherwise unable to generate tumors after independently seeding the skeleton of mice. This niche is established very early following tumor seeding and hints to a role of IL-1beta in promoting early colonization of PCa at the skeletal level. PMID- 27991925 TI - PAX2 function, regulation and targeting in fallopian tube-derived high-grade serous ovarian cancer. AB - The fallopian tube epithelium (FTE) is one of the progenitor populations for high grade serous ovarian cancer (HGSC). Loss of PAX2 is the earliest known molecular aberration in the FTE occurring in serous carcinogenesis followed by a mutation in p53. Pathological studies report consistent loss of PAX2 in benign lesions as well as serous tumors. In the current study, the combined loss of PAX2 and expression of the R273H p53 mutant protein in murine oviductal epithelial (MOE) cells enhanced proliferation and growth in soft agar in vitro but was insufficient to drive tumorigenesis in vivo. A serially passaged model was generated to investigate the role of aging, but was also insufficient to drive tumorigenesis. These models recapitulate early benign lesions and suggest that a latency period exists between loss of PAX2, p53 mutation and tumor formation. Stathmin and fut8 were identified as downstream targets regulated by loss of PAX2 and mutation of p53 in MOE cells. Re-expression of PAX2 in PAX2-null human HGSC cells reduced cell survival via apoptosis. Phosphatase and tensin homolog (PTEN)shRNA negatively regulated PAX2 expression and stable re-expression of PAX2 in MOE:PTENshRNA cells significantly reduced proliferation and peritoneal tumor formation in athymic nude mice. PAX2 was determined to be a direct transcriptional target that was activated by wild-type p53, whereas mutant p53 inhibited PAX2 transcription in MOE cells. A small molecule screen using the proximal PAX2 promoter driving luciferase identified four small molecules that were able to enhance PAX2 mRNA expression in MOE cells. PAX2 re-expression in HGSC cells and PTEN-deficient oviductal tumors may have the potential to induce apoptosis. In summary, mutant p53 and PTEN loss negatively regulated PAX2 and PAX2 re-expression in HGSC cells induced cell death. PMID- 27991926 TI - Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53. AB - Chronic inflammation (CI) is a risk factor for pancreatic cancer (PC) including the most common type, ductal adenocarcinoma (PDAC), but its role and the mechanisms involved are unclear. To investigate the role of CI in PC, we generated genetic mouse models with pancreatic specific CI in the presence or absence of TP53. Mice were engineered to express either cyclooxygenase-2 (COX-2) or IkappaB kinase-2 (IKK2), and TP53+/+ or TP53f/f specifically in adult pancreatic acinar cells by using a full-length pancreatic elastase promoter driven Cre. Animals were followed for >80 weeks and pancreatic lesions were evaluated histologically and immunohistochemically. The presence of K-ras mutations was assessed by direct sequencing, locked nuclei acid (LNA)-based PCR, and immunohistochemistry. We observed that sustained COX-2/IKK2 expression caused histological abnormalities of pancreas, including increased immune cell infiltration, proliferation rate and DNA damage. A minority of animals with CI developed pre-neoplastic lesions, but cancer was not observed in any TP53+/+ animals within 84 weeks. In contrast, all animals with CI-lacking TP53 developed various subtypes of PC, including acinar cell carcinoma, ductal adenocarcinoma, sarcomatoid carcinoma and neuroendocrine tumors, and all died within 65 weeks. No evidence of K-ras mutations was observed. Variations in the activity of the Hippo, pERK and c-Myc pathways were found in the diverse cancer subtypes. In summary, chronic inflammation is extremely inefficient at inducing PC in the presence of TP53. However, in the absence of TP53, CI leads to the development of several rare K-ras-independent forms of PC, with infrequent PDAC. This may help explain the rarity of PDAC in persons with chronic inflammatory conditions. PMID- 27991927 TI - Caspase-2-mediated cell death is required for deleting aneuploid cells. AB - Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2-/-) mice develop normally but show premature ageing related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2-/- mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy. PMID- 27991929 TI - miR-19a promotes colitis-associated colorectal cancer by regulating tumor necrosis factor alpha-induced protein 3-NF-kappaB feedback loops. AB - Chronic inflammation is believed to have a crucial role in colon cancer development. MicroRNA (miRNA) deregulation is common in human colorectal cancers, but little is known regarding whether miRNA drives tumor progression by regulating inflammation. Here, we showed that miR-19a can promote colitis and colitis-associated colon cancer (CAC) development using a CAC mouse model and an acute colitis mouse model. Tumor necrosis factor-alpha (TNF-alpha) stimulation can increase miR-19a expression, and upregulated miR-19a can in turn activate nuclear factor (NF)-kappaB signaling and TNF-alpha production by targeting TNF alpha-induced protein 3 (TNFAIP3). miR-19a inhibition can also alleviate CAC in vivo. Moreover, the regulatory effects of miR-19a on TNFAIP3 and NF-kappaB signaling were confirmed using tumor samples from patients with colon cancer. These new findings demonstrate that miR-19a has a direct role in upregulating NF kappaB signaling and that miR-19a has roles in inflammation and CAC. PMID- 27991931 TI - Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition. AB - Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki) resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1alpha. This metabolic imbalance was reversed by mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Interestingly, neither AKT nor c-MYC was involved in mediating the metabolic phenotype, despite the latter contributing to resistant cells' proliferation. These data suggest that an AKT-independent PI3K/mTORC1 axis operates in these cells. The excessive ROS hampered cell division, and the metabolic phenotype made resistant cells more sensitive to hydrogen peroxide and nutrient starvation. Thus, the proliferative defect of PI3Ki-resistant cells during drug holidays is caused by defective metabolic adaptation to chronic PI3K/mTOR pathway inhibition. This metabolic imbalance may open the therapeutic window for challenge with metabolic drugs during drug holidays. PMID- 27991928 TI - Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. AB - Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure. PMID- 27991930 TI - Rho GTPases: Anti- or pro-neoplastic targets? AB - Rho GTPases are critical signal transducers of multiple pathways. They have been proposed to be useful anti-neoplastic targets for over two decades, especially in Ras-driven cancers. Until recently, however, few in vivo studies had been carried out to test this premise. Several recent mouse model studies have verified that Rac1, RhoA, and some of their effector proteins such as PAK and ROCK, are likely anti-cancer targets for treating K-Ras-driven tumours. Other seemingly contradictory studies have suggested that at least in certain instances inhibition of individual Rho GTPases may paradoxically result in pro-neoplastic effects. Significantly, both RhoA GTPase gain- and loss-of-function mutations have been discovered in primary leukemia/lymphoma and gastric cancer by human cancer genome sequencing efforts, suggesting both pro- and anti-neoplastic roles. In this review we summarize and integrate these unexpected findings and discuss the mechanistic implications in the design and application of Rho GTPase targeting strategies in future cancer therapies. PMID- 27991932 TI - EGF-mediated inhibition of ubiquitin-specific peptidase 24 expression has a crucial role in tumorigenesis. AB - In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation. Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis. In addition, knockdown of USP24 increases cell cycle progression by enhancing the G1-S transition and metaphase-anaphase transition. The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition. In conclusion, the USP24 level was decreased during the early stage of cancer and the mitotic stage of the cell cycle to regulate its substrates p300, Bax, E2F4 and securin, resulting in decreased cell apoptosis and increased cell cycle progression and, thus, cancer formation. PMID- 27991933 TI - Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. AB - Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells. Overexpression of cancer-FOXP3 promoted the tumor growth in immunocompetent syngeneic mice but not in immunocompromised or Treg cell-depleted mice. Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo. This finding has been further reinforced by the evidence that Treg cells recruitment by cancer-FOXP3 was impaired by neutralization of CCL5, thereby inhibiting the growth of PDAC. In conclusion, cancer-FOXP3 serves as a prognostic biomarker and a crucial determinant of immunosuppressive microenvironment via recruiting Treg cells by directly trans-activating CCL5. Therefore, cancer-FOXP3 could be used to select patients with better response to CCL5/CCR5 blockade immunotherapy. PMID- 27991936 TI - Modification of the deoxyribose test to detect strong iron binding. AB - Deoxyribose test has been widely used for determination of reactivities of various compounds for the hydroxyl radical. The test is based on the formation of hydroxyl radical by Fe2+ complex in the Fenton reaction. We propose a modification of the deoxyribose test to detect strong iron binding, inhibiting participation of Fe2+ in the Fenton reaction, on the basis of examination of concentration dependence of deoxyribose degradation on Fe2+ concentration, at a constant concentration of a chelating agent. PMID- 27991934 TI - Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia. AB - Somatic mutations that lead to constitutive activation of NRAS and KRAS proto oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML. PMID- 27991935 TI - Is there a link between TNF gene expression and cognitive deficits in depression? AB - : Neuroinflammation is a known factor in the pathogenesis of recurrent depressive disorders. Depression is accompanied by activated immune-inflammatory pathways including increased levels of TNFalpha, sTNFR1and sTNFR2.The purpose of this study was to analyse the TNF-alpha, TNFRSF1A and TNFRSF1B genes on both mRNA and protein levels in patients with rDD, and to investigate the relationship between TNF-alpha,TNFRSF1A and TNFRSF1B gene expression and cognitive performance. The study comprised 158 subjects: patients with recurrent depressive disorder (n=89) and healthy subjects (n=69). Cognitive function assessment was based on: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. Both mRNA and protein expression levels of all genes were significantly higher in rDD subjects when compared to healthy controls. No statistically significant correlations were observed between the analysed variables in both the rDD group and the HS test group. The only exception was noticed in the HS test group, where increased expression of TNFRSF1A and TNFRSF1B gene negatively affected the performance of the AVLT test. However, statistically significant correlations between TNF, TNFRSF1A, TNFRSF1B mRNA gene expression levels and all the neuropsychological tests used in the survey for the entire group were observed. CONCLUSIONS: 1.The results of our study show increased expression of the TNF, TNFRSF1A and TNFRSF1B genes on both mRNA and protein levels in depression. 2. Elevated expression of TNF-alpha, TNFRSF1A and TNFRSF1B negatively correlates with cognitive efficiency: working memory, executive functions, attention, auditory-verbal memory, effectiveness of learning processes and verbal fluency. PMID- 27991938 TI - Correction: Recent emergence of photon upconversion based on triplet energy migration in molecular assemblies. AB - Correction for 'Recent emergence of photon upconversion based on triplet energy migration in molecular assemblies' by Nobuhiro Yanai et al., Chem. Commun., 2016, 52, 5354-5370. PMID- 27991937 TI - Silver ions as em marker of congo red ligation sites in amyloids and amyloid-like aggregates. AB - Congo red (CR) is a known selective amyloid ligand. The focus of our work is identification (by EM imaging) of dye binding sites and their distribution in amyloids and amyloid-like aggregates formed in vitro. In order to produce the required contrast, CR has been indirectly combined with metal via including Titan yellow (TY) by intercalation which exhibits a relatively strong affinity for silver ions. The resulting combined ligand retains its ability to bind to proteins (which it owes to CR) and can easily be detected in EM studies thanks to TY. We have found, however, that in protein aggregates where unfolding is stabilized by aggregation and therefore is irreversible, TY alone may serve as both, the ligand and the metal carrier. The formation of ordered structures in amyloids was studied using IgG light chains with amyloidogenic properties, converted into amyloids by shaking. The resulting EM images were subjected to interpretation on the basis of the authors' earlier research on the CR/light chain complexation process. Our results indicate that dimeric light chains, which are the subject of our study, produce amyloids or amyloid-like complexes with chain-like properties and strong helicalization tendencies. Cursory analysis suggests that the edge polypeptide loops belonging to unstable light chains form intermolecular bridges which promote creation of loose gel deposits, or are otherwise engaged in the swapping processes leading to higher structural ordering. PMID- 27991939 TI - Detection of a higher energy isomer of the CO-N2O van der Waals complex and determination of two of its intermolecular frequencies. AB - Infrared spectra in the carbon monoxide CO stretch region (~2150 cm-1) and in the nu3 asymmetric stretch region of N2O (~2223 cm-1) are assigned to the previously unobserved O-bonded form of the CO-N2O dimer ("isomer 2"). This van der Waals complex has a planar skewed T-shaped structure like that of the previously observed C-bonded form ("isomer 1"), but with the CO rotated by 180 degrees . The effective intermolecular distance between the centers of mass is 3.51 A for isomer 2 as compared to 3.88 A for isomer 1. In addition to the fundamental band, two combination bands are observed for isomer 2, yielding values for two intermolecular vibrational modes: 14.502(5) cm-1 for the coupled disrotatory motion or the uncoupled CO rock and 21.219(5) cm-1 for the out-of-plane rock. We show that the published ab initio study on this system is inadequate in predicting the intermolecular frequencies for isomer 2 of CO-N2O. PMID- 27991945 TI - First Occurrence and Paleo-Ecological Implications of Insects (Orthoptera: Ensifera Gryllidae) in the Romualdo Member of the Santana Formation, Eo Cretaceous of the Araripe Basin. AB - The Romualdo Member of the Santana Formation, a lithostatigraphic unit attributed to a marine intrusion, is famous for its preserved fossils in calcareous concretions, which stand out for their diversity and excellent preservation levels. This paper aims to record the first occurrence of the Class Insecta in the Romualdo Member of the Santana Formation of the Araripe Basin, as well as to describe and discuss the paleo-ecological implications of such finding. The first occurrence of the order Orthoptera (family Gryllidae) is presented for this unit. This new species is attributed to the genus Araripegryllus, that lasted throughout the deposition of the Crato Member, which is under the Romualdo Member. In reference to its statigraphic origin, the specimens was named Araripegryllus romualdoi sp. nov. PMID- 27991946 TI - Contributions of the complexity paradigm to the understanding of Cerrado's organization and dynamics. AB - The Brazilian Cerrado is a vegetation mosaic composed of different physiognomies. Discussions remain open regarding the factors and processes responsible for the dynamic and spatial organization of the Cerrado - in its different physiognomies. The contributions of the complexity paradigm in this context are still less exploited, despite its great potential for explanations and predictions presented in previous diverse dynamic systems of complex behavior researches, a category in which the Cerrado can be included. This article has the intention of contributing to the construction of this new perspective, discussing - from theoretical concepts - the paradigm of complexity for the understanding of the organization and the dynamics of the Cerrado. PMID- 27991947 TI - Ecohydrological modeling and environmental flow regime in the Formoso River, Minas Gerais State, Brazil. AB - This paper aimed at determining the environmental flow regime in a 1 km stretch of the Formoso River, MG, using River2D model. To carry out the ecohydrological modeling, the following information was used: bathymetry, physical and hydraulic features, and the Habitat Suitability Index for species of the Hypostomus auroguttatus. In the River2D, the Weighted Usable Areas were determined from the average long-term streamflows with percentage from 10% to 100%. Those streamflows were simulated for the later construction of optimization matrices that maximize the habitat area throughout the year. For H. auroguttatus Juvenile, higher values of Weighted Usable Area were associated with the percentage of 60% and 70% of the average long-term streamflows in October and September, respectively. For H. auroguttatus Adult, the highest value of Weighted Usable Area was associated with the percentage of 100% of the average long-term streamflow in September. The environmental flows found for this stretch of the Formoso River varied over the year. The lowest environmental flow was observed in December (2.85 m3 s-1), while the highest was observed in May (4.13 m3 s-1). This paper shows the importance of ecohydrological studies in forming a basis for water resources management actions. PMID- 27991948 TI - Understanding the Cerrado biome, medicinal properties of a Piperaceae, and consequences of seasonal variation in Amazonian upland lakes. PMID- 27991949 TI - On simple Shamsuddin derivations in two variables. AB - We study the subgroup of k -automorphisms of k ? [ x , y ] which commute with a simple derivation d of k ? [ x , y ] . We prove, for instance, that this subgroup is trivial when d is a shamsuddin simple derivation. in the general case of simple derivations, we obtain properties for the elements of this subgroup. PMID- 27991950 TI - On reduced L2 cohomology of hypersurfaces in spheres with finite total curvature. AB - In this paper, we prove that the dimension of the second space of reduced L2 cohomology of M is finite if is a complete noncompact hypersurface in a sphere ??n+1and has finite total curvature (n>=3). PMID- 27991951 TI - On non-Kupka points of codimension one foliations on P3. AB - We study the singular set of a codimension one holomorphic foliation on P 3 . We find a local normal form for these foliations near a codimension two component of the singular set that is not of Kupka type. We also determine the number of non Kupka points immersed in a codimension two component of the singular set of a codimension one foliation on P 3. PMID- 27991952 TI - Enhancement of Hevea brasiliensis properties through chemical application. AB - The effects of four different types of bleaching agents (hydrogen peroxide, sodium hypochlorite, sodium chlorite and oxalic acid) mixed together with 2% boron-based preservative (Celbor SP) were studied on green sawn rubberwood. Two concentration levels (1% and 2%) of were used. Whitish values (W) and colour changes (DeltaE) of sawn rubberwood were assessed before and after chemical treatment using a colour meter. Preliminary observation indicated that timber treated with 1% and 2% hydrogen peroxide produced better and more homogeneous colour properties. Hydrogen peroxide treated timber gave higher whitish values (6.23 and 9.91 for 1% and 2% solution, respectively) and lower colour changes (8.49 and 5.51 for 1% and 2% solution, respectively) when compared to the other three chemicals. Evaluation on the effects of bleaching (hydrogen peroxide with a higher level of concentration) on physical, mechanical and biological properties of rubberwood also have been determined in this study. PMID- 27991954 TI - Geostatistical Approach for Spatial Interpolation of Meteorological Data. AB - Meteorological data are used in many studies, especially in planning, disaster management, water resources management, hydrology, agriculture and environment. Analyzing changes in meteorological variables is very important to understand a climate system and minimize the adverse effects of the climate changes. One of the main issues in meteorological analysis is the interpolation of spatial data. In recent years, with the developments in Geographical Information System (GIS) technology, the statistical methods have been integrated with GIS and geostatistical methods have constituted a strong alternative to deterministic methods in the interpolation and analysis of the spatial data. In this study; spatial distribution of precipitation and temperature of the Aegean Region in Turkey for years 1975, 1980, 1985, 1990, 1995, 2000, 2005 and 2010 were obtained by the Ordinary Kriging method which is one of the geostatistical interpolation methods, the changes realized in 5-year periods were determined and the results were statistically examined using cell and multivariate statistics. The results of this study show that it is necessary to pay attention to climate change in the precipitation regime of the Aegean Region. This study also demonstrates the usefulness of the geostatistical approach in meteorological studies. PMID- 27991953 TI - Barium and its Importance as an Indicator of (Paleo)Productivity. AB - Barium (Ba) is a trace element which occurs predominantly as barite mineral (BaSO4) in the marine environment. Previous work suggests that barite concentrations are related to the organic carbon flux and marine biological debris in the water column suggesting a direct or indirect involvement in the marine biological cycling. In addition, barite has a high preservation rate (~30%) in sediments and it is less affected by early diagenesis than other proxies for productivity such as carbonates (~10%) and organic carbon (~1%), for example. Therefore, Ba is considered an excellent proxy for ocean (paleo)productivity. However, correlating barite to productivity involves some caveats. Specifically, the post-depositional formation of barite in oxic sediments can lead to Ba release into porewaters under anoxic conditions, which can form barite again under oxic conditions. This diagenetic formation is not correlated to export production as the seawater authigenic barite formed with decaying organic matter in the water column. Therefore, the main goal of this work is to briefly review the marine Ba cycle and highlight its importance for (paleo)productivity research. PMID- 27991955 TI - Dating stalagmite from Caverna do Diabo (Devil'S Cave) by TL and EPR techniques. AB - A cylindrical fragment of stalagmite from Caverna do Diabo, State of Sao Paulo, Brazil, has been studied and dated by thermoluminescence and electron paramagnetic resonance techniques. The thermoluminescence glow curves of stalagmite samples and subsequently gamma irradiated, have shown rise of three peaks at 135, 180 and 265 degrees C. From electron paramagnetic resonance spectra of stalagmite was possible to clearly identify three paramagnetic centers in the g = 2.0 region: Centers I, II and III are due to , and , respectively. The additive method was applied to calculate the accumulated dose using thermoluminescence peak at 265 degrees C and the electron paramagnetic resonance signal at g = 1.9973 of CO- 2 radical. The ages of the different slices of stalagmite were determined from the Dac- values and Dan- value, obtaining an average of 86410 for central slice, 53421 for second slice, 31490 for third slice and 46390 years B.P. for the central region of upper end. PMID- 27991956 TI - Cordao Formation: loess deposits in the southern coastal plain of the state of Rio Grande do Sul, Brazil. AB - Loess consists of silt-dominated sediments that cover ~10% of the Earth's surface. In southern South America it occurs in Argentina, Bolivia, Paraguay and Uruguay, and its presence in southern Brazil was never studied in detail. Here is proposed a new lithostratigraphic unit, Cordao Formation, consisting of loess deposits in the southern Brazilian coastal plain. It consists of fine-very fine silt with subordinate sand and clay, found mostly in lowland areas between Pleistocene coastal barriers. These sediments are pale-colored (10YR hue) and forms ~1,5-2,0 meter-thick stable vertical walls. The clay minerals include illite, smectite, interstratified illite/smectite and kaolinite, the coarser fraction is mostly quartz and plagioclase. Caliche and iron-manganese nodules are also present. The only fossils found so far are rodent teeth and a tooth of a camelid (Hemiauchenia paradoxa). Luminescence ages indicate that this loess was deposited in the latest Pleistocene, between ~30 and 10 kyrs ago, and its upper portion was modified by erosion and accumulation of clay and organic matter in the Holocene. The estimated accumulation rate was ~630 g/m2/year. The probable source of this loess is the Pampean Aeolian System of Argentina and it would have been deposited by the increased aeolian processes of the last glacial. PMID- 27991957 TI - Paralavas in the Cretaceous Parana volcanic province, Brazil - A genetic interpretation of the volcanic rocks containing phenocrysts and glass. AB - The occurrences of glassy rocks containing long and curved phenocrysts in the Parana volcanic province, South America, are here interpreted as paralavas. The large number of thin (0.1-0.5 m) dikes and sills of glassy volcanic rocks with hopper, hollow or curved, large crystals of clinopyroxene (up to 10 cm), plagioclase (up to 1 cm), magnetite and apatite are contained in the core of thick (>70 m) pahoehoe flows. They are strongly concentrated in the state of Parana, coincident with the presence of the large number of dikes in the Ponta Grossa arch. These rocks were previously defined as pegmatites, although other names have also been used. A paralava is here interpreted as the product of melting of basaltic rocks following varied, successive processes of sill emplacement in high-kerogen bituminous shale and ascent of the resultant methane. As the gas reached the lower portion of the most recent lava flow of the volcanic pile, the methane reacted with the silicate and oxide minerals of the host volcanic rock (1,000 oC) and thus elevated the local temperature to 1,600 oC. The affected area of host rock remelted (possibly 75 wt.%) and injected buoyantly the central and upper portion of the core. This methane-related mechanism explains the evidence found in the paralavas from this volcanic province, one of the largest in the continents. PMID- 27991958 TI - Influence of seasonal variation on the hydro-biogeochemical characteristics of two upland lakes in the Southeastern Amazon, Brazil. AB - Limnological characteristics of the Violao and Amendoim lakes, in the Serra dos Carajas, Amazon, were studied interannually (2013-2014). Climate data indicate anomalous conditions during the 2013 rainy period with higher rainfall and lower temperature in the beginning (November). Lake levels were influenced after the first and second hour of each rainfall, which showed a strong synchronization between seasonal fluctuation of lake levels and local weather patterns. Based on the water quality, both lakes are classified as classes "1" and "2" in the CONAMA (Conselho Nacional do Meio Ambiente) scheme and as "excellent" to "good" in the WQI (Water Quality Index) categories. However, the limnology is distinctly different between the lakes and seasons. Higher trophic state and phytoplankton productivity were observed mainly during the rainy period in Violao Lake compared to Amendoim Lake. This may be due to deposition of leached nutrients in the former, mainly total phosphorus (TP), which was probably derived from mafic soils and guano. This is consistent with the significant positive correlation between Chlorophyll-a and TP at the end of the rainy period (March-April), whereas this was not observed in the beginning (November). This could possibly be a consequence of the more intense cloud cover, and unusual high rainfall that limits nutrient availability. PMID- 27991959 TI - Local Anesthetic Activity from Extracts, Fractions and Pure Compounds from the Roots of Ottonia anisum Spreng. (Piperaceae). AB - Piperaceae species can be found worldwide in tropical and subtropical areas and many of them have been used for centuries in traditional folk medicine and in culinary. In Brazil, species of Piperaceae are commonly used in some communities as local anesthetic and analgesic. Countrified communities have known some species of the genus Ottonia as "anestesia" and it is a common habit of chewing leaves and roots of Ottonia species to relief toothache. The purpose of this study is to report our findings on new molecules entities obtained from the roots of Ottonia anisum Spreng, in which local anesthetic activity (sensory blockage) is demonstrated for the first time in vivo guinea pig model. Phytochemical investigation led to the isolation of three amides (pipercallosidine, piperine and valeramide) and in an enriched mixture of seven amides (valeramide, 4,5 dihydropiperlonguminine, N-isobutil-6-piperonil-2-hexenamide, piperovatine, dihydropipercallosidine, pipercallosidine and pipercallpsine). Our findings demonstrated the anesthetic potential for the methanolic extract from roots, its n-hexane partition and amides from O. anisum and it is in agreement with ethnobotanical survey. PMID- 27991960 TI - Agaricus subrufescens: substratum nitrogen concentration and mycelial extraction method on antitumor activity. AB - Antitumor activity of Agaricus subrufescens has been shown on vegetative mycelium and basidiocarp. However, few studies have assessed the effect of A. subrufescens cultivation conditions and extraction methods on antitumor activity. This study evaluated the effect of nitrogen concentration on the cultivation medium of A. subrufescens and the extraction method of mycelial antineoplastic actives against sarcoma 180 cells implanted in mice. Two nitrogen sources (isolated soybean protein and NaNO3) and 10 nitrogen concentrations (0.25 to 8.0 g/L) were used. Dried mycelium extract was obtained by hot water infusion (1:10 mass:volume; 90 degrees C) or by aqueous mixture (1:10 mass:volume, ambient temperature) in ultrapure water. The doses were administered daily by gavage to mice implanted with sarcoma 180 cells. Isolated soy protein is more efficient to mycelial biomass production than NaNO3. The mycelial biomass production increases when the cultivation medium is added with high nitrogen concentrations as well as the splenic index and the antitumor activity of the moistened mycelial powder. Hot water extract is more effective than the moistened mycelial powder to reduce tumor. The antitumor activity of hot water mycelial extract is similar to the one of basidiocarps, presenting lower metabolic demand on the spleen, keeping blood parameters normal and promoting animal wellness. PMID- 27991961 TI - Method validation for determination of metals in Vitis labrusca L. grapevine leaf extracts by inductively coupled plasma mass spectrometry (ICP-MS). AB - Vitis labrusca L. is the main species used for wine and juice production in Brazil. The grapevine leaves can be used both as functional foods and as cheapest sources for the extraction of phenolic compounds. Besides the antioxidant activity, grapevine leaves exhibited significant anti-inflammatory activity. Therefore, the aim of this study was to develop and validate an analytical methodology to determine the metals selenium (96Se), chromium (53Cr), nickel (62Ni), cadmium (111Cd) and lead (206Pb) in 30 samples of grapevine leaf extracts (Vitis labrusca, Bordo cultivar) using inductively coupled plasma mass spectrometry (ICP-MS). To obtain the grapevine leaf extracts the samples were milled, weighed and digested in microwave oven with nitric acid. The method showed linearity, precision, accuracy and limits of quantification and detection acceptable for INMETRO protocol validation of analytical methods. Therefore, the method using ICP-MS was developed and validated to determine metals concentrations in grapevine leaves of Vitis labrusca L. and the proposed method could be applied in routine analytical laboratory. PMID- 27991962 TI - The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB. AB - Physiological processes, as autophagy, proliferation and apoptosis are affected during carcinogenesis. Restoring cellular sensitivity to apoptotic stimuli, such as the antineoplastic cocktails, has been explored as a strategy to eliminate cancer cells. Autophagy, a physiological process of recycling organelles and macromolecules can be deviated from homeostasis to support cancer cells survival, proliferation, escape from apoptosis, and therapy resistance. The relationship between autophagy and apoptosis is complex and many stimuli can induce both processes. Most chemotherapeutic agents induce autophagy and it is not clear whether and how this chemotherapy-induced autophagy might contribute to resistance to apoptosis. Here, we review current strategies to sensitize cancer cells by interfering with autophagy. Moreover, we discuss a new link between autophagy and apoptosis: the tumor suppressor retinoblastoma protein (RB). Inactivation of RB is one of the earliest and more frequent hallmarks of cancer transformation, known to control cell cycle progression and apoptosis. Therefore, understanding RB functions in controlling cell fate is essential for an effective translation of RB status in cancer samples to the clinical outcome. PMID- 27991963 TI - Iron restriction increases myoglobin gene and protein expression in Soleus muscle of rats. AB - Iron is an important trace element for proper cell functioning. It is present in cytochromes, hemoglobin and myoglobin (Mb), where it binds to oxygen. It is also an electron acceptor in the respiratory chain. Mb is an 18 kDa heme-protein, highly expressed in skeletal muscle and heart. The expression of several genes involved in the metabolism of iron is post-transcriptionally regulated by this element. Iron was shown to interfere with the polyadenylation step, modifying their poly (A) tail length and, as a consequence, their stability and translation rate. The aim of this study was to investigate whether iron supplementation or long and short-term restriction affects Mb gene and protein expression, as well as Mb mRNA poly(A) tail length, in cardiac and skeletal muscles of rats. Long term iron restriction caused an increase in Mb gene and protein expression in Soleus muscle. No changes were observed in extensor digitorum longus muscle and heart. Short-term iron supplementation after iron deprivation did not alter Mb gene expression and mRNA poly(A) tail length in all tissues studied. These results indicate that Mb gene and protein expression is upregulated in response to iron deprivation, an effect that is tissue-specific and seems to occur at transcriptional level. PMID- 27991964 TI - Analysis of labour risks in the Spanish industrial aerospace sector. AB - Labour risk prevention is an activity integrated within Safety and Hygiene at Work in Spain. In 2003, the Electronic Declaration for Accidents at Work, Delt@ (DELTA) was introduced. The industrial aerospace sector is subject to various risks. Our objective is to analyse the Spanish Industrial Aerospace Sector (SIAS) using the ACSOM methodology to assess its labour risks and to prioritise preventive actions. The SIAS and the Services Subsector (SS) were created and the relevant accident rate data were obtained. The ACSOM method was applied through double contrast (deviation and translocation) of the SIAS or SS risk polygon with the considered pattern, accidents from all sectors (ACSOM G) or the SIAS. A list of risks was obtained, ordered by action phases. In the SIAS vs. ACSOM G analysis, radiation risks were the worst, followed by overstrains. Accidents caused by living beings were also significant in the SS vs. SIAE, which will be able to be used to improve Risk Prevention. Radiation is the most significant risk in the SIAS and the SS. Preventive actions will be primary and secondary. ACSOM has shown itself to be a valid tool for the analysis of labour risks. PMID- 27991965 TI - Popular medicinal uses of Calea uniflora Less. (Asteraceae) and its contribution to the study of Brazilian medicinal plants. AB - Calea uniflora Less. is widely used in southern Santa Catarina (Brazil), but there are no scientific studies which support its use. Then, this study was proposed to determine of the percentage use of C. uniflora in a city of southern Brazil and documentation of the knowledge that the population has about this species. The survey was conducted with semi-structured interviews using a questionnaire applied to 372 participants. In analyzing the results, it was observed that of the 94.1% who recognized C. uniflora, 74.3% utilize it as a medicinal plant and 65.4% of such knowledge originates in childhood, mainly through the family (84.6%). 93% reported using inflorescences macerated in alcohol or rum; this extract is generally used topically for wound healing and muscle pain. Furthermore, some reported using small quantities of this extract orally to treat cold and flu. Regarding effectiveness and safety, 97% stated an improvement in symptoms with the use of the plant, while 98.5% stated that it has no toxicity. In light of these results, future phytochemical, pharmacological and toxicological analyses should be designed in order to ensure rational and safe use of this species. PMID- 27991966 TI - Genotypic carriers of the obesity-associated FTO polymorphism exhibit different cardiometabolic profiles after an intervention. AB - Background:: Children and adolescents with at-risk genotypes (AA/AT) of the rs9939609 polymorphism in FTO, a fat mass and obesity-associated gene, may exhibit different cardiometabolic profile responses than subjects with the TT genotype after an interdisciplinary intervention. Methods:: The sample consisted of 36 school children from southern Brazil. We used DNA quantitation and real time polymerase chain reaction (PCR) for polymorphism genotyping. We measured anthropometric parameters (body mass index (BMI), waist circumference, hip circumference, waist-hip ratio, body fat percentage and skinfold sum), biochemical parameters (glucose, lipid profile, ultra-sensitive C-reactive protein, uric acid, alanine aminotransferase, aspartate aminotransferase, insulin and adiponectin) and blood pressure. The 4-month intervention consisted of physical education classes, nutritional counseling, and postural and oral health counseling. Results:: We observed no significant differences among the groups (AA, AT and TT) after the intervention. However, we observed improvements in three parameters (waist circumference, hip circumference and C-reactive protein) in the AT/AA genotype group and in two parameters (hip circumference and uric acid) in the TT genotype group. Conclusions:: After an intervention program, carriers of at-risk genotypes for obesity (AA/AT) do not exhibit differences in biochemical parameters, blood pressure and anthropometric parameters compared with carriers of the TT genotype. PMID- 27991967 TI - Evaluation of deciduous broadleaf forests mountain using satellite data using neural network method near Caspian Sea in North of Iran. AB - During the recent decades, deciduous forests have been molested by human intervention. Easy access, abundance and diversity of valuable forest products have led to increased population density, creating new residential areas and deforestation activities. Revealing changes is one of the fundamental methods in management and assessment of natural resources. This study is evaluated changes in forests area of 2013 using satellite images. In order to mapping the forest extent condition 2013, images of the mentioned years were digitized and geo referenced by using the ground control points and the maps of mapping organization. After selecting the best set of band using the Bhattacharya distance index, the image classification was performed by using artificial neural network algorithm. Classification by neural network method 2013 in showed that it has a high overall accuracy equal to 95.96%. PMID- 27991968 TI - Genetic structure from the oldest Jatropha germplasm bank of Brazil and contribution for the genetic improvement. AB - Jatropha is a potential oilseed crop, which requires mitigating factors such as the low genetic variability of the species. The solution runs through the research of Brazilian germplasm. Attention should be given to the germplasm of jatropha the north of Minas Gerais, because this is the oldest national collection and because this region may be a regions of jatropha diversity due to selection pressure arising from environmental adversities. Therefore, the objective of this study was to investigate the genetic diversity of 48 accessions of collection from Empresa de Pesquisa Agropecuaria de Minas Gerais (EPAMIG), using SSR and ISSR markers. The results showed low genetic diversity, but some individuals stood out as J. mollissima (48), J. podagrica (47), Mexican accessions (42, 43, 44 and 45) and some national accessions (28, 29, 41 and 46). Therefore, aiming to increase the genetic variability and improve the effectiveness of jatropha breeding programs, it is suggested to explore such as parental accessions to generate commercial hybrids. This fact implies the possibility to support future production of jatropha, since this culture may be an important source of income, especially for small farmers living in semiarid regions of Brazil. PMID- 27991969 TI - Effects of irrigation intervals and organic manure on morphological traits, essential oil content and yield of oregano ( Origanum vulgare L.). AB - In order to evaluate the effect of irrigation intervals and cattle manure levels on morphological traits, essential oil content and yield of oregano, an experiment was conducted at the experimental Farm of the Faculty of Agriculture, Urmia University, Iran. The experimental design was split-plots, arranged in randomized complete blocks with three replications. Main plots including irrigation intervals (1, 2 and 3 weeks) and four levels of cattle manure at 0, 10, 20 and 30 t ha-1 were allocated to sub plots. Our results showed that increasing irrigation intervals reduced values of all morphological traits except for proportion of stems. Also, values for stems number, plant spread, stem diameter, leaf area, fresh and dry herb yield increased by increasing cattle manure levels. On the other hand, morphological traits not influenced by interaction of treatments except for plant spread and leaf area. The highest essential oil content (2.07%) and yield (66.62 kg ha-1) obtained in highest irrigation intervals and cattle manure levels. Whereas, 1 week irrigation interval without use of cattle manure produce lowest essential oil content (1.55%). For essential oil yield, the lowest value (46.37 kg ha-1) was found in 2 weeks irrigation interval with application of 20 t ha-1 cattle manure. PMID- 27991970 TI - Experimental validation of a bearing wear model using the directional response of the rotor-bearing system. AB - The present work gives continuity in the analysis of the wear influence on cylindrical hydrodynamic bearings by presenting an experimental validation of the wear model previously proposed by the authors. This validation is carried on using the frequency response of the rotor-bearings system in directional coordinates. For this purpose, a test rig was assembled in order to evaluate the behavior of the rotating system when supported by hydrodynamic bearings with different wear patterns. The experimental measurements are used to validate the wear model, comparing the anisotropy influence on the experimental and numerical responses. The simulated directional frequency responses showed a good agreement with the experimental ones, demonstrating the potential of the proposed wear model in satisfactorily represent its influence on the rotor-bearings system response in the frequency range where the numerical model was validated. PMID- 27991971 TI - Not so simple as it seems: tackling climate change and implementing the sustainable development goals in the Americas. PMID- 27991972 TI - Air pollution management and control in Latin America and the Caribbean: implications for climate change. AB - Objective: To assess the status of the legal framework for air quality control in all countries of Latin America and Caribbean (LAC); to determine the current distribution of air monitoring stations and mean levels of air pollutants in all capital and large cities (more than 100 000 inhabitants); and to discuss the implications for climate change and public policymaking. Methods: From January 2015-February 2016, searches were conducted of online databases for legislation, regulations, policies, and air pollution programs, as well as for the distribution of monitoring stations and the mean annual levels of air pollution in all LAC countries. Results: Only 117 cities distributed among 17 of 33 LAC countries had official information on ground level air pollutants, covering approximately 146 million inhabitants. The annual mean of inhalable particles concentration in most of the cities were over the World Health Organization Air Quality Guidelines; notably, only Bolivia, Peru, and Guatemala have actually adopted the guidelines. Most of the cities did not have information on particulate matter of 2.5 microns or less, and only a few measured black carbon. Conclusions: The air quality regulatory framework should be updated to reflect current knowledge on health effects. Monitoring and control of ground level pollutants should be extended and strengthened to increase awareness and protect public health. Using the co-benefits of air pollution control for health and climate as a framework for policy and decision-making in LAC is recommended. PMID- 27991973 TI - An effective public health program to reduce urban heat islands in Quebec, Canada. AB - In 2005, the Government of the Province of Quebec, Canada, adopted the Climate Change Action Plan for 2006 - 2012. The Institut national de sante publique du Quebec (National Institute of Public Health of Quebec), charged with implementing the health adaptation component of the Plan, worked to mitigate urban heat islands (UHI) by funding and evaluating 40 pilot projects. These projects explored different methods of fighting UHIs by greening cities in a participative and mobilizing approach led mainly by non-governmental organizations and municipalities. An assessment of temperatures before and after implementing various methods demonstrated that some actions enabled significant gains of coolness and more efficiently mitigated heat (reduction of concrete/asphalt surfaces, increasing vegetation, etc.). An assessment of quality of life showed that projects were positively received by users, especially by those living in vulnerable situations. A lifecycle analysis showed that from the environmental perspective, UHI mitigation measures that do not require fertilization or maintenance are preferable. Finally, communication efforts that raise awareness of UHI and mitigation are of significant importance to program success. PMID- 27991974 TI - An observatory to gather and disseminate information on the health-related effects of environmental and climate change. AB - This report sought to critically examine proposals, potentials, and challenges of environmental health observatories with an emphasis on climate change processes. A critical review of existing environmental health observatories was performed, examining their purposes, potential audiences, and technological platforms. The implementation of the Brazilian Climate and Health Observatory (C&HO) is described, and two stages are defined: (i) the requirement analysis and negotiation stage that identified the national and regional institutional players and their roles as data producers/users; and (ii) thematic health-related workshops that reviewed water-related diseases, vector-borne diseases, extreme climate events, and health problems derived from forest fires. The C&HO is an example of making information on climate and health available through an Internet site where data from different origins can be accessed on a common platform. Complex queries are made by users and can be executed over multiple sites, geographically distributed, with all technical details hidden from the end user. At this stage of the C&HO prototype, alongside the queries, users can also produce semi-qualitative graphs and maps. A multi-scale approach was developed using the platform by setting up sentinel sites. Building a successful observatory is a participatory process that involves choosing indicators, data sources, information technology, and languages to best reach different audiences, such as researchers, citizens, public health professionals, and decisionmakers. PMID- 27991975 TI - Enhancing the sustainability and climate resiliency of health care facilities: a comparison of initiatives and toolkits. AB - Extreme weather events have revealed the vulnerability of health care facilities and the extent of devastation to the community when they fail. With climate change anticipated to increase extreme weather and its impacts worldwide-severe droughts, floods, heat waves, and related vector-borne diseases-health care officials need to understand and address the vulnerabilities of their health care systems and take action to improve resiliency in ways that also meet sustainability goals. Generally, the health sector is among a country's largest consumers of energy and a significant source of greenhouse gas emissions. Now it has the opportunity lead climate mitigation, while reducing energy, water, and other costs. This Special Report summarizes several initiatives and compares three toolkits for implementing sustainability and resiliency measures for health care facilities: the Canadian Health Care Facility Climate Change Resiliency Toolkit, the U.S. Sustainable and Climate Resilient Health Care Facilities Toolkit, and the PAHO SMART Hospitals Toolkit of the World Health Organization/Pan American Health Organization. These tools and the lessons learned can provide a critical starting point for any health system in the Americas. PMID- 27991976 TI - Carbon pollution increases health inequities: lessons in resilience from the most vulnerable. AB - Climate change is a social justice as well as an environmental issue. The magnitude and pattern of changes in weather and climate variables are creating differential exposures, vulnerabilities, and health risks that increase stress on health systems while exacerbating existing and creating new health inequities. Examples from national and local health adaptation projects highlight that developing partnerships across sectors and levels are critical for building climate-resilient health systems and communities. Strengthening current and implementing new health interventions, such as using environmental information to develop early warning systems, can be effective in protecting the most vulnerable. However, not all projected risks of climate change can be avoided by climate policies and programs, so health system strengthening is also critical. Applying a health inequity lens can reduce current vulnerabilities while building resilience to longer-term climate change. Taking inequities into account is critical if societies are to effectively prepare for and manage the challenges ahead. PMID- 27991977 TI - Health in all policies in the partnership for sustainable development. AB - This article analyzes the dynamic interaction between the Health in All Policies (HiAP) agenda and the ongoing implementation of the 2030 Agenda for Sustainable Development. At the World Conference on Social Determinants of Health, held in Rio de Janeiro in October 2011, the Rio Political Declaration pledged to use HiAP as a mechanism to address health inequities. In 2014, the Ministers of Health of the Region of the Americas approved a regional Plan of Action of the Pan American Health Organization (PAHO) that sought to call attention to the health consequences and benefits of policies and actions developed by other sectors. The HiAP approach seeks to integrate activities across the pillars of the sustainable development governance framework (economic, social, and environmental development). Advocates of the process are challenged to consider, using guiding questions outlined at the close of this article, how to pursue action at the country level and in what ways the HiAP approach can contribute to timely and effective implementation of the Sustainable Development Goals (SDGs). The authors propose that coordination between the 2030 Agenda and the regional Plan of Action on HiAP can make an important contribution to the implementation of both processes in the Region. PMID- 27991979 TI - ? PMID- 27991978 TI - Worker health and safety and climate change in the Americas: issues and research needs. AB - SYNOPSIS This report summarizes and discusses current knowledge on the impact that climate change can have on occupational safety and health (OSH), with a particular focus on the Americas. Worker safety and health issues are presented on topics related to specific stressors (e.g., temperature extremes), climate associated impacts (e.g., ice melt in the Arctic), and a health condition associated with climate change (chronic kidney disease of non-traditional etiology). The article discusses research needs, including hazards, surveillance, and risk assessment activities to better characterize and understand how OSH may be associated with climate change events. Also discussed are the actions that OSH professionals can take to ensure worker health and safety in the face of climate change. PMID- 27991980 TI - [Efficiency of the agenda for universal access to health and health coverage in the Americas]. PMID- 27991981 TI - [Financing, organization, costs and services performance of the Argentinean health sub-systems.] AB - Objective:: To analyze the relationship between health system financing and services organization models with costs and health services performance in each of Rosario's health sub-systems. Materials and methods:: The financing and organization models were characterized using secondary data. Costs were calculated using the WHO/SHA methodology. Healthcare quality was measured by a household survey (n=822). Results:: Public subsystem:Vertically integrated funding and primary healthcare as a leading strategy to provide services produced low costs and individual-oriented healthcare but with weak accessibility conditions and comprehensiveness. Private subsystem: Contractual integration and weak regulatory and coordination mechanisms produced effects opposed to those of the public sub-system. Social security: Contractual integration and strong regulatory and coordination mechanisms contributed to intermediate costs and overall high performance. Conclusion:: Each subsystem financing and services organization model had a strong and heterogeneous influence on costs and health services performance. PMID- 27991982 TI - [Chilean health reform ten years since its implementation]. AB - Objective:: To analyze the process of design and implementation of AUGE. Materials and methods:: Literature review of pre-reform background, architecture design and implementation process of reform AUGE and complementary interviews to eight informants involved in its development. Results:: The assessment of health equity was a key element in pre-reform, there are four fundamental dimensions in the design, and the implementation has nine phases. Conclusion:: The results show AUGE strengthening public health by investing in equipment for cost-effective treatments, and also through clinical guidelines that standardize and guide the management of health professionals with patients. PMID- 27991983 TI - [Financial allocations in the System for Social Protection in Health in Mexico: challenges for strategic purchasing]. AB - Objective:: The financial coordination of the System of Social Protection in Health (SPSS) was analyzed to assess its support to strategic purchasing. Materials and methods:: Official reports and surveys were analyzed. Results:: SPSS covers a capita of 2 765 Mexican pesos, equivalent to 0.9% of GDP. The Ministry of Health contributed 35% of the total, state governments 16.7% and beneficiaries 0.06%. The National Commission for Social Protection in Health received 48.3% of resources, allocating 38% to State Social Protection Schemes in Health and paying 7.4% of the total directly to providers.The state contribution is in deficit while family contributions tend not to be charged. Conclusion:: SPSS has not built funds specialized in strategic purchasing, capable of transforming historical budgets.The autonomy of providers is key to reduce out-of pocket spending through the supply of quality services. PMID- 27991984 TI - [Efficiency of human resources for health: an approach to its analysis in Mexico]. AB - Objective:: To analyze efficiency indicators of human resources working at Mexico's Ministry of Health. Materials and methods:: Three dimensions of efficiency were explored: a) labor wastage, b) distribution of human resources (HR) across levels of care, and c) productivity. Results:: Health workers present significant levels of unemployment and underemployment; distribution does not meet international recommendations, and heterogeneous levels of productivity were found among states. Conclusions:: Health and educational authorities should develop and implement a HR plan that takes into consideration the needs and demands of the covered population, and includes a clearly defined set of measures to regulate the future production of HR as well as their distribution among and within state health systems, and that allocates incentives to improve performance. PMID- 27991985 TI - [Administrative efficiency in the Mexican Fund for the Prevention of Catastrophic Expenditures in Health]. AB - Objective:: To show that the administrative regime of specialized hospitals has some influence on the administrative processes to operate the Mexican Fund for Catastrophic Expenditures in Health (FPGC, in Spanish), for providing health care to breast cancer, cervical cancer and child leukemia. Materials and methods:: The variable for estimating administrative efficiency was the time estimated from case notification to reimbursement. For its estimation, semistructured interviews were applied to key actors involved in management of cancer care financed by FPGC. Additionally, a group of experts was organized to make recommendations for improving processes. Results:: Specialized hospitals with a decentralized scheme showed less time to solve the administrative process in comparison with the model on the hospitals dependent on State Health Services, where timing and intermediation levels were higher. Conclusions:: Decentralized hospitals administrative scheme for specialized care is more efficient, because they tend to be more autonomous. PMID- 27991986 TI - [Hospital performance in a segmented and unequal health system: Chile 2001-2010]. AB - Objective:: To analyze the differences in health outcomes by hospital characteristics, focusing on ownership: public, private not-for-profit (PNFP) and private for-profit (PFP). Materials and methods:: We used a discharged patient dataset of Chilean hospitals for the period 2001-2010 with a total of 16 205 314 discharges in 20 public, six PNFP and 15 PFP hospitals.We selected a subsample of two medical conditions: myocardial infarction and stroke.We used probit regression analyses with mortality rates as dependent variable, ownership status as the key explanatory variable, and control variables which included patients' health status and socioeconomic level, and hospital characteristics. Results:: Private hospitals showed lower risk of death relative to public hospitals: 1.3% in PNFP, 0.7% in PFP and 3.5% in public hospitals. Conclusions:: The analysis shows the inequities that exist between public hospitals and the private sector. PMID- 27991987 TI - [Does public health insurance improve health care? The case of prenatal care for adolescents in Mexico]. AB - Objective:: To test the association between public health insurance and adequate prenatal care among female adolescents in Mexico. Materials and methods:: Cross sectional study, using the National Health and Nutrition Survey 2000, 2006, and 2012.We included 3 978 (N=4 522 296) adolescent (12-19) women who reported a live birth.We used logistic regression models to test the association of insurance and adequate (timeliness, frequency and content) prenatal care. Results:: The multivariable predicted probability of timely and frequent prenatal care improved over time, from 0.60 (IC95%:0.56;0.64) in 2000 to 0.71 (IC95%:0.66;0.76) in 2012. In 2012, the probability of adequate prenatal care was 0.54 (IC95%:0.49;0.58); women with Social Security had higher probability than women with Seguro Popular and without health insurance. Conclusion:: Having Social Security is associated with receipt of adequate prenatal care among adolescents in Mexico. PMID- 27991988 TI - [Cost-effectiveness analysis of an alternative for the provision of primary health care for beneficiaries of Seguro Popular in Mexico]. AB - Objective:: To estimate the cost-effectiveness ratio of public and private health care providers funded by Seguro Popular. Materials and methods:: A pilot contracting primary care health care scheme in the state of Hidalgo, Mexico, was evaluated through a population survey to assess quality of care and detection decreased of vision. Costs were assessed from the payer perspective using institutional sources.The alternatives analyzed were a private provider with capitated and performance-based payment modalities, and a public provider funded through budget subsidies. Sensitivity analysis was performed using Monte Carlo simulations. Results:: The private provider is dominant in the quality and cost effective detection of decreased vision. Conclusions:: Strategic purchasing of private providers of primary care has shown promising results as an alternative to improving quality of health services and reducing costs. PMID- 27991989 TI - [Resource allocation in the Seguro Popular program: analysis and recommendations]. AB - Objective:: To describe the mechanisms of allocation and purchase of the Seguro Popular program, the way they operate and how are controls applied.To discuss incentive schemes that can improve performance in general, strengthen primary care and improve access to specialty hospitals. Materials and methods:: The 2014 reforms to the General Health Law are evaluated to understand their intent, which is to strengthen State systems and the relationship with the Federal authority. Options for allocation mechanisms to encourage better primary care and access to specialty treatments towards are discussed, to guarantee access to health services. Conclusions:: To make State schemes of social protection in health agents for the expansion of services, the programmatic approach shall be replaced to achieve a more effective relationship between the Federation and the States. PMID- 27991990 TI - Neurological outcome in patients with inborn errors of metabolism submitted to hematopoietic stem cell transplantation. What should we expect? PMID- 27991991 TI - Attention deficit-hyperactivity disorder in patients in rehabilitation of drug addiction. PMID- 27991993 TI - Caregivers' resilience is independent from the clinical symptoms of dementia. AB - Resilience is the capacity for successful adaptation when faced with the stress of adversity. We aimed to investigate the relationship between caregivers' resilience and the sociodemographic and clinical factors of people with dementia. Cross-sectional assessment of 58 people with dementia and their caregiver dyads showed that most caregivers were female adult children. The caregivers reported moderate to higher levels of resilience, lower levels of anxiety and depressive symptoms and moderate levels of burden. Resilience was not related to the caregiver's gender (p = 0.883), nor clinical (p = 0.807) or emotional problems (p = 0.420). The regression showed that resilience was related to the caregiver's quality of life (p < 0.01) and inversely associated with their depressive symptoms (p < 0.01). There was no relationship between caregivers' resilience and the sociodemographic and clinical characteristics of people with dementia. We can assume that resilience is an individual characteristic. Support groups should also focus on the factors that may increase resilience among caregivers. PMID- 27991992 TI - Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome. AB - Objective: To describe survival and neurological outcomes after HSCT for these disorders. Methods: Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results: Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion: Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor. PMID- 27991994 TI - The correlation between EDSS and cognitive impairment in MS patients. Assessment of a Brazilian population using a BICAMS version. AB - Objectives: To investigate the correlation between the disabilities of MS patients and their cognitive impairment assessed by the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Methods: Forty patients with definitive diagnoses of MS were selected. The correlation coefficient (r) between the Expanded Disability Status Scale (EDSS) and the neuropsychological tests of BICAMS were calculated. Results: The correlation was clinically substantial and significant with r = 0.55 (p < 0.01) in the Symbol Digit Modalities Test (SDMT), 0.54 (p < 0.01) in the Brief Visuospacial Memory Test (BVMT) and 0.40 (p < 0.05) in the California Verbal Learning Test (CVLT). Conclusion: BICAMS has easy and satisfactory application and evaluation for routine visits and presents a significant correlation with the EDSS. Its use may be indicated for screening and monitoring of cognitive impairment in patients with MS. PMID- 27991995 TI - Patients with multiple sclerosis present low levels of empathy. AB - Methods: This is a single center, cross-sectional study, of 34 patients with MS and 34 matched control subjects. A specific questionnaire (empathy quotient) was used. Results: Patients with MS showed significantly lower levels of empathy. This finding was not correlated with disease duration, degree of disability, drugs for treating MS or lesion load on resonance magnetic imaging. Conclusion: Decreased empathy is a frequent condition in patients with MS and should be addressed in order to diminish the psychosocial burden of this neurological disease. PMID- 27991996 TI - Simple prediction model for unfavorable outcome in ischemic stroke after intravenous thrombolytic therapy. AB - Objective: We aimed to develop a model to predict unfavorable outcome in patients with acute ischemic stroke treated with intravenous thrombolytic therapy (IVT), based on simple variables present on admission. Methods: Retrospective analysis of acute ischemic stroke patients treated with IVT in a hospital in Rio de Janeiro. Clinical and radiographic variables were selected for analysis. Multivariate logistic regression was used to develop a predictive model. Results: We analyzed a total of 82 patients. Median National Institutes of Health Stroke Scale (NIHSS) on admission was 9 (3-22), 40.2% presented with a hyperdense artery sign (HAS), 62% had identifiable early parenchymal changes and 61.6% experienced a favorable outcome. An NIHSS score of > 12 on arrival, age > 70 and the presence of HAS were associated with the outcome, even after correction in a logistic regression model. Conclusion: An NIHSS > 12 on arrival, presence of HAS and age > 70 years were predictors of unfavorable outcome at three months in patients with acute ischemic stroke treated with IVT. PMID- 27991997 TI - Prevalence of chronic pain in a metropolitan area of a developing country: a population-based study. AB - Objective: To estimate the prevalence of chronic pain (CP) in the adult population living in the city of Sao Paulo, Brazil, and to identify factors associated with CP in developing countries. Methods: A cross-sectional study using a computer-assisted telephone interview in a two-stage stratified sample of adults living in households. Results: 2,446 subjects were interviewed. The mean age was 39.8 years old. The majority was female and 42.7% had less than 10 years of education. The prevalence of CP was 28.1%. The independent factors associated with CP were female gender (OR = 2.0; p < 0.001), age older than 65 years (OR = 1.4; p = 0.019) and less than 15 years of education (OR = 1.3-1.6; p < 0.04). Conclusions: The prevalence of CP was high and similar to that which has been reported in developed countries. These results raise awareness about CP and may potentially help clinicians and policy makers to design better health care programs for CP treatment in these populations. PMID- 27991998 TI - Migraine in the post-menopausal period is associated with higher levels of mood disorders, disability, and more menopausal symptoms. AB - Objective: To assess the prevalence of headache in post-menopausal women. Methods: Women attending gynecology outpatient services in the coastal region of the state of Sao Paulo, Brazil were invited to participate in this study. Only those with non-surgical menopause and no hormone replacement therapy were included. Prevalence and characterization of headaches were assessed, as well as the burden of migraine, traits of anxiety and depression, and menopausal symptomatology. Results: One hundred and three women were included in the study. Migraine affected 14.7% of them. Some previous type of headache was reported by 86.2% of the women, most of whom improved during menopause but still presented with headache attacks. There was a correlation between higher migraine disability and depressive traits. Conclusions: Many women believe that their headaches, particularly migraine, will end after menopause. This is, unfortunately, not the case for many of them. PMID- 27991999 TI - Attention deficit hyperactivity disorder and drug addiction rehabilitation patients. AB - Objective: Attention deficit hyperactivity disorder (ADHD) is characterized by a persistent pattern of inattention or hyperactivity. This study aimed to investigate the relationship between ADHD and drug dependence. Methods: The presence and severity of ADHD and substance use were evaluated through questionnaires in 80 adult patients in therapeutic communities. Results: No difference in drug use or dependence prevalence between ADHD and non-ADHD patients was found. However, ADHD patients had lower ages on admission (p = 0.004) and at first contact with cocaine (p = 0.033). In ADHD patients, there was a negative correlation between the age at first use of cannabis and the subsequent severity of cannabis use (p = 0.017) and cocaine use (p = 0.033). Conclusions: Though there was no difference in prevalence of drug use among groups, results show that ADHD in patients in therapeutic communities may cause different addiction patterns, such as earlier use of cocaine and admission, and a more severe use of cocaine correlated to earlier contact with cannabis. PMID- 27992001 TI - Factor structure and psychometric properties of the Dispositional Resilience Scale among Brazilian adult patients. AB - Objective: Verifying the psychometrics of a Brazilian version of the Dispositional Resilience Scale (DRS-15). Methods: Cross-cultural adaptation was done interviewing 65 adult patients. Validation was evaluated by application of the Lipp Brazilian Stress Symptoms Inventory (ISSL), Self-Report Questionnaire (SRQ), and other measures to 575 participants from the psychiatric ambulatories (for borderline personality, anxiety or post-traumatic stress disorders) and non psychiatric ambulatories (chronic pain, pre-anesthetic consultation and companions for the latter). Temporal stability was verified with 123 participants. Results: Exploratory factor analysis yielded a three-factor solution. Psychometrics were acceptable (alpha coefficient, 0.71; intraclass correlation coefficient, 0.81). Correlations with the ISSL, SRQ and other measures were noted except for factor 3. In the psychiatric sample, hardiness scores of borderline patients were lower than those of patients with anxiety disorders. Conclusion: This version of the DRS-15 exhibited good reliability in a sample of Brazilian patients; validity was confirmed in two of the scale factors. PMID- 27992002 TI - Neuropsychiatric Lupus in clinical practice. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs, characterized by the production of autoantibodies and the development of tissue injury. The etiology of SLE is partially known, involving multiple genetic and environmental factors. As many as 50% of patients with SLE have neurological involvement during the course of their disease. Neurological manifestations are associated with impaired quality of life, and high morbidity and mortality rates. Nineteen neuropsychiatric syndromes have been identified associated with SLE, and can be divided into central and peripheral manifestations. This article reviews major neuropsychiatric manifestations in patients with SLE and discusses their clinical features, radiological findings and treatment options. PMID- 27992000 TI - Refractory epilepsy in children with brain tumors. The urgency of neurosurgery. AB - In order to verify indications for surgery, 27 patients with refractory epileptic seizures and brain tumor, aged up to 19 years at the time of surgery, were studied between 1996 and 2013 and followed up for at least one year. The mean interval between the onset of seizures and the diagnosis of the tumor was 3.6 years, and from diagnosis to the surgery, 18 months. The location of the tumor was in the temporal lobe in 16, with ganglioglioma and dysembryoplastic neuroepithelial tumors being the most frequent. Among the patients, 92.5% and 90.4% were seizure-free in the first and fifth year after surgery, respectively. Twelve of 16 children were successful in becoming drug-free, with complete withdrawal by 3.2 years. Surgery proved to be potentially curative and safe in these cases, suggesting that the tumor diagnosis and surgery cannot be postponed. PMID- 27992003 TI - Neuromodulation in refractory epilepsy: Brazilian specialists consensus. AB - Epilepsy is a potentially devastating brain disorder characterized by a predisposition to spontaneous epileptic seizures. In patients with medically refractory epilepsy, new non-pharmacological therapeutic approaches may be considered. In this scenario, palliative surgery such as vagus nerve stimulation (VNS) or deep brain stimulation (DBS) may be indicated in a subset of patients. In this paper we make recommendations for the use of VNS and DBS in patients in Brazil with refractory epilepsy. PMID- 27992004 TI - Charcot, Mitchell and Lees: neurology free thinkers and their experiences of psychoactive drugs. AB - Three world-famous neurologists, Charcot and Mitchell, in the 19th century, and Lees, in this century, all of whom had great scientific curiosity, experimented with the psychoactive drugs hashish, mescal and yage, respectively, in an attempt to increase their knowledge of neurological diseases and how the brain works. PMID- 27992005 TI - Guillain-Barre syndrome and dengue fever: report on ten new cases in Brazil. PMID- 27992006 TI - Centenary of the birth of Professor Antonio Branco Lefevre (1916-1981). PMID- 27992007 TI - What to expect from the Michel Temer government in the health care area. PMID- 27992008 TI - Nutrition assessment - Home-based nutritional therapy. PMID- 27992009 TI - Development of exclusively cutaneous sarcoidosis in patient with rheumatoid arthritis during treatment with etanercept. AB - We report the case of a patient with rheumatoid arthritis who, after 2 months of treatment with etanercept, showed disseminated asymptomatic violaceous papules. Biopsy of the skin lesion showed chronic granulomatous dermatitis with negative staining for fungi and acid-fast bacilli (AFB). After discontinuation of etanercept, the patient's condition improved. Although apparently paradoxical, cases of cutaneous and systemic sarcoidosis after anti-TNF medications have been reported in the literature, with very few cases presenting exclusive cutaneous involvement. PMID- 27992010 TI - Spontaneous intracranial epidural hematoma during rivaroxaban treatment. AB - According to our research, this is the first case described in the literature of spontaneous intracranial epidural hematoma secondary to the use of Xareltor. Spontaneous intracranial epidural hematomas are rarely described in the literature. They are associated with infectious diseases of the skull, coagulation disorders, vascular malformations of the dura mater and metastasis to the skull. Long-term post-marketing monitoring and independent reports will probably detect the full spectrum of hemorrhagic complications of the use of rivaroxaban. PMID- 27992011 TI - Muscular cysticercosis: Case report and imaging findings. AB - Cysticercosis is a parasitic disease caused by a worm of the Cestoda class. The most prevalent form affects the nervous system. This case report is from a 78 year-old female patient evaluated at Clinica Mult Imagem, in the city of Santos, Brazil, who presented a form of the disease that differed from the classic neurocysticercosis, in this case muscular cysticercosis. This and other forms of manifestation justify further studies to ensure adequate recognition, diagnosis and treatment of this parasitic disease. PMID- 27992012 TI - Conduct protocol in emergency: Acute adrenal insufficiency. AB - Introduction:: Acute adrenal insufficiency or addisonian crisis is a rare comorbidity in emergency; however, if not properly diagnosed and treated, it may progress unfavorably. Objective:: To alert all health professionals about the diagnosis and correct treatment of this complication. Method:: We performed an extensive search of the medical literature using specific search tools, retrieving 20 articles on the topic. Results:: Addisonian crisis is a difficult diagnosis due to the unspecificity of its signs and symptoms. Nevertheless, it can be suspected in patients who enter the emergency room with complaints of abdominal pain, hypotension unresponsive to volume or vasopressor agents, clouding, and torpor. This situation may be associated with symptoms suggestive of chronic adrenal insufficiency such as hyperpigmentation, salt craving, and association with autoimmune diseases such as vitiligo and Hashimoto's thyroiditis. Hemodynamically stable patients may undergo more accurate diagnostic methods to confirm or rule out addisonian crisis. Delay to perform diagnostic tests should be avoided, in any circumstances, and unstable patients should be immediately medicated with intravenous glucocorticoid, even before confirmatory tests. Conclusion:: Acute adrenal insufficiency is a severe disease that is difficult to diagnose. It should be part of the differential diagnosis in cases of hypotensive patient who is unresponsive to vasoactive agents. Therefore, whenever this complication is considered, health professionals should aim specifically at this pathology. PMID- 27992013 TI - Advanced dementia in a sample of Brazilian elderly: Sociodemographic and morbidity analysis. AB - Introduction:: To investigate the sociodemographic and morbidity profile of advanced dementia patients and sociodemographic data of their primary caregivers. Method:: Data was obtained from 67 elderly recruited for an observational prospective study, through interviews performed with primary caregivers. For statistical analysis, the Statistical Package for the Social Sciences (SPSS(r)) for Windowsr, version 19.0. was employed. Results:: Advanced dementia patients were mostly women, widows, and non-institutionalized, with low-income. An elevated rate of stroke, sarcopenia, and pressure ulcers in this population is noted. Caregivers were mostly women, married, children of the studied patients, and unemployed. Only one third of caregivers were hired for the task. Conclusion:: Patients with advanced dementia present a high morbidity profile, low income, and depend on the care given by family members, mostly unemployed daughters. PMID- 27992014 TI - Prevalence and management of anemia in pre-dialysis Malaysian patients: A hospital-based study. AB - Objective:: Anemia, a common complication of chronic kidney diseases (CKD), is involved in significant cardiovascular morbidity. Therefore, the objective of our study was to investigate the prevalence and severity of anemia in pre-dialysis patients, as well as to determine the predictors of anti-anemic therapy. Method:: A retrospective, observational study was conducted on adult pre-dialysis patients receiving treatment at the Hospital Universiti Sains Malaysia from January 2009 to December 2013. Results:: A total of 615 eligible cases were included. The mean age of patients was 64.1+/-12.0 years. The prevalence of anemia was 75.8%, and the severity of anemia was mild in 47.7% of the patients, moderate in 32.2%, and severe in 20%. Based on morphological classification of anemia, 76.9% of our patients had normochromic-normocytic anemia whereas 21.8 and 1.3% had hypochromic microcytic anemia and macrocytic anemia, respectively. Oral iron supplements were prescribed to 38.0% of the patients and none of the patients was given erythropoietin stabilizing agents (ESA) or intravenous iron preparations. In logistic regression, significant predictors of anti-anemic preparation use were decreased hemoglobin and hematocrit, and advanced stages of CKD. Conclusion:: The results of the present study suggest that the prevalence of anemia in pre dialysis patients is higher than currently accepted and it is found to be correlated with renal function; prevalence increases with declined renal function. An earlier identification as well as appropriate management of anemia will not only have a positive impact on quality of life but also reduce hospitalizations of CKD patients due to cardiovascular events. PMID- 27992015 TI - Analysis of the costs and quality of cardiovascular care in oncological monitoring. AB - Objective:: To analyze the health care costs specifically related to cardiovascular diseases, which were spent by patients of a private healthcare provider in southern Brazil, after their diagnosis of cancer. Method:: We developed an observational, cross-sectional, retrospective study, with a qualitative-quantitative strategy, through the activity of analytical internal audit of medical accounts. Results:: 860 accounts from 2012 to 2015 were analyzed, 73% referred to female users, with average age of 62.38 years, and a total direct cost of BRL 241,103.72. There was prevalence of 37% of breast cancer, 15% of prostate cancer and 9% of colon cancer. In relation to the cardiovascular care, 44% were consultations, 44% were complementary exams, 10% were emergency care, and 3% were hospitalizations. Regarding the health care costs with cardiovascular services, higher costs were in hospitalizations (51%), followed by complementary exams (37%), consultations (8%) and emergency care (4%). Conclusion:: The cancer survivors commonly use health care in other specialties such as cardiology, and the main cost refers to hospitalization. It is recommended to invest in prevention (consultation and complementary exam) as well as in programs of chronic disease management to reduce costs and improve the quality of health care. PMID- 27992016 TI - Breast cancer features in women under the age of 40 years. AB - Objective:: To describe the clinical features, imaging findings and pathological aspects of breast cancer diagnosed in women under the age of 40 years. Method:: A retrospective, descriptive study was performed through analysis of medical records between November 2008 and August 2012. One hundred and twenty (120) patients were included, of whom 112 underwent mammography, 113 underwent ultrasonography, and 105 underwent magnetic resonance imaging (MRI). The histopathological data was obtained in most cases from post-surgical analysis, which was available for 113 patients. Results:: The mean age at diagnosis of primary breast cancer was 34 years. Only 11 patients (9.0%) had a family history of breast or ovarian cancer in first-degree relative. Ninety-two (92) patients sought medical attention after showing breast symptoms, and the presence of a palpable nodule was the main complaint. One hundred and twenty-two (122) primary tumors were diagnosed, of which 112 were invasive (95%). The most common histological type was invasive ductal carcinoma (73.8%). Luminal B was the predominant molecular subtype (42.6%). Ultrasonography was positive in 94.5% of the cases and the most common finding were nodules (94.8%). At mammography, the malignancy was observed in 92.8% and the presence of suggestive calcifications was the dominant feature. The MRI was positive in 98% of patients, and mass lesions were the most common. Conclusion:: Most cases of breast cancer diagnosed in patients under the age of 40 years, in our population, had symptoms at diagnosis and tumor with more aggressive biological behavior. Despite the ultrasound has been the most widely used method, we found improved characterization of breast lesions when also used mammography and MRI. PMID- 27992017 TI - Effectiveness of video resources in nursing orientation before cardiac heart surgery. AB - Objective:: To evaluate the effectiveness of video resources in increasing patient knowledge during preoperative orientation for cardiac surgery compared to standard orientation. Method:: Randomized clinical trial. Patients in the intervention group (IG) received bedside orientation with the aid of a short video and a slide presentation on the day prior to surgery. Patients in the control group (CG) received standard orientation. Allocation and analysis of knowledge were blinded. Analysis was performed according to the intention to treat principle. Results:: We included 90 patients, 45 in each group; 27.8% had incomplete primary education. There were no differences between groups in the baseline. After orientation, IG scored 7.20 (+/-1.56) and scored CG 2.71 (+/ 1.96, p<0,001). The topic "surgical room" had the lowest proportion of correct answers in CG (6.7%), compared to IG (68.9%). The question about "postoperative unit" was the one with the highest proportion of correct answers in IG (93.3%), while in CG the proportion was 22.2%. "Ventilatory support" had a low proportion of correct answers in IG (60%), but still much higher than the correct answers in CG (17.8%). Conclusion:: Orientation performed with the aid of video resources is more effective for knowledge retention in preoperative patients, compared to verbal orientation alone. PMID- 27992018 TI - Psychometric properties of the Brazilian version of the Personal Experience Screening Questionnaire. AB - Introduction:: The Personal Experience Screening Questionnaire (PESQ) is an instrument devised for assessing the magnitude of drug misuse among adolescents. However, its psychometric properties have not been evaluated in adolescent samples outside the United States. Objective:: To assess the internal reliability and validity of the Brazilian version of the PESQ. Method:: A cross-sectional study was carried out with 84 adolescents from a clinical sample and a community based sample. All of them answered the PESQ. Results:: Among adolescents from the community, the PESQ problem severity index, which can vary from 18 to 72, was 26.48+/-9.28, whereas the clinical sample scored 42.89+/-10.02 (p<0.001). Cronbach's alpha was 0.91. Factor analysis resulted in a four-factor solution. Furthermore, both samples also had different mean scores for the other distinct content areas measured by the instrument. Conclusion:: Evidence to support the reliability and validity of the Brazilian version of the Personal Experience Questionnaire was found. PMID- 27992019 TI - Worse prognosis in breast cancer patients can be predicted by immunohistochemical analysis of positive MMP-2 and negative estrogen and progesterone receptors. AB - Introduction:: Breast cancer is the most cause of death, and approximately 90% of these deaths are due to metastases. Matrix metalloproteinase-2 (MMP-2) gelatinase activity is able to degrade a major constituent of the tumor microenvironment, type IV collagen. Two well-established proteins used as markers in clinical practice for breast cancer are the receptors for estrogen (ER) and progesterone (PR). Although the presence of these receptors has been associated with a better prognosis, loss of these proteins can occur during tumor progression, with subsequent resistance to hormone therapy. Objective:: To study the correlation among MMP-2, ER, and PR, as well as the establishment of the metastatic process in primary breast tumors. Method:: Breast cancer samples (n=44) were analyzed by immunohistochemistry for MMP-2, ER, and PR. Results:: We observed that 90% of patients who had metastases and died showed positive staining for MMP-2 (p=0.0082 for both). Using Kaplan-Meier analysis, we found that negative ER patients who were also positive for MMP-2 had even worse disease-free survival (DFS) and overall survival (OS) (p= 0.012 and p=0.005, respectively). Similar results were found in PR-negative patients for DFS (a trend p=0.077) and OS (p=0.038). Conclusion:: Regardless of our small sample size (n=44), the data obtained strongly suggest that MMP-2 in combination with already well-established markers could help to predict the emergence of metastases and death in patients with breast cancer. PMID- 27992020 TI - Emerging radiotherapy technology in a developing country: A single Brazilian institution assessment of stereotactic body radiotherapy application. AB - Objective:: To provide a quantitative profile of the indications and use of stereotactic body radiotherapy (SBRT) in a developing country oncology-based institution. In addition, to describe the patients' and treatment characteristics, and to provide a temporal analysis. Method:: SBRT patients treated from 2007 to 2015 were retrospectively evaluated by two independently investigators. Data were stratified and compared in two periods: first experience (FE) (May 2007 to April 2011), and following experience (FollowE) (May 2011 to April 2015). The following parameters were compared between the groups: total number of treated patients and lesions, treatment site, additional image fusion used, formal protocol adoption, and SBRT planning technique. Results:: One hundred and seventy-six (176) patients with 191 lesions were treated: 34 (18%) lesions in the FE and 157 (82%) lesions in FollowE. The majority of lesions were metastases (60.3%), and lung (60.2%) was the most common treatment site, followed by spine (31%), and others (8.8%). An average of 1.4 (+/-0.6) additional imaging exams for delineation was performed. Conformal 3D radiotherapy planning technique was used in 64.4%, and intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) in the remaining 35.6% (p=0.0001). Higher rates of curative treatments were observed in FE, as well as more lung lesions, patients >= 70 years, 3D conformal, number of additional images and ECOG 0, and all presented p<0.05. The global rate of protocol statement was 79%, lung treatment being the most stated. Conclusion:: SBRT application is rapidly increasing in our setting. Treatment sites and planning techniques are becoming more diversified and complex. PMID- 27992021 TI - Impact of shoe size in a sample of elderly individuals. AB - Introduction:: The use of an improper shoe size is common in older people and is believed to have a detrimental effect on the quality of life related to foot health. The objective is to describe and compare, in a sample of participants, the impact of shoes that fit properly or improperly, as well as analyze the scores related to foot health and health overall. Method:: A sample of 64 participants, with a mean age of 75.3+/-7.9 years, attended an outpatient center where self-report data was recorded, the measurements of the size of the feet and footwear were determined and the scores compared between the group that wears the correct size of shoes and another group of individuals who do not wear the correct size of shoes, using the Spanish version of the Foot Health Status Questionnaire. Results:: The group wearing an improper shoe size showed poorer quality of life regarding overall health and specifically foot health. Differences between groups were evaluated using a t-test for independent samples resulting statistically significant (p<0.05) for the dimension of pain, function, footwear, overall foot health, and social function. Conclusion:: Inadequate shoe size has a significant negative impact on quality of life related to foot health. The degree of negative impact seems to be associated with age, sex, and body mass index (BMI). PMID- 27992022 TI - Salivary gland endoscopy in children: A systematic review. AB - Objective:: To review studies on sialendoscopy (SE) of the salivary glands in children focusing mainly on the indications, endoscopic findings, and effectiveness of the procedure. Method:: The electronic databases searched were Pubmed, Scielo, and Cochrane. The search was conducted by two researchers independently, following inclusion and exclusion criteria. A third author analyzed sources of conflict. In the first stage they were discarded by reading the articles title that had no relation to the purpose of the study and then evaluated the abstracts of each study. In these two initial phases 37 articles were excluded. Articles not excluded by the selection criteria have been retrieved and assessed in full. Seven articles had their data extracted and were compared. Results:: The literature search parameters listed allowed the recovery of 44 articles. After applying the exclusion criteria, seven studies were included in this review representing 207 patients undergoing with ages ranging from 1 to 16 years. All studies except one underwent SE under general anesthesia. The juvenile recurrent parotitis was the main clinical diagnosis related with SE procedures (N=152). The number of inflammatory attacks per patient per year was the parameter for indication of SE. The efficacy of the procedure was considered high by all authors ranging between 83 and 93% in larger series evaluated. Conclusion:: Sialendoscopy is a safe and effective procedure for the diagnosis and treatment of recurrent inflammatory diseases of salivary glands in children. PMID- 27992023 TI - Educational strategies for the prevention of diabetes, hypertension, and obesity. AB - Objective:: The main goal of this work was to produce a review of educational strategies to prevent diabetes, hypertension, and obesity. Method:: PubMed database was consulted using combined descriptors such as [Prevention], [Educational Activities], [Diabetes], [Hypertension], and [Obesity]. Data from randomized trials published between 2002 and 2014 were included in spreadsheets for analysis in duplicate by the reviewers. Results:: A total of 8,908 articles were found, of which 1,539 were selected about diabetes mellitus (DM, n=369), arterial systemic hypertension (ASH, n=200), and obesity (OBES, n=970). The number of free full text articles available was 1,075 (DM = 276, ASH = 118 and OBES = 681). In most of these studies, demographic characteristics such as gender and age were randomized, and the population mainly composed by students, ethnic groups, family members, pregnant, health or education professionals, patients with chronic diseases (DM, ASH, OBES) or other comorbidities. Group dynamics, physical activity practices, nutritional education, questionnaires, interviews, employment of new technologies, people training and workshops were the main intervention strategies used. Conclusion:: The most efficient interventions occurred at community level, whenever the intervention was permanent or maintained for long periods, and relied on the continuous education of community health workers that had a constant interference inside the population covered. Many studies focused their actions in children and adolescents, especially on students, because they were more influenced by educational activities of prevention, and the knowledge acquired by them would spread more easily to their family and to society. PMID- 27992024 TI - Reliability and construct validity of the Instrument to Measure the Impact of Valve Heart Disease on the Patient's Daily Life. AB - Objective: evaluate the practicality, acceptability and the floor and ceiling effects, estimate the reliability and verify the convergent construct's validity with the instrument called the Heart Valve Disease Impact on daily life (IDCV) of the valve disease in patients with mitral and or aortic heart valve disease. Method: data was obtained from 86 heart valve disease patients through 3 phases: a face to face interview for a socio-demographic and clinic characterization and then other two done through phone calls of the interviewed patients for application of the instrument (test and repeat test). Results: as for the practicality and acceptability, the instrument was applied with an average time of 9,9 minutes and with 110% of responses, respectively. Ceiling and floor effects observed for all domains, especially floor effect. Reliability was tested using the test - repeating pattern to give evidence of temporal stability of the measurement. Significant negative correlations with moderate to strong magnitude were found between the score of the generic question about the impact of the disease and the scores of IDCV, which points to the validity of the instrument convergent construct. Conclusion: the instrument to measure the impact of valve heart disease on the patient's daily life showed evidence of reliability and validity when applied to patients with heart valve disease. PMID- 27992025 TI - Construction and validation of a tool to Assess the Use of Light Technologies at Intensive Care Units. AB - Objective: to construct and validate a tool to assess the use of light technologies by the nursing team at Intensive Care Units. Method: methodological study in which the tool was elaborated by means of the psychometric method for construction based on the categorization of health technologies by Merhy and Franco, from the National Humanization Policy, using the Nursing Intervention Classification taxonomy to categorize the domains of the tool. Agreement Percentages and Content Validity Indices were used for the purpose of validation. Results: The result of the application of the Interrater Agreement Percentage exceeded the recommended level of 80%, highlighting the relevance for the proposed theme in the assessment, with an agreement rate of 99%. Conclusion: the tool was validated with four domains (Bond, Autonomy, Welcoming and Management) and nineteen items that assess the use of light technologies at Intensive Care Units. PMID- 27992026 TI - Psychometric properties of the Attitudes Scale facing Alcohol and Alcoholism in nursing students. AB - Objective: to verify the psychometric properties of the Attitudes Scale facing Alcohol and Alcoholism (EAFAA) and people with disorders related to the use of alcohol in nursing students. Method: a convenience sample (n=420) completed the EAFAA, the data were submitted to Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA). Results: the EFA resulted in an instrument composed of 48 items divided into four factors. The CFA has established the validity of the factorial structure. The internal consistency of the scale was considered adequate (alpha=0.85) presenting a sensitivity of 70% and specificity of 75%. Conclusion: the EAFAA constitutes a reliable instrument to identify the attitudes of nursing students towards alcohol, alcoholism and persons with disorders related to alcohol use. PMID- 27992027 TI - Music listening for anxiety relief in children in the preoperative period: a randomized clinical trial. AB - Objective: to investigate the effects of music listening, for 15 minutes, on the preoperative anxiety levels in children undergoing elective surgery in comparison with conventional pediatric surgical care. Method: randomized controlled clinical trial pilot study with 52 children in the preoperative period, aged 3 to 12 years, undergoing elective surgery and randomly allocated in the experimental group (n = 26) and control group (n = 26). Anxiety was assessed in both groups by the application of the modified Yale Preoperative Anxiety Scale and measurement of the physiological variables, upon arrival and 15 minutes after the first measurement. Results: there was a statistically significant difference in preoperative anxiety between the two groups only in relation to the physiological variable, since the respiratory rate of preschool children in the experimental group reduced in the second measurement compared to the control group (p = 0.0453). The experimental group showed a statistically significant reduction in anxiety levels after 15 minutes of music listening (p = 0.0441), specifically with regard to the behavioral domains of activity, vocalization, emotional expression and apparent awakening state. Conclusion: music listening emerges as a potential nursing intervention for relief of preoperative anxiety in children undergoing surgical procedures. RBR-7mcr59. PMID- 27992028 TI - Measurement of the area of venous ulcers using two software programs. AB - Objective: to compare the measurement area of venous ulcers using AutoCAD(r) and Image Tool software. Method: this was an assessment of reproducibility tests conducted in a angiology clinic of a university hospital. Data were collected from 21 patients with venous ulcers, in the period from March to July of 2015, using a collection form and photograph of wounds. Five nurses (evaluators) of the hospital skin wound study group participated. The wounds were measured using both software programs. Data were analyzed using intraclass correlation coefficient, concordance correlation coefficient and Bland-Altman analysis. The study met the ethical aspects in accordance with current legislation. Results: the size of ulcers varied widely, however, without significant difference between the measurements; an excellent intraclass and concordance correlation was found between both software programs, which seem to be more accurate when measuring a wound area >10 cm2. Conclusion: the use of both software programs is appropriate for measurement of venous ulcers, appearing to be more accurate when used to measure a wound area > 10 cm2. PMID- 27992029 TI - Clinical validation of nursing outcome mobility in patients with cerebrovascular accidents. AB - Objective: To clinically validate the nursing outcome Mobility in patients with cerebrovascular accidents. Methods: Descriptive study, conducted in July 2011, with 38 outpatients, in northeastern Brazil. Data collection took place by evaluating two pairs of specialist nurses, where one pair used the instrument containing the constitutive and operational definitions of the indicators and magnitudes of the Mobility Outcome and the other pair without such definitions. Results: When analyzing the evaluations among nurses, all indicators showed significant differences by the Friedman test (p <0.05). Conclusion: The constitutive and operational definitions submitted to the validation process provide greater accuracy in assessing the cerebrovascular accident patient's mobility state. PMID- 27992030 TI - Perceptions of adolescents' family members about therapeutic workshops in a child psychosocial care center. AB - Objective: To learn the perceptions of adolescents' family members about therapeutic workshops in a Child Psychosocial Care Center (CAPSi). Methods: A qualitative, descriptive study conducted in 2013 in Santa Catarina, comprising 18 family members of adolescents being cared for in a CAPSi. Information was gathered through interviews construed based on content analysis. Results: Two themes were identified: (un)awareness about therapeutic workshops and recognition of therapy workshops. Nine family members were not familiar to the activities carried out in therapeutic workshops, whereas the other nine ones said these involve games, cooking, behavior, reading, music, beauty, craft and painting. Therapeutic aspects were highlighted, such as improved self-esteem of adolescents, behavior and coexistence. However, some families perceived no changes. The development of income-generating projects was suggested. Conclusions: Therapeutic workshops nurture social living spaces, health education and social, psychological and pedagogical support. However, family members are hardly included. PMID- 27992031 TI - Evaluating comprehensiveness in children's healthcare. AB - Objective: To evaluate the presence and extent of comprehensiveness in children's healthcare in the context of the Family Health Strategy. Method: Evaluative, quantitative, cross-sectional study conducted with 344 family members of children at the Family Health Units of Joao Pessoa, PB, Brazil. Data were collected using the PCATool Brazil - child version and analysed according to descriptive and exploratory statistics. Results: The attribute of comprehensiveness did not obtain satisfactory scores in the two evaluated dimensions, namely "available services" and "provided services". The low scores reveal that the attribute comprehensiveness is not employed as expected in a primary care unit and points to the issues that must be altered. Conclusion: It was concluded that the services should be restructured to ensure cross-sector performance in the provision of child care. It is also important to improve the relations between professionals and users to promote comprehensive and effective care. PMID- 27992032 TI - Speech of nurse managers related to conditions that (dis)favor the control of tuberculosis in the elderly. AB - Objective: To analyze the discourse of nurse managers related to conditions that (dis)favor the control of tuberculosis in the elderly. Method: This study is qualitative and was held in a city considered a priority in the control of tuberculosis in Paraiba. Data collection was carried out between February and May 2014, through semi-structured interviews with eleven nurse managers. French Discourse Analysis was used the to analyze the empirical material. Results: The following discursive block was identified in the analysis: Conditions that (dis)favor the control of tuberculosis in the elderly. It was made evident that the training processes represent an important component in the effective control of this disease in the elderly. However, the speeches pointed to the maintenance of traditional educational practices in training and that tuberculosis in older people is not perceived as a priority. Conclusion: The nurse managers should trigger training processes to improve the control of tuberculosis in elderly patients based on continuing health education. PMID- 27992033 TI - Patient safety culture in hospitals within the nursing perspective. AB - Objective: Evaluate the atmosphere regarding patient safety from the perspective of active nurses in hospitals in a country town of Rio Grande do Sul State. Methods: Cross-sectional study with 637 nursing professionals from two hospitals. Data collection through Safety Attitudes Questionnaire, in the second half of 2014. Cutoff for positive assessment was >=75 points. Results: The scores for domains in the overall assessment were: 76 (team work atmosphere), 73 (safety atmosphere), 88 (job satisfaction), 59 (perceived stress), 66 (perception of unit management), 65 (perception of hospital management) and 80 (work conditions). When comparing averages between institutions, the private institution showed better working conditions. Conclusions: Results can be used to plan and organize actions, given the low scores in relation to the safety atmosphere, management and stress perception. PMID- 27992034 TI - Electrocardiogram Performance in the Diagnosis of Left Ventricular Hypertrophy in Hypertensive Patients With Left Bundle Branch Block. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is an important risk factor for cardiovascular events, and its detection usually begins with an electrocardiogram (ECG). OBJECTIVE: To evaluate the impact of complete left bundle branch block (CLBBB) in hypertensive patients in the diagnostic performance of LVH by ECG. METHODS: A total of 2,240 hypertensive patients were studied. All of them were submitted to an ECG and an echocardiogram (ECHO). We evaluated the most frequently used electrocardiographic criteria for LVH diagnosis: Cornell voltage, Cornell voltage product, Sokolow-Lyon voltage, Sokolow-Lyon product, RaVL, RaVL+SV3, RV6/RV5 ratio, strain pattern, left atrial enlargement, and QT interval. LVH identification pattern was the left ventricular mass index (LVMI) obtained by ECHO in all participants. RESULTS: Mean age was 11.3 years +/- 58.7 years, 684 (30.5%) were male and 1,556 (69.5%) were female. In patients without CLBBB, ECG sensitivity to the presence of LVH varied between 7.6 and 40.9%, and specificity varied between 70.2% and 99.2%. In participants with CLBBB, sensitivity to LVH varied between 11.9 and 95.2%, and specificity between 6.6 and 96.6%. Among the criteria with the best performance for LVH with CLBBB, Sokolow Lyon, for a voltage of >= 3,0mV, stood out with a sensitivity of 22.2% (CI 95% 15.8 - 30.8) and specificity of 88.3% (CI 95% 77.8 - 94.2). CONCLUSION: In hypertensive patients with CLBBB, the most often used criteria for the detection of LVH with ECG showed significant decrease in performance with regards to sensitivity and specificity. In this scenario, Sokolow-Lyon criteria with voltage >=3,0mV presented the best performance. PMID- 27992036 TI - [Correction of self-reported prevalence in epidemiological studies with large samples]. AB - Disease prevalence rates are useful when formulating and evaluating public policies. Self-reported measurement is commonly used, since it is easy to collect and does not require specific health training or additional cost. However, this measurement process can produce a biased measure. This study aimed to present the existing methods to adjust prevalence, based on self-report, focusing on computational problems in the case of large samples and proposing an alternative solution. The methods were classified as: algebraic, simple to perform, but not applicable to any combination of self-reported prevalence, specificity, and sensitivity; and Bayesian, which does not have the previous strategy limitations, but displays computational problems when applied to large samples in personal computers. These problems impede the existing method's direct implementation, raising the need to present an approximate strategy to make estimation possible. The empirical method proposed here for application to large samples consists of reducing the sample as far as possible to calculate with the statistical package, maintaining the proportion of patients. We found the method adequate, since it converges with the true value. In the example, a self-reported prevalence of 5% with sensitivity = 0.4 and specificity = 0.9 was corrected to 0.17% (95%CI: 0.10 0.24). The study presented the existing methods for adjusting prevalence rates and a new strategy for prevalence rates in large samples, allowing estimates closer to the true values without the need to directly measure all the individuals. PMID- 27992035 TI - Speckle Tracking and Transthyretin Amyloid Cardiomyopathy. AB - BACKGROUND: Amyloidosis is a disease caused by deposits of insoluble fibrils in extracellular spaces. The most common type of familial amyloidosis is mediated by mutation of transthyretin, especially Val30Met. Symptoms and ejection fraction decrease may occur in cardiac amyloidosis only in case of poor prognosis. Myocardial strain detected by two-dimensional speckle tracking echocardiography can indicate changes in myocardial function at early stages of the disease. OBJECTIVE: To determine the accuracy of left ventricular longitudinal strain by two-dimensional speckle tracking echocardiography in patients with familial amyloidosis caused by Val30Met transthyretin mutation. METHODS: Eighteen consecutive patients, carriers of transthyretin mutation, were evaluated by two dimensional speckle tracking echocardiography, by which myocardial strain curves were obtained, following the American Society of Echocardiography recommendations. RESULTS: Patients were divided into three groups: 1- Val30Met with cardiac amyloidosis; 2-Val30Met with extracardiac amyloidosis; 3 - Val30Met without evidence of disease. As the three groups were compared by the Mann Whitney test, we found a statistically significant difference between groups 1 and 2 in the mean longitudinal tension (p=0.01), mean basal longitudinal strain (p=0.014); in mean longitudinal tension and mean longitudinal strain between groups 1 and 3 (p=0.005); and in the ratio of longitudinal strain of apical septum segment to longitudinal strain of basal septum (p=0.041) between groups 2 and 3. CONCLUSION: Left ventricular longitudinal strain detected by two dimensional speckle tracking echocardiography is able to diagnose left ventricular dysfunction in early stages of familial amyloidosis caused by transthyretin Val30Met mutation. PMID- 27992037 TI - The dynamics of the production of AIDS-related stigma among pregnant women living with HIV/AIDS in Rio de Janeiro, Brazil. AB - The study analyses the relationship between AIDS-related stigma and the processes of discrimination prior to diagnosis among pregnant women living with HIV/AIDS. The fieldwork involved interviews about the life trajectories of 29 pregnant women living with HIV/AIDS, recruited at two AIDS services in Rio de Janeiro, Brazil. The analysis revealed that before HIV diagnosis, social and gender inequalities experienced by these women reduced their access to material and symbolic goods that could have enhanced educational and career prospects and their ability and autonomy to exercise sexual and reproductive rights. Being diagnosed with HIV triggered fear of moral judgment and of breakdown in social and family support networks. Given these fears, pregnant women living with HIV/AIDS opt for concealment of the diagnosis. It is necessary for health services, NGOs and government agencies to work together to face the factors that fuel stigma, such as socioeconomic and gender inequalities, taboos and prejudices related to sexuality, and also develop actions to enable women to redefine the meaning of the disease. PMID- 27992039 TI - [Evaluation of the Mobile Emergency Care Service in Santa Catarina State, Brazil]. AB - This case study evaluated the Mobile Emergency Care Service (SAMU) in Santa Catarina State, Brazil, in 2013/2014. The theoretical log frame and evaluation matrix were validated by expert consensus workshops. Two dimensions were proposed: emergency care management and emergency care, analyzed with 22 indicators. Data collection used interviews, direct observation in the eight regional SAMU dispatches, and a questionnaire sent to the coordinators of the municipal SAMU. The analysis and value judgment according to separate dimensions, sub-dimensions, and indicators allowed identifying strengths and weaknesses amenable to intervention. No regional dispatch performed well in both dimensions; all were classified as "fair" in emergency care and "bad" in emergency management. An important strength was agile communication with callers for help, standardization, and external support for care. The mechanisms for internal and external linkage and communication need to be effectively implemented. The quality of advanced support units requires improvement. PMID- 27992038 TI - [High prevalence of inadequate calcium and vitamin D dietary intake in two cohorts of pregnant women]. AB - This study aimed to identify the prevalence of inadequate calcium and vitamin D dietary intake and related factors in two cohorts of pregnant women according to trimester of pregnancy. Two 24-hour dietary recall tests were taken in each trimester, one pertaining to weekends. Variables significantly correlated with intake of these nutrients were included in a multivariate linear regression model, adjusted for energy. Prevalence of inadequate intake was estimated according to the National Cancer Institute method (United States). In cohort A, inadequate vitamin D did not differ between trimesters; in B there was a reduction: from 99.7% in the first trimester to 97.1% in the third. In cohorts A and B, inadequate calcium intake exceeded 70%, falling slightly from the first (89.2% and 81.4%) to the second (79.7% and 69.1%) and third trimesters (82.7% and 72.6%). There was no correlation between maternal variables and the intake of these micronutrients. In conclusion, intake of vitamin D and calcium is seriously inadequate and distributed homogeneously among pregnant women in the primary healthcare network. PMID- 27992040 TI - The New Fiscal Regime and the mitigation of minimum spending on health and education. PMID- 27992041 TI - The Constitutional Amendment Proposition 241/2016 and the Brazilian Unified National Health System: impacts on research and on industry. PMID- 27992042 TI - Private health plans with limited coverage: the updated privatizing agenda in the context of Brazil's political and economic crisis. PMID- 27992043 TI - The Brazilian public health in a universe "worldless": the austerity of the Constitutional Amendment Proposition 241/2016. PMID- 27992044 TI - Impacts of the new fiscal regime on health and education. PMID- 27992045 TI - 2016: a year of perplexity. PMID- 27992046 TI - I think there should be a mutual learning. Interview with Ezra S. Susser. PMID- 27992047 TI - Editors' Note. PMID- 27992048 TI - Culture: by the brain and in the brain? AB - Since the 1990s, several disciplines have emerged at the interface between neuroscience and the social and human sciences. For the most part, they aim at capturing the commonalities that underlay the heterogeneity of human behaviors and experiences. Neuroanthropology and cultural neuroscience, or the "neurodisciplines of culture," appear different, since their goal is to understand specificity rather than commonality and to address how cultural differences are inscribed in the brain. After offering an overview of these disciplines, and of their relation to endeavors such as cultural psychology and social neuroscience, this article discusses some of the most representative studies in the area in order to explore in which ways they are relevant for an understanding of culture. PMID- 27992049 TI - The treatment of madness in the nineteenth and twentieth centuries: discourses about curability in Spanish mental health care, 1890-1917. AB - This article studies the discourses about curability constructed by Spanish mental health practitioners in the transition from the nineteenth to the twentieth century. While in the 1870s and 1880s the predominant discourse promoted by doctors attached to private institutions was extremely optimistic, it subsequently changed and became more pessimistic regarding treatment outcomes. However, given phrenopathists' professional needs, they continued to profess more or less unshakeable confidence in the therapeutic abilities of psychiatry. The reception of new nosologies, such as Kraepelin's, depended in part on contemporary mental health practitioners' stance on curability and was accompanied by ambivalence. PMID- 27992050 TI - The simulators: truth and power in the psychiatry of Jose Ingenieros. AB - Using Michel Foucault's lectures on "Psychiatric power" as its starting point, this article analyzes the book Simulacion de la locura (The simulation of madness), published in 1903 by the Argentine psychiatrist Jose Ingenieros. Foucault argues that the problem of simulation permeates the entire history of modern psychiatry. After initial analysis of Jose Ingenieros's references to the question of simulation in the struggle for existence, the issue of simulation in pathological states in general is examined, and lastly the simulation of madness and the problem of degeneration. Ingenieros participates in the epistemological and political struggle that took place between experts-psychiatrists and simulators over the question of truth. PMID- 27992051 TI - Travel and professional networks in the origins of Spanish psychiatry. AB - This article examines the importance of travel and professional networks in the origins of Spanish psychiatry. After reviewing the early alienists' Enlightenment predecessors and their therapeutic and professional trajectories, it describes the trips to foreign psychiatric institutions made during the second third of the nineteenth century by a group of exiled Spanish doctors, commissioners and pioneers. Later, as they became more socially, institutionally and professionally established, some figures of Spanish psychological medicine cultivated their connections and international profile by organizing or attending conferences and other scientific events. This case illustrates the important role of international relations and scientific and professional networks in the spread of psychiatric discourses and practices. PMID- 27992052 TI - Subnormality under debate: discourses and policies on intellectual disability during the late Franco regime. AB - During the last two decades of the Franco dictatorship, intellectually disabled people became an object of concern on the part of Spanish society and the center of a debate involving the state, the church, certain professional groups and families of those affected. This debate was stoked by ideas circulating in the international setting about the right of the intellectually disabled to integrate into society and enjoy the same opportunities as other individuals. This article seeks to identify the circumstances that led to the emergence of this concern and to note the elements that helped construct the discourses and govern the practices on intellectual disability that developed during the later years of the Franco regime. PMID- 27992053 TI - [Antonio de Saldanha da Gama's proposals to improve the slave trade "for humanitarian and economic reasons," Rio de Janeiro, 1810]. AB - In 1808, Dom Joao VI issued an edict which regulated the shipping and treatment of slaves on the transatlantic crossing from Africa. Two years later, Antonio de Saldanha da Gama, a member of the Treasury Council, drafted a letter discussing some points of the resolution. This key figure in the Portuguese administration of Brazil argued that his respectful considerations concerning the determinations of His Royal Highness were designed to improve them "for humanitarian and economic reasons." Safeguarded in the archives of Arquivo Historico Ultramarino, this letter is transcribed, annotated, and contextualized here, supplying an interesting perspective on the prevailing concerns and justifications about the trafficking of African slaves to Brazil. PMID- 27992054 TI - [Scientists in cartoons: humanizing science]. AB - Published daily from 1994 to 2002 in Correio Popular, a Campinas-based newspaper, Os cientistas (The scientists) comic strips produced by Brazilian researchers and journalists presented science critically and irreverently, exposing the insecurities and frustrations of scientists, as well as the conflicts between them and their communication difficulties with other groups, like journalists. This article shows the diversity of personalities, subjects, graphic styles, and potential meanings in a sample of comic strips published in the first four years. PMID- 27992055 TI - [Workers with signs of smallpox in the collection of Regional Office of Labor, Rio Grande do Sul, 1933-1944]. AB - Work Register Booklet was created in Brazil in 1932. Soon, Regional Labor Inspectorates emerged - after renamed as Regional Office of Labor. In Rio Grande do Sul, this office was settled in 1933 in Porto Alegre. Procedures for making this booklet consisted of filling a professional qualification form with workers' personal and professional information. One of the fields consisted of requester's distinguishing signs, like visible marks and lack of limbs. The purpose of this article is to analyse the presence of one of these distinguishing signs. We use 3x4cm photos of workers who presented smallpox signs, as well as other information written in the fields of their forms. PMID- 27992056 TI - [My experiences as editor and author in history journals (with a special emphasis in Past & Present)]. AB - This text registers my thoughts on the editorial work done in academic journals in the area of history. These are made with special attention to the production on Latin America. The basis of my reflections are my participation in the editorial committee of Past & Present, one of the main history journals in the world, my research on the archives of this journal, and my knowledge of the processes of review and edition of journals devoted to Latin American history. PMID- 27992057 TI - Psychosis and schizophrenia: effects of changes in psychiatric classifications on clinical and theoretical approaches to mental illness. AB - This article discusses changes in the diagnostic classification systems for mental illness, especially the conceptual weakening of the "psychosis" category while schizophrenia became the only psychosis. Current pathological classifications prioritize a physicalist approach. Consequently, conditions that previously were associated with neurosis and subjectivity are being medicalized, conditions previously recognized as psychotic are relocated under the heading of personality disorders, and psychosis has been reduced to schizophrenia and considered a deficit of psychic functions. This article indicates the clinical and operational validity of the notion of "psychosis" as a nosographic category permitting a more complex approach to "schizophrenia", which in psychiatry is the last concept that bears the symbolic weight of madness. PMID- 27992058 TI - An MRI-compatible patient rotation system - design, construction, and first organ deformation results. AB - PURPOSE: Conventionally in radiotherapy, a very heavy beam forming apparatus (gantry) is rotated around a patient. From a mechanical perspective, a more elegant approach is to rotate the patient within a stationary beam. Key obstacles to this approach are patient tolerance and anatomical deformation. Very little information on either aspect is available in the literature. The purpose of this work was therefore to design and test an MRI-compatible patient rotation system such that the feasibility of a patient rotation workflow could be tested. METHODS: A patient rotation system (PRS) was designed to fit inside the bore of a 3T MRI scanner (Skyra, Siemens) such that 3D images could be acquired at different rotation angles. Once constructed, a pelvic imaging study was carried out on a healthy volunteer. T2-weighted MRI images were taken every 45 degrees between 0 degrees and 360 degrees , (with 0 degrees equivalent to supine). The prostate, bladder, and rectum were segmented using atlas-based auto contouring. The images from each angle were registered back to the 0 degrees image in three steps: (a) Rigid registration was based on MRI visible markers on the couch. (b) Rigid registration based on the prostate contour (equivalent to a rigid shift to the prostate). (c) Nonrigid registration. The Dice similarity coefficient (DSC) and mean average surface distance (MASD) were calculated for each organ at each step. RESULTS: The PRS met all design constraints and was successfully integrated with the MRI scanner. Phantom images showed minimal difference in signal or noise with or without the PRS in the MRI scanner. For the MRI images, the DSC (mean +/- standard deviation) over all angles in the prostate, rectum, and bladder was 0.60 +/- 0.11, 0.56 +/- 0.15, and 0.76 +/- 0.06 after rigid couch registration, 0.88 +/- 0.03, 0.81 +/- 0.08, and 0.86 +/- 0.03 after rigid prostate guided registration, and 0.85 +/- 0.03, 0.88 +/- 0.02, 0.87 +/- 0.02 after nonrigid registration. CONCLUSIONS: An MRI-compatible patient rotation system has been designed, constructed, and tested. A pelvic study was carried out on a healthy volunteer. Rigid registration based on the prostate contour yielded DSC overlap statistics in the prostate superior to interobserver contouring variability reported in the literature. PMID- 27992059 TI - A novel physical anthropomorphic breast phantom for 2D and 3D x-ray imaging. AB - PURPOSE: Physical phantoms are central to the evaluation of 2D and 3D breast imaging systems. Currently, available physical phantoms have limitations including unrealistic uniform background structure, large expense, or excessive fabrication time. The purpose of this work is to outline a method for rapidly creating realistic, inexpensive physical anthropomorphic phantoms for use in full field digital mammography (FFDM) and digital breast tomosynthesis (DBT). METHODS: The phantom was first modeled using analytical expressions and then discretized into voxels of a specified size. The interior of the breast was divided into glandular and adipose tissue classes using Voronoi segmentation, and additional structures like blood vessels, chest muscle, and ligaments were added. The physical phantom was then fabricated from the virtual model in a slice by slice fashion through inkjet printing, using parchment paper and a radiopaque ink containing 33% (I33% ) or 25% (I25% ) iohexol by volume. Three types of parchment paper (P1, P2, and P3) were examined. The phantom materials were characterized in terms of their effective linear attenuation coefficients (MUeff ) using full field digital mammography (FFDM) and their energy-dependent linear attenuation coefficients (MU(E)) using a spectroscopic energy discriminating detector system. The printing method was further validated on the basis of accuracy, print consistency, and the reproducibility of ink batches. RESULTS: The MUeff of two types of parchment paper were close to that of adipose tissue, with MUeff = 0.61 +/- 0.05 cm-1 for P1, 0.61 +/- 0.04 cm-1 for P2, and 0.57 +/- 0.03 cm-1 for adipose tissue. The addition of the iodinated ink increased the effective attenuation to that of glandular tissue, with MUeff = 0.89 +/- 0.06 cm-1 for P1 + I25% and 0.94 +/- 0.06 cm-1 for P1 + I33% compared to 0.90 +/- 0.03 cm-1 for glandular tissue. Spectroscopic measurements showed a good match between the parchment paper and reference values for adipose and glandular tissues across photon energies. Good accuracy was found between the model and the printed phantom by comparing a FFDM of the virtual model simulated through Monte Carlo with a real FFDM of the fully printed phantom. High consistency was found over multiple prints, with 3% variability in mean ink signal across various samples. Reproducibility of ink consistency was very high with <1% variation signal from multiple batches of ink. Imaging of the phantom using FFDM and DBT systems showed promising utility for 2D and 3D imaging. CONCLUSIONS: A novel, realistic breast phantom can be created using an analytically defined breast model and readily available materials. The work provides a method to fabricate any virtual phantom in a manner that is accurate, inexpensive, easily accessible, and can be made with different materials or breast models. PMID- 27992061 TI - Area-based study shows most parents follow advice to reduce risk of sudden infant death syndrome. AB - AIM: Guidance on reducing the risk of sudden infant death syndrome (SIDS) was successfully introduced to a number of countries in the early 1990s. The most important recommendations were supine sleeping for infants and non-smoking for mothers. This 2012-2014 study examined adherence to the national Swedish SIDS advice. METHODS: We asked 1000 parents with infants registered at child healthcare centres in western Sweden to complete a questionnaire on infant care from birth to 12 months of age. RESULTS: We analysed 710 responses and found that, in the first three months, 1.3% of the infants were placed in the prone sleeping position and 14.3% were placed on their side. By three to five months, this had risen to 5.6% and 23.6%. In the first three months, 83.1% were breastfed, 84.1% used a pacifier and 44.2% shared their parents' bed, while 5.8% slept in another room. Bed sharing was more likely if infants were breastfed and less likely if they used pacifiers. During pregnancy, 2.8% of the mothers smoked and the mothers who had smoked during pregnancy were less likely to bed share. CONCLUSION: Overall adherence to the SIDS advice was good, but both prone and side sleeping practices should be targeted. PMID- 27992062 TI - Factors predictive of leg-ulcer healing in sickle cell disease: a multicentre, prospective cohort study. AB - BACKGROUND: Leg ulcers (LUs) are a chronic and severe complication of sickle cell disease (SCD). A prospective study in patients with SCD to identify factors associated with complete healing and recurrence of LUs is lacking. OBJECTIVES: To determine clinical and biological factors associated with SCD-LU complete healing and recurrence. METHODS: This prospective, observational cohort study was conducted at two adult SCD referral-centre sites (2009-2015) and included 98 consecutive patients with at least one LU lasting >= 2 weeks. The primary end points compared patients with healed vs. nonhealed LUs at week 24, and patients with vs. without recurrence during follow-up. RESULTS: The median (interquartile range) LU area, duration and follow-up were, respectively, 6.2 cm2 (3-12.8), 9 weeks (4-26) and 65.8 weeks (23.8-122.1). At week 24, LUs were healed in 47% of patients, while 49% of LUs recurred. Univariate analyses identified inclusion LU area < 8 cm2 (82% vs. 35%; P < 0.001), inclusion LU duration < 9 weeks (65% vs. 35%; P = 0.0013) and high median fetal haemoglobin level (P = 0.008) as being significantly associated with complete healing at week 24, and low lactate dehydrogenase level (P = 0.038) as being associated with recurrence. Multivariate analyses retained LU area < 8 cm2 (odds ratio 6.73, 95% confidence interval 2.35 19. 31; P < 0.001) and < 9 weeks' duration (OR 3.19, 95% confidence interval 1.16 8.76; P = 0.024) as being independently associated with healing at week 24. Factors independently associated with recurrence could not be identified. CONCLUSIONS: SCD-LU complete healing is independently associated with the clinical characteristics of LUs rather than the clinical or biological characteristics of SCD. PMID- 27992060 TI - CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma. AB - BACKGROUND: Allergic asthma is a chronic airway inflammatory disease involving the complementary actions of innate and adaptive immune responses. Endogenously generated cannabinoids acting via CB2 receptors play important roles in both homeostatic and inflammatory processes. However, the contribution of CB2-acting eicosanoids to the innate events preceding sensitization to the common house dust mite (HDM) allergen remains to be elucidated. We investigated the role of CB2 activation during allergen-induced pulmonary inflammation and natural killer (NK) cell effector function. METHODS: Lung mucosal responses in CB2-deficient (CB2-/- ) mice were examined and compared with wild-type (WT) littermates following intranasal exposure to HDM allergen. RESULTS: Mice lacking CB2 receptors exhibited elevated numbers of pulmonary NK cells yet were resistant to the induction of allergic inflammation exemplified by diminished airway eosinophilia, type 2 cytokine production and mucus secretion after allergen inhalation. This phenomenon was corroborated when WT mice were treated with a CB2-specific antagonist that caused a pronounced inhibition of HDM-induced airway inflammation and goblet cell hyperplasia. Unexpectedly, the preponderance of NK cells in the lungs of CB2-/- mice correlated with reduced numbers of group 2 innate lymphoid cells (ILC2s). Depletion of NK cells restored the allergen responsiveness in the lungs and was associated with elevated ILC2 numbers. CONCLUSIONS: Collectively, these results reveal that CB2 activation is crucial in regulating pulmonary NK cell function, and suggest that NK cells serve to limit ILC2 activation and subsequent allergic airway inflammation. CB2 inhibition may present an important target to modulate NK cell response during pulmonary inflammation. PMID- 27992064 TI - Survey shows large differences between the Nordic countries in the use of less invasive surfactant administration. AB - AIM: Less invasive surfactant administration (LISA), namely surfactant instillation through a thin catheter in the trachea during spontaneous breathing, is increasingly used for premature infants. We surveyed the use of this technique in the Nordic countries in autumn 2015. METHODS: A link to a web-based survey of surfactant administration methods was emailed to the directors of all neonatal units in the Nordic Region, apart from Finland, where only the five university based departments were invited. RESULTS: Of the 73 units (85%) who responded, 23 (32%) said that they used LISA. The country rates were Iceland 100%, Norway 82%, Finland 60%, Denmark, including Faroe Island and Greenland, 11% and Sweden 9%. LISA was used in 62% of level three units, but only 14% of level two units and most commonly in babies with a gestational age of at least 26 weeks. Premedication was always or sometimes used by 78%. The main reasons for not using LISA were lack of familiarity with the technique (61%), no perceived benefit over other methods (22%) and concerns about patient discomfort (26%). CONCLUSION: Less invasive surfactant administration was used in 32% of Nordic neonatal units, most commonly in level three units. Premedication was used more often than previously reported. PMID- 27992065 TI - Acute megakaryoblastic leukaemia: light microscopy and scanning electron microscopy of blast cells. PMID- 27992063 TI - RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. AB - Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto-HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre-transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto-HCT. Fifty-three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2-year progression free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi-centre transplant trials in MCL. RB achieved a 2-year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL. PMID- 27992067 TI - The role of rhinoviruses is overestimated in the aetiology of community-acquired pneumonia in children. PMID- 27992068 TI - Exploring two novel cases of suspected ictal epileptic headache, a rare form of paediatric epilepsy. AB - AIM: Ictal epileptic headache (IEH) is a rare and underestimated epileptic form, characterised by epileptiform discharges and headache attacks without any other ictal sensory-motor manifestations. IEH is difficult to diagnose, because the epileptiform discharges have to be registered during the headache attack and the headache has to disappear after the intravenous administration of an anti epileptic drug, according to the last diagnostic criteria. This study explored the clinical, neuro-physiological and therapeutic features of IEH in the paediatric population. METHODS: We analysed two novel cases of adolescent female patients with chronic headache and a long history of unsuccessful analgesic oral therapy and without any other ictal sensory-motor events. We also reviewed the entire literature on paediatric IEH. RESULTS: The clinical history and diagnostic process led us to highly suspect IEH in both patients, and the successful therapy with oral anti-epileptic drugs, namely topiramate and ethosuximide, which resolved the chronic headache, enforced our diagnostic hypothesis. Our literature review highlighted the rarity of IEH clinical reports, particularly in the paediatric population, mainly due to the stringent diagnostic criteria. CONCLUSION: Our study sheds further light on IEH in the paediatric population and on the importance of diagnostic electroencephalograms in the clinical management of paediatric patients suffering from chronic headache. PMID- 27992069 TI - An effective placental cotyledons proteins extraction method for 2D gel electrophoresis. AB - Effective protein extraction is essential especially in producing a well-resolved proteome on 2D gels. A well-resolved placental cotyledon proteome, with good reproducibility, have allowed researchers to study the proteins underlying the physiology and pathophysiology of pregnancy. The aim of this study is to determine the best protein extraction protocol for the extraction of protein from placental cotyledons tissues for a two-dimensional gel electrophoresis (2D-GE). Based on widely used protein extraction strategies, 12 different extraction methodologies were carefully selected, which included one chemical extraction, two mechanical extraction coupled protein precipitations, and nine chemical extraction coupled protein precipitations. Extracted proteins were resolved in a one-dimensional gel electrophoresis and 2D-GE; then, it was compared with set criteria: extraction efficacy, protein resolution, reproducibility, and recovery efficiency. Our results revealed that a better profile was obtained by chemical extraction in comparison to mechanical extraction. We further compared chemical extraction coupled protein precipitation methodologies, where the DNase/lithium chloride-dense sucrose homogenization coupled dichloromethane-methanol precipitation (DNase/LiCl-DSH-D/MPE) method showed good protein extraction efficiency. This, however, was carried out with the best protein resolution and proteome reproducibility on 2D-gels. DNase/LiCl-DSH-D/MPE was efficient in the extraction of proteins from placental cotyledons tissues. In addition, this methodology could hypothetically allow the protein extraction of any tissue that contains highly abundant lipid and glycogen. PMID- 27992070 TI - Exercise for haemophilia. AB - BACKGROUND: Haemophilia is a bleeding disorder associated with haemorrhaging into joints and muscles. Exercise is often used to aid recovery after bleeds, and to improve joint function in the presence of arthropathy. OBJECTIVES: Our objective was to systematically review the available evidence on the safety and effectiveness of exercise for people with haemophilia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register and electronic databases PubMed, OVID-Embase, and CINAHL. We hand searched abstracts from congresses of the World Federation of Hemophilia and the European Hematology Association, trial registries and the reference lists of relevant articles.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 14 December 2016. SELECTION CRITERIA: Randomized or quasi-randomized controlled studies comparing any exercise intervention considered relevant in haemophilia management including supervised, unsupervised, aquatic, strengthening, aerobic or cardiovascular, stretching, proprioceptive and balance training exercise programs in males of any age with haemophilia A or B of any severity (those with co morbidities were not excluded). DATA COLLECTION AND ANALYSIS: Two authors reviewed the identified abstracts to determine their eligibility. For studies meeting the inclusion criteria, full articles were obtained. The two authors extracted data and assessed the risk of bias. Any disagreements were resolved by discussion. The authors contacted study investigators to obtain any missing data. MAIN RESULTS: Eight studies were included, which represented 233 males with all severities of haemophilia A and B, ranging in age from eight years to 49 years. Study duration ranged from four to 12 weeks. Exercise interventions varied greatly and included resistance exercises, isometric exercises, bicycle ergometry, treadmill walking and hydrotherapy; therefore, comparison between studies was difficult.None of the studies measured or reported adverse effects from the interventions. None of the studies reported outcomes regarding bleed frequency, quality of life or aerobic activity. Overall risk of bias across all studies was assessed as unclear.Very few studies provided sufficient information for comparison. None of the studies reported data that favoured the control group. One study reported that six weeks of resistance training improved joint health status (Colorado score) compared to controls. The addition of pulsed electromagnetic fields also improved ankle scores compared to exercises alone, but this was not seen in the elbows or knees.Two studies reported statistically significant improvements in pain intensity after exercise interventions compared to controls. Hydrotherapy exercises produced significant decreases in pain compared to controls and land-based exercise groups.Two studies found improvement in joint motion in the exercise group compared to controls. One study compared land- and water-based exercises; there was no difference in the range of motion between the two groups; however, the water-based exercise group did show improvement over the control group.One study, comparing joint traction and proprioceptive neuromuscular facilitation for the elbow to a control group, showed no differences in biceps girth or strength after 12 weeks of intervention.Some studies reported comparisons between interventions. In one study, treadmill training significantly improved balance in children compared to bicycle ergometry. Another study added partial weight bearing exercises to quadriceps exercises and showed improved walking tolerance.Four studies evaluated quadriceps or hamstring strength (or both). The addition of bicycle ergometry and exercises with weights was more effective than static exercises and treadmill walking for strengthening knee flexors and extensors. Partial weight-bearing exercises through range were more effective than static and short arc exercises for improving knee extensor strength. The addition of treadmill walking to ultrasound, stretching and strengthening exercises showed increased peak torque of knee flexors and extensors and decrease in knee effusion.The results should be interpreted with caution due to the quality of evidence (GRADE) as outlined in the summary of findings tables, which demonstrates that all but one of the outcomes assessed were rated as low or very low due to the small sample sizes and potential bias. AUTHORS' CONCLUSIONS: These results must be considered with caution. There is a lack of confidence in the results due to the small number of included studies and the inability to pool the results due to the heterogeneity of outcome measures. Most exercise interventions produced improvement in one or more of the measured outcomes including pain, range of motion, strength and walking tolerance. Hydrotherapy may be more effective than land exercises for pain relief in adults. Functional exercises such as treadmill walking and partial weight bearing exercises seem to be more effective than static or short arc exercises for improving muscle strength. These findings are consistent with the many non-controlled intervention reports in the haemophilia literature. No adverse effects were reported as a result of any of the interventions. However, some groups used prophylactic factor prior to exercise and other groups studied only subjects with moderate haemophilia. Therefore, the safety of these techniques for persons with severe haemophilia remains unclear. PMID- 27992066 TI - Assessing the bioaccumulation potential of ionizable organic compounds: Current knowledge and research priorities. AB - The objective of the present study was to review the current knowledge regarding the bioaccumulation potential of ionizable organic compounds (IOCs), with a focus on the availability of empirical data for fish. Aspects of the bioaccumulation potential of IOCs in fish that can be characterized relatively well include the pH dependence of gill uptake and elimination, uptake in the gut, and sorption to phospholipids (membrane-water partitioning). Key challenges include the lack of empirical data for biotransformation and binding in plasma. Fish possess a diverse array of proteins that may transport IOCs across cell membranes. Except in a few cases, however, the significance of this transport for uptake and accumulation of environmental contaminants is unknown. Two case studies are presented. The first describes modeled effects of pH and biotransformation on the bioconcentration of organic acids and bases, while the second employs an updated model to investigate factors responsible for accumulation of perfluorinated alkyl acids. The perfluorinated alkyl acid case study is notable insofar as it illustrates the likely importance of membrane transporters in the kidney and highlights the potential value of read-across approaches. Recognizing the current need to perform bioaccumulation hazard assessments and ecological and exposure risk assessment for IOCs, the authors provide a tiered strategy that progresses (as needed) from conservative assumptions (models and associated data) to more sophisticated models requiring chemical-specific information. Environ Toxicol Chem 2017;36:882-897. (c) 2016 SETAC. PMID- 27992071 TI - Are behaviour problems in extremely low-birthweight children related to their motor ability? AB - AIM: To investigate whether behaviour problems are independently related to mild motor impairment in 11-13-year-old children born preterm with extremely low birthweight (ELBW). METHODS: The cross-sectional study included 48 (27 males) non disabled, otherwise healthy ELBW children (<1000 g) and 55 (28 males) term-born peers. Parents reported behaviour using the Child Behaviour Checklist (CBCL). Children completed the Movement Assessment Battery for Children (Movement ABC). RESULTS: Extremely low birthweight children had poorer behaviour scores (CBCL Total Problem T score: mean difference = 5.89, 95% confidence interval = 10.29, 1.49, p = 0.009) and Movement ABC Total Motor Impairment Scores (ELBW group median = 17.5, IQR = 12.3; term-born group median = 7.5, IQR = 9, p < 0.01) than term-born peers. Behaviour was related to motor score (regression coefficient 2.16; 95% confidence interval 0.34, 3.97, p = 0.02) independent of gender, socio economic factors or birthweight. Motor score had the strongest association with attention (rho = 0.51; p < 0.01) and social behaviours (rho = 0.50; p < 0.01). CONCLUSION: Behaviour problems of otherwise healthy 11- to 13-year-old ELBW children are not related to prematurity independent of their motor difficulties. Supporting improved motor competence in ELBW preteen children may support improved behaviour, particularly attention and social behaviours. PMID- 27992072 TI - Comparison of intestinal permeability and p-glycoprotein effects on the intestinal absorption of enantiomers of 2-(2-hydroxypropanamido) benzoic acid in rats. AB - The purpose of this study was to compare intestinal permeability between enantiomers of 2-(2-hydroxypropanamido) benzoic acid ((R)-/(S)-HPABA), a marine derived antiinflammatory drug, using an in situ single-pass intestinal perfusion (SPIP) model in rats. Concentrations, isolated regions of small intestine, and p glycoprotein (P-gp) inhibitor were performed to investigate their influences on the intestinal absorption of (R)-/(S)-HPABA. In addition, a molecular docking method was performed to illustrate our prediction. The absorption rate coefficients (Ka ) and permeability values (Peff ) of (R)-/(S)-HPABA were calculated. The permeability of (S)-HPABA was significantly (P < 0.01) higher than that of (R)-HPABA in jejunum, and ileum permeability of (R)-/(S)-HPABA appeared best in ileum; the investigated concentrations ranged from 20 to 80 MUg/mL, Ka and Peff values of (R)-/(S)-HPABA increased linearly; in the presence of P-gp inhibitor (verapamil), Peff values of two enantiomers were increased significantly; and the effect of P-gp on absorption of (R)-HPABA is stronger than that of (S)-HPABA in ileum segment. Based on these results, carrier-mediated transport or passive transport combined with carrier-mediated transport seems to be the mechanism for intestinal absorption of (R)-/(S)-HPABA, and (R)-/(S)-HPABA may be recognized as the P-gp substrate. In addition, the intestinal permeability of (S)-HPABA is higher than that of (R)-HPABA. PMID- 27992073 TI - A rectally administered combination of midazolam and ketamine was easy, effective and feasible for procedural pain in children with cerebral palsy. AB - AIM: The aim of this study was to investigate how effective a combination of rectally administered midazolam and racemic ketamine was for reducing pain in paediatric cerebral palsy patients receiving intramuscular injections of botulinum neurotoxin A. The feasibility and safety of the pain relief were also explored. METHOD: Children with cerebral palsy, aged one to 18 years, were recruited from a regional paediatric rehabilitation unit between April 2012 and May 2014. Pain intensity, feasibility, total time spent in the clinic and side effects were registered. Pain scores were recorded by parents and healthcare professionals using different pain scales. RESULTS: We recorded 128 procedures in 61 children. The median scores were two (range: 0-10) for pain intensity and nine (range: 0-10) for feasibility. The median treatment time in the outpatient unit was 3.25 hours, and the most common side effects were nausea, pain and sleep disturbance. Gross motor function levels showed a negative correlation with the pain scores. This method could be an alternative to nitrous oxide/oxygen mixture for patients who do not tolerate inhalation analgesia. CONCLUSION: Rectally administered midazolam and racemic ketamine provided effective pain relief for paediatric cerebral palsy outpatients receiving painful injections and was a viable alternative to inhalation analgesia. PMID- 27992074 TI - Fabrication of multiwalled carbon nanotube-polyaniline/platinum nanocomposite films toward improved performance for a cholesterol amperometric biosensor. AB - A simple and high sensitive cholesterol amperometric biosensor, which is based on in situ electropolymerization of multi-walled carbon nanotube-polyaniline (MWCNT PANI) nanocomposite and electrodeposition of platinum nanoparticle (nano-Pt) films onto the glassy carbon electrode surface for cholesterol oxidase immobilization, was constructed in this study. The preparation process of the modified electrode was characterized by cyclic voltammetry, electrochemical impedance spectroscopy, scanning electron microscopy, and chronoamperometry. Because of the synergistic electrocatalytic activity between MWCNT-PANI nanocomposites and nano-Pt, the cholesterol biosensor exhibited an excellent performance with a linear range of 2.0-510.0 uM, a detection limit of 0.8 uM (signal-to-noise ratio = 3), a high sensitivity of 109.9 uA mM-1 , and a short response time within 5 Sec. Moreover, the reproducibility, stability, and selectivity of the biosensor were also investigated. PMID- 27992076 TI - MiR-151a is involved in the pathogenesis of atopic dermatitis by regulating interleukin-12 receptor beta2. AB - MicroRNAs (miRNAs) have been reported to circulate in the blood in a highly stable and cell-free form. Dysregulated expression of miRNAs has been detected in various pathological conditions including atopic dermatitis. In our study, human blood plasma miRNAs were identified by high-throughput sequencing and compared among patients of atopic dermatitis and healthy controls. We found that miR-151a was differentially expressed in the plasma of atopic dermatitis patients. MiR 151a regulates the expression of IL12RB2 by targeting two loci in the 3' untranslated region of the Il12rb2 gene. Moreover, IL12RB2 was remarkably downregulated in Jurkat cells overexpressing miR-151a. Jurkat cells treated with phytohemagglutinin also showed reduced expression of IFN-gamma, interleukin-2 (IL 2) and IL-12. Together, these results suggest that miR-151a is involved in the pathogenesis of atopic dermatitis by regulating IL12RB2. PMID- 27992075 TI - Management of veno-occlusive disease: the multidisciplinary approach to care. AB - Although it is considered a relatively rare disorder, veno-occlusive disease (VOD) is one of the main causes of overall, non-relapse mortality associated with haematopoietic stem cell transplantation (HSCT). This article, based on the consensus opinion of haemato-oncology nurses, haemato-oncologists and pharmacists from both adult and paediatric services at the VOD International Multi Disciplinary Advisory Board at the European Society for Blood and Marrow Transplantation (EBMT) meeting, Istanbul, 2015, aims to explore the multidisciplinary approach to care for the management of VOD, with an emphasis on current challenges in this area. The careful monitoring of HSCT patients allows early detection of the symptoms associated with VOD and timely treatment, ultimately improving patient outcomes. As part of a multidisciplinary team, nurses have an essential role to play, from pretransplant assessment to medical management and overall care of the patient. Physicians and pharmacists have a responsibility to facilitate education and training so that nurses can work effectively within that team. PMID- 27992077 TI - Editorial. PMID- 27992078 TI - Basophils and mast cells are crucial for reactions due to epicutaneous sensitization to ovalbumin. AB - The prevalence of food allergies worldwide has increased recently. Epicutaneous sensitization to antigen could be a method to study food allergy. To clarify the mechanisms of food allergy, we established a mouse model of epicutaneous sensitization using ovalbumin (OVA). BALB/c mice were sensitized by three-time application of OVA to tape-stripped skin (1-week sensitization at 2-week intervals) and oral challenge of OVA undertaken. Rectal temperature was monitored. Blood and tissue (skin and jejunum) of challenged mice were taken. Numbers of mast cells (MCs) and basophils were counted. Serum and/or tissue levels of OVA -specific IgE and IgG antibodies and several cytokines were measured using enzyme-linked immunoassay kits. MC and basophil depletion experiments were undertaken. In OVA/epicutaneous-sensitized and orally challenged mice, systemic anaphylaxis (as evidenced by reduced rectal temperature) was observed. Levels of OVA-specific IgE and IgG antibodies were increased in these mice, as were increased number of MCs and basophils. Serum levels of MC protease 1 were increased significantly. Basophil and MC depletion experiments revealed that they both participate in reactions. Increased production of thymic stromal lymphopoietin (TSLP) at skin sites of OVA sensitization was noted. We speculate that TSLP produced from epidermal cells during antigen sensitization can enable basophils to promote a T helper (Th)2 immune reaction, leading to and systemic anaphylaxis by antigen-specific IgE-bearing MCs. This TSLP-basophils-MC axis could be a novel therapeutic target against food allergy. PMID- 27992079 TI - Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38delta. AB - The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, and the prognosis of patients with metastatic disease is poor. There is an emerging need to identify molecular markers for predicting aggressive behaviour of cSCC. Here, we have examined the role of tight junction (TJ) components in the progression of cSCC. The expression pattern of mRNAs for TJ components was determined with RNA sequencing and oligonucleotide array-based expression analysis from cSCC cell lines (n=8) and normal human epidermal keratinocytes (NHEK, n=5). The expression of CLDN11 was specifically elevated in primary cSCC cell lines (n=5), but low or absent in metastatic cSCC cell lines (n=3) and NHEKs. Claudin-11 was detected in cell-cell contacts of primary cSCC cells in culture by indirect immunofluorescence analysis. Analysis of a large panel of tissue samples from sporadic UV-induced cSCC (n=65), cSCC in situ (n=56), actinic keratoses (n=31), seborrhoeic keratoses (n=7) and normal skin (n=16) by immunohistochemistry showed specific staining for claudin-11 in intercellular junctions of keratinizing tumor cells in well and moderately differentiated cSCCs, whereas no staining for claudin-11 was detected in poorly differentiated tumors. The expression of claudin-11 in cSCC cells was dependent on the activity of p38delta MAPK and knock-down of claudin-11 enhanced cSCC cell invasion. These findings provide evidence for the role of claudin-11 in regulation of cSCC invasion and suggest loss of claudin-11 expression in tumor cells as a biomarker for advanced stage of cSCC. PMID- 27992080 TI - Enantioseparation of nine indanone and tetralone derivatives by HPLC using carboxymethyl-beta-cyclodextrin as the mobile phase additive. AB - High-performance liquid chromatography (HPLC) is a powerful method in the area of chiral separation. In this study, a method of HPLC using carboxymethyl-beta cyclodextrin (CM-beta-CD) as chiral selector was developed for enantioseparation of nine indanone and tetralone derivatives. The separation was performed on a conventional C18 column. The optimal mobile phase was a mixture of methanol and 0.05 mol/L phosphate buffer at pH 1.8 (55:45, v/v) containing 22.9 mmol/L CM-beta CD. Under such conditions, the resolutions of all analytes were over 1.8 except for Compound F. The results of the study indicate the presence of a complex with 1:1 stoichiometry of the inclusion complex. In addition, it can be inferred from thermodynamic analysis that the behavior of formation of the inclusion complex and enantioseparation occurred simultaneously, while they were driven by different forces. The effect of analyte structure is also discussed. PMID- 27992081 TI - Non-invasive metabolic imaging of melanoma progression. AB - Skin cancer is associated with abnormal cellular metabolism which if identified early introduces the possibility of intervention to prevent its progress to a deadly metastatic stage. This study combines multiphoton microscopy with fluorescence lifetime imaging (FLIM) using a syngeneic melanoma mouse model, to detect changes in metabolic state of single epidermal cells as a metabolic marker to monitor the progress of tumor growth. This method utilizes imaging of the ratio of the amounts of the free and protein-bound forms of the intracellular autofluorescent metabolic co-enzyme nicotinamide adenine dinucleotide (NADH). Here, we investigate the impact of the primary tumor lesion on the epidermal layers at three different growth stages of melanoma lesion compared to normal skin as a control. We showed a significant increase in the free-to-bound NADH ratio with the growth of the solid melanoma tumor, while concurrently the short and the long lifetime components of NADH remained constant. These results demonstrate the ability of FLIM for rapid, non-invasive and sensitive assessment of melanoma progression revealing its potential as a diagnostic tool for melanoma detection and as an aid for melanoma staging. PMID- 27992082 TI - The expanding microRNA world in psoriasis. AB - Psoriasis skin lesions are characterized by dramatic changes in the transcriptome, reflecting altered activity of multiple signalling pathways in resident and infiltrating cells. miRNAs are small non-coding RNAs that have a large impact on cellular functions by regulating multiple genes simultaneously, and they have been shown to play key roles in skin homoeostasis and inflammation. In this commentary to the review article "MicroRNAs in Psoriasis: Immunological Functions and Potential Biomarkers" by Liu et al., the role of miRNAs in psoriasis and their diagnostic and therapeutic potential are discussed and remaining unanswered questions are highlighted. PMID- 27992083 TI - Melanocyte-protective effect of afzelin is mediated by the Nrf2-ARE signalling pathway via GSK-3beta inactivation. AB - Vitiligo is an acquired condition characterized by depigmented, cutaneous lesions that result from the death of pigment-producing cells, melanocytes. The occurrence of oxidative stress has been proposed as a pathogenetic mechanism for melanocyte degeneration in vitiligo. Therefore, in this study, we investigated the cytoprotective effects of afzelin against oxidative stress and its mechanism of action in human epidermal melanocytes. We found that afzelin significantly inhibited hydrogen peroxide-induced cell death, cellular reactive oxygen species production and lipid peroxidation in melanocytes. In an antioxidant response element (ARE)-luciferase reporter assay, afzelin increased ARE-luciferase reporter activity in a concentration-dependent manner. Consistently, the expression of antioxidant genes, including NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1) and catalase, was enhanced by afzelin treatment. Nuclear translocation of Nrf2 also increased in response to afzelin treatment. In addition, the phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was induced by afzelin treatment. The enhancement of HO-1 gene expression by afzelin treatment was reduced by Nrf2-siRNA expression. Furthermore, we found that the expression of Nrf2-siRNA significantly attenuated the cytoprotective effect of afzelin against hydrogen peroxide. These data suggest that the cytoprotective effects of afzelin against hydrogen peroxide may be mediated by Nrf2-ARE signalling via GSK-3beta inactivation. Our data suggest the novel use of afzelin for the prevention of oxidative stress-induced damage in melanocytes and its potential as a therapeutic agent for vitiligo. PMID- 27992084 TI - A Plasmonic Colloidal Photocatalyst Composed of a Metal-Organic Framework Core and a Gold/Anatase Shell for Visible-Light-Driven Wastewater Purification from Antibiotics and Hydrogen Evolution. AB - Porous coordination polymers (PCP) or metal- organic frameworks (MOF) are promising materials for the generation of photocatalytically active composite materials. Here, a novel synthesis concept is reported, which permits the formation of PCP/MOF-core-Au/anatase-shell materials. These materials are photocatalysts for wastewater purification and hydrogen generation from water under visible-light illumination. MIL-101 (Cr) is utilized as the core material, which directs the size of the core-shell compound and ensures the overall stability. In addition, its excellent reversible large molecule sorption behavior allows the materials synthesis. The crystalline anatase shell is generated stepwise under mild conditions using titanium(IV) isopropoxide as a precursor. The high degree of control of the vapor phase deposition process permits the precise anatase shell formation. The generation of plasmonic active gold particles on the TiO2 shell leads to an efficient material for visible-light driven photocatalysis with a higher activity than gold-decorated P25 (Degussa). PMID- 27992085 TI - Muscle atrophy is associated with cervical spinal motoneuron loss in BACHD mouse model for Huntington's disease. AB - Involuntary choreiform movements are clinical hallmark of Huntington's disease, an autosomal dominant neurodegenerative disorder caused by an increased number of CAG trinucleotide repeats in the huntingtin gene. Involuntary movements start with an impairment of facial muscles and then affect trunk and limbs muscles. Huntington's disease symptoms are caused by changes in cortex and striatum neurons induced by mutated huntingtin protein. However, little is known about the impact of this abnormal protein in spinal cord motoneurons that control movement. Therefore, in this study we evaluated abnormalities in the motor unit (spinal cervical motoneurons, motor axons, neuromuscular junctions and muscle) in a mouse model for Huntington's disease (BACHD). Using light, fluorescence, confocal, and electron microscopy, we showed significant changes such as muscle fibers atrophy, fragmentation of neuromuscular junctions, axonal alterations, and motoneurons death in BACHD mice. Noteworthy, the surviving motoneurons from BACHD spinal cords were smaller than WT. We suggest that this loss of larger putative motoneurons is accompanied by a decrease in the expression of fast glycolytic muscle fibers in this model for Huntington's disease. These observations show spinal cord motoneurons loss in BACHD that might help to understand neuromuscular changes in Huntington's disease. PMID- 27992086 TI - Direct Access to Fused Salicylaldehydes and Salicylketones from Tetraynes. AB - A facile method for the synthesis of fused, multifunctionalized salicylaldehydes and salicylketones by a one-pot, three-step cascade hexadehydro-Diels-Alder (HDDA) reaction of tetraynes followed by an intermolecular aldehyde/ketone reaction and hydroxylation is reported. Target compounds were prepared by the condensation of malonates with 3-bromo-1-propyne, and the resulting 2,2-di(1 propyn-3-yl)malonates underwent cross-coupling with phenylethynyl bromides to afford 2,2-di(5-phenyl-2,4-pentadiynyl)malonates, which underwent intramolecular cyclization to produce bicyclic salicylaldehydes. The overall transformation involves the formation of four new C-C bonds and one new Caryl -O bond through both intramolecular and intermolecular reactions. The reaction is easy to perform, proceeds under mild conditions, and exhibits excellent regioselectivity. Water, a simple and readily available reagent, was employed as the OH source. A plausible reaction mechanism is proposed for this new annulation based on isotopic substitution experiments. PMID- 27992087 TI - Urokinase-type plasminogen activator modulates mammalian circadian clock phase regulation in tissue-type plasminogen activator knockout mice. AB - Glutamate phase shifts the circadian clock in the mammalian suprachiasmatic nucleus (SCN) by activating NMDA receptors. Tissue-type plasminogen activator (tPA) gates phase shifts by activating plasmin to generate m(ature) BDNF, which binds TrkB receptors allowing clock phase shifts. Here, we investigate phase shifting in tPA knockout (tPA-/- ; B6.129S2-Plattm1Mlg /J) mice, and identify urokinase-type plasminogen activator (uPA) as an additional circadian clock regulator. Behavioral activity rhythms in tPA-/- mice entrain to a light-dark (LD) cycle and phase shift in response to nocturnal light pulses with no apparent loss in sensitivity. When the LD cycle is inverted, tPA-/- mice take significantly longer to entrain than C57BL/6J wild-type (WT) mice. SCN brain slices from tPA-/- mice exhibit entrained neuronal activity rhythms and phase shift in response to nocturnal glutamate with no change in dose-dependency. Pre treating slices with the tPA/uPA inhibitor, plasminogen activator inhibitor-1 (PAI-1), inhibits glutamate-induced phase delays in tPA-/- slices. Selective inhibition of uPA with UK122 prevents glutamate-induced phase resetting in tPA-/- but not WT SCN slices. tPA expression is higher at night than the day in WT SCN, while uPA expression remains constant in WT and tPA-/- slices. Casein-plasminogen zymography reveals that neither tPA nor uPA total proteolytic activity is under circadian control in WT or tPA-/- SCN. Finally, tPA-/- SCN tissue has lower mBDNF levels than WT tissue, while UK122 does not affect mBDNF levels in either strain. Together, these results suggest that either tPA or uPA can support photic/glutamatergic phase shifts of the SCN circadian clock, possibly acting through distinct mechanisms. PMID- 27992088 TI - Interhemispheric functional connectivity in anorexia and bulimia nervosa. AB - The functional interplay between hemispheres is fundamental for behavioral, cognitive, and emotional control. Anorexia nervosa (AN) and bulimia nervosa (BN) have been largely studied with brain magnetic resonance imaging (MRI) in relation to the functional mechanisms of high-level processing, but not in terms of possible inter-hemispheric functional connectivity anomalies. Using resting-state functional MRI (fMRI), voxel-mirrored homotopic connectivity (VMHC) and regional inter-hemispheric spectral coherence (IHSC) were studied in 15 AN and 13 BN patients and 16 healthy controls (HC). Using T1-weighted and diffusion tensor imaging MRI scans, regional VMHC values were correlated with the left-right asymmetry of corresponding homotopic gray matter volumes and with the white matter callosal fractional anisotropy (FA). Compared to HC, AN patients exhibited reduced VMHC in cerebellum, insula, and precuneus, while BN patients showed reduced VMHC in dorso-lateral prefrontal and orbito-frontal cortices. The regional IHSC analysis highlighted that the inter-hemispheric functional connectivity was higher in the 'Slow-5' band in all regions except the insula. No group differences in left-right structural asymmetries and in VMHC vs. callosal FA correlations were significant in the comparisons between cohorts. These anomalies, not explained by structural changes, indicate that AN and BN, at least in their acute phase, are associated with a loss of inter-hemispheric connectivity in regions implicated in self-referential, cognitive control and reward processing. These findings may thus gather novel functional markers to explore aberrant features of these eating disorders. PMID- 27992089 TI - The genetics of adaptation to discrete heterogeneous environments: frequent mutation or large-effect alleles can allow range expansion. AB - Range expansions are complex evolutionary and ecological processes. From an evolutionary standpoint, a populations' adaptive capacity can determine the success or failure of expansion. Using individual-based simulations, we model range expansion over a two-dimensional, approximately continuous landscape. We investigate the ability of populations to adapt across patchy environmental gradients and examine how the effect sizes of mutations influence the ability to adapt to novel environments during range expansion. We find that genetic architecture and landscape patchiness both have the ability to change the outcome of adaptation and expansion over the landscape. Adaptation to new environments succeeds via many mutations of small effect or few of large effect, but not via the intermediate between these cases. Higher genetic variance contributes to increased ability to adapt, but an alternative route of successful adaptation can proceed from low genetic variance scenarios with alleles of sufficiently large effect. Steeper environmental gradients can prevent adaptation and range expansion on both linear and patchy landscapes. When the landscape is partitioned into local patches with sharp changes in phenotypic optimum, the local magnitude of change between subsequent patches in the environment determines the success of adaptation to new patches during expansion. PMID- 27992090 TI - Metal-Catalyzed Asymmetric Michael Addition in Natural Product Synthesis. AB - Asymmetric catalysis for chiral compound synthesis is a rapidly growing field in modern organic chemistry. Asymmetric catalytic processes have been indispensable for the synthesis of enantioselective materials to meet demands from various fields. Michael addition has been used extensively for the construction of C-C bonds under mild conditions. With the discovery and development of organo- and metal-catalyzed asymmetric Michael additions, the synthesis of enantioselective and/or diastereoselective Michael adducts has become possible and increasingly prevalent in the literature. In particular, metal-catalyzed asymmetric Michael addition has been employed as a key reaction in natural product synthesis for the construction of contiguous quaternary stereogenic center(s), which is still a difficult task in organic synthesis. Previously reported applications of metal catalyzed asymmetric Michael additions in natural product synthesis are presented here and discussed in depth. PMID- 27992091 TI - EFFECTS OF X-RAY BEAM ANGLE AND GEOMETRIC DISTORTION ON WIDTH OF EQUINE THORACOLUMBAR INTERSPINOUS SPACES USING RADIOGRAPHY AND COMPUTED TOMOGRAPHY-A CADAVERIC STUDY. AB - The widths of spaces between the thoracolumbar processi spinosi (interspinous spaces) are frequently assessed using radiography in sports horses; however effects of varying X-ray beam angles and geometric distortion have not been previously described. The aim of this prospective, observational study was to determine whether X-ray beam angle has an effect on apparent widths of interspinous spaces. Thoracolumbar spine specimens were collected from six equine cadavers and left-right lateral radiographs and sagittal and dorsal reconstructed computed tomographic (CT) images were acquired. Sequential radiographs were acquired with each interspinous space in focus. Measurements were performed for each interspinous space in the focus position and up to eight angled positions as the interspinous space moved away from focus (+/-). Focus position measurements were compared to matching sagittal CT measurements. Effect of geometric distortion was evaluated by comparing the interspinous space in radiographs with sagittal and dorsal reconstructed CT images. A total of 49 interspinous spaces were sampled, yielding 274 measurements. X-ray beam angle significantly affected measured width of interspinous spaces in position +3 (P = 0.038). Changes in width did not follow a consistent pattern. Interspinous space widths in focus position were significantly smaller in radiographs compared to matching reconstructed CT images for backs diagnosed with kissing spine syndrome (P < 0.001). Geometric distortion markedly affected appearance of interspinous space width between planes. In conclusion, X-ray beam angle and geometric distortion influence radiographically measured widths of interspinous spaces in the equine thoracolumbar spine, and this should be taken into consideration when evaluating sport horses. PMID- 27992093 TI - Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: reply. PMID- 27992092 TI - Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation. AB - OBJECTIVES: Deep Brain Stimulation (DBS) has been either approved or is currently under investigation for a number of psychiatric disorders. MATERIALS AND METHODS: We review clinical and preclinical concepts as well as the neurocircuitry that may be of relevance for the implementation of DBS in posttraumatic stress disorder (PTSD). RESULTS: PTSD is a chronic and debilitating illness associated with dysfunction in well-established neural circuits, including the amygdala and prefrontal cortex. Although most patients often improve with medications and/or psychotherapy, approximately 20-30% are considered to be refractory to conventional treatments. In other psychiatric disorders, DBS has been investigated in treatment-refractory patients. To date, preclinical work suggests that stimulation at high frequency delivered at particular timeframes to different targets, including the amygdala, ventral striatum, hippocampus, and prefrontal cortex may improve fear extinction and anxiety-like behavior in rodents. In the only clinical report published so far, a patient implanted with electrodes in the amygdala has shown striking improvements in PTSD symptoms. CONCLUSIONS: Neuroimaging, preclinical, and preliminary clinical data suggest that the use of DBS for the treatment of PTSD may be practical but the field requires further investigation. PMID- 27992095 TI - Faecal occult blood testing screening for colorectal cancer and 'missed' interval cancers: are we ignoring the elephant in the room? Results of a multicentre study. AB - AIM: Biennial faecal occult blood testing (FOBT) is used to screen for colorectal cancer throughout the UK. Interval cancers are tumours that develop in patients between screening rounds who have had a negative FOBT. Through a multicentre study, we compared the demographics of patients with interval cancers, FOBT screen detected cancers and cancers that developed in patients who chose not to participate in the screening programme. METHOD: Five hundred and sixteen colorectal cancers were detected in the screening age group (60-74 years) population in three UK National Health Service hospitals over 2 years. One hundred and twenty seven (25%) were interval cancers, 161 (31%) were screen detected and 228 (44%) were cancers that developed in patients who had declined FOBT. The interval cancer group had a higher incidence of right-sided cancers (38% vs 29% and 24%), a higher proportion of high tumour stages (Dukes C and D) (70% vs 53% and 33%) and a shorter time from diagnosis to death (10 months vs 13 months and 24 months) compared to patients who had declined the FOBT and the FOBT screen detected cancers. Of all the patients studied, those with right-sided interval cancers had the worst outcome. CONCLUSION: A quarter of the colorectal cancers diagnosed in our study were interval cancers. Patients with right-sided interval cancers had the highest proportion of Dukes C and D tumours coupled with the shortest survival time after diagnosis compared with the other groups. PMID- 27992094 TI - A loop-mediated isothermal amplification method for rapid direct detection and differentiation of nonpathogenic and verocytotoxigenic Escherichia coli in beef and bovine faeces. AB - AIM: To develop a multiplex loop-mediated isothermal amplification (LAMP) assay capable of quantifying Escherichia coli and differentiating verocytotoxigenic E. coli (VTEC). METHODS AND RESULTS: Primer sets were selected to amplify the phoA gene (all E. coli strains) and stx1 and/or stx2 genes (VTEC strains only). LAMP calibration curves demonstrated good quantification capability compared with conventional culture. The limits of detection 50% (LOD50 ) of the multiplex LAMP assay were 2.8 (95% CI 2.4-3.3), 3.2 (95% CI 2.5-3.9) and 2.8-3.2 (95% CI 2.1 3.5) log CFU per g for the phoA, stx1 and stx2 genes, respectively. When validated by testing retail beef and bovine faeces samples, good correlation between E. coli counts indicated by the LAMP assay and culture was observed; however, false-negative LAMP assay results were obtained for 12.5-14.7% of samples. CONCLUSIONS: A rapid, multiplex LAMP assay for direct quantification of E. coli and specific detection of VTEC in beef and faeces was successfully developed. Further optimisation of the assay would be needed to improve detection sensitivity. SIGNIFICANCE AND IMPACT OF THE STUDY: The multiplex LAMP assay represents a rapid alternative to culture for monitoring E. coli levels on beef for hygiene monitoring purposes, and, potentially, a method for detection of VTEC in beef and faeces. PMID- 27992096 TI - Soluble N-ethylmaleimide-sensitive factor attachment protein receptors required during Trypanosoma cruzi parasitophorous vacuole development. AB - Trypanosoma cruzi, the etiologic agent of Chagas disease, is an obligate intracellular parasite that exploits different host vesicular pathways to invade the target cells. Vesicular and target soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are key proteins of the intracellular membrane fusion machinery. During the early times of T. cruzi infection, several vesicles are attracted to the parasite contact sites in the plasma membrane. Fusion of these vesicles promotes the formation of the parasitic vacuole and parasite entry. In this work, we study the requirement and the nature of SNAREs involved in the fusion events that take place during T. cruzi infection. Our results show that inhibition of N-ethylmaleimide-sensitive factor protein, a protein required for SNARE complex disassembly, impairs T. cruzi infection. Both TI-VAMP/VAMP7 and cellubrevin/VAMP3, two v-SNAREs of the endocytic and exocytic pathways, are specifically recruited to the parasitophorous vacuole membrane in a synchronized manner but, although VAMP3 is acquired earlier than VAMP7, impairment of VAMP3 by tetanus neurotoxin fails to reduce T. cruzi infection. In contrast, reduction of VAMP7 activity by expression of VAMP7's longin domain, depletion by small interfering RNA or knockout, significantly decreases T. cruzi infection susceptibility as a result of a minor acquisition of lysosomal components to the parasitic vacuole. In addition, overexpression of the VAMP7 partner Vti1b increases the infection, whereas expression of a KIF5 kinesin mutant reduces VAMP7 recruitment to vacuole and, concomitantly, T. cruzi infection. Altogether, these data support a key role of TI-VAMP/VAMP7 in the fusion events that culminate in the T. cruzi parasitophorous vacuole development. PMID- 27992097 TI - Looking for answers to bariatric surgery for losing weight using resting state functional MRI. PMID- 27992098 TI - Candida pyralidae killer toxin disrupts the cell wall of Brettanomyces bruxellensis in red grape juice. AB - AIMS: The control of the wine spoilage yeast Brettanomyces bruxellensis using biological methods such as killer toxins (instead of the traditional chemical methods, e.g. SO2 ) has been the focus of several studies within the last decade. Our previous research demonstrated that the killer toxins CpKT1 and CpKT2 isolated from the wine yeast Candida pyralidae were active and stable under winemaking conditions. In this study, we report the possible mode of action of CpKT1 on B. bruxellensis cells in red grape juice. METHODS AND RESULTS: Brettanomyces bruxellensis cells were exposed to CpKT1 either directly or through co-inoculation with C. pyralidae. This exposure yielded a temporary or permanent decline of the spoilage yeast population depending on the initial cell concentration. Scanning electron microscopy revealed cell surface abrasion while propidium iodide viability staining showed that CpKT1 caused plasma membrane damage on B. bruxellensis cells. Our data show that the exposure to CpKT1 resulted in increased levels of beta-glucan, suggesting a compensatory response of the sensitive cells. CONCLUSIONS: The toxin CpKT1 causes cell membrane and cell wall damage in B. bruxellensis. SIGNIFICANCE AND IMPACT OF THE STUDY: Candida pyralidae shows potential to be used as a biocontrol agent against B. bruxellensis in grape juice/wine. PMID- 27992099 TI - Home-based telerehabilitation via real-time videoconferencing improves endurance exercise capacity in patients with COPD: The randomized controlled TeleR Study. AB - BACKGROUND AND OBJECTIVE: Telerehabilitation has the potential to increase access to pulmonary rehabilitation (PR) for patients with COPD who have difficulty accessing centre-based PR due to poor mobility, lack of transport and cost of travel. We aimed to determine the effect of supervised, home-based, real-time videoconferencing telerehabilitation on exercise capacity, self-efficacy, health related quality of life (HRQoL) and physical activity in patients with COPD compared with usual care without exercise training. METHODS: Patients with COPD were randomized to either a supervised home-based telerehabilitation group (TG) that received exercise training three times a week for 8 weeks or a control group (CG) that received usual care without exercise training. Outcomes were measured at baseline and following the intervention. RESULTS: Thirty-six out of 37 participants (mean +/- SD age = 74 +/- 8 years, forced expiratory volume in 1 s (FEV1 ) = 64 +/- 21% predicted) completed the study. Compared with the CG, the TG showed a statistically significant increase in endurance shuttle walk test time (mean difference = 340 s (95% CI: 153-526, P < 0.001)), an increase in self efficacy (mean difference = 8 points (95% CI: 2-14, P < 0.007)), a trend towards a statistically significant increase in the Chronic Respiratory Disease Questionnaire total score (mean difference = 8 points (95% CI: -1 to 16, P = 0.07)) and no difference in physical activity (mean difference = 475 steps per day (95% CI: -200 to 1151, P = 0.16)). CONCLUSION: This study showed that telerehabilitation improved endurance exercise capacity and self-efficacy in patients with COPD when compared with usual care. PMID- 27992100 TI - Streptomyces effect on the bacterial microbiota associated to Crassostrea sikamea oyster. AB - AIM: To determine the composition and diversity of the microbiota associated to Crassostrea sikamea treated during 30 days with Streptomyces strains N7 and RL8. METHODS AND RESULTS: DNA was extracted from oysters followed by 16S rRNA gene amplification and pyrosequencing. The highest and lowest species diversity richness was observed in the initial and final control group, whereas Streptomyces-treated oysters exhibited intermediate values. Proteobacteria was the most abundant phylum (81.4-95.1%), followed by Bacteroidetes, Actinobacteria and Firmicutes. The genera Anderseniella, Oceanicola, Roseovarius, Ruegeria, Sulfitobacter, Granulosicoccus and Marinicella encompassed the core microbiota of all experimental groups. The genus Bacteriovorax was detected in all groups except in the final control and the depurated N7, whereas Vibrio remained undetected in all Streptomyces-treated groups. RL8 was the only group that harboured the genus Streptomyces in its microbiota. Principal component analysis showed that Streptomyces strains significantly changed oyster microbiota with respect to the initial and final control. CONCLUSIONS: Crassostrea sikamea treated with Streptomyces showed high species diversity and a microbiota composition shift, characterized by keeping the predator genus Bacteriovorax and decreasing the pathogenic Vibrio. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first culture-independent study showing the effect of Streptomyces over the oyster microbiota. It also sheds light about the potential use of Streptomyces to improve mollusc health and safety for consumers after the depuration process. PMID- 27992101 TI - Computational modelling of clot development in patient-specific cerebral aneurysm cases: rebuttal. PMID- 27992102 TI - Natural Product Kuwanon-L Inhibits HIV-1 Replication through Multiple Target Binding. AB - In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Thus, new compounds with original modes of action are continuously required, and natural products have ever been a very interesting class of pharmacologically active molecules. Some of them have been used since ancient times against viral infections. Here we present a work in which we suggest that kuwanon-L, a natural product active as an HIV-1 integrase (IN) inhibitor, might exert its overall antiviral activity through binding to multiple viral targets. Specific enzymatic tests, together with a time-of addition (TOA) experiment, support our hypothesis of binding both to IN and to reverse transcriptase (RT). Overall, this compound can be considered an attractive lead for the development of new classes of antiviral agents able to overcome the problem of resistance, due to its ability to exert its action by binding simultaneously to multiple viral targets. PMID- 27992103 TI - Resting state functional connectivity measures correlate with the response to anodal transcranial direct current stimulation. AB - Responses to non-invasive brain stimulation are highly variable between subjects. Resting state functional connectivity was investigated as a marker of plasticity induced by anodal transcranial direct current stimulation (tDCS). Twenty-six healthy adults (15 male, 26.4 +/- 6.5 years) were tested. Experiment 1 investigated whether functional connectivity could predict modulation of corticospinal excitability following anodal tDCS. Experiment 2 determined test retest reliability of connectivity measures. Three minutes of electroencephalography was recorded and connectivity was quantified with the debiased weighted phase lag index. Anodal (1 mA, 20 min) or sham tDCS was applied to the left primary motor cortex (M1), with a change in motor evoked potential amplitude recorded from the right first dorsal interosseous used as a marker of tDCS response. Connectivity in the high beta frequency (20-30 Hz) between an electrode approximating the left M1 (C3) and electrodes overlying the left parietal cortex was a strong predictor of tDCS response (cross-validated R2 = 0.69). Similar relationships were observed for alpha (8-13 Hz; R2 = 0.64), theta (4-7 Hz; R2 = 0.53), and low beta (14-19 Hz; R2 = 0.58) frequencies, however, test-retest reliability of connectivity measures was strongest for the high beta frequency model (ICC = 0.65; good reliability). Further investigation of the high beta model found that greater connectivity between C3 and a cluster of electrodes approximately overlying the left parietal cortex was associated with stronger responses to anodal (rho = 0.61, P = 0.03), but not sham tDCS (rho = 0.43, P = 0.14). Functional connectivity is a strong predictor of the neuroplastic response to tDCS and may be one important characteristic to assist targeted tDCS application. PMID- 27992104 TI - Insights into the Photophysics and Supramolecular Organization of Congo Red in Solution and the Solid State. AB - Steady-state and time-resolved absorption and fluorescence measurements are reported for Congo Red (CR) in aqueous and dimethylsulfoxide (DMSO) solutions. The very low fluorescence quantum yield (~10-4 ) for CR in dilute solutions together with the absence of a triplet state indicates that internal conversion is the dominant deactivation route with more than 99.99 % of the quanta loss (attributed to the energy gap law for radiationless transitions). Although no direct evidence for trans-cis photoisomerization was obtained from absorption or fluorescence data, the global analysis of fs-transient absorption data indicates the presence of a photoproduct with a lifetime of ~170 ps that is suggested to be associated with such a process. Spectral data for more concentrated CR solutions indicate the presence of oblique or twisted J-type aggregates. These results are compared with spectra for CR in the solid state (sodium salt) and intercalated in a layered double hydroxide via a one-step co-precipitation route. Powder XRD and electronic spectral data for the nanohybrid indicate that the CR guest molecules are intercalated as a monolayer consisting of slipped cofacial J-type aggregates. PMID- 27992105 TI - Cyclobutanone Analogues of beta-Lactam Antibiotics: beta-Lactamase Inhibitors with Untapped Potential? AB - beta-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to beta-lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with beta-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N is substituted by a tertiary C-H alpha to a ketone. Cyclobutanone analogues of various beta-lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the beta-lactamase enzymes that impart resistance to beta-lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of beta-lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of beta-lactamase; other compounds from this family inhibit Streptomyces R61 dd-carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area. PMID- 27992106 TI - Computational modeling of clot development in patient-specific cerebral aneurysm cases: reply. PMID- 27992107 TI - Bioreaction Engineering Leading to Efficient Synthesis of L-Glyceraldehyd-3 Phosphate. AB - Enantiopure L-glyceraldehyde-3-phosphate (L-GAP) is a useful building block in natural biological and synthetic processes. A biocatalytic process using glycerol kinase from Cellulomonas sp. (EC 2.7.1.30) catalyzed phosphorylation of L glyceraldehyde (L-GA) by ATP is used for the synthesis of L-GAP. L-GAP has a half life of 6.86 h under reaction conditions. The activity of this enzyme depends on the Mg2+ to ATP molar ratio showing maximum activity at the optimum molar ratio of 0.7. A kinetic model is developed and validated showing a 2D correlation of 99.9% between experimental and numerical data matrices. The enzyme exhibits inhibition by ADP, AMP, methylglyoxal and Ca2+ , but not by L-GAP and inorganic orthophosphate. Moreover, equal amount of Ca2+ exerts a different degree of inhibition relative to the activity without the addition of Ca2+ depending on the Mg2+ to ATP molar ratio. If the Mg2+ to ATP molar ratio is set to be at the optimum value or less, inorganic hexametaphosphate (PPi6) suppresses the enzyme activity; otherwise PPi6 enhances the enzyme activity. Based on reaction engineering parameters such as conversion, selectivity and specific productivity, evaluation of different reactor types reveals that batchwise operation via stirred-tank reactor is the most efficient process for the synthesis of L-GAP. PMID- 27992108 TI - Local temperature and El Nino Southern Oscillation influence migration phenology of East Asian migratory waterbirds wintering in Poyang, China. AB - Temperature is a critical factor influencing avian phenology, due to its direct impact on food and water availability. Most previous studies have focused on the timing of spring migration and the arrival of birds at breeding grounds along the European and American flyways; little is known about migration ecology at the wintering sites along the Asian flyways. Using linear regression models, this study investigates how local temperature variation and EI Nino Southern Oscillation (ENSO) influences the arrival and departure timing of 9 waterbird species breeding in Mongolia or Siberia and overwintering in Poyang, China from 2002 to 2013. Birds mainly arrive at Poyang in October and depart for their breeding sites in March. Out of the 9 species, 6 show a strong negative relationship between departure time and overwintering temperature in Poyang. Departure dates also show a negative association with overwintering ENSO and March ENSO for two species. Both local and large-scale climate indices show no influence on the arrival timing of waterbirds. We suggest that birds react to the annual variation of overwintering temperature: an earlier departure of waterbirds is facilitated by a warmer overwintering period and vice versa. The long-term accumulated temperature effect is more pronounced than ENSO and the short-term local temperature effect. Our findings could help quantify the potential impact of global warming on waterbirds. PMID- 27992109 TI - The stadium effect: rodent damage patterns in rice fields explored using giving up densities. AB - Rodents are globally important pre-harvest pests of rice. In Southeast Asia, rodent damage to growing rice crops is commonly concentrated towards the center of rice fields, away from the field edge, resulting in a clear pattern known as the "stadium effect." To further understand this behavior of rodent pests and to develop recommendations for future research and management, we examined the relation between giving-up densities (GUDs) and damage patterns. In Tanay, Luzon, Philippines, GUD trays containing pieces of coconut in a matrix of sand were placed at 4 different distances from the field edge to quantify the perceived risk of predation in a rice field pest, Rattus tanezumi. GUDs were recorded during a dry and wet season crop at the reproductive and ripening stages of rice. In addition, assessments of active burrows, tracking tile activity and rodent damage to the rice crop, were conducted in the dry season. GUDs were significantly lower in the center of the rice fields than on the field edges, suggesting that rodent damage to rice is greater in the middle of rice fields due to a lower perceived predation risk. Furthermore, this perception of predation risk (or fear) increases towards the field edge and was greatest on the rice bund, where there was no vegetation cover. We discuss the implications for rodent management and rodent damage assessments in rice fields. This is the first documented use of GUDs in a rice agro-ecosystem in Asia; thus we identify the challenges and lessons learned through this process. PMID- 27992110 TI - Kidney Exchange to Overcome Financial Barriers to Kidney Transplantation. AB - Organ shortage is the major limitation to kidney transplantation in the developed world. Conversely, millions of patients in the developing world with end-stage renal disease die because they cannot afford renal replacement therapy-even when willing living kidney donors exist. This juxtaposition between countries with funds but no available kidneys and those with available kidneys but no funds prompts us to propose an exchange program using each nation's unique assets. Our proposal leverages the cost savings achieved through earlier transplantation over dialysis to fund the cost of kidney exchange between developed-world patient donor pairs with immunological barriers and developing-world patient-donor pairs with financial barriers. By making developed-world health care available to impoverished patients in the developing world, we replace unethical transplant tourism with global kidney exchange-a modality equally benefitting rich and poor. We report the 1-year experience of an initial Filipino pair, whose recipient was transplanted in the United states with an American donor's kidney at no cost to him. The Filipino donor donated to an American in the United States through a kidney exchange chain. Follow-up care and medications in the Philippines were supported by funds from the United States. We show that the logistical obstacles in this approach, although considerable, are surmountable. PMID- 27992111 TI - Comparison of clustering methods for high-dimensional single-cell flow and mass cytometry data. AB - Recent technological developments in high-dimensional flow cytometry and mass cytometry (CyTOF) have made it possible to detect expression levels of dozens of protein markers in thousands of cells per second, allowing cell populations to be characterized in unprecedented detail. Traditional data analysis by "manual gating" can be inefficient and unreliable in these high-dimensional settings, which has led to the development of a large number of automated analysis methods. Methods designed for unsupervised analysis use specialized clustering algorithms to detect and define cell populations for further downstream analysis. Here, we have performed an up-to-date, extensible performance comparison of clustering methods for high-dimensional flow and mass cytometry data. We evaluated methods using several publicly available data sets from experiments in immunology, containing both major and rare cell populations, with cell population identities from expert manual gating as the reference standard. Several methods performed well, including FlowSOM, X-shift, PhenoGraph, Rclusterpp, and flowMeans. Among these, FlowSOM had extremely fast runtimes, making this method well-suited for interactive, exploratory analysis of large, high-dimensional data sets on a standard laptop or desktop computer. These results extend previously published comparisons by focusing on high-dimensional data and including new methods developed for CyTOF data. R scripts to reproduce all analyses are available from GitHub (https://github.com/lmweber/cytometry-clustering-comparison), and pre processed data files are available from FlowRepository (FR-FCM-ZZPH), allowing our comparisons to be extended to include new clustering methods and reference data sets. (c) 2016 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC. PMID- 27992112 TI - Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. AB - Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and >= 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg-1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with <= 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with <= 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds. PMID- 27992113 TI - Systematic interpolation method predicts protein chromatographic elution with salt gradients, pH gradients and combined salt/pH gradients. AB - A methodology is presented to predict protein elution behavior from an ion exchange column using both individual or combined pH and salt gradients based on high-throughput batch isotherm data. The buffer compositions are first optimized to generate linear pH gradients from pH 5.5 to 7 with defined concentrations of sodium chloride. Next, high-throughput batch isotherm data are collected for a monoclonal antibody on the cation exchange resin POROS XS over a range of protein concentrations, salt concentrations, and solution pH. Finally, a previously developed empirical interpolation (EI) method is extended to describe protein binding as a function of the protein and salt concentration and solution pH without using an explicit isotherm model. The interpolated isotherm data are then used with a lumped kinetic model to predict the protein elution behavior. Experimental results obtained for laboratory scale columns show excellent agreement with the predicted elution curves for both individual or combined pH and salt gradients at protein loads up to 45 mg/mL of column. Numerical studies show that the model predictions are robust as long as the isotherm data cover the range of mobile phase compositions where the protein actually elutes from the column. PMID- 27992114 TI - The role of spironolactone on myocardial oxidative stress in rat model of streptozotocin-induced diabetes. AB - BACKGROUND: Diabetes mellitus (DM) is linked to cardiovascular diseases development and progression. Aldosterone contributes to cardiac oxidative stress and remodeling. AIM: To evaluate the impact of spironolactone (an aldosterone antagonist) on markers of myocardial redox status in a rat model of streptozotocin (STZ)-induced DM. METHOD: Adult Sprague Dawley rats were randomized into four groups; controls, spironolactone-treated rats (Spir), diabetic rats (DM), and diabetic rats treated with spironolactone (DM+Spir) for 4 weeks. Blood pressure and cardiac levels of aldosterone and oxidants/antioxidants were measured. RESULT: STZ-induced DM but did not cause hypertension or dyslipidemia in either spironolactone-treated or spironolactone-untreated rats. Aldosterone and aldosterone synthase levels were increased in both the DM and DM+Spir groups compared to control. In parallel, total nitrite and nitrotyrosine levels were increased and vitamin E antioxidant levels were reduced in the DM group. Spironolactone use reduced cardiac total nitrite levels and improved vitamin E levels. Glutathione reductase/peroxidase activities were increased in the DM and DM+Spir groups without changes in the ratio of reduced to oxidized form of glutathione. Superoxide dismutase (SOD) and catalase activities were increased in the DM group. Lipid peroxidation products were similar among the groups. CONCLUSIONS: The increase in total nitrite/nitrotyrosine in DM promoted significant compensatory increases in antioxidant activities of SOD, catalase and glutathione peroxidase/reductase probably to prevent cardiac oxidative damage. The use of spironolactone reduced nitrite generation and improved vitamin E levels independent of blood pressure. PMID- 27992116 TI - Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer: comment. PMID- 27992115 TI - Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide???Heteroarene pi-Stacking Interactions and Chalcogen Bonding in the S3 Pocket. AB - We report an extensive "heteroarene scan" of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate pi-stacking on the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket. This heteroarene???peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki ) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki =4 nm) and benzothiazolyl (Ki =17 nm) ligands was enhanced by intermolecular C-S???O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain. PMID- 27992117 TI - Like or dislike: Response of rodents to the odor of plant secondary metabolites. AB - Rodents, including common voles (Microtus arvalis) and house mice (Mus musculus) cause immense pre-harvest and post-harvest losses. Therefore, developing methods that mitigate these losses while maintaining their role in ecosystems is a priority. Several plant secondary metabolites (PSM) which significantly reduce food intake of both species under laboratory conditions have been identified. However, before these can be used in rodent pest management, they must be tested under more natural conditions where other food sources are available. In this study, the odors of 4 PSMs were evaluated for their repellent effects in experiments conducted in semi-natural enclosures. Soil treated with PSMs or untreated soil (experimental control) was placed in an underground box containing food (rolled oats). We quantified the number of visits to each box and could demonstrate that all 4 PSMs reduced the number of visits to treatment boxes in both rodent species. For common voles the combination of methyl nonyl ketone + black pepper oil was the most repellent PSM. House mice made fewer visits to all PSM boxes; boxes with the anthraquinone were visited least. Furthermore, house mice consumed less food from boxes containing soil treated with all 4 PSMs. Our results suggest that PSMs are repellent in murid and microtine rodents under semi field conditions. In addition, the future use of PSM odors for repelling both pest species, especially house mice, seems promising. Further investigations with other PSMs, different concentrations as well as alternative application methods are needed to repel common voles from attractive crops. PMID- 27992118 TI - Tolerance and pharmacokinetics of a ciprofloxacin-coated sinus stent in a preclinical model. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is often associated with persistent bacterial infection despite the use of systemic antibiotics. Topically administered antibiotics are an alternative strategy, but require effective local concentrations, prolonged mucosal contact time, minor systemic absorption, and minimal depletion. The objectives of the current study were to analyze the in vitro release rate and in vivo drug delivery tolerance and pharmacokinetics of a ciprofloxacin-coated sinus stent (CSS). METHODS: The CSS (2 mg) was created from biodegradable poly-D/L-lactic acid. After analyzing in vitro release profile, CSSs were placed unilaterally in maxillary sinuses of 16 rabbits via dorsal sinusotomy. Animals were euthanized between 1 and 3 weeks postoperatively. Ciprofloxacin concentrations in the sinus tissue and plasmas were assessed using high-performance liquid chromatography. Radiological and histological evaluations were performed. RESULTS: In the in vitro release profile, an initial burst release was observed over the first 24 hours, followed by sustained release through the 14-day time point. In the rabbit model, ciprofloxacin was continuously released from the stent up to 3 weeks at doses >50 ng/mL. Histologic examination found no evidence of inflammation, epithelial ulceration, or bony reaction upon euthanization of the animals at 21 days. Computed tomography also demonstrated no signs of mucosal edema or opacification in the sinus. CONCLUSION: The CSS was safe in this preclinical model and sustained release was observed in both the in vitro and in vivo analyses. The innovative stent design coated with ciprofloxacin may provide a unique therapeutic strategy for chronic rhinosinusitis (CRS). PMID- 27992119 TI - The prognostic role of serum eosinophil and basophil levels in sinonasal polyposis. AB - BACKGROUND: Predicting which patients are at a higher risk for recurrent chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most challenging problems in clinical rhinology. A direct association between CRSwNP recurrence rates and serum eosinophil and basophil counts was reported. This study aimed to identify best-fitting cutoffs for binarizing preoperative serum eosinophils and basophils (counts/percentages) for prognostic purposes in cases of CRSwNP recurrence after surgery. A secondary endpoint was to distinguish said cutoffs for prognosticating recurrence in subcohorts of patients with histologically diagnosed eosinophilic/non-eosinophilic CRSwNP. METHODS: A retrospective study was performed on 280 patients (127 eosinophilic and 153 non-eosinophilic CRSwNP) examining the prognostic role of serum eosinophil and basophil levels. RESULTS: For all patients examined, mean preoperative serum eosinophil and basophil levels were significantly higher in patients whose CRSwNP recurred. Patients with eosinophil counts >=0.24 cells * 109 /L and percentages >=3.7% had odds ratios (ORs) of 2.57 and 2.19 for recurrence; patients with basophil counts >=0.03 cells * 109 /L and percentages >=0.5% had ORs of 2.19 and 2.24, respectively. Among histologically eosinophilic CRSwNP patients, mean eosinophils and basophils (counts/percentages) were significantly higher in cases that recurred. Serum eosinophil and basophil values were directly correlated. The recurrence odds were OR 2.52 for high eosinophils (>=5.9%), and OR 2.52 and 2.69 for high basophils (>=0.04 cells * 109 /L and >=0.5%, respectively). CONCLUSION: High serum eosinophil and basophil values should be further investigated because they could pinpoint patients at higher risk of eosinophilic-type CRSwNP recurrence. These preliminary results support the increasing interest in the role of basophils in CRSwNP. PMID- 27992121 TI - Erratum: Correction to Grupp SA, Dvorak CC, Nieder ML, et al. PMID- 27992120 TI - Dabigatran enhances platelet reactivity and platelet thrombin receptor expression in patients with atrial fibrillation. AB - : Essentials Whether or not dabigatran enhances the risk of myocardial infarction is under discussion. We measured platelet reactivity and thrombin receptor expression in dabigatran patients. Platelet reactivity and thrombin receptor expression is enhanced during dabigatran treatment. This should be considered when choosing the optimal direct oral anticoagulant for individuals. SUMMARY: Background The direct oral anticoagulant (DOAC) dabigatran is a direct thrombin inhibitor. Its landmark trial, the RE-LY study, observed a trend towards a higher incidence of myocardial infarctions (MIs) in dabigatran-treated patients. Since then, there have been discussions on whether dabigatran increases the risk of MI. Objective In this study, we aimed to assess platelet reactivity and platelet thrombin receptor expression in dabigatran-treated patients. Methods We conducted a cross-sectional study in 13 hospitalized patients with planned initiation of dabigatran medication. Platelet reactivity was measured by light-transmission aggregometry and platelet thrombin receptor expression was measured by flow cytometry analysis. Results Platelet reactivity was higher after initiation of dabigatran medication as compared with baseline (baseline 44 +/- 24% vs. dabigatran 70 +/- 25%). Accordingly, the density of both platelet thrombin receptors (protease activated receptor [PAR]-1 and PAR-4) on platelets increased during dabigatran treatment (PAR1, baseline 63 +/- 11% vs. dabigatran 70 +/- 10%; PAR4, baseline 1.1 +/- 0.5% vs. dabigatran 1.6 +/- 0.9%). Conclusions Dabigatran increases platelet reactivity by enhancing the thrombin receptor density on platelets. This finding should be considered while choosing the optimal DOAC in individualized medicine. PMID- 27992123 TI - Seit 15 Jahren bestehende, langsam progrediente Hautveranderung am Bauch. PMID- 27992124 TI - Two brothers with confluent and reticulated papillomatosis. PMID- 27992122 TI - Phosphatase-Stable Phosphoamino Acid Mimetics That Enhance Binding Affinities with the Polo-Box Domain of Polo-like Kinase 1. AB - (2S,3R)-2-Amino-3-methyl-4-phosphonobutanoic acid (Pmab) is a phosphatase-stable analogue of phosphothreonine (pThr), which has been used in a variety of biological contexts. Among these applications are peptidomimetic ligands that bind to the polo-box domain (PBD) of polo-like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr-containing peptides. However, Pmab is not widely used, because there are no direct, high-yield preparations of suitably protected reagent. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3R center. When incorporated into our peptidomimetic scaffold, these new Pmab analogues exhibit Plk1 PBD-binding affinities that are several-fold higher than Pmab, yet retain good selectivity for Plk1 relative to the PBDs of Plk2 and Plk3. These findings will significantly impact the future development of PBD-binding inhibitors, as well as ligands directed against a broad spectrum of pThr-dependent processes. PMID- 27992125 TI - Der Einfluss von Alitretinoin auf die Lebensqualitat bei Patienten mit schwerem chronischen Handekzem: FUGETTA - Beobachtungsstudie unter Praxisbedingungen. AB - HINTERGRUND UND ZIELE: Alitretinoin ist die einzige zugelassene Behandlung fur schweres chronisches Handekzem (CHE), das refraktar gegenuber potenten topischen Corticosteroiden ist. Bei dieser Studie (FUGETTA) wurde die Wirksamkeit von leitliniengerecht angewendetem oralem Alitretinoin sowie dessen Einfluss auf die Lebensqualitat (LQ) bei Patienten mit schwerem refraktarem CHE beurteilt. PATIENTEN UND METHODEN: Multizentrische, offene, nichtinterventionelle Beobachtungsstudie, durchgefuhrt in Deutschland. Die Patienten wurden nach Ermessen ihres behandelnden Arztes mit Alitretinoin 10 mg oder 30 mg einmal taglich uber maximal 24 Wochen behandelt. Die Wirksamkeit wurde anhand des Physician Global Assessment (PGA) und des Dermatology Life Quality Index (DLQI) bewertet. Zudem wurden unerwunschte Ereignisse (UE) erfasst. ERGEBNISSE: Die Studienpopulation bestand aus 658 Patienten (30 mg: n = 581; 10 mg: n = 77). Bei Beobachtungsbeginn litten die meisten Patienten (83 %) gemabeta PGA an einem schweren CHE. Bei Beobachtungsende war das Handekzem bei 48 % der Patienten gemabeta PGA vollstandig oder fast vollstandig abgeheilt (30 mg: 49 %; 10 mg: 43 %). Die mittlere Verbesserung des DLQI-Scores in Woche 24 betrug 58 % (30 mg: mittlere [SD] Veranderung gegenuber dem Ausgangswert -10,4 [8,04]) und 70 % (10 mg: mittlere [SD] Veranderung gegenuber dem Ausgangswert -10,8 [7,29]). Die Gesamtinzidenz von NW war niedrig und in den beiden Gruppen ahnlich. SCHLUSSFOLGERUNGEN: Alitretinoin fuhrte zu einer schnellen, deutlichen Verbesserung der LQ bei Patienten mit schwerem CHE. PMID- 27992128 TI - Kongresskalender 2016. PMID- 27992127 TI - Cutaneous B-cell lymphomas - pathogenesis, diagnostic workup, and therapy. AB - Cutaneous B-cell lymphomas (CBCLs) comprise a group of mature lymphoproliferative B-cell disorders that primarily affect the skin. Characterized by great biological and clinical variability among its various subtypes, CBCLs fundamentally differ from primary nodal or systemic B-cell lymphomas. Given their uncomplicated course and excellent prognosis, lymphoma classifications rank primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) as indolent CBCLs. By contrast, diffuse large B-cell lymphoma, leg type (DLBCL-LT) in particular, represent more aggressive lymphoma variants associated with a poorer prognosis. Therapeutic decisions and diagnostic procedures are based on the exact histological and immunohistochemical classification as well as the exclusion of systemic involvement and thus differentiation from nodal and systemic lymphomas. In this context, the diagnostic workup should also include molecular biology methods. Primary therapeutic options for indolent CBCL lesions include surgery and radiation therapy, as well as systemic treatment with rituximab (anti-CD20 antibody) in case of dissemination. More aggressive CBCLs usually require a combination of rituximab and polychemotherapy, primarily the CHOP regimen or modifications thereof. Given that the pathogenesis and biology of CBCLs has not been conclusively elucidated, and given the limited therapeutic armamentarium available, there is great need for comprehensive research, especially with respect to DLBCL-LT. PMID- 27992129 TI - Arbeitsbedingte Synkanzerogenese an der Haut - Zur kombinatorischen Einwirkung zweier Karzinogene der Berufskrankheiten-Liste. AB - HINTERGRUND: Die Synkanzerogenese am Hautorgan, wissenschaftlich unstrittig, spiegelt sich im monokausal geleiteten Berufskrankheiten (BK)-Recht nicht wider. Nichtmelanozytare Hauttumoren und deren Vorlauferlasionen konnen nur nach Einzelprufung der BK-Nrn. 5103 und 5102 anerkannt werden. METHODIK: Retrospektive Auswertung von 28 zwischen September 2012 und September 2015 begutachteten Fallen (Altersmedian 72,5 J.) mit nichtmelanozytaren Hauttumoren und deren Vorlauferlasionen und arbeitsbedingter Exposition gegenuber naturlicher UV Strahlung und polyzyklischen aromatischen Kohlenwasserstoffen. ERGEBNISSE: In allen 28 Fallen sahen wir die arbeitstechnischen Voraussetzungen nach den BK-Nrn. 5103 und 5102 als erfullt an. In 26 Fallen (93 %) empfahlen wir die Hautkrebserkrankung als BK-Tatbestand nach den Nrn. 5103 und 5102 anzuerkennen. Dem folgte der Unfallversicherungstrager in vier Fallen. Achtmal wurde die Anerkennung nur nach BK-Nr. 5103, zehnmal nur nach BK-Nr. 5102 und viermal gar nicht ausgesprochen. SCHLUSSFOLGERUNGEN: Bei nichtmelanozytaren Hauttumoren oder deren Vorlauferlasionen an UV-exponierten Hautarealen mit ausreichend kumulativer arbeitsbedingter naturlicher UV-Strahlenexposition und bei arbeitsbedingter Exposition gegenuber polyzyklischen aromatischen Kohlenwasserstoffen sollten mittels BK-Anzeige die "BK-Nrn. 5103 und 5102 im Sinne der Synkanzerogenese" gemeldet werden. Neben der gerechteren Wiedergabe der Arbeitsplatzrealitaten in einem solchen Feststellungsverfahren kann es dann im Konkreten auch zur Anerkennung von Basalzellkarzinomen kommen, die ansonsten, bei alleiniger Prufung der BK-Nr. 5103, herausgerechnet wurden. PMID- 27992130 TI - Unilaterale lineare Dermatose. PMID- 27992132 TI - Successful treatment of a boy with hyperplastic granulomatous gingivitis using fumaric acid esters. PMID- 27992131 TI - Exanthematisch aufgetretene kutane Metastasen eines Urothelkarzinoms bei einem 69 jahrigen Patienten. PMID- 27992133 TI - OEGDV Scholarship - Permanent Training Course on STIs 7.06-10.06.2016 in Bertinoro. PMID- 27992135 TI - Zwei Bruder mit Papillomatosis confluens et reticularis. PMID- 27992134 TI - Compression therapy - current practice of care: level of knowledge in patients with venous leg ulcers. AB - BACKGROUND AND OBJECTIVES: Compression therapy is a mainstay in the causal treatment of patients with venous leg ulcers. It facilitates healing, reduces pain and recurrences, and increases quality of life. Up until now, there is a scarcity of scientific data with respect to the level of care and the specific knowledge of patients with venous leg ulcers. PATIENTS AND METHODS: At first presentation, patients with venous leg ulcers anonymously answered a standardized questionnaire. Participating facilities nationwide included 55 outpatient care services, 32 medical practices, four wound centers, and one specialized care center. RESULTS: Overall, 177 patients (mean age of 69.4; 75.1 % women) participated in the study. The average duration of florid venous leg ulcers was 17 months. With regard to compression therapy, 31.1 % of patients received none; 40.1 % used bandages; 28.8 % used stockings. Of the latter, 13.7 % were treated with compression class III; 67.4 %, with compression class II; and 19.6 %; with compression class I. While 70.6 % put on their stockings after getting out of bed in the morning, 21.1 % wore them day and night. In 39.2 % of individuals, the stockings caused them discomfort. Merely 11.7 % owned a donning device. On average, bandages were worn for 40.7 weeks, and 69 % were used without underpadding. In 2.8 % of patients, ankle and calf circumference was measured to monitor therapeutic success. 45.9 % reported doing leg exercises. CONCLUSIONS: Although it is considered a basic therapeutic measure in venous leg ulcers, one third of all patients received no compression treatment. Moreover, given the long duration of ulcers, adequate product selection and correct use have to be questioned, too. Our findings indicate that improvements in the level of knowledge among users and prescribers as well as patient training are required. PMID- 27992137 TI - Erfolgreiche Therapie eines Jungen mit hyperplastischer und granulomatoser Gingivitis unter Verwendung von Fumarsaureestern. PMID- 27992136 TI - Haufigkeit und Einteilung kutaner Manifestationen bei rheumatoider Arthritis. AB - HINTERGRUND UND FRAGESTELLUNG: Hautveranderungen bei rheumatoider Arthritis (RA) sind nur in wenigen Studien an grobetaeren Patientenkollektiven untersucht. Deshalb sollen hier die aktuelle Pravalenz und das Spektrum an Hautveranderungen bei RA unter Berucksichtigung von Krankheitsaktivitats-Scores, Anti-CCP Antikorpern sowie neueren medikamentosen Therapien erfasst werden. PATIENTEN UND METHODIK: Zwischen November 2006 und Juli 2007 wurden prospektiv 214 Patienten, die im Funktionsbereich Rheumatologie mit RA behandelt wurden, erfasst. ERGEBNISSE: Bei 27,5 % der Untersuchten wurden RA-assoziierte Hautveranderungen beobachtet, wobei es sich fast ausschliebetalich um Rheumaknoten handelte. Signifikant gehauft traten Rheumaknoten bei langerer Erkrankungsdauer, Nachweis von Rheumafaktoren und Anti-CCP-Antikorpern, aber auch unter Gabe von Leflunomid und TNFalpha-Blockern auf. Vergleichsweise niedrige Pravalenzen wurden hingegen fur die "palisadenformige neutrophile und granulomatose Dermatitis" und die "rheumatoide Vaskulitis" ermittelt. SCHLUSSFOLGERUNGEN: Trotz zunehmend fruhzeitiger Therapie der RA und dem Einsatz neuerer Medikamente ist die Pravalenz von Rheumaknoten als wichtigste Manifestation der RA am Hautorgan hoch. Deren verstarkte Ausbildung unter Leflunomid und TNFalpha-Blockern konnte ein Hinweis dafur sein, dass bei der Entstehung von Rheumaknoten eine pathogenetische Wegstrecke eine Rolle spielt, die von den Therapeutika nur unzureichend beeinflusst wird. Hingegen scheinen die palisadenformige neutrophile und granulomatose Dermatitis und die "rheumatoide Vaskulitis" durch neuere Medikamente besser beeinflussbar zu sein. PMID- 27992138 TI - Azelainsaure 20 % Creme: Auswirkung auf Lebensqualitat und Krankheitsaktivitat bei erwachsenen Patientinnen mit Acne vulgaris. AB - HINTERGRUND: Zur Wirksamkeit von Aknetherapien und deren Auswirkungen auf die Lebensqualitat erwachsener Patienten liegen kaum Daten vor. ZIEL: Erhebung der Wirkung von Azelainsaure 20 % Creme (Skinoren(r) ) auf Akne-Schweregrad und krankheitsbedingte Lebensqualitat. PATIENTEN UND METHODIK: Nichtinterventionelle Studie bei erwachsenen Patientinnen mit leichter bis mittelschwerer Akne. Wirksamkeitsparameter waren DLQI sowie Akne-Schweregrad im Gesicht, am Dekollete sowie am Rucken im Gesamturteil des Prufarztes (IGA-Skala: Grad 1 = annahernd reine Haut; 2 = leichte Akne; 3 = mittelschwere Akne). Visiten waren zu Studienbeginn sowie nach 4-8 und zwolf Wochen geplant. ERGEBNISSE: Von den 251 eingeschlossenen Patientinnen lag zu Studienbeginn bei 59 %, 31 % bzw. 10 % ein IGA-Grad von 1, 2 bzw. 3 vor; die am haufigsten betroffene Hautpartie war das Gesicht (IGA-Grad 2 oder 3: 79 %). Nach zwolf Behandlungswochen war eine signifikante Besserung der Acne vulgaris im Gesicht (IGA-Grad 0 oder 1: 82 %) sowie auf Dekollete und Rucken feststellbar. Der mediane DLQI-Wert sank von neun zu Studienbeginn auf funf nach zwolf Behandlungswochen. Neunzig Prozent der behandelnden Arzte und Patientinnen beurteilten die Vertraglichkeit der Behandlung als sehr gut oder gut. SCHLUSSFOLGERUNGEN: Die Anwendung von 20%iger Azelainsaure-Creme fuhrt bei erwachsenen Frauen zu einer signifikanten Besserung der Acne vulgaris und der krankheitsbedingten Lebensqualitat. PMID- 27992139 TI - B-Zell-Lymphome der Haut - Pathogenese, Diagnostik und Therapie. AB - Primar kutane B-Zell-Lymphome (PCBCL) beschreiben reifzellige lymphoproliferative Erkrankungen der B-Zell-Reihe, die primar die Haut betreffen. Die Biologie und der klinische Verlauf der einzelnen PCBCL-Subtypen variieren untereinander stark und unterscheiden sich grundsatzlich von primar nodalen und systemischen B-Zell Lymphomen. Primar kutane Marginalzonenlymphome (PCMZL) und primare kutane follikulare Keimzentrumslymphome (PCFCL) werden auf Grund ihres unkomplizierten Verlaufs und ihrer exzellenten Prognose zu den indolenten PCBCL gezahlt. Demgegenuber stellen die diffus grobetazelligen B-Zell-Lymphome, hauptsachlich vom Beintyp (DLBCL, LT) die aggressiveren PCBCL-Varianten mit schlechterer Prognose dar. Fur die Ausbreitungsdiagnostik und die Therapieentscheidung sind eine genaue histologische und immunhistochemische Klassifizierung sowie der Ausschluss einer systemischen Beteiligung in Abgrenzung zu nodalen oder systemischen Lymphomen notwendig. Die Diagnostik sollte dabei durch molekularbiologische Untersuchungen unterstutzt werden. Therapeutisch stehen fur die indolenten PCBCL primar operative und radioonkologische Mabetanahmen im Vordergrund sowie eine Systemtherapie mit dem CD20-Antikorper Rituximab bei disseminiertem Befall. Die aggressiveren Varianten sollten in erster Linie mit Kombinationen aus Rituximab und Polychemotherapieschemata wie z. B. dem CHOP Schema oder Modifikationen davon behandelt werden. Auf Grund der in allen seinen Einzelheiten noch nicht vollstandig verstandenen Pathogenese und Biologie sowie des begrenzten Therapiespektrums der PCBCL besteht hier, speziell beim DLBCL, LT, noch erheblicher Forschungsbedarf. PMID- 27992141 TI - Haut und Rheuma. PMID- 27992142 TI - Unilateral linear dermatosis. PMID- 27992140 TI - Impact on quality of life of alitretinoin in severe chronic hand eczema: FUGETTA real-world study. AB - BACKGROUND AND OBJECTIVES: Alitretinoin is the only approved treatment for severe chronic hand eczema (CHE) refractory to potent topical corticosteroids. This study (FUGETTA) evaluated the effectiveness and impact on quality of life (QoL) of oral alitretinoin in patients with severe refractory CHE in accordance with prescription guidelines. PATIENTS AND METHODS: Open-label, multicenter, noninterventional, observational study conducted in Germany. Patients were treated at their physician's discretion with once-daily alitretinoin 10 mg or 30 mg for a maximum of 24 weeks. Effectiveness was assessed by Physician Global Assessment (PGA) and Dermatology Life Quality Index (DLQI). Adverse events (AEs) were assessed. RESULTS: The study population included 658 patients (30 mg n = 581; 10 mg n = 77). At baseline, most patients had CHE characterized as severe by PGA (83 %). At last visit, 48 % of patients had a PGA response of clear/almost clear (30 mg: 49 %; 10 mg: 43 %). Mean improvement in DLQI scores at week 24 was 58 % (30 mg: mean [SD] change from baseline -10.4 [8.04]) and 70 % (10 mg: mean [SD] change from baseline -10.8 [7.29]). The overall incidence of AEs was low and similar in both groups. CONCLUSIONS: Alitretinoin produced rapid, marked improvement in QoL of patients with severe CHE. PMID- 27992144 TI - Slowly progressive abdominal skin lesion of 15 years' duration. PMID- 27992145 TI - Exanthematous cutaneous spread of metastatic urothelial carcinoma in a 69-year old man. PMID- 27992143 TI - Kompressionstherapie - Versorgungspraxis: Informationsstand von Patienten mit Ulcus cruris venosum. AB - HINTERGRUND UND ZIELE: Eine Saule der kausalen Therapie bei Patienten mit Ulcus cruris venosum ist die Kompressionstherapie. Sie unterstutzt die Abheilung, reduziert Schmerzen und Rezidive und steigert die Lebensqualitat. Bislang existieren kaum wissenschaftliche Daten zu dem Versorgungsstand und fachspezifischem Wissen von Patienten mit Ulcus cruris venosum. PATIENTEN UND METHODIK: Standardisierte Fragebogen wurden bundesweit in 55 Pflegediensten, 32 Arztpraxen, vier Wundzentren und -sprechstunden sowie einem Pflegetherapiestutzpunkt von Patienten mit Ulcus cruris venosum bei Erstvorstellung anonym ausgefullt. ERGEBNISSE: Insgesamt nahmen 177 Patienten (Durchschnittsalter 69,4 Jahre; 75,1 % Frauen) teil. Ein florides Ulcus cruris venosum bestand im Mittel 17 Monate. 31,1 % hatten keine Kompressionstherapie, 40,1 % Binden und 28,8 % Strumpfe. Bei der Bestrumpfung hatten 13,7 % Kompressionsklasse III, 64,7 % Kompressionsklasse II und 19,6 % Kompressionsklasse I. 70,6 % legten die Strumpfe nach dem Aufstehen an, 21,1 % trugen sie Tag und Nacht. 39,2 % bereiteten die Strumpfe Beschwerden. Lediglich 11,7 % hatten eine An- und Ausziehhilfe. Die Binden wurden im Mittel 40,7 Wochen getragen und bei 69 % nicht unterpolstert. Bei 2,8 % wurde der Knochel- und Waden Umfang zur Erfolgskontrolle gemessen. Venensport machten 45,9 %. SCHLUSSFOLGERUNGEN: Ein Drittel hatte keine Kompressionsversorgung, obwohl diese eine Basismabetanahme der Therapie des Ulcus cruris venosum ist. Zudem ist deren korrekte Auswahl und Anwendung angesichts der langen Bestandsdauer der Ulzerationen zu hinterfragen. Weiterfuhrende Fachkenntnisse bei Anwendern und Verordnern sowie Patientenschulungen sind erforderlich. PMID- 27992146 TI - Eosinophile Pneumonie als Komplikation einer mit Dapson therapierten linearen IgA Dermatose. PMID- 27992148 TI - Deutscher Psoriasis-Preis 2016 wurde an Prof. Dr. Jorg Prinz (Munchen) vergeben. PMID- 27992147 TI - Keim oder kein Keim: Herausforderungen bei der Diagnose mykobakterieller Infektionen der Haut. AB - Kutane Mykobakteriosen sind in Deutschland selten. Dennoch ist es fur eine fruhzeitige Diagnose und anschliebetaende wirksame Behandlung erforderlich, dass diese Krankheitsbilder im arztlichen Bewusstsein verankert sind. Daruber hinaus stehen Infektionen mit Mykobakterien auf der Liste der Differentialdiagnosen vieler Hautkrankheiten. Diagnosen kutaner Mykobakteriosen beruhen auf klinischen Merkmalen und auf Laboruntersuchungen, einschliebetalich bakterieller Kulturen, histopathologischer Untersuchungen und PCR-basierten Verfahren. Das Wissen um Moglichkeiten und Grenzen dieser Laboruntersuchungen ist von zentraler Bedeutung, um eine angemessene klinische Entscheidung zu treffen. In diesem Beitrag diskutieren wir die aktuellen diagnostischen Moglichkeiten, die in Verdachtsfallen kutaner Mykobakteriosen zur Verfugung stehen. PMID- 27992149 TI - Verantwortlicher Umgang mit Antibiotika: Notwendigkeit der Antibiotikareduktion in der Aknetherapie. AB - Der ubermabetaige oder unkritische weltweite Einsatz von Antibiotika in der Medizin hat die Ausbreitung von Antibiotikaresistenzen beschleunigt. In einigen Bereichen sind viele Antibiotika bei bakteriellen Infektionen, die zuvor noch gut auf antibakterielle Wirkstoffe reagierten, mittlerweile wirkungslos geworden. Dermatologen/Venerologen setzten orale und topische Antibiotika bei der Behandlung von Acne vulgaris routinemabetaig ein, obwohl Akne weder eine infektiose Erkrankung ist noch alleine durch das Propionibacterium getriggert wird. Vielmehr ist sie eine komplexe, chronische entzundliche Hauterkrankung, die durch verschiedene pathogenetische Faktoren wie follikulare Hyperkeratose, erhohter Sebumproduktion, bakterielle Proliferation und Entzundung zustande kommt. Folglich sollte eine erfolgreiche Therapie auf die Bekampfung verschiedener pathogenetischer Faktoren und nicht nur auf die von Propionibacterium acnes abzielen. Daher wurden topische Retinoide und Benzoylperoxid als Mittel der ersten Wahl definiert. Monotherapien mit lokalen Antibiotika sollten insgesamt vermieden werden. Systemische Antibiotika der Tetrazyklin-Gruppe haben bei bestimmen Krankheitsstadien ihren Sinn, ihre Wirkung konnte aber eher auf der antientzundlichen als auf der antibiotischen Reaktion beruhen. Gesundheitsbehorden ermahnen alle Gesundheitsdienstleister, den Einsatz von Antibiotika einzuschranken. Das Nutzen-Risiko-Verhaltnis muss bei der Entscheidung fur oder gegen eine antibiotische Therapie bei einem einzelnen Patienten immer auch in Bezug auf das offentliche Interesse am Erhalt der Wirksamkeit von Antibiotika abgewogen werden. Im Folgenden werden das aktuelle Krankheitskonzept zu Acne vulgaris und die sich daraus ableitenden Konsequenzen fur den Einsatz von Antibiotika vorgestellt. PMID- 27992150 TI - Multiple aktinische Keratosen durch berufliche UV-Exposition auf dem Boden einer Porokeratosis superficialis disseminata actinica (Chernosky-Freeman). PMID- 27992151 TI - Early Impacts of the Affordable Care Act on Health Insurance Coverage in Medicaid Expansion and Non-Expansion States. AB - The Affordable Care Act (ACA) aimed to achieve nearly universal health insurance coverage in the United States through a combination of insurance market reforms, mandates, subsidies, health insurance exchanges, and Medicaid expansions, most of which took effect in 2014. This paper estimates the causal effects of the ACA on health insurance coverage in 2014 using data from the American Community Survey. We utilize difference-in-difference-in-differences models that exploit cross sectional variation in the intensity of treatment arising from state participation in the Medicaid expansion and local area pre-ACA uninsured rates. This strategy allows us to identify the effects of the ACA in both Medicaid expansion and non-expansion states. Our preferred specification suggests that, at the average pre-treatment uninsured rate, the full ACA increased the proportion of residents with insurance by 5.9 percentage points compared to 2.8 percentage points in states that did not expand Medicaid. Private insurance expansions from the ACA were due to increases in both employer-provided and non-group coverage. The coverage gains from the full ACA were largest for those without a college degree, non-whites, young adults, unmarried individuals, and those without children in the home. We find no evidence that the Medicaid expansion crowded out private coverage. PMID- 27992152 TI - The Effect of the Affordable Care Act Medicaid Expansion on Migration. AB - The expansion of Medicaid to low-income nondisabled adults is a key component of the Affordable Care Act's strategy to increase health insurance coverage, but many states have chosen not to take up the expansion. As a result, for many low income adults, there has been stark variation across states in access to Medicaid since the expansions took effect in 2014. This study investigates whether individuals migrate in order to gain access to these benefits. Using an empirical model in the spirit of a difference-in-differences, this study finds that migration from non-expansion states to expansion states did not increase in 2014 relative to migration in the reverse direction. The estimates are sufficiently precise to rule out a migration effect that would meaningfully affect the number of enrollees in expansion states, which suggests that Medicaid expansion decisions do not impose a meaningful fiscal externality on other states. PMID- 27992153 TI - Federal Employees Health Benefits and Federal Employees Dental and Vision Insurance Programs' Coverage Exception for Children of Same-Sex Domestic Partners. Interim final rule. AB - This action amends the rule to create a regulatory exception that allows children of same-sex domestic partners living overseas to maintain their Federal Employees Health Benefits (FEHB) and Federal Employees Dental and Vision Program (FEDVIP) coverage until September 30, 2018. Due to a recent Supreme Court decision, as of January 1, 2016, coverage of children of same-sex domestic partners under the FEHB Program and FEDVIP will generally only be allowed if the couple is married, as discussed in Benefits Administration Letter (BAL) 15-207 dated October 5, 2015. OPM recognizes there are additional requirements placed on overseas federal employees that may not apply to other civilian employees with duty stations in the United States making it difficult to travel to the United States to marry same-sex partners. PMID- 27992154 TI - Revised Medical Criteria for Evaluating Human Immunodeficiency Virus (HIV) Infection and for Evaluating Functional Limitations in Immune System Disorders. Final rule. AB - We are revising the criteria in the Listing of Impairments (listings) that we use to evaluate claims involving human immunodeficiency virus (HIV) infection in adults and children under titles II and XVI of the Social Security Act (Act). We also are revising the introductory text of the listings that we use to evaluate functional limitations resulting from immune system disorders. The revisions reflect our program experience, advances in medical knowledge, our adjudicative experience, recommendations from a commissioned report, and comments from medical experts and the public. PMID- 27992155 TI - Medical Devices; Neurological Devices; Classification of the Computerized Cognitive Assessment Aid for Concussion. Final order. AB - The Food and Drug Administration (FDA) is classifying the Computerized Cognitive Assessment Aid for Concussion into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the computerized cognitive assessment aid for concussion's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 27992156 TI - Extension of Pharmacy Copayments for Medications. Interim final rule. AB - The Department of Veterans Affairs (VA) amends its medical regulations concerning the copayment required for certain medications. This rulemaking freezes copayments at the current rate for veterans in priority groups 2 through 8 through February 26, 2017. PMID- 27992157 TI - Medicare and State Health Care Programs: Fraud and Abuse; Revisions to the Office of Inspector General's Civil Monetary Penalty Rules. Final rule. AB - This final rule amends the civil monetary penalty (CMP or penalty) rules of the Office of Inspector General to incorporate new CMP authorities, clarify existing authorities, and reorganize regulations on civil money penalties, assessments, and exclusions to improve readability and clarity. PMID- 27992158 TI - Medicare and State Health Care Programs: Fraud and Abuse; Revisions to the Safe Harbors Under the Anti-Kickback Statute and Civil Monetary Penalty Rules Regarding Beneficiary Inducements. Final rule. AB - In this final rule, OIG amends the safe harbors to the anti-kickback statute by adding new safe harbors that protect certain payment practices and business arrangements from sanctions under the anti-kickback statute. The OIG also amends the civil monetary penalty (CMP) rules by codifying revisions to the definition of "remuneration," added by the Balanced Budget Act (BBA) of 1997 and the Patient Protection and Affordable Care Act, Public Law 111-148, 124 Stat. 119 (2010), as amended by the Health Care and Education Reconciliation Act of 2010 (ACA). This rule updates the existing safe harbor regulations and enhances flexibility for providers and others to engage in health care business arrangements to improve efficiency and access to quality care while protecting programs and patients from fraud and abuse. PMID- 27992159 TI - A Nontargeted UHPLC-HRMS Metabolomics Pipeline for Metabolite Identification: Application to Cardiac Remote Ischemic Preconditioning. AB - In recent years, the number of investigations based on nontargeted metabolomics has increased, although often without a thorough assessment of analytical strategies applied to acquire data. Following published guidelines for metabolomics experiments, we report a validated nontargeted metabolomics strategy with pipeline for unequivocal identification of metabolites using the MSMLS molecule library. We achieved an in-house database containing accurate m/z values, retention times, isotopic patterns, full MS, and MS/MS spectra. A UHPLC HRMS Q-Exactive method was developed, and experimental variations were determined within and between 3 experimental days. The extraction efficiency as well as the accuracy, precision, repeatability, and linearity of the method were assessed, the method demonstrating good performances. The methodology was further blindly applied to plasma from remote ischemic pre-conditioning (RIPC) rats. Samples, previously analyzed by targeted metabolomics using completely different protocol, analytical strategy, and platform, were submitted to our analytical pipeline. A combination of multivariate and univariate statistical analyses was employed. Selection of putative biomarkers from OPLS-DA model and S-plot was combined to jack-knife confidence intervals, metabolites' VIP values, and univariate statistics. Only variables with strong model contribution and highly statistical reliability were selected as discriminated metabolites. Three biomarkers identified by the previous targeted metabolomics study were found in the current work, in addition to three novel metabolites, emphasizing the efficiency of the current methodology and its ability to identify new biomarkers of clinical interest, in a single sequence. The biomarkers were identified to level 1 according to the metabolomics standard initiative and confirmed by both RPLC and HILIC-HRMS. PMID- 27992160 TI - Compositionally Dependent Nonlinear Optical Bandgap Behavior of Mixed Anodic Oxides in Niobium-Titanium System. AB - Optical bandgap mapping of Nb-Ti mixed oxides anodically grown on a thin film parent metallic combinatorial library was performed via variable angle spectroscopic ellipsometry (VASE). A wide Nb-Ti compositional spread ranging from Nb-90 at.% Ti to Nb-15 at.% Ti deposited by cosputtering was used for this purpose. The Nb-Ti library was stepwise anodized at potentials up to 10 V SHE, and the anodic oxides optical properties were mapped along the Nb-Ti library with 2 at.% resolution. The surface dissimilarities along the Nb-Ti compositional gradient were minimized by tuning the deposition parameters, thus allowing a description of the mixed Nb-Ti oxides based on a single Tauc-Lorentz oscillator for data fitting. Mapping of the Nb-Ti oxides optical bandgap along the entire compositional spread showed a clear deviation from the linear model based on mixing individual Nb and Ti electronegativities proportional to their atomic fractions. This is attributed to the strong amorphization and an in-depth compositional gradient of the mixed oxides. A systematic optical bandgap decrease toward values as low as 2.0 eV was identified at approximately 50 at.% Nb. Mixing of Nb2O5 and TiO2 with both amorphous and crystalline phases is concluded, whereas the possibility of complex NbaTibOy oxide formation during anodization is unlikely. PMID- 27992161 TI - Thermodynamic Ground States of Complex Oxide Heterointerfaces. AB - The formation mechanism of 2-dimensional electron gases (2DEGs) at heterointerfaces between nominally insulating oxides is addressed with a thermodynamical approach. We provide a comprehensive analysis of the thermodynamic ground states of various 2DEG systems directly probed in high temperature equilibrium conductivity measurements. We unambiguously identify two distinct classes of oxide heterostructures: For epitaxial perovskite/perovskite heterointerfaces (LaAlO3/SrTiO3, NdGaO3/SrTiO3, and (La,Sr)(Al,Ta)O3/SrTiO3), we find the 2DEG formation being based on charge transfer into the interface, stabilized by the electric field in the space charge region. In contrast, for amorphous LaAlO3/SrTiO3 and epitaxial gamma-Al2O3/SrTiO3 heterostructures, the 2DEG formation mainly relies on the formation and accumulation of oxygen vacancies. This class of 2DEG structures exhibits an unstable interface reconstruction associated with a quenched nonequilibrium state. PMID- 27992162 TI - Evaluation of the Optimum Composition of Low-Temperature Fuel Cell Electrocatalysts for Methanol Oxidation by Combinatorial Screening. AB - Combinatorial chemistry and high-throughput screening represent an innovative and rapid tool to prepare and evaluate a large number of new materials, saving time and expense for research and development. Considering that the activity and selectivity of catalysts depend on complex kinetic phenomena, making their development largely empirical in practice, they are prime candidates for combinatorial discovery and optimization. This review presents an overview of recent results of combinatorial screening of low-temperature fuel cell electrocatalysts for methanol oxidation. Optimum catalyst compositions obtained by combinatorial screening were compared with those of bulk catalysts, and the effect of the library geometry on the screening of catalyst composition is highlighted. PMID- 27992163 TI - Oxide-Based Solar Cell: Impact of Layer Thicknesses on the Device Performance. AB - A ZnO/Cu2O-based combinatorial heterojunction device library was successfully fabricated by a simple spray pyrolysis technique using ITO-coated glass as the substrate. The combinatorial approach was introduced to analyze the impact of the ZnO and Cu2O layer thicknesses on the performance of the solar cells. The thickness of the ZnO layer was varied from ~50 to 320 nm, and the Cu2O layer was deposited orthogonal to the ZnO thickness gradient. In the case of Cu2O, the thickness varied from ~200 to 800 nm. The photovoltaic performance of the cells is strongly dependent on the absorber layer thickness for a particular window layer thickness and reaches a maximum short-circuit current density of 3.9 mA/cm2 when the absorber layer thickness just crosses ~700 nm. Reducing the thicknesses of the active layers leads to a sharp decrease in the device performance. It is shown that the entire built-in bias of the heterojunction is created in the absorber layer due to low carrier density. The poor performance of the devices having lower thicknesses is attributed to different interfacial phenomena such as optical losses due to the thin Cu2O layer, back-contact recombination of the carriers due to the low layer thickness because a minimum heterojunction thickness is required for the formation of the full built-in bias that slows down the recombination of the carriers, and other factors. PMID- 27992164 TI - Influence of Graphene Reduction and Polymer Cross-Linking on Improving the Interfacial Properties of Multilayer Thin Films. AB - Graphene is a versatile composite reinforcement candidate due to its strong mechanical, tunable electrical and optical properties, and chemical stability. However, one drawback is the weak interfacial bonding, which results in weak adhesion to substrates. This could be overcome by adding polymer layers to have stronger adherence to the substrate and between graphene sheets. These multilayer thin films were found to have lower resistance to lateral scratch forces when compared to other reinforcements such as polymer/clay nanocomposites. Two additional processing steps are suggested to improve the scratch resistance of these films: graphene reduction and polymer cross-linking. Graphene/polymer nanocomposites consisting of polyvinylamine (PVAm) and graphene oxide (GO) were fabricated using the layer-by-layer assembly (LbL) technique. The reduced elastic modulus and hardness of PVAm/GO films were measured using nanoindentation. Reducing GO enhances mechanical properties by 60-70% while polymer cross-linking maintains this enhancement. Both graphene reduction and polymer cross-linking show significant improvement to scratch resistance. Particularly, polymer cross linking leads to films with higher elastic recovery, 50% lower adhesive and plowing friction coefficient, 140 and 50% higher adhesive and shear strength values, respectively, and lower material pileup and scratch width/depth. PMID- 27992165 TI - Pd-Cu-M (M = Y, Ti, Zr, V, Nb, and Ni) Alloys for the Hydrogen Separation Membrane. AB - Self-supported fcc Pd-Cu-M (M = Y, Ti, Zr, V, Nb, and Ni) alloys were studied as potential hydrogen purification membranes. The effects of small additions (1-2.6 at. %) of these elements on the structure, hydrogen solubility, diffusivity, and permeability were examined. Structural analyses by X-ray diffraction (XRD) showed the fcc phase for all alloys with induced textures from cold rolling. Heat treatment at 650 degrees C for 96 h led to the reorientation in all alloys except the Pd-Cu-Zr alloy, exhibiting the possibility to enhance the structural stability by Zr addition. Hydrogen solubility was almost doubled in the ternary alloys containing Y and Zr compared to Pd65.1Cu34.9 alloy at 300 degrees C. It was noted that hydrogen diffusivity is decreased upon additions of these elements compared to the Pd65.1Cu34.9 alloy, with the Pd-Cu-Zr alloy showing the lowest hydrogen diffusivity. However, the comparable hydrogen permeability of the Pd-Cu Zr alloy with the corresponding binary alloy, as well as its highest hydrogen permeability among the studied ternary alloys at temperatures higher than 300 degrees C, suggested that hydrogen permeation of these alloys within the fcc phase is mainly dominated by hydrogen solubility. Hydrogen flux variations of all ternary alloys were studied and compared with the Pd65.1Cu34.9 alloy under 1000 ppm of H2S + H2 feed gas. Pd-Cu-Zr alloy showed superior resistance to the sulfur poisoning probably due to the less favorable H2S-surface interaction and more importantly slower rate of bulk sulfidation as a result of improved structural stability upon Zr addition. Therefore, Pd-Cu-Zr alloys may offer new potential hydrogen purification membranes with improved chemical stability and hydrogen permeation compared to the binary fcc Pd-Cu alloys. PMID- 27992166 TI - Identification of Isomeric Ephedrines by Cold Ion UV Spectroscopy: Toward Practical Implementation. AB - Ephedrine and pseudoephedrine are stimulant drugs whose use is prohibited in athletic competition by the World Anti-Doping Agency (WADA) at very different threshold doping violation concentrations. We use a recently developed universal approach that integrates UV photofragmentation spectroscopy of cold ions with Orbitrap mass spectrometry (MS) for highly selective and highly sensitive identification of these diastereomers. Both species can be selectively detected at a solution concentration of a few tens of ng/mL, which is almost 3 orders of magnitude lower than the threshold concentration required by WADA. Relative concentrations of the isomers in solutions have been determined with the standard deviation of 3.1%, when the ions were cooled in an ion trap maintained at T = 6 K. Considering practical implementation of the method, we evaluated its performance for a simplified instrumentation. At an affordable elevated temperature of ~70 K and with a low-maintenance midbandwidth optical parametric oscillator, a few second measurement should yield nearly the same selectivity and only ten times lower sensitivity than with the current research grade instrument. PMID- 27992167 TI - The Eye of the Medusa: XRF Imaging Reveals Unknown Traces of Antique Polychromy. AB - The colorful decoration of statues and buildings in antique times is commonly described by the term antique polychromy. It is well-known among scholars but less so to the general public, and its exact form is the subject of research. In this paper we discuss results obtained from the frieze of the Siphnian Treasury in the Sanctuary of Delphi (Greece). We will present the first application of a mobile instrument for macro-XRF imaging for the in situ investigation of antique polychromy and show that it allows one to identify significant traces not visible to the naked eye and not detectable by XRF spot measurements or any other mobile, noninvasive method. These findings allow for a partial reconstruction of the polychromy. Furthermore, we present a novel approach enabling the correct interpretation of artifacts resulting from changes of the detection geometry in the investigation of complexly shaped samples by XRF imaging. This approach is based on the 3D surface model acquired by photogrammetry and fundamental parameter calculations. PMID- 27992168 TI - Feasibility Study Exploring the Potential of Novel Battacin Lipopeptides as Antimicrobial Coatings. AB - Colonization of medical implant surfaces by pathogenic microorganisms causes implant failure and undermines their clinical applicability. Alarming increase in multidrug-resistant bacteria poses serious concerns with the use of medical implants. Antimicrobial peptides (AMPs) that form part of the innate immune system in all forms of life are attractive alternatives to conventional antibiotics to treat multidrug-resistant bacterial biofilms. The aim of this study was to assess the in vitro antibacterial potency of our recently discovered lipopeptides from the battacin family upon immobilization to various surfaces. To achieve this, glass, silicon, and titanium surfaces were functionalized through silanization followed by addition of the heterobifunctional cross-linker, succinimidyl-[N-maleimidopropionamido]-poly(ethylene glycol) ester to generate maleimide-functionalized surfaces. The lipopeptide, GZ3.27, with an added N terminal cysteine was covalently coupled to the surfaces via a thioether bond through a Michael-type addition between the cysteine sulfhydryl group and the maleimide moiety. Success of surface immobilization and antimicrobial activity of the coated surfaces was assessed using water contact angle measurements, X-ray photoelectron spectroscopy, ellipsometry, scanning electron microscopy, colony forming unit assays and biofilm analysis. The lipopeptide-coated surfaces caused significant damage to the cellular envelop of Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli) upon contact and prevented surface colonization by P. aeruginosa and E. coli biofilms. The lipopeptides investigated in this study were not hemolytic to mouse blood cells in solution. Findings from this study indicate that these lipopeptides have the potential to be developed as promising antimicrobial coatings on medical implants. PMID- 27992169 TI - Amine/Hydrido Bifunctional Nanoporous Silica with Small Metal Nanoparticles Made Onsite: Efficient Dehydrogenation Catalyst. AB - Multifunctional catalysts are of great interest in catalysis because their multiple types of catalytic or functional groups can cooperatively promote catalytic transformations better than their constituents do individually. Herein we report a new synthetic route involving the surface functionalization of nanoporous silica with a rationally designed and synthesized dihydrosilane (3 aminopropylmethylsilane) that leads to the introduction of catalytically active grafted organoamine as well as single metal atoms and ultrasmall Pd or Ag-doped Pd nanoparticles via on-site reduction of metal ions. The resulting nanomaterials serve as highly effective bifunctional dehydrogenative catalysts for generation of H2 from formic acid. PMID- 27992170 TI - Analysis of Methanol in the Presence of Ethanol, Using a Hybrid Capillary Electrophoresis Device with Electrochemical Derivatization and Conductivity Detection. AB - Concurrently with ethanol, many other compounds can be formed during the fermentation of grains and fruits. Among those, methanol is particularly important (because of its toxicity) and is typically formed at concentrations much lower than ethanol, presenting a particular challenge that demands the implementation of separation techniques. Aiming to provide an alternative to traditional chromatographic approaches, a hybrid electrophoresis device with electrochemical preprocessing and contactless conductivity detection (hybrid EC CE-C4D) is herein described. The device was applied to perform the electro oxidation of primary alcohols, followed by the separation and detection of the respective carboxylates. According to the presented results, the optimum conditions were obtained when the sample was diluted with 2 mmol L-1 HNO3 and then electro-oxidized by applying a potential of 1.4 V for 60 s. The oxidation products were then electrokinetically injected by applying a potential of 3 kV for 4 s and separated using a potential of 3 kV and a background running electrolyte (BGE) consisting of 10 mmol L-1 N-cyclohexyl-2-aminoethanesulfonic acid (CHES) and 5 mmol L-1 sodium hydroxide (NaOH). n-Propanol was used as an internal standard and the three carboxylate peaks were resolved with baseline separation within <3 min, defining linear calibration curves in the range of 0.10 5.0 mmol L-1. Limits of detection (LODs) of 20, 40, and 50 MUmol L-1 were obtained for ethanol, n-propanol, and methanol, respectively. To demonstrate the applicability of the proposed strategy, a laboratory-made sample (moonshine) was used. Aliquots collected along the beginning of the fractional distillation presented a decreasing methanol ratio (from 4% to <0.5%) and a growing ethanol ratio (from 80% to 100%) in the collected volume. PMID- 27992172 TI - Emissive Molecular Aggregates and Energy Migration in Luminescent Solar Concentrators. AB - Luminescent solar concentrators (LSCs) are light harvesting devices that are ideally suited to light collection in the urban environment where direct sunlight is often not available. LSCs consist of highly luminescent compounds embedded or coated on a transparent substrate that absorb diffuse or direct solar radiation over a large area. The resulting luminescence is trapped in the waveguide by total internal reflection to the thin edges of the substrate where the concentrated light can be used to improve the performance of photovoltaic devices. The concept of LSCs has been around for several decades, and yet the efficiencies of current devices are still below expectations for commercial viability. There are two primary challenges when designing new chromophores for LSC applications. Reabsorption of dye emission by chromophores within the waveguide is a significant loss mechanism attenuating the light output of LSCs. Concentration quenching, particularly in organic dye systems, restricts the quantity of chromophores that can be incorporated in the waveguide thus limiting the light absorbed by the LSC. Frequently, a compromise between increased light harvesting of the incident light and decreasing emission quantum yield is required for most organic chromophore-based systems due to concentration quenching. The low Stokes shift of common organic dyes used in current LSCs also imposes another optimization problem. Increasing light absorption of LSCs based on organic dyes to achieve efficient light harvesting also enhances reabsorption. Ideally, a design strategy to simultaneously optimize light harvesting, concentration quenching, and reabsorption of LSC chromophores is clearly needed to address the significant losses in LSCs. Over the past few years, research in our group has targeted novel dye structures that address these primary challenges. There is a common perception that dye aggregates are to be avoided in LSCs. It became apparent in our studies that aggregates of chromophores exhibiting aggregation-induced emission (AIE) behavior are attractive candidates for LSC applications. Strategic application of AIE chromophores has led to the development of the first organic-based transparent solar concentrator that harvests UV light as well as the demonstration of reabsorption reduction by taking advantage of energy migration processes between chromophores. Further developments led us to the application of perylene diimides using an energy migration/energy transfer approach. To prevent concentration quenching, a molecularly insulated perylene diimide with bulky substituents attached to the imide positions was designed and synthesized. By combining the insulated perylene diimide with a commercial perylene dye as an energy donor-acceptor emitter pair, detrimental luminescence reabsorption was reduced while achieving a high chromophore concentration for efficient light absorption. This Account reviews and reinspects some of our recent work and the improvements in the field of LSCs. PMID- 27992171 TI - Silica-Coated Metal Chelating-Melanin Nanoparticles as a Dual-Modal Contrast Enhancement Imaging and Therapeutic Agent. AB - Bioinspired melanin nanoparticle (Mel NP) synthesized with dopamine has been of great interest in various biomedical applications. However, the utilization of fascinating characters of Mel NP such as innate MR contrast effects, high affinity to metal ions, strong light absorption requires special design with strategic synthetic method for its own purpose. Here, we have introduced paramagnetic Gd3+ metal ions and silica nanocoating on Mel NP for the dual-modal MRI/fluorescent contrast-enhanced imaging and therapeutics. The Gd3+ chelating kinetics of Mel NP by quinone and hydroquinone residues were optimized in various conditions of Gd3+ amounts and pH in solution for improving MRI contrast enhancing properties of the Mel NP. Then, bioinert silica was coated on the surfaces of Gd-chelated Mel NP (Gd-Mel@SiO2 NP) with a modified sol-gel process. The silica nanocoating allowed increased outer sphere water diffusion time, resulting a significantly brighter MR T1 contrast effect of Gd-Mel@SiO2 NP, comparing with a bare Gd-Mel NP or clinical grade T1 contrast agent. Further, when the Gd-Mel@SiO2 NP was labeled with fluorescent molecules, a significantly enhanced fluorescent intensity was achieved by the silica nanocoating that preventing the innate fluorescent deactivation property of melanin. Finally, in vitro/in vivo dual-modal contrast enhanced MRI/fluorescent imaging and feasibility of image-guided cancer therapeutic applications using Gd-Mel@SiO2 NPs were successfully evaluated in a clinically relevant human prostate cancer xenograft mouse model. PMID- 27992173 TI - Fabrication of Slippery Lubricant-Infused Porous Surface with High Underwater Transparency for the Control of Marine Biofouling. AB - Marine optical instruments are bearing serious biofouling problem, which affects the accuracy of data collected. To solve the biofouling problem of marine optical instruments, a novel instance of slippery lubricant-infused porous surface (SLIPS) with high underwater-transparency was designed over glass substrate via infusing lubricant into its porous microstructure fabricated with hydrothermal method. The advantage of SLIPS as antibiofouling strategy to marine optical instruments was proven by comparing its underwater optical and antibiofouling performances with three kinds of samples (hydrophilic glass sample, textured hydrophilic glass sample, and superhydrophobic glass sample). The modification of SLIPS enhances the underwater-transparency of glass sample within the wavelength of 500-800 nm, for the infusion of lubricant with lower refractive index than glass substrate. In contrast with hydrophilic surface, textured hydrophilic surface and superhydrophobic surface, SLIPS can significantly inhibit bacterial and algal settlements, thereby maintaining high underwater-transparency in both dynamic and static seawater. The inhibition of bacterial and algal settlements over SLIPS results from its liquid-like property. The contact angle hysteresis of water over SLIPS increases with immersion time in seawater under different conditions (static, dynamic, and vibration conditions). Both dynamic and vibration conditions accelerate the failure of SLIPS exposed in seawater. This research provides valuable information for solving biofouling problem of marine optical instruments with SLIPS. PMID- 27992174 TI - Bottom-Up Electrochemical Fabrication of Conjugated Ultrathin Layers with Tailored Switchable Properties. AB - A bottom-up electrochemical process for fabricating conjugated ultrathin layers with tailored switchable properties is developed. Ultrathin layers of covalently grafted oligo(bisthienylbenzene) (oligo(BTB)) are used as switchable organic electrodes, and 3,4-ethylenedioxythiophene (EDOT) is oxidized on this layer. Adding only a few (less than 3) nanometers of EDOT moieties (5 to 6 units ) completely changes the switching properties of the layer without changing the surface concentration of the electroactive species. A range of new materials with tunable interfacial properties is created. They consist of oligo(BTB)-oligo(EDOT) diblock oligomers of various relative lengths covalently grafted onto the underlying electrode. These films retain reversible redox on/off switching and their switching potential can be finely tuned between +0.6 and -0.3 V/SCE while the overall thickness remains below 11 nm. PMID- 27992175 TI - Label-Free Electrochemical Biosensor for Monitoring of Chloride Ion in an Animal Model of Alzhemier's Disease. AB - The potential damage of Alzheimer's disease (AD) in brain function has attracted extensive attention. As the most common anion, Cl- has been indicated to play significant roles in brain diseases, particularly in the pathological process of AD. In this work, a label-free selective and accurate electrochemical biosensor was first developed for real-time monitoring of Cl- levels in a mouse brain model of AD and rat brain upon global cerebral ischemia. Silver nanoparticles (AgNPs) were designed and synthesized as selective recognition element for Cl-, while 5' MB-GGCGCGATTTT-SH-3' (SH-DNA-MB, MB = methylene blue) was selected as an inner reference molecule for a built-in correction to avoid the effects from the complicated brain. The electrochemical biosensor showed high accuracy and remarkable selectivity for determination of Cl- over other anions, metal ions, amino acids, and other biomolecules. Furthermore, three-dimensional nanostructures composed of single-walled carbon nanotubes (SWNTs) and Au nanoleaves were assembled on the carbon fiber microelectrode (CFME) surface to enhance the response signal. Finally, the developed biosensor with high analytical performance, as well as the unique characteristic of CFME itself including inertness in live brain and good biocompatibility, was successfully applied to in vivo determination of Cl- levels in three brain regions: striatum, hippocampus, and cortex of live mouse and rat brains. The comparison of average levels of Cl- in normal striatum, hippocampus, and cortex of normal mouse brains and those in the mouse model brains of AD was reported. In addition, the results in rat brains followed by cerebral ischemia demonstrated that the concentrations of Cl- decreased by 19.8 +/- 0.5% (n = 5) in the striatum and 27.2 +/- 0.3% (n = 5) in hippocampus after cerebral ischemia for 30 min, but that negligible change in Cl- concentration was observed in cortex. PMID- 27992177 TI - N,B-Bidentate Boryl Ligand-Supported Iridium Catalyst for Efficient Functional Group-Directed C-H Borylation. AB - Convenient silylborane precursors for introducing N,B-bidentate boryl ligands onto transition metals were designed, prepared, and employed in ready formation of irdium(III) complexes via Si-B oxidative addition. A practical, efficient catalytic ortho-borylation reaction of arenes with a broad range of directing groups was developed using an in situ generated catalyst from the silylborane preligand 3c and [IrCl(COD)]2. PMID- 27992178 TI - Crystal Structure and Thermoelectric Properties of the 7,7L Lillianite Homologue Pb6Bi2Se9. AB - Pb6Bi2Se9, the selenium analogue of heyrovsyite, crystallizes in the orthorhombic space group Cmcm (#63) with a = 4.257(1) A, b = 14.105(3) A, and c = 32.412(7) A at 300 K. Its crystal structure consists of two NaCl-type layers, A and B, with equal thickness, N1 = N2 = 7, where N is the number of edge-sharing [Pb/Bi]Se6 octahedra along the central diagonal. In the crystal structure, adjacent layers are arranged along the c-axis such that bridging bicapped trigonal prisms, PbSe8, are located on a pseudomirror plane parallel to (001). Therefore, Pb6Bi2Se9 corresponds to a 7,7L member of the lillianite homologous series. Electronic transport measurements indicate that the compound is a heavily doped narrow band gap n-type semiconductor, with electrical conductivity and thermopower values of 350 S/cm and -53 MUV/K at 300 K. Interestingly, the compound exhibits a moderately low thermal conductivity, ~1.1 W/mK, in the whole temperature range, owing to its complex crystal structure, which enables strong phonon scattering at the twin boundaries between adjacent NaCl-type layers A and B. The dimensionless figure of merit, ZT, increases with temperature to 0.25 at 673 K. PMID- 27992176 TI - Optical and Magnetic Resonance Imaging Using Fluorous Colloidal Nanoparticles. AB - Improved imaging of cancerous tissue has the potential to aid prognosis and improve patient outcome through longitudinal imaging of treatment response and disease progression. While nuclear imaging has made headway in cancer imaging, fluorinated tracers that enable magnetic resonance imaging (19F MRI) hold promise, particularly for repeated imaging sessions because nonionizing radiation is used. Fluorine MRI detects molecular signatures by imaging a fluorinated tracer and takes advantage of the spatial and anatomical resolution afforded by MRI. This manuscript describes a fluorous polymeric nanoparticle that is capable of 19F MR imaging and fluorescent tracking for in vitro and in vivo monitoring of immune cells and cancerous tissue. The fluorous particle is derived from low molecular-weight amphiphilic copolymers that self-assemble into micelles with a hydrodynamic diameter of 260 nm. The polymer is MR-active at concentrations as low as 2.1 mM in phantom imaging studies. The fluorinated particle demonstrated rapid uptake into immune cells for potential cell-tracking or delineation of the tumor microenvironment and showed negligible toxicity. Systemic administration indicates significant uptake into two tumor types, triple-negative breast cancer and ovarian cancer, with little accumulation in off-target tissue. These results indicate a robust platform imaging agent capable of immune cell tracking and systemic disease monitoring with exceptional uptake of the nanoparticle in multiple cancer models. PMID- 27992179 TI - Synchronized Offset Stacking: A Concept for Growing Large-Domain and Highly Crystalline 2D Covalent Organic Frameworks. AB - Covalent organic frameworks (COFs), formed by reversible condensation of rigid organic building blocks, are crystalline and porous materials of great potential for catalysis and organic electronics. Particularly with a view of organic electronics, achieving a maximum degree of crystallinity and large domain sizes while allowing for a tightly pi-stacked topology would be highly desirable. We present a design concept that uses the 3D geometry of the building blocks to generate a lattice of uniquely defined docking sites for the attachment of consecutive layers, thus allowing us to achieve a greatly improved degree of order within a given average number of attachment and detachment cycles during COF growth. Synchronization of the molecular geometry across several hundred nanometers promotes the growth of highly crystalline frameworks with unprecedented domain sizes. Spectroscopic data indicate considerable delocalization of excitations along the pi-stacked columns and the feasibility of donor-acceptor excitations across the imine bonds. The frameworks developed in this study can serve as a blueprint for the design of a broad range of tailor made 2D COFs with extended pi-conjugated building blocks for applications in photocatalysis and optoelectronics. PMID- 27992180 TI - Fast Diazaborine Formation of Semicarbazide Enables Facile Labeling of Bacterial Pathogens. AB - Bioorthogonal conjugation chemistry has enabled the development of tools for the interrogation of complex biological systems. Although a number of bioorthogonal reactions have been documented in literature, they are less ideal for one or several reasons including slow kinetics, low stability of the conjugated product, requirement of toxic catalysts, and side reactions with unintended biomolecules. Herein we report a fast (>103 M-1 s-1) and bioorthogonal conjugation reaction that joins semicarbazide to an aryl ketone or aldehyde with an ortho-boronic acid substituent. The boronic acid moiety greatly accelerates the initial formation of a semicarbazone conjugate, which rearranges into a stable diazaborine. The diazaborine formation can be performed in blood serum or cell lysates with minimal interference from biomolecules. We further demonstrate that application of this conjugation chemistry enables facile labeling of bacteria. A synthetic amino acid D-AB3, which presents a 2-acetylphenylboronic acid moiety as its side chain, was found to incorporate into several bacterial species through cell wall remodeling, with particularly high efficiency for Escherichia coli. Subsequent D AB3 conjugation to a fluorophore-labeled semicarbazide allows robust detection of this bacterial pathogen in blood serum. PMID- 27992181 TI - Multiparametric Assessment of Gold Nanoparticle Cytotoxicity in Cancerous and Healthy Cells: The Role of Size, Shape, and Surface Chemistry. AB - In recent years, we and others have become interested in evaluating the use of surface-enhanced Raman scattering (SERS) tags for early cancer detection and in designing new approaches to demonstrate the applicability of this spectroscopic technique in the clinic. SERS-based imaging in particular offers ultra sensitivity up to the single molecule, multiplexing capability, and increased photostability and has been shown to outperform fluorescence. However, to employ SERS tags for early cancer detection, it is important to understand their interaction with cells and determine their cytotoxicity. We have been particularly interested for quite some time in determining if and how gold nanostars, which have been demonstrated as outstanding SERS enhancing substrates, can be safely employed in living systems and translated to the clinic. In this study, we carried out a multiparametric in vitro study to look at the cytotoxicity and cellular uptake of gold nanoparticles on human glioblastoma and human dermal fibroblast cell lines. Cytotoxicity was evaluated by incubating cells with three different morphologies of AuNPs, namely nanospheres, nanorods, and nanostars, each having three different surface chemistries (cetyltrimethylammonium bromide (CTAB), poly(ethylene glycol) (PEG), and human serum albumin (HSA)). Our results showed that the surface chemistry of the nanoparticles had predominant effects on cytotoxicity, and the morphology and size of the nanoparticles only slightly affected cell viability. CTAB-coated particles were found to be the most toxic to cells, and PEGylated nanostars were determined to be the least toxic. Caspase-3 assay and LDH assay revealed that cell death occurs via apoptosis for cancerous cells and via necrosis for healthy ones. Cellular uptake studies carried out via TEM showed that the particles retain their shape even at long incubation times, which may be beneficial for in vivo SERS-based disease detection. Overall, this study provides valuable information on gold-nanoparticle-induced cytotoxicity that can be leveraged for the development of safe and effective nanoparticle-based therapeutic and diagnostic systems. PMID- 27992182 TI - Heparin and Methionine Oxidation Promote the Formation of Apolipoprotein A-I Amyloid Comprising alpha-Helical and beta-Sheet Structures. AB - Peptides derived from apolipoprotein A-I (apoA-I), the main component of high density lipoprotein (HDL), constitute the main component of amyloid deposits that colocalize with atherosclerotic plaques. Here we investigate the molecular details of full-length, lipid-deprived apoA-I after assembly into insoluble aggregates under physiologically relevant conditions known to induce aggregation in vitro. Unmodified apoA-I is shown to remain soluble at pH 7 for at least 3 days, retaining its native alpha-helical-rich structure. Upon acidification to pH 4, apoA-I rapidly assembles into insoluble nonfibrillar aggregates lacking the characteristic cross-beta features of amyloid. In the presence of heparin, the rate and thioflavin T responsiveness of the aggregates formed at pH 4 increase and short amyloid-like fibrils are observed, which give rise to amyloid characteristic X-ray reflections at 4.7 and 10 A. Solid-state nuclear magnetic resonance (SSNMR) and synchrotron radiation circular dichroism spectroscopy of fibrils formed in the presence of heparin show they retain some alpha-helical characteristics together with new beta-sheet structures. Interestingly, SSNMR indicates a similar molecular structure of aggregates formed in the absence of heparin at pH 6 after oxidation of the three methionine residues, although their morphology is rather different from that of the heparin-derived fibrils. We propose a model for apoA-I aggregation in which perturbations of a four-helix bundle-like structure, induced by interactions of heparin or methionine oxidation, cause the partially helical N-terminal residues to disengage from the remaining, intact helices, thereby allowing self-assembly via beta-strand associations. PMID- 27992183 TI - Penicisulfuranols A-F, Alkaloids from the Mangrove Endophytic Fungus Penicillium janthinellum HDN13-309. AB - Six new epipolythiodioxopiperazine (ETP) alkaloids, penicisulfuranols A-F (1-6), were isolated from the mangrove endophytic fungus Penicillium janthinellum HDN13 309. All structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data and ECD calculations. They belong to the unusual family of ETPs containing sulfur atoms on both alpha- and beta positions of amino acid residues and a rare 1,2-oxazadecaline core moiety. In addition, compounds 1-6 also possess a rare spiro-furan ring and 1-3 showed cytotoxicity with IC50 values ranging from 0.1 to 3.9 MUM. PMID- 27992184 TI - Importance of Triples Contributions to NMR Spin-Spin Coupling Constants Computed at the CC3 and CCSDT Levels. AB - We present the first analytical implementation of CC3 second derivatives using the spin-unrestricted approach. This allows, for the first time, the calculation of nuclear spin-spin coupling constants (SSCC) relevant to NMR spectroscopy at the CC3 level of theory in a fully analytical manner. CC3 results for the SSCCs of a number of small molecules and their fluorine substituted derivatives are compared with the corresponding coupled cluster singles and doubles (CCSD) results obtained using specialized basis sets. For one-bond couplings the change when going from CCSD to CC3 is typically 1-3%, but much higher corrections were found for 1JCN in FCN, 15.7%, and 1JOF in OF2, 6.4%. The changes vary significantly in the case of multibond couplings, with differences of up to 10%, and even 13.6% for 3JFH in fluoroacetylene. Calculations at the coupled cluster singles, doubles, and triples (CCSDT) level indicate that the most important contributions arising from connected triple excitations in the coupled cluster expansion are accounted for at the CC3 level. Thus, we believe that the CC3 method will become the standard approach for the calculation of reference values of nuclear spin-spin coupling constants. PMID- 27992185 TI - Rational Tuning of Superoxide Sensitivity in SoxR, the [2Fe-2S] Transcription Factor: Implications of Species-Specific Lysine Residues. AB - In Escherichia coli, the [2Fe-2S] transcriptional factor, SoxR, functions as a sensor of oxidative stress. The transcriptional activity in SoxR is regulated by the reversible oxidation and reduction of [2Fe-2S] clusters. We previously proposed that superoxide (O2*-) has a direct role as a signal for E. coli SoxR and that the sensitivity of the E. coli SoxR response to O2*- is 10-fold higher than that of Pseudomonas aeruginosa SoxR. The difference between the two homologues reflects interspecies differences in the regulatory role of O2*- activation. To investigate the determinants of SoxR's sensitivity to O2*-, we substituted several amino acids that are not conserved among enteric bacteria SoxR homologues and investigated the interaction of SoxR with O2*- using pulse radiolysis. The substitution of E. coli SoxR Lys residues 89 and 92 with Ala residues (K89AK92A), located close to [2Fe-2S] clusters, dramatically affected this protein's reaction with O2*-. The second-order rate constant of the reaction was 3.3 * 107 M-1 s-1, which was 10 times smaller than that of wild-type SoxR. Conversely, the corresponding substitution of Ala90 with Lys in P. aeruginosa SoxR increased the rate approximately 10-fold. In contrast, introductions of the Arg127Ser128Asp129 -> Leu127Gln128Ala129 substitution into E. coli SoxR, and the corresponding substitution (Leu125Gln126Ala127 -> Arg125Ser126Asp127) in P. aeruginosa SoxR, did not affect the reaction rates. In addition, the Lys mutation in E. coli SoxR (K89AK92A) showed a defect in vivo transcriptional activity by measuring beta-galactosidase expression in response to paraquat. Our findings clearly support the idea Lys is critical to the response to O2*- and further transcriptional activity of SoxR. PMID- 27992187 TI - Antioxidant Hydroanthraquinones from the Marine Algal-Derived Endophytic Fungus Talaromyces islandicus EN-501. AB - Five new polyhydroxylated hydroanthraquinone derivatives, namely, 8 hydroxyconiothyrinone B (1), 8,11-dihydroxyconiothyrinone B (2), 4R,8 dihydroxyconiothyrinone B (3), 4S,8-dihydroxyconiothyrinone B (4), and 4S,8 dihydroxy-10-O-methyldendryol E (5), were isolated and identified from the culture extract of Talaromyces islandicus EN-501, an endophytic fungus obtained from the inner tissue of the marine red alga Laurencia okamurai. The structures of these compounds were established on the basis of detailed interpretation of their NMR and mass spectroscopic data, and the structures and absolute configurations of compounds 1 and 2 were confirmed by X-ray crystallographic analysis, while the absolute configurations of compounds 3-5 were determined by TDDFT calculations of the ECD spectra. The antimicrobial, antioxidant, and cytotoxic activities of compounds 1-5 were evaluated. PMID- 27992188 TI - Effectiveness of Iron Ethylenediamine-N,N'-bis(hydroxyphenylacetic) Acid (o,o EDDHA/Fe3+) Formulations with Different Ratios of Meso and d,l-Racemic Isomers as Iron Fertilizers. AB - Two o,o-EDDHA/Fe3+ formulations (meso, 93.5% w/w of meso isomer; and d,l-racemic, 91.3% w/w of d,l-racemic mixture) were prepared, and their efficacy to avoid or to relieve iron deficiency in Fe-sufficient and Fe-deficient tomato plants grown on hydroponic solution was compared with that of the current o,o-EDDHA/Fe3+ formulations (50% of meso and d,l-racemic isomers). The effectiveness of the three o,o-EDDHA/Fe3+ formulations was different depending on the iron nutritional status of plants. The three o,o-EDDHA/Fe3+ formulations tested were effective in preventing iron chlorosis in healthy plants. However, the higher the meso concentration in the formulations, the higher the effectiveness in the recovery of iron chlorotic plants from iron deficiency. Accordingly, o,o-EDDHA/Fe3+ formulations rich in meso isomer are recommended in hydroponic systems. PMID- 27992186 TI - Uniform Free-Energy Profiles of the P-O Bond Formation and Cleavage Reactions Catalyzed by DNA Polymerases beta and lambda. AB - Human X-family DNA polymerases beta (Polbeta) and lambda (Pollambda) catalyze the nucleotidyl-transfer reaction in the base excision repair pathway of the cellular DNA damage response. Using empirical valence bond and free-energy perturbation simulations, we explore the feasibility of various mechanisms for the deprotonation of the 3'-OH group of the primer DNA strand, and the subsequent formation and cleavage of P-O bonds in four Polbeta, two truncated Pollambda (tPollambda), and two tPollambda Loop1 mutant (tPollambdaDeltaL1) systems differing in the initial X-ray crystal structure and nascent base pair. The average calculated activation free energies of 14, 18, and 22 kcal mol-1 for Polbeta, tPollambda, and tPollambdaDeltaL1, respectively, reproduce the trend in the observed catalytic rate constants. The most feasible reaction pathway consists of two successive steps: specific base (SB) proton transfer followed by rate-limiting concerted formation and cleavage of the P-O bonds. We identify linear free-energy relationships (LFERs) which show that the differences in the overall activation and reaction free energies among the eight studied systems are determined by the reaction free energy of the SB proton transfer. We discuss the implications of the LFERs and suggest pKa of the 3'-OH group as a predictor of the catalytic rate of X-family DNA polymerases. PMID- 27992190 TI - Unveiling the Variability of "Quartz Hazard" in Light of Recent Toxicological Findings. AB - The variability of quartz hazard stands as one of the most puzzling issues in particle toxicology, notwithstanding the fact that silicosis, the most ancient occupational disease, was the very topic from which the study of the toxicity of particulates developed. Over the years, other adverse effects of silica particles (i.e., lung cancer and autoimmune diseases) were detected and described. However, a few gaps are still present in the physicochemical determinants and cellular pathways involved in the mechanisms of silica pathogenicity. In this perspective, we illustrate how pooling together studies in occupational health and nanotoxicology might fill such gaps, yielding a consistent picture of what imparts toxicity to a given silica source. Recent investigations have shown that crystallinity is not implied in the pathogenic process of silica per se, while patches of disorganized silanols at the surface of both crystalline and amorphous particles can promote membrane damage and inflammation, a process at the origin of silica-related diseases. Introducing these new findings into the accepted multistep model of silica pathogenicity, we obtain a picture of the chemical features of silica governing each cellular step in agreement with the outcomes of major previous studies. We ascribe the origin of the variability of silica hazard mainly to the distribution of various moieties at the particle surface, with silanols playing the major role. Toxicity turns out to be likely predictable by an ad hoc surface characterization. Tailored modifications of the surface can be envisaged to prepare safe materials or blunt toxicity in existing ones. PMID- 27992189 TI - Cationic Amphiphilic Polymers with Antimicrobial Activity for Oral Care Applications: Eradication of S. mutans Biofilm. AB - The antibacterial and antibiofilm activities of cationic amphiphilic methacrylate polymers against cariogenic bacterium S. mutans were investigated. Cationic homopolymer PE0 and copolymer PE31 containing 31 mol % of ethyl methacrylate were synthesized by reversible addition-fragmentation chain transfer polymerization. These polymers displayed bactericidal activity toward S. mutans and prevented biofilm formation by killing the planktonic bacteria. At a concentration of 1000 MUg/mL when incubated for 2 h the polymers reduced >80% of biofilm biomass. When the polymer assay solution with the biofilm was vigorously mixed using a pipet for 30 s, >50% of biofilm mass was removed at a polymer concentration of 250 MUg/mL. Chlorhexidine and a cationic surfactant failed to reduce the biofilm mass at the same concentration. PE0 was the most effective in removing biofilm and did not show any significant cytotoxicity to human gingival fibroblast and periodontal ligament stem cells when incubated for 10 min. PMID- 27992191 TI - Cost-Effective Implementation of Multiconformer Transition State Theory for Peroxy Radical Hydrogen Shift Reactions. AB - Based on a small test system, (R)-CH(OH)(OO.)CH2CHO, we have developed a cost effective approach to the practical implementation of multiconformer transition state theory for peroxy radical hydrogen shift reactions at atmospherically relevant temperatures. While conformer searching is crucial for accurate reaction rates, an energy cutoff can be used to significantly reduce the computational cost with little loss of accuracy. For the reaction barrier, high-level calculations are needed, but the highest level of electronic structure theory is not necessary for the relative energy between conformers. Improving the approach to both transition state theory and electronic structure theory decreases the calculated reaction rate significantly, so low-level calculations can be used to rule out slow reactions. Further computational time can be saved by approximating the tunneling coefficients for each transition state by only that of the lowest energy transition state. Finally, we test and validate our approach using higher level theoretical values for our test system and existing experimental results for additional peroxy radical hydrogen shift reactions in three slightly larger systems. PMID- 27992192 TI - Heparin Enhances Transfection in Concert with a Trehalose-Based Polycation with Challenging Cell Types. AB - Improving the delivery of nucleic acids to diverse tissue types in culture is important for translating genome editing for regenerative cell therapies. Herein, we examine the effect of transfection media additives, such as the sulfated glycosaminoglycan heparin, in dramatically increasing pDNA delivery efficiency and transgene expression in a wide variety of cell types. Polyplexes formed by combining pDNA and Tr4, a cationic glycopolymer containing repeated trehalose and pentaethylenetetramine groups, were treated with low concentrations of heparin prior to in vitro transfection with plasmid DNA. Polyplex formulations were found to be stable and form ternary complexes upon heparin addition according to dynamic light scattering and ethidium bromide dye exclusion assays. Heparin coated polyplexes offer significant increases (approximately 4-fold) in GFP expression compared to polyplexes prepared with Tr4 only in primary fibroblasts, U87, and HepG2 cells. Heparin was also shown to increase GFP expression in a linear, dose-dependent manner. The heparin-treated Tr4 polyplexes exhibited more than 50% higher cellular internalization with HepG2 cells while showing minimal increases with U87 and primary fibroblasts. Pharmacological inhibition was used to further understand the endocytic pathways taken during transfection in the presence and absence of heparin. It was found that heparin-treated polyplexes are endocytosed primarily through macropinocytosis and clathrin-mediated pathways, while Tr4 polyplexes without heparin appear to be internalized primarily via caveolae. Heparin appears to also modify the nuclear localization behavior of Tr4 polyplexes, which likely contributes to increased efficiency and transgene expression. PMID- 27992193 TI - Achieving High-Performance Room-Temperature Sodium-Sulfur Batteries With S@Interconnected Mesoporous Carbon Hollow Nanospheres. AB - Despite the high theoretical capacity of the sodium-sulfur battery, its application is seriously restrained by the challenges due to its low sulfur electroactivity and accelerated shuttle effect, which lead to low accessible capacity and fast decay. Herein, an elaborate carbon framework, interconnected mesoporous hollow carbon nanospheres, is reported as an effective sulfur host to achieve excellent electrochemical performance. Based on in situ synchrotron X-ray diffraction, the mechanism of the room temperature Na/S battery is proposed to be reversible reactions between S8 and Na2S4, corresponding to a theoretical capacity of 418 mAh g-1. The cell is capable of achieving high capacity retention of ~88.8% over 200 cycles, and superior rate capability with reversible capacity of ~390 and 127 mAh g-1 at 0.1 and 5 A g-1, respectively. PMID- 27992194 TI - Identifying Cytosine-Specific Isomers via High-Accuracy Single Photon Ionization. AB - Biological entities, such as DNA bases or proteins, possess numerous tautomers and isomers that lie close in energy, making the experimental characterization of a unique tautomer challenging. We apply VUV synchrotron-based experiments combined with state-of-the-art ab initio methodology to determine the adiabatic ionization energies (AIEs) of specific gas-phase cytosine tautomers produced in a molecular beam. The structures and energetics of neutral and cationic cytosine tautomers were determined using explicitly correlated methods. The experimental spectra correspond to well-resolved bands that are attributable to the specific contributions of five neutral tautomers of cytosine prior to ionization. Their AIEs are experimentally determined for the first time with an accuracy of 0.003 eV. This study also serves as an important showcase for other biological entities presenting a dense pattern of isomeric and tautomeric forms in their spectra that can be investigated to understand the charge redistribution in these species upon ionization. PMID- 27992195 TI - Nuclear Magnetic Resonance Spectroscopy Investigation on Ultralow Melting Temperature Behavior of Dimethyl Sulfoxide-Water Solutions. AB - On the basis of the molecular understanding that DMSO has a trigonal pyramidal geometry with one highly polarized sulfinyl group and two hydrophobic methyl groups, we used NMR technology to rationalize why DMSO can act as antifreeze for aqueous solutions. A series of DMSO-water, DMSO-methanol, and acetone-water binary solutions with various molar ratios were tested in specified low temperature conditions. The freezing test results indicated that only DMSO-water solutions with the DMSO-water molar ratio (nDMSO) in a specific range can form apparent ultralow freezing temperature solutions. Among all DMSO-water solutions, the apparent freezing temperature lower than -130 degrees C was obtained for nDMSO values of 0.25, 0.30, and 0.35, respectively. Multinuclear NMR chemical shifts, 1H diffusion experiment results, and viscosity measurements suggested that molecular rearrangement resulted in the formation of the water-core DMSO shell aggregation unit in DMSO-water solutions. The weak methyl-methyl London dispersion forces among water-core DMSO-shell aggregation units can explain the apparent ultralow freezing temperatures of these DMSO-water solutions. PMID- 27992196 TI - Protein-Tannin Interactions of Tryptic Digests of alpha-Lactalbumin and Procyanidins. AB - Protein-tannin interactions on a molecular level were investigated by using a model system containing peptides of alpha-lactalbumin and berry tannins (procyanidins). Oxidation of isolated tryptic peptide LDQWLCEK (m/z 1034) with procyanidin B2 or procyanidin fraction (PF) isolated from aronia juice was monitored by LC-ESI-MS. Procyanidin B2 and PF showed radical scavenging activities toward oxidation of the peptide with the peptide also preventing procyanidin B2 from degradation. Oxidation enhanced the cleavage of peptide between tryptophan and glutamine. Interaction products arising from WLCEK or WLCE residue and degradation product of procyanidin B2 were also identified using both size exclusion chromatography and LC-MS. Tryptophan and lysine were the amino acids most prone to interact with procyanidin B2. The study shows that protein tannin interaction takes place during oxidation leading to both degradation of the parent compounds and formation of interaction products. This may in turn affect the quality of protein and tannin containing food. PMID- 27992197 TI - Gas-Phase Photolysis of Pyruvic Acid: The Effect of Pressure on Reaction Rates and Products. AB - In this work, we investigate the impact of pressure and oxygen on the kinetics of and products from the gas-phase photolysis of pyruvic acid. The results reveal a decrease in the photolysis quantum yield as pressure of air or nitrogen is increased, a trend not yet documented in the literature. A Stern-Volmer analysis demonstrates this effect is due to deactivation of the singlet state of pyruvic acid when the photolysis is performed in nitrogen, and from quenching of both the singlet and triplet state in air. Consistent with previous studies, acetaldehyde and CO2 are observed as the major products; however, other products, most notably acetic acid, are also identified in this work. The yield of acetic acid increases with increasing pressure of buffer gas, an effect that is amplified by the presence of oxygen. At least two mechanisms are necessary to explain the acetic acid, including one that requires reaction of photolysis intermediates with O2. These findings extend the fundamental understanding of the gas-phase photochemistry of pyruvic acid, highlighting the importance of pressure on the photolysis quantum yields and products. PMID- 27992198 TI - Role of Protecting Groups in Synthesis and Self-Assembly of Glycopolymers. AB - Protection and deprotection are basic procedures in oligosaccharide synthesis. By taking advantage of the processes of attaching and removing the protecting groups, preparation of oligosaccharides with complex structures can be achieved with relatively high yields. However, the role of protecting groups in solution properties and self-assembly of synthetic glycopolymers has been overlooked in the literature. In this paper, we focused on such effects for well-designed copolymers in which different numbers of benzyl (Bn) groups are installed regioselectively in saccharide rings. Thus, three block copolymers P1, P2, and P3 composed of a common block of PNIPAm and a glycopolymer block with trisaccharide triMan side chains differing in the respective number of Bn (0, 2, and 6) were prepared. The solutions of these block copolymers in water were investigated by dynamic and static light scatting and VT-1H NMR. We found that all of the three copolymers P1, P2, and P3 formed association at room temperature. Particularly, P1 associated loosely due to carbohydrate-carbohydrate interaction (CCI) while P3 formed tight aggregates due to hydrophobic interactions between Bn, and P2 behaved between those of P1 and P3. Moreover, upon heating, phase transition of PNIPAm block took place leading to micelle formation. Hydrodynamic radius of P1 and P2 increased significantly as expected, while P3 did not follow this trend, because during heating, collapse and accumulation of the PNIPAm chains would occur within the tight aggregates mainly, so it leads to a little change of the size. PMID- 27992200 TI - Cp*CoIII-Catalyzed syn-Selective C-H Hydroarylation of Alkynes Using Benzamides: An Approach Toward Highly Conjugated Organic Frameworks. AB - Hydroarylation of internal alkynes by cost-effective CoIII-catalysis, directed by N-tert-butyl amides, is achieved to avail mono- or dihydroarylated amide products selectively in an atom and step economic way. Several important functional groups were tolerated under the reaction conditions, and syn-hydroarylation products were exclusively isolated. Notably, a 4-fold C-H hydroarylation provided a highly conjugated organic framework in one step. Kinetic study with extensive deuterium labeling experiments were performed to support the proposed mechanism. PMID- 27992201 TI - Metal-Organic Frameworks as Micromotors with Tunable Engines and Brakes. AB - Herein, we report that UiO-type (UiO = University of Oslo) metal-organic frameworks (MOFs) can be transformed into self-propelled micromotors by employing several different metal-based propulsion systems. Incorporation of a bipyridine ligand into the UiO-67 lattice transforms the crystallites, upon metalation, into single-site, metal-based catalytic "engines" to power the micromotors with chemical fuel. The "engine performance" (i.e., propulsion) of the single-site powered micromotors has been tuned by the choice of the metal ion utilized. In addition, a chemical "braking" system was achieved by adding chelating agents capable of sequestering the metal ion engines and thereby suppressing the catalytic activity, with different chelators displaying different deceleration capacities. These results demonstrate that MOFs can be powered by various engines and halted by different brakes, resulting in a high degree of motion design and control at the nanoscale. PMID- 27992199 TI - Contribution of Shape and Charge to the Inhibition of a Family GH99 endo-alpha 1,2-Mannanase. AB - Inhibitor design incorporating features of the reaction coordinate and transition state structure has emerged as a powerful approach for the development of enzyme inhibitors. Such inhibitors find use as mechanistic probes, chemical biology tools, and therapeutics. Endo-alpha-1,2-mannosidases and endo-alpha-1,2 mannanases, members of glycoside hydrolase family 99 (GH99), are interesting targets for inhibitor development as they play key roles in N-glycan maturation and microbiotal yeast mannan degradation, respectively. These enzymes are proposed to act via a 1,2-anhydrosugar "epoxide" mechanism that proceeds through an unusual conformational itinerary. Here, we explore how shape and charge contribute to binding of diverse inhibitors of these enzymes. We report the synthesis of neutral dideoxy, glucal and cyclohexenyl disaccharide inhibitors, their binding to GH99 endo-alpha-1,2-mannanases, and their structural analysis by X-ray crystallography. Quantum mechanical calculations of the free energy landscapes reveal how the neutral inhibitors provide shape but not charge mimicry of the proposed intermediate and transition state structures. Building upon the knowledge of shape and charge contributions to inhibition of family GH99 enzymes, we design and synthesize alpha-Man-1,3-noeuromycin, which is revealed to be the most potent inhibitor (KD 13 nM for Bacteroides xylanisolvens GH99 enzyme) of these enzymes yet reported. This work reveals how shape and charge mimicry of transition state features can enable the rational design of potent inhibitors. PMID- 27992202 TI - Sensing Ability of Hybrid Cyclic Nanopeptides Based on Thiourea Cryptands for Different Ions, A Joint DFT-D3/MD Study. AB - Theoretical studies, including quantum chemistry (QM) calculations and 25 ns molecular dynamic (MD) simulations, were performed on two types of hybrid cyclic nanopeptides (HCNPs) that are constructed of tren-capped cryptand (HCNP1) and 1,3,5-triethylbenzene-capped cryptand (HCNP2) for selective complex formation with OAC-, NO3-, HSO4-, F-, Br-, and Cl- ions in the gas phase and DMSO. Obtained data by M05-2X, M05-2X-D3, B3LYP, and B3LYP-D3 functionals indicated that HCNPs form a stable complex with F- in comparison to other ions. DFT-D3 results and quantum theory of atoms in molecules (QTAIM) analysis indicated that dispersion and electrostatic interactions are the most important driving forces in HCNP-ion complex formation, respectively. Moreover, HOMO-LUMO analysis reveals that the reactivity of HCNP2, due to a lower band gap, is more than HCNP1. High sensing ability of the studied HCNPs for different ions was confirmed by Fermi level shifting of HNCPs to higher values during the complex formation. Finally, MD simulation results in DMSO are in good agreement with QM calculations and indicate that F- forms the most stable complexes with HCNPs because of stronger electrostatic interactions. PMID- 27992203 TI - SAGE: A Fast Computational Tool for Linear Epitope Grafting onto a Foreign Protein Scaffold. AB - Computational design is becoming a driving force of structural vaccinology, whereby protein antigens are engineered to generate new biomolecules with optimized immunological properties. In particular, the design of new proteins that contain multiple, different epitopes can potentially provide novel highly efficient vaccine candidates. In this context, epitope grafting, which entails the transplantation of an antibody recognition motif from one protein onto a different protein scaffold (possibly containing other immunoreactive sequences) holds great promise for the realization of superantigens. Herein, we present SAGE (strategy for alignment and grafting of epitopes), an automated computational tool for the implantation of immunogenic epitopes onto a given scaffold. It is based on the comparison between the expected secondary structures of the candidates to be grafted with all the secondary structures in the target scaffold. Evaluating the differences both in sequence and in structure between the epitope and the scaffold returns a ranking of most probable molecules containing the new antigenic sequence. We validate this approach identifying the grafting positions obtained in previous works by experimental and computational methods, proving an efficient, flexible, and fast tool to perform the initial scanning for epitope grafting. This approach is fully general and may be applied to any target antigen and candidate epitopes with known 3D structures. PMID- 27992204 TI - Increased Back-Bonding Explains Step-Edge Reactivity and Particle Size Effect for CO Activation on Ru Nanoparticles. AB - Carbon monoxide is a ubiquitous molecule, a key feedstock and intermediate in chemical processes. Its adsorption and activation, typically carried out on metallic nanoparticles (NPs), are strongly dependent on the particle size. In particular, small NPs, which in principle contain more corner and step-edge atoms, are surprisingly less reactive than larger ones. Hereby, first-principles calculations on explicit Ru NP models (1-2 nm) show that both small and large NPs can present step-edge sites (e.g., B5 and B6 sites). However, such sites display strong particle-size-dependent reactivity because of very subtle differences in local chemical bonding. State-of-the-art crystal orbital Hamilton population analysis allows a detailed molecular orbital picture of adsorbed CO on step edges, which can be classified as flat (eta1 coordination) and concave (eta2 coordination) sites. Our analysis shows that the CO pi-metal dpi hybrid band responsible for the electron back-donation is better represented by an oxygen lone pair on flat sites, whereas it is delocalized on both C and O atoms on concave sites, increasing the back-bonding on these sites compared to flat step edges or low-index surface sites. The bonding analysis also rationalizes why CO cleavage is easier on step-edge sites of large NPs compared to small ones irrespective of the site geometry. The lower reactivity of small NPs is due to the smaller extent of the Ru-O interaction in the eta2 adsorption mode, which destabilizes the eta2 transition-state structure for CO direct cleavage. Our findings provide a molecular understanding of the reactivity of CO on NPs, which is consistent with the observed particle size effect. PMID- 27992205 TI - Noncovalent Interactions in Specific Recognition Motifs of Protein-DNA Complexes. AB - In view of the importance of protein-DNA interactions in biological processes, we extracted from the Protein Data Bank several one-to-one complexes of amino acids with nucleotides that matched certain geometric and energetic specificity criteria and investigated them using quantum chemistry methods. The CCSD(T)/CBS interaction energies were used as a benchmark to compare the performance of the MP2.5, MP2-F12, DFT-D3, and PM6-D3H4 methods. All methods yielded good agreement with the reference values, with declining accuracy from MP2.5 to PM6-D3H4. Regardless of the site of interaction, the minima found after full optimization in implicit solvent with high dielectric constant were close to the structures experimentally detected in protein-DNA complexes. According to DFT-SAPT analysis, the nature of noncovalent interactions strongly depends on the type of amino acid. The negatively charged sugar-phosphate backbone of DNA heavily influences the strength of interactions and must be included in the computational model, especially in the case of interactions with charged amino acids. PMID- 27992206 TI - Gel-Like Calcium Carbonate Precursors Observed by in situ AFM. AB - The debate about crystallization processes is still ongoing and nonclassical crystallization mechanisms attract more and more attention. This work indicates that polymer induced liquid precursor (PILP) phases play a role for nonclassical calcium carbonate crystallization and growth processes. Here we report the observation of gel-like precursors for the crystal growth on a calcite surface by means of an in situ AFM study. These precursors spread out on the surface with time supporting their liquid character. This study will give new insights into biomineralization and crystallization processes in general. PMID- 27992207 TI - Predicting CO2-H2O Interfacial Tension Using COSMO-RS. AB - Knowledge about the interaction between fluids and solids and the interfacial tension (IFT) that results is important for predicting behavior and properties in industrial systems and in nature, such as in rock formations before, during, and after CO2 injection for long-term storage. Many authors have studied the effect of the environmental variables on the IFT in the CO2-H2O system. However, experimental measurements above CO2 supercritical conditions are scarce and sometimes contradictory. Molecular modeling is a valuable tool for complementing experimental IFT determination, and it can help us interpret results and gain insight under conditions where experiments are difficult or impossible. Here, we report predictions for CO2-water interfacial tension performed using density functional theory (DFT) combined with the COSMO-RS implicit solvent model. We predicted the IFT dependence as a function of pressure (0-50 MPa), temperature (273-383 K), and salinity (0-5 M NaCl). The results agree well with literature data, within the estimated uncertainty for experiments and for molecular dynamics (MD) simulations, suggesting that the model can be used as a fast alternative to time-consuming computational approaches for predicting the CO2-water IFT over a range of pressures, temperatures, and salinities. PMID- 27992208 TI - Polymer Vesicle Sensor for Visual and Sensitive Detection of SO2 in Water. AB - This study reports the first polymer vesicle sensor for the visual detection of SO2 and its derivatives in water. A strong binding ability between tertiary alkanolamines and SO2 has been used as the driving force for the detection by the graft of tertiary amine alcohol (TAA) groups onto an amphiphilic hyperbranched multiarm polymer, which can self-assemble into vesicles with enriched TAA groups on the surface. The polymer vesicles will undergo proton exchange with cresol red (CR) to produce CR-immobilized vesicles (CR@vesicles). Subsequently, through competitive binding with the TAA groups between CR and SO2 or HSO3-, the CR@vesicles (purple) can quickly change into SO2@vesicles (colorless) with the release of protonated CR (yellow). Such a fast purple to yellow transition in the solution allows the visual detection of SO2 or its derivatives in water by the naked eye. A visual test paper for SO2 gas has also been demonstrated by the adsorption of CR@vesicles onto paper. Meanwhile, the detection limit of CR@vesicles for HSO3- is approximately 25 nM, which is improved by approximately 30 times when compared with that of small molecule-based sensors with a similar structure (0.83 MUM). Such an enhanced detection sensitivity should be related to the enrichment of TAA groups as well as the CR in CR@vesicles. In addition, the CR@vesicle sensors also show selectivity and specificity for the detection of SO2 or HSO3- among anions such as F-, Br-, Cl-, SO42-, NO2-, C2O42-, S2O32-, SCN-, AcO-, SO32-, S2-, and HCO3-. PMID- 27992209 TI - Evaluation of the Hydrolysis Specificity of an Aminopeptidase from Bacillus licheniformis SWJS33 Using Synthetic Peptides and Soybean Protein Isolate. AB - The substrate specificity of aminopeptidases has often been determined against aminoacyl-p-nitroanilide; thus, its specificity toward synthetic peptides and complex substrates remained unclear. The hydrolysis specificity of an aminopeptidase from Bacillus licheniformis SWJS33 (BLAM) was evaluated using a series of synthetic peptides and soybean protein isolate. The aminopeptidase showed high specificity for dipeptides with Leu, Val, Ala, Gly, and Phe at the N terminus, and the specificity was significantly affected by the nature of the penultimate residue. In the hydrolysis of soy protein isolate, BLAM preferred peptides with Leu, Glu, Gly, and Ala at the N-terminus by free amino acid analysis and preferred peptides with Leu, Ala, Ser, Trp, and Tyr at the N terminus by UPLC-MS/MS. The introduction of complex substrates provides a deeper understanding of the aminopeptidase's specificity, which can instruct the application of the enzyme in protein hydrolysis. PMID- 27992210 TI - Embryonic Growth of Face-Center-Cubic Silver Nanoclusters Shaped in Nearly Perfect Half-Cubes and Cubes. AB - Demonstrated herein are the preparation and crystallographic characterization of the family of fcc silver nanoclusters from Nichol's cube to Rubik's cube and beyond via ligand-control (thiolates and phosphines in this case). The basic building block is our previously reported fcc cluster [Ag14(SPhF2)12(PPh3)8] (1). The metal frameworks of [Ag38(SPhF2)26(PR'3)8] (22) and [Ag63(SPhF2)36(PR'3)8]+ (23), where HSPhF2 = 3,4-difluorothiophenol and R' = alkyl/aryl, are composed of 2 * 2 = 4 and 2 * 2 * 2 = 8 metal cubes of 1, respectively. All serial clusters share similar surface structural features. The thiolate ligands cap the six faces and the 12 edges of the cube (or half cube) while the phosphine ligands are terminally bonded to its eight corners. On the basis of the analysis of the crystal structures of 1, 22, and 23, we predict the next "cube of cubes" to be Ag172(SR)72(PR'3)8] (33), in the evolution of growth of this cluster sequence. PMID- 27992211 TI - Automated Fragmentation Polarizable Embedding Density Functional Theory (PE-DFT) Calculations of Nuclear Magnetic Resonance (NMR) Shielding Constants of Proteins with Application to Chemical Shift Predictions. AB - Full-protein nuclear magnetic resonance (NMR) shielding constants based on ab initio calculations are desirable, because they can assist in elucidating protein structures from NMR experiments. In this work, we present NMR shielding constants computed using a new automated fragmentation (J. Phys. Chem. B 2009, 113, 10380 10388) approach in the framework of polarizable embedding density functional theory. We extend our previous work to give both basis set recommendations and comment on how large the quantum mechanical region should be to successfully compute 13C NMR shielding constants that are comparable with experiment. The introduction of a probabilistic linear regression model allows us to substantially reduce the number of snapshots that are needed to make comparisons with experiment. This approach is further improved by augmenting snapshot selection with chemical shift predictions by which we can obtain a representative subset of snapshots that gives the smallest predicted error, compared to experiment. Finally, we use this subset of snapshots to calculate the NMR shielding constants at the PE-KT3/pcSseg-2 level of theory for all atoms in the protein GB3. PMID- 27992212 TI - Variable Levels of Glutathione S-Transferases Are Responsible for the Differential Tolerance to Metolachlor between Maize (Zea mays) Shoots and Roots. AB - Glutathione S-transferases (GSTs) play important roles in herbicide tolerance. However, studies on GST function in herbicide tolerance among plant tissues are still lacking. To explore the mechanism of metolachlor tolerance difference between maize shoots and roots, the effects of metolachlor on growth, GST activity, and the expression of the entire GST gene family were investigated. It was found that this differential tolerance to metolachlor was correlated with contrasting GST activity between the two tissues and can be eliminated by a GST inhibitor. An in vitro metolachlor-glutathione conjugation assay confirmed that the transformation of metolachlor is 2-fold faster in roots than in shoots. The expression analysis of the GST gene family revealed that most GST genes are expressed much higher in roots than shoots, both in control and in metolachlor treated plants. Taken together, higher level expression of most GST genes, leading to higher GST activity and faster herbicide transformation, appears to be responsible for the higher tolerance to metolachlor of maize roots than shoots. PMID- 27992213 TI - Proposed Method for Estimating Health-Promoting Glucosinolates and Hydrolysis Products in Broccoli (Brassica oleracea var. italica) Using Relative Transcript Abundance. AB - Due to the importance of glucosinolates and their hydrolysis products in human nutrition and plant defense, optimizing the content of these compounds is a frequent breeding objective for Brassica crops. Toward this goal, we investigated the feasibility of using models built from relative transcript abundance data for the prediction of glucosinolate and hydrolysis product concentrations in broccoli. We report that predictive models explaining at least 50% of the variation for a number of glucosinolates and their hydrolysis products can be built for prediction within the same season, but prediction accuracy decreased when using models built from one season's data for prediction of an opposing season. This method of phytochemical profile prediction could potentially allow for lower phytochemical phenotyping costs and larger breeding populations. This, in turn, could improve selection efficiency for phase II induction potential, a type of chemopreventive bioactivity, by allowing for the quick and relatively cheap content estimation of phytochemicals known to influence the trait. PMID- 27992214 TI - Photodissociation Dynamics of the i-Methylvinoxy Radical at 308, 248, and 225 nm Using Fast Beam Photofragment Translational Spectroscopy. AB - The photodissociation dynamics of the i-methylvinoxy (CH3COCH2) radical have been studied by means of fast beam coincidence translational spectroscopy. The radical was produced by photodetachment of the i-methylvinoxide anion at 700 nm, followed by dissociation at 225 nm (5.51 eV), 248 nm (5.00 eV), and 308 nm (4.03 eV). At all three dissociation energies, the major products were found to be CH3 + CH2CO, with a small amount of CO + C2H5 produced at the higher dissociation energies. Photofragment mass distributions and translational energy distributions were recorded for each wavelength. Comparison of the mass distributions with dissociation of fully deuterated i-methylvinoxy aided the assignment of the observed channels. Electronic structure calculations were performed to determine the relative energies of minima and transition states involved in the dissociation and to aid interpretation of the experimental results. The proposed dissociation mechanism involves internal conversion from the initially excited electronic state, followed by dissociation over a barrier on the ground state. PMID- 27992215 TI - Infrared Spectroscopy of Gas-Phase M+(CO2)n (M = Co, Rh, Ir) Ion-Molecule Complexes. AB - The structures of gas-phase M+(CO2)n (M = Co, Rh, Ir; n = 2-15) ion-molecule complexes have been investigated using a combination of infrared resonance enhanced photodissociation (IR-REPD) spectroscopy and density functional theory. The results provide insight into fundamental metal ion-CO2 interactions, highlighting the trends with increasing ligand number and with different group 9 ions. Spectra have been recorded in the region of the CO2 asymmetric stretch around 2350 cm-1 using the inert messenger technique and their interpretation has been aided by comparison with simulated infrared spectra of calculated low-energy isomeric structures. All vibrational bands in the smaller complexes are blue shifted relative to the asymmetric stretch in free CO2, consistent with direct binding to the metal center dominated by charge-quadrupole interactions. For all three metal ions, a core [M+(CO2)2] structure is identified to which subsequent ligands are less strongly bound. No evidence is observed in this size regime for complete activation or insertion reactions. PMID- 27992216 TI - Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome. AB - On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNFalpha)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies. PMID- 27992218 TI - Characterization of the Key Aroma Compounds in Heat-Processed Licorice (Succus Liquiritiae) by Means of Molecular Sensory Science. AB - Application of the sensomics concept elucidated the key odorants of heat processed licorice (Succus Liquiritiae). Forty-nine aroma-active compounds with flavor dilution (FD) factors between 16 and 2048 were detected; 47 thereof were identified, 23 for the first time in heated licorice. 4-Hydroxy-2,5-dimethylfuran 3(2H)-one revealed the highest FD factor of 2048, followed by 3-hydroxy-4,5 dimethylfuran-2(5H)-one, 4-hydroxy-3-methoxybenzaldehyde, 3-hydroxy-2-methyl-4H pyran-4-one, and 2-methoxyphenol (all 1024). Forty-two substances were quantitated by stable isotope dilution assays (SIDAs), and odor activity values (OAVs; ratio of concentration to the respective odor threshold) were calculated revealing OAVs >= 1 for 29 compounds. Thereby, 3-hydroxy-4,5-dimethylfuran-2(5H) one, 2,3-butanedione, 2-methoxyphenol, and 1,8-cineole showed the highest OAVs in Succus Liquiritiae. To validate the obtained data, a reconstitution model based on an aqueous sucrose solution (50%) was prepared, containing all 29 odorants with an OAV >= 1 in their naturally occurring concentrations. The recombinate elicited an aroma profile matching very well with the profile of the original heat-processed licorice, proving the correct identification and quantitation of all key aroma compounds of Succus Liquiritiae. PMID- 27992217 TI - Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis. AB - A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24 , 2451 - 2465 ) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease. PMID- 27992219 TI - Pentasila-1,4-diene: Homoconjugation between Si?Si Double Bonds via a SiMe(2) Unit. AB - Although the synthesis of several bis(disilenes) has already been reported, the number of reported conjugation modes between the Si?Si double bonds remains limited. Herein, we report the properties of the stable pentasila-1,4-diene 1, which was obtained from the reaction of two equivalents of disilenide 4 with dichlorodimethylsilane. The pi(Si?Si)->pi*(Si?Si) absorption band of 1 is considerably broadened and red-shifted compared to those of the corresponding monodisilene and hexasila-1,5-diene, but blue-shifted relative to those of typical tetrasila-1,3-dienes. The bathochromic shift and the broadening of the absorption band in 1 should be attributed to the homoconjugation between Si?Si double bonds through the SiMe2 unit. PMID- 27992220 TI - Synthesis of Functionalized 1H-Indenes and Benzofulvenes through Iodocyclization of o-(Alkynyl)styrenes. AB - A convenient method for the preparation of synthetically useful 3-iodoindene derivatives has been developed. This protocol, based on the 5-endo iodocyclization reaction of o-(alkynyl)styrenes, represents one of the scarce examples of halocyclizations using olefins as nucleophilic counterparts and allows the synthesis of both 3-iodo-1H-indenes (from beta-alkyl-beta-alkyl/aryl-o (alkynyl)styrenes) and 3-iodobenzofulvenes (from beta,beta-diaryl-o (alkynyl)styrenes) in good yields under mild reaction conditions. In addition, related alkoxyiodocyclization processes are described, which are particularly interesting in their intramolecular version because they allow the synthesis of heteropolycyclic structures containing the indene core. Finally, the usefulness of the prepared 3-iodoindenes has been demonstrated by the synthesis of several polysubstituted indene derivatives through conventional palladium-catalyzed cross coupling reactions and iodine-lithium exchange processes. PMID- 27992221 TI - Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting Induced Refeeding. AB - Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2 arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets. PMID- 27992222 TI - Krishnadimer A, an Axially Chiral Non-biaryl Natural Product: Discovery and Biomimetic Synthesis. AB - Krishnadimer A (1a), a C2-symmetric limonoid dimer representing a new class of axially chiral nonbiaryl natural products, was isolated and biomimetically semisynthesized by atroposelective 2,3-dichloro-5,6-dicyanobenzoquinone-mediated dienol-oxidative coupling. Single-crystal X-ray diffraction and electronic circular dichroism spectral analysis on the synthesized 1a unambiguously established its absolute configuration, including the P-configuration of the C15 C15' central axis. Antitumor investigations of the synthesized dimers 1a, 2a, and 2b revealed the large impact of axial chirality on bioactivities. PMID- 27992224 TI - Constant Volume Gate-Opening by Freezing Rotational Dynamics in Microporous Organically Pillared Layered Silicates. AB - Microporous organically pillared layered silicates (MOPS) are a class of microporous hybrid materials that, by varying pillar density, allows for optimization of guest recognition without the need to explore different framework topologies. MOPS are found to be capable of discriminating two very similar gases, carbon dioxide and acetylene, by selective gate-opening solely through quenching pillar dynamics. Contrary to conventional gate-opening in metal organic frameworks, the additional adsorption capacity is realized without macroscopic volume changes, thus avoiding mechanical stress on the framework. Of the two gases studied, only CO2 can accomplish freezing of pillar dynamics. Moreover, the shape of the slit-type micropores in MOPS can easily be fine-tuned by reducing the charge density of the silicate layers. This concomitantly reduces the Coulomb attraction of cationic interlayer space and anionic host layers. Surprisingly, we found that reducing the charge density then alters the gate-opening mechanism to a conventional structural gate-opening involving an increase in volume. PMID- 27992225 TI - Iron L-Edge Absorption Spectroscopy of Iron Pentacarbonyl and Ferrocene in the Gas Phase. AB - Fe L-edge X-ray absorption spectra of gas-phase iron pentacarbonyl and ferrocene measured in total-ion yield mode are reported. Comparison to previously published spectra of free iron atoms and gaseous iron chloride demonstrates how the interplay of local atomic multiplet effects and orbital interactions in the metal ligand bonds varies for the different systems. We find changes in the degree of metal-ligand covalency to be reflected in the measured 2p absorption onset. Orbital- or state-specific fragmentation is furthermore investigated in iron pentacarbonyl and ferrocene by analyzing the partial-ion-yield spectra at the Fe L-edge. Strong dependence of the yields of different fragments is observed in ferrocene in contrast to iron pentacarbonyl. This difference is attributed to the different degrees to which the 2p core hole is screened in the two systems and to which charge is rearranged in the Auger final states. We provide experimental benchmark spectra for new ab initio approaches for calculating metal L-edge absorption spectra of metal complexes. PMID- 27992223 TI - Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study. AB - Acid-related gastric diseases are associated with disorder of digestive tract acidification due to the acid secretion by gastric proton pump, H+,K+-ATPase. Omeprazole is one of the persuasive irreversible inhibitor of the proton pump H+,K+-ATPase. However, the reports on the mechanistic pathway of irreversible proton pump inhibitors (PPIs) on the acid activation and formation of disulfide complex are scarce in the literature. We have examined the acid activation PPIs, i.e., timoprazole, S-omeprazole and R-omeprazole using M062X/6-31++G(d,p) in aqueous phase with SMD solvation model. The proton pump inhibitor is a prodrug and activated in the acidic canaliculi of the gastric pump H+,K+-ATPase to sulfenic acid which can either form another acid activate intermediate sulfenamide or a disulfide complex with cysteine amino acid of H+,K+-ATPase. The quantum chemical calculations suggest that the transition state (TS5) for the disulfide complex formation is the rate-determining step of the multistep acid inhibition process by PPIs. The free energy barrier of TS5 is 5.5 kcal/mol higher for timoprazole compared to the S-omeprazole. The stability of the transition state for the formation of disulfide bond between S-omeprazole and cysteine amino acid of H+,K+-ATPase is governed by inter- and intramolecular hydrogen bonding. The disulfide complex for S-omeprazole is thermodynamically more stable by 4.5 kcal/mol in aqueous phase compared to disulfide complex of timoprazole, which corroborates the less efficacy of timoprazole as irreversible PPI for acid inhibition process. It has been speculated that sulfenic acid can either form sulfenamide or a stable disulfide complex with cysteine amino acid residue of H+,K+-ATPase. The M062X/6-31++G(d,p) level of theory calculated results reveal that the formation of tetra cyclic sulfenamide is unfavored by ~17 kcal/mol for S omeprazole and 11.5 kcal/mol for timoprazole compared to the disulfide complex formation in each case. The DFT calculations have further shed light on the acid activation process of R- and S-isomers of omeprazole. The calculated results suggest that the efficacy of these isomers lie on their metabolic pathway and excretion from human body. PMID- 27992226 TI - First-Principles Molecular Dynamics Analysis of Ligand-Free Suzuki-Miyaura Cross Coupling in Water Solvent: Oxidative Addition Step. AB - We investigated the oxidative addition of PhX (X = Cl, Br) to a single Pd(0) atom or a PdX- complex in water using first-principles molecular dynamics simulations, with solvent H2O molecules explicitly included in the calculation models, to clarify the origin of the extremely high reactivity of a ligand-free Pd catalyst in an aqueous solution for the Suzuki-Miyaura reaction. The free-energy profiles are estimated using blue moon ensemble sampling to include the entropy effect in chemical reactions in a water solvent. The free-energy barrier of the oxidative addition step is quite low for PhBr, whereas the barrier for PhCl is sizable, indicating that the reaction can proceed at room temperature with a high rate for PhBr but a rather low rate for PhCl. We also investigated the effect of the additional halogen anion on the Pd catalyst as a "supporting ligand". The activation barrier of the oxidative addition step is not affected by the supporting halogen ligand, but the final state is significantly destabilized, which should be important for the following transmetalation step. The solvent effect has also been investigated and discussed. PMID- 27992227 TI - Adsorption Microcalorimetry of CO2 in Confined Aminopolymers. AB - Aminopolymers confined within mesoporous supports have shown promise as materials for direct capture of CO2 from ambient air. In spite of this, relatively little is known about the energetics of CO2 binding in these materials, and the limited calorimetric studies published to date have focused on materials made using molecular aminosilanes rather than amine polymers. In this work, poly(ethylenimine) (PEI) is impregnated within mesoporous SBA-15, and the heats of CO2 adsorption at 30 degrees C are investigated using a Tian-Calvet calorimeter with emphasis on the role of PEI loading and CO2 pressure in the compositional region relevant to direct capture of CO2 from ambient air. In parallel, CO2 uptakes of these materials are measured using multiple complementary approaches, including both volumetric and gravimetric methods, and distinct changes in uptake as a function of CO2 pressure and amine loading are observed. The CO2 sorption behavior is directly linked to textural data describing the porosity and PEI distribution in the materials. PMID- 27992228 TI - Nonpolar Solvation Free Energy from Proximal Distribution Functions. AB - Using precomputed near neighbor or proximal distribution functions (pDFs) that approximate solvent density about atoms in a chemically bonded context one can estimate the solvation structures around complex solutes and the corresponding solute-solvent energetics. In this contribution, we extend this technique to calculate the solvation free energies (DeltaG) of a variety of solutes. In particular we use pDFs computed for small peptide molecules to estimate DeltaG for larger peptide systems. We separately compute the non polar (DeltaGvdW) and electrostatic (DeltaGelec) components of the underlying potential model. Here we show how the former can be estimated by thermodynamic integration using pDF reconstructed solute-solvent interaction energy. The electrostatic component can be approximated with Linear Response theory as half of the electrostatic solute solvent interaction energy. We test the method by calculating the solvation free energies of butane, propanol, polyalanine, and polyglycine and by comparing with traditional free energy simulations. Results indicate that the pDF-reconstruction algorithm approximately reproduces DeltaGvdW calculated by benchmark free energy simulations to within ~ kcal/mol accuracy. The use of transferable pDFs for each solute atom allows for a rapid estimation of DeltaG for arbitrary molecular systems. PMID- 27992229 TI - Comprehensive Metabolomic and Lipidomic Profiling of Human Kidney Tissue: A Platform Comparison. AB - Metabolite profiling of tissue samples is a promising approach for the characterization of cancer pathways and tumor classification based on metabolic features. Here, we present an analytical method for nontargeted metabolomics of kidney tissue. Capitalizing on different chemical properties of metabolites allowed us to extract a broad range of molecules covering small polar molecules and less polar lipid classes that were analyzed by LC-QTOF-MS after HILIC and RP chromatographic separation, respectively. More than 1000 features could be reproducibly extracted and analyzed (CV < 30%) in porcine and human kidney tissue, which were used as surrogate matrices for method development. To further assess assay performance, cross-validation of the nontargeted metabolomics platform to a targeted metabolomics approach was carried out. Strikingly, from 102 metabolites that could be detected on both platforms, the majority (>90%) revealed Spearman's correlation coefficients >=0.3, indicating that quantitative results from the nontargeted assay are largely comparable to data derived from classical targeted assays. Finally, as proof of concept, the method was applied to human kidney tissue where a clear differentiation between kidney cancer and nontumorous material could be demonstrated on the basis of unsupervised statistical analysis. PMID- 27992231 TI - From Abeta Filament to Fibril: Molecular Mechanism of Surface-Activated Secondary Nucleation from All-Atom MD Simulations. AB - Secondary nucleation pathways in which existing amyloid fibrils catalyze the formation of new aggregates and neurotoxic oligomers are of immediate importance for the onset and progression of Alzheimer's disease. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to study surface activated secondary nucleation pathways at the extended lateral beta-sheet surface of a preformed Abeta9-40 filament. Calculation of free-energy profiles allows us to determine binding free energies and conformational intermediates for nucleation complexes consisting of 1-4 Abeta peptides. In addition, we combine the free-energy profiles with position-dependent diffusion profiles to extract complementary kinetic information and macroscopic growth rates. Single monomers bind to the beta-sheet surface in a disordered, hydrophobically collapsed conformation, whereas dimers and larger oligomers can retain a cross-beta conformation resembling a more ordered fibril structure. The association processes during secondary nucleation follow a dock/lock mechanism consisting of a fast initial encounter phase (docking) and a slow structural rearrangement phase (locking). The major driving forces for surface-activated secondary nucleation are the release of a large number of hydration water molecules and the formation of hydrophobic interface contacts, the latter being in contrast to the elongation process at filament tips, which is dominated by the formation of stable and highly specific interface hydrogen bonds. The calculated binding free energies and the association rates for the attachment of Abeta monomers and oligomers to the extended lateral beta-sheet surface of the filament seed are higher compared to those for elongation at the filament tips, indicating that secondary nucleation pathways can become important once a critical concentration of filaments has formed. PMID- 27992230 TI - pH and Potential Transients of the bc1 Complex Co-Reconstituted in Proteo Lipobeads with the Reaction Center from Rb. sphaeroides. AB - His-tag technology is employed to bind membrane proteins, such as the bc1 complex and the reaction center (RC) from Rhodobacter sphaeroides, to spherical as well as planar surfaces in a strict orientation. Subsequently, the spherical and planar surfaces are subjected to in situ dialysis to form proteo-lipobeads (PLBs) and protein-tethered bilayer membranes, respectively. PLBs based on Ni nitrileotriacetic acid-functionalized agarose beads that have diameters ranging from 50 to 150 MUm are used to assess proton release and membrane potential parameters by confocal laser-scanning microscopy. The pH and potential transients are thus obtained from bc1 activated by the RC. To assess the turnover of bc1 excited by the RC in a similar setting, we used the planar surface of an attenuated total reflection crystal modified with a thin gold layer to carry out time-resolved surface-enhanced IR absorption spectroscopy triggered by flash lamp excitation. The experiments suggest that both proteins interact in a cyclic manner in both environments. The activity of the proteins seems to be preserved in the same manner as that in chromatophores or reconstituted in liposomes. PMID- 27992232 TI - Optically Detected Degradation of NaYF4:Yb,Tm-Based Upconversion Nanoparticles in Phosphate Buffered Saline Solution. AB - In a proof-of-concept study, we assessed different analytical and spectroscopic parameters for stability screening of differently sized beta-NaYF4:20 mol % Yb3+, 2 mol % Tm3+ upconversion nanoparticles (UCNPs) exemplarily in the bioanalytically relevant buffer phosphate buffered saline (PBS; pH 7.4) at 37 and 50 degrees C. This included the potentiometric determination of the amount of released fluoride ions, surface analysis with X-ray photoelectron spectroscopy (XPS), and steady-state and time-resolved fluorescence measurements. Based on these results, the luminescence lifetime of the 800 nm upconversion emission was identified as an optimum parameter for stability screening of UCNPs and changes in particle surface chemistry. PMID- 27992234 TI - Using Dental GPS to Navigate Implant Placement. AB - Digital advances have changed implant planning to improve outcomes in placement and restoration. Layering multiple image inputs, such as volumetric radiology, photography, and 3-dimensional (3D) surface scans, has allowed better assessment of patients with partial or complete edentulism, and this can aid in producing 3D visual predictions, implant guides, and prosthetics to execute the proposed plan. PMID- 27992233 TI - Using Multiorder Time-Correlation Functions (TCFs) To Elucidate Biomolecular Reaction Pathways from Microsecond Single-Molecule Fluorescence Experiments. AB - Recent advances in single-molecule fluorescence imaging have made it possible to perform measurements on microsecond time scales. Such experiments have the potential to reveal detailed information about the conformational changes in biological macromolecules, including the reaction pathways and dynamics of the rearrangements involved in processes, such as sequence-specific DNA "breathing" and the assembly of protein-nucleic acid complexes. Because microsecond-resolved single-molecule trajectories often involve "sparse" data, that is, they contain relatively few data points per unit time, they cannot be easily analyzed using the standard protocols that were developed for single-molecule experiments carried out with tens-of-millisecond time resolution and high "data density." Here, we describe a generalized approach, based on time-correlation functions, to obtain kinetic information from microsecond-resolved single-molecule fluorescence measurements. This approach can be used to identify short-lived intermediates that lie on reaction pathways connecting relatively long-lived reactant and product states. As a concrete illustration of the potential of this methodology for analyzing specific macromolecular systems, we accompany the theoretical presentation with the description of a specific biologically relevant example drawn from studies of reaction mechanisms of the assembly of the single-stranded DNA binding protein of the T4 bacteriophage replication complex onto a model DNA replication fork. PMID- 27992235 TI - Effects of baicalin on alveolar fluid clearance and alpha-ENaC expression in rats with LPS-induced acute lung injury. AB - Baicalin has been reported to attenuate lung edema in the process of lung injury. However, the effect of baicalin on alveolar fluid clearance (AFC) and epithelial sodium channel (ENaC) expression has not been tested. Sprague-Dawley rats were anesthetized and intratracheally injected with either 1 mg/kg lipopolysaccharide (LPS) or saline vehicle. Baicalin with various concentrations (10, 50, and 100 mg/kg) was injected intraperitoneally 30 min before administration of LPS. Then lungs were isolated for measurement of AFC, cyclic adenosine monophosphate (cAMP) level, and cellular localization of alpha-ENaC. Moreover, mouse alveolar type II (ATII) epithelial cell line was incubated with baicalin (30 MUmol/L), adenylate cyclase inhibitor SQ22536 (10 MUmol/L), or cAMP-dependent protein kinase inhibitor (PKA) KT5720 (0.3 MUmol/L) 15 min before LPS (1 MUg/mL) incubation. Protein expression of alpha-ENaC was detected by Western blot. Baicalin increased cAMP concentration and AFC in a dose-dependent manner in rats with LPS-induced acute lung injury. The increase of AFC induced by baicalin was associated with an increase in the abundance of alpha-ENaC protein. SQ22536 and KT5720 prevented the increase of alpha-ENaC expression caused by baicalin in vitro. These findings suggest that baicalin prevents LPS-induced reduction of AFC by upregulating alpha ENaC protein expression, which is activated by stimulating cAMP/PKA signaling pathway. PMID- 27992236 TI - Creating New Opportunities to Educate Families on the Impact of Frailty and Cognitive Impairment in a Trauma Intensive Care Unit: Results of a Quality Improvement Project. AB - BACKGROUND: Older adults comprise a rapidly growing proportion of admissions to acute care hospitals and trauma centers. Older adults admitted to a trauma intensive care unit (TICU) often have a more complicated inpatient and posthospital course. This is the most pronounced in frail elders with cognitive dysfunction. We aimed at integrating validated screening instruments for physical frailty and cognitive impairment into the standard nursing assessment of all older trauma patients admitted to our TICU and stepdown unit. OBJECTIVES: Our goal, for positive screens, was to trigger earlier referrals to palliative care for patient and family education on the range of likely clinical outcomes. METHODS: In February 2015, our study team trained bedside trauma nurses to implement a validated frailty screening process on all patients at least 65 years of age or older who were admitted to the TICU and stepdown unit. Between March and May 2015, the number of older adults admitted, mechanism of injury, numbers of patients screened, and positive screens, along with volume of palliative care referrals, were tracked. RESULTS: During the three-month period, the mean age of all older admissions (N = 131) was 75.5, of which 49% were screened. Among the patients screened, 38% screened positive for frailty, 45% screened positive for possible dementia, and 23% screened positive for both conditions. Palliative care consultations for older adults increased from 13% (before study) to 33% during the study period. CONCLUSION: A screening process designed for older adults to assess both physical frailty and cognitive impairment can be standardized into the routine care of older adults admitted to a busy trauma service. Positive screens can serve as a trigger for earlier palliative care assessments, with opportunities for educating patients and their families on the range of clinical trajectories that these vulnerable patients face. PMID- 27992237 TI - A Community-Based Exergaming Physical Activity Program Improves Readiness-to Change and Self-Efficacy Among Rural-Residing Older Adults. AB - Rural-residing older adults (OA) are not meeting physical activity (PA) recommendations, such that identifying methods of increasing PA among OA remains an ongoing challenge. This study evaluated the effect of a community-based exergaming program on PA readiness-to-change and self-efficacy among rural residing OA (n = 265). There was a significant (p = .008) increase in readiness to-change classification from PRE to POST. Significant increases in self efficacy, or confidence in their ability to be physically active for a prescribed period of time, were detected for 35 (p = .011) and 40 min (p = .035) of continuous PA. PA self-efficacy change for 35 min of continuous PA (F [3,137] = 3.973, p = .010) and 40 min of continuous PA (F [3,137) = 2.893, p = .038) were influenced by the interaction between PRE self-reported health and PRE PA readiness-to-change levels. Results suggest that an exergaming-themed PA intervention is effective at increasing PA participation and self-efficacy for PA among rural-residing OA. PMID- 27992238 TI - Antiangiogenic Effects of Doxazosin on Experimental Choroidal Neovascularization in Mice. AB - PURPOSE: The present study was designed to evaluate the effects of doxazosin on experimental choroidal neovascularization (CNV) in mice. METHODS: Six- to 8-week old male C57BL/6 mice were divided into a control group and a doxazosin-treated group (5 mg/kg, i.p., daily). Experimental CNV was induced by laser photocoagulation. Seven and 14 days after laser induction, fluorescein angiography, choroidal flat mounts, and histological studies were performed to evaluate the fluorescence leakage, area, and thickness of CNV lesions, respectively. In addition, western blot analysis was carried out to assess the inhibitory effects of doxazosin on the PI3K/Akt/mTOR signaling pathway and the expression levels of hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF), which are involved in CNV model. RESULTS: Compared with the control group, the doxazosin-treated group demonstrated significantly less fluorescence leakage on day 7 and 14 after laser induction. Both the area and the thickness of CNV lesions in the doxazosin-treated group were significantly decreased. Mechanistically, PI3K/Akt/mTOR signaling pathway activation was significantly suppressed in the doxazosin-treated group. The expression of HIF-1alpha and VEGF was also notably reduced by systemic doxazosin treatment. CONCLUSIONS: Doxazosin exerts antiangiogenic actions in an experimental mouse model of CNV and may be a potential adjunctive therapy for neovascular age-related macular degeneration in humans. PMID- 27992239 TI - Differential Effects of 2 Rehabilitation Programs Following Anterior Cruciate Ligament Reconstruction. AB - CONTEXT: The muscular function restoration related to the type of physical rehabilitation followed after anterior cruciate ligament reconstruction (ACLR) using autologous hamstring tendon graft in terms of strength and cross-sectional area (CSA) remain controversial. OBJECTIVE: To analyze the CSA and force output of quadriceps and hamstring muscles in subjects following either an Objective Criteria-Based Rehabilitation (OCBR) algorithm or the usual care (UCR) for ACL rehabilitation in Spain, before and 1 year after undergoing an ACLR. DESIGN: Longitudinal clinical double-blinded randomized controlled trial. SETTING: Sports medicine research center. PATIENTS: 40 recreational athletes (30 male, 10 female [24 +/- 6.9 y, 176.55 +/- 6.6 cm, 73.58 +/- 12.3 kg]). INTERVENTION: Both groups conducted differentiated rehabilitation procedures after ACLR. Those belonging to OCBR group were guided in their recovery according to the current evidence-based principles. UCR group followed the national conventional approach for ACL rehabilitation. MAIN OUTCOME MEASURES: Concentric isokinetic knee joint flexor extension torque assessments at 180 degrees /s and Magnetic Resonance Imaging (MRI) evaluations were performed before and 12 months after ACLR. Anatomical muscle CSA (mm2) was assessed, in Quadriceps, Biceps femoris, Semitendinous, Semimembranosus, and Gracilis muscles at 50% and 70% femur length. RESULTS: Reduced muscle CSA was observed in both treatment groups for Semitendinosus and Gracilis 1 year after ACLR. At 1-year follow-up, subjects allocated to the OCBR demonstrated greater knee flexor and extensor peak torque values in their reconstructed limbs in comparison with patients treated by UCR. CONCLUSIONS: Objective atrophy of Semitendinosus and Gracilis muscles related to surgical ACLR was found to persist in both rehabilitation groups. However, OCBR after ACLR lead to substantial gains on maximal knee flexor strength and ensured more symmetrical anterior-posterior laxity levels at the knee joint. PMID- 27992241 TI - The Effect of Joint Mobilization on Dynamic Postural Control in Patients With Chronic Ankle Instability: A Critically Appraised Topic. AB - : Clinical Scenario: Dorsiflexion range of motion is an important factor in the performance of the Star Excursion Balance Test (SEBT). While patients with chronic ankle instability (CAI) commonly experience decreased reach distances on the SEBT, ankle joint mobilization has been suggested to be an effective therapeutic intervention for targeting dorsiflexion range of motion. CLINICAL QUESTION: What is the evidence to support ankle joint mobilization for improving performance on the SEBT in patients with CAI? Summary of Key Findings: The literature was searched for articles examining the effects of ankle joint mobilization on scores of the SEBT. A total of 3 peer-reviewed articles were retrieved, 2 prospective individual cohort studies and 1 randomized controlled trial. Only 2 articles demonstrated favorable results following 6 sessions of ankle joint mobilization. Clinical Bottom Line: Despite the mixed results, the majority of the available evidence suggests that ankle joint mobilization improves dynamic postural control. Strength of Recommendation: In accordance with the Centre of Evidence Based Medicine, the inconsistent results and the limited high-quality studies indicate that there is level C evidence to support the use of ankle joint mobilization to improve performance on the SEBT in patients with CAI. PMID- 27992240 TI - Quality Matters: 2016 Annual Conference of the National Infrastructures for Biobanking. PMID- 27992242 TI - A Multiresolution Graphical Representation for Similarity Relationship and Multiresolution Clustering for Biological Sequences. AB - How we can describe the similarity relationship between the biological sequences is a basic but important problem in bioinformatics. The first graphical representation method for the similarity relationship rather than for single sequence is proposed in this article, which makes the similarity intuitional. Some properties such as sensitivity and continuity of the similarity are proved theoretically, which indicate that the similarity describer has the advantage of both alignment and alignment-free methods. With the aid of multiresolution analysis tools, we can exhibit the similarity's different profiles, from high resolution to low resolution. Then the idea of multiresolution clustering is raised first. A reassortment analysis on a benchmark flu virus genome data set is to test our method and it shows a better performance than alignment method, especially in dealing with problems involving segments' order. PMID- 27992243 TI - The Effect of Teeth Clenching on Dynamic Balance at Jump-Landing: A Pilot Study. AB - The aim of this study was to analyze the effect of teeth clenching on dynamic balance at jump landing. Twenty-five healthy subjects performed jump-landing tasks with or without teeth clenching. The first 3 trials were performed with no instruction; subsequently, subjects were ordered to clench at the time of landing in the following 3 trials. We collected the data of masseter muscle activity by electromyogram, the maximum vertical ground reaction force (vGRFmax) and center of pressure (CoP) parameters by force plate during jump-landing. According to the clenching status of control jump-landing, all participants were categorized into a spontaneous clenching group and no clenching group, and the CoP data were compared. The masseter muscle activity was correlated with vGRFmax during anterior jump-landing, while it was not correlated with CoP. In comparisons between the spontaneous clenching and the no clenching group during anterior jump landing, the spontaneous clenching group showed harder landing and the CoP area became larger than the no clenching group. There were no significant differences between pre- and postintervention in both spontaneous clenching and no clenching groups. The effect of teeth clenching on dynamic balance during jump-landing was limited. PMID- 27992244 TI - Averaging Trials Versus Averaging Trial Peaks: Impact on Study Outcomes. AB - Gait data are commonly presented as an average of many trials or as an average across participants. Discrete data points (eg, maxima or minima) are identified and used as dependent variables in subsequent statistical analyses. However, the approach used for obtaining average data from multiple trials is inconsistent and unclear in the biomechanics literature. This study compared the statistical outcomes of averaging peaks from multiple trials versus identifying a single peak from an average profile. A series of paired-samples t tests were used to determine whether there were differences in average dependent variables from these 2 methods. Identifying a peak value from the average profile resulted in significantly smaller magnitudes of dependent variables than when peaks from multiple trials were averaged. Disagreement between the 2 methods was due to temporal differences in trial peak locations. Sine curves generated in MATLAB confirmed this misrepresentation of trial peaks in the average profile when a phase shift was introduced. Based on these results, averaging individual trial peaks represents the actual data better than choosing a peak from an average trial profile. PMID- 27992245 TI - Isokinetic Evaluation of the Hip Flexor and Extensor Muscles: A Systematic Review. AB - INTRODUCTION: Isokinetic dynamometry testing is a safe and reliable method accepted as the "gold standard" in the evaluation of muscle strength in the open kinetic chain. Isokinetic hip examinations face problems in the standardization of the position of the equipment axis, in the individual being examined, and in the adjustment of the lever arm and in stabilization strategies for the patients during the tests. Identification of the methodologic procedures with best reproducibility is also needed. OBJECTIVE: To review the literature to evaluate the parameters used for the isokinetic evaluation of the hip flexor and extensor muscles and its reproducibility. METHODS: This is a systematic literature review of the Cochrane, LILACS, PEDro, PubMed, and SciELO databases. The inclusion criteria were articles on the evaluation of hip flexor and/or extensor muscular strength with an isokinetic dynamometer and articles that analyzed the ICC or Pearson's reproducibility. The information extracted was positioning of the patient; positioning of the dynamometer axis; positioning of the lever arm; angular speed; sample size, pathology; type of contraction; and ICC and Pearson's results. RESULTS: 204 articles were found, from which 14 were selected that evaluated hip flexor and extensor muscles, involving 550 individuals who were submitted to an isokinetic hip evaluation. Five articles obtained the best result in reproducibility and had their methodology analyzed. CONCLUSION: To obtain better reproducibility of the isokinetic evaluation of the hip flexor and extensor muscles, the following recommendations must be followed: the individual must be positioned in the supine position and the dynamometer axis must be aligned with the greater trochanter of the femur. The positioning of the lever arm must be in the most distal region of the thigh possible. The angular speed used to analyze torque peak and muscle work was 60 degrees /s, and to evaluate the muscle power it was 180 degrees /s, with concentric and eccentric contractions being analyzed. PMID- 27992246 TI - Toe-in Landing Increases the Ankle Inversion Angle and Moment During Single-Leg Landing: Implications in the Prevention of Lateral Ankle Sprains. AB - CONTEXT: Identifying the foot positions that are vulnerable to lateral ankle sprains is important for injury prevention. The effects of foot position in the transverse plane on ankle biomechanics during landing are unknown. OBJECTIVE: To examine the effects of toe-in or toe-out positioning on ankle inversion motion and moment during single-leg landing. DESIGN: Repeated measures. SETTING: Motion analysis laboratory. PARTICIPANTS: 18 healthy participants (9 men and 9 women). INTERVENTIONS: Participants performed single-leg landing trials from a 30-cm high box under 3 conditions: natural landing, foot internally rotated (toe-in), and foot externally rotated (toe-out). MAIN OUTCOME MEASURES: 4 toe-in or toe-out angles were calculated against 4 reference coordinates (laboratory, pelvis, thigh, and shank) in the transverse plane. Ankle inversion angle, angular velocity, and external moment in the 200 ms after initial foot-to-ground contact were compared between the 3 landing conditions. RESULTS: All toe-in or toe-out angles other than those calculated against the shank were significantly different between each of the 3 landing conditions (P < .001). Ankle inversion angle, angular velocity, and moment were highest during toe-in landings (P < .01), while eversion angle and moment were highest during toe-out landings (P < .001). The effect sizes of these differences were large. Vertical ground reaction forces were not different between the 3 landing conditions (P = .290). CONCLUSIONS: Toe in or toe-out positioning during single-leg landings impacts on ankle inversion and eversion motion and moment. Athletes could train not to land with the toe-in positioning to prevent lateral ankle sprains. PMID- 27992247 TI - The Theory of Planned Behavior and Physical Activity Change: Outcomes of the Aging Well and Healthily Intervention Program for Older Adults. AB - The predictive value of the Theory of Planned Behavior (TPB) on intention and physical activity (PA) over time was examined. Data from the Aging Well and Healthily intervention program (targeting perceived behavioral control and attitude, not subjective norm) were analyzed, including pretest (T0), posttest (T1, except subjective norm) and 4-6 months follow-up (T2, PA outcomes only) (N = 387, M age 72 years). Structural equation modeling was used to test a TPB model. PA was measured subjectively using the Voorrips sports subscale (T0 and T2), items measured perceived increase in PA (T1), and adherence to exercises (T1 and T2). Model fit was good. The TPB explained variation in intention well (R2 .54 .60) and some PA behavior (R2 .13-.16). The intervention successfully got participants to exercise independent of the measured TPB concepts. More TPB studies in the context of interventions are needed. PMID- 27992248 TI - Deltoid Electromyography is Reliable During Submaximal Isometric Ramp Contractions. AB - The EMG and load relationship is commonly measured with multiple submaximal isometric contractions. This method is both time consuming and may introduce fatigue. The purpose of this study was to determine if the electromyography (EMG) amplitude from the middle deltoid was reliable during isometric ramp contractions (IRCs) at different angles of elevation and rates of force application. Surface EMG was measured at 3 shoulder elevation angles during IRCs at 4 submaximal levels of maximum voluntary contraction (MVC). Data were reliable in all conditions except during the rate relative to the subjects' MVC at 90 degrees for 30% and 40% MVC. The main effect for angle on EMG amplitude was found to be significant, p < .01. EMG at 90 degrees was greater than at 60 degrees (p < .017) and at 30 degrees (p < .017). The main effect of force level on EMG amplitude was significant, p < .01 and follow-up contrast demonstrated a significant (p < .001) linear increase of EMG amplitude with force level. We conclude that EMG amplitude from IRCs are reliable across all shoulder elevation angles and up to 40% MVC. IRCs are a feasible method for recording EMG at the deltoid. PMID- 27992250 TI - Impact of a Long Run on Injury-Related Biomechanics with Relation to Weekly Mileage in Trained Male Runners. AB - The purposes of this study were to compare selected biomechanical variables before and after a long run, and to assess the relationship between weekly running volume and changes in lower limb biomechanics after the run. Twelve trained habitual rearfoot strike male runners ran overground before and after a treadmill long run while kinematic and kinetic data were recorded. Repeated measures analysis of variance and Cohen's d effect sizes were used to compare kinematic and kinetic variables before and after the run. Loading rate was 6% higher after the run (p < .05) but this difference had a small effect size (d = .32). Moderate effects were found for a 25% increase in peak ankle eversion (d = 0.62) and a 10% increase in hip adduction (d = 0.60) after the run. These findings suggest that the completion of a submaximal long run does not yield potentially injurious lower limb biomechanics in uninjured rearfoot strike runners. Weekly running mileage was not correlated to biomechanical changes observed before and after the long run. Since biomechanical responses to the long run varied among runners, differences in other factors such as specific training regimens and neuromuscular control should be considered in future studies. PMID- 27992251 TI - A Comparative Study of the Effects of Pilates and Latin Dance on Static and Dynamic Balance in Older Adults. AB - The present study was designed to compare the effectiveness of exercise programs with Pilates and Latin dance on older adults' static and dynamic balance. Thirty two older adults were divided into three groups: Pilates group, Dance group, and Control group. Static and dynamic balance was assessed with following tasks: (a) tandem stance, (b) one-leg stance, and (c) periodic sway with and without metronome guidance. Analysis revealed a significant reduction of the trunk sway amplitude during the tandem stance with eyes closed, reduction in the center of pressure (CoP) displacement during one-leg stance, and increase in the amplitude of trunk oscillation during the sway task for both intervention groups, and reduction in the standard deviation of the CoP displacement during the metronome paced task only for the dance group. The differences in specific balance indices between the two programs suggest some specific adaptations that may provide useful knowledge for the selection of exercises that are better tailored to the needs of the old adult. PMID- 27992253 TI - Farm Fairs and Petting Zoos: A Review of Animal Contact as a Source of Zoonotic Enteric Disease. AB - Many public venues such as farms, fairs, and petting zoos encourage animal contact for both educational and entertainment purposes. However, healthy farm animals, including cattle, small ruminants, and poultry, can be reservoirs for enteric zoonotic pathogens, with human infections resulting in nausea, vomiting, diarrhea, and, in some cases, severe complications that can lead to death. As animals shed these organisms in their feces, contamination of themselves and their surroundings is unavoidable. The majority of North Americans reside in urban and suburban settings, and the general public often possess limited knowledge of agricultural practices and minimal contact with farm animals. Furthermore, there is a lack of understanding of zoonotic pathogens, particularly how these pathogens are spread and the human behaviors that may increase the risk of infection. Human risk behaviors include hand-to-mouth contact immediately after physical contact with animals and their environments, a practice that facilitates the ingestion of pathogens. It is often young children who become ill due to their under-developed immune systems and poorer hygienic practices compared with adults, such as more frequent hand-to-mouth behaviors, and infrequent or improper hand washing. These illnesses are often preventable, simply through adequate hygiene and hand washing. Our objective was to use a structured approach to review the main causal organisms responsible for human illnesses acquired in petting zoo and open farm environments, Shiga toxin producing Escherichia coli, nontyphoidal Salmonella, Campylobacter, and Cryptosporidium. Notable outbreaks involving direct contact with farm animals and farm, fair, or petting zoo environments are discussed and recommendations for how public venues can increase safety and hand hygiene compliance among visitors are proposed. The most effective protective measures against enteric illnesses include education of the public, increasing overall awareness of the risks and the importance of hand hygiene, as well as access to hand-washing facilities. PMID- 27992252 TI - Exploring the Objective and Perceived Environmental Attributes of Older Adults' Neighborhood Walking Routes: A Mixed Methods Analysis. AB - Walking is a central form of physical activity among older adults that is associated with the physical environment at various scales. This mixed-methods study employs a concurrent nested design to explore objective and perceived environmental characteristics of older adults' local walking routes. This was achieved by integrating quantitative Geographic Information System (GIS) data with qualitative data obtained using the Stanford Discovery Tool (DT). Fifty-nine community-dwelling middle-aged and older adults (14 men and 45 women aged 50+) were recruited in a snowball approach through community centers in the city of Haifa (Israel). Four neighborhood environment themes were identified: pedestrian infrastructure, access to destinations, aesthetics, and environmental quality. Both geometrical traits (i.e., distance, slope) and urban features (i.e., land uses, greenery) of the route may impact the experience of walking. The findings thus highlight the importance of micro-scale environmental elements in shaping environmental perceptions, which may consequently influence the choice of being active. PMID- 27992254 TI - An Investigation of Structure, Flexibility, and Function Variables that Discriminate Asymptomatic Foot Types. AB - It has been suggested that foot type considers not only foot structure (high, normal, low arch), but also function (overpronation, normal, oversupination) and flexibility (reduced, normal, excessive). Therefore, this study used canonical regression analyses to assess which variables of foot structure, function, and flexibility can accurately discriminate between clinical foot type classifications. The feet of 61 asymptomatic, healthy adults (18-77 years) were classified as cavus (N = 24), rectus (N = 54), or planus (N = 44) using standard clinical measures. Custom jigs assessed foot structure and flexibility. Foot function was assessed using an emed-x plantar pressure measuring device. Canonical regression analyses were applied separately to extract essential structure, flexibility, and function variables. A third canonical regression analysis was performed on the extracted variables to identify a combined model. The initial combined model included 30 extracted variables; however 5 terminal variables (malleolar valgus index, arch height index while sitting, first metatarsophalangeal joint laxity while standing, pressure-time integral and maximum contact area of medial arch) were able to correctly predict 80.7% of foot types. These remaining variables focused on specific foot characteristics (hindfoot alignment, arch height, midfoot mechanics, Windlass mechanism) that could be essential to discriminating foot type. PMID- 27992255 TI - Drosophila H2A and H2A.Z Nucleosome Sequences Reveal Different Nucleosome Positioning Sequence Patterns. AB - Nucleosomes are implicated in transcriptional regulation as well as in packing and stabilizing the DNA. Nucleosome positions affect the transcription by impeding or facilitating the binding of transcription factors. The DNA sequence, especially the periodic occurrences of dinucleotides, is a major factor that affects the nucleosome positioning. We analyzed the Drosophila DNA sequences bound by H2A and H2A.Z nucleosomes. Periodic patterns of dinucleotides (weak weak/strong-strong or purine-purine/pyrimidine-pyrimidine) were identified as WW/SS and RR/YY nucleosome positioning sequence (NPS) patterns. The WW/SS NPS pattern of the H2A nucleosome has a 10-bp period of weak-weak/strong-strong (W = A or T; S = G or C) dinucleotides. The 10-bp periodicity, however, is disrupted in the middle of the sequence. At the dyad, the SS dinucleotide is preferred. On the other hand, the RR/YY NPS pattern has an 18-bp periodicity of purine purine/pyrimidine-pyrimidine (R = A or G; Y = T or C) dinucleotides. The NPS patterns from H2A.Z nucleosomes differ from the NPS patterns from H2A nucleosomes. The RR/YY pattern of H2A.Z nucleosomes has major peaks shifted by 10 bp deviated from the H2A nucleosome pattern. The H2A and H2A.Z nucleosomes have different sequence preferences. The shifted peaks coincide with DNA regions interacting with the histone loops. PMID- 27992256 TI - Effects of a Short-Term Conditioning Intervention on Knee Flexor Sensorimotor and Neuromuscular Performance in Men. AB - CONTEXT: Long-term conditioning programs for enhanced sensorimotor performance have been causally linked to reduced risk of serious ligamentous injury. However, the efficacy of brief, short-term conditioning interventions has not been established. OBJECTIVE: To assess the effects of short-term sensorimotor conditioning on the knee flexors. DESIGN: Randomized controlled trial. SETTING: University research laboratory. PARTICIPANTS: 23 males randomly assigned to conditioning (n = 12; age: 20.5 +/- 1.8 y; height: 1.80 +/- 0.05 m; body mass: 74.3 +/- 6.0 kg [mean +/- SD]) and no-conditioning control (n = 11; age: 20.6 +/- 1.9 y; height: 1.79 +/- 0.05 m; body mass: 73.6 +/- 6.3 kg) groups. INTERVENTION: Sensorimotor conditioning of the nondominant leg (4 sessions/wk; 3 wk). MAIN OUTCOME MEASURES: Sensorimotor (blind force and limb-position-replication errors) and neuromuscular (peak force, electromechanical delay [volitional and magnetically evoked]) performance of the knee flexors of both legs were assessed. The contralateral limb and an antecedent period of no conditioning were controls. RESULTS: The conditioned leg showed decreased force error to 3.8% (3.8 +/- 6.9% vs 6.3 +/- 3.7% [mean +/- SD], post- vs preconditioning, respectively; F1,21 = 5.4; P = .04) and a trend toward decreased positional error to 2.0% (2.0 +/- 6.9% vs 4.7 +/- 7.7%, post- vs preconditioning; F1,21 = 2.7; P = .06). Performances were not altered in the control conditions. Modest improvements were noted for volitional electromechanical delay following conditioning (39.8 +/- 4.3 ms vs 42.3 +/- 5.2 ms [F1,21 = 7.2; P = .01]), but peak force (overall, 202 +/- 78 N) and magnetically evoked electromechanical delay (24.7 +/- 4.2 ms) were not influenced. CONCLUSION: Short-term conditioning offered improved sensorimotor performance and positively affected neuromuscular determinants of knee flexor performance in men. PMID- 27992257 TI - Agitation Management in Pediatric Males with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. AB - OBJECTIVES: Severe agitation is a common symptom in pediatric cases of anti-N methyl-D-aspartate receptor (anti-NMDAR) encephalitis-an autoimmune encephalitis with prominent neuropsychiatric symptoms. Agitation is a major barrier to treatment of the underlying disease process and increases patients' risk of harming themselves and others. Furthermore, male patients often have undetectable tumors and are especially at risk for extended hospitalization, but have been infrequently studied. This report presents a case series of four pediatric male patients with anti-NMDAR encephalitis complicated by agitation, the strategies used to address treatment challenges, and a review of the current literature. METHODS: A chart review of four agitated pediatric male patients with anti-NMDAR encephalitis and a PubMed search of the current literature were conducted. RESULTS: A number of first-generation and second-generation antipsychotics (SGAs) have been reported for use in child and adult patients; however, treatment with these antipsychotics often has been complicated by movement disorders and autonomic instability caused by the underlying encephalitis that appears similar to and can be exacerbated by adverse effects of antipsychotics, including neuroleptic malignant syndrome (NMS), extrapyramidal symptoms (EPS), and tardive dyskinesia. The literature shows SGAs to be less likely to cause NMS and quetiapine to be one of the least likely SGAs to cause EPS. However, quetiapine has rarely been reported for use in patients with anti-NMDAR encephalitis. In the four pediatric male patients, quetiapine was generally effective, well tolerated, and not associated with NMS or significant EPS. CONCLUSION: These cases and review of the literature suggest that quetiapine may be particularly beneficial for treating agitation secondary to anti-NMDAR encephalitis in pediatric patients and have fewer adverse effects. PMID- 27992259 TI - From the Editor-in-Chief's Desk. PMID- 27992258 TI - Challenges in the Psychopharmacological Management of Very Early-Onset Schizophrenia and Anxiety. PMID- 27992260 TI - Improvement of Elite Female Athletes' Physical Performance With a 3-Week Unexpected Disturbance Program. AB - CONTEXT: Sensorimotor training is commonly used in a rehabilitative setting; however, the effectiveness of an unexpected disturbance program (UDP) to enhance performance measures in uninjured elite athletes is unknown. OBJECTIVE: To assess the impact of a 3-wk UDP program on strength, power, and proprioceptive measures. DESIGN: Matched-group, pre-post design. SETTING: National sport institute. PARTICIPANTS: 21 international-level female field hockey athletes. INTERVENTION: Two 45-min UDP sessions were incorporated into each week of a 3-wk training program (total 6 sessions). MAIN OUTCOME MEASURES: 1-repetition-maximum strength, lower-limb power, 20-m running speed, and proprioception tests were performed before and after the experimental period. RESULTS: Substantial improvements in running sprint speed at 5-m (4.4 +/- 2.6%; effect size [ES]: 0.88), 10-m (2.1 +/- 1.9%; ES: 0.51), and 20-m (1.0 +/- 1.6%; ES: 0.23) were observed in the UDP group. Squat-jump performance was also clearly enhanced when compared to the control group (3.1 +/- 6.1%; ES: 0.23). Small but clear improvements in maximal strength were observed in both groups. CONCLUSIONS: A 3-wk UDP can elicit clear enhancements in running sprint speed and concentric-only jump performance. These improvements are suggestive of enhanced explosive strength and are particularly notable given the elite training status of the cohort and relatively short duration of the intervention. Thus, the authors would reiterate the statement by Gruber et al (2004) that sensorimotor training is a "highly efficient" modality for improving explosive strength. PMID- 27992262 TI - The KIT Motion-Language Dataset. AB - Linking human motion and natural language is of great interest for the generation of semantic representations of human activities as well as for the generation of robot activities based on natural language input. However, although there have been years of research in this area, no standardized and openly available data set exists to support the development and evaluation of such systems. We, therefore, propose the Karlsruhe Institute of Technology (KIT) Motion-Language Dataset, which is large, open, and extensible. We aggregate data from multiple motion capture databases and include them in our data set using a unified representation that is independent of the capture system or marker set, making it easy to work with the data regardless of its origin. To obtain motion annotations in natural language, we apply a crowd-sourcing approach and a web-based tool that was specifically build for this purpose, the Motion Annotation Tool. We thoroughly document the annotation process itself and discuss gamification methods that we used to keep annotators motivated. We further propose a novel method, perplexity-based selection, which systematically selects motions for further annotation that are either under-represented in our data set or that have erroneous annotations. We show that our method mitigates the two aforementioned problems and ensures a systematic annotation process. We provide an in-depth analysis of the structure and contents of our resulting data set, which, as of October 10, 2016, contains 3911 motions with a total duration of 11.23 hours and 6278 annotations in natural language that contain 52,903 words. We believe this makes our data set an excellent choice that enables more transparent and comparable research in this important area. PMID- 27992261 TI - Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings From Two Randomized Trials. AB - Context: Endogenous testosterone levels have been negatively associated with QTc interval in small case series; the effects of testosterone therapy on electrocardiographic parameters have not been evaluated in randomized trials. Objective: To evaluate the effects of testosterone replacement on corrected QT interval (QTcF) in two randomized controlled trials. Participants: Men with pre- and postrandomization electrocardiograms (ECGs) from the Testosterone and Pain (TAP) and the Testosterone Effects on Atherosclerosis in Aging Men (TEAAM) Trials. Interventions: Participants were randomized to either placebo or testosterone gel for 14 weeks (TAP) or 36 months (TEAAM). ECGs were performed at baseline and at the end of interventions in both trials; in the TEAAM trial ECGs were also obtained at 12 and 24 months. Outcomes: Difference in change in the QTcF between testosterone and placebo groups was assessed in each trial. Association of changes in testosterone levels with changes in QTcF was analyzed in men assigned to the testosterone group of each trial. Results: Mean total testosterone levels increased in the testosterone group of both trials. In the TAP trial, there was a nonsignificant reduction in mean QTcF in the testosterone group compared with placebo (effect size = -4.72 ms; P = 0.228) and the changes in QTcF were negatively associated to changes in circulating testosterone (P = 0.036). In the TEAAM trial, testosterone attenuated the age-related increase in QTcF seen in the placebo group (effect size= -6.30 ms; P < 0.001). Conclusion: Testosterone replacement attenuated the age-related increase in QTcF duration in men. The clinical implications of these findings require further investigation. PMID- 27992263 TI - Leveraging Large-Scale Semantic Networks for Adaptive Robot Task Learning and Execution. AB - This work seeks to leverage semantic networks containing millions of entries encoding assertions of commonsense knowledge to enable improvements in robot task execution and learning. The specific application we explore in this project is object substitution in the context of task adaptation. Humans easily adapt their plans to compensate for missing items in day-to-day tasks, substituting a wrap for bread when making a sandwich, or stirring pasta with a fork when out of spoons. Robot plan execution, however, is far less robust, with missing objects typically leading to failure if the robot is not aware of alternatives. In this article, we contribute a context-aware algorithm that leverages the linguistic information embedded in the task description to identify candidate substitution objects without reliance on explicit object affordance information. Specifically, we show that the task context provided by the task labels within the action structure of a task plan can be leveraged to disambiguate information within a noisy large-scale semantic network containing hundreds of potential object candidates to identify successful object substitutions with high accuracy. We present two extensive evaluations of our work on both abstract and real-world robot tasks, showing that the substitutions made by our system are valid, accepted by users, and lead to a statistically significant reduction in robot learning time. In addition, we report the outcomes of testing our approach with a large number of crowd workers interacting with a robot in real time. PMID- 27992264 TI - Detection of Subtle Context-Dependent Model Inaccuracies in High-Dimensional Robot Domains. AB - Autonomous robots often rely on models of their sensing and actions for intelligent decision making. However, when operating in unconstrained environments, the complexity of the world makes it infeasible to create models that are accurate in every situation. This article addresses the problem of using potentially large and high-dimensional sets of robot execution data to detect situations in which a robot model is inaccurate-that is, detecting context dependent model inaccuracies in a high-dimensional context space. To find inaccuracies tractably, the robot conducts an informed search through low dimensional projections of execution data to find parametric Regions of Inaccurate Modeling (RIMs). Empirical evidence from two robot domains shows that this approach significantly enhances the detection power of existing RIM detection algorithms in high-dimensional spaces. PMID- 27992265 TI - Recent Data Sets on Object Manipulation: A Survey. AB - Data sets is crucial not only for model learning and evaluation but also to advance knowledge on human behavior, thus fostering mutual inspiration between neuroscience and robotics. However, choosing the right data set to use or creating a new data set is not an easy task, because of the variety of data that can be found in the related literature. The first step to tackle this issue is to collect and organize those that are available. In this work, we take a significant step forward by reviewing data sets that were published in the past 10 years and that are directly related to object manipulation and grasping. We report on modalities, activities, and annotations for each individual data set and we discuss our view on its use for object manipulation. We also compare the data sets and summarize them. Finally, we conclude the survey by providing suggestions and discussing the best practices for the creation of new data sets. PMID- 27992266 TI - Big Data on Robotics. PMID- 27992267 TI - DOOMED: Direct Online Optimization of Modeling Errors in Dynamics. AB - It has long been hoped that model-based control will improve tracking performance while maintaining or increasing compliance. This hope hinges on having or being able to estimate an accurate inverse dynamics model. As a result, substantial effort has gone into modeling and estimating dynamics (error) models. Most recent research has focused on learning the true inverse dynamics using data points mapping observed accelerations to the torques used to generate them. Unfortunately, if the initial tracking error is bad, such learning processes may train substantially off-distribution to predict well on actual observed acceleration rather than the desired accelerations. This work takes a different approach. We define a class of gradient-based online learning algorithms we term Direct Online Optimization of Modeling Errors in Dynamics (DOOMED) that directly minimize an objective measuring the divergence between actual and desired accelerations. Our objective is defined in terms of the true system's unknown dynamics and is therefore impossible to evaluate. However, we show that its gradient is observable online from system data. We develop a novel adaptive control approach based on running online learning to directly correct (inverse) dynamics errors in real time using the data stream from the robot to accurately achieve desired accelerations during execution. PMID- 27992269 TI - Future Challenges for Drug Development in Renal Cell Carcinoma. PMID- 27992268 TI - Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial. AB - Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective. PMID- 27992270 TI - Role of High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Men With Previously Treated Germ Cell Tumors. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 39-year-old, previously healthy man presented with a left testicular mass, confirmed on ultrasound. He underwent left inguinal orchiectomy, which disclosed testicular carcinoma composed of 90% choriocarcinoma, 9% seminoma, and 1% teratoma. Imaging revealed numerous metastases in the lungs, liver, and brain. Prechemotherapy levels of serum tumor markers were alpha-fetoprotein (AFP) 2.0 ng/mL, human chorionic gonadotropin (hCG) 151,111 IU/L, and lactate dehydrogenase 588 U/L. He received four courses of etoposide, ifosfamide, and cisplatin chemotherapy, given without bleomycin because of the anticipated need for postchemotherapy thoracic surgery. He had an incomplete response to induction chemotherapy. The serum hCG level was 8.1 IU/L, and there were residual lesions in the liver and lungs whereas the brain metastases had nearly resolved. His Eastern Cooperative Oncology Group performance status was zero. He had no symptoms of ototoxicity or peripheral neurotoxicity. Repeat serum hCG levels after chemotherapy were 12.3 IU/L at 2 weeks and 325 IU/L at 4 weeks. He was referred to discuss optimal ongoing treatment. PMID- 27992271 TI - Family Perspectives on Hospice Care Experiences of Patients with Cancer. AB - Purpose To determine whether hospice use by patients with cancer is associated with their families' perceptions of patients' symptoms, goal attainment, and quality of end-of-life (EOL) care. Methods We interviewed 2,307 families of deceased patients with advanced lung or colorectal cancer who were enrolled in the Cancer Care Outcomes Research and Surveillance study (a multiregional, prospective, observational study) and died by 2011. We used propensity-score matching to compare family-reported outcomes for patients who did and did not receive hospice care, including the presence and relief of common symptoms (ie, pain, dyspnea), concordance with patients' wishes for EOL care and place of death, and quality of EOL care. We also examined associations between hospice length of stay and these outcomes among hospice enrollees. Results In a propensity-score-matched sample of 1,970 individuals, families of patients enrolled in hospice reported more pain in their patient compared with those not enrolled in hospice. However, families of patients enrolled in hospice more often reported that patients received "just the right amount" of pain medicine (80% v 73%; adjusted difference, 7 percentage points; 95% confidence interval [CI], 1 to 12 percentage points) and help with dyspnea (78% v 70%; adjusted difference, 8 percentage points; 95% CI, 2 to 13 percentage points). Families of patients enrolled in hospice also more often reported that patients' EOL wishes were followed (80% v 74%; adjusted difference, 6 percentage points; 95% CI, 2 to 11 percentage points) and "excellent" quality EOL care (57% v 42%; adjusted difference, 15 percentage points; 95% CI, 11 to 20). Families of patients who received > 30 days of hospice care reported the highest quality EOL outcomes. Conclusion Hospice care is associated with better symptom relief, patient-goal attainment, and quality of EOL care. Encouraging earlier and increased hospice enrollment may improve EOL experiences for patients with cancer and their families. PMID- 27992273 TI - High Occurrence Rate and Contamination Level of Bacillus cereus in Organic Vegetables on Sale in Retail Markets. AB - Organic foods have risen in popularity recently. However, the increased risk of bacterial contamination of organic foods has not been fully evaluated. In this study, 100 samples each of organic and conventional fresh vegetables (55 lettuce samples and 45 sprout samples) sold in South Korea were analyzed for aerobic bacteria, coliforms, Escherichia coli, and Bacillus cereus. Although the aerobic bacteria and coliform counts were not significantly different between the two farming types (p > 0.05), the occurrence rate of B. cereus was higher in organically cultivated vegetables compared with those grown conventionally (70% vs. 30%, respectively). The mean contamination level of B. cereus-positive organic samples was also significantly higher (1.86 log colony-forming unit [CFU]/g vs. 0.69 log CFU/g, respectively) (p < 0.05). In addition, six samples of organic vegetables were found to be contaminated with B. cereus at over 4 log CFU/g categorized as unsatisfactory according to Health Protection Agency guideline. The relatively higher occurrence rate of B. cereus in organic vegetables emphasizes the importance of implementing control measures in organic vegetable production and postharvest processing to reduce the risk of food poisoning. PMID- 27992272 TI - Accrual of Older Patients With Breast Cancer to Alliance Systemic Therapy Trials Over Time: Protocol A151527. AB - Purpose Despite increasing awareness of accrual challenges, it is unknown if accrual of older patients to breast cancer treatment trials is improving. Methods We examined accrual of older patients to Alliance for Clinical Trials in Oncology systemic therapy breast cancer trials during 1985-2012 and compared disease characteristics and reasons for therapy cessation for older (age >= 65 years and >= 70 years) versus younger (age < 65 years and < 70 years) participants. To examine accrual trends, we modeled age as a function of time, using logistic regression. Results Overall, 17% of study participants were >= 65 years of age. Approximately 15%, 24%, and 24% of participants in adjuvant, neoadjuvant, and metastatic trials were age >= 65 years, and 7%, 15%, and 13% were age >= 70 years, respectively. The odds of a patient age >= 65 years enrolling significantly increased over time for adjuvant trials (odds ratio [OR] per year, 1.04; 95% CI, 1.04 to 1.05) but decreased significantly for neoadjuvant and metastatic trials (OR, 0.62; 95% CI, 0.58 to 0.67 and OR, 0.98, 95% CI, 0.97 to 1.00). Similar trends were seen for those age >= 70 years but these were statistically significant for adjuvant and neoadjuvant trials only (OR, 1.05, 95% CI, 1.04 to 1.07; and OR, 0.57, 95% CI, 0.52 to 0.62). In general, those age >= 65 years ( v those < 65 years) in adjuvant studies had a higher mean number of lymph nodes involved and more hormone receptor-negative tumors, although tumor sizes were similar. Early protocol treatment cessation was also more frequent in those age >= 65 years (50%) versus < 65 years (35.9%) across trials. Conclusion Older patients with breast cancer remain largely underrepresented in cooperative group therapeutic trials. We observed some improvement in accrual to adjuvant trials but worsening of accrual for neoadjuvant/metastatic trials. Novel strategies to increase accrual of older patients are critical to meaningfully change the evidence base for this growing patient population. PMID- 27992274 TI - Establishing a nurse practitioner model to enhance continuity between palliative care settings. AB - BACKGROUND: Nurse practitioners (NP) are relatively new in Australia with national registration achieved in 2010. Most NP-related literature is about establishing models and scope of practice. This paper reports on the establishment and 12-month evaluation of an NP model of care, between inpatient and community palliative care services, developed to coordinate client care between hospital and home. AIM: To enhance patient outcomes, in hospital or home; to enhance professional relationships between services and facilitate effective discharges and admissions between services. DESIGN AND SETTING: Both services worked together to develop an evaluation framework, based on agreed key performance indicators. RESULTS: The NP model contributed to earlier discharges from hospital and fewer hospital admissions for those being cared for at home. There are developing opportunities to strengthen professional relationships through clinical and educational collaboration. CONCLUSION: The model has benefited both patient care and clinical cooperation between services. PMID- 27992275 TI - Life transitions of adolescents and young adults with life-limiting conditions. AB - AIMS: A systematic review was conducted to appraise and classify evidence related to the life transitions of adolescents and young adults with life-limiting conditions. METHODS: The databases searched were MEDLINE, CINAHL, PsycINFO, CancerLit, and AMED. Methodological quality was assessed using an established tool and the final articles included in the study were rated as moderate to high quality. Articles were then assessed based on the insight that they provided into life transitions for adolescents and young adults. RESULTS: Eighteen studies were included in the final review, with two major life transitions identified as pertinent: 'illness transition' and 'developmental transition'. These concurrent transitions were found to be relevant to adolescents and young adults with life limiting conditions, generating complex needs. Sub-themes within the transitions were also identified. Furthermore, the illness transition was found to also impact significant others, namely family members, having physical, mental and emotional health implications and requiring them to make adaptations. CONCLUSIONS: Future research is needed to focus on adolescent and young adult perspectives to bring further insight into these key transitions, since such perspectives are currently underrepresented. Attention to the impact of the illness on the whole family would be useful to expand findings from this review. PMID- 27992276 TI - Politics and palliative care: Mali. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 27992277 TI - E-health in palliative care: what do research beginners need to know? PMID- 27992278 TI - Definition of compassion in healthcare: a systematic literature review. AB - AIM: To reflect on the definition of compassion and analyse the concepts encompassed by the term. BACKGROUND: A large number of authors have defined compassion, with certain nuances that differ from case to case. This raises the need for specificity in the definition of the term. DATA SOURCES: First, a systematic search was conducted of scientific databases. Second, a selection of experts were consulted and a request made to them for specific articles. Third, the snowball method was used. DESIGN: The keywords used in the literature search were 'compassion' and 'empathy', a MeSH term given for compassion. There are terms, such as self-compassion, compassion meditation, compassion fatigue and mindfulness, which, owing to their specific nature, were not included, because this study deals with the general aspects of compassion. RESULTS: The systematic search found 104 articles, of which 6 articles were selected after applying the inclusion and exclusion criteria. The eight experts provided a total of 14 references, of which seven articles met the inclusion criteria. Finally, 15 references were identified with the snowball method (n=28). CONCLUSIONS: Compassion originates as an empathic response to suffering, as a rational process which pursues patients' wellbeing, through specific, ethical actions directed at finding a solution to their suffering. We therefore define the term compassion to mean the sensitivity shown in order to understand another person's suffering, combined with a willingness to help and to promote the wellbeing of that person, in order to find a solution to their situation. This should be a duty in healthcare professionals' daily work. PMID- 27992279 TI - Compassion and care at the end of life: oncology nurses' experiences in South East Iran. AB - BACKGROUND: End of life (EOL) care is newly established in the Iranian context. Context, in this case, refers to the internal and external manifestation of the nurse values, norms and experiences that are learnt throughout life. AIM: The aim of this study was to explore nurses' experiences of caring for dying patients in Iran. METHODS: A phenomenological hermeneutic approach, influenced by the philosophy of Ricoeur, was used to analyse 10 oncology nurses' experiences of caring for dying persons. FINDINGS: Three themes emerged from the analysis: 1) seeing the patient as unique person, 2) being present and open to seeing patients as unique persons and 3) personal and professional development as a result of closeness between nurse and patient. Caring for dying persons means assisting them at the end of their lives. CONCLUSION: Caring relationships underlie professional palliative care and are essential in EOL care. Proper palliative education and professionally led supervision should be included in the Iranian nursing curriculum. PMID- 27992280 TI - Outcome measures can enhance palliative care. PMID- 27992281 TI - Analysis of Gauntlet Test Performance and Injury Risk in Intercollegiate Division I Female Soccer (Football) Players: A Retrospective Study. AB - CONTEXT: Injury risk factors and relevant assessments have been identified in women's soccer athletes. Other tests assess fitness (eg, the Gauntlet Test [GT]). However, little empirical support exists for the utility of the GT to predict time loss injury. OBJECTIVES: To examine the GT as a predictor of injury in intercollegiate Division I female soccer athletes. DESIGN: Retrospective, nonexperimental descriptive cohort study. SETTING: College athletic facilities. PARTICIPANTS: 71 female Division I soccer athletes (age 19.6 +/- 1.24 y, BMI 23.0 +/- 2.19). MAIN OUTCOME MEASURES: GT, demographic, and injury data were collected over 3 consecutive seasons. GT trials were administered by coaching staff each preseason. Participation in team-based activities (practices, matches) was restricted until a successful GT trial. Soccer-related injuries that resulted in time loss from participation were recorded. RESULTS: 71 subjects met the inclusion criteria, with 12 lower body time loss injuries sustained. Logistic regression models indicated that with each unsuccessful GT attempt, the odds of sustaining an injury increased by a factor of 3.5 (P < .02). The Youden index was 2 GT trials for success, at which sensitivity = .92 and specificity = .46. For successive GT trials before success (1, 2, or 3), the predicted probabilities for injury were .063, .194, and .463, respectively. CONCLUSIONS: The GT appears to be a convenient and predictive screen for potential lowerbody injuries among female soccer athletes in this cohort. Further investigation into the appropriate application of the GT for injury prediction is warranted given the scope of this study. PMID- 27992282 TI - Mortality Analysis of the Life Span Study (LSS) Cohort Taking into Account Multiple Causes of Death Indicated in Death Certificates. AB - Mortality analyses have been performed using underlying causes of death as reported on death certificates; these are uniquely determined for a deceased person according to the World Health Organization coding system. Comorbidities, the disease conditions other than the underlying cause of death from death certificates recording multiple causes of death, have rarely been explored in Life Span Study subjects. The purpose of this study was to clarify associations between atomic bomb radiation exposure and mortality from combinations of the underlying cause of death and comorbidities. The focused follow-up period was 1977-2003, prior to which death certificate accuracy was unreliable. The study cohort was comprised of 10,017 people for whom the category "all circulatory disease" was listed as the underlying cause of death, of which heart disease (rheumatic, hypertensive and ischemic heart disease) and stroke were major subtypes. Comorbidities considered were pneumonia, renal disease, diabetes mellitus, cancer and the major circulatory disease subtypes listed above. Poisson regression models were used for analyses. Excess relative risks (ERRs) for mortality at 1 Gy were significantly increased when cancer was comorbid with all circulatory disease, heart disease, ischemic heart disease or stroke, ranging from 0.61 [95% confidence interval (CI): 0.13, 1.41; N = 177] for all circulatory diseases to 1.60 (CI: 0.07, 4.86; N = 42) for ischemic heart disease. Among the other comorbidities, only diabetes comorbid with heart disease had a significant radiation dose response (ERR at 1 Gy of 0.62, CI: 0.10, 1.46; N = 128). It remains uncertain if the high ERRs with comorbid cancers were anomalous due to the small number of cases or some dissimilarity in statistical methodologies, or if this might suggest some pathogenetic basis for increased fatality. For this reason, further investigation is required. PMID- 27992283 TI - Transanal Endoscopic Microsurgery Combined with Laparoscopic Colectomy for Synchronous Colorectal Tumors: A Word of Caution. AB - BACKGROUND: The incidence of malignant synchronous colorectal tumors (SCRT) is between 2% and 5%, and the association of synchronous adenomatous polyps in colon cancer has been reported to be 15%-50%. Surgical resection is the primary treatment option for SCRT not amendable to endoscopic resection. Lesions in adjacent segments are usually treated with more extensive resection; however, there is still some controversy on how to best treat synchronous lesions in separate segments, especially when the rectum is involved. In this study, we aimed to report the outcome of patients with SCRT treated by laparoscopic colectomy combined with Transanal Endoscopic Microsurgery. METHODS: Data pertaining patients undergoing combined colectomy and Transanal Endoscopic Microsurgery (TEM) between 2004 and 2014 were retrospectively collected. RESULTS: 141 TEM performed in the study period, 9 (6.5%) with combined laparoscopic colectomy were included. Mean age was 69.1 +/- 10.6 years. There were 6 (66%) right, 2 (22%) left, and one (11%) sigmoid colectomy. All rectal lesions were benign adenomas, with mean tumor size 2.5 cm, and distance from the verge 9 +/- 2.5 cm. Lesions were located in lateral rectal wall in 4, posterior in 4, and anterior in one case. Seven patients had the colectomy before TEM, and 2 had the TEM first. Mean operative time was 245 minutes (range 185-313) for the combined procedures. Median time of hospitalization was 6 days (range 4-11). Six patients (66%) had prolonged postoperative diarrhea. The final rectal pathology reports were adenoma with high-grade dysplasia (HGD) in 5 patients and adenoma with low grade dysplasia in four cases. The colon pathology was T1 N0 in 3, T2 N0 in one, T3 N1 in one, adenoma with HGD in 2, and no residual tumor in 2 patients. Two patients underwent re-TEM for recurrent adenoma of rectum at 14 and 18 months postoperatively. CONCLUSION: The combination of TEM with laparoscopic colectomy is feasible and should be kept in mind as an alternative procedure in case of SCRT. However, more strict selection criteria should be considered and the disadvantages should be discussed with the patient. PMID- 27992285 TI - Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheumatoid arthritis? A systematic review and meta-analysis. AB - AIM: Identifying the predictors of responsiveness and adverse events in methotrexate (MTX) treated patients with rheumatoid arthritis (RA) has been the focus of most concern, but still without consistent consensus. METHODS: PubMed and OVID EMBASE were searched to collect relevant studies that addressed correlations between gene polymorphisms and efficacy and/or toxicity in MTX treated RA patients. Allelic, recessive, dominant and over-dominant model were applied. RESULTS: A total of 68 studies were included. For associations with efficacy, AMPD1 34C>T polymorphism was related to responsiveness in dominant model (odds ratio [OR]: 1.77; 95% CI: 1.19-2.63) and over-dominant model (OR: 1.59; 95% CI: 1.04-2.45). ATIC T675C polymorphism had association with responsiveness in recessive model (OR: 2.54; 95% CI: 1.23-5.26). For associations with toxicity, polymorphisms in TYMS 1494 del6 and FPGS rs10106 were correlated to absenting overall adverse events in recessive model (OR: 0.68; 95% CI: 0.49 0.95) and dominant model (OR: 0.54; 95% CI: 0.35-0.83) respectively while MTHFR C677T was associated with presenting overall adverse events in allelic model (OR: 1.29; 95% CI: 1.02-1.63), recessive model (OR: 1.38; 95% CI: 1.00-1.89) and dominant model (OR: 1.41; 95% CI: 1.02-1.94). CONCLUSION: Polymorphisms in AMPD1 34C>T and ATIC T675C predict responsiveness. The absence of TYMS 1494 del6 and FPGS rs10106 and presence of MTHFR C677T predict adverse events in RA patients treated with MTX. Moreover, variations of the associations were found between Caucasians and non-Caucasians. PMID- 27992286 TI - The Role of Gender in Neuropsychological Assessment in Healthy Adolescents. AB - CONTEXT: Research in college athletes has revealed significant gender differences in areas of verbal memory, visual memory, and reaction time. Additionally, research has focused on differences in neuropsychological components and gender in college populations; however, such differences in gender have not been documented in healthy adolescent populations. PURPOSE: To identify potential differences between males and females using different components of a common computerized neuropsychological test. METHODS: A computerized neuropsychological test battery (ImPACT(r)) was administered to 662 high-school age adolescent athletes (male: n = 451 female: n = 262). Differences between genders were calculated using a 1-way ANOVA. All statistical analyses were conducted using SPSS 23.0. Significance levels were set a priori at P < .05. RESULTS: A 1-way ANOVA revealed statistically significant differences between males and females for composite reaction time (F1,660 = 10.68, P = .001) and total symptom score (F1,660 = 81.20, P < .001). However, no statistically significant differences were found between males and females in composite verbal memory, visual memory, visual motor, or impulse control (P > .05). CONCLUSIONS: Significant differences between males and females were discovered for composite reaction time and total symptom scores, with females reporting more symptoms and slower reaction times at a baseline assessment. Increased symptom reporting by females may be attributed to both hormonal differences and increased honesty. Quicker reaction times in males may support theories that repetition of activities and quicker muscle contraction are gender dependent. However, additional research is necessary to understand gender differences in adolescent athletes during periods of cognitive and physical maturation. PMID- 27992287 TI - Evaluating Postural Control and Ankle Laxity Between Taping and High-Top Cleats in High School Football Players. AB - CONTEXT: Lateral ankle sprains are the most common injuries in high school sports. While ankle taping is a preferred method of external prophylactic support, its restrictive properties decline during exercise. The Under Armour(r) Highlight cleat is marketed on the premise that it provides added support without the need for additional ankle taping. OBJECTIVE: To determine if differences in ankle joint laxity and postural control exist between football players wearing the Under Armour(r) Highlight cleat (Under Armour Inc, Baltimore, MD) as compared to a low/mid-top cleat with ankle tape. DESIGN: Crossover trial. SETTING: Athletic training room and football practice field sideline. PATIENTS: 32 interscholastic football players (15.8 +/- 1.0 y; 178.9 +/- 7.4 cm; 87.1 +/- 21.4 kg). INTERVENTIONS: Ankle laxity was assessed using an instrumented ankle arthrometer (Blue Bay Research Inc, Milton, FL), while postural control testing was performed on the Tekscan MobileMatTM Balanced Error Scoring System (BESS; South Boston, MA). The 2 treatments included Under Armour(r) Highlight cleats and a low/mid-top cleat with ankle tape applied to the nondominant ankle only. Measurements were taken before and immediately after practice. MAIN OUTCOME MEASURES: The independent variable was treatment (Highlight vs low/mid-top cleat with ankle tape). Dependent variables included ankle arthrometry measures of anterior displacement (mm), inversion/eversion rotation (deg), and the modified BESS error scores. A linear mixed-effects model was used for analysis. RESULTS: The low/mid-top cleat with tape condition had significantly higher inversion range-of-motion (ROM) and inversion/eversion rotation postexercise when compared to the Highlight cleat (P < 0.05). CONCLUSIONS: The results of this study provide some evidence that the Under Armour(r) Highlight cleat restricts ankle ROM following a training session better than the taped low/mid-top cleat. Further study is warranted to determine if this high-top style of football cleat can reduce the incidence of ankle sprains and how it might compare to spat taping. PMID- 27992284 TI - Regeneration of Skeletal Muscle After Eccentric Injury. AB - Eccentric-contraction-induced skeletal muscle injuries, included in what is clinically referred to as muscle strains, are among the most common injuries treated in the sports medicine setting. Although patients with mild injuries often fully recover to their preinjury levels, patients who suffer moderate or severe injuries can have a persistent weakness and loss of function that is refractory to rehabilitation exercises and currently available therapeutic interventions. The objectives of this review were to describe the fundamental biophysics of force transmission in muscle and the mechanism of muscle-strain injuries, as well as the cellular and molecular processes that underlie the repair and regeneration of injured muscle tissue. The review also summarizes how commonly used therapeutic modalities affect muscle regeneration and opportunities to further improve our treatment of skeletal muscle strain injuries. PMID- 27992288 TI - Survey for Rickettsiae Within Fleas of Great Gerbils, Almaty Oblast, Kazakhstan. AB - Little is known of the endemicity of flea-borne rickettsiae in Kazakhstan. Thus, a survey for rickettsiae within great gerbil fleas was conducted in Almaty oblast. High prevalence of Rickettsia asembonensis was detected among Xenopsylla gerbilli, demonstrating that flea-borne rickettsiae are endemic to southeastern Kazakhstan. Interestingly, no Rickettsia typhi were detected in these same fleas. PMID- 27992289 TI - Athletes' Perception of Athletic Trainer Empathy: How Important Is It? AB - CONTEXT: Health care practitioners face increasing expectations to provide patient-centered care. Communication skills, specifically empathy, are critical in the provision of patient-centered care. Past work correlates empathy with improved patient satisfaction, compliance, and treatment outcomes. In particular, a predictive relationship exists between clients' ratings of their clinician's empathy and treatment outcomes. There is a dearth of studies examining empathy using qualitative methodology and factors of empathy in athletic training. OBJECTIVE: To gain an understanding of athletes' perceptions of empathy in the patient-clinician relationship. DESIGN: Qualitative interviews were completed using grounded-theory techniques. SETTING: A quiet office. PARTICIPANTS: A typical, purposeful sample of 15 college-age Division I student-athletes (8 female, 7 male; 19.3 +/- 1.2 y) from a variety of sports (football, wrestling, volleyball, baseball, etc) participated. DATA COLLECTION AND ANALYSIS: Researchers utilized an interview protocol designed to understand the factors of empathy related to athletic training. The interview protocol established a concept of empathy to help facilitate discussion of ideas. Data were transcribed, coded, and analyzed for themes and patterns using grounded-theory techniques. Trustworthiness of the data was ensured using an external auditor, member checks, and methods triangulation. RESULTS: Five themes described empathy: advocacy, communication, approachability, access, and competence. Advocacy was described as the athletic trainer (AT) representing the patient. Communication was the ability to listen reflectively; approachability emerged as the comfort and personal connection the patient felt with the AT. Access and technical competence were bridges required for the development of empathy. CONCLUSIONS: Providing patient centered care facilitated by developing good patient-clinician relationships is critical in enabling the best treatment outcomes. ATs portray empathy through advocacy, communication, and approachability. Empathy improves the patient clinician relationship and is critical for patient-centered care delivered by ATs. PMID- 27992290 TI - Patient-Reported Outcomes Following Platelet-Rich Plasma Injections in Treating Osteochondral Lesions of the Talus: A Critically Appraised Topic. AB - : Clinical Scenario: Osteochondral lesions (OCLs) of the talus can result from ankle sprains which are the most common injury in the physically active. Recently, platelet-rich plasma (PRP) has been used to develop an innovate treatment for OCLs of the talus. CLINICAL QUESTION: Do PRP injections improve self-reported pain and ankle function in patients with OCL of the talus? Summary of Key Findings: 3 randomized controlled trials were included. One of the studies compared a single dose of PRP to a single dose of hyaluronic acid (HA) or saline when added as an adjunct to microfracture surgery. Another study compared a group receiving a single dose of PRP after microfracture surgery to a group that only received microfracture surgery. The last study compared a series of 3 PRP injections to a series of 3 HA injections. In all 3 studies PRP appeared to be more effective in pain and function outcomes than comparison treatments. The superior outcomes of PRP were demonstrated at times as short as 4 weeks and as long as 25 months. Clinical Bottom Line: There is moderate to strong evidence that PRP produces favorable, short-term, pain and function results compared to HA, saline, and/or microfracture surgery alone. Strength of Recommendation: Level 2. PMID- 27992292 TI - Obstetric Outcomes in Adolescents Related to Body Mass Index and Compared with Low-Risk Adult Women. AB - OBJECTIVE: To evaluate in adolescents the association between body mass index (BMI) and obstetric outcomes and to determine whether the outcomes in the BMI groups of adolescents differ from those of a low-risk population of adult women. MATERIALS AND METHODS: This is a nationwide population-based register study. Obstetric outcomes of 31,386 singleton primiparous adolescents were evaluated in relation to BMI classes. Furthermore, the outcomes of the adolescents and 178,844 normal weight, nonsmoking, singleton primiparous women, 25-29 years old with no known comorbidity, defined as standard women, were compared. Multiple logistic regression models were used. Results are presented as crude odds ratios (ORs) or adjusted ORs and with a 95% confidence interval. RESULTS: Compared with normal weight adolescents, obese adolescents had a lower chance of a normal vaginal delivery (VD)-76% versus 85% [adjusted OR 0.61 (0.55-0.68)], a higher risk for acute cesarean section (CS)-8.9% versus 4.5% [adjusted OR 2.45 (2.08-2.88)], and stillbirth-0.7% versus 0.2% [adjusted OR 3.17 (1.74-5.77)]. Compared with standard women, overweight adolescents had a higher chance of a normal VD-82% versus 75% [crude OR 1.53 (1.44-1.64)] and a lower risk for acute CS-6.3% versus 7.1% [crude OR 0.85 (0.76-0.95)]. Obese adolescents had a lower risk for instrumental VD-8% versus 13% [crude OR 0.61 (0.53-0.71)] and obstetric anal sphincter injury-1% versus 3% [crude OR 0.38 (0.26-0.57)]. CONCLUSION: Several adverse obstetric outcomes were obesity related among adolescents. Overweight adolescents seemed to have better obstetric outcomes than standard women, something to consider when optimizing resources for women during pregnancy and delivery. PMID- 27992291 TI - Plant and Human MORC Proteins Have DNA-Modifying Activities Similar to Type II Topoisomerases, but Require One or More Additional Factors for Full Activity. AB - To elucidate one or more mechanisms through which microrchidia (MORC) proteins impact immunity, epigenetic gene silencing, and DNA modifications, the enzymatic activities of plant MORCs were characterized. Previously, we showed that plant MORC1s have ATPase and DNA endonuclease activities. Here, we demonstrate that plant MORCs have topoisomerase type II (topo II)-like activities, as they i) covalently bind DNA, ii) exhibit DNA-stimulated ATPase activity, iii) relax or nick supercoiled DNA, iv) catenate DNA, and v) decatenante kinetoplast DNA. Mutational analysis of tomato SlMORC1 suggests that a K loop-like sequence is required to couple DNA binding to ATPase stimulation as well as for efficient SlMORC1's DNA relaxation and catenation activities and in planta suppression of INF1-induced cell death, which is related to immunity. Human MORCs were found to exhibit the same topo II-like DNA modification activities as their plant counterparts. In contrast to typical topo IIs, SlMORC1 appears to require one or more accessory factors to complete some of its enzymatic activities, since addition of tomato extracts were needed for ATP-dependent, efficient conversion of supercoiled DNA to nicked/relaxed DNA and catenanes and for formation of topoisomer intermediates. Both plant and human MORCs bind salicylic acid; this suppresses their decatenation but not relaxation activity. PMID- 27992294 TI - Effects of a Novel Neurodynamic Tension Technique on Muscle Extensibility and Stretch Tolerance: A Counterbalanced Crossover Study. AB - CONTEXT: Neurodynamic tension affects hamstring extensibility and stretch tolerance and is considered important in hamstring injury management. Neurodynamic tension was postulated to affect segmental muscle extensibility and stretch tolerance and potentially also to demonstrate extrasegmental and contralateral effects. OBJECTIVES: To assess the effects of a novel sciatic tibial neurodynamic tension technique, the modified long sit slump (MLSS), on segmental, extrasegmental, and contralateral muscle extensibility and stretch tolerance. STUDY DESIGN: Counterbalanced crossover study. SETTING: University research laboratory. PARTICIPANTS: 13 healthy and active subjects (mean +/- SD age 24 +/- 8 y; BMI, 23.1 +/- 2.8 kg/m2). INTERVENTION: MLSS application (5 s, 5 repetitions, 3 sets) on 2 occasions with a 3-wk washout period, and either stance or skill-leg treated in a counterbalanced manner. MAIN OUTCOME MEASURES: Segmental and extrasegmental muscle extensibility was measured using passive straight-leg raise (PSLR) and prone knee bend (PKB) at pre-, immediately post-, and 1 h postintervention. Stretch-intensity ratings were measured using a simple numerical rating scale (SNRS). RESULTS: MLSS significantly increased PSLR and PKB bilaterally (P < .001). The effect for PSLR was greater in the ipsilateral leg compared to the contralateral leg (baseline to 1 h post: +9 degrees +/- 6 degrees and +5 degrees +/- 5 degrees , respectively, P < .001) but not for PKB (baseline to 1 h post: ipsilateral leg +5 degrees +/- 5 degrees , contralateral leg +5 degrees +/- 4 degrees ). For both PSLR and PKB the effect of the first session was retained at the start of the second session 3 wk later. SNRS data were consistent with increased stretch tolerance. CONCLUSIONS: Application of a novel sciatic-tibial neurodynamic tension technique, the MLSS, increases muscle extensibility and stretch tolerance segmentally, extrasegmentally and contralaterally. LEVEL OF EVIDENCE: 2C outcomes research. PMID- 27992293 TI - Molecular Characterization of Anaplasma sp. in Free-Living Gray Brockets (Mazama gouazoubira). AB - Bacteria in the genus Anaplasma are responsible for diseases in animals and humans. Studies carried out in Brazil have demonstrated that Brazilian deer are able to act as hosts of agents in the family Anaplasmataceae and are possibly potential reservoirs of these pathogens. Molecular and phylogenetic studies have been carried out on samples of two gray brocket specimens (Mazama gouazoubira) from the city of Guarapuava, state of Parana, Brazil, for the detection of Anaplasma sp. in these animals. Partial nucleotide sequences of the genes 16S rRNA and groESL were used for phylogenetic analyses and compared with other 13 and 17 partial sequences of the respective genes obtained in GenBank. These assessments showed topological incongruence among the trees generated in the phylogenetic analyses. Phylogenetic analysis based on the gene 16S rRNA of the genotypes amplified in the samples of this study was similar to those of A. bovis detected in dogs and wild deer in Japan, whereas studies carried out on gene groESL indicated proximity with sequences of Anaplasma sp. that were also isolated in deer in Japan and allocated in the same clade of partial sequences of A. phagocytophilum. As the 16S rRNA gene is highly conserved, with few polymorphic positions, it may show low reliability for studies on phylogenetic positioning. The present study detected an Anaplasma sp. genotype in two specimens of M. gouazoubira in southern Brazil, which may mean that this agent possibly circulates in deer populations, and demonstrated the need for studies related to the possible role of deer in enzootic cycles of Anaplasmataceae in Brazil. PMID- 27992295 TI - The Effect of Contralateral Exercise on Patient Pain and Range of Motion. AB - : Clinical Scenario: Pain and range of motion (ROM) deficits are 2 issues that are commonly treated by clinicians. In certain instances, clinicians are tasked with treating patients who report with both pain and limited mobility. Currently, clinicians utilize a variety of different methods to combat pain and ROM limitations, but in singularity. However, contralateral exercises (CEs) may be a viable option that can have an effect on pain, ROM, or simultaneous effect on both. CLINICAL QUESTION: For patients with pain and/or ROM deficits, will CE decrease pain and increase ROM? SUMMARY OF FINDINGS: CE can have a significant effect on ipsilateral muscle activation, strength, as well as available motion on the contralateral limb. However, there is limited research on CE that explores effects on pain. Clinical Bottom Line: According to current evidence, CE can be a feasible option for clinicians trying to increase a patient's ROM. Furthermore, there can be enhanced effects on stability, muscle strength, and muscle activation due to CE. Strength of Recommendation: Studies that have been included are a level of 4 or higher based on Center for Evidence Based Medicine. However, future studies both of higher levels and variability should be conducted. PMID- 27992296 TI - Comparison of the Therapeutic Effects of a Sling Exercise and a Traditional Stabilizing Exercise for Clinical Lumbar Spinal Instability. AB - CONTEXT: Specific muscle-stabilization training can be relevant to patients with clinical spinal instability symptoms. The authors hypothesized that performing sling exercise using an elastic band in patients with clinical spinal instability would lead to pain reduction and improved lumbar spine stability. OBJECTIVE: To compare supervised sling exercise with an elastic band with traditional stabilizing exercise in chronic lower back pain (LBP) patients with clinical spinal instability. DESIGN: Randomized assessor-blind controlled trial. SETTING: University rehabilitation hospital. MAIN OUTCOME MEASURES: The participants were evaluated thrice at baseline, immediately after, and 3 mo after the last treatment session with the Numeric Pain Rating Scale (NPRS) and by the Oswestry Disability Index (ODI). INTERVENTIONS: Participants were randomly assigned to 1 of 2 treatment groups: a traditional trunk-muscle-stabilizing exercise group or a sling-exercise with elastic bands group. The participants in all treatment groups attended treatment twice a week for 12 wk. RESULTS: The NPRS at immediately and 3 mo after treatments showed significantly higher improvement in the sling-exercise with elastic bands group than in the traditional trunk-muscle-stabilizing exercise group, respectively (P < .05). The ODI at immediately and 3 mo after treatment showed a significantly higher improvement in the sling-exercise with elastic bands group than in the traditional trunk-muscle-stabilizing exercise group, respectively (P < .05). CONCLUSION: A sling exercise with elastic bands leads to a reduction in pain and disability compared with a traditional stabilizing exercise, although traditional stabilizing exercise also shows good results in chronic LBP patients with clinical spinal instability. A sling exercise with an elastic band could be a useful treatment for chronic LBP with clinical spinal instability. PMID- 27992297 TI - Single-Port Robotic Cholecystectomy in Pediatric Patients: Single Institution Experience. AB - INTRODUCTION: Modifications to conventional laparoscopic cholecystectomy are aimed to decrease abdominal pain and improve cosmetic results. Single-port robotic cholecystectomy is a safe and feasible approach that has been reported in adults, though reports are limited in children. This study aims to report our experience with single-port robotic cholecystectomy in children, and to evaluate the safety, feasibility, and outcomes of this approach. METHODS: After single port robotic approach was available at our institution, we prospectively followed our patients who underwent a single-port robotic cholecystectomy from March 2013 to May 2015 in our children's hospital. RESULTS: There were 14 patients [female 11 (79%) versus male 3 (21%)], the average age was 12.20 +/- 4.97 years, with a mean body mass index of 28.01 +/- 8.57 m/kg2. Of the 14 patients, 4 (29%) had cholelithiasis with choledocolithiasis and had undergone an endoscopic retrograde cholangiopancreatography before the operation, 6 (43%) had symptomatic cholelithiasis, and 4 (28%) had acute cholecystitis. The median operative room time was 125 minutes (range 60-202), the median time of operation was 77.5 minutes (range 64-169), the median estimated blood loss was 2 mL (range 2-25), and a median length of stay was 1 day (range 0-2). There were no conversions to another approach. The median follow-up was 7 months (range 3-22). One patient (7%) developed an umbilical port site seroma, which was managed conservatively, no other complications occurred. CONCLUSIONS: Single-port robotic cholecystectomy is a feasible and safe approach for cholecystectomy in the pediatric population. More studies are required to compare it to different approaches. PMID- 27992298 TI - What is the future of pharmacogenomics in pain management? PMID- 27992299 TI - Operative and Immediate Postoperative Differences Between Traditional Multiport and Reduced Port Laparoscopic Total Splenectomy in Pediatric Patients. AB - BACKGROUND: Laparoscopy offers many benefits to splenectomy, such as reduced incisional pain and shortened hospital duration. The purpose of this study is to evaluate procedural and outcome differences between multiport (MP) and reduced port (RP) splenectomy when utilized to treat children. PATIENTS AND METHODS: An institutional review board approved retrospective analysis of all consecutive laparoscopic total splenectomies performed at a single institution between January 2010 and October 2015 was conducted. We evaluated demographics, surgical technique, instance of conversion, operative duration, estimated blood loss, need for intraoperative blood transfusion, postoperative length of stay, time to full feeds, complications, and follow-up duration. RESULTS: Over a 5-year period, 66 patients less than 20 years of age underwent laparoscopic total splenectomy. RP splenectomy was attempted in 14 patients. The remaining 52 were MP operations. Populations were comparable with regard to demographics. Preoperative splenic volumes (mL) were greater in the RP population (median [IQR]: 1377 [747-1508] versus 452 [242-710], P = .039). RP splenectomy demonstrated no difference compared to MP splenectomy in operative time (153 versus 138 minutes, P = .360), estimated blood loss (120 versus 154 mL, P = .634), or percent of cases requiring intraoperative blood transfusion (14 versus 23, P = .716). By the first postoperative day, 57% of RP and 17% of MP patients could be discharged (P = .005). Thirty-day readmission rates were similar, at 7% for RP and 8% for MP operations. Fever was the indication for all readmissions. Mean duration of follow-up is 28 months for MP and 13 months for RP cases. CONCLUSION: A reduced number of ports can be safely utilized for total splenectomy in pediatric patients without increasing procedural duration or need for intraoperative blood transfusion. In addition, rate of discharge on the first postoperative day was significantly higher in the RP splenectomy group. PMID- 27992300 TI - Identification of the Lymphatic Drainage Pattern of Esophageal Cancer with Near Infrared Fluorescent Imaging. AB - OBJECTIVE: Nodal status is one of the most important long-term prognostic factors for esophageal cancer. The aim of this study was to evaluate the ability of near infrared (NIR) light fluorescent imaging to identify the lymphatic drainage pattern of esophageal cancer. METHODS: Patients with distal esophageal cancer or esophagogastric junction cancer scheduled for esophagectomy were enrolled in this study. Before surgery, an endoscopy was performed with submucosal injection of 2 cc of indocyanine green (ICG) around the tumor. Real-time NIR images from the surgical field were obtained for each patient to visualize the lymphatic ICG drainage. RESULTS: A total of nine patients were included in this study. Ivor Lewis esophagectomy was performed in all cases. ICG drainage was visualized to first drain along the left gastric nodes in eight patients (88.9%) and toward the diaphragmatic nodes in one patient (11.1%). The median number of resected nodes was 32. Three patients (33.3%) presented nodal involvement. All of them had positive nodes in the first nodal station identified with ICG. CONCLUSIONS: Evaluation of the lymphatic drainage pattern with real-time NIR light fluorescent technique is feasible. Distal and esophagogastric junction tumors showed to drain first in the left gastric nodes in most of the cases. PMID- 27992302 TI - Abstracts of Presentations at the 2016 Soybean Cyst Nematode Conference. PMID- 27992303 TI - The Hamstrings-Injury-Mechanism Debate: Are We Close to an Agreement? PMID- 27992301 TI - Fine-mapping of antipsychotic response genome-wide association studies reveals novel regulatory mechanisms. AB - AIM: Noncoding variation has demonstrated regulatory effects on disease treatment outcomes. This study investigated the potential functionality of previously implicated noncoding variants on schizophrenia treatment response. MATERIALS & METHODS: Predicted regulatory potential of variation identified from antipsychotic response genome-wide association studies was determined. Prioritized variants were assessed for association(s) with treatment outcomes in a South African first episode schizophrenia cohort (n = 103). RESULTS: Bioinformatic and association results implicated a relationship between regulatory variants, expression of MANBA, COL9A2 and NFKB1, and treatment response. Three SNPs were associated with poor outcomes (rs230493: p = 1.88 * 10 6; rs3774959: p = 1.75 * 10-5; and rs230504: p = 1.48 * 10-4). CONCLUSION: This study has thoroughly investigated previous GWAS to pinpoint variants that may play a causal role in poor schizophrenia treatment outcomes, and provides potential candidate genes for further study in the field of antipsychotic response. PMID- 27992304 TI - The Dynatron Solaris(r) Ultrasound Machine: Slower Heating Than Textbook Recommendations at 3 MHz, 1.0 W/cm2. AB - CONTEXT: Therapeutic ultrasound clinical parameters are provided in many modality textbooks based on research performed with the Omnisound brand. Literature exists to support variability in heating rates with different manufacturers. It is unknown if the Dynatron Solaris heats at rates consistent with textbook recommendations. OBJECTIVE: Determine the rate of tissue-temperature increases in the medial triceps surae with the Dynatron Solaris(r) 708 ultrasound unit. DESIGN: 3 * 13 repeated measures. Independent variables were tissue depth (1.0, 1.75, and 2.5 cm) and time (13 time periods throughout the treatment). SETTING: Research laboratory. PARTICIPANTS: 30 healthy volunteers (female = 11, male = 19; age 21.30 +/- 1.95 y; adipose thickness = 0.54 +/- 0.15 cm). INTERVENTION: Three thermocouples were inserted into the medial triceps surae at 1.0, 1.75, and 2.5 cm depths. A continuous 3-MHz, 1.0-W/cm2 for 20 minutes ultrasound treatment was performed with a Dynatron Solaris 708 machine. MAIN OUTCOME MEASURES: Intramuscular tissue-temperature increases at each depth throughout the 20-min treatment. RESULTS: There was a significant main effect of depth (F2,52 = 29.76, P < 0.001) and time (F12,312 = 181.59, P < .001) and a significant interaction between times and depths (F24,624 = 15.49, P < .001). The 1.0-cm depth increased 4.22 +/- 1.58 degrees C in 6 min (0.70 degrees C/min rate), the 1.75-cm depth increased 3.93 +/- 1.94 degrees C in 10 min (0.39 degrees C/min rate), and the 2.5-cm depth increased 3.60 +/- 1.86 degrees C in 20 min (0.18 degrees C/min rate). CONCLUSIONS: The rate of tissue-temperature increase varied at each depth and the 1.0-cm depth was the only rate similar to textbooks. Clinicians will not reach tissue-temperature goals using Omnisound textbook parameters on the Dynatron Solaris 708 at depths greater than 1.0 cm, which may affect clinicians, educators, and state-certification exams. PMID- 27992305 TI - Healthcare Provider Attitudes of Safety of Intrauterine Devices in the Postpartum Period. AB - OBJECTIVE: Immediate postpartum intrauterine devices (IUDs) have been underutilized in the United States despite their known safety. Understanding how providers' attitudes contribute to underutilization is important in improving access. Our objective was to examine healthcare providers' perceptions of the safety of immediate postpartum IUDs before publication of United States contraceptive guidelines. MATERIALS AND METHODS: We analyzed survey data collected from December 2009 to March 2010 from 635 office-based physicians and 1368 Title X clinic providers (overall response rate of 64.8%). Providers were asked how safe they thought copper and levonorgestrel (LNG) IUDs were in postpartum women (very safe, safe, unsafe, very unsafe, and unsure). Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for characteristics associated with considering immediate and delayed postpartum IUDs to be safe. RESULTS: Less than 40% of respondents considered immediate or delayed IUD insertion to be safe. Providers with <1 day of family planning training had decreased odds of considering immediate postpartum IUD insertion to be safe compared with unsafe/unsure (aOR 0.18, 95% CI 0.04-0.84 for copper IUD and aOR 0.17, 95% CI 0.04-0.81 for LNG-IUD). Providers without training in postpartum or interval copper IUD insertion had decreased odds of considering immediate postpartum copper IUD insertion (aOR 0.40, 95% CI 0.16-0.79) and delayed postpartum insertion for both IUD types to be safe (aOR 0.34, 95% CI 0.18-0.66 for copper IUD and aOR 0.41, 95% CI 0.21-0.77 for LNG-IUD). CONCLUSIONS: Before United States contraceptive guidelines, a majority of providers perceived immediate postpartum IUDs to be unsafe. PMID- 27992306 TI - The Vascular Pathogen Verticillium longisporum Does Not Affect Water Relations and Plant Responses to Drought Stress of Its Host, Brassica napus. AB - Verticillium longisporum is a host-specific vascular pathogen of oilseed rape (Brassica napus L.) that causes economic crop losses by impairing plant growth and inducing premature senescence. This study investigates whether plant damage through Verticillium stem striping is due to impaired plant water relations, whether V. longisporum affects responses of a susceptible B. napus variety to drought stress, and whether drought stress, in turn, affects plant responses to V. longisporum. Two-factorial experiments on a susceptible cultivar of B. napus infected or noninfected with V. longisporum and exposed to three watering levels (30, 60, and 100% field capacity) revealed that drought stress and V. longisporum impaired plant growth by entirely different mechanisms. Although both stresses similarly affected plant growth parameters (plant height, hypocotyl diameter, and shoot and root dry matter), infection of B. napus with V. longisporum did not affect any drought-related physiological or molecular genetic plant parameters, including transpiration rate, stomatal conductance, photosynthesis rate, water use efficiency, relative leaf water content, leaf proline content, or the expression of drought-responsive genes. Thus, this study provides comprehensive physiological and molecular genetic evidence explaining the lack of wilt symptoms in B. napus infected with V. longisporum. Likewise, drought tolerance of B. napus was unaffected by V. longisporum, as was the level of disease by drought conditions, thus excluding a concerted action of both stresses in the field. Although it is evident that drought and vascular infection with V. longisporum impair plant growth by different mechanisms, it remains to be determined by which other factors V. longisporum causes crop loss. PMID- 27992307 TI - Spatial Genetic Structure of Coffee-Associated Xylella fastidiosa Populations Indicates that Cross Infection Does Not Occur with Sympatric Citrus Orchards. AB - Xylella fastidiosa, an economically important plant-pathogenic bacterium, infects both coffee and citrus trees in Brazil. Although X. fastidiosa in citrus is well studied, knowledge about the population structure of this bacterium infecting coffee remains unknown. Here, we studied the population structure of X. fastidiosa infecting coffee trees in Sao Paulo State, Brazil, in four regions where citrus is also widely cultivated. Genotyping of over 500 isolates from coffee plants using 14 genomic microsatellite markers indicated that populations were largely geographically isolated, as previously found with populations of X. fastidiosa infecting citrus. These results were supported by a clustering analysis, which indicated three major genetic groups among the four sampled regions. Overall, approximately 38% of isolates showed significant membership coefficients not related to their original geographical populations (i.e., migrants), characterizing a significant degree of genotype flow among populations. To determine whether admixture occurred between isolates infecting citrus and coffee plants, one site with citrus and coffee orchards adjacent to each other was selected; over 100 isolates were typed from each host plant. No signal of natural admixture between citrus- and coffee-infecting isolates was found; artificial cross-infection assays with representative isolates also yielded no successful cross infection. A comparison determined that X. fastidiosa populations from coffee have higher genetic diversity and allelic richness compared with citrus. The results showed that coffee and citrus X. fastidiosa populations are effectively isolated from each other and, although coffee populations are spatially structured, migration has an important role in shaping diversity. PMID- 27992308 TI - Shielding Therapeutic Drug Carriers from the Mononuclear Phagocyte System: A Review. AB - The mononuclear phagocyte system (MPS) defends the body against the invasion of microorganisms by phagocytosis. In the presence of opsonins, the invading matter is readily recognized by phagocytes because of the interaction between receptors on the phagocytic cell surfaces and the modified conformation of opsonins. The particulate carriers, which are otherwise capable of optimizing drug delivery, are subjected to opsonization and phagocytosis by the MPS immediately following intravenous administration. These drug carriers should remain in the bloodstream in order to spatially locate the drug to the target site and temporally control the drug's release from there on; however, they are devastated by opsonization by serum proteins. Therefore, to restrict opsonization, which is critical for recognition of particulate carriers by the MPS, stealth devices have been developed by engineering the carriers' surface characteristics. Physicochemical properties that influence protein immunogenicity include particle size, surface charge, and surface hydrophobicity. Steric stabilization using polyethylene glycol (PEG) and polyethylene oxide (PEO) chains attached to the particle surface is principally effective in preventing the adsorption of serum opsonins. This article reviews the literature on the MPS and its development and functions, as well as approaches for designing long-circulating carrier particles. It also comprehensively reviews parameters affecting the steric characteristics of drug carriers, such as particle size, shape, surface charge, and surface affinity, including PEGylation of carriers. PMID- 27992309 TI - Advanced Implantable Drug Delivery Systems via Continuous Manufacturing. AB - Polymeric implantable drug delivery systems have remarkable potential for systemic delivery of various therapeutic agents. Generally, drug-loaded implants do not require a vehicle for delivery and can be used to attain prolonged delivery into the systemic circulation of active pharmaceutical ingredients (APIs) with enhanced drug bioavailability. Furthermore, implants can provide drug release ranging from months to years, which improves patient compliance, especially for poorly bioavailable and rapidly metabolized compounds. Continuous manufacturing technology (e.g., hot-melt extrusion, or HME) has been successfully employed to prepare drug-loaded single-unit polymeric implants. Employing heat and mechanical shear, such systems retain the stability of thermolabile therapeutics (e.g., proteins) in implants. HME has emerged as important because of its varied applications that combine economic viability with solvent-free and easy scale-up processing. Moreover, it has been recognized from a quality-by design (QbD) viewpoint by the FDA. PMID- 27992310 TI - A Kinetic Study of Reactive Oxygen Species in Rainbow Trout Hepatocytes by Fluorometry. AB - The kinetics of reactive oxygen species (ROS) formation in a primary culture of rainbow trout hepatocytes was investigated using three fluorescent probes: 5-,6 chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA), dihydrorhodamine 123 (DHR 123), and dihydroethidium (DHE). The cell cultures were loaded with the three probes, separately. Hepatocytes were then exposed to Cu (0.15-10 mM) in serum-free Leibovitz's medium for 30 min before being quantified by a fluorescence plate reader during 30 min. Membrane integrity and glutathione (GSH) content were quantified using the fluorescent probes 5-carboxyfluorescein diacetate-acetoxymethyl ester (CFDA-AM) and monochlorobimane. Increasing ROS formation with increasing concentrations of Cu was shown using CM-H2DCFDA, whereas DHR 123 fluorescence decreased. Significant differences between control and treatment groups were observed at the highest concentrations (2.5 and 10 mM) for both probes. DHE fluorescence was lower than that of the other two probes and did not appear to be affected by any exposure. Additionally, a dose-dependent depletion of GSH and decreasing membrane integrity with increasing Cu concentrations were demonstrated, with significant effects observed at 2.5 and 10 mM for both endpoints. The results showed that both CMH2DCFDA and DHR 123 detected the development of their target Cu-induced ROS in trout hepatocytes but did so in opposite fashions. DHE was found to be unsuitable for detecting kinetics of ROS formation in this model system. PMID- 27992311 TI - Evaluation of the Antioxidant Activity of Extracts and Active Principles of Commonly Consumed Indian Spices. AB - Accumulating evidence suggests that free radical reactions play a key part in the development of degenerative diseases and that an antioxidant-rich diet is a major defense against these free radical reactions. In this study, we explore comparative antioxidant capacities of extracts of some commonly used in Indian spices (anise, cardamom, Ceylon cinnamon, and clove) along with their purified components (anethole, eucalyptol, cinnamaldehyde, and eugenol, respectively). Eugenol shows the highest 1,1-diphenyl-2-picrylhydrazyl, hydroxyl, and superoxide scavenging and reducing power activity in terms of weight; however, this was not found when compared in terms of equivalence. Extracts of the other three spices were found to be more potent antioxidants than their corresponding active components. Interestingly, clove extract, despite possessing the highest phenol and flavonoid content, is not the most potent radical scavenger. At low concentrations, both the crude extracts and their purified components (except for anethole and eugenol) have low hemolytic activity, but at higher concentrations purified components are more toxic than their respective crude extract. This study suggests that spices as a whole are more potent antioxidants than their purified active components, perhaps reflecting the synergism among different phytochemicals present in spice extracts. PMID- 27992312 TI - Effect of Chokeberry Juice on N-Nitrosodiethylamine-Induced Rat Liver Carcinogenesis. AB - Because humans commonly consume chokeberry, especially as a nutritional supplement, it must be checked to determine whether its excessive ingestion can cause adverse effects, in particular, in the case of simultaneous exposure to some xenobiotics. From this point of view, we examined the impact of long-term cotreatment of rats with chokeberry juice and hepatic carcinogen N nitrosodiethylamine (NDEA) on oxidative damages and neoplastic lesions in the liver of rats. Daily exposure to chokeberry juice in a concentration of 10 g/kg feed via diet for 13 wk led to an intensified hepatotoxic effect of NDEA (0.01% in drinking water for 13 wk), as evidenced by changes in histopathological architecture of liver tissue, increased lipid peroxidation, protein carbonyl formation, and DNA degradation. Moreover, we noticed an increase in relative liver weight and a decrease in body weight in this group in comparison to NDEA alone treated animals. Chokeberry juice applied alone did not cause any adverse effects in rats. On the basis of these findings, it can be concluded that high doses and longterm administration of chokeberry juice may enhance tumor-promoting action of some chemical carcinogens. PMID- 27992313 TI - Antitumor Effects of Palladium-alpha-Lipoic Acid Complex Formulation as an Adjunct in Radiotherapy. AB - Several investigations have been initiated to enhance the antitumor effect of radiation and ameliorate its adverse effects such as reducing blood cell counts and causing DNA damage in normal cells. Compounds that enhance the antitumor activity of radiation without reducing blood cell counts or damaging DNA in normal cells can be of immense use as an adjunct in radiotherapy. We evaluated the antitumor effect of a specific set of minerals, vitamins, and amino acids (Poly-MVA) (2 mL/kg, per os), with and without radiation, against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines that were transplanted in a solid-tumor model. Whole-body gamma-radiation exposure (2 Gy) was performed using 60Co. Poly-MVA enhanced the antitumor effect of radiation when administered beforehand. Furthermore, Poly-MVA administered once daily for 2 wk, immediately after 4 Gy irradiation, protected DNA damage in peripheral blood. It also rendered protection against the radiation-induced reduction of platelet count. The unique electronic and redox properties of palladium-alpha-lipoic acid complex in Poly-MVA appear to be responsible for the exhibited effect. The results conclude that the antitumor-enhancing and normal cell-protective effect of Poly-MVA warrants additional studies for its potential clinical application. PMID- 27992314 TI - Cytotoxic and Genotoxic Effects of Electronic Cigarette Liquids on Human Mucosal Tissue Cultures of the Oropharynx. AB - The popularity of electronic cigarettes (ECs) is rapidly growing and ECs are claimed to be an uncritically regarded alternative to conventional cigarettes. The mucosal tissue of the upper aerodigestive tract (UADT) is the first contact organ for xenobiotics such as liquids of ECs. The aim of this study is to investigate the bimolecular effects of e-liquids on human pharyngeal tissue cultures to evaluate whether e-liquids and their components present a risk factor for head and neck squamous cell carcinoma. Fresh tissue samples of healthy oropharyngeal mucosa were assembled into mucosal tissue cultures. Two fruit flavored liquids (FLs), one tobacco-flavored liquid (TL) (all containing nicotine), and the corresponding base mixtures (free of nicotine and flavor) were used in three different dilutions. Cytotoxicity was assessed using the water soluble tetrazolium-8 assay. DNA fragmentation was quantified using alkaline microgel electrophoresis. All liquids caused a significant reduction in cell viability. FLs especially showed a higher toxicity than TL. DNA fragmentation significantly increased by incubation with FL, whereas treatment with TL did not show serious DNA damage. E-liquids are cytotoxic to oropharyngeal tissue, and some liquids can induce relevant DNA damage. Thus, mutagenicity for mucosa of the UADT and e-liquids as risk factors for head and neck cancer cannot entirely be ruled out. Only the implementation of standards and regulations for liquid production and distribution can ensure a valid scientific investigation and assessment of carcinogenic potential of long-term EC use. PMID- 27992315 TI - Inhibition of the p53 Y220C Mutant by 1-Hydroxy-2- Methylanthraquinone Derivatives: A Novel Strategy for Cancer Therapy. AB - Y220C, a substitution mutation in p53, causes major structural changes in the protein and is known to form a new protein cavity. This cavity is reckoned to accommodate small drug candidates that may play a key role in cancer treatment. Present study was aimed at determining a drug candidate that could inhibit the mutant p53 based on structural drug rationale. Docking of mutated p53 was performed to determine the drug of choice from the derivatives of 1-hydroxy-2- methylanthraquinone exhibiting anti-cancer properties. The cavity had been tested for identification of an accurate position vector for molecular docking studies using structure based drug design. The docked structure was validated using discovery studio 3.5. The best choice of two molecules were obtained by docking in specific solvent for 6 nanoseconds at a temperature of 310 K. Out of a library of compounds, acetamido-2-carboxy-4-dimethylamino-2- hydroxybenzophenone satisfied the ADMET and was found to be a potential target for mutant p53. This ligand binds at the active site of the protein. Results of present study offer a rationale of the lead ligands that can rescue oncogenic p53 by targeting the mutation site. Therefore, it is suggestive that small molecules may serve as an effective and novel anti-cancer drug. PMID- 27992316 TI - Glutamate Excitotoxicity and Oxidative Stress in Epilepsy: Modulatory Role of Melatonin. AB - Epilepsy is thought to be associated with oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction. The enhanced synthesis and release of oxygen free radicals is linked to the low and oxidative potential of the central nervous system. Glutamate excitotoxicity also contributes significantly to the production of reactive nitrogen species that cause nitrosative stress. A decrease in adenosine triphosphate synthesis, which leads to free radical formation, is associated with mitochondrial dysfunction. The brain is very much susceptible to degeneration and oxidative stress because of its low antioxidant enzyme activity. Melatonin, a hormone secreted by the pineal gland, has remarkable antioxidant properties. Melatonin and its analogs that bind to melatonin receptors have a significant role in suppressing seizures. Melatonin scavenges oxygen free radicals such as hydroxyl radical, peroxy radical, peroxynitrite anion, and superoxide radical and stimulates synthesis of superoxide dismutase and glutathione peroxidase, which are potent antioxidant enzymes. Melatonin administration has been shown to be effective in both experimental models and patients suffering from epilepsy. In this review, we compile the literature supporting consequences of seizures and the protective role of melatonin during seizures. PMID- 27992317 TI - Effect of Prenatal Exposure to Pesticides on Children's Health. AB - The aim of this study was to summarize the current state of knowledge on pesticide-related fertility problems and disadventeges of childrens due to prenatal pesticides exposure. Available literature was analyzed. Due to the extent of the issue, the study focuses on epidemiological studies conducted in humans, despite evidence from in vitro and animal studies. It seems certain that exposure to harmful chemicals is one of the factors that may cause a decline in fertility and problems with conceiving, whereas exposure during pregnancy can impair foetal development. Prenatal exposure may also result in the occurrence of childhood cancer and neurobehavioral disorders. The meaning of the project is to summarize the role of pesticides in the process of reproduction. This applies especially to people working in agriculture, since they might be occupationally exposed to pesticides. PMID- 27992318 TI - Printed Drug-Delivery Systems for Improved Patient Treatment. AB - The use of various types of printing technologies offer potential solutions for personalized medicine and tailored dosage forms to meet the needs of individual treatments of the future. Many types of scenario for printed dosage form exist and the concepts include, on the simplest level, accurately deposited doses of drug substances. In addition, computer design allows endless opportunities to create suitable geometries with tailored functionality and different levels of complexity to control the release properties of one or multiple drug substances. It will take some time to convert these technological developments in printing to better treatments for patients, because challenges exist. However, printing technologies are developing fast and have the potential to allow the use of versatile materials to manufacture sophisticated drug-delivery systems and biofunctional constructs for personalized treatments. PMID- 27992319 TI - Therapeutics Targeting FGF Signaling Network in Human Diseases. AB - Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence. PMID- 27992320 TI - Deadly Engagement: FcgammaRIIa-Antibody Interaction is Key in Sepsis. PMID- 27992321 TI - Robo-Psychophysics: Extracting Behaviorally Relevant Features from the Output of Sensors on a Prosthetic Finger. AB - Efforts are underway to restore sensorimotor function in amputees and tetraplegic patients using anthropomorphic robotic hands. For this approach to be clinically viable, sensory signals from the hand must be relayed back to the patient. To convey tactile feedback necessary for object manipulation, behaviorally relevant information must be extracted in real time from the output of sensors on the prosthesis. In the present study, we recorded the sensor output from a state-of the-art bionic finger during the presentation of different tactile stimuli, including punctate indentations and scanned textures. Furthermore, the parameters of stimulus delivery (location, speed, direction, indentation depth, and surface texture) were systematically varied. We developed simple decoders to extract behaviorally relevant variables from the sensor output and assessed the degree to which these algorithms could reliably extract these different types of sensory information across different conditions of stimulus delivery. We then compared the performance of the decoders to that of humans in analogous psychophysical experiments. We show that straightforward decoders can extract behaviorally relevant features accurately from the sensor output and most of them outperform humans. PMID- 27992322 TI - Energy Prediction for Teleoperation Systems That Combine the Time Domain Passivity Approach with Perceptual Deadband-Based Haptic Data Reduction. AB - We study the combination of the perceptual deadband (PD)-based haptic packet rate reduction scheme with the time domain passivity approach (TDPA) for time-delayed teleoperation and propose a novel energy prediction (EP) scheme that deals with the conservative behavior of the resulting controller. The PD approach leads to irregular packet transmission, resulting in degraded system transparency and reduced teleoperation quality when the PD approach is combined with the TDPA. The proposed method (PD+TDPA+EP) adaptively predicts the system energy during communication interruptions and allows for larger energy output. This achieves less conservative control and improves the teleoperation quality. Evaluation of the displayed impedance shows that the PD+TDPA+EP method achieves improved system transparency, both objectively and subjectively, when compared with related approaches from literature. According to a subjective user study, the PD+TDPA+EP method allows for a high packet rate reduction (up to 80 percent) without noticeably distorting the perceived interaction quality. We also show that the PD+TDPA+EP method is preferred over related approaches from literature in a direct comparison test. Thus, with the proposed PD+TDPA+EP method, a high data reduction and a high teleoperation quality are simultaneously achieved for time delayed teleoperation. PMID- 27992324 TI - A Dual-Mode Magnetic-Acoustic System for Monitoring Fluid Intake Behavior in Animals. AB - We have developed an unobtrusive magnetic-acoustic fluid intake monitoring (MAFIM) system using a conventional stainless-steel roller-ball nipple to measure licking and drinking behavior in animals. Movements of a small permanent magnetic tracer attached to stainless-steel roller balls that operate as a tongue-actuated valve are sensed by a pair of three-axial magnetometers, and transformed into a time-series indicating the status of the ball (up or down), using a Gaussian mixture model based data-driven classifier. The sounds produced by the rise and fall of the roller balls are also recorded and classified to substantiate the magnetic data by an independent modality for a more robust solution. The operation of the magnetic and acoustic sensors is controlled by an embedded system, communicating via Universal Serial Bus (USB) with a custom-designed user interface, running on a PC. The MAFIM system has been tested in vivo with minipigs, accurately measuring various drinking parameters and licking patterns without constraints imposed by current lick monitoring systems, such as nipple access, animal-nipple contact, animal training, and complex parameter settings. PMID- 27992328 TI - Kronecker-Markov Prior for Dynamic 3D Reconstruction. AB - Recovering dynamic 3D structures from 2D image observations is highly under constrained because of projection and missing data, motivating the use of strong priors to constrain shape deformation. In this paper, we empirically show that the spatiotemporal covariance of natural deformations is dominated by a Kronecker pattern. We demonstrate that this pattern arises as the limit of a spatiotemporal autoregressive process, and derive a Kronecker Markov Random Field as a prior distribution over dynamic structures. This distribution unifies shape and trajectory models of prior art and has the individual models as its marginals. The key assumption of the Kronecker MRF is that the spatiotemporal covariance is separable into the product of a temporal and a shape covariance, and can therefore be modeled using the matrix normal distribution. Analysis on motion capture data validates that this distribution is an accurate approximation with significantly fewer free parameters. Using the trace-norm, we present a convex method to estimate missing data from a single sequence when the marginal shape distribution is unknown. The Kronecker-Markov distribution, fit to a single sequence, outperforms state-of-the-art methods at inferring missing 3D data, and additionally provides covariance estimates of the uncertainty. PMID- 27992329 TI - Delay-Encoded Harmonic Imaging (DE-HI) in Multiplane-Wave Compounding. AB - The development of ultrafast ultrasound imaging brings great opportunities to improve imaging technologies such as shear wave elastography and ultrafast Doppler imaging. In ultrafast imaging, several tilted plane or diverging wave images are coherently combined to form a compounded image, leading to trade-offs among image signal-to-noise ratio (SNR), resolution, and post-compounded frame rate. Multiplane wave (MW) imaging is proposed to solve this trade-off by encoding multiple plane waves with Hadamard matrix during one transmission event (i.e. pulse-echo event), to improve image SNR without sacrificing the resolution or frame rate. However, it suffers from stronger reverberation artifacts in B mode images compared to standard plane wave compounding due to longer transmitted pulses. If harmonic imaging can be combined with MW imaging, the reverberation artifacts and other clutter noises such as sidelobes and multipath scattering clutters should be suppressed. The challenge, however, is that the Hadamard codes used in MW imaging cannot encode the 2nd harmonic component by inversing the pulse polarity. In this paper, we propose a delay-encoded harmonic imaging (DE HI) technique to encode the 2nd harmonic with a one quarter period delay calculated at the transmit center frequency, rather than reversing the pulse polarity during multiplane wave emissions. Received DE-HI signals can then be decoded in the frequency domain to recover the signals as in single plane wave emissions, but mainly with improved SNR at the 2nd harmonic component instead of the fundamental component. DE-HI was tested experimentally with a point target, a B-mode imaging phantom, and in-vivo human liver imaging. Improvements in image contrast-to-noise ratio (CNR), spatial resolution, and lesion-signal-to-noise ratio ( l SNR) have been achieved compared to standard plane wave compounding, MW imaging, and standard harmonic imaging (maximal improvement of 116% on CNR and 115% on l SNR as compared to standard HI around 55 mm depth in the B-mode imaging phantom study). The potential high frame rate and the stability of encoding and decoding processes of DE-HI were also demonstrated, which made DE-HI promising for a wide spectrum of imaging applications. PMID- 27992332 TI - Left Ventricular Myocardial Segmentation in 3-D Ultrasound Recordings: Effect of Different Endocardial and Epicardial Coupling Strategies. AB - Cardiac volume/function assessment remains a critical step in daily cardiology, and 3-D ultrasound plays an increasingly important role. Though development of automatic endocardial segmentation methods has received much attention, the same cannot be said about epicardial segmentation, in spite of the importance of full myocardial segmentation. In this paper, different ways of coupling the endocardial and epicardial segmentations are contrasted and compared with uncoupled segmentation. For this purpose, the B-spline explicit active surfaces framework was used; 27 3-D echocardiographic images were used to validate the different coupling strategies, which were compared with manual contouring of the endocardial and epicardial borders performed by an expert. It is shown that an independent segmentation of the endocardium followed by an epicardial segmentation coupled to the endocardium is the most advantageous. In this way, a framework for fully automatic 3-D myocardial segmentation is proposed using a novel coupling strategy. PMID- 27992333 TI - Subresolution Displacements in Finite Difference Simulations of Ultrasound Propagation and Imaging. AB - Time domain finite difference simulations are used extensively to simulate wave propagation. They approximate the wave field on a discrete domain with a grid spacing that is typically on the order of a tenth of a wavelength. The smallest displacements that can be modeled by this type of simulation are thus limited to discrete values that are integer multiples of the grid spacing. This paper presents a method to represent continuous and subresolution displacements by varying the impedance of individual elements in a multielement scatterer. It is demonstrated that this method removes the limitations imposed by the discrete grid spacing by generating a continuum of displacements as measured by the backscattered signal. The method is first validated on an ideal perfect correlation case with a single scatterer. It is subsequently applied to a more complex case with a field of scatterers that model an acoustic radiation force induced displacement used in ultrasound elasticity imaging. A custom finite difference simulation tool is used to simulate propagation from ultrasound imaging pulses in the scatterer field. These simulated transmit-receive events are then beamformed into images, which are tracked with a correlation-based algorithm to determine the displacement. A linear predictive model is developed to analytically describe the relationship between element impedance and backscattered phase shift. The error between model and simulation is lambda/ 1364 , where lambda is the acoustical wavelength. An iterative method is also presented that reduces the simulation error to lambda/ 5556 over one iteration. The proposed technique therefore offers a computationally efficient method to model continuous subresolution displacements of a scattering medium in ultrasound imaging. This method has applications that include ultrasound elastography, blood flow, and motion tracking. This method also extends generally to finite difference simulations of wave propagation, such as electromagnetic or seismic waves. PMID- 27992331 TI - Quantitative Frequency-Domain Passive Cavitation Imaging. AB - Passive cavitation detection has been an instrumental technique for measuring cavitation dynamics, elucidating concomitant bioeffects, and guiding ultrasound therapies. Recently, techniques have been developed to create images of cavitation activity to provide investigators with a more complete set of information. These techniques use arrays to record and subsequently beamform received cavitation emissions, rather than processing emissions received on a single-element transducer. In this paper, the methods for performing frequency domain delay, sum, and integrate passive imaging are outlined. The method can be applied to any passively acquired acoustic scattering or emissions, including cavitation emissions. To compare data across different systems, techniques for normalizing Fourier transformed data and converting the data to the acoustic energy received by the array are described. A discussion of hardware requirements and alternative imaging approaches is additionally outlined. Examples are provided in MATLAB. PMID- 27992334 TI - A Methodology for Anatomic Ultrasound Image Diagnostic Quality Assessment. AB - This paper discusses the methods for the assessment of ultrasound image quality based on our experiences with evaluating new methods for anatomic imaging. It presents a methodology to ensure a fair assessment between competing imaging methods using clinically relevant evaluations. The methodology is valuable in the continuing process of method optimization and guided development of new imaging methods. It includes a three phased study plan covering from initial prototype development to clinical assessment. Recommendations to the clinical assessment protocol, software, and statistical analysis are presented. Earlier uses of the methodology has shown that it ensures validity of the assessment, as it separates the influences between developer, investigator, and assessor once a research protocol has been established. This separation reduces confounding influences on the result from the developer to properly reveal the clinical value. This paper exemplifies the methodology using recent studies of synthetic aperture sequential beamforming tissue harmonic imaging. PMID- 27992335 TI - Ultrasonic 3-D Vector Flow Method for Quantitative In Vivo Peak Velocity and Flow Rate Estimation. AB - Current clinical ultrasound (US) systems are limited to show blood flow movement in either 1-D or 2-D. In this paper, a method for estimating 3-D vector velocities in a plane using the transverse oscillation method, a 32*32 element matrix array, and the experimental US scanner SARUS is presented. The aim of this paper is to estimate precise flow rates and peak velocities derived from 3-D vector flow estimates. The emission sequence provides 3-D vector flow estimates at up to 1.145 frames/s in a plane, and was used to estimate 3-D vector flow in a cross-sectional image plane. The method is validated in two phantom studies, where flow rates are measured in a flow-rig, providing a constant parabolic flow, and in a straight-vessel phantom ( ?=8 mm) connected to a flow pump capable of generating time varying waveforms. Flow rates are estimated to be 82.1 +/- 2.8 L/min in the flow-rig compared with the expected 79.8 L/min, and to 2.68 +/- 0.04 mL/stroke in the pulsating environment compared with the expected 2.57 +/- 0.08 mL/stroke. Flow rates estimated in the common carotid artery of a healthy volunteer are compared with magnetic resonance imaging (MRI) measured flow rates using a 1-D through-plane velocity sequence. Mean flow rates were 333 +/- 31 mL/min for the presented method and 346 +/- 2 mL/min for the MRI measurements. PMID- 27992342 TI - Representation Learning Based Speech Assistive System for Persons With Dysarthria. AB - An assistive system for persons with vocal impairment due to dysarthria converts dysarthric speech to normal speech or text. Because of the articulatory deficits, dysarthric speech recognition needs a robust learning technique. Representation learning is significant for complex tasks such as dysarthric speech recognition. We focus on robust representation for dysarthric speech recognition that involves recognizing sequential patterns of varying length utterances. We propose a hybrid framework that uses a generative learning based data representation with a discriminative learning based classifier. In this hybrid framework, we propose to use Example Specific Hidden Markov Models (ESHMMs) to obtain log-likelihood scores for a dysarthric speech utterance to form fixed dimensional score vector representation. This representation is used as an input to discriminative classifier such as support vector machine.The performance of the proposed approach is evaluatedusingUA-Speechdatabase.The recognitionaccuracy is much better than the conventional hidden Markov model based approach and Deep Neural Network-Hidden Markov Model (DNN-HMM). The efficiency of the discriminative nature of score vector representation is proved for "very low" intelligibility words. PMID- 27992346 TI - Prediction of HIV Drug Resistance by Combining Sequence and Structural Properties. AB - Drug resistance is a major obstacle faced by therapist in treating HIV infected patients. The reason behind these phenomena is either protein mutation or the changes in gene expression level that induces resistance to drug treatments. These mutations affect the drug binding activity, hence resulting in failure of treatment. Therefore, it is necessary to conduct resistance testing in order to carry out HIV effective therapy. This study combines both sequence and structural features for predicting HIV resistance by applying SVM and Random Forests classifiers. The model was tested on the mutants of HIV-1 protease and reverse transcriptase. Taken together the features we have used in our method, total contact energies among multiple mutations have a strong impact in predicting resistance as they are crucial in understanding the interactions of HIV mutants. The combination of sequence-structure features offers high accuracy with support vector machines as compared to Random Forests classifier. Both single and acquisition of multiple mutations are important in predicting HIV resistance to certain drug treatments. We have discovered the practicality of these features; hence, these can be used in the future to predict resistance for other complex diseases. PMID- 27992347 TI - Network Community Detection based on the Physarum-inspired Computational Framework. AB - Community detection is a crucial and essential problem in the structure analytics of complex networks, which can help us understand and predict the characteristics and functions of complex networks. Many methods, ranging from the optimization based algorithms to the heuristic-based algorithms, have been proposed for solving such a problem. Due to the inherent complexity of identifying network structure, how to design an effective algorithm with a higher accuracy and a lower computational cost still remains an open problem. Inspired by the computational capability and positive feedback mechanism in the wake of foraging process of Physarum, which is a large amoeba-like cell consisting of a dendritic network of tube-like pseudopodia, a general Physarum-based computational framework for community detection is proposed in this paper. Based on the proposed framework, the inter-community edges can be identified from the intra community edges in a network and the positive feedback of solving process in an algorithm can be further enhanced, which are used to improve the efficiency of original optimization-based and heuristic-based community detection algorithms, respectively. Some typical algorithms (e.g., genetic algorithm, ant colony optimization algorithm, and Markov clustering algorithm) and real-world datasets have been used to estimate the efficiency of our proposed computational framework. Experiments show that the algorithms optimized by Physarum-inspired computational framework perform better than the original ones, in terms of accuracy and computational cost. Moreover, a computational complexity analysis verifies the scalability of our framework. PMID- 27992349 TI - Design and Psychophysical Evaluation of the HapSticks: A Novel Non-Grounded Mechanism for Presenting Tool-Mediated Vertical Forces. AB - Force feedback in tool-mediated interactions with the environment is important for the successful performance of complex tasks in daily life as well as in specialized fields such as medicine. Most stylus-based haptic devices require either grounding or attachment to the user's body. Recently, non-grounded haptic devices have attracted a growing interest. In this study, we propose a non grounded rotation mechanism to represent the vertical forces applied on the tip of a tool by mimicking the cutaneous sensations that are caused by such forces. As an example of an application of our method, we developed a non-grounded haptic device called HapSticks, which mimicked the sensation of manipulating objects using chopsticks. First, using an adjustment paradigm, we directly compared a virtual weight rendered by our device and a real weight to investigate the relation of real weight and virtual weight. Next, we used a forced choice constant stimuli paradigm in a virtual and a real weight discrimination task. We conclude that our novel device renders a reliable illusion of sensed weight that leads to a discrimination ability that is typical of virtual-reality applications but worse than the discrimination between real weights. PMID- 27992357 TI - Evolutionary Metric-Learning-Based Recognition Algorithm for Online Isolated Persian/Arabic Characters, Reconstructed Using Inertial Pen Signals. AB - The development of sensors with the microelectromechanical systems technology expedites the emergence of new tools for human-computer interaction, such as inertial pens. These pens, which are used as writing tools, do not depend on a specific embedded hardware, and thus, they are inexpensive. Most of the available inertial pen character recognition approaches use the low-level features of inertial signals. This paper introduces a Persian/Arabic handwriting character recognition system for inertial-sensor-equipped pens. First, the motion trajectory of the inertial pen is reconstructed to estimate the position signals by using the theory of inertial navigation systems. The position signals are then used to extract high-level geometrical features. A new metric learning technique is then adopted to enhance the accuracy of character classification. To this end, a characteristic function is calculated for each character using a genetic programming algorithm. These functions form a metric kernel classifying all the characters. The experimental results show that the performance of the proposed method is superior to that of one of the state-of-the-art works in terms of recognizing Persian/Arabic handwriting characters. PMID- 27992358 TI - Command Filtering-Based Fuzzy Control for Nonlinear Systems With Saturation Input. AB - In this paper, command filtering-based fuzzy control is designed for uncertain multi-input multioutput (MIMO) nonlinear systems with saturation nonlinearity input. First, the command filtering method is employed to deal with the explosion of complexity caused by the derivative of virtual controllers. Then, fuzzy logic systems are utilized to approximate the nonlinear functions of MIMO systems. Furthermore, error compensation mechanism is introduced to overcome the drawback of the dynamics surface approach. The developed method will guarantee all signals of the systems are bounded. The effectiveness and advantages of the theoretic result are obtained by a simulation example. PMID- 27992359 TI - Building Correlations Between Filters in Convolutional Neural Networks. AB - In this paper, a new optimization approach is designed for convolutional neural network (CNN) which introduces explicit logical relations between filters in the convolutional layer. In a conventional CNN, the filters' weights in convolutional layers are separately trained by their own residual errors, and the relations of these filters are not explored for learning. Different from the traditional learning mechanism, the proposed correlative filters (CFs) are initiated and trained jointly in accordance with predefined correlations, which are efficient to work cooperatively and finally make a more generalized optical system. The improvement in CNN performance with the proposed CF is verified on five benchmark image classification datasets, including CIFAR-10, CIFAR-100, MNIST, STL-10, and street view house number. The comparative experimental results demonstrate that the proposed approach outperforms a number of state-of-the-art CNN approaches. PMID- 27992361 TI - Risk factors that affect metabolic health status in obese children. AB - BACKGROUND: While some obese children are metabolically healthy (MHO), some have additional health problems, such as hypertension, dyslipidemia, insulin resistance, and hepatosteatosis, which increase mortality and morbidity related to cardiovascular diseases (CVD) during adulthood. These children are metabolically unhealthy obese (MUO) children. In this study we assessed the factors that affect metabolic health in obesity and the clinical and laboratory findings that distinguish between MHO and MUO children. METHODS: In total, 1085 patients aged 6-18 years, with age- and sex-matched BMI exceeding the 95th percentile were included in the study (mean 11.1+/-2.9 years, 57.6% female, 59.7% pubertal). Patients without dyslipidemia, insulin resistance, hepatosteatosis, or hypertension were considered as MHO. Dyslipidemia was defined as total cholesterol level over 200 mg/dL, triglyceride over 150 mg/dL, LDL over 130 mg/dL, or HDL under 40 mg/dL. Insulin resistance was calculated using the homeostasis model of assesment for insulin resistance (HOMA-IR) index. Hepatosteatosis was evaluated with abdominal ultrasound. Duration of obesity, physical activity and nutritional habits, screen time, and parental obesity were questioned. Thyroid and liver function tests were performed. RESULTS: Six hundred and forty-two cases (59.2%) were MUO. Older age, male sex, increased BMI-SDS, and sedentary lifestyle were associated with MUO. Excessive junk food consumption was associated with MUO particularly among the prepubertal obese patients. CONCLUSIONS: Our results revealed that the most important factors that affect metabolic health in obesity are age and BMI. Positive effects of an active lifestyle and healthy eating habits are prominent in the prepubertal period and these habits should be formed earlier in life. PMID- 27992362 TI - A call to encourage curricular research publications by medical students. PMID- 27992360 TI - Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation. AB - RATIONALE: Patients with chronic kidney disease (CKD) develop hyperhomocysteinemia and have a higher cardiovascular mortality than those without hyperhomocysteinemia by 10-fold. OBJECTIVE: We investigated monocyte differentiation in human CKD and cardiovascular disease (CVD). METHODS AND RESULTS: We identified CD40 as a CKD-related monocyte activation gene using CKD monocyte -mRNA array analysis and classified CD40 monocyte (CD40+CD14+) as a stronger inflammatory subset than the intermediate monocyte (CD14++CD16+) subset. We recruited 27 patients with CVD/CKD and 14 healthy subjects and found that CD40/CD40 classical/CD40 intermediate monocyte (CD40+CD14+/CD40+CD14++CD16 /CD40+CD14++CD16+), plasma homocysteine, S-adenosylhomocysteine, and S adenosylmethionine levels were higher in CVD and further elevated in CVD+CKD. CD40 and CD40 intermediate subsets were positively correlated with plasma/cellular homocysteine levels, S-adenosylhomocysteine and S adenosylmethionine but negatively correlated with estimated glomerular filtration rate. Hyperhomocysteinemia was established as a likely mediator for CKD-induced CD40 intermediate monocyte, and reduced S-adenosylhomocysteine/S adenosylmethionine was established for CKD-induced CD40/CD40 intermediate monocyte. Soluble CD40 ligand, tumor necrosis factor (TNF)-alpha/interleukin (IL) 6/interferon (IFN)-gamma levels were elevated in CVD/CKD. CKD serum/homocysteine/CD40L/increased TNF-alpha/IL-6/IFN-gamma-induced CD40/CD40 intermediate monocyte in peripheral blood monocyte. Homocysteine and CKD serum induced CD40 monocyte were prevented by neutralizing antibodies against CD40L/TNF alpha/IL-6. DNA hypomethylation was found on nuclear factor-kappaB consensus element in CD40 promoter in white blood cells from patients with CKD with lower S adenosylmethionine / S-adenosylhomocysteine ratios. Finally, homocysteine inhibited DNA methyltransferase-1 activity and promoted CD40 intermediate monocyte differentiation, which was reversed by folic acid in peripheral blood monocyte. CONCLUSIONS: CD40 monocyte is a novel inflammatory monocyte subset that appears to be a biomarker for CKD severity. Hyperhomocysteinemia mediates CD40 monocyte differentiation via soluble CD40 ligand induction and CD40 DNA hypomethylation in CKD. PMID- 27992363 TI - Germ cell-specific sustained activation of Wnt signalling perturbs spermatogenesis in aged mice, possibly through non-coding RNAs. AB - Dysregulated Wnt signalling is associated with human infertility and testicular cancer. However, the role of Wnt signalling in male germ cells remains poorly understood. In this study, we first confirmed the activity of Wnt signalling in mouse, dog and human testes. To determine the physiological importance of the Wnt pathway, we developed a mouse model with germ cell-specific constitutive activation of betacatenin. In young mutants, similar to controls, germ cell development was normal. However, with age, mutant testes showed defective spermatogenesis, progressive germ cell loss, and flawed meiotic entry of spermatogonial cells. Flow sorting confirmed reduced germ cell populations at the leptotene/zygotene stages of meiosis in mutant group. Using thymidine analogues based DNA double labelling technique, we further established decline in germ cell proliferation and differentiation. Overactivation of Wnt/betacatenin signalling in a spermatogonial cell line resulted in reduced cell proliferation, viability and colony formation. RNA sequencing analysis of testes revealed significant alterations in the non-coding regions of mutant mouse genome. One of the novel non-coding RNAs was switched on in mutant testes compared to controls. QPCR analysis confirmed upregulation of this unique non-coding RNA in mutant testis. In summary, our results highlight the significance of Wnt signalling in male germ cells. PMID- 27992364 TI - MicroRNA-30e reduces cell growth and enhances drug sensitivity to gefitinib in lung carcinoma. AB - MicroRNAs (miRNAs) play critical roles in variousbiological processes,including malignancy. Here, we demonstrated that miR-30e levels were markedly reduced in human lung carcinoma specimens in comparisonwith adjacent normal tissues.In addition, miR-30eamounts were starkly lower in the resistant PC9/gefitinib (PC9G) cancer cells compared with PC9 cells. Meanwhile, miR-30eoverexpression inPC9G cells resulted in reduced cell proliferation and migration,reversing drug resistance to gefitinib.Conversely,miR-30e silencing in PC9 cells increased proliferation as well as migration, and conferred resistance to gefitinib.Moreover, HOXA1, which was identified asa new miR-30etarget, plays important roles in regulating cell fate, early developmental patterns and organogenesis.Importantly, miR-30ealso inhibited PC9G growth in vivo. Taken together, these findings demonstrated that miR-30eshould be considered a tumor suppressor miRNA, which could be used in treatinghuman lung cancer. PMID- 27992365 TI - Gankyrin promotes epithelial-mesenchymal transition and metastasis in NSCLC through forming a closed circle with IL-6/ STAT3 and TGF-beta/SMAD3 signaling pathway. AB - Our previous research showed that Gankyrin was overexpressed in NSCLC and significantly associated with clinicopathologic features and poor prognosis. In this study, we will explore potential effect of Gankyrin on EMT and metastasis in NSCLC. The ectopic higher expression of Gankyrin markedly increased the migration and invasion in NSCLC cells. In contrast, silencing Gankyrin inhibit this aggressive behavior in NSCLC cells. Further study demonstrated that overexpression of Gankyrin could decrease E-cadherin expression and increase expression of Vimentin and Twist1 at mRNA and protein levels. These data indicated that Gankyrin could facilitate occurrence and development of EMT. Also IHC analysis showed that Gankyrin expression was negatively correlated with E cadherin expression, while positively correlated with Vimentin and Twist1 expression in NSCLC tissues. The mechanism study finally suggested that the Gankyrin-driven EMT was partially due to IL-6/p-STAT3 and TGF-beta/p-SMAD3 pathways activation. Taken together, our data provided a novel mechanism of Gankyrin promoting EMT and metastasis in NSCLC through forming a closed circle with IL-6/p-STAT3 and TGF-beta/p-SMAD3 signaling pathway. PMID- 27992366 TI - Genome-wide analysis of differentially expressed lncRNAs and mRNAs in primary gonadotrophin adenomas by RNA-seq. AB - Recently, long non-coding RNAs (lncRNAs) have received increased research interest owing to their participation via distinct mechanisms in the biological processes of nonfunctional pituitary adenomas. However, changes in the expression of lncRNAs in gonadotrophin adenoma, which is the most common nonfunctional pituitary adenomas, have not yet been reported. In this study, we performed a genome-wide analysis of lncRNAs and mRNAs obtained from gonadotrophin adenoma patients' samples and normal pituitary tissues using RNA-seq. The differentially expressed lncRNAs and mRNAs were identified using fold-change filtering. We identified 839 lncRNAs and 1015 mRNAs as differentially expressed. Gene Ontology analysis indicated that the biological functions of differentially expressed mRNAs were related to transcription regulator activity and basic metabolic processes. Ingenuity Pathway Analysis was performed to identify 64 canonical pathways that were significantly enriched in the tumor samples. Furthermore, to investigate the potential regulatory roles of the differentially expressed lncRNAs on the mRNAs, we constructed general co-expression networks for 100 coding and 577 non-coding genes that showed significantly correlated expression patterns in tumor cohort. In particular, we built a special sub-network of co expression involving 186 lncRNAs interacting with 15 key coding genes of the mTOR pathway, which might promote the pathogenesis of gonadotrophin tumor. This is the first study to explore the patterns of genome-wide lncRNAs expression and co expression with mRNAs, which might contribute to the molecular pathogenesis of gonadotrophin adenoma. PMID- 27992367 TI - Management of salivary gland carcinomas - a review. AB - Salivary gland carcinomas are a heterogeneous group of tumors with many histological subtypes which occur in both major and minor salivary glands. However, they have a relatively low of incidence. Their rarity limits study size and the ability to perform phase III trials. Therefore, to date, the entire management is usually varied. Certain published studies have paid more attention to the systemic therapy in the management of metastatic or locally recurrent salivary gland cancer, while little effort has been made to study the entire management for this lesions. Although results of treatment for patients with salivary gland carcinoma have improved in recent years, the treatment of salivary gland cancers is still not standardized. And some patients who haven't received optimal treatment strategies had a reduced survival. In this review, the topics covered include surgery and radiotherapy, selective neck dissection, chemotherapy, and targeted therapy, which aimed to summarize the optimal management approaches and to develop recommendations for managing this lesions. For these rare cancers, there is also a need for a determined, coordinated effort to conduct high-quality clinical trials. PMID- 27992368 TI - Early detection of rheumatoid arthritis in rats and humans with 99mTc-3PRGD2 scintigraphy: imaging synovial neoangiogenesis. AB - OBJECTIVES: To validate 99mTc-labeled arginylglycylaspartic acid (99mTc-3PRGD2) scintigraphy as a means to image synovial neoangiogenesis in joints afflicted by rheumatoid arthritis and to investigate its potential in the early detection and management of rheumatoid arthritis. METHODS: Rheumatoid arthritis and osteoarthritis were generated in Sprague Dawley rats by type II collagen immunization and papain injection, respectively. Rats were imaged with 99mTc 3PRGD2 and 99mTc- methyl diphosphonate (99mTc MDP). X-ray images were also obtained and assessed by a radiologist. Immunohistochemistry of alphavbeta3 and CD31confirmed the onset of synovial neoangiogenesis. The effect of bevacizumab on rheumatoid arthritis was followed with 99mTc-3PRGD2 scintigraphy. A patient with rheumatoid arthritis and a healthy volunteer were scanned with 99mTc-3PRGD2. RESULTS: Two weeks after immunization, a significant increase in 99mTc-3PRGD2 was observed in the joints of the rheumatoid arthritis model though uptake in osteoarthritis model and untreated controls was low. 99mTc-MDP whole body scans failed to distinguish early rheumatoid arthritis joints from healthy controls. The expression of alphavbeta3 and CD31was significantly higher in the joints of rheumatoid arthritis rats compared to normal controls. In serial 99mTc-3PRGD2 scintigraphy studies, 99mTc-3PRGD2 uptake increased in parallel with disease progression. Bevacizumab anti-angiogenetic therapy both improved the symptoms of the rheumatoid arthritis rats and significantly decreased 99mTc-3PRGD2 uptake. Significantly higher 99mTc-3PRGD2 accumulation was also observed in rheumatoid arthritis joints in the patient. CONCLUSIONS: Our findings indicate that 99mTc 3PRGD2 scintigraphy could detect early rheumatoid arthritis by imaging the associated synovial neoangiogenesis, and may be useful in disease management. PMID- 27992369 TI - The prognostic significance of long noncoding RNAs in non-small cell lung cancer: a meta-analysis. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The overall 5-year survival rate of patients is extremely low and to find a new marker is urgently needed. Numerous studies indicate that long noncoding RNAs (lncRNAs) abnormally express in cancers. However, the results have been disputed, especially in the aspects of tumor prognosis. Therefore, we performed this meta analysis to systematically summarize the relationship between lncRNAs expression and NSCLC. A total of 34 eligible studies including 30 on overall survival, 10 on progression-free survival and 23 on clinicopathological features were identified from the databases. Our results indicated that the levels of lncRNAs were associated with the overall survival (OS; hazard ratios [HR], 1.43; 95% confidence interval [95% CI], 1.17-1.76; P < 0.001). However, there was no relationship between lncRNAs and progression-free survival (PFS; hazard ratios [HR], 1.55; 95% confidence interval [95% CI], 0.91-2.63; P = 0.11). Moreover, lncRNAs were related to lymph node metastasis (odds ratios [OR], 1.70; 95% confidence interval [95% CI], 1.03-2.80; P = 0.04), while no association was observed with other characteristics. In conclusion, our present meta-analysis indicated that lncRNAs transcription levels may serve as a promising marker for prognosis of patients with NSCLC. PMID- 27992371 TI - Relation between baseline plaque features and subsequent coronary artery remodeling determined by optical coherence tomography and intravascular ultrasound. AB - Atherosclerosis often leads to myocardial infarction and stroke. We examined the influence of baseline plaque characteristics on subsequent vascular remodeling in response to changes in plaque size. Using optical coherence tomography (OCT) and intravascular ultrasound (IVUS), we examined 213 plaques from 138 patients with acute coronary syndrome at baseline and repeated IVUS at the 12-month follow-up. The change in external elastic membrane (EEM) area for each 1 mm2 change in plaque area (i.e., the slope of the regression line) was calculated as a measure of vascular remodeling capacity. In plaques with static positive remodeling, the slope was smaller than in plaques without static positive remodeling. In addition, the slope of the regression line for lesions with a large plaque burden was much smaller than that for lesions with a small plaque burden. Multivariate linear regression analysis showed that diabetes, calcification and static positive remodeling were inversely and independently associated with the level of change in EEM area/change in plaque area. Lesions with a large plaque burden, calcifications or static positive remodeling had less remodeling capacity, and calcification and static positive remodeling were independent predictors of reduced subsequent remodeling. Therefore, calcifications and static positive remodeling could be used as morphological biomarkers to predict decreased subsequent arterial remodeling. PMID- 27992370 TI - The crosstalk between lncRNA and microRNA in cancer metastasis: orchestrating the epithelial-mesenchymal plasticity. AB - Noncoding RNAs (ncRNAs) have been demonstrated to closely associate with gene regulation and encompass the well-known microRNAs (miRNAs), as well as the most recently acknowledged long noncoding RNAs (lncRNAs). Current evidence indicates that lncRNAs can interact with miRNAs and these interactions play crucial roles in cancer metastasis, through regulating critical events especially the epithelial-mesenchymal transition (EMT). This review summarizes the types of lncRNA-miRNA crosstalk identified to-date and discusses their influence on the epithelial-mesenchymal plasticity and clinical metastatic implication. PMID- 27992372 TI - How does white matter microstructure differ between the vascular and amnestic mild cognitive impairment? AB - Changes in white matter (WM) microstructure may relate to the pathophysiology of cognitive impairment. Whether WM microstructure differs in two common pre dementia subtypes, vascular mild cognitive impairment (VaMCI) and amnestic mild cognitive impairment (aMCI), is largely unknown. This study included 28 VaMCI (12 men, age: 46 ~ 77 years) and 34 aMCI patients (14 men, age: 51 ~ 79 years). All patients underwent a battery of neuropsychological tests and structural and diffusion magnetic resonance imaging (MRI) scanning. WM microstructure was quantified using diffusion MRI parameters: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD). These parameters were compared between the two patient groups using tract-based spatial statistics (TBSS) after controlling for age, gender, and education. No significant differences in FA/MD/AxD/RD were observed between the VaMCI and aMCI groups, which suggests a similar pattern of WM microstructure in the early stage of cognitive impairment for different dementia types. However, the two groups exhibited significant differences in the relationship between FA and the Auditory Verbal Learning Test (AVLT), which were primarily located around the corona radiate and corpus callosum. Specifically, there were significant positive correlations (R = 0.64, P < 0.001) between the FA and AVLT in the VaMCI group, but the opposite trend was observed in the aMCI group (R = -0.34, P = 0.047). The differential relationship between WM and memory between VaMCI and aMCI indicates an independent neuropathology for specific memory deficits in different types of dementia. PMID- 27992373 TI - Sex chromosome abnormalities and psychiatric diseases. AB - Excesses of sex chromosome abnormalities in patients with psychiatric diseases have recently been observed. It remains unclear whether sex chromosome abnormalities are related to sex differences in some psychiatric diseases. While studies showed evidence of susceptibility loci over many sex chromosomal regions related to various mental diseases, others demonstrated that the sex chromosome aneuploidies may be the key to exploring the pathogenesis of psychiatric disease. In this review, we will outline the current evidence on the interaction of sex chromosome abnormalities with schizophrenia, autism, ADHD and mood disorders. PMID- 27992374 TI - Lycium barbarum polysaccharides inhibit proliferation and migration of bladder cancer cell lines BIU87 by suppressing Pi3K/AKT pathway. AB - The aim of this study was to verify whether Lycium barbarum polysaccharides inhibits proliferation and migration of BIU87 cells through Pi3K/AKT pathway. Different concentrations of Lycium barbarum polysaccharides were used to incubate with BIU87cells. LY-294002 and IGF-1 were used to inhibit and activate Pi3K/AKT pathway respectively. MTT were used to investigate the proliferation of BIU87cells. Transwell chambers and wound healing were used to test the migratory ability of BIU87cells. Western blotting were used to investigate the expressions of P21,P27,MMP-2, MMP-9, AKT and p-AKT in BIU87cells. Compared with the control group, the proliferation and migration of BIU87cells and the expression of p-AKT were significantly decreased in the study group; the inhibitory effect of the downregulation of p-AKT by LY-294002on the induction of BIU87cells proliferation and migration was identical to that of Lycium barbarum polysaccharides; upregulation of p-AKT by IGF-1 reversed the Lycium barbarum polysaccharides induced inhibition of BIU87cells dedifferentiation. In conclusion, LBP inhibits the proliferation and migration of BIU87 cells by suppressing Pi3K/AKT signaling pathway. PMID- 27992376 TI - Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle. AB - Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle. PMID- 27992375 TI - Improved method for prioritization of disease associated lncRNAs based on ceRNA theory and functional genomics data. AB - Although several computational models that predict disease-associated lncRNAs (long non-coding RNAs) exist, only a limited number of disease-associated lncRNAs are known. In this study, we mapped lncRNAs to their functional genomics context using competing endogenous RNAs (ceRNAs) theory. Based on the criteria that similar lncRNAs are likely involved in similar diseases, we proposed a disease lncRNA prioritization method, DisLncPri, to identify novel disease-lncRNA associations. Using a leave-one-out cross validation (LOOCV) strategy, DisLncPri achieved reliable area under curve (AUC) values of 0.89 and 0.87 for the LncRNADisease and Lnc2Cancer datasets that further improved to 0.90 and 0.89 by integrating a multiple rank fusion strategy. We found that DisLncPri had the highest rank enrichment score and AUC value in comparison to several other methods for case studies of alzheimer's disease, ovarian cancer, pancreatic cancer and gastric cancer. Several novel lncRNAs in the top ranks of these diseases were found to be newly verified by relevant databases or reported in recent studies. Prioritization of lncRNAs from a microarray (GSE53622) of oesophageal cancer patients highlighted ENSG00000226029 (top 2), a previously unidentified lncRNA as a potential prognostic biomarker. Our analysis thus indicates that DisLncPri is an excellent tool for identifying lncRNAs that could be novel biomarkers and therapeutic targets in a variety of human diseases. PMID- 27992377 TI - Improved clinical outcomes of patients with ovarian carcinoma arising in endometriosis. AB - BACKGROUND: Despite enormous efforts to dissect the role of endometriosis in ovarian cancer development, the difference in prognosis between ovarian cancer patients with or without endometriosis remains elusive. The purpose of this study is to assess the association between endometriosis and the prognosis in patients with ovarian cancer. RESULTS: Ovarian cancer arising in endometriosis tended to be presented as clear cell histology, early stage, less intraperitoneal metastasis and ascites, and lower CA125 level compared with those without endometriosis. Multivariate Cox regression analysis identified endometriosis as an independent prognostic factor for progression free survival (P = 0.002) and overall survival (P = 0.009) in all patients and especially for early stage. A nomogram integrating endometriosis, FIGO stage and CA125 was established to predict progression free survival and overall survival. MATERIALS AND METHODS: This study retrospectively enrolled 196 ovarian cancers arising or not in endometriosis judged by adjunctive use of CD10 immunohistochemistry in conjunction with H&E staining specimens. Clinicopathologic variables, progression free survival (PFS) and overall survival (OS) were recorded. Kaplan-Meier analysis was performed to compare survival curves. Cox regression models were used to analyze the effect of endometriosis on PFS and OS. A prognostic nomogram was constructed based on the independent prognostic factors identified by multivariate analysis. CONCLUSIONS: Endometriosis is an independent predictor of prognosis in ovarian cancer patients. PMID- 27992379 TI - Gastric acid response to acute exposure to hypergravity. AB - The influence of environmental stressors on the pathogenesis of gastrointestinal disease has received increased awareness. Stress affects different physiological functions of the gastrointestinal tract, including gastric acid secretion and mucosal blood flow. Repeated exposures of rapid-onset, highly-sustained hypergravity cause severe physical stress in the pilot. Although the effects of exposure to hypergravity on cardiovascular and cerebral functions have been the subjects of numerous studies, crucial information regarding pathophysiological changes in the gastrointestinal tract following hypergravity exposure is lacking. In this study, we investigated the effects of acute exposure to hypergravity on gastric secretory activity and gastrin release. Male Sprague-Dawley rats were exposed to +10Gz three times for 3 min. Gastric juice and blood were collected. The volume and total acidity of gastric juice, and the plasma gastrin level was measured. Acute exposure to +10Gz significantly decreased the gastric juice parameters. The gastric juice volume and total acidity of hypergravity-exposed rats were 3.54 +/- 0.32 mL/100 g and 84.90 +/- 5.17 mEq/L, respectively, which were significantly lower than those of the nonexposed rats (4.62 +/- 0.39 mL/100 g and 97.37 +/- 5.42 mEq/L; P < 0.001 and P < 0.001, respectively). In contrast, plasma gastrin level was not significantly altered following hypergravity exposure. We demonstrated that acute exposure to hypergravity led to a significant decrease in the gastric juice volume and acidity but did not alter the plasma gastrin level. PMID- 27992380 TI - Noninvasive amide proton transfer magnetic resonance imaging in evaluating the grading and cellularity of gliomas. AB - Using noninvasive magnetic resonance imaging techniques to accurately evaluate the grading and cellularity of gliomas is beneficial for improving the patient outcomes. Amide proton transfer imaging is a noninvasive molecular magnetic resonance imaging technique based on chemical exchange saturation transfer mechanism that detects endogenous mobile proteins and peptides in biological tissues. Between August 2012 and November 2015, a total number of 44 patients with pathologically proven gliomas were included in this study. We compared the capability of amide proton transfer magnetic resonance imaging with that of noninvasive diffusion-weighted imaging and noninvasive 3-dimensional pseudo continuous arterial spin imaging in evaluating the grading and cellularity of gliomas. Our results reveal that amide proton transfer magnetic resonance imaging is a superior imaging technique to diffusion-weighted imaging and 3-dimensional pseudo-continuous arterial spin imaging in the grading of gliomas. In addition, our results showed that the Ki-67 index correlated better with the amide proton transfer-weighted signal intensity than with the apparent diffusion coefficient value or the cerebral blood flow value in the gliomas. Amide proton transfer magnetic resonance imaging is a promising method for predicting the grading and cellularity of gliomas. PMID- 27992382 TI - Evolution to the quark-gluon plasma. AB - Theoretical studies on the early-time dynamics in the ultra-relativistic heavy ion collisions are reviewed, including pedagogical introductions on the initial condition with small-[Formula: see text] gluons treated as a color glass condensate, the bottom-up thermalization scenario, plasma/glasma instabilities, basics of some formulations such as the kinetic equations and the classical statistical simulation. More detailed discussions follow to make an overview of recent developments on the fast isotropization, the onset of hydrodynamics, and the transient behavior of momentum spectral cascades. PMID- 27992378 TI - Immunotherapy for patients with advanced pancreatic carcinoma: a promising treatment. AB - There are limited data on the safety and efficacy of immunotherapy for patients with advanced pancreatic cancer (APC). A meta-analysis of single-arm trials is proposed to assess the efficacy and safety of immunotherapy for APC. Eighteen relevant studies involving 527 patients were identified. The pooled disease control rate (DCR), overall survival (OS), progression free survival (PFS), and 1 year survival rate were estimated as 59.32%, 7.90 months, 4.25 months, and 30.12%, respectively. Subgroup analysis showed that the pooled OS, PFS, and 1 year survival rate were significantly higher for autologous activated lymphocyte therapy compared with peptide-based vaccine therapy (OS: 8.28 months vs. 7.40 months; PFS: 6.04 months vs. 3.86 months; 1-year survival rate: 37.17% vs. 19.74%). Another subgroup analysis demonstrated that the pooled endpoints were estimated as obviously higher for immunotherapy plus chemotherapy compared with immunotherapy alone (DCR: 62.51% vs. 47.63%; OS: 8.67 months vs. 4.91 months; PFS: 4.91 months vs. 3.34 months; 1-year survival rate: 32.32% vs. 21.43%). Of the included trials, seven trials reported no treatment related adverse events , five trials reported (16.6 +/- 3.9) % grade 3 adverse events and no grade 4 adverse events. In conclusion, immunotherapy is safe and effective in the treatment of APC. PMID- 27992383 TI - Quantification of tumor perfusion using dynamic contrast-enhanced ultrasound: impact of mathematical modeling. AB - Dynamic contrast-enhanced ultrasound has been proposed to monitor tumor therapy, as a complement to volume measurements. To assess the variability of perfusion parameters in ideal conditions, four consecutive test-retest studies were acquired in a mouse tumor model, using controlled injections. The impact of mathematical modeling on parameter variability was then investigated. Coefficients of variation (CV) of tissue blood volume (BV) and tissue blood flow (BF) based-parameters were estimated inside 32 sub-regions of the tumors, comparing the log-normal (LN) model with a one-compartment model fed by an arterial input function (AIF) and improved by the introduction of a time delay parameter. Relative perfusion parameters were also estimated by normalization of the LN parameters and normalization of the one-compartment parameters estimated with the AIF, using a reference tissue (RT) region. A direct estimation (rRTd) of relative parameters, based on the one-compartment model without using the AIF, was also obtained by using the kinetics inside the RT region. Results of test retest studies show that absolute regional parameters have high CV, whatever the approach, with median values of about 30% for BV, and 40% for BF. The positive impact of normalization was established, showing a coherent estimation of relative parameters, with reduced CV (about 20% for BV and 30% for BF using the rRTd approach). These values were significantly lower (p < 0.05) than the CV of absolute parameters. The rRTd approach provided the smallest CV and should be preferred for estimating relative perfusion parameters. PMID- 27992381 TI - Low-dose bortezomib increases the expression of NKG2D and DNAM-1 ligands and enhances induced NK and gammadelta T cell-mediated lysis in multiple myeloma. AB - Multiple myeloma (MM) is an incurable hematological malignancy, although bortezomib has markedly improved its outcomes. Growing clinical evidence indicates that enhancing induced natural killer (NK) or gammadelta T cells for infusion is useful in the treatment of MM. However, whether combination treatment with bortezomib and induced NK and gammadelta T cells further improves outcomes in MM, and how the treatments should be combined, remain unclear. Herein, we found that low-dose bortezomib did not suppress the viability of induced NK and gammadelta T cells, but did induce MM cell apoptosis. Importantly, low-dose bortezomib increased the expression of NKG2D and DNAM-1 ligands on MM cells, which sensitized the multiple myeloma cells to lysis by induced NK and gammadelta T cells. Our results suggested that combination treatment with low-dose bortezomib and induced NK or gammadelta T cells had a synergistic cytotoxic effect on MM cells. This study provided a proof of principle for the design of future trials and investigation of this combination therapeutic strategy for MM treatment. PMID- 27992384 TI - The energy dependence of the lateral dose response functions of detectors with various densities in photon-beam dosimetry. AB - The lateral dose response function is a general characteristic of the volume effect of a detector used for photon dosimetry in a water phantom. It serves as the convolution kernel transforming the true absorbed dose to water profile, which would be produced within the undisturbed water phantom, into the detector measured signal profile. The shape of the lateral dose response function characterizes (i) the volume averaging attributable to the detector's size and (ii) the disturbance of the secondary electron field associated with the deviation of the electron density of the detector material from the surrounding water. In previous work, the characteristic dependence of the shape of the lateral dose response function upon the electron density of the detector material was studied for 6 MV photons by Monte Carlo simulation of a wall-less voxel-sized detector (Looe et al 2015 Phys. Med. Biol. 60 6585-07). This study is here continued for 60Co gamma rays and 15 MV photons in comparison with 6 MV photons. It is found (1) that throughout these photon spectra the shapes of the lateral dose response functions are retaining their characteristic dependence on the detector's electron density, and (2) that their energy-dependent changes are only moderate. This appears as a practical advantage because the lateral dose response function can then be treated as practically invariant across a clinical photon beam in spite of the known changes of the photon spectrum with increasing distance from the beam axis. PMID- 27992385 TI - Noninvasive measurement of radiopharmaceutical time-activity data using external thermoluminescent dosimeters (TLDs). AB - In this study, we present a new method for estimating the time-activity data using serial timely measurements of thermoluminescent dosimeters (TLDs). The approach is based on the combination of the measurement of surface dose using TLD and Monte Carlo (MC) simulation to estimate the radiopharmaceutical time-activity data. It involves four steps: (1) identify the source organs and outline their contours in computed tomography images; (2) compute the S values on the body surface for each source organ using a MC code; (3) obtain a serial measurement of the dose with numerous TLDs placed on the body surface; (4) solve the dose activity equation to generate organ cumulative activity for each period of measurement. The activity of each organ at the time of measurement is simply the cumulative activity divided by the timespan between measurements. The usefulness of this method was studied using a MC simulation based on an Oak Ridge National Laboratory mathematical phantom with 18F-FDG filled in six source organs. Numerous TLDs were placed on different locations of the surface and were repeatedly read and replaced. The time-activity curves (TACs) of all organs were successfully reconstructed. Experiments on a physical phantom were also performed. Preliminary results indicate that it is an effective, robust, and simple method for assessing the TAC. The proposed method holds great potential for a range of applications in areas such as targeted radionuclide therapy, pharmaceutical research, and patient-specific dose estimation. PMID- 27992386 TI - Applying Computer Models to Realize Closed-Loop Neonatal Oxygen Therapy. AB - BACKGROUND: Within the context of automating neonatal oxygen therapy, this article describes the transformation of an idea verified by a computer model into a device actuated by a computer model. Computer modeling of an entire neonatal oxygen therapy system can facilitate the development of closed-loop control algorithms by providing a verification platform and speeding up algorithm development. METHODS: In this article, we present a method of mathematically modeling the system's components: the oxygen transport within the patient, the oxygen blender, the controller, and the pulse oximeter. Furthermore, within the constraints of engineering a product, an idealized model of the neonatal oxygen transport component may be integrated effectively into the control algorithm of a device, referred to as the adaptive model. Manual and closed-loop oxygen therapy performance were defined in this article by 3 criteria in the following order of importance: percent duration of SpO2 spent in normoxemia (target SpO2 +/- 2.5%), hypoxemia (less than normoxemia), and hyperoxemia (more than normoxemia); number of 60-second periods <85% SpO2 and >95% SpO2; and number of manual adjustments. RESULTS: Results from a clinical evaluation that compared the performance of 3 closed-loop control algorithms (state machine, proportional-integral differential, and adaptive model) with manual oxygen therapy on 7 low-birth weight ventilated preterm babies, are presented. Compared with manual therapy, all closed-loop control algorithms significantly increased the patients' duration in normoxemia and reduced hyperoxemia (P < 0.05). The number of manual adjustments was also significantly reduced by all of the closed-loop control algorithms (P < 0.05). CONCLUSIONS: Although the performance of the 3 control algorithms was equivalent, it is suggested that the adaptive model, with its ease of use, may have the best utility. PMID- 27992388 TI - Identification of Severe Mitral Stenosis Using Real-Time Three-Dimensional Transesophageal Echocardiography During a Left Ventricular Assist Device Insertion: Erratum. PMID- 27992389 TI - Contrasting Effects of the gamma-Aminobutyric Acid Type A Receptor beta3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R-mTFD-MPAB: Erratum. PMID- 27992387 TI - Early Detection of Anesthesia Workstation High-Pressure Oxygen Line Leak. PMID- 27992390 TI - The Effect of Cochlear Damage on the Sensitivity to Harmonicity. AB - OBJECTIVES: A sum of simultaneous pure tones with harmonic relationships (i.e., simple frequency ratios) is normally heard as a single sound, with a single pitch, even when its components are fully resolved in the auditory periphery. This perceptual phenomenon called "harmonic fusion" is thought to play an important role in auditory scene analysis as listeners often have to segregate simultaneous harmonic sounds with different fundamental frequencies. The present study explored the consequences of mild or moderate cochlear hearing loss for the sensitivity to harmonicity and the detection of inharmonicity. DESIGN: The subjects were 12 normal-hearing (NH) listeners and 8 listeners with cochlear hearing loss amounting to 30 to 50 dB (mean: 42 dB) from 0.25 to 3 kHz. In each subject, thresholds for the detection of a change in the frequency ratio of simultaneous pure tones were measured with an adaptive forced-choice procedure. The standard frequency ratio was either harmonic (2:1, i.e., one octave) or inharmonic (0.8 or 1.2 octaves). The tones were presented at a low sensation level (at most 15 dB) within broadband noise, to minimize their cochlear interactions. In the main experimental conditions, the frequency register of the stimuli varied randomly within each trial, so that subjects were forced to process frequency ratios to achieve good performance; frequency discrimination was not sufficient. In other conditions, by contrast, frequency discrimination was sufficient to perform the task optimally. RESULTS: For both groups of subjects, thresholds in the main experimental conditions were lower (i.e., better) when the standard frequency ratio was harmonic than when it was inharmonic. This effect, revealing sensitivity to harmonicity, was weak for some members of the hearing-impaired group, but could be observed even in subjects showing a very poor frequency discrimination ability. The two groups, however, differed from each other with respect to the detection of inharmonicity: for the NH group, in agreement with previous results, negative deviations from one octave (i.e., compressions of this frequency ratio) were better detected than positive deviations (stretchings); for the hearing-impaired group, on the other hand, the sign of the deviations had no effect on performance. CONCLUSIONS: Sensitivity to harmonicity appears to be remarkably robust. However, it can be reduced in some listeners with mild or moderate cochlear damage. Moreover, as inharmonicity detection is asymmetric for NH listeners but apparently becomes symmetric in case of cochlear damage, it may be that listeners with cochlear damage do not detect inharmonicity in the same manner as NH listeners do. In some circumstances, inharmonicity can be detected on the basis of "beat" cues available in single frequency channels; however, the subjects tested here were unlikely to use cues of this type. PMID- 27992392 TI - Animal models for central poststroke pain: a critical comprehensive review. AB - Central poststroke pain (CPSP) is a severe type of neuropathic pain that can develop after stroke and is difficult to treat. Research into its underlying mechanisms and treatment options could benefit from a valid CPSP animal model. Nine different CPSP animal models have been published, but there are relatively few reports on successful reproductions of these models and so far only little advances in the understanding or the management of CPSP have been made relying on these models. In general, the construct validity (similarity in underlying mechanisms) of these CPSP animal models is relatively high, although this cannot be evaluated into depth because of lack of understanding the mechanisms through which thalamic stroke can lead to CPSP. The face validity (symptom similarity) is relatively low, mainly because pain in these models is tested almost exclusively through evoked mechanical/thermal hypersensitivity assessed by reflexive measures and given the conflicting results with similar tests in patients with CPSP. The predictive validity (similarity in treatment efficacy) has not been evaluated in most models and incorporates difficulties that are specific to CPSP. We compare the different models regarding these types of validity and discuss the robustness, reproducibility, and problems regarding the design and reporting of the articles establishing these models. We conclude with various proposals on how to improve the validity and reproducibility of CPSP animal models. Until further improvements are achieved, prudence is called for in interpreting results obtained through these models. PMID- 27992391 TI - Auditory Brainstem Response Altered in Humans With Noise Exposure Despite Normal Outer Hair Cell Function. AB - OBJECTIVES: Recent animal studies demonstrated that cochlear synaptopathy, a partial loss of inner hair cell-auditory nerve fiber synapses, can occur in response to noise exposure without any permanent auditory threshold shift. In animal models, this synaptopathy is associated with a reduction in the amplitude of wave I of the auditory brainstem response (ABR). The goal of this study was to determine whether higher lifetime noise exposure histories in young people with clinically normal pure-tone thresholds are associated with lower ABR wave I amplitudes. DESIGN: Twenty-nine young military Veterans and 35 non Veterans (19 to 35 years of age) with normal pure-tone thresholds were assigned to 1 of 4 groups based on their self-reported lifetime noise exposure history and Veteran status. Suprathreshold ABR measurements in response to alternating polarity tone bursts were obtained at 1, 3, 4, and 6 kHz with gold foil tiptrode electrodes placed in the ear canal. Wave I amplitude was calculated from the difference in voltage at the positive peak and the voltage at the following negative trough. Distortion product otoacoustic emission input/output functions were collected in each participant at the same four frequencies to assess outer hair cell function. RESULTS: After controlling for individual differences in sex and distortion product otoacoustic emission amplitude, the groups containing participants with higher reported histories of noise exposure had smaller ABR wave I amplitudes at suprathreshold levels across all four frequencies compared with the groups with less history of noise exposure. CONCLUSIONS: Suprathreshold ABR wave I amplitudes were reduced in Veterans reporting high levels of military noise exposure and in non Veterans reporting any history of firearm use as compared with Veterans and non Veterans with lower levels of reported noise exposure history. The reduction in ABR wave I amplitude in the groups with higher levels of noise exposure cannot be accounted for by sex or variability in outer hair cell function. This change is similar to the decreased ABR wave I amplitudes observed in animal models of noise-induced cochlear synaptopathy. However, without post mortem examination of the temporal bone, no direct conclusions can be drawn concerning the presence of synaptopathy in the study groups with higher noise exposure histories. PMID- 27992393 TI - Manipulating the extracellular matrix: an animal model of the bladder pain syndrome. AB - Bladder pain syndrome (BPS) is associated with breakdown of the protective uroepithelial barrier of the urinary bladder allowing urinary constituents access to bladder sensory neurons. Although there are several animal models of cystitis, none specifically relates to BPS. Here, we aimed to create such a model using enzymatic digestion of the barrier proteoglycans (PGs) in the rat. Twenty female Wistar rats were anaesthetized and transurethrally catheterized. Ten animals were treated with 0.25IU of intravesical chondroitinase ABC and heparanase III to digest chondroitin sulphate and heparin sulphate PGs, respectively. Ten animals received saline. Following PG deglycosylation, bladders showed irregular loss of the apical uroplakin and a significant increase in neutrophils, not evident in the control group. Spinal cord sections were also collected for c-fos analysis. A large and significant increase in fos immunoreactivity in the L6/S1 segments in the treatment vs control bladders was observed. Cystometry was performed on 5 treatment and 5 control animals. Analysis revealed a significant increase in micturition reflex excitability postdeglycosylation. On a further group of 10 animals, von Frey mechanical withdrawal thresholds were tested on abdominal skin before and after PG digestions. There was a significant decrease in abdominal mechanical withdrawal threshold postdeglycosylation compared with controls. The results of this animal study suggest that many of the clinical features of BPS are seen after PG digestion from the bladder lumen. This model can be used to further understand mechanisms of pain in patients with BPS and to test new therapeutic strategies. PMID- 27992394 TI - The Conundrum in the Diagnosis and Management of Atypical Fulminant Measles in a Leukemia Survivor on Maintenance Chemotherapy. AB - We report the diagnostic and therapeutic challenges in an unusually fulminant presentation of measles, presenting as severe necrotizing bronchiolitis with secondary hemophagocytic lymphohistiocytosis (HLH) in the absence of classical clinical features in an immunocompromised host on maintenance chemotherapy. Our patient had presented with features of a viral pneumonitis without the classical exanthem, in combination with HLH. Although rhinovirus-induced HLH was highly unusual, the positive rhinovirus swab result had distracted us from the eventual diagnosis. This calls for greater impetus to increase awareness and public education to improve vaccination rates and herd immunity to curb outbreaks and protect the immunocompromised patients. PMID- 27992395 TI - Vascular Function and Structure in Veteran Athletes after Myocardial Infarction. AB - PURPOSE: Although athletes demonstrate lower cardiovascular risk and superior vascular function compared with sedentary peers, they are not exempted from cardiac events (i.e., myocardial infarction [MI]). The presence of an MI is associated with increased cardiovascular risk and impaired vascular function. We tested the hypothesis that lifelong exercise training in post-MI athletes, similar as in healthy controls, is associated with a superior peripheral vascular function and structure compared with a sedentary lifestyle in post-MI individuals. METHODS: We included 18 veteran athletes (ATH) (>20 yr) and 18 sedentary controls (SED). To understand the effect of lifelong exercise training after MI, we included 20 veteran post-MI athletes (ATH + MI) and 19 sedentary post-MI controls (SED + MI). Participants underwent comprehensive assessment using vascular ultrasound (vascular stiffness, intima-media thickness, and endothelium (in)dependent mediated dilatation). Lifetime risk score was calculated for a 30-yr risk prediction of cardiovascular disease mortality of the participants. RESULTS: ATH demonstrated a lower vascular stiffness and smaller femoral intima-media thickness compared with SED. Vascular function and structure did not differ between ATH + MI and SED + MI. ATH (4.0% +/- 5.1%) and ATH + MI (6.1% +/- 3.7%) had a significantly better lifetime risk score compared with their sedentary peers (SED: 6.9% +/- 3.7% and SED + MI: 9.3% +/- 4.8%). ATH + MI had no secondary events versus two recurrent MI and six elective percutaneous coronary interventions within SED + MI (P < 0.05). CONCLUSION: Although veteran post-MI athletes did not have a superior peripheral vascular function and structure compared with their sedentary post-MI peers, benefits of lifelong exercise training in veteran post-MI athletes relate to a better cardiovascular risk profile and lower occurrence of secondary events. PMID- 27992398 TI - Nutrition and Athletic Performance: Erratum. PMID- 27992396 TI - An Evaluation of Accelerometer-derived Metrics to Assess Daily Behavioral Patterns. AB - INTRODUCTION: The way physical activity (PA) and sedentary behavior (SB) are accumulated throughout the day (i.e., patterns) may be important for health, but identifying measurable and meaningful metrics of behavioral patterns is challenging. This study evaluated accelerometer-derived metrics to determine whether they predicted PA and SB patterns and were reliably measured. METHODS: We defined and measured 55 metrics that describe daily PA and SB using data collected by using the activPAL monitor in four studies. The first two studies were randomized crossover designs that included recreationally active participants. Study 1 experimentally manipulated time spent in moderate-to vigorous-intensity PA and sedentary time, and study 2 held time in exercise constant and manipulated SB. Study 3 included inactive participants who increased exercise, decreased sedentary time, or both. The study conditions induced distinct behavioral patterns; thus, we tested whether the new metrics could improve the prediction of an individual's study condition after adjusting for the overall volume of PA or SB using conditional logistic regression. In study 4, we measured the 3-month reliability for the pattern metrics by calculating intraclass correlation coefficients in a community-dwelling sample who wore the activPAL monitor twice for 7 d. RESULTS: In each of the experimental studies, we identified new metrics that could improve the accuracy for predicting condition beyond SB and moderate-to-vigorous-intensity PA volume. In study 1, 23 metrics were predictive of a highly active condition, and in study 2, 24 metrics were predictive of a highly sedentary condition. In study 4, the median intraclass correlation coefficients (25-75th percentiles) of the metrics were 0.59 (0.46 0.65). CONCLUSIONS: Several new metrics were predictive of patterns of SB, exercise, and nonexercise behavior and are moderately reliable for a 3-month period. Applying these metrics to determine whether daily behavioral patterns are associated with health-outcomes is an important area of future research. PMID- 27992397 TI - Adaptations with Intermittent Exercise Training in Post- and Premenopausal Women. AB - INTRODUCTION: The purposes of the present study was to examine the effect of intermittent exercise training on musculoskeletal and metabolic health in postmenopausal (PM) and premenopausal (PRM) women and, furthermore, to evaluate whether the adaptations can be maintained with a reduced training frequency. METHODS: Eighteen PM (51 +/- 1 yr, mean +/- SEM) and 12 PRM (48 +/- 1 yr) women participated in floorball training approximately two times per week for 12 wk. In a subgroup (n = 9) of PM women (PM40), exercise training was performed for an additional 40 wk with a reduced training frequency of approximately one training session per week. RESULTS: In PM, the body fat percentage decreased (P < 0.05) and the total lean leg mass increased (P < 0.05) during the 12-wk training period, with no changes in PRM. In both PM and PRM, lean body mass and maximal oxygen uptake (VO2max) were higher, and Yo-Yo intermittent endurance test 1 (YYIET-1) performance was better (P < 0.05) after the 12-wk training period. Procollagen type 1 amino-terminal propeptide was higher (P < 0.05) in PM, and total leg bone mineral density (BMD) was higher (P < 0.05) in both PM and PRM after the 12-wk training period. In PM40, total lean leg mass, VO2max, YYIET-1 performance, level of procollagen type 1 amino-terminal propeptide, and total leg BMD were maintained, whereas whole-body BMD and glycated hemoglobin (HbA1c) were reduced (P < 0.05) and the expression of muscle glucose transporter type 4 was higher (P < 0.05). CONCLUSION: Twelve weeks of intermittent exercise training increased BMD, intermittent exercise capacity, and VO2max in PM and PRM, with PM also having positive changes in body composition. Additional 40 wk of training with a reduced frequency was sufficient to preserve these physiological adaptations and also improve blood glucose regulation in PM. PMID- 27992399 TI - Application of Single Voxel 1H Magnetic Resonance Spectroscopy in Hepatic Benign and Malignant Lesions. AB - BACKGROUND To quantify the metabolite changes in hepatic tumors by single-voxel 1H magnetic resonance spectroscopy (MRS) at 3.0 T and explore the application value of 1HMRS in the diagnosis of hepatic benign and malignant lesions. MATERIAL AND METHODS A total of 45 patients (55 lesions) diagnosed with hepatic lesions by ultrasound and/or computer topography (CT) from November 2006 to March 2007 were included in this study. All patients underwent 3D-dynamic enhanced scan with liver acquisition with acceleration volume acquisition (LAVA) sequence and single voxel 1HMRS imaging with PRESS (point-resolved spectroscopy) sequence. The metabolite concentrations such as choline (Cho) and lipids (Lip) were measured. RESULTS There was significant difference regarding the occurrence rate of the obvious elevated Cho peaks between benign and malignant tumors (7/27 vs. 21/28, p=0.000). There was statistical significant differences regarding the Cho/Lip ratios in hepatic benign (0.0686+/-0.0283, 95% CI: 0.0134-0.1245) and malignant (0.1266 +/-0.1124, 95% CI: 0.0937-0.2203) lesions (p<0.05). When compared with the pathological results, the sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were 85.7% (24/28), 92.6% (25/27), 92.3% (24/26), 86.2% (25/29), and 89.1% (49/55) respectively for the MRI assessment, and 92.6% (26/28), 88.9% (24/27), 89.7 (26/29), 92.3 (24/26), and 90.9% (50/55) respectively for 1HMRS combined with MRI assessment. CONCLUSIONS Single Cho peaks or Lip peaks cannot be used for the diagnosis of hepatic benign and malignant lesions. Combined use of 1HMRS and MRI can greatly improve the application value of MRI assessment in the diagnosis of hepatic benign and malignant lesions with a higher sensitivity, negative predictive value, and overall accuracy. PMID- 27992401 TI - Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. AB - Most Foxp3+ regulatory T (Treg) cells develop in the thymus as a functionally mature T cell subpopulation specialized for immune suppression. Their cell fate appears to be determined before Foxp3 expression; yet molecular events that prime Foxp3- Treg precursor cells are largely obscure. We found that Treg cell-specific super-enhancers (Treg-SEs), which were associated with Foxp3 and other Treg cell signature genes, began to be activated in Treg precursor cells. T cell-specific deficiency of the genome organizer Satb1 impaired Treg-SE activation and the subsequent expression of Treg signature genes, causing severe autoimmunity due to Treg cell deficiency. These results suggest that Satb1-dependent Treg-SE activation is crucial for Treg cell lineage specification in the thymus and that its perturbation is causative of autoimmune and other immunological diseases. PMID- 27992402 TI - The ubiquitin E3 ligase TRIM31 promotes aggregation and activation of the signaling adaptor MAVS through Lys63-linked polyubiquitination. AB - The signaling adaptor MAVS forms prion-like aggregates to activate an innate antiviral immune response after viral infection. However, the molecular mechanisms that regulate MAVS aggregation are poorly understood. Here we identified TRIM31, an E3 ubiquitin ligase of the TRIM family of proteins, as a regulator of MAVS aggregation. TRIM31 was recruited to mitochondria after viral infection and specifically regulated antiviral signaling mediated by RLR pattern recognition receptors. TRIM31-deficient mice were more susceptible to infection with RNA virus than were wild-type mice. TRIM31 interacted with MAVS and catalyzed the Lys63 (K63)-linked polyubiquitination of Lys10, Lys311 and Lys461 on MAVS. This modification promoted the formation of prion-like aggregates of MAVS after viral infection. Our findings reveal new insights in the molecular regulation of MAVS aggregation and the cellular antiviral response through TRIM31 mediated K63-linked polyubiquitination of MAVS. PMID- 27992400 TI - The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. AB - Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of iNKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an iNKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated iNKT cell development and that the expression of genes that were targets of both JunB and the iNKT cell master transcription factor PLZF was UTX dependent. We identified iNKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the iNKT cell lineage. Our findings reveal how UTX regulates the development of iNKT cells through multiple epigenetic mechanisms. PMID- 27992403 TI - Themis2 lowers the threshold for B cell activation during positive selection. AB - The positive and negative selection of lymphocytes by antigen is central to adaptive immunity and self-tolerance, yet how this is determined by different antigens is not completely understood. We found that thymocyte-selection associated family member 2 (Themis2) increased the positive selection of B1 cells and germinal center B cells by self and foreign antigens. Themis2 lowered the threshold for B-cell activation by low-avidity, but not high-avidity, antigens. Themis2 constitutively bound the adaptor protein Grb2, src-kinase Lyn and signal transducer phospholipase gamma2 (PLC-gamma2), and increased activation of PLC gamma2 and its downstream pathways following B cell receptor stimulation. Our findings identify a unique function for Themis2 in differential signaling and provide insight into how B cells discriminate between antigens of different quantity and quality. PMID- 27992404 TI - A gene network regulated by the transcription factor VGLL3 as a promoter of sex biased autoimmune diseases. AB - Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjogren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development. PMID- 27992405 TI - Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis. AB - Ageing results in loss of tissue homeostasis across taxa. In the intestine of Drosophila melanogaster, ageing is correlated with an increase in intestinal stem cell (ISC) proliferation, a block in terminal differentiation of progenitor cells, activation of inflammatory pathways, and increased intestinal permeability. However, causal relationships between these phenotypes remain unclear. Here, we demonstrate that ageing results in altered localization and expression of septate junction proteins in the posterior midgut, which is quite pronounced in differentiated enterocytes (ECs) at tricellular junctions (TCJs). Acute loss of the TCJ protein Gliotactin (Gli) in ECs results in increased ISC proliferation and a block in differentiation in intestines from young flies, demonstrating that compromised TCJ function is sufficient to alter ISC behaviour in a non-autonomous manner. Blocking the Jun N-terminal kinase signalling pathway is sufficient to suppress changes in ISC behaviour, but has no effect on loss of intestinal barrier function, as a consequence of Gli depletion. Our work demonstrates a pivotal link between TCJs, stem cell behaviour, and intestinal homeostasis and provides insights into causes of age-onset and gastrointestinal diseases. PMID- 27992406 TI - Nanoscale architecture of cadherin-based cell adhesions. AB - Multicellularity in animals requires dynamic maintenance of cell-cell contacts. Intercellularly ligated cadherins recruit numerous proteins to form supramolecular complexes that connect with the actin cytoskeleton and support force transmission. However, the molecular organization within such structures remains unknown. Here we mapped protein organization in cadherin-based adhesions by super-resolution microscopy, revealing a multi-compartment nanoscale architecture, with the plasma-membrane-proximal cadherin-catenin compartment segregated from the actin cytoskeletal compartment, bridged by an interface zone containing vinculin. Vinculin position is determined by alpha-catenin, and following activation, vinculin can extend ~30 nm to bridge the cadherin-catenin and actin compartments, while modulating the nanoscale positions of the actin regulators zyxin and VASP. Vinculin conformational activation requires tension and tyrosine phosphorylation, regulated by Abl kinase and PTP1B phosphatase. Such modular architecture provides a structural framework for mechanical and biochemical signal integration by vinculin, which may differentially engage cadherin-catenin complexes with the actomyosin machinery to regulate cell adhesions. PMID- 27992407 TI - LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency. AB - Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation. PMID- 27992408 TI - cGAL, a temperature-robust GAL4-UAS system for Caenorhabditis elegans. AB - The GAL4-UAS system is a powerful tool for manipulating gene expression, but its application in Caenorhabditis elegans has not been described. Here we systematically optimize the system's three main components to develop a temperature-optimized GAL4-UAS system (cGAL) that robustly controls gene expression in C. elegans from 15 to 25 degrees C. We demonstrate this system's utility in transcriptional reporter analysis, site-of-action experiments and exogenous transgene expression; and we provide a basic driver and effector toolkit. PMID- 27992409 TI - In vivo high-throughput profiling of CRISPR-Cpf1 activity. AB - CRISPR from Prevotella and Francisella 1 (Cpf1) is an effector endonuclease of the class 2 CRISPR-Cas (clustered regularly interspaced short palindromic repeats CRISPR-associated proteins) gene editing system. We developed a method for evaluating Cpf1 activity, based on target sequence composition in mammalian cells, in a high-throughput manner. A library of >11,000 target sequence and guide RNA pairs was delivered into human cells using lentiviral vectors. Subsequent delivery of Cpf1 into this cell library induced insertions and deletions (indels) at the integrated synthetic target sequences, which allowed en masse evaluation of Cpf1 activity by using deep sequencing. With this approach, we determined protospacer-adjacent motif sequences of two Cpf1 nucleases, one from Acidaminococcus sp. BV3L6 (hereafter referred to as AsCpf1) and the other from Lachnospiraceae bacterium ND2006 (hereafter referred to as LbCpf1). We also defined target-sequence-dependent activity profiles of AsCpf1, which enabled the development of a web tool that predicts the indel frequencies for given target sequences (http://big.hanyang.ac.kr/cindel). Both the Cpf1 characterization profile and the in vivo high-throughput evaluation method will greatly facilitate Cpf1-based genome editing. PMID- 27992410 TI - Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. AB - When nanoparticles are intravenously injected into the body, complement proteins deposit on the surface of nanoparticles in a process called opsonization. These proteins prime the particle for removal by immune cells and may contribute toward infusion-related adverse effects such as allergic responses. The ways complement proteins assemble on nanoparticles have remained unclear. Here, we show that dextran-coated superparamagnetic iron oxide core-shell nanoworms incubated in human serum and plasma are rapidly opsonized with the third complement component (C3) via the alternative pathway. Serum and plasma proteins bound to the nanoworms are mostly intercalated into the nanoworm shell. We show that C3 covalently binds to these absorbed proteins rather than the dextran shell and the protein-bound C3 undergoes dynamic exchange in vitro. Surface-bound proteins accelerate the assembly of the complement components of the alternative pathway on the nanoworm surface. When nanoworms pre-coated with human plasma were injected into mice, C3 and other adsorbed proteins undergo rapid loss. Our results provide important insight into dynamics of protein adsorption and complement opsonization of nanomedicines. PMID- 27992411 TI - Real-time shape approximation and fingerprinting of single proteins using a nanopore. AB - Established methods for characterizing proteins typically require physical or chemical modification steps or cannot be used to examine individual molecules in solution. Ionic current measurements through electrolyte-filled nanopores can characterize single native proteins in an aqueous environment, but currently offer only limited capabilities. Here we show that the zeptolitre sensing volume of bilayer-coated solid-state nanopores can be used to determine the approximate shape, volume, charge, rotational diffusion coefficient and dipole moment of individual proteins. To do this, we developed a theory for the quantitative understanding of modulations in ionic current that arise from the rotational dynamics of single proteins as they move through the electric field inside the nanopore. The approach allows us to measure the five parameters simultaneously, and we show that they can be used to identify, characterize and quantify proteins and protein complexes with potential implications for structural biology, proteomics, biomarker detection and routine protein analysis. PMID- 27992412 TI - Self-assembling DNA nanotubes to connect molecular landmarks. AB - Within cells, nanostructures are often organized using local assembly rules that produce long-range order. Because these rules can take into account the cell's current structure and state, they can enable complexes, organelles or cytoskeletal structures to assemble around existing cellular components to form architectures. Although many methods for self-assembling biomolecular nanostructures have been developed, few can be programmed to assemble structures whose form depends on the identity and organization of structures already present in the environment. Here, we demonstrate that DNA nanotubes can grow to connect pairs of molecular landmarks with different separation distances and relative orientations. DNA tile nanotubes nucleate at these landmarks and grow while their free ends diffuse. The nanotubes can then join end to end to form stable connections, with unconnected nanotubes selectively melted away. Connections form between landmark pairs separated by 1-10 um in more than 75% of cases and can span a surface or three dimensions. This point-to-point assembly process illustrates how self-assembly kinetics can be designed to produce structures with a desired physical property rather than a specific shape. PMID- 27992414 TI - Dynamics of clonal evolution in myelodysplastic syndromes. AB - To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring. PMID- 27992413 TI - Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. AB - Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ~75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 * 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 * 10-15). Our study represents a substantial advance in understanding of the genetics of PSC. PMID- 27992415 TI - A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors. AB - Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell to-cell HIV transmission. We validated these pathways in primary human CD4+ T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention. PMID- 27992418 TI - Dynamic restructuring drives catalytic activity on nanoporous gold-silver alloy catalysts. AB - Bimetallic, nanostructured materials hold promise for improving catalyst activity and selectivity, yet little is known about the dynamic compositional and structural changes that these systems undergo during pretreatment that leads to efficient catalyst function. Here we use ozone-activated silver-gold alloys in the form of nanoporous gold as a case study to demonstrate the dynamic behaviour of bimetallic systems during activation to produce a functioning catalyst. We show that it is these dynamic changes that give rise to the observed catalytic activity. Advanced in situ electron microscopy and X-ray photoelectron spectroscopy are used to demonstrate that major restructuring and compositional changes occur along the path to catalytic function for selective alcohol oxidation. Transient kinetic measurements correlate the restructuring to three types of oxygen on the surface. The direct influence of changes in surface silver concentration and restructuring at the nanoscale on oxidation activity is demonstrated. Our results demonstrate that characterization of these dynamic changes is necessary to unlock the full potential of bimetallic catalytic materials. PMID- 27992419 TI - Static three-dimensional topological solitons in fluid chiral ferromagnets and colloids. AB - Three-dimensional (3D) topological solitons are continuous but topologically nontrivial field configurations localized in 3D space and embedded in a uniform far-field background, that behave like particles and cannot be transformed to a uniform state through smooth deformations. Many topologically nontrivial 3D solitonic fields have been proposed. Yet, according to the Hobart-Derrick theorem, physical systems cannot host them, except for nonlinear theories with higher-order derivatives such as the Skyrme-Faddeev model. Experimental discovery of such solitons is hindered by the need for spatial imaging of the 3D fields, which is difficult in high-energy physics and cosmology. Here we experimentally realize and numerically model stationary topological solitons in a fluid chiral ferromagnet formed by colloidal dispersions of magnetic nanoplates. Such solitons have closed-loop preimages-3D regions with a single orientation of the magnetization field. We discuss localized structures with different linking of preimages quantified by topological Hopf invariants. The chirality is found to help in overcoming the constraints of the Hobart-Derrick theorem, like in two dimensional ferromagnetic solitons, dubbed 'baby skyrmions'. Our experimental platform may lead to solitonic condensed matter phases and technological applications. PMID- 27992416 TI - Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. AB - Chronic sleep disturbances, associated with cardiometabolic diseases, psychiatric disorders and all-cause mortality, affect 25-30% of adults worldwide. Although environmental factors contribute substantially to self-reported habitual sleep duration and disruption, these traits are heritable and identification of the genes involved should improve understanding of sleep, mechanisms linking sleep to disease and development of new therapies. We report single- and multiple-trait genome-wide association analyses of self-reported sleep duration, insomnia symptoms and excessive daytime sleepiness in the UK Biobank (n = 112,586). We discover loci associated with insomnia symptoms (near MEIS1, TMEM132E, CYCL1 and TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR OPHN1) and a composite sleep trait (near PATJ (INADL) and HCRTR2) and replicate a locus associated with sleep duration (at PAX8). We also observe genetic correlation between longer sleep duration and schizophrenia risk (rg = 0.29, P = 1.90 * 10-13) and between increased levels of excessive daytime sleepiness and increased measures for adiposity traits (body mass index (BMI): rg = 0.20, P = 3.12 * 10-9; waist circumference: rg = 0.20, P = 2.12 * 10-7). PMID- 27992420 TI - Negating interfacial impedance in garnet-based solid-state Li metal batteries. AB - Garnet-type solid-state electrolytes have attracted extensive attention due to their high ionic conductivity, approaching 1 mS cm-1, excellent environmental stability, and wide electrochemical stability window, from lithium metal to ~6 V. However, to date, there has been little success in the development of high performance solid-state batteries using these exceptional materials, the major challenge being the high solid-solid interfacial impedance between the garnet electrolyte and electrode materials. In this work, we effectively address the large interfacial impedance between a lithium metal anode and the garnet electrolyte using ultrathin aluminium oxide (Al2O3) by atomic layer deposition. Li7La2.75Ca0.25Zr1.75Nb0.25O12 (LLCZN) is the garnet composition of choice in this work due to its reduced sintering temperature and increased lithium ion conductivity. A significant decrease of interfacial impedance, from 1,710 Omega cm2 to 1 Omega cm2, was observed at room temperature, effectively negating the lithium metal/garnet interfacial impedance. Experimental and computational results reveal that the oxide coating enables wetting of metallic lithium in contact with the garnet electrolyte surface and the lithiated-alumina interface allows effective lithium ion transport between the lithium metal anode and garnet electrolyte. We also demonstrate a working cell with a lithium metal anode, garnet electrolyte and a high-voltage cathode by applying the newly developed interface chemistry. PMID- 27992417 TI - Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. AB - Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement. PMID- 27992421 TI - Selective nitrogen capture by porous hybrid materials containing accessible transition metal ion sites. AB - Selective dinitrogen binding to transition metal ions mainly covers two strategic domains: biological nitrogen fixation catalysed by metalloenzyme nitrogenases, and adsorptive purification of natural gas and air. Many transition metal dinitrogen complexes have been envisaged for biomimetic nitrogen fixation to produce ammonia. Inspired by this concept, here we report mesoporous metal organic framework materials containing accessible Cr(III) sites, able to thermodynamically capture N2 over CH4 and O2. This fundamental study integrating advanced experimental and computational tools confirmed that the separation mechanism for both N2/CH4 and N2/O2 gas mixtures is driven by the presence of these unsaturated Cr(III) sites that allows a much stronger binding of N2 over the two other gases. Besides the potential breakthrough in adsorption-based technologies, this proof of concept could open new horizons to address several challenges in chemistry, including the design of heterogeneous biomimetic catalysts through nitrogen fixation. PMID- 27992422 TI - Role of T3SS-1 SipD Protein in Protecting Mice against Non-typhoidal Salmonella Typhimurium. AB - BACKGROUND: Salmonella enterica species are enteric pathogens that cause severe diseases ranging from self-limiting gastroenteritis to enteric fever and sepsis in humans. These infectious diseases are still the major cause of morbidity and mortality in low-income countries, especially in children younger than 5 years and immunocompromised adults. Vaccines targeting typhoidal diseases are already marketed, but none protect against non-typhoidal Salmonella. The existence of multiple non-typhoidal Salmonella serotypes as well as emerging antibiotic resistance highlight the need for development of a broad-spectrum protective vaccine. All Salmonella spp. utilize two type III Secretion Systems (T3SS 1 and 2) to initiate infection, allow replication in phagocytic cells and induce systemic disease. T3SS-1, which is essential to invade epithelial cells and cross the barrier, forms an extracellular needle and syringe necessary to inject effector proteins into the host cell. PrgI and SipD form, respectively, the T3SS 1 needle and the tip complex at the top of the needle. Because they are common and highly conserved in all virulent Salmonella spp., they might be ideal candidate antigens for a subunit-based, broad-spectrum vaccine. PRINCIPAL FINDINGS: We investigated the immunogenicity and protective efficacy of PrgI and SipD administered by subcutaneous, intranasal and oral routes, alone or combined, in a mouse model of Salmonella intestinal challenge. Robust IgG (in all immunization routes) and IgA (in intranasal and oral immunization routes) antibody responses were induced against both proteins, particularly SipD. Mice orally immunized with SipD alone or SipD combined with PrgI were protected against lethal intestinal challenge with Salmonella Typhimurium (100 Lethal Dose 50%) depending on antigen, route and adjuvant. CONCLUSIONS AND SIGNIFICANCE: Salmonella T3SS SipD is a promising antigen for the development of a protective Salmonella vaccine, and could be developed for vaccination in tropical endemic areas to control infant mortality. PMID- 27992424 TI - The Impact of Lymphatic Filariasis Mass Drug Administration Scaling Down on Soil Transmitted Helminth Control in School-Age Children. Present Situation and Expected Impact from 2016 to 2020. AB - Lymphatic filariasis (LF) and soil-transmitted-helminths (STH) are co-endemic in 58 countries which are mostly in Africa and Asia. Worldwide, 486 million school age children are considered at risk of both diseases. In 2000, the World Health Organization (WHO) established the global programme to eliminate LF by 2020. Since then, the LF elimination programme has distributed ivermectin or diethylcarbamazine citrate (DEC) in combination with albendazole, thereby also treating STH. Consequently, many school-age children have been treated for STH through the LF programme. As treatment targets towards the 2020 LF elimination goal are achieved, many countries are implementing the transmission assessment survey (TAS) and, if the LF prevalence is estimated to be less than 1%, scaling down mass drug administration (MDA). We analysed the 2014 data on preventive chemotherapy (PC) reported from LF STH co-endemic countries and projected the year and location of TAS expected to be conducted between 2016 and 2020 to assess the impact of this scaling down on STH PC. Eighty percent of all co-endemic countries that have already stopped LF MDA nationally were able to establish STH PC through schools. It is estimated that 14% of the total number of children presently covered by the LF programme is at risk of not continuing to receive PC for STH. In order to achieve and maintain the WHO 2020 goal for STH control, there is an urgent need to establish and reinforce school-based deworming programmes in countries scaling-down national LF elimination programmes. PMID- 27992423 TI - Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration. AB - BACKGROUND: The angiotensin-I converting enzyme (ACE) plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II). More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet. AIM: Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration. RESULTS: We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC), and experimental results in CHO cells, demonstrated that the beta3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5) showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril) or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein. CONCLUSION: ACE activation regulates melanoma cell proliferation and migration. PMID- 27992425 TI - Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation. AB - The forelimbs and hindlimbs of vertebrates are bilaterally symmetric. The mechanisms that ensure symmetric limb formation are unknown but they can be disrupted in disease. In Holt-Oram Syndrome (HOS), caused by mutations in TBX5, affected individuals have left-biased upper/forelimb defects. We demonstrate a role for the transcription factor Tbx5 in ensuring the symmetric formation of the left and right forelimb. In our mouse model, bilateral hypomorphic levels of Tbx5 produces asymmetric forelimb defects that are consistently more severe in the left limb than the right, phenocopying the left-biased limb defects seen in HOS patients. In Tbx hypomorphic mutants maintained on an INV mutant background, with situs inversus, the laterality of defects is reversed. Our data demonstrate an early, inherent asymmetry in the left and right limb-forming regions and that threshold levels of Tbx5 are required to overcome this asymmetry to ensure symmetric forelimb formation. PMID- 27992427 TI - Pharyngeal Gonorrhoea: The Willingness of Australian Men Who Have Sex with Men to Change Current Sexual Practices to Reduce Their Risk of Transmission-A Qualitative Study. AB - BACKGROUND: The pharynx is a common site of gonorrhoea among men who have sex with men (MSM) and may serve as a reservoir for infection, with saliva implicated in transmission possibly through oral sex, kissing, and rimming. Reducing sexual activities involving saliva may reduce pharyngeal gonorrhoea. This study aimed to explore MSM's views and knowledge of pharyngeal gonorrhoea and their willingness to change saliva transmitting sexual practices. MSM were also asked their views on using alcohol-containing mouthwash to potentially reduce transmission. METHODS: Using a qualitative descriptive approach, 30 MSM who were part of a larger study (GONE) conducted at the Melbourne Sexual Health Centre agreed to take part in semi-structured interviews between 14th May and 8th September 2015. The 10 interviews conducted face to face and 20 by telephone, lasted between 20 45 minutes. Data were analysed using qualitative content analysis. RESULTS: Most men considered pharyngeal gonorrhoea to be a non-serious sexually transmitted infection and attributed transmission primarily to oral sex. Almost all men reported they would not stop kissing, oral sex, or consider using condoms for oral sex to reduce their risk of pharyngeal gonorrhoea. Kissing and oral sex were commonly practised and considered enjoyable low risk sexual activities. Men were more likely to consider stopping sexual activities they did not enjoy or practice often, in particular insertive rimming. If proven effective, the majority of men reported they would use alcohol-containing mouthwash to reduce or prevent their risk of pharyngeal gonorrhoea. CONCLUSION: Findings from this study suggest MSM are unlikely to stop saliva transmitting sexual practices they enjoy and consider low risk. Men would, however, consider using alcohol-containing mouthwash if found to be effective, highlighting the importance of exploring innovative strategies to reduce pharyngeal gonorrhoea. PMID- 27992426 TI - Glycoside Hydrolases across Environmental Microbial Communities. AB - Across many environments microbial glycoside hydrolases support the enzymatic processing of carbohydrates, a critical function in many ecosystems. Little is known about how the microbial composition of a community and the potential for carbohydrate processing relate to each other. Here, using 1,934 metagenomic datasets, we linked changes in community composition to variation of potential for carbohydrate processing across environments. We were able to show that each ecosystem-type displays a specific potential for carbohydrate utilization. Most of this potential was associated with just 77 bacterial genera. The GH content in bacterial genera is best described by their taxonomic affiliation. Across metagenomes, fluctuations of the microbial community structure and GH potential for carbohydrate utilization were correlated. Our analysis reveals that both deterministic and stochastic processes contribute to the assembly of complex microbial communities. PMID- 27992428 TI - Outcomes of Phacoemulsification Using Different Size of Clear Corneal Incision in Eyes with Previous Radial Keratotomy. AB - OBJECTIVE: To evaluate visual outcomes and complications after phacoemulsification in eyes with cataract and previous radial keratotomy (RK) cuts using different sizes of clear corneal incisions. METHODS: The study was a retrospective study. Thirty eyes with cataract and previous RK underwent phacoemulsification and intraocular lens (IOL) implantation. Among them 7 eyes had 8 RK cuts, 13 eyes had 12 RK cuts, and 10 eyes had 16 RK cuts. Phacoemulsification and IOL implantation were performed through a 2.0-3.2 mm clear corneal incision by a single surgeon. In the 8 RK cuts group, 3.2 mm clear corneal incisions were used in 4 eyes, and 3.0 mm clear corneal incisions were used in 3 eyes. In the 12 RK cuts group, 3.2 mm clear corneal incisions were used in 6 eyes, and 2.2 mm clear corneal incisions were used in 7 eyes. In the 16 RK cuts group, 3.2 mm clear corneal incisions were used in 5 eyes, and 2.0 mm clear corneal incisions were used in 5 eyes. Patients were followed up 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, and 3 years postoperatively and were examined for the dehiscence of RK cuts during or after the surgery, post operative best-corrected visual acuity (BCVA), corneal astigmatism, corneal endothelial cell density and complications. RESULTS: Successful phacoemulsification with IOL implantation was performed in all eyes. No wound dehiscence was noted in any eyes with 8 or 12 RK cuts. Wound dehiscence was noted in 2 eyes with 16 RK cuts. The dehiscence of RK cuts was closed successfully by injecting an air bubble with or without viscoelastic agent into the anterior chamber at the end of surgery. During the follow-up, the cuts were well apposed in all eyes, and no new dehiscence of RK cuts was noted. At the last follow-up, mean BCVA (0.2 +/- 0.18 logMAR) was better than preoperative BCVA(0.45+/-0.19 logMAR) (P < 0.001). There was no significant difference between the long-term preoperative and postoperative mean corneal astigmatism (P = 0.3). However, there was a significant reduction in postoperative corneal endothelial cell density (1866.5+/-773.9 / mm2 vs 2421.7+/-655.7 / mm2) (P < 0.001). CONCLUSIONS: Phacoemulsification and IOL implantation with clear corneal incisions in eyes with previous RK were associated with good surgical outcomes. Wound dehiscence was not specificaly related to the size of clear corneal incision during phacoemulsification in these eyes. PMID- 27992430 TI - Seven Glimpses into the Emotional Brain. PMID- 27992429 TI - High Prevalence of Asymptomatic Neurocysticercosis in an Endemic Rural Community in Peru. AB - BACKGROUND: Neurocysticercosis is a common helminthic infection of the central nervous system and an important cause of adult-onset epilepsy in endemic countries. However, few studies have examined associations between neurologic symptoms, serology and radiographic findings on a community-level. METHODOLOGY: We conducted a population-based study of resident's >=2 years old in a highly endemic village in Peru (pop. 454). We applied a 14 -question neurologic screening tool and evaluated serum for antibodies against Taenia solium cysticercosis using enzyme-linked immunoelectrotransfer blot (LLGP-EITB). We invited all residents >=18 years old to have non-contrast computerized tomography (CT) of the head. PRINCIPAL FINDINGS: Of the 385 residents who provided serum samples, 142 (36.9%) were seropositive. Of the 256 residents who underwent CT scan, 48 (18.8%) had brain calcifications consistent with NCC; 8/48 (17.0%) reported a history of headache and/or seizures. Exposure to T. solium is very common in this endemic community where 1 out of 5 residents had brain calcifications. However, the vast majority of people with calcifications were asymptomatic. CONCLUSION: This study reports a high prevalence of NCC infection in an endemic community in Peru and confirms that a large proportion of apparently asymptomatic residents have brain calcifications that could provoke seizures in the future. PMID- 27992431 TI - Intrinsic Image Decomposition via Structure-Preserving Image Smoothing and Material Recognition. AB - Decoupling shading and reflectance from complex scene-images is a long-standing problem in computer vision. We introduce a framework for decomposing an image into the product of an illumination component and a reflectance component. Due to the ill-posed nature of the problem, prior information on shading and reflectance is mandatory. The proposed method adopts the premise that pixels in a region with similar chromaticity values should have the same reflectance. This assumption was used to minimize the l2 norm of the local per-pixel reflectance gradients to extract the shading and reflectance components. To obtain smooth chromatic regions, texture was treated in a new style. Texture was removed in the first step of the algorithm and the smooth image was processed for intrinsic decomposition. In the final step, texture details were added to the intrinsic components based on the material of each pixel. In addition, user-assistance was used to further refine the results. The qualitative and quantitative evaluation on the MIT intrinsic dataset indicated that the quality of intrinsic image decomposition was improved in comparison with previous methods. PMID- 27992433 TI - A Mathematical Model of the Olfactory Bulb for the Selective Adaptation Mechanism in the Rodent Olfactory System. AB - To predict the odor quality of an odorant mixture, the interaction between odorants must be taken into account. Previously, an experiment in which mice discriminated between odorant mixtures identified a selective adaptation mechanism in the olfactory system. This paper proposes an olfactory model for odorant mixtures that can account for selective adaptation in terms of neural activity. The proposed model uses the spatial activity pattern of the mitral layer obtained from model simulations to predict the perceptual similarity between odors. Measured glomerular activity patterns are used as input to the model. The neural interaction between mitral cells and granular cells is then simulated, and a dissimilarity index between odors is defined using the activity patterns of the mitral layer. An odor set composed of three odorants is used to test the ability of the model. Simulations are performed based on the odor discrimination experiment on mice. As a result, we observe that part of the neural activity in the glomerular layer is enhanced in the mitral layer, whereas another part is suppressed. We find that the dissimilarity index strongly correlates with the odor discrimination rate of mice: r = 0.88 (p = 0.019). We conclude that our model has the ability to predict the perceptual similarity of odorant mixtures. In addition, the model also accounts for selective adaptation via the odor discrimination rate, and the enhancement and inhibition in the mitral layer may be related to this selective adaptation. PMID- 27992432 TI - A Gastric Glycoform of MUC5AC Is a Biomarker of Mucinous Cysts of the Pancreas. AB - Molecular indicators to specify the risk posed by a pancreatic cyst would benefit patients. Previously we showed that most cancer-precursor cysts, termed mucinous cysts, produce abnormal glycoforms of the proteins MUC5AC and endorepellin. Here we sought to validate the glycoforms as a biomarker of mucinous cysts and to specify the oligosaccharide linkages that characterize MUC5AC. We hypothesized that mucinous cysts secrete MUC5AC displaying terminal N-acetylglucosamine (GlcNAc) in either alpha or beta linkage. We used antibody-lectin sandwich assays to detect glycoforms of MUC5AC and endorepellin in cyst fluid samples from three independent cohorts of 49, 32, and 66 patients, and we used monoclonal antibodies to test for terminal, alpha-linked GlcNAc and the enzyme that produces it. A biomarker panel comprising the previously-identified glycoforms of MUC5AC and endorepellin gave 96%, 96%, and 87% accuracy for identifying mucinous cysts in the three cohorts with an average sensitivity of 92% and an average specificity of 94%. Glycan analysis showed that MUC5AC produced by a subset of mucinous cysts displays terminal alpha-GlcNAc, a motif expressed in stomach glands. The alpha linked glycoform of MUC5AC was unique to intraductal papillary mucinous neoplasms (IPMN), whereas terminal beta-linked GlcNAc was increased in both IPMNs and mucinous cystic neoplasms (MCN). The enzyme that synthesizes alpha-GlcNAc, A4GNT, was expressed in the epithelia of mucinous cysts that expressed alpha-GlcNAc, especially in regions with high-grade dysplasia. Thus IPMNs secrete a gastric glycoform of MUC5AC that displays terminal alpha-GlcNAc, and the combined alpha GlcNAc and beta-GlcNAc glycoforms form an accurate biomarker of mucinous cysts. PMID- 27992434 TI - Watch and Wait Management of Inactive Cystic Echinococcosis - Does the Path to Inactivity Matter - Analysis of a Prospective Patient Cohort. AB - BACKGROUND: Overdiagnosis and overtreatment are rarely discussed in the context of NTDs despite their relevance for patients under the care of health services with limited resources where the risks of therapy induced complications are often disproportionate to the benefit. The advantages of cyst staging-based management of patients with cystic echinococcosis (CE) are not yet fully explored. Questions are: Do inactive cysts (CE 4 and CE 5) need treatment and is there a difference between cysts which reach CE4 and CE5 naturally or by benzimidazole therapy? METHODOLOGY/PRINCIPAL FINDINGS: Analysis of long-term follow-up data from a prospective CE patient cohort of 223 patients of a national clinical center for echinococcosis. The event of interest "relapse" was defined as the reversal of a cyst from an inactive stage (CE4, CE5) back to an active stage. The watch &wait (ww) group included 30 patients with 46 inactive cysts who never received medical treatment. The benzimidazole-treated (med) group included 15 patients with 17 cysts. There was no relapse in the ww-group whereas 8/17 cysts showed relapse within 18 months after treatment in the med-group. Loss to follow-up was 15.5%. CONCLUSIONS: Data from the watch & wait group impressively show how stable naturally inactivated cysts are in contrast to cysts which reach inactivity through treatment with benzimidazoles. A substantial proportion of patients can be spared from treatment through cyst staging. Cysts which inactivated through a natural course do not relapse with very high likelihood. We recommend follow up of 5 years to confirm the stability of the inactive stage. Cysts driven into inactivity through benzimidazole therapy instead need careful monitoring to identify those which reactivate (around 50% within 18 months). 5 years follow-up appears safe to make a final decision on the need for further monitoring. PMID- 27992435 TI - A Randomized Controlled Study of Neurofeedback for Chronic PTSD. AB - INTRODUCTION: Brain/Computer Interaction (BCI) devices are designed to alter neural signals and, thereby, mental activity. This study was a randomized, waitlist (TAU) controlled trial of a BCI, EEG neurofeedback training (NF), in patients with chronic PTSD to explore the capacity of NF to reduce PTSD symptoms and increase affect regulation capacities. STUDY DESIGN: 52 individuals with chronic PTSD were randomized to either NF (n = 28) or waitlist (WL) (n = 24). They completed four evaluations, at baseline (T1), after week 6 (T2), at post treatment (T3), and at one month follow up (T4). Assessment measures were:1. Traumatic Events Screening Inventory (T1); 2. the Clinician Administered PTSD Scale (CAPS; T1, T3, T4); 3. the Davidson Trauma Scale (DTS; T1-T4) and 4. the Inventory of Altered Self-Capacities (IASC; T1-T4). NF training occurred two times per week for 12 weeks and involved a sequential placement with T4 as the active site, P4 as the reference site. RESULTS: Participants had experienced an average of 9.29 (SD = 2.90) different traumatic events. Post-treatment a significantly smaller proportion of NF (6/22, 27.3%) met criteria for PTSD than the WL condition (15/22, 68.2%), chi2 (n = 44, df = 1) = 7.38, p = .007. There was a significant treatment condition x time interaction (b = -10.45, t = -5.10, p< .001). Measures of tension reduction activities, affect dysregulation, and affect instability exhibited a significant Time x Condition interaction. The effect sizes of NF (d = -2.33 within, d = - 1.71 between groups) are comparable to those reported for the most effective evidence based treatments for PTSD. DISCUSSION: Compared with the control group NF produced significant PTSD symptom improvement in individuals with chronic PTSD, as well as in affect regulation capacities. NF deserves further investigation for its potential to ameliorate PTSD and to improve affect regulation, and to clarify its mechanisms of action. PMID- 27992437 TI - Prediction and Characterization of High-Activity Events in Social Media Triggered by Real-World News. AB - On-line social networks publish information on a high volume of real-world events almost instantly, becoming a primary source for breaking news. Some of these real world events can end up having a very strong impact on on-line social networks. The effect of such events can be analyzed from several perspectives, one of them being the intensity and characteristics of the collective activity that it produces in the social platform. We research 5,234 real-world news events encompassing 43 million messages discussed on the Twitter microblogging service for approximately 1 year. We show empirically that exogenous news events naturally create collective patterns of bursty behavior in combination with long periods of inactivity in the network. This type of behavior agrees with other patterns previously observed in other types of natural collective phenomena, as well as in individual human communications. In addition, we propose a methodology to classify news events according to the different levels of intensity in activity that they produce. In particular, we analyze the most highly active events and observe a consistent and strikingly different collective reaction from users when they are exposed to such events. This reaction is independent of an event's reach and scope. We further observe that extremely high-activity events have characteristics that are quite distinguishable at the beginning stages of their outbreak. This allows us to predict with high precision, the top 8% of events that will have the most impact in the social network by just using the first 5% of the information of an event's lifetime evolution. This strongly implies that high-activity events are naturally prioritized collectively by the social network, engaging users early on, way before they are brought to the mainstream audience. PMID- 27992436 TI - Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation. AB - Many genes are differentially expressed in the cortex of people with schizophrenia, implicating factors that control transcription more generally. Hormone nuclear receptors dimerize to coordinate context-dependent changes in gene expression. We hypothesized that members of two families of nuclear receptors (NR4As), and retinoid receptors (RARs and RXRs), are altered in the dorsal lateral prefrontal cortex (DLPFC) of people with schizophrenia. We used next generation sequencing and then qPCR analysis to test for changes in mRNA levels for transcripts encoding nuclear receptors: orphan nuclear receptors (3 in the NR4A, 3 in the RAR, 3 in the RXR families and KLF4) in total RNA extracted from the DLPFC from people with schizophrenia compared to controls (n = 74). We also correlated mRNA levels with demographic factors and with estimates of antipsychotic drug exposure (schizophrenia group only). We tested for correlations between levels of transcription factor family members and levels of genes putatively regulated by these transcription factors. We found significantly down regulated expression of NR4A1 (Nurr 77) and KLF4 mRNAs in people with schizophrenia compared to controls, by both NGS and qPCR (p = or <0.01). We also detected decreases in NR4A2 (Nurr1) and RXRB mRNAs by using qPCR in the larger cohort (p<0.05 and p<0.01, respectively). We detected decreased expression of RARG and NR4A2 mRNAs in females with schizophrenia (p<0.05). The mRNA levels of NR4A1, NR4A2 and NR4A3 were all negative correlated with lifetime estimates of antipsychotic exposure. These novel findings, which may be influenced by antipsychotic drug exposure, implicate the orphan and retinoid nuclear receptors in the cortical pathology found in schizophrenia. Genes down stream of these receptors can be dysregulated as well, but the direction of change is not immediately predictable based on the putative transcription factor changes. PMID- 27992438 TI - Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis. AB - BACKGROUND AND AIMS: hADSCs transplantation in cirrhosis models improves liver function and reduces fibrosis. In addition, Ad-huPA gene therapy diminished fibrosis and increased hepatocyte regeneration. In this study, we evaluate the combination of these therapies in an advanced liver fibrosis experimental model. METHODS: hADSCs were expanded and characterized before transplantation. Ad-huPA was simultaneously administrated via the ileac vein. Animals were immunosuppressed by CsA 24 h before treatment and until sacrifice at 10 days post treatment. huPA liver expression and hADSCs biodistribution were evaluated, as well as the percentage of fibrotic tissue, hepatic mRNA levels of Col-alphaI, TGF beta1, CTGF, alpha-SMA, PAI-I, MMP2 and serum levels of ALT, AST and albumin. RESULTS: hADSCs homed mainly in liver, whereas huPA expression was similar in Ad huPA and hADSCs/Ad-huPA groups. hADSCs, Ad-huPA and hADSCs/Ad-huPA treatment improves albumin levels, reduces liver fibrosis and diminishes Collagen alpha1, CTGF and alpha-SMA mRNA liver levels. ALT and AST serum levels showed a significant decrease exclusively in the hADSCs group. CONCLUSIONS: These results showed that combinatorial effect of cell and gene-therapy does not improve the antifibrogenic effects of individual treatments, whereas hADSCs transplantation seems to reduce liver fibrosis in a greater proportion. PMID- 27992439 TI - Does Size Matter? The Multipolar International Landscape of Nanoscience. AB - How do different countries tackle nanoscience research? Are all countries similar except for a trivial size effect, as science is often assumed to be universal? Or does size dictate large differences, as large countries are able to develop activities in all directions of research, while small countries have to specialize in some specific niches? Alternatively, is size irrelevant, as all countries have followed different historical paths, leading to different patterns of specialisation? Here, we develop an original method that uses a bottom-up definition of scientific subfields to map the international structure of any scientific field. Our analysis shows that nanoscience research does not show a universal pattern of specialisation, homothetic of that of a single global leader (e.g., the United States). Instead, we find a multipolar world, with four main ways of doing nanosciences. PMID- 27992440 TI - Microwave Bandpass Filter Based on Mie-Resonance Extraordinary Transmission. AB - Microwave bandpass filter structure has been designed and fabricated by filling the periodically metallic apertures with dielectric particles. The microwave cannot transmit through the metallic subwavelength apertures. By filling the metallic apertures with dielectric particles, a transmission passband with insertion loss 2 dB appears at the frequency of 10-12 GHz. Both simulated and experimental results show that the passband is induced by the Mie resonance of the dielectric particles. In addition, the passband frequency can be tuned by the size and the permittivity of the dielectric particles. This approach is suitable to fabricate the microwave bandpass filters. PMID- 27992441 TI - Where and How Wolves (Canis lupus) Kill Beavers (Castor canadensis). AB - Beavers (Castor canadensis) can be a significant prey item for wolves (Canis lupus) in boreal ecosystems due to their abundance and vulnerability on land. How wolves hunt beavers in these systems is largely unknown, however, because observing predation is challenging. We inferred how wolves hunt beavers by identifying kill sites using clusters of locations from GPS-collared wolves in Voyageurs National Park, Minnesota. We identified 22 sites where wolves from 4 different packs killed beavers. We classified these kill sites into 8 categories based on the beaver-habitat type near which each kill occurred. Seasonal variation existed in types of kill sites as 7 of 12 (58%) kills in the spring occurred at sites below dams and on shorelines, and 8 of 10 (80%) kills in the fall occurred near feeding trails and canals. From these kill sites we deduced that the typical hunting strategy has 3 components: 1) waiting near areas of high beaver use (e.g., feeding trails) until a beaver comes near shore or ashore, 2) using vegetation, the dam, or other habitat features for concealment, and 3) immediately attacking the beaver, or ambushing the beaver by cutting off access to water. By identifying kill sites and inferring hunting behavior we have provided the most complete description available of how and where wolves hunt and kill beavers. PMID- 27992442 TI - Is Implicit Motor Learning Preserved after Stroke? A Systematic Review with Meta Analysis. AB - Many stroke patients experience difficulty with performing dual-tasks. A promising intervention to target this issue is implicit motor learning, as it should enhance patients' automaticity of movement. Yet, although it is often thought that implicit motor learning is preserved post-stroke, evidence for this claim has not been systematically analysed yet. Therefore, we systematically reviewed whether implicit motor learning is preserved post-stroke, and whether patients benefit more from implicit than from explicit motor learning. We comprehensively searched conventional (MEDLINE, Cochrane, Embase, PEDro, PsycINFO) and grey literature databases (BIOSIS, Web of Science, OpenGrey, British Library, trial registries) for relevant reports. Two independent reviewers screened reports, extracted data, and performed a risk of bias assessment. Overall, we included 20 out of the 2177 identified reports that allow for a succinct evaluation of implicit motor learning. Of these, only 1 study investigated learning on a relatively complex, whole-body (balance board) task. All 19 other studies concerned variants of the serial-reaction time paradigm, with most of these focusing on learning with the unaffected hand (N = 13) rather than the affected hand or both hands (both: N = 4). Four of the 20 studies compared explicit and implicit motor learning post-stroke. Meta-analyses suggest that patients with stroke can learn implicitly with their unaffected side (mean difference (MD) = 69 ms, 95% CI[45.1, 92.9], p < .00001), but not with their affected side (standardized MD = -.11, 95% CI[-.45, .25], p = .56). Finally, implicit motor learning seemed equally effective as explicit motor learning post stroke (SMD = -.54, 95% CI[-1.37, .29], p = .20). However, overall, the high risk of bias, small samples, and limited clinical relevance of most studies make it impossible to draw reliable conclusions regarding the effect of implicit motor learning strategies post-stroke. High quality studies with larger samples are warranted to test implicit motor learning in clinically relevant contexts. PMID- 27992445 TI - Window-Based Channel Impulse Response Prediction for Time-Varying Ultra-Wideband Channels. AB - This work proposes channel impulse response (CIR) prediction for time-varying ultra-wideband (UWB) channels by exploiting the fast movement of channel taps within delay bins. Considering the sparsity of UWB channels, we introduce a window-based CIR (WB-CIR) to approximate the high temporal resolutions of UWB channels. A recursive least square (RLS) algorithm is adopted to predict the time evolution of the WB-CIR. For predicting the future WB-CIR tap of window wk, three RLS filter coefficients are computed from the observed WB-CIRs of the left wk-1, the current wk and the right wk+1 windows. The filter coefficient with the lowest RLS error is used to predict the future WB-CIR tap. To evaluate our proposed prediction method, UWB CIRs are collected through measurement campaigns in outdoor environments considering line-of-sight (LOS) and non-line-of-sight (NLOS) scenarios. Under similar computational complexity, our proposed method provides an improvement in prediction errors of approximately 80% for LOS and 63% for NLOS scenarios compared with a conventional method. PMID- 27992444 TI - Evidence of Recent Intricate Adaptation in Human Populations. AB - Recent human adaptations have shaped population differentiation in genomic regions containing putative functional variants, mostly located in predicted regulatory elements. However, their actual functionalities and the underlying mechanism of recent adaptation remain poorly understood. In the current study, regions of genes and repeats were investigated for functionality depending on the degree of population differentiation, FST or DeltaDAF (a difference in derived allele frequency). The high FST in the 5' or 3' untranslated regions (UTRs), in particular, confirmed that population differences arose mainly from differences in regulation. Expression quantitative trait loci (eQTL) analyses using lymphoblastoid cell lines indicated that the majority of the highly population specific regions represented cis- and/or trans-eQTL. However, groups having the highest DeltaDAFs did not necessarily have higher proportions of eQTL variants; in these groups, the patterns were complex, indicating recent intricate adaptations. The results indicated that East Asian (EAS) and European populations (EUR) experienced mutual selection pressures. The mean derived allele frequency of the high DeltaDAF groups suggested that EAS and EUR underwent strong adaptation; however, the African population in Africa (AFR) experienced slight, yet broad, adaptation. The DAF distributions of variants in the gene regions showed clear selective pressure in each population, which implies the existence of more recent regulatory adaptations in cells other than lymphoblastoid cell lines. In-depth analysis of population-differentiated regions indicated that the coding gene, RNF135, represented a trans-regulation hotspot via cis-regulation by the population-specific variants in the region of selective sweep. Together, the results provide strong evidence of actual intricate adaptation of human populations via regulatory manipulation. PMID- 27992446 TI - On the Reconstruction of Text Phylogeny Trees: Evaluation and Analysis of Textual Relationships. AB - Over the history of mankind, textual records change. Sometimes due to mistakes during transcription, sometimes on purpose, as a way to rewrite facts and reinterpret history. There are several classical cases, such as the logarithmic tables, and the transmission of antique and medieval scholarship. Today, text documents are largely edited and redistributed on the Web. Articles on news portals and collaborative platforms (such as Wikipedia), source code, posts on social networks, and even scientific publications or literary works are some examples in which textual content can be subject to changes in an evolutionary process. In this scenario, given a set of near-duplicate documents, it is worthwhile to find which one is the original and the history of changes that created the whole set. Such functionality would have immediate applications on news tracking services, detection of plagiarism, textual criticism, and copyright enforcement, for instance. However, this is not an easy task, as textual features pointing to the documents' evolutionary direction may not be evident and are often dataset dependent. Moreover, side information, such as time stamps, are neither always available nor reliable. In this paper, we propose a framework for reliably reconstructing text phylogeny trees, and seamlessly exploring new approaches on a wide range of scenarios of text reusage. We employ and evaluate distinct combinations of dissimilarity measures and reconstruction strategies within the proposed framework, and evaluate each approach with extensive experiments, including a set of artificial near-duplicate documents with known phylogeny, and from documents collected from Wikipedia, whose modifications were made by Internet users. We also present results from qualitative experiments in two different applications: text plagiarism and reconstruction of evolutionary trees for manuscripts (stemmatology). PMID- 27992443 TI - Pro-Inflammatory Cytokines but Not Endotoxin-Related Parameters Associate with Disease Severity in Patients with NAFLD. AB - Intestinal dysbiosis and elevated lipopolysaccharides (LPS) levels have been implicated in the development of obesity, insulin resistance and non-alcoholic steatohepatitis (NASH). In order to determine if LPS levels are elevated in patients with NASH compared to patients with non-alcoholic fatty liver (NAFL) and, if elevated LPS levels correlated with histological severity of non alcoholic fatty liver disease (NAFLD) we compared LPS, markers of LPS bioactivity and pro-inflammatory cytokines/chemokines in patients undergoing bariatric surgery. At the time of surgery a liver biopsy was taken allowing the stratification into well-delineated subgroups including: No NAFL/NAFL; NASH; NASH with fibrosis and NASH cirrhotics, using the NAFLD Activity Score (NAS). Anthropometric data and plasma were collected for assessment of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), intestinal-type fatty acid binding protein (iFABP), Toll-like receptors 2 and 4 (TLR2, 4) and a panel of cytokines/chemokines. Similar analysis was performed on plasma from a cohort of healthy controls. Our data indicate elevated levels of LPS, LBP, sCD14, iFABP and TLR2,4 in obese patients compared to healthy controls, however, these parameters remained unaltered within patients with limited liver disease (NAFL) compared to NASH/NASH with fibrosis subgroups. Hierarchic cluster analysis using endotoxin-related parameters failed to discriminate between lean controls, NAFLD. While similar cluster analysis implementing inflammation-related parameters clearly distinguished lean controls, NALFD subgroups and NASH cirrhotics. In addition, LPS levels was not associated with disease severity while TNFalpha, IL8, and CCL3 featured a clear correlation with transaminase levels and the histological severity of NALFD. In conclusion our data indicate a stronger correlation for circulating inflammatory- rather than endotoxin-related parameters in progression of NAFLD and highlights the need for additional larger studies in unravelling further mechanistic insights. PMID- 27992447 TI - Heat Sensing Receptor TRPV1 Is a Mediator of Thermotaxis in Human Spermatozoa. AB - The molecular bases of sperm thermotaxis, the temperature-oriented cell motility, are currently under investigation. Thermal perception relies on a subclass of the transient receptor potential [TRP] channels, whose member TRPV1 is acknowledged as the heat sensing receptor. Here we investigated the involvement of TRPV1 in human sperm thermotaxis. We obtained semen samples from 16 normozoospermic subjects attending an infertility survey programme, testis biopsies from 6 patients with testicular germ cell cancer and testis fine needle aspirates from 6 patients with obstructive azoospermia undergoing assisted reproductive technologies. Expression of TRPV1 mRNA was assessed by RT-PCR. Protein expression of TRPV1 was determined by western blot, flow cytometry and immunofluorescence. Sperm motility was assessed by Sperm Class Analyser. Acrosome reaction, apoptosis and intracellular-Ca2+ content were assessed by flow cytometry. We found that TRPV1 mRNA and protein were highly expressed in the testis, in both Sertoli cells and germ-line cells. Moreover, compared to no-gradient controls at 31 degrees C or 37 degrees C (Ctrl 31 degrees C and Ctrl 37 degrees C respectively), sperm migration towards a temperature gradient of 31-37 degrees C (T gradient) in non capacitated conditions selected a higher number of cells (14,9 +/- 4,2*106 cells T gradient vs 5,1+/- 0,3*106 cells Ctrl 31 degrees C and 5,71+/-0,74*106 cells Ctrl 37 degrees C; P = 0,039). Capacitation amplified the migrating capability towards the T gradient. Sperms migrated towards the T gradient showed enriched levels of both TRPV1 protein and mRNA. In addition, sperm cells were able to migrate toward a gradient of capsaicin, a specific agonist of TRPV1, whilst capsazepine, a specific agonist of TRPV1, blocked this effect. Finally, capsazepine severely blunted migration towards T gradient without abolishing. These results suggest that TRPV1 may represent a facilitating mediator of sperm thermotaxis. PMID- 27992448 TI - Automated Multi-Peak Tracking Kymography (AMTraK): A Tool to Quantify Sub Cellular Dynamics with Sub-Pixel Accuracy. AB - Kymographs or space-time plots are widely used in cell biology to reduce the dimensions of a time-series in microscopy for both qualitative and quantitative insight into spatio-temporal dynamics. While multiple tools for image kymography have been described before, quantification remains largely manual. Here, we describe a novel software tool for automated multi-peak tracking kymography (AMTraK), which uses peak information and distance minimization to track and automatically quantify kymographs, integrated in a GUI. The program takes fluorescence time-series data as an input and tracks contours in the kymographs based on intensity and gradient peaks. By integrating a branch-point detection method, it can be used to identify merging and splitting events of tracks, important in separation and coalescence events. In tests with synthetic images, we demonstrate sub-pixel positional accuracy of the program. We test the program by quantifying sub-cellular dynamics in rod-shaped bacteria, microtubule (MT) transport and vesicle dynamics. A time-series of E. coli cell division with labeled nucleoid DNA is used to identify the time-point and rate at which the nucleoid segregates. The mean velocity of microtubule (MT) gliding motility due to a recombinant kinesin motor is estimated as 0.5 MUm/s, in agreement with published values, and comparable to estimates using software for nanometer precision filament-tracking. We proceed to employ AMTraK to analyze previously published time-series microscopy data where kymographs had been manually quantified: clathrin polymerization kinetics during vesicle formation and anterograde and retrograde transport in axons. AMTraK analysis not only reproduces the reported parameters, it also provides an objective and automated method for reproducible analysis of kymographs from in vitro and in vivo fluorescence microscopy time-series of sub-cellular dynamics. PMID- 27992449 TI - Using a Mixed Model to Explore Evaluation Criteria for Bank Supervision: A Banking Supervision Law Perspective. AB - Financial supervision means that monetary authorities have the power to supervise and manage financial institutions according to laws. Monetary authorities have this power because of the requirements of improving financial services, protecting the rights of depositors, adapting to industrial development, ensuring financial fair trade, and maintaining stable financial order. To establish evaluation criteria for bank supervision in China, this study integrated fuzzy theory and the decision making trial and evaluation laboratory (DEMATEL) and proposes a fuzzy-DEMATEL model. First, fuzzy theory was applied to examine bank supervision criteria and analyze fuzzy semantics. Second, the fuzzy-DEMATEL model was used to calculate the degree to which financial supervision criteria mutually influenced one another and their causal relationship. Finally, an evaluation criteria model for evaluating bank and financial supervision was established. PMID- 27992450 TI - Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene. AB - Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90-109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18-97 years old Caucasian sample (N = 1801, p = 0.007). We found a continuous pattern of increase from 18-75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p = 0.003). Our results underlie the importance of investigating non disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population. PMID- 27992451 TI - Phase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer. AB - BACKGROUND: Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer. METHODS: Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug. RESULTS: In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib. CONCLUSION: The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction. TRIAL REGISTRATION: ClinicalTrials.gov NCT00764972. PMID- 27992452 TI - Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade. AB - Browning of white adipose tissue (WAT) has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named 'beige' or 'brite' adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS) plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R). However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R) may affect white-to beige fat conversion in vivo. AT1a receptor knockout (AT1aKO) mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT) compared to wild-type (WT) mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders. PMID- 27992453 TI - Helpful Factors in the Treatment of Depression from the Patient's, Carer's and Professional's Perspective: A Concept Map Study. AB - OBJECTIVE: Depression research has resulted in knowledge about neurobiology, pharmacological strategies and short-term cost-effective treatments. However, more than two-thirds of all depressed patients experience insufficient improvement. Therefore, a better understanding of what patients, carers and professionals perceive as most helpful in the treatment of depression is needed. METHODS: Concept mapping, a mixed-method design, was used to identify the patients (n = 33), carers (n = 22) and professionals (n = 50) perspectives. In six brainstorm sessions, the patients, carers and professionals generated 795 ideas, which were condensed into 55 unique statements. Subsequently, 100 participants prioritized and sorted these statements, which were analysed by multidimensional scaling and cluster analysis and visualized as a two-dimensional map. RESULTS: The 55 statements were clustered in 10 factors and further grouped into four main-factors (meta-clusters): 'Professional therapist', 'Treatment content', 'Structured treatment process' and 'Treatment organisation'. Patients and carers prioritized 'Treatment organisation' higher than professionals, but overall there was considerable agreement about the factors of treatment the participants perceived as most helpful including factors related to the therapeutic relationship and the 'creation of hope'. CONCLUSIONS: Our study identified factors of depression treatment perceived as helpful according to patients, carers and professionals. Findings suggest that in a scientific era with emphasis on biological psychiatry, not only patients and carers, but also professionals consider aspecific factors the most helpful. Further studies might show that factors we found to be helpful in the treatment for depression, can be generalized to mental health treatment in general. PMID- 27992454 TI - The Effects of Swiprosin-1 on the Formation of Pseudopodia-Like Structures and beta-Adrenoceptor Coupling in Cultured Adult Rat Ventricular Cardiomyocytes. AB - BACKGROUND: Recent findings suggest that adult terminally differentiated cardiomyocytes adapt to stress by cellular de- and redifferentiation. In the present study we tested the hypothesis that swiprosin-1 is a key player in this process. Furthermore, the relationship between swiprosin-1 and beta-adrenoceptor coupling was analyzed. METHODS: In order to study the function of swiprosin-1 in adult rat ventricular cardiomyocytes (ARVC) they were isolated and cultured in a medium containing 20% fetal calf serum (FCS). Changes in cell morphology of ARVC during cultivation were quantified by light and confocal laser scan microscopy. Small interfering RNA (siRNA) was used to reduce the expression of swiprosin-1. The impact of calcium on swiprosin-1 dependent processes was investigated with Bapta-AM. Immunoblot techniques and qRT-PCR were performed to measure mRNA and protein expression. RESULTS: In culture, ARVC first lost their contractile elements, which was followed by a formation of pseudopodia-like structures (spreading). Swiprosin-1 was detected in ARVC at all time points. However, swiprosin-1 expression was increased when ARVC started to spread. Reduction of swiprosin-1 expression with siRNA delayed ARVC spreading. Similarly, Bapta-AM attenuated swiprosin-1 expression and spreading of ARVC. Furthermore, swiprosin-1 expression correlated with the expression of G protein-coupled receptor kinase 2 (GRK2). Moreover, silencing of swiprosin-1 was associated with a down regulation of GRK2 and caused a sensitization of beta-adrenergic receptors. CONCLUSION: Swiprosin-1 is required for ARVC to adapt to culture conditions. Additionally, it seems to be involved in the desensitization of beta-adrenergic receptors. Assuming that ARVC adapt to cardiac stress in a similar way, swiprosin-1 may play a key role in cardiac remodeling. PMID- 27992455 TI - Rhamnogalacturonan-I Based Microcapsules for Targeted Drug Release. AB - Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms such as Rhamnogalacturonan-I (RG I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 MUm in diameter) were prepared by an interfacial poly addition reaction. The cross-linked capsules were loaded with a fluorescent dye (model drug). The capsules showed negligible and very little in vitro release when subjected to media simulating gastric and intestinal fluids, respectively. However, upon exposure to a cocktail of commercial RG-I cleaving enzymes, ~ 9 times higher release was observed, demonstrating that the capsules can be opened by enzymatic degradation. The combined results suggest a potential platform for targeted drug delivery in the terminal gastro-intestinal tract. PMID- 27992456 TI - Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis. AB - Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naive (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis. PMID- 27992457 TI - Comparative Serum Fatty Acid Profiles of Captive and Free-Ranging Cheetahs (Acinonyx jubatus) in Namibia. AB - Cheetahs (Acinonyx jubatus) are highly specialised large felids, currently listed as vulnerable on the IUCN red data list. In captivity, they are known to suffer from a range of chronic non-infectious diseases. Although low heterozygosity and the stress of captivity have been suggested as possible causal factors, recent studies have started to focus on the contribution of potential dietary factors in the pathogenesis of these diseases. Fatty acids are an important component of the diet, not only providing a source of metabolisable energy, but serving other important functions in hormone production, cellular signalling as well as providing structural components in biological membranes. To develop a better understanding of lipid metabolism in cheetahs, we compared the total serum fatty acid profiles of 35 captive cheetahs to those of 43 free-ranging individuals in Namibia using gas chromatography-mass spectrometry. The unsaturated fatty acid concentrations differed most remarkably between the groups, with all of the polyunsaturated and monounsaturated fatty acids, except arachidonic acid and hypogeic acid, detected at significantly lower concentrations in the serum of the free-ranging animals. The influence of age and sex on the individual fatty acid concentrations was less notable. This study represents the first evaluation of the serum fatty acids of free-ranging cheetahs, providing critical information on the normal fatty acid profiles of free-living, healthy individuals of this species. The results raise several important questions about the potential impact of dietary fatty acid composition on the health of cheetahs in captivity. PMID- 27992458 TI - Long-Term Effects of Xerophytic Shrub Haloxylon ammodendron Plantations on Soil Properties and Vegetation Dynamics in Northwest China. AB - The xerophytic desert shrub Haloxylon ammodendron (C. A. Mey.) Bunge. is distributed naturally in Asian and African deserts, and is widely used for vegetation restoration in the desert regions of Northern China. However, there are limited long-term chrono-sequence studies on the impact of changed soil properties and vegetation dynamics following establishment of this shrub on mobile sand dunes. In Minqin County, Gansu Province, we investigated soil properties and herbaceous vegetation development of 10, 20, 30, 40, 50-year-old H. ammodendron plantations on mobile sand dunes. Soil sampling at two depths (0-5 and 5-20 cm) under the shrubs determined SOC, nutrition and soil physical characteristics. The results showed that: establishment of H. ammodendron had improved soil physio-chemical properties, increased thickness of soil crusts and coverage of biological soil crusts (BSCs), and promoted development of topsoil over an extended period of 5 decades. Soil texture and soil nutrition improved along the chrono-sequence according to three distinct phases: i) an initial fast development from 0 to 10 years, ii) a stabilizing phase from 10 to 30 years followed by iii) a relatively marked restoration development in 40 and 50-year old plantations. Meanwhile, herbaceous community coverage also markedly increased in 30-year-old plantations. However, both soil and vegetation restoration were very slow due to low annual precipitation in Minqin county compared to other Northern China sand afforestation sites. Canonical Correspondence Analysis results demonstrated that herbaceous plant development was closely associated with changes in soil texture (increased clay and silt percentage) and availability of soil nutrients. Thus our results indicated that selection of the long-lived shrub H. ammodendron is an essential and effective tool in arid desert re-vegetation. PMID- 27992459 TI - A Novel Non-Cumbersome Approach Towards Biosynthesis of Pectic-Oligosaccharides by Non-Aflatoxigenic Aspergillus sp. Section Flavi Strain EGY1 DSM 101520 through Citrus Pectin Fermentation. AB - Pectic-Oligosaccharides (POS) have a growing potential in food and feed industries. To satisfy the demand of worldwide markets from POS and avoid the shortcomings of currently applied methodologies encountered in their preparation, the present study highlights a novel robust approach for POS biosynthesis. In the current approach, Aspergillus sp.section Flavi strain EGY1 DSM 101520 was grown on citrus pectin-based medium as a core POS production medium. POS' levels accumulated in the fungal fermentation broth were optimized through a three step sequential statistical mathematical methodology; Plackett-Burman design (PBD), Box-Behnken design (BBD) and canonical analysis. Three key determinants namely citrus pectin, peptone and NaH2PO4 were pointed out by PBD to impose significant consequences (P<0.05) on the process outcome (POS' levels). Optimal levels of these key determinants along with maximal of POS' levels were set by BBD and canonical analysis to be 2.28% (w/v) citrus pectin, 0.026% (w/v) peptone and 0.28% (w/v) NaH2PO4 to achieve a net amount of 1.3 g POS /2.28 g citrus pectin. Through this approach, a yield of 57% (w/w) POS of the total citrus pectin was obtained after 24 h of fungal growth on optimized citrus pectin-based medium. A fold enhancement of 13 times in POS' levels released in the fermentation fungal broth was realized by the end of the optimization strategy. This novel robust approach is considered a new insight towards POS biosynthesis via efficient, rapid and non-cumbersome procedure. To the best of authors' knowledge, the present work is the first article underlining detailed POS production from the fermentation broth of a fungus growing on citrus pectin-based medium. PMID- 27992461 TI - Long-Term Outcomes of Systemic Lupus Erythematous Patients after Pregnancy: A Nationwide Population-Based Cohort Study. AB - BACKGROUND: Data on long-term maternal outcomes in patients with systemic lupus erythematosus (SLE) are lacking. The study aimed to explore the relationships among SLE, pregnancy, outcomes of end-stage renal disease (ESRD), and overall mortality. METHODS: We established a retrospective cohort study consisting of four cohorts: pregnant (case cohort) and nonpregnant SLE patients, as well as pregnant and nonpregnant non-SLE patients. One case cohort and three comparison cohorts were matched by age at first pregnancy and index date of pregnancy by using the Taiwan National Health Insurance Research Dataset. All study subjects were selected based on the index date to the occurrence of ESRD or overall death. Cox proportional hazard regression models and Kaplan-Meier curves were used in the analysis. RESULTS: SLE pregnant patients exhibited significantly increased risk of ESRD after adjusting for other important confounders, including immunosuppressant and parity (HR = 3.19, 95% CI: 1.35-7.52 for pregnant non-SLE; and HR = 2.77, 95% CI: 1.24-6.15 for nonpregnant non-SLE patients). No significant differences in ESRD incidence were observed in pregnant and nonpregnant SLE patients. Pregnant SLE patients exhibited better clinical condition at the baseline and a significantly lower risk of overall mortality than nonpregnant SLE patients. CONCLUSIONS: Our data support current recommendations for SLE patients to avoid pregnancy until disease activity is quiescent. Multicenter recruitment and clinical information can be used to further examine the association of SLE and ESRD (or mortality) after pregnancy. PMID- 27992460 TI - Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo. AB - The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9'-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9'-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial. PMID- 27992462 TI - Acute Effects of Sugars and Artificial Sweeteners on Small Intestinal Sugar Transport: A Study Using CaCo-2 Cells As an In Vitro Model of the Human Enterocyte. AB - BACKGROUND: The gastrointestinal tract is responsible for the assimilation of nutrients and plays a key role in the regulation of nutrient metabolism and energy balance. The molecular mechanisms by which intestinal sugar transport are regulated are controversial. Based on rodent studies, two models currently exist that involve activation of the sweet-taste receptor, T1R2/3: an indirect model, whereby luminal carbohydrates activate T1R2/3 expressed on enteroendocrine cells, resulting in the release of gut peptides which in turn regulate enterocyte sugar transport capacity; and a direct model, whereby T1R2/3 expressed on the enterocyte regulates enterocyte function. AIMS: To study the direct model of intestinal sugar transport using CaCo-2 cells, a well-established in vitro model of the human enterocyte. METHODS: Uptake of 10mM 14C D-Glucose and D-Fructose into confluent CaCo-2/TC7 cells was assessed following 3hr preincubation with sugars and artificial sweeteners in the presence and absence of the sweet taste receptor inhibitor, lactisole. Expression of the intestinal sugar transporters and sweet-taste receptors were also determined by RT-PCR. RESULTS: In response to short term changes in extracellular glucose and glucose/fructose concentrations (2.5mM to 75mM) carrier-mediated sugar uptake mediated by SGLT1 and/or the facilitative hexose transporters (GLUT1,2,3 and 5) was increased. Lactisole and artificial sweeteners had no effect on sugar transport regulated by glucose alone; however, lactisole increased glucose transport in cells exposed to glucose/fructose. RT-PCR revealed Tas1r3 and SGLT3 gene expression in CaCo-2/TC7 cells, but not Tas1r2. CONCLUSIONS: In the short term, enterocyte sugar transport activities respond directly to extracellular glucose levels, but not fructose or artificial sweeteners. We found no evidence of a functional heterodimeric sweet taste receptor, T1R2/3 in CaCo-2 cells. However, when glucose/fructose is administered together there is an inhibitory effect on glucose transport possibly mediated by T1R3. PMID- 27992463 TI - Rare Freshwater Ciliate Paramecium chlorelligerum Kahl, 1935 and Its Macronuclear Symbiotic Bacterium "Candidatus Holospora parva". AB - Ciliated protists often form symbioses with many diverse microorganisms. In particular, symbiotic associations between ciliates and green algae, as well as between ciliates and intracellular bacteria, are rather wide-spread in nature. In this study, we describe the complex symbiotic system between a very rare ciliate, Paramecium chlorelligerum, unicellular algae inhabiting its cytoplasm, and novel bacteria colonizing the host macronucleus. Paramecium chlorelligerum, previously found only twice in Germany, was retrieved from a novel location in vicinity of St. Petersburg in Russia. Species identification was based on both classical morphological methods and analysis of the small subunit rDNA. Numerous algae occupying the cytoplasm of this ciliate were identified with ultrastructural and molecular methods as representatives of the Meyerella genus, which before was not considered among symbiotic algae. In the same locality at least fifteen other species of "green" ciliates were found, thus it is indeed a biodiversity hot-spot for such protists. A novel species of bacterial symbionts living in the macronucleus of Paramecium chlorelligerum cells was morphologically and ultrastructurally investigated in detail with the description of its life cycle and infection capabilities. The new endosymbiont was molecularly characterized following the full-cycle rRNA approach. Furthermore, phylogenetic analysis confirmed that the novel bacterium is a member of Holospora genus branching basally but sharing all characteristics of the genus except inducing connecting piece formation during the infected host nucleus division. We propose the name "Candidatus Holospora parva" for this newly described species. The described complex system raises new questions on how these microorganisms evolve and interact in symbiosis. PMID- 27992464 TI - Regulation of mRNA Translation Is a Novel Mechanism for Phthalate Toxicity. AB - Phthalates are a group of plasticizers that are widely used in many consumer products and medical devices, thus generating a huge burden to human health. Phthalates have been known to cause a number of developmental and reproductive disorders functioning as endocrine modulators. They are also involved in carcinogenesis with mechanisms less understood. To further understand the molecular mechanisms of phthalate toxicity, in this study we reported a new effect of phthalates on mRNA translation/protein synthesis, a key regulatory step of gene expression. Butyl benzyl phthalate (BBP) was found to directly inhibit mRNA translation in vitro but showed a complicated pattern of affecting mRNA translation in cells. In human kidney embryonic cell (HEK-293T), BBP increased cap-dependent mRNA translation at lower concentrations but showed inhibitory effect at higher concentrations. Cap-independent translation was not affected. On the other hand, mono (2-ethylhexyl) phthalate (MEHP) as a major metabolite of another important phthalate di (2-ethylhexyl) phthalate (DEHP) inhibited both can dependent and -independent mRNA translation in vivo. In contrast, BBP and MEHP exhibited an overall promoting effect on mRNA translation in cancer cells. Mechanistic studies identified that the level and phosphorylation of eIF4E-BP (eIF4E binding protein) and the amount of eIF4GI in eIF4F complex were altered in accordance with the effect of BBP on translation. BBP was also identified to directly bind to eIF4E, providing a further mechanism underlying the regulation of mRNA by phthalate. At the cellular level BBP inhibited normal cell growth but slightly promoted cancer cells (HT29) growth. Overall, this study provides the first evidence that phthalates can directly regulate mRNA translation as a novel mechanism to mediate their biological toxicities. PMID- 27992465 TI - Discovering Genome-Wide Tag SNPs Based on the Mutual Information of the Variants. AB - Exploring linkage disequilibrium (LD) patterns among the single nucleotide polymorphism (SNP) sites can improve the accuracy and cost-effectiveness of genomic association studies, whereby representative (tag) SNPs are identified to sufficiently represent the genomic diversity in populations. There has been considerable amount of effort in developing efficient algorithms to select tag SNPs from the growing large-scale data sets. Methods using the classical pairwise LD and multi-locus LD measures have been proposed that aim to reduce the computational complexity and to increase the accuracy, respectively. The present work solves the tag SNP selection problem by efficiently balancing the computational complexity and accuracy, and improves the coverage in genomic diversity in a cost-effective manner. The employed algorithm makes use of mutual information to explore the multi-locus association between SNPs and can handle different data types and conditions. Experiments with benchmark HapMap data sets show comparable or better performance against the state-of-the-art algorithms. In particular, as a novel application, the genome-wide SNP tagging is performed in the 1000 Genomes Project data sets, and produced a well-annotated database of tagging variants that capture the common genotype diversity in 2,504 samples from 26 human populations. Compared to conventional methods, the algorithm requires as input only the genotype (or haplotype) sequences, can scale up to genome-wide analyses, and produces accurate solutions with more information-rich output, providing an improved platform for researchers towards the subsequent association studies. PMID- 27992466 TI - Optimization of Planar Monopole Wideband Antenna for Wireless Communication System. AB - In this paper, a new compact wideband monopole antenna is presented for wireless communication applications. This antenna comprises of a new radiating patch, a new arc-shaped strip, microstrip feed line, and a notched ground plane. The proposed radiating patch is combined with a rectangular and semi-circular patch and is integrated with a partial ground plane to provide a wide impedance bandwidth. The new arc-shaped strip between the radiating patch and microstrip feed line creates an extra surface on the patch, which helps further widen the bandwidth. Inserting one step notch on the ground plane further enhances the bandwidth. The antenna has a compact size of 16*20*1.6mm3. The measured result indicated that the antenna achieves a 127% bandwidth at VSWR<=2, ranging from 4.9GHz to 22.1GHz. Stable radiation patterns with acceptable gain are achieved. Also, a measured bandwidth of 107.7% at VSWR<=1.5 (5.1-17GHz) is obtained, which is suitable for UWB outdoor propagation. This antenna is compatible with a good number of wireless standards, including UWB band, Wimax 5.4 GHz band, MVDDS (12.2 12.7GHz), and close range radar and satellite communication in the X-band (8 12GHz), and Ku band (12-18GHz). PMID- 27992467 TI - Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability. AB - Exposure to environmental factors can induce the epigenetic transgenerational inheritance of disease. Alterations to the epigenome termed "epimutations" include "primary epimutations" which are epigenetic alterations in the absence of genetic change and "secondary epimutations" which form following an initial genetic change. To determine if secondary epimutations contribute to transgenerational transmission of disease following in utero exposure to the endocrine disruptor vinclozolin, we exposed pregnant female rats carrying the lacI mutation-reporter transgene to vinclozolin and assessed the frequency of mutations in kidney tissue and sperm recovered from F1 and F3 generation progeny. Our results confirm that vinclozolin induces primary epimutations rather than secondary epimutations, but also suggest that some primary epimutations can predispose a subsequent accelerated accumulation of genetic mutations in F3 generation descendants that have the potential to contribute to transgenerational phenotypes. We therefore propose the existence of "tertiary epimutations" which are initial primary epimutations that promote genome instability leading to an accelerated accumulation of genetic mutations. PMID- 27992468 TI - Genetic Diversity and Population Structure of Whitebark Pine (Pinus albicaulis Engelm.) in Western North America. AB - Whitebark pine (WBP, Pinus albicaulis Engelm.) is an endangered conifer species due to heavy mortality from white pine blister rust (WPBR, caused by Cronartium ribicola) and mountain pine beetle (Dendroctonus ponderosae). Information about genetic diversity and population structure is of fundamental importance for its conservation and restoration. However, current knowledge on the genetic constitution and genomic variation is still limited for WBP. In this study, an integrated genomics approach was applied to characterize seed collections from WBP breeding programs in western North America. RNA-seq analysis was used for de novo assembly of the WBP needle transcriptome, which contains 97,447 protein coding transcripts. Within the transcriptome, single nucleotide polymorphisms (SNPs) were discovered, and more than 22,000 of them were non-synonymous SNPs (ns SNPs). Following the annotation of genes with ns-SNPs, 216 ns-SNPs within candidate genes with putative functions in disease resistance and plant defense were selected to design SNP arrays for high-throughput genotyping. Among these SNP loci, 71 were highly polymorphic, with sufficient variation to identify a unique genotype for each of the 371 individuals originating from British Columbia (Canada), Oregon and Washington (USA). A clear genetic differentiation was evident among seed families. Analyses of genetic spatial patterns revealed varying degrees of diversity and the existence of several genetic subgroups in the WBP breeding populations. Genetic components were associated with geographic variables and phenotypic rating of WPBR disease severity across landscapes, which may facilitate further identification of WBP genotypes and gene alleles contributing to local adaptation and quantitative resistance to WPBR. The WBP genomic resources developed here provide an invaluable tool for further studies and for exploitation and utilization of the genetic diversity preserved within this endangered conifer and other five-needle pines. PMID- 27992469 TI - Statins Have No Additional Benefit for Pulmonary Hypertension: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: We performed a meta-analysis to explore the effects of adding statins to standard treatment on adult patients of pulmonary hypertension (PH). METHODS: A systematic search up to December, 2015 of Medline, EMBASE, Cochrane Database of Systematic reviews and Cochrane Central Register of Controlled Trials was performed to identify randomized controlled trials with PH patients treated with statins. RESULTS: Five studies involving 425 patients were included into this meta-analysis. The results of our analysis showed that the statins can't significantly increase 6-minute walking distance (6MWD, mean difference [MD] = 0.33 [CI: -18.25 to 17.59]), decrease the BORG dyspnea score (MD = -0.72 [CI: 2.28 to 0.85]), the clinical worsening risk (11% in statins vs. 10.1% in controls, Risk ratio = 1.06 [CI: 0.61, 1.83]), or the systolic pulmonary arterial pressure (SPAP) (MD = -0.72 [CI: -2.28 to 0.85]). Subgroup analysis for PH due to COPD or non-COPD also showed no significance. CONCLUSIONS: Statins have no additional beneficial effect on standard therapy for PH, but the results from subgroup of PH due to COPD seem intriguing and further study with larger sample size and longer follow-up is suggested. PMID- 27992470 TI - Vaccination Coverage Cluster Surveys in Middle Dreib - Akkar, Lebanon: Comparison of Vaccination Coverage in Children Aged 12-59 Months Pre- and Post-Vaccination Campaign. AB - INTRODUCTION: With the high proportion of refugee population throughout Lebanon and continuous population movement, it is sensible to believe that, in particular vulnerable areas, vaccination coverage may not be at an optimal level. Therefore, we assessed the vaccination coverage in children under 5 in a district of the Akkar governorate before and after a vaccination campaign. During the vaccination campaign, conducted in August 2015, 2,509 children were vaccinated. MATERIALS AND METHODS: We conducted a pre- and post-vaccination campaign coverage surveys adapting the WHO EPI cluster survey to the Lebanese MoPH vaccination calendar. Percentages of coverage for each dose of each vaccine were calculated for both surveys. Factors associated with complete vaccination were explored. RESULTS: Comparing the pre- with the post-campaign surveys, coverage for polio vaccine increased from 51.9% to 84.3%, for Pentavalent from 49.0% to 71.9%, for MMR from 36.2% to 61.0%, while the percentage of children with fully updated vaccination calendar increased from 32.9% to 53.8%. While Lebanese children were found to be better covered for some antigens compared to Syrians at the first survey, this difference disappeared at the post-campaign survey. Awareness and logistic obstacles were the primary reported causes of not complete vaccination in both surveys. DISCUSSION: Vaccination campaigns remain a quick and effective approach to increase vaccination coverage in crisis-affected areas. However, campaigns cannot be considered as a replacement of routine vaccination services to maintain a good level of coverage. PMID- 27992472 TI - Learning from Bees: An Approach for Influence Maximization on Viral Campaigns. AB - Maximisation of influence propagation is a key ingredient to any viral marketing or socio-political campaigns. However, it is an NP-hard problem, and various approximate algorithms have been suggested to address the issue, though not largely successful. In this paper, we propose a bio-inspired approach to select the initial set of nodes which is significant in rapid convergence towards a sub optimal solution in minimal runtime. The performance of the algorithm is evaluated using the re-tweet network of the hashtag #KissofLove on Twitter associated with the non-violent protest against the moral policing spread to many parts of India. Comparison with existing centrality based node ranking process the proposed method significant improvement on influence propagation. The proposed algorithm is one of the hardly few bio-inspired algorithms in network theory. We also report the results of the exploratory analysis of the network kiss of love campaign. PMID- 27992471 TI - Overexpression of Poplar Pyrabactin Resistance-Like Abscisic Acid Receptors Promotes Abscisic Acid Sensitivity and Drought Resistance in Transgenic Arabidopsis. AB - Drought stress is an important environmental factor limiting productivity of plants, especially fast growing species with high water consumption like poplar. Abscisic acid (ABA) is a phytohormone that positively regulates seed dormancy and drought resistance. The PYR1 (Pyrabactin Resistance 1)/ PYRL (PYR-Like)/ RCAR (Regulatory Component of ABA Receptor) (PYR/PYL/RCAR) ABA receptor family has been identified and widely characterized in Arabidopsis thaliana. However, their functions in poplars remain unknown. Here, we report that 2 of 14 PYR/PYL/RCAR orthologues in poplar (Populus trichocarpa) (PtPYRLs) function as a positive regulator of the ABA signal transduction pathway. The Arabidopsis transient expression and yeast two-hybrid assays showed the interaction among PtPYRL1 and PtPYRL5, a clade A protein phosphatase 2C, and a SnRK2, suggesting that a core signalling complex for ABA signaling pathway exists in poplars. Phenotypic analysis of PtPYRL1 and PtPYRL5 transgenic Arabidopsis showed that these two genes positively regulated the ABA responses during the seed germination. More importantly, the overexpression of PtPYRL1 and PtPYRL5 substantially improved ABA sensitivity and drought stress tolerance in transgenic plants. In summary, we comprehensively uncovered the properties of PtPYRL1 and PtPYRL5, which might be good target genes to genetically engineer drought-Resistant plants. PMID- 27992474 TI - Sparse Coding and Counting for Robust Visual Tracking. AB - In this paper, we propose a novel sparse coding and counting method under Bayesian framework for visual tracking. In contrast to existing methods, the proposed method employs the combination of L0 and L1 norm to regularize the linear coefficients of incrementally updated linear basis. The sparsity constraint enables the tracker to effectively handle difficult challenges, such as occlusion or image corruption. To achieve real-time processing, we propose a fast and efficient numerical algorithm for solving the proposed model. Although it is an NP-hard problem, the proposed accelerated proximal gradient (APG) approach is guaranteed to converge to a solution quickly. Besides, we provide a closed solution of combining L0 and L1 regularized representation to obtain better sparsity. Experimental results on challenging video sequences demonstrate that the proposed method achieves state-of-the-art results both in accuracy and speed. PMID- 27992475 TI - A Systematic Investigation of Parameters Influencing Droplet Rain in the Listeria monocytogenes prfA Assay - Reduction of Ambiguous Results in ddPCR. AB - The droplet digital polymerase chain reaction (ddPCR) determines DNA amounts based upon the pattern of positive and negative droplets, according to Poisson distribution, without the use of external standards. However, division into positive and negative droplets is often not clear because a part of the droplets has intermediate fluorescence values, appearing as "rain" in the plot. Despite the droplet rain, absolute quantification with ddPCR is possible, as shown previously for the prfA assay in quantifying Listeria monocytogenes. Nevertheless, reducing the rain, and thus ambiguous results, promotes the accuracy and credibility of ddPCR. In this study, we extensively investigated chemical and physical parameters for optimizing the prfA assay for ddPCR. While differences in the concentration of all chemicals and the dye, quencher and supplier of the probe did not alter the droplet pattern, changes in the PCR cycling program, such as prolonged times and increased cycle numbers, improved the assay. PMID- 27992473 TI - High-Throughput Sequencing of Microbial Community Diversity and Dynamics during Douchi Fermentation. AB - Douchi is a type of Chinese traditional fermented food that is an important source of protein and is used in flavouring ingredients. The end product is affected by the microbial community present during fermentation, but exactly how microbes influence the fermentation process remains poorly understood. We used an Illumina MiSeq approach to investigate bacterial and fungal community diversity during both douchi-koji making and fermentation. A total of 181,443 high quality bacterial 16S rRNA sequences and 221,059 high quality fungal internal transcribed spacer reads were used for taxonomic classification, revealing eight bacterial and three fungal phyla. Firmicutes, Actinobacteria and Proteobacteria were the dominant bacterial phyla, while Ascomycota and Zygomycota were the dominant fungal phyla. At the genus level, Staphylococcus and Weissella were the dominant bacteria, while Aspergillus and Lichtheimia were the dominant fungi. Principal coordinate analysis showed structural separation between the composition of bacteria in koji making and fermentation. However, multivariate analysis of variance based on unweighted UniFrac distances did identify distinct differences (p <0.05), and redundancy analysis identified two key genera that are largely responsible for the differences in bacterial composition between the two steps. Staphylococcus was enriched in koji making, while Corynebacterium was enriched in fermentation. This is the first investigation to integrate douchi fermentation and koji making and fermentation processes through this technological approach. The results provide insight into the microbiome of the douchi fermentation process, and reveal a structural separation that may be stratified by the environment during the production of this traditional fermented food. PMID- 27992476 TI - Using Sub-Network Combinations to Scale Up an Enumeration Method for Determining the Network Structures of Biological Functions. AB - Deduction of biological regulatory networks from their functions is one of the focus areas of systems biology. Among the different techniques used in this reverse-engineering task, one powerful method is to enumerate all candidate network structures to find suitable ones. However, this method is severely limited by calculation capability: due to the brute-force approach, it is infeasible for networks with large number of nodes to be studied using traditional enumeration method because of the combinatorial explosion. In this study, we propose a new reverse-engineering technique based on the enumerating method: sub-network combinations. First, a complex biological function is divided into several sub-functions. Next, the three-node-network enumerating method is applied to search for sub-networks that are able to realize each of the sub functions. Finally, complex whole networks are constructed by enumerating all possible combinations of sub-networks. The optimal ones are selected and analyzed. To demonstrate the effectiveness of this new method, we used it to deduct the network structures of a Pavlovian-like function. The whole Pavlovian like network was successfully constructed by combining robust sub-networks, and the results were analyzed. With sub-network combination, the complexity has been largely reduced. Our method also provides a functional modular view of biological systems. PMID- 27992477 TI - Unravelling the Molecular Epidemiology and Genetic Diversity among Burkholderia pseudomallei Isolates from South India Using Multi-Locus Sequence Typing. AB - There is a slow but steady rise in the case detection rates of melioidosis from various parts of the Indian sub-continent in the past two decades. However, the epidemiology of the disease in India and the surrounding South Asian countries remains far from well elucidated. Multi-locus sequence typing (MLST) is a useful epidemiological tool to study the genetic relatedness of bacterial isolates both with-in and across the countries. With this background, we studied the molecular epidemiology of 32 Burkholderia pseudomallei isolates (31 clinical and 1 soil isolate) obtained during 2006-2015 from various parts of south India using multi locus sequencing typing and analysis. Of the 32 isolates included in the analysis, 30 (93.7%) had novel allelic profiles that were not reported previously. Sequence type (ST) 1368 (n = 15, 46.8%) with allelic profile (1, 4, 6, 4, 1, 1, 3) was the most common genotype observed. We did not observe a genotypic association of STs with geographical location, type of infection and year of isolation in the present study. Measure of genetic differentiation (FST) between Indian and the rest of world isolates was 0.14413. Occurrence of the same ST across three adjacent states of south India suggest the dispersion of B.pseudomallei across the south western coastal part of India with limited geographical clustering. However, majority of the STs reported from the present study remained as "outliers" on the eBURST "Population snapshot", suggesting the genetic diversity of Indian isolates from the Australasian and Southeast Asian isolates. PMID- 27992479 TI - Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study. AB - Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming's one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%-86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents. PMID- 27992480 TI - Vocal Imitations of Non-Vocal Sounds. AB - Imitative behaviors are widespread in humans, in particular whenever two persons communicate and interact. Several tokens of spoken languages (onomatopoeias, ideophones, and phonesthemes) also display different degrees of iconicity between the sound of a word and what it refers to. Thus, it probably comes at no surprise that human speakers use a lot of imitative vocalizations and gestures when they communicate about sounds, as sounds are notably difficult to describe. What is more surprising is that vocal imitations of non-vocal everyday sounds (e.g. the sound of a car passing by) are in practice very effective: listeners identify sounds better with vocal imitations than with verbal descriptions, despite the fact that vocal imitations are inaccurate reproductions of a sound created by a particular mechanical system (e.g. a car driving by) through a different system (the voice apparatus). The present study investigated the semantic representations evoked by vocal imitations of sounds by experimentally quantifying how well listeners could match sounds to category labels. The experiment used three different types of sounds: recordings of easily identifiable sounds (sounds of human actions and manufactured products), human vocal imitations, and computational "auditory sketches" (created by algorithmic computations). The results show that performance with the best vocal imitations was similar to the best auditory sketches for most categories of sounds, and even to the referent sounds themselves in some cases. More detailed analyses showed that the acoustic distance between a vocal imitation and a referent sound is not sufficient to account for such performance. Analyses suggested that instead of trying to reproduce the referent sound as accurately as vocally possible, vocal imitations focus on a few important features, which depend on each particular sound category. These results offer perspectives for understanding how human listeners store and access long-term sound representations, and sets the stage for the development of human-computer interfaces based on vocalizations. PMID- 27992478 TI - Experiencing Lifetime Domestic Violence: Associations with Mental Health and Stress among Pregnant Women in Rural Bangladesh: The MINIMat Randomized Trial. AB - BACKGROUND: Experience of domestic violence has negative mental health consequences for women. The association of cumulative and specific forms of domestic violence, particularly emotional violence and controlling behavior, with common mental disorders and stress has rarely been studied in pregnant women. The aim of this study is to evaluate associations of specific and multiple forms of lifetime domestic violence and controlling behavior with distress and cortisol level during pregnancy in rural Bangladeshi women. METHODS AND FINDINGS: In this observational sub-study of larger MINIMat trial, 3504 pregnant women were interviewed using a shortened Conflict Tactic Scale about their lifetime experience of domestic violence including physical, sexual, emotional domestic violence and controlling behavior. Women's levels of emotional distress were assessed using the self-reported questionnaire (SRQ-20) developed by WHO, and levels of morning salivary cortisol were measured in a subsample (n = 1300) of women during week 28-32 of pregnancy. Regression analyses were used to estimate the associations of lifetime physical, sexual, emotional domestic violence and controlling behavior with levels of distress and cortisol during pregnancy. The prevalence of lifetime domestic violence was 57% and emotional distress was 35% in these pregnant women. All forms of domestic violence were associated with higher levels of emotional distress. Women who experienced either emotional violence or controlling behavior had the highest levels of emotional distress. There was a dose-response relationship between cumulative number of the different forms of domestic violence and women's levels of emotional distress. There was no association between women's experience of domestic violence and level of morning salivary cortisol. CONCLUSION: Including emotional violence and controlling behavior as major types of violence in future research and health interventions is warranted. Furthermore, the extent of the negative impacts of domestic violence on pregnant women, multiple forms of violence and their cumulative effects need to be investigated. PMID- 27992481 TI - Molecular Analysis of Pfs47-Mediated Plasmodium Evasion of Mosquito Immunity. AB - Malaria is a life-threatening disease caused by Plasmodium falciparum parasites that is transmitted through the bites of infected anopheline mosquitoes. P. falciparum dispersal from Africa, as a result of human migration, required adaptation of the parasite to several different indigenous anopheline species. The mosquito immune system can greatly limit infection and P. falciparum evolved a strategy to evade these responses that is mediated by the Pfs47 gene. Pfs47 is a polymorphic gene with signatures of diversifying selection and a strong geographic genetic structure at a continental level. Here, we investigated the role of single four amino acid differences between the Pfs47 gene from African (GB4 and NF54) and a New World (7G8) strains that differ drastically in their ability to evade the immune system of A. gambiae L35 refractory mosquitoes. Wild type NF54 and GB4 parasites can survive in this mosquito strain, while 7G8 parasites are eliminated. Our studies indicate that replacement in any of these four single amino acids in Pfs47 from the NF54 strain by those present in 7G8, completely disrupts the ability of NF54 parasites to hide from the mosquito immune system. One of these amino acid replacements had the opposite effect on A. albimanus mosquitoes, and enhanced infection. We conclude that malaria transmission involves a complex interplay between the genetic background of the parasite and the mosquito and that Pfs47 can be critical in this interaction as it mediates Plasmodium immune evasion through molecular interactions that need to be precise in some parasite/vector combinations. PMID- 27992482 TI - Dry Eye after Small Incision Lenticule Extraction (SMILE) versus Femtosecond Laser-Assisted in Situ Keratomileusis (FS-LASIK) for Myopia: A Meta-Analysis. AB - PURPOSE: To compare dry eye after small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK (FS-LASIK) for correcting myopia. METHODS: CENTRAL, Embase and PubMed were searched in November 2016. All randomized controlled trials (RCTs) and prospective cohorts that compared dry eye after SMILE with FS-LASIK were selected. RESULTS: Five cohorts and one RCT were identified for comparing dry eye after SMILE (291 eyes) and FS-LASIK (277 eyes). The pooled results revealed that the SMILE and FS-LASIK groups did not differ significantly in terms of Schirmer's I test (SIT) and tear film osmolarity (TFO) at any postoperative visits. By contrast, tear break up time (TBUT; p = 0.04 for one month, p < 0.001 for three months, and p = 0.02 for six months) and ocular surface disease index (OSDI; p < 0.001 for one month and three months, and p = 0.006 for six months) were significantly worse in the FS-LASIK group than in the SMILE group at follow-up. At six months postoperatively, TBUT and TFO values in both the SMILE and FS-LASIK groups and OSDI scores in the SMILE group returned to preoperative levels, but SIT values in both groups (p = 0.02 for the SMILE group and p < 0.001 for the FS-LASIK group) and OSDI in the FS-LASIK group (p < 0.001) were still statistically impaired. CONCLUSION: Dry eye after both SMILE and FS LASIK usually occurs transiently. SMILE does not show obvious superiority over FS LASIK by exhibiting similar and acceptable objective parameters, and SMILE may have milder subjective symptoms. PMID- 27992484 TI - Adaptive Appraisals of Anxiety Moderate the Association between Cortisol Reactivity and Performance in Salary Negotiations. AB - Prior research suggests that stress can be harmful in high-stakes contexts such as negotiations. However, few studies actually measure stress physiologically during negotiations, nor do studies offer interventions to combat the potential negative effects of heightened physiological responses in negotiation contexts. In the current research, we offer evidence that the negative effects of cortisol increases on negotiation performance can be reduced through a reappraisal of anxiety manipulation. We experimentally induced adaptive appraisals by randomly assigning 97 male and female participants to receive either instructions to appraise their anxiety as beneficial to the negotiation or no specific instructions on how to appraise the situation. We also measured participants' cortisol responses prior to and following the negotiation. Results revealed that cortisol increases were positively related to negotiation performance for participants who were told to view anxiety as beneficial, and not detrimental, for negotiation performance (appraisal condition). In contrast, cortisol increases were negatively related to negotiation performance for participants given no instructions on appraising their anxiety (control condition). These findings offer a means through which to combat the potentially deleterious effects of heightened cortisol reactivity on negotiation outcomes. PMID- 27992483 TI - Unintentional Injuries among Psychiatric Outpatients with Major Depressive Disorder. AB - BACKGROUND: No study has investigated the percentages of and factors related to unintentional injuries among psychiatric outpatients with major depressive disorder (MDD). This study aimed to investigate these issues. METHODS: One hundred and forty-one outpatients with MDD at baseline were enrolled from psychiatric outpatients by systematic sampling, and 119 subjects attended a one year follow-up. Self-reported unintentional injuries in the past one year were recorded. Psychiatric disorders were diagnosed using the Structured Clinical Interview for DSM-IV-TR. The severity of depression was evaluated by the Hamilton Depression Rating Scale. Other data, including body weight and height, cigarette smoking, headaches, and medications, were collected. Generalized Estimating Equations were used to investigate independent factors related to unintentional injuries. RESULTS: At baseline and follow-up, 40.4% and 27.7% of subjects had experienced at least one unintentional injury in the past one year, respectively. About half of subjects with unintentional injuries needed medical treatment for injuries and had functional impairment due to injuries. A greater severity of depression, cigarette smoking, a higher body mass index, and an older age were independent risk factors related to unintentional injuries. CONCLUSION: Unintentional injuries that increased the medical burden and functional impairment were common among outpatients with MDD and should not be neglected. Treatment of depression, control of body weight, and quitting cigarettes might be helpful to prevent unintentional injuries. PMID- 27992485 TI - An Assessment of Publication Status of Pediatric Liver Transplantation Studies. AB - INTRODUCTION: Pediatric liver transplantation is a highly specialized, challenging field. Selective reporting may introduce bias into evidence based clinical decision making, but the precise extent of unpublished data in pediatric liver transplantation is unknown today. We therefore assessed the public availability of completed clinical trials in pediatric liver transplantation. METHODS: We determined the proportion of published and unpublished pre registered, completed pediatric liver transplantation studies on ClinicalTrials.gov. The major trial and literature databases, i.e., clinicaltrials.gov, Pubmed, and Google Scholar were searched for publications. In addition, principal investigators or sponsors were contacted directly. STROBE criteria were applied for the descriptive analysis. RESULTS: Out of N = 33 studies focusing on pediatric liver transplantation registered as completed until March 2014 on clinicaltrials.gov, N = 19 (58%) studies were published until February 2015, whereas N = 14 (42%) studies remained unpublished. The unpublished trials contain data from N = 2105 (35%) patients out of a total population of N = 6044 study participants. Median time-to-publication, i.e., the period from completion of the trial until public availability of the data was 23 IQR 10 to 28 months. Most pertinent key questions in pediatric liver transplantation, i.e., surgical procedures, immunosuppression, concomitant infections, and graft rejection were addressed in 48% of studies (N = 16/33), half of which were published. CONCLUSION: Half of the clinical trials in pediatric liver transplantation focused on key questions such as surgical procedures, immunosuppression, concomitant infections, and graft rejection. There is still a considerable amount of unpublished studies results in pediatric liver transplantation. Time from study completion to publication was almost twice as long as the 12 months mandatory FDAAA-timeline with a trend towards acceleration over time. The data should serve as a baseline for future progress in the field. More stringent publication of completed trials and focused multicenter research should be encouraged. PMID- 27992486 TI - Evaluation of Surgical Strategy Based on the Intraoperative Superior Oblique Tendon Traction Test. AB - PURPOSE: To clarify the efficacy of a surgical strategy based on the superior oblique tendon traction test. METHODS: A retrospective chart review was performed between January 2002 and June 2015. During that period, a single inferior oblique muscle (IO) myectomy and a combined IO myectomy and superior oblique muscle (SO) tuck procedure were performed based on SO tendon looseness as revealed by a traction test. The surgical effects of both procedures and the number of operations were analyzed. RESULTS: Sixty-five cases were retrieved. Seventy-four surgeries were required. The IO myectomy and simultaneous groups included 48 and 17 cases, respectively. Pre-operative vertical deviation was significantly lower in the IO myectomy (11.8 prism diopters) than in the simultaneous (27.2 prism diopters; Mann-Whitney U-test, P < 0.001) group. The mean induced changes were 9.4 prism diopters and 21.6 prism diopters in the IO myectomy and simultaneous groups, respectively, and the postoperative vertical deviation was not significantly different. On average, 1.13 and 1.18 surgeries per patient were performed in the IO myectomy and simultaneous groups, respectively. CONCLUSION: The simultaneous surgery of inferior oblique myectomy and superior oblique tuck is safe and effective for treating large angle of congenital/idiopathic superior oblique palsy with a lax superior oblique tendon, as determined by the traction test. PMID- 27992487 TI - Changes in Host Cytokine Patterns of TB Patients with Different Bacterial Loads Detected Using 16S rRNA Analysis. AB - BACKGROUND: Tuberculosis (TB) has overtaken HIV as the biggest infectious disease killer, with the majority of deaths occurring in sub-Saharan Africa. However it is unknown how differences in bacterial load alter host immune profiles in the sputum and blood of TB patients. METHODS: 16S ribosomal RNA analysis was used to determine bacterial load in sputum samples obtained from 173 patients with active TB (57 pre-treatment and 116 post-treatment). Host analyte concentrations in sputum and Mycobacterium tuberculosis (Mtb) antigen stimulated whole blood assay supernatants were analysed using multiplex cytokine arrays. RESULTS: Multiple logistic regression adjusting for age, sex and HIV status showed highly significant correlation of bacterial load with IL1beta, IL2, IL1RA, IL4, IL6, IL8, IL9, IL15, IL17, EOTAX, FGF, IFN-gamma, GCSF, MCP1, M1P1alpha, M1P1beta, PDGF, TNFalpha, VEGF in sputum. With increasing time on treatment, FGF levels in sputum displayed the most significant inverse correlation with reduction in bacterial load. CONCLUSIONS: We show that differences in bacterial load correlates with changes in several host biomarkers. These findings have implications for development of tests for TB diagnosis and treatment response. PMID- 27992488 TI - Cholera Rapid Test with Enrichment Step Has Diagnostic Performance Equivalent to Culture. AB - Cholera rapid diagnostic tests (RDT) could play a central role in outbreak detection and surveillance in low-resource settings, but their modest performance has hindered their broad adoption. The addition of an enrichment step may improve test specificity. We describe the results of a prospective diagnostic evaluation of the Crystal VC RDT (Span Diagnostics, India) with enrichment step and of culture, each compared to polymerase chain reaction (PCR), during a cholera outbreak in South Sudan. RDTs were performed on alkaline peptone water inoculated with stool and incubated for 4-6 hours at ambient temperature. Cholera culture was performed from wet filter paper inoculated with stool. Molecular detection of Vibrio cholerae O1 by PCR was done from dry Whatman 903 filter papers inoculated with stool, and from wet filter paper supernatant. In August and September 2015, 101 consecutive suspected cholera cases were enrolled, of which 36 were confirmed by PCR. The enriched RDT had 86.1% (95% CI: 70.5-95.3) sensitivity and 100% (95% CI: 94.4-100) specificity compared to PCR as the reference standard. The sensitivity of culture versus PCR was 83.3% (95% CI: 67.2-93.6) for culture performed on site and 72.2% (95% CI: 54.8-85.8) at the international reference laboratory, where samples were tested after an average delay of two months after sample collection, and specificity was 98.5% (95% CI: 91.7-100) and 100% (95% CI: 94.5-100), respectively. The RDT with enrichment showed performance comparable to that of culture and could be a sustainable alternative to culture confirmation where laboratory capacity is limited. PMID- 27992489 TI - Diagnostic Performance of Magnifying Endoscopy for Helicobacter pylori Infection: A Meta-Analysis. AB - BACKGROUND: Diagnosis of Helicobacter pylori (H. pylori) infection using magnifying endoscopy offers advantages over conventional invasive and noninvasive tests. OBJECTIVE: This meta-analysis aimed to assess the diagnostic performance of magnifying endoscopy in the prediction of H. pylori infection. METHODS: A literature search of the PubMed, Medline, EMBASE, Science Direct and the Cochrane Library databases was performed. A random-effects model was used to calculate the diagnostic efficiency of magnifying endoscopy for H. pylori infection. A summary receiver operator characteristic curve was plotted, and the area under the curve (AUC) was calculated. RESULTS: A total of 18 studies involving 1897 patients were included. The pooled sensitivity and specificity of magnifying endoscopy to predict H. pylori infection were 0.89 [95% confidence interval (CI) 0.87-0.91] and 0.82 (95%CI 0.79-0.85), respectively, with an AUC of 0.9461. When targeting the gastric antrum, the pooled sensitivity and specificity were 0.82 (95%CI 0.78 0.86) and 0.72 (95%CI 0.66-0.78), respectively. When targeting the gastric corpus, the pooled sensitivity and specificity were 0.92 (95%CI 0.90-0.94) and 0.86 (95%CI 0.82-0.88), respectively. The pooled sensitivity and specificity using magnifying white light endoscopy were 0.90 (95%CI 0.87-0.91) and 0.81 (95%CI 0.77-0.84), respectively. The pooled sensitivity and specificity using magnifying chromoendoscopy were 0.87 (95%CI 0.83-0.91) and 0.85 (95%CI 0.80 0.88), respectively. The "pit plus vascular pattern" classification in the gastric corpus observed by magnifying endoscopy was able to accurately predict the status of H. pylori infection, as indicated by a pooled sensitivity and specificity of 0.96 (95%CI 0.94-0.97) and 0.91 (95%CI 0.87-0.93), respectively, with an AUC of 0.9872. CONCLUSIONS: Magnifying endoscopy was able to accurately predict the status of H. pylori infection, either in magnifying white light endoscopy or magnifying chromoendoscopy mode. The "pit plus vascular pattern" classification in the gastric corpus is an optimum diagnostic criterion. PMID- 27992490 TI - Intragenic Deletions in ATP7B as an Unusual Molecular Genetics Mechanism of Wilson's Disease Pathogenesis. AB - Wilson's disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B resulting in copper overload in the liver and brain. Direct sequencing is routinely used to confirm WD diagnosis; however, partial and whole gene deletions in the heterozygous state cannot be detected by exon amplification since the normal allele will mask its presence. The aim of the present work was to search for unusual mutational events in the unexplained WD cases and to provide insight into the mechanisms. Out of 1420 clinically and biochemically confirmed WD samples received between 2000 and 2014 for routine mutation analysis, we were unable to detect mutant alleles in 142 samples, after extensive sequencing analysis. We used selective amplification and MLPA to identify the partial gene deletions and identified three different partial gene deletions in seven different families. All three deletions were fully characterized at the DNA sequence level. We report the first hemizygous case with WD due to intragenic deletion in the ATP7B (c.3134_3556+689del). This novel deletion resulted from an excision event mediated by consensus sequences in an AluSq2 repeat element and could be traced to micro homologous end joining (MMEJ). Finally, we determined the prevalence of the three deletions in DNA samples from a multinational group of WD patients. Our results emphasize the need for searching mutant alleles beyond routine methods and highlight that large ATP7B deletions are rare, but account for a detectable proportion in some WD patients. Screening for gene aberrations will further improve mutation detection in patients with unidentified ATP7B mutations presenting with clinical manifestations of WD. PMID- 27992491 TI - Survivorship Care Plan Information Needs: Perspectives of Safety-Net Breast Cancer Patients. AB - PURPOSE: Despite the Institute of Medicine's (IOM) 2005 recommendation, few care organizations have instituted standard survivorship care plans (SCPs). Low health literacy and low English proficiency are important factors to consider in SCP development. Our study aimed to identify information needs and survivorship care plan preferences of low literacy, multi-lingual patients to support the transition from oncology to primary care and ongoing learning in survivorship. METHODS: We conducted focus groups in five languages with African American, Latina, Russian, Filipina, White, and Chinese medically underserved breast cancer patients. Topics explored included the transition to primary care, access to information, knowledge of treatment history, and perspectives on SCPs. RESULTS: Analysis of focus group data identified three themes: 1) the need for information and education on the transition between "active treatment" and "survivorship"; 2) information needed (and often not obtained) from providers; and 3) perspectives on SCP content and delivery. CONCLUSIONS: Our data point to the need to develop a process as well as written information for medically underserved breast cancer patients. An SCP document will not replace direct communication with providers about treatment, symptom management and transition, a communication that is missing in participating safety-net patients' experiences of cancer care. Women turned to peer support and community-based organizations in the absence of information from providers. IMPLICATIONS FOR CANCER SURVIVORS: "Clear and effective" communication of survivorship care for safety-net patients requires dedicated staff trained to address wide-ranging information needs and uncertainties. PMID- 27992492 TI - Promoting Therapists' Use of Motor Learning Strategies within Virtual Reality Based Stroke Rehabilitation. AB - PURPOSE: Therapists use motor learning strategies (MLSs) to structure practice conditions within stroke rehabilitation. Virtual reality (VR)-based rehabilitation is an MLS-oriented stroke intervention, yet little support exists to assist therapists in integrating MLSs with VR system use. METHOD: A pre-post design evaluated a knowledge translation (KT) intervention incorporating interactive e-learning and practice, in which 11 therapists learned how to integrate MLSs within VR-based therapy. Self-report and observer-rated outcome measures evaluated therapists' confidence, clinical reasoning and behaviour with respect to MLS use. A focus group captured therapists' perspectives on MLS use during VR-based therapy provision. RESULTS: The intervention improved self reported confidence about MLS use as measured by confidence ratings (p <0.001). Chart-Stimulated Recall indicated a moderate level of competency in therapists' clinical reasoning about MLSs following the intervention, with no changes following additional opportunities to use VR (p = .944). On the Motor Learning Strategy Rating Instrument, no behaviour change with respect to MLS use was noted (p = 0.092). Therapists favoured the strategy of transferring skills from VR to real-life tasks over employing a more comprehensive MLS approach. CONCLUSION: The KT intervention improved therapists' confidence but did not have an effect on clinical reasoning or behaviour with regard to MLS use during VR-based therapy. PMID- 27992493 TI - Clinical and Metabolic Characteristics among Mexican Children with Different Types of Diabetes Mellitus. AB - BACKGROUND: Current classification of diabetes mellitus (DM) is based on etiology and includes type 1 (T1DM), type 2 (T2DM), gestational, and other. Clinical and pathophysiological characteristics of T1DM and T2DM in the same patient have been designated as type 1.5 DM (T1.5DM). OBJECTIVES: The aim of this study was to classify pediatric patients with DM based on pancreatic autoimmunity and the presence or absence of overweight/obesity, and to compare the clinical, anthropometric, and biochemical characteristics between children in the different classes of DM. METHODS: A sample of 185 patients, recruited (March 2008-April 2015) as part of the Cohort of Mexican Children with DM (CMC-DM); ClinicalTrials.gov, identifier: NCT02722655. The DM classification was made considering pancreatic autoimmunity (via antibodies GAD-65, IAA, and AICA) and the presence or absence of overweight/obesity. Clinical, anthropometric and biochemical variables, grouped by type of DM were compared (Kruskal-Wallis or chi squared test). RESULTS: The final analysis included 140 children; 18.57% T1ADM, 46.43% T1BDM, 12.14% T1.5DM, and 22.86% T2DM. Fasting C-Peptide (FCP), and hs-CRP levels were higher in T1.5DM and T2DM, and the greatest levels were observed in T1.5DM (p<0.001 and 0.024 respectively). CONCLUSIONS: We clearly identified that the etiologic mechanisms of T1DM and T2DM are not mutually exclusive, and we detailed why FCP levels are not critical for the classification system of DM in children. The findings of this study suggest that T1.5DM should be considered during the classification of pediatric DM and might facilitate more tailored approaches to treatment, clinical care and follow-up. PMID- 27992495 TI - Options to Expand HIV Viral Load Testing in South Africa: Evaluation of the GeneXpert(r) HIV-1 Viral Load Assay. AB - BACKGROUND: Expansion of HIV viral load (VL) testing services are required to meet increased targets for monitoring patients on antiretroviral treatment. South Africa currently tests >4million VLs per annum in 16 highly centralised, automated high-throughput laboratories. The Xpert HIV-1 VL assay (Cepheid) was evaluated against in-country predicates, the Roche Cobas Taqmanv2 and Abbott HIV 1RT, to investigate options for expanding VL testing using GeneXpert's random access, polyvalent capabilities and already established footprint in South Africa with the Xpert MTB/RIF assay (207 sites). Additionally, the performance of Xpert HIV-1VL on alternative, off-label specimen types, Dried Blood Spots (DBS) and whole blood, was investigated. METHOD: Precision, accuracy (agreement) and clinical misclassification (1000cp/ml) of Xpert HIV-1VL plasma was compared to Taqmanv2 (n = 155) and Abbott HIV-1 RT (n = 145). Misclassification of Xpert HIV 1VL was further tested on DBS (n = 145) and whole blood (n = 147). RESULTS: Xpert HIV-1VL demonstrated 100% concordance with predicate platforms on a standardised frozen, plasma panel (n = 42) and low overall percentage similarity CV of 1.5% and 0.9% compared to Taqmanv2 and Abbott HIV-1 RT, respectively. On paired plasma clinical specimens, Xpert HIV-1VL had low bias (SD 0.32-0.37logcp/ml) and 3% misclassification at the 1000cp/ml threshold compared to Taqmanv2 (fresh) and Abbott HIV-1 RT (frozen), respectively. Xpert HIV-1VL on whole blood and DBS increased misclassification (upward) by up to 14% with increased invalid rate. All specimen testing was easy to perform and compatible with concurrent Xpert MTB/RIF Tuberculosis testing on the same instrument. CONCLUSION: The Xpert HIV 1VL on plasma can be used interchangeably with existing predicate platforms in South Africa. Whole blood and DBS testing requires further investigation, but polyvalency of the GeneXpert offers a solution to extending VL testing services. PMID- 27992494 TI - Application of Bacteriophage-containing Aerosol against Nosocomial Transmission of Carbapenem-Resistant Acinetobacter baumannii in an Intensive Care Unit. AB - BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) is associated with nosocomial infections worldwide. Here, we used phage as a potential agent to evaluate the efficacy of daily cleaning practices combined with a bacteriophage containing aerosol against CRAB. METHODS: A two-phase prospective intervention study was performed at a 945-bed public teaching hospital. From March to December 2013, we performed terminal cleaning using standard procedures plus an aerosol with active bacteriophage in the intensive care units to evaluate the impact on nosocomial incidence density, carbapenem-resistance rates and antimicrobial drug consumption amounts. Patients with culture proven CRAB infection were transferred to the isolation room when the phage aerosol cleaning had been completed. RESULTS: A total of 264 new acquisitions of CRAB were identified in the intensive care units (191 in the pre-intervention period and 73 in the intervention period). The rates of new acquisitions of CRAB in the intensive care units decreased from 8.57 per 1000 patient-days in the pre-intervention period to 5.11 per 1000 patient-days in the intervention period (p = 0.0029). The mean percentage of resistant isolates CRAB decreased from 87.76% to 46.07% in the intensive care units (p = 0.001). All of the antimicrobials showed a significant reduction in consumption except imipenem. CONCLUSIONS: The bacteriophage was successful in decreasing the rates of infection caused by CRAB across intensive care units in a large teaching hospital. PMID- 27992496 TI - Field Sandbur (Cenchrus pauciflorus) Seeds in the Same Bur Respond Differently to Temperature and Water Potential in Relation to Germination in a Semi-Arid Environment, China. AB - The success of a biological invasion relies on the environment and is closely linked to factors such as water and temperature. Invasive plant species display different seed characteristics, including shape. Field sandbur (Cenchrus pauciflorus) is a globally widespread invasive species capable of adapting to broad environmental conditions. However, its germination response to water and temperature still remains unclear. C. pauciflorus contains two seeds in the same bur that differ in size: big seeds (M) and small seeds (P). Separate greenhouse experiments were conducted under different temperature regimes (0/10 degrees C, 5/15 degrees C, 10/20 degrees C, 15/25 degrees C, 18/28 degrees C, 20/30 degrees C and 25/35 degrees C) and water potentials (-1.50Mpa, -1.00Mpa, -0.75Mpa, 0.50Mpa, -0.25Mpa and 0Mpa) for M and P seeds. The results support the hypothesis that germination of C. pauciflorus is significantly influenced by seed type, temperature and water potential. M and P seeds responded differently to varied alternative temperatures and water potentials. However, M and P seeds were more sensitive to water potential than to temperature. Optimal conditions for M and P seed germination were measured at 25/35 degrees C (night temperature/day temperature) and 20/30 degrees C, respectively. In contrast, the highest germination rate was observed for the 0Mpa of the water potential treatment. Additionally, base temperature (Tbase) and base water potential (Wbase) were lower for M (7.7 degrees C, -1.11Mpa at 10/20 degrees C, and -1.07Mpa at 20/30 degrees C) than for P (9.4 degrees C, -0.92Mpa at 10/20 degrees C, and -0.52Mpa at 20/30 degrees C). These different germination strategies of M and P seeds with respect to temperature and water potential increased overall plant propagation. These results indicate that tropical and subtropical regions water potentials beyond -0.50Mpa (10/20 degrees C) or -1.00Mpa (20/30 degrees C) face a potential risk of C. pauciflorus invasion. PMID- 27992497 TI - Validation of the International HIV Dementia Scale as a Screening Tool for HIV Associated Neurocognitive Disorders in a German-Speaking HIV Outpatient Clinic. AB - BACKGROUND: HIV-associated neurocognitive disorders (HAND) are widely present among people living with HIV. Especially its milder forms, asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), remain highly prevalent worldwide. Diagnosing these conditions is subject to a time and resource consuming neuropsychological assessment. Selecting patients at a higher risk of cognitive impairment by using a simple but effective screening tool helps to organise access to further neuropsychological diagnosis. The International HIV Dementia Scale (IHDS) has until now been a well-established screening tool in African and American countries, however these populations' demographics defer significantly from ours, so using the same parameters could be ineffective. OBJECTIVES: To calculate the prevalence of this condition among people attending an HIV outpatient clinic in Berlin and to validate the use of the IHDS as a screening tool for HAND in a German-speaking population. METHODS: We screened 480 HIV-infected patients using the IHDS, 89% of them were on a stable antiretroviral treatment. Ninety of them completed a standardised neuropsychological battery of tests and a specific cognitive complaints questionnaire. The same procedure was applied to a control group of 30 HIV-negative participants. HAND diagnosis was established according to the Frascati criteria. RESULTS: The overall prevalence of HAND in our cohort was 43% (20% ANI, 17% MND and 6% HIV-associated dementia). The optimal cut-off on the IHDS for detecting HAND cases was set at 11 and achieved both a sensitivity and a specificity of 80%. When specifically screening for the more severe form of HAND, HIV-associated dementia, a cut-off value of 10 offered an increase in both sensitivity (94%) and specificity (86%). The Youden Index for diagnostic accuracy was 0.6 and 0.8, respectively. CONCLUSIONS: The prevalence of HAND was comparable to the reported by recent studies performed in countries with a similar economic development. The study confirms the IHDS to be a useful HAND screening tool in primary care settings and establishes new recommendations for its use in German-speaking countries. PMID- 27992498 TI - Lack of Impact of Posidonia oceanica Leaf Nutrient Enrichment on Sarpa salpa Herbivory: Additional Evidence for the Generalist Consumer Behavior of This Cornerstone Mediterranean Herbivore. AB - The fish Sarpa salpa (L.) is one of the main macroherbivores in the western Mediterranean. Through direct and indirect mechanisms, this herbivore can exert significant control on the structure and functional dynamics of seagrass beds and macroalgae. Past research has suggested nutritional quality of their diet influences S. salpa herbivory, with the fish feeding more intensively and exerting greater top down control on macrophytes with higher internal nutrient contents. However recent findings have questioned this notion and shown that herbivores do not preferentially feed on macrophytes with higher nutrient contents, but rather feed on a wide variety of them with no apparent selectivity. To contribute to this debate, we conducted a field fertilization experiment where we enriched leaves of the seagrass Posidonia oceanica, a staple diet for S. salpa, and examined the response by the herbivore. These responses included quantification of leaf consumption in fertilized and non-fertilized/control plots within the bed, and food choice assays where fertilized and non fertilized/control leaves were simultaneously offered to the herbivore. Despite the duration of leaf exposure to herbivores (30 days) and abundant schools of S. salpa observed around the plots, leaf consumption was generally low in the plots examined. Consumption was not higher on fertilized than on non-fertilized leaves. Food choice experiments did not show strong evidence for selectivity of enriched leaves. These results add to a recent body of work reporting a broad generalist feeding behavior by S. salpa with no clear selectivity for seagrass with higher nutrient content. In concert, this and other studies suggest S. salpa is often generalist consumers not only dictated by diet nutrient content but by complex interactions between other traits of nutritional quality, habitat heterogeneity within their ample foraging area, and responses to predation risk. PMID- 27992499 TI - Diffusion Tensor Imaging for Evaluating Biliary Atresia in Infants and Neonates. AB - BACKGROUND: Preliminary studies have shown that diffusion tensor imaging (DTI) is helpful in evaluating liver disorders. However, there is no published literature on the use of DTI in the diagnosis of biliary atresia (BA). This study aimed to investigate the diagnostic value of the liver average apparent diffusion coefficient (ADC) and fractional anisotropy (FA) measured using DTI for BA in neonates and infants. METHODS: Fifty-nine patients with infant jaundice were included in this study. DTI was performed with b factors of 0 and 1000 s/mm2. Liver fibrosis in the BA group was determined and graded (F0, F1, F2, F3, F4) based on the pathological findings. Statistical analyses were performed to determine the diagnostic accuracy of DTI for BA. RESULTS: The ADC value was significantly lower in the BA group [(1.262+/-0.127)*10-3 mm2/s] than in the non BA group [(1.430+/-0.149)*10-3 mm2/s, (P<0.001)]. The area under the receiver operating characteristic curve was 0.805+/-0.058 (P<0.001) for ADC. With a cut off value of 1.317*10-3 mm2/s, ADC achieved a sensitivity of 75% and a specificity of 81.5% for the differential diagnosis of BA and non-BA. In the BA group, the ADC value was significantly correlated with fibrotic stage. Further analysis showed that the ADC value of stage F0 was significantly higher than that of stages F1, F2, F3 and F4, whereas there were no significant differences among stages F1, F2, F3 and F4. CONCLUSION: Hepatic ADC measured with DTI can be used as an adjunct to other noninvasive imaging methods in the differential diagnosis of BA and non-BA. ADC was helpful in detecting liver fibrosis but not in differentiating the fibrotic grades. PMID- 27992501 TI - EPSPS Gene Copy Number and Whole-Plant Glyphosate Resistance Level in Kochia scoparia. AB - Glyphosate-resistant (GR) Kochia scoparia has evolved in dryland chemical fallow systems throughout North America and the mechanism of resistance involves 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene duplication. Agricultural fields in four states were surveyed for K. scoparia in 2013 and tested for glyphosate-resistance level and EPSPS gene copy number. Glyphosate resistance was confirmed in K. scoparia populations collected from sugarbeet fields in Colorado, Wyoming, and Nebraska, and Montana. Glyphosate resistance was also confirmed in K. scoparia accessions collected from wheat-fallow fields in Montana. All GR samples had increased EPSPS gene copy number, with median population values up to 11 from sugarbeet fields and up to 13 in Montana wheat-fallow fields. The results indicate that glyphosate susceptibility can be accurately diagnosed using EPSPS gene copy number. PMID- 27992500 TI - Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform. AB - Current anti-VEGF (Vascular Endothelial Growth Factor A) therapies to treat various cancers indiscriminately block VEGF function in the patient resulting in the global loss of VEGF signaling which has been linked to dose-limiting toxicities as well as treatment failures due to acquired resistance. Accumulating evidence suggests that this resistance is at least partially due to increased production of compensatory tumor angiogenic factors/cytokines. VEGF protein production is differentially controlled depending on whether cells are in the normal "homeostatic" state or in a stressed state, such as hypoxia, by post transcriptional regulation imparted by elements in the 5' and 3' untranslated regions (UTR) of the VEGF mRNA. Using the Gene Expression Modulation by Small molecules (GEMSTM) phenotypic assay system, we performed a high throughput screen to identify low molecular weight compounds that target the VEGF mRNA UTR-mediated regulation of stress-induced VEGF production in tumor cells. We identified a number of compounds that potently and selectively reduce endogenous VEGF production under hypoxia in HeLa cells. Medicinal chemistry efforts improved the potency and pharmaceutical properties of one series of compounds resulting in the discovery of PTC-510 which inhibits hypoxia-induced VEGF expression in HeLa cells at low nanomolar concentration. In mouse xenograft studies, oral administration of PTC-510 results in marked reduction of intratumor VEGF production and single agent control of tumor growth without any evident toxicity. Here, we show that selective suppression of stress-induced VEGF production within tumor cells effectively controls tumor growth. Therefore, this approach may minimize the liabilities of current global anti-VEGF therapies. PMID- 27992502 TI - What Is the Value of Surgical Intervention for Sacral Metastases? AB - OBJECTIVE: To investigate the impact of surgery on local control and quality of life for patients with sacral metastases and to determine whether the complications of surgery were acceptable. METHODS: Curettage for metastatic lesions of the sacrum was performed in 154 patients with obvious sacral nerve compression symptoms between July 1997 and July 2014. Potential risk factors were evaluated in univariate analysis for associations with local control; multivariate conditional logistic regression was used to identify the combined effects. Complications were recorded. The pre- and postoperative visual analogue scale of pain, Eastern Cooperative Oncology Group (ECOG) scores, and quality of life scores were collected to evaluate the impact of surgery. RESULTS: The cumulative survival rates were 71.8%, 41.1%, and 22.5% and the local control rates were 95.4%, 90.9%, and 79.4% at 6, 12, and 24 months, respectively. Tumors with rapid growth, the lack of preoperative radiotherapy, and application of aortic balloon occlusion were significantly associated with good local control. There were 29 (18.8%) complications related to surgery. The mean pain scores were 7.04 preoperatively, 1.66 at 1 month postoperatively (p = 0.003), and 1.51 at 3 months postoperatively (p = 0.002). The mean ECOG scores were 2.82 preoperatively and 1.47 3 months postoperatively (p < 0.001). There were significant improvements from preoperatively to 3 months postoperatively in global health status (43.3 vs. 52.1), pain (62.0 vs. 33.2), and constipation (51.4 vs. 30.3) (p < 0.001). CONCLUSIONS: Surgery for sacral metastasis is effective to palliate pain rapidly and improve constipation and quality of life and has a low rate of complications. PMID- 27992503 TI - Proteome Profile of Starch Granules Purified from Rice (Oryza sativa) Endosperm. AB - Starch is the most important food energy source in cereals. Many of the known enzymes involved in starch biosynthesis are partially or entirely granule associated in the endosperm. Studying the proteome of rice starch granules is critical for us to further understand the mechanisms underlying starch biosynthesis and packaging of starch granules in rice amyloplasts, consequently for the improvement of rice grain quality. In this article, we developed a protocol to purify starch granules from mature rice endosperm and verified the quality of purified starch granules by microscopy observations, I2 staining, and Western blot analyses. In addition, we found the phenol extraction method was superior to Tris-HCl buffer extraction method with respect to the efficiency in recovery of starch granule associated proteins. LC-MS/MS analysis showed identification of already known starch granule associated proteins with high confidence. Several proteins reported to be involved in starch synthesis in prior genetic studies in plants were also shown to be enriched with starch granules, either directly or indirectly, in our studies. In addition, our results suggested that a few additional candidate proteins may also be involved in starch synthesis. Furthermore, our results indicated that some starch synthesis pathway proteins are subject to protein acetylation modification. GO analysis and KEGG pathway enrichment analysis showed that the identified proteins were mainly located in plastids and involved in carbohydrate metabolism. This study substantially advances the understanding of the starch granule associated proteome in rice and post translational regulation of some starch granule associated proteins. PMID- 27992504 TI - PptAB Exports Rgg Quorum-Sensing Peptides in Streptococcus. AB - A transposon mutagenesis screen designed to identify mutants that were defective in peptide-pheromone signaling of the Rgg2/Rgg3 pathway in Streptococcus pyogenes generated insertions in sixteen loci displaying diminished reporter activity. Fourteen unique transposon insertions were mapped to pptAB, an ABC-type transporter recently described to export sex pheromones of Enterococcus faecalis. Consistent with an idea that PptAB exports signaling peptides, the pheromones known as SHPs (short hydrophobic peptides) were no longer detected in cell-free culture supernatants in a generated deletion mutant of pptAB. PptAB exporters are conserved among the Firmicutes, but their function and substrates remain unclear. Therefore, we tested a pptAB mutant generated in Streptococcus mutans and found that while secretion of heterologously expressed SHP peptides required PptAB, secretion of the S. mutans endogenous pheromone XIP (sigX inducing peptide) was only partially disrupted, indicating that a secondary secretion pathway for XIP exists. PMID- 27992505 TI - Neural Signatures of the Reading-Writing Connection: Greater Involvement of Writing in Chinese Reading than English Reading. AB - Research on cross-linguistic comparisons of the neural correlates of reading has consistently found that the left middle frontal gyrus (MFG) is more involved in Chinese than in English. However, there is a lack of consensus on the interpretation of the language difference. Because this region has been found to be involved in writing, we hypothesize that reading Chinese characters involves this writing region to a greater degree because Chinese speakers learn to read by repeatedly writing the characters. To test this hypothesis, we recruited English L1 learners of Chinese, who performed a reading task and a writing task in each language. The English L1 sample had learned some Chinese characters through character-writing and others through phonological learning, allowing a test of writing-on-reading effect. We found that the left MFG was more activated in Chinese than English regardless of task, and more activated in writing than in reading regardless of language. Furthermore, we found that this region was more activated for reading Chinese characters learned by character-writing than those learned by phonological learning. A major conclusion is that writing regions are also activated in reading, and that this reading-writing connection is modulated by the learning experience. We replicated the main findings in a group of native Chinese speakers, which excluded the possibility that the language differences observed in the English L1 participants were due to different language proficiency level. PMID- 27992506 TI - Menstrual Cycle Irregularity and Metabolic Disorders: A Population-Based Prospective Study. AB - The regularity of menstrual cycles is considered an indicator of women's reproductive health. Previous studies with a cross-sectional design have documented the relationship between menstrual cycle irregularities, insulin resistance and the future risks for metabolic disorders. Limited data documented by prospective studies can lead to premature conclusions regarding the relationship between menstrual cycle irregularities and other conditions influencing women's health. The present study therefore, using a prospective design aimed to assess the risk of metabolic disorders in women with a history of irregular menstrual cycles, was based on the data gathered from the Tehran Lipid and Glucose study (TLGS) an ongoing prospective cohort study initiated in 1999. Participants of the current study were 2128 women, aged between 18-49 years, followed for 15 years. Based on their menstrual cycles, the women were divided into two groups: (i) women with regular menstrual cycles (n = 1749), and (ii) those with irregular menstrual cycles (n = 379). The proportional COX regression model was used to compare hazard ratios (HRs) between the groups for the proposed events, including diabetes mellitus (DM), pre-diabetes (pre-DM), hypertension (HTN), pre-hypertension (pre-HTN) and dyslipidemia. It was found that during a 15 year follow up, there were 123 cases of DM, 456 cases of pre-DM, 290 cases of HTN, 481 cases of pre-HTN, and 402 cases of dyslipidemia. Compared to those with regular cycles, women with irregular menstrual cycles were found to have an increased risk for DM2 (age adjusted Hazard Ratios (HRs), 2.01; 95% confidence intervals (CI:1.59-3.50), the increased risk for DM, associated with irregular cycles remained significant after the adjustment for Body Mass Index (BMI), fasting blood sugar (FBS), family history of diabetes, and parity (HRS, 1.73; 95% CI: 1.14-2.64). There was no significant difference in the increased risk for pre DM between the groups (age adjusted HRs, 1.33, 95% CI: 1.05-1.69). However, after the adjustment of BMI, FBS and family history of pre-DM, compared to those with regular menstrual cycles, irregular menstrual cycles showed an increased risk for pre-DM (HRs, 1.33; 95% CI: 1.05-1.69). No statistically significant difference was found in the increasing risk for other proposed events between the groups demonstrating that menstrual cycle irregularities could be considered a marker of metabolic disorders and a predisposing factor of the increased risk for diabetes mellitus and pre-diabetes in women with irregular menstrual cycles. PMID- 27992508 TI - Disentangling of Malignancy from Benign Pheochromocytomas/Paragangliomas. AB - OBJECTIVE: Many malignant tumors initially appear benign but subsequently exhibit extensive metastases. Early identification of malignant pheochromocytomas and paragangliomas (PPGLs) before metastasis is important for improved prognosis. However, there are no robust prognostic indices of recurrence and malignancy. The aim of this study was to identify the clinical and histopathological factors that predict malignant PPGLs. DESIGN: Retrospective follow-up study. METHODS: In this study, we included 223 patients with pathologically confirmed PPGLs who were treated between 2000 and 2015 at the Seoul National University Hospital in South Korea. RESULTS: Of these patients, 29 were diagnosed with malignancy, 12 of whom presented with metastatic lesions at the initial diagnosis while 17 developed metastases during follow-up. Nineteen patients with recurrent PPGLs consisted of ones with malignant PPGLs (n = 17) and multifocal PPGLs (n = 2) who had VHL and RET mutations. The mean age at presentation for malignant PPGLs was significantly younger than that for benign PPGLs (43.0 vs. 49.0 years, respectively; p = 0.023). Tumor size was not a distinguishing factor between malignant and benign PPGLs (5.0 vs. 4.5 cm, respectively; p = 0.316) nor did it predict recurrence. Of 119 patients with available pheochromocytoma of adrenal gland scaled score (PASS) data, those with malignant PPGLs presented PASS values >=4. Of 12 parameters of PASS, necrosis, capsular invasion, vascular invasion, cellular monotony, high mitosis, atypical mitotic figures, and nuclear hyperchromasia were significant predictors of malignancy. CONCLUSIONS: Tumor size did not predict malignancy or recurrence of PPGLs. PPGL patients with characteristic pathologic findings and PASS >=4 or germline mutations require close follow-up. PMID- 27992507 TI - TRPC4alpha and TRPC4beta Similarly Affect Neonatal Cardiomyocyte Survival during Chronic GPCR Stimulation. AB - The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca2+ component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na+ and Ca2+ influx. Galphaq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca2+ influx which has been regarded as ideal Ca2+ source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation. Functional properties of TRPC4 are also based on the expression of the TRPC4 splice variants TRPC4alpha and TRPC4beta. Aim of the present study was to analyze cytosolic Ca2+ signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4alpha or TRPC4beta. The analysis of Ca2+ transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4alpha and TRPC4beta affected Ca2+ cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca2+ transient amplitude at baseline and TRPC4beta increasing the Ca2+ peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4beta (Ad C4beta) also responded with a sustained Ca2+ influx when treated with Ang II under non-pacing conditions. Consistent with the Ca2+ data, NRCs infected with TRPC4alpha (Ad-C4alpha) showed an elevated calcineurin/NFAT activity and a baseline hypertrophic phenotype but did not further develop hypertrophy during chronic Ang II/phenylephrine stimulation. Down-regulation of endogenous TRPC4alpha reversed these effects, resulting in less hypertrophy of NRCs at baseline but a markedly increased hypertrophic enlargement after chronic agonist stimulation. Ad-C4beta NRCs did not exhibit baseline calcineurin/NFAT activity or hypertrophy but responded with an increased calcineurin/NFAT activity after GPCR stimulation. However, this effect was not translated into an increased propensity towards hypertrophy but rather less hypertrophy during GPCR stimulation. Further analyses revealed that, although hypertrophy was preserved in Ad-C4alpha NRCs and even attenuated in Ad-C4beta NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4alpha and TRPC4beta differentially affect Ca2+ signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation. PMID- 27992509 TI - Palonosetron and Ramosetron Compared for Effectiveness in Preventing Postoperative Nausea and Vomiting: A Systematic Review and Meta-Analysis. AB - Previous randomized controlled trials have reported conflicting findings on the superiority of palonosetron over ramosetron for preventing postoperative nausea and vomiting (PONV). Therefore, the present systematic review was registered in PROSPERO (CRD42016038120) and performed to compare the efficacy of perioperative administration of palonosetron to that of ramosetron for preventing PONV. We searched MEDLINE, EMBASE, and CENTRAL to identify all randomized controlled trials that compared the effectiveness of perioperative administration of palonosetron to that of ramosetron. The primary endpoints were defined as the incidence of postoperative nausea (PON), postoperative vomiting (POV), and PONV. A total of 695 patients were included in the final analysis. Subgroup analysis was performed through administration times which were divided into two phases: the early phase of surgery and the end of surgery. Combined analysis did not show differences between palonosetron and ramosetron in the overall incidence of PON, POV or PONV. Palonosetron was more effective than ramosetron, when the administration time for the 5-HT3 receptor antagonist was during the early phase of the operation. Otherwise, ramosetron was more effective than palonosetron, when the administration time was at the end of surgery. However, the quality of evidence for each outcome was low or very low and number of included studies was small, limiting our confidence in findings. PMID- 27992510 TI - Noradrenaline Improves Behavioral Contrast Sensitivity via the beta-Adrenergic Receptor. AB - Noradrenaline (NA) is released from the locus coeruleus in the brainstem to almost the whole brain depending on the physiological state or behavioral context. NA modulates various brain functions including vision, but many questions about the functional role of its effects and mechanisms remain unclear. To explore these matters, we focused on three questions, 1) whether NA improves detectability of a behavior-relevant visual stimulus, 2) which receptor subtypes contribute to the NA effects, and 3) whether the NA effects are specific for visual features such as spatial frequency (SF). We measured contrast sensitivity in rats by a two-alternative forced choice visual detection task and tested the effects of NA receptor blockers in three SF conditions. Propranolol, a beta adrenergic receptor inhibitor, significantly decreased contrast sensitivity, but neither prazosin nor idazoxan, alpha1- and alpha2-adrenergic receptor inhibitors, respectively, had an effect. This beta blocker effect was observed only at optimal SF. These results indicate that endogenous NA enhances visual detectability depending on stimulus spatial properties via mainly beta-adrenergic receptors. PMID- 27992511 TI - Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice. AB - Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 MUg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p < 0.05) and reduced kidney inflammation in NX mice. There was no effect of liraglutide on expression of fibrosis markers and/or kidney histology. This study suggests that liraglutide has beneficial effects in a mouse model of moderate uremia by reducing atherosclerosis and attenuating kidney inflammation. PMID- 27992513 TI - Permanent Data Storage in ZnO Thin Films by Filamentary Resistive Switching. AB - Resistive memories are considered the most promising candidates for the next generation of non-volatile memory; however, attention has so far been limited to rewritable memory features for applications in resistive random access memories (RRAM). In this article, we provide a new insight into the applicability of resistive memories. The characteristics of non-rewritable resistive memories (NRRM) were investigated. Devices with Pt/ZnO/ITO architecture were prepared using magnetron sputtering, upon which various bipolar and unipolar resistive switching tests were performed. The results showed excellent distinction between the high resistance state (HRS) and low resistance state (LRS), with RHRS/RLRS = 5.2 * 1011 for the Pt/ZnO/ITO device with deposition time of 1 h. All samples were stable for more than 104 s, indicating that the devices have excellent applicability in NRRMs. PMID- 27992512 TI - 68Ga-TRAP-(RGD)3 Hybrid Imaging for the In Vivo Monitoring of alphavbeta3 Integrin Expression as Biomarker of Anti-Angiogenic Therapy Effects in Experimental Breast Cancer. AB - OBJECTIVES: To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of alphavbeta3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. MATERIALS AND METHODS: Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (alphavbeta3-integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). RESULTS: 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab treated animals (DeltaTBRfollow-up/baseline: therapy -1.07+/-0.83, control +0.32+/-1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Deltavolumetherapy 134+/-77 MUL, Deltavolumecontrol 132+/-56 MUL, p = 1.000). Immunohistochemistry revealed a significant reduction of alphavbeta3-integrin expression (308+/-135 vs. 635+/ 325, p = 0.03), microvascular density (CD31, 168+/-108 vs. 432+/-70, p = 0.002), proliferation (Ki-67, 5,195+/-1,002 vs. 7,574+/-418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432+/-1,974 vs. 3,776+/-1,378, p = 0.002) in the therapy compared to the control group. CONCLUSIONS: 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of alphavbeta3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. PMID- 27992514 TI - Induction of Skin-Derived Precursor Cells from Human Induced Pluripotent Stem Cells. AB - The generation of full thickness human skin from dissociated cells is an attractive approach not only for treating skin diseases, but also for treating many systemic disorders. However, it is currently not possible to obtain an unlimited number of skin dermal cells. The goal of this study was to develop a procedure to produce skin dermal stem cells from induced pluripotent stem cells (iPSCs). Skin-derived precursor cells (SKPs) were isolated as adult dermal precursors that could differentiate into both neural and mesodermal progenies and could reconstitute the dermis. Thus, we attempted to generate SKPs from iPSCs that could reconstitute the skin dermis. Human iPSCs were initially cultured with recombinant noggin and SB431542, an inhibitor of activin/nodal and TGFbeta signaling, to induce neural crest progenitor cells. Those cells were then treated with SKP medium that included CHIR99021, a WNT signal activator. The induction efficacy from neural crest progenitor cells to SKPs was more than 97%. No other modifiers tested were able to induce those cells. Those human iPSC-derived SKPs (hiPSC-SKPs) showed a similar gene expression signature to SKPs isolated from human skin dermis. Human iPSC-SKPs differentiated into neural and mesodermal progenies, including adipocytes, skeletogenic cell types and Schwann cells. Moreover, they could be induced to follicular type keratinization when co cultured with human epidermal keratinocytes. We here provide a new efficient protocol to create human skin dermal stem cells from hiPSCs that could contribute to the treatment of various skin disorders. PMID- 27992515 TI - Using the Three Delays Model to Examine Civil Registration Barriers in Indonesia. AB - The Three Delays Model has proven a useful framework for examining barriers to seeking obstetric care and preventing maternal and child mortality. This article demonstrates the applicability of the Three Delays Model to the case of civil registration in rural Indonesia and examines ways that efforts to strengthen civil registration services can draw on lessons from maternal and child health programming. Twenty focus group discussions were conducted using a participatory ranking exercise in four Indonesian districts. Focus groups were stratified into four groups: (1) government officials involved in civil registration, (2) civil society organization members that assist communities in civil registration, and (3) female and (4) male community members. Transcripts were analyzed using constant comparative method and thematic analysis, revealing barriers that communities commonly faced in accessing civil registration services. In examining the categories and themes related to these barriers, the research team found a significant overlap with the factors and phases of the Three Delays Model. Participants were delayed from seeking registration services by a range of sociocultural factors and by the perceived inaccessibility and poor quality of services. Once they decided to seek care, long distances to services and poor transportation options delayed their access to registration offices. Finally, a series of bottlenecks in service provision created extended delays once applicants reached registration offices. Ownership of civil registration documents in Indonesia remains exceptionally low, with just over half of children and youth possessing a birth certificate. To strengthen civil registration and health systems more generally, it is important to understand the factors that enable and constrain civil registration, how these factors relate to one another, and how they change over a child's life. PMID- 27992516 TI - Do David and Goliath Play the Same Game? Explanation of the Abundance of Rare and Frequent Invasive Alien Plants in Urban Woodlands in Warsaw, Poland. AB - Invasive Alien Plants occur in numbers differing by orders of magnitude at subsequent invasion stages. Effective sampling and quantifying niches of rare invasive plants are quite problematic. The aim of this paper is an estimation of the influence of invasive plants frequency on the explanation of their local abundance. We attempted to achieve it through: (1) assessment of occurrence of self-regenerating invasive plants in urban woodlands, (2) comparison of Random Forest modelling results for frequent and rare species. We hypothesized that the abundance of frequent species would be explained better than that of rare ones and that both rare and frequent species share a common hierarchy of the most important determinants. We found 15 taxa in almost two thirds of 1040 plots with a total number of 1068 occurrences. There were recorded 6 taxa of high frequency Prunus serotina, Quercus rubra, Acer negundo, Robinia pseudoacacia, Impatiens parviflora and Solidago spp.-and 9 taxa of low frequency: Acer saccharinum, Amelanchier spicata, Cornus spp., Fraxinus spp., Parthenocissus spp., Syringa vulgaris, Echinocystis lobata, Helianthus tuberosus, Reynoutria spp. Random Forest's models' quality grows with the number of occurrences of frequent taxa but not of the rare ones. Both frequent and rare taxa share a similar hierarchy of predictors' importance: Land use > Tree stand > Seed source and, for frequent taxa, Forest properties as well. We conclude that there is an 'explanation jump' at higher species frequencies, but rare species are surprisingly similar to frequent ones in their determinant's hierarchy, with differences conforming with their respective stages of invasion. PMID- 27992517 TI - Heritability of Boldness and Hypoxia Avoidance in European Seabass, Dicentrarchus labrax. AB - To understand the genetic basis of coping style in European seabass, fish from a full factorial mating (10 females x 50 males) were reared in common garden and individually tagged. Individuals coping style was characterized through behavior tests at four different ages, categorizing fish into proactive or reactive: a hypoxia avoidance test (at 255 days post hatching, dph) and 3 risk-taking tests (at 276, 286 and 304 dph). We observed significant heritability of the coping style, higher for the average of risk-taking scores (h2 = 0.45 +/- 0.14) than for the hypoxia avoidance test (h2 = 0.19 +/- 0.10). The genetic correlations between the three risk-taking scores were very high (rA = 0.96-0.99) showing that although their repeatability was moderately high (rP = 0.64-0.72), successive risk-taking tests evaluated the same genetic variation. A mild genetic correlation between the results of the hypoxia avoidance test and the average of risk-taking scores (0.45 +/- 0.27) suggested that hypoxia avoidance and risk taking tests do not address exactly the same behavioral and physiological responses. Genetic correlations between weight and risk taking traits showed negative values whatever the test used in our population i.e. reactive individual weights were larger. The results of this quantitative genetic analysis suggest a potential for the development of selection programs based on coping styles that could increase seabass welfare without altering growth performances. Overall, it also contributes to a better understanding of the origin and the significance of individual behavioral differences. PMID- 27992518 TI - Tracing Sources and Contamination Assessments of Heavy Metals in Road and Foliar Dusts in a Typical Mining City, China. AB - Road and foliar dust samples from four land-use districts of Panzhihua City, a famous V-Ti magnetite production area of China, were collected to investigate the sources and distribution characteristics of 9 heavy metals (V, Pb, Cd, Cu, Zn, Ni, Cr, Fe, and Mn). The results suggest that foliar samples had smaller particle size and higher heavy metal contents than road dusts. The contamination assessments of heavy metals were as follows: Pb and V (significant enrichment) > Zn, Ni, Cr, Fe, and Mn (moderate enrichment) > Cd and Ni (minimal enrichment). Statistical analyses showed Pb, as the primary pollution element, originated from waste incineration and lead-fuel combustion. The sources of Zn, Ni, Cr, Fe, V, and Mn were fugitive dust and traffic activities. Potential origins of Cu were corrosion of alloys used in vehicle components, vehicle covers, or other metallic surfaces and materials. The sources of Cd were different from any other heavy metals. Traffic and industrial activities were the main anthropogenic origins of heavy metals in dusts of Panzhihua, and more attention should be paid to heavy metal pollution in agricultural area. PMID- 27992520 TI - Surgical Outcome of Idiopathic Epiretinal Membranes with Intraretinal Cystic Spaces. AB - OBJECTIVE: To investigate the occurrence ratio, localization, and surgical outcomes of intraretinal cystic spaces in idiopathic epiretinal membranes (ERMs). METHODS: We retrospectively reviewed the charts of 432 eyes of 398 consecutive patients with idiopathic ERM who underwent vitrectomy and ERM peeling from January 2012 to September 2015. We selected cases with intraretinal cystic space prior to surgery, detected by spectral-domain optical coherence tomography. We then evaluated the effects of ERM peeling on intraretinal cystic spaces, best corrected visual acuity, and central retinal thickness at 6 months after surgery. RESULTS: Twenty-four eyes (5.5%) showed intraretinal cystic spaces before surgery, present in the inner retinal layer (the inner group) in 9 eyes, in the outer retinal layer (the outer group) in 6 eyes, and in both the inner and the outer retinal layers (the combined group) in 9 eyes. Additionally, 30 eyes with ERM but without any presence of intraretinal cystic space were selected randomly and classified as the no cyst group. At 6 months after surgery, the disappearance rate of cystic spaces was significantly greater for the outer group than for the inner group (83.3% and 11.1%, respectively, P = 0.011). The mean best corrected visual acuity improved significantly after surgery in the inner group, the outer group, and the no cyst group (P < 0.05 for all three groups) but did not improve in the combined group (P = 0.58). The mean central retinal thickness decreased significantly after surgery in the inner group, the combined group, and the no cyst group (P < 0.05). CONCLUSIONS: Intraretinal cystic spaces were observed in 5.5% of preoperative idiopathic ERM cases. Following surgery, the cystic spaces in the outer retinal layer disappeared at higher rates than those in the inner retinal layer, suggesting that the pathophysiologies of these cystic spaces are different. PMID- 27992519 TI - Site-Dependent Differences in DNA Methylation and Their Impact on Plant Establishment and Phosphorus Nutrition in Populus trichocarpa. AB - The propagation via clonal stem cuttings is a frequent practice in tree plantations. Despite their clonal origin, the trees establish differently according to weather, temperature and nutrient availability, as well as the presence of various stresses. Here, clonal Populus trichocarpa (cv. Muhle Larson) cuttings from different sites were transferred into a common, fully nutrient supplied environment. Despite identical underlying genetics, stem cuttings derived from sites with lower phosphorus availability established worse, independent of phosphorus (P) level after transplantation. Differential growth of material from the sites was reflected in differences in the whole genome DNA methylome. Methylation differences were sequence context-dependent, but differentially methylated regions (DMRs) were apparently unrelated to P nutrition genes. Despite the undisputed negative general correlation of DNA promoter methylation with gene repression, only few of the top-ranked DMRs resulted in differential gene expression in roots or shoots. However, differential methylation was associated with site-dependent, different total amounts of microRNAs (miRNAs), with few miRNAs sequences directly targeted by differential methylation. Interestingly, in roots and shoots, the miRNA amount was dependent on the previous habitat and changed in roots in a habitat-dependent way under phosphate starvation conditions. Differentially methylated miRNAs, together with their target genes, showed P-dependent expression profiles, indicating miRNA expression differences as a P-related epigenetic modification in poplar. Together with differences in DNA methylation, such epigenetic mechanisms may explain habitat or seasonal memory in perennials and site-dependent growth performances. PMID- 27992521 TI - Evaluation of the Xpert Carba-R (Cepheid) Assay Using Contrived Bronchial Specimens from Patients with Suspicion of Ventilator-Associated Pneumonia for the Detection of Prevalent Carbapenemases. AB - There is a critical need for rapid diagnostic methods for multidrug-resistant (MDR) pathogens in patients with a suspicion of ventilator-associated pneumonia (VAP). The Xpert Carba-R detects 5 targets for carbapenemase-producing organisms (blaKPC, blaNDM, blaVIM, blaOXA-48, and blaIMP-1). Our objective was to evaluate the performance of this assay directly on bronchial aspirates and to correlate the cycle number for a positive result (Ct) with the bacterial count. Bronchial aspirates from patients with a suspicion of VAP were spiked with a dilution of 1 of 4 MDR organisms carrying the resistance genes detected by the test prepared to a final concentration of 102-105 cfu/mL. We used a ROC curve and provided areas under the curve (AUC) with their 95% confidence intervals (CI). A point of maximum sensitivity (Se) and specificity (Sp) was derived and validity indices were calculated. One hundred contrived tests were performed. Se and Sp were 100% for all bacterial counts. A positive sample with a Ct <=24.7 corresponded to a count >=105 cfu/mL; if the Ct was within the range >24.7-<=26.9, this corresponded to a count >=104 cfu/mL. When the Ct was >26.9, this corresponded to a count <104 cfu/mL. The Xpert Carba-R detects carbapenemase-producing organisms directly in contrived bronchial aspirates. Still, an important issue to consider is that the number of gene copies may vary according to many factors in vivo. If confirmed in further studies, the strong correlation observed between Ct values and the results of semiquantitative cultures suggests this test could serve to differentiate between infection and colonization in routine clinical practice. PMID- 27992522 TI - The Degradation Pathway of the Mitophagy Receptor Atg32 Is Re-Routed by a Posttranslational Modification. AB - The outer mitochondrial membrane protein Atg32 is the central receptor for mitophagy, the mitochondria-specific form of autophagy. Atg32 is an unstable protein, and is rapidly degraded under conditions in which mitophagy is not induced. Here we show that Atg32 undergoes a posttranslational modification upon induction of mitophagy. The modification is dependent on the core autophagic machinery, including Atg8, and on the mitophagy-specific adaptor protein Atg11. The modified Atg32 is targeted to the vacuole where it becomes stabilized when vacuolar proteases are deficient. Interestingly, we find that this degradation pathway differs from the degradation pathway of non-modified Atg32, which neither involves vacuolar proteases, nor the proteasome. These analyses reveal that a posttranslational modification discriminates a form of Atg32 targeting mitochondria for mitophagy from that, which escapes mitophagy by rapid degradation. PMID- 27992524 TI - Optical Coherence Tomographic Features and Prognosis of Pneumatic Displacement for Submacular Hemorrhage. AB - PURPOSE: To identify prognostic factors, including optical coherence tomographic features, of visual outcome in exudative age-related macular degeneration with submacular hemorrhage treated with pneumatic displacement. METHODS: This retrospective interventional case series included 37 eyes with exudative age related macular degeneration and submacular hemorrhage, all of which underwent pneumatic displacement. The best-corrected visual acuity (BCVA) was measured at diagnosis and at 3 and 6 months after treatment. In addition to demographic and funduscopic parameters, tomographic features such as reflectance of the submacular hemorrhage were analyzed with regard to BCVA at 6 months. RESULTS: After pneumatic displacement and a subsequent treatment such as laser or anti vascular endothelial growth factor therapy, the BCVA at 3 and 6 months improved significantly (P < 0.001, respectively). Higher baseline BCVA (P < 0.001), shorter symptom duration (P = 0.007), and younger age (P = 0.014) were significant positive prognostic factors on regression analysis. Among optical coherence tomography characteristics, reflectance of the submacular hemorrhage, the shortest radius of the submacular hemorrhage centered on the fovea, and defects in the ellipsoid zone, and external limiting membrane affected the BCVA at 6 months (P < 0.05). CONCLUSION: A favorable visual outcome was demonstrated after initial pneumatic displacement and subsequent treatment for submacular hemorrhage. The submacular hemorrhages exhibiting lower reflectance on optical coherence tomography and a smaller shortest radius from the foveal center were found to be good candidates for pneumatic displacement. PMID- 27992525 TI - The Combined Effect of High Ambient Temperature and Antihypertensive Treatment on Renal Function in Hospitalized Elderly Patients. AB - BACKGROUND: The aging kidney manifests structural, functional as well as pharmacological changes, rendering elderly patients more susceptible to adverse environmental influences on their health, dehydration in particular. HYPOTHESIS: Higher temperature is associated with renal function impairment in patients 65 years and older who routinely take thiazide and/or ACE-inhibitors/ARBs. METHODS: We obtained health data of patients older than 65 who were admitted to a large tertiary center during the years 2006-2011, with a previous diagnosis of hypertension, and treated with thiazide, ACE-inhibitors/ARBs or both. We collected environmental data of daily temperature, available from collaborative public and governmental institutions. In order to estimate the effect of daily temperature on renal function we performed linear mixed models, separately for each treatment group and creatinine change during hospital admission. RESULTS: We identified 26,286 admissions for 14, 268 patients with a mean age of 75.6 (+/ 6.9) years, of whom 53.6% were men. Increment in daily temperature on admission of 5 degrees C had significant effect on creatinine increase in the no treatment (baseline creatinine adjusted 0.824 mg/dL, % change 1.212, % change 95% C.I 0.082 2.354) and dual treatment groups (baseline creatinine adjusted 1.032mg/dL, % change 3.440, % change 95% C.I 1.227-5.700). Sub-analysis stratified by advanced age, chronic kidney disease and primary diagnosis on hospital admission, revealed a significant association within patients admitted due to acute infection and treated with dual therapy. CONCLUSION: Whereas previous studies analyzed sporadic climate effects during heat waves and/or excluded older population taking anti hypertensive medications, the present study is novel by showing a durable association of temperature and decreased renal function specifically in elderly patients taking anti-hypertensive medications. PMID- 27992526 TI - 3'UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients. AB - Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3'-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69 5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a "risk genotype" of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC. PMID- 27992527 TI - First Report of Group CTX-M-9 Extended Spectrum Beta-Lactamases in Escherichia coli Isolates from Pediatric Patients in Mexico. AB - The aim of this study was to identify the presence of group CTX-M-9 extended spectrum beta-lactamases (ESBL) in clinical Escherichia coli isolates from pediatric patients. A total of 404 non-repeated positive ESBL E. coli isolates were collected from documented clinical infections in pediatric patients over a 2 year period. The identification and susceptibility profiles were determined using an automated system. Isolates that suggested ESBL production based on their resistance profiles to third and fourth generation cephalosporin and monobactam were selected. ESBL production was phenotypically confirmed using a diffusion method with cefotaxime and ceftazidime discs alone and in combination with clavulanic acid. blaESBL gene identification was performed through PCR amplification and sequencing. Pulsed Field Gel Electrophoresis (PFGE) and Multilocus Sequence Typing (MLST) were performed to establish the clonal relationships of the E. coli isolates. CTX-M-9-type ESBLs were detected in 2.5% of the isolates. The subtypes corresponded to blaCTX-M-14 (n = 4) and blaCTX-M-27 (n = 6). Additionally, coexistence with other beta-lactamases was observed. A clonal relationship was established in three isolates; the rest were classified as non-related. We found seven different sequence type (ST) in CTX-M-9- producing E. coli isolates. ST38 was the most frequent. This study is the first report in Mexico to document the presence of group CTX-M-9 ESBLs in E. coli isolates from pediatric patients. PMID- 27992523 TI - Diversity of Staphylococcus aureus Isolates in European Wildlife. AB - Staphylococcus aureus is a well-known colonizer and cause of infection among animals and it has been described from numerous domestic and wild animal species. The aim of the present study was to investigate the molecular epidemiology of S. aureus in a convenience sample of European wildlife and to review what previously has been observed in the subject field. 124 S. aureus isolates were collected from wildlife in Germany, Austria and Sweden; they were characterized by DNA microarray hybridization and, for isolates with novel hybridization patterns, by multilocus sequence typing (MLST). The isolates were assigned to 29 clonal complexes and singleton sequence types (CC1, CC5, CC6, CC7, CC8, CC9, CC12, CC15, CC22, CC25, CC30, CC49, CC59, CC88, CC97, CC130, CC133, CC398, ST425, CC599, CC692, CC707, ST890, CC1956, ST2425, CC2671, ST2691, CC2767 and ST2963), some of which (ST2425, ST2691, ST2963) were not described previously. Resistance rates in wildlife strains were rather low and mecA-MRSA isolates were rare (n = 6). mecC MRSA (n = 8) were identified from a fox, a fallow deer, hares and hedgehogs. The common cattle-associated lineages CC479 and CC705 were not detected in wildlife in the present study while, in contrast, a third common cattle lineage, CC97, was found to be common among cervids. No Staphylococcus argenteus or Staphylococcus schweitzeri-like isolates were found. Systematic studies are required to monitor the possible transmission of human- and livestock-associated S. aureus/MRSA to wildlife and vice versa as well as the possible transmission, by unprotected contact to animals. The prevalence of S. aureus/MRSA in wildlife as well as its population structures in different wildlife host species warrants further investigation. PMID- 27992528 TI - Colistin Dosage without Loading Dose Is Efficacious when Treating Carbapenem Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia Caused by Strains with High Susceptibility to Colistin. AB - OBJECTIVES: This study aims to analyze the mortality and the length of ICU stay (LOS) of A. baumannii VAP compared to respiratory colonization in patients with mechanical ventilation (MV). METHODS: A prospective cohort study was performed in an ICU of adult patients (February 2010-June 2011). One hundred patients on MV with A. baumannii in lower respiratory airways were recruited, and classified as VAP or airways colonization according to CPIS criteria, with a punctuation >=6. LOS, 30-days mortality, A. baumannii bacteremia, and clinical features including antibiotic therapy were recorded. Multivariate analysis (linear and Cox regression) and survival analysis (Kaplan-Meier curves) were performed. RESULTS: Fifty-seven VAP and 43 colonized A. baumannii patients were analyzed. Among the A. baumannii strains, 99% were non-susceptible to carbapenems and the MIC90 of colistin was 0.12 mg/l. Therapy was appropriate in 94.6% of VAP patients, most of them with colistin 6 MIU/day, although in 13 (23.6%) cases colistin was started 48 hours after the onset of VAP. Mortality was similar in both groups (VAP 24.6% vs. colonized 27.9%, p = 0.7). Bacteremia and acute kidney insufficiency were associated with decreased survival (p = 0.02 and p = 0.04, respectively) in VAP patients. LOS was 21.5 (11.5-42.75) vs. 9 (6-22) days for VAP and colonized patients (p = 0.004). VAP (p = 0.003) and age (p = 0.01) were independently related to a longer LOS. CONCLUSIONS: Multidrug-resistant A. baumannii VAP treated with colistin does not have a different mortality compared to lower airways colonization, among patients on mechanical-ventilation, in a setting of high susceptibility to colistin of A. baumannii. PMID- 27992529 TI - Exposure of Bacterial Biofilms to Electrical Current Leads to Cell Death Mediated in Part by Reactive Oxygen Species. AB - Bacterial biofilms may form on indwelling medical devices such as prosthetic joints, heart valves and catheters, causing challenging-to-treat infections. We have previously described the 'electricidal effect', in which bacterial biofilms are decreased following exposure to direct electrical current. Herein, we sought to determine if the decreased bacterial quantities are due to detachment of biofilms or cell death and to investigate the role that reactive oxygen species (ROS) play in the observed effect. Using confocal and electron microscopy and flow cytometry, we found that direct current (DC) leads to cell death and changes in the architecture of biofilms formed by Gram-positive and Gram-negative bacteria. Reactive oxygen species (ROS) appear to play a role in DC-associated cell death, as there was an increase in ROS-production by Staphylococcus aureus and Staphylococcus epidermidis biofilms following exposure to DC. An increase in the production of ROS response enzymes catalase and superoxide dismutase (SOD) was observed for S. aureus, S. epidermidis and Pseudomonas aeruginosa biofilms following exposure to DC. Additionally, biofilms were protected from cell death when supplemented with antioxidants and oxidant scavengers, including catalase, mannitol and Tempol. Knocking out SOD (sodAB) in P. aeruginosa led to an enhanced DC effect. Microarray analysis of P. aeruginosa PAO1 showed transcriptional changes in genes related to the stress response and cell death. In conclusion, the electricidal effect results in death of bacteria in biofilms, mediated, at least in part, by production of ROS. PMID- 27992530 TI - Anti-Inflammatory Effects of Rosiglitazone in Obesity-Impaired Wound Healing Depend on Adipocyte Differentiation. AB - Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Kruppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-gamma and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-gamma, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1beta/TNF-alpha) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-gamma, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-gamma agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-gamma activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-gamma might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions. PMID- 27992531 TI - Health-Related Quality of Life Impairment and Indirect Cost of Crohn's Disease: A Self-Report Study in Poland. AB - BACKGROUND AND AIMS: Evidence on indirect cost of Crohn's disease (CD) is available but typically provides information on the loss of productivity at paid work of patients. In the present study, the quality of life and indirect costs of CD patients were assessed (overall and by disease severity). METHODS: A self report questionnaire-based study among adult Polish patients with CD was performed. We collected data on patients' characteristics, quality of life, loss of productivity, consumption of medical resources, and out-of-pocket expenses. The disease severity was determined using the patient's version of the Harvey Bradshaw index. Productivity costs were assessed from the social perspective, using a human capital approach. The cost of absenteeism, presenteeism and permanent work disability was valuated using the gross domestic product per worker. The patients' productivity loss at unpaid work was measured by time inputs of others to assist patients. The productivity loss among informal caregivers and patients' productivity loss at unpaid work were valuated with the average wage in Poland. The results were adjusted for confounders. RESULTS: The responses from 200 patients (47% in remission) were analysed. The mean utility index was 0.839 (SD 0.171). The total indirect cost was estimated at ?462.47 per patient per month (24.0%, absenteeism; 35.0%, work disability; 30.4%, presenteeism; 0.4%, productivity loss at unpaid work; and 10.4%, informal care). A significant correlation of the quality of life and productivity losses with disease severity was observed. Compared with active disease, the remission subgroup had a higher utility index by 16% (p<0.001) and lower indirect costs by 71% (p = 0.003) for absenteeism, 41% (p = 0.030) for presenteeism, 76% (p<0.001) for productivity loss at unpaid work, and 75% (p<0.001) for informal care. CONCLUSIONS: Our study revealed the social burden of CD and high dependency of indirect costs and quality of life on the severity of CD in Poland. PMID- 27992532 TI - What's the Optimal Lipids Level for Dialysis Patients? A Cohort Study from a Chinese Dialysis Center in a University Hospital. AB - BACKGROUND: With lipid level being a major contributing factor for cardiovascular health, the high cardiovascular mortality among dialysis patients has raised substantial concerns in regard to the optimal lipid level in these patient population. OBJECTIVE: To explore the optimal lipid level for the survival of dialysis patients. METHODS: The lipid profile was measured for each patient. All participants were followed throughout the course of the study. Cox proportional hazards analysis was performed to analyze the prognostic value of lipid level on the survival of these patients. RESULTS: In our study that included 311 stable maintenance dialysis patients, 54.98% of the participants had LDL-C level >=100 mg/dl and 82.91% of the patients with triglycerides >=200 mg/dl had non-HDL level >=130 mg/dl. During the follow-up period of 48.0 (18.0, 55.5) months, 149 (47.91%) participants died. Among those who died, 59 patients died of cardiovascular disease (CVD) and 33 patients died of ischemic CVD (12.0, 4.7, and 2.7 events per 100 patient-years, respectively). Patients with LDL-C 100-130 mg/dl or non-HDL 130-160 mg/dl had a lower all-cause mortality rate than those who did not meet these criteria. After adjusting for the traditional and ESRD related risk factors, non-HDL was found to be the independent risk factor for the all-cause mortality. Compared to those patients with non-HDL 130-160 mg/dl, patients with non-HDL <100 mg/dl, 100-130 mg/dl, 160-190 mg/dl, or >=190 mg/dl all had higher all-cause mortality: HR (95% CI) 3.207 (1.801, 5.713), 2.493 (1.485, 4.184), 2.476 (1.423, 4.307), and 1.917 (1.099, 3.345), respectively. There were no differences in nutrition, comorbidity, and inflammation indices among the patients with different non-HDL groups. However, patients with non-HDL of 130-160 mg/dl had the lowest corrected calcium and calcium phosphate product values as compared with other non-HDL groups. CONCLUSION: Our study demonstrated that non-HDL 130-160 mg/dl might be the most appropriate lipid level in our dialysis patients. Our follow-up data also showed that patients with higher lipid level had poorer prognosis, just as in the general population. PMID- 27992533 TI - Grey Matter Microstructural Integrity Alterations in Blepharospasm Are Partially Reversed by Botulinum Neurotoxin Therapy. AB - OBJECTIVE: Benign Essential Blepharospasm (BEB) and hemifacial spasm (HFS) are the most common hyperkinetic movement disorders of facial muscles. Although similar in clinical presentation different pathophysiological mechanisms are assumed. Botulinum Neurotoxin (BoNT) is a standard evidence-based treatment for both conditions. In this study we aimed to assess grey matter microstructural differences between these two groups of patients and compared them with healthy controls. In patients we furthermore tracked the longitudinal morphometric changes associated with BoNT therapy. We hypothesized microstructural differences between the groups at the time point of maximum symptoms representation and distinct longitudinal grey matter dynamics with symptom improvement. METHODS: Cross-sectional and longitudinal analyses of 3T 3D-T1 MRI images from BEB, HFS patients prior to and one month after BoNT therapy and from a group of age and sex matched healthy controls. Cortical thickness as extracted from Freesurfer was assessed as parameter of microstructural integrity. RESULTS: BoNT therapy markedly improved motor symptoms in patients with BEB and HFS. Significant differences of grey matter integrity have been found between the two patients groups. The BEB group showed lower cortical thickness at baseline in the frontal rostral, supramarginal and temporal regions compared to patients with HFS. In this group BoNT treatment was associated with a cortical thinning in the primary motor cortex and the pre-supplementary motor area (pre-SMA). Contrary patients with HFS showed no longitudinal CT changes. A decreased cortical thickness was attested bilaterally in the temporal poles and in the right superior frontal region in BEB patients in comparison to HC. Patients in the HFS group presented a decreased CT in the left lingual gyrus and temporal pole. CONCLUSIONS: Although patients with BEB and HFS present clinically with involuntary movements of facial muscles, they exhibited differences in cortical thickness. While BoNT therapy was equally effective in both groups, widespread changes of cortical morphology occurred only in BEB patients. We demonstrated specific disease- and therapy dependent structural changes induced by BoNT in the studied hyperkinetic conditions. PMID- 27992534 TI - The Pig: A Relevant Model for Evaluating the Neutrophil Serine Protease Activities during Acute Pseudomonas aeruginosa Lung Infection. AB - The main features of lung infection and inflammation are a massive recruitment of neutrophils and the subsequent release of neutrophil serine proteases (NSPs). Anti-infectious and/or anti-inflammatory treatments must be tested on a suitable animal model. Mice models do not replicate several aspects of human lung disease. This is particularly true for cystic fibrosis (CF), which has led the scientific community to a search for new animal models. We have shown that mice are not appropriate for characterizing drugs targeting neutrophil-dependent inflammation and that pig neutrophils and their NSPs are similar to their human homologues. We induced acute neutrophilic inflammatory responses in pig lungs using Pseudomonas aeruginosa, an opportunistic respiratory pathogen. Blood samples, nasal swabs and bronchoalveolar lavage fluids (BALFs) were collected at 0, 3, 6 and 24 h post insfection (p.i.) and biochemical parameters, serum and BAL cytokines, bacterial cultures and neutrophil activity were evaluated. The release of proinflammatory mediators, biochemical and hematological blood parameters, cell recruitment and bronchial reactivity, peaked at 6h p.i.. We also used synthetic substrates specific for human neutrophil proteases to show that the activity of pig NSPs in BALFs increased. These proteases were also detected at the surface of lung neutrophils using anti-human NSP antibodies. Pseudomonas aeruginosa-induced lung infection in pigs results in a neutrophilic response similar to that described for cystic fibrosis and ventilator-associated pneumonia in humans. Altogether, this indicates that the pig is an appropriate model for testing anti-infectious and/or anti-inflammatory drugs to combat adverse proteolytic effects of neutrophil in human lung diseases. PMID- 27992535 TI - Cleaved Form of Osteopontin in Urine as a Clinical Marker of Lupus Nephritis. AB - We assessed the utility of two forms of osteopontin (OPN), OPN full and its cleaved form (OPN N-half), in plasma and urine as markers of disease activity in lupus nephritis (LN). Samples were collected from patients with systemic lupus erythematosus (SLE) (LN: N = 29, non-LN: N = 27), IgA nephropathy (IgAN) (N = 14), minimal change nephrotic syndrome (MCNS) (N = 5), diabetic nephropathy (DN) (N = 14) and healthy volunteers (HC) (N = 17). While there was no significant difference in urine OPN full concentration between groups, urine OPN N-half concentration was significantly higher in patients with LN than HC (p < 0.05). Moreover, urine OPN N-half was higher in LN patients with overt proteinuria (urine protein/creatinine ratio: P/C > 0.5) than LN patients with minimal proteinuria (P/C < 0.5, p < 0.0001), and also higher than in DN patients with overt proteinuria (P/C > 0.5, p < 0.01). Urine thrombin activity correlated with urine OPN N-half concentration (p < 0.0001), but not with urine OPN full concentration. These results suggest that urine OPN N-half concentration reflects renal inflammation. Thus, urine OPN N-half may be a novel disease activity marker for LN. PMID- 27992536 TI - Broncho Alveolar Dendritic Cells and Macrophages Are Highly Similar to Their Interstitial Counterparts. AB - In human medicine, bronchoalveolar lavage is the main non-traumatic procedure allowing an insight into the respiratory Dendritic Cells (DC) and Macrophages populations. However, it has never been demonstrated in a relevant model that alveolar DC subpopulations were comparable to their interstitial counterparts. In a precedent work we observed that respiratory pig DC and Macrophages were more similar to the human ones than to the mouse ones. In the present work, thanks to our animal model, we were able to collect the rare bronchoalveolar DC and compare them to their interstitial counterparts. We observed that DC presented very similar gene-expression patterns in the alveolar and interstitial compartments, validating the study of human bronchoalveolar DC as surrogate of their interstitium counterparts. PMID- 27992537 TI - Highlighting Astyanax Species Diversity through DNA Barcoding. AB - DNA barcoding has been used extensively to solve taxonomic questions and identify new species. Neotropical fishes are found in a wide variety of shapes and sizes, with a large number of species yet to be described, many of which are very difficult to identify. Characidae is the most species-rich family of the Characiformes, and many of its genera are affected by taxonomic uncertainties, including the widely-distributed, species-rich genus Astyanax. In this study, we present an extensive analysis of Astyanax covering almost its entire area of occurrence, based on DNA barcoding. The use of different approaches (ABGD, GMYC and BIN) to the clustering of the sequences revealed ample consistency in the results obtained by the initial cutoff value of 2% divergence for putative species in the Neighbor-Joining analysis using the Kimura-2-parameter model. The results indicate the existence of five Astyanax lineages. Some groups, such as that composed by the trans-Andean forms, are mostly composed of well-defined species, and in others a number of nominal species are clustered together, hampering the delimitation of species, which in many cases proved impossible. The results confirm the extreme complexity of the systematics of the genus Astyanax and show that DNA barcoding can be an useful tool to address these complexes questions. PMID- 27992538 TI - Racial Disparity in the Associations of Cotinine with Insulin Secretion: Data from the National Health and Nutrition Examination Survey, 2007-2012. AB - BACKGROUND: Although relationships between smoking/high cotinine and type 2 diabetes have consistently been observed, few studies have investigated the relationship between cotinine and underlying pathophysiological defects that characterize diabetes aetiology. This study aimed to test the associations between cotinine and measures of insulin resistance or insulin secretion. METHODS: This analysis included 5,751 non-diabetic adult American from the National Health and Nutrition Examination Survey (NHANES) from 2007-2012. Insulin function was represented with two indexes: insulin resistance index (HOMA-IR) and insulin secretion index (HOMA-B) estimated by homeostasis model assessment. We categorized cotinine levels into quartiles and estimated the odds of HOMA-IR in the 4th quartile and HOMA-B in the 1st quartile among cotinine categories using multiple logistic regression models. RESULTS: Cotinine concentration was not associated with the risk of high HOMA-IR. Association of cotinine with low HOMA-B existed and differed by race/ethnicity (P for interaction<0.05). High cotinine concentration (in the 4th quartile) was associated with an increased risk of low HOMA-B compared with low cotinine concentrations(1st -2nd quartiles) among white (odds ratio[OR], 1.51 [95% confidence interval[CI], 1.16-1.97]) or black participants (OR, 2.98 [95%CI, 1.90-4.69]) but not among Mexican (OR, 1.79 [95%CI, 0.90-3.53]) or other Hispanic(OR, 1.02 [95%CI, 0.56-1.86]) participants. Such associations remained significant even after further adjustment for HOMA-IR. CONCLUSIONS: High cotinine is associated with decreased insulin secretion function only in white and black non-diabetic U.S. adult population. Results evaluating cotinine in ethnically homogeneous populations may not be broadly generalizable to other racial/ethnic groups. PMID- 27992539 TI - Kinetics and Muscle Activity Patterns during Unweighting and Reloading Transition Phases in Running. AB - Amongst reduced gravity simulators, the lower body positive pressure (LBPP) treadmill is emerging as an innovative tool for both rehabilitation and fundamental research purposes as it allows running while experiencing reduced vertical ground reaction forces. The appropriate use of such a treadmill requires an improved understanding of the associated neuromechanical changes. This study concentrates on the runner's adjustments to LBPP-induced unweighting and reloading during running. Nine healthy males performed two running series of nine minutes at natural speed. Each series comprised three sequences of three minutes at: 100% bodyweight (BW), 60 or 80% BW, and 100% BW. The progressive unweighting and reloading transitions lasted 10 to 15 s. The LBPP-induced unweighting level, vertical ground reaction force and center of mass accelerations were analyzed together with surface electromyographic activity from 6 major lower limb muscles. The analyses of stride-to-stride adjustments during each transition established highly linear relationships between the LBPP-induced progressive changes of BW and most mechanical parameters. However, the impact peak force and the loading rate systematically presented an initial 10% increase with unweighting which could result from a passive mechanism of leg retraction. Another major insight lies in the distinct neural adjustments found amongst the recorded lower-limb muscles during the pre- and post-contact phases. The preactivation phase was characterized by an overall EMG stability, the braking phase by decreased quadriceps and soleus muscle activities, and the push-off phase by decreased activities of the shank muscles. These neural changes were mirrored during reloading. These neural adjustments can be attributed in part to the lack of visual cues on the foot touchdown. These findings highlight both the rapidity and the complexity of the neuromechanical changes associated with LBPP-induced unweighting and reloading during running. This in turn emphasizes the need for further investigation of the evolution over time of these neuromechanical changes. PMID- 27992540 TI - iFORM: Incorporating Find Occurrence of Regulatory Motifs. AB - Accurately identifying the binding sites of transcription factors (TFs) is crucial to understanding the mechanisms of transcriptional regulation and human disease. We present incorporating Find Occurrence of Regulatory Motifs (iFORM), an easy-to-use and efficient tool for scanning DNA sequences with TF motifs described as position weight matrices (PWMs). Both performance assessment with a receiver operating characteristic (ROC) curve and a correlation-based approach demonstrated that iFORM achieves higher accuracy and sensitivity by integrating five classical motif discovery programs using Fisher's combined probability test. We have used iFORM to provide accurate results on a variety of data in the ENCODE Project and the NIH Roadmap Epigenomics Project, and the tool has demonstrated its utility in further elucidating individual roles of functional elements. Both the source and binary codes for iFORM can be freely accessed at https://github.com/wenjiegroup/iFORM. The identified TF binding sites across human cell and tissue types using iFORM have been deposited in the Gene Expression Omnibus under the accession ID GSE53962. PMID- 27992541 TI - Variation of Binge Eating One Year after Roux-en-Y Gastric Bypass and Its Relationship with Excess Weight Loss. AB - BACKGROUND: Bariatric surgery is the most effective treatment for obesity classes II and III. However, some patients do not get the desired results or initially lose and then regain the lost weight. Identifying these individuals early on and treating them adequately remains a challenge. As binge eating directly affects food intake, the study of this symptom and its relation to bariatric surgery and its results is increasing, because it appears to have an influence on the results of surgery. OBJECTIVES: This study aimed to see how binge eating changes, measured with the Binge Eating Scale, interferes in the % excess weight loss one year after Roux-en-Y gastric bypass. METHODS: We conducted a cross-sectional study with 149 patients older than 18 years who were evaluated one year after undergoing Roux-en-Y gastric bypass. The variation in the intensity of binge eating was measured with the pre- and postoperative Binge Eating Scale scores. RESULTS: The variation of one unit in the Binge Eating Scale implied an inverse variation of 0.41% of % excess weight loss (p<0.05). The correlation coefficient between the variation of binge eating and the % excess weight loss was -0.186 (p = 0.033). The correlation coefficient between the binge eating symptoms one year after surgery and the % excess weight loss was -0.353 (p<0.001). CONCLUSIONS: There was a correlation between the variation of binge eating one year after gastric bypass and the % excess weight loss. The correlation between binge eating and the % excess weight loss was greater after the surgery than it was at the preoperative stage. This study provides new, valuable information on the intensity and variation of binge eating symptoms one year after gastric bypass, which, to the best of our knowledge, have not been studied in depth earlier. PMID- 27992542 TI - Self-Reported Food Hypersensitivity: Prevalence, Characteristics, and Comorbidities in the Norwegian Women and Cancer Study. AB - BACKGROUND: This study aims to investigate the prevalence of self-reported food hypersensitivity, (SFH), the characteristics of women with SFH, and whether SFH is associated with multiple health complaints among the participants of the Norwegian Women and Cancer study (NOWAC). METHODS: We conducted a cross-sectional study among 64,316 women aged 41-76 years. The women were randomly selected from the Norwegian Central Person Register. Information on SFH and all covariates except age and place of residence was collected by questionnaires in 2002-2005. RESULTS: The prevalence of SFH in our study sample was 6.8% (95% confidence interval: 6.7-7.0). Logistic regression analysis showed a negative association between SFH and age (odds ratio [OR] 0.97). The odds of SFH increased among women living in or near urban centers, women with more than 9 years of education, women who did not have full-time work, women who had experienced poor economic conditions in childhood, those living without a partner, and those who did not consume alcohol or smoke (OR varied from 1.10 to 1.70). Women with a low body mass index had higher odds of SFH (OR 1.37) than those with a moderate body mass index. SFH was positively associated with poor self-perceived health (OR 2.56). The odds of SFH increased with the number of concurrent health complaints, with an OR for 5-6 comorbidities of 4.93. CONCLUSION: We found an association between SFH, poor health, and different socio demographic and lifestyle characteristics. Women with SFH had increased odds of reporting multiple health complaints. PMID- 27992543 TI - MEG Frequency Analysis Depicts the Impaired Neurophysiological Condition of Ischemic Brain. AB - PURPOSE: Quantitative imaging of neuromagnetic fields based on automated region of interest (ROI) setting was analyzed to determine the characteristics of cerebral neural activity in ischemic areas. METHODS: Magnetoencephalography (MEG) was used to evaluate spontaneous neuromagnetic fields in the ischemic areas of 37 patients with unilateral internal carotid artery (ICA) occlusive disease. Voxel based time-averaged intensity of slow waves was obtained in two frequency bands (0.3-4 Hz and 4-8 Hz) using standardized low-resolution brain electromagnetic tomography (sLORETA) modified for a quantifiable method (sLORETA-qm). ROIs were automatically applied to the anterior cerebral artery (ACA), anterior middle cerebral artery (MCAa), posterior middle cerebral artery (MCAp), and posterior cerebral artery (PCA) using statistical parametric mapping (SPM). Positron emission tomography with 15O-gas inhalation (15O-PET) was also performed to evaluate cerebral blood flow (CBF) and oxygen extraction fraction (OEF). Statistical analyses were performed using laterality index of MEG and 15O-PET in each ROI with respect to distribution and intensity. RESULTS: MEG revealed statistically significant laterality in affected MCA regions, including 4-8 Hz waves in MCAa, and 0.3-4 Hz and 4-8 Hz waves in MCAp (95% confidence interval: 0.020-0.190, 0.030-0.207, and 0.034-0.213), respectively. We found that 0.3-4 Hz waves in MCAp were highly correlated with CBF in MCAa and MCAp (r = 0.74, r = 0.68, respectively), whereas 4-8 Hz waves were moderately correlated with CBF in both the MCAa and MCAp (r = 0.60, r = 0.63, respectively). We also found that 4-8 Hz waves in MCAp were statistically significant for misery perfusion identified on 15O-PET (p<0.05). CONCLUSIONS: Quantitatively imaged spontaneous neuromagnetic fields using the automated ROI setting enabled clear depiction of cerebral ischemic areas. Frequency analysis may reveal unique neural activity that is distributed in the impaired vascular metabolic territory, in which the cerebral infarction has not yet been completed. PMID- 27992544 TI - Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics. AB - We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S) in the inhibitor/substrate binding cavity, yet exhibits high resistance to all clinical inhibitors. PRS17 has none of the major mutations (I47V, I50V, I54ML, L76V and I84V) associated with darunavir resistance, but has 10,000-fold weaker binding affinity relative to the wild type PR. Comparable binding affinity of 8000-fold weaker than PR is seen for drug resistant mutant PR20, which bears 3 mutations associated with major resistance to darunavir (I47V, I54L and I84V). Inhibitor-free PRS17 shows an open flap conformation with a curled tip correlating with G48V flap mutation. NMR studies on inactive PRS17 D25N unambiguously confirm that the flaps adopt mainly an open conformation in solution very similar to that in the inhibitor-free crystal structure. In PRS17, the hinge loop cluster of mutations, E35D, M36I and S37D, contributes to the altered flap dynamics by a mechanism similar to that of PR20. An additional K20R mutation anchors an altered conformation of the hinge loop. Flap mutations M46L and G48V in PRS17/DRV complex alter the Phe53 conformation by steric hindrance between the side chains. Unlike the L10F mutation in PR20, L10I in PRS17 does not break the inter-subunit ion pair or diminish the dimer stability, consistent with a very low dimer dissociation constant comparable to that of wild type PR. Distal mutations A71V, L90M and I93L propagate alterations to the catalytic site of PRS17. PRS17 exhibits a molecular mechanism whereby mutations act synergistically to alter the flap dynamics resulting in significantly weaker binding yet maintaining active site contacts with darunavir. PMID- 27992545 TI - Attempts to Image the Early Inflammatory Response during Infection with the Lymphatic Filarial Nematode Brugia pahangi in a Mouse Model. AB - Helminth parasites remain a major constraint upon human health and well-being in many parts of the world. Treatment of these infections relies upon a very small number of therapeutics, most of which were originally developed for use in animal health. A lack of high throughput screening systems, together with limitations of available animal models, has restricted the development of novel chemotherapeutics. This is particularly so for filarial nematodes, which are long lived parasites with a complex cycle of development. In this paper, we describe attempts to visualise the immune response elicited by filarial parasites in infected mice using a non-invasive bioluminescence imaging reagent, luminol, our aim being to determine whether such a model could be developed to discriminate between live and dead worms for in vivo compound screening. We show that while imaging can detect the immune response elicited by early stages of infection with L3, it was unable to detect the presence of adult worms or, indeed, later stages of infection with L3, despite the presence of worms within the lymphatic system of infected animals. In the future, more specific reagents that detect secreted products of adult worms may be required for developing screens based upon live imaging of infected animals. PMID- 27992546 TI - Between the Balkans and the Baltic: Phylogeography of a Common Vole Mitochondrial DNA Lineage Limited to Central Europe. AB - The common vole (Microtus arvalis) has been a model species of small mammal for studying end-glacial colonization history. In the present study we expanded the sampling from central and eastern Europe, analyzing contemporary genetic structure to identify the role of a potential 'northern glacial refugium', i.e. a refugium at a higher latitude than the traditional Mediterranean refugia. Altogether we analyzed 786 cytochrome b (cytb) sequences (representing mitochondrial DNA; mtDNA) from the whole of Europe, adding 177 new sequences from central and eastern Europe, and we conducted analyses on eight microsatellite loci for 499 individuals (representing nuclear DNA) from central and eastern Europe, adding data on 311 new specimens. Our new data fill gaps in the vicinity of the Carpathian Mountains, the potential northern refugium, such that there is now dense sampling from the Balkans to the Baltic Sea. Here we present evidence that the Eastern mtDNA lineage of the common vole was present in the vicinity of this Carpathian refugium during the Last Glacial Maximum and the Younger Dryas. The Eastern lineage expanded from this refugium to the Baltic and shows low cytb nucleotide diversity in those most northerly parts of the distribution. Analyses of microsatellites revealed a similar pattern but also showed little differentiation between all of the populations sampled in central and eastern Europe. PMID- 27992547 TI - The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review. AB - BACKGROUND: Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. OBJECTIVE: To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. METHODS: In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. RESULTS: We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. CONCLUSION: Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin dose. PMID- 27992548 TI - Unveiling the Structure of Cognitive Vulnerability for Depression: Specificity and Overlap. AB - There is extensive literature establishing the influence of rumination, hopelessness, and dysfunctional attitudes on depressive symptoms. However, it is unclear whether these vulnerability factors are distinctly related to depressive symptoms or show substantial overlap. In two large samples of undergraduates (Study #1, n = 304; Study #2, n = 491) and two samples of clinically depressed individuals (Study #3, n = 141; Study #4, n = 109, from published studies), questionnaire data were used to examine the relationship between cognitive vulnerability factors and depressive symptoms, along with additional measures of anxiety and stress symptoms. To decompose model fit into its specific and common partitions, we relied on commonality analysis (CA). CA showed that there is substantial overlap in cognitive risk factors for depression. Moreover, we found strong evidence that hopelessness provides a unique statistical contribution to depression. This pattern of findings was stable in healthy as well as clinical samples. Symptom-levels analysis revealed that a specific subset of depressive symptoms are associated with hopelessness. In closing, we showed that CA provides a powerful tool to map unique and overlapping variance between multiple risk factors. Moreover, hopelessness emerged to be an important focus of clinical attention. PMID- 27992549 TI - Molecular Characterization and Functional Analysis of a Putative Octopamine/Tyramine Receptor during the Developmental Stages of the Pacific Oyster, Crassostrea gigas. AB - Octopamine (OA) and its precursor, tyramine (TA), participate in invertebrate development such as growth, maturation, and reproduction by activating their corresponding G protein-coupled receptors (GPCRs). Although OA was first discovered in mollusks (octopus), subsequent studies on OA, TA and related receptors have primarily been conducted in Ecdysozoa, especially in insects. Accordingly, only limited reports on OA/TA receptors in mollusks are available and their physiological roles remain unclear. Here, a full-length cDNA encoding a putative 524 amino acid OA/TA receptor (CgGPR1) was isolated from the Pacific oyster Crassostrea gigas. CgGPR1 was most closely related to the Lymnaea stagnalis OA receptor OAR2 in sequence. Phylogenetic analysis showed that CgGPR1 belongs to a poorly studied subfamily of invertebrate OA/TA receptors. The spatio temporal expression of CgGPR1 in C. gigas larvae was examined by quantitative real-time PCR and Western blot analysis. CgGPR1 was expressed during all developmental stages of C. gigas with higher levels at mid-developmental stages, indicating its potential role in embryogenesis and tissue differentiation. Immunoreactive fluorescence of CgGPR1 was mainly observed in the velum, foot, gill and mantle of C. gigas larvae. CgGPR1 transcripts were detected in all the tested organs of adult C. gigas, with highest level in the mantle. Pharmacological analysis showed that cAMP and Ca2+ concentrations remained unchanged in HEK293 cells expressing CgGPR1 upon addition of OA, TA or related amines, suggesting that CgGPR1 modulates other unknown molecules rather than cAMP and Ca2+. Our study sheds light on CgGPR1 function in oysters. PMID- 27992551 TI - Affluence and Private Health Insurance Influence Treatment and Survival in Non Hodgkin's Lymphoma. AB - BACKGROUND: The aim of this study was to investigate inequalities in survival for non-Hodgkin's lymphoma (NHL), distinguishing between direct and indirect effects of patient, social and process-of-care factors. METHODS: All cases of NHL diagnosed in Ireland in 2004-2008 were included. Variables describing patient, cancer, stage and process of care were included in a discrete-time model of survival using Structural Equation Modelling software. RESULTS: Emergency admissions were more common in patients with co-morbid conditions or with more aggressive cancers, and less frequent for patients from more affluent areas. Aggressive morphology, female sex, emergency admission, increasing age, comorbidity, treatment in a high caseload hospital and late stage were associated with increased hazard of mortality. Private patients had a reduced hazard of mortality, mediated by systemic therapy, admission to high caseload hospitals and fewer emergency admissions. DISCUSSION: The higher rate of emergency presentation, and consequent poorer survival, of uninsured patients, suggests they face barriers to early presentation. Social, educational and cultural factors may also discourage disadvantaged patients from consulting with early symptoms of NHL. Non-insured patients, who present later and have more emergency admissions would benefit from better access to diagnostic services. Older patients remain disadvantaged by sub-optimal treatment, treatment in non specialist centres and emergency admission. PMID- 27992550 TI - Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study. AB - BACKGROUND: Luminal A breast cancers respond well to anti-hormonal therapy (HT), are associated with a generally favorable prognosis and constitute the majority of breast cancer subtypes. HT is the mainstay of treatment of these patients, accompanied by an acceptable profile of side effects, whereas the added benefit of chemotherapy (CHT), including anthracycline and taxane-based programs, is less clear-cut and has undergone a process of critical revision. METHODS: In the framework of the BRENDA collective, we analyzed the benefits of CHT compared to HT in 4570 luminal A patients (pts) with primary diagnosis between 2001 and 2008. The results were adjusted by nodal status, age, tumor size and grading. RESULTS: There has been a progressive reduction in the use of CHT in luminal A patients during the last decade. Neither univariate nor multivariate analyses showed any statistically significant differences in relapse free survival (RFS) with the addition of CHT to adjuvant HT, independent of the nodal status, age, tumor size or grading. Even for patients with more than 3 affected lymph nodes, there was no significant difference (univariate: p = 0.865; HR 0.94; 95% CI: 0.46-1.93; multivariate: p = 0.812; HR 0.92; 95% CI: 0.45-1.88). CONCLUSIONS: The addition of CHT to HT provides minimal or no clinical benefit at all to patients with luminal A breast cancer, independent of the RFS-risk. Consequently, risk estimation cannot be the initial step in the decisional process. These findings that are in line with several publications-should encourage the critical evaluation of applying adjuvant CHT to patients with luminal A breast cancer. PMID- 27992553 TI - Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) Are Necessary for Light Entrainment of Peripheral Clocks. AB - Light is a powerful entrainer of circadian clocks in almost all eukaryotic organisms promoting synchronization of internal circadian rhythms with external environmental light-dark (LD) cycles. In mammals, the circadian system is organized in a hierarchical manner, in which a central pacemaker in the suprachiasmatic nucleus (SCN) synchronizes oscillators in peripheral tissues. Recent evidence demonstrates that photoentrainment of the SCN proceeds via signaling from a subpopulation of retinal ganglion cells (RGCs) which are melanopsin-expressing and intrinsically photosensitive (ipRGCs). However, it is still unclear whether photoentrainment of peripheral clocks is mediated exclusively by the ipRGC system or if signaling from RGCs that do not express melanopsin also plays a role. Here we have used genetic "silencing" of ipRGC neurotransmission in mice to investigate whether this photoreceptive system is obligatory for the photoentrainment of peripheral circadian clocks. Genetic silencing of ipRGC neurotransmission in mice was achieved by expression of tetanus toxin light chain in melanopsin-expressing cells (Opn4::TeNT mouse line). Rhythms of the clock gene Period 2 in various peripheral tissues were measured by crossbreeding Opn4::TeNT mice with PER2 luciferase knock-in mice (mPER2Luc). We found that in Opn4::TeNT mice the pupillary light reflex, light modulation of activity, and circadian photoentrainment of locomotor activity were severely impaired. Furthermore, ex vivo cultures from Opn4::TeNT, mPER2Luc mice of the adrenal gland, cornea, lung, liver, pituitary and spleen exhibited robust circadian rhythms of PER2::LUC bioluminescence. However, their peak bioluminescence rhythms were not aligned to the projected LD cycles indicating their lack of photic entrainment in vivo. Finally, we found that the circadian rhythm in adrenal corticosterone in Opn4::TeNT mice, as monitored by in vivo subcutaneous microdialysis, was desynchronized from environmental LD cycles. Our findings reveal a non-redundant role of ipRGCs for photic entrainment of peripheral tissues, highlighting the importance of this photoreceptive system for the organismal adaptation to daily environmental LD cycles. PMID- 27992552 TI - Economic Evaluation of Family Planning Interventions in Low and Middle Income Countries; A Systematic Review. AB - BACKGROUND: A significant number of women in low and middle income countries (L MICs) who need any family planning, experience a lack in access to modern effective methods. This study was conducted to review potential cost effectiveness of scaling up family planning interventions in these regions from the published literatures and assess their implication for policy and future research. STUDY DESIGN: A systematic review was performed in several electronic databases i.e Medline (Pubmed), Embase, Popline, The National Bureau of Economic Research (NBER), EBSCOHost, and The Cochrane Library. Articles reporting full economic evaluations of strategies to improve family planning interventions in one or more L-MICs, published between 1995 until 2015 were eligible for inclusion. Data was synthesized and analyzed using a narrative approach and the reporting quality of the included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. RESULTS: From 920 references screened, 9 studies were eligible for inclusion. Six references assessed cost effectiveness of improving family planning interventions in one or more L-MICs, while the rest assessed costs and consequences of integrating family planning and HIV services, concerning sub-Saharan Africa. Assembled evidence suggested that improving family planning interventions is cost effective in a variety of L-MICs as measured against accepted international cost effectiveness benchmarks. In areas with high HIV prevalence, integrating family planning and HIV services can be efficient and cost effective; however the evidence is only supported by a very limited number of studies. The major drivers of cost effectiveness were cost of increasing coverage, effectiveness of the interventions and country-specific factors. CONCLUSION: Improving family planning interventions in low and middle income countries appears to be cost-effective. Additional economic evaluation studies with improved reporting quality are necessary to generate further evidence on costs, cost-effectiveness, and affordability, and to support increased funding and investments in family planning programs. PMID- 27992554 TI - Tree Species Richness Promotes Invertebrate Herbivory on Congeneric Native and Exotic Tree Saplings in a Young Diversity Experiment. AB - Tree diversity in forests is an important driver of ecological processes including herbivory. Empirical evidence suggests both negative and positive effects of tree diversity on herbivory, which can be, respectively, attributed to associational resistance or associational susceptibility. Tree diversity experiments allow testing for associational effects, but evidence regarding which pattern predominates is mixed. Furthermore, it is unknown if herbivory on tree species of native vs. exotic origin is influenced by changing tree diversity in a similar way, or if exotic tree species escape natural enemies, resulting in lower damage that is unrelated to tree diversity. To address these questions, we established a young tree diversity experiment in temperate southwestern Germany that uses high planting density (49 trees per plot; plot size 13 m2). The species pool consists of six congeneric species pairs of European and North American origin (12 species in total) planted in monocultures and mixtures (1, 2, 4, 6 species). We assessed leaf damage by leaf-chewing insects on more than 5,000 saplings of six broadleaved tree species. Plot-level tree species richness increased leaf damage, which more than doubled from monocultures to six-species mixtures, strongly supporting associational susceptibility. However, leaf damage among congeneric native and exotic species pairs was similar. There were marked differences in patterns of leaf damage across tree genera, and only the genera likely having a predominately generalist herbivore community showed associational susceptibility, irrespective of the geographical origin of a tree species. In conclusion, an increase in tree species richness in young temperate forests may result in associational susceptibility to feeding by generalist herbivores. PMID- 27992555 TI - Non-Canonical Role of IKKalpha in the Regulation of STAT1 Phosphorylation in Antiviral Signaling. AB - Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addition to the well-known type I IFN-dependent pathway. IkappaB kinase alpha (IKKalpha) is involved in antiviral signaling induced by dsRNA; however, its role is incompletely understood. Here, we explored the function of IKKalpha in RLR-mediated STAT1 phosphorylation. Silencing of IKKalpha markedly decreased the level of IFN-beta and STAT1 phosphorylation inHeH response to dsRNA. However, the inhibition of IKKalpha did not alter the RLR signaling mediated dimerization of interferon responsive factor 3 (IRF3) or the nuclear translocation of nuclear factor-kappaB (NFkappaB). These results suggest a non canonical role of IKKalpha in RLR signaling. Furthermore, phosphorylation of STAT1 was suppressed by IKKalpha knockdown in cells treated with a specific neutralizing antibody for the type I IFN receptor (IFNAR) and in IFNAR-deficient cells. Collectively, the dual regulation of STAT1 by IKKalpha in antiviral signaling suggests a role for IKKalpha in the fine-tuning of antiviral signaling in response to non-self RNA. PMID- 27992556 TI - Bevacizumab Exacerbates Paclitaxel-Induced Neuropathy: A Retrospective Cohort Study. AB - BACKGROUND: Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, enhances the antitumor effectiveness of paclitaxel (PTX)-based chemotherapy in many metastatic cancers. A recent study in mice showed that VEGF receptor inhibitors can interfere with the neuroprotective effects of endogenous VEGF, potentially triggering the exacerbation of PTX induced neuropathy. In clinical trials, exacerbation of neuropathy in patients who received PTX combined with BEV (PTX+BEV) has generally been explained by increased exposure to PTX owing to the extended duration of chemotherapy. We investigated whether the concurrent use of BEV is associated with the exacerbation of PTX-induced neuropathy. METHODS: Female patients with breast cancer who had received weekly PTX or PTX+BEV from September 2011 through May 2016 were studied retrospectively. PTX-induced neuropathy was evaluated at the same time points (at the 6th and 12th courses of chemotherapy) in both cohorts. A multivariate Cox proportional-hazards model was used to assess the independent effect of BEV on the time to the onset of neuropathy. RESULTS: A total of 107 patients (median age, 55 years; range, 32-83) were studied. Sixty-one patients received PTX as adjuvant chemotherapy, 23 received PTX for metastatic disease, and 23 received PTX+BEV for metastatic disease. Peripheral sensory neuropathy was worse in patients who received PTX+BEV than in those who received PTX alone: at the 6th course, Grade 0/1/2/3 = 4/13/4/0 vs. 25/42/6/0 (P = 0.095); at the 12th course, 2/3/11/3 vs. 7/30/23/2 (P = 0.016). At the 12th course, the incidence of Grade 2 or higher neuropathy was significantly higher in patients treated with PTX+BEV than in those treated with PTX alone (74% vs. 40%; P = 0.017). In multivariate analysis, BEV was significantly associated with an increased risk of neuropathy (HR 2.32, 95% CI 1.21-4.44, P = 0.012). CONCLUSIONS: The concurrent use of BEV could worsen PTX-induced neuropathy in patients with breast cancer. PMID- 27992557 TI - An Analysis of EGFR Mutations among 1506 Cases of Non-Small Cell Lung Cancer Patients in Guangxi, China. AB - An association between epidermal growth factor receptor (EGFR) and clinical characteristics of non-small cell lung cancer (NSCLC) was reported ten years ago. In addition, a different type of relationship was seen in different ethic races. However, the relationship between these factors is not well understood in the Guangxi province. Up to now, there are only very limited data on the association of TTF1/EGFR protein positivity and EGFR mutation status in NSCLC. This study aims to investigate the role of EGFR gene mutation status on the clinical characteristics and the relationship with TTF-1/EGFR protein positivity of patients with NSCLC in Guangxi, China. 1506 samples from different patients with NSCLC were detected by amplification refractory mutation system for 29 hotspot mutations. Analysis of the relationship between clinical characteristics and EGFR mutation status was performed by using the crosstabs Chi-square and SPSS 21.0 software. Of 1506 samples, 537 (35.7%) revealed tyrosine kinase inhibitor (TKI) sensitive EGFR mutations with 27 (1.8%) cases harboring TKI resistant EGFR mutations or union co-existing EGFR-TKIs sensitive mutations. EGFR-TKIs sensitive mutations were not significantly associated with age and TNM-M stage (P = 0.863; P = 0.572, respectively). However, they were significantly associated with p stage, TNM-T stage and TNM-N stage (P = 0.011, P < 0.001, P = 0.036, respectively). Immunohistochemical studies revealed that TTF-1 and EGFR protein expression level were all associated with EGFR mutation status (P < 0.001, P = 0.002, respectively). Of the 537 EGFR-TKIs sensitive mutation cases, the rates of exon 19-del, 18 G719X point, exon 21 L858R and L861Q points were 54.6, 0.9, 42.3 and 0.9%, respectively. EGFR TKI-sensitive mutations commonly occur in female, non-smoking and adenocarcinoma patients. The p-stage, TNM-T stage, TNM-N stage, EGFR and TTF-1 protein expression levels have close relationships with EGFR mutation status. PMID- 27992558 TI - Pelvic Floor Disorders 6 Months after Attempted Operative Vaginal Delivery According to the Fetal Head Station: A Prospective Cohort Study. AB - OBJECTIVE: To evaluate the effect of the fetal head station at attempted operative vaginal delivery (aOVD), and specifically midpelvic or low aOVD, on urinary incontinence (UI), anal incontinence (AI), and perineal pain at 6 months. DESIGN: Prospective cohort study. SETTING: 1941 women with singleton term fetuses in vertex presentation with midpelvic or low aOVD between 2008 and 2013 in a tertiary care university hospital. METHODS: Symptoms of urinary incontinence (UI) using the Bristol Female Lower Urinary Tract Symptoms questionnaire, and symptoms of anal incontinence (AI) severity using Fecal Incontinence Severity Index (FISI) were assessed 6 months after aOVD. We measured the association between midpelvic or low aOVD and symptoms of UI, AI, and perineal pain at 6 months using multiple regression and adjusting for demographics, and risk factors of UI and AI, with adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). RESULTS: The study included 907 women (46.7%) who responded to the questionnaire; 18.4% (167/907) had midpelvic aOVD, and 81.6% (740/907) low; and none of women with symptoms of UI (26.6%, and 22.4%, respectively; p = 0.31), AI (15.9%, and 21.8%; p = 0.09), the FISI score, and perineal pain (17.2%, and 12.7%; p = 0.14) differed significantly between groups. The same was true for stress, urge, and mixed-type UI, severe UI and difficulty voiding. Compared with low pelvic aOVD, the aORs for symptoms of UI in midpelvic aOVD were 0.70 (0.46-1.05) and AI 1.42 (0.85-2.39). Third- and fourth-degree tears were a major risk factor of symptoms of UI (aOR 3.08, 95% CI 1.35-7.00) and AI (aOR 3.47, 95% CI 1.43-8.39). CONCLUSION: Neither symptoms of urinary nor anal incontinence differed at 6 months among women who had midpelvic and low pelvic aOVD. These findings are reassuring and need further studies at long-term to confirm these short-term data. PMID- 27992559 TI - Phylogeography of the Chydorus sphaericus Group (Cladocera: Chydoridae) in the Northern Palearctic. AB - The biodiversity and the biogeography are still poorly understood for freshwater invertebrates. The crustacean Chydorus sphaericus-brevilabris complex (Cladocera: Chydoridae) is composed of species that are important components of Holarctic freshwater food webs. Recent morphological and genetic study of the complex has indicated a substantial species diversity in the northern hemisphere. However, we know little of the geographic boundaries of these novel lineages. Moreover, a large section of the Palearctic remains unexamined at the genetic level. Here we attempt to address the biodiversity knowledge gap for the Chydorus sphaericus group in the central Palearctic and assess its diversity and biogeographic boundaries. We sequenced nuclear (ITS-2) and mitochondrial (COI) gene regions of Chydorus specimens across the Palearctic and compared them with already available Holarctic sequences. We detected six main clades in the C. sphaericus group in the Palearctic, of which two of the groups are novel. Three of the more divergent clades are geographically widespread. The central portion of Eurasia (the Yenisey River basin) appears to be a narrow zone of secondary contact for phylogroups that expanded from European and Beringian refugia. As such, the previously unsampled central Palearctic represents an important region for understanding the evolutionary consequences of Pleistocene climatic oscillations on the Chydorus sphaericus group. PMID- 27992560 TI - Knocking Down the Expression of GMPase Gene OsVTC1-1 Decreases Salt Tolerance of Rice at Seedling and Reproductive Stages. AB - Salinity is a severe environmental stress that greatly impairs production of crops worldwide. Previous studies have shown that GMPase plays an important role in tolerance of plants to salt stress at vegetative stage. However, the function of GMPase in plant responses to salt stress at reproductive stage remains unclear. Studies have shown that heterologous expression of rice GMPase OsVTC1-1 enhanced salt tolerance of tobacco seedlings, but the native role of OsVTC1-1 in salt stress tolerance of rice is unknown. To illustrate the native function of GMPase in response of rice to salt stress, OsVTC1-1 expression was suppressed using RNAi-mediated gene silencing. Suppressing OsVTC1-1 expression obviously decreased salt tolerance of rice varieties at vegetative stage. Intriguingly, grain yield of OsVTC1-1 RNAi rice was also significantly reduced under salt stress, indicating that OsVTC1-1 plays an important role in salt tolerance of rice at both seedling and reproductive stages. OsVTC1-1 RNAi rice accumulated more ROS under salt stress, and supplying exogenous ascorbic acid restored salt tolerance of OsVTC1-1 RNAi lines, suggesting that OsVTC1-1 is involved in salt tolerance of rice through the biosynthesis regulation of ascorbic acid. Altogether, results of present study showed that rice GMPase gene OsVTC1-1 plays a critical role in salt tolerance of rice at both vegetative and reproductive stages through AsA scavenging of excess ROS. PMID- 27992561 TI - MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis. AB - The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs. PMID- 27992563 TI - Impact of Refugees on Local Health Systems: A Difference-in-Differences Analysis in Cameroon. AB - Hosting refugees may represent a drain on local resources, particularly since external aid is frequently insufficient. Between 2004 and 2011, over 100,000 refugees settled in the eastern border of Cameroon. With little known on how refugee influx affects health services of the hosting community, we investigated the impact of refugees on mother and child health (MCH) services in the host community in Cameroon. We used Cameroon's 2004 and 2011 Demographic and Health Surveys to evaluate changes in MCH indicators in the refugee hosting community. Our outcome variables were antenatal care (ANC) coverage, caesarean delivery rate, place of delivery and child vaccination coverage; whereas the exposure variable was residence in the refugee hosting community. We used a difference-in differences analysis to compare indicators of the refugee hosting community to a control group selected through propensity score matching from the rest of the country. A total of 10,656 women were included in our 2004 analysis and 7.6% (n = 826) of them resided in the refugee hosting community. For 2011, 15,426 women were included and 5.8% (n = 902) of them resided in the hosting community. Between 2004 and 2011, both the proportion of women delivering outside health facilities and children not completing DPT3 vaccination in the refugee hosting community decreased by 9.0% (95% Confidence Interval (CI): 3.9-14.1%) and 9.6% (95% CI: 7.9-11.3%) respectively. However, ANC attendance and caesarean delivery did not show any significant change. Our findings demonstrate that none of the evaluated MCH service indicators deteriorated (in fact, two of them improved: delivery in health facilities and completing DPT3 vaccine) with the presence of refugees. This suggests evidence disproving the common belief that refugees always have a negative impact on their hosting community. PMID- 27992562 TI - Two Subclasses of Differentially Expressed TPS1 Genes and Biochemically Active TPS1 Proteins May Contribute to Sugar Signalling in Kiwifruit Actinidia chinensis. AB - Trehalose metabolism and its intermediate trehalose-6-phosphate (T6P) are implicated in sensing and signalling sucrose availability. Four class I TREHALOSE 6-PHOSPHATE SYNTHASE (TPS1) genes were identified in kiwifruit, three of which have both the TPS and trehalose-6-phosphate phosphatase (TPP) domain, while the fourth gene gives rise to a truncated transcript. The transcript with highest sequence homology to Arabidopsis TPS1, designated TPS1.1a was the most highly abundant TPS1 transcript in all examined kiwifruit tissues. An additional exon giving rise to a small N-terminal extension was found for two of the TPS1 transcripts, designated TPS1.2a and TPS1.2b. Homology in sequence and gene structure with TPS1 genes from Solanaceae suggests they belong to a separate, asterid-specific class I TPS subclade. Expression of full-length and potential splice variants of these two kiwifruit TPS1.2 transcripts was sufficient to substitute for the lack of functional TPS1 in the yeast tps1Delta tps2Delta mutant, but only weak complementation was detected in the yeast tps1Delta mutant, and no or very weak complementation was obtained with the TPS1.1a construct. Transgenic Arabidopsis lines expressing kiwifruit TPS1.2 under the control of 35S promoter exhibited growth and morphological defects. We investigated the responses of plants to elevated kiwifruit TPS1 activity at the transcriptional level, using transient expression of TPS1.2a in Nicotiana benthamiana leaves, followed by RNA-seq. Differentially expressed genes were identified as candidates for future functional analyses. PMID- 27992564 TI - MicroRNA-497 Inhibits Cardiac Hypertrophy by Targeting Sirt4. AB - Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to overload pressure of heart. From abundant studies, a conclusion is drawn that many microRNAs (miRNAs) are associated with cardiac hypertrophy and heart failure. To investigate the role of microRNA-497 (miR-497) in myocardial hypertrophy, two models were established in this study from cell level to integral level. Cardiac hypertrophy was induced by using angiotensin II (Ang II) in vitro and was created by transverse abdominal aortic constriction (TAC) in vivo. There was a significant decrease expression of miR-497 in cardiac hypertrophy models. Moreover, overexpression of miR-497 inhibited myocardial hypertrophy both in vitro and in vivo without heart function variation. In addition, luciferase reporter assays demonstrated that Sirt4 was a direct target gene of miR-497. Taking together, our study indicates that miR-497 modulates cardiac hypertrophy by targeting Sirt4 and may serve as a potential therapeutic substance in the course. PMID- 27992566 TI - The Accuracy of Portable Monitoring in Diagnosing Significant Sleep Disordered Breathing in Hospitalized Patients. AB - BACKGROUND: Polysomnograms are not always feasible when sleep disordered breathing (SDB) is suspected in hospitalized patients. Portable monitoring is a practical alternative; however, it has not been recommended in patients with comorbidities. OBJECTIVE: We evaluated the accuracy of portable monitoring in hospitalized patients suspected of having SDB. DESIGN: Prospective observational study. SETTING: Large, public, urban, teaching hospital in the United States. PARTICIPANTS: Hospitalized patients suspected of having SDB. METHODS: Patients underwent portable monitoring combined with actigraphy during the hospitalization and then polysomnography after discharge. We determined the accuracy of portable monitoring in predicting moderate to severe SDB and the agreement between the apnea hypopnea index measured by portable monitor (AHIPM) and by polysomnogram (AHIPSG). RESULTS: Seventy-one symptomatic patients completed both tests. The median time between the two tests was 97 days (IQR 25-75: 24-109). Forty-five percent were hospitalized for cardiovascular disease. Mean age was 52+/-10 years, 41% were women, and the majority had symptoms of SDB. Based on AHIPSG, SDB was moderate in 9 patients and severe in 39. The area under the receiver operator characteristics curve for AHIPM was 0.8, and increased to 0.86 in patients without central sleep apnea; it was 0.88 in the 31 patients with hypercapnia. For predicting moderate to severe SDB, an AHIPM of 14 had a sensitivity of 90%, and an AHIPM of 36 had a specificity of 87%. The mean+/-SD difference between AHIPM and AHIPSG was 2+/-29 event/hr. CONCLUSION: In hospitalized, symptomatic patients, portable monitoring is reasonably accurate in detecting moderate to severe SDB. PMID- 27992568 TI - Correction: Persistence of Low Pathogenic Influenza A Virus in Water: A Systematic Review and Quantitative Meta-Analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0161929.]. PMID- 27992565 TI - Domain-Generality of Timing-Based Serial Order Processes in Short-Term Memory: New Insights from Musical and Verbal Domains. AB - Several models in the verbal domain of short-term memory (STM) consider a dissociation between item and order processing. This view is supported by data demonstrating that different types of time-based interference have a greater effect on memory for the order of to-be-remembered items than on memory for the items themselves. The present study investigated the domain-generality of the item versus serial order dissociation by comparing the differential effects of time-based interfering tasks, such as rhythmic interference and articulatory suppression, on item and order processing in verbal and musical STM domains. In Experiment 1, participants had to maintain sequences of verbal or musical information in STM, followed by a probe sequence, this under different conditions of interference (no-interference, rhythmic interference, articulatory suppression). They were required to decide whether all items of the probe list matched those of the memory list (item condition) or whether the order of the items in the probe sequence matched the order in the memory list (order condition). In Experiment 2, participants performed a serial order probe recognition task for verbal and musical sequences ensuring sequential maintenance processes, under no-interference or rhythmic interference conditions. For Experiment 1, serial order recognition was not significantly more impacted by interfering tasks than was item recognition, this for both verbal and musical domains. For Experiment 2, we observed selective interference of the rhythmic interference condition on both musical and verbal order STM tasks. Overall, the results suggest a similar and selective sensitivity to time-based interference for serial order STM in verbal and musical domains, but only when the STM tasks ensure sequential maintenance processes. PMID- 27992567 TI - Impact of Hyperglycemia and Low Oxygen Tension on Adipose-Derived Stem Cells Compared with Dermal Fibroblasts and Keratinocytes: Importance for Wound Healing in Type 2 Diabetes. AB - AIM: Adipose-derived stem cells (ASC) are currently proposed for wound healing in those with type 2 diabetes mellitus (T2DM). Therefore, this study investigated the impact of diabetes on adipose tissue in relation to ASC isolation, proliferation, and growth factor release and the impact of hyperglycemia and low oxygen tension (found in diabetic wounds) on dermal fibroblasts, keratinocytes, and ASC in vitro. METHODS: Different sequences of hypoxia and hyperglycemia were applied in vitro to ASC from nondiabetic (n = 8) or T2DM patients (n = 4) to study cell survival, proliferation, and growth factor release. Comparisons of dermal fibroblasts (n = 8) and keratinocytes (primary lineage) were made. RESULTS: No significant difference of isolation and proliferation capacities was found in ASC from nondiabetic and diabetic humans. Hypoxia and hyperglycemia did not impact cell viability and proliferation. Keratinocyte Growth Factor release was significantly lower in diabetic ASC than in nondiabetic ASC group in each condition, while Vascular Endothelial Growth Factor release was not affected by the diabetic origin. Nondiabetic ASC exposition to hypoxia (0.1% oxygen) combined with hyperglycemia (25mM glucose), resulted in a significant increase in VEGF secretion (+64%, p<0.05) with no deleterious impact on KGF release in comparison to physiological conditions (5% oxygen and 5 mM glucose). Stromal cell-Derived Factor-1alpha (-93%, p<0.001) and KGF (-20%, p<0.05) secretion by DF decreased in these conditions. CONCLUSIONS: A better profile of growth factor secretion (regarding wound healing) was found in vitro for ASC in hyperglycemia coupled with hypoxia in comparison to dermal fibroblasts and keratinocytes. Interestingly, ASC from T2DM donors demonstrated cellular growth rates and survival (in hypoxia and hyperglycemic conditions) similar to those of healthy ASC (from normoglycemic donors); however, KGF secretion was significantly depleted in ASC obtained from T2DM patients. This study demonstrated the impact of diabetes on ASC for regenerative medicine and wound healing. PMID- 27992570 TI - Chemical Characterization of Lipophilic Constituents in the Skin of Migratory Adult Sea Lamprey from the Great Lakes Region. AB - The sea lamprey (Petromzons marinus) is an invasive ectoparasite of large-bodied fishes that adversely affects the fishing industry and ecology of the Laurentian Great Lakes. Lipid content in the whole sea lamprey and muscles, liver and kidney of metamorphosing larval stages has been reported. Similarly, the fatty acid profile of the rope tissues of sexually-mature male sea lampreys has also been reported. The average body weight of a sub-adult migratory sea lamprey is 250 g, which includes 14.4% skin (36 g). Our preliminary extraction data of an adult sea lamprey skin revealed that it contained approximately 8.5% of lipophilic compounds. Lamprey skin is home to a naturally aversive compound (an alarm cue) that is being developed into a repellent for use in pest management. As part of an ongoing investigation to identify the chemical structure of the sea lamprey alarm cue, we extracted the skin with water and methanol, respectively. The methanolic extract (1.55%) contained exclusively lipophilic compounds and did not include the alarm cue. We chemically characterized all compounds present in the methanolic extract as cholesterol esters (CE), tri- and di-glycerides (TG and DG), cholesterol, free fatty acids (FFA) and minor amounts of plasticizers. The free fatty acids fraction was composed of saturated (41.8%), monounsaturated (40.7%) and polyunsaturated (17.4%) fatty acids, respectively. The plasticizers characterized were phthalate and benzoate and found to be 0.95 mg and 2.54 mg, respectively, per adult sea lamprey skin. This is the first report of the chemical characterization of all the lipophilic constituents in the skin of sub adult migratory sea lamprey. The CEs isolated and characterized from sea lamprey skin are also for the first time. PMID- 27992569 TI - Interleukin-33 and RANK-L Interplay in the Alveolar Bone Loss Associated to Periodontitis. AB - INTRODUCTION: Chronic Periodontitis (CP) is an inflammatory disease of bacterial origin that results in alveolar bone destruction. Porphyromonas gingivalis (Pg), one of the main periopathogens, initiates an inflammatory cascade by host immune cells thereby increasing recruitment and activity of osteoclasts, the bone resorbing cells, through enhanced production of the crucial osteoclastogenic factor, RANK-L. Antibodies directed against some cytokines (IL-1beta, IL-6 and TNF-alpha) failed to exhibit convincing therapeutic effect in CP. It has been suggested that IL-33, could be of interest in CP. OBJECTIVE: the present study aims to analyze whether and how IL-33 and RANK-L and/or their interplay are involved in the bone destruction associated to CP. MATERIAL AND METHODS: mRNAs and protein expressions of IL-33 and RANK-L were analyzed in healthy and CP human gingival samples by immunohistochemistry (IHC) and RT-qPCR. Murine experimental periodontitis (EP) was induced using Pg infected ligature and Pg free ligature around the first maxillary molar. Alveolar bone loss was recorded by MUCT. Mouse gingival explants were stimulated for 24 hours with IL-33 and RANK-L mRNA expression investigated by RT-qPCR. Human oral epithelial cells were infected by Pg for 6, 12; 24 hours and IL-33 and RANK-L mRNA expressions were analyzed by RT qPCR. RESULTS: IL-33 is overexpressed in gingival epithelial cells in human affected by CP as in the murine EP. In human as in murine gingival cells, RANK-L was independently induced by Pg and IL-33. We also showed that the Pg-dependent RANK-L expression in gingival epithelial cells occured earlier than that of IL 33. CONCLUSION: Our results evidence that IL-33 overexpression in gingival epithelial cells is associated with CP and may trigger RANK-L expression in addition to a direct effect of Pg. Finally, IL-33 may act as an extracellular alarmin (danger signal) showing proinflammatory properties in CP perpetuating bone resorption induced by Pg infection. PMID- 27992571 TI - Development of a Recombinase Polymerase Amplification Assay for Rapid Detection of the Mycobacterium avium subsp. paratuberculosis. AB - BACKGROUND: The detection of Mycobacterium avium subsp. paratuberculosis (MAP) infections in ruminants is crucial to control spread among animals and to humans. Cultivation of MAP is seen as the gold standard for detection, although it is very time consuming and labour intensive. In addition, several PCR assays have been developed to detect MAP in around 90 minutes, but these assays required highly sophisticated equipment as well as lengthy and complicated procedure. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have developed a rapid assay for the detection of MAP based on the recombinase polymerase amplification (RPA) assay targeting a MAP specific region, the IS900 gene. The detection limit was 16 DNA molecules in 15 minutes as determined by the probit analysis on eight runs of the plasmid standard. Cross reactivity with other mycobacterial and environmentally associated bacterial strains was not observed. The clinical performance of the MAP RPA assay was tested using 48 MAP-positive and 20 MAP negative blood, sperm, faecal and tissue samples. All results were compared with reads of a highly sensitive real-time PCR assay. The specificity of the MAP RPA assay was 100%, while the sensitivity was 89.5%. CONCLUSIONS/SIGNIFICANCE: The RPA assay is quicker and much easier to handle than real-time PCR. All RPA reagents were cold-chain independent. Moreover, combining RPA assay with a simple extraction protocol will maximize its use at point of need for rapid detection of MAP. PMID- 27992573 TI - Correction: Early Mortality Was Highly and Strongly Associated with Functional Status in Incident Japanese Hemodialysis Patients: A Cohort Study of the Large National Dialysis Registry. AB - [This corrects the article DOI: 10.1371/journal.pone.0156951.]. PMID- 27992572 TI - Usefulness of DNA Methylation Levels in COASY and SPINT1 Gene Promoter Regions as Biomarkers in Diagnosis of Alzheimer's Disease and Amnestic Mild Cognitive Impairment. AB - In order to conduct early therapeutic interventions for Alzheimer's disease (AD), convenient, early diagnosis markers are required. We previously reported that changes in DNA methylation levels were associated with amnestic mild cognitive impairment (aMCI) and AD. As the results suggested changes in DNA methylation levels in the COASY and SPINT1 gene promoter regions, in the present study we examined DNA methylation in these regions in normal controls (NCs, n = 30), aMCI subjects (n = 28) and AD subjects (n = 30) using methylation-sensitive high resolution melting (MS-HRM) analysis. The results indicated that DNA methylation in the two regions was significantly increased in AD and aMCI as compared to NCs (P < 0.0001, P < 0.0001, ANOVA). Further analysis suggested that DNA methylation in the COASY gene promoter region in particular could be a high sensitivity, high specificity diagnosis biomarker (COASY: sensitivity 96.6%, specificity 96.7%; SPINT1: sensitivity 63.8%, specificity 83.3%). DNA methylation in the COASY promoter region was associated with CDR Scale Sum of Boxes (CDR-SB), an indicator of dementia severity. In the SPINT1 promoter region, DNA methylation was negatively associated with age in NCs and elevated in aMCI and AD subjects positive for antibodies to Herpes simplex virus type 1 (HSV-1). These findings suggested that changes in DNA methylation in the COASY and SPINT1 promoter regions are influenced by various factors. In conclusion, DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI. PMID- 27992575 TI - Correction: Severe Changes in Thymic Microenvironment in a Chronic Experimental Model of Paracoccidioidomycosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0164745.]. PMID- 27992574 TI - Comparing Features for Classification of MEG Responses to Motor Imagery. AB - BACKGROUND: Motor imagery (MI) with real-time neurofeedback could be a viable approach, e.g., in rehabilitation of cerebral stroke. Magnetoencephalography (MEG) noninvasively measures electric brain activity at high temporal resolution and is well-suited for recording oscillatory brain signals. MI is known to modulate 10- and 20-Hz oscillations in the somatomotor system. In order to provide accurate feedback to the subject, the most relevant MI-related features should be extracted from MEG data. In this study, we evaluated several MEG signal features for discriminating between left- and right-hand MI and between MI and rest. METHODS: MEG was measured from nine healthy participants imagining either left- or right-hand finger tapping according to visual cues. Data preprocessing, feature extraction and classification were performed offline. The evaluated MI related features were power spectral density (PSD), Morlet wavelets, short-time Fourier transform (STFT), common spatial patterns (CSP), filter-bank common spatial patterns (FBCSP), spatio-spectral decomposition (SSD), and combined SSD+CSP, CSP+PSD, CSP+Morlet, and CSP+STFT. We also compared four classifiers applied to single trials using 5-fold cross-validation for evaluating the classification accuracy and its possible dependence on the classification algorithm. In addition, we estimated the inter-session left-vs-right accuracy for each subject. RESULTS: The SSD+CSP combination yielded the best accuracy in both left-vs-right (mean 73.7%) and MI-vs-rest (mean 81.3%) classification. CSP+Morlet yielded the best mean accuracy in inter-session left-vs-right classification (mean 69.1%). There were large inter-subject differences in classification accuracy, and the level of the 20-Hz suppression correlated significantly with the subjective MI-vs-rest accuracy. Selection of the classification algorithm had only a minor effect on the results. CONCLUSIONS: We obtained good accuracy in sensor-level decoding of MI from single-trial MEG data. Feature extraction methods utilizing both the spatial and spectral profile of MI-related signals provided the best classification results, suggesting good performance of these methods in an online MEG neurofeedback system. PMID- 27992576 TI - Temperature Sensitivity of Soil Respiration to Nitrogen Fertilization: Varying Effects between Growing and Non-Growing Seasons. AB - Nitrogen (N) fertilization has a considerable effect on food production and carbon cycling in agro-ecosystems. However, the impacts of N fertilization rates on the temperature sensitivity of soil respiration (Q10) were controversial. Five N rates (N0, N45, N90, N135, and N180) were applied to a continuous winter wheat (Triticum aestivum L.) crop on the semi-arid Loess Plateau, and the in situ soil respiration was monitored during five consecutive years from 2008 to 2013. During the growing season, the mean soil respiration rates increased with increasing N fertilization rates, peaking at 1.53 MUmol m-2s-1 in the N135 treatment. A similar dynamic pattern was observed during the non-growing season, yet on average with 7.3% greater soil respiration rates than the growing season. In general for all the N fertilization treatments, the mean Q10 value during the non growing season was significantly greater than that during the growing season. As N fertilization rates increased, the Q10 values did not change significantly in the growing season but significantly decreased in the non-growing season. Overall, N fertilization markedly influenced soil respirations and Q10 values, in particular posing distinct effects on the Q10 values between the growing and non growing seasons. PMID- 27992578 TI - Environmental Predictors of Seabird Wrecks in a Tropical Coastal Area. AB - Beached bird surveys have been widely used to monitor the impact of oil pollution in the oceans. However, separating the combined effects of oil pollution, environmental variables and methodological aspects of beach monitoring on seabird stranding patterns is a challenging task. The effects of a comprehensive set of oceanographic and climatic variables and oil pollution on seabird strandings in a tropical area of Brazil were investigated herein, using two robust and innovative methods: Generalized Linear Mixed Models and Structural Equation Modeling. We assessed strandings of four resident seabird species along 480 km of beaches divided into 11 sampling areas, between November 2010 and September 2013. We found that increasing the distance from the nearest breeding island reduce the seabird stranding events. Storm activity and biological productivity were the most important factors affecting the stranding events of brown boobies Sula leucogaster, Cabot's terns Thalasseus acuflavidus and kelp gulls Larus dominicanus. These species are also indirectly affected by warm tropical waters, which reduce chlorophyll-a concentrations. Beach surveys are, thus, useful to investigate the mortality rates of resident species near breeding sites, where individuals are more abundant and exposed to local factors associated with at-sea mortality. In contrast, conservation actions and monitoring programs for far ranging seabird species are needed in more distant foraging areas. Furthermore, beach monitoring programs investigating the impact of oil pollution on seabirds need to account for the effects of environmental factors on stranding patterns. The present study also demonstrated that seabirds inhabiting tropical coastal waters are sensitive to climate conditions such as adverse weather, which are expected to increase in frequency and intensity in next decades. PMID- 27992577 TI - Tolerogenic Plasmacytoid Dendritic Cells Control Paracoccidioides brasiliensis Infection by Inducting Regulatory T Cells in an IDO-Dependent Manner. AB - Plasmacytoid dendritic cells (pDCs), considered critical for immunity against viruses, were recently associated with defense mechanisms against fungal infections. However, the immunomodulatory function of pDCs in pulmonary paracoccidiodomycosis (PCM), an endemic fungal infection of Latin America, has been poorly defined. Here, we investigated the role of pDCs in the pathogenesis of PCM caused by the infection of 129Sv mice with 1 x 106 P. brasiliensis-yeasts. In vitro experiments showed that P. brasiliensis infection induces the maturation of pDCs and elevated synthesis of TNF-alpha and IFN-beta. The in vivo infection caused a significant influx of pDCs to the lungs and increased levels of pulmonary type I IFN. Depletion of pDCs by a specific monoclonal antibody resulted in a less severe infection, reduced tissue pathology and increased survival time of infected mice. An increased influx of macrophages and neutrophils and elevated presence of CD4+ and CD8+ T lymphocytes expressing IFN gamma and IL-17 in the lungs of pDC-depleted mice were also observed. These findings were concomitant with decreased frequency of Treg cells and reduced levels of immunoregulatory cytokines such as IL-10, TGF-beta, IL-27 and IL-35. Importantly, P. brasilienis infection increased the numbers of pulmonary pDCs expressing indoleamine 2,3-dioxygenase-1 (IDO), an enzyme with immunoregulatory properties, that were reduced following pDC depletion. In agreement, an increased immunogenic activity of infected pDCs was observed when IDO-deficient or IDO inhibited pDCs were employed in co-cultures with lymphocytes Altogether, our results suggest that in pulmonary PCM pDCs exert a tolerogenic function by an IDO mediated mechanism that increases Treg activity. PMID- 27992579 TI - Seawater pH Predicted for the Year 2100 Affects the Metabolic Response to Feeding in Copepodites of the Arctic Copepod Calanus glacialis. AB - Widespread ocean acidification (OA) is transforming the chemistry of the global ocean, and the Arctic is recognised as a region where the earliest and strongest impacts of OA are expected. In the present study, metabolic effects of OA and its interaction with food availability was investigated in Calanus glacialis from the Kongsfjord, West Spitsbergen. We measured metabolic rates and RNA/DNA ratios (an indicator of biosynthesis) concurrently in fed and unfed individuals of copepodite stages CII-CIII and CV subjected to two different pH levels representative of present day and the "business as usual" IPCC scenario (RCP8.5) prediction for the year 2100. The copepods responded more strongly to changes in food level than to decreasing pH, both with respect to metabolic rate and RNA/DNA ratio. However, significant interactions between effects of pH and food level showed that effects of pH and food level act in synergy in copepodites of C. glacialis. While metabolic rates in copepodites stage CII-CIII increased by 78% as a response to food under present day conditions (high pH), the increase was 195% in CII-CIIIs kept at low pH-a 2.5 times greater increase. This interaction was absent for RNA/DNA, so the increase in metabolic rates were clearly not a reaction to changing biosynthesis at low pH per se but rather a reaction to increased metabolic costs per unit of biosynthesis. Interestingly, we did not observe this difference in costs of growth in stage CV. A 2.5 times increase in metabolic costs of growth will leave the copepodites with much less energy for growth. This may infer significant changes to the C. glacialis population during future OA. PMID- 27992580 TI - Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy. AB - Chronic kidney disease is a major complication of Fabry disease. Podocytes accumulate globotriaosylceramide inclusions more than other kidney cell types in Fabry patients. Podocyte injury occurs early in age, and is progressive. Since injured podocytes detach into the urine (podocyturia), we hypothesized that podocyturia would increase in Fabry patients and correlate with clinical severity of Fabry nephropathy. Urine specimens from 39 Fabry patients and 24 healthy subjects were evaluated for podocyturia. Most of the Fabry patients and many healthy subjects had podocyturia. The number of podocytes per gram of urine creatinine (UPodo/g Cr) was 3.6 fold greater in Fabry patients (3,741 +/- 2796; p = 0.001) than healthy subjects (1,040 +/- 972). Fabry patients with normoalbuminuria and normoproteinuria had over 2-fold greater UPodo/g Cr than healthy subjects (p = 0.048). UPodo/gCr was inversely related to eGFR in male patients (r = -0.69, p = 0.003). UPodo/gCr was directly related to urine protein creatinine ratio (r = 0.33; p = 0.04) in all Fabry patients. These studies confirm increased podocyturia in Fabry disease, even when proteinuria and albuminuria are absent. Podocyturia correlates with clinical severity of Fabry nephropathy, and potentially may be of prognostic value. PMID- 27992581 TI - GADD34 Keeps the mTOR Pathway Inactivated in Endoplasmic Reticulum Stress Related Autophagy. AB - The balance of protein synthesis and proteolysis (i.e. proteostasis) is maintained by a complex regulatory network in which mTOR (mechanistic target of rapamycin serine/threonine kinase) pathway and unfolded protein response are prominent positive and negative actors. The interplay between the two systems has been revealed; however the mechanistic details of this crosstalk are largely unknown. The aim of the present study was to investigate the elements of crosstalk during endoplasmic reticulum stress and to verify the key role of GADD34 in the connection with the mTOR pathway. Here, we demonstrate that a transient activation of autophagy is present in endoplasmic reticulum stress provoked by thapsigargin or tunicamycin, which is turned into apoptotic cell death. The transient phase can be characterized by the elevation of the autophagic marker LC3II/I, by mTOR inactivation, AMP-activated protein kinase activation and increased GADD34 level. The switch from autophagy to apoptosis is accompanied with the appearance of apoptotic markers, mTOR reactivation, AMP activated protein kinase inactivation and a decrease in GADD34. Inhibition of autophagy by 3-methyladenine shortens the transient phase, while inhibition of mTOR by rapamycin or resveratrol prolongs it. Inhibition of GADD34 by guanabenz or transfection of the cells with siGADD34 results in down-regulation of autophagy-dependent survival and a quick activation of mTOR, followed by apoptotic cell death. The negative effect of GADD34 inhibition is diminished when guanabenz or siGADD34 treatment is combined with rapamycin or resveratrol addition. These data confirm that GADD34 constitutes a mechanistic link between endoplasmic reticulum stress and mTOR inactivation, therefore promotes cell survival during endoplasmic reticulum stress. PMID- 27992582 TI - Dietary Macronutrient Composition Directs ChREBP Isoform Expression and Glucose Metabolism in Mice. AB - Carbohydrate response element binding protein (ChREBP) is a lipogenic transcription factor that is thought to be involved in the development of hepatic steatosis and insulin resistance. Increased ChREBP expression in liver results in increased hepatic steatosis, and the isoform ChREBPbeta in adipose tissue can predict insulin sensitivity in obese humans. As ChREBP is activated by glucose, it was postulated that the composition of diet would regulate ChREBP isoform expression in metabolically relevant tissues. We compared the effects of diets with high complex carbohydrate, high fat, or a normal chow on ChREBP expression and metabolic parameters in C57BL/6 mice. We found that diets high in fat decrease ChREBP expression in adipose tissue, but isocaloric diets high in carbohydrate have no effect. Interestingly, this decrease in adipose ChREBP was associated with increased inflammatory markers. In the same animals a high carbohydrate diet induced a robust increase in hepatic ChREBPbeta expression (~2 fold; p = 0.0002), but little detectable change in the more abundant ChREBPalpha transcript. This change was accompanied by increased expression of target genes liver pyruvate kinase (p<0.0001), acetyl-CoA carboxylase (p = 0.0191) and stearoyl-CoA desaturase-1 (p = 0.0045). This increase in ChREBP expression was associated with increased hepatic steatosis, despite no changes in body weight or body fat when compared to chow-fed mice. Unexpectedly, mice fed a high carbohydrate diet displayed enhanced sensitivity to exogenous insulin, despite having mild glucose intolerance and increased liver steatosis. In summary, we have shown the composition of diet can selectively regulate ChREBP isoform expression in a tissue specific manner. Furthermore, we have shown a high complex carbohydrate diet selectively increases hepatic ChREBPbeta expression, which associates with hepatic steatosis but not insulin resistance. In contrast, a high fat diet reduces adipose ChREBP, which associates with inflammation and insulin resistance. PMID- 27992584 TI - Correction: Correction: Influenza Virus Targets Class I MHC-Educated NK Cells for Immunoevasion. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006021.]. PMID- 27992583 TI - Labour Trafficking among Men and Boys in the Greater Mekong Subregion: Exploitation, Violence, Occupational Health Risks and Injuries. AB - BACKGROUND: Men comprise nearly two-thirds of trafficked and forced labourers in common low-skilled labour sectors including fishing, agriculture and factory work. Yet, most evidence on human trafficking has focused on women and girls trafficked for sex work, with scant research on trafficked men and boys. METHODS: We analyse survey data from the largest systematic consecutive sample of trafficked people collected to date to describe the prevalence of violence, occupational health risks and injuries and associated factors. Participants were labour-trafficked men and boys using post-trafficking support services in Thailand, Cambodia and Vietnam. FINDINGS: Data are presented on 446 males aged 10 58. Men and boys were mainly trafficked for fishing (61.7%), manufacturing (19.1%) and begging (5.2%). Fishermen worked extensive hours (mean 18.8 hours/day, SD 5.9) and factory workers worked on average 11.9 hours/day (SD 2.9). 35.5% of male survivors had been injured while trafficked; 29.4% received no personal protective equipment (e.g. gloves). The most commonly reported injuries among all males were deep cuts (61.8%) and skin injuries (36.7%), injuries for which fewer than one-quarter reported receiving medical care. Six fishermen lost body parts, none of whom received medical care. Most males (80.5%) had no or very few rest breaks. One-third (37.8%) experienced severe violence. Work-related injuries were associated with severe violence (AOR 3.44, CI:1.63-7.26), being in the fishing sector, (AOR 4.12, CI:2.39-7.09) and threats (AOR 2.77, CI:1.62 4.75). Experiencing any violence was associated with threats (AOR 26.86, CI:14.0 51.23), being in the fishing sector (AOR 18.53, CI:8.74-39.28) and fluency in language of destination country (AOR 0.39, CI:0.20-0.75). CONCLUSION: This study highlights the abuse and extreme occupational hazards suffered by trafficked men and boys. Occupational health and safety interventions are urgently needed to protect male migrant labourers working in high-risk sectors, particularly fishing. PMID- 27992586 TI - Neurophysiological Modulations of Non-Verbal and Verbal Dual-Tasks Interference during Word Planning. AB - Running a concurrent task while speaking clearly interferes with speech planning, but whether verbal vs. non-verbal tasks interfere with the same processes is virtually unknown. We investigated the neural dynamics of dual-task interference on word production using event-related potentials (ERPs) with either tones or syllables as concurrent stimuli. Participants produced words from pictures in three conditions: without distractors, while passively listening to distractors and during a distractor detection task. Production latencies increased for tasks with higher attentional demand and were longer for syllables relative to tones. ERP analyses revealed common modulations by dual-task for verbal and non-verbal stimuli around 240 ms, likely corresponding to lexical selection. Modulations starting around 350 ms prior to vocal onset were only observed when verbal stimuli were involved. These later modulations, likely reflecting interference with phonological-phonetic encoding, were observed only when overlap between tasks was maximal and the same underlying neural circuits were engaged (cross talk). PMID- 27992585 TI - Effect of Nickel Levels on Hydrogen Partial Pressure and Methane Production in Methanogens. AB - Hydrogen (H2) consumption and methane (CH4) production in pure cultures of three different methanogens were investigated during cultivation with 0, 0.2 and 4.21 MUM added nickel (Ni). The results showed that the level of dissolved Ni in the anaerobic growth medium did not notably affect CH4 production in the cytochrome free methanogenic species Methanobacterium bryantii and Methanoculleus bourgensis MAB1, but affected CH4 formation rate in the cytochrome-containing Methanosarcina barkeri grown on H2 and CO2. Methanosarcina barkeri also had the highest amounts of Ni in its cells, indicating that more Ni is needed by cytochrome-containing than by cytochrome-free methanogenic species. The concentration of Ni affected threshold values of H2 partial pressure (pH2) for all three methanogen species studied, with M. bourgensis MAB1 reaching pH2 values as low as 0.1 Pa when Ni was available in amounts used in normal anaerobic growth medium. To our knowledge, this is the lowest pH2 threshold recorded to date in pure methanogen culture, which suggests that M.bourgensis MAB1 have a competitive advantage over other species through its ability to grow at low H2 concentrations. Our study has implications for research on the H2-driven deep subsurface biosphere and biogas reactor performance. PMID- 27992589 TI - A Reconfiguration Strategy of Distribution Networks Considering Node Importance. AB - Node importance degree is a vital index in distribution network reconfiguration because it reflects the robustness of the network structure by evaluating node importance. Since the traditional reconfiguration ignores this index, the reconstructed network structure may be vulnerable which would reduce the security and stability of the distribution systems. This paper presents a novel reconfiguration strategy considering the node importance. The optimization objectives are the improvement of the node importance degree and the reduction of power loss. To balance the objectives, the reconfiguration mathematical model is formulated as a compound objective function with weight coefficients. Then the quantum particle swarm algorithm is employed to address this compound objective optimization problem. The strategy can model different scenarios network reconfiguration by adjusting the weight vector based on the tendencies of the utility decision maker. Illustrative examples verify the effectiveness of the proposed strategy. PMID- 27992588 TI - Site-Specific Cleavage of Ribosomal RNA in Escherichia coli-Based Cell-Free Protein Synthesis Systems. AB - Cell-free protein synthesis, which mimics the biological protein production system, allows rapid expression of proteins without the need to maintain a viable cell. Nevertheless, cell-free protein expression relies on active in vivo translation machinery including ribosomes and translation factors. Here, we examined the integrity of the protein synthesis machinery, namely the functionality of ribosomes, during (i) the cell-free extract preparation and (ii) the performance of in vitro protein synthesis by analyzing crucial components involved in translation. Monitoring the 16S rRNA, 23S rRNA, elongation factors and ribosomal protein S1, we show that processing of a cell-free extract results in no substantial alteration of the translation machinery. Moreover, we reveal that the 16S rRNA is specifically cleaved at helix 44 during in vitro translation reactions, resulting in the removal of the anti-Shine-Dalgarno sequence. These defective ribosomes accumulate in the cell-free system. We demonstrate that the specific cleavage of the 16S rRNA is triggered by the decreased concentrations of Mg2+. In addition, we provide evidence that helix 44 of the 30S ribosomal subunit serves as a point-of-entry for ribosome degradation in Escherichia coli. Our results suggest that Mg2+ homeostasis is fundamental to preserving functional ribosomes in cell-free protein synthesis systems, which is of major importance for cell-free protein synthesis at preparative scale, in order to create highly efficient technical in vitro systems. PMID- 27992587 TI - Unit Nonresponse in a Population-Based Study of Prostate Cancer. AB - Low unit response rates can increase bias and compromise study validity. Response rates have continued to fall over the past decade despite all efforts to increase participation. Many factors have been linked to reduced response, yet relatively few studies have employed multivariate approaches to identify characteristics that differentiate respondents from nonrespondents since it is hard to collect information on the latter. We aimed to assess factors contributing to enrollment of prostate cancer (PCa) patients. We combined data from the North Carolina Louisiana (LA) PCa Project's LA cohort, with additional sources such as US census tract and LA tumor registry data. We included specific analyses focusing on blacks, a group often identified as hard to enroll in health-related research. The ability to study the effect of Hurricane Katrina, which occurred amidst enrollment, as a potential determinant of nonresponse makes our study unique. Older age (>= 70) for blacks (OR 0.65) and study phase with respect to Hurricane Katrina for both races (OR 0.59 for blacks, OR 0.48 for whites) were significant predictors of participation with lower odds. Neighborhood poverty for whites (OR 1.53) also was a significant predictor of participation, but with higher odds. Among blacks, residence in Orleans parish was associated with lower odds of participation (OR 0.33) before Katrina. The opposite occurred in whites, with lower odds (OR 0.43) after Katrina. Our results overall underscore the importance of tailoring enrollment approaches to specific target population characteristics to confront the challenges posed by nonresponse. Our results also show that recruitment-related factors may change when outside forces bring major alterations to a population's environment and demographics. PMID- 27992590 TI - Statistical Analysis of Bus Networks in India. AB - In this paper, we model the bus networks of six major Indian cities as graphs in L-space, and evaluate their various statistical properties. While airline and railway networks have been extensively studied, a comprehensive study on the structure and growth of bus networks is lacking. In India, where bus transport plays an important role in day-to-day commutation, it is of significant interest to analyze its topological structure and answer basic questions on its evolution, growth, robustness and resiliency. Although the common feature of small-world property is observed, our analysis reveals a wide spectrum of network topologies arising due to significant variation in the degree-distribution patterns in the networks. We also observe that these networks although, robust and resilient to random attacks are particularly degree-sensitive. Unlike real-world networks, such as Internet, WWW and airline, that are virtual, bus networks are physically constrained. Our findings therefore, throw light on the evolution of such geographically and constrained networks that will help us in designing more efficient bus networks in the future. PMID- 27992591 TI - Relationship of Rice Grain Amylose, Gelatinization Temperature and Pasting Properties for Breeding Better Eating and Cooking Quality of Rice Varieties. AB - A total of 787 non-waxy rice lines- 116 hybrids and 671 inbreds-were used to study the apparent amylose content (AAC), gelatinization temperature (GT), and rapid visco analyzer (RVA) pasting viscosity properties of rice starch to understand their importance in breeding better rice varieties. The investigated traits showed a wide range of diversity for both hybrid (HG) and inbred (IG) groups. The combinations of the different categories of AAC and GT were random in HG but were non-random in IG. For inbred lines, the high level of AAC tended to combine with the low level of GT, the intermediate level of AAC tended to have high or intermediate GT, and the low level of AAC tended to have high or low GT. Some stable correlations of the AAC, GT, and RVA properties may be the results derived from the physicochemical relationships among these traits, which rice breeders could utilize for selection in advanced breeding generations. Through cluster analysis, IG and HG were divided into 52 and 31 sub-clusters, respectively. Identifying the cultivars having AAC, GT, and RVA properties similar to that of popular high-quality rice varieties seems to be an interesting strategy and could be directly used for adaptation trials to breed high-quality rice varieties in targeted areas in a more customized manner. PMID- 27992592 TI - Effects of PI and PIII Snake Venom Haemorrhagic Metalloproteinases on the Microvasculature: A Confocal Microscopy Study on the Mouse Cremaster Muscle. AB - The precise mechanisms by which Snake Venom Metalloproteinases (SVMPs) disrupt the microvasculature and cause haemorrhage have not been completely elucidated, and novel in vivo models are needed. In the present study, we compared the effects induced by BaP1, a PI SVMP isolated from Bothrops asper venom, and CsH1, a PIII SVMP from Crotalus simus venom, on cremaster muscle microvasculature by topical application of the toxins on isolated tissue (i.e., ex vivo model), and by intra-scrotal administration of the toxins (i.e., in vivo model). The whole tissue was fixed and immunostained to visualize the three components of blood vessels by confocal microscopy. In the ex vivo model, BaP1 was able to degrade type IV collagen and laminin from the BM of microvessels. Moreover, both SVMPs degraded type IV collagen from the BM in capillaries to a higher extent than in PCV and arterioles. CsH1 had a stronger effect on type IV collagen than BaP1. In the in vivo model, the effect of BaP1 on type IV collagen was widespread to the BM of arterioles and PCV. On the other hand, BaP1 was able to disrupt the endothelial barrier in PCV and to increase vascular permeability. Moreover, this toxin increased the size of gaps between pericytes in PCV and created new gaps between smooth muscle cells in arterioles in ex vivo conditions. These effects were not observed in the case of CsH1. In conclusion, our findings demonstrate that both SVMPs degrade type IV collagen from the BM in capillaries in vivo. Moreover, while the action of CsH1 is more directed to the BM of microvessels, the effects of BaP1 are widespread to other microvascular components. This study provides new insights in the mechanism of haemorrhage and other pathological effects induced by these toxins. PMID- 27992593 TI - Selection and Validation of Reference Genes for Gene Expression Analysis in Vigna angularis Using Quantitative Real-Time RT-PCR. AB - Adzuki bean (Vigna angularis) is one of the most important legume crops in Asian countries like China, Japan and Korea due to its nutritious protein and starch contents. In spite of its economic importance, gene expression analysis system for gene function verification of adzuki bean is still absent. Therefore, reference genes for gene expression analysis based on the quantitative real time PCR (qRT-PCR) were screened in current study. A total of nine general housekeeping genes, including ACT, Fbox, ZMPP, GAPDH, EF, PP2A, UBC, UBN and PTB were evaluated for their expression stability by qRT-PCR in four adzuki bean cultivars, three different tissues, four abiotic stress and one biotic stress. The best group of candidates as reference genes were as follows: PTB and ACT for different cultivars; EF and UBN for different tissues; ACT and ZMPP for biotic stress and waterlogging stress; Fbox and UBC for salinity-alkalinity stress; Fbox and PTB for drought stress. Our results will provide a more accurate and reliable normalization of qRT-PCR data in adzuki bean. PMID- 27992594 TI - A Hybrid Approach for Improving Image Segmentation: Application to Phenotyping of Wheat Leaves. AB - In this article we propose a novel tool that takes an initial segmented image and returns a more accurate segmentation that accurately captures sharp features such as leaf tips, twists and axils. Our algorithm utilizes basic a-priori information about the shape of plant leaves and local image orientations to fit active contour models to important plant features that have been missed during the initial segmentation. We compare the performance of our approach with three state of-the-art segmentation techniques, using three error metrics. The results show that leaf tips are detected with roughly one half of the original error, segmentation accuracy is almost always improved and more than half of the leaf breakages are corrected. PMID- 27992595 TI - Predictors of Health-Related Quality of Life in Patients with Co-Morbid Diabetes and Chronic Kidney Disease. AB - BACKGROUND: People living with diabetes and chronic kidney disease (CKD) experience compromised quality of life. Consequently, it is critical to identify and understand factors influencing their health-related quality of life (HRQoL). This study examined factors associated with HRQoL among patients with diabetes and CKD. METHODS: A cross sectional study among adults with comorbid diabetes and CKD (eGFR <60 mL/min/1.73m2) recruited from renal and diabetes clinics of four large tertiary referral hospitals in Australia was performed. Each participant completed the Kidney Disease Quality of Life (KDQoL TM -36) questionnaire, which is comprised of two composite measures of physical and mental health and 3 kidney disease specific subscales with possible scores ranging from 0 to 100 with higher values indicating better HRQoL. Demographic and clinical data were also collected. Regression analyses were performed to determine the relationship between HRQoL and potential predictor factors. RESULTS: A total of 308 patients were studied with a mean age of 66.9 (SD = 11.0) years and 70% were males. Mean scores for the physical composite summary, mental composite summary, symptom/problem list, effects of kidney disease and burden of kidney disease scales were 35.2, 47.0, 73.8, 72.5 and 59.8 respectively. Younger age was associated with lower scores in all subscales except for the physical composite summary. Female gender, obese or normal weight rather than overweight, and smoking were all associated with lower scores in one or more subscales. Scores were progressively lower with more advanced stage of CKD (p<0.05) in all subscales except for the mental composite summary. CONCLUSION: In patients with diabetes and CKD, younger age was associated with lower scores in all HRQoL subscales except the physical composite summary and female gender, obese or normal weight and more advanced stages of CKD were associated with lower scores in one or more subscales. Identifying these factors will inform the timely implementation of interventions to improve the quality of life of these patients. PMID- 27992597 TI - Correction: First Report of the Human-Pathogenic Enterocytozoon bieneusi from Red Bellied Tree Squirrels (Callosciurus erythraeus) in Sichuan, China. AB - [This corrects the article DOI: 10.1371/journal.pone.0163605.]. PMID- 27992596 TI - Phospholamban Ablation Using CRISPR/Cas9 System Improves Mortality in a Murine Heart Failure Model. AB - Sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and its inhibitory protein called phospholamban (PLN) are pivotal for Ca2+ handling in cardiomyocyte and are known that their expression level and activity were changed in the heart failure patients. To examine whether PLN inhibition can improve survival rate as well as cardiac function in heart failure, we performed PLN ablation in calsequestrin overexpressing (CSQ-Tg) mice, a severe heart failure model, using clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system. According this method, generation rate of PLN wild type mice (PLN copy >0.95) and PLN homozygous knockout (KO) mice (PLN copy <0.05) were 39.1% and 10.5%, respectively. While CSQ overexpression causes severe heart failure symptoms and premature death, a significant ameliorating effect on survival rate was observed in PLN homozygous KO/CSQ-Tg mice compared to PLN wild type/CSQ-Tg mice (median survival days are 55 and 50 days, respectively). Measurement of cardiac function with cardiac catheterization at the age of 5 weeks revealed that PLN ablation improved cardiac function in CSQ-Tg mice without affecting heart rate and blood pressure. Furthermore, increases in atrial and lung weight, an index of congestion, were significantly inhibited by PLN ablation. These results suggest that PLN deletion would be a promising approach to improve both mortality and cardiac function in the heart failure. PMID- 27992598 TI - Variable and Asymmetric Range of Enslaving: Fingers Can Act Independently over Small Range of Flexion. AB - The variability in the numerous tasks in which we use our hands is very large. However, independent movement control of individual fingers is limited. To assess the extent of finger independency during full-range finger flexion including all finger joints, we studied enslaving (movement in non-instructed fingers) and range of independent finger movement through the whole finger flexion trajectory in single and multi-finger movement tasks. Thirteen young healthy subjects performed single- and multi-finger movement tasks under two conditions: active flexion through the full range of movement with all fingers free to move and active flexion while the non-instructed finger(s) were restrained. Finger kinematics were measured using inertial sensors (PowerGlove), to assess enslaving and range of independent finger movement. Although all fingers showed enslaving movement to some extent, highest enslaving was found in adjacent fingers. Enslaving effects in ring and little finger were increased with movement of additional, non-adjacent fingers. The middle finger was the only finger affected by restriction in movement of non-instructed fingers. Each finger showed a range of independent movement before the non-instructed fingers started to move, which was largest for the index finger. The start of enslaving was asymmetrical for adjacent fingers. Little finger enslaving movement was affected by multi-finger movement. We conclude that no finger can move independently through the full range of finger flexion, although some degree of full independence is present for smaller movements. This range of independent movement is asymmetric and variable between fingers and between subjects. The presented results provide insight into the role of finger independency for different types of tasks and populations. PMID- 27992599 TI - RhoA Proteolysis Regulates the Actin Cytoskeleton in Response to Oxidative Stress. AB - The small GTPase RhoA regulates the actin cytoskeleton to affect multiple cellular processes including endocytosis, migration and adhesion. RhoA activity is tightly regulated through several mechanisms including GDP/GTP cycling, phosphorylation, glycosylation and prenylation. Previous reports have also reported that cleavage of the carboxy-terminus inactivates RhoA. Here, we describe a novel mechanism of RhoA proteolysis that generates a stable amino terminal RhoA fragment (RhoA-NTF). RhoA-NTF is detectable in healthy cells and tissues and is upregulated following cell stress. Overexpression of either RhoA NTF or the carboxy-terminal RhoA cleavage fragment (RhoA-CTF) induces the formation of disorganized actin stress fibres. RhoA-CTF also promotes the formation of disorganized actin stress fibres and nuclear actin rods. Both fragments disrupt the organization of actin stress fibres formed by endogenous RhoA. Together, our findings describe a novel RhoA regulatory mechanism. PMID- 27992600 TI - Methylation-Sensitive Melt Curve Analysis of the Reprimo Gene Methylation in Gastric Cancer. AB - Reprimo (RPRM) is a p53-induced tumor suppressor gene. Its aberrant DNA methylation is correlated with carcinogenesis and may be used as a surrogate marker for the early detection of gastric cancer. However, the detail information regarding its DNA methylation has not been revealed. Here, we investigated the RPRM gene methylation in gastric cancer tumor and plasma samples by methylation sensitive melt curve analysis (MS-MCA) and bisulfite sequencing in depth. We developed a semi-quantitative method based on MS-MCA for detecting DNA methylation and unraveled the RPRM gene methylation pattern in gastric cancer. This study provides a solid foundation for the future application of detecting RPRM gene methylation in human plasma or serum samples to help diagnose gastric cancer or for prognosis evaluation. PMID- 27992601 TI - A Novel Functional Domain of Tab2 Involved in the Interaction with Estrogen Receptor Alpha in Breast Cancer Cells. AB - Tab2, originally described as a component of the inflammatory pathway, has been implicated in phenomena of gene de-repression in several contexts, due to its ability to interact with the NCoR corepressor. Tab2 interacts also with steroid receptors and dismisses NCoR from antagonist-bound Estrogen and Androgen Receptors on gene regulatory regions, thus modifying their transcriptional activity and leading to pharmacological resistance in breast and prostate cancer cells. We demonstrated previously that either Tab2 knock-down, or a peptide mimicking the Estrogen Receptor alpha domain interacting with Tab2, restore the antiproliferative response to Tamoxifen in Tamoxifen-resistant breast cancer cells. In this work, we map the domain of Tab2 responsible of Estrogen Receptor alpha interaction. First, using both co-immunoprecipitation and pull-down with recombinant proteins, we found that the central part of Tab2 is primarily responsible for this interaction, and that this region also interacts with Androgen Receptor. Then, we narrowed down the essential interaction region by means of competition assays using recombinant protein pull-down. The interaction motif was finally identified as a small region adjacent to, but not overlapping, the Tab2 MEKK1 phosphorylation sites. A synthetic peptide mimicking this motif efficiently displaced Tab2 from interacting with recombinant Estrogen Receptor alpha in vitro, prompting us to test its efficacy using derivatives of the MCF7 breast carcinoma cell lines that are spontaneously resistant to Tamoxifen. Indeed, we observed that this mimic peptide, made cell-permeable by addition of the TAT minimal carrier domain, reduced the growth of Tamoxifen-resistant MCF7 cells in the presence of Tamoxifen. These data indicate a novel functional domain of the Tab2 protein with potential application in drug design. PMID- 27992603 TI - Correction: Separating Predicted and Perceived Sensory Consequences of Motor Learning. AB - [This corrects the article DOI: 10.1371/journal.pone.0163556.]. PMID- 27992602 TI - Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer. AB - Structural rearrangements of HIV-1 glycoprotein Env promote viral entry through membrane fusion. Env is a symmetric homotrimer with each protomer composed of surface subunit gp120 and transmembrane subunit gp41. Cellular CD4- and chemokine receptor-binding to gp120 coordinate conformational changes in gp41, first to an extended prehairpin intermediate (PHI) and, ultimately, into a fusogenic trimer of-hairpins (TOH). HIV-1 fusion inhibitors target gp41 in the PHI and block TOH formation. To characterize structural transformations into and through the PHI, we employed asymmetric Env trimers containing both high and low affinity binding sites for individual fusion inhibitors. Asymmetry was achieved using engineered Env heterotrimers composed of protomers deficient in either CD4- or chemokine receptor-binding. Linking receptor engagement to inhibitor affinity allowed us to assess conformational changes of individual Env protomers in the context of a functioning trimer. We found that the transition into the PHI could occur symmetrically or asymmetrically depending on the stoichiometry of CD4 binding. Sequential engagement of multiple CD4s promoted progressive exposure of individual fusion inhibitor binding sites in a CD4-dependent fashion. By contrast, engagement of only a single CD4 molecule led to a delayed, but symmetric, exposure of the gp41 trimer. This complex coupling between Env-CD4 interaction and gp41 exposure explained the multiphasic fusion-inhibitor titration observed for a mutant Env homotrimer with a naturally asymmetric gp41. Our results suggest that the spatial and temporal exposure of gp41 can proceed in a nonconcerted, asymmetric manner depending on the number of CD4s that engage the Env trimer. The findings have important implications for the mechanism of viral membrane fusion and the development of vaccine candidates designed to elicit neutralizing antibodies targeting gp41 in the PHI. PMID- 27992605 TI - Correction: The Role of Diverse Strategies in Sustainable Knowledge Production. AB - [This corrects the article DOI: 10.1371/journal.pone.0149151.]. PMID- 27992604 TI - Incidence and Risk Factors for Incident Syphilis among HIV-1-Infected Men Who Have Sex with Men in a Large Urban HIV Clinic in Tokyo, 2008-2015. AB - BACKGROUND: The epidemiology of incident syphilis infection among HIV-1-infected men who have sex with men (MSM) largely remains unknown. METHODS: The incidence and risk factors for incident syphilis (positive TPHA and RPR> = 1:8) among HIV-1 infected MSM who visited a large HIV clinic in Tokyo for the first time between 2008 and 2013 were determined, using clinical data and stored blood samples taken every three months for screening and determination of the date of incident syphilis. Poisson regression compared the incidence of syphilis at different observation periods. RESULTS: Of 885 HIV-1-infected MSM with baseline data, 34% either presented with active syphilis at baseline (21%) or became infected with syphilis during follow-up (13%). After excluding 214 patients (MSM with syphilis at baseline (n = 190) and no follow-up syphilis test (n = 24)), of 671 men, 112 (17%) developed incident syphilis with an incidence of 43.7/1,000 person-years [95% CI, 36.5-52.3]. The incidence decreased slightly during observation period although the trend was not significant (2008-2009: 48.2/1,000 person-years, 2010 2011: 51.1/1,000 person-years, 2012-2013: 42.6/1,000 person-years, 2014 to 2015: 37.9/1,000 person-years, p = 0.315). Multivariable analysis identified young age (<33 years versus >40, HR 4.0, 95%CI 2.22-7.18, p<0.001), history of syphilis at baseline (HR 3.0, 95%CI 2.03-4.47, p<0.001), positive anti-amoeba antibody (HR 1.8, 95%CI 1.17-2.68, p = 0.006), and high baseline CD4 count (CD4 >=350 /MUL versus CD4 <200, HR 1.6, 95%CI 1.00-2.53, p = 0.050) as risk factors for incident syphilis. Incidence of syphilis was particularly high among young patients (age <33 years: 60.1/1,000 person-years). Interestingly, 37% of patients with incident syphilis were asymptomatic. CONCLUSIONS: Although incidence of syphilis did not increase during the observation period, it was high among HIV-1-infected MSM, especially among young HIV-1-infected MSM and those with history of syphilis, in Tokyo. Regular screening for syphilis needs to be strictly applied to this population. PMID- 27992606 TI - Correction: Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells Correlation to Inflammatory Biomarkers. AB - [This corrects the article DOI: 10.1371/journal.pone.0161346.]. PMID- 27992607 TI - Correction: Associations of Infant Feeding and Timing of Weight Gain and Linear Growth during Early Life with Childhood Blood Pressure: Findings from a Prospective Population Based Cohort Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0166281.]. PMID- 27992608 TI - Correction: Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0160748.]. PMID- 27992609 TI - Use of Oral Cholera Vaccine and Knowledge, Attitudes, and Practices Regarding Safe Water, Sanitation and Hygiene in a Long-Standing Refugee Camp, Thailand, 2012-2014. AB - Oral cholera vaccines (OCVs) are relatively new public health interventions, and limited data exist on the potential impact of OCV use on traditional cholera prevention and control measures-safe water, sanitation and hygiene (WaSH). To assess OCV acceptability and knowledge, attitudes, and practices (KAPs) regarding cholera and WaSH, we conducted cross-sectional surveys, 1 month before (baseline) and 3 and 12 months after (first and second follow-up) a preemptive OCV campaign in Maela, a long-standing refugee camp on the Thailand-Burma border. We randomly selected households for the surveys, and administered questionnaires to female heads of households. In total, 271 (77%), 187 (81%), and 199 (85%) households were included in the baseline, first and second follow-up surveys, respectively. Anticipated OCV acceptability was 97% at baseline, and 91% and 85% of household members were reported to have received 1 and 2 OCV doses at first follow-up. Compared with baseline, statistically significant differences (95% Wald confidence interval not overlapping zero) were noted at first and second follow up among the proportions of respondents who correctly identified two or more means of cholera prevention (62% versus 78% and 80%), reported boiling or treating drinking water (19% versus 44% and 69%), and washing hands with soap (66% versus 77% and 85%); a significant difference was also observed in the proportion of households with soap available at handwashing areas (84% versus 90% and 95%), consistent with reported behaviors. No significant difference was noted in the proportion of households testing positive for Escherichia coli in stored household drinking water at second follow-up (39% versus 49% and 34%). Overall, we observed some positive, and no negative changes in cholera- and WaSH-related KAPs after an OCV campaign in Maela refugee camp. OCV campaigns may provide opportunities to reinforce beneficial WaSH-related KAPs for comprehensive cholera prevention and control. PMID- 27992610 TI - Maternal Preeclampsia and Androgens in the Offspring around Puberty: A Follow-Up Study. AB - BACKGROUND: Children born after preeclampsia may have a dominant androgen profile in puberty compared with other children. Circulating androgen concentrations at 11-12 years of age were compared between offspring born after preeclampsia, and children whose mothers did not have preeclampsia. METHODS: A total of 611 mother offspring pairs were followed up 11 (daughters) or 12 (sons) years after birth: 218 pairs in the preeclampsia group, and 383 pairs without preeclampsia. Circulating total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor I (IGF-I) were measured in the children. In boys, testicular volume was also measured. RESULTS: Among girls born after preeclampsia, DHEAS concentrations were higher than in unexposed girls (p<0.001), however, girls born after preeclampsia with severe features had the lowest DHEAS levels. In contrast, testosterone concentrations were highest in girls born after preeclampsia with severe features, both compared to other girls in the preeclampsia group, and compared to unexposed girls (p<0.001). For boys, testosterone concentrations were higher in the preeclampsia group compared with unexposed boys (p<0.001), and boys born after preeclampsia with severe features had the lowest concentrations of DHEAS. Compared with unexposed boys, testicular volume (p = 0.015) and IGF-I (p = 0.004) were higher for boys in the preeclampsia group, except for boys in the clinically severe preeclampsia group. CONCLUSIONS: In utero exposure to preeclampsia is associated with androgen hormonal patterns in early puberty that depend on clinical severity of preeclampsia and sex of the offspring. The hormonal differences may reflect different timing of pubertal development, and may have consequences for future health of the offspring. PMID- 27992611 TI - A Nomogram to Predict Adequate Lymph Node Recovery before Resection of Colorectal Cancer. AB - Increased lymph node count (LNC) has been associated with prolonged survival in colorectal cancer (CRC), but the underlying mechanisms are still poorly understood. The study aims to identify new predictors and develop a preoperative nomogram for predicting the probability of adequate LNC (>= 12). 501 eligible patients were retrospectively selected to identify clinical-pathological factors associated with LNC >= 12 through univariate and multivariate logistic regression analyses. The nomogram was built according to multivariate analyses of preoperative factors. Model performance was assessed with concordance index (c index) and area under the receiver operating characteristic curve (AUC), followed by internal validation and calibration using 1000-resample bootstrapping. Clinical validity of the nomogram and LNC impact on stage migration were also evaluated. Multivariate analyses showed patient age, CA19-9, circulating lymphocytes, neutrophils, platelets, tumor diameter, histology and deposit significantly correlated with LNC (P < 0.05). The effects were marginal for CEA, anemia and CRC location (0.05 < P < 0.1). The multivariate analyses of preoperative factors suggested decreased age, CEA, CA19-9, neutrophils, proximal location, and increased platelets and diameter were significantly associated with increased probability of LNC >= 12 (P < 0.05). The nomogram achieved c-indexes of 0.75 and 0.73 before and after correction for overfitting. The AUC was 0.75 (95% CI, 0.70-0.79) and the clinically valid threshold probabilities were between 10% and 60% for the nomogram to predict LNC < 12. Additionally, increased probability of adequate LNC before surgery was associated with increased LNC and negative lymph nodes rather than increased positive lymph nodes, lymph node ratio, pN stages or AJCC stages. Collectively, the results indicate the LNC is multifactorial and irrelevant to stage migration. The significant correlations with preoperative circulating markers may provide new explanations for LNC related survival advantage which is reflected by the implication of regional and systemic antitumor immune responses. PMID- 27992612 TI - The Calculator of Anti-Alzheimer's Diet. Macronutrients. AB - The opinions about optimal proportions of macronutrients in a healthy diet have changed significantly over the last century. At the same time nutritional sciences failed to provide strong evidence backing up any of the variety of views on macronutrient proportions. Herein we present an idea how these proportions can be calculated to find an optimal balance of macronutrients with respect to prevention of Alzheimer's Disease (AD) and dementia. These calculations are based on our published observation that per capita personal income (PCPI) in the USA correlates with age-adjusted death rates for AD (AADR). We have previously reported that PCPI through the period 1925-2005 correlated with AADR in 2005 in a remarkable, statistically significant oscillatory manner, as shown by changes in the correlation coefficient R (Roriginal). A question thus arises what caused the oscillatory behavior of Roriginal? What historical events in the life of 2005 AD victims had shaped their future with AD? Looking for the answers we found that, considering changes in the per capita availability of macronutrients in the USA in the period 1929-2005, we can mathematically explain the variability of Roriginal for each quarter of a human life. On the basis of multiple regression of Roriginal with regard to the availability of three macronutrients: carbohydrates, total fat, and protein, with or without alcohol, we propose seven equations (referred to as "the calculator" throughout the text) which allow calculating optimal changes in the proportions of macronutrients to reduce the risk of AD for each age group: youth, early middle age, late middle age and late age. The results obtained with the use of "the calculator" are grouped in a table (Table 4) of macronutrient proportions optimal for reducing the risk of AD in each age group through minimizing Rpredicted-i.e., minimizing the strength of correlation between PCPI and future AADR. PMID- 27992613 TI - The Association of Resting Heart Rate with the Presence of Diabetes in Korean Adults: The 2010-2013 Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Previous epidemiologic studies have shown that elevated resting heart rate (HR) is associated with higher cardiovascular disease (CVD) morbidity and mortality. Although the relationship between elevated HR and CVD is well established, the association between resting HR and diabetes has been relatively understudied, particularly in non-Western populations. OBJECTIVES: We confirmed the association between the presence of type 2 diabetes and resting HR in the Korean adult population using data from the 2010-2013 Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: Among 25,712 adults (>= 19 years of age) who participated in the 2010-2013 KNHANES, a total of 22,512 subjects completed laboratory examinations and were included in this analysis. The fasting plasma glucose (FPG) level was categorized into the following five groups: normal fasting glucose (NFG) 1 (<90 mg/dL), NFG 2 (90-99 mg/dL), impaired fasting glucose (IFG) 1 (100-110 mg/dL), IFG 2 (111-125 mg/dL), and diabetes (>= 126 mg/dL). RESULTS: The unadjusted weighted resting HRs were 69.6, 69.4, 69.8, 70.1, and 72.0 beats per minute (bpm) in the NFG 1, NFG 2, IFG 1, IFG 2, and diabetes groups, respectively (P<0.001). We assessed the adjusted weighted resting HR according to the FPG level after adjusting for age, sex, smoking history, high risk alcohol drinking, daily energy intake, waist circumference, serum total cholesterol level, serum triglyceride (TG) level, serum white blood cell (WBC) count, serum hemoglobin (Hb), and the presence of hypertension. The adjusted weighted resting HR significantly increased across the FPG groups (P<0.001). The weighted prevalence rates of diabetes were 6.8% (6.2-7.5%), 7.6% (6.7-8.5%), 8.0% (7.0-9.1%), and 11.8% (10.8-12.7%) in subjects with HR <= 64, 65-69, 70-75, and >= 76 bpm, respectively (P<0.001), after adjusting for the confounding factors mentioned above. Using resting HR <= 64 bpm as the control, resting HR >= 76 bpm was correlated with the presence of diabetes (adjusted OR 1.83, 95% CI 1.55-2.16, P<0.001). Each 10 bpm increment of HR increased the risk of the presence of diabetes by 35% (P<0.001). This association of high resting HR with the presence of diabetes was not influenced by the status of blood pressure (BP) medication. CONCLUSION: We demonstrated that higher HR was associated with diabetes in a representative sample of Korean adults. These positive associations were independent of age, sex, current smoking, high risk alcohol drinking, daily energy intake, waist circumference, and the presence of hypertension and other potential confounders. This study suggests that individuals with higher resting HR are at risk of diabetes and that HR might provide an easy and simple surrogate marker for the risk of diabetes. PMID- 27992614 TI - A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men. AB - BACKGROUND: Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). METHODS: We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan(r) PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. RESULTS: The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32-4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50-6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. CONCLUSIONS: To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD. PMID- 27992615 TI - Breaking the Cycle of Compounded Adversity in the Lives of Institutionalized Youth. PMID- 27992616 TI - Association of Preoperative Anemia With Postoperative Mortality in Neonates. PMID- 27992617 TI - Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians. AB - Importance: Studies have found differences in practice patterns between male and female physicians, with female physicians more likely to adhere to clinical guidelines and evidence-based practice. However, whether patient outcomes differ between male and female physicians is largely unknown. Objective: To determine whether mortality and readmission rates differ between patients treated by male or female physicians. Design, Setting, and Participants: We analyzed a 20% random sample of Medicare fee-for-service beneficiaries 65 years or older hospitalized with a medical condition and treated by general internists from January 1, 2011, to December 31, 2014. We examined the association between physician sex and 30 day mortality and readmission rates, adjusted for patient and physician characteristics and hospital fixed effects (effectively comparing female and male physicians within the same hospital). As a sensitivity analysis, we examined only physicians focusing on hospital care (hospitalists), among whom patients are plausibly quasi-randomized to physicians based on the physician's specific work schedules. We also investigated whether differences in patient outcomes varied by specific condition or by underlying severity of illness. Main Outcomes and Measures: Patients' 30-day mortality and readmission rates. Results: A total of 1 583 028 hospitalizations were used for analyses of 30-day mortality (mean [SD] patient age, 80.2 [8.5] years; 621 412 men and 961 616 women) and 1 540 797 were used for analyses of readmission (mean [SD] patient age, 80.1 [8.5] years; 602 115 men and 938 682 women). Patients treated by female physicians had lower 30 day mortality (adjusted mortality, 11.07% vs 11.49%; adjusted risk difference, 0.43%; 95% CI, -0.57% to -0.28%; P < .001; number needed to treat to prevent 1 death, 233) and lower 30-day readmissions (adjusted readmissions, 15.02% vs 15.57%; adjusted risk difference, -0.55%; 95% CI, -0.71% to -0.39%; P < .001; number needed to treat to prevent 1 readmission, 182) than patients cared for by male physicians, after accounting for potential confounders. Our findings were unaffected when restricting analyses to patients treated by hospitalists. Differences persisted across 8 common medical conditions and across patients' severity of illness. Conclusions and Relevance: Elderly hospitalized patients treated by female internists have lower mortality and readmissions compared with those cared for by male internists. These findings suggest that the differences in practice patterns between male and female physicians, as suggested in previous studies, may have important clinical implications for patient outcomes. PMID- 27992618 TI - The Women, Infants, and Children Food Package and 100% Fruit Juice. PMID- 27992619 TI - Trends in Marijuana Use Among Pregnant and Nonpregnant Reproductive-Aged Women, 2002-2014. PMID- 27992620 TI - A Maker Movement for Health: A New Paradigm for Health Innovation. PMID- 27992621 TI - Survivorship in Children and Young Adults With Congenital Heart Disease in Sweden. AB - Importance: Mortality in patients with congenital heart disease (CHD) has markedly decreased during recent decades because of advancement in pediatric care. However, there are limited data on survival trends in children and young adults with CHD compared with the general population. Objective: To determine survivorship in children and young adults with CHD compared with matched controls. Design, Setting, and Participants: A registry-based, prospective, matched-cohort study was conducted in Sweden. Data from the national patient and cause of death registers were linked to identify individuals with CHD born between January 1, 1970, and December 31, 1993, who were registered at or after birth. Follow-up and comorbidity data were collected until December 31, 2011. Survival analyses were performed with the Cox proportional hazards model; these analyses were performed from January 1, 1970, to December 31, 2011. A total of 21 982 patients with CHD in Sweden were identified. The mean (SD) follow-up time was 27.0 (8.86) years. Children serving as controls (n = 219 816) (10 for each patient), matched for birth year, sex, and county, were randomly selected from the general population. Main Outcomes and Measures: Survivorship in young patients with CHD and controls. Results: Of the 21 982 patients who were born between 1970 and 1993 and were registered with the diagnosis of CHD, 10 650 were female (48.4%). Median age at index registration was 4.22 years (interquartile range, 17.07 years). Survivorship among children younger than 5 years was increased from 96% in those born in 1970-1979 to 98% in those born in 1990-1993. Hazard ratios (HRs) of death in relation to that in control individuals decreased from 225.84 (95% CI, 136.84-372.70) to 33.47 (95% CI, 22.54-49.70). A substantial, but less pronounced, absolute and relative increase in survivorship was found in older patients (HRs ranged from 24.52; 95% CI, 11.72-51.26, at 5-9 years to 4.27; 95% CI, 2.29-7.95, at 18-29 years). According to a hierarchical CHD classification, the group of patients with the most severe complex defects (ie, common arterial trunk, transposition of the great vessels, double inlet ventricle, hypoplastic left heart syndrome, tetralogy of Fallot, and atrioventricular septal defect) had the highest risk for death (HR, 64.07; 95% CI, 53.39-76.89). Conclusions and Relevance: Despite substantially increasing absolute and relative survivorship in children and young adults with CHD, the mortality risk remains high compared with the risk in matched controls. Further research on reducing the death rate in this vulnerable group is required. PMID- 27992622 TI - The Women, Infants, and Children Food Package and 100% Fruit Juice-Reply. PMID- 27992623 TI - Women in Medicine and Patient Outcomes: Equal Rights for Better Work? PMID- 27992624 TI - Association of Perioperative Statin Use With Mortality and Morbidity After Major Noncardiac Surgery. AB - Importance: The efficacy of statins in reducing perioperative cardiovascular and other organ system complications in patients undergoing noncardiac surgery remains controversial. Owing to a paucity of randomized clinical trials, analyses of large databases may facilitate informed hypothesis generation and more efficient trial design. Objective: To evaluate associations of early perioperative statin use with outcomes in a national cohort of veterans undergoing noncardiac surgery. Design, Setting, and Participants: This retrospective, observational cohort analysis included 180 478 veterans undergoing elective or emergent noncardiac surgery (including vascular, general, neurosurgery, orthopedic, thoracic, urologic, and otolaryngologic) who were admitted within 7 days of surgery and sampled by the Veterans Affairs Surgical Quality Improvement Program (VASQIP). Patients were admitted to Department of Veterans Affairs hospitals and underwent 30-day postoperative follow-up. Data were collected from October 1, 2005, to September 30, 2010, and analyzed from November 28, 2013, to October 31, 2016. Exposure: Statin use on the day of or the day after surgery. Main Outcomes and Measures: All-cause 30-day mortality (primary outcome) and standardized 30-day cardiovascular and noncardiovascular outcomes captured by VASQIP. Use of statins and other perioperative cardiovascular medications was ascertained from the Veterans Affairs Pharmacy Benefits Management research database. Results: A total of 180 478 eligible patients (95.6% men and 4.4% women; mean [SD] age, 63.8 [11.6] years) underwent analysis, and 96 486 were included in the propensity score-matched cohort (96.3% men; 3.7% women; mean [SD] age, 65.9 [10.6] years). At the time of hospital admission, 37.8% of patients had an active outpatient prescription for a statin, of whom 80.8% were prescribed simvastatin and 59.5% used moderate-intensity dosing. Exposure to a statin on the day of or the day after surgery based on an inpatient prescription was noted in 31.5% of the cohort. Among 48 243 propensity score-matched pairs of early perioperative statin-exposed and nonexposed patients, 30-day all-cause mortality was significantly reduced in exposed patients (relative risk, 0.82; 95% CI, 0.75-0.89; P < .001; number needed to treat, 244; 95% CI, 170-432). Of the secondary outcomes, a significant association with reduced risk of any complication was noted (relative risk, 0.82; 95% CI, 0.79-0.86; P < .001; number needed to treat, 67; 95% CI, 55-87); all were significant except for the central nervous system and thrombosis categories, with the greatest risk reduction (relative risk, 0.73; 95% CI, 0.64-0.83) for cardiac complications. Conclusions and Relevance: Early perioperative exposure to a statin was associated with a significant reduction in all-cause perioperative mortality and several cardiovascular and noncardiovascular complications. However, the potential for selection biases in these results must be considered. PMID- 27992625 TI - Association of Periodic and Rhythmic Electroencephalographic Patterns With Seizures in Critically Ill Patients. AB - Importance: Periodic and rhythmic electroencephalographic patterns have been associated with risk of seizures in critically ill patients. However, specific features that confer higher seizure risk remain unclear. Objective: To analyze the association of distinct characteristics of periodic and rhythmic patterns with seizures. Design, Setting, and Participants: We reviewed electroencephalographic recordings from 4772 critically ill adults in 3 academic medical centers from February 2013 to September 2015 and performed a multivariate analysis to determine features associated with seizures. Interventions: Continuous electroencephalography. Main Outcomes and Measures: Association of periodic and rhythmic patterns and specific characteristics, such as pattern frequency (hertz), Plus modifier, prevalence, and stimulation-induced patterns, and the risk for seizures. Results: Of the 4772 patients included in our study, 2868 were men and 1904 were women. Lateralized periodic discharges (LPDs) had the highest association with seizures regardless of frequency and the association was greater when the Plus modifier was present (58%; odds ratio [OR], 2.00, P < .001). Generalized periodic discharges (GPDs) and lateralized rhythmic delta activity (LRDA) were associated with seizures in a frequency-dependent manner (1.5-2 Hz: GPDs, 24%,OR, 2.31, P = .02; LRDA, 24%, OR, 1.79, P = .05; >= 2 Hz: GPDs, 32%, OR, 3.30, P < .001; LRDA, 40%, OR, 3.98, P < .001) as was the association with Plus (GPDs, 28%, OR, 3.57, P < .001; LRDA, 40%, P < .001). There was no difference in seizure incidence in patients with generalized rhythmic delta activity compared with no periodic or rhythmic pattern (13%, OR, 1.18, P = .26). Higher prevalence of LPDs and GPDs also conferred increased seizure risk (37% frequent vs 45% abundant/continuous, OR, 1.64, P = .03 for difference; 8% rare/occasional vs 15% frequent, OR, 2.71, P = .03, vs 23% abundant/continuous, OR, 1.95, P = .04). Patterns associated with stimulation did not show an additional risk for seizures from the underlying pattern risk (P > .10). Conclusions and Relevance: In this study, LPDs, LRDA, and GPDs were associated with seizures while generalized rhythmic delta activity was not. Lateralized periodic discharges were associated with seizures at all frequencies with and without Plus modifier, but LRDA and GPDs were associated with seizures when the frequency was 1.5 Hz or faster or when associated with a Plus modifier. Increased pattern prevalence was associated with increased risk for seizures in LPDs and GPDs. Stimulus-induced patterns were not associated with such risk. These findings highlight the importance of detailed electroencephalographic interpretation using standardized nomenclature for seizure risk stratification and clinical decision making. PMID- 27992626 TI - Sex and Racial/Ethnic Differences in Positive Outcomes in Delinquent Youth After Detention: A 12-Year Longitudinal Study. AB - Importance: Longitudinal studies of delinquent youth have focused on criminal recidivism, not on psychosocial outcomes in adulthood. This omission is critical because after detention most youth return to the community, where they become the responsibility of pediatric health care professionals. Objective: To investigate 8 positive outcomes among delinquent youth 5 and 12 years after detention, focusing on sex and racial/ethnic differences. Design, Setting, and Participants: In the Northwestern Juvenile Project, a longitudinal US study of long-term outcomes of delinquent youth after detention, participants were interviewed in detention between November 20, 1995, and June 14, 1998, and reinterviewed up to 9 times during the 12-year study period, through May 12, 2011. Data analysis was conducted between November 18, 2013, and July 25, 2016. Exposures: Juvenile detention. Main Outcomes and Measures: Achievement of positive outcomes in 8 domains: educational attainment, residential independence, gainful activity, desistance from criminal activity, mental health, abstaining from substance abuse, interpersonal functioning, and parenting responsibility. Outcomes were assessed with widely used measures supplemented by correctional records. Results: The study included 1829 youth at baseline (1172 males and 657 females; mean [SD] age, 14.9 [1.4] years). At the end of the study, 1520 (83.1%) of the original sample remained (944 males and 576 females; mean [SD] age, 27.6 [1.4] years). Twelve years after detention, females were more likely than males to have positive outcomes for gainful activity (odds ratio [OR], 2.53; 95% CI, 1.86 3.44), desistance from criminal activity (OR, 5.89; 95% CI, 4.38-7.92), residential independence (OR, 3.41; 95% CI, 2.57-4.52), parenting responsibility (OR, 18.65; 95% CI, 12.29-28.30), and mental health (OR, 1.48; 95% CI, 1.13 1.92). Twelve years after detention, only 21.9% of males and 54.7% of females had achieved more than half of the outcomes. As youth aged, the number of positive outcomes increased only modestly (mean increase for males, 0.37; 95% CI, 0.13 0.62; for females, 0.29; 95% CI, 0.13-0.45). Among males, non-Hispanic white individuals were significantly more likely to achieve most positive outcomes compared with minorities, but less likely to abstain from substance abuse. For example, 12 years after detention, non-Hispanic white males had nearly 3 times the odds of educational attainment compared with African American (OR, 2.82; 95% CI, 1.77-4.50) and Hispanic males (OR, 2.91; 95% CI, 1.75-4.82), and 2 to 5 times the odds of gainful activity compared with African American (OR, 5.17; 95% CI, 3.16-8.45) and Hispanic males (OR, 2.58; 95% CI, 1.56-4.26). Latent class analysis shows that African American males fared the worst, with lives characterized by incarceration, criminal activity, and few positive outcomes. Conclusions and Relevance: Our findings highlight racial/ethnic disparities among youth in achieving positive outcomes after detention. To improve outcomes, pediatric health care professionals should recognize the importance of psychosocial health, partner with on-site psychosocial services in their practices, and facilitate access to services in the community. PMID- 27992628 TI - The Risks of Marijuana Use During Pregnancy. PMID- 27992627 TI - Associations Between beta-Amyloid Kinetics and the beta-Amyloid Diurnal Pattern in the Central Nervous System. AB - Importance: Recent studies found that the concentration of amyloid-beta (Abeta) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of Abeta kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied. Objective: To determine the association between Abeta kinetics, age, amyloid levels, and the Abeta day/night pattern in humans. Design, Setting, and Participants: We measured Abeta concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of Abeta40 and Abeta42 were measured. Interventions: Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9 hour primed constant infusion of 13C6-leucine. Main Outcomes and Measures: The amplitude, linear increase, and other cosinor measures of each participant's serial cerebrospinal fluid Abeta concentrations and Abeta turnover rates. Results: Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in Abeta concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: Abeta40, -7.42 pM; P < .001; Abeta42, -3.72 pM; P < .001). Amyloid deposition diminished day/night amplitude and linear increase of Abeta42 but not of Abeta40. Increased age diminished day/night amplitude of both Abeta40 and Abeta42. After controlling for amyloid deposition, amplitude of Abeta40 was positively associated with production rates (r = 0.42; P < .001), while the linear rise was associated with turnover rates (r = 0.28; P < .05). The amplitude and linear rise of Abeta42 were both associated with turnover (r = -0.38; P < .001) and production (r = 0.238; P < .05) rates. Conclusions and Relevance: Amyloid deposition is associated with premature loss of normal Abeta42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on Abeta42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night Abeta patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease. PMID- 27992629 TI - Language mapping in children using resting-state functional connectivity: comparison with a task-based approach. AB - Patients with brain tumor or refractory epilepsy may be candidates for neurosurgery. Presurgical evaluation often includes language investigation to prevent or reduce the risk of postsurgical language deficits. Current techniques involve significant limitations with pediatric populations. Recently, near infrared spectroscopy (NIRS) has been shown to be a valuable neuroimaging technique for language localization in children. However, it typically requires the child to perform a task (task-based NIRS), which may constitute a significant limitation. Resting-state functional connectivity NIRS (fcNIRS) is an approach that can be used to identify language networks at rest. This study aims to assess the utility of fcNIRS in children by comparing fcNIRS to more conventional task based NIRS for language mapping in 33 healthy participants: 25 children (ages 3 to 16) and 8 adults. Data were acquired at rest and during a language task. Results show very good concordance between both approaches for language localization (Dice similarity coefficient = 0.81 +/- 0.13 ) and hemispheric language dominance ( kappa = 0.86 , p < 0.006 ). The fcNIRS technique may be a valuable tool for language mapping in clinical populations, including children and patients with cognitive and behavioral impairments. PMID- 27992631 TI - Silicon-on-insulator-based complementary metal oxide semiconductor integrated optoelectronic platform for biomedical applications. AB - Microscale optical devices enabled by wireless power harvesting and telemetry facilitate manipulation and testing of localized biological environments (e.g., neural recording and stimulation, targeted delivery to cancer cells). Design of integrated microsystems utilizing optical power harvesting and telemetry will enable complex in vivo applications like actuating a single nerve, without the difficult requirement of extreme optical focusing or use of nanoparticles. Silicon-on-insulator (SOI)-based platforms provide a very powerful architecture for such miniaturized platforms as these can be used to fabricate both optoelectronic and microelectronic devices on the same substrate. Near-infrared biomedical optics can be effectively utilized for optical power harvesting to generate optimal results compared with other methods (e.g., RF and acoustic) at submillimeter size scales intended for such designs. We present design and integration techniques of optical power harvesting structures with complementary metal oxide semiconductor platforms using SOI technologies along with monolithically integrated electronics. Such platforms can become the basis of optoelectronic biomedical systems including implants and lab-on-chip systems. PMID- 27992632 TI - Interpreting Periodic and Rhythmic Electroencephalographic Patterns in Critically Ill Patients. PMID- 27992630 TI - In vivo super-resolution retinal imaging through virtually structured detection. AB - High resolution is important for sensitive detection of subtle distortions of retinal morphology at an early stage of eye diseases. We demonstrate virtually structured detection (VSD) as a feasible method to achieve in vivo super resolution ophthalmoscopy. A line-scanning strategy was employed to achieve a super-resolution imaging speed up to 127 ?? frames / s with a frame size of 512 * 512 ?? pixels . The proof-of-concept experiment was performed on anesthetized frogs. VSD-based super-resolution images reveal individual photoreceptors and nerve fiber bundles unambiguously. Both image contrast and signal-to-noise ratio are significantly improved due to the VSD implementation. PMID- 27992633 TI - Personality Changes, Executive Dysfunction, and Motor and Memory Impairment. PMID- 27992634 TI - Perioperative Statin Use in Noncardiac Surgery: Who and When? PMID- 27992635 TI - Top of the Basilar Syndrome Presenting With Convulsions. PMID- 27992636 TI - Use of Marijuana for Medical Purposes Among Adults in the United States. PMID- 27992637 TI - Association of Preoperative Anemia With Postoperative Mortality in Neonates Reply. PMID- 27992638 TI - Medial Malleolar Fractures and Associated Deltoid Ligament Disruptions: Current Management Controversies. AB - Operative fixation of medial malleolar fractures, whether isolated or in the setting of bi- or trimalleolar fractures, remains controversial. Increasingly, anatomic reduction and internal fixation is used to treat medial malleolar fractures to avoid long-term sequelae of symptomatic nonunion and posttraumatic osteoarthritis. However, outcomes have not been significantly different between operative and nonoperative cohorts. Repair of associated deltoid ligament disruption is not common because of reportedly poor outcomes. This review provides an overview of the literature on medial malleolar fracture fixation and current treatment options. [Orthopedics. 2017; 40(2):e216-e222.]. PMID- 27992639 TI - Accuracy of Ultrasound-Guided Intra-articular Hip Injections Performed in the Orthopedic Clinic. AB - Intra-articular hip injections have proven clinical value for both diagnostic and therapeutic purposes. Historically, these injections have been performed by radiologists using fluoroscopic guidance. This necessitates a radiology referral, delays the injection, and represents lost productivity for the orthopedist. Ultrasound-guided intra-articular hip injections have been described in the radiology literature with excellent accuracy. These injections were performed by radiologists. The purpose of this study was to determine the accuracy of ultrasound-guided hip injections performed in the orthopedic clinic by orthopedic surgeons and orthopedic physician assistants. Fifty ultrasound-guided hip injections were performed using a standard technique. Contrast was included, and an anteroposterior pelvis radiograph was obtained immediately following injection. Diagnosis, body mass index, procedure time, and visual analog scale scores were recorded. Radiographs were reviewed independently by a musculoskeletal radiologist and an orthopedic surgeon to determine intra articular placement of the injection. A total of 50 hips were injected. There was no identifiable contrast in 2 patients, leaving 48 hips for analysis. Of these, contrast was injected intra-articularly in 46 hips for an accuracy of 96%. Average procedural time was 2.6 minutes, and the average visual analog scale score was 1.9 during the procedure. Revenue value units ranged from 1.72-2.55 for ultrasound-guided hip injections. These findings indicate ultrasound-guided intra articular hip injections performed in the orthopedic clinic by surgeons or physician assistants are accurate, efficient, and patient-friendly. Additionally, they preserve patient continuity and maintain productivity within the orthopedic clinic. [Orthopedics. 2017; 40(2):96-100.]. PMID- 27992640 TI - Complications Associated With Bone Morphogenetic Protein in the Lumbar Spine. AB - Complications associated with the use of recombinant human bone morphogenetic protein in the lumbar spine include retrograde ejaculation, ectopic bone formation, vertebral osteolysis and subsidence, postoperative radiculitis, and hematoma and seroma. These complications are controversial and remain widely debated. This article discusses the reported complications and possible implications for the practicing spine surgeon. Understanding the complications associated with the use of recombinant human bone morphogenetic protein and the associated controversies allows for informed decision making by both the patient and the surgeon. [Orthopedics. 2017; 40(2):e229-e237.]. PMID- 27992641 TI - Treatment of Single-Level Cervical Spondylosis: Cervical Disk Arthroplasty Versus Anterior Cervical Decompression and Fusion. AB - A meta-analysis was performed to compare cervical arthroplasty with anterior cervical diskectomy and fusion for single-level cervical spondylosis. A comprehensive search was conducted with PubMed, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, to April 30, 2015. Random effects models were used for heterogeneous data. Fixed-effects models were used for pooled nonheterogeneous data. Mean difference or standard mean difference was used for continuous outcomes, and odds ratio, risk ratio, or risk difference was used for dichotomous outcomes. [Orthopedics. 2017; 40(1):e23-e34.]. PMID- 27992642 TI - Revision Total Hip Arthroplasty Using the Cement-in-Cement Technique. AB - The cement-in-cement technique is useful in the setting of revision total hip arthroplasty (THA), especially to gain acetabular exposure, change a damaged or loose femoral component, or change the version, offset, or length of a fixed femoral component. The goal of this retrospective study was to assess the clinical and radiographic characteristics of revision THA using the cement-in- cement technique. Between 1971 and 2013, a total of 63 revision THAs used an Omnifit (Osteonics, Mahwah, New Jersey) or Exeter (Howmedica, Mahwah, New Jersey) stem and the cement-in-cement technique at the senior author's institution. Aseptic loosening (74%) was the predominant preoperative diagnosis followed by periprosthetic fracture (14%), instability (8%), and implant fracture (6%). Mean clinical follow-up was 5.5+/-3.8 years. The Harris Hip Score had a statistically significant increase of 18.5 points (P<.001) after revision THA using the cement in-cement technique. There were 13 returns to the operating room, resulting in an overall failure rate of 21%. Eleven (18%) cases required revision THA, but only 1 (2%) revision THA was for aseptic removal of the femoral component. All other femoral implants had no evidence of component migration, cement mantel fracture, or circumferential lucent lines at final follow-up. The patients who underwent cement-in-cement revision THA at the senior author's institution had good restoration of function but a high complication rate. [Orthopedics. 2017; 40(2):e348-e351.]. PMID- 27992643 TI - Recall of the ASR XL Head and Hip Resurfacing Systems. AB - At the beginning of the 21st century, use of large-diameter, metal-on-metal devices was a popular procedure for hip replacement in young and physically active patients; however, within a few years, the number of revisions increased, resulting in a worldwide recall for the articular surface replacement (ASR) system. Complication rates for the ASR devices implanted at the authors' department are reported, with revision rates of 32% and 30% in the ASR XL Head and ASR Resurfacing groups, respectively. Reasons for revision surgery were serum metal ion elevation, luxation or subluxation, aseptic loosening, soft tissue compromise (adverse reactions to metal debris [ARMD]), and infection. The calculated implant survival for the ASR XL Head system and the ASR Resurfacing device (DePuy Orthopaedics Inc, Warsaw, Indiana) in the current series was 79% and 90%, respectively, at 60 months. Symptomatic patients with metal-on-metal devices, with or without elevated metal ion concentrations, should undergo cross sectional imaging to exclude ARMD. In cases of increased metal ion concentrations, local pain, or ARMD, revision surgery has to be evaluated. In the future, closer monitoring of new implants is needed to prevent high failure rates, as seen with the ASR design. Furthermore, the withdrawal of the device highlights the importance of national implant registries. [Orthopedics. 2017; 40(2):e340-e347.]. PMID- 27992644 TI - A Genome-Scale Modeling Approach to Quantify Biofilm Component Growth of Salmonella Typhimurium. AB - Salmonella typhimurium (S. typhimurium) is an extremely dangerous foodborne bacterium that infects both animal and human subjects, causing fatal diseases around the world. Salmonella's robust virulence, antibiotic-resistant nature, and capacity to survive under harsh conditions are largely due to its ability to form resilient biofilms. Multiple genome-scale metabolic models have been developed to study the complex and diverse nature of this organism's metabolism; however, none of these models fully integrated the reactions and mechanisms required to study the influence of biofilm formation. This work developed a systems-level approach to study the adjustment of intracellular metabolism of S. typhimurium during biofilm formation. The most advanced metabolic reconstruction currently available, STM_v1.0, was 1st extended to include the formation of the extracellular biofilm matrix. Flux balance analysis was then employed to study the influence of biofilm formation on cellular growth rate and the production rates of biofilm components. With biofilm formation present, biomass growth was examined under nutrient rich and nutrient deficient conditions, resulting in overall growth rates of 0.8675 and 0.6238 h-1 respectively. Investigation of intracellular flux variation during biofilm formation resulted in the elucidation of 32 crucial reactions, and associated genes, whose fluxes most significantly adapt during the physiological response. Experimental data were found in the literature to validate the importance of these genes for the biofilm formation of S. typhimurium. This preliminary investigation on the adjustment of intracellular metabolism of S. typhimurium during biofilm formation will serve as a platform to generate hypotheses for further experimental study on the biofilm formation of this virulent bacterium. PMID- 27992645 TI - Crystal Structures of Bacterial (6-4) Photolyase Mutants with Impaired DNA Repair Activity. AB - PhrB from Agrobacterium fabrum is the first prokaryotic photolyase which repairs (6-4) UV DNA photoproducts. The protein harbors three cofactors: the enzymatically active FAD chromophore, a second chromophore, 6,7-dimethyl-8 ribityllumazine (DMRL) and a cubane-type Fe-S cluster. Tyr424 of PhrB is part of the DNA-binding site and could provide an electron link to the Fe-S cluster. The PhrBY424F mutant showed reduced binding of lesion DNA and loss of DNA repair. The mutant PhrBI51W is characterized by the loss of the DMRL chromophore, reduced photoreduction and reduced DNA repair capacity. We have determined the crystal structures of both mutants and found that both mutations only affect local protein environments, whereas the overall fold remained unchanged. The crystal structure of PhrBY424F revealed a water network extending to His366, which are part of the lesion-binding site. The crystal structure of PhrBI51W shows how the bulky Trp leads to structural rearrangements in the DMRL chromophore pocket. Spectral characterizations of PhrBI51W suggest that DMRL serves as an antenna chromophore for photoreduction and DNA repair in the wild type. The energy transfer from DMRL to FAD could represent a phylogenetically ancient process. PMID- 27992646 TI - Divalent Cations Increase DNA Repair Activities of Bacterial (6-4) Photolyases. AB - The (6-4) photolyases of the FeS-BCP group can be considered as the most ancient type among the large family of cryptochrome and photolyase flavoproteins. In contrast to other photolyases, they contain an Fe-S cluster of unknown function, a DMRL chromophore, an interdomain loop, which could interact with DNA, and a long C-terminal extension. We compared DNA repair and photoreduction of two members of the FeS-BCP family, Agrobacterium fabrum PhrB and Rhodobacter sphaeroides RsCryB, with a eukaryotic (6-4) photolyase from Ostreococcus, OsCPF, and a member of the class III CPD photolyases, PhrA from A. fabrum. We found that the low DNA repair effectivity of FeS-BCP proteins is largely stimulated by Mg2+ and other divalent cations, whereas no effect of divalent cations was observed in OsCPF and PhrA. The (6-4) repair activity in the presence of Mg2+ is comparable with the repair activities of the other two photolyases. The photoreduction, on the other hand, is negatively affected by Mg2+ in PhrB, but stimulated by Mg2+ in PhrA. A clear relationship of Mg2+ dependency on DNA repair with the evolutionary position conflicts with Mg2+ dependency of photoreduction. We discuss the Mg2+ effect in the context of structural data and DNA binding. PMID- 27992648 TI - Improvement on Physical Properties of Pullulan Films by Novel Cross-Linking Strategy. AB - Pullulan based films possess several advantages, including high transparency, low toxicity, good biodegradability, good mechanical properties, and low oxygen permeability, are preferable for food packaging. The application of pullulan films on food packaging, however, has inherent disadvantage of high water solubility. In this study, glutaraldehyde and glycerol were used as the cross linking reagent and the plasticizer respectively to improve water resistance and physical properties of the pullulan films. Effects of cross-linking degree on physical properties, including water absorptions, swelling behaviors, water vapor permeability and tensile strengths of films were evaluated. FTIR results demonstrated that the pullulan films were successfully cross-linked by glutaraldehyde. The tensile strength of pullulan films could be enhanced significantly (P < 0.05) when glutaraldehyde was between 1% and 5% (w/w); nevertheless, the amount of glutaraldehyde above 20% (w/w) led to films brittleness. With the addition of glycerol as a plasticizer enhanced the extensibility of films as well as the hydrophilicity, resulting in higher water vapor permeability. PMID- 27992650 TI - Monitoring cell-specific neutral lipid accumulation in Phaeodactylum tricornutum (Bacillariophyceae) with Nile Red staining - a new method for FlowCAM. AB - With the fluorescent stain Nile Red (NR), phytoplankton lipid accumulation can be monitored quickly and in situ. In the light of recent results in phytoplankton diversity research, there is also a need for cell- and species-specific lipid measurement techniques. The objective of this work was to investigate whether cell-specific phytoplankton lipid accumulation could be monitored with the image based particle analyzer FlowCAMTM and NR staining. Applying Phaeodactylum tricornutum as a model species, we compared the FlowCAM method to two established lipid quantification methods: spectrofluorometric NR fluorescence measurement and total lipid analysis by gas chromatography. The experiment was carried out in batch cultures under nitrogen limitation to induce lipid accumulation. We showed significant correlation between the three different lipid quantification methods confirming the applicability of the novel FlowCAM method in cell-specific and near real-time lipid quantification. Furthermore, with the method described here, the lipid content of taxonomically distinguished cells can eventually be measured from multispecies cultures, opening several new possibilities to study species specific responses to stress conditions and the complementarity effect. PMID- 27992649 TI - Kinetic Isotope Effects and Hydrogen/Deuterium Exchange Reveal Large Conformational Changes During the Catalysis of the Clostridium acetobutylicum Spore Photoproduct Lyase. AB - Spore photoproduct lyase (SPL) catalyzes the direct reversal of a thymine dimer 5 thyminyl-5,6-dihydrothymine (i.e. the spore photoproduct (SP)) to two thymine residues in germinating endospores. Previous studies suggest that SPL from the bacterium Bacillus subtilis (Bs) harbors an unprecedented radical-transfer pathway starting with cysteine 141 proceeding through tyrosine 99. However, in SPL from the bacterium Clostridium acetobutylicum (Ca), the cysteine (at position 74) and the tyrosine are located on the opposite sides of a substrate-binding pocket that has to collapse to bring the two residues into proximity, enabling the C->Y radical passage as implied in SPL(Bs) . To test this hypothesis, we adopted hydrogen/deuterium exchange mass spectrometry (HDX-MS) to show that C74(Ca) is located at a highly flexible region. The repair of dinucleotide SP TpT by SPL(Ca) is eight-fold to 10-fold slower than that by SPL(Bs) ; the process also generates a large portion of the aborted product TpTSO2- . SPL(Ca) exhibits apparent (D V) kinetic isotope effects (KIEs) of ~6 and abnormally large competitive (D V/K) KIEs (~20), both of which are much larger than the KIEs observed for SPL(Bs) . All these observations indicate that SPL(Ca) possesses a flexible active site and readily undergoes conformational changes during catalysis. PMID- 27992651 TI - Distinct ecological niches of marine symbiotic N2 -fixing cyanobacterium Candidatus Atelocyanobacterium thalassa sublineages. AB - A recently described symbiosis between the metabolically streamlined nitrogen fixing cyanobacterium UCYN-A and a single-celled eukaryote prymnesiophyte alga is widely distributed throughout tropical and subtropical marine waters, and is thought to contribute significantly to nitrogen fixation in these regions. Several UCYN-A sublineages have been defined based on UCYN-A nitrogenase (nifH) sequences. Due to the low abundances of UCYN-A in the global oceans, currently existing molecular techniques are limited for detecting and quantifying these organisms. A targeted approach is needed to adequately characterize the diversity of this important marine cyanobacterium, and to advance understanding of its ecological importance. We present findings on the distribution of UCYN-A sublineages based on high throughput sequencing of UCYN-A nifH PCR amplicons from 78 samples distributed throughout many major oceanic provinces. These UCYN-A nifH fragments were used to define oligotypes, alternative taxonomic units defined by nucleotide positions with high variability. The data set was dominated by a single oligotype associated with the UCYN-A1 sublineage, consistent with previous observations of relatively high abundances in tropical and subtropical regions. However, this analysis also revealed for the first time the widespread distribution of the UCYN-A3 sublineage in oligotrophic waters. Furthermore, distinct assemblages of UCYN-A oligotypes were found in oligotrophic and coastally influenced waters. This unique data set provides a framework for determining the environmental controls on UCYN-A distributions and the ecological importance of the different sublineages. PMID- 27992652 TI - Molecular determination of kleptoplast origins from the sea slug Plakobranchus ocellatus (Sacoglossa, Gastropoda) reveals cryptic bryopsidalean (Chlorophyta) diversity in the Hawaiian Islands. AB - The sacoglossan sea slug species complex Plakobranchus ocellatus is a common algivore throughout the tropical Pacific, including the Hawaiian Islands. Plakobranchus ocellatus is kleptoplastic-it sequesters and retains algal chloroplasts-a characteristic that can be exploited to molecularly characterize diminutive bryopsidalean algae that are typically difficult to locate, collect, and identify. Previous DNA barcode analyses of both P. ocellatus and its kleptoplasts have been conducted primarily in the western Pacific and have only minimally sampled the most eastern populations in the Hawaiian Islands. Using two chloroplast markers, rbcL and tufA, kleptoplast samples from an Oahu population of P. ocellatus were amplified and cloned to identify their algal sources. Plakobranchus ocellatus sequester chloroplasts from up to 11 bryopsidalean algal species, all but one being diminutive in thallus size. Notably, eight of the detected algal species were new records to the Hawaiian Islands. A sequestration preference study demonstrated that the O'ahu population of P. ocellatus preferentially sequesters chloroplasts from diminutive, epilithic taxa. Using coxI barcoding of P. ocellatus, we showed the O'ahu population to be part of a clade that includes sequences from the neighboring island Maui, Australia, and the Philippines. The use of P. ocellatus as a novel sampling tool allows the exploration of the green algal community diversity and composition at a fine scale. PMID- 27992653 TI - Frequency Distribution in Domestic Microwave Ovens and Its Influence on Heating Pattern. AB - In this study, snapshots of operating frequency profiles of domestic microwave ovens were collected to reveal the extent of microwave frequency variations under different operation conditions. A computer simulation model was developed based on the finite difference time domain method to analyze the influence of the shifting frequency on heating patterns of foods in a microwave oven. The results showed that the operating frequencies of empty and loaded domestic microwave ovens varied widely even among ovens of the same model purchased on the same date. Each microwave oven had its unique characteristic operating frequencies, which were also affected by the location and shape of the load. The simulated heating patterns of a gellan gel model food when heated on a rotary plate agreed well with the experimental results, which supported the reliability of the developed simulation model. Simulation indicated that the heating patterns of a stationary model food load changed with the varying operating frequency. However, the heating pattern of a rotary model food load was not sensitive to microwave frequencies due to the severe edge heating overshadowing the effects of the frequency variations. PMID- 27992654 TI - Repair of (6-4) Lesions in DNA by (6-4) Photolyase: 20 Years of Quest for the Photoreaction Mechanism. AB - Exposure of DNA to ultraviolet (UV) light from the Sun or from other sources causes the formation of harmful and carcinogenic crosslinks between adjacent pyrimidine nucleobases, namely cyclobutane pyrimidine dimers and pyrimidine(6 4)pyrimidone photoproducts. Nature has developed unique flavoenzymes, called DNA photolyases, that utilize blue light, that is photons of lower energy than those of the damaging light, to repair these lesions. In this review, we focus on the chemically challenging repair of the (6-4) photoproducts by (6-4) photolyase and describe the major events along the quest for the reaction mechanisms, over the 20 years since the discovery of (6-4) photolyase. PMID- 27992655 TI - Use of 20% intravenous lipid emulsion for the treatment of loperamide toxicosis in a Collie homozygous for the ABCB1-1? mutation. AB - OBJECTIVE: To describe the successful treatment of loperamide toxicosis in a dog using intravenous lipid emulsion (ILE). CASE SUMMARY: An 8-month-old male neutered Rough Collie weighing 20.0 kg was given a total dose of 0.75 mg/kg loperamide over 3 days as treatment for diarrhea. The dog was subsequently evaluated for signs of dull mentation, anxiety, ptyalism and ataxia, thought to be a result of loperamide intoxication. The dog was treated with a 1.5 mL/kg IV bolus of 20% ILE solution followed by 0.25 mL/kg/min of the same solution for 2 hours. The dog's mentation improved rapidly following ILE infusion, and he was neurologically normal 3 hours after initiation of ILE treatment. The dog was subsequently found to be homozygous for the ATP-binding cassette (ABC) transporter gene (ABCB1-1?) mutation. There were no adverse effects noted during or following ILE infusion. NEW OR UNIQUE INFORMATION PROVIDED: ILE was successful in the treatment of loperamide toxicosis in a Collie with the ABCB1-1? mutation. ILE may be of benefit for treatment of other intoxications in dogs with ABCB1 1Delta mutations. PMID- 27992656 TI - Meta-Regression of a Dose-Response Relationship of Methotrexate in Mono- and Combination Therapy in Disease-Modifying Antirheumatic Drug-Naive Early Rheumatoid Arthritis Patients. AB - OBJECTIVE: To investigate a possible short-term dose-response relationship of initial treatment with methotrexate (MTX) in monotherapy and combination therapy in recent-onset rheumatoid arthritis (RA) patients. METHODS: A systematic literature search was performed on trials and cohorts, including early, disease modifying antirheumatic drug (DMARD)-naive RA patients treated with MTX, with data on clinical results within 6 months from treatment start. Cohen's effect sizes were calculated for the Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level, and/or Disease Activity Score (DAS)/in 28 joints (DAS28) in 4 treatment groups: MTX monotherapy, or MTX in combination with synthetic (cs) DMARDs, biologic (b) DMARDs, or glucocorticoids. Random-effects meta-regression analyses were performed for each outcome, with treatment group as the predictor corrected for baseline HAQ or disease activity and assessment point. RESULTS: Thirty-one studies including 5,589 patients were included. The meta-regression did not support higher effectiveness of increasing MTX dose in monotherapy. The number of treatment groups using combination therapy with csDMARDs was too small to perform meta regression analyses. In combination therapy with glucocorticoids, a higher MTX dose was associated with higher (worse) outcome HAQ, but not with DAS/DAS28 or ESR/CRP level. In combination therapy with bDMARDs, a higher MTX dose was associated with higher outcome HAQ and DAS/DAS28, but not with ESR/CRP level. All effect sizes were small. CONCLUSION: In DMARD-naive, early RA patients who start MTX, either as monotherapy or in combination with bDMARDs or glucocorticoids, a higher initial dose of MTX was not associated with better clinical outcomes. This finding suggests that there is little short-term gain from starting with high compared to low MTX doses. PMID- 27992658 TI - Antimicrobial activity of Manuka honey against antibiotic-resistant strains of the cell wall-free bacteria Ureaplasma parvum and Ureaplasma urealyticum. AB - : The susceptibility of the cell wall-free bacterial pathogens Ureaplasma spp. to Manuka honey was examined. The minimum inhibitory concentration (MIC) of Manuka honey for four Ureaplasma urealyticum and four Ureaplasma parvum isolates was determined. Sensitivity to honey was also compared to clinical isolates with resistance to tetracycline, macrolide and fluoroquinolone antibiotics. Finally step-wise resistance training was utilized in an attempt to induce increased tolerance to honey. The MIC was dependent on the initial bacterial load with 7.5 and 18.0% w/v honey required to inhibit U. urealyticum at 1 and 106 colour changing units (CCU), respectively, and 4.8 and 15.3% w/v required to inhibit U. parvum at 1 and 106 CCU respectively. MIC values were consistently lower for U. parvum compared with U. urealyticum. Antimicrobial activity was seen against tetracycline-resistant, erythromycin-resistant and ciprofloxacin-resistant isolates at 105 CCU. No resistance to honey was observed with 50 consecutive challenges at increasing concentrations of honey. This is the first report of the antimicrobial activity of Manuka honey against a cell wall-free bacterial pathogen. The antimicrobial activity was retained against antibiotic-resistant strains and it was not possible to generate resistant mutants. SIGNIFICANCE AND IMPACT OF THE STUDY: Manuka honey is known to have a broad spectrum of antimicrobial activity, with the bacterial cell wall being suggested as a predominant site of action. This study has demonstrated that Manuka honey has activity against Ureaplasma spp., a genus of cell wall-free bacteria which are intrinsically resistant to many available antibiotics making treatment inherently difficult. This is the first report of the antimicrobial activity of Manuka honey against a bacterial pathogen, in the absence of a cell well and opens scope for the use of components of Manuka honey as a therapeutic among Ureaplasma infections. PMID- 27992657 TI - Protection of Penaeus monodon against white spot syndrome by continuous oral administration of a low concentration of Bacillus subtilis spores expressing the VP28 antigen. AB - : In this study, Bacillus subtilis spores expressing a chimeric protein, CotB VP28, were used as a probiotic vaccine to protect black tiger shrimps (Penaeus monodon) against white spot syndrome virus (WSSV) infection. Oral administration of pellets coated with CotB-VP28 spores (at >=1 * 109 CFU per g pellet) to shrimps induced immune-relating phenoloxydase activity (PO) in shrimps after 14 days of feeding (prior challenge) and at day 3 post challenge (1.26 and 1.70 fold increase respectively). A 75% protection rate was obtained by continuous feeding of the spore-coated pellets at >=1 * 109 CFU per g for 14 days prior to WSSV challenge and during all the postchallenge period. Even when the amount of CotB VP28 spores in feed pellets was reduced down to >=5 * 107 CFU per g and >=1 * 106 CFU per g, relatively high protection rates of 70 and 67.5%, respectively, were still obtained. By contrast, feeding pellets without spores (untreated group) and with naked spores (PY79 group) at >=1 * 109 CFU per g could not protect shrimps against WSSV. These data suggest that supplementation of CotB VP28 spores at low dose of >=1 * 106 CFU per g could be effective as a prophylactic treatment of WSS for black tiger shrimps. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports the protective efficacy of Bacillus subtilis CotB VP28 spores on black tiger shrimps (Penaeus monodon) against white spot syndrome virus infection. Oral administration of pellets coated with CotB-VP28 spores (>=1 * 109 CFU per g) conferred 75% protection after white spot syndrome virus challenge. Even after reducing CotB-VP28 spores in feed pellets to >=1 * 106 CFU per g, 67.5% protections was still obtained. These data indicate that supplementation of CotB-VP28 spores at a low dose of >=1 * 106 CFU per g could be effective in prophylaxis against white spot syndrome in black tiger shrimps. PMID- 27992659 TI - A systematic review of serious games in asthma education. AB - BACKGROUND: Serious games may be useful tools for asthma education. The objectives of this systematic review were to identify the available articles on serious games designed to educate patients and the general public about asthma and to assess their impact on patient's knowledge, behavior, and clinical outcomes related to asthma. METHODS: PubMed, EMBASE, Cochrane Library, PsychInfo, and Web of Science were systematically searched from January 1980 to December 2015 for studies investigating serious games in asthma education. Two investigators independently assessed studies against inclusion criteria and rated those included on indicators of quality. Investigators extracted data on serious games' content and learning objectives, and on outcomes following Kirkpatrick classification. RESULTS: A total of 12 articles were found to be relevant, describing a total of 10 serious games. All serious games were directed toward children, with eight games for children with asthma and two for school-based intervention. The average Medical Education Research Study Quality Instrument score was 13.9 of 18, which is high. Most of the serious games were associated with high rates of satisfaction and improvement in children's knowledge. Seven studies evaluated the impact of serious games on clinical outcomes and found no significant difference relative to control groups. CONCLUSIONS: Although serious games designed for asthma education have evolved with advances in technology, results of their evaluation remained similar across studies, with clear improvements in knowledge but little or no change in behaviors and clinical outcomes. PMID- 27992661 TI - Simple lipoma of the eyelid: a rare entity. PMID- 27992660 TI - Challenges of Diagnosing Cognitive Dysfunction With Neuropsychiatric Systemic Lupus Erythematosus in Childhood. PMID- 27992662 TI - Parental perception of their child's quality of life in children with non immunoglobulin-E-mediated gastrointestinal allergies. AB - BACKGROUND: Food allergy can have a significant impact on health-related quality of life (HRQoL). Parental proxy questionnaires are commonly used when children are too young to complete questionnaires themselves. Little data are available on HRQoL in children with non-IgE-mediated gastrointestinal food allergy (GIFA). The aim of this study was to evaluate HRQoL in these children by parent proxy. METHODS: A cross-sectional questionnaire study was conducted with children aged 2 16 years with confirmed GIFA. Parents of these children completed the Pediatric Quality of Life Inventory (PedsQLTM ) and the family impact module of the PedsQL. The PedsQL scores were compared to two published cohorts: functional abdominal pain (FAP) and IgE-mediated food allergy. RESULTS: Fifty-two parents of children with GIFA completed the PedsQLTM parent proxy. The GIFA cohort had significantly better overall HRQoL compared with the FAP cohort, but lower emotional functioning scores. The GIFA cohort also had poorer physical QoL compared with the IgE cohort (all p < 0.05). The more foods excluded, comorbidity of nasal congestion, abdominal pain, back arching, the persistence of flatus and gastrointestinal symptom severity after elimination diet were related to poorer QoL in this non-IgE cohort. Regression analyses showed that number of foods and nasal congestion significantly predicted total QoL score as perceived by parents. CONCLUSIONS: This study has shown that different areas of HRQoL of children with GIFA are affected compared with children with FAP or IgE-mediated food allergy, highlighting the need for a specific GIFA HRQoL questionnaire to better understand the impact on these children. PMID- 27992663 TI - Persistence of alprazolam in river water according to forced and non-forced degradation assays: adsorption to sediment and long-term degradation products. AB - Alprazolam is a pharmaceutical compound that it is detected in surface waters. Some degradation studies in aqueous solutions and pharmaceutical products are available, but there is no reliable information about its stability in river water. Here, assays have been conducted under forced biological, photochemical, and thermal conditions, and under non-forced conditions, to estimate the fate of alprazolam in river water and know its degradation products. The forced assays indicated that the biological and photochemical degradation of alprazolam was negligible; heating at 70 degrees C for a long time barely affected it. The degradation of alprazolam in river water at 100 MUg/L was about 5% after 36 weeks, keeping the water under a natural day-night cycle at room temperature and limiting partially the exposure to sunlight as happens inside a body of water; no change in concentration was observed when the monitoring was performed at 2 MUg/L. The results suggest the persistence of alprazolam in surface water and a possible accumulation over time. Residues were monitored by ultra-pressure liquid chromatography/quadrupole time-of-flight/mass spectrometry after solid-phase extraction; nine degradation products were found and the structures for most of them were proposed from the molecular formulae and fragmentation observed in high resolution tandem mass spectra. (5-chloro-2-(3-methyl-4H-1,2,4-triazol-4 yl)phenyl)(phenyl)methanol was the main long-term transformation product in conditions that simulate those in a mass of water. The degradation rate in presence of sediment was equally very low under non-forced conditions; adsorption coefficients of alprazolam and major degradation products were calculated. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27992664 TI - Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay. AB - BACKGROUND & AIMS: Occult hepatitis B virus (HBV) infection should be evaluated before systemic chemotherapy to prevent HBV reactivation-related hepatitis. We investigated HBV reactivation using high sensitivity HB surface antigen (HBsAg) chemiluminescent enzyme immunoassay (HBsAg-HQ) and ultra-high sensitive HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA). METHODS: Of 120 HBV-resolved patients with haematological malignancy receiving systemic chemotherapy from 2012 to 2015 in our hospital, 13 patients had HBV DNA reactivation (in 12/13 patients HBV DNA became quantifiable) according to HBV DNA monitoring. These patients were applied for Architect HBsAg QT (detection limit:50 mIU/mL), HBsAg-HQ (5 mIU/mL) and ICT-CLEIA (0.5 mIU/mL) using stored samples. RESULTS: When HBV DNA was firstly quantifiable by regular HBV DNA monitoring, HBsAg-QT was detected in 1/12 patients (8%), HBsAg-HQ was detected in 4/12 patients (33%) and ICT-CLEIA was detected in all 12 patients (100%), suggesting that the sensitivity of ICT-CLEIA was comparable to that of HBV DNA quantification. Interestingly, two patients were HBsAg positive by ICT CLEIA before HBV DNA became detectable. Median difference of detectable point between HBV DNA and ICT-CLEIA was zero (range from -28 to 56 days), while median delay by HBsAg-QT or HBsAg-HQ was 52.5 days after HBV DNA became detectable. Although anti-HBs titres were high (131.9 mIU, 80.4 mIU) in two patients with escape mutations (Saa126V, Saa145R), HBsAg by ICT-CLEIA and HBV DNA were detectable concurrently. CONCLUSIONS: ICT-CLEIA is a novel assay for HBV monitoring to prevent hepatitis caused by HBV reactivation. PMID- 27992665 TI - Naloxone Antagonizes Soman-induced Central Respiratory Depression in Rats. AB - The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors. PMID- 27992666 TI - Lithium Toxicity in a Pregnant Woman. AB - Lithium is recommended in bipolar disorder and can be accompanied by significant toxicity in pregnant women. A 25-year-old single-gestation pregnant woman (28 weeks) was referred with suspicion of lithium toxicity. Serum lithium was 2.1 meq/L. Despite conservative therapy with intravenous fluids, lithium concentration increased to 5.0 meq/L 6 hr after admission mandating an emergent haemodialysis during which foetal heart rate decreased to 90 bpm. The gynaecologist ordered termination of pregnancy while the mother was still on haemodialysis. Caesarean section was carried out, but the born baby had an apgar of 2 and died. Autopsy findings of the foetus revealed a cord blood lithium concentration of 4.8 mEq/L with no physical abnormalities. Although the foetus had the signs/symptoms of distress, continuation of haemodialysis could probably have saved it as it saved its mother's life. In lithium toxicity in a pregnant woman, it is reasonable to continue haemodialysis even with the signs and symptoms of foetal distress. In similar situations, emergency haemodialysis instead of immediate caesarean section should be considered. PMID- 27992667 TI - Prognostic impact of postoperative low platelet count after liver transplantation. AB - BACKGROUND: The positive impact of platelets has been recently implicated in liver transplantation (LT). The aim of this study was to determine the risk factors for graft loss and mortality after LT, focusing on perioperative platelet counts. METHODS: We reviewed all deceased donor LT from 2000 to 2012 and enrolled 975 consecutive recipients. The risk factors for graft loss and mortality were analyzed by multivariate analysis, using Cox's regression model. RESULTS: Using cutoff values acquired by receiver operating characteristics curve analysis, multivariate analyses determined that viral hepatitis C (hazard ratio [HR]=1.32), donor age >40 (HR=1.33), higher peak serum alanine aminotransferase (HR=1.01), reoperation within 30 days (HR=1.51), and platelet count <72 500/MUL on postoperative day (POD) 5 (HR=1.30) were independent risk factors for graft loss. Viral hepatitis C (HR=1.33), reoperation within 30 days (HR=1.35), and platelet count <72 500/MUL on POD 5 (HR=1.38) were independent risk factors for mortality. CONCLUSION: A low platelet count on POD 5 was associated with graft loss and mortality after LT. Platelet count <72 500/MUL on POD 5 can be a predictor of poor graft and overall survival. Maintaining higher postoperative platelet counts could potentially improve graft and overall survival rates. PMID- 27992668 TI - Extensively hydrolyzed casein formula alone or with L. rhamnosus GG reduces beta lactoglobulin sensitization in mice. AB - BACKGROUND: Extensively hydrolyzed casein formula (EHCF) has been proposed for the prevention and is commonly used for the treatment of cow's milk allergy (CMA). The addition of the probiotic Lactobacillus rhamnosus GG (LGG) to EHCF may induce faster acquisition of tolerance to cow's milk. The mechanisms underlying this effect are largely unexplored. We investigated the effects of EHCF alone or in combination with LGG on beta-lactoglobulin (BLG) sensitization in mice. METHODS: Three-week-old C3H/HeOuJ mice were sensitized by oral administration of BLG using cholera toxin as adjuvant at weekly intervals for 5 weeks (sensitization period). Two experimental phases were conducted: (i) EHCF or EHCF+LGG given daily, starting 2 weeks before the sensitization period and then given daily for 5 weeks and (ii) EHCF or EHCF+LGG given daily for 4 weeks, starting 1 week after the sensitization period. Diet free of cow's milk protein was used as control. Acute allergic skin response, anaphylactic symptom score, body temperature, intestinal permeability, anti-BLG serum IgE, and interleukin (IL)-4, IL-5, IL-10, IL-13, IFN-gamma mRNA expression were analyzed. Peptide fractions of EHCF were characterized by reversed-phase (RP)-HPLC, MALDI-TOF mass spectrometry, and nano-HPLC/ESI-MS/MS. RESULTS: Extensively hydrolyzed casein formula administration before or after BLG-induced sensitization significantly reduced acute allergic skin reaction, anaphylactic symptom score, body temperature decrease, intestinal permeability increase, IL-4, IL-5, IL-13, and anti-BLG IgE production. EHCF increased expression of IFN-gamma and IL-10. Many of these effects were significantly enhanced by LGG supplementation. The peptide panels were similar between the two study formulas and contained sequences that could have immunoregulatory activities. CONCLUSIONS: The data support dietary intervention with EHCF for CMA prevention and treatment through a favorable immunomodulatory action. The observed effects are significantly enhanced by LGG supplementation. PMID- 27992669 TI - Midkine is overexpressed in acute pancreatitis and promotes the pancreatic recovery in L-arginine-induced acute pancreatitis in mice. AB - BACKGROUND AND AIM: Midkine (MK) is involved in the pathogenesis of numerous malignancies, but the expression and effect of MK in acute pancreatitis (AP) have not been well studied and documented. METHODS: In this study, the expression of MK was assayed in mice with L-arginine-induced AP. A recombinant human MK (rhMK) was introduced in this study to test the effect of MK on the L-arginine-induced AP. Serum amylase and lipase were assayed. Pancreas tissue samples were also collected for the evaluation of histological injury. Western blot and immunochemical staining of alpha-amylase and proliferating cell nuclear antigen were applied for the study of acinar regeneration in the pancreas. RESULTS: The elevation of MK expression was found in mice with AP induced by L-arginine. After rhMK administration, rhMK did not affect the severity of acute pancreatic injury in acute phase in L-arginine-induced pancreatitis in mice, in accordance with changes of serum amylase and lipase and the histological evaluation. But during the recovery phase, the area of remaining acinar cells was increased and the fibrosis was reduced in rhMK-treated mice. Furthermore, the expression of proliferating cell nuclear antigen and alpha-amylase was also upregulated after rhMK treatment. CONCLUSION: Midkine is over-expressed during AP in the animal model. Recombinant MK could promote the recovery of L-arginine-induced pancreatitis in mice. Therefore, MK may be involved in the regeneration of acinar cells in AP, and rhMK may be a possible therapeutic intervention for the repairment of AP. PMID- 27992670 TI - Dissection of the Effects of Quercetin on Mouse Myocardium. AB - Quercetin is a plant flavonoid with several biological activities. This study aimed to describe quercetin effects on contractile and electrophysiological properties of the cardiac muscle as well as on calcium handling. Quercetin elicited positive inotropism that was significantly reduced by propranolol indicating an involvement of the sympathetic nervous system. In cardiomyocytes, 30 MUM quercetin increased ICa,L at 0 mV from -0.95 +/- 0.01 A/F to -1.21 +/- 0.08 A/F. The membrane potential at which 50% of the channels are activated (V0.5 ) shifted towards more negative potentials from -13.06 +/- 1.52 mV to -19.26 +/- 1.72 mV and did not alter the slope factor. Furthermore, quercetin increased [Ca2+ ]i transient by 28% when compared to control. Quercetin accelerated [Ca2+ ]i transient decay time, which could be attributed to SERCA activation. In resting cardiomyocytes, quercetin did not change amplitude or frequency of Ca2+ sparks. In isolated heart, quercetin increased heart rate and decreased PRi, QTc and duration of the QRS complex. Thus, we showed that quercetin activates beta adrenoceptors, leading to increased L-type Ca2+ current and cell-wide intracellular Ca2+ transient without visible changes in Ca2+ sparks. PMID- 27992671 TI - Modulation of Excess Electron Transfer through LUMO Gradients in DNA Containing Phenanthrenyl Base Surrogates. AB - The modulation of excess electron transfer (EET) within DNA containing a dimethylaminopyrene (C-AP) as an electron donor and 5-bromouracil (Br dU) as an electron acceptor through phenanthrenyl pairs (phen-R) could be achieved by modifying the phenanthrenyl base surrogates with electron withdrawing and donating groups. Arranging the phenanthrenyl units to form a descending LUMO gradient increased the EET efficiency compared to the electron transfer through uniform LUMOs or an ascending LUMO gradient. PMID- 27992672 TI - Beyond counting stillbirths to understanding their determinants in low- and middle-income countries: a systematic assessment of stillbirth data availability in household surveys. AB - OBJECTIVE: To systematically map data availability for stillbirths from all countries with Demographic and Health Surveys (DHS) surveys to outline the limitations and challenges with using the data for understanding the determinants and causes of stillbirths, and for cross-country comparisons. METHODS: We assessed data sources from the DHS programme website, including published DHS reports and their associated questionnaires for surveys completed between 2005 and 2015. RESULTS: Between 2005 and 2015, the DHS programme completed 114 surveys across 70 low- and middle-income countries. Ninety-eight (86.0%) surveys from 66 countries collected stillbirth data adequately to calculate a stillbirth rate, while 16 surveys from 12 countries did not. The method used to count stillbirths varied; 96 (84.2%) surveys used a live birth history with a reproductive calendar, while 16 (14.0%) surveys from 12 countries did a full pregnancy history. Based on assessment of questionnaires, antenatal and delivery care information for stillbirths was only available in 15 surveys (13.2%) from 12 countries (17.1%). Data on maternal conditions/complications were captured in 17 surveys (16.0%), but only in six could these be linked to stillbirths. Data on other recognised risk factors were scarce, varying considerably across surveys. Upon further examination of data sets from surveys with maternity care data on non-live births, we found incomplete capture of these data; only two surveys had adequately and completely collected these for stillbirths. CONCLUSION: Substantial variation exists in DHS surveys in the measurement of stillbirths, with limited scope to examine risk factors or causes. Without immediate improvements, our understanding of country-specific trends and determinants for stillbirths will remain hampered, limiting the development and prioritisation of programmatic interventions to prevent these deaths. PMID- 27992673 TI - A Metal-Free, Nonconjugated Polymer for Solar Photocatalysis. AB - Heterogeneous catalysts that can absorb light over the solar range are ideal for green photocatalysis. Recently, attention has been directed towards the generation of novel solar-light photocatalysts, in particular, metal-free polymers. Herein, it is demonstrated that a metal-free, nonconjugated, anthraquinone-based copolymer (poly[1,4-diamine-9,10-dioxoanthracene-alt-(benzene 1,4-dioic acid)] (COP)) with a strong absorption in the visible region is effective as a sunlight heterogeneous photocatalyst. As a proof of concept, it has been used to mineralize 2,5-dichlorophenol (2,5-DCP) in water under air and sunlight irradiation. The photocatalytic efficiency of COP compares well with that of TiO2 -P25 when the reaction is carried out in a solar photoreactor in acid medium. Steady-state and time-resolved (absorption and emission) studies performed on COP suspended in 6:4 DMF/H2 O have provided valuable information about the COP species generated under different pH conditions. Steady-state absorption and fluorescence data are consistent with the existence of a tautomeric equilibrium between the 9,10-keto and 1,10-iminoketo quinoid forms for the anthraquinone in the ground state. Moreover, in basic media, transient absorption measurements showed the presence of two bands ascribed to the tautomeric triplet excited states, whereas only one of the triplets was observed in acid medium. A mechanism for the photocatalyzed degradation of 2,5-DCP by COP is proposed on the basis of these observations. PMID- 27992674 TI - Overexpression of the metastasis-associated gene MTA3 correlates with tumor progression and poor prognosis in hepatocellular carcinoma. AB - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers in the world. However, there remains a lack of effective diagnostic and treatment markers. We aimed to explore metastasis-associated protein 3 (MTA3) expression and function in HCC and its relationship with clinicopathological factors. METHODS: We investigated the expression pattern and clinicopathological significance of MTA3 in 90 patients with HCC via immunohistochemistry and explored MTA3 function via gene knockdown of MTA3. RESULTS: MTA3 was overexpressed in HCC cell nuclei and downregulated in HCC cell cytoplasm. The former finding correlated with metastasis (P = 0.010) and poor prognosis (P = 0.018). In addition, deleting MTA3 inhibited HCC cell growth, invasion, and metastasis in vitro, as shown in the colony formation, migration, and wound-healing assays. CONCLUSIONS: These results indicate that MTA3 is an oncogene of HCC, predicts poor prognosis of HCC, and may be a future marker of HCC treatment. PMID- 27992675 TI - Readmissions after adult congenital heart surgery: Frequency and risk factors. AB - OBJECTIVE: Despite their clinical importance, 30-day readmission after adult congenital heart surgery has been understudied. They sought to determine the frequency of unplanned readmissions after adult congenital heart surgery and to identify any potential associated risk factors. DESIGN: Retrospective cohort study using State Inpatient Databases for Washington, New York, Florida, and California from 2009 to 2011. SETTING: Federal and nonfederal acute care hospitals. PATIENTS: Admissions of patients age 18-49 years with International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating adult congenital heart surgery. OUTCOME MEASURES: Readmission was defined as any nonelective hospitalization for a given patient <=30 days of discharge from the index congenital heart surgery admission. RESULTS: Of 9863 admissions, there were 8912 patients discharged home, of which 1419 were readmitted (14.2%). Unadjusted mortality rate was 2.6%. Most common indications for readmission were cardiac (pericardial disease, atrial fibrillation, heart failure) and infectious (postoperative infection, endocarditis). On multivariable analysis, female gender (adjusted odds ratio [AOR] 1.1; P = .05), black race (AOR 1.2; P = .05), median income <$40,000 (AOR 1.3; P = .01), government-sponsored insurance (AOR 1.4; P < .001), renal insufficiency (AOR 2.1; p < .001), Risk Adjustment for Congenital Heart Surgery-1 (RACHS-1) 3 complexity (AOR 1.3; P = .04), and emergent admissions (AOR 1.5 P < .001) were risk factors for readmission. CONCLUSIONS: One out of seven adult congenital heart surgery hospitalizations results in unplanned readmission. Female gender, lower income status, black race, government-sponsored insurance, renal failure, unscheduled index admission, and RACHS-1 three surgical procedures are risk factors for subsequent unplanned 30-day readmission. These risk factors may serve as potential quality improvement targets to reduce readmissions. PMID- 27992676 TI - Haem oxygenase-1 polymorphisms can affect HCV replication and treatment responses with different efficacy in humanized mice. AB - BACKGROUND & AIMS: Enhancement of host anti-oxidant enzymes, such as haemoxygenase-1, may attenuate virus-mediated hepatocyte injury, while the induction of HO-1 by cobalt-protoporphyrin-IX (CoPP) administration, as the application of its haem degradation product biliverdin (BV), was shown to hinder HCV replication in vitro. In addition, (GT)n -repeats length in the polymorphic region of the HO-1 promoter may affect HO-1 expression and responsiveness to infection and disease severity. Aim of this study was to investigate the antiviral and hepatoprotective effects of CoPP-mediated HO-1 induction, alone or in combination with interferon alpha (peg-IFNalpha), in HCV-infected mice harbouring hepatocytes from donors with different HO-1-promoter polymorphisms. METHODS: Upon establishment of HCV infection, CoPP, BV and peg-IFNalpha were given alone or in combination. Viraemia changes and intrahepatic human gene expression were determined by qRT-PCR and immunohistochemistry. RESULTS: CoPP administration increased human HO-1 expression and significantly reduced viraemia, although changes correlated with promoter length (Delta0.5log and Delta2log reduction with medium- and short-polymorphism respectively). Polymorphisms did not influence BV-mediated antiviral effects (Delta1log). Notably, HO-1 induction attenuated basal HCV-driven enhancement of interferon genes and pro-inflammatory cytokines, both in cells with short- or medium polymorphisms. Moreover, simultaneous administration of CoPP and peg-IFNalpha reduced viraemia even stronger (median 3log), whereas 1log viraemia reduction was determined in mice receiving peg-IFNalpha monotherapy. CONCLUSIONS: Although the protective function of HO-1 could be elicited in vivo with both host polymorphisms, the strength of HO-1 induction and suppression of HCV occurred in a polymorphism-dependent manner, indicating that host-genetic determinants may affect disease progression and infection outcome. PMID- 27992678 TI - Strategy for Extending the Stability of Bio-oil-Derived Phenolic Oligomers by Mild Hydrotreatment with Ionic-Liquid-Stabilized Nanoparticles. AB - The development of catalytic transformations and processes is essential to utilize bio-oil and lignin derivatives. Metal nanoparticles (M-NPs) stabilized in ionic liquids (ILs) are promising for the catalytic hydrotreatment of bio-oil because the properties of the catalyst system can be customized by combining the appropriate IL and metal nanoparticles. Herein, we demonstrate an experimental approach to stabilize lignin-derived phenolics isolated from bio-oil with ruthenium NPs stabilized by an ionic copolymer in 1-ethyl-3-methylimidazolium acetate ([C2 C1 Im][OAc]). The mild hydrotreatment of phenolic oligomers (POs) was performed with the synthesized M-NP catalyst at 100 degrees C for 6 h. Hydrotreatment of the POs resulted in enhanced thermal stability of the POs by as much as a factor of three, as determined by the aging index and by reducing reactive functionalities, which was also confirmed by NMR spectroscopy and GC analysis. The results support our hypothesis that M-NPs stabilized in ILs can effectively stabilize POs under mild conditions, which could be applicable to any lignin-derived phenolic. PMID- 27992677 TI - Mortality and clinical outcomes in children treated with antiretroviral therapy in four African vertical programmes during the first decade of paediatric HIV care, 2001-2010. AB - OBJECTIVE: To assess mortality and clinical outcomes in children treated with antiretroviral therapy (ART) in four African vertical programmes between 2001 and 2010. METHODS: Cohort analysis of data from HIV-infected children (<15 years old) initiating ART in four sub-Saharan HIV programmes in Kenya, Uganda and Malawi, between December 2001 and December 2010. Rates of mortality, programme attrition and first-line clinico-immunological failure were calculated by age group (<2, 2 4 and 5-14 years), 1 or 2 years after ART initiation, and risk factors were examined. RESULTS: A total of 3949 children, 22.7% aged <2 years, 32.2% 2-4 years and 45.1% 5-14 years, were included. At ART initiation, 60.8% had clinical stage 3 or 4, and 46.5% severe immunosuppression. Overall mortality, attrition and 1 year failure rates were 5.1, 10.8 and 9.0 per 100 person-years, respectively. Immunosuppression, stage 3 or 4, and underweight were associated with increased rates of mortality, attrition and treatment failure. Adjusted estimates showed lower mortality hazard ratios (HR) among children aged 2-4 years (HR = 0.57, 95% CI 0.42-0.77 than children aged 5-14 years). One-year treatment failure incidence rate ratios (IRR) were similar regardless of age (IRR = 0.91, 95% CI 0.67-1.25 for <2 years; 1.01, 95% CI 0.83-1.23 for 2-4 years, vs. 5-14 years). CONCLUSIONS: Good treatment outcomes were achieved during the first decade of HIV paediatric care despite the late start of therapy. Encouraging early HIV infant diagnosis in and outside prevention of mother-to-child transmission programmes, and linkage to care services for early ART initiation, is needed to reduce mortality and delay treatment failure. PMID- 27992679 TI - Incomplete and incorrect epinephrine auto-injector training to food-allergic patients by pharmacists in the Netherlands. AB - BACKGROUND: Successful treatment of anaphylaxis in the community relies on early and correct use of epinephrine auto-injectors (EAI). In the Netherlands, pharmacists supply EAIs to patients and have a crucial role in instructing patients in how and when to use EAI. However, there are currently no data in Europe on the quality of such instruction provided by pharmacists. Therefore, the aims of this study were to investigate the knowledge, attitudes, and beliefs regarding food allergy among pharmacists in the Netherlands and to investigate the quality of EAI instructions and demonstrations to patients by pharmacists. METHODS: Pharmacists were asked to complete an online questionnaire. Quality of instructions and demonstration accuracy were assessed in mystery guest visits to randomly selected pharmacies. For the statistical analysis, descriptive methods were used. RESULTS: In total, 25 of 115 questionnaires were completed. Only two (8%) respondents gave correct answers concerning the proper EAI demonstration. Twenty-one (84%) respondents thought that the provision of instructions was the responsibility of pharmacists. In total, ten pharmacies were included in simulated patient visits. Five of them (50%) demonstrated the EAI. None of them demonstrated the EAI use correctly. CONCLUSION: Food-allergic patients at high risk for anaphylaxis who receive their EAI from a community pharmacy are often not instructed on how to use an EAI or receive incorrect instructions. Pharmacists show considerable gaps in knowledge about food allergy and its management. These data suggest that opportunities exist to improve the quality of care provided by pharmacies to high-risk food-allergic patients. PMID- 27992680 TI - Exploring characteristics, predictors, and consequences of fear of cancer recurrence among Asian-American breast cancer survivors. AB - BACKGROUND: To address the fear of cancer recurrence (FCR) research gap, we used prospective data to explore FCR predictors and FCR associations with health related quality of life among Asian-American breast cancer survivors (BCS). METHODS: A total of 208 diverse Asian-American BCS completed T1 survey, and 137 completed T2 survey after 1 year. RESULTS: Fear of cancer recurrence scores (range = 0-4) were 2.01 at T1 and 1.99 at T2 reflecting low-to-moderate FCR. Scores of FCR were stable over the 1-year period (t(126) = .144, P = .886). Multiple regression analyses showed that Chinese women reported lower FCR both at T1 (t(193) = -2.92, P = .004) and T2 (t(128) = -2.56, P = .012) compared to other Asian women. Also, more positive health care experience at T1 predicted lower FCR at T2 (beta = -.18, P = .041). Controlling for other covariates, greater FCR at T1 predicted poorer outcomes 1 year later including lower physical (beta = -.31, P < .001), emotional (beta = -.37, P < .001) and functional (beta = -.16, P = .044) well-being and health-related quality of life specific to breast cancer at T2 (beta = -.31, P < .001). CONCLUSIONS: We found substantial consistencies and some divergences between our findings with Asian-American BCS and the existing literature. This prospective investigation reveals new information suggesting that Asian-American subgroup variation exists and health care system factors may influence FCR. Thus, FCR studies should consider Asian subgroupings, cultural aspects, ie, level of acculturation and health care system factors including provider-patient communication and treatment setting. Future research may benefit from contextualizing FCR within a broader distress framework to advance the science and practice of patient-centered and whole-person care. PMID- 27992681 TI - Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key to viral persistence in chronic hepatitis B infection. Serum hepatitis B core-related antigen (HBcrAg) is a novel marker for HBV disease. We aimed to determine whether HBcrAg could be a surrogate marker for intrahepatic cccDNA. METHODS: Three hundred and five liver biopsies and the corresponding sera collected from 138 nucleos(t)ide analogues-treated patients were analysed. 124 patients had paired liver biopsies at baseline and 1-year post-treatment, and 43 patients had a third biopsy after 6-12 years of treatment. Serum HBcrAg, HBV DNA and hepatitis B surface antigen (HBsAg), and intrahepatic HBV DNA and cccDNA were measured. RESULTS: HBcrAg strongly correlated with cccDNA (r=.70), intrahepatic total HBV DNA (r=.67) and serum HBV DNA (r=.69; all P<.0001). In the 130 samples with undetectable serum HBV DNA, HBcrAg was detectable in 101 (78%) samples, and HBcrAg levels still correlated positively with cccDNA (r=.42, P<.0001). At >=6 years of therapy, the median logarithmic reduction in HBcrAg was 2.7 log kU/mL, which was comparable to the magnitude of reduction in cccDNA. Twenty-one patients had undetectable cccDNA after >=6 years of treatment, in whom 15 (71%) had detectable HBcrAg (range: 1.2-537 kU/mL). CONCLUSIONS: Serum HBcrAg is a reliable surrogate marker for intrahepatic cccDNA. HBcrAg could be a very sensitive marker to reflect the cccDNA content and persistence of disease even with the cccDNA levels below the detection limit of assays. PMID- 27992682 TI - Papers based on data concerning organs from executed prisoners should not be published. PMID- 27992683 TI - Yearly Trends in Elective Shoulder Arthroplasty, 2005-2013. AB - OBJECTIVE: To evaluate the change in incidence rate of shoulder arthroplasty, the utilization of shoulder arthroplasty for specific indications, and the surgeon volume trends associated with these procedures between 2005 and 2013. METHODS: A population-based cohort study was conducted using the more than 7 million members of an integrated health care system in California. Cases of shoulder arthroplasties performed between 2005 and 2013 were identified using a shoulder arthroplasty registry. Annual shoulder arthroplasty incidence rates per 100,000 patients were determined, and adjusted yearly changes in rates were estimated using incidence rate ratios (IRRs). Changes in surgeon volumes by year and number of surgeons performing different procedures were also compared. RESULTS: The incidence of shoulder arthroplasty per 100,000 members increased from 6.1 (95% confidence interval [95% CI] 5.5-6.7) in 2005 to 13.4 (95% CI 12.5-14.2) in 2013. In patients with osteoarthritis, there was increasing utilization of total shoulder arthroplasty (IRR 1.12 [95% CI 1.11-1.14]) and decreasing utilization of hemiarthroplasty (IRR 0.91 [95% CI 0.89-0.94]). For patients with rotator cuff tear arthropathy, there was an increase in utilization of reverse total shoulder arthroplasty (IRR 1.33 [95% CI 1.29-1.37]) but no change in hemiarthroplasty (IRR 0.99 [95% CI 0.92-1.05]). The average surgeon yearly volume increased for total shoulder arthroplasty (P < 0.001) and for reverse total shoulder arthroplasty (P = 0.020). CONCLUSION: Shoulder arthroplasty is being used with greater frequency in this population. Surgeons are performing a greater yearly volume of total shoulder arthroplasty and reverse total shoulder arthroplasty. PMID- 27992685 TI - Biologic Therapy for Eosinophilic Granulomatosis With Polyangiitis (Churg Strauss): Comment on the Article by Jachiet et al. PMID- 27992684 TI - Hip Shape as a Predictor of Osteoarthritis Progression in a Prospective Population Cohort. AB - OBJECTIVE: Hip morphology plays a significant role in the incidence and progression of hip osteoarthritis (OA). We hypothesized that hip shape would also be associated with other key factors and tested this in a longitudinal community based cohort combining radiographic, magnetic resonance imaging (MRI), dual energy x-ray absorptiometry (DXA), and clinical data. METHODS: Baseline DXA images of the left hip of 831 subjects from the Tasmanian Older Adult Cohort were analyzed using an 85-point statistical shape model. Hip pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index, and muscle strength was measured using a dynamometer. Hip structural changes were assessed using MRI and radiographic OA using plain radiographs. RESULTS: Six shape modes accounted for 68% of shape variation. At baseline, modes 1, 2, 4, and 6 were associated with radiographic hip OA; modes 1, 3, 4, and 6 were correlated with hip cartilage volume; and all except mode 2 were correlated with muscle strength. Higher mode 1 and lower mode 3 and mode 6 scores at baseline predicted hip pain at followup and higher mode 1 and mode 2 scores were associated with hip effusion synovitis. Higher scores for mode 2 (decreasing acetabular coverage) and lower scores for mode 4 (nonspherical femoral head) at baseline predicted 10-year total hip replacement (THR), while mode 4 alone was correlated with bone marrow lesions (BMLs), effusion-synovitis, and increased cartilage signal. CONCLUSION: Hip shape is associated with radiographic OA, THR, hip pain, effusion-synovitis, BMLs, muscle strength, and hip structural changes. These data suggest that different shape modes reflect multiple facets of hip OA. PMID- 27992686 TI - Limited Value of the Multi-Biomarker Disease Activity Assay Compared to the Routine Assessment of Patient Index Data 3 (RAPID3) Score in the Prognosis of Important Clinical Outcomes in Rheumatoid Arthritis: Comment on the Article by Fleischmann et al and Accompanying Editorial by Davis. PMID- 27992688 TI - Facet Pain Syndrome and Nonradiographic Axial Spondyloarthritis. PMID- 27992687 TI - Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2. AB - OBJECTIVE: Imbalanced cytokine production by T cells characterizes both patients with systemic lupus erythematosus (SLE) and lupus-prone mice and contributes to immune dysregulation. This study was undertaken to further investigate in detail the production of interleukin-2 (IL-2), interferon-gamma (IFNgamma), IL-4, and IL 17A by CD4+ cell subsets in healthy subjects and patients with SLE, and the signaling response of CD4+ T cells in response to exogenous IL-2. METHODS: Cytokine production by differentiated subsets of CD4+ T cells was assessed by intracellular staining following stimulation with phorbol myristate acetate and ionomycin and by enzyme-linked immunosorbent assay after anti-CD3/anti-CD28 stimulation. The IL-2 signaling pathway was examined by assessing JAK-3/STAT-5 phosphorylation. Cell proliferation in response to IL-2 was examined by carboxyfluorescein succinimidyl ester dilution. RESULTS: Production of IL-2 was defective primarily among naive CD4+ T cells, whereas the production of IFNgamma, IL-4, and IL-17A was not significantly different between patients with SLE and healthy subjects. JAK-3/STAT-5 phosphorylation and proliferation of CD4+ T cells from SLE patients in response to exogenous IL-2 were impaired compared to cells from healthy subjects. CONCLUSION: These data suggest that altered IL-2 production, as well as impaired IL-2-mediated signaling and proliferative responses, characterize SLE CD4+ T cells. Our data demonstrate the need for caution in designing IL-2 treatment trials for patients with SLE. Approaches to restore CD4+ T cell sensitivity to IL-2 should be considered. PMID- 27992689 TI - The Role of Omalizumab in Patients With Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss): Comment on the Article by Jachiet et al. PMID- 27992690 TI - Reply. PMID- 27992692 TI - Rheumatoid Arthritis and Risk of Malignant Lymphoma: Is the Risk Still Increased? AB - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas with a strong correlation with RA disease severity. Given the changes in RA therapy over recent decades, this study was undertaken to assess whether lymphoma risk remains increased, and if so, to explore risk predictors and lymphoma subtypes. METHODS: We identified 12,656 cases of incident RA in the Swedish Rheumatology Quality Register 1997-2012 and obtained information on therapy and inflammatory activity during the first year after diagnosis. Each patient was matched to 10 population comparator subjects. Through linkage to the Swedish Cancer Register, lymphomas, including subtypes, were identified. We assessed hazard ratios (HRs) using Cox regression. RESULTS: Overall, the HR for lymphoma was increased in RA, to 1.6 (95% confidence interval [95% CI] 1.2-2.1). Taking RA duration into account, risks did not appear to have declined over successive calendar years of RA diagnosis. Neither use of methotrexate the first year after RA diagnosis nor ever use of tumor necrosis factor inhibitors (TNFi) increased lymphoma risk (HR 0.9 [95% CI 0.4-1.9]). Use of oral corticosteroids the first year after RA diagnosis was associated with a reduced risk (HR 0.5 [95% CI 0.3-0.9]). Inflammatory activity during the first year after RA diagnosis did not predict future lymphoma risk. Chronic lymphocytic leukemia occurred less frequently, and Hodgkin's lymphoma occurred more frequently, in RA patients than in the general population. CONCLUSION: The average lymphoma risk in recently diagnosed RA is similar in magnitude to that reported in historical cohorts. Standard antirheumatic treatment including TNFi did not predict future lymphoma risk. Distribution of lymphoma subtypes warrants further investigation. PMID- 27992693 TI - Scleroderma Peripheral B Lymphocytes Secrete Interleukin-6 and Transforming Growth Factor beta and Activate Fibroblasts. AB - OBJECTIVE: To study the role of B lymphocytes in systemic sclerosis (SSc). METHODS: Peripheral B cell subpopulations and the production of interleukin-6 (IL 6) and transforming growth factor beta (TGFbeta) were analyzed using flow cytometry and multiplex assay. The fibroblast proliferation rate upon incubation with supernatants from B cells isolated from SSc patients or healthy controls was assessed using XTT, bromodeoxyuridine, and Ki-67. Collagen production was assessed using a collagen assay. RESULTS: Ninety untreated patients (12 males) fulfilling the American College of Rheumatology/European League Against Rheumatism criteria for SSc (23 with diffuse cutaneous SSc [dcSSc] and 67 with limited cutaneous SSc [lcSSc]) and 30 healthy controls were recruited. Increased proportions of B cells expressing CD69 and CD95 were identified among the patients with SSc. B lymphocytes from dcSSc patients versus lcSSc patients and healthy controls expressed increased proportion of cells positive for CD5 (mean +/- SD 24.12 +/- 7.93% versus 14.09 +/- 6.58% [P = 0.03] and 14.21 +/- 5.34% [P = 0.01]), CD86 (39.89 +/- 22.11% versus 17.72 +/- 13.98% [P = 0.0007] and 11.68 +/- 11.09% [P < 0.001]), IL-6 receptor (IL-6R; 33.64 +/- 23.12% versus 17.91 +/- 13.62% [P < 0.0001] and 12.08 +/- 8.68% [P = 0.0009]), or IL-21R (32.55 +/- 20.19% versus 5.76 +/- 4.40% [P < 0.0001] and 5.93 +/- 3.29% [P < 0.0001]). In addition, the levels of IL-6 (mean +/- SD 314.3 +/- 317.8 pg/ml versus 6.10 +/- 2.58 pg/ml; P = 0.0007) and TGFbeta (mean +/- SD 1,020 +/- 569 pg/ml versus 163.8 +/- 98.69 pg/ml; P = 0.001) secreted by B lymphocytes from patients with SSc were increased compared to healthy controls. Fibroblast proliferation and collagen production were also significantly increased in the presence of B cell supernatant from SSc patients as compared to healthy controls. CONCLUSION: The numbers of activated B cells were increased in SSc patients, and the up regulation of CD5, CD86, IL-6R, and IL-21R discriminated between patients with dcSSc and those with lcSSc. Peripheral B lymphocytes from SSc patients secreted both IL-6 and TGFbeta, and they activated fibroblasts in vitro. PMID- 27992695 TI - Reply. PMID- 27992694 TI - A 37-Year-Old Man With Primary Antiphospholipid Syndrome Presenting With Respiratory Distress and Worsening Toe Ischemia. PMID- 27992691 TI - A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure. AB - OBJECTIVE: To investigate whether the Multi-Biomarker Disease Activity (MBDA) score predicts optimal add-on treatment in patients with early rheumatoid arthritis (RA) who were inadequate responders to MTX (MTX-IRs). METHODS: We analyzed data from 157 MTX-IRs (with a Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR] >3.2) from the Swedish Pharmacotherapy (SWEFOT) trial who were randomized to receive triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) versus MTX plus infliximab. The MBDA score as a predictor of the subsequent DAS28-based response to each second-line treatment was analyzed at randomization with the Breslow-Day test for 2 * 2 groups, using both validated categories (low [<30], moderate [30-44], and high [>44]) and dichotomized categories (lower [<=38] versus higher [>38]). RESULTS: Among the 157 patients, 12% had a low MBDA score, 32% moderate, and 56% high. Of those with a low MBDA score, 88% responded to subsequent triple therapy, and 18% responded to MTX plus infliximab (P = 0.006); for those with a high MBDA score, the response rates were 35% and 58%, respectively (P = 0.040). When using 38 as a cutoff for the MBDA score (29% patients with lower scores versus 71% with higher scores), the differential associations with response to triple therapy versus MTX plus infliximab were 79% versus 44% and 36% versus 58%, respectively (P = 0.001). Clinical and inflammatory markers had poorer predictive capacity for response to triple therapy or MTX plus infliximab. CONCLUSION: In patients with RA who had an inadequate response to MTX, the MBDA score categories were differentially associated with response to subsequent therapies. Thus, patients with post-MTX biochemical improvements (lower MBDA scores) were more likely to respond to triple therapy than to MTX plus infliximab. If confirmed, these results may help to improve treatment in RA. PMID- 27992696 TI - Brief Report: Longitudinal Patterns of Response to Standard of Care Therapy for Systemic Lupus Erythematosus: Implications for Clinical Trial Design. AB - OBJECTIVE: To evaluate longitudinal patterns of response to standard of care for systemic lupus erythematosus (SLE) in clinical trials and to identify characteristics that differentiate nonresponders from persistent responders. METHODS: Data on 147 patients with moderately to severely active SLE without acute nephritis who were treated with placebo plus standard of care in two 52 week phase II/III trials were obtained from the Collective Data Analysis Initiative of the Lupus Foundation of America. Cross-sectional and longitudinal analyses of British Isles Lupus Assessment Group (BILAG)-based responses (improvement in all baseline A or B scores without new flare) were performed. Baseline characteristics that discriminated persistent responders from nonresponders were identified using logistic regression. RESULTS: Cross-sectional response rates decreased from 46% to 37% between 12 and 52 weeks. The overall rate of complete and sustained response, i.e., response at all visits, was only 14.3% (95% confidence interval 8.6-19.9%). Agreement between response status at 12 weeks and 36-52 weeks was low (kappa = 0.15-0.29), and only 31% of initial 12 week responders maintained response at all subsequent visits. Baseline factors predictive of persistent response to standard of care included fewer organs with active disease, high C3 levels, and type of background therapy. CONCLUSION: Use of sustained rather than landmark response may reduce high placebo response rates in SLE trials that continue aggressive standard of care. Further exploration to assess the power of this end point to improve discrimination between active and placebo arms is indicated. Lack of temporal stability in response highlights a potential weakness with shorter studies. Rates of response to standard of care are affected by the severity of the disease and the aggressiveness of background immunosuppressive treatments. PMID- 27992699 TI - Lesinurad in Combination With Allopurinol: Risk Without Reward? Comment on the Article by Saag et al. PMID- 27992698 TI - Effects of Hydroxychloroquine in Patients With Cutaneous Lupus Erythematosus: A Multicenter, Double-Blind, Randomized, Parallel-Group Trial. AB - OBJECTIVE: To assess the efficacy and tolerability of hydroxychloroquine (HCQ) in patients with cutaneous lupus erythematosus (CLE), in a phase III clinical trial conducted in Japan. METHODS: We conducted a double-blind, randomized, parallel group clinical trial. This was a baseline-controlled study, and the group differences were evaluated in an exploratory analysis. A total of 103 patients with active CLE (according to a Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score of >=4) were included. Patients were randomized 3:1 to receive HCQ or placebo during the 16-week double-blind period, and all patients were given HCQ during the following 36-week single-blind period. The primary efficacy end point was a reduction in the CLASI activity score at week 16. The secondary end points included the central photo evaluation (5-point scale), patient's global assessment (7-point scale), the Skindex-29 score, and investigator's global assessment (7-point scale, based on the other 3 secondary end points). In patients with systemic lupus erythematosus, fatigue and musculoskeletal pain were assessed. Safety was assessed up to week 55. RESULTS: The mean CLASI score at week 16 was significantly improved from baseline in both the HCQ group and the placebo group: mean change -4.6 (95% confidence interval [95% CI] -6.1, -3.1) (P < 0.0001), and mean change -3.2 (95% CI -5.1, -1.3) (P = 0.002), respectively, without between-group difference (P = 0.197). The investigator's global assessment demonstrated a greater proportion of "improved" and "remarkably improved" patients in the HCQ group (51.4% versus 8.7% in the placebo group [P = 0.0002 between groups]). The other secondary end points supported the efficacy of HCQ. Cellulitis, drug eruption, hepatic dysfunction, and Stevens-Johnson syndrome were shown to be serious adverse events related to HCQ use. CONCLUSION: The results of this randomized clinical trial support the efficacy and tolerability of HCQ in patients with CLE. PMID- 27992697 TI - VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis. AB - OBJECTIVE: The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V-domain Ig-containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1alpha) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathway is a novel strategy for the treatment of human autoimmune disease, and therefore we undertook this study to determine the impact of VISTA genetic deficiency on lupus development in a lupus-prone mouse strain. METHODS: To evaluate whether genetic deficiency of VISTA affects the development of lupus, we interbred VISTA-deficient mice with Sle1.Sle3 mice, a well characterized model of systemic lupus erythematosus (SLE). RESULTS: We demonstrated that the development of proteinuria and glomerulonephritis in these mice, designated Sle1.Sle3 VISTA-/- mice, was greatly accelerated and more severe compared to that in Sle1.Sle3 and C57BL/6 VISTA-/- mice. Analysis of cells from Sle1.Sle3 VISTA-/- mice showed enhanced activation of splenic CD4+ T cells and myeloid cell populations. No increase in titers of autoantibodies was seen in Sle1.Sle3 VISTA-/- mice. Most striking was a significant increase in proinflammatory cytokines, chemokines, and interferon (IFN)-regulated genes associated with SLE, such as IFNalpha, IFNgamma, tumor necrosis factor, interleukin-10, and CXCL10, in Sle1.Sle3 VISTA-/- mice. CONCLUSION: This study demonstrates for the first time that loss of VISTA in murine SLE exacerbates disease due to enhanced myeloid and T cell activation and cytokine production, including a robust IFNalpha signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus. PMID- 27992700 TI - For Disadvantaged Urban Blacks, Condom Use May Vary with Relationship Type and Partner's Drug Use. PMID- 27992701 TI - Mandated State Waiting Periods Linked to Delays In Obtaining Abortion Care. PMID- 27992702 TI - Prevalence of Preconception Care Varies Among Publicly Funded Clinics. PMID- 27992703 TI - Finnish Study Finds No Associations Between Early Abortion and Adverse Outcomes in Young Adulthood. PMID- 27992705 TI - Room for Improvement Remains in Quality and Scope Of U.S. Publicly Funded Family Planning Services. PMID- 27992706 TI - Teenage Pregnancy Risk And Timing Differ By Sexual Orientation. PMID- 27992708 TI - Reply. PMID- 27992707 TI - Inappropriate prescription of cough remedies among children hospitalised with respiratory illness over the period 2002-2015 in Kenya. AB - OBJECTIVE: To examine trends in prescription of cough medicines over the period 2002-2015 in children aged 1 month to 12 years admitted to Kenyan hospitals with cough, difficulty breathing or diagnosed with a respiratory tract infection. METHODS: We reviewed hospitalisation records of children included in four studies providing cross-sectional prevalence estimates from government hospitals for six time periods between 2002 and 2015. Children with an atopic illness were excluded. Amongst eligible children, we determined the proportion prescribed any adjuvant medication for cough. Active ingredients in these medicines were often multiple and were classified into five categories: antihistamines, antitussives, mucolytics/expectorants, decongestants and bronchodilators. From late 2006, guidelines discouraging cough medicine use have been widely disseminated and in 2009 national directives to decrease cough medicine use were issued. RESULTS: Across the studies, 17 963 children were eligible. Their median age and length of hospital stay were comparable. The proportion of children who received cough medicines shrank across the surveys: approximately 6% [95% CI: 5.4, 6.6] of children had a prescription in 2015 vs. 40% [95% CI: 35.5, 45.6] in 2002. The most common active ingredients were antihistamines and bronchodilators. The relative proportion that included antihistamines has increased over time. CONCLUSIONS: There has been an overall decline in the use of cough medicines among hospitalised children over time. This decline has been associated with educational, policy and mass media interventions. PMID- 27992709 TI - Reply. PMID- 27992711 TI - Left ventricular thrombi after simultaneous thrombotic occlusions of multiple coronary arteries presenting acute myocardial infarction: need anticoagulant? PMID- 27992712 TI - Usefulness of Allerkin House Dust Mite Extract for Nasal Provocation Testing. AB - OBJECTIVES: We evaluated the clinical usefulness of Allerkin (Lofarma) for nasal provocation testing (NPT) in patients with rhinitis symptoms, by examining changes in nasal symptoms and acoustic parameters after exposure to house dust mite (HDM) extract. METHODS: Twenty patients (16 males and 4 females, mean age: 29.6+/-14.6 years) were enrolled. We performed skin prick test (SPT) before and 15 and 30 minutes after intranasal challenge with Allerkin HDM extract, and we evaluated symptom changes (nasal obstruction, rhinorrhea, sneezing, and itching) using a visual analogue scale. We also evaluated changes in acoustic parameters such as total nasal volume (TNV) and minimal cross-sectional area (MCA) before and after challenge. RESULTS: Group A (the nonallergic group, n=8) showed negative results for all tested aeroallergens in SPT and nonprovocative results (<25% decrease of TNV and MCA from the baseline value) in NPT. Group B (the allergic group, n=7) exhibited strongly positive results (wheal size larger than that of histamine) for HDM allergens on SPT. Group C (the local allergic group, n=5) showed negative results on SPT, but a provocative response on NPT (>29% decrease in TNV/MCA from the baseline value). Patients in group C showed significant aggravation of nasal obstruction compared to those in group A (P<0.05). Thirty minutes after HDM challenge, patients in groups B and C showed significantly greater decreases in MCA compared to those in group A (P<0.01). CONCLUSION: Allerkin HDM extract can be a useful provocative agent in NPT for diagnosing allergic rhinitis and local allergic rhinitis. PMID- 27992713 TI - Multilayered Approach for TiO2 Hollow-Shell-Protected SnO2 Nanorod Arrays for Superior Lithium Storage. AB - The ability to control the growth of materials with nanosized precision as well as a complex hollow morphology provides rationale for the study of systems comprising both characteristics. This study explores the design of TiO2 hollow nanotube shells deposited by atomic layer deposition (ALD) on vertically aligned SnO2 nanorods grown using the vapor-liquid-solid technique. The sacrificial template approach in combination with highly conformal coating advantages of ALD resulted in a highly reproducible method to create a large surface area covered by TiO2-protected SnO2 nanorods, which are about 60-100 nm in diameter and approximately 1 MUm in length. ZnO was used as a sacrificial layer to create a 30 nm gap between SnO2 nanorods and 10 nm of TiO2 shells. Chemical etching of the sacrificial layer was used to create the desired hollow nanocomposite. A coin half-cell battery has been assembled using the TiO2-protected SnO2 nanorods as an anode electrode and lithium foil as a counter electrode and tested for lithium storage during 70 cycles of charge/discharge in a range of 0.5-2.5 V. The TiO2 hollow shell functioned as a good and robust enhancer for both absolute capacity and current rate capabilities of vertically aligned SnO2 nanorods; an improvement in cyclic stability was also observed. This advanced self-standing hollow configuration provides several unique advantages for energy storage device applications including enhanced lithiation for superior energy storage performance. PMID- 27992710 TI - Subjective and Objective Measures of Dryness Symptoms in Primary Sjogren's Syndrome: Capturing the Discrepancy. AB - OBJECTIVE: To develop a novel method for capturing the discrepancy between objective tests and subjective dryness symptoms (a sensitivity scale) and to explore predictors of dryness sensitivity. METHODS: Archive data from the UK Primary Sjogren's Syndrome Registry (n = 688) were used. Patients were classified on a scale from -5 (stoical) to +5 (sensitive) depending on the degree of discrepancy between their objective and subjective symptoms classes. Sensitivity scores were correlated with demographic variables, disease-related factors, and symptoms of pain, fatigue, anxiety, and depression. RESULTS: Patients were on average relatively stoical for both types of dryness symptoms (mean +/- SD ocular dryness -0.42 +/- 2.2 and -1.24 +/- 1.6 oral dryness). Twenty-seven percent of patients were classified as sensitive to ocular dryness and 9% to oral dryness. Hierarchical regression analyses identified the strongest predictor of ocular dryness sensitivity to be self-reported pain and that of oral dryness sensitivity to be self-reported fatigue. CONCLUSION: Ocular and oral dryness sensitivity can be classified on a continuous scale. The 2 symptom types are predicted by different variables. A large number of factors remain to be explored that may impact symptom sensitivity in primary Sjogren's syndrome, and the proposed method could be used to identify relatively sensitive and stoical patients for future studies. PMID- 27992714 TI - Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase. AB - PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail. PMID- 27992716 TI - Fidelity of the DNA Ligase-Catalyzed Scaffolding of Peptide Fragments on Nucleic Acid Polymers. AB - We describe the development and analysis of the T4 DNA ligase-catalyzed DNA templated polymerization of pentanucleotides modified with peptide fragments toward the generation of ssDNA-scaffolded peptides. A high-throughput duplex DNA sequencing method was developed to facilitate the determination of fidelity for various codon sets and library sizes used during the polymerization process. With this process, we identified several codon sets that enable the efficient and sequence-specific incorporation of peptide fragments along a ssDNA template at fidelities up to 99% and with low sequence bias. These findings mark a significant advance in generating evolvable biomimetic polymers and should find ready application to the in vitro selection of molecular recognition. PMID- 27992715 TI - Enantiocomplementary Synthesis of gamma-Nitroketones Using Designed and Evolved Carboligases. AB - Artificial enzymes created by computational design and directed evolution are versatile biocatalysts whose promiscuous activities represent potentially attractive starting points for divergent evolution in the laboratory. The artificial aldolase RA95.5-8, for example, exploits amine catalysis to promote mechanistically diverse carboligations. Here we report that RA95.5-8 variants catalyze the asymmetric synthesis of gamma-nitroketones via two alternative enantiocomplementary Michael-type reactions: enamine-mediated addition of acetone to nitrostyrenes, and nitroalkane addition to conjugated ketones activated as iminium ions. In addition, a cascade of three aldolase-catalyzed reactions enables one-pot assembly of gamma-nitroketones from three simpler building blocks. Together, our results highlight the chemical versatility of artificial aldolases for the practical synthesis of important chiral synthons. PMID- 27992717 TI - Composition-Modulated Two-Dimensional Semiconductor Lateral Heterostructures via Layer-Selected Atomic Substitution. AB - Composition-controlled growth of two-dimensional layered semiconductor heterostructures is crucially important for their applications in multifunctional integrated photonics and optoelectronics devices. Here, we report the realization of composition completely modulated layered semiconductor MoS2-MoS2(1-x)Se2x (0 < x < 1) lateral heterostructures via the controlled layer-selected atomic substitution of pregrown stacking MoS2, with a bilayer located at the center of a monolayer. Through controlling the reaction time, S at the monolayer MoS2 at the peripheral area can be selectively substituted by Se atoms at different levels, while the bilayer region at the center retains the original composition. Microstructure characterizations demonstrated the formation of lateral heterostructures with a sharp interface, with the composition at the monolayer area gradually modulated from MoS2 to MoSe2 and having high-quality crystallization at both the monolayer and the bilayer areas. Photoluminescence and Raman mapping studies exhibit the tunable optical properties only at the monolayer region of the as-grown heterostructures, which further demonstrates the realization of high-quality composition/bandgap modulated lateral heterostructures. This work offers an interesting and easy route for the development of high-quality layered semiconductor heterostructures for potential broad applications in integrated nanoelectronic and optoelectronic devices. PMID- 27992718 TI - Superwettable Microchips as a Platform toward Microgravity Biosensing. AB - The construction of the Space Station provides a spaceflight laboratory, which enables us to accomplish tremendous short- and long-duration research such as astronomy, physics, material sciences, and life sciences in a microgravity environment. Continuous innovation and development of spaceflight laboratory prompted us to develop a facile detection approach to meet stringent requirements in a microgravity environment that traditional experimental approaches cannot reach. Here we introduce superhydrophilic microwells onto superhydrophobic substrates that are capable of capturing and transferring microdroplets, demonstrating a proof-of-concept study of a biosensing platform toward microgravity application. The capability of manipulating microdroplets originates from the capillary force of the nanoscale dendritic coating in superhydrophilic microwells. Based on theoretical modeling, capillary forces of the superhydrophilic microwells can dominate the behavior of microdroplets against the gravity. Direct naked-eye observation monitoring of daily physiological markers, such as glucose, calcium, and protein can be achieved by colorimetric tests without the requirement of heavy optical or electrical equipment, which greatly reduced the weight, and will bring a promising clue for biodetection in microgravity environments. PMID- 27992719 TI - Chemical Vapor Deposition Growth of Few-Layer MoTe2 in the 2H, 1T', and 1T Phases: Tunable Properties of MoTe2 Films. AB - Chemical vapor deposition allows the preparation of few-layer films of MoTe2 in three distinct structural phases depending on the growth quench temperature: 2H, 1T', and 1T. We present experimental and computed Raman spectra for each of the phases and utilize transport measurements to explore the properties of the 1T MoTe2 phase. Density functional theory modeling predicts a (semi-)metallic character. Our experimental 1T films affirm the former, show facile MUA-scale source-drain currents, and increase in conductivity with temperature, different from the 1T' phase. Variation of the growth method allows the formation of hybrid films of mixed phases that exhibit susceptibility to gating and significantly increased conductivity. PMID- 27992720 TI - From Cooperative Self-Assembly to Water-Soluble Supramolecular Polymers Using Coarse-Grained Simulations. AB - Supramolecular polymers, formed via noncovalent self-assembly of elementary monomers, are extremely interesting for their dynamic bioinspired properties. In order to understand their behavior, it is necessary to access their dynamics while maintaining high resolution in the treatment of the monomer structure and monomer-monomer interactions, which is typically a difficult task, especially in aqueous solution. Focusing on 1,3,5-benzenetricarboxamide (BTA) water-soluble supramolecular polymers, we have developed a transferable coarse-grained model that allows studying BTA supramolecular polymerization in water, while preserving remarkable consistency with the atomistic models in the description of the key interactions between the monomers (hydrophobic, H-bonding, etc.), self-assembly cooperativity, and amplification of order into the growing fibers. This permitted us to monitor the amplification of the key interactions between the monomers (including H-bonding) in the BTA fibers during the dynamic polymerization process. Our molecular dynamics simulations provide a picture of a stepwise cooperative polymerization mechanism, where initial fast hydrophobic aggregation of the BTA monomers in water is followed by the slower reorganization of these disordered aggregates into ordered directional oligomers. Supramolecular polymer growth then proceeds on a slower time scale. We challenged our models via comparison with the experimental evidence, capturing the effect of temperature variations and subtle changes in the monomer structure on the polymerization and on the properties of the fibers seen in the real systems. This work provides a multiscale spatiotemporal characterization of BTA self-assembly in water and a useful platform to study a variety of BTA-based supramolecular polymers toward structure-property relationships. PMID- 27992721 TI - Hamiltonian Matrix Correction Based Density Functional Valence Bond Method. AB - In this work, a valence bond type multireference density functional theory (MRDFT) method, called the Hamiltonian matrix correction based density functional valence bond method (hc-DFVB), is presented. In hc-DFVB, the static electronic correlation is considered by the valence bond self-consistent field (VBSCF) strategy, while the dynamic correlation energy is taken into account by Kohn-Sham density functional theory (KS-DFT). Different from our previous version of DFVB (J. Chem. Theory Comput. 2012, 8, 1608), hc-DFVB corrects the dynamic correlation energy with a Hamiltonian correction matrix, improving the functional adaptability and computational accuracy. The method was tested for various physical and chemical properties, including spectroscopic constants, bond dissociation energies, reaction barriers, and singlet-triplet gaps. The accuracy of hc-DFVB matches that of KS-DFT and high level molecular orbital (MO) methods quite well. Furthermore, hc-DFVB keeps the advantages of VB methods, which are able to provide clear interpretations and chemical insights with compact wave functions. PMID- 27992722 TI - Asymmetric Total Syntheses of Two Possible Diastereomers of Gliomasolide E and Its Structural Elucidation. AB - The first total syntheses of two possible diastereomers of gliomasolide E, a 14 membered macrolides isolated from the marine sponge Phakellia fusca Thiele, which was collected from the South China Sea, is reported. Highlights of the synthesis include macrolactonization through intramolecular Horner-Wadsworth-Emmons olefination, Yamaguchi-Hirao alkynylation, and base-induced elimination reactions for propargyl alcohol synthesis as the key reactions. Detailed comparison of their 1H and 13C NMR (1D and 2D NMR data) and specific rotation with those of the natural product revealed that the absolute stereochemistry of gliomasolide E should be (2E,5R,7R,9R,13R). PMID- 27992723 TI - BF3.OEt2 Mediated Regioselective Reaction of Electron-Rich Arenes with 3-Ylidene Oxindoles. AB - A BF3.OEt2 mediated novel and regioselective protocol for the construction of a C C bond between 3-ylidene oxindoles and electron-rich arenes has been successfully accomplished. The reaction was compatible with a wide variety of electron-rich arenes. A cascade reaction of 3-ylidene oxindoles with phenols and beta-naphthol resulted in 2,3-difunctionalized benzofuran and lactone bearing indoline-2-one scaffolds under same conditions. PMID- 27992724 TI - Folate-Targeted Surface-Enhanced Resonance Raman Scattering Nanoprobe Ratiometry for Detection of Microscopic Ovarian Cancer. AB - Ovarian cancer has a unique pattern of metastatic spread, in that it initially spreads locally within the peritoneal cavity. This is in contrast to most other cancer types, which metastasize early on via the bloodstream to distant sites. This unique behavior opens up an opportunity for local application of both therapeutic and imaging agents. Upon initial diagnosis, 75% of patients already present with diffuse peritoneal spread involving abdominal organs. Complete resection of all tumor implants has been shown to be a major factor for improved survival. Unfortunately, it is currently not possible for surgeons to visualize microscopic implants, impeding their removal and leading to tumor recurrences and poor outcomes in most patients. Thus, there is a great need for new intraoperative imaging techniques that can overcome this hurdle. We devised a method that employs folate receptor (FR)-targeted surface-enhanced resonance Raman scattering (SERRS) nanoparticles (NPs), as folate receptors are typically overexpressed in ovarian cancer. We report a robust ratiometric imaging approach using anti-FR-SERRS-NPs (alphaFR-NPs) and nontargeted SERRS-NPs (nt-NPs) multiplexing. We term this method "topically applied surface-enhanced resonance Raman ratiometric spectroscopy" (TAS3RS ("tasers") for short). TAS3RS successfully enabled the detection of tumor lesions in a murine model of human ovarian adenocarcinoma regardless of their size or localization. Tumors as small as 370 MUm were detected, as confirmed by bioluminescence imaging and histological staining. TAS3RS holds promise for intraoperative detection of microscopic residual tumors and could reduce recurrence rates in ovarian cancer and other diseases with peritoneal spread. PMID- 27992726 TI - Public Health Surveillance Systems: Recent Advances in Their Use and Evaluation. AB - Surveillance is critical for improving population health. Public health surveillance systems generate information that drives action, and the data must be of sufficient quality and with a resolution and timeliness that matches objectives. In the context of scientific advances in public health surveillance, changing health care and public health environments, and rapidly evolving technologies, the aim of this article is to review public health surveillance systems. We consider their current use to increase the efficiency and effectiveness of the public health system, the role of system stakeholders, the analysis and interpretation of surveillance data, approaches to system monitoring and evaluation, and opportunities for future advances in terms of increased scientific rigor, outcomes-focused research, and health informatics. PMID- 27992725 TI - Smoking, Mental Illness, and Public Health. AB - Tobacco use remains the leading preventable cause of death worldwide. In particular, people with mental illness are disproportionately affected with high smoking prevalence; they account for more than 200,000 of the 520,000 tobacco attributable deaths in the United States annually and die on average 25 years prematurely. Our review aims to provide an update on smoking in the mentally ill. We review the determinants of tobacco use among smokers with mental illness, presented with regard to the public health HAVE framework of "the host" (e.g., tobacco user characteristics), the "agent" (e.g., nicotine product characteristics), the "vector" (e.g., tobacco industry), and the "environment" (e.g., smoking policies). Furthermore, we identify the significant health harms incurred and opportunities for prevention and intervention within a health care systems and larger health policy perspective. A comprehensive effort is warranted to achieve equity toward the 2025 Healthy People goal of reducing US adult tobacco use to 12%, with attention to all subgroups, including smokers with mental illness. PMID- 27992727 TI - Organic Food in the Diet: Exposure and Health Implications. AB - The market for organic food products is growing rapidly worldwide. Such foods meet certified organic standards for production, handling, processing, and marketing. Most notably, the use of synthetic fertilizers, pesticides, and genetic modification is not allowed. One major reason for the increased demand is the perception that organic food is more environmentally friendly and healthier than conventionally produced food. This review provides an update on market data and consumer preferences for organic food and summarizes the scientific evidence for compositional differences and health benefits of organic compared with conventionally produced food. Studies indicate some differences in favor of organic food, including indications of beneficial health effects. Organic foods convey lower pesticide residue exposure than do conventionally produced foods, but the impact of this on human health is not clear. Comparisons are complicated by organic food consumption being strongly correlated with several indicators of a healthy lifestyle and by conventional agriculture "best practices" often being quite close to those of organic. PMID- 27992729 TI - An Appraisal of Social Network Theory and Analysis as Applied to Public Health: Challenges and Opportunities. AB - The use of social network theory and analysis methods as applied to public health has expanded greatly in the past decade, yielding a significant academic literature that spans almost every conceivable health issue. This review identifies several important theoretical challenges that confront the field but also provides opportunities for new research. These challenges include (a) measuring network influences, (b) identifying appropriate influence mechanisms, (c) the impact of social media and computerized communications, (d) the role of networks in evaluating public health interventions, and (e) ethics. Next steps for the field are outlined and the need for funding is emphasized. Recently developed network analysis techniques, technological innovations in communication, and changes in theoretical perspectives to include a focus on social and environmental behavioral influences have created opportunities for new theory and ever broader application of social networks to public health topics. PMID- 27992728 TI - Macro Trends and the Future of Public Health Practice. AB - Public health practice in the twenty-first century is in a state of significant flux. Several macro trends are impacting the current practice of governmental public health and will likely have effects for many years to come. These macro trends are described as forces of change, which are changes that affect the context in which the community and its public health system operate. This article focuses on seven such forces of change: the Patient Protection and Affordable Care Act, public health agency accreditation, climate change, health in all policies, social media and informatics, demographic transitions, and globalized travel. Following the description of each of these, this article then turns to possible approaches to measuring, tracking, and understanding the impact of these forces of change on public health practice, including the use of evidence-based public health, practice-based research, and policy surveillance. PMID- 27992731 TI - Impact of Provider Incentives on Quality and Value of Health Care. AB - The use of financial incentives to improve quality in health care has become widespread. Yet evidence on the effectiveness of incentives suggests that they have generally had limited impact on the value of care and have not led to better patient outcomes. Lessons from social psychology and behavioral economics indicate that incentive programs in health care have not been effectively designed to achieve their intended impact. In the United States, Medicare's Hospital Readmission Reduction Program and Hospital Value-Based Purchasing Program, created under the Affordable Care Act (ACA), provide evidence on how variations in the design of incentive programs correspond with differences in effect. As financial incentives continue to be used as a tool to increase the value and quality of health care, improving the design of programs will be crucial to ensure their success. PMID- 27992730 TI - The Affordable Care Act's Impacts on Access to Insurance and Health Care for Low Income Populations. AB - The Patient Protection and Affordable Care Act (ACA) expands access to health insurance in the United States, and, to date, an estimated 20 million previously uninsured individuals have gained coverage. Understanding the law's impact on coverage, access, utilization, and health outcomes, especially among low-income populations, is critical to informing ongoing debates about its effectiveness and implementation. Early findings indicate that there have been significant reductions in the rate of uninsurance among the poor and among those who live in Medicaid expansion states. In addition, the law has been associated with increased health care access, affordability, and use of preventive and outpatient services among low-income populations, though impacts on inpatient utilization and health outcomes have been less conclusive. Although these early findings are generally consistent with past coverage expansions, continued monitoring of these domains is essential to understand the long-term impact of the law for underserved populations. PMID- 27992732 TI - The Link Between Angiogenesis and Endothelial Metabolism. AB - Angiogenesis has traditionally been viewed from the perspective of how endothelial cells (ECs) coordinate migration and proliferation in response to growth factor activation to form new vessel branches. However, ECs must also coordinate their metabolism and adapt metabolic fluxes to the rising energy and biomass demands of branching vessels. Recent studies have highlighted the importance of such metabolic regulation in the endothelium and uncovered core metabolic pathways and mechanisms of regulation that drive the angiogenic process. In this review, we discuss our current understanding of EC metabolism, how it intersects with angiogenic signal transduction, and how alterations in metabolic pathways affect vessel morphogenesis. Understanding EC metabolism promises to reveal new perspectives on disease mechanisms in the vascular system with therapeutic implications for disorders with aberrant vessel growth and function. PMID- 27992734 TI - Correction. PMID- 27992735 TI - Morphological classification of odontogenic keratocysts using Bouligand-Minkowski fractal descriptors. AB - The Odontogenic keratocyst (OKC) is a cystic lesion of the jaws, which has high growth and recurrence rates compared to other cysts of the jaws (for instance, radicular cyst, which is the most common jaw cyst type). For this reason OKCs are considered by some to be benign neoplasms. There exist two sub-types of OKCs (sporadic and syndromic) and the ability to discriminate between these sub-types, as well as other jaw cysts, is an important task in terms of disease diagnosis and prognosis. With the development of digital pathology, computational algorithms have become central to addressing this type of problem. Considering that only basic feature-based methods have been investigated in this problem before, we propose to use a different approach (the Bouligand-Minkowski descriptors) to assess the success rates achieved on the classification of a database of histological images of the epithelial lining of these cysts. This does not require the level of abstraction necessary to extract histologically relevant features and therefore has the potential of being more robust than previous approaches. The descriptors were obtained by mapping pixel intensities into a three dimensional cloud of points in discrete space and applying morphological dilations with spheres of increasing radii. The descriptors were computed from the volume of the dilated set and submitted to a machine learning algorithm to classify the samples into diagnostic groups. This approach was capable of discriminating between OKCs and radicular cysts in 98% of images (100% of cases) and between the two sub-types of OKCs in 68% of images (71% of cases). These results improve over previously reported classification rates reported elsewhere and suggest that Bouligand-Minkowski descriptors are useful features to be used in histopathological images of these cysts. PMID- 27992736 TI - Factors associated with re-arrest following initial resuscitation from cardiac arrest. AB - BACKGROUND: To examine patient- and arrest-level factors associated with the incidence of re-arrest in the hospital setting, and to measure the association between re-arrest and survival to discharge. METHODS: This work represents a retrospective cohort study of adult patients who were successfully resuscitated from an initial out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (ICHA) of non-traumatic origin at two urban academic medical centers. In this study, re-arrest was defined as loss of a pulse following 20min of sustained return of spontaneous circulation (ROSC). RESULTS: Between 01/2005 and 04/2016, 1961 patients achieved ROSC following non-traumatic cardiac arrest. Of those, 471 (24%) experienced at least one re-arrest. In re-arrest patients, the median time from initial ROSC to first re-arrest was 5.4h (IQR: 1.1, 61.8). The distribution of initial rhythms between single- and re-arrest patients did not vary, nor did the median duration of initial arrest. Among 108 re-arrest patients with an initial shockable rhythm, 60 (56%) experienced a shockable re-arrest rhythm. Among 273 with an initial nonshockable rhythm, 31 (11%) experienced a shockable re-arrest rhythm. After adjusting for significant covariates, the incidence of re arrest was associated with a lower likelihood of survival to discharge (OR: 0.32; 95% CI: 0.24-0.43; p<0.001). CONCLUSIONS: Re-arrest is a common complication experienced by cardiac arrest patients that achieve ROSC, and occurs early in the course of their post-arrest care. Moreover, re-arrest is associated with a decreased likelihood of survival to discharge, even after adjustments for relevant covariates. PMID- 27992733 TI - Trefoil Factor Peptides and Gastrointestinal Function. AB - Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract. PMID- 27992737 TI - Characterization and risk of exposure to elements from artisanal gold mining operations in the Bolivian Andes. AB - Artisanal and small-scale gold mining (ASGM) offers low-skilled workers an opportunity to elevate themselves out of poverty. However, this industry operates with little to no pollution controls and the cost to the environment and human health can be large. The objectives of this study were to measure levels of arsenic (As), manganese (Mn), cobalt (Co), lead (Pb), and mercury (Hg) in the environment and characterize health risks to miners and residents in an area with active ASGM operations. An exposure assessment was conducted at two different mining sites and a nearby village in the Bolivian Anders. The resulting measurements were then used to quantify cancerous and noncancerous health risks to children and adults working at and living near ASGM areas. Soil concentrations of As were well above background levels and showed great variations between the village and mining area. Mercury vapor levels at the two mining sites were approximately 30 times larger than the EPA reference concentration. The risk of developing non-cancerous health effects were primarily due to exposure to As and Hg. The probability of individuals developing cancer was considerably increased with adult miners having a probability of 1.3 out of 100. Cancer potential was driven by exposure to As, with de minimus cancer risk from all other elements. Based on the environmental characterization of elements in soils and Hg vapors, the risk of developing cancerous and non-cancerous health outcomes were above a level of concern based on EPA risk assessment guidance. Personal protective equipment was not worn by workers and Hg amalgam is commonly heated in workers' homes. Better education of the risks of ASGM is needed as well as simple controls to reduce exposure. PMID- 27992738 TI - Concentrations of organochlorine pesticides in pooled human serum by age and gender. AB - Organochlorine pesticides (OCPs) have been used for many decades in Australia with cessation of selected persistent and bioaccumulative OCPs ranging from the 1970s to as recently as 2007. The specific aims of this study were to use samples representative of an Australian population to assess age and gender differences in the concentration of OCPs in human blood sera and to investigate temporal trends in these chemicals. Serum was collected from de-identified, surplus pathology samples over five time periods (2002/03, 2006/07, 2008/09, 2010/11 and 2012/13), with 183 serum pools made from 12,175 individual samples; 26 pools in 2002/03, 85 pools in 2006/07 and 24 pools each in 2008/09, 2010/11 and 2012/13. Samples were analyzed for hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), gamma -hexachlorocyclohexane (lindane) (gamma-HCH), oxy-chlordane, trans-nonachlor, p,p'-DDE, o,p'-DDT, p,p'-DDT and Mirex. Stratification criteria included gender and age (0-4; 5-15; 16-30; 31-45; 46-60; and >60 years) with age additionally stratified by adults >16 years and children 0-4 and 5-15 years. All pools from all collection periods had detectable concentrations of OCPs with a detection frequency of >60% for HCB, beta-HCH, trans-nonachlor, p,p'-DDT and p,p' DDE. The overall OCP concentrations increased with age with the highest concentrations in the >60 years groups. Females did not have higher mean OCP concentrations than males except for HCB concentrations (p=0.0006). Temporal trends showed overall decreasing serum concentrations by collection period with the exception of an increase in OCP concentrations between 2006/07 and 2008/09. Excluding this data point, HCB decreased from year to year by 7-76%; beta-HCH concentrations decreased by 14 - 38%; trans-nonachlor concentrations decreased by 10 - 65%; p,p'-DDE concentrations decreased by 6 - 52%; and p,p'-DDT concentrations decreased by 7 - 30%. The results indicate that OCP concentrations have decreased over time as is to be expected following the phase out of these chemicals in Australia. PMID- 27992739 TI - Reply by Authors. PMID- 27992740 TI - Editorial Comment. PMID- 27992741 TI - Reply by Authors. PMID- 27992742 TI - Editorial Comment. PMID- 27992743 TI - Re: Serum Vitamin D is Not Helpful for Predicting Prostate Cancer Aggressiveness Compared with the Prostate Health Index: C. Stephan, M. Lein, J. Matalon, E. Kilic, Z. Zhao, J. Busch and K. Jung J Urol 2016;196:709-714. PMID- 27992744 TI - Editorial Comment. PMID- 27992745 TI - Ultrasonographic Assessment of Testicular Viability Using Heterogeneity Levels in Torsed Testicles. AB - PURPOSE: Gross testicular heterogeneity on ultrasound has been associated with testis loss following testicular torsion in children. We aimed to quantify the extent of temporal heterogeneity associated with testis loss in testicular torsion cases using a noninvasive technique to determine a HI (heterogeneity index) on ultrasound images. MATERIALS AND METHODS: We retrospectively studied the records of patients who presented with acute scrotal pain to the Pediatric Emergency Department over a 6-year period. Ultrasound images of the affected testis and the unaffected contralateral testis were examined using a proprietary program to determine the extent of heterogeneity of each image. The difference between the HI of the torsed testis and that of the contralateral normal testis was termed DeltaHI. Receiver operating characteristics curve analysis was performed to determine the DeltaHI threshold for nonviability. RESULTS: Among 529 patients who presented with acute scrotal pain 147 had testicular torsion based on surgical findings. Of these 147 patients 110 (74.8%) were found to have a viable testis while 37 (25.2%) had a nonviable testis. Using the DeltaHI cutoff of 0.394 or greater for nonviability, sensitivity and specificity were 100% and 94.5%, respectively. Positive and negative predictive values were 86% and 100%, respectively. CONCLUSIONS: Our results demonstrate that a quantifiable temporal gradation of heterogeneity exists and the heterogeneity index can be used as an objective parameter to determine the viability of a torsed testicle. By developing the technology to measure the heterogeneity index in real time, we could potentially identify which patients with testicular torsion have a nonviable testicle and, thus, would not require immediate surgical exploration. PMID- 27992746 TI - Editorial Comment. PMID- 27992747 TI - Editorial Comment. PMID- 27992748 TI - Re: Robotic versus Open Prostatectomy: End of the Controversy: M. O. Koch J Urol 2016;196:9-10. PMID- 27992750 TI - Bacillus Calmette-Guerin Manufacturing and SWOG S1602 Intergroup Clinical Trial. PMID- 27992751 TI - Blunt Abdominal Trauma from Motor Vehicle Collisions from 2007 to 2011: Renal Injury Probability and Severity in Children versus Adults. AB - PURPOSE: There are sparse data directly comparing the probability of renal injury in children and adults. The kidney of the child is believed to be more susceptible to blunt injury for a variety of anatomical reasons. In a large cohort we tested the hypothesis that the pediatric kidney is more susceptible to any renal injury and to higher grade injury. MATERIALS AND METHODS: We queried the NTDB(r) (National Trauma Data Bank(r)) on all hospital admissions following motor vehicle collisions in a pediatric population (age less than 21 years) and a referent adult population (age 30 to 50 years). Of 111,172 children who were admitted after motor vehicle collisions 1,093 had renal injury. RESULTS: Of the 111,172 children admitted to the hospital following motor vehicle collisions 59,385 had abdominal trauma and 1,093 had renal injury. In a multivariate logistic model adjusting for overall ISS (Injury Severity Score), region, year, driver/passenger status, presence of restraint or an airbag, we found that children had 48% higher odds of renal injury compared to adults ages 30 to 50 years (OR 1.48, 95% CI 1.32-1.66, p <0.001). Furthermore, children were at 33% higher risk for high grade renal injury (OR 1.33, 95% CI 1.05-1.69, p = 0.919). The effect remained when restricting analysis to patients with concomitant liver and spleen injuries (p <0.001). CONCLUSIONS: In a large national cohort of children, blunt renal injury following motor vehicle collisions is rare but substantially more common than in adults. The odds of high grade renal injury are approximately 50% higher in children. A greater index of suspicion and a lower threshold for renal imaging is prudent for children with blunt abdominal trauma from motor vehicle collisions. PMID- 27992752 TI - Editorial Comment. PMID- 27992753 TI - Complete Metabolic Evaluation is Indicated after a First Stone Event: Con. PMID- 27992754 TI - Editorial Comment. PMID- 27992755 TI - Editorial Comment. PMID- 27992756 TI - Editorial Comment. PMID- 27992757 TI - Update on Continent Catheterizable Channels and the Timing of their Complications. AB - PURPOSE: We previously reported catheterizable channel associated outcomes and concluded that the incidence of postoperative complications was greatest in the first 2 years after surgery. At that time our followup was short. In this series we sought to determine whether complications continued to accumulate with longer followup in an updated cohort of patients. MATERIALS AND METHODS: We comprehensively reviewed the outcomes in 81 consecutive patients who underwent construction of a MACE (Malone antegrade continence enema) and/or a Mitrofanoff channel in association with complex genitourinary reconstruction. Mean followup was 80.1 months. Outcomes of these 119 stomas were classified by Clavien-Dindo grade and time to complication. RESULTS: The 48 unique, channel related events (40.3%) necessitated a total of 70 interventions with a mean 24.2 months to the first event. Difficult catheterization was the most common event, occurring in 20.1% of channels an average of 29.9 months after surgery. Stomal stenosis was also common, developing in 12.6% of channels at an average of 19.9 months after surgery. Unique complications clustered in the first 2 years, after which there was a statistically significant decline (p = 0.0013). High grade complications similarly clustered (p <0.0001). Channel composition was significantly associated with rates of difficult catheterization events. CONCLUSIONS: Compared to our previous cohort of patients with similar volume but shorter followup, our assumption that channel associated complications cluster postoperatively and then decrease significantly was correct. Our current and more detailed series demonstrates that the rate of postoperative complications decreases with time. However, with longer followup patients continue to experience lower grade events requiring fewer interventions. PMID- 27992759 TI - Enhancing creativity: Proper body posture meets proper emotion. AB - This study tested whether compatibility or incompatibility between body posture and emotion was beneficial for creativity. In Study 1, participants were asked to solve the Alternative Uses Task (AUT) problems when performing open or closed body posture in positive or negative emotional state respectively. The results showed that originality of AUT performance was higher in the compatible conditions (i.e., open-positive and closed-negative) than in the incompatible conditions (i.e., closed-positive and open-negative). In Study 2, the compatibility effect was replicated in both the AUT and the Realistic Presented Problem test (i.e., RPP). Moreover, it was revealed that participants exhibited the highest associative flexibility in the open-positive condition, and the highest persistence in the closed-negative condition. These findings indicate that compatibility between body posture and emotion is beneficial for creativity. This may be because when the implicit emotions elicited by body posture match explicit emotions, the effects of emotions on creativity are enhanced, therefore promoting creativity through the flexibility or the persistence pathway respectively. PMID- 27992760 TI - The antecedents and consequences of a beyond-choice view of decision situations: A construal level theory perspective. AB - Evaluating alternatives and comparing them to each other are integral to decision making. In addition, however, decision makers may adopt a view that goes beyond choice and make inferences about the entire set of alternatives, about the dimensions that are relevant in similar decisions, and about the range of values on a specific dimension. We examined some antecedents and consequences of adopting a beyond-choice view of decision situations. Based on Construal Level Theory we suggest that a beyond-choice view entails high (vs. low) level of construal of the decision situation and hence is more likely to occur for decisions that are more psychologically distant. We further suggest that a consequence of a beyond-choice view might be a later difficulty to remember which attribute belongs to which alternative. To examine these predictions we conducted an experiment in which participants evaluated decision scenarios that were described as being relevant for the distant (vs. the near) future. One day later they answered a decision-related source recognition test in which they were asked to remember which attribute belongs to which alternative. As predicted, people had more source-memory errors in the distant than in the near future condition. These results suggest that a beyond-choice view of decision situations is an important consequence of psychological distance (vs. proximity). PMID- 27992761 TI - Sleep-related vehicle crashes on low speed roads. AB - BACKGROUND: Very little is known about the characteristics of sleep related (SR) crashes occurring on low speed roads compared with current understanding of the role of sleep in crashes occurring on high speed roads e.g. motorways. To address this gap, analyses were undertaken to identify the differences and similarities between (1) SR crashes occurring on roads with low (<=60km/h) and high (>=100km/h) speed limits, and (2) SR crashes and not-SR crashes occurring on roads with low speed limits. METHOD: Police reports of all crashes occurring on low and high speed roads over a ten year period between 2000 and 2009 were examined for Queensland, Australia. Attending police officers identified all crash attributes, including 'fatigue/fell asleep', which indicates that the police believe the crash to have a causal factor relating to falling asleep, sleepiness due to sleep loss, time of day, or fatigue. Driver or rider involvement in crashes was classified as SR or not-SR. All crash-associated variables were compared using Chi-square tests (Cramer's V=effect size). A series of logistic regression was performed, with driver and crash characteristics as predictors of crash category. A conservative alpha level of 0.001 determined statistical significance. RESULTS: There were 440,855 drivers or riders involved in a crash during this time; 6923 (1.6%) were attributed as SR. SR crashes on low speed roads have similar characteristics to those on high speed roads with young (16-24y) males consistently over represented. SR crashes on low speed roads are noticeably different to not-SR crashes in the same speed zone in that male and young novice drivers are over represented and outcomes are more severe. Of all the SR crashes identified, 41% occurred on low speed roads. CONCLUSION: SR crashes are not confined to high speed roads. Low speed SR crashes warrant specific investigation because they occur in densely populated areas, exposing a greater number of people to risk and have more severe outcomes than not-SR crashes on the same low speed roads. PMID- 27992762 TI - Cyclist deceleration rate as surrogate safety measure in Montreal using smartphone GPS data. AB - Urban areas in North American cities with positive trends in bicycle usage also witness a high number of cyclist injuries every year. Previous cyclist safety studies based on the traditional approach, which relies on historical crash data, are known to have some limitations such as the fact that crashes need to happen (a reactive approach). This paper explores the use of GPS deceleration events as a surrogate-proactive measure and investigates the relationship between reported cyclist road injuries and deceleration events. The surrogate safety measure is defined based on deceleration values representing hard breaking situations. This work uses a large sample of GPS cyclist trip data from a smartphone application to extract deceleration rates at intersections and along segments and to explore its relationship with the number of observed injuries and validate deceleration rate (DR) as a surrogate safety measure. Using Spearman's rank correlation coefficient, we compared the ranking of sites based on the expected number of injuries and based on DR. The ranks of expected injuries and dangerous decelerations were found to have a correlation of 0.60 at signalized intersections, 0.53 at non-signalized intersections and 0.57 at segments. Despite the promising results of this study, more granular data and validation work needs to be done to improve the reliability of the measures. The technological limitations and future work are discussed at the end of the paper. PMID- 27992763 TI - Investigating the influence of shame, depression, and distress tolerance on the relationship between internalized homophobia and binge eating in lesbian and bisexual women. AB - There is limited research evidence about the specific factors influencing disordered eating for lesbian and bisexual women. Therefore, this study investigated relationships among binge eating, internalized homophobia, shame, depression, and distress tolerance in a sample of lesbian (n=72) and bisexual women (n=66). Two hypotheses were tested. First, it was hypothesized that shame and depression would mediate the relationship between internalized homophobia and binge eating. Second, it was hypothesized that distress tolerance would moderate the relationship between shame and binge eating and the relationship between depression and binge eating in the mediation relationships proposed in the first hypothesis. Results indicated that shame was a significant mediator for the relationship between internalized homophobia and binge eating, that depression was not a significant mediator, and that distress tolerance did not moderate the significant mediation relationship between shame and binge eating. The data in this study also indicated that the proportions of lesbian and bisexual participants who reported binge eating and compensatory behavior did not differ significantly, but that bisexual participants reported significantly more depression and shame than lesbian participants. PMID- 27992764 TI - MicroRNA-712 restrains macrophage pro-inflammatory responses by targeting LRRK2 leading to restoration of insulin stimulated glucose uptake by myoblasts. AB - Chronic inflammatory diseases such as insulin resistance, Type 2 diabetes, neurodegenerative diseases etc., are shown to be caused due to imbalanced activation states of macrophages. MicroRNAs which are transcriptional/post transcriptional regulators of gene expression drive several pathophysiological processes including macrophage polarization. However the functional role of microRNAs in regulating inflammation induced insulin resistance is ill defined. In our current study we observed that the expression of miR-712 was reduced in macrophages exposed to LPS and IFN-gamma. Ectopic expression of miR-712 in RAW 264.7 mouse macrophages impaired the expression of iNOS protein and secretion of pro-inflammatory cytokines such as TNF-alpha, IL-6 and IFN-beta which in turn led to improved insulin stimulated glucose uptake in co-cultured L6 myoblasts. Mechanistically, we identified that miR-712 targets the 3'UTR of a potent inflammatory gene LRRK2 and dampens the phosphorylation of p38 and ERK1/2 kinases. Taken together, our data underscore the regulatory role of miR-712 in restoring insulin stimulated glucose uptake by myoblasts through down-regulating macrophage mediated inflammatory responses. PMID- 27992765 TI - Kinetics of the association of dengue virus capsid protein with the granular component of nucleolus. AB - Dengue virus (DENV) replicates in the cytoplasm but translocation of the capsid protein (C) to the nucleoli of infected cells has been shown to facilitate virus multiplication for DENV-2. This study demonstrates that the nucleolar localization of C occurs with all four serotypes of DENV. The interaction of C with the nucleolus was found to be dynamic with a mobile fraction of 66% by FRAP. That the C shuttled between the nucleus and cytoplasm was suggested by FLIP and translation inhibition experiments. Colocalization with B23 indicated that DENV C targeted the granular component (GC) of the nucleolus. Presence of DENV C in the nucleolus affected the recovery kinetics of B23 in infected and transfected cells. Sub-nucleolar localization of DENV C of all serotypes to the GC, its mobility in and out of the nucleolus and its affect on the dynamics of B23 is being shown for the first time. PMID- 27992766 TI - A quick behavioral dichotic word test is prognostic for clinical response to cognitive therapy for depression: A replication study. AB - There are no commonly used clinical indicators of whether an individual will benefit from cognitive therapy (CT) for depression. A prior study found right ear (left hemisphere) advantage for perceiving dichotic words predicted CT response. This study replicates this finding at a different research center in clinical trials that included clinically representative samples and community therapists. Right-handed individuals with unipolar major depressive disorder who subsequently received 12-14 weeks of CT at the University of Pittsburgh were tested on dichotic fused words and complex tones tests. Responders to CT showed twice the mean right ear advantage in dichotic fused words performance than non-responders. Patients with a right ear advantage greater than the mean for healthy controls had an 81% response rate to CT, whereas those with performance lower than the mean for controls had a 46% response rate. Individuals with a right ear advantage, indicative of strong left hemisphere language dominance, may be better at utilizing cognitive processes and left frontotemporal cortical regions critical for success of CT for depression. Findings at two clinical research centers suggest that verbal dichotic listening may be a clinically disseminative brief, inexpensive and easily automated test prognostic for response to CT across diverse clinical settings. PMID- 27992767 TI - Changes in cytokine and chemokine expression distinguish dysthymic disorder from major depression and healthy controls. AB - An important area of uncertainty is the inflammatory degree to which depression occurring as part of dysthymic disorder may differ from major depression. Using a 27-plex cytokine assay, we analyzed the serum of 12 patients with dysthymic disorder, 12 with major depression, and an age-, sex-, and body mass index matched control group of 20 healthy volunteers. We observed that patients with dysthymic disorder exhibited aberrant cytokine and chemokine expression compared with healthy controls and patients with major depression. The levels of interferon-gamma-induced protein 10 highly predicted dysthymic disorder. Network analyses revealed that in patients with dysthymic disorder, the vertices were more sparsely connected and adopted a more hub-like architecture, and the connections from neighboring vertices of interleukin 2 and eotaxin-1 increased. After treatment with the same antidepressant, there was no difference between dysthymic disorder and major depression regarding any of the cytokines or chemokines analyzed. For dysthymic disorder, changes in the levels of interferon gamma-induced protein 10 and macrophage inflammatory protein-1alpha correlated with depression improvement. The findings suggest that the cytokine milieu in dysthymic disorder differs either at the level of individual expression or in network patterns. Moreover, chemokines play an important role in driving the pathophysiology of dysthymic disorder. PMID- 27992768 TI - Memory performance of patients with major depression in an everyday life situation. AB - Although patients with major depressive disorder (MDD) report severe memory impairment in their everyday life, memory tests indicate only moderate deficits. In order to clarify these conflicting observations, the present study aimed at the investigation of MDD patients' memory performance in a real everyday life situation. The study included 20 MDD patients and 20 healthy control subjects. Nonverbal memory was assessed by means of the Rey Complex Figure Test whereas verbal memory was assessed by the recall of a 20-item wordlist with supermarket products. For the assessment of everyday life memory, subjects had to purchase as many products as possible of the 20-item wordlist in a real supermarket. Furthermore, subjects were asked for memory complaints. MDD patients' performance in the supermarket resembled memory test results and was not significantly impaired. MDD patients' self-reports, however, indicated severe memory problems that clearly fell below their performance in the supermarket. This study helped to identify everyday life-related factors that do not impair MDD patients' cognitive performance beyond their performance in standard laboratory testing situations. These factors may not be relevant for remediation programs that are specifically developed for depressed patients. PMID- 27992769 TI - Functional food applications of dextran from Weissella cibaria RBA12 from pummelo (Citrus maxima). AB - Weissella cibaria RBA12 isolated from pummelo from Northeast India produces a dextran composed of 97% alpha-(1->6) linkages in the main chain and 3% alpha-(1 >3) branched linkages. The in vitro prebiotic activity of dextran-RBA12 was explored. Dextran-RBA12 displayed enhanced growth of probiotic Bifidobacterium and Lactobacillus spp., and controlled growth of non-probiotic enteric bacteria. Dextran-RBA12 showed superior resistance to physiological barriers with a maximum hydrolysis of 0.51%, 0.31% and 0.24% by artificial gastric juice, alpha-amylase and intestinal fluid, respectively, whereas compared to maximum hydrolysis of 25.23%, 19.13% and 6%, respectively after 5h of incubation shown by commercial prebiotic inulin. The production of dextran from Weissella cibaria RBA12 in sourdough prepared from whole wheat flour, wheat bran and rye bran showed the highest dextran of 3.26+/-0.12% d.w. in rye bran. The overall study summarized that dextran-RBA12 can be used as a prebiotic and also can be easily produced in sourdough. PMID- 27992770 TI - Zinc stress affects ionome and metabolome in tea plants. AB - The research of physiological responses to Zn stress in plants has been extensively studied. However, the ionomics and metabolomics responses of plants to Zn stress remain largely unknown. In present study, the nutrient elements were identified involved in ion homeostasis and metabolomics changes related to Zn deficiency or excess in tea plants. Nutrient element analysis demonstrated that the concentrations of Zn affected the ion-uptake in roots and the nutrient element transportation to leaves, leading to the different distribution of P, S, Al, Ca, Fe and Cu in the tea leaves or roots. Metabolomics analysis revealed that Zn deficiency or excess differentially influenced the metabolic pathways in the tea leaves. More specifically, Zn deficiency affected the metabolism of carbohydrates, and Zn excess affected flavonoids metabolism. Additionally, the results showed that both Zn deficiency and Zn excess led to reduced nicotinamide levels, which speeded up NAD+ degradation and thus reduced energy metabolism. Furthermore, element-metabolite correlation analysis illustrated that Zn contents in the tea leaves were positively correlated with organic acids, nitrogenous metabolites and some carbohydrate metabolites, and negatively correlated with the metabolites involved in secondary metabolism and some other carbohydrate metabolites. Meanwhile, metabolite-metabolite correlation analysis demonstrated that organic acids, sugars, amino acids and flavonoids played dominant roles in the regulation of the tea leaf metabolism under Zn stress. Therefore, the conclusion should be drawn that the tea plants responded to Zn stress by coordinating ion-uptake and regulation of metabolism of carbohydrates, nitrogenous metabolites, and flavonoids. PMID- 27992771 TI - Comparative analysis of cadmium responsive microRNAs in roots of two Ipomoea aquatica Forsk. cultivars with different cadmium accumulation capacities. AB - In plants, microRNAs (miRNAs) play regulatory roles in response to various environmental stresses. In order to illustrate the regulation mechanisms of miRNAs involving the different Cd accumulation abilities between a low-shoot-Cd cultivar (QLQ) and a high-shoot-Cd cultivar (T308) of water spinach (Ipomoea aquatic Forsk.), six sRNA libraries at 3 different time points were constructed. Only 5 miRNAs were exclusively regulated in QLQ, among them, miRNA395 was up regulated, which was supposed to enhance the Cd retention and detoxification in root. Also, the alterations of miRNA5139, miRNA1511 and miRNA8155 contributed to the attenuation of Cd translocation into the shoot of QLQ. More differentially expressed miRNAs were observed in T308, indicating more complex response was adopted by T308 under Cd stress. miRNA397 exclusively regulated in T308 has enhanced the Cd influx of T308 under Cd treatments. Besides, the Cd translocation of T308 was strengthened due to the up-regulation of MATE efflux family, which was targeted by miRNA3627. Our results unraveled the effects of the cultivar dependent expression of these specific miRNAs on the different Cd accumulation and translocation abilities of QLQ and T308. These findings provide a new perspective for the molecular assisted breeding of low-Cd cultivars for leaf vegetables. PMID- 27992772 TI - The role of imperfect surrogate endpoint information in drug approval and reimbursement decisions. AB - Approval of new drugs is increasingly reliant on "surrogate endpoints," which correlate with but imperfectly predict clinical benefits. Proponents argue surrogate endpoints allow for faster approval, but critics charge they provide inadequate evidence. We develop an economic framework that addresses the value of improvement in the predictive power, or "quality," of surrogate endpoints, and clarifies how quality can influence decisions by regulators, payers, and manufacturers. For example, the framework shows how lower-quality surrogates lead to greater misalignment of incentives between payers and regulators, resulting in more drugs that are approved for use but not covered by payers. Efficient price negotiation in the marketplace can help align payer incentives for granting access based on surrogates. Higher-quality surrogates increase manufacturer profits and social surplus from early access to new drugs. Since the return on better quality is shared between manufacturers and payers, private incentives to invest in higher-quality surrogates are inefficiently low. PMID- 27992773 TI - Larger between-task crosstalk in children than in adults: Behavioral results from the backward crosstalk paradigm and a diffusion model analysis. AB - In dual-task settings, one can find influences from Task 2 processing even on Task 1 performance, an effect referred to as the backward crosstalk effect (BCE). The size of the BCE has been taken as an index of how well Task 1 processing can be shielded against concurrently ongoing Task 2 processes. In the current study, we compared the size of the BCE between adults and a group of 5- and 6-year-old children. First, the BCE turned out to be larger in children than in adults. Second, both groups exhibited a comparable adjustment of behavior in response to just experienced conflict; in both groups, the BCE was smaller following conflict trials than following no-conflict trials. Third, a diffusion model analysis suggests that the source for the BCE is different in adults than in children. In particular, not parallel Task 2 response activation appears to be the source of the BCE in children. Rather, non-decisional processes appear to be responsible for the BCE in this age group. Thus, this study shows that (a) 5- and 6-year-old children can perform dual-tasks, but (b) they show slightly larger signs of between-task crosstalk, and (c) the exact reasons for this appear to be different from those responsible in adults. PMID- 27992774 TI - Transcriptome analysis of methicillin-resistant Staphylococcus aureus in response to stigmasterol and lupeol. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen with multiple antibiotic resistance that causes morbidity and mortality worldwide. Multidrug-resistant (MDR) MRSA with increased resistance to currently available antibiotics has challenged the world to develop new therapeutic agents. Stigmasterol and lupeol, from the plant Phyllanthus columnaris, exhibit antibacterial activities against MRSA. The aim of this study was to utilise next generation sequencing (NGS) to provide further insight into the novel transcriptional response of MRSA exposed to stigmasterol and lupeol. METHODS: Time-kill analysis of one MRSA reference strain (ATCC 43300) and three clinical isolates (WM3, BM1 and KJ7) for both compounds was first performed to provide the bacteriostatic/bactericidal profile. Then, MRSA ATCC 43300 strain treated with both compounds was interrogated by NGS. RESULTS: Both stigmasterol and lupeol possessed bacteriostatic properties against all MRSA tested; however, lupeol exhibited both bacteriostatic and bactericidal properties within the same minimum inhibitory concentration and minimum bactericidal concentration values against BM1 (12.5mg/mL). Transcriptome profiling of MRSA ATCC 43300 revealed significant modulation of gene expression with multiple desirable targets by both compounds, which caused a reduction in the translation processes leading to inhibition of protein synthesis and prevention of bacterial growth. CONCLUSIONS: This study highlights the potential of both stigmasterol and lupeol as new promising anti MRSA agents. PMID- 27992775 TI - Weatherfish (Misgurnus fossilis) as a new species for toxicity testing? AB - Selection of appropriate test species is a critical issue when assessing effects of environmental contamination on fish because the ecological relevance of commonly used test species might be restricted due to their exotic origin. In the present study, a European freshwater fish with frequent occurrence in agricultural areas is suggested as a potential alternative: the European weatherfish (Misgurnus fossilis). Its suitability for acute embryo toxicity tests (FET) was investigated with regard to practical implementation, sensitivity to contaminants and tolerance against environmental conditions of concern. For this purpose, weatherfish embryos were exposed (72h) to the reference substance 3,4 dichloroaniline (DCA) in three independent tests. Furthermore, the effects of dissolved oxygen (DO) deficiency on weatherfish embryos were studied to evaluate their suitability e.g. for sediment bioassays. Obtained results revealed that the sensitivity of weatherfish embryos towards DCA (72 h-EC50=0.52mg/l; 72 h LC50=0.71mg/l) was highest compared to other species and three times higher than that reported for the commonly used zebrafish (Danio rerio). Even though knowledge of DO requirements during the embryonic period of European fish species is scarce, weatherfish can be stated as one of the most tolerant native species (LC90 for DO=0.53mg/l after 48h exposure plus 72h post-exposure). Its high ecological relevance for Europe, the particular sensitivity towards DCA and high tolerance against DO depletion highlight the potential of weatherfish as additional species for toxicity testing. PMID- 27992776 TI - Differential response of olfactory sensory neuron populations to copper ion exposure in zebrafish. AB - The peripheral olfactory system of fish is in direct contact with the external aqueous environment, so dissolved contaminants can easily impair sensory functions and cause neurobehavioral injuries. The olfactory epithelium of fish is arranged in lamellae forming a rosette in the olfactory cavity and contains three main types of olfactory sensory neurons (OSNs): ciliated (cOSNs) and microvillous olfactory sensory neurons (mOSNs), common to all vertebrates, and a third minor group of olfactory neurons, crypt cells, absent in tetrapods. Since copper is a ubiquitously diffusing olfactory toxicant and a spreading contaminant in urban runoff, we investigated the effect of low copper concentration on the three different OSNs in the olfactory epithelium of zebrafish, a model system widely used in biological research. Image analysis was applied for morphometry and quantification of immunohistochemically detected OSNs. Copper exposure resulted in an evident decrease in olfactory epithelium thickness. Moreover, after exposure, the lamellae of the dorsal and ventral halves of the olfactory rosettes showed a different increase in their sensory areas, suggesting a lateral migration of new cells into non-sensory regions. The results of the present study provide clear evidence of a differential response of the three neural cell populations of zebrafish olfactory mucosa after 96h of exposure to copper ions at the sublethal concentration of 30MUgL-1. Densitometric values of cONS, immunostained with anti-G alphaolf, decreased of about 60% compared to the control. When the fish were transferred to water without copper addition and examined after 3, 10 and 30days, we observed a partial restoration of anti-G alphaolf staining intensity to normal condition. The recovery of cOSNs appeared sustained by neuronal proliferation, quantified with anti-PCNA immunostaining, in particular in the early days after exposure. The densitometric analysis applied to mOSNs, immunostained with anti-TRPC2, revealed a statistically significant decrease of about 30% compared to the control. For cOSNs and mOSNs, the decrement in staining intensity may be indicative of cell death, but reduction in antigen expression may not be excluded. In the post-exposure period of 1 month we did not find recovery of mOSNs. We hypothesize that cOSNs are more sensitive than mOSNs to copper treatment, but also more prompted to tissue repair. Anti-TrkA immunopositive crypt cells appeared not to be affected by copper exposure since statistical analysis excluded any significant difference between the control and treated fish. Comparative studies on OSNs would greatly enhance our understanding of the mechanisms of olfaction. PMID- 27992777 TI - Neuronal chloride and excitability - the big impact of small changes. AB - Synaptic inhibition is a critical regulator of neuronal excitability, and in the mature brain the majority of synaptic inhibition is mediated by Cl--permeable GABAA receptors. Unlike other physiologically relevant ions, Cl- is dynamically regulated, and alterations in the Cl- gradient can have significant impact on neuronal excitability. Due to changes in the neuronal Cl- concentration, GABAergic transmission can bidirectionally regulate the induction of excitatory synaptic plasticity and gate the closing of the critical period for monocular deprivation in visual cortex. GABAergic circuitry can also provide a powerful restraining mechanism for the spread of excitation, however Cl- extrusion mechanisms can become overwhelmed and GABA can paradoxically contribute to pathological excitation such as the propagation of seizure activity. PMID- 27992778 TI - Comparison of lumbo-pelvic kinematics during trunk forward bending and backward return between patients with acute low back pain and asymptomatic controls. AB - BACKGROUND: Prior studies have reported differences in lumbo-pelvic kinematics during a trunk forward bending and backward return task between individuals with and without chronic low back pain; yet, the literature on lumbo-pelvic kinematics of patients with acute low back pain is scant. Therefore, the purpose of this study was set to investigate lumbo-pelvic kinematics in this cohort. METHODS: A case-control study was conducted to investigate the differences in pelvic and thoracic rotation along with lumbar flexion as well as their first and second time derivatives between females with and without acute low back pain. Participants in each group completed one experimental session wherein they performed trunk forward bending and backward return at self-selected and fast paces. FINDINGS: Compared to controls, individuals with acute low back pain had larger pelvic range of rotations and smaller lumbar range of flexions. Patients with acute low back pain also adopted a slower pace compared to asymptomatic controls which was reflected in smaller maximum values for angular velocity, deceleration and acceleration of lumbar flexion. Irrespective of participant group, smaller pelvic range of rotation and larger lumbar range of flexion were observed in younger vs. older participants. INTERPRETATION: Reduced lumbar range of flexion and slower task pace, observed in patients with acute low back pain, may be the result of a neuromuscular adaptation to reduce the forces and deformation in the lower back tissues and avoid pain aggravation. PMID- 27992779 TI - Achilles tendon morphology, plantar flexors torque and passive ankle stiffness in spastic hemiparetic stroke survivors. AB - BACKGROUND: The present study compared the Achilles tendon morphological characteristics, plantar flexor toque and passive ankle stiffness between hemiparetic spastic stroke survivors and healthy subjects. METHODS: The Achilles tendon length was measured at the affected and contralateral limbs of twelve hemiparetic stroke survivors with ankle spasticity and twelve healthy subjects. The ankle was held at three different angles (20 degrees plantar flexion, 0 degrees and maximum dorsiflexion) while an ultrasound system was used to capture images from the Achilles tendon. Active and passive plantar flexor torque production was measured using an isokinetic dynamometer. FINDINGS: There was no significant difference in tendon length and Achilles tendon complacency between stroke survivors [affected limb: 20.8 (1.59) cm at 0 degrees and 0.11 (0.09) cm/N; contralateral limb: 20.8 (1.7) cm at 0 degrees and 0.12 (0.08) cm/N] and healthy subjects [20 (2.78) cm at 0 degrees and 0.15 (0.1) cm/N]. The contralateral limb was stronger than the affected limb, while healthy participants presented larger active torque in relation to stroke survivors. There was no significant difference in passive ankle stiffness between the affected [0.43 (0.08) N/ degrees ] and the contralateral limb [0.40 (0.11) N/ degrees ], but affected limb was significantly stiffer than the healthy subjects [0.32 (0.07) N/ degrees ]. INTERPRETATION: The larger passive torque and ankle joint stiffness from stroke survivors with similar Achilles tendon length compared to healthy subjects seem to be unrelated to tendon extensibility. PMID- 27992780 TI - Using a logic model to evaluate the Kids Together early education inclusion program for children with disabilities and additional needs. AB - : Despite clear evidence that learning and social opportunities for children with disabilities and special needs are more effective in inclusive not segregated settings, there are few known effective inclusion programs available to children with disabilities, their families or teachers in the early years within Australia. The Kids Together program was developed to support children with disabilities/additional needs aged 0-8 years attending mainstream early learning environments. Using a key worker transdisciplinary team model, the program aligns with the individualised package approach of the National Disability Insurance Scheme (NDIS). AIM: This paper reports on the use of a logic model to underpin the process, outcomes and impact evaluation of the Kids Together program. METHODS: The research team worked across 15 Early Childhood Education and Care (ECEC) centres and in home and community settings. A realist evaluation using mixed methods was undertaken to understand what works, for whom and in what contexts. The development of a logic model provided a structured way to explore how the program was implemented and achieved short, medium and long term outcomes within a complex community setting. DISCUSSION AND CONCLUSION: Kids Together was shown to be a highly effective and innovative model for supporting the inclusion of children with disabilities/additional needs in a range of environments central for early childhood learning and development. The use of a logic model provided a visual representation of the Kids Together model and its component parts and enabled a theory of change to be inferred, showing how a coordinated and collaborative approached can work across multiple environments. PMID- 27992781 TI - Transformation dynamics of Ni clusters into NiO rings under electron beam irradiation. AB - We report the transformation of nickel clusters into NiO rings by an electron beam induced nanoscale Kirkendall effect. High-purity nickel clusters consisting of a few thousand atoms have been used as precursors and were synthesized with the superfluid helium droplet technique. Aberration-corrected, analytical scanning transmission electron microscopy was applied to oxidise and simultaneously analyse the nanostructures. The transient dynamics of the oxidation could be documented by time lapse series using high-angle annular dark field imaging and electron energy-loss spectroscopy. A two-step Cabrera-Mott oxidation mechanism was identified. It was found that water adsorbed adjacent to the clusters acts as oxygen source for the electron beam induced oxidation. The size-dependent oxidation rate was estimated by quantitative EELS measurements combined with molecular dynamics simulations. Our findings could serve to better control sample changes during examination in an electron microscope, and might provide a methodology to generate other metal oxide nanostructures. PMID- 27992782 TI - The importance of system band broadening in modern size exclusion chromatography. AB - In the last few years, highly efficient UHP-SEC columns packed with sub-3MUm particles were commercialized by several providers. Besides the particle size reduction, the dimensions of modern SEC stationary phases (150*4.6mm) was also modified compared to regular SEC columns (300*6 or 300*8mm). Because the analytes are excluded from the pores in SEC, the retention factors are very low, ranging from -1 t of genipin-1-o-glucuronic acid and genipin-monosulfate in blood of diabetic group were 17.68 and 7.58 times than those in normal group, respectively, and AUC0->t of genipin-1-o-glucuronic acid was 2.28 times than that of genipin-monosulfate in blood of diabetic group, which revealed the effect of diabetes on the pharmacokinetic properties of the two metabolites. This study not only provides an approach for pharmacokinetic studies for various metabolites from herb medicines, but also can predict druggability of their bioactive metabolites. The insight obtained should facilitate drug development and toxicity research. PMID- 27992787 TI - Method development and validation for the quantitation of the complement inhibitor Cp40 in human and cynomolgus monkey plasma by UPLC-ESI-MS. AB - Cp40 is a 14-amino acid cyclic analog of the peptidic complement inhibitor compstatin that binds with sub-nanomolar affinity to complement component C3 and has already shown promise in various models of complement-related diseases. The preclinical and clinical development of this compound requires a robust, accurate, and sensitive method for quantitatively monitoring Cp40 in biological samples. In this study, we describe the development and validation of an ultra high performance liquid chromatography electrospray mass spectrometry method for the quantitation of Cp40 in human and non-human primate (NHP) plasma. Isotope labeled Cp40 was used as an internal standard, allowing for the accurate and absolute quantitation of Cp40. Labeled and non-labeled Cp40 were extracted from plasma using reversed phase-solid phase extraction, with recovery rates exceeding 80%, indicating minor matrix effects. The triply charged states of Cp40 and isotope-labeled Cp40 were detected at m/z 596.60 and 600.34, respectively, via a Q-TOF mass spectrometer and were used for quantitation. The method was linear in the range of 0.18-3.58MUg/mL (r2>=0.99), with precision values below 0.71% in NHP and 0.77% in human plasma. The accuracy of the method ranged from -2.17% to 17.99% in NHP and from -0.26% to 15.75% in human plasma. The method was successfully applied to the quantitation of Cp40 in cynomolgus monkey plasma after an initial intravenous bolus of 2mg/kg followed by repetitive subcutaneous administration at 1mg/kg. The high reproducibility, accuracy, and robustness of the method developed here render it suitable for drug monitoring of Cp40, and potentially other compstatin analogs, in both human and NHP plasma samples during pharmacokinetic and pharmacodynamic studies. PMID- 27992788 TI - Efficacy, safety and pharmacokinetics of atazanavir (200mg twice daily) plus raltegravir (400mg twice daily) dual regimen in the clinical setting. AB - BACKGROUND: Unboosted atazanavir with raltegravir has been investigated at 300mg twice daily showing frequent hyperbilirubinemia and selection of resistance associated mutations. OBJECTIVES: Atazanavir 200mg twice daily could increase tolerability and plasma exposure. STUDY DESIGN: Patients on atazanavir/raltegravir (200/400 twice daily), with self-reported adherence >95% and no concomitant interacting drugs were retrospectively evaluated. RESULTS: 102 patients [72.5% male, age 46.4 years (42-54), BMI 24kg/m2 (22-26)] were included. CD4+ T lymphocytes were 417 cell/MUL (302-704) and 76 patients (74.5%) had HIV RNA <50 copies/ml. After 123 weeks 18.6% patients showed virological failure and 3.9% discontinued for intolerance. Available genotypes showed selection of major integrase (7/10 patients) and protease resistance-associated mutations (5/13 patients). In patients switching with dyslipidemia (n=67) total, LDL cholesterol and triglycerides significantly decreased. Patients switching with eCRCL<60ml/min (n=27) had no significant changes while patients with eCRCL >60ml/min showed significant decrease (-9.8ml/min, p=0.003) at 96-weeks. Atazanavir and raltegravir trough concentrations were 321ng/mL (147-720) and 412ng/mL (225-695). Self-reported non-adherence (n=4) was significantly associated with virological failure (p=0.02); patients with virological success had borderline longer previous virological control (33 vs. 18 months, p=0.07). DISCUSSION: Switch to atazanavir/raltegravir was safe and well tolerated allowing optimal drugs' plasma exposure. However, a concerning rate (18.6%) failed with newly selected mutations and stopped ATV/RAL because of DDI and intolerance issues or were lost to follow up. This regimen might be considered in selected patients, without history of protease inhibitors failure or HBV infection, showing optimal adherence and prolonged suppression. PMID- 27992790 TI - Association between high risk human papillomavirus infection and co-infection with Candida spp. and Trichomonas vaginalis in women with cervical premalignant and malignant lesions. AB - BACKGROUND: Human papillomavirus (HPV) is the necessary cause of cervical cancer. Cervico-vaginal infection with pathogens like Chlamydia is a likely cofactor. The interactions between HPV, Trichomonas vaginalis (TV) and Candida spp. are less understood, though inflammation induced by these pathogens has been demonstrated to facilitate oncogenesis. OBJECTIVE: Our study aimed to evaluate the association between Candida spp. and TV co-infection with HPV in cervical oncogenesis. STUDY DESIGN: Women with normal cervix who were high-risk HPV-negative (N=104) and HPV positive (N=105); women with CIN 1 (N=106) and CIN 2/CIN 3 (N=62) were recruited from a community based cervical cancer screening program. Cervical cancer patients (N=106) were recruited from a tertiary care oncology clinic. High-risk HPV was detected by Hybrid Capture II technique; Candida spp. and TV were detected by culturing the high vaginal swabs followed by microscopic examination in all. The disease status was established by histopathology in all the women. RESULT: HPV-positive women had significantly higher risk of having precursor lesions (of any grade) and cancer compared to HPV-negative women. Candida spp. or TV infection did not alter the risk of low grade or high grade lesions among HPV- positive women. HPV positive women co-infected with TV had higher risk of cervical cancer but not those co-infected with Candida spp. CONCLUSION: The higher risk of cancer observed in the women co-infected with HPV and TV without any enhanced risk of CIN 3 suggests secondary infection of the malignant growth by TV rather than any causal role. Co-infection with Candida spp. and/or TV infection did not increase the carcinogenic effect of HPV on cervix. PMID- 27992789 TI - Analysis of Aichi virus and Saffold virus association with pediatric acute gastroenteritis. AB - BACKGROUND: Aichi virus (AiV) and Saffold virus (SAFV) have been reported in children with acute gastroenteritis and respiratory disease worldwide; however, their causative role in acute gastroenteritis remains ambiguous. OBJECTIVES: To assess the clinical association of AiV and SAFV with acute gastroenteritis in the pediatric population. STUDY DESIGN: A case-control study involving 461 paired stool samples from pediatric cases with diarrhea and healthy controls was conducted in China. Quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) was used to screen AiV and SAFV. RESULTS: In the 461 paired samples, AiV and SAFV were more prevalent among asymptomatic children than children with acute gastroenteritis (0.87% vs. 0.43% and 2.8% vs. 1.5%, respectively), with no significant differences between groups (p=0.142 and p=0.478, respectively). Cox regression model analysis revealed no correlation between AiV (odds ratio, OR=2.24; 95% confidence interval, CI, 0.76-6.54) or SAFV infection (OR=1.36; 95% CI, 0.86-2.15) and diarrhea. High viral loads were found in both AiV- and SAFV-positive groups, with no significant difference in viral load between the groups (p=0.507 and p=0.677, respectively). No other known enteric pathogens were found in the AiV-positive samples but common in SAFV positive cases. Phylogenetic analysis revealed that all 6 AiV subjects clustered with genotype B. All 7 SAFV-positive cases and 8 of 13 SAFV-positive controls were genotyped successfully; the genotypes identified included SAFV-1, SAFV-2 SAFV-3, and SAFV-6. CONCLUSION: Our study revealed no association of these viruses in acute gastroenteritis in children. These viruses may have the ability to replicate in humans; however, the infections are usually asymptomatic. PMID- 27992791 TI - Catalpol alleviates ovalbumin-induced asthma in mice: Reduced eosinophil infiltration in the lung. AB - BACKGROUND: Radix Rehmanniae Preparata is a traditional Chinese herbal medicine used to treat asthma, and catalpol is one of the main active ingredients in this herb. In the present study, the effects of catalpol on asthma and the underlying mechanism were explored. METHODS: Mice with ovalbumin (OVA)-induced asthma were given 5 or 10mg/kg catalpol from Day 15 to Day 28 (intraperitoneal injection). Histopathologic changes were detected by Hematoxylin and Eosin staining and Periodic Acid Schiff staining. The levels of IgE, interleukin (IL)-4, IL-5 and eotaxin were measured by ELISA. The numbers of lymphocytes, monocytes, basophils and eosinophils in the bronchoalveolar lavage fluid were determined by Wright Giemsa staining. The expression and distribution of eotaxin and C-C chemokine receptor 3 (CCR3) were detected by immunohistochemistry and immunofluorescence. The expression of interleukin-5 receptor alpha (IL-5Ralpha) was detected by Western blot assay. RESULTS: Catalpol inhibited OVA-induced inflammation and IgE secretion in the lung. OVA-induced type 2 inflammation was suppressed by catalpol as evidenced by decreased levels of IL-4 and IL-5. Moreover, catalpol inhibited the aberrant eosinophil infiltration in the lungs, and also suppressed OVA induced elevation of eosinophil chemokine eotaxin and its receptor CCR3. In addition, IL-5Ralpha expression in the bone marrow cells derived from catalpol treated asthmatic mice was lower than that from the untreated asthmatic mice. CONCLUSION: Our study demonstrated that catalpol attenuated OVA-induced asthma and inhibit the infiltration of inflammatory cells, especially eosinophils, into the lung. This study suggests that catalpol may become a promising drug for the treatment of asthma. PMID- 27992794 TI - A comparison between corn and grain sorghum fermentation rates, Distillers Dried Grains with Solubles composition, and lipid profiles. AB - The aim of this study was to determine if the compositional difference between grain sorghum and corn impact ethanol yields and coproduct value when grain sorghum is incorporated into existing corn ethanol facilities. Fermentation properties of corn and grain sorghum were compared utilizing two fermentation systems (conventional thermal starch liquefaction and native starch hydrolysis). Fermentation results indicated that protease addition influenced the fermentation rate and yield for grain sorghum, improving yields by 1-2% over non-protease treated fermentations. Distillers Dried Grains with Solubles produced from sorghum had a statistically significant higher yields and significantly higher protein content relative to corn. Lipid analysis of the Distillers Dried Grains with Solubles showed statistically significant differences between corn and sorghum in triacylglycerol, diacylglycerol and free fatty acid levels. PMID- 27992792 TI - Brain network dysfunction in youth with obsessive-compulsive disorder induced by simple uni-manual behavior: The role of the dorsal anterior cingulate cortex. AB - In an effort to elucidate differences in functioning brain networks between youth with obsessive-compulsive disorder and controls, we used fMRI signals to analyze brain network interactions of the dorsal anterior cingulate cortex (dACC) during visually coordinated motor responses. Subjects made a uni-manual response to briefly presented probes, at periodic (allowing participants to maintain a "motor set") or random intervals (demanding reactive responses). Network interactions were assessed using psycho-physiological interaction (PPI), a basic model of functional connectivity evaluating modulatory effects of the dACC in the context of each task condition. Across conditions, OCD were characterized by hyper modulation by the dACC, with loci alternatively observed as both condition general and condition-specific. Thus, dynamically driven task demands during simple uni-manual motor control induce compensatory network interactions in cortical-thalamic regions in OCD. These findings support previous research in OCD showing compensatory network interactions during complex memory tasks, but establish that these network effects are observed during basic sensorimotor processing. Thus, these patterns of network dysfunction may in fact be independent of the complexity of tasks used to induce brain network activity. Hypothesis-driven approaches coupled with sophisticated network analyses are a highly valuable approach in using fMRI to uncover mechanisms in disorders like OCD. PMID- 27992793 TI - Wastes valorization from Rhodosporidium toruloides NCYC 921 production and biorefinery by anaerobic digestion. AB - Yeast production and biomass biorefinery processes for lipid and carotenoid extraction generate residues that can be used as substrates for anaerobic digestion. Glucose and carob pulp syrups were used as carbon sources to produce the yeast biomass. The yeast cultivation broth, yeast biomass residues (after carotenoid and lipid extraction) and the carob pulp solid residues obtained from the extraction of sugars were used to produce biogas by applying different Substrate/Inoculum ratios (S/I of 0.5 and 0.75). For all the residues studied, the digestions at the S/I ratio of 0.75 provided higher biogas yields than those carried out at the S/I ratio of 0.5. The best results in terms of biogas production and methane yield were observed for the yeast residue digestion at S/I of 0.75 (65.9mL, 333.7mLg-1VS-1 substrate). As monitored through flow cytometry, its bacterial consortium showed the lowest proportion of injured cells. PMID- 27992795 TI - Feasibility of co-composting of sewage sludge, spent mushroom substrate and wheat straw. AB - In this study, the lab-scale co-composting of sewage sludge (SS) with mushroom substrate (SMS) and wheat straw (WS) conducted for 20days was evaluated. The addition of SMS evidently increased CO2 production and dehydrogenase activity. The combined addition of SMS and WS significantly improved the compost quality in terms of temperature, organic matter degradation and germination index, especially, reduced 21.9% of NH3 emission. That's because SMS and WS possessed the complementarity of free air space and contained plenty of degradable carbon source. The SMS could create a comfortable environment for the nitrifying bacteria and improve nitrification. The carbohydrates from combined addition of SMS and WS could be utilized by thermophilic microorganisms, stimulate ammonia assimilation and reduce NH3 emission. These results suggested that adding SMS and WS could not only improve the degradation of organic matter and the quality of compost product, but also stimulate ammonia assimilation and reduce ammonia emission. PMID- 27992796 TI - A novel microalgal lipid extraction method using biodiesel (fatty acid methyl esters) as an extractant. AB - Although microalgae are considered promising renewable sources of biodiesel, the high cost of the downstream process is a significant obstacle in large-scale biodiesel production. In this study, a novel approach for microalgal biodiesel production was developed by using the biodiesel as an extractant. First, wet microalgae with 70% water content were incubated with a mixture of biodiesel/methanol and penetration of the mixture through the cell membrane and swelling of the lipids contained in microalgae was confirmed. Significant increases of lipid droplets were observed by confocal microscopy. Second, the swelled lipid droplets in microalgae were squeezed out using mechanical stress across the cell membrane and washed with methanol. The lipid extraction efficiency reached 68%. This process does not require drying of microalgae or solvent recovery, which the most energy-intensive step in solvent-based biodiesel production. PMID- 27992797 TI - Comparison of existing models to simulate anaerobic digestion of lipid-rich waste. AB - Models for anaerobic digestion of lipid-rich waste taking inhibition into account were reviewed and, if necessary, adjusted to the ADM1 model framework in order to compare them. Experimental data from anaerobic digestion of slaughterhouse waste at an organic loading rate (OLR) ranging from 0.3 to 1.9kgVSm-3d-1 were used to compare and evaluate models. Experimental data obtained at low OLRs were accurately modeled whatever the model thereby validating the stoichiometric parameters used and influent fractionation. However, at higher OLRs, although inhibition parameters were optimized to reduce differences between experimental and simulated data, no model was able to accurately simulate accumulation of substrates and intermediates, mainly due to the wrong simulation of pH. A simulation using pH based on experimental data showed that acetogenesis and methanogenesis were the most sensitive steps to LCFA inhibition and enabled identification of the inhibition parameters of both steps. PMID- 27992798 TI - Peroxygenases en route to becoming dream catalysts. What are the opportunities and challenges? AB - Peroxygenases are promising catalysts for preparative oxyfunctionalization chemistry as they combine the versatility of P450 monooxygenases with simplicity of cofactor-independent enzymes. Though many interesting applications have been reported, today 'we have only scratched the surface' and significant efforts are necessary to solve issues related to selectivity of the wild type enzymes and low product titers. For this, further elucidation of the vast natural diversity as well as protein and reaction engineering approaches are discussed. PMID- 27992799 TI - Metal homeostasis in infectious disease: recent advances in bacterial metallophores and the human metal-withholding response. AB - A tug-of-war between the mammalian host and bacterial pathogen for nutrients, including first-row transition metals (e.g. Mn, Fe, Zn), occurs during infection. Here we present recent advances about three metal-chelating metabolites that bacterial pathogens deploy when invading the host: staphylopine, staphyloferrin B, and enterobactin. These highlights provide new insights into the mechanisms of bacterial metal acquisition and regulation, as well as the contributions of host defense proteins during the human innate immune response. The studies also underscore that the chemical composition of the microenvironment at an infection site can influence bacterial pathogenesis and the innate immune system. PMID- 27992800 TI - Lead relative bioavailability in soils based on different endpoints of a mouse model. AB - Mouse is an acceptable animal model to measure lead (Pb) relative bioavailability (RBA) in contaminated soils; however, there is a lack of comparisons among Pb-RBA measurements based on different endpoints and dosing approaches. In this study, 12 soils (47.8-8123mg Pbkg-1) were assessed for Pb-RBA using Pb accumulation in mouse liver, kidneys, and/or femur following a 10-d steady state soil dose via diet, with 6 soils being measured using mouse bioassays with area under the mouse blood Pb concentration time curve (AUC) following a single gavaged dose as the endpoint. Based on individual endpoints of the steady state method, Pb-RBA in soils was 2.1-83.4%, being generally consistent among liver, kidneys, and femur with strong linear correlations between them (r2=0.74-0.89). To compensate variation in Pb distribution among different tissues, Pb-RBA was further calculated using a combined endpoint (e.g., sum of Pb accumulation in liver, kidneys, and femur). Compared to Pb-RBA based on individual tissue showing relative standard deviation (RSD) of 11.9-15.8%, Pb-RBA using the combined endpoint showed lower RSD (10.8%), thereby being more robust. For the 6 soils with Pb-RBA based on both mouse single gavaged and steady state dosing approach, no significant difference was observed; however, steady state approach was more repeatable among animals with lower RSD (11.4% vs. 34.5%). To ensure robustness of in vivo data, the steady state dosing approach with Pb accumulation in combined tissues is recommended. PMID- 27992801 TI - Development of a colloidal gold immunochromatographic strip for rapid detection of Streptococcus agalactiae in tilapia. AB - A colloidal gold immunochromatographic strip was developed for rapid detection of Streptococcus agalactiae (S. agalactiae) infection in tilapia. The monoclonal antibodies (mAb) 4C12 and 3A9 were used to target S. agalactiae as colloidal gold mAb conjugate and captured antibody, respectively. The colloidal gold immunochromatographic strip was assembled via routine procedures. Optimal pH and minimum antibody levels in the reaction system for gold colloidal-mAb 4C12 conjugation were pH 7.4 and 18MUg/mL, respectively. Optimal concentrations of the captured antibody 3A9 and goat anti-mouse antibody were 0.6mg/mL and 2mg/mL, respectively. The sensitivity of the strip for detecting S. agalactiae was 1.5*105 colony forming units (CFU). No cross-reaction was observed with other commonly encountered bacteria, including Pseudomonas fluorescens, Aeromonas hydrophila, Vibrio anguillarum and Streptococcus iniae. The assay time for S. agalactiae was less than 15min. Tilapia samples artificially infected with S. agalactiae were tested using the newly developed strip. The results indicated that blood, brain, kidney, spleen, metanephros and intestine specimens of infected fish can be used for S. agalactiae detection. The validity of the strip was maintained for 6 months at 4 degrees C. These findings suggested that the immunochromatographic strip was effective for spot and rapid detection of S. agalactiae infected tilapia. PMID- 27992802 TI - A label-free and high-efficient GO-based aptasensor for cancer cells based on cyclic enzymatic signal amplification. AB - A label-free and high-efficient graphene oxide (GO)-based aptasensor was developed for the detection of low quantity cancer cells based on cell-triggered cyclic enzymatic signal amplification (CTCESA). In the absence of target cells, hairpin aptamer probes (HAPs) and dye-labeled linker DNAs stably coexisted in solution, and the fluorescence was quenched by the GO-based FOrster resonance energy transfer (FRET) process. In the presence of target cells, the specific binding of HAPs with the target cells triggered a conformational alternation, which resulted in linker DNA complementary pairing and cleavage by nicking endonuclease-strand scission cycles. Consequently, more cleaved fragments of linker DNAs with more the terminal labeled dyes could show the enhanced fluorescence because these cleaved DNA fragments hardly combine with GOs and prevent the FRET process. Fluorescence analysis demonstrated that this GO-based aptasensor exhibited selective and sensitive response to the presence of target CCRF-CEM cells in the concentration range from 50 to 105 cells. The detection limit of this method was 25 cells, which was approximately 20 times lower than the detection limit of normal fluorescence aptasensors without amplification. With high sensitivity and specificity, it provided a simple and cost-effective approach for early cancer diagnosis. PMID- 27992803 TI - A green and facile approach for synthesizing imine to develop optical biosensor for wide range detection of bilirubin in human biofluids. AB - Bilirubin, a key biomarker for the jaundice and its clinical diagnosis needs a better analytical tool. A novel and simple fluorescent platform based on (2,2' ((1E,1'E)-((6-bromopyridine-2,3-diyl) bis(azanylylidene)) bis(methanylylidene diphenol) (BAMD) was designed. BAMD showed a remarkable fluorescent intensity with a very good quantum yield of 0.85 and lifetime of 870ps. Hence, it was applied for the determination of bilirubin using both colorimetric and fluorimetric techniques in physiological and basic pH. Under optimized experimental conditions, the probe detects bilirubin selectively in the presence of other interfering biomolecules and metal ions. The linear range of detection is 1pM-500uM at pH=7.4 and LOD is 2.8 and 3.3 pM at pH=7.4 and 9.0, respectively, which were reported so far. The probe detects the bilirubin through FRET mechanism. The practical application of the probe was successfully tested in the human blood and urine samples. Based on all above advantages, this simple idea can be applied to design a simple clinical diagnostic tool for jaundice. PMID- 27992804 TI - Visual colorimetric sensor array for discrimination of antioxidants in serum using MnO2 nanosheets triggered multicolor chromogenic system. AB - Here we report a unique visual colorimetric sensor array for discrimination of antioxidants in serum based on MnO2 nanosheets-3,3',5,5'-tetramethylbenzidine (TMB) multicolor chromogenic system. The absorbance values of the system at 370, 450, and 650nm provide three cross-reactive sensing elements. The presence of antioxidant will inhibit the reaction between TMB and MnO2 nanosheets due to the presence of the competitive reaction of MnO2 nanosheets and antioxidants. Different antioxidants containing uric acid, glutathione, ascorbic acid, cysteine, and melatonin have distinct reducing ability, producing a differential inhibition of MnO2 nanosheets-TMB system, and therefore generating distinct colorimetric response patterns at 370, 450, and 650nm. The obtained patterns for each antioxidant at a concentration of 20MUM were successfully discriminated using principal component analysis both in buffer and when spiked into fetal bovine serum (FBS). The identification accuracy of 45 unknown samples was found to be 100%. Remarkably, this sensor assay can visually discriminate antioxidants in diluted FBS with the naked eye. PMID- 27992805 TI - Selective ex vivo photothermal nano-therapy of solid liver tumors mediated by albumin conjugated gold nanoparticles. AB - We have used albumin (BSA) bound to gold nanoparticles (GNPs) as active vectors to target liver cells. Our incentive to develop an original model of living liver cancer sprang from the ethical drawbacks that hindered the assessment of the selective character and the therapeutic capacity of these nano-biosystems in cancer patients. Ex vivo-perfused liver specimens were obtained from hepatocellular carcinoma patients similarly to the surgical technique of transplantation. Albumin bound to GNPs was inoculated intra-arterially onto the resulting specimen and determined the specific delivery of the nano-bioconjugate into the malignant tissue by means of the capillary bed. The extent of necrosis was considerable following laser therapy and at the same time surrounding parenchyma was not seriously affected. The selective photothermal ablation of the malignant liver tissue was obtained after the selective accumulation of BSA bound to GNPs into tumor cells following ex-vivo intra-vascular perfusion. PMID- 27992806 TI - Environment friendly approach for size controllable synthesis of biocompatible Silver nanoparticles using diastase. AB - A green, facile method for the size selective synthesis of silver nanoparticles (AgNPs) using diastase as green reducing and stabilizing agent is reported. The thiol groups present in the diastase are mainly responsible for the rapid reaction rate of silver nanoparticles synthesis. The variation in the size and morphology of AgNPs were studied by changing the pH of diastase. The prepared silver nanoparticles were characterized by using UV-vis, XRD, FTIR, TEM and SAED. The FTIR analysis revealed the stabilization of diastase molecules on the surface of AgNPs. Additionally, in-vitro cytotoxicity experiments concluded that the cytotoxicity of the as-synthesized AgNPs towards mouse fibroblast (3T3) cell lines is dose and size dependent. Furthermore, the present method is an alternative to the traditional chemical methods of size controlled AgNPs synthesis. PMID- 27992807 TI - Cellular stress and histopathological tools used as biomarkers in Oreochromis mossambicus for assessing metal contamination. AB - In the present study, we have analyzed various biochemical and histopathological biomarkers in the Oreochromis mossambicus collected from 18 sites at Bhima River. The biochemical biomarkers viz. antioxidative enzymes in muscle viz. catalase, SOD, and GST, glycolytic enzymes in kidney viz. LDH and MDH, protein metabolic enzymes in liver, gill, brain, gonad and muscle viz. ALT and AST, neurotransmitter enzymes in muscle AChE, lipid peroxidation and histopathology in the liver and gill have been evaluated. The oxidative biomarkers, glycolytic enzymes, protein metabolic enzymes and lipid peroxidation were significantly (p<0.01) higher and AChE in muscle were significantly inhibited (p<0.01) in fishes from different sampling sites. The histopathology of the liver and gill were altered at different sampling sites. The liver histopathology showed hepatocytes vacuolization, haemorrhage, karyokinesis, necrosis, pyknotic nuclei, dilation of sinusoids and hepatocyte granular degeneration and in the gill histopathology showed distal lamellar gill tissue, diffuse epithelial hyperplasia and multifocal mucus cell hyperplasia, extensive edema of epithelial cells, blood congestion and edema in secondary lamellae. All the indicators are giving strong signals for contamination of the aquatic water bodies. The Bhima River is surrounded by several cities and agriculture land indicates that vigorous industrial activity coupled with intensive use of chemicals in agricultural practices may held. Therefore, based on our results, we could recommend that the investigated tissue and cell alterations may be successfully applied as reliable biomarkers for monitoring contaminated freshwater ecosystems. This study suggests that, the importance of antioxidative enzymes, cellular biomarkers, AChE, and histopathology used as biomarkers in aquatic ecosystem biomonitoring. PMID- 27992809 TI - Much ado about everything: A literature review of insight in first episode psychosis and schizophrenia. PMID- 27992808 TI - Risk factors for suicide in the Israeli army between the years 1992-2012: A case control study. AB - OBJECTIVE: Young age, availability of weapons, and stressful life events, increase the risk of suicide. The aim of the present study was to assess additional risk factors for suicide in the Israeli army. METHODS: We conducted a case-control study, to assess risk factors for suicide. The cases comprised soldiers who died by suicide during their military service (n=462; 0.039% of all soldiers in the cohort). The control group consisted of soldiers who did not commit suicide but were in active service during the investigated period (n=1,170,895; 99.96%). Predictor variables, including socio-demographic and psychiatric diagnoses, were considered. RESULTS: Using a Generalized Linear Model with a Binary Logistic dependent variable to predict suicide, while controlling the effect of intervening variables, we found the following variables enhanced the risk for committing suicide: male (RR=6.703; P<0.001), country of origin: Ethiopia (RR=4.555; P=0.014), low socioeconomic status (RR=1.448; P=0.016) and low adjustment difficulties (RR=2.324; P<0.001). In addition, we found that in males only, Cluster B Personality Disorder (RR=2.548; P=0.027), low (RR=1.657; P=0.002), to average motivation to serve in a combat unit (RR=1.322; P=0.046) increased the risk for suicide. CONCLUSIONS: IDF Soldiers bearing a psychiatric diagnosis or severe adjustment difficulties remained tightly monitored through their military service, and were found to be at a lower risk for suicide. However, those enlisted with mild (low) difficulties, were found to be at greater risk for suicide, as well as soldiers whose country of origin is Ethiopia. Suicide prevention program should focus on monitoring soldiers with these risk factors, together with soldiers' guidance regarding help seeking and de stigmatizing suicide. PMID- 27992810 TI - Age at menarche predicts age at onset of major affective and anxiety disorders. AB - BACKGROUND: Menarche age has been associated inconsistently with the occurrence, timing or severity of major depressive disorder (MDD), but rarely studied in women with bipolar (BDs) or anxiety disorders. METHODS: We investigated women patients at a Sardinian mood disorder center for associations of age at menarche with age at illness onset for major affective or anxiety disorders, year of birth, and other selected factors, using bivariate comparisons and multivariate regression modeling. RESULTS: Among women (n=1139) with DSM-IV MDD (n=557), BD-I (n=223), BD-II (n=178), or anxiety disorders (n=181), born in 1904-1998, of mean age 42.9 years, menarche age averaged 12.8 [CI: 12.7-12.9] years. Illness onset age averaged 30.9 [30.1-31.8] years, ranking: BD-I, 25.8; anxiety disorders, 28.0; BD-II, 30.3; MDD, 34.1 years. Menarche age declined secularly over birth years, and was associated with younger illness-onset, having no or fewer siblings, more psychiatrically ill first-degree relatives, living in rural environments, being suicidal, substance abuse, and being unemployed. Earlier menarche and earlier illness-onset were significantly associated for onset age groups of <= 20, 20-39, and > 40 years. Menarche age versus diagnosis ranked: BD II10% (23.2%, 23.2%, 14.3%, 12.5%, 12.5%, respectively). However, resistances to meropenem, imipenem and minocycline were only sporadically observed (8.3%, 1.2% and 1.2%, respectively). Overall, 51.2% of the strains were considered as multidrug-resistant (MDR) and 9.6% as extensively drug-resistant (XDR). The prevalence of MDR strains within the A. baumannii group (38.7%) was lower than the prevalence within the others species identified (54.1%). Therefore, food of animal origin may be a vehicle of spread Acinetobacter strains resistant to several antibiotics in the community and in the hospital setting environment. This may led to nosocomial and community acquired infections in susceptible individuals. PMID- 27992817 TI - Rapid detection of methicillin-resistant Staphylococcus aureus in pork using a nucleic acid-based lateral flow immunoassay. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is considered as one of the leading causes of food poisonings worldwide. Due to the high prevalence and extensive challenges in clinical treatment, a rapid and accurate detection method is required to differentiate MRSA from other S. aureus isolated from foods. Since the methicillin resistance of S. aureus is due to the acquisition of the mecA gene from staphylococcal chromosome cassette, the presence of the mecA gene is interpreted as a marker for the identification of MRSA. In this study, a low-cost lateral flow immunoassay (LFI) strip was used to detect the mecA amplicons subsequent to polymerase chain reaction (PCR). The specificity of this PCR-LFI assay was tested between MRSA and methicillin-susceptive S. aureus. Both the test line and control line were shown up on the LFI strip for MRSA, whereas only the control line developed for methicillin-susceptive S. aureus. The detection limit of PCR-LFI assay was 20fg for genomic DNA (100 times more sensitive than gel electrophoresis) and 2*100CFU per 100g of pork products after enrichment at 37 degrees C for 48h. The total detection time of using LFI was 3min, which was faster than the conventional electrophoresis (~45min). With the performance of PCR-LFI, 7 out of 42 S. aureus isolates were identified to be MRSA from imported pork products, which was consistent to the standardized minimum inhibitory concentration assay. This mecA-based PCR-LFI strip can be used for rapid and accurate detection of MRSA isolated from commercial pork products. PMID- 27992818 TI - Historical peat loss explains limited short-term response of drained blanket bogs to rewetting. AB - This study assessed the short-term impacts of ditch blocking on water table depth and vegetation community structure in a historically drained blanket bog. A chronosequence approach was used to compare vegetation near ditches blocked 5 years, 4 years and 1 year prior to the study with vegetation near unblocked ditches. Plots adjacent to and 3 m away from 70 ditches within an area of blanket bog were assessed for floristic composition, aeration depth using steel bars, and topography using LiDAR data. No changes in aeration depth or vegetation parameters were detected as a function of ditch-blocking, time since blocking, or distance from the ditch, with the exception of non-Sphagnum bryophytes which had lower cover in quadrats adjacent to ditches that had been blocked for 5 years. Analysis of LiDAR data and the observed proximity of the water table to the peat surface led us to conclude that the subdued ecosystem responses to ditch-blocking were the result of historical peat subsidence within a 4-5 m zone either side of each ditch, which had effectively lowered the peat surface to the new, ditch influenced water table. We estimate that this process led to the loss of around 500,000 m3 peat within the 38 km2 study area following drainage, due to a combination of oxidation and compaction. Assuming that 50% of the volume loss was due to oxidation, this amounts to a carbon loss of 11,000 Mg C over this area, i.e. 3 Mg C ha-1. The apparent 'self-rewetting' of blanket bogs in the decades following drainage has implications for their restoration as it suggests that there may not be large quantities of dry peat left to rewet, and that there is a risk of inundation (potentially leading to high methane emissions) along subsided ditch lines. Many peatland processes are likely to be maintained in drained blanket bog, including support of typical peatland vegetation, but infilling of lost peat and recovery of original C stocks are likely to take longer than is generally anticipated. PMID- 27992819 TI - A comparative study on the influence of different organic amendments on trace element mobility and microbial functionality of a polluted mine soil. AB - A mine soil heavily polluted with zinc and cadmium was employed to evaluate the capacity of organic amendments of different origin to simultaneously reduce soil trace element mobility and enhance soil microbial functionality. With this aim, four organic products, namely olive processing solid waste (OPSW), municipal solid waste compost (MSWC), leonardite and peat, were applied individually at different doses (0, 1, 2 and 5%) to mine soil under controlled laboratory conditions. Extraction studies and analysis of soil microbiological parameters (basal soil respiration and dehydrogenase, beta-glucosidase, urease, arylsulfatase and acid and alkaline phosphatase activities) were performed to assess the effect of such amendments on soil restoration. Their ability to decrease mine soil mobile trace element contents followed the sequence MSWC > OPSW > peat > leonardite, with the former achieving reduction levels of 78 and 73% for Zn and Cd, respectively, when applied at a dose of 5%. This amendment also showed a good performance to restore soil microbial functionality. Thus, basal soil respiration and dehydrogenase, urease and alkaline phosphatase activities experienced increases of 187, 79, 42 and 26%, respectively, when mine soil was treated with 5% MSWC. Among tested organic products, MSWC proved to be the best amendment to perform both the chemical and the microbial soil remediation. PMID- 27992820 TI - GJA1 gene variations in sudden unexplained nocturnal death syndrome in the Chinese Han population. AB - Sudden unexplained nocturnal death syndrome (SUNDS) is a conundrum to both forensic pathologists and physicians, more than 80% of which the molecular pathogenesis remains unclear. Reported studies on both clinical and genetic phenotypes suggest SUNDS is related to congenital and acquired arrhythmias. Recent researches have linked the mutations of gene gap junction alpha 1 (GJA1) with arrhythmogenic cardiac disorders. In the present study, we investigate the potential correlation between GJA1 gene variations and the occurrence of SUNDS. Genomic DNA was extracted from the blood samples of both 124 sporadic SUNDS patients and 125 healthy controls to screen GJA1 gene for candidate variants using polymerase chain reaction (PCR) and direct DNA sequencing. One novel homozygous variant c.169C>T and one heterozygous SNP c.624C>T (rs530633057) were determined in 124 SUNDS cases (one case for each detected variant) and none of the 125 healthy controls. Base C>T transition at nucleotide position 169 led to termination of protein production after glutamine (Q) at codon 57 which is very likely to result in decreased expression of Cx43 gap junction channels and cause arrhythmic sudden death. This is the first report of GJA1 gene variations in SUNDS in the Chinese Han population, which suggests a novel susceptibility gene for Chinese SUNDS. PMID- 27992821 TI - Corrigendum to "Sexual dimorphism of the scapula and the clavicle in a contemporary Greek population: Applications in forensic identification" [Forensic Sci. Int. 217 (2012) 231.e1-231.e7]. PMID- 27992822 TI - Thrombolytic treatment to stroke mimic patients via telestroke. AB - OBJECTIVE: The safety and outcomes of intravenous thrombolysis (IVT) to stroke patients via telestroke (TS) is similar to those presenting to stroke centers. Little is known on the accuracy of TS diagnosis among those receiving IVT. We sought to compare the rate of patients receiving IVT with diagnosis of ischemic stroke as opposed to stroke mimic (SM) in our TS network to those who presented to our comprehensive stroke center (CSC). MATERIALS AND METHODS: Consecutive patients receiving IVT between August 2014 and June 2015 were identified at our CSC and TS network. We compared rates of SM, post-IVT symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, and discharge destination. RESULTS: We evaluated 131 receiving IVT were included in the analysis. Rates of SM receiving IVT were similar (CSC 12% versus 7% TS, p=0.33). Four stroke patients experienced sICH or in-hospital mortality; neither were found among SM patients. Discharge destination was similar between stroke and SM patients (p=0.9). SM patients had higher diagnoses of migraine (p=0.05) and psychiatric illness (p<0.01). CONCLUSION: The accuracy of diagnosing stroke in IVT-eligible patients evaluated via TS is similar to evaluations at our CSC. Continued efforts should be made to minimize exposure of SM patients to IVT in both settings. PMID- 27992823 TI - The effect of renal dysfunction on short-term outcomes after lumbar fusion. AB - OBJECTIVE: To compare post-lumbar decompression and fusion complication rates and mortality for patients without preoperative hemodialysis (HD) use with and without renal dysfunction as estimated by glomerular filtration rate (GFR) and creatinine levels. PATIENTS AND METHODS: Baseline and outcome data were obtained from the 2005-2014 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for patients over the age of 18 who underwent non-emergent lumbar fusion surgery. Preoperative HD status and GFR and creatinine levels were extracted. Variables analyzed included development of at least one complication, development of a major complication, in-hospital mortality, and length of stay. RESULTS: A total of 29,081 patients were identified. Those with severe preoperative kidney dysfunction as estimated by GFR were more likely to develop a complication (GFR=15-30ml/min/1.73m2; OR, 3.82; 95% CI, 2.061-7.082; P=<0.0001 and GFR=30-45ml/min/1.73m2; OR, 2.124; 95% CI, 1.506 2.996; P<0.0001). Compared to patients with normal preoperative creatinine levels (0.75-1.0mg/dL), patients with elevated creatinine were more likely to develop at least one complication. CONCLUSION: Patients with low estimated GFR and elevated creatinine levels were associated with higher perioperative morbidity. This increased risk should be taken into consideration when counselling this patient population. PMID- 27992824 TI - Nanotechnology for sustainable wastewater treatment and use for agricultural production: A comparative long-term study. AB - Nanotechnology applications can be used for filtering low quality waters, allowing under given conditions, the removal of salts and other micropollutants from these waters. A long-term field experiment, implementing nanotechnology in the form of UltraFiltration (UF) and Reverse Osmosis (RO) for salt removal from treated wastewater, was conducted with secondary effluents, aiming to prove the sustainability of agricultural production using irrigation with treated wastewater. Six outdoor field treatments, each under four replications, were conducted for examining the salt accumulation effects on the soil and the crops. The field experiments proved that crop development is correlated with the water quality as achieved from the wastewater filtration capability of the hybrid nanotechnology system. The key goal was to maintain sustainable food production, despite the low quality of the waters. Of the six treatment methods tested, irrigation with RO-treated effluent produced the best results in terms of its effect on soil salinity and crop yield. Nevertheless, it must be kept in mind that this process is not only costly, but it also removes all organic matter content from the irrigation water, requiring the addition of fertilizers to the effluent. PMID- 27992825 TI - Evolutionary studies of ligand binding sites in proteins. AB - Biological processes at their most fundamental molecular aspects are defined by molecular interactions with ligand-protein interactions in particular at the core of cellular functions such as metabolism and signalling. Divergent and convergent processes shape the evolution of ligand binding sites. The competition between similar ligands and binding sites across protein families create evolutionary pressures that affect the specificity and selectivity of interactions. This short review showcases recent studies of the evolution of ligand binding-sites and methods used to detect binding-site similarities. PMID- 27992827 TI - Development of a SNP-based panel for human identification for Indian populations. AB - The widely employed short tandem repeat (STR)-based panels for forensic human identification (HID) have limitations while dealing with challenging forensic samples involving DNA degradation, resulting in dropping-out of higher molecular weight alleles/loci. To address this issue, bialleic markers like single nucleotide polymorphisms (SNPs) and insertion-deletions (indels), which can be scored even when the template DNA is heavily degraded (<100bp), have been suggested as alternative markers for HID testing. Recent studies have highlighted their utility in forensic HID and several panels based on biallelic markers have been described for worldwide populations. However, there has been very little information about the behavior of such DNA markers in Indian populations, which is known to possess great genetic diversity. This study describes a two-step approach for designing a SNP-based panel consisting of 70 SNPs for HID testing in Indian populations. In the first step, candidate SNPs were shortlisted from public databases by screening them for several criteria including allelic distribution, genomic location, potential phenotypic expression or functionality and species specificity. The second step involved genotyping the shortlisted SNPs in various Indian populations followed by shortlisting of the best performers for identity-testing. Starting with 592,652 SNPs listed in Human660W-Quad Beadchip (Illumina Inc.), we shortlisted 275 candidate SNPs for identity-testing and genotyped them in 462 unrelated individuals from different population groups in India. Post genotyping and statistical analyses based on biogeographic regions, 206 SNPs demonstrated desired allelic distribution (Heterozygosity>=0.4 and FST<=0.02), from which 2-4 widely separated (>20 Mb apart) SNPs from each chromosome were finally selected to construct a panel of 70 SNPs. This panel on average possessed match probability 10e-29 and probability of paternity of 0.99999997, which was orders of magnitude higher than most of the currently employed STR-based chemistries and SNP-based panels that were proposed previously for HID testing. For comparison purpose, genotyping previously reported SNPs for HID in our samples led us to conclude that the panel developed in this study is much more efficient and robust and better suited for the Indian populations. PMID- 27992826 TI - Negative rumination in social anxiety: A randomised trial investigating the effects of a brief intervention on cognitive processes before, during and after a social situation. AB - BACKGROUND AND OBJECTIVES: According to cognitive models of Social Anxiety Disorder (SAD), negative rumination is a key maintaining factor in the vicious cycle of social anxiety. However, there is a scarcity of research investigating treatment effects on rumination in social anxiety, as well as other key cognitive variables. The current study aimed to determine the effectiveness of a brief intervention on a range of cognitive processes, most notably negative rumination. Additionally, predictors of negative rumination and state anxiety are also investigated. METHODS: Participants with a diagnosis of SAD were randomly allocated to an intervention (n = 24) or control group (n = 23). Participant's initially completed trait and state based measures with the intervention group also completing a brief cognitive intervention. One-week later participants completed state anxiety and cognitive measures before and after a speech task. Finally, one-week post-speech task participants completed further trait and state based measures. RESULTS: While the brief cognitive intervention had positive effects on some of the cognitive processes measured at different time points of the study, levels of negative rumination remained stable. Predictors of negative rumination and state anxiety were consistent with cognitive models of SAD. LIMITATIONS: The brief nature of the intervention and temporal stance of the intervention (delivered one-week before the speech) may have impacted outcomes. CONCLUSIONS: Cognitive technique can potentially impact a range of key processes that maintain SAD, however, more powerful and tailored interventions are needed that address the different processes at play before, during and after a social situation for socially anxious individuals. PMID- 27992828 TI - Validation of the MicroreaderTM 23sp ID system: A new STR 23-plex system for forensic application. AB - MicroreaderTM 23sp ID system is a new 23-plex STR genotyping system that amplified 21 non-CODIS STR loci (D6S477, D18S535, D19S253, D15S659, D11S2368, D20S470, D1S1656, D22-GATA198B05, D7S3048, D8S1132, D4S2366, D21S1270, D13S325, D9S925, D3S3045, D14S608, D10S1435, D12S391, D2S1338, D17S1290 and D5S2500), one CODIS STR locus (D16S539) and the amelogenin locus in one reaction. MicroreaderTM 23sp ID system was validated according to the guidelines of "Validation Guidelines for DNA Analysis Methods (2012)" described by the Scientific Working Group on DNA Analysis Methods (SWGDAM), including PCR-based studies, sensitivity study, precision and accuracy evaluation, stutter percentage and peak height ratio, inhibitors, species specificity and DNA mixture studies. Our results suggested that MicroreaderTM 23sp ID system is a useful tool for identification and parentage testing. PMID- 27992829 TI - Assessing child maltreatment prevention via administrative data systems: A case example of reproducibility. AB - Critical issues about scientific reproducibility have been raised about biomedical research, including the reliability of data and analyses within a given study. The case example in this article examined a reproducibility issue pertaining to the use of administrative data systems for evaluation of child maltreatment (CM) prevention, making use of a prevention study conducted over a decade ago that provided a unique opportunity. The place-randomization study, which randomized counties to condition, found that community-wide implementation of a parenting and family support intervention produced positive impact on county wide rates for substantiated CM cases and out-of-home placements, documented through a state information system. The key consideration is whether and to what extent the administrative record data re-examined retroactively a decade later for the original study's time period would yield comparable results to those based on data acquired at the time of the study. The results indicated that despite small changes over time, the same data patterns and statistical effects were reproducible for the two archival outcome variables. For substantiated CM, the reproduced analyses reflected higher effect sizes and a clear pattern of reduction as a function of intervention. For out-of-home placements, effect sizes were quite comparable to the original ones, reflecting preventive impact. Overall, this case study illustrated the verifiability of data reproducibility in the context of a population outcome evaluation, which underscores the importance of reliable population-prevalence measurement as an essential part of a comprehensive public health strategy aimed at the prevention of CM. PMID- 27992830 TI - What prevents Chinese parents from reporting possible cases of child sexual abuse to authority? A holistic-interactionistic approach. AB - The reporting of suspected CSA cases to authorities in a timely manner is important in preventing continued abuse and protecting abused children at early ages. The current study seeks to explore parents' intentions of reporting their own children's CSA experiences to authorities as well as their reporting willingness when they become aware of possible CSA cases happening to children in other families. Two rounds of semi-structured interviews were conducted among a sample of 26 parents in Beijing; these parents were purposefully selected so as to be diverse in terms of gender, age, and socioeconomic status. The data were analyzed thematically. The findings showed that the reporting of suspected CSA to authorities was a choice made by only a few Chinese parents; it was often even a last resort. By using a holistic-interactionistic approach, the interaction between Chinese parents' intentions of reporting CSA and the Chinese socio cultural context was analyzed as a dynamic and continuously ongoing process. The impacts of the definition and perceptions of CSA on reporting, the balance of children's rights and parents' power, and the double effect of informal social control are discussed. The implications, both locally and globally, are also discussed. PMID- 27992831 TI - Nanotechnology to the rescue: using nano-enabled approaches in microbiological food safety and quality. AB - Food safety and quality assurance is entering a new era. Interventions along the food supply chain must become more efficient in safeguarding public health and the environment and must address numerous challenges and new consumption trends. Current methods of microbial control to assure the safety of food and minimize microbial spoilage have each shown inefficiencies. Nanotechnology is a rapidly expanding area in the agri/feed/food sector. Nano-enabled approaches such as antimicrobial food-contact surfaces/packaging, nano-enabled sensors for rapid pathogen/contaminant detection and nano-delivered biocidal methods, currently on the market or at a developmental stage, show great potential for the food industry. Concerns on potential risks to human health and the environment posed by use of engineered nanomaterials (ENMs) in food applications must, however, be adequately evaluated at the developmental stage to ensure consumer's acceptance. PMID- 27992832 TI - CT-guided 125I brachytherapy in the treatment of distant metastases in the oral cavity and maxillofacial region. AB - PURPOSE: We aimed to evaluate the feasibility and clinical effectiveness of CT guided 125I brachytherapy for distant oral and maxillofacial metastases. MATERIALS AND METHODS: We retrospectively analyzed 65 patients with 84 distant oral and maxillofacial metastases. Thirty-one patients with 38 lesions received 125I brachytherapy (group A) and 34 with 46 lesions received external beam radiotherapy (EBRT; group B). RESULTS: Median follow-up time was 16 months. The 3 , 6-, 12-, 18-, and 24-month local control rates for group A were 83.9%, 75.9%, 66.7%, 38.4%, and 25.0%, respectively; for group B they were 76.5%, 62.5%, 43.8%, 25.0%, and 0.0%, respectively (P<.05); the median local tumor progression-free survival times were 14 and 9 months, respectively. Group A had a better local tumor progression-free survival (LTPFS) relative to group B (P<.001; HR, 6.961 [95%CI, 2.109, 9.356]). Cox proportional hazards regression analysis indicated that 125I brachytherapy, tumor size, and primary pathological type were the independent factors affecting LTPFS. Additionally, 125I brachytherapy showed better performance in relieving patient clinical symptoms relative to EBRT (P<.05). Group A also had fewer complications than group B, especially regarding grade 3/4 complications according to Radiation Therapy Oncology Group grading criteria. Mean overall survival times in groups A and B were 17.1 and 14.8 months, respectively. CONCLUSION: CT-guided 125I brachytherapy is feasible and safe for distant oral and maxillofacial metastases; it achieved a better local control rate, longer LTPFS and fewer complications without compromising overall survival compared with EBRT. PMID- 27992833 TI - Assessment reactivity: A randomized controlled trial of alcohol-specific measures on alcohol-related behaviors. AB - INTRODUCTION: Completion of alcohol assessments influences treatment outcomes, yet little is known about the aspects of assessment that may contribute to this response. The present study is a randomized controlled trial examining how the themes of alcohol assessments (e.g., assessment of alcohol-related consequences as opposed to drinking patterns) may affect drinking behaviors. METHODS: Undergraduate students (N=290, Mage=19.97, SDage=1.81, 61.7% female), reporting at least one binge drinking episode during the past month, completed one of five baseline assessment batteries that varied thematically: (a) Control (e.g., minimal drinking quantity and frequency questions), (b) Consequences (e.g., College Alcohol Problems Scale; CAPS-r), (c) Norms (e.g., Drinking Norms Rating Form), (d) Diagnostic (e.g., Alcohol Use Disorders Identification Test), and (e) Combined (all themes). Participants completed a one-month follow-up of drinking quantity/frequency and the CAPS-r. RESULTS: All groups decreased their self reported peak drinks consumed (p<0.001, etap2=0.05) and past month frequency of drinking (p=0.002, etap2=0.03; except for the consequences group) from baseline to follow-up. There were no between-group differences. No changes emerged in drinks per week (p=0.09, etap2=0.01) or alcohol-related consequences (p=0.06, etap2=0.03) from baseline to follow-up. CONCLUSION: Minimal assessment of drinking quantity and frequency may result in assessment reactivity. Reductions in markers of risky drinking behaviors did not differ as a function of the type of assessments completed (e.g., Consequences vs Diagnostic). Continued research is needed to determine what other important variables (e.g., treatment seeking) may affect assessment reactivity. PMID- 27992834 TI - Modality shift effect in psychiatric disorders - a new look at an old paradigm. AB - BACKGROUND: There is a long tradition of reaction time studies in experimental psychopathology. Even though a diminishing interest in this paradigm has been seen over the last years, it is in line with more recent biological approaches to examine psychiatric disorders cross-diagnostically. METHODS: Patients (n=95) with a positive subtype of schizophrenia (n=22), a negative subtype of schizophrenia (n=18), a full major depressive episode (n=19), a full manic episode (n=16), or a mood disorder in remission (n=20) and subjects with no known psychiatric disorder (n=30), respectively, participated in a computer-based reaction time test consisting of four trials with 55 short visual and auditory stimuli presented in a random sequence. Each participant's median reaction time in milliseconds to light stimuli ipsimodal (light preceded by light) and cross-modal (light preceded by tone) and the difference between the two conditions (i.e. cross-modal retardation (CMR) to light) were recorded. Likewise, the median reaction time to tone stimuli ipsimodal and cross-modal and the difference between the two (CMR to tone) were recorded. RESULTS: Patient groups performed worse than the control group, with the exception of the group of patients with mood disorders in remission in both CMRs. When comparing patient groups, the schizophrenia negative subtype performed worse than the remission group in both CMRs. CONCLUSIONS: Our data support newer theories about underlying pathophysiological mechanisms and observable behavioural phenomena occurring across the different diagnostic categories, thereby supporting a dimensional approach in the diagnosis and clinical management. PMID- 27992835 TI - Self-reported problem behavior in young children with and without a DSM-disorder in the general population. AB - BACKGROUND: Problem behavior of young children is generally not assessed with structured child interviews. This paper examined how information about problem behavior, obtained by structured interviews with six-year-old children, relates to DSM-disorders obtained from parents and to treatment referral. METHODS: In a population-based cohort, caregivers of 1084 young children (mean age 6.7 years) were interviewed with the DSM-based Diagnostic Interview Schedule-Young Child version (DISC-YC), and they scored the Child Behavior Checklist (CBCL). Children themselves were interviewed about problem behavior using the semi-structured Berkeley Puppet Interview (BPI). Information regarding treatment referral to mental health services was obtained by parent-reported questionnaire when children were on average eight years old. RESULTS: DSM-disorders and CBCL problems in the clinical range were cross-sectionally associated with higher levels of child self-reported problems. Associations were strongest in the externalizing domain (e.g. DISC-YC externalizing disorders with BPI externalizing scores: F(1, 416)=19.39, P<0.001; DISC-YC internalizing disorders with BPI internalizing scores: F(1, 312)=3.75, P=0.054). Moreover, higher BPI internalizing and externalizing problem scores predicted treatment referral two years later. CONCLUSIONS: We conclude that systematically interviewing preschool and young elementary school-aged children should be an integral part of child assessment. This approach may contribute to a better understanding of child development and may predict future problems. PMID- 27992837 TI - Toxoplasma-infected subjects report an Obsessive-Compulsive Disorder diagnosis more often and score higher in Obsessive-Compulsive Inventory. AB - BACKGROUND: Latent toxoplasmosis, the life-long presence of dormant stages of Toxoplasma in immunoprivileged organs and of anamnestic IgG antibodies in blood, affects about 30% of humans. Infected subjects have an increased incidence of various disorders, including schizophrenia. Several studies, as well as the character of toxoplasmosis-associated disturbance of neurotransmitters, suggest that toxoplasmosis could also play an etiological role in Obsessive-Compulsive Disorder (OCD). METHODS: The aim of the present cross-sectional study performed on a population of 7471 volunteers was to confirm the association between toxoplasmosis and OCD, and toxoplasmosis and psychological symptoms of OCD estimated by the standard Obsessive-Compulsive Inventory-Revised (OCI-R). RESULTS: Incidence of OCD was 2.18% (n=39) in men and 2.28% (n=83) in women. Subjects with toxoplasmosis had about a 2.5 times higher odds of OCD and about a 2.7 times higher odds of learning disabilities. The incidence of 18 other neuropsychiatric disorders did not differ between Toxoplasma-infected and Toxoplasma-free subjects. The infected subjects, even the OCD-free subjects, scored higher on the OCI-R. LIMITATIONS: Examined subjects provided the information about their toxoplasmosis and OCD statuses themselves, which could result in underrating the strength of observed associations. CONCLUSIONS: The results confirmed earlier reports of the association between toxoplasmosis and OCD. They also support recent claims that latent toxoplasmosis is in fact a serious disease with many impacts on quality of life of patients. PMID- 27992836 TI - Deconstructing vulnerability for psychosis: Meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk. AB - BACKGROUND: Subjects at ultra high-risk (UHR) for psychosis have an enhanced vulnerability to develop the disorder but the risk factors accounting for this accrued risk are undetermined. METHOD: Systematic review of associations between genetic or environmental risk factors for psychosis that are widely established in the literature and UHR state, based on comparisons to controls. RESULTS: Forty four studies encompassing 170 independent datasets and 54 risk factors were included. There were no studies on association between genetic or epigenetic risk factors and the UHR state that met the inclusion criteria. UHR subjects were more likely to show obstetric complications, tobacco use, physical inactivity, childhood trauma/emotional abuse/physical neglect, high perceived stress, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level as compared to controls. CONCLUSIONS: The increased vulnerability of UHR subjects can be related to environmental risk factors like childhood trauma, adverse life events and affective dysfunction. The role of genetic and epigenetic risk factors awaits clarification. PMID- 27992838 TI - Posttraumatic stress and youth violence perpetration: A population-based cross sectional study. AB - BACKGROUND: Exposure to trauma was found to increase later violent behaviours in youth but the underlying psychopathological mechanisms are unclear. This study aimed to test whether posttraumatic stress disorder (PTSD) is related to violent behaviours and whether PTSD symptoms mediate the relationship between the number of trauma experiences and violent behaviours in adolescents. METHOD: The present study is based on a nationally representative sample of 9th grade students with 3434 boys (mean age=15.5 years) and 3194 girls (mean age=15.5 years) in Switzerland. Lifetime exposure to traumatic events and current PTSD were assessed by the use of the University of California at Los Angeles Posttraumatic Stress Disorder Reaction Index (UCLA-RI). Logistic regression was used to assess associations between PTSD and violent behaviours, and structural equation modelling (SEM) was used to examine the meditation effects of PTSD. RESULTS: PTSD (boys: OR=7.9; girls: OR=5.5) was strongly related to violent behaviours. PTSD symptoms partially mediated the association between trauma exposure and violent behaviours in boys but not in girls. PTSD symptoms of dysphoric arousal were positively related to violent behaviours in both genders. Anxious arousal symptoms were negatively related to violent behaviours in boys but not in girls. CONCLUSIONS: In addition to trauma, posttraumatic stress is related to violent outcomes. However, specific symptom clusters of PTSD seem differently related to violent behaviours and they do not fully explain a trauma-violence link. Specific interventions to improve emotion regulation skills may be useful particularly in boys with elevated PTSD dysphoric arousal in order to break up the cycle of violence. PMID- 27992839 TI - Psychosis prediction in secondary mental health services. A broad, comprehensive approach to the "at risk mental state" syndrome. AB - BACKGROUND: Accuracy of risk algorithms for psychosis prediction in "at risk mental state" (ARMS) samples may differ according to the recruitment setting. Standardized criteria used to detect ARMS individuals may lack specificity if the recruitment setting is a secondary mental health service. The authors tested a modified strategy to predict psychosis conversion in this setting by using a systematic selection of trait-markers of the psychosis prodrome in a sample with a heterogeneous ARMS status. METHODS: 138 non-psychotic outpatients (aged 17-31) were consecutively recruited in secondary mental health services and followed-up for up to 3 years (mean follow-up time, 2.2 years; SD=0.9). Baseline ARMS status, clinical, demographic, cognitive, and neurological soft signs measures were collected. Cox regression was used to derive a risk index. RESULTS: 48% individuals met ARMS criteria (ARMS-Positive, ARMS+). Conversion rate to psychosis was 21% for the overall sample, 34% for ARMS+, and 9% for ARMS-Negative (ARMS-). The final predictor model with a positive predictive validity of 80% consisted of four variables: Disorder of Thought Content, visuospatial/constructional deficits, sensory-integration, and theory-of-mind abnormalities. Removing Disorder of Thought Content from the model only slightly modified the predictive accuracy (-6.2%), but increased the sensitivity (+9.5%). CONCLUSIONS: These results suggest that in a secondary mental health setting the use of trait-markers of the psychosis prodrome may predict psychosis conversion with great accuracy despite the heterogeneity of the ARMS status. The use of the proposed predictive algorithm may enable a selective recruitment, potentially reducing duration of untreated psychosis and improving prognostic outcomes. PMID- 27992840 TI - Wide bandwidth fiber-optic ultrasound probe in MOMS technology: Preliminary signal processing results. AB - An ultrasonic probe consisting of two optical fiber-based miniaturized transducers for wideband ultrasound emission and detection is employed for the characterization of in vitro biological tissues. In the probe, ultrasound generation is obtained by thermoelastic emission from patterned carbon films in Micro-Opto-Mechanical-System (MOMS) devices mounted on the tip of an optical fiber, whereas acousto-optical detection is performed in a similar way by a miniaturized polymeric interferometer. The microprobe presents a wide, flat bandwidth that is a very attractive feature for ultrasonic investigation, especially for tissue characterization. Thanks to the very high ultrasonic frequencies obtained, the probe is able to reveal different details of the object under investigation by analyzing the ultrasonic signal within different frequencies ranges, as shown by specific experiments performed on a patterned cornstarch flour sample in vitro. This is confirmed by measurements executed to determine the lateral resolution of the microprobe at different frequencies of about 70MUm at 120MHz. Moreover, measurements performed with the wideband probe in pulsed-echo mode on a histological finding of porcine kidney are presented, on which two different spectral signal processing algorithms are applied. After processing, the ultrasonic spectral features show a peculiar spatial distribution on the sample, which is expected to depend on different ultrasonic backscattering properties of the analyzed tissues. PMID- 27992841 TI - Structural analyses of the nucleosome complexes with human testis-specific histone variants, hTh2a and hTh2b. AB - Th2a and Th2b are the testis-specific histone variants highly expressed during spermatogenesis. Approximately 4% of the genome is retained in nucleosomes in mature human sperm, which is enriched at loci of developmental importance. Our recent studies revealed that the mouse histone variant homologs TH2a and TH2b are involved in reprogramming. In the present work, we report three nucleosome structures (NCPs) with human testis-specific histone variants hTh2a and hTh2b, [hGcH (hTh2a-hTh2b-H3-H4), hGcHV1 (hTh2a-H2b-H3-H4) and hGcHV2 (H2a-hTh2b-H3-H4)] and a 146-base pair (bp) duplex DNA fragment at ~3.0A resolutions. These crystal structures revealed two major changes within the nucleosomes, either with hTh2a, hTh2b or both variants, as compared to the canonical counterpart. First, the H bonding interactions between the L1-L1' interfaces mediated by the hTh2a/hTh2a' L1-loops are lost. Second, the histone dimer-DNA contacts are considerably reduced, and these changes are localized around +/-31 to 35-bp from the nucleosome entry/exit sites. Thus, the modified functional residues at the N- and C-terminal ends of histone variants are responsible for the observed structural changes and regulate the gene expression through specific structural alterations in the chromatin by modulating the chromatin-associated binding proteins. PMID- 27992842 TI - Strain uncertainties from two digital volume correlation approaches in prophylactically augmented vertebrae: Local analysis on bone and cement-bone microstructures. AB - Combination of micro-focus computed tomography (micro-CT) in conjunction with in situ mechanical testing and digital volume correlation (DVC) can be used to access the internal deformation of materials and structures. DVC has been exploited over the past decade to measure complex deformation fields within biological tissues and bone-biomaterial systems. However, before adopting it in a clinically-relevant context (i.e. bone augmentation in vertebroplasty), the research community should focus on understanding the reliability of such method in different orthopaedic applications involving the use of biomaterials. The aim of this study was to evaluate systematic and random errors affecting the strain computed with two different DVC approaches (a global one, "ShIRT-FE", and a local one, "DaVis-DC") in different microstructures within augmented vertebrae, such as trabecular bone, cortical bone and cement-bone interdigitation. The results showed that systematic error was insensitive to the size of the computation sub volume used for the DVC correlation. Conversely, the random error (which was generally the largest component of error) was lower for a 48-voxel (1872micrometer) sub-volume (64-221 microstrain for ShIRT-FE, 88-274 microstrain for DaVis-DC), than for a 16-voxel (624micrometer) sub-volume (359-1203 microstrain for ShIRT-FE, 960-1771 microstrain for DaVis-DC) for the trabecular and cement regions. Overall, the local random error did not appear to be influenced by either bone microarchitecture or presence of biomaterial. For the 48-voxel sub-volume the global approach was less sensitive to the gradients in grey-values at the cortical surface (random error below 200 microstrain), while the local approach showed errors up to 770 microstrain. Mean absolute error (MAER) and standard deviation of error (SDER) were also calculated and substantially improved when compared to recent literature for the cement-bone interface. The multipass approach for DaVis-DC further reduced the random error for the largest volume of interest. The random error did not follow any recognizable pattern with the six strain components and only ShiRT-FE seemed to produce lower random errors in the normal strains. In conclusion this study has provided, for the first time, a preliminary indication of the reliability and limitations for the application of DVC in estimating the micromechanics of bone and cement-bone interface in augmented vertebrae. PMID- 27992843 TI - Statin use and kidney cancer survival outcomes: A systematic review and meta analysis. AB - BACKGROUND: Statin use has been associated with improved survival outcomes in various malignancies. Randomized controlled trials are currently underway evaluating their utility as adjunctive cancer therapies. However, studies evaluating the association between statin use and outcomes in kidney cancer yield conflicting results. METHODS: We searched MEDLINE and EMBASE to identify studies evaluating the association between statin use and kidney cancer survival outcomes. We evaluated risk of bias with the Newcastle-Ottawa Scale. We pooled hazard ratios for recurrence-free survival, progression-free survival, cancer specific survival, and overall survival using random-effects models. We evaluated publication bias through Begg's and Egger's tests, and the trim and fill procedure. RESULTS: We identified 12 studies meeting inclusion criteria and summarized data from 18,105 patients. No study was considered to be at high risk of bias. Statin use was not significantly associated with recurrence-free survival (pooled HR 0.97, 95% CI 0.89-1.06) or progression-free survival (pooled HR 0.92, 95% CI 0.51-1.65); however, statin use was associated with marked improvements in cancer-specific survival (pooled HR 0.67, 95% CI 0.47-0.94) and overall survival (pooled HR 0.74, 95% CI 0.63-0.88). There was no strong evidence of publication bias for any outcome. CONCLUSIONS: Our results demonstrate that statin use among patients with kidney cancer is associated with significantly improved cancer-specific and overall survival. Further studies are needed to confirm the therapeutic role of statins in kidney cancer. PMID- 27992844 TI - (Very) Early technology assessment and translation of predictive biomarkers in breast cancer. AB - Predictive biomarkers can guide treatment decisions in breast cancer. Many studies are undertaken to discover and translate these biomarkers, yet few biomarkers make it to practice. Before use in clinical decision making, predictive biomarkers need to demonstrate analytical validity, clinical validity and clinical utility. While attaining analytical and clinical validity is relatively straightforward, by following methodological recommendations, the achievement of clinical utility is extremely challenging. It requires demonstrating three associations: the biomarker with the outcome (prognostic association), the effect of treatment independent of the biomarker, and the differential treatment effect between the prognostic and the predictive biomarker (predictive association). In addition, economical, ethical, regulatory, organizational and patient/doctor-related aspects are hampering the translational process. Traditionally, these aspects do not receive much attention until formal approval or reimbursement of a biomarker test (informed by Health Technology Assessment (HTA)) is at stake, at which point the clinical utility and sometimes price of the test can hardly be influenced anymore. When HTA analyses are performed earlier, during biomarker research and development, they may prevent further development of those biomarkers unlikely to ever provide sufficient added value to society, and rather facilitate translation of the promising ones. Early HTA is particularly relevant for the predictive biomarker field, as expensive medicines are under pressure and the need for biomarkers to guide their appropriate use is huge. Closer interaction between clinical researchers and HTA experts throughout the translational research process will ensure that available data and methodologies will be used most efficiently to facilitate biomarker translation. PMID- 27992845 TI - PNIPAM grafted surfaces through ATRP and RAFT polymerization: Chemistry and bioadhesion. AB - Biomaterials surface design is critical for the control of materials and biological system interactions. Being regulated by a layer of molecular dimensions, bioadhesion could be effectively tailored by polymer surface grafting. Basically, this surface modification can be controlled by radical polymerization, which is a useful tool for this purpose. The aim of this review is to provide a comprehensive overview of the role of surface characteristics on bioadhesion properties. We place a particular focus on biomaterials functionalized with a brush surface, on presentation of grafting techniques for "grafting to" and "grafting from" strategies and on brush characterization methods. Since atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization are the most frequently used grafting techniques, their main characteristics will be explained. Through the example of poly(N-isopropylacrylamide) (PNIPAM) which is a widely used polymer allowing tuneable cell adhesion, smart surfaces involving PNIPAM will be presented with their main modern applications. PMID- 27992846 TI - Suicidal ideation and suicidal attempts among adults with chronic diseases: A cross-sectional study. AB - INTRODUCTION: About 14% of the global burden of disease has been attributed to neuropsychiatric disorders. The aim of this study was to show the general picture of suicidal ideation and behavior among Korean, and to test the hypothesis that there is a positive association between diseases and suicidality. METHOD: A total of 19,599 individuals were asked if they had any chronic diseases, suicidal ideation and attempts. The data from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V, 2010-2012) conducted by Korea Centers for Disease Control and Prevention (KCDC) were examined. RESULTS: Stroke and osteoarthritis were associated with a 1.81 and 1.27 times increase in the odds of suicidal ideation, respectively (95% CI=1.24-2.65; 95% CI=1.09-1.48). Angina pectoris and osteoarthritis were associated with a 3.88 and 2.09 times increase in the odds of suicide attempts (95% CI=1.78-8.43; 95% CI=1.24-3.55). Having pulmonary tuberculosis increased the odds of a suicide attempt 12-fold (OR=12.47, 95% CI=1.12-138.66). Having renal failure was associated with a 4.92 times increase in the odds of suicide attempts (95% CI=1.25-19.30). Having lung cancer or cervical cancer increased the odds of suicide attempts more than 10-fold (OR=11.53, 95% CI=1.03-128.80; OR=17.66, 95% CI=1.58-197.01). CONCLUSIONS: Various diseases were risk factors for suicidality. Physicians' communication skills for frank and clear discussions about suicidality should be developed through various training courses. PMID- 27992847 TI - Comparative studies of aerobic and anaerobic biodegradation of methylparaben and propylparaben in activated sludge. AB - The biodegradability of two typical parabens (methylparaben and propylparaben) in activated sludge, at initial concentrations of 1mgL-1 or 10mgL-1, was investigated under aerobic and anaerobic conditions. The results showed that microorganisms played a key role in degradation of parabens in WWTPs, especially in aerobic systems. The half-lives of methylparaben and propylparaben under aerobic conditions have been estimated to range between 15.8 and 19.8min, and benzoic acid was found to be one of the major biodegradation products. The calculated biodegradation efficiency of methylparaben and propylparaben in activated sludge under aerobic conditions was significantly higher than that observed under anaerobic (nitrate, sulfate, and Fe (III) reducing) conditions, as methylparaben and propylparaben exhibited comparatively higher persistence in anaerobic systems, with half-lives >=43.3h and >=8.6h, respectively. Overall, the results of this study imply that the majority of these parabens can be eliminated by aerobic biodegradation during conventional wastewater treatment processes, whereas minor removal is possible in anaerobic systems if an insufficient hydraulic retention time was maintained. PMID- 27992848 TI - Retinoid-like compounds produced by phytoplankton affect embryonic development of Xenopus laevis. AB - Teratogenic effects, which were remarkably similar to those induced by retinoic acids, have been seen in wild frogs indicating possible source of retinoids in the environment. Recent studies indicate that some cyanobacterial species can contain teratogenic retinoic acids (RAs) and their analogues. Retinoids are known to regulate important processes such as differentiation, development, and embryogenesis. The study investigated the effects of exudates (extracellular compounds) of two cyanobacteria species with retinoic-like activity and one algae species on embryonic development of amphibians. The retinoid-like activity determined by in vitro reporter gene assay reached 528ng retinoid equivalents (REQ)/L and 1000ng REQ/L in exudates of Cylindrospermopsis raciborskii and Microcystis aeruginosa, respectively, while algal exudates showed no detectable activity. Total mean of retinoid-like copounds into exudate was 35.6ng ATRA/mil.cells for M.aeruginosa and 6.71ng ATRA/mil.cells for C.raciborskii, respectively. Toxicity tests with amphibian embryos up to 96h of development were carried out according to the standard guide for the Frog Embryo Teratogenesis Assay Xenopus. Lowest observed effect concentrations (LOEC) of malformations (2.5 2.6ug/L REQ) were two times lower than LOEC for ATRA (5ug/L). The exudates of both cyanobacteria were indeed provoking diverse teratogenic effects (e.g. tail, gut and eyes deformation) and interference with growth in frogs embryos, while such effects were not observed for the algae. Xenopus embryos were also exposed to all-trans retinoic acid (ATRA) in concentration range (1-40ug/L) equivalent to the REQs detected in cyanobacterial exudates. ATRA (10ug/L) caused similar teratogenic phenotypes at corresponding REQs as cyanobacterial exudates. The study confirms the ability of some species of cyanobacteria to produce retinoids naturally and excrete them directly into the environment at concentrations which might have adverse influence on the development of amphibians. PMID- 27992849 TI - Motor neuron disease mortality and lifetime petrol lead exposure: Evidence from national age-specific and state-level age-standardized death rates in Australia. AB - BACKGROUND: The age standardized death rate from motor neuron disease (MND) for persons 40-84 years of age in the Australian States of New South Wales, Victoria, and Queensland increased dramatically from 1958 to 2013. Nationally, age-specific MND death rates also increased over this time period, but the rate of the rise varied considerably by age-group. The historic use of lead (Pb) additives in Australian petrol is a candidate explanation for these trends in MND mortality (International Classification of Disease (ICD)-10 G12.2). METHODS: Leveraging temporal and spatial variation in petrol lead exposure risk resulting from the slow rise and rapid phase-out of lead as a constituent in gasoline in Australia, we analyze relationships between (1) national age-specific MND death rates in Australia and age-specific lifetime petrol lead exposure, (2) annual between-age dispersions in age-specific MND death rates and age-specific lifetime petrol lead exposure; and (3) state-level age-standardized MND death rates as a function of age-weighted lifetime petrol lead exposure. RESULTS: Other things held equal, we find that a one percent increase in lifetime petrol lead exposure increases the MND death rate by about one-third of one percent in both national age-specific and state-level age-standardized models of MND mortality. Lending support to the supposition that lead exposure is a driver of MND mortality risk, we find that the annual between-age group standard deviation in age-specific MND death rates is strongly correlated with the between-age standard deviation in age-specific lifetime petrol lead exposure. CONCLUSION: Legacy petrol lead emissions are associated with age-specific MND death rates as well as state-level age standardized MND death rates in Australia. Results indicate that we are approaching peak lead exposure-attributable MND mortality. PMID- 27992850 TI - Quantification of upper body movements during gait in older adults and in those with Parkinson's disease: impact of acceleration realignment methodologies. AB - The upper body accelerations of people with Parkinson's disease (PD) measured by inertial measurement units (IMUs) may contribute towards diagnostic algorithms and help track disease progression. Before extracting variables related to upper body motion, acceleration signals require realignment to a global reference; however, the impact of these techniques on the resulting upper body variables is unclear. Therefore, the aim of this investigation was to examine the impact of four different realignment methods designed to correct acceleration signals on a range of upper body variables in older adults and in patients with PD. Two minutes of continuous gait were measured in 54 community-dwelling older adults (71.1+/-6.7 years) and 60 people with PD (age: 68.5+/-9.1 years). Three IMUs placed on the 5th lumbar vertebra, 7th cervical vertebra and the back of the head recorded the acceleration of the upper body. A selection of upper body variables sensitive to impaired upper body control in PD and four acceleration realignment methods were compared. A mixed-model ANOVA showed that the choice of realignment method significantly affected the values of upper body variables as well as their ability to discriminate between the PD and control group. Our findings indicate researchers and clinicians should be cautious when comparing upper body variables extracted from IMUs using different realignment methods, and consideration of realignment technique will be important when identifying the most sensitive markers of disease presence and progression. Therefore, it's strongly recommend that researchers consider and report their realignment methods when assessing upper body variables during gait. PMID- 27992851 TI - Sepsis as 2 problems: Identifying sepsis at admission and predicting onset in the hospital using an electronic medical record-based acuity score. AB - PURPOSE: Early identification and treatment improve outcomes for patients with sepsis. Current screening tools are limited. We present a new approach, recognizing that sepsis patients comprise 2 distinct and unequal populations: patients with sepsis present on admission (85%) and patients who develop sepsis in the hospital (15%) with mortality rates of 12% and 35%, respectively. METHODS: Models are developed and tested based on 258 836 adult inpatient records from 4 hospitals. A "present on admission" model identifies patients admitted to a hospital with sepsis, and a "not present on admission" model predicts postadmission onset. Inputs include common clinical measurements and the Rothman Index. Sepsis was determined using International Classification of Diseases, Ninth Revision, codes. RESULTS: For sepsis present on admission, area under the curves ranged from 0.87 to 0.91. Operating points chosen to yield 75% and 50% sensitivity achieve positive predictive values of 17% to 25% and 29% to 40%, respectively. For sepsis not present on admission, at 65% sensitivity, positive predictive values ranged from 10% to 20% across hospitals. CONCLUSIONS: This approach yields good to excellent discriminatory performance among adult inpatients for predicting sepsis present on admission or developed within the hospital and may aid in the timely delivery of care. PMID- 27992852 TI - Paracetamol in fever in critically ill patients-an update. AB - Fever, which is arbitrary defined as an increase in body temperature above 38.3 degrees C, can affect up to 90% of patients admitted in intensive care unit. Induction of fever is mediated by the release of pyrogenic cytokines (tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferons). Fever is associated with increased length of stay in intensive care unit and with a worse outcome in some subgroups of patients (mainly neurocritically ill patients). Although fever can increase oxygen consumption in unstable patients, on the contrary, it can activate physiologic systems that are involved in pathogens clearance. Treatments to reduce fever include the use of antipyretics. Thus, the reduction of fever might reduce the ability to develop an efficient host response. This balance, between harms and benefits, has to be taken into account every time we decide to treat or not to treat fever in a given patient. Among the antipyretics, paracetamol is one of the most common used. Paracetamol is a synthetic, nonopioid, centrally acting analgesic, and antipyretic drug. Its antipyretic effect occurs because it inhibits cyclooxygenase-3 and the prostaglandin synthesis, within the central nervous system, resetting the hypothalamic heat-regulation center. In this clinical review, we will summarize the use of paracetamol as antipyretic in critically ill patients (sepsis, trauma, neurological, and medical). PMID- 27992853 TI - CLOCK gene variants associated with the discrepancy between subjective and objective severity in bipolar depression. AB - BACKGROUND: The discrepancy between subjective and objective severity of depressive syndromes has been proposed as a predictor of treatment outcome and suicidal risk in depression, and is associated with depressive cognitive distortions. A recent study reported that evening-type depressed patients showed higher depressive cognitions than morning-type patients. Therefore, it can be hypothesized that genetic factors affecting evening preference, such as carrying of the CLOCK rs1801260*C allele, may influence the discrepancy. METHOD: We tested this hypothesis in 132 patients affected by a major depressive episode in the course of bipolar disorder. The severity of depression was evaluated using self rated (Beck Depression Inventory: BDI) and observer-rated (Hamilton Depression Rating Scale: HDRS) measures. The BDI-HDRS discrepancy score was calculated and the effects of the rs1801260 polymorphism on this score and on depressive cognitive distortions, as measured on the Cognitions Questionnaire, were examined. RESULTS: The rs1801260*C carriers showed higher BDI-HDRS discrepancy scores than T/T homozygotes. Mediation analysis using bootstrapping procedures revealed that the dimension of depressive cognition "hopelessness" fully mediates the association between the rs1801260 polymorphism and the BDI-HDRS discrepancy. LIMITATIONS: Many gene polymorphisms other than CLOCK rs1801260 may also influence the BDI-HDRS discrepancy and depressive cognitive distortions. CONCLUSION: Our current results suggest that factors affecting the biological clock can influence the "non-clock" psychopathological features of mood disorders. PMID- 27992854 TI - Differential associations of affective temperaments and diagnosis of major affective disorders with suicidal behavior. AB - BACKGROUND: Affective temperaments are associated with suicidal risk, but their predictive value relative to diagnosis of major affective disorder is uncertain. METHODS: We compared diagnoses, affective-temperament ratings (TEMPS-A), and other potential risk factors in 956 psychiatric inpatients, using bivariate analyses and multivariable logistic regression modeling for associations with suicidal status. RESULTS: Lifetime suicide-attempt rates were high (43.9% overall), ranking by diagnosis: bipolar-II (58.4%), major depressive (50.0%), bipolar-I (44.6%), other (38.0%), and psychotic (33.9%) disorders. TEMPS-A scores for depressive (dep), cyclothymic (cyc), irritable (irr), and anxious (anx) temperaments and their sum were strongly associated with suicidal risk; hyperthymic (hyp) temperament scores were inversely associated; and a composite measure (dep+cyc+irr+anx - hyp), even more strongly associated. The composite score was highly, independently associated with suicidal behavior (p<0.0001), as was female sex (p=0.0002), but older age and diagnosis of major affective disorder, much less (both p=0.02). CONCLUSIONS: Measures of affective temperament types were independently and more strongly associated with lifetime suicide attempt than was diagnosis of a major affective disorder. However, in this hospitalized cohort, suicide rates were high across diagnoses, possibly limiting the predictive value of diagnosis. PMID- 27992855 TI - Amplified detection of leukemia cancer cells using an aptamer-conjugated gold coated magnetic nanoparticles on a nitrogen-doped graphene modified electrode. AB - The increasing demands for early, accurate and ultrasensitive diagnosis of cancers demonstrate the importance of the development of new amplification strategies or diagnostic technologies. In the present study, an aptamer-based electrochemical biosensor for ultrasensitive and selective detection of leukemia cancer cells has been introduced. The thiolated sgc8c aptamer was immobilized on gold nanoparticles-coated magnetic Fe3O4 nanoparticles (Apt-GMNPs). Ethidium bromide (EB), intercalated into the stem of the aptamer hairpin, provides the read-out signal for the quantification of the leukemia cancer cells. After introduction of the leukemia cancer cells onto the Apt-GMNPs, the hairpin structure of the aptamer is disrupted and the intercalator molecules are released, resulting in a decrease of the electrochemical signal. The immobilization of nitrogen-doped graphene nanosheets on the electrode surface provides an excellent platform for amplifying the read-out signal. Under optimal conditions, the aptasensor exhibits a linear response over a wide dynamic range of leukemia cancer cells from 10 to 1*106cellmL-1. The present protocol provides a highly sensitive, selective, simple, and robust method for early stage detection of leukemia cancer. Furthermore, the fabricated aptasensor was successfully used for the detection of leukemia cancer cells in complex media such as human blood plasma, without any serious interference. PMID- 27992856 TI - Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis. AB - Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-beta signaling. Similar to TGF-beta1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes. PMID- 27992857 TI - TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin. AB - Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2 Hydroxypropyl-beta-cyclodextrin (HPbetaCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. PMID- 27992858 TI - Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans. AB - Protein aggregation increases with age in normal tissues, and with pathology and age in Alzheimer's hippocampus and mouse cardiac muscle. We now ask whether human skeletal muscle accumulates aggregates with age. Detergent-insoluble protein aggregates were isolated from vastus lateralis biopsies from 5 young (23-27 years of age) and 5 older (64-80 years) adults. Aggregates, quantified after gel electrophoresis, contain 2.1-fold more protein (P<0.0001) when isolated from older subjects relative to young. Of 515 proteins identified by liquid chromatography coupled to tandem mass spectrometry, 56 (11%) were significantly more abundant in older muscle, while 21 (4%) were depleted with age (each P<0.05). Orthologs to seven of these proteins were then targeted in C. elegans by RNA interference. Six of the seven knockdown treatments decreased protein aggregation (range 6-45%, P<0.01 to <0.0001) and increased muscle mass (range 1.5 to 1.85-fold, P<0.01 to <0.0001) in aged nematodes, and rescued mobility (range 1.4 to 1.65-fold, P<=0.0005 each) in a nematode amyloidopathy model. We conclude that specific aggregate proteins, discovered as differentially abundant in aging human muscle, have orthologs that contribute functionally to aggregation and age associated muscle loss in nematodes, and thus can be considered potential drug targets for sarcopenia in humans. PMID- 27992859 TI - Altered stoichiometry and nuclear delocalization of NonO and PSF promote cellular senescence. AB - While cellular senescence is a critical mechanism to prevent malignant transformation of potentially mutated cells, persistence of senescent cells can also promote cancer and aging phenotypes. NonO/p54nrb and PSF are multifunctional hnRNPs typically found as a complex exclusively within the nuclei of all mammalian cells. We demonstrate here that either increase or reduction of expression of either factor results in cellular senescence. Coincident with this, we observe expulsion of NonO and PSF-containing nuclear paraspeckles and posttranslational modification at G2/M. That senescence is mediated most robustly by overexpression of a cytoplasmic C-truncated form of NonO further indicated that translocation of NonO and PSF from the nucleus is critical to senescence induction. Modulation of NonO and PSF expression just prior to or coincident with senescence induction disrupts the normally heterodimeric NonO-PSF nuclear complex resulting in a dramatic shift in stoichiometry to heterotetramers and monomer with highest accumulation within the cytoplasm. This is accompanied by prototypic cell cycle checkpoint activation and chromatin condensation. These observations identify yet another role for these multifunctional factors and provide a hitherto unprecedented mechanism for cellular senescence and nuclear-cytoplasmic trafficking. PMID- 27992861 TI - How Much Nutrition for How Much Growth??. AB - BACKGROUND/AIMS: Increasing agreement exists about the use of length-for-age as the indicator of choice in monitoring the long-term impact of chronic nutritional deficiency. Yet, already shortly after World War I, a causal link between nutrition and growth was questioned. Also, modern meta-analyses of controlled nutrition intervention studies show that the net effect of nutrition on body height is small. Broad evidence obtained from historic observations on human starvation made since the 19th century questions an obligatory association between nutrition and growth. Many additional explanations for the apparent shortness of people from developing countries have been published since, focusing on genetic factors, environment, economy, epigenetics, and, recently, psychosocial factors, such as strategic growth adjustments suggesting stature to be a social signal. CONCLUSION: The marked variability in average population height of up to 20 cm within a few generations complicates the use of normative growth charts, even though they have been widely propagated. We support the concept of local growth references, for example using the "Synthetic Growth References" methodology. These references combine local growth information obtained from a given population of interest and common features of human population growth, with LMS values for height, weight, and BMI from birth to maturity.?. PMID- 27992862 TI - Endobronchial Valves for Endoscopic Lung Volume Reduction: Best Practice Recommendations from Expert Panel on Endoscopic Lung Volume Reduction. AB - Endoscopic lung volume reduction (ELVR) is being adopted as a treatment option for carefully selected patients suffering from severe emphysema. ELVR with the one-way endobronchial Zephyr valves (EBV) has been demonstrated to improve pulmonary function, exercise capacity, and quality of life in patients with both heterogeneous and homogenous emphysema without collateral ventilation. In this "expert best practices" review, we will highlight the practical aspects of this therapy. Key selection criteria for ELVR are hyperinflation with a residual volume >175% of predicted, forced expiratory volume <50% of predicted, and a 6 min walking distance >100 m. Patients with repeated infectious complications, severe bronchiectasis, and those with unstable cardiovascular comorbidities should be excluded from EBV treatment. The procedure may be performed with either conscious sedation or general anesthesia and positive pressure mechanical ventilation using a flexible endotracheal tube or a rigid bronchoscope. Chartis and EBV placement should be performed in 1 procedure when possible. The sequence of valve placement should be orchestrated to avoid obstruction and delivery of subsequent valves. If atelectasis has not occurred by 1 month after procedure, evaluate valve position on CT and consider replacing the valves that are not optimally positioned. Pneumothorax is a common complication and typically occurs in the first 2 days following treatment. A management algorithm for pneumothorax has been previously published. Long-term sequelae from EBV therapy do occur but are easily manageable. PMID- 27992860 TI - Proteomic profiling of mitochondria: what does it tell us about the ageing brain? AB - Mitochondrial dysfunction is evident in numerous neurodegenerative and age related disorders. It has also been linked to cellular ageing, however our current understanding of the mitochondrial changes that occur are unclear. Functional studies have made some progress reporting reduced respiration, dynamic structural modifications and loss of membrane potential, though there are conflicts within these findings. Proteomic analyses, together with functional studies, are required in order to profile the mitochondrial changes that occur with age and can contribute to unravelling the complexity of the ageing phenotype. The emergence of improved protein separation techniques, combined with mass spectrometry analyses has allowed the identification of age and cell-type specific mitochondrial changes in energy metabolism, antioxidants, fusion and fission machinery, chaperones, membrane proteins and biosynthesis pathways. Here, we identify and review recent data from the analyses of mitochondria from rodent brains. It is expected that knowledge gained from understanding age-related mitochondrial changes of the brain should lead to improved biomarkers of normal ageing and also age-related disease progression. PMID- 27992863 TI - Effects of High Density Lipoprotein Raising Therapies on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus, with or without Renal Impairment: The Action to Control Cardiovascular Risk in Diabetes Study. AB - BACKGROUND: The role of high density lipoprotein-raising interventions in addition to statin therapy in patients with diabetes remains controversial. Chronic kidney disease (CKD) is a strong modifier of cardiovascular (CV) outcomes. We therefore investigated the impact of CKD status at baseline on outcomes in patients with diabetes randomized to standard statin or statin plus fenofibrate treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. METHODS: Among 5,464 participants in the ACCORD lipid trial, 3,554 (65%) were free of CKD at baseline, while 1,910 (35%) had mild to moderate CKD. Differences in CV outcomes during follow-up between CKD and non-CKD subgroups were examined. In addition, the effect of fenofibrate as compared to placebo on CV outcomes was examined for both subgroups. RESULTS: All CV outcomes were 1.4-3 times higher among patients with CKD as compared to non-CKD patients. In patients with CKD, the addition of fenofibrate had no effect on any of the primary or secondary outcomes. In patients without CKD, however, the addition of fenofibrate was associated with a significant 36% reduction of CV mortality (hazards ratio [HR] 0.64; 95% CI 0.42-0.97; p value for treatment interaction <0.05) and 44% lower rate of fatal or non-fatal congestive heart failure (CHF; HR 0.56; 95% CI 0.37-0.84; p value treatment interaction <0.03). CONCLUSIONS: For patients with type 2 diabetes at high CV risk but no CKD, fenofibrate therapy added to statin reduced the CV mortality and the rate of fatal and non-fatal CHF. PMID- 27992864 TI - Longer Duration of Sleep and Risk of Cognitive Decline: A Meta-Analysis of Observational Studies. AB - BACKGROUND: Previous observational epidemiological studies have reported inconsistent findings about the association between longer durations of sleep and the risk of cognitive impairment and dementia. To investigate the association between longer durations of sleep and the risk of cognitive decline, we performed a meta-analysis of observational studies. METHODS: We searched PubMed, EMBASE, and the bibliographies of relevant articles to retrieve additional studies in July 2015. A total of 53,942 participants (mean age 66.9 years) were included in the final analysis. Three evaluators independently reviewed and selected articles, based on pre-determined selection criteria. RESULTS: Among a total of 695 articles, 10 observational epidemiological studies with 3 case-control studies and 7 cohort studies were included in the final analysis. Compared to the average sleep duration, the odds ratio or relative risk of the longest sleep duration was 1.42 (95% CI 1.27-1.59) for cognitive decline in the fixed-effect meta-analysis, 1.38 for cognitive impairment (95% CI 1.23-1.56), and 1.42 for dementia (95% CI 1.15-1.77). Subgroup meta-analyses by various factors such as study design, type of cognitive decline, gender, region, age, and methodological quality of study showed consistent findings. CONCLUSION: The current meta analysis found that longer duration of sleep is associated with an increased risk of cognitive decline. PMID- 27992865 TI - A Current Estimation of the Early Risk of Stroke after Transient Ischemic Attack: A Systematic Review and Meta-Analysis of Recent Intervention Studies. AB - OBJECTIVE: Recent studies have demonstrated that there is a decrease in the risk of subsequent stroke after transient ischemic attack (TIA) when urgent care (UC) is administered. However, no meta-analysis has been developed with contemporaneous TIA studies. We perform a systematic review and a meta-analysis to establish the risk of early stroke recurrence (SR) considering data from studies that offered UC to TIA patients. METHODS: We searched for studies, without language restriction, from January 2007 to January 2015 according to PRISMA guidelines. We included studies with TIA patients who underwent UC and reported the proportion of SR at 90 days. We excluded studies that were centered on less than 100 patients and cohorts including both stroke and TIA, if stroke risk after TIA was not described. For its relevance, we included the TIAregistry.org study published in 2016. We performed both fixed and random effects meta-analyses to determine SR and assess sources of heterogeneity. RESULTS: From 4,103 identified citations, we selected 15 papers that included 14,889 patients. There was great variation in terms of the number of patients included in each study, ranging from 115 to 4,160. Seven studies were TIA clinic based. The mean age and the percentage of men were similar among studies, ranging from 62.4 to 73.1 years and 45.1-62%, respectively. The reported risk of stroke ranged from 0 to 1.46% 2 days after TIA (9 studies included), 0-2.55% 7 days after TIA (11 studies included), 1.91-2.85% 30 days after TIA (4 studies included), and 0.62-4.76% 90 days after TIA (all studies included). The pooled stroke risk was 3.42% (95% CI 3.14-3.74) at 90 days, 2.78% (95% CI 2.47-3.12) at 30 days, 2.06% (95% CI 1.83-2.33) at 7 days and 1.36% (95% CI 1.15-1.59) at 2 days. Although we did not find statistically significant heterogeneity in SR among studies, those with a higher proportion of patients with motor weakness had a significantly higher risk of SR. No statistically significant association was observed between TIA clinic management and SR. CONCLUSION: The pooled early SR is lower than in previous meta-analyses and homogeneous for all studies with an urgent assessment and management strategy regardless of vascular risk factors and clinical characteristics. Therefore, the best setting for TIA management can be individualized for each center. PMID- 27992866 TI - Lost Productivity in Stroke Survivors: An Econometrics Analysis. AB - BACKGROUND: Stroke leads to a substantial societal economic burden. Loss of productivity among stroke survivors is a significant contributor to the indirect costs associated with stroke. We aimed to characterize productivity and factors associated with employability in stroke survivors. METHODS: We used the Canadian Community Health Survey 2011-2012 to identify stroke survivors and employment status. We used multivariable logistic models to determine the impact of stroke on employment and on factors associated with employability, and used Heckman models to estimate the effect of stroke on productivity (number of hours worked/week and hourly wages). RESULTS: We included data from 91,633 respondents between 18 and 70 years and identified 923 (1%) stroke survivors. Stroke survivors were less likely to be employed (adjusted OR 0.39, 95% CI 0.33-0.46) and had hourly wages 17.5% (95% CI 7.7-23.7) lower compared to the general population, although there was no association between work hours and being a stroke survivor. We found that factors like older age, not being married, and having medical comorbidities were associated with lower odds of employment in stroke survivors in our sample. CONCLUSIONS: Stroke survivors are less likely to be employed and they earn a lower hourly wage than the general population. Interventions such as dedicated vocational rehabilitation and policies targeting return to work could be considered to address this lost productivity among stroke survivors. PMID- 27992867 TI - Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence. AB - We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone's most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M1, M3, and M5 receptors. Furthermore, the quaternary analog N-ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone also modulates Gq-mediated responses at M1 and M3, although in a more discriminating manner. For example, dronedarone markedly enhances pilocarpine-stimulated release of arachidonic acid from CHO cells, via the M3 receptor subtype, but does not affect the acetylcholine stimulated response. Such probe-dependent effects are diagnostic of an allosteric interaction. In comparison to these effects at M3, dronedarone is strongly inhibitory toward both pilocarpine and acetylcholine at the M1 subtype. The effects of dronedarone are consistent with an interaction at the amiodarone site: dronedarone inhibits the enhancement of acetylcholine's response produced by amiodarone at the M3 subtype; also, NEA reverses the enhancement of pilocarpine's response at M3 produced by either dronedarone or amiodarone. In studies with the M1-selective allosteric agonist 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H benzo[1,4]oxazin-3-one (AC-260584), amiodarone enhanced the maximal response observed, whereas dronedarone was inhibitory. On the other hand, benzyl quinolone carboxylic acid, the well-known allosteric ligand that dramatically enhances the potency of acetylcholine at the M1 subtype, had no effect on the response profile of AC-260584. In summary, dronedarone acts at M1 and M3 muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site. PMID- 27992868 TI - Do Abrasives Play a Role in Toothpaste Efficacy against Erosion/Abrasion? AB - Abrasives may counteract the efficacy of anti-erosion toothpastes either due to physical effects or due to interaction with active agents. This study aimed to investigate whether the amount of abrasives is a determinant for the efficacy of Sn2+-containing toothpastes with or without chitosan additive. Enamel samples were eroded (0.50 wt% citric acid, pH 2.5; 6 * 2 min/day) on a shaking desk - 30/min in experiment 1 (E1) and 35/min in experiments 2 (E2) and 3 (E3) - and immersed in toothpaste slurries (2 * 2 min). Half of the samples were additionally brushed (15 s, load 200 g) within the immersion time. The toothpastes contained 0, 5, 10, 15, and 20% silica. In E1 and E2 the active ingredients were F- (700 ppm as amine fluoride, 700 ppm as NaF) and Sn2+ (3,500 ppm as SnCl2); in E3 chitosan (0.5%) was additionally added. The placebo contained 20% silica. Tissue loss was determined profilometrically. In E1, slurries completely inhibited tissue loss; distinct surface deposits occurred. With brushing, tissue loss significantly increased up to an abrasive content of 10%, but decreased significantly with higher amounts; 20% silica revealed similar values as the abrasive-free formulation. In E2, all slurries inhibited tissue loss distinctly irrespective of the amounts of abrasives. With brushing, a similar trend as in E1 was observed but with much less efficacy. The chitosan containing formulations in E3 were much more effective; similar results as in E1 were found. In conclusion, the amount of abrasives had no effect when toothpastes were applied as slurries, but played an important role with brushing. PMID- 27992869 TI - The Contribution of Small-Airway Abnormalities in Chronic Obstructive Pulmonary Disease Clinical Manifestations: More than a Functional Issue. PMID- 27992870 TI - Gamma Knife Radiosurgery of Brainstem Cavernous Malformations. AB - BACKGROUND/AIMS: Our study aimed to evaluate the efficiency and morbidity of Gamma Knife radiosurgery (GKS) in the treatment of hemorrhagic brainstem cavernous malformations (CMs). METHODS: We included in this study all patients who underwent GKS for the treatment of a hemorrhagic brainstem CM(s) in our institution between January 2007 and December 2012. The GKS was privileged when the surgical procedure was evaluated as very risky. The mean dose of radiation was 14.8 Gy, and the mean target volume was 0.282 cm3. All patients participated in a scheduled clinical follow-up. The posttreatment MRI was performed after 6 months and after 1 year, and then all patients had an annual MRI follow-up. RESULTS: There were 19 patients with a mean age of 36.7 years. The mean follow-up period was 51.2 months. The annual hemorrhage rate (AHR) was 27.31% before GKS, 2.46% during the first 2 years following the GKS, and 2.46% after the first 2 years following the GKS. The decrease in AHR after GKS was significant (p < 0.001). CONCLUSION: GKS should be suggested when the surgical procedure harbors a high risk of neurological morbidity in patients with brainstem CM. Compared to prior literature results, a lower dose than applied in this study could be discussed. PMID- 27992871 TI - ERBB2 Expression as Potential Risk-Stratification for Early Cystectomy in Patients with pT1 Bladder Cancer and Concomitant Carcinoma in situ. AB - : Background/Aims/Objectives: It is difficult to identify patients with a non muscle-invasive bladder cancer (NMIBC) at stage pT1 with concomitant carcinoma in situ (Cis) who will benefit from an early cystectomy. METHODS: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues of patients with NMIBC. Messenger ribonucleic acid (mRNA) expression of progesterone receptor (PGR), estrogen receptor (ESR1), ERBB2, and marker of proliferation Ki-67 (MKI67) was measured by single-step reverse transcription quantitative real-time polymerase chain reaction using RNA-specific TaqMan assays. Relative gene expression was determined by the normalization of 2 reference genes (CALM2, B2M) using the 40 DeltaDeltaCT method and relative gene expression was correlated to the histopathological stage and oncological outcome. RESULTS: Of 302 patients with pT1 NMIBC in the initial transurethral resection of the bladder, 65 had a concomitant Cis. Elevated ERBB2 expression (>40.1) significantly correlated with progress in patients with and without concomitant Cis (p = 0.020 and p = 0.049, respectively). For the subgroup of pT1 with concomitant Cis, elevated ERBB2 expression significantly discriminated between a high-risk group of 55% progression-free survival (PFS) and a low-risk group of 90% PFS after a 5-year follow-up (p = 0.020). Cox-regression analysis revealed ERBB2 expression as the only independent prognostic factor for PFS (p = 0.0037). CONCLUSIONS: High mRNA expression of ERBB2 can identify patients with pT1 NMIBC with concomitant Cis, who have a high risk of progression and might benefit from an early cystectomy. PMID- 27992872 TI - Long-Term Anatomical and Functional Outcomes after Combined Cataract and Idiopathic Epiretinal Membrane Surgery. AB - PURPOSE: To describe the 2-year functional and anatomical outcomes in patients operated on for combined cataract and idiopathic epiretinal membrane (ERM) and to study the relationship between best-corrected visual acuity (BCVA) and spectral domain optical coherence tomography (SD-OCT) throughout the follow-up. METHODS: This retrospective observational case series included 72 eyes operated on for combined cataract and idiopathic ERM. They were followed with clinical and SD-OCT examinations preoperatively and 1, 6, 12, and 24 months after surgery. Foveolar thickness (FT), photoreceptor status and morphological parameters were assessed. RESULTS: BCVA and FT substantially improved at 24 months. Postoperatively, no significant improvement was observed beyond 6 months for BCVA and 12 months for FT. Outer limiting membrane and inner and outer segment junction disruption scores were well correlated with BCVA both pre- and postoperatively, and significant visual improvement was demonstrated in each subgroup except in those with the highest scores. FT was correlated with BCVA only from 6 to 24 months postoperatively. CONCLUSION: After combined cataract and idiopathic ERM surgery, BCVA and FT improved rapidly. Most functional and anatomical recovery took place within the first 6 months, but this did not preclude late improvement, in particular in patients with the most disorganized photoreceptor layers. At each time point, the amount of photoreceptor damage seemed closely correlated with visual acuity, but concerning FT, this relationship remains questionable. PMID- 27992873 TI - MMP20 rs1784418 Protects Certain Populations against Caries. AB - This work aimed to further evaluate the association of MMP20 rs1784418 C>T and dental caries experience with the hypothesis that MMP20 rs1784418 C>T is a risk factor for dental caries. 184 children 4-7 years of age had their caries experience determined and buccal cheek swabs collected for DNA extraction to test for association with the MMP20 rs1784418 C>T using standard statistical approaches. A meta-analytic approach was also implemented to compile previous discrepant reports of the same association. We found an association between MMP20 rs1784418 C>T and dental caries experience in primary dentition (p = 0.01). The meta-analysis showed that this association appears to favor individuals born in Brazil and not Turkey. MMP20 rs1784418 C>T appears to protect against dental caries, but its effects are likely to be more marked in certain populations. PMID- 27992874 TI - Differential Expression of Lipoprotein-Associated Phospholipase A2 in Monocyte Subsets: Impact of Uremia and Atherosclerosis. AB - BACKGROUND: Monocytic products, such as lipoprotein-associated phospholipase A2 (Lp-PLA2), may participate in the development of atherosclerosis. Heterogeneity of monocytes is widely acknowledged. Classical, intermediate, and non-classical subsets can be discerned. Recently, an inflammatory, pro-atherogenic monocyte population could be identified in hemodialysis patients. In this study, we investigated the expression of Lp-PLA2 on leucocytes and different monocyte subpopulations and their possible role in uremia, inflammation, and atherosclerosis. METHODS: Chronic kidney disease stage 5-D (CKD5-D; n = 57), healthy control subjects with hs-C-reactive protein (CRP) levels <=1 mg/L (CO-N, n = 22) and a control group with inflammatory activation (CRP levels >1 mg/L, CO I, n = 29) were enrolled in this cross-sectional observation. The CKD5-D cohort was dichotomized into patients with (A+) and without subclinical atherosclerosis (A-) by carotid artery ultrasound measurement. Lp-PLA2 activity was determined in plasma samples, Lp-PLA2 mRNA expression analysis in leucocytes, and sorted monocyte subsets. Effects of Lp-PLA2 overexpression were studied in classical vs. intermediate and non-classical subsets. RESULTS: The classical monocytes expressed the highest Lp-PLA2 mRNA levels as compared to other subpopulations. CKD5-D patients revealed significantly higher Lp-PLA2 transcripts, as well as higher Lp-PLA2 plasma activity as compared to healthy and "inflammatory" controls. In vitro data confirmed that uremia significantly contributes to Lp PLA2 mRNA upregulation. Non-classical monocytes of A+ patients revealed significant higher Lp-PLA2 mRNA compared to A-. CONCLUSION: Uremic environment but not inflammation per se increases plasma Lp-PLA2 activity and upregulates monocytic Lp-PLA2 mRNA expression. The highest Lp-PLA2 levels were found in the classical and not in the inflammatory subsets. Atherosclerosis also contributes to a subset-specific increase in Lp-PLA2 mRNA expression. PMID- 27992875 TI - Calf Resistivity Values in Chronic Kidney Disease in a Caucasian Population. AB - BACKGROUND: Continuous intradialytic calf bioimpedance spectroscopy (cBIS) allows assessment of changes in calf extracellular fluid volume (ECV) to determine dry weight (DW) in hemodialysis patients. During dialysis, calf ECV decreases until excessive ECV has been removed and normalized resistivity rhoN,5 rises to values comparable to those of a normal population (cBIS-DW). It is not clear whether chronic kidney disease (CKD) itself influences rhoN,5 and whether normal values depend on race and ethnicity. METHODS: Therefore, we determined rhoN,5 in 2 populations consisting of 35 healthy Caucasians and 37 with CKD in KDIGO stages G2-G4. Calf resistivity was determined using a bioimpedance spectrum analyzer (Xitron Technologies, San Diego, CA, USA) and was normalized for body mass index. RESULTS: rhoN,5 was significantly higher in healthy subjects than in CKD patients (males: 18.2 +/- 2.2 vs. 15.0 +/- 2.8 * 10-2.Omegam3kg-1, p < 0.001; females: 19.7 +/- 3.2 vs. 16.4 +/- 3.3 * 10-2.Omegam3kg-1, p = 0.009). rhoN,5 in Caucasians was significantly lower than in previously examined North American healthy subjects with prevailing African American race or Hispanic ethnicity (males: 18.2 +/- 2.2 vs. 20.5 +/- 2.0 * 10-2.Omegam3kg-1, p < 0.001; females: 19.7 +/- 3.2 vs. 21.7 +/- 2.6 * 10-2.Omegam3kg-1, p = 0.026). CONCLUSION: We present the first determination of rhoN,5 values in a Caucasian healthy as well as a non-dialysis dependent CKD population. Both groups differ significantly. Due to higher amounts of extracellular water, subclinical fluid overload already occurs in pre-dialysis stages of CKD. rhoN,5 in Caucasians differs significantly from previously established normal ranges in other races/ethnicities. Population based reference ranges should be established and used in the future to determine DW by means of cBIS. PMID- 27992876 TI - Planetary science: Frozen in darkness. PMID- 27992878 TI - Aromatic and antiaromatic ring currents in a molecular nanoring. AB - Aromatic and antiaromatic molecules-which have delocalized circuits of [4n + 2] or [4n] electrons, respectively-exhibit ring currents around their perimeters. The direction of the ring current in an aromatic molecule is such as to generate a magnetic field that opposes the external field inside the ring (a 'diatropic' current), while the ring current in an antiaromatic molecule flows in the reverse direction ('paratropic'). Similar persistent currents occur in metal or semiconductor rings, when the phase coherence of the electronic wavefunction is preserved around the ring. Persistent currents in non-molecular rings switch direction as a function of the magnetic flux passing through the ring, so that they can be changed from diatropic ('aromatic') to paratropic ('antiaromatic') simply by changing the external magnetic field. As in molecular systems, the direction of the persistent current also depends on the number of electrons. The relationship between ring currents in molecular and non-molecular rings is poorly understood, partly because they are studied in different size regimes: the largest aromatic molecules have diameters of about one nanometre, whereas persistent currents are observed in microfabricated rings with diameters of 20 1,000 nanometres. Understanding the connection between aromaticity and quantum coherence effects in mesoscopic rings provides a motivation for investigating ring currents in molecules of an intermediate size. Here we show, using nuclear magnetic resonance spectroscopy and density functional theory, that a six porphyrin nanoring template complex, with a diameter of 2.4 nanometres, is antiaromatic in its 4+ oxidation state (80 pi electrons) and aromatic in its 6+ oxidation state (78 pi electrons). The antiaromatic state has a huge paramagnetic susceptibility, despite having no unpaired electrons. This work demonstrates that a global ring current can be promoted in a macrocycle by adjusting its oxidation state to suppress the local ring currents of its components.The discovery of ring currents around a molecule with a circumference of 7.5 nanometres, at room temperature, shows that quantum coherence can persist in surprisingly large molecular frameworks. PMID- 27992877 TI - In situ structures of the genome and genome-delivery apparatus in a single stranded RNA virus. AB - Packaging of the genome into a protein capsid and its subsequent delivery into a host cell are two fundamental processes in the life cycle of a virus. Unlike double-stranded DNA viruses, which pump their genome into a preformed capsid, single-stranded RNA (ssRNA) viruses, such as bacteriophage MS2, co-assemble their capsid with the genome; however, the structural basis of this co-assembly is poorly understood. MS2 infects Escherichia coli via the host 'sex pilus' (F pilus); it was the first fully sequenced organism and is a model system for studies of translational gene regulation, RNA-protein interactions, and RNA virus assembly. Its positive-sense ssRNA genome of 3,569 bases is enclosed in a capsid with one maturation protein monomer and 89 coat protein dimers arranged in a T = 3 icosahedral lattice. The maturation protein is responsible for attaching the virus to an F-pilus and delivering the viral genome into the host during infection, but how the genome is organized and delivered is not known. Here we describe the MS2 structure at 3.6 A resolution, determined by electron-counting cryo-electron microscopy (cryoEM) and asymmetric reconstruction. We traced approximately 80% of the backbone of the viral genome, built atomic models for 16 RNA stem-loops, and identified three conserved motifs of RNA-coat protein interactions among 15 of these stem-loops with diverse sequences. The stem-loop at the 3' end of the genome interacts extensively with the maturation protein, which, with just a six-helix bundle and a six-stranded beta-sheet, forms a genome delivery apparatus and joins 89 coat protein dimers to form a capsid. This atomic description of genome-capsid interactions in a spherical ssRNA virus provides insight into genome delivery via the host sex pilus and mechanisms underlying ssRNA-capsid co-assembly, and inspires speculation about the links between nucleoprotein complexes and the origins of viruses. PMID- 27992879 TI - Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. AB - The Mycobacterium tuberculosis (Mtb) DosRST two-component regulatory system promotes the survival of Mtb during non-replicating persistence (NRP). NRP bacteria help drive the long course of tuberculosis therapy; therefore, chemical inhibition of DosRST may inhibit the ability of Mtb to establish persistence and thus shorten treatment. Using a DosRST-dependent fluorescent Mtb reporter strain, a whole-cell phenotypic high-throughput screen of a ~540,000 compound small molecule library was conducted. The screen discovered novel inhibitors of the DosRST regulon, including three compounds that were subject to follow-up studies: artemisinin, HC102A and HC103A. Under hypoxia, all three compounds inhibit Mtb persistence-associated physiological processes, including triacylglycerol synthesis, survival and antibiotic tolerance. Artemisinin functions by disabling the heme-based DosS and DosT sensor kinases by oxidizing ferrous heme and generating heme-artemisinin adducts. In contrast, HC103A inhibits DosS and DosT autophosphorylation activity without targeting the sensor kinase heme. PMID- 27992880 TI - A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling. AB - Hundreds of human proteins are modified by reversible palmitoylation of cysteine residues (S-palmitoylation), but the regulation of depalmitoylation is poorly understood. Here, we develop 'depalmitoylation probes' (DPPs), small-molecule fluorophores, to monitor the endogenous activity levels of 'erasers' of S palmitoylation, acylprotein thioesterases (APTs). Live-cell analysis with DPPs reveals rapid growth-factor-mediated inhibition of the depalmitoylation activity of APTs, exposing a novel regulatory mechanism of dynamic lipid signaling. PMID- 27992881 TI - Molecular insights into the enzyme promiscuity of an aromatic prenyltransferase. AB - Aromatic prenyltransferases (aPTases) transfer prenyl moieties from isoprenoid donors to various aromatic acceptors, some of which have the rare property of extreme enzymatic promiscuity toward both a variety of prenyl donors and a large diversity of acceptors. In this study, we discovered a new aPTase, AtaPT, from Aspergillus terreus that exhibits unprecedented promiscuity toward diverse aromatic acceptors and prenyl donors and also yields products with a range of prenylation patterns. Systematic crystallographic studies revealed various discrete conformations for ligand binding with donor-dependent acceptor specificity and multiple binding sites within a spacious hydrophobic substrate binding pocket. Further structure-guided mutagenesis of active sites at the substrate-binding pocket is responsible for altering the specificity and promiscuity toward substrates and the diversity of product prenylations. Our study reveals the molecular mechanism underlying the promiscuity of AtaPT and suggests an efficient protein engineering strategy to generate new prenylated derivatives in drug discovery applications. PMID- 27992882 TI - Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. AB - Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor-ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR-CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand-residue interactions observed in crystallographically characterized GPCRs. GPCR-CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR-CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families. PMID- 27992884 TI - Editorial. AB - no summary. PMID- 27992885 TI - PTSD in victims of terroristic attacks - a comparison with the impact of other traumatic events on patients' lives. AB - OBJECTIVES: To identify possible differences, in terms of duration and severity of Post-Traumatic Stress Disorder, between victims of terrorist attacks and subjects who underwent other types of traumatic events. METHODS: A sample of subjects suffering from PTSD was selected. After a clinical interview aimed at the collection of anamnestic data, CAPS to confirm the diagnosis of PTSD and DTS to assess frequency and severity of post-traumatic symptoms were administered. One-way ANOVA was used in order to compare the differences in the parameters analysed through the DTS scales and its clusters between the victims of terrorist attacks and patients undergone other traumatic events. RESULTS: The duration of PTSD was 258 +/ - 144.9 months for people who underwent a terrorist attack and 41.6 +/ - 11.8 months for victims of other traumatic events. As regards the severity of the disorder, the total score of the DTS scale was 65.6 +/ - 26.9 in victims of terrorist attacks and 78.2 +/ - 28.2 in people who undergone other traumatic events. However, the difference was not statistically significant; Avoidance and Hypervigilance clusters showed an important statistical significance. CONCLUSIONS: No significant differences are present in terms of severity, showing that PTSD is a disabling disorder regardless the type of event that triggers it; however, a significant difference in terms of duration of the disorder leads to reflec on the importance of an early diagnostic process aimed toward the victims of terrorism, in order to avoid the risk of chronicity and progression to other psychiatric disorders such as depression. PMID- 27992886 TI - PTSD prevalence among Polish World War II survivors. AB - OBJECTIVES: Over the past decade research has been published in several Western European countries on the prevalence of PTSD among World War II survivors, mostly civilians. Prevalence rates ranged from 1.9% to 10.8 %. The aim of the study was to measure the frequency of PTSD occurrence among Polish WWII survivors. METHODS: Data from 96 persons: 59 women and 37 men, aged 70-96 were analyzed. All participants were born before 1945. They completed Polish adaptations of: Posttraumatic Diagnostic Scale (PDS), Impact of Events Scale (IES), Beck's Depression Inventory (BDI) and WWII trauma related questionnaire. RESULTS: Prevalence rate of potential PTSD was 32,3% Mean values of both number and severity of symptoms of PTSD were significantly higher for respondents with at least one war related trauma comparing to the participants who did note relate any such trauma. CONCLUSIONS: Comparing to other studies on WWII related PTSD the prevalence rate of possible PTSD was very high. Looking for possible explanation of such results seems to be an important challenge. PMID- 27992883 TI - The Vibrio cholerae Minor Pilin TcpB Initiates Assembly and Retraction of the Toxin-Coregulated Pilus. AB - Type IV pilus (T4P) systems are complex molecular machines that polymerize major pilin proteins into thin filaments displayed on bacterial surfaces. Pilus functions require rapid extension and depolymerization of the pilus, powered by the assembly and retraction ATPases, respectively. A set of low abundance minor pilins influences pilus dynamics by unknown mechanisms. The Vibrio cholerae toxin coregulated pilus (TCP) is among the simplest of the T4P systems, having a single minor pilin TcpB and lacking a retraction ATPase. Here we show that TcpB, like its homolog CofB, initiates pilus assembly. TcpB co-localizes with the pili but at extremely low levels, equivalent to one subunit per pilus. We used a micropillars assay to demonstrate that TCP are retractile despite the absence of a retraction ATPase, and that retraction relies on TcpB, as a V. cholerae tcpB Glu5Val mutant is fully piliated but does not induce micropillars movements. This mutant is impaired in TCP-mediated autoagglutination and TcpF secretion, consistent with retraction being required for these functions. We propose that TcpB initiates pilus retraction by incorporating into the growing pilus in a Glu5 dependent manner, which stalls assembly and triggers processive disassembly. These results provide a framework for understanding filament dynamics in more complex T4P systems and the closely related Type II secretion system. PMID- 27992887 TI - Post-War Research on Post-Traumatic Stress Disorder. Part I. Research before 1989. AB - The paper presents the post-war history of post-traumatic research conducted at the Department of Psychiatry of the Jagiellonian University and the analysis of the main research approaches and selected publications. The time after World War II passed in Poland in two directions: coping with the finished war trauma and simultaneously the experience of communist persecution trauma. First scientific publications appeared in the fifties and were focused on the research of former concentration camps prisoners (KZ-Syndrome). Between 1962 and 1989 a special edition of Przeglad Lekarski, which concentrated entirely on war trauma research, was published. The journal was nominated for the Peace Nobel Prize twice. The research team from the Department of Psychiatry headed by Professor Antoni Kepinski made a very extensive description of KZ-Syndrome issues. The paper summarizes the most important contemporary research findings on psychopathology of KZ-Syndrome (Szymusik), reaction dynamics (Teutsch), after camp adjustment (Orwid), paroxysmal hypermnesia (Poltawska), somatic changes (Gatarski, Witusik). The result of the study was the basis for the development of a methodology and a new look at the classification of the consequences of post-traumatic stress disorder, as well as the development of ethical attitudes towards patients. PMID- 27992888 TI - Post-War Research on Post-Traumatic Stress Disorder. Part II - 1989 onwards. AB - The paper illustrates the research on post-traumatic disorders conducted in Krakow at the Department of Psychotherapy and the Department of Psychiatry of the Jagiellonian University Medical College after 1989. The political changes that occurred in Poland after 1989 allowed the research to be extended with new groups of survivors. Having conducted the research of the former concentration camp prisoners, the study started to be carried out in the two research teams: 1) the former prisoners of the Stalinist period, Siberian deportees, war veterans and others were examined at the former Social Pathology Institute of the Department of Psychiatry, Jagiellonian University Medical College and the work is continued at the Department of Psychotherapy, Jagiellonian University Medical College; 2) at the Child and Adolescent Psychiatric Clinic the research of the Holocaust survivors and their families has been carried on by the same team up to the present day. The paper outlines the historical background of persecution, its course and a typical impact it had on health of each of the group of survivors. All individuals suffer from widely understood post-traumatic disorders (F43.1 and F62.0). However, differences in the profile of symptoms can be noted. The manner in which the research was organised and its modifications are also presented. The aim of this paper is to familiarise the Reader with the presented concepts and contextualise them in a political and historical dimensions, and in the continuity of the previous research on KZ-Syndrome and war neuroses. PMID- 27992889 TI - Autobiographical memory and its meaning in selected mental disorders. AB - This paper presents the general characteristics of the phenomenon of autobiographical memory (AM), the current knowledge of the subject and describes hitherto identified distortions of AM in mental disorders.AM is the part of memory concerning the personal past of an individual. It includes episodic and semantic memories associated with an identity. It affects an activity and structuring of goals, it is set in human experience and emotions and it helps in creating plans. The evolutionary sig-nificance of AM is probably to facilitate short-term goal-oriented behaviors by comparing them with the previous ones. People with AM disorders often have difficulties in social functioning.The disorders of emotional life and affect, which are present in most psychiatric disorders, deform AM. It was confirmed, inter alia, in post-traumatic stress disorder, depression, autism, schizophrenia, and alcohol dependence syndrome. Overgeneral memories (the inability to recall memories that are fully filled with details) being typical of depression, and flashbacks (the involuntary recall of memories which are highly filled with visual-sensory content) being characteristic of PTSD are considered one of the most studied deficiency of AM. The study of AM potentially carries many cognitive and clinical implications. It may facilitate the prediction of the onset of a depressive episode in patients at risk; it can also help to develop psychotherapeutic techniques which are helpful in its treatment, which has in part already taken place. Few studies relate to neurofunctional changes in AM and they need a follow-up. PMID- 27992890 TI - Personality traits in alcohol-dependent individuals in the context of childhood abuse. AB - OBJECTIVES: The aim of this study was to identify groups of alcohol-dependent individuals differing in the severity of childhood physical, emotional and sexual abuse and to find the personality variables that discriminate between those groups. METHODS: The study included 90 individuals dependent on alcohol. The following questionnaires were used: the Temperament and Character Inventory (TCI), the Coping Inventory (COPE), the Buss and Perry Aggression Questionnaire (BPAQ), Cattell's IPAT Anxiety Scale, and the Early Trauma Inventory (ETI). RESULTS: Two groups of subjects addicted to alcohol were identified: group 1 with high and group 2 with low childhood physical, emotional and sexual abuse indices. The subjects in Group 1 had significantly higher scores than the subjects in Group 2 on the TCI Temperament scales of NS and HA and lower scores on the TCI character scales of SD, C2 and C4. Group 1 subjects were significantly more likely than those from Group 2 to use avoidant coping strategies; they were also less likely to use problem-focused strategies and had significantly higher scores on general anxiety, overt anxiety, latent anxiety, level of aggression, physical aggression, hostility and anger. CONCLUSIONS: The higher severity of childhood physical, emotional and sexual abuse in alcoholics is associated with those personality traits that seem to be crucial for maintaining abstinence and the quality of cooperation in therapy. PMID- 27992891 TI - Negative experiences in childhood and the development and course of bipolar disorder. AB - The aim of this paper is to review the effects of negative childhood experiences on the development and course of bipolar disorder (BD) and to discuss the involved mechanisms. The negative childhood experiences that may play a role in BD are critical or traumatic events including all kinds of abuse, loss of a parent or parents resulting from death, suicide, separation, divorce or prolonged separation. Previous studies indicate that in BD patients negative childhood events are more frequent than in control group. In BD patients these events are associated with an earlier onset and more severe course of the illness, including more frequent relapses, suicidal behavior, substance abuse and somatic diseases. This paper presents the possibility of the specific impact of individual events on the clinical outcome of BD. Mechanisms explaining the impact of negative childhood events on the development and course of BD include the interaction between biological predisposition and stress factors, the concept of kindling and activation of negative cognitive schemas. Early negative experiences cause a modification of the expression of the mediators of stress and neurotransmitters in certain areas of the brain. The interaction of these mediators with the development of neural networks may lead to long-lasting structural and functional changes. Molecular genetic studies indicate the possibility of interactions between environmental factors (stress) and the polymorphisms of serotonin transporter, brain-derived neurotrophic factor (BDNF) and toll-like receptor (TLR2). It has also been hypothesized that childhood experiences affect DNA methylation, acting as a form of molecular memory and modifying brain activity over the next decade. PMID- 27992892 TI - Mental states in early and late old age patients and their expectations of their physicians. AB - OBJECTIVES: Understanding and fulfilling expectations of patients attending medical consultations is part and parcel of medical practice. Clinical context in which these expectations arise is crucial in assessing patients' expectations. The objective of this research was to assess patients' expectations of medical doctors depending on patients' mental state. METHODS: Patients attending GP consultations were examined. The research sample consisted of 219 patients, out of which 129 (59%) were female and 90 (41%) were male patients. The mean age of patients was 61 (SD = 9.80). The 28-item General Health Questionnaire (GHQ-28) and the Four Dimensional Symptom Questionnaire (4DSQ) were administered to assess patients' mental state and Patient Request Form (PRF) was used to assess patients' expectations of medical doctors. RESULTS: The study revealed that the youngest patients declared the highest anxiety and insomnia levels and that they differed significantly from the oldest patients. The sampled patients did not differ in terms of other mental state dimensions. It was also documented that younger patients had higher expectations of their medical doctors, required greater explanation of their medical condition and expected more emotional support. Both intensity and duration of somatic symptoms were particularly important in shaping those expectations. CONCLUSIONS: The research findings show the need for systematic assessment of mental state of patients attending medical consultations. Mental state and somatic symptoms intensity are essential indicators of patients' expectations of medical doctors. PMID- 27992893 TI - The efficacy and safety of ECT in population before and after 60 years of age. AB - OBJECTIVES: The aim of the study was to evaluate efficacy and safety of electroconvulsive therapy (ECT), in two age groups: before and after 60 years of age. METHODS: The study included 107 patients, 62 women and 45 men hospitalized in the Institute of Psychiatry and Neurology and treated with ECT in 2013 and 2014. 76 people were below 60 years; 31 people - above 60. The authors analyzed the course of 1086 ECTs, 747 sessions for patients before 60 and 339 in patients over 60 years of age. The efficacy of ECT was diagnosed using CGI Scale. RESULTS: No serious complications such as death, life-threatening condition, hospitalization in another ward or permanent injury occurred. In 67.11% of patients below 60 and 42% of patients after 60 years of age no side effects were observed. Below 60 years of age most frequently reported adverse reactions were headaches (13.16% of patients), above 60 years of age - memory impairment (22.58% of respondents). Arrhythmias occurred in 6 patients aged over 60. Disturbances of consciousness occurred among older patients slightly less frequently than in younger patients (3.25% vs. 3.95%). In patients over 60 years of age remission rate was similar as in younger age group (32.89% vs 32.26%) and significant improvement rate was even higher (61.29% over 60 vs. 48.68 before 60 years of age). No improvement of mental state occurred in 7.89% and worsening occurred in 2.63% of younger patients. All patients ged over 60 years benefited from the treatment. CONCLUSIONS: The effectiveness of ECT in elderly was similar as in younger age group. The tolerance was slightly worse in patients aged over 60 years than in younger patients. The biggest problem in the elderly was not cognitive impairment, but the cardiovascular complications. PMID- 27992894 TI - The functionality of masticatory apparatus and the sense of depression in patients over 55 years of age living in a family environment and social care centres. AB - OBJECTIVES: The aim of this study was to determine the relationship between the masticatory apparatus functionality and a sense of depression in patients over 55 years of age living in a family environment and the Social Care Centres (SCC). METHODS: Shortened version of the Geriatric Depression Scale (GDS) was used to assess the wellbeing of patients and their state/sense of depression. The clinical evaluation of masticatory function was performed during one appointment in the natural light. The clinical criterion for the retention of masticatory function, adopted by the World Health Organization was a contact between at least 20 opposing teeth, natural or artificial. RESULTS: Among patients with a low number of GDS points (0-5), statistically significantly higher proportion of people living in family houses (69.4%) maintained functionality of masticatory apparatus than of people living in SCC (23.5%). In contrast, among patients with a higher number of GDS points (6-15), statistically significantly higher proportion of patients living in SCC (70.8%) did not maintain functionality of masticatory apparatus than of those living in family houses (41.7%). CONCLUSIONS: Patients with a sense of depression living in Social Care Centres were more likely to report lack of functionality of masticatory apparatus than patients with a sense of depression living in family houses. The presence of a growing sense of depression significantly affected a lower rate of preserved functionality of masticatory apparatus or vice versa. PMID- 27992895 TI - Is the Montreal Cognitive Assessment (MoCA) test better suited than the Mini Mental State Examination (MMSE) in mild cognitive impairment (MCI) detection among people aged over 60? Meta-analysis. AB - OBJECTIVES: Screening tests play a crucial role in dementia diagnostics, thus they should be very sensitive for mild cognitive impairment (MCI) assessment. Nowadays, the MiniMental State Examination (MMSE) is the most commonly used scale in cognitive function evaluation, albeit it is claimed to be imprecise for MCI detection. The Montreal Cognitive Assessment (MoCA), was created as an alternative method for MMSE. Aim. MoCA vs. MMSE credibility assessment in detecting MCI, while taking into consideration the sensitivity and specificity by cut-off points. METHODS: A systematic literature search was carried out by the authors using EBSCO host Web, Wiley Online Library, Springer Link, Science Direct and Medline databases. The following medical subject headings were used in the search: mild cognitive impairment, mini-mental state examination, Montreal cognitive assessment, diagnostics value. Papers which met inclusion and exclusion criteria were chosen to be included in this review. At the end, for the evaluation of MoCA 20, and MMSE 13 studies were qualified. Research credibility was established by computing weighted arithmetic mean, where weight is defined as population for which the result of sensitivity and specificity for the cut-off point was achieved. The cut-offs are shown as ROC curve and accuracy of diagnosis for MoCA and MMSE was calculated as the area under the curve (AUC). RESULTS: ROC curve analysis for MoCA demonstrated that MCI best detection can be achieved with a cut-off point of 24/25 (n = 9350, the sensitivity of 80.48% and specificity of 81.19%). AUC was 0.846 (95% CI 0.823-0.868). For MMSE, it turned out that more important cut-off was of 27/28 (n = 882, 66.34% sensitivity and specificity of 72.94%). AUC was 0.736 (95% CI 0.718-0.767). CONCLUSIONS: MoCA test better meets the criteria for screening tests for the detection of MCI among patients over 60 years of age than MMSE. PMID- 27992896 TI - Child molesters' cognitive distortions. Conceptualizations of the term. AB - The concept of cognitive distortion was created by A. T. Beck and it is one of the key-concepts of cognitive psychotherapy. In the 80s of the twentieth century, researchers began to use it in studies of sexual offending, but with reference to the social learning theory rather than to the theory of cognitive psychotherapy. Subsequent authors continued the use of this term in the determinants of child molestation and defined them as products emerging from specific implicit theory of the offender, the judgements resulting from his beliefs, values and actions, dysfunctional cognitive schemas, deviant cognitive practices undertaken in the interaction of internal and external components of perpetrator's cognitive system and his social practices. The primary theoretical background in the description of the concept of cognitive distortions of child molesters was the social cognition theory, but it was complemented with the assumptions of the theory of cognitive psychotherapy, extended theory of mind and discursive psychology perspective. Particular concepts describe the cognitive distortions relating them to different classes of cognitive phenomena: products, processes and structures, and the only thing they have in common is their incompatibility of their content to the social norms. Giving this concept a normative nature leads to internal contradictions within the conceptions that concern it. Moreover, using it to explain the various processes oversimplifies the picture of this phenomenon and leads to contradictions between theories. It is, therefore, necessary to consider replacing the term cognitive distortions with alternative and more precise concepts. PMID- 27992897 TI - Psychooncology in Poland. AB - Psycho-oncology is an interdisciplinary field of medicine that deals with the psychological aspects of cancer. Psycho-oncology is a sub-discipline of clinical oncology, psychiatry, clinical psychology and health psychology. It was formally established in 1975. In Poland, the Polish Psycho-Oncology Association deals with the issues of psycho-oncology since 1992. Despite the dynamic development of psycho-oncology, in Poland psychological help for people with cancer covered under the health insurance is not sufficient. The main tasks facing the Polish psycho-oncology is: to define psycho-oncologist profession and to make it administratively independent profession, to identify psycho-oncological benefits under the health insurance and to determine standards of psycho-oncological care in the National Program of Cancer Prevention. PMID- 27992898 TI - The Scientific Basis of Guideline Recommendations on Sugar Intake: A Systematic Review. AB - Background: The relationship between sugar and health is affected by energy balance, macronutrient substitutions, and diet and lifestyle patterns. Several authoritative organizations have issued public health guidelines addressing dietary sugars. Purpose: To systematically review guidelines on sugar intake and assess consistency of recommendations, methodological quality of guidelines, and the quality of evidence supporting each recommendation. Data Sources: MEDLINE, EMBASE, and Web of Science (1995 to September 2016); guideline registries; and gray literature (bibliographies, Google, and experts). Study Selection: Guidelines addressing sugar intake that reported their methods of development and were published in English between 1995 and 2016. Data Extraction: Three reviewers independently assessed guideline quality using the Appraisal of Guidelines for Research and Evaluation, 2nd edition (AGREE II), instrument. To assess evidence quality, articles supporting recommendations were independently reviewed and their quality was determined by using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods. Data Synthesis: The search identified 9 guidelines that offered 12 recommendations. Each of the reviewed guidelines indicated a suggested decrease in the consumption of foods containing nonintrinsic sugars. The guidelines scored poorly on AGREE II criteria, specifically in rigor of development, applicability, and editorial independence. Seven recommendations provided nonquantitative guidance; 5 recommended less than 25% to less than 5% of total calories from nonintrinsic sugars. The recommendations were based on various health concerns, including nutrient displacement, dental caries, and weight gain. Quality of evidence supporting recommendations was low to very low. Limitation: The authors conducted the study independent of the funding source, which is primarily supported by the food and agriculture industry. Conclusion: Guidelines on dietary sugar do not meet criteria for trustworthy recommendations and are based on low-quality evidence. Public health officials (when promulgating these recommendations) and their public audience (when considering dietary behavior) should be aware of these limitations. Primary Funding Source: Technical Committee on Dietary Carbohydrates of the North American branch of the International Life Sciences Institute. (PROSPERO: CRD42015029182). PMID- 27992899 TI - Length of Storage of Red Blood Cells and Patient Survival After Blood Transfusion: A Binational Cohort Study. AB - Background: Possible negative effects, including increased mortality, among persons who receive stored red blood cells (RBCs) have recently garnered considerable attention. Despite many studies, including 4 randomized trials, no consensus exists. Objective: To study the association between the length of RBC storage and mortality in a large population-based cohort of patients who received transfusions, allowing detection of small yet clinically significant effects. Design: Binational cohort study. Setting: All transfusion recipients in Sweden and Denmark. Patients: 854 862 adult patients who received transfusions from 2003 to 2012. Measurements: Patients were followed from first blood transfusion. Relative and absolute risks for death in 30 days or 1 year in relation to length of RBC storage were assessed by using 3 independent analytic approaches. All analyses were conducted by using Cox proportional hazards regression. Results: Regardless of the analytic approach, no association was found between the length of RBC storage and mortality. The difference in 30-day cumulative mortality between patients receiving blood stored for 30 to 42 days and those receiving blood stored for 10 to 19 days was -0.2% (95% CI, -0.5% to 0.1%). Even among patients who received more than 6 units of RBCs stored for 30 days or longer, the hazard ratio of death was 1.00 (CI, 0.96 to 1.05) compared with those who received no such units. Limitation: Observational study; risk of confounding by indication. Conclusion: Consistent with previous randomized trials, this study found no association between the length of storage of transfused RBCs and patient mortality. Results were homogeneous, with differences in absolute mortality consistently less than 1% among the most extreme exposure categories. These findings suggest that the current practice of storing RBCs for up to 42 days does not need to be changed. Primary Funding Source: The Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Society for Medical Research, Strategic Research Program in Epidemiology at Karolinska Institutet, and Danish Council for Independent Research. PMID- 27992900 TI - Guidelines to Limit Added Sugar Intake: Junk Science or Junk Food? PMID- 27992901 TI - Nivolumab-Induced Recurrence of Rheumatoid Arthritis in a Patient With Advanced Non-Small Cell Lung Cancer: A Case Report. PMID- 27992902 TI - Let's Not SPRINT to Judgment About New Blood Pressure Goals. PMID- 27992903 TI - Let's Not SPRINT to Judgment About New Blood Pressure Goals. PMID- 27992904 TI - Economic Outcomes With Anatomical Versus Functional Diagnostic Testing for Coronary Artery Disease. PMID- 27992905 TI - Economic Outcomes With Anatomical Versus Functional Diagnostic Testing for Coronary Artery Disease. PMID- 27992906 TI - Curbing Firearm Violence. PMID- 27992907 TI - Curbing Firearm Violence. PMID- 27992908 TI - Management of Chronic Insomnia Disorder in Adults. PMID- 27992909 TI - Management of Chronic Insomnia Disorder in Adults. PMID- 27992910 TI - Physicians, Patients, and Firearms. PMID- 27992911 TI - Physicians, Patients, and Firearms. PMID- 27992912 TI - A Vulnerable Moment. PMID- 27992913 TI - Winter Morning. PMID- 27992914 TI - Having Cancer and Seeking the Point. PMID- 27992915 TI - Web Exclusives. Annals for Hospitalists Inpatient Notes - Mistakes in the Hospital-Communicating, Apologizing, and Beyond. PMID- 27992917 TI - Web Exclusives. Annals Consult Guys - Postoperative Calf Venous Thrombosis: Location, Location, Location. PMID- 27992918 TI - In prostate cancer, urinary and sexual function were worse with prostatectomy than active monitoring or radiotherapy. PMID- 27992919 TI - In localized prostate cancer, active monitoring, prostatectomy, and radiotherapy did not differ for 10-y cancer deaths. PMID- 27992920 TI - In type 1 diabetes, adding liraglutide to insulin increased hypoglycemia and hyperglycemia with ketosis. PMID- 27992921 TI - Review: For warfarin reversal, prothrombin complex concentrates reduce mortality compared with fresh frozen plasma. PMID- 27992922 TI - Review: In adults with asthma, vitamin D3 reduces rate of severe exacerbation but does not improve symptoms. PMID- 27992923 TI - Adding glycopyrronium to beclomethasone plus formoterol improved pulmonary function in COPD. PMID- 27992924 TI - Physiotherapy reduced recurrent headaches linked to neck pain and dysfunction in older adults. PMID- 27992925 TI - In chronic severe functional constipation, electroacupuncture increased complete spontaneous bowel movements. PMID- 27992926 TI - Therapeutic hypothermia during CPR did not improve survival to discharge in out of-hospital cardiac arrest. PMID- 27992927 TI - Review: Revascularization and medical treatment may be similar in atherosclerotic renal artery stenosis. PMID- 27992930 TI - Insurance Expansion and Hospital Emergency Department Access: Evidence From the Affordable Care Act. AB - Background: Little is known about whether insurance expansion affects the location and type of emergency department (ED) use. Understanding these changes can inform state-level decisions about the Medicaid expansion under the Patient Protection and Affordable Care Act (ACA). Objective: To investigate the effect of the 2014 ACA Medicaid expansion on the location, insurance status, and type of ED visits. Design: Quasi-experimental observational study from 2012 to 2014. Setting: 126 investor-owned, hospital-based EDs. Participants: Uninsured and Medicaid-insured adults aged 18 to 64 years. Intervention: ACA expansion of Medicaid in January 2014. Measurements: Number of ED visits overall, type of visit (for example, nondiscretionary or nonemergency), and average travel time to the ED. Interrupted time-series analyses comparing changes from the end of 2013 to end of 2014 for patients from Medicaid expansion versus nonexpansion states were done. Results: There were 1.06 million ED visits among patients from 17 Medicaid expansion states, and 7.87 million ED visits among patients from 19 nonexpansion states. The EDs treating patients from Medicaid expansion states saw an overall 47.1% decrease in uninsured visits (95% CI, -65.0% to -29.3%) and a 125.7% (CI, 89.2% to 162.6%) increase in Medicaid visits after 12 months of ACA expansion. Average travel time for nondiscretionary conditions requiring immediate medical care decreased by 0.9 minutes (-6.2% [CI, -8.9% to -3.5%]) among all Medicaid patients from expansion states. We found little evidence of similar changes among patients from nonexpansion states. Limitation: Results reflect shifts in ED care at investor-owned facilities, which limits generalizability to other hospital types. Conclusion: Meaningful changes in insurance status and location and type of ED visits in the first year of ACA Medicaid expansion were found, suggesting that expansion provides patients with a greater choice of hospital facilities. Primary Funding Source: Robert Wood Johnson Foundation. PMID- 27992931 TI - Extrapelvic Endometriosis. AB - Extrapelvic endometriosis is a rare and complex phenomenon. The pathologic mechanism of intrapelvic endometriosis is generally accepted as being largely due to retrograde menstruation through the fallopian tubes; however, the mechanism by which extrapelvic endometriosis forms has proven to be much more elusive. This article reviews the pathophysiology, clinical signs and symptoms, diagnostic techniques, and treatment recommendations for extrapelvic endometriosis of the umbilicus, abdominal wall, thorax, and vulva. PMID- 27992932 TI - Endometriosis in the Adolescent Patient. AB - The recognition and management of endometriosis in the adolescent patient is challenging. A strong clinical suspicion for endometriosis should be maintained in the adolescent who suffers from acyclic pelvic pain as well as absenteeism from school and lack of participation in daily activities. Risk factors include the presence of an obstructive Mullerian anomaly, a family history of endometriosis, and conditions that prolong exposure to endogenous and exogenous estrogens. Empiric medical therapy with nonsteroidal anti-inflammatory drugs and combined oral contraceptive pills may be considered in most adolescents with endometriosis. Failure of empiric therapy may warrant diagnostic laparoscopy, which affords a concomitant opportunity for treatment via excision of endometriosis. Endometriotic implants in the adolescent tend to be more atypical, appearing red/flame-like, clear/polypoid, or vesicular. Endometriosis tends to recur more often in adolescents when compared with adults, and the role of postoperative medical therapy for the suppression of disease progression is not entirely clear. Current knowledge on the impact of adolescent endometriosis on future fertility is limited but overall reassuring. PMID- 27992933 TI - Sonographic Cervical Shortening after Labor Induction is a Predictor of Vaginal Delivery. AB - Objective Analyzing if the sonographic evaluation of the cervix (cervical shortening) is a prognostic marker for vaginal delivery. Methods Women who underwent labor induction by using dinoprostone were enrolled. Before the induction and three hours after it, the cervical length was measured by ultrasonography to obtain the cervical shortening. The cervical shortening was introduced in logistic regression models among independent variables and for calculating receiver operating characteristic (ROC) curves. Results Each centimeter in the cervical shortening increases the odds of vaginal delivery in 24.4% within 6 hours; in 16.1% within 24 hours; and in 10.5% within 48 hours. The best predictions for vaginal delivery are achieved for births within 6 and 24 hours, while the cervical shortening poorly predicts vaginal delivery within 48 hours. Conclusion The greater the cervical shortening 3 hours after labor induction, the higher the likelihood of vaginal delivery within 6, 24 and 48 hours. PMID- 27992934 TI - Novel 99mTc-Radiolabeled Anionic Linear Globular PEG-Based Dendrimer Chlorambucil: Non-Invasive Method for In-Vivo Biodistribution. AB - Chlorambucil (CBL) is an alkylating agent, which widely use in the treatment of various types of tumors. The main purpose of this study is to evaluate the in vivo biodistribution of CBL conjugated to the anionic dendrimer, which has a great ability to labeled with 99mTc through binding to carboxylate terminate groups. Whole body scans were used to analyze the percentage of the injected dose in different times. Radiochemical purity (RCP) and in-vivo biodistribution were also calculated with the SPECT/CT instrument. Our study proposes a new method for RCP determination and shows that this carrier is a promising agent to complex with the 99mTc and biological assessment. PMID- 27992935 TI - QSAR Differential Model for Prediction of SIRT1 Modulation using Monte Carlo Method. AB - Silent information regulator 2 homologue one (SIRT1) modulators have therapeutic potential for a number of diseases like cardiovascular, metabolic, inflammatory and age related disorders. Here, we have studied both activators and inhibitors of SIRT1 and constructed differential quantitative structure activity relationship (QSAR) models using CORAL software by Monte Carlo optimization method and SMILES notation. 3 splits divided into 3 subsets: sub-training, calibration and test sets, were examined and validated with a prediction set. All the described models were statistically significant models. The values of sensitivity, specificity, accuracy and Matthews' correlation coefficient for the validation set of best model were 1.0000, 0.8889, 0.9524 and 0.9058, respectively. In mechanistic interpretation, structural features important for SIRT1 activation and inhibition have been defined. PMID- 27992936 TI - Role of Isradipine Loaded Solid Lipid Nanoparticles on the Pharmacodynamic Effect in Rats. AB - Isradipine (ID), is an antihypertensive drug, having low oral bioavailability (15 24%) due to poor aqueous solubility (0.01 mg/mL) and also hepatic first-pass metabolism. Among various approaches, Solid lipid nanoparticles (SLNs) were developed using stearic acid, glyceryl monostearate as lipid matrices for improving the oral bioavailability of ID. ID-SLNs were prepared by using hot homogenization followed by ultrasonication. The prepared SLNs were characterized for size, PDI, zeta potential (ZP), entrapment efficiency (EE) and drug content. In vitro release studies were performed in 0.1NHCl and pH 6.8 phosphate buffer of by open tube method. Physical stability of the SLNs was observed at refrigerated temperature and room temperature for 90 days. Further, pharmacodynamic study was conducted in wistar rats. SLNs prepared with GMS having size of 188.6+/-3.6 nm, PDI of 0.273+/-0.052, ZP of - 21.8+/-2.7 mV with 86.86+/-0.75% EE were optimized. Differential scanning calorimetric (DSC) study revealed that no interaction between drug and lipid. In vitro release studies showed that more cumulative release of ID in pH 6.8 phosphate buffer than in 0.1NHCl during 24 h. The lyophilized SLN formulation was used in knowing morphology of SLNs, and was found to have spherical shape with increased polydispersity by Scanning electron microscopy. Pharmacodynamic study of SLNs in fructose induced hypertensive rats showed a decrease in systolic blood pressure for 36 h, when compared to suspension, which showed a decrease in systolic blood pressure for only 2 h. Thus, the results conclusively demonstrated the role of SLNs for a significant enhancement in pharmacodynamic effect of ID. PMID- 27992937 TI - Parenteral Fish-Oil Lipid Emulsions in the Prevention of Severe Retinopathy of Prematurity: A Systematic Review and Meta-Analysis. AB - Objective Omega-3 fatty acids are vital for brain and retinal maturation. It is not clear if early use of omega-3 fatty acids in the form of fish-oil lipid emulsions (FLEs) prevents retinopathy of prematurity (ROP) in preterm infants. The aim of this meta-analysis is to evaluate whether early administration of parenteral FLEs reduces ROP requiring laser therapy or severe ROP >=stage 3 in preterm infants. Methods A literature search was performed to identify studies comparing parenteral FLEs with soybean-based lipid emulsions (SLEs) in preventing ROP. The main outcome was incidence of severe ROP or ROP requiring laser therapy. Results Studies met the inclusion criteria (four RCTs and two observational studies). The pooled relative risk of ROP requiring laser therapy or severe ROP >= stage 3 in FLEs group was 0.47 [95% CI: 0.24-0.90] and 0.40 [95% CI: 0.22 0.76] in RCTs and observational studies, respectively. FLEs also reduced cholestasis; however, other secondary outcomes of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), sepsis, intraventricular hemorrhage (IVH), and mortality were similar. Conclusion The use of FLEs may reduce the incidence of severe ROP or need for laser therapy in preterm infants. A large multicenter RCT is required to confirm this. PMID- 27992938 TI - Bortezomib: Potential Key Role in the Treatment of Multiple Myeloma-Related Acquired Hemophilia A. PMID- 27992939 TI - Antiobesity and Lipid Lowering Effects of Orthosiphon stamineus in High-Fat Diet Induced Obese Mice. AB - The present study investigated the antiobesity and lipid lowering effects of an ethanolic extract of leaves obtained from Orthosiphon stamineus (200 and 400 mg/kg) and its major compound (rosmarinic acid, 10 mg/kg) in obese mice (C57BL/6) induced by a high-fat diet. Continuous supplementation with O. stamineus extract (200 and 400 mg/kg) for 8 weeks significantly decreased body weight gain (p < 0.05). However, supplementation with rosmarinic acid, a constituent in the extract, produced only a slight reduction in body weight gain compared to the high-fat diet control group. Food intake between the treatment and the high-fat diet groups was similar, which suggested that the plant extract did not suppress food intake. Further, body weight reduction of the treatment groups was not due to a decreased reduction in energy intake. Compared to the high-fat diet-fed group, serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were significantly reduced in the treated groups, while high density lipoprotein cholesterol levels were not significantly altered. Accumulation of hepatic lipid droplets induced by a high-fat diet was markedly inhibited by O. stamineus extract. In addition, O. stamineus significantly diminished liver malondialdehyde production, and significantly elevated the activities of hepatic superoxidase dismutase. The present study showed that an ethanolic extract prepared from the leaves of O. stamineus can significantly reduce a gain in body weight, enhance antioxidant activity, and possess hypolipidemic and antiobesity effects, thereby protecting against the adverse effects of high-fat diet-induced obesity. PMID- 27992940 TI - Pharmacokinetics of a Standardized Extract of Centella asiatica ECa 233 in Rats. AB - ECa 233, a standardized extract of Centella asiatica, has been found to exhibit various positive neurological effects and to have a good safety profile. The present study aimed to explore the disposition kinetics of ECa 233, containing madecassoside (53.1 %) and asiaticoside (32.3 %), in rats. The extract was intravenously or orally administered at doses from 50 to 200 mg/kg. Plasma, tissues, urine, and feces were collected at time points from 0 to 48 h after dosing. The levels of madecassoside and asiaticoside, as well as their postulated triterpenic metabolites, madecassic acid and asiatic acid, in biological samples, were simultaneously measured by liquid chromatography-tandem mass spectrometry. The results showed that all animals had a good tolerability for ECa 233, whereas madecassic and asiatic acids were found in negligible amounts after pharmacokinetic assessment. Madecassoside and asiaticoside demonstrated rather similar absorption and tissue distribution profiles. They were rapidly absorbed, reaching maximum levels within 5-15 min after oral administration, but they had poor oral bioavailability, less than 1 %. Both triterpenoids were extensively distributed in the brain, stomach, and skin within 1 h and remained there for at least 4 h after dosing. Madecassoside and asiaticoside in ECa 233 were mainly excreted as an unchanged form after being injected, and exclusively as triterpenic acid metabolites in feces after oral administration. The pharmacokinetic results obtained could provide some guidance for an appropriate dosing regimen of ECa 233 in future studies. This study also provided the first evidence demonstrating the presence of madecassoside and asiaticoside in their target tissues. PMID- 27992941 TI - Comparative Analysis of Ultrafine Granular Powder and Decoction Pieces of Salvia miltiorrhiza by UPLC-UV-MSn Combined with Statistical Analysis. AB - Salvia miltiorrhiza is one of the most used herbal medicines for the treatment of a wide range of diseases in China. Decoction pieces and Chinese patent medicines from S. miltiorrhiza are the two main types of products used by patients. Other relatively new products of S. miltiorrhiza, like injections and ultrafine granular powder (D90 < 45 um before granulation), are also increasingly used nowadays. With the growing usage of new products of S. miltiorrhiza, their chemical components and pharmacological effects, compared to the traditional decoction pieces, are attracting attention. In this work, the chemical profiles of two types of products from S. miltiorrhiza (one is traditional "decoction pieces", the other is modern "ultrafine granular powder") were compared via similarity analysis and discriminated via multivariate analysis, e.g., hierarchical cluster analysis, principal component analysis, and partial least squares discrimination analysis. A new adamantane stationary phase column was used to establish informative chemical profiles of them. The mean similarity correlation coefficient (> 0.987) revealed that ultrafine granular powder and decoction pieces of S. miltiorrhiza were consistent between each other and stable between different batches. Two types of S. miltiorrhiza products were clearly resolved from each other by hierarchical cluster analysis, principal component analysis, and partial least squares discrimination analysis. Compounds responsible for the discrimination results were further characterized by ESI MS/MS. Eventually, 62 compounds selected as characteristic markers for evaluation were characterized or tentatively characterized. This result will facilitate the further comparison of these two types of S. miltiorrhiza products in pharmacology and pharmacokinetics. PMID- 27992942 TI - Cardiac Abnormalities in Congenital and Childhood Myotonic Muscular Dystrophy Type 1. AB - Myotonic dystrophy often presents with cardiac abnormalities, particularly conduction defects, that factor into an increased risk of sudden cardiac death. Myotonic dystrophy has two forms, myotonic dystrophy type 1 (DM1) and DM2, and is a multisystemic disorder that presents in a wide, clinical spectrum and age range. A distinguishing feature of DM1 is the existence of a congenital form. Though research on cardiac involvement has been conducted on patients with the adult form of myotonic dystrophy, there have been few studies focused on cardiac involvement in pediatric patients with congenital myotonic dystrophy type 1 (CDM1). In this study, a survey was conducted to determine the prevalence and variations of cardiac abnormalities in pediatric patients with CDM1. This preliminary study found a prevalence of 25.8% CDM1 pediatric patients with cardiac abnormalities in a sample size of 31 patients. PMID- 27992943 TI - Hyperechogenic Bowel: Etiologies, Management, and Outcome according to Gestational Age at Diagnosis in 279 Consecutive Cases in a Single Center. AB - Introduction The aim of the study was to investigate perinatal outcome of fetuses with hyperechogenic bowel (HB) in relation to gestational age at diagnosis. Materials and Methods This is a retrospective observational study of fetal HB cases from 2002 to 2012. Patients were divided into three groups according to trimester at diagnosis. For each group, data from fetal ultrasound examination, fetal medicine investigations, intrapartum cares, and neonatal outcome were obtained. Results A diagnosis of HB was made in 279 fetuses among them 17 (6%) during the first trimester, 186 (67%) during the second trimester, and 75 (27%) during the third trimester. A significant prevalence of maternal comorbidities was noticed in group 1 (12%: p = 0.02). A chromosomal defect was identified in 13% of the fetuses without difference among the three groups. HB was associated with prenatal infection in 11.5% (n = 32) of the cases, with an equal distribution between groups 2 and 3. Intrauterine growth retardation was noticed in 23% (n = 64) of the cases with a slightly high prevalence in groups 1 (35%). HB was the only ultrasonographic intestinal soft marker in 80% (n = 223) of the fetuses, two-third of them were detected during the first and the second trimesters (p = 0.001). However, HB was associated with bowel dilation in 33% of the cases diagnosed during the third trimester (p = 001). Ultrasonographic extraintestinal anomalies were identified in 30% of the fetuses with a higher prevalence in group 1 (59%). HB resolved spontaneously in 55 (19.7%) cases without difference among the three groups. In group 1 we recorded a significant prevalence of intrauterine demise (23.5%, p = 0.004). Two hundred twenty-seven (81.3%) pregnancies resulted in live-born neonates; among them gastrointestinal anomalies were noticed in 12.5% with a significant prevalence in group 3 (36%) compared with 6 and 5.4% in groups 1 and 2, respectively (p = 0.001). Extraintestinal anomalies were confirmed in 27% of the cases, whereas postnatal mortality rate was of 7% without differences between the three groups. Conclusion Detection of HB during the first trimester is associated with an increased risk for maternal comorbidities, intrauterine growth retardation, and adverse pregnancy outcome. Moreover, if HB is detected during the second trimester, it is associated with a favorable prognosis. Otherwise, HB detected during the third trimester is associated with a significant risk of gastrointestinal anomaly. PMID- 27992944 TI - Role of Google Glass in improving patient satisfaction for otolaryngology residents: a pilot study. AB - OBJECTIVES: To demonstrate the feasibility and efficacy of the Google Glass as a tool to improve patient satisfaction and patient-physician communication for otolaryngology residents in the outpatient clinic setting. The primary outcome of the study was to improve patient satisfaction scores based on physician communication-related questions from Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys. STUDY DESIGN: Prospective randomised trial. SETTING: Tertiary care hospital. SUBJECT AND METHODS: To evaluate the effect on patient satisfaction, five residents were recorded using the Google Glass in an outpatient clinic setting by 50 randomised patients. Modified surveys based on the CG-CAHPS survey were completed by patients at the conclusion of each clinic encounter. The recorded videos were evaluated by two independent faculties. Summarised data and video were distributed to each resident for review as the intervention. The residents were recorded again by 45 additional patients with evaluation by patients and faculties. RESULTS: After intervention, the scores from faculty surveys regarding patient satisfaction including the subject of better explanations (P > 0.001), listening carefully (P > 0.001), addressing patient questions (P > 0.001), displaying respect (P > 0.001) and spending adequate time (P = 0.0005) all significantly improved, as well as overall performance (P = 0.014). The scores from patient surveys did significantly improve. CONCLUSION: This study demonstrates the improvements in patient satisfaction and patient-physician communication can be achieved with the use of Google Glass as a first-person recording device in the outpatient otolaryngology clinic setting. PMID- 27992945 TI - Inhibition of poly(ADP-ribose) polymerase may have preventive potential for varicocoele-associated testicular damage in rats. AB - Varicocele is ordinarily accompanied by testicular damage and male infertility. Several theories have been proposed to explain the detrimental effect of varicocele on testis tissue, including the possible effects of oxidative stress. The poly(ADP-ribose) polymerase (PARP) pathway has been established as a major downstream intracellular pathway of oxidative stress. Recently we have reported that PARP pathway has been activated in varicocele-induced rat testicular damage model. The aim of the present study was to investigate the possible protective effect of PARP inhibition in varicocele-associated testicular damage. Fifty male Wistar rats were divided into five groups: control, sham, varicocele-induced, varicocele-induced 1,5-isoquinolinediol (ISO, a PARP inhibitor)-treated, and ISO treated groups. The ISO-treated rats received intraperitoneal injections of 3 mg/kg ISO daily for 13 weeks. After 13 weeks of varicocele induction, body and testes weights were investigated in all groups. Histopathology of testes were evaluated by light microscopy. Expressions of PAR, p53 and cytochrome c were detected by immunohistochemistry and cleaved PARP-1, PAR, p53 and cytochrome c by western blot. The degree of apoptosis was determined by TUNEL. Light microscopy revealed testicular damage comprising various degrees of seminiferous tubule degeneration in varicocele-induced rats and their testes weights decreased significantly, whereas ISO administration prevented it. Expressions of cleaved PARP-1, PAR, cytochrome c, and p53 increased significantly in varicocele-induced rats, whereas the level of these molecules were similar to controls in varicocele induced rats treated with ISO. In conclusion, increased PARP activation in testes seems to be related with testicular damage and apoptosis associated with varicocele and pharmacological inhibition of this pathway might be an effective intervention to prevent varicocele-induced testicular injury. PMID- 27992946 TI - Balloon tuboplasty in patients with Eustachian tube dysfunction: a prospective study in 39 patients (55 ears). PMID- 27992948 TI - Pinnaplasty: improved access to the antihelical fold. PMID- 27992947 TI - Toxoplasma gondii autophagy-related protein ATG9 is crucial for the survival of parasites in their host. AB - Autophagy is a conserved, life-promoting, catabolic process involved in the recycling of nonessential cellular components in response to stress. The parasite Toxoplasma gondii is an early-diverging eukaryote in which part of the autophagy machinery is not exclusively involved in a catabolic process but instead has been repurposed for an original function in organelle inheritance during cell division. This function, depending essentially on protein TgATG8 and its membrane conjugation system, is crucial for parasite survival and prevented an in depth study of autophagy in the mutants generated so far in Toxoplasma. Thus, in order to decipher the primary function of canonical autophagy in the parasites, we generated a cell line deficient for TgATG9, a protein thought to be involved in the early steps of the autophagy process. Although the protein proved to be dispensable for the development of these obligate intracellular parasites in vitro, the absence of TgATG9 led to a reduced ability to sustain prolonged extracellular stress. Importantly, depletion of the protein significantly reduced parasites survival in macrophages and markedly attenuated their virulence in mice. Altogether, this shows TgATG9 is important for the fate of Toxoplasma in immune cells and contributes to the overall virulence of the parasite, possibly through an involvement in a canonical autophagy pathway. PMID- 27992949 TI - Age-stratified outcome of a genotype-guided dosing algorithm for acenocoumarol and phenprocoumon. AB - : Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for phenprocoumon in patients < 75 years. For patients >= 75 years the phenprocoumon algorithm should be revised and further tested. No influence of comorbidities and co-current drug use was found that could explain the differences. SUMMARY: Background Age seemed to affect the interaction between coumarins and genotype in the acenocoumarol and phenprocoumon arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial. Objectives To investigate the effect of genotype-guided dosing stratified by age and the potential factors causing a difference. Patients/Methods Data from the acenocoumarol/phenprocoumon arm of the EU-PACT trial were used. The percentages of time below the therapeutic range, time above the therapeutic range and time in the therapeutic range (TTR) during the initial 12 weeks of therapy were compared between the genotype-guided group and the control group among younger (< 75 years) and older (>= 75 years) patients by the use of independent t-tests, and adjusted for sex, height, weight and co-medications by the use of linear regression. Results Among younger phenprocoumon users, TTR during the first 12 weeks in the genotype-guided group (n = 55) was 9.5% (95% confidence interval [CI] 1.3 to 17.8) higher than in the control group (n = 63), with a remarkably lower percentage of time above this range (difference: - 9.6%, 95% CI - 19.0 to - 0.2) and a similar time below this range. Older patients dosed by the genotype guided algorithm (n = 24) spent more time above the range (difference: 27.5%, 95% CI 12.9 to 42.0). For acenocoumarol users, there were no significant differences between the genotype-guided and control groups for most outcomes, except for a lower percentage of time below the range among older patients. Conclusions The genotype-guided algorithm for phenprocoumon in the EU-PACT trial benefitted younger patients more, but for older patients the algorithm needs to be revised and tested in further research. PMID- 27992951 TI - Limits on carbon sequestration in arid blue carbon ecosystems. AB - Coastal ecosystems produce and sequester significant amounts of carbon ("blue carbon"), which has been well documented in humid and semi-humid regions of temperate and tropical climates but less so in arid regions where mangroves, marshes, and seagrasses exist near the limit of their tolerance for extreme temperature and salinity. To better understand these unique systems, we measured whole-ecosystem carbon stocks in 58 sites across the United Arab Emirates (UAE) in natural and planted mangroves, salt marshes, seagrass beds, microbial mats, and coastal sabkha (inter- and supratidal unvegetated salt flats). Natural mangroves held significantly more carbon in above- and belowground biomass than other vegetated ecosystems. Planted mangrove carbon stocks increased with age, but there were large differences for sites of similar age. Soil carbon varied widely across sites (2-367 Mg C/ha), with ecosystem averages that ranged from 49 to 156 Mg C/ha. For the first time, microbial mats were documented to contain soil carbon pools comparable to vascular plant-dominated ecosystems, and could arguably be recognized as a unique blue carbon ecosystem. Total ecosystem carbon stocks ranged widely from 2 to 515 Mg C/ha (seagrass bed and mangrove, respectively). Seagrass beds had the lowest carbon stock per unit area, but the largest stock per total area due to their large spatial coverage. Compared to similar ecosystems globally, mangroves and marshes in the UAE have lower plant and soil carbon stocks; however, the difference in soil stocks is far larger than with plant stocks. This incongruent difference between stocks is likely due to poor carbon preservation under conditions of weakly reduced soils (200-350 mV), coarse-grained sediments, and active shoreline migration. This work represents the first attempt to produce a country-wide coastal ecosystem carbon accounting using a uniform sampling protocol, and was motivated by specific policy goals identified by the Abu Dhabi Global Environmental Data Initiative. These carbon stock data supported two objectives: to quantify carbon stocks and infer sequestration capacity in arid blue carbon ecosystems, and to explore the potential to incorporate blue carbon science into national reporting and planning documents. PMID- 27992952 TI - Gross primary production responses to warming, elevated CO2 , and irrigation: quantifying the drivers of ecosystem physiology in a semiarid grassland. AB - Determining whether the terrestrial biosphere will be a source or sink of carbon (C) under a future climate of elevated CO2 (eCO2 ) and warming requires accurate quantification of gross primary production (GPP), the largest flux of C in the global C cycle. We evaluated 6 years (2007-2012) of flux-derived GPP data from the Prairie Heating and CO2 Enrichment (PHACE) experiment, situated in a grassland in Wyoming, USA. The GPP data were used to calibrate a light response model whose basic formulation has been successfully used in a variety of ecosystems. The model was extended by modeling maximum photosynthetic rate (Amax ) and light-use efficiency (Q) as functions of soil water, air temperature, vapor pressure deficit, vegetation greenness, and nitrogen at current and antecedent (past) timescales. The model fits the observed GPP well (R2 = 0.79), which was confirmed by other model performance checks that compared different variants of the model (e.g. with and without antecedent effects). Stimulation of cumulative 6 year GPP by warming (29%, P = 0.02) and eCO2 (26%, P = 0.07) was primarily driven by enhanced C uptake during spring (129%, P = 0.001) and fall (124%, P = 0.001), respectively, which was consistent across years. Antecedent air temperature (Tairant ) and vapor pressure deficit (VPDant ) effects on Amax (over the past 3 4 days and 1-3 days, respectively) were the most significant predictors of temporal variability in GPP among most treatments. The importance of VPDant suggests that atmospheric drought is important for predicting GPP under current and future climate; we highlight the need for experimental studies to identify the mechanisms underlying such antecedent effects. Finally, posterior estimates of cumulative GPP under control and eCO2 treatments were tested as a benchmark against 12 terrestrial biosphere models (TBMs). The narrow uncertainties of these data-driven GPP estimates suggest that they could be useful semi-independent data streams for validating TBMs. PMID- 27992950 TI - Hierarchical organization of the hemostatic response to penetrating injuries in the mouse macrovasculature. AB - : Essentials Methods were developed to image the hemostatic response in mouse femoral arteries in real time. Penetrating injuries produced thrombi consisting primarily of platelets. Similar to arterioles, a core-shell architecture of platelet activation occurs in the femoral artery. Differences from arterioles included slower platelet activation and reduced thrombin dependence. SUMMARY: Background Intravital studies performed in the mouse microcirculation show that hemostatic thrombi formed after penetrating injuries develop a characteristic architecture in which a core of fully activated, densely packed platelets is overlaid with a shell of less activated platelets. Objective Large differences in hemodynamics and vessel wall biology distinguish arteries from arterioles. Here we asked whether these differences affect the hemostatic response and alter the impact of anticoagulants and antiplatelet agents. Methods Approaches previously developed for intravital imaging in the mouse microcirculation were adapted to the femoral artery, enabling real-time fluorescence imaging despite the markedly thicker vessel wall. Results Arterial thrombi initiated by penetrating injuries developed the core-and-shell architecture previously observed in the microcirculation. However, although platelet accumulation was greater in arterial thrombi, the kinetics of platelet activation were slower. Inhibiting platelet ADP P2Y12 receptors destabilized the shell and reduced thrombus size without affecting the core. Inhibiting thrombin with hirudin suppressed fibrin accumulation, but had little impact on thrombus size. Removing the platelet collagen receptor, glycoprotein VI, had no effect. Conclusions These results (i) demonstrate the feasibility of performing high-speed fluorescence imaging in larger vessels and (ii) highlight differences as well as similarities in the hemostatic response in the macro- and microcirculation. Similarities include the overall core-and-shell architecture. Differences include the slower kinetics of platelet activation and a smaller contribution from thrombin, which may be due in part to the greater thickness of the arterial wall and the correspondingly greater separation of tissue factor from the vessel lumen. PMID- 27992954 TI - The global pyrogenic carbon cycle and its impact on the level of atmospheric CO2 over past and future centuries. AB - The incomplete combustion of vegetation and dead organic matter by landscape fires creates recalcitrant pyrogenic carbon (PyC), which could be consequential for the global carbon budget if changes in fire regime, climate, and atmospheric CO2 were to substantially affect gains and losses of PyC on land and in oceans. Here, we included global PyC cycling in a coupled climate-carbon model to assess the role of PyC in historical and future simulations, accounting for uncertainties through five sets of parameter estimates. We obtained year-2000 global stocks of (Central estimate, likely uncertainty range in parentheses) 86 (11-154), 47 (2-64), and 1129 (90-5892) Pg C for terrestrial residual PyC (RPyC), marine dissolved PyC, and marine particulate PyC, respectively. PyC cycling decreased atmospheric CO2 only slightly between 1751 and 2000 (by 0.8 Pg C for the Central estimate) as PyC-related fluxes changed little over the period. For 2000 to 2300, we combined Representative Concentration Pathways (RCPs) 4.5 and 8.5 with stable or continuously increasing future fire frequencies. For the increasing future fire regime, the production of new RPyC generally outpaced the warming-induced accelerated loss of existing RPyC, so that PyC cycling decreased atmospheric CO2 between 2000 and 2300 for most estimates (by 4-8 Pg C for Central). For the stable fire regime, however, PyC cycling usually increased atmospheric CO2 (by 1-9 Pg C for Central), and only the most extreme choice of parameters maximizing PyC production and minimizing PyC decomposition led to atmospheric CO2 decreases under RCPs 4.5 and 8.5 (by 5-8 Pg C). Our results suggest that PyC cycling will likely reduce the future increase in atmospheric CO2 if landscape fires become much more frequent; however, in the absence of a substantial increase in fire frequency, PyC cycling might contribute to, rather than mitigate, the future increase in atmospheric CO2 . PMID- 27992953 TI - Age-related Disparities in Trauma Center Access for Severe Head Injuries Following the Release of the Updated Field Triage Guidelines. AB - OBJECTIVE: In 2006, the American College of Surgeons' Committee on Trauma and the Centers for Disease Control and Prevention released field triage guidelines with special consideration for older adults. Additional considerations for direct transport to a Level I or II trauma center (TC) were added in 2011, reflecting perceived undertriage to TCs for older adults. We examined whether age-based disparities in TC care for severe head injury decreased following introduction of the 2011 revisions. METHODS: A pre-post design analyzing the 2009 and 2012 Healthcare Cost and Utilization Project State Emergency Department Databases and State Inpatient Databases with multivariable logistic regressions considered changes in 1) the trauma designation of the emergency department where treatment was initiated and 2) transfer to a TC following initial treatment at a non-TC. RESULTS: Compared with adults aged 18 to 44 years, after multivariable adjustment, in both years TC care was less likely for adults aged 45 to 64 years (odds ratio [OR] = 0.76 in 2009 and 0.74 in 2012), aged 65 to 84 years (OR = 0.61 and 0.59), and aged 85+ years (OR = 0.53 and 0.56). Between 2009 and 2012, the likelihood of TC care increased for all age groups, with the largest increase among those aged 85+ years (OR = 1.18), which was statistically different (p = 0.02) from the increase among adults aged 18 to 44 years (OR = 1.12). The analysis of transfers yielded similar results. CONCLUSIONS: Although patterns of increased TC treatment for all groups with severe head trauma indicate improvements, age-based disparities persisted. PMID- 27992955 TI - Landscape simplification weakens the association between terrestrial producer and consumer diversity in Europe. AB - Land-use change is one of the primary drivers of species loss, yet little is known about its effect on other components of biodiversity that may be at risk. Here, we ask whether, and to what extent, landscape simplification, measured as the percentage of arable land in the landscape, disrupts the functional and phylogenetic association between primary producers and consumers. Across seven European regions, we inferred the potential associations (functional and phylogenetic) between host plants and butterflies in 561 seminatural grasslands. Local plant diversity showed a strong bottom-up effect on butterfly diversity in the most complex landscapes, but this effect disappeared in simple landscapes. The functional associations between plant and butterflies are, therefore, the results of processes that act not only locally but are also dependent on the surrounding landscape context. Similarly, landscape simplification reduced the phylogenetic congruence among host plants and butterflies indicating that closely related butterflies become more generalist in the resources used. These processes occurred without any detectable change in species richness of plants or butterflies along the gradient of arable land. The structural properties of ecosystems are experiencing substantial erosion, with potentially pervasive effects on ecosystem functions and future evolutionary trajectories. Loss of interacting species might trigger cascading extinction events and reduce the stability of trophic interactions, as well as influence the longer term resilience of ecosystem functions. This underscores a growing realization that species richness is a crude and insensitive metric and that both functional and phylogenetic associations, measured across multiple trophic levels, are likely to provide additional and deeper insights into the resilience of ecosystems and the functions they provide. PMID- 27992956 TI - Degree of methylation burden is determined by the exposure period to carcinogenic factors. AB - Aberrant DNA methylation accumulated in normal tissues, namely methylation burden, is associated with risk of carcinogenesis. The levels of methylation burden are known to be influenced by multiple factors, such as genetic factors and strengths of carcinogenic factors. However, the impact of the degree of exposure to a carcinogenic factor is still unclear. Here, using a Mongolian gerbil model of Helicobacter pylori (H. pylori)-induced gastritis, we aimed to clarify the impact of the degree of exposure on methylation burden in normal gastric tissues. DNA methylation levels of four CpG islands, HE6, SA9, SB5, and SD2, increased by H. pylori infection, depending upon the infection period. After eradication of H. pylori, DNA methylation levels decreased, but tended to be higher in gastric mucosae with a longer infection period. DNA molecules with dense methylation, but not those with sparse methylation, increased depending upon the infection period. DNA methylation levels of one of the four CpG islands, SA9, tended to be higher in gastric mucosae of gerbils infected with H. pylori, even 50 weeks after eradication than in those of non-infected gerbils. These results showed for the first time that the levels of methylation burden in normal tissues are influenced by the degree of exposure to a carcinogenic factor. PMID- 27992957 TI - Prescribed burning consumes key forest structural components: implications for landscape heterogeneity. AB - Prescribed burning to achieve management objectives is a common practice in fire prone regions worldwide. Structural components of habitat that are combustible and slow to develop are particularly susceptible to change associated with prescribed burning. We used an experimental, "whole-landscape" approach to investigate the effect of differing patterns of prescribed burning on key habitat components (logs, stumps, dead trees, litter cover, litter depth, and understorey vegetation). Twenty-two landscapes (each ~100 ha) were selected in a dry forest ecosystem in southeast Australia. Experimental burns were conducted in 16 landscapes (stratified by burn extent) while six served as untreated controls. We measured habitat components prior to and after burning. Landscape burn extent ranged from 22% to 89% across the 16 burn treatments. With the exception of dead standing trees (no change), all measures of habitat components declined as a consequence of burning. The degree of loss increased as the extent to which a landscape was burned also increased. Prescribed burning had complex effects on the spatial heterogeneity (beta diversity) of structural components within landscapes. Landscapes that were more heterogeneous pre-fire were homogenized by burning, while those that were more homogenous pre-fire tended to display greater differentiation post-burning. Thus, the notion that patch mosaic burning enhances heterogeneity at the landscape-scale depends on prior conditions. These findings have important management implications. Where prescribed burns must be undertaken, effects on important resources can be moderated via control of burn characteristics (e.g., burn extent). Longer-term impacts of prescribed burning will be strongly influenced by the return interval, given the slow rate at which some structural components accumulate (decades to centuries). Management of habitat structural components is important given the critical role they play in (1) provision of habitat resources for diverse organisms, (2) retention of moisture and nutrients in otherwise dry, low-productivity systems, and (3) carbon storage. PMID- 27992958 TI - Impaired Akt Phosphorylation in Monocytes of Patients with Rheumatoid Arthritis. AB - It has been proposed that the Akt kinase pathway provides a regulatory mechanism to limit the inflammatory response. We examined the activation of Akt upon lipopolysaccharide (LPS) challenge in monocytes of patients with rheumatoid arthritis (RA) and correlated it with disease activity. Twelve subjects with recent-onset, DMARD-naive RA, thirteen patients with chronic, DMARD therapy-non responding RA and 27 healthy volunteers provided whole blood samples for phosphospecific flow cytometric measurement of unstimulated and LPS-stimulated Akt phosphorylation at serine 473 in monocytes, determined in relative fluorescence units (RFU). Activation capability, that is responsiveness of monocytes, was determined as the difference between stimulated and unstimulated samples and compared between groups using Mann-Whitney test. CRP and ESR, swollen and tender joint counts, patients' global assessment of disease activity, DAS28 score and plasma IL-6 determined by ELISA were correlated with Akt activation using Spearman method. Median (interquartile range) Akt activation capability was significantly lower in DMARD-naive (379 RFU [285, 432], P = 0.016) and even lower in DMARD-non-responding RA (258 RFU [213, 338], P < 0.001), compared to healthy controls (505 RFU[408, 639]) and showed a negative correlation with swollen joint count (r = -0.48, CI -0.78 to -0.05, P = 0.014), CRP (r = -0.42, CI -0.80 to 0.02, P = 0.039) and plasma IL-6 levels (r = -0.44, CI -0.65 to -0.17, P = 0.001). In conclusion, Akt activation capability of monocytes is low in early untreated RA and even lower in chronic, DMARD-non-responding RA, suggesting a role for Akt pathway in the pathogenesis of RA. PMID- 27992959 TI - Allergic sensitization at school age is a systemic low-grade inflammatory disorder. AB - BACKGROUND: Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization. METHODS: High-sensitivity C-reactive protein (hs-CRP), interleukin-1beta (IL 1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6 months (N = 214) and 7 years (N = 277) in children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at ages 1/2, 11/2, 4 and 6 years by specific IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principal component analyses (PCAs). RESULTS: Adjusted for gender, recent infections, and a CRP genetic risk score, hs-CRP at 7 years was associated with concurrent elevated specific IgE against any allergen [adjusted OR (aOR) = 1.40; 95% CI, 1.14-1.72; P = 0.001], aeroallergens (aOR, 1.43; 1.15-1.77; P = 0.001), food allergens (aOR, 1.31; 95% CI, 1.02-1.67; P = 0.04), sensitization without any clinical allergy symptoms (aOR = 1.40; 1.06 1.85; P = 0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariately associated with sensitization, but multiparametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6 months were not associated with subsequent development of sensitization phenotypes. CONCLUSIONS: Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early onset NCD. PMID- 27992960 TI - Reply: 'A plea for greater standardization in intraductal carcinoma of the prostate -greater standardization requires greater evidence': let's use the available evidence. PMID- 27992961 TI - Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow-up. AB - OBJECTIVE: Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR) and ACS after prolonged follow-up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow-up. DESIGN: Prospective study in a tertiary hospital. PATIENTS AND MEASUREMENTS: Seventy-one patients with AI [51 nonfunctioning (NFAI) and 20 ACS] and 5.54 +/- 1.7 years follow-up underwent testing for ACS and oral glucose tolerance test to determine IR indices and adrenal imaging. RESULTS: At follow-up, 16/51 (31%) NFAI patients converted to ACS, while two with previous ACS reverted to NFAI; 21% (7/33) of patients who did not covert to ACS exhibited high urinary-free cortisol (H-UFC) levels. All AI patients developed deterioration of IR irrespective of their cortisol secretory status. Eight patients developed newly diagnosed type 2 diabetes (9.8% NFAI and 15% ACS, respectively) and 14 IR (17.6% NFAI and 25% ACS, respectively). Adenoma size increased from 2.1 +/- 0.8 to 2.3 +/- 0.8 cm, whereas IR correlated with postdexamethasone cortisol level and adenoma size increase. IR showed an incremental continuum trend from normal UFC (Nu-UFC), to H-UFC, C-ACS and ACS patients. CONCLUSIONS: New-onset ACS developed in 31% patients with NFAI, whereas 21% of NFAI patients had H-UFC levels. All AI patients as a group and the subgroups of N-UFC, H-UFC, C-ACS and ACS patients developed deterioration of metabolic parameters during follow-up that was more prominent in ACS patients. PMID- 27992962 TI - C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody-mediated rejection episode: a retrospective cohort study. AB - After kidney transplantation, C4d is an incomplete marker of acute antibody mediated rejection (AMR) and C1q-binding donor-specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q-binding impact on allograft survival. We compared clinical, histological and serological features of C4d- and C4d+ AMR, C1q+ and C1q- DSA AMR and analysed C4d and C1q-binding impact on allograft survival. Among 500 for-cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.11-6.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q- AMR. PMID- 27992963 TI - Histological analysis of vasculopathy associated with pulmonary hypertension in combined pulmonary fibrosis and emphysema: comparison with idiopathic pulmonary fibrosis or emphysema alone. AB - AIMS: To evaluate pulmonary vasculopathy in an autopsy series of patients with combined pulmonary fibrosis and emphysema (CPFE), and compare these findings with those of patients with idiopathic pulmonary fibrosis (IPF) alone and emphysema alone. METHODS AND RESULTS: We retrospectively analysed the clinical, radiological and pathological features of 26 patients with CPFE, 11 with IPF, and 23 with emphysema. We evaluated pulmonary vascular, venous-venular and arteriolar tissue changes in the fibrotic, emphysematous and relatively unaffected (preserved) areas by using the Heath-Edwards scoring system. We found moderate-to severe vasculopathy in the CPFE group, but no significant differences in the fibrotic and emphysematous areas among the three groups. However, in the preserved area, the grading was significantly different among the three groups (P < 0.001), and vasculopathy in the CPFE group was the most severe. Although venous venular and arteriolar changes in almost all fibrotic and emphysematous areas in the three groups showed no significant differences, there were significant differences in venous-venular (P = 0.004) and arteriolar (P < 0.001) changes in the preserved area among the three groups, which were most prevalent in the CPFE group. In the CPFE group, venous-venular changes and vasculopathy by Heath Edwards grading were highest in the fibrotic area and lowest in the preserved area. CONCLUSIONS: These results imply that pulmonary vasculopathy in patients with CPFE could occur in the whole lung tissue. This may explain the tendency for it to lead to the development of pulmonary hypertension in CPFE cases. PMID- 27992965 TI - Globular glial inclusions unveil enigmas of MAPT mutations. PMID- 27992964 TI - Double-stranded RNA-dependent protein kinase signalling and paradigms of cardiometabolic syndrome. AB - Metabolic syndrome (Met S) is a collection of the most severe cardiometabolic risk factors that encompasses raised fasting plasma glucose, dyslipidaemia, insulin resistance, obesity and hypertension. The precise mechanism underlying the pathogenesis of Met S remains unclear. More often oxidative stress, inflammation and apoptosis are implicated in its aetiology. Recently, double stranded RNA-dependent protein kinase has been found to intersect at the cross road of oxidative stress, inflammation and apoptosis in several metabolic diseases. Therefore, an effort has been made in the present review to discuss the role of double-stranded RNA-dependent protein kinase and above-mentioned mechanisms in the progression of Met S, along with its interlinking in major clinical manifestations of Met S such as hypertension and diabetic cardiomyopathy. PMID- 27992966 TI - The role of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral nerve sheath tumours. AB - AIMS: STAT3 is a pro-oncogenic transcription factor that requires phosphorylation for transcriptional activation. The aim of this study was to evaluate the role of phosphorylated STAT3 (pSTAT3) expression in neurofibromas, schwannomas, and malignant peripheral nerve sheath tumours (MPNSTs). METHODS AND RESULTS: Twenty six neurofibromas, 62 schwannomas and 39 MPNSTs from a formalin-fixed paraffin embedded tissue microarray were examined. Immunohistochemical analysis was performed with an anti-pSTAT3 (Tyr705) antibody. Nuclear expression was reviewed for both intensity and percentage of tumoral labelling. Distributions of disease specific overall survival (DSOS) and event-free survival (EFS) were estimated with the Kaplan-Meier method, and compared between two pSTAT3 groups by use of the log-rank test. MPNSTs had higher median tumoral labelling than neurofibromas (P = 0.0012) or schwannomas (P = 0.0008). Moderate to strong pSTAT3 expression (defined as at least moderate labelling in >=50% of cells) was found more frequently in MPNSTs than in neurofibromas (P = 0.026). Among MPNSTs, pSTAT3 expression differed between primary, recurrent and metastatic disease (P = 0.063 with increased expression in recurrent and metastatic cases). pSTAT3 expression (at least moderate labelling in >=10% of cells) in primary MPNSTs was associated with worse DSOS (P = 0.048) and trended towards being associated with worse EFS (P = 0.063). Paired specimens revealed no increase in pSTAT3 expression in the recurrences or metastases relative to the primary tumour, suggesting that pSTAT3 expression may be an early indicator of aggressive disease at disease onset. CONCLUSIONS: pSTAT3 is expressed in a higher proportion of MPNSTs than neurofibromas and schwannomas. Moderate to strong pSTAT3 expression in >=10% of cells was found to be a negative prognostic factor for DSOS among primary MPNSTs, suggesting a role of pSTAT3 in the progression of these tumours. PMID- 27992967 TI - Role of fetal MRI in the evaluation of isolated and non-isolated corpus callosum dysgenesis: results of a cross-sectional study. AB - PURPOSE: The aims of this study were to characterize isolated and non-isolated forms of corpus callosum dysgenesis (CCD) at fetal magnetic resonance imaging (MRI) and to identify early predictors of associated anomalies. METHODS: We retrospectively analyzed 104 fetuses with CCD undergoing MRI between 2006 and 2016. Corpus callosum, cavum septi pellucidi, biometry, presence of ventriculomegaly, gyration anomalies, cranio-encephalic abnormalities and body malformations were evaluated. Results of genetic tests were also recorded. RESULTS: At MRI, isolated CCD was 26.9%, the rest being associated to other abnormalities. In the isolated group, median gestational age at MRI was lower in complete agenesis than in hypoplasia (22 vs 28 weeks). In the group with additional findings, cortical dysplasia was the most frequently associated feature (P = 0.008), with a more frequent occurrence in complete agenesis (70%) versus other forms; mesial frontal lobes were more often involved than other cortical regions (P = 0.006), with polymicrogyria as the most frequent cortical malformation (40%). Multivariate analysis confirmed the association between complete agenesis and cortical dysplasia (odds ratio = 7.29, 95% confidence interval 1.51-35.21). CONCLUSIONS: CCD is often complicated by other intra cranial and extra-cranial findings (cortical dysplasias as the most prevalent) that significantly affect the postnatal prognosis. The present study showed CCD with associated anomalies as more frequent than isolated (73.1%). In isolated forms, severe ventriculomegaly was a reliable herald of future appearance of associated features. (c) 2016 John Wiley & Sons, Ltd. PMID- 27992968 TI - Establishment of in vitro model of erectile dysfunction for the study of high glucose-induced angiopathy and neuropathy. AB - Penile erection requires complex interaction between vascular endothelial cells, smooth muscle cells, pericytes, and autonomic nerves. Diabetes mellitus is one of the most common causes of erectile dysfunction (ED) and multiple pathogenic factors, such as cavernous angiopathy and autonomic neuropathy, are associated with diabetic ED. Although a variety of animal models of diabetic ED play an important role in understanding pathophysiologic mechanisms of diabetes-induced ED, these animal models have limitations for addressing the exact cellular or molecular mechanisms involved in ED. Therefore, we established an in vitro model of ED for the study of high-glucose-induced angiopathy and neuropathy. We successfully isolated and cultivated mouse cavernous endothelial cells (MCECs) and mouse cavernous pericytes (MCPs). The cells were exposed to the normal glucose (5 mmoL) or high-glucose (30 mmoL) condition for 48 h. In vitro matrigel assay revealed impairments in tube formation in primary cultured MCECs or MCPs exposed to high-glucose condition. To study cellular interaction between MCECs and MCPs, co-culture systems including indirect contact, indirect non-contact, and direct mixed co-culture system, were established. We observed impaired tube formation and increased permeability in MCECs-MCPs co-culture exposed to high glucose condition. To evaluate the effect of high-glucose on neurite sprouting, the mouse major pelvic ganglion (MPG) tissue was harvested and cultivated in matrigel. Neurite outgrowth and nNOS-positive nerve fibers were significantly lower in MPG tissues exposed to the high-glucose condition than in the tissues exposed to the normal-glucose condition. We believe that in vitro model of ED will aid us to understand the role of each cellular component in the pathogenesis of diabetic ED, and also be a useful tool for determining the efficacy of candidate therapeutics targeting vascular or neuronal function. This model would present a new avenue for drug discovery and development of novel therapeutic modalities for erectile dysfunction. PMID- 27992969 TI - Sexuality and fertility in men with hypospadias; improved outcome. AB - The aim of this study was to investigate sexual function and fertility in adult men born with hypospadias. Patients born with hypospadias, age-matched controls, and a group of circumcised men completed a questionnaire constructed to reflect their psychosexual situation and fertility. Core gender identity, sexual orientation, and gender role behavior was also assessed. 167 patients [63% distal, 24% mid shaft and 13% proximal, mean age 34 (19-54) years], 169 controls from the general population [mean age 33 (19-48) years] and 47 controls circumcised because of phimosis (mean age 26 [19-44]) participated and completed the questionnaire. There were no differences in having a partner, reported fertility, age at sexarche (mean age 17.8), number of sex partners or sexual interest between the patients and controls. More patients than controls reported anejaculation. Reported glanular sensitivity was lower in hypospadias patients and circumcised controls compared with non-circumcised controls. The odds of being satisfied with their sexual life increased with a higher penile perception score in patients (OR = 1.54, p = 0.01). There was no association with penile length. Sexual orientation, core gender identity and gender role behavior were sex-typical in both patients and controls. Patients with proximal hypospadias had a lower reported fertility, experienced anejaculation more often, and were less satisfied with their sexual life. Men born with hypospadias have a good long-term outcome concerning sexual function and fertility. Men born with proximal hypospadias have a more impaired outcome concerning both sexual function and fertility. As satisfaction with genital appearance is important for sexual life satisfaction, clinical, and psychological follow-up into adulthood is especially important in boys born with proximal hypospadias. PMID- 27992970 TI - Pathogen dynamics during invasion and establishment of white-nose syndrome explain mechanisms of host persistence. AB - Disease dynamics during pathogen invasion and establishment determine the impacts of disease on host populations and determine the mechanisms of host persistence. Temporal progression of prevalence and infection intensity illustrate whether tolerance, resistance, reduced transmission, or demographic compensation allow initially declining populations to persist. We measured infection dynamics of the fungal pathogen Pseudogymnoascus destructans that causes white-nose syndrome in bats by estimating pathogen prevalence and load in seven bat species at 167 hibernacula over a decade as the pathogen invaded, became established, and some host populations stabilized. Fungal loads increased rapidly and prevalence rose to nearly 100% at most sites within 2 yr of invasion in six of seven species. Prevalence and loads did not decline over time despite huge reductions in colony sizes, likely due to an extensive environmental reservoir. However, there was substantial variation in fungal load among sites with persisting colonies, suggesting that both tolerance and resistance developed at different sites in the same species. In contrast, one species disappeared from hibernacula within 3 yr of pathogen invasion. Variable host responses to pathogen invasion require different management strategies to prevent disease-induced extinction and to facilitate evolution of tolerance or resistance in persisting populations. PMID- 27992971 TI - Salinization triggers a trophic cascade in experimental freshwater communities with varying food-chain length. AB - The application of road deicing salts in northern regions worldwide is changing the chemical environment of freshwater ecosystems. Chloride levels in many lakes, streams, and wetlands exceed the chronic and acute thresholds established by the United States and Canada for the protection of freshwater biota. Few studies have identified the impacts of deicing salts in stream and wetland communities and none have examined impacts in lake communities. We tested how relevant concentrations of road salt (15, 100, 250, 500, and 1000 mg Cl- /L) interacted with experimental communities containing two or three trophic levels (i.e., no fish vs. predatory fish). We hypothesized that road salt and fish would have a negative synergistic effect on zooplankton, which would then induce a trophic cascade. We tested this hypothesis in outdoor mesocosms containing filamentous algae, periphyton, phytoplankton, zooplankton, several macroinvertebrate species, and fish. We found that the presence of fish and high salt had a negative synergistic effect on the zooplankton community, which in turn caused an increase in phytoplankton. Contributing to the magnitude of this trophic cascade was a direct positive effect of high salinity on phytoplankton abundance. Cascading effects were limited with respect to impacts on the benthic food web. Periphyton and snail grazers were unaffected by the salt-induced trophic cascade, but the biomass of filamentous algae decreased as a result of competition with phytoplankton for light or nutrients. We also found direct negative effects of high salinity on the biomass of filamentous algae and amphipods (Hyalella azteca) and the mortality of banded mystery snails (Viviparus georgianus) and fingernail clams (Sphaerium simile). Clam mortality was dependent on the presence of fish, suggesting a non-consumptive interactive effect with salt. Our results indicate that globally increasing concentrations of road salt can alter community structure via both direct and indirect effects. PMID- 27992972 TI - Protective features of resveratrol on human spermatozoa cryopreservation may be mediated through 5' AMP-activated protein kinase activation. AB - Biochemical and physical modifications during the freeze-thaw process adversely influence the restoration of energy-dependent sperm functions required for fertilization. Resveratrol, a phytoalexin, has been introduced to activate 5' AMP activated protein kinase which is a cell energy sensor and a cell metabolism regulator. The cryoprotection of resveratrol on sperm cryoinjury via activation of AMP-activated protein kinase also remains to be elucidated. Our aim, thus, was to investigate: (i) the presence and intracellular localization of AMP-activated protein kinase protein; (ii) whether resveratrol may exert a protective effect on certain functional properties of fresh and post-thaw human spermatozoa through modulation of AMP-activated protein kinase. Spermatozoa from normozoospermic men were incubated with or without different concentrations of Compound C as an AMP activated protein kinase inhibitor or resveratrol as an AMP-activated protein kinase activator for different lengths of time and were then cryopreserved. AMP activated protein kinase is expressed essentially in the entire flagellum and the post-equatorial region. Viability of fresh spermatozoa was not significantly affected by the presence of Compound C or resveratrol. However, although Compound C caused a potent inhibition of spermatozoa motility parameters, resveratrol did not induce negative effect, except a significant reduction in motility at 25 MUm for 1 h. Furthermore, resveratrol significantly increased AMP-activated protein kinase phosphorylation and mitochondrial membrane potential and decreased reactive oxygen species and apoptosis-like changes in frozen-thawed spermatozoa. Nevertheless, it was not able to compensate decreased sperm viability and motility parameters following cryopreservation. In contrast, Compound C showed opposite effects to resveratrol on AMP-activated protein kinase phosphorylation, reactive oxygen species, apoptosis-like changes, mitochondrial membrane potential, and motility parameters. These findings, although preliminary, suggest that resveratrol-induced improvement of cryopreserved sperm functions may be mediated through activation of AMP-activated protein kinase, indicating the importance of AMP-activated protein kinase activity for human spermatozoa functions. Further investigations are required to elucidate the mechanism by which resveratrol ameliorates oxidative stress-mediated damages in an AMP activated protein kinase-dependent mechanism. PMID- 27992973 TI - Abdominal organ procurement in the Netherlands - an analysis of quality and clinical impact. AB - Between March 2012 and August 2013, 591 quality forms were filled out for abdominal organs in the Netherlands. In 133 cases (23%), there was a discrepancy between the evaluation from the procuring and transplanting surgeons. Injuries were seen in 148 (25%) organs of which 12 (2%) led to discarding of the organ: one of 133 (0.8%) livers, five of 38 (13%) pancreata and six of 420 (1.4%) kidneys (P < 0.001). Higher donor BMI was a risk factor for procurement-related injury in all organs (OR: 1.06, P = 0.011) and donor after cardiac death (DCD) donation in liver procurement (OR: 2.31, P = 0.034). DCD donation is also associated with more pancreata being discarded due to injury (OR: 10.333, P = 0.046). A higher procurement volume in a centre was associated with less injury in pancreata (OR = -0.95, P = 0.013) and kidneys (OR = -0.91, P = 0.012). The quality form system efficiently monitors the quality of organ procurement. Although there is a relatively high rate of organ injury, the discard rate is low and it does not significantly affect 1-year graft survival for any organ. We identified higher BMI as a risk factor for injury in abdominal organs and DCD as a risk factor in livers. A higher procurement volume is associated with fewer injuries. PMID- 27992974 TI - ? PMID- 27992975 TI - [Three cases of de novo multiple myeloma after kidney transplantation]. AB - Light chain-associated kidney compromise is frequent in patients with monoclonal gammopathies; it affects the glomeruli or the tubules, and its most common cause is multiple myeloma. It may develop after a kidney transplant due to recurrence of a preexisting multiple myeloma or it can be a de novo disease manifesting as graft dysfunction and proteinuria. A kidney biopsy is always necessary to confirm the diagnosis.We describe three cases of kidney graft dysfunction due to multiple myeloma in patients without presence of the disease before the transplant. PMID- 27992976 TI - [Idiopathic pulmonary hemosiderosis with dendriform pulmonary ossification]. AB - Pulmonary ossification is a rare and usually asymptomatic finding reported as incidental in lung biopsies. Similarly, idiopathic pulmonary hemosiderosis is a rare cause of pulmonary infiltrates. We report the case of a 64-year old man with chronic respiratory symptoms in whom these two histopathological findings converged. PMID- 27992977 TI - [Measurement of dietary sodium intake in a group of children from one to 18 months of age in a pediatric service in Cali, Colombia]. AB - INTRODUCTION: The fatty streaks in an arterial wall can appear from the third year of age, and they show an association with atherogenic risk factors such as hypertension and sodium in the diet. Given the difficulty of data gathering, few studies report the intake of sodium in the diet. OBJECTIVE: To determine average sodium intake in the diet of children between one and 18 months of age through a three-day dietary survey. MATERIALS AND METHODS: This was a cross-sectional study with 48 children without renal disease or diet restrictions seen in pediatric practice between January and June, 2011. It included a dietary survey for the parents, nutritional status classification by anthropometry, and blood pressure measurements. Sodium content and other nutrients in the diet program were analyzed with the International Food Consumption Program (CERES), anthropometry with the World Health Organization Anthro program, and Epi-info for socio demographic characteristics. RESULTS: In total, 69% of children had high sodium consumption, 6.2% had high blood pressure, and 20.7% were overweight and obese. CONCLUSIONS: The prevalence of hypertension exceeds that reported for Colombia (1 3%). Two of the three children with high blood pressure had high sodium intake and they were overweight and obese, with values above those reported for Colombian children (16%). We suggest to measure blood pressure early, and to restrict salt and sugar in food for infants and children under two years of age. Also, larger studies should be conducted to collect population data on sodium intake and develop appropriate and timely intervention strategies to reduce risks in adulthood. PMID- 27992978 TI - [Concordance between the zinc sulphate flotation and centrifugal sedimentation methods for the diagnosis of intestinal parasites]. AB - INTRODUCTION: The diagnosis of intestinal parasitic infections depends on the parasite load, the specific gravity density of the parasite eggs, oocysts or cysts, and the density and viscosity of flotation or sedimentation medium where faeces are processed. OBJECTIVE: To evaluate the concordance between zinc sulphate flotation and centrifugal sedimentation in the recovery of parasites in faecal samples of children. MATERIALS AND METHODS: Faecal samples of 330 children from day care centers were evaluated by zinc sulphate flotation and centrifugal sedimentation techniques. The frequencies of detection of parasites by each method were determined and the agreement between the diagnostic techniques was evaluated using the kappa index, with 95% confidence intervals. RESULTS: The faecal flotation in zinc sulphate diagnosed significantly more cases of Trichuris trichiura infection when compared to centrifugal sedimentation (39/330; 11.8% vs. 13/330; 3.9%, p<0.001), with low diagnostic concordance between methods (kappa=0.264; 95% CI: 0.102-0.427). Moreover, all positive samples for Enterobius vermicularis eggs (n=5) and Strongyloides stercoralis larvae (n=3) were diagnosed only by zinc sulphate. No statistical differences were observed between methods for protozoa identification. CONCLUSIONS: The results showed that centrifugal flotation in zinc sulphate solution was significantly more likely to detect light helminths eggs such as those of T. trichiura and E. vermicularis in faeces than the centrifugal sedimentation process. PMID- 27992979 TI - [Enteroparasite determination in Lactuca sativa from farms dedicated to its production in Pasto, Colombia]. AB - INTRODUCTION: Currently, vegetables like lettuce are widely recommended as part of the daily diet given their high nutritional value; however, while consumers feel attracted to the benefits provided by the vegetable, they may also be exposed to parasitic intestinal infections. OBJECTIVE: To determine the presence or absence of enteroparasites in lettuce (Lactuca sativa) grown in the rural area in the municipality of Pasto, and to analyze associated factors based on the characterization of the lands. MATERIALS AND METHODS: We conducted a descriptive double blind cross-sectional study. We took a total of 105 samples from 21 properties from June to December, 2013, and we processed them by sedimentation and flotation tests. Additionally, the owners were surveyed in order to obtain information about the possible variables influencing the occurrence of enteroparasites. RESULTS: We detected contamination in 100% of the lettuce samples and we found parasite eggs and larvae as follows: 95.25% with Entamoeba spp. cysts; 71.43% with Isospora spp. oocysts; 61.90% with Strongyloides stercoralis larvae (L3); 28.57% with Toxocara spp. eggs, and 4.76% with Eimeria spp. oocysts. Using the chi-square test we found association between Entamoeba spp. and ditches (p=0.008), dogs (p=0.008) and septic tanks (p=0.029); between Isospora spp. and compost (p=0.0001), dogs (p=0.0001) and slugs (p=0.002); between S. stercoralis and handling (p=0.003), and between Toxocara spp. and no use of biodigesters (p= 0.002). CONCLUSIONS: We found contamination with enteroparasites in lettuce samples from growing areas in the municipality of Pasto with animal and human sources as their main reservoirs, although others were present in the environment. PMID- 27992981 TI - [Years of life lost as a measure of cancer burden in Colombia, 1997-2012]. AB - INTRODUCTION: There is hardly any information regarding years of life lost due to cancer in Colombia. OBJECTIVE: To quantify total and average years of life lost due to cancer in Colombia, and to investigate changes in this burden between 1997 and 2012. MATERIALS AND METHODS: We obtained sex-specific data on age distribution, remaining life expectancy, deaths due to specific cancers and total number of deaths from the Colombian Departamento Administrativo Nacional de Estadisticas. We calculated years of life lost based on each individual's age at death and the remaining life expectancy at that age; as for average years of life, we divided these by the number of deaths due to specific cancers. RESULTS: The total number of cancer deaths increased by 33% between 1997 and 2012, comprising 15% of male and 20% of female deaths in the period 2010-2012. Total years of life lost due to cancer increased by 25.1% for males and 31.1% for females over the study period. The highest increases (>40%) were observed for colorectal, pancreas and kidney cancers in both sexes, for melanomas and bladder cancer in men, and for breast and ovarian cancer in women. Trends in average years of life lost were stable. Almost half (48-50%) of the years of life lost due to childhood cancers were due to leukemia. CONCLUSION: Cancer is an increasing health burden in Colombia. The high average years of life lost illustrate the poor prognosis of the disease compared to other countries. Primary prevention, early detection, and adequate and timely treatments are needed to change this situation. PMID- 27992980 TI - [Factors associated to mortality by non-communicable diseases in Colombia, 2008 2012]. AB - INTRODUCTION: Non-communicable diseases are the leading cause of premature mortality and disability in the world. OBJECTIVE: To describe the trend pattern and to explore which risk factors were associated with mortality rates in Colombia from 2008 to 2012. MATERIALS AND METHODS: A descriptive study was conducted to analyze mortality rate trends from the official vital statistics (death certificates) from 2008 to 2012. RESULTS: Between 2008 and 2012 there were 727,146 deaths due to non-communicable diseases, and 58.5% of them occurred among men aged less than 75 years. The mortality rate during the study period was 319.5 deaths per 100,000 people. The trend showed a statistically significant decline in mortality rates (-3%) across the country. For each woman who died due to external causes (i.e., not related to illness or old age), five men died under the same circumstances (OR=5,295; IC 95%: 5,143-5,454). The five most important causes of mortality were heart diseases, injuries due to aggressions, malignant tumors, chronic lower respiratory diseases and road traffic accidents. CONCLUSION: The cause of death differed significantly by sex and age. The main causes of death in Colombia were heart diseases and injuries (homicide). Mortality was higher among men of all ages than among women, but 15 to 45 year old males were more likely to die due to external causes. PMID- 27992982 TI - [Prevalence of birth defects in Risaralda, 2010-2013]. AB - INTRODUCTION: The data regarding birth defects at local levels in developing countries like Colombia are scarce. OBJECTIVE: To describe the profile of congenital abnormalities in the province of Risaralda, Colombia. MATERIALS AND METHODS: We included the information on infants with structural and functional abnormalities at birth between June, 2010, and December, 2013, from records of the Instituto Nacional de Salud, and compared it with those of children born in the same period in a local clinic participating in the Collaborative Study of Congenital Malformations. We analyzed the data using Stata 10(r). RESULTS: We found a prevalence of nine defects per 1,000 newborns from the total live births in Risaralda. The local clinic registered in the Collaborative Study of Congenital Malformations registered a prevalence of 34 defects per 1,000 births. Most frequent defects were heart defects, followed by cleft lip and palate, abdominal wall defects, skeletal dysplasia, hydrocephalus, polydactyly and Down syndrome. CONCLUSIONS: Having a baseline on the prevalence of congenital defects in Risaralda is very useful in the design of prevention policies oriented to decrease congenital defects incidence and severity. Inclusion of maternity hospitals in the Collaborative Study of Congenital Malformations strengthens national recording and reporting of birth defects. PMID- 27992983 TI - Risk factors for hepatitis C virus infection in the Colombian Caribbean coast: A case-control study. AB - INTRODUCTION: An estimated 6.8-8.9 million people are infected with hepatitis C virus in Latin America, of which less than 1% receives antiviral treatment. Studies so far in Colombia have attempted to determine the prevalence of the disease in some risk groups, thus preventing the identification of other factors potentially involved in the spread of the infection. OBJECTIVES: To identify traditional and non-traditional risk factors for chronic hepatitis C in the Colombian Caribbean coast. MATERIALS AND METHODS: This was a case-control study (1:3) matched by health care provider and age (+/- 10 years) conducted at the primary care level of gastroenterology and hepatology outpatient services. All patients with a positive ELISA underwent a confirmatory viral load test. A multivariate logistic regression analysis identified the independent predictors of infection. RESULTS: Blood transfusion (OR=159.2; 95% CI: 35.4-715; p<0.001) and history of hospitalization before 1994 (OR=4.7; 95% CI: 1.3-17.1; p=0.018) were identified as the only two independent predictors of infection. CONCLUSION: It is necessary to check the reproducibility of these results and to conduct cost effectiveness studies before recommending their use in the design of new screening strategies. PMID- 27992985 TI - [Monitoring the Paraguayan epidemiological dengue surveillance system (2009-2011) using Benford's law]. AB - INTRODUCTION: Dengue is the most widespread arbovirus worldwide. In Paraguay, it reappeared in 1988-1989, with one of the largest epidemic outbreaks occurring in 2011. OBJECTIVE: To evaluate the performance of the dengue epidemiological surveillance system in Paraguay between 2009 and 2011. MATERIALS AND METHODS: We conducted an ecological study with secondary epidemiological surveillance data. We analyzed notified cases of the disease based on the distribution expected by Benford's law. To this end, we used the first and second digits from the global records stratified by region, season, population density, indicators of housing conditions and heads of cattle. RESULTS: The epidemiological surveillance system performed better during non-epidemic periods and in the states with better housing conditions and fewer heads of cattle. CONCLUSION: Given that a difference in the performance existed, we recommended that the system remains operating at the same high alert level even during periods when fewer cases are expected. The technology used by the method proposed to monitor the notification of cases is easy to transfer to operational staff. PMID- 27992984 TI - [Mortality by homicides in Colombia, 1998-2012]. AB - INTRODUCTION: Homicide is a universal indicator of social violence with large public health consequences. OBJECTIVES: To describe mortality by homicides and to analyze its trends and geographic distribution in Colombia between 1998 and 2012. MATERIALS AND METHODS: We conducted a descriptive study of deaths by homicide in Colombia between 1998 and 2012 using official mortality databases and the population projections of the Departamento Administrativo Nacional de Estadistica, DANE. We calculated age- and sex-specific mortality rates, and we analyzed the geographical distribution of mean-adjusted homicide mortality rates at municipal level. RESULTS: Between 1998 and 2012, 331,470 homicides were reported in Colombia. The mean crude rate was 51.5 per 100,000 inhabitants: 95.9 in men and 8.2 in women. Since 2003, a decrease in the number of deaths and rates was observed; 91.9% of the victims were men and the highest mortality rates were reported in the 20-29 years old group. The most frequently involved mechanism was the firearm: Eight of 10 homicides in men, and seven of 10 homicides in women. Out of 1,122 municipalities, 186 were in the highest quintile, accumulating 50.1% of all deaths. CONCLUSIONS: In Colombia, homicides have been one of the leading causes of death with a trend towards reduction since 2002. Its geographical distribution has been heterogeneous. To continue addressing this public health issue we must recur to multidisciplinary analytical methodologies for a better understanding of the phenomenon. PMID- 27992986 TI - [Effect of genetics, epigenetics and variations in the transcriptional expression of cadherin-E in breast cancer susceptibility]. AB - INTRODUCTION: Cadherin-E (CDH1) is an important regulator of epithelial mesenchymal transition, invasion and metastasis in many carcinomas. However, germinal epimutations and mutations effect in breast cancer susceptibility is not clear. OBJECTIVE: To evaluate rs334558 polymorphism, promoter methylation status and CDH1 expression profile in breast cancer patients. MATERIALS AND METHODS: We collected peripheral blood samples from 102 breast cancer patients and 102 healthy subjects. The identification of rs334558 polymorphism was performed using PCR-RFLP, while methylation-specific PCR (MSP) and methylation-sensitive high resolution melting (MS-HRM) were used to explore CDH1 methylation status; finally, CDH1 transcriptional expression profile was evaluated using RT-qPCR. RESULTS: We found no association between rs334558 polymorphism and breast cancer. Aberrant promoter methylation profile was found in breast cancer patients and it was related with early cancer stages. CDH1 down-regulation was significantly associated with metastasis and promoter methylation. CONCLUSION: CDH1 alterations were associated with invasion and metastasis in breast cancer. Our results offer further evidence of CDH1 relevance in breast cancer development and progression. PMID- 27992987 TI - [Cytotoxic effect of palladium (II) inclusion compounds in beta-cyclodextrin]. AB - INTRODUCTION: Thiosemicarbazones and palladium (II) complexes have antineoplastic activities with mild side effects, for which they are considered new alternative antineoplastic drugs. However, the IC50 ranges of these complexes vary due to differences in their structure and solubility and their sensitivities for various cellular targets. Beta-cyclodextrin is an additive used to improve the solubility and stability of various drugs for therapeutic use, but the combination of beta cyclodextrin with palladium (II) complexes and thiosemicarbazones has not been tested yet. OBJECTIVE: To study the cytotoxic effect of palladium (II) inclusion complexes in beta-cyclodextrin. MATERIALS AND METHODS: We tested the cytotoxic activity of palladium complexes combined with beta-cyclodextrin in the breast cancer cell line MCF-7 using a sulforhodamine B assay. RESULTS: We tested the antiproliferative activity of palladium (II) complexes with and without the ligands MePhPzTSC and Ph2PzTSC and with and without beta-cyclodextrin in MCF-7 cells and compared them to that of cisplatin. All combinations showed antiproliferative activity; however, the activity was greater for the combinations that included beta-cyclodextrin: ([Pd (MePhPzTSC) 2] * beta-CD and [Pd (Ph2PzTSC) 2] * beta-CD), at concentrations of 0.14 and 0.49 MUM, respectively. The IC50 for this complex was 5-fold lower than that of the ligand free combinations (1.4 and 2.9 MUM, respectively). The IC50 for free palladium (II) complex was 0.571.24 MUM and that for cisplatin was 6.87 MUM. CONCLUSIONS: Beta-cyclodextrin significantly enhanced the cytotoxic activities of palladium (II) complexes and thiosemicarbazones probably by improving their solubility and bioavailability. The addition of beta-cyclodextrin is a possible strategy for designing new anticancer drugs. PMID- 27992988 TI - [Risk factors for methicillin-resistant Staphylococcus aureus bacteremia: A multicenter matched case-control study]. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus is a frequent pathogen at critical care services. Its presence leads to increased hospital stays and mortality risk in patients with bacteremia. However, the etiology of this resistance marker has not been fully studied. OBJECTIVE: To identify risk factors associated with the emergence of methicillin-resistant S. aureus bacteremia in critically ill patients treated at intensive care units in Bogota, Colombia. MATERIALS AND METHODS: We conducted a retrospective paired case-control study, nested in a cohort of patients diagnosed with S. aureus bacteremia and treated at intensive care units between 2006 and 2008 in Bogota. Cases were patients with positive blood culture to methicillin resistance, matched in a 1:1 ratio with methicillin-sensitive controls isolated from the same institution and hospitalization year. We used conditional logistic regression to analyze the risk factors associated with the presence of resistance, with emphasis on prior antibiotic therapy. RESULTS: We included 372 patients with S. aureus bacteremia. Factors such as the use of pre-hospital devices: vascular (OR=1.986, 95% CI 1.038 to 3.801) and urinary (OR=2.559, 95% CI: 1.170 to 5.596), along with the number of previously used antibiotics, were associated with the emergence of resistance. The number of antibiotics used previously was determined to have a gradient effect, particularly carbapenems. CONCLUSIONS: The rational use of antibiotics and surveillance of exposure to surgical procedures or use of invasive devices are interventions that could diminish the emergence of methicillin-resistant S. aureus bacteremia causes. PMID- 27992989 TI - [Facial nerve injuries cause changes in central nervous system microglial cells]. AB - INTRODUCTION: Our research group has described both morphological and electrophysiological changes in motor cortex pyramidal neurons associated with contralateral facial nerve injury in rats. However, little is known about those neural changes, which occur together with changes in surrounding glial cells. OBJECTIVE: To characterize the effect of the unilateral facial nerve injury on microglial proliferation and activation in the primary motor cortex. MATERIALS AND METHODS: We performed immunohistochemical experiments in order to detect microglial cells in brain tissue of rats with unilateral facial nerve lesion sacrificed at different times after the injury. We caused two types of lesions: reversible (by crushing, which allows functional recovery), and irreversible (by section, which produces permanent paralysis). We compared the brain tissues of control animals (without surgical intervention) and sham-operated animals with animals with lesions sacrificed at 1, 3, 7, 21 or 35 days after the injury. RESULTS: In primary motor cortex, the microglial cells of irreversibly injured animals showed proliferation and activation between three and seven days post lesion. The proliferation of microglial cells in reversibly injured animals was significant only three days after the lesion. CONCLUSIONS: Facial nerve injury causes changes in microglial cells in the primary motor cortex. These modifications could be involved in the generation of morphological and electrophysiological changes previously described in the pyramidal neurons of primary motor cortex that command facial movements. PMID- 27992991 TI - ? PMID- 27992990 TI - Papular urticaria: A review of causal agents in Colombia. AB - Papular urticaria is a chronic allergic reaction induced by insect bites, which is common in the tropics. The objective of this review was to deepen on epidemiological and immunological aspects of this disease, focused on data published in Latin American countries.We conducted a non-systematic review of the literature through electronic search on the epidemiology of papular urticaria, the entomological characteristics of the causative agents and associated immunological mechanisms.Several reports from medical centers suggest that papular urticaria is common in Latin America. Only one epidemiological survey designed to estimate prevalence of papular urticaria has been published, reporting that about a quarter of children under six years of age is affected by this condition in Bogota. There is evidence on the causal relationship among exposure to indoor fleas, poverty and papular urticaria in Bogota, a representative city of the Andean altitudes. Information about causal insects in tropical warmer areas is scarce, although from clinical reports Aedes aegypti and Culex quienquefasciatus appear to be the most common. Th2 cellular-mediated mechanisms are involved in its pathogenesis, which explains its delayed hypersensitivity. The role of immunoglobulin E is not clear in this disease. Insect-derived antigens directly involved in papular urticaria etiology are unknown. However, it is possible that common molecules among causal insects mediate cross-reactive reactions, such as Cte f 2 allergen, found in cat fleas, and its counterparts in mosquitoes.Papular urticaria is a frequent disease in Latin America that should be further investigated. Immunological characterization of the molecular components that cause this condition may solve questions about its pathogenesis. PMID- 27992992 TI - ? PMID- 27992993 TI - Mechanisms of Protein Translocation on DNA Are Differentially Responsive to Water Activity. AB - Water plays important but poorly understood roles in the functions of most biomolecules. We are interested in understanding how proteins use diverse search mechanisms to locate specific sites on DNA; here we present a study of the role of closely associated waters in diverse translocation mechanisms. The bacterial DNA adenine methyltransferase, Dam, moves across large segments of DNA using an intersegmental hopping mechanism, relying in part on movement through bulk water. In contrast, other proteins, such as the bacterial restriction endonuclease EcoRI, rely on a sliding mechanism, requiring the protein to stay closely associated with DNA. Here we probed how these two mechanistically distinct proteins respond to well-characterized osmolytes, dimethyl sulfoxide (DMSO), and glycerol. The ability of Dam to move over large segments of DNA is not impacted by either osmolyte, consistent with its minimal reliance on a sliding mechanism. In contrast, EcoRI endonuclease translocation is significantly enhanced by DMSO and inhibited by glycerol, providing further corroboration that these proteins rely on distinct translocation mechanisms. The well-established similar effects of these osmolytes on bulk water, and their differential effects on macromolecule associated waters, support our results and provide further evidence of the importance of water in interactions between macromolecules and their ligands. PMID- 27992994 TI - A New Cross-Link for an Old Cross-Linking Drug: The Nitrogen Mustard Anticancer Agent Mechlorethamine Generates Cross-Links Derived from Abasic Sites in Addition to the Expected Drug-Bridged Cross-Links. AB - Nitrogen mustard anticancer drugs generate highly reactive aziridinium ions that alkylate DNA. Monoadducts arising from reaction with position N7 of guanine residues are the major DNA adducts generated by these agents. Interstrand cross links in which the drug bridges position N7 of two guanine residues are formed in low yields relative to those of the monoadducts but are generally thought to be central to medicinal activity. The N7-alkylguanine residues generated by nitrogen mustards are depurinated to yield abasic (Ap) sites in duplex DNA. Here, we show that Ap sites generated by the nitrogen mustard mechlorethamine lead to interstrand cross-links of a type not previously associated with this drug. Gel electrophoretic data were consistent with early evolution of the expected drug bridged cross-links, followed by the appearance of Ap-derived cross-links. The evidence is further consistent with a reaction pathway involving alkylation of a guanine residue in a 5'-GT sequence, followed by depurination to generate the Ap site, and cross-link formation via reaction of the Ap aldehyde residue with the opposing adenine residue at this site [Price, N. E., Johnson, K. M., Wang, J., Fekry, M. I., Wang, Y., and Gates, K. S. (2014) J. Am. Chem. Soc. 136, 3483 3490]. The monofunctional DNA-alkylating agents 2-chloro-N,N-diethylethanamine 5, (2-chloroethyl)ethylsulfide 6, and natural product leinamycin similarly were found to induce the formation of Ap-derived cross-links in duplex DNA. This work provides the first characterization of Ap-derived cross-links at sequences in which a cytosine residue is located directly opposing the Ap site. Cross-linking processes of this type could be relevant in medicine and biology because Ap sites with directly opposing cytosine residues occur frequently in genomic DNA via spontaneous or enzymatic depurination of guanine and N7-alkylguanine residues. PMID- 27992995 TI - Calcium Binding Dramatically Stabilizes an Ancestral Crystallin Fold in Tunicate betagamma-Crystallin. AB - The tunicate (Ciona intestinalis) betagamma-crystallin represents an intermediate case between the calcium-binding proteins ancestral to the vertebrate betagamma crystallin fold and the vertebrate structural crystallins. Unlike the structural betagamma-crystallins in the vertebrate eye lens, this betagamma-crystallin strongly binds Ca2+. Furthermore, Ca2+ binding greatly stabilizes the protein, an effect that has previously been observed in microbial betagamma-crystallins but not in those of vertebrates. This relationship between binding and protein stabilization makes the tunicate betagamma-crystallin an interesting model for studying the evolution of the human betagamma-crystallin. We also compare and contrast the binding sites of tunicate betagamma-crystallin with those of other betagamma-crystallins to develop hypotheses about the functional origin of the lack of Ca2+-binding sites in human crystallins. PMID- 27992996 TI - A Kinetic Signature for Parallel Pathways: Conformational Selection and Induced Fit. Links and Disconnects between Observed Relaxation Rates and Fractional Equilibrium Flux under Pseudo-First-Order Conditions. AB - Molecular association plays a ubiquitous role in biochemistry and is often accompanied by conformational exchange in one or both binding partners. Traditionally, two limiting mechanisms are considered for the association of two molecules. In a conformational selection (CS) mechanism, a ligand preferentially binds to a subset of conformations in its binding partner. In contrast, an induced fit (IF) mechanism describes the ligand-dependent isomerization of the binding partner in which binding occurs prior to conformational exchange. Measurements of the ligand concentration dependence of observed rates of relaxation are commonly used to probe whether CS or IF is taking place. Here we consider a four-state thermodynamic cycle subject to detailed balance and demonstrate the existence of a relatively unexplored class of kinetic signatures where an initial decrease in the observed rate is followed by a subsequent increase under pseudo-first-order conditions. We elucidate regions of rate space necessary to generate a nonmonotonic observed rate and show that, under certain conditions, the position of the minimum of the observed rate correlates with a transition in equilibrium flux between CS and IF pathways. Furthermore, we demonstrate that monotonic trends in the observed rate can occur when both CS and IF mechanisms are taking place, suggesting that caution must be taken not to overinterpret monotonic trends as evidence of the absence of either CS or IF. Lastly, we conclude that a nonmonotonic kinetic signature is uniquely unambiguous in the sense that when this trend is observed, one may conclude that both CS and IF mechanistic paths are utilized. PMID- 27992997 TI - Sequential and Coupled Proton and Electron Transfer Events in the S2 -> S3 Transition of Photosynthetic Water Oxidation Revealed by Time-Resolved X-ray Absorption Spectroscopy. AB - The choreography of electron transfer (ET) and proton transfer (PT) in the S state cycle at the manganese-calcium (Mn4Ca) complex of photosystem II (PSII) is pivotal for the mechanism of photosynthetic water oxidation. Time-resolved room temperature X-ray absorption spectroscopy (XAS) at the Mn K-edge was employed to determine the kinetic isotope effect (KIE = tauD2O/tauH2O) of the four S transitions in a PSII membrane particle preparation in H2O and D2O buffers. We found a small KIE (1.2-1.4) for manganese oxidation by ET from Mn4Ca to the tyrosine radical (YZ*+) in the S0n -> S1+ and S1n -> S2+ transitions and for manganese reduction by ET from substrate water to manganese ions in the O2 evolving S3n -> S0n step, but a larger KIE (~1.8) for manganese oxidation in the S2n -> S3+ step (subscript, number of accumulated oxidizing equivalents; superscript, charge of Mn4Ca). Kinetic lag phases detected in the XAS transients prior to the respective ET steps were assigned to S3+ -> S3n (~150 MUs, H2O; ~380 MUs, D2O) and S2+ -> S2n (~25 MUs, H2O; ~120 MUs, D2O) steps and attributed to PT events according to their comparatively large KIE (~2.4, ~4.5). Our results suggest that proton movements and molecular rearrangements within the hydrogen bonded network involving Mn4Ca and its bound (substrate) water ligands and the surrounding amino acid/water matrix govern to different extents the rates of all ET steps but affect particularly strongly the S2n -> S3+ transition, assigned as proton-coupled electron transfer. Observation of a lag phase in the classical S2 > S3 transition verifies that the associated PT is a prerequisite for subsequent ET, which completes Mn4Ca oxidation to the all-Mn(IV) level. PMID- 27993000 TI - Nanoarchitectures for Metal-Organic Framework-Derived Nanoporous Carbons toward Supercapacitor Applications. AB - The future advances of supercapacitors depend on the development of novel carbon materials with optimized porous structures, high surface area, high conductivity, and high electrochemical stability. Traditionally, nanoporous carbons (NPCs) have been prepared by a variety of methods, such as templated synthesis, carbonization of polymer precursors, physical and chemical activation, etc. Inorganic solid materials such as mesoporous silica and zeolites have been successfully utilized as templates to prepare NPCs. However, the hard-templating methods typically involve several synthetic steps, such as preparation of the original templates, formation of carbon frameworks, and removal of the original templates. Therefore, these methods are not favorable for large-scale production. Metal-organic frameworks (MOFs) with high surface areas and large pore volumes have been studied over the years, and recently, enormous efforts have been made to utilize MOFs for electrochemical applications. However, their low conductivity and poor stability still present major challenges toward their practical applications in supercapacitors. MOFs can be used as precursors for the preparation of NPCs with high porosity. Their parent MOFs can be prepared with endless combinations of organic and inorganic constituents by simple coordination chemistry, and it is possible to control their porous architectures, pore volumes, surface areas, etc. These unique properties of MOF-derived NPCs make them highly attractive for many technological applications. Compared with carbonaceous materials prepared using conventional precursors, MOF-derived carbons have significant advantages in terms of a simple synthesis with inherent diversity affording precise control over porous architectures, pore volumes, and surface areas. In this Account, we will summarize our recent research developments on the preparation of three dimensional (3-D) MOF-derived carbons for supercapacitor applications. This Account will be divided into three main sections: (1) useful background on carbon materials for supercapacitor applications, (2) the importance of MOF-derived carbons, and (3) potential future developments of MOF-derived carbons for supercapacitors. This Account focuses mostly on carbons derived from two types of MOFs, namely, zeolite imidazolate framework-8 (ZIF-8) and ZIF-67. By using examples from our previous works, we will show the uniqueness of these carbons for achieving high performance by control of the chemical reactions/conditions as well proper utilization in asymmetric/symmetric supercapacitor configurations. This Account will promote further developments of MOF-derived multifunctional carbon materials with controlled porous architectures for optimization of their electrochemical performance toward supercapacitor applications. PMID- 27992999 TI - Systematic Evaluation of Biophysical and Functional Characteristics of Selenomethylene-Locked Nucleic Acid-Mediated Inhibition of miR-21. AB - miRNAs constitute an important layer of gene regulation mediated by sequence specific targeting of mRNAs. Aberrant expression of miRNAs contributes to a host of pathological states. Promoting cancer, miR-21 is upregulated in variety of cancers and promotes tumor progresion by suppressing a network of tumor suppressor genes. Here we describe a novel class of bicyclic RNA analogues, selenomethylene-locked nucleic acid (SeLNA), that display high affinity, improved metabolic stability, and increased potency for miR-21 inhibition. The thermal stability (Tm) for duplexes was increased significantly with incorporation of SeLNA monomers as compared to that of the unmodified DNA-RNA hybrid. A comprehensive thermodynamic profile obtained by isothermal titration calorimetry revealed a favorable increase in the enthalpy of hybridization for SeLNA containing DNA and target RNA heteroduplexes. SeLNA modifications displayed remarkable binding affinity for miR-21 target RNA with a Ka of <=1.05 * 108 M-1. We also observed enhanced serum stability for SeLNA-RNA duplexes with a half-life of <=36 h. These in vitro results were well correlated with the antisense activity in cancer cells imparting up to ~91% inhibition of miR-21. The functional impact of SeLNA modifications on miR-21 inhibition was further gauged by investigating the migration and invasion characterisitics of cancer cells, which were drastically reduced to ~49 and ~55%, respectively, with SeLNA having four such modifications. Our findings demonstrate SeLNA as a promising candidate for therapeutics for disease-associated miRNAs. PMID- 27992998 TI - Asymmetric Binding and Metabolism of Polyunsaturated Fatty Acids (PUFAs) by CYP2J2 Epoxygenase. AB - Cytochrome P450 (CYP) 2J2 is the primary epoxygenase in the heart and is responsible for the epoxidation of arachidonic acid (AA), an omega-6 polyunsaturated fatty acid (PUFA), into anti-inflammatory epoxide metabolites. It also epoxidizes other PUFAs such as docosahexaenoic acid (DHA), linoleic acid (LA), and eicosapentaenoic acid (EPA). Herein, we have performed detailed thermodynamic and kinetic analyses to determine how DHA, LA, and EPA modulate the metabolism of AA by CYP2J2. We use the Nanodisc system to stabilize CYP2J2 and its redox partner, CYP reductase (CPR). We observe that DHA strongly inhibits CYP2J2-mediated AA metabolism, LA only moderately inhibits AA metabolism, and EPA exhibits insignificant inhibition. We also characterized the binding of these molecules using ebastine competitive binding assays and show that DHA binds significantly tighter to CYP2J2 than AA, EPA, or LA. Furthermore, we utilize a combined approach of molecular dynamics (MD) simulations and docking to predict key residues mediating the tight binding of DHA. We show that although all the tested fatty acids form similar contacts to the active site residues, the affinity of DHA for CYP2J2 is tighter because of the interaction of DHA with residues Arg-321, Thr-318, and Ser-493. To demonstrate the importance of these residues in binding, we mutated these residues to make two mutant variants, CYP2J2-T318A and CYP2J2-T318V/S493A. Both mutant variants showed weaker binding than the wild type (WT) to DHA and AA; DHA inhibition of AA was also mitigated in the mutants compared to the WT. Therefore, using a combined experimental and MD simulation approach, we establish that CYP2J2 inhibition of AA metabolism by DHA, EPA, and LA is asymmetric because of tighter binding of DHA to select residues in the active site. PMID- 27993001 TI - Phosphorescent Platinum(II) Complexes with C?C* Cyclometalated NHC Ligands. AB - This Account describes our achievements toward the development of a new class of platinum(II) complexes with interesting photophysical properties. The general motif of a strongly donating N-heterocyclic carbene with a cyclometalating phenyl group attached to the nitrogen atom together with beta-diketonate based counterligands enabled us to synthesize a new class of phosphorescent emitters for use in organic light-emitting diodes (OLEDs). This Account is divided into sections and introduces imidazolium based as well as triazolium based structures and discusses the effects of structural changes on the photophysical properties. Starting from the basic methylated (substituted) phenylimidalium presursors, we initially extended the pi-system of the phenyl ring to the dibenzofuran ligand, its regioisomer, and thio-derivative. As the substituents of the beta-diketonate ligands turned out to have a strong influence on the photophysical properties (higher quantum yields as well as shorter decay times) a series of dibenzofuranyl 3-methylimidazol as well as diphenylbenzimidazol platinum complexes were synthesized to investigate the different steric and electronic effects, which are described in a separate section. The next section of the Account then describes other extensions of the pi-system. Exchange of the methyl group against a phenyl ring, as well as the extension of the pi-system in the backbone of the NHC-ligand lead to a significant improvement of the photophysical properties, which reached a maximum for the diphenylbenzimidazole (DPBIC) system. Further extension of the pi-system to the diphenylnaphthylimidazol then lead to a unfavorable long decay time. The effect of substitution is discussed for cyano groups, which change the electronic situation and lead to highly emissive complexes. We are currently working on studying the effect of other substituents on the photophysical properties, as well as the introduction of additional heteroatoms into the general motif. Our initial work in that area had been on 1,2,4-triazole complexes. For the basic phenyl/methyl substituted system, two different isomers are accessible, the 4-phenyl-4H-1,2,4-triazoles as well as the 1-phenyl-1H-1,2,4 triazoles. It was interesting to note that the photophysical properties of the corresponding complexes are strongly dependent on the substituent R of the beta diketonate ligand. For R = methyl, the properties are significantly different, while we found almost identical photophysical results for R = mesityl for both 1,2,4-triazole isomers. The last section describes the synthesis of bimetallic complexes. To investigate whether it is possible to cyclometalate twice into the same phenyl ring, we synthesized dicationic NHC precursors from para- and meta disubstituted bis(imidazole)benzenes. The bimetallic complexes show interesting photophysical properties with quantum yields of up to 93%. All experimental work was accompanied by quantum chemical calculations, which turned out to be very useful for the prediction of the emission wavelengths as well as the interpretation of the emissive states of the platinum complexes. PMID- 27993002 TI - Recycling in Asymmetric Catalysis. AB - Cyclic reaction networks consisting of an enantioselective product-forming step and a reverse reaction of the undesired enantiomer back to starting reactant are important for the generation of compounds with high enantiomeric purity. In order to avoid an equilibrium racemic state, a unidirectional cyclic process where product formation and regeneration of starting reactant proceed through different mechanistic pathways is required. Such processes must necessarily include a thermodynamically unfavorable step, since the product of the forward reaction is the reactant of the reverse reaction and vice versa. Thermodynamically uphill processes are ubiquitous to the function of living systems. Such systems gain the required energy by coupling to thermodynamically downhill reactions. In the same way, artificial cyclic reaction networks can be realized in systems open to mass or energy flow, and an out-of equilibrium nonracemic steady state can be maintained as long as the system is supplied with energy. In contrast to a kinetic resolution, a recycling process where the minor enantiomer is converted to starting reactant can result in a quantitative yield, but the enantiomeric purity of the product is limited by the selectivity of the catalysts used for the reactions. On the other hand, in a kinetic resolution, the slowly reacting enantiomer can always be obtained in an enantiomerically pure state, although the yield will suffer. In cyclic reaction systems which use chiral catalysts for both the forward and the reverse processes, a reinforcing effect results, and selectivities higher than those achieved by a single chiral catalyst are observed. A dynamic kinetic resolution can in principle also lead to a quantitative yield, but lacks the reinforcing effect of two chiral catalysts. Most examples of cyclic reaction networks reported in the literature are deracemizations of racemic mixtures, which proceed via oxidation of one enantiomer followed by reduction to the opposite enantiomer. We have developed cyclic reaction networks comprising a carbon-carbon bond formation. In these processes, the product is generated by the addition of a cyanide reagent to a prochiral aldehyde. This is followed by hydrolysis of the minor enantiomer of the product to generate the starting aldehyde. A unidirectional cycle is maintained by coupling to the exergonic transformation of the high potential cyanide reagent to a low potential compound, either a carboxylate or carbon dioxide. The products, which are obtained with high enantiomeric purity, serve as valuable starting materials for a variety of biologically and pharmaceutically active compounds. PMID- 27993004 TI - Toward the Rational Design of Novel Noncentrosymmetric Materials: Factors Influencing the Framework Structures. AB - Solid-state materials with extended structures have revealed many interesting structure-related characteristics. Among many, materials crystallizing in noncentrosymmetric (NCS) space groups have attracted massive attention attributable to a variety of superb functional properties such as ferroelectricity, pyroelectricity, piezoelectricity, and nonlinear optical (NLO) properties. In fact, the characteristics are pivotal to many industrial applications such as laser systems, optical communications, photolithography, energy harvesting, detectors, and memories. Thus, for the past several decades, a great deal of synthetic effort has been vigorously made to realize these technologically important properties by improving the occurrence of macroscopic NCS space groups. A bright approach to increase the incidence of NCS structures was combining local asymmetric units during the initial synthesis process. Although a significant improvement has been achieved in obtaining new NCS materials using this strategy, the majority of solid-state materials still crystallize in centrosymmetric (CS) structures as the locally unsymmetrical units are easily lined up in an antiparallel manner. Therefore, discovering an effective method to control the framework structure and the macroscopic symmetry is an imminent ongoing challenge. In order to more effectively control the overall symmetry of solid-state compounds, it is critical to understand how the backbone and the subsequent centricity are affected during the crystallization. In this Account, several factors influencing the framework structure and centricity of solid-state materials are described in order to more systematically discover novel NCS materials. Recent studies on crystalline solid-state materials suggest three factors affecting the local coordination environment as well as the overall symmetry of the framework structure: (1) size variations of the various template cations, (2) a variable backbone arrangement occurring from the hydrogen bonding interactions, and (3) the presence of framework flexibility. With regard to the first factor, the impact of size of the various metal cations and coordination numbers on the alignment of other adjacent polyhedra, linkers, and lone pairs determining the framework geometries of mixed metal oxides is analyzed. The second factor considers the regulation of crystallographic centricity determined by the availability of hydrogen-bonding interactions between anionic frameworks containing local asymmetric polyhedra and organic cations. Finally, the third factor explores the framework architecture and the space group symmetry influenced by the flexibility of polyhedra revealing variable coordination numbers. The centricity and framework of new solid-state materials might be controlled by using a variety of synthetically controllable asymmetric units such as organic structure-directing cations and linkers with different sizes and functional groups. PMID- 27993005 TI - Quantum Embedding Theories. AB - In complex systems, it is often the case that the region of interest forms only one part of a much larger system. The idea of joining two different quantum simulations-a high level calculation on the active region of interest, and a low level calculation on its environment-formally defines a quantum embedding. While any combination of techniques constitutes an embedding, several rigorous formalisms have emerged that provide for exact feedback between the embedded system and its environment. These three formulations: density functional embedding, Green's function embedding, and density matrix embedding, respectively, use the single-particle density, single-particle Green's function, and single-particle density matrix as the quantum variables of interest. Many excellent reviews exist covering these methods individually. However, a unified presentation of the different formalisms is so far lacking. Indeed, the various languages commonly used, functional equations for density functional embedding, diagrammatics for Green's function embedding, and entanglement arguments for density matrix embedding, make the three formulations appear vastly different. In this Account, we introduce the basic equations of all three formulations in such a way as to highlight their many common intellectual strands. While we focus primarily on a straightforward theoretical perspective, we also give a brief overview of recent applications and possible future developments. The first section starts with density functional embedding, where we introduce the key embedding potential via the Euler equation. We then discuss recent work concerning the treatment of the nonadditive kinetic potential, before describing mean-field density functional embedding and wave function in density functional embedding. We finish the section with extensions to time-dependence and excited states. The second section is devoted to Green's function embedding. Here, we use the Dyson equation to obtain equations that parallel as closely as possible the density functional embedding equations, with the hybridization playing the role of the embedding potential. Embedding a high-level self-energy within a low-level self-energy is treated analogously to wave function in density functional embedding. The numerical computation of the high-level self-energy allows us to briefly introduce the bath representation in the quantum impurity problem. We then consider translationally invariant systems to bring in the important dynamical mean-field theory. Recent developments to incorporate screening and long-range interactions are discussed. The third section concerns density matrix embedding. Here, we first highlight some mathematical complications associated with a simple Euler equation derivation, arising from the open nature of fragments. This motivates the density matrix embedding theory, where we use the Schmidt decomposition to represent the entanglement through bath orbitals. The resulting impurity plus bath formulation resembles that of dynamical mean-field theory. We discuss the numerical self-consistency associated with using a high level correlated wave function with a mean-field low-level treatment, and connect the resulting numerical inversion to that used in density functional embedding. We finish with perspectives on the future of all three methods. PMID- 27993003 TI - Nanoarchitecture Based SERS for Biomolecular Fingerprinting and Label-Free Disease Markers Diagnosis. AB - Surface-enhanced Raman spectroscopy (SERS) fingerprinting is highly promising for identifying disease markers from complex mixtures of clinical sample, which has the capability to take medical diagnoses to the next level. Although vibrational frequency in Raman spectra is unique for each biomolecule, which can be used as fingerprint identification, it has not been considered to be used routinely for biosensing due to the fact that the Raman signal is very weak. Contemporary SERS has been demonstrated to be an excellent analytical tool for practical label-free sensing applications due its ability to enhance Raman signals by factors of up to 108-1014 orders of magnitude. Although SERS was discovered more than 40 years ago, its applications are still rare outside the spectroscopy community and it is mainly due to the fact that how to control, manipulate and amplify light on the "hot spots" near the metal surface is in the infancy stage. In this Account, we describe our contribution to develop nanoachitecture based highly reproducible and ultrasensitive detection capability SERS platform via low-cost synthetic routes. Using one-dimensional (1D) carbon nanotube (CNT), two-dimensional (2D) graphene oxide (GO), and zero-dimensional (0D) plasmonic nanoparticle, 0D to 3D SERS substrates have been designed, which represent highly powerful platform for biological diagnosis. We discuss the major design criteria we have used to develop robust SERS substrate to possess high density "hot spots" with very good reproducibility. SERS enhancement factor for 3D SERS substrate is about 5 orders of magnitude higher than only plasmonic nanoparticle and more than 9 orders of magnitude higher than 2D GO. Theoretical finite-difference time-domain (FDTD) stimulation data show that the electric field enhancement |E|2 can be more than 2 orders of magnitude in "hot spots", which suggests that SERS enhancement factors can be greater than 104 due to the formation of high density "hot spots" in 3D substrate. Next, we discuss the utilization of nanoachitecture based SERS substrate for ultrasensitive and selective diagnosis of infectious disease organisms such as drug resistance bacteria and mosquito-borne flavi-viruses that cause significant health problems worldwide. SERS based "whole-organism fingerprints" has been used to identify infectious disease organisms even when they are so closely related that they are difficult to distinguish. The detection capability can be as low as 10 CFU/mL for methicillin-resistant Staphylococcus aureus (MRSA) and 10 PFU/mL for Dengue virus (DENV) and West Nile virus (WNV). After that, we introduce exciting research findings by our group on the applications of nanoachitecture based SERS substrate for the capture and fingerprint detection of rotavirus from water and Alzheimer's disease biomarkers from whole blood sample. The SERS detection limit for beta-amyloid (Abeta proteins) and tau protein using 3D SERS platform is several orders of magnitude higher than the currently used technology in clinics. Finally, we highlight the promises, major challenges and prospect of nanoachitecture based SERS in biomedical diagnosis field. PMID- 27993006 TI - Classical Challenges in the Physical Chemistry of Polymer Networks and the Design of New Materials. AB - Polymer networks are widely used from commodity to biomedical materials. The space-spanning, net-like structure gives polymer networks their advantageous mechanical and dynamic properties, the most essential factor that governs their responses to external electrical, thermal, and chemical stimuli. Despite the ubiquity of applications and a century of active research on these materials, the way that chemistry and processing interact to yield the final structure and the material properties of polymer networks is not fully understood, which leads to a number of classical challenges in the physical chemistry of gels. Fundamentally, it is not yet possible to quantitatively predict the mechanical response of a polymer network based on its chemical design, limiting our ability to understand and characterize the nanostructure of gels and rationally design new materials. In this Account, we summarize our recent theoretical and experimental approaches to study the physical chemistry of polymer networks. First, our understanding of the impact of molecular defects on topology and elasticity of polymer networks is discussed. By systematically incorporating the effects of different orders of loop structure, we develop a kinetic graph theory and real elastic network theory that bridge the chemical design, the network topology, and the mechanical properties of the gel. These theories show good agreement with the recent experimental data without any fitting parameters. Next, associative polymer gel dynamics is discussed, focusing on our evolving understanding of the effect of transient bonds on the mechanical response. Using forced Rayleigh scattering (FRS), we are able to probe diffusivity across a wide range of length and time scales in gels. A superdiffusive region is observed in different associative network systems, which can be captured by a two-state kinetic model. Further, the effects of the architecture and chemistry of polymer chains on gel nanostructure are studied. By incorporating shear-thinning coiled-coil protein motifs into the midblock of a micelle-forming block copolymer, we are able to responsively adjust the gel toughness through controlling the nanostructure. Finally, we review the development of novel application-oriented materials that emerge from our enhanced understanding of gel physical chemistry, including injectable gel hemostats designed to treat internal wounds and engineered nucleoporin-like polypeptide (NLP) hydrogels that act as biologically selective filters. We believe that the fundamental physical chemistry questions articulated in this Account will provide inspiration to fully understand the design of polymer networks, a group of mysterious yet critically important materials. PMID- 27993007 TI - Van der Waals Perspective on Coarse-Graining: Progress toward Solving Representability and Transferability Problems. AB - Low-resolution coarse-grained (CG) models provide the necessary efficiency for simulating phenomena that are inaccessible to more detailed models. However, in order to realize their considerable promise, CG models must accurately describe the relevant physical forces and provide useful predictions. By formally integrating out the unnecessary details from an all-atom (AA) model, "bottom-up" approaches can, at least in principle, quantitatively reproduce the structural and thermodynamic properties of the AA model that are observable at the CG resolution. In practice, though, bottom-up approaches only approximate this "exact coarse-graining" procedure. The resulting models typically reproduce the intermolecular structure of AA models at a single thermodynamic state point but often describe other state points less accurately and, moreover, tend to provide a poor description of thermodynamic properties. These two limitations have been coined the "transferability" and "representability" problems, respectively. Perhaps, the simplest and most commonly discussed manifestation of the representability problem regards the tendency of structure-based CG models to dramatically overestimate the pressure. Furthermore, when these models are adjusted to reproduce the pressure, they provide a poor description of the compressibility. More generally, it is sometimes suggested that CG models are fundamentally incapable of reproducing both structural and thermodynamic properties. After all, there is no such thing as a "free lunch"; any significant gain in computational efficiency should come at the cost of significant model limitations. At least in the case of structural and thermodynamic properties, though, we optimistically propose that this may be a false dichotomy. Accordingly, we have recently re-examined the "exact coarse-graining" procedure and investigated the intrinsic consequences of representing an AA model in reduced resolution. These studies clarify the origin and inter-relationship of representability and transferability problems. Both arise as consequences of transferring thermodynamic information from the high resolution configuration space and encoding this information into the many-body potential of mean force (PMF), that is, the potential that emerges from an exact coarse-graining procedure. At least in principle, both representability and transferability problems can be resolved by properly addressing this thermodynamic information. In particular, we have demonstrated that "pressure-matching" provides a practical and rigorous means for addressing the density dependence of the PMF. The resulting bottom-up models accurately reproduce the structure, equilibrium density, compressibility, and pressure equation of state for AA models of molecular liquids. Additionally, we have extended this approach to develop transferable potentials that provide similar accuracy for heptane-toluene mixtures. Moreover, these potentials provide predictive accuracy for modeling concentrations that were not considered in their parametrization. More generally, this work suggests a "van der Waals" perspective on coarse-graining, in which conventional structure-based methods accurately describe the configuration dependence of the PMF, while independent variational principles infer the thermodynamic information that is necessary to resolve representability and transferability problems. PMID- 27993008 TI - Spinning around in Transition-Metal Chemistry. AB - The great diversity and richness of transition metal chemistry, such as the features of an open d-shell, opened a way to numerous areas of scientific research and technological applications. Depending on the nature of the metal and its environment, there are often several energetically accessible spin states, and the progress in accurate theoretical treatment of this complicated phenomenon is presented in this Account. The spin state energetics of a transition metal complex can be predicted theoretically on the basis of density functional theory (DFT) or wave function based methodology, where DFT has advantages since it can be applied routinely to medium-to-large-sized molecules and spin-state consistent density functionals are now available. Additional factors such as the effect of the basis set, thermochemical contributions, solvation, relativity, and dispersion, have been investigated by many researchers, but challenges in unambiguous assignment of spin states still remain. The first DFT studies showed intrinsic spin-state preferences of hybrid functionals for high spin and early generalized gradient approximation functionals for low spin. Progress in the development of density functional approximations (DFAs) then led to a class of specially designed DFAs, such as OPBE, SSB-D, and S12g, and brought a very intriguing and fascinating observation that the spin states of transition metals and the SN2 barriers of organic molecules are somehow intimately linked. Among the many noteworthy results that emerged from the search for the appropriate description of the complicated spin state preferences in transition metals, we mainly focused on the examination of the connection between the spin state and the structures or coordination modes of the transition metal complexes. Changes in spin states normally lead only to changes in the metal-ligand bond lengths, but to the best of our knowledge, the dapsox ligand showed the first example of a transition-metal complex where a change in spin state leads also to changes in the coordination, switching between pentagonal-bipyramidal and capped-octahedron. Moreover, we have summarized the results of the thorough study that corrected the experimental assignment of the nature of the recently synthesized Sc3+ adduct of [FeIV(O)(TMC)]2+ (TMC = 1,4,8,11-tetramethylcyclam) and firmly established that the Sc3+-capped iron-oxygen complex corresponds to high-spin FeIII. Last, but not least, we have provided deeper insight and rationalization of the observation that unlike in metalloenzymes, where the FeIV-oxo is usually observed with high spin, biomimetic FeIV-oxo complexes typically have a intermediate spin state. Energy decomposition analyses on the trigonal-bypiramidal (TBP) and octahedral model systems with ammonia ligands have revealed that the interaction energy of the prepared metal ion in the intermediate spin state is much smaller for the TBP structure. This sheds light on the origin of the intermediate spin state of the biomimetic TBP FeIV-oxo complexes. PMID- 27993009 TI - Plasmonic Nanogap-Enhanced Raman Scattering with Nanoparticles. AB - Plasmonic coupling-based electromagnetic field localization and enhancement are becoming increasingly important in chemistry, nanoscience, materials science, physics, and engineering over the past decade, generating a number of new concepts and applications. Among the plasmonically coupled nanostructures, metal nanostructures with nanogaps have been of special interest due to their ultrastrong electromagnetic fields and controllable optical properties that can be useful for a variety of signal enhancements such as surface-enhanced Raman scattering (SERS). The Raman scattering process is highly inefficient, with a very small cross-section, and Raman signals are often poorly reproducible, meaning that very strong, controllable SERS is needed to obtain reliable Raman signals with metallic nanostructures and thus open up new avenues for a variety of Raman-based applications. More specifically, plasmonically coupled metallic nanostructures with ultrasmall (~1 nm or smaller) nanogaps can generate very strong and tunable electromagnetic fields that can generate strong SERS signals from Raman dyes in the gap, and plasmonic nanogap-enhanced Raman scattering can be defined as Raman signal enhancement from plasmonic nanogap particles with ~1 nm gaps. However, these promising nanostructures with extraordinarily strong optical signals have shown limited use for practical applications, largely due to the lack of design principles, high-yield synthetic strategies with nanometer level structural control and reproducibility, and systematic, reliable single molecule/single-particle-level studies on their optical properties. All these are extremely important challenges because even small changes (<1 nm) in the structure of the coupled plasmonic nanogaps can significantly affect the plasmon mode and signal intensity. In this Account, we examine and summarize recent breakthroughs and advances in plasmonic nanogap-enhanced Raman scattering with metal nanogap particles with respect to the design and synthesis of plasmonic nanogap structures, as well as ultrasensitive and quantitative Raman signal detection using these structures. The applications and prospects of plasmonic nanogap particle-based SERS are also discussed. In particular, reliable synthetic and measurement strategies for plasmonically coupled nanostructures with ~1 nm gap, in which both the nanogap size and the position of a Raman-active molecule in the gap can be controlled with nanometer/sub-nanometer-level precision, can address important issues regarding the synthesis and optical properties of plasmonic nanostructures, including structural and signal reproducibility. Further, single-molecule/single-particle-level studies on the plasmonic properties of these nanogap structures revealed that these particles can generate ultrastrong, quantifiable Raman signals in a highly reproducible manner. PMID- 27993010 TI - Flow-Directed Crystallization for Printed Electronics. AB - The solution printability of organic semiconductors (OSCs) represents a distinct advantage for materials processing, enabling low-cost, high-throughput, and energy-efficient manufacturing with new form factors that are flexible, stretchable, and transparent. While the electronic performance of OSCs is not comparable to that of crystalline silicon, the solution processability of OSCs allows them to complement silicon by tackling challenging aspects for conventional photolithography, such as large-area electronics manufacturing. Despite this, controlling the highly nonequilibrium morphology evolution during OSC printing remains a challenge, hindering the achievement of high electronic device performance and the elucidation of structure-property relationships. Many elegant morphological control methodologies have been developed in recent years including molecular design and novel processing approaches, but few have utilized fluid flow to control morphology in OSC thin films. In this Account, we discuss flow-directed crystallization as an effective strategy for controlling the crystallization kinetics during printing of small molecule and polymer semiconductors. Introducing the concept of flow-directed crystallization to the field of printed electronics is inspired by recent advances in pharmaceutical manufacturing and flow processing of flexible-chain polymers. Although flow induced crystallization is well studied in these areas, previous findings may not apply directly to the field of printed electronics where the molecular structures (i.e., rigid pi-conjugated backbone decorated with flexible side chains) and the intermolecular interactions (i.e., pi-pi interactions, quadrupole interactions) of OSCs differ substantially from those of pharmaceuticals or flexible-chain polymers. Another critical difference is the important role of solvent evaporation in open systems, which defines the flow characteristics and determines the crystallization kinetics and pathways. In other words, flow induced crystallization is intimately coupled with the mass transport processes driven by solvent evaporation during printing. In this Account, we will highlight these distinctions of flow-directed crystallization for printed electronics. In the context of solution printing of OSCs, the key issue that flow-directed crystallization addresses is the kinetics mismatch between crystallization and various transport processes during printing. We show that engineering fluid flows can tune the kinetics of OSC crystallization by expediting the nucleation and crystal growth processes, significantly enhancing thin film morphology and device performance. For small molecule semiconductors, nucleation can be enhanced and patterned by directing the evaporative flux via contact line engineering, and defective crystal growth can be alleviated by enhancing mass transport to yield significantly improved coherence length and reduced grain boundaries. For conjugated polymers, extensional and shear flow can expedite nucleation through flow-induced conformation change, facilitating the control of microphase separation, degree of crystallinity, domain alignment, and percolation. Although the nascent concept of flow-directed solution printing has not yet been widely adopted in the field of printed electronics, we anticipate that it can serve as a platform technology in the near future for improving device performance and for systematically tuning thin film morphology to construct structure-property relationships. From a fundamental perspective, it is imperative to develop a better understanding of the effects of fluid flow and mass transport on OSC crystallization as these processes are ubiquitous across all solution processing techniques and can critically impact charge transport properties. PMID- 27993011 TI - Tale of Twisted Molecules. Atropselective Photoreactions: Taming Light Induced Asymmetric Transformations through Non-biaryl Atropisomers. AB - Photochemical transformations are a powerful tool in organic synthesis to access structurally complex and diverse synthetic building blocks. However, this great potential remains untapped in the mainstream synthetic community due to the challenges associated with stereocontrol originating from excited state(s). The finite lifetime of an excited state and nearly barrierless subsequent processes present significant challenges in manipulating the stereochemical outcome of a photochemical reaction. Several methodologies were developed to address this bottleneck including photoreactions in confined media and preorganization through noncovalent interactions resulting in stereoenhancement. Yet, stereocontrol in photochemical reactions that happen in solution in the absence of organized assemblies remained largely unaddressed. In an effort to develop a general and reliable methodology, our lab has been exploring non-biaryl atropisomers as an avenue to perform asymmetric phototransformations. Atropisomers are chiral molecules that arise due to the restricted rotation around a single bond (chiral axis) whose energy barrier to rotation is determined by nonbonding interactions (most often by steric hindrance) with appropriate substituents. Thus, atropisomeric substrates are chirally preorganized during the photochemical transformation and translate their chiral information to the expected photoproducts. This strategy, where "axial to point chirality transfer" occurs during the photochemical reaction, is a hybrid of the successful Curran's prochiral auxiliary approach involving atropisomers in thermal reactions and the Havinga's NEER principle (nonequilibrating excited-state rotamers) for photochemical transformations. We have investigated this strategy in order to probe various aspects such as regio-, enantio-, diastereo-, and chemoselectivity in several synthetically useful phototransformations including 6pi photocyclization, 4pi-ring closure, Norrish-Yang photoreactions, Paterno-Buchi reaction, and [2 + 2]- and [5 + 2]-photocycloaddition. The investigations detailed in this Account clearly signify the scope of our strategy in accessing chirally enriched products during phototransformations. Simple design modifications such as tailoring the steric handle in atropisomers to hold reactive units resulted in permanently locked/traceless axial chirality in addition to incorporating multiple stereocenters in already complex scaffolds obtained from phototransformation. Further improvements allowed us to employ low energy visible light rather than high energy UV light without compromising the stereoenrichment in the photoproducts. Continued investigations on atropisomeric scaffolds have unraveled new design features, with outcomes that are unique and unprecedented for excited state reactivity. For example, we have established that reactive spin states (singlet or triplet excited state) profoundly influence the stereochemical outcome of an atropselective phototransformation. In general, the photochemistry and photophysics of atropisomeric substrates differ significantly from their achiral counterparts irrespective of having the same chromophore initiating the excited state reactivity. The ability of axially chiral chromophores to impart stereoenrichment in the intramolecular photoreactions appears to be promising. A challenging endeavor for the "axial to point chirality transfer" strategy is to enhance stereoenrichment or alter chemical reactivity in intermolecular photoreactions. Insights gained from our investigations will serve as a platform to venture into more complicated yet fruitful research in terms of broad synthetic utility. PMID- 27993013 TI - Template Synthesis of Noble Metal Nanocrystals with Unusual Crystal Structures and Their Catalytic Applications. AB - Noble metal nanocrystals own high chemical stability, unique plasmonic and distinctive catalytic properties, making them outstanding in many applications. However, their practical applications are limited by their high cost and scarcity on the earth. One promising strategy to solve these problems is to boost their catalytic performance in order to reduce their usage amount. To realize this target, great research efforts have been devoted to the size-, composition-, shape- and/or architecture-controlled syntheses of noble metal nanocrystals during the past two decades. Impressively, recent experimental studies have revealed that the crystal structure of noble metal nanocrystals can also significantly affect their physicochemical properties, such as optical, magnetic, catalytic, mechanical, electrical and electronic properties. Therefore, besides the well-established size, composition, shape, and architecture control, the rise of crystal structure-controlled synthesis of noble metal nanocrystals will open up new opportunities to further improve their functional properties, and thus promote their potential applications in energy conversion, catalysis, biosensing, information storage, surface enhanced Raman scattering, waveguide, near-infrared photothermal therapy, controlled release, bioimaging, biomedicine, and so on. In this Account, we review the recent research progress on the crystal structure control of noble metal nanocrystals with a template synthetic approach and their crystal structure-dependent catalytic properties. We first describe the template synthetic methods, such as epitaxial growth and galvanic replacement reaction methods, in which a presynthesized noble metal nanocrystal with either new or common crystal structure is used as the template to direct the growth of unusual crystal structures of other noble metals. Significantly, the template synthetic strategy described here provides an efficient, simple and straightforward way to synthesize unusual crystal structures of noble metal nanocrystals, which might not be easily synthesized by commonly used chemical synthesis. To be specific, by using the epitaxial growth method, a series of noble metal nanocrystals with unusual crystal structures has been obtained, such as hexagonal close-packed Ag, 4H Ag, Pd, Pt, Ir, Rh, Os, and Ru, and face-centered cubic Ru nanostructures. Meanwhile, the galvanic replacement reaction method offers an efficient way to synthesize noble metal alloy nanocrystals with unusual crystal structures, such as 4H PdAg, PtAg, and PtPdAg nanostructures. We then briefly introduce the stability of noble metal nanocrystals with unusual crystal structures. After that, we demonstrate the catalytic applications of the resultant noble metal nanocrystals with unusual crystal structures toward different chemical reactions like hydrogen evolution reaction, hydrogen oxidation reaction and organic reactions. The relationship between crystal structures of noble metal nanocrystals and their catalytic performances is discussed. Finally, we summarize the whole paper, and address the current challenges and future opportunities for the template synthesis of noble metal nanocrystals with unusual crystal structures. We expect that this Account will promote the crystal structure controlled synthesis of noble metal nanocrystals, which can provide a new way to further improve their advanced functional properties toward their practical applications. PMID- 27993012 TI - Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence. AB - The discovery of RNA catalysis in the 1980s and the dissemination of the human genome sequence at the start of this century inspired investigations of the regulatory roles of noncoding RNAs in biology. In fact, the Encyclopedia of DNA Elements (ENCODE) project has shown that only 1-2% of the human genome encodes protein, yet 75% is transcribed into RNA. Functional studies both preceding and following the ENCODE project have shown that these noncoding RNAs have important roles in regulating gene expression, developmental timing, and other critical functions. RNA's diverse roles are often a consequence of the various folds that it adopts. The single-stranded nature of the biopolymer enables it to adopt intramolecular folds with noncanonical pairings to lower its free energy. These folds can be scaffolds to bind proteins or to form frameworks to interact with other RNAs. Not surprisingly, dysregulation of certain noncoding RNAs has been shown to be causative of disease. Given this as the background, it is easy to see why it would be useful to develop methods that target RNA and manipulate its biology in rational and predictable ways. The antisense approach has afforded strategies to target RNAs via Watson-Crick base pairing and has typically focused on targeting partially unstructured regions of RNA. Small molecule strategies to target RNA would be desirable not only because compounds could be lead optimized via medicinal chemistry but also because structured regions within an RNA of interest could be targeted to directly interfere with RNA folds that contribute to disease. Additionally, small molecules have historically been the most successful drug candidates. Until recently, the ability to design small molecules that target non-ribosomal RNAs has been elusive, creating the perception that they are "undruggable". In this Account, approaches to demystify targeting RNA with small molecules are described. Rather than bulk screening for compounds that bind to singular targets, which is the purview of the pharmaceutical industry and academic institutions with high throughput screening facilities, we focus on methods that allow for the rational design of small molecules toward biological RNAs. One enabling and foundational technology that has been developed is two dimensional combinatorial screening (2DCS), a library-versus-library selection approach that allows the identification of the RNA motif binding preferences of small molecules from millions of combinations. A landscape map of the 2DCS defined and annotated RNA motif-small molecule interactions is then placed into Inforna, a computational tool that allows one to mine these interactions against an RNA of interest or an entire transcriptome. Indeed, this approach has been enabled by tools to annotate RNA structure from sequence, an invaluable asset to the RNA community and this work, and has allowed for the rational identification of "druggable" RNAs in a target agnostic fashion. PMID- 27993015 TI - Cytosolic Transport of Nanoparticles through Pressurized Plasma Membranes for Molecular Delivery and Amplification of Intracellular Fluorescence. AB - Transporting nanoparticles into live cells is important for drug delivery and other related applications. We found that cells exposed to hypoosmotic pressures can internalize substantial quantities of gold nanoparticles. Importantly, these nanoparticles can circumvent normal intracellular traffic and be transported directly into the cytosol, without the need for surface functionalization. In contrast, nanoparticles endocytosed at physiological osmolality are segregated inside endocytic organelles and are not able to reach the cytosol. Cytosolic internalization was observed for nanoparticles of various sizes and materials, with minimal short- or long-term damage induced by the internalized particles. Thus, our strategy can be used as a delivery platform for a range of applications from therapeutics to medical imaging. As examples, we demonstrated rapid delivery of membrane-impermeable molecules to the cytosol by using nanoparticles as carriers and the use of nanoparticles assembled within the cytosol as plasmonic nanoantenna to enhance intracellular fluorescence. We propose a model for the mechanisms behind nanoparticle internalization through pressurized plasma membranes via the release of lateral pressures. Such characterizations may constitute a foundation for developing new technologies, including nanoparticle based drug delivery. PMID- 27993014 TI - Modulation of Elasticity and Interactions in Charged Lipid Multibilayers: Monovalent Salt Solutions. AB - We have studied the electrostatic screening effect of NaCl solutions on the interactions between anionic lipid bilayers in the fluid lamellar phase using a Poisson-Boltzmann-based mean-field approach with constant charge and constant potential limiting charge regulation boundary conditions. The full DLVO potential, including the electrostatic, hydration and van der Waals interactions, was coupled to thermal bending fluctuations of the membranes via a variational Gaussian Ansatz. This allowed us to analyze the coupling between the osmotic pressure and the fluctuation amplitudes and compare them both simultaneously with their measured dependence on the bilayer separation, determined by the small angle X-ray scattering experiments. High-structural resolution analysis of the scattering data revealed no significant changes of membrane structure as a function of salt concentration. Parsimonious description of our results is consistent with the constant charge limit of the general charge regulation phenomenology, with fully dissociated lipid charge groups, together with a 6-fold reduction of the membranes' bending rigidity upon increasing NaCl concentration. PMID- 27993016 TI - Controlling Smectic Liquid Crystal Defect Patterns by Physical Stamping-Assisted Domain Separation and Their Use as Templates for Quantum Dot Cluster Arrays. AB - Controlling the organization of self-assembling building blocks over a large area is crucial for lithographic tools based on the bottom-up approach. However, the fabrication of liquid crystal (LC) defect patterns with a particular ordering still remains a challenge because of the limited close-packed morphologies of LC defects. Here, we introduce a multiple-stamping domain separation method for the control of the dimensions and organization of LC defect structures. Prepatterns with various grid shapes on planar polyimide (PI) surfaces were fabricated by pressing a line-shaped stamp into the PI surfaces in two different directions, and then these surfaces were used to prepare LC defect structures confined to these grid domains. The dimensions of the LC defect structures, namely, the equilibrium diameter and the center to center spacing, are controlled by varying the line spacing of the stamps and the film thickness. A variety of arrangements of LC defects, including square, rhombic, hexagonal, and other oblique lattices, can be obtained by simply varying the stamping angle (Omega) between the first and second stamping directions. Furthermore, we demonstrate that the resulting controllable LC defect arrays can be used as templates for generating various patterns of nanoparticle clusters by trapping quantum dots (QDs) within the cores of the LC defects. PMID- 27993017 TI - Pore Model in the Melting Regime of a Lyotropic Biomembrane with an Anionic Phospholipid. AB - Aqueous dispersions of the anionic phospholipid dimyristoyl phosphatidyl glycerol (DMPG) exhibit an unusual "melting regime", at the phase transition between the ordered (gel) and the disordered (fluid liquid crystal) state of hydrocarbon chains, depending on the ionic strength and DMPG concentration, previously attributed to the pore formation. Dispersions with 150 mM DMPG present a lamellar phase above 23 degrees C, within the melting regime. In this study, we present a detailed pore model for the analysis of small-angle X-ray scattering (SAXS) results and their variation with temperature, focused on the surface fractions of pores in the bilayers. Large and small toroidal pores are necessary to explain the SAXS results. Pores have DMPG in the fluid conformation, whereas the flat region of the bilayer has DMPG molecules in fluid and in gel conformations. A particular strategy was developed to estimate the charges due to the localization of mobile ions in the system, which is based on the calculation of electron densities by duly considering all molecular and ionic species that characterize the system, and the temperature dependency of their volumes. The best fit to the model of SAXS curves defines that the gel phase transforms initially, at 19.4 degrees C, in uncoupled bilayers with large pores (radius 93.2 +/- 0.5 A, with water channel diameter 137 +/- 1 A), which transform into small pores along the lamellar phase. The minimum intensity of the SAXS bilayer peak at 30 degrees C corresponds to a maximum number of small pores, and above 35 degrees C, the system enters into the normal lamellar fluid phase, without pores. The charge is estimated and shows that the regions with pores contains less Na+ ions per polar head; hence, when they are forming, there is a release of Na+ ions toward the bulk. PMID- 27993018 TI - Phase Transitions in DNA/Surfactant Adsorption Layers. AB - The adsorption layers of complexes between DNA and oppositely charged surfactants dodecyltrimethylammonium bromide (DTAB) and cetyltrimethylammonium bromide (CTAB) at the solution/air interface were studied with surface tensiometry, dilational surface rheology, atomic force microscopy, Brewster angle microscopy, infrared absorption-reflection spectroscopy, and ellipsometry. Measurements of the kinetic dependencies of the surface properties gave a possibility to discover the time intervals corresponding to the coexistence of two-dimensional phases. One can assume that the observed phase transition is of the first order, unlike the formation of microaggregates in the adsorption layers of mixed solutions of synthetic polyelectrolytes and surfactants. The multitechniques approach together with the calculations of the adsorption kinetics allowed the elucidation of the structure of coexisting surface phases and the distinguishing of four main steps of adsorption layer formation at the surface of DNA/surfactant solutions. PMID- 27993019 TI - Novel Approach to Measuring the Droplet Detachment Force from Fibers. AB - Determining the force required to detach a droplet from a fiber or from an assembly of fibers is of great importance to many applications. A novel technique is developed in this work to measure this force experimentally by using ferrofluid droplets in a magnetic field. Unlike previous methods reported in the literature, our technique does not require air flow or a mechanical object to detach the droplet from the fiber(s); therefore, it simplifies the experiment and also allows one to study the capillarity of the droplet-fiber system in a more isolated environment. In this article, we investigated the effects of the relative angle between intersecting fibers on the force required to detach a droplet from the fibers in the in-plane or out-of-plane direction. The in-plane and through-plane detachment forces were also predicted via numerical simulation and compared with the experimental results. Good agreement was observed between the numerical and experimental results. It was found that the relative angle between intersecting fibers has no significant effect on the detachment force in the out-of-plane direction. However, the detachment force in the in-plane direction depends strongly on the relative angle between the fibers, and it increases as this angle increases. PMID- 27993020 TI - Numerical Study of the Electrothermal Effect on the Kinetic Reaction of Immunoassays for a Microfluidic Biosensor. AB - In this work, we simulate the binding reaction of C-reactive protein in a microchannel of a biosensor. A problem that arises in this device concerns the transport of the analyte toward the reaction surface of the biosensor, which is of a very small dimension. The limitation of mass transport causes the formation of a diffusion boundary layer and restrains the whole kinetic reaction. To enhance the performance of the biosensor by improving the transport, an applied AC electric field and flow confinement are used to stir the flow field. The numerical simulation of these mechanisms on the binding reaction is performed using the finite element method. Swirling patterns are generated in the fluid. They enhance the transport of the analyte and confine it near the reaction surface. The location of the electrode pair on the walls of the microchannel for the design of the biosensor has been studied to find out the effects of varying geometric configurations on the binding efficiency. The best performances of the biosensor are obtained when the electrodes are placed on the same wall of the microchannel as the reaction surface. For the best case, under the effect of the applied electric field alone, the enhancement factors raise up to 2.46 and 2.10 for the association and dissociation phases, respectively. By contrast, under the effect of the electric field with flow confinement, the enhancement factors for the association and the dissociation phases jump to 3.43 and 2.97, respectively, for 30:1 flow confinement (ratio of confining to sample flow). PMID- 27993021 TI - Curcumin-Loaded Amine-Functionalized Mesoporous Silica Nanoparticles Inhibit alpha-Synuclein Fibrillation and Reduce Its Cytotoxicity-Associated Effects. AB - This study aimed to develop a drug carrier based on amine-functionalized mesoporous silica nanoparticles (AAS-MSNPs) for a poorly water-soluble drug, curcumin (CUR), and to study its effects on alpha-synuclein (alpha-Syn) fibrillation and cytotoxicity. Here, we show that AAS-MSNPs possess high values of loading efficiency and capacity (33.5% and 0.45 mg drug/mg MSNPs, respectively) for CUR. It is also revealed that alpha-Syn species interact strongly with the CUR-loaded AAS-MSNPs, leading to a significant inhibition of the fibrillation process. Furthermore, these samples reduce the toxic effects of CUR. However, drug-loaded AAS-MSNPs do not affect the cytotoxic properties of the formed fibrils considerably. In addition, CUR loaded onto AAS-MSNPs shows enhanced stability in comparison with that of the free drug. These remarkable properties introduce AAS-MSNPs as a promising tool for the formulation of poorly water-soluble drugs such as CUR. PMID- 27993022 TI - Electrospun Fibrous Mat with pH-Switchable Superwettability That Can Separate Layered Oil/Water Mixtures. AB - Oil/water separation has inspired much research interest because of the damages caused to our natural environment due to oily wastewater. As a leader of advanced separation materials, electrospun polymeric fibrous mats having the properties of special surface wettability, high specific surface area, and high porosity will be a good membrane material for the separation of oily wastewater. Herein, we first prepared pH-responsive polymer poly(dimethylsiloxane)-block-poly(4 vinylpyridine) (PDMS-b-P4VP) mat using electrospinning technology. The PDMS-b P4VP fibrous mat with a thickness of around 250 MUm exhibits good pH-switchable oil/water wettability and is able to effectively separate oil or water from layered oil/water mixtures by gravity driven through adjusting the pH value. Stemming from its porous structure and pH-switchable superwettability, the electrospun PDMS-b-P4VP fibrous mat achieved controllable separations with high fluxes of approximately 9000 L h-1 m-2 for oil (hexane) and 27 000 L h-1 m-2 for water. In addition, extended studies on the polymer/silica nanoparticulate (silica NP) composite fibrous mats show that the addition of an inorganic component improves the thermal stability, pH-switchable wettability, and separation performance of the fibrous mats (approximately 9000 L h-1 m-2 for hexane and 32 000 L h-1 m-2 for water). It can be concluded from the results that both polymer fibrous mats and silica-filled composite fibrous mats are good candidates for on-demand layered oil/water mixture separation. PMID- 27993023 TI - Transparent Ethylene-Bridged Polymethylsiloxane Aerogels and Xerogels with Improved Bending Flexibility. AB - Transparent, monolithic aerogels with nanosized colloidal skeletons have been obtained from a single precursor of 1,2-bis(methyldiethoxysilyl)ethane (BMDEE) by adopting a liquid surfactant and a two-step process involving strong-acid, followed by strong-base, sol-gel reactions. This precursor BMDEE forms the ethylene-bridged polymethylsiloxane (EBPMS, O2/2(CH3)Si-CH2CH2-Si(CH3)O2/2) network, in which each silicon has one methyl, two bridging oxygens, and one bridging ethylene, exhibiting an analogous structure to that of the previously reported polymethylsilsesquioxane (PMSQ, CH3SiO3/2) aerogels having one methyl and three bridging oxygen atoms. Obtained aerogels consist of fine colloidal skeletons and show high visible-light transparency and a flexible deformation behavior against compression without collapse. Similar to the PMSQ aerogels, a careful tuning of synthetic conditions can produce low-density (0.19 g cm-3) and highly transparent (76% at 550 nm, corresponding to 10 mm thick samples) xerogels via ambient pressure drying by solvent evaporation due to their high strength and resilience against compression. Moreover, EBPMS aerogels exhibit higher bending strength and bending strain at break against the three-point bending mode compared to PMSQ aerogels. This improved bendability is presumably derived from the introduced ethylene-bridging parts, suggesting the potential for realizing transparent and bendable aerogels in such polysiloxane materials with organic linking units. PMID- 27993025 TI - Dip-and-Drag Lateral Force Spectroscopy for Measuring Adhesive Forces between Nanofibers. AB - Adhesive interactions between nanofibers strongly influence the mechanical behavior of soft materials composed of fibrous networks. We use atomic force microscopy in lateral force mode to drag a cantilever tip through fibrous networks, and use the measured lateral force response to determine the adhesive forces between fibers of the order of 100 nm diameter. The peaks in lateral force curves are directly related to the detachment energy between two fibers; the data is analyzed using the Jarzynski equality to yield the average adhesion energy of the weakest links. The method is successfully used to measure adhesion forces arising from van der Waals interactions between electrospun polymer fibers in networks of varying density. This approach overcomes the need to isolate and handle individual fibers, and can be readily employed in the design and evaluation of advanced materials and biomaterials which, through inspiration from nature, are increasingly incorporating nanofibers. The data obtained with this technique may also be of critical importance in the development of network models capable of predicting the mechanics of fibrous materials. PMID- 27993024 TI - Rapid Self-Assembly of Block Copolymers for Flower-Like Particles with High Throughput. AB - The self-assembly of block copolymers has evolved into a foremost bottom-up approach for building polymeric materials. Historical challenges exist within this lively field, including the scalability and elegant simplicity of self assembled aggregates with predictable structures. Here, we report a generally applicable strategy for the rapid self-assembly of poly(ethylene glycol)-block poly(l-lactic acid) with the help of a single oil-in-water emulsion. A kind of flower-like polymer particle with filamentous surface branches is rapidly formed after removing the oil phase from the emulsion system. Moreover, the dimension of the branched filaments and the spherical internal core can be controlled through regulating the block ratio and the emulsification conditions. In particular, we propose an explosion theory as a balance between phase separation and interchain interaction for explaining the formation of the branched structures of the flower like particles. The particles with high throughput are further functionalized with polypyrrole for their use in enhanced photoelectric-sensing applications. PMID- 27993026 TI - Particulate Coacervation of Associative Polymer Brushes-Grafted Nanoparticles To Produce Structurally Stable Pickering Emulsions. AB - This study introduces a new type of associative nanoparticle (ANP) that provides controlled chain-to-chain attraction with an associative polymer rheology modifier (APRM) to produce highly stable Pickering emulsions. The ANPs were synthesized by grafting hydrophobically modified hygroscopic zwitterionic poly(2 methacryloyloxyethyl phosphorylcholine-co-stearyl methacrylate) brushes onto 20 nm sized silica NPs via surface-mediated living radical polymerization. The ANP stabilized Pickering emulsions show significant viscosity enhancement in the presence of the APRM. This indicates that the ANPs act as particulate concentration agents at the interface owing to their hydrophobic association with the APRM in the aqueous phase, which leads to the generation of an ANP-mediated complex colloidal film. Consequently, the described ANP-reinforced Pickering emulsion system exhibits improved resistance to pH and salinity changes. This coacervation approach is advantageous because the complex colloidal layer at the interface provides the emulsion drops with a mechanically robust barrier, thus guaranteeing the improved Pickering emulsion stability against harsh environmental factors. PMID- 27993027 TI - Rapid Immobilization of Oligonucleotides at High Density on Semiconductor Quantum Dots and Gold Nanoparticles. AB - Oligonucleotide-coated nanoparticles (NPs) have been used in numerous applications such as bioassays, as intracellular probes, and for drug delivery. One challenge that is confronted in the preparation of oligonucleotide-NP conjugates is derived from surface charge because nanoparticles are often stabilized and made water-soluble with a coating of negatively charged capping ligands. Therefore, an electrostatic repulsion is present when attempting to conjugate oligonucleotides. The result is that the conjugation can be a slow process, sometimes requiring 1 to 2 days to equilibrate at the highest surface density. The effect is compounded by electrostatic repulsion between neighboring oligonucleotide strands on the NP surfaces, which tends to lower the surface density. Herein, we report a novel method that enables conjugation in less than 1 min with a surface density of oligonucleotides up to the theoretical physical limit of occupancy. Negatively charged NPs are first adsorbed onto the surface of positively charged magnetic beads (MBs) to create MB-NP conjugates. Oligonucleotides are subsequently electrostatically adsorbed onto the MB surfaces when added to a suspension of MB-NP conjugates. This creates an oligonucleotide concentration 105 to 106 greater than in bulk solution in the vicinity of the nanoparticles, resulting in the promotion of the kinetics by over 1000-fold and achieving the maximum density possible for the conjugation reaction. PMID- 27993028 TI - Nanocontact Printing of Proteins on Physiologically Soft Substrates to Study Cell Haptotaxis. AB - Surface bound guidance cues and gradients are vital for directing cellular processes during development and repair. In vivo, these cues are often presented within a soft extracellular matrix with elastic moduli E < 10 kPa, but in vitro haptotaxis experiments have been conducted primarily on hard substrates with elastic moduli in the MPa to GPa range. Here, a technique is presented for patterning haptotactic proteins with nanometer resolution on soft substrates with physiological elasticity. A new nanocontact printing process was developed that circumvented the use of plasma activation that was found to alter the mechanical properties of the substrate. A dissolvable poly(vinyl alcohol) film was first patterned by lift-off nanocontact printing, and in turn printed onto the soft substrate, followed by dissolution of the film in water. An array of 100 unique digital nanodot gradients (DNGs), consisting of millions of 200 * 200 nm2 protein nanodots, was patterned in less than 5 min with with <5% average deviation from the original gradient design. DNGs of netrin-1, a known protein guidance cue, were patterned, and the unpatterned surface was backfilled with a reference surface consisting of 75% polyethylene glycol grafted with polylysine and 25% poly-d-lysine. Haptotaxis of C2C12 myoblasts demonstrated the functionality of the DNGs patterned on soft substrates. In addition, high densities of netrin-1 were observed to induce cell spreading, while live imaging of sinusoidal control gradients highlighted cell migration and navigation by "inching". The nanopatterning technique developed here paves the way for studying haptotactic responses to diverse digital nanodot patterns on surfaces covering the full range of physiological elasticity, and is expected to be applicable to the study of both culture and primary cells, such as neutrophils and neurons. PMID- 27993029 TI - Interfacial Particle Dynamics: One and Two Step Yielding in Colloidal Glass. AB - The yielding behavior of silica nanoparticles partitioned at an air-aqueous interface is reported. Linear viscoelasticity of the particle-laden interface can be retrieved via a time-dependent and electrolyte-dependent superposition, and the applicability of the "soft glassy rheology" (SGR) model is confirmed. With increasing electrolyte concentration (phielect) in the aqueous subphase, a nonergodic state is achieved with particle dynamics arrested first from attraction induced bonding bridges and then from the cage effect of particle jamming, manifesting in a two-step yielding process under large amplitude oscillation strain (LAOS). The Lissajous curves disclose a shear-induced in-cage particle redisplacement within oscillation cycles between the two yielding steps, exhibiting a "strain softening" transitioning to "strain stiffening" as the interparticle attraction increases. By varying phielect and the particle spreading concentration, phiSiO2, a variety of phase transitions from fluid- to gel- and glass-like can be unified to construct a state diagram mapping the yielding behaviors from one-step to two-step before finally exhibiting one-step yielding at high phielect and phiSiO2. PMID- 27993030 TI - Biocompatible Polyion Complex Micelles Synthesized from Arborescent Polymers. AB - Water-dispersible polyion complex (PIC) micelles were prepared by the self assembly of an arborescent polystyrene-graft-poly(2-vinylpyridine) copolymer (denoted G0PS-g-P2VP or G1) serving as core and a poly(acrylic acid)-block-poly(2 hydroxyethyl acrylate) (PAA-b-PHEA) double-hydrophilic block copolymer (DHBC) forming a shell. Varying the density of hydrophilic polymer chains in the stabilizing layer provided control over the size and structure of the entities obtained, from large flocculated species to stable isolated PIC micelles with diameters ranging from 42 to 67 nm. The hydrodynamic radius (determined from dynamic light scattering measurements), and the weight-average molar mass (Mw) and radius of gyration of the scatterers (extracted from static multiangle light scattering data) evidenced the formation of either isolated or aggregated PIC micelles depending on the self-assembly conditions used (pH, concentration and mixing molar ratio f). Changes in the morphology of the arborescent copolymer after complexation were observed by atomic force microscopy (AFM) imaging. In particular, by varying the force applied with the AFM tip on the samples, the core-shell structure of the PIC micelles was clearly evidenced. The PIC micelles displayed no significant cytotoxicity toward mouse fibroblast L929 cells, a standard cell line recommended for toxicity assays, due to the good biocompatibility of the hydrophilic PAA-b-PHEA shell. In spite of a negative residual zeta potential due to an excess of negative charges, fluorescently labeled PIC* micelles were successfully internalized by L929 cells, as confirmed by laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM). PMID- 27993031 TI - Complex Coacervate Core Micelles for the Dispersion and Stabilization of Organophosphate Hydrolase in Organic Solvents. AB - Organophosphate (OP) nerve agents are a class of chemical warfare agents (CWAs) that exist as bulk stocks in current and past war zones. Thus, a technology that can perform on-site decontamination in a safe and timely fashion is desirable. Here, complex coacervate core micelles (C3Ms) were used to encapsulate organophosphate hydrolase (OPH) and chemostabilize it to maintain activity after exposure to organophosphate simulants ethanol and dimethyl methylphosphonate (DMMP). C3Ms were formed by two polymers-poly(acrylic acid) (PAA) and poly(oligo(ethylene glycol) methacrylate)-b-poly(4-vinyl N-methylpyridyl iodide), (POEGMA-b-qP4VP). Complexes of the coacervate micelles with the enzyme OPH were investigated by small angle neutron scattering (SANS), dynamic light scattering (DLS), and transmission electron microscopy (TEM), demonstrating the formation of micellar structures in solution. The activity of OPH against methyl paraoxon in these C3Ms under aqueous conditions was assayed after heat treatment for 3 days at 37 degrees C. The OPH in C3Ms retained 88 +/- 7% of its initial activity, as compared to the 48 +/- 3% activity retained by OPH alone, indicating that the C3Ms were able to stabilize the enzyme to heat treatment. C3Ms transferred into the two organic solvents formed larger structures than inverse micelles formed by the block copolymer alone. The addition of OPH to the C3Ms in organic solvents did not significantly change their structure. The activity of OPH (again, against methyl paraoxon) after 24 h of incubation at 4 degrees C was measured and compared to that of OPH in C3Ms. While OPH alone retained less than 5% of its activity after this incubation in both solvents, OPH in C3Ms retained 35 +/- 3% of its activity in DMMP and 26 +/- 1% of its activity in ethanol. PMID- 27993032 TI - Porous Polymeric Films from Microbubbles Generated Using a T-Junction Microfluidic Device. AB - In this work, a simple microfluidic junction with a T geometry and coarse (200 MUm diameter) capillaries was used to generate monodisperse microbubbles with an alginate polymer shell. Subsequently, these bubbles were used to prepare porous alginate films with good control over the pore structure. The lack of pore size, shape, and surface control in scalable forming of polymeric films is a major application-limiting drawback at present. Controlling the thinning process of the shell of the bubbles to tune the surface of the resulting structures was also explored. Films were prepared with nanopatterned surfaces by controlling the thinning of the bubble shell, with the aid of surfactants, to induce efficient bursting (fragmentation) of bubbles to generate nanodroplets, which become embedded within the film surface. This novel feature greatly expands and enhances the use of hydrophilic polymers in a wide range of biomedical applications, particularly in drug delivery and tissue engineering, such as studying cellular responses to different morphological surfaces. PMID- 27993033 TI - Correction to "Water Touch-and-Bounce from a Soft Viscoelastic Substrate: Wetting, Dewetting, and Rebound on Bitumen". PMID- 27993034 TI - In Vivo Biotransformation Rates of Organic Chemicals in Fish: Relationship with Bioconcentration and Biomagnification Factors. AB - In vivo dietary bioaccumulation experiments for 85 hydrophobic organic substances were conducted to derive the in vivo gastrointestinal biotransformation rates, somatic biotransformation rates, bioconcentration factors (BCF), and biomagnification factors (BMF) for improving methods for bioaccumulation assessment and to develop an in vivo biotransformation rate database for QSAR development and in vitro to in vivo biotransformation rate extrapolation. The capacity of chemicals to be biotransformed in fish was found to be highly dependent on the route of exposure. Somatic biotransformation was the dominant pathway for most chemicals absorbed via the respiratory route. Intestinal biotransformation was the dominant metabolic pathway for most chemicals absorbed via the diet. For substances not biotransformed or transformed exclusively in the body of the fish, the BCF and BMF appeared to be closely correlated. For substances subject to intestinal biotransformation, the same correlation did not apply. We conclude that intestinal biotransformation and bioavailability in water can modulate the relationship between the BCF and BMF. This study also supports a fairly simple rule of thumb that may be useful in the interpretation of dietary bioaccumulation tests; i.e., chemicals with a BMFL of <1 tend to exhibit BCFs based on either the freely dissolved (BCFWW,fd) or the total concentration (BCFWW,t) of the chemical in the water that is less than 5000. PMID- 27993035 TI - Using Continuous Underway Isotope Measurements To Map Water Residence Time in Hydrodynamically Complex Tidal Environments. AB - Stable isotopes present in water (delta2H, delta18O) have been used extensively to evaluate hydrological processes on the basis of parameters such as evaporation, precipitation, mixing, and residence time. In estuarine aquatic habitats, residence time (tau) is a major driver of biogeochemical processes, affecting trophic subsidies and conditions in fish-spawning habitats. But tau is highly variable in estuaries, owing to constant changes in river inflows, tides, wind, and water height, all of which combine to affect tau in unpredictable ways. It recently became feasible to measure delta2H and delta18O continuously, at a high sampling frequency (1 Hz), using diffusion sample introduction into a cavity ring-down spectrometer. To better understand the relationship of tau to biogeochemical processes in a dynamic estuarine system, we continuously measured delta2H and delta18O, nitrate and water quality parameters, on board a small, high-speed boat (5 to >10 m s-1) fitted with a hull-mounted underwater intake. We then calculated tau as is classically done using the isotopic signals of evaporation. The result was high-resolution (~10 m) maps of residence time, nitrate, and other parameters that showed strong spatial gradients corresponding to geomorphic attributes of the different channels in the area. The mean measured value of tau was 30.5 d, with a range of 0-50 d. We used the measured spatial gradients in both tau and nitrate to calculate whole-ecosystem uptake rates, and the values ranged from 0.006 to 0.039 d-1. The capability to measure residence time over single tidal cycles in estuaries will be useful for evaluating and further understanding drivers of phytoplankton abundance, resolving differences attributable to mixing and water sources, explicitly calculating biogeochemical rates, and exploring the complex linkages among time-dependent biogeochemical processes in hydrodynamically complex environments such as estuaries. PMID- 27993036 TI - Mechanisms of Elemental Mercury Transformation on alpha-Fe2O3(001) Surface from Experimental and Theoretical Study: Influences of HCl, O2, and SO2. AB - The reaction mechanisms of a mixture gas of HCl, O2, and SO2 in Hg0 adsorption on alpha-Fe2O3(001) surface are clarified by a group of adsorption experiments and theoretical calculations based on the density functional theory. The role of O2 in removing Hg0 is greatly influenced by the reaction temperature, meanwhile, the O atom coverage could affect the adsorption performance of Hg0. The dissociated O2 competes with the active sites of Cl species on Fe surface at low temperature, however, at medium temperature HCl and O2 could simultaneously facilitate the Hg0 transformation. Combined with the theoretical calculations, the role of SO2 and the probable pathways in removing Hg0 are discussed. Lower concentration of SO2 as well as HCl could dissociate on alpha-Fe2O3(001) surface, and the intermediates combine with gaseous Hg0, forming mercury-sulfur, mercury-chlorine compounds, and so forth. In addition, the different concentrations of SO2 are also discussed, and the corresponding X-ray photoelectron spectroscopy analysis on contrasted samples is conducted to research the morphological characterization, providing a reliable basis for judging the probable pathways of Hg0 transformation. PMID- 27993037 TI - Chemical Composition of Microbe-Derived Dissolved Organic Matter in Cryoconite in Tibetan Plateau Glaciers: Insights from Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Analysis. AB - Cryoconite in mountain glaciers plays important roles in glacial ablation and biogeochemical cycles. In this study, the composition and sources of dissolved organic matter (DOM) in cryoconite from the ablation regions of two Tibetan Plateau glaciers were determined using electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and fluorescence spectrometry. A marked absorbance between 300 and 350 nm in the DOM absorption spectra was observed which was consistent with microbe-derived mycosporine-like amino acids. Fluorescence excitation-emission matrices showed that DOM had intense signals at protein-like substance peaks and weak signals at humic-like substance peaks. The high-resolution mass spectra of FT-ICR-MS showed cryoconite DOM from both glaciers contained diverse lignins, lipids, proteins, and unsaturated hydrocarbons. The lipids and proteins were consistent with material from microbial sources, and the lignins and unsaturated hydrocarbons were probably from vascular plant material supplied in atmospheric aerosols and debris from around the glaciers. Almost one-third of the identified DOM molecules had low C/N ratios (<=20), indicating their high bioavailability. Using a conservative cryoconite distribution on Chinese mountain glacier surfaces (6%) and an average debris mass per square meter of cryoconite (292 +/- 196 g m-2), we found that the amount of DOC produced in cryoconite on Chinese glaciers as much as 0.23 +/- 0.1 Gg per cryoconite formation process. This dissolved organic carbon may absorb solar radiation, accelerate glacial melting, and be an important source of bioavailable DOM to proglacial and downstream aquatic ecosystems. PMID- 27993038 TI - Degradation of DEET and Caffeine under UV/Chlorine and Simulated Sunlight/Chlorine Conditions. AB - Photoactivation of aqueous chlorine could promote degradation of chlorine resistant and photochemically stable chemicals accumulated in swimming pools. This study investigated the degradation of two such chemicals, N,N-diethyl-3 methylbenzamide (DEET) and caffeine, by low pressure ultraviolet (UV) light and simulated sunlight (SS) activated free chlorine (FC) in different water matrices. Both DEET and caffeine were rapidly degraded by UV/FC and SS/FC but exhibited different kinetic behaviors. The degradation of DEET followed pseudo-first-order kinetics, whereas the degradation of caffeine accelerated with reaction. Mechanistic study revealed that, under UV/FC, .OH and Cl. were responsible for degradation of DEET, whereas ClO. related reactive species (ClOrrs), generated by the reaction between FC and .OH/Cl., played a major role in addition to .OH and Cl. in degrading caffeine. Reaction rate constants of DEET and caffeine with the respective radical species were estimated. The imidazole moiety of caffeine was critical for the special reactivity with ClOrrs. Water matrix such as pH had a stronger impact on the UV/FC process than the SS/FC process. In saltwater matrix under UV/FC and SS/FC, the degradation of DEET was significantly inhibited, but the degradation of caffeine was much faster than that in nonsalty solutions. The interaction between Br- and Cl- may play an important role in the degradation of caffeine by UV/FC in saltwater. Reaction product analysis showed similar product patterns by UV/FC and SS/FC and minimal formation of chlorinated intermediates and disinfection byproducts. PMID- 27993039 TI - "Diffusive Gradients in Thin Films" Techniques Provide Representative Time Weighted Average Measurements of Inorganic Nutrients in Dynamic Freshwater Systems. AB - Nutrient concentrations in freshwater are highly variable over time, with changes driven by weather events, anthropogenic sources, modifications to catchment hydrology or habitats, and internal biogeochemical processes. Measuring infrequently collected grab samples is unlikely to adequately represent nutrient concentrations in such dynamic systems. In contrast, in situ passive sampling techniques, such as the "diffusive gradients in thin films" (DGT) technique, provide time-weighted average analyte concentrations over the entire deployment time. A pair of recently developed DGT techniques for nitrate (A520E-DGT) and ammonium (PrCH-DGT), as well as the Metsorb-DGT technique for phosphate, were used to monitor inorganic nutrients in different freshwater systems (i.e., streams and wetlands) with a range of environmental values and that were affected by different catchment types. Measurements of grab samples collected frequently (1-2 times daily, 8-10 a.m. and 2-4 p.m.) showed that concentrations of NH4-N and NO3-N changed dramatically in most of the studied freshwater systems over short time scales, while there were only relatively small fluctuations in PO4-P. The DGT measurements were highly representative in comparison with the average nutrient concentrations obtained from daily grab samples over short-term (24 h) and long-term (72 h) deployments. The ratios of DGT-labile concentrations to the average concentrations from grab samples were between 1.00 and 1.12 over the studied deployment periods. The results of this study confirmed that DGT measurements provided a reliable and robust method for monitoring NH4-N, NO3-N, and PO4-P in a diverse range of dynamic freshwater systems. PMID- 27993041 TI - Migration of Parabens, Bisphenols, Benzophenone-Type UV Filters, Triclosan, and Triclocarban from Teethers and Its Implications for Infant Exposure. AB - Parabens (p-hydroxybenzoic acid esters), bisphenols, benzophenone-type UV filters, triclosan, and triclocarban are used in a variety of consumer products, including baby teethers. Nevertheless, the exposure of infants to these chemicals through the use of teethers is still unknown. In this study, 59 teethers, encompassing three types, namely solid plastic, gel-filled, and water-filled (most labeled "bisphenol A-free"), were collected from the U.S. market and analyzed for 26 potential endocrine-disrupting chemicals (EDCs) from intact surfaces through migration/leaching tests performed with Milli-Q water and methanol. The total amount of the sum of six parent parabens (Sigma6 Parabens) leached from teethers ranged from 2.0 to 1990 ng, whereas that of their four transformation products (Sigma4 Parabens) ranged from 0.47 to 839 ng. The total amount of the sum of nine bisphenols (Sigma9 bisphenols) and 5 benzophenones (Sigma5 benzophenones) leached from teethers ranged from 1.93 to 213 ng and 0.59 to 297 ng, respectively. Triclosan and triclocarban were found in the extracts of teethers at approximately 10-fold less amounts than were bisphenols and benzophenones. Based on the amount leached into Milli-Q water, daily intake of these chemicals was estimated from the use of teethers by infants at 12 months of age. This is the first study to document the occurrence and migration of a wide range EDCs from intact surfaces of baby teethers. PMID- 27993040 TI - Vaporization Mechanisms of Water-Insoluble Cs in Ash During Thermal Treatment with Calcium Chloride Addition. AB - The vaporization mechanisms of water-insoluble Cs in raw ash and Cs-doped ash during thermal treatment with CaCl2 addition was systematically examined in a lab scale electrical heating furnace over a temperature range of 500-1500 degrees C. The results indicate that the water-insoluble Cs in the ash was associated with aluminosilicate as pollucite. Addition of 10% CaCl2 caused the maximum vaporization ratio of Cs in the raw ash to reach approximately 80% at temperatures higher than 1200 degrees C, whereas approximately 95% of Cs was vaporized at temperatures higher than 1300 degrees C when 30% CaCl2 was added. The formation of an intermediate compound, CsCaCl3, through the chemical reaction of Cs with CaCl2 was responsible for Cs vaporization by means of the subsequent decomposition of this intermediate upon the increase in temperature. The indirect chlorination of Cs by the gaseous chlorine released from the decomposition of CaCl2 was insignificant. A high CaCl2 content in the resulting annealed products with 30% CaCl2 addition delayed the decomposition of CsCaCl3 and thus lowered the Cs vaporization ratio compared to that with 10% CaCl2 addition at 900-1250 degrees C. Thermal treatment with CaCl2 addition is a proposed method to remove Cs from Cs-contaminated incineration ash. PMID- 27993042 TI - Identification of Marbon in the Indiana Harbor and Ship Canal. AB - Marbon is isomeric with Dechlorane Plus (DP). Both are produced by the Diels Alder condensation of hexachlorocyclopentadiene with cyclic dienes, and both have elemental compositions of C18H12Cl12. Dechlorane Plus is commonly found in the environment throughout the world, but Marbon has, so far, only been detected at low levels in one sediment core collected near the mouth of the Niagara River in Lake Ontario. Here we report on the concentrations of Marbon and anti-DP in 59 water samples from five Lake Michigan tributaries [the Grand, Kalamazoo, St. Joseph, and Lower Fox Rivers, and the Indiana Harbor and Ship Canal (IHSC)], 10 surface sediment samples from the IHSC, and 2 surface sediment samples from the Chicago Sanitary and Ship Canal. Three Marbon diastereomers were detected in the water and sediment samples from the IHSC, which is far from the location of its previous detection in Lake Ontario. The sum of the concentrations of the three Marbons was greater in the water from the IHSC (N = 11, median =150 pg/L) compared to those in water from the other four tributaries (N = 11-13, medians =0.9-2.0 pg/L). Marbon concentrations in sediment samples from the IHSC were up to 450 ng/g dry weight. Anti-DP was also measured for comparison. Its concentrations were not significantly different among the water samples, but its sediment concentrations in the IHSC were significantly correlated with those of Marbon. The source of Marbon contamination in the IHSC is not clear. PMID- 27993043 TI - Mechanisms of Action of Compounds That Enhance Storage Lipid Accumulation in Daphnia magna. AB - Accumulation of storage lipids in the crustacean Daphnia magna can be altered by a number of exogenous and endogenous compounds, like 20-hydroxyecdysone (natural ligand of the ecdysone receptor, EcR), methyl farnesoate, pyrirproxyfen (agonists of the methyl farnesoate receptor, MfR), and tributyltin (agonist of the retinoid X acid receptor, RXR). This effect, analogous to the obesogenic disruption in mammals, alters Daphnia's growth and reproductive investment. Here we propose that storage lipid accumulation in droplets is regulated in Daphnia by the interaction between the nuclear receptor heterodimer EcR:RXR and MfR. The model was tested by determining changes in storage lipid accumulation and on gene transcription in animals exposed to different effectors of RXR, EcR, and MfR signaling pathways, either individually or in combination. RXR, EcR, and MfR agonists increased storage lipid accumulation, whereas fenarimol and testosterone (reported inhibitors of ecdysteroid synthesis and an EcR antagonist, respectively) decreased it. Joint effects of mixtures with fenarimol, testosterone, and ecdysone were antagonistic, mixtures of juvenoids showed additive effects following a concentration addition model, and combinations of tributyltin with juvenoids resulted in greater than additive effects. Co exposures of ecdysone with juvenoids resulted in deregulation of ecdysone- and farnesoid-regulated genes, accordingly with the observed changes in lipid accumulation These results indicate the requirement of ecdysone binding to the EcR:RXR:MfR complex to regulate lipid storage and that an excess of ecdysone disrupts the whole process, probably by triggering negative feedback mechanisms. PMID- 27993044 TI - Dissolution Behavior of Silver Nanoparticles and Formation of Secondary Silver Nanoparticles in Municipal Wastewater by Single-Particle ICP-MS. AB - Ag nanoparticles (nAg) are used in various consumer products and a significant fraction is eventually discharged with municipal wastewater (WW). In this study we assessed the release of Ag from polyvinylpyrrolidone (PVP)- and citrate-coated 80 nm nAg in aerobic WW effluent and mixed liquor and the related changes in nAg size, using single particle ICP-MS (spICP-MS). The concentration of dissolved (nonparticulate) Ag in WW effluent was 0.89 +/- 0.05 ppb at 168 h and was 71% lower than in deionized (DI) water, in batch reactors spiked with 5 * 106 PVP-nAg particles/mL (10 MUg/L), an environmentally relevant concentration. Dissolved Ag in WW was partly reformed into ~22 nm nAgxSy by inorganic sulfides and organosulfur dissolved organic carbon (DOC) after 120 h, whereas the parent nAg mean diameter decreased to 65.89 +/- 0.9 nm. Reformation of nAgxSy from Ag+ also occurred in cysteine solutions but not in DI water, or humic and fulvic acid solutions. Dissolution experiments with nAg in WW mixed liquor showed qualitatively similar dissolution trends. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) analyses indicated binding of thiol- and amine-containing DOC as well as inorganic sulfides with nAg. Those WW components, as well as limited dissolved oxygen, decreased dissolution in WW. PMID- 27993045 TI - Dynamics of Chromium(VI) Removal from Drinking Water by Iron Electrocoagulation. AB - The potential for new U.S. regulations for Cr(VI) in drinking water have spurred strong interests in improving technologies for Cr(VI) removal. This study examined iron electrocoagulation for Cr(VI) removal at conditions directly relevant to drinking water treatment. Cr(VI) is chemically reduced to less soluble Cr(III) species by the Fe(II) produced from an iron anode, and XANES spectra indicate that the Cr is entirely Cr(III) in solid-phases produced in electrocoagulation. The dynamics of Cr(VI) removal in electrocoagulation at pH 6 and pH 8 at both oxic and anoxic conditions can be described by a new model that incorporates Fe(II) release from the anode and heterogeneous and homogeneous reduction of Cr(VI) by Fe(II). Heterogeneous Cr(VI) reduction by adsorbed Fe(II) was critical to interpreting Cr(VI) removal at pH 6, and the Fe- and Cr containing EC product was found to catalyze the redox reaction. Dissolved oxygen (DO) did not observably inhibit Cr(VI) removal because Fe(II) reacts with DO more slowly than it does with Cr(VI), and Cr(VI) removal was faster at higher pH. Even in the presence of common groundwater solutes, iron electrocoagulation lowered Cr(VI) concentrations to levels well below California's 10 MUg/L. PMID- 27993046 TI - Tissue-Specific Accumulation, Depuration, and Transformation of Triphenyl Phosphate (TPHP) in Adult Zebrafish (Danio rerio). AB - Understanding bioaccumulation and metabolism is critical for evaluating the fate and potential toxicity of compounds in vivo. We recently investigated, for the first time, the bioconcentration and tissue distribution of triphenyl phosphate (TPHP) and its main metabolites in selected tissues of adult zebrafish. To further confirm the metabolites, deuterated TPHP (d15-TPHP) was used in the exposure experiments at an environmentally relevant level (20 MUg/L) and at 1/10 LC50 (100 MUg/L). After 11-14 days of exposure to 100 MUg/L of d15-TPHP, the accumulation and excretion of d15-TPHP reached equilibrium, at which point the intestine contained the highest d15-TPHP (MUg/g wet weight, ww) concentration (3.12 +/- 0.43), followed by the gills (2.76 +/- 0.12) > brain (2.58 +/- 0.19) > liver (2.30 +/- 0.34) ? muscle (0.53 +/- 0.04). The major metabolite of d15-TPHP, d10-diphenyl phosphate (d10-DPHP), was detected at significantly higher contents in the liver and intestine, at levels up to 3.0-3.5 times those of d15-TPHP. The metabolic pathways of TPHP were elucidated, including hydrolysis, hydroxylation, and glucuronic acid conjugation after hydroxylation. Finally, a physiologically based toxicokinetic (PBTK) model was used to explore the key factors influencing the bioaccumulation of d15-TPHP in zebrafish. These results provide important information for the understanding of the metabolism, disposition, and toxicology of TPHP in aquatic organisms. PMID- 27993047 TI - Correction to Growth Retardation and Altered Isotope Composition As Delayed Effects of PCB Exposure in Daphnia magna. PMID- 27993048 TI - Kinetics of Brominated Flame Retardant (BFR) Releases from Granules of Waste Plastics. AB - Plastic components of e-waste contain high levels of brominated flame retardants (BFRs), whose releases cause environmental and human health concerns. This study characterized the release kinetics of polybrominated diphenyl ethers (PBDEs) from millimeter-sized granules processed from the plastic exteriors of two scrap computer displays at environmentally relevant temperatures. The release rate of a substitute of PBDEs, 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), from the waste plastics, was reported for the first time. Deca-BDE was the most abundant PBDE congeners in both materials (87-89%), while BTBPE was also present at relatively high contents. The release kinetics of BFRs could be modeled as one-dimensional diffusion, while the temperature dependence of diffusion coefficients was well described by the Arrhenius equation. The diffusion coefficients of BFRs (at 30 degrees C) in the plastic matrices were estimated to be in the range of 10-27.16 to 10-19.96 m2.s-1, with apparent activation energies between 88.4 and 154.2 kJ.mol-1. The half-lives of BFR releases (i.e., 50% depletion) from the plastic granules ranged from thousands to tens of billions of years at ambient temperatures. These findings suggest that BFRs are released very slowly from the matrices of waste plastics through molecular diffusion, while their emissions can be significantly enhanced with wear-and-tear and pulverization. PMID- 27993049 TI - Relative Importance of Different Water Categories as Sources of N-Nitrosamine Precursors. AB - A comparison of loadings of N-nitrosamines and their precursors from different source water categories is needed to design effective source water blending strategies. Previous research using Formation Potential (FP) chloramination protocols (high dose and prolonged contact times) raised concerns about precursor loadings from various source water categories, but differences in the protocols employed rendered comparisons difficult. In this study, we applied Uniform Formation Condition (UFC) chloramination and ozonation protocols mimicking typical disinfection practice to compare loadings of ambient specific and total N nitrosamines as well as chloramine-reactive and ozone-reactive precursors in 47 samples, including 6 pristine headwaters, 16 eutrophic waters, 4 agricultural runoff samples, 9 stormwater runoff samples, and 12 municipal wastewater effluents. N-Nitrosodimethylamine (NDMA) formation from UFC and FP chloramination protocols did not correlate, with NDMA FP often being significant in samples where no NDMA formed under UFC conditions. N-Nitrosamines and their precursors were negligible in pristine headwaters. Conventional, and to a lesser degree, nutrient removal wastewater effluents were the dominant source of NDMA and its chloramine- and ozone-reactive precursors. While wastewater effluents were dominant sources of TONO and their precursors, algal blooms, and to a lesser degree agricultural or stormwater runoff, could be important where they affect a major fraction of the water supply. PMID- 27993050 TI - China's Soil Pollution Control: Choices and Challenges. PMID- 27993051 TI - A Portable and Autonomous Mass Spectrometric System for On-Site Environmental Gas Analysis. AB - We developed a portable mass spectrometric system ("miniRuedi") for quantificaton of the partial pressures of He, Ne (in dry gas), Ar, Kr, N2, O2, CO2, and CH4 in gaseous and aqueous matrices in environmental systems with an analytical uncertainty of 1-3%. The miniRuedi does not require any purification or other preparation of the sampled gases and therefore allows maintenance-free and autonomous operation. The apparatus is most suitable for on-site gas analysis during field work and at remote locations due to its small size (60 cm * 40 cm * 14 cm), low weight (13 kg), and low power consumption (50 W). The gases are continuously sampled and transferred through a capillary pressure reduction system into a vacuum chamber, where they are analyzed using a quadrupole mass spectrometer with a time resolution of ?1 min. The low gas consumption rate (<0.1 mL/min) minimizes interference with the natural mass balance of gases in environmental systems, and allows the unbiased quantification of dissolved-gas concentrations in water by gas/water equilibration using membrane contractors (gas-equilibrium membrane-inlet mass spectrometry, GE-MIMS). The performance of the miniRuedi is demonstrated in laboratory and field tests, and its utility is illustrated in field applications related to soil-gas formation, lake/atmosphere gas exchange, and seafloor gas emanations. PMID- 27993052 TI - Making America's Water Infrastructure Great Again. PMID- 27993053 TI - Exceptional Visible-Light Activities of TiO2-Coupled N-Doped Porous Perovskite LaFeO3 for 2,4-Dichlorophenol Decomposition and CO2 Conversion. AB - In this work, TiO2-coupled N-doped porous perovskite-type LaFeO3 nanocomposites as highly efficient, cheap, stable, and visible-light photocatalysts have successfully been prepared via wet chemical processes. It is shown that the amount-optimized nanocomposite exhibits exceptional visible-light photocatalytic activities for 2,4-dichlorophenol (2,4-DCP) degradation by ~3-time enhancement and for CO2 conversion to fuels by ~4-time enhancement, compared to the resulting porous LaFeO3 with rather high photoactivity due to its large surface area. It is clearly demonstrated, by means of various experimental data, especially for the .OH amount evaluation, that the obviously enhanced photoactivities are attributed to the increased specific surface area by introducing pores, to the extended visible-light absorption by doping N to create surface states, and to the promoted charge transfer and separation by coupling TiO2. Moreover, it is confirmed from radical trapping experiments that the photogenerated holes are the predominant oxidants in the photocatalytic degradation of 2,4-DCP. Furthermore, a possible photocatalytic degradation mechanism for 2,4-DCP is proposed mainly based on the resultant crucial intermediate, 2-chlorosuccinic acid with m/z = 153, that readily transform into CO2 and H2O. This work opens up a new feasible route to synthesize visible-light-responsive high-activity perovskite-type nanophotocatalysts for efficient environmental remediation and energy production. PMID- 27993054 TI - Nitrogen, Phosphorus, and Potassium Flows through the Manure Management Chain in China. AB - The largest livestock production and greatest fertilizer use in the world occurs in China. However, quantification of the nutrient flows through the manure management chain and their interactions with management-related measures is lacking. Herein, we present a detailed analysis of the nutrient flows and losses in the "feed intake-excretion-housing-storage-treatment-application" manure chain, while considering differences among livestock production systems. We estimated the environmental loss from the manure chain in 2010 to be up to 78% of the excreted nitrogen and over 50% of the excreted phosphorus and potassium. The greatest losses occurred from housing and storage stages through NH3 emissions (39% of total nitrogen losses) and direct discharge of manure into water bodies or landfill (30-73% of total nutrient losses). There are large differences among animal production systems, where the landless system has the lowest manure recycling. Scenario analyses for the year 2020 suggest that significant reductions of fertilizer use (27-100%) and nutrient losses (27-56%) can be achieved through a combination of prohibiting manure discharge, improving manure collection and storages infrastructures, and improving manure application to cropland. We recommend that current policies and subsidies targeted at the fertilizer industry should shift to reduce the costs of manure storage, transport, and application. PMID- 27993055 TI - Superior Performance of Fe1-xWxOdelta for the Selective Catalytic Reduction of NOx with NH3: Interaction between Fe and W. AB - Novel iron-tungsten catalysts were first developed for the selective catalytic reduction of NOx by NH3 in diesel exhaust, achieving an excellent performance with a wide operating temperature window above 90% NOx conversion from 225 or 250 to 450 degrees C (GHSVs of 30 000 or 50 000 h-1). It also exhibited a pronounced stability and relatively high NOx conversion in the presence of H2O, SO2 and CO2. The introduction of W resulted in the formation of alpha-Fe2O3 and FeWO4 species obtained by HRTEM directly. The synergic effect of two species contributed to the high SCR activity, because of the increased surface acidity and electronic property. The FeWO4 with octahedral [FeO6]/[WO6] structure acted as the Bronsted acid sites to form highly active NH4+ species. Combining DFT calculations with XPS and UV-vis results, it was found that the fine electron interaction between alpha-Fe2O3 and FeWO4 made the electron more easily transfer from W6+ sites to Fe3+ sites, which promoted the formation of NO2. Judging by the kinetics and SCR activity studies, the Fe0.75W0.25Odelta with an appropriate W amount showed the strongest interaction, and thereby the lowest activation energy of 39 kJ*mol-1 and optimal catalytic activity. These findings would be conducive to the reasonable design of NH3-SCR catalysts by adjusting the fabrication. PMID- 27993056 TI - Development of Redox-Active Flow Electrodes for High-Performance Capacitive Deionization. AB - An innovative flow electrode comprising redox-active quinones to enhance the effectiveness of water desalination using flow-electrode capacitive deionization (FCDI) is described in this study. The results show that, in addition to carbon particle contact, the presence of the aqueous hydroquinone (H2Q)/benzoquinone (Q) couple in a flowing suspension of carbon particles enhances charge transfer significantly as a result of reversible redox reactions of H2Q/Q. Ion migration through the micropores of the flow electrodes was facilitated in particular with the desalination rate significantly enhanced. The cycling behavior of the quinoid mediators in the anode flow electrode demonstrated a relatively high stability at the low pH induced, suggesting that the mediator would be suitable for long-term operation. PMID- 27993057 TI - Time Resolved Measurements of Speciated Tailpipe Emissions from Motor Vehicles: Trends with Emission Control Technology, Cold Start Effects, and Speciation. AB - Experiments were conducted at the California Air Resources Board Haagen-Smit Laboratory to understand changes in vehicle emissions in response to stricter emissions standards over the past 25 years. Measurements included a wide range of volatile organic compounds (VOCs) for a wide range of spark ignition gasoline vehicles meeting varying levels of emissions standards, including all certifications from Tier 0 up to Partial Zero Emission Vehicle. Standard gas chromatography (GC) and high performance liquid chromatography (HLPC) analyses were employed for drive-cycle phase emissions. A proton-transfer-reaction mass spectrometer measured time-resolved emissions for a wide range of VOCs. Cold start emissions occur almost entirely in the first 30-60 s for newer vehicles. Cold-start emissions have compositions that are not significantly different across all vehicles tested and are markedly different from neat fuel. Hot stabilized emissions have varying importance depending on species and may require a driving distance of 200 miles to equal the emissions from a single cold start. Average commute distances in the U.S. suggest the majority of in-use vehicles have emissions dominated by cold starts. The distribution of vehicle ages in the U.S. suggests that within several years only a few percent of vehicles will have significant driving emissions compared to cold-start emissions. PMID- 27993058 TI - Impacts of Morphology, Natural Organic Matter, Cations, and Ionic Strength on Sulfidation of Silver Nanowires. AB - Silver nanowires (AgNWs) are being widely utilized in an increasing number of consumer products, which could release silver to aquatic environments during the use or washing process, and have received growing concerns on their potential risks to bio-organisms and humans. The present study demonstrated that AgNWs mainly experienced direct oxysulfidation by reacting with dissolved sulfide species (initial S2- concentration at 1.6 mg/L) to produce silver sulfide nanostructures under environmentally relevant conditions. Granular Ag2S nanoparticles were formed on the surface of the nanowires. The sulfidation rate constant (kAg) of AgNWs was compared with those of silver nanoparticles (AgNPs) at different particle sizes. It was found that the kAg positively correlated with the specific surface areas of the silver nanomaterials. Natural organic matter (NOM) suppressed the sulfidation of AgNWs to different extents depending on its concentration. Divalent cations (Mg2+ and Ca2+ ions) substantially accelerated the sulfidation rates of AgNWs compared to monovalent cations (Na+ and K+ ions). At the same ionic strengths, Ca2+ ions displayed the highest promoting effect among the four metallic ions. PMID- 27993059 TI - Influence of Different Sewer Biofilms on Transformation Rates of Drugs. AB - To estimate drug consumption more reliably, wastewater-based epidemiology would benefit from a better understanding of drug residue stability during in-sewer transport. We conducted batch experiments with real, fresh wastewater and sewer biofilms. Experimental conditions mimic small to medium-sized gravity sewers with a relevant ratio of biofilm surface area to wastewater volume (33 m2 m-3). The influences of biological, chemical, and physical processes on the transformation of 30 illicit drug and pharmaceutical residues were quantified. Rates varied among locations and over time. Three substances were not stable-that is, >20% transformation, mainly due to biological processes-at least for one type of tested biofilm for a residence time <=2 h: amphetamine, 6-acetylcodeine, and 6 monoacetylmorphine. Cocaine, ecgonine methyl ester, norcocaine, cocaethylene, and mephedrone were mainly transformed by chemical hydrolysis and, hence, also unstable in sewers. In contrast, ketamine, norketamine, O-desmethyltramadol, diclofenac, carbamazepine, and methoxetamine were not substantially affected by in-sewer processes under all tested conditions and residence times up to 12 h. Our transformation rates include careful quantification of uncertainty and can be used to identify situations in which specific compounds are not stable. This will improve accuracy and uncertainty estimates of drug consumption when applied to the back-calculation. PMID- 27993060 TI - Origin of Sulfur in Diet Drives Spatial and Temporal Mercury Trends in Seabird Eggs From Pacific Canada 1968-2015. AB - Mercury (Hg) is a neurotoxin that can be particularly harmful to top predators because it biomagnifies through the food web. Due to variation in the food web structure, variation in Hg exposure in predators may represent variation in diet rather than Hg availability. We measured Hg in eggs from six seabird species (N = 537) over 47 years. In contrast to expectation, storm-petrels feeding partially on invertebrates had the highest Hg burden while herons feeding on large fish had the lowest Hg burden. A multiple regression showed that Hg correlated with delta34S (R2 = 0.86) rather than trophic level (delta15N of "trophic" amino acids). Sulfate-rich environments (high delta34S) have sulfate-reducing bacteria that produce methylmercury. Variation in Hg within and among seabirds near the top of the food web was associated with variation in delta34S at the base of the food web more so than trophic position within the food web. Hg levels in seabirds only changed over time for those species where delta34S also varied in tandem; after accounting for diet (delta34S), there was no variation in Hg levels. Variation in Hg in seabirds across space and time was associated with the origin of sulfur in the diet. PMID- 27993061 TI - Correction to Consumer Product Chemicals in Indoor Dust: A Quantitative Meta Analysis of U.S. Studies. PMID- 27993062 TI - Assessing Location and Scale of Urban Nonpotable Water Reuse Systems for Life Cycle Energy Consumption and Greenhouse Gas Emissions. AB - Nonpotable water reuse (NPR) is one option for conserving valuable freshwater resources. Decentralization can improve distribution system efficiency by locating treatment closer to the consumer; however, small treatment systems may have higher unit energy and greenhouse-gas (GHG) emissions. This research explored the trade-off between residential NPR systems using a life-cycle approach to analyze the energy use and GHG emissions. Decentralized and centralized NPR options are compared to identify where decentralized systems achieve environmental advantages over centralized reuse alternatives, and vice versa, over a range of scales and spatial and demographic conditions. For high elevation areas far from the centralized treatment plant, decentralized NPR could lower energy use by 29% and GHG emissions by 28%, but in low-elevation areas close to the centralized treatment plant, decentralized reuse could be higher by up to 85% (energy) and 49% (GHG emissions) for the scales assessed (20-2000 m3/day). Direct GHG emissions from the treatment processes were found to be highly uncertain and variable and were not included in the analysis. The framework presented can be used as a planning support tool to reveal the environmental impacts of integrating decentralized NPR with existing centralized wastewater infrastructure and can be adapted to evaluate different treatment technology scales for reuse. PMID- 27993063 TI - Formation of Nanosilver from Silver Sulfide Nanoparticles in Natural Waters by Photoinduced Fe(II, III) Redox Cycling. AB - Nanosilver (nAg) has been repeatedly demonstrated to end up as silver sulfide nanoparticles (Ag2SNPs), but little is known about the potential transformations of Ag2SNPs in natural environments that are very important for comprehensive assessments of nAg risks to human and environmental health. Here we show that Ag2SNPs can release tiny amounts of silver ion via cation exchange reactions between Ag(I) and Fe(III) in the dark, while in the light dramatic dissolution of Ag2SNP occurs, which is mainly attributed to the Ag2SNP oxidation by the hydroxyl radical formed during the reduction of Fe(III) to Fe(II) in water under sunlit conditions. However, silver ions are subsequently reduced to nAg in the light due to the strong reducing power of Fe(II). Thus, the formation of nAg from Ag2SNPs in the presence of Fe(III) under light conditions proceeds through a two-step reaction mechanism, the photoinduced and Fe(III)-dependent dissolution of Ag2SNPs, followed by the reduction of silver ions to nAg by Fe(II). The formation of nAg from Ag2SNPs is also validated in environmental waters under light conditions. It is thus concluded that photoinduced Fe(III)/Fe(II) redox cycling can drive the formation of nAg from Ag2SNPs in natural waters. These findings suggest that the previous consensus about the stability of Ag2SNPs in aquatic environments should be reconsidered. PMID- 27993065 TI - Direct and Indirect Photochemical Reactions in Viral RNA Measured with RT-qPCR and Mass Spectrometry. AB - RNA carries the genetic instructions for many viruses to replicate in their host cells. The photochemical reactions that take place in RNA and affect viral infectivity in natural and engineered environments, however, remain poorly understood. We exposed RNA oligomer segments from the genome of bacteriophage MS2 to UV254, simulated sunlight, and singlet oxygen (1O2) and analyzed the oligomer reaction kinetics with reverse transcription quantitative PCR (RT-qPCR) and quantitative matrix-assisted laser desorption-ionization time-of-flight (MALDI TOF) mass spectrometry (MS). Following UV254 exposure, quantitative MALDI-TOF-MS detected significantly more RNA modifications than did RT-qPCR, suggesting that certain chemical modifications in the RNA were not detected by the reverse transcriptase enzyme. In contrast, MALDI-TOF-MS tracked as much 1O2-induced RNA damage as RT-qPCR. After 5 h of simulated sunlight exposure (5100 J/m2 UVB and 1.2 * 105 J/m2 UVA), neither MALDI-TOF-MS nor RT-qPCR detected significant decreases in the oligomer concentrations. High-resolution electrospray ionization (ESI)-Orbitrap MS analyses identified pyrimidine photohydrates as the major UV254 products, which likely contributed to the discrepancy between the MS- and RT-qPCR based results. Reactions between RNA oligomers and 1O2 resulted in an unidentified major product with a mass change of +6 Da. These results shed light on the photochemical reactions that take place in RNA and suggest that the analytical techniques used to detect RNA reactivity could bias the observed reaction kinetics. PMID- 27993064 TI - Effects of Cellular Sorption on Mercury Bioavailability and Methylmercury Production by Desulfovibrio desulfuricans ND132. AB - Microbial conversion of inorganic mercury (IHg) to methylmercury (MeHg) is a significant environmental concern because of the bioaccumulation and biomagnification of toxic MeHg in the food web. Laboratory incubation studies have shown that, despite the presence of large quantities of IHg in cell cultures, MeHg biosynthesis often reaches a plateau or a maximum within hours or a day by an as yet unexplained mechanism. Here we report that mercuric Hg(II) can be taken up rapidly by cells of Desulfovibrio desulfuricans ND132, but a large fraction of the Hg(II) is unavailable for methylation because of strong cellular sorption. Thiols, such as cysteine, glutathione, and penicillamine, added either simultaneously with Hg(II) or after cells have been exposed to Hg(II), effectively desorb or mobilize the bound Hg(II), leading to a substantial increase in MeHg production. The amount of thiol-desorbed Hg(II) is strongly correlated to the amount of MeHg produced (r = 0.98). However, cells do not preferentially take up Hg(II)-thiol complexes, but Hg(II)-ligand exchange between these complexes and the cell-associated proteins likely constrains Hg(II) uptake and methylation. We suggest that, aside from aqueous chemical speciation of Hg(II), binding and exchange of Hg(II) between cells and complexing ligands such as thiols and naturally dissolved organics in solution is an important controlling mechanism of Hg(II) bioavailability, which should be considered when predicting MeHg production in the environment. PMID- 27993066 TI - Phosphate-Induced Immobilization of Uranium in Hanford Sediments. AB - Phosphate can be added to subsurface environments to immobilize U(VI) contamination. The efficacy of immobilization depends on the site-specific groundwater chemistry and aquifer sediment properties. Batch and column experiments were performed with sediments from the Hanford 300 Area in Washington State and artificial groundwater prepared to emulate the conditions at the site. Batch experiments revealed enhanced U(VI) sorption with increasing phosphate addition. X-ray absorption spectroscopy measurements of samples from the batch experiments found that U(VI) was predominantly adsorbed at conditions relevant to the column experiments and most field sites (low U(VI) loadings, <25 MUM), and U(VI) phosphate precipitation occurred only at high initial U(VI) (>25 MUM) and phosphate loadings. While batch experiments showed the transition of U(VI) uptake from adsorption to precipitation, the column study was more directly relevant to the subsurface environment because of the high solid:water ratio in the column and the advective flow of water. In column experiments, nearly six times more U(VI) was retained in sediments when phosphate-containing groundwater was introduced to U(VI)-loaded sediments than when the groundwater did not contain phosphate. This enhanced retention persisted for at least one month after cessation of phosphate addition to the influent fluid. Sequential extractions and laser-induced fluorescence spectroscopy of sediments from the columns suggested that the retained U(VI) was primarily in adsorbed forms. These results indicate that in situ remediation of groundwater by phosphate addition provides lasting benefit beyond the treatment period via enhanced U(VI) adsorption to sediments. PMID- 27993067 TI - Temporal Trend and Spatial Distribution of Speciated Atmospheric Mercury Emissions in China During 1978-2014. AB - Mercury pollution control has become a global goal. The accurate estimate of long term mercury emissions in China is critical to evaluate the global mercury budget and the emission reduction potentials. In this study, we used a technology-based approach to compile a consistent series of China's atmospheric mercury emissions at provincial level from 1978 to 2014. China totally emitted 13 294 t of anthropogenic mercury to air during 1978-2014, in which gaseous elemental mercury, gaseous oxidized mercury, and particulate-bound mercury accounted for 58.2%, 37.1%, and 4.7%, respectively. The mercury removed during this period were 2085 t in coal-fired power plants (counting 49% of mercury input), 7259 t in Zn smelting (79%), 771 t in coal-fired industrial boilers (25%), and 658 t in cement production plants (27%), respectively. Annual mercury emissions increased from 147 t in 1978 to 530 t in 2014. Both sectoral and spatial emissions of atmospheric mercury experienced significant changes. The largest mercury emission source evolved from coal-fired industrial boilers before 1998, to zinc smelting during 1999-2004, coal-fired power plants during 2005-2008, finally to cement production after 2009. Coal-fired industrial boilers and cement production have become critical hotpots for China's mercury pollution control. PMID- 27993068 TI - Uptake, Translocation, and Metabolism of 8:2 Fluorotelomer Alcohol in Soybean (Glycine max L. Merrill). AB - Biotransformation of fluorotelomer alcohols (FTOHs) is widely considered as an additional source of perfluorocarboxylic acids (PFCAs) in environmental biota. Compared with the extensive studies conducted in animals and microbes, biotransformation pathways of FTOHs in plants are still unclear. In this study, a hydroponic experiment was conducted to investigate the uptake, translocation and metabolism of 8:2 FTOH in soybean (Glycine max L. Merrill) over 144 h. 8:2 FTOH and its metabolites were found in all parts of soybean plants. At the end of the exposure, 7:3 FTCA [F(CF2)7CH2CH2COOH] was the primary metabolite in roots and stems, while PFOA [F(CF2)7COOH] was predominant in leaves. PFOA and 7:3 FTCA in the soybean-solution system accounted for 6.01 and 5.57 mol % of the initially applied 8:2 FTOH, respectively. Low levels of PFHpA [F(CF2)6COOH] and PFHxA [F(CF2)5COOH] in solutions and soybean roots resulted from microbial metabolism and plant root uptake. Glutathione-conjugated metabolites in soybean tissues were also identified. The activities of alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase in soybean roots increased during the exposure, suggesting their roles in 8:2 FTOH metabolism in soybean. This study provides important information for a better understanding of the uptake and metabolism of FTOHs and fluorotelomer-based compounds in plants. PMID- 27993069 TI - New Evidence for High Sorption Capacity of Hydrochar for Hydrophobic Organic Pollutants. AB - This study investigated the sorption potential of hydrochars, produced from hydrothermally carbonizing livestock wastes, toward organic pollutants (OPs) with a wide range of hydrophobicity, and compared their sorption capacity with that of pyrochars obtained from conventional dry pyrolysis from the same feedstock. Results of SEM, Raman, and 13C NMR demonstrated that organic carbon (OC) of hydrochars mainly consisted of amorphous alkyl and aryl C. Hydrochars exhibited consistently higher log Koc of both nonpolar and polar OPs than pyrochars. This, combined with the significantly less energy required for the hydrothermal process, suggests that hydrothermal conversion of surplus livestock waste into value-added sorbents could be an alternative manure management strategy. Moreover, the hydrochars log Koc values were practically unchanged after the removal of amorphous aromatics, implying that amorphous aromatic C played a comparable role in the high sorption capacity of hydrochars compared to amorphous alkyl C. It was thus concluded that the dominant amorphous C associated with both alkyl and aryl moieties within hydrochars explained their high sorption capacity for OPs. This research not only indicates that animal-manure-derived hydrochars are promising sorbents for environmental applications but casts new light on mechanisms underlying the high sorption capacity of hydrochars for both nonpolar and polar OPs. PMID- 27993071 TI - Spatial and Temporal Trends of Particle Phase Organophosphate Ester Concentrations in the Atmosphere of the Great Lakes. AB - The concentrations of six organophosphate esters (OPEs) in atmospheric particle phase samples collected once every 12 days at five sites in the North American Great Lakes basin over the period of March 2012 to December 2014, inclusive, are reported. These OPEs include tris(2-chloroethyl) phosphate (TCEP), tris(2 chloroisopropyl) phosphate (TCIPP), and tris(1,3-dichloroisopropyl) phosphate (TDCIPP), tri-n-butyl phosphate (TNBP), triphenyl phosphate (TPHP), and 2 ethylhexyl diphenyl phosphate (EHDP). Median total OPE concentrations (?OPE) ranged from 93 pg/m3 at Sleeping Bear Dunes to 1046 pg/m3 at Chicago. The ?OPE levels were significantly (P < 0.05) higher at Chicago and Cleveland, our urban sites, than at our rural and remote sites. The composition profiles were dominated by chlorinated OPEs at the urban and rural sites and by nonchlorinated OPEs at the remote sites. The concentrations of all OPEs were significantly (P < 0.001) correlated to one another, suggesting that these compounds share similar sources. Most atmospheric ?OPE concentrations were significantly (P < 0.05) decreasing over time, with halving times of about 3.5 years at the urban sites and about 1.5 years at the rural and remote sites. Interestingly, TCEP and EHDP concentrations were increasing over time at the rural and remote sites with doubling times of 2.2 and 3.7 years, respectively. PMID- 27993070 TI - Urinary Concentrations of the Antibacterial Agent Triclocarban in United States Residents: 2013-2014 National Health and Nutrition Examination Survey. AB - Triclocarban is widely used as an antibacterial agent in personal care products, and the potential for human exposure exists. We present here the first nationally representative assessment of exposure to triclocarban among Americans >=6 years of age who participated in the 2013-2014 National Health and Nutrition Examination Survey. We detected triclocarban at concentrations above 0.1 MUg/L in 36.9% of 2686 urine samples examined. Triclocarban was detected more frequently in adolescents and adults than in children, and in non-Hispanic black compared to other ethnic groups. In univariate analysis, log-creatinine, sex, age, race, and body surface area (BSA) were significantly associated with the likelihood of having triclocarban concentrations above the 95th percentile. In multiple regression models, persons with BSA at or above the median (>=1.86 m2) were 2.43 times more likely than others, and non-Hispanic black and non-Hispanic white were 3.71 times and 2.23 times more likely than "all Hispanic," respectively, to have urinary concentrations above the 95th percentile. We found no correlations between urinary concentrations of triclocarban and triclosan, another commonly used antibacterial agent. Observed differences among demographic groups examined may reflect differences in physiological factors (i.e., BSA) as well as use of personal care products containing triclocarban. PMID- 27993072 TI - Chlorination Revisited: Does Cl- Serve as a Catalyst in the Chlorination of Phenols? AB - The aqueous chlorination of (chloro)phenols is one of the best-studied reactions in the environmental literature. Previous researchers have attributed these reactions to two chlorine species: HOCl (at circum-neutral and high pH) and H2OCl+ (at low pH). In this study, we seek to examine the roles that two largely overlooked chlorine species, Cl2 and Cl2O, may play in the chlorination of (chloro)phenols. Solution pH, chloride concentration, and chlorine dose were systematically varied in order to assess the importance of different chlorine species as chlorinating agents. Our findings indicate that chlorination rates at pH < 6 increase substantially when chloride is present, attributed to the formation of Cl2. At pH 6.0 and a chlorine dose representative of drinking water treatment, Cl2O is predicted to have at best a minor impact on chlorination reactions, whereas Cl2 may contribute more than 80% to the overall chlorination rate depending on the (chloro)phenol identity and chloride concentration. While it is not possible to preclude H2OCl+ as a chlorinating agent, we were able to model our low-pH data by considering Cl2 only. Even traces of chloride can generate sufficient Cl2 to influence chlorination kinetics, highlighting the role of chloride as a catalyst in chlorination reactions. PMID- 27993073 TI - Occurrence of Triclocarban and Triclosan in an Agro-ecosystem Following Application of Biosolids. AB - Triclocarban (TCC) and triclosan (TCS), two of the most commonly used antimicrobial compounds, can be introduced into ecosystems by applying wastewater treatment plant biosolids to agricultural fields. Concentrations of TCC and TCS were measured in different trophic levels within a terrestrial food web encompassing land-applied biosolids, soil, earthworms (Lumbricus), deer mice (Peromyscus maniculatus), and eggs of European starlings (Sturnus vulgaris) and American kestrels (Falco sparverius) at an experimental site amended with biosolids for the previous 7 years. The samples from this site were compared to the same types of samples from a reference (biosolids-free) agricultural site. Inter-site comparisons showed that concentrations of both antimicrobials were higher on the experimental site in the soil, earthworms, mice (livers), and European starling eggs, but not American kestrel eggs, compared to the control site. Inter-species comparisons on the experimental site indicated significantly higher TCC concentrations in mice (TCC: 12.6-33.3 ng/g) and in starling eggs (TCC: 15.4-31.4 ng/g) than in kestrel eggs (TCC: 3.6 ng/g). Nesting success of kestrels only was significantly lower on the experimental site compared to the reference site due to nest abandonment. This study demonstrates that biosolids derived TCC and TCS are present throughout the terrestrial food web, including secondary (e.g., starlings) and tertiary (i.e., kestrels) consumers, after repeated, long-term biosolids application. PMID- 27993074 TI - Precision of Atmospheric Persistent Organic Pollutant Concentration Measurements. AB - Environmental measurement programs are often undertaken with the assumption that measurements at a given location will be comparable to others that would be observed at the same time in the immediate vicinity, but this assumption has seldom been tested. This paper does so. We discuss here the precision of atmospheric concentration measurements of persistent organic pollutants (POPs) near the North American Great Lakes-measurements that we have been conducting since 1994. We report the relative percent differences between the measured values for 100-200 duplicate samples, and through our use of surrogate (recovery) standards, we have separated the analytical error from the sampling error for the target compounds. The error contributions we calculated were on the order of 5% for the analytical error and 20% for the sampling error, suggesting that the latter is the greatest hindrance to increased precision. In a comparison of relative percent differences for measurements among different atmospheric phases, we observed the highest errors for precipitation samples, with an average median of 35 +/- 3, which is more than for vapor-phase samples (27 +/- 3) or particle phase samples (27 +/- 2). We suggest that sampling errors are principally the result of inaccuracies in measuring the sample volume and possibly the result of spatial heterogeneity of the atmosphere. PMID- 27993075 TI - Inverse Problem Optimization Method to Design Passive Samplers for Volatile Organic Compounds: Principle and Application. AB - Passive sampling is an alternative to active sampling for measuring concentrations of gas-phase volatile organic compounds (VOCs). However, the uncertainty or relative error of the measurements have not been minimized due to the limitations of existing design methods. In this paper, we have developed a novel method, the inverse problem optimization method, to address the problems associated with designing accurate passive samplers. The principle is to determine the most appropriate physical properties of the materials, and the optimal geometry of a passive sampler, by minimizing the relative sampling error based on the mass transfer model of VOCs for a passive sampler. As an example application, we used our proposed method to optimize radial passive samplers for the sampling of benzene and formaldehyde in a normal indoor environment. A new passive sampler, which we have called the Tsinghua Passive Diffusive Sampler (THPDS), for indoor benzene measurement was developed according to the optimized results. Silica zeolite was selected as the sorbent for the THPDS. The measured overall uncertainty of THPDS (22% for benzene) is lower than that of most commercially available passive samplers but is quite a bit larger than the modeled uncertainty (4.8% for benzene, the optimized result), suggesting that further research is required. PMID- 27993076 TI - Bayesian Networks Improve Causal Environmental Assessments for Evidence-Based Policy. AB - Rule-based weight of evidence approaches to ecological risk assessment may not account for uncertainties and generally lack probabilistic integration of lines of evidence. Bayesian networks allow causal inferences to be made from evidence by including causal knowledge about the problem, using this knowledge with probabilistic calculus to combine multiple lines of evidence, and minimizing biases in predicting or diagnosing causal relationships. Too often, sources of uncertainty in conventional weight of evidence approaches are ignored that can be accounted for with Bayesian networks. Specifying and propagating uncertainties improve the ability of models to incorporate strength of the evidence in the risk management phase of an assessment. Probabilistic inference from a Bayesian network allows evaluation of changes in uncertainty for variables from the evidence. The network structure and probabilistic framework of a Bayesian approach provide advantages over qualitative approaches in weight of evidence for capturing the impacts of multiple sources of quantifiable uncertainty on predictions of ecological risk. Bayesian networks can facilitate the development of evidence-based policy under conditions of uncertainty by incorporating analytical inaccuracies or the implications of imperfect information, structuring and communicating causal issues through qualitative directed graph formulations, and quantitatively comparing the causal power of multiple stressors on valued ecological resources. These aspects are demonstrated through hypothetical problem scenarios that explore some major benefits of using Bayesian networks for reasoning and making inferences in evidence-based policy. PMID- 27993077 TI - Recent Decline of Atmospheric Mercury Recorded by Androsace tapete on the Tibetan Plateau. AB - We combined the mercury passive sampling method and plant biomonitoring together to understand the long-term changes of atmospheric mercury concentrations on the Tibetan Plateau. Through the analysis of leaves of Androsace tapete that represent growing periods spanning the past decade, we explored the historical records of atmospheric mercury from 2006 to 2015. Mercury concentration was stable in the leaves of Androsace tapete during the period between 2006 and 2009, while a significant decrease occurred after the year of 2010. The decreasing trend is consistent with the monitoring data of the ground-based stations in other regions globally. Despite the potential uncertainties using a passive sampling method and biomonitoring technique, we suggest that Androsace tapete is a potential biomarker that could provide reliable and effective historical records of atmospheric mercury concentrations and offer new perspectives in monitoring mercury and perhaps other atmospheric pollutants in regions where long term active monitoring was missing. PMID- 27993078 TI - Modeling the Acid-Base Properties of Montmorillonite Edge Surfaces. AB - The surface reactivity of clay minerals remains challenging to characterize because of a duality of adsorption surfaces and mechanisms that does not exist in the case of simple oxide surfaces: edge surfaces of clay minerals have a variable proton surface charge arising from hydroxyl functional groups, whereas basal surfaces have a permanent negative charge arising from isomorphic substitutions. Hence, the relationship between surface charge and surface potential on edge surfaces cannot be described using the Gouy-Chapman relation, because of a spillover of negative electrostatic potential from the basal surface onto the edge surface. While surface complexation models can be modified to account for these features, a predictive fit of experimental data was not possible until recently, because of uncertainty regarding the densities and intrinsic pKa values of edge functional groups. Here, we reexamine this problem in light of new knowledge on intrinsic pKa values obtained over the past decade using ab initio molecular dynamics simulations, and we propose a new formalism to describe edge functional groups. Our simulation results yield reasonable predictions of the best available experimental acid-base titration data. PMID- 27993079 TI - A New Film-Based Passive Sampler for Moderately Hydrophobic Organic Compounds. AB - Passive samplers for moderately hydrophobic organic compounds (MHOCs) (i.e., log Kow ranging from 2 to 5) are under-developed compared to those that target polar or strongly hydrophobic compounds. The goal of this study was to identify a suitable polymer and develop a robust and sensitive film-based passive sampler for MHOCs in aquatic systems. Poly(methyl methacrylate) (PMMA) exhibited the highest affinity for fipronil and its three metabolites (i.e., fipronils) (log Kow 2.4-4.8) as model MHOCs compared with polyethylene and nylon films. In addition, a 30-60 min treatment of PMMA in ethyl ether was found to increase its sorption capacity by a factor of 10. Fipronils and 108 additional compounds (log Kow 2.4-8.5) reached equilibrium on solvent-treated PMMA within 120 h under mixing conditions and their uptake closely followed first-order kinetics. PMMA water partition coefficients and Kow revealed an inverse parabolic relationship, with vertex at log Kow of 4.21 +/- 0.19, suggesting that PMMA was ideal for MHOCs. The PMMA sampler was tested in an urban surface stream, and in spiked sediment. The results demonstrated that PMMA film, after a simple solvent swelling treatment, may be used as an effective passive sampler for determining Cfree of MHOCs in aquatic environments. PMID- 27993080 TI - CDOM Sources and Photobleaching Control Quantum Yields for Oceanic DMS Photolysis. AB - Photolysis is a major removal pathway for the biogenic gas dimethylsulfide (DMS) in the surface ocean. Here we tested the hypothesis that apparent quantum yields (AQY) for DMS photolysis varied according to the quantity and quality of its photosensitizers, chiefly chromophoric dissolved organic matter (CDOM) and nitrate. AQY compiled from the literature and unpublished studies ranged across 3 orders of magnitude at the 330 nm reference wavelength. The smallest AQY(330) were observed in coastal waters receiving major riverine inputs of terrestrial CDOM (0.06-0.5 m3 (mol quanta)-1). In open-ocean waters, AQY(330) generally ranged between 1 and 10 m3 (mol quanta)-1. The largest AQY(330), up to 34 m3 (mol quanta)-1), were seen in the Southern Ocean potentially associated with upwelling. Despite the large AQY variability, daily photolysis rate constants at the sea surface spanned a smaller range (0.04-3.7 d-1), mainly because of the inverse relationship between CDOM absorption and AQY. Comparison of AQY(330) with CDOM spectral signatures suggests there is an interplay between CDOM origin (terrestrial versus marine) and photobleaching that controls variations in AQYs, with a secondary role for nitrate. Our results can be used for regional or large scale assessment of DMS photolysis rates in future studies. PMID- 27993081 TI - Contribution of Persistent Organic Pollutant Exposure to the Adipose Tissue Oxidative Microenvironment in an Adult Cohort: A Multipollutant Approach. AB - Despite growing in vitro and in vivo evidence of the putative role of persistent organic pollutants (POPs) in the induction of oxidative damage in cell structures, this issue has been poorly addressed from an epidemiologic perspective. The aim of this study was to explore associations between adipose tissue POP concentrations and the in situ oxidative microenvironment. A cross sectional study was conducted in a subsample (n = 271) of a previously established cohort, quantifying levels of eight POPs and four groups of oxidative stress biomarkers in adipose tissue. Associations were explored using multivariate linear regression analyses adjusted for potential confounders. We assessed the combined effect of POPs on oxidative stress/glutathione system biomarkers using weighted quantile sum regression (WQS). Increased concentrations of p,p'-DDE, HCB, beta-HCH, dicofol, and PCBs (congeners -138, -153, and -180) were predominantly associated with higher lipid peroxidation (TBARS) [exp(beta) = 1.09-1.78, p < 0.01-0.04)] and SOD activity [exp(beta) = 1.13-1.48, p < 0.01 0.05)] levels. However, only a few associations were observed with glutathione system biomarkers, e.g., PCB-180 with total glutathione [exp(beta) = 1.98, p = 0.03]. The WQS index was found to be positively associated with SOD activity, and PCB-138, PCB-180, and beta-HCH were the main contributors to the index. Likewise, the WQS index was positively associated with TBARS levels, with the three PCBs acting as the main contributors. This is the first epidemiological evidence of the putative disruption by POPs of the adipose tissue oxidative microenvironment. Our results indicate that POP exposure may enhance alternative pathways to the glutathione detoxification route, which might result in tissue damage. Further research is warranted to fully elucidate the potential health implications. PMID- 27993082 TI - Stereoselective Degradation of Estradiol and Trenbolone Isomers in Alluvial Sediment. AB - Stereoisomers of estradiol (E2) or trenbolone (TB) can occur together in the environment receiving human or livestock wastes. However, the effect of their co occurrence on persistence has not been well elucidated. A sandy and a silt loam sediment were used to establish microcosms with alpha- and beta-isomers of E2 or TB spiked individually and together. Sediments were sampled periodically and analyzed for E2 and TB isomers and their transformation products using derivatization gas chromatography-mass spectrometry. Results showed that stereoselective degradation was significant for E2 in both sediments and TB in the sandy sediment with beta-isomers decaying more rapidly than alpha-isomers. In the sandy sediment containing limited natural organic carbon and nutrients, co occurrence of both isomers of either E2 or TB decreased the dissipation rates. In the silt loam sediment with abundant organic matter and nutrients, the decay rates of both isomers were not changed in the presence of the other isomer. Estrone (E1) and trendione (TD) were detected as primary metabolites of E2 and TB isomers, respectively. The formation and decay profiles of E1 were similar in both sediments with 92-100% of E2 transformed to E1. The TD profiles were different across sediments with ~100% of TB transformed to TD except in the sandy sediment where 51-60% of 17alpha-TB was converted to TD. These results indicate that the transformation processes of steroid hormone are stereoselective in sediment and co-occurrence of stereoisomers can prolong steroid persistence and thus pose greater environmental risk. PMID- 27993083 TI - Development and Application of a Life Cycle-Based Model to Evaluate Greenhouse Gas Emissions of Oil Sands Upgrading Technologies. AB - A life cycle-based model, OSTUM (Oil Sands Technologies for Upgrading Model), which evaluates the energy intensity and greenhouse gas (GHG) emissions of current oil sands upgrading technologies, is developed. Upgrading converts oil sands bitumen into high quality synthetic crude oil (SCO), a refinery feedstock. OSTUM's novel attributes include the following: the breadth of technologies and upgrading operations options that can be analyzed, energy intensity and GHG emissions being estimated at the process unit level, it not being dependent on a proprietary process simulator, and use of publicly available data. OSTUM is applied to a hypothetical, but realistic, upgrading operation based on delayed coking, the most common upgrading technology, resulting in emissions of 328 kg CO2e/m3 SCO. The primary contributor to upgrading emissions (45%) is the use of natural gas for hydrogen production through steam methane reforming, followed by the use of natural gas as fuel in the rest of the process units' heaters (39%). OSTUM's results are in agreement with those of a process simulation model developed by CanmetENERGY, other literature, and confidential data of a commercial upgrading operation. For the application of the model, emissions are found to be most sensitive to the amount of natural gas utilized as feedstock by the steam methane reformer. OSTUM is capable of evaluating the impact of different technologies, feedstock qualities, operating conditions, and fuel mixes on upgrading emissions, and its life cycle perspective allows easy incorporation of results into well-to-wheel analyses. PMID- 27993084 TI - Novel T-cell-based vaccines via arming polyclonal CD4+ T cells with antigen specific exosomes. PMID- 27993085 TI - Vaccine strategies for the treatment of lymphoma: preclinical progress and clinical trial update. AB - The clonal B-cell immunoglobulin idiotype found on the surface of lymphomas was the first targeted tumor-specific antigen, and combinations of idiotype with classical and novel adjuvants were shown to stimulate robust humoral and cellular responses, though clinical efficacy was more variable. Cellular and in situ vaccination to help target a wider array of tumor-specific antigens have also been able to stimulate tumor-specific cellular responses, though their clinical success has also been limited. Our growing understanding of the role of regulatory cells and the immunosuppressive tumor microenvironment, along with a wide variety of immunomodulatory agents developed as of late, offer promising adjuvants to potentiate the immune responses elicited by these vaccine protocols and to achieve durable remissions. PMID- 27993086 TI - Cancer vaccine clinical trials. PMID- 27993087 TI - Current status and future prospects of peptide-based cancer vaccines. AB - Cancer immunotherapy has attracted attention worldwide owing to the recent development of immune checkpoint inhibitors. However, these therapies have shown limited efficacy, and further advancements are needed before these modalities can progress to widespread use. Immune checkpoint inhibitors are a type of nonspecific cancer immunotherapy, and antitumor effects are only observed when cancer-specific T cells are found within the nonspecifically activated T-cell group. In order to facilitate the development of potent immunotherapies, selective enhancement of cancer-specific T cells is essential. In this report, we discuss current and future perspectives, including the latest clinical trials of cancer-specific immunotherapies, particularly cancer peptide vaccines. PMID- 27993088 TI - Interview with Dr Ghassan K Abou-Alfa. AB - Ghassan K Abou-Alfa joined the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College in New York back in 2001. Dr Abou-Alfa specializes in the treatment of gastrointestinal malignancies. Dr Abou-Alfa received his medical degree from the American University of Beirut, Lebanon, and completed his post-doctoral training at Yale University School of Medicine. His research is dedicated to finding novel therapies and improving the effectiveness of the current therapies for hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer, while continuing to understand the basic mechanisms of the diseases and its therapy. Dr Abou-Alfa has invested several years in helping develop multi-tyrosine kinases and more immune-modulator therapies. Dr Abou-Alfa has many publications in the field. He led on many occasions international teams of investigators. Dr Abou Alfa serves as the chair of the National Cancer Institute (NCI) Task Force for Hepatobiliary Cancers and the chair of the AIDS Malignancy Consortium (AMC) Non AIDS Defining Malignancies (NADC) Liver/GI Task Force. Dr Abou-Alfa also co chairs the hepatobiliary cancers subgroup of the Alliance cooperative group, and is a cadre member of both the gastrointestinal cancers and pharmacogenomics and population pharmacology committees. Dr Abou-Alfa who has lectured worldwide on the subject on gastrointestinal malignancies, is also a strong advocate for raising awareness and support for improving the outcome of patients with this disease, and enhancing oncologic education worldwide. PMID- 27993089 TI - Immunotherapy of colorectal cancer: new perspectives after a long path. AB - Although significant therapeutic improvement has been achieved in the last 10 years, the survival of metastatic colorectal cancer patients remains in a range of 28 to 30 months. Presently, systemic treatment includes combination chemotherapy with oxaliplatin and/or irinotecan together with a backbone of 5 fluorouracil/levofolinate, alone or in combination with monoclonal antibodies to VEGFA (bevacizumab) or EGF receptor (cetuximab and panitumumab). The recent rise of immune checkpoint inhibitors in the therapeutic scenario has renewed scientific interest in the investigation of immunotherapy in metastatic colorectal cancer patients. According to our experience and view, here, we review the immunological strategies investigated for the treatment of this disease, including the use of tumor target-specific cancer vaccines, chemo-immunotherapy and immune checkpoint inhibitors. PMID- 27993090 TI - Wilms' tumor 1 (WT1)-targeted cancer vaccines to extend survival for patients with pancreatic cancer. AB - Despite novel chemotherapy treatments, pancreatic ductal adenocarcinoma (PDA) remains a lethal disease. New targeted cancer vaccines may represent a viable option for patients with PDA. The Wilms' tumor 1 (WT1) antigen is one of the most widely expressed tumor-associated antigens in various types of tumors, including PDA. Recent reports have indicated that WT1-targeted cancer vaccines for patients with PDA mediated a potent antitumor effect when combined with chemotherapy in preclinical and clinical studies. This review summarizes the early-phase clinical trials of WT1-targeted cancer vaccines (peptide vaccines and dendritic cell-based vaccines) for PDA. Moreover, we will discuss future strategies for PDA treatments using WT1-specific cancer vaccines combined with immune checkpoint therapies to maximize the clinical effectiveness of PDA treatments. PMID- 27993091 TI - Interview with Professor Angus Dalgleish. AB - Angus Dalgleish is the Foundation Professor of Oncology at St. George's University of London and Principal of the Institute for Cancer Vaccines and Immunotherapy. PMID- 27993093 TI - Effect of androgen deprivation therapy on intraprostatic tumour volume identified on 18F choline PET/CT for prostate dose painting radiotherapy. AB - OBJECTIVE: Prostate dose painting radiotherapy requires the accurate identification of dominant intraprostatic lesions (DILs) to be used as boost volumes; these can be identified on multiparametric MRI (mpMRI) or choline positron emission tomography (PET)/CT. Planning scans are usually performed after 2-3 months of androgen deprivation therapy (ADT). We examine the effect of ADT on choline tracer uptake and boost volumes identified on choline PET/CT. METHODS: Fluoroethylcholine (18F choline) PET/CT was performed for dose painting radiotherapy planning in patients with intermediate- to high-risk prostate cancer. Initially, they were performed at planning. Owing to low visual tracer uptake, PET/CT for subsequent patients was performed at staging. We compared these two approaches on intraprostatic lesions obtained on PET using both visual and automatic threshold methods [prostate maximum standardized uptake value (SUVmax) 60%] when compared with mpMRI. RESULTS: PET/CT was performed during ADT in 11 patients (median duration of 85 days) and before ADT in 29 patients. ADT significantly reduced overall prostate volume by 17%. During ADT, prostate SUVmax was lower although it did not reach statistical significance (4.2 vs 6.6, p = 0.06); three patients had no visually identifiable PET DIL; and visually defined PET DILs were significantly smaller than corresponding mpMRI DILs (p = 0.03). However, all patients scanned before ADT had at least one visually identifiable PET DIL, with no significant size difference between MRI and visually defined PET DILs. In both groups, threshold PET produced larger DILs than visual PET. Both PET methods have moderate sensitivity (0.50-0.68) and high specificity (0.85 0.98) for identifying MRI-defined disease. CONCLUSION: For visual contouring of boost volumes in prostate dose painting radiotherapy, 18F choline PET/CT should be performed before ADT. For threshold contouring of boost volumes using our PET/CT scanning protocol, threshold levels of above 60% prostate SUVmax may be more suitable. Additional use of PET with MRI for radiotherapy planning can significantly change the overall boost volumes compared with using MRI alone. Advances in knowledge: For prostate dose painting radiotherapy, the additional use of 18F choline PET with MRI can significantly change the overall boost volumes, and PET should be performed before hormone therapy, especially if boost volumes are visually identified. PMID- 27993094 TI - Talonavicular ligament: prevalence of injury in ankle sprains, histological analysis and hypothesis of its biomechanical function. AB - OBJECTIVE: To assess the prevalence of injury of the talonavicular ligament (TNL) in ankle sprains, its anatomy and the stability of the talonavicular joint (TNJ) before and after dividing the TNL in a cadaver. METHODS: During a prospective study of 100 patients to assess the outcome of ankle injuries, we noted high incidence of TNL injuries; we will discuss here the TNL findings. Each patient had undergone ultrasound and cone beam CT examination of the ankle. Six TNLs were dissected off fresh-frozen cadaveric feet for histological analysis. In further six cadaveric feet, the stability of the TNJ was assessed by mechanical stress before and after division of the TNL; movement at the joint was assessed by measuring the distance between the talus and navicular bone [talonavicular distance (TD)] using ultrasound. The TD was measured on ten randomly selected ultrasound images by three independent observers and repeated twice by a single observer to determine the inter- and intraobserver reliability. RESULTS: 21% of the patients had an injury to the TNL. Histological examination demonstrated a dense connective tissue composed of bundles of collagen in parallel arrangement along the ligament length. The interobserver and intraobserver reliability of the TD showed almost perfect agreement. Displacement at the TNJ after stress with the TNL intact measured 0.18 +/- 0.08 cm and 0.29 +/- 0.07 cm (p < 0.005) when divided. CONCLUSION: The TNL is surprisingly commonly injured in ankle sprains. Its anatomy and histology suggest a role in tensile force transmission during the windlass mechanism in gait. Advances in knowledge: Injury to the TNL is common and has not been described. Its anatomy suggests resistance to tensile forces and its injury allows excessive movement at the TNJ. PMID- 27993095 TI - Personnel dose reduction in 90Y microspheres liver-directed radioembolization: from interventional radiology suite to patient ward. AB - OBJECTIVE: To describe a method to reduce the external radiation exposure emitted from the patient after liver-directed radioembolization using 90Y glass microspheres, to quantitatively estimate the occupational dose of medical personnel providing patient care to the patient radioembolized with the use of the method and to discuss radiation exposure to patients who are adjacent if the patient radioembolized needs hospitalization. METHODS: A lead-lined blanket of lead equivalence of 0.5 mm was used to cover the patient abdomen immediately after the 90Y radioembolization procedure, in order to reduce the radiation emitted from the patient. The interventional radiologist used a rod-type puncture site compressor for haemostasis to avoid direct contact with possible residual radioactivity at the puncture site. Dose rates were measured at the interventional radiologist chest and hand positions during puncture site pressing for haemostasis with and without the use of the blanket. The measurement results were applied to estimate the occupational dose of colleagues performing patient care to the patient radioembolized. The exposure to patients adjacent in the ward was estimated if the patient radioembolized was hospitalized. RESULTS: The radiation exposures measured at the radiologist chest and hand positions have been significantly reduced with the lead-lined blanket in place. The radiologist, performing puncture site pressing at the end of radioembolization procedure, would receive an average hand dose of 1.95 MUSv and body dose under his own lead apron of 0.30 MUSv for an average 90Y microsphere radioactivity of 2.54 GBq. Other medical personnel, nurses and porters, would receive occupational doses corresponding to an hour of background radiation. If the patient radioembolized using 90Y needs hospitalization in a common ward, using the lead-lined blanket to cover the abdomen of the patient and keeping a distance of 2 m from the patient who is adjacent would reduce the exposure by 0.42% of dose limit for the general public. CONCLUSION: By placing a lead-lined blanket on the patient abdominal region after 90Y radioembolization, hospital staff receive minimal radiation exposure in order to comply with the radiation protection "as low as reasonably achievable" principle. There will be no increase in radiation level in ward if the patient radioembolized using 90Y needs to be hospitalized. Therefore, the patient radioembolized can be accommodated alternatively at a corner bed of a common ward if an isolation room with private toilet facility is not available. Advances in knowledge: To reduce exposure to personnel providing patient care to patients radioembolized using 90Y. PMID- 27993092 TI - Novel vaccines for glioblastoma: clinical update and perspective. AB - Glioblastoma is the most common primary brain cancer. Aggressive treatment with surgery, radiation therapy and chemotherapy provides limited overall survival benefit. Glioblastomas have a formidable tumor microenvironment that is hostile to immunological effector cells and these cancers produce profound systemic immunosuppression. However, surgical resection of these tumors creates conditions that favor the use of immunotherapeutic strategies. Therefore, extensive surgical resection, when feasible, will remain part of the equation to provide an environment in which active specific immunotherapy has the greatest chance of working. Toward that end, a number of vaccination protocols are under investigation. Vaccines studied to date have produced cellular and humoral antitumor responses, but unequivocal clinical efficacy has yet to be demonstrated. In addition, focus is shifting toward the prospect of therapies involving vaccines in combination with immune checkpoint inhibitors and other immunomodulatory agents so that effector cells remain active against their targets systemically and within the tumor microenvironment. PMID- 27993096 TI - Impact of hybrid iterative reconstruction on unenhanced liver CT. AB - OBJECTIVE: To clarify the impact of hybrid iterative reconstruction (HIR) and filtered back projection (FBP) on unenhanced liver CT. METHODS: 30 patients with hepatocellular carcinoma (HCC) underwent unenhanced CT. The images were reconstructed with FBP and weak (Level 1), mild (Level 4) and strong (Level 7) levels of HIR (iDose4; Philips Medical Systems, Cleveland, OH). Quantitatively, attenuations of the HCC (with the largest lesion in each case), hepatic parenchyma (the average of four segments) and image noise (standard deviation of the attenuations in hepatic parenchyma) were compared between the four kinds of reconstruction using the two-tailed paired t-test. Qualitatively, liver lesion conspicuity and characterization were also compared using the Wilcoxon signed rank test. RESULTS: Attenuation of the liver lesion with the strong level of HIR was significantly higher than that with FBP (p = 0.0005). Attenuations of hepatic parenchyma with all three HIR levels were significantly lower than that with FBP (p <= 0.0002 in all comparisons). Image noise with each of the three HIR levels was significantly smaller than that with FBP (p < 0.0001 in any comparison). There was no significant difference in lesion conspicuity and characterization between FBP and each HIR level (p >= 0.0819 in all comparisons). CONCLUSION: Although attenuations of the liver lesion and hepatic parenchyma were significantly different between HIR and FBP, HIR had no significant effect on lesion conspicuity and characterization. Advances in knowledge: Attenuations of liver lesions and hepatic parenchyma differ significantly between HIR and FBP images. PMID- 27993097 TI - Evaluation of the occurrence of canine congenital sensorineural deafness in puppies of predisposed dog breeds using the brainstem auditory evoked response. AB - Canine congenital sensorineural deafness (CCSD) affects predisposed breeds of dogs and is primarily caused by an atrophy of the stria vascularis of the organ of Corti. The analysis of the brainstem auditory evoked response (BAER) is a reliable method for the evaluation of hearing in animals as it allows an accurate detection of unilateral or bilateral deafness. The occurrence of unilateral and bilateral deafness using the BAER was determined in a representative group of dogs in Poland, including Bull Terriers (n = 117), Australian Cattle Dogs (n = 62), English Setters (n = 32) and the Dogo Argentino (n = 32). Overall deafness, deafness in each dog breed and an association between deafness and phenotype were studied. Among the 243 dogs tested, 156 (81%) had a normal BAER, 27 (11%) were unilaterally deaf, and 12 (5%) were bilaterally deaf. The amplitudes and latencies of waves I, II, III, V, the V/I wave amplitude ratio, and wave I-V, I III and III-V inter-peak intervals were recorded for each dog. Unilaterally and bilaterally deaf dogs were present in all the dog breeds studied. There were 17 (14.5%) deaf Bull Terriers, three (4.8%) deaf Australian Cattle Dogs, seven (21.9%) deaf English Setters, and 12 (37.5%) deaf Dogos Argentinos. Preventive BAER screening should be routinely performed in these four breeds to prevent the spread of genes responsible for deafness. PMID- 27993098 TI - Acute hepatic effects of low-dose fumonisin B(1) in rats. AB - Adult male Wistar rats were enrolled in a study to test the acute hepatic effects of 50 mg/kg fumonisin B1 in feed for 5 days. Fumonisin B1 depressed growth and feed intake, and absolute and relative liver weight showed a significant increase. The proportions of C17:0, C18:3 n3, C22:5 n3 and C22:6 n3 fatty acids decreased in the hepatic phospholipid fraction. All proportional decreases modified the hepatocellular membrane lipids into a more rigid state. The fatty acid profile modifications were partly compensated for by endogenous glutathione (preventing the formation of conjugated dienes and trienes as initial phase lipid peroxidation indicators), while the enzymatic antioxidant defence system (glutathione peroxidase) was unaltered. In contrast, hepatic malondialdehyde, the cytotoxic product of end-phase lipid peroxidation showed a concentration increase even after 5 days of feeding. The results indicate a rather strong and rapid hepatic effect of FB1, immediately impairing membrane phospholipids, even before the enzymatic antioxidant defence is activated. PMID- 27993099 TI - Propiscin--A safe anaesthetic for pikeperch (Sander Lucioperca L.). AB - The aim of this work was to determine the impact of etomidate (Propiscin) dose (1 and 2 ml l-1) and exposure time (2 and 10 min) on the biochemical and haematological parameters of juvenile pikeperch (Sander lucioperca) [mean body length (Lc) 25.9 cm; body weight (W) 189.9 g] that were reared in a recirculating aquaculture system (RAS). Significant changes in the mean values of total protein, globulin, calcium, magnesium, and ammonia were noted in all groups immediately following exposure. The greatest changes in the haematological indicators were observed in groups subjected to 10-min exposure at both doses of the anaesthetic. The specimens from these groups had higher values for white blood cells (WBC), red blood cells (RBC), haemoglobin (HGB), haematocrit (HCT), and mean corpuscular volume (MCV). Statistically significant differences in these same parameters were also noted in the groups of fish exposed to the anaesthetic for 2 min at a dose of 2 ml l-1, but they were not as pronounced. Twenty-four h following exposure to etomidate, all blood parameters in the experimental groups were comparable to those of the control group. Etomidate can be recommended as a safe, effective anaesthetic for pikeperch. PMID- 27993100 TI - Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture. AB - Thyroid hormones (THs) and oestrogens are crucial in the regulation of cerebellar development. TH receptors (TRs) mediate these hormone effects and are regulated by both hormone families. We reported earlier that THs and oestradiol (E2) determine TR levels in cerebellar cell culture. Here we demonstrate the effects of low concentrations (10-10 M) of the endocrine disruptor (ED) bisphenol A (BPA) on the hormonal (THs, E2) regulation of TRalpha,beta in rat cerebellar cell culture. Primary cerebellar cell cultures, glia-containing and glia-destroyed, were treated with BPA or a combination of BPA and E2 and/or THs. Oestrogen receptor and TH receptor mRNA and protein levels were determined by real-time qPCR and Western blot techniques. The results show that BPA alone decreases, while BPA in combination with THs and/or E2 increases TR mRNA expression. In contrast, BPA alone increased receptor protein expressions, but did not further increase them in combination with THs and/or E2. The modulatory effects of BPA were mediated by the glia; however, the degree of changes also depended on the specific hormone ligand used. The results signify the importance of the regulatory mechanisms interposed between transcription and translation and raise the possibility that BPA could act to influence nuclear hormone receptor levels independently of ligand-receptor interaction. PMID- 27993101 TI - Detection and partial genetic characterisation of novel avi- and siadenoviruses in racing and fancy pigeons (Columba livia domestica). AB - Up to now, only a single adenovirus (AdV) isolate seemingly specific for pigeons, hence named pigeon AdV-1 (PiAdV-1), has been characterised at DNA sequence level. In the present work, the prevalence and diversity of AdVs occurring in domestic pigeon were examined by a survey performed on randomly collected samples using a very efficient, consensus nested PCR targeting the viral DNA polymerase gene. The newly detected viruses were characterised by sequencing and phylogeny analysis. Amplification of additional genome fragments was attempted by the use of several other PCR methods aiming at the hexon gene. During a 4-year survey, samples from dead or live, healthy pigeons originating from 27 lofts were examined in Hungary. Almost 50% of the samples (48 out of 97) proved to be positive for AdV. Sequence analysis revealed the presence of four hitherto unknown pigeon AdV types. PiAdV-1 was also identified in one sample. Two novel viruses named PiAdV-2 and -3 were found to belong to the genus Aviadenovirus, and two other novel types (PiAdV-4 and -5) to the genus Siadenovirus. This is the first report on the occurrence of siadenoviruses in birds belonging to the order Columbiformes. Approximately two thirds of the PiAdV-2 genome was sequenced and analysed. PMID- 27993102 TI - Pharmacokinetics and tissue depletion of doxycycline administered at high dosage to broiler chickens via the drinking water. AB - The recommended use of doxycycline (DC) to broiler chicken is 100 mg/L via the drinking water and a 7-day withdrawal time (WDT). However, study of a higher dosage is desirable because of the possible increase of antimicrobial resistance and disease spectrum. Tissue DC residues exceeding the current maximum residue levels (MRL) was our major concern. Therefore, serum concentration and tissue depletion of DC hyclate after administration of 200 mg/L of DC in the drinking water for five consecutive days were studied. The steady-state DC concentration (8.3 +/- 0.9 MUg/mL) was reached on the third day of medication. The elimination constant (0.05 +/- 0.01 1/h), half-life (14.9 +/- 1.4 h), area under concentration versus time curve (81.0 +/- 9.9 h.MUg/mL) and mean residence time (22.7 +/- 2.5 h) were obtained using a non-compartmental pharmacokinetic model. It was determined that the current 7-day WDT regulation was still legitimate for the kidney and liver as well as for the breast and leg muscles, which were estimated by linear regression analysis of the 99% upper distribution limit. The unregulated heart and gizzard were considered safe even when the lowest MRL of muscle (100 ng/g) was applied. While at the present time the extra-label use of drugs is only allowed under specific conditions, in the future it may become necessary to increase the general dosage of DC, and the current results suggest a safe range of DC hyclate in chicken; however, skin/fat tissue residues warrant further studies. PMID- 27993103 TI - Effects of butyrate on the insulin homeostasis of chickens kept on maize- or wheat-based diets. AB - The aim of the present study was to investigate the effects of butyrate as a feed supplement on the expression of insulin signalling proteins as potent regulators of metabolism and growth in Ross 308 broiler chickens fed maize- or wheat-based diets. Both diets were supplemented with non-protected butyrate (1.5 and 3.0 g/kg of diet, respectively) or with protected butyrate (0.2 g/kg of diet); the diet of the control groups was prepared without any additives (control). On day 42 of life, systemic blood samples were drawn for analyses of glucose and insulin concentrations, and tissue samples (liver, gastrocnemius muscle and subcutaneous adipose tissue) were taken for Western blotting examinations. The expression of key insulin signalling proteins (IRbeta, PKCzeta and mTOR) was assessed by semiquantitative Western blotting from the tissues mentioned. The type of diet had a remarkable influence on the insulin homeostasis of chickens. The wheat based diet significantly increased IRbeta and mTOR expression in the liver as well as mTOR and PKCzeta expression in the adipose tissue when compared to animals kept on a maize-based diet. IRbeta expression in the liver was stimulated by the lower dose of non-protected butyrate as well, suggesting the potential of butyrate as a feed additive to affect insulin sensitivity. Based on the results obtained, the present study shows new aspects of nutritional factors by comparing the special effects of butyrate as a feed additive and those of the cereal type, presumably in association with dietary non-starch polysaccharide- (NSP-) driven enteric shortchain fatty acid release including butyrate, influencing insulin homeostasis in chickens. As the tissues of chickens have physiologically lower insulin sensitivity compared to mammals, diet-associated induction of the insulin signalling pathway can be of special importance in improving growth and metabolic health. PMID- 27993104 TI - Short-term effects of T-2 toxin or deoxynivalenol on lipid peroxidation and the glutathione system in common carp. AB - The purpose of this study was to investigate the short-term effects of a single oral dose of T-2 and HT-2 toxin at 0.15, 0.33 and 1.82 mg kg-1 body weight, or deoxynivalenol (DON) and 15-acetyl-DON at 0.13, 0.31 and 1.75 mg kg-1 body weight in common carp. Conjugated dienes and trienes (the early markers of lipid peroxidation) were elevated in all DON-treated groups at the 16th hour, while thiobarbituric acid reactive substances (TBARS; termination marker) were increased at the highest dose of DON at the 16th and 24th hours. T-2 toxin did not cause changes in these parameters. Glutathione content and glutathione peroxidase activity showed higher levels at the 16th hour as the effect of both mycotoxins. The expression of glutathione peroxidase (GPx4) genes (gpx4a and gpx4b) revealed a dual response. Downregulation was observed at the 8th hour, followed by an induction at the 16th hour, at the lowest dose of both mycotoxins. Higher doses revealed long-drawn emergence and an elevation was observed only at the 24th hour. However, at the lowest and highest doses of DON or T-2 toxin the changes in gene expression were delayed, which may be related to the low oxidative stress response, as suggested by the expression profiles of the nrf2, keap1, gpx4a and gpx4b genes. PMID- 27993105 TI - First record of Ixodes ariadnae in Western Europe, Belgium--Short communication. AB - Fourteen long-legged ixodid ticks (6 nymphs and 8 larvae) were collected from Bechstein's bat (Myotis bechsteinii) in Rochefort, Belgium. All ticks were morphologically identified as Ixodes ariadnae, based on their long legs (Haller's organ longer than maximum diameter of tarsus I), broad palps and posteriorly reverse bell-shaped scutum with wavy surface. The DNA was extracted from these ticks, followed by PCR amplification of part of their cytochrome oxidase subunit I (COI) gene. All obtained sequences were 100% identical with each other, and with the COI sequence of I. ariadnae reported previously from Hungary and Germany. Taking into account that the collection site in the present study is close to the French border of Belgium, and migration of Bechstein's bat is known between Belgium and France, it is reasonable to suppose that I. ariadnae also occurs in France. This is the first record of I. ariadnae in Western Europe, outside its formerly known geographical range (Central Europe). PMID- 27993106 TI - Fabrication, Characterization, In vitro Evaluation of Solid Lipid Nanoemulsion of Flunarizine dihydrochloride for Nasal Delivery. AB - BACKGROUND: Flunarizine dihydrochloride (FHC) is used for the prophylaxis to migraine. Flunarizine has solubility problems which is practically insoluble in water and alcohol. Nanoemulsion is the approach to increase the solubility of the insoluble drugs. Nanoemulsions of FHC was prepared which can be given through the alternate route such as nasal drug delivery for migraine. OBJECTIVE: In this research work the solubility of the poorly soluble FHC was successfully improved by preparing it as a nano emulsion. Nanoemulsions can pass through the biological membrane easily so it can be delivered through nasal mucosa by which it may provide a quicker onset of action. The currently available dosage forms are in the form of tablet. METHODS: The formulations were prepared by using Glycerl Monostearate (GMS), Tween 80 as surfactant and PEG 400: Ethanol as co-surfactant in the distilled water. Nanoemulsions were prepared by step by step procedure. The prepared nanoemulsions were analyzed preliminarily by Master Sizer followed by Zeta Sizer by using the technique Dynamic Photon Correlation Spectroscopy. The best nanoemulsion was subjected to Zeta Potential study. The TEM analysis was carried out on the best formulation to gain the detailed information about the formulation. RESULTS: The best formulation was selected based on the physical appearance, homogenecity of the preparation, Preliminary Master Sizer analysis report, Secondary Zeta Sizer analysis report with Zeta Potential and TEM. The best formulation demonstrated the size in nano range with improved solubility. CONCLUSION: The FHC nano emulsion was prepared successfully which improved the solubility of the drug. The drug release study on simulated nasal fluid revealed that the preparation is suitable to be delivered through the nasal route. PMID- 27993107 TI - Anti-Psychotic Activity of Aqueous Root Extract of Hemidesmus indicus: A Time Bound Study in Rats. AB - AIMS AND BACKGROUND: Psychosis is a neurological disorder, which is usually defined as the "loss of contact with reality." As medicine 'Hemidesmusindicus' holds a reputed place in all systems of medicine in India. It is given in the form of infusion, fine particles, or syrup. It is also a component of several medicinal preparations. The present research work is pertaining to find out an anti-psychotic activity of an aqueous root extract of Hemidesmusindicus- a time bound study in rats. METHODS: In the present study, the dried roots of Hemidesmusindicus were crushed to a coarse powder and extracted with water under reflux for 36 hours to obtain the aqueous extract of roots of Hemidesmusindicus (AERHI). The extract was reconstituted in 2% aqueous tragacanth just before use and administered orally at a dose 0f 100 mg/kg, 300 mg/kg and 500 mg/kg. In a single dose study, the parameters were assessed after oral administration of the single dose of the AERHI, whereas in a multiple dose study, the animals daily received the suitable oral dose of the AERHI for a period of 30 days. The parameters were assessed on the 15th and 30th day. The antipsychotic activity was screened using Apomorphine induced Stereotyped behavior in rats and Haloperidol induced catalepsy models were used. In Apomorphine induced Stereotyped behavior inhibition of the Stereotyped behavior was considered to be anti-psychotic activity and in Haloperidol induced catalepsy, we observed whether the AERHI potentate or attenuate the catalepsy in rats. RESULTS: In this study, the extract of Hemidesmusindicus significantly inhibited the stereotyped behavior induced by apomorphine in rats and also potentiate the catalepsy induced by haloperidol, thereby showing its anti-psychotic activity. CONCLUSION: All these observations imply that Hemidesmusindicus extract possesses anti-psychotic activity in experimental animals. PMID- 27993108 TI - Molecular Mechanism of Action and Selectivity of Sodium Ch annel Blocker Insecticides. AB - Sodium channel blocker insecticides (SCBIs) are a relatively new class of insecticides that are represented by two commercially registered compounds, indoxacarb and metaflumizone. SCBIs, like pyrethroids and DDT, target voltage gated sodium channels (VGSCs) to intoxicate insects. In contrast to pyrethroids, however, SCBIs inhibit VGSCs at a distinct receptor site that overlaps those of therapeutic inhibitors of sodium channels, such as local anesthetics, anticonvulsants and antiarrhythmics. This review will recount the development of the SCBI insecticide class from its roots as chitin synthesis inhibitors, discuss the symptoms of poisoning and evidence supporting inhibition of VGSCs as their mechanism of action, describe the current model for SCBI-induced inhibition of VGSCs, present a model for the receptor for SCBIs on VGSCs, and highlight differences between data collected from mammalian and insect experimental models. PMID- 27993110 TI - Recent Advances of Graphene-based Hybrids with Magnetic Nanoparticles for Biomedical Applications. AB - The utilization of graphene-based nanomaterials combined with magnetic nanoparticles offers key benefits in the modern biomedicine. In this minireview, we focus on the most recent advances in hybrids of magnetic graphene derivatives for biomedical applications. We initially analyze the several methodologies employed for the preparation of graphene-based composites with magnetic nanoparticles, more specifically the kind of linkage between the two components. In the last section, we focus on the biomedical applications where these magnetic graphene hybrids are essential and pay special attention on how the addition of graphene improves the resulting devices in magnetic resonance imaging, controlled drug delivery, magnetic photothermal therapy and cellular separation and isolation. Finally, we highlight the use of these magnetic hybrids as multifunctional material that will lead to a next generation of theranostics. PMID- 27993109 TI - Recent Insights into the Development of Preclinical Trastuzumab- Resistant HER2+ Breast Cancer Models. AB - BACKGROUND: Overexpression and amplification of the human epidermal growth factor receptor 2 (HER2) occur in 20% of total breast carcinomas. HER2-overexpression is implicated in disease initiation and progression and associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody, is the standard HER2 targeted therapy for early and metastatic HER2-amplified breast cancer patients. Trastuzumab has significantly increased clinical benefit in HER2+ metastatic and adjuvant settings; however, it is not effective for many patients due to primary or acquired resistance to the drug. During the last decade, many studies have revealed a number of novel molecular traits of HER2+ breast cancer, allowing us to uncover the molecular mechanisms involved in trastuzumab resistance and develop strategies to overcome resistance to therapy. OBJECTIVE: In this review, we comprehensively addressed the current achievements in preclinical studies; we discussed molecular mechanisms of acquired trastuzumab resistance in HER2+ breast cancer models and potential therapeutic approaches based on the molecular features for HER2+ breast cancer. CONCLUSION: Enhanced understanding of the molecular profiles in HER2+ breast cancer may lead to the identification of novel biomarkers for the development of diagnostic approaches and improvement of therapeutic targets for the prevention and treatment of trastuzumab resistant HER2+ breast cancer. PMID- 27993111 TI - Targeting Legumain As a Novel Therapeutic Strategy in Cancers. AB - BACKGROUND: Recent reports indicate that the tumor microenvironment plays a pivotal role in cancer development and progression, leading to a paradigm shift in the way cancer is studied and targeted. In contrast to traditional approaches, where only tumor cells are targeted for the treatment, an emerging approach is to develop therapeutics which target the tumor microenvironment while complementing or enhancing current treatments. Legumain (LGMN) is a newly identified target which is highly expressed in the tumor microenvironment and in tumor cells, and holds potential both as a biomarker and as a therapeutic target. CONCLUSION: This review will be the first to summarize the expression of LGMN in common cancers, as well as its roles in tumorigenesis and metastasis. This review also discusses the current developments and future prospects of targeting LGMN through the development of DNA vaccines, azopeptides, small molecule inhibitors and LGMN activated prodrugs, highlighting the potential of LGMN as a target for cancer therapeutics. PMID- 27993112 TI - Understanding the Pathophysiology of Premature Ejaculation: Bridging the Link between Pharmacological and Psychological Interventions. AB - Premature ejaculation (PE) is one of the commonest male sexual dysfunctions. It is characterized by ejaculation which occurs before or soon after vaginal penetration, which causes significant psychological distress to the individual, and his partner. The exact cause of PE is still unknown but several mechanisms are proposed, and these involve complex interactions of neurophysiological, psychosocial, and cognitive factors. We discuss the role of serotonin, nitric oxide, phosphodiesterase enzymes and other neurotransmitters. Treatment of PE tends to co-occur with other sexual difficulties, especially erectile dysfunction (ED). Treatment with selective serotonin reuptake inhibitors (SSRIs) and Dapoxitene are also discussed in detail. The treatment strategy requires a comprehensive holistic approach incorporating both combination of psychopharmacological agent and cognitive-behavioral therapy (CBT). The present review highlights the integration of the hypothalamic-neural and reverberating emotional circuit and discusses the etiology and treatment for patients with PE. PMID- 27993114 TI - Hitting a Moving Target: Glioma Stem Cells Demand New Approaches in Glioblastoma Therapy. AB - BACKGROUND: Glioblastoma multiforme (GBM) continues to devastate patients and outfox investigators and clinicians despite the preponderance of research directed at its biology, pathogenesis and therapeutic advances. GBM routinely outlasts multidisciplinary treatment protocols, almost inevitably recurring in a yet more aggressive and resistant form with distinct genetic differences from the original tumor. Attempts to glean further insight into GBM point increasingly toward a subpopulation of cells with a stem-like phenotype. These cancer stem cells, similar to those now described in a variety of malignancies, are capable of tumorigenesis from a population of susceptible cells. CONCLUSIONS: Glioma stem cells have thus become a prevalent focus in GBM research for their presumed role in development, maintenance and recurrence of tumors. Glioma stem cells infiltrate the white matter surrounding tumors and often evade resection. They are uniquely suited both biochemically and environmentally to resist the best therapy currently available, intrinsically and efficiently resistant to standard chemo- and radiotherapy. These stem cells create an extremely heterogenous tumor that to date has had an answer for every therapeutic question, with continued dismal patient survival. Targeting this population of glioma stem cells may hold the long-awaited key to durable therapeutic efficacy in GBM. PMID- 27993113 TI - The Role of Mifamurtide in Chemotherapy-induced Osteoporosis of Children with Osteosarcoma. AB - BACKGROUND: Osteosarcoma is the most frequent malignant bone tumor in childhood and young adulthood. Long-term survivors of osteosarcoma patients show high prevalence of osteoporosis and fractures. The immunomodulatory mifamurtide, which modulates macrophages activity, improves disease outcome. OBJECTIVE: To evaluate the role of mifamurtide on macrophage component of bone, the osteoclasts, during chemotherapy in children with osteosarcoma. METHOD: Osteoclasts, obtained from peripheral blood cells of healthy donors were harvested in the presence or not of mifamurtide. Moreover, osteoclast cultures were obtained from osteosarcoma patients, at onset and during chemotherapy, alone or with mifamurtide. Pro osteoporotic tartrateresistant acid phosphatase (TRAP), phosphokinase-beta-2 (PKCbeta2), vanilloid receptor type 1 (TRPV1), and anti-osteoporotic cannabinoid receptor type 2 (CB2) biomarkers were analyzed by bio-molecular (qPCR), biochemical (Western Blotting), and morphological (TRAP assay) approaches. RESULTS: Osteoclasts from osteosarcoma patients show significant increase of TRAP and decrease of CB2 with respect to osteoclasts from healthy donors. This osteoclast hyperactivity is more evident in osteoclasts from osteosarcoma patients during chemotherapy. Mifamurtide reduces pro-osteoporotic TRAP, PKCbeta2, TRPV1 levels and increases CB2 in osteoclasts from healthy donors. Moreover, chemotherapy-induced effects on bone resorption markers are fully reverted in osteoclasts derived from osteosarcoma patients in chemotherapy plus mifamurtide. CONCLUSION: Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma. PMID- 27993115 TI - Virus, Oncolytic Virus and Human Prostate Cancer. AB - BACKGROUND: Prostate cancer (PCa), a disease, is characterized by abnormal cell growth in the prostate - a gland in the male reproductive system. Although older age and a family history of the disease have been recognized as the risk factors of PCa, the cause of this cancer remains unclear. Currently, PCa is one of the leading causes of cancer death among men of all races. METHOD: In this review study, we first discuss the controversy of the contribution of virus infection to PCa, and subsequently summarize the development of oncolytic virotherapy for PCa in the past several years. RESULTS: Mounting evidence suggests that infections with various viruses are causally linked to PCa pathogenesis. Published studies have provided strong evidence that at least two viruses (RXMV and HPV) contribute to prostate tumourigenicity and impact on the survival of patients with malignant PCa. Traditional therapies including chemotherapy and radiotherapy are unable to distinguish cancer cells from normal cells, which are a significant drawback and leads to toxicities for PCa patients undergoing treatment. So far, few other options are available for treating patients with advanced PCa. For PCa treatment, oncolytic virotherapy appears to be much more attractive, which uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cancer cell lysis through virus replication and expression of cytotoxic proteins. CONCLUSION: Virotherapy is being developed to be a novel therapy for cancers, which uses oncotropic and oncolytic viruses with their abilities to find and destroy malignant cells in the body. As oncolytic viruses are a relatively new class of anti-cancer immunotherapy agents, several important barriers still exist on the road to the use of oncolytic viruses for PCa therapy. PMID- 27993116 TI - Molecular Approaches Target to Immunotherapy for HPV-Associated Cancers. AB - BACKGROUND: Infection with human papillomavirus (HPVs) causes many cancers, which account for about 10-20% of total human cancers. Two recently developed prophylactic vaccines against virus infection confer strong immunogenicity to provide long-term protection. The use of these vaccines has contributed to a substantial decrease in the rates of cervical cancer the second most common cancer of women worldwide. However, therapeutic vaccines that can eliminate preexisting HPV infections and treat an existing HPV-caused cancer have not been developed. METHOD: In this short review, we discuss development of immunotherapy for HPV-associated cancers and recent progresses in our understanding of the immunopathology of HPV infection. RESULTS: Recent research advances have shown that molecular approaches target to immunotherapy for HPV infection-induced cancers to have the great potential and promise for developing immunotherapeutic vaccines. So far, the vast majority of the immunotherapeutic vaccines that are being tested are designed to target HPV viral genes and their proteins especially two E6 and E7 oncogenes. CONCLUSION: The developing immunotherapeutic vaccines aim to boost cell-mediated immunity. The boosted cell-mediated immunity strengthens the body's natural defenses to fight active infection and disease, thus to treat the existing cancers. PMID- 27993117 TI - Role of Genomic Alterations in HER2 Positive Breast Carcinoma: Focus on Susceptibility and Trastuzumab-therapy. AB - BACKGROUND: Breast cancer is the most frequently diagnosed life-threatening malignancy among women, across the globe. HER2 positive is a distinct breast cancer subtype, on account of its unique biology and physiological behavior. RESULTS: Amplification of HER2 oncogene/polysomy 17 leads to HER2 overexpression that is a significant causal implication in HER2 positive breast cancer. HER2 gene variants, as well as other genes/gene variants, are involved in its overexpression, disease prognosis and in predicting the susceptibility towards HER2 positive breast cancer. Trastuzumab (Herceptin) is the most commonly used therapy for treating patients with HER2 positive status. Genomic alterations are incriminated in the development of trastuzumab-resistance, which influences the response towards trastuzumab-therapy. CONCLUSION: In the current review article, we have summarized the genomic alterations that are responsible for overexpression of HER2 and therefore, increased risk of breast cancer. In addition, the gene variants affecting response towards trastuzumab-therapy have also been discussed. PMID- 27993118 TI - NSAIDs Induced Regulation of Alternatively Spliced Transcript Isoforms: Possible Role in Cancer and Alzheimer Disease. AB - BACKGROUND: Alternative splicing is one of the post transcriptional modifications through which multiple mRNA isoforms are produced from any gene, also known as splice variants. These are expressed in tissue and developmental stage specific manner that are important during the development. Most human genes undergo alternative splicing, thus contributing to the diversity of proteins. However, many abnormal splicing processes may result in human diseases. Non-steroidal antiinflammatory drugs (NSAIDs) are medications that act as analgesics, anti pyretics and antiinflammatory by affecting Cox genes and their products. Usually NSAIDs cause gastrotoxicity however, isozyme-specific NSAIDs exhibit a comparatively reduced gastrotoxic effect. Such NSAIDs have a broader range of application particularly as chemo-preventive drugs. It is known that changes at the active site of an enzyme may illicit a diverse range of responses. Such changes might explain the underlying reason as to why patients appear to respond differently to different NSAIDs. METHODS: An extensive literature search has been carried out using Pubmed and web of science databases considering the papers in last 10 years mainly on alternative splicing and NSAIDs. CONCLUSION: We have reviewed in detail the insight into the action of NSAIDs targeting specific isoforms of different genes. In future, the complete understanding of NSAIDs associated genes and their expression studies may be helpful in generating drugs with increased specificity. PMID- 27993119 TI - Pathophysiology of Myocardial Infarction and Acute Management Strategies. AB - On an annual basis, 13.2% of all deaths are attributable to coronary artery disease (CAD), which makes CAD - with 7.4 million deaths - the leading cause of death in the world. In this review, we discuss current knowledge in the pathophysiology of atherosclerosis with its progression to stable CAD and its destabilization and complication with thrombus formation - myocardial infarction (MI). Next, we describe mechanisms of myocardial cell death in MI, the ischemia reperfusion injury, leftventricular remodeling and complications of MI. Furthermore, we add acute management strategies concentrating on medical therapy, a decision on the reperfusion strategy, timing and cardiac protection by ischemic preconditioning, post-conditioning and remote ischemic conditioning. PMID- 27993120 TI - In vitro Vasorelaxant Effect of Artemisia herba alba Asso. in Spontaneously Hypertensive Rats. AB - BACKGROUND: The present study aims to evaluate the in vitro vasorelaxant effect of Artemisia herba alba (Ah) aqueous extract. METHOD: Aortic rings were isolated from spontaneously hypertensive rats and incubated in aqueous Ah extract at the following doses: 3, 5, 10 and 20 mg/ml. Incubation of aqueous Ah extract for 30 minutes produced a significant shift of the dose response curve to Norepinephrine (NE) (10-8 to 10-5 M) (p<0.001). RESULTS: Endothelium ablation significantly reduced the vasorelaxant effect of aqueous Ah extract (p<0.001). In addition, inhibition of vascular nitric oxide by Nomega-Nitro-L-Arginine Methyl (LNAME) produced a significant reduction in the vasorelaxant effect of aqueous Ah extract (p<0.001). CONCLUSION: We conclude that aqueous Ah extract at a dose of 20 mg/ml possess an in vitro vasorelaxant effect which seems to be dependent on the endothelium vasorelaxant factors involving nitric oxide synthesis. PMID- 27993121 TI - Trimethyl Chitosan Improves Anti-HIV Effects of Atripla as a New Nanoformulated Drug. AB - BACKGROUND: Highly active antiretroviral therapy (HAART) has been commonly used for HIV treatment. Its main drawbacks like drug resistance and side effects raised researcher's interest to find new approaches for its treatment. Trimethyl chitosan is one of the drug carriers which has been introduced recently. MATERIALS AND METHODS: the conjugated atripla-trimethyl chitosan was designed and characterized by zetasizer, AFM and FTIR techniques. The drug conjugation with trimethyl chitosan and cellular uptake of nano-conjugate were determined by spectrophotometry. XTT test was used to measure the cytotoxicity. Anti-retroviral efficiency was studied by ELISA test. RESULTS: Zetasizer Results proved that the average size of nano-conjugate particles agglomeration was 493.4+/-24.6 nm but the size of the majority of the particles was 177.2+/-7.8 nm with the intensity of 87.9%. AFM technique revealed that the sizes of nano-conjugate and trimethyl chitosan were 129 nm and 59.78 nm, respectively. Zeta potential was -1.35+/-0.04 mv for nano-conjugate and -7.69+/-0.3 mv for drug. Conjugation efficiency of atripla with trimethyl chitosan was 5.27%. Measured cellular uptake with spectrophotometry for nano-conjugate was about twice of the free drug in examined concentrations (P=0.007). Compared to atripla, the nano-conjugate showed a higher inhibitory effect on HIV replication (P=0.0001). CONCLUSION: The result showed that atripla-TMC conjugate does not have a significant cytotoxicity effect. Due to the higher inhibitory effect of nano-conjugate on viral replication, it can be used in lower concentration for antiviral treatment, which resulted in reduction of drug resistance and other side effects. PMID- 27993122 TI - In Models of Intracerebral Hemorrhage, Rivaroxaban is Superior to Warfarin to Limit Blood Brain Barrier Disruption and Hematoma Expansion. AB - BACKGROUND: Intracerebral hemorrhage (ICH) during oral anticoagulation therapy with an oral vitamin K epoxidase reductase such as warfarin is a life-threatening complication. However, whether direct oral anticoagulants (DOACs) are associated with larger hematoma volume and higher mortality rates remains controversial. We evaluated the hematoma volume and pathophysiology of ICH during anticoagulation with warfarin or rivaroxaban, an orally active direct factor Xa inhibitor. METHOD: Mice were orally pretreated with rivaroxaban (10 or 30 mg/kg), warfarin (4 mg/kg), or vehicle. ICH was induced by intrastriatal collagenase-injection. Hematoma volume and neurological deficits 24 h after ICH induction were significantly decreased in the rivaroxaban-pretreated group in comparison with the warfarin-pretreated group. Rivaroxaban did not increase the hematoma volume relative to that observed for vehicle, and improved survival rate 7 days after ICH induction compared with warfarin. RESULT: We evaluated blood-brain barrier (BBB) permeability 6 h after ICH induction using Evans blue spectrophotometry. Evans blue extravasation was significantly reduced in the rivaroxaban group compared with the warfarin group. To investigate the mechanism underlying hematoma expansion and BBB permeability, we focused on thrombin, a clot-derived factor and one of the major contributors to ICH-induced brain injury. To investigate the effects of anticoagulant agents on thrombin-induced injuries, human brain endothelial cells were used in membrane permeability assays. Rivaroxaban, but not warfarin, significantly mitigated the thrombin-induced increase in membrane permeability. CONCLUSION: These findings indicate that rivaroxaban decreases BBB disruption after ICH, and limits early hematoma expansion in these experimental models compared with warfarin. Our study suggests that rivaroxaban has advantages over warfarin with respect to ICH, an important complication during long-term anticoagulation therapy. PMID- 27993123 TI - Long-Range Contacts in Unfolding of Two-State Proteins. AB - Predicting the unfolding rates of proteins remains complicated due to the intricacy present in the unfolding pathway of proteins and further it was observed that the experimental unfolding data were less while compared to folding kinetics. The aim of our present work is to show the variation in long-range contacts observed in various sequence separation bins belonging to all-alpha, all beta and mixed structural classes of 52 two-state proteins. In this work linear regression technique have been used and regression equations were developed using long-range contacts observed from various sequence separation bins. Also nine topological parameters developed from the 3-D structures of proteins are related with their experimental unfolding rates and their variation in correlation coefficient is observed before and after structural classification. The present work aims to show that long-range contacts formed between residues which are sequentially far and spatially close in the 3-D structure of proteins play a crucial role in the unfolding mechanism of proteins. Also importance of long range contacts in various experimental and theoretical studies of protein folding along with NMR studies of the unfolded non-native states of proteins have been discussed. PMID- 27993124 TI - Reduced Fragment Diversity for Alpha and Alpha-Beta Protein Structure Prediction using Rosetta. AB - Protein structure prediction is considered a main challenge in computational biology. The biannual international competition, Critical Assessment of protein Structure Prediction (CASP), has shown in its eleventh experiment that free modelling target predictions are still beyond reliable accuracy, therefore, much effort should be made to improve ab initio methods. Arguably, Rosetta is considered as the most competitive method when it comes to targets with no homologues. Relying on fragments of length 9 and 3 from known structures, Rosetta creates putative structures by assembling candidate fragments. Generally, the structure with the lowest energy score, also known as first model, is chosen to be the "predicted one". A thorough study has been conducted on the role and diversity of 3-mers involved in Rosetta's model "refinement" phase. Usage of the standard number of 3-mers - i.e. 200 - has been shown to degrade alpha and alpha beta protein conformations initially achieved by assembling 9-mers. Therefore, a new prediction pipeline is proposed for Rosetta where the "refinement" phase is customised according to a target's structural class prediction. Over 8% improvement in terms of first model structure accuracy is reported for alpha and alpha-beta classes when decreasing the number of 3- mers. PMID- 27993125 TI - Cellular Membrane Composition Requirement by Antimicrobial and Anticancer Peptide GA-K4. AB - Naturally occurring antimicrobial peptides important for innate immunity are widely studied for their antimicrobial and anticancer activity. The primary target of these AMPs is believed to be the bacterial cytoplasmic membrane. However, the interaction between cytoplasmic membrane and the antimicrobial peptides remains poorly understood. Therefore to focus on the target membrane composition that is required by AMPs to interact with membranes, we have examined the interaction of the antimicrobial and anticancer active 11-residue GA-K4 (FLKWLFKWAKK) peptide with model and intact cell membranes. Effect on the structural conformational properties of GA-K4 peptide was investigated by means of far-UV CD and fluorescence spectroscopic methods. The different conformation of GA-K4 peptide in large unilamellar vesicles (LUV) bilayer and micelle environment suggest that the curvature has an influence on the secondary structure acquired by the peptide. Furthermore, the leakage experiment result confirmed that GA-K4 induced the leakage of cytoplasmic membrane in Staphylococcus aureus bacterial cells. Fluorescence data revealed the interfacial location of GA-K4 peptide in the model membranes. The blue-shift in emission wavelength by tryptophan residues in fluorescence data indicated the penetration of GA-K4 peptide in micelles and phospholipid bilayers. These results showed that the GA-K4 peptide is a membrane-active peptide and its activity depends on membrane curvature and lipid composition. Although further studies are required to confirm the mechanism of action, the data suggest mechanism of toroidal pore formation for the interaction of GA-K4 peptide with membranes. Our studies will be helpful in better understanding of the membrane requirment of peptides to express their therapeutic effects. PMID- 27993126 TI - What influences general practitioners' use of exercise for patients with chronic knee pain? Results from a national survey. AB - BACKGROUND: Exercise is a recommended 'core' treatment for chronic knee pain (CKP), however it appears to be underused by general practitioners (GPs). While behavioural theories suggest that attitudes and beliefs influence behaviours, no single theory reliably predicts GPs' behaviours. A theoretical analysis framework, developed from sociocognitive theories, was used to underpin investigation of the key influences associated with GPs' use of exercise for patients with CKP, to inform future interventions to optimise GPs' use of exercise. METHODS: A cross-sectional postal questionnaire survey investigated UK GPs' reported use of exercise based on a patient case vignette. Factors influencing GPs' exercise use (behaviour) were examined using attitude statements, free-text questions and multiple response option questions related to factors within the analysis framework. Unadjusted logistic regression analyses explored the associations between GPs' attitudes/beliefs and behaviour. RESULTS: From a total sample of 5000 GPs, 835 (17%) returned a questionnaire. Most respondents (n = 729, 87%) reported that they would use exercise. Factors significantly associated with exercise use (OR (95% CI)) included GPs' beliefs about their role (belief that GPs should give information on type, duration and frequency of exercise (30.71 (5.02,188.01)), beliefs about consequences (agreement that knee problems are improved by local (3.23 (1.94,5.39)) and general exercise (2.63 (1.38,5.02))), moral norm (agreement that GPs should prescribe all patients local (3.08 (1.96,4.83)) and general exercise (2.63 (1.45,4.76))), and GP-related beliefs about capabilities (prior experience of insufficient expertise to give detailed exercise information (0.50 (0.33,0.76)). Whilst perceived time limitations were not associated with exercise use (1.00 (0.33,3.01)), GPs who disagreed that they experienced time limitations were more likely to suggest general (2.17 (1.04,4.55)), or demonstrate local (2.16 (1.06,4.42)), exercises. CONCLUSION: GPs' attitudes and beliefs are associated with their use of exercise for patients with CKP, particularly beliefs about role, responsibilities and skills in initiating exercise, and about the efficacy of exercise. Although the low response risks response bias, these results can inform future interventions to optimise GPs' behaviour. The role of GP uncertainty and influences on clinical decision-making need further exploration, thus an amended analysis framework is suggested, which should be tested in future research. PMID- 27993128 TI - High school versus graduate entry in a Saudi medical school - is there any difference in academic performance and professionalism lapses? AB - BACKGROUND: King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) was the first university in the Kingdom of Saudi Arabia offering both high school entry and graduate entry (GE) students into medical school. We compared the academic performance and professionalism lapses of high school entry and GE students who undertook the same curriculum and examinations in the College of Medicine, Riyadh, KSAU-HS. METHODS: Examination scores of 196 high school graduates and 54 GE students over a 4-year period (2010-2014) were used as a measure of academic achievement. For assessment of professionalism lapses, we compared the number of warning letters in both streams of students. RESULTS: In some pre-clinical courses, high school entry students performed significantly better than GE students. There was no significant difference in academic performance of high school entry and GE students in clinical rotations. GE students had a significantly greater number of warning letters per student as compared to high school entry students. DISCUSSION: This is the first Saudi study to compare the performance of high school entry and GE students in a medical school. Overall, both streams of students performed equally well with high school entry students performing better than GE students in a few pre-clinical courses. We compared professionalism lapses and found an increase in number of warning letters for GE students. More studies are needed to evaluate if there are differences in other assessments of professionalism between these two streams of students. PMID- 27993127 TI - Environmental and genetic effects on tomato seed metabolic balance and its association with germination vigor. AB - BACKGROUND: The metabolite content of a seed and its ability to germinate are determined by genetic makeup and environmental effects during development. The interaction between genetics, environment and seed metabolism and germination was studied in 72 tomato homozygous introgression lines (IL) derived from Solanum pennelli and S. esculentum M82 cultivar. Plants were grown in the field under saline and fresh water irrigation during two consecutive seasons, and collected seeds were subjected to morphological analysis, gas chromatograph-mass spectrometry (GC-MS) metabolic profiling and germination tests. RESULTS: Seed weight was under tight genetic regulation, but it was not related to germination vigor. Salinity significantly reduced seed number but had little influence on seed metabolites, affecting only 1% of the statistical comparisons. The metabolites negatively correlated to germination were simple sugars and most amino acids, while positive correlations were found for several organic acids and the N metabolites urea and dopamine. Germination tests identified putative loci for improved germination as compared to M82 and in response to salinity, which were also characterized by defined metabolic changes in the seed. CONCLUSIONS: An integrative analysis of the metabolite and germination data revealed metabolite levels unambiguously associated with germination percentage and rate, mostly conserved in the different tested seed development environments. Such consistent relations suggest the potential for developing a method of germination vigor prediction by metabolic profiling, as well as add to our understanding of the importance of primary metabolic processes in germination. PMID- 27993129 TI - Hepatitis viruses in Ethiopia: a systematic review and meta-analysis. AB - BACKGROUND: The existing seroepidemiological data on viral hepatitis in Ethiopia showed a wide variation in prevalence pattern and the clinical and public health burden have been underestimated. The aim of this systematic review and meta analysis was to provide a clear and comprehensive estimation of viral hepatitis epidemiology and the potential clinical burdens in Ethiopia. METHODS: A comprehensive literature search was carried out from five decades (1968-2015) published studies from biomedical databases; PubMed, Google scholar, Medline and Web of Science. RESULTS: The overall pooled prevalence of hepatitis B virus (HBV) was 7.4% (95%CI: 6.5-8.4). The pooled prevalence among subgroups showed 5.2% (95%CI: 3.7-7.4) in human immunodeficiency virus (HIV) infected individuals, 8.0% (95%CI: 5.9-10.7) in community based studies, 8.4% (95%CI: 5.4-12.7) in blood donors, 11.0% (95%CI: 7.5-15.9) in immigrants and 6.9% (95%CI: 5.6-8.5) in other groups. Among study parameters considered during meta-regression analysis, only study years were associated with a decreasing HBV prevalence rate over time. The overall pooled prevalence of anti-hepatitis C virus antibody (anti-HCV) was 3.1% (95%CI: 2.2-4.4). Unlike HBV, the anti-HCV prevalence in HIV infected individuals was higher (5.5%, 95%CI: 3.8-7.8%, p = 0.01) than the prevalence observed in the other subgroup of study population. Although relatively few data were available, hepatitis virus A (HAV), D (HDV) and E (HEV) were also circulated in Ethiopia. CONCLUSIONS: This review indicates that all types of viral hepatitis origins are endemic in Ethiopia. Adapting a recommended diagnostic and treatment algorithm of viral hepatitis in the routine healthcare systems and implementing prevention and control policies in the general population needs an urgent attention. PMID- 27993131 TI - Oral cancer incidence and survival rates in the Republic of Ireland, 1994-2009. AB - BACKGROUND: Oral cancer is a significant public health problem world-wide and exerts high economic, social, psychological, and physical burdens on patients, their families, and on their primary care providers. We set out to describe the changing trends in incidence and survival rates of oral cancer in Ireland between 1994 and 2009. METHODS: National data on incident oral cancers [ICD 10 codes C01 C06] were obtained from the National Cancer Registry Ireland from 1994 to 2009. We estimated annual percentage change (APC) in oral cancer incidence during 1994 2009 using joinpoint regression software (version 4.2.0.2). The lifetime risk of oral cancer to age 79 was estimated using Irish incidence and population data from 2007 to 2009. Survival rates were also examined using Kaplan-Meier curves and Cox proportional hazard models to explore the influence of several demographic/lifestyle covariates with follow-up to end 2012. RESULTS: Data were obtained on 2,147 oral cancer incident cases. Men accounted for two-thirds of oral cancer cases (n = 1,430). Annual rates in men decreased significantly during 1994-2001 (APC = -4.8 %, 95 % CI: -8.7 to -0.7) and then increased moderately (APC = 2.3 %, 95 % CI: -0.9 to 5.6). In contrast, annual incidence increased significantly in women throughout the study period (APC = 3.2 %, 95 % CI: 1.9 to 4.6). There was an elevated risk of death among oral cancer patients who were: older than 60 years of age; smokers; unemployed or retired; those living in the most deprived areas; and those whose tumour was sited in the base of the tongue. Being married and diagnosed in more recent years were associated with reduced risk of death. CONCLUSION: Oral cancer increased significantly in both sexes between 1999 and 2009 in Ireland. Our analyses demonstrate the influence of measured factors such as smoking, time of diagnosis and age on observed trends. Unmeasured factors such as alcohol use, HPV and dietary factors may also be contributing to increased trends. Several of these are modifiable risk factors which are crucial for informing public health policies, and thus more research is needed. PMID- 27993130 TI - Computational approach to predict species-specific type III secretion system (T3SS) effectors using single and multiple genomes. AB - BACKGROUND: Many gram-negative bacteria use type III secretion systems (T3SSs) to translocate effector proteins into host cells. T3SS effectors can give some bacteria a competitive edge over others within the same environment and can help bacteria to invade the host cells and allow them to multiply rapidly within the host. Therefore, developing efficient methods to identify effectors scattered in bacterial genomes can lead to a better understanding of host-pathogen interactions and ultimately to important medical and biotechnological applications. RESULTS: We used 21 genomic and proteomic attributes to create a precise and reliable T3SS effector prediction method called Genome Search for Effectors Tool (GenSET). Five machine learning algorithms were trained on effectors selected from different organisms and a trained (voting) algorithm was then applied to identify other effectors present in the genome testing sets from the same (GenSET Phase 1) or different (GenSET Phase 2) organism. Although a select group of attributes that included the codon adaptation index, probability of expression in inclusion bodies, N-terminal disorder, and G + C content (filtered) were better at discriminating between positive and negative sets, algorithm performance was better when all 21 attributes (unfiltered) were used. Performance scores (sensitivity, specificity and area under the curve) from GenSET Phase 1 were better than those reported for six published methods. More importantly, GenSET Phase 1 ranked more known effectors (70.3%) in the top 40 ranked proteins and predicted 10-80% more effectors than three available programs in three of the four organisms tested. GenSET Phase 2 predicted 43.8% effectors in the top 40 ranked proteins when tested on four related or unrelated organisms. The lower prediction rates from GenSET Phase 2 may be due to the presence of different translocation signals in effectors from different T3SS families. CONCLUSIONS: The species-specific GenSET Phase 1 method offers an alternative approach to T3SS effector prediction that can be used with other published programs to improve effector predictions. Additionally, our approach can be applied to predict effectors of other secretion systems as long as these effectors have translocation signals embedded in their sequences. PMID- 27993132 TI - Performance of the G4 Xpert(r) MTB/RIF assay for the detection of Mycobacterium tuberculosis and rifampin resistance: a retrospective case-control study of analytical and clinical samples from high- and low-tuberculosis prevalence settings. AB - BACKGROUND: The Xpert(r) MTB/RIF (Xpert) assay is a rapid PCR-based assay for the detection of Mycobacterium tuberculosis complex DNA (MTBc) and mutations associated with rifampin resistance (RIF). An updated version introduced in 2011, the G4 Xpert, included modifications to probe B and updated analytic software. METHODS: An analytical study was performed to assess Xpert detection of mutations associated with rifampin resistance in rifampin-susceptible and -resistant isolates. A clinical study was performed in which specimens from US and non-US persons suspected of tuberculosis (TB) were tested to determine Xpert performance characteristics. All specimens underwent smear microscopy, mycobacterial culture, conventional drug-susceptibility testing and Xpert testing; DNA from isolates with discordant rifampin resistance results was sequenced. RESULTS: Among 191 laboratory-prepared isolates in the analytical study, Xpert sensitivity for detection of rifampin resistance associated mutations was 97.7% and specificity was 90.8%, which increased to 99.0% after DNA sequencing analysis of the discordant samples. Of the 1,096 subjects in the four clinical studies, 49% were from the US. Overall, Xpert detected MTBc in 439 of 468 culture-positive specimens for a sensitivity of 93.8% (95% confidence interval [CI]: 91.2%-95.7%) and did not detect MTBc in 620 of 628 culture-negative specimens for a specificity of 98.7% (95% CI: 97.5%-99.4%). Sensitivity was 99.7% among smear positive cases, and 76.1% among smear-negative cases. Non-determinate MTBc detection and false-positive RIF resistance results were low (1.2 and 0.9%, respectively). CONCLUSIONS: The updated Xpert assay retained the high sensitivity and specificity of the previous assay versions and demonstrated low rates of non determinate and RIF resistance false positive results. PMID- 27993133 TI - Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer. AB - BACKGROUND: Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. RESULTS: Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. CONCLUSIONS: The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising. PMID- 27993134 TI - Epidemic characteristics, high-risk townships and space-time clusters of human brucellosis in Shanxi Province of China, 2005-2014. AB - BACKGROUND: Brucellosis, one of the world's most important zoonosis, has been re emerging in China. Shanxi Province, located in northern China, where husbandry development has been accelerated in recent years, has a rather high incidence of human brucellosis but drew little attention from the researchers. This study aimed to describe the changing epidemiology of human brucellosis in Shanxi Province from 2005 to 2014 and explore high-risk towns and space-time clusters for elucidating the necessity of decentralizing disease control resource to township level in epidemic regions, particularly in hotspot areas. METHODS: We extracted data from the Chinese National Notifiable Infectious Disease Reporting System to describe the incidence and spatiotemporal distribution of human brucellosis in Shanxi Province. Geographic information system was used to identify townships at high risk for the disease. Space-Time Scan Statistic was applied to detect the space-time clusters of human brucellosis during the past decade. RESULTS: From 2005 to 2014, a total of 50,002 cases of human brucellosis were recorded in Shanxi, with a male-to-female ratio of 3.9:1. The reported incidence rate increased dramatically from 7.0/100,000 in 2005 to 23.5/100,000 in 2014, with an average annual increase of 14.5%. There were still 33.8% cases delaying diagnosis in 2014. The proportion of the affected towns increased from 31.5% in 2005 to 82.5% in 2014. High-risk towns spread from the north to the center and then south of Shanxi Province, which were basins and adjacent highlands suitable for livestock cultivation. During the past decade, there were 55 space-time clusters of human brucellosis detected in high risk towns; the clusters could happen in any season. Some clusters' location maintained stable over time. CONCLUSIONS: During the last decade, Shanxi province's human brucellosis epidemic had been aggravated and high-risk areas concentrated in some towns located in basins and adjacent highlands. Space-time clusters existed and some located steadily over time. Quite a few cases still missed timely diagnosis. Greater resources should be allocated and decentralized to mitigate the momentum of rise and improve the accessibility of prompt diagnosis treatment in the high risk townships. PMID- 27993135 TI - What are the factors associated with human immunodeficiency virus/sexually transmitted infection screening behaviour among heterosexual men patronising entertainment establishments who engaged in casual or paid sex? - Results from a cross-sectional survey in an Asian urban setting. AB - BACKGROUND: Late presentation of human immunodeficiency virus (HIV) is associated with heterosexual transmission, particularly among heterosexual men in Asia. Although data on HIV/sexually transmitted infection (STI) testing behaviour is increasing, information is still lacking among heterosexual men who receive far lesser attention and are generally invisible in HIV/ STI prevention, particularly in the Asian urban setting. The aim of this study was to assess the prevalence of HIV/STI testing among heterosexual men patronising entertainment establishments (EEs) who engaged in casual or paid sex in Singapore, and the factors associated with this behaviour. METHODS: This was a cross-sectional survey involving 604 participants using time location sampling between March and May 2015. For multivariable analysis, we used a mixed effects Poisson regression model with backward stepwise approach to account for clustering by venue and to obtain the adjusted prevalence ratio (aPR) for the association of various factors with HIV/STI testing. RESULTS: Among 604 at-risk participants, only 163 (27.0%) had gone for HIV or STI testing in the past 6 months. Of this, 83.4% of them specifically underwent HIV testing. In multivariable analysis, HIV/STI testing increased with being non-Chinese (aPR 1.50; 95% CI: 1.08-2.06), having engaged in anal sex with casual or paid partner in the past 6 months (aPR 1.80; 95% CI: 1.27 2.57), number of partners in the past 6 months (aPR 1.03; 95% CI: 1.01-1.05) and HIV knowledge score (aPR 1.11; 95% CI: 1.05-1.16). Among those who reported non consistent condom use with casual or paid partner, almost half of them (47.9%) perceived that they were at low risk for HIV/STI. Sigmatisation and discrimination was another common barrier for non-testing. CONCLUSIONS: Despite being at risk of HIV/STI, the low prevalence of testing coupled with a high prevalence of risky sexual behaviour among this group of heterosexual men in Singapore calls for a need for HIV/STI prevention interventions in the EE setting. Other than promoting testing and safer sex, the interventions should address the discordance between perceived risk and actual sexual behaviour, in addition to the stigma and discrimination associated with testing for this group. PMID- 27993136 TI - National Influenza Surveillance in the Philippines from 2006 to 2012: seasonality and circulating strains. AB - BACKGROUND: The results of routine influenza surveillance in 13 regions in the Philippines from 2006 to 2012 are presented, describing the annual seasonal epidemics of confirmed influenza virus infection, seasonal and alert thresholds, epidemic curve, and circulating influenza strains. METHODS: Retrospective analysis of Philippine influenza surveillance data from 2006 to 2012 was conducted to determine seasonality with the use of weekly influenza positivity rates and calculating epidemic curves and seasonal and alert thresholds using the World Health Organization (WHO) global epidemiological surveillance standards for influenza. RESULTS: Increased weekly influenza positive rates were observed from June to November, coinciding with the rainy season and school opening. Two or more peaks of influenza activity were observed with different dominant influenza types associated with each peak. A-H1N1, A-H3N2, and two types of B viruses circulated during the influenza season in varying proportions every year. Increased influenza activity for 2012 occurred 8 weeks late in week 29, rather than the expected week of rise of cases in week 21 as depicted in the established average epidemic curve and seasonal threshold. The intensity was severe going above the alert threshold but of short duration. Southern Hemisphere vaccine strains matched circulating influenza virus for more surveillance years than Northern Hemisphere vaccine strains. CONCLUSIONS: Influenza seasonality in the Philippines is from June to November. The ideal time to administer Southern Hemisphere influenza vaccine should be from April to May. With two lineages of influenza B circulating annually, quadrivalent vaccine might have more impact on influenza control than trivalent vaccine. Establishment of thresholds and average epidemic curve provide a tool for policy-makers to assess the intensity or severity of the current influenza epidemic even early in its course, to help plan more precisely resources necessary to control the outbreak. Influenza surveillance activities should be continued in the Philippines and funding for such activities should already be incorporated into the Philippine health budget. PMID- 27993137 TI - Robust differential expression analysis by learning discriminant boundary in multi-dimensional space of statistical attributes. AB - BACKGROUND: Performing statistical tests is an important step in analyzing genome wide datasets for detecting genomic features differentially expressed between conditions. Each type of statistical test has its own advantages in characterizing certain aspects of differences between population means and often assumes a relatively simple data distribution (e.g., Gaussian, Poisson, negative binomial, etc.), which may not be well met by the datasets of interest. Making insufficient distributional assumptions can lead to inferior results when dealing with complex differential expression patterns. RESULTS: We propose to capture differential expression information more comprehensively by integrating multiple test statistics, each of which has relatively limited capacity to summarize the observed differential expression information. This work addresses a general application scenario, in which users want to detect as many as DEFs while requiring the false discovery rate (FDR) to be lower than a cut-off. We treat each test statistic as a basic attribute, and model the detection of differentially expressed genomic features as learning a discriminant boundary in a multi-dimensional space of basic attributes. We mathematically formulated our goal as a constrained optimization problem aiming to maximize discoveries satisfying a user-defined FDR. An effective algorithm, Discriminant-Cut, has been developed to solve an instantiation of this problem. Extensive comparisons of Discriminant-Cut with 13 existing methods were carried out to demonstrate its robustness and effectiveness. CONCLUSIONS: We have developed a novel machine learning methodology for robust differential expression analysis, which can be a new avenue to significantly advance research on large-scale differential expression analysis. PMID- 27993138 TI - Scaling up complex interventions: insights from a realist synthesis. AB - Preventing chronic diseases, such as cancer, cardiovascular disease and diabetes, requires complex interventions, involving multi-component and multi-level efforts that are tailored to the contexts in which they are delivered. Despite an increasing number of complex interventions in public health, many fail to be 'scaled up'. This study aimed to increase understanding of how and under what conditions complex public health interventions may be scaled up to benefit more people and populations.A realist synthesis was conducted and discussed at an in person workshop involving practitioners responsible for scaling up activities. Realist approaches view causality through the linkages between changes in contexts (C) that activate mechanisms (M), leading to specific outcomes (O) (CMO configurations). To focus this review, three cases of complex interventions that had been successfully scaled up were included: Vibrant Communities, Youth Build USA and Pathways to Education. A search strategy of published and grey literature related to each case was developed, involving searches of relevant databases and nominations from experts. Data extracted from included documents were classified according to CMO configurations within strategic themes. Findings were compared and contrasted with guidance from diffusion theory, and interpreted with knowledge users to identify practical implications and potential directions for future research.Four core mechanisms were identified, namely awareness, commitment, confidence and trust. These mechanisms were activated within two broad scaling up strategies, those of renewing and regenerating, and documenting success. Within each strategy, specific actions to change contexts included building partnerships, conducting evaluations, engaging political support and adapting funding models. These modified contexts triggered the identified mechanisms, leading to a range of scaling up outcomes, such as commitment of new communities, changes in relevant legislation, or agreements with new funding partners.This synthesis applies and advances theory, realist methods and the practice of scaling up complex interventions. Practitioners may benefit from a number of coordinated efforts, including conducting or commissioning evaluations at strategic moments, mobilising local and political support through relevant partnerships, and promoting ongoing knowledge exchange in peer learning networks. Action research studies guided by these findings, and studies on knowledge translation for realist syntheses are promising future directions. PMID- 27993139 TI - Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging. AB - BACKGROUND: Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging. RESULTS: Busulphan entrapment efficiency was 83% while the drug release showed a sustained pattern over 10 h. SPION loaded-PEG-PCL micelles showed contrast enhancement in T 2 * weighted MRI with high r 2* relaxivity. In vitro cellular uptake of PEG-PCL micelles labeled with fluorescein in J774A cells was found to be time-dependent. The maximum uptake was observed after 24 h of incubation. The biodistribution of PEG-PCL micelles functionalized with VivoTag 680XL was investigated in Balb/c mice over 48 h using in vivo fluorescence imaging. The results of real-time live imaging were then confirmed by ex vivo organ imaging and histological examination. Generally, PEG-PCL micelles were highly distributed into the lungs during the first 4 h post intravenous administration, then redistributed and accumulated in liver and spleen until 48 h post administration. No pathological impairment was found in the major organs studied. CONCLUSIONS: Thus, with loaded contrast agent and conjugated fluorochrome, PEG-PCL micelles as biodegradable and biocompatible nanocarriers are efficient multimodal imaging agents, offering high drug loading capacity, and sustained drug release. These might offer high treatment efficacy and real-time tracking of the drug delivery system in vivo, which is crucial for designing of an efficient drug delivery system. PMID- 27993140 TI - Post-doctoral research fellowship as a health policy and systems research capacity development intervention: a case of the CHESAI initiative. AB - BACKGROUND: Building capacity in health policy and systems research (HPSR), especially in low- and middle-income countries, remains a challenge. Various approaches have been suggested and implemented by scholars and institutions using various forms of capacity building to address challenges regarding HPSR development. The Collaboration for Health Systems Analysis and Innovation (CHESAI) - a collaborative effort between the Universities of Cape Town and the Western Cape Schools of Public Health - has employed a non-research based post doctoral research fellowship (PDRF) as a way of building African capacity in the field of HPSR by recruiting four post-docs. In this paper, we (the four post docs) explore whether a PDRF is a useful approach for capacity building for the field of HPSR using our CHESAI PDRF experiences. METHODS: We used personal reflections of our written narratives providing detailed information regarding our engagement with CHESAI. The narratives were based on a question guide around our experiences through various activities and their impacts on our professional development. The data analysis process was highly iterative in nature, involving repeated meetings among the four post-docs to reflect, discuss and create themes that evolved from the discussions. RESULTS: The CHESAI PDRF provided multiple spaces for our engagement and capacity development in the field of HPSR. These spaces provided us with a wide range of learning experiences, including teaching and research, policy networking, skills for academic writing, engaging practitioners, co-production and community dialogue. Our reflections suggest that institutions providing PDRF such as this are valuable if they provide environments endowed with adequate resources, good leadership and spaces for innovation. Further, the PDRFs need to be grounded in a community of HPSR practice, and provide opportunities for the post-docs to gain an in-depth understanding of the broader theoretical and methodological underpinnings of the field. CONCLUSION: The study concludes that PDRF is a useful approach to capacity building in HPSR, but it needs be embedded in a community of practice for fellows to benefit. More academic institutions in Africa need to adopt innovative and flexible support for emerging leaders, researchers and practitioners to strengthen our health systems. PMID- 27993141 TI - Colonization of xenograft tumors by oncolytic vaccinia virus (VACV) results in enhanced tumor killing due to the involvement of myeloid cells. AB - BACKGROUND: The mechanisms by which vaccinia virus (VACV) interacts with the innate immune components are complex and involve different mechanisms. iNOS mediated NO production by myeloid cells is one of the central antiviral mechanisms and this study aims to investigate specifically whether iNOS-mediated NO production by myeloid cells, is involved in tumor eradication following the virus treatment. METHODS: Human colon adenocarcinoma (HCT-116) xenograft tumors were infected by VACV. Infiltration of iNOS+ myeloid cell population into the tumor, and virus titer was monitored following the treatment. Single-cell suspensions were stained for qualitative and quantitative flow analysis. The effect of different myeloid cell subsets on tumor growth and colonization were investigated by depletion studies. Finally, in vitro culture experiments were carried out to study NO production and tumor cell killing. Student's t test was used for comparison between groups in all of the experiments. RESULTS: Infection of human colon adenocarcinoma (HCT-116) xenograft tumors by VACV has led to recruitment of many CD11b+ ly6G+ myeloid-derived suppressor cells (MDSCs), with enhanced iNOS expression in the tumors, and to an increased intratumoral virus titer between days 7 and 10 post-VACV therapy. In parallel, both single and multiple rounds of iNOS-producing cell depletions caused very rapid tumor growth within the same period after virus injection, indicating that VACV-induced iNOS+ MDSCs could be an important antitumor effector component. A continuous blockade of iNOS by its specific inhibitor, L-NIL, showed similar tumor growth enhancement 7-10 days post-infection. Finally, spleen-derived iNOS+ MDSCs isolated from virus injected tumor bearing mice produced higher amounts of NO and effectively killed HCT-116 cells in in vitro transwell experiments. CONCLUSIONS: We initially hypothesized that NO could be one of the factors that limits active spreading of the virus in the cancerous tissue. In contrast to our initial hypothesis, we observed that PMN-MDSCs were the main producer of NO through iNOS and NO provided a beneficial antitumor effect, The results strongly support an important novel role for VACV infection in the tumor microenvironment. VACV convert tumor promoting MDSCs into tumor-killing cells by inducing higher NO production. PMID- 27993142 TI - Identification and characterization of cancer stem cells in canine mammary tumors. AB - Cancer stem cells (CSC) represent a small subpopulation of cells in malignant tumors that possess the unique ability to self-renew, differentiate and resist chemo- and radiotherapy. These cells have been postulated to be the basis for some of the difficulties in treating cancer, and therefore, numerous approaches have been developed to specifically target and eliminate CSC in diverse types of cancer, including breast cancer. Spontaneously occurring mammary tumors in canines share clinical and molecular similarities with the human counterpart, making the dog a potentially powerful model for the study of human breast cancer and clinical trials. Studies focused on canine mammary CSC might therefore enhance our understanding of the biology and possible treatment of the disease in both dogs and humans. In this review, we discuss various approaches currently in use to isolate and characterize canine mammary CSC. PMID- 27993143 TI - Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date. Here we describe a rare case of a diagnostically challenging DLBCL-IF involving a lymph node in a patient with a prior history of lymphadenopathy for several years and MZL involving skin. CASE PRESENTATION: A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2-3 month's duration, nausea and mid back rash that was biopsied. PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. The patient was referred to surgery for excisional biopsy of a right inguinal lymph node. Diagnostic H&E stained slides and ancillary studies were reviewed for the lymph node and skin specimens. B-cell clonality by PCR and sequencing studies were performed on both specimens. We demonstrate that this patient's MZL and DLBCL-IF are clonally related, strongly suggesting that transformation of MZL to DLBCL had occurred. Furthermore, we identified a novel deletion of the long arm of chromosome 20 (del(20q12)) and a missense mutation in BIRC3 (Baculoviral IAP repeat-containing protein 3) in this patient's DLBCL that are absent from his MZL, suggesting that these genetic alterations contributed to the large cell transformation. CONCLUSIONS: To our knowledge, this is the first report providing molecular evidence for a previously suspected link between MZL and DLBCL-IF. In addition, we describe for the first time del(20q12) and a missense mutation in BIRC3 in DLBCL. Our findings also raise awareness of DLBCL-IF and discuss the diagnostic pitfalls of this rare entity. PMID- 27993144 TI - Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept. AB - BACKGROUND: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). METHODS: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. RESULTS: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. CONCLUSIONS: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity. PMID- 27993145 TI - Pressure RElieving Support SUrfaces: a Randomised Evaluation 2 (PRESSURE 2): study protocol for a randomised controlled trial. AB - BACKGROUND: Pressure ulcers represent a major burden to patients, carers and the healthcare system, affecting approximately 1 in 17 hospital and 1 in 20 community patients. They impact greatly on an individual's functional status and health related quality of life. The mainstay of pressure ulcer prevention practice is the provision of pressure redistribution support surfaces and patient repositioning. The aim of the PRESSURE 2 study is to compare the two main mattress types utilised within the NHS: high-specification foam and alternating pressure mattresses, in the prevention of pressure ulcers. METHODS/DESIGN: PRESSURE 2 is a multicentre, open-label, randomised, double triangular, group sequential, parallel group trial. A maximum of 2954 'high-risk' patients with evidence of acute illness will be randomised on a 1:1 basis to receive either a high-specification foam mattress or alternating-pressure mattress in conjunction with an electric profiling bed frame. The primary objective of the trial is to compare mattresses in terms of the time to developing a new Category 2 or above pressure ulcer by 30 days post end of treatment phase. Secondary endpoints include time to developing new Category 1 and 3 or above pressure ulcers, time to healing of pre-existing Category 2 pressure ulcers, health-related quality of life, cost-effectiveness, incidence of mattress change and safety. Validation objectives are to determine the responsiveness of the Pressure Ulcer Quality of Life-Prevention instrument and the feasibility of having a blinded endpoint assessment using photography. The trial will have a maximum of three planned analyses with unequally spaced reviews at event-driven coherent cut-points. The futility boundaries are constructed as non-binding to allow a decision for stopping early to be overruled by the Data Monitoring and Ethics Committee. DISCUSSION: The double triangular, group sequential design of the PRESSURE 2 trial will provide an efficient design through the possibility of early stopping for demonstrating either superiority, inferiority of mattresses or futility of the trial. The trial optimises the potential for producing robust clinical evidence on the effectiveness of two commonly used mattresses in clinical practice earlier than in a conventional design. TRIAL REGISTRATION: ISRCTN01151335 . Registered on 14 May 2013. Protocol version: 5.0, dated 25 September 2015 Trial sponsor: Clare Skinner, Faculty Head of Research Support, University of Leeds, Leeds, LS2 9JT; 0113 343 4897; C.E.Skinner@leeds.ac.uk. PMID- 27993146 TI - Erratum to: Rapid scoring of genes in microbial pan-genome-wide association studies with Scoary. PMID- 27993147 TI - Erratum to: Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data. PMID- 27993148 TI - Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats. AB - BACKGROUND: The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis induced acute kidney injury. METHODS: Twenty-seven Wistar albino rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 7), a LPS group that received fluid resuscitation (n = 7), and a LPS group that received blood transfusion (n = 7). The mean arterial blood pressure, renal blood flow, and renal microvascular oxygenation within the kidney cortex were recorded. Acute kidney injury was assessed using the serum creatinine levels, metabolic cost, and histopathological lesions. Nitrosative stress (expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS)) within the kidney was assessed by immunohistochemistry. Hemoglobin levels, pH, serum lactate levels, and liver enzymes were measured. RESULTS: Fluid resuscitation and blood transfusion both significantly improved the mean arterial pressure and renal blood flow after LPS infusion. Renal microvascular oxygenation, serum creatinine levels, and tubular damage significantly improved in the LPS group that received blood transfusion compared to the group that received fluids. Moreover, the renal expression of eNOS was markedly suppressed under endotoxin challenge. Blood transfusion, but not fluid resuscitation, was able to restore the renal expression of eNOS. However, there were no significant differences in lactic acidosis or liver function between the two groups. CONCLUSIONS: Blood transfusion significantly improved renal function in endotoxemic rats. The specific beneficial effect of blood transfusion on the kidney could have been mediated in part by the improvements in renal microvascular oxygenation and sepsis-induced endothelial dysfunction via the restoration of eNOS expression within the kidney. PMID- 27993149 TI - A deep sequencing reveals significant diversity among dominant variants and evolutionary dynamics of avian leukosis viruses in two infectious ecosystems. AB - BACKGROUND: As a typical retrovirus, the evolution of Avian leukosis virus subgroup J (ALV-J) in different infectious ecosystems is not characterized, what we know is there are a cloud of diverse variants, namely quasispecies with considerable genetic diversity. This study is to explore the selection of infectious ecosystems on dominant variants and their evolutionary dynamics of ALV J between DF1 cells and specific-pathogen-free (SPF) chickens. High-throughput sequencing platforms provide an approach for detecting quasispecies diversity more fully. RESULTS: An average of about 20,000 valid reads were obtained from two variable regions of gp85 gene and LTR-U3 region from each sample in different infectious ecosystems. The top 10 dominant variants among ALV-J from chicken plasmas, DF1 cells and liver tumor were completely different from each other. Also there was a difference of shannon entropy and global selection pressure values (omega) in different infectious ecosystems. In the plasmas of two chickens, a large portion of quasispecies contained a 3-peptides "LSD" repeat insertion that was only less than 0.01% in DF1 cell culture supernatants. In parallel studies, the LTR-U3 region of ALV-J from the chicken plasmas demonstrated more variants with mutations in their transcription regulatory elements than those from DF1 cells. CONCLUSIONS: Our data taken together suggest that the molecular epidemiology based on isolated ALV-J in cell culture may not represent the true evolution of virus in chicken flocks in the field. The biological significance of the "LSD" insert and mutations in LTR-U3 needs to be further studied. PMID- 27993150 TI - Erratum to: Rheumatology training experience across Europe: analysis of core competences. PMID- 27993151 TI - Exploring the importance of cancer pathways by meta-analysis of differential protein expression networks in three different cancers. AB - BACKGROUND: It is believed that all cancers occur due to the mutation or change in one or more genes. In order to investigate the significance of the biological pathways which are interrupted by these genetic mutations, we pursue an integrated analysis using multiple cancer datasets released by the International Cancer Genome Consortium (ICGC). This dataset consists of expression profiles for genes/proteins of patients receiving treatment, for three types of cancer - Head and Neck Squamous Cell Carcinoma (HNSC), Lung Adenocarcinoma (LUAD) and Kidney Renal Clear Cell Carcinoma (KIRC). We consider pathway analysis to identify all the biological pathways which are active among the patients and investigate the roles of the significant pathways using a differential network analysis of the protein expression datasets for the three cancers separately. We then integrate the pathway based results of all the three cancers which provide a more comprehensive picture of the three cancers. RESULTS: From our analysis of the protein expression data, overall, RAS and PI3K signaling pathways appear to play the most significant roles in the three cancers - Head and Neck Squamous Cell Carcinoma (HNSC), Lung Adenocarcinoma (LUAD) and Kidney Renal Clear Cell Carcinoma (KIRC). CONCLUSION: This analysis suggests that the RAS and PI3K signaling pathways are the two most important pathways in all the three cancers and should be investigated further for their potential roles in cancers. REVIEWERS: This article was reviewed by Joaquin Dopazo and Samiran Ghosh. PMID- 27993152 TI - Copy number variability of expression plasmids determined by cell sorting and Droplet Digital PCR. AB - BACKGROUND: Plasmids are widely used for molecular cloning or production of proteins in laboratory and industrial settings. Constant modification has brought forth countless plasmid vectors whose characteristics in terms of average plasmid copy number (PCN) and stability are rarely known. The crucial factor determining the PCN is the replication system; most replication systems in use today belong to a small number of different classes and are available through repositories like the Standard European Vector Architecture (SEVA). RESULTS: In this study, the PCN was determined in a set of seven SEVA-based expression plasmids only differing in the replication system. The average PCN for all constructs was determined by Droplet Digital PCR and ranged between 2 and 40 per chromosome in the host organism Escherichia coli. Furthermore, a plasmid-encoded EGFP reporter protein served as a means to assess variability in reporter gene expression on the single cell level. Only cells with one type of plasmid (RSF1010 replication system) showed a high degree of heterogeneity with a clear bimodal distribution of EGFP intensity while the others showed a normal distribution. The heterogeneous RSF1010-carrying cell population and one normally distributed population (ColE1 replication system) were further analyzed by sorting cells of sub-populations selected according to EGFP intensity. For both plasmids, low and highly fluorescent sub-populations showed a remarkable difference in PCN, ranging from 9.2 to 123.4 for ColE1 and from 0.5 to 11.8 for RSF1010, respectively. CONCLUSIONS: The average PCN determined here for a set of standardized plasmids was generally at the lower end of previously reported ranges and not related to the degree of heterogeneity. Further characterization of a heterogeneous and a homogeneous population demonstrated considerable differences in the PCN of sub populations. We therefore present direct molecular evidence that the average PCN does not represent the true number of plasmid molecules in individual cells. PMID- 27993153 TI - Hemodynamic monitoring in the era of evidence-based medicine. AB - Hemodynamic instability frequently occurs in critically ill patients. Pathophysiological rationale suggests that hemodynamic monitoring (HM) may identify the presence and causes of hemodynamic instability and therefore may allow targeting therapeutic approaches. However, there is a discrepancy between this pathophysiological rationale to use HM and a paucity of formal evidence (as defined by the strict criteria of evidence-based medicine (EBM)) for its use. In this editorial, we discuss that this paucity of formal evidence that HM can improve patient outcome may be explained by both the shortcomings of the EBM methodology in the field of intensive care medicine and the shortcomings of HM itself. PMID- 27993154 TI - Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(r)): preclinical and clinical trial in osteoarthritis of the knee joint. AB - BACKGROUND: Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in the knee joint. METHODS: The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(r)) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosaminoglycan (sGAG). The mono-iodoacetate (MIA)-induced preclinical model of OA has been used to demonstrate pain reduction and cartilage formation. In the clinical study, 60 OA patients were randomized to receive different doses of cells (25, 50, 75, or 150 million cells) or placebo. Stempeucel(r) was administered by intra-articular (IA) injection into the knee joint, followed by 2 ml hyaluronic acid (20 mg). Subjective evaluations-visual analog scale (VAS) for pain, intermittent and constant osteoarthritis pain (ICOAP), and Western Ontario and McMaster Universities Osteoarthritis (WOMAC-OA) index-were performed at baseline and at 1, 3, 6, and 12 months of follow-up. Magnetic resonance imaging of the knee was performed at baseline, and at 6 and 12 months follow-up for cartilage evaluation. RESULTS: Stempeucel(r) differentiated into the chondrogenic lineage in vitro with downregulation of Sox9 and upregulation of Col2A genes. Furthermore, Stempeucel(r) differentiated into chondrocytes and synthesized a significant amount of sGAG (30 +/- 1.8 MUg/MUg GAG/DNA). In the preclinical model of OA, Stempeucel(r) reduced pain significantly and also repaired damaged articular cartilage in rats. In the clinical study, IA administration of Stempeucel(r) was safe, and a trend towards improvement was seen in the 25 million-cell dose group in all subjective parameters (VAS, ICOAP, andWOMAC-OA scores), although this was not statistically significant when compared to placebo. Adverse events were predominant in the higher dose groups (50, 75, and 150 million cells). Knee pain and swelling were the most common adverse events. The whole-organ magnetic resonance imaging score of the knee did not reveal any difference from baseline and the placebo group. CONCLUSION: Intra-articular administration of Stempeucel(r) is safe. A twenty-five-million-cell dose may be the most effective among the doses tested for pain reduction. Clinical studies with a larger patient population are required to demonstrate a robust therapeutic efficacy of Stempeucel(r) in OA. TRIAL REGISTRATION: Clinicaltrials.gov NCT01453738 . Registered 13 October 2011. PMID- 27993156 TI - Sensitivity, specificity, and reproducibility of RNA-Seq differential expression calls. AB - BACKGROUND: The MAQC/SEQC consortium has recently compiled a key benchmark that can serve for testing the latest developments in analysis tools for microarray and RNA-seq expression profiling. Such objective benchmarks are required for basic and applied research, and can be critical for clinical and regulatory outcomes. Going beyond the first comparisons presented in the original SEQC study, we here present extended benchmarks including effect strengths typical of common experiments. RESULTS: With artefacts removed by factor analysis and additional filters, for genome scale surveys, the reproducibility of differential expression calls typically exceed 80% for all tool combinations examined. This directly reflects the robustness of results and reproducibility across different studies. Similar improvements are observed for the top ranked candidates with the strongest relative expression change, although here some tools clearly perform better than others, with typical reproducibility ranging from 60 to 93%. CONCLUSIONS: In our benchmark of alternative tools for RNA-seq data analysis we demonstrated the benefits that can be gained by analysing results in the context of other experiments employing a reference standard sample. This allowed the computational identification and removal of hidden confounders, for instance, by factor analysis. In itself, this already substantially improved the empirical False Discovery Rate (eFDR) without changing the overall landscape of sensitivity. Further filtering of false positives, however, is required to obtain acceptable eFDR levels. Appropriate filters noticeably improved agreement of differentially expressed genes both across sites and between alternative differential expression analysis pipelines. REVIEWERS: An extended abstract of this research paper was selected for the CAMDA Satellite Meeting to ISMB 2015 by the CAMDA Programme Committee. The full research paper then underwent one round of Open Peer Review under a responsible CAMDA Programme Committee member, Lan Hu, PhD (Bio-Rad Laboratories, Digital Biology Center-Cambridge). Open Peer Review was provided by Charlotte Soneson, PhD (University of Zurich) and Michal Okoniewski, PhD (ETH Zurich). The Reviewer Comments section shows the full reviews and author responses. PMID- 27993155 TI - The genome of the Gulf pipefish enables understanding of evolutionary innovations. AB - BACKGROUND: Evolutionary origins of derived morphologies ultimately stem from changes in protein structure, gene regulation, and gene content. A well assembled, annotated reference genome is a central resource for pursuing these molecular phenomena underlying phenotypic evolution. We explored the genome of the Gulf pipefish (Syngnathus scovelli), which belongs to family Syngnathidae (pipefishes, seahorses, and seadragons). These fishes have dramatically derived bodies and a remarkable novelty among vertebrates, the male brood pouch. RESULTS: We produce a reference genome, condensed into chromosomes, for the Gulf pipefish. Gene losses and other changes have occurred in pipefish hox and dlx clusters and in the tbx and pitx gene families, candidate mechanisms for the evolution of syngnathid traits, including an elongated axis and the loss of ribs, pelvic fins, and teeth. We measure gene expression changes in pregnant versus non-pregnant brood pouch tissue and characterize the genomic organization of duplicated metalloprotease genes (patristacins) recruited into the function of this novel structure. Phylogenetic inference using ultraconserved sequences provides an alternative hypothesis for the relationship between orders Syngnathiformes and Scombriformes. Comparisons of chromosome structure among percomorphs show that chromosome number in a pipefish ancestor became reduced via chromosomal fusions. CONCLUSIONS: The collected findings from this first syngnathid reference genome open a window into the genomic underpinnings of highly derived morphologies, demonstrating that de novo production of high quality and useful reference genomes is within reach of even small research groups. PMID- 27993157 TI - Early-phase cumulative hypotension duration and severe-stage progression in oliguric acute kidney injury with and without sepsis: an observational study. AB - BACKGROUND: Managing blood pressure in patients with acute kidney injury (AKI) could effectively prevent severe-stage progression. However, the effect of hypotension duration in the early phase of AKI remains poorly understood. This study investigated the association between early-phase cumulative duration of hypotension below threshold mean arterial pressure (MAP) and severe-stage progression of oliguric AKI in critically ill patients, and assessed the difference in association with presence of sepsis. METHODS: This was a single center, observational study conducted in the ICU of a university hospital in Japan. We examined data from adults with oliguric AKI who were admitted to the ICU during 2010-2014 and stayed in the ICU for >=24 h after diagnosis of stage-1 oliguric AKI defined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. The primary outcome was the progression from stage-1 oliguric AKI to stage-3 oliguric AKI (progression to oligoanuria and use of renal replacement therapy) according to the KDIGO criteria. During the first 6 h after oliguric AKI, we analyzed the association between cumulative time the patient had below threshold MAP (65, 70, and 75 mm Hg) and progression to stage-3. RESULTS: Among 538 patients with oliguric AKI, progression to stage-3 increased as the time spent below any threshold MAP was elongated. In the multivariable analysis of all patients, longer hypotension time (3-6 h) showed significant association with stage-3 progression for the time spent below MAP of 65 mm Hg (adjusted odds ratio (OR) 3.73, 95% confidence interval (CI) 1.53-9.09, p = 0.004), but the association was attenuated for the threshold MAP of 70 mm Hg (adjusted OR 2.35, 95% CI 0.96-5.78, p = 0.063) and 75 mm Hg (adjusted OR 1.92, 95% CI 0.72-5.15, p = 0.200). Longer hypotension time with the thresholds of 65 and 70 mm Hg was significantly associated with the risk of stage-3 progression in patients without sepsis, whereas the association was weak and not significant in patients with sepsis. CONCLUSIONS: Even in a short time frame (6 h) after oliguric AKI diagnosis, early-phase cumulative hypotension duration was associated with progression to stage-3 oliguric AKI, especially in patients without sepsis. PMID- 27993158 TI - Inter-platform concordance of gene expression data for the prediction of chemical mode of action. AB - BACKGROUND: It is interesting to study the consistency of outcomes arising from two genomic platforms: Microarray and RNAseq, which are established on fundamentally different technologies. This topic has been frequently discussed from the prospect of comparing differentially expressed genes (DEGs). In this study, we explore the inter-platform concordance between microarray and RNASeq in their ability to classify samples based on genomic information. We use a set of 7 standard multi-class classifiers and an adaptive ensemble classifier developed around them to predict Chemical Modes of Actions (MOA) of data profiled by microarray and RNASeq platforms from Rat Liver samples exposed to a variety of chemical compounds. We study the concordance between microarray and RNASeq data in various forms, based on classifier's performance between two platforms. RESULTS: Using an ensemble classifier we observe improved prediction performance compared to a set of standard classifiers. We discover a clear concordance between each individual classifier's performances in two genomic platforms. Additionally, we identify a set of important genes those specifies MOAs, by focusing on their impact on the classification and later we find that some of these top genes have direct associations with the presence of toxic compounds in the liver. CONCLUSION: Overall there appears to be fair amount of concordance between the two platforms as far as classification is concerned. We observe widely different classification performances among individual classifiers, which reflect the unreliability of restricting to a single classifier in the case of high dimensional classification problems. REVIEWERS: An extended abstract of this research paper was selected for the CAMDA Satellite Meeting to ISMB 2015 by the CAMDA Programme Committee. The full research paper then underwent two rounds of Open Peer Review under a responsible CAMDA Programme Committee member, Lan Hu, PhD (Bio-Rad Laboratories, Digital Biology Center-Cambridge). Open Peer Review was provided by Yiyi Liu and Partha Dey. The Reviewer Comments section shows the full reviews and author responses. PMID- 27993159 TI - Erratum to: Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. PMID- 27993162 TI - TET enzymes: double agents in the transposable element-host genome conflict. AB - The mouse genome is replete with retrotransposon sequences, from evolutionarily young elements with mutagenic potential that must be controlled, to inactive molecular fossils whose sequences can be domesticated over evolutionary time to benefit the host genome. In an exciting new study, de la Rica and colleagues have uncovered a complex relationship between ten-eleven translocation (TET) proteins and retrotransposons in mouse embryonic stem cells (ESCs), implicating TETs as enhancers in the exaptation and function of retroelement sequences. Furthermore, they have demonstrated that active demethylation of retrotransposons does not correlate with their increased expression in ESCs, calling into question long held assumptions regarding the importance of DNA demethylation for retrotransposon expression, and revealing novel epigenetic players in retrotransposon control.Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1096-8. PMID- 27993164 TI - Fostering Effective Early Learning (FEEL) through a professional development programme for early childhood educators to improve professional practice and child outcomes in the year before formal schooling: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: A substantial research base documents the benefits of attendance at high-quality early childhood education and care (ECEC) for positive behavioural and learning outcomes. Research has also found that the quality of many young children's experiences and opportunities in ECEC depends on the skills, dispositions and understandings of the early childhood adult educators. Increasingly, research has shown that the quality of children's interactions with educators and their peers, more than any other programme feature, influence what children learn and how they feel about learning. Hence, we sought to investigate the extent to which evidence-based professional development (PD) - focussed on promoting sustained shared thinking through quality interactions - could improve the quality of ECEC and, as a consequence, child outcomes. METHODS/DESIGN: The Fostering Effective Early Learning (FEEL) study is a cluster randomised controlled trial for evaluating the benefits of a professional development (PD) programme for early childhood educators, compared with no extra PD. Ninety long day care and preschool centres in New South Wales, Australia, will be selected to ensure representation across National Quality Standards (NQS) ratings, location, centre type and socioeconomic areas. Participating centres will be randomly allocated to one of two groups, stratified by centre type and NQS rating: (1) an intervention group (45 centres) receiving a PD intervention or (2) a control group (45 centres) that continues engaging in typical classroom practice. Randomisation to these groups will occur after the collection of baseline environmental quality ratings. Primary outcomes, at the child level, will be two measures of language development: verbal comprehension and expressive vocabulary. Secondary outcomes at the child level will be measures of early numeracy, social development and self-regulation. Secondary outcomes at the ECEC room level will be measures of environmental quality derived from full-day observations. In all cases, data collectors will be blinded to group allocation. DISCUSSION: This is the first randomised controlled trial of a new approach to PD, which is focussed on activities previously found to be influential in children's early language, numeracy, social and self-regulatory development. Results should inform practitioners, policy-makers and families of the value of specific professional development for early childhood educators. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN) identifier ACTRN12616000536460 . Registered on 27 April 2016. This trial was retrospectively registered, given the first participant (centre) had been enrolled at the time of registration. PMID- 27993161 TI - Circulating cell-free DNA-based epigenetic assay can detect early breast cancer. AB - BACKGROUND: Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology. METHODS: Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples. RESULTS: The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively. CONCLUSION: Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC. PMID- 27993165 TI - Isolation and characterization of native Bacillus thuringiensis strains from Saudi Arabia with enhanced larvicidal toxicity against the mosquito vector Anopheles gambiae (s.l.). AB - BACKGROUND: Worldwide, mosquito vectors are transmitting several etiological agents of important human diseases, including malaria, causing millions of deaths every year. In Saudi Arabia, as elsewhere, vector-control is based mostly on chemical insecticides which may be toxic and cause environmental deprivation. Here, to support the development of bio-pesticide alternatives, a study was conducted to identify native Bacillus thuringiensis (Bt) isolates with improved toxicity against the malaria vector, Anopheles gambiae (s.l.). METHODS: Sixty eight Bt isolates were obtained from 300 soil and other samples collected from 16 sites across Saudi Arabia. Bt identification was based on morphological characteristics of colonies, shape of parasporal crystals and biochemical profiles. After characterization of their mosquitocidal activity, larvicidal strains were described through 16S ribosomal DNA gene sequencing, cry, cyt and chi genes PCR-amplification profiles, and SDS-PAGE protein analyses. RESULTS: Spherical Bt crystals were predominant amongst the 68 isolates (34%), while irregular, bi-pyramidal and spore-attached crystals were found in 32, 13 and 21% of strains, respectively. LC50 and LC90 bioassays showed that 23/68 isolates were larvicidal, with distinct biochemical activity profiles compared to non larvicidal Bt strains. Eight larvicidal strains showed larvicidal activity up to 3.4-fold higher (LC50 range: 3.90-7.40 MUg/ml) than the reference Bti-H14 strain (LC50 = 13.33 MUg/ml). Of these, 6 strains had cry and cyt gene profiles similar to Bti-H14 (cry4Aa, cry4Ba, cry10, cry11, cyt1Aa, cyt1Ab, cyt2Aa). The seventh strain (Bt63) displaying the highest larvicidal activity (LC50 = 3.90 MUg/ml) missed the cry4Aa and cyt1Ab genes and had SDS-PAGE protein profiles and spore/crystal sizes distinct from Bti-H14. The eight strain (Bt55) with LC50 of 4.11MUg/ml had cry and cyt gene profiles similar to Bti-H14 but gave a chi gene PCR product size of 2027bp. No strains harbouring cry2, cry17 + 27, cry24 + 40, cry25, cry29, cry30, or cyt2Ba were detected. CONCLUSION: This study represents the first report of several Saudi indigenous Bt strains with significantly higher larvicidal efficacy against An. gambiae than the reference Bti-H14 strain. The very high toxicity of the Bt63 strain, combined with distinct cry and cyt genes and SDS-PAGE-protein profiles makes it a promising candidate for future applications in mosquito bio-control. PMID- 27993160 TI - Erratum to: An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia. PMID- 27993163 TI - Aiming to Improve Readmissions Through InteGrated Hospital Transitions (AIRTIGHT): study protocol for a randomized controlled trial. AB - BACKGROUND: Hospital readmissions remain highly prevalent despite being the target of policies and financial penalties. Evidence comparing the effectiveness and costs of interventions to reduce readmissions is lacking, leaving healthcare systems with little guidance on how to improve quality and avoid costly penalties. Effective interventions likely need to bridge inpatient and outpatient settings, incorporate information technology, and use dedicated providers. Such complex innovations will require rigorous evaluation. The framework of quality improvement research provides an approach that both improves care locally and contributes to closing the current knowledge gaps for readmissions. In this trial, we will study a comprehensive intervention that incorporates these recommendations into an integrated practice unit, called transition services, with an aim of reducing 30-day readmission rates. METHODS/DESIGN: We describe a nonblinded, pragmatic, controlled trial with two parallel groups comprising an evaluation of the effect of referral to a provider-led integrated practice unit, inclusive of comprehensive multidisciplinary care, dedicated paramedicine providers, and virtual visits, on 30-day readmission rates for high-risk hospitalized patients. An automated risk-scoring system will randomly generate referrals to either transition services or usual care for 1520 hospitalized patients who score as high-risk for readmission. Transition services will then engage with patients in the hospital setting using a patient navigator and provide bridging outpatient services for the 30 days following discharge. All outcome data are retrieved electronically from administrative medical records. After reapplication of inclusion and exclusion criteria at the time of hospital discharge, analyses will follow the intention-to-treat principle such that patients will be analyzed on the basis of the referral group to which they were initially randomized. DISCUSSION: The hospital transition program under study is complex and integrates the latest recommendations for readmission reduction strategies. As healthcare systems innovate to address readmissions through such complex interventions, there is significant benefit for stakeholders to have a clear understanding of the potential reach, cost, and real-world effectiveness. The pragmatic methods described here provide a template for conducting quality improvement research that fits seamlessly into existing care delivery and improvement efforts, leading to better-informed strategic decisions and the investments necessary to transform care and value for patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02763202 . Registered 3 March 2016 (retrospectively registered). PMID- 27993167 TI - Prognostic value of cross-omics screening for kidney clear cell renal cancer survival. AB - BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is a type of cancer that is resistant to chemotherapy and radiotherapy and has limited treatment possibilities. Large-scale molecular profiling of KIRC tumors offers a great potential to uncover the genetic and epigenetic changes underlying this disease and to improve the clinical management of KIRC patients. However, in practice the clinicians and researchers typically focus on single-platform molecular data or on a small set of genes. Using molecular and clinical data of over 500 patients, we have systematically studied which type of molecular data is the most informative in predicting the clinical outcome of KIRC patients, as a standalone platform and integrated with clinical data. RESULTS: We applied different computational approaches to preselect on survival-predictive genomic markers and evaluated the usability of mRNA/miRNA/protein expression data, copy number variation (CNV) data and DNA methylation data in predicting survival of KIRC patients. Our analyses show that expression and methylation data have statistically significant predictive powers compared to a random guess, but do not perform better than predictions on clinical data alone. However, the integration of molecular data with clinical variables resulted in improved predictions. We present a set of survival associated genomic loci that could potentially be employed as clinically useful biomarkers. CONCLUSIONS: Our study evaluates the survival prediction of different large-scale molecular data of KIRC patients and describes the prognostic relevance of such data over clinical variable-only models. It also demonstrates the survival prognostic importance of methylation alterations in KIRC tumors and points to the potential of epigenetic modulators in KIRC treatment. REVIEWERS: An extended abstract of this research paper was selected for the CAMDA Satellite Meeting to ISMB 2015 by the CAMDA Programme Committee. The full research paper then underwent one round of Open Peer Review under a responsible CAMDA Programme Committee member, Djork-Arne Clevert, PhD (Bayer AG, Germany). Open Peer Review was provided by Martin Otava, PhD (Janssen Pharmaceutica, Belgium) and Hendrik Luuk, PhD (The Centre for Disease Models and Biomedical Imaging, University of Tartu, Estonia). The Reviewer comments section shows the full reviews and author responses. PMID- 27993166 TI - The effect of community groups and mobile phone messages on the prevention and control of diabetes in rural Bangladesh: study protocol for a three-arm cluster randomised controlled trial. AB - BACKGROUND: Increasing rates of type 2 diabetes mellitus place a substantial burden on health care services, communities, families and individuals living with the disease or at risk of developing it. Estimates of the combined prevalence of intermediate hyperglycaemia and diabetes in Bangladesh vary, and can be as high as 30% of the adult population. Despite such high prevalence, awareness and control of diabetes and its risk factors are limited. Prevention and control of diabetes and its complications demand increased awareness and action of individuals and communities, with positive influences on behaviours and lifestyle choices. In this study, we will test the effect of two different interventions on diabetes occurrence and its risk factors in rural Bangladesh. METHODS/DESIGN: A three-arm cluster randomised controlled trial of mobile health (mHealth) and participatory community group interventions will be conducted in four rural upazillas in Faridpur District, Bangladesh. Ninety-six clusters (villages) will be randomised to receive either the mHealth intervention or the participatory community group intervention, or be assigned to the control arm. In the mHealth arm, enrolled individuals will receive twice-weekly voice messages sent to their mobile phone about prevention and control of diabetes. In the participatory community group arm, facilitators will initiate a series of monthly group meetings for men and women, progressing through a Participatory Learning and Action cycle whereby group members and communities identify, prioritise and tackle problems associated with diabetes and the risk of developing diabetes. Both interventions will run for 18 months. The primary outcomes of the combined prevalence of intermediate hyperglycaemia and diabetes and the cumulative 2-year incidence of diabetes among individuals identified as having intermediate hyperglycaemia at baseline will be evaluated through baseline and endline sample surveys of permanent residents aged 30 years or older in each of the study clusters. Data on blood glucose level, blood pressure, body mass index and hip-to waist ratio will be gathered through physical measurements by trained fieldworkers. Demographic and socioeconomic data, as well as data on knowledge of diabetes, chronic disease risk factor prevalence and quality of life, will be gathered through interviews with sampled respondents. DISCUSSION: This study will increase our understanding of diabetes and other non-communicable disease burdens and risk factors in rural Bangladesh. By documenting and evaluating the delivery, impact and cost-effectiveness of participatory community groups and mobile phone voice messaging, study findings will provide evidence on how population-level strategies of community mobilisation and mHealth can be implemented to prevent and control noncommunicable diseases and risk factors in this population. TRIAL REGISTRATION: ISRCTN41083256 . Registered on 30 Mar 2016 (Retrospectively Registered). TRIAL ACRONYM: D-Magic: Diabetes Mellitus - Action through Groups or mobile Information for better Control. PMID- 27993169 TI - The incidence of training responsiveness to cardiorespiratory fitness and cardiometabolic measurements following individualized and standardized exercise prescription: study protocol for a randomized controlled trial. AB - BACKGROUND: There is individual variability to cardiorespiratory fitness (CRF) training, but the underlying cause is not well understood. Traditionally, a standardized approach to exercise prescription has utilized relative percentages of maximal heart rate, heart rate reserve (HRR), maximal oxygen uptake (VO2max), or VO2 reserve to establish exercise intensity. However, this model fails to take into consideration individual metabolic responses to exercise and may attribute to the variability in training responses. It has been proposed that an individualized approach would take into consideration metabolic responses to exercises to increase responsiveness to training. METHODS: In this randomized control trial, participants will undergo a 12-week exercise intervention using individualized (ventilatory thresholds) and standardized (HRR) methods to prescribe CRF training intensity. Following the intervention, participants will be categorized as responders or non-responders based on changes in maximal aerobic abilities. Participants who are non-responders will complete a second 12 week intervention in a crossover design to determine whether they can become responders with a differing exercise prescription. There are four main research outcomes: (1) determine the cohort-specific technical error to use in the categorization of response rate; (2) determine if an individualized intensity prescription is superior to a standard approach in regards to VO2max and cardiometabolic risk factors; (3) investigate the time course changes throughout 12 weeks of CRF training between the two intervention groups; and (4) determine if non-responders can become responders if the exercise prescription is modified. DISCUSSION: The findings from this research will provide evidence on the effectiveness of individualized exercise prescription related to training responsiveness of VO2max and cardiometabolic risk factors compared to a standardized approach and further our understanding of individual exercise responses. If the individualized approach proposed is deemed effective, it may change the way exercise specialists prescribe exercise intensity to enhance training responsiveness. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02868710 . Registered on 15 August 2016. PMID- 27993168 TI - Mammographic density assessed on paired raw and processed digital images and on paired screen-film and digital images across three mammography systems. AB - BACKGROUND: Inter-women and intra-women comparisons of mammographic density (MD) are needed in research, clinical and screening applications; however, MD measurements are influenced by mammography modality (screen film/digital) and digital image format (raw/processed). We aimed to examine differences in MD assessed on these image types. METHODS: We obtained 1294 pairs of images saved in both raw and processed formats from Hologic and General Electric (GE) direct digital systems and a Fuji computed radiography (CR) system, and 128 screen-film and processed CR-digital pairs from consecutive screening rounds. Four readers performed Cumulus-based MD measurements (n = 3441), with each image pair read by the same reader. Multi-level models of square-root percent MD were fitted, with a random intercept for woman, to estimate processed-raw MD differences. RESULTS: Breast area did not differ in processed images compared with that in raw images, but the percent MD was higher, due to a larger dense area (median 28.5 and 25.4 cm2 respectively, mean ?dense area difference 0.44 cm (95% CI: 0.36, 0.52)). This difference in ?dense area was significant for direct digital systems (Hologic 0.50 cm (95% CI: 0.39, 0.61), GE 0.56 cm (95% CI: 0.42, 0.69)) but not for Fuji CR (0.06 cm (95% CI: -0.10, 0.23)). Additionally, within each system, reader specific differences varied in magnitude and direction (p < 0.001). Conversion equations revealed differences converged to zero with increasing dense area. MD differences between screen-film and processed digital on the subsequent screening round were consistent with expected time-related MD declines. CONCLUSIONS: MD was slightly higher when measured on processed than on raw direct digital mammograms. Comparisons of MD on these image formats should ideally control for this non constant and reader-specific difference. PMID- 27993171 TI - Spatial and space-time distribution of Plasmodium vivax and Plasmodium falciparum malaria in China, 2005-2014. AB - BACKGROUND: Despite the declining burden of malaria in China, the disease remains a significant public health problem with periodic outbreaks and spatial variation across the country. A better understanding of the spatial and temporal characteristics of malaria is essential for consolidating the disease control and elimination programme. This study aims to understand the spatial and spatiotemporal distribution of Plasmodium vivax and Plasmodium falciparum malaria in China during 2005-2009. METHODS: Global Moran's I statistics was used to detect a spatial distribution of local P. falciparum and P. vivax malaria at the county level. Spatial and space-time scan statistics were applied to detect spatial and spatiotemporal clusters, respectively. RESULTS: Both P. vivax and P. falciparum malaria showed spatial autocorrelation. The most likely spatial cluster of P. vivax was detected in northern Anhui province between 2005 and 2009, and western Yunnan province between 2010 and 2014. For P. falciparum, the clusters included several counties of western Yunnan province from 2005 to 2011, Guangxi from 2012 to 2013, and Anhui in 2014. The most likely space-time clusters of P. vivax malaria and P. falciparum malaria were detected in northern Anhui province and western Yunnan province, respectively, during 2005-2009. CONCLUSION: The spatial and space-time cluster analysis identified high-risk areas and periods for both P. vivax and P. falciparum malaria. Both malaria types showed significant spatial and spatiotemporal variations. Contrary to P. vivax, the high risk areas for P. falciparum malaria shifted from the west to the east of China. Further studies are required to examine the spatial changes in risk of malaria transmission and identify the underlying causes of elevated risk in the high-risk areas. PMID- 27993172 TI - Immune reconstitution 20 years after treatment with alemtuzumab in a rheumatoid arthritis cohort: implications for lymphocyte depleting therapies. AB - BACKGROUND: Alemtuzumab, an anti-CD52 monoclonal antibody, was administered to patients with RA between 1991 and 1994. We have followed a cohort of recipients since that time and previously reported significant delays in immune reconstitution. Here we report >20 years of follow-up data from this unique cohort. METHOD: Surviving alemtuzumab recipients were age, sex and disease duration matched with RA controls. Updated mortality and morbidity data were collected for alemtuzumab recipients. For both groups antigenic responses were assessed following influenza, Pneumovax II and combined diphtheria/tetanus/poliovirus vaccines. Circulating cytokines and lymphocyte subsets were also quantified. RESULTS: Of 16 surviving alemtuzumab recipients, 13 were recruited: 9 recipients underwent a full clinical assessment and 4 had case notes review only. Since our last review 10 patients had died from causes of death consistent with long-standing RA, and no suggestion of compromised immune function. Compared with controls the alemtuzumab cohort had significantly reduced CD4+ and CD8+ central memory T-cells, CD5+ B cells, naive B cells and CD19+CD24hiCD38hi transitional (putative regulatory) B cells. Nonetheless vaccine responses were comparable between groups. There were significantly higher serum IL-15 and IFN-gamma levels in the alemtuzumab cohort. IL-15 levels were inversely associated with CD4+ total memory and central memory T cells. CONCLUSION: After 20 years the immune system of alemtuzumab recipients continues to show differences from disease controls. Nonetheless mortality and morbidity data, alongside vaccination responses, do not suggest clinical immune compromise. As lymphodepleting therapies, including alemtuzumab, continue to be administered this work is important with regard to long-term immune monitoring and stages of immune recovery. PMID- 27993173 TI - The immunological characteristics and probiotic function of recombinant Bacillus subtilis spore expressing Clonorchis sinensis cysteine protease. AB - BACKGROUND: Clonorchiasis, a food-borne zoonosis, is caused by Clonorchis sinensis. The intestinal tract and bile ducts are crucial places for C. sinensis metacercariae to develop into adult worms. The endospore of Bacillus subtilis is an ideal oral immunization vehicle for delivery of heterologous antigens to intestine. Cysteine protease of C. sinensis (CsCP) is an endogenous key component in the excystment of metacercariae and other physiological or pathological processes. METHODS: We constructed a fusion gene of CotC (a coat protein)-CsCP and obtained B. subtilis spores with recombinant plasmid of pEB03-CotC-CsCP (B.s CotC-CsCP). CotC-CsCP expressed on spores' surface was detected by Western blotting and immunofluorescence. Immunological characteristics of recombinant spore coat protein were evaluated in a mouse model. The levels of CsCP-specific antibodies were detected by ELISA. Effects of recombinant spores on mouse intestine were evaluated by histological staining. The activities of biochemical enzymes in serum were assayed by microplate. Liver sections of infected mice were evaluated by Ishak score after Masson's trichrome. RESULTS: The B.s-CotC-CsCP spores displayed CsCP on their coat. Specific IgG and isotypes were significantly induced by coat proteins of B.s-CotC-CsCP spores after subcutaneous immunization. IgA levels in intestinal mucus and bile of B.s-CotC-CsCP orally treated mice significantly increased. Additionally, more IgA-secreting cells were observed in enteraden and lamina propria regions of the mouse jejunum, and an increased amount of acidic mucins in intestines were also observed. There were no significant differences in enzyme levels of serum among groups. No inflammatory injury was observed in the intestinal tissues of each group. The degree of liver fibrosis was significantly reduced after oral immunization with B.s-CotC-CsCP spores. CONCLUSIONS: Bacillus subtilis spores maintained the original excellent immunogenicity of CsCP expressed on their surface. Both local and systemic specific immune responses were elicited by oral administration of B.s-CotC-CsCP spores. The spores effectively promoted intestinal health by inducing secretion of acidic mucins, with no other side effects to the liver or intestine. Oral administration of spores expressing CsCP could provide effective protection against C. sinensis. This study may be a cornerstone for development of antiparasitic agents or vaccines against clonorchiasis based on B. subtilis spore expressing CsCP on the surface. PMID- 27993175 TI - Carbohydrate intake and resistance-based exercise: are current recommendations reflective of actual need? AB - Substantial research has been completed examining the impact of carbohydrate (CHO) intake on endurance exercise, whereas its role in resistance-based exercise performance, adaptation and cell signalling has yet to be fully characterised. This empirical shortcoming has precluded the ability to establish specific CHO recommendations for resistance exercise. This results in recommendations largely stemming from findings based on endurance exercise and/or anecdotal evidence despite the distinct energetic demands and molecular responses mediating adaptation from endurance- and resistance-based exercise. Moreover, the topic of CHO and exercise has become one of polarising nature with divergent views - some substantiated, others lacking evidence. Current literature suggests a moderately high daily CHO intake (3-7 g/kg per d) for resistance training, which is thought to prevent glycogen depletion and facilitate performance and adaptation. However, contemporary investigation, along with an emerging understanding of the molecular underpinnings of resistance exercise adaptation, may suggest that such an intake may not be necessary. In addition to the low likelihood of true glycogen depletion occurring in response to resistance exercise, a diet restrictive in CHO may not be detrimental to acute resistance exercise performance or the cellular signalling activity responsible for adaptation, even when muscle glycogen stores are reduced. Current evidence suggests that signalling of the mammalian target of rapamycin complex 1, the key regulatory kinase for gene translation (protein synthesis), is unaffected by CHO restriction or low muscular glycogen concentrations. Such findings may call into question the current view and subsequent recommendations of CHO intake with regard to resistance-based exercise. PMID- 27993170 TI - Choosing the right cell line for renal cell cancer research. AB - Cell lines are still a tool of choice for many fields of biomedical research, including oncology. Although cancer is a very complex disease, many discoveries have been made using monocultures of established cell lines. Therefore, the proper use of in vitro models is crucial to enhance our understanding of cancer. Therapeutics against renal cell cancer (RCC) are also screened with the use of cell lines. Multiple RCC in vitro cultures are available, allowing in vivo heterogeneity in the laboratory, but at the same time, these can be a source of errors. In this review, we tried to sum up the data on the RCC cell lines used currently. An increasing amount of data on RCC shed new light on the molecular background of the disease; however, it revealed how much still needs to be done. As new types of RCC are being distinguished, novel cell lines and the re exploration of old ones seems to be indispensable to create effective in vitro tools for drug screening and more. PMID- 27993176 TI - A Canadian Winter Indirectly Inactivates a Deep Brain Stimulation System. PMID- 27993178 TI - Beneficial effects of enrichment of chicken meat with n-3 polyunsaturated fatty acids, vitamin E and selenium on health parameters: a study on male rats. AB - Consumption of chicken meat enriched with bioactive compounds such as n-3 polyunsaturated fatty acids (PUFAn-3), vitamin E (vE) and selenium (Se) can help prevent many diseases and can be used to deliver those substances to humans. This might be of importance as chicken meat consumption is increasing worldwide. The effects of enriching chicken meat with PUFAn-3, vE and Se through dietary interventions were studied in rats. Four groups of Ross 308 female broilers from day 22 to day 35 of age were fed control diet (L) that contained lard and 80 mg vE and 0.3 mg Se/kg, or diets that contained rape seeds and fish oil with the same level of Se and vE as in the control diet, the same level of Se as in the control and 150 mg vE/kg, or 150 mg of vE and 0.7 mg Se/kg. Broiler carcasses were boiled, deboned, lyophilized and pooled by group. Boiled edible components of chicken carcass (BECC) were included (240 g/kg) in the diets fed to four groups of ten 10-week-old Wistar male rats for 8 weeks. Inclusion of BECCs modulated dietary fatty acid profile in the rat diets. Feeding these diets did not influence parameters related to growth or relative weights of internal organs in the rats. Feeding BECCs with lower PUFAn-6/n-3 decreased the n-6/n-3 ratio in the rat brain and liver, and increased the proportion of docosahexaenoic acid in the brain lipids. Liver cholesterol level was similar among the experimental groups, whereas the concentration of vE in the liver of rats fed BECC with increased vE levels was higher than that in the rats fed BECC with the basal vE level. Haematological and biochemical parameters in blood were within the normal range for rats, but a few rats showed a tendency towards increased levels because of the higher vE and Se level. The health-promoting effect of feeding rats PUFAn 3 enriched BECC was more pronounced when an increased dietary level of vE was used, but the increased level of Se did not provide the rats with additional benefits. Thus, the findings indicate that BECC enriched with PUFAn-3 and vE by a dietary intervention is a functional food with great potential of implementation. PMID- 27993174 TI - Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities. AB - This era of groundbreaking scientific developments in high-resolution, high throughput technologies is allowing the cost-effective collection and analysis of huge, disparate datasets on individual health. Proper data mining and translation of the vast datasets into clinically actionable knowledge will require the application of clinical bioinformatics. These developments have triggered multiple national initiatives in precision medicine-a data-driven approach centering on the individual. However, clinical implementation of precision medicine poses numerous challenges. Foremost, precision medicine needs to be contrasted with the powerful and widely used practice of evidence-based medicine, which is informed by meta-analyses or group-centered studies from which mean recommendations are derived. This "one size fits all" approach can provide inadequate solutions for outliers. Such outliers, which are far from an oddity as all of us fall into this category for some traits, can be better managed using precision medicine. Here, we argue that it is necessary and possible to bridge between precision medicine and evidence-based medicine. This will require worldwide and responsible data sharing, as well as regularly updated training programs. We also discuss the challenges and opportunities for achieving clinical utility in precision medicine. We project that, through collection, analyses and sharing of standardized medically relevant data globally, evidence-based precision medicine will shift progressively from therapy to prevention, thus leading eventually to improved, clinician-to-patient communication, citizen centered healthcare and sustained well-being. PMID- 27993179 TI - Effect of threonine deficiency on intestinal integrity and immune response to feed withdrawal combined with coccidial vaccine challenge in broiler chicks. AB - For this study, threonine (Thr) deficiency was hypothesised to exacerbate the intestinal damage induced by feed withdrawal with coccidial infection because of its high obligatory requirement by the gut; two dietary Thr treatments (0.49 and 0.90 %) were applied to chicks from 0 to 21 d of age. At 13 d of age, feed was withdrawn for 24 h from one-half of birds of each dietary treatment with subsequent gavage of a 25* dose of coccidial vaccine. Overall, there were four treatments with eight replicate cages per treatment. Under combined challenge, birds fed the Thr-deficient diet had 38 % lower 13-21-d body weight gain (P<=0.05) compared with birds fed the Thr-control diet. At 21 d, the challenged group fed low Thr had higher number of oocysts (+40 %, P=0.03) and lower crypt depth (-31 %, P0.05). Overall, Thr deficiency worsened the detrimental effects of combined feed withdrawal and coccidial infection on growth performance and oocyst shedding by impairing intestinal morphology, barrier function, lymphocyte profiles and their cytokine expressions. PMID- 27993177 TI - Diets high in resistant starch increase plasma levels of trimethylamine-N-oxide, a gut microbiome metabolite associated with CVD risk. AB - Production of trimethylamine-N-oxide (TMAO), a biomarker of CVD risk, is dependent on intestinal microbiota, but little is known of dietary conditions promoting changes in gut microbial communities. Resistant starches (RS) alter the human microbiota. We sought to determine whether diets varying in RS and carbohydrate (CHO) content affect plasma TMAO levels. We also assessed postprandial glucose and insulin responses and plasma lipid changes to diets high and low in RS. In a cross-over trial, fifty-two men and women consumed a 2-week baseline diet (41 percentage of energy (%E) CHO, 40 % fat, 19 % protein), followed by 2-week high- and low-RS diets separated by 2-week washouts. RS diets were assigned at random within the context of higher (51-53 %E) v. lower CHO (39 40 %E) intake. Measurements were obtained in the fasting state and, for glucose and insulin, during a meal test matching the composition of the assigned diet. With lower CHO intake, plasma TMAO, carnitine, betaine and gamma-butyrobetaine concentrations were higher after the high- v. low-RS diet (P<0.01 each). These metabolites were not differentially affected by high v. low RS when CHO intake was high. Although the high-RS meal reduced postprandial insulin and glucose responses when CHO intake was low (P<0.01 each), RS did not affect fasting lipids, lipoproteins, glucose or insulin irrespective of dietary CHO content. In conclusion, a lower-CHO diet high in RS was associated with higher plasma TMAO levels. These findings, together with the absence of change in fasting lipids, suggest that short-term high-RS diets do not improve markers of cardiometabolic health. PMID- 27993181 TI - Impact of cow strain and concentrate supplementation on grazing behaviour, milk yield and metabolic state of dairy cows in an organic pasture-based feeding system. AB - As ruminants are able to digest fibre efficiently and assuming that competition for feed v. food use would intensify in the future, cereals and other field crops should primarily be destined to cover the dietary needs of humans and monogastric animals such as poultry and pigs. Farming systems with a reduced or absent concentrate supplementation, as postulated by organic agriculture associations, require adapted dairy cows. The aim of this experiment was to examine the impact of concentrate supplementation on milk production, grazing and rumination behaviour, feed intake, physical activity and blood traits with two Holstein Friesian cow strains and to conclude the consequences for sustainable and organic farming. The experiment was a cross-over study and took place on an organic farm in Switzerland. In all, 12 Swiss Holstein-Friesian (HCH) cows and 12 New Zealand Holstein-Friesian (HNZ) cows, which were paired according to lactation number, days in milk and age for primiparous cows, were used. All cows grazed full time and were supplemented either with 6 kg/day of a commercial, organic cereal-grain mix or received no supplement. After an adaptation period of 21 days, a measurement period of 7 days followed, where milk yield and composition, pasture dry matter intake estimated with the n-alkane double-indicator technique, physical activity based on pedometer measurements, grazing behaviour recorded by automatic jaw movement recorder and blood samples were investigated. Non supplemented cows had a lower milk yield and supplemented HCH cows produced more milk than supplemented HNZ cows. Grazing time and physical activity were greater for non-supplemented cows. Supplementation had no effect on rumination behaviour, but HNZ cows spent longer ruminating compared with HCH cows. Pasture dry matter intake decreased with the concentrate supplementation. Results of blood analysis did not indicate a strong negative energy balance for either non-supplemented or supplemented cows. Minor differences between cow strains in this short-term study indicated that both cow strains are equally suited for an organic pasture-based production system with no concentrate supplementation. Many factors such as milk yield potential, animal welfare and health, efficiency, grazing behaviour and social aspects influence the decision to supplement grazing dairy cows with concentrates. PMID- 27993180 TI - Intake of n-3 fatty acids and long-term outcome in renal transplant recipients: a post hoc analysis of a prospective cohort study. AB - Supplementation with n-3 fatty acids may improve long-term outcomes of renal transplant recipients (RTR). Recent evidence suggests that EPA and DHA have different outcomes compared with alpha-linolenic acid (ALA). We examined the prospective associations of EPA-DHA and ALA intakes with graft failure and all cause mortality in 637 RTR. During 3.1 years (interquartile range 2.7, 3.8) of follow-up, forty-one developed graft failure and sixty-seven died. In age- and sex-adjusted analyses, EPA-DHA and ALA intakes were not associated with graft failure. EPA-DHA intake was not significantly associated with mortality (hazard ratio (HR) 0.79; 95% CI 0.54, 1.15 per 0.1 energy% difference). ALA intake was significantly associated with mortality (HR 1.17; 95% CI 1.04, 1.31 per 0.1 energy% difference). This association remained following adjustments for BMI, proteinuria and intakes of fat, carbohydrate and protein. RTR in the highest tertile of ALA intake exhibited about 2-fold higher mortality risk (HR 2.21; 95% CI 1.23, 3.97) compared with the lowest tertile. In conclusion, ALA intake may be associated with increased mortality in RTR. Future RCT are needed to confirm these results. PMID- 27993182 TI - Young man with persistent calf pain. PMID- 27993184 TI - Empowering mothers. PMID- 27993183 TI - Fatty acid dietary intake in the general French population: are the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) national recommendations met? AB - Quantity and quality of fatty acids (FA) in diet influence CVD risk. Consequently, health authorities promote recommended dietary intakes for FA, looking for optimal intakes in a primary prevention of CVD perspective. In parallel, a few data are available detailing intakes in national populations. The objective of the present study was to perform a large analysis combining the data of the French National Survey INCA 2 on food consumption performed in 2006 and 2007, and the nutritional content of food consumed in France updated in 2013 by the French Information Centre on Food Quality, to explore in details the FA intakes in French adults using the most recent available data. To compare the discrepancies in the observed intake levels with the French recommended levels, a weighted fat adherence score was built combining intakes of the different FA. Individual scores were computed in relation to official recommendations, and potential explanatory factors were identified. These data show that SFA intakes are persistently higher than national recommendations, combined with low intakes of MUFA and PUFA, particularly long-chain n-3 FA. Only 14.6 % of the French population met DHA intake recommendation, 7.8 % for EPA and 21.6 % for SFA. This situation remains unfavourable in terms of primary prevention of CVD. Consuming fish and other sources of n-3 FA, living in the south of France, being female, having a higher education level, and low alcohol consumption were associated with a healthier fat adherence score. PMID- 27993186 TI - Amyloidosis: A rare disease with varied manifestations. PMID- 27993187 TI - Hibernation for space travel: Impact on radioprotection. AB - Hibernation is a state of reduced metabolic activity used by some animals to survive in harsh environmental conditions. The idea of exploiting hibernation for space exploration has been proposed many years ago, but in recent years it is becoming more realistic, thanks to the introduction of specific methods to induce hibernation-like conditions (synthetic torpor) in non-hibernating animals. In addition to the expected advantages in long-term exploratory-class missions in terms of resource consumptions, aging, and psychology, hibernation may provide protection from cosmic radiation damage to the crew. Data from over half century ago in animal models suggest indeed that radiation effects are reduced during hibernation. We will review the mechanisms of increased radioprotection in hibernation, and discuss possible impact on human space exploration. PMID- 27993185 TI - Carbon recovery dynamics following disturbance by selective logging in Amazonian forests. AB - When 2 Mha of Amazonian forests are disturbed by selective logging each year, more than 90 Tg of carbon (C) is emitted to the atmosphere. Emissions are then counterbalanced by forest regrowth. With an original modelling approach, calibrated on a network of 133 permanent forest plots (175 ha total) across Amazonia, we link regional differences in climate, soil and initial biomass with survivors' and recruits' C fluxes to provide Amazon-wide predictions of post logging C recovery. We show that net aboveground C recovery over 10 years is higher in the Guiana Shield and in the west (21 +/-3 Mg C ha-1) than in the south (12 +/-3 Mg C ha-1) where environmental stress is high (low rainfall, high seasonality). We highlight the key role of survivors in the forest regrowth and elaborate a comprehensive map of post-disturbance C recovery potential in Amazonia. PMID- 27993188 TI - Gene expression of rice seeds surviving 13- and 20-month exposure to space environment. AB - Rice seeds were exposed outside of the international space station to assess the risk of space environment exposure on gene expression associated with seed germination. The germination percentages of the space-stored and ground-stored seeds exposed for 13 months were 48 and 96% respectively. Those for 20 months were 7 and 76%, respectively. Germination was defined 3 days after imbibition, except for the space-stored seeds exposed for 20 months, which germinated 5 days after imbibition. Subsequent RNA-seq analyses of the dry seeds, germinated seeds, and roots and shoots of seedlings revealed that the mutation rates of mRNA sequences were not significantly different between space-stored and ground-stored samples exposed for 13 months and 20 months. In all, 4 and 16 transcripts of glycolysis-related genes were increased in the germinated seeds after 13-month and 20-month exposure, respectively. Also, 2 and 39 transcripts of long-lived mRNA required for germination were decreased more than 2-fold in the dry seeds after 13-month and 20-month exposure, respectively. These results suggest that damage to long-lived mRNA in seeds by a space environment delays and reduces germination. PMID- 27993189 TI - Overview of the NASA space radiation laboratory. AB - The NASA Space Radiation Laboratory (NSRL) is a multidisciplinary center for space radiation research funded by NASA and located at the Brookhaven National Laboratory (BNL), Upton NY. Operational since 2003, the scope of NSRL is to provide ion beams in support of the NASA Humans in Space program in radiobiology, physics and engineering to measure the risk and ameliorate the effect of radiation in space. Recently, it has also been recognized as the only facility in the U.S. currently capable of contributing to heavy ion radiotherapy research. This work contains a general overview of NSRL structure, capabilities and operation. PMID- 27993190 TI - Investigation on contribution of neutron monitor data to estimation of aviation doses. AB - Recently, many efforts have appeared to routinely measure radiation exposure (RE) of aircraft crew due to cosmic rays (CR). On the other hand real-time CR data measured with the ground based neutron monitors (NMs) are collected worldwide and available online. This is an opportunity for comparison of long-term observations of RE at altitudes of about 10km, where composition and energy spectra of secondary particles differ from those on the ground, with the data from NMs. Our contribution presents examples of such type of comparison. Analysis of the silicon spectrometer Liulin measurements aboard aircraft is presented over the period May-September 2005 and compared with data from a single NM at middle latitude. While extreme solar driven events observed by NMs have clearly shown an impact on dosimetric characteristics as measured on the airplanes, the transient short time effects in CR of smaller amplitude have been not studied extensively in relation to RE. For the period May-September 2005, when aircraft data become available and several Forbush decreases (FDs) are observed on the ground, a small improvement in the correlation between the dose measured and multiple linear regression fit based on two key parameters (altitude and geomagnetic cut-off rigidity), is obtained, if the CR intensity at a single NM is added into the scheme. PMID- 27993191 TI - Optimizing LED lighting for space plant growth unit: Joint effects of photon flux density, red to white ratios and intermittent light pulses. AB - The aim of this work were to choose a quantitative optimality criterion for estimating the quality of plant LED lighting regimes inside space greenhouses and to construct regression models of crop productivity and the optimality criterion depending on the level of photosynthetic photon flux density (PPFD), the proportion of the red component in the light spectrum and the duration of the duty cycle (Chinese cabbage Brassica shinensis L. as an example). The properties of the obtained models were described in the context of predicting crop dry weight and the optimality criterion behavior when varying plant lighting parameters. Results of the fractional 3-factor experiment demonstrated the share of the PPFD level participation in the crop dry weight accumulation was 84.4% at almost any combination of other lighting parameters, but when PPFD value increased up to 500umol m-2s-1 the pulse light and supplemental light from red LEDs could additionally increase crop productivity. Analysis of the optimality criterion response to variation of lighting parameters showed that the maximum coordinates were the following: PPFD = 500umol m-2s-1, about 70%-proportion of the red component of the light spectrum (PPFDLEDred/PPFDLEDwhite = 1.5) and the duty cycle with a period of 501us. Thus, LED crop lighting with these parameters was optimal for achieving high crop productivity and for efficient use of energy in the given range of lighting parameter values. PMID- 27993192 TI - Polyphenol-enriched Vaccinium uliginosum L. fractions reduce retinal damage induced by blue light in A2E-laden ARPE19 cell cultures and mice. AB - Polyphenols exert beneficial effects on vision. We hypothesized that polyphenol components of Vaccinium uliginosum L. (V.U.) extract protect retinal pigment epithelial (RPE) cells against blue light-induced damage. Our aim was to test extracts containing polyphenol components to ascertain effects to reduce damage against blue light in RPEs. We measured the activity in fractions eluted from water, ethanol, and HP20 resin (FH), and found that the FH fraction had the highest beneficial activity. We isolated the individual active compounds from the FH fraction using chromatographic techniques, and found that FH contained flavonoids, anthocyanins, phenyl propanoids, and iridoids. Cell cultures of A2E laden ARPE-19 exposed to blue light after treatment with V.U. extract fractions and their individual constituents indicated improvement. V uliginosum L extract fractions and constituent compounds significantly reduced A2E photo-oxidation induced RPE cell death and inhibited intracellular A2E accumulation. Furthermore, Balb/c male mice were exposed to blue light at 10000 lux for 1 h/d for 2 weeks to induce retinal damage. One week after the final blue light exposure, retinal damage evaluated revealed that the outer nuclear layer thickness and nuclei count were improved. Histologic examination of murine photoreceptor cells demonstrated that FH, rich in polyphenols, inhibited the loss of outer nuclear layer thickness and nuclei. Our findings suggest that V.U. extract and eluted fractions are a potential source of bioactive compounds that potentially serve a therapeutic approach for age-related macular degeneration. PMID- 27993193 TI - Intake of bilberries (Vaccinium myrtillus L.) reduced risk factors for cardiovascular disease by inducing favorable changes in lipoprotein profiles. AB - Cardiovascular diseases (CVDs) are the leading causes of death, and lifestyle modification, including dietary changes, is recommended to improve this condition. In this study, regular consumption of bilberries was hypothesized to have beneficial effects on CVD risk reduction, by changes in human health indicators such as decreasing low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) and increasing high-density lipoprotein cholesterol (HDL-C). The research involved women (n=25) and men (n=11) who consumed 150 g of frozen stored bilberries 3 times a week for 6 weeks. Anthropometric parameters, blood pressure, lipid profile, glucose, liver enzymes, creatinine, albumin, magnesium, and antiradical activity were measured. Except for the body mass index of women (P=.019), no significant changes were found for anthropometric indicators. The consumption of bilberries led to a decrease in the following parameters: total cholesterol (P=.017), LDL-C (P=.0347), TG (P=.001), glucose (P=.005), albumin (P=.001), gamma-glutamyltransferase (P=.046), and a positive increase in HDL-C (P=.044). In men, additionally, favorable changes were observed in total cholesterol (P=.004), glucose (P=.015), albumin (P=.028), aspartate aminotransferase (P=.012), gamma-glutamyltransferase (P=.013), and HDL-C (P=.009; in this group, LDL-C increased [P=.007]). Changes in other parameters were not significant, for both women and men. Thus, the regular intake of bilberries can be important to reduce CVDs risk, by decreasing LDL-C/TG and increasing HDL-C. PMID- 27993194 TI - Sinonasal papillomas in a private referral otorhinolaryngology centre: Review of 22 years experience. AB - OBJECTIVES: To evaluate the clinical presentation, treatment outcome and follow up of all patients managed with sinonasal papillomas (SP), at a tertiary private otorhinolaryngology centre in Caracas (Venezuela). MATERIAL AND METHODS: We reviewed 94 patients with SP that were treated at our otolaryngology center, from July 1st 1993 to June 31st 2015. The demographic data, clinical features, radiological findings, anatomical origin, disease extension into the adjacent structures, surgical approaches performed, histopathology outcomes, recurrent risk, malignant transformation rate and coadjuvant therapies were assessed. RESULTS: Sixty-five patients (69.1%) were male and 29 (30.9%) female with an average age of 44.5 years (range 9-80 years). All patients underwent endoscopic sinus surgery. The most commont histologic subtypes of SP were inverted papilloma (58 patients; 61.7%), fungiform papilloma (35 patients; 37.2%) and oncocytic papilloma (one patient; 1.1%). SP was associated in 2 patients with undifferentiated squamous cell carcinoma. Twelve patients (12.8%) had disease with extension beyond the sinus without associated malignancy. All these patients received adjuvant treatment with advanced techniques of radiotherapy. The mean duration of the follow-up period was 9 years and 2 months. Eighteen patients (19.1%) had recurrent disease during the entire course of follow-up. CONCLUSIONS: Complete endoscopic surgical removal of SP is the treatment of choice. In less endoscopically accessible tumours, with peripheral extension or incompletely resected, Intensity Modulated Radiotherapy and Volumetric Modulated Arc Therapy may be indicated. Timely post-operative endoscopic follow-up with biopsy of suspected lesions is important for early detection of recurrences and associated malignancy. PMID- 27993195 TI - Minimally invasive thoracoscopic closure versus thoracotomy in children with patent ductus arteriosus. AB - BACKGROUND: Patent ductus arteriosus (PDA) is one of the most common congenital heart defects. Once diagnosed, an immediate pharmacologic or invasive treatment should be performed. The purpose of this work was to evaluate the safety and efficacy of surgical PDA ligation in children using video-assisted thoracoscopic surgery (VATS) in comparison with a conventional muscle-sparing posterolateral thoracotomy technique (MSPLT). MATERIALS AND METHODS: In this single-center, retrospective study 173 children qualified for surgical PDA closure were enrolled. Patients were divided according to their weight and type of surgery performed. The groups consisted of patients operated through thoracotomy (54%) or VATS (46%). Operative characteristics, cosmetic effect, postoperative complications and long-term survival were evaluated. RESULTS: Regardless of weight, fewer complications were noted in children after thoracoscopic clipping. Fifteen VATS patients required intraoperative conversion to thoracotomy; however, adverse sequelae were not observed. Aesthetics seemed to be the major complaint after conventional surgery. We did not observe any statistically significant differences in the long-term survival between both groups. CONCLUSIONS: Both techniques were shown to be safe and effective. Unsuccessfully performed thoracoscopic surgeries were safely converted to conventional thoracotomy. VATS, being a less invasive approach, leads to a better aesthetic effect and lower surgical complication rate. PMID- 27993197 TI - Tranexamic acid prolongs survival after controlled hemorrhage in rats. AB - BACKGROUND: The plasmin/plasminogen inhibitor tranexamic acid (TXA) is mainly used in elective surgeries with a higher blood loss to avoid uncontrolled bleeding. Recently, TXA has also been shown to reduce mortality in trauma patients. It is assumed that its beneficial effects are principally caused by its antifibrinolytic properties. We hypothesize that TXA also improves survival in a modified Wigger's model of hemorrhagic shock by a mechanism other than antifibrinolysis. MATERIALS AND METHODS: Male Wistar rats were intermittently bled until the mean arterial blood pressure was dropped to 25-30 mm Hg (severe shock). After shock induction, the animals received either 0.14-0.15 mL TXA (30 mg/kg) i.v. or the equivalent volume of 0.9% NaCl given as bolus. Adjacent to the shock period, the rats were resuscitated with Ringer's solution within 30 min and observed for another 150 min unless the animals died earlier. RESULTS: In the animals treated with TXA, survival was clearly prolonged and acid-base parameters showed some differences as compared to the animals receiving only NaCl. In the model used, coagulation slightly declined, but an increased fibrinolysis was not observed. CONCLUSIONS: Since in the applied shock model fibrinolysis is negligible, we postulate that TXA is capable of providing protection against hemorrhagic shock independent from its antifibrinolytic properties. PMID- 27993198 TI - A comparison of trends in operative approach and postoperative outcomes for colorectal cancer surgery. AB - BACKGROUND: Data-assessing trends and perioperative outcomes relative to surgical approach for colorectal cancer (CRC) surgery are lacking. We report national trends of CRC surgery and compare postoperative outcomes by surgical approach. METHODS: A total of 261,886 patients undergoing surgery for CRC were identified using the Nationwide Inpatient Sample from 2009 to 2012. Trends in surgical approach were assessed using the Cochrane-Armitage test of trends. Multivariable logistic and linear regression analyses were performed to compare length of stay (LOS), postoperative complications, and cost by surgical approach. RESULTS: At the time of surgery, 57.5% underwent an open procedure, whereas 42.4% underwent either a laparoscopic (39.9%) or robotic (2.5%) colorectal surgery. The use of minimally invasive surgery increased over time (2009 versus 2012: 37.3% versus 46.8%; P < 0.001). Postoperative morbidity was 15.9% and was higher after open surgery (open versus laparoscopic versus robotic: 18.4% versus 12.4% versus 13.3%; P < 0.001). Patients who underwent a minimally invasive surgery had shorter LOS (laparoscopic: OR, 0.55, 95% CI, 0.52-0.58; robotic: OR, 0.58; 95% CI, 0.49-0.69; both P < 0.001). Robotic surgery was consistently associated with the highest mean costs followed by laparoscopic and open surgery (P < 0.001). CONCLUSIONS: Patients undergoing minimally invasive colorectal surgery had a lower postoperative morbidity and shorter LOS compared with patients undergoing open colorectal surgery. PMID- 27993199 TI - The beneficial role of simultaneous splenectomy after extended hepatectomy: experimental study in pigs. AB - BACKGROUND: The role of hepatic hemodynamic modulation in the development of "small-for-size" syndrome (SFSS) after extended hepatectomy (EH) or living-donor liver transplantation is still controversial. We have designed an experimental study to investigate the effect of hemodynamic parameters of the liver circulation on the development of SFSS after EH in a porcine model. METHODS: Eighteen pigs were randomly divided into two groups: group A has received EH (75% 80%) without splenectomy, and group B with EH and simultaneous splenectomy was carried out. Portal hemodynamics, liver function tests, histologic findings, injury and survival rates were compared between groups A and B. RESULTS: The 7-d survival rate in the splenectomy group was significantly improved compared with group A (88.9% versus 44.4%, P < 0.05). Portal vein pressure, portal vein flow, and liver function tests in the splenectomy group were significantly lower than in group A immediately after splenectomy and postoperatively until the day of sacrifice. Histologic findings in group A clearly illustrate severe inflammation, bridging necrosis, ischemic cholangitis, and severe congestion, while in group B there were less serious histologic changes. CONCLUSIONS: Our experimental study indicates that perioperative portal modulation can successfully prevent the manifestation of SFSS after EH. Therefore, by focusing on "flow" rather than on "size," researchers may understand better the pathophysiology of this syndrome. PMID- 27993196 TI - Milk fat globule-epidermal growth factor-factor VIII-derived peptide MSP68 is a cytoskeletal immunomodulator of neutrophils that inhibits Rac1. AB - BACKGROUND: Prolonged neutrophil infiltration leads to exaggerated inflammation and tissue damage during sepsis. Neutrophil migration requires rearrangement of their cytoskeleton. Milk fat globule-epidermal growth factor-factor VIII-derived short peptide 68 (MSP68) has recently been shown to be beneficial in sepsis induced tissue injury and mortality. We hypothesize that MSP68 inhibits neutrophil migration by modulating small GTPase Rac1-dependent cytoskeletal rearrangements. METHODS: Bone marrow-derived neutrophils (BMDNs) or whole lung digest isolated neutrophils were isolated from 8 to 10 wk old C57BL/6 mice by Percoll density gradient centrifugation. The purity of BMDN was verified by flow cytometry with CD11b/Gr-1 staining. Neutrophils were stimulated with N formylmethionine-leucine-phenylalanine (f-MLP) (10 nM) in the presence or absence of MSP68 at 10 nM or cecal ligation and puncture (CLP) was used to induce sepsis, and MSP68 was administered at 1 mg/kg intravenously. Cytoskeletal organization was assessed by phalloidin staining, followed by analysis using fluorescence microscopy. Activity of the Rac1 GTPase in f-MLP or CLP-activated BMDN in the presence or absence of MSP68 was assessed by GTPase enzyme-linked immunosorbent assay. Mitogen-activated protein (MAP) kinase activity was determined by western blot densitometry. RESULTS: BMDN treatment with f-MLP increased cytoskeletal remodeling as revealed by the localization of filamentous actin to the periphery of the neutrophil. By contrast, cells pretreated with MSP68 had considerably reduced filamentous actin polymerization. Cytoskeletal spreading is associated with the activation of the small GTPase Rac1. We found BMDN-treated with f-MLP or that were exposed to sepsis by CLP had increased Rac1 signaling, whereas the cells pretreated with MSP68 had significantly reduced Rac1 activation (P < 0.05). MAP kinases related to cell migration including pp38 and pERK were upregulated by treatment with f-MLP. Upregulation of these MAP kinases was also significantly reduced after pretreatment with MSP68 (P < 0.05). CONCLUSIONS: MSP68 downregulates actin cytoskeleton-dependent, Rac1-MAP kinase-mediated neutrophil motility. Thus, MSP68 is a novel therapeutic candidate for regulating inflammation and tissue damage caused by excessive neutrophil migration in sepsis. PMID- 27993200 TI - A novel mouse model of high flow-induced pulmonary hypertension-surgically induced by right pulmonary artery ligation. AB - BACKGROUND: This study sought to establish a new model of high-flow pulmonary hypertension (PH) in mice. This model may be useful for studies seeking to reduce the pulmonary vascular resistance and delay the development of PH caused by congenital heart disease. MATERIALS AND METHODS: The right pulmonary artery was ligated via a right posterolateral thoracotomy. Pulmonary hemodynamics was evaluated by right heart catheterization immediately after ligation and at 2, 4, 8, and 12 wk postoperatively. The right ventricle (RV) and the left ventricle (LV) with septum (S) were weighed to calculate the RV/(LV + S) ratio as an index of right ventricular hypertrophy. Morphologic changes in the left lungs were analyzed, and percentages of muscularized pulmonary vessels were assessed by hematoxylin and eosin, elastica van Gieson and alpha-smooth muscle actin staining. All the study data were compared with data from a model of PH generated by hypoxic stimulation. RESULTS: A pulmonary hypertensive state was successfully induced by 2 wk after surgery. However, the morphologic analysis demonstrated that pulmonary vascular muscularization, as evaluated using right ventricular systolic pressure and RV/(LV + S), was not significantly increased until 4 wk postoperatively. When mice from the new model and the hypoxic model were compared, no significant differences were observed in any of the evaluated indices. CONCLUSIONS: High-flow PH can be induced within 4 wk after ligation of the right pulmonary artery, which is easily performed in mice. Such mice can be used as a model of high-flow PH. PMID- 27993201 TI - Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia. AB - BACKGROUND: Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice. METHODS: Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2, and high mobility group box 1 expression. RESULTS: Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone (P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS induced endotoxemia. CONCLUSIONS: Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients. PMID- 27993202 TI - Aligning perceptions of mistreatment among incoming medical trainees. AB - BACKGROUND: Learner mistreatment has been a long-standing example of unprofessional behavior in medical training. Alignment of perceptions of professional behavior is a critical component of developing a defined organizational culture. Clinical vignettes addressing learner mistreatment can help to achieve this goal. Our aim was to determine whether using clinical vignettes to address learner mistreatment during onboarding can reduce variability in the perceptions of mistreatment. MATERIALS AND METHODS: External experts in the field of labor and employment relations embedded in the clinical learning environment identified six thematic areas of potential mistreatment. Corresponding clinical case vignettes were developed and presented to incoming trainees during the onboarding process, followed by facilitated discussion. Perceptions of mistreatment before and after discussion were assessed on a Likert scale, with results compared using F-test and t-test. RESULTS: There were 145 participants. Most participants reported previously witnessing or experiencing episodes of mistreatment before matriculation (84%), with the majority reporting multiple events. The most common offenders were faculty (57%), residents/fellows (49%), and nurses (33%). Only 10% of incoming trainees reported a previous incident of mistreatment. Postintervention scores demonstrated decreased variability (P < 0.05) in perceptions of mistreatment in all but one vignette (withholding learning opportunities). Two vignettes demonstrated higher perception of mistreatment after intervention (noneducational tasks and gender or racial discrimination, P < 0.05). CONCLUSIONS: Mistreatment remains a prevalent phenomenon in medical training involving a wide cross-section of healthcare providers. Trainees arrive with discordant definitions of mistreatment. Alignment of individuals' definitions can be achieved through the use of carefully crafted clinical vignettes and facilitated discussion. PMID- 27993203 TI - Prognostic significance of systemic inflammatory response in stage II colorectal cancer. AB - BACKGROUND: It is considered that stage II colorectal cancers have heterogeneous oncological outcomes. It remains to be determined whether inflammatory markers can predict survival after curative surgery in these patients. The aim of this study was to investigate the prognostic impact of preoperative inflammatory markers after curative surgery in stage II colorectal cancers. METHODS: Two hundred sixty-one patients with stage II colorectal cancers who underwent curative surgery between January 2006 and December 2011 were reviewed. Oncologic outcomes were analyzed with neutrophil count, lymphocyte count, monocyte count, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio. RESULTS: Univariate analysis showed that high NLR (hazard ratio (HR), 3.506; 95% confidence interval [CI], 1.415-8.688; P = 0.007) and low LMR (HR, 2.436; 95% CI, 1.010-5.880; P = 0.048) were associated with worse disease-free survival (DFS), and high NLR (HR, 2.834; 95% CI, 1.419-5.662; P = 0.003) and low LMR (HR, 2.374; 95% CI, 1.188-4.742; P = 0.014) were associated with worse overall survival (OS) in stage II colorectal cancer. Cox multivariate analysis demonstrated that high NLR was independently associated with worse DFS (HR, 3.163; 95% CI, 1.058-9.455; P = 0.004) and OS (HR, 3.018; 95% CI, 1.467-6.207; P = 0.003) in stage II colorectal cancer. CONCLUSION: Among the systemic inflammatory markers, NLR is a strong predictor of worse DFS and OS in stage II colorectal cancer. PMID- 27993204 TI - Massive transfusion in pediatric trauma: analysis of the National Trauma Databank. AB - BACKGROUND: Massive transfusion (MT) in pediatric trauma has been described in combat populations and other single institutions studies. We aim to define the incidence of MT in a large US civilian pediatric trauma population, identify predictive parameters of MT, and the mortality associated with MT. METHODS: Data from the National Trauma Databank (2010-2012), a trauma registry maintained by the American College of Surgeons, were analyzed. We included pediatric trauma patients <=14 y that underwent MT, as defined by 40 mL/kg of blood products within the first 24 h after admission. We compared the MT group with children receiving any transfusion within the same time frame. Univariate and multivariate analysis were performed. RESULTS: Of 356,583 pediatric trauma patients, 13,523 (4%) received any transfusion in the first 24 h and 173 (0.04%) had a MT. On multivariate analysis, factors predicting MT were: older patients (5-12: OR 2.71, P = 0.006, and >=12: OR 5.14, P < 0.001), hypothermic patients (temperature <35: OR 2.48, P < 0.025), low Glasgow Coma Scale (Glasgow Coma Scale <8: OR 2.82, P = 0.009), and Injury Severity Scores >=25 (OR 2.01, P = 0.03). Overall mortality for the entire group, any transfusion group, and MT group were 2.5%, 13.6%, and 50.6%, respectively (P < 0.001). CONCLUSIONS: MT in pediatric trauma is an uncommon event associated with a significant mortality. Patients undergoing MT are older, more likely to be hypothermic and have sustained more severe injuries as measured by traditional trauma scoring systems than transfused trauma patients. PMID- 27993205 TI - Trauma experts versus pediatric experts: comparison of outcomes in pediatric penetrating injuries. AB - BACKGROUND: While pediatric trauma centers (PTCs) can uniquely care for pediatric patients, adult trauma centers (ATCs) may be more accessible. Evidence is scarce regarding outcomes of pediatric patients with penetrating trauma treated at PTCs versus ATCs. MATERIALS AND METHODS: We performed a retrospective study using the National Trauma Data Bank to identify pediatric patients aged <=18 y with penetrating injuries from 2007 to 2012, treated at stand-alone PTCs or ATCs. We excluded patients treated at combined PTC or ATC, transferred between hospitals, with gunshot wounds (GSW) to the head, or dead on arrival. Eligible patients numbered 26,276 (PTC, n = 3737; ATC, n = 22,539). The primary outcome was in hospital mortality. The secondary outcome was discharge location as a potential surrogate for functional outcome. Univariate and multivariate analyses assessed trauma center type as an independent risk factor for outcomes. RESULTS: Patients treated at ATCs were more likely to have Injury Severity Score >15, Glasgow Coma Scale <9, GSW, cardiovascular injuries, and emergent operations (P < 0.001). Adjusted odds ratios (ORs) for mortality favored PTCs but without statistical significance (OR, 0.592; P = 0.054). In subgroup analyses, children with aged <=12 y, those with GSW injury mechanism, and those who underwent emergent operations at PTCs were more frequently discharged home versus elsewhere (OR, 0.327, 0.483, and 0.394; P values <0.001, <0.001, and 0.004, respectively). CONCLUSIONS: Children with penetrating injuries demonstrated equivalent survival outcomes whether they were treated at PTCs or ATCs. Younger pediatric patients may have superior functional outcomes when treated at PTCs. PMID- 27993207 TI - Gallbladder abnormalities in children with metachromatic leukodystrophy. AB - BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease that leads to neurological deterioration and visceral involvement, including sulphatide deposition in the gallbladder wall. Using our institution's extensive experience in treating MLD, we examined the incidence of gallbladder abnormalities in the largest cohort of children with MLD to date. METHODS: We conducted a retrospective review of all children with MLD, adrenoleukodystrophy (ALD), or Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) at our institution between 1994 and 2015. Baseline characteristics and unadjusted outcomes were compared using the Kruskal-Wallis test for continuous variables and Pearson chi2 test for categorical variables, with significance defined as P < 0.05. RESULTS: In total, 87 children met study criteria: 29 children with MLD and 58 children with ALD or Krabbe disease. Children with MLD were more likely to demonstrate gallbladder abnormalities on imaging, both before HSCT (41.4% versus 5.2%, P < 0.001) and after HSCT (75.9% versus 41.4%, P = 0.002). Consequently, a larger proportion of children with MLD underwent surgical or interventional management of biliary disease (10.3% versus 3.4%, P = 0.03). CONCLUSIONS: Children with MLD have a significantly greater incidence of gallbladder abnormalities than children with other lysosomal storage diseases. Biliary disease should be considered in children with MLD who develop abdominal pain, and cholecystectomy should be considered for persistent, symptomatic gallbladder abnormalities. PMID- 27993206 TI - Local and systemic Th17 immune response associated with advanced stage colon cancer. AB - BACKGROUND: Little is known about how the immunologic microenvironment changes during tumor progression and metastatic spread. Recently, murine models have shown the T-helper 17 (Th17) pathway to play an important role in promoting colorectal cancer (CRC). The purpose of this study was to compare cytokine profiles in the tumor microenvironment of CRC between local disease (stages I/II) and advanced disease (stages III/IV), and to determine whether these changes were manifest in the systemic circulation of patients with advanced disease. MATERIALS AND METHODS: Serum and tissue cytokine profiles were assayed among patients with documented adenocarcinoma before surgical resection at a single institution from September 2014 to February 2015. Using the Bio-Plex Pro Human Th17 Cytokine Assay Kit (Bio-Rad Laboratories), the concentrations of multiple cytokines were determined. Multiple logistic regression analyses were used to evaluate the association between TNM staging and cytokine levels. RESULTS: A total of 33 patients with documented adenocarcinoma were included. None of the patients received neoadjuvant chemotherapy. American Joint Commission on Cancer TNM classification was used. Advanced disease was associated with elevated tumor levels of tumor necrosis factor-alpha, interleukin (IL)-4, IL-10, IL-17A, and IL 17F, and only stage IV showed elevated systemic levels of Th17-associated cytokines IL-17F, IL-23, and IL-25. CONCLUSIONS: The Th17 pathway likely has important mechanistic implications in human CRC. Metastatic disease was associated with elevated Th17-associated cytokines both in colonic tissue and systemically. These changes in systemic expression of Th17-associated cytokines could establish novel pathways for CRC and warrant further investigation. PMID- 27993208 TI - The price of surgery: markup of operative procedures in the United States. AB - BACKGROUND: Despite cost containment efforts, the price for surgery is not subject to any regulations. We sought to characterize and compare variability in pricing for commonly performed major surgical procedures across the United States. METHODS: Medicare claims corresponding to eight major surgical procedures (aortic aneurysm repair, aortic valvuloplasty, carotid endartectomy, coronary artery bypass grafting, esophagectomy, pancreatectomy, liver resection, and colectomy) were identified using the Medicare Provider Utilization and Payment Data Physician and Other Supplier Public Use File for 2013. For each procedure, total charges, Medicare-allowable costs, and total payments were recorded. A procedure-specific markup ratio (MR; ratio of total charges to Medicare-allowable costs) was calculated and compared between procedures and across states. Variation in MR was compared using a coefficient of variation (CoV). RESULTS: Among all providers, the median MR was 3.5 (interquartile range: 3.1-4.0). MR was noted to vary by procedure; ranging from 3.0 following colectomy to 6.0 following carotid endartectomy (P < 0.001). MR also varied for the same procedure; varying the least after liver resection (CoV = 0.24), while coronary artery bypass grafting pricing demonstrated the greatest variation in MR (CoV = 0.53). Compared with the national average, MR varied by 36% between states ranging from 1.8 to 13.0. Variation in MR was also noted within the same state varying by 15% within the state of Arkansas (CoV = 0.15) compared with 51% within the state of Wisconsin (CoV = 0.51). CONCLUSIONS: Significant variation was noted for the price of surgery by procedure as well as between and within different geographical regions. Greater scrutiny and transparency in the price of surgery is required to promote cost containment. PMID- 27993210 TI - Recombinant human lubricin for prevention of postoperative intra-abdominal adhesions in a rat model. AB - BACKGROUND: Postoperative intra-abdominal adhesions are a major cause of morbidity and mortality and contribute to a heavy burden on health care resources. At present, numerous introduced adhesion prevention products have demonstrated some benefit but none are consistently effective. The aim of this study was to examine the effectiveness of recombinant human lubricin in preventing intra-abdominal adhesion formation. MATERIALS AND METHODS: A total of 62 male Wistar Albino rats were randomly assigned to the study. Six rats were used to the initial pilot study and 56 rats were randomized into four groups: (1) control cecal abrasion; (2) treatment cecal abrasion with 0.5 mg/mL lubricin solution; (3) control cecal enterotomy and primary closure; and (4) treatment cecal enterotomy and primary closure with 0.5 mg/mL lubricin solution. Rats were sacrificed at 3 d and 21 d postoperatively for the pilot and main studies, respectively. Macroscopic and microscopic adhesion severity was graded by blinded investigators. RESULTS: For the pilot study, all six rats successfully reached the end point indicating safety of the lubricin gel. In the main randomized study, adhesions in the treated cecal abrasion group were significantly reduced both macroscopically (P = 0.001) and microscopically (fibrosis P = 0.009, inflammation P < 0.0001), when compared with the control group. In the cecal enterotomy group, adhesions were reduced for the treatment group in macroscopic (P = 0.011) and microscopic grading (fibrosis P = 0.500, inflammation P = 0.206) compared with the control group. CONCLUSIONS: Recombinant human lubricin significantly reduced both macroscopic and microscopic intra-abdominal adhesions in the cecal abrasion group. The cecal enterotomy group showed modest macroscopic adhesion reduction. Future study using higher concentration of lubricin solution are needed to investigate its toxicity and more profound antiadhesion properties in significant operations. PMID- 27993209 TI - Enhanced serotonin signaling stimulates ordered intestinal mucosal growth. AB - BACKGROUND: Significant quantities of serotonin (5-hydroxytryptamine; 5-HT) are found in the intestine, and studies have demonstrated that 5-HT can stimulate enterocyte cell division, suggesting regulatory roles in mucosal homeostasis and intestinal adaptation. We hypothesized that excess enteric 5-HT signaling enhances mucosal growth without changing intestinal villous cellular makeup. METHODS: Mice lacking the serotonin reuptake transporter (SERT) and wild-type littermates (WTLM) were euthanized and their ileum analyzed. Villus height (VH), crypt depth (CD), and enterocyte height (EH) were measured. Enterocyte cell division was measured using Ki-67 immunofluorescence to calculate crypt proliferation index (CPI). Cellular distribution along villi was investigated by immunofluorescent staining for enterocytes, enteroendocrine cells, and goblet cells. Group measurements were compared using t-test and chi-squared test. RESULTS: SERT knock-out (SERTKO) mice had significantly taller villi, deeper crypts, and taller enterocytes compared with WTLM (P < 0.0001). Similarly, enterocyte proliferation was greater in SERTKO compared with WTLM (P < 0.01). For SERTKO, mean values were: VH, 255.6 MUm; CD, 66.7 MUm; EH, 21.2 MUm; and CPI, 52.8%. For WTLM, corresponding values were: VH, 207.8 MUm; CD, 56.1 MUm; EH, 19.5 MUm; and CPI, 31.9%. The cellular composition along villi was not significantly different between genotypes (P > 0.05). CONCLUSIONS: Enhancing 5-HT signaling in mice increases VH, CD, EH, and crypt cell proliferation in the intestinal mucosa. 5-HT-associated growth did not alter the cellular composition of the villi. Serotonin may represent an important physiologic regulator of intestinal growth and adaptation and holds promise as a target for therapies aimed at enhancing intestinal recovery after injury or mucosal surface area loss. PMID- 27993211 TI - Trauma patients who present in a delayed fashion: a unique and challenging population. AB - BACKGROUND: A proportion of trauma patients present for evaluation in a delayed fashion after injury, likely due to a variety of medical and nonmedical reasons. There has been little investigation into the characteristics and outcomes of trauma patients who present delayed. We hypothesize that trauma patients who present in a delayed fashion are a unique population at risk of increased trauma related complications. MATERIALS AND METHODS: This was a retrospective review from 2010-2015 at a Level I trauma center. Patients were termed delayed if they presented >24 hours after injury. Patients admitted within 24 hours of their injury were the comparison group. Charts were reviewed for demographics, mechanism, comorbidities, complications and outcomes. A subgroup analysis was done on patients who suffered falls. RESULTS: During the 5-y period, 11,705 patients were admitted. A total of 588 patients (5%) presented >24 h after their injury. Patients in the delayed group were older (65 versus 55 y, P < 0.001) and more likely to have psychiatric comorbidities (33% vs. 24%, P = 0.0001) than the control group. They were also more likely to suffer substance withdrawal (8.9% vs. 4.1%, P < 0.001) but had toxicology testing for drugs and alcohol done at significantly lower rates. Patients that presented delayed after falls were similar in age and injury severity score (ISS) but more likely to suffer substance withdrawal when compared to those with falls that presented within 24 hours. Patients with falls that presented delayed had toxicology testing at significantly lower rates than the comparison group. CONCLUSIONS: Trauma patients that present to the hospital in a delayed fashion have unique characteristics and are more likely to suffer negative outcomes including substance withdrawal. Future goals will include exploring strategies for early intervention, such as automatic withdrawal monitoring and social work referral for all patients who present in a delayed fashion. PMID- 27993212 TI - Criteria derived from serum markers can precisely evaluate axillary status in breast cancer patients. AB - BACKGROUND: A noninvasive method to confirm the presence of lymph node metastases (LNM) in breast cancer patients is lacking. This study aimed to identify markers from peripheral blood that have diagnostic value in evaluating axillary LNM. METHODS: We tested 26 factors in serum from 57 patients with resectable breast cancer by the Luminex assay. Differences between node-negative and node-positive patients were assessed. The diagnostic value of the factors was determined by further analyses and a validation test. RESULTS: Matrix metalloproteinase-1, hepatocyte growth factor, and chemokine ligand 5 were independent risk factors for LNM. However, receiver operating characteristic analysis showed that these factors alone were not ideal predictors. The LNM score (LNMS), derived from combining these markers, correlated significantly with numbers of positive lymph nodes. Patients with LNMS of 0 had few LNM, axillary lymph node dissection (ALND) could be avoided, and sentinel lymph node biopsy (SLNB) was unnecessary. Very high accuracy was achieved for patients with LNMS of 1 with SLNB using only methylene blue, patients with LNMS of 3 required ALND, and patients with LNMS of 2 needed SLNB using both a radioactive isotope and methylene blue, and ALND. CONCLUSIONS: The LNMS derived from matrix metalloproteinase-1, hepatocyte growth factor, and chemokine ligand 5 serum levels identified the axillary lymph node status with high accuracy. Patients with higher LNMS had a greater probability of LNM. PMID- 27993213 TI - An ex vivo comparison of adenosine and lidocaine solution and University of Wisconsin solution for hypothermic machine perfusion of porcine kidneys: potential for development. AB - BACKGROUND: The optimal hypothermic machine perfusion (HMP) solution has not yet been developed. An adenosine and lidocaine (AL) solution has been shown to be protective in cardiac preservation. The aim of the present study was to examine a modified AL solution with low Ca2+, 16 mM Mg2+, and 4% albumin on kidney preservation compared with University Wisconsin solution (UW). METHODS: Twenty donation of organs after cardiac death porcine kidneys underwent HMP for 10 h (AL, n = 10; UW, n = 10) and then 2 h of normothermic reperfusion. Perfusion dynamics, functional parameters, histology, and real-time microdialysis were used to assess kidney responses and viability. RESULTS: During HMP, modified AL perfused kidneys maintained higher flow rates (21.5 versus 17.9 mL/min/100 g, P = 0.01), with perfusion flow index during the first 3 h 25% greater than with UW (AL = 0.50 +/- 0.2, UW = 0.40 +/- 0.17 mL/min/100 g/mmHg; P = 0.03), followed by an increase in UW kidneys which was not significantly different to AL over the remaining 7 h (0.54 versus 0.55 mL/min/100 g/mmHg, respectively). During warm reperfusion, there were no significant differences between the two HMP groups in creatinine clearance, oxygen, and glucose consumption between groups. Modified AL kidneys had significantly lower perfusate lactates (3.1 versus 4.1 mmol/L, P = 0.04) during reperfusion and lower cortical lactate levels (AL = 0.66 +/- 0.31, UW = 0.89 +/- 0.53 mM, P = 0.33). Histology showed similar degrees of reperfusion injury. CONCLUSIONS: We conclude that HMP with modified AL solution showed improved perfusion compared with UW and lower perfusate lactate levels during warm reperfusion. Further modification of the AL composition is warranted and may lead to more rapid kidney stabilization and improved graft viability assessment, potentially expanding donor pools. PMID- 27993214 TI - Predictors of residual disease after unplanned excision of soft tissue sarcomas. AB - BACKGROUND: Unplanned excision of soft tissue sarcomas (STS) is an important quality of care issue given the morbidity related to tumor bed excision. Since not all patients harbor residual disease at the time of reexcision, we sought to determine predictors of residual STS following unplanned excision. METHODS: We identified 76 patients from a prospective database (January 1, 2008-September 30, 2014) who received a diagnosis of primary STS following unplanned excision on the trunk or extremities. We used univariable and multivariable analyses to evaluate predictors of residual STS as the primary endpoint. We calculated the sensitivity, specificity, and accuracy of interval magnetic resonance imaging (MRI) to predict residual sarcoma at reexcision. RESULTS: Mean age was 52 y, and 63.2% were male. 50% had fragmented unplanned excision. Among patients undergoing reexcision, residual STS was identified in 70%. On univariable analysis, MRI showing gross disease and fragmented excision were significant predictors of residual STS (odds ratio, 10.59; 95% CI, 2.14-52.49; P = 0.004 and odds ratio, 3.61; 95% CI, 1.09-11.94; P = 0.035, respectively). On multivariable analysis, tumor size predicted distant recurrence and overall survival. When we combined equivocal and positive MRI, the sensitivity and specificity of MRI for predicting residual STS were 86.7% (95% CI, 73.2%-95.0%) and 57.9% (95% CI, 33.5%-79.8%), with an overall accuracy of 78.1% (95% CI, 66.0%-87.5%). CONCLUSIONS: About 70% of patients undergoing repeat excision after unplanned excision of STS harbor residual sarcoma. Although interval MRI and fragmented excision appear to be the most significant predictors of residual STS, the accuracy of MRI remains modest, especially given the incidence of equivocal MRI. PMID- 27993215 TI - Anti-PD-L1 peptide improves survival in sepsis. AB - BACKGROUND: Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (compound 8) that inhibits PD-1:PD-L1 signaling in a clinically relevant second-hit fungal sepsis model. METHODS: Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans. Forty-eight hours after Candida infection, mice were treated with compound 8 or inactive peptide. The effect of Candida infection on expression of coinhibitory molecules, PD-1, and PD-L1 were quantitated by flow cytometry on CD4+ cells, CD8+ cells, natural killer (NK) cells, and natural killer T-cells (NKT). The effect of compound 8 on survival was also examined. RESULTS: Four days after fungal infection, PD-1 and PD-L1 expressions were markedly increased on CD4+, NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4+, 11.9% versus 2.8%; and %PD-L1 on NKT, 14.8% versus 0.5%). Compared with control, compound 8 caused a 2-fold increase in survival from 30% to 60%, P < 0.05. CONCLUSIONS: Compound 8 significantly improved survival in a clinically relevant immunosuppressive model of sepsis. These results support immunoadjuvant therapy targeting T-cell exhaustion in this lethal disease. PMID- 27993216 TI - Vascular endothelial growth factor expression is an independent poor prognostic factor for human epidermal growth factor receptor 2 positive gastric cancer. AB - BACKGROUND: The positive expression of human epidermal growth factor receptor 2 (HER-2) is phenotypically associated with differentiated gastric cancer (GC) and is a prognostic factor for resectable GC. The aim of this study was to explore the clinical significance of vascular endothelial growth factor (VEGF), protein kinase B, and p38 mitogen-activated protein kinase (MAPK) regarding outcome in patients with HER-2 positive GC, and to analyze the relationship between these molecules and clinicopathologic parameters. MATERIALS AND METHODS: Between January 2001 and December 2012, radical-intent gastrectomy specimens from GC patients were evaluated for HER-2 expression by immunohistochemistry (IHC); and with HER-2 expression levels of 2+ were further subjected to fluorescence in situ hybridization analysis. HER-2 positivity was defined by a HER-2 3+ score on IHC or a HER-2 2+ score on IHC and HER-2 amplification by fluorescence in situ hybridization. The expression of VEGF, phosphorylated protein kinase B, and phosphorylated p38 MAPK in HER-2 positive specimens was scored using IHC. RESULTS: Fifty-four patients with HER-2 positive stage I-III GCs were identified. Univariate analysis of prognostic factors showed that tumor differentiation, the presence of vascular invasion, and overexpression of p-p38 MAPK, and VEGF significantly affected prognosis. Multivariate analysis identified vascular invasion (hazard ratio = 2.704; 95% confidence interval = 1.074-7.088; P < 0.033) and the overexpression of VEGF (hazard ratio = 2.760; 95% confidence interval = 1.083-6.753; P < 0.035) to be independent prognostic predictors of HER-2 positive GC. CONCLUSIONS: VEGF overexpression and the presence of vascular invasion were independent poor prognostic factors for HER-2 positive GCs. PMID- 27993217 TI - Comparing industry compensation of cardiothoracic surgeons and interventional cardiologists. AB - BACKGROUND: The purpose of this study was to compare payment trends between cardiothoracic surgeons and interventional cardiologists using the Open Payments website made available for the public by the Center for Medicare and Medicaid Services. MATERIAL AND METHODS: Data were extracted from the second release of the Open Payments database, which includes payments made between August 1, 2013 and December 31, 2014. Total payments to individual physicians were aggregated based on specialty, region of the country, and payment type. The Gini index was calculated for each specialty to measure income disparity. A Gini index of 1 indicates all the payments went to one individual, whereas a Gini index of 0 indicates all individuals received equal payments. RESULTS: During the study period of interest, data were made available for 3587 (80%) cardiothoracic surgeons compared with 2957 (99%) interventional cardiologists. Mean total payments to cardiothoracic surgeons were $7770 (standard deviation, $52,608) compared with a mean of $15,221 (standard deviation, $98,828) for interventional cardiologists. The median total payments to cardiothoracic surgeons was $1050 (interquartile range, $233-$3612) compared with $1851 (interquartile range, $607 $5462) for interventional cardiologists. The overall Gini index was 0.932, whereas the Gini index was 0.862 for interventional cardiologists and 0.860 for cardiothoracic surgeons. CONCLUSIONS: The vast majority of interventional cardiologists and cardiothoracic surgeons received payments from drug and device manufacturers. The mean total payments to interventional cardiologists were higher than any other specialty. However, like cardiothoracic surgery, they were among the most equitably distributed compared with other specialties. PMID- 27993218 TI - Magnetic compression anastomosis for enteroenterostomy under peritonitis conditions in dogs. AB - BACKGROUND: The risk of complications and mortality are high after enteroenterostomy in severe peritonitic conditions. Magnetic compression anastomosis (MCA) is a sutureless technique of high efficacy and safety. The purpose of this study was to compare the efficacy of MCA for enteroenterostomy with stapled and hand-sewn techniques under peritonitic conditions. METHODS: The peritonitic conditions were created by puncturing the colon with a circular blade in 27 mongrel dogs. Eight hours later, the peritoneal cavity was washed with warm, sterilized normal saline solution. The animals were then randomly divided into three groups and underwent colonic anastomosis with MCA, stapled, or hand sewn techniques, respectively. Animals were euthanized at 1, 2, and 4 w after the operation; anastomoses were compared on the basis of gross appearance and histology. RESULTS: All magnetic devices formed patent anastomoses without a leak. However, one stapled anastomosis and three hand-sewn anastomoses resulted in leaks. The anastomosis time was significantly less in the MCA group than that of the other two groups (P < 0.05). All magnetic devices were expelled naturally. The pathologic observation showed that the healing of anastomoses for MCA was smoother than that of the other two groups. CONCLUSION: MCA is a feasible, safe, and effective alternative for enteroenterostomy under peritonitic conditions in the canine model. PMID- 27993219 TI - Behavior of a new long-chain cyanoacrylate tissue adhesive used for mesh fixation in hernia repair. AB - BACKGROUND: Synthetic tissue adhesives (TA) are sometimes used in hernia repair surgery. This study compares the use of a new, noncommercial, long-chain cyanoacrylate (n-octyl) TA and Ifabond for mesh fixation. MATERIALS AND METHODS: In two implant models in the rabbit, expanded polytetrafluorethylene meshes were fixed to the parietal peritoneum using a TA or tacks (intraperitoneal model), or polypropylene meshes used to repair partial abdominal wall defects were fixed with a TA or sutures (extraperitoneal model). Animals were euthanized 14 or 90 d postsurgery and implant specimens were processed for microscopy (labeling of macrophages and apoptotic cells), peritoneal fluid and biomechanical strength testing. Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were determinated in peritoneal fluid. RESULTS: Mesothelial cell deposition on the intraperitoneal implants fixed using the new TA and Ifabond was adequate and similar IL-6 and TNF-alpha levels were detected in these implants. Intraperitoneal meshes fixed with tacks showed IL-6 overexpression. Three months after surgery, macrophage and apoptotic cell rates were higher for the intraperitoneal implants fixed with Ifabond versus the new TA or tacks. In the extraperitoneal model, reduced macrophage and cell damage responses were observed in the meshes fixed with sutures versus both TA. Tensile strengths were greater for the tacks versus TA in the intraperitoneal implants and similar for the sutures and TA in the extraperitoneal implants (90 d). CONCLUSIONS: Both TA showed a good cell response in both models. Their use in an intraperitoneal location resulted in reduced tensile strength compared with the tacks. However, strengths were comparable when extraperitoneal implants were fixed with these adhesives or sutures. PMID- 27993220 TI - Intestinal alkaline phosphatase decreases intraperitoneal adhesion formation. AB - BACKGROUND: Damage to the peritoneum initiates an inflammatory response leading to the formation of adhesions, which subsequently cause significant morbidity in some patients. Intestinal alkaline phosphatase (IAP) is a gut enzyme capable of detoxifying various inflammatory mediators such as lipopolysaccharide, lipoteichoic acid, CpG DNA, and adenosine triphosphate. In this study, we aimed to examine the anti-inflammatory effects of IAP on postoperative adhesions in mice. METHODS: C57BL/6 mice were subjected to a midline laparotomy and then six musculoperitoneal buttons (MPBs) were created by pinching and ligating the peritoneum and underlying muscle. The buttons were half-excised and E-cauterized, and then cecal abrasion was performed. Five hundred microliters of vehicle with IAP 5000 U or vehicle alone were applied over the peritoneal cavity. In some experiments, the mice were euthanized on the first and second postoperative day (POD), and cytokines analysis was done on the MPB, peritoneal tissue, and peritoneal fluid. In separate experiments, the mice were sacrificed on the 21st POD, and adhesion to each button was scored based on type and tenacity. RESULTS: IAP group mice had significantly lower adhesion scores compared with controls (21.5 +/- 1.7 versus 13.2 +/- 1.3; P = 0.0014, n = 15). MPB from IAP group mice had significantly lower interleukin-1beta and tumor necrosis factor-alpha protein level compared to control mice (105.66 +/- 4.5 versus 69.8 +/- 4.8 versus pg/mg, P = 0.0001; 45.25 +/- 2.8 pg/mg versus 24.88 +/- 4.1 pg/mg; P = 0.0007, n = 10). IAP treatment significantly decreased interleukin-1beta and tumor necrosis factor alpha mRNA expression in MPB in the first POD (1.14 +/- 0.25 versus 0.33 +/- 0.07; P = 0.0068; 1.33 +/- 0.31 versus 0.33 +/- 0.08; P = 0.0064, n = 10). CONCLUSIONS: Application of IAP during laparotomy could represent a novel approach to prevent postoperative adhesions. PMID- 27993221 TI - Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing. AB - BACKGROUND: Diabetes disregulates inflammatory responses and impairs vascular function in wounds. Glucagon-like peptide-1 receptor (Glp-1R) agonists are hypoglycemic agents with pleiotropic vascular protective and anti-inflammatory effects. The therapeutic potential of a Glp-1 analogue in a diabetic rat model of excisional wound injury was investigated. MATERIALS AND METHODS: Excisional wounds were created on the dorsum of streptozotocin-induced diabetic rats, which received placebo or Glp-1 analogue exendin-4 (Ex4; 0.5 MUg/kg/d, i.p.) for 2 wk. The final-to-initial wound area ratio was measured for 14 d. Levels of superoxide anions and proinflammatory cytokines in the wound were determined. Angiogenesis was assessed using the Matrigel assay. Expression levels of proangiogenic factors and extracellular matrix proteins were measured. RESULTS: Ex4 restored wound closure in diabetic rats and significantly suppressed the generation of superoxide anions and interleukin-6 in wounds. The number of circulating endothelial progenitor (CD34+/KDR+) cells increased significantly in Ex4-treated diabetic rats, which also showed increased capillary tube formation. Protein levels of vascular endothelial growth factor receptor-2, phosphorylated endothelial nitric oxide synthase, matrix metalloproteinase-2, and transforming growth factor-beta were increased in diabetic rats receiving Ex4 therapy. Ex4 enhanced vascularity, dermal regeneration, and epidermal regeneration, while it decreased hemorrhaging and increased the number of proliferative cells in the dermis. CONCLUSIONS: Ex4 accelerated excisional wound healing in subjects with diabetes. Glp-1R activation attenuates inflammatory response and enhances angiogenesis during the early proliferation phase of wound healing in diabetic subjects, while it enhances transforming growth factor-beta/matrix metalloproteinase-mediated regeneration during the maturation phase. These results suggest that Ex4 could be used as a standard hypoglycemic agent in diabetic patients with wound injury. PMID- 27993222 TI - Here/In This Issue and There/Abstract Thinking: From Families to Mechanisms. PMID- 27993223 TI - Therapist-Guided, Internet-Delivered Cognitive-Behavioral Therapy for Adolescents With Obsessive-Compulsive Disorder: A Randomized Controlled Trial. AB - OBJECTIVE: Cognitive-behavioral therapy (CBT) is the first-line treatment for young people with obsessive-compulsive disorder (OCD), but most patients do not have access to this treatment. Thus, innovative ways to increase the accessibility of CBT are needed. The objective of this trial was to evaluate the efficacy of therapist-guided internet-based CBT (ICBT) for adolescents with OCD. METHOD: Sixty-seven adolescents (12-17 years old) with OCD were randomly assigned to a 12-week clinician- and parent-supported ICBT program (BiP OCD) or a waitlist condition. The primary outcome was the Children Yale-Brown Obsessive Compulsive Scale (CY-BOCS) administered by blinded assessors before and after the intervention. All patients were followed up 3 months after the intervention. RESULTS: In intention-to-treat analyses, BiP OCD was superior to waitlist on the CY-BOCS (time-by-group interaction, B = -4.53, z = -3.74, p < .001; Cohen's d = 0.69; 95% CI 0.19-1.18) and on most secondary outcome measurements. Patients randomized to BiP OCD also showed further improvement from post-treatment to 3 month follow-up, with a within-group pretreatment to follow-up effect size (Cohen's d) equal to 1.68 (95% CI 1.00-2.36). Patient satisfaction with BiP OCD was high. There were no relevant adverse events. Average clinician support time was 17.5 minutes per patient per week. CONCLUSION: Therapist-guided ICBT is a promising low-intensity intervention for adolescents with OCD and has the potential to increase access to CBT. It might be particularly useful in a stepped care approach, in which a large proportion of patients with moderately severe OCD could first be offered ICBT, thus freeing limited resources for more complex cases. Clinical trial registration information-Internet-Delivered CBT for Adolescents With OCD: A Randomized Controlled Study (BiPOCD); http://clinicaltrials.gov; NCT02191631. PMID- 27993224 TI - Maternal Depression Across the First Years of Life Impacts the Neural Basis of Empathy in Preadolescence. AB - OBJECTIVE: Exposure to maternal depression across the first years of life markedly increases children's susceptibility to psychopathology, yet no study has tested its effects on the maturation of children's social brain. METHOD: Using a birth cohort of mothers with no contextual risk (N = 1,983), families were followed at 7 time points from birth to 11 years and repeatedly assessed for maternal depression across the first 6 years to form 2 cohorts: mothers continuously depressed from birth to 6 years and controls without depression. At 11 years of age, children's (n = 72; depressed, n = 27; nondepressed, n = 45) brain response to others' pain was measured by magnetoencephalography. RESULTS: Preadolescents displayed a unique oscillatory pattern with higher alpha power to pain versus no pain expressing as alpha rebound, not alpha suppression, at a late time window (1,100-1,300 ms post-stimulus) in the supplementary motor area. This suggests that top-down processing in areas of the pain matrix can underpin the maturation of vicarious empathy. Children of mothers with depression showed enhanced alpha rebound to pain in the right posterior superior temporal gyrus, which was unrelated to emotion detection abilities, pointing to decreased late processing of others' overwhelming experiences in socio-cognitive areas. Alpha power in the posterior superior temporal gyrus was predicted by higher maternal intrusiveness and lower synchrony across early childhood. CONCLUSION: These findings, from the first study to examine maternal depression and early caregiving as long-term predictors of children's neural empathic response, pinpoint a decrease in top-down socio-cognitive mechanisms as potential pathways for the cross-generational transfer of vulnerability from mothers with depression to their offspring and highlight the need for early interventions focused on enhancing maternal attunement. PMID- 27993225 TI - Name No Names: The Role of the Media in Reporting Mass Shootings. PMID- 27993226 TI - Maternal Depressive Symptoms During and After Pregnancy and Psychiatric Problems in Children. AB - OBJECTIVE: Maternal depressive symptoms during pregnancy are associated with increased risk of psychiatric problems in children. A more precise understanding of the timing of the symptoms during pregnancy and their independence of other prenatal and postnatal factors in predicting child psychopathology risk is needed. We examined whether maternal depressive symptoms during pregnancy predict child psychiatric problems, whether these associations are trimester- or gestational-week-specific and/or independent of pregnancy disorders, and whether maternal depressive symptoms after pregnancy mediate or add to the prenatal effects. METHOD: The study sample comprised 2,296 women and their children born in Finland between 2006-2010, participating in the prospective pregnancy cohort study Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) and followed up from 1.9 to 5.9 years of age. The women completed the Center for Epidemiologic Studies Depression Scale biweekly between gestational weeks+days 12+0/13+6 and 38+0/39+6 or delivery. In the follow-up, they completed the Beck Depression Inventory-II and Child Behavior Checklist 11/2 5. RESULTS: Maternal depressive symptoms during pregnancy predicted significantly higher internalizing (0.28 SD unit per SD unit increase [95% CI = 0.24-0.32]), externalizing (0.26 [0.23-0.30]), and total problems (0.31 [0.27-0.35]) in children. These associations were nonspecific to gestational week and hence pregnancy trimester, independent of pregnancy disorders, and independent of, although partially mediated by, maternal depressive symptoms after pregnancy. Psychiatric problems were greatest in children whose mothers reported clinically significant depressive symptoms across pregnancy trimesters and during and after pregnancy. CONCLUSION: Maternal depressive symptoms during pregnancy predict increased psychiatric problems in young children. Preventive interventions from early pregnancy onward may benefit offspring mental health. PMID- 27993228 TI - i-Therapy: Asynchronous Telehealth Expands Access to Mental Health Care and Challenges Tenets of the Therapeutic Process. PMID- 27993227 TI - Association of Preterm Birth With Attention-Deficit/Hyperactivity Disorder-Like and Wider-Ranging Neurophysiological Impairments of Attention and Inhibition. AB - OBJECTIVE: Preterm birth has been associated with an increased risk of attention deficit/hyperactivity disorder (ADHD)-like symptoms and cognitive impairments similar to those seen in ADHD, including attention and inhibitory control difficulties. Yet data on direct comparisons across ADHD and preterm birth on cognitive-neurophysiological measures are limited. METHOD: We directly compared 186 preterm-born adolescents to 69 term-born adolescents with ADHD and 135 term born controls on cognitive-performance and event-related potential measures associated with attentional and inhibitory processing from a cued continuous performance test (CPT-OX), which we have previously shown to discriminate between the adolescents with ADHD and controls. We aimed to elucidate whether the ADHD like symptoms and cognitive impairments in preterm-born individuals reflect identical cognitive-neurophysiological impairments in term-born individuals with ADHD. RESULTS: Go-P3 amplitude was reduced, reflecting impaired executive response control, in preterm-born adolescents compared to both controls and adolescents with ADHD. Moreover, in preterm-born adolescents, as in term-born adolescents with ADHD, contingent negative variation amplitude was attenuated, reflecting impairments in response preparation compared to controls. Although the ADHD group showed significantly increased NoGo-P3 amplitude at FCz compared to preterm group, at Cz preterm-born adolescents demonstrated significantly decreased NoGo-P3 amplitude compared to the control group, similar to term-born adolescents with ADHD. CONCLUSION: These findings indicate impairments in response preparation, executive response control, and response inhibition in preterm-born adolescents. Although the response preparation and response inhibition impairments found in preterm-born adolescents overlap with those found in term-born adolescents with ADHD, the preterm group also shows unique impairments, suggesting more wide-ranging impairments in the preterm group compared to the ADHD group. PMID- 27993229 TI - Development of Two Dimensional Measures of Restricted and Repetitive Behavior in Parents and Children. AB - OBJECTIVE: Restricted and repetitive behaviors (RRBs) are a heterogeneous set of behaviors common across a wide range of neurodevelopmental disorders (NDDs) and neuropsychiatric disorders (NPDs) that extend well into the general population. This study introduces 2 dimensional measurements of RRBs for use in typical and clinical populations from infancy to adulthood. METHOD: The Childhood Routines Inventory-Revised (CRI-R) and the Adult Routines Inventory (ARI) were created and administered online to a nationally representative cohort of 3,108 parents with 3,032 children (range 12 months to 17 years 11 months). Twenty-six percent of children and 36% of adults had at least 1 NDD or NPD. RESULTS: Principal axis factoring exploratory analysis showed a 2-factor structure for the 2 instruments (motor behaviors/compulsions and rigidity/insistence on sameness). Analyses for convergent and discriminant validity, internal consistency (Cronbach alpha >= 0.94), and test-retest reliability (r >= 0.87) indicated strong psychometric properties. Item response theory analyses indicated strong reliability across the score range for the 2 instruments. RRB rates varied across development, peaking between the preschool and school years. Children with NDDs or NPDs (particularly those with autism spectrum disorder, schizophrenia/bipolar disorder, or obsessive compulsive disorder/tic disorders) had increased RRBs compared with those with no diagnosis. Parent-child (0.69-0.84) and sibling-sibling (0.76-0.87) intraclass correlations indicated high heritability. Children of parents with an NDD or an NPD exhibited more RRBs compared with children of parents without NDDs or NPDs. CONCLUSION: The CRI-R and ARI are open-source instruments with excellent psychometric properties and will be useful for developmental, clinical, and family genetic studies and for the identification of prodromal conditions involving RRBs. PMID- 27993230 TI - Trends in Antipsychotic Prescribing in Medicaid-Eligible Youth. AB - OBJECTIVE: To examine trends in the use of antipsychotic medication in Medicaid eligible youth from 2008 to 2013 and the factors associated with this use. METHOD: Youth aged 0 to 17 years with at least one claim indicating antipsychotic medication use were identified from the network of a behavioral health managed care organization (BHMCO). Demographic and clinical variables were derived from state eligibility data and service claims data from the BHMCO. Overall and specific prevalence rates of antipsychotic drug use were calculated over the course of 6 years (2008-2013). The probability of antipsychotic use during 2013 was further explored with logistic regression that included demographic and diagnostic groups. RESULTS: The overall trend in prevalence for antipsychotics for youth decreased from 49.52 per 1,000 members in 2008 to 30.54 in 2013 (p < .0001). Although rates decreased for all age groups, the rate per 1,000 members in 2013 for the youngest children was 3.79, versus 39.23 for 6- to 12-year-olds and 64.33 for 13- to 17-year-olds. Controlling for demographic and clinical variables, children 0 to 5 years old were 79% less likely to be prescribed antipsychotic medications compared to the oldest youth, 13 to 17 years of age (p < .0001). Rates were higher for males versus females regardless of age (odds ratio [95% CI] =1.48 [1.36-1.62], p < .0001). Children with a diagnosis of attention-deficit/hyperactivity disorder were less likely to be prescribed antipsychotics compared to those with diagnoses of autism spectrum disorder, bipolar disorder, psychoses, and depression. CONCLUSION: Prevalence rates decreased significantly over time for all socio-demographic groups. The largest decrease was observed for the youngest children, ages 0 to 5 years, with a rate in 2013 under half the rate for 2008. Clinical, policy, and managed care implications are discussed. PMID- 27993231 TI - Neural Markers in Pediatric Bipolar Disorder and Familial Risk for Bipolar Disorder. AB - OBJECTIVE: Bipolar disorder (BD) is highly heritable. Neuroimaging studies comparing unaffected youth at high familial risk for BD (i.e., those with a first degree relative with the disorder; termed "high-risk" [HR]) to "low-risk" (LR) youth (i.e., those without a first-degree relative with BD) and to patients with BD may help identify potential brain-based markers associated with risk (i.e., regions where HR+BD?LR), resilience (HR?BD+LR), or illness (BD?HR+LR). METHOD: During functional magnetic resonance imaging (fMRI), 99 youths (i.e., adolescents and young adults) aged 9.8 to 24.8 years (36 BD, 22 HR, 41 LR) performed a task probing face emotion labeling, previously shown to be impaired behaviorally in youth with BD and HR youth. RESULTS: We found three patterns of results. Candidate risk endophenotypes (i.e., where BD and HR shared deficits) included dysfunction in higher-order face processing regions (e.g., middle temporal gyrus, dorsolateral prefrontal cortex). Candidate resilience markers and disorder sequelae (where HR and BD, respectively, show unique alterations relative to the other two groups) included different patterns of neural responses across other regions mediating face processing (e.g., fusiform), executive function (e.g., inferior frontal gyrus), and social cognition (e.g., default network, superior temporal sulcus, temporo-parietal junction). CONCLUSION: If replicated in longitudinal studies and with additional populations, neural patterns suggesting risk endophenotypes could be used to identify individuals at risk for BD who may benefit from prevention measures. Moreover, information about risk and resilience markers could be used to develop novel treatments that recruit neural markers of resilience and attenuate neural patterns associated with risk. Clinical trial registration information-Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder and Child and Adolescent Bipolar Disorder Brain Imaging and Treatment Study; http://clinicaltrials.gov/; NCT00025935 and NCT00006177. PMID- 27993232 TI - Cortical Morphology Characteristics of Young Offspring of Patients With Schizophrenia or Bipolar Disorder. AB - OBJECTIVE: Cortical surface area and thickness abnormalities have been observed in patients with schizophrenia and bipolar disorders; however, no study thus far has examined cortical morphologic measurements in children and adolescents at genetic risk for the disorders comparatively. METHOD: One hundred thirty-seven participants, including 36 offspring of patients with schizophrenia (SzO), 54 offspring of patients with bipolar disorder (BpO), and 47 offspring of community controls (CcO), 6 to 17 years old, were assessed with clinical and neuroimaging methods. Sixty-nine percent of the sample was reassessed at a 27.6-month (mean) follow-up. Cortical surface reconstruction was applied to measure cortical area and thickness using FreeSurfer; mixed-effects models were used to investigate cross-sectional and longitudinal differences in global and lobar morphologic measurements. RESULTS: The SzO group exhibited a cross-sectional decrease in global, parietal, and occipital lobe surface area compared with the CcO group, and in the occipital lobe compared with the BpO group. In the SzO group, global and parietal surface area values were inversely associated with attenuated positive and negative prodromal symptom scores. No cross-sectional differences in cortical thickness were observed. Division of the sample by pubertal status showed group-by-time interactions in the pubertal and postpubertal SzO subgroup, with less longitudinal decrease in cortical surface area and thickness than in the CcO and BpO subgroups, respectively. CONCLUSION: The SzO, but not the BpO, group was characterized by cross-sectional decreases in surface area, and this was associated with prodromal symptoms. Longitudinal changes in cortical morphology associated with risk for schizophrenia may be expressed differently according to developmental stage. PMID- 27993233 TI - Does Exposure to Persistent Maternal Depression Alter the Developing Brain's Empathetic Circuitry? PMID- 27993234 TI - Multidimensional Treatment Foster Care and Psychotic Symptoms. PMID- 27993237 TI - Erratum. PMID- 27993235 TI - Dr. Leve et al. reply. PMID- 27993238 TI - The American Journal of Pathology, Value Beyond Simple Metrics. AB - This Editorial highlights the value of The American Journal of Pathology beyond normal metrics. PMID- 27993239 TI - Retractions. PMID- 27993240 TI - Corrigenda. PMID- 27993241 TI - Sirtuin 1 Activation Reduces Transforming Growth Factor-beta1-Induced Fibrogenesis and Affords Organ Protection in a Model of Progressive, Experimental Kidney and Associated Cardiac Disease. AB - Most forms of chronic, progressive kidney disease are characterized by fibrosis whereby the prototypical prosclerotic growth factor, transforming growth factor beta (TGF-beta), is thought to play a pivotal role. With the recent understanding that TGF-beta's canonical signaling pathway may be modified by acetylation as well as phosphorylation, we explored the role of the NAD+-dependent lysine deacetylase, sirtuin 1 (SIRT1) in fibrogenesis in the cell culture, animal model, and human settings. In vitro, the increase in collagen production that results from TGF-beta1 stimulation was ameliorated by the allosteric modifier of Sirt1 deacetylase, SRT3025, in association with a reduction in Smad3 reporter activity. In the remnant kidney model (subtotally or 5/6 nephrectomized rats) that develops progressive kidney disease in association with TGF-beta overexpression, administration of SRT3025 attenuated glomerular filtration rate decline and proteinuria without affecting blood pressure. Glomerulosclerosis and tubulointerstitial fibrosis were similarly reduced with Sirt1 activation as were cardiac structure and function in this rodent model of primary kidney and secondary cardiac disease. Relating these findings to the human setting, we noted a reduction in SIRT1 mRNA in kidney biopsies obtained from individuals with focal glomerulosclerosis. Together these studies highlight the potential of SIRT1 activation as a therapeutic strategy in progressive, fibrotic kidney disease. PMID- 27993243 TI - [National Mental Health Survey- NMHST 2015]. PMID- 27993244 TI - [A Cross-sectional Study of School dropout in adolescents: National Mental Health Survey Colombia 2015]. AB - INTRODUCTION: School dropout in adolescents can have negative consequences, not only for the individual and the family, but also for the society. To identify the characteristics associated with the occurrence of this event might contribute to the planning of a prevention strategy. OBJECTIVES: To evaluate the relationship between the individual and home characteristics and school dropout in adolescents from 12 to 17 years old in Colombia. METHODS: A cross sectional study was conducted from information taken from the results obtained in the 2015 National Mental Health Survey. A study was made of the relationship between the individual and home characteristics and school dropout in adolescents from 12 to 17 years old RESULTS: A higher percentage of school dropouts was found in the older adolescents, females, and those who have children. Among the home characteristics, it was observed that those homes with more than two people, located in rural area, or that are classified as poor, have an increased percentage of school dropout adolescents. CONCLUSIONS: Strategies for which the main goal is to prevent school dropout should consider populations with higher prevalence of out-of-school adolescents (female, homes in rural area, or household poverty). Preventive actions of adolescent pregnancy might contribute to reduce the school dropout rate. PMID- 27993245 TI - [Mental Problems, Mood and Anxiety Disorders in The Population Displaced by Violence in Colombia; Results of The National Mental Health Survey 2015]. AB - INTRODUCTION: Colombia has a large population exposed to violence. Our data suggest a significant number displaced by the conflict. As there is an increased risk of vulnerability, their problems and mental disorders need to be assessed in order to determine specific treatments. OBJECTIVES: To determine the prevalence of problems and mental disorders in those internally displaced by the conflict. METHODS: Data was obtained from the National Mental Health Survey 2015. The diagnostic tools used were the composite international diagnosis interview (CIDI CAPI), Self-reporting questionnaire (SQR). Alcohol consumption was assessed with the Alcohol Use Disorders Identification test (AUDIT). A survey based on the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was developed. The modified Post-traumatic Stress Disorder (PTSD) Checklist-Civilian version (PCL-C) was used to determine possible post-traumatic stress Disorder. Multidimensional poverty index (MPI) and Family-Apgar questionnaire were applied to general individual and household data. RESULTS: A total of 943 persons displaced by the conflict were reported, with self-report of symptoms in 16.4% (95% CI, 13.2-20.1). The prevalence of any of the measured mental disorders (CIDI CAPI) ever in life was 15.9% (95% CI, 11.9-21.1), with a suicidal ideation of 12.5% (95%CI, 9.0-17.1), and excessive alcohol consumption in 10.1% (95% CI, 7.2 13.9). More than one-third (35.6%, (95% CI, 30.7-40.8) of people report having experienced, witnessed, or been told that someone close had had a traumatic event related to the armed conflict. An increased risk of PTSD is reported by 3.6% (95% CI, 2.2-5.9) displaced people that had reported at least one traumatic event. Family dysfunction in the displaced population is absent (74.8% (95%.CI, 70.4 78.8). CONCLUSIONS: The displaced population has a high prevalence of problems and mental disorders, which confirms their disadvantaged situation. PMID- 27993242 TI - HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via beta-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. AB - Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2alpha and enhanced translation of beta-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced beta-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders. PMID- 27993246 TI - [Mental Health, Emotional Suffering, Mental Problems and Disorders in Indigenous Colombians. Data From the National Mental Health Survey 2015]. AB - BACKGROUND: Indigenous people represent 5% of the world population and one-third of the poor ones. Alcoholism rates, substance abuse problems, and mental disorders are shown to be higher than the general population. METHODS: An analysis was made of the data from the National Mental Health Survey 2015. In this survey, it was asked if self-recognition as a native was according to the culture, the people, or physical features. RESULTS: A total of 902 indigenous people were surveyed, corresponding to 8.3% of the surveyed adult population. The majority (39.5%) lived in the Pacific region, with 23.7% Atlantic region, and 20% in the Eastern region. More than one-quarter (26.6%) reported a status of poverty, 31.7% spoke the language of their people, and 17.8% reported displacement due to violence. Mental health was defined as, "having good physical health, to eat, sleep and rest, by 42.9%. As regards problems and mental disorders, 8% reported excessive consumption and 7.9% a risk consumption of alcohol. As regards general psychopathology, measured by the (Self-reporting questionnaire) SRQ, 8.1% of the population had symptoms. The life prevalences of anxiety and depressive mental disorders were reported by 6.7% women and 8.4% men, and the associated risk factors that show higher risk were: aged between 18 to 44 years, not speaking the language of their people, living in Bogota, living in urban areas, and consuming psychoactive substances and tobacco. CONCLUSIONS: People who recognised themselves as indigenous have higher rates of displacement by violence, report problems and common mental disorders that are associated with factors consistent with loss of cultural characteristics. PMID- 27993247 TI - [Personality Traits Screening in a Colombian Adult Population Sample - Colombian National Survey of Mental Health-2015]. AB - INTRODUCTION: Personality refers to the individual style in characteristic patterns of thinking, feeling and behaving. Traits may configure a personality disorder when there is a long-lasting rigid pattern of inner experience that deviates from the expectations of the individual's culture, are inflexible and form maladaptative schemes in different interpersonal scenarios. Given the pervasiveness of this structure, they cause impairment of functioning in the affected person. OBJECTIVE: To establish the prevalence of personality traits in all selected adults, using the module-structured interview WHO WHM-CIDI-CAPI for clusters A, B and C of personality traits. METHODS: Colombian National Survey on Mental Health with persons older than 18 years of age. RESULTS: Personality traits that are the most frequently described: Cluster A 46% (95%CI, 45.2-48.1) of people believe they are convinced that there are conspiracies behind many things in the world. Regarding the features of cluster B, 35.6% (95%CI, 34.2 37.0) of the population reports that generally they do not feel bad when offending or upsetting someone and 35.4% (95%CI, 33.9-36.8) refer to show feelings to anyone. The highest proportion of traits were found to the probable borderline personality disorder, as 4.6% (95%CI, 4.1-5.2) of the Colombian population aged 18 and older has 6 or more features of this type, and is the widely reported as an individual entity with similar rates in men and women. CONCLUSIONS: The high prevalence of disruptive personality traits requires more research. The high prevalence reported for borderline personality traits suggests the need to implement measures to improve and integrate a collaborative model of care for people afflicted with a possible borderline personality disorder. PMID- 27993248 TI - [Probable Mental Health Disorders Prevalence in Children With Chronic Conditions. Results From the National Mental Health Survey of Colombia 2015]. AB - INTRODUCTION: The prevalence of chronic conditions is increasing globally and this phenomenon covers pediatric populations. There is a relationship between chronic conditions and mental health problems, which has been insufficiently studied in the case of children. OBJECTIVE: To measure the frequency of problems and mental disorders in the Colombian population between 7 and 11 years, depending on the presence or absence of chronic conditions. METHODS: The information pertains to the National Survey of Mental Health of Colombia 2015, an observational cross-sectional nationally representative for the group between 7 and 11 years old. Mental problems where measure with the Reporting Questionnaire for Children (RQC), the 12 month prevalence of seven mental disorders were assessed using the Diagnostic Interview Schedule for Children Version parents (DISC-P) and a list of chronic conditions. Univariate and stratification analysis of the data were performed. RESULTS: 41.6% of the children with no chronic conditions, 56.7% of the children with 1 chronic condition and 70.8% in those with 2 or more have at least one RQC symptom; the highest prevalence of mental health symptoms are those with chronic inflammatory lung disease, followed by diabetes mellitus and allergies. The prevalence of one or more mental disorders in children without chronic conditions is 3.1% while those with at least 1 is 13.8%. CONCLUSIONS: A higher prevalence of mental disorders in children and its association with chronic conditions justifies further studies that address this issue and develop strategies with multidisciplinary interventions. PMID- 27993249 TI - [Prevalence of Mood and Anxiety Disorders on People with Chronic Conditions. Results from the National Mental Health Survey in Colombia 2015]. AB - INTRODUCTION: The study of mental disorders in people with chronic conditions recognises the importance of actively seeking and treating both, since chronic conditions have a higher prevalence than mental disorders and their comorbidity generates greater burden than if each one was considered separately. OBJECTIVES: To measure the prevalence of mood disorders and anxiety in a Colombian population of 12 years and older and with and without different chronic conditions. METHODS: The information is taken from the National Mental Health Survey 2015 in Colombia, which was an observational cross-sectional study with national representativeness for the age groups measured 12-17, 18-44, and 45 and older. Disorders measured where mood disorders and anxiety social phobia, generalised anxiety disorder, and panic disorder in the past 12 months, and several chronic conditions. Univariate and bivariate analyses were performed for these conditions. RESULTS: The highest prevalence of mood and anxiety disorders were found in people with gastrointestinal diseases, followed by those with chronic pain, heart, and lung diseases, which corresponded to 27.1%, 13.3%, 12.2%, and 11.5%, respectively, in those between 18 and 44 years old, and 15.9%, 12.2%, 8.0%, and 7.4% of those 45 and older, respectively. This was greater than the prevalence of these mental disorders in people with no chronic condition, where the prevalence is 3.5% in the younger, and 1.1% in the older group. However, the risk of these mental disorders is higher in older people. Thus, in those with gastrointestinal diseases when compared to people of the same age without any chronic condition the prevalence is 14.9 times higher, but for the same disease in the younger group it is 7.8. CONCLUSIONS: These findings link chronic conditions with a higher prevalence of mental disorders, which in the present study also highlights the greater comorbidity of mood and anxiety disorders in the elderly. PMID- 27993250 TI - [Violence due to Armed Conflict and Prevalence of Mood Disorders, Anxiety and Mental Problems in the Colombian Adult Population]. AB - BACKGROUND: Violence in Colombia has a history of over 50 years. Between 1985 and 2012 an estimated of 220,000 Colombians have died and about 6,000,000 have been displaced by violence. OBJECTIVE: To describe and compare the prevalence of some problems and mental disorders in the adult population in Colombia, taking into account the characteristics of the municipality, as regards its history of violence or armed conflict. METHODS: The results for adults (over 18 years) of some problems and mental disorders were taken from the ENSM-2015. The municipalities were classified according to the presence and intensity of the conflict using the classification proposed by the CERAC. Disorders were measured using CIDI-CAPI, and problems with AUDIT, modified PCL (Post-Traumatic Stress Disorder Checklist). An estimate was also made of psychoactive substances consumption. RESULTS: A total of 10,870 people were interviewed, of whom 5,429 had not changed residence. There was had permanent conflict in 21.8% of the municipalities, 65.5% had a discontinued conflict, and only 12.7% had been pacified or had no conflict. The intensity of the conflict was reported as high by 31.8% of the people. Violent municipalities have a higher prevalence of anxiety disorders, depression, possible Post-Traumatic Stress Disorder, and smoking. Alcohol consumption was more common in municipalities with less intense conflict. CONCLUSIONS: The municipalities classified as having high levels of violence have a higher prevalence of mental disorders and the majority of the mental problems. PMID- 27993251 TI - [The Construction of a Mental Health Component for the National Survey: NMHS 2015, Colombia]. AB - INTRODUCTION: Usually, mental health has been defined as the absence of mental disorders. In order to approach this concept in a plain sanitas way, it was considered necessary to crosslink a component for the National Mental Health Survey 2015 (NMHS; ENSM for its acronym in Spanish), that would respond to the specific orientation and particularities of the country. OBJECTIVE: To describe the structure and contents of the mental health component of the NMHS 2015 for the Colombian population over 7 years of age. METHODS: Review, documentary analysis and discussion regarding the concepts and tools with the team in charge of the NMHS and other groups. RESULTS: 353 documents were reviewed, and 180 were analyzed and discussed. The component model is presented, considering the ethic dimension of relationship care as a main element; it merges two inquiry dimensions or categories: subjective-relational, and social-collective. CONCLUSIONS: The structured mental health component provides information regarding the entire population. It also allows understanding and approaching the concept of mental health as a personal and collective "good life". PMID- 27993252 TI - [Colombia 2015 National Mental Health Survey. Study Protocol]. AB - INTRODUCTION: The 2015 National Mental Health Survey (NMHS) is the fourth mental survey conducted in Colombia, and is part of the National System of Surveys and Population Studies for health. METHODS: A narrative description is used to explain the background, references, the preparation, and characteristics of the 2015 NMHS. The 2015 NMHS and its protocol emerge from the requirements that support the national and international policies related to mental health. Together with the Ministry of Health and Social Protection, the objectives, the collection tools, the sample, and the operational plan are defined. The main objective was to obtain updated information about the mental health, mental problems and disorders, accessibility to health services, and an evaluation of health conditions. Participants were inhabitants from both urban and rural areas, over 7 years old, and in whom the comprehension of social determinants and equity were privileged. An observational cross-sectional design with national, regional and age group representativity, was used. The age groups selected were 7-11, 12 17, and over 18 years old. The regions considered were Central, Orient, Atlantic, Pacific, and Bogota. The calculated sample had a minimum of 12,080 and a maximum of 14,496 participants. CONCLUSIONS: A brief summary of the protocol of the 2015 NMHS is presented. The full document with all the collection tools can be consulted on the Health Ministry webpage. PMID- 27993253 TI - [Methodological Aspects of the Sampling Design for the 2015 National Mental Health Survey]. AB - INTRODUCTION: The WHO has encouraged the development, implementation and evaluation of policies related to mental health all over the world. In Colombia, within this framework and promoted by the Ministry of Health and Social Protection, as well as being supported by Colciencias, the fourth National Mental Health Survey (NMHST) was conducted using a observational cross sectional study. According to the context and following the guidelines and sampling design, a summary of the methodology used for this sampling process is presented. The fourth NMHST used the Homes Master Sample for Studies in Health from the National System of Studies and Population Surveys for Health to calculate its sample. This Master Sample was developed and implemented in the year 2013 by the Ministry of Social Protection. METHODS: This study included non-institutionalised civilian population divided into four age groups: children 7-11 years, adolescent 12-17 years, 18-44 years and 44 years old or older. The sample size calculation was based on the reported prevalences in other studies for the outcomes of mental disorders, depression, suicide, associated morbidity, and alcohol use. A probabilistic, cluster, stratified and multistage selection process was used. Expansions factors to the total population were calculated. RESULTS: A total of 15,351 completed surveys were collected and were distributed according to the age groups: 2727, 7-11 years, 1754, 12-17 years, 5889, 18-44 years, and 4981, >=45 years. All the surveys were distributed in five regions: Atlantic, Oriental, Bogota, Central and Pacific. CONCLUSIONS: A sufficient number of surveys were collected in this study to obtain a more precise approximation of the mental problems and disorders at the regional and national level. PMID- 27993254 TI - [Poverty and Mental Disorders in the Colombian Population: National Mental Health Survey 2015]. AB - INTRODUCTION: Poverty has been associated in some studies with poorer outcomes in mental problems and disorders. A circular relationship has been considered in which poverty fosters the appearance of mental illness and this facilitates greater poverty. There are no studies in Colombia on this subject. OBJECTIVE: To describe the association between mental problems and disorders and poverty according to the Multidimensional Poverty Index (MPI) in Colombia. MATERIAL AND METHODS: Using the 2015 National Mental Health Survey, adjusted with the expansion factors for the population. The prevalences of mental problems and disorders obtained through semi-structured interviews employing the instruments SRQ-20, AUDIT C and A, modified PCL, familiar APGAR and CIDI CAPI. The poverty status was determined by the MPI. RESULTS: A total of 13,200 households were interviewed, of which 13.5% were classified as in a poverty condition, 6.3% of the adolescents of poor households reported a life-time prevalence of any mental disorder, and 4.6% in the last 12 months. On the other hand, the prevalences for the same age group not in a poverty condition were 7.2% and 3.3%, respectively. For adults in poverty, the prevalence of life-time mental disorders were 9.2%, with 4.3% in the last year, while those not considered poor showed prevalences of 9.1% and 3.9% for the same time periods. CONCLUSIONS: For the population of Colombia, there is a relationship between not being able to access the basic basket of goods and the presence of mental diseases, although there does not seems to be an association between an increase in poverty and the deterioration of mental health. PMID- 27993255 TI - [Prevalence and Associated Factors of Mental Disorders in Colombian Child Population, the 2015 National Mental Health Survey]. AB - INTRODUCTION: The 2015 National Mental Health Survey aimed to expand our knowledge about the real mental state of children in Colombia, taking into account the fact that most mental disorders in adults begin during childhood or adolescence. It is essential to have an improved knowledge of the magnitude of this issue and to design timely interventions that reduce long term complications. OBJECTIVE: The aim of the study was to determine the prevalence of the disorders in the last 12 months and 30 days according to the DSM-IV, as well as to collect data about social and demographic variables. METHODS: The structured Diagnostic Interview Schedule for Children (DISC-P), which provides DSM-IV diagnoses, was applied to carers of non-institutionalised children between 7 and 11 years old. The disorders evaluated included: major depressive disorder, dysthymia, generalised anxiety disorder, separation anxiety disorder, attention deficit hyperactivity disorder in its three kinds (mixed, inattentive, and hyperactive), oppositional defiant disorder, and conduct disorder. The instrumentation was computer-assisted. RESULTS: Prevalences of the disorders are present both in the last 30 days and in the last 12 months. In general, there is a prevalence of any of the disorders of 3% (95% CI, 2.2-4.0) in the last 30 days, and 4.7% (95% CI, 3.6-6.2) in the last 12 months. When evaluated individually, attention deficit hyperactivity disorder is the most frequent disorder, with a prevalence of 2.3% and 3.0% in the last 30 days and the last 12 months, respectively. In addition, the disorders that are known to frequently begin during childhood are the most common disorders in the age group studied, with a prevalence of 2.5% in the last 30 days and 3.2% in the last year. CONCLUSIONS: The 2015 National Mental Health Survey provides precise information about the real mental situation in children between the ages of 7 and 11 years in Colombia, compared with past epidemiological studies in the country, which were restricted to specific populations. By improving the reliability on knowledge about mental disorders in children, it will be possible to design more appropriate and precise strategies for prevention, diagnosis, and treatment. PMID- 27993256 TI - [Depression and Anxiety Disorders and Associated Factors in the Adolescent Colombian Population, 2015 National Mental Health Survey]. AB - INTRODUCTION: There was a prevalence of mental disorders of 17% in adolescents in the past year. These tended to be chronic and their appearance at this age is associated with a worse prognosis than those in adulthood. OBJECTIVES: To determine the prevalence and mental factors associated with major depression and anxiety disorders. METHODS: Data were obtained from the IV National Mental Health Survey representing 5 regions. A structured computerised survey was conducted using the Computer Assisted Personal Interview-Composite International Diagnostic Interview-Adolescent Version (CAPI-CIDI-A), focused on the most common depression and anxiety disorders. It included a sample of 1754 adolescents between 12 and 17 years old. RESULTS: The prevalence of any disorder at some point in life was 7.2% (95%CI, 5.8-8.9). The most common disorder corresponded to social phobia manifested sometime in life in 4.8% (95%CI, 3.7-6.2). Less frequent were panic disorder in girls (0.2%; 95% CI, 0.1-1.0) and other bipolar disorders in boys (0.2%; 95%CI, 0.1-0.7). Among the associated factors of suffering from any disorder were, being female (OR=2.1), having little family support (OR=2.0), having witnessed at least one traumatic event (OR=2.6), and having had a previous suicide attempt (OR=3.4). Participation in at least one group was a protective factor (OR=0.5). CONCLUSIONS: Mental disorders of anxiety and depression represent a major burden of disease for Colombia. PMID- 27993257 TI - [Depression and Anxiety Disorders and Associated Factors in the Adult Colombian Population, 2015 National Mental Health Survey]. AB - INTRODUCTION: Mental disorders are the first causes of disability adjusted life years (DALY), contributing with the 7.4%. This value increases as the DALYs of the transmittable diseases decrease. OBJECTIVES: To determine the prevalence and associated factors of the major depressive and anxious disorders. METHODS: Data obtained from the IV Mental Health Survey with representation from 5 regions. A computerised interview was conducted, focusing on the most frequent anxiety and depressive disorders, using the CIDI CAPI 3.0. A sample of 10,870 adults over 18 years old was obtained. RESULTS: The lifetime prevalence of any of these disorders is 10.1% (95% CI: 8.8-11.5) in the population between 18 and 44 years, and of 7.7% (95% CI: 6.5-9.1) in those older than 45 years. The prevalence in the last 12 months was 5.1% (95% CI: 4.3-6.0) in the younger group, and 2.3% (95% CI: 1.8-3.0) in the older group. Of the people with evaluated mental disorders, 17.6% (95% CI: 13.1-23.4) had 2 or more disorders, a comorbidity that is more common in the female population (20.4%, 95% CI: 14.2-28.3) than in males (13.5%, 95% CI: 7.9-22.0). Major depressive disorder is the most prevalent of the disorders, with a lifetime prevalence of 4.3% (95% CI: 3.7-5.0). After adjusting in a multivariate model, being divorced or widowed (OR=1.3), previous suicide attempt (OR=3.3), and having 6 or more features of border-line personality, were associated with an increased risk of presenting with any of the studied disorders. CONCLUSIONS: Anxiety and depressive mental disorders are an important health burden in Colombia. PMID- 27993258 TI - [Suicidal Behaviour and Associated Factors in Colombia. Results from the 2015 National Mental Health Survey]. AB - INTRODUCTION: Suicidal behaviour leads to a significant cause of mortality in the world. It is important to know the factors associated with this behaviour in order to design public health policies that may decrease its incidence. OBJECTIVE: Describe the results of the Colombian National Survey of Mental Health related to suicidal behaviour in adults. RESULTS: It was observed that 5.5% (95% CI, 4.5-6.7) of men and 7.6% (95% CI, 6.6-8.7) of women had suicidal thoughts. A suicide plan was reported in 2.7% of women (95% CI, 2.1-3.0), and attempted suicide observed in 1.9% of men (95% CI, 1.4-2.5) and 3.3% of women (95% CI, 2.6 4.1). The region with the highest frequency of suicidal ideation was Bogota, with 10.3% (95% CI, 7.6-13.8) and was the lowest in the Atlantic region with 3.8% (95% CI, 3.0-4.8). It was found that the presence of any mental illness, especially depressive, anxiety disorders and borderline personality traits, as well as people who have been displaced by violence at least once in life, are associated with serious suicidal ideation. No differences were found in suicidal ideation as regards poverty or problems arising from alcohol consumption. CONCLUSIONS: Suicidal behaviour is common in the Colombian adult population, which warrants the design and implementation of interventions in the most vulnerable groups in order to reduce this risk. PMID- 27993259 TI - [Alcohol Consumption in the Colombian Population, 2015 National Mental Health Survey]. AB - INTRODUCTION: National Survey of Mental Health (ENSM) in 2015 in Colombia asks, among other conditions, about alcohol consumption in people 12-17 years old, and 18 and older. Data were presented by age and region, with no cross-references to other categories of mental health problems, disorders, access to services, and health status. OBJECTIVE: To assess alcohol consumption in Colombia, taking into account sociodemographic and clinical screening categories included. METHODS: Secondary database analysis, sample size: 15,231 people from 13,200 households of five regions (Atlantic, Bogota, Central, Eastern, and Pacific), with an age range from 12 to 96 years. AUDIT and AUDIT-C were used and stratified according to score and other variables included in the survey analysis. RESULTS: The high-risk drinking category was observed in 2.7% of children studied, with the highest percentage of drinking risk lying in the range of 18 to 44 years, with a clear majority of men. CONCLUSIONS: The study finds that a positive AUDIT-C in adults is associated with a higher percentage of non-anxiety, less anxiety problems, and traumatic events and traumatic events related to armed conflict. This requires further studies. Adults with positive AUDIT-C have a greater perception of well being, but also a higher percentage of households in poverty. The study of individual, social, family and environmental factors in specific populations should be developed in order to make more appropriate interventions. PMID- 27993260 TI - [Determining Factors in the Access to Mental Health Services by the Adult Colombian Population]. AB - INTRODUCTION: Access to mental health services by people with mental disorders has traditionally been limited, and is associated with attitudinal, social, and structural variables. OBJECTIVE: To analyse the factors that determine access to mental health services by the adult population (18-44 years old) in Colombia, from the results obtained in the 2015 National Mental Health Survey. MATERIAL AND METHODS: Analysis of variables of access to attention in mental health care for adults. The reasons for not consulting were classified as barriers of behavioural supply and demand. To analyse the factors associated with access to mental health services in the Colombian adult population, the use of health services in the last 12 months for emotional, nervous or mental health problems was taken into account, as well as associated variables such as demographic characteristics, occupational activity, affiliation to social security, and health status variables. The relationships between these variables were estimated using bivariate multinomial logistic regression models. RESULTS: Rural residence, being married, and having a chronic disease were associated with the decision to consult or not to consult the doctor. CONCLUSIONS: Further studies should be conducted to evaluate the situation as regards mental health care access, as well as to determine the potential factors associated with these limitations. PMID- 27993261 TI - [Design and Implementation of the Data Collection Tools for National Mental Health Survey of Colombia, 2015]. AB - INTRODUCTION: Population surveys on mental health are performed as part of the inputs required for the creation, implementation and evaluation of policies related to mental health, worldwide, and as an initiative of the World Health Organisation (WHO). was held The fourth National Survey of Mental Health (ENSM 2015) was carried out during the first half of 2015 on a representative sample of 2,727 children between 7 and 11 years of age, 1,754 adolescents, and 10, 870 adults who were selected throughout the country. OBJECTIVE: To describe the selection and definition of the tools used to measure mental health (including social cognition and violence), problems, mental disorders, and the evaluation of health states, as well as to describe the process used to develop the data collection tools finally used. RESULTS: The measurement of mental disorders in children was performed using the Diagnostic Interview Schedule for Children (DISC), and the Composite International Diagnostic Interview (CIDI) was used for adolescents and adults. For the remaining components evaluated in the survey, a search was conducted on the tools used at a national and international level. The selection of the toos used for the evaluation was based on the questions made by each tool, as well as the scientific validity that could be obtained from the results. In some cases the complete tool (as published) was used, in other cases the tools were constructed unifying parts of different ones, or questions were written based on the concepts or characteristics to be measured. Subsequently, a validation of content, concept and semantic of every tool was carried out, including the CIDI and DISC. The resulting tools were used on a group of people with different characteristics. It was noted that further clarification was necessary for some people to fully understand what was being asked. Because the collection of all the information in the survey would be computer assisted, a stream format was generated to guide the implementation in Blaise software, after the creation and wording of each tool in order to review the validation process of the survey and to ensure the integrity in the order of questions and their format. Fictitious cases were generated during the process, and volunteers participated in the testing. CONCLUSIONS: The tools for information collection used in the National Survey of Mental Health 2015 are presented. PMID- 27993262 TI - [The Recognition of Emotions, Empathy and Moral Judgment in the National Mental Health Survey in Colombia, 2015]. AB - BACKGROUND: Social cognition refers to the mental processes involved in social interactions. Different aspects, such as the perception of others, self knowledge, motivation and the cultural context, can modulate empathy responses and moral judgments regarding the actions of others. The National Mental Health Survey (ENSM for its acronym in Spanish) explored aspects of social cognition such as the perception of emotions, empathy and moral judgment in situations in which another person experiences pain. OBJECTIVE: To describe the overall findings of the ENSM in relation to the emotional perception and empathic responses to situations where pain is inflicted on others in an intentional or accidental manner. METHODS: A total of 3863 people aged 18-96 years old completed the social cognition module. They were asked to identify the emotions expressed in the images of several faces. A modified version of the awareness of social inference test (TASIT) was used. Additionally, the cognitive, affective, and moral elements of empathy were assessed with a modified version of the empathy for pain task (EPT), which uses a sequence of images in which someone is being hurt. RESULTS: Happiness was identified by 91.5% of those interviewed; neutral or emotionless faces were identified by 65%; 55% of respondents correctly identified surprise. Only 19.7%, 21.8% and 27.4% could identify negative emotions like fear, disgust and sadness, respectively. When the data were analysed by age, poverty status, and different regions of the country, the results tend to vary. As regards empathy, 73.7% correctly identified intentional actions, and accidental actions were identified by 56.6%. According to the moral judgment of some respondents, even in situations where the pain was caused by accident, there must be some kind of punishment (20.7% deserved a low punishment and 26.8% a moderate one). CONCLUSIONS: Noteworthy findings include the high recognition of happiness by the respondents, in contrast to the apparent difficulty in recognising sadness, and paradoxical results regarding punishment and empathy. This should be studied in greater detail, but these results can contribute to a deeper understanding of the complex Colombian social context. PMID- 27993263 TI - Haab's Striae. PMID- 27993264 TI - Leiomyoma of the Palpebral Conjunctiva. PMID- 27993265 TI - Medicare's New Quality Payment Program for Physicians. PMID- 27993266 TI - Optic Disc Shape Change With Glaucomatous Progression. PMID- 27993267 TI - Angiolymphoid Hyperplasia with Eosinophilia Accompanying Vernal Conjunctivitis. PMID- 27993268 TI - The Boston Keratoprosthesis: Highs and Lows of Intraocular Pressure and Outcomes. PMID- 27993269 TI - Re: Whitman et al.: Bifocals fail to improve stereopsis outcomes in high AC/A accommodative esotropia (Ophthalmology 2016;123:690-696). PMID- 27993270 TI - Reply. PMID- 27993271 TI - Re: Ianchulev et al.: Office-based cataract surgery: population health outcomes study of more than 21 000 cases in the United States (Ophthalmology 2016;123:723 728). PMID- 27993272 TI - Re: Sadiq et al.: Effect of vitreomacular adhesion on treatment outcomes in the ranibizumab for edema of the macula in diabetes (READ-3) study (Ophthalmology 2016;123:324-329). PMID- 27993273 TI - Reply. PMID- 27993274 TI - Reply. PMID- 27993275 TI - Reply. PMID- 27993276 TI - Re: Jabbarvand et al.: Endophthalmitis occurring after cataract surgery: outcomes of more than 480 000 cataract surgeries, epidemiologic features, and risk factors (Ophthalmology 2016;123:295-301). PMID- 27993277 TI - Reply. PMID- 27993278 TI - Re: Wells et al.: Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial (Ophthalmology 2016;123:1351-1359). PMID- 27993279 TI - Re: Brandt et al.: Human factors and ophthalmic drug packaging: time for a global standard (Ophthalmology 2015;122:2368-2370). PMID- 27993280 TI - Re: Javitt JC: Intracameral antibiotics reduce the risk of endophthalmitis after cataract surgery: does the preponderance of the evidence mandate a global change in practice? (Ophthalmology 2016;123:226-231). PMID- 27993281 TI - Reply. PMID- 27993282 TI - Re: Javitt JC: Intracameral antibiotics reduce the risk of endophthalmitis after cataract surgery: does the preponderance of the evidence mandate a global change in practice? (Ophthalmology 2016;123:226-231). PMID- 27993283 TI - Reply. PMID- 27993284 TI - Non-persistence and non-adherence to long-acting COPD medication therapy: A retrospective cohort study based on a large German claims dataset. AB - OBJECTIVES: The main objectives of this study, based on a large cohort of German COPD patients, were to assess the level of non-persistence (NP) and non-adherence (NA) with long-acting COPD inhaler treatment and to describe factors that may be associated with NP and NA. METHODS: This was a retrospective cohort analysis based on claims data provided by a German statutory health insurance fund (years 2010-2012). NP was analyzed for treatment-naive patients only; it was defined as a gap of >90 days in medication availability. With regard to NA, first the overall yearly medication possession ratio (MPR) was analyzed, NA was defined as MPR<80%. Secondly, adherence was explored only for the period in which a patient continued therapy with a long-acting COPD agent (no gap>90 days). RESULTS: 45,937 COPD patients who received at least one prescription of any long-acting COPD agent were identified (mean age 71.4 years; 45.2% female). Among these, 22,276 (42.4%) were classified as newly treated. The percentage of NP patients after 12 months was 65.3% on an overall patient level. Agent-specific NP rates were: 58.5% for LABA, 47.9% for LAMA, 78.0% for ICS, and 69.4% for single-device LABA/ICS combination treatment. The overall 12-month MPR across all agent classes on a patient level was 57.9% (70.0% of patients classified as non-adherent). During periods of general treatment continuation, the mean MPR/NA rates were 85.0%/30.1% (patient level across all agents), 89.3%/28.2% (LABA), 92.1%/16.2% (LAMA), 84.2%/43.8% (ICS) and 84.1%/42.8% (LABA/ICS combination). In the Cox regression analyses, several factors like female gender, higher CCI or lower number of specialist' visits were associated with earlier discontinuation of therapy. In comparison to LABA therapy, LAMA therapy was less likely to be associated with early NP, whereas patients who initiated ICS therapy or a single-device LABA/ICS combination therapy faced a higher NP risk. CONCLUSIONS: In German COPD patients, persistence and adherence with respect to long-acting bronchodilator therapy is poor. Approximately two thirds of patients fail to continue treatment after 12 months. In addition, about one third implement their treatment poorly during periods of general therapy continuation. PMID- 27993285 TI - Analysis of discrepant results between the Genotype(r) MTBDRplus assay and an antimicrobial drug susceptibility test for isoniazid-resistant tuberculosis. AB - BACKGROUND: We investigated discrepant results determined using the Genotype(r)MTBDRplus assay and a conventional antimicrobial drug susceptibility test (ADST) for isoniazid (INH) resistance using sequencing analysis and analyzed the clinical course of patients with discrepant results. METHODS: Among 1373 MTBDRplus assays performed at our tertiary referral center in South Korea between August 2009 and December 2015, the results for 46 (3.4%) differed from those for ADST. KatG and inhA gene sequencing analysis results were available for 23 patients. ADSTs were carried out using the absolute concentration method with Lowenstein-Jensen media. RESULTS: Results from 11 patients indicated INH susceptibility by MTBDRplus assay and INH resistance by ADST. For 5 of these patients, sequencing revealed no evidence of mutations, whereas specific mutations were detected in the remaining 6 patients. These should have been detected using the MTBDRplus assay. The other 12 patients had isolates with the opposite discrepancy, that is INH resistance by MTBDRplus assay but INH susceptibility by ADST. For 7 of these cases, sequencing results were consistent with those of the MTBDRplus assay. However, sequencing analysis did not explain the discrepancies in the remaining 5 patients. All 23 patients with discrepant results received individualized treatment regimens determined by the attending physician according to their test results and susceptibility to other drugs, such as rifampin. Good outcomes were reported for the majority. CONCLUSION: Discrepancies between test results for INH resistance on the MTBDRplus assay and ADST appear to be infrequent. Gene sequencing analysis is useful for identifying the cause of the discrepancy. PMID- 27993286 TI - Pulse transit time changes in subjects exhibiting sleep disordered breathing. AB - INTRODUCTION: Pulse Transit Time (PTT) represents a non-invasive marker of sleep fragmentation in OSAS. Little is known regarding PTT in sleepy subjects exhibiting nocturnal Inspiratory Flow Limitation (IFL) in the absence of apneas or desaturation. MATERIALS AND METHODS: The IFL cohort was gender and age matched to subjects with OSAS and a cohort where Sleep Disordered Breathing (SBD)/IFL was absent ("Non Flow Limited" or NFL cohort); PTT Arousal index (PTT Ar) defined by number of PTT arousals per hour. RESULTS: 20 subjects meeting criteria for the IFL cohort were aged and gender matched with OSAS and "NFL" subjects. Females comprised 65% of the IFL cohort; the mean BMI of the IFL cohort was significantly higher than the NFL cohort (34.25 v 28.90; p = 0.016) but not when compared to the OSAS cohort (34.25 v 36.31; p = 0.30). The PTT Ar in the IFL cohort (33.67 h) was significantly higher than the NFL cohort (23.89 h) but significantly lower than the OSAS cohort (55.21 h; F = 8.76; p < 0.001). PTT Ar was found to positively correlate with AHI (CC = 0.46; p < 0.001), ODI (CC = 0.47; p < 0.001) and RDI (CC = 0.49; p < 0.001). Within the IFL cohort, PTT Ar positively correlated with age (CC = 0.501; p = 0.024) but not gender and BMI. CONCLUSION: The PTT Arousal Index increased proportionately with severity of SDB with significantly higher markers of arousal in sleepy subjects exhibiting nocturnal IFL when compared to controls. Subjects exhibiting IFL were predominantly female with an elevated BMI. IFL may thus represent a significant pathogenic entity in the development of daytime sleepiness. PMID- 27993287 TI - Addition of vitamin B12 to exercise training improves cycle ergometer endurance in advanced COPD patients: A randomized and controlled study. AB - Vitamin B12 is essential in the homocysteine, mitochondrial, muscle and hematopoietic metabolisms, and its effects on exercise tolerance and kinetics adjustments of oxygen consumption (V'O2p) in rest-to-exercise transition in COPD patients are unknown. This randomized, double-blind, controlled study aimed to verify a possible interaction between vitamin B12 supplementation and these outcomes. After recruiting 69 patients, 35 subjects with moderate-to-severe COPD were eligible and 32 patients concluded the study, divided into four groups (n = 8 for each group): 1. rehabilitation group; 2. rehabilitation plus B12 group; 3. B12 group; and 4. placebo group. The primary endpoint was cycle ergometry endurance before and after 8 weeks and the secondary endpoints were oxygen uptake kinetics parameters (time constant). The prevalence of vitamin B12 deficiency was high (34.4%) and there was a statistically significant interaction (p < 0.05), favoring a global effect of supplementation on exercise tolerance in the supplemented groups compared to the non-supplemented groups, even after adjusting for confounding variables (p < 0.05). The same was not found for the kinetics adjustment variables (tauV'O2p and MRTV'O2p, p > 0.05 for both). Supplementation with vitamin B12 appears to lead to discrete positive effects on exercise tolerance in groups of subjects with more advanced COPD and further studies are needed to establish indications for long-term supplementation. PMID- 27993288 TI - Diagnosis of complicated parapneumonic effusion by pleural pH measurement is jeopardized by inadequate physician knowledge and guideline-discordant laboratory practice. AB - Pleural fluid pH is a crucial determinant of complicated parapneumonic effusion diagnosis and the need for drainage. It is best measured by blood gas analyzer. We examined whether physicians were aware of this, and whether their laboratories measured pleural pH according to their expectations. Only 53% of physicians understood the need for blood gas analyzer measurements, only 50% of laboratories used blood gas analyzers, and only 35% of physicians correctly identified the method performed in their laboratory. Diagnosis of complicated parapneumonic effusion is jeopardized by inadequate physician knowledge and guideline discordant laboratory practice. We recommend cooperation between thoracic and biochemistry specialty societies to rectify this issue. PMID- 27993289 TI - Beneficial effects of Omalizumab therapy in allergic bronchopulmonary aspergillosis: A synthesis review of published literature. AB - Omalizumab, a humanized mAb that binds to IgE, has been an effective therapy for patients with severe allergic asthma; however, there are few clinical trials examining the efficacy of Omalizumab in patients with allergic bronchopulmonary aspergillosis (ABPA) except some case reports. To assess the clinical and immunological effects of Omalizumab in ABPA patients, we made a synthesis review of 102 cases from 30 published literature, analyzed the effects of Omalizumab therapy in ABPA and conducted subgroup analyses to determine factors that influenced the therapy endpoints. We found that Omalizumab treatment not only provided a clinically important reduction in serum IgE, exacerbation rates and steroid requirement, but also showed attenuated asthma symptoms and improved pulmonary function parameters in patients with ABPA. Moreover, further discussion was made when interpretating the results. Double-blind, randomized, placebo controlled trials are necessary to establish the efficacy and safety of this novel therapeutic intervention for ABPA patients. PMID- 27993290 TI - Increased levels of prostaglandin E-major urinary metabolite (PGE-MUM) in chronic fibrosing interstitial pneumonia. AB - BACKGROUND: Dysregulation of the prostaglandin E2 (PGE2) signaling pathway has been implicated in interstitial pneumonia (IP) pathogenesis. Due to the unstable nature of PGE2, available detection methods may not precisely reflect PGE2 levels. We explored the clinical usefulness of measuring stable prostaglandin E major urinary metabolite (PGE-MUM) with respect to pathogenesis and extent of chronic fibrosing IP (CFIP), including idiopathic pulmonary fibrosis (IPF), as PGE-MUM is reflective of systemic PGE2 production. METHODS: PGE-MUM was measured by radioimmunoassay in controls (n = 124) and patients with lung diseases (bronchial asthma (BA): n = 78, chronic obstructive pulmonary disease (COPD): n = 33, CFIP: n = 44). Extent of lung fibrosis was assessed by fibrosing score (FS) of computed tomography (CT) (FS1-4). Immunohistochemical evaluation of COX-2 was performed to find PGE2 producing cells in IPF. Human bronchial epithelial cells (HBEC) and lung fibroblasts (LFB) were used in in vitro experiments. RESULTS: Compared to control, PGE-MUM levels were significantly elevated in CFIP. PGE-MUM levels were positively correlated with FS, and inversely correlated with %DLCO in IP (FS 1-3). COX-2 was highly expressed in metaplastic epithelial cells in IPF, but lower expression of EP2 receptor was demonstrated in LFB derived from IPF. TGF-beta induced COX-2 expression in HBEC. CONCLUSIONS: PGE-MUM, elevated in CFIP, is a promising biomarker reflecting disease activity. Metaplastic epithelial cells can be a source of elevated PGE-MUM in IPF. PMID- 27993291 TI - Validation of asthma control questionnaire and risk factors affecting uncontrolled asthma among the Lebanese children's population. AB - OBJECTIVES: To validate the Arabic version of the Asthma Control Test (ACT) in asthmatic children in Lebanon and identify risk factors that might affect asthma control in these children. METHODS: This study, conducted between December 2015 and April 2016, included 300 children. RESULTS: A high Cronbach's alpha was found for the full scale (0.959). The correlation factors between each item of the ACT scale and the whole scale ranged between 0.710 and 0.775(p < 0.001 for all items). Low mother's educational level as well as the history of asthma in the mother and the father would significantly increase the risk of uncontrolled asthma (p = 0.001; Beta = 1.862; p < 0.001; Beta = 3.534; p < 0.001; Beta = 1.885respectively). Cigarette smoking during breastfeeding and waterpipe smoking by the mother during pregnancy were both significantly associated with uncontrolled asthma (p = 0.005; Beta = 2.105 and p = 0.041; Beta = 2.325 respectively). The high mother's level of education was significantly associated with more asthma control (p = 0.008; Beta = -0.715). CONCLUSION: The Arabic version of the asthma control questionnaire is a valid tool to use in pediatric patients in the Lebanese population to assess asthma control. Waterpipe smoking during pregnancy and cigarette smoking during breastfeeding, as well as the lower education level are risk factors for uncontrolled asthma. Spreading awareness among health care professionals, as well as reinforcing health education seem to be an important step toward a better asthma control. PMID- 27993293 TI - Effect of psychological and other factors on quality of life amongst asthma outpatients in Lagos, Nigeria. AB - BACKGROUND: This study aimed to assess the effect of psychological and other possible factors associated with poor health related quality of life (HRQOL) in outpatient with asthma in Lagos, Nigeria. METHODS: Patients (n = 201) recruited from the adult asthma outpatient clinic were assessed for sociodemographic and asthma related variables. Levels of social support (with Oslo 3-Item Social Support Scale), disability (with WHO Disability Assessment Scale) were assessed. The presence of anxiety and depression was assessed using the Mini International Neuropsychiatric Interview (M.I.N.I) and asthma related quality of life was assessed with the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ). RESULTS: Of the 4 domains of Mini-AQLQ, the "environmental" domain has the lowest weighted mean score of 2.43 (SD = 1.64) while the "activity limitation" domain has the highest mean score of 4.74 (SD = 1.57). Poor asthma related QOL was independently associated with being unemployed (p = 0.028), poor social support (p = 0.002), nocturnal asthma (p = 0.046), clinically rated "severe asthma" (p = 0.002), patients rated "severe asthma" (p < 0.001), high level of disability (p < 0.001) and presence of Anxiety/Depression (p < 0.001). CONCLUSION: Our study has shown that psychological variables, disability, patients' subjective severity rating and social support are the most important factors independently associated with asthma related QOL. These factors should be considered in planning health care services or formulating a predictive intervention model. PMID- 27993292 TI - Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease. AB - BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting beta2-agonists and long-acting muscarinic antagonists, given potential cardiovascular effects. METHODS: Two 52-week Phase III trials (TONADO(r)) investigated tiotropium/olodaterol (5/5 and 2.5/5 MUg) versus tiotropium 2.5, 5 MUg and olodaterol 5 MUg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities. RESULTS: This analysis comprised 3100 patients with moderate to very severe COPD, treated for <=1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups. CONCLUSIONS: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 MUg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity. TRIAL REGISTRY: ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287. PMID- 27993294 TI - The effect of habitual waterpipe tobacco smoking on pulmonary function and exercise capacity in young healthy males: A pilot study. AB - BACKGROUND: Evidence regarding the health effects of habitual waterpipe smoking is limited, particularly in young smokers. Respiratory health and cardiopulmonary exercise tests were compared in young male habitual waterpipe smokers (WPS) versus non-smokers. METHODS: 69 WPS (>=3 times/week for three years) and 69 non smokers were studied. Respiratory health was assessed through the American Thoracic Society and the Division of Lung Diseases (ATS-DLD-78) adult questionnaire. Pulmonary function and cardiopulmonary exercise tests were performed. Self-reported respiratory symptoms, forced expiratory volume in first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, forced expiratory flow between 25 and 75% of FVC (FEF25-75%), peak expiratory flow (PEF), exercise time, peak end-tidal CO2 tension (PetCO2), subject-reported leg fatigue and dyspnea; peak O2 uptake (VO2 max), and end-expiratory lung volume (EELV) change from baseline (at peak exercise) were measured. RESULTS: WPS were more likely than non-smokers to report respiratory symptoms. WPS also demonstrated: shorter exercise time; lower peak VO2; higher perceived dyspnea at mid-exercise; lower values of the following: FEV1, FVC, PEF, and EELV change. CONCLUSION: Habitual waterpipe tobacco smoking in young seemingly healthy individuals is associated with a greater burden of respiratory symptoms and impaired exercise capacity. PMID- 27993295 TI - Viruses are prevalent in non-ventilated hospital-acquired pneumonia. AB - BACKGROUND: Hospital-acquired pneumonia arising in non-ventilated patients (NVHAP) is traditionally thought to be caused by bacteria, and little is known about viral etiologies in this syndrome. We sought to describe the prevalence of viruses causing NVHAP and to determine factors independently associated with the isolation of a virus. METHODS: We identified patients with NVHAP over one year and reviewed their cultures to determine etiologies. Patients with a viral process were compared to those with either negative cultures or a bacterial infection to determine variables independently associated with the recovery of a virus. RESULTS: Among 174 cases, cultures were positive in 46.0%, with viruses identified in 22.4%. Bacterial pathogens arose 23.6% of subjects. The most common viruses included rhinovirus, influenza, and parainfluenza. We noted no seasonality in the isolation of viral organisms, and most cases of viral NVHAP developed after more than a week length of stay (LOS). Outcomes in viral NVHAP were similar to those with bacterial NVHAP. Patients with viral and bacterial NVHAP were generally similar. Two variables were independently associated with isolation of a virus: a history of coronary artery disease (adjusted odds ratio: 5.16, 95% CI: 1.14-22.44) and a LOS of greater than 10 days prior to NVHAP diagnosis (adjusted odds ratio: 2.97, 95% CI: 1.35-6.51). As a screening test for a virus, neither had a good sensitivity or specificity. CONCLUSIONS: Viruses represent a common cause of NVHAP. Clinicians should consider viral diagnostic testing in NVHAP, as this may represent a means to enhance antimicrobial stewardship. PMID- 27993296 TI - Adult Female With Abdominal Pain. PMID- 27993297 TI - Young Child With Breathlessness. PMID- 27993299 TI - Commentary. PMID- 27993298 TI - Making Sense of a Negative Clinical Trial Result: A Bayesian Analysis of a Clinical Trial of Lorazepam and Diazepam for Pediatric Status Epilepticus. AB - STUDY OBJECTIVE: We demonstrate the application of a Bayesian approach to a recent negative clinical trial result. A Bayesian analysis of such a trial can provide a more useful interpretation of results and can incorporate previous evidence. METHODS: This was a secondary analysis of the efficacy and safety results of the Pediatric Seizure Study, a randomized clinical trial of lorazepam versus diazepam for pediatric status epilepticus. We included the published results from the only prospective pediatric study of status in a Bayesian hierarchic model, and we performed sensitivity analyses on the amount of pooling between studies. We evaluated 3 summary analyses for the results: superiority, noninferiority (margin <-10%), and practical equivalence (within +/-10%). RESULTS: Consistent with the original study's classic analysis of study results, we did not demonstrate superiority of lorazepam over diazepam. There is a 95% probability that the true efficacy of lorazepam is in the range of 66% to 80%. For both the efficacy and safety outcomes, there was greater than 95% probability that lorazepam is noninferior to diazepam, and there was greater than 90% probability that the 2 medications are practically equivalent. The results were largely driven by the current study because of the sample sizes of our study (n=273) and the previous pediatric study (n=61). CONCLUSION: Because Bayesian analysis estimates the probability of one or more hypotheses, such an approach can provide more useful information about the meaning of the results of a negative trial outcome. In the case of pediatric status epilepticus, it is highly likely that lorazepam is noninferior and practically equivalent to diazepam. PMID- 27993300 TI - Resuscitation Can Save Lives: Training the Public. PMID- 27993301 TI - Epic Finger. PMID- 27993302 TI - Ambulance. PMID- 27993303 TI - Loperamide Will Stop You Up but It Can Also Bring You Down: January 2017 Annals of Emergency Medicine Journal Club. PMID- 27993304 TI - Postpartum Woman With Seizures. PMID- 27993305 TI - Postpartum Headaches. PMID- 27993306 TI - Elderly Man With Abdominal Discomfort and Circulatory Failure. PMID- 27993307 TI - Young Man With Scrotal Swelling and Pain. PMID- 27993309 TI - Improving the Safety of Rapid Sequence Intubation in the Emergency Department. PMID- 27993308 TI - Comparison of Etomidate and Ketamine for Induction During Rapid Sequence Intubation of Adult Trauma Patients. AB - STUDY OBJECTIVE: Induction doses of etomidate during rapid sequence intubation cause transient adrenal dysfunction, but its clinical significance on trauma patients is uncertain. Ketamine has emerged as an alternative for rapid sequence intubation induction. Among adult trauma patients intubated in the emergency department, we compare clinical outcomes among those induced with etomidate and ketamine. METHODS: The study entailed a retrospective evaluation of a 4-year (January 2011 to December 2014) period spanning an institutional protocol switch from etomidate to ketamine as the standard induction agent for adult trauma patients undergoing rapid sequence intubation in the emergency department of an academic Level I trauma center. The primary outcome was hospital mortality evaluated with multivariable logistic regression, adjusted for age, vital signs, and injury severity and mechanism. Secondary outcomes included ICU-free days and ventilator-free days evaluated with multivariable ordered logistic regression using the same covariates. RESULTS: The analysis included 968 patients, including 526 with etomidate and 442 with ketamine. Hospital mortality was 20.4% among patients induced with ketamine compared with 17.3% among those induced with etomidate (adjusted odds ratio [OR] 1.41; 95% confidence interval [CI] 0.92 to 2.16). Patients induced with ketamine had ICU-free days (adjusted OR 0.80; 95% CI 0.63 to 1.00) and ventilator-free days (adjusted OR 0.96; 95% CI 0.76 to 1.20) similar to those of patients induced with etomidate. CONCLUSION: In this analysis spanning an institutional protocol switch from etomidate to ketamine as the standard rapid sequence intubation induction agent for adult trauma patients, patient-centered outcomes were similar for patients who received etomidate and ketamine. PMID- 27993311 TI - Elderly Man with Syncope. PMID- 27993310 TI - Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Acute Carbon Monoxide Poisoning. PMID- 27993312 TI - Wrist Pain after a Fall. PMID- 27993313 TI - Elderly Man With Headache and Neck Pain. PMID- 27993314 TI - Young Man With Abdominal Pain. PMID- 27993315 TI - Effect of physical effort on mental workload of cyclists in real traffic in relation to age and use of pedelecs. AB - To improve cycling safety, insight is required into the factors that contribute to road safety of older cyclists. From the wide range of possible factors, this paper addresses the role of physical effort on mental workload of cyclists with the aim to investigate whether physical effort affects mental workload of cyclists in real traffic in a field experiment. Two instrumented bicycles, a conventional bicycle and a pedelec, were used. Mental workload of cyclists in two age groups - 30-45 years and 65 years and over - was measured by means of a secondary cognitive task requiring the detection and reaction to visual stimuli on a cycle route that varied in physical effort and task complexity. We expected physical effort to impair performance on the secondary task in complex traffic sections and not in simple sections, and that this impairment would be greater for older cyclists because of age related reduced muscle strength than for younger cyclists. We expected this impairment to be smaller if a pedelec was used. If such would be the case, this would indicate pedelecs to be beneficial for this older age group, because of a lower mental workload. Our study confirmed that increased physical effort in complex traffic sections deteriorated the detection of relevant stimuli in both age groups. Overall, older cyclists had longer reaction times and lower hit rates than younger cyclists. Mental workloads of cyclists are basically the same when cycling on a conventional bicycle or on a pedelec. In theory, pedelecs may be beneficial to reduce physical effort in cycling in order to maintain enough mental capacity to handle complex traffic situations. However, this study did not demonstrate these benefits. As pedelecs are often used for longer trips, by elderly with low muscle strength, future studies should also explore the effect of higher physical effort over longer periods of time, and also specifically in elderly with low muscle strength. PMID- 27993317 TI - Corrigendum to "Screening for Prostate Cancer: Practical Analysis of the ERSPC and PLCO Trials" [Eur Urol 2011;59:365-9]. PMID- 27993316 TI - Corrigendum to "Effects of Once-Daily Tadalafil on Erectile Function in Men with Erectile Dysfunction and Signs and Symptoms of Benign Prostatic Hyperplasia" [Eur Urol 2009;56:727-36]. PMID- 27993318 TI - Introduction. PMID- 27993319 TI - Lymphatic Anatomy. AB - Recent development of new lymphatic imaging and intervention techniques, such as intranodal lymphangiogram, dynamic contrast enhanced magnetic resonance lymphangiography and lymphatic embolization, have resulted in the resurgence of interest in the lymphatic anatomy. The lymphatic system is a continuous maze of interlacing vessels and lymph nodes and is extremely complex and variable. This presents a significant challenge for interpretation of imaging and performance of interventions on this system. There is an embryological reason for this complexity and variability; the lymphatic system sprouts off of primordia from several locations in the body, which later fuse together at different stages of development of the embryo. The lymphatic system can be divided in three distinct parts: soft tissue lymphatics, intestinal lymphatics, and liver lymphatics. Liver and intestinal lymphatics generate approximately 80% of the body lymph and are functionally the most important parts of the lymphatic system. However, their normal anatomy and pathological changes are relatively unknown. In this chapter we will explore the anatomy of these three systems relevant to lymphatic imaging and interventions. PMID- 27993320 TI - Novel Lymphatic Imaging Techniques. AB - The lymphatic system plays an important role in immune regulation, transport of metabolites, and fluid balance. The key circulatory role of the lymphatic system is to transport fluid from tissue back into the venous system via lymphovenous connections. Despite the centuries-old recognition of this key role, there has been poor understanding of lymphatic flow pathophysiology because of a lack of a simple reliable noninvasive clinical lymphatic imaging method. This lack of clinical imaging has limited the treatment options for patients with lymphatic flow disorders. Recent development of noncontrast magnetic resonance (MR) lymphangiogram and dynamic contrast MR lymphangiography make it possible to visualize central lymphatic anatomy and flow dynamics with high spatial and temporal resolution. Dynamic contrast MR lymphangiography has provided insight into understanding the pathophysiology of several pulmonary lymphatic flow disorders and provides guidance for interventional procedures. Another important development has been intranodal lymphangiogram, which has now replaced pedal lymphangiogram as the main lymphatic interventional modality, and which provides quick and reliable access to the central lymphatic ducts for interventional procedures. These new techniques have led to a resurgence in interest in the lymphatic system and the development of new treatments for patients with lymphatic flow disorders. PMID- 27993321 TI - Peripheral Magnetic Resonance Lymphangiography: Techniques and Applications. AB - Peripheral lymphedema is a chronic progressive and debilitating disorder that results from abnormal lymphatic drainage. Advances in microsurgical techniques have led to the development of new treatment options for lymphedema that benefit from preoperative imaging to select the most appropriate surgical repair. Magnetic resonance (MR) lymphangiography is a noninvasive imaging modality capable of providing high-resolution 3D images of the lower extremities to define the severity and extent of lymphedema and depict individual lymphatic channels. The MR examination consists of 2 primary sequences. The first is a 3D heavily T2 weighted sequence to depict the severity and extent of the lymphedema. The second is a fat-suppressed 3D spoiled gradient-echo sequence performed after the intracutaneous injection of an extracellular gadolinium-based MR contrast agent. As venous enhancement almost always occurs, one of the interpretative challenges is differentiating enhancing lymphatic channels from superficial veins. MR techniques that can help with venous contamination include the addition of a contrast-enhanced MR venogram to the examination protocol, or the use of an iron based blood-pool contrast agent to selectively suppress venous enhancement. PMID- 27993322 TI - Lymphoscintigraphy for Imaging of the Lymphatic Flow Disorders. AB - Lymphoscintigraphy has introduced with the great advantage for diagnostic imaging of the lymphatic flow disorders. Lymphoscintigraphy can be performed in patients of any age, including neonates, and even in patient in critical conditions. The procedure is quite simple, and it needs only subcutaneous injection of small amounts of radiotracers. From subcutaneous tissue the radiotracer is taken by the lymphatic vessels and gives off energy in the form of gamma radiation detected by a gamma camera. Radiotracers rarely cause the allergic reaction and can be administered to the patients with allergy to iodine contrast media. Comparing with the Lipiodol, radiotracers cannot cause pulmonary embolism; therefore, it is safe for the patients with respiratory dysfunction. The objective of this article is to describe the indication, technique, equipment, pitfalls, safety, and effectiveness of lymphoscintigraphy for imaging of the lymphatic flow disorders. PMID- 27993323 TI - Lymphangiography for Thoracic Duct Interventions. AB - Lymph leaks resulting in chylous pleural effusions can be life-threatening. Minimally invasive thoracic duct embolization and disruption have been gaining acceptance as first-line treatment for these leaks. This review discusses the techniques for both pedal and intranodal lymphangiography in detail. It also discusses the use of lymphangiography as a means of targeting a retroperitoneal lymphatic to facilitate thoracic duct interventions for chyle leaks. Finally, outcomes and adverse events pertaining to these thoracic duct interventions are discussed. PMID- 27993324 TI - Nontraumatic Chylothorax: Diagnostic Algorithm and Treatment Options. AB - Nontraumatic chylothorax is a relatively rare condition in which the intestinal lymph (chyle) leaks into the pleural cavity. Nontraumatic chylothorax is more difficult to treat than the more common traumatic chylothorax because the site of chylous leak may occur in less predictable locations. In the past, patients with nontraumatic chylothoraces were offered traditional fluoroscopically guided lymphangiography and thoracic duct embolization similar to traumatic chylothorax. However, the observation that thoracic duct embolization outcomes for nontraumatic chylothorax differed based on the imaging findings during lymphangiography has led to the development of a treatment algorithm, which incorporates noninvasive diagnostic studies, such as magnetic resonance lymphangiography. The development of this systematic approach allows better delineation of the source of the chylous leak and selection of the appropriate method of embolization. In this article, we will review the etiologies of nontraumatic chylothorax, the diagnostic work-up for managing this condition, and the treatment algorithm to care for these patients. PMID- 27993325 TI - Percutaneous Treatment of Chylous Ascites. AB - Chylous ascites occurs as a result of lymphatic leakage, which contains high concentration of triglycerides. The leakage is caused by various benign or malignant etiologies ranging from congenital lymphatic abnormality to trauma. Lymphangiography has been shown to be effective in the diagnosis of lymphatic leakage and has also been reported to have therapeutic outcome. The development of intranodal technique for lymphangiography has recently made the procedure more widespread. As an adjunctive procedure, percutaneous embolization may be performed which involves use of embolic agents such as N-butyl cyanoacrylate and coil to occlude the leak. Embolization in the lymphatic system was first made popular by the introduction of thoracic duct embolization by Cope et al and has recently led to the development of various techniques for percutaneous embolization. This article reviews the options and techniques for percutaneous treatment of lymphatic leaks in patients presenting with chylous ascites. PMID- 27993327 TI - Percutaneous Treatment of Lymphatic Malformations. AB - Lymphatic malformations are slow-flow vascular anomalies composed of dilated lymphatic channels and cysts of varying sizes. Percutaneous treatments, particularly sclerotherapy, play an important role in the treatment of these lesions, often obviating the need for surgical intervention. Owing to the complex nature of these lesions, a multidisciplinary approach should be used to guide diagnosis and management. This submission focuses on the workup and treatment of pediatric lymphatic malformations at our institution, with a focus on sclerotherapy. Therapeutic outcomes and the management of postprocedural complications are also discussed. PMID- 27993326 TI - Interventional Treatment of Pulmonary Lymphatic Anomalies. AB - Pulmonary lymphatic diseases have been recognized for many years and have been referred as pulmonary lymphangiectasia, pulmonary lymphangiomatosis, plastic bronchitis, and idiopathic chylothorax or chylopericardium. The lymphatic etiology of these conditions has been determined by detection of cystic lymphatic structures on biopsy or postmortem examination. Development of new imaging techniques such as dynamic contrast-enhanced magnetic resonance lymphangiography has allowed better understanding of pathophysiology of these conditions. Dynamic contrast-enhanced magnetic resonance lymphangiography demonstrated that the common denominator of these disorders is an abnormal pulmonary lymphatic flow from the thoracic duct toward pulmonary parenchyma. This abnormal lymphatic flow propagates into mediastinum, lung parenchyma, pleural surfaces, and bronchial submucosa and has been termed as pulmonary lymphatic perfusion syndrome (PLPS). Known clinical presentation of PLPS includes spontaneous chylothorax or pericardium, neonatal chylous effusions, and plastic bronchitis. PLPS has been observed in all age groups and can be considered as a congenital anatomical lymphatic variant. The onset of the clinical symptoms can be provoked by increase of the lymphatic flow owing to elevated central venous pressure that results in lymphatic distention, trauma, and severe upper respiratory infection. Reported treatment of PLPS is obliteration of these abnormal lymphatic pathways by percutaneous embolization, a technique similar to thoracic duct embolization in chylothorax. PMID- 27993328 TI - Diagnostic Quality Assurance Pilot: A Model to Demonstrate Comparative Laboratory Test Performance with an Oncology Companion Diagnostic Assay. AB - This Editorial highlights a model demonstrating laboratory test performance with a companion diagnostic assay. PMID- 27993329 TI - An mRNA Gene Expression-Based Signature to Identify FGFR1-Amplified Estrogen Receptor-Positive Breast Tumors. AB - Fibroblast growth factor receptor 1 (FGFR1) amplification drives poor prognosis and is an emerging therapeutic target. We sought to construct a multigene mRNA expression signature to efficiently identify FGFR1-amplified estrogen receptor positive (ER+) breast tumors. Five independent breast tumor series were analyzed. Genes discriminative for FGFR1 amplification were screened transcriptome-wide by receiver operating characteristic analyses. The METABRIC series was leveraged to construct/evaluate four approaches to signature composition. A locked-down signature was validated with 651 ER+ formalin-fixed, paraffin-embedded tissues (the University of British Columbia-tamoxifen cohort). A NanoString nCounter assay was designed to profile selected genes. For a gold standard, FGFR1 amplification was determined by fluorescent in situ hybridization (FISH). Prognostic effects of FGFR1 amplification were assessed by survival analyses. Eight 8p11-12 genes (ASH2L, BAG4, BRF2, DDHD2, LSM1, PROSC, RAB11FIP1, and WHSC1L1) together with the a priori selected FGFR1 gene, highly discriminated FGFR1 amplification (area under the receiver operating characteristic curve >=0.82, all genes and all cohorts). The nine-gene signature Call-FGFR1-amp accurately identified FGFR1 FISH-amplified ER+ tumors in the University of British Columbia-tamoxifen cohort (specificity, 0.94; sensitivity, 0.96) and exhibited prognostic effects (disease-specific survival hazard ratio, 1.57; 95% CI, 1.14-2.16; P = 0.005). Call-FGFR1-amp includes several understudied 8p11-12 amplicon-driven oncogenes and accurately identifies FGFR1-amplified ER+ breast tumors. Our study demonstrates an efficient approach to diagnosing rare amplified therapeutic targets with FISH as a confirmatory assay. PMID- 27993331 TI - Honoring the Past and Looking to the Future: Updates on Seminal Behavior Therapy Publications on Current Therapies and Future Directions. AB - This is the introduction to the second of two special issues in honor of the 50th anniversary of the Association for Behavioral and Cognitive Therapies. The goal of this issue is to pay tribute to prior seminal Behavior Therapy publications on current therapies and future directions, to provide an updated review of important topics covered by these papers, and to make recommendations for the future. Each invited paper in this issue highlights a particular Behavior Therapy publication's contribution to our understanding and also provides an updated review or meta-analysis on the topic of the original paper. The topics covered here include review papers on current therapies such as cognitive and behavioral therapies, youth and family psychotherapy, unified protocols, and third-wave therapies. In addition, we include a review paper on implementation science, and meta-analyses on individualized psychotherapy, and culturally adapted interventions. With the two 50th anniversary issues of Behavior Therapy, we hope to inspire additional research and discussion. PMID- 27993332 TI - Cognitive Therapy: Nature and Relation to Behavior Therapy - Republished Article. AB - Recent innovations in behavior modification have, for the most part, detoured around the role of cognitive processes in the production and alleviation of symptomatology. Although self-reports of private experiences are not verifiable by other observers, these introspective data provide a wealth of testable hypotheses. Repeated correlations of measures of inferred constructs with observable behaviors have yielded consistent findings in the predicted direction. Systematic study of self-reports suggests that an individual's belief systems, expectancies, and assumptions exert a strong influence on his state of well being, as well as on his directly observable behavior. Applying a cognitive model, the clinician may usefully construe neurotic behavior in terms of the patient's idiosyncratic concepts of himself and of his animate and inanimate environment. The individual's belief systems may be grossly contradictory; i.e., he may simultaneously attach credence to both realistic and unrealistic conceptualizations of the same event or object. This inconsistency in beliefs may explain, for example, why an individual may react with fear to an innocuous situation even though he may concomitantly acknowledge that this fear is unrealistic. Cognitive therapy, based on cognitive theory, is designed to modify the individual's idiosyncratic, maladaptive ideation. The basic cognitive technique consists of delineating the individual's specific misconceptions, distortions, and maladaptive assumptions, and of testing their validity and reasonableness. By loosening the grip of his perseverative, distorted ideation, the patient is enabled to formulate his experiences more realistically. Clinical experience, as well as some experimental studies, indicate that such cognitive restructuring leads to symptom relief. PMID- 27993333 TI - Cognitive-Behavioral Therapy: Nature and Relation to Non-Cognitive Behavioral Therapy. AB - Since the introduction of Beck's cognitive theory of emotional disorders, and their treatment with psychotherapy, cognitive-behavioral approaches have become the most extensively researched psychological treatment for a wide variety of disorders. Despite this, the relative contribution of cognitive to behavioral approaches to treatment are poorly understood and the mechanistic role of cognitive change in therapy is widely debated. We critically review this literature, focusing on the mechanistic role of cognitive change across cognitive and behavioral therapies for depressive and anxiety disorders. PMID- 27993334 TI - A Comparative Evaluation of a Parent-Training Program -Republished Article. AB - This report is one of a series of outcome evaluation studies for parent-training procedures tailored specifically to families of preadolescent antisocial children. Referred families were screened to identify 19 problem children who were observed in their homes to be high-rate social aggressors. Cases were randomly assigned to the parent-training procedures or to a waiting-list comparison group. All but one of the latter accepted a referral for treatment elsewhere in the community. After an average of 17hours of therapy time, the cases in the experimental group were terminated. Posttreatment observation data were collected in the homes of both the experimental and the comparison groups. The results indicated that, relative to the changes in the comparison sample, the parent-training sample showed a significantly greater reduction in the observed rates of deviant child behavior. PMID- 27993330 TI - Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. AB - Widespread clinical laboratory implementation of next-generation sequencing-based cancer testing has highlighted the importance and potential benefits of standardizing the interpretation and reporting of molecular results among laboratories. A multidisciplinary working group tasked to assess the current status of next-generation sequencing-based cancer testing and establish standardized consensus classification, annotation, interpretation, and reporting conventions for somatic sequence variants was convened by the Association for Molecular Pathology with liaison representation from the American College of Medical Genetics and Genomics, American Society of Clinical Oncology, and College of American Pathologists. On the basis of the results of professional surveys, literature review, and the Working Group's subject matter expert consensus, a four-tiered system to categorize somatic sequence variations based on their clinical significances is proposed: tier I, variants with strong clinical significance; tier II, variants with potential clinical significance; tier III, variants of unknown clinical significance; and tier IV, variants deemed benign or likely benign. Cancer genomics is a rapidly evolving field; therefore, the clinical significance of any variant in therapy, diagnosis, or prognosis should be reevaluated on an ongoing basis. Reporting of genomic variants should follow standard nomenclature, with testing method and limitations clearly described. Clinical recommendations should be concise and correlate with histological and clinical findings. PMID- 27993336 TI - Toward a Unified Treatment for Emotional Disorders - Republished Article. AB - Over 40 years of development of cognitive behavioral approaches to treating anxiety and related emotional disorders have left us with highly efficacious treatments that are increasingly widely accepted. Nevertheless, these manualized protocols have become numerous and somewhat complex, restricting effective training and dissemination. Deepening understanding of the nature of emotional disorders reveals that commonalities in etiology and latent structure among these disorders supercedes differences. This suggests the possibility of distilling a set of psychological procedures that would comprise a unified intervention for emotional disorders. Based on theory and data emerging from the fields of learning, emotional development and regulation, and cognitive science, we identify three fundamental therapeutic components relevant to the treatment of emotional disorders generally. These three components include (a) altering antecedent cognitive reappraisals; (b) preventing emotional avoidance; and (c) facilitating action tendencies not associated with the emotion that is dysregulated. This treatment takes place in the context of provoking emotional expression (emotional exposure) through situational, internal, and somatic (interoceptive cues), as well as through standard mood-induction exercises, and differs from patient to patient only in the situational cues and exercises utilized. Theory and rationale supporting this new approach are described along with some preliminary experience with the protocol. This unified treatment may represent a more efficient and possibly a more effective strategy in treating emotional disorders, pending further evaluation. PMID- 27993337 TI - Toward a Unified Treatment for Emotional Disorders: Update on the Science and Practice. AB - Mental health professionals have long been concerned with describing and proscribing a structure around the myriad variations of psychological and emotional distress that are deemed to be disordered. This has frequently been characterized as a conflict between so-called "lumpers" and "splitters"-those who advocate broad categorizations based on overarching commonalities versus those who endeavor toward a highly refined structure emphasizing unique characteristics. Many would argue that with the era of the modern Diagnostic and Statistical Manual of Mental Disorders (DSM-III to DSM-5), a splitting ideology has been dominant despite re-emerging concerns that some groups of diagnoses, particularly disorders of anxiety and other emotions, may be more similar than different. As a result of such concerns, transdiagnostic or unified models of psychopathology have burgeoned. In this review, we describe the work of Barlow, Allen, and Choate (2004), whose invited paper "Toward a Unified Treatment for Emotional Disorders" reignited transdiagnostic perspectives of emotional disorders. We provide an update on the scientific models and evidence-based treatments that have followed in the wake of this 2004 publication, including key areas for future study in the advancement of transdiagnostic and unified treatment of emotional disorders. PMID- 27993335 TI - The Oregon Model of Behavior Family Therapy: From Intervention Design to Promoting Large-Scale System Change. AB - This paper reviews the evolution of the Oregon model of family behavior therapy over the past four decades. Inspired by basic research on family interaction and innovation in behavior change theory, a set of intervention strategies were developed that were effective for reducing multiple forms of problem behavior in children (e.g., Patterson, Chamberlain, & Reid, 1982). Over the ensuing decades, the behavior family therapy principles were applied and adapted to promote children's adjustment to address family formation and adaptation (Family Check-Up model), family disruption and maladaptation (Parent Management Training-Oregon model), and family attenuation and dissolution (Treatment Foster Care-Oregon model). We provide a brief overview of each intervention model and summarize randomized trials of intervention effectiveness. We review evidence on the viability of effective implementation, as well as barriers and solutions to adopting these evidence-based practices. We conclude by proposing an integrated family support system for the three models applied to the goal of reducing the prevalence of severe problem behavior, addiction, and mental problems for children and families, as well as reducing the need for costly and largely ineffective residential placements. PMID- 27993338 TI - Acceptance and Commitment Therapy, Relational Frame Theory, and the Third Wave of Behavioral and Cognitive Therapies - Republished Article. AB - The first wave of behavior therapy countered the excesses and scientific weakness of existing nonempirical clinical traditions through empirically studied first order change efforts linked to behavioral principles targeting directly relevant clinical targets. The second wave was characterized by similar direct change efforts guided by social learning and cognitive principles that included cognitive in addition to behavioral and emotive targets. Various factors seem to have set the stage for a third wave, including anomalies in the current literature and philosophical changes. Acceptance and Commitment Therapy (ACT) is one of a number of new interventions from both behavioral and cognitive wings that seem to be moving the field in a different direction. ACT is explicitly contextualistic and is based on a basic experimental analysis of human language and cognition, Relational Frame Theory (RFT). RFT explains why cognitive fusion and experiential avoidance are both ubiquitous and harmful. ACT targets these processes and is producing supportive data both at the process and outcome level. The third-wave treatments are characterized by openness to older clinical traditions, a focus on second order and contextual change, an emphasis of function over form, and the construction of flexible and effective repertoires, among other features. They build on the first- and second-wave treatments, but seem to be carrying the behavior therapy tradition forward into new territory. PMID- 27993339 TI - Considering Meta-Analysis, Meaning, and Metaphor: A Systematic Review and Critical Examination of "Third Wave" Cognitive and Behavioral Therapies. AB - In this review, we examine common usage of the term "third wave" in the scientific literature, systematically review published meta-analyses of identified "third wave" therapies, and consider the implications and options for the use of "third wave" as a metaphor to describe the nature of and relationships among cognitive and behavioral therapies. We demonstrate that the "third wave" term has grown in its use over time, that it is commonly linked with specific therapies, and that the majority of such therapies have amassed a compelling evidence base attesting to their clinical and public health value. We also consider the extent to which the "third wave" designation is an effective guide for the future, and we encourage scientific inquiry and self-reflection among those concerned with cognitive and behavioral therapies and the scientific basis of psychotherapy more broadly. PMID- 27993340 TI - Bridging the Gap Between Scientists and Practitioners: The Challenge Before Us - Republished Article. AB - The need to develop effective and efficient strategies for the dissemination of evidence-based health care has been recognized by governments, researchers, and clinicians alike. However, recognition and implementation are separate issues. If scientists are to have a significant impact on clinical practice, they will have to learn a new way of "doing business." Lessons from the business community and from the field of diffusion of innovations research (dissemination research) have direct applicability to disseminating science-based clinical procedures. This paper presents two examples of the successful integration of science and clinical practice. The goal in each case was to address problems fundamental to dissemination research, specifically for addictions treatment. The first example demonstrates how scientists and practitioners successfully worked hand-in-hand to integrate science and practice, by creating a clinical protocol that subsequently served almost 300 clients. The second example describes the successful dissemination of a clinical research intervention into community settings. The key to effective dissemination was to make practitioners true partners in the research, development, and dissemination process. For the effective wedding of clinical science and practice on a wide scale, dissemination must be adopted as a value and become a major objective of health care organizations. Current health care emphasis on evidence-based practice suggests that alliances between practitioners and scientists will point the way to clinical standards of practice for the next millennium. PMID- 27993341 TI - Bridging the Gap Between Research and Practice in Mental Health Service Settings: An Overview of Developments in Implementation Theory and Research. AB - Twenty years after Sobell's (1996) influential call to integrate advances in behavior therapy into clinical settings, significant progress has been made in implementation science. In this narrative review, we provide an overview of implementation research findings and highlight recent findings that can inform efforts to bridge the gap between research and practice in mental health service settings. Key findings are summarized, organized according to levels of influence described in two implementation frameworks: The Exploration, Planning, Implementation, and Sustainment Framework (EPIS; Aarons et al., 2011) and the Consolidated Framework for Implementation Research (CFIR; Damschroder et al., 2009). Important levels of influence to consider when implementing new treatments include the outer context, inner context, characteristics of the individual, and characteristics of the innovation. Research on strategies to prepare clinicians to deliver evidence-based psychosocial treatments (EBPTs) and to address contextual barriers to implementation at each level is described, with discussion of implications for the implementation of EBPTs and next steps for research. PMID- 27993342 TI - Individualized Behavior Therapy for Alcoholics - Republished Article. AB - A behavior therapy for alcoholism was designed based on the rationale that alcoholic drinking is a discriminated, operant response. Treatment emphasized determining setting events for each subject's drinking and training equally effective alternative responses to those situations. Seventy male, hospitalized, Gamma alcoholics were assigned to a treatment goal of either nondrinking (N=30) or controlled drinking (N=40). Subjects of each group were then randomly assigned to either an experimental group receiving 17 behavioral treatment sessions or a control group receiving only conventional treatment. Treatment of experimental groups differed only in drinking behaviors allowed during sessions and electric shock avoidance schedules. Nondrinker experimental subjects shaped to abstinence, while controlled drinker experimental subjects practiced appropriate drinking behaviors with little shaping, a result attributed to instructions. Follow-up measuring drinking and other behaviors found that experimental subjects functioned significantly better after discharge than control subjects, regardless of treatment goal. Successful experimental subjects could apply treatment principles to setting events not considered during treatment, suggesting the occurrence of rule learning. Results are discussed as evidence that some "alcoholics" can acquire and maintain controlled drinking behaviors. Traditional treatment of alcoholics may be handicapped by unvalidated beliefs concerning the nature of the disorder. PMID- 27993343 TI - The Heterogeneity of Obesity: Fitting Treatments To Individuals - Republished Article. AB - Body weight is regulated by a complex interaction of biological, behavioral, and cultural factors. The population as a whole is at risk for obesity because of increased intake of dietary fat, the consumption of calories in fewer meals per day, striking accessibility to palatable foods, and decreased physical activity. This risk may become a reality in individuals with certain biological predispositions (genetic tendency, low metabolic rate, increased fat cell number), specific eating patterns, and susceptibility to the extreme cultural pressure to be lean. These factors must be considered in establishing goals for treatment, which fall into medical and psychosocial categories. This includes defining a "reasonable" as opposed to "ideal" weight. A three-stage process is proposed for identifying the best treatment for an individual. This involves a classification decision, a stepped care decision, and then a matching decision. Criteria are provided for a comprehensive assessment of the overweight individual, and treatment options are reviewed for programs of varying intensity, cost, and risk. PMID- 27993345 TI - Cultural Diversity: A Wake-Up Call for Parent Training - Republished Article. AB - The United States is becoming increasingly culturally diverse. As a consequence, behavior therapists who utilize parent training as a therapeutic intervention for child behavior problems will likely encounter clients from various ethnic and cultural backgrounds. Unfortunately, the influence of cultural values on parenting behavior has been ignored in behavior therapy research. We examine the cultural context of parenting for four ethnic groups, consider the influence of cultural factors on parent training, and propose new research questions to be addressed by behavior therapists in the near future. PMID- 27993344 TI - Personalized Psychotherapy for Adult Depression: A Meta-Analytic Review. AB - Personalized medicine is aimed at identifying which characteristics of an individual predict the outcome of a specific treatment, in order to get a better match between the individual and the treatment received. We conducted a systematic review and meta-analysis of randomized trials comparing two psychotherapies directly in a group of depressed patients with a specific characteristic. We focused on the six most examined types of psychotherapy for adult depression. Our searches resulted in 41 studies with 2,741 patients who met inclusion criteria. These 41 studies examined 27 specific characteristics of patients. Power calculations indicated that we would need 4 studies for each characteristic to find a clinically relevant effect size set at g = 0.50 and 16 studies for an effect size of 0.24. Only 3 patient characteristics were found to have sufficient power and to significantly moderate treatment outcomes. Cognitive behavioral therapy was found to be more effective than other therapies in older adults (g = 0.29), in patients with comorbid addictive disorders (g = 0.31), and in university students (g = 0.46). Risk of bias was considerable in most of the included studies. It was estimated that it will take another 326 years to have sufficient statistical power for showing an effect size of g = 0.50 of the 27 characteristics, and 1,372 years to show an effect size of 0.24. Although several dozens of studies have compared the effects of psychotherapies in specific target groups, we will need to develop more powerful alternatives to comparative outcome studies in order to identify personalized treatments for depression. PMID- 27993346 TI - A Meta-Analysis of Cultural Adaptations of Psychological Interventions. AB - Forehand and Kotchick (1996) issued a wake-up call to the field to develop culturally responsive interventions. Since that time, 11 meta-analyses on culturally adapted interventions have been conducted. To reconcile the differences of the previous meta- analyses, a new meta-analysis was conducted that included 13,998 participants, 95% of whom were non-European American, in 78 studies evaluating culturally adapted interventions with psychopathology outcomes. Using a random effects multilevel regression model, the overall effect size (g = 0.67, p < .001) favored the effectiveness of culturally adapted interventions over other conditions (no intervention, other interventions). There was a medium effect size favoring the effectiveness of culturally adapted interventions over unadapted versions of the same intervention (g = .52). The overall effect size was moderated by whether the study involved treatment (g = .76) vs. prevention (g = .25, p = .03) and whether the study involved specific measures of mood or anxiety symptoms (g = .76) vs. general measures of psychopathology (g = .48, p = .02). Culturally adapted interventions had 4.68 times greater odds than other conditions to produce remission from psychopathology (p < .001) in 16 studies that reported remission. There were greater effects in no intervention control designs (marginal odds ratio = 9.80) than in manualized intervention (marginal odds ratio = 3.47, p = .03) or another active, nonmanualized intervention (marginal odds ratio = 3.38, p = .04) comparison designs in remission studies. Research has yet to adequately investigate whether culturally adapted or unadapted interventions impact culture specific psychopathology. These findings indicate a continuing need for rigor in the conceptualization and measurement of culture- specific psychopathology and in developing culturally responsive interventions. PMID- 27993347 TI - Corrigendum to "Effects of forage family on apparent ruminal synthesis of B vitamins in lactating dairy cows" (J. Dairy Sci. 99:1884-1894). PMID- 27993348 TI - Corrigendum to "Effects of dietary nitrogen levels and carbohydrate sources on apparent ruminal synthesis of some B vitamins in dairy cows" (J. Dairy Sci. 99:2730-2739). PMID- 27993349 TI - Corrigendum to "Particle length of silages affects apparent ruminal synthesis of B vitamins in lactating dairy cows" (J. Dairy Sci. 99:6229-6236). PMID- 27993350 TI - Monoclonal antibody binding to the macrophage-specific receptor sialoadhesin alters the phagocytic properties of human and mouse macrophages. AB - Sialoadhesin (Sn) is a surface receptor expressed on macrophages in steady state conditions, but during inflammation, Sn can be upregulated both on macrophages and on circulating monocytes. It was shown for different species that Sn becomes internalized after binding with monoclonal antibodies. These features suggest that Sn is a potential target for immunotherapies. In this study, human and mouse macrophages were treated with anti-Sn monoclonal antibodies or F(ab')2 fragments and the effect of their binding to Sn on phagocytosis was analyzed. Binding of antibodies to Sn resulted in delayed and reduced phagocytosis of fluorescent beads. No effect was observed on Fc-mediated phagocytosis or phagocytosis of bacteria by human macrophages. In contrast, an enhanced phagocytosis of bacteria by mouse macrophages was detected. These results showed that stimulation of Sn could have different effects on macrophage phagocytosis, depending both on the type of phagocytosis and cellular background. PMID- 27993351 TI - Mesenchymal stem cells overexpressing IL-35 effectively inhibit CD4+ T cell function. AB - Mesenchymal stem cells (MSCs) have recently emerged as promising candidates for cell-based immune tolerance therapy. Interleukin 35 (IL-35) is a relatively newly identified cytokine required for the regulatory and suppressive functions of regulatory T cells (Treg), playing an important role in the prevention of autoimmune diseases. In this study, we isolated adipose tissue-derived MSCs, a good vehicle for cell therapy, which were transfected with a lentivirus vector for the overexpression of the therapeutic murine IL-35 gene. IL-35 levels in transfected MSCs (IL-35-MSCs) were quantified by ELISA. Co-culture of CD4+ T cells and IL-35-MSCs resulted in the inhibition of CD4+ T cell proliferation and IL-17A secretion. In addition, IL-35-MSCs induced IL-10 production by CD4+ T cells, but did not affect IFN-gamma. These findings suggested that MSCs over expressing IL-35 had higher immunosuppressive capacity compared with non transfected MSCs, and may provide a useful approach for basic research on gene therapy for autoimmune disorders. PMID- 27993352 TI - Constructing a molecular theory of self-assembly: Interplay of ideas from surfactants and block copolymers. AB - Low molecular weight surfactants and high molecular weight block copolymers display analogous self-assembly behavior in solutions and at interfaces, generating nanoscale structures of different shapes. Understanding the link between the molecular structure of these amphiphiles and their self-assembly behavior has been the goal of theoretical studies. Despite the analogies between surfactants and block copolymers, models predicting their self-assembly behavior have evolved independent of one another, each overlooking the molecular feature considered critical to the other. In this review, we focus on the interplay of ideas pertaining to surfactants and block copolymers in three areas of self assembly. First, we show how improved free energy models have evolved by applying ideas from surfactants to block copolymers and vice versa, giving rise to a unitary theoretical framework and better predictive capabilities for both classes of amphiphiles. Second we show that even though molecular packing arguments are often used to explain aggregate shape transitions resulting from self-assembly, the molecular packing considerations are more relevant in the case of surfactants whereas free energy criteria are relevant for block copolymers. Third, we show that even though the surfactant and block copolymer aggregates are small nanostructures, the size differences between them is significant enough to make the interfacial effects control the solubilization of molecules in surfactant micelles while the bulk interactions control the solubilization in block copolymer micelles. Finally, we conclude by identifying recent theoretical progress in adapting the micelle model to a wide variety of self-assembly phenomena and the challenges to modeling posed by emerging novel classes of amphiphiles with complex biological, inorganic or nanoparticle moieties. PMID- 27993353 TI - [Neurosurgical position causes peripheral nerve injuries?] AB - BACKGROUND: Positioning during neurosurgical procedures is a challenge for surgical teams even if precautions are taken, the mechanisms underlying peripheral nerve injury (elongation, compression or ischaemia) are latent and it is important to know the frequency of occurrence in our environment. OBJECTIVE: To analyze the frequency of peripheral nerve injury secondary to surgical positioning. MATERIALS AND METHODS: Prospective study including 163 patients scheduled for neurosurgical procedures. Four groups: supine, lateral, ventral and park bench were analyzed by neurological exploration in order to detect injury and relate with risk factors already described. RESULTS: In this study 112 patients were included, two patients who were under park bench position experienced paresthesias in ulnar region of less than 24 hours' duration; statistically significant correlation with body weight greater than 85kg. CONCLUSION: The incidence of peripheral nerve injury is low, understanding the mechanisms that may originate it helps towards prevention and early detection of complications. PMID- 27993354 TI - [Case report: Occlusion and intestinal necrosis by obturator hernia]. AB - BACKGROUND: Obturator hernia is a rare variety of abdominal hernia, it accounts for 0.07%-1.0% of all hernias, and occurs most often in women of advanced age and multiparous. CLINICAL CASE: A 78-year-old female was admitted to the Emergency Department due to nausea, vomiting, complaints of abdominal discomfort and obstipation for the last 7 days. Abdominal CT scan showed dilated small bowel loops and multiple air-fluid levels near to a small bowel loop obturator hernia, between external obturator and pectineus muscle. Emergency laparotomy was performed and during the surgery, loop of small intestine was revealed herniated into the obturator foramen, 130cm from the angle of Treitz. Necrosis of small intestine was found, without perforation. Resection of the 10cm affected jejunal segment was performed and a side-to-side bowel anastomosis was fashioned. Also simple suture closure of obturator foramen was performed. CONCLUSION: Obturator hernia is relatively rare. However physicians should keep it in mind and have clinical suspicion for obturator hernia as a cause of intestinal obstruction in female, elderly and multiparous patients in order to make an appropriate diagnosis and avoid bowel ischaemia. PMID- 27993356 TI - Multiple incipient sensor faults diagnosis with application to high-speed railway traction devices. AB - This paper deals with the problem of incipient fault diagnosis for a class of Lipschitz nonlinear systems with sensor biases and explores further results of total measurable fault information residual (ToMFIR). Firstly, state and output transformations are introduced to transform the original system into two subsystems. The first subsystem is subject to system disturbances and free from sensor faults, while the second subsystem contains sensor faults but without any system disturbances. Sensor faults in the second subsystem are then formed as actuator faults by using a pseudo-actuator based approach. Since the effects of system disturbances on the residual are completely decoupled, multiple incipient sensor faults can be detected by constructing ToMFIR, and the fault detectability condition is then derived for discriminating the detectable incipient sensor faults. Further, a sliding-mode observers (SMOs) based fault isolation scheme is designed to guarantee accurate isolation of multiple sensor faults. Finally, simulation results conducted on a CRH2 high-speed railway traction device are given to demonstrate the effectiveness of the proposed approach. PMID- 27993355 TI - Intra-arterial therapies for colorectal cancer liver metastases (radioembolization excluded). AB - During the past 20 years, advances in systemic therapies have improved overall survival of patients with Colorectal cancer Liver metastases (CRLM) from 6 to 24 months. By reaching CRLM via their preferential arterial vascularization, hepatic arterial infusion of chemotherapy (HAIC) has demonstrated improvement in response rate and deepness of response. Improvement in deepness of response is potentially helpful to convert no surgical patient to surgery. Recent HAIC regimens, including HAIC-FUDR plus systemic oxaliplatin/irinotecan, or HAIC-oxaliplatin plus systemic 5FU and cetuximab yielded a 92% and 90% response rate respectively, and conversion to R0 surgery in 47% and 42% of patients, respectively. When HAIC delivered a drug ineffective through intravenous delivery, this rechallenge provided 62% response rate for HAIC. Nowadays, port-catheter implanted percutaneously by radiologists has 95% feasibility with primary patency equivalent to that of surgically implanted catheters, and secondary patency superior after radiologic revision. Retrospective studies demonstrated prolonged DFS of HAIC over IV chemotherapy in the adjuvant setting after surgery of CRLM. Drug eluting beads loaded with irinotecan (DEBIRI) were developed as drug carrier and embolization platform for treatment of CRLM by chemoembolization. DEBIRI allows for a very high level of SN-38 (SN-38 is the active compound of irinotecan) and a very high rate of complete l response at pathologic studies of treated metastases. DEBIRI was compared to systemic FOLFIRI in a phase III randomized trial including 74 patients with benefit in overall survival and disease-free survival. PMID- 27993357 TI - Amputation: Not a failure for severe lower extremity combat injury. AB - INTRODUCTION: The use of improvised explosive devices is a frequent method of insurgents to inflict harm on deployed military personnel. Consequently, lower extremity injuries make up the majority of combat related trauma. The wounding pattern of an explosion is not often encountered in a civilian population and can lead to substantial disability. It is therefore important to study the impact of these lower extremity injuries and their treatment (limb salvage versus amputation) on functional outcome and quality of life. PATIENTS AND METHODS: All Dutch repatriated service members receiving treatment for wounds on the lower extremity sustained in the Afghan theater between august 2005 and August 2014, were invited to participate in this observational cohort study. We conducted a survey regarding their physical and mental health using the Short Form health survey 36, EuroQoL 6 dimensions and Lower Extremity Functional Scale questionnaires. Results were collated in a specifically designed electronic database combined with epidemiology and hospital statistics gathered from the archive of the Central Military Hospital. Statistical analyses were performed to identify differences between combat and non-combat related injuries and between limb salvage treatment and amputation. RESULTS: In comparison with non-battle injury patients, battle casualties were significantly younger of age, sustained more severe injuries, needed more frequent operations and clinical rehabilitation. Their long-term outcome scores in areas concerning well-being, social and cognitive functioning, were significantly lower. Regarding treatment, amputees experienced higher physical well-being and less pain compared to those treated with limb salvage surgery. CONCLUSION: Sustaining a combat injury to the lower extremity can lead to partial or permanent dysfunction. However, wounded service members, amputees included, are able to achieve high levels of activity and participation in society, proving a remarkable resilience. These long-term results demonstrate that amputation is not a failure for casualty and surgeon, and strengthen a life before limb (damage control surgery) mindset in the initial phase. For future research, we recommend the use of adequate coding and injury scoring systems to predict outcome and give insight in the attributes that are supportive for the resilience that is needed to cope with a serious battle injury. PMID- 27993358 TI - Involvement of Matrix Metalloproteinases and their Inhibitors in Bovine Cystic Ovarian Disease. AB - The most important regulators of tissue remodelling during ovarian follicular growth, development, ovulation and atresia are gonadotropins, steroid hormones, growth factors and different proteolytic enzymes. Matrix metalloproteinases (MMPs) such as collagenase or gelatinase (i.e. MMP-1, -8, -2 and -9) and associated tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4) control connective tissue remodelling during follicular rupture. In this study, we hypothesized that an imbalance in the MMP-TIMP system may be an intra-ovarian component that contributes to the pathogenesis of cystic ovarian disease (COD) in cows. Taking into account that the control of MMP activity by TIMPs could determine their effects in both physiological and pathological conditions, MMP and TIMP mRNA and protein expression was examined by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC), respectively, in ovaries from control cows and cows with COD. Expression of mRNA encoding MMP-2, TIMP-1 and TIMP-2 was lower in follicular cysts than in control pre-ovulatory follicles, while the results by IHC showed this imbalance only for TIMP-2 protein expression. Additional analysis by zymography to evaluate the gelatinase activity of MMP-2 and MMP-9 demonstrated higher MMP-2 activity in follicular fluid (FF) of cysts than in FF of pre-ovulatory follicles. On the other hand, MMP-9 activity was increased in follicular cysts and absent in the FF of pre-ovulatory follicles. These findings suggest that the altered mRNA expression and activities of the MMP-TIMP system may be related to the failure in ovulation and follicular development observed in COD. PMID- 27993359 TI - Perioperative management and outcomes of esophageal atresia and tracheoesophageal fistula. AB - BACKGROUND/PURPOSE: Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a rare congenital anomaly lacking contemporary data detailing patient demographics, medical/surgical management and outcomes. Substantial variation in the care of infants with EA/TEF may affect both short- and long-term outcomes. The purpose of this study was to characterize the demographics, management strategies and outcomes in a contemporary multi-institutional cohort of infants diagnosed with EA/TEF to identify potential areas for standardization of care. METHODS: A multi institutional retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals between 2009 and 2014 was performed. Over the 5year period, 396 cases were identified in the 11 centers (7+/-5 per center per year). All infants with a diagnosis of EA/TEF made within 30days of life who had surgical repair of their defect defined as esophageal reconstruction with or without ligation of TEF within the first six months of life were included. Demographic, operative, and outcome data were collected and analyzed to detect associations between variables. RESULTS: Prenatal suspicion or diagnosis of EA/TEF was present in 53 (13%). The most common anatomy was proximal EA with distal TEF (n=335; 85%) followed by pure EA (n=27; 7%). Clinically significant congenital heart disease (CHD) was present in 137 (35%). Mortality was 7.5% and significantly associated with CHD (p<0.0001). Postoperative morbidity occurred in 62% of the population, including 165 (42%) cases with anastomotic stricture requiring intervention, anastomotic leak in 89 (23%), vocal cord paresis/paralysis in 26 (7%), recurrent fistula in 19 (5%), and anastomotic dehiscence in 9 (2%). Substantial variation in practice across our institutions existed: bronchoscopy prior to repair was performed in 64% of cases (range: 0%-100%); proximal pouch contrast study in 21% (0%-69%); use of interposing material between the esophageal and tracheal suture lines in 38% (0%-69%); perioperative antibiotics >=24h in 69% (36%-97%); and transanastomotic tubes in 73% (21%-100%). CONCLUSION: Contemporary treatment of EA/TEF is characterized by substantial variation in perioperative management and considerable postoperative morbidity and mortality. Future studies are planned to establish best practices and clinical care guidelines for infants with EA/TEF. LEVEL OF EVIDENCE: Type of study: Treatment study. Level IV. PMID- 27993360 TI - The quality of clinical practice guidelines for chronic respiratory diseases and the reliability of the AGREE II: an observational study. AB - OBJECTIVES: To survey the quality of evidence-based clinical practice guidelines for chronic respiratory diseases relevant to physiotherapy practice using the Appraisal of Guidelines for Research and Evaluation version II instrument (AGREE II) and to evaluate the inter-rater reliability of AGREE II. DESIGN: Observational survey. PROCEDURES: Guidelines indexed in the Physiotherapy Evidence Database (PEDro) on chronic respiratory diseases were evaluated by four assessors using AGREE II. MAIN OUTCOME MEASURES: The six domains and two global items of AGREE II. RESULTS: Thirty-three guidelines were evaluated (58% were published in the last 5 years and 36% were for chronic obstructive pulmonary disease). The domains with the highest scores were scope and purpose (79%, SD 10%) and clarity of presentation (79%, SD 10%). The domain with the lowest score was applicability (37%, SD 23%). Mean overall quality was five out of seven (SD 1). Intraclass correlation coefficients ranged from 0.66 to 0.93 for the six domains and first global item, suggesting good to excellent reliability. The second global item had very poor reliability (Kappa 0.097). CONCLUSION: The quality of evidence-based clinical practice guidelines for chronic respiratory diseases relevant to physiotherapy could be improved, particularly in consideration with applicability. The number of assessors for AGREE II could be reduced because of the good inter-rater reliability. PMID- 27993361 TI - Care partner: A concept analysis. AB - BACKGROUND: The use of the term care partner has increased, particularly in the chronic disease literature; however, the concept has not been well defined. PURPOSE: The purpose of this concept analysis was to define and assist nurses to better understand the concept of care partner. METHODS: The method by Walker and Avant was used for this literature-based concept analysis. DISCUSSION: Care partnering includes providing assistance to an individual with a health condition to meet their self-care deficits, the commitment to a care partner relationship, and the recognition that people with self-care deficits are care partners contributing to their own care. CONCLUSION: Emphasizing the care partner dyad in nursing may contribute to improved patient care outcomes both in the acute and chronic settings. It is recommended that nurses view the person with the condition as a contributor and partner in their own care in the context of a larger care partnership. PMID- 27993362 TI - Factors associated with decisional regret among patients undergoing major thoracic and abdominal operations. AB - BACKGROUND: No study has specifically investigated patient attitudes on decisional regret concerning major operative procedures. The objective of the present study was to define the prevalence of regret among patients who had undergone a major abdominal or thoracic operative procedure and to identify factors associated with postoperative regret. METHODS: Decisional regret was assessed using the validated Decision Regret Scale, which consisted of 5 items with Likert-scale responses. Data on preoperative decision-making preferences and postoperative regret, quality of life, and symptoms of anxiety and depression were collected and analyzed. RESULTS: Overall, 157 (68.9%) patients agreed to participate and completed the survey, while 12 (5.3%) patients declined citing lack of time or interest. The types of operative procedures varied, with 65 (41.7%) patients undergoing a thoracic operation, 59 (37.8%) resection of the pancreas, liver or bile duct, and 32 (20.5%) patients having a colorectal/enteric operation. Although most patients (n = 98, 62.4%) expressed no degree of regret, a subset of patients did; specifically, 59 (37.6%) patients conveyed a varied degree of postoperative regret, with 20 (12.7%) patients expressing a moderate degree of regret, and 13 patients (8.3%) experiencing substantial regret. Postoperative regret was associated with a history of postoperative complications (odds ratio 4.7, 95% confidence interval 1.2-17.7, P < .01) and with discordance between a patient's preferred and actual perceived decision-making role (odds ratio 5.3, 95% confidence interval 1.6-17.4, P < .01). Patients experiencing regret were 5 times more likely than patients not experiencing regret to demonstrate borderline or abnormal depression scores (odds ratio 5.4, 95% confidence interval 1.6-18.0, P < .01); anxiety scores directly correlated with regret (rho 0.254, P < .01). CONCLUSION: Patient-reported decisional regret after major abdominal and thoracic operations was present in 37% of patients, with roughly 1 in 12 patients reporting substantial regret and distress over the decision to have undergone operation. Discordance between patients' preferred and actual involvement in operative decision-making was associated with postoperative regret, as was poor quality of life, anxiety, and depression. PMID- 27993363 TI - It's in 3D, but is it truly the next dimension? PMID- 27993364 TI - A curious course of an intramural anomalous left coronary artery from the pulmonary artery. PMID- 27993365 TI - Building a bioartificial heart: A 3-song saga. PMID- 27993366 TI - Kicking the habit of routine preoperative laboratory testing in children undergoing cardiac surgery. PMID- 27993367 TI - Destination therapy with ventricular assist devices for patients with dystrophinopathies: A new way of life. PMID- 27993368 TI - Does type of prosthesis affect long-term outcomes after aortic valve replacement for infective endocarditis? How should we properly answer this question? PMID- 27993369 TI - Marine litter abundance and distribution on beaches on the Isle of Rugen considering the influence of exposition, morphology and recreational activities. AB - The abundance, weight and composition of marine debris were determined at the northwest coast of the Isle of Rugen in 2015. A total number of 1115 macrolitter items were registered, resulting in an abundance of 304+/-88.96 items per 100m of beach length and therefore being greater than the abundances found for other beaches at the Baltic Sea. Macrolitter items were predominantly composed of plastic, on average 83%. The four beaches under investigation have different exposition as well as touristic levels. The differing influence of wind and water currents as well as recreational activities on the macrolitter at these beaches was detectable. The distribution of items within a beach segment was analyzed by implementing D-GPS and drone aerial photography. The results of this analysis suggested that the identity of the substrate as well as the presence of vegetation are both major influencing factors in the macrolitter distribution. PMID- 27993370 TI - Seasonal characterisation of maritime traffic and the relationship with cetacean presence in the Western Mediterranean Sea. AB - Seasonal maritime traffic was investigated in relation to cetaceans, through direct observations (July 2013-June 2015) along three fixed transects in Western Mediterranean. Visually obtained vessel abundance was compared with Automatic Identification System data to explore if the two methods provided different results. Traffic intensity and composition were characterised by seasons and vessel categories. Finally, cetacean presence was investigated in relation to traffic by measuring the difference of vessel abundance in the presence and absence of animal sightings. Results showed that visual sampling was consistent with AIS data, providing more information on small-medium vessels. Traffic was more intense and diverse in Spring/Summer, and the highest vessel abundance and seasonal variations in composition emerged for inshore subareas. The difference of traffic in the presence and absence of cetaceans was higher in most offshore subareas in Spring/Summer, verified for B. physalus and S. coeruleoalba; in inshore waters, mostly occupied by T. truncatus, no significant differences emerged. PMID- 27993371 TI - Evaluation of AhR-agonists and AhR-agonist activity in sediments of Liaohe River protected areas, China. AB - A total of 9 sediment samples of Liaohe River protected areas were collected to evaluate aryl hydrocarbon receptor agonists (AhR-agonists) and AhR-agonist activity via chemical analysis and in vitro H4IIE cell bioassay. Results indicated that bioassay-derived 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (Bio-TEQs) ranged from 89.1 to 251.1pg/g dry weight. Concentrations of 16 EPA polycyclic aromatic hydrocarbons (PAHs), 12 dioxin-like polychlorinated biphenyls (PCBs), and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) ranged from 256.8 to 560.1ng/g, 79.2 to 416.2pg/g, and 199.6 to 538.4pg/g, respectively. According to potency balance analysis, TEQchems based on PAHs, PCBs, and PCDD/Fs could contribute 16.56% to 26.11% of Bio-TEQs. This could be explained by the potential existence of unidentified AhR-agonists and the potential non-additive interactions among AhR-agonists in sediment extracts. Through the different contributions to Bio-TEQs, this study confirms that PCDD/Fs were the main pollutants that induced significantly AhR-agonist activity in sediments of Liaohe River protected areas. PMID- 27993373 TI - Rehearsing for life: Applied theatre - A worthwhile pedagogic addition to those working and training in health and social care? The practitioner's perspective. PMID- 27993372 TI - Laboratory mechanical parameters of composite resins and their relation to fractures and wear in clinical trials-A systematic review. AB - OBJECTIVE: To evaluate a range of mechanical parameters of composite resins and compare the data to the frequency of fractures and wear in clinical studies. METHODS: Based on a search of PubMed and SCOPUS, clinical studies on posterior composite restorations were investigated with regard to bias by two independent reviewers using Cochrane Collaboration's tool for assessing risk of bias in randomized trials. The target variables were chipping and/or fracture, loss of anatomical form (wear) and a combination of both (summary clinical index). These outcomes were modelled by time and material in a linear mixed effect model including random study and experiment effects. The laboratory data from one test institute were used: flexural strength, flexural modulus, compressive strength, and fracture toughness (all after 24-h storage in distilled water). For some materials flexural strength data after aging in water/saliva/ethanol were available. Besides calculating correlations between clinical and laboratory outcomes, we explored whether a model including a laboratory predictor dichotomized at a cut-off value better predicted a clinical outcome than a linear model. RESULTS: A total of 74 clinical experiments from 45 studies were included involving 31 materials for which laboratory data were also available. A weak positive correlation between fracture toughness and clinical fractures was found (Spearman rho=0.34, p=0.11) in addition to a moderate and statistically significant correlation between flexural strength and clinical wear (Spearman rho=0.46, p=0.01). When excluding those studies with "high" risk of bias (n=18), the correlations were generally weaker with no statistically significant correlation. For aging in ethanol, a very strong correlation was found between flexural strength decrease and clinical index, but this finding was based on only 7 materials (Spearman rho=0.96, p=0.0001). Prediction was not consistently improved with cutoff values. SIGNIFICANCE: Correlations between clinical and laboratory outcomes were moderately positive with few significant results, fracture toughness being correlated with clinical fractures and flexural strength with clinical wear. Whether artificial aging enhances the prognostic value needs further investigations. PMID- 27993374 TI - Effects of RFamide-related peptide-1 (RFRP-1) microinjections into the central nucleus of amygdala on passive avoidance learning in rats. AB - The amygdaloid body (AMY) plays an important role in memory, learning and reward related processes. RFRP-1 immunoreactive fibers and NPFF receptors were identified in the AMY, and previously we verified that RFRP-1 infused into the central nucleus of AMY (CeA) induced place preference. The aim of the present study was to examine the possible effects of RFRP-1 in the CeA on passive avoidance learning. Male Wistar rats were examined in two-compartment passive avoidance paradigm. Animals were shocked with 0.5mA current and subsequently were microinjected bilaterally with 50ng or 100ng RFRP-1 in volume of 0.4MUl, or 20ng NPFF receptor antagonist RF9 (ANT) alone, or antagonist 15min before 50ng RFRP-1 treatments into the CeA. Fifty nanogram dose of RFRP-1 significantly increased the step-through latency time, the 100ng RFRP-1 and the ANT alone were ineffective. The effect of 50ng RFRP-1 was eliminated by the ANT pretreatment. Our results suggest that intraamygdaloid RFRP-1 enhances learning processes and memory in aversive situations and this effect can specifically be prevented by ANT pretreatment. PMID- 27993375 TI - Role of hemokinin-1 in health and disease. AB - Hemokinin-1 (HK-1), the newest tachykinin encoded by the Tac4 gene was discovered in 2000. Its name differs from that of the other members of this peptide family due to its first demonstration in B lymphocytes. Since tachykinins are classically found in the nervous system, the significant expression of HK-1 in blood cells is a unique feature of this peptide. Due to its widespread distribution in the whole body, HK-1 is involved in different physiological and pathophysiological functions involving pain inflammation modulation, immune regulation, respiratory and endocrine functions, as well as tumor genesis. Furthermore, despite the great structural and immunological similarities to substance P (SP), the functions of HK-1 are often different or the opposite. They both have the highest affinity to the tachykinin NK1 receptor, but HK-1 is likely to have a distinct binding site and signalling pathways. Moreover, several actions of HK-1 different from SP have been suggested to be mediated via a presently not identified own receptor/target molecule. Therefore, it is very important to explore its effects at different levels and compare its characteristics with SP to get a deeper insight in the different cellular mechanisms. Since HK-1 has recently been in the focus of intensive research, in the present review we summarize the few clinical data and experimental results regarding HK-1 expression and function in different model systems obtained throughout the 16years of its history. Synthesizing these findings help to understand the complexity of HK-1 actions and determine its biomarker values and/or drug development potentials. PMID- 27993376 TI - Unplanned Readmission After Lung Resection: Complete Follow-Up in a 1-Year Cohort With Identification of Associated Risk Factors. AB - BACKGROUND: Unplanned readmissions are adverse clinical events that negatively impact patients and affect the use of health care resources. Identifying risk factors that can predict readmissions might permit individualized patient management. We compiled a complete account of readmissions after all lung resections over a year to identify potentially modifiable risk factors. METHODS: All patients undergoing elective lung resection between August 1, 2013 and July 31, 2014 were contacted directly to determine whether they had been readmitted to any institution within 30 days of discharge from our service. Demographic data were supplemented from our prospectively maintained database. Follow-up was complete in 100% of patients. RESULTS: Over the 12-month study period, 582 lung resections were performed. Five hundred fifty-four resections in 532 patients were performed with the thoracic surgical service as the primary service. Of these patients, 505 undergoing 521 resections consented for their data to be included in the study, and they all survived to 30 days. Mean age was 62.3 years (standard deviation [SD], 13.8 years). The male to female ratio was 265:240. Fifteen pneumonectomies, 222 lesser anatomic resections in 215 patients, and 270 nonanatomic (wedge) resections in 261 patients were performed; 14 other miscellaneous resections were performed in 14 patients. Thirty-day mortality was 1% (5 of 510 patients). There were 4 in-hospital deaths and 1 additional mortality within 30 days. Unplanned readmissions occurred in 42 patients (42 of 505 patients [8.3%])-28 (67%) at our institution and 14 (33%) at other institutions. The median interval to readmission was 14 days. Readmissions occurred in 7.3% of patients discharged home, whereas 19.4% of patients discharged to a nursing home or other facility required readmission (p = 0.041). The most common reason for readmission was respiratory complications (47%). Significant factors (p < 0.05) associated with increased risk of readmission were lower percent predicted forced expiratory volume in 1 second (FEV1), longer operative time, perioperative furosemide administration, pain score of 6 or greater between 12 and 24 hours after the operation, prolonged air leakage (>5 days), blood transfusion, and discharge to a nursing home. Length of stay after lung resection was not a risk factor for unplanned readmission. CONCLUSIONS: The unplanned readmission rate after lung resection for our cohort was 8.3%, with half resulting from respiratory issues. Risk factors in the preoperative, perioperative, and postoperative setting were identified that may provide opportunities for mitigating these adverse events. PMID- 27993377 TI - Recurrence Pattern of Pathologic Stage I Lung Adenocarcinoma With Visceral Pleural Invasion. AB - BACKGROUND: Visceral pleural invasion (VPI) is well known to be a poor prognostic factor in lung adenocarcinoma. There were few studies reporting postoperative recurrence pattern in lung adenocarcinoma with VPI. This study was to evaluate the clinical effect of VPI on recurrence pattern in pathologic stage I lung adenocarcinoma after curative resection. METHODS: Among 574 patients with pathologic stage I lung adenocarcinoma after complete resection between 2003 and 2012, the clinicopathologic characteristics of 89 patients (16%) who had recurrence were retrospectively reviewed. The pathologic findings, postrecurrence survival, and patterns of recurrence were compared between patients with VPI and without VPI. RESULTS: Median follow-up duration was 53.6 months. The VPI was found in 43 patients (group I) and not found in 46 patients (group II). Both total tumor size and invasive size were larger in group I (3.2 versus 2.7 cm and 2.5 versus 2.1 cm; p < 0.05). The median duration of overall survival was 58 months in group I and 76 months in group II. As patterns of recurrence, pleural seeding was found in 25 patients, and the percentage of pleural seeding was significantly higher in group I than group II (44.2% versus 13.0%; p = 0.001). In group I, bilateral lung metastasis was significantly common (39.5% versus 13.0%; p = 0.004), and increasing percentage of pleural seeding was observed as the invasive tumor size grows. CONCLUSIONS: The presence of VPI was a significant predictable factor for pleural seeding and bilateral lung metastasis as patterns of recurrence after complete resection in pathologic stage I lung adenocarcinoma. PMID- 27993378 TI - Aortic Remodeling After Endovascular Repair of Complicated Acute Type B Aortic Dissection. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is the optimal therapy for complicated acute type B aortic dissection (aTBAD). This study examined clinical outcomes and aortic remodeling parameters after TEVAR for patients with complicated aTBAD. METHODS: From January 2012 to December 2015, 51 patients underwent TEVAR for complicated aTBAD. Preoperative and postoperative imaging studies were analyzed for sizes of the true lumen (TL) and false lumen (FL) and for the FL thrombosis status at five locations in the thoracic and abdominal aorta. RESULTS: In-hospital and 1-year mortality rates were 3.9% and 5.8%, respectively. The incidence of stroke and paraparesis were 3.9% and 5.8%, respectively. In DeBakey 3a patients, TEVAR resulted in complete FL thrombosis and/or obliteration in 73% of patients. In DeBakey 3b patients, TEVAR resulted in complete FL thrombosis and/or obliteration in 100% of patients in the proximal descending thoracic aorta and 78% in the midpoint of the descending thoracic aorta. The infrarenal FL remained patent in 78% of patients. TEVAR stabilized the size of the proximal descending thoracic aorta (pre-TEVAR 43 +/- 9 mm vs post TEVAR 39 +/- 7 mm; p = 0.07). However, significant aortic expansion was observed in all other downstream aortic segments. TEVAR resulted in a significant expansion in the TL volume (pre-TEVAR 99 +/- 51 cm3 vs post-TEVAR 185 +/- 70 cm3; p < 0.01) and total aortic volume (pre-TEVAR 314 +/- 97 cm3 vs post-TEVAR 391 +/- 120 cm3; p = 0.02) while inhibiting expansion of FL volume (pre-TEVAR 215 +/- 67 cm3 vs post-TEVAR 204 +/- 79 cm3; p = 0.91). CONCLUSIONS: TEVAR for complicated aTBAD results in low 30-day and 1-year mortality rates, with higher reintervention rates than observed with open operations. TEVAR is effective in thrombosing and stabilizing the size of the thoracic FL. The abdominal aortic FL remains patent and must be carefully scrutinized for long-term aneurysm formation. PMID- 27993379 TI - Hyperuricemia: A causal player or a bystander linking inflammatory signaling and atrial fibrillation? PMID- 27993380 TI - Corrigendum to: "Hydrogen sulfide ameliorates learning memory impairment in APP/PS1 transgenic mice: A novel mechanism mediated by the activation of Nrf2" [Pharmacol. Biochem. Behav. 150-151 (2016) 207-216]. PMID- 27993382 TI - Syphilis. AB - Syphilis is a chronic bacterial infection caused by Treponema pallidum that is endemic in low-income countries and and occurs at lower rates in middle-income and high-income countries. The disease is of both individual and public health importance and, in addition to its direct morbidity, increases risk of HIV infection and can cause lifelong morbidity in children born to infected mothers. Without treatment the disease can progress over years through a series of clinical stages and lead to irreversible neurological or cardiovascular complications. Although syphilis is an ancient disease and the principles of recommended management have been established for decades, diagnosis and management are often challenging because of its varied manifestations and difficulty in interpretation of serological tests used to confirm diagnosis and evaluate response to therapy. In North America and western Europe, incidence of syphilis has increased dramatically in the past decade among men who have sex with men, particularly those with coexistent HIV infection. Only one drug, penicillin, is recommended for syphilis treatment and response to therapy is assessed based on changes over months in serological test titres. Treatment for patients who cannot receive penicillin and management of patients who do not serologically respond to treatment are common clinical problems. PMID- 27993384 TI - Understanding cardiovascular risk in rheumatoid arthritis: Still a long way to go. PMID- 27993381 TI - Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease. AB - The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m2 (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25-60 ml/min/1.73 m2 (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (-0.07 ml/min/1.73m2/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (-0.09 ml/min/1.73m2/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD. PMID- 27993383 TI - Old challenges and new opportunities in the clinical management of heterozygous familial hypercholesterolemia (HeFH): The promises of PCSK9 inhibitors. AB - Heterozygous familial hypercholesterolemia (HeFH) is a common (early estimates suggested a prevalence of 1 in 500 individuals, but recent studies have indicated that it may be higher) genetic disorder characterized by markedly elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C). HeFH is associated with an elevated risk of premature coronary heart disease, stroke, and peripheral vascular disease. Despite the availability of reliable diagnostic criteria (high LDL-C levels, family history or premature CHD and hypercholesterolemia, cerebral/peripheral vascular disease, and the presence of tendon xanthomata or presence of arcus cornealis before age of 45), HeFH is underdiagnosed and undertreated worldwide. Moreover, while there are effective treatments available to decrease LDL-C and prevent early-onset heart disease in individuals with HeFH, because of the high baseline levels of LDL-C, the achievement of target LDL-C levels remains a challenge. In recent years, a number of novel therapies to lower LDL-C levels in HeFH have been developed, including the monoclonal antibodies against serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab and evolocumab, which have the potential to reduce LDL-C by an additional 50%-60% when prescribed in combination with standard lipid-lowering drugs. This review summarizes the challenges in clinical management of subjects with HeFH, with a focus on emerging treatments, and highlights the status of HeFH diagnosis and treatment in Italy. PMID- 27993386 TI - Reply to: "Monitoring antivitamin K anticoagulants in antiphospholipid syndrome: A challenge in quality". PMID- 27993385 TI - Association of tobacco use and cessation with coronary atherosclerosis. AB - BACKGROUND AND AIMS: The impact of tobacco use and cessation on atherogenesis remains unclear. We aimed to study the association of tobacco use and prior cessation with the presence, extent and severity of atherosclerosis on coronary computed tomographic angiography (CTA). METHODS: We examined 1798 consecutive symptomatic patients without known coronary artery disease (CAD) referred for CTA, stratified by smoking status (never, current [within 30 days], or former [>30 days before CTA]). Plaque severity (none, <50%, >=50% stenosis), composition (non-calcified [NCP], partially calcified [PCP], or calcified plaque [CP]), and segment involvement score (SIS) were visually graded. Multivariate analysis was performed, adjusting for CAD risk factors and cholesterol lowering medication use. RESULTS: The median age of patients was 50 years [IQR:42-58] (61% male), with 74% never smokers, 12% current smokers, and 14% former smokers (median quit duration = 12 years [IQR:3-26]). Smoking exposure in former versus current smokers was 11 [IQR:5-25] and 10 [IQR:2-20] pack-years, respectively (p = 0.01). Compared to never smokers, current smokers demonstrated an increased odds ratio of all plaque types (adjusted OR: any NCP = 1.55 [95% CI 1.04-2.32], p = 0.03; any PCP = 1.61 [1.10-2.37], p = 0.02; any CP = 1.93 [1.32-2.81], p = 0.001), non obstructive CAD (aOR = 1.47 [1.04, 2.07], p = 0.03), obstructive CAD (aOR = 1.81 [1.01-3.24], p = 0.047), and SIS > 4 (aOR = 1.60 [1.04-2.46], p = 0.03). Compared to current smoking, prior smoking cessation (>=12 years) was associated with a decreased odds ratio of any NCP (aOR = 0.42 [0.19-0.90], p = 0.03), CP (aOR = 0.43 [0.22-0.84], p = 0.02), and obstructive CAD (aOR = 0.40, [0.15-0.98], p = 0.048). CONCLUSIONS: Current smoking is independently associated with the presence and extent of coronary plaque, and a higher risk of non-obstructive and obstructive CAD compared to never smoking. Prior smoking cessation correlated with improvements in CTA-identified plaque measures. PMID- 27993387 TI - Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain. AB - BACKGROUND AND AIMS: Low vitamin D (VITD) may contribute to statin-associated muscle symptoms (SAMS). We examined the influence of baseline and change in VITD in patients with verified SAMS. METHODS: SAMS was verified in 120 patients with prior statin muscle complaints using 8-week randomized, double-blind crossover trials of simvastatin (SIMVA) 20 mg/d and placebo. 25 (OH)vitamin D was measured at each phase of the trial. RESULTS: Forty-three patients (35.8%) experienced muscle pain on SIMVA but not placebo, exhibiting confirmed SAMS. VITD (mean +/- standard deviation) prior to SIMVA treatment was not different between patients who did (31.7 +/- 12.1 ng/mL, n = 43) or did not (31.6 +/- 10.3 ng/mL, n = 77) develop SAMS and did not predict SAMS (p = 0.96). The change in VITD with SIMVA treatment was not different between patients with and without SAMS (0.3 +/- 5.9 vs. 0.2 +/- 8.3 ng/mL, respectively) and did not predict SAMS (p = 0.96). The proportion of patients classified as VITD deficient (<20 ng/mL) did not differ between patients with (n = 16) and without (n = 10) SAMS (chi2 = 1.45; p = 0.23), nor did the proportion of patients classified as VITD insufficient (<30 ng/mL) (n = 42 vs. 48; chi2 < 0.01 and p = 0.94). Both baseline and on-statin VITD were inversely related to the change in creatine kinase (CK) with statin therapy (p = 0.01 and 0.02, respectively), independent of SAMS (p = 0.36 and 0.35). CONCLUSIONS: Baseline VITD, VITD deficiency/insufficiency and changes in VITD with statin therapy do not predict SAMS in patients with rigorously verified SAMS. However, low VITD may exacerbate statin-induced muscle injury and could contribute to SAMS development with a longer duration of statin treatment. PMID- 27993388 TI - Screening of circulating microRNA biomarkers for prevalence of abdominal aortic aneurysm and aneurysm growth. AB - BACKGROUND AND AIMS: MicroRNA (miR) are important regulators of gene expression and biological processes and have recently been suggested as possible biomarkers for abdominal aortic aneurysm (AAA) disease. The aim of the present study was to assess the role of miR as biomarkers for initiation and progression of AAA disease, through evaluation of a wide range of miRs in a large population-based cohort, with AAA patients with linked clinical data regarding risk factors, AAA size and growth, as well as controls. METHODS: The expression of the 172 most commonly expressed miRs in plasma was analyzed by real-time PCR in samples from 169 screening-detected AAA patients and 48 age-matched controls. RESULTS: For 103 miRs, there was a significant difference in expression between AAA and controls. Of these, 20 miRs were differently expressed between fast and slow growing aneurysms. These miRs target genes known to be involved in AAA disease as well as novel genes and pathways. By combining the top altered miRs together with clinical variables, strong predictive values, determining growth of AAA, were obtained (area under curve = 0.86, p < 0.001). CONCLUSIONS: This large cohort study identified several novel miRs with altered expression in AAA patients when compared to controls. Assessment of miR expression may offer an opportunity to predict disease progression and aneurysm growth. PMID- 27993389 TI - Editorial Comment. PMID- 27993390 TI - Celebratory reflections, appreciations, clarifications, and comments. PMID- 27993391 TI - Injury Threshold of Rectus Capitis Muscles at the Atlanto-occipital Joint. AB - OBJECTIVE: The objective of this study was to collect muscle stiffness data from the 4 rectus capitis (RC) muscles to better understand their role in stabilizing the atlanto-occipital joint. The passive load displacement properties of these muscles have not been previously reported. METHODS: Rectus capitis muscles were removed from 3 unembalmed head and neck specimens. Passive length-force (stiffness) data were collected by using a servo-controlled hydraulic test machine. Multivariate analysis of variance with Bonferroni correction was used to assess the significance of the differences among passive stiffness within the elastic region of each muscle and the load and strain at the yield points. RESULTS: Rectus capitis lateralis (RCL) muscles failed at significantly higher levels of load and strain compared with the other 3 pairs of muscles. Passive stiffness of both RCL and RC anterior muscles was significantly higher than the other 2 pairs of muscles. CONCLUSION: The anatomic location of the RCL muscles, along with their high levels of passive stiffness, would be expected to facilitate the maintenance of atlanto-occipital joint congruence during normal daily activities. The level at which the RC posterior minor muscles failed could put them at risk of a strain injury during a rear end motor vehicle accident. Diagnostic and treatment protocols that apply forces to the upper cervical spine should be tailored to consider the patient's age, gender, and history of previous injuries to avoid overstretching RC muscles. PMID- 27993392 TI - An inverse gas chromatographic methodology for studying gas-liquid mass transfer. AB - A novel methodology of reversed flow inverse gas chromatography (RF-IGC) is presented. It permits the simultaneous determination of mass transfer coefficients across the gas liquid interface as well as the respective solubility parameters and thermodynamic functions of dissolution of gases into liquids. The standard deviation of the experimentally determined parameters is estimated for first time, which combined with the successful comparison of the values of the present parameters with other literature ones ascertain the reliability of the methodology. Another novelty of the present work is that the chromatographic sampling of the physicochemical phenomena is done without performing the usual flow reversals procedure. Vinyl chloride monomer's (VCM) interaction with various composition liquid foods: orange juice, milk and olive oil was used as model system. The present transfer rates are controlled by the gas film at lower temperatures, but at higher temperatures the resistances in both films tend to become equal. The found liquid diffusivity values express the total mass transfer from the gas phase into the liquid's bulk and they decrease with rising temperature, as the solubilities of gases in liquids do. Solubility, expressed by Henry's law constant and the mean values of interfacial thickness are of the same order of magnitude to literature ones. From the thermodynamic point of view, VCM dissolution in all liquids is accompanied by significant heat release and it is a slightly non-spontaneous process, near equilibrium, while the entropy change values are negative. PMID- 27993393 TI - Quantification of short chain amines in aqueous matrices using liquid chromatography electrospray ionization tandem mass spectrometry. AB - A new liquid chromatography-electrospray ionization-tandem Mass Spectrometry (LC ESI-MS/MS) method was developed for the determination of more than 20 C1-C6 alkyl and alkanolamines in aqueous matrices. The method employs Hydrophilic Interaction Liquid Chromatography Multiple Reaction Monitoring (HILIC-MRM) with a ZIC-pHILIC column and four stable isotope labeled amines as internal standards for signal normalization and quantification of the amines. The method was validated using a refinery process water sample that was obtained from a cooling cycle of crude oil distillation. The averaged within run precision, between run precision and accuracy were generally within 2-10%, 1-9% and 80-120%, respectively, depending on the analyte and concentration level. Selected aqueous process samples were analyzed with the method. PMID- 27993394 TI - Monolithic column modified with bifunctional ionic liquid and styrene stationary phases for capillary electrochromatography. AB - A novel monolithic column with ionic liquid and styrene-modified bifunctional group was prepared for capillary electrochromatography (CEC) by in situ copolymerization in a ternary porogenic solvent. Ionic liquid (1-allyl methylimidazolium chloride, AlMeIm+Cl-) and styrene served as the bifunctional monomer, while ethylene dimethacrylate (EDMA) was used as the cross-linker. The monomer of AlMeIm+Cl- was introduced as anion-exchange group, while styrene as hydrophobic and aromatic group; the similar conjugated structure in AlMeIm+Cl- and styrene was beneficial for offeing obvious synergistic effect. The bifunctional stationary phase possessed powerful selectivity for the separation of neutral compounds, acidic analytes and phenols. The highest column efficiency was 2.70*105 platesm-1 (theoretical plates, N) for toluene. A relatively strong electroosmotic flow (EOF) was obtained in a wide range of pH values from 2.0 to 12.0, which could successfully achieve the rapid separation of the analytes within 10min. The proposed monolithic column was characterized by scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR). The results indicated that the resultant monolithic column had good permeability and excellent mechanical stability. Good reproducibility was obtained with relative standard deviations (RSDs) of the retention time in the range of 0.24-0.47% and 0.81-2.17% for run-to-run (n=5) and day-to-day (n=5), while 1.09-2.70% and 0.98 1.70% for column-to-column (n=3) and batch-to-batch (n=3), respectively. The combination of AlMeIm+Cl- and styrene was a promising option in the fabrication of the organic polymer monolithic column. PMID- 27993395 TI - A sensitive and accurate method for the determination of perfluoroalkyl and polyfluoroalkyl substances in human serum using a high performance liquid chromatography-online solid phase extraction-tandem mass spectrometry. AB - A selective, sensitive, and accurate analytical method for the measurement of perfluoroalkyl and polyfluoroalkyl substances (PFASs) in human serum, utilizing LC-MS/MS (liquid chromatography-tandem mass spectrometry), was developed and validated according to the Centers for Disease Control and Prevention (CDC) guidelines for biological sample analysis. Tests were conducted to determine the optimal analytical column, mobile phase composition and pH, gradient program, and cleaning procedure. The final analytical column selected for analysis was an extra densely bonded silica-packed reverse-phase column (Agilent XDB-C8, 3.0*100mm, 3.5MUm). Mobile phase A was an aqueous buffer solution containing 10mM ammonium acetate (pH=4.3). Mobile phase B was a mixture of methanol and acetonitrile (1:1, v/v). The gradient program was programmed by initiating a fast elution (%B, from 40 to 65%) between 1.0 and 1.5min, followed by a slow elution (%B: 65-80%) in the period of 1.5-7.5min. The cleanup procedures were augmented by cleaning with (1) various solvents (isopropyl alcohol, methanol, acetonitrile, and reverse osmosis-purified water); (2) extensive washing steps for the autosampler and solid phase extraction (SPE) cartridge; and (3) a post-analysis cleaning step for the whole system. Under the above conditions, the resolution and sensitivity were significantly improved. Twelve target PFASs were baseline separated (2.5-7.0min) within a 10-min of acquisition time. The limits of detection (LODs) were 0.01ng/mL or lower for all of the target compounds, making this method 5 times more sensitive than previously published methods. The newly developed method was validated in the linear range of 0.01-50ng/mL, and the accuracy (recovery between 80 and 120%) and precision (RSD<20%) were acceptable at three spiked levels (0.25, 2.5, and 25ng/mL). The method development and validation results demonstrated that this method was precise, accurate, and robust, with high-throughput (~10min per sample); thus suitable for large-scale epidemiological studies. PMID- 27993396 TI - Size-exclusion chromatography using core-shell particles. AB - Size-exclusion chromatography (SEC) is an indispensable technique for the separation of high-molecular-weight analytes and for determining molar-mass distributions. The potential application of SEC as second-dimension separation in comprehensive two-dimensional liquid chromatography demands very short analysis times. Liquid chromatography benefits from the advent of highly efficient core shell packing materials, but because of the reduced total pore volume these materials have so far not been explored in SEC. The feasibility of using core shell particles in SEC has been investigated and contemporary core-shell materials were compared with conventional packing materials for SEC. Columns packed with very small core-shell particles showed excellent resolution in specific molar-mass ranges, depending on the pore size. The analysis times were about an order of magnitude shorter than what could be achieved using conventional SEC columns. PMID- 27993397 TI - Hydrodynamic sample injection into short electrophoretic capillary in systems with a flow-gating interface. AB - An electrophoretic apparatus with a flow-gating interface has been developed, enabling hydrodynamic sequence injection of the sample into the separation capillary from the liquid flow by underpressure generated in the outlet electrophoretic vessel. The properties of the apparatus were tested on an artificial sample of an equimolar mixture of 100MUM potassium and sodium ions and arginine. The repeatability of the injection of the tested ions expressed as RSD (in%) for the peak area, peak height and migration time was in the range 0.76 2.08, 0.18-0.68 and 0.28-0.48, respectively. Under optimum conditions, the apparatus was used for sequence monitoring of the reaction between the antidiabetic drug phenyl biguanide and the glycation agent methyl glyoxal. The reaction solution was continuously sampled by a microdialysis probe from a thermostated external vessel using a syringe pump at a flow rate of 3MULmin-1 and was injected into a separation capillary at certain time intervals. The electrophoretic separation progressed in a capillary with an internal diameter of 50MUm with a length of 11.5cm and was monitored using a contactless conductivity detector. PMID- 27993398 TI - Review: Placental transport and metabolism of energy substrates in maternal obesity and diabetes. AB - Maternal obesity is growing in prevalence and is associated with increased morbidity and mortality for both mother and child. Women who are obese during pregnancy have a greater risk of metabolic complications such as gestational diabetes mellitus (GDM) as well as type 2 diabetes after pregnancy. Children of obese and/or GDM mothers have an increased susceptibility to congenital abnormalities and a range of cardio-metabolic disorders. The placenta is at the interface of the maternal and fetal environments and, its function per se, plays a major role in dictating the impact of maternal health on fetal development. Here, we review the literature on how placental function is affected in pregnancies complicated by obesity, and pre-gestational and gestational diabetes. The focus is on the availability of three key substrates in these conditions: glucose, lipids, and amino acids, and their impact on placental metabolic activity. Maternal obesity and diabetes are not always associated with fetal compromise and the adaptation of the placenta may partially determine the outcome. Understanding the differences in metabolic adaptation may open avenues for therapeutic development. PMID- 27993399 TI - [Boyer's conditions hygieniques actuelles de Beyrouth [current sanitary conditions in Beirut]: The first document on the epidemiology of venereal disease in Lebanon]. PMID- 27993400 TI - [Perisudoral lipoma]. PMID- 27993401 TI - Rapid systematic review and meta-analysis of the evidence for effectiveness of primary production interventions to control Salmonella in beef and pork. AB - Non-typhoidal Salmonella spp. (hereafter referred to as Salmonella) on beef and pork is an important cause of foodborne illness and death globally. A systematic review of the effectiveness of interventions to reduce Salmonella prevalence or concentration in beef and pork was undertaken. A broad search was conducted in Scopus and CAB abstracts. Each citation was appraised using screening tools tested a priori. Level 1 relevance screening excluded irrelevant citations; level 2 confirmed relevance and categorized studies. Data were then extracted, and intervention categories were descriptively summarized. Meta-analysis was performed to provide a summary estimate of treatment effect where two or more studies investigated the same intervention in comparable populations. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to assess the confidence in the estimated measures of intervention effect for data subgroups. PMID- 27993402 TI - Competencies for government veterinary services of the future: Summary of ISVEE 14 Yucatan 2015 roundtable discussion. AB - This short communication summarizes the strengths and weaknesses of current organisational structures in government veterinary services, as well as future technical, financial and societal challenges and related necessary competencies for government veterinary services of the future as discussed by an expert panel at ISVEE2015. First, participating representatives of veterinary services of diverse geographical backgrounds and statements from the audience confirmed that non-technical skills such as ability to work in teams, adaptability to new environments and situations, social and communication skills are increasingly seen as important. The second challenge faced by veterinary services is related to capacity issues, i.e. to have enough manpower to plan and deliver according to legislation in a period of shrinking budgets. New and emerging diseases can result in sudden, massive increases in the workload of veterinary services. Technical complexity has also increased for some hazards. Staff skills in veterinary services therefore need to be continuously updated, and it is essential to establish cross technical collaboration with other sectors including food safety, public health and environment. ISVEE conferences were seen as an opportunity to provide a global platform to develop skills needed by veterinary services, now and in the future. PMID- 27993403 TI - Biopsy of the sentinel node in lung cancer. AB - INTRODUCTION AND OBJECTIVE: Mediastinal lymph node involvement can be understaged in cases of lung cancer (up to 20% in stage i). Sentinel node detection is a standard technique recommended in breast cancer and melanoma action guidelines, and could also be useful in cases of lung cancer. MATERIAL AND METHODS: Considering the detection of the sentinel node in non-small cell lung cancer (NSCLC) as feasible, a prospective cohort study was carried out on 48 patients with resectable NSCLC, using the intraoperative injection of colloid sulphate technetium-99. RESULTS: The radioisotope migrated in all cases. The procedure's sensitivity was 88.24%, its accuracy was 95.83%, its negative predictive value was 93.94% and the false negative rate was 11.76%. No complications were associated with this technique. CONCLUSIONS: The detection of a sentinel node in NSCLC with the intraoperative injection of the isotope is feasible and safe, and allows for detection and sensitivity rates comparable to those of other tumour types. PMID- 27993404 TI - Level of daily physical activity in chronic obstructive pulmonary disease (COPD) patients according to GOLD classification. AB - INTRODUCTION AND OBJECTIVE: The Global Initiative for Chronic Obstructive Lung Disease (GOLD guideline) for patients with chronic obstructive pulmonary disease does not adequately reflect the impact of the disease because does not take into account daily physical activity (DPA). PATIENTS AND METHODS: Forty eight patients (12 in each GOLD group) were prospectively recruited. DPA was evaluated by accelerometer. Patients were classified into 3 levels of activity (very inactive, sedentary, active). RESULTS: No significant differences in levels of physical activity among GOLD groups (P=.361) were observed. The percentages of very inactive patients were 33% in group A, 42% in group B, 42% in group C and 59% in group D. In addition, high percentage of sedentary patients were observed through 4 groups, in group A (50%), B and C (42%, each), and group D (41%). DISCUSSION: COPD patients has very low levels of physical activity at all stages of GOLD classification even those defined as low impact (such as GOLD A). Is necessary to detect patients at risk who might benefit from specific interventions. PMID- 27993405 TI - Relationship between patients' month of birth and the prevalence of chronic diseases. AB - BACKGROUND AND OBJECTIVES: Patients' month of birth can reflect exposure to certain factors during pregnancy and the first few months of life, which could influence the onset of chronic diseases during adulthood. The aim of this study is to evaluate the association between a patient's month of birth and the presence of chronic diseases in the Spanish population, by analysing the National Health Survey for the year 2006. PATIENTS AND METHODS: We measured the association between 27 common chronic diseases and the month of birth, estimating the odds ratios and confidence intervals at 95%, using multivariate logistical models and adjusting the results for month of birth and potentially confounding variables. RESULTS: The sample population was made up of a total of 29,478 individuals, representing approximately 44.7 million Spanish residents on 1 January 2007. Significant associations were found between the month of birth and several chronic diseases. There is a gender-differentiated risk pattern of developing chronic diseases according to the month of birth, with more significant associations and of greater magnitude being detected among men compared to women. CONCLUSIONS: The associations detected might reflect early exposure to environmental factors in the uterus and during the first few months of life. More specific studies are required to gain a more in-depth understanding of these associations. PMID- 27993406 TI - Tumor lysis syndrome in solid tumors: Clinical characteristics and prognosis. AB - INTRODUCTION AND OBJECTIVE: Tumour lysis syndrome (TLS) is an uncommon complication in solid tumors following treatment initiation, and its spontaneous development (STLS) is exceptional. In this study, we analyse the main clinical and prognostic features of a case series with TLS and STLS. MATERIAL AND METHODS: Observational retrospective study in which we included all patients with solid tumours diagnosed with TLS and STLS over a period of 16 years, according to Cairo Bishop criteria. RESULTS: Nineteen patients were included in the study (mean age 63+/-16 years): 10 patients (53%) with TLS, and 9 (47%) STLS. The primary tumour in 8 cases (42%) was lung cancer. All patients had severe renal impairment at the time of diagnosis along with hyperuricemia (16+/-6mg/dl) and hyperkalemia (6+/ 0.9mmol/l). Despite treatment with intravenous fluids, urinary alkalinisation and rasburicase, 3 patients (16%) required dialysis, and 12 (63%) died during the follow-up period. CONCLUSIONS: The development of TLS in solid tumors is associated with increased mortality and therefore, a high index of suspicion is essential for early diagnosis and treatment initiation. PMID- 27993407 TI - Evaluation of the effect of an intervention on the nutritional status of hospitalized patients. AB - BACKGROUND AND OBJECTIVES: To compare the nutritional status of a population of hospitalized patients, divided into 2 different groups, both at admission and hospital discharge, and to assess the influence of nutritional alteration during the hospital stay. MATERIAL AND METHODS: Quasi-experimental study comprising 2 groups of patients (N=581); an intervention group (n=303), in which nurses received specific training on managing care methodology, and a control group (n=278), in which nurses continued their usual dynamics. Each group was made up of 2 care units with patients from both surgical and medical specialties. INCLUSION CRITERIA: patients admitted to the selected units with a minimum stay of 5 days. The sample selection was performed prospectively and consecutively after implementing the training. RESULTS: Of the 581 patients studied, 49.4% were women and 50.6% were men. Mean patient age was 68.29 (SD 16.23) years. In the intervention group, the odds ratio (OR) associated with good nutritional status was multiplied by 1.7 (OR=1.67) compared to the control group in the first evaluation and by 1.4 times (OR=1.43) at hospital discharge. The average stay in days was higher in the control group (13.71, SD 10.19) than in the intervention group (10.89, SD 7.49) (P<.001). CONCLUSION: The systematic methodology-based intervention in the chosen units was positive. Patients admitted to the intervention units had a lower nutritional alteration and a shorter hospital stay than those admitted to the control units. PMID- 27993408 TI - Antithrombotic treatment and characteristics of elderly patients with non valvular atrial fibrillation hospitalized at Internal Medicine departments. NONAVASC registry. AB - BACKGROUND AND OBJETIVES: The prevalence of non-valvular atrial fibrillation (NVAF) increases with the patient's age and is associated with high morbi mortality rates. The main goal of this study was to describe the characteristics of hospitalized elderly patients with NVAF and to identify the clinical and functional factors which determine the use of different antithrombotic strategies. PATIENTS AND METHODS: Observational, prospective, multicentre study carried out on patients with NVAF over the age of 75, who had been admitted for any medical condition to Internal Medicine departments. RESULTS: We evaluated 804 patients with a mean age of 85 years (range 75-101), of which 53.9% were females. The prevalence of risk factors and cardiovascular disease was high: hypertension (87.6%), heart failure (65.4%), ischemic cardiomyopathy (24.4%), cerebrovascular disease (22.4%) and chronic kidney disease (45%). Among those cases with previous diagnoses of NVAF, antithrombotic treatment was prescribed in 86.2% of patients: anticoagulants (59.7%), antiplatelet medication (17.8%) and double therapy (8.7%). The factors associated with the use of antithrombotic treatment were history of acute coronary syndrome and atrial fibrillation progression longer than one year. Older age, atrial fibrillation for less than one year, higher HAS BLED scores and severe cognitive impairment were associated with the use of anti platelet drugs. Permanent atrial fibrillation favoured the use of anticoagulants. CONCLUSIONS: Hospitalized patients older than 75 years old with NVAF showed numerous comorbidities. The percentage of anticoagulation was small and 18% received only anti-platelet therapy. The patient's age, atrial fibrillation's progression time and the severity of the cognitive impairment influenced this therapy choice. PMID- 27993409 TI - Short- and long-term prognosis of critically-ill patients referred to the ICU from the Emergency Department of a tertiary hospital. AB - BACKGROUND AND OBJECTIVE: A frequent source of critically-ill patients admitted to the ICU is the Emergency Department. It is essential to analyse the short-term prognosis of these patients, but also their evolution after their discharge from the hospital, since this is one of the major concerns of these patients. The aim of this study is to describe the epidemiological characteristics of patients admitted to the ICU from the Emergency Department and to analyse their outcome. PATIENTS AND METHOD: This consisted of an observational prospective cohorts study which included 269 Emergency Department patients consecutively admitted to the ICU over an 18-month period. Factors associated with hospital mortality were presented as an odds ratio (OR) and factors associated with long-term mortality were presented as a hazard ratio (HR). A P-value lower than .05 was accepted as significant. The overall survival was analysed on the basis of the Kaplan-Meier curves. RESULTS: Hospital mortality was 15%, ICU complications where the variables with the greatest impact on short-term mortality: acute renal failure (OR 22.7) and respiratory distress syndrome (OR 51.2). After hospital discharge, the cumulative mortality at 12, 24 and 36 months was 6, 11 and 15%, respectively. The degree of functional dependence (HR 3.7), cancer (HR 3.4) and arrhythmias (HR 2.4) were factors related to long-term mortality. CONCLUSIONS: The short-term outcome of ICU patients is related to age and comorbidity, but more significantly to the characteristics of the acute illness. However, the long-term outcome is more closely associated with the patients' characteristics. PMID- 27993410 TI - Consensus document for the use of the Polypill in the secondary prevention of cardiovascular disease. AB - Cardiovascular disease is a chronic disorder which is usually already at an advanced stage when the first symptoms develop. The fact that the initial clinical presentation can be lethal or highly incapacitating emphasizes the need for primary and secondary prevention. It is estimated that the ratio of patients with good adherence to secondary prevention of cardiovascular disease is low and also decreases gradually over time. The Polypill for secondary prevention of cardiovascular disease is the first fixed-dose combination therapy of salicylic acid, atorvastatin and ramipril approved in Spain. The purpose of this consensus document was to define and recommend, through the evidence available in the literature and clinical expert opinion, the impact of treatment adherence in the secondary prevention of cardiovascular disease and the use of the Polypill in daily clinical practice as part of a global strategy including adjustments in patient lifestyle. A RAND/UCLA methodology based on scientific evidence, as well as the collective judgment and clinical expertise of an expert panel was used for this assessment. As a result, a final report of recommendations on the impact of the lack of adherence to treatment of secondary prevention of cardiovascular disease and the effect of using a Polypill in adherence of patients was produced. The recommendations included in this document have been addressed to all those specialists, cardiologists, internists and primary care physicians with competence in prescribing and monitoring patients with high and very high cardiovascular risks. PMID- 27993411 TI - Ischemic colitis as pseudocarcinoma: An unusual presentation. PMID- 27993412 TI - Usefulness of positron emission tomography with 18F-fluorodeoxyglucose in Still's disease. PMID- 27993413 TI - Prevalence of hypertension and other cardiovascular risk factors in subjects with subclinical hypothyroidism. AB - BACKGROUND AND OBJECTIVE: To assess the prevalence of hypertension, diabetes, and dyslipidaemia in subjects with subclinical hypothyroidism (SH) in comparison with an age- and sex-matched control group. PATIENTS AND METHODS: Case-control study with 240 subjects with SH and 480 controls carried out on patients aged 35-75 years admitted to a Primary Care Centre. The prevalence of hypertension, diabetes and dyslipidaemia, as well as blood pressure, plasma glucose, and lipid profilses, were evaluated in both groups. RESULTS: No differences were observed neither in the prevalence of hypertension (34.2% vs. 29.6%) or diabetes (12.1% vs. 10%) nor in mean values of blood pressure or plasma fasting glucose. Subjects with SH had an increased prevalence of lipid abnormalities (72.1% vs. 57.7%; P<.001), and increased mean values of total cholesterol (205+/-34 vs. 193+/ 35mg/dL; P<.001), compared to the control group. CONCLUSION: Patients with SH have an increased prevalence of lipid abnormalities. This can be responsible for an increased cardiovascular risk in such patients. PMID- 27993414 TI - Benefits of early specialized nutritional support in malnourished patients. AB - INTRODUCTION AND OBJECTIVE: Disease related malnutrition (DRM) is highly prevalent in Spain, affecting 23% of in-hospital patients, and is associated with clinical complications. Specialized nutritional support (SNS) can reduce these complications. MATERIAL AND METHODS: Prospective study carried out in standard clinical practice conditions to test if SNS during the first 5 days of hospitalization, or subsequently, was associated to a lower length of stay or reduced complications in patients with a NRS-2002 score>=3 points. RESULTS: In the group of patients who initiated early SNS, the length of stay was 8.83 days shorter than in the group with a later introduction (95% CI 3.55-14.10); nevertheless, the higher prevalence of male and oncological patients in this group could have impacted the results. A tendency towards a statistically significant lower mortality rate and a reduced amount of total complications was described. CONCLUSION: The early introduction of SNS (within the first 5 days of hospitalization) in patients with DRM was associated with a 32.4% reduction in the length of stay. PMID- 27993415 TI - Orally-transmitted Chagas disease. AB - Chagas disease is a zoonosis caused by protozoan parasite Trypanosoma cruzi, which is most frequently associated with a vectorial transmission. However, in recent years we have observed a significant increase in the oral transmission of the disease, associated mainly with the consumption of drinks made from fruit or other vegetables contaminated with triatomine faeces or secretions from infected mammals. After a latency period of 3 to 22 days after ingestion, the oral infection is characterized by more severe manifestations than those associated with vectorial transmission: prolonged fever, acute myocarditis with heart failure and, in some cases, meningoencephalitis. Mortality can reach up to 33% of those infected. The aim of this paper is to review this matter and to promote prevention practices. PMID- 27993416 TI - Phase I study of stereotactic body radiation therapy for peripheral T2N0M0 non small cell lung cancer (JCOG0702): Results for the group with PTV?100cc. AB - PURPOSE: A dose escalation study to determine the recommended dose (RD) with stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinomas (NSCLC) was conducted. The results of the group with PTV?100cc are reported in this paper. MATERIALS AND METHODS: The continual reassessment method (CRM) was used to determine the dose level that patients should be assigned to and to estimate the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was Grade 3 or higher radiation pneumonitis (RP), and Grade 2 or higher RP was used as a surrogate DLT. The RD was equal to the MTD. The dose was prescribed at D95 of the PTV. RESULTS: Thirteen patients were accrued. More patients should have been enrolled but we decided not to prolong the study period. No patients experienced Grade 3 RP. Two patients experienced Grade 2 RP at 50Gy in 4 fractions. The predicted MTD was 50.2Gy. The posterior probability of the Grade 2 RP frequency over 40% was 5.3% for the dose level of 50Gy. The RD was determined to be 50Gy. CONCLUSIONS: The RD was determined to be 50Gy in 4 fractions in this population. PMID- 27993417 TI - [Methods of rapid diagnosis in clinical microbiology: Clinical needs]. AB - The diagnostic methods of infectious diseases should be fast, accurate, simple and affordable. The speed of diagnosis can play a crucial role in healing the patient, allowing the administration of appropriate antibiotic treatment. One aspect that increasingly determines the need for rapid diagnostic techniques is the increased rates of serious infections caused by multidrug resistant bacteria, which cause a high probability of error in the empirical treatment. Some of the conventional methods such as Gram staining or antigen detection can generate results in less than 1 hour but lack sensitivity. Today we are witnessing a major change in clinical microbiology laboratories with the technological advances such as molecular diagnostics, digital microbiology and mass spectrometry. There are several studies showing that these changes in the microbiological diagnosis reduce the generation time of the test results, which has an obvious clinical impact. However, if we look into the future, other new technologies which will cover the needs required for a rapid microbiological diagnosis are on the horizon. This review provides an in depth analysis of the clinical impact that the implementation of rapid diagnostic techniques will have on unmet clinical needs. PMID- 27993418 TI - Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. AB - STUDY OBJECTIVE: Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. METHODS: We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. RESULTS: We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per group, of which the most common were dizziness, nausea, and headache. CONCLUSION: Ketorolac has similar analgesic efficacy at intravenous doses of 10, 15, and 30 mg, showing that intravenous ketorolac administered at the analgesic ceiling dose (10 mg) provided effective pain relief to ED patients with moderate to severe pain without increased adverse effects. PMID- 27993419 TI - Environmental water chemistry and possible correlation with Kaschin-Beck Disease (KBD) in northwestern Sichuan, China. AB - During the past several decades, etiological and geochemical studies tend to link the Kaschin-Beck Disease (KBD) to the deficiency of some specific trace elements (e.g., selenium and iodine) in the environment; however the link has been proven inconclusive. In this work, we have investigated the relationship between KBD and the environment in a broader scope by examining comprehensively the chemistry of the surface waters in northwestern Sichuan, China, in relation to the KBD prevalence. The surface waters in the study area were found to be near neutral to slightly alkaline (pH6.70 to 8.85 with a mean of 7.91) and mostly soft (total hardness 35.2 to 314.3mg/L, mean 118.8mg/L) with low salinity (total dissolved solids (TDS) 44.5mg/L to 376.6mg/L, mean 146.6mg/L). The waters were dominated by cations Ca2+ and Mg2+ and anion HCO3-; whereas the alkali metal ions K+ and Na+ and the anions Cl- and S042- were relatively scarce. Spatially, the hardness/salinity of the surface waters exhibited a characteristic of being lower towards the center of the study area where most severe KBD endemic has been observed. Even though it is not conclusive at this stage, a correlation between KBD prevalence and the salinity/hardness of the surface waters of an area has been demonstrated. As a postulate, the long-term consumption of such low salinity waters may lead to a deficiency of some essential elements such as Ca, Mg, Se and I in humans, which may be a factor in inducing KBD. However, other factors such as high altitude and cold climate, poor nutrition and sanitary conditions may play an important role in the disease endemic. PMID- 27993421 TI - The scientific careers of Robert Sinclair and Nestor Zaluzec - A brief sketch. AB - Robert (Bob) Sinclair and Nestor Zaluzec have been working for many years at the leading edge of developments in electron microscopy techniques and applications. Their distinguished careers and some of their notable scientific achievements are briefly highlighted. PMID- 27993420 TI - LAM study: Effects of lacosamide on behaviour and quality of life in patients with epilepsy. AB - INTRODUCTION: Psychiatric comorbidities are common in epileptic patients, and evaluating the impact of antiepileptic drugs on patients' moods is therefore essential. The aim of this study is to assess the effects of lacosamide on behaviour and quality of life in people with epilepsy. METHODS: We conducted a multicentre prospective observational study of poorly-controlled epileptic patients who received lacosamide as an adjuvant treatment. Patients were evaluated on 4 occasions during a 12-month period. The impact of lacosamide on patients' mood and quality of life was assessed with the Quality of Life in Epilepsy Inventory-10 (QOLIE-10), the Hospital Anxiety and Depression Scale (HADS), and the Barratt Impulsiveness Scale (BIS-11). As a secondary objective, we evaluated the effectiveness and safety of lacosamide. RESULTS: We included 55 patients with a mean age of 47.1+/-18.4 years. At baseline, 34.5% of the patients had psychiatric comorbidities; the mean number of crises in the previous month was 3.6+/-4.3. The QOLIE-10 and HADS scales revealed statistically significant improvements in patients with a poor baseline condition (anxiety, depression, and/or poor quality of life). The BIS-11 scale detected no impulsive behaviour during follow-up. After 12 months of treatment, 51.9% of the patients were seizure-free and 77.8% experienced a reduction of at least 50% in seizure frequency. Adverse effects were mild in most cases; lacosamide was discontinued in 10 patients (18.2%). CONCLUSIONS: Lacosamide is a safe and effective treatment option for patients with epilepsy and psychiatric comorbidities. PMID- 27993422 TI - Emergence of sequence type 11 Klebsiella pneumoniae coproducing NDM-1 and VIM-1 metallo-beta-lactamases in a Greek hospital. AB - Sequence type 11 Klebsiella pneumoniae, coproducing NDM-1 and VIM-1 metallo-beta lactamases, were isolated in a Greek hospital. blaNDM-1 was part of a Tn125 derivative, located on an ~90-kb plasmid similar to the NDM-1-encoding plasmid pB 3002cz. blaVIM-1 was located in an In-e541-like integron, carried on a multireplicon (IncA/C and IncR) plasmid of ~180kb. PMID- 27993423 TI - Corrigendum to "Carbapenem susceptibility among Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates obtained from patients in intensive care units in Taiwan in 2005, 2007, and 2009" [Diagn Microbiol Infect Dis 2015;81(4):290-295]. PMID- 27993425 TI - Serum Testosterone Levels in Early Prediction of Prostate Cancer Risk. PMID- 27993424 TI - Remote sensing and in situ measurements of methane and ammonia emissions from a megacity dairy complex: Chino, CA. AB - Methane (CH4) and ammonia (NH3) directly and indirectly affect the atmospheric radiative balance with the latter leading to aerosol generation. Both have important spectral features in the Thermal InfraRed (TIR) that can be studied by remote sensing, with NH3 allowing discrimination of husbandry from other CH4 sources. Airborne hyperspectral imagery was collected for the Chino Dairy Complex in the Los Angeles Basin as well as in situ CH4, carbon dioxide (CO2) and NH3 data. TIR data showed good spatial agreement with in situ measurements and showed significant emissions heterogeneity between dairies. Airborne remote sensing mapped plume transport for ~20 km downwind, documenting topographic effects on plume advection. Repeated multiple gas in situ measurements showed that emissions were persistent on half-year timescales. Inversion of one dairy plume found annual emissions of 4.1 * 105 kg CH4, 2.2 * 105 kg NH3, and 2.3 * 107 kg CO2, suggesting 2300, 4000, and 2100 head of cattle, respectively, and Chino Dairy Complex emissions of 42 Gg CH4 and 8.4 Gg NH3 implying ~200k cows, ~30% more than Peischl et al. (2013) estimated for June 2010. Far-field data showed chemical conversion and/or deposition of Chino NH3 occurs within the confines of the Los Angeles Basin on a four to six h timescale, faster than most published rates, and likely from higher Los Angeles oxidant loads. Satellite observations from 2011 to 2014 confirmed that observed in situ transport patterns were representative and suggests much of the Chino Dairy Complex emissions are driven towards eastern Orange County, with a lesser amount transported to Palm Springs, CA. Given interest in mitigating husbandry health impacts from air pollution emissions, this study highlights how satellite observations can be leveraged to understand exposure and how multiple gas in situ emissions studies can inform on best practices given that emissions reduction of one gas could increase those of others. PMID- 27993426 TI - Mortality Is Linked to Low Serum Testosterone Levels in Younger and Middle-aged Men. PMID- 27993428 TI - Corrigendum to "Effects of fiber-glass-reinforced composite restorations on fracture resistance and failure mode of endodontically treated molars" [J. Dent. 53 (2016) 82-87]. PMID- 27993427 TI - Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. AB - OBJECTIVE: To provide insight into the wide spectrum of migraine during childhood to establish practical and comprehensive treatment strategies. BACKGROUND: Although recent studies have confirmed the effect of anti-migraine agents in childhood headaches fulfilling the criteria of migraine without aura, there have been no studies regarding the efficacy of these drugs in childhood migraine without aura not filling the diagnostic criteria. METHODS: In total, 154 patients with a clinical diagnosis of migraine, with onset of repetitive headaches at the age of ?15years, were retrospectively included from clinics in seven tertiary medical centers. RESULTS: Patients' diagnoses included migraine with aura (n=49), migraine without aura (n=65), clinical migraine without aura not fulfilling International Classification of Headache Disorders-3 beta criteria (suspected migraine without aura; n=38), and hemiplegic migraine (n=2). Abortive medicine was effective in 74 of 97 patients, and preventive medicine was effective in 61 of 84 patients. Drugs with high efficacy were acetaminophen and ibuprofen for abortive therapy and cyproheptadine, amitriptyline, and propranolol for preventive therapy. Psychosocial problems were less common, and abnormalities on electroencephalography were more common in the suspected migraine without aura group. Otherwise, clinical features and drug responsibility were comparable among the migraine with aura, migraine without aura, and suspected migraine without aura groups. Retrospectively, experts clinically diagnosed childhood migraine without aura when the headache met at least one of the three criteria B, C, and D in International Classification of Headache Disorders-3 beta in addition to A and E. Abortive and preventive medication including paroxetine (n=2) benefited 10 and 15 of the 33 patients with daily headache, respectively. Psychotherapy/counseling (n=4), treatment for orthostatic dysregulation (n=4), and elimination of stressors (n=3) markedly alleviated headache in this group. CONCLUSION: Our results indicated that those with suspected migraine without aura not filling International Classification of Headache Disorders diagnostic criteria should be included in the treatment for migraine. Treatment should also be targeted to comorbid developmental disorders, orthostatic dysregulation, and psychosocial problems in patients with refractory daily headaches. PMID- 27993429 TI - A comparison of the Macintosh laryngoscope and blind intubation via I-gel in intubating an entrapped patient: A randomized crossover manikin study. PMID- 27993430 TI - Profiling of sperm gene transcripts in crossbred (Bos taurus x Bos indicus) bulls. AB - Crossbred cattle in some sectors of the world have a significant role in enhancing milk production thereby enhancing the per capita milk availability as a human food source. However, there are certain constraints associated with crossbred animals, such as disease susceptibility, increased reproductive problems, repeat breeding and poor seminal quality. The semen of crossbred bulls has a poor freezing capacity, increased cryo-damage, poor mass cell motility, greater percentages of dead/abnormal sperm and poor initial and post-freeze cell motility. The rejection rate of crossbred bulls for cryostorage of semen has been reported to be as great as 50% as a result of unacceptable semen quality. The identification of superior bulls using molecular technologies is needed which necessitates identification of the genes having a role in sperm function. The present study was, therefore, conducted to gain information on identification and expression of genes having a role in sperm motility in crossbred bulls. The gene transcripts in bulls with sperm of superior and inferior quality were profiled in Vrindavani crossbred cattle by microarray analyses and the results were verified by real time-quantitative PCR. Microarray analyses revealed 19,454 genes which were differentially expressed. At a two-fold cut off, 305 genes were differentially (P<0.01) expressed with 160 genes upregulated and 145 genes down regulated. Some of the upregulated candidate genes were further validated by RT qPCR. These genes had a four to 16 fold upregulation in sperm with inferior motility as compared to sperm of crossbred bulls with superior motility. PMID- 27993431 TI - The potentials and limitations of neuro-biomarkers as predictors of outcome in neonates with birth asphyxia. AB - Perinatal asphyxia and its complication, hypoxic-ischemic encephalopathy, are still among the major causes of perinatal mortality and morbidity. Despite accurate standard postnatal monitoring procedures, the post-insult period is crucial because at a time when radiologic pictures are still silent, brain damage may already be at a subclinical stage. Against this background, the measurement of quantitative parameters, such as constituents of nervous tissue, that are able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent, could be particularly useful. Therefore, in the present review we report the potentials and limitations of biomarkers in predicting outcome in neonates complicated by perinatal asphyxia. PMID- 27993432 TI - Hydrophilic interaction liquid chromatography method development and validation for the assay of HEPES zwitterionic buffer. AB - HEPES is a zwitterionic buffer component used as a raw material in the GMP manufacturing of advanced therapy medicinal products (ATMPs), hence requiring an adequate assay method with sufficient selectivity toward related impurities. Therefore, a hydrophilic interaction chromatography (HILIC) method was developed. Different factors were investigated towards the retention behavior of HEPES, its analogue EPPS and its starting material isethionate: pH, ion concentration and organic solvent ratio of the mobile phase, as well as column temperature. Moreover, stress testing resulted in the N-oxide degradant, identified by high resolution MS. The final method consisted of an isocratic system with an aqueous (pH 2.0 with H3PO4) acetonitrile (35:65, v/v) mobile phase on a zwitterionic HILIC (Obelisc N) column with a flow rate of 0.5mL/min and UV detection at 195nm. The assay method of HEPES was validated, obtaining adequate linearity (R2=0.999), precision (RSD of 0.5%) and accuracy (recovery of 100.08%). Finally, the applicability of the validated method was demonstrated by analysis of samples from different suppliers. PMID- 27993434 TI - Competition policy for health care provision in France. AB - There are more than two thousand hospitals in France, about equally divided between government-owned and privately-owned hospitals. Activity-based payment, which has been generalized in 2008 for acute care hospitals, has raised competition issues as DRG tariffs differ according to ownership status. Furthermore, the payment rule has been criticized for preventing the realization of potential hospital synergies, and as a result a recent reform has mandated close cooperation between public hospitals. The physician market is dual, with most GPs being subject to fee regulation and many self-employed, private practice, specialist doctors being allowed to set their prices freely. Government regulation and centralized negotiations have traditionally been preferred to market mechanisms in this industry. PMID- 27993433 TI - Sodium Restriction in Patients With CKD: A Randomized Controlled Trial of Self management Support. AB - BACKGROUND: To evaluate the effectiveness and sustainability of self-managed sodium restriction in patients with chronic kidney disease. STUDY DESIGN: Open randomized controlled trial. SETTING & PARTICIPANTS: Patients with moderately decreased kidney function from 4 hospitals in the Netherlands. INTERVENTION: Regular care was compared with regular care plus an intervention comprising education, motivational interviewing, coaching, and self-monitoring of blood pressure (BP) and sodium. OUTCOMES: Primary outcomes were sodium excretion and BP after the 3-month intervention and at 6-month follow-up. Secondary outcomes were protein excretion, kidney function, antihypertensive medication, self-efficacy, and health-related quality of life (HRQoL). RESULTS: At baseline, mean sodium excretion rate was 163.6+/-64.9 (SD) mmol/24 h; mean estimated glomerular filtration rate was 49.7+/-25.6mL/min/1.73m2; median protein excretion rate was 0.8 (IQR, 0.4-1.7) g/24 h; and mean 24-hour ambulatory systolic and diastolic BPs were 129+/-15 and 76+/-9mmHg, respectively. Compared to regular care only (n=71), at 3 months, the intervention group (n=67) showed reduced sodium excretion rate (mean change, -30.3 [95% CI, -54.7 to -5.9] mmol/24 h), daytime ambulatory diastolic BP (mean change, -3.4 [95% CI, -6.3 to -0.6] mmHg), diastolic office BP (mean change, -5.2 [95% CI, -8.4 to -2.1] mmHg), protein excretion (mean change, 0.4 [95% CI, -0.7 to -0.1] g/24h), and improved self-efficacy (mean change, 0.5 [95% CI, 0.1 to 0.9]). At 6 months, differences in sodium excretion rates and ambulatory BPs between the groups were not significant, but differences were detected in systolic and diastolic office BPs (mean changes of -7.3 [95% CI, 12.7 to -1.9] and -3.8 [95% CI, -6.9 to -0.6] mmHg, respectively), protein excretion (mean changes, -0.3 [95% CI, -0.6 to -0.1] g/24h), and self-efficacy (mean change, 0.5 [95% CI, 0.0 to 0.9]). No differences in kidney function, medication, and HRQoL were observed. LIMITATIONS: Nonblinding, relatively low response rate, and missing data. CONCLUSIONS: Compared to regular care only, this self-management intervention modestly improved outcomes, although effects on sodium excretion and ambulatory BP diminish over time. PMID- 27993435 TI - Evaluation of a standardized patient education program for inpatient asthma rehabilitation: Impact on patient-reported health outcomes up to one year. AB - OBJECTIVES: To modify and evaluate a patient education program for adult asthma patients in consideration of quality criteria for teaching. METHODS: This was a prospective single-center controlled trial in an inpatient rehabilitation center. The control group (n=215) received the usual lecture-based education program, and the intervention group (n=209) the modified patient education program. Data were assessed at admission, discharge, 6 and 12 months post discharge. The primary outcome was asthma control, the secondary outcomes were asthma knowledge, quality of life, and program acceptance. Analysis of change was performed by ANCOVA for each follow-up, adjusting for baseline values. RESULTS: Statistically significant increases in all health outcomes and in asthma control were maintained in both groups at 12 months: CG: +1.9 (95%-CI 1.3-2.6) IG: +1.6 (95%-CI 0.8-2.3). We observed no significant differences between the programs for asthma control and quality of life. Regarding practical asthma knowledge, after 12 months, a group*time interaction emerged with a small effect size (P=0.06, eta2=0.01). CONCLUSION: The modified program was not superior to traditional patient education concerning asthma control. It permanently increased self-management knowledge. PRACTICAL IMPLICATIONS: Structured and behavioral patient education fosters patient's disease management ability. Possible ways of improving asthma control need to be explored. PMID- 27993436 TI - Changing hospitals, choosing chemotherapy and deciding you've made the right choice: Understanding the role of online support groups in different health decision-making activities. AB - OBJECTIVE: To investigate the ways in which people use online support groups (OSGs) in relation to their health decision-making and to identify the key features of the resource that support those activities. METHOD: Eighteen participants who used OSGs for a range of health conditions participated in qualitative study in which they were interviewed about their experiences of using OSGs in relation to decision-making. Exploration of their experiences was supported by discussion of illustrative quotes. RESULTS: Across the health conditions OSGs supported two main decision-making activities: (i) prompting decision making and (ii) evaluating and confirming decisions already made. Depending on the activity, participants valued information about the process, the experience and the outcome of patient narratives. The importance of forum interactivity was highlighted in relation to advice-seeking and the selection of relevant personal experiences. CONCLUSION: People use OSGs in different ways to support their health related decision-making valuing the different content types of the narratives and the interactivity provided by the resource. PRACTICE IMPLICATIONS: Engaging with OSGs helps people in a number of different ways in relation to decision-making. However, it only forms one part of people's decision making strategies and appropriate resources should be signposted where possible. PMID- 27993437 TI - Response. PMID- 27993438 TI - Modifying the One-Minute Preceptor Model for Use in the Emergency Department with a Critically Ill Patient. PMID- 27993439 TI - Evaluation of temporal bone pneumatization with growth using 3D reconstructed image of computed tomography. AB - OBJECTIVE: To evaluate temporal bone pneumatization with growth using 3D reconstructed computed tomography (CT) images. PATIENTS AND METHODS: Eighty-four temporal bones of 42 patients under the age of 16 years who had undergone head and facial bone CT were included in this retrospective study. The bony growth of the temporal bone and the head size were evaluated with horizontal- and vertical plane CT images. Pneumatization of the temporal bone was investigated with 3D reconstruction software using axial CT images, dividing them as follows: medially, anterosuperiorly, posterolaterally, and inferiorly. Pneumatization of each individual part was compared with that of other parts and was also evaluated according to the aging process. RESULTS: The mean pneumatization was measured as 1696.7mm3 in patients aged under 2 years, 3609.1mm3 in those aged 2-4 years, 5351.1mm3 in those aged 5-7 years, 7295.9mm3 in those aged 8-10 years, 7797.5mm3 in those aged 11-13 years, and 8526.6mm3 in those aged 14-16 years. The degree of temporal bone pneumatization of each part was correlated with that of other parts (p<0.05). The volume of pneumatization increased with growth of the temporal bone and with aging. The degree of pneumatization of specific parts might be related to developmental periods. CONCLUSION: The pneumatization of one part might affect the pneumatization of other nearby parts, or all parts might be affected by the same driving force of pneumatization. PMID- 27993440 TI - A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders. AB - Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ T-LPD) represent a spectrum encompassing lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL) and borderline lesions. They share the expression of CD30 as a common phenotypic marker. They differ however in their clinical presentation, the histological features and clinical course. Moreover, LyP and PcALCL show numerous clinical, histological and phenotypic variants. Overlapping features of LyP and pcALCL with themselves and with other cutaneous and systemic lymphomas emphasize the importance of careful clinicopathologic correlation and staging in the diagnosis of CD30+ T-LPD. Furthermore, an increasing number of inflammatory and infectious skin disorders harboring medium-sized to large CD30+ cells have to be considered in the differential diagnosis. Whereas the expression of CD30 in cutaneous CD30+ T-LPD stands for a favourable prognosis, its expression in other cutaneous and systemic lymphomas has a divergent impact. The assessment of CD30 expression does not only provide prognostic information, but is of potential therapeutic relevance as CD30 can serve as a therapeutic target. This review focuses on the clinicopathological and phenotypic spectrum of CD30+ T LPD, its differential diagnoses and the role of CD30 as a diagnostic, prognostic and therapeutic marker. PMID- 27993441 TI - Spent lithium-ion battery recycling - Reductive ammonia leaching of metals from cathode scrap by sodium sulphite. AB - Recycling of spent lithium-ion batteries has attracted wide attention because of their high content of valuable and hazardous metals. One of the difficulties for effective metal recovery is the separation of different metals from the solution after leaching. In this research, a full hydrometallurgical process is developed to selectively recover valuable metals (Ni, Co and Li) from cathode scrap of spent lithium ion batteries. By introducing ammonia-ammonium sulphate as the leaching solution and sodium sulphite as the reductant, the total selectivity of Ni, Co and Li in the first-step leaching solution is more than 98.6% while it for Mn is only 1.36%. In detail understanding of the selective leaching process is carried out by investigating the effects of parameters such as leaching reagent composition, leaching time (0-480min), agitation speed (200-700rpm), pulp density (10-50g/L) and temperature (323-353K). It was found that Mn is primarily reduced from Mn4+ into Mn2+ into the solution as [Formula: see text] while it subsequently precipitates out into the residue in the form of (NH4)2Mn(SO3)2.H2O. Ni, Co and Li are leached and remain in the solution either as metallic ion or amine complexes. The optimised leaching conditions can be further obtained and the leaching kinetics is found to be chemical reaction control under current leaching conditions. As a result, this research is potentially beneficial for further optimisation of the spent lithium ion battery recycling process after incorporating with metal extraction from the leaching solution. PMID- 27993442 TI - Comparative dose levels between CT-scanner and slot-scanning device (EOS system) in pregnant women pelvimetry. AB - PURPOSE: To estimate fetal absorbed doses for pregnant women pelvimetry, a comparative study between EOS imaging system and low-dose spiral CT-scanner was carried out. For this purpose three different studies were investigated: in vivo, in vitro and Monte Carlo calculations. METHODS: In vivo dosimetry was performed, using OSL NanoDot dosimeters, to determine the dose to the skin of twenty pregnant women. In vitro studies were established by using a cubic phantom of water, in order to estimate the out of field doses. In the latter study, OSLDs were placed at depths corresponding to the lowest, average and highest position of the uterus. Monte Carlo calculations of effective doses to high radio sensitive organs were established, using PCXMC and CTExpo software suites for EOS imaging system and CT-scanner, respectively. RESULTS: The EOS imaging system reduces radiation exposure 4 to 8 times compared to the CT-scanner. The entrance skin doses were 74% (p-values <0.01) higher with the CT-scanner than with the EOS system. In the out of field region, the measured doses of the EOS system were reduced by 80% (p-values <0.02). Monte Carlo calculations confirmed that effective doses to organs are less accentuated for EOS than for CT pelvimetry. CONCLUSIONS: The EOS system is less irradiating than the CT exam. The out-of field dose which is significant, is lower in the EOS than in the CT-scanner and could be reduced even further by optimizing the time used for image acquisition. PMID- 27993443 TI - [Percutaneous closure of persistent ductus arteriosus in low-weight infants]. AB - INTRODUCTION: The persistent ductus arteriosus remains a common congenital pathology. Although percutaneous closure of wide channels using an Amplatzer Duct Occluder is an attractive alternative to the surgical treatment, this prosthesis is not recommended for infants weighing less than 6kg. AIM OF THE STUDY: The objective was to evaluate the efficacy and safety of this prosthesis in low weight children. PATIENTS AND METHODS: The records of children weighing less than 6kg who underwent closure with the Amplatzer Duct Occluder prosthesis between January 2010 and December 2014 were retrospectively analyzed. RESULTS: Fourteen patients (mean weight: 5.7kg [range: 4.8-6]; mean age: 6.5months [range: 3-12]) were included. The main circumstance for discovery was difficulty in breathing (93% of children). The average angiographic persistent ductus arteriosus diameter was 3.5mm (range: 3-6mm), correlating well with that found on ultrasound (r=0.68). The prosthesis was implanted successfully in 93% of cases. The only failure was explained by the increased risk of aortic subocclusion. The immediate angiographic occlusion rate was 71%. The average duration of the procedure was 46+/-12min. Three children had a channel C-type on the Krichenko classification. Two complications occurred in two patients: a case of cardiac tamponade drained during the procedure without incident and one case of partial protrusion of the Amplatzer disk into the aortic lumen. C-type (tubular) persistent ductus arteriosus and a ratio of the diameter of the persistent ductus arteriosus/weight greater than 0.95 were significantly associated with intervention failure and/or major complications during the percutaneous closure, while weight of less than 6kg was not retained as a predictor of procedure failure. No late embolization occurred after 11months of median follow-up. During this monitoring, we noted a marked clinical improvement with normalization of pulmonary pressure. CONCLUSION: This study includes the few records reported in the literature assessing the feasibility of percutaneous closure in persistent ductus arteriosus in infants weighing up to 6kg. It confirms the effectiveness of the procedure with a relatively low prevalence of complications. PMID- 27993444 TI - Two-stage revisions for culture-negative infected total knee arthroplasties: A five-year outcome in comparison with one-stage and two-stage revisions for culture-positive cases. AB - BACKGROUND: Culture-negative periprosthetic joint infection (PJI) is very intractable when dealing with an infected total knee arthroplasty (TKA) patient. Two-stage revision has been proved to be a reliable solution for PJI patients. Whether it is still credible for culture-negative infected patients remains uncertain. METHODS: Our group retrospectively reviewed all total knee revision patients from January 2003 to January 2014, 145 PJI patients were diagnosed as infection with the PJI diagnostic criteria and 129 patients were successfully followed. As different treating strategies were utilized, these patients were divided into culture-negative (18 cases, CN) group, culture-positive with one stage revision group (CP1, 21 cases) and culture-positive with two-stage revision group (CP2, 87 cases) groups. The CN group and CP2 group underwent two-stage revision with antibiotic loaded cement spacers and intravenous antibiotics, CP1 group received one-stage revision. All the culture results and relevant medical records were thoroughly reviewed. RESULTS: The mean follow-up time was 59.5 +/- 32.3 months (range 12-158 months). The culture-negative rate was 14.2%. The overall infection control rate was 92.12%. Infection recurrence was observed in two cases in CP1 group (9.09%), six cases in CP2 group (6.90%) and two cases in CN group (11.1%). The reinfection rate of culture-negative patients and culture positive patients was 7.34% and 11.1% with no significant difference (p = 0.94). No statistically difference was observed between CP2 group and CN group (p = 0.90). No Spacer fracture or dislocation was observed. CONCLUSION: With combined or broad spectrum antibiotics, two-stage revision showed comparable outcome when treating culture-negative infected TKA patients at five-year follow-up. PMID- 27993445 TI - A possible water-soluble inducer for synthesis of cellulase in Aspergillus niger. AB - The synthesis of cellulase in filamentous fungi can be triggered by several inducers. In this study, a bamboo-shoot shell pretreated with Pleurotus ostreatus could promote the formation of cellulases in Aspergillus niger. Further identification, including UPLC-TOF-MS, ultrafiltration, and FT-IR, denoted that the soluble inducer was not a traditional disaccharide but a type of modified lignin polymer. This revelation may result in incipient strategies to ameliorate cellulase productivity. PMID- 27993446 TI - Multiple Thromboembolic Cerebral Infarctions from the Aorta in a Patient with Churg-Strauss Syndrome. AB - BACKGROUND: Ischemic stroke is a rare complication of Churg-Strauss syndrome (CSS) and its pathogenesis has not been well clarified yet. We report a case of cerebral infarction in a patient with CSS due to embolism from a thrombus on the wall of the aorta. CASE: A 39-year-old man had multiple cerebral infarctions with symptoms of mild left hemiparesis and reduced vision. He was clinically diagnosed to have CSS based on remarkable eosinophilia, history of asthma, sinusitis, pulmonary infiltrates, and histologically proven extravascular eosinophilic infiltrates in the specimen of gastric mucosa. Cerebral angiography did not show any stenotic lesions in cerebral arteries. A thrombus was detected on the wall of the aorta by transesophageal echocardiography, which was considered as the source of embolism. The thrombus resolved on follow-up examination 3 months after the onset of the stroke. CONCLUSIONS: This is the first case report on cerebral infarction caused by aortogenic thromboembolism in a CSS patient. Other than cerebral vasculitis, embolism from cardiovascular system, including the wall of the aorta, is a possible cause of cerebral infarctions in a CSS patient. PMID- 27993448 TI - Introduction - Cognitive penetration and predictive coding. Pushing the debate forward with the recent achievements of cognitive science. PMID- 27993447 TI - A safe and accurate method to perform esthetic mandibular contouring surgery for Far Eastern Asians. AB - A tapered mandibular contour is popular with Far Eastern Asians. This study describes a safe and accurate method of using preoperative virtual surgical planning (VSP) and an intraoperative ostectomy guide to maximize the esthetic outcomes of mandibular symmetry and tapering while mitigating injury to the inferior alveolar nerve (IAN). Twelve subjects with chief complaints of a wide and square lower face underwent this protocol from January to June 2015. VSP was used to confirm symmetry and preserve the IAN while maximizing the surgeon's ability to taper the lower face via mandibular inferior border ostectomy. The accuracy of this method was confirmed by superimposition of the perioperative computed tomography scans in all subjects. No subjects complained of prolonged paresthesia after 3 months. A safe and accurate protocol for achieving an esthetic lower face in indicated Far Eastern individuals is described. PMID- 27993449 TI - Growth and final height of children with Gaucher disease: A 15-year follow-up at an Israeli Gaucher center. AB - BACKGROUND: It is held that enzyme replacement therapy (ERT) accelerates the growth rate in children with Gaucher disease, but its effect on final height has not been established with certainty. This study presents final heights of Gaucher patients followed up for 15years. METHODS: The study included 41 adults with non neuronopathic Gaucher disease. The final height of the patients and age at puberty was compared to their mid-parental target height and to their siblings' heights. RESULTS: Mean final height standard deviation score (HSDS) in the patients was -0.22, but none of the patients was abnormally short (HSDS of less than -2.2). Mean age at menarche of the female patients (14.7years) was significantly delayed compared to that of their mothers (P=0.0005), and mean age at first shaving in the boys was 16years. CONCLUSION: Our study showed that the mean final height of Gaucher patients fell below the mean of the 2000 CDC growth charts, but the patients were not of short stature (height less than the 3rd percentile). ERT treatment did not significantly impact the mean final HSDS. The onset of puberty, as indicated by the age at menarche, was delayed in girls with Gaucher disease. PMID- 27993450 TI - Predictive patterns of sensory evoked potentials in comatose brain injured patients evolving to brain death. AB - OBJECTIVE: To assess whether Somatosensory Evoked Potentials (SEPs), recorded within 24h after ICU admission, are reliable predictors of brain death (BD) in comatose patients with acquired brain injury of various aetiologies. METHODS: SEPs were classified as absent (A), pathological (P), and normal (N). Considering SEP recordings from both hemispheres, 6 patterns were identified: NN, NP, PP, NA, AP, and AA. The final endpoint was BD. RESULTS: Of the 203 patients included in the study, 70 (34%) evolved toward BD. The survival analysis indicated that the combination of SEP patterns in a two-graded scale (grade 1: NN-NP-PP-NA, and grade 2: AP-AA), allowed for prediction of BD with the best accuracy. This aggregation predicted BD with a sensitivity of 75.7% (CI: 64-84), a specificity of 76.6% (CI: 68-83), a positive predictive value of 64.2% (CI: 53-74) and a negative predictive value of 84.3% (CI: 77-90) in overall patients, and with a sensitivity of 75.0% (CI: 63-84), a specificity of 84.9% (CI: 75-90), a positive predictive value of 77.5% (CI: 63-88) and a negative predictive value of 84.3% (CI: 74-91) when excluding cardiac arrest. CONCLUSION: It is worth including SEPs, in association with other investigations and clinical signs, in prognostic scores of BD. The early identification of patients at high risk of evolving towards BD could help physicians to optimise management. PMID- 27993451 TI - Familial Hypercholesterolemia: Awareness, Appraisal, and Action. PMID- 27993452 TI - New Drugs for Atherosclerosis. AB - Atherosclerosis, the underlying process that ultimately leads to clinical cardiovascular disease (CVD), is caused by the multifactorial interaction of various conditions, and dyslipidemia is widely acknowledged as 1 of the crucial risk factors in this process. Statin drugs have been shown to decrease low density lipoprotein cholesterol and CVD morbidity as well as mortality and are therefore pivotal in CVD prevention. Despite the use of statin drugs, CVD remains a leading cause of mortality worldwide, which suggests that additional lipid lowering therapies are warranted. Several novel therapeutic agents, which are described in this review, are now well on their way in their respective development paths and might revolutionize anti-atherosclerotic drug therapy. PMID- 27993453 TI - Transcatheter Aortic Valve Replacement Complicated by Migrated Coronary Stent. PMID- 27993454 TI - Editor's Choice - Incidence of Stroke Following Thoracic Endovascular Aortic Repair for Descending Aortic Aneurysm: A Systematic Review of the Literature with Meta-analysis. AB - OBJECTIVE: Stroke is an increasingly recognised complication following thoracic endovascular aortic repair (TEVAR). The aim of this study was to systematically synthesise the published data on perioperative stroke incidence during TEVAR for patients with descending thoracic aneurysmal disease and to assess the impact of left subclavian artery (LSA) coverage on stroke incidence. METHODS: A systematic review of English and German articles on perioperative (in-hospital or 30 day) stroke incidence following TEVAR for descending aortic aneurysm was performed, including studies with >=50 cases, using MEDLINE and EMBASE (2005-2015). The pooled prevalence of perioperative stroke with 95% CI was estimated using random effect analysis. Heterogeneity was examined using I2 statistic. RESULTS: Of 215 studies identified, 10 were considered suitable for inclusion. The included studies enrolled a total of 2594 persons (61% male) between 1997 and 2014 with a mean weighted age of 71.8 (95% CI 71.1-73.6) years. The pooled prevalence for stroke was 4.1% (95% CI 2.9-5.5) with moderate heterogeneity between studies (I2 = 49.8%, p = .04). Five studies reported stroke incidences stratified by the management of the LSA, that is uncovered versus covered and revascularised versus covered and not-revascularised. In cases where the LSA remained uncovered, the pooled stroke incidence was 3.2% (95% CI 1.0-6.5). There was, however, an indication that stroke incidence increased following LSA coverage, to 5.3% (95% CI 2.6-8.6) in those with a revascularisation and 8.0% (95% CI 4.1-12.9) in those without revascularisation. CONCLUSION: Stroke incidence is an important morbidity after TEVAR, and probably increases if the LSA is covered during the procedure, particularly in those without revascularisation. PMID- 27993455 TI - Re. "Fate of the Distal False Aneurysms Complicating Internal Carotid Artery Dissection: Systematic Review". PMID- 27993456 TI - Commentary on "Patients with Small Abdominal Aortic Aneurysms are at Significant Risk of Cardiovascular Events and this Risk is not Addressed Sufficiently". PMID- 27993457 TI - Commentary on "Tip Design of Hemodialysis Catheters Influences Thrombotic Events and Replacement Rate". PMID- 27993458 TI - Differences in Niemann-Pick disease Type C symptomatology observed in patients of different ages. AB - BACKGROUND: Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression is more pronounced in patients with early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. Here we describe the prevalence of signs and symptoms observed in patients with NP-C and analyse the relationship between these symptoms in different age groups. METHODS: The combined patient cohort used in the analyses comprised NP-C cases (n=164) and controls (n=135) aged 0 to 60years from two previously published cohorts; a cohort of all ages from which patients <=4years of age were excluded and a cohort with early-onset NP-C and age-matched controls. The analysis of relationships between different signs and symptoms was performed for both NP-C cases and controls in two sub groups, <=4 and >4years of age, using cluster analyses. The threshold of 4years of age was selected to reflect the minimum age cut-off for satisfactory discriminatory power of the original NP-C SI. To assess the prevalence of individual signs and symptoms at age of diagnosis, patients were categorised by age into 5-year sub-groups, and prevalence values estimated for each sign and symptom of NP-C. RESULTS: Two main clusters of symptoms were clearly defined for NP-C cases in each age sub-group, whereas clusters were not as clearly defined for controls. For NP-C cases <=4years of age, one cluster comprised exclusively visceral symptoms; the second cluster combined all other signs and symptoms in this age group. For NP-C cases >4years of age, each cluster contained a mixture of visceral, neurological and psychiatric items. Prevalence estimations showed that visceral symptoms (e.g. isolated unexplained splenomegaly) were most common in NP-C cases <=4years of age. Neurological symptoms were generally more common in NP-C cases >4years of age than in younger patients, with the exception of hypotonia and delayed developmental milestones. CONCLUSIONS: These analyses provide a comprehensive overview of symptomatology observed in a large combined cohort of patients with NP-C and controls across a wide range of ages. The results largely reflect observations from clinical practice and support the importance of multi-disciplinary approaches for identification of patients with NP-C, taking into account age-specific manifestations and their possible correlations. PMID- 27993459 TI - Corneal epithelial bullae after short-term wear of small diameter scleral lenses. AB - Complications of scleral lens wear are not well documented or understood. While multiple studies focus on oxygen transmission during scleral lens wear and associated corneal swelling, little is known about the effects of varying scleral lens fitting relationships, especially when there is corneal interaction. Scleral lenses, by convention, are designed to completely clear the corneal surface and rest on the conjunctival and scleral tissue. However, some designs maximize oxygen transmission by reducing the lens diameter, thickness, and recommended corneal clearance.While the modifications increase oxygen transmission in any scleral lens design, they also distribute the lens mass closer to the limbus and make visualization of corneal clearance, especially narrow in the limbal region, more difficult. The sequelae from mechanical interaction between scleral lenses and the ocular surface, in particular the cornea, remain uncertain. This case series will describe corneal epithelial bullae, molding, and epithelial erosions as unintended scleral lens complications. These corneal changes corresponded to areas of contact lens-corneal bearing confirmed utilizing a combined scanning laser ophthalmoscopy (SLO) and anterior segment OCT. This case series will discuss epithelial bullae detection, their etiology, and suggestions for application of this information into scleral lens fitting protocols. PMID- 27993461 TI - Designing geriatric-specific trials in advanced lung cancer: What, who and how to study? PMID- 27993460 TI - Declining Well-Being in Young Swedes Born in 1990 Versus 1974. AB - PURPOSE: Well-being is affected by the environment, including societal changes. In this study, specific dimensions of well-being were compared in two cohorts of Swedish adolescents born 16 years apart. METHODS: Two groups of 18-year-olds, "Grow up Gothenburg" 1974 and 1990 birth cohorts, completed a self-reported questionnaire including the Gothenburg Well-Being in adolescence scale (GWBa). In addition, height and weight were measured, resulting in 4,362 participants (1974 birth cohort) and 5,151 participants (1990 birth cohort) with age, height, weight, and well-being data. The GWBa consists of a total score and five dimensions: mood, physical condition, energy, self-esteem, and stress balance. RESULTS: Total well-being was significantly lower in the later-born cohort, and the greatest difference was seen for the dimension stress balance (feeling calm, unconcerned, unstressed, and relaxed), although effect sizes were modest. In both boys and girls, well-being was lower for all dimensions in the later-born cohort, with the exception of Self-esteem in girls, which was higher in the later-born cohort. In both cohorts, boys reported higher well-being than girls for all dimensions. The mean body mass index z-score was higher in boys from the later born cohort, but after adjusting for weight status, the differences in well-being between the cohorts persisted. CONCLUSIONS: Well-being was lower in the later born cohort, particularly for the dimension stress balance. Differences were not explained by the shift in weight status indicating that other societal changes have had an impact on well-being levels. Managing high levels of stress might be an area of intervention in adolescents for improved well-being. PMID- 27993462 TI - Complex Medial Meniscus Tears Are Associated With a Biconcave Medial Tibial Plateau. AB - PURPOSE: To determine whether an association exists between a biconcave medial tibial plateau and complex medial meniscus tears. METHODS: A consecutive series of stable knees undergoing arthroscopy were evaluated retrospectively with the use of preoperative magnetic resonance imaging (MRI), radiographs, and arthroscopy documented by intraoperative videos. Investigators independently performed blinded reviews of the MRI or videos. Based on the arthroscopy findings, medial tibial plateaus were classified as either biconcave or not biconcave. A transverse coronal plane ridge, separating the front of the tibial plateau from the back near the inner margin of the posterior body of the medial meniscus, was defined as biconcave. The medial plateau slope was calculated with MRI sagittal views. General demographic information, body mass index, and arthroscopically confirmed knee pathology were recorded. RESULTS: A total of 179 consecutive knees were studied from July 2014 through August 2015; 49 (27.2%) biconcave medial tibial plateaus and 130 (72.8%) controls were identified at arthroscopy. Complex medial meniscus tears were found in 103. Patients with a biconcave medial tibial plateau were found to have more complex medial meniscus tears (69.4%) than those without a biconcavity (53.1%) (P = .049) despite having lower body mass index (P = .020). No difference in medial tibial plateau slope was observed for biconcavities involving both cartilage and bone, bone only, or an indeterminate group (P = .47). CONCLUSIONS: Biconcave medial tibial plateaus were present in 27.4% of a consecutive series of patients undergoing knee arthroscopy. A biconcave medial tibial plateau was more frequently associated with a complex medial meniscus tear. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 27993463 TI - Testing the Construct Validity of a Virtual Reality Hip Arthroscopy Simulator. AB - PURPOSE: To test the construct validity of the hip diagnostics module of a virtual reality hip arthroscopy simulator. METHODS: Nineteen orthopaedic surgeons performed a simulated arthroscopic examination of a healthy hip joint using a 70 degrees arthroscope in the supine position. Surgeons were categorized as either expert (those who had performed 250 hip arthroscopies or more) or novice (those who had performed fewer than this). Twenty-one specific targets were visualized within the central and peripheral compartments; 9 via the anterior portal, 9 via the anterolateral portal, and 3 via the posterolateral portal. This was immediately followed by a task testing basic probe examination of the joint in which a series of 8 targets were probed via the anterolateral portal. During the tasks, the surgeon's performance was evaluated by the simulator using a set of predefined metrics including task duration, number of soft tissue and bone collisions, and distance travelled by instruments. No repeat attempts at the tasks were permitted. Construct validity was then evaluated by comparing novice and expert group performance metrics over the 2 tasks using the Mann-Whitney test, with a P value of less than .05 considered significant. RESULTS: On the visualization task, the expert group outperformed the novice group on time taken (P = .0003), number of collisions with soft tissue (P = .001), number of collisions with bone (P = .002), and distance travelled by the arthroscope (P = .02). On the probe examination, the 2 groups differed only in the time taken to complete the task (P = .025) with no significant difference in other metrics. CONCLUSIONS: Increased experience in hip arthroscopy was reflected by significantly better performance on the virtual reality simulator across 2 tasks, supporting its construct validity. CLINICAL RELEVANCE: This study validates a virtual reality hip arthroscopy simulator and supports its potential for developing basic arthroscopic skills. LEVEL OF EVIDENCE: Level III. PMID- 27993465 TI - Epithelial dysplasia must be treated. PMID- 27993464 TI - Impact of medical or surgical admission on outcomes of patients with acute cholecystitis. AB - BACKGROUND: Although acute cholecystitis (AC) is a surgical disease, patients with the condition may be admitted to medical-related services (MS). This may lead to delayed cholecystectomy thereby affecting outcomes and quality of care. METHODS: Between July 2010 and March 2013, 329 patients under 70 years old presented to a community-based tertiary care hospital with AC and underwent same admission cholecystectomy. Outcomes were compared between patients admitted to MS and surgical services (SS). RESULTS: Two hundred fifteen patients (65.3%) were admitted to a MS. Patients under the MS had longer LOS (3.0 days vs. 2.0 days, p < 0.001), waiting time to surgical consultation (7.3 h vs. 5.0 h, p < 0.001) and to cholecystectomy (1.0, 0-2 days vs. 1.0, 0-1 day, p < 0.001), and increased hospital costs ($3685 vs. $4,688, p < 0.001) compared to the SS. Readmission and mortality rates were not significantly different between groups. CONCLUSION: Patients under 70 years old with AC undergoing cholecystectomy admitted to MS had increased LOS, delay to the operation, and hospital costs compared to those admitted to a SS. Admission of patients with AC to a SS needs to be emphasized to reduce costs and improve quality of care. PMID- 27993466 TI - Truth or myth: Definitive chemoradiotherapy doesn't work for HPV/p16 negative oropharyngeal squamous cell carcinoma? PMID- 27993467 TI - Dissolution kinetics of volatile organic compound vapors in water: An integrated experimental and computational study. AB - In this study we performed batch experiments to investigate the dissolution kinetics of trichloroethylene (TCE) and toluene vapors in water at room temperature and atmospheric pressure. The batch systems consisted of a water reservoir and a connected headspace, the latter containing a small glass cylinder filled with pure volatile organic compound (VOC). Results showed that air phase concentrations of both TCE and toluene increased relatively quickly to their maximum values and then became constant. We considered subsequent dissolution into both stirred and unstirred water reservoirs. Results of the stirred experiments showed a quick increase in the VOC concentrations with time up to their solubility limit in water. VOC vapor dissolution was found to be independent of pH. In contrast, salinity had a significant effect on the solubility of TCE and toluene vapors. VOC evaporation and vapor dissolution in the stirred water reservoirs followed first-order rate processes. Observed data could be described well using both simplified analytical solutions, which decoupled the VOC dynamics in the air and water phases, as well as using more complete coupled solutions. However, the estimated evaporation (ke) and dissolution (kd) rate constants differed by up to 70% between the coupled and uncoupled formulations. We also numerically investigated the effects of fluid withdrawal from the small water reservoir due to sampling. While decoupling the VOC air and water phase mass transfer processes produced unreliable estimates of kd, the effects of fluid withdrawal on the estimated rate constants were found to be less important. The unstirred experiments showed a much slower increase in the dissolved VOC concentrations versus time. Molecular diffusion of the VOCs within the aqueous phase became then the limiting factor for mass transfer from air to water. Fluid withdrawal during sampling likely caused some minor convection within the reservoir, which was simulated by increasing the apparent liquid diffusion coefficient. PMID- 27993468 TI - Heavy metal removal capacity of individual components of permeable reactive concrete. AB - Permeable reactive barriers (PRBs) are a well-known technique for groundwater remediation using industrialized reactive media such as zero-valent iron and activated carbon. Permeable reactive concrete (PRC) is an alternative reactive medium composed of relatively inexpensive materials such as cement and aggregate. A variety of multimodal, simultaneous processes drive remediation of metals from contaminated groundwater within PRC systems due to the complex heterogeneous matrix formed during cement hydration. This research investigated the influence coarse aggregate, portland cement, fly ash, and various combinations had on the removal of lead, cadmium, and zinc in solution. Absorption, adsorption, precipitation, co-precipitation, and internal diffusion of the metals are common mechanisms of removal in the hydrated cement matrix and independent of the aggregate. Local aggregates can be used as the permeable structure also possessing high metal removal capabilities, however calcareous sources of aggregate are preferred due to improved removal with low leachability. Individual adsorption isotherms were linear or curvilinear up, indicating a preferred removal process. For PRC samples, metal saturation was not reached over the range of concentrations tested. Results were then used to compare removal against activated carbon and aggregate-based PRBs by estimating material costs for the remediation of an example heavy metal contaminated Superfund site located in the Midwestern United States, Joplin, Missouri. PMID- 27993469 TI - Stabilization and prolonged reactivity of aqueous-phase ozone with cyclodextrin. AB - Recalcitrant organic groundwater contaminants, such as 1,4-dioxane, may require strong oxidants for complete mineralization. However, their efficacy for in-situ chemical oxidation (ISCO) is limited by oxidant decay and reactivity. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) was examined for its ability to stabilize aqueous-phase ozone (O3) and prolong oxidation potential through inclusion complex formation. Partial transformation of HPbetaCD by O3 was observed. However, HPbetaCD proved to be sufficiently recalcitrant, because it was only partially degraded in the presence of O3. The formation of a HPbetaCD:O3 clathrate complex was observed, which stabilized decay of O3. The presence of HPbetaCD increased the O3 half-life linearly with increasing HPbetaCD:O3 molar ratio. The O3 half-life in solutions increased by as much as 40-fold relative to HPbetaCD-free O3 solutions. Observed O3 release from HPbetaCD and indigo oxidation confirmed that the formation of the inclusion complex is reversible. This proof-of-concept study demonstrates that HPbetaCD can complex O3 while preserving its reactivity. These results suggest that the use of clathrate stabilizers, such as HPbetaCD, can support the development of a facilitated transport enabled ISCO for the O3 treatment of groundwater contaminated with recalcitrant compounds. PMID- 27993470 TI - Application and further characterization of the snap bean S156/R123 ozone biomonitoring system in relation to ambient air temperature. AB - Increased mixing ratios of ground-level ozone (O3) threaten individual plants, plant communities and ecosystems. In this sense, O3 biomonitoring is of great interest. The O3-sensitive S156 and the O3-tolerant R123 genotypes of snap bean (Phaseolus vulgaris L.) have been proposed as a potential tool for active biomonitoring of ambient O3. In the present study, an O3 biomonitoring was conducted, with the S156/R123 tool, along with a monitoring of O3 and other environmental conditions in an urban area in Athens, Greece, during the growing seasons of 2012 and 2013. Plant yield was evaluated to assess the effectiveness of AOT40 in interpreting O3-induced phytotoxicity. Across the two genotypes, an approximately two times lower total number of pods - and consequently lower bulk mass of seeds - was found in 2012 than in 2013, although there was no significant difference in the final AOT40 between the two years. No significant differences were observed in the stomatal density or conductance between the two genotypes, whereas it was estimated that, in both genotypes, the abaxial leaf surface contributes 2.7 fold to O3 intake in comparison to the adaxial one. By testing the role of ambient air temperature in outdoor plant environment chambers (OPECs), it was found that increased temperature limits mature pod formation and complicates interpretation of O3 impacts in terms of S156/R123 yields ratios. This is the first study providing evidence for a hormetic response of plants to ambient air temperature. This study also points out the complexity of using yield as a measure of O3 impact across different environments with the snap bean system, whereas visible foliar injury is more consistently related to O3 effects. PMID- 27993471 TI - Environmental metal contamination and health impact assessment in two industrial regions of Romania. AB - We investigated two Romanian industrial regions- Copsa Mica and Zlatna, to assess the current situation of soil pollution and bioaccumulation of Pb, Cd, Cu and Zn in different vegetable species and possible risks to consumers. Both total and mobile forms of the metals were determined in soil samples, and metal content in the edible parts of root vegetable samples was also assessed. The concentrations of Pb and Zn in soil were higher in Copsa Mica than in Zlatna (566mg/kg vs 271mg/kg for Pb and 1143mg/kg vs 368mg/kg for Zn).The metal mobility in soil from Copsa Mica decreases in the order Zn>Cu>Cd>Pb (1.88mg/kg, 0.40mg/kg, 0.22mg/kg, 0.16mg/kg, respectively), while in Zlatna, the order was Cu>Zn>Pb>Cd (0.88mg/kg, 0.29mg/kg, 0.04mg/kg, 0.01mg/kg, respectively), apparently depending on metal and soil conditions. In Copsa Mica, the amount of Pb and Cd in vegetable samples exceeded the maximum permissible limits in carrots (median concentration 0.32mg/kg for Pb and Cd) and in yellow onions (median concentration 0.24mg/kg for Cd). In Zlatna region, the content of Cd exceeded the maximum limits in yellow onions (median concentration 0.11mg/kg). The amount of Pb was higher than the maximum acceptable level in carrots from the Zlatna region (median concentration 0.12mg/kg). Cu and Zn levels were within the normal range in all vegetable samples. In the Zlatna region, the transfer factors for Pb and Cd were higher in carrots (median values of 9.9 for Pb and 21.0 for Cd) compared to carrots harvested in Copsa Mica (median values of 4.0 for Pb and 2.0 for Cd). Daily intake rates of metals through local vegetable consumption exceeded the limit values established by the European Food Safety Authority for Pb (1.2 to 2.4 times) and Cd (5.5 to 9.1 times) in both regions, with potential adverse health effects for the local population. The results highlight the need for total soil remediation action before fruit and vegetables produced in these polluted areas can be safely consumed. PMID- 27993472 TI - Occurrence of Cryptosporidium and Giardia in raw and finished drinking water in north-eastern Spain. AB - This paper collects the first large-sample-size study on the presence of Cryptosporidium oocysts and Giardia cysts in drinking water plants at the 20 most populated towns in Aragon (north-eastern Spain). Samples of influent raw water and effluent finished water were collected from each plant during different seasons and processed according to USEPA Method 1623. Cryptosporidium oocysts and Giardia cysts were detected in samples collected from 55% and 70% plants, respectively, with nine plants being positive for both protozoa and only four plants being negative over the study period. Both parasites were identified in the raw water throughout the year, with a lower frequency in autumn and a peak in winter, at a mean concentration of 67+/-38 oocysts per 100l and 125+/-241 cysts per 100l. The turbidity of raw water was not related to the presence or concentration of (oo)cysts, and the (oo)cyst removal efficiency was not related to the type of water treatment. One or both pathogens were identified in the finished water in 7 out of 11 plants with a conventional treatment process (coagulation, flocculation, sedimentation, filtration, and disinfection processes) compared to 4 out of 9 plants that did not apply one of the pre chlorination treatment steps. Protozoa were detected in the finished water of positive plants at a mean concentration of 88+/-55 oocysts per 100l and 37+/-41 cysts per 100l, and most of them excluded propidium iodide so were considered potentially viable. The ubiquity of these parasites in the drinking water sources and the inefficiency of conventional water treatment in reducing/inactivating them may present a serious public health issue in this geographical area. PMID- 27993473 TI - Evaluation of beta-d-glucuronidase and particle-size distribution for microbiological water quality monitoring in Northern Vietnam. AB - In many karst regions in developing countries, the populations often suffer from poor microbial water quality and are frequently exposed to bacterial pathogens. The high variability of water quality requires rapid assays, but the conventional cultivation-based analysis of fecal indicator bacteria, such as Escherichia coli (E. coli), is very time-consuming. In this respect, the measurement of the enzymatic activity of E. coli could prove to be a valuable tool for water quality monitoring. A mobile automated prototype device was used for the investigation of beta-d-glucuronidase (GLUC) activity at a remote karst spring, connected to a sinking surface stream, in Northern Vietnam. To assess the relationship between GLUC activity, discharge dynamics and contamination patterns, multiple hydrological, hydrochemical, physicochemical and microbiological parameters, including discharge, turbidity, particle-size distributions, and E. coli, were measured with high temporal resolution during ten days of on-site monitoring. A complex contamination pattern due to anthropogenic and agricultural activities led to high E. coli concentrations (270 to >24,200 MPN/100ml) and a GLUC activity between 3.1 and 102.2 mMFU/100ml. A strong daily fluctuation pattern of GLUC activity and particle concentrations within small size classes (<10MUm) could be observed, as demonstrated by autocorrelations. A Spearman's rank correlation analysis resulted in correlation coefficients of rs=0.56 for E. coli and GLUC activity and rs=0.54 for GLUC activity and the concentration of 2-3MUm particles. On an event scale, correlations were found to be higher (rs=0.69 and 0.87, respectively). GLUC activity and E. coli displayed a general contamination pattern, but with significant differences in detail, which may be explained by interferences of e. g. viable but non-culturable cells. Although further evaluations are recommended, GLUC activity is a promising, complementary parameter for on-site and near real-time water quality monitoring. PMID- 27993474 TI - In-vitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests. AB - This paper reports the evaluation of in-vitro physiologically relevant extraction tests for ascertainment of the bioaccessible fractions of emerging flame retardants from indoor dust in the gastric and gastrointestinal compartments. Standardized bioaccessibility tests under both fasting (UBM-like test) and fed (FOREhST test) conditions simulating the macronutrient composition of an average child diet were harnessed for investigation of the oral bioaccessibility of chlorinated organophosphate esters, namely, tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCP), in household and automobile cabin dust samples with varying concentration levels of contaminants. Minimal processing of the biomimetic extracts (only protein precipitation using acetonitrile) was proven feasible by analysis with liquid chromatography-mass spectrometric detection (LC-MS/MS). An inversely proportional relationship was identified between log Kow and oral bioaccessibility concentrations for TCEP, TCPP and TDCP in both dust samples with maximum bioaccessibility fractions for TCEP within the range of 50-103%. Non bioaccessible fractions were determined by matrix-solid phase dispersion. Limits of quantification of LC-MS/MS in surrogate digestive fluids ranging from 0.4 0.8ng/mL suffice for determination of freely dissolved fractions of the two less hydrophobic species. Our results indicate that lipophilic food commodities used under fed-state gastrointestinal extraction conditions do not increase availability of TCEP, TCPP and TDCP in body fluids, and therefore conservative conditions in human health risk explorations for the target moderately polar flame retardants might be obtained with simplified tests under fasting conditions. This also holds true for the UBM/FOREhST bioaccessibility data for SRM 2585 (organic contaminants in house dust). Estimated average daily intake doses for toddlers incorporating oral bioaccessibility data afforded body burdens for the three chlorinated alkyl phosphates of ca. 3000 to 700 times below reference dose values, which indicate that long-term exposure to chlorinated organophosphate esters via accidental ingestion of indoor dust does not pose health risks to toddlers. PMID- 27993475 TI - In vitro and in silico investigations of the binary-mixture toxicity of phthalate esters and cadmium (II) to Vibrio qinghaiensis sp.-Q67. AB - Phthalate esters (PAEs) are widely used as plasticizers and have become one of the emerging contaminants with an increasing public concern. The residues of PAEs frequently co-exist with heavy metals such as cadmium (Cd) in waters; however, their joint ecotoxicity remains largely unknown. We herein investigated the single and joint toxicity of commonly used PAEs and Cd using freshwater luminescent bacteria Vibrio qinghaiensis sp.-Q67. The median effective concentration (EC50) of benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), diethyl phthalate (DEP), dimethyl phthalate (DMP), diisooctyl phthalate (DIOP) and di-n-octyl phthalate (DOP) were determined to be in the range from 134.4mg/L to as high as 1000mg/L, indicating very weak toxicity to Vibrio qinghaiensis sp. Q67. The toxicity of single PAEs showed a significant linear relationship with Log Kow, indicating the dependence of the elevated toxicity on the increasing hydrophilicity. The toxicity of binary mixture of PAEs was further evaluated in silico using the independent action (IA) model and concentration addition (CA) model. DMP-DEP, DEP-DBP or DMP-DBP exhibited antagonistic effects with the toxic unit value higher than 1.2. The CA and IA models poorly predicted the joint toxicity of DMP-DEP, DEP-DBP or DMP-DBP. The joint toxicity of the binary mixtures of DMP, DEP or DBP with Cd was simple additive as predicted by the CA and IA models. Our results indicated the potentially higher risk of PAEs in the presence of Cd, emphasizing the importance of determining the impact of their joint effects on aquatic organisms. The integrated in vitro and in silico methods employed in this study will be beneficial to study the joint toxicity and better assess the aquatic ecological risk of PAEs. PMID- 27993476 TI - Urinary oxidative stress biomarkers among local residents measured 6years after the Hebei Spirit oil spill. AB - In December 2007, the Hebei Spirit oil spill occurred on the west coast of South Korea. Association between crude oil exposure and the levels of urinary oxidative stress biomarkers was reported among the local residents, 1.5years after the accident. The aim of this study was to follow-up possible longer-term effects of the oil spill among the residents near the oil spill. Six years after the accident, urinary oxidative stress biomarkers of the residents were associated with surrogates of oil exposure. The target subjects were divided into two groups based on the distance of their residence to the spill site, i.e., those near the spill site ('Near' group, n=476), and those far from the spill ('Far' group, n=152). A questionnaire was administered by trained interviewers or self reporting, and demographic information and other parameters of the participants, such as socioeconomic status, smoking and drinking behaviors, disease history, and duration of clean-up activities after the spill, were collected. The participants' levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in 12 h urine samples were measured as indicators of oxidative DNA damage and lipid peroxidation, respectively. A general linear model was used for statistical analysis. Urinary MDA and 8-OHdG levels measured from 'Near' group, i.e., geometric mean of 2.19MUmol/g creatinine, and 5.41MUg/g creatinine, respectively, were higher than those of 'Far' group. Especially, urinary 8-OHdG levels in the 'Near' group were significantly higher than those of 'Far' after adjusting relevant covariates. In addition, the duration of clean-up activities showed a significant association with both urinary 8-OHdG and MDA levels. Even 6years after the oil spill, positive associations between oxidative stress biomarkers and surrogates of oil exposure were evident. While the present study design lacks biomarkers of exposure, the results of this study suggest that the consequences of oil pollution may last for years. PMID- 27993477 TI - Exploiting Knowledge on Leishmania Drug Resistance to Support the Quest for New Drugs. AB - New drugs are needed to control leishmaniasis and efforts are currently on-going to counter the neglect of this disease. We discuss here the utility and the impact of associating drug resistance (DR) studies to drug discovery pipelines. We use as paradigm currently used drugs, antimonials and miltefosine, and complement our reflection by interviewing three experts in the field. We suggest DR studies to be involved at two different stages of drug development: (i) the efficiency of novel compounds should be confirmed on sets of strains including recent clinical isolates with DR; (ii) experimental DR should be generated to promising compounds at an early stage of their development, to further optimize them and monitor clinical trials. PMID- 27993478 TI - Pharmaceutical aerosols deposition patterns from a Dry Powder Inhaler: Euler Lagrangian prediction and validation. AB - This study uses Computational Fluid Dynamics (CFD) to predict, analyze and validate the deposition patterns in a human lung for a Budesonide drug delivered from the Novolizer Dry Powder Inhaler device. We used a test case of known deposition patterns to validate our computational Euler Lagrangian-based deposition predictions. Two different lung models are used: (i) a basic ring-less trachea model and (ii) an advanced Human Zygote5 model. Unlike earlier attempts, the current simulations do not include the device in the computational domain. This greatly reduces the computational effort. To mimic the device, we model the inlet particle jet stream from the device as a spray entering the mouth in a conical fashion. Deposition studies in the various lung regions were performed. We were able to computationally predict and then demonstrate the enhanced deposition in the tracheal and first generation rings/ridges. The enhanced vorticity creation due to the ring structure and the geometrical design contributes to larger deposition in the Zygote5 model. These are in accord with existing data, unlike the ring-less model. Our validated results indicate the need to (i) introduce the ridges in the experimental casts and the CFD surface meshes to be anatomically consistent and obtain physiologically consistent depositions; (ii) introduce a factor to account for the recirculating lighter particles in empirical models. PMID- 27993480 TI - Bokhman Redux: Endometrial cancer "types" in the 21st century. AB - In 1983 Jan V. Bokhman, M.D. published a landmark paper entitled "Two Pathogenetic Types of Endometrial Carcinoma" in which an enduring dualistic view of endometrial cancer was first proposed. "Type I" cancers are thought to represent estrogen driven mostly low grade endometrioid tumors strongly associated with obesity and other components of the metabolic syndrome. "Type II" cancers represent higher grade non-endometrioid tumors for which the latter associations are less significant. Basic tenets of this dichotomy including significant prognostic differences have been abundantly confirmed by later literature. The construct has in turn contributed a useful framework for decades of teaching and scientific advancement across disciplines. However, recent large epidemiologic studies indicate a more complex web of risk factors with obesity and hormones likely playing an important role across the entire endometrial cancer histologic and clinical spectrum. Moreover, high quality molecular data and refinements in pathologic classification challenge any simplistic classification of endometrial cancer. For example, the Cancer Genome Atlas (TCGA) recently defined four clinically distinct endometrial cancer types based on their overall mutational burden, specific p53, POLE and PTEN mutations, microsatellite instability and histology. Additionally, new histologic categories with clear prognostic implications have been accepted and it is becoming evident from an epidemiologic point of view that metabolic factors may play an important role in endometrial cancer overall. While Bokhman's intuitive dualistic model remains relevant when working with large registries and databases lacking granular information; most other efforts should integrate clinical, pathological and molecular specifics into more nuanced classifications. PMID- 27993479 TI - Feasibility and outcome of interval debulking surgery (IDS) after carboplatin paclitaxel-bevacizumab (CPB): A subgroup analysis of the MITO-16A-MaNGO OV2A phase 4 trial. AB - BACKGROUND: Few data are available on the outcome of surgery after a bevacizumab containing regimen. The MITO 16A- MaNGO OV2A phase 4 trial evaluates the outcomes of first-line CPB in a clinical-practice-like setting. Here we present the results of the subgroup of patients undergoing IDS after neoadjuvant treatment or suboptimal primary surgery. METHODS: 400 chemonaive epithelial ovarian cancer patients, age>=18, ECOG PS 0-2 were eligible to receive C (AUC 5 d1, q21) plus P (175mg/m2 d1, q21) and B (15mg/kg d1 q21) for 6cycles followed by B maintenance until cycle 22nd. RESULTS: 79 patients (20%) underwent IDS. Overall, 74 patients received at least one administration of B before IDS. Median age was 61.2, 70% of the patients had FIGO IIIC disease. The median number of cycles before IDS was 3 both for chemotherapy and bevacizumab respectively. A residual disease <=1cm was achieved in 64 patients (86.5%). Four percent of the patients experienced fever and 4% required blood transfusion after surgery. Surgical wound infection and/or dehiscence, pelvic abscess, intestinal sub-occlusion and fistula were experienced by one patient each. CONCLUSIONS: In the MITO16A-MaNGO OV2A phase 4 trial, combined chemotherapy and bevacizumab did not hamper IDS and the rate of perioperative complications was similar to what expected without bevacizumab. These data support the hypothesis that adding bevacizumab to first line chemotherapy for ovarian cancer might not be denied to patients for whom IDS is planned. PMID- 27993481 TI - Examining state health agency epidemiologists and their training needs. AB - PURPOSE: Despite increases in formal education, changing trends affecting epidemiologic practice prompted concerns over whether epidemiologists had sufficient training. METHODS: This study sought to explain factors that predicted low self-reported proficiency levels among daily important work tasks of state health agencies' epidemiologists. The number of knowledge gaps, instances where epidemiologists identified a work-related task both as 'very' important in their daily work and felt they were "unable to perform" or performed at a "beginner" level, was studied, and predictor variables were assessed. A total of 681 epidemiologists responded to the 2014 Public Health Workforce Interests and Needs Survey, a national survey of state health agency workers; epidemiologists represented 7% of all respondents. RESULTS: Epidemiologists at state health agencies worked mostly in communicable disease (31%) or general surveillance (26%). Epidemiologists reported eight key daily work-related activities with an average of three training gaps. Factors that decreased the likelihood of epidemiologists' low proficiency in performing key activities were the presence of internal trainings (adjusted odds ratio = 0.69, 95% confidence interval, 0.49 0.99) and length of time working in public health (adjusted odds ratio = 0.95, 95% confidence interval, 0.93-0.98). CONCLUSION: Although formal education of epidemiologists is on the rise, state health agencies' epidemiologists feel unprepared to tackle one-third of their important daily tasks. PMID- 27993482 TI - Bevacizumab Plus Pemetrexed Versus Pemetrexed Alone as Maintenance Therapy for Patients With Advanced Nonsquamous Non-Small-cell Lung Cancer: Update From the Swiss Group for Clinical Cancer Research (SAKK) 19/09 Trial. AB - BACKGROUND: Pemetrexed and bevacizumab as single agents have been approved for maintenance therapy after platinum-based induction in patients with advanced nonsquamous non-small-cell lung cancer. It is currently unknown whether bevacizumab plus pemetrexed is superior to pemetrexed alone. PATIENTS AND METHODS: We conducted a nonrandomized phase II trial with 2 sequential cohorts. In the first cohort, 77 patients were treated with 4 cycles of cisplatin, bevacizumab, and pemetrexed every 3 weeks, followed by bevacizumab plus pemetrexed maintenance until progression. In the second cohort, we treated 52 patients without bevacizumab, using maintenance with pemetrexed alone. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), adverse events, and the treatment costs of the 2 cohorts were compared. RESULTS: The median PFS from the time of registration was 6.9 months in cohort 1 and 5.6 months in cohort 2. The ORR was 62.3% in cohort 1% and 44.2% in cohort 2. The PFS (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0; P = .041) and ORR (odds ratio, 2.1; 95% CI, 1.0-4.3; P = .049) were better in cohort 1 than in cohort 2. No OS difference was found (hazard ratio, 1.0; 95% CI, 0.7-1.6; P = .890) after a median follow-up period of 47 months for cohort 1 and 27 months for cohort 2. The rate of grade >= 3 adverse events was greater in cohort 1. The treatment costs per patient were on average 1.4 times greater for cohort 1. CONCLUSION: The addition of bevacizumab increased the ORR and PFS, but not OS, in our nonrandomized trial. Furthermore, the addition of bevacizumab was associated with greater toxicity and higher costs. PMID- 27993483 TI - Lens Power, Axial Length-to-Corneal Radius Ratio, and Association with Diabetic Retinopathy in the Adult Population with Type 2 Diabetes. AB - PURPOSE: To calculate crystalline lens power and to determine the relationship between ocular biometry and diabetic retinopathy (DR) in an adult population with type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional, population-based study. PARTICIPANTS: Patients with T2DM from the Beixinjing community, Changning district, Shanghai. METHODS: Random clustering sampling was used to identify adults with T2DM in the Beixinjing community. Spherical equivalent (SE) was determined by subjective refraction that achieved the best corrected vision. Axial length (AL), corneal power (CP), and anterior chamber depth (ACD) were measured using the IOLMaster. Diabetic retinopathy and diabetic macular edema (DME) were assessed according to the international DR classification. MAIN OUTCOME MEASURES: The crystalline lens power was calculated using the Bennett Rabbetts formula. The AL-to-corneal radius ratio (AL/CR ratio) was defined as the axial length divided by the mean corneal radius of curvature. RESULTS: A total of 4011 eyes of 2057 subjects with T2DM were included in the analysis. In multivariate logistic models adjusting for age, sex, duration of diabetes, glycosylated hemoglobin A1c, serum creatinine, body mass index, systolic blood pressure, and cataract, after categorizing values into quartiles, there were trend associations between lens power and any DR (P = 0.01), between AL/CR ratio and any DR (P = 0.02), and between AL and any DR (P = 0.03), between lens power and moderate DR (P = 0.02), and between AL and moderate DR (P = 0.02); eyes with higher AL/CR ratio were less likely to have any DR (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.24-0.78; P = 0.01 per 1 increase) and moderate DR (OR, 0.44; 95% CI, 0.21-0.93; P = 0.03 per 1 increase), eyes with longer AL were less likely to have any DR (OR, 0.88; 95% CI, 0.81-0.95; P = 0.002 per millimeter increase) or moderate DR (OR, 0.89; 95% CI, 0.80-0.98; P = 0.02 per millimeter increase), and eyes with higher SE were more likely to have any DR (OR, 1.08; 95% CI, 1.03-1.13; P = 0.003 per diopter increase). CONCLUSIONS: In persons with T2DM, lens power, AL/CR ratio, and AL were associated with the presence of any DR and moderate DR. These findings suggested that globe elongation plays a major role in protective effects against DR, with contributions from lens power and other refractive components. PMID- 27993484 TI - Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals. AB - PURPOSE: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. MAIN OUTCOME MEASURES: Glaucoma clinical parameters and age at presentation. RESULTS: At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6+/-12.5 vs. 47.5+/-16.7 years; P = 0.018). The mean highest intraocular pressure (32.2+/-9.7 vs. 17.6+/-3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65+/-0.27 vs. 0.48+/-0.13; P = 0.006), and mean deviation on visual field testing (-10.0+/-10.3 vs. -1.2+/-1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. CONCLUSIONS: Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma. PMID- 27993485 TI - Racial Disparities in Screening Mammography in the United States: A Systematic Review and Meta-analysis. AB - PURPOSE: Many studies have suggested that disparities exist in the use of medical screening tests. The purpose of this study was to assess racial disparities in screening mammography in the United States via a systematic review and meta analysis. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus for comparative studies published between 1946 and 2015 comparing utilization of mammography among various racial groups. Two independent reviewers extracted data and appraised study. Meta-analysis was conducted when appropriate using the random-effects model. RESULTS: A total of 5,818,380 patients were included across 39 relevant studies; 43.1% of patients were white, 33.3% were black, 17.4% were Hispanic, and 6.2% were Asian/Pacific Islander. Black and Hispanic populations had lower odds of utilizing screening mammography when compared with the white population (odds ratio [OR] = 0.81; 95% confidence interval [CI], 0.72-0.91; I2 = 89.4% and OR = 0.83; 95% CI, 0.74-0.93, respectively). For African Americans, these disparities were present in both the 40 to 65 age group and the >65 age group; for Hispanics, these differences were present only in the 40 to 65 age group. There was no difference in mammography utilization between Asians/Pacific Islanders and whites (OR = 1.82; 95% CI, 0.09-38.41). CONCLUSIONS: Racial disparities in utilization of screening mammography are evident in black and Hispanic populations in the United States. Further studies are needed to understand reasons for disparities, trends over time, and the effectiveness of interventions targeting these disparities. PMID- 27993486 TI - Fairness in evaluating DNA mixtures. PMID- 27993487 TI - The Use of Telehealth to Reduce Inequalities in Cardiovascular Outcomes in Australia and New Zealand: A Critical Review. AB - Telehealth, the delivery of health care services at a distance using information and communications technology, is one means of redressing inequalities in cardiovascular outcomes for disadvantaged groups in Australia. This critical review argues that there is sufficient evidence to move to larger-scale implementation of telehealth for acute cardiac, acute stroke, and cardiac rehabilitation services. For cardiovascular chronic disease and risk factor management, telehealth-based services can deliver value but the evidence is less compelling, as the outcomes of these programs are variable and depend upon the context of their implementation. PMID- 27993488 TI - Long-term home and community-based exercise programs improve function in community-dwelling older people with cognitive impairment: a systematic review. AB - QUESTION: Do long-term (> 3 months) home or community-based exercise programs improve function, reduce falls and prevent hospital readmissions in older people with cognitive impairment? DESIGN: Systematic review and meta-analysis of randomised, controlled trials. Electronic databases (CINAHL, PubMed, Medline, Embase, AMED) were searched from the earliest date possible until March 2016. PARTICIPANTS: Older adults (>= 65 years) with cognitive impairment living in the community. INTERVENTION: Supervised home or community-based exercise programs longer than 3 months. OUTCOME MEASURES: The primary outcomes were function (including balance and activities of daily living), falls and hospital readmissions. RESULTS: Of 1011 studies identified, seven trials with 945 participants met the inclusion criteria. Compared with no intervention, long-term exercise programs improved functional independence in basic activities of daily living by a moderate and significant amount (SMD 0.77, 95% CI 0.17 to 1.37, I2=67%), and improved functional independence in instrumental activities of daily living by a small and significant amount (SMD 0.44, 95% CI 0.03 to 0.86, I2=42%). Long-term exercise improved balance (mean difference in functional reach test 5.2cm, 95% CI 0.5 to 9.9, I2=76%). Data from two individual trials suggest that long-term exercise programs also reduce falls in older people with cognitive impairment. However, there was limited reporting of the effect of exercise on hospital readmissions for this group of people. CONCLUSIONS: Long-term home and community-based exercise programs improve function in older adults living in the community with cognitive impairment. Review registration: PROSPERO CRD42015029602. [Lewis M, Peiris CL, Shields N (2016) Long-term home and community-based exercise programs improve function in community-dwelling older people with cognitive impairment: a systematic review.Journal of Physiotherapy63: 23-29]. PMID- 27993489 TI - A multifactorial intervention for frail older people is more than twice as effective among those who are compliant: complier average causal effect analysis of a randomised trial. AB - QUESTION: What is the effect of a multifactorial intervention on frailty and mobility in frail older people who comply with their allocated treatment? DESIGN: Secondary analysis of a randomised, controlled trial to derive an estimate of complier average causal effect (CACE) of treatment. PARTICIPANTS: A total of 241 frail community-dwelling people aged >= 70 years. INTERVENTION: Intervention participants received a 12-month multidisciplinary intervention targeting frailty, with home exercise as an important component. Control participants received usual care. OUTCOME MEASURES: Primary outcomes were frailty, assessed using the Cardiovascular Health Study criteria (range 0 to 5 criteria), and mobility measured using the 12-point Short Physical Performance Battery. Outcomes were assessed 12 months after randomisation. The treating physiotherapist evaluated the amount of treatment received on a 5-point scale. RESULTS: 216 participants (90%) completed the study. The median amount of treatment received was 25 to 50% (range 0 to 100). The CACE (ie, the effect of treatment in participants compliant with allocation) was to reduce frailty by 1.0 frailty criterion (95% CI 0.4 to 1.5) and increase mobility by 3.2 points (95% CI 1.8 to 4.6) at 12 months. The mean CACE was substantially larger than the intention-to treat effect, which was to reduce frailty by 0.4 frailty criteria (95% CI 0.1 to 0.7) and increase mobility by 1.4 points (95% CI 0.8 to 2.1) at 12 months. CONCLUSION: Overall, compliance was low in this group of frail people. The effect of the treatment on participants who comply with allocated treatment was substantially greater than the effect of allocation on all trial participants. TRIAL REGISTRATION: Australian and New Zealand Trial Registry ANZCTRN12608000250336. [Fairhall N, Sherrington C, Cameron ID, Kurrle SE, Lord SR, Lockwood K, Herbert RD (2016) A multifactorial intervention for frail older people is more than twice as effective among those who are compliant: complier average causal effect analysis of a randomised trial.Journal of Physiotherapy63: 40-44]. PMID- 27993490 TI - Comment on: Temporal changes in plasma markers of oxidative stress following laparoscopic sleeve gastrectomy in patients with impaired glucose regulation. PMID- 27993491 TI - How to treat stenosis after sleeve gastrectomy? AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has increasingly gained worldwide acceptance among bariatric surgeons during the past 10 years. Numerous articles have been written about the different approaches to the management of gastric fistulas, but limited data can be found concerning gastric stenosis after LSG. SETTING: Private hospital, France. METHODS: A total of 18 patients received endoscopic treatment for stenosis after LSG between May 2007 and June 2015. Stenosis was classified according to the endoscopic findings as functional (the passage of the endoscope was possible, but the sleeve was twisted with various degrees of rotation) or mechanical (the passage of the endoscope was very difficult or impossible). RESULTS: This study included 13 women and 5 men, with an average age of 37.2+/-8.4 years and an average body mass index of 41.6+/-8.7 kg/m2. The average number of endoscopic procedures was 1.3 (range, 1-4). No patient had stent migration. The successful rate of endoscopic approach for stenosis of LSG was 94.4%, with one patient requiring conversion to Roux-en-Y gastric bypass. The mean time from the LSG to the first endoscopic intervention was 28.2 days. All patients presented with midsleeve stricture, located near the incisura angularis, and no patient showed a stenosis in the upper part of the gastric tube. CONCLUSIONS: The treatment of stenosis after LSG must be tailored to the clinical status of the patient and endoscopic findings. Both balloon dilation and stent deployment are useful and safe tools and must be used when appropriate. PMID- 27993492 TI - Possible infectious etiology among Kawasaki disease patients and their families. PMID- 27993493 TI - [Lung transplantation in Reunion Island, current situation from January 2005 till May 2015]. AB - Lung transplantation (LT) is a therapeutic option for patients with terminal respiratory failure and high risk of mortality in two years. Until now, this activity is not performed in Reunion Island. The candidate potential are thus directed to the metropolitan reference centres causing logistics and financials constraints. This work presents a current situation of the pulmonary transplantation in Reunion Island. This retrospective study includes patients from Reunion Island with respiratory insufficiency who have been transferred to metropolitan centres to apply to LT. The selection was made from January, 2005 till May, 2015. Twenty-nine patients included, aged from 14 to 64 years, were transferred to metropolitan France: 13 patients with cystic fibrosis, 13 patients with pulmonary fibrosis, 1 patients with bronchiectasis, 1 patient with chronic obstructive pulmonary disease (COPD) and 1 patient with pulmonary arterial hypertension. Fifteen patients underwent LT (4 live in Reunion Island, 5 live in metropolitan France and 6 are dead), 1 patient is alive on waiting list, 3 died on the waiting list, 7 patients were refused for transplantation and 3 patients are lost to follow-up. The number of patients transferred for LT increases over 10 years with a maximal incidence in 2013 of 7 repatriated patients including 3 transplanted patients. LT could be performed in half of our patients with possible come back and follow-up on Reunion Island. Indications follow the current trends except an under representation of COPD. PMID- 27993494 TI - Management of diabetes patients during the year prior to initiation of dialysis in France. AB - AIM: This study looked at the management of diabetes patients during the year prior to the initiation of dialysis. METHODS: For this observational study, data were extracted from the National Health Insurance database for general-scheme beneficiaries (77% of the French population). Diabetes patients were identified by at least three reimbursements for antidiabetic drugs in 2012, while the initiation of dialysis was identified by specific refunds in 2013. RESULTS: Of the 6412 patients initiating dialysis, 37% (n=2378) had diabetes (men: 61%, median age: 71 years, haemodialysis: 92%). Six months prior to dialysis, 68% had filled at least one prescription for insulin, 38% for other antidiabetics (25% glinides, 8% sulphonylureas, 8% metformin, 6% DPP-4 inhibitors), 69% for three or more classes of antihypertensive drugs and 55% for erythropoiesis-stimulating agents. Within 12 months to 1 month of dialysis, 81% were hospitalized, 28% with a main diagnosis of kidney disease. No nephrologist referral or hospitalization was identified at 6-0 months before dialysis in 6% of patients or in 24% at 12-7 months. One in five patients with diabetes consulted a private endocrinologist within 6 months of dialysis. An arteriovenous fistula was created 1 month before haemodialysis in 43% of patients. CONCLUSION: The quality of preparation for dialysis was variable despite frequent hospitalizations. These data illustrate the need to mobilize patients with diabetes, and for healthcare professionals to more effectively anticipate and coordinate dialysis. PMID- 27993495 TI - Myocarditis in different experimental models infected by Trypanosoma cruzi is correlated with the production of IgG1 isotype. AB - This study was designed to verify the relationship between IgG antibodies isotypes and myocarditis in Trypanosoma cruzi infection using mice and dogs infected with different T. cruzi strains. The animals were infected with benznidazole-susceptible Berenice-78 and benznidazole-resistant AAS and VL-10 strains. The IgG subtypes were measured in serum samples from dogs (IgG, IgG1, and IgG2) and mice (IgG, IgG1, IgG2a, and IgG2b). The infection of dogs with VL 10 strain induced the highest levels of heart inflammation while intermediate and lower levels were detected with Berenice-78 and AAS strains, respectively. Similar results were found in mice infected with VL-10, but not in those infected with AAS or Berenice-78 strains. The AAS strain induced higher levels of heart inflammation in mice, while Berenice-78 strain was not able to induce it. Correlation analysis between myocarditis and antibody reactivity index revealed very interesting results, mainly for IgG and IgG1, the latter being the most exciting. High IgG1 showed a significant correlation with myocarditis in both experimental models, being more significant in dogs (r=0.94, p<0.0001) than in mice (r=0.58, p=0.047). Overall, our data suggest that IgG1 could be a good marker to demonstrate myocarditis intensity in Chagas disease. PMID- 27993496 TI - No Difference in Periprosthetic Bone Loss and Fixation Between a Standard-Length Stem and a Shorter Version in Cementless Total Hip Arthroplasty. A Randomized Controlled Trial. AB - BACKGROUND: Cementless femoral stems in total hip arthroplasty provide dependable clinical and radiographic results in the treatment of osteoarthritis. Stem length might affect the preservation of proximal bone stock and stability. We hypothesized that a shorter stem decreases proximal bone loss without affecting implant stability. METHODS: We randomly assigned 60 patients aged between 50 and 70 years to either a standard cementless femoral stem or a 35-mm shorter version. Patients were followed with dual-energy X-ray absorptiometry, radiostereometric analysis, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index score, and clinical follow-up at 3, 6, 12, and 24 months. The trial is registered on ClinicalTrials.gov/. RESULTS: After 24 months, short stems had on average 3.8% (95% confidence interval, 1.2%-8.9%) more bone loss in zone 1 compared to standard stems (P = .14). In zone 7, the bone loss was on average 6.5% (95% confidence interval, 6.6%-19.7%) higher compared to standard stems (P = .33). After 24 months, standard stems had migrated 0.93 mm (range, 0.25-4.66 mm) and short stems 0.93 mm (range, 0.17-2.96 mm; Student t-test after log transformation, P = .3). Patient-reported outcome measures were similar in both groups. One patient in the standard stem group was diagnosed with infection, one with a posterior dislocation, and one with a deep venous thrombosis. No stems were revised. CONCLUSION: There were no statistically significant differences in periprosthetic bone loss or fixation between the stems at 24 months. PMID- 27993497 TI - Factors Associated With HIV Testing in Youth in the United States: An Integrative Review. AB - We used an integrative review to synthesize existing literature on the factors associated with HIV testing by youth ages 13 to 24 years in the United States. PubMed, CINAHL, PsycINFO, and Google Scholar were systematically searched and 44 original research studies met our criteria. A directed qualitative content analysis was conducted to integrate findings according to the personal, relationship, community, and society levels of the social-ecological model. Female gender, African American race, age, and physical illness were some of the factors more consistently associated with HIV testing. Modifiable factors such as fear, drug use, poor condom use, partner communication, and multiple sexual partners were also noted as influencing HIV testing in youth. Our integrative review revealed gaps in the literature that need further exploration, particularly in the area of community and society influences on HIV testing for youth. Implications for research, practice, and policy are discussed. PMID- 27993498 TI - Pediatric Vocal Fold Nodule Etiology: What Are Its Usual Causes in Children? AB - OBJECTIVES: In this study, the relation between phonotrauma and presence of siblings and social activities was investigated, and the incidence of voice disorders in the mothers of children with vocal fold nodules was studied with objective (clinical voice analysis) and subjective (laryngostroboscopy, Voice Handicap Index) methods. METHODS: Twenty-nine children with vocal fold nodules (age range 5-14 years), 45 age-matched children without any voice disorders as a control group, and their mothers were included in the study. All patients had laryngostroboscopy and clinical voice analysis, and their mothers filled out the Pediatric Voice Handicap Index. We noted the most common place or situation where children used their voice in excessively high volume according to their mothers, including home, school, sportive activities, and singing or reciting poem activities, to recognize the major cause of phonotrauma. In addition, presence of siblings was recorded. RESULTS: It was found that 15 patients (51.7%) had younger siblings, seven patients (24.1%) had older siblings, five patients (17.2%) had both younger and older siblings, and two patients (6.8%) did not have any siblings. It was seen that excessive usage of high-volume voice at home had a correlation with presence of only younger siblings, and both younger and older siblings tended to cause phonotrauma at home (86.7%). Additionally, eight boys (44.4%) reported presence of sportive activities, whereas none of the girls had such an activity (P = 0.012). CONCLUSION: Presence of siblings seems to be an important factor for vocal nodule formation. Maternal relationship does not seem to be a major factor for vocal misuse. PMID- 27993499 TI - A Cepstral Analysis of Normal and Pathologic Voice Qualities in Iranian Adults: A Comparative Study. AB - INTRODUCTION: The use of frequency-based analysis as an accurate method of voice analysis motivated us to evaluate the voice qualities of healthy versus dysphonic Iranian people. METHODS: Two hundred normal and dysphonic participants aged between 20 and 50 years in either gender were divided into four different equal groups. For the tasks, 5-second prolongation of vowel /a/ and a sample of reading text were used for the analysis. "Speech Tool" software was employed for Cepstral peak prominence (CPP) and cepstral peak prominence-smoothed (CPPS) analyses. The t test and Mann-Whitney U test were used for statistical analysis. RESULTS: Significant differences between the dysphonic and controls were discovered based on CPP and CPPS in the reading tasks (males and females) and CPPS in the sustained vowel (males and females). Nevertheless, the two male groups showed no differences in the sustained vowel in CPP. Moreover, significantly lower CPP and CPPS were observed in the sustained vowel and reading tasks for the dysphonic females compared to the control group and either group of males. DISCUSSION AND CONCLUSION: In spite of the different characteristics of consonant-vowel contexts in Persian language, the results of this study suggested that both CPP and CPPS are appropriate to differentiate between normal and dysphonic voices in connected speech and CPPS is promising for sustained phonation in Persian. The results of this research also suggested that the male group in the normal and dysphonic samples had better CPP and CPPS values. PMID- 27993500 TI - Vocal Function Exercises for Muscle Tension Dysphonia: Auditory-Perceptual Evaluation and Self-Assessment Rating. AB - OBJECTIVE: Muscle tension dysphonia (MTD) is a functional dysphonia, which appears with an excessive tension in the intrinsic and extrinsic laryngeal musculatures. MTD can affect voice quality and quality of life. The purpose of the present study was to assess the effectiveness of vocal function exercises (VFEs) on perceptual and self-assessment ratings in a group of 15 subjects with MTD. METHODS: The study comprised 15 subjects with MTD (8 men and 7 women, mean age 39.8 years, standard deviation 10.6, age range 24-62 years). All participants were native Persian speakers who underwent a 6-week course of VFEs. The Voice Handicap Index (VHI) (the self-assessment scale) and Grade, Roughness, Breathiness, Asthenia, Strain (GRBAS) scale (perceptual rating of voice quality) were used to compare pre- and post-VFEs. RESULTS: GRBAS data of patients before and after VFEs were compared using Wilcoxon signed-rank test, and VHI data of patients pre- and post-VFEs were compared using Student paired t test. These perceptual parameters showed a statistically significant improvement in subjects with MTD after voice therapy (significant at P < 0.05 (*) and P < 0.004 (**)). Also results indicated statistically noticeable reduction in the mean VHI scores across subjects with MTD (significant at P < 0.05 (*) and P < 0.004 (**)). CONCLUSIONS: Significant improvement after therapy for participants has been observed by the aid of auditory-perceptual ratings of voice quality (with the GRBAS scale) and the patient's self-assessment ratings measurements (with the VHI). As a result, the data provide evidence regarding the efficacy of VFEs in the treatment of patients with MTD. PMID- 27993501 TI - Are Instructions to Manipulate Specific Parameters of Laryngeal Function Associated with Auditory-Perceptual Ratings of Voice Quality in Nondisordered Speakers? AB - OBJECTIVES/HYPOTHESIS: This preliminary study investigated whether auditory perceptual judgments of voice quality by experienced speech language pathologists were associated with instructions given to speakers to manipulate specific laryngeal postures. STUDY DESIGN: Experimental, within-subject design. METHODS: Nine speakers were instructed and trained to manipulate three vocal parameters implicated in functional voice disorders-false vocal fold constriction, vocal fold mass, and larynx height-while reading a standard passage. Experienced judges rated these standard passages in terms of the widely used perceptual voice qualities breathiness, roughness, vocal strain, glottal fry, tone onset, tone color, loudness, and pitch. RESULTS: Between-subject factorial analysis of variance, controlling for judge unreliability, revealed some evidence that perceptual judgments are strongly associated with underlying laryngeal muscle activity that can then serve clinical planning of goals for intervention. Eta2 effect sizes were large for all dependent measures, ranging from 0.39 for pitch to 0.77 for strained. CONCLUSIONS: Although these results are encouraging, they were obtained under ideal conditions. Further research is warranted. PMID- 27993502 TI - Curious case of the bilaterally absent omohyoid muscle. PMID- 27993503 TI - Comparison of Type II Endoleak Embolizations: Embolization of Endoleak Nidus Only versus Embolization of Endoleak Nidus and Branch Vessels. AB - PURPOSE: To compare outcomes of type II endoleak embolization involving embolization of the endoleak nidus only vs embolization of the endoleak nidus and branch vessels in patients treated with endovascular repair of abdominal aortic aneurysms. MATERIALS AND METHODS: Twenty-nine consecutive patients (mean age, 77.9 y; range, 63-88 y) with type II endoleak who underwent embolization from 2004 to 2015 were retrospectively reviewed. Patients were divided into 2 groups: embolization of endoleak nidus only (group A) and embolization of endoleak nidus and branch vessels (group B). Mean follow-up intervals were 20.5 months +/- 14.7 in group A and 24.3 months +/- 18.5 in group B. Outcomes were compared between groups by Mann-Whitney U and Pearson chi2 tests. RESULTS: Mean interval from endovascular aneurysm repair to embolization was 47.6 months +/- 42.9, and mean presentation time of endoleak before embolization was 23.1 months +/- 25.8. Coils (n = 28) and liquid embolic agents (n = 23) were used for embolization. There were no significant differences in rates of residual endoleak (50% vs 53.8%; P = .96) or sac decrease/stabilization (62.5% vs 61.5%; P = .64). Procedure time and radiation exposure in group B (132.3 min +/- 78.1; 232.4 Gy.cm2 +/- 130.7) were greater than in group A (63.4 min +/- 11.9; 61.5 Gy.cm2 +/- 35.5; P < .01). There were no procedure-related complications. CONCLUSIONS: Embolization of the endoleak nidus and branch vessels is not superior to embolization of only the nidus in terms of occlusion of type II endoleak and change in sac size despite requiring longer procedure times and resulting in greater patient radiation exposure. PMID- 27993504 TI - IR and the Sunshine Act: Two-Year Analysis of the Open Payments Database and Comparison with Related Specialties. AB - PURPOSE: To characterize medical industry-based payments made to US-based interventional radiology (IR) physicians, identify trends in compensation, and compare their payment profile with those of other related specialties, including vascular surgery (VS) and interventional cardiology (IC). Payments made to orthopedic surgery (OS) physicians are reported as a historical control. MATERIALS AND METHODS: For each group, the total payment number, amount, and mean and median numbers and amounts were calculated. The data were then reanalyzed after correcting for statistical outliers. For IR, VS, and IC, leading industry sponsors, payment amount, and differences in payments from 2013 to 2014 were highlighted. Payments to IR were grouped by category and geographic location. The Kruskal-Wallis test was used for statistical analysis. RESULTS: A total of $26,857,622 went to 1,831 IR physicians, representing 70.9% of active IR physicians, and the corrected mean payment was $597 +/- 832.2 (standard deviation). The respective values were $18,861,041, 3,383, 80.6%, and $851.59 for VS; $32,008,213, 7,939, 78.6%, and $417.16 for IC; and $357,528,020, 21,829, 77.8%, and $598.48 for OS. OS had the largest number of payments (295,465 vs 24,246 for IR, 84,635 for VS, and 160,443 for IC) and greatest total payment amount. VS had a significantly higher corrected median payment amount ($463; P < .0001) than IR ($214) and IC ($99). Covidien and Sirtex Medical were the leading industry sponsors to IR, and 64.6% of IR payments were compensation for services other than consulting. There was no significant difference in median payment received per geographic region (P = .32). CONCLUSIONS: OS received the largest number and total payment amount, and VS received a significantly greater corrected median payment amount, versus IR and IC. As the Open Payments program continues to be implemented, it remains to be seen how this information will affect relationships among physicians, patients, and industry. PMID- 27993505 TI - Microwave Ablation for Lung Neoplasms: A Retrospective Analysis of Long-Term Results. AB - PURPOSE: To determine the long-term safety and efficacy of microwave (MW) ablation in the treatment of lung tumors at a single academic medical center. MATERIALS AND METHODS: Retrospective review was performed of 108 patients (42 female; mean age, 72.5 y +/- 10.3 [standard deviation]) who underwent computed tomography (CT)-guided percutaneous MW ablation for a single lung malignancy. Eighty-two were primary non-small-cell lung cancers and 24 were metastatic tumors (9 colorectal carcinoma, 2 renal-cell carcinoma, 4 sarcoma, 2 lung, and 7 other). Mean maximum tumor diameter was 29.6 mm +/- 17.2. Patient clinical and imaging data were reviewed. Statistical analysis was performed by Kaplan-Meier modeling and logistic regression. RESULTS: Odds of primary technical success were 11.1 times higher for tumors < 3 cm vs those > 3 cm (95% confidence interval [CI], 2.97-41.1; P = .0003). For every millimeter increase in original tumor maximal diameter (OMD), the odds of not attaining success increased by 7% (95% CI, 3% 10%; P = .0002). For every millimeter increase in OMD, the odds of complications increased by 3% (95% CI, 0.1%-5%; P = .04). Median time to tumor recurrence was 62 months (95% CI, 29, upper bound not reached; range, 0.2-96.6 mo). Recurrence rates were estimated at 22%, 36%, and 44% at 1, 2, and 3 years, respectively. Recurrence rates were estimated at 31% at 13 months for tumors > 3 cm and 17% for those < 3 cm. Complications included pneumothorax (32%), unplanned hospital admission (28%), pain (20%), infection (7%), and postablation syndrome (4%). CONCLUSIONS: This study further supports the safe and effective use of MW ablation for the treatment of lung tumors. PMID- 27993506 TI - Effects of Aspirin Therapy on Ultrasound-Guided Renal Allograft Biopsy Bleeding Complications. AB - PURPOSE: To determine if patient aspirin exposure and timing affect bleeding risk after renal allograft biopsy. MATERIALS AND METHODS: Review of 6,700 renal allograft biopsies (in 2,362 unique patients) was performed. Median patient age was 53.0 years [interquartile range 43.0, 62.0]; 56.2% of patients were male. Of biopsies, 4,706 (70.2%) were performed in patients with no aspirin exposure within 10 days of biopsy; 664 (9.9%), were performed within 8-10 days of aspirin exposure; 855 (12.8%), within 4-7 days; and 475 (7.1%), within 0-3 days. Follow up to 3 months after the procedure was completed in all patients. Biopsies were categorized as protocol or indication; 19.7% were indication biopsies. Bleeding complications were graded based on SIR criteria. Logistic regression models examined the association between aspirin use and bleeding events. RESULTS: Rate [95% confidence interval] of major bleeding complications was 0.24% [0.14, 0.39], and rate of any bleeding complication was 0.66% [0.46, 0.90]. Bleeding events were significantly associated with patients undergoing indication biopsies compared with protocol biopsies (odds ratio [OR] 2.27, P = .012). Patient factors associated with major bleeding complications in multivariate models included estimated glomerular filtration rate (OR 0.61, P = .016) and platelet count (OR 0.64, P = .033). Aspirin use was not significantly associated with increased risk of bleeding complication except for use of 325 mg of aspirin within 3 days of biopsy (any complication OR 3.87 [1.12, 13.4], P = .032; major complication OR 6.30 [1.27, 31.3], P = .024). CONCLUSIONS: Renal allograft biopsy bleeding complications are very rare, particularly for protocol biopsies. Use of 325 mg of aspirin within 3 days of renal allograft biopsy was associated with increased bleeding complications. PMID- 27993507 TI - Percutaneous Image-Guided Irreversible Electroporation for the Treatment of Unresectable, Locally Advanced Pancreatic Adenocarcinoma. AB - PURPOSE: To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC). MATERIALS AND METHODS: This retrospective study included 50 patients (23 women, 27 men; age range, 46-91 y; median age, 62.5 y) with biopsy-proven, unresectable LAPC who received percutaneous computed tomography (CT)-guided IRE. The primary objective was to assess the safety profile of the procedure; the secondary objective was to determine overall survival (OS). All patients had prior chemotherapy (1-5 lines, median 2), and 30 (60%) of 50 patients had prior radiation therapy. Follow-up included CT at 1 month and at 3 month intervals thereafter. RESULTS: There were no treatment-related deaths and no 30-day mortality. Serious adverse events occurred in 10 (20%) of 50 patients (abdominal pain [n = 7], pancreatitis [n = 1], sepsis [n = 1], gastric leak [n = 1]). Median OS was 27.0 months (95% confidence interval [CI], 22.7-32.5 months) from time of diagnosis and 14.2 months (95% CI, 9.7-16.2 months) from time of IRE. Patients with tumors <= 3 cm (n = 24) had significantly longer median OS than patients with tumors > 3 cm (n = 26): 33.8 vs 22.7 months from time of diagnosis (P = .002) and 16.2 vs 9.9 months from time of IRE (P = .031). Tumor size was confirmed as the only independent predictor of OS at multivariate analysis. CONCLUSIONS: Percutaneous image-guided IRE of unresectable LAPC is associated with an acceptable safety profile. PMID- 27993508 TI - Society of Interventional Radiology: Occupational Back and Neck Pain and the Interventional Radiologist. PMID- 27993509 TI - Reggie-1 and reggie-2 (flotillins) participate in Rab11a-dependent cargo trafficking, spine synapse formation and LTP-related AMPA receptor (GluA1) surface exposure in mouse hippocampal neurons. AB - Reggie-1 and -2 (flotillins) reside at recycling vesicles and promote jointly with Rab11a the targeted delivery of cargo. Recycling is essential for synapse formation suggesting that reggies and Rab11a may regulate the development of spine synapses. Recycling vesicles provide cargo for dendritic growth and recycle surface glutamate receptors (AMPAR, GluA) for long-term potentiation (LTP) induced surface exposure. Here, we show reduced number of spine synapses and impairment of an in vitro correlate of LTP in hippocampal neurons from reggie-1 k.o. (Flot2-/-) mice maturating in culture. These defects apparently result from reduced trafficking of PSD-95 revealed by live imaging of 10 div reggie-1 k.o. (Flot2-/-) neurons and likely impairs co-transport of cargo destined for spines: N-cadherin and the glutamate receptors GluA1 and GluN1. Impaired cargo trafficking and fewer synapses also emerged in reggie-1 siRNA, reggie-2 siRNA, and reggie-1 and -2 siRNA-treated neurons and was in siRNA and k.o. neurons rescued by reggie-1-EGFP and CA-Rab11a-EGFP. While correlative expressional changes of specific synapse proteins were observed in reggie-1 k.o. (Flot2-/-) brains in vivo, this did not occur in neurons maturating in vitro. Our work suggests that reggie-1 and reggie-2 function at Rab11a recycling containers in the transport of PSD-95, N-cadherin, GluA1 and GluN1, and promote (together with significant signaling molecules) spine-directed trafficking, spine synapse formation and the in vitro correlate of LTP. PMID- 27993510 TI - A rapid and precise method for measuring plasma apoE-rich HDL using polyethylene glycol and cation-exchange chromatography: a pilot study on the clinical significance of apoE-rich HDL measurements. AB - BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents only a small portion of plasma HDL. Reliable methods for determining and isolating apoE-rich HDL have not been well studied. METHODS: We established a novel analytical method for apoE-rich HDL using polyethylene glycol and a cation-exchange column (PEG-column method). Furthermore, we examined biochemical correlates of apoE-rich HDL-cholesterol (HDL-C) in 36 patients who underwent coronary computed tomographic angiography. RESULTS: Our PEG-column method demonstrated high reproducibility (coefficient of variation <3.52%) and linearity up to 15mg/dl for apoE-rich HDL-C concentrations. Isolated apoE-rich HDL exhibited a larger diameter (14.8nm) than apoE-poor HDL (10.8nm) and contained both apoE and apoA-I. ApoE-rich HDL-C concentrations correlated significantly with triglycerides (rs=-0.646), LDL size (rs=0.472), adiponectin (rs=0.476), and other lipoprotein components. No significant correlation was obtained with the coronary calcium score. Multiple regression analysis revealed that plasma triglycerides and adiponectin concentrations remained significant independent predictors of apoE-rich (adjusted R2=0.486) but not apoE-poor HDL-C. CONCLUSIONS: The PEG-column method demonstrated, to various degrees, significant correlations between HDL subfractions and several lipid-related biomarkers involved in an atherogenic lipoprotein profile. Our separation technique for apoE rich HDL is useful to clarify the role of apoE-rich HDL in atherosclerosis. PMID- 27993511 TI - Homonymous hemianopsia after MR-guided stereotactic laser amygdalohippocampectomy. PMID- 27993512 TI - Audiogenic seizure activity following HSV-1 GAD65 sense or antisense injection into inferior colliculus of Long-Evans rat. AB - Herpes virus technology involving manipulation of GAD65 was used to study effects on audiogenic seizures (AGS). Audiogenic seizure behaviors were examined following injections of replication-defective herpes simplex virus (HSV-1) vectors incorporating sense or antisense toward GAD65 along with 10% lac-Z into the central nucleus of inferior colliculus (CNIC) of Long-Evans rats. In seizure sensitive animals developmentally primed by intense sound exposure, injection of GAD65 in the sense orientation increased wild running latencies and reduced incidence of clonus compared with lac-Z only, unoperated, and vehicle seizure groups. In contrast, infection of CNIC with GAD65 antisense virus resulted in 100% incidence of wild running and clonus behaviors in AGS animals. Unprimed animals not operated continued to show uniform absence of seizure activity. Administration of GAD65 antisense virus into CNIC produced novel wild running and clonus behaviors in some unprimed animals. Staining for beta-galactosidase in all vector animals revealed no differences in pattern or numbers of immunoreactive cells at injection sites. Qualitatively, typical small and medium multipolar/stellate and medium fusiform neurons appeared in the CNIC of vector animals. These results demonstrate that HSV-1 vector constructs implanted into the CNIC can predictably influence incidence and severity of AGS and suggest that viral vectors can be useful in studying GABA mechanisms with potential for therapeutic application in epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 27993513 TI - Late-stage research for diabetes and related NCDs receives little funding: evidence from the NIH RePORTER tool. PMID- 27993514 TI - Non-communicable disease funding. PMID- 27993515 TI - Cardiometabolic risk is associated with the severity of sleep-disordered breathing in children with obesity. AB - BACKGROUND: The alarming progression of pediatric obesity is associated with the development of sleep-disordered breathing (SDB), and both exhibit similar adverse cardiometabolic health outcomes. Physical activity level (PAL) may counteract sleep and metabolic disturbances. The present study investigates i) the association between the metabolic syndrome in childhood obesity and SDB, ii) the impact of SDB severity on cardiometabolic risk scores and PAL in children with obesity. METHODS: Maturation status (Tanner stages), anthropometric (height, weight, body mass index, waist circumference, body adiposity index) and cardiometabolic characteristics (systolic and diastolic blood pressure, lipid and glycemic profiles) were assessed in 83 obese children (mean+/-SD, age: 10.7+/ 2.7years). PAL and SDB were investigated with a step test and interviews, and an overnight sleep monitor, respectively. The presence or absence of metabolic syndrome (MS) was established and continuous cardiometabolic risk scores were calculated (MetScoreBMI and MetScoreWC). RESULTS: Obese children with (61.4%) and without (38.6%) MS present similar SDB. SDB severity is associated with increased insulin concentrations, MetScoreBMI and MetScoreWC (p<0.05) in obese children. There is no association between SDB and PAL. CONCLUSIONS: In a context where no consensus exists for SDB diagnosis in children, our results suggest the influence of SDB severity on cardiometabolic risk factors. Further studies are needed to explore the association between PAL and both metabolic and sleep alterations in obese children. PMID- 27993516 TI - Phenylpropanoids from Juglans mandshurica exhibit cytotoxicities on liver cancer cell lines through apoptosis induction. AB - Three new phenylpropanoids (1-3) together with six known congeners (4-9) were isolated from the bark of Juglans mandshurica Maxim using anti-hepatoma activity as a guide. Their structures were determined by comprehensive NMR and HRESIMS spectroscopic data analyses. All the isolated compounds were evaluated for their growth inhibitory activities against two kinds of liver cancer cell lines (HepG2 and Hep3B). Among them, compound 4 showed moderate cytotoxic activities against HepG2 and Hep3B cell lines with IC50 values of 58.58 and 69.87MUM. Compound 5 exhibited 50% cell death rate in HepG2 and Hep3B cell lines at 63.70 and 46.45MUM, respectively. Further observation of morphological changes and Western blot demonstrated that compounds 4 and 5 exhibited their cytotoxic activities through the induction of apoptosis. A structure-activity relationship study suggested that an alpha, beta-unsaturated aldehyde might be the most important functional group. PMID- 27993517 TI - Development of spiroguanidine-derived alpha7 neuronal nicotinic receptor partial agonists. AB - We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective alpha7 nAChR partial agonist, N-(6-methyl-1,3 benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.2.2]octane-2,4'-imidazole]-2' amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of alpha7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the alpha7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors. PMID- 27993518 TI - Design, synthesis, and biological evaluation of novel 1-oxo-1,2,3,4 tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs in MCF-7 and MDA-MB-468 breast cancer cell lines. AB - A series of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs were designed and synthesized for developing pyrazinoindolone scaffolds as anti-breast cancer agents. Compounds 1h and 1i, having a furan-2-yl methylamide and benzylamide group, respectively, exhibited more potent cytotoxicity in MDA-MB-468 triple-negative breast cancer (TNBC) cells than compounds possessing aliphatic groups. Compounds 2a and 2b, as (R)-enantiomers of 1h and 1i, also had inhibitory activity against MDA-MB-468 cells. Moreover, analogs (3a-b and 3d-e) bearing a benzyl group at the N-2 position showed more potent activity than gefitinib, as a potent EFGR-TK inhibitor. Especially, compound 3a exhibited selective cytotoxic activity against MDA-MB-468 cells; it also had a synergistic effect in combination with gefitinib against MDA-MB-468 cells. In addition, we confirmed that compounds 3a and 3d inhibit phosphorylation of Akt in MDA-MB-468 cells using western blot analysis. Therefore, these 1-oxo 1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs may be helpful for investigating new anti-TNBC agents. PMID- 27993519 TI - Quo vadis G protein-coupled receptor ligands? A tool for analysis of the emergence of new groups of compounds over time. AB - Exponential growth in the number of compounds with experimentally verified activity towards particular target has led to the emergence of various databases gathering data on biological activity. In this study, the ligands of family A of the G Protein-Coupled Receptors that are collected in the ChEMBL database were examined, and special attention was given to serotonin receptors. Sets of compounds were examined in terms of their appearance over time, they were mapped to the chemical space of drugs deposited in DrugBank, and the emergence of structurally new clusters of compounds was indicated. In addition, a tool for detailed analysis of the obtained visualizations was prepared and made available online at http://chem.gmum.net/vischem, which enables the investigation of chemical structures while referring to particular data points depicted in the figures and changes in compounds datasets over time. PMID- 27993520 TI - Overexpression of betaCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the dentate gyrus. AB - Behavioral flexibility is in close proximity to dentate gyrus (DG) function and long-term depression (LTD), but the role of DG LTD in behavioral flexibility has hitherto been unexplored. Although the functions of alpha-Ca2+/calmodulin dependent protein kinase II (CaMKII) have been studied extensively, the role of betaCaMKII, a constituent of the CaMKII holoenzyme, in LTD and behavioral flexibility has not been investigated in vivo. Here using the betaCaMKII-F90G transgenic (TG) mice, in which the inducible and reversible overexpression of betaCaMKII is restricted to dentate gyrus (DG), we found that TG mice exhibited defective behavioral flexibility in two reversal tasks and seriously impaired N methyl-d-aspartic acid receptor (NMDAR)-dependent LTD in DG medial perforant path (MPP). Consistent with the deficit in NMDAR-LTD, GluA1-Ser845, GluA1-Ser831 dephosphorylation and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization were also disrupted during NMDAR-LTD in TG mice. Furthermore, these deficits were due to decreased activities of protein phosphatases (PP) 1/2A and glycogen synthesis kinase 3 beta (GSK3beta), and overexpressed synaptic stargazin in TG mice. Importantly, all the deficits above could be reversed by 1-naphthylmethyl (NM)-PP1, a specific inhibitor of the exogenous betaCaMKII-F90G. Taken together, our findings for the first time demonstrate that betaCaMKII overexpression impairs behavioral flexibility and NMDAR-dependent LTD in DG MPP, which further confirms the close relationship between NMDAR-dependent LTD and behavioral flexibility. PMID- 27993522 TI - Non-motor symptoms and the quality of life in multiple system atrophy with different subtypes. AB - BACKGROUND: The differences in non-motor symptoms (NMS) and quality of life (QOL) between MSA patients with different subtypes remain unknown, so do the determinants of poor QOL in both subtypes. METHODS: A total of 172 MSA patients were enrolled in the study. NMS of patients with MSA were assessed using the non motor symptoms scale (NMSS) and Parkinson's Disease Questionnaire-39 item version (PDQ-39) was used to evaluate the QOL of patients with MSA. RESULTS: The most prevalent NMS domain was urinary (91.3%) in both subtypes. The mood/apathy domain was more severe in MSA-P than MSA-C patients (P < 0.05). Drooling, constipation, and pain symptoms were more prevalent and severe in the MSA-P patients compared to the MSA-C patients (P < 0.05). We found that the MSA-C patients had a higher score of mobility than the MSA-P patients (P = 0.002); However, the MSA-P patients had a higher score of bodily discomfort than the MSA-C patients (P = 0.036). There were close correlations between NMS and PDQ-39 in both subtypes. Disease severity, cardiovascular symptoms, sleep/fatigue symptoms and gastrointestinal symptoms were determinants of poor QOL in MSA-P patients. While in MSA-C patients, longer disease duration, disease severity and mood/apathy symptoms were determinants of poor QOL. CONCLUSION: NMS are more severe and prevalent in MSA-P patients, especially for mood/apathy and gastrointestinal symptoms. There is a close relationship between NMS and QOL in both MSA subtypes. Disease severity, longer disease duration and severe NMS are determinants of poor QOL in MSA. PMID- 27993521 TI - Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons. AB - AMPA receptor (AMPAR) transmission onto medium spiny neurons (MSNs) of the adult rat nucleus accumbens (NAc) is normally dominated by GluA2-containing, Ca2+ impermeable AMPAR (CI-AMPARs). However, GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) accumulate after prolonged withdrawal from extended-access cocaine self-administration and thereafter their activation is required for the intensified (incubated) cue-induced cocaine craving that characterizes prolonged withdrawal from such regimens. These findings suggest the existence of mechanisms in NAc MSNs that differentially regulate CI-AMPARs and CP-AMPARs. Here, we compared trafficking of GluA1A2 CI-AMPARs and homomeric GluA1 CP-AMPARs using immunocytochemical assays in cultured NAc MSNs plated with prefrontal cortical neurons to restore excitatory inputs. We began by evaluating constitutive internalization of surface receptors and found that this occurs more rapidly for CP-AMPARs. Next, we studied receptor insertion into the membrane; combined with past results, the present findings suggest that activation of protein kinase A accelerates insertion of both CP-AMPARs and CI-AMPARs. We also studied constitutive cycling (net loss of receptors from the membrane under conditions where internalization and recycling are both occurring). Interestingly, although CP-AMPARs exhibit faster constitutive internalization, they cycle at similar rates as CI-AMPARs, suggesting faster reinsertion of CP-AMPARs. In studies of synaptic scaling, long-term (24 h) activity blockade increased surface expression and cycling rates of CI-AMPARs but not CP-AMPARs, whereas long-term increases in activity produced more pronounced scaling down of CI-AMPARs than CP-AMPARs but did not alter receptor cycling. These findings can be used to evaluate and generate hypotheses regarding AMPAR plasticity in the rat NAc following cocaine exposure. PMID- 27993523 TI - Diabetic foot ulcer severity predicts mortality among veterans with type 2 diabetes. AB - AIM: Diabetic foot ulcers are associated with an increased risk of death. We evaluated whether ulcer severity at presentation predicts mortality. METHODS: Patients from a national, retrospective, cohort of veterans with type 2 diabetes who developed incident diabetic foot ulcers between January 1, 2006 and September 1, 2010, were followed until death or the end of the study period, January 1, 2012. Ulcers were characterized as early stage, osteomyelitis, or gangrene at presentation. Cox proportional hazard regression identified independent predictors of death, controlling for comorbidities, laboratory parameters, and healthcare utilization. RESULTS: 66,323 veterans were included in the cohort and followed for a mean of 27.7months: 1-, 2-, and 5-year survival rates were 80.80%, 69.01% and 28.64%, respectively. Compared to early stage ulcers, gangrene was associated with an increased risk of mortality (HR 1.70, 95% CI 1.57-1.83, p<0.001). The magnitude of this effect was greater than diagnosed vascular disease, i.e., coronary artery disease, peripheral arterial disease, or stroke. CONCLUSION: Initial diabetic foot ulcer severity is a more significant predictor of subsequent mortality than coronary artery disease, peripheral arterial disease, or stroke. Unrecognized or under-estimated vascular disease and/or sepsis secondary to gangrene should be explored as possible causal explanations. PMID- 27993524 TI - Severe hypoglycemia, impaired awareness of hypoglycemia, and self-monitoring in adults with type 1 diabetes: Results from Diabetes MILES-Australia. AB - AIMS: To assess prevalence of severe hypoglycemia, awareness and symptoms of hypoglycemia, and their associations with self-monitoring of blood glucose. METHODS: Diabetes MILES-Australia Study participants completed validated questionnaires and study-specific items. RESULTS: Of 642 adults with type 1 diabetes, 21% reported >=1 severe hypoglycemic event in the past six months, and 21% reported impaired awareness of hypoglycemia (IAH). Severe hypoglycemia was increased four-fold for those with IAH compared with intact awareness (1.4+/-3.9 versus 0.3+/-1.0). Of those with IAH, 92% perceived autonomic and 88% neuroglycopenic symptoms, albeit at lower glucose thresholds compared to people with intact awareness. Those with IAH were more likely to perceive both symptom types at the same glucose level or to perceive neuroglycopenic symptoms first (all p<0.001). Eighteen percent with IAH treated hypoglycemia only when they perceived symptoms and another 18% only when their capillary glucose was <3.0mmol/L. CONCLUSIONS: One in five adults with type 1 diabetes had IAH or experienced severe hypoglycemia in the past sixmonths. Total loss of hypoglycemia symptoms was rare; most people with IAH retained autonomic symptoms, perceived at relatively low glucose levels. Frequent self-monitoring of blood glucose prompted early recognition and treatment of hypoglycemia, suggesting severe hypoglycemia risk can be minimized. PMID- 27993525 TI - Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. AB - BACKGROUND & AIMS: Wheat amylase-trypsin inhibitors (ATIs) are nutritional activators of innate immunity, via activation of the toll-like receptor 4 (TLR4) on myeloid cells. We aimed to characterize the biologic activity of ATIs in various foods and their effect on intestinal inflammation. METHODS: We selected 38 different gluten-containing and gluten-free products, either unprocessed (such as wheat, rye, barley, quinoa, amaranth, soya, lentils, and rice) or processed (such as pizza, pasta, bread, and biscuits). ATIs were extracted and their biological activities determined in TLR4-responsive mouse and human cell lines. Effects of oral ATIs on intestinal inflammation were determined in healthy C57BL/6 mice on a gluten-free or ATI-free diet and in mice given low-level polyinosinic:polycytidylic acid or dextran sodium sulfate to induce colitis. Parameters of innate and adaptive immune activation were determined in duodenum, ileum, colon, and mesenteric lymph nodes. RESULTS: Modern gluten-containing staples had levels of TLR4-activating ATIs that were as much as 100-fold higher than in most gluten-free foods. Processed or baked foods retained ATI bioactivity. Most older wheat variants (such as Emmer or Einkorn) had lower bioactivity than modern (hexaploid) wheat. ATI species CM3 and 0.19 were the most prevalent activators of TLR4 in modern wheat and were highly resistant to intestinal proteolysis. Their ingestion induced modest intestinal myeloid cell infiltration and activation, and release of inflammatory mediators-mostly in the colon, then in the ileum, and then in the duodenum. Dendritic cells became prominently activated in mesenteric lymph nodes. Concentrations of ATIs found in a normal daily gluten-containing diet increased low-level intestinal inflammation. CONCLUSIONS: Gluten-containing cereals have by far the highest concentrations of ATIs that activate TLR4. Orally ingested ATIs are largely resistant to proteases and heat, and increase intestinal inflammation by activating gut and mesenteric lymph node myeloid cells. PMID- 27993526 TI - First report of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae sternum osteomyelitis relapsing 6 years after mediastinitis following cardiac surgery. PMID- 27993527 TI - Use of electric field sensors for recording respiration, heart rate, and stereotyped motor behaviors in the rodent home cage. AB - BACKGROUND: Numerous environmental and genetic factors can contribute significantly to behavioral and cardiorespiratory variability observed experimentally. Affordable technologies that allow for noninvasive home cage capture of physio-behavioral variables should enhance understanding of inter animal variability including after experimental interventions. NEW METHOD: We assessed whether EPIC electric field sensors (Plessey Semiconductors) embedded within or attached externally to a rodent's home cage could accurately record respiration, heart rate, and motor behaviors. COMPARISON WITH EXISTING METHODS: Current systems for quantification of behavioral variables require expensive specialty equipment, while measures of respiratory and heart rate are often provided by surgically implanted or chronically affixed devices. RESULTS: Sensors accurately encoded imposed sinusoidal changes in electric field tested at frequencies ranging from 0.5-100Hz. Mini-metronome arm movements were easily detected, but response magnitude was highly distance dependent. Sensors accurately reported respiration during whole-body plethysmography. In anesthetized rodents, PVC tube-embedded sensors provided accurate mechanical detection of both respiratory and heart rate. Comparable success was seen in naturally behaving animals at rest or sleeping when sensors were attached externally. Video-verified motor behaviors (sniffing, grooming, chewing, and rearing) were detectable and largely separable by their characteristic voltage fluctuations. Larger movement-related events had comparably larger voltage dynamics that easily allowed for a broad approximation of overall motor activity. Spectrograms were used to quickly depict characteristic frequencies in long lasting recordings, while filtering and thresholding software allowed for detection and quantification of movement-related physio-behavioral events. CONCLUSIONS: EPIC electric field sensors provide a means for affordable non contact home cage detection of physio-behavioral variables. PMID- 27993528 TI - [Prognostic factors of hyperbaric oxygen therapy in hemorrhagic radiation cystitis]. AB - OBJECTIVE: To emphasize prognostic factors of hyperbaric oxygen therapy (HBOT) on hematuria at 3 and 12 months in the context of a radiation cystitis. MATERIAL AND METHODS: A cohort of 134 patients was treated from 2008 to 2013 in the hyperbaric medicine center of Toulouse University Hospital, France for radiation cystitis. Hematuria was ranked using the SOMA score. HBOT has been applied according to a standardized protocol of 20 renewable sessions, with pure oxygen to 2.5 ATA. The median number of sessions at 12 months was 50. RESULTS: HBOT had an efficacy of 83% at 3 months and 81% at 12 months. Twenty percent of patients had minor side effects. Compared to the pre-HBOT period, the number of hospitalizations decreased by 75% following treatment. The efficacy at 3 months was predictive of efficacy at 12 months (P<0.0001). There was an inverse correlation between the initial grade and efficacy at 3 months (P=0.026) and 12 months (P=0.001). A high WHO status diminished HBOT efficacy at 3 and 12 months (P=0.0014 and P<0.0001, respectively). An anticoagulant intake decreased the HBOT response at 12 months (P=0.002). Other parameters had no effects on efficacy. CONCLUSION: The efficacy at 3 months seems to be predictive of efficacy at 12 months. The initial hematuria grade is inversely correlated with efficacy at 3 and 12 months. It appears necessary to achieve at least 32 HBOT sessions. Moreover, a high WHO status and an anticoagulant intake seem to have a negative prognostic value. LEVEL OF EVIDENCE: 4. PMID- 27993529 TI - Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells. AB - Antioxidant-based chemotherapy has been intensely debated. Herein, we show that sulforaphane (SFN) induced mitochondrial biogenesis followed by mitochondrial fusion in a kidney cell line commonly used in nephroprotective models. At the same concentration and exposure time, SFN induced cell death in prostate cancer cells accompanied by mitochondrial biogenesis and fragmentation. Stabilization of the nuclear factor E2-related factor-2 (Nrf2) could be associated with these effects in the tumor cell line. An increase in the peroxisome proliferator activated receptor-gamma co-activator-1alpha (PGC1alpha) level and a decrease in the hypoxia-inducible factor-1alpha (HIF1alpha) level would suggest a possible metabolic shift. The knockdown in the nuclear respiratory factor-1 (NRF1) attenuated the SFN-induced effect on prostate cancer cells demonstrating that mitochondrial biogenesis plays an important role in cell death for this kind of tumor cells. This evidence supports SFN as a potential antineoplastic agent that could inhibit tumor development and could protect normal tissues by modulating common processes. PMID- 27993530 TI - Genetic variants of TLR4 and TLR9 are risk factors for chronic Helicobacter pylori infection in South Indian Tamils. AB - Toll like receptors (TLRs) are a class of molecular pattern recognition receptors, elicits a strong inflammatory immune response against pathogens. Helicobacter pylori (H. pylori), a gram negative flagellate colonizes the human stomach, is responsible for the development of chronic gastritis and gastric carcinoma. The higher incidence of H. pylori infection and gastric cancer in South Indian Tamils demands a genetic study to unravel the influence of TLR4 and TLR9 polymorphisms associated with chronic H. pylori infection. In this study, 230 healthy individuals and 77 patients diagnosed with H. pylori infection were screened for TLR4 (rs1927914, rs4986790, rs4986791) and TLR9 (rs352140, rs34399053, rs150459369) polymorphisms by PCR-RFLP and ARMS-PCR. We observed that the individuals harboring heterozygous and homozygous polymorphic variants of TLR4 conferred a significant risk to develop chronic H. pylori infection and peptic ulcer disease [rs4986790 AG, p=0.001, OR-2.7, 95%CI: 1.5-5.03; GG, p=0.0006, OR-9.8, 95%CI: 2.4-39.4; rs4986791CT, p=0.0001, OR-7.2, 95%CI: 3.7-7.2; TT, p=0.0001, OR-7.9, 95%CI: 2.6-23.7]. Also, the heterozygous variant of TLR9 rs352140, favoured the persistence of the H. pylori infection [p=0.037, OR-1.87, 95%CI: 1.07-3.29]. Thus our findings suggest that TLR4 rs4986790, rs4986791 and TLR9 rs352140 polymorphisms are potential genetic risk factors influencing the disease susceptibility and clinical manifestation of chronic H. pylori infection in Indian Tamils. PMID- 27993531 TI - Effect of smoking on risperidone pharmacokinetics - A multifactorial approach to better predict the influence on drug metabolism. AB - PURPOSE: To disentangle an association between tobacco smoking, smoking habits and pharmacokinetic patterns such as plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM, (RIS+9-OH-RIS) in a naturalistic sample. METHODS: Plasma concentrations, dose adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between smokers (n=401) and non-smokers (n=292). RESULTS: Daily dosage of risperidone differed significantly with smokers receiving higher doses than patients in the control group (p=0.001). No differences were detected in plasma concentrations of the active moiety, RIS and 9-OH-RIS (p=0.8 for AM, p=0.646 for RIS and p=0.538 for 9 OH-RIS). However, dose corrected concentrations (C/D) of metabolite (C/D 9-OH RIS) and active moiety (C/D AM) differed between significantly between groups (p=0.002 and p=0.007). After stratifying smokers to a group of moderate smokers (<20cigarettes/day) (RS1, n=109) and a group of heavy smokers (>=20cigarettes/day) (RS2, n=135), the comparison between non-smokers and both groups only showed lower values of C/D for 9-OH-RIS (p=0.011) for the group of moderate smokers while other pharmacokinetic parameters did not differ. CONCLUSIONS: Apart from the well-known induction of CYP1A2 activity by polycyclic aromatic hydrocarbons, smoking might exert an effect on other CYP isoenzymes as well. A possible interpretation proposes a slight inducing effect of smoking on risperidone metabolism most likely via CYP3A4. PMID- 27993532 TI - Context matters: Anterior and posterior cortical midline responses to sad movie scenes. AB - Narrative movies can create powerful emotional responses. While recent research has advanced the understanding of neural networks involved in immersive movie viewing, their modulation within a movie's dynamic context remains inconclusive. In this study, 24 healthy participants passively watched sad scene climaxes taken from 24 romantic comedies, while brain activity was measured using functional magnetic resonance (fMRI). To study effects of context, the sad scene climaxes were presented with either coherent scene context, replaced non-coherent context or without context. In a second viewing, the same clips were rated continuously for sadness. The ratings varied over time with peaks of experienced sadness within the assumed climax intervals. Activations in anterior and posterior cortical midline regions increased if presented with both coherent and replaced context, while activation in the temporal gyri decreased. This difference was more pronounced for the coherent context condition. Psycho-Physiological interactions (PPI) analyses showed a context-dependent coupling of midline regions with occipital visual and sub-cortical reward regions. Our results demonstrate the pivotal role of midline structures and their interaction with perceptual and reward areas in processing contextually embedded socio-emotional information in movies. PMID- 27993533 TI - Transverse water relaxation in whole blood and erythrocytes at 3T, 7T, 9.4T, 11.7T and 16.4T; determination of intracellular hemoglobin and extracellular albumin relaxivities. AB - Blood is a physiological substance with multiple water compartments, which contain water-binding proteins such as hemoglobin in erythrocytes and albumin in plasma. Knowing the water transverse (R2) relaxation rates from these different blood compartments is a prerequisite for quantifying the blood oxygenation level dependent (BOLD) effect. Here, we report the Carr-Purcell-Meiboom-Gill (CPMG) based transverse (R2CPMG) relaxation rates of water in bovine blood samples circulated in a perfusion system at physiological temperature in order to mimic blood perfusion in humans. R2CPMG values of blood plasma, lysed packed erythrocytes, lysed plasma/erythrocyte mixtures, and whole blood at 3 T, 7 T, 9.4 T, 11.7 T and 16.4 T were measured as a function of hematocrit or hemoglobin concentration, oxygenation, and CPMG inter-echo spacing (taucp). R2CPMG in lysed cells showed a small taucp dependence, attributed to the water exchange rate between free and hemoglobin-bound water to be much faster than taucp. This was contrary to the tangential dependence in whole blood, where a much slower exchange between cells and blood plasma applies. Whole blood data were fitted as a function of taucp using a general tangential correlation time model applicable for exchange as well as diffusion contributions to R2CPMG, and the intercept R20blood at infinitely short taucp was determined. The R20blood values at different hematocrit and the R2CPMG values of lysed erythrocyte/plasma mixtures at different hemoglobin concentration were used to determine the relaxivity of hemoglobin inside the erythrocyte (r2Hb) and albumin (r2Alb) in plasma. The r2Hb values obtained from lysed erythrocytes and whole blood were comparable at full oxygenation. However, while r2Hb determined from lysed cells showed a linear dependence on oxygenation, this dependence became quadratic in whole blood. This possibly suggests an additional relaxation effect inside intact cells, perhaps due to hemoglobin proximity to the erythrocyte membrane. However, we cannot exclude that this is a consequence of the simple tangential model used to remove relaxation contributions from exchange and diffusion. The extensive data set presented should be useful for future theory development for the transverse relaxation of blood. PMID- 27993534 TI - Assessment of the link between quantitative biexponential diffusion-weighted imaging and contrast-enhanced MRI in the liver. AB - PURPOSE: To investigate if intravoxel incoherent motion (IVIM) modeled diffusion weighted imaging (DWI) can be linked to contrast-enhanced (CE-)MRI in liver parenchyma and liver lesions. METHODS: Twenty-five patients underwent IVIM-DWI followed by multiphase CE-MRI using Gd-EOB-DTPA (n=20) or Gd-DOTA (n=5) concluded with IVIM-DWI. Diffusion (Dslow), microperfusion (Dfast), its fraction (ffast), wash-in-rate (Rearly) and late-enhancement-rate (Rlate) of Gd-EOB-DTPA were calculated voxel-wise for the liver. Parenchyma and lesions were segmented. Pre contrast IVIM was compared 1) between low, medium and high Rearly for parenchyma 2) to post-contrast IVIM substantiated with simulations 3) between low and high Rlate per lesion type. RESULTS: Dfast and ffast increased (P<0.001) with 25.6% and 33.8% between low and high Rearly of Gd-EOB-DTPA. Dslow decreased (-15.0%; P<0.001) with increasing Rearly. Gd-DOTA demonstrated similar observations. ffast (+10%; P<0.001) and Dfast (+6.6%; P<0.001) increased after Gd-EOB-DTPA, while decreasing after Gd-DOTA (-4.2% and -5.7%, P<0.001) and were confirmed by simulations. For focal nodular hyperplasia lesions (n=5) Dfast and ffast increased (P<0.001) with increasing Rlate, whereas for hepatocellular carcinoma (n=4) and adenoma (n=7) no differences were found. CONCLUSION: Microperfusion measured by IVIM reflects perfusion in a way resembling CE-MRI. Also IVIM separated intra- and extracellular MR contrast media. This underlines the potential of IVIM in quantitative liver imaging. PMID- 27993535 TI - Vitamin D status through the first 10 years of life: A vital piece of the puzzle in asthma inception. PMID- 27993537 TI - It's a lot of work to be nonallergic. PMID- 27993538 TI - SAPHO syndrome in childhood. A case report. AB - The acronym of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) combines a cluster of cutaneous and musculoskeletal manifestations, such as hyperostosis of bones of the anterior chest wall associated with acne fulminans and hidradenitis suppurativa. There are no validated diagnostic criteria in children. Nonsteroidal anti-inflammatory drugs are not always sufficient, and the use of corticosteroids, disease-modifying agents, tumor necrosis factor-alpha inhibitors or bisphosphonates may be necessary. We present the case of a child with polyarticular involvement, osteoarthritis of the sternoclavicular joint with severe inflammatory disorders and acne conglobata, with an excellent response to intravenous pamidronate. PMID- 27993536 TI - Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease. AB - BACKGROUND: We have previously shown that oncostatin M (OSM) levels are increased in nasal polyps (NPs) of patients with chronic rhinosinusitis (CRS), as well as in bronchoalveolar lavage fluid, after segmental allergen challenge in allergic asthmatic patients. We also showed in vitro that physiologic levels of OSM impair barrier function in differentiated airway epithelium. OBJECTIVE: We sought to determine which hematopoietic or resident cell type or types were the source of the OSM expressed in patients with mucosal airways disease. METHODS: Paraffin embedded NP sections were stained with fluorescence-labeled specific antibodies against OSM, GM-CSF, and hematopoietic cell-specific markers. Live cells were isolated from NPs and matched blood samples for flow cytometric analysis. Neutrophils were isolated from whole blood and cultured with the known OSM inducers GM-CSF and follistatin-like 1, and OSM levels were measured in the supernatants. Bronchial biopsy sections from control subjects, patients with moderate asthma, and patients with severe asthma were stained for OSM and neutrophil elastase. RESULTS: OSM staining was observed in NPs, showed colocalization with neutrophil elastase (n = 10), and did not colocalize with markers for eosinophils, macrophages, T cells, or B cells (n = 3-5). Flow cytometric analysis of NPs (n = 9) showed that 5.1% +/- 2% of CD45+ cells were OSM+, and of the OSM+ cells, 56% +/- 7% were CD16+Siglec-8-, indicating neutrophil lineage. Only 0.6 +/- 0.4% of CD45+ events from matched blood samples (n = 5) were OSM+, suggesting that increased OSM levels in patients with CRS was locally stimulated and produced. A majority of OSM+ neutrophils expressed arginase 1 (72.5% +/- 12%), suggesting an N2 phenotype. GM-CSF levels were increased in NPs compared with those in control tissue and were sufficient to induce OSM production (P < .001) in peripheral blood neutrophils in vitro. OSM+ neutrophils were also observed at increased levels in biopsy specimens from patients with severe asthma. Additionally, OSM protein levels were increased in induced sputum from asthmatic patients compared with that from control subjects (P < .05). CONCLUSIONS: Neutrophils are a major source of OSM-producing cells in patients with CRS and severe asthma. PMID- 27993540 TI - Diabetes mellitus and high blood pressure in relation to BMI among adult non pregnant women in Bangladesh. AB - PURPOSE: To investigate the association between overweight and obesity (in terms of BMI) and diabetes, HBP and diabetes-HBP comorbidity among adult women non pregnant in Bangladesh. METHODS: Information about demographics, socioeconomic, blood pressure and blood glucose levels were collected for 2022 women ageing above 35 years were collected from Bangladesh Demographic and Health Survey (BDHS 2011). The primary outcome variables were diabetes and high blood pressure. Diabetes was defined as fasting plasma glucose value >=7.0mmol/L and HBP as systolic blood pressure >=140mmHg or diastolic blood pressure >=90mmHg. Blood pressure and plasma glucose measurement were performed by standard clinical procedures. Data were analysed using cross-tabulation, chi-square tests and logistic regression methods. RESULTS: Mean age of the participants was 41.42 (SD=4.37). 38.7% of the women had BMI values >=25. The prevalence of HBP, diabetes, and diabetes-HBP comorbidity was respectively 18% and 5.1%, and 2%. The adjusted odds of having diabetes, HBP and Diabetes-HBP comorbidity were respectively 2.14 (p=0.002; 95%CI=1.31-3.48), 2.3 (p=<0.0001; 95%CI=1.70-2.98), and 3.4 (p=0.004; 95%CI=1.47-7.81) times higher among overweight/obese women compared to those with normal weight. CONCLUSIONS: Overweight and obesity account for a major proportion of diabetes, HBP and the comorbidity of these two among non-pregnant women. There remains a considerable risk for future expansion of diabetes and HBP as the prevalence of overweight/obesity is rising constantly. Maintaining a healthy BMI needs to be regarded as among the most important diabetes and HBP preventive strategies among Bangladeshi women. PMID- 27993539 TI - The association between HDL particle concentration and incident metabolic syndrome in the multi-ethnic Dallas Heart Study. AB - AIMS: Metabolic syndrome (MetS) increases atherosclerotic cardiovascular disease (ASCVD) risk. Low HDL cholesterol (HDL-C) is a diagnostic criterion of MetS and a major ASCVD risk factor. HDL particle concentration (HDL-P) associates with incident ASCVD independent of HDL-C, but its association with incident MetS has not been studied. We hypothesized that HDL-P would be inversely associated with incident metabolic syndrome independent of HDL-C and markers of adiposity and insulin resistance. MATERIALS AND METHODS: HDL-P was measured by NMR and visceral fat by MRI in participants of the Dallas Heart Study, a probability-based population sample of adults age 30-65. Participants with prevalent MetS, DM, CVD, and any systemic illlness were excluded. Incident MetS as defined by NCEP ATPIII criteria was determined in all participants after median follow-up period of 7.0 years. RESULTS: Among 1120 participants without DM or MetS at baseline (57% women, 45% Black, mean age 43), 22.8% had incident MetS at follow-up. HDL-P and HDL-C were modestly correlated (r=0.54, p<0.0001). In models adjusted for traditional risk factors and MetS risk factors including visceral fat, HS-CRP, triglyceride to HDL-C ratio, and HOMA-IR, the lowest quartile of HDL-P was associated with a 2-fold increased risk of incident MetS (OR 2.1, 95%CI 1.4-3.1; p=0.0003). CONCLUSIONS: Low HDL-P is independently associated with incident MetS after adjustment for traditional risk factors, lipid parameters, adiposity, inflammation, and markers of insulin resistance. Further studies are warranted to validate these findings and elucidate the mechanisms underpinning this association. PMID- 27993541 TI - Diabetes microvascular complications-A clinical update. AB - BACKGROUND: The purpose of this study is to summarise the empirical evidence addressing diabetes microvascular complications and management. The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs. Microvascular disease tends to occur predominantly in tissues where glucose uptake is independent of insulin activity because these tissues are exposed to glucose levels that correlate very closely with blood glucose levels. These metabolic injuries cause altered blood flow and changes in endothelial permeability, extravascular protein deposition and coagulation resulting in organ dysfunction which in turn lead to microvascular complications. METHOD: A systematic search of the literature from 2000 to 2016 was conducted using four databases (Medline, Pubmed, Cochrane central and Google scholar) using search terms such as diabetic microvascular complications', pathogenesis, screening, risk factors, pharmacological and non-pharmacological interventions and management. RESULTS: The current evidence supports a direct relationship between blood pressure (BP) and glycaemic control and progression of nephropathy and retinopathy. These are now considered as independent risk factors for microvascular disease progression. New fields of research addressing new drugs as potential therapeutic targets of the future will be presented. CONCLUSION: The prevention of microvascular disease involves paying attention to aggravating risk factors and implementing screening programmes to improve early detection. PMID- 27993542 TI - Modification of citrus and apple pectin by power ultrasound: Effects of acid and enzymatic treatment. AB - Pectin-derived oligosaccharides are emerging as a new generation of functional ingredients with new or improved technological and/or bioactive properties as compared to pectin. This work addresses the impact of power ultrasound (US) on the structure of citrus and apple pectin under different experimental conditions of power, amplitude and pectin concentration in aqueous and acid media, as well as in the presence of a pectinase. Results indicated that depolymerisation of both pectin increased with time and intensity of US in aqueous media and their polydispersity decreased. In general, a higher depolymerisation was observed in pectin treated by US in the presence of nitric and citric acids than in water, and hardly any difference was detected between both types of acids. Most of the assays gave rise to high-methoxylated pectin with a degree of esterification above 50%, pointing out their suitability for potential gelling agents. Finally, US did not have any impact in assisted enzymatic hydrolysis on the degree and/or rate of depolymerisation at low and medium levels of pectin concentration (0.5 and 2%), whereas a higher diversity of pectin fragments was found at 5% which could be indicative of a more controlled depolymerisation. These findings highlight the importance of the selection of appropriate US processing conditions to diversify the applications of modified pectin, as well as the potential of US as a prospective alternative to currently used depolymerisation techniques. PMID- 27993543 TI - [Nodular hidradenoma]. PMID- 27993544 TI - [A false Nelson's syndrome]. PMID- 27993545 TI - Effect of patient position on endotracheal cuff pressure in mechanically ventilated critically ill patients. AB - BACKGROUND: Endotracheal tube cuff pressure must be maintained within 20-30mH2O to prevent complications. There is limited literature reporting the impact of nursing care on endotracheal cuff pressure. However, few studies have reported the effect of nursing care on endotracheal cuff pressure. OBJECTIVES: This study was performed to investigate the effects of body position on endotracheal cuff pressure. METHODS: Twenty-five patients receiving mechanical ventilatory therapy were placed in a baseline position (semirecumbent position with the head of the bed elevated at 30 degrees and head in a neutral position) with endotracheal tube cuff was adjusted to 25cmH2O. The patients were moved into 16 different positions: anteflexion of the head; hyperextension of the head; left lateral flexion of the head; right lateral flexion of the head; rotation of the head to the left; rotation of the head to the right; semirecumbent position with 45 degrees elevation of the head of the bed; recumbent position with 10 degrees elevation of the head of the bed; supine position; trendelenburg position 10 degrees ; left lateral position at 30 degrees , 45 degrees , and 90 degrees ; and right lateral position at 30 degrees , 45 degrees , and 90 degrees . The endotracheal tube cuff pressure was measured and recorded after each position change. RESULTS: Among the 400 endotracheal tube cuff pressure measurements (25 patients*16 positions) 10 (2.5%) were lower than 20cmH2O; 201 (50.3%) were between 20-30cmH2O and 189 (47.3%) were higher than 30cmH2O. Mean endotracheal tube cuff pressure increased from 25 to 32.59+/-4.08cmH2O after changing the patients' position. Friedman test indicated a statistically significant deviation in the ETCP across the 16 positions (X2: 122.019, p: 0.0001). CONCLUSIONS: Body positioning during daily nursing care effected the endotracheal tube cuff pressure, suggesting that endotracheal tube cuff pressure should be measured after changing a patient's position and adjusted within the recommended range. PMID- 27993546 TI - Post resuscitation management of cardiac arrest patients in the critical care environment: A retrospective audit of compliance with evidence based guidelines. AB - BACKGROUND: There is a clear relationship between evidence-based post resuscitation care and survival and functional status at hospital discharge. The Australian Resuscitation Council (ARC) recommends protocol driven care to enhance chance of survival following cardiac arrest. Healthcare providers have an obligation to ensure protocol driven post resuscitation care is timely and evidence based. OBJECTIVES: The aim of this study was to examine adherence to best practice guidelines for post resuscitation care in the first 24h from Return of Spontaneous Circulation for patients admitted to the intensive care unit from the emergency department having suffered out of hospital or emergency department cardiac arrest and survived initial resuscitation. METHOD: A retrospective audit of medical records of patients who met the criteria for survivors of cardiac arrest was conducted at two health services in Melbourne, Australia. Criteria audited were: primary cardiac arrest characteristics, oxygenation and ventilation management, cardiovascular care, neurological care and patient outcomes. FINDINGS: The four major findings were: (i) use of fraction of inspired oxygen (FiO2) of 1.0 and hyperoxia was common during the first 24h of post resuscitation management, (ii) there was variability in cardiac care, with timely 12 lead Electrocardiograph and majority of patients achieving systolic blood pressure (SBP) greater than 100mmHg, but delays in transfer to cardiac catheterisation laboratory, (iii) neurological care was suboptimal with a high incidence of hyperglycaemia and failure to provide therapeutic hypothermia in almost 50% of patients and (iv) there was an association between in-hospital mortality and specific elements of post resuscitation care during the first 24h of hospital admission. CONCLUSION: Evidence-based context-specific guidelines for post resuscitation care that span the whole patient journey are needed. Reliance on national guidelines does not necessarily translate to evidence based care at a local level, so strategies to ensure effective guideline implementation are urgently required. PMID- 27993547 TI - Large variation between hospitals in immediate breast reconstruction rates after mastectomy for breast cancer in the Netherlands. AB - BACKGROUND: The present study aimed to describe the use of immediate breast reconstruction (IBR) after mastectomy for invasive breast cancer and ductal carcinoma in situ (DCIS) in hospitals in the Netherlands and determine whether patient and tumor factors account for the variation. METHODS: Patients undergoing mastectomy for primary invasive breast cancer or DCIS diagnosed between January 1, 2011 and December 31, 2013 were selected from the NABON Breast Cancer Audit. All the 92 hospitals in the Netherlands were included. The use of IBR in all hospitals was compared using unadjusted and adjusted analyses. Patient and tumor factors were evaluated by univariate and multivariate analyses. RESULTS: In total, 16,953 patients underwent mastectomy: 15,072 for invasive breast cancer and 1881 for DCIS. Unadjusted analyses revealed considerable variation between hospitals in postmastectomy IBR rates for invasive breast cancer (mean 17%; range 0-64%) and DCIS (mean 42%; range 0-83%). For DCIS, younger age and multifocal disease were factors that significantly increased IBR rates. For patients diagnosed with invasive breast cancer, IBR was more often used in younger patients, multifocal tumors, smaller tumors, tumors with a lower grade, absence of lymph node involvement, ductal carcinomas, or hormone-receptor positive/HER2 positive tumors. After case-mix adjustments for these factors, the variation in the use of IBR between hospitals remained large (0-43% for invasive breast cancer and 0-74% for DCIS). CONCLUSIONS: A large variation between hospitals was found in postmastectomy IBR rates in the Netherlands for both invasive breast cancer and DCIS even after adjustment for patient and tumor factors. PMID- 27993548 TI - Anomalous muscle during axillary sentinel lymph node biopsy for melanoma. PMID- 27993550 TI - Are SAR tables obsolete? PMID- 27993551 TI - Dose-response of serum 25-hydroxyvitamin D in association with risk of colorectal cancer: A meta-analysis. AB - Fifteen nested case-control or cohort studies in 14 countries have examined the association between serum 25-hydroxyvitamin D [25(OH)D] and risk of colorectal cancer. A meta-analysis of these studies would provide a useful dose-response gradient curve based on pooling of the results of known studies to date. An up-to date dose-response curve that combines the findings of these studies has not been reported, to our knowledge. This curve would help in designing interventions for future studies. A new meta-analysis would be more precise than any previous analysis due to its larger sample size. Therefore a search of PubMed and other resources was performed in May 2016 for all cohort or nested case-control observational studies that reported risk of colon or colorectal cancer by quantiles of 25(OH)D. All but two of the 15 studies found a trend toward lower risk of colorectal cancer associated with higher serum 25(OH)D. There was a linear reduction in the odds ratio (OR) with each 10ng/ml-increment in 25(OH)D concentration. The lowest quantile of the serum 25(OH)D concentration was generally<20ng/ml. The downward trend in ORs associated with higher serum 25(OH)D concentrations was statistically significant in 3 studies. The pooled OR from all studies comparing highest with lowest quantile of 25(OH)D was 0.67 (95% confidence interval [CI], 0.59-0.76), meaning there was a 33% lower risk associated with the highest compared with the lowest quantile of serum 25(OH)D. A dose-response analysis revealed that a serum 25(OH)D of 50ng/ml was associated with an OR of 0.4 (95% CI, 0.2-1.0) compared with a concentration of 5ng/ml. The formula for the linear relationship was OR=0.008x. For example, individuals with a 25(OH)D concentration of 50ng/ml had an approximately 60% lower risk of colorectal cancer than those with a concentration of 5ng/ml. Those with a 25(OH)D concentration of 30ng/ml had a 33% lower risk than those with a concentration of 5ng/ml. The inverse association between serum 25(OH)D and risk of colorectal cancer overall was strong and statistically significant. There also was a mostly linear dose response relationship between serum 25(OH)D and risk of colorectal cancer when all studies were combined. No study reported significant adverse effects, and there was no evidence of publication bias. Misclassification in some studies could have influenced the association, causing it to appear weaker than the true association. PMID- 27993549 TI - Higher Nevus Count Exhibits a Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma. AB - High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 (P = 1.2 * 10-6) and CTC1 (region: P = 6.3 * 10-4), and other genes including ARRDC1 (P = 3.1 * 10-7). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation (P = 6.33 * 10-6). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 * 10-49) and NID1 (P = 6.4 * 10-14), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 * 10-10). Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis. PMID- 27993552 TI - New PCOS-like phenotype in older infertile women of likely autoimmune adrenal etiology with high AMH but low androgens. AB - How anti-Mullerian hormone (AMH) and testosterone (T) interrelate in infertile women is currently largely unknown. We, therefore, in a retrospective cohort study investigated how infertile women with high-AMH (AMH >=75th quantile; n=144) and with normal-AMH (25th-75th quantile; n=313), stratified for low-T (total testosterone <=19.0ng/dL), normal-T (19.0-29.0ng/dL) and high-T (>29.0ng/dL) phenotypically behaved. Patient age, follicle stimulating hormone (FSH), dehyroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol (C), adrenocorticotrophic hormone (ACTH), IVF outcomes, as well as inflammatory and immune panels were then compared between groups, with AMH and T as variables. We identified a previously unknown infertile PCOS-like phenotype, characterized by high-AMH but, atypically, low-T, with predisposition toward autoimmunity. It presents with incompatible high-AMH and low-T (<19.0ng/dL), is restricted to lean PCOS-like patients, presenting delayed for tertiary fertility services. Since also characterized by low DHEAS, low-T is likely of adrenal origina, and consequence of autoimmune adrenal insufficiency since also accompanied by low-C and evidence of autoimmunity. DHEA supplementation in such patients equalizes low to normal-T and normalizes IVF cycle outcomes. Once recognized, this high AMH/low-T phenotype is surprisingly common in tertiary fertility centers but, currently, goes unrecognized. Its likely adrenal autoimmune etiology offers interesting new directions for investigations of adrenals control over ovarian function via adrenal androgen production. PMID- 27993553 TI - Screening ubiquitin specific protease activities using chemically synthesized ubiquitin and ubiquitinated peptides. AB - Ubiquitin, a 76 amino acid protein, is a key component that contributes to cellular protein homeostasis. The specificity of this modification is due to a series of enzymes: ligases, attaching the ubiquitin to a lysine, and deubiquitinases, which remove it. More than a hundred of such proteins are implicated in the regulation of protein turnover. Their specificities are only partially understood. We chemically synthesized ubiquitin, attached it to lysines belonging to the protein sequences known to be ubiquitinated. We chose the model protein "murine double minute 2" (mdm2), a ubiquitin ligase, itself ubiquitinated and deubiquitinated. We folded the ubiquitinated peptides and checked their tridimensional conformation. We assessed the use of these substrates with a series of fifteen deubiquitinases to show the potentiality of such an enzymological technique. By manipulating the sequence of the peptide on which ubiquitin is attached, we were able to detect differences in the enzyme/substrate recognition, and to determine that these differences are deubiquitinase dependent. This approach could be used to understand the substrate/protein relationship between the protagonists of this reaction. The methodology could be customized for a given substrate and used to advance our understanding of the key amino acids responsible for the deubiquitinase specificities. PMID- 27993554 TI - Racial and Ethnic Differences in Longitudinal Patterns of Family Mealtimes: Link to Adolescent Fruit and Vegetable Consumption. AB - OBJECTIVE: To examine the longitudinal patterns of family mealtimes across racial/ethnic groups and to investigate whether the associations between longitudinal patterns of family mealtimes, baseline family and demographic characteristics, and healthy food consumption in adolescence differ by race/ethnicity. METHODS: Data from the Early Childhood Longitudinal Study spanning from kindergarten to eighth grade were used for this study. Longitudinal patterns of family mealtimes and their link to baseline characteristics and healthy food consumption in adolescence, as defined by fruit and vegetable intakes, were determined using latent growth curves. RESULTS: From childhood to adolescence, family mealtimes were stable among Asian families. Although Hispanic families displayed a downward pattern, mealtimes declined more steeply in non Hispanic white and black families. The links among family mealtimes, baseline characteristics, and healthy food consumption were not observed equally across racial/ethnic groups. CONCLUSIONS AND IMPLICATIONS: Differences in longitudinal patterns of family mealtimes and in the association between family mealtimes and adolescent healthy food consumption across racial/ethnic groups call for targeted intervention in this nutritionally vulnerable period. PMID- 27993555 TI - College Students' Perceived Differences Between the Terms Real Meal, Meal, and Snack. AB - OBJECTIVE: To assess qualitatively and quantitatively college students' perceived differences between a real meal, meal, and snack. DESIGN: A descriptive study design was used to administer an 11-item online survey to college students. SETTING: Two university campuses in the western US. PARTICIPANTS: Pilot testing was conducted with 20 students. The final survey was completed by 628 ethnically diverse students. MAIN OUTCOME MEASURES: Students' perceptions of the terms real meal, meal, and snack. ANALYSIS: Three researchers coded the data independently, reconciled differences via conference calls, and agreed on a final coding scheme. Data were reevaluated based on the coding scheme. Means, frequencies, Pearson chi square, and t test statistics were used. RESULTS: More than half of students perceived a difference between the terms real meal and meal. Most (97.6%) perceived a difference between the terms meal and snack. A marked difference in the way students defined these terms was evident, with a real meal deemed nutritious and healthy and meeting dietary recommendations, compared with meals, which were considered anything to eat. CONCLUSIONS AND IMPLICATIONS: These findings suggest that the term real meal may provide nutrition educators with a simple phrase to use in educational campaigns to promote healthful food intake among college students. PMID- 27993556 TI - Extracellular functions of 14-3-3 adaptor proteins. AB - 14-3-3s are a family of adaptor proteins with a wide range of roles in cell signaling. Although they are primarily localized within the cytosol, 14-3-3s are also known to be present in the extracellular environment. Externalization of 14 3-3 can occur as a result of cell death or physiologically via release in exosomes. Interesting biological activities with relevance for tissue homeostasis and disease are now being described for extracellular 14-3-3s. Moreover, aminopeptidase N (APN) has been identified as a cell surface receptor for 14-3 3s. Here we review the array of bioactivities that have been ascribed to extracellular 14-3-3s and discuss applications as biomarkers and as targets for drug development. PMID- 27993557 TI - Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury. AB - Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro, NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro. Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway. PMID- 27993558 TI - Higher Prescription Opioid Dose is Associated With Worse Patient-Reported Pain Outcomes and More Health Care Utilization. AB - : Some previous research has examined pain-related variables on the basis of prescription opioid dose, but data from studies involving patient-reported outcomes have been limited. This study examined the relationships between prescription opioid dose and self-reported pain intensity, function, quality of life, and mental health. Participants were recruited from 2 large integrated health systems, Kaiser Permanente Northwest (n = 331) and VA Portland Health Care System (n = 186). To be included, participants had to have musculoskeletal pain diagnoses and be receiving stable doses of long-term opioid therapy. We divided participants into 3 groups on the basis of current prescription opioid dose in daily morphine equivalent dose (MED): low dose (5-20 mg MED), moderate dose (20.1 50 mg MED), and higher dose (50.1-120 mg MED) groups. A statistically significant trend emerged where higher prescription opioid dose was associated with moderately sized effects including greater pain intensity, more impairments in functioning and quality of life, poorer self-efficacy for managing pain, greater fear avoidance, and more health care utilization. Rates of potential alcohol and substance use disorders also differed among groups. Findings from this evaluation reveal significant differences in pain-related and substance-related factors on the basis of prescription opioid dose. PERSPECTIVE: This study included 517 patients who were prescribed long-term opioid therapy and compared differences on pain- and mental health-related variables on the basis of prescription opioid dose. Findings reveal small- to medium-sized differences on pain-related variables, alcohol and substance use, and health care utilization on the basis of the dose of opioid prescribed. PMID- 27993559 TI - Causal Mediation in the Development of Painful Temporomandibular Disorder. AB - : We explored causal mediation of sleep quality and perceived stress in development of painful temporomandibular disorder (TMD). Sleep quality and perceived stress were assessed at baseline and quarterly intervals thereafter in 2,737 initially TMD-free adults in the Orofacial Pain Prospective Evaluation and Risk Assessment study (OPPERA) prospective cohort study. During follow-up, incident TMD cases were classified using research diagnostic criteria. Mediation analysis was conducted using a weighted Cox proportional hazards regression model that estimated hazard ratios (HRs) and 95% confidence limits (CL) of first-onset TMD. Models determined whether: 1) poor sleep quality during follow-up mediated the effect of baseline perceived stress on first-onset TMD, and 2) perceived stress during follow-up mediated the effect of baseline poor sleep quality on first-onset TMD. In both analyses, the total effect was decomposed into natural direct and indirect effects. Poor baseline sleep quality led to heightened perceived stress that then contributed to TMD development. When the total effect of poor sleep quality (HR = 2.10, CL = 1.76, 2.50) was decomposed, 34% of its effect was mediated by perceived stress (indirect effect HR = 1.29, CL = 1.06, 1.58). The effect of perceived stress on first-onset TMD was not mediated by sleep quality. Improving sleep may avert escalation of stress, limiting effects of both factors on TMD development. PERSPECTIVE: Causal mediation analysis highlights mechanisms by which poor sleep quality promotes development of TMD. First, poor sleep quality exerts a direct effect on pain. Second, it triggers a heightened perception of stress, which acts as an intermediate factor in the causal pathway between poor sleep quality and first-onset TMD pain. PMID- 27993560 TI - Step changes in leaf oil accumulation via iterative metabolic engineering. AB - Synthesis and accumulation of plant oils in the entire vegetative biomass offers the potential to deliver yields surpassing those of oilseed crops. However, current levels still fall well short of those typically found in oilseeds. Here we show how transcriptome and biochemical analyses pointed to a futile cycle in a previously established Nicotiana tabacum line, accumulating up to 15% (dry weight) of the storage lipid triacylglycerol in leaf tissue. To overcome this metabolic bottleneck, we either silenced the SDP1 lipase or overexpressed the Arabidopsis thaliana LEC2 transcription factor in this transgenic background. Both strategies independently resulted in the accumulation of 30-33% triacylglycerol in leaf tissues. Our results demonstrate that the combined optimization of de novo fatty acid biosynthesis, storage lipid assembly and lipid turnover in leaf tissue results in a major overhaul of the plant central carbon allocation and lipid metabolism. The resulting further step changes in oil accumulation in the entire plant biomass offers the possibility of delivering yields that outperform current oilseed crops. PMID- 27993561 TI - Loss of smooth muscle cell disintegrin and metalloproteinase 17 transiently suppresses angiotensin II-induced hypertension and end-organ damage. AB - Hypertension is associated with hypertrophy and hyperplasia of smooth muscle cells (SMCs). Disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme reported to mediate SMC hypertrophy through activation of epidermal growth factor receptor (EGFR). We investigated the role of ADAM17 in Ang II-induced hypertension and end-organ damage. VSMC was isolated from mice with intact ADAM17 expression (Adam17f/f) or lacking ADAM17 in the SMC (Adam17f/f/CreSm22). Human VSMCs were isolated from the aorta of donors, and ADAM17 deletion was achieved by siRNA transfection. Ang II suppressed proliferation and migration of Adam17 deficient SMCs, but did not affect apoptosis (mouse and human), this was associated with reduced activation of EGFR and Erk1/2 signaling. Adam17f/f/CreSm22 and littermate Adam17f/f mice received saline or Ang II (Alzet pumps, 1.5mg/kg/d; 2 or 4weeks). Daily blood pressure measurement in conscious mice (telemetry) showed suppressed hypertension in Adam17f/f/CreSm22 mice during the first week of Ang II infusion, but by the second week, it become comparable to that in Adam17f/f mice. EGFR activation remained suppressed in Adam17f/f/CreSm22-Ang II arteries. Ex vivo vascular function and compliance assessed in mesenteric arteries were comparable between genotypes. Consistent with the transient protection against Ang II-induced hypertension, Adam17f/f/CreSm22 mice exhibited significantly lower cardiac hypertrophy and fibrosis, and renal fibrosis at 2weeks post-Ang II, however this protection was abolished by the fourth week of Ang II infusion. In conclusion, while Adam17 deficiency suppresses Ang II-induced SMC remodeling in vitro, in vivo Adam17 deficiency provides only a transient protective effect against Ang II-mediated hypertension and end-organ damage. PMID- 27993562 TI - Superior parietal cortex and the attention to delayed intention: An rTMS study. AB - Prospective memory (PM) is the ability to remember to carry out an intention when the appropriate cue occurs. This study aimed to investigate whether the superior parietal cortex is causally involved in PM and, if so, what is its functional role. We applied repetitive transcranial magnetic stimulation (rTMS) to the left and right superior parietal cortex, and we evaluated the TMS effects on two different PM tasks that required to direct the attention towards either the external stimuli ('Monitoring-load' task) or the intention in memory ('Retrospective-load' task). rTMS of left parietal cortex produced a facilitation of PM performance in both tasks. This was coupled by slower responses to the ongoing activity, for left and right parietal stimulation, but selectively in the 'Retrospective-load' condition. The present results suggest that superior parietal cortex is causally involved in biasing top-down attentional resources between the external, ongoing stimuli and the internal, PM intentions. The possible physiological mechanisms underlying the TMS-related improvement in PM performance are discussed. PMID- 27993563 TI - The effect of repeated lateral compression and expansions mimicking blinking on selected tear film polar lipid monofilms. AB - The tear film lipid layer is formed on the anterior surface of the eye, functioning as a barrier to excess evaporation and foreign particles, while also providing stability to the tear film. The lipid layer is organized into a polar lipid layer consisting of phospholipids, ceramides, and free fatty acids that act as a surfactant to a non-polar multilayer of wax and cholesterol esters. Due to shear forces from eye movement and the compression and expansion of blinking, the tear lipids are under constant stress. However, tear film is able to resist immediate rupture and remains intact over multiple blinks. This work aimed to better understand the lateral organization of selected tear film polar lipids. The polar lipid biomimetic studied here consisted of dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), palmitoyl glucosylceramide (PGC), and palmitoyl sphingomyelin (PSM). Surface pressure-area isocycles mimicked blinking and films were visualized by Brewster angle microscopy (BAM). All lipid systems formed relatively reversible films as indicated by limited hysteresis. However, pure DPPC and PSM films experienced greater changes in lipid packing upon compression and expansion compared to pure PGC and DPPE. This suggests that the driving force behind maintaining the lateral organization of the polar lipids from tear film may be the hydrogen bonding propensities of the head groups. Additionally, isocycles of films containing DPPC, DPPE, and PGC mixtures exhibited evidence for reversible multilayer formation or folding. This was supported by 3D analysis of structures that formed during compression but reintegrated back into the bulk lipid film during expansion near the in vitro tear film surface pressure of the open eye. Therefore, the polar lipids of tear film may be directly involved in preventing film rupture during a blink. PMID- 27993564 TI - Interfacial activation of M37 lipase: A multi-scale simulation study. AB - Lipases are enzymes of biotechnological importance that function at the interface formed between hydrophobic and aqueous environments. Hydrophobic interfaces can induce structural transitions in lipases that result in an increase in enzyme activity, although the detailed mechanism of this process is currently not well understood for many lipases. Here, we present a multi-scale molecular dynamics simulation study of how different interfaces affect the conformational dynamics of the psychrophilic lipase M37. Our simulations show that M37 lipase is able to interact both with anionic lipid bilayers and with triglyceride surfaces. Interfacial interactions with triglyceride surfaces promote large-scale motions of the lid region of M37, spanning residues 235-283, revealing an entry pathway to the catalytic site for substrates. Importantly, these results suggest a potential activation mechanism for M37 that deviates from other related enzymes, such as Thermomyces lanuginosus lipase. We also investigated substrate binding in M37 by using steered MD simulations, confirming the open state of this lipase. The exposure of hydrophobic residues within lid and active site flap regions (residues 94-110) during the activation process provides insights into the functional effect of hydrophobic surfaces on lipase activation. PMID- 27993565 TI - Acylation of the Bordetella pertussis CyaA-hemolysin: Functional implications for efficient membrane insertion and pore formation. AB - Previously, the ~130-kDa CyaA-hemolysin domain (CyaA-Hly) from Bordetella pertussis co-expressed with CyaC-acyltransferase in Escherichia coli was demonstrated to be palmitoylated at Lys983 and thus activated its hemolytic activity against target erythrocytes. Here, we report the functional importance of Lys983-palmitoylation for membrane insertion and pore formation of CyaA-Hly. Intrinsic fluorescence emissions of both non-acylated CyaA-Hly (NA/CyaA-Hly) and CyaA-Hly were indistinguishable, suggesting no severe conformational change upon acylation at Lys983. Following pre-incubation of sheep erythrocytes with NA/CyaA Hly, there was a drastic decrease in CyaA-Hly-induced hemolysis. Direct interactions between NA/CyaA-Hly and target erythrocyte membranes were validated via membrane-binding assays along with Western blotting, suggestive of acylation independent capability of NA/CyaA-Hly to interact with erythrocyte membranes. As compared with CyaA-Hly, NA/CyaA-Hly displayed a slower rate of incorporation into DOPC:DOPE:Ch or DiPhyPC bilayers under symmetrical conditions (1M KCl, 10mM HEPES, pH7.4) and formed channels exhibiting different conductance. Further analysis revealed that channel-open lifetime in DOPC:DOPE:Ch bilayers of NA/CyaA Hly was much shorter than that of the acylated form, albeit slightly shorter lifetime found in DiPhyPC bilayers. Sequence alignments of the Lys983-containing CyaA-segment with those of related RTX-cytolysins revealed a number of highly conserved hydrophobic residues and a Lys/Arg cluster that is predicted be important for toxin-membrane interactions. Altogether, our data disclosed that the Lys983-linked palmitoyl group is not directly involved in either binding to target erythrocyte membranes or toxin-induced channel conductivity, but rather required for efficient membrane insertion and pore formation of the acylated CyaA Hly domain. PMID- 27993567 TI - Cell cycle dependent changes in the plasma membrane organization of mammalian cells. AB - Lipid membranes are major structural elements of all eukaryotic and prokaryotic organisms. Although many aspects of their biology have been studied extensively, their dynamics and lateral heterogeneity are still not fully understood. Recently, we observed a cell-to-cell variability in the plasma membrane organization of CHO-K1 cells (Schwarzer et al., 2014). We surmised that cell cycle dependent changes of the individual cells from our unsynchronized cell population account for this phenomenon. In the present study, this hypothesis was tested. To this aim, CHO-K1 cells were arrested in different cell cycle phases by chemical treatments, and the order of their plasma membranes was determined by various fluorescent lipid analogues using fluorescence lifetime imaging microscopy. Our experiments exhibit significant differences in the membrane order of cells arrested in the G2/M or S phase compared to control cells. Our single cell analysis also enabled the specific selection of mitotic cells, which displayed a significant increase of the membrane order compared to the control. In addition, the lipid raft marker GPImYFP was used to study the lateral organization of cell cycle arrested cells as well as mitotic cells and freely cycling samples. Again, significant differences were found between control and arrested cells and even more pronounced between control and mitotic cells. Our data demonstrate a direct correlation between cell cycle progression and plasma membrane organization, underlining that cell-to-cell heterogeneities of membrane properties have to be taken into account in cellular studies especially at the single-cell level. PMID- 27993566 TI - Beta2-adrenergic receptor homodimers: Role of transmembrane domain 1 and helix 8 in dimerization and cell surface expression. AB - Even though there are hundreds of reports in the published literature supporting the hypothesis that G protein-coupled receptors (GPCR) form and function as dimers this remains a highly controversial area of research and mechanisms governing homodimer formation are poorly understood. Crystal structures revealing homodimers have been reported for many different GPCR. For adrenergic receptors, a potential dimer interface involving transmembrane domain 1 (TMD1) and helix 8 (H8) was identified in crystal structures of the beta1-adrenergic (beta1-AR) and beta2-AR. The purpose of this study was to investigate a potential role for TMD1 and H8 in dimerization and plasma membrane expression of functional beta2-AR. Charged residues at the base of TMD1 and in the distal portion of H8 were replaced, singly and in combination, with non-polar residues or residues of opposite charge. Wild type and mutant beta2-AR, tagged with YFP and expressed in HEK293 cells, were evaluated for plasma membrane expression and function. Homodimer formation was evaluated using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and fluorescence correlation spectroscopy. Amino acid substitutions at the base of TMD1 and in the distal portion of H8 disrupted homodimer formation and caused receptors to be retained in the endoplasmic reticulum. Mutations in the proximal region of H8 did not disrupt dimerization but did interfere with plasma membrane expression. This study provides biophysical evidence linking a potential TMD1/H8 interface with ER export and the expression of functional beta2-AR on the plasma membrane. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova. PMID- 27993568 TI - Quaternary structure of the yeast pheromone receptor Ste2 in living cells. AB - Transmembrane proteins known as G protein-coupled receptors (GPCRs) have been shown to form functional homo- or hetero-oligomeric complexes, although agreement has been slow to emerge on whether homo-oligomerization plays functional roles. Here we introduce a platform to determine the identity and abundance of differing quaternary structures formed by GPCRs in living cells following changes in environmental conditions, such as changes in concentrations. The method capitalizes on the intrinsic capability of FRET spectrometry to extract oligomer geometrical information from distributions of FRET efficiencies (or FRET spectrograms) determined from pixel-level imaging of cells, combined with the ability of the statistical ensemble approaches to FRET to probe the proportion of different quaternary structures (such as dimers, rhombus or parallelogram shaped tetramers, etc.) from averages over entire cells. Our approach revealed that the yeast pheromone receptor Ste2 forms predominantly tetramers at average expression levels of 2 to 25 molecules per pixel (2.8.10-6 to 3.5.10-5molecules/nm2), and a mixture of tetramers and octamers at expression levels of 25-100 molecules per pixel (3.5.10-5 to 1.4.10-4molecules/nm2). Ste2 is a class D GPCR found in the yeast Saccharomyces cerevisiae of the mating type a, and binds the pheromone alpha-factor secreted by cells of the mating type alpha. Such investigations may inform development of antifungal therapies targeting oligomers of pheromone receptors. The proposed FRET imaging platform may be used to determine the quaternary structure sub-states and stoichiometry of any GPCR and, indeed, any membrane protein in living cells. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova. PMID- 27993570 TI - Radiation oncology enters the era of individualised medicine. PMID- 27993569 TI - A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study. AB - BACKGROUND: Despite its common use in cancer treatment, radiotherapy has not yet entered the era of precision medicine, and there have been no approaches to adjust dose based on biological differences between or within tumours. We aimed to assess whether a patient-specific molecular signature of radiation sensitivity could be used to identify the optimum radiotherapy dose. METHODS: We used the gene-expression-based radiation-sensitivity index and the linear quadratic model to derive the genomic-adjusted radiation dose (GARD). A high GARD value predicts for high therapeutic effect for radiotherapy; which we postulate would relate to clinical outcome. Using data from the prospective, observational Total Cancer Care (TCC) protocol, we calculated GARD for primary tumours from 20 disease sites treated using standard radiotherapy doses for each disease type. We also used multivariable Cox modelling to assess whether GARD was independently associated with clinical outcome in five clinical cohorts: Erasmus Breast Cancer Cohort (n=263); Karolinska Breast Cancer Cohort (n=77); Moffitt Lung Cancer Cohort (n=60); Moffitt Pancreas Cancer Cohort (n=40); and The Cancer Genome Atlas Glioblastoma Patient Cohort (n=98). FINDINGS: We calculated GARD for 8271 tissue samples from the TCC cohort. There was a wide range of GARD values (range 1.66 172.4) across the TCC cohort despite assignment of uniform radiotherapy doses within disease types. Median GARD values were lowest for gliomas and sarcomas and highest for cervical cancer and oropharyngeal head and neck cancer. There was a wide range of GARD values within tumour type groups. GARD independently predicted clinical outcome in breast cancer, lung cancer, glioblastoma, and pancreatic cancer. In the Erasmus Breast Cancer Cohort, 5-year distant-metastasis-free survival was longer in patients with high GARD values than in those with low GARD values (hazard ratio 2.11, 95% 1.13-3.94, p=0.018). INTERPRETATION: A GARD-based clinical model could allow the individualisation of radiotherapy dose to tumour radiosensitivity and could provide a framework to design genomically-guided clinical trials in radiation oncology. FUNDING: None. PMID- 27993571 TI - Delayed tongue necrosis simultaneous with bilateral osteoradionecrosis of the jaw secondary to head and neck irradiation. AB - We present a rare case of massive tongue necrosis occurring simultaneously with bilateral osteoradionecrosis (ORN) of the jaw in a patient with a history of treatment, including surgery and postoperative radiotherapy, for a retromolar trigone carcinoma 8 years earlier. There is a distinct possibility that the extractions and administration of local anesthesia with a vasoconstrictor contributed to the onset of ORN; together, these events may have influenced the blood supply to the tongue. A glossectomy was performed after hyperbaric oxygen therapy. One month after the surgical procedure, the patient responded satisfactorily to the treatment, showing significant improvement in speech and oral food intake, as well as significant decrease in lingual pain. Although the simultaneous occurrence of these oral complications is rare, the practitioner must be aware of the factors that instigate ORN and compromise vasculature as well as the clinical signs of tongue necrosis. Additionally, the possibility of tongue necrosis secondary to irradiation of the head and neck should be taken into consideration when an irradiated patient undergoes tooth extractions under local anesthesia with agents containing epinephrine. PMID- 27993572 TI - Chills During Hemodialysis: Prediction and Prevalence of Bacterial Infections - A Retrospective Cohort Study. AB - INTRODUCTION: Chills are a complication of patients undergoing hemodialysis. The rate of infection among hemodialysis patients presenting with chills is not well established, and empirical broad-spectrum antibiotics are usually the rule. METHODS: We performed a retrospective study aiming to assess the rates of infection and bacteremia in hemodialysis patients presenting with chills. We evaluated risk factors for infection and bacteremia and tested a prediction model for infection. RESULTS: Overall, 269 hemodialysis patients with a first episode of chills were included. Ninety patients (33.5%) had bacteremia and 162 (60.2%) had an infection. Risk factors for bacteremia in multivariate analysis included fever (odds ratio [OR] 1.6; 95% confidence interval [CI], 1.1-2.3; P = .009) and vascular catheter as dialysis access (OR 6.2; 95% CI, 3.2-12.0, P <.001). Leukocytosis was an additional risk factor in multivariate analysis for any type of infection (OR 1.265; 95% CI, 1.113-1.438; P <.001). Using a prediction model to evaluate patients without obvious source of infection, we found that patients with fistula or graft as their access, without fever, abnormal leukocytes, or hypoalbuminemia, had a low rate (1/17, 6%) of bacteremia. CONCLUSIONS: Hemodialysis patients presenting with chills during dialysis, with or without fever, have high rates (~60%) of infection. Patients with no obvious source of infection, with fistula or graft as access, presenting without fever, leukocytosis, or hypoalbuminemia have low risk for bacteremia and may be investigated without prompt antibiotic treatment. All other patients should receive antibiotic coverage immediately following a chills episode. PMID- 27993573 TI - Clinical Utility of a Precision Medicine Test Evaluating Outpatients with Suspected Obstructive Coronary Artery Disease. AB - BACKGROUND: Identifying patients with obstructive coronary artery disease can be challenging for primary care physicians. Advances in precision medicine may help augment clinical tools and redefine the paradigm for evaluating coronary artery disease in the outpatient setting. A blood-based age/sex/gene expression score (ASGES) incorporating key features of precision medicine has shown clinical validity with a 96% negative predictive value and 89% sensitivity in estimating a symptomatic patient's current likelihood of obstructive coronary artery disease. To better characterize the clinical utility of the ASGES and measure its impact on clinician decision-making, a community-based registry was established. METHODS: The prospective PRESET Registry (NCT01677156) enrolled stable, nonacute adult patients presenting with typical or atypical symptoms suggestive of obstructive coronary artery disease from 21 US primary care practices from August 2012 to August 2014. Demographics, clinical characteristics, and ASGES results (predefined as low [ASGES <=15] or elevated [ASGES >15]) were collected, as were referrals to Cardiology or further functional/anatomic cardiac testing after ASGES testing. Patients were followed for 1 year post ASGES testing. RESULTS: Among the 566-patient cohort (median age 56 years), clinicians referred 26/252 (10%) of patients with low scores vs 137/314 (44%) of patients with elevated scores to Cardiology or advanced cardiac testing for further evaluation (unadjusted odds ratio 0.15, P <.0001; adjusted odds ratio after accounting for clinical covariates = 0.18, P <.0001). Data on 84 patients referred for advanced cardiac testing showed abnormal findings in 0 of 13 (0%) low ASGES and 10 of 71 (14%) elevated ASGES patients. Major adverse cardiovascular events and revascularization were noted in 3/252 (1.2%) patients with low ASGES and 14/314 (4.5%) patients with elevated ASGES score (P <.03). CONCLUSIONS: In this community-based cardiovascular registry, the ASGES demonstrated clinical utility in the evaluation of patients with suspected obstructive coronary artery disease. Low-score patients were less likely to undergo cardiac referral, were unlikely to have positive findings on further cardiac work-up, and had a low rate of adverse cardiovascular events in 1-year follow-up. Our work provides evidence supporting the value of using precision medicine in the delivery of cardiovascular care. PMID- 27993574 TI - A nasolabial swelling. PMID- 27993575 TI - B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry. AB - In this retrospective study from one institution, we performed a clinicopathological study of a cohort of patients with posttransplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein-Barr virus (EBV) by in situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, Myc, and BCL2. All 17 of the posttransplant and none of 11 de novo cases were EBV positive (P < .005). Morphologic patterns identified in the PTLD cases were monomorphic diffuse large B-cell lymphoma pattern (10 patients) and "T-cell-rich" pattern (7 patients). The monomorphic posttransplant cases were more likely to be Myc negative (P = .015) and CD30 positive (P < .005) than the de novo cases, and showed a similarly low rate of p53 positivity by immunohistochemistry. No prognostic factors for overall survival were identified. Central nervous system PTLD is EBV positive, typically lacks p53 and Myc expression by immunohistochemistry, and can present with numerous background T lymphocytes. PMID- 27993576 TI - Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4, and MAGEA1. AB - Synovial sarcoma (SS) is regarded as a relatively chemosensitive sarcoma, but the prognosis of advanced SSs remains poor. Here we identified highly expressed cancer-testis antigens that could be promising immunotherapy targets for SS, using a previously conducted cDNA microarray, and we assessed the clinicopathological or prognostic relationships of these antigens in SS. We compared the gene expression profiles of 11 SSs with those of 3 normal adipose tissues. Among the up-regulated cancer-testis antigens, we analyzed PRAME, MAGEA1, and MAGEA4 and another cancer-testis antigen (NY-ESO-1) together, by immunohistochemistry and real-time polymerase chain reaction in 108 SSs. Immunohistochemically, NY-ESO-1, PRAME, MAGEA4, and MAGEA1 were positive in 66 (61%), 93 (86%), 89 (82%), and 16 (15%) of 108 SSs, respectively, and 104 (96%) of 108 SSs showed the immunohistochemical expression of at least 1 of NY-ESO-1, PRAME, and MAGEA4. Moreover, the high expression of at least 1 of these 3 antigens was observed in 83% of the SSs. High expression of NY-ESO-1 and MAGEA4 was significantly correlated with the presence of necrosis and advanced clinical stage. The immunohistochemical expression of these cancer-testis antigens was not correlated with prognosis, but the coexpression of NY-ESO-1, PRAME, and MAGEA4 was significantly associated with adverse prognosis. The real-time polymerase chain reaction results were closely related to the immunohistochemical results: NY-ESO-1 (P = .0019), PRAME (P = .039), MAGEA4 (P = .0149), and MAGEA1 (P = .0766). These data support the potential utility of NY-ESO-1, PRAME, and MAGEA4 as immunotherapy targets and ancillary prognostic parameters, suggesting the possible benefit of the combined use of these cancer-testis antigens as an SS immunotherapy target. PMID- 27993577 TI - Estrogen receptor alpha (ERalpha) status evaluation using RNAscope in situ hybridization: a reliable and complementary method for IHC in breast cancer tissues. AB - Estrogen receptor alpha (ERalpha) plays a significant role in the development of breast cancer and has been used clinically as an endocrine therapeutic target. Currently, clinical laboratories use immunohistochemistry (IHC) to determine the ERalpha status of patients in order to distinguish those who would benefit from endocrine therapy. This method is highly subjective, requires a large amount of tumor tissue, and may generate false-negative results. To improve the detection of ERalpha, we used a new RNA in situ hybridization technique (RNAscope) and compared its use with IHC in 72 breast cancer tissues (47 ERalpha positive and 25 ERalpha negative). Then we evaluated ERalpha mRNA by RT-qPCR with RNAscope. An unobvious difference was found between reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and IHC, but a positive correlation was found between RNAscope and IHC. In addition, breast cancer is a highly heterogeneous cancer, and RNAscope could easily reveal the heterogeneity in breast cancer. Moreover, we found that some ERalpha IHC-based negative and RNAscope-based positive test results were detected as positive after testing with IHC again. Our findings suggest that RNAscope may be a complementary method for improving the detection of patient ERalpha status and has potential clinical utility. PMID- 27993578 TI - "Sarcomatoid" carcinomas of the lung: a clinicopathological study of 86 cases with a new perspective on tumor classification. AB - Pulmonary sarcomatoid carcinoma includes a heterogenous group of tumors difficult to diagnose and treat. We report the clinicopathological features of 86 such tumors, including 74 pleomorphic and 12 spindle cell carcinomas, and propose a novel approach to the classification of these neoplasms in an attempt to better guide patient management. The patients were 47 men and 39 women aged 36 to 87 years (mean, 63 years) who primarily presented with shortness of breath, cough, and chest pain. Eighty-six percent of patients had a smoking history. Histologically, the pleomorphic carcinomas consisted of spindle and/or giant cells with varying proportions of conventional non-small cell carcinoma in the form of adenocarcinoma (n=29), squamous cell carcinoma (n=10), or large cell carcinoma (n=18); 17 cases contained a mix of spindle and giant cells only. The 12 spindle cell carcinomas consisted of spindle cells only. Based on the combined histopathologic and immunohistochemical features of these tumors, we were able to reanalyze the spectrum of these lesions and reclassify them accordingly. Statistical analysis revealed an overall survival at 3, 5, and 10 years of 42.9%, 34.6%, and 23.5%, respectively, and a median survival of 15 months. Log-rank test showed that in multivariate analysis, only pathological T stage was a factor associated with prognosis. The current classification of pulmonary sarcomatoid carcinomas precludes optimal triaging of these tumors with the risk of denying patients access to novel treatment. Our proposal for a reclassification of these tumors would more accurately guide patient management and facilitate targeted therapies. PMID- 27993579 TI - Does the gross prosector impact pT3 subclassification or lymph node counts in bladder cancer? AB - Gross prosector analysis of perivesicular adipose tumor invasion is the sole differentiator between pT3 substages, and gross evaluation is critical to lymph node identification. Gross prosector impact on pT3 subclassification and lymph node counts in cystectomy specimens resected for bladder cancer has not been previously analyzed. Both pT3 subclassification and total number of lymph nodes removed at radical cystectomy for bladder cancer are considered important components of the pathology report; however, both have controversial prognostic significance. Our objective was to assess the impact of the gross prosector on pT3 substaging and lymph node count. Pathology reports from 560 cystectomy cases performed for primary bladder cancer were reviewed. Educational interventions regarding cystectomy gross prosector documentation were conducted. Gross prosectors did not document the presence or absence of macroscopic perivesicular adipose invasion in 17% of cases. There was a decrease in the frequency of cases lacking documentation after educational intervention (33% to 5%, P<.01). Most pT3 cases lacking documentation were classified as pT3a (75%). The percentage of pT3 cases classified as pT3a decreased after intervention (68% to 35%, P<.01). Overcounting of lymph nodes by gross prosectors was more common than undercounting (22% versus 2%). Pathology residents and prosectors with lower caseloads had more uncounted lymph packets (P<.01). In conclusion, we demonstrated an impact of the gross prosector on pT3 substaging and lymph node counts within bladder cancer resection specimens. This novel variable may confound the relationship of these parameters upon oncologic outcomes and should be incorporated into quality assurance programs. PMID- 27993580 TI - High expression of heat shock protein 10 correlates negatively with estrogen/progesterone receptor status and predicts poor prognosis in invasive ductal breast carcinoma. AB - Heat shock proteins (HSPs) usually are associated with stress response and tolerance. HSP10 is a co-chaperone for HSP60, which is involved in the mitochondrial protein-folding machinery. To the best of our knowledge, the expression of HSP10 in invasive ductal breast carcinoma (IDBC) has never been reported. In the present study, HSP10 expression in 242 cases of IDBC and 46 cases of noncancerous breast tissues was detected by immunohistochemistry staining. High expression was significantly more common in IDBC than in noncancerous breast tissues (P<.001). Also, high expression was significantly more common in poorly differentiated than in well- and moderately differentiated IDBC (P=.023). Furthermore, high expression correlated negatively with estrogen receptor and progesterone receptor expression (P=.031 and P=.042, respectively). The most interesting result of the study was that high expression of HSP10 was significantly associated with shorter overall survival by both univariate and multivariate analyses (P=.013 and P=.036, respectively). In conclusion, we report for the first time that high expression of HSP10 is negatively associated with estrogen receptor/progesterone receptor status and might be a novel independent biomarker for poor prognosis in IDBC. PMID- 27993581 TI - The effect of limited (tertiary) Gleason pattern 5 on the new prostate cancer grade groups. AB - The risk of recurrence for prostatic adenocarcinoma after prostatectomy, as detected by prostate-specific antigen or other modalities, is based primarily on Gleason score along with pathologic tumor stage and surgical margin status. Recent large multi-institutional data spanning the last decade have supported modification of risk of recurrence stratification based on grade groups: grade group 1 (3+3=6), grade group 2 (3+4=7), grade group 3 (4+3=7), grade group 4 (4+4=8), and grade group 5 (Gleason scores 9 and 10). Using currently accepted grading definitions of grade patterns and grading rules, this study examines how the introduction of a limited, less than 5%, Gleason pattern 5 component at prostatectomy affects prognosis and fits into the grade group schema and reporting. The aggregate data from 2 independent major academic medical centers comprising 7606 patient records were analyzed with respect to biochemical recurrence-free survival. The presence of a limited (tertiary) Gleason pattern 5 component in the context of Gleason scores 3+4=7 (grade group 2) and 4+3=7 (grade group 3) imparts an intermediate prognosis relative to the next highest grade group. As such, we suggest that an additional comment and designation to the grade groups be provided reflecting the increased risk of recurrence in such cases (such as grade group 2+ or 3+). In contrast, the presence of limited (<5%) Gleason pattern 5 in the context of Gleason score 4+4=8 imparts a poor prognosis equivalent to grade group 5 and therefore should be reported as grade group 5. PMID- 27993583 TI - Depression in Individuals With Traumatic and Nontraumatic Spinal Cord Injury Living in the Community. AB - OBJECTIVE: To assess depression in a sample of individuals with spinal cord injury (SCI) living in the community, and to determine the prevalence of probable major depressive disorder (PMDD) among those with traumatic spinal cord injury (T SCI) and those with nontraumatic spinal cord injury (NT-SCI). DESIGN: Cross sectional. SETTING: Data were collected on individuals with SCI now living in the community, who completed a comprehensive follow-up assessment at the hospital. PARTICIPANTS: Individuals with T-SCI or NT-SCI (N=831) completed the Patient Health Questionnaire-9 (PHQ-9) and were included. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The PHQ-9 was used to detect the presence of PMDD and to measure the severity of the depression. RESULTS: The most frequent etiology of SCI was T-SCI (66.9%). Overall, 16.2% of participants met the criteria for PMDD; however, a higher prevalence was noted for individuals with NT-SCI (21.1%) than for individuals with T-SCI (13.8%). Risk factors between T-SCI and NT-SCI did not differ greatly. Female sex, chronic pain, and lower levels of/difficulties in participation were associated with the presence of PMDD. CONCLUSIONS: PMDD appears to occur at a higher rate in individuals with NT-SCI, with greater symptom severity. The finding that problems with participation are directly associated with depression raises the need for specific treatment goals, with the aim of empowering individuals with SCI to reintegrate into the community. Potential stress factors (eg, environmental barriers, limited participation options) should be addressed accordingly. PMID- 27993582 TI - Association Between Orthostatic Hypotension and Handgrip Strength With Successful Rehabilitation in Elderly Hip Fracture Patients. AB - OBJECTIVE: To investigate the relationship between orthostatic hypotension (OH) and muscle strength versus time to successful rehabilitation within elderly patients with hip fracture. DESIGN: A prospective, observational cohort study. Handgrip strength was measured at the day of admission and OH as soon as possible after surgery. Cox proportional hazard modeling was used to investigate the relationship between OH or handgrip strength (kg) and time to successful rehabilitation, expressed as hazard ratios (HRs). OH was defined as a decrease in systolic blood pressure of >=20mmHg or diastolic blood pressure of >=10mmHg after postural change (dichotomous). Handgrip strength was measured with a hand dynamometer (continuous). SETTING: General hospital. PARTICIPANTS: Patients (N=116) aged >=70 years with a hip fracture were recruited on the day of hospital admission. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Primary outcome was time to successful rehabilitation, which was defined as discharge to patients' own homes. RESULTS: During a median follow-up period of 36 days (interquartile range, 9-57d), 103 patients (89%) were successfully rehabilitated. No statistically significant relationships were found between OH and time to successful rehabilitation (HR=1.05; 95% confidence interval [CI], .67-1.66). Also, handgrip strength and successful rehabilitation were not statistically significantly related (HR=1.03; 95% CI, .99-1.06). CONCLUSIONS: OH measured during the first days of hospitalization is not related to time to successful rehabilitation in patients with hip fracture who have undergone surgery. Although no significant relationship was seen in the present study, the width of the CIs does not exclude a relevant relationship between handgrip strength and time to successful rehabilitation. PMID- 27993584 TI - Functional Independence: A Comparison of the Changes During Neurorehabilitation Between Patients With Nontraumatic Subarachnoid Hemorrhage and Patients With Intracerebral Hemorrhage or Acute Ischemic Stroke. AB - OBJECTIVE: To compare the changes in functional independence measured by the FIM after specialized neurorehabilitation between patients with nontraumatic subarachnoid hemorrhage (SAH) and patients with intracerebral hemorrhage (ICH) or acute ischemic stroke (AIS). DESIGN: Historical cohort study comparing changes in functional independence between patients with nontraumatic SAH and those with ICH/AIS, using FIM scores from a local database and clinical information from the Danish National Patient Registry. SETTING: Postacute specialized inpatient neurorehabilitation. PARTICIPANTS: Participants (N=660) comprised patients with a first-time nontraumatic SAH (n=212) and age-matched patients with a first-time ICH/AIS (n=448). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Crude and adjusted comparisons of FIM (total and item by item) measured at baseline and at discharge. RESULTS: Patients with nontraumatic SAH were admitted with a lower functional level compared with patients with ICH/AIS (median total FIM score, 25 [interquartile range (IQR), 18-81] vs 78.5 [IQR, 47-107]), and discharged with a lower functional level (median total FIM score, 98 [IQR, 40-116] vs 110 [IQR, 82.5-119]), although they made more progress during neurorehabilitation (median change in total FIM score, 27 [IQR, 4-60] vs 17 [IQR, 7-35]). Statistically, patients with nontraumatic SAH had significantly better odds for obtaining functional independence than did patients with ICH/AIS in 6 of the 18 FIM items: eating (odds ratio [OR]=3.2; 95% confidence interval [CI], 1.7-5.8); dressing upper body (OR=2.0; 95% CI, 1.1-3.5); transfer tub/shower (OR=2.0; 95% CI, 1.1 3.6); stair walking (OR=2.2; 95% CI, 1.3-3.7); comprehension (OR=2.3; 95% CI, 1.3 3.9); and expression (OR=3.6; 95% CI, 2.0-6.5). CONCLUSIONS: Patients with nontraumatic SAH made significantly more progress during neurorehabilitation, although they were discharged with a lower level of functional independence compared with patients with ICH/AIS. However, both patients with nontraumatic SAH and those with ICH/AIS improved their functional outcome significantly. Also, patients with nontraumatic SAH admitted with severe functional outcome were shown to be capable of recovering to a moderate level of functional independence. PMID- 27993585 TI - Resilience and Function in Adults With Physical Disabilities: An Observational Study. AB - OBJECTIVES: To determine if resilience is uniquely associated with functional outcomes (satisfaction with social roles, physical functioning, and quality of life) in individuals with physical disabilities, after controlling for measures of psychological health (depression and anxiety) and symptom severity (pain, fatigue, and sleep disturbance); and to examine the potential moderating effect of sex, age, and diagnosis on the hypothesized associations between resilience and function. DESIGN: Cross-sectional survey study. SETTING: Surveys were mailed (81% response rate) to a community sample of 1949 individuals with multiple sclerosis, muscular dystrophy, postpoliomyelitis syndrome, or spinal cord injury. Participants were recruited through the Internet or print advertisement (28%), a registry of previous research participants who indicated interest in future studies (21%), a departmental registry of individuals interested in research (19%), disability-specific registries (18%), word of mouth (10%), or other sources (3%). PARTICIPANTS: Convenience sample of community-dwelling adults aging with physical disabilities (N=1574), with a mean Connor-Davidson Resilience Scale (10 items) score of 29. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient-Reported Outcomes Measurement Information System measures of Satisfaction with Social Roles and Activities and Physical Functioning, the World Health Organization's brief Older People's Quality of Life Questionnaire, and the Connor Davidson Resilience Scale (10 items). RESULTS: After controlling for age, age squared, sex, diagnosis, psychological health, and symptom severity, resilience was significantly and positively associated with satisfaction with social roles (beta=.17, P<.001) and quality of life (beta=.39, P<.001), but not physical function (beta=.04, P>.05). For every 1-point increase in scores of resilience, there was an increase of .50 in the quality of life score and .20 in the satisfaction with social roles score. Sex also moderated the association between resilience and satisfaction with social roles (F1,1453=4.09, P=.043). CONCLUSIONS: The findings extend past research, providing further evidence indicating that resilience plays a unique role in nonphysical functional outcomes among individuals with physical disabilities. PMID- 27993586 TI - Imposed Faster and Slower Walking Speeds Influence Gait Stability Differently in Parkinson Fallers. AB - OBJECTIVE: To evaluate the effect of imposed faster and slower walking speeds on postural stability in people with Parkinson disease (PD). DESIGN: Cross-sectional cohort study. SETTING: General community. PARTICIPANTS: Patients with PD (n=84; 51 with a falls history; 33 without) and age-matched controls (n=82) were invited to participate via neurology clinics and preexisting databases. Of those contacted, 99 did not respond (PD=36; controls=63) and 27 were not interested (PD=18; controls=9). After screening, a further 10 patients were excluded; 5 had deep brain stimulation surgery and 5 could not accommodate to the treadmill. The remaining patients (N=30) completed all assessments and were subdivided into PD fallers (n=10), PD nonfallers (n=10), and age-matched controls (n=10) based on falls history. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Three dimensional accelerometers assessed head and trunk accelerations and allowed calculation of harmonic ratios and root mean square (RMS) accelerations to assess segment control and movement amplitude. RESULTS: Symptom severity, balance confidence, and medical history were established before participants walked on a treadmill at 70%, 100%, and 130% of their preferred speed. Head and trunk control was lower for PD fallers than PD nonfallers and older adults. Significant interactions indicated head and trunk control increased with speed for PD nonfallers and older adults, but did not improve at faster speeds for PD fallers. Vertical head and trunk accelerations increased with walking speed for PD nonfallers and older adults, while the PD fallers demonstrated greater anteroposterior RMS accelerations compared with both other groups. CONCLUSIONS: The results suggest that improved gait dynamics do not necessarily represent improved walking stability, and this must be respected when rehabilitating gait in patients with PD. PMID- 27993587 TI - Percutaneous Needle Tenotomy for the Treatment of Muscle and Tendon Contractures in Adults With Brain Damage: Results and Complications. AB - OBJECTIVE: To study the results and complications of percutaneous needle tenotomy for superficial retracted tendons in patients with brain damage. DESIGN: Prospective observational study. SETTING: University hospital. PARTICIPANTS: Patients with severe brain damage (N=38; mean age, 60.7y; age range, 24-93y; 21 women) requiring surgical management of contractures and eligible for percutaneous needle tenotomy were enrolled between February 2015 and February 2016. INTERVENTIONS: The percutaneous needle tenotomy gesture was performed by a physical medicine and rehabilitation physician trained by an orthopedic surgeon, under local or locoregional anesthesia. Treated tendons varied among patients. MAIN OUTCOME MEASURES: All patients were evaluated at 1, 3, and 6 months to assess surgical outcomes (joint range of motion [ROM], pain, and functional improvement) while screening for complications. RESULTS: Improvements in ROM (37/38) and contractures-related pain (12/12) were satisfactory. Functional results were satisfactory (Goal Attainment Scale score >=0) for most patients (37/38): nursing (n=12), putting shoes on (n=8), getting in bed or sitting on a chair (n=6), verticalization (n=7), transfers and gait (n=8), and grip (n=2). Five patients had complications related to the surgical gesture: cast-related complications (n=2), hand hematoma (n=2), and cutaneous necrosis of the Achilles tendon in a patient with previous obliterative arteriopathy of the lower limbs (n=1). CONCLUSIONS: Percutaneous needle tenotomy yields good results in the management of selected superficial muscle and tendon contractures. The complications rate is very low, and this treatment can be an alternative to conventional surgery in frail patients with neurologic diseases. PMID- 27993588 TI - Effect of a Single Administration of Focused Extracorporeal Shock Wave in the Relief of Delayed-Onset Muscle Soreness: Results of a Partially Blinded Randomized Controlled Trial. AB - OBJECTIVE: To examine the effects of a single administration of focused extracorporeal shock wave therapy on eccentric exercise-induced delayed-onset muscle soreness (DOMS). DESIGN: Three-arm randomized controlled study. SETTING: University research center. PARTICIPANTS: Participants (N=46; 23 women) had a mean age of 29.0+/-3.0 years and a mean body mass index of 23.8+/-2.8kg/m2. INTERVENTIONS: Participants were randomly allocated to verum- (energy flux density, .06-.09mJ/mm2; pulse ratio per point, 200) or sham-focused extracorporeal shock wave therapy (no energy) at 7 equidistant points along the biceps muscle or no intervention. MAIN OUTCOME MEASURES: The primary outcome was the difference in pain intensity. Secondary outcomes included maximum isometric voluntary force (MIVF), pressure pain threshold (PPT), and impairment in daily life. RESULTS: Despite descriptive clinically meaningful differences, mixed effects analysis (group * time) of changes to baseline did not reveal significant differences in the reduction of pain intensity between groups (F2,42=2.5, P=.094). MIVF was not significantly different between groups (F2,43=1.9, P=.159). PTT (F2,43=0.2, P=.854) and daily life impairment (F2,42=1.4, P=.248) were not significantly decreased over time, and there were no differences between groups in the post hoc analysis. CONCLUSIONS: DOMS is a common symptom in people participating in exercise, sports, or recreational physical activities. A single treatment with focused extracorporeal shock wave therapy causes clinically relevant effects in the relief of pain, increase in force, and improvement of pain-associated impairments of daily living. Still, results need to be cautiously interpreted because of the pilot character of this study. Focused extracorporeal shock wave therapy might present an option in the midterm recovery from DOMS (72h) and be an approach to enhance the return to play in athletes. PMID- 27993589 TI - Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: A Randomized Trial. AB - PURPOSE: To assess adherence to treatment with fixed-combination travoprost 0.004%/timolol 0.5% (TTFC) compared with separate containers of travoprost 0.004% and timolol 0.5% (TRAV+TIM; unfixed) using electronic dosing aids. DESIGN: Randomized, controlled, observer-masked clinical trial. METHODS: setting: Two US clinical sites. PATIENT POPULATION: Eligible patients were adults diagnosed with open-angle glaucoma or ocular hypertension. Patients (n = 81) were sequentially randomized 1:1 to receive TTFC or TRAV+TIM for 12 months. INTERVENTION: TTFC was administered once daily in the morning or evening with a single dosing aid. Patients randomized to TRAV+TIM administered TRAV once daily in the evening and TIM once daily in the morning using separate dosing aids. MAIN OUTCOME MEASURE: Adherence with administered medication, as recorded by the dosing aids. RESULTS: Mean +/- SD patient age was 60 +/- 10 years; most patients were male and white. Compared with TRAV+TIM (n = 40), patients receiving TTFC (n = 41) were consistently adherent on a greater percentage of days through month 12 (60% vs 43%). At months 1, 3, 6, and 12, 80% adherence was achieved by 71% vs 38%, 53% vs 30%, 45% vs 16%, and 32% vs 11% of patients receiving TTFC vs TRAV+TIM, respectively. Significantly more patients were adherent on >=80% of days with TTFC compared with TRAV+TIM (P < .001 to P = .041). Both treatments reduced IOP from baseline, and no safety issues were identified in either group. Ocular hyperemia was the most common treatment-related adverse event (n = 3/group). CONCLUSIONS: Patients receiving TTFC maintained better treatment adherence compared with patients receiving TRAV+TIM through 12 months of on-therapy evaluation. This suggests that, for patients requiring multiple IOP-lowering medications, a fixed combination may provide improved long-term adherence compared with unfixed therapy. PMID- 27993590 TI - Prevalence of Antiretinal Antibodies in Acute Zonal Occult Outer Retinopathy: A Comprehensive Review of 25 Cases. AB - PURPOSE: To perform a comprehensive review and to investigate the presence and role of autoimmune antibodies in 25 cases of acute zonal occult outer retinopathy (AZOOR) identified using the classification originally proposed by J. Donald Gass. DESIGN: Observational case series. METHODS: Setting: Institutional. STUDY POPULATION: Twenty-five patients were identified by characteristic symptoms (abrupt onset of photopsias, followed by large scotomata at or connected to the blind spot), ocular findings (paucity of pigmentary changes with no sign of vitreous inflammation and abnormal electroretinogram in at least 1 eye), and a negative family history for retinitis pigmentosa. OBSERVATION PROCEDURES: Patients underwent a full comprehensive ophthalmologic examination, fundus retinography, Goldmann kinetic visual field (GVF), and full-field electroretinogram (ffERG). Blood samples were also obtained to verify for the presence of antiretinal antibodies by Western blot analysis. MainOutcome Measures: Clinical presentation, best-corrected visual acuity (BCVA), fundus abnormalities, visual field defects, ffERG changes, and presence of antiretinal antibodies. RESULTS: Sixteen patients (64%) presented with photopsias, 56% (14/25) with night blindness, and 56% (14/25) with loss of peripheral vision. Sixty-four percent (16/25) of cases were bilateral. All patients demonstrated retinal vascular attenuation, optic nerve head pallor, and mottling of retinal pigment epithelium. The most common visual field changes included enlargement and expansion of the blind spot extending into large pericentral or other types of scotomata (64%). Both scotopic and photopic ffERG values were abnormal and affected to a similar degree in our patients. Nine patients (36%) had a greater than 20% asymmetry in ERG values between the 2 eyes. All patients had antiretinal antibodies on Western blot with an average of 6.6 bands. CONCLUSION: Evidence suggests that AZOOR is a unique form of autoimmune retinopathy and retinal manifestation suggests possible antiretinal antibody leakage from the disc margin with spread of immune products under the retina, resulting in large scotomata that connect to the optic nerve head. PMID- 27993591 TI - Histopathologic Characterization of the Expression of Vascular Endothelial Growth Factor in a Case of Retinopathy of Prematurity Treated With Ranibizumab. AB - PURPOSE: To characterize the expression of vascular endothelial growth factor (VEGF) in a patient with retinopathy of prematurity (ROP) treated with ranibizumab (Case 1) and compare it with a case of ROP without treatment (Case 2), a case of a premature baby without ROP (Case 3), and a case of a baby without history of ROP or prematurity (Case 4). DESIGN: Observational case series. METHODS: The eyes of the deceased babies were removed postmortem and were sent to the Florida Lions Ocular Pathology Laboratory, where they were processed. The specimens were immunostained using an antibody against VEGF. RESULTS: All eyes except for the eyes in Case 4 disclosed positive VEGF staining. Positive staining was present within the nerve fiber layer, inner plexiform layer, and inner and outer nuclear layers and within the spindle-shaped cell population in the vanguard in Case 1. In the posterior pole, positive staining was only observed at the level of the nerve fiber layer. This case also demonstrated less positive staining when compared with Case 2, where positive staining was found within all layers of the retina. CONCLUSION: Less VEGF staining was observed within the retina of the eyes treated with ranibizumab when compared with the VEGF staining in Case 2. This supports the idea that anti-VEGF agents are effective in reducing the amount of VEGF present in the retina. Furthermore, the fact that some expression of VEGF remains in the immature retina after injection supports the idea that anti-VEGF agents can suppress uncontrolled neovascularization without completely blocking the vascular drive for the vascularization of the immature retina. PMID- 27993592 TI - Insights Into Epiretinal Membranes: Presence of Ectopic Inner Foveal Layers and a New Optical Coherence Tomography Staging Scheme. AB - PURPOSE: To describe the presence of continuous ectopic inner foveal layers associated with epiretinal membranes (ERMs) and to present a new optical coherence tomography (OCT) staging system of ERMs. DESIGN: Retrospective multicenter observational case series. METHODS: Clinical charts and spectral domain OCT images of 194 eyes of 172 consecutive patients diagnosed with ERMs were reviewed and analyzed. RESULTS: The presence of continuous ectopic inner foveal layers was identified in 63 out of 194 eyes (32.5%) and this morphology was significantly associated with lower visual acuity. ERMs were divided into 4 stages. Stage 1 (43 out of 194 eyes, 22.1%) ERMs were mild and thin and a foveal depression was present. Stage 2 (88 out of 194 eyes, 45.4%) ERMs were associated with widening of the outer nuclear layer and loss of the foveal depression. Stage 3 (51 out of 194 eyes, 26.3%) ERMs were associated with continuous ectopic inner foveal layers crossing the entire foveal area. In stages 1, 2, and 3 all retinal layers were clearly defined on OCT. Stage 4 ERMs (12 out of 194 eyes, 6.2%) were thick and associated with continuous ectopic inner foveal layers. In addition, retinal layers were disrupted. Visual acuity progressively declined from stage 1 through stage 4 (P < .001). CONCLUSIONS: The presence of continuous ectopic inner foveal layers in ERMs is a newly described OCT finding associated with significant vision loss and is an essential element of a novel OCT-based grading scheme of ERMs that may influence visual prognosis. PMID- 27993593 TI - Repeatability and Agreement of Orbscan II, Pentacam HR, and Galilei Tomography Systems in Corneas With Keratoconus. AB - PURPOSE: To assess the repeatability and agreement of keratometry and pachymetry measurements obtained using 3 tomographers in eyes with keratoconus. DESIGN: Reliability analysis. METHODS: setting: Institutional. STUDY POPULATION: Fifty eyes of 50 participants with keratoconus. observational procedure: Steep keratometry, flat keratometry, central corneal thickness (CCT), and thinnest corneal thickness (TCT) measurements using Galilei, Orbscan II, and Pentacam HR. MAIN OUTCOME MEASURES: Repeatability was assessed using within-subject standard deviation (SW), coefficient of variation (CV), and intraclass correlation coefficient (ICC). Bland-Altman plots and 95% limits of agreement (LoA) were used to evaluate agreement between device pairs. RESULTS: For all studied parameters, ICC was >0.97 with the least repeatable measurements obtained using Orbscan II. Mean steep keratometry values were similar while mean flat keratometry values were significantly different between all devices. The Galilei and Pentacam HR had the lowest 95% LoA for both CCT and TCT. There were no significant differences in mean CCT between Galilei and Pentacam HR. Mean Orbscan II CCT measurements were not significantly different overall but had wide 95% LoA with Pentacam HR (-47.95 to 58.09 MUm) and Galilei (-43.70 to 53.91 MUm). Mean Orbscan II CCT measurements were significantly lower when an acoustic factor of 0.92 was applied (-33.6 MUm vs Pentacam HR, P < .001; -33.6 MUm vs Galilei; P < .001). CONCLUSIONS: Keratometric and pachymetric measurements of keratoconic eyes obtained by Galilei, Orbscan II, and Pentacam were disparate. Measurements were less repeatable with Orbscan II compared with Pentacam HR and Galilei, although overall repeatability was high for all instruments. PMID- 27993594 TI - The Effectiveness of Community Health Workers for CVD Prevention in LMIC. AB - Community health workers (CHW) may be effective in tackling the burden of cardiovascular diseases in low- and middle-income countries (LMIC). This review examines whether CHWs can improve the identification and control of cardiovascular risk factors in LMIC. We searched for studies that used CHW as a basis for cardiovascular risk factor management. Our search yielded 11 articles that targeted cardiovascular risk factor assessment, hypertension, diabetes, smoking, diet and physical activity. There were 4 randomized controlled trials, 3 quasi-experimental studies, 3 cross-sectional studies, and 1 retrospective analysis. Eight studies reported positive results with CHW being able to effectively screen for cardiovascular risk factors, decrease systolic blood pressure, decrease fasting blood glucose, increase quit rates of smoking, decrease weight, and improve diet and physical activity. Our review demonstrates that CHW may be effective in helping tackle the burden of cardiovascular disease in LMIC. PMID- 27993595 TI - Bone fracture nonunion rate decreases with increasing age: Bias in the prediction model. PMID- 27993596 TI - Molecular detection assay of five Salmonella serotypes of public interest: Typhimurium, Enteritidis, Newport, Heidelberg, and Hadar. AB - Foodborne illnesses due to Salmonella represent an important public-health concern worldwide. In the United States, a majority of Salmonella infections are associated with a small number of serotypes. Furthermore, some serotypes that are overrepresented among human disease are also associated with multi-drug resistance phenotypes. Rapid detection of serotypes of public-health concern might help reduce the burden of salmonellosis cases and limit exposure to multi drug resistant Salmonella. We developed a two-step real-time PCR-based rapid method for the identification and detection of five Salmonella serotypes that are either overrepresented in human disease or frequently associated with multi-drug resistance, including serotypes Enteritidis, Typhimurium, Newport, Hadar, and Heidelberg. Two sets of four markers were developed to detect and differentiate the five serotypes. The first set of markers was developed as a screening step to detect the five serotypes; whereas, the second set was used to further distinguish serotypes Heidelberg, Newport and Hadar. The utilization of these markers on a two-step investigation strategy provides a diagnostic specificity of 97% for the detection of Typhimurium, Enteritidis, Heidelberg, Infantis, Newport and Hadar. The diagnostic sensitivity of the detection makers is >96%. The availability of this two-step rapid method will facilitate specific detection of Salmonella serotypes that contribute to a significant proportion of human disease and carry antimicrobial resistance. PMID- 27993597 TI - A comparison of blood nitric oxide metabolites and hemoglobin functional properties among diving mammals. AB - The ability of marine mammals to hunt prey at depth is known to rely on enhanced oxygen stores and on selective distribution of blood flow, but the molecular mechanisms regulating blood flow and oxygen transport remain unresolved. To investigate the molecular mechanisms that may be important in regulating blood flow, we measured concentration of nitrite and S-nitrosothiols (SNO), two metabolites of the vasodilator nitric oxide (NO), in the blood of 5 species of marine mammals differing in their dive duration: bottlenose dolphin, South American sea lion, harbor seal, walrus and beluga whale. We also examined oxygen affinity, sensitivity to 2,3-diphosphoglycerate (DPG) and nitrite reductase activity of the hemoglobin (Hb) to search for possible adaptive variations in these functional properties. We found levels of plasma and red blood cells nitrite similar to those reported for terrestrial mammals, but unusually high concentrations of red blood cell SNO in bottlenose dolphin, walrus and beluga whale, suggesting enhanced SNO-dependent signaling in these species. Purified Hbs showed similar functional properties in terms of oxygen affinity and sensitivity to DPG, indicating that reported large variations in blood oxygen affinity among diving mammals likely derive from phenotypic variations in red blood cell DPG levels. The nitrite reductase activities of the Hbs were overall slightly higher than that of human Hb, with the Hb of beluga whale, capable of longest dives, having the highest activity. Taken together, these results underscore adaptive variations in circulatory NO metabolism in diving mammals but not in the oxygenation properties of the Hb. PMID- 27993599 TI - CD73 specific siRNA loaded chitosan lactate nanoparticles potentiate the antitumor effect of a dendritic cell vaccine in 4T1 breast cancer bearing mice. AB - The efficacy of conventional anti-tumor immunotherapeutic approaches is markedly affected by the immunosuppressive microenvironment of tumor. Since adenosine is one of the main orchestra leaders in immunosuppression symphony of tumor, targeting its producing molecules such as CD73 can help to achieve a better clinical outcome following conventional cancer immunotherapeutic approaches. In the present study, we evaluated the efficacy of CD73-specific siRNA-loaded chitosan-lactate nanoparticles (ChLa NPs) in combination with tumor lysate pulsed dendritic cells (DCs) vaccine in treatment of 4T1 (murine derived) breast cancer bearing mice. Our results showed that intravenous administration of CD73-specific siRNA-loaded NPs led to reduced expression of CD73 in tumor cells which was associated with decreased tumor growth and metastasis, and improved mice survival. Furthermore, we found that the mechanism by which combination therapy inhibits tumor growth is in part related to downregulation of regulatory T (Treg), myeloid derived suppressor cells (MDSCs), and tumor associated macrophages, an augmented CTL effector function, improved proliferation status of T cells, increased production of inflammatory cytokines interferon (IFN)-gamma and interleukin (IL)-17 and reduced levels of IL-10. Moreover, this treatment protocol attenuated the expression and activities of matrix metalloproteinases (MMPs) 2 and 9 which could be associated to the prevention of lung metastasis. In conclusion, our findings indicate that the use of CD73-specific siRNA-loaded NPs provides an immune potentiating function, thereby improves the efficacy of DC based cancer immunotherapy. PMID- 27993600 TI - Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E alpha-tocotrienol. AB - The therapeutic potential of tocotrienol, a member of the vitamin E family of compounds with potent in vitro anti-cancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study is to determine whether a novel tumor-targeted vesicular formulation of tocotrienol would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo. In this work, we demonstrated that novel transferrin-bearing multilamellar vesicles entrapping alpha-T3 resulted in a dramatically improved (by at least 52-fold) therapeutic efficacy in vitro on A431 cell line, compared to the free drug. In addition, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles resulted in tumor suppression for 30% of A431 and 60% of B16-F10 tumors, without visible toxicity. Mouse survival was enhanced by >13days compared to controls administered with the drug solution only. This tumor-targeted, tocotrienol-based nanomedicine therefore significantly improved the therapeutic response in cancer treatment. PMID- 27993601 TI - Mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity. AB - Mitochondria play an essential role in ageing and longevity. During ageing, a general deregulation of metabolism occurs, affecting molecular, cellular and physiological activities in the organism. Dysfunction of mitochondria has been associated with ageing and age-related diseases indicating their importance in the maintenance of cell homeostasis. Three major nutritional sensors, mTOR, AMPK and Sirtuins are involved in the control of mitochondrial physiology. These nutritional sensors control mitochondrial biogenesis, dynamics by regulating fusion and fission processes, and turnover through mito- and autophagy. Apart of the known factors involved in fusion, OPA1 and mitofusins, and fission, DRP1 and FIS1, emerging factors such as prohibitins and sestrins can play important functions in mitochondrial dynamics regulation. Mitochondria is also affected by sexual hormones that suffer drastic changes during ageing. The recent literature demonstrates the complex interaction between nutritional sensors and mitochondrial homeostasis in the physiology of adipose tissue and in the accumulation of fat in other organs such as muscle and liver. In this article, the role of mitochondrial homeostasis in ageing and age-dependent fat accumulation is revised. This review highlights the importance of mitochondria in the accumulation of fat during ageing and related diseases such as obesity, metabolic syndrome or type 2 diabetes mellitus. PMID- 27993598 TI - Role of neurotoxicants and traumatic brain injury in alpha-synuclein protein misfolding and aggregation. AB - Protein misfolding and aggregation are key pathological features of many neurodegenerative diseases including Parkinson's disease (PD) and other forms of human Parkinsonism. PD is a complex and multifaceted disorder whose etiology is not fully understood. However, several lines of evidence support the multiple hit hypothesis that genetic vulnerability and environmental toxicants converge to trigger PD pathology. Alpha-synuclein (alpha-Syn) aggregation in the brain is an important pathophysiological characteristic of synucleinopathies including PD. Epidemiological and experimental studies have shown that metals and pesticides play a crucial role in alpha-Syn aggregation leading to the onset of various neurodegenerative diseases including PD. In this review, we will emphasize key findings of several epidemiological as well as experimental studies of metal- and pesticide-induced alpha-Syn aggregation and neurodegeneration. We will also discuss other factors such as traumatic brain injury and oxidative insult in the context of alpha-Syn-related neurodegenerative processes. PMID- 27993602 TI - The neurological effects of ghrelin in brain diseases: Beyond metabolic functions. AB - Ghrelin, a peptide released by the stomach that plays a major role in regulating energy metabolism, has recently been shown to have effects on neurobiological behaviors. Ghrelin enhances neuronal survival by reducing apoptosis, alleviating inflammation and oxidative stress, and accordingly improving mitochondrial function. Ghrelin also stimulates the proliferation, differentiation and migration of neural stem/progenitor cells (NS/PCs). Additionally, the ghrelin is benefit for the recovery of memory, mood and cognitive dysfunction after stroke or traumatic brain injury. Because of its neuroprotective and neurogenic roles, ghrelin may be used as a therapeutic agent in the brain to combat neurodegenerative disease. In this review, we highlight the pre-clinical evidence and the proposed mechanisms underlying the role of ghrelin in physiological and pathological brain function. PMID- 27993603 TI - The neural diathesis-stress model of schizophrenia revisited: An update on recent findings considering illness stage and neurobiological and methodological complexities. AB - Over the past decade, our understanding of the role of stress in serious mental illness has become more sophisticated. In this paper, we revisit the neural diathesis-stress model of schizophrenia that was initially proposed in 1997 and updated in 2008. In light of cumulative research findings, we must now encompass evidence on the premorbid periods of psychosis, and our more nuanced understanding of hypothalamic-pituitary-adrenal (HPA) axis function and its association with neurodevelopmental, epigenetic, neurotransmitter, and inflammatory processes, as well as brain structure and function. Giving consideration to the methodological complexities that have become more apparent as research in this area has burgeoned, the various indices of HPA axis function, and the different stages of illness, we review relevant research published since the 2008 update of the model. We conclude by proposing an extended neural diathesis-stress model that addresses the broader neurobiological context of stress psychobiology in psychosis progression. Implications of this model for best practice, with regards to both future research and treatment strategies, are discussed. PMID- 27993604 TI - Rhythm in language acquisition. AB - Spoken language is governed by rhythm. Linguistic rhythm is hierarchical and the rhythmic hierarchy partially mimics the prosodic as well as the morpho-syntactic hierarchy of spoken language. It can thus provide learners with cues about the structure of the language they are acquiring. We identify three universal levels of linguistic rhythm - the segmental level, the level of the metrical feet and the phonological phrase level - and discuss why primary lexical stress is not rhythmic. We survey experimental evidence on rhythm perception in young infants and native speakers of various languages to determine the properties of linguistic rhythm that are present at birth, those that mature during the first year of life and those that are shaped by the linguistic environment of language learners. We conclude with a discussion of the major gaps in current knowledge on linguistic rhythm and highlight areas of interest for future research that are most likely to yield significant insights into the nature, the perception, and the usefulness of linguistic rhythm. PMID- 27993605 TI - A comparative neurological approach to emotional expressions in primate vocalizations. AB - Different approaches from different research domains have crystallized debate over primate emotional processing and vocalizations in recent decades. On one side, researchers disagree about whether emotional states or processes in animals truly compare to those in humans. On the other, a long-held assumption is that primate vocalizations are innate communicative signals over which nonhuman primates have limited control and a mirror of the emotional state of the individuals producing them, despite growing evidence of intentional production for some vocalizations. Our goal is to connect both sides of the discussion in deciphering how the emotional content of primate calls compares with emotional vocal signals in humans. We focus particularly on neural bases of primate emotions and vocalizations to identify cerebral structures underlying emotion, vocal production, and comprehension in primates, and discuss whether particular structures or neuronal networks solely evolved for specific functions in the human brain. Finally, we propose a model to classify emotional vocalizations in primates according to four dimensions (learning, control, emotional, meaning) to allow comparing calls across species. PMID- 27993606 TI - Classification of navigation impairment: A systematic review of neuropsychological case studies. AB - The neurocognitive architecture of navigation ability has been investigated by extensively studying the navigation problems of individual neurological patients. These neuropsychological case reports have applied highly variable approaches to establish navigation impairment in their patients. This review provides a systematic and up-to-date inventory of all relevant case studies and presents an analysis of the types of navigation impairments that have been described. The systematic literature search revealed 58 relevant papers reporting on 67 neurological patients. Close analysis of their patterns of navigation performance suggests three main categories of navigation impairments. These categories are related to three types of representations that are considered highly relevant for accurate navigation: knowledge of landmarks, locations, and paths. The resulting model is intended to serve both clinical and theoretical advances in the study of navigation ability and its neural correlates. PMID- 27993607 TI - A biological perspective on differences and similarities between burnout and depression. AB - To compare and contrast burnout and depression is not only a conceptual issue, but may deliver important directions for treatment approaches and stabilize the awareness of disease which is essential for affected individuals. Because of the symptomatic overlap, it is a subject of multidimensional research and discussion to find specific signatures to differentiate between the two phenomena or to present evidence that they are different aspects of the same disorder. Both pathologies are regarded as stress-related disorders. Therefore, in this review burnout and depression are discussed on the basis of biological parameters, mainly heart rate variability (HRV) and brain-derived neurotrophic factor (BDNF), which are crucial to the stress response system. It emerges that instead of finding one specific discriminating marker, future research should rather concentrate on elaborating indices for burnout and depression which integrate combinations of parameters found in genetics, neurobiology, physiology and environment. PMID- 27993608 TI - The Cardio-Renal Interrelationship. AB - The heart and the kidney are of utmost importance for the maintenance of cardiovascular (CV) homeostasis. In healthy subjects, hemodynamic changes in either organ may affect hemodynamics of the other organ. This interaction is fine tuned by neurohumoral activity, including atrial natriuretic peptides, renin angiotensin aldosterone system and sympathetic activity. Dysfunction or disease of one organ may initiate, accentuate, or precipitate dysfunction or disease state in the other organ, often leading to a vicious cycle. Further, the interaction between the heart and the kidney may occur in the setting of processes and diseases that may affect both organs simultaneously, such as advanced age, hypertension, diabetes mellitus, atherosclerosis, etc. In this regard, a stiff aorta that occurs with aging due to mechanical stress may independently initiate or precipitate dysfunction and disease in the heart and the kidney. All of these factors contribute to a high prevalence of coexistent CV and kidney disease, especially in the elderly. In advanced kidney disease, hemodynamic and neurohumoral homeostasis are lost, volume and pressure overload may coexist, and the elimination of certain pharmacologic agents may be substantially impaired. Thus, coexistence of CV and kidney disease complicates diagnosis, propagates pathophysiology, adversely affects prognosis, and hinders management. PMID- 27993609 TI - Chlorpyrifos induces endoplasmic reticulum stress in JEG-3 cells. AB - Chlorpyrifos (CPF) is an organophosphorous pesticide widely used in agricultural, industrial, and household applications. We have previously shown that JEG-3 cells are able to attenuate the oxidative stress induced by CPF through the adaptive activation of the Nrf2/ARE pathway. Considering that there is a relationship between oxidative stress and endoplasmic reticulum stress (ER), herein we investigated whether CPF also induces ER stress in JEG-3 cells. Cells were exposed to 50MUM or 100MUM CPF during 24h in conditions where cell viability was not altered. Western blot and PCR assays were used to explore the protein and mRNA levels of ER stress biomarkers, respectively. CPF induced an increase of the typical ER stress-related proteins, such as GRP78/BiP and IRE1alpha, a sensor for the unfolded protein response, as well as in phospho-eIF2alpha and XBP1 mRNA splicing. Additionally, CPF led to a decrease in p53 protein expression. The downregulation of p53 levels induced by CPF was partially blocked when cells were exposed to CPF in the presence of the proteasome inhibitor MG132. Altogether, these findings point out that CPF induces ER stress in JEG-3 cells; however these cells are able to attenuate it downregulating the levels of the pro-apoptotic protein p53. PMID- 27993612 TI - Associations among self-perceived work and life stress, trouble sleeping, physical activity, and body weight among Canadian adults. AB - We investigated the associations among self-perceived work and life stress, trouble sleeping, physical activity and body weight among Canadian adults, and tested whether trouble sleeping and physical activity moderated the relationship between work/life stress and body weight, and whether work/life stress and physical activity moderated the relationship between trouble sleeping and body weight. Data on 13,926 Canadian adults aged 20years and older were derived from the nationally representative 2012 Canadian Community Health Survey. After adjusting for age, sex, education level, household income, marital status and job insecurity, self-perceived work and life stress and trouble sleeping were associated with a higher BMI. The associations of work and life stress with higher BMI were independent of trouble sleeping and physical activity in addition to other covariates, while that of trouble sleeping and higher BMI was independent of work and life stress. Results further indicated that trouble sleeping among inactive participants was related to a higher BMI; however, this relationship was almost null for adults who self-reported being physically active for about 8h/week. These findings suggest that work and life stress are both associated with excess weight in adults, regardless of physical activity level, while the link of trouble sleeping with BMI varies by physical activity level. Future research is necessary to determine whether reducing work and life stress and improving sleep habits would benefit the prevention of weight gain and obesity. PMID- 27993610 TI - A KCNJ6 gene polymorphism modulates theta oscillations during reward processing. AB - Event related oscillations (EROs) are heritable measures of neurocognitive function that have served as useful phenotype in genetic research. A recent family genome-wide association study (GWAS) by the Collaborative Study on the Genetics of Alcoholism (COGA) found that theta EROs during visual target detection were associated at genome-wide levels with several single nucleotide polymorphisms (SNPs), including a synonymous SNP, rs702859, in the KCNJ6 gene that encodes GIRK2, a G-protein inward rectifying potassium channel that regulates excitability of neuronal networks. The present study examined the effect of the KCNJ6 SNP (rs702859), previously associated with theta ERO to targets in a visual oddball task, on theta EROs during reward processing in a monetary gambling task. The participants were 1601 adolescent and young adult offspring within the age-range of 17-25years (800 males and 801 females) from high-dense alcoholism families as well as control families of the COGA prospective study. Theta ERO power (3.5-7.5Hz, 200-500ms post-stimulus) was compared across genotype groups. ERO theta power at central and parietal regions increased as a function of the minor allele (A) dose in the genotype (AA>AG>GG) in both loss and gain conditions. These findings indicate that variations in the KCNJ6 SNP influence magnitude of theta oscillations at posterior loci during the evaluation of loss and gain, reflecting a genetic influence on neuronal circuits involved in reward-processing. Increased theta power as a function of minor allele dose suggests more efficient cognitive processing in those carrying the minor allele of the KCNJ6 SNPs. Future studies are needed to determine the implications of these genetic effects on posterior theta EROs as possible "protective" factors, or as indices of delays in brain maturation (i.e., lack of frontalization). PMID- 27993611 TI - Socio-emotionally significant experience and children's processing of irrelevant auditory stimuli. AB - Theory and research indicate considerable influence of socio-emotionally significant experiences on children's functioning and adaptation. In the current study, we examined neurophysiological correlates of children's allocation of information processing resources to socio-emotionally significant events, specifically, simulated marital interactions. We presented 9- to 11-year-old children (n=24; 11 females) with 15 videos of interactions between two actors posing as a married couple. Task-irrelevant brief auditory probes were presented during the videos, and event-related potentials (ERPs) elicited to the auditory probes were measured. As hypothesized, exposure to higher levels of interparental conflict was associated with smaller P1, P2, and N2 ERPs to the probes. This finding is consistent with the idea that children who had been exposed to more interparental conflict attended more to the videos and diverted fewer cognitive resources to processing the probes, thereby producing smaller ERPs to the probes. In addition, smaller N2s were associated with more child behavior problems, suggesting that allocating fewer processing resources to the probes was associated with more problem behavior. Results are discussed in terms of implications of socio-emotionally significant experiences for children's processing of interpersonal interactions. PMID- 27993613 TI - Do novel noninvasive ECG techniques improve patient selection for CRT? PMID- 27993614 TI - Performance of Celera RUO integrase resistance assay across multiple HIV-1 subtypes. AB - BACKGROUND: HIV-1 sequence variation is a major obstacle to developing molecular based assays for multiple subtypes. This study sought to independently assess performance characteristics of the ViroSeqTM HIV-1 Integrase RUO Genotyping Kit (Celera, US) for samples of multiple different HIV-1 subtypes. METHODS: 264 samples were tested in the validation, 106 from integrase inhibitor naive patients' sent for routine HIV-1 drug resistance testing after failing a 1st- or 2nd-line regimen, and 158 samples from an external virology quality assurance program (VQA). For the latter, 53 unique VQA samples were tested in two to five different laboratories to assess assay reproducibility. For all assays, viral RNA was extracted using the ViroSeq extraction module, reverse transcribed, and amplified in a one-step reaction. Four sequencing primers were used to span codons 1-288 of integrase. The Rega subtyping tool was used for subtype assignment. Integrase polymorphisms and mutations were determined as differences from the HXB2 sequence and by the Stanford database, respectively. Sequences obtained from the different laboratories were aligned and sequence homology determined. RESULTS: HIV-1 RNA in the 264 samples ranged from 3.15 to 6.74logcopies/ml. Successful amplification was obtained for 97% of samples (n=256). The 8 samples that failed to amplify were subtype D (n=3), subtype C (n=1), CRF01_AE (n=1), subtype A1 (n=2), and an unassigned subtype (n=1). Of the 256 that successfully amplified samples, 203 (79%) were successfully sequenced with bidirectional coverage. Of the 53 unsuccessful samples, 13 (5%) failed sequencing and 40 (16%) did not have full bidirectional sequence, as a result of failure of sequencing primers: Primer A (n=1); Primer B (n=18); Primer C (n=1); Primer D (n=7) or short sequences (n=16). For the 135 VQA samples (30 unique samples) that were assayed by different laboratories, homology of the sequences obtained ranged from 92.1% to 100%. However, Laboratory 2 detected more mixtures (74%) compared to the other four laboratories, whereas Laboratory 1 detected the least number of mixtures (35%), likely due to differences between the labs in the methods of sequence analysis. Mutations associated with integrase resistance were observed in seven of the 106 (7%) clinical samples [one sample: Q148K; E138K; G140A; two samples: T97A and four samples: L74I]. Of the four samples with L74I, 3 were subtype G. CONCLUSION: Of the total 264 samples tested, 243 (92%) of samples were able to be amplified and sequenced to generate an integrase genotype. Sequencing results were similar between the testing laboratories with the exception of mixture detection. Mutations associated with integrase inhibitor resistance were observed in only 7% of integrase inhibitor naive samples, and some of these mutations are likely to be due to subtype-specific polymorphisms rather than selection by an integrase inhibitor. PMID- 27993616 TI - Quantitative multi-target RNA profiling in Epstein-Barr virus infected tumor cells. AB - Epstein-Barr virus (EBV) is etiologically linked to multiple acute, chronic and malignant diseases. Detection of EBV-RNA transcripts in tissues or biofluids besides EBV-DNA can help in diagnosing EBV related syndromes. Sensitive EBV transcription profiling yields new insights on its pathogenic role and may be useful for monitoring virus targeted therapy. Here we describe a multi-gene quantitative RT-PCR profiling method that simultaneously detects a broad spectrum (n=16) of crucial latent and lytic EBV transcripts. These transcripts include (but are not restricted to), EBNA1, EBNA2, LMP1, LMP2, BARTs, EBER1, BARF1 and ZEBRA, Rta, BGLF4 (PK), BXLF1 (TK) and BFRF3 (VCAp18) all of which have been implicated in EBV-driven oncogenesis and viral replication. With this method we determine the amount of RNA copies per infected (tumor) cell in bulk populations of various origin. While we confirm the expected RNA profiles within classic EBV latency programs, this sensitive quantitative approach revealed the presence of rare cells undergoing lytic replication. Inducing lytic replication in EBV tumor cells supports apoptosis and is considered as therapeutic approach to treat EBV driven malignancies. This sensitive multi-primed quantitative RT-PCR approach can provide broader understanding of transcriptional activity in latent and lytic EBV infection and is suitable for monitoring virus-specific therapy responses in patients with EBV associated cancers. PMID- 27993615 TI - Translation of a laboratory-validated equine herpesvirus-1 specific real-time PCR assay into an insulated isothermal polymerase chain reaction (iiPCR) assay for point-of-need diagnosis using POCKITTM nucleic acid analyzer. AB - Equine herpesvirus myeloencephalopathy (EHM), a major problem for the equine industry in the United States, is caused by equine herpesvirus-1 (EHV-1). In addition, EHV-1 is associated with upper respiratory disease, abortion, and chorioretinal lesions in horses. Here we describe the development and evaluation of an inexpensive, user-friendly insulated isothermal PCR (iiPCR) method targeting open reading 30 (ORF30) to detect both neuropathogenic and non neuropathogenic strains on the field-deployable POCKITTM device for point-of-need detection of EHV-1. The analytical sensitivity of the EHV-1 iiPCR assay was 13 genome equivalents per reaction. The assay did not cross react with ten non target equine viral pathogens. Performance of the EHV-1 iiPCR assay was compared to two previously described real-time PCR (qPCR) assays in two laboratories by using 104 archived clinical samples. All 53 qPCR-positive and 46 of the 51 qPCR negative samples tested positive and negative, respectively, by the iiPCR. The agreement between the two assays was 95.19% (confidence interval 90.48-99.90%) with a kappa value of 0.90. In conclusion, the newly developed EHV-1 iiPCR assay is robust to provide specificity and sensitivity comparable to qPCR assays for the detection of EHV-1 nucleic acid in clinical specimens. PMID- 27993617 TI - Parahepatospora carcini n. gen., n. sp., a parasite of invasive Carcinus maenas with intermediate features of sporogony between the Enterocytozoon clade and other microsporidia. AB - Parahepatospora carcini n. gen. n. sp., is a novel microsporidian parasite discovered infecting the cytoplasm of epithelial cells of the hepatopancreas of a single Carcinus maenas specimen. The crab was sampled from within its invasive range in Atlantic Canada (Nova Scotia). Histopathology and transmission electron microscopy were used to show the development of the parasite within a simple interfacial membrane, culminating in the formation of unikaryotic spores with 5-6 turns of an isofilar polar filament. Formation of a multinucleate meront (>12 nuclei observed) preceded thickening and invagination of the plasmodial membrane, and in many cases, formation of spore extrusion precursors (polar filaments, anchoring disk) prior to complete separation of pre-sporoblasts from the sporogonial plasmodium. This developmental feature is intermediate between the Enterocytozoonidae (formation of spore extrusion precursors within the sporont plasmodium) and all other Microsporidia (formation of spore extrusion precursors after separation of sporont from the sporont plasmodium). SSU rRNA-based gene phylogenies place P. carcini within microsporidian Clade IV, between the Enterocytozoonidae and the so-called Enterocytospora-clade, which includes Enterocytospora artemiae and Globulispora mitoportans. Both of these groups contain gut-infecting microsporidians of aquatic invertebrates, fish and humans. According to morphological and phylogenetic characters, we propose that P. carcini occupies a basal position to the Enterocytozoonidae. We discuss the discovery of this parasite from a taxonomic perspective and consider its origins and presence within a high profile invasive host on the Atlantic Canadian coastline. PMID- 27993618 TI - The role of viruses in coral health and disease. AB - Metagenomic and electron microscopy studies confirm that the coral microbiome contains a rich diversity and abundance of viruses. While there have been no definitive tests of disease causation by viruses in corals, viruses have been implicated as coral pathogens in a number of studies. Growing evidence also indicates that latent viral infections can compromise the algal symbionts under environmental stress and may be involved in the coral bleaching response. Conversely, bacteriophages and archaeal phage viruses are abundant in the microbiome of healthy corals and are likely to be involved in complex ecological networks, genetic material transfer and selective co-evolution within the surface mucus layers and tissues. The relative importance of viral control of bacterial and archaeal populations is unknown, but they are almost certain to be exerting some level of control on the composition and maintenance of the coral microbiome. While rapid leaps in the capability to detect viruses have been made due to advances in metagenomics and bioinformatics, these approaches need now to be integrated with in vitro culture and challenge experiments to assess the functional roles of viruses in health and disease, and it is imperative that interactions with other members of the coral microbiome are taken into account when assessing disease causation. PMID- 27993619 TI - Pandora formicae, a specialist ant pathogenic fungus: New insights into biology and taxonomy. AB - Among fungi from the order Entomophthorales (Entomophthoromycota), there are many specialized, obligatory insect-killing pathogens. Pandora formicae (Humber & Balazy) Humber is a rare example of an entomophthoralean fungus adapted to exclusively infect social insects: wood ants from the genus Formica. There is limited information available on P. formicae; many important aspects of this host pathogen system remain hitherto unknown, and the taxonomical status of the fungus is unclear. Our study fills out some main gaps in the life history of P. formicae, such as seasonal prevalence and overwintering strategy. Field studies of infection prevalence show a disease peak in late summer and early autumn. Typical thick-walled entomophthoralean resting spores of P. formicae are documented and described for the first time. The proportion of cadavers with resting spores increased from late summer throughout autumn, suggesting that these spores are the main overwintering fungal structures. In addition, the phylogenetic status of Pandora formicae is outlined. Finally, we review the available taxonomical literature and conclude that the name P. formicae should be used rather than the name P. myrmecophaga for ant-infecting fungi displaying described morphological features. PMID- 27993620 TI - Characterization of putative virulence factors of Serratia marcescens strain SEN for pathogenesis in Spodoptera litura. AB - Two Serratia marcescens strains, SEN and ICC-4, isolated from diseased insect cadavers were observed to differ considerably in their virulence towards Spodoptera litura. The present study was aimed to characterize the possible virulence factors present in the virulent Serratia marcescens strain SEN. Both the S. marcescens strains were evaluated for the presence of various lytic enzymes such as chitinase, lipase, protease and phospholipase. The virulent S. marcescens strain SEN was observed to possess considerably higher activity of chitinase and protease enzymes; activity of phospholipase enzyme was also higher. Although, all the three toxin genes shlA, phlA and swr could be detected in both the S. marcescens strains, there was a higher expression of these genes in the virulent strain SEN. S. marcescens strain ICC-4 showed greater reduction in overall growth yield in the post-exponential phase in the presence of midgut juice and hemolymph of S. litura larvae, as compared to S. marcescens strain SEN. Proliferation of the S. marcescens strain SEN was also considerably higher in foregut, midgut and hemolymph of S. litura larvae, as compared to strain ICC-4. Peritrophic membrane treated with broth culture of the S. marcescens strain SEN showed higher damage as compared to strain ICC-4. The peritrophic membrane of larvae fed on diet treated with the virulent strain showed considerable damage while the peritrophic membrane of larvae fed on diet treated with the non virulent strain showed no damage. This is the first report documenting the fate of ingested S. marcescens in S. litura gut and the relative expression of toxin genes from two S. marcescens strains differing in their virulence towards S. litura. PMID- 27993621 TI - On the Need for Phase III Studies of Risk-Adapted Therapy in Multiple Myeloma. PMID- 27993622 TI - Genome-wide SNP Genotyping Resolves Signatures of Selection and Tetrasomic Recombination in Peanut. AB - Peanut (Arachis hypogaea; 2n = 4x = 40) is a nutritious food and a good source of vitamins, minerals, and healthy fats. Expansion of genetic and genomic resources for genetic enhancement of cultivated peanut has gained momentum from the sequenced genomes of the diploid ancestors of cultivated peanut. To facilitate high-throughput genotyping of Arachis species, 20 genotypes were re-sequenced and genome-wide single nucleotide polymorphisms (SNPs) were selected to develop a large-scale SNP genotyping array. For flexibility in genotyping applications, SNPs polymorphic between tetraploid and diploid species were included for use in cultivated and interspecific populations. A set of 384 accessions was used to test the array resulting in 54 564 markers that produced high-quality polymorphic clusters between diploid species, 47 116 polymorphic markers between cultivated and interspecific hybrids, and 15 897 polymorphic markers within A. hypogaea germplasm. An additional 1193 markers were identified that illuminated genomic regions exhibiting tetrasomic recombination. Furthermore, a set of elite cultivars that make up the pedigree of US runner germplasm were genotyped and used to identify genomic regions that have undergone positive selection. These observations provide key insights on the inclusion of new genetic diversity in cultivated peanut and will inform the development of high-resolution mapping populations. Due to its efficiency, scope, and flexibility, the newly developed SNP array will be very useful for further genetic and breeding applications in Arachis. PMID- 27993623 TI - Promises and pitfalls of Illumina sequencing for HIV resistance genotyping. AB - Genetic sequencing ("genotyping") plays a critical role in the modern clinical management of HIV infection. This virus evolves rapidly within patients because of its error-prone reverse transcriptase and short generation time. Consequently, HIV variants with mutations that confer resistance to one or more antiretroviral drugs can emerge during sub-optimal treatment. There are now multiple HIV drug resistance interpretation algorithms that take the region of the HIV genome encoding the major drug targets as inputs; expert use of these algorithms can significantly improve to clinical outcomes in HIV treatment. Next-generation sequencing has the potential to revolutionize HIV resistance genotyping by lowering the threshold that rare but clinically significant HIV variants can be detected reproducibly, and by conferring improved cost-effectiveness in high throughput scenarios. In this review, we discuss the relative merits and challenges of deploying the Illumina MiSeq instrument for clinical HIV genotyping. PMID- 27993625 TI - How Knowledge Relates to Confidence in Orthopedics and Emergency Medicine Regarding Return to Sport and Rehabilitation in Foot and Ankle Trauma. AB - OBJECTIVE: The aim of this study was to survey the knowledge of registrars in emergency medicine and orthopedics on 5 common injuries to the foot and ankle and compare this knowledge, and self-reported confidence in giving it, with that of consultants and physiotherapists of various levels of experience. DESIGN: An online survey was used to gather the information using scenario-based open and closed questions. PARTICIPANTS: A total of 102 health care professionals, who regularly deal with sports injuries, were recruited. These included consultant orthopedic surgeons with a subspecialty interest in foot and ankle surgery, orthopedic surgeons in other specialties, extended scope physiotherapy practitioners (ESPs) in foot and ankle and general musculoskeletal practice, emergency medicine consultants, emergency medicine registrars, orthopedic registrars, senior physiotherapists, and junior physiotherapists. SETTING: The participants were drawn from various health care institutions in the North East of England. RESULTS: Consultant foot and ankle surgeons and extended scope practitioners in foot and ankle both scored significantly on knowledge of rehabilitation program design than either set of registrars. For 2 of the case scenarios, there was a significant difference in scores between either orthopedic consultants or ESPs and registrars (p < 0.05). For total score, there was a trend for extended scope practitioners to score higher than both sets of registrars, but this did not reach significance. Correlation coefficients for knowledge and self-reported confidence ranged between 0.009 and 0.33, demonstrating only weak positive linear correlation between scenario score and reported confidence in advice given. CONCLUSIONS: The most significant area of gaps in knowledge among the 2 groups of registrars was in the specifics of rehabilitation programs. There was markedly higher confidence with greater seniority. Registrars in emergency medicine and orthopedics are likely to benefit from case-based teaching in sports injury rehabilitation. PMID- 27993626 TI - Influence of Social Media on the Dissemination of a Traditional Surgical Research Article. AB - OBJECTIVE: Many institutions use social media to share research with the general public. However, the influence of social media on the dissemination of a surgical research article itself is unknown. Our objective was to determine whether a blog post highlighting the findings of a surgical research article would lead to increased dissemination of the article itself. DESIGN: We prospectively followed the online page views of an article that was published online in Surgery in May 2015 and published in print in August 2015. The authors subsequently released a blog post in October 2015 to promote the research. The number of article page views from the journal's website was obtained before and after the blog post, along with the page views from the blog post itself. Social media influence data were collected, including social activity in the form of mentions on social media sites, scholarly activity in online libraries, and scholarly commentary. RESULTS: The article's online activity peaked in the first month after online publication (475 page views). Online activity plateaued by 4 months after publication, with 118 monthly page views, and a blog post was subsequently published. The blog post was viewed by 1566 readers, and readers spent a mean of 2.5 minutes on the page. When compared to the projected trend, the page views increased by 33% in the month after the blog post. The blog post resulted in a 9% increase in the social media influence score and a 5% absolute increase in total article page views. CONCLUSIONS: Social media is an important tool for sharing surgical research. Our data suggest that social media can increase distribution of an article's message and also potentially increase dissemination of the article itself. We believe that authors should consider using social media to increase the dissemination of traditionally published articles. PMID- 27993624 TI - Introducing a cleavable signal peptide enhances the packaging efficiency of lentiviral vectors pseudotyped with Japanese encephalitis virus envelope proteins. AB - Research into the properties of Japanese encephalitis virus (JEV) has been facilitated by use of pseudotyped viruses. The signal peptide is a key determinant for membrane targeting and membrane insertion, which could affect packaging of pseudotyped viruses. In this study, we generated three lentiviral vectors pseudotyped with JEV envelope proteins that co-express either a strong signal peptide from vesicular stomatitis virus (VSV)-G (VSVMEpv) or a weak signal peptide of JEV (SPMEpv), or a virus without a signal peptide in front of the JEV prM/E (MEpv). Western blot demonstrated that JEV E protein and HIV p24 were present in the same particles of the three pseudotyped JEV-E based lentiviral vectors. Electron microscopy revealed that the three pseudotyped JEV-E based lentiviral vectors were 120-180nm in diameter. Real-time quantitative reverse transcriptase polymerase chain reaction showed that the titer of VSVMEpv was 17 fold higher than that of MEpv, while the titer of SPMEpv was six-fold higher than that of MEpv. Inclusion of a signal peptide enhanced packaging efficiency of pseudotyped JEV-E based lentiviral vectors. With a strong signal peptide helping they generate a higher number of viral particles. Green fluorescent protein and luciferase expression showed that the transduction titer or relative fluorescence units of VSVMEpv, SPMEpv and MEpv were not significantly different. We suggest that the signal peptide does not influence the infectivity of pseudotyped JEV-E based lentiviral vectors. In addition, our findings indicated that pseudotyped JEVs show preferential tropism for BHK-21 cells, supporting the mimic function displayed by parental JEV. Therefore, our study provided a cost-effective method to generate pseudotyped JEV-E based lentiviral vectors, which may represent a valid model to investigate some of the infectious properties of JEV. PMID- 27993627 TI - An open-loop approach to calculate noise-induced transitions. AB - Bistability permits the co-existence of two distinct cell fates in a population of genetically identical cells. Noise induced transitions between two fates of a bistable system are difficult to calculate due to the intricate interplay between nonlinear dynamics and noise in bistable positive feedback loops. Here we opened multivariable feedback loops at the slowest variable to obtain the open-loop function and the fluctuations in the open-loop output. By the subsequent reclosing of the loop, we calculated the mean first passage time (MFPT) using the Fokker-Planck equation in good agreement with the exact stochastic simulation. When an external component interacts with a feedback component, it amplifies the extrinsic noise in the loop. Consequently, the open-loop function is shifted and the transition rates between the two states in the closed loop are increased. Despite this shift, the open-loop output reflects the system faithfully to predict the MFPT in the feedback loop. Therefore, the open-loop approach can help theoretical analysis. Furthermore, the measurement of the mean value, variance, and the reaction time-scale of the open-loop output permits the prediction of MFPT simply from experimental data, which underscores the practical value of the stochastic open-loop approach. PMID- 27993628 TI - Exosomal microRNA concentrations in colorectal cancer: A mathematical model. AB - Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States. Early detection increases survival very significantly. Indeed, five year survival for people diagnosed at stage I-II is 90%, while for those diagnosed at stage IV it is only 13%. The gold standard for early detection is colonoscopy, but this procedure is limited due to its invasive nature and its high cost. Hence there is a need to identify non-invasive biomarkers for CRC. Exosomal miRs secreted by cancer cells and overexpressed in the blood have been suggested as biomarkers for cancer. In particular, exosomal miRs 21, 23a, 92a and 1246 are overexpressed in CRC, and thus have the potential to be used as serum biomarkers for early detection of the disease. The present paper develops for the first time a mathematical model for early stage of CRC which includes the effect of these miRs on the growth of the cancer. The model is represented by a system of partial differential equations. Simulations of the model show a relationship between the growth of the tumor diameter and the total mass of these miRs under some of the common mutations which occur in CRC, namely, KRAS, PI3K, APC, p53 and SMAD mutations. The model may serve as a step toward establishing miRs 21, 23a, 92a and 1246 as reliable blood biomarkers for CRC as more experimental results and clinical data become available. PMID- 27993629 TI - Neuropeptidomics in Triatoma infestans. Comparative transcriptomic analysis among triatomines. AB - Chagas' disease, affecting up to 6-7 million people worldwide, is transmitted to humans through the feces of triatomine kissing bugs. From these, Rhodnius prolixus, Triatoma dimidiata, Triatoma infestans and Triatoma pallidipennis are important vectors distributed throughout the Latin American subcontinent. Resistance to pyrethroids has been developed by some triatomine populations, especially T. infestans, obstructing their control. Given their role in the regulation of physiological processes, neuroendocrine-derived factors have been proposed as a source of molecular targets for new-generation insecticides. However, the involvement of neuropeptides in insecticide metabolism and resistance in insects has been poorly studied. In the present work, the sequences of 20 neuropeptide precursor genes in T. infestans, 16 in T. dimidiata, and 13 in T. pallidipennis detected in transcriptomic databases are reported, and a comparative analysis in triatomines is presented. A total of 59 neuropeptides were validated by liquid chromatography-tandem mass spectrometry in brain and nervous ganglia from T. infestans, revealing the existence of differential post translational modifications, extended and truncated forms. The results suggest a high sequence conservation in some neuropeptide systems in triatomines, whereas remarkable differences occur in several others within the core domains. Comparisons of the basal expression levels for several neuropeptide precursor genes between pyrethroid sensitive and resistant population of T. infestans are also presented here, in order to introduce a proof of concept to test the involvement of neuropeptides in insecticide resistance. From the precursors tested, NVP and ITG peptides are significantly higher expressed in the resistant population. To our knowledge, this is the first report to associate differential neuropeptide expression with insecticide resistance. The information provided here contributes to creating conditions to widely extend functional and genetic studies involving neuropeptides in triatomines. PMID- 27993630 TI - Low level of PDZ domain containing 1 (PDZK1) predicts poor clinical outcome in patients with clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is the most lethal neoplasm of the urologic system. Clinical therapeutic effect varies greatly between individual ccRCC patients, so there is an urgent need to develop prognostic molecular biomarkers to help clinicians identify patients in need of early aggressive management. In this study, samples from primary ccRCC tumor and their corresponding nontumor adjacent tissues (n=18) were analyzed by quantitative proteomic assay. Proteins downregulated in tumors were studied by GO and KEGG pathways enrichment analyses. Six proteins were found both downregulated and annotated with cell proliferation in ccRCC patients. Of these proteins, PDZK1 and FABP1 were also involved in the lipid metabolism pathway. The downregulation of PDZK1 was further validated in TCGA_KIRC dataset (n=532) and independent set (n=202). PDZK1 could discriminate recurrence, metastasis and prognosis between ccRCC patients. Low level of PDZK1 in both mRNA and protein was associated with reduced overall survival (OS) and disease-free survival (DFS) in two independent sets. In univariate and multivariate analyses, PDZK1 was defined as an independent prognostic factor for both OS and DFS. These findings indicated that low level of PDZK1 could predict poor clinical outcome in patients with ccRCC. PMID- 27993631 TI - Infectious complications after out-of-hospital cardiac arrest-A comparison between two target temperatures. AB - BACKGROUND: It has been suggested that target temperature management (TTM) increases the probability of infectious complications after cardiac arrest. We aimed to compare the incidence of pneumonia, severe sepsis and septic shock after out-of-hospital cardiac arrest (OHCA) in patients with two target temperatures and to describe changes in biomarkers and possible mortality associated with these infectious complications. METHODS: Post-hoc analysis of the TTM-trial which randomized patients resuscitated from OHCA to a target temperature of 33 degrees C or 36 degrees C. Prospective data on infectious complications were recorded daily during the ICU-stay. Pneumonia, severe sepsis and septic shock were considered infectious complications. Procalcitonin (PCT) and C-reactive-protein (CRP) levels were measured at 24h, 48h and 72h after cardiac arrest. RESULTS: There were 939 patients in the modified intention-to-treat population. Five hundred patients (53%) developed pneumonia, severe sepsis or septic shock which was associated with mortality in multivariate analysis (Hazard ratio [HR] 1.39; 95%CI 1.13-1.70; p=0.001). There was no statistically significant difference in the incidence of infectious complications between temperature groups (sub distribution hazard ratio [SHR] 0.88; 95%CI 0.75-1.03; p=0.12). PCT and CRP were significantly higher for patients with infections at all times (p<0.001), but there was considerable overlap. CONCLUSIONS: Patients who develop pneumonia, severe sepsis or septic shock after OHCA might have an increased mortality. A target temperature of 33 degrees C after OHCA was not associated with an increased risk of infectious complications compared to a target temperature of 36 degrees C. PCT and CRP are of limited value for diagnosing infectious complications after cardiac arrest. PMID- 27993632 TI - ECMO Cardio-Pulmonary Resuscitation (ECPR), trends in survival from an international multicentre cohort study over 12-years. AB - BACKGROUND: Use of Extracorporeal Membrane Oxygenation during cardiopulmonary resuscitation (ECPR) is increasingly being deployed as an adjunct to conventional CPR. It is unknown if this has been associated with improved outcomes. AIMS: To describe trends in survival and patient demographics for ECPR patients in the international Extracorporeal Life Support Organisation (ELSO) database over the past 12 years and identify factors associated with changes in survival. METHODS: Patients greater than 16 years of age who received ECPR between January 2003 and December 2014 were extracted from the ELSO registry and were divided into three 4 year cohorts (Cohort 1: 2003-2006, Cohort 2: 2007-2010, Cohort 3: 2011-2014). Univariable analysis was performed to compare demographics and outcomes of patients across the three cohorts. Univariable and multivariable analyses were then performed to identify factors independently associated with survival. RESULTS: 1796 patients treated with ECPR were extracted from the registry, aged 50 (+/-18.5) years. Annual ECPR episodes increased over 10-fold, from 35 to over 400 per year. Survival to hospital discharge was 29% overall (27% cohort 1, 28% cohort 2, 30% cohort 3 (p=0.71)). Age, body weight and documented comorbidities increased over time. There was a reduction in complications associated with ECMO usage. After adjusting for confounders there was no change in the odds of survival over the time period examined. INTERPRETATION: Over the period 2003 2014, survival to hospital discharge was 29% for patients who require ECPR. Despite advances in provision of ECMO care and increasing co-morbidities of patients, there has been no change in risk-adjusted survival over time. PMID- 27993633 TI - Davallia bilabiata exhibits anti-angiogenic effect with modified MMP-2/TIMP-2 secretion and inhibited VEGF ligand/receptors expression in vascular endothelial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Davallia bilabiata Hosokawa (D. bilabiata), also called GuSuiBu, is popularly used as a substitute for Drynaria fortunei J. Sm for rheumatoid and degenerative arthritis in traditional Chinese medicine. Little is known about the underlying mechanisms of anti-angiogenesis responsible for arthritis in D. bilabiata which needs to be elucidated. AIM OF THE STUDY: The present study is intended to investigate the anti-angiogenic effect of D. bilabiata associated with the modulation of matrix metalloproteinases (MMPs) and down regulation of vascular endothelial growth factor (VEGF) ligand/receptors both in vivo and in vitro. MATERIALS AND METHODS: We investigated the potential anti-angiogenic effect of D. bilabiata by the in vivo neovascularization of chick chorioallantoic membranes (CAM) assay, and the in vitro migration and matrix induced tube formation assay using human umbilical vascular endothelial cells (HUVECs). The expressions of MMP-2, TIMP-2, RECK and VEGF/VEGFR were analyzed by real-time RT-PCR or Western blot method. RESULTS: One major compound from water extract of D. bilabiata was identified as Epicatechin 3-O-beta-D-allopyranoside. D. bilabiata was confirmed to inhibit in vivo angiogenesis by CAM assay. D. bilabiata also exhibited in vitro anti-angiogenic and anti-regrowth effects as demonstrated by tube formation assay, transwell migration assay and wound healing assay. The mRNA expressions of MMP-2, and MMP-14 were decreased. On the contrary, tissue inhibitor of metalloproteinase-2 (TIMP-2), reversion-inducing cysteine rich protein with kazal motifs (RECK) were increased by D. bilabiata. The extracellular MMP-2 activity was found to be reduced both in vitro and in vivo by D. bilabiata as determined by gelatin zymography. Results from western blot analysis and ELISA further demonstrated the decrease of MMP-2 and increase of TIMP-2 secretion after D. bilabiata treatment. The gene expressions of VEGF-A, B, -C, -D and VEGFR-1, -2, -3 were all inhibited by D. bilabiata. CONCLUSION: We concluded that the anti-angiogenic effect of D. bilabiata was associated with the decreased MMP-2 activity mediated by the upregulation of TIMP-2 and RECK, and the suppression of VEGF/VEGFRs expression. PMID- 27993634 TI - An ex vivo evaluation of the efficacy of andrographolide in modulating differential expression of transcription factors and target genes in periodontal cells and its potential role in treating periodontal diseases. AB - ETHANOPHARMACOLOGICAL RELEVANCE: Andrographolide is a herbal extract traditionally used in South Asian countries for treating inflammatory diseases. AIM OF THE STUDY: To evaluate the efficacy of andrographolide in management of periodontal disease which is a highly prevalent oral disease. MATERIALS AND METHODS: Periodontal ligament fibroblasts (PDLF) were cultured from healthy and diseased periodontium using explant culture methods. The safe dose of AG was determined using MTT assay. LPS (lipopolysaccharide) of the most important periodontopathogen, P gingivalis was used to activate NF-kappaB and STAT3 in PDLF. The efficacy of AG in inhibiting NF-kappaB and STAT3 was analyzed using immunofluorescence. Down regulation of expression of target genes of these transcription factors related to inflammation and bone resorption were analyzed using real time PCR. RESULTS: AG up to the concentration of 25MUM was found to be safe as determined by MTT assay. Statistically significant activation of NF kappaB and STAT3 in cultured PDLF was observed in diseased group compared to healthy controls before and after LPS challenge. 5MUM AG pretreatment significantly inhibited activation of NF-kappaB and STAT3 and down regulated expression of inflammatory and bone resorptive genes in cultured PDLF. CONCLUSIONS: The findings of the present study propose the adjunctive use of a novel herbal drug andrographolide as a promising host modulation agent for periodontal therapy by inhibiting NF-kappaB and STAT3 activation and inhibition of inflammation and bone resorption related genes. PMID- 27993635 TI - The potential of aqueous extracts of Bellucia dichotoma Cogn. (Melastomataceae) to inhibit the biological activities of Bothrops atrox venom: A comparison of specimens collected in the states of Para and Amazonas, Brazil. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: The effectiveness of aqueous extract of Bellucia dichotoma Cogn. (Melastomataceae) specimems collected in Santarem, PA, against some biological activities of Bothrops atrox venom (BaV) has been scientifically proven. Here, we analyzed the components and assessed the anti-snakebite potential of aqueous extracts of bark of B. dichotoma collected in Manaus, AM, (AEBd-MAO) and Santarem, PA, (AEBd-STM), both in Brazil. MATERIALS AND METHODS: The phytochemical profiles of the aqueous extracts were identified using thin layer chromatography (TLC), and the concentrations of phenolics were determined by colorimetric assay. The inhibitory potential of the extracts was tested against the phospholipase A2, coagulant and gelatinolytic activities of BaV in vitro and its defibrinating and edema-inducing activities in vivo. Interaction between BaV and the extracts was investigated using SDS-Page electrophoresis and Western blotting. Extract cytotoxicity and antioxidant potential were assessed using the human fibroblast cell line MRC-5 and the DPPH assay in cell culture, respectively. RESULTS: While there was no difference between the phytochemical profiles of the extracts, AEBd-MAO had higher concentrations of total phenolics, total tannins and hydrolysable tannins. The extracts inhibited 100% of the phospholipase and coagulant activity of BaV when pre-incubated. Without pre incubation, however, there was no reduction in phospholipase activity, although significant inhibition of coagulant activity was observed. In the doses used in folk medicine, without pre-incubation, both extracts inhibited 100% of the coagulant activity of BaV. In vivo, the extracts were unable to inhibit the defibrinating activity of the venom but were effective in inhibiting its edema inducing activity. In the profiles of the extracts pre-incubated with BaV, not all the protein bands revealed by SDS-PAGE and Western blot were observed. Both extracts had a high antioxidant potential and neither had a cytotoxic effect. CONCLUSION: Although the concentrations of phenolics in each extract were different, the anti-snakebite potential was similar for the concentrations of extract tested. Our findings are of importance for the quality control of this raw material, which, once tested in accordance with Brazilian National Health Surveillance Agency recommendations, may be suitable for use as a phytomedicine to complement treatment of the local effects induced by Bothrops venoms. PMID- 27993636 TI - Anti-PTSD-like effects of albiflorin extracted from Radix paeoniae Alba. AB - ETHNOPHARMACOLOGY RELEVANCE: Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that is characterized by symptoms of re-experiencing, avoidance and hyperarousal, as well as social and professional dysfunction at least one month after the exposure to a traumatic event. Biosynthesis of allopregnanolone has been suggested as one of the important contributors to PTSD. Albiflorin (AF) extracted from Radix paeoniae Alba had been shown to be effective in the therapy of depression. However, few studies were concerned about the anti PTSD-like effects of AF. AIM OF THE STUDY: The current study aimed to evaluate the anti-PTSD-like effects of AF in an animal model and its possible mechanism. MATERIALS AND METHODS: To evaluate this, the single prolonged stress (SPS) model was used in the present study. The SPS rats were administered by AF (at doses of 3.5, 7 and 14.0mg/kg, i.g.) after induction of SPS from days 2-13. After the exposure to SPS, behavioral assessments were conducted, including contextual fear paradigm (CFP), elevated plus-maze test (EPMT), open-field test (OFT). The rats were decapitated at the end of the behavioral tests and levels of allopregnanolone in prefrontal cortex, hippocampus and amygdala were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: It had been shown that behavioral deficits of SPS rats were reversed by AF (7.0 and 14.0mg/kg, i.g.), which attenuated the PTSD-like associated contextual freezing behavior in CFP and improved PTSD-like associated anxiogenic behavior in EPMT without affecting locomotor activity in OFT. Moreover, decreased levels of allopregnanolone in prefrontal cortex, hippocampus, and amygdala were reversed by AF (7.0 and 14.0mg/kg, i.g.), respectively. CONCLUSION: In summary, the present study indicated that AF exerted the anti-PTSD-like effects, which maybe associated with allopregnanolone biosynthesis in the brain. PMID- 27993637 TI - Three-dimensional hepatic lobule-like tissue constructs using cell-microcapsule technology. AB - The proper functioning of the liver and tissues containing hepatocytes greatly depends upon the intricate organization of the cells. Consequently, controlling the shape of three-dimensional (3D) cellular constructs is an important issue for in vitro applications of fabricated artificial livers. However, the precise control of tissue shape at the microscale cannot be achieved with various commonly used 3D tissue-engineered building units, such as spheroids. Here, we present the fabrication of hepatic lobule-shaped microtissue (HLSM) containing rat liver (RLC-18) cells. By using cell-microcapsule technology, RLC-18 cells were encapsulated in the core region of poly-l-lysine-alginate microcapsules. After 14days of long-term cultivation, RLC-18 cells self-assembled into HLSM, and the cells fully occupied the microcapsule. By monitoring the cell number and albumin secretion during culture and characterizing the dimensions of the fabricated tissue, we demonstrated that the HLSM showed higher hepatic function as compared with normal cell spheroids. We also showcased the assembly of these microtissues into a 3D four-layered hepatic lobule model by a facile micromanipulation method. Our technology for fabricating 3D multilayer hepatic lobule-like, biofunctional tissue enables the precise control of tissue shape in three dimensions. Furthermore, these constructs can serve as tissue-engineered building blocks for larger organs and cellular implants in clinical treatment. PMID- 27993638 TI - Sustained tobramycin release from polyphosphate double network hydrogels. AB - : Sustained local delivery of antibiotics from a drug reservoir to treat or prevent bacterial infections can avoid many of the drawbacks of systemic administration of antibiotics. Prolonged local release of high concentrations of antibiotics may also be more effective at treating bacteria in established biofilm populations that are resistant to systemic antibiotics. A double network hydrogel comprising an organic polyphosphate pre-polymer network polymerized within a polyacrylamide network de-swelled to about 50% of its initial volume when the polyphosphate network was crosslinked with polycationic tobramycin, an aminoglycoside antibiotic. The antibiotic-loaded hydrogels contained approximately 200mg/ml of tobramycin. The hydrogels continuously released daily amounts of tobramycin above the Pseudomonas aeruginosa minimal bactericidal concentration for greater than 50days, over the pH range 6.0-8.0, and completely eradicated established P. aeruginosa biofilms within 72h in a flow cell bioreactor. The presence of physiological concentrations of Mg2+ and Ca2+ ions doubled the cumulative release over 60days. The polyphosphate hydrogels show promise as materials for sustained localized tobramycin delivery to prevent post operative P. aeruginosa infections including infections established in biofilms. STATEMENT OF SIGNIFICANCE: Polyphosphate hydrogels were loaded with high concentrations of tobramycin. The hydrogels provided sustained release of bactericidal concentrations of tobramycin for 50days, and were capable of completely eradicating P. aeruginosa in established biofilms. The hydrogels have potential for localized prevention or treatment of P. aeruginosa infections. PMID- 27993640 TI - Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat. AB - The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio toxicity occurs through calcium ions (Ca2+) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca2+ and cause an increase in activity of calcium pumps, including Ca2+-ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats. PMID- 27993641 TI - AS2553627, a novel JAK inhibitor, prevents chronic rejection in rat cardiac allografts. AB - Janus family kinases (JAKs) are essential molecules for cytokine responses and attractive targets for the treatment of transplant rejection and autoimmune diseases. Several JAK inhibitors have shown demonstrable effects on acute rejection in experimental cardiac transplant models. However, little is known about the potential benefits of JAK inhibitors on chronic rejection outcomes such as vasculopathy and fibrosis. Here, we examined the pharmacological profile of a novel JAK inhibitor, AS2553627, and explored its therapeutic potential in chronic rejection as well as acute rejection in a rat cardiac transplant model. AS2553627 potently inhibited JAK kinases but showed no inhibition of other kinases, including TCR-associated molecules. The compound also suppressed proliferation of IL-2 stimulated human and rat T cells. In a rat cardiac transplant model, oral administration of AS2553627 alone or co-administration with a sub-therapeutic dose of tacrolimus effectively prolonged cardiac allograft survival, suggesting the efficacy in treating acute rejection. To evaluate the effect on chronic rejection, recipient rats were administered a therapeutic dose of tacrolimus for 90 days. In combination with tacrolimus, AS2553627 significantly reduced cardiac allograft vasculopathy and fibrosis that tacrolimus alone did not inhibit. AS2553627 at the effective dose in rat transplantation models did not significantly reduce reticulocyte counts in peripheral whole blood after in vivo erythropoietin administration, indicating a low risk for anemia. These results suggest that AS2553627 may be a therapeutic candidate for the prevention of not only acute but also chronic rejection in cardiac transplantation. PMID- 27993639 TI - The impact of detergents on the tissue decellularization process: A ToF-SIMS study. AB - : Biologic scaffolds are derived from mammalian tissues, which must be decellularized to remove cellular antigens that would otherwise incite an adverse immune response. Although widely used clinically, the optimum balance between cell removal and the disruption of matrix architecture and surface ligand landscape remains a considerable challenge. Here we describe the use of time of flight secondary ion mass spectroscopy (ToF-SIMS) to provide sensitive, molecular specific, localized analysis of detergent decellularized biologic scaffolds. We detected residual detergent fragments, specifically from Triton X-100, sodium deoxycholate and sodium dodecyl sulphate (SDS) in decellularized scaffolds; increased SDS concentrations from 0.1% to 1.0% increased both the intensity of SDS fragments and adverse cell outcomes. We also identified cellular remnants, by detecting phosphate and phosphocholine ions in PAA and CHAPS decellularized scaffolds. The present study demonstrates ToF-SIMS is not only a powerful tool for characterization of biologic scaffold surface molecular functionality, but also enables sensitive assessment of decellularization efficacy. STATEMENT OF SIGNIFICANCE: We report here on the use of a highly sensitive analytical technique, time of flight secondary ion mass spectroscopy (ToF-SIMS) to characterize detergent decellularized scaffolds. ToF-SIMS detected cellular remnants and residual detergent fragments; increased intensity of the detergent fragments correlated with adverse cell matrix interactions. This study demonstrates the importance of maintaining a balance between cell removal and detergent disruption of matrix architecture and matrix surface ligand landscape. This study also demonstrates the power of ToF-SIMS for the characterization of decellularized scaffolds and capability for assessment of decellularization efficacy. Future use of biologic scaffolds in clinical tissue reconstruction will benefit from the fundamental results described in this work. PMID- 27993642 TI - The effect of arsenite on spatial learning: Involvement of autophagy and apoptosis. AB - Spatial learning plays a major role in one's information recording. Arsenic is one of ubiquitous environmental toxins with known neurological effects. However, studies investigating the effects of arsenic on spatial learning and related mechanisms are limited. This study was planned toexaminethe effects of bilateral intra-hippocampal infusion of different concentrations of sodium arsenite (5, 10 and 100nM, 5ul/side) on spatial learning in Wistar rats. Moreover, we evaluated levels of LC3-II, Atg7 and Atg12 as reliable biomarkers of autophagy and caspase 3 and Bax/Bcl-2 ratio as indicators of apoptosis in the hippocampus. Interestingly, low concentrations of sodium arsenite (5 and 10nM) significantly increased spatial acquisition but pre-training administration of sodium arsenite100nM did not significantly alter spatial learning. LC3-II levels were significantly increased in groups treated with sodium arsenite 5 and 10nM and decreased in the group receiving arsenite 100nM compared to the control group. Atg7 and Atg12 levels were obviously higher in all groups treated with sodium arsenite compared to control. However, caspase-3 cleavage and Bax/Bcl-2 ratio were notably greater in 100nM, and lesser in 5nM arsenite group in comparison with control animals. The results of this study showed that the low concentrations of sodium arsenite could facilitate spatial learning. This facilitation could be attributed to neuronal autophagy induced by low concentrations of sodium arsenite. These findings may help to clarify the regulatory pathways for apoptosis and autophagy balance due to sodium arsenite. PMID- 27993643 TI - Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction. AB - Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1beta isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans. PMID- 27993644 TI - How Educators Conceptualize and Teach Reflective Practice: A Survey of North American Pediatric Medical Educators. AB - OBJECTIVE: The objectives of this study were to explore pediatric undergraduate medical educators' understanding of reflective practice, the barriers they face in teaching this, the curricular activities they use, and the value they assign to reflective practice. METHODS: Nine survey questions were sent to members of the Council on Medical Student Education in Pediatrics, an international pediatric undergraduate medical educator group. Quantitative data were analyzed using descriptive statistics. Open-ended responses were analyzed qualitatively through an iterative process to establish themes representing understanding of reflective practice and barriers in teaching this. RESULTS: Respondents representing 56% of all North American schools answered at least 1 survey question. Qualitative analysis of understanding of reflection revealed 11 themes spanning all components of reflective practice, albeit with a narrow view on triggers for reflection and a lower emphasis on understanding the why of things and on perspective-taking. The most frequent barriers in teaching this were the lack of skilled educators and limited time. Most respondents valued reflective skills but few reported confidence in their ability to teach reflection. Several curricular activities were used to teach reflection, the most common being narrative writing. CONCLUSIONS: Pediatric undergraduate medical educators value reflection and endorse its teaching. However, many do not have a complete understanding of the construct and few report confidence in teaching this. Implementing longitudinal curricula in reflective practice may require a culture change; opportunities exist for faculty development about the meaning and value of reflective practice and how best to teach this. PMID- 27993646 TI - The CD24 surface antigen in neural development and disease. AB - A cell's surface molecular signature enables its reciprocal interactions with the associated microenvironments in development, tissue homeostasis and pathological processes. The CD24 surface antigen (heat-stable antigen, nectadrin; small cell lung cancer antigen cluster-4) represents a prime example of a neural surface molecule that has long been known, but whose diverse molecular functions in intercellular communication we have only begun to unravel. Here, we briefly summarize the molecular fundamentals of CD24 structure and provide a comprehensive review of CD24 expression and functional studies in mammalian neural developmental systems and disease models (rodent, human). Striving for an integrated view of the intracellular signaling processes involved, we discuss the most pertinent routes of CD24-mediated signaling pathways and functional networks in neurobiology (neural migration, neurite extension, neurogenesis) and pathology (tumorigenesis, multiple sclerosis). PMID- 27993645 TI - The transcription factor Npas4 contributes to adolescent development of prefrontal inhibitory circuits, and to cognitive and emotional functions: Implications for neuropsychiatric disorders. AB - The adolescent brain is marked by functional and structural modifications, particularly within the inhibitory system of the prefrontal cortex (PFC). These changes are necessary for the acquisition of adult cognitive functions and emotion regulation, and impairments in these processes are associated with neuropathologies such as schizophrenia and affective disorders. The molecular mechanisms regulating this adolescent refinement of prefrontal inhibitory circuits remain largely unknown. Here we demonstrate that the transcription factor Npas4 plays a major role in this process. Using a series of behavioral, molecular, pharmacological and genetic approaches in mice, we demonstrate that deficiency in Npas4 affects adolescent expression of multiple markers of GABAergic transmission in the PFC, including parvalbumin and GAD67, in a sex specific manner. This abnormal pattern of expression of GABAergic markers is associated with sex-specific cognitive and emotional impairments that occur only when Npas4 deficiency begins at adolescence but not post-adolescence. Finally, we show that chronic treatment with the GABA enhancing drug sodium valproate during adolescence is sufficient to induce long-lasting recovery of the molecular and behavioral abnormalities observed in Npas4 deficient mice. Altogether, we provide evidence for the involvement of the transcription factor Npas4 to the structural changes that affect prefrontal inhibitory circuits during adolescence. Further investigations of Npas4 role in the adolescent brain might provide new insights on the molecular mechanisms underlying neuropsychiatric disorders that emerge during adolescence. PMID- 27993647 TI - The effect of the long anchor duration on performance in the temporal bisection procedure. AB - The present study investigated how the value of the long anchor duration influences the bisection point (BP) in the temporal bisection procedure. The ratio similarity rule (Gibbon, 1981, On the form and location of the psychometric bisection function for time. Journal of Mathematical Psychology, 24(1), 58-87) hypothesizes that the location of the BP is determined by a ratio comparison between the short and long anchor durations. The Short/no short hypothesis (Machado and Keen, 2003, Temporal discrimination in a long operant chamber. Behavioural Processes, 62(1), 157-182) indicates that the location of the BP is influenced mainly by the short duration. Two experiments with pigeons manipulated the long anchor duration while fixing the short anchor duration in a series of anchor pairs. The results showed that the location of the BP depended on the initial training condition, a primacy effect. When the initial training condition used anchors of 3- vs. 9-s, a relatively strong influence of the long anchor duration was observed as predicted by the ratio similarity rule. On the other hand, when anchors were 3- vs. 27-s in the initial training condition, the effect of the long duration was relatively small, conforming more closely to the Short/no short hypothesis. Keypecking to the sample key during a trial, sample cue responding, was also observed. The functions relating sample-cue responding to elapsed trial time also indicated the primacy effect. PMID- 27993649 TI - Preliminary evidence for a role of the personality trait in visual perceptual learning. AB - Recent research has shown that reinforcement can facilitate visual perceptual learning (VPL), but no study has examined the relations between individual differences in reinforcement sensitivity and VPL. This study tested the hypothesis that when monetary incentive was involved, the personality traits of harm avoidance and reward dependence (HA and RD, two measures of reinforcement sensitivity) would be linked to VPL performance. We trained two groups of subjects with a visual motion direction discrimination task for six days. The experimental group received monetary incentive feedback, whereas the control group received non-monetary feedback. As expected, the score of HA was negatively correlated with VPL for the experimental group, but not for the control group. RD was not a significant predictor. These results were discussed in terms of the role of non-perceptual factors such as reinforcement, personality, higher cognition, and motivation in VPL. PMID- 27993648 TI - Contribution of the basolateral amygdala NMDA and muscarinic receptors in rat's memory retrieval. AB - The present study was designed to investigate the involvement of the muscarinic cholinergic receptors in the basolateral amygdala (BLA) in memory retrieval. Also, the possible relationship between the BLA muscarinic cholinergic and the NMDA receptor systems was evaluated in the inhibitory avoidance learning. Male Wistar rats were bilaterally cannulated into the BLAs and memory retrieval was measured in a step-through type inhibitory avoidance apparatus. Intra-BLA microinjection of different doses of a non-selective muscarinic receptor antagonist, scopolamine (0.5-1MUg/rat, intra-BLA), 5min before the testing phase dose-dependently induced amnesia. Pre-test intra-BLA microinjection of different doses of NMDA (0.005-0.05MUg/rat) reversed scopolamine-induced amnesia and improved memory retrieval. In addition, different doses of a selective NMDA receptor antagonist, D-AP5 (0.001-0.005MUg/rat, intra-BLA) potentiated the response of an ineffective dose of scopolamine (0.5MUg/rat) to inhibit memory retrieval. It should be considered that pre-test intra-BLA microinjection of the same doses of NMDA or D-AP5 by themselves had no effect on memory retrieval. Similar to ANOVA analysis, our cubic interpolation analysis also predicted that the activation or inactivation of the NMDA receptors by different doses of drugs can affect the scopolamine response. On the other hand, pre-test intra-BLA microinjection of D-AP5 inhibited the reversal effect of NMDA on scopolamine induced amnesia. It can be concluded that the BLA cholinergic system, via muscarinic receptors, has a critical role in memory retrieval. Our results also suggest that a cooperative interaction between the BLA NMDA and muscarinic acetylcholine receptors modulates memory formation of inhibitory avoidance task in rats. PMID- 27993650 TI - Glucose modulates antimicrobial photodynamic inactivation of Candida albicans in biofilms. AB - Candida albicans biofilm is a main cause of infections associated with medical devices such as catheters, contact lens and artificial joint prosthesis. The current treatment comprises antifungal chemotherapy that presents low success rates. Photodynamic inactivation (PDI) involves the combination of a photosensitizing compound (PS) and light to generate oxidative stress that has demonstrated effective antimicrobial activity against a broad-spectrum of pathogens, including C. albicans. This fungus senses glucose inducing an upregulation of membrane transporters that can facilitate PS uptake into the cell. The aim of this study was to evaluate the effects of glucose on methylene blue (MB) uptake and its influence on PDI efficiency when combined to a red LED with central wavelength at lambda=660nm. C. albicans biofilms were grown on hydrogel disks. Prior to PDI assays, MB uptake tests were performed with and without glucose-sensitization. In this system, the optimum PS administration was determined as 500MUM of MB in contact with the biofilm during 30min before irradiation. Irradiation was performed during 3, 6, 9, 12, 15 and 18min with irradiance of 127.3mW/cm2. Our results showed that glucose was able to increase MB uptake in C. albicans cells. In addition, PDI without glucose showed a higher viability reduction until 6min; after 9min, glucose group demonstrated a significant decrease in cell viability when compared to glucose-free group. Taken together, our data suggest that glucose is capable to enhance MB uptake and modulate photodynamic inactivation of C. albicans biofilm. PMID- 27993651 TI - NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition. AB - Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides, cholesterol and toxic free fatty acids and is related to low vitamin D levels. In an analysis of specific gene sets we elucidate to what extent NAFLD associates to epigenetic and related transcriptional changes in gene networks regulating lipid, energy and vitamin D balance. Two gene clusters responsible for lipid homeostasis (74 genes) and vitamin D and energy balance (31 genes) were investigated with regard to average epigenetic shifts within the first 1500bp next to the transcriptional start site. Three cohorts from two published genome wide driven studies that used a microarray approach were investigated including altogether 103 NAFLD and 75 liver healthy subjects. In the first two steps associations between NAFLD abundance, strength of fibrosis and methylation were investigated in two cohorts by multiple linear regression analyses, correcting for important clinical and demographic parameters. Methylation associated strength of transcription in genes showing significant NAFLD related methylation changes were studied in a third step using a third cohort and applying Pearson's correlation and robust linear regression analyses. 41 genes in gene cluster 1 and 14 genes in cluster 2 were significantly differentially methylated in dependency of NAFLD and hepatic fibrosis. We detect new genes significantly changed in methylation, including APO family members (lipid transport), NPC1L1, STARD (cholesterol transport) and GRHL (energy homeostasis). Our results allow novel insights into the hepatic epigenetic regulation of genes important for lipid and vitamin D balance in NAFLD. PMID- 27993653 TI - In vitro metabolism of [14C]-benalaxyl in hepatocytes of rats, dogs and humans. AB - The in vitro comparative animal metabolism study is now a data requirement under EU Directive 1107/2009 for registration of plant protection products. This type of study helps determine the extent of metabolism of a chemical in each surrogate species and whether any unique human metabolite(s) are formed. In the present study, metabolism of racemic [14C]-benalaxyl, a fungicide was investigated in cryopreserved rat, dog and human hepatocytes. The metabolites generated were identified/characterized by LC/MS/MS with radiometric detection and comparison with reference standards. [14C]-glucuronide conjugates of benalaxyl metabolites in rat, dog and human hepatocytes were confirmed via additional experiments in which known reference standards were incubated with dog liver microsomes in the presence of UDPGA. After 4 h of incubation, benalaxyl was extensively metabolized in all the species with the following trend: dog (100%) > human (86%) > rat (75%). In all species, the major metabolic pathways consisted of hydroxylation of the methyl group in the xylene moiety to 2-hydroxymethyl-benalaxyl, further oxidation to its carboxylic acid analogue (benalaxyl-2-benzoic acid), and hydrolysis of the methyl ester to yield benalaxyl acid or 2-hydroxymethyl benalaxyl acid. In addition, glucuronidation of phase I metabolites occurred in all species, to a higher extent in dog hepatocytes in which 2-hydroxymethyl benalaxyl-glucuronide conjugate constituted the most significant metabolite. No major unique metabolite was observed in human hepatocytes. Also, benalaxyl did not undergo stereo-selective metabolism in rat or human hepatocytes. PMID- 27993654 TI - Immunomodulatory and therapeutic potential of a mucin-specific mycelial lectin from Aspergillus panamensis. AB - The present study reports the evaluation of immunomodulatory and therapeutic potential of a purified Aspergillus panamensis lectin. The immunomodulatory potential of the purified lectin was determined in swiss albino mice by studying its effect on anaphylaxis reaction, arthus reaction, respiratory burst activity, nitric oxide production and quantification of cytokine levels. The therapeutic potential of the lectin was evaluated in male wistar rat models by studying its curative effect on ulcerative colitis. The purified lectin inhibited systemic anaphylaxis and arthus reaction. It enhanced the functional ability of macrophages which was evident from increase in reduction of nitroblue tetrazolium dye and nitric oxide production. It also stimulated the production of Th-1 cytokine IFN-gamma and Th-2 cytokine IL-6. Maximum immunomodulatory effect was seen at lectin concentration of 1.5mg/kg body weight. The lectin also showed curative effect against trinitrobenzene sulphonic acid induced ulcerative colitis. The results of this study adequately reflect the role of purified A. panamensis lectin in improving the immune status of mice models. They also show the effect of lectin in reducing the severity of incidence and decrease in clinical symptoms of ulcerative colitis. PMID- 27993652 TI - Effects of pre and post-treatments with dipyridamole in gentamicin-induced acute nephrotoxicity in the rat. AB - This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection. PMID- 27993655 TI - Chitosan based nanofibers in bone tissue engineering. AB - Bone tissue engineering involves biomaterials, cells and regulatory factors to make biosynthetic bone grafts with efficient mineralization for regeneration of fractured or damaged bones. Out of all the techniques available for scaffold preparation, electrospinning is given priority as it can fabricate nanostructures. Also, electrospun nanofibers possess unique properties such as the high surface area to volume ratio, porosity, stability, permeability and morphological similarity to that of extra cellular matrix. Chitosan (CS) has a significant edge over other materials and as a graft material, CS can be used alone or in combination with other materials in the form of nanofibers to provide the structural and biochemical cues for acceleration of bone regeneration. Hence, this review was aimed to provide a detailed study available on CS and its composites prepared as nanofibers, and their associated properties found suitable for bone tissue engineering. PMID- 27993656 TI - Protective effect of Anoectochilus roxburghii polysaccharide against CCl4-induced oxidative liver damage in mice. AB - This study investigated the isolation and characterization of Anoectochilus roxburghii polysaccharides (ARP), and further evaluated whether ARP possessed hepatoprotective activities against CCl4-induced oxidative liver damage in mice. ARP is comprised of glucose and galactose in a 1.9:1 molar ratio, and the molecular weight is 19.5kDa. ARP displayed significant scavenging effects against hydroxyl radical, superoxide anion radical, DPPH radical and a strong reducing power. In vivo experiment demonstrated ARP (150mg/kg) administrated to mice for 7days prior to carbon tetrachloride treatment, attenuated the elevated expression levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG) in serum and inhibited the formation of hepatic malondialdehyde (MDA). ARP pretreatment also increased antioxidant enzyme activities such as glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (T AOC) in the liver of CCl4-induced mice. Furthermore, hepatic histopathological changes induced by CCl4 were significantly normalized by ARP pretreatment. These findings demonstrated that ARP possessed hepatoprotective effect against acute CCl4-induced liver damage by reducing lipid oxidation. PMID- 27993657 TI - Genome analysis of Chlamydia trachomatis for functional characterization of hypothetical proteins to discover novel drug targets. AB - C. trachomatis is a Gram-negative bacterium that causes trachoma and sexually transmitted disease (STD) Chlamydia in humans. Chlamydial genital infections are the most frequent among all communicable diseases. The D/UW-3/Cx strain of C. trachomatis contains 935 genes and three pseudogenes. Out of these genes, 887 genes code for proteins while six for rRNA, 37 tRNA, and three genes translate into other RNAs. The proteome of C. trachomatis made of 887 proteins contains 269 Hypothetical proteins (HPs) that are subjected to functional characterization. This study suggests some known methods of functional characterization of such HPs. All of these methods are explicitly used to assign functions to the HPs with the accuracy of more than 90%. After extensive analysis of all the HPs, we have successfully assigned functions to 89 HPs with high precision. In the newly assigned HPs, there are enzymes, transporters, binding proteins, proteins involved in biosynthesis and regulatory processes and proteins with miscellaneous functions. The study suggests that the functionally annotated HPs may play a vital role in the growth and pathogenesis of this organism. Therefore, they can be considered potential drug targets. PMID- 27993658 TI - Membrane-assisted viral DNA ejection. AB - Genome packaging and delivery are fundamental steps in the replication cycle of all viruses. Icosahedral viruses with linear double-stranded DNA (dsDNA) usually package their genome into a preformed, rigid procapsid using the power generated by a virus-encoded packaging ATPase. The pressure and stored energy due to this confinement of DNA at a high density is assumed to drive the initial stages of genome ejection. Membrane-containing icosahedral viruses, such as bacteriophage PRD1, present an additional architectural complexity by enclosing their genome within an internal membrane vesicle. Upon adsorption to a host cell, the PRD1 membrane remodels into a proteo-lipidic tube that provides a conduit for passage of the ejected linear dsDNA through the cell envelope. Based on volume analyses of PRD1 membrane vesicles captured by cryo-electron tomography and modeling of the elastic properties of the vesicle, we propose that the internal membrane makes a crucial and active contribution during infection by maintaining the driving force for DNA ejection and countering the internal turgor pressure of the host. These novel functions extend the role of the PRD1 viral membrane beyond tube formation or the mere physical confinement of the genome. The presence and assistance of an internal membrane might constitute a biological advantage that extends also to other viruses that package their linear dsDNA to high density within an internal vesicle. PMID- 27993659 TI - Study of ferritin self-assembly and heteropolymer formation by the use of Fluorescence Resonance Energy Transfer (FRET) technology. AB - The high stability and strong self-assembly properties made ferritins the most used proteins for nanotechnological applications. Human ferritins are made of 24 subunits of the H- and L-type that coassemble in an almost spherical nanocage 12nm across, delimiting a large cavity. The mechanism and kinetics of ferritin self-assembly and why H/L heteropolymers formation is favored over the homopolymers remain unclarified. In order to study this, we used the Fluorescence Resonance Energy Transfer (FRET) tool by binding multiple donor or acceptor Alexa Fluor fluorophores on the outer surface of human H and L ferritins and then denaturing and reassembling them in different proportions and conditions. The FRET efficiency increase from <0.3 of the disassembled to >0.7 in the assembled allowed to study the assembly kinetics. We found that their assembly was complete in about one hour, and that the initial rate of self-assembly of H/L heteropolymers was slightly faster than that of the H/H homopolymers. Then, by adding various proportions of unlabeled H or L-chains to the FRET system we found that the presence of the L-chains displaced the formation of H-H dimers more efficiently than that of the H-chains. This favored formation of H/L heterodimers, which is the initial step in ferritin self-assembly, contributes to explain the preferred formation of H/L heteropolymers over the H or L homopolymers. Moreover, we found that the H-chains arrange at distant positions on the heteropolymeric shell until they reach a number above eight, when they start to co-localize. PMID- 27993660 TI - Much more than you expected: The non-DHFR-mediated effects of methotrexate. AB - BACKGROUND: For decades, methotrexate (MTX; amethopterin) has been known as an antifolate inhibitor of dihydrofolate reductase (DHFR), and it is widely used for the treatment of various malignancies and autoimmune diseases. Although the inclusion of MTX in various therapeutic regimens is based on its ability to inhibit DHFR and consequently to suppress the synthesis of pyrimidine and purine precursors, recent studies have shown that MTX is also able to target other intracellular pathways that are independent of folate metabolism. SCOPE OF REVIEW: The main aim of this review is to summarize the most important, up-to date findings of studies regarding the non-DHFR-mediated mechanisms of MTX action. MAJOR CONCLUSIONS: The effectiveness of MTX is undoubtedly caused by its capability to affect various intracellular pathways at many levels. Although the most important therapeutic mechanism of MTX is strongly based on the inhibition of DHFR, many other effects of this compound have been described and new studies bring new insights into the pharmacology of MTX every year. GENERAL SIGNIFICANCE: Identification of these new targets for MTX is especially important for a better understanding of MTX action in new protocols of combination therapy. PMID- 27993662 TI - Complete Metabolic Evaluation is Indicated after a First Stone Event: Pro. PMID- 27993661 TI - Impact of labile metal nanoparticles on cellular homeostasis. Current developments in imaging, synthesis and applications. AB - BACKGROUND: The use of nanomaterials is constantly increasing in electronics, cosmetics, food additives, and is emerging in advanced biomedical applications such as theranostics, bio-imaging and therapeutics. However their safety raises concerns and requires appropriate methods to analyze their fate in vivo. SCOPE OF REVIEW: In this review, we describe the current knowledge about the toxicity of labile metal (ZnO, CuO and Ag) nanoparticles (NPs) both at the organism and cellular levels, and describe the pathways that are triggered to maintain cellular homeostasis. We also describe advanced elemental imaging approaches to analyze intracellular NP fate. Finally, we open the discussion by presenting recent developments in terms of synthesis and applications of Ag and CuO NPs. MAJOR CONCLUSIONS: Labile metal nanoparticles (MeNPs) release metal ions that trigger a cellular response involving biomolecules binding to the ions followed by regulation of the redox balance. In addition, specific mechanisms are set up by the cell in response to physiological ions such as Cu(I) and Zn(II). Among all types of NPs, labile MeNPs induce the strongest inflammatory responses which are most probably due to the combined effects of the NPs and of its released ions. Interestingly, recent developments in imaging technologies enable the intracellular visualization of both the NPs and their ions and promise new insights into nanoparticle fate and toxicity. GENERAL SIGNIFICANCE: The exponential use of nanotechnologies associated with the difficulties of assessing their impact on health and the environment has prompted scientists to develop novel methodologies to characterize these nanoobjects in a biological context. PMID- 27993664 TI - Post-Prostatectomy Radiation Therapy: Balancing Disease Control and Functional Outcomes. PMID- 27993663 TI - Risks of Serious Toxicities from Intermittent versus Continuous Androgen Deprivation Therapy for Advanced Prostate Cancer: A Population Based Study. AB - PURPOSE: Randomized trials have shown that intermittent androgen deprivation therapy for patients with advanced prostate cancer may improve sexual and physical functioning compared to continuous androgen deprivation therapy without compromising survival. To our knowledge it is unknown whether intermittent androgen deprivation therapy alters the risk of serious toxicities associated with continuous androgen deprivation therapy. MATERIALS AND METHODS: We performed a population based cohort study of 9,772 men 66 years old or older who were diagnosed with advanced prostate cancer from 2002 to 2011 and treated with androgen deprivation therapy. Intermittent androgen deprivation therapy was defined as a single 90-day interval between 2 androgen deprivation therapy sessions during which patients visited their physicians or underwent prostate specific antigen testing. Outcomes included acute myocardial infarction, stroke, heart failure, type 2 diabetes and fracture. We used Cox proportional hazard models to estimate the HRs of the comparative risk of serious toxicities between intermittent and continuous androgen deprivation therapy. RESULTS: A total of 2,113 (22%), 769 (9%) and 899 men (9%) had a new cardiovascular event, diabetes or fracture, respectively, within 5 years of starting androgen deprivation therapy. Compared to the continuous androgen deprivation therapy group, the intermittent therapy group was at lower risk for serious cardiovascular events (HR 0.64, 95% CI 0.53-0.77), particularly in reducing the risk of heart failure (HR 0.62, 95% CI 0.49-0.78) and fracture (HR 0.52, 95% CI 0.38-0.70, each p <0.0001). CONCLUSIONS: Intermittent androgen deprivation therapy was associated with a lower risk of heart failure and fracture compared to continuous androgen deprivation therapy. This raises toxicity concerns for continuous relative to intermittent therapy and suggests that intermittent androgen deprivation therapy may represent a safer therapeutic choice in elderly men with advanced prostate cancer. PMID- 27993665 TI - Active Surveillance for Favorable Risk Prostate Cancer in African Caribbean Men: Results of a Prospective Study. AB - PURPOSE: Active surveillance is a treatment option for favorable risk prostate cancer. However, data are missing on populations of African descent. We evaluated the safety and benefit of active surveillance in an African Caribbean cohort with favorable risk prostate cancer. MATERIALS AND METHODS: Between 2005 and 2016, a single center, prospective cohort study was performed in Guadeloupe, French West Indies, including patients on active surveillance who had low risk prostate cancer (prostate specific antigen 10 ng/ml or less and Gleason score 6 or less) or favorable intermediate risk prostate cancer (prostate specific antigen 10 to 20 ng/ml, Gleason score 3 + 4 or less and life expectancy less than 10 years). Treatment was recommended in case of grade progression, increased tumor volume, prostate cancer doubling time less than 36 months or patient wish. Overall survival, disease specific survival and duration of active surveillance were calculated with the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards model to identify predictors of active surveillance termination. RESULTS: A total of 234 patients with a median age of 64 years were enrolled in study. Median followup was 4 years (IQR 2.3-5.5). Overall survival at 30 months, 5 years and 10 years was 99.5%, 98.5% and 90.7%, respectively. Disease specific survival at 30 months, and 5 and 10 years was 100%. At 30 months, 5 years and 10 years 72.7%, 52.6% and 40.4% of patients, respectively, remained untreated and on active surveillance. Age (HR 0.96 per additional year, 95% CI 0.93-0.99) and prostate specific antigen density (HR 1.52 per additional 0.1 ng/ml, 95% CI 1.20-1.89) were found to be independent predictors of active surveillance termination. CONCLUSIONS: Active surveillance is safe and beneficial for highly selected African Caribbean patients. It seems to be feasible for patients at low risk and intermediate favorable risk. Prostate specific antigen density could help better select these patients. PMID- 27993666 TI - Patterns and Predictors of Recurrence after Partial Nephrectomy for Kidney Tumors. AB - PURPOSE: We sought to identify patterns and predictors of recurrence in patients with clinically localized renal cell carcinoma managed by partial nephrectomy. MATERIALS AND METHODS: We performed a retrospective study of 830 consecutive cases of partial nephrectomy done between 2007 and 2015 for clinically localized renal cell carcinoma at a single institution. Patient demographics and pathological characteristics were correlated with recurrence patterns (overall, local and distant) and overall survival using Kaplan-Meier and Cox regression analyses. Differences in the recurrence patterns were evaluated. RESULTS: Median patient age was 61 years and median tumor size was 3.1 cm. Overall, 11.6% of tumors were stage pT3, 39.3% were high grade, 2.9% had lymphovascular invasion and 7.1% had positive margins. Higher grade, higher stage, positive surgical margins and increased R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of deepest tumor portion to collecting system or sinus, anterior/posterior and location relative to polar line) score were associated with shorter disease-free survival on Kaplan-Meier analysis. On multivariable regression pT (p <0.01), grade (p <0.01) and R.E.N.A.L. score (p = 0.03) remained independent predictors of disease-free survival. Predictors of metastasis were pT stage (HR 4.5) and grade (HR 3.9, both p <0.01), while R.E.N.A.L. score (HR 3.2, p = 0.03) was the single predictor of local recurrence. Five-year disease-free and overall survival probabilities were 91% and 94%, respectively. Local recurrence manifested and developed earlier than metastasis (median 13 vs 22 months, p <0.01). CONCLUSIONS: High pT stage, high grade and high R.E.N.A.L. score increase the risk of disease recurrence after partial nephrectomy. The pT stage and grade are predictors of metastasis, while R.E.N.A.L. score predicts local recurrence. Because relapse features and risk factors differ between the 2 recurrence patterns, they should be studied separately in the future. PMID- 27993667 TI - Convective Thermal Therapy: Durable 2-Year Results of Randomized Controlled and Prospective Crossover Studies for Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia. AB - PURPOSE: We report 2-year outcomes of a multicenter randomized controlled trial plus 1-year results of a crossover trial after treatment with convective radiofrequency water vapor thermal energy for lower urinary tract symptoms due to benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 197 men at least 50 years old with I-PSS (International Prostate Symptom Score) 13 or greater, maximum flow rate 15 ml per second or less and prostate size 30 to 80 cc were randomized 2:1 to thermal therapy with the Rezum(r) System or a control group. Rigid cystoscopy with simulated active treatment sounds served as the control procedure. After unblinding at 3 months control subjects could requalify for crossover study. Convectively delivered radiofrequency thermal energy was delivered into obstructive prostate tissue, including the median lobe as needed. The primary efficacy end point was a change in severity of symptom scores. RESULTS: Convective radiofrequency thermal therapy improved urinary symptoms significantly over controls at 3 months and provided a sustained 51% reduction from baseline at 24 months (p <0.0001). This produced a 5 and 8-point or greater score decrease in 84% and 74% of subjects, respectively, at 24 months. Crossover subject symptoms, flow rate and quality of life measures were markedly improved after thermal therapy compared to after the control procedure (p = 0.024 to <0.0001). No de novo erectile dysfunction was reported. CONCLUSIONS: Convective radiofrequency water vapor thermal therapy is a minimally invasive office or outpatient procedure that provides early effective symptom relief that remains durable for 2 years and is applicable to the median lobe. PMID- 27993669 TI - Contrasting effects of glutamine deprivation on apoptosis induced by conventionally used anticancer drugs. AB - Tumor cells dependence on glutamine offers a rationale for their elimination via targeting of glutamine metabolism. The aim of this work was to investigate how glutamine deprivation affects the cellular response to conventionally used anticancer drugs. To answer this question, neuroblastoma cells were pre-incubated in a glutamine-free medium and treated with cisplatin or etoposide. Obtained results revealed that glutamine withdrawal affected cellular response to therapeutic drugs in a different manner. Glutamine deprivation suppressed etoposide-induced, but markedly stimulated cisplatin-induced apoptosis. Suppression of etoposide-induced cell death correlated with a downregulation of p53 expression, which, among other functions, regulates the expression of death receptor 5, one of the activators of caspase-8. In contrast, stimulation of cisplatin-induced cell death involved reactive oxygen species-mediated downregulation of FLIP-S, an inhibitor of caspase-8. As a result, the activity of caspase-8 was stimulated causing cleavage of the pro-apoptotic protein Bid, which is involved in the permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic factors, such as cytochrome c from mitochondria. Thus, suppression of glutamine metabolism can sensitize tumor cells to treatment and could be utilized for anti-cancer therapy. However, it should be done cautiously, since adverse effects may occur when combined with an inappropriate therapeutic drug. PMID- 27993668 TI - Early Oncologic Failure after Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium. AB - PURPOSE: We sought to investigate the prevalence and variables associated with early oncologic failure. MATERIALS AND METHODS: We retrospectively reviewed the IRCC (International Radical Cystectomy Consortium) database of patients who underwent robot-assisted radical cystectomy since 2003. The final cohort comprised a total of 1,894 patients from 23 institutions in 11 countries. Early oncologic failure was defined as any disease relapse within 3 months of robot assisted radical cystectomy. All institutions were surveyed for the pneumoperitoneum pressure used, breach of oncologic surgical principles, and techniques of specimen and lymph node removal. A multivariate model was fit to evaluate predictors of early oncologic failure. The Kaplan-Meier method was applied to depict disease specific and overall survival, and Cox proportional regression analysis was used to evaluate predictors of disease specific and overall survival. RESULTS: A total of 305 patients (22%) experienced disease relapse, which was distant in 220 (16%), local recurrence in 154 (11%), peritoneal carcinomatosis in 17 (1%) and port site recurrence in 5 (0.4%). Early oncologic failure developed in 71 patients (5%) at a total of 10 institutions. The incidence of early oncologic failure decreased from 10% in 2006 to 6% in 2015. On multivariate analysis the presence of any complication (OR 2.87, 95% CI 1.38-5.96, p = 0.004), pT3 or greater disease (OR 3.73, 95% CI 2.00-6.97, p <0.001) and nodal involvement (OR 2.14, 95% CI 1.21-3.80, p = 0.008) was a significant predictor of early oncologic failure. Patients with early oncologic failure demonstrated worse disease specific and overall survival (23% and 13%, respectively) at 1 and 3 years compared to patients who experienced later or no recurrences (log rank p <0.001). CONCLUSIONS: The incidence of early oncologic failure following robot-assisted radical cystectomy has decreased with time. Disease related rather than technical related factors have a major role in early oncologic failure after robot-assisted radical cystectomy. PMID- 27993670 TI - Interactome of the inhibitory isoform of the nuclear transporter Importin 13. AB - Importin 13 (Imp13) is a bidirectional nuclear transporter of proteins involved in a range of important cellular processes, with an N-terminally truncated inhibitory isoform (tImp13) specifically expressed in testis. To gain insight into tImp13 function, we performed a yeast-2-hybrid screen from a human testis cDNA library, identifying for the first time a suite of interactors with roles in diverse cellular process. We validated the interaction of tImp13 with Eukaryotic translation initiation factor 4gamma2 (EIF4G2) and High mobility group containing protein 20A (HMG20A), benchmarking that with glucocorticoid receptor (GR), a known Imp13 interactor expressed in testis. Coimmunoprecipitation assays indicated association of both tImp13 and Imp13 with EIF4G2, HMG20A and GR. Quantitative confocal microscopic analysis revealed the ability of tImp13 to inhibit the nuclear localisation of EIF4G2, HMG20A and GR, as well as that of Imp13 to act as a nuclear exporter for both EIF4G2 and HMG20A, and as a nuclear importer for GR. The physiological relevance of these results was highlighted by the cytoplasmic localisation of EIF4G2, HMG20A and GR in pachytene spermatocytes/round spermatids in the murine testis where tImp13 is present at high levels, in contrast to the nuclear localisation of HMG20A and GR in spermatogonia, where tImp13 is largely absent. Interestingly, Imp13, EIF4G2, HMG20A and GR were found together in the acrosome vesicle of murine epididymal spermatozoa. Collectively, our findings show, for the first time, that tImp13 may have a functional role in the mature spermatozoa, in addition to that in the meiotic germ cells of the testis. PMID- 27993671 TI - Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function. AB - Autophagy is a catabolic process that targets and degrades cytoplasmic materials. In skeletal muscle, autophagy is required for the control of mass under catabolic conditions, but is also basally active in the maintenance of myofiber homeostasis. In this study, we found that some specific autophagic markers (LC3 I, LC3-II, SQSTM1) were basally lower in glycolytic muscle compared to oxidative muscle of autophagy competent mice. In contrast, basal autophagic flux was higher in glycolytic muscle. In addition, we used several skeletal muscle-specific Atg7 transgenic mouse models to investigate the effect of acute (iAtg7-/-) and chronic (cAtg7-/-) autophagy deficiency on skeletal muscle morphology, contractility, and apoptotic signaling. While acute autophagy ablation (iAtg7-/-) resulted in increased centralized nuclei in glycolytic muscle, it did not alter contractile properties or measures of apoptosis and proteolysis. In contrast, with chronic autophagy deficiency (cAtg7-/-) there was an increased proportion of centralized nuclei, as well as reduced force and altered twitch kinetics in glycolytic muscle. Glycolytic muscle of cAtg7-/- mice also displayed an increased level of the pro-apoptotic protein BAX, as well as calpain and proteasomal enzymatic activity. Collectively, our data demonstrate cumulative damage from chronic skeletal muscle-specific autophagy deficiency with associated apoptotic and proteasomal upregulation. These findings point towards the importance of investigating different muscle/fiber types when studying skeletal muscle autophagy, and the critical role of autophagy in the maintenance of myofiber function, integrity, and cellular health. PMID- 27993674 TI - Beyond the FFA: Brain-behavior correspondences in face recognition abilities. AB - Despite the thousands of papers investigating the neural basis of face perception in both humans and non-human primates, very little is known about how activation within this neural architecture relates to face processing behavior. Here, we investigated individual differences in brain-behavior correspondences within both core and extended regions of the face-processing system in healthy typically developing adults. To do so, we employed a set of behavioral and neural measures to capture a multifaceted perspective on assessing these brain-behavior relations. This included quantifying face and object recognition behavior, the magnitude and size of functional activation within each region, as well as a measure of global activation across regions. We report that face, but not object, recognition behavior was associated with 1) the magnitude of face-selective activation in the left FFA1, 2) larger face-related regions in multiple bilateral face-patches in the fusiform gyri as well as the bilateral anterior temporal lobe and amygdala, and 3) more distributed global face-network activation. In contrast, face recognition behavior was not associated with any measure of object or place-selective activation. These findings suggest that superior behavior is served by engaging sufficiently large, distributed patches of neural real estate, which might reflect the integration of independent populations of neurons that enables the formation of richer representations. PMID- 27993672 TI - Comparison of fMRI analysis methods for heterogeneous BOLD responses in block design studies. AB - A large number of fMRI studies have shown that the temporal dynamics of evoked BOLD responses can be highly heterogeneous. Failing to model heterogeneous responses in statistical analysis can lead to significant errors in signal detection and characterization and alter the neurobiological interpretation. However, to date it is not clear that, out of a large number of options, which methods are robust against variability in the temporal dynamics of BOLD responses in block-design studies. Here, we used rodent optogenetic fMRI data with heterogeneous BOLD responses and simulations guided by experimental data as a means to investigate different analysis methods' performance against heterogeneous BOLD responses. Evaluations are carried out within the general linear model (GLM) framework and consist of standard basis sets as well as independent component analysis (ICA). Analyses show that, in the presence of heterogeneous BOLD responses, conventionally used GLM with a canonical basis set leads to considerable errors in the detection and characterization of BOLD responses. Our results suggest that the 3rd and 4th order gamma basis sets, the 7th to 9th order finite impulse response (FIR) basis sets, the 5th to 9th order B spline basis sets, and the 2nd to 5th order Fourier basis sets are optimal for good balance between detection and characterization, while the 1st order Fourier basis set (coherence analysis) used in our earlier studies show good detection capability. ICA has mostly good detection and characterization capabilities, but detects a large volume of spurious activation with the control fMRI data. PMID- 27993673 TI - Propofol attenuates low-frequency fluctuations of resting-state fMRI BOLD signal in the anterior frontal cortex upon loss of consciousness. AB - Recent studies indicate that spontaneous low-frequency fluctuations (LFFs) of resting-state functional magnetic resonance imaging (rs-fMRI) blood oxygen level dependent (BOLD) signals are driven by the slow (<0.1Hz) modulation of ongoing neuronal activity synchronized locally and across remote brain regions. How regional LFFs of the BOLD fMRI signal are altered during anesthetic-induced alteration of consciousness is not well understood. Using rs-fMRI in 15 healthy participants, we show that during administration of propofol to achieve loss of behavioral responsiveness indexing unconsciousness, the fractional amplitude of LFF (fALFF index) was reduced in comparison to wakeful baseline in the anterior frontal regions, temporal pole, hippocampus, parahippocampal gyrus, and amygdala. Such changes were absent in large areas of the motor, parietal, and sensory cortices. During light sedation characterized by the preservation of overt responsiveness and therefore consciousness, fALFF was reduced in the subcortical areas, temporal pole, medial orbital frontal cortex, cingulate cortex, and cerebellum. Between light sedation and deep sedation, fALFF was reduced primarily in the medial and dorsolateral frontal areas. The preferential reduction of LFFs in the anterior frontal regions is consistent with frontal to sensory-motor cortical disconnection and may contribute to the suppression of consciousness during general anesthesia. PMID- 27993675 TI - The cyclophilin D/Drp1 axis regulates mitochondrial fission contributing to oxidative stress-induced mitochondrial dysfunctions in SH-SY5Y cells. AB - Oxidative stress plays a central role in the pathogenesis of various neurodegenerative diseases. Increasing evidences have demonstrated that structural abnormalities in mitochondria are involved in oxidative stress related nerve cell damage. And Drp1 plays a critical role in mitochondrial dynamic imbalance insulted by oxidative stress-derived mitochondria. However, the status of mitochondrial fusion and fission pathway and its relationship with mitochondrial properties such as mitochondrial membrane permeability transition pore (mPTP) have not been fully elucidated. Here, we demonstrated for the first time the role of Cyclophilin D (CypD), a crucial component for mPTP formation, in the regulation of mitochondrial dynamics in oxidative stress treated nerve cell. We observed that CypD-mediated phosphorylation of Drp1 and subsequently augmented Drp1 recruitment to mitochondria and shifts mitochondrial dynamics toward excessive fission, which contributes to the mitochondrial structural and functional dysfunctions in oxidative stress-treated nerve cells. CypD depletion or over expression accompanies mitochondrial dynamics/functions recovery or aggravation separately. We also demonstrated first time the link between the CypD to mitochondrial dynamics. Our data offer new insights into the mechanism of mitochondrial dynamics which contribute to the mitochondrial dysfunctions, specifically the role of CypD in Drp1-mediated mitochondrial fission. The protective effect of CsA, or other molecules affecting the function of CypD hold promise as a potential novel therapeutic strategy for governing oxidative stress pathology via mitochondrial pathways. PMID- 27993676 TI - Fucosyltransferases produce N-glycans containing core l-galactose. AB - l-Galactose (l-Gal) containing N-glycans and cell wall polysaccharides have been detected in the l-Fuc deficient mur1 mutant of Arabidopsis thaliana. The l-Gal residue is thought to be transferred from GDP-l-Gal, which is a structurally related analog of GDP-l-Fuc, but in vitrol-galactosylation activity has never been detected. In this study, we carried out preparative scale GDP-l-Gal synthesis using recombinant A. thaliana GDP-mannose-3',5'-epimerase. We also demonstrated the l-galactosylation assay of mouse alpha1,6-fucosyltransferase (MmFUT8) and A. thaliana alpha1,3-fucosyltransferase (AtFucTA). Both fucosyltransferases showed l-galactosylation activity from GDP-l-Gal to asparagine-linked N-acetyl-beta-d-glucosamine of asialo-agalacto-bi-antennary N glycan instead of l-fucosylation. In addition, the apparent Km values of MmFUT8 and AtFucTA suggest that l-Fuc was preferentially transferred to N-glycan compared with l-Gal by fucosyltransferases. Our results clearly demonstrate that MmFUT8 and AtFucTA transfer l-Gal residues from GDP-l-Gal and synthesize l-Gal containing N-glycan in vitro. PMID- 27993677 TI - Identification of miR-601 as a novel regulator in the development of pancreatic cancer. AB - Pancreatic cancer (PC) is one of the most aggressive malignancies, with a high mortality. Distant metastasis and recurrence are the main causes of PC-related deaths. MicroRNAs (miRNAs) have been reported in the serum or tumor tissue of cancer patients, including PC, which makes them potential biomarkers. The dysfunction of many miRNAs has been linked to PC occurrence and metastasis. In the current study, we found that miR-601 expression was significantly lower in PC samples, especially in metastatic compared to non-metastatic PC tissues. Gain-of function and loss-of-function analysis showed that miR-601 suppressed PC cell proliferation and migration. One potential mechanism is that miR-601 inhibited the expression of Sirtuin 1 (SIRT1), which is a well-known regulator of PC development. We found that overexpression of SIRT1 could reverse the effect of miR-601 on PC cells. Our investigation therefore suggests that both miR-601 and SIRT1 are possible biomarkers for the early detection, and targets for the treatment of PC. PMID- 27993678 TI - Chemical inhibition of the histone acetyltransferase activity in Arabidopsis thaliana. AB - Chemical inhibition of chromatin regulators provides an effective approach to investigate the roles of chromatin modifications in plant and animals. In this work, chemical inhibition of the Arabidopsis histone acetyltransferase activity by gamma-butyrolactone (MB-3), the inhibitor of the catalytic activity of mammalian GENERAL CONTROL NON-REPRESSIBLE 5 (GCN5) is evaluated. Arabidopsis seedlings were germinated in LS medium supplemented with different concentrations of MB-3, and inhibition in the root length and yellowed leaves were observed. The yellowed leaves phenotype of the plants grown in 100 MUM of MB-3 was reverted when plants were additionally treated with 1 MUM of TSA, a histone deacetylase inhibitor. Using an immunoblot assay with specific antibodies revealed a reduction of H3K14 acetylation levels at 3 and 24 h post-treatment. At 24 h post treatment a reduction of H3K9 acetylation levels was observed. Targets of GCN5 related to stress were downregulated at 3 h post-treatment but no change was observed in target genes related to developmental transition. Our results indicate that MB-3 is a chemical inhibitor of the histone acetyltransferase in Arabidopsis and suggest that this inhibitor could function in other plants species. PMID- 27993679 TI - Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition. AB - Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays. Consistently, knockdown of SIN1 inhibited the proliferation of these cells. In transwell assay, overexpression of SIN1 increased the migration of A549 and H1299 cells, while SIN1 knockdown reduced their migration. In a tumor xenograft model, overexpression of SIN1 promoted tumor growth of A549 cells in vivo, while SIN1 knockdown suppresses the tumor growth. We also found a mechanistic link between SIN1 and H3K4me3, H3K4me3 is involved in SIN1 upregulation. Moreover, SIN1 can significantly promote the in vitro migration and invasion of NSCLC cells via induction epithelial mesenchymal transition (EMT) process, which subsequently leads to transcriptional downregulation of epithelial marker E-cadherin and upregulation of mesenchymal markers N-cadherin and Vimentin expression. Together, our results reveal that SIN1 plays an important role in NSCLC and SIN1 is a potential biomarker and a promising target in the treatment of NSCLC. PMID- 27993680 TI - Co-crystal structures of PTK6: With Dasatinib at 2.24 A, with novel imidazo[1,2 a]pyrazin-8-amine derivative inhibitor at 1.70 A resolution. AB - Human Protein tyrosine kinase 6 (PTK6)(EC:2.7.10.2), also known as the breast tumor kinase (BRK), is an intracellular non-receptor Src-related tyrosine kinase expressed five-fold or more in human breast tumors and breast cancer cell lines but its expression being low or completely absent from normal mammary gland. There is a recent interest in targeting PTK6-positive breast cancer by developing small molecule inhibitor against PTK6. Novel imidazo[1,2-a]pyrazin-8-amines (IPA) derivative compounds and FDA approved drug, Dasatinib are reported to inhibit PTK6 kinase activity with IC50 in nM range. To understand binding mode of these compounds and key interactions that drive the potency against PTK6, one of the IPA compounds and Dasatinib were chosen to study through X-ray crystallography. The recombinant PTK6 kinase domain was purified and co-crystallized at room temperature by the sitting-drop vapor diffusion method, collected X-ray diffraction data at in-house and resolved co-crystal structure of PTK6-KD with Dasatinib at 2.24 A and with IPA compound at 1.70 A resolution. Both these structures are in DFG-in & alphaC-helix-out conformation with unambiguous electron density for Dasatinib or IPA compound bound at the ATP-binding pocket. Relative difference in potency between Dasatinib and IPA compound is delineated through the additional interactions derived from the occupation of additional pocket by Dasatinib at gatekeeper area. Refined crystallographic coordinates for the kinase domain of PTK6 in complex with IPA compound and Dasatinib have been submitted to Protein Data Bank under the accession number 5DA3 and 5H2U respectively. PMID- 27993681 TI - Lysophosphatidic acid (LPA) signaling via LPA4 and LPA6 negatively regulates cell motile activities of colon cancer cells. AB - Lysophosphatidic acid (LPA) is an extracellular biological lipid and interacts with six subtypes of G protein-coupled LPA receptors (LPA1 to LPA6). LPA receptors exhibit a variety of cellular functions, depending on types of cancer cells. In this study, to assess the roles of LPA4 and LPA6 in cell growth and motile activities of colon cancer cells, LPA4 and LPA6 knockdown cells were established from DLD1 and HCT116 cells. LPA treatment increased the cell growth activities of LPA4 and LPA6 knockdown cells, compared with control cells. The cell motile activities of LPA4 and LPA6 knockdown cells were significantly higher than those of control cells. To evaluate the effects of LPA4 and LPA6 on cell motile activity induced by anticancer drug, long-term fluorouracil (5-FU) treated (DLD-5FU) cells were generated. The expression levels of LPAR1, LPAR4 and LPAR6 genes were significantly increased in DLD-5FU cells. DLD-5FU cells showed the high cell motile activity, compared with DLD1 cells. The increased cell motile activity was markedly stimulated by LPA4 and LPA6 knockdown. In contrast, the cell motile activity enhanced by 5-FU treatment was suppressed by LPA1 knockdown. These results suggest that LPA signaling via LPA4 and LPA6 negatively regulates the cell motile activities of DLD1 and HCT116 cells as well as long-term 5-FU treated cells. PMID- 27993682 TI - Trastuzumab stimulation of ribosomal protein S6 kinase 1 (S6K1) predicts de novo trastuzumab resistance. AB - Breast cancer is a complex disease with at least five different molecular subtypes identified. The breast tumor molecular subtypes guide stratification of patients for specific targeted therapy regimens and each subtype is associated with significantly different patient outcomes. For example, patients with the HER2 positive molecular subtype benefit from the HER2 targeted therapy trastuzumab. Unfortunately, women with the HER2 positive molecular subtype have the worst overall prognosis and nearly 70% of women with HER2 positive breast cancer exhibit de novo or acquired resistance to trastuzumab. Identification of tumor markers predicting trastuzumab response can be used to further stratify patients for life-saving personalized therapeutic options. The aim of this study was to identify clinically useful tumor markers predicting de novo tumor cell resistance to trastuzumab treatment. To identify oncogenic signaling pathways activated in response to trastuzumab treatment, we performed a Human Phospho Kinase Proteome Profiler Array analysis comparing trastuzumab sensitive MCF 7/HER2.2 and trastuzumab resistant MCF-7/HER2Delta16H cells following acute treatment with 20 MUg/ml of trastuzumab for 2 h. We found that of the 43 phosphorylation activated human kinases represented on the array, S6K1 was the only kinase altered greater than 1.5-fold in response to trastuzumab treatment of the trastuzumab resistant MCF-7/HER2Delta16H cells. Trastuzumab activation of S6K1 was confirmed in the two trastuzumab resistant SUM190 and SUM225 cell lines. Significantly, trastuzumab failed to stimulate S6K1 activation in the trastuzumab sensitive MCF-7/HER2.2, BT474, and SKBR3 cell lines suggesting that trastuzumab activation of S6K1 is a tumor cell marker for trastuzumab resistance. Consistent with a role for mTORC1/S6K1 signaling promoting trastuzumab resistance, all cell lines were sensitive to S6K1 inactivation with significant growth inhibition following treatment with the mTORC1 inhibitor rapamycin. In conclusion, characterizing rapid trastuzumab induced molecular alterations resulted in the identification of activated S6K1 as an early breast tumor cell marker for trastuzumab resistance. Our results further suggest that trastuzumab resistant breast tumor cells are addicted to mTORC1/S6K1 oncogenic signaling and targeting mTORC1 with rapamycin reverses trastuzumab resistance. PMID- 27993683 TI - Autoacetylation of NAT10 is critical for its function in rRNA transcription activation. AB - NAT10, an important member of GNAT family, harbors histone acetyltransferase and participates in many cellular processes such as ribosome production and cell cycle. Here, we report that NAT10 is acetylated in vivo and autoacetylated in vitro. The lysine residue at 426 (K426) is the acetylation site of NAT10. K426R mutant of NAT10 fails to activate rRNA transcription. NAT10 K426R loses its capability of acetylating UBF though it still binds UBF, which fails to recruit PAF53 and RNA polymerase I to rDNA, eventually resulting in inhibition of pre rRNA transcription. Therefore, acetylation of K426 in NAT10 is required for its function in activating rRNA transcription. These findings identify a new post translational modification on NAT10 which regulates its function. PMID- 27993684 TI - Modified mesoporous silica nanoparticles for enhancing oral bioavailability and antihypertensive activity of poorly water soluble valsartan. AB - The aim was to improve the oral bioavailability and antihypertensive activity of poorly soluble drug valsartan (VAL) by modifying the design and delivery of mesoporous silica nanoparticles (MSNs). The synthesized MSNs were functionalized with aminopropyl groups (AP-MSN) through postsynthesis and coated with pH sensitive polymer Eudragit L100-55 (AP-MSN-L100-55) for pH dependant sustain release of anionic VAL. MSNs were characterized by Brauner-Emmett-Teller (BET) surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope (FESEM), Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC). Functionalized MSNs showed highest entrapment efficiency (59.77%) due to strong ionic interaction with VAL. In vitro dissolution of M-MSN [MSN-VAL and AP MSN-VAL-L100-55 mixed equally] at physiological conditions demonstrated immediate release (MSN-VAL fraction) followed by sustained release (AP-MSN-VAL-L100-55 fraction) of 96% VAL in 960min. The dramatic improvement in dissolution was attributed to the amorphization of crystalline VAL by MSNs as evidenced by DSC and PXRD studies. No noticeable cytotoxicity was observed for MSN, AP-MSN and AP MSN-L100-55 in MTT assay. Pharmacokinetic study of M-MSN confirmed 1.82 fold increases in bioavailability compared to commercial Diovan tablet in fasted male rabbits. Blood pressure monitoring in rats showed that the morning dosing of Diovan tablet efficiently controlled BP for just over 360min whereas the effect of M-MSN lasted for >840min. PMID- 27993685 TI - Simvastatin inhibits homocysteine-induced CRP generation via interfering with the ROS-p38/ERK1/2 signal pathway in rat vascular smooth muscle cells. AB - Inflammation plays a pivotal role throughout the formation and progression of atherosclerosis. As the most representative inflammatory marker, C-reactive protein (CRP) directly participates in the initiation and development of atherosclerosis. The elevated homocysteine (Hcy) level in plasma is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by stimulating CRP expression in vascular smooth muscle cells (VSMCs). The present study observed the effect of simvastatin on Hcy-induced CRP expression in VSMCs and the molecular mechanisms. The in vitro experiments revealed that pretreatment of VSMCs with simvastatin decreased Hcy induced mRNA and protein expression of CRP in a concentration-dependent fashion. The in vivo results showed that simvastatin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further experiments displayed that simvastatin reduced Hcy-induced reactive oxygen species (ROS) generation, ameliorated Hcy-activated phosphorylations of ERK1/2 and p38, and antagonized Hcy downregulated peroxisome proliferator-activated receptor gamma expression in VSMCs. These data demonstrate that simvastatin is able to inhibit Hcy-induced CRP generation in VSMCs so to relieve the vascular inflammatory response via interfering with the ROS-MAPK signal pathway. The present results provide new evidence for understanding of the potential anti-inflammatory and anti atherosclerotic effects of simvastatin. As the high level of Hcy in plasma is related to atherosclerosis formation and mediates cardiovascular risk, our findings emphasize the importance and necessity of therapy with statins for hyperhomocysteinemia in atherosclerosis. PMID- 27993687 TI - A literary approach to tuberculosis: lessons learned from Anton Chekhov, Franz Kafka, and Katherine Mansfield. AB - Letters by notable writers from the past century can provide valuable information on the times in which they lived. In this article, attention is drawn to the lessons learned from three famous writers who died of tuberculosis: Anton Chekhov, Franz Kafka, and Katherine Mansfield. The characteristics of the course of the disease in the pre-antibiotic era and the importance of addressing mental health in the management of tuberculosis are discussed. PMID- 27993686 TI - MicroRNA-126 suppresses inflammation in endothelial cells under hyperglycemic condition by targeting HMGB1. AB - MicroRNA-126(miR-126) targets involved in inflammation need to be identified. In this study, we aim to investigate whether high-mobility group box 1(HMGB1), an inflammation-related gene, is the target of miR-126 in diabetic vascular endothelium. The diabetic apoE-/- mice model, a classical diabetic atherosclerosis model, was established. The aorta of diabetic apoE-/- mice showed decrease of miR-126 and elevation of HMGB1 and inflammation. Next, we employed several in vitro experiments to address the role of miRNA-126 on the regulation of HMGB1 in endothelial cells under hyperglycemic and inflammatory conditions. Manipulation of miRNA levels in human umbilical vein endothelial cells (HUVECs) was achieved by transfecting cells with miR-126 mimic and antagomir. Overexpression of miR-126 could decrease the expression of downstream components of HMGB1 including TNF-alpha, ROS, and NADPH oxidase activity in HUVECs under hyperglycemic condition. Nevertheless, such phenomenon was completely reversed by miR-126 antagomir. The expression of HMGB1 protein rather than HMGB1 mRNA was down-regulated after transfection with miR-126 mimic, which indicated the modulation of HMGB1 mediated by miR-126 was at the posttranslational level. Luciferase reporter assay confirmed the 3'-UTR of HMGB1 gene was a direct target of miR-126. Western blot analysis also indicated that overexpression of miR-126 contributed to the elevation of p-eNOS, eNOS and p-AKT expressions, respectively. In summary, our findings suggest that miR-126 may suppress inflammation and ROS production in endothelial cells treated by high glucose through modulating the expression of HMGB1. Our study provides a novel pathogenic link between dysregulated miRNA expression and inflammation in diabetic vascular endothelium. PMID- 27993688 TI - Improving access to tuberculosis preventive therapy and treatment for children. AB - Children suffer a huge burden of disease in tuberculosis (TB) endemic countries. This disease burden was largely invisible when TB control programmes focused exclusively on adults with sputum smear-positive disease. High-level advocacy and better data have improved visibility, but the establishment of functional paediatric TB programmes remains challenging. The key issues that limit children's access to TB preventive therapy and treatment in endemic areas are briefly discussed. Barriers to preventive therapy include (1) the perceived inability to rule out active disease, (2) fear of creating drug resistance, (3) non-implementation of existing guidelines in the absence of adequate monitoring, and (4) poor adherence with long preventive therapy courses. Barriers to TB treatment include (1) perceived diagnostic difficulties, (2) non-availability of chest radiography, (3) young children presenting to unprepared maternal and child health (MCH) services, and (4) the absence of child-friendly formulations. With drug-resistant disease there is currently no guidance on the use of preventive therapy and treatment is usually restricted to cases with bacteriologically confirmed disease, which excludes most young children from care, even if their likely source case has documented drug-resistant TB. PMID- 27993689 TI - Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia. AB - Despite pain being a sensory experience, studies of spinal cord ventral root damage have demonstrated that motor neuron injury can induce neuropathic pain. Whether injury of cranial motor nerves can also produce nociceptive hypersensitivity has not been addressed. Herein, we demonstrate that chronic constriction injury (CCI) of the buccal branch of the facial nerve results in long-lasting, unilateral allodynia in the rat. An anterograde and retrograde tracer (3000MW tetramethylrhodamine-conjugated dextran) was not transported to the trigeminal ganglion when applied to the injury site, but was transported to the facial nucleus, indicating that this nerve branch is not composed of trigeminal sensory neurons. Finally, intracisterna magna injection of interleukin 1 (IL-1) receptor antagonist reversed allodynia, implicating the pro-inflammatory cytokine IL-1 in the maintenance of neuropathic pain induced by facial nerve CCI. These data extend the prior evidence that selective injury to motor axons can enhance pain to supraspinal circuits by demonstrating that injury of a facial nerve with predominantly motor axons is sufficient for neuropathic pain, and that the resultant pain has a neuroimmune component. PMID- 27993691 TI - Effects of ZnSO4-induced peripheral anosmia on zebrafish behavior and physiology. AB - Olfaction plays a key role in modulating behavioral and physiological responses of various animal species, including fishes. Olfactory deficits can be induced in fish experimentally, and utilized to examine the role of olfaction in their normal and pathological behaviors. Here, we examine whether experimental anosmia, evoked by ZnSO4 in adult zebrafish can be associated with behavioral and/or physiological responses. We show that experimental ZnSO4-induced anosmia caused acute, but not prolonged, anxiogenic-like effects on zebrafish behavior tested in the novel tank test. The procedure also elevated whole-body cortisol levels in zebrafish. Moreover, ZnSO4 treatment, but not sham, produced damage to olfactory epithelium, inducing overt basal cell vacuolization and intercellular edema. The loss of olfaction, assessed by the fish food preference behavior in the aquatic Y maze, was present 1h, but not 24h, after the treatment. Collectively, this suggests that transient experimental anosmia by ZnSO4 modulates zebrafish behavior and olfaction, which can be used to evoke and assess their stress related anxiety-like states. PMID- 27993693 TI - Whole-brain functional connectivity during acquisition of novel grammar: Distinct functional networks depend on language learning abilities. AB - In an effort to advance the understanding of brain function and organisation accompanying second language learning, we investigate the neural substrates of novel grammar learning in a group of healthy adults, consisting of participants with high and average language analytical abilities (LAA). By means of an Independent Components Analysis, a data-driven approach to functional connectivity of the brain, the fMRI data collected during a grammar-learning task were decomposed into maps representing separate cognitive processes. These included the default mode, task-positive, working memory, visual, cerebellar and emotional networks. We further tested for differences within the components, representing individual differences between the High and Average LAA learners. We found high analytical abilities to be coupled with stronger contributions to the task-positive network from areas adjacent to bilateral Broca's region, stronger connectivity within the working memory network and within the emotional network. Average LAA participants displayed stronger engagement within the task-positive network from areas adjacent to the right-hemisphere homologue of Broca's region and typical to lower level processing (visual word recognition), and increased connectivity within the default mode network. The significance of each of the identified networks for the grammar learning process is presented next to a discussion on the established markers of inter-individual learners' differences. We conclude that in terms of functional connectivity, the engagement of brain's networks during grammar acquisition is coupled with one's language learning abilities. PMID- 27993690 TI - A seasonal switch in histone deacetylase gene expression in the hypothalamus and their capacity to modulate nuclear signaling pathways. AB - Seasonal animals undergo changes in physiology and behavior between summer and winter conditions. These changes are in part driven by a switch in a series of hypothalamic genes under transcriptional control by hormones and, of recent interest, inflammatory factors. Crucial to the control of transcription are histone deacetylases (HDACs), generally acting to repress transcription by local histone modification. Seasonal changes in hypothalamic HDAC transcripts were investigated in photoperiod-sensitive F344 rats by altering the day-length (photoperiod). HDAC4, 6 and 9 were found to change in expression. The potential influence of HDACs on two hypothalamic signaling pathways that regulate transcription, inflammatory and nuclear receptor signaling, was investigated. For inflammatory signaling the focus was on NF-kappaB because of the novel finding made that its expression is seasonally regulated in the rat hypothalamus. For nuclear receptor signaling it was discovered that expression of retinoic acid receptor beta was regulated seasonally. HDAC modulation of NF-kappaB-induced pathways was examined in a hypothalamic neuronal cell line and primary hypothalamic tanycytes. HDAC4/5/6 inhibition altered the control of gene expression (Fos, Prkca, Prkcd and Ptp1b) by inducers of NF-kappaB that activate inflammation. These inhibitors also modified the action of nuclear receptor ligands thyroid hormone and retinoic acid. Thus seasonal changes in HDAC4 and 6 have the potential to epigenetically modify multiple gene regulatory pathways in the hypothalamus that could act to limit inflammatory pathways in the hypothalamus during long-day summer-like conditions. PMID- 27993692 TI - Suboptimal choice in rats: Incentive salience attribution promotes maladaptive decision-making. AB - Stimuli that are more predictive of subsequent reward also function as better conditioned reinforcers. Moreover, stimuli attributed with incentive salience function as more robust conditioned reinforcers. Some theories have suggested that conditioned reinforcement plays an important role in promoting suboptimal choice behavior, like gambling. The present experiments examined how different stimuli, those attributed with incentive salience versus those without, can function in tandem with stimulus-reward predictive utility to promote maladaptive decision-making in rats. One group of rats had lights associated with goal tracking as the reward-predictive stimuli and another had levers associated with sign-tracking as the reward-predictive stimuli. All rats were first trained on a choice procedure in which the expected value across both alternatives was equivalent but differed in their stimulus-reward predictive utility. Next, the expected value across both alternatives was systematically changed so that the alternative with greater stimulus-reward predictive utility was suboptimal in regard to primary reinforcement. The results demonstrate that in order to obtain suboptimal choice behavior, incentive salience alongside strong stimulus-reward predictive utility may be necessary; thus, maladaptive decision-making can be driven more by the value attributed to stimuli imbued with incentive salience that reliably predict a reward rather than the reward itself. PMID- 27993694 TI - Effects of chronic methamphetamine on psychomotor and cognitive functions and dopamine signaling in the brain. AB - Methamphetamine (MA) studies in animals usually involve acute, binge, or short term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed. PMID- 27993696 TI - Long-Term Outcomes after Abdominal Wall Reconstruction with Acellular Dermal Matrix. AB - BACKGROUND: Long-term outcomes data for hernia recurrence rates after abdominal wall reconstruction (AWR) with acellular dermal matrix (ADM) are lacking. The aim of this study was to assess the long-term durability of AWR using ADM. STUDY DESIGN: We studied patients who underwent AWR with ADM at a single center in 2005 to 2015 with a minimum follow-up of 36 months. Hernia recurrence was the primary end point and surgical site occurrence (SSO) was a secondary end point. The recurrence-free survival curves were estimated by Kaplan-Meier product limit method. Univariate and multivariable Cox proportional hazards regression models and logistic regression models were used to evaluate the associations of risk factors at surgery with subsequent risks for hernia recurrence and SSO, respectively. RESULTS: A total of 512 patients underwent AWR with ADM. After excluding those with follow-up less than 36 months, 191 patients were included, with a median follow-up of 52.9 months (range 36 to 104 months). Twenty-six of 191 patients had a hernia recurrence documented in the study. The cumulative recurrence rates were 11.5% at 3 years and 14.6% by 5 years. Factors significantly predictive of hernia recurrence developing included bridged repair, wound skin dehiscence, use of human cadaveric ADM, and coronary disease; component separation was protective. In a subset analysis excluding bridged repairs and human cadaveric ADM patients, cumulative hernia recurrence rates were 6.4% by 3 years and 8.3% by 5 years. The crude rate of SSO was 25.1% (48 of 191). Factors significantly predictive of the incidence of SSO included at least 1 comorbidity, BMI >=30 kg/m2, and defect width >15 cm. CONCLUSIONS: Use of ADM for AWR was associated with 11.5% and 14.6% hernia recurrence rates at 3- and 5-years follow-up, respectively. Avoiding bridged repairs and human cadaveric ADM can improve long-term AWR outcomes using ADM. PMID- 27993695 TI - Effects of orally administered Augmentin on glutamate transporter 1, cystine glutamate exchanger expression and ethanol intake in alcohol-preferring rats. AB - Alcohol dependence is associated with deficits in glutamate uptake and impairment of glutamate homeostasis in different brain reward regions. Glutamate transporter subtype 1 (GLT-1), cystine-glutamate exchanger (xCT) and glutamate/aspartate transporter (GLAST) are one of the key players in regulating extracellular glutamate concentration in the brain. Parenteral treatment with ceftriaxone, beta lactam antibiotic, has been reported to attenuate ethanol consumption and reinstatement to cocaine-seeking behavior, in part, by restoring the expression of GLT-1 and xCT in mesocorticolimbic brain regions in rats. In this study, we focused to test Augmentin (amoxicillin/clavulanate), which can be administered orally to subjects. Therefore, we examined the effects of orally administered Augmentin on ethanol intake as well as GLT-1, xCT and GLAST expression in male alcohol-preferring (P) rats. We found that orally administered Augmentin significantly attenuated ethanol consumption in P rats as compared to the vehicle treated group. Importantly, the attenuation in ethanol consumption was associated with a significant upregulation of GLT-1 and xCT expression in nucleus accumbens (NAc) and prefrontal cortex (PFC). There was no effect of orally administered Augmentin on GLAST expression in either NAc or PFC. These findings present strong evidence that oral administration of Augmentin can be used as an alternative to parenteral treatment. PMID- 27993697 TI - National Accreditation Program for Breast Centers Demonstrates Improved Compliance with Post-Mastectomy Radiation Therapy Quality Measure. AB - BACKGROUND: The National Accreditation Program for Breast Centers (NAPBC) was established in 2008 by the American College of Surgeons as a quality-improvement program for patients with breast disease. An NAPBC quality measure states post mastectomy patients with >=4 positive lymph nodes should receive lymph node radiation therapy (PMRT). Our objective was to examine how NAPBC accreditation has affected compliance with this quality measure. STUDY DESIGN: Women who underwent mastectomy at either an NAPBC-accredited center or a Commission on Cancer-only accredited hospital were identified (2006 to 2013) in the National Cancer Data Base. The NAPBC centers accredited from 2009 to 2011 were included in the analysis. Patients were nested within centers using a mixed effects model to identify PMRT rates at each center before and after accreditation, adjusting for patient and tumor characteristics. RESULTS: Of 34,752 patients from 477 NAPBC accredited centers and 958 Commission on Cancer-only accredited hospitals who underwent mastectomy with >=4 positive lymph nodes, 21,638 patients received PMRT during the study period (62.3%). The NAPBC centers yielded a significantly higher rate of PMRT than Commission on Cancer hospitals (66.0% vs 59.2%; p < 0.001). For each year of accreditation (2009 to 2011), centers had significantly higher rates of radiation in the accreditation year compared with the year before accreditation (p < 0.001). Within those centers, the rate of radiation increased post-accreditation in each accreditation year (2009: 62.1% to 71.9%; 2010: 65.5% to 73.2%; 2011: 67.5% to 70.4%). CONCLUSIONS: The NAPBC accreditation is associated with higher PMRT rates and better adherence to the PMRT quality measure. Future studies with more centers and longer follow-up are needed to determine whether this trend continues. PMID- 27993698 TI - Lead-Time Bias and Interhospital Transfer after Injury: Trauma Center Admission Vital Signs Underpredict Mortality in Transferred Trauma Patients. AB - BACKGROUND: Admission physiology predicts mortality after injury, but may be improved by resuscitation before transfer. This phenomenon, which has been termed lead-time bias, may lead to underprediction of mortality in transferred patients and inaccurate benchmarking in centers receiving large numbers of transfer patients. We sought to determine the impact of using vital signs on arrival at the referring center vs on arrival at the trauma center in mortality prediction models for transferred trauma patients. STUDY DESIGN: We performed a retrospective cohort study using a state-wide trauma registry including all patients age 16 years or older, with Abbreviated Injury Scale scores >= 3, admitted to level I and II trauma centers in Pennsylvania, from 2011 to 2014. The primary outcomes measure was the risk-adjusted association between mortality and interhospital transfer (IHT) when adjusting for physiology (as measured by Revised Trauma Score [RTS]) using the referring hospital arrival vital signs (model 1) compared with trauma center arrival vital signs (model 2). RESULTS: After adjusting for patient and injury factors, IHT was associated with reduced mortality (odds ratio [OR] 0.85; 95% CI 0.77 to 0.93) using the RTS from trauma center admission, but with increased mortality (OR 1.15; 95% CI 1.05 to 1.27) using RTS from the referring hospital. The greater the number of transfer patients seen by a center, the greater the difference in center-level mortality predicted by the 2 models (beta -0.044; 95% CI -0.044 to -0.0043; p <= 0.001). CONCLUSIONS: Trauma center vital signs underestimate mortality in transfer patients and may lead to incorrect estimates of expected mortality. Where possible, benchmarking efforts should use referring hospital vital signs to risk adjust IHT patients. PMID- 27993699 TI - Gastroesophageal Mucosal Injury after Cholecystectomy: An Indication for Surveillance? AB - BACKGROUND: Cholecystectomy alters bile release dynamics from pulsatile meal stimulated to continuous, and results in retrograde duodeno-gastric bile reflux (DGR). Bile is implicated in mucosal injury after gastric surgery, but whether cholecystectomy causes esophagogastric mucosal inflammation, therefore increasing the risk of metaplasia, is unclear. STUDY DESIGN: This study examined whether cholecystectomy-induced DGR promotes chronic inflammatory mucosal changes of the stomach and/or the esophagogastric junction (EGJ). Four groups of patients were studied and compared with controls. A group of patients was studied before and 1 year after cholecystectomy; 2 further groups were studied long-term post cholecystectomy (LTPC) at 5 to 10 years and 10 to 20 years. All underwent abdominal ultrasound and upper gastrointestinal endoscopy with gastric antral and EGJ biopsies, noting the presence of gastric bile pooling. Biopsy specimens were stained for Ki67 and p53 overexpression, and the bile reflux index (BRI) was calculated. RESULTS: At endoscopy, bile pooling was observed in 9 of 26 (34.6%) controls, in 8 of 25 (32%) patients pre-cholecystectomy, in 15 of 25 (60%) 1 year post-cholecystectomy patients (p = 0.047), and 23 of 29 (79.3%) LTPC patients (p = 0.001). Bile reflux index positivity at the EGJ increased from 19% of controls through 41% of LTPC patients (p = 0.032). Ki67 was overexpressed at the EGJ in 19% of controls, but in 62% of LTPC patients (p = 0.044); p53 was overexpressed at the EGJ in 19% of controls compared with 66% of LTPC patients (p = 0.001). CONCLUSIONS: Duodeno-gastric bile reflux was more common in patients with gallstones than in controls, and its incidence doubled after cholecystectomy. This was associated with inflammatory changes in the gastric antrum and the EGJ, evident in most LTPC patients. Ki67 and p53 overexpression at the EGJ suggests cellular damage attributable to chronic bile exposure post-cholecystectomy, increasing the likelihood of dysplasia. Further studies are required to determine whether DGR-mediated esophageal mucosal injury is reversible or avoidable, and whether surveillance endoscopy is indicated after cholecystectomy. PMID- 27993700 TI - Adhesiveness of opportunistic Staphylococcus aureus to materials used in dental office: In vitro study. AB - Staphylococcus aureus (S. aureus) is one of several opportunistic microbial pathogens associated with many healthcare problems. In the present study, S. aureus was assessed for its biofilm-forming ability on materials routinely used in dental offices, including stainless steel (SS), polyethylene (PE), and polyvinyl chloride (PVC). Materials that were tested were characterized for roughness (Ra) and surface free energy (SFE). The adhesion forces exerted by S. aureus to each substratum were investigated using atomic force microscopy (AFM), and biofilm formation was quantitatively assessed by crystal violet staining assay. AFM measurements demonstrated that the strongest adhesion forces (20 nN) were exerted on the PE surfaces (P < 0.05) and depended more on Ra. In addition, the results of biofilm formation capability indicated that S. aureus exhibited more affinity to SS materials when compared to the other materials (P < 0.05). This ability of biofilm formation seems to be more correlated to SFE (R = 0.65). Hence, control of the surface properties of materials used in dental practices is of crucial importance for preventing biofilm formation on dental materials to be used for patients' dental care. PMID- 27993701 TI - Comprehensive expression analysis of pathogenicity genes in uropathogenic Escherichia coli strains. AB - In this study, we investigated distinct expression patterns of genes encoding iron-acquisition systems, adhesins, protectins, and toxins in human uroepithelial cells infected with 194 uropathogenic Escherichia coli (UPEC) strains in vitro. We assessed the association of these genes with antibiotic resistance genes in this group of UPEC strains, previously characterised by polymerase chain reaction (PCR). Strains were isolated from patients with urinary tract infections (UTIs) from Unidad Medica Familiar de Salud Publica, located in Estado de Mexico, Mexico. Antibiotic resistance genes were identified by PCR, and the expression of virulence genes was detected by reverse-transcriptase-PCR after in vitro infection of cultured A431 human keratinocytes derived from a vulvar epidermoid carcinoma. The most frequently expressed virulence genotypes among the investigated UPEC strains included usp (68%), iha (64.9%), kpsMT (61.3%), fim (58.2%), irp2 (48.4), papC (33.5%), set (31.4%) and astA (30.9%), whereas the most frequently detected antibiotic resistance genes were tet(A) (34%), sul1 (31.4%) and TEM (26.3%). Furthermore, the most abundant pattern of gene expression (irp2/fim/iha/kpsMT/usp), associated with 8 different combinations of antibiotic resistance genotypes, was exhibited by 28 strains (14.4%). Taken together, these results indicate collective participation of distinct virulence UPEC genotypes during in vitro infection of cultured human epithelial cells, suggesting their potential involvement in UTI pathogenesis. PMID- 27993702 TI - Computational identification of potent inhibitors for Streptomycin 3" adenylyltransferase of Serratia marcescens. AB - Serratia marcescens is an opportunistic pathogen responsible for the respiratory and urinary tract infections in humans. The antibiotic resistance mechanism of S. marcescens is mediated through aminoglycoside modification enzyme that transfer adenyl group from substrate to antibiotic through regiospecific transfers for the inactivation of antibiotics. Streptomycin 3"-adenylyltransferase acts on the 3' position of the antibiotic and considered as a novel drug target to overcome bacterial antibiotic resistance. Till now, there is no experimentally solved crystal structure of Streptomycin 3"-adenylyltransferase in S. marcescens. Hence, the present study was initiated to construct the three dimensional structure of Streptomycin 3"-adenylyltransferase in order to understand the binding mechanism. The modeled structure was subjected to structure-based virtual screening to identify potent compounds from the five chemical structure databases. Furthermore, different computational methods such as molecular docking, molecular dynamics simulations, ADME toxicity assessment, free energy and density functional theory calculations predicted the structural, binding and pharmacokinetic properties of the best five compounds. Overall, the results suggested that stable binding confirmation of the five potent compounds were mediated through hydrophobic, pi-pi stacking, salt bridges and hydrogen bond interactions. The identified compounds could pave way for the development of anti pathogenic agents as potential drug entities. PMID- 27993703 TI - The influence of concentration of inactivated Edwardsiella tarda bacterin and immersion time on antigen uptake and expression of immune-related genes in Japanese flounder (Paralichthys olivaceus). AB - Our previous work has demonstrated that the immune response of Japanese flounder was associated with the concentration of formalin-inactivated Edwardsiella tarda and immersion time. In order to further investigate the influence of immersion vaccine dose and bath time on the antigen uptake, formalin-killed Edwardsiella tarda bacterin was prepared and adjusted to four concentrations (109, 108, 107, 106 cfu ml-1) for 30, 60 and 90 min immersion in Japanese flounder model, respectively. Absolute quantitative real-time PCR was employed to examine the bacterin uptake in gill, skin, spleen and kidney at 3 and 6 h post vaccination. The results showed that the antigen uptaken in gills and skin were significant higher than spleen and kidney, and the antigen amounts in gill and skin both declined from 3 to 6 h, whereas the antigen amounts in spleen and kidney gradually increased. Significant higher antigen amounts were detected in 109-30, 109-60, 108-60, 108-90 and 108-90 groups than other groups (P < 0.05), especially the 108-60min group displayed the highest antigen uptaken. Meanwhile, the expression profiles of antigen recognization and presentation genes (MHCIIalpha, TcRalpha, CD4-1), immunoglobulins (IgM, IgT), inflammatory cytokines (IL-1beta, IL-6), heat shock protein 70 (HSP70) and c-type lysozyme were analyzed using real time PCR. On the whole, the transcription levels of the eight genes exhibited to be higher in 107-90, 108 and 109 cfu ml-1 groups than other groups (P < 0.05), especially the 108-60 group displayed the highest up-regulation. These results demonstrated that immersion with formalin-inactivated E. tarda, especially under 108-60 min condition could efficiently enhance the antigen uptake and the expression of immune-related genes, which provided evidences for an enhanced vaccination effects under an optimized combination of vaccine dose and immersion time. PMID- 27993704 TI - De novo transcriptome analysis reveals insights into different mechanisms of growth and immunity in a Chinese soft-shelled turtle hybrid and the parental varieties. AB - The Chinese soft-shelled turtle (Pelodiscus sinensis) is a highly important freshwater aquaculture species in China. The molecular mechanisms underlying changes in immunity and growth in hybrid vigor are not well understood. In the present study, the transcriptomes from significantly different P. sinensis strains (Qingxi black turtle, B and Japanese strain, J) and the resulting hybrid (Zajiao-1, F) were sequenced using an Illumina sequencing platform. Differentially expressed genes (DEGs) between Zajiao-1 and the Qingxi black turtle were enriched mainly in the HTLV-I infection and Hippo signaling pathways, while DEGs between the Zajiao-1 and Japanese strain were enriched mainly in tryptophan metabolism, caner-associated pathways, transcriptional dysregulation in cancer, amebiasis, Fcgamma-mediated phagocytosis and the peroxisome pathway. Highly expressed genes involved in the regulation of disorders of the fatty acid biosynthesis, immune and cardiovascular systems in P. sinensis were found among the DEGs. Enrichment categories for gene ontology included cellular processes, metabolic pathways, and the actin cytoskeleton pathway. The reliability of the sequencing data was verified through quantitative real-time polymerase chain reaction analysis of 20 immunity or growth-related genes. These findings offer new insights into heterosis of growth traits and resistance to stresses and potential strategies for selective breeding. PMID- 27993705 TI - Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability. AB - Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID. PMID- 27993707 TI - p53 participates in the protective effects of ischemic post-conditioning against OGD-reperfusion injury in primary cultured spinal cord neurons. AB - Spinal cord ischemia-reperfusion (I/R) injury is a severe clinical condition, while the mechanism is still not clarified and the therapeutic approach is limited. Ischemia post-conditioning (PC) has been found to have the protective effects against I/R injury in brain. Recently p53 has been reported to take part in the regulation and protection of I/R injury. We hypothesize that PC has the protective effects in primary cultured spinal cord neurons against ischemia reperfusion injury, and MDM2-p53 signaling pathway may involve in its protective mechanism. In this study, we used an OGD (oxygen and glucose deprivation) reperfusion model in primary cultured spinal cord neurons to simulate the I/R injury of spinal cord in vitro, and PC was conducted by 3 cycles of 15min restoration of glucose and oxygen with 15min OGD, followed by 6h fully restoration as reperfusion. Lentiviral vectors were used to knock down MDM2 or over-express p53 genes in primary cultured spinal cord neurons. The results showed that 3 cycles of 15min PC generated the most significant protective effects in primary cultured spinal cord neurons against OGD-reperfusion injury. The levels of MDM2 were decreased while p53, Bax, and cleaved Caspase 3 were increased under OGD-reperfusion condition. PC could significantly reverse the down-regulation of MDM2 and up-regulation of p53, Bax, and cleaved Caspase 3 by OGD-reperfusion injury. Moreover, MDM2 knockdown or p53 over-expression could induce the cleaved Caspase 3 expression and blocked the protective effects of PC in primary cultured spinal cord neurons against OGD-reperfusion injury. In conclusion, our work demonstrated that MDM2-p53 pathway plays a pivotal role in the protective effect of PC against OGD-reperfusion injury and PC may be a feasible therapy strategy in the treatment for spinal cord I/R injury. PMID- 27993706 TI - RNA interactome capture in yeast. AB - RNA-binding proteins (RBPs) are key players in post-transcriptional regulation of gene expression in eukaryotic cells. To be able to unbiasedly identify RBPs in Saccharomyces cerevisiae, we developed a yeast RNA interactome capture protocol which employs RNA labeling, covalent UV crosslinking of RNA and proteins at 365nm wavelength (photoactivatable-ribonucleoside-enhanced crosslinking, PAR-CL) and finally purification of the protein-bound mRNA. The method can be easily implemented in common workflows and takes about 3days to complete. Next to a comprehensive explanation of the method, we focus on our findings about the choice of crosslinking in yeast and discuss the rationale of individual steps in the protocol. PMID- 27993708 TI - Subtypes evaluation of motor dysfunction in Parkinson's disease using neuromelanin-sensitive magnetic resonance imaging. AB - Parkinson's disease (PD) is characterized by the loss of neuromelanin (NM) containing neurons in the substantia nigra pars compacta (SNc), and it is divided into two motor subtypes: the postural instability gait difficulty (PIGD) and the tremor dominant (TD) subtypes. With NM-sensitive Magnetic Resonance Imaging (NM MRI), investigators have been able to accurately detect signal attenuation in SNc of PD; however, the difference of NM loss between PIGD and TD subtypes is still unclear. Thus, the aim of this study was to evaluate the differences in NM-MRI between PD motor subtypes. PD patients were classified into PIGD (n=14) and TD groups (n=9); 20 age and sex matched controls were recruited. We compared the signal intensity contrast ratios in medial and lateral regions of the SNc using NM-MRI in PIGD, TD, and controls, respectively. Remarkable signal attenuation was observed in the lateral part of SNc in PD when compared with the controls, and we were able to detect more severe signal attenuation in the medial part of SNc in PIGD patients in comparison with that in the TD group. Also, the medial part of SNc, ipsilateral to the most clinically affected side, showed the highest power to discriminate the PD motor subtypes (AUC, 81%; sensitivity, 71.4%; specificity, 77.8%). Our results indicated a potential diagnostic value of NM-MRI to discriminate the PD motor subtypes, providing new evidence for the neuropathology based differences between the two subtypes. PMID- 27993709 TI - Divergence and inheritance of neocortical heterotopia in inbred and genetically engineered mice. AB - Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination. PMID- 27993710 TI - Antinociception induced by galanin in anterior cingulate cortex in rats with acute inflammation. AB - The present study was performed to explore the role of galanin in nociceptive modulation in anterior cingulate cortex (ACC) of rats with acute inflammation, and the changes in galanin and galanin receptor 2 (Gal R2) expressions in rats with acute inflammation. Intra-ACC injection of galanin induced antinociception in rats with acute inflammation, the antinociceptive effects induced by galanin were attenuated significantly by intra-ACC injection of the Gal R2 antagonist M871, indicating an involvement of Gal R2 in nociceptive modulation in ACC in rats with acute inflammation. Furthermore, we found that both the galanin mRNA expression and galanin content increased significantly in ACC in rats with acute inflammation than that in normal rats. Moreover, both the mRNA levels of Gal R2 and the content of Gal R2 in ACC increased significantly in rats with acute inflammation than that in normal rats. These results demonstrated that galanin induced antinociception in ACC in rats with acute inflammation. And there were changes in the expression of galanin and Gal R2 in rats with acute inflammation. PMID- 27993711 TI - Late-onset Uretero-vesical Junction Obstruction Following Endoscopic Injection of Bulking Material for the Treatment of Vesico-ureteral Reflux. AB - OBJECTIVE: To characterize patients who develop late obstruction after subureteral injection of bulking agent for the treatment of pediatric vesicoureteral reflux (VUR). METHODS: We retrospectively evaluated the medical records of all patients who underwent endoscopic injection for the correction of VUR during 2008-2015 in 2 centers in Israel: Bnai-Zion Medical Center, Haifa, and Schneider Children's Medical Center, Petah Tikva. Nine patients who developed late-onset obstruction were included in the study, and their data were reviewed and analyzed. RESULTS: Three boys and 6 girls with mean age of 3 years were included in the study. All patients had moderate-to-high grade VUR. Following injection, all children had a radiographic evidence showing resolution of the reflux. During follow-up, patients were diagnosed with late obstruction in a mean time of 13.4 months. All patients underwent open re-implantation. CONCLUSION: Late-onset obstruction may develop in patients treated with subureteral injection for VUR. Patients with high grade reflux and dilated ureters are at risk of late obstruction. Long-term follow-up with ultrasound is mandatory following endoscopic treatment of VUR. PMID- 27993712 TI - Perineal Hernia Is an Unusual Complication Post Perineal Bladder Neck Closure: A Case Report. AB - Bladder neck closure (BNC) is the ultimate bladder neck reconstruction. If reconstruction fails, closure must be considered as it gives the highest continence rate. The vast majority of BNCs are performed through an abdominal approach (either transvesical or extravesical approach), but perineal approach remains an option for BNC with considerable success rate. Perineal hernia, which is defined as protrusion of abdominal contents through the perineal defect, is a very rare complication after urologic procedures. We report a case of perineal hernia post perineal BNC. PMID- 27993714 TI - Re: Kajbafzadeh et al.: Maternal Urinary Carbohydrate Antigen 19-9 as a Novel Biomarker for Evaluating Fetal Hydronephrosis: A Pilot Study (Urology 2016;101:90 93). PMID- 27993713 TI - Clinical Risk Factors Associated With Urethral Atrophy. AB - OBJECTIVE: To analyze a series of clinical risk factors associated with pretreatment urethral atrophy. METHODS: We retrospectively reviewed 301 patients who underwent artificial urinary sphincter (AUS) placement between September 2009 and November 2015; of these, 60 (19.9%) transcorporal cuff patients were excluded. Patients were stratified into 2 groups based on intraoperative spongiosal circumference measurements. Men with urethral atrophy (3.5 cm cuff size) were compared to controls (>=4 cm cuff size). Chi-square test, Mann-Whitney U test, and logistic regression analyses were performed to determine risk factors for urethral atrophy. RESULTS: Among 241 AUS patients analyzed, urethral atrophy was present in 151 patients (62.7%) compared to 90 patients (37.3%) who received larger cuffs (range 4-5.5 cm). Patients with urethral atrophy were older (71.1years vs 68.3 years; P < .02), more likely to have received radiation (52.9% vs. 33.3%; P < .007), and had a longer time interval between prostate cancer treatment and AUS surgery (8.9 years vs. 6.6 years; P < .033). On multivariable analysis, radiation therapy was independently associated with risk of urethral atrophy (odds ratio 1.77, 95% confidence interval: 1.01-3.13; P = .046), whereas greater time between cancer therapy and incontinence surgery approached clinical significance (odds ratio 1.05, 95% confidence interval 1.00-1.09; P = .05). CONCLUSION: History of radiation therapy and increasing length of time from prostate cancer treatment are associated with urethral atrophy before AUS placement. PMID- 27993715 TI - Appearance of Pyelitis Emphysematosa on Computed Tomography. AB - Pyelitis emphysematosa is a gas-forming infection characterized by gas located within the wall of the collecting system and renal pelvis. There are only 2 reported cases of pyelitis emphysematosa in the literature, neither of which occurred in the era of cross-sectional imaging. Here we present a case of pyelitis emphysematosa occurring in an elderly female with congenital left renal atrophy and chronic right hydronephrosis secondary to ureteropelvic junction obstruction. PMID- 27993716 TI - The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. AB - BACKGROUND & AIMS: Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. METHODS: In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl4, 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. RESULTS: PX decreased portal pressure in non-cirrhotic PPVL (12.6+/-1.7 vs. 10.4+/-1.1mmHg; p=0.020) and cirrhotic CCl4 (15.2+/-0.5 vs. 11.8+/-0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor alpha levels (-39%; p=0.044) after PX treatment. In CCl4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; p<0.001), and expression of profibrogenic proteins (Col1a1, alpha smooth muscle actin, transforming growth factor beta). CCl4-PX rats had significantly lower transaminase levels and reduced hepatic macrophage infiltration. Moreover, PX induced sinusoidal vasodilation (upregulation of cystathionase, dimethylaminohydrolase (DDAH)1, endothelial nitric oxide synthase (eNOS), GTP-cyclohydrolase1) and reduced intrahepatic vasoconstriction (downregulation of endothelin-1, p-Moesin). In cirrhosis, PX improved endothelial dysfunction (decreased von-Willebrand factor) and normalized overexpression of vascular endothelial growth factor, platelet derived growth factor and angiopoietins. While short-term 3-day PX treatment reduced portal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. CONCLUSIONS: The non steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. LAY SUMMARY: The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut. PMID- 27993717 TI - Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling. AB - Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N-terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR2, while small organic molecules show promising PAR2 antagonism. Developing PAR2 ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR2. Guided by PAR2 homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR2 models based on ORL-1 and PAR1, site-directed mutagenesis of PAR2 was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR2 signaling. Effects of 28 PAR2 mutations were examined for PAR2-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR2 mutations reduced the potency of at least one ligand by >10 fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR2, differentially influence intracellular Ca2+ induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR2 TM regions for receptor activation by synthetic PAR2 agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR2 was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR2 physiology. PMID- 27993718 TI - Topical use of platelet-rich plasma can improve the clinical outcomes after total knee arthroplasty: A systematic review and meta-analysis of 1316 patients. AB - OBJECTIVE: Platelet-rich plasma (PRP) is extracted by centrifuging whole blood and characterized with a high concentration of platelets. The purpose of this systematic review and meta-analysis of randomized controlled trials (RCTs) and non-RCTs is to evaluate the efficacy and safety of platelet-rich plasma (PRP) versus placebo after total knee arthroplasty (TKA). METHODS: The Electronic databases of PubMed, Web of Science, Embase and Cochrane Database of Systematic Reviews were searched from inception to November 2016 and any studies involving PRP versus placebo for patients prepared for TKA were selected by two reviewers. The primary endpoint is the range of motion (ROM), which represents the function after TKA. The Western Ontario McMaster Universities Osteoarthritis Index Bellamy (WOMAC), pain at 24 h, 48 h and 7 day are also assessed the effect of PRP on the function and pain after TKA. The complications of infection is also compiled to assess the safety of PRP. Stata 12.0 was used to synthesis the final results. RESULTS: Eleven clinical trials with 1316 patients are included in the meta analysis. The pooled results indicate that administration PRP significantly increase ROM on the third day (MD = 4.72, 95% CI 2.74, 6.69; P = 0.000) and 3 month postoperatively (MD = 7.55, 95% CI 5.91, 9.19; P = 0.000). There is no statistical difference between the two groups in terms of WOMAC questionnaire score in 3 months (MD = -4.88, 95% CI -12.12, 2.41; P = 0.190). There were no statistical significance between the two groups in pain intensity at 24 h, 48 h and 7 day. There is no statistically significant difference between the PRP versus placebo in terms of the occurrence of infection (RR = 0.64, 95%CI: 0.19 2.14, P = 0.464). CONCLUSION: Current meta-analysis indicates that PRP is associated with increasing the ROM after TKA in short term and long term. What's more, PRP can also decrease the WOMAC score and pain intensity without increasing the occurrence of infection. PMID- 27993719 TI - Minimally invasive percutaneous plates versus conventional fixation techniques for distal tibial fractures: A meta-analysis. AB - OBJECTIVE: This meta-analysis was performed to determine the effects of minimally invasive percutaneous plate osteosynthesis (MIPO) versus conventional fixation techniques (CFT) for treating distal tibial fractures. METHODS: A literature search was performed in EMBASE, Medline, the Cochrane Library, and Web of Science. The trials searched were evaluated for eligibility. The Cochrane Collaboration's Review Manager software was used to perform meta-analyses. RESULTS: Eight studies were enrolled, including five randomized controlled trials, one control-matched trial and two retrospective cohort trials. The meta analysis revealed that MIPO has a longer operating time, longer radiation time and higher incidence rate of soft tissue irritation symptoms than those of CFT. There was no significant difference between the two techniques with regard to union time, the American Orthopedic Foot and Ankle Society (AOFAS), infection rate and various other complications. CONCLUSIONS: The present meta-analysis showed that MIPO did not have obvious advantages over CFT in the treatment of distal tibia fracture. However, more rigorous randomized controlled trials are required in the future. PMID- 27993720 TI - Synergistic anticancer activity of combined histone deacetylase and proteasomal inhibitor-loaded zein nanoparticles in metastatic prostate cancers. AB - The development of resistance and subsequent metastasis makes prostate cancer a leading cause of cancer-related death among men. Hence, nanoparticle-based combination chemotherapeutics could be a viable treatment strategy. We aimed to prepare vorinostat (Vor) and bortezomib (Bor) combination-loaded zein nanoparticles (ZNP, ZNP/VB) for treating metastatic prostate cancers. Our results revealed the successful preparation of ZNP/VB with a small particle size (~160nm) and polydispersity index (~0.20). Importantly, controlled and pH-dependent drug release profiles were observed. ZNP/VB exhibited high uptake in different prostate cancer cells and, thereby, exhibited higher cytotoxicity and apoptosis. Additionally, the enhanced anti-migration effect of and induction of pro apoptotic proteins by ZNP/VB suggest its potential effectiveness in cancer treatment. ZNP/VB showed enhanced in vivo antitumor effects compared to that observed for each free drug and their combination, with minimal toxicity. Taken together, ZNP/VB could be a potential formulation for the effective treatment of metastatic prostate cancers. PMID- 27993721 TI - Foot-and-mouth disease virus-like particles as integrin-based drug delivery system achieve targeting anti-tumor efficacy. AB - The surface of foot-and-mouth disease virus (FMDV)-like particles (VLPs) contains a conserved arginine-glycine-aspartic acid (RGD) motif. Natural FMDV specifically attaches to overexpressed integrin receptors in several cancer cells. The FMDV VLPs produced in Escherichia coli were used for the first time as a delivery system of anti-tumor drug doxorubicin (DOX). The DOX-loaded VLPs exhibited a distinct release profile in different physiological conditions. The effects of FMDV-VLPs-DOX on cellular internalization and viability were evaluated in vitro by cell imaging, MTT assay and apoptosis, respectively. The anti-tumor efficacy in vivo was also determined in a nude mouse xenograft model based on tumor volume/weight and histological changes. The FMDV-VLPs-DOX complex significantly inhibited the proliferation of tumor and improved the pathological damage of DOX to non-targeting tissues. All results supported the potential of FMDV VLPs as a platform for specific targeted delivery of drugs or chemical reagents. PMID- 27993722 TI - Use of polymer conjugates for the intraperoxisomal delivery of engineered human alanine:glyoxylate aminotransferase as a protein therapy for primary hyperoxaluria type I. AB - Alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme whose deficit causes the rare disorder Primary Hyperoxaluria Type I (PH1). We now describe the conjugation of poly(ethylene glycol)-co-poly(L-glutamic acid) (PEG PGA) block-co-polymer to AGT via the formation of disulfide bonds between the polymer and solvent-exposed cysteine residues of the enzyme. PEG-PGA conjugation did not affect AGT structural/functional properties and allowed the enzyme to be internalized in a cellular model of PH1 and to restore glyoxylate-detoxification. The insertion of the C387S/K390S amino acid substitutions, known to favor interaction with the peroxisomal import machinery, reduced conjugation efficiency, but endowed conjugates with the ability to reach the peroxisomal compartment. These results, along with the finding that conjugates are hemocompatible, stable in plasma, and non-immunogenic, hold promise for the development of polypeptide-based AGT conjugates as a therapeutic option for PH1 patients and represent the base for applications to other diseases related to deficits in peroxisomal proteins. PMID- 27993723 TI - Fluorescent nanodiamonds engage innate immune effector cells: A potential vehicle for targeted anti-tumor immunotherapy. AB - Fluorescent nanodiamonds (FNDs) are nontoxic, infinitely photostable, and emit fluorescence in the near infrared region. Natural killer (NK) cells and monocytes are part of the innate immune system and are crucial to the control of carcinogenesis. FND-mediated stimulation of these cells may serve as a strategy to enhance anti-tumor activity. FNDs were fabricated with a diameter of 70+/-28 nm. Innate immune cell FND uptake, viability, surface marker expression, and cytokine production were evaluated in vitro. Evaluation of fluorescence emission from the FNDs was conducted in an animal model. In vitro results demonstrated that treatment of immune cells with FNDs resulted in significant dose-dependent FND uptake, no compromise in cell viability, and immune cell activation. FNDs were visualized in an animal model. Hence, FNDs may serve as novel agents with "track and trace" capabilities to stimulate innate immune cell anti-tumor responses, especially as FNDs are amenable to surface-conjugation with immunomodulatory molecules. PMID- 27993724 TI - Stimuli-responsive nanocomposites for magnetic targeting synergistic multimodal therapy and T1/T2-weighted dual-mode imaging. AB - Anticancer drug doxorubicin hydrochloride (DOX)-loaded photothermal nanocomposite MnFe2O4@mSiO2 with magnetic targeting and T1/T2-weighted dual-mode magnetic resonance imaging of MnFe2O4 core and NIR/pH-coupling sensitive mesoporous silica shell nanocarriers was designed and synthesized successfully. The anticancer drug DOX can be absorbed into mesoporous layer of MnFe2O4@mSiO2 nanocomposite, which shows obvious photothermal/chemo dual-modal synergistic therapies triggered by NIR/pH. Under 808 nm irradiation, MnFe2O4 can transform light into thermo, which can not only ablate tumor cells directly but also promote chemotherapy drugs releasing from mesoporous layer to kill tumor cells. The lower pH can also promote DOX releasing from mesoporous layer to enhance tumor inhibitory effect. It is confirmed that biocompatible DOX-MnFe2O4@mSiO2 nanocomposites can act as a potential multifunctional platform for effective magnetic targeting photothermal/chemo dual-modal synergistic therapies with enhanced anti-tumor efficacy and T1/T2-weighted dual-mode magnetic resonance imaging (MRI) applications in vivo. PMID- 27993725 TI - Point of care assessment of melanoma tumor signaling and metastatic burden from MUNMR analysis of tumor fine needle aspirates and peripheral blood. AB - This study evaluates MUNMR technology for molecular profiling of tumor fine needle aspirates and peripheral blood of melanoma patients. In vitro assessment of melanocyte (MART-1, HMB45) and MAP kinase signaling (pERK, pS6K) molecule expression was performed in human cell lines, while clinical validation was performed in an IRB-approved study of melanoma patients undergoing biopsy and blood sampling. Tumor FNA and blood specimens were compared with BRAF genetic analysis and cross-sectional imaging. MUNMR in vitro analysis showed increased expression of melanocyte markers in melanoma cells as well as increased expression of phosphorylated MAP kinase targets in BRAF-mutant melanoma cells. Melanoma patient FNA samples showed increased pERK and pS6K levels in BRAF mutant compared with BRAF WT melanomas, with MUNMR blood circulating tumor cell level increased with higher metastatic burden visible on imaging. These results indicate that MUNMR technology provides minimally invasive point-of-care evaluation of tumor signaling and metastatic burden in melanoma patients. PMID- 27993726 TI - Size-dependent cellular uptake of exosomes. AB - The ability of exosomes to elicit specific cellular responses suggests that they may be increasingly used as therapeutics. Their vesicular nature makes them suitable as potential nanocarriers for drugs or nucleic acids delivery. Here we address the question whether the method of preparation of enriched exosomal fractions can affect their uptake by cells and their ability to trigger a response. We compared ultracentrifugation and polymer-based precipitation methods on supernatants of glioma-associated stem cells isolated from a high-grade glioma patient. We determined particle size distributions after purification and their correlation with uptake, proliferation and migration in glioblastoma cell cultures. Our findings indicate that polymer-based precipitation leads to smaller particle size distributions, faster uptake by target cells and increased cellular motility. The different effect that isolation method-dependent populations of particles have on cell motility suggests their size distribution could also profoundly affect exosomes therapeutic potential. PMID- 27993727 TI - Quantum dot interactions and flow effects in angiogenic zebrafish (Danio rerio) vessels and human endothelial cells. AB - Nanoparticle (NP) interactions with biological tissues are affected by the size, shape and surface chemistry of the NPs. Here we use in vivo (zebrafish) and in vitro (HUVEC) models to investigate association of quantum dots (QDs) with endothelial cells and the effect of fluid flow. After injection into the developing zebrafish, circulating QDs associate with endothelium and penetrate surrounding tissue parenchyma over time. Amino-functionalized QDs cluster, interact with cells, and clear more rapidly than carboxy-functionalized QDs in vivo, highlighting charge influences. QDs show stronger accumulation in slow flowing, small caliber venous vessels than in fast-flowing high caliber arterial vessels. Parallel-plate flow experiments with HUVEC support these findings, showing reduced QD-EC association with increasing flow. In vivo, flow arrest after nanoparticle injection still results in venous accumulation at 18 h. Overall our results suggest that both QD charge and blood flow modulate particle endothelial cell interactions. PMID- 27993728 TI - Strong genetic structure revealed by multilocus patterns of variation in Giardia duodenalis isolates of patients from Galicia (NW-Iberian Peninsula). AB - We report a survey of genetic variation at three coding loci in Giardia duodenalis of assemblages A and B obtained from stool samples of patients from Santiago de Compostela (Galicia, NW-Iberian Peninsula). The mean pooled synonymous diversity for assemblage A was nearly five times lower than for assemblage B (0.77%+/-0.30% and 4.14%+/-1.65%, respectively). Synonymous variation in both assemblages was in mutation-drift equilibrium and an excess of low-frequency nonsynonymous variants suggested the action of purifying selection at the three loci. Differences between isolates contributed to 40% and 60% of total genetic variance in assemblages A and B, respectively, which revealed a significant genetic structure. These results, together with the lack of evidence for recombination, support that (i) Giardia assemblages A and B are in demographic equilibrium and behave as two genetically isolated populations, (ii) infections are initiated by a reduced number of individuals, which may be genetically diverse and even belong to different assemblages, and (iii) parasites reproduce clonally within the host. However, the observation of invariant loci in some isolates means that mechanisms for the homogenization of the genetic content of the two diploid nuclei in each individual must exist. PMID- 27993730 TI - Contribution of the HNE-immunohistochemistry to modern pathological concepts of major human diseases. AB - Excessive production of reactive oxygen species can induce peroxidation of the polyunsaturated fatty acids thus generating reactive aldehydes like 4-hydroxy-2 nonenal (HNE), denoted as "the second messenger of free radicals". Because HNE has high binding affinity for cysteine, histidine and lysine it forms relatively stable and hardly metabolized protein adducts. By changing structure and function of diverse structural and regulatory proteins, HNE achieves not only cytotoxic, but also regulatory functions in various pathophysiological processes. Numerous animal model studies and clinical trials confirmed HNE as one of the crucial factors in development and progression of many disorders, in particular of cancer, (neuro)degenerative, metabolic and inflammatory diseases. Since HNE has multiple biological effects and is in the living system usually bound to proteins and peptides, many research groups work on development of specific immunochemical methods targeting the HNE-histidine adducts as major bioactive marker of lipid peroxidation, following the research pathway initiated by Hermann Esterbauer, who discovered HNE in 60's. Such immunohistochemical studies did not only prove the high biomedical importance of HNE, but have also given new insights into major diseases of the modern man. Immunohistochemical studies have shown reversibility of formation of the HNE-protein adducts, as well as differential onset of the HNE mediated lipid peroxidation between age- associated atherosclerosis and photoaging, revealing eventually selective anti-cancer effects of HNE produced by non-malignant cells in vicinity of cancer. This review summarizes some of the HNE histidine immunohistochemistry findings we believe are of broad biomedical interest and could inspire new studies in the field. PMID- 27993731 TI - Nontraumatic orbital roof encephalocele. AB - Intraorbital meningoencephaloceles occur most commonly as a complication of traumatic orbital roof fractures. Nontraumatic congenital orbital meningoncephaloceles are very rare, with most secondary to destructive processes affecting the orbit and primary skull defects. Treatment for intraorbital meningoencephaloceles is surgical repair, involving the excision of herniated brain parenchyma and meninges and reconstruction of the osseous defect. Most congenital lesions present in infancy with obvious globe and orbital deformities; we report an orbital meningoencephalocele in a 3-year-old girl who presented with ptosis. PMID- 27993729 TI - Modulation of signaling mechanisms in the heart by thioredoxin 1. AB - Myocardial ischemia/reperfusion and heart failure are the major cardiac conditions in which an imbalance between oxidative stress and anti-oxidant mechanisms is observed. The myocardium has endogenous reducing mechanisms, including the thioredoxin (Trx) and glutathione systems, that act to scavenge reactive oxygen species (ROS) and reduce oxidized proteins. The Trx system consists of Trx, Trx reductase (TrxR), and an electron donor, NADPH, where Trx is maintained in a reduced state in the presence of TrxR and NADPH. Trx1, a major isoform of Trx, is abundantly expressed in the heart and exerts its oxidoreductase activity through conserved Cys32 and Cys35, reducing oxidized proteins through thiol disulfide exchange reactions. In this review, we will focus on molecular targets of Trx1 in the heart, including transcription factors, microRNAs, histone deactylases, and protein kinases. We will then discuss how Trx1 regulates the functions of its targets, thereby affecting the extent of myocardial injury caused by myocardial ischemia/reperfusion and the progression of heart failure. PMID- 27993733 TI - Microcontainers as an oral delivery system for spray dried cubosomes containing ovalbumin. AB - The purpose of this study was to prepare cubosomes encapsulating the model antigen ovalbumin (OVA) via spray drying, and to characterise such cubosomes with a view for their potential application in oral vaccine delivery. Furthermore the cubosome formulation was loaded into polymeric microcontainers intended as an oral drug delivery system. The cubosomes consisted of commercial glyceryl monooleate, Dimodan(r), containing OVA and were surrounded with a dextran shell prepared by spray drying. Cryo-TEM was used to confirm that cubosomes were formed after hydration of the spray dried precursor powder. The precursor powder had a mean particle size of 1.3+/-0.1MUm, whereas the mean diameter of the dispersed cubosomes was 282+/-7nm (PDI: 0.18) measured by dynamic light scattering. 8.5+/ 0.3% (w/w) of OVA was present in the cubosome powder and OVA was found released slowly over the first 70h, followed by a more rapid release. Total release of 47.9+/-2.8% of loaded OVA occurred over 96h in a buffer at pH 6.8. When the powder was filled into microcontainers, and the opening covered with the pH sensitive polymer Eudragit S100, the pH sensitive 'lid' was intact at gastric pH, but release of OVA from the cubosomes and microcontainers occurred at pH 6.8, releasing 44.1+/-5.6% of the OVA in 96h. Small-angle X-ray scattering (SAXS) revealed that the 'dry' particles possessed an internal ordered lipid structure (lamellar and inverse micellar phase) by virtue of a small amount of residual water, and after hydration in buffer at pH 6.8, the particles formed the hexagonal inverse cubic phases, thereby indicating that cubosomes were formed when released from microcontainers. PMID- 27993732 TI - Fast therapeutic DNA internalization - A high potential transfection system based on a peptide mimicking cationic lipid. AB - The delivery of nucleic acids into cells is a determining factor for successful gene therapy. In this study we investigate the uptake and time dependent processing of a lipid-based non-viral nucleic acid delivery system composed of a peptide-mimicking cationic lipid (N-{6-amino-1-[N-(9Z)-octadec-9-enylamino]-1 oxohexan-(2S)-2-yl}-N'-{2-[N,N-bis(2-aminoethyl)amino]ethyl}-2 hexadecylpropandiamide - OH4) and a phospholipid (1,2-dioleoyl-sn-glycero-3 phosphoethanolamine - DOPE). Studies by confocal laser scanning microscopy (CLSM) indicate a rapid internalization of fluorescent labelled DNA within 1h. Furthermore, vesicular structures on the lipid surface were reported, which are associated with the application of the lipid-based non-viral vector. Time dependent investigations of the gene expression of a reporter gene encoding for enhanced green fluorescent protein (eGFP) or luciferase in 4 different cell lines demonstrate an initial gene expression soon after 4h followed by a boost in gene expression beginning from 12h to 24h. Investigations with selective blocking of endocytic pathways using low molecular weight inhibitors suggested clathrin mediated endocytosis as main internalization route in 3 cell lines. Our research presents a new horizon in rapid gene therapy using non-viral vectors; due to the modifications of the lipid components, fast nucleic acid internalizations could be achieved using our delivery systems. PMID- 27993734 TI - Encapsulating darunavir nanocrystals within Eudragit L100 using coaxial electrospraying. AB - Electrospraying is renowned for its simplicity and versatility, and which can effectively produce particles with well-controlled size, size distribution, particle shape, morphology and microstructure at the nano/microscale. In this study, coaxial electrospraying was used to investigate its feasibility for preparing nanoparticles made up of nanocrystals encapsulated within a polymer shell. Firstly, aqueous nanosuspensions of darunavir were prepared by wet media milling. Then the nanosuspension and solutions of an enteric polymer, Eudragit L100, were used as the inner/core liquid and outer/shell liquid in a coaxial electrospraying setup, respectively. As long as a sufficiently high voltage was applied, a stable Taylor cone-jet mode was obtained to produce very fine core shell structure nanoparticles with high darunavir encapsulation efficiency of approximately 90%. The influence of the starting nanosuspension and the flow rates on the characteristics of the final electrosprayed particles was also evaluated. Using an optimized nanosuspension with reasonable size, size distribution and flow rates, the enteric coating layer reduced the percentage of DRV release in acidic medium in the in vitro dissolution test to ca. 20%. This study indicates that coaxial electrospraying is a potential and unique technique for encapsulating drug nanocrystals within a polymeric shell. PMID- 27993735 TI - It takes more than a coating to get nanoparticles through the intestinal barrier in vitro. AB - Size and shape are crucial parameters which have impact on the potential of nanoparticles to penetrate cell membranes and epithelial barriers. Current research in nanotoxicology additionally focuses on particle coating. To distinguish between core- and coating-related effects in nanoparticle uptake and translocation, two nanoparticles equal in size, coating and charge but different in core material were investigated. Silver and iron oxide nanoparticles coated with poly (acrylic acid) were chosen and extensively characterized by small-angle x-ray scattering, nanoparticle tracing analysis and transmission electron microscopy (TEM). Uptake and transport were studied in the intestinal Caco-2 model in a Transwell system with subsequent elemental analysis. TEM and ion beam microscopy were conducted for particle visualization. Although equal in size, charge and coating, the behavior of the two particles in Caco-2 cells was different: while the internalized amount was comparable, only iron oxide nanoparticles additionally passed the epithelium. Our findings suggest that the coating material influenced only the uptake of the nanoparticles whereas the translocation was determined by the core material. Knowledge about the different roles of the particle coating and core materials in crossing biological barriers will facilitate toxicological risk assessment of nanoparticles and contribute to the optimization of pharmacokinetic properties of nano-scaled pharmaceuticals. PMID- 27993736 TI - The Clinical Value of Assessing Lumbar Posteroanterior Segmental Stiffness: A Narrative Review of Manual and Instrumented Methods. AB - : Abnormal spinal segmental motion/stiffness is purported to be a cause, or an effect of, low back pain. Therefore, the assessment of posteroanterior segmental spinal stiffness is a common practice in clinical and research settings. In clinical settings, manipulative practitioners routinely assess spinal stiffness manually to guide clinical decision-making. Unfortunately, the reliability of manual segmental spinal stiffness assessment is poor. As a result, various spinal stiffness-testing devices have been developed to improve the reliability and accuracy of spinal stiffness measures. Although previous critical and systematic reviews have summarized the evidence regarding the reliability and confounding factors of manual and/or instrumented spinal stiffness measurements, no available review has summarized the principles of various spinal stiffness measurement methods nor pragmatic recommendations to optimize these measurements. Importantly, although posteroanterior segmental spinal stiffness is hypothesized to be related closely to low back pain or clinical outcomes after treatments, no review has been conducted to summarize evidence related to these premises and to discuss factors that can confound these relations. Against this background, this narrative review revisits the concept of both manual and instrumented spinal stiffness assessments, summarizes the pragmatic recommendations for minimizing measurement errors, reviews the potential relations between segmental spinal stiffness and low back pain, and provides future clinical research directions that can benefit clinicians and researchers alike. LEVEL OF EVIDENCE: Not applicable. PMID- 27993737 TI - Bolstering the Nasoseptal Flap Using Sphenoid Sinus Fat Packing: A Technical Case Report. AB - BACKGROUND: Resection of extensive skull base lesions often necessitates relatively large dural openings and arachnoid, resulting in skull base defects with the potential for a postoperative cerebrospinal fluid leak. A nasoseptal flap (NSF) is a vascularized graft that has greatly diminished the incidence of cerebrospinal fluid leak. Annealing of flaps against the ventral skull base can be tenuous within the first few days after surgery. We report the use of sphenoid sinus fat packing as a buttress to support the nasoseptal flap during skull base reconstruction. CASE DESCRIPTION: A 37-year-old man presented with pan hypopituitarism, bitemporal hemianopsia, and imaging consistent with a craniopharyngioma. He underwent an endoscopic endonasal approach with resection of the planum and tuberculum sphenoidale for resection of this mass. An NSF was harvested, and a combination of suprasellar fat packing, tensor fasciae lata graft, and Porex plate along with the flap were used to reconstruct the skull base. Postoperatively, he precipitously experienced copious rhinorrhea necessitating surgical re-exploration. A redundant segment of the NSF had retracted into the sphenoid sinus, and was no longer supported against the ventral skull base. We repositioned the NSF and used sphenoid sinus fat packing to help support the graft against the ventral skull base. A postoperative computed tomographic scan demonstrated a clear delineation between the vascularized graft and the fat packing, confirming proper positioning of the flap. CONCLUSION: Sphenoid sinus fat packing can be an important technical adjunct in bolstering the nasoseptal flap against the ventral skull base in the tenuous early perioperative period. PMID- 27993739 TI - Septic Arthritis of an Atlantoaxial Facet Joint with Normal Inflammatory Markers: Case Report and Literature Review. AB - BACKGROUND: Septic arthritis of the atlantoaxial facet joint is extremely rare. Contiguous spread to the median atlantoaxial joints with subsequent dens erosion can lead to atlantoaxial instability. Misleading normal inflammatory markers can result in delayed diagnosis and catastrophic consequences. CASE DESCRIPTION: A 56 year-old man presented with right-sided neck pain that had lasted for 2 days. He did not have fever or chills, and his serum C-reactive protein and erythrocyte sedimentation rate were normal. The patient was diagnosed with acute neck strain and treated conservatively. The pain continued for the next 3 weeks; cervical spine radiographs demonstrated normal findings with the exception of degenerative changes. The patient was treated with physical rehabilitation for the presumed neck strain and degenerative changes of the cervical vertebrae. Worsening neck pain and stiffness prompted a magnetic resonance imaging study obtained 5 weeks after the initial presentation, which showed an epidural collection with septic arthritis of the right facet and median atlantoaxial joints. Computed tomography demonstrated severe dens erosion. Surgical evacuation of the abscess and occipitocervical fusion were performed. Pathologic evaluation of tissue obtained during surgery demonstrated the presence of an infection, and Streptococcus anginosus grew from cultures. CONCLUSIONS: Infection must be considered in the differential diagnosis for neck pain when imaging findings are suggestive of an infectious process, even in an afebrile patient with normal C-reactive protein and erythrocyte sedimentation rate levels. Magnetic resonance imaging and computed tomography can play a critical role in such cases, potentially leading to a more timely diagnosis. PMID- 27993738 TI - Increased Utilization of Cervical Disk Arthroplasty in University Hospitals with Regional Variation and Socioeconomic Discrepancies. AB - OBJECTIVE: Treatment of cervical radiculopathy with disk arthroplasty has been approved by the U.S. Food and Drug Administration since 2007. Recently, a significant increase in clinical data including mid- and long-term follow-up has become available, demonstrating the superiority of disk arthroplasty compared with anterior discectomy and fusion. The aim of this project is to assess the nationwide use of cervical disk arthroplasty. METHODS: The University Healthcare Consortium database was accessed for all elective cases of patients treated for cervical radiculopathy caused by disk herniation (International Classification of Diseases [ICD] 722.0) from the fourth quarter of 2012 to the third quarter of 2015. Within this 3-year window, temporal and socioeconomic trends in the use of cervical disk replacement for this diagnosis were assessed. RESULTS: Three thousand four hundred forty-six cases were identified. A minority of cases (10.7%) were treated with disk arthroplasty. Median hospital charges were comparable for cervical disk replacement ($15,606) and anterior cervical fusion ($15,080). However, utilization was seen to increase by nearly 70% during the timeframe assessed. Disk arthroplasty was performed in 8% of patients in 2012 to 2013, compared with 13% of cases in 2015. Disk replacement use was more common for self-paying patients, patients with private insurance, and patients with military-based insurance. There was widespread variation in the use of cervical disk replacement between regions, with a nadir in northeastern states (8%) and a peak in western states (20%). CONCLUSION: Over a short, 3 -year period there has been an increase in the treatment of symptomatic cervical radiculopathy with disk arthroplasty. The authors predict a further increase in cervical disk arthroplasty in upcoming years. PMID- 27993740 TI - A Technically Simple and Safe Method for Preparing an Anterior Pericranial Flap Using Saline Injection into the Subgaleal Space: A Technical Note. AB - BACKGROUND: Cranial defects following anterior cranial base surgery have been frequently reconstructed using the pericranial flap. METHODS: We present a simple technique for preparing the flap using injection of saline into the subgaleal space. RESULTS: We inserted a 20-gauge needle perpendicular to 8-10 spots in the frontal area and injected 5-7 mL of saline at each spot 10 minutes before skin incision. Distinctive swelling of the scalp was then observed. After the scalp was incised, the layers were dissected with a monopolar electrocautery device. The layer containing saline allowed us to better localize its exact position and harvest the flap without injury. Dissection in the subgaleal plane was performed mainly using the tip of a surgical blade. After the periosteum was stripped from the calvaria, the flap that had been considerably thickened by saline injection was harvested. CONCLUSIONS: Because pericranium thickness in the frontal areas is reported to be thinner than in other areas, a beginning neurosurgeon may have difficulty harvesting an anteriorly based flap of sufficient size. The technique presented here can help increase awareness of the subgaleal layer, facilitate the dissection process, and reduce additional tissue injury resulting from electrocautery manipulation. PMID- 27993741 TI - Spinal Intradural Arachnoid Webs Causing Spinal Cord Compression with Inconclusive Preoperative Imaging: A Report of 3 Cases and a Review of the Literature. AB - OBJECTIVE: Spinal arachnoid webs are a rare variant of spinal arachnoid cysts where 1 or multiple focal membranes of arachnoid tissue obstruct the subarachnoid space. Only 11 prior cases of arachnoid webs have been reported in the literature. We present a series of 3 consecutive cases of arachnoid webs from our institution and review the literature on this rare condition to provide recommendations for its management. METHODS: Retrospective chart review was performed for 3 consecutive cases of intradural arachnoid webs causing spinal cord compression at our institution, with inconclusive preoperative imaging, treatment with surgical decompression, and resection. There were no external sources of funding. RESULTS: Our cases occurred dorsally in the thoracic spine and were associated with syringomyelia. Preoperative magnetic resonance imaging, computed tomography myelography, and cine magnetic resonance imaging were inconclusive, and the definitive diagnosis was made with intraoperative ultrasound. Patients underwent laminectomies and resection of arachnoid webs. Unique from prior reports of arachnoid webs, the webs in the present cases were composed of multiple septated longitudinal membranes rather than a transverse band. All patients had improvement of presenting symptoms postoperatively. CONCLUSIONS: Intradural arachnoid webs causing spinal cord compression are rare. Preoperative imaging may be inconclusive. Because of the septated longitudinal nature of the visualized membranes, we propose a 1-way valve mechanism of cerebrospinal fluid obstruction causing gradual cord compression and resultant syringomyelia. PMID- 27993742 TI - Immediate Titanium Mesh Implantation for Patients with Postcraniotomy Neurosurgical Site Infections: Safe and Aesthetic Alternative Procedure? AB - BACKGROUND: Surgical site infection (SSI) is one of the main complications after craniotomy. The incidence is up to 11% in the literature. The established procedure is debridement, removal of the bone flap, and delayed cranioplasty. Delayed cranioplasty has several disadvantages. A promising approach is the immediate titanium mesh implantation at the time of wound revision. We report our experience with this technique regarding outcome measured by reinfection rates and patient satisfaction. METHODS: Patients treated in our department from January 2013 to October 2014 with SSI after craniotomy for brain tumor, trauma, or vascular pathologies were prospectively collected. In all these patients, immediate titanium mesh implantation after bone flap removal was performed. Primary outcome parameters were the reinfection rate and patient satisfaction via self-designed questionnaires in a follow-up period >3 months. RESULTS: Twenty four patients were included within the study period. Main risk factors causing SSI were previous steroid medication (62.5%), cranial radiation therapy (42%), cerebrospinal fluid fistula after initial surgery (12.5%), and diabetes mellitus (25%). The follow-up was >3 months after titanium mesh cranioplasty (mean 4.6 months; range 3-6 months). No recurrent infection was detected in the study group. In 2 cases, reoperation was necessary. The returning questionnaires showed a high satisfaction rate with the cosmetic result. CONCLUSIONS: Our small series seems to confirm that immediate titanium mesh implantation for patients with postcraniotomy SSI is a cost-effective, safe, and cosmetically suitable alternative to delayed cranioplasty in selected patients without hydrocephalus or persistent cerebrospinal fluid fistula. PMID- 27993743 TI - Time Is Brain! Analysis of 245 Cases with Decompressive Craniectomy due to Subarachnoid Hemorrhage. AB - OBJECTIVE: Decompressive craniectomy (DC) may become a life-saving measure for patients with subarachnoid hemorrhage (SAH). However, the benefit of early DC has not been shown yet. We aimed at identifying the clinical value of DC timing. METHODS: We retrospectively analyzed 245 patients with SAH who underwent DC between January 2003 and December 2015. The cohort was stratified into primary (at admission, n = 171) and secondary DC (n = 74). In addition, primary DC was subdivided into early (<=24 hours after ictus, n = 120) and delayed (n = 51). RESULTS: There was no difference between primary and secondary DC (65.5% and 74.3%, P = 0.1828) with regard to unfavorable outcome at 6 months after SAH (defined as modified Rankin scale >3). However, individuals with early primary DC presented with significantly better functional outcome than the remaining cohort (P = 0.014, odds ratio [OR] = 2.02) and even compared with the subgroup with delayed primary DC (P = 0.023, OR = 2.42). Among individuals with World Federation of Neurosurgical Societies Grade <5 at admission, the benefits of early DC were more impressive: lower rates of unfavorable outcome (P = 0.003, OR = 0.28), in-hospital mortality (P = 0.031, OR = 0.37), and cerebral infarctions (P = 0.028, OR = 0.38) on the follow-up computed tomography scans. CONCLUSIONS: Not the timing of DC indication (primary/secondary), but rather the actual time left between the ictus and DC is crucial for the functional improvement of patients with SAH requiring DC. Especially, individuals without the signs of severe early brain injury strongly benefit from early DC. PMID- 27993745 TI - Clinicoradiologic Features and Surgical Outcomes of Sellar Xanthogranulomas: A Single-Center 10-Year Experience. AB - BACKGROUND: Xanthogranulomas are uncommon granulomatous entities, and xanthogranulomas occurring in the sellar region are extremely rare, with a limited number of cases reported in the literature. Diagnosis, management, and prognosis of sellar xanthogranulomas are poorly understood. METHODS: We retrospectively reviewed 14 patients with histologically proven sellar xanthogranulomas treated at our institution between January 2006 and July 2016. Clinical manifestations, radiologic features, operative records, and follow-up outcomes were analyzed. RESULTS: There were 9 male and 5 female patients with a mean age of 29.2 years. Clinical manifestations included headache (n = 12; 85.7%), visual deficiencies (n = 10; 71.4%), and endocrine disturbances (n = 6; 42.9%). On magnetic resonance imaging, sellar xanthogranulomas revealed isointensity to hyperintensity on T1-weighted imaging and hyperintensity or heterogeneous intensity on T2-weighted imaging with variable enhancement. Gross total resection of the lesion was achieved in 10 cases, and subtotal resection was achieved in 4 cases. Postoperatively, headache was relieved in all cases; transient diabetes insipidus was observed in 2 cases. There were no procedure related complications. During a mean follow-up period of 52.9 months, visual deficiencies were improved in 7 (70.0%) cases, whereas endocrine disturbances were improved in only 2 (33.3%) cases. No recurrence or regrowth of the residual lesions was observed. CONCLUSIONS: Sellar xanthogranuloma should be considered in the differential diagnosis of lesions in the sellar region. Some radiologic characteristics, including hyperintensity on T1-weighted imaging, heterogeneous hyperintensity on T2-weighted imaging, variable enhancement, and absence of calcification, can assist in making the preoperative diagnosis. Surgical outcomes are favorable. PMID- 27993744 TI - omega-3 Fatty Acids Ethyl Esters Suppress Cerebral Vasospasm and Improve Clinical Outcome Following Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: Occurrence of cerebral vasospasm after onset of aneurysmal subarachnoid hemorrhage (SAH) is a critical factor determining clinical prognosis. Eicosapentaenoic acid and docosahexaenoic acid, both omega-3 fatty acids (omega-3FA), can suppress cerebral vasospasm, and docosahexaenoic acid can relax vessel vasoconstriction and have neuroprotective effects. We investigated whether administration of omega-3FA prevented cerebral vasospasm occurrence and improved clinical outcomes after aneurysmal SAH. METHODS: From 2012 to 2015, 100 consecutive patients with aneurysmal SAH were divided into 2 periods. Between 2012 and 2013 (control period), 45 patients received standard management. Between 2014 and 2015 (omega-3FA period), 55 patients were prospectively treated with additional omega-3FA. Occurrence of cerebral vasospasm, occurrence of cerebral infarction caused by vasospasm, and modified Rankin Scale scores at 30 days and 90 days after onset of SAH for each period were evaluated and compared. RESULTS: The frequency of angiographic cerebral vasospasm in the omega-3FA period was significantly lower than in the control period (12 patients vs. 23 patients, P = 0.004). The frequency of new infarction caused by vasospasm in the omega-3FA period was also significantly lower than in the control period (5 patients vs. 14 patients, P = 0.011). There was a significant difference in modified Rankin Scale scores at 90 days after onset of SAH between the groups (P = 0.031). No adverse events were associated with omega-3FA administration. CONCLUSIONS: Administration of omega-3FA after aneurysmal SAH may reduce the frequency of cerebral vasospasm and may improve clinical outcomes. PMID- 27993746 TI - Neurosurgery in Lebanon: History, Development, and Future Challenges. AB - Lebanon stands out as the one of the first countries in the Middle East and the Arab world to practice the medical specialty of neurosurgery. In addition, Lebanon has one of the best reputations for neurosurgery in this region. This article documents the history and current status of Lebanese neurosurgery. Residency and fellowship trainings are also highlighted, and political, socioeconomic, and academic challenges for the future of the profession are presented. PMID- 27993747 TI - Accuracy of an automated knowledge base for identifying drug adverse reactions. AB - INTRODUCTION: Drug safety researchers seek to know the degree of certainty with which a particular drug is associated with an adverse drug reaction. There are different sources of information used in pharmacovigilance to identify, evaluate, and disseminate medical product safety evidence including spontaneous reports, published peer-reviewed literature, and product labels. Automated data processing and classification using these evidence sources can greatly reduce the manual curation currently required to develop reference sets of positive and negative controls (i.e. drugs that cause adverse drug events and those that do not) to be used in drug safety research. METHODS: In this paper we explore a method for automatically aggregating disparate sources of information together into a single repository, developing a predictive model to classify drug-adverse event relationships, and applying those predictions to a real world problem of identifying negative controls for statistical method calibration. RESULTS: Our results showed high predictive accuracy for the models combining all available evidence, with an area under the receiver-operator curve of ?0.92 when tested on three manually generated lists of drugs and conditions that are known to either have or not have an association with an adverse drug event. CONCLUSIONS: Results from a pilot implementation of the method suggests that it is feasible to develop a scalable alternative to the time-and-resource-intensive, manual curation exercise previously applied to develop reference sets of positive and negative controls to be used in drug safety research. PMID- 27993748 TI - Coordinating clinic and surgery appointments to meet access service levels for elective surgery. AB - Providing timely access to surgery is crucial for patients with high acuity diseases like cancer. We present a methodological framework to make efficient use of scarce resources including surgeons, operating rooms, and clinic appointment slots with a goal of coordinating clinic and surgery appointments so that patients with different acuity levels can see a surgeon in the clinic and schedule their surgery within a maximum wait time target that is clinically safe for them. We propose six heuristic scheduling policies with two underlying ideas behind them: (1) proactively book a tentative surgery day along with the clinic appointment at the time an appointment request is received, and (2) intelligently space out clinic and surgery appointments such that if the patient does not need his/her surgery appointment there is sufficient time to offer it to another patient. A 2-stage stochastic discrete-event simulation approach is employed to evaluate the six scheduling policies. In the first stage of the simulation, the heuristic policies are compared in terms of the average operating room (OR) overtime per day. The second stage involves fine-tuning the most-effective policy. A case study of the division of colorectal surgery (CRS) at the Mayo Clinic confirms that all six policies outperform the current scheduling protocol by a large margin. Numerical results demonstrate that the final policy, which we refer to as Coordinated Appointment Scheduling Policy considering Indication and Resources (CASPIR), performs 52% better than the current scheduling policy in terms of the average OR overtime per day under the same access service level. In conclusion, surgical divisions desiring stratified patient urgency classes should consider using scheduling policies that take the surgical availability of surgeons, patients' demographics and indication of disease into consideration when scheduling a clinic consultation appointment. PMID- 27993749 TI - Ultra-hydrophilic stent platforms promote early vascular healing and minimise late tissue response: a potential alternative to second-generation drug-eluting stents. AB - AIMS: Simple surface modifications can enhance coronary stent performance. Ultra hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. METHODS AND RESULTS: UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01). CONCLUSIONS: Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial. PMID- 27993750 TI - AMPLATZER versus Figulla occluder for transcatheter patent foramen ovale closure. AB - AIMS: The aim of this observational study was to compare acute and 12-month results of percutaneous closure of patent foramen ovale (PFO) with two occluder devices. METHODS AND RESULTS: Between June 2007 and October 2014, 406 consecutive patients (48.1+/-13.3 years, 243 women) underwent percutaneous PFO closure with either the AMPLATZER (n=179) or the Figulla (n=227) device after a stroke or a transient ischaemic attack ascribed to the PFO. A right-to-left shunt grade >1 was previously detected in all patients and atrial septal aneurysm was present in 111 (27.5%) patients. Patients were followed up with a contrast transthoracic echocardiogram and clinically at 24 hours, six months, and 12 months after the procedure. A high procedural success was observed in both groups. Despite a trend towards a higher incidence of acute residual shunt immediately after device deployment among Figulla occluder patients, a residual grade >=2 right-to-left shunt was observed in 4.5% of patients, independently of the device used for PFO closure. The only difference reported after Figulla device implantation was a lower rate of supraventricular arrhythmias (9% vs. 17%, p=0.02). CONCLUSIONS: According to this two-centre study, PFO closure appears safe and effective with the Figulla occluder as well as with the AMPLATZER device. PMID- 27993751 TI - Call-to-balloon time dashboard in patients with ST-segment elevation myocardial infarction results in significant improvement in the logistic chain. AB - AIMS: Timely reperfusion with primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI) patients is associated with superior clinical outcomes. Aiming to reduce ischaemic time, an innovative system for home-to-hospital (H2H) time monitoring was implemented, which enabled real time evaluation of ischaemic time intervals, regular feedback and improvements in the logistic chain. The objective of this study was to assess the results after implementation of the H2H dashboard for monitoring and evaluation of ischaemic time in STEMI patients. METHODS AND RESULTS: Ischaemic time in STEMI patients transported by emergency medical services (EMS) and treated with pPCI in the Noordwest Ziekenhuis, Alkmaar before (2008-2009; n=495) and after the implementation of the H2H dashboard (2011-2014; n=441) was compared. Median time intervals were significantly shorter in the H2H group (door-to-balloon time 32 [IQR 25-43] vs. 40 [IQR 28-55] minutes, p-value <0.001, FMC-to-balloon time 62 [IQR 52-75] vs. 80 [IQR 67-103] minutes, p-value <0.001, and treatment delay 142 [IQR 103-221] vs. 159 [IQR 123-253] minutes, p-value <0.001). The H2H time dashboard was independently associated with shorter time delays. CONCLUSIONS: Real-time monitoring and feedback on time delay with the H2H dashboard improves the logistic chain in STEMI patients, resulting in shorter ischaemic time intervals. PMID- 27993752 TI - Clinical outcomes of bioresorbable versus durable polymer-coated everolimus eluting stents in real-world complex patients. AB - AIMS: The aim of this study was to evaluate the safety and efficacy profile of new-generation, SYNERGY everolimus-eluting stents (S-EES) as compared to XIENCE everolimus-eluting stents (X-EES) with a durable polymer coating in "complex patients". METHODS AND RESULTS: We included 2,001 consecutive patients treated with S-EES (n=400) or X-EES (n=1,601) at two Italian centres between May 2013 and May 2015. We used propensity score matching to obtain two cohorts of patients with similar baseline risk profiles. Patients were stratified according to baseline complexity based on the EVOLVE II trial exclusion criteria. The primary outcome was major adverse cardiac events (MACE), defined as the composite of all cause death, myocardial infarction (MI), and target lesion revascularisation (TLR), at one year. Among 391 matched pairs of patients treated with S-EES or X EES, we identified 253 (63%) as complex. At one-year follow-up, among "complex" patients, MACE rates did not differ between the S-EES and X-EES groups (9.9% vs. 9.5%, p=0.830, HR 1.04, CI: 0.72-1.48). Similarly, death, MI, and TLR, stratified for complexity, were comparable between S-EES and X-EES treated patients at one year. Of note, no definite ST was observed in either the S-EES or the X-EES cohort. CONCLUSIONS: New-generation S-EES with a bioresorbable polymer coating appear to be safe and effective irrespective of patient complexity as compared to X-EES. PMID- 27993753 TI - Reactive myocardial hyperaemia for functional assessment of coronary stenosis severity. AB - AIMS: Our aim was to compare functional assessment of coronary stenosis severity by fractional flow reserve (FFR) measurement, as induced by systemic adenosine, and by regional reactive myocardial hyperaemia. METHODS AND RESULTS: The primary study endpoints were coronary pressure-derived FFR values in response to intravenous adenosine infusion (140 ug/min/kg), and to a one-minute proximal coronary artery balloon occlusion (reactive hyperaemia) for the same stenosis of interest. The secondary study endpoint was coronary collateral flow index (CFI) during the same occlusion. CFI is the ratio between simultaneous mean arterial occlusive pressure and mean aortic pressure, both subtracted by central venous pressure. As a reference, coronary artery stenoses were assessed quantitatively as percent diameter reduction (%S). One hundred and twenty-five patients with coronary artery disease were included in the study. There was an inverse association between quantitatively determined structural stenosis severity and adenosine-induced FFR as well as post-ischaemic reactive hyperaemia FFR (%S=1 0.004 FFR; both at p<0.0001). Sensitivity and specificity for detecting a stenosis of >=50% at an FFR threshold of 0.80 was 0.891 and 0.605 (adenosine induced FFR), and 0.817 and 0.684 (post-ischaemic FFR), respectively. The FFR difference for a given stenosis (post-ischaemic minus adenosine-induced FFR) was directly related to CFI. CONCLUSIONS: Regional reactive hyperaemia FFR is not inferior to systemic adenosine FFR in detecting structurally relevant coronary stenosis. Depending on the absence or presence of functional collaterals, systemic adenosine-induced FFR may underestimate or overestimate stenosis severity, respectively. PMID- 27993754 TI - The interaction of de novo and pre-existing aortic regurgitation after TAVI: insights from a new quantitative aortographic technique. AB - AIMS: The aim of this study was to evaluate the intermediate-term clinical impact of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) using a novel quantitative angiographic method taking into account the influence of pre-existing AR. METHODS AND RESULTS: AR after TAVI was quantified in 338 patients (age 82 [78-86] years; 55% male) and the influence on intermediate-term all-cause mortality was evaluated. In 228 aortograms, AR was quantitated using a dedicated videodensitometric method focused in the left ventricular outflow tract (LVOT-AR). Patients with LVOT-AR >0.17 had a significantly increased all-cause mortality at three years, compared with patients who had LVOT-AR <=0.17 (adjusted hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.05-2.86, p=0.032). Taking the influence of pre-existing AR into account, patients with post procedural LVOT-AR >0.17 and <=mild pre-existing AR had a significantly increased mortality at two years, compared to patients with LVOT-AR >0.17 and >mild pre existing AR (HR: 2.55, 95% CI: 1.16-5.58, p=0.029). In those with >mild pre existing AR (n=70), post-TAVI LVOT-AR >0.17 was not associated with increased mortality (HR: 0.77, 95% CI: 0.31-1.91, p=0.578). CONCLUSIONS: AR after TAVI could be quantitated utilising LVOT-AR. The cut-point of >0.17 indicates a significant AR pertaining to increased intermediate-term mortality, especially in those with no significant pre-existing AR. PMID- 27993755 TI - Clinical, angiographic, IVUS, and OCT predictors for irregular protrusion after coronary stenting. AB - AIMS: Irregular protrusion identified by optical coherence tomography (OCT) immediately following stent implantation has been reported as an independent predictor for adverse cardiac events at one year. However, baseline characteristics for the development of irregular protrusion are unknown. The aim of the study was to identify predictors for irregular protrusion following stent implantation. METHODS AND RESULTS: A total of 900 lesions in 786 patients who had post-stent OCT imaging were analysed. The patients were divided into two groups: those with (484 lesions, 456 patients) and those without (416 lesions, 330 patients) irregular protrusion. Baseline characteristics (n=786) as well as pre stent angiogram (n=786), intravascular ultrasound (IVUS; n=31) and OCT (n=159) findings were compared between the two groups. Multivariate analysis showed that patients with irregular protrusion had higher low-density lipoprotein (LDL) cholesterol levels and lesions with greater stent length, greater percent atheroma volume on IVUS, greater lipid content and a higher prevalence of thrombus on OCT before stent implantation. CONCLUSIONS: Irregular protrusion was found more frequently in patients with higher LDL cholesterol levels. In addition, lesions treated with longer stents, with greater plaque burden, larger lipid content and a higher prevalence of thrombus were identified as predictors for irregular protrusion following stent implantation. PMID- 27993756 TI - Change in lumen eccentricity and asymmetry after treatment with Absorb bioresorbable vascular scaffolds in the ABSORB cohort B trial: a five-year serial optical coherence tomography imaging study. AB - AIMS: The aim of the study was to investigate long-term changes in lumen eccentricity and asymmetry at five years after implantation of the Absorb bioresorbable vascular scaffold (BVS). METHODS AND RESULTS: Out of 101 patients from the ABSORB cohort B trial, 28 patients (29 lesions) with serial optical coherence tomography (OCT) examination at four different time points (cohort B1: post-procedure, six months, two, and five years [n=13]; cohort B2: post procedure, one, three, and five years [n=16]) were evaluated. The longitudinal variance in lumen diameter was assessed by asymmetry index (AI). An asymmetric lesion was defined as AI >0.3. The circularity of the lumen or scaffold was evaluated by the eccentricity index calculated as minimal divided by maximal luminal or scaffold diameter per cross-section. The lowest lumen eccentricity index within a scaffold segment (EIL) <0.7 was defined as an eccentric lesion. Post procedure, an eccentric lesion was observed in 72.4% and became concentric in 93.1% at five years (post EIL 0.67+/-0.05 vs. five-year EIL 0.80+/-0.10, p=0.03) with a modest reduction of the lumen area from baseline to five years by 0.75+/-0.32 mm2. Asymmetric lumen morphology was observed in 93.1% (n=27) post implantation and persisted until five-year follow-up. On serial OCT analyses, there was a substantial increase in the scaffold EI during the first two years (post 0.70+/-0.06, six months 0.76+/-0.08, two years 0.85+/-0.07); then, it remained stable whereas the lumen circularity improved further. There were no significant differences in major adverse cardiac events regarding the lumen morphology over the five-year follow-up. CONCLUSIONS: In patients treated with the Absorb BVS, the cross-sectional circularity improved over five years while the variance in longitudinal diameters remained. Regaining of lumen circularity is mainly caused by reshaping of the scaffold during the first two years. PMID- 27993757 TI - Percutaneous intervention in chronic total coronary occlusions caused by in-stent restenosis: procedural results and long-term clinical outcomes in the TORO (Spanish registry of chronic TOtal occlusion secondary to an occlusive in-stent RestenOsis) multicentre registry. AB - AIMS: Limited data exist on the treatment and outcomes of patients with chronic total occlusions due to in-stent restenosis (CTO-ISR). We sought to evaluate results and clinical outcomes in percutaneous interventions over CTO-ISR. METHODS AND RESULTS: We conducted a registry in 16 centres involving consecutive patients undergoing attempted percutaneous intervention over CTO-ISR. A total of 233 patients were included, 192 (82.4%) with a successful acute result. The success rate was significantly lower in patients with: lesion in the circumflex artery, ostial lesions, J score >3 and no femoral access. The presence of tandem lesions (OR 0.19, 95% CI: 0.06-0.68; p=0.01) was identified as an independent predictor for outcome. After a median follow-up of 20 months, cardiac death in the successful vs. failed groups was 3% and 8.3%, respectively (p=0.09). Independent predictors for mortality were previous CABG (HR 8, 95% CI: 1.3-50; p=0.02) and multivessel disease (HR 2.3, 95% CI: 1.2-4.3; p=0.01). In the successful group, TLR was 15%, re-occlusion 6% and definite/probable stent thrombosis 1.8%. CONCLUSIONS: Percutaneous treatment of CTO due to ISR in contemporary practice shows a high success rate, resulting in good long-term results. The angiographic and procedural predictors identified may contribute to improving procedural outcome through better patient selection. PMID- 27993758 TI - First-in-man six-month results of a surface-modified coronary stent system in native coronary stenosis. AB - AIMS: In preclinical studies, a bare metal cobalt-chromium stent with an active surface oxide layer modification (BMSmod) has been shown to inhibit neointimal hyperplasia effectively. We sought to assess both the clinical safety and feasibility of the BMSmod. METHODS AND RESULTS: In this prospective, non randomised, first-in-man multicentre study, a total of 31 patients with de novo coronary lesions, reference lumen diameters of 2.5-3.5 mm and lesion length <=16 mm, were enrolled. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at baseline and six-month follow-up. Primary angiographic and OCT endpoints included in-stent late lumen loss (LLL) and mean neointimal thickness at six months. The device-oriented composite endpoint (DoCE), defined as cardiac death, myocardial infarction not clearly attributable to a non-intervention vessel, and clinically indicated target lesion revascularisation (CI-TLR), was analysed according to the intention-to-treat principle. In 31 patients (33 lesions), the procedural success rate was 93.5%. At six months, angiographic LLL was 0.91+/-0.45 mm and binary angiographic restenosis occurred in 23.3% of lesions. Out of 33 lesions, OCT was performed in 27 lesions at both time points. Mean neointimal thickness amounted to 348+/-116 um. At six months, the DoCE was 19.4% due to the occurrence of CI-TLR in five patients (including one late definite stent thrombosis of a non-study stent). CONCLUSIONS: In contrast to previous preclinical pathophysiological work, the BMSmod did not prevent neointimal hyperplasia in a first-in-man clinical setting. PMID- 27993759 TI - Short-Term Effectiveness of a Mobile Phone App for Increasing Physical Activity and Adherence to the Mediterranean Diet in Primary Care: A Randomized Controlled Trial (EVIDENT II Study). AB - BACKGROUND: The use of mobile phone apps for improving lifestyles has become generalized in the population, although little is still known about their effectiveness in improving health. OBJECTIVE: We evaluate the effect of adding an app to standard counseling on increased physical activity (PA) and adherence to the Mediterranean diet, 3 months after implementation. METHODS: A randomized, multicenter clinical trial was carried out. A total of 833 participants were recruited in six primary care centers in Spain through random sampling: 415 in the app+counseling group and 418 in the counseling only group. Counseling on PA and the Mediterranean diet was given to both groups. The app+counseling participants additionally received training in the use of an app designed to promote PA and the Mediterranean diet over a 3-month period. PA was measured with the 7-day Physical Activity Recall (PAR) questionnaire and an accelerometer; adherence to the Mediterranean diet was assessed using the Mediterranean Diet Adherence Screener questionnaire. RESULTS: Participants were predominantly female in both the app+counseling (249/415, 60.0%) and counseling only (268/418, 64.1%) groups, with a mean age of 51.4 (SD 12.1) and 52.3 (SD 12.0) years, respectively. Leisure-time moderate-to-vigorous physical activity (MVPA) by 7-day PAR increased in the app+counseling (mean 29, 95% CI 5-53 min/week; P=.02) but not in the counseling only group (mean 17.4, 95% CI -18 to 53 min/week; P=.38). No differences in increase of activity were found between the two groups. The accelerometer recorded a decrease in PA after 3 months in both groups: MVPA mean 55.3 (95% CI -75.8 to -34.9) min/week in app+counseling group and mean -30.1 (95% CI -51.8 to -8.4) min/week in counseling only group. Adherence to the Mediterranean diet increased in both groups (8.4% in app+counseling and 10.4% in counseling only group), with an increase in score of 0.42 and 0.53 points, respectively (P<.001), but no difference between groups (P=.86). CONCLUSIONS: Leisure-time MVPA increased more in the app+counseling than counseling only group, although no difference was found when comparing the increase between the two groups. Counseling accompanied by printed materials appears to be effective in improving adherence to the Mediterranean diet, although the app does not increase adherence. CLINICALTRIAL: Clinicaltrials.gov NCT02016014; https://clinicaltrials.gov/ct2/show/NCT02016014 (Archived by WebCite at http://www.webcitation.org/6mnopADbf). PMID- 27993760 TI - Teaching Shared Decision Making to Family Medicine Residents: A Descriptive Study of a Web-Based Tutorial. AB - BACKGROUND: DECISION+2, a Web-based tutorial, was designed to train family physicians in shared decision making (SDM) regarding the use of antibiotics for acute respiratory infections (ARIs). It is currently mandatory for second-year family medicine residents at Universite Laval, Quebec, Canada. However, little is known about how such tutorials are used, their effect on knowledge scores, or how best to assess resident participation. OBJECTIVE: The objective of our study was to describe the usage of this Web-based training platform by family medicine residents over time, evaluate its effect on their knowledge scores, and identify what kinds of data are needed for a more comprehensive analysis of usage and knowledge acquisition. METHODS: We identified, collected, and analyzed all available data about participation in and current usage of the tutorial and its before-and-after 10-item knowledge test. Residents were separated into 3 log-in periods (2012-2013, 2013-2014, and 2014-2015) depending on the day of their first connection. We compared residents' participation rates between entry periods (Cochran-Armitage test), assessed the mean rank of the difference in total scores and category scores between pre- and posttest (Wilcoxon signed-rank test), and compared frequencies of each. Subsequent to analyses, we identified types of data that would have provided a more complete picture of the usage of the program and its effect on knowledge scores. RESULTS: The tutorial addresses 3 knowledge categories: diagnosing ARIs, treating ARIs, and SDM regarding the use of antibiotics for treating ARIs. From July 2012 to July 2015, all 387 second-year family medicine residents were eligible to take the Web-based tutorial. Out of the 387 eligible residents, 247 (63.8%) logged in at least once. Their participation rates varied between entry periods, most significantly between the 2012-2013 and 2013-2014 cohorts (P=.006). For the 109 out of 387 (28.2%) residents who completed the tutorial and both tests, total and category scores significantly improved between pre- and posttest (all P values <.001). However, the frequencies of those answering correctly on 2 of the 3 SDM questions did not increase significantly (P>.99, P=.25). Distribution of pre- or posttest total and category scores did not increase between entry periods (all P values >.1). Available data were inadequate for evaluating the associations between the tutorial and its impact on the residents' scores and therefore could tell us little about its effect on increasing their knowledge. CONCLUSION: Residents' use of this Web-based tutorial appeared to increase between entry periods following the changes to the SDM program, and the tutorial seemed less effective for increasing SDM knowledge scores than for diagnosis or treatment scores. However, our results also highlight the need to improve data availability before participation in Web-based SDM tutorials can be properly evaluated or knowledge scores improved. PMID- 27993761 TI - Patient-Facing Mobile Apps to Treat High-Need, High-Cost Populations: A Scoping Review. AB - BACKGROUND: Self-management is essential to caring for high-need, high-cost (HNHC) populations. Advances in mobile phone technology coupled with increased availability and adoption of health-focused mobile apps have made self-management more achievable, but the extent and quality of the literature supporting their use is not well defined. OBJECTIVE: The purpose of this review was to assess the breadth, quality, bias, and types of outcomes measured in the literature supporting the use of apps targeting HNHC populations. METHODS: Data sources included articles in PubMed and MEDLINE (National Center for Biotechnology Information), EMBASE (Elsevier), the Cochrane Central Register of Controlled Trials (EBSCO), Web of Science (Thomson Reuters), and the NTIS (National Technical Information Service) Bibliographic Database (EBSCO) published since 2008. We selected studies involving use of patient-facing iOS or Android mobile health apps. Extraction was performed by 1 reviewer; 40 randomly selected articles were evaluated by 2 reviewers to assess agreement. RESULTS: Our final analysis included 175 studies. The populations most commonly targeted by apps included patients with obesity, physical handicaps, diabetes, older age, and dementia. Only 30.3% (53/175) of the apps studied in the reviewed literature were identifiable and available to the public through app stores. Many of the studies were cross-sectional analyses (42.9%, 75/175), small (median number of participants=31, interquartile range 11.0-207.2, maximum 11,690), or performed by an app's developers (61.1%, 107/175). Of the 175 studies, only 36 (20.6%, 36/175) studies evaluated a clinical outcome. CONCLUSIONS: Most apps described in the literature could not be located on the iOS or Android app stores, and existing research does not robustly evaluate the potential of mobile apps. Whereas apps may be useful in patients with chronic conditions, data do not support this yet. Although we had 2-3 reviewers to screen and assess abstract eligibility, only 1 reviewer abstracted the data. This is one limitation of our study. With respect to the 40 articles (22.9%, 40/175) that were assigned to 2 reviewers (of which 3 articles were excluded), inter-rater agreement was significant on the majority of items (17 of 30) but fair-to-moderate on others. PMID- 27993763 TI - A doubly robust estimator for the average treatment effect in the context of a mean-reverting measurement error. AB - One of the main limitations of causal inference methods is that they rely on the assumption that all variables are measured without error. A popular approach for handling measurement error is simulation-extrapolation (SIMEX). However, its use for estimating causal effects have been examined only in the context of an additive, non-differential, and homoscedastic classical measurement error structure. In this article we extend the SIMEX methodology, in the context of a mean reverting measurement error structure, to a doubly robust estimator of the average treatment effect when a single covariate is measured with error but the outcome and treatment and treatment indicator are not. Throughout this article we assume that an independent validation sample is available. Simulation studies suggest that our method performs better than a naive approach that simply uses the covariate measured with error. PMID- 27993762 TI - Smartphone Apps for Measuring Human Health and Climate Change Co-Benefits: A Comparison and Quality Rating of Available Apps. AB - BACKGROUND: Climate change and the burden of noncommunicable diseases are major global challenges. Opportunities exist to investigate health and climate change co-benefits through a shift from motorized to active transport (walking and cycling) and a shift in dietary patterns away from a globalized diet to reduced consumption of meat and energy dense foods. Given the ubiquitous use and proliferation of smartphone apps, an opportunity exists to use this technology to capture individual travel and dietary behavior and the associated impact on the environment and health. OBJECTIVE: The objective of the study is to identify, describe the features, and rate the quality of existing smartphone apps which capture personal travel and dietary behavior and simultaneously estimate the carbon cost and potential health consequences of these actions. METHODS: The Google Play and Apple App Stores were searched between October 19 and November 6, 2015, and a secondary Google search using the apps filter was conducted between August 8 and September 18, 2016. Eligible apps were required to estimate the carbon cost of personal behaviors with the potential to include features to maximize health outcomes. The quality of included apps was assessed by 2 researchers using the Mobile Application Rating Scale (MARS). RESULTS: Out of 7213 results, 40 apps were identified and rated. Multiple travel-related apps were identified, however no apps solely focused on the carbon impact or health consequences of dietary behavior. None of the rated apps provided sufficient information on the health consequences of travel and dietary behavior. Some apps included features to maximize participant engagement and encourage behavior change towards reduced greenhouse gas emissions. Most apps were rated as acceptable quality as determined by the MARS; 1 was of poor quality and 10 apps were of good quality. Interrater reliability of the 2 evaluators was excellent (ICC=0.94, 95% CI 0.87-0.97). CONCLUSIONS: Existing apps capturing travel and dietary behavior and the associated health and environmental impact are of mixed quality. Most apps do not include all desirable features or provide sufficient health information. Further research is needed to determine the potential of smartphone apps to evoke behavior change resulting in climate change and health co-benefits. PMID- 27993765 TI - GP performance tracker shows where costs could be saved. PMID- 27993764 TI - Implementation of solutions to reduce opioid-induced oversedation and respiratory depression. AB - PURPOSE: The implementation of interventions to mitigate the causes of opioid induced oversedation and respiratory depression (OSRD) is reported. SUMMARY: A single-site retrospective review of eligible rescue naloxone cases was conducted to identify the causes of opioid-induced OSRD in a hospital as well as to identify risk factors. A survey was used to assess potential opioid knowledge deficits among hospitalist prescribers. Based on the findings of the case reviews and results of the opioid knowledge assessments, a series of interventions to address noted deficiencies was implemented over the ensuing months, including enhanced monitoring for sedation, improved clinical decision support in the electronic medical record (EMR), and various adjustments to dosing for high-risk patients. The primary endpoint of our analysis was naloxone use for documented cases of opioid-induced OSRD to determine the effectiveness of the interventions. A mean of 16 OSRD events occurred per quarter before intervention implementation. An average of five risk factors (range, two to six) was found among OSRD cases, most commonly age of >60, obesity, and comorbidities of the kidneys and lungs. Deficiencies of clinical care were found in four inter-related domains: knowledge deficits, inadequate monitoring, failure to leverage the EMR, and cultural issues regarding pain assessments and sedation management. CONCLUSION: Implementation of solution bundles that utilized an EMR to create meaningful clinical decision support and cultural changes related to pain goals and communication about sedation level at an acute care hospital resulted in a fivefold reduction in OSRD events that has been sustained for two years. PMID- 27993766 TI - Hospitals are advised to halt elective surgery to free beds for winter. PMID- 27993767 TI - Peer reviewer stole article and published it as his own. PMID- 27993768 TI - Psychiatrists urge Obama to request neuropsychiatric review of Trump. PMID- 27993770 TI - Let's Not Do Away with Comprehensive Cognitive Assessments Just Yet. AB - We review rational and empirical reasons that comprehensive cognitive assessments are useful sources of information in the evaluation and treatment of learning disabilities. However, the existing evidence base that demonstrates the value of comprehensive cognitive assessments for this purpose is not nearly as strong as it needs to be. Proponents of comprehensive cognitive assessments for learning disability identification must do more to rigorously evaluate their beliefs or else concede the argument to those with better evidence. PMID- 27993771 TI - States sue generic drug makers for alleged price fixing. PMID- 27993774 TI - KODAMA: an R package for knowledge discovery and data mining. AB - Summary: KODAMA, a novel learning algorithm for unsupervised feature extraction, is specifically designed for analysing noisy and high-dimensional datasets. Here we present an R package of the algorithm with additional functions that allow improved interpretation of high-dimensional data. The package requires no additional software and runs on all major platforms. Availability and Implementation: KODAMA is freely available from the R archive CRAN ( http://cran.r-project.org ). The software is distributed under the GNU General Public License (version 3 or later). Contact: s.cacciatore@imperial.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993773 TI - EGAD: ultra-fast functional analysis of gene networks. AB - Summary: Evaluating gene networks with respect to known biology is a common task but often a computationally costly one. Many computational experiments are difficult to apply exhaustively in network analysis due to run-times. To permit high-throughput analysis of gene networks, we have implemented a set of very efficient tools to calculate functional properties in networks based on guilt-by association methods. ( xtending ' uilt-by- ssociation' by egree) allows gene networks to be evaluated with respect to hundreds or thousands of gene sets. The methods predict novel members of gene groups, assess how well a gene network groups known sets of genes, and determines the degree to which generic predictions drive performance. By allowing fast evaluations, whether of random sets or real functional ones, provides the user with an assessment of performance which can easily be used in controlled evaluations across many parameters. Availability and Implementation: The software package is freely available at https://github.com/sarbal/EGAD and implemented for use in R and Matlab. The package is also freely available under the LGPL license from the Bioconductor web site ( http://bioconductor.org ). Contact: JGillis@cshl.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993775 TI - GENIUS: web server to predict local gene networks and key genes for biological functions. AB - Summary: GENIUS is a user-friendly web server that uses a novel machine learning algorithm to infer functional gene networks focused on specific genes and experimental conditions that are relevant to biological functions of interest. These functions may have different levels of complexity, from specific biological processes to complex traits that involve several interacting processes. GENIUS also enriches the network with new genes related to the biological function of interest, with accuracies comparable to highly discriminative Support Vector Machine methods. Availability and Implementation: GENIUS currently supports eight model organisms and is freely available for public use at http://networks.bio.puc.cl/genius . Contact: genius.psbl@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993776 TI - fCCAC: functional canonical correlation analysis to evaluate covariance between nucleic acid sequencing datasets. AB - Summary: Computational evaluation of variability across DNA or RNA sequencing datasets is a crucial step in genomic science, as it allows both to evaluate reproducibility of biological or technical replicates, and to compare different datasets to identify their potential correlations. Here we present fCCAC, an application of functional canonical correlation analysis to assess covariance of nucleic acid sequencing datasets such as chromatin immunoprecipitation followed by deep sequencing (ChIP-seq). We show how this method differs from other measures of correlation, and exemplify how it can reveal shared covariance between histone modifications and DNA binding proteins, such as the relationship between the H3K4me3 chromatin mark and its epigenetic writers and readers. Availability and Implementation: An R/Bioconductor package is available at http://bioconductor.org/packages/fCCAC/ . Contact: pmb59@cam.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993778 TI - LEAP: constructing gene co-expression networks for single-cell RNA-sequencing data using pseudotime ordering. AB - Summary: To construct gene co-expression networks based on single-cell RNA Sequencing data, we present an algorithm called LEAP, which utilizes the estimated pseudotime of the cells to find gene co-expression that involves time delay. Availability and Implementation: R package LEAP available on CRAN. Contact: jun.li@nd.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993779 TI - Recon2Neo4j: applying graph database technologies for managing comprehensive genome-scale networks. AB - Summary: The goal of this work is to offer a computational framework for exploring data from the Recon2 human metabolic reconstruction model. Advanced user access features have been developed using the Neo4j graph database technology and this paper describes key features such as efficient management of the network data, examples of the network querying for addressing particular tasks, and how query results are converted back to the Systems Biology Markup Language (SBML) standard format. The Neo4j-based metabolic framework facilitates exploration of highly connected and comprehensive human metabolic data and identification of metabolic subnetworks of interest. A Java-based parser component has been developed to convert query results (available in the JSON format) into SBML and SIF formats in order to facilitate further results exploration, enhancement or network sharing. Availability and Implementation: The Neo4j-based metabolic framework is freely available from: https://diseaseknowledgebase.etriks.org/metabolic/browser/ . The java code files developed for this work are available from the following url: https://github.com/ibalaur/MetabolicFramework . Contact: ibalaur@eisbm.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993780 TI - RBPPred: predicting RNA-binding proteins from sequence using SVM. AB - Motivation: Detection of RNA-binding proteins (RBPs) is essential since the RNA binding proteins play critical roles in post-transcriptional regulation and have diverse roles in various biological processes. Moreover, identifying RBPs by computational prediction is much more efficient than experimental methods and may have guiding significance on the experiment design. Results: In this study, we present the RBPPred (an RNA-binding protein predictor), a new method based on the support vector machine, to predict whether a protein binds RNAs, based on a comprehensive feature representation. By integrating the physicochemical properties with the evolutionary information of protein sequences, the new approach RBPPred performed much better than state-of-the-art methods. The results show that RBPPred correctly predicted 83% of 2780 RBPs and 96% out of 7093 non RBPs with MCC of 0.808 using the 10-fold cross validation. Furthermore, we achieved a sensitivity of 84%, specificity of 97% and MCC of 0.788 on the testing set of human proteome. In addition we tested the capability of RBPPred to identify new RBPs, which further confirmed the practicability and predictability of the method. Availability and Implementation: RBPPred program can be accessed at: http://rnabinding.com/RBPPred.html . Contact: liushiyong@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993781 TI - Message from the ISCB: The 5th ISCB Wikipedia competition: coming to a classroom near you? PMID- 27993777 TI - A comprehensive benchmark of RNA-RNA interaction prediction tools for all domains of life. AB - Motivation: The aim of this study is to assess the performance of RNA-RNA interaction prediction tools for all domains of life. Results: Minimum free energy (MFE) and alignment methods constitute most of the current RNA interaction prediction algorithms. The MFE tools that include accessibility (i.e. RNAup, IntaRNA and RNAplex) to the final predicted binding energy have better true positive rates (TPRs) with a high positive predictive values (PPVs) in all datasets than other methods. They can also differentiate almost half of the native interactions from background. The algorithms that include effects of internal binding energies to their model and alignment methods seem to have high TPR but relatively low associated PPV compared to accessibility based methods. Availability and Implementation: We shared our wrapper scripts and datasets at Github (github.com/UCanCompBio/RNA_Interactions_Benchmark). All parameters are documented for personal use. Contact: sinan.umu@pg.canterbury.ac.nz. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993782 TI - ReconMap: an interactive visualization of human metabolism. AB - Motivation: A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualize its content integrated with omics data and simulation results. Results: We manually drew a comprehensive map, ReconMap 2.0, that is consistent with the content of Recon 2. We present it within a web interface that allows content query, visualization of custom datasets and submission of feedback to manual curators. Availability and Implementation: ReconMap can be accessed via http://vmh.uni.lu , with network export in a Systems Biology Graphical Notation compliant format released under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. A Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension to interact with ReconMap is available via https://github.com/opencobra/cobratoolbox . Contact: ronan.mt.fleming@gmail.com. PMID- 27993784 TI - Hum-mPLoc 3.0: prediction enhancement of human protein subcellular localization through modeling the hidden correlations of gene ontology and functional domain features. AB - Motivation: Protein subcellular localization prediction has been an important research topic in computational biology over the last decade. Various automatic methods have been proposed to predict locations for large scale protein datasets, where statistical machine learning algorithms are widely used for model construction. A key step in these predictors is encoding the amino acid sequences into feature vectors. Many studies have shown that features extracted from biological domains, such as gene ontology and functional domains, can be very useful for improving the prediction accuracy. However, domain knowledge usually results in redundant features and high-dimensional feature spaces, which may degenerate the performance of machine learning models. Results: In this paper, we propose a new amino acid sequence-based human protein subcellular location prediction approach Hum-mPLoc 3.0, which covers 12 human subcellular localizations. The sequences are represented by multi-view complementary features, i.e. context vocabulary annotation-based gene ontology (GO) terms, peptide-based functional domains, and residue-based statistical features. To systematically reflect the structural hierarchy of the domain knowledge bases, we propose a novel feature representation protocol denoted as HCM (Hidden Correlation Modeling), which will create more compact and discriminative feature vectors by modeling the hidden correlations between annotation terms. Experimental results on four benchmark datasets show that HCM improves prediction accuracy by 5-11% and F 1 by 8-19% compared with conventional GO-based methods. A large-scale application of Hum-mPLoc 3.0 on the whole human proteome reveals proteins co-localization preferences in the cell. Availability and Implementation: www.csbio.sjtu.edu.cn/bioinf/Hum-mPLoc3/. Contacts: hbshen@sjtu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993785 TI - Predict drug permeability to blood-brain-barrier from clinical phenotypes: drug side effects and drug indications. AB - Motivation: Blood-Brain-Barrier (BBB) is a rigorous permeability barrier for maintaining homeostasis of Central Nervous System (CNS). Determination of compound's permeability to BBB is prerequisite in CNS drug discovery. Existing computational methods usually predict drug BBB permeability from chemical structure and they generally apply to small compounds passing BBB through passive diffusion. As abundant information on drug side effects and indications has been recorded over time through extensive clinical usage, we aim to explore BBB permeability prediction from a new angle and introduce a novel approach to predict BBB permeability from drug clinical phenotypes (drug side effects and drug indications). This method can apply to both small compounds and macro molecules penetrating BBB through various mechanisms besides passive diffusion. Results: We composed a training dataset of 213 drugs with known brain and blood steady-state concentrations ratio and extracted their side effects and indications as features. Next, we trained SVM models with polynomial kernel and obtained accuracy of 76.0%, AUC 0.739, and F 1 score (macro weighted) 0.760 with Monte Carlo cross validation. The independent test accuracy was 68.3%, AUC 0.692, F 1 score 0.676. When both chemical features and clinical phenotypes were available, combining the two types of features achieved significantly better performance than chemical feature based approach (accuracy 85.5% versus 72.9%, AUC 0.854 versus 0.733, F 1 score 0.854 versus 0.725; P < e -90 ). We also conducted de novo prediction and identified 110 drugs in SIDER database having the potential to penetrate BBB, which could serve as start point for CNS drug repositioning research. Availability and Implementation: https://github.com/bioinformatics-gao/CASE-BBB-prediction-Data. Contact: rxx@case.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993787 TI - Improved VCF normalization for accurate VCF comparison. AB - Motivation: The Variant Call Format (VCF) is widely used to store data about genetic variation. Variant calling workflows detect potential variants in large numbers of short sequence reads generated by DNA sequencing and report them in VCF format. To evaluate the accuracy of variant callers, it is critical to correctly compare their output against a reference VCF file containing a gold standard set of variants. However, comparing VCF files is a complicated task as an individual genomic variant can be represented in several different ways and is therefore not necessarily reported in a unique way by different software. Results: We introduce a VCF normalization method called Best Alignment Normalisation (BAN) that results in more accurate VCF file comparison. BAN applies all the variations in a VCF file to the reference genome to create a sample genome, and then recalls the variants by aligning this sample genome back with the reference genome. Since the purpose of BAN is to get an accurate result at the time of VCF comparison, we define a better normalization method as the one resulting in less disagreement between the outputs of different VCF comparators. Availability and Implementation: The BAN Linux bash script along with required software are publicly available on https://sites.google.com/site/banadf16. Contact: A.Bayat@unsw.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993786 TI - DeFCoM: analysis and modeling of transcription factor binding sites using a motif centric genomic footprinter. AB - Motivation: Identifying the locations of transcription factor binding sites is critical for understanding how gene transcription is regulated across different cell types and conditions. Chromatin accessibility experiments such as DNaseI sequencing (DNase-seq) and Assay for Transposase Accessible Chromatin sequencing (ATAC-seq) produce genome-wide data that include distinct 'footprint' patterns at binding sites. Nearly all existing computational methods to detect footprints from these data assume that footprint signals are highly homogeneous across footprint sites. Additionally, a comprehensive and systematic comparison of footprinting methods for specifically identifying which motif sites for a specific factor are bound has not been performed. Results: Using DNase-seq data from the ENCODE project, we show that a large degree of previously uncharacterized site-to-site variability exists in footprint signal across motif sites for a transcription factor. To model this heterogeneity in the data, we introduce a novel, supervised learning footprinter called Detecting Footprints Containing Motifs (DeFCoM). We compare DeFCoM to nine existing methods using evaluation sets from four human cell-lines and eighteen transcription factors and show that DeFCoM outperforms current methods in determining bound and unbound motif sites. We also analyze the impact of several biological and technical factors on the quality of footprint predictions to highlight important considerations when conducting footprint analyses and assessing the performance of footprint prediction methods. Finally, we show that DeFCoM can detect footprints using ATAC-seq data with similar accuracy as when using DNase-seq data. Availability and Implementation: Python code available at https://bitbucket.org/bryancquach/defcom. Contact: bquach@email.unc.edu or tsfurey@email.unc.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993788 TI - MRUniNovo: an efficient tool for de novo peptide sequencing utilizing the hadoop distributed computing framework. AB - Summary: Tandem mass spectrometry-based de novo peptide sequencing is a complex and time-consuming process. The current algorithms for de novo peptide sequencing cannot rapidly and thoroughly process large mass spectrometry datasets. In this paper, we propose MRUniNovo, a novel tool for parallel de novo peptide sequencing. MRUniNovo parallelizes UniNovo based on the Hadoop compute platform. Our experimental results demonstrate that MRUniNovo significantly reduces the computation time of de novo peptide sequencing without sacrificing the correctness and accuracy of the results, and thus can process very large datasets that UniNovo cannot. Availability and Implementation: MRUniNovo is an open source software tool implemented in java. The source code and the parameter settings are available at http://bioinfo.hupo.org.cn/MRUniNovo/index.php. Contact: s131020002@hnu.edu.cn ; taochen1019@163.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993789 TI - SPADEVizR: an R package for visualization, analysis and integration of SPADE results. AB - Motivation: Flow, hyperspectral and mass cytometry are experimental techniques measuring cell marker expressions at the single cell level. The recent increase of the number of markers simultaneously measurable has led to the development of new automatic gating algorithms. Especially, the SPADE algorithm has been proposed as a novel way to identify clusters of cells having similar phenotypes in high-dimensional cytometry data. While SPADE or other cell clustering algorithms are powerful approaches, complementary analysis features are needed to better characterize the identified cell clusters. Results: We have developed SPADEVizR, an R package designed for the visualization, analysis and integration of cell clustering results. The available statistical methods allow highlighting cell clusters with relevant biological behaviors or integrating them with additional biological variables. Moreover, several visualization methods are available to better characterize the cell clusters, such as volcano plots, streamgraphs, parallel coordinates, heatmaps, or distograms. SPADEVizR can also generate linear, Cox or random forest models to predict biological outcomes, based on the cell cluster abundances. Additionally, SPADEVizR has several features allowing to quantify and to visualize the quality of the cell clustering results. These analysis features are essential to better interpret the behaviors and phenotypes of the identified cell clusters. Importantly, SPADEVizR can handle clustering results from other algorithms than SPADE. Availability and Implementation: SPADEVizR is distributed under the GPL-3 license and is available at https://github.com/tchitchek-lab/SPADEVizR . Contact: nicolas.tchitchek@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27993790 TI - Incidence of second tumors after treatment with or without radiation for rectal cancer. AB - Background: The aim of this study was to analyze the association between radiation therapy (RT) for rectal cancer and the development of second tumors. Patients and methods: Data on all surgically treated non-metastatic primary rectal cancer patients diagnosed between 1989 and 2007 were retrieved from the Netherlands population-based cancer registry. Fine and Gray's competing risk model was used for estimation of the cumulative incidence of second tumors. Multivariable analysis was conducted using Cox regression. Results: The cohort consisted of 29 027 patients of which 15 467 patients had undergone RT. Median follow-up was 7.7 years (range 0-27). Among all 4398 patients who were diagnosed with a second primary tumor, 1030 had one or more pelvic tumors. The standardized incidence risk for any second tumor was 1.16 (95% confidence interval [CI] 1.12 1.19), resulting in 27.7/10 000 excess cancer cases per year in patients treated for rectal cancer compared with the general population. RT reduced the cumulative incidence of second pelvic tumors compared with patients who did not receive RT (subhazard ratio [SHR] 0.77, CI 0.68-0.88). Second prostate tumors were less common in patients who received RT (SHR 0.54, CI 0.46-0.64), gynecological tumors were more frequently observed in patients who received RT (SHR 1.49, CI 1.11 2.00). Conclusions: Patients with previous rectal cancer had a marginally increased risk of a second tumor compared with the general population. Gynecological tumors occurred more often in females who received RT, but this did not result in an overall increased risk for a second cancer. RT even seemed to have a protective effect on the development of other second pelvic tumors, pre dominantly for prostate cancer. These findings are highly important and can contribute to improved patient counseling. PMID- 27993791 TI - Multiplex KRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction. AB - Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy. Patients and methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care. Results: Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of >= 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001). Conclusion(s): Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival. PMID- 27993792 TI - Network-guided modeling allows tumor-type independent prediction of sensitivity to all-trans-retinoic acid. AB - Background: All-trans-retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia (APL) and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires the development of predictive tools allowing identification of sensitive cancer types and responsive individuals. Materials and methods: RNA sequencing data for 10 080 patients and 33 different tumor types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was carried out using machine learning methods and network analysis. Results: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor types for which higher ATRA-21 predictions are associated with better outcomes. Conclusions: In summary, we generated a tumor-type independent ATRA sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor types that are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity. PMID- 27993793 TI - Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. AB - Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions >=0.5 cm to assess response. Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1 68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3 34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity. PMID- 27993794 TI - Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours. AB - This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies. PMID- 27993795 TI - Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen deprivation therapy for prostate cancer with implications of oxidative stress. AB - Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background. Patients and methods: The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide resistant cells. Results: In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24 0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration resistant and enzalutamide-resistant cells. Conclusions: Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT. PMID- 27993797 TI - Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury. PMID- 27993798 TI - 3D waterfall plots: a better graphical representation of tumor response in oncology. PMID- 27993796 TI - Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. AB - Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone. PMID- 27993799 TI - Moving beyond sorafenib alone in advanced hepatocellular carcinoma: is hepatic arterial infusion chemotherapy the best option? PMID- 27993801 TI - Adding extra dimensions in rectal cancer theory. PMID- 27993802 TI - Atypical autoimmune adverse effects with checkpoint blockade therapies. PMID- 27993800 TI - Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials. AB - Background: To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types. Patients and methods: 2530 aCRC patients were assessed from three randomised trials. End points were progression-free survival, response rate, disease control rate, post progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status. Results: 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months. Conclusions: BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression. PMID- 27993803 TI - Better use of immune checkpoint inhibition: Treating higher risk patients and examining neurologic toxicity. PMID- 27993804 TI - Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial. AB - Background: Several studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients' tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial. Patients and methods: The primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physician's choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over. Results: Among 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm. Conclusions: The cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3. PMID- 27993806 TI - Impact of primary metastatic bone disease in germ cell tumors: results of an International Global Germ Cell Tumor Collaborative Group G3 Registry Study. AB - Background: Bone metastases (BM) are rare in germ cell tumor (GCT) patients. Systematic data on risk factors, treatment and outcome are largely lacking. Patients and methods: A database created by an international consortium including 123 GCT patients with BM at primary diagnosis was retrospectively analysed. Survival estimates were calculated by the method of Kaplan-Meier and compared by log-rank testing. Cox regression analysis was applied for risk factor analyses. Results: In our cohort of patients, BM at primary diagnosis more often affected multiple sites (61%) and BM as the only metastatic site were scarce (9%). Histology was non-seminoma in 77% and seminoma in 23% of patients. After a median follow-up of 18 months (range, 0-228), estimated median PFS and OS were 21 (range, 0-225) and 98 months (95%CI, 36-160), respective 2-year PFS and OS rates were 34% and 45%. Negative prognosticators in univariate analysis were a mediastinal primary (PFS; HR 1.92; 95%CI, 1.05-3.50; OS; HR 2.16; 95%CI, 1.14 4.09) and the presence of liver and/or brain metastases (PFS; HR 1.89; 95%CI, 1.13-3.17; OS; HR 1.91; 95%CI, 0.024) Seminomatous histology was the strongest predictor for favorable PFS (multivariate Cox regression; HR, 0.32; P=0.011) with respective 2-year PFS and OS rates of 68% and 75% compared with 24% and 36% for non-seminoma patients. Conclusions: Outcome of GCT patients with primary metastatic bone disease is particularly poor in non-seminoma patients, even worse than the expected outcomes of the general IGCCCG 'poor prognosis' group. This series does not indicate that mutlimodal treatment improves the prognosis over stage-adapted chemotherapy alone, however, the statistical power of these results is limited due to low patient numbers in each specific subgroup. PMID- 27993805 TI - Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease. AB - This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD). PMID- 27993807 TI - Integrating communication as a core skill in the global curriculum for medical oncology. PMID- 27993808 TI - Pembrolizumab induced bulbar myopathy and respiratory failure with necrotizing myositis of the diaphragm. PMID- 27993810 TI - What is the optimal neoadjuvant treatment for locally advanced oesophageal adenocarcinoma? PMID- 27993811 TI - Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial. AB - Background: High-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial. Patients and methods: From August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60-74) and 442 were <=60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged <=60.0 and >60.0 years. Results: Patient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged >60.0 versus 43.0% for those aged <=60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and <=60.0 years, P = 0.42), or 4-year EFS (20% versus 28%, P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%). Conclusion: This subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable toxicity. ClinicalTrials.gov Identifier: NCT00078949. PMID- 27993812 TI - Different efficacy of ramucirumab in patients with metastatic gastric and gastroesophageal junction cancer according to ECOG performance status. PMID- 27993813 TI - High incidence of interstitial lung disease following practical use of osimertinib in patients who had undergone immediate prior nivolumab therapy. PMID- 27993814 TI - Adjuvant sunitinib for high-risk-resected renal cell carcinoma: a meta-analysis of ASSURE and S-TRAC trials. PMID- 27993815 TI - Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes. AB - Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC. PMID- 27993816 TI - Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer. AB - Background: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). Methods: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive >=4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. Results: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74 1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86 90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade >=3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. Conclusion: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. ClinicalTrials.gov: NCT00528567. PMID- 27993817 TI - Use of chemotherapy near the end of life: what factors matter? AB - Background: Use of chemotherapy near the end of life in patients with metastatic cancer is often ineffective and toxic. Data about the factors associated with its use remain scarce, especially in Europe. Methods: Nationwide, register-based study including all hospitalized patients aged >=20 years who died from metastatic solid tumors in France between 2010 and 2013. Results: A total of 279 846 hospitalized patients who died from metastatic cancer were included. During the last month before death, 19.5% received chemotherapy (including 11.3% during the last 2 weeks). Female sex (OR= 0.96, 95% CI= 0.93-0.98), older age (OR= 0.70, 95% CI= 0.69-0.71 for each 10-year increase) and higher number of chronic comorbidities (OR= 0.83, 95% CI= 0.82-0.84) were independently associated with lower rates of chemotherapy. Although patients with chemosensitive tumors were statistically more likely to receive chemotherapy during the last month before death (OR= 1.21, 1.18-1.25), this association was mostly fueled by testis and ovary tumors and we found no obvious pattern between the expected chemosensitivity of different cancers and the rates of chemotherapy use close to death. Compared with university hospitals, patients who died in for-profit clinics/hospital (OR= 1.40, 95% CI= 1.34-1.45), or comprehensive cancer centers (OR= 1.43, 95% CI= 1.36-1.50) were more likely to receive chemotherapy. Finally, high-volume centers and hospitals without palliative care units reported greater than-average rates of chemotherapy near the end of life. Conclusion: among hospitalized patients with cancer, young individuals, treated in comprehensive cancer centers or in high-volume centers without palliative care units were the most likely to receive chemotherapy near the end of life. We found no evident pattern between the expected chemosensitivity of different cancers and the probability for patients to receive chemotherapy close to death. PMID- 27993818 TI - Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation. AB - Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of antiapoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1. Inhibition of SRSF1 expression or mTOR activity abolishes the oncogenic properties of MALAT1, suggesting that SRSF1 induction and mTOR activation are essential for MALAT1-induced transformation. Our results reveal a mechanism by which lncRNA MALAT1 acts as a proto-oncogene in hepatocellular carcinoma, modulating oncogenic alternative splicing through SRSF1 upregulation. Cancer Res; 77(5); 1155-67. (c)2016 AACR. PMID- 27993819 TI - Parsing the Role of the Hippocampus in Approach-Avoidance Conflict. AB - The hippocampus plays a central role in the approach-avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach avoidance conflict while controlling for spatial processing. We fit subjects' behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach-avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study. PMID- 27993821 TI - Sturge-Weber syndrome type 3 manifesting as 'Status migrainosus'. AB - Sturge-Weber syndrome (SWS) is a rare neurocutaneous syndrome characterised by facial naevus and leptomeningeal angiomatosis resulting in neurological and ophthalmological complications. In its rare variant, SWS type 3, the clinical hallmark of facial naevus is absent which poses a diagnostic challenge. Here, we present an interesting case of SWS type 3 where a child presented twice with prolonged severe unilateral headache mimicking migraine status followed on both occasions with focal seizures. He developed a dense right-sided homonymous hemianopia, and an urgent brain MRI scan was performed which pointed towards the diagnosis of SWS type 3. PMID- 27993820 TI - Adaptation to Leftward Shifting Prisms Alters Motor Interhemispheric Inhibition. AB - Adaptation to rightward shifting prisms (rightward prism adaptation, RPA) ameliorates neglect symptoms in patients while adaptation to leftward shifting prisms (leftward prism adaptation, LPA) induces neglect-like behaviors in healthy subjects. It has been hypothesized that prism adaptation (PA) modulates interhemispheric balance between the parietal cortices by inhibiting the posterior parietal cortex (PPC) contralateral to the prismatic deviation, but PA's effects on interhemispheric inhibition (IHI) have not been directly investigated. Since there are hyper-excitable connections between the PPC and primary motor cortex (M1) in the left hemisphere of neglect patients, we reasoned that LPA might mimic right hemisphere lesions by reducing parietal IHI, hyper exciting the left PPC and PPC-M1 connections, and in turn altering IHI at the motor level. Namely, we hypothesized that LPA would increase IHI from the left to the right M1. We examined changes in left-to-right and right-to-left IHI between the 2 M1s using the ipsilateral silent period (iSP) (Meyer et al. 1995) before and after either LPA or RPA. The iSP was significantly longer after LPA but only from left-to-right and it did not change at all after RPA. This is the first physiological demonstration that LPA alters IHI in the healthy brain. PMID- 27993822 TI - Calcitriol mediated hypercalcaemia with silicone granulomas due to cosmetic injection. AB - We present a case of a 41-year-old woman with medical history significant for urolithiasis presenting to our hospital for psychiatric evaluation due to worsening depression and suicidal ideations for the past 2 weeks. Initial laboratory results show hypercalcaemia of 13.5 mg/mL that led to consulting internal medicine. On further questioning, the patient admitted to cosmetic silicone injections in her buttocks which were causing calcium deposition under her skin, leading to disfigurement of the sacrum and lumbar regions. She underwent further evaluation with CT and laboratory testing, which effectively ruled out malignancy and primary hyperparathyroidism. The hypercalcaemia was diagnosed as non-PTH-dependent with high levels of 1,25-dihydroxyvitamin D and low PTH. She eventually underwent tissue biopsy confirming the presence of silicone granulomas responsible for the calcitriol-mediated hypercalcaemia. This case reminds one to keep a broad differential especially in patients with hypercalcaemia in which malignancy and primary hyperparathyroidism have been ruled out. PMID- 27993823 TI - Polyomavirus nephropathy after kidney transplantation. PMID- 27993824 TI - Acute abdominal pain caused by superior mesenteric artery syndrome in a healthy young boy. PMID- 27993825 TI - Invasive group G streptococcal infection in a paediatric patient. AB - We present a paediatric case of group G streptococcal bacteraemia and vertebral osteomyelitis. The patient is a 14-year-old girl with Gaucher disease type 1 who presented with severe thoracolumbar pain. She was treated with a 4-week course of antibiotics for presumed osteomyelitis with clinical improvement. PMID- 27993826 TI - Minimal change disease associated with malignant pleural mesothelioma: case report and review of the literature. AB - A 77-year-old man with a history of asbestos exposure was admitted to our internal medicine division for generalised weakness, fatigue, loss of weight, night sweats and difficulty for breathing since 3 months. Clinical examination revealed left fine crackles and bilateral leg oedema. Blood test showed elevated C reactive protein level at 142 mg/L, lactate dehydrogenase level at 421 UI, creatinine level at 5.75 mg/dL. Serum albumin level at 30 g/L, urinalysis showed significant proteinuria at 6.4 g/L. Chest X-ray showed left pleural effusion. Renal ultrasonography was normal. Thoracic CT and positron emission tomography showed mediastinal enlargement with lymphadenopathies and left pleural effusion and thickening. A pleural biopsy showed features compatible with malignant epithelioid mesothelioma. Renal biopsy showed minimal change disease and acute tubular necrosis. A diagnosis of malignant mesothelioma associated with minimal change disease and acute tubular necrosis secondary was then made. Given the poor general condition, palliative care was initiated and the patient died from respiratory failure 3 months later. PMID- 27993827 TI - Frantz's tumour, solid pseudopapillary epithelial neoplasm (SPEN). PMID- 27993828 TI - Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). AB - OBJECTIVES: To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX). METHODS: In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a >=4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12. RESULTS: Overall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (>=65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (~40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Over 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01894516. PMID- 27993829 TI - Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). AB - OBJECTIVES: To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. METHODS: In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. RESULTS: Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100 or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01888874. PMID- 27993830 TI - Secondhand Smoke Exposure and Subclinical Cardiovascular Disease: The Multi Ethnic Study of Atherosclerosis. AB - BACKGROUND: Few studies have evaluated the association between secondhand smoke (SHS) and subclinical cardiovascular disease among ethnically diverse populations. This study assesses the impact of SHS on inflammation and atherosclerosis (carotid intima-media thickness, coronary artery calcification, and peripheral arterial disease). METHODS AND RESULTS: We examined 5032 nonsmoking adults aged 45 to 84 years without prior cardiovascular disease participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 2000 to 2002. SHS exposure was determined by self-report, and urinary cotinine was measured in a representative subset (n=2893). The multi-adjusted geometric mean ratios (95% CIs) for high-sensitivity C-reactive protein and interleukin-6 comparing 407 participants with SHS >=12 h/wk versus 3035 unexposed participants were 1.13 (1.02-1.26) and 1.04 (0.98-1.11), respectively. The multi-adjusted geometric mean ratio for carotid intima-media thickness was 1.02 (0.97-1.07). Fibrinogen and coronary artery calcification were not associated with SHS. The prevalence of peripheral arterial disease (ankle-brachial index <=0.9 or >=1.4) was associated with detectable urinary cotinine (odds ratio, 2.10; 95% CI, 1.09 4.04) but not with self-reported SHS. Urinary cotinine was not associated with inflammation or carotid intima-media thickness. CONCLUSIONS: Despite limited exposure assessment, this study supports the association of SHS exposure with inflammation and peripheral arterial disease. PMID- 27993831 TI - Relationship Between Endothelial Wall Shear Stress and High-Risk Atherosclerotic Plaque Characteristics for Identification of Coronary Lesions That Cause Ischemia: A Direct Comparison With Fractional Flow Reserve. AB - BACKGROUND: Wall shear stress (WSS) is an established predictor of coronary atherosclerosis progression. Prior studies have reported that high WSS has been associated with high-risk atherosclerotic plaque characteristics (APCs). WSS and APCs are quantifiable by coronary computed tomography angiography, but the relationship of coronary lesion ischemia-evaluated by fractional flow reserve-to WSS and APCs has not been examined. METHODS AND RESULTS: WSS measures were obtained from 100 evaluable patients who underwent coronary computed tomography angiography and invasive coronary angiography with fractional flow reserve. Patients were categorized according to tertiles of mean WSS values defined as low, intermediate, and high. Coronary ischemia was defined as fractional flow reserve <=0.80. Stenosis severity was determined by minimal luminal diameter. APCs were defined as positive remodeling, low attenuation plaque, and spotty calcification. The likelihood of having positive remodeling and low-attenuation plaque was greater in the high WSS group compared with the low WSS group after adjusting for minimal luminal diameter (odds ratio for positive remodeling: 2.54, 95% CI 1.12-5.77; odds ratio for low-attenuation plaque: 2.68, 95% CI 1.02-7.06; both P<0.05). No significant relationship was observed between WSS and fractional flow reserve when adjusting for either minimal luminal diameter or APCs. WSS displayed no incremental benefit above stenosis severity and APCs for detecting lesions that caused ischemia (area under the curve for stenosis and APCs: 0.87, 95% CI 0.81-0.93; area under the curve for stenosis, APCs, and WSS: 0.88, 95% CI 0.82-0.93; P=0.30 for difference). CONCLUSIONS: High WSS is associated with APCs independent of stenosis severity. WSS provided no added value beyond stenosis severity and APCs for detecting lesions with significant ischemia. PMID- 27993832 TI - Avoiding Pitfalls With Implementation of Randomized Controlled Multicenter Trials: Strategies to Achieve Milestones. PMID- 27993835 TI - Supervised injection centers could save millions of dollars in health costs, US study finds. PMID- 27993833 TI - Nkx2-5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E-Deficient Mice. AB - BACKGROUND: NK2 homeobox 5 (Nkx2-5) is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages. Embryos lacking Nkx2-5 are nonviable attributed to growth retardation and gross abnormalities of the heart. However, the role of Nkx2-5 in atherosclerosis remains elusive. This study aims to elucidate the specific functions of Nkx2-5 during atherogenesis and in established atherosclerotic plaques. METHODS AND RESULTS: Two types of atherosclerotic lesions were created in ApoE-/- mice through 2 different dietary manipulations. Mice fed a standard chow diet were sacrificed at 20 weeks old, a time point at which mice developed early-stage atherosclerotic lesions. The other half of mice were fed a western diet from 6 to 22 weeks old and then sacrificed. These mice demonstrated advanced atherosclerosis. No Nkx2-5 was detected in normal arteries; however, it was abundantly present in the intima of atherosclerotic lesions and localized in macrophages and smooth muscle cells. Adenovirus gene transfer of Nkx2-5 markedly ameliorated and stabilized the atherosclerotic plaques, and knockdown of Nkx2-5 significantly exacerbated the disease. Molecular studies indicated that expression of specific members of matrix metalloproteinases and tissue inhibitor of metalloproteinases, which play a crucial role in the progression of atherosclerosis, were directly regulated by Nkx2-5. Furthermore, we demonstrated that the compromised endothelial function, which was considered as a hallmark of early atherosclerosis, could be improved by Nkx2-5 gene transfer. CONCLUSIONS: Nkx2-5 exerts antiatherogenic effects, which may partly be attributed to regulation on matrix metalloproteinases and tissue inhibitor of metalloproteinases, thus stabilizing atherosclerotic plaque; besides, it improves endothelial function by inhibiting leukocyte adhesion to the endothelium. PMID- 27993837 TI - Suicide strategy has failed, and GPs need better training in assessing risk, say MPs. PMID- 27993834 TI - Safety and Preclinical Efficacy of Aerosol Pioglitazone on Lung Adenoma Prevention in A/J Mice. AB - Pioglitazone is a PPARgamma agonist commonly prescribed for the clinical treatment of diabetes. We sought to expand its use to lung cancer prevention in a benzo[a]pyrene (B[a]P) mouse model with direct lung delivery via inhalation. Initially, we conducted inhalational toxicity experiments with 0, 15, 50, 150, and 450 MUg/kg body weight/day pioglitazone in 40 A/J mice. We examined the animals for any physical toxicity and bronchoalveolar lavage fluids for inflammatory and cytotoxicity markers. Doses up to and including 450 MUg/kg bw/d failed to demonstrate toxicity with aerosol pioglitazone. For chemoprevention experiments, A/J mice were randomized to treatment groups of inhaled doses of 0, 50, 150, or 450 MUg/kg bw/d pioglitazone 1 or 8 weeks after the last dose of B[a]P. For the early treatment group, we found up to 32% decrease in lung adenoma formation with 450 MUg/kg bw/d pioglitazone. We repeated the treatments in a second late-stage experiment and found up to 44% decreases in lung adenoma formation in doses of pioglitazone of 150 and 450 MUg/kg bw/day. Both the early- and the late-stage experiments demonstrated biologically relevant and statistically significant decreases in adenoma formation. We conclude that aerosol pioglitazone is well-tolerated in the A/J mouse model and a promising chemoprevention agent for the lower respiratory tract. Cancer Prev Res; 10(2); 124-32. (c)2016 AACR. PMID- 27993838 TI - Arterial Destiffening in Previously Untreated Mild Hypertensives After 1 Year of Routine Clinical Management. AB - BACKGROUND: Arterial stiffness, measured with pulse wave velocity (PWV), is now classified as a marker of target organ damage (TOD) alongside left ventricular hypertrophy and moderately increased albuminuria. Interventional studies on treated hypertensive patients have shown that PWV could be improved. Our aim was to assess changes in arterial stiffness after 1 year of routine clinical practice in never-treated hypertensive patients. PATIENTS AND METHODS: We studied 356 never-treated patients with suspected hypertension. After standard clinical assessment during which presence of TOD was evaluated, hypertension diagnosis was confirmed in 231 subjects who subsequently received standard routine care. Both hypertensive and the 125 controls came back for a follow-up visit after 1 year. RESULTS: Hypertensive patients were slightly older (46 +/- 12 vs. 50 +/- 12 years, P < 0.001), with higher mean arterial pressure (MAP)-adjusted PWV compared to controls (8.6 +/- 2.0 vs. 8.0 +/- 1.7 m/s, P < 0.001) and 47% of them presented 1 or more TOD. After 1 year of treatment, MAP was similar in both groups (94.9 vs. 96.2 mm Hg; P = ns), but adjusted PWV remained significantly higher in the hypertensive patients (7.8 +/- 1.4 vs. 8.3 +/- 1.7 m/s, P = 0.004). The prevalence of elevated PWV was reduced from 20% to 12%. All antihypertensive drugs achieved the same blood pressure (BP) and PWV reduction with the exception of vasodilating beta-blockers which gave slightly better results probably due to heart rate reduction. CONCLUSION: BP reduction in newly diagnosed hypertensive patients improves arterial stiffness within a year of real-life clinical practice. Patients with the highest PWV and the largest reduction of BP "destiffened" the most whatever antihypertensive class was used. PMID- 27993839 TI - Improvement in Liquid Chromatographic Performance of Organic Polymer Monolithic Capillary Columns with Controlled Free-Radical Polymerization. AB - Capillary columns containing butyl or lauryl methacrylate monoliths were prepared using two different free-radical polymerization methods: conventional free radical polymerization and controlled/living free-radical polymerization, both initiated thermally, and these methods were compared for the first time. Both monolith morphology and chromatographic efficiency were compared for the synthesized stationary phases using scanning electronic microscopy (SEM) and capillary liquid chromatography, respectively. Columns prepared using controlled method gave better chromatographic performance for both monomers tested. The lauryl-based monolith showed 7-fold improvement in chromatographic efficiency with a plate count of 42,000 plates/m (corrected for dead volume) for a non retained compound. Columns fabricated using controlled polymerization appeared more homogenous radially with fused small globular morphologies, evaluated by SEM, and lower column permeability. The columns were compared with respect to resolving power of a series of alkylbenzenes under isocratic and gradient elution conditions. PMID- 27993840 TI - Simultaneous Determination of Valproic Acid and Its Major Metabolites by UHPLC MS/MS in Chinese Patients: Application to Therapeutic Drug Monitoring. AB - A specific and sensitive Ultra-high Performance Liquid Chromatography-tandem Mass spectrometry (UHPLC-MS/MS) method was developed for the simultaneous determination of the concentrations of valproic acid (VPA) and its clinically relevant metabolites (4-ene-VPA, 2,4-diene-VPA and 2-ene-VPA) in human serum. After solid-phase extraction, VPA, its metabolites and the internal standard were subjected to chromatographic separation by gradient elution of acetonitrile and 10 mM ammonium acetate as mobile phase at a flow rate of 0.6 mL/min on an EC-C18 column. The method was validated over the concentration ranges of 1-200 MUg/mL for VPA, 0.5-10 MUg/mL for 2-ene-VPA, 10-500 ng/mL for 4-ene-VPA and 25-500 ng/mL for 2,4-diene-VPA. The inter-day and intra-day accuracy and precision were within the acceptable limits of <15 %. The recoveries and matrix effects met the requirement for the analysis of biological samples. No obvious degradation was observed under various storage conditions including room temperature for 12 h, three freeze-thaw cycles and -80 degrees C for 1 month. The assay method was successfully applied to monitor the concentration of VPA and its three metabolites in epileptic patients. The UHPLC-MS/MS method demonstrated a good analytical performance essential for therapeutic drug monitoring, which would potentially lead to clinically relevant improvements in VPA dosage and patient management. PMID- 27993841 TI - An integer programming framework for inferring disease complexes from network data. PMID- 27993843 TI - Reliability of specific physical examination tests for the diagnosis of shoulder pathologies: a systematic review and meta-analysis. AB - BACKGROUND: Shoulder pain in the general population is common and to identify the aetiology of shoulder pain, history, motion and muscle testing, and physical examination tests are usually performed. OBJECTIVE: The aim of this systematic review was to summarise and evaluate intrarater and inter-rater reliability of physical examination tests in the diagnosis of shoulder pathologies. METHODS: A comprehensive systematic literature search was conducted using MEDLINE, EMBASE, Allied and Complementary Medicine Database (AMED) and Physiotherapy Evidence Database (PEDro) through 20 March 2015. Methodological quality was assessed using the Quality Appraisal of Reliability Studies (QAREL) tool by 2 independent reviewers. RESULTS: The search strategy revealed 3259 articles, of which 18 finally met the inclusion criteria. These studies evaluated the reliability of 62 test and test variations used for the specific physical examination tests for the diagnosis of shoulder pathologies. Methodological quality ranged from 2 to 7 positive criteria of the 11 items of the QAREL tool. CONCLUSIONS: This review identified a lack of high-quality studies evaluating inter-rater as well as intrarater reliability of specific physical examination tests for the diagnosis of shoulder pathologies. In addition, reliability measures differed between included studies hindering proper cross-study comparisons. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014009018. PMID- 27993844 TI - Comparison of four alternative national universal anterior cruciate ligament injury prevention programme implementation strategies to reduce secondary future medical costs. AB - BACKGROUND/AIM: Anterior cruciate ligament (ACL) injury is a common and devastating sporting injury. With or without ACL reconstruction, the risk of knee osteoarthritis (OA) and permanent disability later in life is markedly increased. While neuromuscular training programmes can prevent 50-80% of ACL injuries, no national implementation strategies exist in Australia. The aim of this study was to compare the ability of four alternative national universal ACL injury prevention programme implementation strategies to reduce future medical costs secondary to ACL injury. METHODS: A Markov economic decision model was constructed to estimate the value in lifetime future medical costs prevented by implementing a national ACL prevention programme among four hypothetical cohorts: high-risk sport participants (HR) aged 12-25 years; HR 18-25 years; HR 12-17 years; all youths (ALL) 12-17 years. RESULTS: Of the four programmes examined, the HR 12-25 programme provided the greatest value, averting US$693 of direct healthcare costs per person per lifetime or US$221 870 880 in total. Without training, 9.4% of this cohort will rupture their ACL and 16.8% will develop knee OA. Training prevents 3764 lifetime ACL ruptures per 100 000 individuals, a 40% reduction in ACL injuries. 842 lifetime cases of OA per 100 000 individuals and 584 TKRs per 100 000 are subsequently averted. Numbers needed to treat ranged from 27 for the HR 12-25 to 190 for the ALL 12-17. CONCLUSIONS: The HR 12-25 programme was the most effective implementation strategy. Estimation of the break even cost of health expenditure savings will enable optimal future programme design, implementation and expenditure. PMID- 27993842 TI - Exercise-induced biochemical changes and their potential influence on cancer: a scientific review. AB - AIM: To review and discuss the available international literature regarding the indirect and direct biochemical mechanisms that occur after exercise, which could positively, or negatively, influence oncogenic pathways. METHODS: The PubMed, MEDLINE, Embase and Cochrane libraries were searched for papers up to July 2016 addressing biochemical changes after exercise with a particular reference to cancer. The three authors independently assessed their appropriateness for inclusion in this review based on their scientific quality and relevance. RESULTS: 168 papers were selected and categorised into indirect and direct biochemical pathways. The indirect effects included changes in vitamin D, weight reduction, sunlight exposure and improved mood. The direct effects included insulin-like growth factor, epigenetic effects on gene expression and DNA repair, vasoactive intestinal peptide, oxidative stress and antioxidant pathways, heat shock proteins, testosterone, irisin, immunity, chronic inflammation and prostaglandins, energy metabolism and insulin resistance. SUMMARY: Exercise is one of several lifestyle factors known to lower the risk of developing cancer and is associated with lower relapse rates and better survival. This review highlights the numerous biochemical processes, which explain these potential anticancer benefits. PMID- 27993845 TI - Establishing Genotypic Cutoff Values To Measure Antimicrobial Resistance in Salmonella. AB - Whole-genome sequencing (WGS) has transformed our understanding of antimicrobial resistance, helping us to better identify and track the genetic mechanisms underlying phenotypic resistance. Previous studies have demonstrated high correlations between phenotypic resistance and the presence of known resistance determinants. However, there has never been a large-scale assessment of how well resistance genotypes correspond to specific MICs. We performed antimicrobial susceptibility testing and WGS of 1,738 nontyphoidal Salmonella strains to correlate over 20,000 MICs with resistance determinants. Using these data, we established what we term genotypic cutoff values (GCVs) for 13 antimicrobials against Salmonella For the drugs we tested, we define a GCV as the highest MIC of isolates in a population devoid of known acquired resistance mechanisms. This definition of GCV is distinct from epidemiological cutoff values (ECVs or ECOFFs), which currently differentiate wild-type from non-wild-type strains based on MIC distributions alone without regard to genetic information. Due to the large number of isolates involved, we observed distinct MIC distributions for isolates with different resistance gene alleles, including for ciprofloxacin and tetracycline, suggesting the potential to predict MICs based on WGS data alone. PMID- 27993846 TI - Nonnucleoside Reverse Transcriptase Inhibitors Reduce HIV-1 Production from Latently Infected Resting CD4+ T Cells following Latency Reversal. AB - Therapeutic strategies that target the latent HIV-1 reservoir in resting CD4+ T cells of infected individuals are always administered in the presence of combination antiretroviral therapy. Using a primary cell of HIV-1 latency, we evaluated whether different antiviral drug classes affected latency reversal (as assessed by extracellular virus production) by anti-CD3/CD28 monoclonal antibodies or bryostatin 1. We found that the nonnucleoside reverse transcriptase inhibitors efavirenz and rilpivirine significantly decreased HIV-1 production, by >=1 log. PMID- 27993847 TI - Various Sequence Types of Escherichia coli Isolates Coharboring blaNDM-5 and mcr 1 Genes from a Commercial Swine Farm in China. AB - Sixteen different sequence types (STs) of Escherichia coli isolates from a commercial swine farm in China were confirmed to coharbor the carbapenem resistance gene blaNDM-5 and the colistin resistance gene mcr-1 Whole-genome sequencing revealed that blaNDM-5 and mcr-1 were located on a 46-kb IncX3 plasmid and a 32-kb IncX4 plasmid, respectively. The two plasmids can transfer together with a low fitness cost, which might explain the presence of various STs of E. coli coharboring blaNDM-5 and mcr-1. PMID- 27993848 TI - Mycobacterium tuberculosis Is Selectively Killed by Rifampin and Rifapentine in Hypoxia at Neutral pH. AB - The activities of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant) Mycobacterium tuberculosis H37Rv under conditions of hypoxia at pHs 5.8 and 7.3, mimicking environments of cellular granulomas and caseous granulomas, respectively. At pH 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. At pH 7.3, only rifampin and rifapentine efficiently killed dormant bacilli, while all other drugs showed little activity. PMID- 27993849 TI - In Vivo Fitness Adaptations of Colistin-Resistant Acinetobacter baumannii Isolates to Oxidative Stress. AB - The loss of fitness in colistin-resistant (CR) Acinetobacter baumannii was investigated using longitudinal isolates from the same patient. Early CR isolates were outcompeted by late CR isolates for growth in broth and survival in the lungs of mice. Fitness loss was associated with an increased susceptibility to oxidative stress since early CR strains had reduced in vitro survival in the presence of hydrogen peroxide and decreased catalase activity compared to that of late CR and colistin-susceptible (CS) strains. PMID- 27993850 TI - Pharmacological Blockade of the Chemokine Receptor CCR1 Protects Mice from Systemic Candidiasis of Hematogenous Origin. AB - Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida-infected mice. Here, we found that treatment of immunocompetent Candida-infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury. PMID- 27993851 TI - Analysis of Ribonucleotide 5'-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays. AB - Zika virus (ZIKV) is an emerging human pathogen that is spreading rapidly through the Americas and has been linked to the development of microcephaly and to a dramatically increased number of Guillain-Barre syndrome cases. Currently, no vaccine or therapeutic options for the prevention or treatment of ZIKV infections exist. In the study described in this report, we expressed, purified, and characterized full-length nonstructural protein 5 (NS5) and the NS5 polymerase domain (NS5pol) of ZIKV RNA-dependent RNA polymerase. Using purified NS5, we developed an in vitro nonradioactive primer extension assay employing a fluorescently labeled primer-template pair. Both purified NS5 and NS5pol can carry out in vitro RNA-dependent RNA synthesis in this assay. Our results show that Mn2+ is required for enzymatic activity, while Mg2+ is not. We found that ZIKV NS5 can utilize single-stranded DNA but not double-stranded DNA as a template or a primer to synthesize RNA. The assay was used to compare the efficiency of incorporation of analog 5'-triphosphates by the ZIKV polymerase and to calculate their discrimination versus that of natural ribonucleotide triphosphates (rNTPs). The 50% inhibitory concentrations for analog rNTPs were determined in an alternative nonradioactive coupled-enzyme assay. We determined that, in general, 2'-C-methyl- and 2'-C-ethynyl-substituted analog 5' triphosphates were efficiently incorporated by the ZIKV polymerase and were also efficient chain terminators. Derivatives of these molecules may serve as potential antiviral compounds to be developed to combat ZIKV infection. This report provides the first characterization of ZIKV polymerase and demonstrates the utility of in vitro polymerase assays in the identification of potential ZIKV inhibitors. PMID- 27993852 TI - Increased Costs Associated with Bloodstream Infections Caused by Multidrug Resistant Gram-Negative Bacteria Are Due Primarily to Patients with Hospital Acquired Infections. AB - The clinical and economic impacts of bloodstream infections (BSI) due to multidrug-resistant (MDR) Gram-negative bacteria are incompletely understood. From 2009 to 2015, all adult inpatients with Gram-negative BSI at our institution were prospectively enrolled. MDR status was defined as resistance to >=3 antibiotic classes. Clinical outcomes and inpatient costs associated with the MDR phenotype were identified. Among 891 unique patients with Gram-negative BSI, 292 (33%) were infected with MDR bacteria. In an adjusted analysis, only history of Gram-negative infection was associated with MDR BSI versus non-MDR BSI (odds ratio, 1.60; 95% confidence interval [CI], 1.19 to 2.16; P = 0.002). Patients with MDR BSI had increased BSI recurrence (1.7% [5/292] versus 0.2% [1/599]; P = 0.02) and longer hospital stay (median, 10.0 versus 8.0 days; P = 0.0005). Unadjusted rates of in-hospital mortality did not significantly differ between MDR (26.4% [77/292]) and non-MDR (21.7% [130/599]) groups (P = 0.12). Unadjusted mean costs were 1.62 times higher in MDR than in non-MDR BSI ($59,266 versus $36,452; P = 0.003). This finding persisted after adjustment for patient factors and appropriate empirical antibiotic therapy (means ratio, 1.18; 95% CI, 1.03 to 1.36; P = 0.01). Adjusted analysis of patient subpopulations revealed that the increased cost of MDR BSI occurred primarily among patients with hospital acquired infections (MDR means ratio, 1.41; 95% CI, 1.10 to 1.82; P = 0.008). MDR Gram-negative BSI are associated with recurrent BSI, longer hospital stays, and increased mean inpatient costs. MDR BSI in patients with hospital-acquired infections primarily account for the increased cost. PMID- 27993853 TI - In Vitro Activities of MCB3681 and Eight Comparators against Clostridium difficile Isolates with Known Ribotypes and Diverse Geographical Spread. AB - Treatments for Clostridium difficile infection remain limited, despite the introduction of fidaxomicin, and development of new agents is necessary. We determined the in vitro susceptibilities of 199 prevalent or emerging Clostridium difficile PCR ribotypes to MCB3681, a novel investigational quinolonyl oxazolidinone, and 8 comparators (metronidazole, vancomycin, fidaxomicin, moxifloxacin, ciprofloxacin, clindamycin, tigecycline, and linezolid). MCB3681 showed good activity against C. difficile with no evidence of MCB3681 resistance in isolates showing either moxifloxacin or linezolid resistance or both moxifloxacin and linezolid resistance. PMID- 27993854 TI - Activities of Omadacycline and Comparator Agents against Staphylococcus aureus Isolates from a Surveillance Program Conducted in North America and Europe. AB - Omadacycline is a new broad-spectrum aminomethylcycline in late-stage clinical development for acute bacterial skin and skin structure infections and community acquired bacterial pneumonia as a once-daily formulation taken orally or intravenously. In this study, omadacycline and comparator agents were tested against 502 isolates of Staphylococcus aureus selected from a 2014 global surveillance program, and the results were compared with those for 7,740 isolates from a 2010 surveillance program. For the 2014 isolates, testing was completed on 252 isolates from Europe and 250 isolates from North America. Each set of isolates was composed of ~100 hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) isolates (isolated >48 h after hospital admission), 100 community-acquired MRSA (CA-MRSA) isolates (isolated <48 h after hospital admission), and 50 methicillin-susceptible S. aureus (MSSA) isolates. The omadacycline MIC50 and MIC90 for all S. aureus collected during 2014 was 0.12 and 0.12 MUg/ml, respectively. The MIC90 values were identical for MRSA, HA-MRSA, and CA-MRSA (0.12 MUg/ml). The MIC90 values for isolates from 2010 for S. aureus, MRSA, and CA-MRSA were 0.25 MUg/ml (0.5 MUg/ml for HA-MRSA; 87.8% were at <=0.25 MUg/ml). All 2014 and 2010 MRSA isolates were susceptible to vancomycin, and >=99.8% were susceptible to daptomycin, linezolid, and tigecycline. The activity of omadacycline was similar for North American and European isolates, including MRSA (CA-MRSA or HA-MRSA). There was no evidence for emerging resistance to omadacycline between 2010 and 2014. The potent activity of omadacycline against S. aureus indicates that omadacycline merits further study in serious infections where multidrug resistance may be a concern. PMID- 27993855 TI - Obatoclax Inhibits Alphavirus Membrane Fusion by Neutralizing the Acidic Environment of Endocytic Compartments. AB - As new pathogenic viruses continue to emerge, it is paramount to have intervention strategies that target a common denominator in these pathogens. The fusion of viral and cellular membranes during viral entry is one such process that is used by many pathogenic viruses, including chikungunya virus, West Nile virus, and influenza virus. Obatoclax, a small-molecule antagonist of the Bcl-2 family of proteins, was previously determined to have activity against influenza A virus and also Sindbis virus. Here, we report it to be active against alphaviruses, like chikungunya virus (50% effective concentration [EC50] = 0.03 MUM) and Semliki Forest virus (SFV; EC50 = 0.11 MUM). Obatoclax inhibited viral entry processes in an SFV temperature-sensitive mutant entry assay. A neutral red retention assay revealed that obatoclax induces the rapid neutralization of the acidic environment of endolysosomal vesicles and thereby most likely inhibits viral fusion. Characterization of escape mutants revealed that the L369I mutation in the SFV E1 fusion protein was sufficient to confer partial resistance against obatoclax. Other inhibitors that target the Bcl-2 family of antiapoptotic proteins inhibited neither viral entry nor endolysosomal acidification, suggesting that the antiviral mechanism of obatoclax does not depend on its anticancer targets. Obatoclax inhibited the growth of flaviviruses, like Zika virus, West Nile virus, and yellow fever virus, which require low pH for fusion, but not that of pH-independent picornaviruses, like coxsackievirus A9, echovirus 6, and echovirus 7. In conclusion, obatoclax is a novel inhibitor of endosomal acidification that prevents viral fusion and that could be pursued as a potential broad-spectrum antiviral candidate. PMID- 27993856 TI - Real-Time Monitoring of nfxB Mutant Occurrence and Dynamics in Pseudomonas aeruginosa Biofilm Exposed to Subinhibitory Concentrations of Ciprofloxacin. AB - Biofilm infections caused by Pseudomonas aeruginosa are frequently treated with ciprofloxacin (CIP); however, resistance rapidly develops. One of the primary resistance mechanisms is the overexpression of the MexCD-OprJ pump due to a mutation in nfxB, encoding the transcriptional repressor of this pump. The aim of this study was to investigate the effect of subinhibitory concentrations of CIP on the occurrence of nfxB mutants in the wild-type PAO1 flow cell biofilm model. For this purpose, we constructed fluorescent reporter strains (PAO1 background) with an mCherry tag for constitutive red fluorescence and chromosomal transcriptional fusion between the P mexCD promoter and gfp leading to green fluorescence upon mutation of nfxB We observed a rapid development of nfxB mutants by live confocal laser scanning microscopy (CLSM) imaging of the flow cell biofilm (reaching 80 to 90% of the whole population) when treated with 1/10 minimal biofilm inhibitory concentration of CIP for 24 h and 96 h. Based on the observed developmental stages, we propose that nfxB mutants emerged de novo in the biofilm during CIP treatment from filamentous cells, which might have arisen due to the stress responses induced by CIP. Identical nfxB mutations were found in fluorescent colonies from the same flow cell biofilm, especially in 24-h biofilms, suggesting selection and clonal expansion of the mutants during biofilm growth. Our findings point at the significant role of high-enough antibiotic dosages or appropriate combination therapy to avoid the emergence of resistant mutants in biofilms. PMID- 27993858 TI - Repurposing Toremifene for Treatment of Oral Bacterial Infections. AB - The spread of antibiotic resistance and the challenges associated with antiseptics such as chlorhexidine have necessitated a search for new antibacterial agents against oral bacterial pathogens. As a result of failing traditional approaches, drug repurposing has emerged as a novel paradigm to find new antibacterial agents. In this study, we examined the effects of the FDA approved anticancer agent toremifene against the oral bacteria Porphyromonas gingivalis and Streptococcus mutans We found that the drug was able to inhibit the growth of both pathogens, as well as prevent biofilm formation, at concentrations ranging from 12.5 to 25 MUM. Moreover, toremifene was shown to eradicate preformed biofilms at concentrations ranging from 25 to 50 MUM. In addition, we found that toremifene prevents P. gingivalis and S. mutans biofilm formation on titanium surfaces. A time-kill study indicated that toremifene is bactericidal against S. mutans Macromolecular synthesis assays revealed that treatment with toremifene does not cause preferential inhibition of DNA, RNA, or protein synthesis pathways, indicating membrane-damaging activity. Biophysical studies using fluorescent probes and fluorescence microscopy further confirmed the membrane-damaging mode of action. Taken together, our results suggest that the anticancer agent toremifene is a suitable candidate for further investigation for the development of new treatment strategies for oral bacterial infections. PMID- 27993860 TI - Simultaneous Determination of Eight Pesticide Residues in Cowpeas by GC-ECD. AB - A sensitive and effective method, using gas chromatography (GC) and an electron capture detector (ECD), for the simultaneous quantitative determination of bifenthrin, chlorothalonil, cyfluthrin, cypermethrin, difenoconazole, fenvalerate, procymidone and pyridaben residues in cowpea was developed and validated. The method involved extracting with acetonitrile, purification with a graphitized carbon black/amino solid phase extraction cartridge, and then determining by GC-ECD. Recovery studies were carried out at three spiked levels (0.01, 0.1 and 0.5 mg/kg). The average recoveries at the three spiked levels ranged from 76.6 to 107.0% with relative standard deviations in the range of 1.2 5.6% for all analytes. The quantification limit was 0.01 mg/kg for each pesticide and was less than or equal to the relevant MRLs set by China, the Codex Alimentarius or the European Union. The developed analyzing method was convenient, time and cost saving, environment-friendly and readily available than the traditional methods. PMID- 27993857 TI - Simvastatin Attenuates Endothelial Activation through 15-Epi-Lipoxin A4 Production in Murine Chronic Chagas Cardiomyopathy. AB - Current treatments for chronic Chagas cardiomyopathy, a disease with high mortality rates and caused by the protozoan Trypanosoma cruzi, are unsatisfactory. Myocardial inflammation, including endothelial activation, is responsible for the structural and functional damage seen in the chronic phase. The clinical efficacy of benznidazole could be improved by decreasing chronic inflammation. Statins, which have anti-inflammatory properties, may improve the action of benznidazole. Here, the action of simvastatin in a murine model of chronic Chagas cardiomyopathy and the link with the production of the proresolving eicosanoid 15-epi-lipoxin A4, produced by 5-lipoxygenase, are evaluated. Simvastatin decreased the expression of the adhesion molecules E selectin, intracellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1) in T. cruzi-infected mice. However, when this drug was administered to 5-lipoxygenase-deficient mice, the anti-inflammatory effect was not observed unless exogenous 15-epi-lipoxin A4 was administered. Thus, in chronic Chagas disease, 5-epi-lipoxin A4 induced by simvastatin treatment could improve the pathophysiological condition of patients by increasing the trypanocidal action of benznidazole. PMID- 27993859 TI - Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B? AB - Nephrotoxicity is a common adverse effect of the clinically used polymyxins, colistin and polymyxin B. This adverse effect is dose limiting for both polymyxins, as the plasma polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, colistimethate) and polymyxin B (administered as the active form). Both polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with colistimethate compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies. PMID- 27993862 TI - Pharmacokinetic Study of Swertisin by HPLC-MS/MS After Intravenous Administration in Rats. AB - A sensitive and reliable high-performance liquid chromatography with tandem mass spectrometry was developed and validated for the quantification of swertisin in rat plasma. The samples were prepared with methanol by protein precipitation. Swertisin was separated by using an Agilent Poroshell 120 EC-C18 column (4.6 mm * 50 mm, 2.7 MUm) with the mobile phase consisted of acetonitrile and water containing 0.1% formic acid running at a flow rate of 0.3 mL/min for 5 min. The analytes were detected with the multiple reaction monitoring in the negative electrospray ionization source for quantitative response of swertisin [M-H]- (445.1->281.7) and puerarin (internal standard) [M-H]- (415.1->295.0). Precision (relative standard deviation, RSD%) of the inter-day and the intra-day was <9.89% and 11.34% while accuracy (relative error, RE%) ranged from -6.01% to 4.92% and 3.97% to 4.39%, respectively. Interestingly, the expression of the gamma aminobutyric acid (GABA) receptor subunits (GABAAalpha1, GABAAalpha5 and GABAAbeta1) mRNAs was enhanced in the rat hippocampal neurons treated with swertisin as analyzed by real-time polymerase chain reaction. Moreover, the method was successfully applied to determine the pharmacokinetic of swertisin in rats after tail vein injection with 4.0 mg/kg of the compound. Our results provide useful pharmacokinetic information for swertisin in vivo and suggest that the sedative function of this compound may be through inducing the expression of the GABAA receptor subunits. PMID- 27993861 TI - Novel Validated RP-HPLC Method for Bendamustine Hydrochloride Based on Ion-pair Chromatography: Application in Determining Infusion Stability and Pharmacokinetics. AB - Ion pair chromatography was used for quantifying bendamustine hydrochloride (BH) in its marketed vial. The permissive objective was to investigate time duration for which highly susceptible drug content of the marketed vial remained stable after reconstitution. However, the method could also be used to measure extremely low levels of drug in rat plasma and a pharmacokinetic study was accordingly conducted to further showcase method's applicability. Optimized separation was achieved on C-18 Purospher(r)STAR (250 mm * 4.6 mm, 5 MUm particle size) column. Mobile phase flowing at 1.5 mL/min consisted of 5 mM sodium salt of octane sulfonic acid dissolved in methanol, water and glacial acetic acid (55:45:0.075) maintained at pH 6. Detection was carried out at 233 nm with BH eluting after 7.8 min. Validation parameters were determined as per ICH guidelines. Limit of detection and limit of quantification were found to be 0.1 ug/mL and 0.33 ug/mL, respectively. The recoveries were 98-102% in bulk and 85-91% in plasma. The developed method was specific for BH, and utilized for assessing its short-term stability in physiologic solvents and forced degradation products in acid, base, oxidative, light and temperature induced stress environments. PMID- 27993863 TI - Characterization of a Porous Nano-electrospray Capillary Emitter at Ultra-low Flow Rates. AB - Biopharmaceuticals, especially therapeutic monoclonal antibodies, have emerged as a very promising new generation of protein-based drugs. However, their comprehensive analysis continues to pose new challenges for the bioanalytical field. Hyphenation of capillary electrophoresis with electrospray ionization (CE MS) is a promising technique to address these challenges. One of the main advantages of CE-MS is the ability to produce stable electrospray at ultra-low flow rates (5-20 nl/min range). In this short communication we report on the characterization of a porous nano-electrospray capillary emitter focusing on the effects of ultra-low flow rate on ionization efficiency, ion suppression and detection sensitivity. Ion suppression effect of a poorly-ionizable sugar in the presence of an easily-ionized peptide was reduced by almost 2-fold. Intact therapeutic antibody infusion analysis demonstrated that MS detection sensitivity increased by an order of magnitude with the decrease of flow rate from 250 nL/min to 20 nL/min using the nano-electrospray capillary emitter. PMID- 27993864 TI - Studies on Behaviors of Interactions Between New Polymer-based ZIC-HILIC Stationary Phases and Carboxylic Acids. AB - Zwitterionic stationary phases with nearly identical capacities were prepared by graft polymerization of a series of sulfobetaine precursors onto the surface of porous PS/DVB particles. The different spacer lengths are used as an investigative tool for the retention behavior of carboxylic acids; namely malonic, succinic, glutaric and maleic acid. In zwitterionic ion chromatography hydrophilic interaction liquid chromatography (ZIC-HILIC) separation mode, the retention characteristic of carboxylic acids was examined using sodium acetate/acetonitrile eluents and UV detection. The retention is based on partitioning in reversed as well as in HILIC mode and zwitterionic ion exchange resulting in a mixed separation mode for the carboxylic acids. This ion exchange behavior has never been observed before for sulfobetaine-based zwitterionic stationary phases. PMID- 27993867 TI - Retention Characteristics of a pH Tunable Water Stationary Phase in Supercritical Fluid Chromatography. AB - The retention characteristics of a novel pH tunable water stationary phase are presented. The method utilizes a change in mobile phase from N2 to CO2 to acidify the water phase in situ and control the ionization and elution of organic acids. With N2 present the phase pH > 5.4 and the acids are ionized and strongly retained. Conversely, with CO2 present the pH < 3.8 and the acids are neutralized and can elute. This effect is reasonably independent of time. For example, at 80 degrees C hexanoic acid readily elutes from a 10 m column after switching to CO2 at any point over a 1 h period. Beyond this, however, some broadening and peak erosion is noted. Acids are also retained on 10 and 2 m columns similarly, since their elution primarily depends upon the change in stationary phase pH. Altering the CO2 solubility in the water phase alone (i.e., through changing system temperature and pressure without using N2) also produces similar changes in stationary phase acidity. However, this approach yields greater system noise and instability. The N2/CO2 switching mode is used to analyze organic acids in various samples and is found to provide high selectivity for them over other matrix components. Therefore, this approach can potentially simplify the analysis of such acids in complex samples. PMID- 27993865 TI - Simultaneous Determination of Five Specific and Sensitive Nephrotoxicity Biomarkers in Serum and Urine Samples of Four Drug-Induced Kidney Injury Models. AB - In clinical diagnosis, serum creatinine (CR) was commonly used as the routine markers for the evaluation of kidney injury. To investigate the specific and sensitive nephrotoxicity biomarkers in different drug-induced kidney injury (DKI) models, receiver operating characteristic (ROC) analysis was applied in this study. The quantification data were acquired by the LC-MS determination. Histopathology results showed that different kinds of kidney injuries were observed in different DKI models (gentamycin, cisplatin, methotrexate and amphotericin B models), indicating the injuries might be caused by different mechanisms. Then, five typical biomarkers were simultaneously determined by a newly developed and validated LC-MS method. Uric acid, CR, hippuric acid, 3 indoxyl sulfate and phenaceturic acid were separated by an Apollo C18 column and a methanol/water (5 mM ammonium acetate) gradient program. The prepared calibration curves showed good linearity with regression coefficients all above 0.9927. Of all the analytes, the precision were below 9.9% and the accuracy were from -10.3% to 9.2%. ROC results showed that different nephrotoxicity biomarkers were specific in different DKI models. The changes of different biomarkers might be induced by different nephrotoxic mechanisms in the DKI models. These specific and sensitive biomarkers in combination with serum CR are promising in the clinical diagnosis of DKI. PMID- 27993866 TI - Separation and Purification of Ombuoside from Gynostemma Pentaphyllum by Microwave-Assisted Extraction Coupled with High-Speed Counter-current Chromatography. AB - A rapid and efficient method for the separation and purification of ombuoside from Gynostemma pentaphyllum by microwave-assisted extraction coupled with high speed counter-current chromatography (HSCCC) was successfully developed. Using an orthogonal array design L9 (34), the extraction conditions, including microwave power, irradiation time, solid-to-liquid ratio and extraction times, were optimized. Ombuoside was isolated and purified from the crude extraction by HSCCC with two-phase solvent system composed of n-hexane:ethyl acetate:ethanol:water (5:6:5:5, v/v) in a single run. A 210 mg quantity of the crude extract containing 2.16% ombuoside was loaded, yielding 3.9 mg of ombuoside at 96.7% purity. The chemical structure of ombuoside was determined by comparison with the high performance liquid chromatography retention time of standard substance as well as UV, FT-IR, ESI-MS, 1H NMR and 13C NMR spectra. The purified ombuoside had strong 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radical scavenging activities. PMID- 27993868 TI - Optimization of Recovery and Analysis of RNA in Sorted Cells in mRNA Quantification After Fluorescence-activated Cell Sorting. AB - In our previous studies, we established a method to analyze cells collected by fluorescence-activated cell sorting (FACS), named mRNA quantification after FACS (FACS-mQ), in which cells are labeled with fluorescent dyes in a manner that minimizes RNA degradation, and then cells sorted by FACS are examined by analyzing their gene expression profile. In this study, we examined methods to maximize the yield of recovered RNA after in-tube immunocytochemistry in addition to RNA analysis using a small dose of extracted RNA. Paraformaldehyde fixation resulted in reduced RNA recovery, while preservation at 4 degrees C with 40 mM dithiothreitol was suitable for preventing RNA degradation in cells after immunocytochemistry. Using extracted RNA, four methods of analysis: quantitative reverse transcription - polymerase chain reaction (qRT-PCR), a combination of whole transcriptome amplification (WTA) or linear amplification and quantitative polymerase chain reaction (qPCR), and 2-step qRT-PCR, were compared. The combination of WTA and qPCR was less sensitive compared with the other methods. When RNAs from a small number of cells were used, qRT-PCR and 2-step qRT-PCR showed a greatly elevated relative expression level to ACTB mRNA in analyses of genes with a low expression level. These results suggested that among these methods, linear amplification was the most promising. PMID- 27993869 TI - The Promotion of Neural Regeneration in A Rat Facial Nerve Crush Injury Model Using Collagen-Binding NT-3. AB - Traumatic facial nerve injury, an important cause of facial paralysis, has a number of adverse effects, including facial muscle dysfunction and facial asymmetry. It has been demonstrated in our previous work that native human NT-3 fused with a collagen-binding domain (CBD-NT-3) could bind to collagen, specifically to exert neurotrophic effects, promoting axonal regeneration. To evaluate the effect of CBD-NT-3 in inducing facial nerve regeneration and functional recovery, the differing effects of CBD-NT-3 and native neurotrophin-3 (NAT-NT-3) were observed using the results of facial nerve functional recovery, electrophysiological testing, and axonal and myelin changes in a rat model of facial nerve crush injury. The rats were injected in the epineurium in crushed fibers of the facial nerve with CBD-NT-3, NAT-NT-3, and PBS respectively. After 4 weeks, the CBD-NT-3 group demonstrated significantly more ordered growth of axons and nerve functional recovery than the NAT-NT-3 group. The results suggest that CBD-NT-3 considerably enhances facial nerve regeneration and functional recovery. PMID- 27993870 TI - Possible Implication of GSTP1 and NQO1 Polymorphisms on Natalizumab Response in Multiple Sclerosis. AB - Oxidative stress plays a pivotal role in the pathogenesis of multiple sclerosis (MS). Inactivating polymorphism of genes encoding detoxification enzymes, such as NQO1 and GSTP1 could influence susceptibility to MS. The monoclonal antibody natalizumab is an effective treatment in MS. Natalizumab's efficacy in MS patients with regard to NQO1 and GSTP1 genetic polymorphisms is investigated. 130 patients with definite MS according to the Mc Donald's criteria treated monthly with natalizumab were included in the study. MS patients were classified with regard to their clinical subtype, gender and clinical outcome after Natalizumab administration. GSTP1 and NQO1 genotyping was performed using Real-Time PCR and PCR-RFLP assays. Among our cohort of MS patients, 88.5% responded and 11.5% manifested clinical deterioration after natalizumab treatment. Statistical analysis revealed a significantly increased frequency of double NQO1 and GSTP1 mutant polymorphisms in non responders compared to the responders. Therefore, patients who carry the wild type genotype or only one polymorphism for either NQO1 or GSTP1 gene have possibly a better clinical outcome after the natalizumab therapy. Our findings indicate that antioxidant efficiency might reflect a better clinical outcome after natalizumab administration. Hence, oxidative stress reduction might be another mechanism through which natalizumab exerts its protective effect. PMID- 27993871 TI - FLT3 Internal Tandem Duplication Mutation, cMPL and CD34 Expressions Predict Low Survival in Acute Myeloid Leukemia Patients. AB - OBJECTIVES: To detect FMS-like tyrosine kinase-3 internal tandem duplicate (FLT3 ITD) mutation, Myeloproliferative leukemia virus oncogene (cMPL) and Ephrin A 4 receptor (EphA4) expressions in Acute myeloid leukemia (AML) and their correlation to patient's clinicopathological characteristics and survival. METHODS: RNA was extracted from blood samples of 58 AML patients (39 adults and 19 children) and 20 age and sex matched controls. FLT3 ITD mutation, cMPL and EphA4 expression was studied using RT-PCR and correlated to the clinical and survival data of the patients. RESULTS: FLT3 ITD mutation, cMPL and EphA4 expression was positive in 35.9%, 76.9% and 56.4% of adult AML patients respectively and in 15.8%, 47.4% and 36.8% of pediatric AML patients respectively. 76.9% of adult and 89.5% of pediatric patients expressed CD33. 64.1 % of adults and 42.1% of children expressed CD34. CD34 expression was significantly associated with both FLT3 ITD mutation and cMPL expression. CD34, FLT3 and cMPL negative cases have significantly higher overall survival than positive cases. CONCLUSION: CD34 expression is significantly associated with both FLT3 ITD mutation and cMPL expression which could be used as a marker for low survival. Normal FLT3 and negative expression of CD34 and cMPL may predict a longer overall survival. Further studies are needed to investigate the mechanism that may correlate CD34 to both markers. PMID- 27993872 TI - Endocan, TGF-beta, and ADMA as Risk Factors for Endothelial Dysfunction and Possible Vascular Disease in Patients with Subclinical Hypothyroidism. AB - PURPOSE: Although the relationship between atherosclerosis and overt hypothyroidism has been confirmed, it remains controversial in cases of subclinical hypothyroidism. Higher TSH and similar T4 suggest differences in set points or differences due to diagnostic limitations regarding subclinical hypothyroidism. Endothelial dysfunction (ED) is a marker rather than a precursor of cardiovascular disease. Asymmetric dimethylarginine (ADMA) and endocan are known as novel markers of ED in various diseases. Transforming growth factor-beta (TGF-beta) has a protective role against autoimmune diseases such as thyroiditis. This study aimed to determine the relationships between serum ADMA, endocan, TGF beta, and the high-sensitivity C-reactive protein (hs-CRP) levels, a proven indicator of ED, in patients with SH. METHODS: Thirty-five patients with SH and 21 age- and sex-matched euthyroid subjects were included in the study. The levels of TSH, FT4, lipid parameters, endocan, ADMA, TGF-beta, and hs-CRP were measured. RESULTS: No significant differences in age or sex were found between the patient and control groups (p=0.294 and 0.881, respectively). Mean TSH level was higher in the patient group (p=0.005), whereas mean fT4 level was similar in two groups (p=0.455). The average hs-CRP, endocan, TGF-beta l level in the patient group was higher than control group (p=0.001; P=0.012; P=0.025; P<0.01 respectively). A positive correlation was found between the endocan and ADMA levels (r=0.760, p=0.000). ADMA levels also were positively correlated with hs-CRP. Both the TSH and low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with the hs-CRP level. CONCLUSIONS: Subclinical hypothyroidism is associated with increased levels of serum endocan, ADMA, and TGF-beta, which are new markers for ED. In particular, ADMA was correlated with both endocan and hs-CRP levels. These findings are suggestive for increased risk of ED and subsequent development of atherosclerosis in patients with SH. PMID- 27993874 TI - Diagnosis of Pulmonary Tuberculosis and Detection of Resistance to Rifampin and Isoniazid through Direct Molecular Methods in Stool Samples. AB - BACKGROUND: Tuberculosis (TB) is an infectious disease that is caused by Mycobacterium tuberculosis (M.tb). TB has high morbidity and mortality around the world. OBJECTIVE: To evaluate molecular-based methods performed directly on stool samples for the diagnosis of pulmonary tuberculosis (PTB) and to determine the susceptibility to Rifampicin (RMP) and Isoniazid (INH). STUDY DESIGN: This is a descriptive study evaluating the performance of the PCR-based method for direct PTB diagnosis and to determine the susceptibility of RMP and INH using stool samples from PTB patients. The study was conducted between March 2011 and March 2014. METHODS: Three stool samples and three sputum samples (n=300 stool and 300 sputum) were collected from 100 PTB patients (75 pretreatment and 25 follow up). Stool samples (n=60) were also collected from 20 healthy individuals to serve as controls. DNA was extracted from stool samples using Chelex(r)-100. PTB was diagnosed using a Genekam(r) kit. RMP and INH susceptibility testing was performed using the Genotype MTBDRplus(r) assay. The sputum Lowenstein Jensen (LJ) culture and agar proportion method (PM) of drug susceptibility testing for INH and RMP were considered to be the gold standard methods for comparing the results of the molecular methods. RESULTS: The Genekam kit showed 100% sensitivity and 95.24% specificity for diagnosing new patients and showed 100% sensitivity and 80% specificity for follow-up patients. The Genotype MTBDR-plus assay showed 86.4% and 100% sensitivity and 98.1% and 97.8% specificity for determining INH and RMP sensitivity, respectively, in newly diagnosed patients and 85.7% and 94.4% sensitivity and specificity, respectively, for both INH and RMP in follow-up patients. CONCLUSION: Molecular-based methods are promising techniques for the diagnosis and susceptibility testing of PTB when the ease of sample collection and the speed of diagnosis are taken into consideration. However, they are not as useful for assessing follow-up patients. PMID- 27993873 TI - Adenomatous Colon Polyps in Diabetes: Increased Prevalence in Patients with Chronic Kidney Disease and Its Association with Parathyroid Hormone. AB - Previous studies have shown a higher prevalence of malignancy in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). The purpose of this study was to investigate the prevalence of adenomatous colon polyps (ACP) as they occur in subjects with DM and coexisting CKD. This is a retrospective cohort study of patients with DM (n=565) who had undergone colonoscopy between 2000 2010. The cohort was further bifurcated into those with CKD (n=296) and those with normal renal function (n=269). Presence or absence of ACP was measured in both groups. Concentrations of serum parathyroid hormone (PTH), Calcium (Ca), and phosphorous (P) were recorded for the CKD group. The levels of these variables in patients with ACP (n=171) were compared with the levels from those without ACP (n=175). Nonparametric statistical methods were applied with statistical significance suggested by p<0.05 (two-sided). The presence of CKD in this cohort demonstrated a significant association with ACP (OR: 2.96; 95% CI: 2.02 to 4.34; p<0.0001). We did not detect a statistically significant difference in P or Ca between the groups. There was, however, a statistically significant difference in PTH; for the group with ACP, PTH: 387.7+/-351.3 ng/L vs. 172.2+/-196.7 ng/L; p<0.0001. This data suggests that CKD is associated with ACP in subjects with DM and those with ACP exhibit higher PTH levels when compared to those without ACP. PMID- 27993875 TI - Alterations of Intestinal Labile Zinc and Cytokine Production Following Subarachnoid Hemorrhage in Rats. AB - Intestinal mucosal injury can be frequently observed in the patients suffering from subarachnoid hemorrhage (SAH). Labile zinc and inflammatory mediators participate in many pathophysiological processes. This study aimed to investigate the increase of intestinal labile zinc, wet/dry weight ratio, and the expression of inflammatory mediators after SAH. As a result, SAH caused a gradual increase of intestinal labile zinc as demonstrated by fluorescence staining with Zinpyr-4 (ZP4). The levels of TNF-alpha and IL-6 and the intestinal wet/dry weight ratios were higher in the SAH groups compared to the control group following SAH (p<0.05). The results suggest that SAH induces increases of labile zinc and inflammatory mediators in gut, which may participate in the pathogenesis of acute intestinal mucosal injury. PMID- 27993876 TI - Emerging Role of MDM2 as Target for Anti-Cancer Therapy: A Review. AB - The mouse/murine protein, MDM2, and its human homolog, HDM2, are important negative regulators of the p53 tumor suppressor protein. In normal, untransformed cells, MDM2 levels are tightly regulated to control expression of p53 and apoptosis. Conversely, MDM2 expression appears inherently higher in multiple types of cancer cells, thereby supporting its role as a suppressor of p53 pro apoptotic activity. MDM2 amplification ranges between two- and ten-fold as reported in brain, breast, lung, and soft tissue tumors. MDM2 regulates p53 by two mechanisms: acting as a physical blockade of the transcriptional activation domain and E3 ubiquitin ligase. In addition to its relationship with p53, MDM2 behaves as an independent oncogene. These inherent characteristics make MDM2 a promising target for developing anti-cancer therapies. Investigators are now exploring both p53- dependent and independent cancer cell death pathways by targeting MDM2. Disrupting MDM2-p53 interaction with resultant increase in p53 induces cancer cell cycle arrest and apoptosis. Targeting over-expressed MDM2 on cancer cell membranes disrupts membrane integrity by pore formation, causing membrane destabilization and rapid cancer cell-specific necrosis. In this review, evidence supporting the evolving role of MDM2 as an anti-cancer target and a molecular-based tumor biomarker will be discussed. PMID- 27993877 TI - Specific Immunoglobulin (Ig) G Reference Intervals for Common Food, Insect, and Mold Allergens. AB - BACKGROUND: The clinical utility of serum IgG measurement in the diagnosis of allergy and food-induced hypersensitivity has been largely discredited. Recent studies, however, have shown that specific IgG can inhibit IgE mediated allergies, and may play a role in allergen specific desensitization. Accurate reference intervals for IgG specific allergens have not been widely established and are needed for better interpretation of serum antibody concentrations. In this study we established 64 IgG reference intervals for 48 common food allergens, 5 venoms, and 11 molds. DESIGN: Specific IgG concentrations were determined employing an automated fluorescent enzyme immunoassay on serum samples from 130 normal adults (65 males and 65 females), age range 18-69 y, mean 37.3 y. RESULTS: The lower reference interval limit for all allergens tested (n=64) was <2 mcg/mL. The median upper reference interval value for all 64 allergens was 12.9 mcg/mL, with Tuna (f40) having the lowest upper interval limit at 3.8 mcg/mL, and the mold Setomelanomma rostrate (m8) demonstrating the highest upper interval limit at 131 mcg/L. CONCLUSIONS: The considerable variation observed among the upper reference interval limits emphasizes the need for the establishment of allergen specific ranges for IgG. These newly established ranges should be a useful aid for clinicians in the interpretation of laboratory serum IgG results. PMID- 27993878 TI - Relationship between Glutathione Peroxidase, Platelet Reactivity, and Reactive Oxygen Species in an Acute Coronary Syndrome Population. AB - Low activity levels of the antioxidant enzyme, glutathione peroxidase (GPx), have been implicated in adverse clinical outcomes in coronary artery disease. A potential mechanistic link for this relationship is that low GPx activity predisposes patients to thrombotic complications due to impaired reactive oxygen species (ROS) metabolism. GPx potentially regulates the bioavailability of nitric oxide (NO) - a potent platelet inhibitor - therefore indirectly affecting platelet activation. This study examined the relationship between levels of GPx activity, ROS, and platelet activation in 51 acute coronary syndrome (ACS) patients. No relationship was observed between GPx activity and platelet reactivity nor between ROS levels and platelet reactivity. However patients with low GPx activity had significantly higher ROS levels (r2=0.1, p<0.05), suggesting a differential capacity to upregulate antioxidant defence in response to oxidative stress. Low levels of GPx activity may contribute to increased clinical risk by an inability to protect against oxidant-mediated damage. PMID- 27993879 TI - A Rapid and Simple Liquid-Chromatography-Tandem Mass Spectrometry Method for Measuring 25-Hydroxyvitamin D2 and 25-Hydroxyvitamin D3 in Human Serum: Comparison with Two Automated Immunoassays. AB - BACKGROUND: Total 25-hydroxyvitamin D (25(OH)D) is well-known to be a reliable biomarker of human vitamin D status, with the recognition of widespread vitamin D insufficiency in general populations. The aims of this study are to validate a fast and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying 25(OH)D2 and 25(OH)D3 in serum and to compare two automated immunoassays with the LC-MS/MS method. METHODS: Samples were prepared by protein precipitation with ethanol including 25(OH)D3-d6, followed by a liquid-liquid extraction with hexane. The analytes were separated within a total run time of 3 min. Accuracy was evaluated with standard reference materials (SRM) 972a. Using 150 samples, the LC-MS/MS method was compared with the LIAISON(r) assay and ADVIA Centaur(r) assay. RESULTS: The LC-MS/MS method had a limit of quantitation of 1 ng/mL for the 25(OH)D2 and 25(OH)D3 with linear responses between 1 and 100 ng/mL. Intra- and inter-assay precision were <8.8% and <13.2%, respectively. It also showed a smallest mean difference (+0.9%) for the SRM level 1 to 3, compared to the two immunoassays. Compared to the LC-MS/MS, the mean biases of the RIAISON and ADVIA were +2.4 and +7.9 ng/mL, respectively. Also, the agreement of the LC MS/MS with the RIAISON was better than that with the ADVIA. CONCLUSION: This study suggests that the LC-MS/MS method traceable to the SRM can be reliably applied in routine quantification of 25(OH)D2 and 25(OH)D3. PMID- 27993880 TI - Providing Hemostatic and Blood Conservation Options for Jehovah's Witness Patients in a Large Medical System. AB - People of the Jehovah's Witness faith believe that they shall "abstain from blood." Because of this belief, we encounter the challenges from Jehovah's Witness patients who actively seek medical care for themselves and their children, but refuse the transfusion of blood products, which may result in increased morbidity and mortality in this patient population. With the development/availability of new hemostatic/coagulation products and the advances in medical technology, we, in collaboration with our clinical colleagues and our local Jehovah's Witness leadership, have developed a clinical guideline comprising medical protocol and surgical strategy for patients refusing blood products. Included in the medical protocol is an informative handout on related details to help treating physicians and patients make informed decisions about transfusion alternatives. Together, we have entered the medical protocol into the entire Memorial Hermann Hospital's electronic system. We report the detailed development and implementation process in order to share our experience and encourage others to develop their own management plan for this patient population. PMID- 27993881 TI - Flow Cytometric Panel-Reactive Antibody Results and the Ability to Find Transfusion-Compatible Platelets after Antibody-Desensitization for Allogeneic Bone Marrow Transplant. AB - BACKGROUND: Panel reactive antibody (PRA) reduction protocols are used to decrease anti-HLA antibodies with concomitant PRA monitoring as a measure of successful treatment prior to organ and haploidentical blood and marrow transplant (BMT). We hypothesized that the more sensitive flow cytometry (FC) based assays for PRA [FlowPRA(r) and Luminex(r) based Single Antigen Bead (SAB)] would also correlate with the ability to find compatible platelets for allosensitized recipients. METHODS: A female patient with myelodysplastic syndrome and a high HLA class I PRA [>90% PRA and cPRA by complement-dependent cytotoxicity (CDC) assay and Flow PRA] required allogeneic BMT. Baseline HLA Class I and class II antigen typing was performed and a matched sibling donor was identified. Although baseline anti-HLA class I and class II antibodies measured by FC and CDC revealed no donor specific antibodies (DSA), the decision was made to attempt antibody desensitization to facilitate platelet transfusion during BMT. FC and CDC assays were performed to determine anti-HLA class I antibodies and cPRA/%PRA prior to starting desensitization and at the end of desensitization. Over the course of desensitization and BMT, a total of 194 apheresis platelet units underwent cross-match (XM) using Capture-P(r). We compared temporally-related PRA results with platelet XM results. RESULTS: High PRA by FC or CDC assays correlates with a high % of XM-positive (incompatible) platelet units. When the CDC PRA fell to 2% after desensitization, platelet XM incompatibility fell from 100% to 63% positive (incompatible). When the FC PRA fell to 5% the positive platelet XM fell to 5%. CONCLUSIONS: Antibody desensitization facilitated platelet transfusion. PRA determination by FC appeared better correlated than determination by CDC with the ability to find XM compatible platelets. PMID- 27993882 TI - MicroRNA-506 Inhibits Malignancy of Colorectal Carcinoma Cells by Targeting LAMC1. AB - OBJECTIVE: To investigate the effects of microRNA-506 (miR-506) on malignancy of colorectal carcinoma (CRC) cells and to elucidate the underlying mechanism. METHODS: Human colorectal carcinoma cell lines SW480, SW620, HCT116, and HT29 were served as model. Five experimental groups are established in this study, including cell control, pcDNA3 blank vector control, miR-506 over-expression, pSIH1 blank vector control, and miR-506 suppression groups. Quantitative reverse transcription PCR (qRT-PCR) assay was performed to measure miR-506 level. Transwell, Cell counting kit8 (CCK-8), and colony formation assays were performed to detect migration and invasion, viability, and colony formation abilities of CRC cell lines, respectively. Furthermore, bioinformatics method was applied to predict potential target genes of miR-506. Green fluorescent protein (GFP) reporter assays were used to verify the direct regulation of miR-506 on target mRNA in CRC cell lines. The LAMC1 mRNA and protein levels were detected by qRT PCR and Western blot, respectively. RESULTS: In the CRC cell lines, miR-506 level increased in the miR-506 over-expression group (P<0.05), compared with the blank vector control group. In the miR-506 over-expression group, cellular viability was significantly reduced (P<0.05). Migrated and invasive cell numbers and cell colony numbers were decreased (P<0.05). LAMC1 mRNA and protein levels in the miR 506 over-expression groups were lower than those in the control groups (P<0.05). However, there were no difference on the above indexes between pSIH1 blank vector control and miR-506 suppression groups. CONCLUSION: miR-506 acts as a tumor suppressor and inhibits malignancy of colorectal cancer cells through directly targeting LAMC1. PMID- 27993883 TI - Association of Reduced Heme Oxygenase-1 with Decreased MicroRNA-196a2 Expression in Peripheral Blood Mononuclear Cells of Patients with Intestinal Behcet's Disease. AB - AIMS: To examine the expression of miRNAs and mRNAs of heme oxygenase 1 (HO-1) in patients with active intestinal Behcet's disease (BD). METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from BD patients with active ileocecal ulcers or from healthy donors. Expression levels of four miRNAs were studied using real-time PCR. The levels of mRNAs of ho-1, bach1, and CD14 were measured by qRT-PCR. Serum levels of cytokines were analyzed by ELISA. RESULTS: Among four miRNAs, only levels of miR-196a2 were significantly decreased from BD patients with active ileocecal ulcers as compared with healthy controls. Moreover, level of mRNA ho-1 expression in PBMCs from patients with BD was reduced. No significant difference on bach1 and CD14 mRNA levels was observed. Levels of IFN gamma, IL-17, IL-10, IL-1beta, and TNF-alpha were higher in patients with active intestinal BD than those in healthy controls. CONCLUSION: The present results suggest that miR-196a2 expression is decreased in active intestinal BD patients. Down regulated miR-196a2 may be involved in intestinal BD pathogenesis by targeting Bach1/ho-1. Consequently, pro-inflammatory cytokines are closely implicated in the evolution of intestinal BD. PMID- 27993884 TI - Misdiagnosis Analysis of Cervical Minimal Deviation Adenocarcinoma: a Report of Three Rare Cases and Literature Review. AB - Cervical minimal deviation adenocarcinoma (MDA) is a rare variant of cervical adenocarcinoma that is difficult to diagnose due to the deep location, endogenous growth pattern, deceptively benign appearance of tumor cells, and lack of connection to human papillomavirus (HPV). Cytological evaluation and biopsies offer suboptimal detection and transvaginal sonography or Magnetic Resonance Imaging (MRI) only reveal multiple lesions that mimic multiple benign nabothian cysts. Besides, standard screening, diagnostic tools, and treatments are not established. Thus, MDA tends to be misdiagnosed with other gynecological diseases. In this study, we examine three cases with extensive abdominal metastasis and adhesions, which are not initially associated clinically with HPV and cervical malignancies. All cases were misdiagnosed as nabothian cysts, endometrial adenocarcinoma or ovarian cancer, though finally diagnosed as MDA by postoperative pathology. Delay in diagnosis and treatment can result in irreversible outcomes. Misdiagnoses are analyzed and suggestions for improving early detection are discussed with a brief review of the literature. PMID- 27993885 TI - Pulmonary Adenofibroma: Report of a Case with Multiple Masses. AB - We are reporting one case of multiple pulmonary adenofibromas in a 57-year-old non-smoking female. Ten well-circumscribed masses were identified in both lungs. The masses are characterized by gland-like structures lined by a single layer of simple cuboidal or columnar epithelium. The stroma is abundant and demonstrates compact spindle-cells. The epithelial component is generally positive for CK7, TTF-1, Napsin A. The stromal component displays expression of vimentin, desmin, SMA, h-CALD, ER, PR, Bcl-2, and is negative for CD34, CD117, CD99. We are postulating that the possible histogenesis of these lesions is via proliferation of mesenchymal component of the peribronchial wall, which entraps the epithelium as it expands. Hitherto, this is the first case with multiple lesions reported. Currently, the patient is 11 months post-surgery and doing well. PMID- 27993886 TI - Acquired Dysfibrinogenemia Caused by Autoantibody Inhibiting Fibrin Polymerization in a Patient with MELAS Syndrome and Bleeding Tendency. AB - We present a case of acquired dysfibrinogenemia caused by an autoantibody that inhibited fibrin polymerization in a patient previously diagnosed with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes). The patient showed prolonged PT, aPTT, and thrombin time. There was no factor deficiency but fibrinogen antigen and activity were decreased. ELISA for detection of fibrinogen antibodies were performed and IgG purified from the patient's plasma bound to fibrinogen more strongly than did control IgG, indicating the presence of a fibrinogen-specific antibody. Thrombin-mediated fibrin polymerization was severely impaired in the patient, although thrombin induced fibrinopeptide A release was normal. Scanning electron microscopy was used to investigate the structure of fibrin clots and revealed many pores on the surface of patient's fibrin clots. Since MELAS is often associated with autoimmune disorders, a work-up for the presence of anti-fibrinogen antibody is necessary when bleeding tendency occurs in MELAS patients along with prolonged thrombin time. PMID- 27993887 TI - Communication: Homocysteine, Thioretinaco Ozonide, Oxidative Phosphorylation, Biosynthesis of Phosphoadenosine Phosphosulfate and the Pathogenesis of Atherosclerosis. AB - The formation of phosphoadenosine phosphosulfate (PAPS) is accomplished by the action of the enzyme 3'-phosphoadenosine 5'-phosphosulfate synthase (PAPSS) in two sequential reactions, consisting of (1) reaction of inorganic sulfate with adenosine triphosphate (ATP) to form adenosine phosphosulfate (APS) and pyrophosphate and (2) reaction of APS with inorganic phosphate to form PAPS and adenosine diphosphate (ADP). The hydrolysis of guanosine triphosphate (GTP) is coordinated with synthesis of APS in a reaction sequence which provides the chemical energy for synthesis of APS. The present proposal is that the active site of oxidative phosphorylation, thioretinaco ozonide oxygen (TR2CoO3O2), functions as the source of APS synthesis from nicotinamide adenine dinucleotide (NAD+) and hydrosulfate (HSO4-) by reduction of the complex with electrons from electron transport complexes, releasing APS and thioretinaco hydroperoxide (TR2CoO3O2H) upon protonation. Subsequently, APS reacts with GTP, which is produced from the active site of oxidative phosphorylation, TR2CoO3O2ATP, to phosphorylate APS to PAPS. These proposed reactions for PAPS synthesis in atherosclerosis explain the metabolic pathway for formation of PAPS from homocysteine through the intermediate formation of thioretinamide (TR) and explain how hyperhomocysteinemia stimulates production of sulfated glycosaminoglycans (GAG), which are essential components of atherosclerotic plaques. PMID- 27993888 TI - Treatable mitochondrial diseases: cofactor metabolism and beyond. PMID- 27993889 TI - Reply: Contributions of visual and motor signals in cervical dystonia. PMID- 27993890 TI - Contributions of visual and motor signals in cervical dystonia. PMID- 27993891 TI - Reply: Towards a neurocomputational account of social dysfunction in neurodegenerative disease. PMID- 27993892 TI - Towards a neurocomputational account of social dysfunction in neurodegenerative disease. PMID- 27993893 TI - Genome-wide ChIP-seq analysis of EZH2-mediated H3K27me3 target gene profile highlights differences between low- and high-grade astrocytic tumors. AB - Enhancer of zeste homolog-2(EZH2) is a key epigenetic regulator that functions as oncogene and also known for inducing altered trimethylation of histone at lysine 27 (H3K27me3) mark in various tumors. However, H3K27me3 targets and their precise relationship with gene expression are largely unknown in astrocytic tumors. In this study, we checked EZH2 messenger RNA and protein expression in 90 astrocytic tumors of different grades using quantitative PCR and immunohistochemistry, respectively. Further, genome-wide ChIP-seq analysis for H3K27me3 modification was also performed on 11 glioblastomas (GBMs) and 2 diffuse astrocytoma (DA) samples. Our results showed EZH2 to be highly overexpressed in astrocytic tumors with a significant positive correlation with grade. Interestingly, ChIP-seq mapping revealed distinct differences in genes and pathways targeted by these H3K27me3 modifications between GBM versus DA. Neuroactive ligand receptor pathway was found most enriched in GBM (P = 9.4 * 10-25), whereas DA were found to be enriched in metabolic pathways. Also, GBM showed a higher enrichment of H3K27me3 targets reported in embryonic stem cells and glioma stem cells as compared with DAs. Our results show majority of these H3K27me3 target genes were downregulated, not only due to H3K27me3 modification but also due to concomitant DNA methylation. Further, H3K27me3 modification-associated gene silencing was not restricted to promoter but also present in gene body and transcription start site regions. To the best of our knowledge, this is the first high-resolution genome wide mapping of H3K27me3 modification in adult astrocytic primary tissue samples of human, highlighting the differences between grades. Interestingly, we identified SLC25A23 as important target of H3K27me3 modification, which was downregulated in GBM and its low expression was associated with poor prognosis in GBMs. PMID- 27993894 TI - Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma. AB - Increasing evidence has shown that zinc-alpha2-glycoprotein (AZGP1) is associated with the progression and prognosis of several tumor types. However, little is known regarding the underlying molecular mechanisms of AZGP1 in hepatocellular carcinoma (HCC). In this study, we report that transcription factor Ikaros bound to the AZGP1 promoter and increased its expression in HCC cells. The downregulation of AZGP1 was associated with histone deacetylation in HCC. In addition, the positive feedback regulation via acetylation of histone H4-mediated transactivation of the Ikaros promoter and the Ikaros-mediated transactivation of the acetylation of histone H4 were crucial for regulating AZGP1 expression in HCC cells. Moreover, low serum AZGP1 level in HCC patients was associated with poor prognosis. The ectopic overexpression of AZGP1 or recombinant AZGP1 protein inhibited HCC cell proliferation, migration and invasion in vitro and in vivo, whereas silencing AZGP1 expression resulted in increased cell proliferation, migration and invasion in vitro. In addition, we found that AZGP1 inhibited cell migration and invasion through the regulation of the PTEN/Akt and CD44s pathways. Collectively, our findings revealed the molecular mechanism of AZGP1 expression in HCC, providing new insights into the mechanisms underlying tumor progression. PMID- 27993895 TI - Mutation patterns in small cell and non-small cell lung cancer patients suggest a different level of heterogeneity between primary and metastatic tumors. AB - Several studies have shown heterogeneity in lung cancer, with parallel existence of multiple subclones characterized by their own specific mutational landscape. The extent to which minor clones become dominant in distinct metastasis is not clear. The aim of our study was to gain insight in the evolution pattern of lung cancer by investigating genomic heterogeneity between primary tumor and its distant metastases. Whole exome sequencing (WES) was performed on 24 tumor and five normal samples of two small cell lung carcinoma (SCLC) and three non-SCLC (NSCLC) patients. Validation of somatic variants in these 24 and screening of 33 additional samples was done by single primer enrichment technology. For each of the three NSCLC patients, about half of the mutations were shared between all tumor samples, whereas for SCLC patients, this percentage was around 95. Independent validation of the non-ubiquitous mutations confirmed the WES data for the vast majority of the variants. Phylogenetic trees indicated more distance between the tumor samples of the NSCLC patients as compared to the SCLC patients. Analysis of 30 independent DNA samples of 16 biopsies used for WES revealed a low degree of intra-tumor heterogeneity of the selected sets of mutations. In the primary tumors of all five patients, variable percentages (19-67%) of the seemingly metastases-specific mutations were present albeit at low read frequencies. Patients with advanced NSCLC have a high percentage of non ubiquitous mutations indicative of branched evolution. In contrast, the low degree of heterogeneity in SCLC suggests a parallel and linear model of evolution. PMID- 27993897 TI - Impact of coronary heart disease on cognitive decline in Alzheimer's disease: a prospective longitudinal cohort study in primary care. AB - BACKGROUND: Arteriosclerotic disorders increase the risk of dementia. As they have common causes and risk factors, coronary heart disease (CHD) could influence the course of dementia. AIM: To determine whether CHD increases the speed of cognitive decline in Alzheimer's disease, and to discuss the potential for secondary cardiovascular prevention to modify this decline. DESIGN AND SETTING: Prospective multicentre cohort study in general practices in six cities in Germany. METHOD: Participants were patients with probable mild-to-moderate Alzheimer's dementia or mixed dementia (n = 118; mean age 85.6 [+/-3.4] years, range 80-96 years). The authors assessed the presence of CHD according to the family physicians' diagnosis. Cognitive performance was measured during home visits for up to 3 years in intervals of 6 months, using Mini Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR-SoB). The authors also recorded whether patients died in the observation period. RESULTS: At baseline, 65 patients (55%) had CHD and/or a heart condition following a myocardial infarction. The presence of CHD accelerated cognitive decline (MMSE, P<0.05) by about 66%, and reduced cognitive-functional ability (CDR-SoB, P<0.05) by about 83%, but had no impact on survival. CONCLUSION: The study shows that CHD has a significant influence on cognitive decline in older patients with late onset dementia. The dementia process might therefore be positively influenced by cardiovascular prevention, and this possible effect should be further investigated. PMID- 27993898 TI - GPs' opinions of health assessment instruments for people with intellectual disabilities: a qualitative study. AB - BACKGROUND: GPs provide health care to people with intellectual disabilities (ID). People with ID find it difficult to express themselves concerning health related matters. Applying health assessments is an effective method to reveal health needs, and can play a role in prevention and health promotion. AIM: The aim of this qualitative study was to explore GPs' considerations about applying a health assessment for people with ID. DESIGN AND SETTING: This focus group study was conducted among a selection of Dutch GPs. METHOD: An interview guide was developed. All discussions were audiorecorded and transcribed. Analysis was performed using the framework analysis approach. Two researchers independently applied open coding and identified a thematic framework. This framework and the summaries of views per theme were discussed in the research team. RESULTS: After four focus groups, with 23 GPs, saturation was reached. Three main themes evolved: health assessments in relation to GPs' responsibility; the usefulness and necessity of health assessments; and barriers to using health assessments on people with ID. A health assessment instrument for people with ID can help GPs to focus on certain issues that are not so common in the general population. GPs are motivated to use such a tool if it is scientifically tested, and results in significant health gains. However, GPs identify barriers at the level of GP, patient, and organisation. CONCLUSION: Most GPs in the focus groups consider providing medical care to people with ID their responsibility and indicate that a health assessment instrument could be a valuable tool. In order to deliver good care, they need education and support. Many barriers need to be overcome before a health assessment instrument can be implemented. PMID- 27993899 TI - Barriers to self-management of chronic pain in primary care: a qualitative focus group study. AB - BACKGROUND: Supported self-management is a recommended intervention for chronic pain. Effective self-management should enable an individual to reduce the impact of pain on their everyday life. Clinical guidelines suggest primary care services have a role to play in supporting self-management of chronic pain. AIM: To examine the opinions of primary care healthcare professionals (HCPs) and people with chronic pain and their carers, in order to identify possible barriers to the facilitation and adoption of self-management. DESIGN AND SETTING: A qualitative study using focus groups in locations throughout Scotland. METHOD: Eighteen focus groups were held with patients and HCPs. Fifty-four patients, nine carers, and 38 HCPs attended the groups. RESULTS: Four categories of barriers were found. 1) Patient-HCP consultation: some patients felt a discussion about self-management came too late or not at all. Communication and building positive relations were sometimes challenging. 2) Patient experience: the emotional impact of pain was difficult and patients often felt unsupported by HCPs. 3) Limited treatment options: some participants felt there was a tendency for overmedicalisation. 4) Organisational constraints: short appointment times, long waiting lists, and a compartmentalised NHS created challenges. CONCLUSION: This study illustrates some of the barriers faced by HCPs and patients in the facilitation and adoption of self-management of chronic pain. If self-management is to be an important approach to chronic pain, primary care services need to be designed to address the barriers identified. PMID- 27993896 TI - Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. AB - Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production ('lactagenesis'), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate producing ('lactagenic') cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a 'lactormone') with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery. PMID- 27993900 TI - RCGP Research and Surveillance Centre Annual Report 2014-2015: disparities in presentations to primary care. AB - BACKGROUND: The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) comprises over 100 general practices in England, with a population of around 1 million, providing a public health surveillance system for England and data for research. AIM: To demonstrate the scope of data with the RCGP Annual Report 2014-2015 (May 2014 to April 2015) by describing disparities in the presentation of six common conditions included in the report. DESIGN AND SETTING: This is a report of respiratory and communicable disease incidence from a primary care sentinel network in England. METHOD: Incidence rates and demographic profiles are described for common cold, acute otitis media, pneumonia, influenza-like illness, herpes zoster, and scarlet fever. The impact of age, sex, ethnicity, and deprivation on the diagnosis of each condition is explored using a multivariate logistic regression. RESULTS: With the exception of herpes zoster, all conditions followed a seasonal pattern. Apart from pneumonia and scarlet fever, the odds of presenting with any of the selected conditions were greater for females (P<0.001). Older people had a greater probability of a pneumonia diagnosis (>=75 years, odds ratio [OR] 6.37; P<0.001). Common cold and influenza-like illness were more likely in people from ethnic minorities than white people, while the converse was true for acute otitis media and herpes zoster. There were higher odds of acute otitis media and herpes zoster diagnosis among the less deprived (least deprived quintile, OR 1.32 and 1.48, respectively; P<0.001). CONCLUSION: The RCGP RSC database provides insight into the content and range of GP workload and provides insight into current public health concerns. Further research is needed to explore these disparities in presentation to primary care. PMID- 27993901 TI - NHS Health Check comorbidity and management: an observational matched study in primary care. AB - BACKGROUND: The NHS Health Check programme completed its first 5 years in 2014, identifying those at highest risk of cardiovascular disease and new comorbidities, and offering behavioural change support and treatment. AIM: To describe the coverage and impact of this programme on cardiovascular risk management and identification of new comorbidities. DESIGN AND SETTING: Observational 5-year study from April 2009 to March 2014, in 139 of 143 general practices in three clinical commissioning groups (CCGs) in east London. METHOD: A matched analysis compared comorbidity in NHS Health Check attendees and non attendees. RESULTS: A total of 252 259 adults aged 40-74 years were eligible for an NHS Health Check and, of these, 85 122 attended in 5 years. Attendance increased from 7.3% (10 900/149 867) in 2009 to 17.0% (18 459/108 525) in 2013 to 2014, representing increasing coverage from 36.4% to 85.0%. Attendance was higher in the more deprived quintiles and among South Asians. Statins were prescribed to 11.5% of attendees and 8.2% of non-attendees. In a matched analysis, newly diagnosed comorbidity was more likely in attendees than non-attendees, with odds ratios for new diabetes 1.30 (95% confidence interval [CI] = 1.21 to 1.39), hypertension 1.50 (95% CI = 1.43 to 1.57), and chronic kidney disease 1.83 (95% CI = 1.52 to 2.21). CONCLUSION: The NHS Health Check programme provision in these CCGs was equitable, with recent coverage of 85%. Statins were 40% more likely to be prescribed to attendees than non-attendees, providing estimated absolute benefits of public health importance. More new cases of diabetes, hypertension, and chronic kidney disease were identified among attendees than a matched group of non-attendees. PMID- 27993902 TI - Views on mandatory reporting of impaired health practitioners by their treating practitioners: a qualitative study from Australia. AB - OBJECTIVE: To explore the views and experiences of health sector professionals in Australia regarding a new national law requiring treating practitioners to report impaired health practitioners whose impairments came to their attention in the course of providing treatment. METHOD: We conducted a thematic analysis of in depth, semistructured interviews with 18 health practitioners and 4 medicolegal advisors from Australia's 6 states, each of whom had experience with applying the new mandatory reporting law in practice. RESULTS: Interviewees perceived the introduction of a mandatory reporting law as a response to failures of the profession to adequately protect the public from impaired practitioners. Mandatory reporting of impaired practitioners was reported to have several benefits: it provides treating practitioners with a 'lever' to influence behaviour, offers protections to those who make reports and underscores the duty to protect the public from harm. However, many viewed it as a blunt instrument that did not sufficiently take account of the realities of clinical practice. In deciding whether or not to make a report, interviewees reported exercising clinical discretion, and being influenced by three competing considerations: protection of the public, confidentiality of patient information and loyalty to their profession. CONCLUSIONS: Competing ethical considerations limit the willingness of Australian health practitioners to report impaired practitioner patients under a mandatory reporting law. Improved understanding and implementation of the law may bolster the public protection offered by mandatory reports, reduce the need to breach practitioner-patient confidentiality and help align the law with the loyalty that practitioners feel to support, rather than punish, their impaired colleagues. PMID- 27993903 TI - Study protocol for a prospective, non-controlled, multicentre clinical study to evaluate the diagnostic accuracy of a stepwise two-photon excited melanin fluorescence in pigmented lesions suspicious for melanoma (FLIMMA study). AB - INTRODUCTION: Non-invasive, nanosecond, stepwise two-photon laser excitation of skin tissue was shown to induce melanin fluorescence spectra that allow for the differentiation of melanocytic nevi from cutaneous melanoma. METHODS AND ANALYSIS: This prospective, non-controlled, multicentre clinical study is performed to evaluate the diagnostic performance of the stepwise two-photon excited melanin fluorescence in the detection of cutaneous melanoma. The comparator will be the histopathological diagnosis. A total of 620 pigmented skin lesions suspicious for melanoma and intended for excision will be enrolled. ETHICS AND DISSEMINATION: Ethics approval was provided by the local ethics committees of the medical faculties of the University of Tuebingen, Heidelberg and Berlin. STUDY REGISTRATION: The FLIMMA study NCT02425475. PMID- 27993904 TI - Effect of peripheral arterial disease on the onset of lactate threshold during cardiopulmonary exercise test: study protocol. AB - INTRODUCTION: Cardiopulmonary exercise test (CPET) is widely used in preoperative assessment and cardiopulmonary rehabilitation. The effect of peripheral arterial disease (PAD) on oxygen delivery (VO2) measured by CPET is not known. The aim of this study was to investigate the effect of PAD on VO2 measurements during CPET. METHODS AND ANALYSIS: We designed a prospective cohort study, which will recruit 30 patients with PAD, who will undergo CPET before and after treatment of iliofemoral occlusive arterial disease. The main outcome measure is the difference in VO2 at the lactate threshold (LT) between the 2 CPETs. The secondary outcome measure is the relationship between change in VO2 at the LT and peak exercise pretreatment and post-treatment and haemodynamic measures of PAD improvement (ankle-brachial index differential). For VO2 changes, only simple paired bivariate comparisons, not multivariate analyses, are planned, due to the small sample size. The correlation between ABI and VO2 rise will be tested by linear regression. ETHICS AND DISSEMINATION: The study was approved by the North West-Lancaster Research and Ethics committee (reference 15/NW/0801). Results will be disseminated through scientific journal and scientific conference presentation. Completion of recruitment is expected by the end of 2016, and submission for publication by March 2017. TRIAL REGISTRATION NUMBER: NCT02657278. PMID- 27993905 TI - Enhancing risk stratification for use in integrated care: a cluster analysis of high-risk patients in a retrospective cohort study. AB - OBJECTIVE: To show how segmentation can enhance risk stratification tools for integrated care, by providing insight into different care usage patterns within the high-risk population. DESIGN: A retrospective cohort study. A risk score was calculated for each person using a logistic regression, which was then used to select the top 5% high-risk individuals. This population was segmented based on the usage of different care settings using a k-means cluster analysis. Data from 2008 to 2011 were used to create the risk score and segments, while 2012 data were used to understand the predictive abilities of the models. SETTING AND PARTICIPANTS: Data were collected from administrative data sets covering primary and secondary care for a random sample of 300 000 English patients. MAIN MEASURES: The high-risk population was segmented based on their usage of 4 different care settings: emergency acute care, elective acute care, outpatient care and GP care. RESULTS: While the risk strata predicted care usage at a high level, within the high-risk population, usage varied significantly. 4 different groups of high-risk patients could be identified. These 4 segments had distinct usage patterns across care settings, reflecting different levels and types of care needs. The 2008-2011 usage patterns of the 4 segments were consistent with the 2012 patterns. DISCUSSION: Cluster analyses revealed that the high-risk population is not homogeneous, as there exist 4 groups of patients with different needs across the care continuum. Since the patterns were predictive of future care use, they can be used to develop integrated care programmes tailored to these different groups. CONCLUSIONS: Usage-based segmentation augments risk stratification by identifying patient groups with different care needs, around which integrated care programmes can be designed. PMID- 27993906 TI - Effect of investigation intensity and treatment differences on prostate cancer survivor's physical symptoms, psychological well-being and health-related quality of life: a two country cross-sectional study. AB - AIM: To investigate effects on men's health and well-being of higher prostate cancer (PCa) investigation and treatment levels in similar populations. PARTICIPANTS: PCa survivors in Ireland where the Republic of Ireland (RoI) has a 50% higher PCa incidence than Northern Ireland (NI). METHOD: A cross-sectional postal questionnaire was sent to PCa survivors 2-18 years post-treatment, seeking information about current physical effects of treatment, health-related quality of life (HRQoL; EORTC QLQ-C30; EQ-5D-5L) and psychological well-being (21 question version of the Depression, Anxiety and Stress Scale, DASS-21). Outcomes in RoI and NI survivors were compared, stratifying into 'late disease' (stage III/IV and any Gleason grade (GG) at diagnosis) and 'early disease' (stage I/II and GG 2-7). Responses were weighted by age, jurisdiction and time since diagnosis. Between-country differences were investigated using multivariate logistic and linear regression. RESULTS: 3348 men responded (RoI n=2567; NI n=781; reflecting population sizes, response rate 54%). RoI responders were younger; less often had comorbidities (45% vs 38%); were more likely to present asymptomatically (66%; 41%) or with early disease (56%; 35%); and less often currently used androgen deprivation therapy (ADT; 2%; 28%). Current prevalence of incontinence (16%) and impotence (56% early disease, 67% late disease) did not differ between RoI and NI. In early disease, only current bowel problems (RoI 12%; NI 21%) differed significantly in multivariate analysis. In late disease, NI men reported significantly higher levels of gynaecomastia (23% vs 9%) and hot flashes(41% vs 19%), but when ADT users were analysed separately, differences disappeared. For HRQoL, in multivariate analysis, only pain (early disease: RoI 11.1, NI 19.4) and financial difficulties (late disease: RoI 10.4, NI 7.9) differed significantly between countries. There were no significant between country differences in DASS-21 or index ED-5D-5L score. CONCLUSIONS: Treatment side effects were commonly reported and increased PCa detection in RoI has left more men with these side effects. We recommended that men be offered a PSA test only after informed discussion. PMID- 27993907 TI - Prevalence and correlates of sexual and gender-based violence against Chinese adolescent women who are involved in commercial sex: a cross-sectional study. AB - OBJECTIVES: Despite the vast quantity of research among Chinese female sex workers (FSWs) to address concerns regarding HIV/sexually transmitted infection (STI) risk, there is a paucity of research on issues of sexual and gender-based violence (SGBV) and the missed opportunity for sexual and reproductive health (SRH) promotion among young FSWs. Our research aimed to assess the prevalence and correlates of SGBV among Chinese adolescent FSWs, and to explore SRH service utilisation. DESIGN AND METHODS: A cross-sectional study using a one-stage cluster sampling method was employed. A semistructured questionnaire was administered by trained peer educators or health workers. Multivariable logistic regression was conducted to determine individual and structural correlates of SGBV. SETTING AND PARTICIPANTS: Between July and September 2012, 310 adolescent women aged 15-20 years, and who self-reported having received money or gifts in exchange for sex in the past 6 months were recruited and completed their interview in Kunming, Yunnan Province, China. RESULTS: Findings confirm the high prevalence of SGBV against adolescent FSWs in China, with 38% (118/310) of participants affected in the past year. Moreover, our study demonstrated the low uptake of public health services and high rates of prior unwanted pregnancy (52%; 61/118), abortion (53%; 63/118) and self-reported STI symptoms (84%; 99/118) in participants who were exposed to SGBV. Forced sexual debut was reported by nearly a quarter of FSWs (23%; 70/310) and was independently associated with having had a drug-using intimate partner and younger age (<17 years old) at first abortion. When controlling for potential confounders, having experienced SGBV was associated with frequent alcohol use, having self-reported symptoms of STI, having an intimate partner and having an intimate partner with illicit drug use. CONCLUSIONS: This study calls for effective and integrated interventions addressing adolescent FSWs' vulnerability to SGBV and broader SRH consequences. PMID- 27993908 TI - Implantable Cardioverter-Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis. PMID- 27993909 TI - Participatory research: What is the history? Has the purpose changed? PMID- 27993911 TI - The management of the third stage of labour in women with heart disease. AB - OBJECTIVE: In women with heart disease (HD), the third stage of labour is managed with a reduced dose of oxytocin because it can have significant adverse cardiovascular effects. However, women with HD have high rates of postpartum haemorrhage (PPH); consequently, we designed a prospective study to investigate whether higher doses of oxytocin can be given safely and would reduce rates of PPH. METHODS: We performed a single centre, prospective, cohort study comparing the standard 'low-dose' oxytocin infusion (10 U of oxytocin in 500 mL of normal saline given intravenously at 36 mL/hour for 4 hours (12 mU/min), n=29) to the low-dose infusion and an additional 2 U of oxytocin given over 10 min immediately after birth (n=30). Maternal blood pressure was measured every minute for 10 min, continuous ECG (Holter) monitoring was performed and any symptoms (chest pain, dyspnoea) were recorded. Total blood loss and serum troponins were measured at 12 hours. RESULTS: There were no cardiac symptoms, arrhythmias, change in the ST segment or increase in serum troponins. The fall in blood pressure and increase in heart rate were greater with the additional oxytocin, but neither were statistically or clinically significant. The blood loss was significantly less in women receiving additional oxytocin (505 vs 849 mL) and the proportion of women having a PPH was lower. CONCLUSIONS: The use of an additional 2 U of oxytocin for the management of third stage in women with HD had no cardiac consequences and was associated with a significantly lower blood loss. Further larger studies on a larger population of women with HD are needed. PMID- 27993910 TI - A 38-year-old man with progressive dyspnoea and ventricular tachycardia. AB - CLINICAL INTRODUCTION: A previously healthy 38-year-old man presented with a 3 month history of progressive dyspnoea and ventricular tachycardia (VT). He suffered a viral illness 4 months earlier. There was no family history of cardiac disease or sudden cardiac death (SCD). ECG showed left bundle branch block (LBBB). Echocardiography revealed a dilated left ventricle with severely impaired systolic function. Coronary angiogram showed angiographically normal coronary arteries. He was diagnosed as having dilated cardiomyopathy and was referred for further assessment with cardiovascular magnetic resonance (CMR) (figure 1) and subsequently CT thorax. QUESTION: What is the most likely diagnosis? Dilated cardiomyopathy secondary to HIVGranulomatosis with polyangiitis (GPA)SarcoidosisTuberculosisUnderlying malignancy with lung and cardiac metastases. PMID- 27993912 TI - Transoesophageal echocardiography: what the general cardiologist needs to know. PMID- 27993913 TI - Direct stamp of technology or origin on the genotypic and phenotypic variation of indigenous Saccharomyces cerevisiae population in a natural model of boiled grape juice fermentation into traditional Msalais wine in China. AB - Saccharomyces cerevisiae strains worldwide show genetic and phenotypic diversity and their population substructures are greatly affected by their technological application or geographical origins. Msalais is a traditional wine obtained via a unique method of spontaneous fermentation of local boiled grape juice in Southern Xinjiang. We analyzed 436 indigenous S. cerevisiae strains associated with Msalais fermentation. These strains were highly diverse with respect to the interdelta region and 24 phenotypic traits, with apparent differentiation according to strain origins and technologies used to produce Msalais. The genetic and phenotypic diversity of strains from traditional workshops was higher than in strains from modern plants. These local strains had different origin- or technology-specific fermentative characteristics. Strains growing in large-scale fermentation tanks tolerated high temperature, whereas strains from traditional workshops tolerated high alcohol content (16%) and low temperature (13 degrees C). Almost all the strains were characterized by the highest fermenting vigor, with weak H2S production and no histamine, cadaverine, phenethylamine and tryptamine production. Majority of strains had pronounced autolytic activity with high beta-glucosidase and polygalacturonase activity and alcohol production. Our study reveals a direct stamp of technology or origin on genotypic and phenotypic variation of an indigenous S. cerevisiae population. PMID- 27993915 TI - Quebec program combats RSV in northern babies. PMID- 27993916 TI - A six-year-old boy with autism and left hip pain. PMID- 27993914 TI - Advances and challenges in logical modeling of cell cycle regulation: perspective for multi-scale, integrative yeast cell models. AB - The eukaryotic cell cycle is robustly designed, with interacting molecules organized within a definite topology that ensures temporal precision of its phase transitions. Its underlying dynamics are regulated by molecular switches, for which remarkable insights have been provided by genetic and molecular biology efforts. In a number of cases, this information has been made predictive, through computational models. These models have allowed for the identification of novel molecular mechanisms, later validated experimentally. Logical modeling represents one of the youngest approaches to address cell cycle regulation. We summarize the advances that this type of modeling has achieved to reproduce and predict cell cycle dynamics. Furthermore, we present the challenge that this type of modeling is now ready to tackle: its integration with intracellular networks, and its formalisms, to understand crosstalks underlying systems level properties, ultimate aim of multi-scale models. Specifically, we discuss and illustrate how such an integration may be realized, by integrating a minimal logical model of the cell cycle with a metabolic network. PMID- 27993917 TI - Visceral artery aneurysms: an atypical presentation of large-vessel vasculitis. PMID- 27993919 TI - Treating iron deficiency. PMID- 27993918 TI - Conflicts of interest and expertise of independent commenters in news stories about medical research. AB - BACKGROUND: Media coverage of medical research influences the views and behaviours of clinicians, scientists and members of the public. We examined how frequently commenters in news stories about medical research have relevant expertise and have academic and financial conflicts, how often such conflicts are reported and whether there are associations between the conflicts and the disposition of the comments toward the findings of the source research. METHODS: We analyzed 104 independent comments in news stories on original clinical research published in high-impact medical journals from Jan. 1 to Mar. 31, 2013, and 21 related journal editorials. Main outcomes were prevalence of relevant academic and clinical expertise, prevalence and reporting of academic and financial conflicts of interest, and disposition of comments toward study findings. RESULTS: Only 1 in 6 news stories included independent comments. Overall, 25% of commenters and 0% of editorialists had neither relevant academic nor clinical expertise (p = 0.007). Among the 104 comments, an academic conflict of interest was present for 56 (54%), of which 25 (45%) were reported in the news stories. A financial conflict of interest was present for 33 (32%) of the comments, of which 11 (33%) were reported. When commenters' conflicts of interest were congruent with the findings of the source research, 97% and 93% of comments associated with academic and financial conflicts of interest, respectively, were favourably disposed toward the research. These values were 16% and 17%, respectively, when the conflicts of interest were not congruent with the research findings. INTERPRETATION: Independent commenters in new stories about medical research may lack relevant academic or clinical expertise. Academic or financial conflicts of interest were frequently present among independent commenters but infrequently reported, and were often associated with the disposition of comments about the source research. PMID- 27993920 TI - Lives uncovered: reflections on encounters with newly arrived Syrians. PMID- 27993921 TI - New warning on hepatitis C drugs. PMID- 27993922 TI - Federal suicide prevention framework underwhelms. PMID- 27993923 TI - Improving coverage of medical research in a changing media environment. PMID- 27993924 TI - Limited Effectiveness of a Skills and Drills Intervention to Improve Emergency Obstetric and Newborn Care in Karnataka, India: A Proof-of-Concept Study. AB - OBJECTIVE: The majority of the maternal and perinatal deaths are preventable through improved emergency obstetric and newborn care at facilities. However, the quality of such care in India has significant gaps in terms of provider skills and in their preparedness to handle emergencies. We tested the feasibility, acceptability, and effectiveness of a "skills and drills" intervention, implemented between July 2013 and September 2014, to improve emergency obstetric and newborn care in the state of Karnataka, India. METHODS: Emergency drills through role play, conducted every 2 months, combined with supportive supervision and a 2-day skills refresher session were delivered across 4 sub-district, secondary-level government facilities by an external team of obstetric and pediatric specialists and nurses. We evaluated the intervention through a quasi experimental design with 4 intervention and 4 comparison facilities, using delivery case sheet reviews, pre- and post-knowledge tests among providers, objective structured clinical examinations (OSCEs), and qualitative in-depth interviews. Primary outcomes consisted of improved diagnosis and management of selected maternal and newborn complications (postpartum hemorrhage, pregnancy induced hypertension, and birth asphyxia). Secondary outcomes included knowledge and skill levels of providers and acceptability and feasibility of the intervention. RESULTS: Knowledge scores among providers improved significantly in the intervention facilities; in obstetrics, average scores between the pre- and post-test increased from 49% to 57% (P=.006) and in newborn care, scores increased from 48% to 56% (P=.03). Knowledge scores in the comparison facilities were similar but did not improve significantly over time. Skill levels were significantly higher among providers in intervention facilities than comparison facilities (mean objective structured clinical examination scores for obstetric skills: 55% vs. 46%, respectively; for newborn skills: 58% vs. 48%, respectively; P<.001 for both obstetric and newborn), along with their confidence in managing complications. However, this did not result in significant differences in correct diagnosis and management of complications between intervention and comparison facilities. Shortage of trained nurses and doctors along with unavailability of a consistent supply chain was cited by most providers as major health systems barriers affecting provision of care. CONCLUSIONS: Improvements in knowledge, skills, and confidence levels of providers as a result of the skills and drills intervention was not sufficient to translate into improved diagnosis and management of maternal and newborn complications. System-level changes including adequate in-service training may also be necessary to improve maternal and newborn outcomes. PMID- 27993925 TI - Limits of "Skills And Drills" Interventions to Improving Obstetric and Newborn Emergency Response: What More Do We Need to Learn? PMID- 27993926 TI - Oxidized LDL Is Associated With Metabolic Syndrome Traits Independently of Central Obesity and Insulin Resistance. AB - This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baseline data from 3,987 subjects without diabetes in the Progression of Early Subclinical Atherosclerosis (PESA) Study. For the second, third, and fourth ox-LDL quartiles versus the first, the odds ratios (95% CI) for MS were 0.84 (0.52, 1.36), 1.47 (0.95, 2.32), and 2.57 (1.66, 4.04) (P < 0.001 for trend) once adjusted for age, sex, smoking, LDL-cholesterol, BMI, waist circumference, and HOMA-insulin resistance (HOMA-IR). Results showing the same trend were found for all MS components except glucose concentration. Ox-LDL mediated 13.9% of the association of waist circumference with triglycerides and only 1-3% of the association with HDL-cholesterol, blood pressure, and insulin concentration. HOMA-IR did not mediate the association between ox-LDL and MS components. This study found higher ox-LDL concentrations were associated with MS and its components independently of central obesity and insulin resistance. Ox-LDL may reflect core mechanisms through which MS components develop and progress in parallel with insulin resistance and could be a clinically relevant predictor of MS development. PMID- 27993927 TI - Deletion of ATF4 in AgRP Neurons Promotes Fat Loss Mainly via Increasing Energy Expenditure. AB - Although many functions of activating transcription factor 4 (ATF4) are identified, a role of ATF4 in the hypothalamus in regulating energy homeostasis is unknown. Here, we generated adult-onset agouti-related peptide neuron-specific ATF4 knockout (AgRP-ATF4 KO) mice and found that these mice were lean, with improved insulin and leptin sensitivity and decreased hepatic lipid accumulation. Furthermore, AgRP-ATF4 KO mice showed reduced food intake and increased energy expenditure, mainly because of enhanced thermogenesis in brown adipose tissue. Moreover, AgRP-ATF4 KO mice were resistant to high-fat diet-induced obesity, insulin resistance, and liver steatosis and maintained at a higher body temperature under cold stress. Interestingly, the expression of FOXO1 was directly regulated by ATF4 via binding to the cAMP-responsive element site on its promoter in hypothalamic GT1-7 cells. Finally, Foxo1 expression was reduced in the arcuate nucleus (ARC) of the hypothalamus of AgRP-ATF4 KO mice, and adenovirus-mediated overexpression of FOXO1 in ARC increased the fat mass in AgRP ATF4 KO mice. Collectively, our data demonstrate a novel function of ATF4 in AgRP neurons of the hypothalamus in energy balance and lipid metabolism and suggest hypothalamic ATF4 as a potential drug target for treating obesity and its related metabolic disorders. PMID- 27993928 TI - Development and antilisterial activity of PE-based biological preservative films incorporating plantaricin BM-1. AB - In recent years, bacteriocin, as a natural antimicrobial compound, provides enormous promise to be used in food safety preservation. In this work, the polyethylene(PE)-based biological preservative films incorporating plantaricin BM 1, a typical IIa bacteriocin produced by Lactobacillus plantarum BM-1, were developed and characterized. The results showed that PE, low-density PE (LDPE) and high-density PE (HDPE) films soaked in plantaricin BM-1 solution had obvious antimicrobial activities against Listeria monocytogenes. And the volume of plantaricin BM-1 solution absorbed by PE, LDPE and HDPE films continued to increase and reached the maximum during exposure for up to 10, 6 and 16 h, respectively. And the maximum absorption volumes of plantaricin BM-1 solution had no significant difference (P > 0.05) between the PE, LDPE and HDPE films. When soaking in water, the release amount of plantaricin BM-1 from active PE, LDPE and HDPE films reached the maximum potency at 16, 12 and 20 h, respectively. And the maximum release amount of plantaricin BM-1 from PE and LDPE active films was dramatically more than the HDPE active film (P < 0.05). Moreover, the inhibitory effect of active films incorporating plantaricin BM-1 maintained stability for at least 120 days against L. monocytogenes stored at 25 degrees C, which suggest a potential application of the biological preservative films on the control of foodborne pathogen L. monocytogenes. PMID- 27993929 TI - Variants of astA gene among extra-intestinal Escherichia coli of human and avian origin. AB - Many Escherichia coli strains harbour astA, which is the gene encoding the enteroaggregative E. coli heat-stable enterotoxin (EAST1). This gene is embedded in a putative transposase (ORF1) and presents polymorphism in diarrheagenic strains. Although astA and orf1 are detected in extraintestinal strains, little is known about polymorphism and differential gene transcription in this pathotype. In the present work, extraintestinal E. coli from humans (ExPEC - Extraintestinal Pathogenic E. coli) and poultry (APEC - Avian Pathogenic E. coli) were assayed to verify the presence of astA/orf1 and possible polymorphisms in these genes. Three astA/orf1 patterns were detected via Sanger sequencing. Pattern 1 was novel and represented an astA pseudogene. Pattern 2 and pattern 3 presented distinct amino acids within the reading frame encoding astA and were identical to the sequences found in EAEC 17-2 and EAEC 042, respectively. Regarding the frame encoding ORF1, all mutations detected in the three patterns were neutral. The transcripts of astA/orf1 in vitro were underregulated in strains possessing the pattern 1 sequence. The results demonstrate that the same astA sequences may be detected in diarrheagenic and extra-intestinal E. coli. However, extraintestinal isolates may also present an astA pseudogene that has not been reported in diarrheagenic E. coli. PMID- 27993930 TI - Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites. AB - Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (~66% of the administered dose). ~33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4 (((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5 dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the alpha-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl 1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4 (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5 yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities. PMID- 27993931 TI - Evidence of ocular side effects of SSRIs and new warnings. PMID- 27993932 TI - Involvement of patients in planning their future treatment may reduce compulsory admissions to hospital. PMID- 27993933 TI - Pharmacological and non-pharmacological treatment of adults with ADHD: a meta review. AB - Attention-deficit/hyperactivity disorder (ADHD) is characterised by a persistent and impairing pattern of inattention and/or hyperactivity/impulsivity and it is one of the most common neuropsychiatric conditions. Evidence about interventions of adults with ADHD is growing rapidly and clinicians need a reliable summary of all the best available information in order to better inform their daily practice. We searched MEDLINE, PubMed, PsycINFO and Cochrane databases until 31 May 2016 for systematic reviews about pharmacological and non-pharmacological treatments in adults with ADHD and carried out a meta-review to address clinically relevant questions. We identified a total of 40 papers. Psychostimulants-such as methylphenidate, dexamphetamine, mixed amphetamine salts and lisdexamfetamine-and non-psychostimulants-such as atomoxetine-were the most studied agents. Overall, pharmacological treatments were significantly more efficacious than placebo (standardised mean difference (SMD) 0.45, 95% CI 0.37 to 0.52), albeit less well accepted (OR 1.18, 95% CI 1.02 to 1.36) and tolerated (OR 2.29, 95% CI 1.97 to 2.66). The effects of pharmacological treatment for individuals with co-occurring ADHD and substance use disorder are still uncertain. The evidence for the efficacy and effectiveness of non-pharmacological treatments of ADHD in adults, as well as the combination of pharmacological and non-pharmacological strategies, is only preliminary. In conclusion, while available evidence addressed mainly the efficacy and tolerability of psychostimulants and non-psychostimulants for ADHD core symptoms in the short term, we still need further empirical support for the non-pharmacological and multimodal treatments. A comprehensive evidence-informed hierarchy of ADHD drugs based on their efficacy and tolerability is not yet available but it should be the next research priority in the field. PMID- 27993934 TI - Cell cycle-regulated ubiquitination of tankyrase 1 by RNF8 and ABRO1/BRCC36 controls the timing of sister telomere resolution. AB - Timely resolution of sister chromatid cohesion in G2/M is essential for genome integrity. Resolution at telomeres requires the poly(ADP-ribose) polymerase tankyrase 1, but the mechanism that times its action is unknown. Here, we show that tankyrase 1 activity at telomeres is controlled by a ubiquitination/deubiquitination cycle depending on opposing ubiquitin ligase and deubiquitinase activities. In late S/G2 phase, the DNA damage-responsive E3 ligase RNF8 conjugates K63-linked ubiquitin chains to tankyrase 1, while in G1 phase such ubiquitin chains are removed by BRISC, an ABRO1/BRCC36-containing deubiquitinase complex. We show that K63-linked ubiquitin chains accumulate on tankyrase 1 in late S/G2 to promote its stabilization, association with telomeres, and resolution of cohesion. Timing of this posttranslational modification coincides with the ATM-mediated DNA damage response that occurs on functional telomeres following replication in G2. Removal of ubiquitin chains is controlled by ABRO1/BRCC36 and occurs as cells exit mitosis and enter G1, ensuring that telomere cohesion is not resolved prematurely in S phase. Our studies suggest that a cell cycle-regulated posttranslational mechanism couples resolution of telomere cohesion with completion of telomere replication to ensure genome integrity. PMID- 27993936 TI - Mid-arm circumference can be used to estimate weight of adult and adolescent patients. AB - OBJECTIVES: Many drug and fluid regimens in emergency medicine are weight dependent in adults, but no standard adult weight estimation tools exist. Paediatric weight is often estimated in emergency situations using methods based on age or height when direct measurement is not possible, and recently, methods based on mid-arm circumference (MAC) have also been developed. The aim of this study was to derive and validate an accurate MAC-based method for weight estimation for use in all age groups. METHODS: Data were obtained from the US National Health and Nutrition Examination Survey (NHANES). MAC-based methods of weight estimation were derived in 8498 subjects (5595 adults aged 16-80 years, 2903 children aged 1-15.9 years) from the NHANES 2011-2012 dataset, using linear regression. NHANES 2009-2010 was used for validation in 9022 subjects (6049 adults aged 16-79 years, 2973 children aged 1-15.9 years). RESULTS: A simplified method of MAC-based weight estimation was derived from linear regression equation: weight in kg=4*MAC (in cm)-50. On validation, results in children aged 1-10.9 years were poor. In adults and children aged 11-15.9 years, over 60%, 90% and 98% of estimates fell, respectively, within 10%, 20% and 30% of actual weights when using the simplified formula. CONCLUSIONS: In this description of a method for estimating weight in adults, we have derived and validated a simplified formula that is at least as precise in adults and adolescents as commonly used paediatric weight estimation tools in children. PMID- 27993935 TI - miRNA profiling of human naive CD4 T cells links miR-34c-5p to cell activation and HIV replication. AB - Cell activation is a vital step for T-cell memory/effector differentiation as well as for productive HIV infection. To identify novel regulators of this process, we used next-generation sequencing to profile changes in microRNA expression occurring in purified human naive CD4 T cells in response to TCR stimulation and/or HIV infection. Our results demonstrate, for the first time, the transcriptional up-regulation of miR-34c-5p in response to TCR stimulation in naive CD4 T cells. The induction of this miR was further consistently found to be reduced by both HIV-1 and HIV-2 infections. Overexpression of miR-34c-5p led to changes in the expression of several genes involved in TCR signaling and cell activation, confirming its role as a novel regulator of naive CD4 T-cell activation. We additionally show that miR-34c-5p promotes HIV-1 replication, suggesting that its down-regulation during HIV infection may be part of an anti viral host response. PMID- 27993937 TI - Validity of the Manchester Triage System in patients with sepsis presenting at the ED: a first assessment. AB - BACKGROUND: The Manchester Triage System (MTS) does not have a specific presentational flow chart for sepsis. The goal of this investigation was to determine adequacy of acuity assignment for patients with sepsis presenting at the ED and triaged using the MTS. MATERIALS AND METHODS: This retrospective analysis included patients >16 presenting to an ED in Bonn, Germany, on the first 12 days of each month between June 2012 and March 2014. Patients were classified into one of three septic groups, or no sepsis. For those with sepsis, adequacy of acuity assignment was based on the criteria of the first consensus conference of the American College of Chest Physicians and Society of Critical Care Medicine, first published in 1992. Adequacy of prioritisation is expressed as sensitivity and likelihood ratio (LR-). RESULTS: Among 20 836 patients evaluated, 801 (3.8%) were septic; of these, 581 (72.5%) had sepsis, 194 (24.2%) had severe sepsis and 26 (3.2%) had severe sepsis with circulation dysfunction. Patients who met the criteria for sepsis were correctly prioritised with a sensitivity of 70.4% (95% CI 66.5 to 74.0). The LR- was 0.628 (95% CI 0.564 to 0.698). Patients with severe sepsis were appropriately prioritised with a sensitivity of 84.5% (95% CI 78.1 to 89.4), and LR- was 0.330 (95% CI 0.243 to 0.450). In the group with severe sepsis and circulation dysfunction, sensitivity of MTS was 61.5% (95% CI 39.3 to 79.8), and LR- was 0.466 (95% CI 0.286 to 0.757). CONCLUSIONS: The MTS has some weaknesses regarding priority levels in emergency patients with septic illness. Overall, target key symptoms (discriminators) which aim at identifying systemic infection and ascertaining vital parameters are insufficiently considered. PMID- 27993938 TI - Direct-to-Consumer Testing. PMID- 27993940 TI - Bin1 and CD2AP polarize Abeta generation in neurons. PMID- 27993941 TI - Scoping systematic review on the extent, nature and quality of evidence underlying ophthalmic and paraophthalmic education. AB - BACKGROUND: Effective education of relevant professionals underpins provision of quality eye healthcare. OBJECTIVES: This scoping systematic review had 2 aims: first to investigate the extent and nature of scholarly output published on ophthalmic and paraophthalmic education, and second to focus on the quality of reporting of randomised controlled trials (RCTs) identified. STUDY SELECTION: A search strategy was created and applied to PubMed. Any scholarly publications on any aspect of education of those involved in the care of patients with visual problems as the main theme or context was selected. Predefined data were extracted. FINDINGS: Of 255 studies included, the most common type of scholarly publications were descriptions of an educational innovation, opinion pieces and descriptive studies. RCTs made up 5.5% of the sample. Most of the 14 RCTs failed to report most of the items recommended in the CONSORT guidelines. CONCLUSIONS: This review highlights the need for investigators, ethical committees and journals to insist on a better quality of RCT conduct than is presently apparent, but also that clinicians should not be blind to the strengths of non-RCT-based studies in the field of education. PMID- 27993939 TI - Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition. AB - Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to "100 MUM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-kappaB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas. PMID- 27993943 TI - 2016 AHA/ACC Clinical Performance and Quality Measures for Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. PMID- 27993942 TI - The minimum information required for a glycomics experiment (MIRAGE) project: improving the standards for reporting glycan microarray-based data. AB - MIRAGE (Minimum Information Required for A Glycomics Experiment) is an initiative that was created by experts in the fields of glycobiology, glycoanalytics and glycoinformatics to produce guidelines for reporting results from the diverse types of experiments and analyses used in structural and functional studies of glycans in the scientific literature. As a sequel to the guidelines for sample preparation (Struwe et al. 2016, Glycobiology, 26:907-910) and mass spectrometry data (Kolarich et al. 2013, Mol. Cell Proteomics, 12:991-995), here we present the first version of guidelines intended to improve the standards for reporting data from glycan microarray analyses. For each of eight areas in the workflow of a glycan microarray experiment, we provide guidelines for the minimal information that should be provided in reporting results. We hope that the MIRAGE glycan microarray guidelines proposed here will gain broad acceptance by the community, and will facilitate interpretation and reproducibility of the glycan microarray results with implications in comparison of data from different laboratories and eventual deposition of glycan microarray data in international databases. PMID- 27993944 TI - Effects of airborne toxicants on pulmonary function and mitochondrial DNA damage in rodent lungs. AB - Inhalation of airborne toxicants such as cigarette smoke and ozone is a shared health risk among the world's populations. The use of toxic herbicides like paraquat (PQ) is restricted by many countries, yet in the developing world PQ has demonstrable ill effects. The present study examined changes in pulmonary function, mitochondrial DNA (mtDNA) integrity and markers of DNA repair induced by acute or repeated exposure of PQ to rats. Similar to cigarette smoke and ozone, PQ promotes oxidative stress, and the impact of PQ on mtDNA was compared with that obtained with these agents. Tracheal instillation (i.t.) of PQ (0.01 0.075 mg/kg) dose dependently increased Penh (dyspnoea) by 48 h while body weight and temperature declined. Lung wet weight and the wet/dry weight ratio rose; for the latter, by as much as 52%. At low doses (0.02 and 0.03 mg/kg), PQ increased Penh by about 7.5-fold at 72 h. It quickly waned to near baseline levels. The lung wet/dry weight ratio remained elevated 7 days after administration coincident with marked inflammatory cell infiltrate. Repeated administration of PQ (1 per week for 8 weeks) resulted in a similar rise in Penh on the first instillation, but the magnitude of this response was markedly attenuated upon subsequent exposures. Pulmonary [lactate] and catalase activity, [8-oxodG] and histone fragmentation (cell death) were significantly increased. Repeated PQ instillation downregulated the expression of the mitochondrial-encoded genes, mtATP8, mtNd2 and mtcyB and nuclear ones for the DNA glycosylases, Ogg1, Neil1, Neil2 and Neil3. Ogg1 protein content decreased after acute and repeated PQ administration. mtDNA damage or changes in mtDNA copy number were evident in lungs of PQ-, cigarette smoke- and ozone-exposed animals. Taken together, these data indicate that loss of pulmonary function and inflammation are coupled to the loss of mtDNA integrity and DNA repair capability following exposure to airborne toxicants. PMID- 27993945 TI - Human polyomavirus DNA detection in keratoacanthoma and Spitz naevus: no evidence for a causal role. AB - Keratoacanthomas (KA) and Spitz naevus (SN) are both lesions with unknown aetiology; therefore, the possibility of a viral involvement, more specifically the involvement of human polyomaviruses (HPyV), was investigated. In total, 22 cases of KA and 25 cases of SN were tested for the presence of HPyVs. DNA was extracted and amplified by multiplex PCR and thereafter tested with a multiplex bead-based assay for HPyVs (BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, TSPyV, HPyV6, 7 and 9) and two primate viruses (SV40 and LPyV). HPyV DNA was found in 20 of the 47 lesions. There was no significant difference in HPyV DNA detection frequency between patients diagnosed with KA and patients diagnosed with SN, nor any over representation of a specific HPyV type in any of the two patient categories. In conclusion, evidence for a specific aetiological role of any of the above tested HPyVs in either KA or SN was not disclosed. PMID- 27993946 TI - Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: correlations with clinical outcome. AB - AIMS: To study anaplastic lymphoma kinase (ALK) protein expression and possible underlying gene alterations in glioblastoma (GBM), correlating them with clinical outcome. METHODS: We studied ALK immunohistochemical expression and fluorescent in situ hybridisation (FISH)-detected ALK gene alterations in 51 GBMs (46 isocitrate dehydrogenase-1 (IDH1)R132H-negative and 5 IDH-mutant (IDH1R132H positive)). We compared two anti-ALK antibodies and immunohistochemical detection systems (5Alpha4/Nichirei Biosciences, D5F3/Ventana). The results were correlated with tumour cell proliferation and clinical outcome. RESULTS: Intense granular cytoplasmic ALK immunostaining was observed in 10/51 (19.61%) GBM and correlated with high Ki67 proliferation index; only 1 in 10 ALK-positive cases displayed multiple alk gene signals by FISH. Moderate ALK immunostaining was observed in 21 (41.17%), weak immunostaining in 5 (9.80%) while 15 (29.42%) cases were negative. p53 was expressed in 26/51 GBM (50.9%) (10% cut-off). IDH1R132H-negative GBM showed higher ALK expression compared with IDH-mutant GBM (65.2% vs 20%). ALK overexpression was more common in older patients but did not correlate with other clinicopathological variables or patient overall survival. CONCLUSIONS: ALK overexpression can be identified in up to 70% of GBMs and does not correlate with underlying alk gene amplification. Despite being more common in rapidly growing, clinically aggressive GBM, ALK overexpression did not show correlation with prognosis in this study. PMID- 27993947 TI - Shared decision-making following disclosure of coronary heart disease genetic risk: results from a randomized clinical trial. AB - : Whether disclosure of genetic risk for coronary heart disease (CHD) influences shared decision-making (SDM) regarding use of statins to reduce CHD risk is unknown. We randomized 207 patients, age 45-65 years, at intermediate CHD risk, and not on statins, to receive the 10-year risk of CHD based on conventional risk factors alone (n=103) or in combination with a genetic risk score (n=104). A genetic counselor disclosed this information followed by a physician visit for SDM regarding statin therapy. A novel decision aid was used in both encounters to disclose the CHD risk estimates and facilitate SDM regarding statin use. Patients reported their decision quality and physician visit satisfaction using validated surveys. There were no statistically significant differences between the two groups in the SDM score, satisfaction with the clinical encounter, perception of the quality of the discussion or of participation in decision-making and physician visit satisfaction scores. Quantitative analyses of a random subset of 80 video-recorded encounters using the OPTION5 scale also showed no significant difference in SDM between the two groups. Disclosure of CHD genetic risk using an electronic health record-linked decision aid did not adversely affect SDM or patients' satisfaction with the clinical encounter. TRIAL REGISTRATION NUMBER: NCT01936675; Results. PMID- 27993948 TI - Preferential hydrolysis of truncated oxidized glycerophospholipids by lysosomal phospholipase A2. AB - Truncated oxidized glycerophospholipids (ox-PLs) are bioactive lipids resulting from oxidative stress. The catabolic pathways for truncated ox-PLs are not fully understood. Lysosomal phospholipase A2 (LPLA2) with phospholipase A and transacylase activities is a key enzyme in phospholipid homeostasis. The present study assessed whether LPLA2 could hydrolyze truncated ox-PLs. Incubation of LPLA2 with liposomes consisting of 1,2-O-octadecenyl-sn-glycero-3-phosphocholine (DODPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or truncated oxidized phosphatidylcholine (ox-PC)/N-acetylsphingosine (NAS) under acidic conditions resulted in the preferential deacylation at the sn-1 position of the truncated ox PCs. Additionally, the release of free fatty acid from the truncated ox-PCs preferentially occurred compared with the NAS-acylation. Incubation of LPLA2 with the liposomes consisting of DODPC/DOPC/truncated ox-PC/NAS resulted in the same preferential fatty acid release from the truncated ox-PC. The cationic amphiphilic drug, amiodarone, did not inhibit such fatty acid release, indicating that truncated ox-PCs partition from the lipid membrane into the aqueous phase and react with free LPLA2. Consistent with this mechanism, the hydrolysis of some truncated ox-PCs, but not DOPC, by LPLA2 was detected at neutral pH. Additionally, LPLA2-overexpressed Chinese hamster ovary cells efficiently catabolized truncated ox-PC and were protected from growth inhibition. These findings support the existence of a novel catabolic pathway for truncated ox-PLs via LPLA2. PMID- 27993950 TI - In-situ straining and time-resolved electron tomography data acquisition in a transmission electron microscope. AB - This paper reports the preliminary results of a new in-situ three-dimensional (3D) imaging system for observing plastic deformation behavior in a transmission electron microscope (TEM) as a directly relevant development of the recently reported straining-and-tomography holder [Sato K et al. (2015) Development of a novel straining holder for transmission electron microscopy compatible with single tilt-axis electron tomography. Microsc. 64: 369-375]. We designed an integrated system using the holder and newly developed straining and image acquisition software and then developed an experimental procedure for in-situ straining and time-resolved electron tomography (ET) data acquisition. The software for image acquisition and 3D visualization was developed based on the commercially available ET software TEMographyTM. We achieved time-resolved 3D visualization of nanometer-scale plastic deformation behavior in a Pb-Sn alloy sample, thus demonstrating the capability of this system for potential applications in materials science. PMID- 27993949 TI - Unsupervised analysis of combined lipid and coagulation data reveals coagulopathy subtypes among dialysis patients. AB - Hemodialysis (HD) and peritoneal dialysis (PD) are the primary means of managing end stage renal disease (ESRD). However, these treatment modalities are associated with the onset of coagulation abnormalities. Effective management of coagulation risk among these patients requires the identification of surrogate markers that provide an early indication of the coagulation abnormalities. The role of sphingolipids in the manifestation and prediction of coagulation abnormalities among dialysis patients have never been investigated. Herein, we report the first instance of an in depth investigation into the sphingolipid changes among ESRD patients undergoing HD and PD. The results reveal distinct differences in terms of perturbations to specific sphingolipid biosynthetic pathways that are highly dependent on the treatment modality. Our studies also demonstrated strong correlation between specific sphingolipids and coagulation parameters, such as HexCer(d18:1/26:0) and maximal amplitude (MA), SM(d18:1/24:1) and tissue factor pathway inhibitor, and sphingosine 1-phosphate d18:1 and FX (Spearman rho of 0.93, 0.89, and -0.89, respectively). Furthermore, our study revealed the potential for using HexCer(d18:1/22:0), HexCer(d18:1/24:0), and HexCer(d18:1/26:0) (r2 = 0.71, 0.82, and 0.63, respectively) and coagulation parameter MA (r2 = 0.7) for successful diagnosis of differential coagulopathies among ESRD patients undergoing HD, providing an opportunity toward personalized disease management. PMID- 27993951 TI - The structure of binding curves and practical identifiability of equilibrium ligand-binding parameters. AB - A critical but often overlooked question in the study of ligands binding to proteins is whether the parameters obtained from analyzing binding data are practically identifiable (PI), i.e., whether the estimates obtained from fitting models to noisy data are accurate and unique. Here we report a general approach to assess and understand binding parameter identifiability, which provides a toolkit to assist experimentalists in the design of binding studies and in the analysis of binding data. The partial fraction (PF) expansion technique is used to decompose binding curves for proteins with n ligand-binding sites exactly and uniquely into n components, each of which has the form of a one-site binding curve. The association constants of the PF component curves, being the roots of an n-th order polynomial, may be real or complex. We demonstrate a fundamental connection between binding parameter identifiability and the nature of these one site association constants: all binding parameters are identifiable if the constants are all real and distinct; otherwise, at least some of the parameters are not identifiable. The theory is used to construct identifiability maps from which the practical identifiability of binding parameters for any two-, three-, or four-site binding curve can be assessed. Instructions for extending the method to generate identifiability maps for proteins with more than four binding sites are also given. Further analysis of the identifiability maps leads to the simple rule that the maximum number of structurally identifiable binding parameters (shown in the previous paper to be equal to n) will also be PI only if the binding curve line shape contains n resolved components. PMID- 27993952 TI - Structural identifiability of equilibrium ligand-binding parameters. AB - Understanding the interactions of proteins with their ligands requires knowledge of molecular properties, such as binding site affinities and the effects that binding at one site exerts on binding at other sites (cooperativity). These properties cannot be measured directly and are usually estimated by fitting binding data with models that contain these quantities as parameters. In this study, we present a general method for answering the critical question of whether these parameters are identifiable (i.e., whether their estimates are accurate and unique). In cases in which parameter estimates are not unique, our analysis provides insight into the fundamental causes of nonidentifiability. This approach can thus serve as a guide for the proper design and analysis of protein-ligand binding experiments. We show that the equilibrium total binding relation can be reduced to a conserved mathematical form for all models composed solely of bimolecular association reactions and to a related, conserved form for all models composed of arbitrary combinations of binding and conformational equilibria. This canonical mathematical structure implies a universal parameterization of the binding relation that is consistent with virtually any physically reasonable binding model, for proteins with any number of binding sites. Matrix algebraic methods are used to prove that these universal parameter sets are structurally identifiable (SI; i.e., identifiable under conditions of noiseless data). A general approach for assessing and understanding the factors governing practical identifiability (i.e., the identifiability under conditions of real, noisy data) of these SI parameter sets is presented in the companion paper by Middendorf and Aldrich (2017. J. Gen. Physiol. https://doi.org/10.1085/jgp.201611703). PMID- 27993953 TI - Discourse versus practice: are traditional practices and beliefs in pregnancy and childbirth included or excluded in the Ecuadorian health care system? AB - Background: Traditional beliefs, knowledge and practices are formally integrated into the Ecuadorian health system. We sought to understand whether they are integrated in practice. Methods: Qualitative data were collected in two rural parishes in the central highlands of Ecuador through four focus group discussions (30 participants), eight key informant interviews, three participatory exercises (24 participants), structured observations of health facilities and analysis of official documents. Results: We found different levels of integration, coexistence, tolerance, and intolerance of traditional health beliefs and practices in health facilities. One parish has undergone dramatic social and cultural transformation, and the role of traditional birth attendants is limited. In the other parish, traditional indigenous norms and values persist, and traditional birth attendants are sought during pregnancy and childbirth. The degree to which traditional birth attendants, indigenous women and their families are included or excluded from public health services depends largely on decisions taken by local health professionals. Conclusions: Formal policies in Ecuador stipulate that health care should be intercultural, but the role of traditional birth attendants is not necessarily incorporated in practice. The integration of culturally-informed beliefs and practices is critical for providing appropriate health services to members of vulnerable populations. PMID- 27993954 TI - Arterial Stiffness and Risk of Overall Heart Failure, Heart Failure With Preserved Ejection Fraction, and Heart Failure With Reduced Ejection Fraction: The Health ABC Study (Health, Aging, and Body Composition). AB - Higher arterial stiffness is associated with increased risk of atherosclerotic events. However, its contribution toward risk of heart failure (HF) and its subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), independent of other risk factors is not well established. In this study, we included Health ABC study (Health, Aging, and Body Composition) participants without prevalent HF who had arterial stiffness measured as carotid-femoral pulse wave velocity (cf-PWV) at baseline (n=2290). Adjusted Cox-proportional hazards models were constructed to determine the association between continuous and data-derived categorical measures (tertiles) of cf-PWV and incidence of HF and its subtypes (HFpEF [ejection fraction >45%] and HFrEF [ejection fraction <=45%]). We observed 390 HF events (162 HFpEF and 145 HFrEF events) over 11.4 years of follow-up. In adjusted analysis, higher cf PWV was associated with greater risk of HF after adjustment for age, sex, ethnicity, mean arterial pressure, and heart rate (hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref] =1.35 [1.05-1.73]). However, this association was not significant after additional adjustment for other cardiovascular risk factors (hazard ratio [95% confidence interval], 1.14 [0.88-1.47]). cf-PWV velocity was also not associated with risk of HFpEF and HFrEF after adjustment for potential confounders (most adjusted hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref]: HFpEF, 1.06 [0.72-1.56]; HFrEF, 1.28 [0.83-1.97]). In conclusion, arterial stiffness, as measured by cf-PWV, is not independently associated with risk of HF or its subtypes after adjustment for traditional cardiovascular risk factors. PMID- 27993955 TI - Uric Acid Is Associated With Inflammation, Coronary Microvascular Dysfunction, and Adverse Outcomes in Postmenopausal Women. AB - Uric acid is a risk factor for coronary artery disease in postmenopausal women, but the association with inflammation and coronary endothelial dysfunction (CED) is not well defined. The aim of this study was to determine the relationship of serum uric acid (SUA), inflammatory markers, and CED. In this prospective cohort study, SUA, high-sensitivity C-reactive protein levels, and neutrophil count were measured in 229 postmenopausal women who underwent diagnostic catheterization, were found to have no obstructive coronary artery disease, and underwent coronary microvascular function testing, to measure coronary blood flow response to intracoronary acetylcholine. The average age was 58 years (interquartile range, 52-66 years). Hypertension was present in 48%, type 2 diabetes mellitus in 5.6%, and hyperlipidemia in 61.8%. CED was diagnosed in 59% of postmenopausal women. Mean uric acid level was 4.7+/-1.3 mg/dL. Postmenopausal women with CED had significantly higher SUA compared with patients without CED (4.9+/-1.3 versus 4.4+/-1.3 mg/dL; P=0.02). There was a significant correlation between SUA and percent change in coronary blood flow to acetylcholine (P=0.009), and this correlation persisted in multivariable analysis. SUA levels were significantly associated with increased neutrophil count (P=0.02) and high-sensitivity C reactive protein levels (P=0.006) among patients with CED, but not among those without CED. SUA is associated with CED in postmenopausal women and may be related to inflammation. These findings link SUA levels to early coronary atherosclerosis in postmenopausal women. PMID- 27993958 TI - Socioeconomic position and delays in lung cancer diagnosis: should we target the more deprived? PMID- 27993956 TI - Association of Kidney Function and Early Kidney Injury With Incident Hypertension in HIV-Infected Women. AB - Subclinical kidney disease is associated with developing hypertension in the general population, but data are lacking among HIV-infected people. We examined associations of kidney function and injury with incident hypertension in 823 HIV infected and 267 HIV-uninfected women in the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected and uninfected women in the United States. Baseline kidney biomarkers included estimated glomerular filtration rate using cystatin C, urine albumin-to-creatinine ratio, and 7 urine biomarkers of tubular injury: alpha-1-microglobulin, interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, liver fatty acid binding protein, N-acetyl-beta-d-glucosaminidase, and alpha1-acid-glycoprotein. We used multivariable Poisson regression to evaluate associations of kidney biomarkers with incident hypertension, defined as 2 consecutive visits of antihypertensive medication use. During a median follow-up of 9.6 years, 288 HIV infected women (35%) developed hypertension. Among the HIV-infected women, higher urine albumin-to-creatinine ratio was independently associated with incident hypertension (relative risk =1.13 per urine albumin-to-creatinine ratio doubling, 95% confidence interval, 1.07-1.20), as was lower estimated glomerular filtration rate (relative risk =1.10 per 10 mL/min/1.73 m2 lower estimated glomerular filtration rate; 95% confidence interval, 1.04-1.17). No tubular injury and dysfunction biomarkers were independently associated with incident hypertension in HIV-infected women. In contrast, among the HIV-uninfected women, urine albumin to-creatinine ratio was not associated with incident hypertension, whereas higher urine interleukin-18, alpha1-acid-glycoprotein, and N-acetyl-beta-d glucosaminidase levels were significantly associated with incident hypertension. These findings suggest that early glomerular injury and kidney dysfunction may be involved in the pathogenesis of hypertension in HIV-infected people. The associations of tubular markers with hypertension in HIV-uninfected women should be validated in other studies. PMID- 27993960 TI - Patterns of informal patient payments in Bulgaria, Hungary and Ukraine: a comparison across countries, years and type of services. AB - Informal payments for health care are a well-known phenomenon in many health care systems around the world. While informal payments could be an important source of health care financing, they have an adverse impact on efficiency and access to care, and are a major impediment to ongoing health care reforms. This paper aims to study the scale and patterns of informal patient payments for out-patient and in-patient services in three former-socialist countries: Bulgaria, Hungary and Ukraine. The data are collected in 2010 and 2011 based on national representative samples and are analysed in pooled models to explain variations in payments. The results of the cross-country comparison suggest a relatively higher prevalence of informal patient payments in Ukraine and Hungary than in Bulgaria, where patients also have to pay formal user charges in the public sector. Nevertheless, informal payments for hospitalization in Bulgaria are quite extensive. We observe some differences in informal payments across the years. Variations in payment size are mainly explained by the nature, type and need for services, fee awareness and, on some occasions, by household income. Interpreted within the context of structural differences (e.g. reform paths, regulations, funding, user fees, anti-corruption policies), the findings of our study have implications on how to address informal payments for health care. PMID- 27993957 TI - Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity. AB - A high-fructose diet is shown to induce salt-sensitive hypertension, but the underlying mechanism largely remains unknown. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. In Sprague Dawley rats, high-fructose intake increased renal expression of full-length PRR, which were attenuated by allopurinol. High-fructose intake also upregulated renal mRNA and protein expression of sodium/hydrogen exchanger 3 and Na/K/2Cl cotransporter, as well as in vivo Na/K/2Cl cotransporter activity, all of which were nearly completely blocked by a PRR decoy inhibitor PRO20 or allopurinol treatment. Parallel changes were observed for indices of intrarenal renin angiotensin-system including renal and urinary renin and angiotensin II levels. Radiotelemetry demonstrated that high-fructose or a high-salt diet alone did not affect mean arterial pressure, but the combination of the 2 maneuvers induced a ~10-mm Hg increase of mean arterial pressure, which was blunted by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid increased protein expression of soluble PRR in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via uric acid stimulates renal expression of PRR/soluble PRR that stimulate sodium/hydrogen exchanger 3 and Na/K/2Cl cotransporter expression and intrarenal renin-angiotensin system to induce salt-sensitive hypertension. PMID- 27993962 TI - The impact of prenatal care quality on neonatal, infant and child mortality in Zimbabwe: evidence from the demographic and health surveys. AB - The impact of the quality of prenatal care on child mortality outcomes has received less attention in sub-Saharan Africa. This study endeavoured to explore the effect of the quality of prenatal care and its individual components on neonatal, infant and under-five mortality. The empirical analysis uses data from the three most recent waves of the nationally representative Demographic and Health Survey for Zimbabwe conducted in 1999, 2005/06 and 2010/11. The results indicate that a one-unit increase in the quality of prenatal care lowers the prospect of neonatal, infant and under-five mortality by approximately 42.33, 30.86 and 28.65%, respectively. These findings remained roughly the same even after adjusting for potential mediating factors. Examining the effect of individual prenatal care components on child mortality revealed that women who receive information on possible complications arising during pregnancy are less liable to experience a neonatal death. Similarly, women who had blood pressure checks and tetanus immunizations were less likely to experience an infant or under-five death. We did not find any statistically meaningful impact on child mortality outcomes of blood and urine sample checks, iron tablet consumption, and the receipt of malarial tablets. Overall, our results suggest the need for public health policymakers to focus on ensuring high-quality prenatal care to enhance the survival prospects of Zimbabwe's infants. PMID- 27993961 TI - Support and performance improvement for primary health care workers in low- and middle-income countries: a scoping review of intervention design and methods. AB - Primary health care workers (HCWs) in low- and middle-income settings (LMIC) often work in challenging conditions in remote, rural areas, in isolation from the rest of the health system and particularly specialist care. Much attention has been given to implementation of interventions to support quality and performance improvement for workers in such settings. However, little is known about the design of such initiatives and which approaches predominate, let alone those that are most effective. We aimed for a broad understanding of what distinguishes different approaches to primary HCW support and performance improvement and to clarify the existing evidence as well as gaps in evidence in order to inform decision-making and design of programs intended to support and improve the performance of health workers in these settings. We systematically searched the literature for articles addressing this topic, and undertook a comparative review to document the principal approaches to performance and quality improvement for primary HCWs in LMIC settings. We identified 40 eligible papers reporting on interventions that we categorized into five different approaches: (1) supervision and supportive supervision; (2) mentoring; (3) tools and aids; (4) quality improvement methods, and (5) coaching. The variety of study designs and quality/performance indicators precluded a formal quantitative data synthesis. The most extensive literature was on supervision, but there was little clarity on what defines the most effective approach to the supervision activities themselves, let alone the design and implementation of supervision programs. The mentoring literature was limited, and largely focused on clinical skills building and educational strategies. Further research on how best to incorporate mentorship into pre-service clinical training, while maintaining its function within the routine health system, is needed. There is insufficient evidence to draw conclusions about coaching in this setting, however a review of the corporate and the business school literature is warranted to identify transferrable approaches. A substantial literature exists on tools, but significant variation in approaches makes comparison challenging. We found examples of effective individual projects and designs in specific settings, but there was a lack of comparative research on tools across approaches or across settings, and no systematic analysis within specific approaches to provide evidence with clear generalizability. Future research should prioritize comparative intervention trials to establish clear global standards for performance and quality improvement initiatives. Such standards will be critical to creating and sustaining a well-functioning health workforce and for global initiatives such as universal health coverage. PMID- 27993964 TI - Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker. AB - PURPOSE: Despite recent therapeutic advances, prognosis of patients with pancreatic adenocarcinoma remains poor. Analyses from tumor tissues present limitations; identification of informative marker from blood might be a promising alternative. The aim of this study was to assess the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: From 2011 to 2015, blood samples were prospectively collected from all consecutive patients with pancreatic adenocarcinoma treated in our center. Identification of ctDNA was done with next-generation sequencing targeted on referenced mutations in pancreatic adenocarcinoma and with picoliter droplet digital PCR. RESULTS: A total of 135 patients with resectable (n = 31; 23%), locally advanced (n = 36; 27%), or metastatic (n = 68; 50%) pancreatic adenocarcinoma were included. In patients with advanced pancreatic adenocarcinoma (n = 104), 48% (n = 50) had ctDNA detectable with a median mutation allelic frequency (MAF) of 6.1%. The presence of ctDNA was strongly correlated with poor overall survival (OS; 6.5 vs. 19.0 months; P < 0.001) in univariate and multivariate analyses (HR = 1.96; P = 0.007). To evaluate the impact of ctDNA level, patients were grouped according to MAF tertiles: OS were 18.9, 7.8, and 4.9 months (P < 0.001). Among patients who had curative intent resection (n = 31), 6 had ctDNA detectable after surgery, with an MAF of 4.4%. The presence of ctDNA was associated with a shorter disease-free survival (4.6 vs.17.6 months; P = 0.03) and shorter OS (19.3 vs. 32.2 months; P = 0.027). CONCLUSIONS: ctDNA is an independent prognostic marker in advanced pancreatic adenocarcinoma. Furthermore, it arises as an indicator of shorter disease-free survival in resected patients when detected after surgery. Clin Cancer Res; 23(1); 116-23. (c)2016 AACR. PMID- 27993963 TI - Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure. AB - PURPOSE: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. EXPERIMENTAL DESIGN: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. RESULTS: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). CONCLUSIONS: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 23(1); 43-51. (c)2016 AACR. PMID- 27993965 TI - Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models. AB - Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2MUT patient-derived xenograft (PDX) model.Results: PARPi monotherapy resulted in a decrease in BRCAMUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCAMUT cells. Notably, PARPi led to G2 phase accumulation, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2MUT PDX with the PARPi ATRi combination inducing tumor regression and in most cases, complete remission.Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUT models. Clin Cancer Res; 23(12); 3097 108. (c)2016 AACR. PMID- 27993967 TI - An FDA Perspective on the Regulatory Implications of Complex Signatures to Predict Response to Targeted Therapies. AB - As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368-72. (c)2016 AACR. PMID- 27993966 TI - Characterization of an Abiraterone Ultraresponsive Phenotype in Castration Resistant Prostate Cancer Patient-Derived Xenografts. AB - Purpose: To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).Experimental Design: SCID mice bearing LuCaP 136CR, 77CR, 96CR, and 35CR PDXs were treated with AA. Tumor volume and prostate-specific antigen were monitored, and tumors were harvested 7 days after treatment or at end of study for gene expression and immunohistochemical studies.Results: Three phenotypic groups were observed based on AA response. An ultraresponsive phenotype was identified in LuCaP 136CR with significant inhibition of tumor progression and increased survival, intermediate responders LuCaP 77CR and LuCaP 96CR with a modest tumor inhibition and survival benefit, and LuCaP 35CR with minimal tumor inhibition and no survival benefit upon AA treatment. We identified a molecular signature of secreted proteins associated with the AA ultraresponsive phenotype. Upon resistance, AA ultraresponder LuCaP 136CR displayed reduced androgen receptor (AR) signaling and sustainably low nuclear glucocorticoid receptor (nGR) localization, accompanied by steroid metabolism alteration and epithelial-mesenchymal transition phenotype enrichment with increased expression of NF-kappaB-regulated genes; intermediate and minimal responders maintained sustained AR signaling and increased tumoral nGR localization.Conclusions: We identified a molecular signature of secreted proteins associated with AA ultraresponsiveness and sustained AR/GR signaling upon AA resistance in intermediate or minimal responders. These data will inform development of noninvasive biomarkers predicting AA response and suggest that further inhibition along the AR/GR signaling axis may be effective only in AA resistant patients who are intermediate or minimal responders. These findings require verification in prospective clinical trials. Clin Cancer Res; 23(9); 2301 12. (c)2016 AACR. PMID- 27993969 TI - Klebsiella pneumoniae of suspected human origin from free-living common seals on the east coast of England. PMID- 27993968 TI - Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib. AB - Purpose: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY 1215.Experimental Design: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model.Results: Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC50 values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma. In vivo confirmation of antitumor synergy was demonstrated with a xenograft of DLBCL.Conclusions: The development of this ACY-1215-resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway. Clin Cancer Res; 23(12); 3084-96. (c)2016 AACR. PMID- 27993971 TI - The CD9, CD81, and CD151 EC2 domains bind to the classical RGD-binding site of integrin alphavbeta3. AB - Tetraspanins play important roles in normal (e.g. cell adhesion, motility, activation, and proliferation) and pathological conditions (e.g. metastasis and viral infection). Tetraspanins interact with integrins and regulate integrin functions, but the specifics of tetraspanin-integrin interactions are unclear. Using co-immunoprecipitation with integrins as a sole method to detect interaction between integrins and full-length tetraspanins, it has been proposed that the variable region (helices D and E) of the extracellular-2 (EC2) domain of tetraspanins laterally associates with a non-ligand-binding site of integrins. We describe that, using adhesion assays, the EC2 domain of CD81, CD9, and CD151 bound to integrin alphavbeta3, and this binding was suppressed by cRGDfV, a specific inhibitor of alphavbeta3, and antibody 7E3, which is mapped to the ligand-binding site of beta3. We also present evidence that the specificity loop of beta3 directly bound to the EC2 domains. This suggests that the EC2 domains specifically bind to the classical ligand-binding site of alphavbeta3. alphavbeta3 was a more effective receptor for the EC2 domains than the previously known tetraspanin receptors alpha3beta1, alpha4beta1, and alpha6beta1. Docking simulation predicted that the helices A and B of CD81 EC2 bind to the RGD-binding site of alphavbeta3. Substituting Lys residues at positions 116 and 144/148 of CD81 EC2 in the predicted integrin-binding interface reduced the binding of CD81 EC2 to alphavbeta3, consistent with the docking model. These findings suggest that, in contrast with previous models, the ligand-binding site of integrin alphavbeta3, a new tetraspanin receptor, binds to the constant region (helices A and B) of the EC2 domain. PMID- 27993970 TI - Identification of a multifunctional docking site on the catalytic unit of phosphodiesterase-4 (PDE4) that is utilised by multiple interaction partners. AB - Cyclic AMP (cAMP)-specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by mitogen-activated protein kinase activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A. Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory upstream conserved region 1 (UCR1) domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering). Located with the second site is a critical core Phe693, Glu694, Phe695 (FQF) motif that is also employed in the sequestering of PDE4 long forms by an array of other signalling proteins, including the signalling scaffold beta-arrestin, the tyrosyl kinase Lyn, the SUMOylation E2 ligase UBC9, the dynein regulator Lis1 (PAFAH1B1) and the protein kinase Erk. We propose that the FQF motif lies at the heart of a multifunctional docking (MFD) site located within the PDE4 catalytic unit. It is clear from our data that, as well as aiding fidelity of interaction, the MFD site confers exclusivity of binding between PDE4 and a single specific partner protein from the cohort of signalling proteins whose interaction with PDE4 involves the FQF motif. PMID- 27993972 TI - Differential Macrophage Polarization from Pneumocystis in Immunocompetent and Immunosuppressed Hosts: Potential Adjunctive Therapy during Pneumonia. AB - We explored differential polarization of macrophages during infection using a rat model of Pneumocystis pneumonia. We observed enhanced pulmonary M1 macrophage polarization in immunosuppressed (IS) hosts, but an M2 predominant response in immunocompetent (IC) hosts following Pneumocystis carinii challenge. Increased inflammation and inducible nitric oxide synthase (iNOS) levels characterized the M1 response. However, macrophage ability to produce nitric oxide was defective. In contrast, the lungs of IC animals revealed a prominent M2 gene signature, and these macrophages effectively elicited an oxidative burst associated with clearance of Pneumocystis In addition, during P. carinii infection the expression of Dectin-1, a critical receptor for recognition and clearance of P. carinii, was upregulated in macrophages of IC animals but suppressed in IS animals. In the absence of an appropriate cytokine milieu for M2 differentiation, Pneumocystis induced an M1 response both in vitro and in vivo The M1 response induced by P. carinii was plastic in nature and reversible with appropriate cytokine stimuli. Finally, we tested whether macrophage polarization can be modulated in vivo and used to help manage the pathogenesis of Pneumocystis pneumonia by adoptive transfer. Treatment with both M1 and M2 cells significantly improved survival of P. carinii-infected IS hosts. However, M2 treatment provided the best outcomes with efficient clearance of P. carinii and reduced inflammation. PMID- 27993973 TI - Anaplasma marginale Outer Membrane Protein A Is an Adhesin That Recognizes Sialylated and Fucosylated Glycans and Functionally Depends on an Essential Binding Domain. AB - Anaplasma marginale causes bovine anaplasmosis, a debilitating and potentially fatal tick-borne infection of cattle. Because A. marginale is an obligate intracellular organism, its adhesins that mediate entry into host cells are essential for survival. Here, we demonstrate that A. marginale outer membrane protein A (AmOmpA; AM854) contributes to the invasion of mammalian and tick host cells. AmOmpA exhibits predicted structural homology to OmpA of A. phagocytophilum (ApOmpA), an adhesin that uses key lysine and glycine residues to interact with alpha2,3-sialylated and alpha1,3-fucosylated glycan receptors, including 6-sulfo-sialyl Lewis x (6-sulfo-sLex). Antisera against AmOmpA or its predicted binding domain inhibits A. marginale infection of host cells. Residues G55 and K58 are contributory, and K59 is essential for recombinant AmOmpA to bind to host cells. Enzymatic removal of alpha2,3-sialic acid and alpha1,3-fucose residues from host cell surfaces makes them less supportive of AmOmpA binding. AmOmpA is both an adhesin and an invasin, as coating inert beads with it confers adhesiveness and invasiveness. Recombinant forms of AmOmpA and ApOmpA competitively antagonize A. marginale infection of host cells, but a monoclonal antibody against 6-sulfo-sLex fails to inhibit AmOmpA adhesion and A. marginale infection. Thus, the two OmpA proteins bind related but structurally distinct receptors. This study provides a detailed understanding of AmOmpA function, identifies its essential residues that can be targeted by blocking antibody to reduce infection, and determines that it binds to one or more alpha2,3-sialylated and alpha1,3-fucosylated glycan receptors that are unique from those targeted by ApOmpA. PMID- 27993974 TI - The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes. AB - As an exclusively human pathogen, Streptococcus pyogenes (the group A streptococcus [GAS]) has specifically adapted to evade host innate immunity and survive in multiple tissue niches, including blood. GAS can overcome the metabolic constraints of the blood environment and expresses various immunomodulatory factors necessary for survival and immune cell resistance. Here we present our investigation of one such factor, the predicted LysR family transcriptional regulator CpsY. The encoding gene, cpsY, was initially identified as being required for GAS survival in a transposon-site hybridization (TraSH) screen in whole human blood. CpsY is homologous with transcriptional regulators of Streptococcus mutans (MetR), Streptococcus iniae (CpsY), and Streptococcus agalactiae (MtaR) that regulate methionine transport, amino acid metabolism, resistance to neutrophil-mediated killing, and survival in vivo Our investigation indicated that CpsY is involved in GAS resistance to innate immune cells of its human host. However, GAS CpsY does not manifest the in vitro phenotypes of its homologs in other streptococcal species. GAS CpsY appears to regulate a small set of genes that is markedly different from the regulons of its homologs. The differential expression of these genes depends on the growth medium, and CpsY modestly influences their expression. The GAS CpsY regulon includes known virulence factors (mntE, speB, spd, nga [spn], prtS [SpyCEP], and sse) and cell surface-associated factors of GAS (emm1, mur1.2, sibA [cdhA], and M5005_Spy0500). Intriguingly, the loss of CpsY in GAS does not result in virulence defects in murine models of infection, suggesting that CpsY function in immune evasion is specific to the human host. PMID- 27993976 TI - Osteocrin, a peptide secreted from the heart and other tissues, contributes to cranial osteogenesis and chondrogenesis in zebrafish. AB - The heart is an endocrine organ, as cardiomyocytes (CMs) secrete natriuretic peptide (NP) hormones. Since the discovery of NPs, no other peptide hormones that affect remote organs have been identified from the heart. We identified osteocrin (Ostn) as an osteogenesis/chondrogenesis regulatory hormone secreted from CMs in zebrafish. ostn mutant larvae exhibit impaired membranous and chondral bone formation. The impaired bones were recovered by CM-specific overexpression of OSTN. We analyzed the parasphenoid (ps) as a representative of membranous bones. In the shortened ps of ostn morphants, nuclear Yap1/Wwtr1-dependent transcription was increased, suggesting that Ostn might induce the nuclear export of Yap1/Wwtr1 in osteoblasts. Although OSTN is proposed to bind to NPR3 (clearance receptor for NPs) to enhance the binding of NPs to NPR1 or NPR2, OSTN enhanced C-type NP (CNP) dependent nuclear export of YAP1/WWTR1 of cultured mouse osteoblasts stimulated with saturable CNP. OSTN might therefore activate unidentified receptors that augment protein kinase G signaling mediated by a CNP-NPR2 signaling axis. These data demonstrate that Ostn secreted from the heart contributes to bone formation as an endocrine hormone. PMID- 27993975 TI - Streptococcus oralis Neuraminidase Modulates Adherence to Multiple Carbohydrates on Platelets. AB - Adherence to host surfaces is often mediated by bacterial binding to surface carbohydrates. Although it is widely appreciated that some bacterial species express glycosidases, previous studies have not considered whether bacteria bind to multiple carbohydrates within host glycans as they are modified by bacterial glycosidases. Streptococcus oralis is a leading cause of subacute infective endocarditis. Binding to platelets is a critical step in disease; however, the mechanisms utilized by S. oralis remain largely undefined. Studies revealed that S. oralis, like Streptococcus gordonii and Streptococcus sanguinis, binds platelets via terminal sialic acid. However, unlike those organisms, S. oralis produces a neuraminidase, NanA, which cleaves terminal sialic acid. Further studies revealed that following NanA-dependent removal of terminal sialic acid, S. oralis bound exposed beta-1,4-linked galactose. Adherence to both these carbohydrates required Fap1, the S. oralis member of the serine-rich repeat protein (SRRP) family of adhesins. Mutation of a conserved residue required for sialic acid binding by other SRRPs significantly reduced platelet binding, supporting the hypothesis that Fap1 binds this carbohydrate. The mechanism by which Fap1 contributes to beta-1,4-linked galactose binding remains to be defined; however, binding may occur via additional domains of unknown function within the nonrepeat region, one of which shares some similarity with a carbohydrate binding module. This study is the first demonstration that an SRRP is required to bind beta-1,4-linked galactose and the first time that one of these adhesins has been shown to be required for binding of multiple glycan receptors. PMID- 27993977 TI - Derivation of a robust mouse mammary organoid system for studying tissue dynamics. AB - Advances in stem cell research have enabled the generation of 'mini organs' or organoids that recapitulate phenotypic traits of the original biological specimen. Although organoids have been demonstrated for multiple organ systems, there are more limited options for studying mouse mammary gland formation in vitro Here, we have built upon previously described culture assays to define culture conditions that enable the efficient generation of clonal organoid structures from single sorted basal mammary epithelial cells (MECs). Analysis of Confetti-reporter mice revealed the formation of uni-colored structures and thus the clonal nature of these organoids. High-resolution 3D imaging demonstrated that basal cell-derived complex organoids comprised an inner compartment of polarized luminal cells with milk-producing capacity and an outer network of elongated myoepithelial cells. Conversely, structures generated from luminal MECs rarely contained basal/myoepithelial cells. Moreover, flow cytometry and 3D microscopy of organoids generated from lineage-specific reporter mice established the bipotent capacity of basal cells and the restricted potential of luminal cells. In summary, we describe optimized in vitro conditions for the efficient generation of mouse mammary organoids that recapitulate features of mammary tissue architecture and function, and can be applied to understand tissue dynamics and cell-fate decisions. PMID- 27993978 TI - CenpH regulates meiotic G2/M transition by modulating the APC/CCdh1-cyclin B1 pathway in oocytes. AB - Meiotic resumption (G2/M transition) and progression through meiosis I (MI) are two key stages for producing fertilization-competent eggs. Here, we report that CenpH, a component of the kinetochore inner plate, is responsible for G2/M transition in meiotic mouse oocytes. Depletion of CenpH by morpholino injection decreased cyclin B1 levels, resulting in attenuation of maturation-promoting factor (MPF) activation, and severely compromised meiotic resumption. CenpH protects cyclin B1 from destruction by competing with the action of APC/CCdh1 Impaired G2/M transition after CenpH depletion could be rescued by expression of exogenous cyclin B1. Unexpectedly, blocking CenpH did not affect spindle organization and meiotic cell cycle progression after germinal vesicle breakdown. Our findings reveal a novel role of CenpH in regulating meiotic G2/M transition by acting via the APC/CCdh1-cyclin B1 pathway. PMID- 27993979 TI - mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis. AB - Radial glial cells (RCGs) are self-renewing progenitor cells that give rise to neurons and glia during embryonic development. Throughout neurogenesis, these cells contact the cerebral ventricles and bear a primary cilium. Although the role of the primary cilium in embryonic patterning has been studied, its role in brain ventricular morphogenesis is poorly characterized. Using conditional mutants, we show that the primary cilia of radial glia determine the size of the surface of their ventricular apical domain through regulation of the mTORC1 pathway. In cilium-less mutants, the orientation of the mitotic spindle in radial glia is also significantly perturbed and associated with an increased number of basal progenitors. The enlarged apical domain of RGCs leads to dilatation of the brain ventricles during late embryonic stages (ventriculomegaly), which initiates hydrocephalus during postnatal stages. These phenotypes can all be significantly rescued by treatment with the mTORC1 inhibitor rapamycin. These results suggest that primary cilia regulate ventricle morphogenesis by acting as a brake on the mTORC1 pathway. This opens new avenues for the diagnosis and treatment of hydrocephalus. PMID- 27993980 TI - Genetic mosaics and time-lapse imaging identify functions of histone H3.3 residues in mouse oocytes and embryos. AB - During development from oocyte to embryo, genetic programs in mouse germ cells are reshaped by chromatin remodeling to orchestrate the onset of development. Epigenetic modifications of specific amino acid residues of core histones and their isoforms can dramatically alter activation and suppression of gene expression. H3.3 is a histone H3 variant that plays essential roles in mouse oocytes and early embryos, but the functional role of individual amino acid residues has been unclear because of technical hurdles. Here, we describe two strategies that successfully investigated the functions of three individual H3.3 residues in oogenesis, cleavage-stage embryogenesis and early development. We first generated genetic mosaic ovaries and blastocysts with stochastic expression of wild-type or mutant H3.3 alleles and showed dominant negative effects of H3.3R26 and H3.3K27 in modulating oogenesis and partitioning cells to the inner cell mass of the early embryo. Time-lapse imaging assays also revealed the essential roles of H3.3K56 in efficient H2B incorporation and paternal pronuclei formation. Application of these strategies can be extended to investigate roles of additional H3.3 residues and has implications for use in other developmental systems. PMID- 27993981 TI - Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex. AB - The precise control of neuronal migration and morphological changes during differentiation is essential for neocortical development. We hypothesized that the transition of progenitors through progressive stages of differentiation involves dynamic changes in levels of mitochondrial reactive oxygen species (mtROS), depending on cell requirements. We found that progenitors had higher levels of mtROS, but that these levels were significantly decreased with differentiation. The Prdm16 gene was identified as a candidate modulator of mtROS using microarray analysis, and was specifically expressed by progenitors in the ventricular zone. However, Prdm16 expression declined during the transition into NeuroD1-positive multipolar cells. Subsequently, repression of Prdm16 expression by NeuroD1 on the periphery of ventricular zone was crucial for appropriate progression of the multipolar phase and was required for normal cellular development. Furthermore, time-lapse imaging experiments revealed abnormal migration and morphological changes in Prdm16-overexpressing and -knockdown cells. Reporter assays and mtROS determinations demonstrated that PGC1alpha is a major downstream effector of Prdm16 and NeuroD1, and is required for regulation of the multipolar phase and characteristic modes of migration. Taken together, these data suggest that Prdm16 plays an important role in dynamic cellular redox changes in developing neocortex during neural differentiation. PMID- 27993982 TI - A vertebrate-specific and essential role for osterix in osteogenesis revealed by gene knockout in the teleost medaka. AB - osterix (osx; sp7) encodes a zinc-finger transcription factor that controls osteoblast differentiation in mammals. Although identified in all vertebrate lineages, its role in non-mammalian bone formation remains elusive. Here, we show that an osx mutation in medaka results in severe bone defects and larval lethality. Pre-osteoblasts fail to differentiate leading to severe intramembranous and perichondral ossification defects. The notochord sheath mineralizes normally, supporting the idea of an osteoblast-independent mechanism for teleost vertebral centra formation. This study establishes a key role for Osx for bone formation in a non-mammalian species, and reveals conserved and non conserved features in vertebrate bone formation. PMID- 27993983 TI - Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors. AB - Myogenic regulatory factors (MRFs), including Myf5, MyoD (Myod1) and Myog, are muscle-specific transcription factors that orchestrate myogenesis. Although MRFs are essential for myogenic commitment and differentiation, timely repression of their activity is necessary for the self-renewal and maintenance of muscle stem cells (satellite cells). Here, we define Ascl2 as a novel inhibitor of MRFs. During mouse development, Ascl2 is transiently detected in a subpopulation of Pax7+ MyoD+ progenitors (myoblasts) that become Pax7+ MyoD- satellite cells prior to birth, but is not detectable in postnatal satellite cells. Ascl2 knockout in embryonic myoblasts decreases both the number of Pax7+ cells and the proportion of Pax7+ MyoD- cells. Conversely, overexpression of Ascl2 inhibits the proliferation and differentiation of cultured myoblasts and impairs the regeneration of injured muscles. Ascl2 competes with MRFs for binding to E-boxes in the promoters of muscle genes, without activating gene transcription. Ascl2 also forms heterodimers with classical E-proteins to sequester their transcriptional activity on MRF genes. Accordingly, MyoD or Myog expression rescues myogenic differentiation despite Ascl2 overexpression. Ascl2 expression is regulated by Notch signaling, a key governor of satellite cell self-renewal. These data demonstrate that Ascl2 inhibits myogenic differentiation by targeting MRFs and facilitates the generation of postnatal satellite cells. PMID- 27993984 TI - An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation. AB - The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation of axin2 expression, a direct Wnt/beta-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/beta-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells, resulting in congenital cataracts. PMID- 27993985 TI - Patterning of brain precursors in ascidian embryos. AB - In terms of their embryonic origins, the anterior and posterior parts of the ascidian central nervous system (CNS) are associated with distinct germ layers. The anterior part of the sensory vesicle, or brain, originates from ectoderm lineages following a neuro-epidermal binary fate decision. In contrast, a large part of the remaining posterior CNS is generated following neuro-mesodermal binary fate decisions. Here, we address the mechanisms that pattern the anterior brain precursors along the medial-lateral axis (future ventral-dorsal) at neural plate stages. Our functional studies show that Nodal signals are required for induction of lateral genes, including Delta-like, Snail, Msxb and Trp Delta like/Notch signalling induces intermediate (Gsx) over medial (Meis) gene expression in intermediate cells, whereas the combinatorial action of Snail and Msxb prevents the expression of Gsx in lateral cells. We conclude that despite the distinct embryonic lineage origins within the larval CNS, the mechanisms that pattern neural precursors are remarkably similar. PMID- 27993986 TI - TAEL: a zebrafish-optimized optogenetic gene expression system with fine spatial and temporal control. AB - Here, we describe an optogenetic gene expression system optimized for use in zebrafish. This system overcomes the limitations of current inducible expression systems by enabling robust spatial and temporal regulation of gene expression in living organisms. Because existing optogenetic systems show toxicity in zebrafish, we re-engineered the blue-light-activated EL222 system for minimal toxicity while exhibiting a large range of induction, fine spatial precision and rapid kinetics. We validate several strategies to spatially restrict illumination and thus gene induction with our new TAEL (TA4-EL222) system. As a functional example, we show that TAEL is able to induce ectopic endodermal cells in the presumptive ectoderm via targeted sox32 induction. We also demonstrate that TAEL can be used to resolve multiple roles of Nodal signaling at different stages of embryonic development. Finally, we show how inducible gene editing can be achieved by combining the TAEL and CRISPR/Cas9 systems. This toolkit should be a broadly useful resource for the fish community. PMID- 27993988 TI - A MAPK cascade couples maternal mRNA translation and degradation to meiotic cell cycle progression in mouse oocytes. AB - Mammalian oocyte maturation depends on the translational activation of stored maternal mRNAs upon meiotic resumption. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) is a key oocyte factor that regulates maternal mRNA translation. However, the signal that triggers CPEB1 activation at the onset of mammalian oocyte maturation is not known. We provide evidence that a mitogen activated protein kinase (MAPK) cascade couples maternal mRNA translation to meiotic cell cycle progression in mouse oocytes by triggering CPEB1 phosphorylation and degradation. Mutations of the phosphorylation sites or ubiquitin E3 ligase binding sites in CPEB1 have a dominant-negative effect in oocytes, and mimic the phenotype of ERK1/2 knockout, by impairing spindle assembly and mRNA translation. Overexpression of the CPEB1 downstream translation activator DAZL in ERK1/2-deficient oocytes partially rescued the meiotic defects, indicating that ERK1/2 is essential for spindle assembly, metaphase II arrest and maternal-zygotic transition (MZT) primarily by triggering the translation of key maternal mRNAs. Taken together, ERK1/2-mediated CPEB1 phosphorylation/degradation is a major mechanism of maternal mRNA translational activation, and is crucial for mouse oocyte maturation and MZT. PMID- 27993987 TI - The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal beta-cell maturation. AB - The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5' conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (-2139 to -1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature beta cells in vivo Pdx1DeltaAREAII/- mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Creating an Area II-deleted state within already specified Neurog3-expressing endocrine progenitor cells increased the proportion of glucagon+ alpha relative to insulin+ beta cells, associated with the transcriptional and epigenetic derepression of the alpha-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and beta cells that were incapable of maturation. Creating the Pdx1DeltaAREAII state after cells entered an insulin-expressing stage led to immature and dysfunctional islet beta cells carrying abnormal chromatin marking in vital beta-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and beta cell-specific Pdx1 functions. PMID- 27993989 TI - The transcription factor mohawk homeobox regulates homeostasis of the periodontal ligament. AB - The periodontal ligament (PDL), which connects the teeth to the alveolar bone, is essential for periodontal tissue homeostasis. Although the significance of the PDL is recognized, molecular mechanisms underlying PDL function are not well known. We report that mohawk homeobox (Mkx), a tendon-specific transcription factor, regulates PDL homeostasis by preventing its degeneration. Mkx is expressed in the mouse PDL at the age of 10 weeks and expression remained at similar levels at 12 months. In Mkx-/- mice, age-dependent expansion of the PDL at the maxillary first molar (M1) furcation area was observed. Transmission electron microscopy (TEM) revealed that Mkx-/- mice presented collagen fibril degeneration in PDL with age, while the collagen fibril diameter gradually increased in Mkx+/+ mice. PDL cells lost their shape in Mkx-/- mice, suggesting changes in PDL properties. Microarray and quantitative polymerase chain reaction (qPCR) analyses of Mkx-/- PDL revealed an increase in osteogenic gene expression and no change in PDL- and inflammatory-related gene expression. Additionally, COL1A1 and COL1A2 were upregulated in Mkx-overexpressing human PDL fibroblasts, whereas osteogenic genes were downregulated. Our results indicate that Mkx prevents PDL degeneration by regulating osteogenesis. PMID- 27993994 TI - Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously. AB - With the aim to improve the efficacy of therapeutic vaccines that target self antigens, we have developed a novel fusion protein vaccine on the basis of the C terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abs were analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinated mice displayed a 2- to 10 fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generated Abs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.-Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.-O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.-K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously. PMID- 27993996 TI - Fluoxetine for Maintenance of Remission and to Improve Quality of Life in Patients with Crohn's Disease. PMID- 27993995 TI - In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. AB - The high susceptibility of newborn infants to sepsis is ascribed to an immaturity of the neonatal immune system, but the molecular mechanisms remain unclear. Newborn monocytes massively release the alarmins S100A8/S100A9. In adults, these are major regulators of immunosuppressive myeloid-derived suppressor cells (MDSCs). We investigated whether S100A8/S100A9 cause an expansion of monocytic MDSCs (Mo-MDSCs) in neonates, thereby contributing to an immunocompromised state. Mo-MDSCs have been assigned to CD14+/human leukocyte antigen (HLA)-DR-/low/CD33+ monocytes in humans and to CD11b+/Gr-1int/Ly6G-/Ly6Chi cells in mice. We found monocytes with these phenotypes significantly expanded in their respective newborns. Functionally, however, they did not prove immunosuppressive but rather responded inflammatorily to microbial stimulation. Their expansion did not correlate with high S100A8/S100A9 levels in cord blood. Murine studies revealed an excessive expansion of CD11b+/Gr-1int/Ly6G-/Ly6Chi monocytes in S100A9-/- neonates compared to wild-type neonates. This strong baseline expansion was associated with hyperinflammatory responses during endotoxemia and fatal septic courses. Treating S100A9-/- neonates directly after birth with S100A8/S100A9 alarmins prevented excessive expansion of this inflammatory monocyte population and death from septic shock. Our data suggest that a specific population of inflammatory monocytes promotes fatal courses of sepsis in neonates if its expansion is not regulated by S100A8/S100A9 alarmins.-Heinemann, A. S., Pirr, S., Fehlhaber, B., Mellinger, L., Burgmann, J., Busse, M., Ginzel, M., Friesenhagen, J., von Kockritz-Blickwede, M., Ulas, T., von Kaisenberg, C. S., Roth, J., Vogl, T., Viemann, D. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. PMID- 27993997 TI - Letter: Vedolizumab in Pregnancy. PMID- 27994000 TI - The natural history of endometrial polyps. AB - STUDY QUESTION: What is the natural history of endometrial polyps in women who are managed expectantly? SUMMARY ANSWER: The growth rates of expectantly managed polyps vary considerably and cannot be accurately predicted. WHAT IS KNOWN ALREADY: The majority of polyps detected on ultrasound are treated surgically, and therefore little is known about their natural history. Some polyps have been reported to regress spontaneously without the need for treatment; however, the factors predictive of regression are unknown. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study conducted at the Department of Gynaecology, University College London Hospitals. We searched our ultrasound clinic database between July 1997 and September 2015, to identify women aged 18 years or older with endometrial polyps that were managed expectantly for >=6 months. All women attended for a minimum of two ultrasound scans. PARTICIPANTS/MATERIALS, SETTING, METHODS: A single expert operator performed all ultrasound scans. Those with <6 month follow-up and those who were taking hormonal contraception, HRT or tamoxifen were excluded from the study. The mean diameter of each polyp was calculated from the measurements in three perpendicular planes. The polyp growth rate was expressed as annual percentage change in the mean diameter. Non parametric tests and the Fisher's exact test were used to compare differences in polyp mean diameters and growth rates between women of different demographic characteristics. To correct for multiple significance testing, we used the Bonferroni method, giving the level of probability at which findings were considered significant as P < 0.0029 (as 17 tests were undertaken). MAIN RESULTS AND THE ROLE OF CHANCE: We included 112 women with endometrial polyps, which were expectantly managed over a median period of 22.5 months (range, 6-136). The annual endometrial polyp growth rate varied with a median of 1.0% (interquartile range, -6.5 to 14.3). There was no association between women's demographic characteristics or polyps' morphology and their growth rates. Eleven out of 75 (15% (95% CI, 6.9%-23.1%)) women who initially did not have abnormal uterine bleeding subsequently developed abnormal bleeding during the follow-up period. Polyp growth rate was not associated with the subsequent development of abnormal uterine bleeding (P = 0.397). Seven out of 112 (6.3% (95% CI, 1.8%-10.8%)) women had complete regression of their polyps without treatment during a median follow up period of 28 months (range, 9-56). Spontaneous regression appeared to occur more frequently in premenopausal women (P = 0.016) and in those who presented with abnormal uterine bleeding at diagnosis (P = 0.004); however, the differences did not reach statistical significance after correction for multiple comparisons. LIMITATIONS, REASONS FOR CAUTION: This study was retrospective and therefore may be prone to selection and information biases. The lack of histological confirmation on all ultrasound diagnoses may also be considered as a limitation. WIDER IMPLICATIONS OF THE FINDINGS: Women should be advised that the growth pattern of an individual polyp cannot be accurately predicted; however, a small proportion of polyps do regress spontaneously. There was no correlation between polyps' growth rate and the subsequent development of abnormal uterine bleeding. In view of that, routine monitoring of asymptomatic polyps by ultrasound is not helpful and encouraging women to report clinical symptoms is more useful in deciding whether treatment is required. In contrast to previous studies, we found that polyps may regress more frequently in premenopausal women and in those who presented with abnormal uterine bleeding; a larger sample size would give us greater power to detect a difference in these subgroups of women. STUDY FUNDING/COMPETING INTERESTS: No study funding was received and no competing interests are present. TRIAL REGISTRATION NUMBER: N/A. PMID- 27993999 TI - Natural conception: repeated predictions over time. AB - STUDY QUESTION: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility? SUMMARY ANSWER: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic. WHAT IS KNOWN ALREADY: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management. STUDY DESIGN, SIZE, DURATION: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 * 106 were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup. LIMITATIONS, REASONS FOR CAUTION: The dynamic prediction model needs to be validated in an external population. WIDER IMPLICATIONS OF THE FINDINGS: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup. STUDY FUNDING/COMPETING INTERESTS: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests. PMID- 27993998 TI - The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans. AB - Background and Aims: NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10-/- mice and humans. Methods: NLRP3 inflammasome in colonic mucosa, macrophages, and colonic epithelial cells were analysed by western blotting. The NLRP3 inflammasome components were studied by sucrose density gradient fractionation, chemical cross-linking, and co immunoprecipitation. The role of NLPR3 inflammasome in the pathogenesis of colitis was extensively evaluated in IL-10-/- mice, using a specific NLPR3 inflammasome inhibitor glyburide. Results: NLRP3 inflammasome was upregulated in colonic mucosa of both IL-10-/- mice and Crohn's patients. NLRP3 inflammasome activity in IL-10-/- mice was elevated prior to colitis onset; it progressively increased as disease worsened and peaked as macroscopic disease emerged. NLRP3 inflammasome was found in both intestinal epithelial cells and colonic macrophages, as a large complex with a molecular weight of >= 360 kDa in size. In the absence of IL-10, NLRP3 inflammasome was spontaneously active and more robustly responsive when activated by LPS and nigericin. Glyburide markedly suppressed NLRP3 inflammasome expression/activation in IL-10-/- mice, leading to not only alleviation of ongoing colitis but also prevention/delay of disease onset. Glyburide also effectively inhibited the release of proinflammatory cytokines/chemokines by mucosal explants from Crohn's patients. Conclusions: Abnormal activation of NLRP3 inflammasome plays a major pathogenic role in the development of chronic colitis in IL-10-/- mice and humans. Glyburide, an FDA approved drug, may have great potential in the management of inflammatory bowel diseases. PMID- 27994003 TI - Correction to: "A Small Molecule with Anticancer and Antimetastatic Activities Induces Rapid Mitochondrial-Associated Necrosis in Breast Cancer. PMID- 27994001 TI - Stability of the human sperm DNA methylome to folic acid fortification and short term supplementation. AB - STUDY QUESTION: Do short-term and long-term exposures to low-dose folic acid supplementation alter DNA methylation in sperm? SUMMARY ANSWER: No alterations in sperm DNA methylation patterns were found following the administration of low dose folic acid supplements of 400 MUg/day for 90 days (short-term exposure) or when pre-fortification of food with folic acid and post-fortification sperm samples (long-term exposure) were compared. WHAT IS KNOWN ALREADY: Excess dietary folate may be detrimental to health and DNA methylation profiles due to folate's role in one-carbon metabolism and the formation of S-adenosyl methionine, the universal methyl donor. DNA methylation patterns are established in developing male germ cells and have been suggested to be affected by high-dose (5 mg/day) folic acid supplementation. STUDY DESIGN, SIZE, DURATION: This is a control versus treatment study where genome-wide sperm DNA methylation patterns were examined prior to fortification of food (1996-1997) in men with no history of infertility at baseline and following 90-day exposure to placebo (n = 9) or supplement containing 400 MUg folic acid/day (n = 10). Additionally, pre fortification sperm DNA methylation profiles (n = 19) were compared with those of a group of post-fortification (post-2004) men (n = 8) who had been exposed for several years to dietary folic acid fortification. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood and seminal plasma folate levels were measured in participants before and following the 90-day treatment with placebo or supplement. Sperm DNA methylation was assessed using the whole-genome and genome wide techniques, MassArray epityper, restriction landmark genomic scanning, methyl-CpG immunoprecipitation and Illumina HumanMethylation450 Bead Array. MAIN RESULTS AND THE ROLE OF CHANCE: Following treatment, supplemented individuals had significantly higher levels of blood and seminal plasma folates compared to placebo. Initial first-generation genome-wide analyses of sperm DNA methylation showed little evidence of changes when comparing pre- and post-treatment samples. With Illumina HumanMethylation450 BeadChip arrays, no significant changes were observed in individual probes following low-level supplementation; when compared with those of the post-fortification cohort, there were also few differences in methylation despite exposure to years of fortified foods. LARGE SCALE DATA: Illumina HumanMethylation450 BeadChip data from this study have been submitted to the NCBI Gene Expression Omnibus under the accession number GSE89781. LIMITATIONS, REASONS FOR CAUTION: This study was limited to the number of participants available in each cohort, in particular those who were not exposed to early (pre-1998) fortification of food with folic acid. While genome-wide DNA methylation was assessed with several techniques that targeted genic and CpG-rich regions, intergenic regions were less well interrogated. WIDER IMPLICATIONS OF THE FINDINGS: Overall, our findings provide evidence that short-term exposure to low-dose folic acid supplements of 400 MUg/day, over a period of 3 months, a duration of time that might occur during infertility treatments, has no major impact on the sperm DNA methylome. STUDY FUNDING/COMPETING INTERESTS: This work was supported by a grant to J.M.T. from the Canadian Institutes of Health Research (CIHR: MOP-89944). The authors have no conflicts of interest to declare. PMID- 27994002 TI - Effects of Framing Proximal Benefits of Quitting and Motivation to Quit as a Query on Communications About Tobacco Constituents. AB - Introduction: Little is known on how to communicate messages on tobacco constituents to tobacco users. This study manipulated three elements of a message in the context of a theory-based communication campaign about tobacco constituents: (1) latency of response efficacy (how soon expected health benefits would accrue), (2) self-efficacy (confidence about quitting), and (3) interrogative cue ("Ready to be tobacco-free?"). Methods: Smokers (N = 1669, 55.4% women) were recruited via an online platform, and were randomized to a 3 (Latency of response efficacy) * 2 (Self-efficacy) * 2 (Interrogative cue) factorial design. The dependent variables were believability, credibility, perceived effectiveness of the communication message, and action expectancies (likelihood of seeking additional information and help with quitting). Results: Latency of response efficacy influenced believability, perceived effectiveness, credibility, and action expectancies. In each case, scores were higher when specific health benefits were said to accrue within 1 month, as compared to general health benefits occurring in a few hours. The interrogative cue had a marginal positive effect on perceived effectiveness. The self-efficacy manipulation had no reliable effects, and there were no significant interactions among conditions. Conclusions: Smokers appear less persuaded by a communication message on constituents where general health benefits accrue immediately (within a few hours) than specific benefits over a longer timeframe (1 month). Additionally, smokers appeared to be more persuaded by messages with an interrogative cue. Such findings may help design more effective communication campaigns on tobacco constituents to smokers. Implications: This paper describes, for the first time, how components of tobacco constituent messages are perceived. We now know that smokers appear to be less persuaded by communication messages where general health benefits accrue immediately (within a few hours) than specific benefits over a longer timeframe (1 month). Additionally, including an interrogative cue ("Ready to be tobacco free?") may make messages more effective, whereas the self-efficacy manipulation designed to increase confidence about quitting had no effect. While messages were universally impactful across smoker subpopulations, everyday smokers and smokers with less trust in the government may be less receptive to communication campaigns. PMID- 27994004 TI - Biological Aging and the Future of Geriatric Psychiatry. AB - Advances in understanding the biological bases of aging have intellectually revitalized the field of geriatric psychiatry and broadened its scope to include promoting successful aging and studying resilience factors in older adults. To describe the process by which this paradigm shift has occurred and illustrate its implications for treatment and research of late-life brain disorders, late-life depression is discussed as a prototype case. Prior phases of geriatric psychiatry research were focused on achieving depressive symptom relief, outlining pharmacokinetic and pharmacodynamic differences between older and younger adults, and identifying moderators of treatment response. Building on this work, current geriatric psychiatry researchers have begun to disentangle the etiologic complexity in late-life depression by focusing on the causative aging-related processes involved, identifying both neurobiological and behavioral intermediates, and finally delineating depression subtypes that are distinguishable by their underlying biology and the treatment approach required. In this review, we discuss several age-related processes that are critical to the development of late-life mood disorders, outline implications of these processes for the clinical evaluation and management of later-life psychiatric disorders, and finally put forth suggestions for better integrating aging and developmental processes into the National Institute of Mental Health's Research Domain Criteria. PMID- 27994005 TI - Associations of Brain Structure With Adiposity and Changes in Adiposity in a Middle-Aged and Older Biracial Population. AB - Background: Studies of adiposity and brain pathology in African Americans (AA) are sparse despite higher rates of obesity, dementia, and dementia-associated brain pathology in AA. This study examined relations of adiposity to white matter hyperintensities (WMH) and total brain volume (TBV) in AA and non-Hispanic whites (NHW). Methods: Waist circumference (WC) and body mass index (BMI) were measured in the Genetic Epidemiology Network of Arteriopathy study at Visits 1 (mean age 57 [+/-11]) and 2 (mean age 61 [+/-10], mean 5.2 years later). Brain MRIs were obtained shortly after Visit 2 in 1,702 participants (64% women, 48% AA). Multilevel linear regression using generalized estimating equation estimated associations of adiposity (cross-sectional) or adiposity changes with WMH (accounting for intracranial size) or TBV adjusting for demographics, cardiovascular risk factors, and incorporating adiposity-by-race interactions. Adiposity-by-age interactions were examined. Results: Concurrent TBV was inversely associated with BMI (beta = -2.76 [95% confidence interval (CI): -4.99, -0.53]) and WC (beta = -2.19 [CI: -4.04, -0.34]). Concurrent WMH were negatively associated with BMI (beta = -0.04 [CI: -0.06, -0.01]) and, among NHW, with WC (beta = -0.04 [CI: -0.06, -0.02]) but not with changes in BMI or WC. BMI increases were associated with lower TBV (beta = -16.20, [CI: -30.34, -2.06]) in AA but not in NHW (beta = -2.76 [CI: -14.02, 8.51]), although race-by-adiposity interactions were not supported. WC increases were not associated with MRI outcomes. Conclusion: Greater measures of obesity and increases in measures of obesity, which are common in mid-life, could be detrimental to brain health, particularly in AA. PMID- 27994006 TI - Attenuation of Cocaine-Induced Conditioned Place Preference and Motor Activity via Cannabinoid CB2 Receptor Agonism and CB1 Receptor Antagonism in Rats. AB - Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine's reinforcing and psychomotor effects. PMID- 27994008 TI - Mesothelial inclusion cyst: a rare occurrence. AB - Mesothelial inclusion cyst is a rare benign tumour that has only 130 cases reported in the literature. Accurate diagnosis and optimal management of this condition remains uncertain. We report a 51-year-old African gentleman, whom presents with abdominal pain and constipation. A computed tomography scan was performed and revealed a large cystic lesion in the right paracolic gutter. The differential diagnosis included appendiceal mucinous neoplasm, cystic tuberculosis and duplication cyst. A laparotomy was performed due to his symptoms and size of the cyst. Macroscopically, the tumour had a size of 25 * 10 * 10 cm and revealed a necrotic lymph node. It was resected en bloc with the appendix and an ileocolic anastomosis performed. Histology revealed a diagnosis of mesothelial inclusion cyst and acute appendicitis. The patient recovered well and had no recurrence at 2-year follow-up. PMID- 27994009 TI - Stent graft repair of anastomotic pseudoaneurysm of femoral-popliteal bypass graft following patch angioplasty. AB - Pseudoaneurysm (PA) following vascular reconstruction is a complication of bypass surgery. Historically, the mainstay of treatment was an open repair; the surgical management consisted of resection of the initial graft with reimplantation of a new bypass either into the original arteriotomy or to a more distal target. Placement of a stent graft to exclude the PA is a viable option. We present a case of an 85-year-old man with prior history of polytetrafluoroethylene femoral popliteal bypass now with an 8 * 5.6 cm PA of the distal anastomosis site treated with endovascular placement of a Viabahn stent. PMID- 27994010 TI - Successful surgical excision of a massive symptomatic partially obstructing Brunner's gland hamartoma: a case report. AB - Brunner gland function within the duodenal epithelium is secretion of alkaline mucin to counteract acidic chyme. These glands may grow beyond the duodenal wall to become hamartomas. Rarely, they become large enough to cause obstructive symptoms in the upper gastrointestinal tract. We report a case of one of the largest lesions identified in the literature causing obstruction symptoms. A previously asymptomatic 65-year-old gentleman presented to the emergency department with a single-day history of colicky abdominal pain, cramping and vomiting. After initial imaging with computed tomography was inconclusive, a subsequent esophagogastroduodenoscopy with biopsy and small bowel series was performed indicating a pedunculated polypoid mass. Our patient underwent an uncomplicated exploratory laparotomy with duodenotomy and Heineke-Mikulicz pyloroplasty for resection of a massive Brunner's gland hamartoma. For similar presentations, we recommend this technique. PMID- 27994007 TI - Connecting the Molecular Structure of Cutin to Ultrastructure and Physical Properties of the Cuticle in Petals of Arabidopsis. AB - The plant cuticle is laid down at the cell wall surface of epidermal cells in a wide variety of structures, but the functional significance of this architectural diversity is not yet understood. Here, the structure-function relationship of the petal cuticle of Arabidopsis (Arabidopsis thaliana) was investigated. Applying Fourier transform infrared microspectroscopy, the cutin mutants long-chain acyl coenzyme A synthetase2 (lacs2), permeable cuticle1 (pec1), cyp77a6, glycerol-3 phosphate acyltransferase6 (gpat6), and defective in cuticular ridges (dcr) were grouped in three separate classes based on quantitative differences in the nu(C=O) and nu(C-H) band vibrations. These were associated mainly with the quantity of 10,16-dihydroxy hexadecanoic acid, a monomer of the cuticle polyester, cutin. These spectral features were linked to three different types of cuticle organization: a normal cuticle with nanoridges (lacs2 and pec1 mutants); a broad translucent cuticle (cyp77a6 and dcr mutants); and an electron-opaque multilayered cuticle (gpat6 mutant). The latter two types did not have typical nanoridges. Transmission electron microscopy revealed considerable variations in cuticle thickness in the dcr mutant. Different double mutant combinations showed that a low amount of C16 monomers in cutin leads to the appearance of an electron translucent layer adjacent to the cuticle proper, which is independent of DCR action. We concluded that DCR is not only essential for incorporating 10,16 dihydroxy C16:0 into cutin but also plays a crucial role in the organization of the cuticle, independent of cutin composition. Further characterization of the mutant petals suggested that nanoridge formation and conical cell shape may contribute to the reduction of physical adhesion forces between petals and other floral organs during floral development. PMID- 27994011 TI - Role of Cwc24 in the First Catalytic Step of Splicing and Fidelity of 5' Splice Site Selection. AB - Cwc24 is an essential splicing factor but only transiently associates with the spliceosome, with an unknown function. The protein contains a RING finger and a zinc finger domain in the carboxyl terminus. The human ortholog of Cwc24, RNF113A, has been associated with the disorder trichothiodystrophy. Here, we show that the zinc finger domain is essential for Cwc24 function, while the RING finger domain is dispensable. Cwc24 binds to the spliceosome after the Prp19 associated complex and is released upon Prp2 action. Cwc24 is not required for Prp2-mediated remodeling of the spliceosome, but the spliceosome becomes inactive if remodeling occurs before the addition of Cwc24. Cwc24 binds directly to pre mRNA at the 5' splice site, spanning the splice junction. In the absence of Cwc24, U5 and U6 modes of interaction with the 5' splice site are altered, and splicing is very inefficient, with aberrant cleavage at the 5' splice site. Our data suggest roles for Cwc24 in orchestrating organization of the spliceosome into an active configuration prior to Prp2-mediated spliceosome remodeling and in promoting specific interaction of U5 and U6 with the 5' splice site for fidelity of 5' splice site selection. PMID- 27994012 TI - Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans. AB - Protein arginine methyltransferase 1 (PRMT-1) catalyzes asymmetric arginine dimethylation on cellular proteins and modulates various aspects of biological processes, such as signal transduction, DNA repair, and transcriptional regulation. We have previously reported that the null mutant of prmt-1 in Caenorhabditis elegans exhibits a slightly shortened life span, but the physiological significance of PRMT-1 remains largely unclear. Here we explored the role of PRMT-1 in mitochondrial function as hinted by a two-dimensional Western blot-based proteomic study. Subcellular fractionation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that PRMT-1 is almost entirely responsible for asymmetric arginine dimethylation on mitochondrial proteins. Importantly, isolated mitochondria from prmt-1 mutants represent compromised ATP synthesis in vitro, and whole-worm respiration in prmt 1 mutants is decreased in vivo Transgenic rescue experiments demonstrate that PRMT-1-dependent asymmetric arginine dimethylation is required to prevent mitochondrial reactive oxygen species (ROS) production, which consequently causes the activation of the mitochondrial unfolded-protein response. Furthermore, the loss of enzymatic activity of prmt-1 induces food avoidance behavior due to mitochondrial dysfunction, but treatment with the antioxidant N-acetylcysteine significantly ameliorates this phenotype. These findings add a new layer of complexity to the posttranslational regulation of mitochondrial function and provide clues for understanding the physiological roles of PRMT-1 in multicellular organisms. PMID- 27994013 TI - Role of Tim17 Transmembrane Regions in Regulating the Architecture of Presequence Translocase and Mitochondrial DNA Stability. AB - Mitochondrial life cycle and protein import are intricate cellular processes, which require precise coordination between the transport machineries of outer and inner mitochondrial membranes. Presequence translocase performs the indispensable function of translocating preproteins having N-terminal targeting sequences across the inner membrane. Tim23 forms the core of the voltage-gated import channel, while Tim17 is presumed to maintain the stoichiometry of the translocase. However, mechanistic insights into how Tim17 coordinates these regulatory events within the complex remained elusive. We demonstrate that Tim17 harbors conserved G/AXXXG/A motifs within its transmembrane regions and plays an imperative role in the translocase assembly through interaction with Tim23. Tandem motifs are highly essential, as most of the amino acid substitutions lead to nonviability due to the complete destabilization of the TIM23 channel. Importantly, Tim17 transmembrane regions regulate the dynamic assembly of translocase to form either the TIM23 (PAM)-complex or TIM23 (SORT)-complex by recruiting the presequence translocase-associated motor (PAM) machinery or Tim21, respectively. To a greater significance, tim17 mutants displayed mitochondrial DNA (mtDNA) instability, membrane potential loss, and defective import, resulting in organellar dysfunction. We conclude that the integrity of Tim17 transmembrane regions is critical for mitochondrial function and protein turnover. PMID- 27994014 TI - Human Apurinic/Apyrimidinic Endonuclease (APE1) Is Acetylated at DNA Damage Sites in Chromatin, and Acetylation Modulates Its DNA Repair Activity. AB - Apurinic/apyrimidinic (AP) sites, the most frequently formed DNA lesions in the genome, inhibit transcription and block replication. The primary enzyme that repairs AP sites in mammalian cells is the AP endonuclease (APE1), which functions through the base excision repair (BER) pathway. Although the mechanism by which APE1 repairs AP sites in vitro has been extensively investigated, it is largely unknown how APE1 repairs AP sites in cells. Here, we show that APE1 is acetylated (AcAPE1) after binding to the AP sites in chromatin and that AcAPE1 is exclusively present on chromatin throughout the cell cycle. Positive charges of acetylable lysine residues in the N-terminal domain of APE1 are essential for chromatin association. Acetylation-mediated neutralization of the positive charges of the lysine residues in the N-terminal domain of APE1 induces a conformational change; this in turn enhances the AP endonuclease activity of APE1. In the absence of APE1 acetylation, cells accumulated AP sites in the genome and showed higher sensitivity to DNA-damaging agents. Thus, mammalian cells, unlike Saccharomyces cerevisiae or Escherichia coli cells, require acetylation of APE1 for the efficient repair of AP sites and base damage in the genome. Our study reveals that APE1 acetylation is an integral part of the BER pathway for maintaining genomic integrity. PMID- 27994018 TI - Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria. AB - Brucella abortus sigmaE1 is an EcfG family sigma factor that regulates the transcription of dozens of genes in response to diverse stress conditions and is required for maintenance of chronic infection in a mouse model. A putative ATP binding cassette transporter operon, bab1_0223-bab1_0226, is among the most highly activated gene sets in the sigmaE1 regulon. The proteins encoded by the operon resemble quaternary ammonium-compatible solute importers but are most similar in sequence to the broadly conserved YehZYXW system, which remains largely uncharacterized. Transcription of yehZYXW is activated by the general stress sigma factor sigmaS in Enterobacteriaceae, which suggests a functional role for this transport system in bacterial stress response across the classes Alphaproteobacteria and Gammaproteobacteria We present evidence that B. abortus YehZYXW does not function as an importer of known compatible solutes under physiological conditions and does not contribute to the virulence defect of a sigmaE1-null strain. The sole in vitro phenotype associated with genetic disruption of this putative transport system is reduced growth in the presence of high Li+ ion concentrations. A crystal structure of B. abortus YehZ revealed a class II periplasmic binding protein fold with significant structural homology to Archaeoglobus fulgidus ProX, which binds glycine betaine. However, the structure of the YehZ ligand-binding pocket is incompatible with high-affinity binding to glycine betaine. This is consistent with weak measured binding of YehZ to glycine betaine and related compatible solutes. We conclude that YehZYXW is a conserved, stress-regulated transport system that is phylogenetically and functionally distinct from quaternary ammonium-compatible solute importers.IMPORTANCEBrucella abortus sigmaE1 regulates transcription in response to stressors encountered in its mammalian host and is necessary for maintenance of chronic infection in a mouse model. The functions of the majority of genes regulated by sigmaE1 remain undefined. We present a functional/structural analysis of a conserved putative membrane transport system (YehZYXW) whose expression is strongly activated by sigmaE1 Though annotated as a quaternary ammonium osmolyte uptake system, experimental physiological studies and measured ligand-binding properties of the periplasmic binding protein (PBP), YehZ, are inconsistent with this function. A crystal structure of B. abortus YehZ provides molecular insight into differences between bona fide quaternary ammonium osmolyte importers and YehZ-related proteins, which form a distinct phylogenetic and functional group of PBPs. PMID- 27994021 TI - Stop Randomizing All Cardiac Arrests. PMID- 27994017 TI - Legionella pneumophila OxyR Is a Redundant Transcriptional Regulator That Contributes to Expression Control of the Two-Component CpxRA System. AB - Nominally an environmental organism, Legionella pneumophila is an intracellular parasite of protozoa but is also the causative agent of the pneumonia termed Legionnaires' disease, which results from inhalation of aerosolized bacteria by susceptible humans. Coordination of gene expression by a number of identified regulatory factors, including OxyR, assists L. pneumophila in adapting to the stresses of changing environments. L. pneumophila OxyR (OxyRLp) is an ortholog of Escherichia coli OxyR; however, OxyRLp was shown elsewhere to be functionally divergent, such that it acts as a transcription regulator independently of the oxidative stress response. In this study, the use of improved gene deletion methods has enabled us to generate an unmarked in-frame deletion of oxyR in L. pneumophila Lack of OxyRLp did not affect in vitro growth or intracellular growth in Acanthamoeba castellanii protozoa and U937-derived macrophages. The expression of OxyRLp does not appear to be regulated by CpxR, even though purified recombinant CpxR bound a DNA sequence similar to that reported for CpxR elsewhere. Surprisingly, a lack of OxyRLp resulted in elevated activity of the promoters located upstream of icmR and the lpg1441-cpxA operon, and OxyRLp directly bound to these promoter regions, suggesting that OxyRLp is a direct repressor. Interestingly, a strain overexpressing OxyRLp demonstrated reduced intracellular growth in A. castellanii but not in U937-derived macrophages, suggesting that balanced expression control of the two-component CpxRA system is necessary for survival in protozoa. Taken together, this study suggests that OxyRLp is a functionally redundant transcriptional regulator in L. pneumophila under the conditions evaluated herein.IMPORTANCELegionella pneumophila is an environmental pathogen, with its transmission to the human host dependent upon its ability to replicate in protozoa and survive within its aquatic niche. Understanding the genetic factors that contribute to L. pneumophila survival within each of these unique environments will be key to limiting future point source outbreaks of Legionnaires' disease. The transcriptional regulator L. pneumophila OxyR (OxyRLp) has been previously identified as a potential regulator of virulence traits warranting further investigation. This study demonstrated that oxyR is nonessential for L. pneumophila survival in vitro and in vivo via mutational analysis. While the mechanisms of how OxyRLp expression is regulated remain elusive, this study shows that OxyRLp negatively regulates the expression of the cpxRA two-component system necessary for intracellular survival in protozoa. PMID- 27994020 TI - Resuscitation Science in Circulation: A Timely Topic. PMID- 27994019 TI - Quorum Sensing in a Methane-Oxidizing Bacterium. AB - Aerobic methanotrophic bacteria use methane as their sole source of carbon and energy and serve as a major sink for the potent greenhouse gas methane in freshwater ecosystems. Dissecting the molecular details of how these organisms interact in the environment may increase our understanding of how they perform this important ecological role. Many bacterial species use quorum sensing (QS) systems to regulate gene expression in a cell density-dependent manner. We have identified a QS system in the genome of Methylobacter tundripaludum, a dominant methane oxidizer in methane enrichments of sediment from Lake Washington (Seattle, WA). We determined that M. tundripaludum produces primarily N-3 hydroxydecanoyl-l-homoserine lactone (3-OH-C10-HSL) and that its production is governed by a positive feedback loop. We then further characterized this system by determining which genes are regulated by QS in this methane oxidizer using transcriptome sequencing (RNA-seq) and discovered that this system regulates the expression of a putative nonribosomal peptide synthetase biosynthetic gene cluster. Finally, we detected an extracellular factor that is produced by M. tundripaludum in a QS-dependent manner. These results identify and characterize a mode of cellular communication in an aerobic methane-oxidizing bacterium.IMPORTANCE Aerobic methanotrophs are critical for sequestering carbon from the potent greenhouse gas methane in the environment, yet the mechanistic details of chemical interactions in methane-oxidizing bacterial communities are not well understood. Understanding these interactions is important in order to maintain, and potentially optimize, the functional potential of the bacteria that perform this vital ecosystem function. In this work, we identify a quorum sensing system in the aerobic methanotroph Methylobacter tundripaludum and use both chemical and genetic methods to characterize this system at the molecular level. PMID- 27994022 TI - Doubling Cardiac Arrest Survival by 2020: Achieving the American Heart Association Impact Goal. PMID- 27994023 TI - Improving Care of Out-of-Hospital Cardiac Arrest: Next Steps. PMID- 27994024 TI - Measured Progress in Cardiopulmonary Resuscitation. PMID- 27994025 TI - Is It Time to Stop Teaching Bystanders Ventilation as Part of Pediatric Cardiopulmonary Resuscitation? PMID- 27994026 TI - Factors Associated With Pulmonary Embolism-Related Sudden Cardiac Arrest. PMID- 27994027 TI - Ticagrelor Versus Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest Undergoing Percutaneous Coronary Intervention and Hypothermia: A Randomized Study. PMID- 27994028 TI - Association of Mechanical Cardiopulmonary Resuscitation Device Use With Cardiac Arrest Outcomes: A Population-Based Study Using the CARES Registry (Cardiac Arrest Registry to Enhance Survival). PMID- 27994029 TI - Applicability of a computational design approach for synthetic riboswitches. AB - Riboswitches have gained attention as tools for synthetic biology, since they enable researchers to reprogram cells to sense and respond to exogenous molecules. In vitro evolutionary approaches produced numerous RNA aptamers that bind such small ligands, but their conversion into functional riboswitches remains difficult. We previously developed a computational approach for the design of synthetic theophylline riboswitches based on secondary structure prediction. These riboswitches have been constructed to regulate ligand-dependent transcription termination in Escherichia coli. Here, we test the usability of this design strategy by applying the approach to tetracycline and streptomycin aptamers. The resulting tetracycline riboswitches exhibit robust regulatory properties in vivo. Tandem fusions of these riboswitches with theophylline riboswitches represent logic gates responding to two different input signals. In contrast, the conversion of the streptomycin aptamer into functional riboswitches appears to be difficult. Investigations of the underlying aptamer secondary structure revealed differences between in silico prediction and structure probing. We conclude that only aptamers adopting the minimal free energy (MFE) structure are suitable targets for construction of synthetic riboswitches with design approaches based on equilibrium thermodynamics of RNA structures. Further improvements in the design strategy are required to implement aptamer structures not corresponding to the calculated MFE state. PMID- 27994030 TI - Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control. AB - SLM2 and Sam68 are splicing regulator paralogs that usually overlap in function, yet only SLM2 and not Sam68 controls the Neurexin2 AS4 exon important for brain function. Herein we find that SLM2 and Sam68 similarly bind to Neurexin2 pre mRNA, both within the mouse cortex and in vitro. Protein domain-swap experiments identify a region including the STAR domain that differentiates SLM2 and Sam68 activity in splicing target selection, and confirm that this is not established via the variant amino acids involved in RNA contact. However, far fewer SLM2 and Sam68 RNA binding sites flank the Neurexin2 AS4 exon, compared with those flanking the Neurexin1 and Neurexin3 AS4 exons under joint control by both Sam68 and SLM2. Doubling binding site numbers switched paralog sensitivity, by placing the Neurexin2 AS4 exon under joint splicing control by both Sam68 and SLM2. Our data support a model where the density of shared RNA binding sites around a target exon, rather than different paralog-specific protein-RNA binding sites, controls functional target specificity between SLM2 and Sam68 on the Neurexin2 AS4 exon. Similar models might explain differential control by other splicing regulators within families of paralogs with indistinguishable RNA binding sites. PMID- 27994031 TI - Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer. AB - Clustering is used widely in 'omics' studies and is often tackled with standard methods, e.g. hierarchical clustering. However, the increasing need for integration of multiple data sets leads to a requirement for clustering methods applicable to mixed data types, where the straightforward application of standard methods is not necessarily the best approach. A particularly common problem involves clustering entities characterized by a mixture of binary data (e.g. presence/absence of mutations, binding, motifs and epigenetic marks) and continuous data (e.g. gene expression, protein abundance, metabolite levels). Here, we present a generic method based on a probabilistic model for clustering this type of data, and illustrate its application to genetic regulation and the clustering of cancer samples. We show that the resulting clusters lead to useful hypotheses: in the case of genetic regulation these concern regulation of groups of genes by specific sets of transcription factors and in the case of cancer samples combinations of gene mutations are related to patterns of gene expression. The clusters have potential mechanistic significance and in the latter case are significantly linked to survival. The method is available as a stand-alone software package (GNU General Public Licence) from http://github.com/BioToolsLeeds/FlexiCoClusteringPackage.git. PMID- 27994032 TI - Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition. AB - Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA through EVs has been extensively studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by a recipient cell remains to be determined. Here, we identify the ex-miRNA-directed phenotype to be transient due to the rapid decay of ex-miRNA. We demonstrate that the ex-miR-223 3p transferred from polymorphonuclear leukocytes to cancer cells were functional, as demonstrated by the decreased expression of its target FOXO1 and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within 8 h. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. In conclusion, we showed that the 'steady step' level of engulfed miRNA and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNA. PMID- 27994034 TI - Ribonucleotide incorporation by human DNA polymerase eta impacts translesion synthesis and RNase H2 activity. AB - Ribonucleotides (rNs) incorporated in the genome by DNA polymerases (Pols) are removed by RNase H2. Cytidine and guanosine preferentially accumulate over the other rNs. Here we show that human Pol eta can incorporate cytidine monophosphate (rCMP) opposite guanine, 8-oxo-7,8-dihydroguanine, 8-methyl-2?-deoxyguanosine and a cisplatin intrastrand guanine crosslink (cis-PtGG), while it cannot bypass a 3 methylcytidine or an abasic site with rNs as substrates. Pol eta is also capable of synthesizing polyribonucleotide chains, and its activity is enhanced by its auxiliary factor DNA Pol delta interacting protein 2 (PolDIP2). Human RNase H2 removes cytidine and guanosine less efficiently than the other rNs and incorporation of rCMP opposite DNA lesions further reduces the efficiency of RNase H2. Experiments with XP-V cell extracts indicate Pol eta as the major basis of rCMP incorporation opposite cis-PtGG. These results suggest that translesion synthesis by Pol eta can contribute to the accumulation of rCMP in the genome, particularly opposite modified guanines. PMID- 27994033 TI - Extreme mutation bias and high AT content in Plasmodium falciparum. AB - For reasons that remain unknown, the Plasmodium falciparum genome has an exceptionally high AT content compared to other Plasmodium species and eukaryotes in general - nearly 80% in coding regions and approaching 90% in non-coding regions. Here, we examine how this phenomenon relates to genome-wide patterns of de novo mutation. Mutation accumulation experiments were performed by sequential cloning of six P. falciparum isolates growing in human erythrocytes in vitro for 4 years, with 279 clones sampled for whole genome sequencing at different time points. Genome sequence analysis of these samples revealed a significant excess of G:C to A:T transitions compared to other types of nucleotide substitution, which would naturally cause AT content to equilibrate close to the level seen across the P. falciparum reference genome (80.6% AT). These data also uncover an extremely high rate of small indel mutation relative to other species, primarily associated with repetitive AT-rich sequences, in addition to larger-scale structural rearrangements focused in antigen-coding var genes. In conclusion, high AT content in P. falciparum is driven by a systematic mutational bias and ultimately leads to an unusual level of microstructural plasticity, raising the question of whether this contributes to adaptive evolution. PMID- 27994035 TI - Arabidopsis SWI/SNF chromatin remodeling complex binds both promoters and terminators to regulate gene expression. AB - ATP-dependent chromatin remodeling complexes are important regulators of gene expression in Eukaryotes. In plants, SWI/SNF-type complexes have been shown critical for transcriptional control of key developmental processes, growth and stress responses. To gain insight into mechanisms underlying these roles, we performed whole genome mapping of the SWI/SNF catalytic subunit BRM in Arabidopsis thaliana, combined with transcript profiling experiments. Our data show that BRM occupies thousands of sites in Arabidopsis genome, most of which located within or close to genes. Among identified direct BRM transcriptional targets almost equal numbers were up- and downregulated upon BRM depletion, suggesting that BRM can act as both activator and repressor of gene expression. Interestingly, in addition to genes showing canonical pattern of BRM enrichment near transcription start site, many other genes showed a transcription termination site-centred BRM occupancy profile. We found that BRM-bound 3? gene regions have promoter-like features, including presence of TATA boxes and high H3K4me3 levels, and possess high antisense transcriptional activity which is subjected to both activation and repression by SWI/SNF complex. Our data suggest that binding to gene terminators and controlling transcription of non-coding RNAs is another way through which SWI/SNF complex regulates expression of its targets. PMID- 27994036 TI - Microhomology-mediated end joining is activated in irradiated human cells due to phosphorylation-dependent formation of the XRCC1 repair complex. AB - Microhomology-mediated end joining (MMEJ), an error-prone pathway for DNA double strand break (DSB) repair, is implicated in genomic rearrangement and oncogenic transformation; however, its contribution to repair of radiation-induced DSBs has not been characterized. We used recircularization of a linearized plasmid with 3? P-blocked termini, mimicking those at X-ray-induced strand breaks, to recapitulate DSB repair via MMEJ or nonhomologous end-joining (NHEJ). Sequence analysis of the circularized plasmids allowed measurement of relative activity of MMEJ versus NHEJ. While we predictably observed NHEJ to be the predominant pathway for DSB repair in our assay, MMEJ was significantly enhanced in preirradiated cells, independent of their radiation-induced arrest in the G2/M phase. MMEJ activation was dependent on XRCC1 phosphorylation by casein kinase 2 (CK2), enhancing XRCC1's interaction with the end resection enzymes MRE11 and CtIP. Both endonuclease and exonuclease activities of MRE11 were required for MMEJ, as has been observed for homology-directed DSB repair (HDR). Furthermore, the XRCC1 co-immunoprecipitate complex (IP) displayed MMEJ activity in vitro, which was significantly elevated after irradiation. Our studies thus suggest that radiation-mediated enhancement of MMEJ in cells surviving radiation therapy may contribute to their radioresistance and could be therapeutically targeted. PMID- 27994038 TI - Inducible super-enhancers are organized based on canonical signal-specific transcription factor binding elements. AB - Super-enhancers are established through the interactions of several enhancers and a large number of proteins, including transcription factors and co-regulators; however, the formation of these interactions is poorly understood. By re analysing previously published estrogen receptor alpha (ERalpha) ChIP-seq data sets derived from the MCF-7 cell line, we observed that in the absence of stimulation, future super-enhancers are represented by one or a few transcription factor binding event(s) and these extraordinary enhancers possess a response element largely specific to the ERalpha dimer. Upon hormonal stimulation, these primary binding sites are surrounded by a large amount of ERalpha and the critical components of active enhancers, such as P300 and MED1, and together with neighbouring sites bound by newly recruited ERalpha, they generate the functional super-enhancers. To further validate the role of canonical elements in super enhancer formation, we investigated some additional signal-dependent transcription factors, confirming that certain, distinguished binding elements have a general organizer function. These results suggest that certain signal specific transcription factors guide super-enhancer formation upon binding to strong response elements. These findings may reshape the current understanding of how these regulatory units assemble, highlighting the involvement of DNA elements instead of protein-protein interactions. PMID- 27994040 TI - Association between adherence to the Mediterranean diet and semen quality parameters in male partners of couples attempting fertility. AB - STUDY QUESTION: Is adherence to the Mediterranean diet (MedDiet) associated with better semen quality in men of subfertile couples attempting fertility? SUMMARY ANSWER: Greater adherence to the MedDiet, as assessed through the validated Mediterranean diet score (MedDietScore), was significantly associated with higher sperm concentration, total sperm count and sperm motility. WHAT IS KNOWN ALREADY: A-posteriori dietary pattern approaches have revealed that dietary patterns characterized by high intakes of fruits, vegetables, whole grains, fish and low intake of meat are associated with better semen quality. Yet, whether adherence to the MedDiet is associated with better semen profile remains largely unexplored. STUDY DESIGN, SIZE, AND DURATION: This was a cross-sectional study of 225 men from couples attending a fertility clinic in Athens, Greece, recruited between November 2013 and May 2016. The study was designed to evaluate the influence of habitual dietary intake and lifestyle on fertility outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 26-55 years, 51.1% overweight or obese, 20.9% smokers, with complete dietary data were analyzed. Diet was assessed via a food-frequency questionnaire and adherence to the MedDiet was assessed through the MedDietScore (range: 0-55; higher scores indicating greater adherence to MedDiet). Semen quality was evaluated according to World Health Organization 2010 guidelines. Multiple logistic regression analysis was used to evaluate associations between tertiles of the MedDietScore and the likelihood of having abnormal semen parameters, after adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to men in the highest tertile of the MedDietScore (>=37, N = 66), a higher percentage of men in the lowest tertile of the score (<=30, N = 76) exhibited below the WHO reference values for sperm concentration (47.4% vs 16.7%, P < 0.001), total sperm count (55.3% vs 22.7%, P < 0.001), total motility (65.8% vs 31.8%, P < 0.001), progressive motility (84.2 vs 62.1%, P = 0.011) and sperm morphology (50.0 vs 28.8%, P = 0.023). In the multivariable adjusted models, men in the lowest tertile of the MedDietScore had ~2.6 times higher likelihood of having abnormal sperm concentration, total sperm count and motility, compared to men in the highest tertile of the score. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study stems from its cross-sectional nature, limiting our ability to determine causality. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that greater compliance to the MedDiet may help improve semen quality. Whether this translates into differences in male fertility remains to be elucidated. Our findings are consistent with previous studies showing that dietary patterns with some of the characteristics of the MedDiet, i.e. rich in fruit, vegetables, legumes and whole grains, are associated with better measures of semen quality. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a. PMID- 27994037 TI - Destabilization of the PCNA trimer mediated by its interaction with the NEIL1 DNA glycosylase. AB - The base excision repair (BER) pathway repairs oxidized lesions in the DNA that result from reactive oxygen species generated in cells. If left unrepaired, these damaged DNA bases can disrupt cellular processes such as replication. NEIL1 is one of the 11 human DNA glycosylases that catalyze the first step of the BER pathway, i.e. recognition and excision of DNA lesions. NEIL1 interacts with essential replication proteins such as the ring-shaped homotrimeric proliferating cellular nuclear antigen (PCNA). We isolated a complex formed between NEIL1 and PCNA (+/-DNA) using size exclusion chromatography (SEC). This interaction was confirmed using native gel electrophoresis and mass spectrometry. Stokes radii measured by SEC hinted that PCNA in complex with NEIL1 (+/-DNA) was no longer a trimer. Height measurements and images obtained by atomic force microscopy also demonstrated the dissociation of the PCNA homotrimer in the presence of NEIL1 and DNA, while small-angle X-ray scattering analysis confirmed the NEIL1 mediated PCNA trimer dissociation and formation of a 1:1:1 NEIL1-DNA-PCNA(monomer) complex. Furthermore, ab initio shape reconstruction provides insights into the solution structure of this previously unreported complex. Together, these data point to a potential mechanistic switch between replication and BER. PMID- 27994042 TI - Male bumblebees perform learning flights on leaving a flower but not when leaving their nest. AB - Female bees and wasps demonstrate, through their performance of elaborate learning flights, when and where they memorise features of a significant site. An important feature of these flights is that the insects look back to fixate the site that they are leaving. Females, which forage for nectar and pollen and return with it to the nest, execute learning flights on their initial departure from both their nest and newly discovered flowers. To our knowledge, these flights have so far only been studied in females. Here, we describe and analyse putative learning flights observed in male bumblebees Bombus terrestris L. Once male bumblebees are mature, they leave their nest for good and fend for themselves. We show that, unlike female foragers, males always fly directly away from their nest, without looking back, in keeping with their indifference to their natal nest. In contrast, after males have drunk from artificial flowers, their flights on first leaving the flowers resemble the learning flights of females, particularly in their fixation of the flowers. These differences in the occurrence of female and male learning flights seem to match the diverse needs of the two sexes to learn about disparate, ecologically relevant places in their surroundings. PMID- 27994041 TI - Non-genetic diversity modulates population performance. AB - Biological functions are typically performed by groups of cells that express predominantly the same genes, yet display a continuum of phenotypes. While it is known how one genotype can generate such non-genetic diversity, it remains unclear how different phenotypes contribute to the performance of biological function at the population level. We developed a microfluidic device to simultaneously measure the phenotype and chemotactic performance of tens of thousands of individual, freely swimming Escherichia coli as they climbed a gradient of attractant. We discovered that spatial structure spontaneously emerged from initially well-mixed wild-type populations due to non-genetic diversity. By manipulating the expression of key chemotaxis proteins, we established a causal relationship between protein expression, non-genetic diversity, and performance that was theoretically predicted. This approach generated a complete phenotype-to-performance map, in which we found a nonlinear regime. We used this map to demonstrate how changing the shape of a phenotypic distribution can have as large of an effect on collective performance as changing the mean phenotype, suggesting that selection could act on both during the process of adaptation. PMID- 27994043 TI - Onset of fights and mutual assessment in ant founding queens. AB - In animals, the progress and outcome of contests can be influenced by an individual's own condition, their opponent's condition or a combination of the two. The use of chemical information to assess the quality of rivals has been underestimated despite its central role in the regulation of social interactions in many taxa. Here, we studied pairwise contests between founding queens of the ant Lasius niger to investigate whether the decision to engage in agonistic interactions relies on self-assessment or mutual assessment. Queens modulated their aggressive behaviours depending on both their own status and their opponent's status. We found no influence of lipid stores or size on the onset of fights. However, differences in cuticular chemical signatures linked to fertility status accurately predicted the probability of behaving aggressively in pairs. Our study thus suggests that ant queens could rely on mutual assessment via chemical cues to make informed decisions about fight initiation. PMID- 27994044 TI - Both thyroid hormone levels and resting metabolic rate decrease in African striped mice when food availability decreases. AB - In response to variation in food availability and ambient temperature (Ta), many animals show seasonal adaptations in their physiology. Laboratory studies showed that thyroid hormones are involved in the regulation of metabolism, and their regulatory function is especially important when the energy balance of an individual is compromised. However, little is known about the relationship between thyroid hormones and metabolism in free-living animals and animals inhabiting seasonal environments. Here, we studied seasonal changes in triiodothyronine (T3) levels, resting metabolic rate (RMR) and two physiological markers of energy balance (blood glucose and ketone bodies) in 61 free-living African striped mice (Rhabdomys pumilio) that live in an semi-arid environment with food shortage during the dry season. We predicted a positive relationship between T3 levels and RMR. Further, we predicted higher T3 levels, blood glucose levels and RMR, but lower ketone body concentrations, during the moist season when food availability is high compared with summer when food availability is low. RMR and T3 levels were negatively related in the moist season but not in the dry season. Both RMR and T3 levels were higher in the moist than in the dry season, and T3 levels increased with increasing food availability. In the dry season, blood glucose levels were lower but ketone body concentrations were higher, indicating a change in substrate use. Seasonal adjustments in RMR and T3 levels permit a reduction of energy expenditure when food is scarce, and reflect an adaptive response to reduced food availability in the dry season. PMID- 27994046 TI - Frances Gage. Painting as Medicine in Early Modern Rome: Giulio Mancini and the Efficacy of Art. PMID- 27994045 TI - Effects of activation on the elastic properties of intact soleus muscles with a deletion in titin. AB - Titin has long been known to contribute to muscle passive tension. Recently, it was also demonstrated that titin-based stiffness increases upon Ca2+ activation of wild-type mouse psoas myofibrils stretched beyond overlap of the thick and thin filaments. In addition, this increase in titin-based stiffness was impaired in single psoas myofibrils from mdm mice, characterized by a deletion in the N2A region of the Ttn gene. Here, we investigated the effects of activation on elastic properties of intact soleus muscles from wild-type and mdm mice to determine whether titin contributes to active muscle stiffness. Using load-clamp experiments, we compared the stress-strain relationships of elastic elements in active and passive muscles during unloading, and quantified the change in stiffness upon activation. Results from wild-type muscles show that upon activation, the elastic modulus increases, elastic elements develop force at 15% shorter lengths, and there was a 2.9-fold increase in the slope of the stress strain relationship. These results are qualitatively and quantitatively similar to results from single wild-type psoas myofibrils. In contrast, mdm soleus showed no effect of activation on the slope or intercept of the stress-strain relationship, which is consistent with impaired titin activation observed in single mdm psoas myofibrils. Therefore, it is likely that titin plays a role in the increase of active muscle stiffness during rapid unloading. These results are consistent with the idea that, in addition to the thin filaments, titin is activated upon Ca2+ influx in skeletal muscle. PMID- 27994048 TI - Corrigendum. PMID- 27994047 TI - Contaminants in commercial preparations of 'purified' small leucine-rich proteoglycans may distort mechanistic studies. AB - The present study reports the perplexing results that came about because of seriously impure commercially available reagents. Commercial reagents and chemicals are routinely ordered by scientists and expected to have been rigorously assessed for their purity. Unfortunately, we found this assumption to be risky. Extensive work was carried out within our laboratory using commercially sourced preparations of the small leucine-rich proteoglycans (SLRPs), decorin and biglycan, to investigate their influence on nerve cell growth. Unusual results compelled us to analyse the composition and purity of both preparations of these proteoglycans (PGs) using both mass spectrometry (MS) and Western blotting, with and without various enzymatic deglycosylations. Commercial 'decorin' and 'biglycan' were found to contain a mixture of PGs including not only both decorin and biglycan but also fibromodulin and aggrecan. The unexpected effects of 'decorin' and 'biglycan' on nerve cell growth could be explained by these impurities. Decorin and biglycan contain either chondroitin or dermatan sulfate glycosaminoglycan (GAG) chains whereas fibromodulin only contains keratan sulfate and the large (>2500 kDa), highly glycosylated aggrecan contains both keratan and chondroitin sulfate. The different structure, molecular weight and composition of these impurities significantly affected our work and any conclusions that could be made. These findings beg the question as to whether scientists need to verify the purity of each commercially obtained reagent used in their experiments. The implications of these findings are vast, since the effects of these impurities may already have led to inaccurate conclusions and reports in the literature with concomitant loss of researchers' funds and time. PMID- 27994049 TI - Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum. AB - ABC transporters are polytopic membrane proteins that utilize ATP binding and hydrolysis to facilitate transport across biological membranes. Forty-eight human ABC transporters have been identified in the genome, and the majority of these are linked to heritable disease. Mutations in the ABCC6 (ATP binding cassette transporter C6) ABC transporter are associated with pseudoxanthoma elasticum, a disease of altered elastic properties in multiple tissues. Although ~200 mutations have been identified in pseudoxanthoma elasticum patients, the underlying structural defects associated with the majority of these are poorly understood. To evaluate the structural consequences of these missense mutations, a combination of biophysical and cell biological approaches were applied to evaluate the local and global folding and assembly of the ABCC6 protein. Structural and bioinformatic analyses suggested that a cluster of mutations, representing roughly 20% of the patient population with identified missense mutations, are located in the interface between the transmembrane domain and the C-terminal nucleotide binding domain. Biochemical and cell biological analyses demonstrate these mutations influence multiple steps in the biosynthetic pathway, minimally altering local domain structure but adversely impacting ABCC6 assembly and trafficking. The differential impacts on local and global protein structure are consistent with hierarchical folding and assembly of ABCC6. Stabilization of specific domain-domain interactions via targeted amino acid substitution in the catalytic site of the C-terminal nucleotide binding domain restored proper protein trafficking and cell surface localization of multiple biosynthetic mutants. This rescue provides a specific mechanism by which chemical chaperones could be developed for the correction of ABCC6 biosynthetic defects. PMID- 27994050 TI - Modeling Protein Excited-state Structures from "Over-length" Chemical Cross links. AB - Chemical cross-linking coupled with mass spectroscopy (CXMS) provides proximity information for the cross-linked residues and is used increasingly for modeling protein structures. However, experimentally identified cross-links are sometimes incompatible with the known structure of a protein, as the distance calculated between the cross-linked residues far exceeds the maximum length of the cross linker. The discrepancies may persist even after eliminating potentially false cross-links and excluding intermolecular ones. Thus the "over-length" cross-links may arise from alternative excited-state conformation of the protein. Here we present a method and associated software DynaXL for visualizing the ensemble structures of multidomain proteins based on intramolecular cross-links identified by mass spectrometry with high confidence. Representing the cross-linkers and cross-linking reactions explicitly, we show that the protein excited-state structure can be modeled with as few as two over-length cross-links. We demonstrate the generality of our method with three systems: calmodulin, enzyme I, and glutamine-binding protein, and we show that these proteins alternate between different conformations for interacting with other proteins and ligands. Taken together, the over-length chemical cross-links contain valuable information about protein dynamics, and our findings here illustrate the relationship between dynamic domain movement and protein function. PMID- 27994051 TI - Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses. AB - Over half a century ago, D. S. Falconer first reported a mouse with a reeling gate. Four decades later, the Reln gene was isolated and identified as the cause of the reeler phenotype. Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Reln gene, results in abnormal neuronal layering throughout several regions of the brain. In the years since, the known functions of Reelin signaling in the brain have expanded to include multiple postdevelopmental neuromodulatory roles, revealing an ever increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation of synaptic function. In writing this review, we intend to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromodulatory effects shape and protect synapses. PMID- 27994052 TI - BciD Is a Radical S-Adenosyl-l-methionine (SAM) Enzyme That Completes Bacteriochlorophyllide e Biosynthesis by Oxidizing a Methyl Group into a Formyl Group at C-7. AB - Green bacteria are chlorophotorophs that synthesize bacteriochlorophyll (BChl) c, d, or e, which assemble into supramolecular, nanotubular structures in large light-harvesting structures called chlorosomes. The biosynthetic pathways of these chlorophylls are known except for one reaction. Null mutants of bciD, which encodes a putative radical S-adenosyl-l-methionine (SAM) protein, are unable to synthesize BChl e but accumulate BChl c; however, it is unknown whether BciD is sufficient to convert BChl c (or its precursor, bacteriochlorophyllide (BChlide) c) into BChl e (or BChlide e). To determine the function of BciD, we expressed the bciD gene of Chlorobaculum limnaeum strain DSMZ 1677T in Escherichia coli and purified the enzyme under anoxic conditions. Electron paramagnetic resonance spectroscopy of BciD indicated that it contains a single [4Fe-4S] cluster. In assays containing SAM, BChlide c or d, and sodium dithionite, BciD catalyzed the conversion of SAM into 5'-deoxyadenosine and BChlide c or d into BChlide e or f, respectively. Our analyses also identified intermediates that are proposed to be 71-OH-BChlide c and d Thus, BciD is a radical SAM enzyme that converts the methyl group of BChlide c or d into the formyl group of BChlide e or f This probably occurs by a mechanism involving consecutive hydroxylation reactions of the C-7 methyl group to form a geminal diol intermediate, which spontaneously dehydrates to produce the final products, BChlide e or BChlide f The demonstration that BciD is sufficient to catalyze the conversion of BChlide c into BChlide e completes the biosynthetic pathways for all "Chlorobium chlorophylls." PMID- 27994053 TI - Apelin-36 Modulates Blood Glucose and Body Weight Independently of Canonical APJ Receptor Signaling. AB - Apelin-36 was discovered as the endogenous ligand for the previously orphan receptor APJ. Apelin-36 has been linked to two major types of biological activities: cardiovascular (stimulation of cardiac contractility and suppression of blood pressure) and metabolic (improving glucose homeostasis and lowering body weight). It has been assumed that both of these activities are modulated through APJ. Here, we demonstrate that the metabolic activity of apelin-36 can be separated from canonical APJ activation. We developed a series of apelin-36 variants in which evolutionarily conserved residues were mutated, and evaluated their ability to modulate glucose homeostasis and body weight in chronic mouse models. We found that apelin-36(L28A) retains full metabolic activity, but is 100 fold impaired in its ability to activate APJ. In contrast to its full metabolic activity, apelin-36(L28A) lost the ability to suppress blood pressure in spontaneously hypertensive rats (SHR). We took advantage of these findings to develop a longer-acting variant of apelin-36 that could modulate glucose homeostasis without impacting blood pressure (or activating APJ). Apelin-36 [L28C(30kDa-PEG)] is 10,000-fold less potent than apelin-36 at activating the APJ receptor but retains its ability to significantly lower blood glucose and improve glucose tolerance in diet-induced obese mice. Apelin-36-[L28C(30kDa-PEG)] provides a starting point for the development of diabetes therapeutics that are devoid of the blood pressure effects associated with canonical APJ activation. PMID- 27994054 TI - Trp-Asp (WD) Repeat Domain 1 Is Essential for Mouse Peri-implantation Development and Regulates Cofilin Phosphorylation. AB - Trp-Asp (WD) repeat domain 1 (WDR1) is a highly conserved actin-binding protein across all eukaryotes and is involved in numerous actin-based processes by accelerating Cofilin severing actin filament. However, the function and the mechanism of WDR1 in mammalian early development are still largely unclear. We now report that WDR1 is essential for mouse peri-implantation development and regulates Cofilin phosphorylation in mouse cells. The disruption of maternal WDR1 does not obviously affect ovulation and female fertility. However, depletion of zygotic WDR1 results in embryonic lethality at the peri-implantation stage. In WDR1 knock-out cells, we found that WDR1 regulates Cofilin phosphorylation. Interestingly, WDR1 is overdosed to regulate Cofilin phosphorylation in mouse cells. Furthermore, we showed that WDR1 interacts with Lim domain kinase 1 (LIMK1), a well known phosphorylation kinase of Cofilin. Altogether, our results provide new insights into the role and mechanism of WDR1 in physiological conditions. PMID- 27994055 TI - SMAD3 Regulates Follicle-stimulating Hormone Synthesis by Pituitary Gonadotrope Cells in Vivo. AB - Pituitary follicle-stimulating hormone (FSH) is an essential regulator of fertility in females and of quantitatively normal spermatogenesis in males. Pituitary-derived activins are thought to act as major stimulators of FSH synthesis by gonadotrope cells. In vitro, activins signal via SMAD3, SMAD4, and forkhead box L2 (FOXL2) to regulate transcription of the FSHbeta subunit gene (Fshb). Consistent with this model, gonadotrope-specific Smad4 or Foxl2 knock-out mice have greatly reduced FSH and are subfertile. The role of SMAD3 in vivo is unresolved; however, residual FSH production in Smad4 conditional knock-out mice may derive from partial compensation by SMAD3 and its ability to bind DNA in the absence of SMAD4. To test this hypothesis and determine the role of SMAD3 in FSH biosynthesis, we generated mice lacking both the SMAD3 DNA binding domain and SMAD4 specifically in gonadotropes. Conditional knock-out females were hypogonadal, acyclic, and sterile and had thread-like uteri; their ovaries lacked antral follicles and corpora lutea. Knock-out males were fertile but had reduced testis weights and epididymal sperm counts. These phenotypes were consistent with those of Fshb knock-out mice. Indeed, pituitary Fshb mRNA levels were nearly undetectable in both male and female knock-outs. In contrast, gonadotropin releasing hormone receptor mRNA levels were significantly elevated in knock-outs in both sexes. Interestingly, luteinizing hormone production was altered in a sex specific fashion. Overall, our analyses demonstrate that SMAD3 is required for FSH synthesis in vivo. PMID- 27994057 TI - FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage. AB - Accumulation of damaged DNA in hematopoietic stem cells (HSC) is associated with chromosomal abnormalities, genomic instability, and HSC aging and might promote hematological malignancies with age. Despite this, the regulatory pathways implicated in the HSC DNA damage response have not been fully elucidated. One of the sources of DNA damage is reactive oxygen species (ROS) generated by both exogenous and endogenous insults. Balancing ROS levels in HSC requires FOXO3, which is an essential transcription factor for HSC maintenance implicated in HSC aging. Elevated ROS levels result in defective Foxo3-/- HSC cycling, among many other deficiencies. Here, we show that loss of FOXO3 leads to the accumulation of DNA damage in primitive hematopoietic stem and progenitor cells (HSPC), associated specifically with reduced expression of genes implicated in the repair of oxidative DNA damage. We provide further evidence that Foxo3-/- HSPC are defective in DNA damage repair. Specifically, we show that the base excision repair pathway, the main pathway utilized for the repair of oxidative DNA damage, is compromised in Foxo3-/- primitive hematopoietic cells. Treating mice in vivo with N-acetylcysteine reduces ROS levels, rescues HSC cycling defects, and partially mitigates HSPC DNA damage. These results indicate that DNA damage accrued as a result of elevated ROS in Foxo3-/- mutant HSPC is at least partially reversible. Collectively, our findings suggest that FOXO3 serves as a protector of HSC genomic stability and health. PMID- 27994056 TI - Inducible Inhibition of Gbetagamma Reveals Localization-dependent Functions at the Plasma Membrane and Golgi. AB - Heterotrimeric G proteins signal at a variety of endomembrane locations, in addition to their canonical function at the cytoplasmic surface of the plasma membrane (PM), where they are activated by cell surface G protein-coupled receptors. Here we focus on betagamma signaling at the Golgi, where betagamma activates a signaling cascade, ultimately resulting in vesicle fission from the trans-Golgi network (TGN). To develop a novel molecular tool for inhibiting endogenous betagamma in a spatial-temporal manner, we take advantage of a lipid association mutant of the widely used betagamma inhibitor GRK2ct (GRK2ct-KERE) and the FRB/FKBP heterodimerization system. We show that GRK2ct-KERE cannot inhibit betagamma function when expressed in cells, but recruitment to a specific membrane location recovers the ability of GRK2ct-KERE to inhibit betagamma signaling. PM-recruited GRK2ct-KERE inhibits lysophosphatidic acid-induced phosphorylation of Akt, whereas Golgi-recruited GRK2ct-KERE inhibits cargo transport from the TGN to the PM. Moreover, we show that Golgi-recruited GRK2ct KERE inhibits model basolaterally targeted but not apically targeted cargo delivery, for both PM-destined and secretory cargo, providing the first evidence of selectivity in terms of cargo transport regulated by betagamma. Last, we show that Golgi fragmentation induced by ilimaquinone and nocodazole is blocked by betagamma inhibition, demonstrating that betagamma is a key regulator of multiple pathways that impact Golgi morphology. Thus, we have developed a new molecular tool, recruitable GRK2ct-KERE, to modulate betagamma signaling at specific subcellular locations, and we demonstrate novel cargo selectivity for betagamma regulation of TGN to PM transport and a novel role for betagamma in mediating Golgi fragmentation. PMID- 27994058 TI - Signal Transducer and Activator of Transcription 1 Plays a Pivotal Role in RET/PTC3 Oncogene-induced Expression of Indoleamine 2,3-Dioxygenase 1. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAFV600E- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways. BRAFV600E-expressing PcCL3 cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells were characterized by a high IDO1 expression. Moreover, we found that, the STAT1 IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation appeared to require activation of the canonical NF-kappaB pathway. Conversely, activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, followed by a direct tyrosine phosphorylation event, was necessary for STAT1 Tyr-701 phosphorylation. These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways. Moreover, they suggest possible novel molecular targets for the abrogation of tumor microenvironment immunosuppression. The detection of those targets is becoming increasingly important to yield the full function of novel immune checkpoint inhibitors. PMID- 27994059 TI - Assessing Oxidative Stress in Tumors by Measuring the Rate of Hyperpolarized [1 13C]Dehydroascorbic Acid Reduction Using 13C Magnetic Resonance Spectroscopy. AB - Rapid cancer cell proliferation promotes the production of reducing equivalents, which counteract the effects of relatively high levels of reactive oxygen species. Reactive oxygen species levels increase in response to chemotherapy and cell death, whereas an increase in antioxidant capacity can confer resistance to chemotherapy and is associated with an aggressive tumor phenotype. The pentose phosphate pathway is a major site of NADPH production in the cell, which is used to maintain the main intracellular antioxidant, glutathione, in its reduced state. Previous studies have shown that the rate of hyperpolarized [1 13C]dehydroascorbic acid (DHA) reduction, which can be measured in vivo using non invasive 13C magnetic resonance spectroscopic imaging, is increased in tumors and that this is correlated with the levels of reduced glutathione. We show here that the rate of hyperpolarized [1-13C]DHA reduction is increased in tumors that have been oxidatively prestressed by depleting the glutathione pool by buthionine sulfoximine treatment. This increase was associated with a corresponding increase in pentose phosphate pathway flux, assessed using 13C-labeled glucose, and an increase in glutaredoxin activity, which catalyzes the glutathione-dependent reduction of DHA. These results show that the rate of DHA reduction depends not only on the level of reduced glutathione, but also on the rate of NADPH production, contradicting the conclusions of some previous studies. Hyperpolarized [1-13C]DHA can be used, therefore, to assess the capacity of tumor cells to resist oxidative stress in vivo However, DHA administration resulted in transient respiratory arrest and cardiac depression, which may prevent translation to the clinic. PMID- 27994060 TI - Twisting a beta-Carotene, an Adaptive Trick from Nature for Dissipating Energy during Photoprotection. AB - Cyanobacteria possess a family of one-helix high light-inducible proteins (Hlips) that are homologous to light-harvesting antenna of plants and algae. An Hlip protein, high light-inducible protein D (HliD) purified as a small complex with the Ycf39 protein is evaluated using resonance Raman spectroscopy. We show that the HliD binds two different beta-carotenes, each present in two non-equivalent binding pockets with different conformations, having their (0,0) absorption maxima at 489 and 522 nm, respectively. Both populations of beta-carotene molecules were in all-trans configuration and the absorption position of the farthest blue-shifted beta-carotene was attributed entirely to the polarizability of the environment in its binding pocket. In contrast, the absorption maximum of the red-shifted beta-carotene was attributed to two different factors: the polarizability of the environment in its binding pocket and, more importantly, to the conformation of its beta-rings. This second beta-carotene has highly twisted beta-rings adopting a flat conformation, which implies that the effective conjugation length N is extended up to 10.5 modifying the energetic levels. This increase in N will also result in a lower S1 energy state, which may provide a permanent energy dissipation channel. Analysis of the carbonyl stretching region for chlorophyll a excitations indicates that the HliD binds six chlorophyll a molecules in five non-equivalent binding sites, with at least one chlorophyll a presenting a slight distortion to its macrocycle. The binding modes and conformations of HliD-bound pigments are discussed with respect to the known structures of LHCII and CP29. PMID- 27994061 TI - Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth. AB - Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux. PMID- 27994062 TI - Engineering an IgG Scaffold Lacking Effector Function with Optimized Developability. AB - IgG isotypes can differentially bind to Fcgamma receptors and complement, making the selection of which isotype to pursue for development of a particular therapeutic antibody important in determining the safety and efficacy of the drug. IgG2 and IgG4 isotypes have significantly lower binding affinity to Fcgamma receptors. Recent evidence suggests that the IgG2 isotype is not completely devoid of effector function, whereas the IgG4 isotype can undergo in vivo Fab arm exchange leading to bispecific antibody and off-target effects. Here an attempt was made to engineer an IgG1-based scaffold lacking effector function but with stability equivalent to that of the parent IgG1. Care was taken to ensure that both stability and lack of effector function was achieved with a minimum number of mutations. Among the Asn297 mutants that result in lack of glycosylation and thus loss of effector function, we demonstrate that the N297G variant has better stability and developability compared with the N297Q or N297A variants. To further improve the stability of N297G, we introduced a novel engineered disulfide bond at a solvent inaccessible location in the CH2 domain. The resulting scaffold has stability greater than or equivalent to that of the parental IgG1 scaffold. Extensive biophysical analyses and pharmacokinetic (PK) studies in mouse, rat, and monkey further confirmed the developability of this unique scaffold, and suggest that it could be used for all Fc containing therapeutics (e.g. antibodies, bispecific antibodies, and Fc fusions) requiring lack of effector function or elimination of binding to Fcgamma receptors. PMID- 27994063 TI - Biological Characterization of a Stable Effector Functionless (SEFL) Monoclonal Antibody Scaffold in Vitro. AB - The stable effector functionLess (SEFL) antibody was designed as an IgG1 antibody with a constant region that lacks the ability to interact with Fcgamma receptors. The engineering and stability and pharmacokinetic assessments of the SEFL scaffold is described in the accompanying article (Jacobsen, F. W., Stevenson, R., Li, C., Salimi-Moosavi, H., Liu, L., Wen, J., Luo, Q., Daris, K., Buck, L., Miller, S., Ho, S-Y., Wang, W., Chen, Q., Walker, K., Wypych, J., Narhi, L., and Gunasekaran, K. (2017) J. Biol. Chem 292). The biological properties of these SEFL antibodies were assessed in a variety of human and cynomolgus monkey in vitro assays. Binding of parent molecules and their SEFL variants to human and cynomolgus monkey FcgammaRs were evaluated using flow cytometry-based binding assays. The SEFL variants tested showed decreased binding affinity to human and cynomolgus FcgammaRs compared with the wild-type IgG1 antibody. In addition, SEFL variants demonstrated no antibody-dependent cell-mediated cytotoxicity in vitro against Daudi cells with cynomolgus monkey peripheral blood mononuclear cells, and had minimal complement-dependent cytotoxicity activity similar to that of the negative control IgG2 in a CD20+ human Raji lymphoma cell line. SEFL mutations eliminated off-target antibody-dependent monocyte phagocytosis of cynomolgus monkey platelets, and cynomolgus platelet activation in vitro These experiments demonstrate that the SEFL modifications successfully eliminated Fc-associated effector binding and functions. PMID- 27994064 TI - A novel NFIA-NFkappaB feed-forward loop contributes to glioblastoma cell survival. AB - Background: The nuclear factor I-A (NFIA) transcription factor promotes glioma growth and inhibits apoptosis in glioblastoma (GBM) cells. Here we report that the NFIA pro-survival effect in GBM is mediated in part via a novel NFIA-nuclear factor-kappaB (NFkappaB) p65 feed-forward loop. Methods: We examined effects of gain- and loss-of-function manipulations of NFIA and NFkappaB p65 on each other's transcription, cell growth, apoptosis and sensitivity to chemotherapy in patient derived GBM cells and established GBM cell lines. Results: NFIA enhanced apoptosis evasion by activating NFkappaB p65 and its downstream anti-apoptotic factors tumor necrosis factor receptor-associated factor 1 (TRAF1) and cellular inhibitor of apoptosis proteins (cIAPs). Induction of NFkappaB by NFIA was required to protect cells from apoptosis, and inhibition of NFkappaB effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NFkappaB and anti-apoptotic genes TRAF1 and cIAPs, and increased baseline apoptosis. NFIA positively regulated NFkappaB transcription and NFkappaB protein level. Interestingly, NFkappaB also activated the NFIA promoter and increased NFIA level, and knockdown of NFIA was sufficient to attenuate the NFkappaB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFkappaB in governing GBM cell survival. Supporting this, NFIA and NFkappaB expression levels were highly correlated in human GBM and patient-derived GBM cells. Conclusions: These data define a previously unknown NFIA-NFkappaB feed forward regulation that may contribute to GBM cell survival. PMID- 27994065 TI - Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial. AB - Background: Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities. Methods: Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS). Results: Multivariate analysis showed that objective response at 2 months (P < .001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (>11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions. Conclusions: Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences. PMID- 27994066 TI - Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813. AB - Background: The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. Methods: Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met. Results: Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade >=3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81). Conclusions: RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival. PMID- 27994070 TI - Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury. AB - The meningeal space is occupied by a diverse repertoire of immune cells. Central nervous system (CNS) injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation remains poorly understood. Here, we describe type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that are activated after CNS injury. ILC2s are present throughout the naive mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile. After spinal cord injury (SCI), meningeal ILC2s are activated in an IL-33-dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild-type lung-derived ILC2s into the meningeal space of IL-33R-/- animals partially improves recovery after SCI. These data characterize ILC2s as a novel meningeal cell type that responds to SCI and could lead to new therapeutic insights for neuroinflammatory conditions. PMID- 27994068 TI - Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. AB - Regulatory T (T reg) cell deficiency causes lethal, CD4+ T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency-mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3+ T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota-inosine-A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction. PMID- 27994069 TI - Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE. AB - Noncoding transcripts originating upstream of the immunoglobulin constant region (I transcripts) are required to direct activation-induced deaminase to initiate class switching in B cells. Differential regulation of Iepsilon and Igamma1 transcription in response to interleukin 4 (IL-4), hence class switching to IgE and IgG1, is not fully understood. In this study, we combine novel mouse reporters and single-cell RNA sequencing to reveal the heterogeneity in IL-4 induced I transcription. We identify an early population of cells expressing Iepsilon but not Igamma1 and demonstrate that early Iepsilon transcription leads to switching to IgE and occurs at lower activation levels than Igamma1. Our results reveal how probabilistic transcription with a lower activation threshold for Iepsilon directs the early choice of IgE versus IgG1, a key physiological response against parasitic infestations and a mediator of allergy and asthma. PMID- 27994071 TI - Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. AB - The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1beta, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL 1beta, and their cells also secreted more IL-18 but not IL-1beta in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation. PMID- 27994072 TI - HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration. AB - A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4+ and CD8+ T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB. PMID- 27994075 TI - In This Issue of Occupational Medicine. PMID- 27994076 TI - Jacques-Louis David, Belisarius Begging for Alms 1781. PMID- 27994078 TI - Shaking All Over. PMID- 27994074 TI - Novel Resolvin D2 Receptor Axis in Infectious Inflammation. AB - Resolution of acute inflammation is an active process governed by specialized proresolving mediators, including resolvin (Rv)D2, that activates a cell surface G protein-coupled receptor, GPR18/DRV2. In this study, we investigated RvD2-DRV2 dependent resolution mechanisms using DRV2-deficient mice (DRV2-knockout [KO]). In polymicrobial sepsis initiated by cecal ligation and puncture, RvD2 (~2.7 nmol/mouse) significantly increased survival (>50%) of wild-type mice and reduced hypothermia and bacterial titers compared with vehicle-treated cecal ligation and puncture mice that succumbed at 48 h. Protection by RvD2 was abolished in DRV2-KO mice. Mass spectrometry-based lipid mediator metabololipidomics demonstrated that DRV2-KO infectious exudates gave higher proinflammatory leukotriene B4 and procoagulating thromboxane B2, as well as lower specialized proresolving mediators, including RvD1 and RvD3, compared with wild-type. RvD2-DRV2-initiated intracellular signals were investigated using mass cytometry (cytometry by time of-flight), which demonstrated that RvD2 enhanced phosphorylation of CREB, ERK1/2, and STAT3 in WT but not DRV2-KO macrophages. Monitored by real-time imaging, RvD2-DRV2 interaction significantly enhanced phagocytosis of live Escherichia coli, an action dependent on protein kinase A and STAT3 in macrophages. Taken together, we identified an RvD2/DRV2 axis that activates intracellular signaling pathways that increase phagocytosis-mediated bacterial clearance, survival, and organ protection. Moreover, these results provide evidence for RvD2-DRV2 and their downstream pathways in pathophysiology of infectious inflammation. PMID- 27994073 TI - Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. AB - Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-alpha or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-alpha induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes. PMID- 27994077 TI - Why I might become an occupational physician. PMID- 27994079 TI - Response to Cooke and Sadhra's letter. PMID- 27994080 TI - Power to which people? PMID- 27994081 TI - Vascular hand-arm vibration syndrome-magnetic resonance angiography. PMID- 27994083 TI - Hair Analysis in Clinical and Forensic Toxicology. PMID- 27994082 TI - The Short Musculoskeletal Function Assessment (SMFA) questionnaire. PMID- 27994084 TI - Ernsting's Aviation and Space Medicine. PMID- 27994085 TI - Patient Health Questionnaire-4. PMID- 27994088 TI - Occupational Medicine Editorial team vacancy. PMID- 27994086 TI - General Lifestyle App Reviews. PMID- 27994090 TI - A common class of transcripts with 5'-intron depletion, distinct early coding sequence features, and N1-methyladenosine modification. AB - Introns are found in 5' untranslated regions (5'UTRs) for 35% of all human transcripts. These 5'UTR introns are not randomly distributed: Genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5'UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5'UTR intron status, we developed a classifier that can predict 5'UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5' proximal-intron-minus-like-coding regions ("5IM" transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5' cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the exon junction complex (EJC) at noncanonical 5' proximal positions. Finally, N1-methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising ~20% of human transcripts. This class is defined by depletion of 5' proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N1-methyladenosines in the early coding region, and enrichment for noncanonical binding by the EJC. PMID- 27994092 TI - Timing of glucocorticoid administration: a cross-sectional survey of glucocorticoid users in an online social network for health. PMID- 27994091 TI - Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and gastrointestinal adverse events. AB - Objective: The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial. Methods: The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies. Results: Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%). Conclusion: This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00405275. PMID- 27994094 TI - The global burden of anti-neutrophil cytoplasmic antibody vasculitis: High but unquantified. PMID- 27994093 TI - Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis. AB - Objective: High levels of ACPAs in RA are associated with more severe arthritis and worse prognosis. However, the role of ACPAs in mediating the increased risk of heart failure in RA remains undefined. We examined whether specific ACPAs were associated with subclinical left ventricular (LV) phenotypes that presage heart failure. Methods: Sera from RA patients without clinical cardiovascular disease were assayed for specific ACPAs using a custom Bio-Plex bead assay, and their cross-sectional associations with cardiac magnetic resonance-derived LV measures were evaluated. High ACPA level was defined as ? 75th percentile. Findings were assessed in a second independent RA cohort with an expanded panel of ACPAs and LV measures assessed by 3D-echocardiography. Results: In cohort 1 (n = 76), higher levels of anti-citrullinated fibrinogen 41-60 and anti-citrullinated vimentin antibodies were associated with a 10 and 6% higher adjusted mean LV mass index (LVMI), respectively, compared with lower antibody levels (P < 0.05). In contrast, higher levels of anti-citrullinated biglycan 247-266 were associated with a 13% lower adjusted mean LVMI compared with lower levels (P < 0.001). In cohort 2 (n = 74), the association between ACPAs targeting citrullinated fibrinogen and citrullinated vimentin peptides or protein and LVMI was confirmed: higher anti-citrullinated fibrinogen 556-575 and anti-citrullinated vimentin 58 77 antibody levels were associated with a higher adjusted mean LVMI (19 and 15%, respectively; P < 0.05), but no association with biglycan was found. Conclusion: Higher levels of antibodies targeting citrullinated fibrinogen and vimentin peptides or protein were associated with a higher mean LVMI in both RA cohorts, potentially implicating autoimmune targeting of citrullinated proteins in myocardial remodelling in RA. PMID- 27994097 TI - Recognizing the clinical triad and dural calcification in adult hypophosphatasia. PMID- 27994096 TI - Paediatric rheumatology clinic population in Southeast Asia: are we different? AB - Objectives: To examine the descriptive epidemiology of the patient population referred to paediatric rheumatology centres (PRCs) in Southeast Asia (SEA) and to compare the frequency of conditions encountered with other PRC populations. Methods: A web-based Registry for Childhood Onset Paediatric Rheumatic Diseases was established in 2009 and seven PRCs in four SEA countries, where paediatric rheumatologists are available, participated in a prospective 24 month data collection (43 months for Singapore). Results: The number of patients analysed was 4038 (788 from Malaysia, 711 from the Philippines, 1943 from Singapore and 596 from Thailand). Over 70% of patients evaluated in PRCs in Malaysia, the Philippines and Thailand had rheumatic diseases (RDs), as compared with one-half of the proportion seen in Singaporean PRCs, which was similar to the Western PRC experience. Among RDs diagnosed (n = 2602), JIA was the most common disease encountered in Malaysia (41%) and Thailand (61%) as compared with systemic vasculitides in the Philippines (37%) and Singapore (35%) among which Henoch Schonlein purpura was the most prevalent. SLE and related diseases were more common, but idiopathic pain syndrome and abnormal immunological laboratory tests were rarer than those seen in the West. JIA subtype distributions were different among countries. Among non-RDs (n = 1436), orthopaedic and related conditions predominated (21.7-59.4%). Conclusion: The frequencies of RDs seen by SEA PRCs were different from those in the West. Systemic vasculitides and SLE were common in addition to JIA. Paediatric rheumatologist availability and healthcare accessibility partially explain these observed discrepancies. PMID- 27994098 TI - 7th Advances Against Aspergillosis: Basic, diagnostic, clinical and therapeutic studies. PMID- 27994095 TI - Diffusion-weighted imaging is a sensitive biomarker of response to biologic therapy in enthesitis-related arthritis. AB - Objective: The aim was to evaluate diffusion-weighted imaging (DWI) as a tool for measuring treatment response in adolescents with enthesitis-related arthropathy (ERA). Methods: Twenty-two adolescents with ERA underwent routine MRI and DWI before and after TNF inhibitor therapy. Each patient's images were visually scored by two radiologists using the Spondyloarthritis Research Consortium of Canada system, and sacroiliac joint apparent diffusion coefficient (ADC) and normalized ADC (nADC) were measured for each patient. Therapeutic clinical response was defined as an improvement of ? 30% physician global assessment and radiological response defined as ? 2.5-point reduction in Spondyloarthritis Research Consortium of Canada score. We compared ADC and nADC changes in responders and non-responders using the Mann-Whitney-Wilcoxon test. Results: For both radiological and clinical definitions of response, reductions in ADC and nADC after treatment were greater in responders than in non-responders (for radiological response: ADC: P < 0.01; nADC: P = 0.055; for clinical response: ADC: P = 0.33; nADC: P = 0.089). ADC and nADC could predict radiological response with a high level of sensitivity and specificity and were moderately sensitive and specific predictors of clinical response (the area under the receiver operating characteristic curves were as follows: ADC: 0.97, nADC: 0.82 for radiological response; and ADC: 0.67, nADC: 0.78 for clinical response). Conclusion: DWI measurements reflect the response to TNF inhibitor treatment in ERA patients with sacroiliitis as defined using radiological criteria and may also reflect clinical response. DWI is more objective than visual scoring and has the potential to be automated. ADC/nADC could be used as biomarkers of sacroiliitis in the clinic and in clinical trials. PMID- 27994099 TI - Is Exposure to Animal Feces Harmful to Child Nutrition and Health Outcomes? A Multicountry Observational Analysis. AB - AbstractIt has recently been hypothesized that exposure to livestock constitutes a significant risk factor for diarrhea and environmental enteric disorder in young children, which may significantly contribute to undernutrition. To date, though, very little research has documented the extent of exposure to animal feces and whether this exposure is associated with child anthropometry in large samples and diverse settings. This study investigates these issues using data from the Alive and Thrive study conducted in rural areas of Ethiopia, Bangladesh, and Vietnam. These surveys used spot-checks to collect data on proxies of hygiene behaviors such as the cleanliness of mothers, young children, and the homestead environment, including the presence of animal feces. Animal feces were visible in 38-42% of household compounds across the three countries and were positively associated with household livestock ownership and negatively associated with maternal and child cleanliness. One-sided tests from multivariate least squares models for children 6-24 months of age indicate that the presence of animal feces is significantly and negatively associated with child height-for-age z scores in Ethiopia (beta = -0.22), Bangladesh (beta = -0.13), and in a pooled sample (beta = -0.11), but not in Vietnam. There is also suggestive evidence that animal feces may be positively associated with diarrhea symptoms in Bangladesh. The results in this article, therefore, contribute to a growing body of evidence suggesting that animal ownership may pose a significant risk to child nutrition and health outcomes in developing countries. PMID- 27994100 TI - The Impact of Systematic Point-of-Care Ultrasound on Management of Patients in a Resource-Limited Setting. AB - Although target point-of-care (POC) ultrasonography has been shown to benefit patients in resource-limited settings, it is not clear whether a systematic POC ultrasound assessment in these settings can also lead to similar changes in patient management. A predefined systematic set of POC ultrasound scans were performed on inpatients at a tertiary referral hospital in Tanzania to see if this resulted in changes to patient management. Of the 55 patients scanned, an abnormality was detected in 75% (N = 41), and a change in patient management was recommended or implemented on the basis of POC ultrasound findings in 53% (N = 29). The main impact was earlier initiation of treatment due to more rapid and accurate diagnosis. Further research is warranted to determine whether systematic POC ultrasonography would result in improved patient outcomes in resource-limited settings. PMID- 27994102 TI - Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine: More Than Just an Antimalarial? PMID- 27994101 TI - An Outbreak of Diarrhea in Mandera, Kenya, Due to Escherichia coli Serogroup O Nontypable Strain That Had a Coding Gene for Enteroaggregative E. coli Heat Stable Enterotoxin 1. AB - In an outbreak of gastroenteritis in December 2009, in Mandera, Kenya, Escherichia coli O-nontypable (ONT) strain was isolated from stool specimens of patients (18/24, 75%). The E. coli ONT organisms could not be assigned to any of the recognized diarrheagenic groups of E. coli However, they possessed the enteroaggregative E. coli heat-stable enterotoxin-1 gene. The cell-free culture filtrates of the E. coli ONT strain isolated from the outbreak cases induced considerable amount of fluid accumulation in suckling mouse intestine, indicating production of an enterotoxic factor(s). These results identify E. coli that did not have any diarrheagenic characteristics except astA as the etiological agent of the diarrheal outbreak in Mandera. It is however considered necessary to characterize the fluid accumulation factor(s) to determine whether any novel toxins were responsible for the fluid accumulation. Moreover, it is important to study dissemination of strains producing the enterotoxic factor(s) to assess their public health significance distribution in the environment. PMID- 27994105 TI - Awareness of Sickle Cell Trait Status: A Cross-Sectional Survey of Antenatal Women in Ghana. AB - This study was conducted to evaluate pregnant women's awareness of sickle cell disease and sickle cell trait and the factors that contribute to it. Two hundred and six pregnant women with at least 20 weeks gestation answered a questionnaire regarding awareness of their trait status and questions to test their knowledge of sickle cell disease. Although the majority of patients were aware of their trait status (87.4%), only 29% of knowledge questions were answered correctly; patients who self-identified as having sickle cell trait did not do better. Patients who responded that they knew a good deal about sickle cell disease scored an average of 3.5 points (number of correct responses to nine questions) more than individuals who responded that they knew nothing (P < 0.001). Individuals who knew they had been tested for the sickle cell trait scored approximately 2 points higher than those who did not know whether they had been tested (P = 0.004). Respondents with at least secondary education scored on average 1 point higher on the knowledge test than those with less education (P = 0.004). Knowing someone with sickle cell disease was associated with a mean score of 1.25 points higher than individuals who did not know any affected individual (P = 0.000).There is a deficit in the knowledge of sickle cell disease among Ghanaian pregnant women. Therefore, there is the need for public education on sickle cell disease. PMID- 27994103 TI - Development of Immunoassays for Burkholderia pseudomallei Typical and Atypical Lipopolysaccharide Strain Typing. AB - Burkholderia pseudomallei is the causative agent of melioidosis, a severe infection endemic to many tropical regions. Lipopolysaccharide (LPS) is recognized as an important virulence factor used by B. pseudomallei Isolates of B. pseudomallei have been shown to express one of four different types of LPS (typical LPS, atypical LPS types B and B2, and rough LPS) and in vitro studies have demonstrated that LPS types may impact disease severity. The association between LPS types and clinical manifestations, however, is still unknown, in part because an effective method for LPS type identification is not available. Thus, we developed antigen capture immunoassays capable of distinguishing between the LPS types. Mice were injected with B or B2 LPS for atypical LPS-specific monoclonal antibody (mAb) isolation; only two mAbs (3A2 and 5B4) were isolated from mice immunized with B2 LPS. Immunoblot analysis and surface plasmon resonance demonstrated that 3A2 and 5B4 are reactive with both B2 and B LPS where 3A2 was shown to possess higher affinity. Assays were then developed using capsular polysaccharide-specific mAb 4C4 for bacterial capture and 4C7 (previously shown to bind typical LPS) or 3A2 mAbs for typical or atypical LPS strain detection, respectively. The evaluations performed with 197 strains of Burkholderia and non-Burkholderia species showed that the assays are reactive to B. pseudomallei and Burkholderia mallei strains and have an accuracy of 98.8% (zero false positives and two false negatives) for LPS typing. The results suggest that the assays are effective and applicable for B. pseudomallei LPS typing. PMID- 27994104 TI - Surveillance at Private Laboratories Identifies Small Outbreaks of Hepatitis E in Urban Bangladesh. AB - Although large outbreaks of hepatitis E are regularly identified in south Asia, the majority of south Asian countries lack surveillance systems for this disease, which has hindered burden of disease estimates and prioritization of resources for prevention. Our study aimed to identify small hepatitis E outbreaks through a sentinel private laboratory in Dhaka, Bangladesh. We identified patients with detectable IgM antibody against hepatitis E virus. We defined a small outbreak as at least two laboratory-confirmed cases or >= 2 acute jaundice cases from the sentinel cases' family, neighborhood, or workplace. From November 2008 to November 2009, we identified 29 small outbreaks of hepatitis E from one private laboratory. The median number of cases in each outbreak was three. Cases were identified every month. Eighteen outbreaks occurred among families or neighbors, and 11 in the workplace. Among 103 cases identified as part of outbreaks, 31 (30%) sought care for diagnosis. In Bangladesh, collaboration between government public health surveillance and private laboratories can strengthen capacity for outbreak detection and improve estimates of disease burden. PMID- 27994106 TI - Resistance to First-Line Antituberculosis Drugs in Washington State by Region of Birth and Implications for Latent Tuberculosis Treatment Among Foreign-Born Individuals. AB - The United States has a low burden of drug resistance among tuberculosis (TB) cases compared with other world regions. TB is increasingly concentrated among foreign-born individuals who have higher rates of drug resistance than U.S.-born individuals. While universal drug susceptibility testing is the standard for detecting active tuberculosis, there are limited guidelines for latent tuberculosis infection (LTBI) treatment based on risk factors for drug resistance. To quantify the variable risk of drug resistance among foreign-born individuals, all TB cases in Washington State between 1994 and 2014 with drug resistance data for isoniazid, rifampin, pyrazinamide, and ethambutol were divided into eight regions of birth. Logistic regression was used to characterize regional differences in resistance patterns. Genotypic cluster and lineage data were compared against drug resistance in a subanalysis. Among 4,298 cases, isoniazid resistance was more common in foreign-born individuals (12.6% versus 4.8%; P < 0.001), with the highest burden among individuals from the Asia-Pacific (14.8%) region. Rifampin resistance was slightly higher among foreign-born individuals (1.9% versus 1.1%; P = 0.063). Multivariate logistic regression demonstrated that older age was associated with a lower risk of resistance to isoniazid and rifampin (odds ratio [OR] = 0.86, P = 0.006 and OR = 0.64, P = 0.003 for each 20-year interval, respectively). These data suggest drug resistance in LTBI will remain a challenge and that rifampin-based regimens for treatment of LTBI in non-human immunodeficiency virus-infected adults may be preferable for individuals born in regions with high levels of isoniazid resistance. However, further research is needed to demonstrate whether LTBI treatment based on region of birth further decreases TB reactivation. PMID- 27994108 TI - Prevalence of and Factors Associated with Nephropathy in Diabetic Patients Attending an Outpatient Clinic in Harare, Zimbabwe. AB - There is limited information on the burden of diabetic nephropathy in developing countries. This study aimed to determine the prevalence of and factors associated with nephropathy among diabetic patients attending an outpatient clinic in Harare, Zimbabwe. In an analytical cross-sectional study, diabetic patients were consecutively enrolled and a questionnaire administered, clinical assessment conducted, and blood samples collected for human immunodeficiency virus testing and measurement of lipids, creatinine, fructosamine, and glycosylated hemoglobin levels. Urine samples were collected for determination of albumin and creatinine levels, which were used to categorize albuminuria. A total of 344 diabetic patients were enrolled. Overall, just over a third (35.8%) of patients had moderately increased albuminuria and 9.0% had severely increased albuminuria giving an overall prevalence of nephropathy of 44.8%. Prevalence of moderately increased albuminuria was slightly higher (36.5% versus 33.3%) and severely increased albuminuria slightly lower (8.8% versus 9.5%) in type 2 than type 1 diabetes patients, but the difference was not statistically significant (P = 0.866). Higher fructosamine and retinopathy were associated with nephropathy in both univariate and multivariate analysis {higher fructosamine (odds ratio [OR] = 1.00, confidence interval [CI] = 1.00-1.01), and retinopathy (OR = 2.80, CI = 1.64-4.97)}. We report a higher prevalence of moderately increased albuminuria and a lower prevalence of severely increased albuminuria compared with findings reported a decade ago among type 1 and type 2 diabetes mellitus patients attending the same clinic. High fructosamine and retinopathy were independent predictors of nephropathy. PMID- 27994107 TI - Evaluation of the GeneXpert for Human Monkeypox Diagnosis. AB - Monkeypox virus (MPXV), a zoonotic orthopoxvirus (OPX), is endemic in the Democratic Republic of Congo (DRC). Currently, diagnostic assays for human monkeypox (MPX) focus on real-time quantitative polymerase chain reaction (PCR) assays, which are typically performed in sophisticated laboratory settings. Herein, we evaluated the accuracy and utility of a multiplex MPX assay using the GeneXpert platform, a portable rapid diagnostic device that may serve as a point of-care test to diagnose infections in endemic areas. The multiplex MPX/OPX assay includes a MPX-specific PCR test, OPX-generic PCR test, and an internal control PCR test. In total, 164 diagnostic specimens (50 crusts and 114 vesicular swabs) were collected from suspected MPX cases in Tshuapa Province, DRC, under national surveillance guidelines. The specimens were tested with the GeneXpert MPX/OPX assay and an OPX PCR assay at the Institut National de Recherche Biomedicale (INRB) in Kinshasa. Aliquots of each specimen were tested in parallel with a MPX specific PCR assay at the Centers for Disease Control and Prevention. The results of the MPX PCR were used as the gold standard for all analyses. The GeneXpert MPX/OPX assay performed at INRB had a sensitivity of 98.8% and specificity of 100%. The GeneXpert assay performed well with both crust and vesicle samples. The GeneXpert MPX/OPX test incorporates a simple methodology that performs well in both laboratory and field conditions, suggesting its viability as a diagnostic platform that may expand and expedite current MPX detection capabilities. PMID- 27994109 TI - Meningoencephalitis Caused by Reactivation of Chagas Disease in Patient Without Known Immunosuppression. AB - Central nervous system (CNS) involvement in Chagas disease (CD) is an uncommon complication that can result from direct involvement of the parasite or from thromboembolic phenomena. Direct involvement of CNS can occur in both acute and chronic forms of CD, and can also be secondary to reactivation. Reactivation of CD generally occurs in immunosuppressed patients such as those with human immunodeficiency infection or malignancies being rarely described in patients without apparent immunosuppression. We report a case of a patient living for many years in a nonendemic area for CD that presented to the emergency department with sudden onset of neurological symptoms as a result of reactivation of the disease. The microorganism was isolated from cerebrospinal fluid, and despite appropriate use of benznidazole, the patient died of sepsis after 22 days of treatment. Further investigation did not show any apparent cause of immunosuppression. This case report shows the importance of considering the diagnostic possibility of neurological complications from CD reactivation in patients that have ever lived in CD-endemic areas even without apparent underlying immunosuppression. PMID- 27994111 TI - Donor Human Milk for the High-Risk Infant: Preparation, Safety, and Usage Options in the United States. AB - The use of donor human milk is increasing for high-risk infants, primarily for infants born weighing <1500 g or those who have severe intestinal disorders. Pasteurized donor milk may be considered in situations in which the supply of maternal milk is insufficient. The use of pasteurized donor milk is safe when appropriate measures are used to screen donors and collect, store, and pasteurize the milk and then distribute it through established human milk banks. The use of nonpasteurized donor milk and other forms of direct, Internet-based, or informal human milk sharing does not involve this level of safety and is not recommended. It is important that health care providers counsel families considering milk sharing about the risks of bacterial or viral contamination of nonpasteurized human milk and about the possibilities of exposure to medications, drugs, or herbs in human milk. Currently, the use of pasteurized donor milk is limited by its availability and affordability. The development of public policy to improve and expand access to pasteurized donor milk, including policies that support improved governmental and private financial support for donor milk banks and the use of donor milk, is important. PMID- 27994113 TI - Parsing Language and Measures Around Child Maltreatment. PMID- 27994112 TI - Safe Sleep Guideline Adherence in Nationwide Marketing of Infant Cribs and Products. AB - BACKGROUND: Sudden infant death syndrome and sleep-related sudden unexpected infant death remain leading causes of infant mortality in the United States despite 4 safe sleep guideline restatements over the previous 24 years. Advertising and retail crib displays often promote infant sleep environments that are counter to the most recent American Academy of Pediatrics (AAP) guidelines. METHODS: Magazine advertisements featuring sleep in parenting magazines from 1992, 2010, and 2015 were reviewed for adherence. Crib displays from nationwide retailers were surveyed for adherence to the latest AAP safe sleep guidelines. The primary outcome was adherence to the guidelines. RESULTS: Of 1758 retail crib displays reviewed, only half adhered to the latest AAP guidelines. The most common reasons for nonadherence were the use of bumper pads and loose bedding. The depiction of infant cribs and sleep products in magazine advertising has become significantly more adherent over time; however, 35% of current advertisements depict nonadherent, unsafe sleep environments. Magazine advertising portraying safe sleep environments revealed racial and ethnic disparities. CONCLUSIONS: Although improvements have been made over time with increased adherence to AAP safe sleep guidelines, significant deficiencies remain. Advertising continues to depict unsafe sleep environments. Crib manufacturers and retail establishments continue to market and sell bedding and sleep products considered unsafe by the AAP in approximately half of retail crib displays. Pediatric and public health care providers should continue educational and advocacy efforts aimed at the public, but should also include retailers, manufacturers, and advertising professionals to foster improved sleep environments for all children. PMID- 27994110 TI - Dynamics and Trends in Fecal Biomarkers of Gut Function in Children from 1-24 Months in the MAL-ED Study. AB - Growth and development shortfalls that are disproportionately prevalent in children living in poor environmental conditions are postulated to result, at least in part, from abnormal gut function. Using data from The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal cohort study, we examine biomarkers of gut inflammation and permeability in relation to environmental exposures and feeding practices. Trends in the concentrations of three biomarkers, myeloperoxidase (MPO), neopterin (NEO), and alpha-1-antitrypsin (AAT), are described from fecal samples collected during the first 2 years of each child's life. A total of 22,846 stool samples were processed during the longitudinal sampling of 2,076 children 0-24 months of age. Linear mixed models were constructed to examine the relationship between biomarker concentrations and recent food intake, symptoms of illness, concurrent enteropathogen infection, and socioeconomic status. Average concentrations of MPO, NEO, and AAT were considerably higher than published references for healthy adults. The concentration of each biomarker tended to decrease over the first 2 years of life and was highly variable between samples from each individual child. Both MPO and AAT were significantly elevated by recent breast milk intake. All three biomarkers were associated with pathogen presence, although the strength and direction varied by pathogen. The interpretation of biomarker concentrations is subject to the context of their collection. Herein, we identify that common factors (age, breast milk, and enteric infection) influence the concentration of these biomarkers. Within the context of low- and middle-income communities, we observe concentrations that indicate gut abnormalities, but more appropriate reference standards are needed. PMID- 27994114 TI - Nicotine and Tobacco as Substances of Abuse in Children and Adolescents. AB - Nicotine is the primary pharmacologic component of tobacco, and users of tobacco products seek out its effects. The highly addictive nature of nicotine is responsible for its widespread use and difficulty with quitting. This technical report focuses on nicotine and discusses the stages of use in progression to dependence on nicotine-containing products; the physiologic characteristics, neurobiology, metabolism, pharmacogenetics, and health effects of nicotine; and acute nicotine toxicity. Finally, some newer approaches to cessation are noted. PMID- 27994115 TI - Child Maltreatment and Adult Living Standards at 50 Years. AB - BACKGROUND AND OBJECTIVE: Child maltreatment (abuse and neglect) has established effects on mental health. Less is known about its influence on adult economic circumstances. We aimed to establish associations of child maltreatment with such outcomes and explore potential pathways. METHODS: We used 1958 British birth cohort data (N = 8076) to examine associations of child neglect and abuse with adult (50 years) long-term sickness absence, not in employment, education or training (NEET), lacking assets, income-related support, poor qualifications, financial insecurity, manual social class, and social mobility. We assessed mediation of associations by 16-year cognition and mental health. RESULTS: Abuse prevalence varied from 1% (sexual) to 10% (psychological); 16% were neglected. A total of 21% experienced 1 maltreatment type, 10% experienced >=2 types. Sexual and nonsexual abuse were associated with several outcomes; eg, for sexual abuse, adjusted odds ratio (aOR) of income-related support was 1.75 (95% confidence interval [CI], 1.12-2.72). Associations were little affected by potential mediating factors. Neglect was associated with several adult outcomes (eg, aOR of NEET was 1.43 [95% CI, 1.10-1.85]) and associations were mediated by cognition and mental health (primarily by cognition): percent explained varied between 4% (NEET) to 70% (poor qualifications). In general, the risk of poor outcome increased by number of maltreatment types (eg, aOR for long-term sickness absence increased from 1.0 [reference] to 1.76 [95% CI, 1.32-2.35] to 2.69 [95% CI, 1.96 3.68], respectively, for 0, 1, and >=2 types of maltreatment. CONCLUSIONS: Childhood maltreatment is associated with poor midadulthood socioeconomic outcomes, with accumulating risk for those experiencing multiple types of maltreatment. Cognitive ability and mental health are implicated in the pathway to outcome for neglect but not abuse. PMID- 27994116 TI - Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era. AB - A fundamental question in biology is how the extraordinary range of living organisms arose. In this theme issue, we celebrate how evolutionary studies on the origins of morphological diversity have changed over the past 350 years since the first publication of the Philosophical Transactions of The Royal Society Current understanding of this topic is enriched by many disciplines, including anatomy, palaeontology, developmental biology, genetics and genomics. Development is central because it is the means by which genetic information of an organism is translated into morphology. The discovery of the genetic basis of development has revealed how changes in form can be inherited, leading to the emergence of the field known as evolutionary developmental biology (evo-devo). Recent approaches include imaging, quantitative morphometrics and, in particular, genomics, which brings a new dimension. Articles in this issue illustrate the contemporary evo devo field by considering general principles emerging from genomics and how this and other approaches are applied to specific questions about the evolution of major transitions and innovations in morphology, diversification and modification of structures, intraspecific morphological variation and developmental plasticity. Current approaches enable a much broader range of organisms to be studied, thus building a better appreciation of the origins of morphological diversity.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994117 TI - Alternative splicing and the evolution of phenotypic novelty. AB - Alternative splicing, a mechanism of post-transcriptional RNA processing whereby a single gene can encode multiple distinct transcripts, has been proposed to underlie morphological innovations in multicellular organisms. Genes with developmental functions are enriched for alternative splicing events, suggestive of a contribution of alternative splicing to developmental programmes. The role of alternative splicing as a source of transcript diversification has previously been compared to that of gene duplication, with the relationship between the two extensively explored. Alternative splicing is reduced following gene duplication with the retention of duplicate copies higher for genes which were alternatively spliced prior to duplication. Furthermore, and unlike the case for overall gene number, the proportion of alternatively spliced genes has also increased in line with the evolutionary diversification of cell types, suggesting alternative splicing may contribute to the complexity of developmental programmes. Together these observations suggest a prominent role for alternative splicing as a source of functional innovation. However, it is unknown whether the proliferation of alternative splicing events indeed reflects a functional expansion of the transcriptome or instead results from weaker selection acting on larger species, which tend to have a higher number of cell types and lower population sizes.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994118 TI - Deep homology in the age of next-generation sequencing. AB - The principle of homology is central to conceptualizing the comparative aspects of morphological evolution. The distinctions between homologous or non-homologous structures have become blurred, however, as modern evolutionary developmental biology (evo-devo) has shown that novel features often result from modification of pre-existing developmental modules, rather than arising completely de novo. With this realization in mind, the term 'deep homology' was coined, in recognition of the remarkably conserved gene expression during the development of certain animal structures that would not be considered homologous by previous strict definitions. At its core, it can help to formulate an understanding of deeper layers of ontogenetic conservation for anatomical features that lack any clear phylogenetic continuity. Here, we review deep homology and related concepts in the context of a gene expression-based homology discussion. We then focus on how these conceptual frameworks have profited from the recent rise of high throughput next-generation sequencing. These techniques have greatly expanded the range of organisms amenable to such studies. Moreover, they helped to elevate the traditional gene-by-gene comparison to a transcriptome-wide level. We will end with an outlook on the next challenges in the field and how technological advances might provide exciting new strategies to tackle these questions.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994119 TI - Origin of animal multicellularity: precursors, causes, consequences-the choanoflagellate/sponge transition, neurogenesis and the Cambrian explosion. AB - Evolving multicellularity is easy, especially in phototrophs and osmotrophs whose multicells feed like unicells. Evolving animals was much harder and unique; probably only one pathway via benthic 'zoophytes' with pelagic ciliated larvae allowed trophic continuity from phagocytic protozoa to gut-endowed animals. Choanoflagellate protozoa produced sponges. Converting sponge flask cells mediating larval settling to synaptically controlled nematocysts arguably made Cnidaria. I replace Haeckel's gastraea theory by a sponge/coelenterate/bilaterian pathway: Placozoa, hydrozoan diploblasty and ctenophores were secondary; stem anthozoan developmental mutations arguably independently generated coelomate bilateria and ctenophores. I emphasize animal origin's conceptual aspects (selective, developmental) related to feeding modes, cell structure, phylogeny of related protozoa, sequence evidence, ecology and palaeontology. Epithelia and connective tissue could evolve only by compensating for dramatically lower feeding efficiency that differentiation into non-choanocytes entails. Consequentially, larger bodies enabled filtering more water for bacterial food and harbouring photosynthetic bacteria, together adding more food than cell differentiation sacrificed. A hypothetical presponge of sessile triploblastic sheets (connective tissue sandwiched between two choanocyte epithelia) evolved oogamy through selection for larger dispersive ciliated larvae to accelerate benthic trophic competence and overgrowing protozoan competitors. Extinct Vendozoa might be elaborations of this organismal grade with choanocyte-bearing epithelia, before poriferan water channels and cnidarian gut/nematocysts/synapses evolved.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994121 TI - New genes from old: asymmetric divergence of gene duplicates and the evolution of development. AB - Gene duplications and gene losses have been frequent events in the evolution of animal genomes, with the balance between these two dynamic processes contributing to major differences in gene number between species. After gene duplication, it is common for both daughter genes to accumulate sequence change at approximately equal rates. In some cases, however, the accumulation of sequence change is highly uneven with one copy radically diverging from its paralogue. Such 'asymmetric evolution' seems commoner after tandem gene duplication than after whole-genome duplication, and can generate substantially novel genes. We describe examples of asymmetric evolution in duplicated homeobox genes of moths, molluscs and mammals, in each case generating new homeobox genes that were recruited to novel developmental roles. The prevalence of asymmetric divergence of gene duplicates has been underappreciated, in part, because the origin of highly divergent genes can be difficult to resolve using standard phylogenetic methods.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994120 TI - Phylogenetic evidence for the modular evolution of metazoan signalling pathways. AB - Communication among cells was paramount to the evolutionary increase in cell type diversity and, ultimately, the origin of large body size. Across the diversity of Metazoa, there are only few conserved cell signalling pathways known to orchestrate the complex cell and tissue interactions regulating development; thus, modification to these few pathways has been responsible for generating diversity during the evolution of animals. Here, we summarize evidence for the origin and putative function of the intracellular, membrane-bound and secreted components of seven metazoan cell signalling pathways with a special focus on early branching metazoans (ctenophores, poriferans, placozoans and cnidarians) and basal unikonts (amoebozoans, fungi, filastereans and choanoflagellates). We highlight the modular incorporation of intra- and extracellular components in each signalling pathway and suggest that increases in the complexity of the extracellular matrix may have further promoted the modulation of cell signalling during metazoan evolution. Most importantly, this updated view of metazoan signalling pathways highlights the need for explicit study of canonical signalling pathway components in taxa that do not operate a complete signalling pathway. Studies like these are critical for developing a deeper understanding of the evolution of cell signalling.This article is part of the themed issue 'Evo devo in the genomics era, and the origins of morphological diversity'. PMID- 27994122 TI - Cranial shape evolution in adaptive radiations of birds: comparative morphometrics of Darwin's finches and Hawaiian honeycreepers. AB - Adaptive radiation is the rapid evolution of morphologically and ecologically diverse species from a single ancestor. The two classic examples of adaptive radiation are Darwin's finches and the Hawaiian honeycreepers, which evolved remarkable levels of adaptive cranial morphological variation. To gain new insights into the nature of their diversification, we performed comparative three dimensional geometric morphometric analyses based on X-ray microcomputed tomography (uCT) scanning of dried cranial skeletons. We show that cranial shapes in both Hawaiian honeycreepers and Coerebinae (Darwin's finches and their close relatives) are much more diverse than in their respective outgroups, but Hawaiian honeycreepers as a group display the highest diversity and disparity of all other bird groups studied. We also report a significant contribution of allometry to skull shape variation, and distinct patterns of evolutionary change in skull morphology in the two lineages of songbirds that underwent adaptive radiation on oceanic islands. These findings help to better understand the nature of adaptive radiations in general and provide a foundation for future investigations on the developmental and molecular mechanisms underlying diversification of these morphologically distinguished groups of birds.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994123 TI - The origins, scaling and loss of tetrapod digits. AB - Many of the great morphologists of the nineteenth century marvelled at similarities between the limbs of diverse species, and Charles Darwin noted these homologies as significant supporting evidence for descent with modification from a common ancestor. Sir Richard Owen also took great care to highlight each of the elements of the forelimb and hindlimb in a multitude of species with focused attention on the homology between the hoof of the horse and the middle digit of man. The ensuing decades brought about a convergence of palaeontology, experimental embryology and molecular biology to lend further support to the homologies of tetrapod limbs and their developmental origins. However, for all that we now understand about the conserved mechanisms of limb development and the development of gross morphological disturbances, little of what is presented in the experimental or medical literature reflects the remarkable diversity resulting from the 450 million year experiment of natural selection. An understanding of conserved and divergent limb morphologies in this new age of genomics and genome engineering promises to reveal more of the developmental potential residing in all limbs and to unravel the mechanisms of evolutionary variation in limb size and shape. In this review, we present the current state of our rapidly advancing understanding of the evolutionary origin of hands and feet and highlight what is known about the mechanisms that shape diverse limbs.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994124 TI - Major evolutionary transitions and innovations: the tympanic middle ear. AB - One of the most amazing transitions and innovations during the evolution of mammals was the formation of a novel jaw joint and the incorporation of the original jaw joint into the middle ear to create the unique mammalian three bone/ossicle ear. In this review, we look at the key steps that led to this change and other unusual features of the middle ear and how developmental biology has been providing an understanding of the mechanisms involved. This starts with an overview of the tympanic (air-filled) middle ear, and how the ear drum (tympanic membrane) and the cavity itself form during development in amniotes. This is followed by an investigation of how the ear is connected to the pharynx and the relationship of the ear to the bony bulla in which it sits. Finally, the novel mammalian jaw joint and versatile dentary bone will be discussed with respect to evolution of the mammalian middle ear.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994126 TI - Waiting in the wings: what can we learn about gene co-option from the diversification of butterfly wing patterns? AB - A major challenge is to understand how conserved gene regulatory networks control the wonderful diversity of form that we see among animals and plants. Butterfly wing patterns are an excellent example of this diversity. Butterfly wings form as imaginal discs in the caterpillar and are constructed by a gene regulatory network, much of which is conserved across the holometabolous insects. Recent work in Heliconius butterflies takes advantage of genomic approaches and offers insights into how the diversification of wing patterns is overlaid onto this conserved network. WntA is a patterning morphogen that alters spatial information in the wing. Optix is a transcription factor that acts later in development to paint specific wing regions red. Both of these loci fit the paradigm of conserved protein-coding loci with diverse regulatory elements and developmental roles that have taken on novel derived functions in patterning wings. These discoveries offer insights into the 'Nymphalid Ground Plan', which offers a unifying hypothesis for pattern formation across nymphalid butterflies. These loci also represent 'hotspots' for morphological change that have been targeted repeatedly during evolution. Both convergent and divergent evolution of a great diversity of patterns is controlled by complex alleles at just a few genes. We suggest that evolutionary change has become focused on one or a few genetic loci for two reasons. First, pre-existing complex cis-regulatory loci that already interact with potentially relevant transcription factors are more likely to acquire novel functions in wing patterning. Second, the shape of wing regulatory networks may constrain evolutionary change to one or a few loci. Overall, genomic approaches that have identified wing patterning loci in these butterflies offer broad insight into how gene regulatory networks evolve to produce diversity.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994125 TI - Human evolution: a tale from ancient genomes. AB - The field of human ancient DNA (aDNA) has moved from mitochondrial sequencing that suffered from contamination and provided limited biological insights, to become a fully genomic discipline that is changing our conception of human history. Recent successes include the sequencing of extinct hominins, and true population genomic studies of Bronze Age populations. Among the emerging areas of aDNA research, the analysis of past epigenomes is set to provide more new insights into human adaptation and disease susceptibility through time. Starting as a mere curiosity, ancient human genetics has become a major player in the understanding of our evolutionary history.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994127 TI - The genetic and molecular architecture of phenotypic diversity in sticklebacks. AB - A major goal of evolutionary biology is to identify the genotypes and phenotypes that underlie adaptation to divergent environments. Stickleback fish, including the threespine stickleback (Gasterosteus aculeatus) and the ninespine stickleback (Pungitius pungitius), have been at the forefront of research to uncover the genetic and molecular architecture that underlies phenotypic diversity and adaptation. A wealth of quantitative trait locus (QTL) mapping studies in sticklebacks have provided insight into long-standing questions about the distribution of effect sizes during adaptation as well as the role of genetic linkage in facilitating adaptation. These QTL mapping studies have also provided a basis for the identification of the genes that underlie phenotypic diversity. These data have revealed that mutations in regulatory elements play an important role in the evolution of phenotypic diversity in sticklebacks. Genetic and molecular studies in sticklebacks have also led to new insights on the genetic basis of repeated evolution and suggest that the same loci are involved about half of the time when the same phenotypes evolve independently. When the same locus is involved, selection on standing variation and repeated mutation of the same genes have both contributed to the evolution of similar phenotypes in independent populations.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994128 TI - Cavefish and the basis for eye loss. AB - Animals have colonized the entire world from rather moderate to the harshest environments, some of these so extreme that only few animals are able to survive. Cave environments present such a challenge and obligate cave animals have adapted to perpetual darkness by evolving a multitude of traits. The most common and most studied cave characteristics are the regression of eyes and the overall reduction in pigmentation. Studying these traits can provide important insights into how evolutionary forces drive convergent and regressive adaptation. The blind Mexican cavefish (Astyanax mexicanus) has emerged as a useful model to study cave evolution owing to the availability of genetic and genomic resources, and the amenability of embryonic development as the different populations remain fertile with each other. In this review, we give an overview of our current knowledge underlying the process of regressive and convergent evolution using eye degeneration in cavefish as an example.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994129 TI - The bald and the beautiful: hairlessness in domestic dog breeds. AB - An extraordinary amount of genomic variation is contained within the chromosomes of domestic dogs, manifesting as dramatic differences in morphology, behaviour and disease susceptibility. Morphology, in particular, has been a topic of enormous interest as biologists struggle to understand the small window of dog domestication from wolves, and the division of dogs into pure breeding, closed populations termed breeds. Many traits related to morphology, including body size, leg length and skull shape, have been under selection as part of the standard descriptions for the nearly 400 breeds recognized worldwide. Just as important, however, are the minor traits that have undergone selection by fanciers and breeders to define dogs of a particular appearance, such as tail length, ear position, back arch and variation in fur (pelage) growth patterns. In this paper, we both review and present new data for traits associated with pelage including fur length, curl, growth, shedding and even the presence or absence of fur. Finally, we report the discovery of a new gene associated with the absence of coat in the American Hairless Terrier breed.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994130 TI - Insulin receptors and wing dimorphism in rice planthoppers. AB - Wing polymorphism contributes significantly to the success of a wide variety of insects. However, its underlying molecular mechanism is less well understood. The migratory planthopper (BPH), Nilaparvata lugens, is one of the most extensively studied insects for wing polymorphism, due to its natural features of short- and long-winged morphs. Using the BPH as an example, we first surveyed the environmental cues that possibly influence wing developmental plasticity. Second, we explained the molecular basis by which two insulin receptors (InR1 and InR2) act as switches to determine alternative wing morphs in the BPH. This finding provides an additional layer of regulatory mechanism underlying wing polymorphism in insects in addition to juvenile hormones. Further, based on a discrete domain structure between InR1 and InR2 across insect species, we discussed the potential roles by which they might contribute to insect polymorphism. Last, we concluded with future directions of disentangling the insulin signalling pathway in the BPH, which serves as an ideal model for studying wing developmental plasticity in insects.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994133 TI - Automatic design of fiber-reinforced soft actuators for trajectory matching. AB - Soft actuators are the components responsible for producing motion in soft robots. Although soft actuators have allowed for a variety of innovative applications, there is a need for design tools that can help to efficiently and systematically design actuators for particular functions. Mathematical modeling of soft actuators is an area that is still in its infancy but has the potential to provide quantitative insights into the response of the actuators. These insights can be used to guide actuator design, thus accelerating the design process. Here, we study fluid-powered fiber-reinforced actuators, because these have previously been shown to be capable of producing a wide range of motions. We present a design strategy that takes a kinematic trajectory as its input and uses analytical modeling based on nonlinear elasticity and optimization to identify the optimal design parameters for an actuator that will follow this trajectory upon pressurization. We experimentally verify our modeling approach, and finally we demonstrate how the strategy works, by designing actuators that replicate the motion of the index finger and thumb. PMID- 27994131 TI - Development and genetics in the evolution of land plant body plans. AB - The colonization of land by plants shaped the terrestrial biosphere, the geosphere and global climates. The nature of morphological and molecular innovation driving land plant evolution has been an enigma for over 200 years. Recent phylogenetic and palaeobotanical advances jointly demonstrate that land plants evolved from freshwater algae and pinpoint key morphological innovations in plant evolution. In the haploid gametophyte phase of the plant life cycle, these include the innovation of mulitcellular forms with apical growth and multiple growth axes. In the diploid phase of the life cycle, multicellular axial sporophytes were an early innovation priming subsequent diversification of indeterminate branched forms with leaves and roots. Reverse and forward genetic approaches in newly emerging model systems are starting to identify the genetic basis of such innovations. The data place plant evo-devo research at the cusp of discovering the developmental and genetic changes driving the radiation of land plant body plans.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994132 TI - Evolution of floral diversity: genomics, genes and gamma. AB - A salient feature of flowering plant diversification is the emergence of a novel suite of floral features coinciding with the origin of the most species-rich lineage, Pentapetalae. Advances in phylogenetics, developmental genetics and genomics, including new analyses presented here, are helping to reconstruct the specific evolutionary steps involved in the evolution of this clade. The enormous floral diversity among Pentapetalae appears to be built on a highly conserved ground plan of five-parted (pentamerous) flowers with whorled phyllotaxis. By contrast, lability in the number and arrangement of component parts of the flower characterize the early-diverging eudicot lineages subtending Pentapetalae. The diversification of Pentapetalae also coincides closely with ancient hexaploidy, referred to as the gamma whole-genome triplication, for which the phylogenetic timing, mechanistic details and molecular evolutionary consequences are as yet not fully resolved. Transcription factors regulating floral development often persist in duplicate or triplicate in gamma-derived genomes, and both individual genes and whole transcriptional programmes exhibit a shift from broadly overlapping to tightly defined expression domains in Pentapetalae flowers. Investigations of these changes associated with the origin of Pentapetalae can lead to a more comprehensive understanding of what is arguably one of the most important evolutionary diversification events within terrestrial plants.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'. PMID- 27994135 TI - Chemical distinctions between Stradivari's maple and modern tonewood. AB - Violins made by Antonio Stradivari are renowned for having been the preferred instruments of many leading violinists for over two centuries. There have been long-standing questions about whether wood used by Stradivari possessed unique properties compared with modern tonewood for violin making. Analyses of maple samples removed from four Stradivari and a Guarneri instrument revealed highly distinct organic and inorganic compositions compared with modern maples. By solid state 13C NMR spectroscopy, we observed that about one-third of hemicellulose had decomposed after three centuries, accompanied by signs of lignin oxidation. No apparent changes in cellulose were detected by NMR and synchrotron X-ray diffraction. By thermogravimetric analysis, historical maples exhibited reduced equilibrium moisture content. In differential scanning calorimetry measurements, only maples from Stradivari violins, but not his cellos, exhibited unusual thermooxidation patterns distinct from natural wood. Elemental analyses by inductively coupled plasma mass spectrometry suggested that Stradivari's maples were treated with complex mineral preservatives containing Al, Ca, Cu, Na, K, and Zn. This type of chemical seasoning was an unusual practice, unknown to later generations of violin makers. In their current state, maples in Stradivari violins have very different chemical properties compared with their modern counterparts, likely due to the combined effects of aging, chemical treatments, and vibrations. These findings may inspire further chemical experimentation with tonewood processing for instrument making in the 21st century. PMID- 27994134 TI - Common and heritable components of white matter microstructure predict cognitive function at 1 and 2 y. AB - Previous studies indicate that the microstructure of individual white matter (WM) tracts is related to cognitive function. More recent studies indicate that the microstructure of individual tracts is highly correlated and that a property common across WM is related to overall cognitive function in adults. However, little is known about whether these common WM properties exist in early childhood development or how they are related to cognitive development. In this study, we used diffusion tensor imaging (DTI) to investigate common underlying factors in 12 fiber tracts, their relationship with cognitive function, and their heritability in a longitudinal sample of healthy children at birth (n = 535), 1 y (n = 322), and 2 y (n = 244) of age. Our data show that, in neonates, there is a highly significant correlation between major WM tracts that decreases from birth to 2 y of age. Over the same period, the factor structure increases in complexity, from one factor at birth to three factors at age 2 y, which explain 50% of variance. The identified common factors of DTI metrics in each age group are significantly correlated with general cognitive scores and predict cognitive ability in later childhood. These factors are moderately heritable. These findings illustrate the anatomical differentiation of WM fiber from birth to 2 y of age that correlate with cognitive development. Our results also suggest that the common factor approach is an informative way to study WM development and its relationship with cognition and is a useful approach for future imaging genetic studies. PMID- 27994136 TI - Enhanced strength and temperature dependence of mechanical properties of Li at small scales and its implications for Li metal anodes. AB - Most next-generation Li ion battery chemistries require a functioning lithium metal (Li) anode. However, its application in secondary batteries has been inhibited because of uncontrollable dendrite growth during cycling. Mechanical suppression of dendrite growth through solid polymer electrolytes (SPEs) or through robust separators has shown the most potential for alleviating this problem. Studies of the mechanical behavior of Li at any length scale and temperature are limited because of its extreme reactivity, which renders sample preparation, transfer, microstructure characterization, and mechanical testing extremely challenging. We conduct nanomechanical experiments in an in situ scanning electron microscope and show that micrometer-sized Li attains extremely high strengths of 105 MPa at room temperature and of 35 MPa at 90 degrees C. We demonstrate that single-crystalline Li exhibits a power-law size effect at the micrometer and submicrometer length scales, with the strengthening exponent of 0.68 at room temperature and of -1.00 at 90 degrees C. We also report the elastic and shear moduli as a function of crystallographic orientation gleaned from experiments and first-principles calculations, which show a high level of anisotropy up to the melting point, where the elastic and shear moduli vary by a factor of ~4 between the stiffest and most compliant orientations. The emergence of such high strengths in small-scale Li and sensitivity of this metal's stiffness to crystallographic orientation help explain why the existing methods of dendrite suppression have been mainly unsuccessful and have significant implications for practical design of future-generation batteries. PMID- 27994137 TI - Edge effects enhance carbon uptake and its vulnerability to climate change in temperate broadleaf forests. AB - Forest fragmentation is a ubiquitous, ongoing global phenomenon with profound impacts on the growing conditions of the world's remaining forest. The temperate broadleaf forest makes a large contribution to the global terrestrial carbon sink but is also the most heavily fragmented forest biome in the world. We use field measurements and geospatial analyses to characterize carbon dynamics in temperate broadleaf forest fragments. We show that forest growth and biomass increase by 89 +/- 17% and 64 +/- 12%, respectively, from the forest interior to edge, but ecosystem edge enhancements are not currently captured by models or approaches to quantifying regional C balance. To the extent that the findings from our research represent the forest of southern New England in the United States, we provide a preliminary estimate that edge growth enhancement could increase estimates of the region's carbon uptake and storage by 13 +/- 3% and 10 +/- 1%, respectively. However, we also find that forest growth near the edge declines three times faster than that in the interior in response to heat stress during the growing season. Using climate projections, we show that future heat stress could reduce the forest edge growth enhancement by one-third by the end of the century. These findings contrast studies of edge effects in the world's other major forest biomes and indicate that the strength of the temperate broadleaf forest carbon sink and its capacity to mitigate anthropogenic carbon emissions may be stronger, but also more sensitive to climate change than previous estimates suggest. PMID- 27994138 TI - Structural and mutational analysis of the nonribosomal peptide synthetase heterocyclization domain provides insight into catalysis. AB - Nonribosomal peptide synthetases (NRPSs) are a family of multidomain, multimodule enzymes that synthesize structurally and functionally diverse peptides, many of which are of great therapeutic or commercial value. The central chemical step of peptide synthesis is amide bond formation, which is typically catalyzed by the condensation (C) domain. In many NRPS modules, the C domain is replaced by the heterocyclization (Cy) domain, a homologous domain that performs two consecutive reactions by using hitherto unknown catalytic mechanisms. It first catalyzes amide bond formation, and then the intramolecular cyclodehydration between a Cys, Ser, or Thr side chain and the backbone carbonyl carbon to form a thiazoline, oxazoline, or methyloxazoline ring. The rings are important for the form and function of the peptide product. We present the crystal structure of an NRPS Cy domain, Cy2 of bacillamide synthetase, at a resolution of 2.3 A. Despite sharing the same fold, the active sites of C and Cy domains have important differences. The structure allowed us to probe the roles of active-site residues by using mutational analyses in a peptide synthesis assay with intact bacillamide synthetase. The drastically different effects of these mutants, interpreted by using our structural and bioinformatic results, provide insight into the catalytic mechanisms of the Cy domain and implicate a previously unexamined Asp Thr dyad in catalysis of the cyclodehydration reaction. PMID- 27994140 TI - Observing the formation of ice and organic crystals in active sites. AB - Heterogeneous nucleation is vital to a wide range of areas as diverse as ice nucleation on atmospheric aerosols and the fabrication of high-performance thin films. There is excellent evidence that surface topography is a key factor in directing crystallization in real systems; however, the mechanisms by which nanoscale pits and pores promote nucleation remain unclear. Here, we use natural cleavage defects on Muscovite mica to investigate the activity of topographical features in the nucleation from vapor of ice and various organic crystals. Direct observation of crystallization within surface pockets using optical microscopy and also interferometry demonstrates that these sharply acute features provide extremely effective nucleation sites and allows us to determine the mechanism by which this occurs. A confined phase is first seen to form along the apex of the wedge and then grows out of the pocket opening to generate a bulk crystal after a threshold saturation has been achieved. Ice nucleation proceeds in a comparable manner, although our resolution is insufficient to directly observe a condensate before the growth of a bulk crystal. These results provide insight into the mechanism of crystal deposition from vapor on real surfaces, where this will ultimately enable us to use topography to control crystal deposition on surfaces. They are also particularly relevant to our understanding of processes such as cirrus cloud formation, where such topographical features are likely candidates for the "active sites" that make clay particles effective nucleants for ice in the atmosphere. PMID- 27994139 TI - Triazoles inhibit cholesterol export from lysosomes by binding to NPC1. AB - Niemann-Pick C1 (NPC1), a membrane protein of lysosomes, is required for the export of cholesterol derived from receptor-mediated endocytosis of LDL. Lysosomal cholesterol export is reportedly inhibited by itraconazole, a triazole that is used as an antifungal drug [Xu et al. (2010) Proc Natl Acad Sci USA 107:4764-4769]. Here we show that posaconazole, another triazole, also blocks cholesterol export from lysosomes. We prepared P-X, a photoactivatable cross linking derivative of posaconazole. P-X cross-linked to NPC1 when added to intact cells. Cross-linking was inhibited by itraconazole but not by ketoconazole, an imidazole that does not block cholesterol export. Cross-linking of P-X was also blocked by U18666A, a compound that has been shown to bind to NPC1 and inhibit cholesterol export. P-X also cross-linked to purified NPC1 that was incorporated into lipid bilayer nanodiscs. In this in vitro system, cross-linking of P-X was inhibited by itraconazole, but not by U18666A. P-X cross-linking was not prevented by deletion of the N-terminal domain of NPC1, which contains the initial binding site for cholesterol. In contrast, P-X cross-linking was reduced when NPC1 contained a point mutation (P691S) in its putative sterol-sensing domain. We hypothesize that the sterol-sensing domain has a binding site that can accommodate structurally different ligands. PMID- 27994141 TI - Decline in the negative association between low birth weight and cognitive ability. AB - Low birth weight predicts compromised cognitive ability. We used data from the 1958 National Child Development Study (NCDS), the 1970 British Cohort Study (BCS), and the 2000-2002 Millennium Cohort Study (MCS) to analyze how this association has changed over time. Birth weight was divided into two categories, <2,500 g (low) and 2,500-4,500 g (normal) and verbal cognitive ability was measured at the age of 10 or 11 y. A range of maternal and family characteristics collected at or soon after the time of birth were considered. Linear regression was used to analyze the association between birth weight and cognitive ability in a baseline model and in a model that adjusted for family characteristics. The standardized difference (SD) in cognitive scores between low-birth-weight and normal-birth-weight children was large in the NCDS [-0.37 SD, 95% confidence interval (CI): -0.46, -0.27] and in the BCS (-0.34, 95% CI: -0.43, -0.25) cohorts, and it was more than halved for children born in the MCS cohort (-0.14, 95% CI: -0.22, -0.06). The adjustment for family characteristics did not explain the cross-cohort differences. The results show that the association between low birth weight and decreased cognitive ability has declined between the 1950s and 1970s birth cohorts and the 2000--2002 birth cohort, despite a higher proportion of the low-birth-weight babies having a very low birth weight (<1,500 g) in the more recent birth cohort. Advancements in obstetric and neonatal care may have attenuated the negative consequences associated with being born small. PMID- 27994143 TI - Spatial heterogeneity of climate change as an experiential basis for skepticism. AB - We postulate that skepticism about climate change is partially caused by the spatial heterogeneity of climate change, which exposes experiential learners to climate heuristics that differ from the global average. This hypothesis is tested by formalizing an index that measures local changes in climate using station data and comparing this index with survey-based model estimates of county-level opinion about whether global warming is happening. Results indicate that more stations exhibit cooling and warming than predicted by random chance and that spatial variations in these changes can account for spatial variations in the percentage of the population that believes that "global warming is happening." This effect is diminished in areas that have experienced more record low temperatures than record highs since 2005. Together, these results suggest that skepticism about climate change is driven partially by personal experiences; an accurate heuristic for local changes in climate identifies obstacles to communicating ongoing changes in climate to the public and how these communications might be improved. PMID- 27994142 TI - Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival. AB - The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein quality-control capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation. PMID- 27994145 TI - Global risk model for vector-borne transmission of Zika virus reveals the role of El Nino 2015. AB - Zika, a mosquito-borne viral disease that emerged in South America in 2015, was declared a Public Health Emergency of International Concern by the WHO in February of 2016. We developed a climate-driven R0 mathematical model for the transmission risk of Zika virus (ZIKV) that explicitly includes two key mosquito vector species: Aedes aegypti and Aedes albopictus The model was parameterized and calibrated using the most up to date information from the available literature. It was then driven by observed gridded temperature and rainfall datasets for the period 1950-2015. We find that the transmission risk in South America in 2015 was the highest since 1950. This maximum is related to favoring temperature conditions that caused the simulated biting rates to be largest and mosquito mortality rates and extrinsic incubation periods to be smallest in 2015. This event followed the suspected introduction of ZIKV in Brazil in 2013. The ZIKV outbreak in Latin America has very likely been fueled by the 2015-2016 El Nino climate phenomenon affecting the region. The highest transmission risk globally is in South America and tropical countries where Ae. aegypti is abundant. Transmission risk is strongly seasonal in temperate regions where Ae. albopictus is present, with significant risk of ZIKV transmission in the southeastern states of the United States, in southern China, and to a lesser extent, over southern Europe during the boreal summer season. PMID- 27994144 TI - Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. AB - Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse (GFAP-IL-15tg) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8+ T and natural killer (NK) cells was augmented in these GFAP-IL-15tg mice after brain ischemia. Of note, depletion of CD8+ T or NK cells attenuated ischemic brain injury in GFAP-IL-15tg mice. Furthermore, knockdown of the IL-15 receptor alpha or blockade of cell-to-cell contact diminished the activation and effector function of CD8+ T and NK cells in GFAP-IL-15tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8+ T and NK cell-mediated immunity. PMID- 27994146 TI - Persistence and biodegradation of oil at the ocean floor following Deepwater Horizon. AB - The 2010 Deepwater Horizon disaster introduced an unprecedented discharge of oil into the deep Gulf of Mexico. Considerable uncertainty has persisted regarding the oil's fate and effects in the deep ocean. In this work we assess the compound specific rates of biodegradation for 125 aliphatic, aromatic, and biomarker petroleum hydrocarbons that settled to the deep ocean floor following release from the damaged Macondo Well. Based on a dataset comprising measurements of up to 168 distinct hydrocarbon analytes in 2,980 sediment samples collected within 4 y of the spill, we develop a Macondo oil "fingerprint" and conservatively identify a subset of 312 surficial samples consistent with contamination by Macondo oil. Three trends emerge from analysis of the biodegradation rates of 125 individual hydrocarbons in these samples. First, molecular structure served to modulate biodegradation in a predictable fashion, with the simplest structures subject to fastest loss, indicating that biodegradation in the deep ocean progresses similarly to other environments. Second, for many alkanes and polycyclic aromatic hydrocarbons biodegradation occurred in two distinct phases, consistent with rapid loss while oil particles remained suspended followed by slow loss after deposition to the seafloor. Third, the extent of biodegradation for any given sample was influenced by the hydrocarbon content, leading to substantially greater hydrocarbon persistence among the more highly contaminated samples. In addition, under some conditions we find strong evidence for extensive degradation of numerous petroleum biomarkers, notably including the native internal standard 17alpha(H),21beta(H)-hopane, commonly used to calculate the extent of oil weathering. PMID- 27994147 TI - Ownership of an artificial limb induced by electrical brain stimulation. AB - Replacing the function of a missing or paralyzed limb with a prosthetic device that acts and feels like one's own limb is a major goal in applied neuroscience. Recent studies in nonhuman primates have shown that motor control and sensory feedback can be achieved by connecting sensors in a robotic arm to electrodes implanted in the brain. However, it remains unknown whether electrical brain stimulation can be used to create a sense of ownership of an artificial limb. In this study on two human subjects, we show that ownership of an artificial hand can be induced via the electrical stimulation of the hand section of the somatosensory (SI) cortex in synchrony with touches applied to a rubber hand. Importantly, the illusion was not elicited when the electrical stimulation was delivered asynchronously or to a portion of the SI cortex representing a body part other than the hand, suggesting that multisensory integration according to basic spatial and temporal congruence rules is the underlying mechanism of the illusion. These findings show that the brain is capable of integrating "natural" visual input and direct cortical-somatosensory stimulation to create the multisensory perception that an artificial limb belongs to one's own body. Thus, they serve as a proof of concept that electrical brain stimulation can be used to "bypass" the peripheral nervous system to induce multisensory illusions and ownership of artificial body parts, which has important implications for patients who lack peripheral sensory input due to spinal cord or nerve lesions. PMID- 27994148 TI - Mere experience of low subjective socioeconomic status stimulates appetite and food intake. AB - Among social animals, subordinate status or low social rank is associated with increased caloric intake and weight gain. This may reflect an adaptive behavioral pattern that promotes acquisition of caloric resources to compensate for low social resources that may otherwise serve as a buffer against environmental demands. Similarly, diet-related health risks like obesity and diabetes are disproportionately more prevalent among people of low socioeconomic resources. Whereas this relationship may be associated with reduced financial and material resources to support healthier lifestyles, it remains unclear whether the subjective experience of low socioeconomic status may alone be sufficient to stimulate consumption of greater calories. Here we show that the mere feeling of lower socioeconomic status relative to others stimulates appetite and food intake. Across four studies, we found that participants who were experimentally induced to feel low (vs. high or neutral) socioeconomic status subsequently exhibited greater automatic preferences for high-calorie foods (e.g., pizza, hamburgers), as well as intake of greater calories from snack and meal contexts. Moreover, these results were observed even in the absence of differences in access to financial resources. Our results demonstrate that among humans, the experience of low social class may contribute to preferences and behaviors that risk excess energy intake. These findings suggest that psychological and physiological systems regulating appetite may also be sensitive to subjective feelings of deprivation for critical nonfood resources (e.g., social standing). Importantly, efforts to mitigate the socioeconomic gradient in obesity may also need to address the psychological experience of low social status. PMID- 27994149 TI - FGF14 is a regulator of KCNQ2/3 channels. AB - KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we show that fibroblast growth factor 14 (FGF14), previously described as a VGSC regulator, also affects KCNQ function and localization. FGF14 knockdown leads to a reduction of KCNQ2 in the AIS and a reduction in whole-cell KCNQ currents. FGF14 positively regulates KCNQ2/3 channels in a simplified expression system. FGF14 interacts with KCNQ2 at a site distinct from the FGF14-VGSC interaction surface, thus enabling the bridging of NaV1.6 and KCNQ2. These data implicate FGF14 as an organizer of channel localization in the AIS and provide insight into the coordination of KCNQ and VGSC conductances in the regulation of membrane potential. PMID- 27994150 TI - Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. AB - Double-positive (DP) thymocytes respond to intrathymic T-cell receptor (TCR) signals by undergoing positive selection and lineage differentiation into single positive (SP) mature cells. Concomitant with these well-characterized events is the acquisition of a mature T-cell gene expression program characterized by the induction of the effector molecules IL-7Ralpha, S1P1, and CCR7, but the underlying mechanism remains elusive. We report here that transcription repressor Growth factor independent 1 (Gfi1) orchestrates the fidelity of the DP gene expression program and developmental maturation into SP cells. Loss of Gfi1 resulted in premature induction of effector genes and the transcription factors forkhead box protein O1 (Foxo1) and Klf2 in DP thymocytes and the accumulation of postselection intermediate populations and accelerated transition into SP cells. Strikingly, partial loss of Foxo1 function, but not restored survival fitness, rectified the dysregulated gene expression and thymocyte maturation in Gfi1 deficient mice. Our results establish the Gfi1-Foxo1 axis and the transcriptional circuitry that actively maintain DP identity and shape the proper generation of mature T cells. PMID- 27994151 TI - Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol. AB - The activation mechanism of the classical transient receptor potential channels TRPC4 and -5 via the Gq/11 protein-phospholipase C (PLC) signaling pathway has remained elusive so far. In contrast to all other TRPC channels, the PLC product diacylglycerol (DAG) is not sufficient for channel activation, whereas TRPC4/5 channel activity is potentiated by phosphatidylinositol 4,5-bisphosphate (PIP2) depletion. As a characteristic structural feature, TRPC4/5 channels contain a C terminal PDZ-binding motif allowing for binding of the scaffolding proteins Na+/H+ exchanger regulatory factor (NHERF) 1 and 2. PKC inhibition or the exchange of threonine for alanine in the C-terminal PDZ-binding motif conferred DAG sensitivity to the channel. Altogether, we present a DAG-mediated activation mechanism for TRPC4/5 channels tightly regulated by NHERF1/2 interaction. PIP2 depletion evokes a C-terminal conformational change of TRPC5 proteins leading to dynamic dissociation of NHERF1/2 from the C terminus of TRPC5 as a prerequisite for DAG sensitivity. We show that NHERF proteins are direct regulators of ion channel activity and that DAG sensitivity is a distinctive hallmark of TRPC channels. PMID- 27994153 TI - Polycomb "polypacks" the chromatin. PMID- 27994152 TI - Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. AB - MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFalpha indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFkappaB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL+ neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68+ macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials. PMID- 27994154 TI - Mg2+-dependent translational speed bump acts to regulate gene transcription. PMID- 27994155 TI - Fisheries management impacts on target species status. AB - Fisheries management systems around the world are highly diverse in their design, operation, and effectiveness at meeting objectives. A variety of management institutions, strategies, and tactics are used across disparate regions, fishing fleets, and taxonomic groups. At a global level, it is unclear which particular management attributes have greatest influence on the status of fished populations, and also unclear which external factors affect the overall success of fisheries management systems. We used expert surveys to characterize the management systems by species of 28 major fishing nations and examined influences of economic, geographic, and fishery-related factors. A Fisheries Management Index, which integrated research, management, enforcement, and socioeconomic attributes, showed wide variation among countries and was strongly affected by per capita gross domestic product (positively) and capacity-enhancing subsidies (negatively). Among 13 management attributes considered, three were particularly influential in whether stock size and fishing mortality are currently in or trending toward desirable states: extensiveness of stock assessments, strength of fishing pressure limits, and comprehensiveness of enforcement programs. These results support arguments that the key to successful fisheries management is the implementation and enforcement of science-based catch or effort limits, and that monetary investment into fisheries can help achieve management objectives if used to limit fishing pressure rather than enhance fishing capacity. Countries with currently less-effective management systems have the greatest potential for improving long-term stock status outcomes and should be the focus of efforts to improve fisheries management globally. PMID- 27994157 TI - Retraction for Wenz et al., Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. PMID- 27994156 TI - Linking parasite populations in hosts to parasite populations in space through Taylor's law and the negative binomial distribution. AB - The spatial distribution of individuals of any species is a basic concern of ecology. The spatial distribution of parasites matters to control and conservation of parasites that affect human and nonhuman populations. This paper develops a quantitative theory to predict the spatial distribution of parasites based on the distribution of parasites in hosts and the spatial distribution of hosts. Four models are tested against observations of metazoan hosts and their parasites in littoral zones of four lakes in Otago, New Zealand. These models differ in two dichotomous assumptions, constituting a 2 * 2 theoretical design. One assumption specifies whether the variance function of the number of parasites per host individual is described by Taylor's law (TL) or the negative binomial distribution (NBD). The other assumption specifies whether the numbers of parasite individuals within each host in a square meter of habitat are independent or perfectly correlated among host individuals. We find empirically that the variance-mean relationship of the numbers of parasites per square meter is very well described by TL but is not well described by NBD. Two models that posit perfect correlation of the parasite loads of hosts in a square meter of habitat approximate observations much better than two models that posit independence of parasite loads of hosts in a square meter, regardless of whether the variance-mean relationship of parasites per host individual obeys TL or NBD. We infer that high local interhost correlations in parasite load strongly influence the spatial distribution of parasites. Local hotspots could influence control and conservation of parasites. PMID- 27994158 TI - Glacial ocean circulation and stratification explained by reduced atmospheric temperature. AB - Earth's climate has undergone dramatic shifts between glacial and interglacial time periods, with high-latitude temperature changes on the order of 5-10 degrees C. These climatic shifts have been associated with major rearrangements in the deep ocean circulation and stratification, which have likely played an important role in the observed atmospheric carbon dioxide swings by affecting the partitioning of carbon between the atmosphere and the ocean. The mechanisms by which the deep ocean circulation changed, however, are still unclear and represent a major challenge to our understanding of glacial climates. This study shows that various inferred changes in the deep ocean circulation and stratification between glacial and interglacial climates can be interpreted as a direct consequence of atmospheric temperature differences. Colder atmospheric temperatures lead to increased sea ice cover and formation rate around Antarctica. The associated enhanced brine rejection leads to a strongly increased deep ocean stratification, consistent with high abyssal salinities inferred for the last glacial maximum. The increased stratification goes together with a weakening and shoaling of the interhemispheric overturning circulation, again consistent with proxy evidence for the last glacial. The shallower interhemispheric overturning circulation makes room for slowly moving water of Antarctic origin, which explains the observed middepth radiocarbon age maximum and may play an important role in ocean carbon storage. PMID- 27994159 TI - Genetic risk for obesity predicts nucleus accumbens size and responsivity to real world food cues. AB - Obesity is a major public health concern that involves an interaction between genetic susceptibility and exposure to environmental cues (e.g., food marketing); however, the mechanisms that link these factors and contribute to unhealthy eating are unclear. Using a well-known obesity risk polymorphism (FTO rs9939609) in a sample of 78 children (ages 9-12 y), we observed that children at risk for obesity exhibited stronger responses to food commercials in the nucleus accumbens (NAcc) than children not at risk. Similarly, children at a higher genetic risk for obesity demonstrated larger NAcc volumes. Although a recessive model of this polymorphism best predicted body mass and adiposity, a dominant model was most predictive of NAcc size and responsivity to food cues. These findings suggest that children genetically at risk for obesity are predisposed to represent reward signals more strongly, which, in turn, may contribute to unhealthy eating behaviors later in life. PMID- 27994160 TI - Hierarchy stability moderates the effect of status on stress and performance in humans. AB - High social status reduces stress responses in numerous species, but the stress buffering effect of status may dissipate or even reverse during times of hierarchical instability. In an experimental test of this hypothesis, 118 participants (57.3% female) were randomly assigned to a high- or low-status position in a stable or unstable hierarchy and were then exposed to a social evaluative stressor (a mock job interview). High status in a stable hierarchy buffered stress responses and improved interview performance, but high status in an unstable hierarchy boosted stress responses and did not lead to better performance. This general pattern of effects was observed across endocrine (cortisol and testosterone), psychological (feeling in control), and behavioral (competence, dominance, and warmth) responses to the stressor. The joint influence of status and hierarchy stability on interview performance was explained by feelings of control and testosterone reactivity. Greater feelings of control predicted enhanced interview performance, whereas increased testosterone reactivity predicted worse performance. These results provide direct causal evidence that high status confers adaptive benefits for stress reduction and performance only when the social hierarchy is stable. When the hierarchy is unstable, high status actually exacerbates stress responses. PMID- 27994163 TI - Identification of IgE as the Allergy-Associated Ig Isotype. PMID- 27994161 TI - One Health approach to cost-effective rabies control in India. AB - Over 20,000 rabies deaths occur annually in India, representing one-third of global human rabies. The Indian state of Tamil Nadu has pioneered a "One Health" committee to address the challenge of rabies in dogs and humans. Currently, rabies control in Tamil Nadu involves postexposure vaccination of humans after dog bites, whereas potential supplemental approaches include canine vaccination and sterilization. We developed a data-driven rabies transmission model fit to human rabies autopsy data and human rabies surveillance data from Tamil Nadu. Integrating local estimates for canine demography and costs, we predicted the impact of canine vaccination and sterilization on human health outcomes and evaluated cost-effectiveness according to the WHO criteria for India, which correspond to thresholds of $1,582 and $4,746 per disability-adjusted life-years (DALYs) for very cost-effective and cost-effective strategies, respectively. We found that highly feasible strategies focused on stray dogs, vaccinating as few as 7% of dogs annually, could very cost-effectively reduce human rabies deaths by 70% within 5 y, and a modest expansion to vaccinating 13% of stray dogs could cost-effectively reduce human rabies by almost 90%. Through integration over parameter uncertainty, we find that, for a cost-effectiveness threshold above $1,400 per DALY, canine interventions are at least 95% likely to be optimal. If owners are willing to bring dogs to central point campaigns at double the rate that campaign teams can capture strays, expanded annual targets become cost effective. This case study of cost-effective canine interventions in Tamil Nadu may have applicability to other settings in India and beyond. PMID- 27994164 TI - Pillars Article: Physico-Chemical Properties of Human Reaginic Antibody: IV. Presence of a Unique Immunoglobulin as a Carrier of Reaginic Activity. J. Immunol. 1966. 97: 75-85. PMID- 27994165 TI - Pillars Article: Physicochemical Properties of Reaginic Antibody: V. Correlation of Reaginic Activity with gammaE-Globulin Antibody. J. Immunol. 1966. 97: 840 853. PMID- 27994166 TI - Intratumoral Delivery of Immunotherapy-Act Locally, Think Globally. AB - Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell-mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes. PMID- 27994167 TI - Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation: Time To T Up the Thymus. AB - The success of allogeneic hematopoietic stem cell transplantation, a key treatment for many disorders, is intertwined with T cell immune reconstitution. The thymus plays a key role post allogeneic hematopoietic stem cell transplantation in the generation of a broad but self-tolerant T cell repertoire, but it is exquisitely sensitive to a range of insults during the transplant period, including conditioning regimens, corticosteroids, infections, and graft versus-host disease. Although endogenous thymic repair is possible it is often suboptimal, and there is a need to develop exogenous strategies to help regenerate the thymus. Therapies currently in clinical trials in the transplant setting include keratinocyte growth factor, cytokines (IL-7 and IL-22), and hormonal modulation including sex steroid inhibition and growth hormone administration. Such regenerative strategies may ultimately enable the thymus to play as prominent a role after transplant as it once did in early childhood, allowing a more complete restoration of the T cell compartment. PMID- 27994168 TI - The Allostery Model of TCR Regulation. AB - The activity of the alphabeta TCR is controlled by conformational switches. In the resting conformation, the TCR is not phosphorylated and is inactive. Binding of multivalent peptide-MHC to the TCR stabilizes the active conformation, leading to TCR signaling. These two conformations allow the TCRs to be allosterically regulated. We review recent data on heterotropic allostery where peptide-MHC and membrane cholesterol serve opposing functions as positive and negative allosteric regulators, respectively. In resting T cells cholesterol keeps TCRs in the resting conformation that otherwise would become spontaneously active. This regulation is well described by the classical Monod-Wyman-Changeux model of allostery. Moreover, the observation that TCRs assemble into nanoclusters might allow for homotropic allostery, in which individual TCRs could positively cooperate and thus enhance the sensitivity of T cell activation. This new view of TCR regulation will contribute to a better understanding of TCR functioning. PMID- 27994171 TI - Changes in DNA methylation levels during seed development in Jatropha curcas. PMID- 27994169 TI - Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the Frog Xenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type. AB - Gene duplication confers genetic redundancy that can facilitate subfunctionalization, the partitioning of ancestral functions between paralogs. We capitalize on a recent genome duplication in Xenopus laevis (African clawed frog) to interrogate possible functional differentiation between alloalleles of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates toxicity of dioxin-like compounds and plays a role in the physiology and development of the cardiovascular, hepatic, and immune systems in vertebrates. X. laevis has 2 AHR genes, AHR1alpha and AHR1beta To test the hypothesis that the encoded proteins exhibit different molecular functions, we used TALENs in XLK-WG cells, generating mutant lines lacking functional versions of each AHR and measuring the transcriptional responsiveness of several target genes to the toxic xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the candidate endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). Mutation of either AHR1alpha or AHR1beta reduced TCDD induction of the canonical AHR target, Cytochrome P4501A6, by 75%, despite the much lower abundance of AHR1beta in wild type cells. More modestly induced target genes, encoding aryl hydrocarbon receptor repressor (AHRR), spectrin repeat-containing nuclear envelope protein 1 (SYNE-1), and gap junction protein gamma 1 (GJC1), were regulated solely by AHR1alpha. AHR1beta was responsible for CYP1A6 induction by FICZ, while AHR1alpha mediated FICZ induction of AHRR We conclude that AHR1alpha and AHR1beta have distinct transcriptional functions in response to specific agonists, even within a single cell type. Functional analysis of frog AHR paralogs advances the understanding of AHR evolution and as well as the use of frog models of developmental toxicology such as FETAX. PMID- 27994172 TI - Microsatellite markers suggest high genetic diversity in an urban population of Cooper's hawks (Accipiter cooperii). PMID- 27994170 TI - How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology. AB - Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. PMID- 27994173 TI - Transgenic overexpression of BAFF regulates the expression of immune-related genes in zebrafish, Danio rerio. AB - The B-cell activating factor (BAFF) is a member of tumour necrosis factor (TNF) superfamily that specifically regulates B lymphocyte proliferation and survival. Excess BAFF leads to overproduction of antibodies for secretion, anti-dsDNA antibodies and a lupus-like syndrome in mice. To investigate whether transgenic overexpression of the zebrafish BAFF leads to immunoglobulin changes and/or early maturing of the immune system, a Tol2-GFP-2A-BAFF/His recombinant plasmid was constructed by inserting a 2A peptide between the green fluorescent protein (GFP) and BAFF sequences. Functional GFP and BAFF proteins were expressed separately and confirmed in HeLa cells. The relative expression of immune-related genes (IgLC-1, IgLC-2, IgLC-3, IgD, IgM and IL-4), early lymphoid markers (Ikaros, Rag 1 and TCRAC), and the protooncogene Bcl-2 were evaluated by quantitative polymerase chain reaction (PCR) in F0 founder of transgenic zebrafish juveniles and adults. Ectopic expression of BAFF in adults was confirmed using Western blots and was shown to upregulate IgLC-1, IgLC-2, IgD, IgM, IgZ/T, Ikaros, Rag-1, TCRAC, IL-4 and Bcl-2 expression in juveniles on day 21 and IgLC-1, IgLC-2, IgD, IgM,IgZ/T, Rag-1, TCRAC and Bcl-2 expression in zebrafish three months postfertilization. The relative titers of specific IgM against Edwardsiella tarda WED were assessed using modified enzyme-linked immunosorbent assay (ELISA) with the whole body homogenate of zebrafish and demonstrated a significant increase in BAFF-transgenic group. Therefore, our findings provided novel insight into further exploration of modulating adaptive immunity and studying autoimmune diseases caused by regulating BAFF. PMID- 27994175 TI - Phylogeography, genetic diversity and demographic history of the Iranian Kurdish groups based on mtDNA sequences. AB - Throughout the history of modern humans, the current Kurdish-inhabited area has served as part of a tricontinental crossroad for major human migrations. Also, a significant body of archaeological evidence points to this area as the site of Neolithic transition. To investigate the phylogeography, origins and demographic history, mtDNA D-loop region of individuals representing four Kurdish groups from Iran were analysed. Our data indicated that most of the Kurds mtDNA lineages belong to branches of the haplogroups with the Western Eurasian origin; with small fractions of the Eastern Eurasian and sub-Saharan African lineages. The low level of mtDNA diversity observed in the Havrami group presented a bias towards isolation or increased drift due to small population size; while in the Kurmanji group it indicated a bias towards drift or mass migration events during the 5 18th century AD. The Mantel test showed strong isolation by distance, and AMOVA results for global and regional scales confirmed that the geography had acted as the main driving force in shaping the current pattern of mtDNA diversity, rather than linguistic similarity. The results of demographic analyses, in agreement with archaeological data, revealed a recent expansion of the Kurds (~9,500 years before present) related to the Neolithic transition from hunting and gathering, to farming and cattle breeding in the Near East. Further, the high frequencies of typical haplogroups for early farmers (H; 37.1%) and hunter-gatherers (U; 13.8%) in the Kurds may testify the earlier hunter-gatherers in the Kurdish-inhabited area that adopted and admixed the Kurds ancestors following the Neolithic transition. PMID- 27994174 TI - Evidence of digenic inheritance in autoinflammation-associated genes. AB - Familial Mediterranean fever (FMF) has traditionally been considered as a monogenic autosomal recessive disorder caused by mutations in the MEFV gene with highest incidence among Mediterranean populations. In a considerable number of patients with typical FMF, only one MEFV mutation was identified and the possibility that more than one autoinflammatory gene may be responsible for their disease was investigated. In the present study, an extensive search for possible mutations in three hereditary recurrent fever (HRF) genes was performed in 128 MEFV heterozygous Greek-Cypriots clinically diagnosed based on their phenotype with FMF-like disease from a previous study. Sequence analysis was performed for MVK, TNFRSF1A and NLRP3 genes which is also known to cause HRFs. In total, three patients were identified with heterozygous mutations and a second mutation in an autoinflammatory gene. Two patients carried a MEFV mutation and a NLRP3 mutation, and an additional third carried a MEFV mutation and a TNFRSF1A mutation. Patient 1 carried MEFV p.[Val726Ala] (NM_000243.2:c.2177T>C) and NLRP3 p.[Val198Met] (NM_001243133.1:c.592G>A) variants and patient 2 carried MEFV p.[Glu148Gln] (NM_000243.2:c.442G>C) variant which is of uncertain significance and NLRP3 p.[Arg176Trp] (NM_001243133.1:c.526C>T). Lastly, patient 3 was identified to carry MEFV p.[Met694Val] (NM_000243.2:c.2080A>G) and TNFRSF1A p.[Arg121Gln] (NM_001065.3:c.362G>A) variants. The results from this study indicate that screening of genes known to cause HRFs in patients already identified with a single MEFV mutation, can reveal quite rare but potentially causative mutational combinations at different loci. Such interaction provide further evidence for possible locus-locus interactions and phenotypes resulting from digenic inheritance. PMID- 27994176 TI - Genetic variation in ecoraces of tropical tasar silkworm, Antheraea mylitta using SSR markers. AB - The tropical tasar silkworm, Antheraea mylitta, polyphagous sericigenous insect mostly found in the tropical areas of India. It is found in these regions as ecotypes or ecoraces. It feeds primarily on plants, a variety of secondary plants like Terminalia arjuna and T. tomentosa. Tasar culture is a traditional livelihood for lakhs of tribal populace in the areas of Jharkhand, Chhatisgarh, Orissa, Maharashtra, Andhra Pradesh, West Bengal and Uttar Pradesh. In the present study, the genetic diversity of these ecoraces is identified by DNA markers, namely simple sequence repeats (SSRs), most of which produced polymorphic bands. PMID- 27994177 TI - Cytological behaviour of floral organs and in silico characterization of differentially expressed transcript-derived fragments associated with 'floral bud distortion' in soybean. AB - An attempt was made to understand the 'floral bud distortion' (FBD), an unexplored disorder prevailing in soybean. Cytological behaviour of floral reproductive organs and in silico characterization of differentially expressed transcript-derived fragments (TDFs) in symptomatic and asymptomatic soybean plants were carried out. Pollens in asymptomatic plants do not have defects in number, size, shape and function. However, in symptomatic plant, pollens were found nonviable, abnormal in shape and with reduced germination ability. Here, we employed a computational approach, exploring invaluable resources. The tissue specific transcript profile of symptomatic and asymptomatic sources was compared to determine differentially expressed TDFs associated with FBD to improve its basic understanding. A total of 60 decamer primers produced 197 scorable amplicons, ranged 162-1130 bp, of which 171 were monomorphic and 26 were differentially regulated. Reproducible TDFs were sequenced and characterized for their homology analysis, annotation, protein-protein interaction, subcellular localization and their physical mapping. Homology-based annotation of TDFs in soybean revealed presence of two characterized and seven uncharacterized hits. Annotation of characterized sequences showed presence of genes, namely auxin response factor 9 (ARF9) and forkhead-associated (FHA) domain, which are directly involved in plant development through various pathways, such as hormonal regulation, plant morphology, embryogenesis and DNA repair. PMID- 27994178 TI - Application of high resolution SNP arrays in patients with congenital oral clefts in south China. AB - Chromosome microarray analysis (CMA) has proven to be a powerful tool in postnatal patients with intellectual disabilities. However, the diagnostic capability of CMA in patients with congenital oral clefts remain mysterious. Here, we present our clinical experience in implementing whole-genome high resolution SNP arrays to investigate 33 patients with syndromic and nonsyndromic oral clefts in whom standard karyotyping analyses showed normal karyotypes. We aim to identify the genomic aetiology and candidate genes in patients with congenital oral clefts. CMA revealed copy number variants (CNVs) in every patient, which ranged from 2 to 9 per sample. The size of detected CNVs varied from 100 to 3.2 Mb. In 33 patients, we identified six clinically significant CNVs. The incidence of clinically significant CNVs was 18.2% (6/33). Three of these six CNVs were detected in patients with nonsyndromic clefts, including one who presented with isolated cleft lip with cleft palate (CLP) and two with cleft palate only (CPO). The remaining three CNVs were detected in patients with syndromic clefts. However, no CNV was detected in patients with cleft lip only (CLO). The six clinically significant CNVs were as follows: 8p23.1 microduplication (198 kb); 10q22.2-q22.3 microdeletion (1766 kb); 18q12.3 microduplication (638 kb); 20p12.1 microdeletion (184 kb); 6q26 microdeletion (389 kb); and 22q11.21-q11.23 microdeletion (3163 kb). In addition, two novel candidate genes for oral clefts, KAT6B and MACROD2, were putatively identified. We also found a CNV of unknown clinical significance with a detection rate of 3.0% (1/33). Our results further support the notion that CNVs significantly contributed to the genetic aetiology of oral clefts and emphasize the efficacy of whole-genome high-resolution SNP arrays to detect novel candidate genes in patients with syndromic and nonsyndromic clefts. PMID- 27994179 TI - Association between smoking behaviour and genetic variants of glial cell line derived neurotrophic factor. AB - Glial cell line-derived neurotrophic factor (GDNF) promotes development and differentiation of dopaminergic neurons, thus it has an important role in dopamine-related neuropsychiatric disorders. Since the role of dopamine system in smoking is well established, we hypothesized that GDNF gene variants may affect smoking behaviour. Self-reported data on smoking behaviour (never smoked, quit, occasional, or regular smokers) and level of nicotine addiction (Hooked on Nicotine Checklist and Fagerstrom Nicotine Addiction Scale), anxiety, as well as buccal samples were obtained from 930 Hungarian young adults (18-35 years). Genetic analysis involved eight GDNF single-nucleotide polymorphisms (SNP) (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111). Allele-wise association analyses of the eight GDNF SNPs provided a significant association between smoking behaviour and rs3096140 (P=0.0039). The minor allele (C) was more frequent in those groups who smoked in some form (quit, occasional or regular smokers) as compared to those who never smoked (P = 0.0046). This result remained significant after Bonferroni correction for multiple testing. In the ever smoking group, no significant differences were found in the level of nicotine addiction by the alleles of these polymorphisms. Also, no significant interaction of rs3096140 and smoking categories were observed on anxiety mean scores. Although previous data demonstrated an association between GDNF rs2910704 and severity of methamphetamine use to the best of our knowledge, this is the first study on the role of GDNF genetic variations in smoking behaviour. Our results suggest that GDNF rs3096140 might be involved in the genetic background of smoking, independent of anxiety characteristics. PMID- 27994180 TI - Chromosomal structural changes and microsatellite variations in newly synthesized hexaploid wheat mediated by unreduced gametes. AB - Allohexaploid wheat was derived from interspecific hybridization, followed by spontaneous chromosome doubling. Newly synthesized hexaploid wheat by crossing Triticum turgidum and Aegilops tauschii provides a classical model to understand the mechanisms of allohexaploidization in wheat. However, immediate chromosome level variation and microsatellite level variation of newly synthesized hexaploid wheat have been rarely reported. Here, unreduced gametes were applied to develop synthesized hexaploid wheat, NA0928, population by crossing T. turgidum ssp. dicoccum MY3478 and Ae. tauschii SY41, and further S0-S3 generations of NA0928 were assayed by sequential cytological and microsatellite techniques. We demonstrated that plentiful chromosomal structural changes and microsatellite variations emerged in the early generations of newly synthesized hexaploid wheat population NA0928, including aneuploidy with whole-chromosome loss or gain, aneuploidy with telosome formation, chromosome-specific repeated sequence elimination (indicated by fluorescence in situ hybridization) and microsatellite sequence elimination (indicated by sequencing), and many kinds of variations have not been previously reported. Additionally, we reported a new germplasm, T. turgidum accession MY3478 with excellent unreduced gametes trait, and then succeeded to transfer powdery mildew resistance from Ae. tauschii SY41 to synthesized allohexaploid wheat population NA0928, which would be valuable resistance resources for wheat improvement. PMID- 27994181 TI - High CpG island methylation of p16 gene and loss of p16 protein expression associate with the development and progression of tetralogy of Fallot. AB - We examined CpG island methylation in p16 gene and its effect on p16 protein expression in tetralogy of Fallot (ToF) patients to explore its potential implications in the development and progression of ToF. The study subjects consisted of 75 healthy controls and 63 ToF patients recruited at Linyi People's Hospital between January 2012 and June 2014. The 4 mL of peripheral venous blood of each subject was obtained and saved in ethylene diamine tetraacetic acid (EDTA) tubes. Methylation-specific polymerase chain reaction (MSP) was employed to detect CpG island methylation in p16 promoter region andWestern blotting was used to detect p16 expression of all subjects. Real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) was performed to test p16 mRNA expression. The results showed that p16-methylation rates in ToF group were significantly higher than the control group (ToF group, 58.73%; control group, 13.33%; P < 0.001). Remarkably, Western blotting and FQ-PCR results derived from RVOT revealed that p16 protein expression was significantly lower in ToF group compared tothe control group (0.76 +/- 0.21 versus 2.31 +/- 0.35; P < 0.001), and p16 gene expression was also markedly decreased in ToF group (1.212 +/- 0.152 versus 1.346 +/- 0.191, P < 0.001). Additionally, our analysis suggested that CpG island methylation in p16 promoters in ToF patients was negatively correlated with p16 protein and gene expression (both P < 0.05). Our study reports that high CpG island methylation of p16 gene and loss of p16 protein expression associate with the development and progression of ToF, which may have significant therapeutic applications for ToF. PMID- 27994183 TI - An efficient method to handle the 'large p, small n' problem for genomewide association studies using Haseman-Elston regression. AB - The 'large p, small n' problem in genomewide association studies (GWAS) is an important subject in genetic studies. Many approaches have been proposed for this issue, but none of them successfully combine the Haseman-Elston (H-E) regression with sliding-window scan approaches in GWAS. In this article, we extended H-E regression to GWAS, and replaced original data with different measurements of phenotype of sib pairs. Meanwhile, we also applied hidden Markov model to infer identity by state. Using subsequent simulation studies, we found that it had higher statistical power than the corresponding single-marker association studies. The advantage of the H-E regression was also sufficient to capture about 48.01% of the quantitative trait locus (QTL). Meanwhile, the results show that the power decreases with the increase in the number of QTLs, and the power of H-E regression is sensitive to heritability. PMID- 27994182 TI - Identification of a novel 15.5 kb SHOX deletion associated with marked intrafamilial phenotypic variability and analysis of its molecular origin. AB - Haploinsufficiency of the short stature homeobox contaning SHOX gene has been shown to result in a spectrum of phenotypes ranging from Leri-Weill dyschondrosteosis (LWD) at the more severe end to SHOX-related short stature at the milder end of the spectrum. Most alterations are whole gene deletions, point mutations within the coding region, or microdeletions in its flanking sequences. Here, we present the clinical and molecular data as well as the potential molecular mechanism underlying a novel microdeletion, causing a variable SHOX related haploinsufficiency disorder in a three-generation family. The phenotype resembles that of LWD in females, in males, however, the phenotypic expression is milder. The 15523-bp SHOX intragenic deletion, encompassing exons 3-6, was initially detected by array-CGH, followed by MLPA analysis. Sequencing of the breakpoints indicated an Alu recombination-mediated deletion (ARMD) as the potential causative mechanism. PMID- 27994184 TI - Complete mitochondrial genome of threatened mahseer Tor tor (Hamilton 1822) and its phylogenetic relationship within Cyprinidae family. AB - The mahseers (Tor, Neolissochilus and Naziritor) are an important group of fishes endemic to Asia with the conservation status of most species evaluated as threatened. Conservation plans to revive these declining wild populations are hindered by unstable taxonomy. Molecular phylogeny studies with mitochondrial genome have been successfully used to reconstruct the phylogenetic tree and to resolve taxonomic ambiguity. In the present study, complete mitochondrial genome of Tor tor has been sequenced using ion torrent next-generation sequencing platform with coverage of more than 1000 x. Comparative mitogenome analysis shows higher divergence value at ND1 gene than COI gene. Further, occurrence of a distinct genetic lineage of T. tor is revealed. The phylogenetic relationship among mahseer group has been defined as Neolissochilus hexagonolepis ((T. sinensis (T. putitora, T. tor), (T. khudree, T. tambroides)). PMID- 27994185 TI - In silico characterization of functional SNP within the oestrogen receptor gene. AB - Single-nucleotide polymorphism (SNP) association studies have become crucial in uncovering the genetic correlations of genomic variants with complex diseases, quantitative traits and physiological responses to drugs. However, the identification of SNPs responsible for specific phenotypes is a difficult problem to solve, requiring multiple testing of hundreds or thousands of SNPs in candidate genes. In this study, we performed an analysis of the genetic variations that can alter the structure and function of oestrogen receptor alpha using different computational tools. Among the nonsynonymous SNPs, a total of four SNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (polyphen-2, SNAP), as well as by the ESEfinder program, and one nonsense nsSNP was found. For noncoding SNPs, we found that one SNP in 5' UTR may potentially change protein expression level, nine SNPs were found to affect miRNA binding site and 28 SNPs might affect transcriptional regulation of the ESR1 gene. Reviewing the literature, 89 SNPs were found to be functional among which only four were located in exons. PMID- 27994186 TI - LcMKK, a MAPK kinase from Lycium chinense, confers cadmium tolerance in transgenic tobacco by transcriptional upregulation of ethylene responsive transcription factor gene. AB - Cadmium (Cd) is a highly toxic element to plants. Ethylene is an important phytohormone in the regulation of plant growth, development and stress response. Mitogen-activated protein kinase (MAPK) activation has been observed in plants exposed to Cd stress and was suggested to be involved in ethylene biosynthesis. We hypothesized that there may be a link between MAPK cascades and ethylene signalling in Cd-stressed plants. To test this hypothesis, the expression of LcMKK, LchERF and LcGSH1 genes, endogenous ethylene accumulation, GSH content and Cd concentration in Lycium chinense with or without Cd stress treatment were studied. Our results showed that LcMKK gene expression can be induced by the treatment of Cd in L. chinense. The transgenic tobacco expressing 35S::LcMKK showed greater tolerance to Cd stress and enhanced expression of NtERF and NtGSH1 genes, indicating that LcMKK is associated with the enhanced expression level of ERF and GSH synthesis-related genes in tobacco. We also found that endogenous ethylene and GSH content can be induced by Cd stress in L. chinense, and inhibited by cotreatment with PD98059, an inhibitor of MAPK kinase. Evidences presented here suggest that under Cd stress, GSH accumulation occurred at least partially by enhanced LcMKK gene expression and the ethylene signal transduction pathways might be involved in this accumulation. PMID- 27994188 TI - Marker-assisted improvement of the elite restorer line of rice, RPHR-1005 for resistance against bacterial blight and blast diseases. AB - This study was carried out to improve the RPHR-1005, a stable restorer line of the popular medium slender grain type rice hybrid, DRRH-3 for bacterial blight (BB) and blast resistance through marker-assisted backcross breeding (MABB). Two major BB resistance genes, Xa21 and Xa33 and a major blast resistance gene, Pi2 were transferred to RPHR-1005 as two individual crosses. Foreground selection for Xa21, Xa33, Pi2, Rf3 and Rf4 was done by using gene-specific functional markers, while 59 simple sequence repeat (SSR) markers polymorphic between the donors and recipient parents were used to select the best plant possessing target resistance genes at each backcross generation. Backcrossing was continued till BC2F2 and a promising homozygous backcross derived line possessing Xa21+ Pi2 and another possessing Xa33 were intercrossed to stack the target resistance genes into the genetic background of RPHR-1005. At ICF4, 10 promising lines possessing three resistance genes in homozygous condition along with fine-grain type, complete fertility restoration, better panicle exertion and taller plant type (compared to RPHR-1005) were identified. PMID- 27994187 TI - Cytogenetic analysis in couples with recurrent miscarriages: a retrospective study from Punjab, north India. AB - Human reproduction is considered as the most inefficient event as ~15-20% of human pregnancies end in miscarriage and in the product of miscarriages, chromosomal anomalies are a common occurrence. The aim of the present retrospective study was to assess the frequency of chromosomal aberrations in couples with recurrent miscarriages in the region of Punjab and to compare with worldwide frequencies. In this study, a total of 440 cases were referred between the period 1995-2015. After lymphocyte culturing, giemsa-trypsin banding was done for each case to assess the chromosomal anomalies. The frequency of chromosomal aberrations among couples was found to be 3.41% in our study. Among these aberrations, balanced reciprocal translocations formed the largest group with 60% anomalies. We would conclude that clinicians should understand the importance of chromosomal analysis in these couples and refer them for karyotyping after two miscarriages to rule out the possible genetic cause of recurrent miscarriages. PMID- 27994189 TI - Novel mutations in the transmembrane natriuretic peptide receptor NPR-B gene in four Indian families with acromesomelic dysplasia, type Maroteaux. AB - Acromesomelic dysplasia, type Maroteaux is a disorder characterized by disproportionate short stature predominantly affecting the middle and distal segments of the upper and lower limbs. It is an autosomal recessive disorder due to mutation in NPR2 gene which impairs skeletal growth. To screen the mutations in the gene NPR2, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected individuals of four families and sequenced. Four homozygous mutations in four different families were identified. These include three novel mutations including a deletion frameshift mutation (p.Cys586Ter), one nonsense mutation (p.Arg479Ter), one missense mutation (p.Val187Asp) and one reported missense mutation (p.Tyr338Cys). The study describes phenotypes of Indian patients and expands the mutation spectrum of the disorder. PMID- 27994190 TI - Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. AB - Molecular characterization of 23 cytogenetically confirmed XY females was attempted by screening coding regions of SRY and androgen receptor (AR) genes. Five of the index cases showed sequence variations in various exons of the AR gene: a deletion (n.1911delG) and substitutions n.1761G>A and n.1317C>T in exon 1; n.3510C>T transition in exon 6 and deletion mutation (n.3672delT) in exon 7. Four mutations identified here lead to the formation of truncated receptor protein, involving a substantial loss of AR functional domains which explains the phenotype in the subjects. The n.1761G>A substitution has been previously reported in cases with mild androgen insensitivity. Although the ligand-binding domain was considered as the mutational hot spot in AR gene, we report here 3/5 variations in the N-terminal domain emphasizing the significance of considering the N-terminal domain of AR as well for mutation screening. Our present observation also strengthens the role of AR gene and its direct association with AIS. PMID- 27994191 TI - Adenosine monophosphate-activated protein kinase from the mud crab, Scylla paramamosain: cDNA cloning and profiles under cold stress. AB - Adenosine monophosphate-activated protein kinase (AMPK), an important energy sensor, is crucial for organism survival under adverse conditions. In this study, the roles of this gene under cold stress in a warm-water mud crab, Scylla paramamosain was investigated. The full-length cDNA (SpAMPK) was 1884 bp and its open reading frame of 1566 bp was isolated and characterized. The expressions of SpAMPK detected by quantitative real-time PCR (qRT-PCR) in various tissues revealed that the highest expression was in the hepatopancreas. The profiles of SpAMPK gene in the hepatopancreas, chela muscle and gill were detected when the subadult crabs were exposed to the four temperature conditions of 10, 15, 20 and 25 degrees C. The results showed that the expression patterns of SpAMPK mRNA in the three tissues were significantly higher when crabs were exposed to 15 degrees C than the other three temperature treatments, while at 10 degrees C treatment, the SpAMPK mRNA was lowest among the four temperature treatments. These findings suggested that the high expression of SpAMPK mRNA might initiate ATP-producing pathways to generate energy to cope with cold stress at 15 degrees C treatment, which was slightly below the range of optimum temperatures; while treatment at 10 degrees C, far lower than optima, the low expression of SpAMPK mRNA could reduce the energy expenditure and thus induce the crabs into cold anesthesia. The results of SpAMPK in this study might contribute to the understanding of the molecular mechanism of acclimation to cold hardiness in S. paramamosain. PMID- 27994192 TI - Mapping of stripe rust resistance gene in an Aegilops caudate introgression line in wheat and its genetic association with leaf rust resistance. AB - A pair of stripe rust and leaf rust resistance genes was introgressed from Aegilops caudata, a nonprogenitor diploid species with the CC genome, to cultivated wheat. Inheritance and genetic mapping of stripe rust resistance gene in backcrossrecombinant inbred line (BC-RIL) population derived from the cross of a wheat-Ae. caudata introgression line (IL) T291- 2(pau16060) with wheat cv. PBW343 is reported here. Segregation of BC-RILs for stripe rust resistance depicted a single major gene conditioning adult plant resistance (APR) with stripe rust reaction varying from TR-20MS in resistant RILs signifying the presence of some minor genes as well. Genetic association with leaf rust resistance revealed that two genes are located at a recombination distance of 13%. IL T291-2 had earlier been reported to carry introgressions on wheat chromosomes 2D, 3D, 4D, 5D, 6D and 7D. Genetic mapping indicated the introgression of stripe rust resistance gene on wheat chromosome 5DS in the region carrying leaf rust resistance gene LrAc, but as an independent introgression. Simple sequence repeat (SSR) and sequence-tagged site (STS) markers designed from the survey sequence data of 5DS enriched the target region harbouring stripe and leaf rust resistance genes. Stripe rust resistance locus, temporarily designated as YrAc, mapped at the distal most end of 5DS linked with a group of four colocated SSRs and two resistance gene analogue (RGA)-STS markers at a distance of 5.3 cM. LrAc mapped at a distance of 9.0 cM from the YrAc and at 2.8 cM from RGA-STS marker Ta5DS_2737450, YrAc and LrAc appear to be the candidate genes for marker-assisted enrichment of the wheat gene pool for rust resistance. PMID- 27994194 TI - Gene interactions and genetics for yield and its attributes in grass pea (Lathyrus sativus L.). AB - Grain yield is a complex character representing a multiplicative end product of many yield attributes. However, understanding the genetics and inheritance that underlies yield and its component characters pose a prerequisite to attain the actual yield potential of any crop species. The knowledge pertaining to gene actions and interactions is likely to direct and strengthen the crop breeding programmes. With this objective, the present investigation was undertaken by using six generations derived from three different crosses in grass pea. The study underscores the significance of additive-dominance model, gene action involved in inheritance of quantitative characters and heritability. Of note, nonallelic interactions influencing the traits were detected by both scaling test and joint scaling test, indicating the inadequacy of the additive-dominance model alone in explaining the manifestation of complex traits such as yield. Besides, additive (d) and dominance (h) gene effects, different types of interallelic interactions (i, j, l) contributed towards the inheritance of traits in the given crosses. Nevertheless, predominance of additive variance suggests a difference between homozygotes at a locus with positive and negative alleles being distributed between the parents. Duplicate epistasis was prevalent in most of the cases for traits like plant height, seeds/pod, 100-seed weight and pod width. In view of the diverse gene actions, i.e. additive, dominant and epistasis, playing important roles in the manifestation of complex traits like yield, we advocate implementation of population improvement techniques in particular reciprocal recurrent selection to improve productivity gains in grass pea. PMID- 27994193 TI - Association and expression analyses of the Ucp2 and Ucp3 gene polymorphisms with body measurement and meat quality traits in Qinchuan cattle. AB - The uncoupling proteins (UCPs) belong to the mitochondrial inner membrane anion carrier superfamily and play an important role in energy homeostasis. Genetic studies have demonstrated that Ucp2 and Ucp3 gene variants are involved in obesity and metabolic syndrome. The aim of this study was to identify associations between polymorphisms of Ucp2 and Ucp3 genes and economically important traits in Qinchuan cattle. In the present study, one single-nucleotide polymorphism (SNP) in the 5'UTR region (SNP1:g.C-754G) of the Ucp2 gene was identified by direct sequencing of 441 Qinchuan cattle. Two SNPs in exon 3 (SNP2: g.G4877A: SNP3: g.C4902T) of the Ucp3 gene were identified by sequencing and polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) among 441 Qinchuan cattle. Association analysis showed that SNP1 and SNP2 were associated with the meat quality traits (MQTs) including back fat thickness, loin muscle area and intramuscular fat content. SNP3 was found to be associated with part of the body measurement traits (BMTs) which referred to withers height and chest depth. In addition, QTL pyramiding analysis showed that individuals with diplotype P3P3 (GG-GG-CC) exhibited the best performance in terms of back fat thickness, loin muscle area, intramuscular fat content, rump length, hip width, chest depth and chest circumference. With regard to the G4877A mutation, real time PCR analysis revealed that individuals with AA genotype of the Ucp3 gene expressed higher mRNA levels than those with GG genotype. These results suggest that the diplotype P3P3 (GG-GG-CC) could be used as a molecular marker of the combined genotypes for future selection of body measurement traits and meat quality traits in Qinchuan cattle. PMID- 27994195 TI - Identification of vernalization responsive genes in the winter wheat cultivar Jing841 by transcriptome sequencing. AB - This study aimed to identify vernalization responsive genes in the winter wheat cultivar Jing841 by comparing the transcriptome data with that of a spring wheat cultivar Liaochun10. For each cultivar, seedlings before and after the vernalization treatment were sequenced by Solexa/Illumina sequencing. Genes differentially expressed after and before vernalization were identified as differentially expressed genes (DEGs) using false discovery rate (FDR) <= 0.001 and |log2 (fold change)|>1 as cutoffs. The Jing841-specific DEGs were screened and subjected to functional annotation using gene ontology (GO) database. Vernalization responsive genes among the specific genes were selected for validation by quantitative reverse transcription polymerase chain reaction (qRT PCR) and the expression change over the time was investigated for the top 11 genes with the most significant expression differences. A total of 138,062 unigenes were obtained. Overall, 636 DEGs were identified as vernalization responsive genes including some known genes such as VRN-1 and COR14a, and some unknown contigs. The qRT-PCR validated changes in the expression of 18 DEGs that were detected by RNA-seq. Among them, 11 genes displayed four different types of expression patterns over time during the 30-day-long vernalization treatment. Genes or contigs such as VRN-A1, COR14a, IRIP, unigene1806 and Cl18953. Contig2 probably have critical roles in vernalization. PMID- 27994196 TI - Dual modified antiphospho (Ser10)-acetyl (Lys14)-histone H3 predominantly mark the pericentromeric chromatin during mitosis in monokinetic plants. AB - Epigenetic regulatory posttranslational histone modification marks not only function individually but also capable to act in combination as a unique pattern. A total of 16 plant species belonging to 11 genera of eight families (five dicots and three monocots) including land plants, epiphytes (orchids) and the holokinetic taxa (Drosera spp.) were analysed for chromosomal distribution of dual modified antiphospho (Ser10)-acetyl (K14)-histone H3 (H3S10phK14ac) to understand the combinatorial chromatin dynamics during mitotic cell division in plants. The anti-H3S10phK14ac evidently mark the pericentromeric chromatin on mitotic chromosomes of the plants excluding the holokinetic Drosera species, which revealed the immunolabelling of whole chromosomes all along the arms. The dual modified immunosignals were absent during early stages of mitosis, appeared intensively at metaphase and remained visible until late-anaphase/telophase however, labelled the whole chromosomes during meiotic metaphase I. Colocalization of anti-H3S10phK14ac with an onion's CENH3 antibody on mitotic chromosomes of Allium revealed the chromosomal location of anti-H3S10phK14ac in the region between signals for CENH3 detection. Overall analysis suggests that the unique localization of combinatorial histone modification mark at pericentromeric chromatin might have attributed through 'phospho-acetyl' cross talk that ultimately facilitate the sister chromatid cohesion at pericentromeres following condensation events in mitotic chromosomes. Here, we propose that dual modified H3S10phK14ac histone may serve as an additional cytogenetic landmark to identify pericentromeric chromatin during mitosis in plants. The plausible role of histone cross talk and future perspectives of combinatorial histone modification marks in plant cytogenetics with special reference to chromatin dynamics have been discussed. PMID- 27994197 TI - Different responses of soybean cyst nematode resistance between two RIL populations derived from Peking x 7605 under two ecological sites. AB - The soybean cyst nematode (SCN), Heterodera glycines Ichinohe, is a plant parasitic nematode that feeds on the roots of soybean and most economically devastating pathogen of soybean (Glycine max (L.) Merr.) worldwide. Host plant resistance is the most effective control method. To understand SCN resistance in different environments, two recombinant-inbred lines (RILs) populations NJ(RN)P7 (217 F2:8:11 lines) and JN(RN)P7 (248 F2:7:9 lines) were developed from the cross of the cultivars Peking x 7605 in Nanjing and Jinan, respectively, and examined in this study. Peking is resistant to SCN race 1 (HG types 2.5.7), while 7605 is highly susceptible. Chi-square test of frequency distribution of families' female index (FI) showed that resistance to SCN was significantly different between NJ(RN)P7 and JN(RN)P7 populations. Three recessive genes conditioned the inheritance of resistance to SCN race 1 in both populations, but significant difference was detected for the mean of FI on two populations (DM= -16.68, P< 0.01). This indicated that natural selection may affect resistance to SCN. By analysing the variation of phenotype, the genetic structure of the two populations was determined to be different. The inheritance and variation of resistance were confirmed by simple sequence repeat (SSR) markers. For the two populations, 10 SSR markers showed polymorphism of resistant and susceptible DNA bulks. Some markers associated with the resistance of SCN races 1, 2, 3 and 5, and two markers, Satt163 and Satt309, reportedly related to rgh1 were detected both in NJ(RN)P7 and JN(RN)P7 populations. The results support the view that a disease acts as a selective force on plant resistance characteristics, which may alter the relative fitness of resistance alleles. PMID- 27994198 TI - Osteoprotegerin polymorphisms are associated with alcohol-induced osteonecrosis of femoral head in Chinese Han population from Henan province. AB - Alcohol-induced osteonecrosis of femoral head (ONFH) is one of the most important pathogenesis of nontraumatic ONFH. However, its pathogenesis mechanism is still unknown. Osteoprotegerin (OPG) has been implicated in multiple functions including blocking osteoclast maturation, controlling vascular calcifications, promoting tumour growth and metastasis. This study is focussed on OPG gene polymorphisms associated with alcohol-induced ONFH. A total of 509 participants (209 patients and 300 normal individuals) were recruited, and we selected 13 single-nucleotide polymorphisms (SNPs) to evaluate the association between genetic susceptibility variants and alcohol-induced ONFH by using the chi2 test and genetic model analysis. Overall, OPG SNPs (rs1485286, rs1032128 and rs11573828) were confirmed the strongest increasing risks on alcohol-induced osteoporosis of femoral head in recessive model (rs1485286: OR, 1.71; 95% CI, 1.07-2.73; P = 0.025 for T/T); (rs1032128: OR, 1.73; 95% CI, 1.08- 2.77; P = 0.022 for G/G); (rs11573828: OR, 3.89; 95% CI, 1.02- 14.85; P = 0.033 for T/T). SNP rs11573856 was considered as a protective effect to the occurrence of alcohol induced ONFH, while adjusted for age and gender in dominant and log-additive models (rs11573856: adjusted OR, 0.60; 95% CI, 0.37- 0.96; P = 0.033 for G/A- A/A); (rs11573856: adjusted OR, 0.63; 95% CI, 0.41- 0.96; P = 0.042). We conclude that OPG gene polymorphisms were associated with the occurrence of alcohol induced ONFH. PMID- 27994199 TI - Upregulation of miR-222 in both Helicobacter pylori- infected and noninfected gastric cancer patients. AB - Despite of promising improvements in treatment of gastric cancer, the mortality rate of this malignancy remains high. Chronic infection by Helicobacter pylori, interfering with intracellular signalling pathways, is the main risk factor for gastric cancer. Some evidence suggests that microRNAs (miRNA), the small noncoding RNA molecules, can play role as oncogenes or tumour suppressors in the cells. MiR-222 is one of the remarkable miRNAs undergoing upregulation in gastric cancer. However, the association between miR-222 upregulation and H. pylori infection in gastric cancer tissues remains unclear. The aim of this study was to analyse the expression level of miR-222 in gastric cancer tissues, evaluating the relationship between miR-222 expression level and H. pylori infection and also finding novel miR-222 targets based on in silico investigations. MiR-222 expression level in 200 patients including 112 H. pylori positive and 88 H. pylori negative was relatively measured using RT-qPCR and compared with 88 healthy samples. In silico enrichment analysis of miR-222 targets was performed by DAVID database to evaluate the possible role(s) of miR-222 in gastric tumourigenesis. We observed upregulated level of miR-222 in gastric cancer tissues compared with normal samples (P<0.05). However, no significant difference between miR-222 expression in H. pylori-positive and H. pylori-negative cases was observed. Our in silico analyses showed the possible role of p53, p27, PTEN and Elongin B in gastric cancer tumourigenesis. MiR-222 functions as an onco-miRNA and its overexpression can be involved in pathogenesis of gastric cancer, independent of H. pylori infection. PMID- 27994200 TI - Genomewide analysis of NBS-encoding genes in kiwi fruit (Actinidia chinensis). PMID- 27994201 TI - Is the ancient permafrost bacteria able to keep DNA stable? PMID- 27994203 TI - Genetic dissection of seed vigour traits in maize (Zea mays L.) under low temperature conditions. PMID- 27994202 TI - Studies on genetics, stability and possible mechanism of deltamethrin resistance in Phenacoccus solenopsis Tinsley (Homoptera: Pseudococcidae) from Pakistan. PMID- 27994204 TI - Genomewide analyses of pathogenic and regulatory T cells of NOD mice reveal a significant difference in DNA methylation on chromosome X. PMID- 27994205 TI - Polymorphism in ficolin-1 (FCN1) gene is associated with an earlier onset of type 1 diabetes mellitus in children and adolescents from northeast Brazil. PMID- 27994206 TI - Cytosine deletion at AP2-box region of HSP70 promoter and its influence on semen quality traits in crossbred bulls. PMID- 27994209 TI - Another explanation for the cause of heterosis phenomenon. AB - The explanation for heterosis phenomenon is based on ideas: (i) every trait of an organism depends on many genes. (ii) Inbreeding depression and heterosis are related to individual genetic diversity. To assess individual genetic diversity of an organism, I suggest the term number of genetic properties. Assessing the changes of individual genetic diversity caused by self-pollination and cross pollination reveals that self-pollinating plants of natural cross-pollinating leads to the decrease in individual genetic diversity of offspring and crossing between pure lines of genetic difference leads to the increase in individual genetic diversity of hybrids. Therefore, I propose that the decrease in individual genetic diversity is the cause the of depression and the increase in individual genetic diversity is the cause of heterosis. PMID- 27994208 TI - The genus Drosophila is characterized by a large number of sibling species showing evolutionary significance. AB - Mayr (1942) defined sibling species as sympatric forms which are morphologically very similar or indistinguishable, but which possess specific biological characteristics and are reproductively isolated. Another term, cryptic species has also been used for such species. However, this concept changed later. Sibling species are as similar as twins. This category does not necessarily include phylogenetic siblings as members of a superspecies. Since the term sibling species was defined by Mayr, a large number of cases of sibling species pairs/groups have been reported and thus they are widespread in the animal kingdom. However, they seem to be more common in some groups such as insects. In insects, they have been reported in diptera, lepidoptera, coleoptera, orthoptera, hymenoptera and others. Sibling species are widespread among the dipteran insects and as such are well studied because some species are important medically (mosquitoes), genetically (Drosophila) and cytologically (Sciara and Chironomus). The well-studied classical pairs of sibling species in Drosophila are: D. pseudoobscura and D. persimilis, and D. melanogaster and D. simulans. Subsequently, a number of sibling species have been added to these pairs and a large number of other sibling species pairs/groups in different species groups of the genus Drosophila have been reported in literature. The present review briefly summarizes the cases of sibling species pairs/groups in the genus Drosophila with their evolutionary significance. PMID- 27994207 TI - Useful parasites: the evolutionary biology and biotechnology applications of transposable elements. AB - Transposable elements usually comprise the most abundant nongenic fraction of eukaryotic genomes. Because of their capacity to selfreplicate and to induce a wide range of mutations, transposable elements have long been considered as 'parasitic' or 'selfish'. Today, we recognize that the findings about genomic changes affected by transposable elements have considerably altered our view of the ways in which genomes evolve and work. Numerous studies have provided evidences that mobile elements have the potential to act as agents of evolution by increasing, rearranging and diversifying the genetic repertoire of their hosts. With large-scale sequencing becoming increasingly available, more and more scientists come across transposable element sequences in their data. I will provide examples that transposable elements, although having signatures of 'selfish' DNA, play a significant biological role in the maintainance of genome integrity and providing novel regulatoty networks. These features, along with the transpositional and mutagenic capacity to produce a raw genetic diversity, make the genome mobile fraction, a key player in species adaptation and microevolution. The last but not least, transposable elements stand as informative DNA markers that may complement other conventional DNA markers. Altogether, transposable elements represent a promising, but still largely unexplored research niche and deserve to be included into the agenda of molecular ecologists, evolutionary geneticists, conservation biologists and plant breeders. PMID- 27994210 TI - Mycobacterium vaccae induces a strong Th1 response that subsequently declines in C57BL/6 mice. AB - Mycobacterium (M.) vaccae is a fast-growing species of saprophytic bacteria that is widely distributed. To understand the host immune responses induced by M. vaccae isolated from bovine submaxillary lymph nodes, C57BL/6 mice were infected with reference strain M. bovis Bacillus Calmette-Guerin (BCG) and isolated M. vaccae using intraperitoneal injections. Comparison of the bacterial replication and organ pathology between M. vaccae and M. bovis BCG revealed that M. vaccae was more malignant than M. bovis in mice. We also demonstrated that serum from the M. vaccae-infected mice contained a higher expression level of gamma interferon (IFN-gamma), tumor necrosis factor alpha, monocyte chemoattractant protein-1, interleukin (IL)-4, IL-12, IL-10 and transforming growth factor beta than did the other groups, especially after week 4. Furthermore, when the numbers of CD3+CD4+IFN-gamma+ and CD3+CD4+IL4+cells in the infected mice were observed by flow cytometry, we found that a powerful T helper 1 (Th1) response was induced by M. vaccae infection, which was associated with the emergence of CD3+CD4+IFN gamma+cells. However, the Th1 response declined over time, which was associated with appearance of the CD4+CD25+FoxP3+ and CD4+CD25+CD152+Treg cell reaction. In addition, a strong Th2 response was found. Finally, we found that M. vaccae infection increased the production of type I IFNs, which was associated with a reduced Th1 response. PMID- 27994211 TI - Proteome Changes in Penicillium expansum Grown in a Medium Derived from Host Plant. AB - Penicillium expansum causes blue mold rot, a prevalent postharvest disease of pome fruit, and is also the main producer of the patulin. However, knowledge on the molecular mechanisms involved in this pathogen-host interaction remains largely unknown. In this work, a two-dimensional gel electrophoresis-based proteomic approach was applied to probe changes in P. expansum 3.3703 cultivated in apple juice medium, which was used to mimic the in planta condition. The results showed that the pH value and reducing sugar content in the apple juice medium decreased whereas the patulin content increased with the growing of P. expansum. A total of 28 protein spots that were up-regulated in P. expansum when grown in apple juice medium were identified. Functional categorization revealed that the identified proteins were mainly related to carbohydrate metabolism, secondary metabolism, protein biosynthesis or degradation, and redox homeostasis. Remarkably, several induced proteins, including glucose dehydrogenase, galactose oxidase, and FAD-binding monooxygenase, which might be responsible for the observed medium acidification and patulin production, were also detected. Overall, the experimental results provide a comprehensive interpretation of the physiological and proteomic responses of P. expansum to the host plant environment, and future functional characterization of the identified proteins will deepen our understanding of fungi-host interactions. PMID- 27994212 TI - Intracellular Trafficking Modulation by Ginsenoside Rg3 Inhibits Brucella abortus Uptake and Intracellular Survival within RAW 264.7 Cells. AB - Ginsenoside Rg3, a saponin extracted from ginseng, has various pharmacological and biological activities; however, its effects against Brucella infection are still unclear. Herein, the inhibitory effects of ginsenoside Rg3 against intracellular parasitic Brucella infection were evaluated through bacterial infection, adherence assays, and LAMP-1 colocalization, as well as immunoblotting and FACS for detecting MAPK signaling proteins and F-actin polymerization, respectively. The internalization, intracellular growth, and adherence of Brucella abortus in Rg3-treated RAW 264.7 cells were significantly decreased compared with the Rg3-untreated control. Furthermore, an apparent reduction of F actin content and intensity of F-actin fluorescence in Rg3-treated cells was observed compared with B. abortus-infected cells without treatment by flow cytometry analysis and confocal microscopy, respectively. In addition, treating cells with Rg3 decreased the phosphorylation of MAPK signaling proteins such as ERK 1/2 and p38 compared with untreated cells. Moreover, the colocalization of B. abortus-containing phagosomes with LAMP-1 was markedly increased in Rg3-treated cells. These findings suggest that ginsenoside Rg3 inhibits B. abortus infection in mammalian cells and can be used as an alternative approach in the treatment of brucellosis. PMID- 27994213 TI - Host Cell Nuclear Localization of Shigella flexneri Effector OspF Is Facilitated by SUMOylation. AB - When Shigella infect host cells, various effecter molecules are delivered into the cytoplasm of the host cell through the type III secretion system (TTSS) to facilitate their invasion process and control the host immune responses. Among these effectors, the S. flexneri effector OspF dephosphorylates mitogen-activated protein kinases and translocates itself to the nucleus, thus preventing histone H3 modification to regulate expression of proinflammatory cytokines. Despite the critical role of OspF, the mechanism by which it localizes in the nucleus has remained to be elucidated. In the present study, we identified a potential small ubiquitin-related modifier (SUMO) modification site within OspF and we demonstrated that Shigella TTSS effector OspF is conjugated with SUMO in the host cell and this modification mediates the nuclear translocation of OspF. Our results show a bacterial virulence factor can exploit host post-translational machinery to execute its intracellular trafficking. PMID- 27994214 TI - Microbial beta-Galactosidase of Pediococcus pentosaceus ID-7: Isolation, Cloning, and Molecular Characterization. AB - Pediococcus pentosaceus ID-7 was isolated from kimchi, a Korean fermented food, and it showed high activity for lactose hydrolysis. The beta-galactosidase of P. pentosaceus ID-7 belongs to the GH2 group, which is composed of two distinct proteins. The heterodimeric LacLM type of beta-galactosidase found in P. pentosaceus ID-7 consists of two genes partially overlapped, lacL and lacM encoding LacL (72.2 kDa) and LacM (35.4 kDa). In this study, Escherichia coli MM294 was used for the production of LacL, LacM, and LacLM. These three types of recombinant proteins were expressed, purified, and characterized. The specific activities of LacLM and LacL were 339 and 31 U/mg, respectively. However, activity was not detected with LacM alone. The optimal pH of LacLM and LacL was pH 7.5 and pH 7.0, and the optimal temperature of LacLM and LacL was 40 degrees C and 50 degrees C, respectively. The optimal temperature changes indicate that LacLM is able to achieve higher activity at a relatively lower temperature. LacLM was strongly activated by Mg2+, Mn2+, and Zn2+, which was not true for LacL. Consistent with this, EDTA strongly inactivated LacLM and LacL, but the presence of reducing agents did not dramatically alter the activity. Taken together, multiple alignment of amino acid sequences and phylogenetic analysis results of LacL and LacM of P. pentosaceus ID-7 suggest the evolution of LacL into LacLM and that the use of divalent metal ions results in higher activity. PMID- 27994215 TI - Antimicrobial Activity of Basil, Oregano, and Thyme Essential Oils. AB - For centuries, plants have been used for a wide variety of purposes, from treating infectious diseases to food preservation and perfume production. Presently, the increasing resistance of microorganisms to currently used antimicrobials in combination with the appearance of emerging diseases requires the urgent development of new, more effective drugs. Plants, due to the large biological and structural diversity of their components, constitute a unique and renewable source for the discovery of new antibacterial, antifungal, and antiparasitic compounds. In the present paper, the history, composition, and antimicrobial activities of the basil, oregano, and thyme essential oils are reviewed. PMID- 27994216 TI - Transforming Growth Factor-beta1 Induces Endothelial-to-Mesenchymal Transition via Akt Signaling Pathway in Renal Transplant Recipients with Chronic Allograft Dysfunction. AB - BACKGROUND Chronic allograft dysfunction (CAD) is the major cause of chronic loss of allograft in kidney transplant recipients. Kidney interstitial fibrosis is identified to be strongly associated with CAD in kidney transplantation. Recently, endothelial-to-mesenchymal transition (EndMT) has been identified as one of the potential mechanisms in kidney interstitial fibrosis. MATERIAL AND METHODS Kidney tissue samples from 25 renal transplant recipients (RTRs) with CAD and healthy volunteers were collected for HE (hematoxylin-eosin), Masson trichrome, and immunohistochemical staining, and indirect immunofluorescence double-staining assay. Moreover, human umbilical vascular endothelial cells (HUVECs) were cultured and treated with TGF-beta1 at different doses or intervals. The protein expressions of alpha-SMA and CD31 were determined by Western blot assay. Furthermore, potential signaling pathways involved in EndMT induced by TGF-beta1were also investigated by Western blotting. RESULTS Typical interstitial fibrosis was observed in transplanted renal tissues from the CAD group. We also found a significant increase of TGF-beta1 expression in renal tissues from RTRs with CAD compared with the normal group. Moreover, significant over-expressions of alpha-SMA, collagen-I, and collagen-III and under-expression of CD31 were detected in kidney specimens of the CAD group. Similar expressive tendencies of alpha-SMA and CD31 proteins were found in HUVECs treated with TGF beta1 in both time-dependent and dose-dependent manners. The activation of the Akt signaling pathway was found in HUVECs induced by TGF-beta1 and selective inhibitors. CONCLUSIONS EndMT was observed in kidney tissues from RTRs with CAD, and TGF-beta1 can induce the process of EndMT in both time-dependent and does dependent manners through the Akt signaling pathway. PMID- 27994217 TI - Desmoid Fibromatosis Presenting as Deep Venous Thrombosis: A Case Report and Discussion. AB - BACKGROUND Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, serious cardiovascular event. Predisposing factors include genetic disorders, immobility, and underlying malignancy. Soft tissue tumors are by contrast rare, but should be included in the differential etiology of DVT, especially when the patient is young and has few thrombotic risk factors. CASE REPORT We present a 40-year-old patient whose initial diagnosis was spontaneous DVT of the lower leg, treated conventionally. Subsequently, he developed progressive calf swelling, which was diagnosed as multifocal desmoid fibromatosis, a rare and complex soft tissue tumor. CONCLUSIONS DVT is common but soft tissue tumors are rare. The disparity in incidence of these very distinct pathologies may contribute to late diagnosis of occult soft tissue pathology. We discuss the incidence, etiology, pathology, diagnosis, and best management of both desmoid fibromatosis and DVT, which may co exist in a causative way. PMID- 27994218 TI - MiR-206 Suppresses the Progression of Coronary Artery Disease by Modulating Vascular Endothelial Growth Factor (VEGF) Expression. AB - BACKGROUND We investigated whether microRNA-206 (miR-206) is abnormally expressed in patients with coronary artery disease (CAD). The potential mechanism by which miR-206 may regulate CAD progression was also studied. MATERIAL AND METHODS A total of 78 CAD patients in the case group and 65 subjects in the control group were enrolled in this study so that the correlation between miR-206 and CAD could be accurately determined. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were detected using a biochemistry analyzer. MiR-206 and vascular endothelial growth factor (VEGF) expression levels were tested using either reverse transcription polymerase chain reaction or western blot. Associations between miR-206 expression and different clinicopathological features of CAD patients were also analyzed. CAD cells were transfected with miR-206 mimic (miR-206), its negative control (miR-NC), miR-206 inhibitor (anti-miR-206), and its negative control (anti-miR-NC), respectively. Flow cytometry was conducted to explore the function of miR-206 in CAD cell apoptosis after transfection. Moreover, transwell assay was carried out to study the migratory ability of endothelial progenitor cells (EPCs) in CAD patients. RESULTS MiR-206 expression was enriched in both diseased EPCs and plasma of CAD patients. No significant correlation was found between decrease in miR-206 expression and different clinicopathological features. In addition, miR-206 significantly suppressed the viability and invasion of EPCs in CAD patients, and it promoted the apoptosis of their EPCs. Moreover, we found that miR-206 is able to inhibit VEGF expression. CONCLUSIONS As suggested by our study, MiR-206 can be a novel benign biomarker for CAD because it may regulate VEGF expression. PMID- 27994220 TI - Structural dysconnectivity of key cognitive and emotional hubs in young people at high genetic risk for bipolar disorder. AB - Emerging evidence suggests that psychiatric disorders are associated with disturbances in structural brain networks. Little is known, however, about brain networks in those at high risk (HR) of bipolar disorder (BD), with such disturbances carrying substantial predictive and etiological value. Whole-brain tractography was performed on diffusion-weighted images acquired from 84 unaffected HR individuals with at least one first-degree relative with BD, 38 young patients with BD and 96 matched controls (CNs) with no family history of mental illness. We studied structural connectivity differences between these groups, with a focus on highly connected hubs and networks involving emotional centres. HR participants showed lower structural connectivity in two lateralised sub-networks centred on bilateral inferior frontal gyri and left insular cortex, as well as increased connectivity in a right lateralised limbic sub-network compared with CN subjects. BD was associated with weaker connectivity in a small right-sided sub-network involving connections between fronto-temporal and temporal areas. Although these sub-networks preferentially involved structural hubs, the integrity of the highly connected structural backbone was preserved in both groups. Weaker structural brain networks involving key emotional centres occur in young people at genetic risk of BD and those with established BD. In contrast to other psychiatric disorders such as schizophrenia, the structural core of the brain remains intact, despite the local involvement of network hubs. These results add to our understanding of the neurobiological correlates of BD and provide predictions for outcomes in young people at high genetic risk for BD. PMID- 27994223 TI - Autoimmunity: Human gut bacteria induce TH17 cells. PMID- 27994221 TI - Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4. AB - Contrary to acute pain, chronic pain does not serve as a warning signal and must be considered as a disease per se. This pathology presents a sensory and psychological dimension at the origin of affective and cognitive disorders. Being largely refractory to current pharmacotherapies, identification of endogenous systems involved in persistent and chronic pain is crucial. The amygdala is a key brain region linking pain sensation with negative emotions. Here, we show that activation of a specific intrinsic neuromodulatory system within the amygdala associated with type 4 metabotropic glutamate receptors (mGlu4) abolishes sensory and affective symptoms of persistent pain such as hypersensitivity to pain, anxiety- and depression-related behaviors, and fear extinction impairment. Interestingly, neuroanatomical and synaptic analysis of the amygdala circuitry suggests that the effects of mGlu4 activation occur outside the central nucleus via modulation of multisensory thalamic inputs to lateral amygdala principal neurons and dorso-medial intercalated cells. Furthermore, we developed optogluram, a small diffusible photoswitchable positive allosteric modulator of mGlu4. This ligand allows the control of endogenous mGlu4 activity with light. Using this photopharmacological approach, we rapidly and reversibly inhibited behavioral symptoms associated with persistent pain through optical control of optogluram in the amygdala of freely behaving animals. Altogether, our data identify amygdala mGlu4 signaling as a mechanism that bypasses central sensitization processes to dynamically modulate persistent pain symptoms. Our findings help to define novel and more precise therapeutic interventions for chronic pain, and exemplify the potential of optopharmacology to study the dynamic activity of endogenous neuromodulatory mechanisms in vivo. PMID- 27994222 TI - Connective tissue diseases: Refining the classification criteria for primary Sjogren syndrome. PMID- 27994232 TI - Substance Index for Volume 69. PMID- 27994233 TI - Corrigendum: Tripropeptins, novel antimicrobial agents produced by Lysobacter sp. II. structure elucidation. PMID- 27994231 TI - Disease surveillance based on Internet-based linear models: an Australian case study of previously unmodeled infection diseases. AB - Effective disease surveillance is critical to the functioning of health systems. Traditional approaches are, however, limited in their ability to deliver timely information. Internet-based surveillance systems are a promising approach that may circumvent many of the limitations of traditional health surveillance systems and provide more intelligence on cases of infection, including cases from those that do not use the healthcare system. Infectious disease surveillance systems built on Internet search metrics have been shown to produce accurate estimates of disease weeks before traditional systems and are an economically attractive approach to surveillance; they are, however, also prone to error under certain circumstances. This study sought to explore previously unmodeled diseases by investigating the link between Google Trends search metrics and Australian weekly notification data. We propose using four alternative disease modelling strategies based on linear models that studied the length of the training period used for model construction, determined the most appropriate lag for search metrics, used wavelet transformation for denoising data and enabled the identification of key search queries for each disease. Out of the twenty-four diseases assessed with Australian data, our nowcasting results highlighted promise for two diseases of international concern, Ross River virus and pneumococcal disease. PMID- 27994235 TI - Corrigendum: A new type of tripropeptin with anteiso-branched chain fatty acid from Lysobacter sp. BMK333-48F3. PMID- 27994236 TI - Co-activation of VEGF and NMDA receptors promotes synaptic targeting of AMPA receptors. PMID- 27994238 TI - Metasurface lens: Shrinking the camera size. PMID- 27994239 TI - Porous catalysts: The platinum rush. PMID- 27994237 TI - Energy and fuels from electrochemical interfaces. AB - Advances in electrocatalysis at solid-liquid interfaces are vital for driving the technological innovations that are needed to deliver reliable, affordable and environmentally friendly energy. Here, we highlight the key achievements in the development of new materials for efficient hydrogen and oxygen production in electrolysers and, in reverse, their use in fuel cells. A key issue addressed here is the degree to which the fundamental understanding of the synergy between covalent and non-covalent interactions can form the basis for any predictive ability in tailor-making real-world catalysts. Common descriptors such as the substrate-hydroxide binding energy and the interactions in the double layer between hydroxide-oxides and H---OH are found to control individual parts of the hydrogen and oxygen electrochemistry that govern the efficiency of water-based energy conversion and storage systems. Links between aqueous- and organic-based environments are also established, encouraging the 'fuel cell' and 'battery' communities to move forward together. PMID- 27994240 TI - Materials for sustainable energy. PMID- 27994242 TI - Material Witness: A recipe for growth. PMID- 27994243 TI - Dealing with data. PMID- 27994241 TI - Materials for solar fuels and chemicals. AB - The conversion of sunlight into fuels and chemicals is an attractive prospect for the storage of renewable energy, and photoelectrocatalytic technologies represent a pathway by which solar fuels might be realized. However, there are numerous scientific challenges in developing these technologies. These include finding suitable materials for the absorption of incident photons, developing more efficient catalysts for both water splitting and the production of fuels, and understanding how interfaces between catalysts, photoabsorbers and electrolytes can be designed to minimize losses and resist degradation. In this Review, we highlight recent milestones in these areas and some key scientific challenges remaining between the current state of the art and a technology that can effectively convert sunlight into fuels and chemicals. PMID- 27994244 TI - Retraction: Fast and long-range triplet exciton diffusion in metal-organic frameworks for photon upconversion at ultralow excitation power. PMID- 27994246 TI - Retraction: Framing upconversion materials. PMID- 27994247 TI - Topological insulators: Engineered heterostructures. PMID- 27994245 TI - Photovoltaic concepts inspired by coherence effects in photosynthetic systems. AB - The past decade has seen rapid advances in our understanding of how coherent and vibronic phenomena in biological photosynthetic systems aid in the efficient transport of energy from light-harvesting antennas to photosynthetic reaction centres. Such coherence effects suggest strategies to increase transport lengths even in the presence of structural disorder. Here we explore how these principles could be exploited in making improved solar cells. We investigate in depth the case of organic materials, systems in which energy and charge transport stand to be improved by overcoming challenges that arise from the effects of static and dynamic disorder - structural and energetic - and from inherently strong electron vibration couplings. We discuss how solar-cell device architectures can evolve to use coherence-exploiting materials, and we speculate as to the prospects for a coherent energy conversion system. We conclude with a survey of the impacts of coherence and bioinspiration on diverse solar-energy harvesting solutions, including artificial photosynthetic systems. PMID- 27994248 TI - Elastic sheets: Cracks by design. PMID- 27994249 TI - Energy conversion approaches and materials for high-efficiency photovoltaics. AB - The past five years have seen significant cost reductions in photovoltaics and a correspondingly strong increase in uptake, with photovoltaics now positioned to provide one of the lowest-cost options for future electricity generation. What is becoming clear as the industry develops is that area-related costs, such as costs of encapsulation and field-installation, are increasingly important components of the total costs of photovoltaic electricity generation, with this trend expected to continue. Improved energy-conversion efficiency directly reduces such costs, with increased manufacturing volume likely to drive down the additional costs associated with implementing higher efficiencies. This suggests the industry will evolve beyond the standard single-junction solar cells that currently dominate commercial production, where energy-conversion efficiencies are fundamentally constrained by Shockley-Queisser limits to practical values below 30%. This Review assesses the overall prospects for a range of approaches that can potentially exceed these limits, based on ultimate efficiency prospects, material requirements and developmental outlook. PMID- 27994250 TI - Thermal transport: Harmony with superatoms. PMID- 27994252 TI - Perovskite photovoltaics: Slow recombination unveiled. PMID- 27994251 TI - Sustainability and in situ monitoring in battery development. AB - The development of improved rechargeable batteries represents a major technological challenge for this new century, as batteries constitute the limiting components in the shift from petrol (gasoline) powered to electric vehicles, while also enabling the use of more renewable energy on the grid. To minimize the ecological implications associated with their wider use, we must integrate sustainability of battery materials into our research endeavours, choosing chemistries that have a minimum footprint in nature and that are more readily recycled or integrated into a full circular economy. Sustainability and cost concerns require that we greatly increase the battery lifetime and consider second lives for batteries. As part of this, we must monitor the state of health of batteries continuously during operation to minimize their degradation. It is thus important to push the frontiers of operando techniques to monitor increasingly complex processes. In this Review, we will describe key advances in both more sustainable chemistries and operando techniques, along with some of the remaining challenges and possible solutions, as we personally perceive them. PMID- 27994253 TI - The path towards sustainable energy. AB - Civilization continues to be transformed by our ability to harness energy beyond human and animal power. A series of industrial and agricultural revolutions have allowed an increasing fraction of the world population to heat and light their homes, fertilize and irrigate their crops, connect to one another and travel around the world. All of this progress is fuelled by our ability to find, extract and use energy with ever increasing dexterity. Research in materials science is contributing to progress towards a sustainable future based on clean energy generation, transmission and distribution, the storage of electrical and chemical energy, energy efficiency, and better energy management systems. PMID- 27994254 TI - Using Biosynthetic Models of Heme-Copper Oxidase and Nitric Oxide Reductase in Myoglobin to Elucidate Structural Features Responsible for Enzymatic Activities. AB - In biology, a heme-Cu center in heme-copper oxidases (HCOs) is used to catalyze the four-electron reduction of oxygen to water, while a heme-nonheme diiron center in nitric oxide reductases (NORs) is employed to catalyze the two-electron reduction of nitric oxide to nitrous oxide. Although much progress has been made in biochemical and biophysical studies of HCOs and NORs, structural features responsible for similarities and differences within the two enzymatic systems remain to be understood. Here, we discuss the progress made in the design and characterization of myoglobin-based enzyme models of HCOs and NORs. In particular, we focus on use of these models to understand the structure-function relations between HCOs and NORs, including the role of nonheme metals, conserved amino acids in the active site, heme types and hydrogen-bonding network in tuning enzymatic activities and total turnovers. Insights gained from these studies are summarized and future directions are proposed. PMID- 27994255 TI - Review of Venoarterial Extracorporeal Membrane Oxygenation and Development of Intracardiac Thrombosis in Adult Cardiothoracic Patients. AB - Venoarterial extracorporeal membrane oxygenation (VA ECMO) has become an indispensable treatment option for adult cardiothoracic patients experiencing acute refractory cardiogenic shock. VA ECMO is not without inherent complications as in-hospital mortality has ranged from 45% to 65% (1-3). Intracardiac thrombosis (ICT) is a rare but life-threatening complication associated with VA ECMO. VA ECMO cases complicated by ICT were searched for using the MEDLINE (PubMed and OVID), Society of Cardiovascular Anesthesiology Headquarters, and Google Scholar databases. Twelve cases of VA ECMO-associated ICT were discovered for review. Indications for VA ECMO were postcardiotomy cardiogenic shock and heart failure. The primary location of thrombus was the left ventricle and aortic root. Majority of the cases did not report subtherapeutic systemic anticoagulation. Two patients survived after the development of ICT. VA ECMO associated ICT is a devastating consequence with high mortality. The majority of ICT occurred in cases with perceived adequate anticoagulation, but this may not result in complete suppression of the coagulation response. Continued exposure to procoagulant stimuli and worsening ventricular function and intracardiac stasis can shift the balance toward a hypercoagulable state and development of thrombosis. PMID- 27994256 TI - A Novel Centrifugation Method Using a Cell Salvage Device Offers an Alternative to the Use of Leukocyte-Depleting Filters for Autologous Blood Transfusions. AB - Autotransfusion protocols often use the use of costly filters, such as leukocyte depleting filters (LDFs), to minimize reinfusion of activated leukocytes and inflammatory mediators associated with reperfusion injury (RI). LDFs are used extensively in hospital settings; however, they represent an additional capital expenditure for hospitals, as well as a constraint on the reinfusion rate of blood products for health-care providers. We compared a commonly used LDF to a novel centrifugation method employing a widely used cell salvage device. Complete blood counts and enzyme-linked immunosorbent assays (ELISAs) measuring tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) were performed to compare the efficacy of these methodologies. The LDF removed, on average, 94% of all leukocytes, including 96% of neutrophils. The centrifugation method removed, on average, 89% of all leukocytes, including 91% of neutrophils and resulted in a highly concentrated red blood cell product. Our results suggest both methods offer equivalent leukocyte reduction. TNF-alpha was also comparably reduced following our novel centrifugation method and the LDF method and IL-2 levels were undetectable in all samples. These results indicate our novel centrifugation method may preclude the need for a LDF during select autotransfusion applications. PMID- 27994257 TI - Changes in Cerebral Oxygenation during Transfusion Therapy. AB - This study assesses the effects of transfusion of autologous or allogeneic blood on cerebral and tissue oxygenation during spinal surgery. Packed red blood cell transfusions are indicated to improve oxygen delivery to tissues. There are limited data demonstrating changes in tissue oxygenation with blood administration. Tissue (deltoid) and cerebral oxygenation were monitored using near-infrared spectroscopy during spinal surgery in patients. As indicated, cell saver or allogeneic blood was administered. Tissue and cerebral oxygenation were recorded before and after transfusion. The study enrolled 50 patients, 33 of whom (17 males and 16 females) received allogeneic blood (n = 8) or autologous blood (n = 25). Patients ranged in age from 9 to 19 years (14.0 +/- 2.3 years) and in weight from 16.8 to 122.7 kg (54.6 +/- 25.7 kg). Tissue oxygenation increased from 83 +/- 9 (pretransfusion) to 86 +/- 7 at the end of transfusion (p = .002) and remained at the same level (86 +/- 7) in the post-transfusion period. Cerebral oxygenation increased from 76 +/- 8 (pretransfusion) to 84 +/- 8 at the end of transfusion (p < .001) and remained at 84 +/- 8 in the post-transfusion period. Changes in tissue and cerebral oxygenation were similar between cell saver and allogeneic blood and between starting hemoglobin value <8 gm/dL and starting hemoglobin >=8 gm/dL. In conclusion, although both cerebral and tissue oxygenation increased during the administration of either allogeneic or autologous blood, the clinical impact was likely limited given the high initial tissue and cerebral oxygenation values. No differences were noted between autologous (cell saver) and allogeneic blood or based on the starting hemoglobin value. PMID- 27994258 TI - Results of the 2015 Perfusionist Salary Study. AB - Presently, there exists no published valid and reliable salary study of clinical perfusionists. The objective of the 2015 Perfusionist Salary Study was to gather verifiable employee information to determine current compensation market rates (salary averages) of clinical perfusionists working in the United States. A salary survey was conducted between April 2015 and March 2016. The survey required perfusionists to answer questions about work volume, scheduling, and employer-paid compensation including benefits. Participants were also required to submit a de-identified pay stub to validate the income they reported. Descriptive statistics were calculated for all survey questions (e.g., percentages, means, and ranges). The study procured 481 responses, of which 287 were validated (i.e., respondents provided income verification that matched reported earnings). Variables that were examined within the validated sample population include job title, type of institution of employment, education level, years of experience, and geographic region, among others. Additional forms of compensation which may affect base compensation rates were also calculated including benefits, call time, bonuses, and pay for ancillary services (e.g., extracorporeal membrane oxygenation and ventricular assist device). In conclusion, in 2015, the average salary for all perfusionists is $127,600 with 19 years' experience. This research explores the average salary within subpopulations based on other factors such as position role, employer type, and geography. Information from this study is presented to guide employer compensation programs and suggests the need for further study in consideration of attrition rates and generational changes (i.e., perfusionists reaching retirement age) occurring alongside the present perfusionist staffing shortage affecting many parts of the country. PMID- 27994259 TI - The Relationship between Intra-Operative Transfusions and Nadir Hematocrit on Post-Operative Outcomes after Cardiac Surgery. AB - Uncertainty exists regarding the optimal strategy for the management of anemia in the setting of cardiac surgery. We sought to improve our understanding of the role of intra-operative hematocrit (HCT) and transfusions on peri-operative outcomes following cardiac surgery. A total of 18,886 patients undergoing on-pump cardiac surgery were identified from a multi-institutional registry including surgical and perfusion data. Patients were divided into four groups based on their intra-operative nadir HCT (<21 or >=21) and whether or not they received intra-operative red blood cell (+RBC or -RBC) transfusions. Outcomes were adjusted for the Society of Thoracic Surgeons predicted risk of mortality (PROM), pre-operative HCT, and medical center. Regardless of nadir HCT cohort, those who received a transfusion had higher PROM relative to patients who did not receive a transfusion. The mean PROM was significantly higher among those HCT >=21 + RBC (5.3%) vs. HCT >= 21 - RBC (1.9%), p < .001. Similarly, the PROM was significantly higher among HCT <21 + RBC (5.1%) vs. those HCT <21 - RBC (3.1%), p < .001. Adjusted outcomes demonstrated an increased impact of RBC transfusions on adverse outcomes irrespective of nadir HCT including stroke (p < .001), renal failure (p < .001), prolonged ventilation (p < .001), and mortality (p < .001). This study demonstrates that transfusions have a more profound effect on post operative cardiac surgery outcomes than anemia. PMID- 27994260 TI - A Case of Successful Thromboelastographic Guided Resuscitation after Postpartum Hemorrhage and Cardiac Arrest. AB - Amniotic fluid embolism (AFE) is an unusual cause of life threatening peri partum hemorrhage (PPH). AFE resuscitation is often associated with renal and respiratory insufficiency, and a coagulopathy similar to disseminated intravascular coagulation (DIC). Resuscitation requires immediate recognition and limited use of crystalloid. We present a case of PPH caused by AFE with resultant cardiac arrest, renal and respiratory failure, and DIC-like coagulopathy, whose successful resuscitation was guided by perfusionist-directed serial thromboelastography (TEG). Viscoelastic tests (VET)s, including the TEG and rotational thromboelastometry (ROTEM), may provide more individualized blood component therapy (BCT) in the treatment of severe PPH associated with AFE as has been previously noted with trauma resuscitation in the literature. However, VET's efficacy is often limited by a lack of standardization, quality assurance norms, and consistent operator proficiency. We suggest that there may be a role for perfusionsts adept at utilizing TEG in the optimization of BCT and adjunctive hemostatic agents in severely hemorrhagic patients. This patient's successful resuscitation demonstrates the importance of resuscitation guided by the perfusionist or other medical professionals with expertise in TEG guided resuscitation and how the administration of specific blood products and hemostatic agents guided by the TEG can help optimize patient outcomes in comparison to traditional 1:1:1 packed red blood cells (PRBC) /fresh frozen plasma (FFP) /platelets ratios given to severely hemorrhaging patients. PMID- 27994261 TI - Use of Cardiopulmonary Bypass for Management of Massive Air Embolism During Hysteroscopic Metroplasty. AB - The patient was a 32-year-old woman who presented with infertility secondary to uterine didelphys. Hysteroscopic metroplasty was chosen as the corrective surgical procedure for this anatomical defect. During the surgical repair, the patient developed a massive air embolism (MAE) leading to hypotension, arrhythmia, and cardiogenic shock. Resuscitation was started by placing the patient in the right-side up position, and emplacement of central venous catheter, but it was unsuccessful. The decision was then made to bypass the patient's cardiopulmonary system to effectively treat the MAE. Cannulation was done via femoral vein and artery. During cardiopulmonary bypass (CPB), the MAE was quickly eliminated, oxygen saturation was normalized, and the patient was hemodynamically stabilized. The surgical repair was successfully completed and the patient was decannulated and recovered without any incident. PMID- 27994262 TI - Abstraction Techniques for the STS National Database. PMID- 27994263 TI - Technology Use and Patient Safety: At the Intersection of Change. PMID- 27994264 TI - New evidence for a role of bone marrow in the pathogenesis of rheumatoid arthritis. PMID- 27994265 TI - Symptom-modifying effects of oral avocado/soybean unsaponifiables in routine treatment of knee osteoarthritis in Poland. An open, prospective observational study of patients adherent to a 6-month treatment. AB - OBJECTIVES: Observational studies provide insights into real-life situations. Therefore, we assessed the effects of oral avocado/soybean unsaponifiable (ASU) capsules on pain relief and functional ability in patients, while they were receiving a routine treatment for knee osteoarthritis (OA). MATERIAL AND METHODS: An open, prospective, observational 6-month study was conducted in 99 centers in Poland in a group of 4822 patients with symptomatic knee OA receiving one 300 mg ASU capsule/day as a routine medication. The patients had no diagnoses of other rheumatic diseases and were not treated with other symptomatic slow-acting drugs for osteoarthritis (SYSADOAs). Data on OA symptoms and therapy were collected from the initiation of ASU treatment (visit 0) and during 3 consecutive control visits performed every 2 months (visits 1-3). Functional Lequesne index, severity of joint pain of one symptomatic knee (Laitinen index and VAS), use of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), adherence to treatment and adverse events were evaluated and recorded using electronic Case Report Forms. RESULTS: Four thousand one hundred and eighty-six patients (86.8%) attended all 4 visits. In 94.2% of patients (mean age 60.7 +/-11.6 years SD, 73.4% female) at least one OA risk factor was identified. There was a significant improvement in functional ability between the last and baseline visits as evidenced by the median Lequesne index decreasing from 8 to 4 points (p < 0.001). Measures of pain intensity also fell significantly (p < 0.001) throughout the study: median Laitinen score decreased from 6 to 3 points, median pain at rest VAS - from 1.8 to 0 cm and median pain during walking VAS - from 5.6 to 1.9 cm. The significant differences were also noted between consecutive visits. The proportion of patients using analgesics and NSAIDs declined from 58.8% at the baseline visit to 24.9% at the last visit 3 (p < 0.001). Defined daily dose of NSAIDs decreased significantly from 1 at the baseline visit to 0.67 at the visit 3. Severe adverse events associated with ASU treatment were not observed. CONCLUSIONS: It was the first observational study in Poland evaluating the effects of routine knee OA treatment with oral ASU. Only a small group of patients (13.2%) treated with ASU discontinued the study. The majority of patients adherent to the ASU treatment for 6 months showed gradual alleviation of joint pain, improvement in functional ability and a significant reduction in NSAIDs intake. PMID- 27994266 TI - Secretory activity of subcutaneous abdominal adipose tissue in male patients with rheumatoid arthritis and osteoarthritis - association with clinical and laboratory data. AB - INTRODUCTION: Adipose tissue exerts widespread effects on the metabolism and immune system, but its activity differs between the genders. In the general population low-grade adipose tissue inflammation contributes to development of diseases of affluence. Little is known about the systemic impact of peripheral fat tissue in osteoarthritis (OA) and rheumatoid arthritis (RA), characterized by chronic, low- and high-grade systemic inflammation, respectively. To clarify this we evaluated the secretory activity of subcutaneous abdominal adipose tissue (SAAT) obtained from male patients affected with RA (n = 21) and OA (n = 13), and assessed its association with body mass and composition, demographic, clinical and laboratory data. MATERIAL AND METHODS: Basal and interleukin (IL)-1beta triggered secretion of selected adipocytokines from SAAT explants was measured by specific enzyme-linked immunosorbent assays (ELISA). Patients' body composition was evaluated by bioelectric impendence technique. RESULTS: Rheumatoid SAAT secreted more adiponectin and macrophage migration inhibitory factor (MIF) than respective osteoarthritis tissue. In both RA and OA patient groups, stimulation of SAAT explants with IL-1beta (1 ng/ml/100 mg tissue) significantly up-regulated release of pro-(IL-6, IL-8, tumor necrosis factor - TNF) and anti-inflammatory (IL-10) cytokines but had no effect on the secretion of adiponectin, leptin, MIF and hepatocyte growth factor (HGF). Compared with RA, patients with OA were more obese. In RA patients SAAT-released adiponectin and TNF inversely correlated with body mass index (BMI) and visceral fat rating (FVSC). In addition, SAAT-secreted adiponectin and leptin positively correlated with DAS28 and disease duration, respectively. In the OA group tissue-released TNF positively correlated with patients' age. CONCLUSIONS: We conclude that in RA male patients adipocytokines originating from SAAT are of clinical importance because: (i) adiponectin and TNF may contribute to maintenance of normal body composition and mass, (ii) in addition adiponectin may play a pathogenic role. Moreover, in both RA and OA male patients secretory activity of SAAT may vary with time. PMID- 27994267 TI - Widespread headache as the first clinical manifestation of giant cell arteritis in patients affected by polymyalgia rheumatica. AB - INTRODUCTION: In giant cell arteritis (GCA) headache of new onset due to inflammatory involvement of the temporal artery (TA) represents a diagnostic criterion. A widespread headache (WH) with scalp tenderness due to cranial arteritis can represent another manifestation of GCA. MATERIAL AND METHODS: In 225 elderly patients with polymyalgia rheumatica (PMR) followed in our rheumatologic outpatient clinic from 2004 until June 2016, the frequency of WH as the first clinical manifestation of GCA was evaluated. RESULTS: Among 26 patients with GCA+PMR (11.6% of total), 5 (23.07%) had WH as first clinical manifestation of GCA without TA. In all these patients TA colour duplex sonography (CDS) and 18 fluorodeoxyglucose positron emission tomography (FDG-PET) with total body contrast-enhanced CT was consistent with the diagnosis of arteritis. TA biopsy was not performed. High doses of prednisone (1 mg/kg/day) led to the immediate and total disappearance of the headache. CONCLUSIONS: The widespread headache should be considered as the first symptom GCA and in cases of suspicion of vasculitis patients should have a full diagnostics examination. Colour duplex sonography and FDG-PET with total body contrast-enhanced CT are useful tools for non-invasive diagnosis of GCA. PMID- 27994268 TI - Automated assessment of joint synovitis activity from medical ultrasound and power doppler examinations using image processing and machine learning methods. AB - OBJECTIVES: Rheumatoid arthritis is the most common rheumatic disease with arthritis, and causes substantial functional disability in approximately 50% patients after 10 years. Accurate measurement of the disease activity is crucial to provide an adequate treatment and care to the patients. The aim of this study is focused on a computer aided diagnostic system that supports an assessment of synovitis severity. MATERIAL AND METHODS: This paper focus on a computer aided diagnostic system that was developed within joint Polish-Norwegian research project related to the automated assessment of the severity of synovitis. Semiquantitative ultrasound with power Doppler is a reliable and widely used method of assessing synovitis. Synovitis is estimated by ultrasound examiner using the scoring system graded from 0 to 3. Activity score is estimated on the basis of the examiner's experience or standardized ultrasound atlases. The method needs trained medical personnel and the result can be affected by a human error. RESULTS: The porotype of a computer-aided diagnostic system and algorithms essential for an analysis of ultrasonic images of finger joints are main scientific output of the MEDUSA project. Medusa Evaluation System prototype uses bone, skin, joint and synovitis area detectors for mutual structural model based evaluation of synovitis. Finally, several algorithms that support the semi automatic or automatic detection of the bone region were prepared as well as a system that uses the statistical data processing approach in order to automatically localize the regions of interest. CONCLUSIONS: Semiquantitative ultrasound with power Doppler is a reliable and widely used method of assessing synovitis. Activity score is estimated on the basis of the examiner's experience and the result can be affected by a human error. In this paper we presented the MEDUSA project which is focused on a computer aided diagnostic system that supports an assessment of synovitis severity. PMID- 27994269 TI - Health-related quality of life in children with juvenile idiopathic arthritis - child's and parent's point of view. AB - OBJECTIVES: To assess the quality of life (QoL) of children suffering from juvenile idiopathic arthritis (JIA) in Poland, to compare QoL of children with JIA and healthy children, and to compare children's and parents' assessments of QoL. MATERIAL AND METHODS: The KIDSCREEN-52 questionnaire (children's and parents' version) was used to assess the quality of life. The QoL in JIA patients and healthy peers from European and Polish reference groups was compared by the t test. The Bland-Altman method was used to evaluate child and parent assessment agreement. RESULTS: Eighty-nine questionnaires were obtained from children (median age: 14 years; 62% female; JIA history longer than 1 year) and 84 questionnaires from parents. The QoL of JIA patients was lower than in healthy peers from the European reference group in terms of physical well-being (p < 0.001), psychological well-being (p = 0.011), autonomy (p < 0.001) and social support and peers (p < 0.001). The QoL of JIA patients compared with the QoL of children from the Polish reference group was lower only in terms of physical well being (p < 0.001), whereas it was higher in terms of moods and emotions (p = 0.023), parent relations and home life (p = 0.005) and financial resources (p < 0.001). In most terms the assessment performed by the parent was lower than the child's. The most significant differences were observed for physical well-being (p < 0.001), psychological well-being (p = 0.016), and self-perception (p = 0.013). CONCLUSIONS: The present study is the first assessment of QoL of JIA children in Poland. In our study the quality of life in JIA children was lower than in healthy peers. Discrepancies between the assessment of the child's QoL performed by the child and the parent were found. Both assessments should be taken into account in clinical practice as well as in research studies. PMID- 27994270 TI - Esophageal transit scintigraphy in systemic sclerosis. AB - Systemic sclerosis is a rare connective tissue disease, distinctive features of which are fibrosis and microangiopathy. The esophagus is one of the most commonly involved internal organs. Most patients experience dysphagia, difficulties in swallowing and gastro-esophageal reflux. However, in up to one third of cases, the initial onset of esophageal disease may be clinically silent. There are several diagnostic modalities available for assessing both morphological and functional abnormalities of the esophagus. If structural abnormalities are suspected, endoscopy is the method of choice. Functional evaluation is best achieved with manometry. Both endoscopy and manometry are invasive techniques, with low patient acceptance. Barium-contrast study is well tolerated, but qualitative assessment of functional abnormalities is imprecise. Esophageal scintigraphy is an easy, non-invasive, sensitive and specific diagnostic modality. It can detect esophageal dysfunction even in asymptomatic patients. In patients already diagnosed with systemic sclerosis, scintigraphy is useful in evaluating severity and progression of the disease. PMID- 27994272 TI - Alveolar hemorrhage as the initial presentation of systemic lupus erythematosus. AB - Alveolar hemorrhage (AH) is a rare syndrome that can often occur in autoimmune diseases, blood clotting disorders, infection or by acute inhalation injury, presenting rapid evolution and high mortality, especially with late diagnosis and treatment. Among the autoimmune diseases, there are reported cases in patients with primary antiphospholipid syndrome (PAPS), vasculitis and systemic lupus erythematosus (SLE). An early diagnosis is an essential tool in the successful management of this complication, requiring aggressive treatment based on vigorous immunosuppression and broad-spectrum antibiotic. We describe here a case of alveolar hemorrhage associated with glomerulonephritis as the open presentation in a patient with SLE. PMID- 27994271 TI - Retroperitoneal fibrosis - the state-of-the-art. AB - Retroperitoneal fibrosis (RPF) is a rare disease, hallmarked by inflammation and deposition of fibrous tissue around the abdominal aorta. This process may spread contiguously and involve adjacent structures, leading to many complications, among which the most frequent and most severe is ureteral obstruction. The condition usually has idiopathic origin (idiopathic retroperitoneal fibrosis - IRF), but can also develop secondarily to a number of factors. The etiology of the disease remains unclear. Current research suggests that about half of the cases of IRF may be a symptom of a recently discovered, clinically heterogeneous immunoglobulin G4-related disease (IgG4-RD). Corticosteroids are the first-line treatment for IRF, but effective attempts to use immunosuppressants are also made. This paper presents the current state of knowledge on the etiopathogenesis, clinical presentation, diagnosis and therapeutic possibilities in different forms of RPF. Based on the latest research, an analysis of the relationship between IRF and IgG4-RD was performed. PMID- 27994273 TI - Tophi - surgical treatment. AB - Gout is an inflammatory joint disease associated with deposition of monosodium urate crystals in the bones forming the joints, in periarticular tissues and in other organs. The disease is one of the most frequent causes of disability. This paper presents the case of a 57-year-old male patient treated for generalised gout. A "clinical mask" suggesting another disease was the cause of making the correct diagnosis only six years after the occurrence of the first manifestations. The patient, with high values of inflammatory markers, severe pain and advanced joint destruction, was given an aggressive anti-inflammatory treatment. The unsatisfactory effect of the conservative treatment forced the authors to perform surgical resection of the gouty nodules in the hands. After several operations the function of the hand joints operated on, appearance of the hands and the quality of the patient's life improved significantly. PMID- 27994275 TI - Clarifying WHO's position on the FRAX(r) tool for fracture prediction. PMID- 27994277 TI - Public health round-up. PMID- 27994276 TI - From global health security to global health solidarity, security and sustainability. PMID- 27994278 TI - Towards an HIV-free generation in Cuba. AB - Last year Cuba became the first country in the world to eliminate mother-to-child transmission of HIV and syphilis as public health problems. Other countries are following suit. Andreia Azevedo Soares reports. PMID- 27994279 TI - Promoting health with human rights in Indonesia. AB - Nafsiah Mboi tells Fiona Fleck why technical know-how, insistence on human rights and gentle persuasion were essential ingredients for the modernization of public health in Indonesia. PMID- 27994280 TI - Quantifying cause-related mortality by weighting multiple causes of death. AB - OBJECTIVE: To investigate a new approach to calculating cause-related standardized mortality rates that involves assigning weights to each cause of death reported on death certificates. METHODS: We derived cause-related standardized mortality rates from death certificate data for France in 2010 using: (i) the classic method, which considered only the underlying cause of death; and (ii) three novel multiple-cause-of-death weighting methods, which assigned weights to multiple causes of death mentioned on death certificates: the first two multiple-cause-of-death methods assigned non-zero weights to all causes mentioned and the third assigned non-zero weights to only the underlying cause and other contributing causes that were not part of the main morbid process. As the sum of the weights for each death certificate was 1, each death had an equal influence on mortality estimates and the total number of deaths was unchanged. Mortality rates derived using the different methods were compared. FINDINGS: On average, 3.4 causes per death were listed on each certificate. The standardized mortality rate calculated using the third multiple-cause-of-death weighting method was more than 20% higher than that calculated using the classic method for five disease categories: skin diseases, mental disorders, endocrine and nutritional diseases, blood diseases and genitourinary diseases. Moreover, this method highlighted the mortality burden associated with certain diseases in specific age groups. CONCLUSION: A multiple-cause-of-death weighting approach to calculating cause-related standardized mortality rates from death certificate data identified conditions that contributed more to mortality than indicated by the classic method. This new approach holds promise for identifying underrecognized contributors to mortality. PMID- 27994281 TI - Assay optimization for molecular detection of Zika virus. AB - OBJECTIVE: To examine the diagnostic performance of real-time reverse transcription (RT)-polymerase chain reaction (PCR) assays for Zika virus detection. METHODS: We compared seven published real-time RT-PCR assays and two new assays that we have developed. To determine the analytical sensitivity of each assay, we constructed a synthetic universal control ribonucleic acid (uncRNA) containing all of the assays' target regions on one RNA strand and spiked human blood or urine with known quantities of African or Asian Zika virus strains. Viral loads in 33 samples from Zika virus-infected patients were determined by using one of the new assays. FINDINGS: Oligonucleotides of the published real-time RT-PCR assays, showed up to 10 potential mismatches with the Asian lineage causing the current outbreak, compared with 0 to 4 mismatches for the new assays. The 95% lower detection limit of the seven most sensitive assays ranged from 2.1 to 12.1 uncRNA copies/reaction. Two assays had lower sensitivities of 17.0 and 1373.3 uncRNA copies/reaction and showed a similar sensitivity when using spiked samples. The mean viral loads in samples from Zika virus-infected patients were 5 * 104 RNA copies/mL of blood and 2 * 104 RNA copies/mL of urine. CONCLUSION: We provide reagents and updated protocols for Zika virus detection suitable for the current outbreak strains. Some published assays might be unsuitable for Zika virus detection, due to the limited sensitivity and potential incompatibility with some strains. Viral concentrations in the clinical samples were close to the technical detection limit, suggesting that the use of insensitive assays will cause false-negative results. PMID- 27994282 TI - Pulse oximetry for children with pneumonia treated as outpatients in rural Malawi. AB - OBJECTIVE: To investigate implementation of outpatient pulse oximetry among children with pneumonia, in Malawi. METHODS: In 2011, 72 health-care providers at 18 rural health centres and 38 community health workers received training in the use of pulse oximetry to measure haemoglobin oxygen saturations. Data collected, between 1 January 2012 and 30 June 2014 by the trained individuals, on children aged 2-59 months with clinically diagnosed pneumonia were analysed. FINDINGS: Of the 14 092 children included in the analysis, 13 266 (94.1%) were successfully checked by oximetry. Among the children with chest indrawing and/or danger signs, those with a measured oxygen saturation below 90% were more than twice as likely to have been referred as those with higher saturations (84.3% [385/457] vs 41.5% [871/2099]; P < 0.001). The availability of oximetry appeared to have increased the referral rate for severely hypoxaemic children without chest indrawing or danger signs from 0% to 27.2% (P < 0.001). In the absence of oximetry, if the relevant World Health Organization (WHO) guidelines published in 2014 had been applied, 390/568 (68.7%) severely hypoxaemic children at study health centres and 52/84 (61.9%) severely hypoxaemic children seen by community health workers would have been considered ineligible for referral. CONCLUSION: Implementation of pulse oximetry by our trainees substantially increased the referrals of Malawian children with severe hypoxaemic pneumonia. When data from oximetry were excluded, retrospective application of the guidelines published by WHO in 2014 failed to identify a considerable proportion of severely hypoxaemic children eligible only via oximetry. PMID- 27994283 TI - Summary indices for monitoring universal coverage in maternal and child health care. AB - OBJECTIVE: To compare two summary indicators for monitoring universal coverage of reproductive, maternal, newborn and child health care. METHODS: Using our experience of the Countdown to 2015 initiative, we describe the characteristics of the composite coverage index (a weighted average of eight preventive and curative interventions along the continuum of care) and co-coverage index (a cumulative count of eight preventive interventions that should be received by all mothers and children). For in-depth analysis and comparisons, we extracted data from 49 demographic and health surveys. We calculated percentage coverage for the two summary indices, and correlated these with each other and with outcome indicators of mortality and undernutrition. We also stratified the summary indicators by wealth quintiles for a subset of nine countries. FINDINGS: Data on the component indicators in the required age range were less often available for co-coverage than for the composite coverage index. The composite coverage index and co-coverage with 6+ indicators were strongly correlated (Pearson r = 0.73, P < 0.001). The composite coverage index was more strongly correlated with under five mortality, neonatal mortality and prevalence of stunting (r = -0.57, -0.68 and -0.46 respectively) than was co-coverage (r = -0.49, -0.43 and -0.33 respectively). Both summary indices provided useful summaries of the degrees of inequality in the countries' coverage. Adding more indicators did not substantially affect the composite coverage index. CONCLUSION: The composite coverage index, based on the average value of separate coverage indicators, is easy to calculate and could be useful for monitoring progress and inequalities in universal health coverage. PMID- 27994284 TI - Assessment of Ebola virus disease preparedness in the WHO South-East Asia Region. AB - OBJECTIVE: To conduct assessments of Ebola virus disease preparedness in countries of the World Health Organization (WHO) South-East Asia Region. METHODS: Nine of 11 countries in the region agreed to be assessed. During February to November 2015 a joint team from WHO and ministries of health conducted 4-5 day missions to Bangladesh, Bhutan, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste. We collected information through guided discussions with senior technical leaders and visits to hospitals, laboratories and airports. We assessed each country's Ebola virus disease preparedness on 41 tasks under nine key components adapted from the WHO Ebola preparedness checklist of January 2015. FINDINGS: Political commitment to Ebola preparedness was high in all countries. Planning was most advanced for components that had been previously planned or tested for influenza pandemics: multilevel and multisectoral coordination; multidisciplinary rapid response teams; public communication and social mobilization; drills in international airports; and training on personal protective equipment. Major vulnerabilities included inadequate risk assessment and risk communication; gaps in data management and analysis for event surveillance; and limited capacity in molecular diagnostic techniques. Many countries had limited planning for a surge of Ebola cases. Other tasks needing improvement included: advice to inbound travellers; adequate isolation rooms; appropriate infection control practices; triage systems in hospitals; laboratory diagnostic capacity; contact tracing; and danger pay to staff to ensure continuity of care. CONCLUSION: Joint assessment and feedback about the functionality of Ebola virus preparedness systems help countries strengthen their core capacities to meet the International Health Regulations. PMID- 27994285 TI - Cost-effectiveness thresholds: pros and cons. AB - Cost-effectiveness analysis is used to compare the costs and outcomes of alternative policy options. Each resulting cost-effectiveness ratio represents the magnitude of additional health gained per additional unit of resources spent. Cost-effectiveness thresholds allow cost-effectiveness ratios that represent good or very good value for money to be identified. In 2001, the World Health Organization's Commission on Macroeconomics in Health suggested cost effectiveness thresholds based on multiples of a country's per-capita gross domestic product (GDP). In some contexts, in choosing which health interventions to fund and which not to fund, these thresholds have been used as decision rules. However, experience with the use of such GDP-based thresholds in decision-making processes at country level shows them to lack country specificity and this - in addition to uncertainty in the modelled cost-effectiveness ratios - can lead to the wrong decision on how to spend health-care resources. Cost-effectiveness information should be used alongside other considerations - e.g. budget impact and feasibility considerations - in a transparent decision-making process, rather than in isolation based on a single threshold value. Although cost-effectiveness ratios are undoubtedly informative in assessing value for money, countries should be encouraged to develop a context-specific process for decision-making that is supported by legislation, has stakeholder buy-in, for example the involvement of civil society organizations and patient groups, and is transparent, consistent and fair. PMID- 27994286 TI - A global database of food and nutrient consumption. PMID- 27994287 TI - A human rights-based approach to the reimbursement of expensive medicines. PMID- 27994289 TI - The Relationship Between Hemodialysis and the Echocardiographic Findings in Patients with Chronic Kidney Disease. AB - BACKGROUND: The incidence of cardiac morbidity and mortality is high in patients treated with hemodialysis (HD). The aim of this study was to evaluate the relationship between HD and the echocardiographic findings in patients with chronic kidney disease (CKD). METHODS: Between 2012 and 2014, 150 patients with CKD. The echocardiographic data were done based on American Society of Cardiology (ASE). Measurement method for Ejection Fraction was E balling and for Diastolic Function was Tissue Doppler. Anemia, thyroid conditions and dialysis through an arteriovenous fistula or permanent catheter of dialysis for the patients are not considered. RESULTS: The mean age at diagnosis for the patients was 57.8 years, 52.7% were males. Out of 150 patients, 112 patients (74.7%) had diabetes and 117 patients (78%) had a history of hypertension. The prevalence of all echocardiographic findings was more after the first dialysis compared with before the first dialysis in diabetic patients (P<0.05), but in non-diabetic patients, was not for the tricuspid valve stenosis, impaired right ventricular volume, systolic dysfunction and pulmonary hypertension (P>0.05). CONCLUSIONS: According to the findings of this study, seems that more accurate selection of patients for dialysis, paying special attention to hemodynamic change during dialysis, patient education about diet and better control of uremia and diabetes is essential. PMID- 27994288 TI - Plasma Cathepsin S and Cathepsin S/Cystatin C Ratios Are Potential Biomarkers for COPD. AB - Purpose. This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD. Patients and Methods. We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction ("at risk"; AR). In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA. Data were analyzed using simple and logistic regression and receiver operating characteristic analyses. Results. Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups (p < 0.01). Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation (% FEV1 predicted < 50%; p = 0.005) and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans (LAA >= 8.0; p = 0.001). Conclusion. Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD. PMID- 27994290 TI - Plasmapheresis in Pediatric Intensive Care Unit. AB - INTRODUCTION: Plasmapheresis also known as a therapeutic plasma exchange (TPE) is extracorporeal procedure by which individual components of plasma that are harmful or blood cells can be removed from organism by using a blood separation technology. AIM: To present the results of the implementation of plasmapheresis in children in the Department of Pediatric Intensive Care of Pediatric Clinic, Clinical center of Sarajevo University, Bosnia and Herzegovina. PATIENTS AND METHODS: Research (period from December 2011 to June 2016) analyzed 66 plasmapheresis (11 patients-6 plasmapheresis per patient). RESULTS: Out of 11 patients, 7 (63.6%) were girls and 4 (36.4%) were boys. The average age of patients was 11.6 +/- 3.9 years (the youngest patient had 4 years and 7 months, while the oldest had 16 years and 10 months). Plasmapheresis were significantly more often done in the winter and summer. Underlying disease was in 54.5% of cases of neurological origin. The treatment was in form of receiving IVIG in 7 patients, or the application of mechanical ventilation in 6 patients. The most common complication was hypotension, which occurred in 45.5% of patients, followed by bleeding in 36.3%, hypercoagulability in 27.2% of patients and hematoma in 27.2% of patients. Lethal outcome occurred in 3 (27.2%) patients. CONCLUSION: Plasmapheresis represents an invasive method due to need for placement of centralized venous catheter that provides adequate blood flow during the procedure. Although complications can be serious, they are rare and are mainly related to the presence of central venous catheter, hemostasis disorders due to use of anticoagulant therapy, and hypotension of the cardiovascular system. It should be noted that for success of plasmapheresis in children multidisciplinary approach is necessary (children's nephrologist, neuropediatrician, intensive care doctor) as well as well-trained team of doctors and nurses with the acquired knowledge and skills. PMID- 27994291 TI - The Discrepancy Between Subjective and Objective Findings After Septoplasty. AB - INTRODUCTION: Surgical and medical treatments of nasal obstruction are a common parts of otolaryngologist practice. The definitive treatment of deviated nasal septum is septoplasty. AIM: In this study was to evaluate the values of subjective parameters, and active anterior rhinomanometry parameters prior and three months after the septoplasty. PATIENTS AND METHODS: We analyzed the subjective parameters ("NOSE" scale), the active anterior rhinomanometry parameters according to International Committee on Standardization of Rhinomanometry, on 40 patients. Thirty healthy adult volunteers participated belonged to the control group. None of the patients or healthy volunteers had previous history of nasal surgery or active rhinological disease. RESULTS: The post-operative improvement in symptoms of nasal obstruction obtained in 92,5% patients and improvement parameters of the active anterior rhinomanometry in 42,5% patients. CONCLUSION: The correlation between the findings with rhinomanometry and subjective sensation of nasal patency remains uncertain. There still seems to be only a limited argument for the use of rhinomanometry for quantifying surgical results. Three months postoperative findings are very early results to interpret the permanent effects. PMID- 27994292 TI - Brain Edema After Ischaemic Stroke. AB - OBJECTIVES: To determine the incidence of brain edema after ischaemic stroke and its impact on the outcome of patients in the acute phase of ischaemic stroke. PATIENTS AND METHODS: We retrospectively analyzed 114 patients. Ischaemic stroke and brain edema are verified by computed tomography. The severity of stroke was determined by National Institutes of Health Stroke Scale. Laboratory findings were made during the first four days of hospitalization, and complications were verified by clinical examination and additional tests. RESULTS: In 9 (7.9%) patients developed brain edema. Pneumonia was the most common complication (12.3%). Brain edema had a higher incidence in women, patients with hypertension and elevated serum creatinine values, and patients who are suffering from diabetes. There was no significant correlation between brain edema and survival in patients after acute ischaemic stroke. Patients with brain edema had a significantly higher degree of neurological deficit as at admission, and at discharge (p = 0.04, p = 0.004). CONCLUSION: The cerebral edema is common after acute ischaemic stroke and no effect on survival in the acute phase. The existence of brain edema in acute ischaemic stroke significantly influence the degree of neurological deficit. PMID- 27994293 TI - Expression IRF/MUM1>25% Predictor to Three-year Survival of Diffuse Large B Cell Lymphoma in the Immunochemotherapy Era. AB - INTRODUCTION: Non Hodgkin lymphoma-Diffuse large B cell lymphoma (DLBC) is composed of more varieties of one disease. Analysis and understanding of a wide range of characteristics of the disease, which include: clinical, immunohistochemical, cytogenetic and molecular characteristics may improve treatment results. AIM: achieving the estimated three-year survival and influence of IRF/MUM1 expression to three-year survival. MATERIAL AND METHODS: A study was retrospective-prospective, patients were followed for seven years a period of dine. The study included 60 patients de novo DLBCL. Age was 18-72 years old, the average age 45 years, male 31 (51,7%) and female 29 (48.3%). Median follow-up was 47 months (3-91 months). To determine differentiation immunophenotype antibodies those were used anti-CD20, anti-CD10, anti-Bcl-6, IRF-4/MUM1, CD 138. RESULTS: Included the GCB type was 65%. Impact prognostic index IPI>2 GBC vs non GBC p=0,038 X2. Statistically significant difference was confirmed compared to the IPI> 2 to 3 year OS p<0,0005 X2. Significantly longer three-year survival was provided in the group GCB 36 (92,3%) vs. non GCB 8 (38,1%) p=0,003 X2. Clinical and immunohistochemical factors showed a significant impact to three-year survival by univariate: LDH p=0,005, MUM1 p=0,003, while CD10 p=0,069 was confirmed on the level of borderline impact. Using multivariate analysis, expression MUM1 has the greatest impact p<0.0005 OR=0.083 (95% CI 0.23-0.303) on the disease outcome - three-year survival. CONCLUSION: expression MUM1 >25% has the greatest impact on the disease outcome - three-year survival. PMID- 27994294 TI - Association of Beta-2 Microglobulin with Inflammation and Dislipidemia in High Flux Membrane Hemodialysis Patients. AB - BACKGROUND: Higher than expected cardiovascular mortality in hemodialysis patients, has been attributed to dyslipidemia as well as inflammation. Beta2 Microglobulin (beta2M) is an independent predictor of outcome for hemodialysis patients and a representative substance of middle molecules. RESULTS: In 40 patients in high-flux membrane hemodialysis, we found negative correlation of beta2M with high density lipoprotein (r=-0.73, p<0.001) and albumin (r= -0.53, p<0.001) and positive correlation with triglycerides (r=0.69, p<0.001), parathyroid hormone (r=0.58, p < 0.05) and phosphorus (r= 0.53, p<0.001). There was no correlation of beta2M with C- reactive protein (CRP) and interleukin-6 (IL 6). During the follow-up period of three years, 6 out of 40 patients have died from cardiovascular events. CONCLUSION: In high-flux membrane hemodialysis patients, we observed a significant relationship of beta2M with dyslipidemia and mineral bone disorders, but there was no correlation with inflammation. PMID- 27994295 TI - The Results of Single Bundle Versus Double Bundle ACL Reconstruction Surgery, a Retrospective Study and Review of Literature. AB - OBJECTIVE: The purpose of this study was to evaluate the results of single bundle and double bundle surgical techniques for anterior cruciate ligament (ACL) reconstruction. METHODS: In this study, all single bundle and double bundle ACL reconstruction surgeries that were done in our university hospital from January 2008 to December 2012 were enrolled. All patients were followed at 2,6,12, 24 weeks and 1 a 2 years post operatively. On last follow up all patients were evaluated by clinical examination, KT-1000 and Lysholm questionnaire. RESULTS: Seventy five patients were operated using single bundle and eighty five patients with double bundle technique. Fifty seven percent of patients in single bundle and 80% of patients in double bundle group had experienced pain during follow-up period. None of cases had knee extension or flexion loss. The average side to side differences using KT-1000 was 3.5 +/- 0.38 (2.9-4.1) millimeters in single bundle group and 3.39 +/- 0.39 (2.8-4) millimeters in double bundle group. These results showed no significant difference between two groups (P= 0.31). Lysholm score improved significantly in both groups, but there was no significant difference between them. CONCLUSION: According to this study the clinical results of single bundle ACL reconstruction was similar to double bundle reconstruction in short term follow up. Further studies are needed to evaluate the long term results. PMID- 27994296 TI - The Most Common Detected Bacteria in Sputum of Patients with Community Acquired Pneumonia (CAP) Treated In Hospital. AB - INTRODUCTION: Community acquired pneumonia (CAP) is the most common infective pulmonary disease. OBJECTIVE: To show the most common detected bacteria in bacterial culture of sputum in patients with CAP hospitalized in Clinic for Pulmonary Diseases and TB "Podhrastovi" in four-year period: from 2012 to 2015. MATERIAL AND METHODS: This is the retrospective analysis. Each patient gave sputum 3 days in a row when admitted to hospital. Sputum has been examined: bacterial culture with antibiotics sensitivity, Gram stain, Mycobacterium tuberculosis; in cases with high temperature blood cultures were done; when we were suspicious about bronchial carcinoma bronchoscopy with BAL (bronchoalveolar lavage) was done. We show analyzed patients according to age, sex, whether they had pneumonia or bronchopneumonia, bacteria isolated in sputum and in BAL. RESULTS: 360 patients with CAP were treated in four-year period (247 males and 113 females). 167 or 43, 39 % had pneumonia (119 males and 48 females). Number of males was significantly bigger (chi2 = 30,186; p<0,001). 193 or 53, 61 % had bronchopneumonia (128 males and 65 females). Number of males was significantly bigger (chi2 = 20,556; p<0,001). Number of patients with negative bacterial culture of sputum (131-78, 44%) was significantly bigger than number of patients with positive culture (36-21, 56%) (chi2 = 50,042; p<0,001) in pneumonia. Number of patients with negative bacterial culture of sputum (154- 79, 79%) was significantly bigger than number of patients with positive culture (39- 20, 21%) (chi2 = 68,523; p<0,001) in bronchopneumonia. Streptococcus pneumoniae was significantly most common detected bacterium compared with the number of other isolated bacteria; in pneumonia (chi2 =33,222; p<0,001) and in bronchopneumonia (chi2 =51,231; p<0,001). CONCLUSION: It is very important to detect the bacterial cause of CAP to administrate the targeted antibiotic therapy. PMID- 27994297 TI - Musculoskeletal Health of 40-65 Year Old Males and Females in Kosova and the Impact of N05B, A02B (PPI, H2RA), H02AB and Lifestyle Factors on It. AB - BACKGROUND: This observational, cross-sectional study investigates the impact of medication usage, physical activity (PA) and nutritional status on musculoskeletal health (MSH) in males and females aged 40-65 in the population of a post conflict, developing country. METHODS: Bone Mineral Density (BMD), T-score and Z-score at distal forearm regions (measured by DEXA scan), together with isometric hand grip strength (dynamometer) were evaluated in a total of 162 subjects (53 Males, average age 55.15+/-7.12 and 109 Females, 54.27+/-5.1). Additionally, bio-anthropometric assessments, medication usage, PA level and nutritional status were assessed. RESULTS: Significant differences (p<0.05) were found in total subjects Body Mass Index (BMI), PA, BMD, T-score and Hand grip between genders. 42% of total participants met the diagnostic criteria of, out of which 6.8% with T-score below -2, while no cases of Osteoporosis was recorded. N05B Anxiolytics and A02B Drugs for peptic ulcer and gastro-oesophageal reflux disease medication groups consumption turned to have no significant differences (p>0.05) in BMD, T-score, and hand grip in total population, except for A02B where p<0.05 were found in Hand grip, as well as between female consumers and no consumers in all variables. Meanwhile, in total subjects consuming H02AB Glucocorticoids p<0.05 were observed in BMD and T-score, but not on hand grip. CONCLUSIONS: This study shows a low risk for MSH problems amongst the studied population in Kosova, while the consumption of H02AB medication group in both genders and A02B in females only for extended periods might effect MSH, therefore appropriate benefit/risk assessment should be made before prescribing these medications, notwithstanding age, gender, PA or nutritional status. PMID- 27994298 TI - Relationship Between Genotype Variants Follicle-stimulating Hormone Receptor Gene Polymorphisms (FSHR) and Morphology of Oocytes Prior to ICSI Procedures. AB - INTRODUCTION: This study investigated association of Asn680Ser FSHR polymorphism with the ovarian response in 104 women of Albanian ethnic population enrolled in ICSI program. The reason of infertility in all cases has been identified as male factor. METHODS: Analysis of the Asn680Ser polymorphism was performed using TaqMan(r) SNP Genotyping Assay. Clinical and endocrinologic parameters were analyzed based on the genotype, age, BMI, oocyte yield, number of transferred embryos and pregnancy rate. RESULTS: The frequencies of the Asn680 Ser genotype variants were as follows: Asn/Asn 22.1%, Asn/Ser 47.1%, and Ser/Ser 30.8%, respectively. BMI was significantly higher in the Ser/Ser group as compared to those from the Asn/Ser or the Asn/Asn group (p= 0.0010). The genotype variants Ser/Ser indicates a higher rate of oocyte retrieval (25.9%) in the immature form, metaphase I (MI) as opposed to the other two groups (Asn/Asn 23.7 % vs. Asn/Ser 21.9%), which was statistically significant (p = 0.3020). CONCLUSIONS: FSH receptor polymorphism is associated with different ovarian response to controlled ovarian stimulation (COS), but is not an important factor in increasing the degree of pregnancy. Polymorphisms of the FSH receptor is associated with normal morphology and genetic maturation (metaphase II) oocytes in dependence of genotypic variation polymorphisms. PMID- 27994299 TI - Evaluation of Risk Factors of Surgical Wound Dehiscence in Adults After Laparotomy. AB - OBJECTIVES: The percentage of patients with difficult and prolonged healing of the wound is still high, while the immediate complications such as wound dehiscence occurs in up to 3 % of all treated patients in abdominal surgery. The aim of study was to analyze the risk factors and comorbidities in the group patients undergoing laparotomy and associated with early postoperative wound dehiscence. METHODS: The retrospective study included all patients treated surgically at Clinic of General and Abdominal surgery, Clinical Center of the University of Sarajevo in the period from January 1, 2013 until January 1, 2016, with clinically verified surgical wound dehiscence. RESULTS: The results showed statistically proportion of male patients (70%) compared to female (30%). The largest number of respondents were in age group 71-80. Surgical wound infection was evident in 61% of patients, malignant staining in 52%, hypoproteinemia was found in 50% of patients, anemia in 43%, peritonitis in 36% and diabetes in 14% of respondents. Of the total respondents with surgical wound dehiscence, 30 (68%) had comorbidities present. By analyzing the prevalence of comorbidity and risk factors recorded in relation to comorbidity, it was noted that hypertension is most often associated with hypoproteinemia (X2=4.399; p=0.036), wound infection (X2=4.112; p=0.043) and malignant diseases (X2=4.016; p=0.045). The frequency of the anemia, peritonitis and diabetes in the sample was not different in relation to the comorbidity conditions (p >0.05). CONCLUSIONS: The risk factors occurrence of surgical wound dehiscence in our study were identified as hypoproteinemia, malignant disease, anemia and peritonitis. The highest incidence of dehiscence was in patients operated on in medical emergencies, and in patients with malignant disease. PMID- 27994300 TI - Does Remote Ischaemic Preconditioning Protect Kidney and Cardiomyocytes After Coronary Revascularization? A Double Blind Controlled Clinical Trial. AB - OBJECTIVE: To investigate efficacy of remote ischaemic preconditioning on reducing kidney injury and myocardial damage after coronary artery bypass grafting surgery (CABG). BACKGROUND: Ischaemic preconditioning of a remote organ reduces ischaemia-reperfusion injury of kidney and myocardium after CABG. METHOD: To reduce myocardial damage and kidney injury by applying Remote Ischaemic Preconditioning we recruited 100 consecutive patients undergoing elective coronary artery bypass grafting surgery. We applied three cycles of lower limb tourniquet, inflated its cuff for 5 minutes in study group or left un-inflated (sham or control group) before the procedure. The primary outcome was serum creatinine, creatinine clearance and troponin-I Levels at time 0, 6, 12, 24 and 48 h. Secondary outcomes were serum C-reactive protein, inotrope score, ventilation time and ICU stay. Data's were analyzed by MedCalc (MedCalc Software bvba, Acacialaan, Belgium). We compared the two group by student t test, chi square and Mann-Whitney tests. RESULTS: The two groups were not statistically different in terms of age, gender, smoking habits, drug use, hypertension, hyperlipidemia and diabetes mellitus. This study showed a higher CRP level in study group comparing with control group (P=0.003), creatinine clearance was slightly higher in study group specially 24 h after procedure but was not statistically significant (p=0.11). Troponin-I level was significantly lower in study group (p=0.001). CONCLUSION: This study showed a lower Troponin-I level in study group which suggest a cardio-myocyte protective function of RIPC. It also showed slightly lower Creatinine clearance in control group, gap between two group increases significantly 24 hours after procedure which may suggest a potential kidney protection by RIPC. Serum CRP level was higher in study group. A multi-center randomized controlled trial with a longer time for creatinine clearance measurement may show the potential effectiveness of this non-invasive inexpensive intervention on reducing kidney injury after CABG. PMID- 27994301 TI - Pressure Ulcers: Developing Clinical Indicators in Evidence-based Practice. A Prospective Study. AB - AIMS AND OBJECTIVES: It is widely recognized that Intensive Care Unit (ICU) patients have a greater likelihood of developing pressure ulcers in comparison to hospital or home care patients. Accordingly, this study aimed to evaluate whether specific clinical characteristics could be used as clinical indicators towards pressure ulcers prevention. METHOD: We monitored 210 hospitalized ICU patients during a 12-month period. Pressure ulcers were assessed following the current guidelines. Clinical characteristics such as gender, age, hospitalized days, hemodialysis treatment, hematocrit, and serum albumin levels were considered as the most common predictors for pressure ulcers development. The significance of associations was controlled using multiple logistic regression after adjusting for clinical characteristics and was presented as adjusted odds ratio (AOR). RESULTS: The prevalence of pressure ulcers was 24.3%. Logistic regression revealed that patients with increased age AOR=1.04; (CI: 1.01-1.07) and last-long hospitalization AOR=1.17; (CI: 1.11-1.23) were significantly more likely to present pressure ulcers compared to the younger ones and patients with less length of stay, respectively. We also found that patients under hemodialysis treatment were more likely to present pressure ulcers AOR=4.09; (CI: 1.12-14.98) compared to patients that did not underwent hemodialysis and the risk of pressure ulcers development was decreased by 9% for every single unit of hematocrit value increase AOR=0.91; (CI: 0.82-0.99). CONCLUSION: Our data analysis confirms that the clinical characteristics that were studied are independently associated with pressure ulcers development, and therefore, it is a crucial incentive to consider that these specific clinical characteristics are important indicators in the evidence-based practice. PMID- 27994302 TI - Modern Strategy for Identification of Congenital Heart Defects in the Neonatal Period. AB - INTRODUCTION: Congenital heart defects are the most common congenital anomalies and occur with an incidence from 0.8 to 1% per 1000 live births. In recent years, the pulse oximetry has become a strong candidate for detecting cyanogen congenital heart defects and in combination with routine clinical exam can improve diagnostic of congenital heart diseases. OBJECTIVE: To apply the modern algorithm for early detection of congenital heart defects in order to improve the diagnosis in the neonatal period. PATIENTS AND METHODS: This was a prospective study that included children born in Bihac Cantonal Hospital during 2012. The diagnostic algorithm included a clinical examination of the newborn, measuring of transcutaneous oxygen saturation with the pulse oximeter between 24 and 48 hours of life, and, in some cases, additional tests (cardiac ultrasound). RESULTS: A total of 1,865 children were examined. The application of diagnostic protocol identified the existence of congenital heart defects in 29 children. In re evaluating the auscultator and ultrasound findings, we identified congenital heart defects in 19 children. CONCLUSION: The application of the modern algorithm for early detection of congenital heart diseases in the neonatal period can significantly improve the making of diagnosis of these anomalies. The concept is simple, inexpensive and applicable in most maternity wards. PMID- 27994303 TI - Accessory Spleen in the Splenic Hilum: a Cadaveric Study with Clinical Significance. AB - AIM: An accessory spleen is an additional tissue of the spleen that may be found near the spleen. It is a congenital anomaly of the spleen that its incidence has been reported 10-30% of the population. Hence, the objective of this study was evaluation the incidence of accessory spleen in Iranian cadavers. METHOD: Sixty hundred and ninety three spleens (541 males, 152 females) were excised from cadavers in the dissection hall of Mashhad Forensic Medicine Organization cadavers. Inclusion criteria were as follows: Fresh Iranian cadavers with no history of alcohol, poisoning or drug abuse, and no evidence of pathologic abnormality or injury to the spleen. The presence of accessory spleens, its dimension and weight investigated in cadavers. RESULTS: During routine postmortem examination, five cases with an accessory spleen were found in the autopsy laboratory of Mashhad legal Medicine Organization between June 2014 and July 2015. Of the cases, 3 were male and 2 were female. The accessory spleens were observed at the splenic hilum. The length of the accessory spleens ranged from 2 3.5 cm, while the range of width was between 0.5 and 2.5 cm. The accessory spleens were confirmed by histological examination. CONCLUSION: An accessory spleen has clinical importance in some locations. When an accessory spleen is situated in another site, it may mimic some tumors such as pancreatic tumor and adrenal tumor. In addition, accessory spleen may cause hyperplasia after splenectomy and be responsible for a recurrence of the hematological disorders. PMID- 27994304 TI - Adenoid Cystic Carcinoma of the Breast: A Clinical Case Report. AB - INTRODUCTION: Adenoid cystic carcinoma (ACC) is an uncommon tumor of the breast, accounting for approximately 0.1% to 1% of all breast cancers. It is characterized by rare lymph node involvement and distant metastasis, and associated with a favorable prognosis with excellent survival, despite its triple negative status. In the current state of knowledge, results of breast-conserving treatment with postoperative radiotherapy seem to be equivalent to mastectomy alone, with respect to survival for ACC of the breast. Due to its rarity, there is no consensus on optimal treatment for patients with ACC. Otherwise, the role of chemotherapy and hormonal therapy remains controversial. Further clinical studies are required to compare treatment options for ACC. But, a long-term follow-up is very important and mandatory for affected patients, due to the late onset of local relapse and occurrence of distant metastasis. CASE REPORT: Here, we report the case of a patient who presented with a palpable breast mass in the left breast that turned out to be an ACC of the breast. PMID- 27994305 TI - Colonic Perforation in a Young Tetraplegic Male Caused by Zucchini. AB - INTRODUCTION: Colonic perforation is a clinical condition which occurs due to variety of reasons, such as intrinsic disorders of the intestine, extrinsic causes, but also due to presence of foreign bodies. Foreign objects enter gastrointestinal tract by oral or transanal introduction. CASE REPORT: we present an uncommon case of a 26- year-old tetraplegic male, whose death was a consequence of a widespread purulent peritonitis provoked by colonic perforation inflicted by an unusual foreign body, transanally introduced 28 centimeters long zucchini (Cucurbita pepo L.). CONCLUSIONS: we share our experience in order to emphasize the importance of consideration and early recognition of foreign body presence in the alimentary tract as possible diagnosis. PMID- 27994306 TI - A Rare Case of Hamartoma Chest Wall Following Trauma in a 42-year-old Man. AB - BACKGROUND: Chest wall mesenchymal hamartoma (CWH) is a distinct and extremely rare tumor-like lesion of the thorax. It usually presents in the neonatal period or in infancy. The common presentation is in the form of a visible chest wall mass with or without respiratory distress. CASE PRESENTATION: A 42-year-old man with a history of chest wall trauma since 5 years ago was admitted with a swelling of the anterior of the chest wall and during this period has grown slowly. Physical examination showed a left anterior chest wall deformity. Chest radiographs and chest CT showed a left anterolateral chest wall mass involving the fourth and fifth ribs. Thoracotomy was performed. The tumor and involved ribs were resected with a 5cm safe margin. The histopathologic examination showed hamartoma. The patient has been fallowed up since 60 month ago, and has not had any complaints in this time. RESULT: Despite the rarity of chest wall hematoma, this side effect must always be taken into consideration while studying the chest wall injuries especially in the case of trauma history due to other differential diagnosis and her side effects such as respiratory problems. CONCLUSION: Although rare, this condition ought to be kept in mind while dealing with hamartoma Chest wall following trauma in order to avoid its complications such as respiratory problems. Surgical excision is usually curative in combination with conservative therapy if possible. PMID- 27994307 TI - Quantile Regression Models for Current Status Data. AB - Current status data arise frequently in demography, epidemiology, and econometrics where the exact failure time cannot be determined but is only known to have occurred before or after a known observation time. We propose a quantile regression model to analyze current status data, because it does not require distributional assumptions and the coefficients can be interpreted as direct regression effects on the distribution of failure time in the original time scale. Our model assumes that the conditional quantile of failure time is a linear function of covariates. We assume conditional independence between the failure time and observation time. An M-estimator is developed for parameter estimation which is computed using the concave-convex procedure and its confidence intervals are constructed using a subsampling method. Asymptotic properties for the estimator are derived and proven using modern empirical process theory. The small sample performance of the proposed method is demonstrated via simulation studies. Finally, we apply the proposed method to analyze data from the Mayo Clinic Study of Aging. PMID- 27994308 TI - J Conserv Dent: 2008 - 2016: An appraisal. PMID- 27994309 TI - Effect of carbodiimide on the structural stability of resin/dentin interface. AB - Clinical longevity of composite resin restorations is a significant problem in adhesive dentistry. Most of the current simplified adhesives present good immediate bonding, but the bond strength gradually falls over a period due to biodegradation at the resin-dentin interface. Various strategies have been proposed to improve the durability of resin-dentin bond including the use of matrix metalloproteinases inhibitors and collagen cross-linkers, biomimetic remineralization, ethanol wet bonding, to improve the physical and mechanical properties of the bonding substrate, i.e., dentin. However, all are under preliminary research and without any conclusive evidence. Therefore, this paper addresses the current challenge in dental adhesion, i.e., poor durability of resin-dentin bond and introduces the concept of dentin biomodification as an alternative way for improving the long-term bonding effectiveness of current adhesives to dentin and also provides an overview of a synthetic collagen cross linking agent carbodiimide (EDC) including its mechanism of action, literature review of studies evaluating EDC, variables associated with its use and its cytotoxicity. Search was performed across the electronic databases (PubMed, Ebsco host, and Google search engine) to identify manuscripts for inclusion, using the keywords: carbodiimide, dentin bonding, durability, resin-dentin interface, and collagen cross-linking. Thirty-five articles were finally included, and the last search was made in February 2016. PMID- 27994310 TI - Clinical performance of Class I nanohybrid composite restorations with resin modified glass-ionomer liner and flowable composite liner: A randomized clinical trial. AB - BACKGROUND: Liners play a vital role in minimizing polymerization shrinkage stress by elastic bonding concept and increase the longevity and favorable outcome for composite restorations. AIMS: The aim of this study was to evaluate the clinical performance of nanohybrid composite restorations using resin modified glass-ionomer and flowable composite liners. SETTINGS AND DESIGN: A single-centered, double-blinded randomized clinical trial, with split-mouth design and equal allocation ratio that was conducted in the Department of Conservative Dentistry and Endodontics. MATERIALS AND METHODS: In forty patients, a total of eighty Class I restorations were placed with resin-modified glass ionomer cement (RMGIC) liner (FUJI II LC, GC America) in one group and flowable composite liner (smart dentin replacement/SDR, Dentsply Caulk, Milford, DE, USA) in another group. All restorations were clinically evaluated by two examiners, immediately (baseline), 3, 6, and 12 months using US Public Health Service modified criteria. STATISTICAL ANALYSIS USED: Statistical analysis was performed using McNemar's test (P < 0.05). RESULTS: There was no significant difference in the color match, marginal discoloration, surface roughness, and marginal adaptation. Restorations with RMGIC liner group show 20% Bravo scores on anatomic form at 12 months but are still clinically acceptable. CONCLUSION: Nanohybrid composite restorations with RMGIC (Fuji II LC) and flowable composite liner (SDR) demonstrated clinically acceptable performance after 12 months. PMID- 27994311 TI - The influence of the lining material on the repair of the infected dentin in young permanent molars after restoration: A randomized clinical trial. AB - AIM: This study evaluated the impact of liner material on the fluorescence, morphological and mineral characteristics of permanent carious dentin after cavity sealing. METHODS: Thirty children (11.0 +/- 2.7 years old) presenting at least one active deep carious lesion in permanent molars were selected. Fragments of carious dentin were removed from teeth before lining the cavity (baseline samples) with high-viscosity glass ionomer cement (G1) or an inert material (wax G2). Cavities were restored with composite resin and reopened 60 days later, and other fragments were removed (60-day sample). The laser fluorescence (LF) readings and morphological and mineral changes of both groups were compared. RESULTS: After 60 days, forty teeth were available for evaluation. Lower LF means were obtained (Wilcoxon signed-rank test; P < 0.05), and enhanced calcium and phosphorus levels were detected for both groups (t-test, P < 0.05). An uptake of fluorine was observed only in G1 (t-test; P < 0.05). Regardless of the group, baseline samples exhibited clear signs of bacterial invasion, and the collagen fibers were exposed; the 60-day samples showed a better-organized tissue with a more compact intertubular dentin. CONCLUSION: Caries arrestment with dentin reorganization occurs regardless of the lining material placed in contact with the infected dentin. PMID- 27994312 TI - Cytotoxicity of two available mineral trioxide aggregate cements and a new formulation on human gingival fibroblasts. AB - AIM: The purpose of this study was to investigate the cytotoxicity of nanohybrid mineral trioxide aggregate (MTA) in comparison with calcium-enriched mixture (CEM) cement and MTA-Angelus, using human gingival fibroblasts (HGFs). MATERIALS AND METHODS: Nine disc-shaped specimens of each material (in 2 set stat: A, set for 24 h; B, set for 30 min; and C, fresh stat) were prepared. HGFs were exposed to tested materials' extracts or control media. Cytotoxicity testing was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay in two time intervals. STATISTICAL ANALYSIS: Results were evaluated by one way ANOVA and t-test. Statistical significance was set at P < 0.05. RESULTS: CEM cement demonstrated favorable cell viability values when completely set (24 h set MTA = 24 h set CEM) at both time intervals. Interestingly, 24 h after incubation, CEM in Groups B and C demonstrated higher cell viability values than MTA (P < 0.05). However, after 72 h of incubation, these groups of CEM and MTA showed equal cell viability. All samples of nanohybrid MTA had slight cytotoxic effects after 24 h of incubation, and moderate cytotoxic effects after 72 h of incubation. CONCLUSION: Set CEM and set MTA-Angelus exerted similar, favorable effects on cell viability. However, within the limitations of this in vitro study, the results suggest that nanohybrid MTA could not be recommended as a material of choice for cervical root resorption. PMID- 27994313 TI - A comparative evaluation of anesthetic efficacy of articaine 4% and lidocaine 2% with anterior middle superior alveolar nerve block and infraorbital nerve block: An in vivo study. AB - BACKGROUND: The ideal maxillary injection should produce a rapid onset of profound pulpal anesthesia for multiple teeth from a single needle penetration. The main objective is to compare the efficacy of articaine 4% and lidocaine 2% and to compare anterior middle superior alveolar nerve block (AMSANB) and infraorbital nerve block (IONB) for anesthesia of maxillary teeth. MATERIALS AND METHODS: Forty patients undergoing root canal treatment of maxillary anteriors and premolars were included and randomly divided into four groups of ten each. Group I: patients receiving AMSANB with articaine, Group II: Patients receiving IONB with articaine, Group III: Patients receiving AMSANB with lidocaine, Group IV: Patients receiving IONB with lidocaine. The scores of onset of anesthesia and pain perception were statistically analyzed. RESULTS: Onset of action was fastest for articaine with AMSANB and slowest for lidocaine with IONB by Tukey's test. A significant change was observed in the electrical pulp test readings at onset and at 30 min by paired t-test. All patients experienced mild pain during the procedure recorded by visual analog scale. CONCLUSION: Articaine 4% proved to be more efficacious than lidocaine 2%, and AMSANB was more advantageous than IONB in securing anesthesia of maxillary anteriors and premolars. PMID- 27994314 TI - Comparative evaluation of the microtensile bond strength of bulk fill and low shrinkage composite for different depths of Class II cavities with the cervical margin in cementum: An in vitro study. AB - AIM: The aim of this study was to evaluate the microtensile bond strength (MUTBS) of bulk fill and low shrinkage composite for different depths of Class II cavities with the cervical margin in cementum. MATERIALS AND METHODS: Standardized conservative box-shaped Class II cavities were prepared on sixty sound-impacted human third molars. The samples were randomly divided into two groups: Group I (n = 30) - horizontal incremental technique and Group II (n = 30) - bulk fill technique (SonicFill). They were further subdivided into three subgroups of (n = 10) samples each according to the different occluso-gingival height: subgroup (A - 4 mm, B - 5 mm, and C - 6 mm). The gingival margins for all the samples were located 1 mm below the cementoenamel junction. The restored samples were subjected to thermocycling (500 cycles) followed by MUTBS testing. The scores were statistically analyzed using ANOVA and post hoc test using SPSS software version 16. RESULTS: Subgroups IA and IB showed lower MUTBS than subgroups IIA and IIB (P < 0.05) whereas subgroup IC showed higher MUTBS than subgroup IIC (P < 0.05). SonicFill showed a significant reduction in MUTBS as the depth increased. CONCLUSION: SonicFill should be used in two increments for cavities with a depth of more than 5 mm. PMID- 27994315 TI - Histological evaluation of mineral trioxide aggregate and enamel matrix derivative combination in direct pulp capping: An in vivo study. AB - AIM: The aim of this study is to evaluate the response of human pulp tissue to mineral trioxide aggregate (MTA), Emdogain (EMD), and combination of MTA/EMD. MATERIALS AND METHODS: This study was performed on sixty intact first and second premolars of human maxillary and mandibular teeth. A standard pulpal exposure was done on all the teeth and was divided into three groups of twenty teeth each and was capped with MTA, EMD, and MTA/EMD combination. The final restoration was done with resin-modified glass ionomer cement. The teeth were then extracted on the 15th or 45th day and histological evaluation done. RESULTS: Differences in inflammatory response and thickness of dentin bridge formation of the exposed pulp to the three different groups were statistically evaluated using Chi-square and Mann-Whitney tests and were found to be significant. No significant difference was found between MTA/EMD and MTA in terms of calcified bridge formation and pulp inflammatory response to the capping materials. CONCLUSIONS: MTA and MTA/EMD combination produced a better quality hard tissue response compared with the use of EMD. PMID- 27994316 TI - Evaluation of Enterococcus faecalis adhesion, penetration, and method to prevent the penetration of Enterococcus faecalis into root cementum: Confocal laser scanning microscope and scanning electron microscope analysis. AB - AIM: To ascertain the role of Enterococcus faecalis in persistent infection and a possible method to prevent the penetration of E. faecalis into root cementum. METHODOLOGY: One hundred and twenty human single-rooted extracted teeth divided into five groups. Group I (control): intact teeth, Group II: no apical treatment done, Group III divided into two subgroups. In Groups IIIa and IIIb, root apex treated with lactic acid of acidic and neutral pH, respectively. Group IV: apical root cementum exposed to lactic acid and roughened to mimic the apical resorption. Group V: apical treatment done same as Group IV and root-end filling done using mineral trioxide aggregate (MTA). Apical one-third of all samples immersed in E. faecalis broth for 8 weeks followed by bone morphogenetic protein and obturation and again immersed into broth for 8 weeks. Teeth split into two halves and observed under confocal laser scanning microscope and scanning electron microscope, organism identified by culture and polymerase chain reaction techniques. RESULTS: Adhesion and penetration was observed in Group IIIa and Group IV. Only adhesion in Group II and IIIB and no adhesion and penetration in Group I and V. CONCLUSION: Adhesion and penetration of E. faecalis into root cementum providing a long-term nidus for subsequent infection are the possible reason for persistent infection and root-end filling with MTA prevents the adhesion and penetration. PMID- 27994317 TI - Scanning electron microscopic evaluation of the influence of manual and mechanical glide path on the surface of nickel-titanium rotary instruments in moderately curved root canals: An in-vivo study. AB - AIM: The aim of this study was to evaluate the influence of manual versus mechanical glide path (GP) on the surface changes of two different nickel titanium rotary instruments used during root canal therapy in a moderately curved root canal. MATERIALS AND METHODS: Sixty systemically healthy controls were selected for the study. Controls were divided randomly into four groups: Group 1: Manual GP followed by RaCe rotary instruments, Group 2: Manual GP followed by HyFlex rotary instruments, Group 3: Mechanical GP followed by RaCe rotary instruments, Group 4: Mechanical GP followed by HyFlex rotary instruments. After access opening, GP was prepared and rotary instruments were used according to manufacturer's instructions. All instruments were evaluated for defects under standard error mean before their use and after a single use. The scorings for the files were given at apical and middle third. STATISTICAL ANALYSIS USED: Chi squared test was used. RESULTS: The results showed that there is no statistical difference between any of the groups. Irrespective of the GP and rotary files used, more defects were present in the apical third when compared to middle third of the rotary instrument. CONCLUSION: Within the limitations of this study, it can be concluded that there was no effect of manual or mechanical GP on surface defects of subsequent rotary file system used. PMID- 27994318 TI - Resin bond strength to water versus ethanol-saturated human dentin pretreated with three different cross-linking agents. AB - CONTEXT: Resin-dentin bonds are unstable owing to hydrolytic and enzymatic degradation. Several approaches such as collagen cross-linking and ethanol-wet bonding (EWB) have been developed to overcome this problem. Collagen cross linking improves the intrinsic properties of the collagen matrix. However, it leaves a water-rich collagen matrix with incomplete resin infiltration making it susceptible to fatigue degradation. Since EWB is expected to overcome the drawbacks of water-wet bonding (WWB), a combination of collagen cross-linking with EWB was tested. AIM: The aim of this study was to compare the effect of pretreatment with different cross-linking agents such as ultraviolet A (UVA) activated 0.1% riboflavin, 1 M carbodiimide, and 6.5 wt% proanthocyanidin on the immediate and long-term bond strengths of an etch and rinse adhesive system to water- versus ethanol-saturated dentin within clinically relevant application time periods. SETTINGS AND DESIGN: Long-term in vitro study evaluating the microtensile bond strength of adhesive-dentin interface after different surface pretreatments. SUBJECTS AND METHODS: Eighty freshly extracted human molars were prepared to expose dentin, etched with 37% phosphoric acid for 15 s rinsed, and grouped randomly. They were blot-dried and pretreated with different cross linkers: 0.1% riboflavin for 2 min followed by UVA activation for 2 min; 1 M carbodiimide for 2 min; 6.5 wt% proanthocyanidin for 2 min and rinsed. They were then bonded with Adper Single Bond Adhesive (3M ESPE), by either WWB or EWB, followed by resin composite build-ups (Filtek Z350, 3M ESPE). Bonded specimens in each group were then sectioned and divided into two halves. Microtensile bond strength was tested in one half after 24 h and the other after 6 months storage in artificial saliva. STATISTICAL ANALYSIS USED: Analysis was done using SPSS version 18 software (SPSS Inc., Chicago, IL, USA). Intergroup comparison of bond strength was done using ANOVA with post hoc Tukey's test, and intragroup comparison was done using paired t-test. RESULTS: The microtensile bond strength of cross-linked groups was higher compared to control group (P < 0.001). EWB showed much higher bond strength values on cross-linked dentin compared to noncross-linked dentin. UVA-activated riboflavin group exhibited highest bond strengths followed by carbodiimide and proanthocyanidin groups, respectively, on both water- as well as ethanol-saturated dentin. Even after 6 months storage, cross-linked groups showed significantly higher values compared to initial bond strength values of control group (P < 0.001). CONCLUSIONS: 0.1% riboflavin pretreatment of dentin followed by UVA activation for 2 min exhibited highest increase in bond strength values at 24 h and least reduction in bond strength values after 6 months storage compared to other groups. Biomodification of dentin using collagen cross-linking followed by EWB exhibited a synergistic effect in improving the resin-dentin bond durability. PMID- 27994319 TI - Comparative evaluation of microhardness of dentin treated with 4% titanium tetrafluoride and 1.23% acidic phosphate fluoride gel before and after exposure to acidic pH: An ex vivo study. AB - AIM: The aim of this study was to comparatively evaluate the effect of 4% titanium tetrafluoride (TiF4) and 1.23% acidic phosphate fluoride (APF) gel on the microhardness of human coronal dentin. MATERIALS AND METHODS: Thirty noncarious extracted premolars were collected and sectioned buccolingually with the help of diamond disk. Exposing the sectioned surface, teeth were embedded in self-cure acrylic. Exposed coronal dentin was polished with abrasive papers starting with 220-5000 grit. Microhardness was evaluated by Vickers microhardness evaluator, at four different stages as follows - stage 1: Baseline values, Stage 2: Exposure of specimens to acidic environment at a pH 1 for 5 min, Stage 3: Application of 1.23% APF gel and 4% TiF4 (after dividing the specimens into two groups, i.e., Group A and B, respectively), and Stage 4: Followed by exposure of fluoridated specimens to acidic protocol as mentioned above. RESULTS: Paired t test was used to compare the readings between Groups A and B. Group B has shown greater resistance to decrease in microhardness of coronal dentin (P < 0.05) on exposure to acidic protocol. CONCLUSION: Due to acidic pH (1.5) of 4% TiF4, amount of increase in microhardness of dentin is <1.23% APF gel. 4% TiF4 was more effective in resisting demineralization than 1.23% APF gel. PMID- 27994320 TI - Comparative assessment of efficacy of two different pretreatment single oral doses of betamethasone on inter-appointment and postoperative discomfort: An in vivo clinical evaluation. AB - AIM: Study aimed to evaluate the efficacy of two different pretreatment single oral doses of betamethasone on the incidence of inter-appointment flare up and postoperative discomfort. MATERIALS AND METHODS: Fifty-four patients aged 18-59 years requiring endodontic treatment were selected and randomly assigned to three groups; single pretreatment oral dose of placebo or betamethasone in two different oral doses of 0.5 mg and 1 mg, respectively. Endodontic therapy was completed in two visits using triple antibiotic paste as intracanal medicament. Patients were given a questionnaire to record their pain at 1, 2, 3, and 7 days after treatment. In the second visit, obturation was done, and the patients were again instructed to record their pain scores after treatment and discharged. The verbal rating scale was used for recording the pain scores. Statistical analysis was done using ANOVA and the Friedman test. RESULTS: 0.5 mg betamethasone group showed least mean pain scores among all experimental groups; however, there was no statistically significant difference between any of the groups (P > 0.05). CONCLUSION: Pretreatment single oral dose of betamethasone is an effective in managing endodontic flare-ups; however, the results were statistically insignificant. PMID- 27994321 TI - Comparison of the antimicrobial activity of direct pulp-capping materials: Mineral trioxide aggregate-Angelus and Biodentine. AB - PURPOSE: To compare the antimicrobial activity of the tricalcium silicate-based Biodentine (BD) and mineral trioxide aggregate (MTA)-Angelus cement with the aid of agar diffusion test. MATERIALS AND METHODS: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecium were inoculated in the Brucella liquid medium and were incubated at 37 degrees C for 24 h. Thereafter, 100 >MUl of the liquid culture of bacteria inoculated in the Mueller-Hinton agar with spread plate technique. Petri plates were dried in room temperature. For every microorganism, 3 petri plates were prepared (12 in total). In the medium, in every petri plate, 2 holes with 5 mm diameter and 2 mm depth were made. Afterward, BD and MTA-Angelus were filled into these holes under aseptic conditions according to the instructions of the manufacturing company. Then, the plates were kept in the incubator at 37 degrees C for 24 h, and the diameters of the inhibition zones were measured with a digital caliper. RESULTS: Inhibition zones formed by BD against E. coli and S. aureus were significantly larger than the zones formed by MTA-Angelus (P < 0.05). However, the inhibition zones formed by MTA-Angelus against P. aureus and E. faecium were larger than the zones formed by BD (P < 0.05). CONCLUSION: Within the limits of the present study, tricalcium silicate-based MTA-Angelus and BD have antimicrobial activity against E. coli, S. aureus, P. aureus, and E. faecium. PMID- 27994322 TI - Accuracy in the diagnosis of vertical root fractures, external root resorptions, and root perforations using cone-beam computed tomography with different voxel sizes of acquisition. AB - AIM: The aim of this study is to assess the accuracy of images acquired with cone beam computed tomography (CBCT) in the identification of three different root alterations. MATERIALS AND METHODS: Forty human premolars were allocated to four experimental groups (n = 10): sound teeth (control), vertical root fracture (VRF), external root resorption (ERR), and root perforation (RP). After the root alterations had been produced, four teeth were randomly assembled into 10 macerated mandibles and submitted to CBCT. Images were acquired with five voxel sizes (0.125, 0.200, 0.250, 0.300, and 0.400 mm) and assessed by three experienced dental radiologists. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver operating characteristic curve (accuracy) were calculated. The accuracy of imaging in different voxel sizes was compared with Tukey exact binomial test (alpha=5%). RESULTS: Accuracy with voxel sizes 0.125, 0.200, and 0.250 mm was significantly higher in the detection of ERRs and VRFs than voxel sizes 0.300 and 0.400 mm. No statistical difference was found in terms of accuracy among any of the studied voxel sizes in the identification of RPs. CONCLUSIONS: Voxel size 0.125 mm produced images with the best resolution without increasing radiation levels to the patient when compared to voxel sizes 0.200 and 0.250 mm. Voxel sizes 0.300 and 0.400 mm should be avoided in the identification of root alterations. PMID- 27994323 TI - Shaping ability of reciprocating motion of WaveOne and HyFlex in moderate to severe curved canals: A comparative study with cone beam computed tomography. AB - INTRODUCTION: M-Wire and reciprocating motion of WaveOne and controlled memory (CM) wire) of HyFlex were the recent innovations using thermal treatment. Therefore, a study was planned to evaluate the shaping ability of reciprocating motion of WaveOne and HyFlex using cone beam computed tomography (CBCT). METHODOLOGY: Forty-five freshly extracted mandibular teeth were selected and stored in saline until use. All teeth were scanned pre- and post-operatively using CBCT (Kodak 9000). All teeth were accessed and divided into three groups. (1) Group 1 (control n = 15): Instrumented with ProTaper. (2) Group 2 (n = 15): Instrumented with primary file (8%/25) WaveOne. (3) Group 3 (n = 15): Instrumented with (4%/25) HyFlex CM. Sections at 1, 3, and 5 mm were obtained from the pre- and post-operative scans. Measurement was done using CS3D software and Adobe Photoshop software. Apical transportation and degree of straightening were measured and statistically analyzed. RESULTS: HyFlex showed lesser apical transportation when compared to other groups at 1 and 3 mm. WaveOne showed lesser degree of straightening when compared to other groups. CONCLUSION: This present study concluded that all systems could be employed in routine endodontics whereas HyFlex and WaveOne could be employed in severely curved canals. PMID- 27994324 TI - Push-out bond strength of different translucent fiber posts cemented with self adhesive resin cement. AB - PURPOSE: Evaluate the bond strength of different translucent fiber posts in the cervical, middle, and apical root thirds cemented with self-adhesive resin cement. MATERIALS AND METHODS: Sixty single-rooted teeth were randomly divided into five groups according to the fiber post used: Reforpost (opaque [control]), exacto, white post, radix, and Macro-Lock Illusion X-RO. The roots were subjected to chemomechanical preparation and cemented with self-adhesive resin cement. The teeth were sectioned into slices of the different root thirds and tested for bond strength (push-out). Two-way analysis of variance and Bonferroni test were used to verify statistical differences between groups (P < 0.05). RESULTS: No significant difference between the root thirds was detected (P > 0.05). However, the performance of the posts demonstrated a significant difference (P < 0.05). RDX had a lower performance in the apical third (P < 0.05). The other fiber posts had the same performance irrespective of the root third evaluated. The predominant failure pattern was adhesive between resin cement and root dentin. CONCLUSION: In general, the different translucent fiber posts showed the same performance. Yet, translucent fiber posts did not show superior bond strength compared with the opaque fiber post in any of the root thirds evaluated. PMID- 27994325 TI - Successful orthograde treatment of dens invaginatus Type 3 with a main C-shaped canal based on cone-beam computed tomography evaluation. AB - Dens invaginatus is a rare anatomic variation that is found primarily in maxillary lateral incisors. The management of dens invaginatus is challenging for clinicians; diagnosing the type of malformation, choosing the most appropriate treatment, and carrying out treatment are complicated by the intricate root system of these teeth. The following case report describes the diagnosis and treatment planning of dens invaginatus Type 3 after cone-beam computed tomography evaluation. PMID- 27994327 TI - Revisiting Chemistry for Surgeons. PMID- 27994326 TI - 2nd International and 5th National Conference of Endodontics and Conservative Dentistry Clinical Research 2016: Report. PMID- 27994328 TI - Unexpected Benefit of the Positron Emission Tomography/Computed Tomography Using 18F-Fluorodeoxyglucose: Report of a Case. AB - The positron emission tomography/computed tomography (PET/CT) has been a new tool utilized in the diagnosis and staging of various cancers. However, common worldwide utilization of the PET/CT includes some economic, legal, and ethic controversies. Although PET/CT scanning can detect colorectal premalignant lesions in an early treatable stage, most governments' health care system does not pay for it as a screening test because of its economic burden. Thus, people are forced to make vital decisions about their health because of health policies of their governments. Here, we present an unusual case and discuss the utilization of PET/CT for detection of incidental neoplasms. PMID- 27994329 TI - Bypass Operation for Unresectable Esophageal Cancer: Postoperative Complications After Thoracotomy Versus No Thoracotomy. AB - Patients with unresectable esophageal cancer suffer from dysphagia, causing severe malnutrition and reduced quality of life (QOL). We elect to perform bypass because patients can have greater long-term survival with chemoradiation following this operation. We sought to compare complications in cases of bypass without thoracotomy versus those with thoracotomy. Thirty-four locally advanced esophageal cancer patients between 2007 and 2014 were studied. Eighteen patients underwent thoracotomy, and 16 patients did not have a thoracotomy. CT was obtained to check the anastomosis and the oral stump of the esophagus and to measure the diameter of the intrathoracic esophagus. In the thoracotomy group, the rate of postoperative pulmonary complications was high. On the other hand, in the non-thoracotomy group, the rates of anastomotic leak and recurrent nerve paralysis were high. The stump of the esophagus was 2 cm lower in the T group than in the nT group. As the esophagus shortens after division, the final difference in esophageal height between the groups was only around 1 cm. We concluded that a viable gastric tube with a good blood supply as well as a careful cervical operation are the most important aspects of the esophageal bypass operation. PMID- 27994330 TI - A Prospective Study in Comparison of Ambulatory Phlebectomy and Duplex Guided Foam Sclerotherapy in the Management of Varicosities with Isolated Perforator Incompetence. AB - Perforators are those which connect the superficial and deep venous system either directly to main veins or indirectly through the muscular and soleal venous plexus. The emergence of minimally invasive techniques like ambulatory phlebectomy (AP) and foam sclerotherapy (FS) has led to increasing interest about the appropriate therapy for the treatment of isolated perforator incompetence. There have been no studies which have compared the effectiveness of these in office procedures in isolated perforator incompetence due to the low prevalence of cases. The primary goal of this study is to compare the clinical parameters (return to normal activity, primary symptom relief), functional parameters (procedure time, change in disease severity, course of venous ulcer), and duplex parameters (recurrence in treated veins, complete occlusion of treated veins) in the management of leg varicosities having isolated primary perforator incompetence by ambulatory phlebectomy and duplex guided foam sclerotherapy. Though the procedure time was shorter with FS than AP, the other parameters of primary symptom relief such as change in disease severity, faster healing of venous ulcer, complete occlusion of treated veins in follow-up duplex examination, and lower recurrence of treated veins are better with AP than FS. In conclusion, the interruption of perforators is effective in decreasing the symptoms of chronic venous insufficiency and for the rapid healing of ulcers. The interruption of the incompetent perforating veins appears to be essential to decrease ambulatory venous hypertension. It is apparent from this study that ambulatory phlebectomy stands distinct with enormous benefits and serves as a superior alternative to foam sclerotherapy in treating patients with isolated perforator incompetence. PMID- 27994331 TI - Primary Closure Following Laparoscopic Common Bile Duct Reexploration for the Patients Who Underwent Prior Biliary Operation. AB - To assess feasibility of primary closure following laparoscopic common bile duct reexploration for the patients who underwent prior biliary operation, we retrospectively studied 50 patients with recurrent or residual common bile duct (CBD) stones who underwent laparoscopic biliary reoperation between June 2008 and June 2013. Endoscopic sphincterotomy (EST) was treated for all these patients and validated failed. They were divided into two groups. Primary closure following laparoscopic common bile duct exploration (LCBDE) was performed in 25 cases (group A); LCBDE plus T-tube drainage was performed in others (group B). The items of operation were compared. The duration of the operation in group A was shorter than that in group B (141 +/- 85 vs 158 +/- 71 min, p < 0.05), as was postoperative hospital stay (16 +/- 2.3 vs 23 +/- 2.3 h, p < 0.05) and the times of postoperative gastrointestinal function recovery (16 +/- 2.3 vs 23 +/- 2.3 h, p < 0.05). Just one duodenum was damaged in group B. Postoperative clinically significant bile leakage occurred in two patients in group A and one case in group B. The median follow-up was 18 months. No postoperative pancreatitis, postoperative bleeding, bile peritonitis after T-tube removal, stricture of bile duct, and death occurred in the two groups. Just two cases in group B were verified residual stones after 1 month. Primary closure following laparoscopic common bile duct reexploration for the patients who underwent prior biliary operation appears to be a minimally invasive, safe, feasible, and effective procedure when done by expert laparoscopic surgeons. PMID- 27994332 TI - Thoracotomy for Traumatic Diaphragmatic Hernia. AB - The aim of this retrospective study is to review our experience in the diagnosis and role of thoracotomy for traumatic diaphragmatic hernia (TDH). Between January 2008 and June 2014, 23 patients from Yangzhou Medical College (Yangzhou China) and Lishui Center Hospital (Lishui China), who underwent thoracotomy for TDH, were analyzed. The clinical features, imaging findings, operative findings, and outcome of treatment in these patients are presented. There were 23 patients (18 males and 5 females) who underwent surgical procedures due to TDH. The median age of the patients was 43.2 years (range, 15-68 years). The cause of rupture was penetrating trauma in 1 (4.3 %) patient and blunt trauma in 22 (95.7 %) patients. The TDH was left sided in 21 patients and right sided in two patients. The diagnosis was made by chest X-ray (n = 2) and chest or abdominal CT (n = 13) and at thoracotomy based on a high index of suspicion (n = 8). Associated injuries were seen in 21 patients (91.3 %). Twenty-two patients underwent thoracotomy, and one underwent thoracotomy with laparotomy. The mean operating time was 112 min (range, 60-185 min) and the mean blood loss was 116 mL (range, 20-400 mL). The most common herniated organs were the omentum (n = 15), stomach (n = 14), spleen (n = 11), colon (n = 10), small bowel (n = 2), and liver (n = 1). All diaphragmatic defects were repaired using interrupted prolene sutures. The overall mortality rate was 4.3 % (n = 1). The diagnosis of TDH is easily missed or delayed. Chest X-ray and computer tomography (CT), especially chest and abdominal CT, are useful in the diagnosis of diaphragmatic ruptures, and thoracotomy is an effective and successful treatment for TDH. PMID- 27994333 TI - Comparative Study of Outcome of Duplex Ultrasound-Guided, Catheter-Directed Foam Sclerotherapy and Radio-frequency Ablation in the Management of Great Saphenous Varicose Veins. AB - Chronic venous insufficiency of lower limbs is a common problem in adults. We compared the two modalities, namely duplex ultrasound-guided, catheter-directed foam sclerotherapy (UGFS) and radio-frequency ablation (RFA), in the management of great saphenous varicose veins using clinical assessment (Venous Clinical Severity Score, Venous Disability Score) and duplex imaging. Patients presenting with great saphenous vein (GSV) varicosity due to incompetent saphenofemoral junction (SFJ) were selected and randomly assigned in each arm, i.e., duplex UGFS group and RFA group. Patients were assessed on days 7, 30, and 90 both clinically and sonologically. Clinical assessment was based on the Venous Clinical Severity Score (VCSS) and Venous Disability Score (VDS). Obliteration of the treated GSV segment was noted in all the limbs of the RFA group (31/31) on duplex sonography on days 7, 30, and 90, while in the UGFS group, out of 30 limbs, obliteration was successful in 28 (28/30) and 2 had treatment failure. However, outcome of both the groups were statistically comparable (P value > 0.05). After the procedure, improvement in the VCSS was noted in both the study arms in every follow-up and both the modalities were found to be equally effective. Improvement in the Venous Disability Score was there on every follow-up, but maximum improvement was seen on the second visit, i.e., post-treatment day 30. Improvement was statistically significant and equal in both arms after the initial 1 week. Foam sclerotherapy, especially catheter-directed, is as effective as radio-frequency ablation in achieving anatomical obliteration and yielding relief in clinical signs and symptoms in patients with GSV varicosity with SFJ incompetence. PMID- 27994334 TI - Dual-Time 18F-FDG PET/CT Imaging in Initial Locoregional Staging of Breast Carcinoma: Comparison with Conventional Imaging and Pathological Prognostic Factors. AB - The aims of this retrospective study were to consider the diagnostic role of dual time 18F-fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET/CT) in detection of breast carcinoma and axillary lymph node (ALN) status and to evaluate the primary tumor 18F-FDG uptake pattern. Preoperative staging was performed by 18F-FDG PET/CT in 78 female patients with breast carcinoma. Conventional imaging results were evaluated by breast magnetic resonance imaging (MRI) of 79 lesions in 78 patients, bilateral mammography (MMG) of 40 lesions in 40 patients, and breast ultrasonography (USG) of 47 lesions in 46 patients. The primary tumor detection rate using 18F-FDG PET/CT was higher than those using MRI, USG, and MMG. The sensitivity and specificity of 18F-FDG PET/CT scans for detecting multifocality were higher than those of MRI. The specificity of ALN metastasis detection with MRI was higher than that with 18F FDG PET/CT, but 18F-FDG PET/CT had higher sensitivity. Higher 18F-FDG uptake levels were detected in patients with ALN metastasis, histologic grade 3, estrogen-progesterone-negative receptor status, lymphatic invasion, and moderate to poor prognostic groups. There was no statistical difference for the retention index in categorical pathological parameters except for progesterone-negative status. In conclusion, 18F-FDG PET/CT scans may be a valuable imaging technique for evaluating primary tumor and axillary status in staging breast carcinoma and 18F-FDG uptake may be a prognostic factor that indicates aggressive tumor biology and poor prognosis. Dual-time imaging in breast carcinoma staging may not be used for predicting pathological criteria and the aggressiveness of primary lesions. PMID- 27994335 TI - Perforated Gastrointestinal Stromal Tumor of the Meckel's Diverticulum: a Case Report and Review of Literature. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, they have a wide spectrum of clinical manifestations, and a small proportion of them present as an acute abdomen due to obstruction, perforation, or hemoperitoneum. We present a case of a perforated GIST of the Meckel's diverticulum and review the current literature on perforated GISTs. We ran a search on Pubmed and Google Scholar with the following terms "perforated GIST," "perforated Meckel's diverticulum," "GIST with peritonitis," and "GIST in Meckel's diverticulum." After selecting the relevant articles, we tabulated our results and analyzed the data. Out of the 45 cases, 32 (71.1 %) were male and 13 (28.8 %) were female. Out of the 45 reported cases, 41 (91.1 %) were from the small intestine, 2 (4.44 %) cases from the stomach, and 2 (4.44 %) from the small bowel. In 15 (33.33 %) cases, the site of perforation was the Meckel's diverticulum (MD). Forty-year-old male, presented with features of peritonitis localized to the right iliac fossa, was diagnosed as acute appendicitis and subjected to a diagnostic laparoscopy. Intraoperatively, a perforated Meckel's diverticulum was found, which on histopathological examination contained a low grade GIST. Our literature search revealed that in reported cases of perforated GISTs, there is a slight male preponderance. Small bowel appears to be the most common site for a perforated GIST, and a significant proportion (30.23 %) arise from the Meckel's diverticulum. And most importantly, the commonest tumor to cause perforation of a Meckel's diverticulum is a GIST. PMID- 27994336 TI - What Is a False Negative Sentinel Node Biopsy: Definition, Reasons and Ways to Minimize It? AB - Sentinel node biopsy helps in assessing the involvement of axillary lymph node without the morbidity of full axillary lymph node dissection, namely arm and shoulder pain, paraesthesia and lymphoedema. The various methods described in the literature identify the sentinel lymph nodes in approximately 96 % of cases and associated with a false negativity rate of 5 to 10 %. A false negative sentinel node is defined as the proportion of cases in whom sentinel node biopsy is reported as negative, but the rest of axillary lymph node(s) harbours cancer cells. The possible causes of a false negative sentinel lymph node may be because of blocked lymphatics either by cancer cells or following fibrosis of previous surgery/radiotherapy, and an alternative pathway opens draining the blue dye or isotope to another uninvolved node. The other reasons may be two lymphatic pathways for a tumour area, the one opening to a superficial node and the other in deep nodes. Sometimes, lymphatics do not relay into a node but traverse it going to a higher node. In some patients, the microscopic focus of metastasis inside a lymph node is so small-micrometastasis (i.e. between 0.2 and 2 mm) or isolated tumour cells (i.e. less than 0.2 mm) that is missed by the pathologist. The purpose of this review is to clear some fears lurking in the mind of most surgeons about the false negative sentinel lymph node (FNSLN). PMID- 27994337 TI - Management of Graft Duodenal Leak in Simultaneous Pancreas Kidney Transplant-a Case Report from India and Review of Literature. AB - Pancreatic transplantation is currently the only effective cure for Type 1 diabetes mellitus. It allows long-term glycemic control without exogenous insulin and amelioration of secondary diabetic complications. In India, pancreas transplant has not yet established with only a single successful transplant reported so far in the literature. We report a 24-year-old Type 1 diabetic patient with renal failure who underwent a simultaneous pancreas kidney transplant. On postoperative day 15, he had leak from the graft duodenal stump for which a tube duodenostomy and proximal diversion enterostomy was done. He had a high output pancreatic fistula following the procedure which was managed conservatively. The tube duodenostomy was removed at three and half months and enterostomy closure with restoration of bowel continuity was done at 6 months. After a follow up of 7 months, patient is doing well with a serum creatinine of 0.8 mg/dl and normal blood sugars, not requiring any exogenous insulin or oral hypoglycemic drugs. Managing patients with graft duodenal complications after pancreas transplant is challenging. Tube duodenostomy is a safe option in management of duodenal leak, although can lead to a persistent pancreatic fistula. A proximal diversion enterostomy allows early oral feeding and avoids the cost as well as the long term complications associated with parenteral nutrition. PMID- 27994338 TI - Chylous Ascites in Advanced Gallbladder Cancer. AB - Chylous ascites is a very rare occurrence in a patient with gallbladder cancer (GBC), and only six cases have been reported. We report here one such case in a 55-year-old lady who presented to us with upper abdominal pain for 6 months. A polypoidal gallbladder mass with minimal liver invasion but with multiple subcentimeter pericholedochal, common hepatic, mesenteric, and para-aortic lymph nodes was found on contrast-enhanced computed tomography scan. At laparotomy, the abdomen had milky fluid with engorged beaded lymphatics all over the small intestine. The abdomen was closed over a drain after a lymph node biopsy and collection of the ascetic fluid for analysis. Histopathology confirmed metastatic adenocarcinoma in the lymph node. The triglyceride levels in the ascetic fluid were elevated to 817.00 mg/dl. The patient was put on medium-chain triglyceride diet and a diuretic and recovered well. She was discharged when drain output was nil. Chylous ascites could be a result of abdominal malignancy, post surgery, cirrhosis, and disseminated infections like tuberculosis and filariasis. Treatment is primarily conservative and includes paracentesis/drainage of the peritoneal cavity supplemented by fasting, total parenteral nutrition, and/or diet modification with medium-chain triglyceride diet. PMID- 27994339 TI - Carcinoma of the Ampulla of Vater Associated with Annular Pancreas. AB - Carcinoma of the ampulla of Vater associated with annular pancreas is a rare entity. Only seven cases have been reported so far in the English literature. We herein report one such case in a 42-year-lady who presented with progressively increasing jaundice and pain in the upper abdomen for past 2 months. A magnetic resonance cholangiopancreaticography (MRCP) and MRI revealed an annular pancreas with an ampullary mass and a dilated CBD. An upper gastrointestinal endoscopic biopsy from the ampullary mass revealed a moderately differentiated adenocarcinoma. She was diagnosed as having annular pancreas with periampullary cancer that was subsequently confirmed at laparotomy. Histological examination confirmed a complete annular pancreas with a 2 cm * 2 cm moderately differentiated adenocarcinoma of the ampulla of Vater. The management, however, remains as in any case of periampullary malignancy. This highlights the importance that obstructive jaundice in an adult patient presenting with annular pancreas may be associated with a coexisting periampullary malignancy. PMID- 27994340 TI - Liposuction Technique Used as a Treatment Modality for Suicide Attempt by Injection of Mercury. AB - Elemental mercury poisoning commonly occurs through vapour inhalation as it is well absorbed through the lungs. Administering subcutaneous and intravenous elemental mercury is very uncommon with only a few isolated case reports in literature. We present a case of attempted suicide by subcutaneous injection of elemental mercury, an unusual substance used for suicide. As the attempt at self injury was not confessed by the patient, diagnosis was challenging. Patient was treated with an initial diagnosis of cellulitis, but with repeated and persistent questioning, a history of self-injection of mercury into the arm was revealed. On confirmation, mercury was aspirated from subcutaneous space similar to liposuction technique under X-ray guidance. Management of subcutaneous injection of elemental mercury with particular emphasis on the need for surgical removal of all available mercury is discussed. PMID- 27994341 TI - Anesthetic Management of Clinically Silent Familial Pheochromocytoma with MEN 2A: A Report of Four Cases. AB - Familial pheochromocytomas are commonly associated with multiple endocrine neoplasia type 2 (MEN 2) syndrome. Majority of the patients present with normal clinical and biochemical parameters in the preoperative period, the incidence of hypertension being only 50 %. Even though patients may be clinically asymptomatic, surveillance and proper preoperative evaluation is important, as surgery for associated tumors may precipitate a hypertensive crisis and result in severe complications. A family of 19 members, of which 12 were positive for MEN 2A syndrome, presented to our hospital. Seven of the 12 patients had pheochromocytoma and medullary thyroid carcinoma (MTC), while the other 5 had only raised plasma calcitonin levels. Two of the 7 patients presented with bilateral pheochromocytoma and underwent an open adrenalectomy. The other 5 patients had a left-sided adrenal tumor and underwent left laparoscopic adrenalectomy under combined general and epidural anesthesia. We present our experience with four of these five cases. We here state that how paucity of literature on perioperative preparation of clinically and biochemically silent pheochromocytomas led to serious intraoperative complications in one of four cases. PMID- 27994342 TI - A Rare Case of Unusually Large Lower Ureter Calculus. AB - We report an unusual large and "s" shaped left lower ureteric calculus which has been never reported in any manuscript to the best of our knowledge. Calculus in genitourinary happen to occur in various shapes and sizes; here we report unusual shaped calculi. PMID- 27994343 TI - Neonatal Intrathoracic Stomach without Gastric Volvulus. AB - Intrathoracic stomach is a rare and serious congenital abnormality. The anomaly may be complicated by gastric volvulus and can lead to ischemic gastric infarction in the neonate. If diagnosed antenatally, neonatal management can be planned in advance so as to reduce morbidity. This anomaly must be differentiated from the more common congenital diaphragmatic hernia, as associated pulmonary hypoplasia is common in the latter and rare with gastric herniation. We report a case of intrathoracic stomach in a neonate without volvulus, fortunately a rare entity which was managed operatively, and the child has been under regular follow up. PMID- 27994344 TI - Percutaneous Placement of Pancreatico-biliary Drainage Catheter for the Treatment of Complicated Pancreatic Anastomotic Leakage: an Alternative Treatment Option. AB - A 58-year-old female patient who had anastomotic leakage after a Whipple operation was treated with a percutaneously placed pancreatico-biliary drainage catheter. Complete secondary healing of the anastomotic defect and leakage was seen on control cholangiography examination on the 35th postoperative day, and the pancreatico-biliary drainage catheter was removed. She was discharged on the 39th postoperative day uneventfully. Percutaneous pancreatico-biliary drainage should be kept in mind as an alternative treatment option of complicated pancreatic anastomotic leakage after a Whipple operation. PMID- 27994345 TI - Reduced Port Laparoscopic Cholecystectomy: Single and a Half Incision Lap Chole. AB - : Laparoscopic cholecystectomy has almost replaced the age-old procedure of open cholecystectomy for gall stone disease. Further attempts are made to reduce the number of ports to give maximum benefits of minimally invasive surgery. The author has developed a technique where 10-mm port in supraumbilical area and 5-mm port in epigastric area are used and hence the nomenclature of single and a half incision laparoscopic cholecystectomy. It is different from two-port laparoscopic cholecystectomy where the second port is 10 mm. In total, 69 cases are performed without any complication. CONCLUSION: In our technique of single and a half incision laparoscopic cholecystectomy patients' safety is as much as in a conventional four-port surgery. Surgeon is comfortable to perform this operation. Cosmetically, it is better than four-port laparoscopic cholecystectomy without increase in cost. So, in our opinion, our technique should be acceptable to all surgeons and can give benefits of minimal access surgery to masses of people. PMID- 27994346 TI - Communications Through WhatsApp by Medical Professionals. PMID- 27994347 TI - Heterotopic Pancreas in the Gallbladder. PMID- 27994348 TI - A call for neurologists to take up stroke intervention. AB - Recent data have provided overwhelming evidence in favor of benefits of emergent endovascular intervention in large vessel acute ischemic stroke (AIS). India with its large population has a huge burden of AIS. Hence, neurologists need to gear up to the new challenge of providing interventional care to huge populations of AIS in the country. The best way to cover this unprecedented unmet need is to encourage neurologists to take up interventional subspecialty interests through new but sound training pathways. PMID- 27994349 TI - Approach to a tremor patient. AB - Tremors are commonly encountered in clinical practice and are the most common movement disorders seen. It is defined as a rhythmic, involuntary oscillatory movement of a body part around one or more joints. In the majority of the population, tremor tends to be mild. They have varying etiology; hence, classifying them appropriately helps in identifying the underlying cause. Clinically, tremor is classified as occurring at rest or action. They can also be classified based on their frequency, amplitude, and body part involved. Parkinsonian tremor is the most common cause of rest tremor. Essential tremor (ET) and enhanced physiological tremor are the most common causes of action tremor. Isolated head tremor is more likely to be dystonic rather than ET. Isolated voice tremor could be considered to be a spectrum of ET. Psychogenic tremor is not a diagnosis of exclusion; rather, demonstration of various clinical signs is needed to establish the diagnosis. Severity of tremor and response to treatment can be assessed using clinical rating scales as well as using electrophysiological measurements. The treatment of tremor is symptomatic. Medications are effective in half the cases of essential hand tremor and in refractory patients; deep brain stimulation is an alternative therapy. Midline tremors benefit from botulinum toxin injections. It is also the treatment of choice in dystonic tremor and primary writing tremor. PMID- 27994350 TI - An elderly male with tingly legs and a heavy heart: Persisting with the diagnosis! AB - Pursuing a diagnosis despite a negative nerve biopsy report requires a strong clinical conviction. Paying attention to clinical details and a diligent review of medical records is needed to solve cases in which the diagnosis is not obvious despite numerous tests. We present once such case of an elderly man with chronic diarrhea, weight loss, and peripheral neuropathy and elaborate on a step by step basis on how the clinical thought process evolved after sifting through the reports of scan and tests done during his work up. PMID- 27994351 TI - Godfrey Newbold Hounsfield (1919-2004): The man who revolutionized neuroimaging. AB - Godfrey Hounsfield, a biomedical engineer contributed enormously towards the diagnosis of neurological and other disorders by virtue of his invention of the computed axial tomography scan for which he was awarded the Nobel Prize in 1979. Working for the Electrical and Musical Industry (EMI) Limited and in collaboration with two radiologists, James Ambrose and Louis Kreel, he introduced the use of this machine in 1971 at the Atkinson Morley's Hospital in Wimbledon. He continued to improve the quality of the devise and the human head was scanned for the first time in 1972. He continued his work on imaging of the human body was later concentrated on the next step in diagnostic radiology namely, magnetic resonance imaging. PMID- 27994352 TI - Assessment of fatigue in Parkinson's disease: Indian perspective. AB - CONTEXT: Fatigue is one of the most frequent nonmotor manifestations in Parkinson's disease (PD), having a major effect on quality of life but is not reported in Indian patients. AIMS: To evaluate the frequency of fatigue in a cohort of PD population and its correlation with disease. SETTINGS AND DESIGN: Fatigue Severity Scale (FSS) was translated and validated in local vernacular language. All patients of PD visiting neurology outpatient department of a tertiary care hospital. SUBJECTS AND METHODS: A total of 150 patients were screened, and 104 were included in this study. They were divided into - Group I with fatigue (score of >4 in each item) and Group II without fatigue. STATISTICAL ANALYSIS: Data were analyzed by SPSS software version 20.0. Spearman correlation was used to evaluate the convergent validity of the FSS-Ind score with PD-related variables. The principal components analysis was applied to detect the domain structure of the FSS. RESULTS: Of the total 104 patients, 68 (65.3%) patients experienced fatigue. The duration of disease was significantly more (P = 0.021) in Group I (4.39 +/- 3.8 years) than in the Group II (3.13 +/- 1.6 years). The severity of disease also showed a positive correlation with fatigue with 50.9% patients in H and Y stage >3 experiencing fatigue. 69.1% patients of tremor phenotype experienced fatigue as compared to 32.3% of rigid phenotype. There was no relation of fatigue with age, gender, H and Y stage, levodopa equivalent dose and mean Unified PD Rating Scale motor III score. CONCLUSIONS: Translated version of the FSS, FSS-Ind has high internal consistency and validity which supports its application as an effective tool in detecting fatigue in patients with PD. Fatigue in PD was related to duration and phenotype of the disease. PMID- 27994353 TI - Diagnosis and management of narcolepsy in the Indian scenario. AB - INTRODUCTION: The diagnosis and management of narcolepsy in the Indian context needs to be revisited especially in the wake of concerns raised by sleep medicine experts that the entity could be formidably underdiagnosed, as well as undertreated in our setting. MATERIALS AND METHODS: The history, clinical records, polysomnographic/multiple sleep latency test data, and treatment records of five hundred consecutive patients attending a dedicated sleep clinic between the years 2013 and 2016 were retrospectively analyzed. The response to treatment measures and improvement in daytime functioning were periodically assessed by personal/telephonic interview and E-mail communication. RESULTS: Thirteen patients were diagnosed with narcolepsy based on the standard criteria of which three had cataplexy. The mean age of presentation was 23.23 years and the male:female ratio was 2.25:1. The mean duration from the onset of symptoms to diagnosis was 4.2 years. Two patients responded to nonpharmacological interventions alone, and six to modafinil, while two patients remained symptomatic and required treatment with methylphenidate. One patient was lost to follow-up, while two others are due for their first follow-up. CONCLUSION: A refurbished outlook of the diagnostic methodology and treatment paths tailored to our clinical scenario can potentially impact the future of narcolepsy management and research in our country. PMID- 27994354 TI - Role of brain natriuretic peptide as a novel prognostic biomarker in acute ischemic stroke. AB - AIM: We investigated to study the prognostic importance of brain natriuretic peptide (BNP) in ischemic stroke. MATERIALS AND METHODS: We prospectively enrolled 100 patients with acute ischemic stroke and measured plasma BNP levels and compared with age- and sex-matched healthy controls. Risk factors, biochemical parameters, lipid profile, carotid and vertebral Doppler, imaging, and cardiac evaluation were done. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) score on admission and functional disability by Barthel Index (BI) at 3 months. Ischemic stroke subtype was classified according to the Oxfordshire Community Stroke Project (OCSP). Data were entered in MS Excel, and appropriate statistical analysis was done using the SPSS software version 21.0. A P = 0.05 was considered as significant. RESULTS: Mean age of patients was 55.17 +/- 11.37 years with a male:female ratio 3:1. OCSP showed total anterior circulation infarct (TACI) 35, partial anterior circulation infarct 9, lacunar infarct 12, and posterior circulation infarct 44. NIHSS on admission was average 10 +/- 7 and BI was 57 +/- 30. BNP in patients (435 ng/ml) was very high as compared to controls (<60 ng/ml) (P < 0.001). There was a positive correlation between age and BNP (R2 = 0.34; P < 0.00); NIHSS and BNP (R2 = 0.255; P < 0.01), negative correlation between BI and BNP (R2 = -0.064; P < 0.01). Mean BNP levels across the OCSP showed higher values in TACI (F = 4.609 P = 0.005). Regression analysis showed that BNP can predict BI which was statistically significant. CONCLUSION: Plasma BNP levels was significantly elevated in patients with ischemic stroke. Our study concludes that high BNP levels are seen in large anterior circulation stroke and is a predictor for the poor functional outcome at 3 months. Determination of BNP levels as a biomarker could be helpful in predicting the outcome in stroke patients. PMID- 27994355 TI - Interaction of incidental microbleeds and prior use of antithrombotics with early hemorrhagic transformation: Causative or protective? AB - BACKGROUND: Gradient echo (GRE) sequence of magnetic resonance imaging (MRI) is a sensitive tool to detect hemorrhagic transformation (HT) and old cerebral microbleeds (CMBs). Presence of CMBs and prior use of antithrombotics pose a risk of HT in ischemic stroke. We evaluated the association of CMBs and antithrombotic use with resultant HT in acute ischemic stroke (AIS). METHODS: This retrospective study included AIS patients admitted to our center between January 2009 and August 2010 who underwent GRE-weighted MRI within 48 h of admission. Demographic and clinical data including diabetes mellitus, hypertension, hyperlipidemia, prior intake of antiplatelets/anticoagulants/statins, and presence of CMBs at admission were collected and compared between patients who developed HT and those who did not. We did a multivariate analysis using logistic regression to assess the effect of CMBs and prior use of antithrombotic agents on the risk of development for early HT in ischemic stroke. RESULTS: Of 529 AIS patients, 81 (15%) were found to have HT during the initial hospital course. CMBs were found in only 9 of 81 patients (11%) with HT and in 40 out of remaining 448 patients (9%) who did not develop HT. The presence of CMBs was not associated with increased risk of HT (P = 0.53). However, prior use of antiplatelets (33% vs. 47% in the patients without HT, P = 0.02) was associated with decreased risk of HT in ischemic stroke. CONCLUSION: Presence of incidental CMBs was not associated with increased risk for early HT of an ischemic stroke. Interestingly, the prior intake of antiplatelets was found to be protective against HT of ischemic stroke. PMID- 27994356 TI - A double-blind, randomized, controlled trial to compare the efficacy and tolerability of fixed doses of ropinirole, bupropion, and iron in treatment of restless legs syndrome (Willis-Ekbom disease). AB - BACKGROUND: We aimed to compare the efficacy of fixed doses of bupropion and ropinirole and iron alone for the treatment of restless legs syndrome (RLS) and to look for the tolerability of these medications. MATERIALS AND METHODS: Patients diagnosed with RLS were randomly divided into three groups with thirty patients in each group (Group A: Bupropion [300 mg/day], Group B: Ropinirole [0.25-0.5 mg/day], and Group C: Oral iron [150 mg elemental iron] along with folic acid [500 MUg]). Each participant was then assessed for severity of RLS, as well as RLS-related quality at the baseline, and thereafter, every 14th day till 6 weeks based on the International Restless Legs Scale (IRLS) severity rating scale and Restless Legs Syndrome Quality of Life (RLSQoL) Questionnaire, respectively. RESULTS: IRLS scores differed significantly from baseline visit to last (F = 4.85; P = 0.01). The interaction between the time x treatment group was significant (F = 10.37; P < 0.001) showing an improvement with the therapy in all the groups. Pair-wise comparison depicted that ropinirole group differed from other two groups in IRLS score (F = 7.06; P = 0.001), which were comparable to each other. Regarding quality of life of these cases, within each group scores differed among all the four visits (F = 5.12; P = 0.002). Unlike IRLS, there was no significant difference among the RLSQOL scores between groups at any point of time (F = 1.2; P = 0.28). CONCLUSION: RLS severity decreased across time in all three groups; however, the ropinirole treatment was better than the bupropion and iron-folate therapy. Moreover, RLS-related quality of life although improved among all groups, it was comparable among three groups. PMID- 27994357 TI - Clinical correlates of leukoaraiosis: A study of 175 patients. AB - BACKGROUND: In India, the correlates of leukoaraiosis (LA) have not been widely reported. This study was designed to investigate the factors which correlate with LA. MATERIALS AND METHODS: We included patients with LA who consented for the study and graded their severity on the basis of Fazekas scale. We excluded patients with LA who did not consent/cooperate for the study as also patients with other white matter changes which mimic LA. RESULTS: LA is a common and under rated cause of disability. Presentations include cognitive decline, gait disturbance, dysarthria, bladder/bowel sphincter disturbances, and increased risk of stroke. The comorbidities include hyperhomocysteinemia, hypertension, dyslipidemia, tobacco use, ischemic heart disease, previous stroke, atrial fibrillation, chronic renal failure, and bariatric surgery. PMID- 27994358 TI - Retrospective analysis of multiplex polymerase chain reaction-based molecular diagnostics (SES) in 70 patients with suspected central nervous system infections: A single-center study. AB - BACKGROUND: Central nervous system (CNS) infections present a grave health care challenge due to high morbidity and mortality. Clinical findings and conventional laboratory assessments are not sufficiently distinct for specific etiologic diagnosis. Identification of pathogens is a key to appropriate therapy. AIM: In this retrospective observational study, we evaluated the efficacy and clinical utility of syndrome evaluation system (SES) for diagnosing clinically suspected CNS infections. MATERIALS AND METHODS: This retrospective analysis included inpatients in our tertiary level neurointensive care unit (NICU) and ward from February 2010 to December 2013. Cerebrospinal fluid (CSF) samples of 70 patients, clinically suspected of having CNS infections, were subjected to routine laboratory tests, culture, imaging, and SES. We analyzed the efficacy of SES in the diagnosis of CNS infections and its utility in therapeutic decision-making. RESULTS: SES had a clinical sensitivity of 57.4% and clinical specificity of 95.6%. Streptococcus pneumoniae and Pseudomonas aeruginosa were the top two bacterial pathogens, whereas Herpes simplex virus (HSV) was the most common viral pathogen. Polymicrobial infections were detected in 32.14% of SES-positive cases. SES elicited a change in the management in 30% of the patients from initial empiric therapy. At discharge, 51 patients recovered fully while 11 patients had partial recovery. Three-month follow-up showed only six patients to have neurological deficits. CONCLUSION: In a tertiary care center, etiological microbial diagnosis is central to appropriate therapy and outcomes. Sensitive and accurate multiplex molecular diagnostics play a critical role in not only identifying the causative pathogen but also in helping clinicians to institute appropriate therapy, reduce overuse of antimicrobials, and ensure superior clinical outcomes. PMID- 27994359 TI - CD6 gene polymorphism rs17824933 is associated with multiple sclerosis in Indian population. AB - BACKGROUND: Multiple sclerosis (MS) prevalence has increased worldwide. The known genetic association for MS in the west has not been studied in detail in nonwhite populations and particularly Indians. OBJECTIVE: The objective of this study was to evaluate some known genetic variations outside the major histocompatibility complex (MHC) region associated with MS in patients of Indian origin. MATERIALS AND METHODS: We investigated 10 gene-associated single nucleotide polymorphisms (SNP's) outside the MHC region in 300 patients and 720 unrelated controls. Genotyping was performed on an ABI7500 real-time polymerase chain reaction genotyping platform using predesigned TaqMan SNP genotyping assays. RESULTS: CD6 gene associated SNP (rs17824933) showed significant association with MS (P = 4.2 * 10-5, odds ratio [OR] = 2.24, confidence interval (CI) = 1.51-3.33). A modest association was also noted for TMEM39A rs1132200 (P = 0.023, OR = 1.41, CI = 1.05 1.91) and IL2RA rs2104286 (P = 0.04, OR = 1.3, CI = 1.006-1.67). In the remaining SNPs, the allele frequencies were overexpressed in patients when compared to healthy controls. CONCLUSION: Our data illustrate the similarity in risk association between Indian and European populations for MS. PMID- 27994360 TI - The clinical significance of brain microbleeds in patients with Alzheimer's disease: Preliminary study. AB - BACKGROUND: Microbleeds (MBs) are observed frequently in Alzheimer's disease (AD) and suggested to play a crucial role in the pathophysiology, but their clinical significance remains unclear. MATERIALS AND METHODS: The study recruited 100 patients with AD who were diagnosed at the memory clinic in Seoul Medical Center in 2014. For each patient, baseline characteristics, neuropsychological tests, cerebrovascular risk factors, medial temporal lobe atrophy (MTLA), and severity of small vessel disease (SVD) according to the existence of MBs were evaluated. RESULTS: The prevalence of MBs in patients with AD was 33%. The percentage of male gender, the severity of SVD and MTLA were significantly increased in MB(+) group. The MB(+) group showed more severe MTLA and SVD than MB(-) group. CONCLUSIONS: These results suggested that MBs might reflect the burden of amyloid and ischemic vascular pathology. PMID- 27994361 TI - Validation of a modified Hindi version of the Epworth Sleepiness Scale among a North Indian population. AB - BACKGROUND: Since a majority of population in India does not drive automobiles, one item on the Epworth Sleepiness Scale (ESS) requires modification and validation. In addition, data collected by us indicated that a majority of rural and urban Indians regularly spend time in prayer/spiritual activity. The main purpose of this study was to develop a cross-cultural adaptation of the ESS for a North Indian population, in Hindi language (ESS-I). The study also provides evidence of reliability and validity of the modified version. METHODOLOGY: The subjects included were normal volunteers aged 18-75 years (Group 1) (n = 70), compared with patients with complaints of excessive daytime sleepiness, who had undergone polysomnography (Group 2) (n = 22) and patients who had undergone multiple sleep latency test (Group 3) (n = 10). The study was carried out in four phases: Translation and retranslation of the original scale with modification of item 8 (mainly addition of option of question on "while offering prayers or in spiritual activity"); reliability (test-retest) (n = 30); internal consistency (using Cronbach's alpha index) (n = 102); and sensitivity to change (n = 8). RESULTS: Group 1 showed spiritual activity as a significantly more commonly practiced activity than driving. The Cronbach's alpha for the modified version was 0.892 (excellent), and this was not improved by removing the modified item. The alpha value for Group 1 versus Groups 2 and 3 was 0.667 and 0.892, respectively. The scale was reliable over time (test-retest), and it was sensitive to sleepiness change in patients with obstructive sleep apnea during treatment. CONCLUSION: The ESS-I, is comparable to the original scale. It is reliable, valid, and change-sensitive. It is proposed that the modified version can be very useful for detecting sleepiness among Indian population, especially those who do not drive their own vehicles. PMID- 27994362 TI - Serological markers associated with neuromyelitis optica spectrum disorders in South India. AB - BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSDs) represent 20% of all demyelinating disorders in South India. No studies have determined the seroprevalence to both antibodies against aquaporin-4* and antimyelin oligodendrocyte glycoprotein antibody (anti-MOG+) in this population. OBJECTIVE: To identify and characterize seropositive patients for anti-aquaporin-4 antibody (anti-AQP4+) and anti-MOG+ in South India. MATERIALS AND METHODS: We included 125 consecutive patients (15 children) who were serologically characterized using live transfected cells to human M23-AQP4 or full-length MOG. RESULTS: Among a total of 125 patients, 30.4% of patients were anti-AQP4+, 20% were anti-MOG+, and 49.6% were seronegative. No patient was positive for both. Anti-MOG+ patients represented 28.7% (25/87) of seronegative NMOSD. In comparison to anti-AQP4+ patients, anti-MOG+ patients were commonly male, had less frequent attacks and milder disability on expanded disability status score scale. Seronegative patients were also predominantly male, 36% (9/25) had monophasic longitudinally extensive transverse myelitis and disability was comparable with anti-AQP4+ patients. Lumbar cord involvement was common in anti-MOG+ and seronegatives, whereas anti-AQP4+ patients had more cervical lesions. CONCLUSION: Anti AQP4+/anti-MOG + patients accounted for nearly half of the patients suspected of having NMOSD in South India, indicating that antibody testing may be useful on the management of subgroups with different prognosis. PMID- 27994363 TI - Bilateral abducens and facial nerve palsies as a localizing sign due to reduction in intracranial pressure after fourth ventriculoperitoneal shunting. AB - A trapped fourth ventricle often requires fourth ventriculoperitoneal shunting (4VP). Complications of this procedure include shunt blockage, infection, shunt migration, and overdrainage. Cranial nerve palsies are very rare after 4VP shunting and have been described with over drainage and brainstem distortion. We present an unusual case of bilateral abducens and facial nerve palsies after 4VP shunting after normalization of 4th ventricular parameters. Measurement of various brainstem angles presented us with a plausible hypothesis to explain the cranial nerve dysfunction. PMID- 27994364 TI - Idiopathic intracranial hypertension with spontaneous cerebrospinal fluid leak into the orbit. PMID- 27994365 TI - Bilateral "Swirl Sign": A predictor of rebleed. PMID- 27994366 TI - The brightening splenium: An imaging hallmark of dengue encephalopathy? PMID- 27994367 TI - Brainstem dysfunction in patients with late-onset Lennox-Gastaut syndrome: Voxel based morphometry and tract-based spatial statistics study. AB - BACKGROUND: There have been a few reports of patients who developed Lennox Gastaut syndrome (LGS) in the second decades of their life. OBJECTIVES: The aim of this study was to investigate electroclinical presentation in patients with late-onset LGS. In addition, we evaluated structural abnormalities of the brain, which may give some clue about the common pathogenic pathway in LGS. MATERIALS AND METHODS: We enrolled the patients with late-onset LGS. We collected electroclinical characteristics of the patients and evaluated structural abnormalities using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analysis. RESULTS: The three subjects were diagnosed with late onset LGS. The patients have no mental retardation and normal background activities on electroencephalography (EEG), and they had generalized paroxysmal fast activities on EEG, especially during sleep. The TBSS analysis revealed that fractional anisotropy values in the patients were significantly reduced in the white matter of brainstem compared with normal controls. However, VBM analysis did not show any significant difference between the patients and normal controls. CONCLUSIONS: Patients with late-onset LGS have different clinical and EEG characteristics from those with early-onset LGS. In addition, we demonstrated that brainstem dysfunction might contribute to the pathogenesis of late-onset LGS. PMID- 27994369 TI - Vitamin D deficiency in antiphospholipid syndrome. PMID- 27994368 TI - Efficacy and tolerability of the modified Atkins diet in young children with refractory epilepsy: Indian experience. AB - BACKGROUND: The modified Atkins diet (MAD) has been used predominantly in older children, adolescents, and adults. There is a paucity of data on the use of the MAD in refractory epilepsy in young children. OBJECTIVES: This study was planned to evaluate the efficacy and tolerability of the MAD in refractory epilepsy in young children. METHODS: This study recruited children aged 9 months to 3 years with refractory seizures. Children received MAD for 6-month with the on-going anticonvulsant medications being continued unchanged. Reduction in seizure frequency was the primary outcome measure. Adverse effects were also studied. RESULTS: Thirty-one children with daily seizures were studied with a median age of 18-month (range 9-30 months). West syndrome was the most common epilepsy syndrome (26, 86.6%). Twenty-one children remained on diet at 3 months and 13 at 6 months. The children who achieved >50% seizure reduction were 17 (54.8%) at 3 months and 9 (29%) at 6 months. Refusal to eat was a significant problem seen in eight children. Three children discontinued the diet due to adverse effects. CONCLUSION: The MAD was found to be feasible, effective, and well-tolerated. PMID- 27994370 TI - Acute encephalopathy: A novel presentation of mineralizing microangiopathy of childhood. PMID- 27994372 TI - Another gap in epilepsy care. PMID- 27994371 TI - Case series of organophosphorus-induced polyneuropathy. PMID- 27994373 TI - Cerebral venous thrombosis in refractory idiopathic thrombocytopenia treated with eltrombopag. PMID- 27994374 TI - A genetically proven case of Pelizaeus-Merzbacher disease: Clinicoradiological clues. PMID- 27994375 TI - A case of "main en succulente" in high cervical myelopathy. PMID- 27994376 TI - Erratum: Report: Stem cell applications in neurological practice, an expert group consensus appraisal. AB - [This corrects the article on p. 367 in vol. 19, PMID: 27570390.]. PMID- 27994377 TI - Risk factors for early invasive fungal disease in critically ill patients. AB - BACKGROUND: The incidence of invasive fungal disease (IFD) is increasing worldwide in the past two to three decades. Critically ill patients in Intensive Care Units are more vulnerable to fungal infection. Early detection and treatment are important to decrease morbidity and mortality in critically ill patients. OBJECTIVE: Our study aimed to assess factors associated with early IFD in critically ill patients. MATERIALS AND METHODS: This prospective cohort study was conducted in critically ill patients, from March to September 2015. Total number of patients (74) in this study was drawn based on one of the risk factors (human immunodeficiency virus). Specimens were collected on day 5-7 of hospitalization. Multivariate analysis with logistic regression was performed for factors, with P < 0.25 in bivariate analysis. RESULTS: Two hundred and six patients were enrolled in this study. Seventy-four patients were with IFD, majority were males (52.7%), mean age was 58 years (range 18-79), mean Leon's score was 3 (score range 2-5), majority group was nonsurgical/nontrauma (72.9%), and mean fungal isolation was positive on day 5. Candida sp. (92.2%) is the most frquently isolated fungal infection. Urine culture yielded the highest number of fungal isolates (70.1%). Mortality rate in this study was 50%. In multivariate analysis, diabetes mellitus (DM) (P = 0.018, odds ratio 2.078, 95% confidence interval 1.135-3.803) was found as an independent factor associated with early IFD critically ill patients. CONCLUSION: DM is a significant factor for the incidence of early IFD in critically ill patients. PMID- 27994378 TI - Pediatric trauma BIG score: Predicting mortality in polytraumatized pediatric patients. AB - BACKGROUND: Trauma is a worldwide health problem and the major cause of death and disability, particularly affecting the young population. It is important to remember that pediatric trauma care has made a significant improvement in the outcomes of these injured children. AIM OF THE WORK: This study aimed at evaluation of pediatric trauma BIG score in comparison with New Injury Severity Score (NISS) and Pediatric Trauma Score (PTS) in Tanta University Emergency Hospital. MATERIALS AND METHODS: The study was conducted in Tanta University Emergency Hospital to all multiple trauma pediatric patients attended to the Emergency Department for 1 year. Pediatric trauma BIG score, PTS, and NISS scores were calculated and results compared to each other and to observed mortality. RESULTS: BIG score >=12.7 has sensitivity 86.7% and specificity 71.4%, whereas PTS at value <=3.5 has sensitivity 63.3% and specificity 68.6% and NISS at value >=39.5 has sensitivity 53.3% and specificity 54.3%. There was a significant positive correlation between BIG score value and mortality rate. CONCLUSION: The pediatric BIG score is a reliable mortality-prediction score for children with traumatic injuries; it uses international normalization ratio (INR), Base Excess (BE), and Glasgow Coma Scale (GCS) values that can be measured within a few minutes of sampling, so it can be readily applied in the Pediatric Emergency Department, but it cannot be applied on patients with chronic diseases that affect INR, BE, or GCS. PMID- 27994379 TI - Preoperative red cell distribution width: Not a useful prognostic indicator for 30-day mortality in patients who undergo major- or ultra-major noncardiac surgery. AB - BACKGROUND: Red cell distribution width (RDW) has been shown to be associated with mortality in cardiac surgical patients. This study investigates the association of RDW with the 30-day mortality for those patients who undergo major or ultra-major noncardiac surgery. METHODS: Patients who received major- or ultra-major noncardiac surgery between July 2012 and May 2013 were included in the study and patients those with preoperative hemoglobin <10 g/day were excluded from the study. Patients were followed till day 30 from the date of surgery or death, whichever occurred earlier. RESULTS: The overall 30-day mortality for major- and ultra-major surgery was 11.4%. The mean RDW of the 30-day survivors was 13.6 +/- 1.6 and that of nonsurvivors was 14.2 +/- 2.1 (P < 0.001). Other factors that were significantly different (P < 0.05) between survivors and nonsurvivors included age, sex, preoperative pulse rate, current or ex-alcoholic, the American Society of Anesthesiologists score, diabetes mellitus, use of antihypertensives, sepsis with 48 h before surgery, preoperative hemoglobin, white cell count, sodium, urea, creatinine, albumin, international normalized ratio (INR), pH, base excess, estimated blood loss, and emergency surgery. Logistic regression revealed that preoperative RDW > 13.35% (P = 0.025, odds ratio [OR]: 1.52), INR (P = 0.008, OR: 4.49), albumin level (P < 0.001, OR: 1.10), use of antihypertensives (P = 0.001, OR: 1.82), and preoperative pulse rate (P = 0.006, OR: 1.02) independently predicted the 30-day mortality. However, the area under receiver operating characteristic curve for the prediction of 30 day mortality using RDW was only 0.614. CONCLUSIONS: Although preoperative RDW independently predicted 30-day mortality in patients who underwent major- or ultra-major noncardiac surgery, it may not serve as an influential prognostic indicator in view of its low sensitivity and specificity. PMID- 27994380 TI - Validity of bedside blood glucose measurement in critically ill patients with intensive insulin therapy. AB - BACKGROUND AND AIMS: There have been variable results on the practice of tight glycemic control, and studies have demonstrated that point-of-care (POC) glucometers have variable accuracy. Glucometers must be accurate, and many variables can affect blood glucose levels. The purpose of this study was to determine the difference between blood glucose concentrations obtained from POC glucometers and laboratory results in critically ill patients with intensive insulin therapy. MATERIALS AND METHODS: This was a descriptive study which enrolled 300 critically ill patients. Four samples of arterial blood were collected and analyzed at the bedside with the POC glucometer and also in the central laboratory to obtain the blood glucose level. To define the effect of various factors on this relation, we noted the levels of hemoglobin (Hb), PaO2, body temperature, bilirubin, history of drug usage, and sepsis. RESULTS: There were not any significant differences between blood sugar levels using laboratory and glucometer methods of measurements. There was a good and significant correlation between glucose levels between two methods (r = 0.81, P < 0.001). Among evaluated factors (body temperature, bilirubin level, blood pressure, Hb level, PaO2, sepsis, and drugs) which added one by one in model, just drugs decreased the correlation more than others (r = 0.78). CONCLUSIONS: The results of POC glucometer differ from laboratory glucose concentrations, especially in critically ill patients with unstable hemodynamic status while receiving several drugs. This may raise the concern about using POC devices for tight glycemic control in critically ill patients. These results should be interpreted with caution because of the large variation of accuracy among different glucometer devices. PMID- 27994381 TI - Using the first drop of blood for monitoring blood glucose values in critically ill patients: An observational study. AB - CONTEXT: Using the first drop or second drop of blood while measuring blood glucose (BG) values. OBJECTIVE: The study was planned to compare the BG values from the first and second drops of blood. RESEARCH SETTINGS: The study was conducted at the Main Intensive Care Unit, PGIMER, Chandigarh, India. RESEARCH DESIGN: This study was a comparative study. MATERIALS AND METHODS: Ninety patients aged 2-93 years were enrolled in this study. BG values from the first and second drops of blood were taken and compared. STATISTICAL ANALYSIS USED: Agreement between two drops was assessed using Bland-Altman analysis. A bias of <10 mg/dl was considered clinically acceptable. Linear regression of the mean difference (bias) with the BG readings was performed. RESULTS: One thousand four hundred and seven pairs of BG readings were taken from the enrolled patients. BG values had a bias of 3.9 +/- 14.9 mg/dl. Nearly 96.7% of BG readings were within the limits of agreement. The absolute difference between first and second drops of blood was calculated; nearly 75.4% of the readings had fallen between 0 and 10 mg/dl, i.e. clinically acceptable range. CONCLUSION: There is no compete concordance of values of blood glucose between the first and the second drops of blood; any of the drops can be used for measuring BG values as the difference is not statistically significant. However, if hands are visibly clean and to decrease the blood loss in the critically ill patients where the BG values are measured frequently, using the first drop of blood is advised. PMID- 27994383 TI - Acute carbolic acid poisoning: A report of four cases. AB - Phenol (carbolic acid) is one of the oldest antiseptic agents. Apart from being used in many commercially available products, in rural India, it is often used in the household to prevent snake infestation. We hereby present four cases of acute carbolic acid poisoning which we saw over the last monsoon. The cases highlight the multiple routes of absorption of carbolic acid as well as its multi-organ complications which often necessitate intensive care of local therapy decreases systemic phenol absorption from cutaneous exposure and may help in reducing severity. PMID- 27994382 TI - Nasal intubation: A comprehensive review. AB - Nasal intubation technique was first described in 1902 by Kuhn. The others pioneering the nasal intubation techniques were Macewen, Rosenberg, Meltzer and Auer, and Elsberg. It is the most common method used for giving anesthesia in oral surgeries as it provides a good field for surgeons to operate. The anatomy behind nasal intubation is necessary to know as it gives an idea about the pathway of the endotracheal tube and complications encountered during nasotracheal intubation. Various techniques can be used to intubate the patient by nasal route and all of them have their own associated complications which are discussed in this article. Various complications may arise while doing nasotracheal intubation but a thorough knowledge of the anatomy and physics behind the procedure can help reduce such complications and manage appropriately. It is important for an anesthesiologist to be well versed with the basics of nasotracheal intubation and advances in the techniques. A thorough knowledge of the anatomy and the advent of newer devices have abolished the negative effect of blindness of the procedure. PMID- 27994384 TI - Severe acute respiratory distress syndrome caused by unintentional sewing machine lubricant ingestion: A case report. AB - Sewing machine oil ingestion is rare but is possible due to its availability at home. Chemically, it belongs to hydrocarbon family which is toxic if aspirated, owing to their physical properties such as high volatility and low viscosity. On the contrary, sewing machine lubricant has high viscosity and low volatility which makes it aspiration less likely. The main danger of hydrocarbon ingestion is chemical pneumonitis which may be as severe as acute respiratory distress syndrome (ARDS). We report a case of a 5-year-old girl with accidental ingestion of sewing machine lubricant oil, who subsequently developed ARDS refractory to mechanical ventilation. There was much improvement with airway pressure release ventilation mode of ventilation, but the child succumbed to death due to pulmonary hemorrhage. PMID- 27994385 TI - Exchange transfusion for babesiosis when, how, and how long? AB - Babesiosis is a zoonotic disease transmitted by Ixodes ticks seen in the United States and parts of Europe. Because of the typically mild course of most infections, the disease is uncommonly seen in clinical practice. However, asplenic patients can develop a life-threatening infection. The first line of therapy for Babesia infections is antiparasitic medications; however, red blood cell (RBC) exchange transfusion has been described as an adjunct therapy. We describe a severe case of babesiosis in an asplenic patient and review the evidence, indications, and protocols for RBC exchange transfusion in this setting. PMID- 27994386 TI - Diagnosis of a missed central line guidewire using critical care ultrasound. AB - Central venous catheterization, though an imperative tool in the management of critically ill patient, is associated with a variety of complications and some of which can be life-threatening. Here, we report an index case in the field of critical care of detecting a missed guidewire primarily using a bedside critical care ultrasound. PMID- 27994387 TI - Refractory pediatric cardiogenic shock: A case for mechanical support. AB - Acute left ventricular dysfunction in children justifies aggressive treatment because of the high potential for complete recovery. The options for providing mechanical support to the failing heart in a child include extracorporeal membrane oxygenation, left ventricular assist devices, and the use of the intra aortic balloon pump (IABP). The IABP is a commonly used method of temporary circulatory support in adults. However, despite the availability of pediatric size balloons, the usage of IABP for temporary circulatory support in children has not been widespread. Current case report, first from India in pediatric age group, aims to aware the pediatric intensivist about the role of IABP in providing temporary mechanical cardiovascular support in managing patients with refractory low cardiac output state. PMID- 27994388 TI - Hypoglycemia - Old foe with a new face - Masquerading as an acute stroke. PMID- 27994389 TI - Characteristics of Keratoconic Patients Attending a Specialist Contact Lens Clinic in Kenya. AB - PURPOSE: To describe the characteristics of keratoconus (KC) patients seen in a contact lens clinic of a children's hospital in Kenya. RESULTS: A total of 254 patients' records were analyzed. Mean age at presentation to the clinic was 20.97 +/- 11.13 year (range, 6-84 years) with 75% between the ages of 6 and 25 years. There was a preponderance of males (59.8%). Most patients were referred by an ophthalmologist. All patients were Africans. The most common complaints were blurred vision (50%), poor visual acuity with spectacles (33.5%), contact lens intolerance (11.8%), and other (unspecified). Most cases were severe (71%) followed by moderate (22.9%) and mild (6.2%). Mean BCVA was 0.24 +/- 0.23 (6/11). An optical correction was provided in 98% of cases; 34.6% with spectacles, 31.1% with gas permeable lenses and the remaining with both. Referral for keratoplasty was warranted in 16.5%. CONCLUSION: This is the first study of KC conducted in Kenya. KC presented at a very early age and tended to be severe. Ophthalmologists were the main source of referral. The main presenting symptom was reduced vision. Optical correction was the most common management and the percentage of patients referred for surgery concurred with other studies. PMID- 27994390 TI - Comparison of Anterior Segment Measurements with Optical Low-coherence Reflectometry and Partial-coherence Interferometry Optical Biometers. AB - AIMS: To evaluate a new noncontact optical biometer using partial-coherence interferometry and to compare the clinical measurements with those obtained from the device using optical low-coherence reflectometry (OLCR). SETTING AND DESIGN: Ondokuz Mayis University, Samsun, Turkey. Nonrandomized, prospective clinical trial. SUBJECTS AND METHODS: The study was performed on the healthy phakic eyes of volunteers in the year 2014. Measurements of axial length (AL), anterior chamber depth (ACD), central corneal thickness (CCT), mean keratometry (K), and white-to-white (WTW) measurements obtained with the low-time coherence interferometry (LTCI) were compared with those obtained with the OLCR. STATISTICAL ANALYSIS USED: The results were evaluated using Bland-Altman analyses. The differences between both methods were assessed using the paired t test, and its correlation was evaluated by Pearson's coefficient. RESULTS: We examined seventy participants with a mean age of 33.06 (+/-9.7) (range: 19-53) years. AL measurements with LTCI and OLCR were 23.7 (+/-1.08) mm and 23.7 (+/ 1.1) mm, respectively. ACD was 3.6 (+/-0.4) mm and 3.5 (+/-0.4) mm for LTCI and OLCR, respectively. The mean CCT measurements for both devices were 533 (+/-28) mm and 522 (+/-28) mm, respectively. The mean K readings measurements for LTCI and OLCR were 43.3 (+/-1.5) D and 43.3 (+/-1.5) D, respectively. The mean WTW distance measurements for both devices were 12.0 (+/-0.5) mm and 12.1 (+/-0.5) mm, respectively. CONCLUSIONS: Measurements with LTCI correlated well with those with the OLCR. These two devices showed good agreement for the measurement of all parameters. PMID- 27994391 TI - Causes of Phakic Implantable Collamer Lens Explantation/Exchange at King Khaled Eye Specialist Hospital. AB - PURPOSE: The purpose of this study is to evaluate the causes of phakic implantable collamer lens (ICL) explantation/exchange at an eye hospital in Saudi Arabia. MATERIALS AND METHODS: A retrospective chart review was performed for patients who underwent ICL implantation from 2007 to March 2014 and data were collected on cases that underwent ICL explantation. RESULTS: Of the 787 ICL implants, 30 implants (3.8% [95% confidence interval 2.6%; 5.3%]) were explanted. The causes of explantation included incorrect lens size (22), cataract (4), high residual astigmatism (2), rhegmatogenous retinal detachment (1), and intolerable glare (1). Corrective measures mainly included an exchange with an appropriately sized lens (9), ICL explantation (11), with phacoemulsification and posterior chamber intraocular lens implantation (6), or replacement with an ICL of correct power (2). CONCLUSION: Incorrect ICL size was the most common cause of ICL explantation. More accurate sizing methods for ICL are required to reduce the explantation/exchange rate. PMID- 27994392 TI - Bottle Characteristics of Topical International Glaucoma Medications versus Local Brands in Saudi Arabia. AB - WHAT IS KNOWN AND OBJECTIVE: Physical bottle characteristics differ of brand name topical glaucoma medications and local generic equivalents. This study compares the bottle characteristics of international topical glaucoma brands versus local brands from the Kingdom of Saudi Arabia. METHODS: Data were collected on bottle drum volume, drop volume, bottle squeezability, bottle tip diameter, labels and instructions, cap color coding, and clarity of the drug label. Density-based calculations of drops in bottle volume were assessed using an analytic balance. Bottle tip diameter was measured using 0.05 mm Vernier calipers. A Likert scale based questionnaire was used to evaluate the subjective opinions of patients on bottle squeezability, clarity of usage and storage instructions, and the consistency of the cap color coding. RESULTS: The volumes of international brands were statistically significantly higher than the local brands (P < 0.001). A number of drops per bottle and tip diameter were comparable between the international local brands. Cap color coding was inconsistent for international and local brands. Patients were dissatisfied with the label font size. Patients reported that the international and local brands were similar in terms of the ease of opening the bottle, instilling a drop, and the clarity of the instructions; but the local brands were subjectively easier to squeeze than international brands. WHAT IS NEW AND CONCLUSIONS: This is the first study to compare bottle characteristics of local Saudi Arabia brands with international brands. The bottle characteristics and patient feedback were similar between the local and international topical glaucoma medications. However, there were differences between the local and international brands in drug volume, bottle squeezability. Hence, patient compliance and drop dosage may differ based on the origin of manufacture. PMID- 27994393 TI - The Evaluation of Reading Performance with Minnesota Low Vision Reading Charts in Patients with Age-related Macular Degeneration. AB - PURPOSE: To evaluate the reading performance using the Minnesota low vision reading (MNREAD) charts, of patients with age-related macular degeneration (AMD) who use low vision aid (LVA) devices. MATERIALS AND METHODS: This prospective study enrolled 27 patients with AMD. Distance visual acuity (VA) was evaluated with a distance chart designed for patients with low vision. Near vision and reading performance were evaluated with the Turkish version of the MNREAD charts. Unaided vision and vision with LVA devices and high spherical add near glasses was measured. P <0.05 was considered statistically significant. RESULTS: The mean unaided near VA was 1.05 +/- 0.27 log of the minimum angle of resolution (LogMAR). The mean VA with the LVA devices was 0.71 +/- 0.41 LogMAR. Reading acuity ranged between 1.15 and 0.21 LogMAR, critical print size was between - 1.2 and 0.2 LogMAR. Maximum reading speeds were between 0 and 103 words/min. The cases are divided into groups in terms of reading speed according to age, gender, diagnosis, and education. Reading speed was negatively correlated to increasing age. CONCLUSION: MNREAD reading charts can be used to evaluate reading performance in patients with AMD with low vision. The outcomes of the present study indicate that optical correction is adequate for near VA requirements in this patient population. However, optical correction was inadequate for improving reading performance. Appropriate rehabilitation programs can be used to increase reading speed. PMID- 27994394 TI - Comparison of Olive Tipped and Conventional Steven's Cannula for Sub-Tenon Ophthalmic Anesthesia. AB - PURPOSE: To compare the efficacy of the olive tipped (OT) cannula to the conventional Steven's cannula for sub-Tenon block (STB) before cataract surgery. METHODS: This prospective, randomized, double-masked compared STB delivered in cataract surgery patients with an OT cannula or a conventional Steven's cannula (ST). Outcome variables included the akinesia score and lid movement scores at 5 and 10 min. The patient perception of pain during delivery of the STB and surgery were also compared between groups. Surgeon satisfaction with anesthesia was compared between groups. P <0.05 was statistically significant. RESULTS: There were sixty patients in each group. The age between groups was not statistically different (P = 0.4). The body mass index was higher in the ST group compared to the OT group (P < 0.001). The akinesia score at 5 and 10 min did not differ between groups (P = 0.07 and P = 0.6, respectively). The patient perception of pain during STB and surgery were similar between groups (P = 0.1 and P = 0.06, respectively). There were six patients with mild chemosis and redness in the OT group and 15 patients in the ST group. CONCLUSION: An OT cannula is equally effective as the conventional Steven's cannula for delivering STB anesthesia before cataract surgery. PMID- 27994395 TI - Lower Eyelid Retraction Repair with Resorbable Polydioxanone Implants. AB - PURPOSE: To report a unique technique to repair lower eyelid retraction using resorbable polydioxanone implants. PATIENTS AND METHODS: This was a retrospective, consecutive, nonrandomized interventional case series. Patients with lower eyelid retraction after trauma repaired facial fracture, thyroid eye disease, lower eyelid blepharoplasty, and long-standing facial palsy were treated with middle lamellar spacer using absorbable polydioxanone implant. All patients were recruited from the King Abdulaziz University Hospital, Riyadh, Saudi Arabia. Only patients with minimum follow-up of 12 months were included in the study. RESULTS: Eight patients (4 males and 4 females) underwent lower eyelid retraction repair using absorbable polydioxanone implant. The mean age was 43 years (range, 23-63 years). All patients noted improved ocular surface symptoms. The improvement in eyelid retraction ranged from 1.5 to 4 mm with an average of 2.7 mm postoperatively. The implant was well tolerated with no major complications. CONCLUSIONS: Several options for spacer materials are available. Absorbable polydioxanone implants seem to be an effective middle lamellar spacer that is a good alternative for repairing middle lamella related lower eyelid retraction and lower eyelid support. PMID- 27994396 TI - Surgical Treatment of Corneal Ectasia with Motowa's Trephine and Selective Suturing Technique. AB - A 40-year-old male presented with bilateral ectasia, contact lens intolerance, and astigmatism >10 D in both eyes. The patient had end-stage pellucid marginal degeneration that warranted surgical treatment. We present a unique surgical technique to stabilize the cornea, minimize astigmatism, improve vision and corneal status, and avoid penetrating keratoplasty. PMID- 27994398 TI - Risk of Breaking Haptic of Trifocal IOL and Its Management. AB - Fracture of an intraocular lens (IOL) haptic is a rare complication of cataract surgery. A broken haptic can cause serious damage in the anterior and posterior segments. To the best of our knowledge, a broken haptic in a high-quality, commercially available trifocal IOL has not been documented in the literature. Prompt and proactive action at 1 day postoperatively aided in addressing the complication and restoring the vision. We suggest that the ophthalmologist performed a thorough evaluation on the 1st postoperative day and take immediate action after a discussion with the patient and relatives. PMID- 27994397 TI - Phacoantigenic Reaction Masquerading as Postoperative Endophthalmitis in a Silicone Oil-filled Eye. AB - A 72-year-old phakic male with immature cataract underwent vitrectomy with silicone oil injection in his left eye for rhegmatogenous retinal detachment. The surgery was uneventful except for lens touch during vitrectomy. Two weeks postoperatively, he presented with circumcorneal congestion, hypopyon, and absent fundal glow suggestive of postoperative endophthalmitis. The patient was managed conservatively as he refused further intervention. Five weeks later, ocular inflammation subsided following posterior dislocation of the cataractous lens, thus revealing the error in our initial diagnosis. Following surgical intervention, the inflammation gradually settled. However, the eye progressed to the prephthisical stage. Phacoantigenic reaction following lens touch during vitreoretinal surgery is very rare. Hence, surgeons should maintain a high index of suspicion in similar case, and prompt intervention is warranted to prevent further complications. PMID- 27994399 TI - Serous Retinal Detachment in Dome-shaped Macula with 7 Years Follow-up. AB - Dome-shaped macula (DSM) was first described by Gaucher et al. as a convex protrusion of macula within a staphyloma in highly myopic eyes that cause visual impairment associated with serous foveal detachment (SFD). We describe a patient with persistent SFD in DSM documented by serial spectral domain optical coherence tomography for 7 years with stable vision. PMID- 27994400 TI - In Vivo Confocal Microscopic Architecture of Corneal Nerves in a Case of Multiple Endocrine Neoplasia Type 2b. AB - A detailed ocular examination and in vivo confocal microscopy (IVCM) using the Heidelberg retinal tomograph 3 with Rostock cornea module were performed in a patient with multiple endocrine neoplasia (MEN) 2b syndrome. Ocular findings included ptosis secondary to thickening of the lid margins, subconjunctival and perilimbal neuromas, and prominent corneal nerves extending up to the pupillary area. IVCM demonstrated structural alterations of both the main nerve trunks and the smaller branches. The main nerve trunks were grossly thickened while the smaller fibers were present in an intertwining manner in the anterior stroma. Some fibers showed prominent looping and nodular dilatations at irregular intervals along the length of the nerves. These nodular dilatations were in all probability ganglioneuromas of corneal nerves demonstrated by histopathology in earlier reports of MEN 2b. IVCM may be potentially useful in detecting the nerve alterations in MEN 2b even before other ocular or systemic features become apparent clinically. PMID- 27994401 TI - Streptococcus agalactiae Endophthalmitis in Boston Keratoprosthesis in a Patient with Steven-Johnson Syndrome. AB - A 25-year-old Syrian male with a previous episode of Stevens-Johnson syndrome with bilateral corneal cicatrization previously underwent surgery for Type 1 Boston Keratoprosthesis (K-Pro). Sixteen months after the K-Pro surgery, the patient presented with decreased vision to hand motion and microbial keratitis of the graft around the K-Pro with purulent discharge. Corneal scrapings were nonrevealing. B-scan in 3 days showed increased debris in the vitreous cavity and thickened retinochoroidal layer. Intravitreal tap and injections of vancomycin and ceftazidime were performed. The vitreous culture revealed beta-hemolytic Streptococcus agalactiae; fungal cultures were negative. Repeat B-scan 3 days later demonstrated decreased vitreous opacity, and the patient felt more comfortable and was without pain. His visual acuity improved to 20/70, ocular findings have been stable for 9 months, and the patient continues to be monitored. PMID- 27994403 TI - Erratum: Cataract Surgery Audit at a Private Hospital in Saudi Arabia. AB - [This corrects the article on p. 502 in vol. 22, PMID: 26692725.]. PMID- 27994402 TI - Erratum: Oestrus ovis as a Cause of Red Eye in Aljabal Algharbi, Libya. AB - [This corrects the article on p. 305 in vol. 18, PMID: 22224020.]. PMID- 27994404 TI - Eco-friendly green dentistry: The future of dentistry? PMID- 27994405 TI - Learned helplessness. PMID- 27994406 TI - A retrospective study to compare improvement of implant maintenance by Medical Treatment Model. AB - BACKGROUND: Study comparing the improvement of implant maintenance is limited. Clinicians must be aware of implant maintenance to improve long-term success of implant. AIMS: The aim of this retrospective study was to evaluate whether the Medical Treatment Model (MTM), which is a comprehensive treatment, includes initial risk assessment, lifestyle instructions, such as diet and habits, and a customized maintenance program to improve implant prognosis. MATERIALS AND METHODS: Patients who were comprehensively treated were included and divided into two groups, test and control groups. The test group included patients who started treatment with MTM, whereas control group included patients who started treatment without MTM introduction. Moreover, subsequently, compliance with maintenance, occurrence of biological complications, and implant failure were evaluated. RESULTS: About 199 patients with 515 implants were analyzed in the control group and 38 patients with 59 implants in the test group. In the control and test groups, the percentages of patients in the four compliance categories were, respectively, 73.9% and 89.5% for excellent compliance, 7.0% and 7.9% for good compliance, 14.6% and 0% for fair compliance, and 4.5% and 2.6% for poor compliance. There was a statistically significant difference in the compliance with periodontal and implant maintenance between the test and control groups (P = 0.029). CONCLUSIONS: Within the limitation of this study, MTM significantly enhanced the compliance of patients treated with implants. PMID- 27994407 TI - Determination of sexual dimorphism in humans by measurements of mandible on digital panoramic radiograph. AB - BACKGROUND: Identification of sex is the first step in forensic science obtained from skeletal remains. Mandible, being a strong bone that is difficult to damage and disintegrate, is an important tool in sex determination. The present study is aimed to assess, compare, and evaluate the mandibular measurements as seen on digital panoramic radiographs to analyze their use in sexual dimorphism assessment. MATERIALS AND METHODS: This retrospective study was conducted using digital panoramic images of 100 each in both genders. Mandibular measurements were carried out utilizing RadiAnt DICOM Viewer 2.2.9 (32 bit) software (Medixant Company, Poland) and subjected to statistical analysis. RESULTS: Descriptive statistics for all the parameters on the right and left sides of mandible in both males and females were analyzed. Inferential statistics were performed using t test to compare males and females with different variables. A statistical significance of P < 0.001 has been demonstrated for all the variables (except linear measurement of mandibular foramen). All variables showed increased measurements in males than in females. The accuracy of sex determination in mandibular ramus measurements is 79.5% on right side and 77% on left side, where as, in linear mandibular measurements it is 76% on right side and 79.5% on left side. CONCLUSION: Mandibular measurements on digital radiograph are useful in sex determination, and this study can be compared with other similar studies. PMID- 27994408 TI - Comparative evaluation of efficacy of ethylenediaminetetraacetic acid, maleic acid, and dimercaptosuccinic acid against the combination of these with sodium hypochlorite for removal of smear layer: An in vitro scanning electron microscope study. AB - CONTEXT: The effect of dimercaptosuccinic acid (DMSA) and maleic acid (MA) when used alone on smear layer has been evaluated with mixed results, but their effect when combined with sodium hypochlorite (NaOCl) has not been studied. AIM: To compare the effectiveness of ethylenediaminetetraacetic acid, MA, and DMSA against the combination of these with NaOCl in the removal of smear layer. SETTINGS AND DESIGN: n = 4pq/L2 q = 1 - p p = Incident rate L = Allowable error. METHODS: One hundred and forty extracted, anterior teeth were radiovisiographically assessed. Access preparation was done; apical patency was established. Cleaning and shaping was accomplished using step-back technique. The specimens were randomly allocated as per the final irrigation protocol. After final irrigation, teeth were prepared for scanning electron microscope analysis, and the middle and apical thirds of radicular dentin were evaluated at *1000 for evaluation of severity of occlusion of dentinal tubules with smear layer. STATISTICAL ANALYSIS: The data were statistically analyzed using the Student's t test and kappa test. RESULTS: For combined irrigation, 10% DMSA + NaOCl was significantly better than all other groups both in the middle third and the apical third. It was more effective in the middle third than at apical third. CONCLUSION: Ten percent DMSA in combination with NaOCl removes the smear layer more effectively at both the middle and apical third. PMID- 27994409 TI - Impact of malocclusion on oral health-related quality of life in 10-14-year-old children of Mumbai, India. AB - AIMS AND OBJECTIVES: The aim and objective of this study was to establish the relationship of oral health-related quality of life (OHRQoL) as assessed by the Child Perception Questionnaire (CPQ 11-14) with the Index of Orthodontic Treatment Need (IOTN) and the child's apprehension with his/her dental appearance and how upset the child would feel if he/she is unable to obtain orthodontic treatment. MATERIALS AND METHODS: An observational cross-sectional study was conducted among 604 children between the age group of 10-14 years to analyze the effect of malocclusion on the quality of life of children on the basis of impact on oral symptoms, functional limitation, emotional well-being, and social well being. Malocclusion was evaluated using the IOTN, and the CPQ 11-14 was used to study the OHRQoL in children. The collected data were then subjected to statistical analysis. STATISTICAL ANALYSIS: Spearman's correlation coefficient was used to analyze the data statistically. RESULTS: Out of the 604 children examined, boys showed effect on emotional well-being, whereas girls showed a significant correlation on both emotional and social well-being. There was a statistically significant correlation between IOTN and all the four domains of CPQ scores with respect to the two questions that were added to the CPQ questionnaire. CONCLUSION: A questionnaire when developed specifically for determining the effect of malocclusion on OHRQoL focusing more on emotional and psychological impact and less on oral symptoms and functional limitation will provide advantages of having limited questions, being less time-consuming, and providing better understanding of the patients' concern. PMID- 27994410 TI - Estimation of salivary sialic acid in oral premalignancy and oral squamous cell carcinoma. AB - AIMS: Oral cancer is the most life-threatening disease of oral tissues. In societies where the incidence of oral cancer is high, clinically recognizable premalignant lesions are particularly common. Diagnosing oral cancers at an early stage is critical in improving the survival rate and reducing the morbidity associated with the disease. Alterations in the sialic acid levels in cancer patients have stimulated interest in this sugar residue as a possible tumor marker. SETTINGS AND DESIGN: The purpose of this study was to estimate the salivary sialic acid levels in patients with oral premalignancy and squamous cell carcinoma and to correlate it with their grades to develop a cost-effective and noninvasive diagnostic parameter. MATERIALS AND METHODS: Unstimulated whole saliva was collected from the groups under study and subjected to biochemical analysis for determination of sialic acid levels. STATISTICAL ANALYSIS USED: The salivary sialic acid levels were correlated with the clinical stage and histological grade by one-way ANOVA (SPSS software version 15). RESULTS: Salivary sialic acid was elevated in oral squamous cell carcinoma (OSCC) compared to oral premalignancy and control group. A statistically significant correlation was observed between the grades of squamous cell carcinoma, grades of dysplasia in premalignancy, and sialic acid level. CONCLUSION AND CLINICAL SIGNIFICANCE: Evaluation of salivary sialic acid levels in premalignant and malignant lesions can serve as a screening tool. The mortality and morbidity of OSCC can be reduced if the lesions are diagnosed in early precancerous states using such noninvasive diagnostic methods for screening and monitoring of the population. PMID- 27994411 TI - Comparative evaluation of calcium silicate-based dentin substitute (Biodentine(r)) and calcium hydroxide (pulpdent) in the formation of reactive dentin bridge in regenerative pulpotomy of vital primary teeth: Triple blind, randomized clinical trial. AB - BACKGROUND: Considering the biological concerns of calcium hydroxide (CH) as a pulpotomy agent, an alternative silicate based dentin substitute i.e. Biodentine (Ca3SiO5) was evaluated clinically and radiographically. AIMS: To evaluate the effectiveness of dentin substitute (Biodentine) in regenerative pulpotomy of vital primary teeth that would giv a biological base to its use in forming reactive dentin bridge and overcoming the drawbacks of calcium hydroxide. MATERIAL AND METHODS: Randomised clinical trial on 40 bilateral carious primary molars in 20 participant children (aged 5-10 years) was carried out by same operator using Ca3SiO5(group-1) and CH (group-2) as vital pulpotomy agents. Blinded clinical and radiographic outcomes were observed at 3, 6 and 12 months interval. RESULTS: Clinical outcomes of both protocols were analysed using Pearson's chi-square test applied at P < 0.05. Descriptive statistics were expressed as mean increase in dentin bridge formation in mms from two reference points in standardized radiographs using paired 't'- test at baseline and 12 months and found to be statistically significant (P < 0.05) in group-1 when compared with group-2. CONCLUSION: Group-1 revealed statistically favourable regenerative potential along with clinical success compared to group 2 thereby sharing both indications and mode of action with CH, but without its drawbacks of physical and clinical properties. PMID- 27994412 TI - A comparative study to assess the effect of oral alprazolam as premedication on vital parameters of patients during surgical removal of impacted mandibular third molars. AB - PURPOSE: The aim of this study was to evaluate and monitor the changes in vital parameters of patients during surgical removal of impacted mandibular third molars. METHODS: This was an in vivo study conducted in Oral and Maxillofacial Surgery Department of Terna Dental College. Sixty patients were randomly selected. Thirty patients were given a preoperative single dose of oral tablet alprazolam 0.5 mg as premedication (test group), whereas the other thirty were treated without any premedication (control group). RESULTS: It was found that the mean systolic blood pressure during surgical removal of impacted mandibular third molar was raised in the control group and exhibited minimal fluctuation in the test group. CONCLUSION: The use of tablet alprazolam as premedication before surgical removal of impacted mandibular third molars resulted in stability of vital parameters, secondary to reduced patient anxiety. PMID- 27994413 TI - Effects of probiotic drop containing Lactobacillus rhamnosus, Bifidobacterium infantis, and Lactobacillus reuteri on salivary Streptococcus mutans and Lactobacillus levels. AB - AIMS: The aim of the present study was to evaluate the effect of a probiotic drop containing Lactobacillus rhamnosus, Bifidobacterium infantis, and Lactobacillus reuteri on salivary counts of Streptococcus mutans (SM) and Lactobacillus (LB) in children 3-6 years of age. SETTINGS AND DESIGN: Sixty-one healthy children were randomly allocated into two parallel blocks in this double-blind, randomized controlled trial (IRCT2014120320202N1) from May to June 2015. SUBJECTS AND METHODS: Finally 53 participants consumed five drops of placebo (n = 23) or probiotic (n = 30) every night for 2 weeks. Before intervention and 1 day after completion of the intervention, unstimulated salivary samples were collected, and microbiologic evaluations were carried out. STATISTICAL ANALYSIS: Data were analyzed with descriptive statistical methods Wilcoxon signed ranks, Mann Whitney, and logistic regression. RESULTS: SM level decreased significantly in probiotic group after intervention (P = 0.045), and there were significant differences in salivary SM counts after intervention between two groups (P = 0.04). In probiotic group, LB counts decreased significantly after intervention (P = 0.048); however, there were no significant differences between two groups (P = 0.216). CONCLUSIONS: Use of this probiotic drop decreased salivary counts of SM; however, LB counts did not change. In addition, use of the drop in children with higher salivary counts appeared to be more effective. PMID- 27994414 TI - Clinical and radiographic comparison of indirect pulp treatment using light-cured calcium silicate and mineral trioxide aggregate in primary molars: A randomized clinical trial. AB - AIM: To clinically and radiographically evaluate the reparative dentin formation in indirect pulp treatment (IPT) using mineral trioxide aggregate (MTA) and light cured calcium silicate (TheraCal) in primary molars over a period of 6 months. MATERIALS AND METHODS: A clinical trial on IPT on 43 primary molars in 21 patients between the age of 4-7 years, divided into two groups: 22 teeth in MTA group and 21 in TheraCal group. Measurement of the variation in dentin thickness was done on the digitalized radiograph at baseline, 3 months and 6 months using CorelDRAW X3 software. RESULTS: Statistical analysis using an independent t-test for intragroup and intergroup comparison showed a significant increase in dentin thickness in both the MTA and TheraCal group (intragroup comparison [P < 0.05]). However, intergroup comparison between MTA and TheraCal showed no statistical difference in reparative dentin formation (P > 0.05). CONCLUSION: Clinically and radiographically, both MTA and TheraCal are good IPT materials. The better handling characteristics and comparable reparative dentin-forming ability of TheraCal make this material an alternative to MTA in pediatric restorative procedures. PMID- 27994415 TI - Detection of Porphyromonas gingivalis and Treponema denticola in chronic and aggressive periodontitis patients: A comparative polymerase chain reaction study. AB - BACKGROUND: The detection frequency of Porphyromonas gingivalis and Treponema denticola in chronic periodontitis (CP) and aggressive periodontitis (AgP) is not explored well in Indian population. AIM: The study was undertaken to detect P. gingivalis and T. denticola in CP as well as in AgP patients using polymerase chain reaction (PCR), and to determine the relationship between the frequency of these two microorganisms and the severity of clinical periodontal parameters. MATERIALS AND METHODS: Subgingival plaque samples were collected from ninety participants (thirty CP patients, thirty AgP patients, and thirty healthy participants) and the aforementioned two microorganisms were detected using PCR. RESULTS: However, when CP and AgP were compared for the detection frequency of two microorganisms, no statistically significant difference was noted. A statistically significant increase in the number of bacteria-positive sites increased as the score of plaque index (PI), gingival index (GI), and clinical attachment level of CP and AgP patients increased. Coexistence of P. gingivalis and T. denticola was frequently observed in deep periodontal pockets. CONCLUSIONS: Study findings suggest that P. gingivalis and T. denticola are significantly associated with the severity of periodontal tissue destruction. Statistically significant association exists between clinical periodontal parameters such as PI, GI, periodontal pocket depth (PPD), and clinical attachment loss and presence of both the microorganisms. PMID- 27994416 TI - Sealing ability of mineral trioxide aggregate PlusTM and BiodentineTM for repair of furcal perforation in primary molars: An in vitro study. AB - BACKGROUND: One of the unfavorable outcomes of endodontic treatment in primary molars is furcal perforation. During treatment, bacterial infection at the site of perforation should be prevented for better prognosis. AIM: This study aims to compare sealing ability of mineral trioxide aggregate (MTA) PlusTM and BiodentineTM for the repair of furcal perforation in primary molars using spectrophotometry. MATERIALS AND METHODS: Access opening was done for all ninety extracted teeth. Perforation was made in furcation area in all the teeth. The sample size consisted of ninety extracted teeth. They were divided into four groups, Group 1 (n = 30) in which perforations were repaired with MTA PlusTM, Group 2 (n = 30) in which perforations were repaired with BiodentineTM. The other two groups were considered as control groups, Group 3 (n = 15) in which perforations were left unsealed (positive control) and Group 4 (n = 15) without perforations (negative control). Dye extraction method was used to compare the sealing ability of MTA PlusTM and BiodentineTM. Statistical analysis was done using ANOVA test to compare the mean between the different groups. Intergroup comparison was performed using post hoc Scheffe test. RESULTS: The highest dye absorbance was seen in the positive control group with a mean value of 0.080 +/- 0.033. The mean value of MTA PlusTM was 0.031 +/- 0.026 and BiodentineTM was 0.024 +/- 0.031. CONCLUSION: The mean value of dye absorption of MTA PlusTM was greater than BiodentineTM but it was statistically insignificant. PMID- 27994417 TI - A study of Ki-67 expression and its clinicopathological determinants in nondysplastic oral leukoplakia. AB - CONTEXT: Oral cancer is the third most prevalent malignancy in India. Leukoplakia is its most common precursor lesion. AIMS: This study aimed at evaluation of the Ki-67 expression and thereby detection of the dysplastic potential in histopathologically nondysplastic oral leukoplakia (OL). Secondarily, another purpose was to correlate various clinicopathological factors with the labeling indices (LIs) of Ki-67 in those cases as well. SETTINGS AND DESIGN: In total, 97 OL cases were examined. Relevant clinical and demographic information was retrieved from the pro forma, prefilled by the patients themselves during their first visit. SUBJECTS AND METHODS: Ki-67 immunohistochemical staining was performed on paraffin-embedded tissue samples. Its LIs were calculated and correlated with different clinicopathological parameters using statistical software SPSS version 16.0. RESULTS: 58.8% (57 cases) lesions exhibited a Ki-67 positivity of <=5%, and 25.8% (25 cases) lesions exhibited it in the range of 6% 25%. Only 15 (15.4%) patches were stained positively between 26% and 60%. Patients' age beyond 50 years, nonhomogeneous leukoplakia, and tobacco addiction were the significant risk factors for high Ki-67 scores (P < 0.05). CONCLUSIONS: Ki-67 is an essential immunohistochemical marker for epithelial dysplasia in OL, especially when the conventional histopathology fails to appreciate the same. In this purpose, Ki-67 labeling on a routine basis delivers the most convenient results for patients aged above 50 years, and/or addicted to tobacco products, and/or suffering from nonhomogeneous patches. PMID- 27994418 TI - A retrospective cross-sectional study on the prevalence of hypodontia in a target population of Al-Jouf Province, Saudi Arabia. AB - AIM: The purpose of this retrospective study was to determine the prevalence of hypodontia and to ascertain the need of interdisciplinary treatment for ensuing esthetic and functional problems in a target population of Al-Jouf Province, Saudi Arabia. SUBJECTS AND METHODS: Using a dental administration software tool, a total of 1267 patients who presented to the outpatient clinics of the Orthodontic and Prosthodontic Departments between March 2015 and January 2016 were identified. Of those, 694 were females and 573 were males. All permanent teeth were investigated, except third molars. RESULTS: The prevalence of hypodontia was 6.1%. The difference between genders was not statistically significant (P = 0.597) although female hypodontia prevalence was higher than males (6.6% and 5.5%, respectively). The majority of patients had one or two missing teeth. There were no significant differences between right and left sides for any particular tooth. The most commonly missing teeth were mandibular second premolar (40.1%), followed by the maxillary lateral incisor (20.4%) and then the maxillary second premolars (12.6%). CONCLUSIONS: The prevalence of hypodontia in Al-Jouf Province, Saudi Arabia, was within the average values portrayed in the majority of the published literature. The majority of affected individuals had one or two missing teeth. None of the patients examined had more than four missing teeth. There were no significant differences in the distribution of hypodontia between the affected jaws according to gender. Although less prevalent, considerable cases of bilateral missing teeth were found in the present study which necessitates the need for urgent interdisciplinary intervention and management. PMID- 27994419 TI - Influence of sex hormone levels on gingival enlargement in adolescent patients undergoing fixed orthodontic therapy: A pilot study. AB - BACKGROUND: Sex hormones may be a modifying factor in the periodontal disease pathogenesis. AIM: The association between gingival enlargement and sex hormone levels in adolescent patients undergoing fixed orthodontic therapy needs to be determined. SETTINGS AND DESIGN: This study was conducted in the Department of Periodontology in association with the Department of Orthodontics, Yenepoya Dental College, Yenepoya University, Mangaluru. MATERIALS AND METHODS: A pilot study was conducted on 21 adolescent patients between the age group of 13-19 years, who had undergone fixed orthodontic therapy for at least 3 months. Apicocoronally, the gingival enlargement was assessed by the index described by Miller and Damm. Miranda and Brunet index was used to assess gingival overgrowth in the buccal-lingual direction in the interdental papilla. Furthermore, the patients were assigned to two groups - Group 1-GE and Group 2-non-GE. Sex hormones assessed were estradiol and progesterone in females and testosterone in males in both groups. RESULTS: 57.1% of the study population had enlargement of the gingiva. The mean plaque score was 0.59 and 0.56, respectively, in both groups. A statistically significant relationship was found between estradiol and testosterone levels with gingival enlargement. However, a significant relationship was not obtained for progesterone levels with the gingival enlargement. CONCLUSION: Direct correlation between estradiol, testosterone, and gingival enlargement was seen. PMID- 27994420 TI - Comparative evaluation of platelet-rich fibrin, mineral trioxide aggregate, and calcium hydroxide as pulpotomy agents in permanent molars with irreversible pulpitis: A randomized controlled trial. AB - BACKGROUND: Pulpotomy has been proposed as an alternative for the management of irreversible pulpitis in permanent molars with closed apices. AIM: To compare the performances of calcium hydroxide (CH), mineral trioxide aggregate (MTA), and platelet-rich fibrin (PRF) as pulpotomy agents in mature permanent molars with irreversible pulpitis. MATERIALS AND METHODS: Fifty-four permanent mandibular molars with carious exposure and symptoms of irreversible pulpitis were randomly allocated to three groups, and full pulpotomy was performed using CH, MTA, or PRF as pulpotomy agents. Pain intensity was recorded using numeric rating scale score at baseline, 24 h, 7 days, 6 months, and 1 year. Clinical and radiographic assessments were done at 6 months and 1 year. STATISTICAL ANALYSIS: Kruskal Wallis test and Friedman test were used for intergroup and intragroup comparison of pain scores, respectively. The radiographic outcomes between the three study arms were compared using Chi-square test. RESULTS: Clinical success rate was 94.4% at 7 days, which dropped to 85.4% at 12 months. All three agents were equally effective in providing pain relief at all the intervals tested, with no significant difference between them (P > 0.05 at all intervals). However, at 6 months and 12 months, 26.2% and 52.4% teeth depicted slight widening of periodontal ligament space. No significant difference was observed between the radiographic success rates observed with the three groups (P = 0.135 at 6 months, 0.717 at 12 months). CONCLUSION: Pulpotomy exhibited a high clinical success rate in mature molars with irreversible pulpitis and selection of biomaterial did not affect its outcome. PMID- 27994421 TI - Evaluation of melatonin levels in saliva in gingivitis and periodontitis cases: A pilot study. AB - OBJECTIVE: To evaluate the melatonin levels in saliva in gingivitis and periodontitis cases. BACKGROUND: Melatonin has strong antioxidant, free radical scavenging, and immunomodulating properties, acts on osteoblasts directly to stimulate cell proliferation and synthesis of Type I collagen, and promotes bone formation. MATERIALS AND METHODS: A total of thirty participants were selected and divided into three groups (control group, gingivitis group, and periodontitis group). In each group, ten participants were taken. Salivary melatonin was estimated in each of the three groups. RESULTS: Results from this study showed that the mean levels of salivary melatonin increased as severity increased from control to periodontitis, i.e., the mean levels were highest in periodontitis followed by gingivitis and least in control group. The melatonin level of all participants was positively and significantly (P < 0.01) correlated with their gingival index (r = 0.85, P < 0.01) and probing depth (r = 0.72, P < 0.01). CONCLUSION: Salivary melatonin level varied with the severity of gingivitis and periodontitis. With increased severity of periodontal disease, the level of salivary melatonin also increased suggesting that salivary melatonin may act as a diagnostic biomarker for periodontal diseases. PMID- 27994422 TI - Immunohistochemical expression of phosphatase and tensin homolog in histologic gradings of oral squamous cell carcinoma. AB - CONTEXT: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located on chromosome 10q23. PTEN has its major function in the regulation of cell adhesion, cell cycle arrest, migration, apoptosis programming, and differentiation. This genomic region suffers loss of heterozygosity in many human cancers. AIMS: The aim of this study was to compare the immunohistochemical expression of PTEN in normal oral mucosa and oral squamous cell carcinoma (OSCC) and to correlate the PTEN expression in gradings of OSCC. MATERIALS AND METHODS: Thirty cases of paraffin tissue sections of previously diagnosed OSCC were taken. Of thirty cases, ten were well differentiated, ten were moderately differentiated, and ten were poorly differentiated. As a control, ten paraffin sections of oral normal mucosa tissue specimens were taken from patients undergoing extractions. The sections were stained for immunohistochemical expression of PTEN. The cells stained by PTEN antibody were counted, and an immunohistochemical score was obtained. STATISTICAL ANALYSIS USED: Statistical analysis was done using Mann-Whitney's test and Kruskal-Wallis test. RESULTS: Statistical analysis revealed that there was a significant difference between normal mucosa and OSCC in immunohistochemistry staining. However, there was no significant difference in PTEN expression among gradings of OSCC. CONCLUSIONS: The study concluded that there was a decrease in PTEN expression in OSCC than normal mucosa. It also concluded that PTEN is a tumor suppressor gene which has a wide role in oral carcinogenesis. PMID- 27994424 TI - Correlation of gingival thickness with gingival width, probing depth, and papillary fill in maxillary anterior teeth in students of a dental college in Navi Mumbai. AB - CONTEXT: The gingival biotype is of utmost importance for esthetics and biologic function. Anatomical characteristic of periodontium such as gingival thickness (GT), width of keratinized gingiva, and alveolar bone morphology will determine the behavior of periodontium when subjected to physical, chemical, or bacterial insult or during therapeutic procedure. AIMS: The aim of this study was to correlate the GT with gingival width (GW), probing depth (PD), and papillary fill (PF) in relation to maxillary anterior region. SETTINGS AND DESIGN: Undergraduate dental students and interns from a dental college in Navi Mumbai were enrolled in the study according to the inclusion criteria. Six teeth per subject were assessed; a total of 2178 maxillary anterior teeth were examined. SUBJECTS AND METHODS: Subjects were examined clinically for GT, width of keratinized gingiva, pocket depth, and interdental PF. The data obtained was tabulated and subjected to statistical analysis. STATISTICAL ANALYSIS USED: Spearman's correlation analysis test was performed to find the correlation of GT with GW, PD, and PF. RESULTS: Positive correlation was found between GT and GW (r = 0.241). No significant correlation could be found between GT and PD; and between GT and PF. CONCLUSIONS: The present study confirmed a positive correlation between GT and GW. A weak negative correlation was found between GT and PD. PMID- 27994423 TI - Assessment of Streptococcus mutans in healthy versus gingivitis and chronic periodontitis: A clinico-microbiological study. AB - BACKGROUND: Dental caries and periodontal disease are most common oral diseases. Streptococcus mutans are considered to be the major pathogens in initiation of dental caries. Evidence shows that periodontal disease and caries share a number of contributory factors. Thus in view of these findings it would be worthwhile to examine whether Streptococcus mutans persist within the saliva and subgingival environment of the periodontitis patients and to determine whether there is any association between Streptococcus mutans colonization, pH of saliva and sub gingival plaque pH in periodontal diseases before therapy. METHODS: The study comprises of 75 subjects aged between 20-70 years, reporting to department of Periodontology, KLEs Institute of Dental Sciences, Bangalore. Subjects were divided into 3 groups of 25 each. Group 1 - Healthy controls, Group 2 - Gingivitis Group, 3 - Chronic periodontitis. Unstimulated saliva was collected in sterile container and immediately pH was evaluated. Subgingival plaque samples were collected from four deepest periodontal pockets in chronic periodontitis and from first molars in healthy subjects using 4 sterile paper points. In gingivitis subjects samples were collected from areas showing maximum signs of inflammation. All paper points and saliva samples were cultured on mitis salivarius agar culture media with bacitracin for quantification of the Streptococcus mutans colonies. RESULTS: Increased colonization of Streptococcus mutans was seen in chronic periodontitis subjects both in saliva and sub-gingival plaque samples. There was also a positive correlation seen with the periodontal parameters. CONCLUSION: More severe forms of periodontal disease may create different ecological niches for the proliferation of Streptococcus mutans. PMID- 27994425 TI - Oral manifestations of human immunodeficiency virus/acquired immunodeficiency syndrome and their correlation to cluster of differentiation lymphocyte count in population of North-East India in highly active antiretroviral therapy era. AB - BACKGROUND: The human immunodeficiency virus (HIV) infection which manifests as acquired immunodeficiency syndrome (AIDS) is a disease involving the defects of the T-lymphocyte arm of the immune system. Certain laboratory parameters such as the cluster of differentiation (CD4) count and clinical parameters have long been used as markers of disease progression. In industrialized countries, many studies show a highly correlation between the incidence of oral lesions and immunosuppression and hence, can be used as a marker of immunosuppression. This might not be applicable to a developing country like India. In this study, efforts have been made to supplement the present knowledge on various aspects of oral manifestations in HIV patients in the Indian subcontinent. AIMS: To correlate the oral manifestations in HIV/AIDS patients to the level of circulating CD4+ T-lymphocyte count and their effect in anti-retroviral therapy (ART). SUBJECTS AND METHODS: A total of 104 HIV positive patients were examined for oral lesions. The CD4 count estimated on the same day by fluorescent activated cell sort count machine was then correlated with various oral lesions. RESULTS: Oral manifestations appeared when CD4 count decreased below 500 cells/mm3. Moreover, oral lesions found at different stages showed very strong correlation to their respective CD4 count. Furthermore, there was considerable decline in the incidence of oral manifestations in patients undergoing highly active ART. CONCLUSIONS: Oral manifestations are highly predictive markers of severe immune deterioration and disease progression in HIV patients. PMID- 27994426 TI - Modified coronally advanced flap with and without orthodontic button application in management of multiple proximate gingival recession defects: A randomized clinical trial. AB - BACKGROUND: Gingival recession indicates oral display of the root surface due to apical movement of gingival margin. Coronally advanced flap (CAF) is often used periodontal plastic surgical technique to accomplish root coverage. The purpose of this clinical trial is to assess and compare the effectiveness of modified CAF with orthodontic button application (CAF+B) and without orthodontic button application (CAF) for the correction of multiple recession defects. MATERIALS AND METHODS: Twenty patients exhibiting bilateral multiple proximate Millers Class I and/or Class II gingival recession defects were included in the study. Each set of proximate recession defects was designated randomly to test or control group. Control group was treated by CAF alone and test group by CAF+B. Baseline and postoperative clinical parameters at 2, 4, and 6 months time interval were recorded. RESULTS: Mean root coverage percentage from baseline to 6 months in control group was 78.30% +/- 20.75% and in test group was 92.23% +/- 15.6%. Complete root coverage was 43.8% in control group and 77.47% in test group. Visual analog scale pain measurements did not reveal any difference among both the groups. Patient satisfaction with esthetics was very high in CAF+B group when compared with CAF group. CONCLUSION: Both treatment modalities, i.e., CAF and CAF+B are effectual in the treatment of proximate Miller's Class I and Class II gingival recession defects, but CAF+B showed significantly superior clinical results. PMID- 27994427 TI - Endodontic management of maxillary first molar with atypical canal morphology: Report of three cases. AB - Maxillary first molar with three roots and 3-4 canals is a common occurrence. However, extreme variations in their canal morphology have been reported ranging from one single canal and one root to as many as eight root canals. This article presents three cases of successful endodontic management of maxillary first molars with atypical canal morphologies, thus highlighting the fact that variations do occur and an endodontist should always be aware of aberrancies in root canal system apart from the knowledge of normal root canal anatomy. PMID- 27994428 TI - Labial ankyloglossia: A rare case report. AB - Tongue-tie or ankyloglossia is the congenital short thick lingual frenulum resulting in reduced mobility of the tongue. It limits the possibilities of the extension such as the protrusion and elevation of the tip of the tongue due to either the short of frenulum or genioglossus muscle or both. It can be observed at different ages with specific indications for treatment for each group and cause problems in the feeding, dental hygiene, speech, appearance, and self esteem of affected patients. Although various degrees of the tongue-tie are mostly observed from the tip of tongue to the base of tongue, sometimes it may present unusually. The present article reports an unusual unique pattern of ankyloglossia where lingual frenum was exceptionally extended and merged with mandibular labium frenum. Reported case is one of the rarest types of ankyloglossia and emphasizes on its clinical implications, need for modifying diagnostic criteria, surgical management, and postoperative exercises. PMID- 27994429 TI - Odontogenic myxofibroma of gingiva in a pediatric patient with tuberous sclerosis: A rare case report. AB - Tuberous sclerosis complex (TSC) is a rare multisystem genetic disease, with an estimated incidence of 1 in 6000-1 in 10,000. TSC is an autosomal dominant syndrome involving heart, kidneys, lungs, and skin. The classic triad of TSC is seizures, mental retardation, and angiofibromas; this triad occurs in only 29% of patients. The clinical diagnostic guidelines on TSC are prepared based on clinical features, radiographic findings. The most common oral manifestations of TSC are fibroma, gingival hyperplasia, and enamel hypoplasia. Odontogenic myxofibroma represents a rare slow-growing benign neoplasm found rarely in children below 10 years or adults over 50 years of age. The prevalence of myxoma is between 0.04% and 3.7%. Here, we are reporting a rare case of myxofibroma of gingiva in an 8-year-old female TSC patient. PMID- 27994430 TI - Nonsurgical endodontic therapy along with minimal invasive treatment utilizing Bhasker's hypothesis for the management of infected radicular cystic lesion: A rare case report. AB - Radicular cyst (RC) is the most common odontogenic cyst of inflammatory origin affecting the jaws; involves the roots of the carious or traumatic non-vital tooth. Different therapeutic modalities, such as nonsurgical endodontic therapy or surgical enucleation with primary closure, decompression etc., were proposed for the management of such lesions. Presenting a case of a 28-year-old otherwise healthy male patient who reported with pain and swelling with respect to tooth #41, 31. Diagnosis of infected RC at a rare location was established on the basis of clinical, radiographical and fine needle aspiration cytological examination. Looking after the clinical characteristics, origin, extension, size of cystic lesion and patient cooperation; nonsurgical endodontic therapy utilizing Bhasker's hypothesis was opted. One year post-operative result suggested that nonsurgical endodontic therapy along with minimally invasive treatment utilizing Bhasker's hypothesis is an effective tool to transform infected radicular cystic lesion to healthy periapical periodontal tissue. PMID- 27994431 TI - Congenital bilateral syngnathia and tracheoesophageal fistula: A rare presentation. AB - Congenital syngnathia (CS), first reported by Burket in 1936, is a rare condition, with <50 reported cases and is associated with other conditions and syndromes. CS restricts mouth opening, causing difficulty in feeding, swallowing, and respiration. This report puts forth the clinical findings and management of this challenging condition in association with tracheoesophageal fistula in a neonate. PMID- 27994432 TI - Presurgical nasoalveolar molding: A boon to facilitate the surgical repair in infants with cleft lip and palate. AB - Cleft lip and palate (CLP) is the most common congenital craniofacial anomaly. Rehabilitation of CLP generally requires a team approach. Alveolar and nasal reconstruction for these patients is a challenge for the reconstructive surgeon. Various procedures have been attempted to reduce the cleft gap, so as to obtain esthetic results postsurgically. The presurgical nasoalveolar molding (PNAM) technique, developed by Grayson, is a new approach to presurgical infant orthopedics. PNAM reduces the severity of the initial cleft alveolar and nasal deformity. Thus, it enables the surgeon and the patient to enjoy the benefits associated with repair of a cleft deformity that is minimal in severity. This article presents a brief insight into PNAM with a case series of three different cases (one unilateral and two bilateral) which underwent PNAM treatment and gave an excellent surgical prognosis. PMID- 27994433 TI - Management of severe skeletal Class III malocclusion with bimaxillary orthognathic surgery. AB - Orthognathic surgery in conjunction with fixed orthodontics is a common indication for interdisciplinary management of severe skeletal Class III malocclusion. A thorough analysis of pretreatment investigations and development of a surgical visual treatment objective is essential to plan the type of surgical technique required. Bimaxillary orthognathic surgery is the most common type of surgical procedure for severe skeletal discrepancies. The present case report is a combined ortho-surgical team management of a skeletally Class III patient. The severity of the case required bilateral upper first premolar extraction for dentoalveolar decompensation and simultaneous "Two-jaw surgery" with maxillary advancement of 4 mm and mandibular setback of 7 mm. Postsurgery, a pleasing good facial profile was achieved with Class II molar relation and positive overjet. PMID- 27994434 TI - Increased serum level of homocysteine correlates with retinal nerve fiber layer thinning in diabetic retinopathy. AB - PURPOSE: To study the correlation between serum levels of vitamin B12, folic acid, and homocysteine and the severity of diabetic retinopathy and the correlation with retinal nerve fiber layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT). METHODS: In a tertiary care center-based prospective cross-sectional study, 60 consecutive cases and 20 healthy controls in the age group of 40-65 years were included. The eyes of the cases were divided into three groups according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus without retinopathy (n = 20), non-proliferative diabetic retinopathy with macular edema (n = 20), and proliferative diabetic retinopathy with macular edema (n = 20). The serum levels of vitamin B12 and folic acid were measured using a standard protocol. The serum homocysteine assay was performed using an enzyme-linked immunosorbent assay (ELISA) kit. Average RNFL thickness was measured using SD-OCT. Statistical analysis was used to assess the correlations between the study variables. RESULTS: Increased severity of diabetic retinopathy was found to correlate with an increase in the serum levels of homocysteine (F = 53.79; p<0.001). The mean serum levels of vitamin B12 and folic acid were found to be within the normal reference range. A positive correlation was found between retinal nerve fiber layer thinning and serum levels of homocysteine (p<0.001). CONCLUSIONS: This study, for the first time, demonstrated a correlation between increased homocysteine with a decrease in RNFL thickness and increased severity of diabetic retinopathy. PMID- 27994436 TI - Role of endogenous insulin gene enhancer protein ISL-1 in angiogenesis. AB - OBJECTIVE: To elucidate the role of insulin gene enhancer protein ISL-1 (Islet-1) in angiogenesis and regulation of vascular endothelial growth factor (VEGF) expression in vitro and in vivo. METHODS: siRNA targeting Islet-1 was transfected to human umbilical vein endothelial cell lines (HUVECs). The expression of Islet 1 and VEGF in the cultured cells was measured using real-time PCR and immunoblotting. 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide; thiazolyl blue (MTT) assay was used to analyze the proliferation of HUVECs affected by Islet-1. Wound healing and Transwell assays were conducted to assess the motility of HUVECs. The formation of capillary-like structures was examined using growth factor-reduced Matrigel. siRNA targeting Islet-1 was intravitreally injected into the murine model of oxygen-induced retinopathy (OIR). Retinal neovascularization was evaluated with angiography using fluorescein-labeled dextran and then quantified histologically. Real-time PCR and immunoblotting were used to determine whether local Islet-1 silencing affected the expression of Islet-1 and VEGF in murine retinas. RESULTS: The expression of Islet-1 and VEGF in HUVECs was knocked down by siRNA. Reduced endogenous Islet-1 levels in cultured cells greatly inhibited the proliferation, migration, and tube formation in HUVECs in vitro. Retinal neovascularization following injection of Islet-1 siRNA was significantly reduced compared with that of the contralateral control eye. Histological analysis indicated that the neovascular nuclei protruding into the vitreous cavity were decreased. Furthermore, the Islet-1 and VEGF expression levels were downregulated in murine retinas treated with siRNA against Islet-1. CONCLUSIONS: Reducing the expression of endogenous Islet-1 inhibits proliferation, migration, and tube formation in vascular endothelial cells in vitro and suppresses retinal angiogenesis in vivo. Endogenous Islet-1 regulates angiogenesis via VEGF. PMID- 27994435 TI - PKR promotes choroidal neovascularization via upregulating the PI3K/Akt signaling pathway in VEGF expression. AB - PURPOSE: The aim of this study was to investigate the functions of dsRNA activated protein kinase (PKR) in choroidal neovascularization (CNV) and related signaling pathways in the production of vascular endothelial growth factor (VEGF). METHODS: A chemical hypoxia model of in vitro RF/6A cells, a rhesus choroid-retinal endothelial cell line, was established by adding cobalt chloride (CoCl2) to the culture medium. PKR, phosphophosphatidylinositol 3-kinase (p PI3K), phosphoprotein kinase B (p-Akt), and VEGF protein levels in RF/6A cells were detected with western blotting. PKR siRNA and the PI3K inhibitor LY294002 were used to evaluate the roles of the PKR and PI3K signaling pathways in VEGF expression with western blotting. In an ARPE-19 (RPE cell line) and RF/6A cell coculture system, proliferation, migration, and tube formation of RF/6A cells under hypoxic conditions were measured with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT), Transwell, and Matrigel Transwell assays, respectively. In vivo CNV lesions were induced in C57BL/6J mice using laser photocoagulation. The mice were euthanized in a timely manner, and the eyecups were dissected from enucleated eyes. PKR, p-PI3K, p-Akt, and VEGF protein levels in tissues were detected with western blotting. To evaluate the leakage area, fundus fluorescein angiography and choroidal flat mount were performed on day 7 after intravitreal injection of an anti-PKR monoclonal antibody. RESULTS: The in vitro RF/6A cell chemical hypoxia model showed that PKR expression was upregulated in parallel with p-PI3K, p-Akt, and VEGF expression, peaking at 12 h. PKR siRNA downregulated PKR, p-PI3K, p-Akt, and VEGF expression. In addition, the PI3K inhibitor LY294002 greatly decreased the p-PI3K, p-Akt, and VEGF protein levels, but PKR expression was unaffected, indicating that Akt was a downstream molecule of PKR that upregulated VEGF expression. In the ARPE-19 (RPE cell line) and RF/6A cell coculture system, PKR siRNA reduced the migration and tube formation of the RF/6A cells. In vivo, PKR, p-PI3K, p-Akt, and VEGF expression increased and peaked at 7 days in the mouse CNV model induced by laser photocoagulation. Furthermore, on the RPE and choroid cryosections, PKR colocalized with CD31, suggesting that PKR was expressed by the vascular endothelium. The intravitreal injection of an anti-PKR monoclonal antibody decreased the progression and leakage area of CNV in mice. CONCLUSIONS: PKR promotes CNV formation via the PI3K/Akt signaling pathway in VEGF expression. Additionally, the anti-PKR monoclonal antibody significantly decreased CNV in a mouse model, showing the antibody may have therapeutic potential in human CNV. PMID- 27994437 TI - Systemic side effects of eye drops: a pharmacokinetic perspective. AB - When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amounts can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concentration of active ingredients in such medicinal preparations is usually very high, so that despite the correct application of the recommended dose, considerable amounts may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not weight adjusted and physiological development (eg, liver status) differs from that of adults. There is a lack of information about pediatric dosing in the current literature. This review summarizes the most important clinically relevant systemic side effects that may occur during ophthalmic eye treatments. In this review, we discuss general pharmacokinetic considerations as well as the advantages, disadvantages, and consequences of administering drugs from some important drug groups to the eye. PMID- 27994438 TI - Comorbidity and health care visit burden in working-age commercially insured patients with diabetic macular edema. AB - PURPOSE: To examine the comorbidity profile and update estimates of health care resource utilization for commercially insured, working-age adults with diabetic macular edema (DME) relative to a matched comparison group of diabetic adults without DME. Additional comparisons were made in the subgroup of pseudophakic patients. PATIENTS AND METHODS: A retrospective matched-cohort study of commercially insured diabetic adults aged 18-63 years was conducted using medical and outpatient pharmacy claims (July 1, 2008-June 30, 2013). Outcomes included diabetes-related and ocular comorbidities and health care resource utilization (any health care visit days, outpatient visit days, inpatient visit days, emergency room visits, eye care-related visit days, unique medications) in the 12 month post-index period. RESULTS: All diabetes-related and ocular comorbidities were significantly more prevalent in DME cases versus non-DME controls (P<0.05). A significantly greater proportion of DME cases utilized eye care-related visits compared with non-DME controls (P<0.001). DME cases had almost twice the mean number of total health care visit days compared to non-DME controls (28.6 vs 16.9 days, P<0.001), with a minority of visit days being eye care-related (mean 5.1 vs 1.5 days, P<0.001). Similar trends were observed in pseudophakic cohorts. CONCLUSION: This working-age DME population experienced a mean of 29 health care visit days per year. Eye care-related visit days were a minority of the overall visit burden (mean 5 days) emphasizing the trade-offs DME patients face between managing DME and their overall diabetic disease. Insights into the complex comorbidity profile and health care needs of diabetic patients with DME will better inform treatment decisions and help optimize disease management. PMID- 27994439 TI - Impact of prostaglandin glaucoma drops on platelet-activating factor action: an in vitro study. AB - AIM: The aim of this study was to investigate the effect of different prostaglandin analogs on platelet-activating factor (PAF) levels. METHODS: Three prostaglandin analogs were selected: bimatoprost 0.3 mg/mL, latanoprost 50 MUg/mL, and tafluprost 15 MUg/mL. Each drug sample was tested for its ability to cause platelet aggregation, which was measured as PAF-induced aggregation, before and after the addition of various concentrations of the examined sample, creating a linear curve of percentage inhibition (ranging from 0% to 100%) versus different concentrations of the sample. The concentration of the sample that inhibited 50% PAF-induced aggregation was calculated based on this curve, and this value was defined as IC50. In addition, the effect of eye drops on PAF metabolism was examined, through an in vitro analysis on PAF basic metabolic enzymes (PAF-cholinephosphotransferase, PAF-acetyl-CoA:1-O-alkyl-sn-glycero-3 phosphocholine acetyltransferase, and PAF-acetylhydrolase). RESULTS: The IC50 values for Lumigan UD(r) (bimatoprost 0.3 mg/mL), Monoprost(r) (latanoprost 50 MUg/mL), and Saflutan (tafluprost 15 MUg/mL) were 8.7, 0.28, and 1.4 MUg/mL, respectively. DISCUSSION: All three prostaglandin analogs suspended PAF, but bimatoprost induced the most potent inhibition, compared to tafluprost and to the weak effect of latanoprost. PMID- 27994441 TI - Comparison of oral absorption models for pregabalin: usefulness of transit compartment model. AB - Pregabalin is an anticonvulsant used for the treatment of neuropathic pain and partial seizure in adults. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the absorption characteristics of pregabalin given fasted or after meals. Data from five healthy subject PK studies (n=88) of single- or multiple-dose pregabalin (150 mg) were used. Pregabalin was administered twice daily, without meals or 30 min after a meal (regular or high fat diet) in the morning and 30 min or 4 h after a meal (regular diet) in the evening. Serial plasma samples were collected up to 24 h after the last dose for PK analysis. Because the peak concentrations were not properly modeled by a conventional first-order absorption model, Erlang frequency distribution, Weibull type absorption, and transit compartment models were tested on a two-compartment linear PK model using a nonlinear mixed-effects method (NONMEM; version 7.3). The transit compartment model best described the absorption characteristics of pregabalin regardless of meal status. We conclude that the absorption model should be carefully chosen based on the principle of model development and validation and not by following a conventional first-order absorption model for its popularity and simplicity, especially when the PK dataset includes densely sampled absorption-phase data. PMID- 27994440 TI - Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations. AB - Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo(r) (bedaquiline) and Deltyba(r) (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients. Possible alterations in the pharmacokinetics of these novel drugs induced by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy in diabetes patients, and possible drug-drug interactions with hypoglycemic agents, are of special interest, since the efficacy of bedaquiline and delamanid is concentration dependent. Moreover, it is of fundamental importance to avoid possible additive or synergistic effects of adverse drug reactions in this already vulnerable patient group. We reviewed clinical particularities related to the use of bedaquiline and delamanid in patients with type 1 and 2 diabetes mellitus (DM), as well as pharmacological aspects of the concurrent use of these agents with oral and injectable hypoglycemic agents. Bedaquiline shares liver metabolic pathways with several oral hypoglycemic agents, whereas delamanid may compete with several oral hypoglycemic agents and insulin analogs at protein binding sites. Special concern exists regarding the use of bedaquiline and delamanid in diabetes patients aged >65 years and patients with severe renal or hepatic impairment or electrolyte disturbances. Concurrent use of bedaquiline and delamanid with insulin analogs, and other hypoglycemic agents that prolong the heart rate-corrected QT interval, such as sulfonylureas and glinides, may enhance this adverse reaction. Hepatic-related adverse reactions may develop more frequently when these drugs are combined with thiazolidinediones and acarbose. Data from Phase III and postmarketing studies are needed to elucidate the effect of DM and hypoglycemic agents on bedaquiline and delamanid effects in MDR-TB patients. PMID- 27994443 TI - Relationship between patients' knowledge and medication adherence among patients with hypertension. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between knowledge on arterial hypertension (AH) and its management, and adherence to pharmaceutical treatment. METHODS: The study included 233 patients diagnosed with AH and treated with hypotensive drugs for at least 1 year. The 8-item (c) Morisky Medication Adherence Scale (MMAS-8) and the Hypertension Knowledge-Level Scale (HK-LS) were used. RESULTS: Sixty-three percent of the patients had a low level of knowledge on AH, with the smallest proportion of correct answers provided for items related to non-pharmaceutical treatment, diet, hypertension definition, and drug adherence. When compared to patients with a high level of knowledge, those with a low knowledge had lower scores in the MMAS (6.45+/-1.45 vs 7.08+/-1.04; P=0.038). Multiple-factor analysis showed that statistically significant independent determinants of good adherence included a high level of knowledge (beta=0.208; P=0.001), non-pharmaceutical treatment (beta=0.182; P=0.006), and frequent blood pressure measurements (beta=0.183; P=0.004). The most significant factor in MMAS was knowledge in the "drug adherence" domain (rho=0.303; P<0.001). CONCLUSION: Patients' knowledge on hypertension is a significant independent determinant of good adherence. Other independent determinants include non pharmaceutical treatment and regular blood pressure measurements. IMPLICATION FOR PRACTICE: The identification of knowledge deficits as a factor contributing to lack of adherence and poor hypertension control remains a key challenge for multidisciplinary team caring for patients with hypertension. PMID- 27994442 TI - Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013. AB - A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011-2013 than in 1990-2007 (31.6% vs 6.3%, P=0.036), reflecting a slow, but steady acceptance of the European Medicines Agency's guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2-53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster. PMID- 27994445 TI - Are older people more vulnerable to long-term impacts of disasters? AB - BACKGROUND: Despite the growing interest in the study of disasters, there is limited research addressing the elderly population that lead to prejudiced beliefs that older adults are more vulnerable to disasters than younger adults. This study aimed to compare positive mental health between elderly and young earthquake survivors. METHOD: Data for this study, consisting of 324 earthquake survivors, were obtained from a population-based cross-sectional survey conducted in Iran, 2015. The long-term effect of earthquake was assessed using the Mental Health Continuum-Short Form questionnaire. A one-way multivariate analysis of covariance (MANCOVA) using SPSS (version 22) was used in data analysis. RESULTS: Older adults scored significantly a higher level of overall positive mental health (mean [M]=34.31, standard deviation [SD]=10.52) than younger age group (M=27.48, SD=10.56, t=-4.41; P<0.001). Results of MANCOVA revealed a statistically significant difference between older and young adults on the combined positive mental health subscales (F(3,317)=6.95; P<0.001), after controlling for marital status, sex, and employment status. CONCLUSION: The present findings showing a higher level of positive mental health among elderly earthquake survivors compared with their younger counterparts in the wake of natural disasters suggest that advancing age per se does not contribute to increasing vulnerability. PMID- 27994444 TI - The influence of frailty syndrome on medication adherence among elderly patients with hypertension. AB - BACKGROUND: Hypertension affects about 80% of people older than 80 years; however, diagnosis and treatment are difficult because about 55% of them do not adhere to treatment recommendations due to low socioeconomic status, comorbidities, age, physical limitations, and frailty syndrome. AIMS: The purposes of this study were to evaluate the influence of frailty on medication adherence among elderly hypertensive patients and to assess whether other factors influence adherence in this group of patients. METHODS AND RESULTS: The study included 296 patients (mean age 68.8+/-8.0) divided into frail (n=198) and non frail (n=98) groups. The Polish versions of the Tilburg Frailty Indicator (TFI) for frailty assessment and 8-item Morisky Medication Adherence Scale for adherence assessment were used. The frail patients had lower medication adherence in comparison to the non-frail subjects (6.60+/-1.89 vs 7.11+/-1.42; P=0.028). Spearman's rank correlation coefficients showed that significant determinants with negative influence on the level of adherence were physical (rho =-0.117), psychological (rho =-0.183), and social domain (rho =-0.163) of TFI as well as the total score of the questionnaire (rho =-0.183). However, multiple regression analysis revealed that only knowledge about complications of untreated hypertension (beta=0.395) and satisfaction with the home environment (beta=0.897) were found to be independent stimulants of adherence level. CONCLUSION: Frailty is highly prevalent among elderly hypertensive patients. Higher level of frailty among elderly patients can be considered as a determinant of lower adherence. However, social support and knowledge about complications of untreated hypertension are the most important independent determinants of adherence to pharmacological treatment. PMID- 27994446 TI - Exacerbations and health care resource utilization in patients with airflow limitation diseases attending a primary care setting: the PUMA study. AB - BACKGROUND: COPD, asthma, and asthma-COPD overlap increase health care resource consumption, predominantly because of hospitalization for exacerbations and also increased visits to general practitioners (GPs) or specialists. Little information is available regarding this in the primary care setting. OBJECTIVES: To describe the prevalence and number of GP and specialist visits for any cause or due to exacerbations in patients with COPD, asthma, and asthma-COPD overlap. METHODS: COPD was defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio <0.70; asthma was defined as prior medical diagnosis, wheezing in the last 12 months, or wheezing plus reversibility (post-bronchodilator FEV1 or FVC increase >=200 mL and >=12%); asthma-COPD overlap was defined as post-bronchodilator FEV1/FVC <0.70 plus prior asthma diagnosis. Health care utilization was evaluated as GP and/or specialist visits in the previous year. RESULTS: Among the 1,743 individuals who completed the questionnaire, 1,540 performed acceptable spirometry. COPD patients had a higher prevalence of any medical visits to any physician versus those without COPD (37.2% vs 21.8%, respectively) and exacerbations doubled the number of visits. The prevalence of any medical visits to any physician was also higher in asthma patients versus those without asthma (wheezing: 47.2% vs 22.7%; medical diagnosis: 54.6% vs 21.6%; wheezing plus reversibility: 46.2% vs 23.8%, respectively). Asthma patients with exacerbations had twice the number of visits versus those without an exacerbation. The number of visits was higher (2.8 times) in asthma-COPD overlap, asthma (1.9 times), or COPD (1.4 times) patients versus those without these respiratory diseases; the number of visits due to exacerbation was also higher (4.9 times) in asthma-COPD overlap, asthma (3.5 times), and COPD (3.8 times) patients. CONCLUSION: COPD, asthma, and asthma-COPD overlap increase the prevalence of medical visits and, therefore, health care resource utilization. Attempts to reduce health care resource use in these patients require interventions aimed at preventing exacerbations. PMID- 27994447 TI - Interpreting patient-reported outcomes from clinical trials in COPD: a discussion. AB - One of the challenges faced by the practising physician is the interpretation of patient-reported outcomes (PROs) in clinical trials and the relevance of such data to their patients. This is especially true when caring for patients with progressive diseases such as COPD. In an attempt to incorporate the patient perspective, many clinical trials now include assessments of PROs. These are formalized methods of capturing patient-centered information. Given the importance of PROs in evaluating the potential utility of an intervention for a patient with COPD, it is important that physicians are able to critically interpret (and critique) the results derived from them. Therefore, in this paper, a series of questions is posed for the practising physician to consider when reviewing the treatment effectiveness as assessed by PROs. The focus is on the St George's Respiratory Questionnaire for worked examples, but the principles apply equally to other symptom-based questionnaires. A number of different ways of presenting PRO data are discussed, including the concept of the minimum clinically important difference, whether there is a ceiling effect to PRO results, and the strengths and weaknesses of responder analyses. Using a worked example, the value of including a placebo arm in a study is illustrated, and the influence of the study on PRO results is considered, in terms of the design, patient withdrawal, and the selection of the study population. For the practising clinician, the most important consideration is the importance of individualization of treatment (and of treatment goals). To inform such treatment, clinicians need to critically review PRO data. The hope is that the questions posed here will help to build a framework for this critical review. PMID- 27994448 TI - Clinical and radiological outcome following pneumothorax after endoscopic lung volume reduction with valves. AB - INTRODUCTION: Valve implantation has evolved as a therapy for patients with advanced emphysema. Although it is a minimally invasive treatment, it is associated with complications, the most common being pneumothorax. Pneumothorax occurs due to the rapid target lobe volume reduction and may be a predictor of clinical benefit despite this complication. OBJECTIVE: The objective of this study was to conduct an exploratory data analysis of patients who developed a pneumothorax following endoscopic valve therapy for emphysema. MATERIALS AND METHODS: This study performed a retrospective evaluation of pneumothorax management and the impact of pneumothorax on clinical outcomes in 70 patients following valve therapy in 381 consecutive patients. RESULTS: Pneumothorax rate following valve therapy was 18%. Pneumothorax management consisted of chest tube insertion, valve removal, and surgical intervention in 87% (61/70), 44% (31/70), and 19% (13/70) of the patients, respectively. Despite pneumothorax, patients experienced modest but significant improvements in lung function parameters (forced expiratory volume in 1 second: 55+/-148 mL, residual volume: -390+/-964 mL, total lung capacity: -348+/-876; all P<0.05). Persistent lobar atelectasis 3 months after recovering from pneumothorax, which was associated with relevant clinical improvement, was observed in only 21% (15/70) of the patients. CONCLUSION: Pneumothorax is a frequent severe complication following valve therapy that requires further intervention. Nevertheless, the pneumothorax does not impair the clinical status in the majority of patients. Patients with lobar atelectasis benefit after recovering from pneumothorax in terms of lung function parameters. PMID- 27994449 TI - An evaluation of early medication use for COPD: a population-based cohort study. AB - PURPOSE: The aim of this study was to evaluate the first initiation, sequence of addition, and appropriate prescribing of COPD medications in Manitoba, Canada. PATIENTS AND METHODS: A population-based cohort study of COPD medication use was conducted using administrative health care data (1997-2012). Those aged >=35 years with COPD based on three or more COPD-related outpatient visits over a rolling 24-month window or at least one COPD-related hospitalization were included. The first medication(s) dispensed on or after the date of COPD diagnosis were determined based on pharmacy claims. The next medication(s) in sequence were determined to be additions or switches to the previous regimen. Evaluation of guideline-based appropriateness to receive inhaled corticosteroids (ICS) was based on exacerbation history and past medication use. RESULTS: Of 13,369 patients dispensed COPD medications after diagnosis, 66.0% were dispensed short-acting bronchodilators as first medications. Although long-acting bronchodilators alone were uncommonly used as first or subsequent medications, ICS were dispensed as first medications in 28.2% of patients. Over the study period, use of short-acting bronchodilators as first medications declined from 70.6% to 59.4% (P<0.0001), whereas the use of ICS as a first medication increased from 23.5% to 34.4% (P<0.0001). Dispensation of an ICS plus a long-acting beta agonist increased dramatically from 1.2% to 27.3% (P<0.0001). By the end of the study period, the majority of patients (53.3%) were being initiated on two or more medications. Of 5,823 patients dispensed an ICS, 52.4% met Canadian guideline criteria for initiating an ICS, whereas 0.3% met Global Initiative for Chronic Obstructive Lung Disease guideline criteria. CONCLUSION: The use of first line medications has declined over time, replaced primarily by combination inhalers prescribed early without prior trials of appropriate next step medications. This, along with an increasingly predominant use of multiple first medications, indicates a significant degree of medication burden in this already complex patient population. PMID- 27994450 TI - How do general practitioners implement decision-making regarding COPD patients with exacerbations? An international focus group study. AB - PURPOSE: To explore the decision-making of general practitioners (GPs) concerning treatment with antibiotics and/or oral corticosteroids and hospitalization for COPD patients with exacerbations. METHODS: Thematic analysis of seven focus groups with 53 GPs from urban and rural areas in Norway, Germany, Wales, Poland, Russia, the Netherlands, and Hong Kong. RESULTS: Four main themes were identified. 1) Dealing with medical uncertainty: the GPs aimed to make clear medical decisions and avoid unnecessary prescriptions and hospitalizations, yet this was challenged by uncertainty regarding the severity of the exacerbations and concerns about overlooking comorbidities. 2) Knowing the patient: contextual knowledge about the individual patient provided a supplementary framework to biomedical knowledge, allowing for more differentiated decision-making. 3) Balancing the patients' perspective: the GPs considered patients' experiential knowledge about their own body and illness as valuable in assisting their decision-making, yet felt that dealing with disagreements between their own and their patients' perceptions concerning the need for treatment or hospitalization could be difficult. 4) Outpatient support and collaboration: both formal and informal caregivers and organizational aspects of the health systems influenced the decision-making, particularly in terms of mitigating potentially severe consequences of "wrong decisions" and concerning the negotiation of responsibilities. CONCLUSION: Fear of overlooking severe comorbidity and of further deteriorating symptoms emerged as a main driver of GPs' management decisions. GPs consider a holistic understanding of illness and the patients' own judgment crucial to making reasonable decisions under medical uncertainty. Moreover, GPs' decisions depend on the availability and reliability of other formal and informal carers, and the health care systems' organizational and cultural code of conduct. Strengthening the collaboration between GPs, other outpatient care facilities and the patients' social network can ensure ongoing monitoring and prompt intervention if necessary and may help to improve primary care for COPD patients with exacerbations. PMID- 27994451 TI - Exercise training alone or with the addition of activity counseling improves physical activity levels in COPD: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Physical inactivity is associated with poor outcomes in COPD, and as a result, interventions to improve physical activity (PA) are a current research focus. However, many trials have been small and inconclusive. OBJECTIVE: The aim of this systematic review and meta-analysis was to study the effects of randomized controlled trials (RCTs) targeting PA in COPD. METHODS: Databases (Physiotherapy Evidence Database [PEDro], Embase, MEDLINE, CINAHL and the Cochrane Central Register for Controlled Trials) were searched using the following keywords: "COPD", "intervention" and "physical activity" from inception to May 20, 2016; published RCTs that aimed to increase PA in individuals with COPD were included. The PEDro scale was used to rate study quality. Standardized mean differences (effect sizes, ESs) with 95% confidence intervals (CIs) were determined. Effects of included interventions were also measured according to the minimal important difference (MID) in daily steps for COPD (599 daily steps). RESULTS: A total of 37 RCTs with 4,314 participants (mean forced expiratory volume in one second (FEV1) % predicted 50.5 [SD=10.4]) were identified. Interventions including exercise training (ET; n=3 studies, 103 participants) significantly increased PA levels in COPD compared to standard care (ES [95% CI]; 0.84 [0.44-1.25]). The addition of activity counseling to pulmonary rehabilitation (PR; n=4 studies, 140 participants) showed important effects on PA levels compared to PR alone (0.47 [0.02-0.92]), achieving significant increases that exceeded the MID for daily steps in COPD (mean difference [95% CI], 1,452 daily steps [549-2,356]). Reporting of methodological quality was poor in most included RCTs. CONCLUSION: Interventions that included ET and PA counseling during PR were effective strategies to improve PA in COPD. PMID- 27994452 TI - COPD assessment test score and serum C-reactive protein levels in stable COPD patients. AB - BACKGROUND: An eight-item questionnaire of the COPD assessment test (CAT) is widely used to quantify the impact of COPD on the patient's health status. C reactive protein (CRP) is associated with disease severity and adverse health outcomes of patients with COPD. This study aimed to evaluate the relationship between CAT score and serum CRP levels in stable COPD patients. METHODS: We evaluated the medical records of 226 patients with CAT and serum CRP measured within a week at Samsung Medical Center between October 2013 and October 2015. RESULTS: Serum CRP levels had a significantly positive relationship with CAT score (Spearman's r=0.20, P=0.003). Patients with elevated serum CRP levels (>0.3 mg/dL) were significantly more likely to have CAT scores of >=14. The adjusted odds ratio for elevated serum CRP levels in total CAT score was 1.06 (95% confidence interval, 1.02-1.09). Among CAT components, cough (adjusted P=0.005), phlegm (adjusted P=0.001), breathlessness going up hills/stairs (adjusted P=0.005), low confidence leaving home (adjusted P=0.002), and feeling low in energy (adjusted P=0.019) were independently associated with elevated serum CRP levels. CONCLUSION: In stable COPD patients, serum CRP levels were independently associated with total CAT score and CAT components related to respiratory symptoms, confidence leaving home, and energy. PMID- 27994453 TI - Drop in lung function during asthma and COPD exacerbations - can it be assessed without spirometry? AB - BACKGROUND: When assessing patients with exacerbation of asthma or COPD, it may be useful to know the drop in forced expiratory volume in 1 second (FEV1) compared with stable state, in particular when considering treatment with oral corticosteroids. The objective of the study was to identify indicators of drop in FEV1 during exacerbations. METHODS: In this prospective multicenter study from primary care, patients diagnosed with asthma or COPD were examined at stable state and during exacerbations the following year. Symptoms, chest findings, and pulse oximetry were recorded, and spirometry was performed. A fixed drop in FEV1 (10% and >=200 mL) and percentage change in FEV1 were outcomes when possible indicators were evaluated. RESULTS: Three hundred and eighty patients attended baseline examination, and 88 with a subsequent exacerbation were included in the analysis. Thirty (34%) had a significant drop in FEV1 (10% and 200 mL). Increased wheezing was the only symptom associated with this drop with a likelihood ratio of 6.4 (95% confidence interval, 1.9-21.7). Crackles and any new auscultation finding were also associated with a significant drop in FEV1, as was a >=2% drop in oxygen saturation (SpO2) to <=92% in the subgroup diagnosed with COPD. Very bothersome wheezing and severe decrease in SpO2 were also very strong predictors of change in FEV1 in linear regression adjusted for age, gender, and baseline FEV1% predicted. CONCLUSION: Increased wheezing, as experienced by the patient, and a decreased SpO2 value strongly indicated a drop in lung function during asthma and COPD exacerbations and should probably be taken into account when treatment with oral corticosteroids is considered. PMID- 27994454 TI - The role of the intestinal microvasculature in inflammatory bowel disease: studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro. AB - The microvascular endothelium of the gut barrier plays a crucial role during inflammation in inflammatory bowel disease. We have modified a commonly used intestinal cell model based on the Caco-2 cells by adding microvascular endothelial cells (ISO-HAS-1). Transwell filters were used with intestinal barrier-forming Caco-2 cells on top and the ISO-HAS-1 on the bottom of the filter. The goal was to determine whether this coculture mimics the in vivo situation more closely, and whether the model is suitable to evaluate interactions of, for example, prospective nanosized drug vehicles or contrast agents with this coculture in a physiological and inflamed state as it would occur in inflammatory bowel disease. We monitored the inflammatory responsiveness of the cells (release of IL-8, soluble intercellular adhesion molecule 1, and soluble E-selectin) after exposure to inflammatory stimuli (lipopolysaccharide, TNF-alpha, INF-gamma, IL1-beta) and a nanoparticle (Ba/Gd: coprecipitated BaSO4 and Gd(OH)3), generally used as contrast agents. The barrier integrity of the coculture was evaluated via the determination of transepithelial electrical resistance and the apparent permeability coefficient (Papp) of NaFITC. The behavior of the coculture Caco-1/ISO-HAS-1 was compared to the respective monocultures Caco-2 and ISO-HAS-1. Based on transepithelial electrical resistance, the epithelial barrier integrity of the coculture remained stable during incubation with all stimuli, whereas the Papp decreased after exposure to the cytokine mixture (TNF-alpha, INF-gamma, IL1-beta, and Ba/Gd). Both the endothelial and epithelial monocultures showed a high inflammatory response in both the upper and lower transwell-compartments. However, in the coculture, inflammatory mediators were only detected on the epithelial side and not on the endothelial side. Thus in the coculture, based on the Papp, the epithelial barrier appears to prevent a potential inflammatory overreaction in the underlying endothelial cells. In summary, this coculture model exhibits in vivo like features, which cannot be observed in conventional monocultures, making the former more suitable to study interactions with external stimuli. PMID- 27994455 TI - Reduced Staphylococcus aureus biofilm formation in the presence of chitosan coated iron oxide nanoparticles. AB - Staphylococcus aureus can adhere to most foreign materials and form biofilm on the surface of medical devices. Biofilm infections are difficult to resolve. The goal of this in vitro study was to explore the use of chitosan-coated nanoparticles to prevent biofilm formation. For this purpose, S. aureus was seeded in 96-well plates to incubate with chitosan-coated iron oxide nanoparticles in order to study the efficiency of biofilm formation inhibition. The biofilm bacteria count was determined using the spread plate method; biomass formation was measured using the crystal violet staining method. Confocal laser scanning microscopy and scanning electron microscopy were used to study the biofilm formation. The results showed decreased viable bacteria numbers and biomass formation when incubated with chitosan-coated iron oxide nanoparticles at all test concentrations. Confocal laser scanning microscopy showed increased dead bacteria and thinner biofilm when incubated with nanoparticles at a concentration of 500 ug/mL. Scanning electron microscopy revealed that chitosan-coated iron oxide nanoparticles inhibited biofilm formation in polystyrene plates. Future studies should be performed to study these nanoparticles for anti-infective use. PMID- 27994456 TI - Biomechanical and histological evaluation of the osseointegration capacity of two types of zirconia implant. AB - The purpose of this study was to evaluate the biomechanical and histological behavior of a ceria-stabilized zirconia-alumina nanocomposite (NanoZr) in comparison with that of 3 mol% yttria-stabilized tetragonal zirconia polycrystalline (3Y-TZP) in Sprague Dawley rats. Cylindrical NanoZr and 3Y-TZP implants (diameter 1 mm, length 2 mm) were used. Implant-surface morphology and surface roughness were determined by scanning white-light interferometry and scanning electron microscopy, respectively. The cylindrical zirconia implants were placed at the distal edge of the femur of Sprague Dawley rats. At weeks 2, 4, and 8, the interfacial shear strength between implant and bone was measured by push-in test. Histological analysis was performed using hard-tissue sections. Bone-implant contact (BIC), the thickness of new bone around the implant within the bone marrow area, and osteoclast numbers were evaluated. The average surface roughness of 3Y-TZP (Sa 0.788 MUm) was significantly higher than that of NanoZr (Sa 0.559 MUm). The shear strengths of 3Y-TZP and NanoZr were similar at 2 weeks, but at 4 and 8 weeks the shear strength of NanoZr was higher than that of 3Y-TZP. The average BIC values within the bone marrow area for 3Y-TZP and NanoZr were 25.26% and 31.51% at 2 weeks, 46.78% and 38% at 4 weeks, and 47.88% and 56.81% at 8 weeks, respectively. The average BIC values within the cortical area were 38.86% and 58.42% at 2 weeks, 66.82% and 57.74% at 4 weeks, and 79.91% and 78.97% at 8 weeks, respectively. The mean BIC value did not differ significantly between the two zirconia materials at any time point. The NanoZr implants were biocompatible, capable of establishing close BIC, and may be preferred for metal free dental implants. PMID- 27994457 TI - Nanomechanical measurement of adhesion and migration of leukemia cells with phorbol 12-myristate 13-acetate treatment. AB - The adhesion and traction behavior of leukemia cells in their microenvironment is directly linked to their migration, which is a prime issue affecting the release of cancer cells from the bone marrow and hence metastasis. In assessing the effectiveness of phorbol 12-myristate 13-acetate (PMA) treatment, the conventional batch-cell transwell-migration assay may not indicate the intrinsic effect of the treatment on migration, since the treatment may also affect other cellular behavior, such as proliferation or death. In this study, the pN-level adhesion and traction forces between single leukemia cells and their microenvironment were directly measured using optical tweezers and traction-force microscopy. The effects of PMA on K562 and THP1 leukemia cells were studied, and the results showed that PMA treatment significantly increased cell adhesion with extracellular matrix proteins, bone marrow stromal cells, and human fibroblasts. PMA treatment also significantly increased the traction of THP1 cells on bovine serum albumin proteins, although the effect on K562 cells was insignificant. Western blots showed an increased expression of E-cadherin and vimentin proteins after the leukemia cells were treated with PMA. The study suggests that PMA upregulates adhesion and thus suppresses the migration of both K562 and THP1 cells in their microenvironment. The ability of optical tweezers and traction force microscopy to measure directly pN-level cell-protein or cell-cell contact was also demonstrated. PMID- 27994458 TI - Intranasal delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nanoparticles for Parkinson's disease treatment. AB - Sustainable and safe delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate biodegradable poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG PLGA) nanoparticles (NPs), which were surface-modified with lactoferrin (Lf), for efficient intranasal delivery of rotigotine to the brain for the treatment of PD. Rotigotine NPs were prepared by nanoprecipitation, and the effect of various independent process variables on the resulting properties of NPs was investigated by a Box-Behnken experimental design. The physicochemical and pharmaceutical properties of the NPs and Lf-NPs were characterized, and the release kinetics suggested that both NPs and Lf-NPs provided continuous, slow release of rotigotine for 48 h. Neither rotigotine NPs nor Lf-NPs reduced the viability of 16HBE and SH-SY5Y cells; in contrast, free rotigotine was cytotoxic. Qualitative and quantitative cellular uptake studies demonstrated that accumulation of Lf-NPs was greater than that of NPs in 16HBE and SH-SY5Y cells. Following intranasal administration, brain delivery of rotigotine was much more effective with Lf-NPs than with NPs. The brain distribution of rotigotine was heterogeneous, with a higher concentration in the striatum, the primary region affected in PD. This strongly suggested that Lf-NPs enable the targeted delivery of rotigotine for the treatment of PD. Taken together, these results demonstrated that Lf-NPs have potential as a carrier for nose-to-brain delivery of rotigotine for the treatment of PD. PMID- 27994459 TI - The nasal delivery of nanoencapsulated statins - an approach for brain delivery. AB - PURPOSE: Along with their cholesterol-lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases. However, such effects are extremely elusive via the conventional oral administration. The purpose of the present study was to prepare and characterize the physicochemical properties and the in vivo biodistribution of simvastatin loaded lecithin/chitosan nanoparticles (SVT-LCNs) suitable for nasal administration in view of an improved delivery of the statins to the brain. MATERIALS AND METHODS: Chitosan, lecithin, and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Particle size distribution, surface charge, structure, simvastatin loading and release, and interaction with mucus of nanoparticles were determined. The nanoparticle nasal toxicity was evaluated in vitro using RPMI 2651 nasal cell lines. Finally, in vivo biodistribution was assessed by gamma scintigraphy via Tc99m labeling of the particles. RESULTS: Among the different types of nanoparticles produced, the SVT LCN_MaiLab showed the most ideal physicochemical characteristics, with small diameter (200 nm), positive surface charge (+48 mV) and high encapsulation efficiency (EE; 98%). Size distribution was further confirmed by nanoparticle tracking analysis and electron microscopy. The particles showed a relatively fast release of simvastatin in vitro (35.6%+/-4.2% in 6 hours) in simulated nasal fluid. Blank nanoparticles did not show cytotoxicity, evidencing that the formulation is safe for nasal administration, while cytotoxicity of simvastatin loaded nanoparticles (IC50) was found to be three times lower than the drug solution (9.92 vs 3.50 MUM). In rats, a significantly higher radioactivity was evidenced in the brain after nasal delivery of simvastatin-loaded nanoparticles in comparison to the administration of a similar dose of simvastatin suspension. CONCLUSION: The SVT-LCNs developed presented some of the most desirable characteristics for mucosal delivery, that is, small particle size, positive surface charge, long-term stability, high EE, and mucoadhesion. In addition, they displayed two exciting features: First was their biodegradability by enzymes present in the mucus layer, such as lysozyme. This indicates a new Trojan-horse strategy which may enhance drug release in the proximity of the nasal mucosa. Second was their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma scintigraphy studies. PMID- 27994460 TI - Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery. AB - Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with the challenge being to deliver it in a sustained manner. The combination of mesoporous silica nanoparticles (MSNs) and polycations in the confined pore space allows for incorporation and controlled release of therapeutic siRNA payloads. We hereby constructed MSNs with expanded mesopores and pore-surface-hyperbranched poly(ethyleneimine) (PEI) tethered with redox-cleavable linkers that could carry a high payload of siRNA (120 mg.g-1). The developed nanocarriers were efficiently taken up by cancer cells and were subsequently able to escape to the cytoplasm from the endosomes, most likely owing to the integrated PEI. Triggered by the intracellular redox conditions, the siRNA was sustainably released inside the cells over a period of several days. Functionality of siRNAs was demonstrated by using cell-killing siRNA as cargo. Despite not being the aim of the developed system, in vitro experiments using cell-killing siRNAs showed that the efficacy of siRNA transfection was comparable to the commercial in vitro transfection agent Lipofectamine. Consequently, the developed MSN-based delivery system offers a potential approach to hybrid nanocarriers for more efficient and long-term siRNA delivery and, in a longer perspective, in vivo gene silencing for RNA interference (RNAi) therapy. PMID- 27994461 TI - Biofabrication of a novel biomolecule-assisted reduced graphene oxide: an excellent biocompatible nanomaterial. AB - Graphene has been shown much interest, both in academics and industry due to its extraordinary physical, chemical, and biological proprieties. It shows great promises in biotechnological and biomedical applications as an antibacterial and anticancer agent, nanocarrier, sensor, etc. However, many studies demonstrated the toxicity of graphene in several cell lines, which is an obstacle to its use in biomedical applications. In this study, to improve the biocompatibility of graphene, we used nicotinamide (NAM) as a reducing and stabilizing agent to catalyze the reduction of graphene oxide (GO) to reduced graphene oxide (rGO). The resulted smaller-sized GO (NAM-rGO) showed excellent biocompatibility with mouse embryonic fibroblast cells, evidenced by various cellular assays. Furthermore, NAM-rGO had no effect on mitochondrial membrane permeability and caspase-3 activity compared to GO. Reverse transcription polymerase chain reaction analysis allowed us to identify the molecular mechanisms responsible for NAM-rGO-induced biocompatibility. NAM-rGO significantly induced the expression of genes encoding tight junction proteins (TJPs) such as zona occludens-1 (Tjp1) and claudins (Cldn3) without any effect on the expression of cytoskeleton proteins. Furthermore, NAM-rGO enhances the expression of alkaline phosphatase (ALP) gene, and it does this in a time-dependent manner. Overall, our study depicted the molecular mechanisms underlying NAM-rGO biocompatibility depending on upregulation of TJPs and ALP. This potential quality of graphene could be used in diverse applications including tissue regeneration and tissue engineering. PMID- 27994462 TI - Novel guanidinylated bioresponsive poly(amidoamine)s designed for short hairpin RNA delivery. AB - Two different disulfide (SS)-containing poly(amidoamine) (PAA) polymers were constructed using guanidino (Gua)-containing monomers (ie, arginine [Arg] and agmatine [Agm]) and N,N'-cystamine bisacrylamide (CBA) by Michael-addition polymerization. In order to characterize these two Gua-SS-PAA polymers and investigate their potentials as short hairpin RNA (shRNA)-delivery carriers, pSilencer 4.1-CMV FANCF shRNA was chosen as a model plasmid DNA to form complexes with these two polymers. The Gua-SS-PAAs and plasmid DNA complexes were determined with particle sizes less than 90 nm and positive zeta-potentials under 20 mV at nucleic acid:polymer weight ratios lower than 1:24. Bioresponsive release of plasmid DNA was observed from both newly constructed complexes. Significantly lower cytotoxicity was observed for both polymer complexes compared with polyethylenimine and Lipofectamine 2000, two widely used transfection reagents as reference carriers. Arg-CBA showed higher transfection efficiency and gene-silencing efficiency in MCF7 cells than Agm-CBA and the reference carriers. In addition, the cellular uptake of Arg-CBA in MCF7 cells was found to be higher and faster than Agm-CBA and the reference carriers. Similarly, plasmid DNA transport into the nucleus mediated by Arg-CBA was more than that by Agm-CBA and the reference carriers. The study suggested that guanidine and carboxyl introduced into Gua-SS-PAAs polymers resulted in a better nuclear localization effect, which played a key role in the observed enhancement of transfection efficiency and low cytotoxicity. Overall, two newly synthesized Gua-SS-PAAs polymers demonstrated great potential to be used as shRNA carriers for gene therapy applications. PMID- 27994463 TI - A novel double-targeted nondrug delivery system for targeting cancer stem cells. AB - Instead of killing cancer stem cells (CSCs), the conventional chemotherapy used for cancer treatment promotes the enrichment of CSCs, which are responsible for tumor growth, metastasis, and recurrence. However, most therapeutic agents are only able to kill a small proportion of CSCs by targeting one or two cell surface markers or dysregulated CSC pathways, which are usually shared with normal stem cells (NSCs). In this study, we developed a novel nondrug delivery system for the dual targeting of CSCs by conjugating hyaluronic acid (HA) and grafting the doublecortin-like kinase 1 (DCLK1) monoclonal antibody to the surface of poly(ethylene glycol) (PEG)-poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs), which can specifically target CD44 receptors and the DCLK1 surface marker the latter was shown to possess the capacity to distinguish between CSCSs and NSCs. The size and morphology of these NPs were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). This was followed by studies of NP encapsulation efficiency and in vitro drug release properties. Then, the cytotoxicity of the NPs was tested via Cell Counting Kit-8 assay. Finally, the 4T1 CSCs were obtained from the alginate-based platform, which we developed as an in vitro tumor model. Tumor bearing nude mice were used as in vivo models to systematically detect the ability of NPs to target CSCs. Our results showed that the DCLK1-HA-PEG-PLGA NPs exhibited a targeting effect toward CSCs both in vitro and in vivo. These findings have important implications for the rational design of drug delivery systems that target CSCs with high efficacy. PMID- 27994464 TI - Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis. AB - Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs), which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF 1alpha protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis. PMID- 27994466 TI - A randomized controlled trial of a mindfulness-based intervention program for people with schizophrenia: 6-month follow-up. AB - Mindfulness-based interventions have been increasingly evidenced to be effective in different mental illnesses but limited in schizophrenia. This single-blind, multisite randomized controlled trial tested the effects of a mindfulness-based psychoeducation group program (MPGP in addition to usual care) versus a conventional psychoeducation group program (CPGP) versus treatment-as-usual (TAU) alone, in schizophrenia spectrum disorders over a 6-month follow-up. In each of the two study sites (outpatient clinics), 69 outpatients with schizophrenia or its subtypes (N=138) were randomly allocated to one of the three study groups (n=46) after baseline measurements and underwent 6 months of intervention. Primary outcomes including patients' mental state and rehospitalization rate and other secondary outcomes were assessed at entry and at 1 week and 6 months. One hundred and thirty-one (95%) participants completed the interventions assigned and one to two post-tests. Multivariate analyses of variance (followed by univariate contrast tests) indicated that the MPGP participants reported greater reductions in their psychotic symptoms (P=0.003) and length/duration of rehospitalizations (P=0.005) at 6-month follow-up. Patients in the MPGP group also reported greater improvements in their insight into illness/treatment (P=0.0008) and level of functioning (P=0.002) than the CPGP and TAU alone at the 1-week and 6-month follow-up. Overall, the findings suggest that MPGP can be useful in improving the short- to medium-term clinical outcomes of outpatients with schizophrenia spectrum disorders, not only in terms of their mental state and risk of relapse but also their insight into illness/treatment and psychosocial functioning. PMID- 27994465 TI - Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis. AB - Hepatocarcinoma is the third leading cause of cancer-related deaths around the world. Recently, a novel emerging nanosystem as anticancer therapeutic agents with intrinsic therapeutic properties has been widely used in various medical applications. In this study, surface decoration of functionalized silver nanoparticles (AgNPs) by polyethylenimine (PEI) and paclitaxel (PTX) was synthesized. The purpose of this study was to evaluate the effect of Ag@ PEI@PTX on cytotoxic and anticancer mechanism on HepG2 cells. The transmission electron microscope image and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that Ag@PEI@PTX had satisfactory size distribution and high stability and selectivity between cancer and normal cells. Ag@PEI@PTX-induced HepG2 cell apoptosis was confirmed by accumulation of the sub-G1 cells population, translocation of phosphatidylserine, depletion of mitochondrial membrane potential, DNA fragmentation, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. Furthermore, Ag@PEI@PTX enhanced cytotoxic effects on HepG2 cells and triggered intracellular reactive oxygen species; the signaling pathways of AKT, p53, and MAPK were activated to advance cell apoptosis. In conclusion, the results reveal that Ag@ PEI@PTX may provide useful information on Ag@PEI@PTX induced HepG2 cell apoptosis and as appropriate candidate for chemotherapy of cancer. PMID- 27994467 TI - Diminished autonomic neurocardiac function in patients with generalized anxiety disorder. AB - BACKGROUND: Generalized anxiety disorder (GAD) is a chronic and highly prevalent disorder that is characterized by a number of autonomic nervous system symptoms. The purpose of this study was to investigate the linear and nonlinear complexity measures of heart rate variability (HRV), measuring autonomic regulation, and to evaluate the relationship between HRV parameters and the severity of anxiety, in medication-free patients with GAD. METHODS: Assessments of linear and nonlinear complexity measures of HRV were performed in 42 medication-free patients with GAD and 50 healthy control subjects. In addition, the severity of anxiety symptoms was assessed using the State-Trait Anxiety Inventory and Beck Anxiety Inventory. The values of the HRV measures of the groups were compared, and the correlations between the HRV measures and the severity of anxiety symptoms were assessed. RESULTS: The GAD group showed significantly lower standard deviation of RR intervals and the square root of the mean squared differences of successive normal sinus intervals values compared to the control group (P<0.01). The approximate entropy value, which is a nonlinear complexity indicator, was also significantly lower in the patient group than in the control group (P<0.01). In correlation analysis, there were no significant correlations between HRV parameters and the severity of anxiety symptoms. CONCLUSION: The present study indicates that GAD is significantly associated with reduced HRV, suggesting that autonomic neurocardiac integrity is substantially impaired in patients with GAD. Future prospective studies are required to investigate the effects of pharmacological or non-pharmacological treatment on neuroautonomic modulation in patients with GAD. PMID- 27994468 TI - Relationship between suicide rate and economic growth and stock market in the People's Republic of China: 2004-2013. AB - OBJECTIVES: The objective of this study was to estimate the features of suicide rate and its association with economic development and stock market during the past decade in the People's Republic of China. METHODS: Official data were gathered and analyzed in the People's Republic of China during the period 2004 2013. Nationwide suicide rate was stratified by four year age-groups, sex, urban/rural areas, and regions (East, Central, and West). Annual economic indexes including gross domestic product (GDP) per capita and rural and urban income per capita were all adjusted for inflation. Variation coefficient of market index (VCMI) was also included as an economic index to measure the fluctuation of the stock market. Negative binomial regression was performed to examine the time trend of region-level suicide rates and effects of sex, age, urban/rural area, region, and economic index on the suicide rates. RESULTS: Suicide rates of each age-group, sex, urban/rural area, and region were generally decreased from 2004 to 2013, while annual GDP per capita and rural and urban income per capita were generally increased by year. VCMI fluctuated largely, which peaked around 2009 and decreased after that time. Negative binomial regression showed that the decreased suicide rate in East and Central rural areas was the main cause of the decrease in suicide rate in the People's Republic of China. Suicide rate in the People's Republic of China for the study period increased with age and was higher in rural than in urban area, higher in males than in females, and the highest in the Central region. When GDP per capita increased by 2,787 RMB, the suicide rate decreased by 0.498 times. VCMI showed no significant relationship with suicide rate in the negative binomial regression. CONCLUSION: Suicide rate decreased in 2004-2013; varied among different age-groups, sex, urban/rural areas, and regions; and was negatively associated with the economic growth in the People's Republic of China. Stock market showed no relationship with suicide rate, but this finding needs to be verified in a future study. PMID- 27994469 TI - Association between proto-oncogene mutations and clinicopathologic characteristics and overall survival in colorectal cancer in East Azerbaijan, Iran. AB - BACKGROUND: Colorectal cancer (CRC) is the third-most common cancer in Iran. The increasing incidence of CRC in the past three decades has made it a major public health burden in the country. This study aimed to determine any relationship of specific mutations in CRCs with clinicopathologic aspects and outcome of patients. MATERIALS AND METHODS: This study was conducted on 100 CRC patients by the case-only method. Polymerase chain-reaction products were analyzed by Sanger sequencing, and sequence results were compared with the significant KRAS and BRAF gene mutations in the My Cancer Genome database. Logistic regression models were used to detect associations of clinicopathologic characteristics with each of the mutations. Kaplan-Meier and Cox regression models were constructed to estimate overall survival in patients. RESULTS: A total of 26 subjects (26%) had heterozygote-mutant KRAS, and mutations were not detected in the amplified exon of BRAF in both tumor and normal tissues of the 100 CRCs. Rectal tumors had 1.53 fold higher likelihood of KRAS mutations than colon tumors, and men had 1.37-fold higher odds than women. The presence of metastasis increased the likelihood of KRAS mutations 2.36-fold over those with nonmetastatic CRCs. Compared to patients with KRAS wild-type cancers, those with KRAS mutations had significantly higher mortality (hazard ratio 3.74, 95% confidence interval 1.44-9.68; log-rank P=0.003). CONCLUSION: Better understanding of the causality of CRC can be established by combining epidemiology and research on molecular mechanisms of the disease. PMID- 27994470 TI - Identification of feature genes for smoking-related lung adenocarcinoma based on gene expression profile data. AB - This study aimed to identify the genes and pathways associated with smoking related lung adenocarcinoma. Three lung adenocarcinoma associated datasets (GSE43458, GSE10072, and GSE50081), the subjects of which included smokers and nonsmokers, were downloaded to screen the differentially expressed feature genes between smokers and nonsmokers. Based on the identified feature genes, we constructed the protein-protein interaction (PPI) network and optimized feature genes using closeness centrality (CC) algorithm. Then, the support vector machine (SVM) classification model was constructed based on the feature genes with higher CC values. Finally, pathway enrichment analysis of the feature genes was performed. A total of 213 down-regulated and 83 up-regulated differentially expressed genes were identified. In the constructed PPI network, the top ten nodes with higher degrees and CC values included ANK3, EPHA4, FGFR2, etc. The SVM classifier was constructed with 27 feature genes, which could accurately identify smokers and nonsmokers. Pathways enrichment analysis for the 27 feature genes revealed that they were significantly enriched in five pathways, including proteoglycans in cancer (EGFR, SDC4, SDC2, etc.), and Ras signaling pathway (FGFR2, PLA2G1B, EGFR, etc.). The 27 feature genes, such as EPHA4, FGFR2, and EGFR for SVM classifier construction and cancer-related pathways of Ras signaling pathway and proteoglycans in cancer may play key roles in the progression and development of smoking-related lung adenocarcinoma. PMID- 27994471 TI - Association between CHFR gene hypermethylation and gastric cancer risk: a meta analysis. AB - BACKGROUND: The association between the hypermethylation of CHFR gene and gastric cancer risk has been investigated by a number of studies. However, the sample size of the majority of these studies was very small. To get a more a convincing conclusion, here we performed a meta-analysis of the previously published studies to assess the association between CHFR methylation and the risk of gastric cancer. METHODS: Eligible studies were identified by searching the MEDLINE/PubMed, Embase, and Web of Science databases before May 2016 without any language restriction. The strength of the association was estimated by odds ratio with its 95% confidence interval (CI). RESULTS: Totally 1,399 samples, including 758 gastric cancer cases and 641 controls, from 13 studies were included in the present meta-analysis. Compared with non-cancer controls, the pooled OR of CHFR methylation in gastric cancer patients was 9.08 (95% CI: 6.40-12.88, P<0.001), suggesting that the methylation of CHFR was significantly associated with increased risk of gastric cancer. Similar results were observed when subgroup analyses were performed stratified by country, ethnicity, and methylation testing methods. CONCLUSION: Our meta-analysis showed a strong positive correlation between CHFR methylation and risk of gastric cancer, suggesting that CHFR methylation might be a promising biomarker for the diagnosis of gastric cancer. PMID- 27994472 TI - Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population. AB - Colorectal cancers (CRCs) exhibiting microsatellite instability (MSI) have special biological behavior. The clinical predictors for MSI and its survival relevance for the Chinese population were still unclear. Seven hundred ninety five CRC patients were retrospectively assessed. Mismatch repair (MMR) proteins (MSH2, MSH6, PMS1, and MLH1) expression was detected by immunohistochemistry using tumor tissues of all patients. DNA MSI status was analyzed by polymerase chain reaction in 182 samples randomly selected from the 795 cases. Among all CRC tumor tissues, 97 cases (12.2%) were with an MMR protein-deficient (MMR-D) phenotype, whereas 698 cases (87.8%) were with an MMR proteins intact (MMR-I) phenotype. A total of 21 (11.5%) CRCs were identified as having high microsatellite instability, 156 (85.7%) tumors were having microsatellite stability (MSS), and five (2.7%) were having low microsatellite instability. Importantly, MMR status was demonstrated to be moderately consistent with MSI status (kappa=0.845, 95% confidence interval [CI] 0.721, 0.969). Unconditional logistic regression analysis revealed age, number of lymph node, tumor diameter, and tumor site as predictors for MSI with a substantial ability to discriminate different MSI status by area under curve of 80.62% using receiver operation curve. Compared with MMR-I, MMR-D was an independent prognostic factor for longer overall survival (hazard ratio =0.340, 95% CI 0.126, 0.919; P=0.034). MMR-D is an independent prognostic factor for better outcome. Our results may provide evidence for individualized diagnosis and treatment of CRC, but this will require further validation in larger sample studies. PMID- 27994473 TI - Prognostic value of p53 mutation for poor outcome of Asian primary liver cancer patients: evidence from a cohort study and meta-analysis of 988 patients. AB - Several previous studies have investigated the association between gene p53 (p53) mutation and the poor outcome of primary liver cancer (PLC) patients; however, the results remain inconsistent. In the present study, p53 mutation in 60 paired tumor and corresponding nontumor tissues derived from a cohort of 60 PLC patients was systematically analyzed. The results showed that p53 mutation was only an independent risk factor for overall survival (OS), not for recurrence-free survival (RFS), and a meta-analysis was performed to verify this. Online databases were searched up to July 1, 2016. Studies about the association between p53 mutation and the postsurgery survival of PLC patients were collected. A total of 988 patients from eight studies were analyzed; among them, 341 (34.51%) patients had p53 mutation. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were 2.03 (1.64, 2.41) and 2.36 (1.31, 3.42) for OS and RFS, respectively. In conclusion, both the cohort study and meta-analysis suggested that the p53 mutation was associated with postsurgery OS in Asian PLC patients. However, the relationship between p53 mutation and recurrence should be confirmed by further studies. PMID- 27994474 TI - Probiotics improve the efficacy of standard triple therapy in the eradication of Helicobacter pylori: a meta-analysis. AB - INTRODUCTION: Helicobacter pylori colonization is present in half of the world's population and can lead to numerous gastrointestinal diseases if left untreated, including peptic ulcer disease and gastric cancer. Although concurrent triple therapy remains the recommended treatment regimen for H. pylori eradication, its success rate and efficacy have been declining. Recent studies have shown that the addition of probiotics can significantly increase eradication rates by up to 50%. This meta-analysis examines the impact of probiotic supplementation on the efficacy of standard triple therapy in eradicating H. pylori. METHODS: A comprehensive literature search was conducted using PubMed, Cochrane Central Registry of Controlled Trials, and Google Scholar (time of inception to 2016) to identify all published randomized control trials (RCTs) assessing the use of probiotics in addition to triple therapy for the treatment of H. pylori. Searches were conducted using the keywords "probiotics", "triple therapy", and "Helicobacter pylori". RCTs comparing the use of probiotics and standard triple therapy with standard triple therapy alone for any duration in patients of any age diagnosed with H. pylori infection were included. H. pylori eradication rates (detected using urea breath test or stool antigen) were analyzed as-per-protocol (APP) and intention-to-treat (ITT). RESULTS: A total of 30 RCTs involving 4,302 patients APP and 4,515 patients ITT were analyzed. The addition of probiotics significantly increased eradication rates by 12.2% (relative risk [RR] =1.122; 95% confidence interval [CI], 1.091-1.153; P<0.001) APP and 14.1% (RR =1.141; 95% CI, 1.106-1.175; P<0.001) ITT. Probiotics were beneficial among children and adults, as well as Asians and non-Asians. No significant difference was observed in efficacy between the various types of probiotics. The risk of diarrhea, nausea, vomiting, and epigastric pain was also reduced. CONCLUSION: The addition of probiotics is associated with improved H. pylori eradication rates in both children and adults, as well as Asians and non-Asians. Lactobacillus, Bifidobacterium, Saccharomyces, and mixtures of probiotics appear beneficial in H. pylori eradication. Furthermore, the reduction in antibiotic-associated side effects such as nausea, vomiting, diarrhea, and epigastric pain improves medication tolerance and patient compliance. Given the consequences associated with chronic H. pylori infection, the addition of probiotics to the concurrent triple therapy regimen should be considered in all patients with H. pylori infection. However, further studies are required to identify the optimal probiotic species and dose. PMID- 27994476 TI - A novel combination approach of human polyclonal IVIG and antibiotics against multidrug-resistant Gram-positive bacteria. AB - BACKGROUND: Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA) and enterococci, have shown a remarkable ability to develop resistance to antimicrobial agents. OBJECTIVE: We aimed to assess possible enhancement of the antimicrobial activity of vancomycin, amoxicillin, clarithromycin, and azithromycin by human polyclonal intravenous immunoglobulin G (IVIG) against 34 multidrug-resistant (MDR) bacterial isolates, including MRSA, Enterococcus faecium, and Enterococcus faecalis. MATERIALS AND METHODS: Double combinations of the antibiotics with the IVIG were assessed by checkerboard assay, where the interaction was evaluated with respect to the minimum inhibitory concentration (MIC) of the antibiotics. The results of the checkerboard assay were verified in vitro using time-kill assay and in vivo using an invasive sepsis murine model. RESULTS: The checkerboard assay showed that IVIG enhanced the antimicrobial activity of amoxicillin and clarithromycin against isolates from the three groups of bacteria, which were resistant to the same antibiotics when tested in the absence of IVIG. The efficacy of vancomycin against 15% of the tested isolates was enhanced when it was combined with the antibodies. Antagonism was demonstrated in 47% of the E. faecalis isolates when clarithromycin was combined with the IVIG. Synergism was proved in the time-kill assay when amoxicillin was combined with the antibodies; meanwhile, antagonism was not demonstrated in all tested combinations, even in combinations that showed such response in checkerboard assay. CONCLUSION: The suggested approach is promising and could be helpful to enhance the antimicrobial activity of not only effective antibiotics but also antibiotics that have been proven to be ineffective against MDR bacteria. To our knowledge, this combinatorial approach against MDR bacteria, such as MRSA and enterococci, has not been investigated before. PMID- 27994475 TI - Isavuconazole for the treatment of invasive aspergillosis and mucormycosis: current evidence, safety, efficacy, and clinical recommendations. AB - The majority of invasive mold infections diagnosed in immunocompromised cancer patients include invasive aspergillosis (IA) and mucormycosis. Despite timely and effective therapy, mortality remains considerable. Antifungal agents currently available for the management of these serious infections include triazoles, polyenes, and echinocandins. Until recently, posaconazole has been the only triazole with a broad spectrum of anti-mold activity against both Aspergillus sp. and mucorales. Other clinically available triazoles voriconazole and itraconazole, with poor activity against mucorales, have significant drug interactions in addition to a side effect profile inherent for all triazoles. Polyenes including lipid formulations pose a problem with infusion-related side effects, electrolyte imbalance, and nephrotoxicity. Echinocandins are ineffective against mucorales and are approved as salvage therapy for refractory IA. Given that all available antifungal agents have limitations, there has been an unmet need for a broad-spectrum anti-mold agent with a favorable profile. Following phase III clinical trials that started in 2006, isavuconazole (ISZ) seems to fit this profile. It is the first novel triazole agent recently approved by the United States Food and Drug Administration (FDA) for the treatment of both IA and mucormycosis. This review provides a brief overview of the salient features of ISZ, its favorable profile with regard to spectrum of antifungal activity, pharmacokinetic and pharmacodynamic parameters, drug interactions and tolerability, clinical efficacy, and side effects. PMID- 27994478 TI - Dialysis-related amyloidosis: challenges and solutions. AB - Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low-molecular-weight subunits of a variety of proteins. These deposits may result in a wide range of clinical manifestations depending upon their type, location, and the amount of deposition. Dialysis-related amyloidosis is a serious complication of long-term dialysis therapy and is characterized by the deposition of amyloid fibrils, principally composed of beta2 microglobulins (beta2M), in the osteoarticular structures and viscera. Most of the beta2M is eliminated through glomerular filtration and subsequent reabsorption and catabolism by the proximal tubules. As a consequence, the serum levels of beta2M are inversely related to the glomerular filtration rate; therefore, in end-stage renal disease patients, beta2M levels increase up to 60-fold. Serum levels of beta2M are also elevated in several pathological conditions such as chronic inflammation, liver disease, and above all, in renal dysfunction. Retention of amyloidogenic protein has been attributed to several factors including type of dialysis membrane, prolonged uremic state and/or decreased diuresis, advanced glycation end products, elevated levels of cytokines and dialysate. Dialysis treatment per se has been considered to be an inflammatory stimulus, inducing cytokine production (such as interleukin 1, tumor necrosis factor-alpha, interleukin-6) and complement activation. The released cytokines are thought to stimulate the synthesis and release of beta2M by the macrophages and/or augment the expression of human leukocyte antigens (class I), increasing beta2M expression. Residual renal function is probably the best determinant of beta2M levels. Therefore, it has to be maintained as long as possible. In this article, we will focus our attention on the etiology of dialysis-related amyloidosis, its prevention, therapy, and future solutions. PMID- 27994477 TI - Acarbose promotes remission of both early and late dumping syndromes in post bariatric patients. AB - OBJECTIVE: Acarbose is a glucosidase inhibitor that slows carbohydrate digestion. It could thus be effective to promote remission of dumping syndrome (DS). Previous studies associating acarbose and late dumping, although not early dumping, have been reported. Herein, we aimed to evaluate the role of acarbose in dumping syndrome prevention and treatment and in resistive exercises resistance in bariatric subjects. METHODS: Bariatric patients with DS and complete adherence to diet plan and resistive exercises were included (n=25). Number of early and late episodes, self-referred intensity of each episode, and ability to increase intensity of resistive exercise were evaluated, on a 0-10 scale. Acarbose was administered orally (50 mg) for 6 months, 4-5 times a day before meals. RESULTS: Acarbose administration was associated with a decrease in the number of early (2.18-0.31) and late (2.79-0.12) episodes per week and intensity of each episode (6.10-1.65) and an increase in the ability to perform resistive exercises (3.03 7.12). Complete remission of DS was seen in 21 patients (84%), which persisted for 6 months with the use of acarbose. CONCLUSION: Acarbose prevented dumping in almost all studied subjects and helped improve exercise capacity. PMID- 27994479 TI - Transsacrococcygeal approach to ganglion impar: radiofrequency application for the treatment of chronic intractable coccydynia. AB - OBJECTIVE: Coccydynia is defined as pain in the coccygeal region. Among the many causes of coccydynia, the most common cause is trauma as a result of falling on the buttocks, repetitive microtrauma, or childbirth. Several methods are currently used for the treatment of coccydynia, including nonsteroidal anti inflammatory drugs, intrarectal manipulation, epidural injections, ganglion impar blocks, and radiofrequency treatment (RFT). Wemm and Saberski used the transacrococcygeal methods to reduce tissue trauma. RFT is a percutaneous minimally invasive procedure. In this study, we aimed to assess the effect of the transsacrococcygeal approach on ganglion impar RFT in patients with chronic coccydynia. METHODS: We retrospectively examined the data of 41 patients at the Department of Anesthesiology and Reanimation, Faculty of Medicine, Maltepe University (Pain Clinic), between January 1, 2010, and December 31, 2012. RESULTS: The mean age of the patients was 46.68+/-11.00 years (range 28-67 [46] years). The average pain duration was 3.10+/-1.37 years. The difference between visual analog scale scores of the pre-and postprocedure was statistically significant. In the examinations carried out in the sixth month of the treatment, 90.2% of patients had a successful outcome, whereas treatment failed in 9.8% of patients. According to our patients' data, most of them had pain due to a trauma, were female, and overweight. Visual analog scale difference between preprocedure and early postprocedure, preprocedure and first month, preprocedure and sixth month were statistically significant (P=0.001). CONCLUSION: Based on the lower pain scores and low complication rates after the operations, the results suggest that application of RFT on ganglion impar by the transsacrococcygeal approach is an effective and safe method for the treatment of chronic coccydynia. Patient selection, technique, and experience are the most important factors affecting the success of this method. PMID- 27994481 TI - Pharmacotherapeutic considerations for chronic pain in chronic kidney and end stage renal disease. PMID- 27994482 TI - Dysesthesia symptoms produced by sensorimotor incongruence in healthy volunteers: an electroencephalogram study. AB - OBJECTIVES: Pathological pain such as phantom limb pain is caused by sensorimotor incongruence. Several studies with healthy participants have clearly indicated that dysesthesia, which is similar to pathological pain, is caused by incongruence between proprioception and/or motor intention and visual feedback. It is not clear to what extent dysesthesia may be caused by incongruence between motor intention and visual feedback or by incongruence between proprioception and visual feedback. The aim of this study was to clarify the neurophysiology of these factors by analyzing electroencephalograms (EEGs). METHODS: In total, 18 healthy participants were recruited for this study. Participants were asked to perform repetitive flexion/extension exercises with their elbows in a congruent/incongruent position while viewing the activity in a mirror. EEGs were performed to determine cortical activation during sensorimotor congruence and incongruence. RESULTS: In the high-frequency alpha band (10-12 Hz), numeric rating scale scores of a feeling of peculiarity were significantly correlated with event-related desynchronization/synchronization under the incongruence and proprioception conditions associated with motor intention and visual feedback (right inferior parietal region; r=-0.63, P<0.01) and between proprioception and visual feedback (right temporoparietal region; r=-0.49 and r=-0.50, P<0.05). In these brain regions, there was a region in which incongruence between proprioception and visual feedback and between motor intention and visual feedback caused an increase in activity. CONCLUSION: The present findings suggest that neural mechanisms of dysesthesia are caused by incongruence between proprioception associated with motor intention and visual feedback and, in particular, are a result of incongruence between proprioception only and visual feedback. PMID- 27994480 TI - Combining pain therapy with lifestyle: the role of personalized nutrition and nutritional supplements according to the SIMPAR Feed Your Destiny approach. AB - Recently, attention to the lifestyle of patients has been rapidly increasing in the field of pain therapy, particularly with regard to the role of nutrition in pain development and its management. In this review, we summarize the latest findings on the role of nutrition and nutraceuticals, microbiome, obesity, soy, omega-3 fatty acids, and curcumin supplementation as key elements in modulating the efficacy of analgesic treatments, including opioids. These main topics were addressed during the first edition of the Study In Multidisciplinary Pain Research workshop: "FYD (Feed Your Destiny): Fighting Pain", held on April 7, 2016, in Rome, Italy, which was sponsored by a grant from the Italian Ministry of Instruction on "Nutraceuticals and Innovative Pharmacology". The take-home message of this workshop was the recognition that patients with chronic pain should undergo nutritional assessment and counseling, which should be initiated at the onset of treatment. Some foods and supplements used in personalized treatment will likely improve clinical outcomes of analgesic therapy and result in considerable improvement of patient compliance and quality of life. From our current perspective, the potential benefit of including nutrition in personalizing pain medicine is formidable and highly promising. PMID- 27994484 TI - Role of natural herbs and phytochemicals to minimize tumor and economic burden in breast cancer treatment. PMID- 27994483 TI - Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study. AB - Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received >=2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naive patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5 months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in >=5% of patients) in patients who received prior trastuzumab versus trastuzumab naive patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14.3% vs 25.8%), febrile neutropenia (14.3% vs 3.2%), fatigue (9.5% vs 6.5%), nausea (9.5% vs 0%), vomiting (9.5% vs 3.2%), and leukopenia (9.5% vs 3.2%). In patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, first-line eribulin/trastuzumab treatment demonstrated substantial antitumor activity and was well tolerated, regardless of prior neo/adjuvant trastuzumab treatment. PMID- 27994485 TI - Pattern of chemotherapy-related adverse effects among adult cancer patients treated at Gondar University Referral Hospital, Ethiopia: a cross-sectional study. AB - BACKGROUND: Adverse drug reactions (ADRs) are a global problem and constitute a major clinical problem in terms of human suffering. The high toxicity and narrow therapeutic index of chemotherapeutic agents makes oncology pharmacovigilance essential. The objective of the present study was to assess the pattern of ADRs occurring in cancer patients treated with chemotherapy in a tertiary care teaching hospital in Ethiopia. METHODS: A cross-sectional study over a 2-year period from September 2013 to August 2015 was conducted on cancer patients undergoing chemotherapy at Gondar University Referral Hospital Oncology Center. Data were collected directly from patients and their medical case files. The reported ADRs were assessed for causality using the World Health Organization's causality assessment scale and Naranjo's algorithm. The severities of the reported reactions were also assessed using National Cancer Institute Common Terminology CTCAE version 4.0. The Pear-son's chi-square test was employed to examine the association between two categorical variables. RESULTS: A total of 815 ADRs were identified per 203 patients included in the study. The most commonly occurring ADRs were nausea and vomiting (18.9%), infections (16.7%), neutropenia (14.7%), fever and/or chills (11.3%), and anemia (9.3%). Platinum compounds (31.4%) were the most common group of drugs causing ADRs. Of the reported ADRs, 65.8% were grades 3-4 (severe level), 29.9% were grades 1-2 (mild level), and 4.3% were grade 5 (toxic level). Significant association was found between age, number of chemotherapeutic agents, as well as dose of chemotherapy with the occurrence of grades 3-5 toxicity. CONCLUSION: The high incidence of chemotherapy-related ADRs among cancer patients is of concern. Setting up an effective ADR monitoring and reporting system (onco-pharmacovigilance) and creating awareness among health care professionals regarding the importance of ADR reporting may help prevent the problem. PMID- 27994486 TI - A cost-effectiveness evaluation comparing originator follitropin alfa to the biosimilar for the treatment of infertility. AB - OBJECTIVES: To perform a cost-effectiveness evaluation comparing the originator follitropin alfa (Gonal-f(r)) to the biosimilar (Bemfola(r)) in the Italian and Spanish contexts, with an assessment of the German and UK backgrounds. METHODS: Starting from the study by Rettenbacher et al, a cost-effectiveness model was developed in the Italian and Spanish contexts. Clinical data on subjects, doses of gonadotropin, pregnancies, live-born children, and ovarian hyperstimulation syndrome were used to feed the model. Costs related to drugs, hospitalizations, specialist visits, and examinations were retrieved from Italian and Spanish tariffs. Gonadotropin acquisition costs for Germany and the UK were also taken into account to expand the economical assessment to the other countries. The evaluation was done based on the National Health Service perspective. Sensitivity analyses, both univariate and probabilistic, as long as scenario analyses, tested the robustness of the model. RESULTS: Originator follicle-stimulating hormone (FSH) costs were ?3,663 and ?6,387 in Italy and Spain, respectively, whereas biosimilar FSH costs were ?3,483 and ?6,342. The efficacy was found to be 0.52 for the originator and 0.47 for the biosimilar. The average cost per live birth was estimated to be ?7,044 and ?12,283 for the originator FSH and ?7,411 and ?13,494 for the biosimilar for Italy and Spain, respectively. Furthermore, the originator FSH generated an incremental cost-effectiveness ratio of ?3,600 for Italy and ?900 for Spain compared to the biosimilar. Sensitivity analyses confirmed the results of the base case model. CONCLUSION: This analysis indicated that the originator FSH is a cost-efficient treatment strategy for Italian and Spanish health services compared to the biosimilar and it would be worthwhile extending this evaluation to other countries. PMID- 27994487 TI - The experiences of prepregnancy care for women with type 2 diabetes mellitus: a meta-synthesis. AB - BACKGROUND: Diabetes is one of the most common medical conditions affecting pregnancy and is associated with a number of adverse fetal, infant, and maternal outcomes. These adverse outcomes can be avoided or minimized with appropriate prepregnancy care (PPC). However, the uptake of PPC is limited in women with type 2 diabetes mellitus (T2DM). The reasons for poor uptake are multifactorial, reflecting both women's understanding of pregnancy risks, and limitations in care delivery. METHODS: A systematic literature review with meta-synthesis was undertaken to identify qualitative studies exploring experiences of PPC for women with T2DM incorporating the views of women with T2DM and health care professionals (HCPs). Identified studies included were synthesized in a meta ethnography to develop an understanding of the elements contributing to the uptake of PPC among women with T2DM. RESULTS: The systematic review identified seven studies yielding data from 28 women with T2DM and 83 HCPs. The following six third-order constructs were identified from the synthesis: understanding PPC, emotive catalysts, beliefs about reproduction among women with T2DM, relationships and social factors, HCP behaviors and perspectives, and health care system factors. These constructs were used to develop a multifactorial model expressing the interactive issues that shape the reproductive health-seeking behaviors of women with T2DM to identify potential areas for intervention. CONCLUSION: The uptake of PPC among women with T2DM seems to be informed by their personal orientation to their reproductive needs, their interactions with HCPs, and system-level influences. Future interventions to enhance PPC uptake need to address these underlying issues. PMID- 27994488 TI - An unfortunate case of acquired hemochromatosis: a case report review of the clinical presentation, diagnosis, management, and prognosis. AB - BACKGROUND: While blood transfusions are commonly used for prophylaxis and treatment for acute chest syndromes and strokes in sickle cell patients, accumulation of excess iron resulting in secondary hemochromatosis remains a rare disease. Chelation is the mainstay for preventing and treating iron overload to deter potential end-organ damages; it is rare when therapy fails. CASE REPORT: A 52-year-old African American woman with chronic anemia secondary to sickle cell anemia and history of multiple blood transfusions presented with elevated serum ferritin (8000 ng/mL) and bilirubin (16.8 mg/dL). She had no previous personal or family history of liver disease. A magnetic resonance cholangiopancreatography (MRCP) and a liver biopsy confirmed the secondary hemochromatosis with marked fibrosis and 4+ iron deposits, but since she was therapeutically on deferasirox, her treatment regimen involved only closer monitoring. Her hemochromatosis led to readmission within a year for rapid progression of cardiac and hepatic failure. CONCLUSION: Since chronically transfused sickle cell patients are at a significantly higher risk of mortality due to the secondary hemochromatosis and end-stage organ damage, knowledge of prophylactic iron chelation is important. Minimizing unnecessary transfusions should be strongly emphasized to reduce the sequelae as iron burden remains a threat. The effectiveness of iron-chelating therapy is best monitored via periodic magnetic resonance imaging, liver transaminases, bilirubin, creatinine, ferritin, and cardiac function tests. Despite the prophylactic treatment and quarterly blood work, in this case the initial presentation did not correlate with the severity of end-stage liver failure. The damage was not discovered until proven by liver biopsy and MRCP, too late to deter the sequelae and the mortality exactly 1 year after diagnosis of the secondary hemochromatosis. PMID- 27994490 TI - Relationship among temporary separation, attachment styles, and adjustment in first-grade Iranian children. AB - If mothers work outside the home, some degree of mother-child separation will be experienced and mother-child attachment will be affected. In this study, regarding the attachment styles, sociobehavioral problems in first-grade children with experience of preschool and in those taught by their mothers at-home are compared. A casual-comparative method was used to compare children in the two groups. A total of 320 first-grade children participated in the study. The study measures included a separation anxiety test, an adaptive behavior scale, and a children's symptom inventory. Data were analyzed using multivariate statistics. Secure attachment in the group with experience of preschool was significantly higher than that in the at-home group. None of the variables, including parents' education and father's income, significantly affected attachment style. Neither father's education, father's income, or attachment significantly influenced adjustment. Father's education significantly influenced children's symptoms. Attachment style and hours of preschool attendance had no effect on Child Symptom Inventory scores. Associations among age at joining preschool, attachment style, and behavioral and adaptive problems in first-grade children were nonlinear and multivariate. By taking into account parents' awareness, sensitivity, and responsiveness, relative welfare, appropriate quality of child-care centers, and having fewer hours of preschool attendance, the risk factors for early parent child separation and institutional care can be reduced. PMID- 27994489 TI - Age- and sex-related differences in the anthropometry and neuromuscular fitness of competitive taekwondo athletes. AB - Anthropometry and neuromuscular fitness have been shown to relate with taekwondo (TKD) performance; however, little information is available on the variation of these fitness components by sex and age in athletes practicing this sport. The aim of the present study was to examine the anthropometry and neuromuscular fitness of TKD athletes by sex and age. A total of 393 athletes (7-48 years old), separated into six age groups (7-9, 10-11, 12-13, 14-17, 18-32, and 33+), were examined for anthropometry and performed a series of neuromuscular fitness tests (flexibility, agility, muscle power, and isometric strength). An age * sex interaction on body mass, body height, and body fat percentage (BF, p<=0.003, eta2>=0.045), but not on body mass index (p=0.172, eta2=0.020), was shown, where a larger increase in body mass and body height from 12-13 to 14-17 groups was observed in males than in females, and the sex difference in BF increased from 12 13 to 14-17 age group. An age * sex interaction on sit-and-reach (SAR) test, mean power output in the Bosco test, and Abalakov jump (p<=0.038, eta2>=0.031) was observed with larger differences between 12-13 and 18-32 groups in males than in females. In SAR, it was remarkable that the male athletes achieved similar scores as female athletes in the 18-32 group. An age * sex group interaction on measures of isometric muscle strength (right and left handgrip, trunk, and legs) was also shown (p<=0.002, eta2>=0.068), where larger differences in male than female athletes were observed between the 12-13 and 14-17 groups. From a practical perspective, coaches can use these findings as reference for the evaluation of their athletes. Because the anthropometric characteristics and neuromuscular fitness varied by sex (i.e., highest scores in males, except flexibility) and age (i.e., highest scores in the 18-32 age group) with unique sport-specific patterns in TKD athletes, these findings would be important for the development of specific training programs. PMID- 27994491 TI - Physician distribution and attrition in the public health sector of Ethiopia. AB - BACKGROUND: Shortages and imbalances in physician workforce distribution between urban and rural and among the different regions in Ethiopia are enormous. However, with the recent rapid expansion in medical education training, it is expected that the country can make progress in physician workforce supply. Therefore, the aim of this study was to examine the distribution of physician workforce in Ethiopia and assess the role of retention mechanisms in the reduction of physician migration from the public health sector of Ethiopia. METHODS: This organizational survey examined physician workforce data from 119 hospitals from 5 regions (Amhara, Oromia, Southern Nations Nationalities and Peoples Region [SNNPR], Tigray, and Harari) and 2 city administrations (Addis Ababa and Dire Dawa City). Training opportunity, distribution, and turnover between September 2009 and July 2015 were analyzed descriptively. Poisson regression model was used to find the association of different covariates with physician turnover. RESULTS: There were 2,300 medical doctors in 5 regions and 2 city administrations in ~6 years of observations. Of these, 553 (24.04%) medical doctors moved out of their duty stations and the remaining 1,747 (75.96%) were working actively. Of the actively working, the majority of the medical doctors, 1,407 (80.5%), were males, in which 889 (50.9%) were born after the year 1985, 997 (57%) had work experience of <3 years, and most, 1,471 (84.2%), were general practitioners. Within the observation period, physician turnover among specialists ranged from 21.4% in Dire Dawa to 43.3% in Amhara region. The capital, Addis Ababa, was the place of destination for 32 (82%) of the physicians who moved out to other regions from elsewhere in the country. The Poisson regression model revealed a decreased incidence of turnover among physicians born between the years 1975 and 1985 (incident rate ratio [IRR]: 0.63; 95% confidence interval [CI]: 0.51, 0.79) and among those who were born prior to 1975 (IRR: 0.24; 95% CI: 0.17, 0.34) compared to those who were born after 1985. Female physicians were 1.4 times (IRR: 1.44; 95% CI: 1.14, 1.81) more likely to move out from their duty stations compared to males. In addition, physicians working in district hospitals were 2 times (IRR: 2.14; 95% CI: 1.59, 2.89) more likely to move out and those working in general hospitals had 1.39 times (IRR: 1.39; 95% CI: 1.08, 1.78) increased rate of turnover in comparison with those who were working in referral hospitals. Physicians working in the Amhara region had 2 times (IRR: 2.01; 95% CI: 1.49, 2.73) increased risk of turnover in comparison with those who were working in the capital, Addis Ababa. The probability of migration did not show a statistically significant difference in all other regions (P>0.05). CONCLUSION: The public health sector physician workforce largely constituted of male physicians, young and less experienced. High turnover rate among females, the young and less experienced physicians, and those working in distant places (district hospitals) indicate the need for special attention in devising human resources management and retention strategies. PMID- 27994492 TI - The National Acupuncture Detoxification Association protocol, auricular acupuncture to support patients with substance abuse and behavioral health disorders: current perspectives. AB - The National Acupuncture Detoxification Association (NADA)-standardized 3- to 5 point ear acupuncture protocol, born of a community-minded response to turbulent times not unlike today, has evolved into the most widely implemented acupuncture assisted protocol, not only for substance abuse, but also for broad behavioral health applications. This evolution happened despite inconsistent research support. This review highlights the history of the protocol and the research that followed its development. Promising, early randomized-controlled trials were followed by a mixed field of positive and negative studies that may serve as a whole to prove that NADA, despite its apparent simplicity, is neither a reductive nor an independent treatment, and the need to refine the research approaches. Particularly focusing on the last decade and its array of trials that elucidate aspects of NADA application and effects, the authors recommend that, going forward, research continues to explore the comparison of the NADA protocol added to accepted treatments to those treatments alone, recognizing that it is not a stand-alone procedure but a psychosocial intervention that affects the whole person and can augment outcomes from other treatment modalities. PMID- 27994493 TI - Noninvasive Ventilation with Heliox for Respiratory Distress Syndrome in Preterm Infant: A Systematic Review and Meta-Analysis. AB - Objectives. To assess whether noninvasive ventilation with Heliox reduces the need for endotracheal ventilation and subsequent complications in preterm infants with respiratory distress syndrome (RDS). Methods. A search of major electronic databases, including MEDLINE and the Cochrane Central Register of Controlled Trials, for randomized or quasi-randomized controlled trials that compared noninvasive ventilation with Heliox versus noninvasive ventilation with standard gas for preterm infants with RDS was performed. The primary outcome was the incidence of intubation. The secondary outcomes were the level of PaCO2, the use of surfactant, and other complications. Results. Two randomized and one quasi randomized controlled trials including 123 preterm infants were assessed. Heliox was found to significantly decrease the incidence of intubation (RR: 0.42; 95% CI: 0.23 to 0.78), the level of PaCO2 (MD: -9.61; 95% CI: -15.76 to -03.45), and the use of surfactant (RR: 0.25; 95% CI: 0.10 to 0.61) as compared with standard gas. No significant differences were found in other secondary outcomes. Conclusions. Noninvasive ventilation with Heliox decreases the incidence of intubation in preterm infants suffering from RDS. However, data on clinical outcomes are limited. Larger trials are needed to verify the beneficial effects. PMID- 27994494 TI - Association of physical performance and biochemical profile of mice with intrinsic endurance swimming. AB - We aimed to investigate the potential mediators and relationship affecting congenital exercise performance in an animal model with physical activity challenge from physiological and biochemical perspectives. A total of 75 male ICR mice (5 weeks old) were adapted for 1 week, then mice performed a non-loading and exhaustive swimming test and were assigned to 3 groups by exhaustive swimming time: low exercise capacity (LEC) (<3 hr), medium exercise capacity (MEC) (3-5 hr), and high exercise capacity (HEC) (>5 hr). After a 1-week rest, the 3 groups of mice performed an exhaustive swimming test with a 5% and 7.5% weight load and a forelimb grip-strength test, with a 1-week rest between tests. Blood samples were collected immediately after an acute exercise challenge and at the end of the experiment (resting status) to evaluate biochemical blood variables and their relation with physical performance. Physical activity, including exhaustive swimming and grip strength, was greater for HEC than other mice. The swimming performance and grip strength between groups were moderately correlated (r=0.443, p<0.05). Resting serum ammonium level was moderately correlated with endurance with a 7.5% weight load (r=-0.447, p<0.05) and with lactate level (r=0.598, p<0.05). The pulmonary morphology of the HEC group seemed to indicate benefits for aerobic exercise. Mice showed congenital exercise performance, which was significantly correlated with different physical challenges and biochemical variable values. This study may have implications for interference in intrinsic characteristics. PMID- 27994497 TI - Menthol inhibiting parasympathetic function of tracheal smooth muscle. AB - Menthol is used as a constituent of food and drink, tobacco and cosmetics nowadays. This cold receptor agonist has been used as a nasal inhalation solution in the daily life. The effect of menthol on nasal mucosa in vivo is well known; however, the effect of the drug on tracheal smooth muscle has been rarely explored. Therefore, during administration of the drug for nasal symptoms, it might also affect the trachea via oral intake or inhalation. We used our preparation to test the effectiveness of menthol on isolated rat tracheal smooth muscle. A 5 mm long portion of rat trachea was submersed in 30 ml Krebs solution in a muscle bath at 37oC. Changes in tracheal contractility in response to the application of a parasympathetic mimetic agent were measured using a transducer connected to a Pentium III computer equipped with polygraph software. The following assessments of menthol were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10-6 M methacholine as a parasympathetic mimetic; (3) effect of the drug on electrically induced tracheal smooth muscle contractions. Results indicated that addition of a parasympathetic mimetic to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of menthol at doses of 10-5 M or above elicited a relaxation response to 10-6 M methacholine-induced contraction. Menthol could also inhibit electrical field stimulation (EFS) induced spike contraction. However, it alone had a minimal effect on the basal tension of trachea as the concentration increased. We concluded that the degree of drug induced tracheal contraction or relaxation was dose-dependent. In addition, this study indicated that high concentrations of menthol might actually inhibit parasympathetic function of the trachea. PMID- 27994495 TI - Circulating Tumor Cells and Circulating Tumor DNA Provide New Insights into Pancreatic Cancer. AB - Pancreatic cancer has a rather dismal prognosis mainly due to high malignance of tumor biology. Up to now, the relevant researches on pancreatic cancer lag behind seriously partly due to the obstacles for tissue biopsy, which handicaps the understanding of molecular and genetic features of pancreatic cancer. In the last two decades, liquid biopsy, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), is promising to provide new insights into the biological and clinical characteristics of malignant tumors. Both CTCs and ctDNA provide an opportunity for studying tumor heterogeneity, drug resistance, and metastatic mechanism for pancreatic cancer. Furthermore, they can also play important roles in detecting early-stage tumors, providing prognostic information, monitoring tumor progression and guiding treatment regimens. In this review, we will introduce the latest findings on biological features and clinical applications of both CTCs and ctDNA in pancreatic cancer. In a word, CTCs and ctDNA are promising to promote precision medicine in pancreatic cancer. PMID- 27994496 TI - Overexpression of lncRNA H19/miR-675 promotes tumorigenesis in head and neck squamous cell carcinoma. AB - There is accumulating evidence indicating that long non-coding RNA H19 and its mature product miR-675 play essential roles for tumor growth and progression. However, their prognostic value in human head and neck squamous cell carcinoma (HNSCC), particular in laryngeal carcinoma, remains to be elucidated. In this study, we observed that both H19 and miR-675 were significantly overexpressed in a cohort of 65 primary tumor samples and two HNSCC cell lines. Importantly, when paired with patient follow-up data, higher expression of either H19 or miR-675 was significantly correlated with higher risk of patient relapse, and associated with worse overall survival and poor disease-free survival. Knockdown miR-675 caused significant reduction of cell viability, migratory and invasive capabilities. Taken together, these results suggest that the strong correlation of H19 overexpression together with higher miR-675 and lymph node metastases could be useful predictive markers, indicating a potentially therapeutic strategy for HNSCC patients. PMID- 27994498 TI - Association between survivin genetic polymorphisms and epidermal growth factor receptor mutation in non-small-cell lung cancer. AB - Survivin is an anti-apoptotic protein that is implicated in the regulation of apoptosis and cell cycle in various types of cancers. The current study explored the effect of survivin gene polymorphisms and EGFR mutations in non-small-cell lung carcinoma (NSCLC) patients. A total of 360 participants, including 291 adenocarcinoma lung cancer and 69 squamous cell carcinoma lung cancer patients, were selected for the analysis of three survivin genetic variants (survivin -31, +9194, and +9809) by using real-time PCR genotyping. The results indicated that GC+CC genotypes of survivin -31 were significant association with EGFR mutation in lung adenocarcinoma patients (adjusted odds ratio=3.498, 95% CI = 1.171 10.448; p<0.01). Moreover, The GC+CC genotypes of survivin -31 were associated with EGFR L858R mutation but not in exon 19 in-frame deletions. Furthermore, among patients in exon 19 in-frame deletions, those who have at least one polymorphic G allele of survivin -31 have an increased incidence to develop late stage when compared with those patients homozygous for C/C (OR, 4.800; 95% CI, 1.305-17.658). In conclusion, our results showed that survivin genetic variants were related to EGFR mutation in lung adenocarcinoma patients and might contribute to pathological development to NSCLC. PMID- 27994499 TI - Adhesion Prevention Efficacy of Composite Meshes Parietex(r), Proceed(r) and 4DryField(r) PH Covered Polypropylene Meshes in an IPOM Rat Model. AB - Background: Adhesions to intraperitoneally implanted meshes (IPOM) are a common problem following hernia surgery and may cause severe complications. Recently, we showed that missing peritoneal coverage of the intestine is a decisive factor for adhesion formation and 4DryField(r) PH (4DF) gel significantly prevents intestine to-mesh adhesions even with use of uncoated Ultrapro(r) polypropylene mesh (UPM). The present study investigates adhesion prevention capability of coated Parietex(r) mesh (PTM) and Proceed(r) mesh (PCM) in comparison to 4DF treated UPM. Methods: 20 rats were randomized into two groups. A 1.5 x 2 cm patch of PTM or PCM was attached to the abdominal wall and the cecum was depleted from peritoneum by abrasion. After seven days incidence of intestine-to-mesh adhesions was evaluated using Lauder and Hoffmann adhesion scores. Histological specimens were evaluated; statistics were performed using student's t-test. The data were compared with recently published data of 4DF treated uncoated UPM. Results: Use of PTM or PCM did not significantly diminish development of intestine-to-mesh adhesions (adhesion reduction rate PTM: 29%, p = 0.069 and PCM: 25%, p = 0.078). Histological results confirmed macroscopic finding of agglutination of intestine and abdominal wall with the mesh in between. Compared to these data, the use of UPM combined with 4DF gel reveals significantly better adhesion prevention capability (p < 0.0001) as shown in earlier studies. However, in clinical situation interindividual differences in adhesion induction mechanisms cannot be excluded by this experimental approach as healing responses towards the different materials might vary. Conclusion: This study shows that in case of impaired intestinal peritoneum coated PTM and PCM do not provide significant adhesion prevention. In contrast, use of UPM combined with 4DF gel achieved a significant reduction of adhesions. Hence, in case of injury of the visceral peritoneum, application of a polysaccharide barrier device such as 4DF gel might be considered more effective in reducing intestine-to-mesh adhesions than coated mesh devices. PMID- 27994501 TI - Blockade of Central GLP-1 Receptors Deteriorates the Improvement of Diabetes after Ileal Transposition. AB - Background: The mechanism of improvement of type 2 diabetes mellitus induced by ileal transposition (IT) is undefined. Our aim was to investigate the possible role of central glucagon-like peptide 1 (GLP-1) after IT. Methods: Ninety male diabetic rats were randomly divided into the IT, sham IT (S-IT) and control group. The food intake, glucose metabolism and GLP-1 level were measured. Subsequently, we administered GLP-1 antagonist via lateral brain ventricle cannula to block central GLP-1 receptor, and verified whether the food intake, glucose metabolism changed. And the activated pro-opiomelanocortin (POMC) neurons in different groups were compared after sacrifice. Results: IT induced significant diabetic improvement with decreased maximum food intake and higher postprandial GLP-1 level. The GLP-1 level in cerebrospinal fluid increased in correlation with the plasma GLP-1 level. When the central GLP-1 receptor antagonist was given to the IT group rats, the improvement of the glucose level declined. The glucose level surged (169.9 +/- 14.2) % during the oral glucose tolerance test, the range was larger than that before central blockade ((67.1 +/- 14.2) %, P < 0.001). Moreover, the POMC neuron number in the arcuate nucleus of the hypothalamus were reduced (12.7 +/- 6.1 at a magnification of 100*). The relative content level of POMC-derived peptides in the pituitary was lower (0.1 +/- 0.05). Conclusions: The central GLP-1 might play an important role in the remission of diabetes after IT. POMC neurons in the hypothalamus may be activated by the enhanced level of GLP-1 after IT. PMID- 27994502 TI - Decreased Tumor Suppressor Candidate 3 Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma. AB - TUSC3 was recently identified as a potential tumor suppressor gene in a variety of human malignancies. However, no data are currently available regarding the expressions of TUSC3 in esophageal cancer (ESCC).The purposes of this study was to investigated the expressions of TUSC3 in ESCC tissues and assess the relationship between TUSC3 levels and clinico-pathological characteristics of ESCC patients. TUSC3 protein expressions were evaluated by immunohistochemistry (IHC) on tissue microarray slides in esophageal cancer, which included 95 esophageal squamous carcinoma specimens (ESCC), and 75 normal esophageal mucosa (NEM). We found that TUSC3 in ESCC was significant lower than that in NEM (P=0.000). According to multi-clinical classifications, TUSC3 level varied significantly with TNM stage, T stage, and N stage (p<0.001, p=0.0368, p<0.0001, respectively). Univariate analysis showed that gender, TNM stage, T stage, N stage, TUSC3 expression were prognostic factors for survival. Multivariate analysis showed that in our study, only TUSC3 expression was independent prognostic factors for ESCC. Our results indicated for the first time, a combined analysis of TUSC3 expressions as well as the clinical variables will help predict the prognosis of ESCC patients. Further large-sample validation and functional analysis should be performed to evaluate its potential prognostic and therapeutic values for ESCC patients. PMID- 27994500 TI - Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats. AB - Resveratrol, a plant-derived polyphenolic compound and a phytoestrogen, was shown to possess multiple protective effects including anti-inflammatory response and anti-oxidative stress. Hypoxic pulmonary hypertension (HPH) is a progressive disease characterized by sustained vascular resistance and marked pulmonary vascular remodeling. The exact mechanisms of HPH are still unclear, but inflammatory response and oxidative stress was demonstrated to participate in the progression of HPH. The present study was designed to investigate the effects of resveratrol on HPH development. Sprague-Dawley rats were challenged by hypoxia exposure for 28 days to mimic hypoxic pulmonary hypertension along with treating resveratrol (40 mg/kg/day). Hemodynamic and pulmonary pathomorphology data were then obtained, and the anti-proliferation effect of resveratrol was determined by in vitro assays. The anti-inflammation and anti-oxidative effects of resveratrol were investigated in vivo and in vitro. The present study showed that resveratrol treatment alleviated right ventricular systolic pressure and pulmonary arterial remodeling induced by hypoxia. In vitro experiments showed that resveratrol notably inhibited proliferation of pulmonary arterial smooth muscle cells in an ER-independent manner. Data showed that resveratrol administration inhibited HIF 1 alpha expression in vivo and in vitro, suppressed inflammatory cells infiltration around the pulmonary arteries, and decreased ROS production induced by hypoxia in PAMSCs. The inflammatory cytokines' mRNA levels of tumor necrosis factor alpha, interleukin 6, and interleukin 1beta were all suppressed by resveratrol treatment. The in vitro assays showed that resveratrol inhibited the expression of HIF-1 alpha via suppressing the MAPK/ERK1 and PI3K/AKT pathways. The antioxidant axis of Nuclear factor erythroid-2 related factor 2/ Thioredoxin 1 (Nrf-2/Trx-1) was up-regulated both in lung tissues and in cultured PASMCs. In general, the current study demonstrated that resveratrol may prevent pulmonary hypertension through its anti-proliferation, anti-inflammation and antioxidant effects. Hence, the present data may offer novel targets and promising pharmacological perspective for treating hypoxic pulmonary hypertension. PMID- 27994503 TI - Association of Far-Infrared Radiation Therapy and Ankle-Brachial Index of Patients on Hemodialysis with Peripheral Artery Occlusive Disease. AB - Background and Aim: The ankle-brachial index (ABI) is recognized to be a good marker for atherosclerosis, and is useful in the diagnosis of peripheral artery occlusive disease (PAOD) which is prevalent among patients on hemodialysis (HD). Methods: This randomized trial aimed to evaluate the effect of far-infrared radiation (FIR) therapy on ABI in HD patients with PAOD. PAOD was defined as patients with ABI < 0.95. One hundred and eight HD patients were enrolled, including 50 in the control group and 58 in the FIR group. A WS TY101 FIR emitter was applied for 40 minutes during each HD session, three times per week for six months. The ABI was measured before and after the FIR therapy. Results: Regardless of FIR therapy, the bilateral ABI decreased (in the FIR group, left: 0.88+/-0.22 to 0.85+/-0.24, p = 0.188; right: 0.92+/-0.20 to 0.90+/-0.23, p = 0.372; in control group, left: 0.91+/-0.23 to 0.88+/-0.21, p = 0144; right: 0.93+/-0.17 to 0.89+/-0.21, p = 0.082). Multivariate logistic analysis of the FIR group revealed that high uric acid (odds ratio [OR]: 2.335; 95% confidence interval [CI]: 1.117-4.882; p=0.024) and aspirin use (OR: 16.463; 95% CI: 1.787 151.638; p=0.013) were independently associated with increased bilateral ABI after FIR therapy. Conclusions: This study demonstrates that ABI is not increased after FIR therapy in HD patients with PAOD. However, in the FIR group, patients with higher uric acid level or those who used aspirin have increased bilateral ABI after FIR therapy. PMID- 27994504 TI - Genetic Analysis of BDNF, GNB3, MTHFR, ACE and APOE Variants in Major and Recurrent Depressive Disorders in Russia. AB - This study was conducted to explore the possibility of association between the single-nucleotide polymorphisms rs6264 of BDNF, rs5443 of GNB3, and rs1801133 of MTHFR; the In/Del polymorphism of ACE; and the epsilon2 allele of APOE and major depressive disorder (MDD) and recurrent depressive disorder (RDD) in an East Slavic population. Generalized multifactor dimensionality reduction (GMDR) method was applied to detect gene-gene interactions. One hundred fifty patients with RDD (101 females and 49 males) and 208 patients with MDD (115 females and 93 males) were included in the study. The comparison group consisted of 200 unrelated individuals. There was no significant difference in genotype distributions or allele frequencies between the controls and any of the diagnostic groups. Nevertheless, the frequency of the G allele of rs1801133 of MTHFR was higher in the RDD group and the frequency of the C allele of rs6264 of BDNF was higher in the MDD group. The difference between the controls and specific disease groups almost reached statistical significance (P = 0.08). A GMDR did not reveal optimal two- and three-dimensional models with significant prediction accuracies (P ? 0.05) for the MDD or RDD groups. PMID- 27994505 TI - Pulsed radiofrequency attenuates diabetic neuropathic pain and suppresses formalin-evoked spinal glutamate release in rats. AB - BACKGROUND: Pulsed radiofrequency (PRF) has been used to treat chronic pain for years, but its effectiveness and mechanism in treating diabetic neuropathic pain are still unexplored. The aim of this study was to elucidate the modulation of diabetic neuropathic pain induced by streptozotocin and the release of spinal excitatory amino acids by PRF. METHODS: Diabetes was induced by intraperitoneal administration of streptozotocin. Pulsed radiofrequency was applied to L5 and L6 dorsal roots at 42 degrees C for 2 min. The responses of all of the groups to thermal, mechanical and cold stimuli were measured for a period of 6 d after this process. Seven days after PRF treatment, intrathecal microdialysis was used to examine the effect of pulsed radiofrequency on the formalin-evoked spinal release of excitatory amino acids and concurrent behaviour responses from diabetic rats. RESULTS: Three weeks after intraperitoneal streptozotocin treatment and before PRF application, mechanical, thermal and cold hypersensitivity occurred. Application of PRF significantly alleviated hyperglycaemia-induced mechanical, thermal and cold hypersensitivity and also attenuated the increase in formalin evoked CSF glutamate concentration, compared with sham treated diabetic rats. CONCLUSION: It may be concluded that PRF has an analgesic effect on neuropathic pain by suppressing the nociception-induced release of excitatory neurotransmitters. PRF may provide a novel promising therapeutic approach for managing diabetic neuropathic pain. PMID- 27994506 TI - Distributed Features of Vimentin-Containing Neural Precursor Cells in Olfactory Bulb of SOD1G93A Transgenic Mice: a Study about Resource of Endogenous Neural Stem Cells. AB - No any effective treatments can prevent from the motor neuron degeneration in amyotrophic lateral sclerosis (ALS) at present. In order to modulating the endogenous neural precursor cells (NPCs) to repairing the degenerative motor neurons in ALS, we studied the alteration of endogenous vimentin-containing NPCs in olfactory bulb (OB) at the different stages of SOD1 wlid-type and G93A transgenic mice. The results showed that the vimentin-containing cells (VCCs) were mainly distributed in the glomerular layer (Gl), the accessory OB (AOB), the OB core, the granular cell layer (GRO) and the mitral cell layer (MI)+the internal plexiform layer (IPL) of the OB of adult mice. Almost all VCCs in Gl, OB core and GRO were the GFAP positive cells. Almost all VCCs in AOB were the Oligo 2 positive cells. Fewer VCCs in MI+IPL were the NeuN positive cells. VCCs significantly increased in the OB core and Gl of adult OB at the pre-onset, onset and progression stages of ALS-like G93A transgenic disease, particularly in OB core. All increased VCCs were the GFAP positive cells. Our data suggested that there extensively existed the endogenous vimentin-containing NPCs in the OB of adult mice, which was a potential resource of neural stem cells, they could differentiate into astrocyte, oligodendrocyte and neuron cells, were a potential astrocyte neuroregenerative response in adult OB in the ALS-like disease, were a potential pathway to repair the degenerated motor neurons. PMID- 27994507 TI - Catalpol Protects Pre-Myelinating Oligodendrocytes against Ischemia-induced Oxidative Injury through ERK1/2 Signaling Pathway. AB - The vulnerability of pre-myelinating oligodendrocytes (PreOLs) to ischemic injury plays an important role in the pathogenesis and progression of perinatal white matter injury. Although oxidative stress is thought to be a major pathogenic mechanism predisposing the PreOLs to injury, no effective therapies have been identified to date. The present study aimed to investigate the direct protective effects of catalpol, a potent antioxidant and free radical scavenger, on ischemia induced oxidative damage in PreOLs and to explore whether the ERK1/2 signaling pathway contributed to the protection provided by catalpol. Primary cultures of PreOLs exposed to oxygen-glucose deprivation (OGD) followed by reperfusion were used as an in vitro model of ischemia. Pretreatment with 0.5 mM catalpol for 1 h prior to OGD treatment significantly reversed ischemia-induced apoptosis in PreOLs and myelination deficits by inhibiting intracellular Ca2+ increase, reducing mitochondrial damage, and ameliorating overproduction of reactive oxygen species (ROS). The expression levels of phosphorylated ERK1/2 (p-ERK1/2) and activated poly-ADP-ribose polymerase-1 (PARP-1) were also markedly decreased by catalpol treatment. Blocking the ERK1/2 signaling pathway with the MEK inhibitor U0126 and catalpol significantly protected PreOLs from ROS-mediated apoptosis under OGD. Taken together, these results suggest that catalpol protects PreOLs against ischemia-induced oxidative injury through ERK1/2 signaling pathway. Catalpol may be a candidate for treating ischemic white matter damage. PMID- 27994508 TI - CRISPR-Cas9: from Genome Editing to Cancer Research. AB - Cancer development is a multistep process triggered by innate and acquired mutations, which cause the functional abnormality and determine the initiation and progression of tumorigenesis. Gene editing is a widely used engineering tool for generating mutations that enhance tumorigenesis. The recent developed clustered regularly interspaced short palindromic repeats-CRISPR-associated 9 (CRISPR-Cas9) system renews the genome editing approach into a more convenient and efficient way. By rapidly introducing genetic modifications in cell lines, organs and animals, CRISPR-Cas9 system extends the gene editing into whole genome screening, both in loss-of-function and gain-of-function manners. Meanwhile, the system accelerates the establishment of animal cancer models, promoting in vivo studies for cancer research. Furthermore, CRISPR-Cas9 system is modified into diverse innovative tools for observing the dynamic bioprocesses in cancer studies, such as image tracing for targeted DNA, regulation of transcription activation or repression. Here, we view recent technical advances in the application of CRISPR-Cas9 system in cancer genetics, large-scale cancer driver gene hunting, animal cancer modeling and functional studies. PMID- 27994509 TI - MiR-99a and MiR-491 Regulate Cisplatin Resistance in Human Gastric Cancer Cells by Targeting CAPNS1. AB - Cisplatin is the first-line agent utilized for the clinical treatment of a wide variety of solid tumors including gastric cancer. However, the intrinsic or acquired cisplatin resistance is often occurred in patients with gastric cancer and resulted in failure of cisplatin therapy. In order to investigate if miRNA involves in cisplatin resistance of human gastric cancer, we first screened and compared the expression of miRNAs between cisplatin resistant gastric cancer cell lines SGC-7901/DDP and BGC-823/DDP and their sensitive parental cells by miRNAs microarray and followed by analysis of 2D-GE/MS to identify their target proteins. We found both miR-99a and miR-491 were upregulated while their target gene calpain small subunit 1 (CAPNS1) was downregulated in resistant gastric cancer cells. Dual-luciferase- reporter assays with wild-type and mutated CAPNS1 3'-UTR confirmed their specificity of targeting. Inhibition of miR-99a and miR 491, or overexpress CAPNS1 can enhance cisplatin sensitivity of the resistant cells while transfection of two miRNAs' mimics or si-CAPNS1 in the sensitive cells can induce their resistance. Moreover, our results demonstrated CAPNS1 positively regulated calpain1 and calpain2, the catalytic subunits of CAPNS1, and cleaved caspase3 which further cleaved PARP1 and directly induced apoptosis. Therefore, miR-99a and miR-491 might be work as novel molecules regulate cisplatin resistance by directly targeting CAPNS1 associated pathway in human gastric cancer cells. PMID- 27994510 TI - Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4. AB - Bluetongue virus (BTV) replicates in lymphoid tissues where infected mononuclear leukocytes secrete proinflammatory and vasoactive mediators that can contribute to bluetongue (BT) pathogenesis. Using the well-characterized IFNAR(-/-) mice animal model, we have now studied the histopathology and dynamics of leukocyte populations in different target tissues (spleen, thymus, and lung) during BTV-4 infection by histological and immunohistochemical techniques. The spleen and thymus of BTV-4 infected mice showed severe lymphoid depletion on H&E stained sections. This finding was confirmed by IHC, showing moderate decreased immunopositivity against CD3 in the thymus, and scarce immunoreactivity against CD3 and CD79 in the rest of the white pulp in the spleen, together with an increase in MAC387 immunostaining. BTV-4 infection also induced the expression of active caspase-3 in the spleen, where apoptotic debris was observed by H&E. A dramatic increase in iNOS immunoreactivity associated to necrotic areas of the white pulp was observed, being less noticeable in the thymus and the lung. The induction of pro-inflammatory cytokines in tissues where BTV replicates was evaluated by measuring transcript levels by RT-qPCR. BTV-4 infection led to enhance transcription of IFN-gamma, TNF, IL-6, IL-12-p40, and IL-1beta mRNA in the thymus, spleen and lung, correlating with the level of virus replication in these tissues. Disease progression and pathogenesis in IFNAR(-/-) mice closely mimics hallmarks of bluetongue disease in ruminants. IFNAR(-/-) mice are a good choice to facilitate a faster advance in the field of orbiviruses. PMID- 27994511 TI - Autophagy activation protects shock wave induced renal tubular epithelial cell apoptosis may through modulation of Akt/ GSK-3beta pathway. AB - PURPOSE: Extracorporeal shock wave lithotripsy (ESWL) is well documented to exert destructive effect to renal cells and its mechanism is not clear. Autophagy is one of cell basic response for stressful conditions and it is important to determine cell's fate. The aim of this study is to elucidate the role of autophagy in the process of shock wave-induced renal cells injury. METHODS: NRK 52E cell, a rat renal tubular epithelial cell, was exposed to shock wave at the voltage of 14KV. GFP-LC3 puncta was used to monitor Autophagy flux in the process of shock wave injury. Autophagic relative proteins, such as light chain 3 (LC3), beclin-1 and p62, were also examined. Cell variability and apoptosis were detected when inhibition autophagy with 3-methyladenine (3MA) or stimulating its activity with rapamycin during the process of shock wave injury. The role of Akt/ GSK-3beta and its connection with autophagy in the process of shock wave injury were also investigated. RESULTS: Shock wave was confirmed to activate autophagy in renal cells, which was manifested in LC3-II turnover, beclin-1 induction and degradation of p62. Inhibition autophagy enhanced cell damage or apoptosis, whereas its stimulating was able to exert protection from shock wave injury. Akt/ GSK-3beta, a cell-survival signaling pathway, can also be activated during the process. And its activation could be suppressed by blockade autophagy. CONCLUSION: Autophagy is a self-protective response for renal cells from shock wave injury. The cyto-protection of autophagy may be connected with modulation Akt/ GSK-3beta pathway. PMID- 27994512 TI - Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling. AB - Chronic skin wounds represent one of the most common and disabling complications of diabetes. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and can enhance diabetic wound repair by facilitating neovascularization. Recent studies indicate that the transplanted cells exert therapeutic effects primarily via a paracrine mechanism and exosomes are an important paracrine factor that can be directly used as therapeutic agents for regenerative medicine. However, application of exosomes in diabetic wound repair has been rarely reported. In this study, we demonstrated that the exosomes derived from human umbilical cord blood-derived EPCs (EPC-Exos) possessed robust pro-angiogenic and wound healing effects in streptozotocin-induced diabetic rats. By using a series of in vitro functional assays, we found that EPC-Exos could be incorporated into endothelial cells and significantly enhance endothelial cells' proliferation, migration, and angiogenic tubule formation. Moreover, microarray analyses indicated that exosomes treatment markedly altered the expression of a class of genes involved in Erk1/2 signaling pathway. It was further confirmed with functional study that this signaling process was the critical mediator during the exosomes-induced angiogenic responses of endothelial cells. Therefore, EPC-Exos are able to stimulate angiogenic activities of endothelial cells by activating Erk1/2 signaling, which finally facilitates cutaneous wound repair and regeneration. PMID- 27994513 TI - LIS1 Regulates Osteoclastogenesis through Modulation of M-SCF and RANKL Signaling Pathways and CDC42. AB - We have previously reported that depletion of LIS1, a key regulator of microtubules and cytoplasmic dynein motor complex, in osteoclast precursor cells by shRNAs attenuates osteoclastogenesis in vitro. However, the underlying mechanisms remain unclear. In this study, we show that conditional deletion of LIS1 in osteoclast progenitors in mice led to increased bone mass and decreased osteoclast number on trabecular bone. In vitro mechanistic studies revealed that loss of LIS1 had little effects on cell cycle progression but accelerated apoptosis of osteoclast precursor cells. Furthermore, deletion of LIS1 prevented prolonged activation of ERK by M-CSF and aberrantly enhanced prolonged JNK activation stimulated by RANKL. Finally, lack of LIS1 abrogated M-CSF and RANKL induced CDC42 activation and retroviral transduction of a constitutively active form of CDC42 partially rescued osteoclastogenesis in LIS1-deficient macrophages. Therefore, these data identify a key role of LIS1 in regulation of cell survival of osteoclast progenitors by modulating M-CSF and RANKL induced signaling pathways and CDC42 activation. PMID- 27994514 TI - The Correlation Between PARP1 and BRCA1 in AR Positive Triple-negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression and thus cannot benefit from conventional hormonal or anti-HER2 targeted therapies. Anti-androgen therapy has shown a certain effect on androgen receptor (AR) positive TNBC. The emerging researches have proved that poly (ADP-ribose) polymerase (PARP) inhibitor is effective in BRCA1-deficient breast cancers. We demonstrated that combination of AR antagonist (bicalutamide) and PARP inhibitor (ABT-888) could inhibit cell viability and induce cell apoptosis significantly whatever in vitro or in vivo setting in AR-positive TNBC. Previous studies have proved that both BRCA1 and PARP1 have close connections with AR in prostate cancer. We explored the correlation among AR, PARP1 and BRCA1 in TNBC for the first time. After BRCA1 overexpression, the expression of AR and PARP1 were decreased in mRNA and protein levels. Additionally, AR positively regulated PARP1 while PARP1 also up-regulated AR expression in vitro. We also confirmed BRCA1 expression was negatively correlated with AR and PARP1 in TNBC patients using a tissue microarray with TNBC patient samples. These results suggest that the combination of bicalutamide and PARP inhibitor may be a potential strategy for TNBC patients and merits further evaluation. PMID- 27994515 TI - Dose-dependent Effects of Strontium Ranelate on Ovariectomy Rat Bone Marrow Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells. AB - In clinic, strontium ranelate (SrR) is a useful drug to treat osteoporosis by orally taken method, but some side effect appeared in recent years. The aim of this study is to evaluate the effectiveness and safety of SrR on cells by direct application, to study the possibility of local application of this drug. Qualitative ALP staining, quantitative ALP activity assay, alizarin red staining, realtime PCR and westernblot assay were used to evaluate the osteogenesis ability of SrR under normal or osteogenic induction environment of ovariectomy bone marrow mesenchymal stem cells (OVX-BMSCs). The angiogenesis ability of SrR was studied by immunofluorescence staining of CD31 and vWF of OVX-BMSCs under angiogenesis induction environment, transwell, tubeformation and realtime PCR assay of HUVECs. Signaling pathway of PI3K/AKT/mTOR was also studied. The result demonstrated that SrR could enhance proliferation and osteogenic differentiation of OVX-BMSCs. The osteogenesis effect of SrR has been proved by the better performed of ALP activity, alizarin red staining and the remarkable up-regulation of ALP, Col-I, Runx2, OCN, BMP-2, BSP, OPG of the OVX-BMSCs, and reduction of RANKL. In addition, SrR promotes angiogenesis differentiation of both OVX-BMSCs and HUVECs. Higher intensity of immunostaining of CD31 and vWF, better result of transwell and tubeformation assay could be observed in SrR treated group, and increasing mRNA levels of VEGF and Ang-1 in the OVX-BMSCs, VEGF in HUVECs were learnt. Signaling pathway assay showed that PI3K/AKT/mTOR signaling pathway was involved in this SrR triggered angiogenesis procedure. The thrombosis marker ET 1, PAI-1 and t-PA were up-regulated, but no significant differences for low concentration (<0.5mM). The concentration between 0.25-0.5mM may be more appropriate for local application, and locally application of SrR could be considered as a promising way for bone regeneration. PMID- 27994516 TI - Genes involved in angiogenesis and mTOR pathways are frequently mutated in Asian patients with pancreatic neuroendocrine tumors. AB - Introduction: To address the issue of limited data on and inconsistent findings for genetic alterations in pancreatic neuroendocrine tumors (pNETs), we analyzed sequences of known pNET-associated genes for their impact on clinical outcomes in a Taiwanese cohort. Methods: Tissue samples from 40 patients with sporadic pNETs were sequenced using a customized sequencing panel that analyzed 43 genes with either an established or potential association with pNETs. Genetic mutations and clinical outcomes were analyzed for potential associations. Results: Thirty-three patients (82.5%) survived for a median 5.9 years (range, 0.3-18.4) of follow up. The median number of mutations per patient was 3 (range, 0-16). The most frequent mutations were in ATRX (28%), MEN1 (28%), ASCL1 (28%), TP53 (20%), mTOR (20%), ARID1A (20%), and VHL (20%). The mutation frequencies in the MEN1 (including MEN1/PSIP1/ARID1A), mTOR (including mTOR/PIK3CA/AKT1/PTEN /TS1/TSC2/ATM), DAXX/ATRX, and angiogenesis (including VHL/ANGPT1/ANGPT2 /HIF1A) pathways were 48%, 48%, 38%, and 45%, respectively. Mutations in ATRX were associated with WHO grade I pNET (vs. grade II or III, p = 0.043), and so were those in genes involved in angiogenesis (p = 0.002). Patients with mutated MEN1 and DAXX/ATRX pathways showed a trend toward better survival, compared to patients with the wild-type genes (p = 0.08 and 0.12, respectively). Conclusion: Genetic profiles of Asian patients with pNETs were distinct from Caucasian patient profiles. Asian patients with pNETs were more frequently mutated for the mTOR and angiogenesis pathways. This could partially explain the better outcome observed for targeted therapy in Asian patients with pNETs. PMID- 27994517 TI - Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway. AB - Tumor-associated macrophages (TAMs) promote cancer development and progression by releasing various cytokines and chemokines. Previously, we have found that the number of COX-2+ TAMs was associated with lymph node metastasis in breast cancer. However, the mechanism remains enigmatic. In this study, we show that COX-2 in breast TAMs enhances the metastatic potential of breast cancer cells. COX-2 in TAMs induces MMP-9 expression and promotes epithelial-mesenchymal transition (EMT) in breast cancer cells. In addition, COX-2/PGE2 induces IL-6 release in macrophages. Furthermore, we find that the activation of Akt pathway in cancer cells is crucial for the pro-metastatic effect of COX-2+ TAMs by regulating MMP-9 and EMT. These findings indicate that TAMs facilitate breast cancer cell metastasis through COX-2-mediated intercellular communication. PMID- 27994521 TI - From the WARMTH President's Desk. PMID- 27994522 TI - From the Desk of Congress President ICRT 2016. PMID- 27994518 TI - Signal transduction mechanism for glucagon-induced leptin gene expression in goldfish liver. AB - Leptin is a peripheral satiety hormone that also plays important roles in energy homeostasis in vertebrates ranging from fish to mammals. In teleost fish, however, the regulatory mechanism for leptin gene expression still remains unclear. In this study, we found that glucagon, a key hormone in glucose homeostasis, was effective at elevating the leptin-AI and leptin-AII transcript levels in goldfish liver via both in vivo intraperitoneal injection and in vitro cells incubation approaches. The responses of leptin-AI and leptin-AII mRNA to glucagon treatment were highly comparable. In contrast, blockade of local glucagon action could reduce the basal and induced leptin-AI and leptin-AII mRNA expression. The stimulation of leptin levels by glucagon was caused by the activation of adenylate cyclase (AC)/cyclic-AMP (cAMP)/ protein kinase A (PKA), and probably cAMP response element-binding protein (CREB) cascades. Our study described the effect and signal transduction mechanism of glucagon on leptin gene expression in goldfish liver, and may also provide new insight into leptin as a mediator in the regulatory network of energy metabolism in the fish model. PMID- 27994519 TI - Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding. AB - The sirtuins (SIRTs), a family of NAD+-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated. We investigated the anticancer effects of a novel SIRT inhibitor, MHY2256, and its efficacy was compared to that of salermide in MCF-7 (wild-type p53) and SKOV-3 (null-type p53) cells. Cell viability, SIRT1 enzyme activity, cell cycle regulation, apoptosis, and autophagic cell death were measured. We compared sensitivity to cytotoxicity in MCF-7 and SKOV-3 cells. MHY2256 significantly decreased the viability of MCF-7 (IC50, 4.8 MUM) and SKOV-3 (IC50, 5.6 MUM) cells after a 48 h treatment period. MHY2256 showed potent inhibition (IC50, 0.27 mM) against SIRT1 enzyme activity compared with nicotinamide (IC50, >1 mM). Moreover, expression of SIRT (1, 2, or 3) protein levels was significantly reduced by MHY2256 treatment in both MCF-7 and SKOV-3 cells. Flow cytometry analysis revealed that MHY2256 significantly induced cell cycle arrest in the G1 phase, leading to an effective increase in apoptotic cell death in MCF 7 and SKOV-3 cells. A significant increase in acetylated p53, a target protein of SIRT, was observed in MCF-7 cells after MHY2256 treatment. MHY2256 up-regulated LC3-II and induced autophagic cell death in MCF-7 cells. Furthermore, MHY2256 markedly inhibited tumor growth in a tumor xenograft model of MCF-7 cells. These results suggest that a new SIRT inhibitor, MHY2256, has anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. PMID- 27994520 TI - Evaluation of Breast Cancer Stem Cells and Intratumor Stemness Heterogeneity in Triple-negative Breast Cancer as Prognostic Factors. AB - Triple-negative breast cancer (TNBC) is a tumor subtype with aggressive behavior and poor clinical outcome for lacking effective therapies. Breast cancer stem cells (BCSCs) have been suggested to have tumor-initiating properties, but it remains unclear whether their presence contributes to the increased aggressiveness and poor prognosis of TNBC. Also, the breast cancers display frequent inter- and intra-tumor heterogeneity, which adds the complexity in diagnosis and predicting prognosis. Here we investigated the clinical relevance and prognostic value of the BCSC markers, CD44+/CD24-, aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and CD133 in 88 TNBC cases. We found that a few patients displayed spatial heterogeneity of the BCSC markers in expression, which was defined as intratumor stemness heterogeneity (ITSH) below. There was no significant correlation between any BCSC marker alone or ITSH and progression free survival (PFS). Interestingly, the combined BCSC phenotype by CD44+/CD24- and ALDH1A1 was significantly associated with worse PFS (P = 0.009). Further stratification analysis revealed that this combined BCSC phenotype was an independent prognostic factor for PFS in some subgroups. In conclusion, we demonstrated the existence of ITSH in TNBC and found that the ITSH as well as a single BCSC marker was not significantly associated with survival, whereas combing the analysis of BCSC markers could improve prognostic value. Our findings may lead to an improvement of prognostic indicators in TNBC. PMID- 27994523 TI - Estimation of Radiological Dose From Progeny of 222Rn and 220Rn Using DTPS/DRPS and Wire-Mesh-Capped Progeny Sensors. AB - Radon (222Rn) and its decay products are the major sources of natural radiation exposure to general population. The activity concentrations of unattached and attached short-lived 222Rn and thoron (220Rn) progeny in indoor environment of some dwellings of the Jalandhar and Kapurthala districts of Punjab had been calculated using the deposition-based progeny sensors (DRPS/DTPS) and wire-mesh capped (DRPS/DTPS) progeny sensors. The observed concentration of attached 222Rn and 220Rn progeny showed the variation from 5 to 21 Bq.m-3 and 0.3 to 1.7 Bq.m-3, respectively. The activity concentration of the unattached 222Rn and 220Rn progeny varies from 1 to 5 Bq.m-3 and 0.1 to 0.6 Bq.m-3, respectively. The average unattached fraction of 222Rn and 220Rn progeny is 0.2 and 0.1. The average value of the indoor aerosol concentration attachment rate of 222Rn and 220Rn progeny is 2251 cm-3, 24 ms-1, and 617 ms-1. Relation among the unattached fraction and attachment rate is established, and the obtained results of dose conversion factors show the significance of the nano-sized 222Rn decay products in 222Rn dosimetry. PMID- 27994525 TI - Changing the 30-min Rule in Canada: The Effect of Room Temperature on Bacterial Growth in Red Blood Cells. AB - BACKGROUND: To maintain product quality and safety, the '30-min rule' requires the discard of red blood cells (RBCs) that are exposed to uncontrolled temperatures for more than 30 min. Recent studies suggest this rule may safely be extended to a 60-min rule. METHODS: A pool-and-split design study (N = 4) was run in parallel at Canadian Blood Services (SAGM RBCs) and Hema-Quebec (AS-3 RBCs). RBCs were spiked with ~1 colony-forming unit/ml of mesophilic and psychrophilic bacteria. Control units remained in storage at 1-6 degrees C for 42 days. Test 30 (T30) and T60 units were exposed to room temperature (RT) six times during storage, each time for 30 and 60 min, respectively. Bacterial proliferation was monitored. RESULTS: Mesophilic bacteria do not proliferate in RBCs. The growth of psychrophilic bacteria is not significantly different in RBCs exposed for 30 or 60 min to RT (p < 0.05). CONCLUSION: The study findings were the final evidence to support extension from a 30-min rule to a 60-min rule in Canada. PMID- 27994524 TI - Blood Product Supply in Germany: The Impact of Apheresis and Pooled Platelet Concentrates. AB - BACKGROUND: In Germany, about 60% of all produced platelet concentrates (PCs) are apheresis PCs (APCs). Ongoing discussions on APC reimbursement and costs might lead to a potential shift in pooled PC (PPC)/APC production. Objective of this analysis was to build a comprehensive model from the societal perspective to evaluate consequences associated with shifts in platelet supply and demand. METHODS: Literature search, desktop researches on platelet supply and demand. Model calculations, time horizon one year: model input from the Paul-Ehrlich Institute, data 2013. Base case: 19.2% of annual whole blood donations (WBDs) were used for production of 38.5% PPCs, decay of 46,218 PCs (8.0%). Scenarios calculated: variation in PPC proportion of 10-100%. RESULTS: Base case: during PPC production 41,957-83,913 red blood cell concentrates (RBCCs) are estimated to be lost, which corresponds to 1-2% of annual RBCCs in Germany. Scenarios were calculated for a production of 60-100% PPCs: loss is estimated to be 1.5-5.0% of annual RBCCs (65,430-218,099), decay 54,189-69,022 PCs (9.4-12.0%). CONCLUSION: Production of different blood components is interlinked and sensitive to unidimensional decisions. Increasing PPC proportion has negative impact on the RBCC production and on the antigen-matched APC donor pool. Completion of the model calculations to predict the optimal PPC/APC proportion would require evidence on the number of refractory patients, donor pool sizes, and incidences of diseases requiring platelet transfusions. PMID- 27994526 TI - Too Many Blood Donors - Response Bias in the Swiss Health Survey 2012. AB - BACKGROUND: Data on blood donor status obtained from general surveys and health interview surveys have been widely used. However, the integrity of data on self reported blood donor status from surveys may be threatened by sampling and non sampling error. Our study aimed to compare self-reported blood donors (including one-time as well as regular donors) from the Swiss Health Survey 2012 (SHS) with register-based blood donors recorded by blood establishments and evaluate the direction and magnitude of bias in the SHS. METHODS: We compared population weighted SHS point estimates of the number of blood donors with their corresponding 95% confidence intervals to the respective figures from blood donor registries (birth cohorts 1978-1993) and estimates of donors based on period donor tables derived from blood donor registries (birth cohorts 1920-1993). RESULTS: In the birth cohorts 1978-1993, the SHS-predicted number of donors was 1.8 times higher than the respective number of donors based on registry data. Adjusting for foreign and naturalized Swiss nationals that immigrated after their 18th birthday, the SHS overall predicted number of donors was 1.6 times higher. Similarly, SHS estimates for the 1920-1993 birth cohorts were 2.4 and 2.1 times higher as compared to register-based estimates. Generally, the differences between SHS and register-based donors were more pronounced in men than in women. CONCLUSION: Self-reported blood donor status in the SHS is biased. Estimates of blood donors are substantially higher than respective estimates based on blood donor registries. PMID- 27994527 TI - Generalizability of Dutch Prediction Models for Low Hemoglobin Deferral: A Study on External Validation and Updating in Swiss Whole Blood Donors. AB - BACKGROUND: Sex-specific prediction models for low hemoglobin (Hb) deferral have been developed in Dutch whole blood donors. In this study, we validated and updated the models in a cohort of Swiss whole blood donors. METHODS: Prospectively collected data from 53,772 Swiss whole blood donors were used. The predictive performance of the Dutch models was assessed in terms of calibration (agreement between predicted probabilities and observed frequencies) and discrimination (ability to discriminate between deferred and approved donors). The models were updated by revising the strength of the individual predictors in the models. RESULTS: A total of 1,065 men (3.3%) and 2,063 women (9.7%) were deferred from donation because of a low Hb level. Validation in Swiss donors demonstrated underestimation of predicted risks and significantly lower discriminative ability. The predictive effects of most predictors were weaker in Swiss donors. Updating the models increased the calibration for both men and women, and slightly increased the discriminative ability in men. CONCLUSION: Validation of the Dutch prediction models in Swiss whole blood donors showed lower, though adequate performance. In general, the Dutch prediction models can reliably predict the risk of Hb deferral, although for application in other countries small adaptations are necessary. PMID- 27994528 TI - A Case of Possible Chagas Transmission by Blood Transfusion in Switzerland. AB - BACKGROUND: Transfusion-transmitted Chagas disease has been reported from endemic countries in Latin America. Switzerland is a non-endemic country but high prevalence of antibodies against Trypanosoma cruzi was found among immigrants. Immigrants may participate in blood donation; therefore, risk-adapted anti-T. cruzi screening for blood donors was implemented in Switzerland in 2013. METHODS: Between January 2013 and July 2015, 1 out of 1,183 at-risk donors, tested at Blood Transfusion Service Zurich, was found anti-T. cruzi IgG-positive. RESULTS AND CONCLUSION: Out of 54 donations given by the index donor (ID), we identified 77 blood products which were delivered to hospitals. Archived serum samples from the donations given during the prior 5 years were available for retrospective testing. All samples from ID revealed positive findings for anti-T. cruzi IgG. Donor-triggered look-back procedure identified a 70-year-old male recipient of a platelet concentrate (PC) donated by ID. The recipient succumbed of acute T. cruzi infection 2 years after transfusion of the PC. PMID- 27994529 TI - Anti-D Antibodies in Pregnant D Variant Antigen Carriers Initially Typed as RhD. AB - BACKGROUND: To evaluate the incidence, the consequences, and the prevention strategy of anti-D alloimmunizations of D variant carriers in the obstetric population of Split-Dalmatia County, Croatia. METHODS: RhD immunization events were evaluated retrospectively for the period between 1993 and 2012. Women were tested for RhD antigen and irregular antibodies. Those with anti-D antibody who were not serologically D- were genotyped for RHD. They were evaluated for their obstetric and transfusion history and their titer of anti-D. The neonates were evaluated for RhD status, direct antiglobulin test (DAT), hemoglobin and bilirubin levels, transfusion therapy as well as phototherapy and outcome. RESULTS: Out of 104,884 live births 102,982 women were tested for RhD antigen. Anti-D immunization occurred in 184 women which accounts for 0.9% of individuals at risk of anti-D formation. 181 cases occurred in women serologically typed as D . Three women were partial D carriers (DVa n = 2, DNB n = 1), initially typed RhD+, and recognized as D variant carriers after the immunization occurred. Anti D titer varied from 1:1 to 1:16. Six children were RhD+, four had positive DAT, and two underwent phototherapy. CONCLUSION: Anti-D immunization occurred in pregnant partial D carriers (DVa, DNB). RhD+ children had serologic markers of hemolytic disease of the fetus and newborn (HDFN), with no cases of severe HDFN. PMID- 27994530 TI - Knowledge Is Safety: The Time Is Ripe for Hepatitis E Virus Blood Donor Screening. PMID- 27994531 TI - Kinship Testing Based on SNPs Using Microarray System. AB - BACKGROUND: Kinship testing using biallelic SNP markers has been demonstrated to be a promising approach as a supplement to standard STR typing, and several systems, such as pyrosequencing and microarray, have been introduced and utilized in real forensic cases. The Affymetrix microarray containing 169 autosomal SNPs developed for forensic application was applied to our practical case for kinship analysis that had remained inconclusive due to partial STR profiles of degraded DNA and possibility of inbreeding within the population. CASE REPORT: 169 autosomal SNPs were typed on array with severely degraded DNA of two bone samples, and the kinship compared to genotypes in a reference database of their putative family members. RESULTS: Two bone samples remained unidentified through traditional STR typing with partial profiles of 10 or 14 of 16 alleles. Because these samples originated from a geographically isolated population, a cautious approach was required when analyzing and declaring true paternity only based on PI values. In a supplementary SNP typing, 106 and 78 SNPs were obtained, and the match candidates were found in each case with improved PI values than using only STRs and with no discrepant SNPs in comparison. CONCLUSION: Our case showed that the utility of multiple SNPs on array is expected in practical forensic caseworks with an establishment of reference database. PMID- 27994532 TI - Severe Hypoxemia in a Healthy Donor for Allogeneic Hematopoietic Stem Cell Transplantation after Only the First Administration of Granulocyte-Colony Stimulating Factor. AB - BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) in healthy donors. A few reports have shown that some healthy donors developed acute respiratory distress syndrome or capillary leak syndrome after more than several rounds of G-CSF administration or leukapheresis. CASE REPORT: We report the case of a healthy donor for allogeneic stem cell transplantation who developed severe hypoxemia 1 h after only the first administration of G-CSF. The donor was administered 10 MUg/kg G CSF (lenograstim) subcutaneously for PBSC mobilization. 1 h after the first administration of G-CSF, the donor suddenly presented with dry cough and dyspnea. The oxygen saturation by pulse oximetry (SpO2) in the room air was 88%. An electrocardiogram and chest radiography revealed no abnormalities. We excluded other causes of severe hypoxemia and diagnosed the donor with hypoxemia due to G CSF administration, which was subsequently terminated. The donor was administered 2 l/min oxygen via a nasal cannula and 100 mg hydrocortisone intravenously. He subsequently recovered, and SpO2 in the room air returned to 98% 10 h after hypoxemia. CONCLUSION: These respiratory symptoms might be related to anaphylactoid or hypersensitivity reaction. The donors should be observed for at least 1 h after the first administration of G-CSF. PMID- 27994534 TI - Influence of Group on Individual Subject Maps in SPM Voxel Based Morphometry. AB - Voxel based morphometry (VBM) is a widely utilized neuroimaging technique for spatially normalizing brain structural MRI (sMRI) onto a common template. The DARTEL technique of VBM takes into account the spatial intensity distribution of sMRIs to construct a study specific group template. The group template is then used to create final individual normalized tissue maps (FINTM) for each subject in the group. In this study, we investigate the effect of group on FINTM, i.e., we evaluate the variability of a constant subject's FINTM when other subjects in the group are iteratively changed. We examine this variability under the following scenarios: (1) when the demographics of the iterative groups are similar, (2) when the average age of the iterative groups is increased, and (3) when the number of subjects with a brain disorder (here we use subjects with autism) is increased. Our results show that when subject demographics of the group remains similar the mean standard deviation (SD) of FINTM gray matter (GM) of the constant subject was around 0.01. As the average age of the group is increased, mean SD of GM increased to around 0.03 and at certain brain locations variability was as high as 0.23. A similar increase in variability was observed when the number of autism subjects in the group was increased where mean SD was around 0.02. Further, we find that autism vs. control GM differences are in the range of -0.05 to +0.05 for more than 97% of the voxels and note that the magnitude of the differences are comparable to GM variability. Finally, we report that opting not to modulate during normalization or increasing the size of the smoothing kernel can decrease FINTM variability but at the loss of subject specific features. Based on the findings of this study, we outline precautions that should be considered by investigators to reduce the impact of group on FINTM and thereby derive more meaningful group differences when comparing two cohorts of subjects. PMID- 27994533 TI - Zika Virus (ZIKV). PMID- 27994535 TI - 3Mo: A Model for Music-Based Biofeedback. AB - In the domain of sports and motor rehabilitation, it is of major importance to regulate and control physiological processes and physical motion in most optimal ways. For that purpose, real-time auditory feedback of physiological and physical information based on sound signals, often termed "sonification," has been proven particularly useful. However, the use of music in biofeedback systems has been much less explored. In the current article, we assert that the use of music, and musical principles, can have a major added value, on top of mere sound signals, to the benefit of psychological and physical optimization of sports and motor rehabilitation tasks. In this article, we present the 3Mo model to describe three main functions of music that contribute to these benefits. These functions relate the power of music to Motivate, and to Monitor and Modify physiological and physical processes. The model brings together concepts and theories related to human sensorimotor interaction with music, and specifies the underlying psychological and physiological principles. This 3Mo model is intended to provide a conceptual framework that guides future research on musical biofeedback systems in the domain of sports and motor rehabilitation. PMID- 27994537 TI - Alignment of Tractograms As Graph Matching. AB - The white matter pathways of the brain can be reconstructed as 3D polylines, called streamlines, through the analysis of diffusion magnetic resonance imaging (dMRI) data. The whole set of streamlines is called tractogram and represents the structural connectome of the brain. In multiple applications, like group analysis, segmentation, or atlasing, tractograms of different subjects need to be aligned. Typically, this is done with registration methods, that transform the tractograms in order to increase their similarity. In contrast with transformation-based registration methods, in this work we propose the concept of tractogram correspondence, whose aim is to find which streamline of one tractogram corresponds to which streamline in another tractogram, i.e., a map from one tractogram to another. As a further contribution, we propose to use the relational information of each streamline, i.e., its distances from the other streamlines in its own tractogram, as the building block to define the optimal correspondence. We provide an operational procedure to find the optimal correspondence through a combinatorial optimization problem and we discuss its similarity to the graph matching problem. In this work, we propose to represent tractograms as graphs and we adopt a recent inexact sub-graph matching algorithm to approximate the solution of the tractogram correspondence problem. On tractograms generated from the Human Connectome Project dataset, we report experimental evidence that tractogram correspondence, implemented as graph matching, provides much better alignment than affine registration and comparable if not better results than non-linear registration of volumes. PMID- 27994536 TI - A Novel Technique for Region and Linguistic Specific nTMS-based DTI Fiber Tracking of Language Pathways in Brain Tumor Patients. AB - Navigated transcranial magnetic stimulation (nTMS) has recently been introduced as a non-invasive tool for functional mapping of cortical language areas prior to surgery. It correlates well with intraoperative neurophysiological monitoring (IONM) findings, allowing defining the best surgical strategy to preserve cortical language areas during surgery for language-eloquent tumors. Nevertheless, nTMS allows only for cortical mapping and postoperative language deficits are often caused by injury to subcortical language pathways. Nowadays, the only way to preoperatively visualize language subcortical white matter tracts consists in DTI fiber tracking (DTI-FT). However, standard DTI-FT is based on anatomical landmarks that vary interindividually and can be obscured by the presence of the tumor itself. It has been demonstrated that combining nTMS with DTI-FT allows for a more reliable visualization of the motor pathway in brain tumor patients. Nevertheless, no description about such a combination has been reported for the language network. The aim of the present study is to describe and assess the feasibility and reliability of using cortical seeding areas defined by error type-specific nTMS language mapping (nTMS-positive spots) to perform DTI-FT in patients affected by language-eloquent brain tumors. We describe a novel technique for a nTMS-based DTI-FT to visualize the complex cortico-subcortical connections of the language network. We analyzed quantitative findings, such as fractional anisotropy values and ratios, and the number of visualized connections of nTMS-positive spots with subcortical pathways, and we compared them with results obtained by using the standard DTI-FT technique. We also analyzed the functional concordance between connected cortical nTMS-positive spots and subcortical pathways, and the likelihood of connection for nTMS positive vs. nTMS-negative cortical spots. We demonstrated, that the nTMS-based approach, especially what we call the "single-spot" strategy, is able to provide a reliable and more detailed reconstruction of the complex cortico-subcortical language network as compared to the standard DTI-FT. We believe this technique represents a beneficial new strategy for customized preoperative planning in patients affected by tumors in presumed language eloquent location, providing anatomo-functional information to plan language-preserving surgery. PMID- 27994538 TI - Auditory Motion Elicits a Visual Motion Aftereffect. AB - The visual motion aftereffect is a visual illusion in which exposure to continuous motion in one direction leads to a subsequent illusion of visual motion in the opposite direction. Previous findings have been mixed with regard to whether this visual illusion can be induced cross-modally by auditory stimuli. Based on research on multisensory perception demonstrating the profound influence auditory perception can have on the interpretation and perceived motion of visual stimuli, we hypothesized that exposure to auditory stimuli with strong directional motion cues should induce a visual motion aftereffect. Here, we demonstrate that horizontally moving auditory stimuli induced a significant visual motion aftereffect-an effect that was driven primarily by a change in visual motion perception following exposure to leftward moving auditory stimuli. This finding is consistent with the notion that visual and auditory motion perception rely on at least partially overlapping neural substrates. PMID- 27994539 TI - Dynamic Control of Neurotransmitter Release by Presynaptic Potential. AB - Action potentials (APs) in the mammalian brain are thought to represent the smallest unit of information transmitted by neurons to their postsynaptic targets. According to this view, neuronal signaling is all-or-none or digital. Increasing evidence suggests, however, that subthreshold changes in presynaptic membrane potential before triggering the spike also determines spike-evoked release of neurotransmitter. We discuss here how analog changes in presynaptic voltage may regulate spike-evoked release of neurotransmitter through the modulation of biophysical state of voltage-gated potassium, calcium and sodium channels in the presynaptic compartment. The contribution of this regulation has been greatly underestimated and we discuss the impact for information processing in neuronal circuits. PMID- 27994540 TI - Abeta and Inflammatory Stimulus Activate Diverse Signaling Pathways in Monocytic Cells: Implications in Retaining Phagocytosis in Abeta-Laden Environment. AB - Background: Accumulation of amyloid beta (Abeta) is one of the main hallmarks of Alzheimer's disease (AD). The enhancement of Abeta clearance may provide therapeutic means to restrict AD pathology. The cellular responses to different forms of Abeta in monocytic cells are poorly known. We aimed to study whether different forms of Abeta induce inflammatory responses in monocytic phagocytes and how Abeta may affect monocytic cell survival and function to retain phagocytosis in Abeta-laden environment. Methods: Monocytic cells were differentiated from bone marrow hematopoietic stem cells (HSC) in the presence of macrophage-colony stimulating factor. Monocytic cells were stimulated with synthetic Abeta42 and intracellular calcium responses were recorded with calcium imaging. The formation of reactive oxygen species (ROS), secretion of cytokines and cell viability were also assessed. Finally, monocytic cells were introduced to native Abeta deposits ex vivo and the cellular responses in terms of cell viability, pro-inflammatory activation and phagocytosis were determined. The ability of monocytic cells to phagocytose Abeta plaques was determined after intrahippocampal transplantation in vivo. Results: Freshly solubilized Abeta induced calcium oscillations, which persisted after removal of the stimulus. After few hours of aggregation, Abeta was not able to induce oscillations in monocytic cells. Instead, lipopolysaccharide (LPS) induced calcium responses divergent from Abeta-induced response. Furthermore, while LPS induced massive production of pro-inflammatory cytokines, neither synthetic Abeta species nor native Abeta deposits were able to induce pro-inflammatory activation of monocytic cells, contrary to primary microglia. Finally, monocytic cells retained their viability in the presence of Abeta and exhibited phagocytic activity towards native fibrillar Abeta deposits and congophilic Abeta plaques. Conclusion: Monocytic cells carry diverse cellular responses to Abeta and inflammatory stimulus LPS. Even though Abeta species cause specific responses in calcium signaling, they completely lack the ability to induce pro-inflammatory phenotype of monocytic cells. Monocytes retain their viability and function in Abeta-laden brain. PMID- 27994541 TI - Localization of Brain Natriuretic Peptide Immunoreactivity in Rat Spinal Cord. AB - Brain natriuretic peptide (BNP) exerts its functions through NP receptors. Recently, BNP has been shown to be involved in a wide range of functions. Previous studies reported BNP expression in the sensory afferent fibers in the dorsal horn (DH) of the spinal cord. However, BNP expression and function in the neurons of the central nervous system are still controversial. Therefore, in this study, we investigated BNP expression in the rat spinal cord in detail using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RT-PCR analysis showed that BNP mRNA was present in the spinal cord and dorsal root ganglion (DRG). BNP immunoreactivity was observed in different structures of the spinal cord, including the neuronal cell bodies and neuronal processes. BNP immunoreactivity was observed in the DH of the spinal cord and in the neurons of the intermediate column (IC) and ventral horn (VH). Double-immunolabeling showed a high level of BNP expression in the afferent fibers (laminae I-II) labeled with calcitonin gene-related peptide (CGRP), suggesting BNP involvement in sensory function. In addition, BNP was co-localized with CGRP and choline acetyltransferase (ChAT) in the motor neurons of the VH. Together, these results indicate that BNP is expressed in sensory and motor systems of the spinal cord, suggesting its involvement in several biological actions on sensory and motor neurons via its binding to NP receptor-A (NPR-A) and/or NP receptor-B (NPR-B) at the spinal cord level. PMID- 27994542 TI - The Retrograde Connections and Anatomical Segregation of the Gottingen Minipig Nucleus Accumbens. AB - Nucleus accumbens (NAcc) has been implicated in several psychiatric disorders such as treatment resistant depression (TRD), and obsessive-compulsive disorder (OCD), and has been an ongoing experimental target for deep brain stimulation (DBS) in both rats and humans. In order to translate basic scientific results from rodents to the human setting a large animal model is needed to thoroughly study the effect of such therapeutic interventions. The aim of the study was, accordingly, to describe the basic anatomy of the Gottingen minipig NAcc and its retrograde connections. Tracing was carried out by MRI-guided stereotactic unilateral fluorogold injections in the NAcc of Gottingen minipigs. After 2 weeks the brains were sectioned and subsequently stained with Nissl-, autometallographic (AMG) development of myelin, and DARPP-32 and calbindin immunohistochemistry. The minipig NAcc was divided in a central core and an outer medial, ventral and lateral shell. We confirmed the NAcc to be a large and well segregated structure toward its medial, ventral and lateral borders. The fluorogold tracing revealed inputs to NAcc from the medial parts of the prefrontal cortex, BA 25 (subgenual cortex), insula bilaterally, amygdala, the CA1-region of hippocampus, entorhinal cortex, subiculum, paraventricular and anterior parts of thalamus, dorsomedial parts of hypothalamus, substantia nigra, ventral tegmental area (VTA), the retrorubral field and the dorsal and median raphe nuclei. In conclusion the Gottingen minipig NAcc is a large ventral striatal structure that can be divided into a core and shell with prominent afferent connections from several subrhinal and infra-/prelimbic brain areas. PMID- 27994544 TI - Seeking Temporal Predictability in Speech: Comparing Statistical Approaches on 18 World Languages. AB - Temporal regularities in speech, such as interdependencies in the timing of speech events, are thought to scaffold early acquisition of the building blocks in speech. By providing on-line clues to the location and duration of upcoming syllables, temporal structure may aid segmentation and clustering of continuous speech into separable units. This hypothesis tacitly assumes that learners exploit predictability in the temporal structure of speech. Existing measures of speech timing tend to focus on first-order regularities among adjacent units, and are overly sensitive to idiosyncrasies in the data they describe. Here, we compare several statistical methods on a sample of 18 languages, testing whether syllable occurrence is predictable over time. Rather than looking for differences between languages, we aim to find across languages (using clearly defined acoustic, rather than orthographic, measures), temporal predictability in the speech signal which could be exploited by a language learner. First, we analyse distributional regularities using two novel techniques: a Bayesian ideal learner analysis, and a simple distributional measure. Second, we model higher-order temporal structure-regularities arising in an ordered series of syllable timings testing the hypothesis that non-adjacent temporal structures may explain the gap between subjectively-perceived temporal regularities, and the absence of universally-accepted lower-order objective measures. Together, our analyses provide limited evidence for predictability at different time scales, though higher-order predictability is difficult to reliably infer. We conclude that temporal predictability in speech may well arise from a combination of individually weak perceptual cues at multiple structural levels, but is challenging to pinpoint. PMID- 27994543 TI - Repetitive TMS on Left Cerebellum Affects Impulsivity in Borderline Personality Disorder: A Pilot Study. AB - The borderline personality disorder (BPD) is characterized by a severe pattern of instability in emotional regulation, interpersonal relationships, identity and impulse control. These functions are related to the prefrontal cortex (PFC), and since PFC shows a rich anatomical connectivity with the cerebellum, the functionality of the cerebellar-PFC axis may impact on BPD. In this study, we investigated the potential involvement of cerebello-thalamo-cortical connections in impulsive reactions through a pre/post stimulation design. BPD patients (n = 8) and healthy controls (HC; n = 9) performed an Affective Go/No-Go task (AGN) assessing information processing biases for positive and negative stimuli before and after repetitive transcranial magnetic stimulation (rTMS; 1 Hz/10 min, 80% resting motor threshold (RMT) over the left lateral cerebellum. The AGN task consisted of four blocks requiring associative capacities of increasing complexity. BPD patients performed significantly worse than the HC, especially when cognitive demands were high (third and fourth block), but their performance approached that of HC after rTMS (rTMS was almost ineffective in HC). The more evident effect of rTMS in complex associative tasks might have occurred since the cerebellum is deeply involved in integration and coordination of different stimuli. We hypothesize that in BPD patients, cerebello-thalamo-cortical communication is altered, resulting in emotional dysregulation and disturbed impulse control. The rTMS over the left cerebellum might have interfered with existing functional connections exerting a facilitating effect on PFC control. PMID- 27994545 TI - More than a Rumor Spreads in Parkinson's Disease. AB - As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (alphaSyn) neuronal inclusions called Lewy bodies and Lewy neurites. Inclusions first appear in olfactory bulb and enteric neurons then in ascendant neuroanatomical interconnected areas, and finally, in late stages of the disease, Lewy bodies are observed in a substantia nigra pars compacta with clear signs of neuronal loss. It is believed that the spreading of Lewy bodies through the nervous system is a consequence of the cell to-cell propagation of alphaSyn, that can occur via sequential steps of secretion and uptake. Certain pathological forms of transmitted alphaSyn are able to seed endogenous counterparts in healthy recipient cells, thus promoting the self sustained cycle of inclusion formation, amplification and spreading, that ultimately underlies disease progression. Here we review the cell-to-cell propagation of alphaSyn focusing on its role in the progression of Parkinson's disease. PMID- 27994547 TI - Commentary: Utility of EEG measures of brain function in patients with acute stroke. PMID- 27994546 TI - Decreased Subcortical and Increased Cortical Degree Centrality in a Nonclinical College Student Sample with Subclinical Depressive Symptoms: A Resting-State fMRI Study. AB - Abnormal functional connectivity (FC) at rest has been identified in clinical depressive disorder. However, very few studies have been conducted to understand the underlying neural substrates of subclinical depression. The newly proposed centrality analysis approach has been increasingly used to explore the large scale brain network of mental diseases. This study aimed to identify the degree centrality (DC) alteration of the brain network in subclinical depressive subjects. Thirty-seven candidates with subclinical depression and 34 well-matched healthy controls (HCs) were recruited from the same sample of college students. All subjects underwent a resting-state fMRI (rs-fMRI) scan to assess the DC of the whole brain. Compared with controls, subclinical depressive subjects displayed decreased DC in the right parahippocampal gyrus (PHG), left PHG/amygdala, and left caudate and elevated DC in the right posterior parietal lobule (PPL), left inferior frontal gyrus (IFG) and left middle frontal gyrus (MFG). In addition, by using receiver operating characteristic (ROC) analysis, we determined that the DC values in the regions with altered FC between the two groups can be used to differentiate subclinical depressive subjects from HCs. We suggest that decreased DC in subcortical and increased DC in cortical regions might be the neural substrates of subclinical depression. PMID- 27994548 TI - Functional Brain Activity Changes after 4 Weeks Supplementation with a Multi Vitamin/Mineral Combination: A Randomized, Double-Blind, Placebo-Controlled Trial Exploring Functional Magnetic Resonance Imaging and Steady-State Visual Evoked Potentials during Working Memory. AB - This study explored the neurocognitive effects of 4 weeks daily supplementation with a multi-vitamin and -mineral combination (MVM) in healthy adults (aged 18-40 years). Using a randomized, double-blind, placebo-controlled design, participants underwent assessments of brain activity using functional Magnetic Resonance Imaging (fMRI; n = 32, 16 females) and Steady-State Visual Evoked Potential recordings (SSVEP; n = 39, 20 females) during working memory and continuous performance tasks at baseline and following 4 weeks of active MVM treatment or placebo. There were several treatment-related effects suggestive of changes in functional brain activity associated with MVM administration. SSVEP data showed latency reductions across centro-parietal regions during the encoding period of a spatial working memory task following 4 weeks of active MVM treatment. Complementary results were observed with the fMRI data, in which a subset of those completing fMRI assessment after SSVEP assessment (n = 16) demonstrated increased BOLD response during completion of the Rapid Visual Information Processing task (RVIP) within regions of interest including bilateral parietal lobes. No treatment-related changes in fMRI data were observed in those who had not first undergone SSVEP assessment, suggesting these results may be most evident under conditions of fatigue. Performance on the working memory and continuous performance tasks did not significantly differ between treatment groups at follow-up. In addition, within the fatigued fMRI sample, increased RVIP BOLD response was correlated with the change in number of target detections as part of the RVIP task. This study provides preliminary evidence of changes in functional brain activity during working memory associated with 4 weeks of daily treatment with a multi-vitamin and -mineral combination in healthy adults, using two distinct but complementary measures of functional brain activity. PMID- 27994549 TI - Research Lumbar Punctures among African Americans and Caucasians: Perception Predicts Experience. AB - African Americans are under-represented in Alzheimer's disease (AD)-related biomarker studies, and it has been speculated that mistrust plays a major factor in the recruitment of African Americans for studies involving invasive procedures such as the lumbar puncture (LP). We set out to determine factors associated with non-participation in a biomarker study aiming to explore cerebrospinal fluid (CSF) AD biomarker differences between older African Americans and Caucasians. We also surveyed participants' procedure-related perception (a standard medical procedure vs. a frightening invasive procedure) and reluctance, as well as the rate and type of post-procedure discomfort and complications. Among 288 subjects approached for study participation, 145 (50.3%) refused participation with concerns over LP being the most commonly reported reason. Relatively more African Americans than Caucasians reported concerns over LP as the main reason for non participation (46% vs. 25%, p = 0.03), but more African Americans also did not provide a specific reason for non-participation. Among those who completed study participation (including the LP), African Americans and Caucasians were similar in pre-LP perceptions and reluctance, as well as post-LP rates of discomfort or complication. Perceiving LP as a frightening invasive procedure, not race, is associated with increased likelihood of post-LP discomfort or complication (RR 6.2, 95% confidence interval 1.1-37.0). Our results indicate that LP is a well perceived procedure in a cohort of African American and Caucasian research participants, and is associated with few serious complications. The pre-procedure perception that the LP is a frightening invasive procedure significantly increases the risk of self-reported discomfort of complications, and African Americans may be more likely to turn down study participation because of the LP. Future studies will need to address factors associated with negative LP perceptions to further assure participants and reduce complication rates. PMID- 27994550 TI - Anti-Proliferative and Apoptosis-Inducing Effect of Theabrownin against Non-small Cell Lung Adenocarcinoma A549 Cells. AB - With the highest cancer incidence rate, lung cancer, especially non-small cell lung cancer (NSCLC), is the leading cause of cancer death in the world. Tea (leaves of Camellia sinensis) has been widely used as a traditional beverage beneficial to human health, including anti-NSCLC activity. Theabrownin (TB) is one major kind of tea pigment responsible for the beneficial effects of tea liquor. However, its effect on NSCLC is unknown. The aim of the present study was to evaluate anti-proliferative and apoptosis-inducing effect of TB on NSCLC (A549) cells, using MTT assay, morphological observation (DAPI staining), in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and annexin-V/PI flow cytometry. Subsequently, the expression of several genes associated with cell proliferation and apoptosis were detected by real time PCR assay to explore its potential underlying mechanism. TB was revealed to inhibit cell proliferation of A549 cells in a concentration-dependent and time-dependent manner. Morphological observation, TUNEL assay and flow cytometric analysis evidenced an apoptosis-inducing effect of TB on A549 cells in a concentration dependent manner. The real time PCR assay demonstrated that TB down-regulated the expression of TOPO I, TOPO II, and BCL-2, and up-regulated the expression of E2F1, P53, GADD45, BAX, BIM, and CASP 3,7,8,9, which suggests an activation of P53-mediated apoptotic (caspase-dependent) pathway in response to TB treatment. The western blot analysis showed a similar trend for the corresponding protein expression (P53, Bax, Bcl-2, caspase 3,9, and PARP) and further revealed DNA damage as a trigger of the apoptosis (phosphorylation of histone H2A.X). Accordingly, TB can be speculated as a DNA damage inducer and topoisomerase (Topo I and Topo II) inhibitor that can up-regulate P53 expression and subsequently modulate the expression of the downstream genes to induce cell proliferation inhibition and apoptosis of A549 cells. Our results indicate that TB exhibits its anti-NSCLC activity via a P53-dependent mechanism, which may be a promising candidate of natural product for anti-cancer drug development in the treatment of NSCLC. PMID- 27994551 TI - The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties. AB - Tigecycline (TIG), the first member of glycylcycline bacteriostatic agents, has been approved to treat complicated infections in the clinic because of its expanded-spectrum antibiotic potential. Recently, an increasing number of studies have emphasized the anti-tumor effects of TIG. The inhibitory effects of TIG on cancer depend on several activating signaling pathways and abnormal mitochondrial function in cancer cells. The aim of this review is to summarize the cumulative anti-tumor evidence supporting TIG activity against different cancer types, including acute myeloid leukemia (AML), glioma, non-small cell lung cancer (NSCLC), among others. In addition, the efficacy and side effects of TIG in cancer patients are summarized in detail. Future clinical trials are also to be discussed that will evaluate the security and validate the underlying the tumor killing properties of TIG. PMID- 27994552 TI - Exercise Training Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Stenosis. AB - Introduction: Pulmonary arterial stenosis (PAS) is a congenital defect that causes outflow tract obstruction of the right ventricle (RV). Currently, negative issues are reported in the PAS management: not all patients may be eligible to surgeries; there is often the need for another surgery during passage to adulthood; patients with mild stenosis may have later cardiac adverse repercussions. Thus, the search for approaches to counteract the long-term PAS effects showed to be a current target. At the study herein, we evaluated the cardioprotective role of exercise training in rats submitted to PAS for 9 weeks. Methods and Results: Exercise resulted in improved physical fitness and systolic RV function. Exercise also blunted concentric cavity changes, diastolic dysfunction, and fibrosis induced by PAS. Exercise additional benefits were also reported in a pro-survival signal, in which there were increased Akt1 activity and normalized myocardial apoptosis. These findings were accompanied by microRNA 1 downregulation and microRNA-21 upregulation. Moreover, exercise was associated with a higher myocardial abundance of the sarcomeric protein alpha-MHC and proteins that modulate calcium handling-ryanodine receptor and Serca 2, supporting the potential role of exercise in improving myocardial performance. Conclusion: Our results represent the first demonstration that exercise can attenuate the RV remodeling in an experimental PAS. The cardioprotective effects were associated with positive modulation of RV function, survival signaling pathway, apoptosis, and proteins involved in the regulation of myocardial contractility. PMID- 27994553 TI - Parameter Identifiability of Fundamental Pharmacodynamic Models. AB - Issues of parameter identifiability of routinely used pharmacodynamics models are considered in this paper. The structural identifiability of 16 commonly applied pharmacodynamic model structures was analyzed analytically, using the input output approach. Both fixed-effects versions (non-population, no between-subject variability) and mixed-effects versions (population, including between-subject variability) of each model structure were analyzed. All models were found to be structurally globally identifiable under conditions of fixing either one of two particular parameters. Furthermore, an example was constructed to illustrate the importance of sufficient data quality and show that structural identifiability is a prerequisite, but not a guarantee, for successful parameter estimation and practical parameter identifiability. This analysis was performed by generating artificial data of varying quality to a structurally identifiable model with known true parameter values, followed by re-estimation of the parameter values. In addition, to show the benefit of including structural identifiability as part of model development, a case study was performed applying an unidentifiable model to real experimental data. This case study shows how performing such an analysis prior to parameter estimation can improve the parameter estimation process and model performance. Finally, an unidentifiable model was fitted to simulated data using multiple initial parameter values, resulting in highly different estimated uncertainties. This example shows that although the standard errors of the parameter estimates often indicate a structural identifiability issue, reasonably "good" standard errors may sometimes mask unidentifiability issues. PMID- 27994555 TI - Physiological Adjustments and Circulating MicroRNA Reprogramming Are Involved in Early Acclimatization to High Altitude in Chinese Han Males. AB - Background: Altitude acclimatization is a physiological process that restores oxygen delivery to the tissues and promotes oxygen use under high altitude hypoxia. High altitude sickness occurs in individuals without acclimatization. Unraveling the molecular underpinnings of altitude acclimatization could help understand the beneficial body responses to high altitude hypoxia as well as the altered biological events in un-acclimatized individuals. This study assessed physiological adjustments and circulating microRNA (cmiRNA) profiles in individuals exposed to high altitude, aiming to explore altitude acclimatization in humans. Methods: Ninety volunteers were enrolled in this study. Among them, 22 individuals provided samples for microRNA arrays; 68 additional individuals constituted the validation set. Un-acclimatized individuals were identified by the Lake Louise Scoring System. Thirty-three phenotypes were recorded pre- and post-exposure to high altitude, including stress hormones, lipid profiles, hematological indices, myocardial enzyme spectrum, and liver and kidney function related enzymes. CmiRNA expression profiles were assessed using miRCURYTM LNA Array (v.18.0) screening, with data validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, associations of plasma microRNA expression with physiological adjustments were evaluated. The biological relevance of the main differentially expressed cmiRNAs was explored by bioinformatics prediction. Results: Nineteen of the 33 phenotypes were significantly altered during early altitude acclimatization, including hematological indices, lipid profiles, and stress hormones; meanwhile, 86 cmiRNAs (79 up-regulated and 7 down-regulated) showed differential expression with statistical significance. Among them, 32 and 25 microRNAs were strongly correlated with low-density lipoprotein-cholesterol and total cholesterol elevations, respectively. In addition, 22 microRNAs were closely correlated with cortisol increase. In un-acclimatized individuals, 55 cmiRNAs were up-regulated and 36 down-regulated, compared with acclimatized individuals. The HIF signaling pathway was suppressed in un-acclimatized individuals. Conclusion: Physiological adjustments, including the hematological system, stress hormones, and lipid molecules contributed to early altitude acclimatization, and showed strong correlations with cmiRNA reprogramming. Moreover, acclimatized and un acclimatized individuals showed different cmiRNA profile. Suppression of the HIF 1 signaling pathway by microRNA regulation may play a key role in the pathogenesis of un-acclimatization with high altitude hypoxia. PMID- 27994556 TI - Endurance Performance during Severe-Intensity Intermittent Cycling: Effect of Exercise Duration and Recovery Type. AB - Slow component of oxygen uptake (VO2SC) kinetics and maximal oxygen uptake (VO2max) attainment seem to influence endurance performance during constant-work rate exercise (CWR) performed within the severe intensity domain. In this study, it was hypothesized that delaying the attainment of VO2max by reducing the rates at which VO2 increases with time (VO2SC kinetics) would improve the endurance performance during severe-intensity intermittent exercise performed with different work:recovery duration and recovery type in active individuals. After the estimation of the parameters of the VO2SC kinetics during CWR exercise, 18 males were divided into two groups (Passive and Active recovery) and performed at different days, two intermittent exercises to exhaustion (at 95% IVO2max, with work: recovery ratio of 2:1) with the duration of the repetitions calculated from the onset of the exercise to the beginning of the VO2SC (Short) or to the half duration of the VO2SC (Long). The active recovery was performed at 50% IVO2max. The endurance performance during intermittent exercises for the Passive (Short = 1523 +/- 411; Long = 984 +/- 260 s) and Active (Short = 902 +/- 239; Long = 886 +/- 254 s) groups was improved compared with CWR condition (Passive = 540 +/- 116; Active = 489 +/- 84 s). For Passive group, the endurance performance was significantly higher for Short than Long condition. However, no significant difference between Short and Long conditions was found for Active group. Additionally, the endurance performance during Short condition was higher for Passive than Active group. The VO2SC kinetics was significantly increased for CWR (Passive = 0.16 +/- 0.04; Active = 0.16 +/- 0.04 L.min-2) compared with Short (Passive = 0.01 +/- 0.01; Active = 0.03 +/- 0.04 L.min-2) and Long (Passive = 0.02 +/- 0.01; Active = 0.01 +/- 0.01 L.min-2) intermittent exercise conditions. No significant difference was found among the intermittent exercises. It can be concluded that the endurance performance is negatively influenced by active recovery only during shorter high-intensity intermittent exercise. Moreover, the improvement in endurance performance seems not be explained by differences in the VO2SC kinetics, since its values were similar among all intermittent exercise conditions. PMID- 27994554 TI - Effect of Environmental and Feedback Interventions on Pacing Profiles in Cycling: A Meta-Analysis. AB - In search of their optimal performance athletes will alter their pacing strategy according to intrinsic and extrinsic physiological, psychological and environmental factors. However, the effect of some of these variables on pacing and exercise performance remains somewhat unclear. Therefore, the aim of this meta-analysis was to provide an overview as to how manipulation of different extrinsic factors affects pacing strategy and exercise performance. Only self paced exercise studies that provided control and intervention group(s), reported trial variance for power output, disclosed the type of feedback received or withheld, and where time-trial power output data could be segmented into start, middle and end sections; were included in the meta-analysis. Studies with similar themes were grouped together to determine the mean difference (MD) with 95% confidence intervals (CIs) between control and intervention trials for: hypoxia, hyperoxia, heat-stress, pre-cooling, and various forms of feedback. A total of 26 studies with cycling as the exercise modality were included in the meta-analysis. Of these, four studies manipulated oxygen availability, eleven manipulated heat stress, four implemented pre-cooling interventions and seven studies manipulated various forms of feedback. Mean power output (MPO) was significantly reduced in the middle and end sections (p < 0.05), but not the start section of hypoxia and heat-stress trials compared to the control trials. In contrast, there was no significant change in trial or section MPO for hyperoxic or pre-cooling conditions compared to the control condition (p > 0.05). Negative feedback improved overall trial MPO and MPO in the middle section of trials (p < 0.05), while informed feedback improved overall trial MPO (p < 0.05). However, positive, neutral and no feedback had no significant effect on overall trial or section MPO (p > 0.05). The available data suggests exercise regulation in hypoxia and heat stress is delayed in the start section of trials, before significant reductions in MPO occur in the middle and end of the trial. Additionally, negative feedback involving performance deception may afford an upward shift in MPO in the middle section of the trial improving overall performance. Finally, performance improvements can be retained when participants are informed of the deception. PMID- 27994557 TI - Intervertebral Disc Swelling Demonstrated by 3D and Water Content Magnetic Resonance Analyses after a 3-Day Dry Immersion Simulating Microgravity. AB - Background: Vertebral deconditioning is commonly experienced after space flight and simulation studies. Disc herniation is quadrupled after space flight. Purpose: The main hypothesis formulated by the authors is that microgravity results in intervertebral disc (IVD) swelling. Study Design: The aim of the study was to identify the morphological changes of the spine and their clinical consequences after simulated microgravity by 3-day dry immersion (DI). The experimental protocol was performed on 12 male volunteers using magnetic resonance imaging and spectroscopy before and after DI. Methods: All the experiment was financially supported by CNES (Centre national d'etudes spatiales i.e., French Space Agency). Results: We observed an increase in spine height of 1.5 +/- 0.4 cm and a decrease in curvature, particularly for the lumbar region with a decrease of -4 +/- 2.5 degrees . We found a significant increase in IVD volume of +8 +/- 9% at T12-L1 and +11 +/- 9% at L5-S1. This phenomenon is likely associated with the increase in disc intervertebral water content (IWC), 17 +/- 27%. During the 3 days in DI, 92% of the subjects developed back pain in the lumbar region below the diaphragmatic muscle. This clinical observation may be linked to the morphological changes of the spine. Conclusions: The morphological changes observed and, specifically, the disc swelling caused by increased IWC may contribute to understanding disc herniation after microgravity exposure. Our results confirmed the efficiency of the 3-day DI model to reproduce quickly the effects of microgravity on spine morphology. Our findings raise the question of the subject selection in spatial studies, especially studies about spine morphology and reconditioning programs after space flight. These results may contribute to a better understanding of the mechanisms underlying disc herniation and may serve as the basis to develop countermeasures for astronauts and to prevent IVD herniation and back pain on Earth. PMID- 27994558 TI - Epigallocatechin-3-Gallate Accelerates Relaxation and Ca2+ Transient Decay and Desensitizes Myofilaments in Healthy and Mybpc3-Targeted Knock-in Cardiomyopathic Mice. AB - Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disease with left ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction. Increased myofilament Ca2+ sensitivity could be the underlying cause of diastolic dysfunction. Epigallocatechin-3-gallate (EGCg), a catechin found in green tea, has been reported to decrease myofilament Ca2+ sensitivity in HCM models with troponin mutations. However, whether this is also the case for HCM-associated thick filament mutations is not known. Therefore, we evaluated whether EGCg affects the behavior of cardiomyocytes and myofilaments of an HCM mouse model carrying a gene mutation in cardiac myosin-binding protein C and exhibiting both increased myofilament Ca2+ sensitivity and diastolic dysfunction. Methods and Results: Acute effects of EGCg were tested on fractional sarcomere shortening and Ca2+ transients in intact ventricular myocytes and on force-Ca2+ relationship of skinned ventricular muscle strips isolated from Mybpc3 targeted knock-in (KI) and wild-type (WT) mice. Fractional sarcomere shortening and Ca2+ transients were analyzed at 37 degrees C under 1-Hz pacing in the absence or presence of EGCg (1.8 MUM). At baseline and in the absence of Fura-2, KI cardiomyocytes displayed lower diastolic sarcomere length, higher fractional sarcomere shortening, longer time to peak shortening and time to 50% relengthening than WT cardiomyocytes. In WT and KI neither diastolic sarcomere length nor fractional sarcomere shortening were influenced by EGCg treatment, but relaxation time was reduced, to a greater extent in KI cells. EGCg shortened time to peak Ca2+ and Ca2+ transient decay in Fura-2-loaded WT and KI cardiomyocytes. EGCg did not influence phosphorylation of phospholamban. In skinned cardiac muscle strips, EGCg (30 MUM) decreased Ca2+ sensitivity in both groups. Conclusion: EGCg hastened relaxation and Ca2+ transient decay to a larger extent in KI than in WT cardiomyocytes. This effect could be partially explained by myofilament Ca2+ desensitization. PMID- 27994559 TI - Impaired Attentional Control in Pedophiles in a Sexual Distractor Task. AB - Pedophilic disorder, a subtype of paraphilia, is defined as a recurrent sexual interest in prepubescent children, which is characterized by persistent thoughts, fantasies, urges, sexual arousal, or behavior. Besides a deviant sexual preference, sexual preoccupation was found to be a dynamic risk factor for reoffending. Thus, it is conceivable that sex offenders and especially sex offenders against children have difficulties to control their responses to sexual stimuli. In the current study pedophiles, forensic and non-forensic control subjects had to solve a cognitive task, while sexual distractors were presented simultaneously. This kind of task also requires control functions. Therefore, data were analyzed with respect to attentional control while comparing eye movements toward sexual distractors and toward the cognitive task. We were mainly interested in how early (fixation latency) and late (relative fixation time) attentional processes were allocated to both, the cognitive target stimuli and the sexual distractors. Pedophiles demonstrated significantly lower attentional control in the sexual distractor task than both control groups (non-pedophiles). They showed a shorter fixation latency and longer fixation time for sexual distractors than non-pedophiles. Furthermore, pedophiles demonstrated a longer fixation latency and shorter fixation time for cognitive target stimuli. For classification analyses, an attentional control index (ACI) was built, i.e., the difference between eye movements on cognitive target stimuli and sexual distractors. For the ACI of early attentional processes, i.e., fixation latency, a good classification between pedophiles and non-pedophiles was found. We assumed that the measured attentional control represents inhibitory executive functions, specifically interference control. Further studies should examine if low attentional control in pedophiles is due to low motivation to solve the task or rather to a lack of ability to control attention with respect to sexual and/or neutral distractors. Prospectively, this design could be useful to generate hypotheses about clinical important aspects of controllability, the capacity of self-control, and the severity of a paraphilic disorder. PMID- 27994560 TI - Editorial: Models of Reference. PMID- 27994561 TI - How Is Existential Threat Related to Intergroup Conflict? Introducing the Multidimensional Existential Threat (MET) Model. AB - Existential threat lies at the heart of intergroup conflict, but the literature on existential concerns lacks clear conceptualization and integration. To address this problem, we offer a new conceptualization and measurement of existential threat. We establish the reliability and validity of our measure, and to illustrate its utility, we examine whether different existential threats underlie the association between political ideology and support for specific political policies. Study 1 (N = 798) established the construct validity of the scale, and revealed four distinct existential threats: personal death (PD), physical collective annihilation (PA), symbolic collective annihilation (SA), and past victimization (PV). Study 2 (N = 424) confirmed the 4-factor structure, and the convergent and discriminant validity of the scale. Study 3 (N = 170) revealed that the association between a hawkish political ideology and support for hardline policies was mediated by PV, whereas the association between a dovish political ideology and conciliatory policies was mediated by concerns over collective symbolic annihilation. Study 4 (N = 503) conceptually replicated the pattern of findings found in Study 3, and showed that at times of conflict, PA concerns also mediate the relationship between hawkish ideologies and support for hardline policies. In both Studies 3 and 4, when controlling for other threats, PD did not play a significant role. These results underscore the need to consider the multidimensional nature of existential threat, especially in the context of political conflict. PMID- 27994562 TI - The ToMenovela - A Photograph-Based Stimulus Set for the Study of Social Cognition with High Ecological Validity. AB - We present the ToMenovela, a stimulus set that has been developed to provide a set of normatively rated socio-emotional stimuli showing varying amount of characters in emotionally laden interactions for experimental investigations of (i) cognitive and (ii) affective Theory of Mind (ToM), (iii) emotional reactivity, and (iv) complex emotion judgment with respect to Ekman's basic emotions (happiness, anger, disgust, fear, sadness, surprise, Ekman and Friesen, 1975). Stimuli were generated with focus on ecological validity and consist of 190 scenes depicting daily-life situations. Two or more of eight main characters with distinct biographies and personalities are depicted on each scene picture. To obtain an initial evaluation of the stimulus set and to pave the way for future studies in clinical populations, normative data on each stimulus of the set was obtained from a sample of 61 neurologically and psychiatrically healthy participants (31 female, 30 male; mean age 26.74 +/- 5.84), including a visual analog scale rating of Ekman's basic emotions (happiness, anger, disgust, fear, sadness, surprise) and free-text descriptions of the content of each scene. The ToMenovela is being developed to provide standardized material of social scenes that are available to researchers in the study of social cognition. It should facilitate experimental control while keeping ecological validity high. PMID- 27994563 TI - Estimation and Identifiability of Model Parameters in Human Nociceptive Processing Using Yes-No Detection Responses to Electrocutaneous Stimulation. AB - Healthy or pathological states of nociceptive subsystems determine different stimulus-response relations measured from quantitative sensory testing. In turn, stimulus-response measurements may be used to assess these states. In a recently developed computational model, six model parameters characterize activation of nerve endings and spinal neurons. However, both model nonlinearity and limited information in yes-no detection responses to electrocutaneous stimuli challenge to estimate model parameters. Here, we address the question whether and how one can overcome these difficulties for reliable parameter estimation. First, we fit the computational model to experimental stimulus-response pairs by maximizing the likelihood. To evaluate the balance between model fit and complexity, i.e., the number of model parameters, we evaluate the Bayesian Information Criterion. We find that the computational model is better than a conventional logistic model regarding the balance. Second, our theoretical analysis suggests to vary the pulse width among applied stimuli as a necessary condition to prevent structural non-identifiability. In addition, the numerically implemented profile likelihood approach reveals structural and practical non-identifiability. Our model-based approach with integration of psychophysical measurements can be useful for a reliable assessment of states of the nociceptive system. PMID- 27994564 TI - The Temporal Order of Word Presentation Modulates the Amplitudes of P2 and N400 during Recognition of Causal Relations. AB - The processing of causal relations has been constantly found to be asymmetrical once the roles of cause and effect are assigned to objects in interactions. We used a relationship recognition paradigm and recorded electroencephalographic (EEG) signals to explore the neural mechanism underlying the asymmetrical representations of causal relations in semantic memory. The results revealed that the verification of causal relations is faster if two words appear in "cause effect" order (e.g., virus-epidemic) than if they appear in "effect-cause" order (e.g., epidemic-virus), whereas no such asymmetrical representation was found for the verification of hierarchical relations with reverse orders (e.g., bird sparrow vs. sparrow-bird) in Experiment 1. Furthermore, the P2 amplitude elicited by "superordinate-subordinate" order was larger than that when in reverse order, whereas the N400 effect elicited by "cause-effect" order was smaller (more positive) than when in reverse order. However, no such asymmetry, as well as P2 and N400 components, were observed when verifying the existence of a general associative relation in Experiment 2. We suggested that the smaller N400 in cause effect order indicates their increased salience in semantic memory relative to the effect-cause order. These results provide evidence for dissociable neural processes, which are related to role binding, contributing to the generation of causal asymmetry. PMID- 27994565 TI - Have We Forgotten Auditory Sensory Memory? Retention Intervals in Studies of Nonverbal Auditory Working Memory. AB - Researchers have shown increased interest in mechanisms of working memory for nonverbal sounds such as music and environmental sounds. These studies often have used two-stimulus comparison tasks: two sounds separated by a brief retention interval (often 3-5 s) are compared, and a "same" or "different" judgment is recorded. Researchers seem to have assumed that sensory memory has a negligible impact on performance in auditory two-stimulus comparison tasks. This assumption is examined in detail in this comment. According to seminal texts and recent research reports, sensory memory persists in parallel with working memory for a period of time following hearing a stimulus and can influence behavioral responses on memory tasks. Unlike verbal working memory studies that use serial recall tasks, research paradigms for exploring nonverbal working memory especially two-stimulus comparison tasks-may not be differentiating working memory from sensory memory processes in analyses of behavioral responses, because retention interval durations have not excluded the possibility that the sensory memory trace drives task performance. This conflation of different constructs may be one contributor to discrepant research findings and the resulting proliferation of theoretical conjectures regarding mechanisms of working memory for nonverbal sounds. PMID- 27994566 TI - Cultural and Personality Predictors of Facebook Intrusion: A Cross-Cultural Study. AB - The increase in the number of users of social networking sites (SNS) has inspired intense efforts to determine intercultural differences between them. The main aim of the study was to investigate the cultural and personal predictors of Facebook intrusion. A total of 2628 Facebook users from eight countries took part in the study. The Facebook Intrusion Questionnaire, the Ten-Item Personality Inventory, and the Singelis Scale were used. We found that two variables related to Country were significantly related to Facebook intrusion: uniqueness (negatively) and low context (positively); of the personality variables, conscientiousness, and emotional stability were negatively related to the dependent variable of Facebook intrusion across different countries, which may indicate the universal pattern of Facebook intrusion. The results of the study will contribute to the international debate on the phenomenon of SNS. PMID- 27994567 TI - Subliminal Impending Collision Increases Perceived Object Size and Enhances Pupillary Light Reflex. AB - Fast detection of ambient danger is crucial for the survival of biological entities. Previous studies have shown that threatening information can bias human visual perception and enhance physiological reactions. It remains to be delineated whether the modulation of threat on human perceptual and physiological responses can take place below awareness. To probe this issue, we adopted visual looming stimuli and created two levels of threat by varying their motion trajectories to the observers, such that the stimuli could move in a path that either collided with the observers' heads or just nearly missed. We found that when the observers could not explicitly discriminate any difference between the collision and the near-miss stimuli, the visual stimuli on the collision course appeared larger and evoked greater pupil constrictions than those on the near miss course. Furthermore, the magnitude of size overestimation was comparable to when the impending collision was consciously perceived. Our findings suggest that threatening information can bias human visual perception and strengthen pupil constrictions independent of conscious representation of the threat, and imply the existence of the subcortical visual pathway dedicated to automatically processing threat-related signals in humans. PMID- 27994568 TI - The Impact of Self-Narratives of Motherhood for Mothers of Children with Autism. AB - The main goal of this study was to identify the impact of a narrative construction of a life challenge - discovering to have a child with autism - on the meaning of life and on resources for coping depending on the challenge's novelty, i.e., the number of years from the diagnosis. Three hundred and sixty four mothers of children with autism participated in a long-term 3 * 2 experiment. Half of the mothers had children with autism at the age of 9-12 years. For the remaining half, having children with autism was a new and stressful life situation. Their children were 2-3 years old and just diagnosed by a medical center as having autism spectrum disorder. The mothers were assigned to one of three study conditions: they were either asked to write stories of their motherhood or to describe their children's behavior on a questionnaire or they did not participate in any tasks. One month and then 4 months after this task the participants completed measures of meaning of life and several well-being scales. The results indicated that following the narrative writing the participants had the highest scores on the meaning of life and well-being scales. This affect was sustained over 4 months and was significant only for mothers with older children. The mediation analysis showed that the effects of the experimental conditions on different well-being scales were mediated by the changes in perceived meaning of life. The results suggest that construction of self-narratives of difficult ongoing challenges facilitates meaning making and subsequently strengthens resources for coping. However, it seems that a meaning-making construction of such self-story may be blocked by the uncertainty and stress caused by novelty of the challenging situation. PMID- 27994569 TI - Developmental Changes in Children's Processing of Redundant Modifiers in Definite Object Descriptions. AB - This paper investigates developmental changes in children's processing of redundant information in definite object descriptions. In two experiments, children of two age groups (6 or 7, and 9 or 10 years old) were presented with pictures of sweets. In the first experiment (pairwise comparison), two identical sweets were shown, and one of these was described with a redundant modifier. After the description, the children had to indicate the sweet they preferred most in a forced-choice task. In the second experiment (graded rating), only one sweet was shown, which was described with a redundant color modifier in half of the cases (e.g., "the blue sweet") and in the other half of the cases simply as "the sweet." This time, the children were asked to indicate on a 5-point rating scale to what extent they liked the sweets. In both experiments, the results showed that the younger children had a preference for the sweets described with redundant information, while redundant information did not have an effect on the preferences for the older children. These results imply that children are learning to distinguish between situations in which redundant information carries an implicature and situations in which this is not the case. PMID- 27994571 TI - Rupture Risk Assessment for Mirror Aneurysms with Different Outcomes in the Same Patient. AB - BACKGROUND: The purpose of this research was to analyze the effect of morphologic and hemodynamic characteristics on mirror aneurysms in which one ruptured and the other did not, within the same patient, and to identify reliable predictors of rupture. METHODS: We performed three-dimensional angiographic imaging in 56 patients with intracranial mirror aneurysms for computational fluid dynamic studies from January 2009 to December 2015. The ruptured aneurysm simulations were conducted with geometry obtained after rupture. The significance of morphologic and hemodynamic parameters with respect to rupture was analyzed. Multivariate logistic regression analysis was applied to significant parameters to identify independent discriminators. RESULTS: Three morphologic factors (aneurysm size, aspect ratio, and size ratio) and two hemodynamic factors [time averaged mean wall shear stress (WSS) and low WSS area] were statistically associated with aneurysm rupture (p < 0.05). On multivariate logistic regression, a larger size (OR 2.572, p = 0.001) and lower WSS (OR 0.609, p = 0.045) were independent significant factors for rupture. CONCLUSION: Larger aneurysm size and lower WSS were independently associated with the rupture status of aneurysms. These findings need to be confirmed by large multicenter and multi-population studies. PMID- 27994570 TI - Historical Review of the Fluid-Percussion TBI Model. AB - Traumatic brain injury (TBI) is a major health concern worldwide. Laboratory studies utilizing animal models of TBI are essential for addressing pathological mechanisms of brain injury and development of innovative treatments. Over the past 75 years, pioneering head injury researchers have devised and tested a number of fluid percussive methods to reproduce the concussive clinical syndrome in animals. The fluid-percussion brain injury technique has evolved from early investigations that applied a generalized loading of the brain to more recent computer-controlled systems. Of the many preclinical TBI models, the fluid percussion technique is one of the most extensively characterized and widely used models. Some of the most important advances involved the development of the Stalhammer device to produce concussion in cats and the later characterization of this device for application in rodents. The goal of this historical review is to provide readers with an appreciation for the time and effort expended by the pioneering researchers who have led to today's state of the art fluid-percussion animal models of TBI. PMID- 27994572 TI - Examining Subcortical Infarcts in the Era of Acute Multimodality CT Imaging. AB - BACKGROUND: Lacunar infarct has been characterized as small subcortical infarct. It is postulated to occur from "in situ microatheroma or lipohyalinosis" in small vessel or lacunar mechanism. Based on this idea, such infarcts by lacunar mechanism should not be associated with large area of perfusion deficits that extend beyond the subcortical region to the cortical region. By contrast, selected small subcortical infarcts, as defined by MR imaging in the subacute and chronic stage, may initially have large perfusion deficit or related large vessel occlusions. These infarcts with "lacunar" phenotype may also be caused by disease in the parent vessel and may have very different stroke mechanism from small vessel disease. Our aim is to describe differences in imaging characteristics between patients with small subcortical infarction with "lacunar phenotype" from those with lacunar mechanism. MATERIALS AND METHODS: Patients undergoing acute CT perfusion/angiography (CTP/CTA) within 6 h of symptom onset and follow-up magnetic resonance imaging (MRI) for ischemic stroke were included (2009-2013). Lacunar infarct was defined as a single subcortical infarct <=20 mm on follow-up MRI. Presence of perfusion deficits, vessel occlusion, and infarct dimensions was compared between lacunar infarcts and other topographical infarct types. RESULTS: Overall, 182 patients (mean age 66.4 +/- 15.3 years, 66% males) were included. Lacunar infarct occurred in 31 (17%) patients. Of these, 12 (39%) patients had a perfusion deficit compared with those with any cortical infarction (120/142, 67%), and the smallest lacunar infarct with a perfusion deficit had a diameter of <5 mm. The majority of patients with lacunar infarction (8/12, 66.7%) had a relevant vessel occlusion. A quarter of lacunar infarcts had a large artery stroke mechanism evident on acute CTP/CTA. Lacunar mechanism was present in 3/8 patients with corona radiata, 5/10 lentiform nucleus, 5/6 posterior limb of internal capsule (PLIC), 3/5 thalamic infarcts, 1/2 miscellaneous locations. There was a trend to significant with regards to finding lacunar mechanism among patients with thalamic and PLIC infarcts versus lentiform nucleus and corona radiata infarcts (p = 0.13). CONCLUSION: Diverse stroke mechanisms were present among subcortical infarcts in different locations. When available acute CTP/CTA should be combined with subacute imaging of subcortical infarct to separate "lacunar phenotype" from those with lacunar mechanism. PMID- 27994574 TI - Commentary: Tumefactive Demyelinating Lesions as a First Clinical Event: Clinical, Imaging, and Follow-up Observations. PMID- 27994573 TI - Sudden Infant Death Syndrome - Role of Trigeminocardiac Reflex: A Review. AB - Sudden infant death syndrome (SIDS) is an unexplained death in infants, which usually occurs during sleep. The cause of SIDS remains unknown and multifactorial. In this regard, the diving reflex (DR), a peripheral subtype of trigeminocardiac reflex (TCR), is also hypothesized as one of the possible mechanisms for this condition. The TCR is a well-established neurogenic reflex that manifests as bradycardia, hypotension, apnea, and gastric hypermotility. The TCR shares many similarities with the DR, which is a significant physiological adaptation to withstand hypoxia during apnea in many animal species including humans in clinical manifestation and mechanism of action. The DR is characterized by breath holding (apnea), bradycardia, and vasoconstriction, leading to increase in blood pressure. Several studies have described congenital anomalies of autonomic nervous system in the pathogenesis of SIDS such as hypoplasia, delayed neuronal maturation, or decreased neuronal density of arcuate nucleus, hypoplasia, and neuronal immaturity of the hypoglossal nucleus. The abnormalities of autonomic nervous system in SIDS may explain the role of TCR in this syndrome involving sympathetic and parasympathetic nervous system. We reviewed the available literature to identify the role of TCR in the etiopathogenesis of SIDS and the pathways and cellular mechanism involved in it. This synthesis will help to update our knowledge and improve our understanding about this mysterious, yet common condition and will open the door for further research in this field. PMID- 27994575 TI - High-Level Heat Resistance of Spores of Bacillus amyloliquefaciens and Bacillus licheniformis Results from the Presence of a spoVA Operon in a Tn1546 Transposon. AB - Bacterial endospore formers can produce spores that are resistant to many food processing conditions, including heat. Some spores may survive heating processes aimed at production of commercially sterile foods. Recently, it was shown that a spoVA operon, designated spoVA2mob, present on a Tn1546 transposon in Bacillus subtilis, leads to profoundly increased wet heat resistance of B. subtilis spores. Such Tn1546 transposon elements including the spoVA2mob operon were also found in several strains of Bacillus amyloliquefaciens and Bacillus licheniformis, and these strains were shown to produce spores with significantly higher resistances to wet heat than their counterparts lacking this transposon. In this study, the locations and compositions of Tn1546 transposons encompassing the spoVA2mob operons in B. amyloliquefaciens and B. licheniformis were analyzed. Introduction of these spoVA2mob operons into B. subtilis 168 (producing spores that are not highly heat resistant) rendered mutant 168 strains that produced high-level heat resistant spores, demonstrating that these elements in B. amyloliquefaciens and B. licheniformis are responsible for high level heat resistance of spores. Assessment of growth of the nine strains of each species between 5.2 degrees C and 57.7 degrees C showed some differences between strains, especially at lower temperatures, but all strains were able to grow at 57.7 degrees C. Strains of B. amyloliquefaciens and B. licheniformis that contain the Tn1546 elements (and produce high-level heat resistant spores) grew at temperatures similar to those of their Tn1546-negative counterparts that produce low-level heat resistant spores. The findings presented in this study allow for detection of B. amyloliquefaciens and B. licheniformis strains that produce highly heat resistant spores in the food chain. PMID- 27994576 TI - Intraclade Heterogeneity in Nitrogen Utilization by Marine Prokaryotes Revealed Using Stable Isotope Probing Coupled with Tag Sequencing (Tag-SIP). AB - Nitrogen can greatly influence the structure and productivity of microbial communities through its relative availability and form. However, the roles of specific organisms in the uptake of different nitrogen species remain poorly characterized. Most studies seeking to identify agents of assimilation have been correlative, indirectly linking activity measurements (e.g., nitrate uptake) with the presence or absence of biological markers, particularly functional genes and their transcripts. Evidence is accumulating of previously underappreciated functional diversity in major microbial subpopulations, which may confer physiological advantages under certain environmental conditions leading to ecotype divergence. This microdiversity further complicates our view of genetic variation in environmental samples requiring the development of more targeted approaches. Here, next-generation tag sequencing was successfully coupled with stable isotope probing (Tag-SIP) to assess the ability of individual phylotypes to assimilate a specific N source. Our results provide the first direct evidence of nitrate utilization by organisms thought to lack the genes required for this process including the heterotrophic clades SAR11 and the Archaeal Marine Group II. Alternatively, this may suggest the existence of tightly coupled metabolisms with primary assimilators, e.g., symbiosis, or the rapid and efficient scavenging of recently released products by highly active individuals. These results may be connected with global dominance often seen with these clades, likely conferring an advantage over other clades unable to access these resources. We also provide new direct evidence of in situ nitrate utilization by the cyanobacterium Prochlorococcus in support of recent findings. Furthermore, these results revealed widespread functional heterogeneity, i.e., different levels of nitrogen assimilation within clades, likely reflecting niche partitioning by ecotypes. PMID- 27994578 TI - Comparative In silico Analysis of Butyrate Production Pathways in Gut Commensals and Pathogens. AB - Biosynthesis of butyrate by commensal bacteria plays a crucial role in maintenance of human gut health while dysbiosis in gut microbiome has been linked to several enteric disorders. Contrastingly, butyrate shows cytotoxic effects in patients with oral diseases like periodontal infections and oral cancer. In addition to these host associations, few syntrophic bacteria couple butyrate degradation with sulfate reduction and methane production. Thus, it becomes imperative to understand the distribution of butyrate metabolism pathways and delineate differences in substrate utilization between pathogens and commensals. The bacteria utilize four pathways for butyrate production with different initial substrates (Pyruvate, 4-aminobutyrate, Glutarate and Lysine) which follow a polyphyletic distribution. A comprehensive mining of complete/draft bacterial genomes indicated conserved juxtaposed genomic arrangement in all these pathways. This gene context information was utilized for an accurate annotation of butyrate production pathways in bacterial genomes. Interestingly, our analysis showed that inspite of a beneficial impact of butyrate in gut, not only commensals, but a few gut pathogens also possess butyrogenic pathways. The results further illustrated that all the gut commensal bacteria (Faecalibacterium, Roseburia, Butyrivibrio, and commensal species of Clostridia etc) ferment pyruvate for butyrate production. On the contrary, the butyrogenic gut pathogen Fusobacterium utilizes different amino acid metabolism pathways like those for Glutamate (4 aminobutyrate and Glutarate) and Lysine for butyrogenesis which leads to a concomitant release of harmful by-products like ammonia in the process. The findings in this study indicate that commensals and pathogens in gut have divergently evolved to produce butyrate using distinct pathways. No such evolutionary selection was observed in oral pathogens (Porphyromonas and Filifactor) which showed presence of pyruvate as well as amino acid fermenting pathways which might be because the final product butyrate is itself known to be cytotoxic in oral diseases. This differential utilization of butyrogenic pathways in gut pathogens and commensals has an enormous ecological impact taking into consideration the immense influence of butyrate on different disorders in humans. The results of this study can potentially guide bioengineering experiments to design therapeutics/probiotics by manipulation of butyrate biosynthesis gene clusters in bacteria. PMID- 27994579 TI - Intraclonal Genome Stability of the Metallo-beta-lactamase SPM-1-producing Pseudomonas aeruginosa ST277, an Endemic Clone Disseminated in Brazilian Hospitals. AB - Carbapenems represent the mainstay therapy for the treatment of serious P. aeruginosa infections. However, the emergence of carbapenem resistance has jeopardized the clinical use of this important class of compounds. The production of SPM-1 metallo-beta-lactamase has been the most common mechanism of carbapenem resistance identified in P. aeruginosa isolated from Brazilian medical centers. Interestingly, a single SPM-1-producing P. aeruginosa clone belonging to the ST277 has been widely spread within the Brazilian territory. In the current study, we performed a next-generation sequencing of six SPM-1-producing P. aeruginosa ST277 isolates. The core genome contains 5899 coding genes relative to the reference strain P. aeruginosa PAO1. A total of 26 genomic islands were detected in these isolates. We identified remarkable elements inside these genomic islands, such as copies of the blaSPM-1 gene conferring resistance to carbapenems and a type I-C CRISPR-Cas system, which is involved in protection of the chromosome against foreign DNA. In addition, we identified single nucleotide polymorphisms causing amino acid changes in antimicrobial resistance and virulence-related genes. Together, these factors could contribute to the marked resistance and persistence of the SPM-1-producing P. aeruginosa ST277 clone. A comparison of the SPM-1-producing P. aeruginosa ST277 genomes showed that their core genome has a high level nucleotide similarity and synteny conservation. The variability observed was mainly due to acquisition of genomic islands carrying several antibiotic resistance genes. PMID- 27994577 TI - Metabiotics: One Step ahead of Probiotics; an Insight into Mechanisms Involved in Anticancerous Effect in Colorectal Cancer. AB - Colorectal cancer is closely associated with environment, diet and lifestyle. Normally it is treated with surgery, radiotherapy or chemotherapy but increasing systemic toxicity, resistance and recurrence is prompting scientists to devise new potent and safer alternate prophylactic or therapeutic strategies. Among these, probiotics, prebiotics, synbiotics, and metabiotics are being considered as the promising candidates. Metabiotics or probiotic derived factors can optimize various physiological functions of the host and offer an additional advantage to be utilized even in immunosuppressed individuals. Interestingly, anti colon cancer potential of probiotic strains has been attributable to metabiotics that have epigenetic, antimutagenic, immunomodulatory, apoptotic, and antimetastatic effects. Thus, it's time to move one step further to utilize metabiotics more smartly by avoiding the risks associated with probiotics even in certain normal/or immuno compromised host. Here, an attempt is made to provide insight into the adverse effects associated with probiotics and beneficial aspects of metabiotics with main emphasis on the modulatory mechanisms involved in colon cancer. PMID- 27994580 TI - Correlation of rpoB Mutations with Minimal Inhibitory Concentration of Rifampin and Rifabutin in Mycobacterium tuberculosis in an HIV/AIDS Endemic Setting, South Africa. AB - Treatment of tuberculosis (TB) and HIV co-infections is often complicated by drug to-drug interactions between anti-mycobacterial and anti-retroviral agents. Rifabutin (RFB) is an alternative to rifampin (RIF) for TB regimens and is recommended for HIV patients concurrently receiving protease inhibitors because of reduced induction of CYP3A4. This study sought to determine the proportion of RFB susceptible isolates among RIF-resistant strains in a high HIV prevalence setting in South Africa. In addition, the study explored the association between rpoB mutations and minimum inhibitory concentrations (MIC) of RIF and RFB. A total of 189 multidrug resistant (MDR) Mycobacterium tuberculosis isolates from the Centre for Tuberculosis repository were analyzed. The MICs were determined using a MYCOTB Sensititre plate method and the rpoB gene was sequenced. Of the 189 MDR isolates, 138 (73%) showed resistance to both RIF and RFB, while 51 (27%) isolates were resistant to RIF but retained susceptibility to RFB. The S531L was the most frequent rpoB point mutation in 105/189 (56%) isolates, followed by H526Y in 27/189 (14%) isolates. Resistance to both RIF and RFB was found predominantly in association with mutations S531L (91/105, 87%), H526Y (20/27, 74%), and H526D (15/19, 79%), while D516V (15/17, 88%), and L533P (3/4, 75%) were found in RIF-resistant, RFB-susceptible isolates. This study has shown that up to 27% of MDR-TB patients in South Africa may benefit from a treatment regimen that includes RFB. PMID- 27994581 TI - Disturbance Increases Microbial Community Diversity and Production in Marine Sediments. AB - Disturbance strongly impacts patterns of community diversity, yet the shape of the diversity-disturbance relationship remains a matter of debate. The topic has been of interest in theoretical ecology for decades as it has practical implications for the understanding of ecosystem services in nature. One of these processes is the remineralization of organic matter by microorganisms in coastal marine sediments, which are periodically impacted by disturbances across the sediment-water interface. Here we set up an experiment to test the hypothesis that disturbance impacts microbial diversity and function during the anaerobic degradation of organic matter in coastal sediments. We show that during the first 3 weeks of the experiment, disturbance increased both microbial production, derived from the increase in microbial abundance, and diversity of the active fraction of the community. Both community diversity and phylogenetic diversity increased, which suggests that disturbance promoted the cohabitation of ecologically different microorganisms. Metagenome analysis also showed that disturbance increased the relative abundance of genes diagnostic of metabolism associated with the sequential anaerobic degradation of organic matter. However, community composition was not impacted in a systematic way and changed over time. In nature, we can hypothesize that moderate storm disturbances, which impact coastal sediments, promote diverse, and productive communities. These events, rather than altering the decomposition of organic matter, may increase the substrate turnover and, ultimately, remineralization rates. PMID- 27994582 TI - Disruption of Protein Mannosylation Affects Candida guilliermondii Cell Wall, Immune Sensing, and Virulence. AB - The fungal cell wall contains glycoproteins that interact with the host immune system. In the prominent pathogenic yeast Candida albicans, Pmr1 acts as a Golgi resident ion pump that provides cofactors to mannosyltransferases, regulating the synthesis of mannans attached to glycoproteins. To gain insight into a putative conservation of such a crucial process within opportunistic yeasts, we were particularly interested in studying the role of the PMR1 homolog in a low virulent species that rarely causes candidiasis, Candida guilliermondii. We disrupted C. guilliermondii PMR1 and found that loss of Pmr1 affected cell growth and morphology, biofilm formation, susceptibility to cell wall perturbing agents, mannan levels, and the wall composition and organization. Despite the significant increment in the amount of beta1,3-glucan exposed at the wall surface, this positively influenced only the ability of the mutant to stimulate IL-10 production by human monocytes, suggesting that recognition of both mannan and beta1,3-glucan, is required to stimulate strong levels of pro-inflammatory cytokines. Accordingly, our results indicate C. guilliermondii sensing by monocytes was critically dependent on the recognition of N-linked mannans and beta1,3-glucan, as reported in other Candida species. In addition, chemical remotion of cell wall O-linked mannans was found to positively influence the recognition of C. guilliermondii by human monocytes, suggesting that O-linked mannans mask other cell wall components from immune cells. This observation contrasts with that reported in C. albicans. Finally, mice infected with C. guilliermondii pmr1Delta null mutant cells had significantly lower fungal burdens compared to animals challenged with the parental strain. Accordingly, the null mutant showed inability to kill larvae in the Galleria mellonella infection model. This study thus demonstrates that mannans are relevant for the C. guilliermondii-host interaction, with an atypical role for O-linked mannans. PMID- 27994584 TI - Diverse Profiles of AI-1 Type Quorum Sensing Molecules in Cultivable Bacteria from the Mangrove (Kandelia obovata) Rhizosphere Environment. AB - Mangrove rhizosphere environment harbors diverse populations of microbes, and some evidence showed that rhizobacteria behavior was regulated by quorum sensing (QS). Investigating the diverse profiles of QS molecules in mangrove ecosystems may shed light on the bacterial roles and lead to a better understanding of the symbiotic interactions between plants and microbes. The aims of the current study focus on identifying AI-1 type QS signals, i.e., acyl homoserine lactones (AHLs), in Kandelia obovata rhizosphere environment. Approximately 1200 rhizobacteria were screened and 184 strains (15.3%) tested were positive. Subsequent 16s rRNA gene sequencing and dereplication analyses identified 24 species from the positive isolates, which were affiliated to three different phyla, including Proteobacteria, Firmicutes, and Actinobacteria. Thin-layer chromatography separation of extracts revealed diverse AHL profiles and detected at least one active compound in the supernatant of these 24 cultivable AHL-producers. The active extracts from these bacterial isolates were further evaluated by ultra performance liquid chromatography-mass spectrometry, and the carbon side chain length ranged from C4 to C14. This is the first report on the diversity of AI-1 type auto-inducers in the mangrove plant K. obovata, and it is imperative to expand our knowledge of plant-bacteria interactions with respect to the maintenance of wetland ecosystem health. PMID- 27994583 TI - Beyond Traditional Antimicrobials: A Caenorhabditis elegans Model for Discovery of Novel Anti-infectives. AB - The spread of antibiotic resistance amongst bacterial pathogens has led to an urgent need for new antimicrobial compounds with novel modes of action that minimize the potential for drug resistance. To date, the development of new antimicrobial drugs is still lagging far behind the rising demand, partly owing to the absence of an effective screening platform. Over the last decade, the nematode Caenorhabditis elegans has been incorporated as a whole animal screening platform for antimicrobials. This development is taking advantage of the vast knowledge on worm physiology and how it interacts with bacterial and fungal pathogens. In addition to allowing for in vivo selection of compounds with promising anti-microbial properties, the whole animal C. elegans screening system has also permitted the discovery of novel compounds targeting infection processes that only manifest during the course of pathogen infection of the host. Another advantage of using C. elegans in the search for new antimicrobials is that the worm itself is a source of potential antimicrobial effectors which constitute part of its immune defense response to thwart infections. This has led to the evaluation of effector molecules, particularly antimicrobial proteins and peptides (APPs), as candidates for further development as therapeutic agents. In this review, we provide an overview on use of the C. elegans model for identification of novel anti-infectives. We highlight some highly potential lead compounds obtained from C. elegans-based screens, particularly those that target bacterial virulence or host defense to eradicate infections, a mechanism distinct from the action of conventional antibiotics. We also review the prospect of using C. elegans APPs as an antimicrobial strategy to treat infections. PMID- 27994585 TI - Saccharomyces and non-Saccharomyces Competition during Microvinification under Different Sugar and Nitrogen Conditions. AB - The inoculation of wines with autochthonous yeast allows obtaining complex wines with a peculiar microbial footprint characteristic from a wine region. Mixed inoculation of non-Saccharomyces yeasts and S. cerevisiae is of interest for the wine industry for technological and sensory reasons. However, the interactions between these yeasts are not well understood, especially those regarding the availability of nutrients. The aim of the present study was to analyze the effect of nitrogen and sugar concentration on the evolution of mixed yeast populations on controlled laboratory-scale fermentations monitored by density, plate culturing, PCR-DGGE and sugar and nitrogen consumption. Furthermore, the effect of the time of inoculation of Saccharomyces cerevisiae respect the initial co inoculation of three non-Saccharomyces yeasts was evaluated over the evolution of fermentation. Our results have shown that S. cerevisiae inoculation during the first 48 h conferred a stabilizing effect over the fermentations with non Saccharomyces strains tested and, generally, reduced yeast diversity at the end of the fermentation. On the other hand, nitrogen limitation increased the time of fermentation and also the proportion of non-Saccharomyces yeasts at mid and final fermentation. High sugar concentration resulted in different proportions of the inoculated yeast depending on the time of S. cerevisiae inoculation. This work emphasizes the importance of the concentration of nutrients on the evolution of mixed fermentations and points to the optimal conditions for a stable fermentation in which the inoculated yeasts survived until the end. PMID- 27994586 TI - Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone. AB - Immune-suppressive cell populations impair antitumor immunity and can contribute to the failure of immune therapeutic approaches. We hypothesized that the non steroidal anti-inflammatory drug licofelone, a dual cyclooxygenase-2/5-LO inhibitor, would improve therapeutic melanoma vaccination by reducing immune suppressive cell populations. Therefore, licofelone was administered after tumor implantation, either alone or in combination with a peptide vaccine containing a long tyrosinase-related protein 2-peptide and the adjuvant alpha galactosylceramide, all formulated into cationic liposomes. Mice immunized with the long-peptide vaccine and licofelone showed delayed tumor growth compared to mice given the vaccine alone. This protection was associated with a lower frequency of immature myeloid cells (IMCs) in the bone marrow (BM) and spleen of tumor-inoculated mice. When investigating the effect of licofelone on IMCs in vitro, we found that the prostaglandin E2-induced generation of IMCs was decreased in the presence of licofelone. Furthermore, pre-incubation of BM cells differentiated under IMC-inducing conditions with licofelone reduced the secretion of cytokines interleukin (IL)-10 and -6 upon lipopolysaccharides (LPS) stimulation as compared to untreated cells. Interestingly, licofelone increased IL-6 and IL-10 secretion when administered after the LPS stimulus, demonstrating an environment-dependent effect of licofelone. Our findings support the use of licofelone to reduce tumor-promoting cell populations. PMID- 27994587 TI - Inflammasomes and Their Role in Innate Immunity of Sexually Transmitted Infections. AB - Inflammasomes are multiprotein complexes present in the cytosol as pattern recognition receptors or as sensors of damage-associated molecular patterns. After recognition of microbe-associated molecular patterns or host-derived danger signals, nucleotide oligomerization domain-like receptors oligomerize to form inflammasomes. The activation of inflammasomes results in an alarm, which is raised to alert adjacent cells through the processing and release of a number of other substrates present in the cytosol. A wide array of inflammasomes and their adapter molecules have been identified in the host's innate immune system in response to various pathogens. Components of specific pathogens activate different inflammasomes, which once activated in response to pathogen-induced infection, induce the activation of caspases, and the release of mature forms of interleukin-1beta (IL-1beta) and IL-18. Identifying the mechanisms underlying pathogen-induced inflammasome activation is important if we are to develop novel therapeutic strategies to target sexually transmitted infections (STIs) related pathogens. This information is currently lacking in literature. In this review, we have discussed the role of various inflammasomes in sensing different STIs, as well as the beneficial or detrimental effects of inflammasome signaling in host resistance. Additionally, we have discussed both canonical and non-canonical processing of IL-1beta induced with respect to particular infections. Overall, these findings transform our understanding of both the basic biology and clinical relevance of inflammasomes. PMID- 27994588 TI - Genetic Causes of Human NK Cell Deficiency and Their Effect on NK Cell Subsets. AB - Human NK cells play critical roles in human host defense, particularly the control of viral infection and malignancy, and patients with congenital immunodeficiency affecting NK cell function or number can suffer from severe illness. The importance of NK cell function is particularly underscored in patients with primary immunodeficiency in which NK cells are the primary or sole affected population (NK cell deficiency, NKD). While NKD may lead to the absence of NK cells, we are also gaining an increasing appreciation of the effect that NKD may have on the generation of specific NK cell subsets. In turn, this leads to improved insights into the requirements for human NK cell subset generation, as well as their importance in immune homeostasis. The presence of inherently abnormally developed or functionally impaired NK cells, in particular, appears to be problematic in the way of interfering with normal human host defense and may be more impactful than low numbers of NK cells alone. Here, we review the known genetic causes of NKD and the insight that is derived by these into the requirements for human subset generation and, by extension, for NK cell-mediated immunity. PMID- 27994589 TI - Transitional B Cells in Early Human B Cell Development - Time to Revisit the Paradigm? AB - The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes and consequently an equally large number of potential specificities for antigen. As the process is essentially random, the cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre-B ? immature ? transitional ? naive phenotypes. Using long-read, high throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood, and our results describe the effects of tolerance selection on the B cell repertoire at the Ig gene level. Most strong effects of selection are seen within the heavy chain repertoire and can be seen both in gene usage and in CDRH3 characteristics. Age related changes are small, and only the size of the CDRH3 shows constant and significant change in these data. The paucity of significant changes in either kappa or lambda light chain repertoires implies that either the heavy chain has more influence over autoreactivity than light chain and/or that switching between kappa and lambda light chains, as opposed to switching within the light chain loci, may effect a more successful autoreactive rescue by receptor editing. Our results show that the transitional cell population contains cells other than those that are part of the pre-B ? immature ? transitional ? naive development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre-B and naive stages. PMID- 27994590 TI - Cigarette Smoke Induction of Interleukin-27/WSX-1 Regulates the Differentiation of Th1 and Th17 Cells in a Smoking Mouse Model of Emphysema. AB - IFN-gamma-producing CD4+ T (Th1) cells and IL-17-producing CD4+ T (Th17) cells play a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immune regulation between Th1 and Th17 cells remains unclear. Previous studies have demonstrated that interleukin-27 (IL-27)/WSX-1 exerted pro- or anti-inflammatory effects in many acute inflammatory diseases by modulating T cell-mediated immune response, but little was known about its role in chronic inflammatory disease, especially in smoking-related lung diseases. Considering IL-27 is an important regulator in T lymphocytes immune responses and was found markedly increased in patients with COPD, we hypothesized that IL 27/WSX-1 may exert immuno-regulatory effects on the differentiation of Th1 and Th17 cells in smoking-related COPD. In this study, we aimed to evaluate the expression of IL-27 in patients with COPD and explore the role of IL-27/WSX-1 on Th1 and Th17 cells differentiation in a smoking mouse model of emphysema. We found that elevated expression of IL-27 was associated with increased proportion of Th1 cells and Th17 cells in patients with COPD and demonstrated parallel findings in cigarette smoke-exposed mice. In addition, cigarette smoke exposure upregulated the expression of IL-27R (WSX-1) by naive CD4+ T cells in mice. In vitro, IL-27 significantly augmented the secretion of IFN-gamma by naive CD4+ T cells via a T-bet, p-STAT1, and p-STAT3-dependent manner, but inhibited the production of IL-17 by a ROR-gammat and p-STAT1-dependent way. Furthermore, anti IL27 treatment dramatically decreased the expression of IFN-gamma-producing CD4+ T cells in cigarette smoke-exposed mice. These findings proposed that IL-27 has functions for promoting the expression of Th1 cells but inhibiting the expression of Th17 cells in vitro and IL-27 neutralization-attenuated Th1-mediated inflammation in vivo, suggesting targeting IL-27/WSX-1 may provide a new therapeutic approach for smoking-related COPD. PMID- 27994592 TI - KIR Genes and Their Ligands Predict the Response to Anti-EGFR Monoclonal Antibodies in Solid Tumors. AB - Killer-cell immunoglobulin-like receptors (KIRs) regulate the killing function of natural killer cells, which play an important role in the antibody-dependent cell mediated cytotoxicity response exerted by therapeutic monoclonal antibodies (mAbs). However, it is unknown whether the extensive genetic variability of KIR genes and/or their human leukocyte antigen (HLA) ligands might influence the response to these treatments. This study aimed to explore whether the variability in KIR/HLA genes may be associated with the variable response observed to mAbs based anti-epidermal growth factor receptor (EGFR) therapies. Thirty-nine patients treated with anti-EGFR mAbs (trastuzumab for advanced breast cancer, or cetuximab for advanced colorectal or advanced head and neck cancer) were included in the study. All the patients had progressed to mAbs therapy and were grouped into two categories taking into account time to treatment failure (TTF <=6 and >=10 months). KIR genotyping (16 genetic variability) was performed in genomic DNA from peripheral blood by PCR sequence-specific primer technique, and HLA ligand typing was performed for HLA-B and -C loci by reverse polymerase chain reaction sequence-specific oligonucleotide methodology. Subjects carrying the KIR/HLA ligand combinations KIR2DS1/HLAC2C2-C1C2 and KIR3DS1/HLABw4w4-w4w6 showed longer TTF than non-carriers counterparts (14.76 vs. 3.73 months, p < 0.001 and 14.93 vs. 4.6 months, p = 0.005, respectively). No other significant differences were observed. Two activating KIR/HLA ligand combinations predict better response of patients to anti-EGFR therapy. These findings increase the overall knowledge on the role of specific gene variants related to responsiveness to anti-EGFR treatment in solid tumors and highlight the importance of assessing gene polymorphisms related to cancer medications. PMID- 27994591 TI - Emerging Roles for the Immune System in Traumatic Brain Injury. AB - Traumatic brain injury (TBI) affects an ever-growing population of all ages with long-term consequences on health and cognition. Many of the issues that TBI patients face are thought to be mediated by the immune system. Primary brain damage that occurs at the time of injury can be exacerbated and prolonged for months or even years by chronic inflammatory processes, which can ultimately lead to secondary cell death, neurodegeneration, and long-lasting neurological impairment. Researchers have turned to rodent models of TBI in order to understand how inflammatory cells and immunological signaling regulate the post injury response and recovery mechanisms. In addition, the development of numerous methods to manipulate genes involved in inflammation has recently expanded the possibilities of investigating the immune response in TBI models. As results from these studies accumulate, scientists have started to link cells and signaling pathways to pro- and anti-inflammatory processes that may contribute beneficial or detrimental effects to the injured brain. Moreover, emerging data suggest that targeting aspects of the immune response may offer promising strategies to treat TBI. This review will cover insights gained from studies that approach TBI research from an immunological perspective and will summarize our current understanding of the involvement of specific immune cell types and cytokines in TBI pathogenesis. PMID- 27994593 TI - Intestinal Innate Antiviral Immunity and Immunobiotics: Beneficial Effects against Rotavirus Infection. AB - The mucosal tissues of the gastrointestinal tract are the main portal entry of pathogens such as rotavirus (RV), which is a leading cause of death due to diarrhea among young children across the globe and a major cause of severe acute intestinal infection in livestock animals. The interactions between intestinal epithelial cells (IECs) and immune cells with RVs have been studied for several years, and now, it is known that the innate immune responses triggered by this virus can have both beneficial and detrimental effects for the host. It was demonstrated that natural RV infection in infants and experimental challenges in mice result in the intestinal activation of pattern recognition receptors (PRRs) such as toll-like receptor 3 (TLR3) and striking secretion of proinflammatory mediators that can lead to increased local tissue damage and immunopathology. Therefore, modulating desregulated intestinal immune responses triggered by PRRs activation are a significant promise for reducing the burden of RV diseases. The ability of immunoregulatory probiotic microorganisms (immunobiotics) to protect against intestinal infections, such as those caused by RVs, is among the oldest effects studied for these important group of beneficial microbes. In this review, we provide an update of the current status on the modulation of intestinal antiviral innate immunity by immunobiotics and their beneficial impact on RV infection. In addition, we describe the research of our group that demonstrated the capacity of immunobiotic strains to beneficially modulated TLR3-triggered immune response in IECs, reduce the disruption of intestinal homeostasis caused by intraepithelial lymphocytes, and improve the resistance to RV infections. PMID- 27994594 TI - Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection. AB - Elicitation of type I interferon (IFN-I) has been shown to both enhance and impair cell-mediated immune responses in acute and persistent viral infections, respectively. Here, we show that, in addition to its effect on T cells, IFN-I drives impairment of specific antibody responses through interaction with B cells in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. This impairment was limited to the T cell-dependent B cell response and was associated with disruption of B cell follicles, development of hypergammaglobulinemia (HGG), and expansion of the T follicular helper cell population. Antigen-specific antibody responses were restored by ablation of IFN-I signaling through antibody mediated IFN-I receptor blockade and B cell-specific IFN-I receptor knockout. Importantly, IFN-I receptor deficiency in B cells also accelerated the development of LCMV neutralizing antibodies and alleviated HGG. These results provide a potential therapeutic target toward efficient treatment measures that limit immunopathology in persistent viral infections. PMID- 27994595 TI - Multimodal Regulation of NET Formation in Pregnancy: Progesterone Antagonizes the Pro-NETotic Effect of Estrogen and G-CSF. AB - Human pregnancy is associated with a mild pro-inflammatory state, characterized by circulatory neutrophil activation. In order to explore the mechanism underlying this alteration, we examined NETosis during normal gestation. Our data indicate that neutrophils exhibit a pro-NETotic state, modulated in a multimodal manner during pregnancy. In general, circulatory granulocyte colony-stimulating factor, the levels of which increase during gestation, promotes neutrophil extracellular trap (NET) formation. Early in pregnancy, NETosis is enhanced by chorionic gonadotropin, whereas toward term is stimulated by estrogen. A complex interaction between estrogen and progesterone arises, wherein progesterone restrains the NETotic process. In this state, extensive histone citrullination is evident, yet full NETosis is inhibited. This coincides with the inability of neutrophil elastase to translocate from the cytoplasm to the nucleus and is regulated by progesterone. Our findings provide new insight concerning gestational and hormone-driven pathologies, since neutrophil recruitment, activation, and NET release could be associated with excessive endothelial and placental injury. PMID- 27994596 TI - Cytoplasm-Translocated Ku70/80 Complex Sensing of HBV DNA Induces Hepatitis Associated Chemokine Secretion. AB - Chronic hepatitis B virus (HBV) infection remains a serious disease, mainly due to its severe pathological consequences, which are difficult to cure using current therapies. When the immune system responds to hepatocytes experiencing rapid HBV replication, effector cells (such as HBV-specific CD8+ T cells, NK cells, NKT cells, and other subtypes of immune cells) infiltrate the liver and cause hepatitis. However, the precise recruitment of these cells remains unclear. In the present study, we found that the cytoplasm-translocated Ku70/80 complex in liver-derived cells sensed cytosolic HBV DNA and promoted hepatitis-associated chemokine secretion. Upon sensing HBV DNA, DNA-dependent protein kinase catalytic subunit and PARP1 were assembled. Then, IRF1 was activated and translocated into the nucleus, which upregulated CCL3 and CCL5 expression. Because CCR5, a major chemokine receptor for CCL3 and CCL5, is known to be critical in hepatitis B, Ku70/80 sensing of HBV DNA likely plays a critical role in immune cell recruitment in response to HBV infection. PMID- 27994597 TI - Aging Male Spontaneously Hypertensive Rat as an Animal Model for the Evaluation of the Interplay between Contrast-Induced Acute Kidney Injury and Cardiorenal Syndrome in Humans. AB - BACKGROUND: Although there are some animal models for biomarkers of contrast induced acute kidney injury (CI-AKI), for cardiorenal syndrome (CRS) and for acute renal failure, the interplay between CI-AKI and CRS has yet to be evaluated. Insight into the pathogenesis of CRS is urgently needed from animal models in order to foster the discovery and implementation of novel biomarkers for this disease. Specially designed animal models for type 1 and 3 CRS, particularly CI-AKI, have not yet emerged. SUMMARY: We hypothesize that the aging male spontaneously hypertensive rat (SHR) is likely to be a suitable model. The SHR model is able to mimic risk factors for preclinical CRS that appears in the clinical setting, specifically hypertension, age, preexisting damage and dysfunction of the heart and kidney, endothelial dysfunction, increased level of reactive oxygen species, decreased level and bioavailability of nitric oxide (NO), impairment of the L-arginine-NO pathway, and insulin resistance. In the SHR, CI-AKI results in a different profile of AKI biomarkers than is seen with preexisting chronic kidney injury. KEY MESSAGES: The SHR model can be used to evaluate the interaction between CI-AKI and CRS type 1 and 3 and to verify neutrophil gelatinase-associated lipocalin (NGAL) as a reliable CI-AKI biomarker for clinical application. Further research is warranted with a large number of aging male SHRs to prove NGAL as a sensitive, specific, highly predictive, early biomarker for CI-AKI. PMID- 27994598 TI - Matrix Metalloproteinase Neutrophil Gelatinase-Associated Lipocalin Complex Predicts Atrial Fibrillation Recurrence after Electrical Cardioversion in Obese Patients. AB - BACKGROUND: There is not much data on matrix metalloproteinase neutrophil gelatinase-associated lipocalin (MMP-NGAL) complex in patients with atrial fibrillation (AF). AIM: The aim of the study was to assess the value of MMP-NGAL complex in predicting AF recurrence after electrical cardioversion. METHODS: The serum levels of NGAL, cystatin C, interleukin-6, high-sensitivity C-reactive protein, copeptin, MMP-NGAL complex, matrix metalloproteinase 2, tissue inhibitor of metalloproteinase 1, Von Willebrand factor, B-type natriuretic peptide and the urinary level of NGAL were evaluated before cardioversion. RESULTS: A total of 83 patients with persistent AF were enrolled in the study. Left atrial diameter (LA) >=4.5 cm was significantly associated with AF recurrence at follow-up (p = 0.009). In selected 39 obese patients, MMP-NGAL complex was associated with AF recurrence (p = 0.03). If the concentration of MMP-NGAL complex increased by 1 ng/ml, the odds of AF recurrence increased by 4% (OR 1.04; CI: 1.00-1.08; p = 0.03). MMP-NGAL complex did not correlate with AF recurrence in patients with a first episode of AF, in patients >=65 years of age and in patients with a LA >=4.5 cm or with chronic kidney disease. CONCLUSIONS: It is known that the greater the BMI at baseline, the higher the likelihood of progression from paroxysmal to permanent AF. However, European Society of Cardiology (ESC) guidelines do not consider obese patients a population with a low likelihood of success of cardioversion. That is why we need a sensitive marker to predict sinus rhythm maintenance in such a population. We found that MMP-NGAL complex may predict AF recurrence after successful cardioversion in obese patients. PMID- 27994599 TI - Possible Inhibitory Effect of Erythropoiesis-Stimulating Agents at the Predialysis Stage on Early-Phase Coronary Events after Hemodialysis Initiation. AB - BACKGROUND: We examined whether the use of erythropoiesis-stimulating agents (ESAs) to correct anemia at the predialysis stage could inhibit early-phase coronary events after hemodialysis initiation. METHODS: We enrolled 242 patients with chronic kidney disease who had received continued medical treatments and initiated maintenance hemodialysis from 1 September 2000 to 31 December 2014 at Toujinkai Hospital. Patients with a previous history of blood transfusion or any cardiovascular events or interventions were excluded. The coronary events were followed for 1 year after initiation of hemodialysis. RESULTS: Coronary events occurred in 51 of 242 patients: 10 patients had acute coronary syndrome [9 with percutaneous coronary intervention (PCI), 1 without intervention], and 41 had elective coronary revascularization (38 PCI and 3 coronary artery bypass graft). ESA was administered in 118 of 242 patients (48.8%). In stepwise logistic analysis, coronary events were positively associated with nonuse of ESA at the predialysis stage (odds ratio 2.66, p = 0.005) and diabetes mellitus (odds ratio 5.33, p < 0.001). When dividing the patients into 4 subgroups by blood hemoglobin (Hb) level (8.5 g/dl) and the use/nonuse of ESA, coronary event-free survival rates were higher (p = 0.005) in those with Hb >=8.5 g/dl, ESA+ (86.6%, n = 82) and tended to be higher (p = 0.055) in those with Hb <8.5 g/dl, ESA+ (86.1%, n = 36) than in patients with Hb <8.5 g/dl, ESA- (68.6%, n = 86) in a Kaplan-Meier analysis. CONCLUSIONS: The use of ESA to correct anemia at the predialysis stage may inhibit early-phase coronary events after hemodialysis initiation. PMID- 27994600 TI - Oxidized Low-Density Lipoprotein Predicts the Development of Renal Dysfunction in Atrial Fibrillation. AB - BACKGROUND/AIM: To investigate the role of oxidative stress (OS) in the development of chronic kidney disease (CKD) in atrial fibrillation (AF). METHODS: We compared OS burden, determined at study inclusion as plasma concentrations of oxidized low-density lipoprotein (oxLDL), between stable AF patients (n = 256, mean age: 62.8 +/- 9.3 years; 60.9% males) with preserved renal function, defined as an estimated glomerular filtration rate (eGFR) >=60 ml/min/1.73 m2, and a matched control group in sinus rhythm (n = 138, mean age: 61.5 +/- 11.2 years; 60.9% males). During the prospective follow-up of AF patients, we investigated the association and prognostic validity of oxLDL for CKD development, diagnosed as a sustained decline in eGFR to <60 ml/min/1.73 m2. RESULTS: AF patients had a higher mean oxLDL (76.2 +/- 21.7 U/l) compared to sinus rhythm controls (61.6 +/- 13.1 U/l; p < 0.001). AF presence independently predicted increased oxLDL levels in the study cohort [beta = 14.7; 95% confidence interval (CI), 10.7-18.7; p < 0.001]. Over a median 4-year follow-up, 19.9% of AF patients developed CKD. Adjusting for all clinical covariates, oxLDL (per tertile) was associated with a hazard ratio of 2.17 for CKD occurrence (95% CI, 1.40-3.35; p < 0.001). AF patients in the upper oxLDL tertile (>=88.7 U/l) had a 3.70-fold (95% CI, 1.55 8.81) higher risk for CKD compared to the lower oxLDL tertile (<67.0 U/l) patients (p < 0.001). oxLDL improved discriminative validity (c-statistic increment: 0.041, 95% CI, 0.007-0.075, p = 0.017), and increased the net reclassification and integrated discrimination for CKD risk by 12.4 and 6.0%, respectively (both p < 0.001). CONCLUSIONS: oxLDL is increased in AF patients compared to sinus rhythm controls. oxLDL has an independent association and an incremental predictive value that might complement clinical CKD risk assessment in AF patients following further research. PMID- 27994601 TI - The Renal Arterial Resistance Index Predicts Worsening Renal Function in Chronic Heart Failure Patients. AB - BACKGROUND/AIM: The renal arterial resistance index (RRI) is a Doppler measure, which reflects abnormalities in the renal blood flow. The aim of this study was to verify the value of RRI as a predictor of worsening renal function (WRF) in a group of chronic heart failure (CHF) outpatients. METHODS: We enrolled 266 patients in stable clinical conditions and on conventional therapy. Peak systolic velocity and end diastolic velocity of a segmental renal artery were obtained by pulsed Doppler flow, and RRI was calculated. Creatinine serum levels were evaluated at baseline and at 1 year, and the changes were used to assess WRF occurrence. RESULTS: During follow-up, 34 (13%) patients showed WRF. RRI was associated with WRF at univariate (OR: 1.13; 95% CI: 1.07-1.20) as well as at a forward stepwise multivariate logistic regression analysis (OR: 1.09; 95% CI: 1.03-1.16; p = 0.005) including the other univariate predictors. CONCLUSIONS: Quantification of arterial renal perfusion provides a new parameter that independently predicts the WRF in CHF outpatients. Its possible role in current clinical practice to better define the risk of cardiorenal syndrome progression is strengthened. PMID- 27994602 TI - Vasodilation and Exercise Capacity in Patients with End-Stage Renal Disease: A Prospective Proof-of-Concept Study. AB - BACKGROUND: Previous data have pointed to the fact that vascular function is significantly impaired in patients with end-stage renal disease (ESRD). We aimed to better characterise vasodilation and exercise capacity in both ESRD and chronic heart failure (CHF) patients. METHODS: A total of 30 ESRD patients (23 male; mean age 45.7 +/- 9.9 years) were included in a prospective proof-of concept study at a tertiary care academic centre. The patients underwent forearm venous plethysmography with post-ischaemic peak blood flow (PF) and flow dependent flow (FDF) testing as well as cardiopulmonary exercise testing during the morning of the day following the last haemodialysis. After matching for age, gender, and body mass index, the data were compared to 30 patients with CHF and 20 age-matched healthy controls. RESULTS: PF in ESRD patients was reduced when compared to that in CHF patients (12.5 +/- 4.2 vs. 15.6 +/- 6.9 ml/100 ml/min; p = 0.048) and healthy controls (26.4 +/- 9.3 ml/100 ml/min; p < 0.001). When compared to controls, FDF was significantly reduced in ESRD patients (7.6 +/- 3.1 vs. 6.0 +/- 2.5 ml/100 ml/min; p = 0.03), but not in CHF patients, whereas resting blood flow did not differ between the ESRD, CHF, and healthy control groups. In contrast to indices of vasodilative capacity, maximum exercise capacity (peakVO2) was higher in ESRD when compared to CHF patients (23.8 +/- 7.3 vs. 18.8 +/- 5.2 ml/min/kg), but significantly impaired when compared to controls (32.8 +/- 6.7 ml/min/kg; p < 0.001). CONCLUSION: In this proof-of-concept study, exercise capacity was relatively preserved, while vasodilative capacity was substantially impaired in ESRD patients. Additional studies are warranted to examine the underlying mechanisms and potential clinical implications of our findings. PMID- 27994603 TI - Fibroblast Growth Factor 23 and Hypophosphatemia: A Case of Hypophosphatemia along the Rickets-Osteomalacia Spectrum. AB - Phosphorus is a key component of bone, and a deficiency results in poor mineralization along with other systemic symptoms of hypophosphatemia. Various causes of hypophosphatemia with renal wasting of phosphorus have been identified. These include the Fanconi syndrome, various genetic mutations of fibroblast growth factor 23 (FGF23) handling and the sodium/phosphate cotransporter, and those due to FGF23 secretion by mesenchymal tumors. Depending on the cause, vitamin D metabolism may also be impaired, which may amplify the deficiency in phosphorus and render treatment more challenging. Here, we report a case of hypophosphatemia and multiple stress fractures in a 20-year-old male college student living with chronic bone pain and anxiety about suffering further fractures. We further review the literature regarding this spectrum. PMID- 27994604 TI - Asymptomatic Ventricular Arrhythmia and Clinical Outcomes in Chronic Kidney Disease: A Pilot Study. AB - BACKGROUND/AIMS: Ventricular arrhythmia is associated with increased risk of cardiovascular events and death in the general population. Sudden death is a leading cause of death in end-stage renal disease. We aimed at evaluating the effects of ventricular arrhythmia on clinical outcomes in patients with earlier stages of chronic kidney disease (CKD). METHODS: In a prospective study of 109 nondialyzed CKD patients (estimated glomerular filtration rate 34.8 +/- 16.1 ml/min/1.73 m2, 57 +/- 11.4 years, 61% male, 24% diabetics), we tested the hypothesis that the presence of subclinical complex ventricular arrhythmia, assessed by 24-hour electrocardiogram, is associated with increased risks of cardiovascular events, hospitalization, and death and with their composite outcome during 24 months of follow-up. Complex ventricular arrhythmia was defined as the presence of multifocal ventricular extrasystoles, paired ventricular extrasystoles, nonsustained ventricular tachycardia, or R wave over T wave. RESULTS: We identified complex ventricular arrhythmia in 14% of participants at baseline. During follow-up, 11 cardiovascular events, 15 hospitalizations, and 4 deaths occurred. The presence of complex ventricular arrhythmia was associated with cardiovascular events (p < 0.001), hospitalization (p = 0.018), mortality (p < 0.001), and the composite outcome (p < 0.001). In multivariate Cox regression analysis, adjusting for demographic characteristics, complex ventricular arrhythmia was associated with increased risk of the composite outcome (HR 4.40; 95% CI 1.60-12.12; p = 0.004). CONCLUSION: In this pilot study, the presence of asymptomatic complex ventricular arrhythmia was associated with poor clinical outcomes in nondialyzed CKD patients. PMID- 27994605 TI - The Triad of Sleep Apnea, Hypertension, and Chronic Kidney Disease: A Spectrum of Common Pathology. AB - Obstructive sleep apnea (OSA), hypertension, and chronic kidney disease (CKD) are different entities and are generally managed individually most of the time. However, CKD, OSA, and hypertension share many common risk factors and it is not uncommon to see this complex triad together. In fact, they share similar pathophysiology and have been interlinked with each other. The common pathophysiology includes chronic volume overload, hyperaldosteronism, increased sympathetic activity, endothelial dysfunction, and increased inflammatory markers. The combination of this triad has significant negative impact on the cardiovascular health, and increases the mortality and morbidity in this complicated group of patients. On one hand, progression of CKD can lead to the worsening of OSA and hypertension; similarly, worsening sleep apnea can make the hypertension difficult to treat and enhance the progression of CKD. This review article highlights the bidirectional interlink among these apparently different disease processes which share common pathophysiological mechanisms and emphasizes the importance of treating them collectively to improve outcomes. PMID- 27994607 TI - Multicolor Fluorescence Imaging as a Candidate for Disease Detection in Plant Phenotyping. AB - The negative impact of conventional farming on environment and human health make improvements on farming management mandatory. Imaging techniques are implemented in remote sensing for monitoring crop fields and plant phenotyping programs. The increasingly large size and complexity of the data obtained by these techniques, makes the implementation of powerful mathematical tools necessary in order to identify informative parameters and to apply them in precision agriculture. Multicolor fluorescence imaging is a useful approach for the study of plant defense responses to stress factors at bench scale. However, it has not been fully applied to plant phenotyping. This work evaluates the possible application of multicolor fluorescence imaging in combination with thermography for the particular case of zucchini plants affected by soft-rot, caused by Dickeya dadantii. Several statistical models -based on logistic regression analysis (LRA) and artificial neural networks (ANN)- were obtained for the experimental system zucchini-D. dadantii, which classify new samples as "healthy" or "infected." The LRA worked best in identifying high dose-infiltrated leaves (in infiltrated and non-infiltrated areas) whereas ANN offered a higher accuracy at identifying low dose-infiltrated areas. To assess the applicability of these results to cucurbits in a more general way, these models were validated for melon infected by the same pathogen, achieving accurate predictions for the infiltrated areas. The values of accuracy achieved are comparable to those found in the literature for classifiers identifying other infections based on data obtained by different techniques. Thus, MCFI in combination with thermography prove useful at providing data at lab scale that can be analyzed by machine learning. This approach could be scaled up to be applied in plant phenotyping. PMID- 27994606 TI - Lineage-Specific Evolutionary Histories and Regulation of Major Starch Metabolism Genes during Banana Ripening. AB - Starch is the most widespread and abundant storage carbohydrate in plants. It is also a major feature of cultivated bananas as it accumulates to large amounts during banana fruit development before almost complete conversion to soluble sugars during ripening. Little is known about the structure of major gene families involved in banana starch metabolism and their evolution compared to other species. To identify genes involved in banana starch metabolism and investigate their evolutionary history, we analyzed six gene families playing a crucial role in plant starch biosynthesis and degradation: the ADP-glucose pyrophosphorylases (AGPases), starch synthases (SS), starch branching enzymes (SBE), debranching enzymes (DBE), alpha-amylases (AMY) and beta-amylases (BAM). Using comparative genomics and phylogenetic approaches, these genes were classified into families and sub-families and orthology relationships with functional genes in Eudicots and in grasses were identified. In addition to known ancestral duplications shaping starch metabolism gene families, independent evolution in banana and grasses also occurred through lineage-specific whole genome duplications for specific sub-families of AGPase, SS, SBE, and BAM genes; and through gene-scale duplications for AMY genes. In particular, banana lineage duplications yielded a set of AGPase, SBE and BAM genes that were highly or specifically expressed in banana fruits. Gene expression analysis highlighted a complex transcriptional reprogramming of starch metabolism genes during ripening of banana fruits. A differential regulation of expression between banana gene duplicates was identified for SBE and BAM genes, suggesting that part of starch metabolism regulation in the fruit evolved in the banana lineage. PMID- 27994608 TI - DNA Barcoding Evaluation and Its Taxonomic Implications in the Recently Evolved Genus Oberonia Lindl. (Orchidaceae) in China. AB - The orchid genus Oberonia Lindl., is a taxonomically complex genus characterized by recent species radiations and many closely related species. All Oberonia species are under conservation as listed in the CITES and the IUCN Red List Categories and Criteria. Given its difficulties in taxonomy and conservation status, Oberonia is an excellent model for developing DNA barcodes. Three analytical methods and five DNA barcoding regions (rbcL, matK, trnH-psbA, ITS, and ITS2) were evaluated on 127 individuals representing 40 species and 1 variety of Oberonia from China. All the three plastid candidates tested (rbcL, matK, and trnH-psbA) have a lower discriminatory power than the nuclear regions (ITS and ITS2), and ITS had the highest resolution rate (82.14%). Two to four combinations of these gene sets were not better than the ITS alone, but when considering modes of inheritance, rbcL+ITS and matK+ITS were the best barcodes for identifying Oberonia species. Furthermore, the present barcoding system has many new insights in the current Oberonia taxonomy, such as correcting species identification, resolving taxonomic uncertainties, and the underlying presence of new or cryptic species in a genus with a complex speciation history. PMID- 27994609 TI - Reporter Gene-Facilitated Detection of Compounds in Arabidopsis Leaf Extracts that Activate the Karrikin Signaling Pathway. AB - Karrikins are potent germination stimulants generated by the combustion of plant matter. Treatment of Arabidopsis with karrikins triggers a signaling process that is dependent upon a putative receptor protein KARRIKIN INSENSITIVE 2 (KAI2). KAI2 is a homolog of DWARF 14 (D14), the receptor for endogenous strigolactone hormones. Genetic analyses suggest that KAI2 also perceives endogenous signal(s) that are not strigolactones. Activation of KAI2 by addition of karrikins to Arabidopsis plants induces expression of transcripts including D14-LIKE 2 (DLK2). We constructed the synthetic reporter gene DLK2:LUC in Arabidopsis, which comprises the firefly luciferase gene (LUC) driven by the DLK2 promoter. Here we describe a luminescence-based reporter assay with Arabidopsis seeds to detect chemical signals that can activate the KAI2 signaling pathway. We demonstrate that the DLK2:LUC assay can selectively and sensitively detect karrikins and a functionally similar synthetic strigolactone analog. Crucially we show that crude extracts from Arabidopsis leaves can also activate DLK2:LUC in a KAI2-dependent manner. Our work provides the first direct evidence for the existence of endogenous chemical signals that can activate the KAI2-mediated signaling pathway in Arabidopsis. This sensitive reporter system can now be used for the bioassay guided purification and identification of putative endogenous KAI2 ligands or their precursors, and endogenous compounds that might modulate the KAI2 signaling pathway. PMID- 27994610 TI - Genome-Wide Analysis of Soybean JmjC Domain-Containing Proteins Suggests Evolutionary Conservation Following Whole-Genome Duplication. AB - Histone modifications, such as methylation and demethylation, play an important role in regulating chromatin structure and gene expression. The JmjC domain containing proteins, an important family of histone lysine demethylases (KDMs), play a key role in maintaining homeostasis of histone methylation in vivo. In this study, we performed a comprehensive analysis of the jumonji C (JmjC) gene family in the soybean genome and identified 48 JmjC genes (GmJMJs) distributed unevenly across 18 chromosomes. Phylogenetic analysis showed that these JmjC domain-containing genes can be divided into eight groups. GmJMJs within the same phylogenetic group share similar exon/intron organization and domain composition. In addition, 16 duplicated gene pairs were formed by a Glycine-specific whole genome duplication (WGD) event approximately 13 million years ago (Mya). By investigating the expression profiles of these gene pairs in various tissues, we showed that the expression pattern is conserved in the polyploidy-derived JmjC duplicates, demonstrating that the majority of GmJMJs were preferentially retained after the most recent WGD event and suggesting important roles for demethylase duplications in soybean evolution. These results shed light on the evolutionary history of this family in soybean and provide insights into the JmjCs which will be helpful to reveal their functions in controlling soybean development. PMID- 27994611 TI - Linking Expression of Fructan Active Enzymes, Cell Wall Invertases and Sucrose Transporters with Fructan Profiles in Growing Taproot of Chicory (Cichorium intybus): Impact of Hormonal and Environmental Cues. AB - In chicory taproot, the inulin-type fructans serve as carbohydrate reserve. Inulin metabolism is mediated by fructan active enzymes (FAZYs): sucrose:sucrose 1-fructosyltransferase (1-SST; fructan synthesis), fructan:fructan-1 fructosyltransferase (1-FFT; fructan synthesis and degradation), and fructan 1 exohydrolases (1-FEH1/2a/2b; fructan degradation). In developing taproot, fructan synthesis is affected by source-to-sink sucrose transport and sink unloading. In the present study, expression of FAZYs, sucrose transporter and CWI isoforms, vacuolar invertase and sucrose synthase was determined in leaf blade, petiole and taproot of young chicory plants (taproot diameter: 2 cm) and compared with taproot fructan profiles for the following scenarios: (i) N-starvation, (ii) abscisic acid (ABA) treatment, (iii) ethylene treatment (via 1-aminoyclopropane-1 carboxylic acid [ACC]), and (iv) cold treatment. Both N-starvation and ABA treatment induced an increase in taproot oligofructans. However, while under N starvation this increase reflected de novo synthesis, under ABA treatment gene expression profiles indicated a role for both de novo synthesis and degradation of long-chain fructans. Conversely, under ACC and cold treatment oligofructans slightly decreased, correlating with reduced expression of 1-SST and 1-FFT and increased expression of FEHs and VI. Distinct SUT and CWI expression profiles were observed, indicating a functional alignment of SUT and CWI expression with taproot fructan metabolism under different source-sink scenarios. PMID- 27994612 TI - Barley Brassinosteroid Mutants Provide an Insight into Phytohormonal Homeostasis in Plant Reaction to Drought Stress. AB - Brassinosteroids (BRs) are a class of steroid phytohormones, which regulate various processes of morphogenesis and physiology-from seed development to regulation of flowering and senescence. An accumulating body of evidence indicates that BRs take part in regulation of physiological reactions to various stress conditions, including drought. Many of the physiological functions of BRs are regulated by a complicated, and not fully elucidated network of interactions with metabolic pathways of other phytohormones. Therefore, the aim of this study was to characterize phytohormonal homeostasis in barley (Hordeum vulgare) in reaction to drought and validate role of BRs in regulation of this process. Material of this study included the barley cultivar "Bowman" and five Near Isogenic Lines (NILs) representing characterized semi-dwarf mutants of several genes encoding enzymes participating in BR biosynthesis and signaling. Analysis of endogenous BRs concentrations in these NILs confirmed that their phenotypes result from abnormalities in BR metabolism. In general, concentrations of 18 compounds, representing various classes of phytohormones, including brassinosteroids, auxins, cytokinins, gibberellins, abscisic acid, salicylic acid and jasmonic acid were analyzed under control and drought conditions in the "Bowman" cultivar and the BR-deficient NILs. Drought induced a significant increase in accumulation of the biologically active form of BRs-castasterone in all analyzed genotypes. Another biologically active form of BRs-24-epi brassinolide-was identified in one, BR-insensitive NIL under normal condition, but its accumulation was drought-induced in all analyzed genotypes. Analysis of concentration profiles of several compounds representing gibberellins allowed an insight into the BR-dependent regulation of gibberellin biosynthesis. The concentration of the gibberellic acid GA7 was significantly lower in all NILs when compared with the "Bowman" cultivar, indicating that GA7 biosynthesis represents an enzymatic step at which the stimulating effect of BRs on gibberellin biosynthesis occurs. Moreover, the accumulation of GA7 is significantly induced by drought in all the genotypes. Biosynthesis of jasmonic acid is also a BR-dependent process, as all the NILs accumulated much lower concentrations of this hormone when compared with the "Bowman" cultivar under normal condition, however the accumulation of jasmonic acid, abscisic acid and salicylic acid were significantly stimulated by drought. PMID- 27994613 TI - The E-Subgroup Pentatricopeptide Repeat Protein Family in Arabidopsis thaliana and Confirmation of the Responsiveness PPR96 to Abiotic Stresses. AB - Pentatricopeptide repeat (PPR) proteins are extensive in all eukaryotes. Their functions remain as yet largely unknown. Mining potential stress responsive PPRs, and checking whether known PPR editing factors are affected in the stress treatments. It is beneficial to elucidate the regulation mechanism of PPRs involved in biotic and abiotic stress. Here, we explored the characteristics and origin of the 105 E subgroup PPRs in Arabidopsis thaliana. Phylogenetic analysis categorized the E subgroup PPRs into five discrete groups (Cluster I to V), and they may have a common origin in both A. thaliana and rice. An in silico expression analysis of the 105 E subgroup PPRs in A. thaliana was performed using available microarray data. Thirty-four PPRs were differentially expressed during A. thaliana seed imbibition, seed development stage(s), and flowers development processes. To explore potential stress responsive PPRs, differential expression of 92 PPRs was observed in A. thaliana seedlings subjected to different abiotic stresses. qPCR data of E subgroup PPRs under stress conditions revealed that the expression of 5 PPRs was responsive to abiotic stresses. In addition, PPR96 is involved in plant responses to salt, abscisic acid (ABA), and oxidative stress. The T-DNA insertion mutation inactivating PPR96 expression results in plant insensitivity to salt, ABA, and oxidative stress. The PPR96 protein is localized in the mitochondria, and altered transcription levels of several stress responsive genes under abiotic stress treatments. Our results suggest that PPR96 may important function in a role connecting the regulation of oxidative respiration and environmental responses in A. thaliana. PMID- 27994615 TI - Impairment of Sulfite Reductase Decreases Oxidative Stress Tolerance in Arabidopsis thaliana. AB - As an essential enzyme in the sulfate assimilation reductive pathway, sulfite reductase (SiR) plays important roles in diverse metabolic processes such as sulfur homeostasis and cysteine metabolism. However, whether plant SiR is involved in oxidative stress response is largely unknown. Here, we show that SiR functions in methyl viologen (MV)-induced oxidative stress in Arabidopsis. The transcript levels of SiR were higher in leaves, immature siliques, and roots and were markedly and rapidly up-regulated by MV exposure. The SiR knock-down transgenic lines had about 60% residual transcripts and were more susceptible than wild-type when exposed to oxidative stress. The severe damage phenotypes of the SiR-impaired lines were accompanied by increases of hydrogen peroxide (H2O2), malondialdehyde (MDA), and sulfite accumulations, but less amounts of glutathione (GSH). Interestingly, application of exogenous GSH effectively rescued corresponding MV hypersensitivity in SiR-impaired plants. qRT-PCR analysis revealed that there was significantly increased expression of several sulfite metabolism-related genes in SiR-impaired lines. Noticeably, enhanced transcripts of the three APR genes were quite evident in SiR-impaired plants; suggesting that the increased sulfite in the SiR-impaired plants could be a result of the reduced SiR coupled to enhanced APR expression during oxidative stress. Together, our results indicate that SiR is involved in oxidative stress tolerance possibly by maintaining sulfite homeostasis, regulating GSH levels, and modulating sulfite metabolism-related gene expression in Arabidopsis. SiR could be exploited for engineering environmental stress-tolerant plants in molecular breeding of crops. PMID- 27994614 TI - MtNF-YA1, A Central Transcriptional Regulator of Symbiotic Nodule Development, Is Also a Determinant of Medicago truncatula Susceptibility toward a Root Pathogen. AB - Plant NF-Y transcription factors control a wide array of biological functions enabling appropriate reproductive and developmental processes as well as adaptation to various abiotic and biotic environments. In Medicago truncatula, MtNF-YA1 was previously identified as a key determinant for nodule development and establishment of rhizobial symbiosis. Here, we highlight a new role for this protein in compatibility to Aphanomyces euteiches, a root pathogenic oomycete. The Mtnf-ya1-1 mutant plants showed better survival rate, reduced symptoms, and increased development of their root apparatus as compared to their wild-type (WT) background A17. MtNF-YA-1 was specifically up-regulated by A. euteiches in F83005.5, a highly susceptible natural accession of M. truncatula while transcript level remained stable in A17, which is partially resistant. The role of MtNF-YA1 in F83005.5 susceptibility was further documented by reducing MtNF YA1 expression either by overexpression of the miR169q, a microRNA targeting MtNF YA1, or by RNAi approaches leading to a strong enhancement in the resistance of this susceptible line. Comparative analysis of the transcriptome of WT and Mtnf ya1-1 led to the identification of 1509 differentially expressed genes. Among those, almost 36 defense-related genes were constitutively expressed in Mtnf-ya1 1, while 20 genes linked to hormonal pathways were repressed. In summary, we revealed an unexpected dual role for this symbiotic transcription factor as a key player in the compatibility mechanisms to a pathogen. PMID- 27994616 TI - The rs4646 and rs12592697 Polymorphisms in CYP19A1 Are Associated with Disease Progression among Patients with Breast Cancer from Different Racial/Ethnic Backgrounds. AB - Given the racial/ethnic disparities in breast cancer, we evaluated the association between CYP19A1 single nucleotide polymorphisms (SNPs) on disease progression in women with breast cancer from different racial/ethnic backgrounds. This is a cross-sectional analysis of data from 327 women with breast cancer in the Expanded Breast Cancer Registry program of the University of New Mexico. Stored DNA samples were analyzed for CYP19A1 SNPs using a custom designed microarray panel. Genotype-phenotype correlations were analyzed. Of the 384 SNPs, 2 were associated with clinically significant outcomes, the rs4646 and rs12592697. The T allele for the rs4646 was associated with advanced stage of the disease at the time of presentation (odds ratio [OR]:1.8, confidence intervals [CI]: 1.05-3.13, p < 0.05) and a more progressive disease (OR: 2.1 [CI: 1.1-4.0], p = 0.04). For the rs12592697, the variant T allele was more frequent in Hispanic women and associated with a more progressive disease (OR: 2.05 [CI: 1.0-4.0], p = 0.04). However, further analysis according to menopausal status showed that the association between these 2 SNPs with disease progression or the stage at diagnosis are confined only to postmenopausal women. The odds ratios of disease progression among postmenopausal women carrying the T allele for the rs4646 and rs12592697 are 3.05 (1.21, 7.74, p = 0.02) and 3.80 (1.24, 11.6, p = 0.02), respectively. Regardless, differences in disease progression among the different genotypes for both SNPs disappeared after adjustment for treatment. In summary, the rs4646 and the rs12592697 SNPs in CYP19A1 are associated with differences in disease progression in postmenopausal women. However, treatment appears to mitigate the differences in genetic risk. PMID- 27994617 TI - Preliminary Experience Using Full-Spectrum Endoscopy for Colorectal Cancer Screening: Matched Case Controlled Study. AB - Background/Aim. High-quality colonoscopy is needed to reduce the morbidity and mortality of colorectal cancer. Full-spectrum endoscopy (FUSE) has recently shown potential in improving adenoma detection during colonoscopy. This study aimed to evaluate the feasibility and utility of FUSE colonoscopy. Methods. From April 2015 to February 2016, 130 patients underwent FUSE colonoscopy for screening at a tertiary cancer center. Cecal intubation rate (CIR), procedure time, polyp/adenoma detection rate (PDR/ADR), and mean number of adenomas per colonoscopy (APC) were compared in matched-control patients (n = 260) who underwent standard colonoscopy (SC). Accordingly, endoscopists subjectively evaluated the utility of FUSE colonoscopy. Results. The CIR of FUSE colonoscopy was 94.6%. Cecal intubation time (8.8 min versus 5.1 min, P < 0.001) and total procedure time (21.6 min versus 17.3 min, P < 0.001) in the FUSE group were significantly longer than those in the SC group. PDR (68.3 versus 71.2%, P = 0.567), ADR (63.4% versus 58.5%, P = 0.355), and APC (1.4 versus 1.4, P = 0.917) were not significantly different between the two groups. The wide view of FUSE colonoscopy was superior to that of SC based on the questionnaires. Conclusions. FUSE colonoscopy did not demonstrate superiority to SC in a clinical setting. PMID- 27994618 TI - Younger Age Is Associated with Poorer Survival in Patients with Signet-Ring Cell Carcinoma of the Colon without Distant Metastasis. AB - Background. In general, younger age is associated with better survival in patients with colon cancer. In this study, we aim to analyze the impact of age on cancer-specific survival (CSS) in patients with signet-ring cell carcinoma (SRCC) of the colon, a particularly aggressive type of colon cancer. Methods. Information on patients with SRCC of the colon with no distant metastasis was extracted from the US Surveillance, Epidemiology, and End Results (SEER) database. An X-tile plot was used to determine the optimal cutoff age at diagnosis. Results. A total of 776 patients were included in data analysis. The X tile program revealed an optimal cutoff at 35 years of age. A higher percentage of stage III disease and a higher percentage of N2 disease were observed in patients <= 35 years of age. The multivariate Cox proportional model demonstrated that patients <= 35 years of age were more likely to have a poorer survival outcome compared with patients aged >35 years (HR 1.411, 95% CI 1.032-1.929, and P = 0.031). Conclusion. In contrast to the association of younger age with better survival in colon cancer patients, younger age (<=35 years) is associated with poorer survival outcome in patients with SRCC of the colon without distant metastasis. PMID- 27994619 TI - Some Risk Factors of Chronic Functional Constipation Identified in a Pediatric Population Sample from Romania. AB - We conducted an observational study over a 1-year period, including 234 children aged 4-18 years and their caregivers and a matching control group. 60.73% of the children from the study group were males. Average age for the onset of constipation was 26.39 months. The frequency of defecation was 1/4.59 days (1/1.13 days in the control group). 38.49% of the patients in the sample group had a positive family history of functional constipation. The majority of children with functional constipation come from single-parent families, are raised by relatives, or come from orphanages. Constipated subjects had their last meal of the day at later hours and consumed fast foods more frequently than the children in the control sample. We found a statistically significant difference between groups regarding obesity/overweight and constipation (chi2 = 104.94, df = 2, p < 0.001) and regarding physical activity and constipation (chi2 = 18.419; df = 3; p < 0.001). There was a positive correlation between the number of hours spent watching television/using the computer and the occurrence of the disease (F = 92.162, p < 0.001, and 95% Cl). Children from broken families, with positive family history, defective dietary habits, obesity and sedentary behavior, are at higher risk to develop chronic functional constipation. PMID- 27994620 TI - Novel Visual Nasogastric Tube Insertion System: A Feasibility and Efficiency Study in a Manikin. AB - Background. Conventional nasogastric tube placement is an essential clinical procedure; however, complications may arise from blind manipulation. We tested the feasibility and efficiency of a visual nasogastric tube insertion system (VNGS) using a manikin. Methods. A microimaging fiber (0.8 mm) was integrated into the nasogastric tube to create the VNGS. Twenty inexperienced physicians were enrolled and assigned to the visual or conventional group. Each physician performed 10 repeated nasogastric tube insertions with visual guidance or the conventional method; another 20 inexperienced medical students received nasogastric tube insertion training using visual guidance or the conventional method. Results. The nasogastric tube successfully reached the stomach and the narrow anatomic structures were visualized with the VNGS. Time required for insertion was significantly shorter in the visual group compared to the conventional group (22.56 +/- 3.08 versus 37.30 +/- 4.12 seconds, P < 0.001). Tube misplacement was observed in 19/100 cases (19%) in the conventional group; no misplacement was observed in the visual group. Less mucosal damage was noted in the visual group (3.43 +/- 1.63 versus 9.86 +/- 2.31 cm2). Medical students performed better NGT insertions (shorter insertion time and less procedure related complications) after undergoing the visual guidance training. Conclusions. The VNGS may provide a new technique for nasogastric tube insertion applicable to clinical use or simulation training. PMID- 27994621 TI - Antimicrobial Stewardship: A Cross-Sectional Survey Assessing the Perceptions and Practices of Community Pharmacists in Ethiopia. AB - Background. Community pharmacists are key healthcare professionals for antimicrobial stewardship programs owing to their role in dispensing of antimicrobials. The aim of the present study was to assess the perception and practices of community pharmacists towards antimicrobial stewardship (AMS) in Ethiopia. Methods. A cross-sectional survey was conducted by selecting pharmacy sites through stratified simple random sampling technique. Descriptive and inferential statistics were used to analyze the data. Results. Majority of respondents strongly agreed or agreed that AMS program is vital for the improvement of patient care. Almost all of respondents agreed that pharmacists can play a prominent role in AMS and infection prevention (93.2%, median = 5; IQR = 2-5). However, only 26.5% of respondents strongly agreed or agreed that AMS should be practiced at community pharmacy level (median = 4, IQR = 1-3) and more than half of community pharmacists (59.9%) often/always dispense antimicrobial without a prescription. Conclusion. The present study revealed positive perceptions and practices of community pharmacists towards antimicrobial stewardship. Yet, some weak areas like integration of AMS program in community pharmacies, the significance of interprofessional involvement, and dispensing of antimicrobials without a valid prescription still need improvement. PMID- 27994622 TI - Bone Formation by Sheep Stem Cells in an Ectopic Mouse Model: Comparison of Adipose and Bone Marrow Derived Cells and Identification of Donor-Derived Bone by Antibody Staining. AB - Background. Scaffolds for bone tissue engineering (BTE) can be loaded with stem and progenitor cells (SPC) from different sources to improve osteogenesis. SPC can be found in bone marrow, adipose tissue, and other tissues. Little is known about osteogenic potential of adipose-derived culture expanded, adherent cells (A CEAC). This study compares in vivo osteogenic capacity between A-CEAC and bone marrow derived culture expanded, adherent cells (BM-CEAC). Method. A-CEAC and BM CEAC were isolated from five female sheep and seeded on hydroxyapatite granules prior to subcutaneous implantation in immunodeficient mice. The doses of cells in the implants were 0.5 * 106, 1.0 * 106, or 1.5 * 106 A-CEAC and 0.5 * 106 BM CEAC, respectively. After eight weeks, bone volume versus total tissue volume (BV/TV) was quantified using histomorphometry. Origin of new bone was assessed using human vimentin (HVIM) antibody staining. Results. BM-CEAC yielded significantly higher BV/TV than any A-CEAC group, and differences between A-CEAC groups were not statistically significant. HVIM antibody stain was successfully used to identify sheep cells in this model. Conclusion. A-CEAC and BM-CEAC were capable of forming bone, and BM-CEAC yielded significantly higher BV/TV than any A-CEAC group. In vitro treatment to enhance osteogenic capacity of A-CEAC is suggested for further research in ovine bone tissue engineering. PMID- 27994623 TI - Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis. AB - Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs. PMID- 27994625 TI - Effect of Mesenchymal Stem Cells and Platelet-Rich Plasma on the Bone Healing of Ovariectomized Rats. AB - We evaluated the efficacy of platelet-rich plasma (PRP) in combination with allogeneic bone marrow mesenchymal stem cells (BMSCs) for the treatment of osteoporotic bone defects in an ovariectomized rat model. By day 42 after injury, in vivo microcomputed tomography (micro-CT) imaging revealed that bone defects of control rats and ovariectomized rats treated with PRP and BMSCs were completely repaired, whereas those of ovariectomized rats treated with PRP or BMSCs alone exhibited slower healing. Histological data were consistent with these results. We also assessed changes to bone trabeculae in the proximal tibial growth plate. In ovariectomized rats treated with PRP or with a combination of PRP and BMSCs, the trabecular connectivity densities (Conn.D), bone volume ratios (BV/TV), and numbers (Tb.N) in the defect areas increased significantly from day 7 to day 42. These results indicate that PRP treatment enhances bone microarchitecture in osteoporosis. Moreover, expression levels of osteogenesis-specific marker genes including RUNX2, OSX, and OPN were significantly upregulated in rats treated with PRP and BMSCs compared to those of other groups. Thus, we conclude that treatment with PRP combined with BMSCs significantly promotes healing of osteoporotic bone defects. This study provides an alternative strategy for the treatment of osteoporotic bone loss. PMID- 27994624 TI - Regulatory Mechanisms of the Ihh/PTHrP Signaling Pathway in Fibrochondrocytes in Entheses of Pig Achilles Tendon. AB - This study is aimed at exploring the effect of stress stimulation on the proliferation and differentiation of fibrochondrocytes in entheses mediated via the Indian hedgehog (Ihh)/parathyroid hormone-related protein (PTHrP) signaling pathway. Differential stress stimulation on fibrochondrocytes in entheses was imposed. Gene expression and protein levels of signaling molecules including collagen type I (Col I), Col II, Col X, Ihh, and PTHrP in the cytoplasm of fibrochondrocytes were detected. Ihh signal blocking group was set up using Ihh signaling pathway-specific blocking agent cyclopamine. PTHrP enhancement group was set up using PTHrP reagent. Ihh/PTHrP double intervention group, as well as control group, was included to study the regulatory mechanisms of the Ihh/PTHrP signaling pathway in fibrochondrocytes. Under low cyclic stress tensile (CTS), PTHrP, Col I, and Col II gene expression and protein synthesis increased. Under high CTS, Ihh and Col X gene expression and protein synthesis increased. Blocking Ihh signaling with cyclopamine resulted in reduced PTHrP gene expression and protein synthesis and increased Col X gene expression and protein synthesis. Ihh and PTHrP coregulate fibrochondrocyte proliferation and differentiation in entheses through negative feedback regulation. Fibrochondrocyte is affected by the CTS. This phenomenon is regulated by stress stimulation through the Ihh/PTHrP signaling pathway. PMID- 27994626 TI - Congenital Lumbar Hernia: A 15-Year Experience at a Single Tertiary Centre. AB - Aim. Congenital lumbar hernia is an uncommon anomaly with only few cases reported in the English literature. This study was done to study the incidence, age at presentation, sex, associated anomalies, surgical management, and postoperative morbidity and mortality of congenital lumbar hernia in pediatric patients. Methods. Retrospective analysis of all patients of CLH over a period of 15 years (January 2000 to December 2015) was analyzed. Results. A total of 14 patients were encountered in this series. All presented within first 2 years of age. 12 were males and 2 were females. All of them presented with swelling in lumbar region. 13 were unilateral and 1 was bilateral. Left sided hernia was observed in 2 cases only. Lumbocostovertebral syndrome was found in all the patients in addition to other rare anomalies. All cases were managed with open surgical repair. Wound infection was seen in 2 cases. There was no mortality in our series. Conclusion. CLH is very rare among hernias. Surgery should be carried out within 1 year of age. For a defect of <5 cm, primary repair is done. For a defect of >5 cm, meshplasty should be considered. Prognosis is excellent. PMID- 27994627 TI - Protocol for Acupuncture Treatment of Lateral Elbow Pain: A Multisite Randomised Controlled Trial in China, Hong Kong, Australia, and Italy. AB - Background. Lateral elbow pain is one of the most common musculoskeletal pains associated with the upper limb and has an estimated population incidence of 1-3%. Methods/Design. This study protocol is for a multisite randomised controlled study and is designed to evaluate the clinical efficacy of acupuncture in the treatment of chronic (over three months' duration) lateral elbow pain. Four study sites, in the People's Republic of China, Hong Kong, Italy, and Australia, will recruit 24 participants each. A total of 96 participants will be randomised to either an acupuncture group or a sham laser control group. The primary outcome measure will be the Disabilities of Arm, Shoulder, and Hand questionnaire with secondary outcome measures of Pain-Free Grip Strength Test, Muscle Tension Test, and a pain visual analogue scale. Discussion. Key features for conducting a multisite international acupuncture randomised clinical trial have been detailed in this protocol. Trial Registration. This trial is registered at Australian and New Zealand Clinical Trial Registry ACTRN12613001138774 on 11 October, 2013. PMID- 27994628 TI - The Extract of Fructus Psoraleae Promotes Viability and Cartilaginous Formation of Rat Chondrocytes In Vitro. AB - This study aimed to investigate the extract components of FP on rat chondrocyte function and cartilaginous formation in vitro. Petroleum ether extract (P-e) of FP extract components was selected to treat Sprague-Dawley rat chondrocytes. Cell viability was tested with different concentrations (0.1, 1, 10, and 100 MUg/mL) of P-e treatment. Concentrations of 0.1 and 1 MUg/mL P-e conditioned culture mediums were used for treating chondrocytes in experiments. Cell proliferation was measured via DNA incorporation assay. Type II collagen, aggrecan, and Sox-9 genes expression levels were measured with RT-PCR. Additionally, cartilaginous formation was analyzed with type II collagen immunofluorescence, H&E, and alcian blue staining. Concentrations of 0.1 and 1 MUg/mL P-e showed low cytotoxicity and demonstrated stimulatory effects on chondrocyte proliferation in early stages. Following 6 days of P-e culture, aggrecan and Sox-9 gene expression levels of the 1 MUg/mL P-e group were upregulated by 1.82- (p < 0.05) and 2.06-fold (p < 0.05), respectively, versus controls. Moreover, 1 MUg/mL P-e significantly stimulated cell aggregation and type II collagen deposits after 1 week of treatment. Noteworthy, tight cartilaginous structures formed in the 10-day 1 MUg/mL P-e conditioned culture. These findings suggest that P-e has the potential to treat cartilage degeneration induced by chondrocyte failure. PMID- 27994629 TI - The Needs and Priorities for Government Grants for Traditional Korean Medicine: Comparing the Public and Traditional Korean Medicine Doctors. AB - This study was conducted to compare the need for research and development (R&D) of Traditional Korean Medicine (TKM) perceived by the public and Traditional Korean Medicine doctor (KMD) in. Survey data from 2462 people and KMD were utilized for this study. Overall, 25.10% of the public and 90.91% of KMD answered that government grants for TKM R&D were "extremely necessary." The majority of respondents reported that grants were needed "for the advancement of science and technology in TKM" (public, 46.28%; KMD, 34.08%). Research regarding herbal medicine was the top priority of TKM R&D in both groups. However, "research facilities and training for researchers (27.85%)" was a close second priority of the public, but not KMD. Moreover, the public believed that safety from adverse effects and toxicity was a more important area of R&D in each discipline, but KMD did not find these to be important. The public and KMD generally agreed on the need for government grants for TKM R&D, but the public was more interested in safety than KMD. Therefore, government policy decision makers must consider opinions of both the public and KMD when planning government grants. PMID- 27994630 TI - Corrigendum to "Use of Ethnomedicinal Plants by the People Living around Indus River". AB - [This corrects the article DOI: 10.1155/2014/212634.]. PMID- 27994631 TI - Evaluation of Beeswax Influence on Physical Properties of Lipstick Using Instrumental and Sensory Methods. AB - The aim of this study was to optimize the lipsticks formulation according to the physical properties and sensory attributes and investigate the relationship between instrumental and sensory analyses and evaluate the influence of the main ingredients, beeswax and oil, with analysis of lipsticks properties. Central composite design was used to optimize the mixture of oils and beeswax and cocoa butter for formulation of lipsticks. Antioxidant activity was evaluated by DPPH free radical scavenging method spectrophotometrically. Physical properties of lipsticks melting point were determined in a glass tube; the hardness was investigated with texture analyzer. Sensory analysis was performed with untrained volunteers. The optimized mixture of sea buckthorn oil and grapeseed oil mixture ratio 13.96 : 6.18 showed the highest antioxidative activity (70 +/- 0.84%) and was chosen for lipstick formulation. According to the sensory and instrumental analysis results, optimal ingredients amounts for the lipstick were calculated: 57.67% mixture of oils, 19.58% beeswax, and 22.75% cocoa butter. Experimentally designed and optimized lipstick formulation had good physical properties and high scored sensory evaluation. Correlation analysis showed a significant relationship between sensory and instrumental evaluations. PMID- 27994632 TI - Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa). AB - Calycosin and formononetin are two structurally similar isoflavonoids that have been shown to induce vasodilation in aorta and conduit arteries, but study of their actions on endothelial functions is lacking. Here, we demonstrated that both isoflavonoids relaxed rat mesenteric resistance arteries in a concentration dependent manner, which was reduced by endothelial disruption and nitric oxide synthase (NOS) inhibition, indicating the involvement of both endothelium and vascular smooth muscle. In addition, the endothelium-dependent vasodilation, but not the endothelium-independent vasodilation, was blocked by BKCa inhibitor iberiotoxin (IbTX). Using human umbilical vein endothelial cells (HUVECs) as a model, we showed calycosin and formononetin induced dose-dependent outwardly rectifying K+ currents using whole cell patch clamp. These currents were blocked by tetraethylammonium chloride (TEACl), charybdotoxin (ChTX), or IbTX, but not apamin. We further demonstrated that both isoflavonoids significantly increased nitric oxide (NO) production and upregulated the activities and expressions of endothelial NOS (eNOS) and neuronal NOS (nNOS). These results suggested that calycosin and formononetin act as endothelial BKCa activators for mediating endothelium-dependent vasodilation through enhancing endothelium hyperpolarization and NO production. Since activation of BKCa plays a role in improving behavioral and cognitive disorders, we suggested that these two isoflavonoids could provide beneficial effects to cognitive disorders through vascular regulation. PMID- 27994633 TI - Electroacupuncture Restores 5-HT System Deficit in Chronic Mild Stress-Induced Depressed Rats. AB - Objective. The current study is designed to investigate the antidepressant efficacy of electroacupuncture (EA) treatment by evaluating its effect on the synthesis, metabolism, reuptake, and receptors of 5-hydroxytryptamine (5-HT), so as to clarify the molecular mechanisms of EA for antidepression. Materials and Methods. Solitary combined with the chronic unpredictable mild stress (CUMS) was used to establish the rat model with depression. The depressed rats were supplied with EA treatment for 4 weeks, and the behavior change and the following indices including 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase A (MAO-A), tryptophan hydroxylase (TPH), 5-HT transporter (SERT), 5-HT1A, and 5-HT2A in hippocampus and prefrontal cortex were examined. Results. EA treatment significantly improved the behavior of rats and increased 5-HT level in hippocampus of depressed rats. Similarly, EA treatment could significantly increase protein and mRNA expression of TPH and 5-HT1A during 5-HT synthesis process in hippocampus of depressed rats. However, EA treatment had no effect on the activity of MAO-A and the expression of SERT protein and mRNA. Conclusion. Antidepressant efficacy of EA treatment can be accomplished through enhancing 5 HT synthesis, upregulating 5-HT1A level, and improving 5-HT content in brain and synaptic gaps. PMID- 27994634 TI - Serum MicroRNA Profiling and Bioinformatics of Patients with Spleen-Deficiency Syndrome. AB - To investigate serum microRNA (miRNA) profile and bioinformatics of patients with spleen-deficiency syndrome (SDS) and explore pathogenesis of SDS patients from miRNA levels, 10 patients with type 2 diabetes mellitus (T2DM), within which 5 patients were with SDS and the remaining were with blood stasis syndrome (BSS), and 5 healthy volunteers were recruited. Serum miRNA profiles of SDS patients were identified by quantitative PCR array. Target prediction and functional annotation for miRNAs were performed by miRSystem database. The present study identified 11 candidate serum miRNAs for SDS patients, and their targets were significantly enriched in 18 KEGG pathways and 7 GO molecular functions. Those enriched KEGG pathways included (1) metabolisms of carbohydrate, protein, amino acid, and fatty acid, (2) signaling pathways of insulin, ErbB, chemokine, calcium, and type II diabetes mellitus, (3) invasions of bacterium, Escherichia coli, and Shigella (Shigellosis), and (4) endocytosis and phagocytosis. Those enriched GO molecular functions were mainly involved in transcription regulation and regulation of metabolism. Our findings might elucidate the pathogenesis of SDS patients with disorders of substance metabolism and hypoimmunity from miRNA levels, as well as providing some miRNA biomarkers for clinical syndrome differentiation of SDS. PMID- 27994635 TI - Diagnostic utility of double immunostaining of a urine cytology preparation for cytokeratin 20/p53 expression in a young woman with micropapillary urothelial carcinoma of the renal pelvis presenting as an unknown primary malignancy. AB - Atypical urine cytology (CYT) triggers a cystoscopic or another ancillary investigation that targets urothelial neoplasms. We report a case presenting as an unknown primary malignancy, which illustrated the diagnostic utility of direct double immunostaining for cytokeratin 20 (CK20)/p53 expression in a urine CYT specimen. A 42-year-old woman visited the emergency room for pain in her right lower abdominal quadrant. Computed tomography revealed postrenal obstructive hydronephrosis, and her urine CYT showed malignancy, type undetermined. Atypical cells that are positive for cytoplasmic expression of CK20 and nuclear expression of p53 could facilitate the decision to perform a nephroureterectomy for urothelial carcinoma. PMID- 27994636 TI - The effect of the small amount of formaldehyde in the SurePath liquid when establishing protocols for immunocytochemistry. AB - BACKGROUND: SurePath(r) is an ethanol-based liquid fixative. In addition to ethanol, it also contains a small amount of formaldehyde (<0.2%). The aim of this study was to investigate the immunoreactivity of cells stored for different lengths of time in the SurePath liquid. MATERIALS AND METHODS: Rest material from one malignant and three benign effusions were fixed in SurePath for 1-12 days. Cytospins were incubated with cytokeratin 7 antibody (AB) to evaluate the staining intensity of carcinoma cells and benign, reactive mesothelial cells. Protocols varied as to pretreatment and AB incubation time. RESULTS: Reduced immunostaining intensity was seen within 5 days of storage in the SurePath liquid. It was restored when the pretreatment time was prolonged. CONCLUSIONS: The small amount of formaldehyde in the SurePath liquid seems to affect the immunoreactivity. Local immunocytochemistry protocols in the cytology laboratories should consider this when optimizing their procedures. Postfixation with formalin should be omitted. PMID- 27994637 TI - Surface-based molecular self-assembly: Langmuir-Blodgett films of amphiphilic Ln(III) complexes. AB - The unique photophysical properties of the Ln(III) series has led to significant research efforts being directed towards their application in sensors. However, for "real-life" applications, these sensors should ideally be immobilised onto surfaces without loss of function. The Langmuir-Blodgett (LB) technique offers a promising method in which to achieve such immobilisation. This mini-review focuses on synthetic strategies for film formation, the effect that film formation has on the physical properties of the Ln(III) amphiphile, and concludes with examples of Ln(III) LB films being used as sensors. PMID- 27994638 TI - Platelet-12 lipoxygenase targeting via a newly synthesized curcumin derivative radiolabeled with technetium-99m. AB - BACKGROUND: One of the most popular techniques for cancer detection is the nuclear medicine technique. The present research focuses on Platelet-12 lipoxygenase (P-12-LOX) as a promising target for treating and radio-imaging tumor tissues. Curcumin was reported to inhibit this enzyme via binding to its active site. RESULTS: A novel curcumin derivative was successfully synthesized and characterized with yield of 74%. It was radiolabeled with the diagnostic radioisotope technetium-99m with 84% radiochemical yield and in vitro stability up to 6 h. The biodistribution studies in tumor bearing mice confirmed the high affinity predicted by the docking results with a free binding energy value of (DeltaG -50.10 kcal/mol) and affinity (13.64 pki) showing high accumulation in solid tumor with target/non-target ratio >6. CONCLUSION: The newly synthesized curcumin derivative, as a result of a computational study on platelet-12 lipoxygenase, showed its excellent free binding energy (?G -50.10 kcal/mol) and high affinity (13.64 pKi). It could be an excellent radio-imaging agent that targeting tumor cells via targeting of P-12-LOX.Graphical abstractThis novel curcumin derivative was successfully synthesized and radiolabeled with technetium 99m and biologically evaluated in tumor bearing mice that showed high accumulation in solid tumor with target/non-target ratio >6 confirming the affinity predicted by the docking results. Predicted binding mode of a new curcumin derivative in complex with 12-LOX active site. b Curcumin itself in the 12-LOX active site biological distribution of 99mTc-curcumin derivative complex in solid tumor bearing Albino mice. PMID- 27994639 TI - Interpreting comprehensive two-dimensional gas chromatography using peak topography maps with application to petroleum forensics. AB - BACKGROUND: Comprehensive two-dimensional gas chromatography [Formula: see text] provides high-resolution separations across hundreds of compounds in a complex mixture, thus unlocking unprecedented information for intricate quantitative interpretation. We exploit this compound diversity across the [Formula: see text] topography to provide quantitative compound-cognizant interpretation beyond target compound analysis with petroleum forensics as a practical application. We focus on the [Formula: see text] topography of biomarker hydrocarbons, hopanes and steranes, as they are generally recalcitrant to weathering. We introduce peak topography maps (PTM) and topography partitioning techniques that consider a notably broader and more diverse range of target and non-target biomarker compounds compared to traditional approaches that consider approximately 20 biomarker ratios. Specifically, we consider a range of 33-154 target and non target biomarkers with highest-to-lowest peak ratio within an injection ranging from 4.86 to 19.6 (precise numbers depend on biomarker diversity of individual injections). We also provide a robust quantitative measure for directly determining "match" between samples, without necessitating training data sets. RESULTS: We validate our methods across 34 [Formula: see text] injections from a diverse portfolio of petroleum sources, and provide quantitative comparison of performance against established statistical methods such as principal components analysis (PCA). Our data set includes a wide range of samples collected following the 2010 DeepwaterHorizon disaster that released approximately 160 million gallons of crude oil from the Macondo well (MW). Samples that were clearly collected following this disaster exhibit statistically significant match [Formula: see text] using PTM-based interpretation against other closely related sources. PTM-based interpretation also provides higher differentiation between closely correlated but distinct sources than obtained using PCA-based statistical comparisons. In addition to results based on this experimental field data, we also provide extentive perturbation analysis of the PTM method over numerical simulations that introduce random variability of peak locations over the [Formula: see text] biomarker ROI image of the MW pre-spill sample (sample [Formula: see text] in Additional file 4: Table S1). We compare the robustness of the cross-PTM score against peak location variability in both dimensions and compare the results against PCA analysis over the same set of simulated images. Detailed description of the simulation experiment and discussion of results are provided in Additional file 1: Section S8. CONCLUSIONS: We provide a peak cognizant informational framework for quantitative interpretation of [Formula: see text] topography. Proposed topographic analysis enables [Formula: see text] forensic interpretation across target petroleum biomarkers, while including the nuances of lesser-known non-target biomarkers clustered around the target peaks. This allows potential discovery of hitherto unknown connections between target and non-target biomarkers. PMID- 27994640 TI - Analysis of tilianin and acacetin in Agastache rugosa by high-performance liquid chromatography with ionic liquids-ultrasound based extraction. AB - Ionic liquid 1-butyl-3-methylimidazolium bromide-methanol-based ultrasonic assisted extraction (ILUAE) was used to extract tilianin and acacetin from the aerial parts of Agastache rugose (A. rugose), and simultaneously determined by reversed phase high performance liquid chromatographic (RP-HPLC) method with ultraviolet detection (RP-HPLC-UV). An InertSustain RP-C18 column was used with the mobile phase consisting of methanol and 0.2% acetic acid as gradient elution at the detection wavelength of 332 nm. The flow rate was 0.8 mL/min, and the column temperature was 30 degrees C. Under the optimized conditions, tilianin and acacetin displayed good linearity in the ranges of 0.0595-4.76 and 0.0585 4.68 MUg/mL, respectively, with the average recoveries being 96.93 and 97.88%, respectively. The method of ILUAE was compared with the traditional methods, it exhibited higher efficiency, higher reproducibility and environmental friendly in analyzing the active compounds in traditional Chinese medicines (TCMs). PMID- 27994641 TI - Colon targeted drug delivery of branch-chained disulphide cross-linked polymers: design, synthesis, and characterisation studies. AB - Drug delivery directly to the colon is a very useful approach for treating localised colonic diseases such as inflammatory bowel disease, ulcerative colitis, and Crohn's disease. The use of disulphide cross-linked polymers in colon targeted drug delivery systems has received much attention because these polymers are redox sensitive, and the disulphide bonds are only cleaved by the low redox potential environment in the colon. The goal of this study was to synthesise tricarballylic acid-based trithiol monomers for polymerisation into branch-chained disulphide polymers. The monomer was synthesised via the amide coupling reaction between tricarballylic acid and (triphenylmethyl) thioethylamine using two synthesis steps. The disulphide cross-linked polymers which were synthesised using the air oxidation method were completely reduced after 1 h of reduction with different thiol concentrations detected for the different disulphide polymers. In simulated gastric and intestinal conditions, all polymers had low thiol concentrations compared to the thiol concentrations in the simulated colon condition with Bacteroides fragilis present. Degradation was more pronounced in polymers with loose polymeric networks, as biodegradability relies on the swelling ability of polymers in an aqueous environment. Polymer P15 which has the loosest polymeric networks showed highest degradation. PMID- 27994642 TI - Close cooperation with Health Technology Assessment expertise is crucial for implementation and ultimately reimbursement of innovations in oncology. AB - The Organisation of European Cancer Institutes OECI working group on Health Economics and Cost Benefit in Oncology suggests four actions that are needed to improve alignment and integration between clinicians, researchers, and Health Technology Assessment (HTA) experts and agencies: 1) HTA expertise is necessary close to or within the comprehensive cancer centres (CCC); 2) HTA expertise should be physically present throughout the translational research process; 3) Appropriate knowledge is necessary within the research staff; 4) Close cooperation between translational researchers, clinicians, and health economists guarantees clinical ownership. Fulfilling these conditions may help the translational research field in oncology to interact with agencies and efficiently move innovative technologies through the translational research stages into that of implementation and diffusion. This brings innovative treatments faster to the patient with a greater chance of reimbursement. PMID- 27994643 TI - The cost of cancer care is not related to its outcomes. AB - Solid tumours make up 90% of all proliferative diseases and the main action for cure remains surgery, removing the visible tumour as well as the surrounding tissue. Radiotherapy is an added value for eliminating local microscopic as well as regional disease. Systemic treatment has a small impact on the outcome but has a cost, which is as much as all the other actions such as diagnostic tools and treatments. PMID- 27994644 TI - Predictors of survival of natural killer/T-cell lymphoma, nasal type, in a non Asian population: a single cancer centre experience. AB - BACKGROUND: Natural killer/T-cell lymphoma (NKTCL), part of T-cell and NK-cell neoplasms in the World Health Organisation (WHO) classification, is an aggressive lymphoma with poor prognosis more predominantly seen in Asian and South American countries. This study evaluates the factors associated with survival among patients with newly diagnosed NKTCL in Peru. METHODS: Information was abstracted from medical records (MR) for all NKTCL patients >13 years of age at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 2002 and 2011. The estimate of the survival curves was performed by the Kaplan-Meier method, and the difference was computed by the log-rank test. RESULTS: Around 226 MR were reviewed, 153 met the selection criteria, the median age was 40 years (14-84). The median progression-free survival (PFS) was 20 months, five year PFS was 42.6%, univariable analysis (UA) showed statistical significance (p < 0.05) for male sex, non-nasal primary site, advanced clinical stages, B symptoms, poor performance status, regional nodal involvement (RNI). In the multivariate analysis the only poor prognostic factors was primary non-nasal (Hazard ratio (HR) = 2.40, 95% confidence interval (CI) = 1.43- 4.02, P = 0.01). The median overall survival (OS) was 49 months, five year OS was 48.9%, UA showed statistical significance for non-nasal primary site, advanced clinical stages, B symptoms, lactate dehydrogenase (LDH) > normal, RNI and local tumour invasion. In the multivariate analysis, primary non-nasal was the only poor prognostic factor with HR = 2.57, 95% CI = 1.37-4.83, P = 0.03. CONCLUSIONS: In Peru, OS of NKTCL is similar to other countries. This result suggests that non-nasal NKTCL is the only poor prognostic factor of OS and PFS. PMID- 27994647 TI - Cancer immunotherapy: from the lab to clinical applications-Potential impact on cancer centres' organisation. AB - This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th 17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual's immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present. PMID- 27994646 TI - Postoperative radiotherapy in the management of keloids. AB - BACKGROUND: The high recurrence rate following keloid resection has generated interest in adjuvant treatments for this disease. OBJECTIVE: This study assesses keloid recurrence when treated with surgery and adjuvant radiotherapy. METHODS: Retrospective analysis of resected keloids in patients referred to a Chilean radiation oncology centre between 2006 and 2013. Local recurrence was defined as new tissue growth on the surgical scar margin. RESULTS: Around103 keloids were analysed in 63 patients treated with 15 Gy in three fraction radiotherapy which was initiated on the same day as the surgery (75% of cases). The median keloid diameter was 6 cm; the most common site was thoracic (22%); the most common cause was prior surgery (35%); 37% caused symptoms, and several (47%) had received prior treatment with corticosteroids (32%), or surgery (30%). The median follow up was three years, and 94% of recurrences occurred during the first year following treatment. Uni and multivariate analyses showed that an absence of symptoms was a protective factor for recurrence (OR: 0.24), while the time interval from onset to treatment with surgery plus radiotherapy >4.2 years was a risk factor (OR: 2.23). The first year recurrence rate was 32% and stabilised at 32% by the second year with no recurrences after 15 months. CONCLUSIONS: The combination of surgery and radiotherapy proved to be a good therapeutic alternative in the management of keloids. Our results are similar to those described in the literature for a dose of 15 Gy. Given these results, our centre will implement a new dose escalation protocol to improve future outcomes. PMID- 27994648 TI - Sinonasal glomangiopericytoma treated with preoperative embolisation and endoscopic sinus surgery. AB - Sinonasal glomangiopericytoma is a benign rare tumour of pericytes that accounts for less than 0.5% of all sinonasal tumours. It is an indolent tumour with a macroscopic appearance of common inflammatory polyps. We report the case of a 55 year-old male who presented with right nasal obstruction. CT and MRI examinations demonstrated a soft-tissue mass that obstructed mainly the right nasal cavity. Biopsy revealed glomangiopericytoma. The tumour was treated with preoperative embolisation followed by complete endoscopic resection. Very few cases have been reported to be treated in this way. PMID- 27994645 TI - Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai. AB - The 5th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6th - 8th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies. PMID- 27994649 TI - European cancer research: from bench to bedside and to breakfast table. AB - We examined the outputs, sources of funding, and impact of European cancer research from 2002-13. Outputs were compared with the disease burden and individual countries' wealth. Funding came from a huge number of sources, particularly private-non-profit ones in northern and western Europe. Impacts were determined from citations on cancer clinical guidelines and in European newspaper stories about cancer research. PMID- 27994650 TI - Prediction of reacting atoms for the major biotransformation reactions of organic xenobiotics. AB - BACKGROUND: The knowledge of drug metabolite structures is essential at the early stage of drug discovery to understand the potential liabilities and risks connected with biotransformation. The determination of the site of a molecule at which a particular metabolic reaction occurs could be used as a starting point for metabolite identification. The prediction of the site of metabolism does not always correspond to the particular atom that is modified by the enzyme but rather is often associated with a group of atoms. To overcome this problem, we propose to operate with the term "reacting atom", corresponding to a single atom in the substrate that is modified during the biotransformation reaction. The prediction of the reacting atom(s) in a molecule for the major classes of biotransformation reactions is necessary to generate drug metabolites. RESULTS: Substrates of the major human cytochromes P450 and UDP-glucuronosyltransferases from the Biovia Metabolite database were divided into nine groups according to their reaction classes, which are aliphatic and aromatic hydroxylation, N- and O glucuronidation, N-, S- and C-oxidation, and N- and O-dealkylation. Each training set consists of positive and negative examples of structures with one labelled atom. In the positive examples, the labelled atom is the reacting atom of a particular reaction that changed adjacency. Negative examples represent non reacting atoms of a particular reaction. We used Labelled Multilevel Neighbourhoods of Atoms descriptors for the designation of reacting atoms. A Bayesian-like algorithm was applied to estimate the structure-activity relationships. The average invariant accuracy of prediction obtained in leave-one out and 20-fold cross-validation procedures for five human isoforms of cytochrome P450 and all isoforms of UDP-glucuronosyltransferase varies from 0.86 to 0.99 (0.96 on average). CONCLUSIONS: We report that reacting atoms may be predicted with reasonable accuracy for the major classes of metabolic reactions-aliphatic and aromatic hydroxylation, N- and O-glucuronidation, N-, S- and C-oxidation, and N- and O-dealkylation. The proposed method is implemented as a freely available web service at http://www.way2drug.com/RA and may be used for the prediction of the most probable biotransformation reaction(s) and the appropriate reacting atoms in drug-like compounds.Graphical abstract. PMID- 27994651 TI - Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors. AB - Background: Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large /small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed. Material and methods: 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology. Results: A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular, EGFR expression was observed in the investigated tumors in a noteworthy manner. Additionally, MDM2 was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor, CDKN2A, was nearly absent in all low-grade tumors. TP53 showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids. Conclusion: Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors. PMID- 27994652 TI - To Excavate Biomarkers Predictive of the Response for Capecitabine plus RAD001 through Nanostring-Based Multigene Assay in Advanced Gastric Cancer Patients. AB - Comprehensive characterization of individual patients' tumour is important to realize personalized medicine. Here, we investigate to identify subsets that benefit from capecitabine plus RAD001 in advanced gastric cancer (GC) patients by comprehensive high-throughput genomic analysis (nCounter assay). Archival tumour tissue blocks, if possible, were collected at phase II trial of capecitabine plus RAD001 in 47 refractory GC patients (at clinicaltrials.gov NCT#01099527). A total of 42 formalin-fixed, paraffin-embedded (FFPE) tumour samples were available for nanostring based-multigene Assay. An nCounter assay of 519 kinase panels has been used. We performed correlation analyses between expression levels of kinase genes and response for capecitabine plus RAD001. Among 42 patients with An nCounter assay of 519 kinase panels, 4 patients achieved confirmed partial response and 15 patients revealed stable disease, resulting in an overall response rate (ORR) of 9.5%. No difference in ORR was observed in terms of gender, performance status, primary tumour site, gastric resection, histologic subtype, Lauren classification, No. of metastatic site and No. of chemotherapy. In subgroups with response for capecitabine plus RAD001, there is significant overexpression of 6 genes among 519 kinase gene such as EPHA2 (P = 0.0025), PIM1 (P = 0.0031), KSR1 (P = 0.0033), and EIF2AK4 (P = 0.0046) that are related to the activation of mTOR signalling. This study is first report that investigated to identify biomarkers predictive of the response for RAD001 containing treatment in refractory GC patients, by comprehensive high-throughput genomic analysis (nCounter assay). PMID- 27994653 TI - Association of common variants in MTAP with susceptibility and overall survival of osteosarcoma: a two-stage population-based study in Han Chinese. AB - Osteosarcoma (OS) is a common malignant tumor, which exists widely in the bone of children and adolescents, and genetic factors may influence its susceptibility. Recently, the gene MTAP has been reported to be associated with OS in a Caucasian population. To investigate the association of common variants in MTAP with OS risk in Han Chinese individuals, we designed a two-stage case-control study with 392 OS patients and 1,578 unrelated healthy controls of Han Chinese individuals. A total of 17 tagging single nucleotide polymorphisms (SNPs) were firstly genotyped in the discovery stage, and single-SNP association and haplotypic association analyses have been performed. The SNP rs7023329 was found to be strongly associated with the OS risk (adjusted P = 0.002908), and the results of odds ratios (ORs) and 95% confidence intervals (CI) revealed increased risks from A allele of the SNP on OS (OR=1.33, 95% CI=1.13-1.62). The results were confirmed with a similar pattern in the validation stage (adjusted P = 0.006737, OR=1.49, 95% CI=1.11-2.00). Moreover, haplotypic analyses indicated that one haplotype block containing rs7023329 was significantly associated with OS risk in both stages (both global P<0.0001). The statistically significant association between the rs7023329 genotype and poor survival in OS patients was also observed. To sum up, our results prove that MTAP plays an important role in the etiology of OS, suggesting this gene as a potential genetic modifier for OS development. PMID- 27994654 TI - Downregulation of RNF128 Predicts Progression and Poor Prognosis in Patients with Urothelial Carcinoma of the Upper Tract and Urinary Bladder. AB - Background: The TP53 tumor suppressor gene plays a crucial role in the carcinogenesis of many malignancies, including urothelial carcinoma (UC). Overexpression of p53 is associated with poor prognosis in UC. Recently, RING finger protein 128 (RNF128) was shown to be involved in p53-induced apoptosis, forming a negative feedback loop. However, the significance of RNF128 in patients with UC remains unknown. In this study, our aim was to evaluate the expression of RNF128 in UC and to assess its predictive and prognostic value in a well established cohort. Methods: Through data mining from a published transcriptome (GSE31684), RNF128 was identified as the most differentially expressed gene in UC among those associated with negative regulation of the cytokine biosynthetic process (GO:0042036). Its immunoexpression was further evaluated using the H scores of 340 patients with upper urinary tract UC (UTUC) and 295 with urinary bladder UC (UBUC). The scores were correlated with clinicopathological features, disease-specific survival (DSS) and metastasis-free survival (MeFS). We also used Western blot analysis to evaluate RNF128 protein expression in human urothelial cell (HUC) lines. Results: Downregulation of RNF128 expression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), nodal metastasis (UTUC, p<0.001; UBUC, p=0.001), vascular invasion (UTUC, p<0.001; UBUC, p=0.008) and high mitotic rate (UTUC, p=0.003; UBUC, p=0.023). Low expression of RNF128 was an adverse prognosticator for DSS (UTUC, p<0.0001; UBUC, p<0.0001) and MeFS (UTUC, p<0.0001; UBUC, p=0.0002). Moreover, low expression was predictive of poor DSS (UTUC, p=0.006; UBUC, p=0.003) and MeFS (UTUC, p=0.009; UBUC, p=0.036) in multivariate comparisons. Western blot analysis showed that the RNF128 protein was downregulated in invasive urothelial cancer cell lines. Conclusion: Our findings showed that downregulation of RNF128 was correlated with cancer invasiveness and metastasis as well as reduced survival in patients with UTUC and UBUC, identifying RNF128 as a prognostic factor in UC. PMID- 27994655 TI - Alteration status and prognostic value of MET in head and neck squamous cell carcinoma. AB - The MET pathway plays a key role in various cancers, and its inhibition represents a potential treatment target. However, appropriate biomarkers are needed to facilitate the selection of patients who would benefit from MET inhibiting therapy. We herein conducted a robust confirmatory evaluation of the MET copy number alteration status and prognostic significance of c-Met expression in a large series of patients (n = 396) who underwent standard surgical resection and adjuvant chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC). Surgically resected HNSCC samples were subjected to immunohistochemical and H score analysis of c-Met expression and silver in situ hybridization analysis of MET amplification and copy number gains. c-Met expression varied, with mean and median H-scores (scale: 0-300 scale) of 61.2 and 60.0, respectively. The lowest and highest expression levels were observed in SCC of the larynx and oral cavity, respectively. MET copy number gains were observed in 16.9% of cases (67/339) and were associated with c-Met protein expression. High c-Met expression, determined according to MET gain status, was associated with an inferior overall survival rate, especially among completely resected cases. In conclusion, our robust analysis revealed that c-Met expression in HNSCCs varied according to anatomical site, correlated with MET copy number gains, and was associated with poor prognosis. This c-Met expression analysis method, which is based on the MET gain status, appears to appropriately predict high-risk HNSCC patients in the context of anti-MET therapeutic decisions. PMID- 27994656 TI - Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population. AB - Introduction: The incidence of echinoderm microtubule-associated protein-like4 anaplastic lymphoma kinase (EML4-ALK) mutation among surgically treated patients with adenocarcinoma of the lung of the Eastern European ethnicity is underreported. The aim of this trial was the determination of EML4-ALK mutation frequency in investigated population, and the evaluation of correlations between lung adenocarcinoma subtype and clinical characteristics with mutation status. Patients and methods: This was a prospective trial which included 195 patients with adenocarcinoma of the lung who underwent surgical treatment. ALK mutation screening was performed by immunohistochemistry (IHC). IHC scores of 2+ and 3+ were regarded as positive. Confirmatory FISH was performed in all IHC positive and in 2:1 ratio in negative patients. Results: Overall ALK mutation rate established by IHC was 6.2%, while FISH confirmed rate of 5.1%. The FISH confirmed ALK positivity in 7.6% Hungarians, 5.5% Serbians, and 6.6% Slovakians. Acinar subtype of adenocarcinoma of the lung was significantly (p=0.02) related to EML4-ALK positive mutation status. Most of the patients were males (56.9%), smokers (50.8%), or former smokers (28.7%) with acinar (55.4%) or solid (35.9%) adenocarcinoma of the lung. Sensitivity and specificity of IHC were 100% and 98.9% respectively. Conclusions: ALK mutation rate in surgically treated patients with adenocarcinoma of the lung was found to be 6.2% by IHC and 5.1% by FISH. Acinar subtype of the adenocarcinoma of the lung was significantly related to ALK positive mutation. PMID- 27994658 TI - High Expression of 17beta-hydroxysteroid Dehydrogenase Type 2 is Associated with a Better Prognosis in Urothelial Carcinoma of the Urinary Tract. AB - Object: To identify associations between 17beta-hydroxysteroid dehydrogenase type 2 (HSD17B2) expression and clinicopathological variables and prognoses in patients with urothelial carcinoma of the urinary tract. Materials and Methods: We analyzed one public transcriptome dataset (GSE31684) from the Gene Expression Omnibus. HSD17B2 showed the highest log2-transformed fold-change in expression, and it was therefore further analyzed. We enrolled 340 upper urinary tract and 295 urinary bladder tissue samples that were obtained from patients with urothelial carcinoma between 1996 and 2004 to evaluate the expression of HSD17B2 using immunohistochemistry. The endpoints were disease-specific survival and metastasis-free survival. Univariate and multivariate analyses were performed to assess the relationships between HSD17B2, survival and clinicopathological parameters. Results: High expression of HSD17B2 was significantly associated with better clinicopathological parameters, including the following parameters in urothelial carcinoma of upper urinary tracts: Ta (non-invasive papillary carcinoma) and T1 (invaded subepithelial connective tissue) disease, without nodal metastasis, without vascular invasion, without perineal invasion and with a low histological grade, and the following parameters specifically in urothelial carcinoma of the urinary bladder: Ta (noninvasive papillary carcinoma) and T1 (invaded into the lamina propria but not into the muscularis propria) disease, without nodal metastasis (all P<0.05). Additionally, HSD17B2 high expression predicted a better prognosis, including improved disease-specific survival and metastasis-free survival in urothelial carcinomas of the urinary tract system. Conclusions: High expression of HSD17B2 is associated with a better prognosis and is therefore a prognostic biomarker that can be used to predict favorable survival in patients with urothelial carcinoma of the urinary tract system. PMID- 27994657 TI - Multidimensional Roles of Collagen Triple Helix Repeat Containing 1 (CTHRC1) in Malignant Cancers. AB - Tumor is one of the principal diseases that seriously threaten human health. Insight into sensitive cancer markers may open a new avenue for the early diagnosis and treatment of this disease. CTHRC1 has been identified as a cancer related gene. It is a secretory glycoprotein that possesses multidimensional roles associated with wound repair, bone remodeling, hepatocytes fibrosis, adipose tissue formation, and so on. Our previous studies and numerous reports from other researchers have revealed that the ascended expression of CTHRC1 tends to go hand in hand with tumorigenesis, proliferation, invasion and metastasis in various human malignancies through a series of molecular mechanisms and signaling pathways. However, the detailed pathogenic mechanisms of CTHRC1 overexpression in human malignant cancers are not yet clear. Here, we shall focus our description on the functions, expression profile in several representative malignant tumors and a number of molecular mechanisms and signaling pathways involved with CTHRC1. This introductory discussion of CTHRC1 will serve as a reference for further research in understanding this intriguing cancer-related protein. PMID- 27994659 TI - Interferon-Tau has Antiproliferative effects, Represses the Expression of E6 and E7 Oncogenes, Induces Apoptosis in Cell Lines Transformed with HPV16 and Inhibits Tumor Growth In Vivo. AB - Interferon tau (IFN-tau) is a promising alternative antiviral and immunotherapeutic agent in a wide variety of diseases including infectious, neurodegenerative, autoimmune and cancer due to its low toxicity in comparison with other type I interferon's. The objective of our study was established the effect of the bovine IFN-tau on human (SiHa) and murine (BMK-16/myc) cells transformed with HPV 16 and evaluates the antitumor effect in a murine tumor model HPV 16 positive. We determine that bovine IFN-tau has antiproliferative effects, pro-apoptotic activity and induces repression of viral E6 and E7 oncogenes (time- and dose-dependent) on human and murine cells transformed with HPV 16 similar to the effects of IFN-beta. However, IFN-tau induces greater antiproliferative effect, apoptosis and repression of both oncogenes in BMK 16/myc cells compared to SiHa cells. The differences were explained by the presence and abundance of the type I interferon receptor (IFNAR) in each cell line. On the other hand, we treated groups of tumor-bearing mice (HPV16 positive) with IFN-tau and showed the inhibition tumor growth effect in vivo. Our finding indicates that bovine IFN-tau may be a good candidate for immunotherapy against cervical cancer. PMID- 27994660 TI - Incidence and Impact of Lymph Node Metastases in Advanced Ovarian Cancer: Implications for Surgical Treatment. AB - Background: This study aimed to clarify the impact of node involvement (affected to resected nodes) in optimally cytoreduced (residual tumour <=1cm) stage IIIC/IV ovarian cancer. Methods: 108 consecutive patients with primary stage IIIC/IV ovarian cancer underwent stage-related surgery and got adjuvant platinum-based chemotherapy. Median follow-up: 53.5 months. All patients got systematic para aortic and pelvic lymphadenectomy. Clinical parameters were retrospectively evaluated. Patients were stratified into 3 groups to evaluate node affection: 1) no (0%), 2) minor (>0%, <=50%) >0 and 3) major (>50% of affected nodes). Kaplan Meier survival curve was used to evaluate the prognostic value. Results: On average, 21.3 pelvic and para-aortic nodes were removed per patient (range 1-60 nodes). Minor nodal involvement (node ratio >0-<=0.5: (59%) was most often detected. Increasing node ratio leads to significant decreased overall survival (p<0.001). Significant best overall survival was associated with minor node involvement (node ratio >0 to <=0.5). Complete cytoreduction correlated with node affection shows significant best prognostic impact in minor node affection compared to incomplete resection (R>0-<=1cm) independent to nodal status (OS p<0.001). Conclusion: Radical surgery is the main factor of improved overall and tumor free survival. Paraaortal and iliacal lymphadenectomy seems to play an important role for prognostic and therapeutic reasons: Prognostic in accurate staging and therapeutic in case of achieved optimal cytoreduction including lymph nodes with histology proven minor node involvement. PMID- 27994662 TI - TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment. AB - The deregulation of gene expression is a characteristic of cancer cells, and malignant cells require very high levels of transcription to maintain their cancerous phenotype and survive. Therefore, components of the basal transcription machinery may be considered as targets to preferentially kill cancerous cells. TFIIH is a multisubunit basal transcription factor that also functions in nucleotide excision repair. The recent discoveries of some small molecules that interfere with TFIIH and that preferentially kill cancer cells have increased researchers' interest to elucidate the complex mechanisms by which TFIIH operates. In this review, we summarize the knowledge generated during the 25 years of TFIIH research, highlighting the recent advances in TFIIH structural and mechanistic analyses that suggest the potential of TFIIH as a target for cancer treatment. PMID- 27994661 TI - The Effects of Anti-inflammatory Drug Treatment in Gastric Cancer Prevention: an Update of a Meta-analysis. AB - Gastric cancer has high incidence and fatality rates, making chemoprevention agents necessary. There is an ongoing debate about aspirin/nonsteroidal anti inflammatory drugs (NSAIDs) use can significant reduce the risk of GC. We conducted a meta-analysis of existing studies evaluating the association of anti inflammatory drug and GC. We performed a systematic literature search of PubMed, Web of Science, Embase, OVID, Cochrane Library and Clincialtrials.gov up to August 31, 2015. Either a fixed-effects or a random-effects model using was based on the result of homogeneity analysis. Subgroup, sensitivity, meta-regression, and publication bias analyses were evaluated. Forty-seven studies were finally included in this meta-analysis. The overall GC risk reduction benefit associated with anti-inflammatory drug use represented an RR of 0.78 (95% CI 0.71 to 0.85) and an adjusted RR of 0.74 (95% CI 0.71 to 0.77). Besides, the prevention benefit of aspirin/NSAIDs ingestion appeared to be confined to those patients with regiment of short or middle-term (<=5 years), high-frequency (>30 times per month) and low dose (<200 mg per day). Further, our data also suggest that COX-2 inhibitors use is a more effective approach in GC prevention (RR, 0.45; 95% CI, 0.29-0.70). In this meta-analysis, our finding support short or middle-term (<=5 years), high-frequency (>30 times per month) and low dose (<200 mg per day) aspirin/NSAIDs intake is a well method for GC prevention and also confirm the inverse association between aspirin/NSAIDs use and GC risk. Additionally, selective COX-2 inhibitors use probably a more effective approach to reduce GC risk. PMID- 27994663 TI - New panel of microsatellite alterations detectable in the EBC for lung cancer prognosis. AB - Our research group demonstrated, in a precedent study, the prognostic power of the 3p microsatellites alterations (MAs) detectable in exhaled breath condensate (EBC) in NSCLC patients. The analysis of genetic markers in the EBC might have precious clinical and economic consequences when inserted in diagnostic and follow up programs for lung cancer. The aim of this study was to evaluate the prognostic value of a new panel of MAs in the EBC of patients with NSCLC. We enrolled 45 NSCLC patients during a period of 36 months and the follow-up period was 156 weeks. We analyzed MAs for eight markers in EBC samples: D3S2338, D3S1266, D3S1300, D3S1304, D3S1289, D5S2094, D3S1313, and AFMa305ye1. Our study showed that the presence of more than 2 simultaneous MAs reduces outcome in NSCLC patients. The new panel of eight microsatellites markers proposed in EBC samples could have a potential clinical role in assessing survival in lung cancer patients. PMID- 27994664 TI - Nucleophosmin Mutations Induce Chemosensitivity in THP-1 Leukemia Cells by Suppressing NF-kappaB Activity and Regulating Bax/Bcl-2 Expression. AB - Nucleophosmin (NPM1) - a gene that encodes for a nuclear protein with multiple functions. Mutations in NPM1 are seen in approximately one-third of acute myeloid leukemia (AML) and are generally associated with good response to induction chemotherapy. However, the mechanisms underlying this chemosensitivity are still unknown. Recent studies have established that nuclear factor-kappaB (NF-kappaB) activation is a key response of leukemia cell to chemotherapy. In this study, we transfected human monocytic leukemia THP-1 cells with the vector expressing NPM1 mutation variant (NPM1mA), and confirmed overexpression of NPM1mA at mRNA and protein levels by reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. The effects of NPM1 mutations on chemotherapeutical agents induced apoptosis, NF-kappaB activity and gene expression were examined using flow cytometry, luciferase reporter assays, quantitative real time PCR (qRT-PCR) and Western blot. We found that overexpression of NPM1mA in THP-1 cells sensitized these cells to apoptosis induced by chemotherapeutical agents such as daunorubicin (DNR) and cytarabine (Ara-C). Moreover, we demonstrated that expression of NPM1 mA reduced the NF-kappaB transcription activity of THP-1 cells upon drug treatment. In addition, restoration of NF-kappaB activity via TNF-alpha stimulation could attenuate the effect of NPM1mA overexpression on DNR-and Ara-C induced apoptosis. Interestingly, expression of NPM1mA could upregulate Bax and downregulate Bcl-2 at mRNA and protein levels in THP-1 cells when treated with DNR or Ara-C. We also demonstrated that restoration of NF-kappaB activity via TNF alpha pre-treatment reversed the effect of NPM1mA on the Bax/Bcl-2 expression. Furthermore, evaluation of gene expression data from The Cancer Genome Atlas (TCGA) dataset revealed that NPM1-mutated patients showed a higher expression of Bax and a lower expression of Bcl-2. These results suggest that the NPM1 gene mutations could confer increased sensitivity to chemotherapeutic agents, at least in part, by suppressing NF-kappaB activity and regulating Bax/Bcl-2 expression. PMID- 27994665 TI - Aberrant methylation of CDH13 can be a diagnostic biomarker for lung adenocarcinoma. AB - Background: Aberrant methylation of CpG islands in tumor cells in promoter regions is a critical event in non-small cell lung carcinoma (NSCLC) tumorigenesis and can be a potential diagnostic biomarker for NSCLC patients. The present study systemically and quantitatively reviewed the diagnostic ability of CDH13 methylation in NSCLC as well as in its subsets. Eligible studies were identified through searching PubMed, Web of Science, Cochrane Library and Embase. The pooled odds of CDH13 promoter methylation in lung cancer tissues versus normal controls were calculated by meta-analysis method. Simultaneously, four independent DNA methylation datasets of NSCLC from TCGA and GEO database were downloaded and analyzed to validate the results from meta-analysis. Results: Thirteen studies, including 1850 samples were included in this meta-analysis. The pooled odds ratio of CDH13 promoter methylation in cancer tissues was 7.41 (95% CI: 5.34 to 10.29, P < 0.00001) compared with that in controls under fixed-effect model. In validation stage, 126 paired samples from TCGA were analyzed and 5 out of the 6 CpG sites in the CpG island of CDH13 were significantly hypermethylated in lung adenocarcinoma tissues but none of the 6 CpG sites was hypermethylated in squamous cell carcinoma tissues. Concordantly, the results from other three datasets, which were subsequently obtained from GEO database consisting of 568 tumors and 256 normal tissues, also consisted with those from TCGA dataset. Conclusion: The pooled data showed that the methylation status of the CDH13 promoter is strongly associated with lung adenocarcinoma. The CDH13 methylation status could be a promising diagnostic biomarker for diagnosis of lung adenocarcinoma. PMID- 27994666 TI - A Retrospective Review of Chemotherapy for Patients with Small Bowel Adenocarcinoma in British Columbia. AB - Background: Small bowel adenocarcinoma (SBA) is associated with a poor prognosis. It is an uncommon malignancy and therefore difficult to study. Randomized phase III trials are not available to guide best approaches. The Provincial Cancer Registry of the British Columbia Cancer Agency contains long-term data on patients with SBA. The authors analyzed characteristics and treatment outcomes for SBA patients diagnosed between 1990 and 2008. Material and methods: Charts of 150 patients with a histological diagnosis of SBA were retrospectively analyzed. Epidemiological and treatment data were collected. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Baseline characteristics, such as median age at diagnosis (64.5 years), tumor stage (I-II 33%, III-IV 58%, unknown 9%), and location (duodenum 48%, jejunum 31%, ileum 21%) were consistent with published data. 55% of patients had a positive family history of cancer. DFS and OS of 29 patients treated with adjuvant chemotherapy were not significantly different to that of 47 patients without (p = 1 and p = 0.211, respectively). In the palliative setting patients treated with polychemotherapy (21 patients) had statistically better OS than patients treated with monochemotherapy (12 patients) (p = 0.0228). Conclusions: Our study suggests a survival benefit for advanced-stage SBA patients treated with poly- versus monochemotherapy. This, however, was a retrospective analysis with several potential confounders. Nevertheless, our study adds to the evidence suggesting that chemotherapy may be beneficial for patients with SBA, at least in the palliative setting. PMID- 27994668 TI - The learning curves of robotic and three-dimensional laparoscopic surgery in cervical cancer. AB - BACKGROUND: The 3D laparoscopy systems and robotic systems have been introduced into clinical practice for a few years. But the comparison of robotic and 3D laparoscopic gynecologic surgery is still needed. OBJECTIVE: To retrospectively compare the learning curves of robotic and 3D laparoscopic hysterectomy and pelvic lymphadenectomy in cervical cancer. STUDY DESIGN: The operational duration, blood loss, peritoneal drainage of first 24 hours after operation, total hospitalization days, hospitalization days after operation, lymph nodes collected, learning curves and cost of robotic and 3D laparoscopic hysterectomy and pelvic lymphadenectomy in cervical cancer performed by one experienced surgeon were studied. RESULTS: There was one surgeon who performed 37 cases of robotic and 24 cases of 3D laparoscopic hysterectomy and pelvic lymphadenectomy, and the turning point of learning curves was case 13th and case 10th. The differences of duration of operation, blood loss, peritoneal drainage of first 24 hours after operation, total hospitalization days, hospitalization days after operation, lymph nodes collected and perioperative complications were not statistically significant. But the cost of each robotic operation was higher than 3D operation. CONCLUSIONS: The turning point of the learning curve of 3D laparoscopic hysterectomy and pelvic lymphadenectomy is earlier than that of robotic sugery in patients with cervical cancer, and there is no obvious benefit from robotic surgery than 3D surgery in the terms of short-term medical index and hospitalization cost. PMID- 27994667 TI - Advances and Challenges on Cancer Cells Reprogramming Using Induced Pluripotent Stem Cells Technologies. AB - Cancer cells transformation into a normal state or into a cancer cell population which is less tumorigenic than the initial one is a challenge that has been discussed during last decades and it is still far to be solved. Due to the highly heterogeneous nature of cancer cells, such transformation involves many genetic and epigenetic factors which are specific for each type of tumor. Different methods of cancer cells reprogramming have been established and can represent a possibility to obtain less tumorigenic or even normal cells. These methods are quite complex, thus a simple and efficient method of reprogramming is still required. As soon as induced pluripotent stem cells (iPSC) technology, which allowed to reprogram terminally differentiated cells into embryonic stem cells (ESC)-like, was developed, the method strongly attracted the attention of researches, opening new perspectives for stem cell (SC) personalized therapies and offering a powerful in vitro model for drug screening. This technology is also used to reprogram cancer cells, thus providing a modern platform to study cancer-related genes and the interaction between these genes and the cell environment before and after reprogramming, in order to elucidate the mechanisms of cancer initiation and progression. The present review summarizes recent advances on cancer cells reprogramming using iPSC technology and shows the progress achieved in such field. PMID- 27994669 TI - Pre-treatment serum alkaline phosphatase and lactate dehydrogenase as prognostic factors in triple negative breast cancer. AB - Background: Serum parameters as prognostic parameters are studied widely. We aim to examine the prognostic significance of the serum alkaline phosphatase (ALP) level and lactate dehydrogenase (LDH) level in triple negative breast cancer (TNBC). Methods: Total of 253 TNBC patients from Sun Yat-sen University Cancer Center who underwent treatment between January 2004 and December 2009 was conducted in this retrospective study. Before treatment serum ALP and LDH levels were routinely measured. We use the receiver operating characteristic (ROC) curve analysis to estimate the cutoff value of serum ALP and LDH levels. The Kaplan Meier method and multivariable Cox regression analysis were used for Disease free survival (DFS) and overall survival (OS) assessed. Results: The ROC curves determined that the optimum cutoff point for ALP and LDH were 66.5u/L and 160.5u/L, respectively. The elevated ALP and LDH were both significantly associated with decreased DFS and OS (both P < 0.001). In addition, the entire cohort was stratified into three subgroups basis of ALP levels and LDH levels. TNBC Patients who with ALP >66.5 u/L and LDH >160.5u/L had the worst DFS and OS (both P < 0.001). In TNBC patients, univariate and multivariate Cox regression analyses conformed ALP and LDH were independent unfavorable prognostic factors for DFS and OS. Conclusions: The serum levels of ALP and LDH before treatment are independent prognostic parameters and may serve as complement to help predict survival in TNBC. PMID- 27994670 TI - Rab14 Suppression Mediated by MiR-320a Inhibits Cell Proliferation, Migration and Invasion in Breast Cancer. AB - We found that microRNA-320a (miR-320a) was an attractive prognostic biomarker in breast cancer (BC) previously, whereas its regulatory mechanism in BC was not well understood. Our aim was to identify miR-320a target gene, examine the clinical relationship between miR-320a and its target, and further explore the functions of its target in BC. In this study, miR-320a downstream target gene was determined in HEK-293T cells by dual luciferase reporter assay. Then western blotting and immunohistochemistry were used to assess miR-320a target gene expression in fresh frozen (n=19, breast cancer and matched non-malignant adjacent tissue samples) and formalin-fixed paraffin-embedded (FFPE) (n=130, invasive BC tissues, the same panel detected for miR-320a expression previously) breast tissues, respectively. The results suggested that miR-320a could significantly suppressed Rab14 3'-untranslated region luciferase-reporter activity, and thus Rab14 was first identified as miR-320a target in BC. In 19 matched breast tissues, 12 (63%) breast cancer tissues showed high expression of Rab14 compared with the corresponding normal tissues. Rab14 immunoreactivity was mainly detected in the cytoplasm, 77/130 (59.2%) showed high expression. Furthermore, Rab14 expression was found to be inversely correlated with miR-320a expression in fresh-frozen breast tissues as well as in FFPE invasive breast cancer samples. In addition, Rab14 expression levels were positively related to tumor size (P = 0.034), lymph node metastasis (P < 0.001), distant metastasis (P = 0.001), histological grade (P = 0.035) and clinical tumor lymph-node metastasis stage (P = 0.001). Patients with higher Rab14 expression showed shorter overall survival time. Moreover, silencing of Rab14 could suppress proliferation, migration and invasion in breast cancer cell lines. Collectively, our results indicate that miR-320a could target Rab14 and that they could interact biologically in BC. PMID- 27994671 TI - Reduction of CA125 Levels During Neoadjuvant Chemotherapy Can Predict Cytoreduction to No Visible Residual Disease in Patients with Advanced Epithelial Ovarian Cancer, Primary Carcinoma of Fallopian tube and Peritoneal Carcinoma. AB - Background and aims. To determine whether reduction of CA125 levels is a predictive factor for cytoreduction to no visible residual disease (NVRD) and chemotherapeutic sensitivity in advanced epithelial ovarian carcinoma (EOC), primary carcinoma of fallopian tube and peritoneal carcinoma patients who received neoadjuvant chemotherapy followed by interval debulking surgery (NAC IDS). Methods. This was a single-team-based study of advanced EOC, primary carcinoma of fallopian tube and peritoneal carcinoma patients diagnosed between 1996 and 2015 at Peking Union Medical College Hospital. Patients were treated with NAC-IDS by one gynecologic oncologist. Demographic data, CA125 levels, radiographic data, and chemotherapy and surgical-pathologic information were obtained. Univariate and multivariate analyses were performed to evaluate variables associated with optimal cytoreduction to NVRD and chemotherapy sensitivity. Results. One hundred and eighteen patients met the study inclusion criteria. Thirty-seven (31.4%) patients underwent resection to NVRD. The median serum CA125 level at presentation and before IDS was 1814.5 U/ml and 205.9 U/ml, respectively. In the univariate analysis, histology, a preoperative CA125 of <=200 U/ml and a >80% reduction of CA125 between presentation and IDS were significantly associated with the likelihood of NVRD (P=0.014, 0.000, 0.000, respectively). Multivariate analysis revealed that, of the various CA125 parameters tested, preoperative CA125 <=200 U/ml was the only independent predictor of NVRD (odds ratio 3.667, 95% confidence interval 1.337-10.057; P=0.012). Preoperative CA125 <=200 U/ml was also significantly associated with chemotherapy-sensitive disease in the univariate analysis (P=0.037). Conclusions. EOC patients who received NAC-IDS and had a preoperative CA125 level of <=200 U/ml were highly likely to be cytoreduced to NVRD and to exhibit chemotherapeutic sensitivity. PMID- 27994672 TI - An In Vitro Inverted Vertical Invasion Assay to Avoid Manipulation of Rare or Sensitive Cell Types. AB - The ability to quantify cell migration and invasion is critical in the study of cancer metastasis. Current invasion assays, such as the Boyden Chamber, present difficulties in the measurement of the invasion of cells that are few in number and are intrinsically tied to the cell microenvironment. There exists a need for a three-dimensional invasion assay that is easily reproduced, accessible for most laboratories, and requires no displacement of cells from their original microenvironment. Here we present a simple design for an inverted vertical invasion assay able to assess the invasion capabilities of cells in a three dimensional, extracellular matrix-based environment without displacement from the original culture location. We used the assay to determine the migratory capacity of hybrids between mesenchymal/multipotent stem/stroma cells (MSCs) and breast cancer cells MCF7. These hybrids are formed reliably but rarely (1 in 1,000 cells) and for this reason require an invasion assay that does not involve extensive cell manipulation. Using this assay, we found that MSCs, breast cancer cells, and corresponding fusion products are able to migrate and invade through the extracellular matrix and that hybrids invade in a manner more similar to stromal cells than cancer cells. Thus, this assay can aid the study of the invasive capacity of both cancerous cells and associated fusion hybrids and could augment testing of therapeutic strategies to inhibit metastatic spread. PMID- 27994673 TI - Antimicrobial peptide LL-37 participates in the transcriptional regulation of melanoma cells. AB - Antimicrobial peptides are an ancient family of molecules that emerged millions of years ago and have been strongly conserved during the evolutionary process of living organisms. Recently, our group described that the human antimicrobial peptide LL-37 migrates to the nucleus, raising the possibility that LL-37 could directly modulate transcription under certain conditions. Here, we showed evidence that LL-37 binds to gene promoter regions, and LL-37 gene silencing changed the transcriptional program of melanoma A375 cells genes associated with histone, metabolism, cellular stress, ubiquitination and mitochondria. PMID- 27994675 TI - C-Reactive Protein/Albumin Ratio (CAR) as a Prognostic Factor in Patients with Non-Metastatic Nasopharyngeal Carcinoma. AB - Background: The C-reactive protein/albumin (CRP/ALB) ratio has recently been associated with clinical outcomes in patients suffering various types of cancer. In this retrospective study, we investigated the prognostic value of the pre treatment CRP/ALB ratio (CAR) in non-metastatic nasopharyngeal carcinoma (NPC) patients. Methods: The cohort included 2685 patients with non-metastatic NPC. Univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of CAR with overall survival (OS), distant metastasis free survival (DMFS), disease-free survival (DFS), and locoregional recurrence free survival (LRRFS) in patients with NPC. Kaplan-Meier survival analyses was used to compare groups classified by CAR. Results: Patients were categorised by the CAR using a cut-off value of 0.064. Multivariate Cox proportional hazard analysis verified that high CAR level was a significant predictor for inferior OS (P = 0.003), DMFS (P = 0.035), and LRRFS (P = 0.024), but not for DFS (P = 0.093). CAR was also an independent prognostic factor for OS when stratified by Epstein-Barr virus DNA level ( >= 2560 or < 2560 copies ml-1). Conclusions: High CAR provides prognostication regarding OS, DMFS, DFS, and LRRFS in patients with NPC. CAR is a valuable coadjutant for Epstein-Barr virus DNA levels for identifying survival differences. PMID- 27994677 TI - Positive Prehabilitative Effect of Intense Treadmill Exercise for Ameliorating Cancer Cachexia Symptoms in a Mouse Model. AB - Due to the importance of exercise in prehabilitation, we conducted this study to understand the effects of different exercise intensities on cancer-related cachexia. Forty adult male CDF1 mice were randomly divided into a non-cancer control group (N=10, NC), cancer control group (N=10, CC), cancer with moderate exercise group (N=10, ME, 70% maxHR), and cancer with intense exercise group (N=10, SE, 90% maxHR) for obtaining data such as tissue weight and body weight changes, quality of life (QoL) indicators, and levels of cytokines and a muscle homeostasis regulatory protein. We verified that mouse colonic carcinoma cancer cells metastasized based on our observation that the weight of CC group lungs was almost 87% greater than NC group lungs. Survival rates of SE, NC, ME, and CC groups were 100%, 100%, 80%, and 50%, respectively (p<0.01). Other results such as tissue and body weight changes, QoL indicators, and protein analyses also supported our hypothesis that the SE group had improved survival compared to CC and ME groups (p<0.05 and p<0.01, respectively). Our results suggest that exercise, especially intense exercise, improves QoL and survival rate and prevents muscle atrophy. These data suggest that exercise is an optimal prehabilitation choice to alleviate the negative impacts of cancer cachexia. PMID- 27994676 TI - Pre-clinical evaluation of a novel class of anti-cancer agents, the Pyrrolo-1, 5 benzoxazepines. AB - Microtubules are currently ranked one of the most validated targets for chemotherapy; with clinical use of microtubule targeting agents (MTAs) extending beyond half a century. Recent research has focused on the development of novel MTAs to combat drug resistance and drug associated toxicities. Of particular interest are compounds structurally different to those currently used within the clinic. The pyrrolo-1, 5-benzoxazepines (PBOXs) are a structurally distinct novel group of anti-cancer agents, some of which target tubulin. Herein, we review the chemistry, mechanism of action, preclinical development of the PBOXs and comparisons with clinically relevant chemotherapeutics. The PBOXs induce a range of cellular responses including; cell cycle arrest, apoptosis, autophagy, anti vascular and anti-angiogenic effects. The apoptotic potential of the PBOXs extends across a wide spectrum of cancer-derived cell lines, by targeting tubulin and multiple molecular pathways frequently deregulated in human cancers. Extensive experimental data suggest that combining the PBOXs with established chemotherapeutics or radiation is therapeutically advantageous. Pre-clinical highlights of the PBOXs include; cancer specificity and improved therapeutic efficacy as compared to some current first line therapeutics. PMID- 27994674 TI - Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation. AB - Adipose tissue in addition to its ability to keep lipids is now recognized as a real organ with both metabolic and endocrine functions. Recent studies demonstrated that in obese animals is established a status of adipocyte hypoxia and in this hypoxic state interaction between adipocytes and stromal vascular cells contribute to tumor development and progression. In several tumors such as breast, colon, liver and prostate, obesity represents a poor predictor of clinical outcomes. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors and a consequent alteration of key signaling mediators which may be an active local player in establishing the peritumoral environment promoting tumor growth and progression. Therefore, adipose tissue hypoxia might contribute to cancer risk in the obese population. To date the precise mechanisms behind this obesity-cancer link is not yet fully understood. In the light of information provided in this review that aims to identify the key mechanisms underlying the link between obesity and cancer we support that inflammatory state specific of obesity may be important in obesity-cancer link. PMID- 27994678 TI - The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer. AB - Breast Cancer Associated gene 2 (BCA2) is an E3 ubiquitin ligase that is over expressed in >50% of primary breast cancers, and has been shown to increase in vitro cell proliferation and invasion. The protein has been linked to alterations in EGFR degradation; however there is some dispute as to its role and influence on the biology of this receptor. Our work aimed to ascertain the role of BCA2 in EGFR endocytosis and down-regulation and to examine its links with breast cancer outcome. Data generated with the online expression analysis tool KM-Plotter showed that high BCA2 levels are associated with poor prognosis in ovarian, gastric and breast cancer, particularly HER2 over-expressing breast cancers. Experimentally, we demonstrate that over-expression of BCA2 induced a reduction in total EGFR levels. BCA2 over-expressing cells stimulated with EGF exhibited reduced lysosomal degradation of both this ligand and its receptor. Signalling downstream of EGFR in BCA2 over-expressing cells was characterized by a lower magnitude but increased duration. Our findings support a role for BCA2 in receptor endocytosis. Consistent with this we show that BCA2 over-expression reduces the level of vesicle-associated Rab7, a regulator of late endocytosis and documented interaction partner of BCA2. Levels of transferrin receptor and the uptake of transferrin were unaltered by over-expression of BCA2 indicating that trafficking changes may be limited to late endocytic sorting events. This report offers a thorough exploration of BCA2 biology and suggests a context-dependent role for the protein in the endocytic regulation of EGFR and as a prognostic biomarker in cancer. PMID- 27994679 TI - Brown Seaweed Fucoidan Inhibits Cancer Progression by Dual Regulation of mir 29c/ADAM12 and miR-17-5p/PTEN Axes in Human Breast Cancer Cells. AB - In this study, we observed that brown seaweed fucoidan inhibited human breast cancer progression by upregulating microRNA (miR)-29c and downregulating miR-17 5p, thereby suppressing their target genes, a disintegrin and metalloproteinase 12 (ADAM12) and phosphatase and tensin homolog (PTEN), respectively. Moreover, fucoidan reduced the luciferase activity of 3'-untranslated region reporter; treatment of cells with the miR-29c mimic or miR-17-5p inhibitor also produced similar results. These effects of fucoidan inhibited the epithelial-mesenchymal transition in breast cancer cells, as evidenced by an increase in E-cadherin and a drop in N-cadherin, and inhibited breast cancer cell survival, as evidenced by the activation of the phosphoinositide 3-kinase/Akt pathway. Taken together, these findings demonstrate that fucoidan inhibits breast cancer progression by regulating the miR-29c/ADAM12 and miR-17-5p/PTEN axes. Fucoidan is a potential chemopreventive/chemotherapeutic agent for breast cancer. PMID- 27994680 TI - Association between the KRAS Gene Polymorphisms and Papillary Thyroid Carcinoma in a Chinese Han Population. AB - Several studies have reported the association between MAPK signaling pathway gene polymorphisms and papillary thyroid carcinoma (PTC). KRAS gene, an oncogene from the mammalian RAS gene family plays an important role in the MAPK pathway. This study aimed to identify the potential association of KRAS gene polymorphisms with susceptibility to PTC in a Han Chinese population. A total of 861 patients with PTC, 562 disease controls with nodular goiter and 897 healthy controls were recruited. Four tagSNP polymorphisms (rs12427141, rs712, rs7315339 and rs7960917) of KRAS gene were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Statistical analyses and haplotype estimations were conducted using Haploview and Unphased softwares. Only significant differences were observed in genotypic frequencies of the rs7315339 polymorphism (chi2 =7.234, df=2, p=0.027) between PTC and disease controls. Statistically significant differences in both allelic and genotypic genotypes frequencies for rs712 (Genotype, chi2=8.258, p=0.016) and rs12427141 (Allele, chi2=3.992, p=0.046; Genotype, chi2=8.140, p=0.017) were observed between PTC patients and controls. Haplotype analyses revealed higher frequencies of GA and TA haplotypes (p=0.039 and p=0.003, respectively) from rs712- rs12427141 (two SNP) or TGA and TTG haplotype containing the alleles from rs7960917, rs712 and rs12427141, as well as the GAT haplotype containing the alleles from rs712, rs12427141 and rs7315339 in PTC patients than in healthy controls (p=0.042, p=0.037, p=0.027, respectively). Inversely, the haplotype TTA from rs7960917, rs712 and rs12427141 or the haplotype TAC from rs712, rs12427141 and rs7315339 was significantly less frequent in the PTC patients than in normal control (p=0.003, p=0.003, respectively). These findings suggest the role of these KRAS gene variants in susceptibility to PTC. Moreover, significant differences of the KRAS gene polymorphisms may occur between nodular goiter and PTC. PMID- 27994681 TI - Molecular Pain Imaging by Nuclear Medicine: Where Does It Stand and Where Is It Going? PMID- 27994682 TI - Stem Cell Monitoring with a Direct or Indirect Labeling Method. AB - The molecular imaging techniques allow monitoring of the transplanted cells in the same individuals over time, from early localization to the survival, migration, and differentiation. Generally, there are two methods of stem cell labeling: direct and indirect labeling methods. The direct labeling method introduces a labeling agent into the cell, which is stably incorporated or attached to the cells prior to transplantation. Direct labeling of cells with radionuclides is a simple method with relatively fewer adverse events related to genetic responses. However, it can only allow short-term distribution of transplanted cells because of the decreasing imaging signal with radiodecay, according to the physical half-lives, or the signal becomes more diffuse with cell division and dispersion. The indirect labeling method is based on the expression of a reporter gene transduced into the cell before transplantation, which is then visualized upon the injection of an appropriate probe or substrate. In this review, various imaging strategies to monitor the survival and behavior change of transplanted stem cells are covered. Taking these new approaches together, the direct and indirect labeling methods may provide new insights on the roles of in vivo stem cell monitoring, from bench to bedside. PMID- 27994683 TI - Recent Advances in the Development of PET/SPECT Probes for Atherosclerosis Imaging. AB - The rupture of vulnerable atherosclerotic plaques and subsequent thrombus formation are the major causes of myocardial and cerebral infarction. Accordingly, the detection of vulnerable plaques is important for risk stratification and to provide appropriate treatment. Inflammation imaging using 2 deoxy-2-[18F]fluoro-D-glucose (18F-FDG) has been most extensively studied for detecting vulnerable atherosclerotic plaques. It is of great importance to develop PET/SPECT probes capable of specifically visualizing the biological molecules involved in atherosclerotic plaque formation and/or progression. In this article, we review recent advances in the development of PET/SPECT probes for visualizing atherosclerotic plaques and their application to therapy monitoring, mainly focusing on experimental studies. PMID- 27994684 TI - Indeterminate Findings on Oncologic PET/CT: What Difference Does PET/MRI Make? AB - BACKGROUND: Positron emission tomography/computed tomography (PET/CT) with 2 deoxy-2-[18F]fluoro-D-glucose (FDG) has become the standard of care for the initial staging and subsequent treatment response assessment of many different malignancies. Despite this success, PET/CT is often supplemented by MRI to improve assessment of local tumor invasion and to facilitate detection of lesions in organs with high background FDG uptake. Consequently, PET/MRI has the potential to expand the clinical value of PET examinations by increasing reader certainty and reducing the need for subsequent imaging. This study evaluates the ability of FDG-PET/MRI to clarify findings initially deemed indeterminate on clinical FDG-PET/CT studies. METHODS: A total of 190 oncology patients underwent whole-body PET/CT, immediately followed by PET/MRI utilizing the same FDG administration. Each PET/CT was interpreted by our institution's nuclear medicine service as a standard-of-care clinical examination. Review of these PET/CT reports identified 31 patients (16 %) with indeterminate findings. Two readers evaluated all 31 PET/CT studies, followed by the corresponding PET/MRI studies. A consensus was reached for each case, and changes in interpretation directly resulting from PET/MRI review were recorded. Interpretations were then correlated with follow-up imaging, pathology results, and other diagnostic studies. RESULTS: In 18 of 31 cases with indeterminate findings on PET/CT, PET/MRI resulted in a more definitive interpretation by facilitating the differentiation of infection/inflammation from malignancy (15/18), the accurate localization of FDG avid lesions (2/18), and the characterization of incidental non-FDG-avid solid organ lesions (1/18). Explanations for improved reader certainty with PET/MRI included the superior soft tissue contrast of MRI and the ability to assess cellular density with diffusion-weighted imaging. The majority (12/18) of such cases had an appropriate standard of reference; in all 12 cases, the definitive PET/MRI interpretation proved correct. These 12 patients underwent six additional diagnostic studies to clarify the initial indeterminate PET/CT findings. In the remaining 13 of 31 cases with indeterminate findings on both PET/CT and PET/MRI, common reasons for uncertainty included the inability to distinguish reactive from malignant lymphadenopathy (4/13) and local recurrence from treatment effect (2/13). CONCLUSIONS: Indeterminate PET/CT findings can result in equivocal reads and additional diagnostic studies. PET/MRI may reduce the rate of indeterminate findings by facilitating better tumor staging, FDG activity localization, and lesion characterization. In our study, PET/MRI resulted in more definitive imaging interpretations with high accuracy. PET/MRI also showed potential in reducing the number of additional diagnostic studies prompted by PET/CT findings. Our results suggest that whole-body PET/MRI provides certain diagnostic advantages over PET/CT, promotes more definitive imaging interpretations, and may improve the overall clinical utility of PET. PMID- 27994685 TI - Intra-patient Variability of FDG Standardized Uptake Values in Mediastinal Blood Pool, Liver, and Myocardium during R-CHOP Chemotherapy in Patients with Diffuse Large B-cell Lymphoma. AB - PURPOSE: 18F-fluorodeoxyglucose (FDG) PET/CT is useful for staging and evaluating treatment response in patients with diffuse large B-cell lymphoma (DLBCL). A five point scale model using the mediastinal blood pool (MBP) and liver as references is a recommended method for interpreting treatment response. We evaluated the variability in standardized uptake values (SUVs) of the MBP, liver, and myocardium during chemotherapy in patients with DLBCL. METHODS: We analyzed 60 patients with DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) treatment and underwent baseline, interim, and final FDG PET/CT scans. The FDG uptakes of lymphoma lesions, MBP, liver, and myocardium were assessed, and changes in the MBP and liver SUV and possible associated factors were evaluated. RESULTS: The SUV of the liver did not change significantly during the chemotherapy. However, the SUVmean of MBP showed a significant change though the difference was small (p = 0.019). SUVmean of MBP and liver at baseline and interim scans was significantly lower in patients with advanced Ann Arbor stage on diagnosis. The SUVmean of the MBP and liver was negatively correlated with the volumetric index of lymphoma lesions in baseline scans (r = -0.547, p < 0.001; r = -0.502, p < 0.001). Positive myocardial FDG uptake was more frequently observed in interim and final scans than in the baseline scan, but there was no significant association between the MBP and liver uptake and myocardial uptake. CONCLUSIONS: The SUV of the liver was not significantly changed during R-CHOP chemotherapy in patients with DLBCL, whereas the MBP SUV of the interim scan decreased slightly. However, the SUV of the reference organs may be affected by tumor burden, and this should be considered when assessing follow-up scans. Although myocardial FDG uptake was more frequently observed after R-CHOP chemotherapy, it did not affect the SUV of the MBP and liver. PMID- 27994686 TI - Visual Pattern and Serial Quantitation of 18F-Sodium Fluoride PET/CT in Asymptomatic Patients After Hip and Knee Arthroplasty. AB - PURPOSE: We investigated the visual tracer distribution pattern and serial changes in uptake ratio in different anatomical zones during the natural postoperative course in order to establish a reference for evaluation of patients with complications. METHODS: A total of 36 patients without symptoms after hip or knee arthroplasty were grouped according to the interval between surgery and the scan. The serial changes in SUVmean in each periprosthetic zone were quantified using the volume of interest isocontour method. Images were classified according to the uptake distribution pattern. The uptake ratios in the postoperative period groups were then compared using the Kruskal-Wallis test. The correlation between uptake ratio and postoperative period was then determined. RESULTS: Tracer distribution patterns in hip prostheses were classified into three types and the patterns in knee prostheses into five types. In hip prostheses, intense osteoblastic activity was observed during 3-6 months and then declined in most patients, but showed a slight increase over 15-25 months in 5-10 % of patients. The correlation coefficients varied among the zones. Significant differences in uptake ratios among the period groups was found for all zones, except zone 8. Porous coated areas showed higher uptake than uncoated areas only for the period the 3-6 months. In knee prostheses, uptake ratios showed a curvilinear pattern, increasing from 3-6 to 8-15 months and declining later. The uptake ratios were different among the period groups. Every zone showed a positive correlation from 3-6 to 8-15 months, and negative correlations from 8-15 to 22-25 months. CONCLUSIONS: This is the first 18F-sodium fluoride PET/CT study investigating the stability of implants and sets a reference for evaluation of patients with complications. PMID- 27994687 TI - Clinical Meaning of Hot Uptake on Bone Scan in Symptomatic Accessory Navicular Bones. AB - INTRODUCTION: We analyzed clinical factors related to uptake on a Tc-99 m HDP bone scan of the accessory navicular (AN). MATERIALS AND METHODS: We retrospectively reviewed patients who had been examined by an orthopedic surgeon and underwent bone scan due to suspected symptomatic AN. A three-point grading system was used to evaluate uptake on bone scan. Relationships between grade, symptoms, age, gender, symptom duration, and bone size were analyzed. RESULTS: In total, 73 ANs (30 asymptomatic, 43 symptomatic) were enrolled. The majority of asymptomatic ANs had no uptake but some had grade 1 (n = 8) or 2 (n = 2) uptake. All asymptomatic ANs with uptake remained asymptomatic during follow-up. For the asymptomatic ANs, larger bones showed a higher grade. With a cut-off value of size <=6.8 mm, there is no chance of uptake. All symptomatic ANs showed uptake on bone scan. For symptomatic ANs, larger size and shorter pain duration were related to a higher grade. Age, gender, and left-/right-sideness were not related to grade. Multiple regressions revealed that only uptake grade, not size or symptom duration, was the significant risk factor for a symptomatic AN. With a cut-off value of grade <1, a symptomatic AN could be ruled out with a negative predictive value of 100 %. CONCLUSION: Bone scanning is useful for symptomatic ANs with a high negative predictive value. Higher grade is related to larger size and shorter pain duration. For asymptomatic ANs, grade was related to size but did not predict symptom development. PMID- 27994688 TI - Iodine Uptake Patterns on Post-ablation Whole Body Scans are Related to Elevated Serum Thyroglobulin Levels After Radioactive Iodine Therapy in Patients with Papillary Thyroid Carcinoma. AB - PURPOSE: Serum thyroglobulin (Tg) level is frequently elevated shortly after radioactive iodine (RAI) ablation therapy. The authors studied the relationship between the elevation of serum Tg after RAI therapy and iodine uptake pattern on post-ablation whole body scans (RxWBSs) in patients with papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: The study subjects were patients with PTC that had undergone first RAI therapy with thyroid hormone withdrawal after total thyroidectomy. Patients with a high level of serum anti-Tg antibody (TgAb, >= 60 U/mL), possible regional or distant metastasis as determined by pre-ablation or post-ablation studies, and negative iodine uptake of the anterior neck on RxWBS were excluded. Serum Tg was checked twice, that is, 7 days after (post-ablation Tg) and on the day of RAI therapy (pre-ablation Tg). Ratio of pre-ablation Tg to post-ablation Tg (Tg ratio) was used to assess changes in serum Tg levels after RAI therapy. Patients were classified into two groups according to the presence of midline uptake above the thyroidectomy bed on RxWBS (negative (group 1) or positive (group 2) midline uptake). Variables were subjected to analysis to identify differences between the two groups. RESULTS: Two hundred and fifty patients were enrolled in this study; 101 in group 1 and 149 in group 2. Based on univariate analysis, post-ablation Tg (8.12 +/- 11.05 vs. 34.12 +/- 54.31; P < 0.001) and Tg ratio (7.81 +/- 8.98 vs. 20.01 +/- 19.84; P < 0.001) were significantly higher in group 2. On the other hand, gender, tumor (T) stage, lymph node (N) stage, size, multiplicity or bilaterality of primary tumor, dose of 131I, serum TgAb and thyroid-stimulating hormone (TSH) level (before or after RAI therapy) were not significantly different in the two groups. Variables with P values of < 0.25 by univariate analysis were subjected to multivariate analysis, which showed post-ablation Tg (OR 1.060, 95 % CI = 1.028-1.092; P < 0.001) and Tg ratio (OR 1.059, 95 % CI = 1.028-1.092; P = 0.001) were significantly higher in group 2. CONCLUSION: Serum Tg level after RAI therapy was significantly higher in patients with midline uptake on RxWBS, compared with patients without midline uptake on RxWBS. Further investigations are needed to reveal the correlation between serum Tg elevation and clinical outcome according to the presence of midline uptake. PMID- 27994689 TI - Random Assay in Radioimmunoassay: Feasibility and Application Compared with Batch Assay. AB - PURPOSE: The batch assay has been conventionally used for radioimmunoassay (RIA) because of its technical robustness and practical convenience. However, it has limitations in terms of the relative lag of report time due to the necessity of multiple assays in a small number of samples compared with the random assay technique. In this study, we aimed to verify whether the random assay technique can be applied in RIA and is feasible in daily practice. METHODS: The coefficients of variation (CVs) of eight standard curves within a single kit were calculated in a CA-125 immunoradiometric assay (IRMA) for the reference of the practically ideal CV of the CA-125 kit. Ten standard curves of 10 kits from 2 prospectively collected lots (pLot) and 85 standard curves of 85 kits from 3 retrospectively collected lots (Lot) were obtained. Additionally, the raw measurement data of both 170 control references and 1123 patients' sera were collected retrospectively between December 2015 and January 2016. A standard curve of the first kit of each lot was used as a master standard curve for a random assay. The CVs of inter-kits were analyzed in each lot, respectively. All raw measurements were normalized by decay and radioactivity. The CA-125 values from control samples and patients' sera were compared using the original batch assay and random assay. RESULTS: In standard curve analysis, the CVs of inter kits in pLots and Lots were comparable to those within a single kit. The CVs from the random assay with normalization were similar to those from the batch assay in the control samples (CVs % of low/high concentration; Lot1 2.71/1.91, Lot2 2.35/1.83, Lot3 2.83/2.08 vs. Lot1 2.05/1.21, Lot2 1.66/1.48, Lot3 2.41/2.14). The ICCs between the batch assay and random assay using patients' sera were satisfactory (Lot1 1.00, Lot2 0.999, Lot3 1.00). CONCLUSION: The random assay technique could be successfully applied to the conventional CA-125 IRMA kits. The random assay showed strong agreement with the batch assay. The random assay procedure could increase the flexibility and decrease the turnaround time of the radioimmunoassay technique. PMID- 27994690 TI - Unusual Uptake of Prostate Specific Tracer 68Ga-PSMA-HBED-CC in a Benign Thyroid Nodule. AB - 68Ga-Prostate specific membrane antigen- N,N'-bis[2-hydroxy-5 (carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid- positron emission tomography/computed tomography or 68 Ga- HBED-CC-PSMA PET/CT, popularly known as PSMA PET/CT, is able to detect a small volume of recurrent prostate carcinoma (PC) when there is a prostate specific antigen (PSA) rise on follow-up after prostatectomy or other definitive treatment for PC. The use of PSMA PET/CT in the initial staging in PC is uncertain at this time. Clinical studies are underway to define its exact role in the management of the disease. At the same time it is important to be aware of unexpected sites of uptake of this ligand. We present here the case of a 62-year-old male patient who underwent prostatectomy for adenocarcinoma prostate. He also had a long-standing left solitary thyroid nodule (STN). Four months after surgery, he had a rising trend in serum PSA levels on three occasions, but the absolute value was less than 4 at all times. He underwent a 68Ga-PSMA-HBED-CC PET/CT, but it did not reveal any recurrent/metastatic site of disease. However, there was increased tracer uptake in the left STN. Fine needle aspiration cytology revealed features of atypia of undetermined significance, Bethesda category III. The patient underwent a left hemithyroidectomy and the histopathology showed features of a follicular adenoma. PMID- 27994691 TI - Giant Cell Tumor with Secondary Aneurysmal Bone Cyst Shows Heterogeneous Metabolic Pattern on 18F-FDG PET/CT: A Case Report. AB - Giant cell tumor (GCT) is a generally benign bone tumor accounting for approximately 5 % of all primary bone neoplasms. Cystic components in GCTs that indicate secondary aneurysmal bone cysts (ABCs) are reported in 14 % of GCTs. Although both of them have been described separately in previous reports that may show considerable fluorodeoxyglucose (FDG) uptake despite their benign nature, the findings of GCT with secondary ABC on 18F-FDG positron emission tomography/computed tomography (PET/CT) have not been well-known. We report a case of GCT with secondary ABC in a 26-year-old woman. 18F-FDG PET/CT revealed a heterogeneous hypermetabolic lesion in the left proximal femur with the maximum standardized uptake value of 4.7. The solid components of the tumor showed higher FDG uptake than the cystic components. These observations suggest that the ABC components in GCTs show heterogeneous metabolic patterns on 18F-FDG PET/CT. PMID- 27994692 TI - Incidental Findings of Intense Radioiodine Uptake in Struma Ovarii and Bilateral Nonlactating Breasts Simultaneously on Postablation 131I SPECT/CT for Papillary Thyroid Cancer. AB - A 52-year-old woman diagnosed with papillary thyroid carcinoma was referred for 131I therapy following total thyroidectomy. She was given 4,810 MBq (130 mCi) of 131I following 4 weeks of thyroid hormone withdrawal. A posttherapy scan showed intense, focal activity in the pelvis and intense, diffuse activity on both sides of the chest, which was localized to the right ovary and both breasts on SPECT/CT examination. She had bilateral nipple pain and a history of antidopaminergic drugs as combination medication for her rheumatoid arthritis and prokinetics during radioiodine therapy. On a 123I whole-body scan 9 months later after stopping the drugs, bilateral breast uptake was not visible; however, right ovarian focal uptake was still visualized. Bilateral salpingo-oophorectomy was performed, and revealed struma ovarii with substantial internal necrosis due to radioiodine therapy. This case is interesting as two rare entities, 131I therapy related struma ovarii and drug-related breast uptake, were simultaneously visualized. PMID- 27994693 TI - Systemic Immune Response to Vaccination on FDG-PET/CT. AB - A patient with newly diagnosed right lung cancer had transient 18F fluorodeoxyglucose (FDG)-avid left axillary lymph nodes and intense splenic FDG uptake on positron emission tomography (PET)/computed tomography (CT). History revealed that the patient received a left-sided influenza vaccine 2-3 days before the examination. Although inflammatory FDG uptake in ipsilateral axillary nodes is reported, to our knowledge, this is the first report of visualization of the systemic immune response in the spleen related to the influenza vaccination on FDG-PET/CT. The history, splenic uptake and time course on serial FDG-PET/CT helped to avoid a false-positive interpretation for progressing lung cancer and alteration of the radiation therapy plan. PMID- 27994694 TI - (99m)Tc-MIBI Uptake in a Thyroid Adenoma with Diffuse Adipose Metaplasia. AB - A 71-year-old female underwent a (99m)Tc-MIBI scan to characterize a cold nodule (30 mm) of the left thyroid lobe. The nodule showed diffuse uptake and retention of the radiotracer. After resection, histological examination demonstrated a microfollicular adenoma with diffuse white adipose metaplasia. Although mitochondria in brown adipose tissue have been widely studied, we have only a limited understanding of the relevance of mitochondria in white adipose tissue. Active mitochondria are present in white adipocytes, and this may account for the MIBI uptake, mimicking a hyperproliferation pattern, in our patient. PMID- 27994695 TI - CT Angiographic Evaluation of Pattern and Distribution of Stenosis and its Association with Risk Factors Among Indian Ischemic Stroke Patients. AB - BACKGROUND: Stroke is the major cause of disability and third major cause of death. Ischemia causes about 80% of stroke cases; stenosis and occlusion are the predominant cause of stroke. Our purpose for this study was to evaluate the pattern and distribution of stenosis and its association with risk factors in Indian ischemic stroke patients and in other countries, for comparison. MATERIAL/METHODS: We evaluated 60 patients after ischemic stroke with CT angiography. The degree of stenosis was measured by the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The results were analyzed by descriptive statistics and chi-square test. RESULTS: Out of 60 cases, 32 cases were positive for significant stenosis and a total number of stenotic segments was 45. Out of 45 stenotic segments, 29 were single stenotic segments (16 intracranial and 13 extracranial) and 16 were multiple stenotic segments (8 intracranial and 8 extracranial). In the total number of stenotic segments (single and multiple), there were 24 (53.33%) intracranial and 21 (46.67%) extracranial. The most commonly involved intracranial stenosis segment was MCA, present in 10 (41.6%) out of 24 intracranial segments. Most commonly involved extracranial stenosis segment was ICA, present in 14 (66.6%) out of 21 extracranial segments. Diabetes is found to be the most common risk factor of intracranial stenosis while hypertension and hypercholesterolemia are the major risk factors of extracranial stenosis. CONCLUSIONS: In the Indian population, intracranial stenosis is more common than extracranial one, anterior circulation stenosis is more common than posterior circulation stenosis; single stenosis is more common than multiple stenosis. PMID- 27994696 TI - Primary Hydatid Cyst of the Brain in a Child: A Case Report. AB - BACKGROUND: Primary intracranial hydatid cyst is a rare location of human echinococcosis whose spontaneous, traumatic or even iatrogenic rupture, as in case of misdiagnosis, may cause anaphylactic reactions and dissemination. CASE REPORT: We discuss the management of a 9-year-old boy who was admitted to our Emergency Department with an intracranial hypertension syndrome. Head CT scan and brain MRI showed a huge intra-axial right temporo-parieto-occipital cyst with a marginal calcification, associated with left ventricular uncompensated hydrocephalus. DTI showed displacement of the ipsilateral corticospinal tract, whereas MR spectroscopy showed absence of normal brain metabolites and presence of succinate and lactate within the cyst. A diagnosis of hydatid cyst was then presumed on the basis of the neuroradiological findings. Empiric chemotherapy with albendazole was instituted and surgical en bloc removal of the cyst was obtained, allowing the patient to recover without complications. Diagnosis of brain echinococcosis was confirmed by laboratory tests. CONCLUSIONS: HE is still an endemic manifestation in some rural areas of the world, and it should be included in the differential diagnosis of children living in or coming from an endemic country who present with an intracerebral cyst. Early diagnosis and complete surgical removal of the intact cyst are the main factors that determine a favourable outcome. PMID- 27994697 TI - Acute Reversible Duodenitis Following Non-Therapeutic Upper Gastrointestinal Endoscopy. Is Duodenal Diverticulum a Predisposing Factor? AB - BACKGROUND: Diagnostic upper gastrointestinal (UGI) endoscopy has been regarded as a safe procedure. CASE REPORT: We report of a 67-year-old woman who developed epigastric pain and dyspeptic complaints following an uneventful upper gastrointestinal endoscopy. The diagnosis of an acute reversible duodenitis was made on the basis of imaging studies. A duodenal diverticulum was also found on CT images, which raised the suspicion that duodenal diverticulum could be a predisposing factor for duodenitis. CONCLUSIONS: Despite significant inflammation the patient demonstrated rapid clinical improvement with conservative treatment. Presence of a duodenal diverticulum may predispose to acute duodenitis following diagnostic UGI endoscopy. PMID- 27994698 TI - Quality Improvement of Dual-Energy Lung Perfusion Image by Reduction of Low Energy X-Ray Spectrum: An Evaluation on Clinical Images. AB - BACKGROUND: The effects of the reduction of low-energy X-ray spectrum on lung perfusion images created by dual-energy CT have not been well evaluated. The aim of this study is to investigate the reliability of lung perfusion blood volume (PBV) images created by dual-energy CT (DECT) equipped with or without a tin filter, focusing on its accuracy adjacent to high-attenuation areas. MATERIAL/METHODS: Among 176 patients who underwent DECT for suspicion of pulmonary embolism, 38 patients (mean age, 64; range, 16 to 83 years) without apparent evidence of pulmonary embolism were evaluated in this study. They underwent DECT at 100/140 kVp with a tin filter on 140 kVp tube (Group A; n=18) or at 80/140 kVp without the filter (Group B; n=20). On the lung PBV images, the degrees of artifacts - pulmonary enhancement defect (PED) and pseudo-enhancement in the trachea (PTE) adjacent to the vena cava were evaluated using a four-point scale (0=minimal to 3=prominent). RESULTS: The mean degrees of artifact in Group A were significantly lower than those in Group B (0.8 vs. 1.9; P<0.0001 for PED, respectively, and 1.1 vs. 2.2; P<0.0001 for TPE, respectively). The mean CTDIvols were 4.90+/-1.14 and 12.98+/-3.15 mGy (P<0.0001) for Group A and Group B, respectively. CONCLUSIONS: The quality and accuracy of dual-energy lung perfusion image will be improved by using the tin filter technique. PMID- 27994699 TI - Diphenyl Dimethyl Bicarboxylate in the Treatment of Viral Hepatitis, Adjuvant or Curative? AB - Diphenyl dimethyl bicarboxylate (DDB) has been used in some countries as hepatoprotectant adjuvant in the treatment of liver diseases, such as chronic viral hepatitis, chemical or drug induced hepatic damage. Its early confirmed efficacy is to normalize elevated blood alanine aminotransferase (ALT) from different etiologies, however, it can rarely affect the rest hepatic enzymes. In addition, the lowering or normalization of ALT in most cases occurs during DDB treatment, withdrawal of DDB administration results in ALT re-elevated. Hence, for a long time, it has been only used as adjuvant of liver disease therapy. It is still controversial that whether DDB can be beneficial to liver histology. The normalization of ALT in hepatitis does not indicate therapeutic efficacy if without substantial liver histology improvement. In recent years, more studies showed that DDB might have new therapeutical potentials in liver diseases, it may have the effect of anti-viral, anti-malignancy. These new findings were mostly based on the in vitro or animal experiments, more basic studies and clinical trials are needed to ascertain these efficacies, prior to that stage, it is recommended to be cautious to apply DDB clinically for anti-virus and anti malignancy purposes. PMID- 27994700 TI - Cellular Transplantation for Liver Diseases. AB - Presently, the orthotropic liver transplantation (OLT) is still the most effective therapeutic for patients with acute or chronic hepatic failure. However, due to the shortage of donor livers, the number of patients benefited from this approach is limited. Therefore, some alternative modalities have been paid attention for restoring the liver function. The cell transplantation is one of the promising modalities to realize this purpose. The types of cells used in the cell transplantation include syngeneic hepatocytes, allogeneic hepatocytes, immortalized hepatocytes, and stem cells derived heptocytes. The stem cells, especially the adult stem cells from bone marrow, are shown as a promising cell source for liver repopulation. The mesenchymal bone marrow stem cells and embryonic stem cells can be induced to differentiate into the hepatic lineage and might be used in the cell transplantation for liver diseases. Compared to OLT, the advantages of cell-based therapy for liver disease are, but not limited to, less invasive, less expensive, easy manipulated, easy expansion of cells in vitro. Cells can be stored in a cell bank for future use. Though most of the current studies are experimental and animal based, the cellular therapy for liver disease is expected to be an effective alternative in clinical settings in near future. PMID- 27994701 TI - Clinical Trials of Antiangiogenesis Therapy on Gastric Cancer. AB - Both malignant tumor growth and metastasis are dependent upon angiogenesis, a process of new blood vessel formation. Inhibition of this process by specific inhibitors might be able to control tumor growth and metastasis. Therefore, antiangiogenesis thereapy is considered a promising strategy and being studied worldwide. A wide variety of angiogenesis inhibitors have been identified and some of them are under clinical trials in the advanced patients with cancer including gastric cancer. This review summarizes the development and progress of angiogenesis inhibitors in recent decades, and discusses the future direction of antiangiogenesis research, and the potential antiangiogenic agents which are most likely to be translated into standard treatment for gastrointestinal cancer patients either alone or combined with other therapies. PMID- 27994702 TI - Ginkgo Biloba Extract EGb 761 Alleviates Hepatic Fibrosis and Sinusoidal Microcirculation Disturbance in Patients with Chronic Hepatitis B. AB - BACKGROUND: Few clinical data are available regarding the effect of Ginkgo biloba extract (EGb 761) on liver microcirculation and fibrosis. This randomized, controlled trial is to investigate the effect of Ginko biloba extract EGb 761 on liver fibrosis and hepatic microcirculation in patients with chronic hepatitis B. METHODS: Sixty-four patients with chronic hepatitis B were randomized for intention-to-treat. Thirty-two patients were assigned to treated group receiving EGb 761 plus polyunsaturated phosphatidylcholine (Essentiale), 32 patients received Essentiale as controls. Blood samples were taken for measurement of transforming growth factor beta-1 (TGF-beta1), platelet activate factor (PAF), endothelin 1 (ET-1). Twenty-six patients in treated group and 21 patients in control group underwent liver biopsies for histology before and after treatment. Ultrastructural study for sinusoidal microcirculation before and after treatment was carried out on 10 randomly selected patients in each group. RESULTS: In the treated group, after EGb 761 treatment, there was a significant reduction of blood TGF- beta1, PAF and ET-1 (p<0.05), whereas this was not observed in the controls. After treatment in both groups, there were significant decrease of ALT, TBil and PT (p<0.05), and significant increase of ALB (p<0.05). Hepatic inflammation and fibrosis significantly alleviated in the treated group, but not in the controls. After EGb 761 treatment, electron microscopy showed red blood cell aggregates and microthrombosis disappeared or decreased in sinusoids; collagen deposits in sinusoidal lumen and Disse space reduced; sinusoidal capillarization alleviated. CONCLUSIONS: EGb 761 can improve sinusoidal microcirculation, alleviate inflammation and inhibit fibrosis through multiple mechanisms, it is effective in the treatment of chronic liver diseases. PMID- 27994703 TI - Cholecystectomy or Cholelithiasis - a Missed Marker for Hyperlipidaemia? A Combined Retrospective and Prospective Study. AB - BACKGROUND: Multiple studies have shown an association between gallstones and abnormal lipids and the latter increases the risk of coronary artery disease and stroke. Our study investigates the current incidence of lipid abnormalities in patients who have undergone cholecystectomy (retrospective study) and who have gallstones (prospective study). METHODS: We conducted a retrospective analysis of the lipid profiles of 715 patients who underwent cholecystectomy in a rural district general hospital from 2003 to 2006. Details of the cholecystectomy patients were obtained from Patient Information and Management System (PIMS) and cross-referenced with biochemical and histological databases. Following this a prospective study was undertaken of 129 patients presenting with gallstones. RESULTS: Of the 715 patients, three quarters were women. Only 36.2% of women and 36.9% of men who had a cholecystectomy had a full lipid profile including high density lipoproteins (HDL) and low density lipoproteins (LDL). Of these, 76.4% of women and 70.7% of men had an abnormal lipid profile. In the prospective group, 91.1 % of women and 96.3 % of men had a full lipid profile. These were abnormal in 81.4% of women and 70.4 % of men. Hypercholesterolemia and raised LDL were the most common abnormalities in both sexes. Hypertriglyceridaemia was common in both sexes in both the groups. CONCLUSIONS: Patients who have had a cholecystectomy or gallstones should have a full fasting lipid profile, including HDL and LDL, as a large proportion will be abnormal. Current guidelines suggest they are at an increased risk of cardiovascular disease and should be treated. PMID- 27994705 TI - Management of Malignant Gastric Outlet Obstruction with Expandable Metallic Stent Placement. AB - BACKGROUND: To investigate the efficacy and procedural skills of metallic stent placement for malignant gastric outlet obstruction. METHODS: Nine patients with malignant gastric outlet obstruction were performed metallic stent placement. Two stent placement methods were employed, the first, stents were placed under guidance of endoscopy in 7 patients (stent introducer: 140 mm in length and 4-6 mm in diameter); the second, duodenal stents were placed through endoscopic biopsy channel (3.2 or 4.2 mm in diameter) in 2 patients. RESULTS: The stent placement succeeded at the first attempt in all 9 patients. Among the 9 patients, 3 placed with 2 x 10 cm stents, and 6 with 2 x 8 cm stents. Pylorus stents, duodenal stents, and esophageal stents were placed in 2 patients, 6 patients and 1 patient, respectively. Stents expanded about 90% confirmed by fluoroscopy 24 - 48 h after the procedure. the patients started liquid food 24 h after stent placement. The common post-procedural complications included nausea, vomiting, upper digestive tract hemorrhage and upper abdominal pain. Post-procedural obstructive jaundice occurred in 1 patient. During the 3 months follow-up, no stent migration, removal and occlusion occurred. Of the 9 patients, 3 survived 10 15 days and 2 survived 1-2 months, the rest 4 patients survived 3 months. The mean stent patency was 53.4 days. CONCLUSIONS: Expandable metallic stents placed in patients with malignant obstruction of gastric outlet effectively palliate the obstructive symptoms. Technical skills play important roles in stent placement in treatment of malignant gastric outlet obstruction, and the efficacy of metallic stent placement is associated with the location of metallic stents and therapeutic indications. PMID- 27994704 TI - Inhibition of de novo Methyltransferase 3B is a Potential Therapy for Hepatocellular Carcinoma. AB - BACKGROUND: Aberrant epigenetic patterns, including inactivation of tumor suppressor genes due to DNA methylation, have been described in many human cancers. Epigenetic therapeutic is a new and rapidly developing area of tumor treatment because DNA methyltransferase (DNMT) inhibitors can reverse its changes. We attempted to identify potential approach for epigenetic therapy of hepatocellular carcinoma. METHODS: We knocked down the expression of DNMT 1 or DNMT 3B by siRNA, and inhibited DNA methyltranferases by 5-Aza-2'-deoxycytidine. We used high-density oligonucleotide gene expression microarrays to examine the induced genes in human hepatocellular carcinoma cell line SMMC-7721 after suppressing DNA methyltranferases. The 5' ends of up-regulated genes were analyzed by BLAST database to determine whether they have promoter CpG islands, and then the identical induced genes were compared among different inhibition of DNA methyltranferases. RESULTS: Our results show that 9 genes were found to be over expressed by more than two-fold induced by DNMT1 siRNA and 5-Aza-CdR, and 30 genes were found to be over expressed by more than two-fold induced by DNMT3B siRNA and 5-Aza-CdR in SMMC-7721. Among them, 76.6% up-regulated genes conjectural contained 5' CpG islands. The DNMT3B siRNA could induce more genes identical to demethylation agent in SMMC-7721. CONCLUSIONS: DNMT3B might be a new potential target for therapy of hepatocellular carcinoma. PMID- 27994706 TI - Increased Plasma Superoxide Radical in Patients with Non-Metastatic Colorectal Cancer. AB - BACKGROUND: Several studies have investigated the potential role of oxidative stress in the evolution of colorectal cancer. In most of these studies, oxidative stress was assessed indirectly by measurements of indices like lipid peroxidation, protein oxidation or antioxidant status. The present study was undertaken to directly assess systemic oxidative stress by measuring plasma superoxide radical (O2-.) in patients with non-metastatic colorectal cancer. METHODS: Twelve patients (6 males and 6 females) with a recent diagnosis of colorectal cancer and no signs of metastases and 12 healthy volunteers matched for age and gender were enrolled in the study. O2-. levels in plasma were assessed by application of a new ultra-sensitive fluorescent assay. Also lipid peroxidation levels in plasma were measured as thiobarbituric acid reactive species (TBARS). RESULTS: In the plasma fraction of whole blood, there was a significant increase (47%) of O2-. levels in colorectal carcinoma patients as compared to healthy volunteers (P < 0.001). In fractionated plasma, no O2-. was detected in both groups. Plasma TBARS levels were increased by 81% in colorectal carcinoma patients as compared to controls (P < 0.001). CONCLUSIONS: These data show that colorectal cancer, even at early (non-metastatic) stages, induces systemic oxidative stress as evidenced by increased O2.- levels measured in plasma. Given the important role of oxidative stress in carcinogenesis and the fact that O2.- is considered its primary parameter, our findings if confirmed in larger studies might establish the potential validity of O2.- as a new biomarker for colorectal cancer. PMID- 27994707 TI - Dynamic Changes of Soluble Fas and IL-2/IL-10 in serum and Fas Expression in Lung in the Rats of Acute Necrotizing Pancreatitis. AB - BACKGROUND: To investigate the dynamic changes of serum IL-2, IL-10, sFas and IL 2/IL-10 in a rat model with acute necrotizing pancreatitis (ANP). To explore the role of Th1/Th2 polarization and the Fas expression in the lung of rats with ANP. METHODS: A total of 64 Sprague-Dawley rats were randomly divided into normal control group and ANP model group. ANP models were induced by injection of 50 g/L sodium taurocholate (4 mL/kg) under the pancreatic membrane. In the normal control group, the rats received isovolumetric injection of 9 g/L normal saline solution. The blood samples in each group were obtained via superior mesenteric vein for measuring IL-2, IL-10 and soluble Fas. The levels of IL-2, IL-10 and soluble Fas were determined by ELISA. The severity of lung injury was evaluated by pathologic score. The expression of Fas in lung was measured by immunohistochemistry. RESULTS: In the ANP model group, levels of serum IL-2 were significantly higher than those of control group (P < 0.01), and peaked at 6 hours; levels of serum IL-10 were significantly higher than those of control group at 6 and 12 hours (P < 0.01); the ratios of IL-2/IL-10 were significantly higher than those of control group at 0.5 hours and 2 hours, however, they were significantly lower than those of control group at 6 hours, (P < 0.01), and returned to the normal level (P > 0.05). In Fas/APO-1 assay, there was no significant difference between the two groups. The pathological changes were aggravated significantly in model group compared with the control group. Immunohistochemistry stain showed Fas expression was absent in normal pulmonary tissue, whereas in pulmonary tissue Fas expression gradually increased 0.5 hours after induction of pancreatitis, and reached their peaks at 12 hours. CONCLUSIONS: Fas are involved in the pathogenesis of pancreatitis associated lung injury, the mechanism might be related to the Fas mediated T helper cell apoptosis. PMID- 27994708 TI - EGF-R Protein Expression and Gene Amplification do not Correlate in Pancreas Cancer. AB - In a series of 13 pancreas cancer specimens, EGF-R was evaluated by means of both immunohistochemistry (IHC) for protein expression and FISH for genetic amplification. The results were discording in 7 cases (IHC positive, FISH negative), while in the remaining 6 cases both IHC and FISH were negative. The possible clinical implications of these results are discussed. PMID- 27994709 TI - Refractory Chylous Ascites. AB - A 34-year-old woman with primary chylous ascites due to lymphangiectasias was treated with sclerotherapy of dilated lymphatics and a lymphovenous shunt. She was referred to our institution after a thorough diagnostic and therapeutic approach in her community hospital. After four weeks of intensive diagnostic study, no secondary etiology for her chylous disorder was established. Conservative treatment did not prove useful, and a laparotomy was done. Lymphangiectasias and a lymphatic leak were demonstrated, but primary closure was ineffective. A second surgery with derivative intention was done, but six months later ascites recurred. A new sclerosing surgery was done; afterwards, the patient remained free of symptoms. Primary chyloperitoneum is a rare and complex disorder; its treatment and outcome depend on a multidisciplinary approach and an experienced medical team. PMID- 27994712 TI - Examining the Value of Subsidies of Health Plans and Cost-Sharing for Prescription Drugs in the Health Insurance Marketplace. AB - BACKGROUND: The Affordable Care Act (ACA) initiated federally and state-run health insurance exchanges, or marketplaces, with health plans offering subsidies for plan members as well as coverage for essential health benefits, to help individuals, families, and small businesses find health plans that fit their specific needs. A recent study found that the value of these healthcare subsidies varied with the number of health plans in the different geographic rating areas, but that study only examined the premiums and the deductibles of those health plans. OBJECTIVES: To examine the value of subsidies of health plans, including cost-sharing for prescription drugs in the health insurance marketplace. METHODS: We have used publicly available health plan data from HealthCare.gov and from county population data obtained from the US Census Bureau in June 2015. The average-weighted premium; medical deductible; medical maximum out-of-pocket spending; and cost-sharing for generic drugs, preferred and nonpreferred brand name drugs, and specialty drugs were calculated for the second lowest-cost silver plan in each geographic rating area. These were then compared across geographic areas with different numbers of plans to determine the value of the subsidies. We also compared the difference between the cost of the average silver plan and the second lowest-cost silver plan for each area to determine the cost to enrollees if they selected the average silver plan. RESULTS: The monetary value of the subsidies provided by health plans was lower in areas with a larger number of plans, because the second lowest-cost silver plans in these areas tended to have lower premiums and higher deductibles. For the most common type of cost-sharing for generic and for preferred brand-name drugs, plan enrollees would likely have a lower or similar copayment if they selected the average-cost silver plan instead of the second lowest-cost silver plan. However, they may end up paying approximately $8 less in copayment for nonpreferred branded drugs and approximately 4% less for coinsurance after a deductible for specialty drugs if they resided in a geographic area with fewer than 11 plans. CONCLUSION: The value of subsidies provided by the ACA-initiated health plans in the healthcare marketplace, including cost-sharing for prescription drugs, varies across geographic areas with different numbers of health plans. This suggests that potential enrollees should consider cost-sharing for prescription drugs in addition to health plans' premiums and deductibles when choosing their health plan. PMID- 27994711 TI - Oxidant Status following Cardiac Surgery with Phosphorylcholine-Coated Extracorporeal Circulation Systems. AB - Introduction. Extracorporeal circulation (ECC) related systemic oxidative stress is a well-known entity but the underlying mechanisms are not clearly described. Our aim was to investigate the relation between the oxidative stress indices, inflammatory markers, and phosphorylcholine-coated (PCC) ECC systems. Patients and Methods. Thirty-two consecutive coronary artery bypass grafting (CABG) cases were randomly assigned to Group I (PCC, n = 18) and Group II (noncoated, n = 14) ECC circuits. Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-1beta (IL-beta), Interleukin-6 (IL 6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), and Procalcitonin (PCT) levels were measured at 5 different time points. The association between the oxidative indices levels and PCC system used was analyzed. Results. In Group I TOS and TAS statuses were increased at T1, T2, T3, and T4, while IL-10 and TNF-alpha levels accompanied those raises only at T2 (Group I-Group II, 4.73 +/- 2.04 versus 2.79 +/- 0.63, p = 0.002, and 30.56 +/- 8.11 versus 23.97 +/- 7.8, p = 0.031, resp.). In contrast, mean TAS and TOS levels were similar to baseline at all time points in Group II but IL-6 and IL-8 levels were increased at T2 (Group I-Group II, 16.84 +/- 5.63 versus 44.81 +/- 17.0, p = 0.001, and 38.88 +/- 9.8 versus 46.14 +/- 9.25, p = 0.038, resp.). Conclusion. Even coated ECC systems are still incapable of attenuating the inflammatory response to cardiopulmonary bypass (CPB). PMID- 27994710 TI - Serum from Varicose Patients Induces Senescence-Related Dysfunction of Vascular Endothelium Generating Local and Systemic Proinflammatory Conditions. AB - Although the role of endothelium in varicose vein development is indisputable, the effect of the pathology on biological properties of endothelial cells remains unclear. Here we examined if the presence of varicose veins affects senescence of endothelial cells (HUVECs) and, if so, what will be the local and systemic outcome of this effect. Experiments showed that HUVECs subjected to serum from varicose patients display improved proliferation, increased expression of senescence marker, SA-beta-Gal, and increased generation of reactive oxygen species (ROS), as compared with serum from healthy donors. Both increased SA-beta Gal activity and ROS release were mediated by TGF-beta1, the concentration of which in varicose serum was elevated and the activity of which in vitro was prevented using specific neutralizing antibody. Senescent HUVECs exposed to varicose serum generated increased amounts of ICAM-1, VCAM-1, P-selectin, uPA, PAI-1, and ET-1. Direct comparison of sera from varicose and healthy donors showed that pathological serum contained increased level of ICAM-1, VCAM-1, P selectin, uPA, and ET-1. Calendar age of healthy subjects correlated positively with serum uPA and negatively with P-selectin. Age of varicose patients correlated positively with ICAM-1, VCAM-1, and ET-1. Collectively, our findings indicate that the presence of varicose veins causes a senescence-related dysfunction of vascular endothelium, which leads to the development of local and systemic proinflammatory environment. PMID- 27994713 TI - Evaluating Adherence to Dilated Eye Examination Recommendations Among Patients with Diabetes, Combined with Patient and Provider Perspectives. AB - BACKGROUND: Diabetes mellitus remains the leading cause of new cases of blindness among US adults. Routine dilated eye examinations can facilitate early detection and intervention for diabetes-related eye disease, providing an opportunity to reduce the risk for diabetes-related blindness in working-aged Americans. The Healthcare Effectiveness Data and Information Set (HEDIS) established criteria for performing dilated eye examination in patients with diabetes. OBJECTIVES: To obtain information about adherence and nonadherence to diabetic eye examinations among insured patients to understand the barriers to routine dilated eye examinations, and to identify ways to improve the quality of care for these patients. METHODS: This retrospective claims analysis is based on administrative claims from the HealthCore Integrated Research Database, a broad database representing claims from a large commercially insured population. Patients with diabetes and who had >=1 dilated eye examinations between August 1, 2011, and July 31, 2013, were defined as adherent to the HEDIS recommendations. The analysis was augmented with findings from focus groups. The patient focus groups included adherent and nonadherent patients. The provider focus group participants were general practice or internal medicine physicians and ophthalmologists who provided medical care for the study population. For the administrative claims analysis, comparisons between the adherent and nonadherent patients were performed using t-tests for continuous data and chi-square tests for categorical data. RESULTS: Of 339,646 patients with diabetes identified in a claims data set, 43% were adherent and 57% were nonadherent to the HEDIS eye examination performance measure. The common barriers to routine eye examination cited by 29 patients across 4 focus groups included a lack of understanding of insurance benefits (N = 15), a lack of awareness of the importance of dilated eye examinations (N = 12), and time constraints (N = 12). The common barriers cited by 18 providers included the patient's level of education (N = 13), eye examinations as a lower priority than the management of other diabetes-related health issues (N = 12), and a lack of symptoms (N = 11). CONCLUSION: Several reasons for patient nonadherence to routine eye examination were identified, including a lack of understanding of insurance benefits, a lack of awareness or low prioritization of having an examination, patient education level, time constraints, and a lack of symptoms. These may be considered by providers and payers when developing programs to increase the rates of eye examinations and improve outcomes among patients with diabetes. PMID- 27994715 TI - Ankle Cartilage Repair. PMID- 27994714 TI - Factors Associated with Adherence to the HEDIS Quality Measure in Medicaid Patients with Schizophrenia. AB - BACKGROUND: Treatment continuity is a major challenge in the long-term management of patients with schizophrenia; poor patient adherence to antipsychotic drugs has been associated with negative clinical outcomes. Long-acting injectable therapies may improve adherence and lessen the risk for psychiatric-related relapse, often leading to rehospitalization and higher healthcare costs. Therefore, understanding the determinants of adherence to antipsychotics is critical in the management of patients with schizophrenia. OBJECTIVE: To assess the impact of baseline patient characteristics on adherence as measured by the Healthcare Effectiveness Data and Information Set (HEDIS) measure of continuity of antipsychotic medications among patients with Medicaid coverage. METHODS: Medicaid healthcare claims data between 2008 and 2011 from 5 states were used to identify patients who were diagnosed with schizophrenia (aged 25-64 years) and received >=1 antipsychotic prescriptions in baseline year 2010 and in measurement year 2011. The HEDIS continuity of antipsychotic medications (ie, adherence) measure was defined as the proportion of days covered with any antipsychotic medication >=80% during the measurement year. The 2 cohorts compared paliperidone palmitate with any other antipsychotics, including quetiapine, risperidone, and haloperidol. The baseline-year characteristics were evaluated as potential predictive factors of adherence in the measurement year using multivariate logistic regressions. The regression models incorporated the inverse probability of treatment weights to control for differences in baseline characteristics between the paliperidone palmitate and the other antipsychotics cohort. RESULTS: Among the 12,990 patients who received an antipsychotic during the study period, 48.6% successfully achieved the continuity criteria in the measurement year. After controlling for other covariates, the odds of adherence were improved by adherence at baseline (odds ratio [OR], 9.42; 95% confidence interval [CI], 8.55 10.39). The use of paliperidone palmitate was associated with a 26% increase in the odds of achieving adherence compared with the use of the other antipsychotics studied (OR, 1.26; 95% CI, 1.14-1.39). In addition, female sex (OR, 1.11; 95% CI, 1.01-1.22), age 55 to 64 years (OR, 1.26; 95% CI, 1.09-1.46) versus age 25 to 34 years, Hispanic race (OR, 1.37; 95% CI, 1.05-1.81) versus white race, and an increase of $10,000 in baseline inpatient costs (OR, 1.11; 95% CI, 1.08-1.15) were associated with greater odds of treatment continuity. CONCLUSIONS: In addition to sex, age, and race, the baseline characteristics that were associated with achieving the HEDIS continuity of antipsychotic medication measure included previous-year adherence, inpatient costs, and the use of paliperidone palmitate. These findings offer insight to healthcare plans that cover Medicaid populations on the effects that patient characteristics and treatment types may have on adherence among patients with schizophrenia. PMID- 27994716 TI - Peculiarities in Ankle Cartilage. AB - Posttraumatic osteoarthritis (PTOA) is the most common form of osteoarthritis (OA) of the ankle joint. PTOA occurs as a result of several factors, including the poor regenerative capacity of hyaline articular cartilage as well as increased contact stresses following trauma. The purpose of this article is to review the epidemiology, pathogenesis, and potential targets for treatment of PTOA in the ankle joint. Previous reviews primarily addressed clinical approaches to ankle PTOA, while the focus of the current article will be specifically on the newly acquired knowledge of the cellular mechanisms that drive PTOA in the ankle joint and means for potential targeted therapeutics that might halt the progression of cartilage degeneration and/or improve the outcome of surgical interventions. Three experimental treatment strategies are discussed in this review: (1) increasing the anabolic potential of chondrocytes through treatment with growth factors such as bone morphogenetic protein-7; (2) limiting chondrocyte cell death either through the protection of cell membrane with poloxamer 188 or inhibiting activity of intracellular proteases, caspases, which are responsible for cell death by apoptosis; and (3) inhibiting catabolic/inflammatory responses of chondrocytes by treating them with anti inflammatory agents such as tumor necrosis factor-alpha antagonists. Future studies should focus on identifying the appropriate timing for treatment and an appropriate combination of anti-inflammatory, chondro- and matrix-protective biologics to limit the progression of trauma-induced cartilage degeneration and prevent the development of PTOA in the ankle joint. PMID- 27994717 TI - Evaluation and Management of Osteochondral Lesions of the Talus. AB - Osteochondral lesions of the talus are common injuries that affect a wide variety of active patients. The majority of these lesions are associated with ankle sprains and fractures though several nontraumatic etiologies have also been recognized. Patients normally present with a history of prior ankle injury and/or instability. In addition to standard ankle radiographs, magnetic resonance imaging and computed tomography are used to characterize the extent of the lesion and involvement of the subchondral bone. Symptomatic nondisplaced lesions can often be treated conservatively within the pediatric population though this treatment is less successful in adults. Bone marrow stimulation techniques such as microfracture have yielded favorable results for the treatment of small (<15 mm) lesions. Osteochondral autograft can be harvested most commonly from the ipsilateral knee and carries the benefit of repairing defects with native hyaline cartilage. Osteochondral allograft transplant is reserved for large cystic lesions that lack subchondral bone integrity. Cell-based repair techniques such as autologous chondrocyte implantation and matrix-associated chondrocyte implantation have been increasingly used in an attempt to repair the lesion with hyaline cartilage though these techniques require adequate subchondral bone. Biological agents such as platelet-rich plasma and bone marrow aspirate have been more recently studied as an adjunct to operative treatment but their use remains theoretical. The present article reviews the current concepts in the evaluation and management of osteochondral lesions of the talus, with a focus on the available surgical treatment options. PMID- 27994718 TI - New Technology in Imaging Cartilage of the Ankle. AB - The incidence of osteochondral lesions, as well as osteoarthritis of the ankle joint following osteochondritis dissecans and trauma, has been reappraised in recent years. Consequently, an increasing number of surgical interventions using different cartilage repair techniques is performed in the ankle joint, which has resulted in a growing demand for repetitive and objective assessment of cartilage tissue and its repair. While morphological imaging does enable monitoring of macroscopic changes with increasing precision, it fails to provide information about the ultrastructural composition of cartilage. The significance of molecular changes in cartilage matrix composition, however, is increasingly recognized, as it is assumed that macroscopic cartilage degeneration is preceded by a loss in glycosaminoglycans and a disorganization of the collagen network. Recent advances in biochemical magnetic resonance imaging (MRI) have yielded sequences sensitive to these changes, thus providing invaluable insight into both early cartilage degeneration and maturation of repair tissue, on a molecular level. The aim of this review was to provide a comprehensive overview of these techniques, including water and collagen-sensitive T2/T2* mapping, as well as glycosaminoglycan-sensitive sequences such as delayed gadolinium-enhanced MRI of cartilage dGEMRIC, and sodium imaging, and describe their applications for the ankle joint. PMID- 27994719 TI - Operative Treatment for Osteochondral Lesions of the Talus: Biologics and Scaffold-Based Therapy. AB - OBJECTIVE: Numerous basic science articles have published evidence supporting the use of biologic augmentation in the treatment of osteochondral lesions of the talus (OLT). However, a comprehensive evaluation of the clinical outcomes of those treatment modalities in OLT has yet to be published. The purpose of this review is to provide an evidence-based overview of clinical outcomes following biologic augmentation to surgical treatments for OLT. DESIGN: A comprehensive literature review was performed. Two commonly used surgical techniques for the treatment of OLT-bone marrow stimulation and osteochondral autograft transfer-are first introduced. The review describes the operative indications, step-by- step operative procedure, clinical outcomes, and concerns associated with each treatment. A review of the currently published basic science and clinical evidence on biologic augmentation in the surgical treatments for OLT, including platelet-rich plasma, concentrated bone marrow aspirate, and scaffold-based therapy follows. RESULTS: Biologic agents and scaffold-based therapies appear to be promising agents, capable of improving both clinical and radiological outcomes in OLT. Nevertheless, variable production methods of these biologic augmentations confound the interpretation of clinical outcomes of cases treated with these agents. CONCLUSIONS: Current clinical evidence supports the use of biologic agents in OLT cases. Nonetheless, well-designed clinical trials with patient specific, validated and objective outcome measurements are warranted to develop standardized clinical guidelines for the use of biologic augmentation for the treatment of OLT in clinical practice. PMID- 27994721 TI - Particulated Juvenile Articular Cartilage Allograft Transplantation for Osteochondral Talar Lesions. AB - OBJECTIVE: To report on our institution's early results from juvenile particulate cartilage allograft transplantation of the talus. DESIGN: Because of the relative rarity of the procedure at the talus, it was decided to provide a comprehensive understanding of the currently available evidence via a 2-part study with (1) a systematic review of the literature and (2) a retrospective single-center cohort study of the authors' patients, their demographics, and their early outcomes. RESULTS: (1) Four studies were included with 33 ankles with a weighted mean follow-up of 14.3 months. Only 1 ankle (3.3%) was converted to a revision open osteochondral allograft with medial malleolar osteotomy at 16 months postoperative; 6 (18.2%) required nonrevision type reoperations at an average of 15 months postoperative. (2) Six patients with mean age 35.7 +/- 14.4 years were evaluated from the authors' institution at mean 13.04 +/- 8.35 months' follow-up. All reported subjective improvements in pain and motion, and functional improvements, although postoperative magnetic resonance imaging in 3 patients at time points between 3 months and 2 years postoperative demonstrate persistent subchondral edema and nonuniform chondral surface in the talus. There were no intraoperative or postoperative complications, and there have been no reoperations. CONCLUSION: Preliminary data suggest that treatment of large, traumatic or atraumatic, symptomatic osteochondral talar defects with particulated juvenile cartilage transplantation may improve patient subjective complaints of pain and function. Systematic review of the available literature highlights the need for future prospective, larger cohort studies of its use on the talus but suggests similar potential for the technology. PMID- 27994720 TI - Repair Potential of Matrix-Induced Bone Marrow Aspirate Concentrate and Matrix Induced Autologous Chondrocyte Implantation for Talar Osteochondral Repair: Patterns of Some Catabolic, Inflammatory, and Pain Mediators. AB - OBJECTIVE: The low regenerative potential of cartilage contributed to the development of different cell therapies aimed to improve the clinical outcome in young patients with Osteochondral Lesions of the Talus (OLT). This study is designed to assess the regenerative potential of autologous matrix-induced Bone Marrow Aspirate Concentrate (mBMAC) and matrix-induced Autologous Chondrocyte Implantation (mACI) evaluating, on a small number of osteochondral biopsies, the expression of some catabolic, inflammatory, and pain mediators. DESIGN: Twenty two patients with OLT were analyzed in this study; 7 were treated with mACI and 15 with mBMAC. Informed consent was obtained from all the patients. Clinical assessments were performed pre-operatively and at 12, 24, and 36 months after surgery using the American Orthopedic Foot and Ankle Society (AOFAS). Histology and immunohistochemistry were used to assess cartilage repair at 24 months. Data were analyzed using non-parametric Wilcoxon-Mann-Whitney and Spearman tests. RESULTS: A remarkable improvement in AOFAS score was noticed for both treatments up to 36 months; however, patients treated with mACI reported the best AOFAS score. Various degrees of tissue remodeling were observed by histological analysis for both cell strategies. However, mBMAC treatment showed a higher expression of some fibrous and hypertrophic markers compared to mACI group. A mild positivity for nerve growth factor, as pain mediator, was noticed for both treatments.M. CONCLUSIONS: Our findings demonstrated the best histological and clinical results following mACI treatment since different fibrotic and hypertrophic features were evident in the mBMAC group at 24-month follow-up. PMID- 27994722 TI - Immediate Unrestricted Postoperative Weightbearing and Mobilization after Bone Marrow Stimulation of Large Osteochondral Lesions of the Talus. AB - OBJECTIVE: There remains no consensus on a postoperative protocol following arthroscopic treatment of osteochondral lesions of the talus (OLTs) and most studies report a period of immobilization and nonweightbearing. Outcomes are believed to decrease with larger size. The purpose of our study was to evaluate patients who underwent arthroscopic treatment of large (>=150 mm2) OLTs with immediate unrestricted weightbearing and mobilization postoperatively. DESIGN: Patients who underwent arthroscopic bone marrow stimulation for osteochondral defects were identified. Exclusion criteria included lesions less than 150 mm2, additional procedures other than ligament reconstruction, incongruent ankle joint, arthritis, and tibial plafond lesions. Postoperatively, all patients were placed into a soft dressing and were allowed immediate weightbearing as tolerated. Patients were considered failures if their AOFAS (American Orthopaedic Foot and Ankle Society) score was less than 80 or if they underwent osteochondral transplant. RESULTS: Thirteen patients were available for follow-up. Two patients underwent osteochondral transplant and were considered failures. Of the remaining 11, the average follow-up time after surgery was 33 months (range, 7-59 months). Average age was 37 years (range, 15-56 years), and lesion size averaged 239 mm2 (range, 150-400 mm2). Average postoperative scores included foot function index 50 (range, 23-136), visual analog scale 3 (range, 0-8), and AOFAS hindfoot 82 (range, 40-100). The group's overall success rate was 54% (7/13). CONCLUSION: The results of our study are higher than those previously published studies on large lesions with a more restricted postoperative rehabilitation, suggesting that unrestricted weightbearing and range of motion does not diminish patient outcomes. LEVEL OF EVIDENCE: IV, Case series. PMID- 27994724 TI - Communicating Our Science to Our Customers: The Vital Role of Passionate Public Advocacy. AB - As scientists, we are comfortable communicating our work to our peers. However, communicating with equal passion to those outside our field is something we as a community often shy away from. This reticence has often been exploited by those wishing to present their own view of the science we practice. Herein, we urge the scientific community to actively re-engage with the general public, openly and creatively sharing our endeavors beyond these pages, in order to reconnect with the real consumers of the work we produce. PMID- 27994723 TI - Return to Sports After Bone Marrow-Derived Cell Transplantation for Osteochondral Lesions of the Talus. AB - OBJECTIVE: Arthroscopic "one-step" technique based on bone marrow-derived cell transplantation (BMDCT) have achieved good results in repairing osteochondral lesions of the talus (OLT), overcoming important drawbacks of older techniques. It may be particularly adequate for the treatment of athletes in order to permit a safe and stable return to sports. The aim of this study was to report the results at 48 months of a series of athletes and the factors influencing the return to sports. DESIGN: Case series. A total of 140 athletes underwent a "one step" BMDCT repair of OLT. All the patients had the cells harvested from the iliac crest, condensed and loaded on a scaffold, and then implanted. Patients were evaluated clinically by the American Orthopaedic Foot and Ankle Society (AOFAS) scores and Halasi score. RESULTS: AOFAS score improved from 58.7 +/- 13.5 preoperatively to 90.6 +/- 8.6 (P < 0.005) at 24 months, and to 90.9 +/- 10.7 at 48 months. Halasi score was 6.88 +/- 1.8 preinjury, 4.08 +/- 1.7 preoperatively, and 5.56 +/- 2.0 at final follow-up. At the final follow-up, all the patients (beside 1 failure and 3 lost) were able to return to activity and 72.8% were able to resume sports at preinjury level. CONCLUSIONS: "One-step" BMDCT repair of OLT had good clinical results that was durable over time in athletes, permitting a return to sports at preinjury level in the majority of patients. The preoperative presence of impingement and articular degeneration were the main negative prognostic factors. PMID- 27994725 TI - Imidazopyridazine Inhibitors of PI3Kbeta. PMID- 27994726 TI - Quinazoline Carboxamides as Selective Antagonists of Adenosine 2A Receptor. PMID- 27994727 TI - Benzyl-methyl-tetrazole Ligands of Autotaxin for PET Imaging Techniques and Diagnostic. PMID- 27994728 TI - Pyrazole Inhibitors of GluN2B NMDA Receptor Subunit. PMID- 27994729 TI - Macrocyclic Inhibitors of ERK2 Kinase. PMID- 27994730 TI - Pyridyl Isonicotinamide Inhibitors of RAF Kinase. PMID- 27994731 TI - Identification of Triptophenolide from Tripterygium wilfordii as a Pan-antagonist of Androgen Receptor. AB - A compound, triptophenolide, derived from Tripterygium wilfordii was identified as an antiandrogen. Triptophenolide inhibits the activity of both wild-type and F876L mutant androgen receptors. Triptophenolide exhibits its antiandrogenic activity through competitive binding with androgen in the hormone-binding pocket, decreasing the expression of androgen receptor, and reducing the nuclear translocation of androgen receptor. PMID- 27994732 TI - Development of N-(4-Phenoxyphenyl)benzenesulfonamide Derivatives as Novel Nonsteroidal Progesterone Receptor Antagonists. AB - We report here development of N-(4-phenoxyphenyl)benzenesulfonamide derivatives as a novel class of nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are candidates for clinical treatment of multiple diseases, including uterine leiomyoma, endometriosis, breast cancer, and some psychiatric disorders. We found that the benzenesulfonanilide skeleton functions as a novel scaffold for PR antagonists, and we adopted 3-chlorobenzenesulfonyl derivative 20a as a lead compound for structural development. Among the synthesized compounds, 3-trifluoromethyl derivative 32 exhibited the most potent PR-antagonistic activity, with high binding affinity for PR and selectivity over androgen receptor (AR). It is structurally distinct from other nonsteroidal PR antagonists, including cyanopyrrole derivatives, and further modification is expected to afford novel selective PR modulators. PMID- 27994733 TI - Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950. AB - MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite. Further synthesis of individual enantiomers and coelution studies using a chiral column in HPLC-MS/MS showed the metabolite was R-(+)- N-((1 hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2 yl)furan-2-sulfonamide (2a). Incubation of MCC950 with a panel of cytochrome P450 enzymes showed P450s 2A6, 2C9, 2C18, 2C19, 2J2, and 3A4 catalyze the formation of the major metabolite 2a, with a lower level of activity shown by P450s 1A2 and 2B6. All of the synthesized compounds were tested for inhibition of NLRP3-induced production of the pro-inflammatory cytokine IL-1beta from human monocyte derived macrophages. The identified metabolite 2a was 170-fold less potent than MCC950, while one regioisomer had nanomolar inhibitory activity. These findings also give first insight into the SAR of the hexahydroindacene moiety. PMID- 27994734 TI - New Peptidomimetic Boronates for Selective Inhibition of the Chymotrypsin-like Activity of the 26S Proteasome. AB - Proteasome is a large proteinase complex that degrades proteins via its three catalytic activities. Among these activities, the "chymotrypsin-like" activity has emerged as the focus of drug discovery in cancer therapy. Here, we report new peptidomimetic boronates that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new specific proteasome inhibitors were demonstrated to have higher in vitro potency and selective cytotoxicity for cancer cells compared to benchmark proteasome inhibitors: bortezomib and carfilzomib. In breast cancer cell lines, treatment with 1a or 2a induced accumulation of the high molecular weight polyubiqutinated proteins at similar levels observed for bortezomib and carfilzomib, indicating that cancer cell death caused by 1a/2a is chiefly due to proteasome inhibition. PMID- 27994735 TI - Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors. AB - Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue 3 complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound 16 (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study. PMID- 27994736 TI - Discovery of Novel Bruton's Tyrosine Kinase (BTK) Inhibitors Bearing a N,9 Diphenyl-9H-purin-2-amine Scaffold. AB - Based on the pyrimidine skeleton of EGFRT790M inhibitors, a series of N,9 diphenyl-9H-purin-2-amine derivatives were identified as effective BTK inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC50 values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of BTK with concentrations of 7.75 and 12.6 MUM. The activity of the subject compound as determined by the CCK-8 method and apoptosis analysis validated that inhibitor 10j is slightly more potent than AVL-292 and ibrutinib. The results of these experimental explorations suggested that 10j could serve as a valuable molecule for control of leukemia pending further developments. PMID- 27994737 TI - Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIalpha-Inhibiting Anticancer Agents. AB - Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIalpha (hTopoIIalpha)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2-aminopyridine with 2,3-epoxyesters toward synthesis of 2 arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIalpha selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIalpha inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research. PMID- 27994739 TI - New Series of BPL Inhibitors To Probe the Ribose-Binding Pocket of Staphylococcus aureus Biotin Protein Ligase. AB - Replacing the labile adenosinyl-substituted phosphoanhydride of biotinyl-5'-AMP with a N1-benzyl substituted 1,2,3-triazole gave a new truncated series of inhibitors of Staphylococcus aureus biotin protein ligase (SaBPL). The benzyl group presents to the ribose-binding pocket of SaBPL based on in silico docking. Halogenated benzyl derivatives (12t, 12u, 12w, and 12x) proved to be the most potent inhibitors of SaBPL. These derivatives inhibited the growth of S. aureus ATCC49775 and displayed low cytotoxicity against HepG2 cells. PMID- 27994740 TI - Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain. AB - Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with Ki values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors. PMID- 27994738 TI - Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement. AB - Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine induced scratching bouts in a mouse behavioral model following oral dosing. PMID- 27994741 TI - Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors. AB - Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7 chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency. PMID- 27994742 TI - Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators. AB - The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory. PMID- 27994743 TI - On-Demand Drug Delivery System Using Micro-organogels with Gold Nanorods. AB - In this study, we designed a biocompatible drug carrier: micro-organogels prepared by emulsification using vegetable oils and self-assembled gelator fibers. Flurbiprofen was chosen as a hydrophobic model drug and is classified as a nonsteroidal anti-inflammatory drug. In the absence of NIR light, flurbiprofen encapsulated in micro-organogels with gold nanorods (GNRs) was released slowly, while release was accelerated in the presence of NIR light due to the increase in the temperature surrounding the GNRs that transforms the gels into liquid. These results suggest that our system can be efficiently used as a versatile scaffold for on-demand drug delivery systems. PMID- 27994744 TI - Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors. AB - Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contributions of the amide group to the binding affinities of these inhibitors. Cell-based hemolysis assay confirmed these compounds inhibit factor D mediated complement activation via the alternative pathway. Our study highlights the important interactions contributing to the high potency of factor D inhibitors reported recently. PMID- 27994745 TI - Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore. AB - Benzoxaboroles are a class of five-membered hemiboronic acids that recently attracted significant attention as a new pharmacophore on account of their unique structural and physicochemical properties and their ability to interact selectively with biomolecules. Their structural behavior in water and its effect on their physiological properties remain unclear, especially the question of dynamic hydrolytic equilibrium of the oxaborole ring. Herein, we used NMR spectroscopy, in mixed aqueous-organic solvent, to confirm the strong preference for the closed form of benzoxaborole and its six- and seven-membered homologues over the open boronic acid form. Only with the eight-membered homologue does the cyclic form become unfavorable. Using dynamic VT-NMR studies with designed probe compound 20, we demonstrate that the oxaborole ring undergoes rapid hydrolytic ring closing-opening at ambient temperature at a rate of >100 Hz via a mechanism featuring rate-limiting proton-transfer steps. This knowledge can help provide a better understanding of the behavior of benzoxaboroles in biological systems. PMID- 27994746 TI - Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8. AB - SETD8 is a histone H4-K20 methyltransferase that plays an essential role in the maintenance of genomic integrity during mitosis and in DNA damage repair, making it an intriguing target for cancer research. While some small molecule inhibitors for SETD8 have been reported, the structural binding modes for these inhibitors have not been revealed. Using the complex structure of the substrate peptide bound to SETD8 as a starting point, different natural and unnatural amino acid substitutions were tested, and a potent (Ki 50 nM, IC50 0.33 MUM) and selective norleucine containing peptide inhibitor has been obtained. PMID- 27994748 TI - Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia. AB - Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions. PMID- 27994747 TI - Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes. AB - GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes. PMID- 27994749 TI - Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors. AB - Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology. PMID- 27994750 TI - Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design. AB - Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 < 10 MUM and >2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach. PMID- 27994751 TI - Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents. AB - A series of imidazo[1,2-a]pyridine carboxamides (IPAs) bearing an N-(2 phenoxyethyl) moiety was designed and synthesized as new antitubercular agents. Seven 2,6-dimethyl IPAs demonstrated excellent in vitro activity (MIC: 0.025 0.054 MUg/mL) against the drug susceptive H37Rv strain and two clinically isolated multidrug-resistant Mycobacterium tuberculosisstrains. Compound 10j displayed acceptable safety and pharmacokinetic properties, opening a new direction for further development. PMID- 27994752 TI - Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist. AB - GPR40/FFAR1 is a G protein-coupled receptor predominantly expressed in pancreatic beta-cells and activated by long-chain free fatty acids, mediating enhancement of glucose-stimulated insulin secretion. A novel series of substituted 3-(4 aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound 5, which is highly potent in in vitro assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity. PMID- 27994754 TI - Polyamine Conjugation as a Promising Strategy To Target Amyloid Aggregation in the Framework of Alzheimer's Disease. AB - Spermine conjugates 2-6, carrying variously decorated 3,5-dibenzylidenepiperidin 4-one as bioactive motives, were designed to direct antiaggregating properties into mitochondria, using a polyamine functionality as the vehicle tool. The study confirmed mitochondrial import of the catechol derivative 2, which displayed effective antiaggregating activity and neuroprotective effects against Abeta induced toxicity. Notably, a key functional role for the polyamine motif in Abeta molecular recognition was also unraveled. This experimental readout, which was supported by in silico studies, gives important new insight into the polyamine's action. Hence, we propose polyamine conjugation as a promising strategy for the development of neuroprotectant leads that may contribute to decipher the complex picture of Abeta toxicity. PMID- 27994753 TI - Discovery and Characterization of a Peptoid with Antifungal Activity against Cryptococcus neoformans. AB - Studies show there is an increasing rate of fungal infections, especially in immunocompromised patients and treatments for fungal genera, such as Aspergillus, Candida, and Cryptococcus, carry significant cytotoxicity with an increasing prevalence of antifungal resistance. We have previously reported a high throughput assay for identifying peptoids with antimicrobial properties from combinatorial libraries. Here we report the application of this assay in identifying a peptoid with antifungal properties against Cryptococcus neoformans. Termed AEC5, this peptoid has comparable potency to existing clinical antifungal agents, excellent stability, and minimal cytotoxicity in mammalian cells. PMID- 27994755 TI - Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization. AB - Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain. PMID- 27994756 TI - Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents. AB - Catechol diethers that incorporate a 7-cyano-2-naphthyl substituent are reported as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Many of the compounds have 1-10 nM potencies toward wild-type HIV-1. An interesting conformational effect allows two unique conformers for the naphthyl group in complexes with HIV-RT. X-ray crystal structures for 4a and 4f illustrate the alternatives. PMID- 27994758 TI - Fused Heterocyclic Compounds as Potent Indoleamine-2,3-dioxygenase 1 Inhibitors. AB - Uncontrolled metabolism of l-tryptophan (l-Trp) in the immune system has been recognized as a critical cellular process in immune tolerance. Indoleamine 2,3 dioxygenase 1 (IDO1) enzyme plays an important role in the metabolism of a local l-Trp through the kynurenine pathway in the immune systems. In this regard, IDO1 has emerged as a therapeutic target for the treatment of diseases that are associated with immune suppression like chronic infections, cancer, and others. In this study, we synthesized a series of pyridopyrimidine, pyrazolopyranopyrimidine, and dipyrazolopyran derivatives. Further lead optimizations directed to the identification of potent compounds, 4j and 4l (IC50 = 260 and 151 nM, respectively). These compounds also exhibited IDO1 inhibitory activities in the low nanomolar range in MDA-MB-231 cells with very low cytotoxicity. Stronger selectivity for the IDO1 enzyme (>300-fold) over tryptophan 2,3-dioxygenase (TDO) enzyme was also observed for these compounds. Hence, these fused heterocyclic compounds are attractive candidates for the advanced study of IDO1-dependent cellular function and immunotherapeutic applications. PMID- 27994757 TI - Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kdelta. AB - The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kdelta are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kdelta as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases. PMID- 27994759 TI - Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors. AB - A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values <=10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well. PMID- 27994760 TI - PAR2 Modulators Derived from GB88. AB - PAR2 antagonists have potential for treating inflammatory, respiratory, gastrointestinal, neurological, and metabolic disorders, but few antagonists are known. Derivatives of GB88 (3) suggest that all four of its components bind at distinct PAR2 sites with the isoxazole, cyclohexylalanine, and isoleucine determining affinity and selectivity, while the C-terminal substituent determines agonist/antagonist function. Here we report structurally similar PAR2 ligands with opposing functions (agonist vs antagonist) upon binding to PAR2. A biased ligand AY117 (65) was found to antagonize calcium release induced by PAR2 agonists trypsin and hexapeptide 2f-LIGRLO-NH2 (IC50 2.2 and 0.7 MUM, HT29 cells), but it was a selective PAR2 agonist in inhibiting cAMP stimulation and activating ERK1/2 phosphorylation. It showed anti-inflammatory properties both in vitro and in vivo. PMID- 27994761 TI - Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins. AB - A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins. PMID- 27994762 TI - Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents. AB - Series of N-substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents from a molecular hybridization approach. The representative compound 19 showed an MIC = 1 MUg/mL against a panel of MRSA clinical isolates as it possessed comparable in vitro activities to that of vancomycin. Moreover, compound 19 also exhibited MIC = 1 MUg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant Enterococcus faecalis (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound 19 was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new N substituted carbazoles as potential anti-MRSA agents. PMID- 27994763 TI - Discovery of 2'-alpha-C-Methyl-2'-beta-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus. AB - 2'-alpha-C-Methyl-2'-beta-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 +/- 0.19, 0.88 +/- 0.12, and 2.24 +/- 0.22 MUM, respectively. The docking study revealed that the recognition of the 2'-beta-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain. PMID- 27994764 TI - Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3-b] Pyridazines as Antitubulin Agents. AB - A series of 3,6-diaryl-[1,2,4]triazolo[4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo[4,3-b]pyridazine scaffold. Twenty-one target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound 4q with a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC50 = 0.009-0.012 MUM), displayed the highly active antiproliferative activity against SGC-7901, A549, and HT-1080 cell lines with IC50 values of 0.014, 0.008, and 0.012 MUM, respectively. Tubulin polymerization experiments indicated that 4q effectively inhibited tubulin polymerization, and immunostaining assay revealed that 4q significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound 4q dramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that 4q could bind to the colchicine binding site on microtubules. PMID- 27994766 TI - Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening. AB - The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains. High-resolution crystal structures of the complexes of key fragments binding to BRD4(1), CREBBP, and PCAF were determined to provide binding mode data to aid the development of potent and selective inhibitors of PCAF, CREBBP, and BRD4. PMID- 27994765 TI - Discovery of Highly Potent Liver X Receptor beta Agonists. AB - Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRbeta activity (>70%) with low partial LXRalpha agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human alpha-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile. PMID- 27994767 TI - Discovery and Optimization of Two Eis Inhibitor Families as Kanamycin Adjuvants against Drug-Resistant M. tuberculosis. AB - Drug-resistant tuberculosis (TB) is a global threat and innovative approaches such as using adjuvants of anti-TB therapeutics are required to combat it. High throughput screening yielded two lead scaffolds of inhibitors of Mycobacterium tuberculosis (Mtb) acetyltransferase Eis, whose upregulation causes resistance to the anti-TB drug kanamycin (KAN). Chemical optimization on these scaffolds resulted in potent Eis inhibitors. One compound restored the activity of KAN in a KAN-resistant Mtb strain. Model structures of Eis-inhibitor complexes explain the structure-activity relationship. PMID- 27994768 TI - Hypertension and Angiotensin System Inhibitors in Patients with Metastatic Renal Cell Carcinoma. AB - Arterial hypertension (HTN) is a class effect of anti-vascular endothelial growth factor (VEGF) therapies, including the monoclonal antibody bevacizumab. Data are conflicting regarding the role of the renin-angiotensin system on angiogenesis and recent data suggest that the use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) is associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with VEGF targeted therapies. The aim of this review is to discuss the available treatment options for mRCC and associated incidence of hypertension as well as summarize the known data about ASIs use and mRCC. Additionally, given that the optimal management of HTN remains unclear, we will focus on prevention strategies and propose potential therapeutic approaches. PMID- 27994769 TI - Targeting Hepatocellular Carcinoma: What did we Discover so Far? AB - Hepatocellular carcinoma (HCC) is increasingly considered an issue of global importance. Its rates of incidence and mortality have been markedly increasing over the last decades. Among risk factors, some should be highlighted, namely the infections by hepatitis B and C virus, as well as clinical cases of cirrhosis. HCC is characterized as asymptomatic disease in the initial stages which most often leads to a late diagnosis. At molecular and genetic level HCC represents a highly complex tumor entity, including a wide variety of mutations, thus accounting for different mechanisms of resistance towards therapeutic approaches. In particular, mutations of the TP53 gene, as well as a deregulation between the expression of pro- and anti-apoptotic proteins of the BCL-2 family are observed. Regarding treatment modalities, surgical procedures offer the best chance of cure, however, due to a late diagnosis, most of concerned patients cannot be subjected to them. Chemotherapy and radiotherapy are also ineffective, and currently, the treatment with sorafenib is the most commonly used systemic therapy although it can only increase the patient survival for some months. In this sense, a quick and accurate investigation is of utmost importance in order to develop ways of early diagnosis as well as new therapies for HCC. PMID- 27994770 TI - Bone Marrow Blood Vessels: Normal and Neoplastic Niche. AB - Blood vessels are among the most important factors in the transport of materials such as nutrients and oxygen. This study will review the role of blood vessels in normal bone marrow hematopoiesis as well as pathological conditions like leukemia and metastasis. Relevant literature was identified by a Pubmed search (1992-2016) of English-language papers using the terms bone marrow, leukemia, metastasis, and vessel. Given that blood vessels are conduits for the transfer of nutrients, they create a favorable situation for cancer cells and cause their growth and development. On the other hand, blood vessels protect leukemia cells against chemotherapy drugs. Finally, it may be concluded that the vessels are an important factor in the development of malignant diseases. PMID- 27994771 TI - A Novel Role of Lamins from Genetic Disease to Cancer Biomarkers. AB - Lamins are the key components of the nuclear lamina and by virtue of their interactions with chromatin and binding partners act as regulators of cell proliferation and differentiation. Of late, the diverse roles of lamins in cellular processes have made them the topic of intense debate for their role in cancer progression. The observations about aberrant localization or misexpression of the nuclear lamins in cancerous tissues have often led to the speculative role of lamins as a cancer risk biomarker. Here we discuss the involvement of lamins in several cancer subtypes and their potential role in predicting the tumor progression. PMID- 27994772 TI - Effect of RNA Interference-Mediated Suppression of p75 on the Viability of Rat Notochordal Cells. AB - STUDY DESIGN: In vitro cell culture model. PURPOSE: To investigate the effects of RNA interference (RNAi) on p75 expression and viability of rat notochordal cells treated with serum deprivation. OVERVIEW OF LITERATURE: RNAi enables the inhibition of specific genes by sequence-specific gene silencing using a double stranded RNA. METHODS: Notochordal cells were isolated, cultured, and placed in 10% (control) or 0% (apoptosis-promoting) fetal bovine serum (FBS) for 48 hours. The expression of p75, apoptosis, and cell proliferation were determined. To suppress p75 expression, a small interfering RNA (siRNA) was synthesized against p75 (p75 siRNA) and transfected into cells. The suppression of p75 mRNA expression was investigated using the reverse transcription-polymerase chain reaction. The degree of p75 suppression was semiquantitatively analyzed using densitometry. The effect of p75 siRNA on apoptosis and proliferation of cells was determined. Solutions of an unrelated siRNA and transfection agent alone served as controls. RESULTS: Serum deprivation significantly increased apoptosis by 40.3%, decreased proliferation of notochordal cells by 45.3% (both, p<0.001), and upregulated p75 expression. The p75 siRNA suppressed p75 expression in cells cultured in 0% FBS. The rate of suppression by p75 siRNA of p75 mRNA was 72.9% (p<0.001). Suppression of p75 expression by p75 siRNA inhibited apoptosis by 7% and increased proliferation by 14% in cells cultured in 0% FBS (both, p<0.05). CONCLUSIONS: siRNA-mediated suppression of p75 inhibited apoptosis and increased proliferation of notochordal cells under conditions of serum deprivation, suggesting that RNAi might serve as a novel therapeutic approach for disc degeneration caused by insufficient viability of disc cells through the suppression of the expression of harmful genes. PMID- 27994773 TI - Biomechanical Analysis of a Pedicle Screw-Rod System with a Novel Cross-Link Configuration. AB - STUDY DESIGN: The strength effects of a pedicle screw-rod system supplemented with a novel cross-link configuration were biomechanically evaluated in porcine spines. PURPOSE: To assess the biomechanical differences between a conventional cross-link pedicle screw-rod system versus a novel cross-link instrumentation, and to determine the effect of the cross-links. OVERVIEW OF LITERATURE: Transverse cross-link systems affect torsional rigidity, but are thought to have little impact on the sagittal motion of spinal constructs. We tested the strength effects in pullout and flexion-compression tests of novel cross-link pedicle screw constructs using porcine thoracic and lumbar vertebrae. METHODS: Five matched thoracic and lumbar vertebral segments from 15 porcine spines were instrumented with 5.0-mm pedicle screws, which were then connected with 6.0-mm rods after partial corpectomy in the middle vertebral body. The forces required for construct failure in pullout and flexion-compression tests were examined in a randomized manner for three different cross-link configurations: un-cross-link control, conventional cross-link, and cross-link passing through the base of the spinous process. Statistical comparisons of strength data were analyzed using Student's t-tests. RESULTS: The spinous process group required a significantly greater pullout force for construct failure than the control group (p=0.036). No difference was found between the control and cross-link groups, or the cross-link and spinous process groups in pullout testing. In flexion-compression testing, the spinous processes group required significantly greater forces for construct failure than the control and cross-link groups (p<0.001 and p=0.003, respectively). However, there was no difference between the control and cross link groups. CONCLUSIONS: A novel cross-link configuration that features cross link devices passing through the base of the spinous processes increased the mechanical resistance in pullout and flexion-compression testing compared to un cross-link constructs. This configuration provided more resistance to middle column damage under flexion-compression testing than conventional cross-link configuration. PMID- 27994774 TI - Does Minimally Invasive Spine Surgery Minimize Surgical Site Infections? AB - STUDY DESIGN: Retrospective review of prospectively collected data. PURPOSE: To evaluate the incidence of surgical site infections (SSIs) in minimally invasive spine surgery (MISS) in a cohort of patients and compare with available historical data on SSI in open spinal surgery cohorts, and to evaluate additional direct costs incurred due to SSI. OVERVIEW OF LITERATURE: SSI can lead to prolonged antibiotic therapy, extended hospitalization, repeated operations, and implant removal. Small incisions and minimal dissection intrinsic to MISS may minimize the risk of postoperative infections. However, there is a dearth of literature on infections after MISS and their additional direct financial implications. METHODS: All patients from January 2007 to January 2015 undergoing posterior spinal surgery with tubular retractor system and microscope in our institution were included. The procedures performed included tubular discectomies, tubular decompressions for spinal stenosis and minimal invasive transforaminal lumbar interbody fusion (TLIF). The incidence of postoperative SSI was calculated and compared to the range of cited SSI rates from published studies. Direct costs were calculated from medical billing for index cases and for patients with SSI. RESULTS: A total of 1,043 patients underwent 763 noninstrumented surgeries (discectomies, decompressions) and 280 instrumented (TLIF) procedures. The mean age was 52.2 years with male:female ratio of 1.08:1. Three infections were encountered with fusion surgeries (mean detection time, 7 days). All three required wound wash and debridement with one patient requiring unilateral implant removal. Additional direct cost due to infection was $2,678 per 100 MISS-TLIF. SSI increased hospital expenditure per patient 1.5-fold after instrumented MISS. CONCLUSIONS: Overall infection rate after MISS was 0.29%, with SSI rate of 0% in non-instrumented MISS and 1.07% with instrumented MISS. MISS can markedly reduce the SSI rate and can be an effective tool to minimize hospital costs. PMID- 27994775 TI - Addressing Stretch Myelopathy in Multilevel Cervical Kyphosis with Posterior Surgery Using Cervical Pedicle Screws. AB - STUDY DESIGN: Technique description and retrospective data analysis. PURPOSE: To describe the technique of cervical kyphosis correction with partial facetectomies and evaluate the outcome of single-stage posterior decompression and kyphosis correction in multilevel cervical myelopathy. OVERVIEW OF LITERATURE: Kyphosis correction in multilevel cervical myelopathy involves anterior and posterior surgery. With the advent of cervical pedicle screw-rod instrumentation, single stage posterior kyphosis correction is feasible and can address stretch myelopathy by posterior shortening. METHODS: Nine patients underwent single-stage posterior decompression and kyphosis correction for multilevel cervical myelopathy using cervical pedicle screw instrumentation from March 2011 to February 2014 and were evaluated preoperatively and postoperatively with modified Japanese Orthopaedic Association (mJOA) scoring and computed tomography scans for radiological measurements. Kyphosis assessment was made with Ishihara curvature index and C2-C7 Cobb's angle. The linear length of the spinal canal and the actual spinal canal length were also evaluated. The average follow-up was 40.56 months (range, 20 to 53 months). RESULTS: The average preoperative C2-7 Cobb's angle of 6.3 degrees (1 degrees to 12 degrees ) improved to 2 degrees (10 degrees to -9 degrees ). Ishihara index improved from -15.8% (-30.5% to -4.7%) to -3.66% (-14.5% to +12.6%). The actual spinal canal length decreased from 83.64 mm (range, 76.8 to 91.82 mm) to 82.68 mm (range, 75.85 to 90.78 mm). The preoperative mJOA score of 7.8 (range, 3 to 11) improved to 15.0 (range, 13 to 17). CONCLUSIONS: Single-stage posterior decompression and kyphosis correction using cervical pedicle screws for multilevel cervical myelopathy may address stretch myelopathy, in addition to decompression in the transverse plane. However, cervical lordosis was not achieved with this method as predictably as by the anterior approach. The present study shows evidence of mild shortening of cervical spinal canal and a positive correlation between canal shortening and clinical improvement. PMID- 27994776 TI - Antimicrobial Prophylaxis in Instrumented Spinal Fusion Surgery: A Comparative Analysis of 24-Hour and 72-Hour Dosages. AB - STUDY DESIGN: Prospective study. PURPOSE: To compare the efficacy of 24-hour and 72-hour antibiotic prophylaxis in preventing surgical site infections (SSIs). OVERVIEW OF LITERATURE: Antimicrobial prophylaxis in surgical practice has become a universally accepted protocol for minimizing postoperative complications related to infections. Although prophylaxis is an accepted practice, a debate exists with regard to the antibiotic type and its administration duration for various surgical procedures. METHODS: Our institute is a tertiary care hospital with more than 100 spinal surgeries per year for various spine disorders in the department of orthopedics. We conducted this prospective study in our department from June 2012 to January 2015. A total of 326 patients were enrolled in this study, with 156 patients in the 72-hour antibiotic prophylaxis group (group A) and 170 patients in the 24-hour group (group B). Cefazolin was the antibiotic used in both groups. Two surgeons were involved in conducting all the spinal procedures. Our study compared SSIs among patients undergoing instrumented spinal fusion. RESULTS: The overall rate of SSIs was 1.8% with no statistical difference between the two groups. CONCLUSIONS: The 24-hour antimicrobial prophylaxis is as effective as the 72-hour dosage in instrumented spinal fusion surgery. PMID- 27994777 TI - Mini-Open Anterior Lumbar Interbody Fusion Combined with Lateral Lumbar Interbody Fusion in Corrective Surgery for Adult Spinal Deformity. AB - STUDY DESIGN: Prospective observational study. PURPOSE: To introduce the techniques and present the surgical outcomes of mini-open anterior lumbar interbody fusion (ALIF) at the most caudal segments of the spine combined with lateral lumbar interbody fusion (LLIF) for the correction of adult spinal deformity. OVERVIEW OF LITERATURE: Although LLIF is increasingly used to correct adult spinal deformity, the correction of sagittal plane deformity with LLIF alone is reportedly suboptimal. METHODS: Thirty-two consecutive patients with adult spinal deformity underwent LLIF combined with mini-open ALIF at the L5-S1 or L4-S1 levels followed by 2-stage posterior fixation. ALIF was performed for a mean 1.3 levels and LLIF for a mean 2.7 levels. Then, percutaneous fixation was performed in 11 patients (percutaneous group), open correction with facetectomy with or without laminectomy in 16 (open group), and additional pedicle subtraction osteotomy (PSO) in 5 (PSO group). Spinopelvic parameters were compared preoperatively and postoperatively. Hospitalization data and clinical outcomes were recorded. RESULTS: No major medical complications developed, and clinical outcomes improved postoperatively in all groups. The mean postoperative segmental lordosis was greater after ALIF (17.5 degrees +/-5.5 degrees ) than after LLIF (8.1 degrees +/-5.3 degrees , p <0.001). Four patients (12.5%) had lumbar lordosis with a pelvic incidence of +/-9 degrees preoperatively, whereas this outcome was achieved postoperatively in 30 patients (93.8%). The total increase in lumbar lordosis was 14.7 degrees in the percutaneous group, 35.3 degrees in the open group, and 57.0 degrees in the PSO group. The ranges of potential lumbar lordosis increase were estimated as 4 degrees -25 degrees , 23 degrees -42 degrees , and 45 degrees -65 degrees , respectively. CONCLUSIONS: Mini-open ALIF combined with LLIF followed by posterior fixation may be a feasible technique for achieving optimal sagittal balance and reducing the necessity of more extensive surgery. PMID- 27994778 TI - Intrinsic Vertebral Markers for Spinal Level Localization in Anterior Cervical Spine Surgery: A Preliminary Report. AB - STUDY DESIGN: Prospective clinical study. PURPOSE: To observe the usefulness of anterior cervical osteophytes as intrinsic markers for spinal level localization (SLL) during sub-axial cervical spinal surgery via the anterior approach. OVERVIEW OF LITERATURE: Various landmarks, such as the mandibular angle, hyoid bone, thyroid cartilage, first cricoid ring, and C6 carotid tubercle, are used for gross cervical SLL; however, none are used during cervical spinal surgery via the anterior approach. We present our preliminary assessment of SLL over anterior vertebral surfaces (i.e., intrinsic markers) in 48 consecutive cases of anterior cervical spinal surgeries for the disc-osteophyte complex (DOC) in degenerative diseases and granulation or tumor tissue associated with infectious or neoplastic diseases, respectively, at an ill-equipped center. METHODS: This prospective study on patients undergoing anterior cervical surgery for various sub-axial cervical spinal pathologies aimed to evaluate the feasibility and accuracy of SLL via intraoperative palpation of disease-related morphological changes on anterior vertebral surfaces visible on preoperative midline sagittal T1/2-weighted magnetic resonance images. RESULTS: During a 3-year period, 48 patients (38 males,10 females; average age, 43.58 years) who underwent surgery via the anterior approach for various sub-axial cervical spinal pathologies, including degenerative disease (n= 42), tubercular infection (Pott's disease; n=3), traumatic prolapsed disc (n=2), and a metastatic lesion from thyroid carcinoma (n=1), comprised the study group. Intrinsic marker palpation yielded accurate SLL in 79% of patients (n=38). Among those with degenerative diseases (n=42), intrinsic marker palpation yielded accurate SLL in 76% of patients (n=32). CONCLUSIONS: Intrinsic marker palpation is an attractive potential adjunct for SLL during cervical spinal surgeries via the anterior approach in well-selected patients at ill-equipped centers (e.g., those found in developing countries). This technique may prove helpful when radiographic visualization is occasionally inadequate. PMID- 27994779 TI - Lymphopenia at 4 Days Postoperatively Is the Most Significant Laboratory Marker for Early Detection of Surgical Site Infection Following Posterior Lumbar Instrumentation Surgery. AB - STUDY DESIGN: Case control study. PURPOSE: To identify the most significant laboratory marker for early detection of surgical site infection (SSI) using multiple logistic regression analysis. OVERVIEW OF LITERATURE: SSI is a serious complication of spinal instrumentation surgery. Early diagnosis and treatment are crucial. METHODS: We retrospectively reviewed the laboratory data of patients who underwent posterior lumbar instrumentation surgery for degenerative spinal disease from January 2003 to December 2014. Six laboratory markers for early SSI detection were considered: renewed elevation of the white blood cell count, higher at 7 than 4 days postoperatively; renewed elevation of the C-reactive protein (CRP) level, higher at 7 than 4 days postoperatively; CRP level of >10 mg/dL at 4 days postoperatively; neutrophil percentage of >75% at 4 days postoperatively; lymphocyte percentage of <10% at 4 days postoperatively; and lymphocyte count of <1,000/uL at 4 days postoperatively. RESULTS: Ninety patients were enrolled; five developed deep SSI. Multivariate regression analysis showed that a lymphocyte count of <1,000/uL at 4 days postoperatively was the sole significant independent laboratory marker for early detection of SSI (p=0.037; odds ratio, 11.9; 95% confidence interval, 1.2-122.7). CONCLUSIONS: A lymphocyte count of <1,000/uL at 4 days postoperatively is the most significant laboratory marker for early detection of SSI. PMID- 27994780 TI - Single Posterior Approach for En-Bloc Resection and Stabilization for Locally Advanced Pancoast Tumors Involving the Spine: Single Centre Experience. AB - STUDY DESIGN: Monocentric prospective study. PURPOSE: To assess the safety and effectiveness of the posterior approach for resection of advanced Pancoast tumors. OVERVIEW OF LITERATURE: In patients with advanced Pancoast tumors invading the spine, most surgical teams consider the combined approach to be necessary for "en-bloc" resection to control visceral, vascular, and neurological structures. We report our preliminary experience with a single-stage posterior approach. METHODS: We included all patients who underwent posterior en-bloc resection of advanced Pancoast tumors invading the spine in our institution between January 2014 and May 2015. All patients had locally advanced tumors without N2 nodes or distant metastases. All patients, except 1, benefited from induction treatment consisting of a combination of concomitant chemotherapy (cisplatin-VP16) and radiation. RESULTS: Five patients were included in this study. There were 2 men and 3 women with a mean age of 55 years (range, 46-61 years). The tumor involved 2 adjacent levels in 1 patient, 3 levels in 1 patient, and 4 levels in 3 patients. There were no intraoperative complications. The mean operative time was 9 hours (range, 8-12 hours), and the mean estimated blood loss was 3.2 L (range, 1.5-7 L). No patient had a worsened neurological condition at discharge. Four complications occurred in 4 patients. Three complications required reoperation and none was lethal. The mean follow-up was 15.5 months (range, 9-24 months). Four patients harbored microscopically negative margins (R0 resection) and remained disease free. One patient harbored a microscopically positive margin (R1 resection) and exhibited local recurrence at 8 months following radiation treatment. CONCLUSIONS: The posterior approach was a valuable option that avoided the need for a second-stage operation. Induction chemoradiation is highly suitable for limiting the risk of local recurrence. PMID- 27994781 TI - Traumatic Cervical Spondyloptosis of the Subaxial Cervical Spine: A Case Series with a Literature Review and a New Classification. AB - STUDY DESIGN: This is a retrospective study on patients with traumatic subaxial cervical spondyloptosis and includes a review of the available literature regarding the management of this injury. PURPOSE: This study aimed to assess the biomechanics and varied clinical presentations of this rare but devastating injury. OVERVIEW OF LITERATURE: This is a case series of three patients and a review of the available literature on subaxial cervical spondyloptosis. Traumatic cervical spondyloptosis of the subaxial spine is rare, with varied clinical presentations. METHODS: The management of cervical subaxial spondyloptosis represents a challenge to all spine care specialists, and there is a paucity of literature on the best methods for managing this condition. Our experience includes three such patients who visited our tertiary trauma center. This article explains the diverse clinical features of the injury as well as the management of these patients and includes a review of the available literature. RESULTS: Subaxial cervical spondyloptosis is a devastating injury with diverse clinical features. We present a classification of these fractures based on clinical presentation and magnetic resonance imaging results, which can help in decision making regarding the management of such patients. CONCLUSIONS: This article may help physicians assess this injury in an evidence-based manner and also elucidates the management strategies available for such patients. PMID- 27994782 TI - Non-Caseating Granulomatous Infective Spondylitis: Melioidotic Spondylitis. AB - STUDY DESIGN: Retrospective clinical analysis. PURPOSE: To delineate the clinical presentation of melioidosis in the spine and to create awareness among healthcare professionals, particularly spine surgeons, regarding the diagnosis and treatment of melioidotic spondylitis. OVERVIEW OF LITERATURE: Melioidosis is an emerging disease, particularly in developing countries, associated with a high mortality rate. Its causative pathogen, Burkholderia pseudomallei, has been labeled as a bio-terrorism agent. METHODS: We performed a retrospective analysis of patients who were culture positive for B. pseudomallei. Assessment of patients was performed using clinical, radiological, and blood parameters. Clinical measures included pain, neurological deficit, and return to work. Radiological measures included plain radiography of the spine and magnetic resonance imaging. Blood tests included erythrocyte sedimentation rate and C-reactive protein levels. RESULTS: Four patients having melioidosis with spondylitis were evaluated. All of them had diabetes mellitus; three had multiple abscesses which required incision and drainage. Their clinical spectrum was similar to that of tuberculous spondylitis; all had back pain and radiology revealed infective spondylodiscitis with prevertebral and paravertebral collections with psoas abscess. Three patients underwent ultrasound-guided drainage of the psoas abscess and one had aspiration of the subcutaneous abscess. Bacteriological cultures showed presence of B. pseudomallei, and histopathology showed non-caseating granulomatous inflammation. All patients were treated with intravenous Ceftazidime for 2 weeks, followed by oral bactrim double strength and Doxycycline for 20 weeks. All patients improved with treatment and were healed at follow up. CONCLUSIONS: Melioidosis presents with a clinical spectrum similar to that of tuberculosis. A diagnosis of melioidotic spondylitis should be considered, particularly in patients with diabetes with neutrophilic leukocytosis and clinical-radiological features suggestive of infective spondylodiscitis. Bacteriological culture and histopathology helps in differentiating the two conditions. Health education for healthcare professionals is important for correctly diagnosing this disease. PMID- 27994783 TI - Closed Drainage versus Non-Drainage for Single-Level Lumbar Disc Surgery: Relationship between Epidural Hematoma and Fibrosis. AB - STUDY DESIGN: A prospective clinical series with prospectively collected data. PURPOSE: The efficacy of using closed suction drains (CSD) after single-level lumbar disc surgery was evaluated. Postoperative CSD are regularly fitted to prevent postoperative epidural hematomas (EH) after multilevel lumbar decompression, although it remains unclear whether CSD also reduces postoperative EH following single-level lumbar disc surgery. OVERVIEW OF LITERATURE: Few articles have addressed the clinical outcome in patients with single-level lumbar disc disease who were treated by two different operative methods (with and without drainage). METHODS: Between 2012 and 2014, 115 patients with a single level discectomy underwent two surgical procedures: with CSD (group A, 60 cases) and without CSD (group B, 55 cases). There were no significant differences in age, sex, segment level, herniation type, or disease duration between the groups. Wound infection, EH, and epidural fibrosis (EF) were evaluated by magnetic resonance imaging. Pain intensity was evaluated using the visual analog scale (VAS) and Oswestry disability index (ODI). Reduction in analgesic treatment and patient satisfaction were also recorded. RESULTS: The overall rate of postoperative EH was 5% and 16.3% in group A and B, respectively, whereas the rate of postoperative EF was 11.6% in group A and 21.8% in group B. The postoperative VAS score was 0.32 (standard deviation [SD], 0.45) for group A and 2.62 (SD, 06.9) for group B, whereas ODI was 9.11 (SD, 0.68) and 8.23 (SD, 0.78) for group A and and group B, respectively, with no significant differences observed. CONCLUSIONS: In patients operated on by unilateral, single-level lumbar disc surgery, the use of suction CSD into the operation site results in lower levels of EH and EF radiologically, thereby providing a better clinical outcome. PMID- 27994784 TI - Tumor Occupation in the Spinal Canal and Clinical Symptoms of Cauda Equina Schwannoma: An Analysis of 22 Cases. AB - STUDY DESIGN: Retrospective, radiological study. PURPOSE: To determine the relationship between clinical symptoms and the extent of tumor occupation of the spinal canal by cauda equina schwannoma. OVERVIEW OF LITERATURE: Little is known about the relationship between the size of tumors of the cauda equina and the manifestation of clinical symptoms. We analyzed this relationship by estimating the percentage of tumor occupation (PTO) in the spinal canal in cauda equina schwannomas and by correlating this parameter with the presence and severity of clinical symptoms. METHODS: Twenty-two patients (9 men and 13 women; age, 19-79 years; mean age, 55.3 years) who were radiologically diagnosed with schwannomas of the cauda equina between April 2004 and July 2014 were retrospectively analyzed. PTO was measured in axial and sagittal magnetic resonance imaging slices in which the cross-sectional area of the tumor was the largest. Data regarding clinical symptoms and results of physical examinations were collected from patient medical records. PTO differences between symptom-positive and negative groups were analyzed for each variable. RESULTS: In the 4 cases in which tumor presence was not related to clinical symptoms, PTO was 5%-10% (mean, 9%) in axial slices and 23%-31% (mean, 30%) in sagittal slices. In the 18 cases in which symptoms were associated with the tumor, PTO was 11%-86% (mean, 50%) in axial slices and 43%-88% (mean, 71%) in sagittal slices. PTO in axial slices was significantly higher in the presence of Dejerine symptoms and/or muscle weakness, a positive straight leg raise test, and a positive Kemp sign. CONCLUSIONS: PTO >20% in axial slices and >40% in sagittal slices can be an indication of symptomatic cauda equina schwannoma. PMID- 27994786 TI - Bone Morphogenic Protein Is a Viable Adjunct for Fusion in Minimally Invasive Transforaminal Lumbar Interbody Fusion. AB - STUDY DESIGN: Comparison of prospectively collected data of patients undergoing minimally invasive surgery transforaminal lumbar interbody fusion (MIS-TLIF) with and without recombinant human bone morphogenic protein 2 (BMP). PURPOSE: To compare the clinical, radiological outcome and complications of patients undergoing MIS-TLIF with and without BMP. OVERVIEW OF LITERATURE: BMP is an effective fusion enhancer with potential complications. Direct comparison of MIS TLIF with and without BMP is limited to retrospective studies with short follow up. METHODS: From June 2005 to February 2011, consecutive cases of MIS-TLIF performed by a single surgeon were included. North American Spine Society (NASS) score, Oswestry disability index (ODI), Short Form-36 (SF-36), and visual analogue score (VAS) were assessed preoperatively and at 6 and 24 months postoperatively. Fusion rates and complications were noted. RESULTS: The 252 cases comprised 104 non-BMP and 148 BMP cases. The BMP group was significantly older (mean age, 60.2 vs. 53.9; p<0.01). Preoperative scores were similar. Immediate postoperative morphine usage was significantly lower in the BMP group (12.4 mg vs. 20.1 mg, p<0.01). At 6 months, the BMP group had lower VAS back and leg pain scores (p<0.01). At 2 years, the BMP group had better leg pain scores (p<0.01), ODI (15.4 vs. 20.3, p=0.04) and NASS scores (8.8 vs. 15.8, p<0.01). Both groups showed significant clinical improvement compared to their preoperative levels. The BMP group attained a significantly higher rate of fusion at 6 months follow-up (88.4% vs. 76.8%, p=0.016) with no difference at 2 years. The non-BMP and BMP group had 12 (11.5%) and 9 (6.1%) complications and 5 (4.8%) and 2 (1.4%) reoperations, respectively. CONCLUSIONS: The use of BMP to augment fusion in MIS-TLIF is an acceptable alternative that has potential benefits of less pain in early and intermediate postoperative follow-up. PMID- 27994785 TI - Baastrup's Disease Is Associated with Recurrent of Sciatica after Posterior Lumbar Spinal Decompressions Utilizing Floating Spinous Process Procedures. AB - STUDY DESIGN: Retrospective case-control study. PURPOSE: To determine whether kissing spine is a risk factor for recurrence of sciatica after lumbar posterior decompression using a spinous process floating approach. OVERVIEW OF LITERATURE: Kissing spine is defined by apposition and sclerotic change of the facing spinous processes as shown in X-ray images, and is often accompanied by marked disc degeneration and decrement of disc height. If kissing spine significantly contributes to weight bearing and the stability of the lumbar spine, trauma to the spinous process might induce a breakdown of lumbar spine stability after posterior decompression surgery in cases of kissing spine. METHODS: The present study included 161 patients who had undergone posterior decompression surgery for lumbar canal stenosis using a spinous process floating approaches. We defined recurrence of sciatica as that resolved after initial surgery and then recurred. Kissing spine was defined as sclerotic change and the apposition of the spinous process in a plain radiogram. Preoperative foraminal stenosis was determined by the decrease of perineural fat intensity detected by parasagittal T1-weighted magnetic resonance imaging. Preoperative percentage slip, segmental range of motion, and segmental scoliosis were analyzed in preoperative radiographs. Univariate analysis followed by stepwise logistic regression analysis determined factors independently associated with recurrence of sciatica. RESULTS: Stepwise logistic regression revealed kissing spine (p=0.024; odds ratio, 3.80) and foraminal stenosis (p<0.01; odds ratio, 17.89) as independent risk factors for the recurrence of sciatica after posterior lumbar spinal decompression with spinous process floating procedures for lumbar spinal canal stenosis. CONCLUSIONS: When a patient shows kissing spine and concomitant subclinical foraminal stenosis at the affected level, we should sufficiently discuss the selection of an appropriate surgical procedure. PMID- 27994788 TI - Results of Single-Staged Posterior Decompression and Circumferential Fusion Using a Transpedicular Approach to Correct a Kyphotic Deformity due to Thoracolumbar Spinal Tuberculosis. AB - STUDY DESIGN: This is a prospective study. PURPOSE: The aim of this study was to investigate the results of single-staged posterior decompression and circumferential fusion using a transpedicular approach to correct a kyphotic deformity due to thoracolumbar spinal tuberculosis. OVERVIEW OF LITERATURE: Surgical management is frequently an imperative choice to achieve spinal decompression and deformity correction due to tuberculosis to relieve pain, improve neurology, and reconstruct the spine stability. Since the time anterior radical debridement and noninstrumented fusion was described, it has become apparent that even anterior debridement and bone grafting was often unsatisfactory in correcting or preventing the progression of kyphosis deformity. With the advent of modern segmental spinal instrumentation systems, isolated posterior instrumentation; combined anterior and posterior fusion; and single staged posterior decompression and circumferential fusion have been described by many authors for correcting angular deformity and stabilizing the spine; however, there is a lack of consensus regarding the most effective means of correcting the deformity due to thoracolumbar spinal tuberculosis. METHODS: This is a prospective study of 20 patients with thoracolumbar spinal tuberculosis who underwent surgery at our institute. RESULTS: Twenty patients who were started on antituberculosis treatment underwent surgery using a single-staged posterior approach involving fixation, decompression, and kyphosis correction. Preoperatively, all patients had varying degrees of neurological deficit and a 27.45 degrees average kyphotic angle, which improved. At the 1-year follow-up, correction was maintained at 6.9 degrees , and 55% of patients showed neurological improvement. None of the patients experienced neurological deterioration. Two patients with lumbar spine tuberculosis underwent revision surgery because of nonunion. CONCLUSIONS: The procedure of posterior decompression, fixation, and circumferential fusion using a transpedicular approach performed for thoracolumbar spinal tuberculosis is effective, safe, and excellent in correcting and maintaining kyphosis. PMID- 27994787 TI - Long-Term Outcomes of Posterior Lumbar Interbody Fusion Using Stand-Alone Ray Threaded Cage for Degenerative Disk Disease: A 20-Year Follow-Up. AB - STUDY DESIGN: Retrospective study. PURPOSE: To analyze outcomes of posterior lumbar interbody fusion (PLIF) stand-alone cages. OVERVIEW OF LITERATURE: PLIF for degenerative disk disease using stand-alone cages has lost its popularity owing to implant-related complications and pseudoarthrosis. METHODS: We analyzed the records of 45 patients (18 women, 27 men), operated between January 1994 and December 1996, with a mean follow-up of 18 years 3 months (20 years 3 months-22 years 3 months). Clinical outcomes were measured using visual analogue score (VAS), Oswestry disability index (ODI), Odom's criteria, and radiological measurements of fusion rate, Cobb angle, and implant-related complications conducted at the preoperative evaluation, hospital discharge, 12-month follow-up, and final follow-up. RESULTS: Preoperative mean VAS (back) was 6.9 and VAS (radicular) was 7.2, with mean improvements (p <0.05) of 2.9 and 3.1, respectively, at the final follow-up. Median preoperative ODI was 64.5, with a mean improvement to 34 and 42 at the 12-month and final follow-ups, respectively (p <0.05). Odom's criteria at the 12-month follow-up were excellent in 11.2% patients, good in 57.7%, fair in 31.1%, and poor in none of the patients; at the final follow-up, no patient was classified as excellent, 71.1% as good, 22.2% as fair, and 6.7% as poor (p <0.05). Pseudoarthrosis was observed in five patients (11.1%), of whom, three (6.6%) required re-operation. Preoperative disk height was 9.23 mm, which increased to 13.33 mm in the immediate postoperative evaluation and was maintained at 10.0 mm at the final follow-up (p <0.05). The preoperative mean L1-S1 Cobb angle was 34.7 degrees , which changed to 44.7 degrees in the immediate postoperative evaluation and dropped to 39.7 degrees at the final follow-up (p <0.005). CONCLUSIONS: PLIF stand-alone cages were associated with good clinical outcomes. Although the fusion rate was excellent, maintenance of disk heights and a lordotic alignment were not achieved in the long term. PMID- 27994789 TI - Correlation of 1.5 Tesla Magnetic Resonance Imaging with Clinical and Intraoperative Findings for Lumbar Disc Herniation. AB - STUDY DESIGN: A single-center prospective study. PURPOSE: A magnetic resonance imaging (MRI) scan is undeniably the gold standard for the diagnosis of a lumbar disc prolapse. Unfortunately it shares a strong association with incidental findings. In this study, we aimed to determine the extent to which a 1.5 Tesla MRI correlates with the clinical features and intraoperative findings in cases of lumbar disc prolapse. OVERVIEW OF LITERATURE: Few studies have correlated MRI with clinical findings, and none have extended this correlation to intraoperative findings. METHODS: Over a 2-year period, 50 consecutive patients with lumbar disc herniation requiring discectomy were studied. The MRI findings we observed consisted of the prolapse level, type, position, migration, high-intensity zones (HIZ), lateral recess, and foraminal stenosis. A logistic regression analysis was performed to determine the significance for the various MRI findings. Finally, the MRI observations were confirmed with intraoperative findings and inferences were drawn. RESULTS: MRI scan sensitivity and specificity for determining surgically significant levels was 100% and 94.94%, respectively. Straight leg raising test was positive in 74% of patients, with 85%, 43%, and 75% for paracentral, central, and foraminal levels, respectively. A foraminal compromise was the only MRI parameter to share a significant association with neurological deficits. Patients with a HIZ on the MRI had a significant increase in back pain and 63% exhibited identifiable annular tears intraoperatively. The intraoperative anatomical findings correlated extensively with the MRI findings. CONCLUSIONS: MRI findings strongly correlate with intraoperative features and can serve as a useful tool when planning surgery due to the accurate depiction of the morphometric features. However, the decision for surgery should be made only when detailed clinical findings in conjunction with MRI findings allow for an accurate identification of the culprit fragment and pain generators. PMID- 27994790 TI - A Nationwide Retrospective Study of Opioid Management Patterns in 2,468 Patients with Spinal Pain in Korea. AB - STUDY DESIGN: Retrospective patient data collection and investigator survey. PURPOSE: To investigate patterns of opioid treatment for pain caused by spinal disorders in Korea. OVERVIEW OF LITERATURE: Opioid analgesic prescription and adequacy of consumption measures in Korea have markedly increased in the past decade, suggesting changing patterns in pain management practice; however, there is lack of integrated data specific to Korean population. METHODS: Patient data were collected from medical records at 34 university hospitals in Korea. Outpatients receiving opioids for pain caused by spinal disorders were included in the study. Treatment patterns, including opioid types, doses, treatment duration, outcomes, and adverse drug reactions (ADRs), were evaluated. Investigators were interviewed on their perceptions of opioid use for spinal disorders. RESULTS: Among 2,468 analyzed cases, spinal stenosis (42.8%) was the most common presentation, followed by disc herniation (24.2%) and vertebral fracture (17.5%). In addition, a greater proportion of patients experienced severe pain (73.9%) rather than moderate (19.9%) or mild (0.7%) pain. Oxycodone (51.9%) and fentanyl (50.8%) were the most frequently prescribed opioids; most patients were prescribed relatively low doses. The median duration of opioid treatment was 84 days. Pain relief was superior in patients with longer treatment duration (>=2 months) or with nociceptive pain than in those with shorter treatment duration or with neuropathic or mixed-type pain. ADRs were observed in 8.6% of cases. According to the investigators' survey, "excellent analgesic effect" was a perceived advantage of opioids, while safety concerns were a disadvantage. CONCLUSIONS: Opioid usage patterns in patients with spinal disorders are in alignment with international guidelines for spinal pain management. Future prospective studies may address the suitability of opioids for spinal pain treatment by using appropriate objective measurement tools. PMID- 27994792 TI - Prevalence of High-Riding Vertebral Artery and Morphometry of C2 Pedicles Using a Novel Computed Tomography Reconstruction Technique. AB - STUDY DESIGN: Cross-sectional, matched-pair comparative study. PURPOSE: To determine whether a thin-sliced pedicular-oriented computed tomography (TPCT) scan reconstructed from an existing conventional computed tomography (CCT) scan is more accurate for identifying vertebral artery groove (VAG) anomalies than CCT. OVERVIEW OF LITERATURE: Posterior atlantoaxial transarticular screw fixation and C2 pedicle screws can cause vertebral artery (VA) injury. Two anatomic variations of VAG anomalies are associated with VA injury: a high-riding VA (HRVA) and a narrow pedicle of the C2 vertebra. CCT scan is a reliable method used to evaluate VAG anomalies; however, its accuracy level remains debatable. Literature comparing the prevalence of C2 VAG anomalies between CCT and TPCT is limited. METHODS: A total of 200 computed tomography scans of the upper cervical spine obtained between January 2008 and December 2011 were evaluated for C2 VAG anomalies (HRVA and narrow pedicular width) using CCT and TPCT. The prevalence of C2 VAG anomalies was compared using these two different measurement methods via a McNemar's test. RESULTS: Of the 200 patients studied, 23 HRVA (6.01%; 95% confidence interval [CI], 3.61%-8.39%) were detected with CCT, whereas 66 HRVA (16.54%; 95% CI, 12.85%-20.23%) were detected with TPCT (p<0.001). Sixty-two narrow pedicles (15.58%; 95% CI, 11.99%-19.15%) were detected with CCT, whereas 90 narrow pedicles (22.83%; 95% CI, 18.58%-26.87%) were detected with TPCT (p<0.001). CONCLUSIONS: VAG anomalies are commonly observed. A preoperative evaluation using TPCT reconstructed from an existing CCT revealed a significantly higher prevalence of C2 VAG anomalies than did CCT and showed comparable prevalence to previously published studies using more sophisticated and higher risk techniques. Therefore, we propose TPCT as an alternative preoperative evaluation for C2 screw placement and trajectory planning. PMID- 27994793 TI - Bone Union Rate Following Instrumented Posterolateral Lumbar Fusion: Comparison between Demineralized Bone Matrix versus Hydroxyapatite. AB - STUDY DESIGN: Retrospective study. PURPOSE: To compare the union rate of posterolateral lumbar fusion (PLF) using demineralized bone matrix (DBM) versus hydroxyapatite (HA) as bone graft extender. OVERVIEW OF LITERATURE: To our knowledge, there has been no clinical trial to compare the outcomes of DBM versus HA as a graft material for PLF. METHODS: We analyzed prospectively collected data from consecutive 79 patients who underwent instrumented PLF. Patients who received DBM were assigned to group B (n=38), and patients who received HA were assigned into group C (n=41). The primary study outcome was fusion rate assessed with radiographs. The secondary outcomes included pain intensity using a visual analogue scale, functional outcome using Oswestry disability index score, laboratory tests of inflammatory profiles and infection rate. RESULTS: One year postoperatively, bone fusion was achieved in 73% in group B and 58% in group C without significant difference between the groups (p=0.15). There were no differences between the groups with respect to secondary outcomes. CONCLUSIONS: DBM would provide noninferior outcomes compared to the HA as a fusion material for PLF, and could be a notable alternative. PMID- 27994791 TI - Analysis of the Relationship between Ligamentum Flavum Thickening and Lumbar Segmental Instability, Disc Degeneration, and Facet Joint Osteoarthritis in Lumbar Spinal Stenosis. AB - STUDY DESIGN: Cross-sectional study. PURPOSE: To investigate the relationship between ligamentum flavum (LF) thickening and lumbar segmental instability and disc degeneration and facet joint osteoarthritis. OVERVIEW OF LITERATURE: Posterior spinal structures, including LF thickness, play a major role in lumbar spinal canal stenosis pathogenesis. The cause of LF thickening is multifactorial and includes activity level, age, and mechanical stress. LF thickening pathogenesis is unknown. METHODS: We examined 419 patients who underwent computed tomography (CT) myelography and magnetic resonance imaging after complaints of clinical symptoms. To investigate LF hypertrophy, 57 patients whose lumbar vertebra had normal disc heights at L4-5 were selected to exclude LF buckling as a hypertrophy component. LF thickness, disc space widening angulation in flexion, segmental angulation, presence of a vacuum phenomenon, and lumbar lordosis at T12 S1 were investigated. Disc and facet degeneration were also evaluated. Facet joint orientation was measured via an axial CT scan. RESULTS: The mean LF thickness in all patients was 4.4+/-1.0 mm at L4-5. There was a significant correlation between LF thickness and disc degeneration; LF thickness significantly increased with severe disc degeneration and facet joint osteoarthritis. There was a tendency toward increased LF thickness in more sagittalized facet joints than in coronalized facet joints. Logistic regression analysis showed that LF thickening was influenced by segmental angulation and facet joint osteoarthritis. Patient age was associated with LF thickening. CONCLUSIONS: LF hypertrophy development was associated with segmental instability and severe disc degeneration, severe facet joint osteoarthritis, and a sagittalized facet joint orientation. PMID- 27994794 TI - A New Radiological Sign for Severe Angular Kyphosis: "The Baltalimani Sign". AB - STUDY DESIGN: Retrospective diagnostic study. PURPOSE: To define a new radiological sign, "Baltalimani sign," in severe angular kyphosis (SAK) and to report its relationship with the risk of neurological deficits and deformity severity. OVERVIEW OF LITERATURE: Baltalimani sign was previously undefined in the literature. METHODS: We propose Baltalimani sign as the axial orientation of the vertebrae that are located above or below the apex of angular kyphosis on anteroposterior radiographs. Patients with SAK of various etiologies with kyphotic angles >=90 degrees were selected and evaluated for the presence of Baltalimani sign. Demographic data of the patients including age, gender, etiology, neurological status, local kyphosis angles, and the location of the kyphosis apex were recorded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of Baltalimani sign for the risk of the neurological deficits were evaluated by the IBM SPSS ver. 20.0. A p-values of <0.05 were considered statistically significant. Cohen's kappa was used for analysis of interrater agreement. RESULTS: The mean local kyphosis angle in all patients was 124.2 degrees (range, 90 degrees -169 degrees ), and 15 of 40 (37.5%) patients had neurological deficits. Baltalimani sign was seen in 13 of 15 patients with neurological deficits (p=0.001). Baltalimani sign showed a sensitivity and specificity PPV and NPV of 61.9%, 86.7%, 89.5%, and 68.8% for the risk of the neurological deficits in SAK patients, respectively. Cohen's kappa value was moderate (kappa=0.506). CONCLUSIONS: The detection of Baltalimani sign in SAK may indicate severity of deformity and the risk of neurological deficits. PMID- 27994795 TI - Long-Term Effects of Untreated Adolescent Idiopathic Scoliosis: A Review of the Literature. AB - Currently, adolescent idiopathic scoliosis (AIS) is principally regarded as benign, but some researchers have cited serious or extreme effects, including severe pain, cardiopulmonary compromise, social isolation, and even early death. Therefore, exploration of the long-term effects of AIS, the most common type of idiopathic scoliosis, is warranted. The purpose of this review was to examine the long-term studies on the natural history of AIS and/or reviews concerning the long-term effects of untreated AIS. A PubMed search was conducted using the key words idiopathic scoliosis, long-term effects and idiopathic scoliosis, natural history. For further analysis, references cited in those studies were reviewed for additional, related evidence not retrieved in the initial PubMed search. A review of the pertinent bibliography showed that older natural history studies did not distinguish between late-onset scoliosis (referred to in this paper as AIS) and early-onset scoliosis (EOS). The more recent studies offer such important distinction and reach to the general conclusion that untreated AIS does not lead to severe consequences with respect to signs and symptoms of scoliosis. It is possible that earlier studies may have included patient populations with EOS, leading to the perception of untreated scoliosis as having an unusually high morbidity rate. Studies on the long-term effects of AIS that specifically excluded EOS patients conclude that AIS is a benign disorder. This indicates that for research and reporting purposes, it is important to distinguishing between AIS and EOS. This will allow the practitioner and patient and their families to decide on an optimal treatment plan based on the most appropriate prognosis. PMID- 27994796 TI - A Comparison of Patient-Reported Outcome Measures Following Different Treatment Approaches for Adolescents with Severe Idiopathic Scoliosis: A Systematic Review. AB - Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine which is usually not symptomatic and which can progress during growth and cause a surface deformity. In adulthood, if the final spinal curvature surpasses a certain critical threshold, the risk of health problems and curve progression is increased. Although surgery is usually recommended for curvatures exceeding 40 degrees to 50 degrees to stop curvature progression, recent reviews have shed some light on the long-term complications of such surgery and to the lack of evidence for such complicated procedures within the scientific literature. Furthermore, a number of patients are very fearful of having surgery and refuse this option or live in countries where specialist scoliosis surgery is not available. Other patients may be unable to afford the cost of specialist scoliosis surgery. For these patients the only choice is an alternative non surgical treatment option. To examine the impact of different management options in patients with severe AIS, with a focus on trunk balance, progression of scoliosis, cosmetic issues, quality of life, disability, psychological issues, back pain, and adverse effects, at both the short-term (a few months) and the long-term (over 20 years). We searched CENTRAL, MEDLINE, EMBASE, CINHAL and two other databases up to January 2016 with no language limitations. We also checked the reference lists of relevant articles and conducted an extensive hand search of the grey literature. We searched for randomised controlled trials as well as prospective and retrospective controlled trials comparing spinal fusion surgery with no treatment or conservative treatment in AIS patients with a Cobb angle greater than 40 degrees . We did not identify any evidence of superiority of effectiveness of operative compared to nonoperative interventions for patients with severe AIS. Within the present literature there is no clear evidence to suggest that a specific type of treatment is superior to other types of treatment. PMID- 27994798 TI - Mining textural knowledge in biological images: Applications, methods and trends. AB - Texture analysis is a major task in many areas of computer vision and pattern recognition, including biological imaging. Indeed, visual textures can be exploited to distinguish specific tissues or cells in a biological sample, to highlight chemical reactions between molecules, as well as to detect subcellular patterns that can be evidence of certain pathologies. This makes automated texture analysis fundamental in many applications of biomedicine, such as the accurate detection and grading of multiple types of cancer, the differential diagnosis of autoimmune diseases, or the study of physiological processes. Due to their specific characteristics and challenges, the design of texture analysis systems for biological images has attracted ever-growing attention in the last few years. In this paper, we perform a critical review of this important topic. First, we provide a general definition of texture analysis and discuss its role in the context of bioimaging, with examples of applications from the recent literature. Then, we review the main approaches to automated texture analysis, with special attention to the methods of feature extraction and encoding that can be successfully applied to microscopy images of cells or tissues. Our aim is to provide an overview of the state of the art, as well as a glimpse into the latest and future trends of research in this area. PMID- 27994797 TI - Spinal Cord Stimulation in Failed Back Surgery Syndrome: Review of Clinical Use, Quality of Life and Cost-Effectiveness. AB - Failed back surgery syndrome (FBSS) is complex and recurrent chronic pain after spinal surgery. Several important patient and surgery related risk factors play roles in development of FBSS. Inadequate selection of the candidates for the spinal surgeries is one of the most crucial causes. The guidelines suggest that conservative management featuring pharmacologic approaches and rehabilitation should be introduced first. For therapy-refractory FBSS, spinal cord stimulation (SCS) is recommended in selected patients. Treatment efficacy for FBSS has increased over the years with the majority of patients experiencing pain relief and reduced medicinal load. Improved quality of life can also be achieved using SCS. Cost-effectiveness of SCS still remains unclear. However evidence for SCS role in FBSS is controversial, SCS can be beneficial for carefully classified patients. PMID- 27994800 TI - DMEK Calling. PMID- 27994799 TI - Worsening of Verbal Fluency After Deep Brain Stimulation in Parkinson's Disease: A Focused Review. AB - Worsening of verbal fluency after treatment with deep brain stimulation in Parkinson's disease patients is one of the most often reported cognitive adverse effect. The underlying mechanisms of this decline are not well understood. The present focused review assesses the evidence for the reliability of the often reported decline of verbal fluency, as well as the evidence for the suggested mechanisms including disease progression, reduced medication levels, electrode positions, and stimulation effect vs. surgical effects. Finally, we highlight the need for more systematic investigations of the large degree of heterogeneity in the prevalence of verbal fluency worsening after DBS, as well as provide suggestions for future research. PMID- 27994802 TI - Comparison of Higher Order Aberrations after Wavefront-guided LASIK and PRK: One Year Follow-Up Results. AB - PURPOSE: To evaluate the changes and predictability of higher order aberrations (HOAs) after personalized laser in situ keratomileusis (LASIK) and personalized photorefractive keratectomy (PRK) for simple myopia and compound myopic astigmatism. METHODS: In this prospective cross-sectional study, 100 eyes were included. A total of 50 eyes underwent personalized LASIK and 50 eyes underwent personalized PRK. Preoperative and postoperative wavefront data were compared between the two groups. The influential factors and predictability of HOAs were also assessed. RESULT: Total HOA increased in the amount of 0.01 +/- 0.14 MUm for the 5 mm pupil (P = 0.55) and 0.08 +/- 0.22 MUm for the 6 mm pupil (P = 0.02) after PRK; however after LASIK the corresponding values for the 5 and 6 mm pupil sizes were 0.05 +/- 0.12 and 0.15 +/- 0.18 MUm, respectively (P < 0. 001). Mean changes were not significantly different between the PRK and LASIK groups for both 5 and 6 mm pupil sizes (P = 0.21 and P = 0.13, respectively). Spherical aberration increased following LASIK more than following PRK (P < 0.001). Changes in the root mean square (RMS) of total HOA had a statistically significant negative correlation (P < 0.001) with its preoperative value. HOA and spherical aberration reduced in majority of eyes when the preoperative spherical equivalent refraction was low. CONCLUSION: For the 6mm pupil size, the total HOA increased following both personalized PRK and LASIK with no significant difference between the two groups. Change of the total HOA RMS was influenced by the preoperative values. The known influencing factors could predict nearly 50% of the changes in total HOA. PMID- 27994801 TI - Histopathology of Conjunctivochalasis Compared to Normal Conjunctiva. AB - PURPOSE: To evaluate the histopathologic changes in the conjunctiva of patients with conjunctivochalasis (CCh) compared to age-matched controls. METHODS: This cross-sectional, controlled study included 27 eyes of 27 patients with CCh and 16 eyes of 16 age-matched controls. A biopsy of the bulbar conjunctiva was performed along the temporal lower lid margin before cataract surgery in both groups. Histopathologic evaluation of the specimens was done with light microscopy using staining with hematoxylin/eosin, periodic acid Schiff, and van Gieson elastic stain. Various histopathologic features of the conjunctival epithelium and stroma were compared between the two groups. RESULTS: The mean age of patients was 62.4 +/- 6.9 years in the CCh group and 65.1 +/- 6.3 years in the control group (P = 0.54). No significant differences were noted between the two groups in terms of conjunctival epithelial changes including papillomatosis, epithelial clefts, epithelial goblet cells, or infiltration of inflammatory cells. Mean thickness of the conjunctival stroma was 0.21 +/- 0.08 mm in the CCh group and 0.26 +/- 0.21 mm in the control group (P = 0.10). For the conjunctival stroma, there were no significant differences between the two groups in terms of elastosis, fibrosis, lymphangiectasia, or infiltration of inflammatory cells. CONCLUSION: No noticeable differences were found in the histopathologic features by light microscopy between eyes with CCh and those of age-matched controls. Therefore, the primary pathology of CCh may not be within the conjunctiva itself. Instead, loose attachment of the conjunctiva to the underlying tissue may be the reason for the redundant folds in the bulbar conjunctiva. PMID- 27994803 TI - Transepithelial Photorefractive Keratectomy for Low to Moderate Myopia in Comparison with Conventional Photorefractive Keratectomy. AB - PURPOSE: To compare the effectiveness, safety and stability of the results of transepithelial photorefractive keratectomy (tPRK) with conventional photorefractive keratectomy (PRK) for low to moderate myopia. METHODS: In this prospective non-randomized case-control study, patients with low to moderate myopia were assigned to the tPRK group (cases) or the PRK group (controls). In the tPRK group, eyes were treated using the Amaris excimer laser (SCHWIND eye tech-solutions GmbH and Co. KG, Germany). Outcome measures included postoperative pain using McGill Pain Questionnaire, epithelial healing time, uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), manifest refraction, and safety and efficacy indexes which were compared between the study groups. RESULTS: Three hundred forty eyes of 170 patients were enrolled in this study. Each study group comprised of 170 eyes of 85 patients. There was a significant difference between the two groups regarding the postoperative pain scores in favor of the tPRK group (P = 0.04). The tPRK group had a shorter epithelial healing time than the conventional PRK group postoperatively (P = 0.01). Mean UCVA was significantly better in the case group than in the control group at the postoperative month 2 (P = 0.01). Regarding the safety and efficacy indexes, the tPRK group had better results than the conventional PRK group (P < 0.01 for both comparisons). CONCLUSION: Transepithelial PRK seems to be superior to conventional PRK for treatment of low to moderate myopia in terms of postoperative pain, epithelial healing time, visual recovery and safety and efficacy indexes. PMID- 27994804 TI - Microbial Profile of Corneal Ulcers in a Tertiary Care Hospital in South India. AB - PURPOSE: To identify the prevalence and microbial profile of infectious keratitis in a tertiary eye care hospital, and to test for the in vitro antimicrobial resistance of the bacterial isolates. METHODS: A total of 312 patients presenting to a tertiary eye care hospital with infected corneal ulcer were enrolled in this study. Their socio-demographic data and risk factors were recorded. Corneal scrapings collected from the edge of the ulcer were processed for direct gram stain and KOH mount. Culture was recovered on blood agar, chocolate agar, MacConkey agar and Sabouraud's dextrose (SDA) agar in multiple C shaped streaks. After overnight incubation, bacterial culture was followed by standard biochemical tests and antimicrobial sensitivity according to the clinical and laboratory standards institute (CLSI) guidelines. Inoculated SDA was inspected daily for up to 10 days and the growth was identified by its colony morphology, pigment production and lacto-phenol cotton blue mount examination. RESULTS: Of 312 patients, a microbial etiology was established in 117 cases (37.5%). Of these, 72 (61.5%) were male. The age range of 41-60 years was the most affected group. Of 117 positive cases, 52 (44.5%) were bacterial, 58 (49.5%) were fungal and 7 (6%) patients showed mixed bacterial and fungal infection. The most common isolated fungus was Fusarium which was detected in 36 (31%) cases, followed by Aspergillus spp in 13 (11%) subjects. Staphylococcus aureus was the most common isolated bacteria. All Gram positive cocci were susceptible to vancomycin followed by gatifloxacin, whereas all Gram negative bacilli were susceptible to gatifloxacin. CONCLUSION: Routine microbiological examination of patients with corneal ulcer is necessary in order to analyze and compare the changing trends of the etiology and their susceptibility patterns. PMID- 27994805 TI - Descemet's Membrane Endothelial Keratoplasty in South Asian Population. AB - PURPOSE: To evaluate visual outcomes, endothelial cell density and complications following Descemet's membrane endothelial keratoplasty (DMEK). METHODS: This study included 40 consecutive eyes that underwent DMEK for various pathologies involving the corneal endothelium. Best corrected visual acuity (BCVA) and endothelial cell density (ECD) were measured and compared before and 6 months after surgery. RESULTS: Out of 40 eyes, 34 eyes (85%) had BCVA ranging from 0.5 to 0.7 LogMAR 6 months postoperatively. Mean donor ECD was 2367.96 +/- 47.87 (range, 2314.0-2472.0) cells/mm2 preoperatively, which was reduced to 1798.42 +/- 45.79 (range, 1736.0-1902.0) cells/mm2 6 months after DMEK surgery, indicating a mean reduction of 569.54 cells/mm2 (24%) in ECD. CONCLUSION: DMEK is an emerging and a more advanced alternative to penetrating keratoplasty (PKP) and Descemet's stripping endothelial keratoplasty (DSEK) for corneal pathologies involving the corneal endothelium. Compared to PK and DSEK, however, DMEK has a longer learning curve, and its safety and efficacy need to be confirmed through more experience on a large volume of cases. PMID- 27994806 TI - Descemet Stripping Automated Endothelial Keratoplasty in Fuchs' Endothelial Dystrophy versus Pseudophakic Bullous Keratopathy. AB - PURPOSE: To compare clinical and confocal scan outcomes after Descemet stripping automated endothelial keratoplasty (DSAEK) performed for Fuchs' endothelial dystrophy (FED) versus pseudophakic bullous keratopathy (PBK). METHODS: This retrospective comparative study included 47 consecutive eyes of 39 patients with the diagnosis of FED (n = 29, group 1) or PBK (n = 18, group 2) that underwent DSAEK. Clinical outcomes were compared between the study groups. At the final follow-up examination, confocal microscopy was used to measure and compare central corneal and graft thickness as well as endothelial cell density and morphology between the two groups. RESULTS: Mean age at the time of surgery was 65.2 +/- 11.8 and 69.4 +/- 12.5 years in groups 1 and 2, respectively (P = 0.27). Follow-up period was 23.6 +/- 14.0 months in group 1 and 25.6 +/- 15.7 months in group 2 (P = 0.79). Postoperative best spectacle-corrected visual acuity was significantly better in group 1 than in group 2 until postoperative month 6. Afterwards, the two study groups were comparable in this regard. At the final follow-up examination, spherical equivalent refractive error was + 0.39 +/- 1.46 diopters (D) in group 1 and + 0.80 +/- 1.47 D in group 2 (P = 0.45). Postoperative keratometric astigmatism was 1.02 +/- 0.83 D and 2.36 +/- 0.67 D, respectively (P < 0.001). Mean central graft thickness was 98.0 +/- 33.3 MUm in group 1 and 107.6 +/- 28.0 MUm in group 2 (P = 0.45). No statistically significant difference was observed between the two groups in terms of the postoperative endothelial cell density. CONCLUSION: The outcomes of DSAEK surgery were comparable between FED and PBK. All grafts were clear despite the lower than normal endothelial cell counts. PMID- 27994807 TI - Cultivation of Retinoblastoma Cells: Correlation Between In Vitro Growth Pattern and Histopathology. AB - PURPOSE: To investigate the correlation between floating versus adherent growth pattern of cultivated retinoblastoma (RB) cells from three patients with RB and their histopathologic features. METHODS: RB cells from three Iranian patients (MM, NR, and MS) were cultivated in Dulbecco's modified eagle medium (DMEM) supplemented with 15% fetal bovine serum (FBS) for four weeks in each passage. Fresh medium was added on a weekly basis and immunocytochemistry for Synaptophysin was performed. All experiments were performed in duplicate. Growth pattern of the cultivated RB cells was studied during the three consecutive passages and compared among three cases in the light of histopathologic data. RESULTS: Cultivated RB cells from MM and NR demonstrated an adherent growth pattern in the 2nd week and the pattern was enhanced by the 4th week. The RB tumorspheres adhered to the bottom of the flask while surrounded by fibroblasts. Histopathologic diagnosis in MM and NR was a well-differentiated RB without optic nerve involvement. Such an adherent growth was not observed in cultivated RB cells from MS, in which the histopathologic analysis revealed a poorly differentiated RB with optic nerve intrusion and prominent choroidal invasion. CONCLUSION: The adherent growth pattern of cultivated RB cells might be associated with tumor differentiation and the lack of optic nerve involvement in histopathology. PMID- 27994808 TI - Effects of Benzo(e)pyrene on Reactive Oxygen/Nitrogen Species and Inflammatory Cytokines Induction in Human RPE Cells and Attenuation by Mitochondrial-involved Mechanism. AB - PURPOSE: To identify inhibitors that could effectively lower reactive oxygen/nitrogen species (ROS/RNS), complement and inflammatory cytokine levels induced by Benzo(e)pyrene [B(e)p], an element of cigarette smoke, in human retinal pigment epithelial cells (ARPE-19) in vitro. METHODS: ARPE-19 cells were treated for 24 hours with 200 MUM, 100 MUM, and 50 MUM B(e)p or DMSO (dimethyl sulfoxide)-equivalent concentrations. Some cultures were pre-treated with ROS/RNS inhibitors (NG nitro-L-arginine, inhibits nitric oxide synthase; Apocynin, inhibits NADPH oxidase; Rotenone, inhibits mitochondrial complex I; Antimycin A, inhibits mitochondria complex III) and ROS/RNS levels were measured with a fluorescent H2 DCFDA assay. Multiplex bead arrays were used to measure levels of Interleukin-6 (IL-6), Interleukin-8 (IL-8), Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), Transforming Growth Factor alpha (TGF-alpha) and Vascular Endothelial Growth Factor (VEGF). IL-6 levels were also measured by an enzyme-linked immunosorbent assay. Real-time qPCR analyses were performed with primers for C3 (component 3), CFH (inhibits complement activation), CD59 (inhibitor of the complement membrane attack complex (MAC)) and CD55/DAF (accelerates decay of target complement target proteins). RESULTS: The ARPE-19 cultures treated with B(e)p showed significantly increased ROS/RNS levels (P < 0.001), which were then partially reversed by 6 MUM Antimycin A (19%, P = 0.03), but not affected by the other ROS/RNS inhibitors. The B(e)p treated cultures demonstrated increased levels of IL-6 (33%; P = 0.016) and GM-CSF (29%; P = 0.0001) compared to DMSO-equivalent controls, while the expression levels for components of the complement pathway (C3, CFH, CD59 and CD55/DAF) were not changed. CONCLUSION: The cytotoxic effects of B(e)p include elevated ROS/RNS levels along with pro-inflammatory IL-6 and GM-CSF proteins. Blocking the Qi site of cytochrome c reductase (complex III) with Antimycin A led to partial reduction in B(e)p induced ROS production. Our findings suggest that inhibitors for multiple pathways would be necessary to protect the retinal cells from B(e)p induced toxicity. PMID- 27994810 TI - Prevalence and Severity of Ocular Surface Neoplasia in African Nations and Need for Early Interventions. AB - Ocular surface squamous neoplasia (OSSN) is a common ocular surface tumor with an increased incidence in African countries (3.4 and 3.0 cases/year/100,000). Despite its potential for vision loss and death, OSSN remains largely neglected by both eye and HIV care programs in Africa. The purpose of this review is to identify the barriers to timely diagnosis and early interventions for OSSN in Africa. PubMed searches were conducted targeting previous use of topical chemotherapy (interferon alpha 2b, Mitomycin-C, 5-Fluorouracil) and Human papillomavirus (HPV) vaccination in Africa. We found that OSSN is a significant vision and life-threatening health problem in Africa leading to significant loss of vision, as well as facial disfigurement and social stigma. We did not find any reports on the use of topical interferon, Mitomycin-C or HPV vaccination for OSSN in Africa. One report on the use of topical 5-FU for OSSN in Africa was found. Common barriers to early detection and management of OSSN in Africa include lack of sufficient laboratory infrastructure, lack of trained healthcare personnel, lack of compliance with follow-up visits, cost of topical chemotherapies, and cultural preferences for traditional medicines. In conclusion, OSSN is a significant vision and life-threatening health problem in Africa. There is not much literature on prevention or treatment options for early stages of OSSN in Africa. The use of topical chemotherapy as early interventions and judicious use of smart phone Apps to help with remote diagnosis of early OSSN should be further explored. PMID- 27994811 TI - Phakic Intraocular Lenses and their Special Indications. AB - Phakic intraocular lenses revolutionize refractive surgery and continue to serve as an excellent option for vision correction in patients who are not ideal candidates for laser vision correction. This article will review special indications of phakic intraocular lenses in the clinical practice. PMID- 27994813 TI - Conjunctival Leiomyoma; a Rare Tumor of the Ocular Surface. AB - PURPOSE: To report a case of conjuctival leiomyoma. CASE REPORT: An 18-year-old female patient presented with a conjunctival growth in the left eye for a 2-year period with no change in size. She merely presented for cosmetic reasons. Visual acuity was 20/20 in each eye. The lesion had prominent vessels and was not adherent to the sclera. The growth resembled a benign lesion of the conjunctiva. The tough and vascular tissue was excised and sent for histopathology. The defect was covered by an end to end conjunctival suturing. Histopathology showed the lesion to be conjunctival leiomyoma. Trichome was used to highlight the spindle shaped cells and immuno-histochemistry using anti-smooth muscle actin antibody and Vimentin was applied to confirm the diagnosis. CONCLUSION: This case adds to the total number of cases of conjuctival leiomyoma reported in the literature to date. An ophthalmologist needs to think beyond a common mass when encountering a conjunctival growth extending onto the cornea. PMID- 27994812 TI - Idiopathic Multifocal Choroiditis. AB - Idiopathic multifocal choroiditis (MFC) and/or punctate inner choroidopathy (PIC) describe a chronic progressive bilateral inflammatory chorioretinopathy that predominantly affect healthy myopic white women with no known associated systemic or ocular diseases. The principal sites of involvement are the retinal pigment epithelium (RPE) and outer retinal spaces; the choroid is not affected during the active phase of the disease. Idiopathic MFC with atrophy is a recently described variant. Although there is no generally accepted standard treatment, anti inflammatory and anti-VEGF (vascular endothelial growth factor) agents are necessary in the acute stage to control the inflammation and choroidal neovascularization (CNV). PMID- 27994814 TI - Bilateral Photic Maculopathy Following Pterygium Excision: Spectral Domain Optical Coherence Tomography Findings. AB - PURPOSE: To report high resolution spectral domain optical coherence tomography (SD-OCT) findings in a case with bilateral photic maculopathy and resultant central scotoma following pterygium excision. CASE REPORT: A 38-year-old man with a history of pterygium excision complained of visual disturbance and annoying central scotoma in both eyes. Although he had subtle funduscopic and angiographic changes, SD-OCT precisely showed disruption of the photoreceptors inner segment/outer segment in the foveal center. CONCLUSION: Phototoxic macular damage following ocular surgeries may be diagnosed with difficulty due to subtle funduscopic findings. SD-OCT is a precise imaging in revealing characteristic retinal alterations in different foveal injuries. Ophthalmologists should be aware of the possibility of photic maculopathy following various ophthalmic operations including pterygium surgery. PMID- 27994815 TI - Pleomorphic Adenoma of the Eyelid with Apocrine Gland Origin; an Atypical Location. AB - PURPOSE: To describe the clinical presentation and treatment of a patient with a cutaneous pleomorphic adenoma of the eyelid. CASE REPORT: A 73-year-old male patient presented with a nodular mass on the lateral third of his right upper eyelid, which had slowly enlarged over 10 years. Radiologic features were of an extra-conical mass, with no invasion of adjacent structures. An excisional biopsy of the lesion was performed. The histopathological examination revealed a biphasic tumor, composed of tubules with a double layer of epithelial cells arranged in a chondromyxoid stroma. The inner epithelial cells were positive for pancytokeratins AE1/AE3 and carcinoembryonic antigen. The outer epithelial cells and stromal component expressed vimentin and S100 protein. These pathologic findings were consistent with a palpebral pleomorphic adenoma, with an apocrine gland origin. CONCLUSION: Pleomorphic adenomas of the skin are rare tumors, and even less frequent as tumors of the ocular adnexa. These lesions should be considered in the differential diagnosis of palpebral nodular masses, and complete excision should be attempted due to the possibility of malignant transformation. PMID- 27994816 TI - Horner Syndrome Following Thyroid Surgery: The Clinical and Pharmacological Presentations. AB - PURPOSE: To report the clinical and pharmacological findings of a patient with iatrogenic Horner syndrome (HS) which occurred after thyroid surgery. CASE REPORT: A 29-year-old man was referred to our emergency ward due to anisocoria and unilateral eyelid ptosis reported by the patient immediately after a recent thyroidectomy for a papillary carcinoma. Ophthalmologic examination revealed 3 mm ptosis of the right eyelid. In dim illumination, the right and left pupil size was measured 3 and 6 mm, respectively. In bright illumination, the amount of anisocoria decreased; the near pupillary reaction was intact. Brain and neck magnetic resonance imaging and chest radiography were normal. Pharmacological tests with 10% cocaine, 1% hydroxyamphetamine and 1% phenylephrine localized the interruption of the oculosympathetic pathway with postganglionic third-order neuron involvement. After 6 months of follow-up, no sign of recovery was recorded. CONCLUSION: Despite HS could appear to be a rare complication of thyroid surgery, it is of importance for the neck surgeons to be aware that oculosympathetic pathway (OSP) is a potentially vulnerable structure with close anatomical relationship with the thyroid gland, and for the ophthalmologists that HS may occur secondary to neck surgery and taking an accurate history is mandatory. PMID- 27994817 TI - Multimodal Imaging after Electric Shock Retinopathy. PMID- 27994818 TI - Autofluorescence and Infrared Fundus Imaging for Detection of Retinal Emboli and Unmasking Undiagnosed Systemic Abnormalities. PMID- 27994819 TI - Intraoperative Optical Coherence Tomography Guided Bleb Needling. AB - Two patients with history of trabeculectomy presented with uncontrolled intraocular pressure (IOP) postoperatively. The first patient had a flat and vasularized bleb 10 weeks after the surgery, and the second subject developed encapsulated bleb 3 months postoperatively. Both patients were taken to the operating room and intraoperative optical coherence tomography (OCT) guided bleb needling was performed to restore aqueous egress into the subconjunctival space. Postoperatively, IOP of the operated eyes ranged 14-18 mmHg at week 6 and month 3. None of the eyes had any intraoperative or postoperative complications. This novel application of the intraoperative OCT for bleb needling facilitates precision surgery under direct visualization and reduces the risk of complications. PMID- 27994820 TI - Comments on Retinal Sensitivity Over Hard Exudates in Diabetic Retinopathy. PMID- 27994821 TI - Erratum: Descemet's Membrane Detachment Management Following Trabeculectomy. AB - [This corrects the article on p. 323 in vol. 11, PMID: 27621793.]. PMID- 27994809 TI - Diabetic Retinopathy Clinical Practice Guidelines: Customized for Iranian Population. AB - PURPOSE: To customize clinical practice guidelines (CPGs) for management of diabetic retinopathy (DR) in the Iranian population. METHODS: Three DR CPGs (The Royal College of Ophthalmologists 2013, American Academy of Ophthalmology [Preferred Practice Pattern 2012], and Australian Diabetes Society 2008) were selected from the literature using the AGREE tool. Clinical questions were designed and summarized into four tables by the customization team. The components of the clinical questions along with pertinent recommendations extracted from the above-mentioned CPGs; details of the supporting articles and their levels of evidence; clinical recommendations considering clinical benefits, cost and side effects; and revised recommendations based on customization capability (applicability, acceptability, external validity) were recorded in 4 tables, respectively. Customized recommendations were sent to the faculty members of all universities across the country to score the recommendations from 1 to 9. RESULTS: Agreed recommendations were accepted as the final recommendations while the non-agreed ones were approved after revision. Eventually, 29 customized recommendations under three major categories consisting of screening, diagnosis and treatment of DR were developed along with their sources and levels of evidence. CONCLUSION: This customized CPGs for management of DR can be used to standardize the referral pathway, diagnosis and treatment of patients with diabetic retinopathy. PMID- 27994822 TI - The Effect of Nutrition Consultation on Dietary Diversity Score of Cardiac Patients Referred to Cardiac Rehabilitation Research Center Isfahan Cardiovascular Research Institute during 2008-2013. AB - BACKGROUND: Dietary diversity score (DDS) measurement was used to assessment of diet quality in different disease like cardiovascular disease. One way to improve the cardiovascular patient's ability is cardiac rehabilitation program that include exercise training, nutrition consultation and psychological treatment. No study was designed to compare the DDS before and after dietary consultation among cardiac rehabilitation patients, so this study was designed to examine this purpose. METHODS: Subjects were participated in the 2-month cardiac rehabilitation program. All patients that completed the cardiac rehabilitation program and 2 dietary records (before and after nutritional counseling in cardiac rehabilitation program) enrolled in study. Kant et al method was used for scoring dietary diversity. Data were analyzed using the statistical package for social sciences (SPSS version 20). Wilcoxon test were used to compare DDS score for each subgroup and pair sample T test was used to compare total DDS after and before nutrition counseling. P < 0.05 was considered as statistically significant. RESULTS: The differences between DDS of grain, fruit, vegetable and meat before and after nutrition counseling were not significant (P = 0.635, P = 0.423, P = 0.826, P = 0.207 respectively), but differences of DDS for dairy and total DDS before and after nutrition counseling were significant (P = 0, P = 0.001). CONCLUSIONS: Dietary diversity was increased after nutrition counseling among patients with cardiac disease. PMID- 27994823 TI - Satisfaction Rate Regarding Health-care Services and Its Determinant Factors in South-West of Iran: A Population-based Study. AB - BACKGROUND: The aim of this study was to evaluate clients' satisfaction regarding health-care services and its determinant factors in South-West of Iran. METHODS: Totally, 3400 households were randomly selected for this cross-sectional study, carried out in Shiraz, Iran, from December 2013 to March 2014. Data were collected using a checklist that includes insurance status of the household, enrollment in family physician program, and client's satisfaction level with received health services. The level of statistical significance was set at P < 0.05. RESULTS: The mean age of the interviewees was 51.71 (+/-14.01) years, including 2427 (71.4%) females. 9.4% were insured while 72.3% had registered in family physician program. With respect to the family physician and governmental clinics, most subjects were "satisfied" or "very satisfied" with distance, time for admission, time spent at the clinic, privacy, and cost. As for private clinics, specialist clinics, and private hospitals, the studied subjects were more "dissatisfied" with cost but were more satisfied with other items. Living in higher socioeconomic regions (P = 0.001), dissatisfaction with family physician (P < 0.001, odds ratio [OR] = 2.3), scarcity of prescribed medication (P = 0.02, OR = 1.6), medication cost (P < 0.001, OR = 1.9), and existing chronic diseases in the household (P = 0.03, OR = 1.4) had determinant role in dissatisfaction with health system. CONCLUSIONS: Results of the present study demonstrated a high level of satisfaction with the health-care system and family physician in Shiraz, Iran. Moreover, dissatisfaction with family physicians, socioeconomic status, scarcity and cost of drugs, and existing chronic disease(s) were important predictors for dissatisfaction with the health-care system. PMID- 27994824 TI - Erratum: Ground Water Arsenic Contamination: A Local Survey in India. AB - [This corrects the article on p. 100 in vol. 7, PMID: 27625765.]. PMID- 27994825 TI - Effects of Pomegranate Seed Oil on Metabolic State of Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: Rapid increasing prevalence of diabetes mellitus is a serious health concern in the world. New data determined that the pathogenesis of diabetes mellitus is chronic low-grade inflammation, resulting insulin resistance. Pomegranate seed oil (PSO) has anti-inflammatory effects; though it may reduce insulin resistance and improve glycemia in diabetes mellitus. The present study has been designed to investigate the effects of PSO as a natural dietary component on metabolic state of patients with Type 2 diabetes mellitus. METHODS: In a randomized double-blind clinical trial study, 80 patients (28 men) with Type 2 diabetes were randomly allocated to the intervention and control groups. The intervention group consumed PSO capsules, containing 1000 mg PSO twice daily (2000 mg PSO), whereas controls take placebo for 8 weeks. The participants followed their previous dietary patterns and medication use. Dietary factors and metabolic factors including lipid profile, fasting plasma sugar, and insulin and were assayed at the baseline and after 8 weeks. RESULTS: Participants in two intervention and control group were similar regarding anthropometric and the dietary factors at baseline and after trial (P > 0.05). Mean level of total cholesterol, triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein was not different significantly between groups after trial (P > 0.05). Consumption of PSO did not significantly affect the levels of parameters such as fasting blood sugar (FBS), insulin, HbA1c, alanine transferase, and homeostasis model assessment-insulin resistance. CONCLUSIONS: Consumption of 2000mg PSO per day for 8 weeks had no effect on FBS, insulin resistance and lipid profile in diabetic patients. PMID- 27994826 TI - CrossFit(r) Instructor Demographics and Practice Trends. AB - CrossFit(r) is an increasingly popular exercise modality that uses high intensity power training. The literature to date regarding CrossFit(r) has focused on its benefits to VO2 Max, body composition and the motivational variables of participants of CrossFit(r). A computerized survey was distributed to CrossFit(r) instructors using Survey Monkey(r) (Palo Alto, CA, USA). One hundred and ninety three CrossFit(r) instructors responded to the survey. Of these 86.6% (155/179) reported being a certified CrossFit(r) instructor with 26.7% (48/180) having a bachelor's degree in an exercise-related field. Instructors with a CrossFit(r) certification have less bachelor's (P=0.04) or master's (P=0.0001) degrees compared to those without a CrossFit(r) certification, more utilization of Olympic weightlifting (P=0.03), one-on-one teaching (P=0.0001), 1-RM max on snatch (P=0.004), 1-RM on clean and jerk or hang clean (P=0.0003), kettlebell use (P=0.0001) and one-on-one training (P=0.0001). Instructors report differences in their education and differences in use of weightlifting platforms and various types of footwear. Non-certified instructors differ from CrossFit(r) certified instructors in regards to teaching of Olympic weightlifting and exercise programming. PMID- 27994828 TI - Prevalence of Asymptomatic Neurophysiological Carpal Tunnel Syndrome in 130 Healthy Individuals. AB - Diagnosis of carpal tunnel syndrome (CTS) is frequently confirmed by performing nerve conduction studies. Previous studies demonstrated that abnormal nerve conduction study (NCS) is suggestive of CTS among asymptomatic individuals. However, previous studies included individuals with risk factors for the syndrome. A NCS was performed on the median and ulnar nerves in 130 healthy individuals. About 15% of individuals in this study demonstrated electrodiagnostic evidence of carpal tunnels syndrome. Four cases have shown signs of isolated median neuropathy with normal median sensory component. Results indicated that the most widely used method for confirming diagnosis of CTS may have up to 15% of false positives. However, most of those showed changes of minimal CTS. Isolated prolongation of the median motor latency should be investigated further as they are usually classified as moderate to severe CTS and may undergo unnecessary surgeries. PMID- 27994827 TI - Cervical Spondylotic Myelopathy: What the Neurologist Should Know. AB - Cervical spondylotic myelopathy is a well-known cause of disability among older people. A significant amount of these patients is asymptomatic. Once the symptoms start, the worsening may follow a progressive manner. We should suspect of spondylotic myelopathy in any individual over 55 years presenting progressive changes in gait or losing fine motor control of the upper limbs. Despite its frequent prevalence, this condition is still neglected and many times confused with other supratentorial lesions regarding diagnostic. Here we address some of most important aspects of this disease, calling attention to pathophysiology, the natural history, presentation, differential diagnosis, clinical assessment, and treatment. PMID- 27994829 TI - Severe Cold Lower Limbs in Patients with Parkinson's Disease During the Summer. AB - Parkinson's disease (PD) is frequently associated with vasomotor symptoms such as distal cold limbs or sensitivity to cold. Coldness of the lower limbs (COL) usually occurs in winter and is often accompanied by pain, potentially causing difficulty in walking or standing. A standard dopaminergic treatment for such symptoms is yet to be established. We describe two patients with PD, who had severe COL during summer. For example, the patients wore many pairs of socks or used heating appliances in the summer. Severe COL can occur in summertime and can be intolerable or unpleasant, since it can worsen disability. The treatment with a dopamine agonist did not sufficiently decrease the severity of COL. PMID- 27994830 TI - Primary Intimal Sarcoma of the Left Atrium: An Incidental Finding on Routine Echocardiography. AB - Cardiac sarcomas are extremely rare primary malignant tumors of the heart. In this article, we present the case of a 70-year-old female, who was found to have a left atrial mass during a routine outpatient transthoracic echocardiography. Further investigation with cardiac magnetic resonance imaging confirmed the presence of a bilobulated mass with heterogeneous enhancement. Left atrial myxoma was the first diagnostic consideration, followed by other primary cardiac tumors, and thrombus. The patient subsequently underwent resection of the mass, utilizing cardiopulmonary bypass. Upon pathological examination, the mass was found to be an intimal sarcoma. The objective of this report is to describe a case of this rare disease entity, and to discuss its presentation, pathological findings and management. PMID- 27994832 TI - Mayo Clinic Cancer Center Experience of Metastatic Extramammary Paget Disease 1998-2012. AB - Extramammary Paget disease (EMPD) is a rare cutaneous malignancy. The most common presentation of EMPD is the vulva followed by perianal involvement. Most cases are localized to the dermis with treatment focused on surgery, topical treatment or radiotherapy. Recurrence is frequent despite therapies utilized. Metastatic extramammary Paget disease is uncommon and, as such, standard treatment guidelines do not exist. This study sought to evaluate the treatment regimens and outcomes of patients treated at a Mayo Clinic Center from 1998-2012. Cancer registry inquiry revealed 261 patients with report advanced Paget disease during these years. Ten cases of metastatic EPMD were identified with sufficient documentation for review. This review reveals support for utilizing localized radiation therapy for bulky disease sequentially with systemic chemotherapy consisting of carboplatin and paclitaxel or irinotecan. Further studies are necessary to define the optimal treatment regimen. PMID- 27994831 TI - Primary Intraosseous Smooth Muscle Tumor of Uncertain Malignant Potential: Original Report and Molecular Characterization. AB - We report the first case of primary intraosseous smooth muscle tumor of uncertain malignant potential (STUMP) which is analogous to borderline malignant uterine smooth muscle tumors so designated. The tumor presented in the femur of an otherwise healthy 30-year-old woman. Over a 3-year period, the patient underwent 11 biopsies or resections and 2 cytologic procedures. Multiple pathologists reviewed the histologic material including musculoskeletal pathologists but could not reach a definitive diagnosis. However, metastases eventually developed and were rapidly progressive and responsive to gemcitabine and docetaxel. Molecular characterization and ultrastructural analysis was consistent with smooth muscle origin, and amplification of unmutated chromosome 12p and 12q segments appears to be the major genomic driver of this tumor. Primary intraosseous STUMP is thought to be genetically related to leiomyosarcoma of bone, but likely representing an earlier stage of carcinogenesis. Wide excision and aggressive follow-up is warranted for this potentially life-threatening neoplasm. PMID- 27994833 TI - A Case of Mania Presenting with Hypersexual Behavior and Gender Dysphoria that Resolved with Valproic Acid. AB - Hypersexuality and gender dysphoria have both been described in the literature as symptoms of mania. Hypersexuality is listed in the Diagnostic and Statistical Manual of Mental Disorders 5 as part of the diagnostic criteria for bipolar disorder. Gender dysphoria is less often described and its relation to mania remains unclear. This case report describes a young homosexual man presenting in a manic episode with co-morbid amphetamine abuse whose mania was marked by hypersexuality and the new onset desire to be a woman. Both of these symptoms resolved with the addition of valproic acid to antipsychotics. This case report presents the existing literature on hypersexuality and gender dysphoria in mania and describes a treatment option that has not been previously reported. PMID- 27994834 TI - Lady with Erotic Preference for Diapers. AB - A patient in her 20s was referred to us for psychological assessment due to her depression and suicide attempts. She mentioned being anorgasmic except when diapered and emphasized her erotic preference for diapers. Her childhood included maternal deprivation in an impecunious family headed by an irritable physically disabled father on social assistance. Given the maternal deprivation in childhood, her erotic fixation on diapers parallels the emotional attachment to diapers observed by Harlow in mother deprived infant monkeys. Etiological hypotheses should also include the paradigm of avoidance learning from theories of behavior therapy. Our patient does not wish to change her sexual preference: in such cases, fetishism is not considered as an illness by DSM5. However, she needs to be treated for pathological levels of depression with suicidal ideation and low self-esteem. PMID- 27994835 TI - Delirium, Caused by Suspending Treatment of Hypothyroidism. AB - Delirium, or acute confusional syndrome, is a set of symptoms whose care involves not only psychiatry, but also many other medical specialties. Being as how the syndrome is caused by multiple factors, it is important to recognize each risk factor affecting the patient in order to anticipate and prevent it. In case of diagnosis, identifying and treating the root cause that triggered is important, given that it has a high rate of comorbidity and an elevated cost of medical care. We describe a case where a patient with hypothyroidism began suffering from delirium due to an abrupt discontinuation of levothyroxine treatment. Previously, the patient was seemingly healthy. After the medical treatment was interrupted, sensory processing and behavior were altered, and symptoms fluctuated, for a short period of time, showing disorientation and memory and language impairment. PMID- 27994836 TI - An Unexpected Fever Post Serogroup B Meningococcal Sepsis. AB - This case report describes an invasive meningococcal group B infection followed by the development of Kawasaki disease (KD) complicated by macrophage activation syndrome (MAS) in a 2-year-old child. The presented case indicates the possible etiologic relationship between meningococcal sepsis and KD as support of bacterial toxin induced theory. It's important to maintain a high grade of suspicious for KD in every relapse of fever also during convalescence phase of severe infection. Usually, initial treatment with intravenous immunoglobulin is sufficient to control the disease; but, in case of refractory KD complicated by MAS, corticosteroid therapy represents a good option inducing prompt fever resolution and clinical improvement. PMID- 27994837 TI - Treatment of Refractory Anemia with Ring Sideroblasts Associated with Marked Thrombocytosis with Lenalidomide in a Patient Testing Negative for 5q Deletion and JAK2 V617F and MPL W515K/L Mutations. AB - Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a hematologic malignancy that often results in transfusion dependency and a hypercoagulable state. This rare disease currently lacks formal guidelines for treatment; however, various case reports have demonstrated efficacy in the use of lenalidomide. This immunomodulatory drug has shown promise in patients with 5q deletions, with reports of achieving transfusion independence and normalization of platelet counts. Herein we present the case of a 68-year-old African American woman with RARS-T who tested negative for 5q deletion and JAK2 V617F and MPL W515K/L mutations. Her treatment with lenalidomide therapy resulted in a five-year durable complete clinical response. PMID- 27994839 TI - Romidepsin Controls Chronic Lymphocytic Leukemia in a Patient with Mycosis Fungoides. AB - Romidepsin belongs to a class of medications called histone deacetylase inhibitors and is currently approved for treatment of cutaneous and peripheral T cell lymphomas. Romidepsin was previously investigated for the treatment of chronic lymphocytic leukemia (CLL), and demonstrated potential benefit, but interest in its use declined following phase I clinical trials that showed poor tolerance of a significant side effect profile. We presented a patient with a history of stage II CLL, referred to dermatology for treatment of new-onset of mycosis fungoides (MF), who was treated with romidepsin over seven months. The patient achieved a partial response with 50% decrease in body surface area occupied by MF, thinning of remaining plaques, and near complete response in his CLL. His absolute lymphocyte count remained within the normal range for four months following discontinuation of romidepsin. Side effects were well-tolerated and did not limit therapy. Current literature on romidepsin is reviewed and compared to existing treatments for CLL. PMID- 27994838 TI - Reversible Cerebral Vasoconstriction Syndrome Promptly Diagnosed with Magnetic Resonance Imaging Including Magnetic Resonance Angiography During Immunosuppressive Therapy in a 16-Year-Old Girl with Refractory Cytopenia of Childhood. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome characterized by severe headache with segmental vasoconstriction of the cerebral arteries that resolves within 12 weeks. A 16-year-old girl with refractory cytopenia of childhood, who was receiving the immunosuppressant cyclosporine, developed severe headache and was diagnosed with RCVS using magnetic resonance imaging, including magnetic resonance angiography (MRA). MRA is a non-invasive and very effective technique for diagnosing RCVS. MRA should be performed at the onset of severe headache during immunosuppressant administration for children with hematological disorders and may prevent sequelae such as posterior reversible encephalopathy syndrome or ischemic attack. PMID- 27994840 TI - Intraspinal Lumbar Juxtaarticular Cyst Treatment Through CT-Guided Percutaneus Induced Rupture Results in a Favorable Patient Outcome. AB - Juxta-articular cysts are synovial cysts originating from the facet joints or the flava ligaments. If they grow intra-spinally they can compress nervous structures and cause a variety of symptoms. Micro-neurosurgery is usually the treatment of choice. Alternatively to surgical treatment the cyst can be approached and treated with a CT guided percutaneous injection inducing rupture. After fulfilling strict selection criteria twenty patients (25% of all treated lumbar synovial cyst patients), were treated minimally invasive by this method from 2010 2016. The facet joint was punctured under CT guidance and a mixture of a local anesthetic and contrast liquid was injected until the cyst was blasted. The mean follow-up period was 1.1 years (range 2 weeks - 5 years). Fifteen of twenty procedures were successful and cyst rupture was confirmed by CT-scans. Twelve of these fifteen patients experienced a significant improvement of their symptoms and needed no further intervention or surgical procedure up until now, three patients showed no clinical improvement and were treated surgically within one week after cyst rupture. In five patients it was technically not possible to rupture the cyst. These patients were treated microsurgically by cyst resection and dynamic stabilization or fusion procedures. The percutaneus rupture of juxtaarticular cysts has fewer risks and is cost effective compared to microsurgical resection. It may be an alternative to surgical treatment for a selected group of patients. However there are some limitations to the procedure though, such as difficult patient selection, unpredictable outcome or technical problems due to highly degenerated facet joints. PMID- 27994841 TI - Do all Critical Aortic Stenosis with Chest Pain Need Aortic Valve Replacement? A Case Report. AB - Aortic valve replacement (AVR) remains the cornerstone of treatment for symptomatic critical aortic stenosis (AS). It is a Class I indication that symptomatic patients with critical AS undergo either surgical or transcatheter aortic valve replacement (TAVR). We present a patient with critical AS and new angina that was managed successfully with percutaneous coronary intervention (PCI) of the Right coronary artery. Physicians should consider that not all patients with critical AS and angina necessarily require AVR. Concomitant pathology leading to the symptoms should be carefully ruled out. This leads to a less invasive, cost effective care plan especially in patients with advanced age and comorbidities for which any type of surgical valvular intervention may pose high risk. PMID- 27994842 TI - Diode Laser Versus Scalpel in the Treatment of Hereditary Gingival Fibromatosis in a 6-Year Old Boy. AB - Hereditary gingival fibromatosis (HGF) is a rare disease characterized by a benign enlargement of the gingiva involving both the mandible and the maxilla. This case is about a 6-year-old child with non syndromic HGF showing a severe gingival enlargement covering almost all surfaces of the teeth, in both arches, hence causing major aesthetic, phonetic and masticatory problems. The aim of the present article is to compare the outcomes of two therapeutical approaches: i) classical surgical removal with scalpel; and ii) diode laser resection. Compared to the surgical approach, the clinical results show that the main advantages of the diode laser technique are a better visibility during the intervention, minimal postoperative discomfort combined to a better gingival recontouring. However, the time consumption and the high cost of the laser equipment remain the main disadvantages of the systematic use of this technique. PMID- 27994843 TI - The Role of Vertical Disparity in Distance and Depth Perception as Revealed by Different Stereo-Camera Configurations. AB - Vertical binocular disparity is a source of distance information allowing the portrayal of the layout and 3D metrics of the visual space. The role of vertical disparity in the perception of depth, size, curvature, or slant of surfaces was revealed in several previous studies using cue conflict paradigms. In this study, we varied the configuration of stereo-cameras to investigate how changes in the horizontal and vertical disparity fields, conflicting with the vergence cue, affect perceived distance and depth. In four experiments, observers judged the distance of a cylinder displayed in front of a large fronto-parallel surface. Experiment 1 revealed that the presence of a background surface decreases the uncertainty in judgments of distance, suggesting that observers use the relative horizontal disparity between the target and the background as a cue to distance. Two other experiments showed that manipulating the pattern of vertical disparity affected both distance and depth perception. When vertical disparity specified a nearer distance than vergence (convergent cameras), perceived distance and depth were underestimated as compared with the condition where vertical disparity was congruent with vergence cues (parallel cameras). When vertical disparity specified a further distance than vergence, namely an infinite distance, distance and depth were overestimated. The removal of the vertical distortion lessened the effect on perceived distance. Overall, the results suggest that the vertical disparity introduced by the specific camera configuration is mainly responsible for the effect. These findings outline the role of vertical disparity in distance and depth perception and support the use of parallel cameras for designing stereograms. PMID- 27994844 TI - Circling Around the Uncanny Valley: Design Principles for Research Into the Relation Between Human Likeness and Eeriness. AB - The uncanny valley effect (UVE) is a negative emotional response experienced when encountering entities that appear almost human. Research on the UVE typically investigates individual, or collections of, near human entities but may be prone to methodological circularity unless the properties that give rise to the emotional response are appropriately defined and quantified. In addition, many studies do not sufficiently control the variation in human likeness portrayed in stimulus images, meaning that the nature of stimuli that elicit the UVE is also not well defined or quantified. This article describes design criteria for UVE research to overcome the above problems by measuring three variables (human likeness, eeriness, and emotional response) and by using stimuli spanning the artificial to human continuum. These criteria allow results to be plotted and compared with the hypothesized uncanny valley curve and any effect observed can be quantified. The above criteria were applied to the methods used in a subset of existing UVE studies. Although many studies made use of some of the necessary measurements and controls, few used them all. The UVE is discussed in relation to this result and research methodology more broadly. PMID- 27994845 TI - Crossmodal Modulation of Spatial Localization by Mimetic Words. AB - The present study investigated whether aurally presented mimetic words affect the judgment of the final position of a moving object. In Experiment 1, horizontal apparent motion of a visual target was presented, and an auditory mimetic word of "byun" (representing rapid forward motion), "pitari" (representing stop of motion), or "nisahi" (nonsense syllable) was presented via headphones. Observers were asked to judge which of two test stimuli was horizontally aligned with the target. The results showed that forward displacement in the "pitari" condition was significantly smaller than in the "byun" and "nisahi" conditions. However, when non-mimetic but meaningful words were presented (Experiment 2), this effect did not occur. Our findings suggest that the mimetic words, especially that meaning stop of motion, affect spatial localization by means of mental imagery regarding "stop" established by the phonological information of the word. PMID- 27994846 TI - Hybrid polyurea elastomers with enzymatic degradation and tunable mechanical properties. AB - Herein, we report on the synthesis and characterization of enzymatically labile polyureas for use as a tissue-engineered ligament scaffold. Polyureas were selected due to their excellent tensile properties, fatigue resistance, and highly tunable nature. Incorporation of a collagenase-sensitive peptide into the backbone of the polyurea provided a means to confer cell-responsive degradation to the synthetic polymer. Chemical, morphological, and mechanical testing were used to confirm incorporation of the peptide and characterize polyurea films. Notably, the incorporation of the peptide resulted in an increase in modulus, elongation, and tensile strength. This was attributed to an increase in phase mixing and an increase in hydrogen bonding between the hard and soft segments. Candidate polyureas with varying levels of collagen-mimetic peptide (0%, 10%, 20%) were then subjected to degradation in collagenase media or buffer at 37 degrees C over 4 weeks. Statistically significant decreases in strength and elongation were observed in polyureas with 20% peptide content after collagenase treatment, whereas specimens in phosphate-buffered saline showed no statistically significant difference. These observations confirmed that enzyme-specific degradation was conferred to the polyurea. Overall, these polyureas hold great promise as a material for ligament reconstruction due to the promising mechanical properties and potential for cell-mediated degradation. PMID- 27990259 TI - Anterior single odontoid screw placement for type II odontoid fractures: our modified surgical technique and initial results in a cohort study of 15 patients. AB - Objective: Anterior odontoid screw fixation for type II odontoid fracture is the ideal management option. However in the context of unavailability of an O-arm or neuro-navigation and poor images from the available C-arm may be an obstacle to ideal trajectory and placement of the odontoid screw. We herein detail our surgical technique so as to ensure a correct trajectory and subsequent good fusion in Type II odontoid fractures. This may be advantageous in clinical set ups lacking state of the art facilities. Methods and Results: In this cohort study we included 15 consecutive patients who underwent anterior odontoid screw placement. We routinely dissect the longus colli to completely visualize the entire width of C3 body. We then perform a median C2-C3 disectomy followed by creating a gutter in the superior end of C3 body. We then guide the Kirchsner (K) wire purchasing adequate anterior cortex of C2. Rest of the procedure follows the similar steps as described for odontoid screw placement. We achieved 100% correct trajectory and screw placement in our study. There were no instances of screw break out, pull out or nonunion. There was one patient mortality following myocardial infarction in our study. Conclusion: Preoperative imaging details, proper patient positioning, meticulous dissection, thorough anatomical knowledge and few added surgical nuances are the cornerstones in ideal odontoid screw placement. This may be pivotal in managing patients in developing nations having rudimentary neurosurgical set up. PMID- 27990260 TI - Genomic variant annotation workflow for clinical applications. AB - Annotation and interpretation of DNA aberrations identified through next generation sequencing is becoming an increasingly important task. Even more so in the context of data analysis pipelines for medical applications, where genomic aberrations are associated with phenotypic and clinical features. Here we describe a workflow to identify potential gene targets in aberrated genes or pathways and their corresponding drugs. To this end, we provide the R/Bioconductor package rDGIdb, an R wrapper to query the drug-gene interaction database (DGIdb). DGIdb accumulates drug-gene interaction data from 15 different resources and allows filtering on different levels. The rDGIdb package makes these resources and tools available to R users. Moreover, rDGIdb queries can be automated through incorporation of the rDGIdb package into NGS sequencing pipelines. PMID- 27990264 TI - Creating a driving profile for older adults using GPS devices and naturalistic driving methodology. AB - Background/Objectives: Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. Our objective was to describe the process and associated challenges in adapting an existing, commercial, off-the-shelf (COTS), in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers. Design: The Azuga G2 Tracking Device TM was installed in each participant's vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven. Setting: The Knight Alzheimer's Disease Research Center at Washington University School of Medicine. Participants: Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance. Participants were aged 65+ years and had normal cognition. Measurements: Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations. Temporal components included number of trips taken during different times of the day. Behavioral components included number of hard braking, speeding and sudden acceleration events. Methods: Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS. Results: Primary locations were confirmed to be 100% accurate when compared to known addresses. Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns. Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night. Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period. Conclusions: Compared to cameras and highly instrumented vehicle in other naturalistic studies, the compact COTS device was quickly installed and transmitted high volumes of data. Driving Profiles for older adults can be created and compared month-to-month or year-to year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions. PMID- 27990265 TI - Building pathway graphs from BioPAX data in R. AB - Biological pathways are increasingly available in the BioPAX format which uses an RDF model for data storage. One can retrieve the information in this data model in the scripting language R using the package rBiopaxParser, which converts the BioPAX format to one readable in R. It also has a function to build a regulatory network from the pathway information. Here we describe an extension of this function. The new function allows the user to build graphs of entire pathways, including regulated as well as non-regulated elements, and therefore provides a maximum of information. This function is available as part of the rBiopaxParser distribution from Bioconductor. PMID- 27994851 TI - Prediction of abdominal aortic aneurysm calcification by means of variation of high-sensitivity C-reactive protein. AB - OBJECTIVE: Abdominal aortic aneurysms are a major cause of death in developed countries, and thrombus and calcification of the aneurysm have been linked to increased complications. This study was conducted in order to identify the biochemical marker associated to the presence of intraluminal thrombus or calcification progression of the aneurysm. DESIGN: Several clinical laboratory parameters were measured in patients with abdominal aortic aneurysms, in particular those already demonstrated to be related to the pathology, such as lipoprotein (a), white blood cell count, fibrinogen and high-sensitivity C reactive protein. Most of the patients were analysed for the presence of thrombus or aorta calcification using CT angiography. RESULTS: Unlike previous findings, we found no association between intraluminal thrombus formation and lipoprotein (a), but we evidenced that patients with lower grade of calcification tend to have higher plasma high-sensitivity C-reactive protein values compared with patients with a higher degree of calcification. Instead, no association was found with either white blood cell count or fibrinogen level. CONCLUSIONS: This study suggests that high-sensitivity C-reactive protein is a useful biomarker to assess the evolution of calcification and could be used in triaging patients to identify those who should undergo a rapid imaging, thus allowing prompt initiation of treatment or rule-out suspicious patients from non-essential imaging repetition. PMID- 27994852 TI - Macrophage in chronic kidney disease. AB - Chronic kidney disease (CKD) has become a major health problem worldwide. This review describes the role of macrophages in CKD and highlights the importance of anti-inflammatory M2 macrophage activation in both renal fibrosis and wound healing processes. Furthermore, the mechanisms by which M2 macrophages induce renal repair and regeneration are still under debate and currently demand more attention. The M1/M2 macrophage balance is related to the renal microenvironment and could influence CKD progression. In fact, an inflammatory renal environment and M2 plasticity can be the major hurdles to establishing macrophage cell-based therapies in CKD. M2 macrophage cell-based therapy is promising if the M2 phenotype remains stable and is 'fixed' by in vitro manipulation. However, a greater understanding of phenotype polarization is still required. Moreover, better strategies and targets to induce reparative macrophages in vivo should guide future investigations in order to abate kidney diseases. PMID- 27994853 TI - HIV and kidney diseases: 35 years of history and consequences. AB - Kidney diseases in human immunodeficiency virus (HIV)-infected patients are often misdiagnosed. Despite reductions in morbidity and mortality owing to widespread use of highly effective combination antiretroviral therapy (cART), acute kidney injury (AKI) and chronic kidney disease (CKD) are still more common in these patients than in the general population, and are associated with poor health outcomes. HIV-associated nephropathy and HIV immune complex kidney diseases are the more recognizable HIV-related kidney diseases. However, a broad spectrum of kidney disorders related or not directly related with HIV infection can be observed, including cART-induced AKI, CKD, proximal tubular dysfunction, crystalluria and urolithiasis, among others. This review summarizes the major epidemiologic studies of kidney diseases in HIV-infected patients, discusses novel approaches that may potentially limit nephrotoxicity such as the use of tenofovir alafenamide, and outlines current screening measures for early diagnosis of kidney dysfunction or tubular damage, and for accurate detection of increased risk for acute or chronic kidney diseases. PMID- 27994854 TI - Consequences of morbid obesity on the kidney. Where are we going? AB - Obesity and morbid obesity are modifiable risk factors for the development and progression of kidney disease. Obesity has reached epidemic proportions and is currently an important health problem in Europe, so it is necessary to develop therapeutic and preventive strategies. The obesity-related glomerulopathy has been defined as a secondary form of focal segmental glomerulosclerosis, and its most characteristic feature is glomerulomegaly. The renal evolution of patients with obesity-related glomerulopathy (ORG) who have not been treated is unfavourable. However, morbidly obese patients with ORG that underwent bariatric surgery and drastic weight loss had a better outcome. Many inflammatory factors have been implicated in the pathogenic mechanism of renal disease in obesity. Hypoadiponectinaemia, hyperleptinaemia and hyperaldosteronism have been associated with glomerular injury in obese patients. The application of modern techniques has provided important insights that increase the current understanding of ORG. However, further investigation is needed. PMID- 27994855 TI - Treatment with rituximab in idiopathic membranous nephropathy. AB - BACKGROUND: Rituximab represents a valid therapeutic option to induce remission in patients with primary glomerulonephritis. Despite several studies proving its efficacy in improving outcomes in patients with membranous nephropathy (MN), its role in therapeutic protocols is not yet defined. METHODS: We studied 38 patients with idiopathic MN treated with rituximab (in 13 patients as first-line therapy, in the remaining 25 after conventional immunosuppressive therapy). The patients were analyzed for a 15-month median (interquartile range 7.7-30.2) follow-up, with serial monitoring of 24-h proteinuria, renal function and circulating CD19+ B cells. RESULTS: The percentages of patients who achieved complete remission, partial remission and the composite endpoint (complete or partial remission) were 39.5% (15 patients), 36.8% (14 patients) and 76.3% (29 patients), respectively. The 24-h proteinuria was reduced significantly during the entire period of follow up (from a baseline value of 6.1 to 0.9 g/day in the last visit; P < 0.01), while albuminemia increased constantly (from a baseline value of 2.6 to 3.5 g/dL in the last observation; P < 0.01). Renal function did not significantly change during the observation period. Circulating CD19+ B cells were reduced significantly from the baseline value to the 24-month value (P < 0.01); data about anti phospholipase A2 receptor antibodies were available in 14 patients, 10 of which experienced a decreasing trend after treatment. No significant adverse events were described during and after infusions. CONCLUSIONS: The present study confirmed that treatment with rituximab was remarkably safe and allowed for a large percentage of complete or partial remissions in patients with MN. PMID- 27994856 TI - C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome. AB - BACKGROUND: C3 glomerulopathy (C3G) includes both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) and is defined by C3-dominant deposits on immunofluorescence. Dysfunction of the alternative pathway (AP) of complement is central to the pathophysiology of C3G and young patients often harbor genetic alterations of AP mediators. Recently, a link between C3G and paraproteinemia has been established. We performed this study to better characterize older patients with C3G where this association is more frequently seen. METHODS: Fourteen biopsies from 12 patients meeting diagnostic criteria for C3G were identified in patients > 49 years of age from 2005 to 2015 after exclusion of cases containing masked monotypic immunoglobulin deposits. Pathologic and clinical features were reviewed. RESULTS: The median age was 63.5 years and 75% of patients were male. All had renal insufficiency at presentation. Kidney biopsy showed DDD in three patients and C3GN in the remainder. Serum protein electrophoresis revealed a paraprotein in 10 patients, 8 of which had a plasma cell dyscrasia on bone marrow biopsy. A membranoproliferative pattern of glomerular injury was seen in 64% of biopsies, while mesangial proliferative and endocapillary proliferative patterns were seen less frequently. Among patients with at least 1 year of follow-up (n = 9), five were on renal replacement therapy, three showed stable (but impaired) kidney function and one demonstrated improvement. CONCLUSIONS: C3G is an uncommon but important cause of kidney injury in older adults and associates with a high prevalence of paraproteinemia. In adult patients with C3G, prognosis is guarded as most patients showed either progression to end-stage kidney disease or stable but impaired kidney function. PMID- 27994858 TI - Renal tubular dysgenesis: antenatal ultrasound scanning and molecular investigations in a Saudi Arabian family. AB - Autosomal recessive renal tubular dysgenesis (RTD) is a rare lethal disease affecting renal development before birth. RTD is manifested by anuria and severe hypotension resulting in oligohydramnios and birth defects known as Potter's syndrome. Homozygous or compound heterozygous mutations in genes encoding components of the renin-angiotensin system (ACE, AGT, AGTR1 and REN) have been reported to cause RTD. A consanguineous family with a history of multiple stillbirths was investigated using prenatal ultrasound and molecular genetic analysis of an affected foetus. Prenatal ultrasound scan suggested RTD, and a novel homozygous frameshift mutation c.299_300delAA (p.Lys100Serfs*4) in the REN gene was identified by whole-exome sequencing, which segregated with parental DNA samples. RTD remains a rare but important cause of prenatal and perinatal death and may present with antenatally hyperechogenic kidneys. PMID- 27994857 TI - Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey. AB - BACKGROUND: Adenine phosphoribosyltransferase deficiency is an inborn error of metabolism that can cause kidney disease from crystalline nephropathy or kidney stones. METHODS: We present three cases from a single centre with varied presentations to illustrate how increasing awareness led to better patient identification. We then undertook a cross-sectional survey of all the patients identified from the Purine Research Laboratory in the UK since 1974. RESULTS: Our index case presented with recurrent nephrolithiasis and was diagnosed on stone analysis, the second case presented with acute kidney injury and the third case was identified from a biopsy undertaken for acute on chronic kidney injury. Genetic studies identified two novel mutations. Twenty patients were retrospectively identified. The mean age at diagnosis was 25 years (range 2-70); eight were <20 years, seven were 20-40 years and five were >40 years. Five of the 20 patients were deceased, 3 after end-stage renal disease (ESRD). Twelve have normal renal function, one had CKD stage 3, one had severe kidney disease and one was on dialysis. CONCLUSIONS: Adenine phosphoribosyltransferase deficiency presents in a wide spectrum in all age groups. Patients can be completely asymptomatic and kidney disease may be incorrectly attributed to other conditions. Outcome is poor in late diagnosis and there is a high prevalence of ESRD. Patients with unexplained renal stone disease or deterioration in kidney function should be considered for screening. Identification and surveillance of patients in the UK can improve. There is now a rare disease registry with meetings organized that include patients, families and health care providers to improve awareness. PMID- 27994859 TI - Primary sclerosing cholangitis: a new cause of distal renal tubular acidosis. AB - We describe the first case of distal renal tubular acidosis (dRTA) associated with primary sclerosing cholangitis. A 26-year-old Lao-Thai male patient presented with severe jaundice, metabolic acidosis and hypokalaemia. He was diagnosed of dRTA. Liver transplantation resulted in correction of electrolyte disturbances and hyperbilirubinaemia. A fludrocortisone-furosemide test revealed normal urinary acidification, demonstrating no residual dRTA. This observation suggests that dRTA may be an early manifestation of bilirubin-associated nephropathy or the consequence of an immune mechanism. PMID- 27994860 TI - The rise and rise of randomized clinical evidence in Sub-Saharan Africa. AB - Sub-Saharan Africa is facing a rising tide of chronic disease, including chronic kidney disease, but the current research literature provides little evidence to guide the practice of nephrology in resource-poor settings. In this issue of CKJ, Waziri & Bello present a trial of two formulations of intravenous iron for patients with anaemia of chronic kidney disease in Nigeria. This study typifies a growing body of work from researchers from low-middle income countries addressing the evidence gaps that they meet in their everyday practice. Collaboration with clinical trialists and health economists from the global renal research community is suggested as an important way to expand, at low cost, the randomized evidence base in this region. PMID- 27994861 TI - Comparison of intravenous low molecular weight iron dextran and intravenous iron sucrose for the correction of anaemia in pre-dialysis chronic kidney disease patients: a randomized single-centre study in Nigeria. AB - BACKGROUND: Intravenous low molecular weight iron dextran and iron sucrose have been used for correction of iron deficiency for many years and have been shown to improve anaemia in chronic kidney disease (CKD). However, there is a paucity of head to head comparisons of these parenteral iron preparations. Such comparative efficacy data would be of particular interest in resource-limited African countries, where the majority of CKD patients are unable to afford erythropoiesis stimulating agents. Therefore, the aim of this study was to compare the effects of these two intravenous iron preparations in pre-dialysis CKD patients. METHODS: Sixty-seven anaemic pre-dialysis CKD patients were randomized to one of two treatment groups. The low molecular weight iron dextran group (n = 33) received 1000 mg of low molecular weight iron dextran intravenously in four divided doses of 250 mg. The iron sucrose group (n = 34) received 1000 mg of iron sucrose intravenously in five divided doses of 200 mg. Complete blood count, serum creatinine, serum iron, unsaturated iron binding capacity, serum ferritin and transferrin saturation were assessed at baseline. The baseline parameters were repeated in all patients on Day 24. The primary outcome was the proportion of patients achieving a rise in haemoglobin (Hb) concentration of >=1.0 g/dL after iron therapy. RESULTS: There was no significant difference in the proportion of patients achieving the primary end point between both arms of the study: [7 (21.9%) low molecular weight iron dextran versus 11 (32.4%) iron sucrose; relative risk 0.68, 95% confidence interval (CI): 0.19-1.70; P = 0.23]. At Day 24, the mean increase in Hb concentration from baseline was comparable between the two groups: low molecular weight iron dextran 0.4 +/- 0.7 g/dL versus iron sucrose 0.6 +/- 0.9 g/dL, mean difference 0.2 g/dL (95% CI: -0.26-0.61; P = 0.28). The proportion of patients that experienced at least one or more adverse events was 27.3% in the iron dextran group versus 14.7% in the iron sucrose arm (P = 0.21). CONCLUSION: Both intravenous low molecular weight iron dextran and intravenous iron sucrose are effective in correcting iron deficiency and anaemia in pre-dialysis CKD patients. PMID- 27994862 TI - Dialysis modality selection: physician guided or patient led? AB - The process of choosing dialysis modality for patients is complex and requires input from the expert renal team. Although it is commonplace for nephrologists to recommend dialysis modalities to patients, this might not always lead to the patient receiving treatment which they regard as most suitable. Nephrologists should consider whether it is appropriate for pre-dialysis education to be directive, or whether the choice between treatment options should be led by the patient. PMID- 27994863 TI - GUIDE, a structured pre-dialysis programme that increases the use of home dialysis. AB - BACKGROUND: Despite the many advantages it offers, the percentage of dialysis patients that receive home dialysis [peritoneal dialysis (PD) or home haemodialysis (HHD)] in the Netherlands has declined over the last decade. Pre dialysis education could stimulate the use of home dialysis. This article presents the results of the pre-dialysis programme GUIDE, with regard to the following question: Does the implementation of a structured pre-dialysis programme with a home-focused approach increase the number of pre-dialysis patients that choose and receive home dialysis? METHODS: The GUIDE process starts when a patient has an eGFR of 15 mL/min/1.73 m2. The process begins with a home visit from a case manager and the completion of questionnaires by the patient, the case manager and the nephrologist. A multidisciplinary meeting (MDM) is held to determine a specific patient profile (or treatment recommendation). This is followed by patient education, a second MDM and finally the selection of the treatment by the patient and the nephrologist. This retrospective observational study describes the selection process of all patients that received a treatment recommendation between 12 September 2013 and 18 December 2014 at Meander Medical Centre. Data were collected by file research and analysis of questionnaires. RESULTS: One hundred and two patients were included. They started the process at a mean eGFR of 12.3 mL/min/1.73 m2. Home dialysis was recommended for 62.8% of the patients who were advised to have dialysis treatment. Of the patients that opted for dialysis, 34.2% chose PD and 8.2% chose HHD; 22.9% started home dialysis as their first therapy, compared with 17.6% in the months before implementation of GUIDE. Finally, 32.1% of the patients that received dialysis therapy received home dialysis. In the months before GUIDE, an average of just 19.5% of the patients that received dialysis received home dialysis. CONCLUSIONS: In comparison to historical data, the pre-dialysis programme GUIDE increases the number of patients that choose and receive home dialysis. PMID- 27994864 TI - Diabetic kidney disease patients on hemodialysis: a retrospective survival analysis across different socioeconomic groups. AB - BACKGROUND: Diabetic kidney disease is the leading cause of stage 5 chronic kidney disease (CKD) in India. Renal replacement therapy (RRT) is accessible to very few patients because of socioeconomic deprivation. We studied the effect of diabetes and socioeconomic status on the outcome of patients on maintenance hemodialysis (MHD). METHODS: We retrospectively analyzed the outcome of 897 patients (629 males/268 females; mean age +/- standard deviation 48.69 +/- 14.27 years) initiated on MHD from 2003 to 2009 at five dialysis centers in south India. There were 335 type 2 diabetic patients and 562 non-diabetic patients. Group 1 comprised the self-paying patients (518 patients) and Group 2 included the TANKER Foundation charity dialysis patients (379 patients). We compared the 5 year survival rates of Group 1 versus Group 2 and also those of diabetic versus non-diabetic patients, using the Kaplan-Meier survival estimator. RESULTS: Of the 897 patients, 166 patients survived, 350 died, 234 were lost to follow-up, 137 had renal transplantation and 10 patients were transferred to peritoneal dialysis. The 5-year survival rates after censoring were 20.7 and 38.2% for diabetic and non-diabetic patients, respectively (P < 0.001). The survival rate of diabetic patients was significantly lower, compared with non-diabetic patients, in Group 2 (P < 0.001), but not significantly lower in Group 1 (P = 0.226). CONCLUSIONS: Diabetic patients have poor survival rates on MHD, especially those from poor socioeconomic groups. Due to scarce RRT facilities and poor survival rates of diabetic patients, prevention, early detection and management of diabetic CKD patients should be the way to go forward. PMID- 27994865 TI - Morbidity, mortality and quality of life in the ageing haemodialysis population: results from the ELDERLY study. AB - BACKGROUND: The physical-functional and social-emotional health as well as survival of the elderly (>=75 years of age) haemodialysis patient is commonly thought to be poor. In a prospective, multicentre, non-interventional, observational study, the morbidity, mortality and quality of life (QoL) in this patient group were examined and compared with a younger cohort. METHODS: In 92 German dialysis centres, 2507 prevalent patients 19-98 years of age on haemodialysis for a median of 19.2 months were included in a drug monitoring study of darbepoetin alfa. To examine outcome and QoL parameters, 24 months of follow-up data in the age cohorts <75 and >=75 years were analysed. Treatment parameters, adverse and intercurrent events, hospitalizations, morbidity and mortality were assessed. QoL was evaluated by means of the 47-item Functional Assessment of Chronic Illness Therapy-Anaemia score (FACT-An, version 4). RESULTS: The 2-year mortality rate was 34.7% for the older cohort and 15.8% for the younger cohort. The mortality rate for the haemodialysed elderly patients was 6.2% higher in absolute value compared with the age-matched background population. A powerful predictor of survival was the baseline FACT-An score and a close correlation with the 20-item anaemia subscale (AnS) was demonstrated. While the social QoL in the elderly patients was more stable than in the younger cohort (leading to equivalent values at the end of the study period), a pronounced deterioration of physical and functional status was observed. The median number of all-cause hospital days per patient-year was 12.3 for the elderly cohort and 8.9 for the younger patient population. The overall 24-month hospitalization rate was only marginally higher in the elderly cohort (34.0 versus 33.3%). CONCLUSIONS: In this observational study, the mortality rate of elderly haemodialysis patients was not exceedingly high compared with the age-matched background population. Furthermore, the hospitalization rate was only slightly higher compared with the younger age group and the median yearly hospitalization time trended lower compared with registry data. The social well-being of elderly haemodialysis patients showed a less pronounced decline over time and was equal to the score of the younger cohort at the end of the study period. The physical and functional status in the elderly patients was lower and showed a sharper decline over time. The baseline FACT-An score correlated closely with the 24 month survival probability. PMID- 27994866 TI - Facilitating access to the renal transplant waiting list does not increase the number of transplantations: comparative study of two French regions. AB - BACKGROUND: In France, there are important regional disparities of access to the renal transplant waiting list and transplantation. Our objectives were to compare the characteristics of patients with end-stage renal disease (ESRD) of two French regions (Ile-de-France and Bretagne) and to identify determinants of access to the waiting list and subsequent transplantation, with a focus on temporary inactive status (TIS) periods. METHODS: All 18-80-year-old incident patients who started dialysis in Ile-de-France or Bretagne between 2006 and 2009 were included (n = 6160). Associations between patients' characteristics and placement on the waiting list or transplantation were assessed using a Fine and Gray model to take into account the competing risk of death and living donor transplantation. RESULTS: At the end of the follow-up (31 December 2013), more patients had undergone transplantation in Bretagne than in Ile-de-France (30 versus 27%), although the percentage of waitlisted patients was higher in Ile-de-France than in Bretagne (47 versus 33%). More patients were on TIS and with a longer median TIS duration in Ile-de-France. Independent of age and clinical characteristics, patients in Bretagne were less likely to be waitlisted than those in Ile-de France [subdistribution hazard ratio 0.77 (95% confidence interval 0.7-0.9)]. After waitlisting, patients in Bretagne were four times more likely to be transplanted. CONCLUSIONS: Our study highlights clinical practice differences in Bretagne and Ile-de-France and shows that facilitating access to the waiting list is not sufficient to improve access to renal transplantation, which also depends on organ availability. PMID- 27994867 TI - An observational study of health literacy and medication adherence in adult kidney transplant recipients. AB - BACKGROUND: There is a high prevalence of non-adherence to immunosuppressants in kidney transplant recipients. Although limited health literacy is common in kidney recipients and is linked to adverse outcomes in other medical populations, its effect on medication adherence in kidney transplant recipients remains poorly understood. The objective was to investigate the effect of lower health literacy on immunosuppressant adherence. METHODS: Kidney recipients who were at least 6 months post-transplant and outpatients of Vancouver General Hospital in B.C., Canada were recruited through invitation letters. A total of 96 recipients completed the Health Literacy Questionnaire, which provides a multifactorial profile of self-reported health literacy and the Transplant Effects Questionnaire Adherence subscale measuring self-reported immunosuppressant adherence. Hierarchical linear regression was used to analyze the association between health literacy and adherence after controlling for identified risk factors of non adherence. RESULTS: Our sample was on average 53 years old, 56% male and 9 years post-transplant. Kidney recipients reported low levels of health literacy on scales measuring active health management and critical appraisal of information and 75% reported non-perfect adherence. Worse adherence was associated with poorer overall health literacy (DeltaR2 = 0.08, P = 0.004) and lower scores on six of nine of the health literacy factors. CONCLUSIONS: Poorer health literacy is associated with lower immunosuppressant adherence in adult kidney transplant recipients suggesting the importance of considering a recipient's level of health literacy in research and clinical contexts. Medication adherence interventions can target the six factors of health literacy identified as being risk factors for lower medication adherence. PMID- 27994869 TI - Erratum: A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis. AB - [This corrects the article on p. 424 in vol. 9, PMID: 27274828.]. PMID- 27994868 TI - Outcomes of living kidney donors with medullary sponge kidney. AB - BACKGROUND: Patients with medullary sponge kidney (MSK) commonly encounter recurrent nephrolithiasis. The existing knowledge on safety of donors with MSK has not been studied. METHODS: We conducted a retrospective cohort study at a tertiary referral hospital to assess the outcomes of living kidney donors with MSK. All adults with MSK (N = 26) who underwent nephrectomy as living kidney donors between January 2000 and September 2014 were included. Non-donors with MSK (N = 78) were randomly selected by matching the year of birth and the comorbidity score with a ratio of 1:3 for comparison. RESULTS: The incident rates of symptomatic stone were 0.7, 0.4 and 4.9 events/100 patient-years in donors, recipients and non-donors, respectively. After adjusting for history of kidney stones and baseline estimated glomerular filtration rate (eGFR), the kidney stone related event was significantly lower in donors than in non-donors (hazard ratio 0.14; 95% confidence interval 0.01-0.66). One recipient of MSK living donor had symptomatic stone at median follow-up time of 8.4 years (interquartile range 5.6 12.4 years). None of MSK donors had hypercalciuria, hypocitraturia or hyperoxaluria prior to kidney donation. At 5 years after the index surgery date, there was no significant difference in eGFR between donors and non-donors (76.1 versus 70.9 mL/min/1.73 m2, P = 0.12). CONCLUSIONS: These findings are reassuring for the safety of MSK kidney donors with normal kidney function, low kidney stone risk and no significant comorbidity. PMID- 27994870 TI - Right hypochondrial abscess: A rare consequence of supportive cholecystitis. AB - INTRODUCTION: Spontaneous cholecystocutaneous abscess is an extremely uncommon complication of acute suppurative cholecystitis. Over the past century very few cases of spontaneous cholecystocutaneous fistulas have been described in the medical literature. We, here, report a case of abdominal wall abscess secondary to cholecystocutaneous fistula. CASE REPORT: A 78 -year-old male presented as an emergency with a 2 days history of fever, malaise and a right subcostal mass. CT scan of abdomen showed huge abdominal wall abscess communicating intraabdominally to subhepatic area related to gallbladder. CONCLUSION: A high index of suspicion is necessary to diagnose this entity preoperatively and to avoid associated morbidity. PMID- 27994871 TI - Short-term outcomes after distal pancreatectomy: Laparotomy vs. laparoscopy - A single-center series. AB - BACKGROUND: Laparoscopic distal pancreatectomy was introduced 15 years ago, but it is still not widely used. The aim of the study was to compare the postoperative complications and length of stay between open and laparoscopic distal pancreatectomy. MATERIALS AND METHODS: A search of our institutional pancreas database was performed. All consecutive distal pancreatectomy patients from 2000 to 2015 were identified. Demographics, peri- and postoperative outcomes were reviewed. Postoperative complications were graded using Clavien classification. Standard statistical analyses were performed. RESULTS: One hundred and five patients underwent distal pancreatectomy (45 women, 60 men, median age of 63 years). Seventy-nine cases were performed open and 26 by laparoscopy (conversion rate from laparoscopy to laparotomy: 7/26). Characteristics of both groups were similar. The tumor proportion was similar in both groups (56/79 and 23/26, p = 0.114). Overall complication rate was 41/79 (52%) in the open group and 9/26 (36%) in the laparoscopy group (p = 0.175). Two patients died during hospital stay in the open group compared to 0 in the laparoscopy group (p = 1). The fistula rates were comparable (17/79 and 5/26, p = 1). Median length of stay was shorter for the laparoscopy group (8 vs. 12 days, p < 0.001), as well as the median intermediate care stay (1 vs. 3 days, p = 0.004). CONCLUSION: Short-term outcomes after open and laparoscopic distal pancreatectomy regarding postoperative complications and mortality were similar, but length of stay was significantly shorter for the laparoscopic approach. Hence, laparoscopic distal pancreatectomy should be offered to all suitable patients. PMID- 27994872 TI - Air bubbles are released by thoracic endograft deployment: An in vitro experimental study. AB - PURPOSE: Embolic stroke is a dreaded complication of thoracic endovascular aortic repair. The prevailing theory about its cause is that particulate debris from atherosclerotic lesions in the aortic wall are dislodged by endovascular instruments and embolize to the brain. An alternative source of embolism might be air trapped in the endograft delivery system. The aim of this experimental study was to determine whether air is released during deployment of a thoracic endograft. METHODS: In an experimental benchtop study, eight thoracic endografts (five Medtronic Valiant Thoracic and three Gore TAG) were deployed in a water filled transparent container drained from air. Endografts were prepared and deployed according to their instructions for use. Deployment was filmed and the volume of air released was collected and measured in a calibrated syringe. RESULTS: Air was released from all the endografts examined. Air volumes ranged from 0.1 to 0.3 mL for Medtronic Valiant Thoracic and from <0.025 to 0.04 mL for Gore TAG. The largest bubbles had a diameter of approximately 3 mm and came from the proximal end of the Medtronic Valiant device. CONCLUSION: Air bubbles are released from thoracic endografts during deployment. Air embolism may be an alternative cause of stroke during thoracic endovascular aortic repair. PMID- 27994873 TI - Submental thyroid ectopy might cause subclinical hypothyroidism in early childhood. AB - OBJECTIVE: Thyroid ectopy is a rare condition resulting from abnormal embryologic development and migration of the gland. Sublingual is the most common thyroid ectopy; all other ectopic thyroid locations occur very rare. There are no reports in the literature that describe the clinical course of patients with congenital hypothyroidism due to thyroid ectopy. METHODS AND RESULTS: We present a child with congenital hypothyroidism detected on neonatal screening which had a subclinical course during follow-up. Scintigraphy revealed submental thyroid ectopy, a rare ectopic location and no orthotopic thyroid gland. CONCLUSION: Our case is unique because of the rare ectopic thyroid location but also of the unexpected clinical course; however, further thyroid monitoring is required for the therapy adjustment and detection of any changes in the ectopic tissue. PMID- 27994874 TI - Pelvic congestion syndrome masquerading as osteoarthritis of the hip. AB - OBJECTIVES: Pelvic congestion syndrome (PCS) is associated with pelvic vein reflux (PVR), occasionally secondary to venous compression. Its symptoms, usually intra-pelvic, are alleviated following the abolition of this reflux by pelvic vein embolisation (PVE). The objective of this report is to present two cases of left hip pain, erroneously diagnosed as osteoarthritis, which disappeared after successful PVE and abolition of PVR. METHODS: Two females presented with lower limb varicose veins, and also had a history of left-sided hip pain. Both had previously been investigated for the hip pain and diagnosed as osteoarthritis despite minimal arthritic changes on pelvic X-rays. During investigation for lower limb varicose veins, both showed a pelvic origin for their leg veins and hence underwent transvaginal duplex ultrasound. This revealed PVR, and PVE was planned in both patients. RESULTS: Both patients underwent PVE and reported 'miraculous' resolution of left hip pain and also PCS symptoms including pelvic pain, irritable bowel issues and the disappearance of pelvic dragging, with almost immediate disappearance of vulval and vaginal varicosities. One patient also noted reduced clitoral sensitivity. CONCLUSION: Manifestations of PCS may vary in terms of intra- or extra-pelvic signs. PCS and PVR should be considered in the differential diagnosis of patients with arthritic symptoms in the hip without evident radiographic evidence. PMID- 27994875 TI - Management of metastatic thyroid cancer in pregnancy: risk and uncertainty. AB - : Metastatic thyroid cancer is an uncommon condition to be present at the time of pregnancy, but presents a challenging paradigm of care. Clinicians must balance the competing interests of long-term maternal health, best achieved by iatrogenic hyperthyroidism, regular radioiodine therapy and avoidance of dietary iodine, against the priority to care for the developing foetus, with inevitable compromise. Additionally, epidemiological and cellular data support the role of oestrogen as a growth factor for benign and malignant thyrocytes, although communicating the magnitude of this risk to patients and caregivers, as well as the uncertain impact of any pregnancy on long-term prognosis, remains challenging. Evidence to support treatment decisions in this uncommon situation is presented in the context of a case of a pregnant teenager with known metastatic papillary thyroid cancer and recent radioiodine therapy. LEARNING POINTS: Pregnancy is associated with the growth of thyroid nodules due to stimulation from oestrogen receptors on thyrocytes and HCG cross-stimulation of the TSH receptor.Thyroid cancer diagnosed during pregnancy has not been shown to be associated with increased rates of persistent or recurrent disease in most studies.There is little evidence to guide the management of metastatic thyroid cancer in pregnancy, where both maternal and foetal wellbeing must be carefully balanced. PMID- 27994876 TI - Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A. AB - : Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon-intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification. LEARNING POINTS: C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing. PMID- 27994878 TI - The impact of hair coat color on longevity of Holstein cows in the tropics. AB - BACKGROUND: Over two decades of observations in the field in South East Asia and Hawai'i suggest that majority of the commercial dairy herds are of black hair coat. Hence a simple study to determine the accuracy of the observation was conducted with two large dairy herds in Hawaii in the mid-1990s. METHODS: A retrospective study on longevity of Holstein cattle in the tropics was conducted using DairyComp-305 lactation information coupled with phenotypic evaluation of hair coat color in two large dairy farms. Cows were classified into 3 groups: a) black (B, >90%); b) black/white (BW, 50:50) and c) white (W, >90%). Cows with other hair coat distribution were excluded from the study. In farm A, 211 out of 970 cows were identified having 4 or more lactations. In farm B, 690 out of 1,350 cows were identified with 2 or more lactations for the study. RESULTS: The regression analyses and the Wilcoxon-Log-rank test for survival probability showed that Holstein cattle with 90% black hair coat had greater longevity compared to Holstein cattle with 90% white hair coat. CONCLUSIONS: This study suggests that longevity of Holstein cattle in tropical regions was influenced by hair coat color and characteristics. PMID- 27994877 TI - 'Halomonas saudii' sp. nov., a new bacterial species isolated from marine plant Halocnemum strobilaceum. AB - We report here the main characteristics of 'Halomonas saudii' strain Saudii DR2 (CSUR P2512), a new species of the Halomonas genus that was isolated from a rhizosphere of Halocnemum strobilaceum in April 2015. PMID- 27994879 TI - Diametric measurement of foveal avascular zone in healthy young adults using optical coherence tomography angiography. AB - BACKGROUND: The objective of this study is to measure the diameter size of foveal avascular zone (FAZ) in both eyes of healthy young adults using optical coherence tomography (OCT) angiography. METHODS: A cross sectional study to measure the foveal avascular zone in healthy young adults. Subjects underwent OCT angiography using Zeiss AngioPlex OCT angiography in both eyes. RESULTS: 30 eyes of 15 healthy young adults were evaluated. The mean horizontal FAZ diameter of superficial vascular plexus was 661.166 +/- 119.99 microns and mean vertical FAZ diameter was 660.033 +/- 96.169 microns (P = 0.9442). The mean horizontal FAZ diameter of deep vascular plexus was 1011.2 +/- 154.526 microns and the mean vertical FAZ diameter of deep vascular plexus was 818.033 +/- 102.108 microns. There was no difference between the contralateral eyes of subjects in FAZ diameter of both superficial and deep capillary plexuses. CONCLUSION: The mean diametric size of FAZ in superficial capillary plexus is 660.599 +/- 0.801 microns and deep capillary plexus is 914.616 +/- 136.589 microns. There was no significant difference with the contralateral eyes. PMID- 27994880 TI - A computer-assisted systematic quality monitoring method for cervical hip fracture radiography. AB - BACKGROUND: A thorough quality analysis of radiologic performance is cumbersome. Instead, the prevalence of missed cervical hip fractures might be used as a quality indicator. PURPOSE: To validate a computer-based quality study of cervical hip fracture radiography. MATERIAL AND METHODS: True and false negative and positive hip trauma radiography during 6 years was assessed manually. Patients with two or more radiologic hip examinations before surgery were selected by computer analysis of the databases. The first of two preoperative examinations might constitute a missed fracture. These cases were reviewed. RESULTS: Out of 1621 cervical hip fractures, manual perusal found 51 (3.1%) false negative radiographic diagnoses. Among approximately 14,000 radiographic hip examinations, there were 27 (0.2%) false positive diagnoses. Fifty-seven percent of false negative reports were occult fractures, the other diagnostic mistakes. There were no significant differences over the years. Diagnostic sensitivity was 96.9% and specificity 99.8%. Computer-assisted analysis with a time interval of at least 120 days between the first and the second radiographic examination discovered 39 of the 51 false negative reports. CONCLUSION: Cervical hip trauma radiography has high sensitivity and specificity. With computer-assisted analysis, 76% of false negative reports were found. PMID- 27994881 TI - Endovascular treatment of spontaneous isolated abdominal aortic dissection. AB - Isolated abdominal aortic dissection is a rare clinical disease representing only 1.3% of all dissections. There are a few case series reported in the literature. The causes of this pathology can be spontaneous, iatrogenic, or traumatic. Most patients are asymptomatic and symptoms are usually abdominal or back pain, while claudication and lower limb ischemia are rare. Surgical and endovascular treatment are two valid options with acceptable results. We herein describe nine cases of symptomatic spontaneous isolated abdominal aortic dissection, out of which four successfully were treated with an endovascular approach between July 2003 and July 2013. All patients were men, smokers, symptomatic (either abdominal or back pain or lower limb ischemia), with a history of high blood pressure, with a medical history negative for concomitant aneurysmatic dilatation or previous endovascular intervention. Diagnosis of isolated abdominal aortic dissection were established by contrast-enhanced computed tomography angiography (CTA) of the thoracic and abdominal aorta. All nine patients initially underwent medical treatment. In four symptomatic cases, non-responsive to medical therapy, bare metal stents or stent grafts were successfully positioned. All patients completed a CTA follow-up of at least 12 months, during which they remained symptom-free. Endovascular management of this condition is associated with a high rate of technical success and a low mortality; therefore, it can be considered the treatment of choice when it is feasible. PMID- 27994883 TI - Ultrasound Microbubbles Enhance the Neuroprotective Effect of Mouse Nerve Growth Factor on Intraocular Hypertension-Induced Neuroretina Damage in Rabbits. AB - Ultrasound microbubble combined optic protection drugs have obvious protective effect on optic nerve damage. This way of targeting drug delivery is becoming more simple, not through the whole body metabolism, avoiding drug via blood circulation when facing the decomposition and the environment in the interference and destruction process of drugs, to maximize the guarantee to reach target organs of drug concentration and to reache the maximum therapeutic effect. The technique of ultrasound microbubbles is safe, controllable, nonimmunogenic, and repeatable. It provides us with a novel idea in the administration of neuroprotective drugs. PMID- 27994882 TI - Jugular venous reflux on magnetic resonance angiography and radionuclide venography. AB - BACKGROUND: The relationship between the signal from retrograde venous flow on magnetic resonance angiography (MRA) and retrograde upward flow from the left brachiocephalic vein has not been explored. PURPOSE: To reveal the frequency of jugular venous reflux using MRA and nuclear venography in patients being evaluated for cerebral volume and blood flow. MATERIAL AND METHODS: A total of 229 patients with cognitive disturbance who had undergone brain magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) on the same day to evaluate cerebral blood flow were evaluated. Jugular venous reflux was measured on MRA and nuclear venography, which was conducted just after injection of N-isopropyl-123I-p-iodoamphetamine for the SPECT study. RESULTS: MRA showed jugular reflux in seven patients on the right side, and in 22 on the left. Nuclear venography showed jugular reflux in six patients on the right side, and in 20 on the left. CONCLUSION: Jugular venous reflux was observed mostly on the left side. Retrograde flow was observed on both MRA and nuclear venography in half of the cases, with the rest only on one of the modalities. PMID- 27994884 TI - Preservation of Preloaded DMEK Lenticules in Dextran and Non-Dextran-Based Organ Culture Medium. AB - Purpose. To determine the optimum preservation conditions for preloading DMEK lenticules using organ culture system. Methods. 8.5 mm DMEK lenticules were stripped and preserved with endothelium flap-in for 4 days at RT in an IOL cartridge that was blocked with rubber stoppers from each end. In C1, tissues were collected from tissue culture medium (TCM) and preserved in TCM. In C2, tissues were collected from transport medium (TCM + 6% dextran T500) (TM) and preserved in TM. In C3, tissues were collected from TCM and preserved in TM. Mortality, glucose uptake, histological staining, tight junctions and cell apoptosis were studied post-preservation. Results. Mortality in C1, C2, and C3 were 49.40%, 8.53%, and 27.74%, with 40.7%, 13%, and 41.8% uncovered areas. Glucose uptake (mg/mL) was 0.32, 0.43, and 0.56 in C1, C2, and C3. PAS staining showed presence of DM and endothelium in C2 but not in C1 and with fewer cells in C3. ZO-1 was expressed in all the conditions. Polymorphism was higher in C1 and C3. Mild apoptosis was observed in C3. Conclusions. Dextran may play an important role in preserving the endothelial cells before and after stripping for trifolded (endothelium-in) preloaded DMEK lenticules. PMID- 27994885 TI - Impaired Visual Motor Coordination in Obese Adults. AB - Objective. To investigate whether obesity alters the sensory motor integration process and movement outcome during a visual rhythmic coordination task. Methods. 88 participants (44 obese and 44 matched control) sat on a chair equipped with a wrist pendulum oscillating in the sagittal plane. The task was to swing the pendulum in synchrony with a moving visual stimulus displayed on a screen. Results. Obese participants demonstrated significantly (p < 0.01) higher values for continuous relative phase (CRP) indicating poorer level of coordination, increased movement variability (p < 0.05), and a larger amplitude (p < 0.05) than their healthy weight counterparts. Conclusion. These results highlight the existence of visual sensory integration deficiencies for obese participants. The obese group have greater difficulty in synchronizing their movement with a visual stimulus. Considering that visual motor coordination is an essential component of many activities of daily living, any impairment could significantly affect quality of life. PMID- 27994886 TI - Does Obesity Predispose Medical Intensive Care Unit Patients to Venous Thromboembolism despite Prophylaxis? A Retrospective Chart Review. AB - Background. Obesity is a significant issue in the critically ill population. There is little evidence directing the dosing of venous thromboembolism (VTE) prophylaxis within this population. We aimed to determine whether obesity predisposes medical intensive care unit patients to venous thromboembolism despite standard chemoprophylaxis with 5000 international units of subcutaneous heparin three times daily. Results. We found a 60% increased risk of venous thromboembolism in the body mass index (BMI) >= 30 kg/m2 group compared to the BMI < 30 kg/m2 group; however, this difference did not reach statistical significance. After further utilizing our risk model, neither obesity nor mechanical ventilation reached statistical significance; however, vasopressor administration was associated with a threefold risk. Conclusions. We can conclude that obesity did increase the rate of VTE, but not to a statistically significant level in this single center medical intensive care unit population. PMID- 27994887 TI - Acute Myocardial Infarction in a Patient with Two-Vessel Occlusion and a Large Lambl's Excrescence. AB - A 59-year-old man underwent an echocardiography study after myocardial infarction and it showed a thin, mobile mass attached to the aortic valve. A diagnosis of Lambl's excrescence (LE) was suspected. Coronary occlusion as a consequence of embolism of LE's material could not be excluded and the patient underwent surgical excision. Histology confirmed the diagnosis; however a differential diagnosis with papillary fibroelastoma could not be established because both of these structures are histologically indistinguishable. A brief survey of the literature is presented. Evidence-based recommendations for treatment have not been established yet. PMID- 27994888 TI - A Rare Malignant Peripheral Nerve Sheath Tumor of the Maxilla Mimicking a Periapical Lesion. AB - Malignant peripheral nerve sheath tumor is a malignant neoplasm that is rarely found in the oral cavity. About 50% of this tumor occurs in patients with neurofibromatosis type I and comprises approximately 10% of all soft tissue sarcomas of head and neck region. Intraosseous malignant peripheral nerve sheath tumor of the maxilla is rare. This article is the first to address malignant peripheral nerve sheath tumor of the maxilla presenting as a periapical radiolucency on nonvital endodontically treated teeth in the English medical literature. Surgical approaches to malignant soft tissue tumor vary based on the extent of the disease, age of the patient, and pathological findings. A rare case of intraosseous malignant peripheral nerve sheath tumor is reported in a 16-year old woman. The patient presented clinically with a pain involving the upper left incisors region and with defined unilocular periapical radiolucency lesion involved between the upper left incisors. An incisional biopsy was made. Histological and immunohistochemical examination were positive for S-100 protein and glial fibrillary acidic protein showed that the lesion was an intraosseous malignant peripheral nerve sheath tumor of the maxilla. Nine years after the surgery, no regional recurrence was observed. PMID- 27994889 TI - Sclerotherapy of Intraoral Superficial Hemangioma. AB - Hemangioma is the clinical term for a benign vascular neoplasm due to proliferation of the endothelial lining of blood vessels. Their most frequent location is the body skin and oral mucosa. One of the treatment modalities for hemangiomas is intralesional injection of sclerosing agents which cause the damage of blood vessels followed by their obliteration. The objective of the study was to describe the facility of application and evaluate the efficiency of sclerotherapy with aethoxysklerol 1%. Method. The case presented with intraoral submucosal hemangioma of the cheek was treated by intralesional injection of aethoxysklerol 3% diluted in water for injections at a 4 : 1 ratio (0.75%) at the first appointment and 3 : 1 (1%) at the second appointment. The effect of sclerotherapy was evaluated on the following visits in time intervals of two weeks. Results. The hemangioma disappeared without complications after the second injection of aethoxysklerol 1%. The successful results of the study were comparable to the data of literature with variations according to the used sclerosant agent, its concentration, the number of injections, and the intervals between each session. Conclusion. Since sclerotherapy is a very effective, inexpensive, and easy-to-apply treatment, it should be the treatment of choice, especially for intraoral superficial hemangiomas. PMID- 27994891 TI - The Use of Miswak as Toothbrush for Orthodontic Patient. AB - This case report presents a patient who is undergoing orthodontic treatment with upper and lower fixed appliance. An interesting point on this case is that the patient only uses Miswak as her oral hygiene tool due to her religious belief. The oral hygiene protocol was allowed and her oral health was closely monitored throughout her orthodontic treatment. PMID- 27994890 TI - New Approach to Managing Onychophagia. AB - Onychophagia is defined as a chronic habit of biting nails, commonly observed in both children and young adults. This oral habit may lead to various medical and dental problems. To date, onychophagia is considered an unsolved problem in medicine and dentistry. In this paper we describe an exclusive nonpunitive fixed appliance utilizing a stainless steel twisted round wire bonded from canine to canine, in the mandibular arch, as a treatment of onychophagia. It was used successfully in young adult patients and maintained for a month. With 9-month follow-up the treatment has satisfied the patients' expectations which may eventually yield promising implications of this new treatment to similar situations. PMID- 27994892 TI - Natural Tooth Pontic: An Instant Esthetic Option for Periodontally Compromised Teeth-A Case Series. AB - Sudden tooth loss in the esthetic zone of the maxillary or mandibular anterior region can be due to trauma, periodontal disease, or endodontic failure. The treatment options for replacing the missing tooth can vary between removable prosthesis, tooth-supported prosthesis, and implant-supported prosthesis. Irrespective of the final treatment, the first line of management would be to provisionally restore the patient's esthetic appearance at the earliest, while functionally stabilizing the compromised arch. Using the patient's own natural tooth as a pontic offers the benefits of being the right size, shape, and color and provides exact repositioning in its original intraoral three-dimensional position. Additionally, using the patient's platelet concentrate (platelet rich fibrin) facilitates early wound healing and preservation of alveolar ridge shape following tooth extraction. The abutment teeth can also be preserved with minimal or no preparation, thus keeping the technique reversible, and can be completed at the chair side thereby avoiding laboratory costs. This helps the patient better tolerate the effect of tooth loss psychologically. The article describes a successful, immediate, and viable technique for rehabilitation of three different patients requiring replacement of a single periodontally compromised tooth in an esthetic region. PMID- 27994893 TI - Cholecystocolonic Fistulas from Diverticulosis: A Potentially Missable Cause of Liver Abscesses. AB - Cholecystocolonic fistulas (CCF) due to colonic diverticulosis are a rare cause of liver abscesses. It is even rarer to simultaneously have choledocholithiasis, another cause for liver abscesses. In this case report, we found both pathologies and emphasise the need to study cholangiograms carefully so as not to miss alternative diagnoses. PMID- 27994894 TI - Ischemic Monomeric Neuropathy in a Woman with Sickle Cell Anaemia. AB - Sickle cell disease is an inherited haemoglobinopathy that can affect multiple organs and systems. The most common neurological complication in sickle cell disease is stroke and silent cerebral infarcts. Peripheral nervous system involvement has been described but is exceedingly rare. Herein, we describe the case of a young woman who presented with acute flaccid paralysis and sensory loss of the left lower extremity in the context of a painful vasoocclusive crisis which resolved rapidly after receiving an emergency automated red cell exchange transfusion. PMID- 27994896 TI - Proximal Limb Weakness in a Patient with Celiac Disease: Copper Deficiency, Gluten Sensitivity, or Both as the Underlying Cause? AB - Celiac disease has been associated with several neurologic disorders which may result from micronutrient deficiencies, coexisting autoimmune conditions, or gluten sensitivity. Copper deficiency can produce multiple neurologic manifestations. Myeloneuropathy is the most common neurologic syndrome and it is often irreversible, despite copper replacement. We report the case of a 55-year old man who presented with progressive proximal limb weakness and weight loss in the setting of untreated celiac disease without gastrointestinal symptoms. He had anemia, neutropenia, and severe hypocupremia. The pattern of weakness raised the suspicion that there was an underlying myopathy, although this was not confirmed by electrodiagnostic studies. Weakness and hematologic abnormalities resolved completely within 1 month of total parenteral nutrition with copper supplementation and a gluten-free diet. Myopathy can rarely occur in patients with celiac disease, but the mechanism is unclear. Pure proximal limb weakness has not been previously reported in copper deficiency. We propose that this may represent a novel manifestation of hypocupremia and recommend considering copper deficiency and gluten sensitivity in patients presenting with proximal limb weakness. PMID- 27994895 TI - Surgical Management of Multiple Valve Endocarditis Associated with Dialysis Catheter. AB - Endocarditis associated with dialysis catheter is a disease that must be suspected in every patient with hemodialysis who develops fever. Multiple valve disease is a severe complication of endocarditis that needs to be managed in a different way. There is very limited data for treatment and every case must be considered individually. We present a patient with this complication and describe the medical treatment and surgical management. We report the case of a 15-year old patient with acute renal failure that develops trivalvular endocarditis after the hemodialysis catheter was placed, with multiple positive blood culture for Staphylococcus aureus. Transesophageal echocardiography was done and aortic and tricuspid valvular vegetations and mitral insufficiency were reported. Patient was successfully treated by surgery on the three valves, including aortic valve replacement. There is limited data about the appropriate treatment for multiple valvular endocarditis; it is important to consider this complication in the setting of hemodialysis patients that develop endocarditis and, despite the appropriate treatment, have a torpid evolution. In countries where endovenous drug abuse is uncommon, right sided endocarditis is commonly associated with vascular catheters. Aggressive surgical management should be the treatment of choice in these kinds of patients. PMID- 27994898 TI - Recurrence of Solid Pseudopapillary Tumor: A Rare Pancreatic Tumor. AB - Solid pseudopapillary tumor of the pancreas (SPTP) is a rare disease of young females that does not usually recur after resection. Here we report a case of an elderly female with history of SPTP ten years ago who presented with anorexia and a palpable left lower quadrant abdominal mass. Imaging revealed metastatic disease and US-guided biopsy of the liver confirmed the diagnosis of SPTP. Due to her advanced age and comorbidities, she elected to undergo hospice care. The objective of this case report is to increase awareness of this tumor and its possibility of recurrence, necessitating further guidelines for follow-up. PMID- 27994897 TI - Progressive Multifocal Leukoencephalopathy in a Multiple Sclerosis Patient Diagnosed after Switching from Natalizumab to Fingolimod. AB - Background. Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion. We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed. PMID- 27994899 TI - Low Grade Lymphoma Mimicking Metastatic Urothelial Carcinoma: When Do We Need Further Histologic Staging? AB - Introduction. Patients with urothelial carcinoma of the bladder often present with metastases to regional lymph nodes, with lymphadenopathy on physical examination or radiographic imaging. Case Presentation. We present the case of a 73-year-old Caucasian man with presumed metastatic urothelial carcinoma of the bladder to regional pelvic and retroperitoneal lymph nodes. He underwent systemic chemotherapy for treatment of urothelial carcinoma and was discovered on restaging to have findings suggestive of disease progression but ultimately was found to have a concurrent secondary malignancy. Conclusion. Our case suggests that in patients with urothelial carcinoma, the concurrent presentation of regional lymphadenopathy may not be metastatic urothelial carcinoma and may warrant further investigation. PMID- 27994900 TI - Bacillus Panophthalmitis with Posterior Extension to the Prechiasmatic Optic Nerve. AB - A rare case of Bacillus panophthlamitis with extension to the prechiasmatic optic nerve secondary to hematogenous spreading after intravenous drug use is presented. A 27-year-old man with a recent history of trauma to the left eye presented with severe left eye pain following a binge of intravenous drug use. Visual acuity (VA) was LP. On examination he had chemosis, proptosis, elevated intraocular pressure, and a complete hyphema. CT-scan identified preseptal swelling, but no evidence of any posterior extension of the anterior process or orbital fractures. Topical and systemic therapy were initiated. On follow-up clinical examination less than 12 hours after presentation he had signs of a keratitis with worsening ophthalmoplegia and repeat imaging demonstrated posterior extension to the prechiasmatic optic nerve. Shortly after the cornea ruptured with cultures growing Bacillus. The patient underwent enucleation and has had no further progression of infection. To the best of our knowledge, this is the first report of Bacillus panophthalmitis presenting with signs of trauma with posterior extension to the prechiasmatic optic nerve. PMID- 27994901 TI - Avulsion Fracture of the Coracoid Process at the Coracoclavicular Ligament Insertion: A Report of Three Cases. AB - Avulsion fracture at the site of attachment of the coracoid process of the coracoclavicular ligament (CCL) is extremely rare. We presented three adult cases of this unusual avulsion fracture associated with other injuries. Case 1 was a 25-year-old right-handed male with a left distal clavicular fracture with an avulsion fracture of the coracoid attachment of the CCL; this case was treated surgically and achieved an excellent outcome. Case 2 was a 39-year-old right handed male with dislocation of the left acromioclavicular joint with two avulsion fractures: one at the posteromedial surface of the coracoid process at the attachment of the conoid ligament and one at the inferior surface of the clavicle at the attachment site of the trapezoid ligament; this case was treated conservatively, and unfavorable symptoms such as dull pain at rest and sharp pain during some daily activities remained. Case 3 was a 41-year-old right-handed female with a right distal clavicular fracture with an avulsion fracture of the coracoid attachment of the conoid ligament; this case was treated conservatively, and the distal clavicular fracture became typical nonunion. These three cases corresponded to type I fractures according to Ogawa's classification as the firm scapuloclavicular connection was destroyed and also to double disruption of the superior shoulder suspensory complex. We recommend surgical intervention when treating patients with this type of acute or subacute injury, especially in those engaging in heavy lifting or overhead work. PMID- 27994902 TI - Gastric Adenocarcinoma of the Fundic Gland Type Treated by Endoscopic Mucosal Resection: A Case Report and Review of the Literature. AB - Gastric adenocarcinoma of the fundic gland type (GA-FG) is a rare entity that has only recently been described and defined. There is ongoing controversy regarding the malignant potential of this lesion. We report the case of a GA-FG in a 49 year-old Caucasian man who was referred to endoscopy for management of an incidentally found gastric polyp. Endoscopy showed a single polypoid lesion in the gastric fundus which was successfully removed with endoscopic resection. Grossly, the polyp measured 1.1 cm in greatest dimension. Microscopic examination showed irregularly branched neoplastic glands covered with a nonneoplastic foveolar epithelium. The continuity between the neoplastic glands and the fundic glands is clearly identified, indicating the tumor arose from the fundic glands. The tumor cells exhibited occasional oxyntic cytoplasm with enlarged atypical nuclei. The tumor invaded the submucosa with complete disruption of the muscularis mucosae and mild lymphocytic and fibroblastic stromal reaction. No necrosis, mitosis, or lymph-vascular invasion was identified. Although some authors have proposed reclassification of GA-FGs as oxyntic gland polyps/adenomas, in light of several reported cases with submucosal invasion as well as lymphatic invasion, we maintain that this neoplasm is best categorized as an extremely well-differentiated adenocarcinoma to reflect its invasive potential. PMID- 27994903 TI - Congenital Hypothyroidism: An Unusual Combination of Biochemical Abnormalities. AB - A forty-five-day-old female infant presented with prolonged jaundice with clinical features suggestive of congenital hypothyroidism (CHT). On investigations, the infant was noted to have indirect hyperbilirubinemia (13.8 mg/dl) with increased levels of AST (298 IU/dl) and ALT (174 IU/dl) in the serum. The child had low levels of free T3 (<1 pg/ml) and free T4 (0.4 ng/dl) secondary to thyroid agenesis detected on radionuclide scan and ultrasonography of the neck and raised levels of TSH (>500 microIU/ml) in the serum. The combination of indirect hyperbilirubinemia and raised levels of hepatic transaminases has not been reported in babies with CHT. Following institution of oral thyroxin therapy, the serum bilirubin levels ameliorated (2.9 mg/dl) considerably by 15 days of therapy and the serum levels of AST (40 IU/dl) and ALT (20 IU/dl) got normalized. The case demonstrates that raised levels of hepatic transaminases can occur in infants with CHT and these can resolve just with thyroxin therapy, obviating the need for extensive investigative laboratory work-up. PMID- 27994904 TI - Bronchial Foreign Body Alerting of a Bronchial Tumor: The Need of a Follow-Up Radiography. AB - Lung tumors are extremely rare in the pediatric population, comprising only 0.2% of all malignancies in children. Among them, mucoepidermoid carcinoma (MEC) is even rarer with a reported frequency of 0.1% to 0.2%. MEC is defined by the World Health Organization as a tumor characterized by a combination of mucus-secreting, squamous, and intermediate cell types. We describe the case of a 4-year-old girl who presented with a history of intermittent fever and nonproductive cough of 1 month duration after foreign body aspiration. The chest X-ray showed complete collapse of the left lung. After removal of the foreign body, the lung expanded well after. However, the control chest X-ray done after 5 days showed again complete collapse of the left lung. The biopsy specimen taken during bronchoscopy confirmed the diagnosis of low-grade MEC. Fluorescence in situ hybridization (FISH) confirmed the presence of MAML2 rearrangement. Complete surgical resection with preservation of lung parenchyma was performed. No adjuvant therapy was needed. Repeat bronchoscopy was performed 2 months after surgery and showed no recurrence of the tumor. In conclusion, a remote chest X-ray after removal of a foreign body is necessary to avoid missing a rare serious underlying disease such as MEC. According to the size and the location of the tumor, complete surgical removal is sufficient without additional treatment in case of low-grade tumor. The presence of MAML2 rearrangement confers a favorable outcome and may have long term implications for the clinical management. PMID- 27994905 TI - Dilated Cardiomyopathy Induced by Chronic Starvation and Selenium Deficiency. AB - Protein energy malnutrition (PEM) has been rarely documented as a cause of cardiovascular abnormalities, including dilated cardiomyopathy. Selenium is responsible for antioxidant defense mechanisms in cardiomyocytes, and its deficiency in the setting of PEM and disease related malnutrition (DRM) may lead to exacerbation of the dilated cardiomyopathy. We report a rare case of a fourteen-year-old boy who presented with symptoms of congestive heart failure due to DRM and PEM (secondary to chronic starvation) along with severe selenium deficiency. An initial echocardiogram showed severely depressed systolic function consistent with dilated cardiomyopathy. Aggressive nutritional support and replacement of selenium and congestive heart failure medications that included diuretics and ACE inhibitors with the addition of carvedilol led to normalization of the cardiac function within four weeks. He continues to have significant weight gain and is currently completely asymptomatic from a cardiovascular standpoint. PMID- 27994906 TI - Swift and Complete Healing of Digital Ulcers after Macitentan Treatment. AB - Digital ulcers are a burdensome and painful condition with sparse options of treatment. We report the case of a 78-year-old female patient with limited cutaneous systemic sclerosis that sequentially developed digital ulcers. After the appearance of digital ulcers in the soles of her feet she was successfully treated with bosentan. The report of two new digital ulcers in her hands 9 months later alongside with elevated transaminase levels led to a switch to macitentan treatment. A swift and complete healing of both digital ulcers was observed after 3 months, with the restoration of normal biochemical values. PMID- 27994907 TI - The Impact of Social Structures on Deviant Behaviors: The Study of 402 High Risk Street Drug Users in Iran. AB - This study is a sociological analysis of the three dimensions of social structure including institutional, relational, and embodied structures that have an impact on the individuals' deviant behaviors in the society. The authors used a mix method to analyze the qualitative and quantitative data of 402 high risk abandoned substance users in 2008 in Tehran, capital city of Iran. The leading reasons of substance use were categorized into four fundamental themes as follows: stress, deviant social networks, and low social capital and weak social support sources. In addition, the epidemiology model of regression analysis provides a brief explanation to assess the association between the demographical and etiological variables, and the drug users' deviant behaviors. In sum, substance use is discussed as a deviant behavior pattern which stems from a comorbidity of weak social structures. PMID- 27994909 TI - Assessment of Ten-Year-Long Results of Kidney Biopsies Performed on Children in the Thrace Region of Turkey. AB - BACKGROUND: Many children with kidney diseases can be diagnosed and treated without a biopsy. However, biopsy is a valuable method for the diagnostic and prognostic evaluation of children with kidney diseases. AIMS: To evaluate the clinical and pathological profiles of the kidney biopsies in our department to provide epidemiological data for clinical practice. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Kidney biopsies and patient's charts in pediatric patients performed between May 2005 and February 2015 at the Pediatric Nephrology Department, Trakya University School of Medicine were assessed retrospectively. RESULTS: A total of 100 patients were examined. Their mean age was 9.62+/-4.26 years (range: 1-17 years); 54% of the patients were girls and 46% were boys. The most frequent indication for kidney biopsy was nephrotic syndrome (33%). The most common kidney disease was primary glomerulonephritis, which was observed in 65% of cases. IgA nephropathy (24%) was the most frequently observed subtype in primary glomerulonephritis groups. Secondary glomerulonephritis was diagnosed in 35% of cases. Systemic lupus erythematosus (51%) was the most frequently observed subtype in the secondary glomerulonephritis groups. CONCLUSION: IgA nephropathy and systemic lupus erythematosus were the most frequent primary and secondary glomerulonephritis in our region among children, respectively. PMID- 27994908 TI - Qualitative Insights from the Osteoporosis Research: A Narrative Review of the Literature. AB - Purpose. Much of the research on osteoporosis has been generated quantitatively. However, the qualitative osteoporosis literature provides valuable information on patient and clinician experiences and perspectives, informing the design and implementation of health research and healthcare services. To identify knowledge gaps and inform the design of future qualitative research, a narrative review was conducted to consolidate and synthesize the existing insights available within the qualitative osteoporosis research. Methods. Search terms reflecting the domains of osteoporosis and qualitative research were entered into the Scopus database to generate a comprehensive survey of qualitative research in the area of osteoporosis. Articles were thematically analysed and the results are presented in the form of a narrative review. Results. Forty-four articles were included in the narrative review. Qualitative research in the field of osteoporosis research can be summarized by 3 thematic areas: the meaning of osteoporosis for patients and the public, the lived experience of an osteoporosis diagnosis, and the programmatic approach to osteoporosis prevention and treatment. Conclusions. Qualitative studies provide clinically valuable insights in how osteoporosis is conceptualized and managed and programmatic aspects of osteoporosis treatment. The findings of this narrative review suggest the need for balance between presenting osteoporosis as a serious health condition and producing unwarranted anxiety and inactivity so as to ensure the best possible outcomes for individuals with osteoporosis. PMID- 27994910 TI - Resveratrol Protects Sepsis-Induced Oxidative DNA Damage in Liver and Kidney of Rats. AB - BACKGROUND: The increases of free radicals have been proposed to be involved in the pathogenesis of sepsis, which leads to multiple-organ dysfunction syndromes. The uses of antioxidants as a complementary tool in the medical care of oxidative stress-related diseases have attracted attention of researchers. Resveratrol (RV) has suggested being antioxidant, anti-proliferative, and anti-inflammatory effects in various experimental models and clinical settings. AIMS: This study was undertaken to evaluate the protective effects of RV on oxidative DNA damage induced by sepsis in the liver and kidney tissues of Wistar albino rats. STUDY DESIGN: Animal experimentation. METHODS: Four experimental groups consisting of eight animals for each was created using a total of thirty-two male Wistar albino rats. Sham group was given 0.5 mL of saline intra-peritoneal (ip) only following laparatomy. Sepsis group was given 0.5 mL saline ip only following the induction of sepsis. RV-treated group was given a dose of 100 mg/kg ip RV in 0.5 mL saline following laparatomy. RV-treated sepsis group was given 100 mg/kg ip RV in 0.5 mL saline following the induction of sepsis. A model of sepsis was created by cecal ligation and puncture technique. In the liver and kidney tissues, oxidative stress parameters (malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPX)) and a proinflammatory cytokine (tumor necrosis factor alpha (TNF-alpha)), were evaluated spectrophotometrically and DNA damage was determined by the alkaline single cell gel electrophoresis (comet assay) technique using formamidopyrimidine DNA glycosylase protein. RESULTS: In the RV-treated sepsis group, the levels of MDA and TNF-alpha were lower and GSH levels, SOD and GPX activities were higher than in the septic rats (p<0.05). RV treatment significantly reduced the sepsis-induced oxidative DNA damage in the liver and kidney cells (p<0.05). CONCLUSION: It is suggested that RV treatment might reduce the sepsis-induced oxidative DNA damages in sepsis related diseases; however, there is a need for more studies to clear up the protective mechanisms of RV against sepsis. PMID- 27994911 TI - Liver Apparent Diffusion Coefficient Changes during Telaprevir-Based Therapy for Chronic Hepatitis C. AB - BACKGROUND: Diffusion-weighted imaging (DWI) has become an established diagnostic modality for the evaluation of liver parenchymal changes in diseases such as diffuse liver fibrosis. AIMS: To evaluate the parenchymal apparent diffusion coefficient value (ADC) changes using diffusion-weighted imaging (DWI) during telaprevir-based triple therapy. STUDY DESIGN: Diagnostic accuracy study. METHODS: Seventeen patients with chronic hepatitis C virus (HCV) virus and twenty five normal volunteers were included. All of the patients took 12-weeks of telaprevir-based triple therapy followed by 12-weeks of PEGylated interferon and ribavirin therapy. They were examined before treatment (BT), as well as 12-weeks (W12) and 24-weeks (W24) after treatment by 3 Tesla magnetic resonance imaging (MRI). DWI was obtained using a breath-hold single-shot echo-planar spin echo sequence. Histopathologically, liver fibrosis was classified in accordance with the modified Knodell score described by Ishak. Quantitatively, liver ADCs were compared between patients and normal volunteers to detect the contribution of DWI in the detection of fibrosis. In addition, liver ADCs were compared during the therapy to analyze the effect of antiviral medication on liver parenchyma. RESULTS: The liver ADC values of fibrotic liver parenchyma were significantly lower than those of the healthy liver parenchyma (p<0.001). However, we were not able to reach a sufficiently discriminative threshold value. The ADC values showed a declining trend with increasing fibrotic stage. No statistically significant correlation (p=0.204) was observed. Compared with those before treatment, the liver ADC values after telaprevir-based triple therapy were significantly decreased at W12. A significant increase in the liver ADC values was also observed after the cessation of telaprevir therapy at W24 with a return to initial values. CONCLUSION: Liver ADC values appear to indicate the present but not the stage of liver fibrosis. DWI may be a helpful research tool for the assessment of antiviral drug effects. PMID- 27994912 TI - Diffusion Tensor Imaging of the Uterine Zones Related to the Menstrual Cycle and Menopausal Status at 3 Tesla MRI. AB - BACKGROUND: Diffusion and diffusion tensor imaging techniques (DTI) are widely available and used both in central nervous system and body imaging, including gynecological diseases. AIMS: The aims of this study were to assess the capability of DTI of uterine zones in relation to the menstrual cycle and ascertain the normal apparent diffusion coefficient and fractional anisotropy values at 3T magnetic resonance imaging (MRI). STUDY DESIGN: Prospective clinical study. METHODS: A total of 13 young reproductive and 12 postmenopausal healthy volunteers were included in the study. MRI examination included sagittal T2 weighted and single-shot echo planar imaging DTI obtained under free breathing. Fractional anisotropy (FA) values of the endometrium, junctional zone, and myometrium were determined. RESULTS: The median (minimum-maximum) FA of the endometrium, myometrium, and junctional zone of the reproductive group were 0.31 (0.260-0.465), 0.42 (0.302-0.664), and 0.58 (0.420-0.745), respectively, in the proliferative phase and 0.26 (0.180-0.413), 0.48 (0.357-0.656), and 0.59 (0.490 0.675)], respectively, in the secretory phase. In the postmenopausal group, the FA values of the endometrium, myometrium, and junctional zone were 0.275 (0.136 0.425), 0.255 (0.191-0.553), and 0.27 (0.129-0.397), respectively. Apparent diffusion coefficient (ADC) values of the endometrium, myometrium, and junctional zone of the reproductive group were 1.25+/-0.254 (0.970-1.463), 1.67 (1.213 1.854), and 1.23 (0.853-1.301), respectively, in the proliferative phase and 1.32+/-0.283 (1.165-1.706), 1.55 (1.360-1.791), and 1.17 (1.163-1.705), respectively, in the secretory phase. In the postmenopausal group, the ADC values of the endometrium, myometrium, and junctional zone were measured as 1.100+/ 0.192 (0.850-1.302), 1.14 (0.864-1.283), and 1.09 (0.912-1.291). The FA values of the endometrium and myometrium were lower in the secretory phase of the reproductive group, while ADC values were higher. However, both the FA and ADC values were lower in the postmenopausal group. CONCLUSION: The present study showed that uterine DTI is feasible when used quantitatively. While FA values tend to decrease, ADC values increase significantly in all zones in the secretory phase except the junctional zone. Zonal FA and ADC values of postmenopausal women are lower in comparison to those in young women. PMID- 27994913 TI - Evaluation of MIF -173 G/C Polymorphism in Turkish Patients with Ankylosing Spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease mainly affecting the spine and sacroiliac joints. Macrophage migration inhibitory (MIF) factor is a regulatory cytokine that inhibits random immune cell migration. MIF gene promoter polymorphisms play a role in the progression of several inflammatory disorders. AIMS: To investigate the relationship between the MIF gene -173 G/C single-nucleotide polymorphism (SNP) and AS. STUDY DESIGN: Cross sectional study. METHODS: In this study, a total of 161 AS and 194 normal controls were recruited. The MIF gene -173 G/C SNP was analyzed by polymerase chain reaction using the restriction fragment length polymorphism method. RESULTS: There was no significant difference between groups in terms of genotype distribution (p>0.05). When wild-type G/G and G/C+C/C genotypes are compared in terms of clinical characteristics, there is a significant difference between the average age and the duration of disease in AS patients (p<0.05). CONCLUSION: No significant relationship between AS disease and MIF -173 G/C polymorphism was found. MIF -173 G/C polymorphism (C allele) may affect the time of onset and the duration of disease in AS patients. PMID- 27994915 TI - Intravenous Colistin Use for Multidrug-Resistant Gram-Negative Infections in Pediatric Patients. AB - BACKGROUND: The emergence of infections due to multidrug-resistant Gram-negative bacilli (MDR-GNB) has led to the resurrection of colistin use. The data on colistin use and drug-related adverse effects in children are scarce. AIMS: In this study, we aimed to evaluate the clinical efficacy and safety of colistin use in critically ill pediatric patients. STUDY DESIGN: This study has a retrospective study design. METHODS: Sixty-one critically ill children were identified through the department's patient files archive during the period from January 2011 to November 2014. RESULTS: Twenty-nine females and thirty-two males with a mean+/-standard deviation (SD) age of 61+/-9 months (range 0-216, median 12 months) received IV colistin due to MDR-GNB infections. Bacteremia (n=23, 37.7%) was the leading diagnosis, followed by pneumonia (n=19, 31%), clinical sepsis (n=7, 11.4%), wound infection (n=6, 9.8%), urinary tract infection (n=5, 8.1%) and meningitis (n=1, 1.6%). All of the isolates were resistant to carbapenems; however, all were susceptible to colistin. The isolated microorganisms in decreasing order of frequency were: Acinetobacter baumanni (n=27, 44.2%), Pseudomonas aeruginosa (n=17, 27.8%), Klebsiella pneumoniae (n=6, 9.8%), K. pneumoniae and Stenotrophomonas maltophilia (n=1, 1.6%), K. pneumoniae and A. baumanni (n=1, 1.6%), K. oxytoca (n=1, 1.6%) and Enterobacter cloacae (n=1, 1.6%). In seven patients, no microorganisms were detected; however, five of these patients were colonized by carbapenem-resistant K. pneumoniae. The mean duration of colistin therapy was 12 days (range 3-45). Colistin was administered concomitantly with one of the following antibiotics: carbapenem (n=50, %82), ampicillin-sulbactam (n=5, 8%), quinolones (n=5, 8%), rifampicin (n=1, 1.6%). Carbapenem was the most frequently used antibiotic. Nephrotoxicity was observed in only 1 patient, and we did not observe neurotoxicity in this study. All the patients received intravenous colistin (colisthimethate) at a dosage of 5 mg/kg daily by dividing it in three equal doses. Seven (11.4%) patients died during the study period. CONCLUSION: Colistin appears to be a safe and efficacious drug for treating MDR-GNB infections in children. PMID- 27994914 TI - Inhibitory Effect of Pycnogenol(r) on Airway Inflammation in Ovalbumin-Induced Allergic Rhinitis. AB - BACKGROUND: The supplement Pycnogenol(r) (PYC) has been used for the treatment of several chronic diseases including allergic rhinitis (AR). However, the in vivo effects on allergic inflammation have not been identified to date. AIMS: To investigate the treatment results of PYC on allergic inflammation in a rat model of allergic rhinitis. STUDY DESIGN: Animal experimentation. METHODS: Allergic rhinitis was stimulated in 42 rats by intraperitoneal sensitization and intranasal challenge with Ovalbumin. The animals were divided into six subgroups: healthy controls, AR group, AR group treated with corticosteroid (dexamethasone 1 mg/kg; CS+AR), healthy rats group that were given only PYC of 10 mg/kg (PYC10), AR group treated with PYC of 3mg/kg (PYC3+AR), and AR group treated with PYC of 10 mg/kg (PYC10+AR). Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10), and OVA-specific immunoglobulin E (Ig-E) levels of serum were measured. Histopathological changes in nasal mucosa and expression of tumor necrosis factor-alpha (TNF-alpha) and IL-1beta were evaluated. RESULTS: The levels of the IL-4 were significantly decreased in the PYC3+AR, PYC10+AR and CS+AR groups compared with the AR group (p=0.002, p<0.001, p=0.006). The production of the IFN-gamma was significantly decreased in the PYC3+AR and PYC10+AR groups compared with the AR group (p=0.013, p=0.001). The administration of PYC to allergic rats suppressed the elevated IL-10 production, especially in the PYC3+AR group (p=0.006). Mucosal edema was significantly decreased respectively after treatment at dose 3 mg/kg and 10 mg/kg PYC (both, p<0.001). The mucosal expression of TNF-alpha has significantly decreased in the PYC3+AR and PYC10+AR groups (p=0.005, p<0.001), while the IL-1beta expression significantly decreased in the CS+AR, PYC3+AR, and PYC10+AR groups (p<0.001, p=0.003, p=0.001). CONCLUSION: PYC has multiple suppressive effects on allergic response. Thus, PYC may be used as a supplementary agent in allergic response. PMID- 27994916 TI - MyD 88 Polymorphisms in Children Diagnosed with Sepsis. AB - BACKGROUND: Myeloid differentiation primary response gene 88 (MyD 88) is an intracellular adapter protein that mediates the early immune response to pathogens. Toll-like receptors (except TLR-3) induce the immune response through a MyD 88-dependent signal pathway. AIMS: We aimed to investigate the MyD 88 polymorphisms that play important roles in the immune response in septic children and to evaluate whether or not they were risk factors in the development of sepsis. STUDY DESIGN: Case-control study. METHODS: Sixty-five patients diagnosed with sepsis in the Pediatric Intensive Care Unit during the period from April 2010 to January 2012 were included as the study group. Sixty-five children without sepsis were included as controls. After DNA was obtained from blood samples in the study and control groups, MyD 88 polymorphisms were analyzed. According to the genotype and allele frequencies, the distributions of MyD 88 polymorphisms [Single nucleotide polymorphism (SNP) - 938 C/A (rs4988453), MyD 88 SNP 1944 C/G (rs4988457)] were analyzed in both the study and control groups. RESULTS: The C/C genotype of MyD 88 SNP -938 was significantly more common than the C/A genotype in the patient group (p=0.002). No statistically significant difference in the frequency of the MyD 88 SNP 1944 genotype was found between the study and control groups (p=0.272). CONCLUSION: Gene polymorphism studies could elucidate our understanding of sepsis in terms of prevalence and the management of treatment. It was shown in this study that children with the MyD 88 SNP -938 C/C genotype had a greater tendency toward sepsis. However, additional studies should be performed. PMID- 27994917 TI - Altered Chondrocyte Apoptosis Status in Developmental Hip Dysplasia in Rabbits. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is an important factor leading to early adult osteoarthritis. Chondrocyte apoptosis has been proven to be an important factor causing osteoarthritis. AIMS: The current study aims to explore whether a rabbit model of developmental dysplasia of the hip through cast immobilization in the legs results in chondrocyte apoptosis. STUDY DESIGN: Animal experimentation. METHODS: Thirty-two New Zealand white rabbits were divided in three groups with cast plaster-induced dislocation at 2, 4 and 6 weeks. The contralateral hip joint was utilized as a control group. Ten rabbits in each group were sacrificed, and hip specimens were obtained. Bcl-2/Bax, cleaved caspase-3 and cleaved caspase-8 expression were examined by western blot analysis. Chondrocyte apoptosis was analyzed through transmission electron microscopy (TEM) and TUNEL analysis. All experiments were repeated at least three times. RESULTS: In the experimental group, Bcl-2/Bax, cleaved caspase-3 and cleaved caspase-8 expression were significantly altered. The Bcl-2/Bax ratio decreased with time (all p<0.01), whereas levels of cleaved caspase-3 (p<0.01 and p<0.05) and cleaved caspase-8 (all p<0.05) gradually increased. Chondrocyte apoptosis was observed through transmission electron microscopy (TEM) and TUNEL analysis (p<0.05 at 4 weeks and p<0.01 at 6 weeks). CONCLUSION: Prolonged immobilization of rabbit hip caused chondrocyte apoptosis. Reduction of the hip joint may protect chondrocytes from apoptosis, thus preventing secondary osteoarthritis. PMID- 27994918 TI - Use of Systemic Rosmarinus Officinalis to Enhance the Survival of Random-Pattern Skin Flaps. AB - BACKGROUND: Skin flaps are commonly used in soft-tissue reconstruction; however, necrosis can be a frequent complication. Several systemic and local agents have been used in attempts to improve skin flap survival, but none that can prevent flap necrosis have been identified. AIMS: This study aims to determine whether the use of systemic Rosmarinus officinalis (R. officinalis) extract can prevent flap necrosis and improve skin flap recovery. STUDY DESIGN: Animal experimentation. METHODS: Thirty-five Wistar albino rats were divided in five groups. A rectangular random-pattern flaps measuring 8*2 cm was elevated from the back of each rat. Group I was the control group. In Group II, 0.2 ml of R. officinalis oil was given orally 2h before surgery. R. officinalis oil was then applied orally twice a day for a week. In Group III, R. officinalis oil was given orally twice a day for one week before surgery. At the end of the week, 0.2 mL of R. officinalis oil was given orally 2 h before surgery. In Group IV, 0.2 mL of R. officinalis oil was injected subcutaneously 2 h before surgery. After the surgery, 0.2 mL R. officinalis oil was injected subcutaneously twice a day for one week. In Group V, 0.2 mL R. officinalis oil was injected subcutaneously twice a day for one week prior to surgery. At the end of the week, one last 0.2 mL R. officinalis oil injection was administered subcutaneously 2 h before surgery. After the surgery, 0.2 mL R. officinalis oil was injected subcutaneously twice a day for one week. RESULTS: The mean percentage of viable surface area was significantly greater (p<0.05) in Groups II, III, IV, and V as compared to Group I. Mean vessel diameter was significantly greater (p<0.05) in Groups II, III, IV, and V as compared to Group I. CONCLUSION: We have determined that, in addition to its anti-inflammatory and anti-oxidant effects, R. officinalis has vasodilatory effects that contribute to increased skin flap survival. PMID- 27994920 TI - Does Preoperative Diagnosis of Endometrial Hyperplasia Necessitate Intraoperative Frozen Section Consultation? AB - BACKGROUND: In women with endometrial hyperplasia, there is a risk for co existent endometrial cancer when patients are subjected to immediate surgical treatment. AIMS: The aim of this study was to investigate the frequency of endometrial cancer and the accuracy of frozen section analysis at the time of hysterectomy among patients with endometrial hyperplasia, to reveal whether or not a preoperative diagnosis of endometrial hyperplasia necessitates frozen section consultation. STUDY DESIGN: Retrospective cross-sectional study. METHODS: A department database review was performed to identify patients who were subjected to hysterectomy with a preoperative diagnosis of endometrial hyperplasia, during the period from 2007 to 2014. RESULTS: The study group included 189 cases. The final pathological examination revealed endometrial cancer in 16 women (8.4%). The risk of cancer in patients with endometrial hyperplasia was 1 of 125 (0.8%) in simple hyperplasia without atypia, 1 of 21 (4.8%) in complex hyperplasia without atypia and 14 of 43 (32.5%) in atypical hyperplasia. Of women with cancer, 2 of 16 (12.5%) had high-risk features. Frozen section analysis was requested in 46 cases. Frozen sections helped to identify six out of 11 cases of endometrial cancer (54.5%). The sensitivity, specificity and positive and negative predictive values of frozen section analysis for the detection of endometrial cancer among women with endometrial hyperplasia were 54.4%, 97.2%, 85.7% and 87.5%, respectively. CONCLUSION: Although a significant proportion of patients with atypical endometrial hyperplasia are diagnosed with endometrial cancer following hysterectomy, most of these cases have low-risk features and do not require surgical staging. Additionally, intraoperative frozen section analysis if not helpful for diagnosing concurrent endometrial cancer in patients with endometrial hyperplasia. Therefore, it seems that patients with endometrial hyperplasia can be operated upon in settings with no available method for obtaining frozen sections intraoperatively. PMID- 27994921 TI - The Burden of Premature Mortality in Turkey in 2001 and 2008. AB - BACKGROUND: Standard expected years of life lost (SEYLL) is a measure that is used to evaluate losses due to premature deaths. AIMS: The present study provides an analysis of premature mortality in Turkey for the years 2001 and 2008 and supplies evidence for making policies and setting health agendas over the long term. STUDY DESIGN: Cross-sectional study. METHODS: This study calculated SEYLL by gender, age group and causes of death in Turkey in 2014. The SEYLL measure counts the years lost in a population as a result of premature mortality and is computed by multiplying the number of deaths and standard life expectancy at the age at which death occurs. RESULTS: The burden of premature mortality in Turkey was calculated as 4 104 253 SEYLL and 4 472 443 SEYLL in 2001 and 2008, respectively. Among these 42.7% and 43.9% of SEYLL were in females in 2001 and 2008, respectively. The leading five causes of premature mortality in the Turkish population in 2001 were cardiovascular system diseases (34.72%), perinatal conditions (12.69%), neoplasms (12.51%), external causes of injury (7.66%), and infections and parasitic diseases (6.57%). In 2008, the major causes were cardiovascular diseases (41.17%), neoplasms (14.63%), respiratory system diseases (9.81%), perinatal conditions (5.59%), and external causes of injury (5.29%). CONCLUSION: The majority of the burden of premature mortality in Turkey is attributable to non-communicable diseases. While premature deaths from infections and parasitic diseases, perinatal conditions and congenital anomalies decreased between 2001 and 2008, deaths from cardiovascular diseases, neoplasms and respiratory system diseases increased dramatically. Coordinated efforts for effective national prevention programs (such as regular monitoring of adults for early diagnosis of cardiovascular diseases and for malignancies by family physicians) should be developed by policy makers to decrease preventable and premature deaths from non-communicable diseases. PMID- 27994919 TI - Frequency of Nerve Root Sleeve Cysts in Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: There is sporadic data about the occurrence of spinal meningeal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD). We suggest that there is a relationship with the frequency and size of spinal meningeal cysts and headache, intracranial aneurysms, and cerebrospinal fluid leakage in patients with ADPKD. AIM: To investigate the relationship with spinal meningeal cyst, cerebrospinal fluid leakage, and headache in patients with ADPKD. STUDY DESIGN: Cross-sectional study. METHODS: We enrolled 50 patients with ADPKD and 37 healthy volunteers. This cross-sectional study included patients with ADPKD and matched healthy volunteers. Magnetic resonance imaging myelography was performed using the 3D-T2 HASTE technique in an MRI scanner. We questioned our subjects regarding presence of headache and evaluated headache severity using a visual analog scale. The relationship between the number and size of spinal meningeal cysts with headache, intracranial aneurysms, and liver cysts was also investigated. RESULTS: Spinal meningeal cysts were more numerous and larger in patients than in controls (14.8+/-11.6 vs. 6.4+/-4.6 cysts respectively, p<0.001, 68.3+/-49.3 vs. 25.4+/-20.1 mm, p<0.001, respectively). Spinal cyst number and size were similar in APDKD patients with or without intracranial aneurysms. Headache score was correlated with the size and number of spinal meningeal cysts. This was valid only in patients with ADPKD. CONCLUSION: Abnormality involving the vessel wall in ADPKD may explain the increased number of spinal meningeal cysts in ADPKD. Moreover, leakage of cerebrospinal fluid secondary to spinal meningeal cyst may be responsible for recurrent severe headache by causing spontaneous intracranial hypotension in these patients. PMID- 27994922 TI - Diagnostic and Prognostic Value of Presepsin for Subclinical Chorioamnionitis in Pregnancies between 23-28 Week with Preterm Premature Rupture of the Membranes. AB - BACKGROUND: Presepsin is an inflammatory marker released from monocytes and macrophages as an acute reaction to microbial infection. We hypothesized that it may be useful in pregnancies with preterm premature rupture of the membranes (PPROM) for early diagnosis of subclinical chorioamnionitis. AIMS: To determine whether the plasma presepsin level has any diagnostic or prognostic value for subclinical chorioamnionitis in pregnancies complicated with PPROM. STUDY DESIGN: Prospective cohort study. METHODS: Fifty-three singleton pregnancies between 23 and 28 weeks of gestation diagnosed with PPROM were prospectively included in the study. Venous blood samples were collected at admission, at the 48th hour of admission, and at the time of delivery to determine presepsin and C-reactive Protein (CRP) levels and white blood cell (WBC) counts. Chorioamnionitis was diagnosed by microscopic examination of the placenta and cords. RESULTS: Of the 53 PPROM cases included in the study, 41 (77.4%) had histologically confirmed chorioamnionitis. Neonatal sepsis developed in 24 (45.3%) of the newborns. The median presepsin level at admission was 135.0 pg/mL for pregnancies with subclinical chorioamnionitis and 113.5pg/mL for pregnancies without chorioamnionitis (p=0.573). There was also no significant difference between subclinical chorioamnionitis (+) and (-) cases in terms presepsin levels at the 48th hour and at delivery. However, chorioamnionitis (+) cases showed a significant decrease in both presepsin level and WBC count at the 48th hour after the administration of antibiotics, which increased significantly at delivery (p<0.001 and p=0.011, respectively). CONCLUSION: The striking fluctuations in presepsin level after the diagnosis of PPROM can be used to predict subclinical chorioamnionitis and determine the optimal timing of delivery before the clinical signs of chorioamnionitis are established. However, presepsin level itself was neither diagnostic nor prognostic for neonatal sepsis. PMID- 27994923 TI - Microbiological Features of Upper Respiratory Tract Infections in Bulgarian Children for the Period 1998-2014. AB - BACKGROUND: Across the globe, upper respiratory tract infections (URTIs) are the most prevalent cause of morbidity in childhood. AIMS: The aim of our study is to analyze the incidence and etiology of bacterial URTIs in Bulgarian children, as well as the increasing antimicrobial resistance to the most common etiologic agents over a period of 17 years. STUDY DESIGN: Retrospective study. METHODS: The study material comprised the data from 4768 patients (aged 1-16 years) with URTI during the period from 1998-2014. Specific microbiology agent detection was performed by culture examination. Susceptibilities to the investigated pathogens were determined by the disk diffusion method and minimal inhibitory concentration according to the criteria of the Clinical and Laboratory Standards Institute (CLSI). Polymerase chain reaction was used to detect the presence of beta-lactam resistance genes. RESULTS: We identified the following as the most common URTI bacterial pathogens: Streptococcus pneumoniae (40.94%), Streptococcus pyogenes (34.16%), Haemophilus influenzae (44.23%), Moraxella catarrhalis (39.19%) and Staphylococcus aureus (23.88%). In more than 70% of cases, a polymicrobial etiology was found. The most commonly affected individuals were pre-school-aged children, which accounted for more than 36% of all patients. During the study period, a dramatic increase in resistance to antibiotic agents was observed. The most frequent types of resistance were the enzymatic inactivation of penicillins and cephalosporins (close to 100% in staphylococci and moraxellae) and inducible macrolide-lincozamide resistance (about 20% of Gram-positive cocci). CONCLUSION: Due to mandatory immunization against pneumococci and H. influenzae in Bulgaria and the vast expanding resistance to the most popular antimicrobial agents changes in the etiology of URTI have recently been noted. Regular analysis of this etiological dynamic and the antimicrobial resistance of respiratory pathogens is important for choosing the correct therapy and successful treatment. PMID- 27994925 TI - Acute Eosinophilic Pneumonia with Respiratory Failure Induced by Synthetic Cannabinoid Inhalation. AB - BACKGROUND: In recent days, synthetic cannabinoid derivatives have become life threatening for young people. Here, we want to share a case of acute eosinophilic pneumonia triggered by inhalation of synthetic cannabinoid, new side effects of which are being detected day by day. CASE REPORT: A 21-year-old male, who had no history of pulmonary diseases, was admitted to the clinic with shortness of breath. His oxygen saturation was measured as 85-86% in room air. Common irregular ground-glass opacities were observed in thorax radiology. His peripheral blood eosinophil count was 1100 cell/mm3 with a leukocyte differential of 12%. Sputum eosinophilia was also observed. The patient was diagnosed with acute eosinophilic pneumonia in terms of current clinical, radiological and laboratory findings. Rapid remission was achieved with corticosteroid therapy. CONCLUSION: This is the first reported case of acute eosinophilic pneumonia induced by synthetic cannabinoid inhalation. PMID- 27994924 TI - Correlation between Amitriptyline-Induced Cardiotoxic Effects and Cardiac S100b Protein in Isolated Rat Hearts. AB - BACKGROUND: Amitriptyline is an important cause of mortality due to its cardiovascular toxicity. AIMS: To investigate the changes in levels of cardiac S100b protein on amitriptyline-induced cardiotoxicity and also to examine the correlation between amitriptyline-induced cardiotoxic effects and cardiac S100b protein in an isolated rat heart model. STUDY DESIGN: Animal experimentation, isolated heart model. METHODS: After a stabilization period, isolated hearts were randomized to two groups (n=5 and n=7). In the control group, isolated hearts were subjected to an infusion of 5% dextrose for 60 minutes. In the amitriptyline group, 5.5*10-5 M amitriptyline was infused for 60 minutes to achieve amitriptyline toxicity. After the infusion period, heart tissues were removed for histological examination. RESULTS: In comparison to control treatment, amitriptyline infusion decreased left ventricular developed pressure (LVDP), dp/dtmax and heart rate (HR) and significantly prolonged QRS duration (p<0.05). The semiquantitative scores for S100b protein levels in amitriptyline-infused hearts were higher than in the control group (p<0.01). At the end of the experiment, in the amitriptyline-infused group, significant correlations were found between LVDP and S100b protein scores (r=-0.807, p=0.003) and between QRS duration and S100b protein scores (r=0.859, p=0.001). CONCLUSION: Our results indicate that the S100b protein may be a helpful indicator or biomarker in studying the cardiotoxic effects of amitriptyline. PMID- 27994927 TI - An Unusual Neck Mass: Ingested Chicken Bone. AB - BACKGROUND: Foreign bodies in the upper aerodigestive tract are frequently seen in otolaryngological practice, but migration of an ingested foreign body to the neck is a very rare condition. CASE REPORT: We present a 66-year-old woman admitted to our outpatient department with a painful neck mass. She had a history of emergency department admission 4 months prior with odynophagia after eating chicken meal. A physical examination revealed a painful and hyperemic mass on the left neck. Antibiotherapy did not relieve the patient's symptoms and signs. A 3 cm linear foreign body was observed in X-ray and computed tomography scans. The symptoms of the patient were relieved after excision of the foreign body. CONCLUSION: Although it is a rare situation, migration of a foreign body ingested through the aerodigestive tract to the neck should be kept in mind in the differential diagnosis of patients who present with neck masses. PMID- 27994926 TI - Intraarticular Giant Size Angiolipoma of the Knee Causing Lateral Patellar Dislocation. AB - BACKGROUND: Angiolipomas are benign tumors usually seen in patients during their 2nd and 3rd decades. The subcutaneous region of the trunk, neck and extremities are the places where they generally settle. There is only one case report on angiolipoma in the knee joint that was resected by arthroscopic procedure in the English literature. CASE REPORT: We present a case of a giant-size multilobular non-infiltrating angiolipoma, extending outside of the right knee joint and causing lateral patellar dislocation in a thirteen-year-old boy. A large encapsulated mass with fatty and soft-tissue components on magnetic resonance imaging was suggestive of a liposarcoma. However, the diagnosis after the tru-cut biopsy was angiolipoma. The Quadriceps angle was 25 degrees . Complete resection of the tumoral mass and repair of the medial retinaculum were performed with open surgery. Patellofemoral alignment was provided by transferring the tibial tuberosity medially. One year after the surgery, there was no evidence of recurrence. CONCLUSION: Intra-articular angiolipomas are rarely seen masses in the knee joint. To our knowledge, this case report is the first to demonstrate that angiolipoma causes patellar dislocation. PMID- 27994928 TI - A Solitary Fibrous Tumor of the Subglottic Larynx: Case Report and Literature Review. AB - BACKGROUND: Solitary fibrous tumors (SFT) arising from the larynx are extremely rare; most occur in the supraglottic larynx. CASE REPORT: Herein, we detail a new case of a subglottic SFT presenting as a well-encapsulated soft-tissue tumor with hoarseness. It showed isoattenuation, similar to the adjacent muscle on pre contrast computed tomography (CT) images, and strong, heterogeneous enhancement following contrast material administration, which may reflect hypervascularity. On pathological examination, it consisted of spindle cells, squeezed between abundant collagen, and focally prominent vascularity in a staghorn feature. The tumor cells were immunoreactive for CD34, BCL2 and CD99. Based on the combination of architectural and immunohistochemical criteria, we ultimately diagnosed this case as an SFT. CONCLUSION: Until now, only 14 cases of laryngeal SFT have been described in the literature: 13 located in the supraglottic areas and only one located in the subglottic/tracheal area. Therefore the present case is the second case of a subglottic SFT reported. Although rare, SFT should be included in the differential diagnosis of a well-marginated laryngeal mass with highly intense contrast enhancement, which suggests rich tumor vascularity. PMID- 27994929 TI - Multimodality Imaging Findings of a Renal Aspergilloma. AB - BACKGROUND: Renal aspergillosis is a rare infection that usually occurs in persons with a predisposition for this condition. Its differential diagnosis includes primary and metastatic renal malignancies, pyelonephritis and secondary abscess formation, granulomatous disorders, and renal infarction. We aim to stress the role of multimodality imaging and percutaneous biopsy in the diagnosis of this condition. CASE REPORT: We present diffusion weighted imaging (DWI) and positron emission tomography-computed tomography (PET-CT) findings in addition to conventional imaging modalities in a 55-year-old man with secondary renal aspergilloma. CONCLUSION: Radiological imaging methods are an integral part of diagnostic workup for renal aspergillosis. A definitive diagnosis is made by histopathological and/or microbiological examination of the material obtained via percutaneous biopsy under guidance of imaging methods. PMID- 27994930 TI - Cortisol and Hippocampal Volume as Predictors of Active Suicidal Behavior in Major Depressive Disorder: Case Report. AB - BACKGROUND: Suicide is frequently encountered in patients suffering from major depressive disorder (MDD). Since only a third of treated depressed patients are able to achieve remission, in the last few years, new theories have been proposed to better understand the mechanism of this illness. Our paper analyzes the interrelation between cortisol as a marker of neuroendocrine theory as a response to stress, and hippocampal volume subfields in depression as a marker of neurogenesis and neuroplasticity theory. CASE REPORT: Here we present the case of a 52-year-old male patient with known history of MDD, who died as a result of completed suicide by hanging. The patient had been recently discharged from a psychiatric clinic, after being hospitalized for a major depressive episode (MDE). The result of the autopsy, medical records, laboratory analysis and a magnetic resonance image (MRI) of the patient were analyzed. Both the right and left volumes of the hippocampus were found to be smaller when compared to normal values reported in the literature. The morning level of cortisol was higher than the normal value. CONCLUSION: In a depressed patient with an acute stressful event, high levels of cortisol associated with decreased volume of the hippocampus could represent predictors for an increased risk of suicide. PMID- 27994931 TI - Letter to the Editor concerning "New Predictive Parameters of Bell's Palsy: Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio". PMID- 27994932 TI - Prothrombin Complex Concentrates in Life-Threatening Bleeding. PMID- 27994933 TI - Another Reason to Omit Induction Radiotherapy: Save It for Last. PMID- 27994934 TI - Purple Urine Bag Syndrome in a Male Patient with Chronic Hemodialysis. PMID- 27994935 TI - Diffuse Alveolar Hemorrhage after Clopidogrel Use. PMID- 27994936 TI - The impact of deep brain stimulation on tinnitus. AB - BACKGROUND: Tinnitus is a disorder of the nervous system that cannot be adequately treated with current therapies. The effect of neuromodulation induced by deep brain stimulation (DBS) on tinnitus has not been studied well. This study investigated the effect of DBS on tinnitus by use of a multicenter questionnaire study. METHODS: Tinnitus was retrospectively assessed prior to DBS and at the current situation (with DBS). From the 685 questionnaires, 443 were returned. A control group was one-to-one matched to DBS patients who had tinnitus before DBS (n = 61). Tinnitus was assessed by the tinnitus handicap inventory (THI) and visual analog scales (VAS) of loudness and burden. RESULTS: The THI decreased significantly during DBS compared to the situation prior to surgery (from 18.9 to 15.1, P < .001), which was only significant for DBS in the subthalamic nucleus (STN). The THI in the control group (36.9 to 35.5, P = 0.50) and other DBS targets did not change. The VAS loudness increased in the control group (5.4 to 6.0 P < .01). CONCLUSION: DBS might have a modulatory effect on tinnitus. Our study suggests that DBS of the STN may have a beneficial effect on tinnitus, but most likely other nuclei linked to the tinnitus circuitry might be even more effective. PMID- 27994937 TI - The growing need for microservices in bioinformatics. AB - OBJECTIVE: Within the information technology (IT) industry, best practices and standards are constantly evolving and being refined. In contrast, computer technology utilized within the healthcare industry often evolves at a glacial pace, with reduced opportunities for justified innovation. Although the use of timely technology refreshes within an enterprise's overall technology stack can be costly, thoughtful adoption of select technologies with a demonstrated return on investment can be very effective in increasing productivity and at the same time, reducing the burden of maintenance often associated with older and legacy systems. In this brief technical communication, we introduce the concept of microservices as applied to the ecosystem of data analysis pipelines. Microservice architecture is a framework for dividing complex systems into easily managed parts. Each individual service is limited in functional scope, thereby conferring a higher measure of functional isolation and reliability to the collective solution. Moreover, maintenance challenges are greatly simplified by virtue of the reduced architectural complexity of each constitutive module. This fact notwithstanding, rendered overall solutions utilizing a microservices-based approach provide equal or greater levels of functionality as compared to conventional programming approaches. Bioinformatics, with its ever-increasing demand for performance and new testing algorithms, is the perfect use-case for such a solution. Moreover, if promulgated within the greater development community as an open-source solution, such an approach holds potential to be transformative to current bioinformatics software development. CONTEXT: Bioinformatics relies on nimble IT framework which can adapt to changing requirements. AIMS: To present a well-established software design and deployment strategy as a solution for current challenges within bioinformatics. CONCLUSIONS: Use of the microservices framework is an effective methodology for the fabrication and implementation of reliable and innovative software, made possible in a highly collaborative setting. PMID- 27994938 TI - The utility of including pathology reports in improving the computational identification of patients. AB - BACKGROUND: Celiac disease (CD) is a common autoimmune disorder. Efficient identification of patients may improve chronic management of the disease. Prior studies have shown searching International Classification of Diseases-9 (ICD-9) codes alone is inaccurate for identifying patients with CD. In this study, we developed automated classification algorithms leveraging pathology reports and other clinical data in Electronic Health Records (EHRs) to refine the subset population preselected using ICD-9 code (579.0). MATERIALS AND METHODS: EHRs were searched for established ICD-9 code (579.0) suggesting CD, based on which an initial identification of cases was obtained. In addition, laboratory results for tissue transglutaminse were extracted. Using natural language processing we analyzed pathology reports from upper endoscopy. Twelve machine learning classifiers using different combinations of variables related to ICD-9 CD status, laboratory result status, and pathology reports were experimented to find the best possible CD classifier. Ten-fold cross-validation was used to assess the results. RESULTS: A total of 1498 patient records were used including 363 confirmed cases and 1135 false positive cases that served as controls. Logistic model based on both clinical and pathology report features produced the best results: Kappa of 0.78, F1 of 0.92, and area under the curve (AUC) of 0.94, whereas in contrast using ICD-9 only generated poor results: Kappa of 0.28, F1 of 0.75, and AUC of 0.63. CONCLUSION: Our automated classification system presented an efficient and reliable way to improve the performance of CD patient identification. PMID- 27994940 TI - Reflex test reminders in required cancer synoptic templates decrease order entry error: An analysis of mismatch repair immunohistochemical orders to screen for Lynch syndrome. AB - BACKGROUND: Endometrial carcinoma (EC) is the most common extracolonic malignant neoplasm associated with Lynch syndrome (LS). LS is caused by autosomal dominant germline mutations in DNA mismatch repair (MMR) genes. Screening for LS in EC is often evaluated by loss of immunohistochemical (IHC) expression of DNA MMR enzymes MLH1, MSH2, MSH6, and PMS2 (MMR IHC). In July 2013, our clinicians asked that we screen all EC in patients <=60 for loss of MMR IHC expression. Despite this policy, several cases were not screened or screening was delayed. We implemented an informatics-based approach to ensure that all women who met criteria would have timely screening. SUBJECTS AND METHODS: Reports are created in PowerPath (Sunquest Information Systems, Tucson, AZ) with custom synoptic templates. We implemented an algorithm on March 6, 2014 requiring pathologists to address MMR IHC in patients <=60 with EC before sign out (S/O). Pathologists must answer these questions: is patient <=60 (yes/no), if yes, follow-up questions (IHC done previously, ordered with addendum to follow, results included in report, N/A, or not ordered), if not ordered, one must explain. We analyzed cases from July 18, 2013 to August 31, 2016 preimplementation (PreImp) and postimplementation (PostImp) that met criteria. Data analysis was performed using the standard data package included with GraphPad Prism(r) 7.00 (GraphPad Software, Inc., La Jolla, CA, USA). RESULTS: There were 147 patients who met criteria (29 PreImp and 118 PostImp). IHC was ordered in a more complete and timely fashion PostImp than PreImp. PreImp, 4/29 (13.8%) cases did not get any IHC, but PostImp, only 4/118 (3.39%) were missed (P = 0.0448). Of cases with IHC ordered, 60.0% (15/25) were ordered before or at S/O PreImp versus 91.2% (104/114) PostImp (P = 0.0004). Relative to day of S/O, the mean days of order delay were longer and more variable PreImp versus PostImp (12.9 +/- 40.7 vs. 0.660 +/- 1.15; P = 0.0227), with the average being before S/O PostImp. CONCLUSION: This algorithm ensures MMR IHC ordering in women <=60 with EC and can be applied to similar scenarios. Ancillary tests for management are increasing, especially genetic and molecular-based methods. The burden of managing orders and results remains with the pathologist and relying on human intervention alone is ineffective. Ordering IHC before or at S/O prevents oversight and the additional work of retrospective ordering and reporting. PMID- 27994939 TI - Pointwise mutual information quantifies intratumor heterogeneity in tissue sections labeled with multiple fluorescent biomarkers. AB - BACKGROUND: Measures of spatial intratumor heterogeneity are potentially important diagnostic biomarkers for cancer progression, proliferation, and response to therapy. Spatial relationships among cells including cancer and stromal cells in the tumor microenvironment (TME) are key contributors to heterogeneity. METHODS: We demonstrate how to quantify spatial heterogeneity from immunofluorescence pathology samples, using a set of 3 basic breast cancer biomarkers as a test case. We learn a set of dominant biomarker intensity patterns and map the spatial distribution of the biomarker patterns with a network. We then describe the pairwise association statistics for each pattern within the network using pointwise mutual information (PMI) and visually represent heterogeneity with a two-dimensional map. RESULTS: We found a salient set of 8 biomarker patterns to describe cellular phenotypes from a tissue microarray cohort containing 4 different breast cancer subtypes. After computing PMI for each pair of biomarker patterns in each patient and tumor replicate, we visualize the interactions that contribute to the resulting association statistics. Then, we demonstrate the potential for using PMI as a diagnostic biomarker, by comparing PMI maps and heterogeneity scores from patients across the 4 different cancer subtypes. Estrogen receptor positive invasive lobular carcinoma patient, AL13-6, exhibited the highest heterogeneity score among those tested, while estrogen receptor negative invasive ductal carcinoma patient, AL13 14, exhibited the lowest heterogeneity score. CONCLUSIONS: This paper presents an approach for describing intratumor heterogeneity, in a quantitative fashion (via PMI), which departs from the purely qualitative approaches currently used in the clinic. PMI is generalizable to highly multiplexed/hyperplexed immunofluorescence images, as well as spatial data from complementary in situ methods including FISSEQ and CyTOF, sampling many different components within the TME. We hypothesize that PMI will uncover key spatial interactions in the TME that contribute to disease proliferation and progression. PMID- 27994941 TI - A multisite validation of whole slide imaging for primary diagnosis using standardized data collection and analysis. AB - CONTEXT: Text-based reporting and manual arbitration for whole slide imaging (WSI) validation studies are labor intensive and do not allow for consistent, scalable, and repeatable data collection or analysis. OBJECTIVE: The objective of this study was to establish a method of data capture and analysis using standardized codified checklists and predetermined synoptic discordance tables and to use these methods in a pilot multisite validation study. METHODS AND STUDY DESIGN: Fifteen case report form checklists were generated from the College of American Pathology cancer protocols. Prior to data collection, all hypothetical pairwise comparisons were generated, and a level of harm was determined for each possible discordance. Four sites with four pathologists each generated 264 independent reads of 33 cases. Preestablished discordance tables were applied to determine site by site and pooled accuracy, intrareader/intramodality, and interreader intramodality error rates. RESULTS: Over 10,000 hypothetical pairwise comparisons were evaluated and assigned harm in discordance tables. The average difference in error rates between WSI and glass, as compared to ground truth, was 0.75% with a lower bound of 3.23% (95% confidence interval). Major discordances occurred on challenging cases, regardless of modality. The average inter-reader agreement across sites for glass was 76.5% (weighted kappa of 0.68) and for digital it was 79.1% (weighted kappa of 0.72). CONCLUSION: These results demonstrate the feasibility and utility of employing standardized synoptic checklists and predetermined discordance tables to gather consistent, comprehensive diagnostic data for WSI validation studies. This method of data capture and analysis can be applied in large-scale multisite WSI validations. PMID- 27994942 TI - Effect of telmisartan on kidney function in patients with chronic kidney disease: an observational study. AB - Background: Globally the burden of chronic kidney disease (CKD) is rising, an important cause of death and loss of disability-adjusted life years. Activation of the renin-angiotensin-aldosterone system is involved in its pathogenesis. The aim of the present study was to examine the effects of telmisartan (40 mg/day), an angiotensin receptor blocker (ARB) in Indian patients with CKD in real-life setting. Method: This was a prospective observational study. Fifty-six patients (>18 years) diagnosed with CKD were enrolled into the study. Serum creatinine, 24 h urinary protein, spot urine protein-to-creatinine ratio, glomerular filtration rate (GFR) and blood pressure (BP) were assessed along with safety. Results: A total of 55 patients (96.36% hypertensive; 63.61% diabetic) with mean age of 48.23 years completed the study. At the end of 3 months treatment with telmisartan, 24-h urinary protein, spot urine protein-to-creatinine, serum creatinine and BP significantly reduced (p < .05) by 806.78 mg, 0.95, 0.44 mg/dl and 8.9/4.7 mmHg in the overall population. GFR increased from the baseline value of 52.13 to 65.01 ml/min. Telmisartan was well tolerated and treatment was discontinued in one patient because of hyperkalemia. Conclusion: This study demonstrated that telmisartan effectively and safely reduces proteinuria in chronic kidney disease patients. PMID- 27994943 TI - Vildagliptin efficacy in combination with metformin among Jordanian patients with type 2 diabetes mellitus inadequately controlled with metformin. AB - Objective: To assess the efficacy and safety of vildagliptin added to metformin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy. Methods: This was a 12-week prospective observational study where vildagliptin 50 mg twice daily was added to patients with T2DM inadequately controlled (glycosylated hemoglobin type A1c (Hba1c) 7-10%) by a daily dose of metformin >=1700 mg between June 2012 and May 2013. Efficacy was assessed by change in Hba1c and fasting plasma glucose (FPG) levels, and safety was assessed by reported adverse events (AEs). Results: A total of 58 patients were enrolled in this study. Their age ranged between 39.0 and 71.0 years, with a mean of 52.6 years, and a standard deviation (SD) of 7.8. The average duration of diabetes mellitus (DM) was 4.0 years (SD 3.0) and half of the patients have had DM for more than three years. The mean baseline levels of Hba1c and FPG were 8% and 10.8 mmol/L, respectively. Patients treated with vildagliptin achieved clinically significant reductions in Hba1c of 1.1% (p value <.005) and reduction in FPG of 1.8 mmol/L (p value <.005) from baseline. Overall, 62.1% had achieved the target of Hba1c of <7% after vildagliptin use. Greater reductions in Hba1c were linked to higher baseline levels as well as to the daily frequency of metformin use. Mild AEs were reported by 16 patients. There was no incidence of hypoglycemia and there were no significant changes in body weight after treatment. Conclusions: Vildagliptin as add-on therapy to metformin improved glycemic control and was highly tolerable in T2DM patients who were inadequately controlled by metformin monotherapy. PMID- 27994944 TI - Placental Abruption Revealed by Hemoperitoneum: A Case Report. AB - Background Hemoperitoneum is a life-threatening surgical emergency. Diagnosis of the cause is often difficult, in particular, during pregnancy when it may be either obstetric or nonobstetric. Case We report the case of a hemoperitoneum caused by the backflow of blood through a uterine tube, due to placental abruption. Conclusion Hemoperitoneum in pregnant women with no other signs can reveal placental abruption. The difficulty in identifying the cause may delay appropriate management. PMID- 27994945 TI - Early Postnatal Seizures in a Neonate with Wolf-Hirschhorn Syndrome. AB - Background Wolf-Hirschhorn syndrome (WHS), which is characterized by a typical facial appearance, growth retardation, mental retardation, seizures, and congenital cardiac defects, has an estimated incidence of 1 per 50,000 births. Case We report a case of a low birth weight neonate with WHS and seizures, as well as persistent pulmonary hypertension in the early neonatal period. Apgar scores were 6 (1 minute) and 8 (5 minutes) with evident retraction. After admission to the neonatal intensive care unit, the patient had tonic-clonic seizures with epilepticus 30 minute after birth. Although the seizures were uncontrollable, continuous thiopental administration was effective for seizure mitigation. Conclusion Neonatal seizures with WHS occur rarely. This is the first case report on seizures just after birth in a neonate with WHS. PMID- 27994946 TI - How WWII and the old Turkish mass standard led a Greek to a scientific career. PMID- 27994948 TI - Quantitative assessment of adipocyte differentiation in cell culture. AB - Adipocyte cell culture is an important tool for mechanistic studies of energy metabolism. Many factors affect the differentiation of adipocytes in culture. Oil red O staining can be used to assess the degree of differentiation. However, the validity of this method for quantitative analysis has not yet been established. Here we show that a protocol with arbitrarily chosen parameters does not measure in the linear range and is not suitable for quantitative analysis (R2 = 0.077, p = 0.382), and develop and validate an optimized protocol for quantitative oil red O staining of cultured adipocytes. 3T3-L1 preadipocytes and adipocytes are fixed with 4% formaldehyde and stained with 0.2% oil red O solution in 40% 2-propanol for 30 minutes. Dye is eluted with 2-propanol, and absorption of the eluate is measured photometrically at 510 nm. This optimized protocol achieves excellent correlation between defined amounts of differentiated adipocytes on constant-size culture plates and photometric absorption (R2 = 0.972, p = 6.585E-14). The performance of the method is independent of the culture plates used. Thus, the optimized oil red O staining protocol can be universally employed to quantitatively assess adipocyte differentiation. PMID- 27994949 TI - Branched short-chain fatty acids modulate glucose and lipid metabolism in primary adipocytes. AB - Short-chain fatty acids (SCFAs), e.g. acetic acid, propionic acid and butyric acid, generated through colonic fermentation of dietary fibers, have been shown to reach the systemic circulation at micromolar concentrations. Moreover, SCFAs have been conferred anti-obesity properties in both animal models and human subjects. Branched SCFAs (BSCFAs), e.g., isobutyric and isovaleric acid, are generated by fermentation of branched amino acids, generated from undigested protein reaching colon. However, BSCFAs have been sparsely investigated when referring to effects on energy metabolism. Here we primarily investigate the effects of isobutyric acid and isovaleric acid on glucose and lipid metabolism in primary rat and human adipocytes. BSCFAs inhibited both cAMP-mediated lipolysis and insulin-stimulated de novo lipogenesis at 10 mM, whereas isobutyric acid potentiated insulin-stimulated glucose uptake by all concentrations (1, 3 and 10 mM) in rat adipocytes. For human adipocytes, only SCFAs inhibited lipolysis at 10 mM. In both in vitro models, BSCFAs and SCFAs reduced phosphorylation of hormone sensitive lipase, a rate limiting enzyme in lipolysis. In addition, BSCFAs and SCFAs, in contrast to insulin, inhibited lipolysis in the presence of wortmannin, a phosphatidylinositide 3-kinase inhibitor and OPC3911, a phosphodiesterase 3 inhibitor in rat adipocytes. Furthermore, BSCFAs and SCFAs reduced insulin mediated phosphorylation of protein kinase B. To conclude, BSCFAs have effects on adipocyte lipid and glucose metabolism that can contribute to improved insulin sensitivity in individuals with disturbed metabolism. PMID- 27994950 TI - Cytokine signaling regulating adipose stromal cell trafficking. AB - Adipocyte progenitors, known as adipose stromal cells (ASC), can become mobilized, recruited by tumors, and contribute to cancer progression. Mechanisms underlying ASC trafficking have remained obscure. We recently reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing CXCR1 in obesity. As a candidate mechanism of CXCL1 activation, we identified interleukin (IL)-22, systemic circulation of which is increased in obesity. It has been reported that IL-22 signaling through IL-22R is upstream of CXCL1. Here, we provide evidence that IL-22 expression by leukocytes infiltrating WAT and IL-22R expression by tumors is obesity-dependent. We propose that obesity-associated adipocyte death and the resulting recruitment of leukocytes triggers the IL-22 signaling cascade that induces CXCL1 secretion by cancer cells responsible for ASC trafficking to tumors. PMID- 27994951 TI - Subcutaneous abdominal adipose tissue is associated with an index of insulin sensitivity/resistance. AB - To assess whether there is any clinical significance for determining the normal range of subcutaneous abdominal fat area, we compared fat area with insulin sensitivity. Visceral and subcutaneous abdominal fat area the L4-L5 thoracic level was determined by computed tomography (CT). Plasma glucose and insulin levels were determined after an overnight fast and calculated by the homeostatic model assessment of insulin resistance (HOMA-IR). We analyzed 350 (180 male and 170 female) subjects whose BMI was 18.5<=BMI<25. The subcutaneous abdominal fat area of the female subjects was 124.7 +/- 46.13 cm2 and that of male subjects was 77.53 +/- 37.53 cm2 (mean +/- SD). We compared HOMA-IR between subjects whose visceral abdominal fat area was above 100 cm2 and subcutaneous abdominal fat area below the mean + 2SD (15 subjects, 6 male and 9 female) with subjects whose visceral abdominal fat area was also above 100 cm2 but whose subcutaneous abdominal fat area was above the mean + 2SD (20 subjects, 7 male and 13 female). The HOMA-IR of the former subjects group was 8.17+/-6.22 and that of the latter subjects group was 3.37+/-2.07 (p = 0.0486). Subjects with increased subcutaneous abdominal fat area displayed lower HOMA-IR values, demonstrating a protective effect of subcutaneous fat for individuals with visceral fat area above 1002 cm. PMID- 27994947 TI - Recent advances in the understanding of how neuropeptide Y and alpha-melanocyte stimulating hormone function in adipose physiology. AB - Communication between the brain and the adipose tissue has been the focus of many studies in recent years, with the "brain-fat axis" identified as a system that orchestrates the assimilation and usage of energy to maintain body mass and adequate fat stores. It is now well-known that appetite-regulating peptides that were studied as neurotransmitters in the central nervous system can act both on the hypothalamus to regulate feeding behavior and also on the adipose tissue to modulate the storage of energy. Energy balance is thus partly controlled by factors that can alter both energy intake and storage/expenditure. Two such factors involved in these processes are neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (alpha-MSH). NPY, an orexigenic factor, is associated with promoting adipogenesis in both mammals and chickens, while alpha-MSH, an anorexigenic factor, stimulates lipolysis in rodents. There is also evidence of interaction between the 2 peptides. This review aims to summarize recent advances in the study of NPY and alpha-MSH regarding their role in adipose tissue physiology, with an emphasis on the cellular and molecular mechanisms. A greater understanding of the brain-fat axis and regulation of adiposity by bioactive peptides may provide insights on strategies to prevent or treat obesity and also enhance nutrient utilization efficiency in agriculturally-important species. PMID- 27994952 TI - Retinoic acid is abundantly detected in different depots of adipose tissue by SERS. AB - Retinoic acid (RA) is essential for early developmental processes and stem cell differentiation, but less is known about its contributions to adult tissues and stem cells including adipose tissue. We previously demonstrated that many genes involved in RA synthesis and downstream pathway are differentially expressed in adipose-derived stem cells (ASCs) from visceral fat compared to those from subcutaneous fat, leading to changes in their early adipogenic functions. In order to study potential contributions of RA in adipose tissue, we measured tissue RA levels using a technique based on surface-enhanced Raman spectroscopy (SERS). The data indicate heretofore underappreciated abundance of endogenous RA in mouse adipose tissue compared to other tissues and dynamic changes of RA concentrations after high fat diet feeding. Our results lay the foundation for further investigation on the functional role of RA in adipose tissue development and metabolism. PMID- 27994953 TI - TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte. AB - Chronic low grade inflammation is one of the major metabolic disorders in case of obesity and associated pathologies. By its important secretion function, the role of adipose tissue in this metabolic low grade inflammation is well known. Recently, it was demonstrated that the alarmin high mobility group box protein 1 (HMGB1) is involved in obesity-related pathologies by its increased serum levels in obese compared to normal weight individuals, and by its pro-inflammatory effects. However, the role of HMGB1 on adipocytes inflammation is poorly documented and we propose to investigate this point. Primary culture of human subcutaneous adipocytes were performed from human adipose tissue samples. Cells were treated with recombinant HMGB1 with/without anti-TLR4 antibody and inhibitors of NF-kappaB and P38 MAPK. Supernatants were collected for IL-6 and MCP-1 ELISA. HMGB1 initiates Toll-like receptor 4 (TLR4)-dependent activation of inflammation through the downstream NF-kappaB and P38 MAPK signaling pathway to upregulate the secretion of the pro-inflammatory cytokine IL-6. HMGB1 has pro inflammatory effects on adipocytes. This reinforces the role of TLR4 in adipose tissue inflammation and antagonizing the HMGB1 inflammatory pathway could bring on new therapeutic targets to counteract obesity-associated pathologies. PMID- 27994955 TI - In this issue of Adipocyte. PMID- 27994954 TI - Communication between natural killer T cells and adipocytes in obesity. AB - Adipose tissue contains various types of immunocompetent cells, and these cells of innate and adaptive immunity control adipose tissue inflammation that blunts insulin sensitivity. Recent studies have shown that adipocytes express CD1d and present lipid antigen(s) to activate natural killer T (NKT) cells. The function of adipocytes is in turn modulated by cytokines that NKT cells produce to alter the expression of anti-inflammatory adipokine(s) and the production of inflammatory and chemoattractant cytokines. These in vitro studies imply that the interaction between adipocytes and NKT cells might affect the development of not only obesity but also obesity-related diseases. To test the importance of the interaction between NKT cells and adipocytes, we examined whether an adipocyte specific CD1d deletion affected the development of obesity, which had been demonstrated with B6.CD1d-/- (CD1d KO). We found that the interaction is indeed important to induce adipose tissue inflammation and insulin resistance in response to lipid excess. In this commentary, the advances and controversies on NKT cells and obesity are discussed based on our recent report that NKT cells play a pivotal role in the regulation of adipose tissue by communicating with adipocytes via CD1d. PMID- 27994956 TI - Identifying suitable reference genes for gene expression analysis in developing skeletal muscle in pigs. AB - The selection of suitable reference genes is crucial to accurately evaluate and normalize the relative expression level of target genes for gene function analysis. However, commonly used reference genes have variable expression levels in developing skeletal muscle. There are few reports that systematically evaluate the expression stability of reference genes across prenatal and postnatal developing skeletal muscle in mammals. Here, we used quantitative PCR to examine the expression levels of 15 candidate reference genes (ACTB, GAPDH, RNF7, RHOA, RPS18, RPL32, PPIA, H3F3, API5, B2M, AP1S1, DRAP1, TBP, WSB, and VAPB) in porcine skeletal muscle at 26 different developmental stages (15 prenatal and 11 postnatal periods). We evaluated gene expression stability using the computer algorithms geNorm, NormFinder, and BestKeeper. Our results indicated that GAPDH and ACTB had the greatest variability among the candidate genes across prenatal and postnatal stages of skeletal muscle development. RPS18, API5, and VAPB had stable expression levels in prenatal stages, whereas API5, RPS18, RPL32, and H3F3 had stable expression levels in postnatal stages. API5 and H3F3 expression levels had the greatest stability in all tested prenatal and postnatal stages, and were the most appropriate reference genes for gene expression normalization in developing skeletal muscle. Our data provide valuable information for gene expression analysis during different stages of skeletal muscle development in mammals. This information can provide a valuable guide for the analysis of human diseases. PMID- 27994957 TI - Functional characterisation of phagocytes in the Pacific oyster Crassostrea gigas. AB - Invertebrates lack canonical adaptive immunity and mainly rely on innate immune system to fight against pathogens. The phagocytes, which could engulf and kill microbial pathogens, are likely to be of great importance and have to undertake significant roles in invertebrate immune defense. In the present study, flow cytometry combined with histological and lectin staining was employed to characterise functional features of phagocytes in the Pacific oyster Crassostrea gigas. Based on the cell size and cellular contents, haemocytes were categorised into three cell types, i.e., granulocytes, semigranulocytes and agranulocytes. Agranulocytes with smaller cell volume and lower cytoplasmic-to-nuclear ratio did not show phagocytic activity, while semigranulocytes and agranulocytes exhibited larger cell volume, higher cytoplasmic-to-nuclear ratio and phagocytic activity. In addition, granulocytes with higher side scatter (SSC) exhibited higher phagocytic activity than that of semigranulocytes. When beta-integrin and lectin like receptors were blocked by RGD tripeptide and carbohydrates, respectively, the phagocytic activity of both granulocytes and semigranulocytes was significantly inhibited, indicating that beta-integrin and certain lectin-like receptors were involved in phagocytosis towards microbes. Moreover, lipopolysaccharide but not peptidylglycan could enhance phagocytic activity of granulocytes and semigranulocytes towards Vibrio splendidus and Staphylococcus aureus. Lectin staining analysis revealed that Lycopersicon esculentum lectin (LEL), binding the epitope polylactosamine, was highly distributed on the extracellular cell surface of phagocytes, and could be utilized as a potential molecular marker to differentiate phagocytes from non-phagocytic haemocytes. The results, collectively, provide knowledge on the functional characters of oyster phagocytes, which would contribute to deep investigation of cell typing and cellular immunity in bivalves. PMID- 27994958 TI - Feasibility of nuclear ribosomal region ITS1 over ITS2 in barcoding taxonomically challenging genera of subtribe Cassiinae (Fabaceae). AB - PREMISE OF THE STUDY: The internal transcribed spacer (ITS) region is situated between 18S and 26S in a polycistronic rRNA precursor transcript. It had been proved to be the most commonly sequenced region across plant species to resolve phylogenetic relationships ranging from shallow to deep taxonomic levels. Despite several taxonomical revisions in Cassiinae, a stable phylogeny remains elusive at the molecular level, particularly concerning the delineation of species in the genera Cassia, Senna and Chamaecrista. This study addresses the comparative potential of ITS datasets (ITS1, ITS2 and concatenated) in resolving the underlying morphological disparity in the highly complex genera, to assess their discriminatory power as potential barcode candidates in Cassiinae. METHODOLOGY: A combination of experimental data and an in-silico approach based on threshold genetic distances, sequence similarity based and hierarchical tree-based methods was performed to decipher the discriminating power of ITS datasets on 18 different species of Cassiinae complex. Lab-generated sequences were compared against those available in the GenBank using BLAST and were aligned through MUSCLE 3.8.31 and analysed in PAUP 4.0 and BEAST1.8 using parsimony ratchet, maximum likelihood and Bayesian inference (BI) methods of gene and species tree reconciliation with bootstrapping. DNA barcoding gap was realized based on the Kimura two-parameter distance model (K2P) in TaxonDNA and MEGA. PRINCIPAL FINDINGS: Based on the K2P distance, significant divergences between the inter- and intra-specific genetic distances were observed, while the presence of a DNA barcoding gap was obvious. The ITS1 region efficiently identified 81.63% and 90% of species using TaxonDNA and BI methods, respectively. The PWG-distance method based on simple pairwise matching indicated the significance of ITS1 whereby highest number of variable (210) and informative sites (206) were obtained. The BI tree-based methods outperformed the similarity-based methods producing well resolved phylogenetic trees with many nodes well supported by bootstrap analyses. CONCLUSION: The reticulated phylogenetic hypothesis using the ITS1 region mainly supported the relationship between the species of Cassiinae established by traditional morphological methods. The ITS1 region showed a higher discrimination power and desirable characteristics as compared to ITS2 and ITS1 + 2, thereby concluding to be the locus of choice. Considering the complexity of the group and the underlying biological ambiguities, the results presented here are encouraging for developing DNA barcoding as a useful tool for resolving taxonomical challenges in corroboration with morphological framework. PMID- 27994959 TI - RNA interference as a gene silencing tool to control Tuta absoluta in tomato (Solanum lycopersicum). AB - RNA interference (RNAi), a gene-silencing mechanism that involves providing double-stranded RNA molecules that match a specific target gene sequence, is now widely used in functional genetic studies. The potential application of RNAi mediated control of agricultural insect pests has rapidly become evident. The production of transgenic plants expressing dsRNA molecules that target essential insect genes could provide a means of specific gene silencing in larvae that feed on these plants, resulting in larval phenotypes that range from loss of appetite to death. In this report, we show that the tomato leafminer ( Tuta absoluta ), a major threat to commercial tomato production, can be targeted by RNAi. We selected two target genes (Vacuolar ATPase-A and Arginine kinase) based on the RNAi response reported for these genes in other pest species. In view of the lack of an artificial diet for T. absoluta, we used two approaches to deliver dsRNA into tomato leaflets. The first approach was based on the uptake of dsRNA by leaflets and the second was based on "in planta-induced transient gene silencing" (PITGS), a well-established method for silencing plant genes, used here for the first time to deliver in planta-transcribed dsRNA to target insect genes. Tuta absoluta larvae that fed on leaves containing dsRNA of the target genes showed an ~60% reduction in target gene transcript accumulation, an increase in larval mortality and less leaf damage. We then generated transgenic 'Micro-Tom' tomato plants that expressed hairpin sequences for both genes and observed a reduction in foliar damage by T. absoluta in these plants. Our results demonstrate the feasibility of RNAi as an alternative method for controlling this critical tomato pest. PMID- 27994960 TI - Malagasy Conostigmus (Hymenoptera: Ceraphronoidea) and the secret of scutes. AB - We revise the genus Conostigmus Dahlbom 1858 occurring in Madagascar, based on data from more specimens than were examined for the latest world revision of the genus. Our results yield new information about intraspecific variability and the nature of the atypical latitudinal diversity gradient (LDG) observed in Ceraphronoidea. We also investigate cellular processes that underlie body size polyphenism, by utilizing the correspondence between epidermal cells and scutes, polygonal units of leather-like microsculpture. Our results reveal that body size polyphenism in Megaspilidae is most likely related to cell number and not cell size variation, and that cell size differs between epithelial fields of the head and that of the mesosoma. Three species, Conostigmus ballescoracas Dessart, 1997, C. babaiax Dessart, 1996 and C. longulus Dessart, 1997, are redescribed. Females of C. longulus are described for the first time, as are nine new species: C. bucephalus Miko and Trietsch sp. nov., C. clavatus Miko and Trietsch sp. nov., C. fianarantsoaensis Miko and Trietsch sp. nov., C. lucidus Miko and Trietsch sp. nov., C. macrocupula, Miko and Trietsch sp. nov., C. madagascariensis Miko and Trietsch sp. nov., C. missyhazenae Miko and Trietsch sp. nov., C. pseudobabaiax Miko and Trietsch sp. nov., and C. toliaraensis Miko and Trietsch sp. nov. A fully illustrated identification key for Malagasy Conostigmus species and a Web Ontology Language (OWL) representation of the taxonomic treatment, including specimen data, nomenclature, and phenotype descriptions, in both natural and formal languages, are provided. PMID- 27994961 TI - Self-reported frequency, severity of, and awareness of hypoglycemia in type 2 diabetes patients in Turkey. AB - OBJECTIVES: Hypoglycemia is a common side effect of insulin therapy in type 1 and type 2 diabetes. Limited data exist on the frequency of hypoglycemic events in type 2 diabetic patients in Turkey. Our study investigated self-reported hypoglycemic events and awareness of hypoglycemia in Turkish patients with type 2 diabetes. METHODS: People with type 2 diabetes older than 18 years of age were recruited from the two university hospital diabetes clinics. The frequency and severity of hypoglycemia and awareness of hypoglycemia during the preceding year were determinated using questionnaires by the face-to-face interview method. RESULTS: In this study of 187 patients with type 2 diabetes, 83.4% had impaired awareness of their hypoglycemia, and 62% reported that they had missed some of the symptoms of hypoglycemia. Of the patients reporting hypoglycemic symptoms and severity level, 84.1% experienced mild hypoglycemia, 60% moderate, and 15.5% severe hypoglycemia in the past year. No significant association was made between hypoglycemia awareness and age, body-mass index (BMI), years of diabetes, dose of insulin, duration of insulin use, number of meals, or amount of snacking. A significant correlation was found between A1c levels and hypoglycemia awareness and severity of hypoglycemia. A significant correlation was found between dose of insulin, amount of snacking, and severity of hypoglycemia. No significant association was made between severity of hypoglycemia and age, BMI, years of diabetes, duration of insulin use, or the number of meals. However, the group with severe hypoglycemia had diabetes longer, and the average daily dose of insulin use was higher than in other groups. CONCLUSIONS: According to the study results, the percentage of patients with impaired awareness of hypoglycemia is high, and 62% of patients reported that they had missed some of the symptoms of hypoglycemia in type 2 diabetes. In addition, the percentage of severe hypoglycemic events is not low. Impaired awareness of hypoglycemia is a major risk factor for severe hypoglycemic events. Patients should be educated about the danger of hypoglycemia. Education should be improved, and a determined attempt should be made to eradicate the problem. PMID- 27994962 TI - Regulation of S1P receptors and sphingosine kinases expression in acute pulmonary endothelial cell injury. AB - BACKGROUND: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is a severe clinical syndrome with mortality rate as high as 30-40%. There is no treatment yet to improve pulmonary endothelial barrier function in patients with severe pulmonary edema. Developing therapies to protect endothelial barrier integrity and stabilizing gas exchange is getting more and more attention. Sphingosine-1-phosphate (S1P) is able to enhance the resistance of endothelial cell barrier. S1P at physiological concentrations plays an important role in maintaining endothelial barrier function. Proliferation, regeneration and anti inflammatory activity that mesenchymal stem cells (MSCs) exhibit make it possible to regulate the homeostatic control of S1P. METHODS: By building a pulmonary endothelial cell model of acute injury, we investigated the regulation of S1P receptors and sphingosine kinases expression by MSCs during the treatment of acute lung injury using RT-PCR, and investigated the HPAECs Micro-electronics impedance using Real Time Cellular Analysis. RESULTS: It was found that the down regulation of TNF-alpha expression was more significant when MSC was used in combination with S1P. The combination effection mainly worked on S1PR2, S1PR3 and SphK2. The results show that when MSCs were used in combination with S1P, the selectivity of S1P receptors was increased and the homeostatic control of S1P concentration was improved through regulation of expression of S1P metabolic enzymes. DISCUSSIONS: The study found that, as a potential treatment, MSCs could work on multiple S1P related genes simultaneously. When it was used in combination with S1P, the expression regulation result of related genes was not simply the superposition of each other, but more significant outcome was obtained. This study establishes the experimental basis for further exploring the efficacy of improving endothelial barrier function in acute lung injury, using MSCs in combination with S1P and their possible synergistic mechanism. PMID- 27994963 TI - Probabilistic adaptation in changing microbial environments. AB - Microbes growing in animal host environments face fluctuations that have elements of both randomness and predictability. In the mammalian gut, fluctuations in nutrient levels and other physiological parameters are structured by the host's behavior, diet, health and microbiota composition. Microbial cells that can anticipate environmental fluctuations by exploiting this structure would likely gain a fitness advantage (by adapting their internal state in advance). We propose that the problem of adaptive growth in structured changing environments, such as the gut, can be viewed as probabilistic inference. We analyze environments that are "meta-changing": where there are changes in the way the environment fluctuates, governed by a mechanism unobservable to cells. We develop a dynamic Bayesian model of these environments and show that a real-time inference algorithm (particle filtering) for this model can be used as a microbial growth strategy implementable in molecular circuits. The growth strategy suggested by our model outperforms heuristic strategies, and points to a class of algorithms that could support real-time probabilistic inference in natural or synthetic cellular circuits. PMID- 27994965 TI - Harvest year effects on Apulian EVOOs evaluated by 1H NMR based metabolomics. AB - Nine hundred extra virgin olive oils (EVOO) were extracted from individual olive trees of four olive cultivars (Coratina, Cima di Mola, Ogliarola, Peranzana), originating from the provinces of Bari and Foggia (Apulia region, Southern Italy) and collected during two consecutive harvesting seasons (2013/14 and 2014/15). Following genetic identification of individual olive trees, a detailed Apulian EVOO NMR database was built using 900 oils samples obtained from 900 cultivar certified single trees. A study on the olive oil lipid profile was carried out by statistical multivariate analysis (Principal Component Analysis, PCA, Partial Least-Squares Discriminant Analysis, PLS-DA, Orthogonal Partial Least-Squares Discriminant Analysis, OPLS-DA). Influence of cultivar and weather conditions, such as the summer rainfall, on the oil metabolic profile have been evaluated. Mahalanobis distances and J2 criterion have been measured to assess the quality of resulting scores clusters for each cultivar in the two harvesting campaigns. The four studied cultivars showed non homogeneous behavior. Notwithstanding the geographical spread and the wide number of samples, Coratina showed a consistent behavior of its metabolic profile in the two considered harvests. Among the other three Peranzana showed the second more consistent behavior, while Cima di Mola and Ogliarola having the biggest change over the two years. PMID- 27994964 TI - Dendrobium alkaloids prevent Abeta25-35-induced neuronal and synaptic loss via promoting neurotrophic factors expression in mice. AB - BACKGROUND: Neuronal and synaptic loss is the most important risk factor for cognitive impairment. Inhibiting neuronal apoptosis and preventing synaptic loss are promising therapeutic approaches for Alzheimer's disease (AD). In this study, we investigate the protective effects of Dendrobium alkaloids (DNLA), a Chinese medicinal herb extract, on beta-amyloid peptide segment 25-35 (Abeta25-35) induced neuron and synaptic loss in mice. METHOD: Abeta25-35(10 ug) was injected into the bilateral ventricles of male mice followed by an oral administration of DNLA (40 mg/kg) for 19 days. The Morris water maze was used for evaluating the ability of spatial learning and memory function of mice. The morphological changes were examined via H&E staining and Nissl staining. TUNEL staining was used to check the neuronal apoptosis. The ultrastructure changes of neurons were observed under electron microscope. Western blot was used to evaluate the protein expression levels of ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex. RESULTS: DNLA significantly attenuated Abeta25-35-induced spatial learning and memory impairments in mice. DNLA prevented Abeta25-35 induced neuronal loss in the hippocampus and cortex, increased the number of Nissl bodies, improved the ultrastructural injury of neurons and increased the number of synapses in neurons. Furthermore, DNLA increased the protein expression of neurotrophic factors BDNF, CNTF and GDNF in the hippocampus and cortex. CONCLUSIONS: DNLA can prevent neuronal apoptosis and synaptic loss. This effect is mediated at least in part via increasing the expression of BDNF, GDNF and CNTF in the hippocampus and cortex; improving Abeta-induced spatial learning and memory impairment in mice. PMID- 27994966 TI - The effect of changing topography on the coordinated marching of locust nymphs. AB - Collective motion has traditionally been studied in the lab in homogeneous, obstacle-free environments, with little work having been conducted with changing landscapes or topography. Here, the impact of spatial heterogeneity on the collective motion exhibited by marching desert locust nymphs was studied under controlled lab conditions. Our experimental circular arenas, incorporating a funnel-like narrowing followed by re-widening, did not constitute a major barrier to the locusts but, rather, mimicked a changing topography in the natural environment. We examined its effects on macroscopic features of the locust collective behavior, as well as the any changes in their marching kinematics. A major finding was that of the limited extent to which the changing topography affected system-level features of the marching locust group, such as the order parameter and the fraction of walking individuals, despite increased crowding at the funnel. Overall, marching kinematics was also very little affected, suggesting that locust marching bands adjust to the environment, with little effect on the overall dynamics of the group. These findings are in contrast to recent theoretical results predicting that environmental heterogeneities qualitatively alter the dynamics of collectively moving particles; and highlight the crucial role of rapid individual plasticity and adaptability in the dynamics of flocks and swarms. Our study has revealed other important features of the marching behavior of the desert locust in addition to its robustness: the locusts demonstrated both, clear thigmotaxis and a tendency to spread-out and fill the available space. PMID- 27994967 TI - Biodiversity data obsolescence and land uses changes. AB - BACKGROUND: Primary biodiversity records (PBR) are essential in many areas of scientific research as they document the biodiversity through time and space. However, concerns about PBR quality and fitness-for-use have grown, especially as derived from taxonomical, geographical and sampling effort biases. Nonetheless, the temporal bias stemming from data ageing has received less attention. We examine the effect of changes in land use in the information currentness, and therefore data obsolescence, in biodiversity databases. METHODS: We created maps of land use changes for three periods (1956-1985, 1985-2000 and 2000-2012) at 5 kilometres resolution. For each cell we calculated the percentage of land use change within each period. We then overlaid distribution data about small mammals, and classified each data as 'non-obsolete or 'obsolete,' depending on both the amount of land use changes in the cell, and whether changes occurred at or after the data sampling's date. RESULTS: A total of 14,528 records out of the initial 59,677 turned out to be non-obsolete after taking into account the changes in the land uses in Navarra. These obsolete data existed in 115 of the 156 cells analysed. Furthermore, more than one half of the remaining cells holding non-obsolete records had not been visited at least for the last fifteen years. CONCLUSION: Land use changes challenge the actual information obtainable from biodiversity datasets and therefore its potential uses. With the passage of time, one can expect a steady increase in the availability and use of biological records-but not without them becoming older and likely to be obsolete by land uses changes. Therefore, it becomes necessary to assess records' obsolescence, as it may jeopardize the knowledge and perception of biodiversity patterns. PMID- 27994968 TI - A retrospective study: cardiac MRI of fulminant myocarditis in children-can we evaluate the short-term outcomes? AB - BACKGROUND: Fulminant myocarditis (FM) is an inflammatory disease of the myocardium that results in ventricular systolic dysfunction and causes acute onset heart failure. Cardiac magnetic resonance (CMR) has become the primary noninvasive tool for the diagnosis and evaluation of myocarditis. The aim of our study was to assess the CMR findings at different course of FM and the short-term outcomes of fulminant myocarditis (FM) in children. METHODS: Eight FM children with CMR examinations were included in our study. Initial baseline CMR was performed 10 days (range, 7-20 days) after onset of FM and follow-up CMR after 55 days (range, 33-75 days). Cardiac morphology and function and myocardial tissue characterization at baseline and follow-up CMR were compared using paired T-test and Mann-Whitney U test. The clinical data and initial CMR findings were also compared to predict short-term outcomes. RESULTS: The median age of eight FM children was 8.5 years old (range, 3-14). The initial CMR findings were most common with early gadolinium enhancement (EGE, 100%), followed by signal increasing on T2WI and late gadolinium enhancement (LGE, 87.5%), increased septal thickness (75.0%) and increased left ventricle ejection fraction (LVEF, 50.0%). Only three LGE (37.5%), one signal increasing on T2WI (12.5%) and one increased LVEF (12.5%) were found at follow-up. Statistically significant differences were found between initial and follow-up CMR abnormalities in the septal thickness, left ventricular end-diastolic diameter (LVEDD), end-systolic volume (ESV), LVEF, left ventricular mass, T2 ratio and LGE area (P = 0.011, P = 0.042, P = 0.016, P = 0.001, P = 0.003, P = 0.011, P = 0.020). The children with full recovery performed higher incidence of III degrees atrioventricular block (AVB, five cases VS 0 case) and smaller LGE area (104.0 +/- 14.5 mm2 VS 138.0 +/- 25.2 mm2) at baseline CMR. DISCUSSION: The CMR findings of FM in children were characteristic and useful for early diagnosis. Full recovery of clinical manifestations, immunological features and CMR findings could be found in most FM children. The presence of III degrees AVB and smaller LGE area at baseline CMR might indicate better short-term outcomes. PMID- 27994969 TI - In situ earthworm breeding in orchards significantly improves the growth, quality and yield of papaya (Carica papaya L.). AB - The aim of this study was to compare the effects of four fertilizer applications control (C), chemical fertilizer (F), compost (O), and in situ earthworm breeding (E)-on the growth, quality and yield of papaya (Carica papaya L.). In this study, 5 g plant-1 urea (CH4N2O, %N = 46.3%) and 100 g plant-1 microelement fertilizer was applied to each treatment. The fertilizer applications of these four treatments are different from each other. The results showed that the E treatment had the highest growth parameters over the whole growth period. At 127 days after transplantation, the order of plant heights from greatest to smallest was E > F > O > C, and the stem diameters were E > F > O > C, with significant differences between all treatments. Soluble-solid, sugar, vitamin C, and protein content significantly increased in the E treatment. In addition, the total acid and the electrical conductivity of the fruit significantly decreased in the E treatment. Fruit firmness clearly increased in the O treatment, and decreased in the F treatment. The fresh individual fruit weights, fruit numbers, and total yields were greatly improved in the F and E treatments, and the total yield of the E treatment was higher than that in the F treatment. In conclusion, the in situ earthworm breeding treatment performed better than conventional compost and chemical fertilizer treatments. Furthermore, in situ earthworm breeding may be a potential organic fertilizer application in orchards because it not only improves the fruit quality and yield but also reduces the amount of organic wastes from agriculture as a result of the activities of earthworms. PMID- 27994970 TI - In vitro gastrointestinal digestion study of a novel bio-tofu with special emphasis on the impact of microbial transglutaminase. AB - We have developed a novel bio-tofu, made from mixed soy and cow milk (MSCM), using Lactobacillus helveticus MB2-1 and Lactobacillus plantarum B1-6 incorporated with microbial transglutaminase (MTGase) as coagulant. MTGase was added to improve the textural properties and suit for cooking. However, the effect of MTGase on the digestion of mixed-protein fermented by lactic acid bacteria was unclear. This study aimed at evaluating the effect of MTGase on protein digestion of bio-tofu under simulated gastrointestinal digestion condition. The results showed that addition of MTGase could affect the particle size distribution, degree of hydrolysis, the content of soluble proteins and free amino acids. Based on the electrophoresis data, MTGase addition enhanced protein polymerization. During gastric and intestinal digestion process, proteins from bio-tofu were degraded into low molecular mass peptides. Our results suggested that incorporation of MTGase could lead to enzymatic modification of proteins of bio-tofu which may help in controlling energy intake and decrease the chance of food allergy. PMID- 27994971 TI - Discovery of novel inhibitors disrupting HIF-1alpha/von Hippel-Lindau interaction through shape-based screening and cascade docking. AB - Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein-protein interaction between HIF 1alpha and the von Hippel-Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1alpha/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751), showed comparable activity to pVHL with an IC50 of 2.0 +/- 0.14 uM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1alpha/von Hippel-Lindau interaction. PMID- 27994973 TI - Using a thermistor flowmeter with attached video camera for monitoring sponge excurrent speed and oscular behaviour. AB - A digital, four-channel thermistor flowmeter integrated with time-lapse cameras was developed as an experimental tool for measuring pumping rates in marine sponges, particularly those with small excurrent openings (oscula). Combining flowmeters with time-lapse imagery yielded valuable insights into the contractile behaviour of oscula in Cliona orientalis. Osculum cross-sectional area (OSA) was positively correlated to measured excurrent speeds (ES), indicating that sponge pumping and osculum contraction are coordinated behaviours. Both OSA and ES were positively correlated to pumping rate (Q). Diel trends in pumping activity and osculum contraction were also observed, with sponges increasing their pumping activity to peak at midday and decreasing pumping and contracting oscula at night. Short-term elevation of the suspended sediment concentration (SSC) within the seawater initially decreased pumping rates by up to 90%, ultimately resulting in closure of the oscula and cessation of pumping. PMID- 27994972 TI - Pursuing the quest for better understanding the taxonomic distribution of the system of doubly uniparental inheritance of mtDNA. AB - There is only one exception to strict maternal inheritance of mitochondrial DNA (mtDNA) in the animal kingdom: a system named doubly uniparental inheritance (DUI), which is found in several bivalve species. Why and how such a radically different system of mitochondrial transmission evolved in bivalve remains obscure. Obtaining a more complete taxonomic distribution of DUI in the Bivalvia may help to better understand its origin and function. In this study we provide evidence for the presence of sex-linked heteroplasmy (thus the possible presence of DUI) in two bivalve species, i.e., the nuculanoid Yoldia hyperborea(Gould, 1841)and the veneroid Scrobicularia plana(Da Costa,1778), increasing the number of families in which DUI has been found by two. An update on the taxonomic distribution of DUI in the Bivalvia is also presented. PMID- 27994974 TI - Distribution and characteristic of nitrite-dependent anaerobic methane oxidation bacteria by comparative analysis of wastewater treatment plants and agriculture fields in northern China. AB - Nitrite-dependent anaerobic methane oxidation (n-damo) is a recently discovered biological process which has been arousing global attention because of its potential in minimizing greenhouse gases emissions. In this study, molecular biological techniques and potential n-damo activity batch experiments were conducted to investigate the presence and diversity of M. oxyfera bacteria in paddy field, corn field, and wastewater treatment plant (WWTP) sites in northern China, as well as lab-scale n-damo enrichment culture. N-damo enrichment culture showed the highest abundance of M. oxyfera bacteria, and positive correlation was observed between potential n-damo rate and abundance of M. oxyfera bacteria. Both paddy field and corn field sites were believed to be better inoculum than WWTP for the enrichment of M. oxyfera bacteria due to their higher abundance and the diversity of M. oxyfera bacteria. Comparative analysis revealed that long biomass retention time, low NH[Formula: see text] and high NO[Formula: see text] content were suitable for the growth of M. oxyfera bacteria. PMID- 27994975 TI - A large and unusually colored new snake species of the genus Tantilla (Squamata; Colubridae) from the Peruvian Andes. AB - A new colubrid species of the genus Tantilla from the dry forest of the northern Peruvian Andes is described on the basis of two specimens, which exhibit a conspicuous sexual dimorphism. Tantilla tjiasmantoi sp. nov. represents the third species of the genus in Peru. The new species is easily distinguished from its congeners by the combination of scalation characteristics and the unusual transversely-banded color pattern on the dorsum. A detailed description of the skull morphology of the new species is given based on micro-computed tomography images. The habitat of this new species is gravely threatened due to human interventions. Conservation efforts are urgently needed in the inter-Andean valley of the Maranon River. PMID- 27994977 TI - Blood circulation in the ascidian tunicate Corella inflata (Corellidae). AB - The body of the ascidian tunicate Corella inflata is relatively transparent. Thus, the circulatory system can be visualized by injecting high molecular weight fluorescein labeled dextran into the heart or the large vessels at the ends of the heart without surgery to remove the body wall. In addition, after staining with neutral red, the movement of blood cells can be easily followed to further characterize the circulatory system. The heart is two gently curved concentric tubes extending across the width of the animal. The inner myocardial tube has a partial constriction approximately in the middle. As in other tunicates, the heart is peristaltic and periodically reverses direction. During the branchial phase blood leaves the anterior end of the heart by two asymmetric vessels that connect to the two sides of the branchial basket. Blood then flows in both transverse directions through a complex system of ducts in the basket into large ventral and dorsal vessels which carry blood back to the visceral organs in the posterior of the animal. During the visceral phase blood leaves the posterior end of the heart in two vessels that repeatedly bifurcate and fan into the stomach and gonads. Blood velocity, determined by following individual cells in video frames, is high and pulsatory near the heart. A double peak in velocity at the maximum may be due to the constriction in the middle of the heart tube. Blood velocity progressively decreases with distance from the heart. In peripheral regions with vessels of small diameter blood cells frequently collide with vessel walls and cell motion is erratic. The estimated volume of blood flow during each directional phase is greater than the total volume of the animal. Circulating blood cells are confined to vessels or ducts in the visible parts of the animal and retention of high molecular weight dextran in the vessels is comparable to that seen in vertebrates. These are characteristics of a closed circulatory system. PMID- 27994976 TI - Diversity, taxonomic composition, and functional aspects of fungal communities in living, senesced, and fallen leaves at five sites across North America. AB - BACKGROUND: Fungal endophytes inhabit symptomless, living tissues of all major plant lineages to form one of earth's most prevalent groups of symbionts. Many reproduce from senesced and/or decomposing leaves and can produce extracellular leaf-degrading enzymes, blurring the line between symbiotrophy and saprotrophy. To better understand the endophyte-saprotroph continuum we compared fungal communities and functional traits of focal strains isolated from living leaves to those isolated from leaves after senescence and decomposition, with a focus on foliage of woody plants in five biogeographic provinces ranging from tundra to subtropical scrub forest. METHODS: We cultured fungi from the interior of surface sterilized leaves that were living at the time of sampling (i.e., endophytes), leaves that were dead and were retained in plant canopies (dead leaf fungi, DLF), and fallen leaves (leaf litter fungi, LLF) from 3-4 species of woody plants in each of five sites in North America. Our sampling encompassed 18 plant species representing two families of Pinophyta and five families of Angiospermae. Diversity and composition of fungal communities within and among leaf life stages, hosts, and sites were compared using ITS-partial LSU rDNA data. We evaluated substrate use and enzyme activity by a subset of fungi isolated only from living tissues vs. fungi isolated only from non-living leaves. RESULTS: Across the diverse biomes and plant taxa surveyed here, culturable fungi from living leaves were isolated less frequently and were less diverse than those isolated from non-living leaves. Fungal communities in living leaves also differed detectably in composition from communities in dead leaves and leaf litter within focal sites and host taxa, regardless of differential weighting of rare and abundant fungi. All focal isolates grew on cellulose, lignin, and pectin as sole carbon sources, but none displayed ligninolytic or pectinolytic activity in vitro. Cellulolytic activity differed among fungal classes. Within Dothideomycetes, activity differed significantly between fungi from living vs. non-living leaves, but such differences were not observed in Sordariomycetes. DISCUSSION: Although some fungi with endophytic life stages clearly persist for periods of time in leaves after senescence and incorporation into leaf litter, our sampling across diverse biomes and host lineages detected consistent differences between fungal assemblages in living vs. non-living leaves, reflecting incursion by fungi from the leaf exterior after leaf death and as leaves begin to decompose. However, fungi found only in living leaves do not differ consistently in cellulolytic activity from those fungi detected thus far only in dead leaves. Future analyses should consider Basidiomycota in addition to the Ascomycota fungi evaluated here, and should explore more dimensions of functional traits and persistence to further define the endophytism-to saprotrophy continuum. PMID- 27994978 TI - Anthropogenic impacts in protected areas: assessing the efficiency of conservation efforts using Mediterranean ant communities. AB - In countries with high levels of urbanization, protected areas are often subject to human disturbance. In addition to dealing with fragmentation, land managers also have to confront the loss of characteristic ecosystems due to biotic homogenization, which is the increasing similarity of species assemblages among geographically separate regions. Using ants as a model system, we explored whether anthropogenic factors negatively affect biodiversity of protected areas of a regional network. We first analysed the effect of fragmentation and human activity on ant biodiversity within protected areas. Secondly, we tested whether homogenization could occur among protected areas. We sampled 79 plots in the most common habitats of 32 protected areas in southern Spain and calculated ant community richness and diversity indices, endemic richness, and Bray-Curtis similarity indices (between pairs of plots). We related these indices with patch fragmentation and human disturbance variables, taking into account environmental, spatial and landscape covariates. We used ANOSIM to test for differences between similarity indices, specifically among levels of anthropogenic disturbance. Species richness was positively correlated with the distance from the border of the protected areas and the number of endemic species was negatively correlated with the degree of fragmentation. Ant communities were similar within each protected area but differed across regions. Human disturbance was not correlated with community similarity among sampling points. Our approach suggests how the ability of European protected areas to sustain biodiversity is limited because they remain susceptible to anthropogenic impacts. Although ant communities maintained their biological distinctiveness, we reveal how fragmentation within protected areas is important for community richness and endemism maintenance. PMID- 27994979 TI - Diet of the endangered big-headed turtle Platysternon megacephalum. AB - Populations of the big-headed turtle Platysternon megacephalum are declining at unprecedented rates across most of its distribution in Southeast Asia owing to unsustainable harvest for pet, food, and Chinese medicine markets. Research on Asian freshwater turtles becomes more challenging as populations decline and basic ecological information is needed to inform conservation efforts. We examined fecal samples collected from P. megacephalum in five streams in Hong Kong to quantify the diet, and we compared the germination success of ingested and uningested seeds. Fruits, primarily of Machilus spp., were most frequently consumed, followed by insects, plant matter, crabs and mollusks. The niche breadth of adults was wider than that of juveniles. Diet composition differed between sites, which may be attributable to the history of illegal trapping at some sites, which reduced the proportion of larger and older individuals. Digestion of Machilus spp. fruits by P. megacephalum enhanced germination success of seeds by about 30%. However, most digested seeds are likely defecated in water in this highly aquatic species, which limits the potential benefit to dispersal. The results of our study can be used by conservation-related captive breeding programs to ensure a more optimal diet is provided to captive P. megacephalum. PMID- 27994980 TI - Next-generation sequencing of mixed genomic DNA allows efficient assembly of rearranged mitochondrial genomes in Amolops chunganensis and Quasipaa boulengeri. AB - Recent improvements in next-generation sequencing (NGS) technologies can facilitate the obtainment of mitochondrial genomes. However, it is not clear whether NGS could be effectively used to reconstruct the mitogenome with high gene rearrangement. These high rearrangements would cause amplification failure, and/or assembly and alignment errors. Here, we choose two frogs with rearranged gene order, Amolops chunganensis and Quasipaa boulengeri, to test whether gene rearrangements affect the mitogenome assembly and alignment by using NGS. The mitogenomes with gene rearrangements are sequenced through Illumina MiSeq genomic sequencing and assembled effectively by Trinity v2.1.0 and SOAPdenovo2. Gene order and contents in the mitogenome of A. chunganensis and Q. boulengeri are typical neobatrachian pattern except for rearrangements at the position of "WANCY" tRNA genes cluster. Further, the mitogenome of Q. boulengeri is characterized with a tandem duplication of trnM. Moreover, we utilize 13 protein coding genes of A. chunganensis, Q. boulengeri and other neobatrachians to reconstruct the phylogenetic tree for evaluating mitochondrial sequence authenticity of A. chunganensis and Q. boulengeri. In this work, we provide nearly complete mitochondrial genomes of A. chunganensis and Q. boulengeri. PMID- 27994981 TI - One-year mortality after severe COPD exacerbation in Bulgaria. AB - INTRODUCTION: One-year mortality in COPD patients is reported to be between 4% and 43%, depending on the group examined. AIM: To examine the one-year mortality in COPD patients after severe exacerbation and the correlation between mortality and patients' characteristics and comorbidities. METHODS: A total of 152 COPD patients hospitalized for severe exacerbation were assessed for vitamin D status, diabetes mellitus (DM), arterial hypertension (AH), and metabolic syndrome (MS). Data were gathered about smoking status and number of exacerbations in previous year. CAT and mMRC questionnaires were completed by all patients. Pre- and post bronchodilatory spirometry was performed. One-year mortality was established from national death register. RESULTS: One-year mortality is 7.2%. DM, MS, and VD are not predictors for one-year mortality. However there is a trend for increased mortality in patients with AH (9.5% vs. 2.1%, p = 0.107). There is increased mortality in patients with mMRC > 2 (11.1 vs. 0%, p = 0.013). The presence of severe exacerbation in the previous year is a risk factor for mortality (12.5% vs. 1.4%, p = 0.009). There is a trend for increased mortality in the group with FEV1 < 50% (11.5 vs. 4.4%, p = 0.094). Cox regression shows 3.7% increase in mortality rate for 1% decrease in FEV1, 5.2% for 1% decrease in PEF, 7.8% for one year age increase and 8.1% for 1 CAT point increase (all p < 0.05). CONCLUSIONS: This study finds relatively low one-year mortality in COPD patients after surviving severe exacerbation. Grade C and FEV1 > 80% may be factors for good prognosis. Risk factors for increased mortality are age, FEV1 value, severe exacerbation in previous year and reduced quality of life. PMID- 27994982 TI - Species interactions in an Andean bird-flowering plant network: phenology is more important than abundance or morphology. AB - Biological constraints and neutral processes have been proposed to explain the properties of plant-pollinator networks. Using interactions between nectarivorous birds (hummingbirds and flowerpiercers) and flowering plants in high elevation forests (i.e., "elfin" forests) of the Andes, we explore the importance of biological constraints and neutral processes (random interactions) to explain the observed species interactions and network metrics, such as connectance, specialization, nestedness and asymmetry. In cold environments of elfin forests, which are located at the top of the tropical montane forest zone, many plants are adapted for pollination by birds, making this an ideal system to study plant pollinator networks. To build the network of interactions between birds and plants, we used direct field observations. We measured abundance of birds using mist-nets and flower abundance using transects, and phenology by scoring presence of birds and flowers over time. We compared the length of birds' bills to flower length to identify "forbidden interactions"-those interactions that could not result in legitimate floral visits based on mis-match in morphology. Diglossa flowerpiercers, which are characterized as "illegitimate" flower visitors, were relatively abundant. We found that the elfin forest network was nested with phenology being the factor that best explained interaction frequencies and nestedness, providing support for biological constraints hypothesis. We did not find morphological constraints to be important in explaining observed interaction frequencies and network metrics. Other network metrics (connectance, evenness and asymmetry), however, were better predicted by abundance (neutral process) models. Flowerpiercers, which cut holes and access flowers at their base and, consequently, facilitate nectar access for other hummingbirds, explain why morphological mis-matches were relatively unimportant in this system. Future work should focus on how changes in abundance and phenology, likely results of climate change and habitat fragmentation, and the role of nectar robbers impact ecological and evolutionary dynamics of plant-pollinator (or flower-visitor) interactions. PMID- 27994984 TI - Examination of Mycobacterium avium subspecies paratuberculosis mixed genotype infections in dairy animals using a whole genome sequencing approach. AB - Many pathogenic mycobacteria are known to cause severe disease in humans and animals. M. avium subspecies paratuberculosis (Map) is the causative agent of Johne's disease-a chronic wasting disease affecting ruminants such as cattle and sheep, responsible for significant economic losses in the dairy and beef industries. Due to the lack of treatment options or effective vaccines, mitigating losses can be difficult. In addition, the early stages of Map infection may occur in asymptomatic hosts that continue to shed viable bacteria in their faeces, leading to the infection of other healthy animals. Using multi locus short sequence repeat (ML-SSR) analysis we previously reported that individual Johne's positive dairy cattle from farms across the island of Newfoundland were infected by Map with multiple SSR-types simultaneously. The occurrence of multiple mixed genotype infections has the potential to change pathogen and disease dynamics as well as reduce the efficacy of treatments and vaccines. Therefore, we conducted whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) analysis on a subset of these isolates for a more in-depth examination. We also implemented a PCR assay using two discriminatory SNPs and demonstrated the incidence of a mixed infection by three genotypically diverse Map isolates in a single animal. In addition, results show that WGS and SNP analysis can provide a better understanding of the relationship between Map isolates from individual and different animals. In the future such studies on the occurrence of mixed genotype infections could potentially lead to the identification of variable pathogenicity of different genotypes and allow for better tracking of Map isolates for epidemiological studies. PMID- 27994983 TI - Psychometric properties of the Perceived Stress Scale (PSS): measurement invariance between athletes and non-athletes and construct validity. AB - BACKGROUND: Although Perceived Stress Scale (PSS, Cohen, Kamarack & Mermelstein, 1983) has been validated and widely used in many domains, there is still no validation in sports by comparing athletes and non-athletes and examining related psychometric indices. PURPOSE: The purpose of this study was to examine the measurement invariance of PSS between athletes and non-athletes, and examine construct validity and reliability in the sports contexts. METHODS: Study 1 sampled 359 college student-athletes (males = 233; females = 126) and 242 non athletes (males = 124; females = 118) and examined factorial structure, measurement invariance and internal consistency. Study 2 sampled 196 student athletes (males = 139, females = 57, Mage = 19.88 yrs, SD = 1.35) and examined discriminant validity and convergent validity of PSS. Study 3 sampled 37 student athletes to assess test-retest reliability of PSS. RESULTS: Results found that 2 factor PSS-10 fitted the model the best and had appropriate reliability. Also, there was a measurement invariance between athletes and non-athletes; and PSS positively correlated with athletic burnout and life stress but negatively correlated with coping efficacy provided evidence of discriminant validity and convergent validity. Further, the test-retest reliability for PSS subscales was significant (r = .66 and r = .50). DISCUSSION: It is suggested that 2-factor PSS 10 can be a useful tool in assessing perceived stress either in sports or non sports settings. We suggest future study may use 2-factor PSS-10 in examining the effects of stress on the athletic injury, burnout, and psychiatry disorders. PMID- 27994985 TI - Mortality in tongue cancer patients treated by curative surgery: a retrospective cohort study from CGRD. AB - BACKGROUND: Our study aimed to compare the outcomes of surgical treatment of tongue cancer patients in three different age groups. METHODS: From 2004 to 2013, we retrospectively analyzed the clinical data of 1,712 patients who were treated in the four institutions constituting the Chang Gung Memorial Hospitals (CGMH). We divided and studied the patients in three age groups: Group 1, younger (<65 years); Group 2, young old (65 to <75); and Group 3, older old patients (>=75 years). RESULTS: Multivariate analyses determined the unfavorable, independent prognostic factors of overall survival to be male sex, older age, advanced stage, advanced T, N classifications, and surgery plus chemotherapy. No significant differences were found in adjusted hazard ratios (HR) of death in early-stage disease (stage I-II) among Group 1 (HR 1.0), Group 2 (HR 1.43, 95% confidence interval (CI) [0.87-2.34], p = 0.158), and Group 3 (HR 1.22, 95% CI [0.49-3.03], p = 0.664) patients. However, amongst advanced-stage patients (stage (III-IV)), Group 3 (HR 2.53, 95% CI [1.46-4.38], p = 0.001) showed significantly worse survival than the other two groups after other variables were adjusted for. Fourteen out of 21 older old, advanced-staged patients finally died, and most of the mortalities were non-cancerogenic (9/14, 64.3%), and mostly occurred within one year (12/14, 85%) after cancer diagnosis. These non-cancer cause of death included underlying diseases in combination with infection, pneumonia, poor nutrition status, and trauma. CONCLUSIONS: Our study showed that advanced T classification (T3-4), positive nodal metastasis (N1-3) and poorly differentiated tumor predicted poor survival for all patients. Outcome of early-stage patients (stage I-II) among three age groups were not significantly different. However, for advanced-stage patients (stage III-IV), the older old patients (>=75) had significantly worse survival than the other two patient groups. Therefore, for early-stage patients, age should not deny them to receive optimal treatments. However, older old patients (>=75) with advanced cancer should be comprehensively assessed by geriatric tools before surgical treatment and combined with intensive postoperative care to improve outcome, especially the unfavorable non cancerogenic mortalities within one year after cancer diagnosis. PMID- 27994988 TI - Teaching Near and Far - Broome, Western Australia. AB - Broome is a remote coastal town in Western Australia. As a general practitioner working in Broome, I have been involved in the education of general practice trainee registrars both locally and remotely, as a supervisor with two different training programs. PMID- 27994987 TI - Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain. AB - BACKGROUND: There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. METHODS: The reaction latency to thermal stimuli (hot plate test; at 55 degrees C) and cold stimuli (cold plate test; at 4 degrees C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. RESULTS: The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO 711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. CONCLUSIONS: These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711's antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects. PMID- 27994986 TI - Age-congruency and contact effects in body expression recognition from point light displays (PLD). AB - Recognition of older people's body expressions is a crucial social skill. We here investigate how age, not just of the observer, but also of the observed individual, affects this skill. Age may influence the ability to recognize other people's body expressions by changes in one's own ability to perform certain action over the life-span (i.e., an own-age bias may occur, with best recognition for one's own age). Whole body point light displays of children, young adults and older adults (>70 years) expressing six different emotions were presented to observers of the same three age-groups. Across two variations of the paradigm, no evidence for the predicted own-age bias (a cross-over interaction between one's own age and the observed person's age) was found. Instead, experience effects were found with children better recognizing older actors' expressions of 'active emotions,' such as anger and happiness with greater exposure in daily life. Together, the findings suggest that age-related changes in one own's mobility only influences body expression categorization in young children who interact frequently with older adults. PMID- 27994990 TI - Refractory Case of Takayasu Arteritis in a Young Woman: A Clinical Challenge. AB - Takayasu arteritis (TA) is an idiopathic chronic inflammatory vasculitis of the aorta and its main branches, which if not treated can lead to severe vascular damage and fatal vascular events. Glucocorticoids (GCs) are the mainstay of the therapy of TA but a significant proportion of patients tend to experience flare ups when their GCs are tapered. We report a case of a 42-year-old female with TA, diagnosed according to the 1990 American College of Rheumatology Criteria for TA. Cardiovascular assessment showed normal carotid upstrokes with bilateral carotid bruits and soft right and left subclavian bruits with weak peripheral pulses. A computed tomography (CT) aortogram of the chest showed severe stenosis of bilateral subclavian arteries and mild stenosis of right and left common carotid arteries at the origin. A CT aortogram of the abdomen showed an occluded left renal artery, a very small left kidney, and mild narrowing of the abdominal aorta below the level of renal arteries. She was initially managed with GCs along with immunosuppressive therapy including methotrexate, azathioprine, and cyclophosphamide, but her disease remained active. She was then sequentially treated with inhibitor etanercept (ETN), inhibitor tocilizumab (TCZ) and monoclonal anti-CD20 antibody rituximab (RTX), and in spite of aggressive biologic therapy she continued to have active disease. To the best of our knowledge, this is the first case of refractory TA treated sequentially with three different biologic drugs. PMID- 27994989 TI - The Influence of the Menstrual Phases on Polysomnography. AB - PURPOSE: The primary objective of this study is to determine how the phases of the menstrual cycle influence the results of polysomnography (PSG). METHODS: Twenty-eight adult subjects who reported regular menstrual periods, last menstrual period (LMP) within 26 days of their PSG, no exogenous hormone use, no history of polycystic ovarian syndrome, and who were scheduled for diagnostic PSG at Boston Medical satisfied inclusion criteria for the study. These subjects were divided into a Follicular Cohort (days 0-13 of the cycle) or Luteal Cohort (days 14-26 of the cycle), and a one-way analysis using a t-test was performed to test the hypothesis that the follicular phase confers protection against obstructive sleep apnea (OSA). A likelihood-ratio chi-square test was also applied to assess for a statistically significant association between menstrual stage and the presence of moderate-to-severe sleep apnea (apnea-hypopnea index (AHI) > 15/h). Thus, the statistical analysis was performed using AHI as both a continuous and a categorical outcome. RESULTS: The mean AHI for patients in the Follicular Cohort (6.1/h) was significantly lower than the Luteal Cohort (14.3/h, p = 0.033). In the Follicular Cohort, 12% of patients had moderate to severe OSA. In the Luteal Cohort, 46% of patients had moderate to severe OSA (p = 0.045). CONCLUSIONS: Subjects undergoing PSG during the follicular phase have significantly lower AHIs than those in the luteal phase. Thus, the timing of PSG acquisition for regularly menstruating women should be considered when interpreting results. PMID- 27994991 TI - Dynamics of a Pregnancy When Two Become Four: A Case Report and Literature Review. AB - The incidence of pregnancies with multiple gestational sacs has increased with the use of assisted reproductive technology because more than one embryo is frequently transferred. The splitting of one or more embryos further complicates the pregnancy. Some of these complications include intrauterine fetal death, growth restriction, discordant birth weight, and preterm delivery. Monozygotic twins suffer from a few unique complications including twin-twin transfusion syndrome, twin reversed arterial perfusion sequence, and twin anemia-polycythemia sequence. Therefore, patients should be informed about the possible obstetric complications regarding monozygotic twinning after embryo transfer as poor obstetric/perinatal outcome is significantly impacted by the presence of an "extra" fetus. The etiology of monozygotic twinning is not fully understood although a few risk factors have been identified. The objective of this communication is to report successful management of a pregnancy resulting in four gestational sacs after transfer of two embryos on day-three post retrieval. PMID- 27994992 TI - Ligaments of the Costovertebral Joints including Biomechanics, Innervations, and Clinical Applications: A Comprehensive Review with Application to Approaches to the Thoracic Spine. AB - Few studies have examined the costovertebral joint and its ligaments in detail. Therefore, the following review was performed to better elucidate their anatomy, function and involvement in pathology. Standard search engines were used to find studies concerning the costovertebral joints and ligaments. These often overlooked ligaments of the body serve important functions in maintaining appropriate alignment between the ribs and spine. With an increasing interest in minimally invasive approaches to the thoracic spine and an improved understanding of the function and innervation of these ligaments, surgeons and clinicians should have a good working knowledge of these structures. PMID- 27994993 TI - Clinical and Economic Benefits of Autologous Epidermal Grafting. AB - Chronic wounds are an increasingly prevalent disease with a significant healthcare burden. These wounds often do not respond to standard of care therapy alone, requiring the use of adjuvant therapies. Epidermal grafting, previously utilized primarily for correction of leukoderma, is increasingly being recognized as a beneficial therapy for wounds, both acute and chronic. Epidermal grafting has been shown to be effective in the management of chronic wounds, with successful healing in refractory patients. It has not only been shown to be effective, but it is also associated with lower cost and morbidity than traditional skin grafting techniques as well as improved donor site healing. Through the use of a novel epidermal harvesting system, the CelluTomeTM Epidermal Harvesting System (KCI, an Acelity company, San Antonio, TX), this treatment modality has become more standardized, reproducible, and easy to use as well as less time consuming, making its use in the clinical setting more convenient and beneficial. Epidermal grafting, therefore, represents a promising, efficacious, and cost-effective option for treatment of refractory non-healing wounds. PMID- 27994994 TI - Erratum to: Genetic diversity and population differentiation of small giant clam Tridacna maxima in Comoros islands assessed by microsatellite markers. AB - [This corrects the article DOI: 10.1186/s40064-016-3513-6.]. PMID- 27994995 TI - Identification of differentially methylated regions (DMRs) of neuronatin in mice. AB - BACKGROUND: Neuronatin (NNAT) is a paternal-inherited imprinted gene, first discovered in the rat neonatal brain, where it plays vital roles for neuronal growth, brain development, and metabolic regulation. The maternal imprint of NNAT has been identified in mice; however, the differentially methylated regions (DMRs) involved in the monoallelic expression of NNAT have not yet been investigated. RESULTS: In this study, we confirmed expression of two isoforms of the NNAT (alpha and beta) in the mice brain via quantitative RT-PCR. Additionally, the methylation profile of the CpG island located in the NNAT gene locus was determined in the mice liver, brain, sperm, and the MII oocyte via bisulfite sequencing PCR. CONCLUSION: In summary, we provide the first evidence for tissue- and gamete-specific methylation patterns of CpG3 that are located on exon 1, to be putative DMR of NNAT in mice. PMID- 27994996 TI - Influence of the renewal of removable dentures on oral health related quality of life. AB - BACKGROUND: The renewal of removable dentures is often suggested to denture wearers subject to discomfort. However, the impact of this rehabilitation on patients' oral health related quality of life and their removable dentures related satisfaction is still unknown. This study was aimed at assessing these patient-centered outcomes and the potential impact of different factors. METHODS: A cohort of 116 patients in need of removable dental prostheses rehabilitation was recruited at a dental hospital over a period of 1 year. The subjects were separated into two groups according to their prosthesis experience (group in need of removable dentures renewal/group needing an removable dentures for the first time). Subjects were asked to answer the "Geriatric Oral Health Assessment Index" (GOHAI) and the "McGill Denture Satisfaction Instrument" before and after a prosthesis integration period (9-12 weeks). RESULTS: GOHAI scores were slightly higher for patients with removable dentures renewal (from 40.6 +/- 10.3 to 47.1 +/- 10.0, p < 0.001), independently of the type of prosthetic rehabilitation. However, the scores of the GOHAI functional field did not change. Subjects with no removable dentures experience presented an increase in their functional GOHAI score (p < 0.001). Regarding patient removable dentures related satisfaction, only the "Esthetic" (p < 0.001), "Chewing efficiency" (p < 0.001) and "Oral condition" (p < 0.01) items increased after prosthesis renewal. CONCLUSIONS: This study showed that renewing removable dentures only moderately improved the oral health related quality of life and removable dentures related satisfaction of patients, regardless of age, gender or type of rehabilitation. Other tasks are necessary such as the analysis of physiological parameters and qualitative research on patient's expectations. PMID- 27994997 TI - Ability of dairy fat in inducing metabolic syndrome in rats. AB - BACKGROUND: The risk of heart diseases, diabetes and stroke is increased with higher metabolic risk factors. Models of diseases resulting from high-calorie diets have a significant role in pathophysiologic analysis of metabolic syndrome in rodents; but, these diets are considerably different from each other in various studies and may not be very similar to the metabolic syndrome model in humans. This study sought to make a model close to the disease in humans. 20 five week old male Wistar rats were randomly assigned to two groups. For one of the groups, a high-calorie diet with 416 calories per 100 g with dairy-based fat was considered and, for another group, a control diet was given for 12 weeks. Weight changes, lipid profile, glucose values, Blood pressure, insulin and HOMA indices, were measured for both groups and weight changes were compared using repeated measures and independent t test; also, serum results were compared using independent t test. RESULTS: Values of weight, glucose, insulin, lipid profile and blood pressure, except HDL, had a tangible difference between two groups at the end of the study. HOMA-IR, HOMA-B and HOMA-S indicates a significant difference between the two groups after consumption high-energy diet. CONCLUSION: The present study showed ability of dairy fat in gaining weight, insulin resistance and metabolic syndrome and provided the necessity of paying serious attention to the amount of fat intake from dairy sources. PMID- 27994998 TI - Smoking related attitudes, motives, and behaviors of male secondary school students in an urban setting of China. AB - BACKGROUND: Most smokers have their first experience of cigarette use when they are teenagers (i.e. at schools). Aiming tobacco control initiatives at secondary school students offers preventive measures to eliminate or reduce tobacco use initiation by students. This study assessed smoking-related attitudes, motives and behavior as well as other factors associated with smoking among male secondary school students in an urban setting in China. METHODS: A cross sectional survey was conducted in urban areas of Chongqing using a structured questionnaire administered to 1297 male secondary school students. Logistic regression analysis was employed to investigate the factors that affect smoking. RESULTS: Of the participants (n = 1297), 27.7% were secondary and 72.3% were middle school students. Overall, 30.5% of the participants were smokers. The majority of the students procured their first cigarette from friends. The motivations of middle school students to smoke their first cigarette were curiosity (70.5%) and imitation (13.1%). The motivations of high school students for smoking their first cigarette were to satisfy their curiosity (51.8%), relief of stress and social pressures (17.1%), and imitation of smoker friends (15.9%). Respondents from poor family financial conditions were more likely to smoke than those from rich family financial conditions [odds ratio (OR) 1.59, 95% confidence intervals (CI) 1.00, 2.52]. Respondents whose fathers were smokers were more likely to smoke than those whose fathers were non-smokers (OR 1.65, 95% CI 1.25, 2.17). Respondents who had one or two smoker friends (OR 2.98, 95% CI 1.93, 4.60) and three or more smoker friends (OR 5.92, 95% CI 4.35, 8.05) were more likely to smoke than those who did not have any. Respondents who were neutral (OR 0.43, 95% CI 0.20, 0.91) and disagreed about the item "friends smoking" (OR 0.18, 95% CI 0.08, 0.39) were less likely to smoke than those who agreed with the item. CONCLUSIONS: This study indicates that male students who have negative attitudes toward smoking, who do not have a father or friends who smoke, and are from affluent backgrounds exhibit low tendency to start smoking at a young age. This study provides some implications for tobacco control policies among male secondary school students in urban settings. PMID- 27994999 TI - Impact of nickel mining in New Caledonia assessed by compositional data analysis of lichens. AB - The aim of this study is to explore the use of lichens as biomonitors of the impact of nickel mining and ore treatment on the atmosphere in the New Caledonian archipelago (South Pacific Ocean); both activities emitting also Co, Cr and possibly Fe. Metal contents were analysed in thirty-four epiphytic lichens, collected in the vicinity of the potential sources, and in places free from known historical mining. The highest Ni, Co, and Cr concentrations were, as expected, observed in lichens collected near ore deposits or treatment areas. The elemental composition in the lichens was explored by multivariate analysis, after appropriately transforming the variables (i.e. using compositional data analysis). The sample score of the first principal component (PC1) makes the largest (positive) multiplicative contribution to the log-ratios of metals originating from mining activities (Ni, Cr, Co) divided by Ti. The PC1 scores are used here as a surrogate of pollution levels related to mining and metallurgical activity. They can be viewed as synthetic indicators mapped to provide valuable information for the management and protection of ecosystems or, as a first step, to select locations where air filtration units could be installed, in the future, for air quality monitoring. However, as this approach drastically simplifies the problem, supplying a broadly efficient picture but little detail, recognizing the different sources of contamination may be difficult, more particularly when their chemical differences are subtle. It conveys only relative information: about ratios, not levels, and is therefore recommended as a preliminary step, in combination with close examination of raw concentration levels of lichens. Further validation using conventional air-monitoring by filter units should also prove beneficial. PMID- 27995000 TI - Permutation transformations of tensors with an application. AB - The permutation transformation of tensors is introduced and its basic properties are discussed. The invariance under permutation transformations is studied for some important structure tensors such as symmetric tensors, positive definite (positive semidefinite) tensors, Z-tensors, M-tensors, Hankel tensors, P-tensors, B-tensors and H-tensors. Finally, as an application of permutation transformations of tensors, the canonical form theorem of tensors is given. The theorem shows that some problems of higher dimension tensors can be translated into the corresponding problems of lower dimension weakly irreducible tensors so as to handle easily. PMID- 27995001 TI - Evaluation of the patients with colorectal cancer undergoing emergent curative surgery. AB - BACKGROUND: The aim of our study is to evaluate perioperative and mid-term oncologic outcomes of the patients with colorectal cancer, who underwent emergent curative surgery. METHODS: The study included all patients with colorectal cancer, who underwent surgery for curative intent between 1 January 2012 and 31 December 2014 in General Surgery Department of Kartal Training and Research Hospital. The patients were divided into two groups according to the type of admission (emergent or elective). The data of the patients were retrospectively collected with chart review. Demographic characteristics of the patients, ASA scores, emergent indications and surgical interventions, postoperative complications, pathological findings, oncological therapy, and follow-up findings were investigated. RESULTS: Fifty-one and 209 patients were evaluated in both groups, respectively. Rate of right sided and sigmoid/recto-sigmoid tumors were significantly higher in emergent group. Ostomy rate, early morbidity, ICU need, transfusion, and mortality rates in emergent group were significantly higher than elective group. Average length of hospital stay in emergent group was also significantly longer in elective group (11.2 +/- 3.2 vs. 8.4 +/- 2.4 days). The patients in emergent group had a much lower survival rate than those in elective group. CONCLUSION: In our study, emergency presentation of colorectal cancer was found associated with increased morbidity, a longer length of stay, increased in hospital mortality, advanced pathologic stage and worsened long term survival in even same stages. PMID- 27995002 TI - Reproductive biology and breeding system of Saraca asoca (Roxb.) De Wilde: a vulnerable medicinal plant. AB - Ashoka (Saraca asoca) is a perennial, evergreen tree valued for its ornamental flowers and medicinal values. This species is classified as 'vulnerable' under IUCN list due to its dwindling population because of destructive harvesting from natural habitats. Therefore, conservation and multiplication of this species is need of the hour to utilize its astonishing medicinal uses eternally. Conservation approaches of any plant species require in-depth study of its reproductive biology, which is lacking in this species. The present study is the first detailed report on reproductive biology of S. asoca. This tree bears fragrant flowers in paniculate corymbose inflorescence from December end to May, with peak flowering during February-March. The fruits attain its maturity during last week of May-July. Seeds were dispersed from the pod to the tree premises upon complete maturity. The time of anthesis in this species is noticed in the early morning from 3.00 to 5.30 am, which coincided with anther dehiscence, stigma receptivity and insect activity. The length of the stamen and pistil points towards the pollination compatibility in both male and female parts. Pollen viability was maximum within 2 h of anthesis, which decreased thereafter and no pollens were viable after 6 h. The stigma was receptive at the time of anthesis and continued for 24 h. The tree produces bright colour attractive flowers, which changed from yellow/light orange to scarlet/red from the inception of buds to wilting. The bright color of the flowers attracted floral visitors/pollinators thereby facilitated the pollination in this species. The observations of the floral biology and breeding system indicated the cross pollination behaviour, which limited the production of selfed seeds and would help to maintain the sustainable levels of heterozygosity among the various populations. Considerable amount of seeds produced in this species indicated that the species is capable of sustaining its progenies in the natural populations. Polyembryony to an extent of 5% was also recorded in this species. PMID- 27995003 TI - Genetic divergence among toxic and non-toxic cyanobacteria of the dry zone of Sri Lanka. AB - Sri Lanka has rich cyanobacterial diversity, however, only few studies have been conducted to identify the potential toxin producers in water bodies used for human consumption. As the detection of cyanotoxin is vital in water quality management, a study was done by employing 16S rRNA gene to explore the genetic divergence, phylogenetic relationships and potential toxin producing cyanobacteria in reservoirs and well waters in the dry zone of Sri Lanka. Forty five, 16S rRNA gene sequences were assayed and phylogenetic tree was constructed. Among 45 isolates, 20 isolates were classified as unidentified cyanobacteria and considered as novel cyanobacterial genera. Of 25 identified isolates, seven isolates were identified up to species level. With 16S rRNA phylogeny, 20 unidentified cyanobacterial isolates were able to place on their taxonomic positions up to order level. Results revealed that water samples understudy had vast cyanobacterial diversity with potential microcystin (MC) and cylindrospermopsin (CYN) producers and eleven clusters clearly demonstrated five cyanobacterial orders with more than 90% similarity irrespective to their toxicity which showed the suitability of 16S rRNA gene for taxonomic differentiation. Sixteen isolates had the potential to produce MC and two isolates to produce CYN. Findings of the study confirm the rich cyanobacterial diversity and the divergence among the potential cyanotoxin producers in the dry zone water bodies of Sri Lanka. PMID- 27995004 TI - Omphalomesenteric duct remnant adenocarcinoma in adults: a case study. AB - INTRODUCTION: The omphalomesenteric duct (OMD) or the vitelline duct (VD) is the embryonic structure connecting the vitelline sac to the primitive gut. It undergoes obliteration at 5-9 weeks of gestation. Failure of this duct to close, which occurs in approximately 2% of the population, can lead to various types of VD residual diseases. A persistent OMD remnant is pathological, and it typically presents in the pediatric population. Meckel diverticulum is the most common anomaly that results from failure of resorption of the OMD. In extremely rare instances, OMD remnant adenocarcinomas have been reported in the adult population. CASE DESCRIPTION: In this study, we present a case of OMD remnant adenocarcinoma with axillary lymph node metastases in an adult male. DISCUSSION AND EVALUATION: Because OMD remnant adenocarcinoma is rare, few relevant studies have been reported. The final diagnosis of navel VD residual adenocarcinoma depends on postoperative pathology and immunohistochemical analysis. The follow up treatment in OMD is similar to the chemotherapy regimens of postoperative gastrointestinal malignant tumors. CONCLUSIONS: In this report, the patient experienced no complications after surgery and was discharged on the seventh postoperative day, followed by 12 courses of postoperative FOLFOX6 scheme chemotherapy. By the end of chemotherapy, the patient had no evidence of recurrent disease and metastasis across the reexamination of PET-CT. PMID- 27995005 TI - Genetic algorithm based hybrid approach to solve fuzzy multi-objective assignment problem using exponential membership function. AB - This paper presents a genetic algorithm based hybrid approach for solving a fuzzy multi-objective assignment problem (FMOAP) by using an exponential membership function in which the coefficient of the objective function is described by a triangular possibility distribution. Moreover, in this study, fuzzy judgment was classified using alpha-level sets for the decision maker (DM) to simultaneously optimize the optimistic, most likely, and pessimistic scenarios of fuzzy objective functions. To demonstrate the effectiveness of the proposed approach, a numerical example is provided with a data set from a realistic situation. This paper concludes that the developed hybrid approach can manage FMOAP efficiently and effectively with an effective output to enable the DM to take a decision. PMID- 27995006 TI - Factors affecting RFID adoption in the agricultural product distribution industry: empirical evidence from China. AB - We conducted an exploratory investigation of factors influencing the adoption of radio frequency identification (RFID) methods in the agricultural product distribution industry. Through a literature review and field research, and based on the technology-organization-environment (TOE) theoretical framework, this paper analyzes factors influencing RFID adoption in the agricultural product distribution industry in reference to three contexts: technological, organizational, and environmental contexts. An empirical analysis of the TOE framework was conducted by applying structural equation modeling based on actual data from a questionnaire survey on the agricultural product distribution industry in China. The results show that employee resistance and uncertainty are not supported by the model. Technological compatibility, perceived effectiveness, organizational size, upper management support, trust between enterprises, technical knowledge, competitive pressure and support from the Chinese government, which are supported by the model, have significantly positive effects on RFID adoption. Meanwhile, organizational size has the strongest positive effect, while competitive pressure levels have the smallest effect. Technological complexities and costs have significantly negative effects on RFID adoption, with cost being the most significantly negative influencing factor. These research findings will afford enterprises in the agricultural products supply chain with a stronger understanding of the factors that influence RFID adoption in the agricultural product distribution industry. In addition, these findings will help enterprises remain aware of how these factors affect RFID adoption and will thus help enterprises make more accurate and rational decisions by promoting RFID application in the agricultural product distribution industry. PMID- 27995007 TI - Direct new oral anticoagulants: follow-up, guidelines and bleeding complications in general practice-a survey of Swiss general internal medicine practitioners. AB - BACKGROUND: The present study investigated how much Swiss general internal medicine practitioners (GPs) know about new direct oral anticoagulants (NOACs), particularly the relevant guidelines, follow-up tests, dosing adjustments, indications and complications. We conducted a paper-based survey of GPs, performed in Bern, Switzerland. Our questionnaire assessed the physicians' preference for NOACs rather than vitamin K antagonists (VKA), prevalence and choice of NOAC, clinical follow-up including follow-up blood testing, and bleeding complications. RESULTS: 53 GPs participated in our pilot investigation. They treated 32.7% +/- 19 of their patients requiring oral anticoagulation with NOACs. New patients who had started oral anticoagulation received NOACs from 49 GPs (92.5%) but most GPs would not switch patients from existing VKA therapy to NOACs. Clinical controls are scheduled by a majority of GPs (67.9%) at least every 3 months; creatinine and haemoglobin are monitored by most GPs (51 (96.2%) and 39 (73.6%), respectively). In the preceding 2 years, GPs had seen 1.9 +/- 2.87 bleeding complications in patients with NOACs. 0.5 +/- 0.95 (range 0-5) of these required hospital treatment. CONCLUSION: NOACs are broadly accepted by investigated Swiss GPs as the first choice for patients newly requiring oral anticoagulation. This was in preference to VKAs and especially if recommended by a haematologist or cardiologist. As, in our population, only about two-thirds of GPs adhere to recommendations on clinical and blood test follow-ups, further efforts to implement follow-up guidelines seem necessary. Further research in a large representative GP population is recommended; this should compare NOACs and VKAs. Bleeding complications were rare in our population and could mostly be handled without hospital admission. PMID- 27995008 TI - Desflurane inhalation before ischemia increases ischemia-reperfusion-induced vascular leakage in isolated rabbit lungs. AB - BACKGROUND: Isoflurane and sevoflurane protect lungs with ischemia-reperfusion (IR) injury. We examined the influence of desflurane on IR lung injury using isolated rabbit lungs perfused with a physiological salt solution. METHODS: The isolated lungs were divided into three groups: IR, desflurane-treated ischemia reperfusion (DES-IR), and ventilation/perfusion-continued control (Cont) groups (n = 6 per group). In the DES-IR group, inhalation of desflurane at 1 minimum alveolar concentration (MAC) was conducted in a stable 30-min phase. In the IR and DES-IR groups, ventilation/perfusion was stopped for 75 min after the stable phase. Subsequently, they were resumed. Each lung was placed on a balance, and weighed. Weight changes were measured serially throughout this experiment. The coefficient of filtration (Kfc) was determined immediately before ischemia and 60 min after reperfusion. Furthermore, bronchoalveolar lavage fluid (BALF) was collected from the right bronchus at the completion of the experiment. After the completion of the experiment, the left lung was dried, and the lung wet-to-dry weight ratio (W/D) was calculated. RESULTS: The Kfc values at 60 min after perfusion were 0.40 +/- 0.13 ml/min/mmHg/100 g in the DES-IR group, 0.26 +/- 0.07 ml/min/mmHg/100 g in the IR group, and 0.22 +/- 0.08 (mean +/- SD) ml/mmHg/100 g in the Cont group. In the DES-IR group, the Kfc at 60 min after the start of reperfusion was significantly higher than in the other groups. In the DES-IR group, W/D was significantly higher than in the Cont group. In the DES-IR group, the BALF concentrations of nitric oxide metabolites were significantly higher than in the other groups. In the DES-IR group, the total amount of vascular endothelial growth factor in BALF was significantly higher than in the Cont group. CONCLUSIONS: The pre-inhalation of desflurane at 1 MAC exacerbates pulmonary IR injury in isolated/perfused rabbit lungs. PMID- 27995009 TI - Therapeutic effects of electrical stimulation on overactive bladder: a meta analysis. AB - BACKGROUND: To systematically evaluate the therapeutic effect of electrical stimulation (ES) on overactive bladder (OB). METHOD: We retrieved information by searching databases from PubMed, CBM-disc, The Cochrane Library, ScienceDirect (from Elsevier publishers) and Springer publishers up to March 2016. We looked for randomized controlled trials that studied ES in OB treatment with subject headings and keywords using literature searches and manual retrieval. References of included studies were reviewed. Literature was screened independently by two investigators according to inclusion and exclusion criteria. After extracting data and evaluating their quality, meta-analysis was undertaken with RevMan v5.2. RESULTS: Ten randomized controlled trials involving 719 patients were included. Meta-analysis results demonstrated ES to have better effects for improving bladder compliance, reducing residual urine, and decreasing the frequency of enuresis in OB patients compared with the control group. ES elicited significantly better effects for diminishing the maximum detrusor pressure in children than in controls, but there was no significant difference in the maximum detrusor pressure between adults and controls. The therapeutic effect of ES combined with other therapies for increasing the maximum bladder capacity was better compared with other therapies alone. No significant difference was noted between ES alone and other therapies alone. CONCLUSIONS: Based on current evidence, ES has certain effects on OBs. Severe adverse reactions are not observed. ES is safe, efficacious, and worthy of clinical use. PMID- 27995010 TI - Tsukamurella tyrosinosolvens bacteremia with coinfection of Mycobacterium bovis pneumonia: case report and literature review. AB - INTRODUCTION: We describe an immunocompromised patient with Tsukamurella tyrosinosolvens bacteremia and coinfection of Mycobacterium bovis pneumonia. CASE DESCRIPTION: A 75-year-old male was admitted to our hospital complaining of persistent fever with general malaise. His medical history showed that he had diabetes mellitus (HbA1C 9.2%). A chest computed tomography (CT) showed left upper lung consolidation . Two sets of blood culture at admission finally showed Tsukamurella tyrosinosolvens. Moreover, three transbronchoscopy washing specimen cultures revealed Mycobacterium bovis. DISCUSSION AND EVALUATION: The organism Tsukamurella tyrosinosolvens was identified using conventional biochemical identification methods, PCR-restriction DNA fragment analysis, and 16S rRNA gene sequencing. The clinical mycobacterial isolates were identified to the species level by combining Polymerase Chain Reaction (PCR) with an oligonucleotide microarray to detect the M. bovis amplicons. CONCLUSION: According to our literature review, our patient's case was the first of a coinfection with Tsukamurella tyrosinosolvens and Mycobacterium bovis. Prolonged antibiotic treatment and underlying disease control are necessary for this type of patient. PMID- 27995011 TI - Associations of IL-10 genetic polymorphisms with the risk of urologic cancer: a meta-analysis based on 18,415 subjects. AB - BACKGROUND: Interleukin-10 (IL-10) is a powerful modulator of anti-tumor immune responses. The IL-10 promoter region polymorphisms are known to regulate IL-10 production, and thus are thought to be implicated in tumorigenesis. Recently, the roles of these polymorphisms in urologic cancer have been extensively studied, with conflicting results. Therefore, we conducted the present meta-analysis to better elucidate the correlations between IL-10 polymorphisms and urologic cancer risk. METHODS: Eligible articles were searched in PubMed, Medline, Embase, Scopus and CNKI up to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between IL-10 polymorphisms and the risk of urologic cancer. RESULTS: A total of 22 case-control studies including 8572 patients and 9843 controls were analyzed. The overall meta analysis results showed that IL-10 -592C>A polymorphism was significantly associated with urologic cancer in CA versus AA (P = 0.04, OR 0.87, 95% CI 0.76 0.99) and AA versus CC+CA (P = 0.03, OR 1.15, 95% CI 1.02-1.31). Subgroup analyses by cancer types suggested there were significant associations between all the three investigated IL-10 polymorphisms and bladder cancer. However, subgroup analyses by ethnicity only detected a weak association between IL-10 819C>T and Asian population. CONCLUSIONS: Our findings suggests that IL-10 592C>A polymorphism may implicate with urologic cancer risk. Besides, promoter region polymorphisms of IL-10 may serve as potential biological markers, especially for bladder cancer. Furthermore, IL-10 -819C>T polymorphism may contribute to urologic cancer susceptibility in Asians while all the three studied variants of IL-10 did not relate to Caucasian urologic cancer predisposition. PMID- 27995012 TI - DCBRP: a deterministic chain-based routing protocol for wireless sensor networks. AB - BACKGROUND: Wireless sensor networks (WSNs) are a promising area for both researchers and industry because of their various applications The sensor node expends the majority of its energy on communication with other nodes. Therefore, the routing protocol plays an important role in delivering network data while minimizing energy consumption as much as possible. The chain-based routing approach is superior to other approaches. However, chain-based routing protocols still expend substantial energy in the Chain Head (CH) node. In addition, these protocols also have the bottleneck issues. METHODS: A novel routing protocol which is Deterministic Chain-Based Routing Protocol (DCBRP). DCBRP consists of three mechanisms: Backbone Construction Mechanism, Chain Head Selection (CHS), and the Next Hop Connection Mechanism. The CHS mechanism is presented in detail, and it is evaluated through comparison with the CCM and TSCP using an ns-3 simulator. RESULTS: It show that DCBRP outperforms both CCM and TSCP in terms of end-to-end delay by 19.3 and 65%, respectively, CH energy consumption by 18.3 and 23.0%, respectively, overall energy consumption by 23.7 and 31.4%, respectively, network lifetime by 22 and 38%, respectively, and the energy*delay metric by 44.85 and 77.54%, respectively. CONCLUSION: DCBRP can be used in any deterministic node deployment applications, such as smart cities or smart agriculture, to reduce energy depletion and prolong the lifetimes of WSNs. PMID- 27995014 TI - Equivalent modeling of PMSG-based wind power plants considering LVRT capabilities: electromechanical transients in power systems. AB - Hardware protection and control action are two kinds of low voltage ride-through technical proposals widely used in a permanent magnet synchronous generator (PMSG). This paper proposes an innovative clustering concept for the equivalent modeling of a PMSG-based wind power plant (WPP), in which the impacts of both the chopper protection and the coordinated control of active and reactive powers are taken into account. First, the post-fault DC link voltage is selected as a concentrated expression of unit parameters, incoming wind and electrical distance to a fault point to reflect the transient characteristics of PMSGs. Next, we provide an effective method for calculating the post-fault DC link voltage based on the pre-fault wind energy and the terminal voltage dip. Third, PMSGs are divided into groups by analyzing the calculated DC link voltages without any clustering algorithm. Finally, PMSGs of the same group are equivalent as one rescaled PMSG to realize the transient equivalent modeling of the PMSG-based WPP. Using the DIgSILENT PowerFactory simulation platform, the efficiency and accuracy of the proposed equivalent model are tested against the traditional equivalent WPP and the detailed WPP. The simulation results show the proposed equivalent model can be used to analyze the offline electromechanical transients in power systems. PMID- 27995013 TI - Complete plastid genome of Eriobotrya japonica (Thunb.) Lindl and comparative analysis in Rosaceae. AB - Eriobotrya japonica (Thunb.) Lindl (loquat) is an evergreen Rosaceae fruit tree widely distributed in subtropical regions. Its leaves are considered as traditional Chinese medicine and are of high medical value especially for cough and emesis. Thus, we sequenced the complete plastid genome of E. japonica to better utilize this important species. The complete plastid genome of E. japonica is 159,137 bp in length, which contains a typical quadripartite structure with a pair of inverted repeats (IR, 26,326 bp) separated by large (LSC, 89,202 bp) and small (SSC, 19,283 bp) single-copy regions. The E. japonica plastid genome encodes 112 unique genes which consist of 78 protein-coding genes, 30 tRNA genes and 4 rRNA genes. Gene structure and content of E. japonica plastid genome are quite conserved and show similarity among Rosaceous species. Five large indels are unique to E. japonica in comparison with Pyrus pyrifolia and Prunus persica, which could be utilized as molecular markers. A total of 72 simple sequence repeats (SSRs) were detected and most of them are mononucleotide repeats composed of A or T, indicating a strong A or T bias for base composition. The Ka and Ks ratios of most genes are lower than 1, which suggests that most genes are under purifying selection. The phylogenetic analysis described the evolutionary relationship within Rosaceae and fully supported a close relationship between E. japonica and P. pyrifolia. PMID- 27995016 TI - New hospital structure in the twenty-first century: the position of level III (tertiary) neurological and stroke care in a changing healthcare system. AB - AIM: The determination of the necessary capacity and number of neurology wards of level III progressivity that can be defined in the system of criteria detailed in this article and which possess optimal operating conditions in Hungarian terms. METHODS: We used the National Health Insurance Company's database to calculate case numbers and capacity for different levels of neurological and stroke care. We also revised the allocation of advanced diagnostic and therapeutic technologies, and proposed changes, based on health insurance data. We also discussed these propositions with clinical experts to test their viability. RESULTS: We determined the adequate number of organisational units capable of providing special neurological healthcare services on the basis of the basic data of the Hungarian healthcare system, specifying this number as 6 instead of the current 11. CONCLUSIONS: In our study, we have identified significant bias in the nationwide level of neurological and stroke care organisation, which needs revised allocation of healthcare resources. Naturally, this can only be carried out through the restructuring of the emergency care system and the expansion of pre-hospital care. PMID- 27995017 TI - Influence of physician years on urological journal publication productivity among Japanese urologists. AB - PURPOSE: To evaluate the urological journal publication productivity of Japanese urologists based on their physician years. METHODS: All original articles written by Japanese urologists and published from Japanese institutions in 6 primary urological journals between 2010 and 2014 were reviewed (N = 529 articles). RESULTS: The median post-graduate years of the first and corresponding authors of all articles were 16 and 21 years, respectively. The publication productivities of the first and corresponding authors peaked from 11 to 15 and both 16-20 and 21 25 post-graduate years, respectively. In 187 publications in which the first and corresponding authors were different, first and corresponding author publication productivities peaked from 11 to 15 and 21-25 post-graduate years, respectively. In 342 publications in which the first author served as the corresponding author, first author publication productivity peaked from 16 to 20 post-graduate years. Of all articles examined, 130 (24.6%) were written by young urologists who had obtained their national medical license not less than 11 years ago. Only 0.9% (5/529) of all articles were written by female Japanese urologists, who account for 5.0% (332/6,649) of all Japanese Board Certified Urologists. CONCLUSIONS: The present study revealed that from 11 to 15 post-graduate years was the most productive time for Japanese urologists as the first author of urological publications and also that the role in manuscript preparation changed with increases in physician years. These results provide an insight into reconstructing future post-graduate training and educational urological programs in Japan. PMID- 27995018 TI - Who reports high company performance? A quantitative study of Chinese listed companies in the energy industry. AB - In the increasingly competitive environment, top managers' background characteristics are undoubtedly vital factors for company performance. This study examines whether the performance of Chinese listed companies in the energy industry differs with respect to top managers' background characteristics and explores the exact distribution interval of top managers' background characteristics when company performance reaches the highest level. The initial sample was collected from the CSMAR database (2005-2014) for listed companies in the energy industry. After removing the outlier and missing data, the final number of observations was determined as 780. Descriptive statistics were used to investigate the present distribution of top managers' background characteristics, factor analysis was used to determine the dimensions of company performance, and one-way ANOVA was used to analyze the differences in company performance and its dimensions with respect to top managers' background characteristics. The findings show that both the age and length of service of top managers present an increasing trend over the years of the study period, whereas the educational level shows no significant changes. The performance of listed companies has three dimensions: profit performance, growth performance, and operating performance. Companies behave differently with regard to their top managers' background characteristics; when the top manager is 40-45 years old, with a doctoral degree and above, and in the 2nd-3rd year of his service period, his company will achieve a higher level of performance. This study contributes to the growing literature on company performance in the Chinese energy industry by demonstrating the differences in the performance of Chinese listed companies in the energy industry with regard to top managers' background characteristics, and reaching conclusions on the optimum distribution interval of top managers' background characteristics when company performance reaches the highest level. This study also provides a valuable reference for organizational reform and performance enhancement, which are urgent problems for the Chinese energy industry. PMID- 27995015 TI - The prognostic factors for patients with hematological malignancies admitted to the intensive care unit. AB - Owing to the nature of acute illness and adverse effects derived from intensive chemotherapy, patients with hematological malignancies (HM) who are admitted to the Intensive Care Unit (ICU) often present with poor prognosis. However, with advances in life-sustaining therapies and close collaborations between hematologists and intensive care specialists, the prognosis for these patients has improved substantially. Many studies from different countries have examined the prognostic factors of these critically ill HM patients. However, there has not been an up-to-date review on this subject, and very few studies have focused on the prognosis of patients with HM admitted to the ICU in Asian countries. Herein, we aim to explore the current situation and prognostic factors in patients with HM admitted to ICU, mainly focusing on studies published in the last 10 years. PMID- 27995019 TI - Colombeau products of distributions. AB - In this paper, some products of distributions are derived. The results are obtained in Colombeau algebra of generalized functions, which is the most relevant algebraic construction for dealing with Schwartz distributions. Colombeau algebra [Formula: see text] contains the space [Formula: see text] of Schwartz distributions as a subspace, and has a notion of 'association' that allows us to evaluate the results in terms of distributions. PMID- 27995020 TI - Influence of viscous dissipation and Joule heating on MHD bio-convection flow over a porous wedge in the presence of nanoparticles and gyrotactic microorganisms. AB - BACKGROUND: The flow over a porous wedge, in the presence of viscous dissipation and Joule heating, has been investigated. The wedge is assumed to be saturated with nanofluid containing gyrotactic microorganisms. For the flow, magneto hydrodynamic effects are also taken into consideration. The problem is formulated by using the passive control model. The partial differential equations, governing the flow, are transformed into a set of ordinary differential equations by employing some suitable similarity transformations. RESULTS: A numerical scheme, called Runge-Kutta-Fehlberg method, has been used to obtain the local similarity solutions for the system. Variations in the velocity, temperature, concentration and motile micro-organisms density profiles are highlighted with the help of graphs. The expressions for skin friction coefficient, Nusselt number, Sherwood number and motile micro-organisms density number are obtained and plotted accordingly. For the validity of the obtained results, a comparison with already existing results (special cases) is also presented. CONCLUSION: The magnetic field increases the velocity of the fluid. Injection at the walls can be used to reduce the velocity boundary layer thickness. Thermal boundary layer thickness can be reduced by using the magnetic field and the suction at the wall. The motile microorganisms density profile is an increasing function of the bioconvection Pecket number and bioconvection constant. The same is a decreasing function of m, M and Le. The skin friction coefficient increases with increasing m and [Formula: see text]. Nusselt number and the density number of motile microorganisms are higher for the case of suction as compared to the injection case. The density number of motile microorganisms is an increasing function for all the involved parameters. PMID- 27995021 TI - Effect of shallow angles on compressive strength of biaxial and triaxial laminates. AB - BACKGROUND: Biaxial (BX) and triaxial (TX) composite laminates with +/-45 degrees angled plies have been widely used in wind turbine blades. As the scale of blades increases, BX and TX laminates with shallow-angled plies (i.e. off-axis ply angle <45 degrees ) might be utilized for reducing mass and/or improving performance. The compressive properties of shallow-angled BX and TX laminates are critical considering their locations in a wind turbine blade, and therefore in this study, the uniaxial static compression tests were conducted using BX and TX laminates with angled-plies of +/-45 degrees , +/-35 degrees , and +/-25 degrees , for the purpose of evaluation. On the other hand, Mori-Tanaka mean field homogenization method was employed to predict elastic constants of plies in BX and TX laminates involved in tests; linear regression analyses of experimentally measured ply strengths collected from various sources were then performed to estimate strengths of plies in BX and TX laminates; finally, Tsai-Wu, Hashin, and Puck failure criteria were chosen to predict compressive strengths of BX and TX laminates. Comparison between theoretical predictions and test results were carried out to illustrate the effectiveness of each criterion. RESULTS: The compressive strength of BX laminate decreases as ply angle increases, and the trend was successfully predicted by all three failure criteria. For TX laminates, +/-35 degrees angled plies rather than +/-45 degrees angled plies led to the lowest laminate compressive strength. Hashin and Puck criteria gave good predictions at certain ply angles for TX laminates, but Tsai-Wu criterion was able to capture the unexpected strength variation of TX laminates with ply angle. CONCLUSION: It was concluded that the transverse tensile stress in 0 degrees plies of TX laminates, which attains its maximum when the off-axis ply angle is 35 degrees , is the dominant factor in failure determination if using Tsai-Wu criterion. This explains the unexpected strength variation of TX laminates with ply angle, and also indicates that proper selection of ply angle is the key to fully utilizing the advantages of shallow-angled laminates. PMID- 27995022 TI - Multilevel hybrid method for optimal buffer sizing and inspection stations positioning. AB - Designing competitive manufacturing systems with high levels of productivity and quality at a reasonable cost is a complex task. Decision makers must face numerous decision variables which involve multiple and iterative analysis of the estimated cost, quality and productivity of each design alternative. This paper adresses this issue by providing a fast algorithm for solving the buffer sizing and inspection positioning problem of large production lines by combining heuristic and exact algorithms. We develop a multilevel hybrid search method combining a genetic algorithm and tabu search to identify promising locations for the inspection stations and an exact method that optimizes rapidly (in polynomial time) the buffers' sizes for each location. Our method gives valuable insights into the problem, and its solution time is a small fraction of that required by the exact method on production lines with 10-30 machines. PMID- 27995023 TI - Exploring key factors in online shopping with a hybrid model. AB - INTRODUCTION: Nowadays, the web increasingly influences retail sales. An in-depth analysis of consumer decision-making in the context of e-business has become an important issue for internet vendors. However, factors affecting e-business are complicated and intertwined. CASE DESCRIPTION: To stimulate online sales, understanding key influential factors and causal relationships among the factors is important. To gain more insights into this issue, this paper introduces a hybrid method, which combines the Decision Making Trial and Evaluation Laboratory (DEMATEL) with the analytic network process, called DANP method, to find out the driving factors that influence the online business mostly. DISCUSSION AND EVALUATION: By DEMATEL approach the causal graph showed that "online service" dimension has the highest degree of direct impact on other dimensions; thus, the internet vendor is suggested to made strong efforts on service quality throughout the online shopping process. CONCLUSIONS: In addition, the study adopted DANP to measure the importance of key factors, among which "transaction security" proves to be the most important criterion. Hence, transaction security should be treated with top priority to boost the online businesses. From our study with DANP approach, the comprehensive information can be visually detected so that the decision makers can spotlight on the root causes to develop effectual actions. PMID- 27995024 TI - Molecular characterization of new described kobuvirus in dogs with diarrhea in China. AB - Canine kobuvirus (CaKVs) was a newly described virus detected in dogs in the US and Italy. To learn more about CaKVs, 5 of 106 fecal samples from diarrhea dogs were positive with CaKVs in China, and the full genome of CaKVs strain CH-1 isolated from dog with diarrhea was sequenced. The genome consists of 8186 nucleotides, excluding the 3' poly (A) tail, and an open reading frame that maps between nucleotide positions 601 and 7943 which encodes a 2446 amino acid polyprotein. Based on the complete amino acid sequence of polyprotein, phylogenetic analysis showed that CH-1 was grouped along with other canine kobuvirus strains detected in the USA (US-PC0082, AN211D). PMID- 27995025 TI - Application of 1-D discrete wavelet transform based compressed sensing matrices for speech compression. AB - BACKGROUND: Compressed sensing is a novel signal compression technique in which signal is compressed while sensing. The compressed signal is recovered with the only few numbers of observations compared to conventional Shannon-Nyquist sampling, and thus reduces the storage requirements. In this study, we have proposed the 1-D discrete wavelet transform (DWT) based sensing matrices for speech signal compression. The present study investigates the performance analysis of the different DWT based sensing matrices such as: Daubechies, Coiflets, Symlets, Battle, Beylkin and Vaidyanathan wavelet families. RESULTS: First, we have proposed the Daubechies wavelet family based sensing matrices. The experimental result indicates that the db10 wavelet based sensing matrix exhibits the better performance compared to other Daubechies wavelet based sensing matrices. Second, we have proposed the Coiflets wavelet family based sensing matrices. The result shows that the coif5 wavelet based sensing matrix exhibits the best performance. Third, we have proposed the sensing matrices based on Symlets wavelet family. The result indicates that the sym9 wavelet based sensing matrix demonstrates the less reconstruction time and the less relative error, and thus exhibits the good performance compared to other Symlets wavelet based sensing matrices. Next, we have proposed the DWT based sensing matrices using the Battle, Beylkin and the Vaidyanathan wavelet families. The Beylkin wavelet based sensing matrix demonstrates the less reconstruction time and relative error, and thus exhibits the good performance compared to the Battle and the Vaidyanathan wavelet based sensing matrices. Further, an attempt was made to find out the best proposed DWT based sensing matrix, and the result reveals that sym9 wavelet based sensing matrix shows the better performance among all other proposed matrices. Subsequently, the study demonstrates the performance analysis of the sym9 wavelet based sensing matrix and state-of-the-art random and deterministic sensing matrices. CONCLUSIONS: The result reveals that the proposed sym9 wavelet matrix exhibits the better performance compared to state-of-the-art sensing matrices. Finally, speech quality is evaluated using the MOS, PESQ and the information based measures. The test result confirms that the proposed sym9 wavelet based sensing matrix shows the better MOS and PESQ score indicating the good quality of speech. PMID- 27995026 TI - A simple and efficient total genomic DNA extraction method for individual zooplankton. AB - Molecular approaches are widely applied in species identification and taxonomic studies of minute zooplankton. One of the most focused zooplankton nowadays is from Subclass Copepoda. Accurate species identification of all life stages of the generally small sized copepods through molecular analysis is important, especially in taxonomic and systematic assessment of harpacticoid copepod populations and to understand their dynamics within the marine community. However, total genomic DNA (TGDNA) extraction from individual harpacticoid copepods can be problematic due to their small size and epibenthic behavior. In this research, six TGDNA extraction methods done on individual harpacticoid copepods were compared. The first new simple, feasible, efficient and consistent TGDNA extraction method was designed and compared with the commercial kit and modified available TGDNA extraction methods. The newly described TGDNA extraction method, "Incubation in PCR buffer" method, yielded good and consistent results based on the high success rate of PCR amplification (82%) compared to other methods. Coupled with its relatively consistent and economical method the "Incubation in PCR buffer" method is highly recommended in the TGDNA extraction of other minute zooplankton species. PMID- 27995027 TI - Plasma image edge detection based on the visible camera in the EAST device. AB - The controlling of plasma shape and position are essential to the success of Tokamak discharge. A real-time image acquisition system was designed to obtain plasma radiation image during the discharge processes in the Experimental Advanced Superconducting Tokamak (EAST) device. The hardware structure and software design of this visible camera system are introduced in detail. According to the general structure of EAST and the layout of the observation window, spatial location of the discharging plasma in the image was measured. An improved Sobel edge detection algorithm using iterative threshold was proposed to detect plasma boundary. EAST discharge results show that the proposed method acquired plasma position and boundary with high accuracy, which is of great significance for better plasma control. PMID- 27995028 TI - Cost-effectiveness analysis of ultrasound-guided Seldinger peripherally inserted central catheters (PICC). AB - BACKGROUND: Ultrasound-guided cannulation of deep mid-arm veins by a modified Seldinger (US-Seldinger) technique has been demonstrated to yield better puncture success rates and lower postoperative complication rates than direct cannulation of superficial veins near the elbow with a short peripheral cannula and peripherally inserted central catheter (PICC) insertion through the cannula (non US conventional method). Economic factors have been evaluated across different operators (i.e. nurses, radiologists, and general practitioners) and different venous catheter types (i.e. PICCs vs. central venous catheters). However, to our knowledge, data describing the economic evaluation on the aforementioned modified Seldinger technique are lacking. Hence, the aim of this study was to evaluate the cost-effectiveness of US-Seldinger technique (experimental group) compared with that of the non-US conventional method based on direct vein visualization (control group). RESULTS: A cohort of 360 subjects were assigned randomly to the experimental and control groups. Cost-effectiveness ratio (CER) analyses indicated that the effectiveness index (EI) for the experimental group was 89.29% (final CER = 3732.75), whereas that for the control group was 59.18% (final CER = 2492.98). CONCLUSION: The US-Seldinger technique was found to be more cost effective than the non-US conventional method. These findings support the use of the former in place of the traditional latter technique as a routine puncture technique and suggest that the update would improve intravenous therapy treatment for patients needing PICCs. This study should serve as a reference for national healthcare policy. Trial registration ChiCTR-TRC-14004993. PMID- 27995029 TI - Thermal-hydraulic analysis of the coil test facility for CFETR. AB - BACKGROUND: Performance test of the China Fusion Engineering Test Reactor (CFETR) central solenoid (CS) and toroidal field (TF) insert coils is of great importance to evaluate the CFETR magnet performance in relevant operation conditions. The superconducting magnet of the coil test facility for CFETR is being designed with the aim of providing a background magnetic field to test the CFETR CS insert and TF insert coils. RESULTS: The superconducting magnet consists of the inner module with Nb3Sn coil and the outer module with NbTi coil. The superconducting magnet is designed to have a maximum magnetic field of 12.59 T and a stored energy of 436.6 MJ. An active quench protection circuit and the positive temperature coefficient dump resistor were adopted to transfer the stored magnetic energy. CONCLUSIONS: The temperature margin behavior of the test facility for CFETR satisfies the design criteria. The quench analysis of the test facility shows that the cable temperature and the helium pressure inside the jacket are within the design criteria. PMID- 27995030 TI - Novel device for creating continuous curvilinear capsulorhexis. AB - PURPOSE: The purpose of this paper is to develop a novel capsulorhexis system. SETTING: Mechatronics Laboratory, University of Erciyes and Kayseri Maya Eye Hospital. DESIGN: A 3D model was created and simulations were conducted to develop a new device which was designed, fabricated and tested for continuous curvilinear capsulorhexis (CCC). The name of this system is the electro mechanical capsulorhexis system (EMCS). METHODS: The 3D model was created by using a commercial design software and a 3D printer was used to fabricate the EMCS Finite element analysis and geometrical relation tests of the EMCS for different sized lenses were performed. RESULTS: The results show that the EMCS is a perfect solution for capsulorhexis surgeries, without mechanical or geometrical problems. CONCLUSIONS: The EMCS can open the anterior lens capsule more easily and effectively than manual CCC applications and needs less experience. PMID- 27995031 TI - Simultaneous detection of influenza A subtypes of H3N2 virus, pandemic (H1N1) 2009 virus and reassortant avian H7N9 virus in humans by multiplex one-step real time RT-PCR assay. AB - BACKGROUND: Influenza A virus is a leading causative pathogen of human acute respiratory infection. Recently, the co-circulation of pandemic (H1N1) 2009 and seasonal H3N2 viruses was reported, and sporadic cases with reassortant avian H7N9 virus are continually reported in China. We aimed to establish a multiplex one-step real-time reverse transcription-polymerase chain reaction (rRT-PCR) assay to simultaneously detect and discriminate FluA subtypes, including human seasonal H3N2 virus, pandemic (H1N1) 2009 virus and reassortant avian H7N9 virus, in one reaction tube. METHODS: Clinical samples, including throat swabs and sputum, were collected from the patients with influenza-like illness (ILIs). Total viral RNA from each sample or viral culture was extracted, and the specific detection of FluA virus and its subtypes was performed using a multiplex rRT-PCR assay. RESULTS: The limitation of detection (LOD) of the multiplex assay was 5.4 * 10-2 50% tissue culture infective dose (TCID50) per reaction or 4.8 * 101 copies per reaction for each virus of the three viruses. For simultaneously detecting the three viruses, the LOD was 1.8 * 10-2 TCID50 per reaction or 1.6 * 10 copies per reaction for testing the total FluA virus RNA and 5.6 * 10-2 TCID50 per reaction or 5.1 * 10 copies per reaction for the H3, H1, and H7 genes in one reaction tube. The multiplex assay specifically detected these viruses, and no cross-reaction with other pathogens was found. Moreover, the assay had reliable clinical sensitivity (100%) and valuable clinical specificity (>95%). The detection of FluA with the matrix (M) gene contributed to the further determination of these subtypes, and the Rnase P gene (RP) was considered an internal control to favourably evaluate the quality of the clinical samples. CONCLUSIONS: These findings indicate that the multiplex assay can simultaneously detect and discriminate FluA subtypes with reliable sensitivity and specificity, which is required for the early clinical diagnosis and viral surveillance of patients with FluA infection. PMID- 27995032 TI - Successful pregnancy and delivery in a patient with chronic myeloid leukemia: a case report and review of the literature. AB - INTRODUCTION: Complications associated with chronic myeloid leukemia (CML) during pregnancy are rare, and management is challenging because very limited data are available on this patient group. CASE DESCRIPTION: We herein report a successful pregnancy and delivery in a patient diagnosed with CML. The patient was treated with imatinib (400 mg/day) as a first-line therapy. However, she became pregnant while she was in complete hematological remission and had a complete cytogenetic response. Because she elected to continue the pregnancy to term, imatinib treatment was stopped after 5 months of gestation and the patient was then treated with interferon-alpha for the remainder of her pregnancy. However, the CML did not relapse. She successfully gave birth to a male infant at 39 weeks by cesarean section with no adverse sequelae or malformations. DISCUSSION AND EVALUATION: The treatment of pregnant women with CML is difficult because of few available therapeutic options and limited data regarding the potential harm to the fetus. Conception should be planned and TKI therapy discontinued in female patients during pregnancy, and individual risks need to be considered when an unplanned pregnancy occurs. CONCLUSIONS: Our experience will be useful for counseling patients inadvertently exposed to tyrosine kinase inhibitors such as imatinib during pregnancy. PMID- 27995033 TI - Extremely high expression of serum alpha-fetoprotein level of gastric adenocarcinoma: a rare case with an unexpected well-prognosis. AB - INTRODUCTION: Alpha-fetoprotein (AFP)-producing gastric cancer is a relatively rare form of stomach malignancy. Patients with higher serum AFP level (>300 ng/mL) will have a poorer prognosis. CASE DESCRIPTION: In this study, we present a case of 77-year-old woman with an extremely high expression of serum AFP level (>10,000 ng/mL) of gastric cancer. Histological examination revealed gastric adenocarcinoma (Bormann III gastric tumor) invading into the serosal layer and vessel. After receiving a successful total gastrectomy with D2 dissection, this patient underwent chemotherapy with SOX [oxaliplatin (130 mg/m2/day) iv. at day 1 + S-1 (80 mg/m2/day) from day 1-day 14]. The patient remains alive without disease for 29 months after surgery. Serum AFP level decreased to normal range. DISCUSSION AND EVALUATION: We have evaluated the level of AFP, and discussed the reason for the good prognosis for this patient. CONCLUSIONS: The good prognosis may be related with her early stage (N0 and without liver metastasis) and radical surgery. PMID- 27995035 TI - Clinical and imaging analysis of subclinical hemophilia combined with coxarthrosis: case report and literature review. AB - INTRODUCTION: The incidence of subclinical hemophilic arthritis is low, with this case reports and literature review, we hope clinicians could pay more attention to the diagnosis of subclinical hemophilic arthritis and prevent the misdiagnosis and mistreatment. CASE PRESENTATION: We analyzed the imaging feature, and therapy of a subclinical hemophilia case with hip lesion by reporting its clinical manifestations, imaging features and therapy procedure, and reviewing literatures. RESULTS: Hemophilia is a sex-linked recessive hereditary hemorrhagic disease, and the pathogenesis of subclinic hemophilia is concealed, which often involves joint lesion. The imaging of joint lesion of hemophilia cases is typical, which facilitates the differential diagnosis with other joint diseases. The current treatment is mainly supplementary or replacement therapy. CONCLUSION: Hemophilic arthritis cases, especially the mild or subclinical cases without family history and with an older age of onset, are not common. The disease should be further understood, and early diagnosis and treatment is crucial to prevent the progressive development of joint diseases. PMID- 27995034 TI - Adipose-derived human stem/stromal cells: comparative organ specific mitochondrial bioenergy profiles. AB - BACKGROUND: Adipose-derived stem/stromal cells (ASCs) isolated from the stromal vascular fraction are a source of mesenchymal stem cells that have been shown to be beneficial in many regenerative medicine applications. ASCs are an attractive source of stem cells in particular, due to their lack of immunogenicity. This study examines differences between mitochondrial bioenergetic profiles of ASCs isolated from adipose tissue of five peri-organ regions: pericardial, thymic, knee, shoulder, and abdomen. RESULTS: Flow cytometry showed that the majority of each ASC population isolated from the adipose tissue of 12 donors, with an n = 3 for each tissue type, were positive for MSC markers CD90, CD73, and CD105, and negative for hematopoietic markers CD34, CD11B, CD19, and CD45. Bioenergetic profiles were obtained for ASCs with an n = 4 for each tissue type and graphed together for comparison. Mitochondrial stress tests provided the following measurements: basal respiration rate (measured as oxygen consumption rate [pmol O2/min], ATP production, proton leak, maximal respiration, respiratory control ratio, coupling efficiency, and non-mitochondrial respiration. Glycolytic stress tests provided the following measurements: basal glycolysis rate (measured as extracellular acidification rate [mpH/min]), glycolytic capacity, glycolytic reserve, and non-glycolytic acidification. CONCLUSIONS: The main goal of this manuscript was to provide baseline reference values for future experiments and to compare bioenergetic potentials of ASCs isolated from adipose tissue harvested from different anatomical locations. Through an investigation of mitochondrial respiration and glycolysis, it was demonstrated that bioenergetic profiles do not significantly differ by region due to depot-dependent and donor-dependent variability. Thus, although the physiological function, microenvironment and anatomical harvest site may directly affect the characteristics of ASCs isolated from different organ regions, the ultimate utility of ASCs remains independent of the anatomical harvest site. PMID- 27995036 TI - The effects for PM2.5 exposure on non-small-cell lung cancer induced motility and proliferation. AB - BACKGROUND: Increasing urbanization and associated air pollution, including elevated levels of particulate matter (PM), are strongly correlated with the development of various respiratory diseases. In particular, PM2.5 has been implicated in promoting lung cancer initiation, growth and progression. Cell migration and proliferation are crucial for the progression of cancer. However, the molecular signatures and biological networks representing the distinct and shared features of non-small cell lung cancer (NSCLC) after PM2.5 exposure are unknown. RESULTS: Functional assays demonstrated higher proliferation, migration and invasion of cancer cells stimulated with PM2.5. To investigate the complicated mechanisms, we performed global transcriptome profiling of the A549 cell line. Particularly, transcriptome sequencing revealed invasive characteristics reminiscent of cancer cells. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining the invasive and proliferative properties of PM2.5-exposed cells, respectively. Interestingly, under the PM2.5-stimulated condition, the A549 and H1299 cells strengthened obviously properties in motility and proliferation. Based on the network model reconstructing the shared protein-protein interactions, we selected the two most up-regulated genes, interleukin-1beta (IL1beta) and matrix metalloprotease 1 (MMP1), as key regulators responsible for the effects of PM2.5 exposure. Notably, IL1beta and MMP1 expression was elevated in independent assays, which was further enhanced by PM2.5. CONCLUSION: Taken together, our systems approach to investigating PM2.5 exposure provides a basis to identify key regulators responsible for the pathological features of NSCLC. PMID- 27995037 TI - A study of implementation of national language policies in a local higher institution: a case study from China. AB - BACKGROUND: College English syllabi have been a guide for English teaching in China for decades. In order to explore how the 2007 version of the College English Curriculum Requirement can succeed in local implementation, this case study chose Binzhou Medical University as a participant institution to find out the influential factors of the implementation of national language policies. CASE PRESENTATION: Binzhou Medical University implemented the College English Curriculum Requirements of 2004 and 2007 versions gradually in terms of course setting. Differentiating Instruction was conducted in 2005 and improved in 2012. It was warmly welcomed by students. The diversity of English courses was advocated in 2007, and the management of the courses was enhanced in 2012. The practices tended to satisfy students' continuous change of academic interests. English for Specific Purpose instruction was introduced in 2012, but further improvements were required. Internet-based teaching system was introduced in 2014 and micro-lessons were strongly advocated in 2015. The effects remained to be seen in the future. CONCLUSIONS: Several factors influenced the College English reform. First, the ideology of national and local administrations was a key factor for the College English reform. Second, professional identity of the teachers affected the development of the course setting. Third, globalization attracted attention to students' communication competence and provided new ways for training teachers. The findings of this article can be valuable references for drawing up an updated syllabus. PMID- 27995038 TI - Studies on the quality of duck meat sausages during refrigeration. AB - Duck farming is on the raise in the current scenario, but processed products from duck meat are still uncommon to find. Investigating the duck meat qualities during storage will provide information to enhance duck meat utilization. Development of ready-to-eat and ready-to-cook duck meat products is expected to increase and improve non-chicken meat-based protein. The Study was aimed to evaluate the changes in quality characteristics of duck meat sausages preserved by refrigeration (7 +/- 1 degrees C). Duck meat sausages were prepared by utilizing raw and partially cooked duck meat with addition of soy flour at 10% level as a binder. Different quality characteristics like physical and chemical characteristics, proximate composition, and organoleptic characteristics were evaluated. Cooking loss of partially cooked meat sausages was lower than raw duck meat sausages, whereas emulsion stability and 2-thiobarbituric acid (TBA) values of raw duck meat sausages were lesser than partially cooked meat sausages. Cooking loss and emulsion stability decreased in both types of meat sausages, while, 2-TBA values increased as refrigerated storage progressed for 14 days. Percent moisture content of raw duck meat sausages was higher than partially cooked meat sausages, which decreased in both types of meat sausages as refrigerated storage progressed for 14 days. Percent crude protein (CP) and percent ether extract (EE) content of partially cooked duck meat sausages were higher than raw duck meat sausages. Regardless of type of meat used, refrigerated storage of sausages increased CP and EE up to 10th day but decreased upon further storage up to 14th day. Organoleptic scores for raw duck meat sausages were higher than partially cooked duck meat sausages and all the scores decreased with an increase in the storage period. However the scores were within the acceptable limits. The findings prove that, duck meat can be effectively acclaimed as an alternative avenue to meet the escalating protein demand in the form of ready-to eat product. The quality of sausages is also retained during refrigerated storage. PMID- 27995040 TI - Memetic computing through bio-inspired heuristics integration with sequential quadratic programming for nonlinear systems arising in different physical models. AB - BACKGROUND: In this study, bio-inspired computing is exploited for solving system of nonlinear equations using variants of genetic algorithms (GAs) as a tool for global search method hybrid with sequential quadratic programming (SQP) for efficient local search. The fitness function is constructed by defining the error function for systems of nonlinear equations in mean square sense. The design parameters of mathematical models are trained by exploiting the competency of GAs and refinement are carried out by viable SQP algorithm. RESULTS: Twelve versions of the memetic approach GA-SQP are designed by taking a different set of reproduction routines in the optimization process. Performance of proposed variants is evaluated on six numerical problems comprising of system of nonlinear equations arising in the interval arithmetic benchmark model, kinematics, neurophysiology, combustion and chemical equilibrium. Comparative studies of the proposed results in terms of accuracy, convergence and complexity are performed with the help of statistical performance indices to establish the worth of the schemes. CONCLUSIONS: Accuracy and convergence of the memetic computing GA-SQP is found better in each case of the simulation study and effectiveness of the scheme is further established through results of statistics based on different performance indices for accuracy and complexity. PMID- 27995039 TI - Sociodemographic characteristics associated with frequency and duration of eating family meals: a cross-sectional analysis. AB - INTRODUCTION: Children who frequently eat family meals are less likely to develop risk- and behavior-related outcomes, such as substance misuse, sexual risk, and obesity. Few studies have examined sociodemographic characteristics associated with both meal frequency (i.e., number of meals) and duration (i.e., number of minutes spent at mealtimes). METHODS: We examine the association between sociodemographics and family meal frequency and duration among a sample of 85 parents in a large New England city that was recruited through the public-school system. Additionally, we examined differences in family meals by race/ethnicity and parental nativity. Unadjusted ANOVA and adjusted ANCOVA models were used to assess the associations between sociodemographic characteristics and frequency and duration of meals. RESULTS: Sociodemographic characteristics were not significantly associated with the frequency of family meals; however, in the adjusted models, differences were associated with duration of meals. Parents who were born outside the U.S. spent an average of 135.0 min eating meals per day with their children compared to 76.2 for parents who were born in the U.S. (p < 0.01). Additionally, parents who reported being single, divorced, or separated on average, spent significantly more time per day eating family meals (126.7 min) compared to parents who reported being married or partnered (84.4; p = 0.02). Differences existed in meal duration by parental nativity and race/ethnicity, ranging from 63.7 min among multi-racial/other parents born in the U.S. to 182.8 min among black parents born outside the U.S. DISCUSSION: This study builds a foundation for focused research into the mechanisms of family meals. Future longitudinal epidemiologic research on family meals may help to delineate targets for prevention of maladaptive behaviors, which could affect family-based practices, interventions, and policies. PMID- 27995041 TI - Radiation dose reduction based on CNR index with low-tube voltage scan for pediatric CT scan: experimental study using anthropomorphic phantoms. AB - BACKGROUND: To figure out the relationship between image noise and contrast noise ratio (CNR) at different tube voltages, using anthropomorphic new-born and 1-year old phantoms, and to discuss the feasibility of radiation dose reduction, based on the obtained CNR index from image noise. We performed helical scans of the anthropomorphic new-born and 1-year-old phantoms. The CT numbers of the simulated aorta and image noise of the simulated mediastinum were measured; then CNR was calculated on 80, 100, and 120-kVp images reconstructed with filtered back projection (FBP) and iterative reconstruction (IR). We also measured the center and surface dose in the case of CNR of 14 using radio-photoluminescence glass dosimeters. RESULTS: The CT number of the simulated aorta was increased with decreasing tube voltage from 120 to 80 kVp (362.5-535.1 HU for the new-born, 358.9-532.6 HU for the 1-year-old). At CNR of 14, the center dose was 0.4, 0.6 and 0.9 mGy at FBP and 0.5, 0.6 and 0.9 mGy at IR and with the new-born phantom acquired at 80, 100 and 120 kVp, respectively. The center dose for FBP image was reduced by 56% at 80 kVp, 34% at 100 kVp for the new-born and 36% at 80 kVp, 22% at 100 kVp for the 1-year-old compared with that at 120 kVp. We obtained a relationship between image noise and CNR at different tube voltages using the anthropomorphic new-born and 1-year-old phantoms. CONCLUSION: The use of index of CNR with low-tube voltage may achieve further radiation dose reduction in pediatric CT examination. PMID- 27995042 TI - Improvement of the detection efficiency calibration and homogeneity measurement of Si-SPAD detectors. AB - BACKGROUND: Silicon single-photon avalanche diodes (Si-SPADs) are the most used devices for measuring ultra-weak optical radiant fluxes in many quantum technology fields, such as quantum optics, quantum communication, quantum computing, etc. In all these fields, the detection efficiency is the main parameter, which has to be accurately known for achieving reliable measurements. In this paper we present the improvements performed on the setup described in Lopez et al. (J Mod Opt 62:S21-S27, 2015) for determining the detection efficiency of Si-SPAD detectors with a low measurement uncertainty. The improvement arises from the precise alignment of the Si-SPAD detector and the low deviation reached between the total calculated filter transmission and the individual filter transmission measurements (<=0.05%) performed with an integrating sphere with attached Si-photodiode as standard detector. RESULTS: The relative standard uncertainty of the Si-SPAD detection efficiency measurement achieved is now as low as ~0.16%. Furthermore, the investigation of the detection efficiency homogeneity of two commercial Si-SPAD detectors from different manufacturers and with different sensor diameters is also presented. The obtained homogeneity is <=2.2% within a region of diameter of 40 MUm. CONCLUSIONS: The detailed analysis presented in this paper shows the potential for achieving low measurement uncertainties for Si-SPAD detector calibration even in the low photon flux range. The low uncertainties are only to be realized for reproducible measurement conditions, i.e. in specific for equal beam sizes and beam shapes and well as for an irradiation of equal active areas of the detector. This, however, will be difficult to obtain when measurements are performed at different national metrology institutes. PMID- 27995043 TI - Influence of WeChat on sleep quality among undergraduates in Chongqing, China: a cross-sectional study. AB - BACKGROUND: Previous studies showed that social media is associated with sleep quality. WeChat (a native social media in China) is very popular in China, especially among the youth. In the second quarter of 2016, Tencent's WeChat had 806 million monthly active users. The study sought to identify the influence of WeChat on the sleep quality among undergraduate students. METHODS: A cross sectional survey adopted a multi-stage stratified sampling survey to investigate undergraduates in Chongqing, China. Data were collected on 1979 eligible adults, aged 20.27 (SD: 1.26) years old, using Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality. RESULTS: Respondents aged 20.27 +/- 1.26 years included 535 (27.0%) males, and 1311 (66.3%) reported as having poor sleep quality. Of the 1979 participants, 1320 (66.70%) were WeChat users. In multivariable analyses, gender, grade, nationality, living costs, the student leader, the only child, type of university, WeChat usage was associated with domains of PSQI among undergraduates (p < 0.05 for all). Compared with non-users, WeChat users had a lower score of subjective quality of sleep, sleep latency, use of sleeping medication, daytime dysfunction, and global PSQI score (p < 0.05 for all). CONCLUSIONS: WeChat users may have better sleep quality than non-WeChat users among undergraduates. To determine causal relationships, further longitudinal studies will be required to test for the association between WeChat users and sleep quality. This study may also provide some implications for health promotion on sleep quality of undergraduate students. PMID- 27995044 TI - A concise drug alerting rule set for Chinese hospitals and its application in computerized physician order entry (CPOE). AB - BACKGROUND: A minimized and concise drug alerting rule set can be effective in reducing alert fatigue. OBJECTIVES: This study aims to develop and evaluate a concise drug alerting rule set for Chinese hospitals. The rule set covers not only western medicine, but also Chinese patent medicine that is widely used in Chinese hospitals. SETTING: A 2600-bed general hospital in China. METHODS: In order to implement the drug rule set in clinical information settings, an information model for drug rules was designed and a rule authoring tool was developed accordingly. With this authoring tool, clinical pharmacists built a computerized rule set that contains 150 most widely used and error-prone drugs. Based on this rule set, a medication-related clinical decision support application was built in CPOE. Drug alert data between 2013/12/25 and 2015/07/01 were used to evaluate the effect of the rule set. MAIN OUTCOME MEASURE: Number of alerts, number of corrected/overridden alerts, accept/override rate. RESULTS: Totally 18,666 alerts were fired and 2803 alerts were overridden. Overall override rate is 15.0% (2803/18666) and accept rate is 85.0%. CONCLUSIONS: The rule set has been well received by physicians and can be used as a preliminary medical order screening tool to reduce pharmacists' workload. For Chinese hospitals, this rule set can serve as a starter kit for building their own pharmaceutical systems or as a reference to tier commercial rule set. PMID- 27995045 TI - In vitro interaction of Metarhizium anisopliae Ma9236 and Beauveria bassiana Bb9205 with Heterorhabditis bacteriophora HNI0100 for the control of Plutella xylostella. AB - The diamondback moth (Plutella xylostella) is a major pest of broccoli crops in Colombia. To control P. xylostella, we evaluated the interaction of Beauveria bassiana Bb9205 and Metarhizium anisopliae Ma9236 with Heterorhabditis bacteriophora HNI0100 and its bacterial symbiont Photorhabdus luminescens HNI0100. We used antagonism and disk diffusion assays with fungal extracts to test the interaction between symbiotic bacterium and fungi. P. luminescens inhibited the growth of B. bassiana and M. anisopliae up to 40% by the secretion of secondary metabolites, whereas fungal extracts did not inhibit P. luminescens; this explains the in vivo interactions of these biological control agents. To test the interaction between fungi and nematodes, we first inoculated the fungi followed by the nematodes on different days (0, 2, 4, and 6). We identified the type of interaction using the formula by Nishimatsu and Jackson (J Econ Entomol 91:410-418, 1998) and established that on days 0, 2 and 4 there was an antagonistic interaction, while a synergistic interaction occurred on day 6. Therefore, the use of the interaction between H. bacteriophora HNI0100 with M. anisopliae Ma9236 and B. bassiana Bb9205 is an innovative alternative for the control of P. xylostella. PMID- 27995046 TI - A C-band broadband ortho-mode transducer for radioastronomy polarimetry. AB - BACKGROUND: We describe the design, the construction and performance of a narrow band ortho-mode transducer, currently used in the 5 GHz polarimetric receiver of the Galactic Emission Mapping project. RESULTS: The ortho-mode transducer was designed to achieve a high degree of transmission within the 400 MHz of the GEM band around the 5 GHz (4.8-5.2 GHz). It is composed of a circular-to-square waveguide transition, a septum polarizer, a thin waveguide coupler and a smooth square-to-rectangular waveguide transition with custom waveguide bends to the output ports. CONCLUSION: Our simulations and measurements show a very low level of cross-polarization of about -60 dB and a good impedance match for all three ports (S11; S22; S33 < -30 dB) with only 0:25 dB of insertion loss offset across the 400 MHz (4.8-5.2 GHz) of the reception bandwidth. PMID- 27995048 TI - Proposal for optimal placement platform of bikes using queueing networks. AB - In recent social experiments, rental motorbikes and rental bicycles have been arranged at nodes, and environments where users can ride these bikes have been improved. When people borrow bikes, they return them to nearby nodes. Some experiments have been conducted using the models of Hamachari of Yokohama, the Niigata Rental Cycle, and Bicing. However, from these experiments, the effectiveness of distributing bikes was unclear, and many models were discontinued midway. Thus, we need to consider whether these models are effectively designed to represent the distribution system. Therefore, we construct a model to arrange the nodes for distributing bikes using a queueing network. To adopt realistic values for our model, we use the Google Maps application program interface. Thus, we can easily obtain values of distance and transit time between nodes in various places in the world. Moreover, we apply the distribution of a population to a gravity model and we compute the effective transition probability for this queueing network. If the arrangement of the nodes and number of bikes at each node is known, we can precisely design the system. We illustrate our system using convenience stores as nodes and optimize the node configuration. As a result, we can optimize simultaneously the number of nodes, node places, and number of bikes for each node, and we can construct a base for a rental cycle business to use our system. PMID- 27995047 TI - The relationship between epilepsy and sexual dysfunction: a review of the literature. AB - BACKGROUND AND OBJECTIVES: Regardless of the disease states that people suffer from, maintaining sexual function is an important indicator of quality of life. The objective of this review was to figure out the relationship between epilepsy, antiepileptic drugs (AEDs) and sexual dysfunction. RESULTS: In various epidemiological and clinical studies, epilepsy has been correlated with a reduction in sexual function. This sexual dysfunction is not always detected in epileptic patients until systematic efforts are put in place, as part of the assessment and treatment process. Therefore, precise evaluations of the incidence of treatment related sexual dysfunction in epileptic patients is still lacking. CONCLUSIONS: This literature review concluded that sexual function is influenced by the pathophysiology of epilepsy, as well as through the use of AEDs. To maximize quality of care in patients with epilepsy and those patients with other disease states who receive AEDs, it is important to address the status of the patient's sexual function as part of the initial routine assessment and with any treatment related follow-up. Minimizing the effects of AED related sexual dysfunction can be achieved by raising awareness among patients, providing education and training for physicians regarding sexual dysfunction and obtaining a baseline sexual history from the patient so are important recommendations. In addition, systematic studies are needed to explore the risk and mechanism of such treatment related side effects on sexual function. PMID- 27995049 TI - Annexin A3 Knockdown Suppresses Lung Adenocarcinoma. AB - Our previous study identified an elevated abundance of annexin A3 (Anxa3) as a novel prognostic biomarker of lung adenocarcinoma (LADC) through quantitative proteomics analysis. However, the biological functions of Anxa3 in LADC are not fully clear. In this study, in vitro and in vivo assays were performed to investigate the effects of Anxa3 downregulation on the growth, migration, invasion, metastasis, and signaling pathway activation of LADC cells. After Anxa3 downregulation, the growth of A549 and LTEP-a2 LADC cells was slowed and they showed decreased migration and invasion in vitro. Anxa3 knockdown significantly inhibited tumor formation by A549 cells in vivo; while many metastases were formed by control A549 cells, there were obvious reductions in the numbers of lung, liver, and brain metastases formed by Anxa3 knockdown in A549 cells. Furthermore, Anxa3 knockdown significantly decreased MMP-2 and N-cadherin expression and increased E-cadherin expression both in cell lines in vitro and in tumor nodules examined during in vivo tumorigenesis assays. Interestingly, Anxa3 downregulation reduced the phosphorylated levels of MEK and ERK. In summary, Anxa3 knockdown inhibited the growth, migration, invasion, and metastasis of LADC, decreased the activation of the MEK/ERK signaling pathway, and modulated the expression of MMP-2, E-cadherin, and N-cadherin. PMID- 27995051 TI - Bilateral adrenal histoplasmosis in an immunocompetent man from Texas. AB - Disseminated histoplasmosis affecting the adrenal gland(s) of immunocompetent adults is a very rare infection. Here, we present a case of bilateral adrenal histoplasmosis in an immunocompetent, 62-year-old gentleman from Texas along with a brief review of the published literature. Given the risk of patient decompensation secondary to adrenal insufficiency and the wide availability of effective treatments, adrenal histoplasmosis must be considered even in immunocompetent adults who acquire adrenal masses. PMID- 27995050 TI - Cutaneous pythiosis in a Red Brangus beef calf cured by immunotherapy. AB - Pythiosis in Southern USA have been increasingly reported in the past ten years. The infection occurs more frequently in dogs and horses inhabiting the endemic areas. Cases of the disease are rarely diagnosed in other species including humans. Herein, we describe the first case of bovine pythiosis in a breed other than Brahman successfully treated by the used of immunotherapy. PMID- 27995052 TI - First case of Arthrographis kalrae fungemia in a patient with cystic fibrosis. AB - Arthrographis kalrae is a hyalin fungus. It is a saprophyte of the environment, mainly found in soil and compost. In recent years, cases of opportunistic infections attributed to this pathogen have been described. Our patient was a 19 year-old woman with cystic fibrosis. She presented a bacterial and fungal pulmonary colonization with Aspergillus fumigatus and Arthrographis. kalrae. After her lung transplantation, she developed an A. kalrae fungemia, treated with caspofungin 50 mg/day associated to liposomal amphotericin B i.v. 3 mg/kg/day. The patient died 8 months after her transplantation as the result of a bacterial septic shock. PMID- 27995053 TI - Chronic Paracoccidioidomycosis with adrenal involvement mimicking tuberculosis - A case report from Austria. AB - Paracoccidioidomycosis is a systemic fungal infection caused by Paracoccidioides brasiliensis and endemic in certain areas of Central and South America. We report a case of a 62-year-old-man with a complex history of tuberculosis and imaging findings of a cerebral lesion and bilateral adrenal enlargement. Biopsy of adrenal gland revealed Paracoccidioides brasiliensis. This case highlights the importance of travel history for diagnosis of paracoccidioidomycosis in non endemic areas and emphasizes the clinical and histopathological similarities with tuberculosis. PMID- 27995054 TI - Cases of disseminated cryptococcosis in intravenous drug abusers without HIV infection: A new risk factor? AB - Cryptococcosis is a fungal disease which has been characterized by its identified risk groups. There are many risk factors identified. We present a surprising four cases of disseminated cryptococcosis in intravenous drug abuse (IVDA) patients in a short period of time and in one geographical area, this observation suggest that there may be a new association with IVDA and cryptococosis. PMID- 27995055 TI - Recurrent episodes of Candidemia due to Candida glabrata, Candida tropicalis and Candida albicans with acquired echinocandin resistance. AB - Mixed fungal infection and acquired echinocandin resistance of Candida spp. remain infrequent. In this study we have reported the case of a patient hospitalized for tuberculosis who experienced multiple infections due to three common Candida species (C. albicans, C. glabrata, C. tropicalis). Furthermore, consecutive isolates from blood cultures and heart valve were found resistant to azoles (C. tropicalis) and to echinocandin with either novel (C. tropicalis) or previously described (C. albicans) missense mutations in the Fks gene. PMID- 27995056 TI - Ralstonia mannitolilytica in cystic fibrosis: A new predictor of worse outcomes. AB - BACKGROUND: Patients with Cystic Fibrosis are subject to repeated respiratory tract infections, with recent increasing isolation of unusual pathogens. Ralstonia species have lately been isolated at our institution, an organism historically frequently misidentified as Burkholderia or Pseudomonas. The prevalence of Ralstonia spp. in cystic fibrosis populations has yet to be determined, along with its clinical implications. CASE PRESENTATIONS: Seven patients out of the 301 followed at our cystic fibrosis clinic have had Ralstonia strains identified in their respiratory tract. Most strains identified were multi drug resistant. After aquisition of Ralstonia spp., the patients' clinical course was characterized by more frequent and more severe respiratory infections along with prolonged hospitalizations, greater decline of lung function, and greater mortality. The mortality rate in this group of patients was 86%. No other factor that could explain such a dramatic evolution was identified upon review of patient data. Some of the strains involved were recognized as clones on Pulse Field Electrophoresis Gel, raising the question of person-to-person transmission. CONCLUSION: New pathogens are identified with the evolution of the microbiota in cystic fibrosis respiratory tracts. In our cohort of patients, acquisition of Ralstonia spp. was associated with dramatic outcomes in terms of disease acceleration and raised mortality rates. It is of critical importance to continue to better define the prevalence and clinical impact of Ralstonia in cystic fibrosis populations. PMID- 27995057 TI - Rapidly progressive interstitial lung disease due to anti-MDA-5 antibody-positive clinically amyopathic dermatomyositis complicated with cervical cancer: Successful treatment with direct hemoperfusion using polymyxin B-immobilized fiber column therapy. AB - The anti-melanoma differentiation-associated gene 5 (MDA-5) antibody is a marker of clinically amyopathic dermatomyositis (CADM) and rapidly progressive interstitial lung disease (ILD) with acute respiratory failure. A 35-year-old woman with cervical cancer showed Gottron's papules, severe hypoxemia, and diffuse ground-glass opacities on chest computed tomography. She was diagnosed with rapidly progressive ILD associated with CADM. Her serum was positive for the anti-MDA-5 antibody. Combination therapy with corticosteroids, immunosuppressants, and direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP) improved her respiratory dysfunction. Eventually, surgery for the cancer was performed successfully. This is the first case to demonstrate the efficacy of PMX-DHP for rapidly progressive ILD with anti-MDA-5 antibody-positive CADM and a malignancy. PMID- 27995058 TI - Erdheim-Chester disease, moving away from the orphan diseases: A case report. AB - With approximately 750 cases reported, Erdheim-Chester disease is an exceedingly rare histiocyte cell disorder. Affected sites typically include long bones, large vessels and central nervous system. However, cutaneous and pulmonary involvement can also occur. The diagnosis is ascertained by identification of foamy histiocytes positive for CD68, CD163, and factor XIIIa on immunoperoxidase staining. Recently published literature have described an association between Erdheim-Chester disease and BRAF V600E mutation. This finding prompted the investigation of therapeutic possibilities with BRAF inhibitors, successful agents against other BRAF mutation-positive diseases. Vemurafenib, a BRAF kinase inhibitor, has been shown to be effective in BRAF V600E mutation-positive malignancies, such as NSCLC and melanoma, as well as in several case reports of Erdheim-Chester disease. We report a case of Erdheim-Chester disease diagnosed at our institution, treated with vemurafenib. PMID- 27995059 TI - Working memory circuit as a function of increasing age in healthy adolescence: A systematic review and meta-analyses. AB - Working memory ability matures through puberty and early adulthood. Deficits in working memory are linked to the risk of onset of neurodevelopmental disorders such as schizophrenia, and there is a significant temporal overlap between the peak of first episode psychosis risk and working memory maturation. In order to characterize the normal working memory functional maturation process through this critical phase of cognitive development we conducted a systematic review and coordinate based meta-analyses of all the available primary functional magnetic resonance imaging studies (n = 382) that mapped WM function in healthy adolescents (10-17 years) and young adults (18-30 years). Activation Likelihood Estimation analyses across all WM tasks revealed increased activation with increasing subject age in the middle frontal gyrus (BA6) bilaterally, the left middle frontal gyrus (BA10), the left precuneus and left inferior parietal gyri (BA7; 40). Decreased activation with increasing age was found in the right superior frontal (BA8), left junction of postcentral and inferior parietal (BA3/40), and left limbic cingulate gyrus (BA31). These results suggest that brain activation during adolescence increased with age principally in higher order cortices, part of the core working memory network, while reductions were detected in more diffuse and potentially more immature neural networks. Understanding the process by which the brain and its cognitive functions mature through healthy adulthood may provide us with new clues to understanding the vulnerability to neurodevelopmental disorders. PMID- 27995060 TI - Hippocampal volume predicts antidepressant efficacy in depressed patients without incomplete hippocampal inversion. AB - BACKGROUND: Incomplete hippocampal inversion (IHI), also called malrotation, is a frequent atypical anatomical pattern of the hippocampus. Because of the crucial implication of the hippocampus in Major Depressive Disorder (MDD) and the neurodevelopmental hypothesis of MDD, we aimed to assess the prevalence of IHI in patients with MDD, the link of IHI with hippocampal volume (HV) and the impact of IHI on the predictive value of HV for response and remission after antidepressant treatment. METHODS: IHI (right and left, partial and total and IHI scores) and HV were assessed in 60 patients with a current Major Depressive Episode (MDE) in a context of MDD and 60 matched controls. Patients were prospectively assessed at baseline and after one, three and six months of antidepressant treatment for response and remission. RESULTS: The prevalence of IHI did not significantly differ between MDD patients (right = 23.3%; left = 38.3%) and controls (right = 16.7%; left = 33.3%). IHI was not significantly associated with MDD clinical characteristics. IHI alone did not predict response and remission after antidepressant treatment. However, an interaction between left HV and left IHI predicted six-month response (p = 0.04), HDRS score decrease (p = 0.02) and both three-month (p = 0.04) and six-month (p = 0.03) remission. A case-control design in 30 matched patients with or without left IHI confirmed that interaction. In patients without left IHI, left HV at baseline were smaller in six-month non remitters as compared to remitters (2.2(+/- 0.43) cm3 vs 2.97(+/- 0.5) cm3 p = 0.02), and in six-month non-responders as compared to responders (2.18(+/- 0.42) cm3 vs 2.86(+/- 0.54) cm3, p = 0.03). In patients with left IHI, no association was found between left HV at baseline and antidepressant response and remission. CONCLUSION: IHI is not more frequent in MDD patients than in controls, is not associated with HV, but is a confounder that decreases the predictive value of hippocampal volume to predict response or remission after antidepressant treatment. IHI should be systematically assessed in future research studies assessing hippocampal volume in MDD. PMID- 27995061 TI - Neural basis of distorted self-face recognition in social anxiety disorder. AB - BACKGROUND: The observer perspective causes patients with social anxiety disorder (SAD) to excessively inspect their performance and appearance. This study aimed to investigate the neural basis of distorted self-face recognition in non-social situations in patients with SAD. METHODS: Twenty patients with SAD and 20 age- and gender-matched healthy controls participated in this fMRI study. Data were acquired while participants performed a Composite Face Evaluation Task, during which they had to press a button indicating how much they liked a series of self faces, attractively transformed self-faces, and attractive others' faces. RESULTS: Patients had a tendency to show more favorable responses to the self face and unfavorable responses to the others' faces compared with controls, but the two groups' responses to the attractively transformed self-faces did not differ. Significant group differences in regional activity were observed in the middle frontal and supramarginal gyri in the self-face condition (patients < controls); the inferior frontal gyrus in the attractively transformed self-face condition (patients > controls); and the middle frontal, supramarginal, and angular gyri in the attractive others' face condition (patients > controls). Most fronto-parietal activities during observation of the self-face were negatively correlated with preference scores in patients but not in controls. CONCLUSION: Patients with SAD have a positive point of view of their own face and experience self-relevance for the attractively transformed self-faces. This distorted cognition may be based on dysfunctions in the frontal and inferior parietal regions. The abnormal engagement of the fronto-parietal attentional network during processing face stimuli in non-social situations may be linked to distorted self-recognition in SAD. PMID- 27995062 TI - Magnetic susceptibility in the deep layers of the primary motor cortex in Amyotrophic Lateral Sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disorder that entails degeneration of both upper and lower motor neurons. The primary motor cortex (M1) in patients with upper motor neuron (UMN) impairment is pronouncedly hypointense in Magnetic Resonance (MR) T2* contrast. In the present study, 3D gradient-recalled multi-echo sequences were used on a 7 Tesla MR system to acquire T2*-weighted images targeting M1 at high spatial resolution. MR raw data were used for Quantitative Susceptibility Mapping (QSM). Measures of magnetic susceptibility correlated with the expected concentration of non-heme iron in different regions of the cerebral cortex in healthy subjects. In ALS patients, significant increases in magnetic susceptibility co-localized with the T2* hypointensity observed in the middle and deep layers of M1. The magnetic susceptibility, hence iron concentration, of the deep cortical layers of patients' M1 subregions corresponding to Penfield's areas of the hand and foot in both hemispheres significantly correlated with the clinical scores of UMN impairment of the corresponding limbs. QSM therefore reflects the presence of iron deposits related to neuroinflammatory reaction and cortical microgliosis, and might prove useful in estimating M1 iron concentration, as a possible radiological sign of severe UMN burden in ALS patients. PMID- 27995063 TI - Integrity of the arcuate fasciculus in patients with schizophrenia with auditory verbal hallucinations: A DTI-tractography study. AB - Auditory verbal hallucinations (AVH) of schizophrenia are associated with a disrupted connectivity between frontal and temporoparietal language areas. We hypothesized that this dysconnectivity is underpinned by white matter abnormalities in the left arcuate fasciculus, the main fiber bundle connecting speech production and perception areas. We therefore investigated the relationship between AVH severity and the integrity of the arcuate fasciculus measured by diffusion tensor imaging (DTI) tractography in patients with schizophrenia. Thirty-eight patients with treatment-resistant schizophrenia were included: 26 presented with daily severe treatment-resistant AVH, 12 reported prominent negative symptoms and no AVH. Fractional anisotropy (FA) was measured along the length of the left and right anterior arcuate fasciculi and severity of AVH was assessed using P3 PANSS item. FA values were significantly higher in the left arcuate fasciculus in patients with AVH than in no AVH patients (F(1,35) = 3.86; p = 0.05). No difference was observed in the right arcuate fasciculus. There was a significant positive correlation between FA value in the left arcuate fasciculus and the severity of AVH (r = 0.36; p = 0.02). No correlation was observed between FA values and PANSS total score suggesting a specific relationship between AVH severity and the left arcuate fasciculus integrity. These results support the hypothesis of a relationship between left frontotemporal connectivity and AVH in patients with schizophrenia and suggest that whilst a disruption of frontotemporal connectivity might be present to ensure the emergence of AVH, more severe anatomical alterations may prevent the occurrence of AVH in patients with schizophrenia. PMID- 27995064 TI - Combined 18F-FDG-PET and diffusion tensor imaging in mesial temporal lobe epilepsy with hippocampal sclerosis. AB - OBJECTIVES: Several studies using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) or diffusion tensor imaging (DTI) have found both temporal and extratemporal abnormalities in patients with mesial temporal lobe epilepsy with ipsilateral hippocampal sclerosis (MTLE-HS), but data are lacking about the findings of both techniques in the same patients. We aimed to determine whether the extent of 18F-FDG-PET hypometabolism is related to DTI abnormalities. METHODS: Twenty-one patients with MTLE-HS underwent comprehensive preoperative evaluation; 18 (86%) of these underwent epilepsy surgery. We analyzed and compared the pattern of white matter (WM) alterations on DTI and cortical hypometabolism on 18F-FDG-PET. RESULTS: We found widespread temporal and extratemporal 18F-FDG-PET and DTI abnormalities. Patterns of WM abnormalities and cortical glucose hypometabolism involved similar brain regions, being more extensive in the left than the right MTLE-HS. We classified patients into three groups according to temporal 18F-FDG-PET patterns: hypometabolism restricted to the anterior third (n = 7), hypometabolism extending to the middle third (n = 7), and hypometabolism extending to the posterior third (n = 7). Patients with anterior temporal hypometabolism showed DTI abnormalities in anterior association and commissural tracts while patients with posterior hypometabolism showed WM alterations in anterior and posterior tracts. CONCLUSIONS: Patients with MTLE-HS have widespread metabolic and microstructural abnormalities that involve similar regions. The distribution patterns of these gray and white matter abnormalities differ between patients with left or right MTLE, but also with the extent of the 18F-FDG-PET hypometabolism along the epileptogenic temporal lobe. These findings suggest a variable network involvement among patients with MTLE-HS. PMID- 27995065 TI - Classification of amyloid status using machine learning with histograms of oriented 3D gradients. AB - Brain amyloid burden may be quantitatively assessed from positron emission tomography imaging using standardised uptake value ratios. Using these ratios as an adjunct to visual image assessment has been shown to improve inter-reader reliability, however, the amyloid positivity threshold is dependent on the tracer and specific image regions used to calculate the uptake ratio. To address this problem, we propose a machine learning approach to amyloid status classification, which is independent of tracer and does not require a specific set of regions of interest. Our method extracts feature vectors from amyloid images, which are based on histograms of oriented three-dimensional gradients. We optimised our method on 133 18F-florbetapir brain volumes, and applied it to a separate test set of 131 volumes. Using the same parameter settings, we then applied our method to 209 11C-PiB images and 128 18F-florbetaben images. We compared our method to classification results achieved using two other methods: standardised uptake value ratios and a machine learning method based on voxel intensities. Our method resulted in the largest mean distances between the subjects and the classification boundary, suggesting that it is less likely to make low-confidence classification decisions. Moreover, our method obtained the highest classification accuracy for all three tracers, and consistently achieved above 96% accuracy. PMID- 27995066 TI - Functional resting-state fMRI connectivity correlates with serum levels of the S100B protein in the acute phase of traumatic brain injury. AB - The S100B protein is an intra-cellular calcium-binding protein that mainly resides in astrocytes in the central nervous system. The serum level of S100B is used as biomarker for the severity of brain damage in traumatic brain injury (TBI) patients. In this study we investigated the relationship between intrinsic resting-state brain connectivity, measured 1-22 days (mean 8 days) after trauma, and serum levels of S100B in a patient cohort with mild-to-severe TBI in need of neuro-intensive care in the acute phase. In line with previous investigations, our results show that the peak level of S100B acquired during the acute phase of TBI was negatively correlated with behavioral measures (Glasgow Outcome Score, GOS) of functional outcome assessed 6 to 12 months post injury. Using a multi variate pattern analysis-informed seed-based correlation analysis, we show that the strength of resting-state brain connectivity in multiple resting-state networks was negatively correlated with the peak of serum levels of S100B. A negative correspondence between S100B peak levels recorded 12-36 h after trauma and intrinsic connectivity was found for brain regions located in the default mode, fronto-parietal, visual and motor resting-state networks. Our results suggest that resting-state brain connectivity measures acquired during the acute phase of TBI is concordant with results obtained from molecular biomarkers and that it may hold a capacity to predict long-term cognitive outcome in TBI patients. PMID- 27995067 TI - Brain imaging correlates of recovered swallowing after dysphagic stroke: A fMRI and DWI study. AB - Neurogenic dysphagia frequently occurs after stroke and deglutitive aspiration is one of the main reasons for subacute death after stroke. Although promising therapeutic interventions for neurogenic dysphagia are being developed, the functional neuroanatomy of recovered swallowing in this population remains uncertain. Here, we investigated 18 patients post-stroke who recovered from dysphagia using an event related functional magnetic resonance imaging (fMRI) study of swallowing. Patients were characterized by initial dysphagia score (mild to severe), lesion mapping, white matter fractional anisotropy (FA) of the pyramidal tracts, and swallowing performance measurement during fMRI scanning. Eighteen age matched healthy participants served as a control group. Overall, patients showed decreased fMRI-activation in the entire swallowing network apart from an increase of activation in the contralesional primary somatosensory cortex (S1). Moreover, fMRI activation in contralesional S1 correlated with initial dysphagia score. Finally, when lesions of the pyramidal tract were more severe, recovered swallowing appeared to be associated with asymmetric activation of the ipsilesional anterior cerebellum. Taken together, our data support a role for increased contralesional somatosensory resources and ipsilesional anterior cerebellum feed forward loops for recovered swallowing after dysphagia following stroke. PMID- 27995070 TI - Corrigendum to "Developmental synergy between thalamic structure and interhemispheric connectivity in the visual system of preterm infants" [NeuroImage: Clinical 8 (2015) 462-472]. AB - [This corrects the article DOI: 10.1016/j.nicl.2015.05.014.]. PMID- 27995068 TI - Shared white matter alterations across emotional disorders: A voxel-based meta analysis of fractional anisotropy. AB - BACKGROUND: White matter (WM) integrity may represent a shared biomarker for emotional disorders (ED). Aims: To identify transdiagnostic biomarkers of reduced WM by meta-analysis of findings across multiple EDs. METHOD: Web of Science was searched systematically for studies of whole brain analysis of fractional anisotropy (FA) in adults with major depressive disorder, bipolar disorder, social anxiety disorder, obsessive-compulsive disorder or posttraumatic stress disorder compared with a healthy control (HC) group. Peak MNI coordinates were extracted from 37 studies of voxel-based analysis (892 HC and 962 with ED) and meta-analyzed using seed-based d Mapping (SDM) Version 4.31. Separate meta analyses were also conducted for each disorder. RESULTS: In the transdiagnostic meta-analysis, reduced FA was identified in ED studies compared to HCs in the left inferior fronto-occipital fasciculus, forceps minor, uncinate fasciculus, anterior thalamic radiation, superior corona radiata, bilateral superior longitudinal fasciculi, and cerebellum. Disorder-specific meta-analyses revealed the OCD group had the most similarities in reduced FA to other EDs, with every cluster of reduced FA overlapping with at least one other diagnosis. The PTSD group was the most distinct, with no clusters of reduced FA overlapping with any other diagnosis. The BD group were the only disorder to show increased FA in any region, and showed a more bilateral pattern of WM changes, compared to the other groups which tended to demonstrate a left lateralized pattern of FA reductions. CONCLUSIONS: Distinct diagnostic categories of ED show commonalities in WM tracts with reduced FA when compared to HC, which links brain networks involved in cognitive and affective processing. This meta-analysis facilitates an increased understanding of the biological markers that are shared by these ED. PMID- 27995069 TI - Longitudinal imaging in C9orf72 mutation carriers: Relationship to phenotype. AB - Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6 month time frame, and appears to be faster in patients with cognitive impairment. PMID- 27995071 TI - Minimum statistical standards for submissions to Neuroimage: Clinical. PMID- 27995072 TI - Application of texture analysis to DAT SPECT imaging: Relationship to clinical assessments. AB - Dopamine transporter (DAT) SPECT imaging is increasingly utilized for diagnostic purposes in suspected Parkinsonian syndromes. We performed a cross-sectional study to investigate whether assessment of texture in DAT SPECT radiotracer uptake enables enhanced correlations with severity of motor and cognitive symptoms in Parkinson's disease (PD), with the long-term goal of enabling clinical utility of DAT SPECT imaging, beyond standard diagnostic tasks, to tracking of progression in PD. Quantitative analysis in routine DAT SPECT imaging, if performed at all, has been restricted to assessment of mean regional uptake. We applied a framework wherein textural features were extracted from the images. Notably, the framework did not require registration to a common template, and worked in the subject-native space. Image analysis included registration of SPECT images onto corresponding MRI images, automatic region-of-interest (ROI) extraction on the MRI images, followed by computation of Haralick texture features. We analyzed 141 subjects from the Parkinson's Progressive Marker Initiative (PPMI) database, including 85 PD and 56 healthy controls (HC) (baseline scans with accompanying 3 T MRI images). We performed univariate and multivariate regression analyses between the quantitative metrics and different clinical measures, namely (i) the UPDRS (part III - motor) score, disease duration as measured from (ii) time of diagnosis (DD-diag.) and (iii) time of appearance of symptoms (DD-sympt.), as well as (iv) the Montreal Cognitive Assessment (MoCA) score. For conventional mean uptake analysis in the putamen, we showed significant correlations with clinical measures only when both HC and PD were included (Pearson correlation r = - 0.74, p-value < 0.001). However, this was not significant when applied to PD subjects only (r = - 0.19, p-value = 0.084), and no such correlations were observed in the caudate. By contrast, for the PD subjects, significant correlations were observed in the caudate when including texture metrics, with (i) UPDRS (p-values < 0.01), (ii) DD-diag. (p values < 0.001), (iii) DD-sympt (p-values < 0.05), and (iv) MoCA (p-values < 0.01), while no correlations were observed for conventional analysis (p-values = 0.94, 0.34, 0.88 and 0.96, respectively). Our results demonstrated the ability to capture valuable information using advanced texture metrics from striatal DAT SPECT, enabling significant correlations of striatal DAT binding with clinical, motor and cognitive outcomes, and suggesting that textural features hold potential as biomarkers of PD severity and progression. PMID- 27995074 TI - De novo transcriptome assembly of the mycoheterotrophic plant Monotropa hypopitys. AB - Monotropa hypopitys (pinesap) is a non-photosynthetic obligately mycoheterotrophic plant of the family Ericaceae. It obtains the carbon and other nutrients from the roots of surrounding autotrophic trees through the associated mycorrhizal fungi. In order to understand the evolutionary changes in the plant genome associated with transition to a heterotrophic lifestyle, we performed de novo transcriptomic analysis of M. hypopitys using next-generation sequencing. We obtained the RNA-Seq data from flowers, flower bracts and roots with haustoria using Illumina HiSeq2500 platform. The raw data obtained in this study can be available in NCBI SRA database with accession number of SRP069226. A total of 10.3 GB raw sequence data were obtained, corresponding to 103,357,809 raw reads. A total of 103,025,683 reads were filtered after removing low-quality reads and trimming the adapter sequences. The Trinity program was used to de novo assemble 98,349 unigens with an N50 of 1342 bp. Using the TransDecoder program, we predicted 43,505 putative proteins. 38,416 unigenes were annotated in the Swiss Prot protein sequence database using BLASTX. The obtained transcriptomic data will be useful for further studies of the evolution of plant genomes upon transition to a non-photosynthetic lifestyle and the loss of photosynthesis related functions. PMID- 27995075 TI - Cardiac failure in very long chain acyl-CoA dehydrogenase deficiency requiring extracorporeal membrane oxygenation (ECMO) treatment: A case report and review of the literature. AB - Fatty acid oxidation (FAO) defects often present with multi-system involvement, including several life-threatening cardiac manifestations, such as cardiomyopathy, pericardial effusion and arrhythmias. We report herein a fatal case of cardiac dysfunction and rapid-onset tamponade following an acute illness in a neonate with molecularly proven very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (harboring the known del799_802 mutation), requiring 15 days of extracorporeal membrane oxygenation (ECMO) treatment. As data regarding the use of ECMO in FAO defects in general, and VLCAD in particular, are scarce, we review the literature and discuss insights from in vitro models and several successful reported cases. PMID- 27995073 TI - Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults. AB - One of the most salient long-term implications of a childhood diagnosis of ADHD is an increased risk for substance use, abuse, or dependence in adolescence and adulthood. The extent to which cannabis use affects ADHD-related alterations in brain functional organization is unknown, however. To address this research gap, we recruited a sample of 75 individuals aged 21-25 years with and without a childhood diagnosis of ADHD Combined Type, who were either frequent users or non users of cannabis. These participants have been followed longitudinally since age 7-9.9 years as part of a large multi-site longitudinal study of ADHD, the Multimodal Treatment Study of Children with ADHD (MTA). We examined task independent intrinsic functional connectivity (iFC) within 9 functional networks using a 2 * 2 design, which compared four groups of participants: (1) individuals with a childhood diagnosis of ADHD who currently use cannabis (n = 23); (2) individuals with ADHD who do not currently use cannabis (n = 22); (3) comparisons who currently use cannabis (n = 15); and (4) comparisons who do not currently use cannabis (n = 15). The main effects of childhood ADHD were primarily weakened iFC in networks supporting executive function and somatomotor control. Contrary to expectations, effects of cannabis use were distinct from those of diagnostic group and no interactions were observed. Exploratory brain-behavior analyses suggested that ADHD-related effects were primarily linked with poorer neurocognitive performance. Deficits in the integrity of functional networks supporting executive function and somatomotor control are consistent with the phenotypic and neurocognitive features of ADHD. Our data suggest that cannabis use does not exacerbate ADHD-related alterations, but this finding awaits replication in a larger sample. Longitudinal neuroimaging studies are urgently required to delineate the neurodevelopmental cascade that culminates in positive and negative outcomes for those diagnosed with ADHD in childhood. PMID- 27995076 TI - Diagnosis of LCHAD/TFP deficiency in an at risk newborn using umbilical cord blood acylcarnitine analysis. AB - Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency. PMID- 27995077 TI - Comparing expression and activity of PCSK9 in SPRET/EiJ and C57BL/6J mouse strains shows lack of correlation with plasma cholesterol. AB - OBJECTIVE: Low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are opposing regulators of plasma LDL-cholesterol levels. The PCSK9 gene exhibits many single or compound polymorphisms within or among mammalian species. This is case between the SPRET/EiJ (SPRET) and C57BL/6J (B6) mouse strains. We examined whether these polymorphisms could be associated with differential expression and activity of their respective PCSK9 molecules. METHODS: Liver expression of LDLR and PCSK9 transcripts were assessed by RT-PCR, and that of their corresponding proteins by immunoblotting. Purified recombinant PCSK9 proteins were assayed for their ability to degrade LDLR. Pcsk9 gene proximal promoters were tested for activation of a luciferase reporter gene. RESULTS: SPRET and B6 mice carried comparable levels of plasma cholesterol in spite of the fact that SPRET mice expressed less PCSK9 and more LDLR in liver. There were indels and single-base differences between their Pcsk9 cDNA and promoter sequences. Ex vivo, SPRET PCSK9 protein was less secreted but was more active at degrading LDLR. Its gene promoter was more active at driving expression of the luciferase reporter. CONCLUSIONS: Collectively, these results suggest that, compared to the B6 mouse, the SPRET mouse may represent an example of absence of direct correlation between PCSK9 and cholesterol levels in plasma, due to genetic variations leading to reduced secretion of PCSK9 associated with greater LDLR-degrading activity. PMID- 27995078 TI - Phenotypic heterogeneity of MELAS. PMID- 27995079 TI - Onset of MELAS due to the m.3243A > G mutation is early if the large phenotypic variability is considered. PMID- 27995080 TI - Electrochemotherapy increases local control after incomplete excision of a recurring penile fibrosarcoma in a stallion. AB - An eleven-year-old stallion was referred for adjuvant treatment of an incompletely excised, recurring penile fibrosarcoma. The horse was bright, alert and responsive with a 15 x 12 cm ulcerated lesion on the ventral side of the penis. The lesion was the tumor bed of an incompletely excised fibrosarcoma. After complete staging procedures, the owner elected to treat the horse with electrochemotherapy (ECT) using cisplatin as chemotherapy agent. Two sessions of ECT were performed at two-week intervals using local cisplatin followed by trains of biphasic electric pulses applied using different electrodes until complete coverage of the area was achieved. The treatment was well tolerated, and the patient is still disease free after 12 months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in equines carrying soft tissue tumors. PMID- 27995081 TI - Thoracic duct lymphography by subcutaneous contrast agent injection in a dog with chylothorax. AB - A 4-year-old male Japanese Shiba Inu presented with recurrent chylothorax. The thoracic duct was successfully imaged using computed tomography after the injection of an iodine contrast agent into the subcutaneous tissue surrounding the anus. The thoracic duct was successfully ligated and pericardectomy performed via an open thoracotomy. Pleural effusion improved but relapsed a week after the surgery. A second lymphography revealed a collateral thoracic duct that was not detected during the first lymphography. The collateral duct was ligated and chylothorax was resolved after the second surgery. The lymphography applied in this study was minimally-invasive and easily provided images of the thoracic duct in a dog with chylothorax. PMID- 27995082 TI - Immune Checkpoint Blockade in Hepatocellular Carcinoma: 2017 Update. PMID- 27995083 TI - EWALT: East Meets West in a Multidisciplinary Setting to Improve the Management of Liver Tumors. PMID- 27995084 TI - Hepatocellular Carcinoma: Therapeutic Guidelines and Medical Treatment. AB - Western and Eastern perspectives on therapeutic guidelines for hepatocellular carcinoma (HCC) have many commonalities but may also differ in certain aspects, as described in this article. In view of the limited therapeutic options for advanced HCC, evidence-based therapies are few, and thus there is a dependence on consensus-based guidelines. This article focuses on the Italian Association for the Study of the Liver guidelines and the Japanese approaches to therapy, while drawing attention to certain controversies from other academic bodies where applicable and appropriate. PMID- 27995085 TI - Transarterial Therapies for Hepatocellular Carcinoma. AB - BACKGROUND: The treatment of hepatocellular carcinoma (HCC) is still a major health issue because of its increasing incidence and because of the complexity of its management. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are two widely used locoregional therapies in the treatment of HCC, especially for unresectable intermediate and advanced HCCs. SUMMARY: The modern use of TAE and TACE opens new scenarios for the treatment of unresectable HCC and has yielded interesting results. The present work describes the role of transarterial therapies for HCC and focuses on the different Western and Eastern approaches to the study of response predictors. KEY MESSAGES: Recent refinements in interventional radiology techniques and in HCC patient selection have facilitated better local control of the disease. The molecular profiling of HCC to predict the response to TACE and TAE will greatly help clinicians identify the optimum therapy. PMID- 27995086 TI - Hepatocellular Carcinoma: The Role of Interventional Oncology. AB - BACKGROUND: Hepatocellular carcinoma (HCC) remains a major health issue because of its increasing incidence and because of the complexity of its management. In addition to the traditional potentially curative treatments, i.e., liver transplantation and surgical resection, other new and emerging local therapies have been applied with promising results. SUMMARY: Radiotherapy (RT) and interstitial treatments, such as radiofrequency ablation (RFA), microwave ablation (MWA), and irreversible electroporation (IRE), have recently opened new and interesting treatment scenarios for HCC and are associated with promising results in selected patients. Herein, we describe the emerging role of interventional oncology for the treatment of HCC and focus on the different Western and Eastern approaches. KEY MESSAGES: Modern RT and modern interstitial therapies, such as RFA, MWA, and IRE, should be considered for inclusion in HCC therapy guidelines. PMID- 27995087 TI - Surgery and Hepatocellular Carcinoma. AB - The optimal surgical strategy for hepatocellular carcinoma (HCC) is under active debate. Bio-markers of the liver functional reserve as well as volumetric analysis of the future liver remnant are essential for safe liver resection of HCC. The present algorithms applied to surgical strategies for HCC are not ideal because many patients who could potentially undergo safe resection are deemed liver transplant candidates in Western countries, whereas the opposite is the case in Eastern countries. In addition, there is too much focus on expanded criteria for patients with HCC to undergo liver transplantation. The transplantation benefit for patients with HCC should be considered based not only on the individual's benefit, but also on the effect of other patients waiting for LT for other indications. PMID- 27995088 TI - Current Technical Issues for Surgery of Primary Liver Cancer. AB - Primary liver cancer is the fifth most common cancer worldwide. Apart from liver transplantation, surgical resection has been accepted as the effective local treatment for hepatocellular carcinoma (HCC), one of the most common primary liver cancers. Recent technological innovations including navigation technology and intraoperative real-time fluorescence guidance have been utilized for liver resections in clinical practice. With respect to liver resection techniques, the laparoscopic approach has been increasingly gaining popularity as one of the minimally-invasive treatments of HCC. These technological innovations and technical advancements are expected to further improve the safety and efficacy of liver resections. PMID- 27995089 TI - Current Status on Cholangiocarcinoma and Gallbladder Cancer. AB - BACKGROUND: Cholangiocarcinomas (CC) as well as gallbladder cancers are relatively rare and intractable diseases. Clinical, pathological, and epidemiological studies on these tumors have been under investigation. The current status and/or topics on biliary tract cancers have been reported in the East West Association of Liver Tumor (EWALT), held in Milano, Italy in 2015. SUMMARY: All the authors, herein, specifcally reported the current status and leading-edge findings on biliary tract cancers as the following sequence: epidemiology of CC, surgical therapy for intrahepatic CC, surgical therapy for perihilar CC, surgical therapy for gallblad der cancer, chemotherapy for biliary tract cancers, and new histological features in CC. KEY MESSAGE: The present review article will update the knowledge on biliary tract cancers, en hancing the quality of daily clinical practice. However, many features about these cancers remain unknown; further studies are required to establish disease-specific optimal treatment strategies. PMID- 27995090 TI - Colorectal Liver Metastases: A Critical Review of State of the Art. AB - BACKGROUND: Over 50% of patients with colorectal cancer will develop liver metastases. Only a minority of patients present with technically resectable disease. Around 40% of those undergoing surgical resection are alive five years after their diagnosis compared with less than 1% for those with disseminated disease treated with systemic chemotherapy. Surgical resection remains the only possibility for long-term survival for these patients and great efforts have been made to increase the rates of resection whilst improving long-term outcomes. SUMMARY: This review considers current technical and oncological criteria for resection, as well as targeted approaches to stratify underlying tumor biology in order to better predict long-term benefit. The role of neoadjuvant and perioperative systemic chemotherapy is critically reviewed, with suggestions for patient stratification in order to identify those who are likely to derive the greatest benefit. The key role of multidisciplinary assessment and decision making for these complex patients is also discussed. KEY MESSAGES: Surgery remains the optimal treatment for colorectal liver metastases (CRLM). Despite the curative intent of surgical resection, the majority of patients develop recurrence. Surgical strategies should therefore be adopted to maximize the potential for repeat resections in the event of recurrence. Although a number of preoperative prognostic markers have been identified, none are absolute contraindications to resection. In order to reduce postoperative recurrence, neo adjuvant chemotherapy is now the standard of care in a number of countries. The evidence base for this approach is contentious, and the potential benefit of such a strategy is likely to be greatest in patients with high oncological risk disease. Multidisciplinary care is essential to ensure the optimal management of these complex patients. In addition, all patients with CRLM should be discussed with specialist hepatobiliary surgeons. PMID- 27995091 TI - Recent Advances in Chemotherapy and Surgery for Colorectal Liver Metastases. AB - BACKGROUND: The liver is the most common site of metastases for colorectal cancer, and combined resection with systemic chemotherapy is the most effective strategy for survival. The aim of this article is to provide a comprehensive summary on four hot topics related to chemotherapy and surgery for colorectal liver metastases (CLM), namely: (1) chemotherapy-related liver injuries: prediction and impact, (2) surgery for initially unresectable CLM, (3) the emerging role of RAS mutations, and (4) the role of hepatic arterial infusion of chemotherapy (HAIC). SUMMARY AND KEY MESSAGES: (1) The use of chemotherapy before liver resection for CLM leads to drug-specific hepatic toxicity, which negatively impacts posthepatectomy outcomes. (2) Curative liver resection of initially unresectable CLM following conversion chemotherapy should be attempted whenever possible, provided that a safe future liver remnant volume is achieved. (3) For CLM, RAS mutation status is needed to guide the use of targeted chemotherapy with anti-epithelial growth factor receptor (EGFR) agents, and is a major prognostic factor that may contribute to optimize surgical strategy. (4) HAIC agents increase the rate of objective response and the rate of complete pathological response. PMID- 27995092 TI - Surgery of Colorectal Liver Metastases: Pushing the Limits. AB - BACKGROUND: The recent advent of more effective chemotherapy and the development of surgical procedures have expanded the pool of resectable patients with colorectal liver metastases (CLM). Two-stage hepatectomy (TSH), associated liver partition and portal vein ligation for staged hepatectomy (ALPPS), and ultrasound guided enhanced one-stage hepatectomy (e-OSH) are the surgical solutions proposed for these patients, but the range of indications for these procedures vary from institution to institution. SUMMARY: The advantages and disadvantages of each approach are herein discussed. Patients who drop out between the staged operations of TSH limit its success rate, although predictive scores may help with patient selection and thereby optimize the results. Safety and oncological suitability are concerns to be addressed when considering ALPPS. These concerns notwithstanding, ALPPS has introduced an innovative concept in surgery: the monosegmental remnant liver. Studies involving e-OSH have proven the oncological suitability of tumor exposure once the CLM is detached from major intrahepatic vessels. This finding could expand the indications for e-OSH, although the technical challenges that it entails limit its spread among the surgical community. The liver-first approach involves the clearance of tumors from the liver before the colorectal primary is tackled. This approach fully justifies the complexity of e-OSH. KEY MESSAGES: Predictive scores limiting the interstage dropout of TSH, partial and monosegmental ALPPS, and R1 vascular e-OSH justified by solid long-term results represent new insights that could help refne the patient assignment to each of these approaches. Additionally, liver transplantation is an emerging treatment for CLM that should be taken into account. PMID- 27995093 TI - New Perspectives in the Treatment of Colorectal Metastases. AB - BACKGROUND: In recent years, the management of metastatic colorectal cancer has become more aggressive and more multidisciplinary. New treatment options have been proposed in addition to the standard approach of resection of liver metastases and chemotherapy. SUMMARY: Selected patients with synchronous limited peritoneal and liver disease (peritoneal cancer index <12 and <3 liver metastases) can be scheduled for aggressive treatment, including cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and liver resection. This approach has achieved survival benefits, even if the treatment is unlikely to be curative in most patients. Moreover, liver transplantation has been recently reconsidered for liver-only metastases, resulting in the de facto reinstatement of the chance of surgery for some unresectable patients. Even though indications for liver transplantation remain to be standardized, preliminary studies have reported extremely promising outcomes. Radio-embolization has proven to be an effective additional tool for the treatment of unresectable tumors, and its potential role in association with chemotherapy for resectable disease is currently being investigated. Stereotactic body radiation therapy is a safe, non invasive, and effective therapeutic option for patients with inoperable oligometastatic disease. Thanks to recent technical progress, high radiation doses can now be delivered in fewer fractions with excellent local disease control and a low risk of radiation-induced liver injury. Finally, radiofrequency ablation (RFA) for colorectal metastases has become more effective, with results approaching those of surgical series. New interstitial treatments, such as microwave ablation and irreversible electroporation, could overcome some of the limitations of RFA, thereby further expanding indications and optimizing outcomes. KEY MESSAGES: Currently, a multidisciplinary approach to patients with colorectal liver metastases is mandatory. Aggressive surgical treatments should be integrated with all the available non-surgical options to maximize disease control and patient survival. PMID- 27995095 TI - Roles of the Putative Type IV-like Secretion System Key Component VirD4 and PrsA in Pathogenesis of Streptococcus suis Type 2. AB - Streptococcus suis type 2 (SS2) is a zoonotic pathogen causing septic infection, meningitis and pneumonia in pigs and humans. SS2 may cause streptococcal toxic shock syndrome (STSS) probably due to excessive release of inflammatory cytokines. A previous study indicated that the virD4 gene in the putative type IV like secretion system (T4SS) within the 89K pathogenicity island specific for recent epidemic strains contributed to the development of STSS. However, the functional basis of VirD4 in STSS remains unclear. Here we show that deletion of virD4 led to reduced virulence as shown by about 65% higher LD50, lower bacterial load in liver and brain, and lower level of expression of inflammatory cytokines in mice and cell lines than its parent strain. The DeltaVirD4 mutant was more easily phagocytosed, suggesting its role as an anti-phagocytic factor. Oxidative stress that mimic bacterial exposure to respiratory burst of phagocytes upregulated expression of virD4. Proteomic analysis identified 10 secreted proteins of significant differences between the parent and mutant strains under oxidative stress, including PrsA, a peptidyl-prolyl isomerase. The SS2 PrsA expressed in E. coli caused a dose-dependent cell death and increased expression of proinflammatory IL-1beta, IL-6 and TNF-alpha in murine macrophage cells. Our data provide novel insights into the contribution of the VirD4 factor to STSS pathogenesis, possibly via its anti-phagocytic activity, upregulation of its expression upon oxidative stress and its involvement in increased secretion of PrsA as a cell death inducer and proinflammatory effector. PMID- 27995097 TI - Monitoring the Presence of Domoic Acid in the Production Areas of Bivalve Molluscs. AB - Algal biotoxins, chemical compounds produced by some microscopic algae, constitute the phytoplankton. The mussels, feeding on phytoplankton, can accumulate these compounds to become themselves toxic. There have been several cases of food poisoning by consumption of contaminated shellfish. Such food poisoning have pushed our health care system to provide monitoring of shellfish in the framework of the monitoring plans carried out by AASSLL. In this paper we report the results obtained monitoring the presence of amnesic shellfish poisoning biotoxins, like domoic acid and its isomers, produced by Pseudonitzschia algae. The analyses were carried out by using both the high performance liquid chromatography-ultraviolet official method and an experimental method performed with a time-of-flight mass spectrometer (ESI-TOF). The 100% of samples analysed by the official method have always been below the limits of sensitivity (except one sample), and the 65% of samples analysed by ESI-TOF showed the presence of domoic acid. PMID- 27995096 TI - The Amino-Terminal Part of the Needle-Tip Translocator LcrV of Yersinia pseudotuberculosis Is Required for Early Targeting of YopH and In vivo Virulence. AB - Type III secretion systems (T3SS) are dedicated to targeting anti-host effector proteins into the cytosol of the host cell to promote bacterial infection. Delivery of the effectors requires three specific translocator proteins, of which the hydrophilic translocator, LcrV, is located at the tip of the T3SS needle and is believed to facilitate insertion of the two hydrophobic translocators into the host cell membrane. Here we used Yersinia as a model to study the role of LcrV in T3SS mediated intracellular effector targeting. Intriguingly, we identified N terminal lcrV mutants that, similar to the wild-type protein, efficiently promoted expression, secretion and intracellular levels of Yop effectors, yet they were impaired in their ability to inhibit phagocytosis by J774 cells. In line with this, the YopH mediated dephosphorylation of Focal Adhesion Kinase early after infection was compromised when compared to the wild type strain. This suggests that the mutants are unable to promote efficient delivery of effectors to their molecular targets inside the host cell upon host cell contact. The significance of this was borne out by the fact that the mutants were highly attenuated for virulence in the systemic mouse infection model. Our study provides both novel and significant findings that establish a role for LcrV in early targeting of effectors in the host cell. PMID- 27995098 TI - Evaluation of Hygienic Quality and Labelling of Fish Distributed in Public Canteens of Northeast Italy. AB - Over the past few years, the demand for the introduction of fish products in public canteens (schools, hospitals and nursing-homes) has grown due to their good nutritional proprieties. The particular health conditions and sensitivity of some groups of consumers exposes them to greater risks of food poisoning. It is therefore important to monitor the raw materials that end up in mass catering implementing strategies of mass catering control, both with self-monitoring strategies and with regular controls performed by the competent health authorities. The purpose of this study is to assess the overall quality of seafood dealt out from public catering services located in Northeast Italy. In this paper we illustrate the results of microbiological analysis performed on 135 fish samples (58% of samples were raw fishes, 27% cooked fishes, 6% raw fish products, 9% cooked fish products) and species identification performed on 102 fish samples. Additionally, 135 environmental swabs were collected to determine the effectiveness of cleaning and sanitation of food contact (cutting boards, cooking equipment and food processing surfaces) and non-contact (refrigerator wall and handle, tap lever) surfaces. Of raw seafood samples, 24% had total aerobic mesophilic bacteria count >105 CFU/g and for Enterobacteriaceae the faecal contamination was excluded since no Salmonella spp. and Escherichia coli were isolated. Just 3.8% of raw seafood samples resulted positive for Listeria monocytogenes. The results of swab samples of cooking utensils and surfaces showed that sanitation practices should be improved. Molecular analysis for fish species identification revealed a mislabelling for 25% of sampled fishes. The results of this survey can provide valuable information for monitoring and surveillance programmes for the control of quality of fish and fish products. PMID- 27995099 TI - Mislabelling of Doner Kebab Sold in Italy. AB - The aim of this study was to assess whether Doner kebabs sold in Italy comply with legal labelling requirements. A checklist of EU labelling requirements was drawn up and nine labels of Doner kebab marketed in the province of Modena were collected to evaluate the mandatory information laid down in article 9 of Regulation (EU) No 1169/2011 together with the mandatory requirements of Regulation (EC) 853/2004 for meat preparations. The study showed that different additives are commonly used in Doner kebabs, including E 621 (monosodium glutamate). This additive is not included among the ingredients authorized for the meat preparation food category. Eight frozen Doner kebab samples were taken and a visual assessment and a histologic examination were performed to verify potential changes in the meat's inner muscle fibre structure that could allow the product to be considered among meat preparations or meat products. The Doner kebab labels showed several systematically deficient regulatory requirements in both extrinsic defects (not related to food composition) and aspects concerning the protection of consumers' health. Histological examination showed that the tissue was moderately swollen, but the muscle fibre structure was intact. Kebab can be reasonably classified as a meat preparation thereby precluding the use monosodium glutamate (E 621) as an ingredient. PMID- 27995094 TI - The Cytolethal Distending Toxin Contributes to Microbial Virulence and Disease Pathogenesis by Acting As a Tri-Perditious Toxin. AB - This review summarizes the current status and recent advances in our understanding of the role that the cytolethal distending toxin (Cdt) plays as a virulence factor in promoting disease by toxin-producing pathogens. A major focus of this review is on the relationship between structure and function of the individual subunits that comprise the AB2 Cdt holotoxin. In particular, we concentrate on the molecular mechanisms that characterize this toxin and which account for the ability of Cdt to intoxicate multiple cell types by utilizing a ubiquitous binding partner on the cell membrane. Furthermore, we propose a paradigm shift for the molecular mode of action by which the active Cdt subunit, CdtB, is able to block a key signaling cascade and thereby lead to outcomes based upon programming and the role of the phosphatidylinositol 3-kinase (PI-3K) in a variety of cells. Based upon the collective Cdt literature, we now propose that Cdt is a unique and potent virulence factor capable of acting as a tri-perditious toxin that impairs host defenses by: (1) disrupting epithelial barriers; (2) suppressing acquired immunity; (3) promoting pro-inflammatory responses. Thus, Cdt plays a key role in facilitating the early stages of infection and the later stages of disease progression by contributing to persistence and impairing host elimination. PMID- 27995100 TI - The efficacy of fibrin glue injection in the prostatic fossa on decreasing postoperative bleeding following transurethral resection of prostate. AB - BACKGROUND: To evaluate the efficacy of fibrin glue injection in the prostatic fossa at the end of transurethral resection of prostate (TURP), in decreasing postoperative bleeding in patient with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In this prospective randomized clinical trial, sixty patients with BPH, who were a candidate for TURP, were randomly divided into two equal groups. In the intervention group, 10cc of fibrin glue was injected in the prostatic fossa at the end of the surgery; through a 5 Fr feeding tube attached to Foley catheter and its tip was proximal to the balloon of catheter. The other thirty patients created the control group. Hemoglobin (Hb) level and lower urinary tract symptoms (LUTS) score were recorded before and 6, 24, 48 h, and 5 days after TURP. RESULTS: The mean age of the patients and prostate volumes were comparable between the groups. The mean Hb level before and 6 h after TURP were not different between the two groups, however, 24 and 48 h and 5 days after TURP, there was a significant difference as well as a higher decrease in the mean Hb level of the control group (P = 0.023). The mean LUTS score was not statistically different between the two groups. CONCLUSION: Fibrin glue injection in the prostatic after TURP reduces postoperative bleeding without any effect on LUTS score in patients with BPH. PMID- 27995102 TI - A simple and sensitive high-performance liquid chromatography method for determination of ciprofloxacin in bioavailability studies of conventional and gastroretentive prolonged-release formulations. AB - BACKGROUND: A very simple, sensitive, and accurate high-performance liquid chromatography (HPLC) method with ultraviolet detector was developed and applied to determine ciprofloxacin in human plasma following administration of a gastroretentive formulation developed in our laboratory. MATERIALS AND METHODS: HPLC analysis was performed on a C18 MU-Bondapack column (250 mm * 3.9 mm) using acetonitrile: potassium dihydrogen phosphate solution 0.1 M (20:80, v/v, pH 3) at a flow rate of 1.5 ml/min and eluate was monitored at 276 nm. After addition of phenacetin as internal standard, plasma samples were treated with 0.1 M phosphate buffer (pH: 7) and followed by extraction with dichloromethane. The method was validated for linearity, precision, accuracy, limit of quantitation (LOQ), robustness, stability, and applied in bioavailability studies of our developed gastroretentive formulation in healthy volunteers. RESULTS: The calibration curves were linear over the concentration range 0.025-4 MUg/ml with the detection limit of 15 ng/ml. Accuracy % were within 93-115 and the coefficient of variance % ranged from 0.20 to 12.8. The very low LOQ (25 ng/ml) allowed avoiding fluorometric detection which is more expensive and is not available in all laboratories. Ciprofloxacin was stable in samples with no evidence of degradation during 3 freeze-thaw cycles and 3 months storage at -70 degrees C. CONCLUSION: This validated HPLC method was successfully used for the determination of ciprofloxacin in human plasma following oral administration of controlled release formulation, conventional immediate-release tablets and when administered concomitantly with divalent and trivalent cations such as aluminum-, magnesium-, or calcium-containing products under which the bioavailability of ciprofloxacin is significantly reduced. PMID- 27995101 TI - A comparison of liquid-based cytology with conventional Papanicolaou smears in cervical dysplasia diagnosis. AB - BACKGROUND: Due to the high number of women affected by cervical cancer and the importance of an early diagnosis, combined with the frequent incidence of false negative Papanicolaou (Pap) smear screening results for this disease, several studies have been conducted in recent years in order to find better tests. Liquid based cytology (LBC) tests, including the liquid-based thin layer method, have demonstrated the highest potential for reducing false-negative cases and improved sample quality. This study aimed to compare the strength of the Pap smear test with fluid cytology and conventional tests in detecting cervical dysplasia. MATERIALS AND METHODS: This descriptive-analytic study was conducted on 366 women who attended private laboratories for a Pap smear. The Pap smear sampling was conducted simultaneously using two methods: conventional Pap (CP) smear and LBC), from the cervix. RESULTS: The mean age of the participants was 32 +/- 8.8 years. Diagnostic results of endocervical cells, epithelial cells, vaginitis cells, and metaplastia were consistent with both conventional and liquid cytology smears, and the kappa coefficient was determined to be significant (P < 0.001). In total, 40.5% of diagnostic cases indicated bacterial inflammation 80.3% of the diagnoses in both methods were P1 and 3.9% of cases diagnosed were P2, the overall diagnostic consistency was 83.9% between the two sampling methods. The inflammation diagnosis was 40.5% and this was consistent in both methods of LBC and CP. There was one case of a false-negative diagnosis in the LBC method and 14 cases in the CP method. CONCLUSION: Results showed that the LBC may improve the sample's quality and reduce the number of unsatisfactory cases more than with the CP method. PMID- 27995103 TI - PROTAMINE1 and PROTAMINE2 genes expression in the sperms of oligoasthenospermic individuals and intrauterine insemination candidates couples: Is there any significant differences? AB - BACKGROUND: Male infertility refers to a male's inability to cause pregnancy in a fertile female. It seems the large portion of this category of infertility, has roots in genetic factors. PROTAMINE family is one of the most important genes which are involved in male factor infertility. Hence, the aim of this study is to evaluate PROTAMINE1 and PROTAMINE2 (P1 and P2) genes expression in oligoasthenospermic individuals and intrauterine insemination (IUI) candidate couples' sperms. MATERIALS AND METHODS: Samples were gathered from the patients referred to the Isfahan Infertility Center of Shahid Beheshti, 80 semen samples were in IUI candidates groups and 16 semen samples were in oligoasthenospermia group was collected. The outcome of IUI procedure was followed up after 14 days. Through these samples, 16 couples achieved pregnancy (IUI+) and from the top of the list, 16 semen samples with negative beta-HCG were obtained (IUI-). After RNA extraction from sperms, PROTAMINE genes family expression was evaluated in our three groups by real time-reverse transcription polymerase chain reaction. RESULTS: Our study revealed that P1 gene expression has no significant differences between IUI-, IUI+, and oligoasthenospermia groups, whereas P2 gene expression showed significant differences between oligoasthenospermia with two IUI groups. Main sperm parameters have no significant differences between IUI groups. CONCLUSION: This study reveals P1 and P2 genes expression value have no significant differences between IUI- and IUI+. On the other hand, P2 gene expression value has significant differences between oligoasthenospermia with two IUI groups. PMID- 27995104 TI - Myocardial capillary density after neuropeptide Y antagonist administration in normal and high-fat diet C57BL6 mice. AB - BACKGROUND: Neuropeptide Y (NPY), a 36 amino acid peptide, has several effects on cardiovascular system. It is demonstrated that the angiogenic activity of NPY is similar to fibroblast growth factor and vascular endothelial growth factor (VEGF). The aim of this study was to evaluate the effect of systemic administration of antagonist of NPY receptor (BIIE0742) on coronary angiogenesis in normal and diet-induced obese animals. MATERIALS AND METHODS: Twenty-four male mice were received high-fat diet (HFD) or normal diet (ND) for 14 weeks. Then, each group was randomized to the treatment of antagonist of NPY receptor (BIIE0246) or saline as following: ND+ BIIE0246 (100 MUl/kg; i.p.), ND+ saline, HFD+ BIIE0246, HFD+ saline. After 14 days, blood samples were taken, and myocardial tissue (left ventricle) from all experimental groups was evaluated by immunohistochemistry. RESULTS: Serum VEGF concentration and VEGF: Soluble VEGF receptor (sVEGFR)-1 ratio in obese animals was higher than normal group. Administration of BIIE0246 significantly reduced serum VEGF and VEGF: sVEGFR-1 ratio and increased serum sVEGFR-1 concentrations in obese animals (P < 0.05). In normal animals, BIIE0246 increased serum sVEGFR-1 level and decreased VEGF: sVEGFR-1 ratio. Serum nitrite did not alter after administration of BIIE0246 in both groups (P > 0.05). Myocardial capillary density expressed as the number of CD31 positive cells/mm2 was reduced after NPY antagonist treatment in obese and normal animals (P > 0.05). CONCLUSION: Administration of NPY antagonist impairs myocardial capillary density, reduces angiogenic factors and elevates anti angiogenic factors, and there are no differences between obese and normal animals. PMID- 27995105 TI - Electrical stimulation of prelymbic with different currents intensities on morphine induced spatial memory deficit in rats. AB - BACKGROUND: The medial prefrontal cortex (mPFC) is a part of brain reward system involved in cognitive functions such as learning and memory. Previous studies showed that electrical stimulation of prelymbic produced different effects on morphine-induced condition place preference. In this study, we investigated the electrical stimulation with different current intensities on spatial memory in rats. MATERIALS AND METHODS: In this study, male Wister rats weighing approximately 200-300 g were used. The effect of prelymbic electrical stimulation with 25 and 150 MUA currents intensities in healthy and addicted rats on spatial memory was studied. Spatial memory was investigated using the Morris water maze test in addicted rats after 9 days of electrical stimulation. RESULTS: Our findings have shown that morphine reduces the memory and learning, whereas the present results indicated that electrical stimulation of prelymbic area with current intensity of the 25 MUA shortened the time and distance to reach to platform that indicated improvement in spatial memory on addicted rats. Whereas the electrical stimulation of prelymbic area with the current intensity of 150 MUA has special weakening effects on spatial memory and prolongs the time and distance to reach the platform. CONCLUSIONS: The electrical stimulations of prelymbic with 25 MUA current intensity improved the spatial memory in addicted rats while with 150 MUA current intensity weakened spatial memory in rats. It is possible that increase in the release of some neurotransmitters reverses the effect of morphine on spatial memory. PMID- 27995106 TI - Comparing prophylactic effect of phenylephrine and ephedrine on hypotension during spinal anesthesia for hip fracture surgery. AB - BACKGROUND: Spinal anesthesia is an accepted technique in hip fracture surgery and prevention of this complication by sympathomimetic agents is of potential clinical significance. The aim of this study is to compare the effect of prophylactic phenylephrine versus ephedrine in the prevention of hypotension during spinal anesthesia in hip fracture surgery. MATERIALS AND METHODS: Ninety two patients undergoing hip fracture surgery with the American Society of Anesthesiologists I and II were randomized to receive prophylaxis with ephedrine or phenylephrine immediately before the spinal anesthesia. Patients in the ephedrine group received an intravenous (IV) bolus of 10 mg ephedrine, and patients in the phenylephrine group received an IV bolus of 50 MUg phenylephrine. We recorded mean arterial pressure (MAP), systolic and diastolic blood pressure, heart rate every 3 min in the first 10 min and then every 5 min until 30 min after spinal anesthesia, nausea and vomiting, additional vasopressor, and atropine administration. RESULTS: The frequency of hypotension was significantly lower in MAP, systolic and diastolic pressure in group phenylephrine in 3, 6, and 9 min after spinal anesthesia (P = 0.002, P = 0.001). There were no significant differences between two groups in heart rate at different time of study. In the phenylephrine group, lower additional vasopressor was used (8.7% and 23.9%) (P = 0.04). There were no significant differences between two groups in the use of atropine (P = 0.24), nausea and vomiting. CONCLUSION: At the doses of ephedrine and phenylephrine administered in this trial, phenylephrine was better to prevent hypotension during hip fracture surgery with spinal anesthesia. Higher frequency of hypotension was observed in the ephedrine group. PMID- 27995107 TI - Evaluating the effectiveness of adding magnesium chloride to conventional protocol of citrate alkali therapy on kidney stone size. AB - BACKGROUND: Potassium citrate (K-Cit) is one of the therapeutic solutions broadly used in patients with urolithiasis. However, recent studies have shown that it is not so effective. Therefore, the goal of our study was to evaluate the effect of a combination of K-Cit - MgCl2 oral supplements, on urinary stone size. MATERIALS AND METHODS: This study was performed on 70 asymptomatic urolithiasis cases. The supplements included K-Cit and magnesium chloride (MgCl2), purchased from (Merck Company, Germany). The patients were randomly divided into two groups. The urinary stone size was measured in the control group after prescribing K-Cit alone and the treated group with combination of K-Cit and MgCl2 for 4 weeks by ultrasonography and also urinary parameter was measured in each groups. RESULTS: The mean age of patients was 16.26 +/- 5.70 years. Hyperoxaluria and hypercalciuria were seen in 70% and 52% of patients, respectively. Initially, the mean urinary stone size was measured in each groups and there is not any significant different. However, we find a significant decrease in urinary stone size in group which is treated with combination of K-Cit and MgCl2 for 4 weeks in comparison with control group treated with K-Cit alone in the same duration of therapeutic course (5.1 +/- 0.8 vs. 2.5 +/- 1.2, P < 0.05). All ultrasonography were performed by one radiologist and device. CONCLUSION: Our results suggested that a combination of K-Cit and MgCl2 chloride is more effective on decreasing urinary stone size than K-Cit alone. PMID- 27995108 TI - Operative management of acetabular fracture: A 10-year experience in Isfahan, Iran. AB - BACKGROUND: Pelvic and acetabular fractures constitute 2% of all fractures. The aim of the present study was to present acetabular fracture outcome in patients who underwent operative treatment. MATERIALS AND METHODS: This study was a prospective cohort study, which was performed in Isfahan, Iran. During the period study, all patients who admitted to Alzahra Hospital with acetabular fracture and underwent acetabular surgery were evaluated. Data about age, sex, associated fractures, Intensive Care Unit admission, the time between admission and surgery were gathered. Patients were encouraged to return to the hospital after 1 week, 4 weeks, 6 months, and then yearly for the follow-up. RESULTS: Sixty-five patients with acetabular fractures were referred to our hospital. Of them, 30 patients were indicated for surgical intervention and recruited in the study. The most frequent type of fracture involved posterior wall accounting for 49.9% of all fractures. More than 80% of study patients reached satisfactory results (excellent or good) based on Harris Hip Score (HHS). Female patients had significantly lower HHS in comparison with male patients (P = 0.01). Heterotopic ossification (HO) formation was more common in whom surgery was performed after 2 weeks (P = 0.005), however, there was no significant difference in HHS between these groups (P = 0.28). CONCLUSIONS: It is concluded that the female gender had an impact on the surgical outcome of acetabular fracture and indicated the lower functional outcome. Although there is an increase in HO formation in patients who do not undergo surgery during 2 weeks after the trauma, however, it does not influence the surgical outcome. PMID- 27995109 TI - Chitosan-myristate nanogel as an artificial chaperone protects neuroserpin from misfolding. AB - BACKGROUND: Molecular chaperon-like activity for protein refolding was studied using nanogel chitosan-myristic acid (CMA) and the protein neuroserpin (NS), a member of the serine proteinase inhibitor superfamily (serpin). MATERIALS AND METHODS: Recombinant his-tag fusion NS was expressed in Escherichia coli. For confirmation of refolding of the purified NS, structural analysis was performed by circular dichroism and spectrofluorometric along with its inhibitory activity, which was assayed by single-chain tissue plasminogen activator. For evaluating NS aggregation during preparation, the samples were separated on a 7.5% (w/v) nondenaturing polyacrylamide gel electrophoresis. MA and chitosan covalently join together by the formation of amide linkages through the 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide-mediated reaction. The morphology and size of the prepared CM nanogel were characterized by transmission electron microscopy and scanning electron microscopy. RESULTS: Heating at different temperatures (25 degrees C, 37 degrees C, 45 degrees C, 65 degrees C, 80 degrees C) results in a further rise in beta-structures accompanied by a fall of helices and no significant change in random coils. Structural changes in NS in the presence of CMA nanogel were less than that in the absence of CMA nanogel. Mater nanogel effectively prevented aggregation of NS during temperature induced protein refolding by the addition of cyclodextrins. The nanogel activity resembled the host-guest chaperon activity. CONCLUSION: These conditions, called conformational disorders, include Alzheimer's, Parkinson's, Huntington's disease, the transmissible spongiform encephalopathies, prion diseases, and dementia. Nanogels can be useful in recovery of the structural normality of proteins in these diseases. PMID- 27995110 TI - Prostate cancer screening with prostate-specific antigen: A guide to the guidelines. AB - BACKGROUND: Prostate cancer remains the most common non-skin cancer malignancy in men. Prostate-specific antigen (PSA) is recognized as a biomarker for the diagnosis, monitoring, and risk prediction of prostate cancer. Its use in the setting of prostate cancer screening has been controversial due to the risk of over diagnosis and over treatment. OBJECTIVE: Within Australia, there are inconsistent recommendations surrounding the use of PSA screening in clinical practice. In light of the 2016 PSA-screening guidelines by the major Australian health authorities, the current review aims to highlight the controversies and objectively outline the current recommendations within Australia. DISCUSSION: Health-care authorities across Australia have issued conflicting guidelines for prostate cancer screening culminating in confusion amongst health care practitioners and members of the public alike. A general consensus is held by other countries across the globe but differences amongst the specific details in how to best employ a PSA screening program still exist. PMID- 27995111 TI - Prostate cancer biomarkers: Are we hitting the mark? AB - PURPOSE: Localised prostate cancer diagnosis and management is increasingly complex due to its heterogeneous progression and prognostic subgroups. Pitfalls in current screening and diagnosis have prompted the search for accurate and invasive molecular and genetic biomarkers for prostate cancer. Such tools may be able to distinguish clinically significant cancers from less aggressive variants to assist with prostate cancer risk stratification and guide decisions and healthcare algorithms. We aimed to provide a comprehensive review of the current prostate cancer biomarkers available and in development. METHODS: MEDLINE and EMBASE databases searches were conducted to identify articles pertaining to the use of novel biomarkers for prostate cancer. RESULTS: A growing number of novel biomarkers are currently under investigation. Such markers include urinary biomarkers, serology-based markers or pathological tissue assessments of molecular and genetic markers. While limited clinical data is present for analysis, early results appear promising. Specifically, a combination of serum and urinary biomarkers (Serum PSA + Urinary PCA3 + Urinary TMPRSS2-ERG fusion) appears to provide superior sensitivity and specificity profiles compared to traditional diagnostic approaches (AUC 0.88). CONCLUSION: The accurate diagnosis and risk stratification of prostate cancer is critical to ensure appropriate intervention. The development of non-invasive biomarkers can add to the information provided by current screening practices and allows for individualised risk stratification of patients. The use of these biomarkers appears to increase the sensitivity and specificity of diagnosis of prostate cancer. Further studies are necessary to define the appropriate use and time points of each biomarker and their effect on the management algorithm of prostate cancer. PMID- 27995112 TI - Primary care follow-up of radical prostatectomy patients: A regional New Zealand experience. AB - BACKGROUND: Contemporary recommendations regarding the duration of follow-up after radical prostatectomy (RP) are highly heterogeneous. Protocol-based follow up schemes have been implemented to facilitate the expeditious identification of patients with recurrence. The aim of this study is to assess the reliability and comfort of general practitioners (GPs) in follow-up of RP. METHODS: Following institutional ethical approval, we performed a retrospective review in patients undergoing follow-up after RP between January 2004 and December 2010. Patient factors, disease variables, and follow-up prostate specific antigen (PSA) compliance was collected. "Noncompliant" follow-up care was defined as: patients that had not received a PSA for a 14 month period within 5 years of prostatectomy. Patient and disease-based risk factors for noncompliant follow-up were assessed. GPs were also surveyed in their follow-up practice of RP patients, to assess their familiarity in caring for these patients. RESULTS: In total, 65 cases were identified that met the inclusion criteria. At 60 months of follow-up, 66% (43/65) of patients had a compliant follow-up regime. For patients with noncompliant follow-up at 60 months, median time of compliance did not differ significantly when assessing preoperative PSA, Gleason sum, extraprostatic extension, or surgical margin status. Of the GPs surveyed, 68% of GPs felt comfortable in follow-up of RP patients. Some 62% of GPs would expect the PSA to be < 0.1 and 25% of GPs would measure the PSA annually. CONCLUSION: Our study identified that follow-up by GPs after RP is insufficient. Accordingly, there is a requirement for formal educational programs if primary care is to take a greater role in follow-up of these patients. PMID- 27995113 TI - Feasibility of classical secondary hormonal therapies prior to docetaxel therapy in Japanese patients with castration-resistant prostate cancer: Multicenter retrospective study. AB - BACKGROUND: We retrospectively analyzed castration-resistant prostate cancer (CRPC) patients treated with secondary hormonal therapies (SHTs) prior to docetaxel therapy. METHODS: The cases of 73 CRPC patients who underwent docetaxel therapy in 2005-2011 at four hospitals in Ibaraki, Japan were analyzed. We determined the cause-specific survival (CSS) from the start of docetaxel therapy and the time point of CRPC diagnosis, and we compared the CSS achieved with/without prior classical SHTs, which were defined as low-dose steroid and estramustine phosphate. RESULTS: Of the 73 enrolled patients, 26 underwent docetaxel therapy (DOC group), and 47 underwent SHTs (SHTs-DOC group) as the initial treatment for CRPC. In the docetaxel therapy, the rate of prostate specific antigen responses were higher in the DOC group compared with the SHTs DOC group (76.9% vs. 44.7%, P = 0.0066). The median CSS from the docetaxel therapy initiation was not significant but longer in the DOC group than in the SHTs-DOC group (23.4 months vs. 16.6 months, P = 0.0969). However, the median CSS from the time of CRPC diagnosis did not significantly differ between the DOC and SHTs-DOC groups (23.4 months vs. 24.7 months, P = 0.9233). In a univariate analysis, pain and visceral metastasis appeared to be risk factors for the CSS in the SHTs-DOC group. The patients with pain and/or visceral metastasis had significantly poorer survival than those without these factors in the SHTs-DOC group (31.5 months vs. 16.8 months, P = 0.0053). CONCLUSION: The induction of SHTs prior to docetaxel therapy is an acceptable treatment option with some survival benefits for CRPC patients without pain and visceral metastases. PMID- 27995114 TI - Gleason group concordance between biopsy and radical prostatectomy specimens: A cohort study from Prostate Cancer Outcome Registry - Victoria. AB - BACKGROUND: A new prostate cancer (PCa) prognostic grading system [Gleason groups (GGs)] has been proposed based on the contemporary Gleason scores (GSs), which has five simplified prognostic categories. The objective of this study was to evaluate the agreement between the GGs of prostate biopsy and radical prostatectomy specimens and to identify predictive factors for upgrading GGs. METHODS: A total of 5339 cases of RP notified to the Prostate Cancer Outcomes Registry, Victoria, Australia over 6 years (2009-2014) from 46 hospitals, were included. The upgrading was evaluated using the new PCa prognostic grading system, the International Society of Urologic Pathology grade groups, which has five prognostic categories. GG 1 is GS <= 6, GG 2 is GS 3 + 4 = 7, GG 3 is GS 4 + 3 = 7, GG 4 is GS 8, and GG 5 is GS 9 and 10. Predictors of upgrading were assessed using univariate and multivariate models. RESULTS: The GG of prostate biopsies and RP specimens were concordant in 54.5% of cases, while 31.1% were upgraded and 14.3% were downgraded. Longer time interval between biopsy and RP [44-99 days: odds ratio (OR) = 1.3, 95% confidence interval (CI) = 1.1-1.6; > 99 days: OR = 3.0, 95% CI = 2.4-3.8), and RP performed in a metropolitan hospital (biopsy in a regional hospital: OR = 2.2, 95% CI = 1.6-3.2, biopsy in a metropolitan hospital: OR = 1.7, 95% CI = 1.2-2.2) were significant predictors of GG upgrading. Patients who were diagnosed by transperineal biopsy compared to transrectal ultrasound (OR = 0.6, 95% CI = 0.5-0.8) and higher percentage of positive biopsy cassettes (25-62.5%: OR = 0.7, 95% CI = 0.6-0.8, > 62.5: OR = 0.6, 95% CI = 0.5-0.8) were significantly associated with less likelihood of upgrade. CONCLUSION: The lack of concordance among hospitals may be attributable to the specialist expertise of the pathologist. Expert review of specimens may help to overcome this discordance. Clinicians should consider clinical parameters and potential limitations of the GG at biopsy when making treatment decisions with regard to PCa. PMID- 27995115 TI - Impact of Gleason Pattern 5 on outcomes of patients with prostate cancer and iodine-125 prostate brachytherapy. AB - BACKGROUND: The Gleason grading system is a powerful predictor of prostate cancer (PCa) prognosis. Gleason scores (GS) of 8-10 are considered as a single high-risk grade category, and Gleason Pattern 5 (GP5) predicts biochemical recurrence. We report the clinical outcomes of patients treated with 125I prostate brachytherapy for clinically localized PCa and prognosis in the presence or absence of GP5. METHODS: We enrolled 316 patients with T1c-T2N0M0 PCa and undergoing prostate brachytherapy treatment. All patients were followed up for >= 1 year. The primary endpoint was biochemical recurrence-free survival. Biochemical recurrence was defined by the Phoenix criteria. Survival curves were calculated by the Kaplan Meier method, and the prognostic impact of biochemical recurrence was analyzed using a Cox proportional hazards model. RESULTS: The 5-year biochemical recurrence-free survival rate for all patients was 95.2%, and according to the D'Amico risk classification criteria, the rates were 98.7% for patients in low risk, 96.9% in intermediate-risk, and 81.1% in high-risk groups (P < 0.0001). The 5-year biochemical recurrence-free survival rates for patients with GS8 or GS9-10 were 87.7% and 61.5%, respectively (P = 0.0057). Multivariate analysis found that GS and clinical T stage were independent predictors of biochemical recurrence. CONCLUSIONS: The presence of GP5 in GS9-10 prostate cancer has a worse prognosis than GS8 prostate cancer in the absence of GP5 for patients undergoing prostate brachytherapy. PMID- 27995116 TI - Studying the effect of type 2 diabetes mellitus on prostate-related parameters: A prospective single institutional study. AB - BACKGROUND: To examine the effects of type 2 diabetes mellitus (DM) on the variables associated with prostatic growth including serum prostate-specific antigen (PSA), serum testosterone, and prostate volume, and to correlate these variables with the duration of diabetes treatment. METHODS: Our study was conducted over 3 months recruiting 501 men aged >= 55 years; of whom 207 had type 2 DM. Exclusion criteria were active urinary tract infection, suspicious rectal examination, urologic cancer, end-organ damage, and recent urological manipulations. Serum PSA and serum testosterone were measured. Prostate volume was determined by abdominal ultrasonography using an ellipsoid formula. RESULTS: The mean patient age was 60.21 +/- 5.95 years. The mean PSA, testosterone, and prostate volume for diabetic men were 2.3 ng/mL, 3 ng/mL, and 56 g, respectively. The corresponding values for nondiabetic men were 3.5 ng/mL, 4 ng/mL, and 51 g, respectively (P = 0.001, P = 0.001, P = 0.03, respectively). The mean PSA density was 0.049 +/- 0.043 ng/mL/cm3 in diabetics versus 0.080 +/- 0.056 ng/mL/cm3 in non-diabetics (P < 0.001). CONCLUSION: Type 2 DM is significantly associated with lower serum PSA and testosterone, and larger prostate volume. PMID- 27995117 TI - Utility of sodium tetradecyl sulfate sclerotherapy from benign oral vascular lesion. AB - BACKGROUND: Hemangioma and vascular malformation are benign vascular lesions that often occur in cephalic and cervical region. Currently, surgical resection, laser therapy, angiographic embolization, use of steroids, and sclerotherapy are used as treatments. CASE PRESENTATION: This study reports three cases of benign vascular lesions that are remarkably treated by sodium tetradecyl sulfate (STS) injection, of which occurred in oral cavity and around the mouth. Three percent of STS was diluted with 0.9 % of normal saline, and it was injected to the lesion site at least once. The result of treatment was evaluated based on clinical findings. CONCLUSION: Surgical treatment of hemangioma and vascular malformation occurred in oral cavity is not normally used because of esthetic issues and potential hemorrhage. On the other hand, sclerotherapy using STS is an effective therapy compare to surgical treatment. Despite the number of STS injection was different for each patient, all three patients had reached satisfactory level through the treatment with gradual diminution of lesions. PMID- 27995118 TI - Use of mandibular chin bone for alveolar bone grafting in cleft patients. AB - BACKGROUND: We evaluated and compared the outcomes of different ossification processes in patients with alveolar cleft in whom correction was performed using endochondral bone graft or intramembranous bone graft. METHODS: The patients were divided into two groups: the endochondral bone (iliac bone or rib bone) graft group and the intramembranous bone (mandibular bone) graft group. Medical records and radiologic images of patients who underwent alveolar bone grafting due to alveolar cleft were analyzed retrospectively. Through postoperative and follow-up radiologic images, the height of the interdental bone septum was classified into four types based on the highest point of alveolar ridge. Then, the height of the interdental bone septum and the area of the bone graft were evaluated according to the type of bone graft. In addition, the occurrence of complications and the need for an additional bone graft, the result of postoperative orthodontic treatment, and the eruption of impacted teeth were investigated. RESULTS: Thirty patients were included in this study. There was no significant difference in the change of the interdental bone height and the area of the bone graft according to the type of bone. There was no significant difference in the success rate of the surgery according to the type of bone. One patient underwent an additional bone graft surgery during the follow-up period. CONCLUSIONS: The outcomes of alveolar bone grafting were not significantly different according to the type of bone graft. If appropriate to the size of the recipient site, the chin bone is a useful graft material in alveolar cleft, as is the iliac bone. PMID- 27995119 TI - Fibular flap for mandible reconstruction in osteoradionecrosis of the jaw: selection criteria of fibula flap. AB - BACKGROUND: Osteoradionecrosis is the most dreadful complication after head and neck irradiation. Orocutaneous fistula makes patients difficult to eat food. Fibular free flap is the choice of the flap for mandibular reconstruction. Osteocutaneous flap can reconstruct both hard and soft tissues simultaneously. This study was to investigate the success rate and results of the free fibular flap for osteoradionecrosis of the mandible and which side of the flap should be harvested for better reconstruction. METHODS: A total of eight consecutive patients who underwent fibula reconstruction due to jaw necrosis from March 2008 to December 2015 were included in this study. Patients were classified according to stages, primary sites, radiation dose, survival, and quality of life. RESULTS: Five male and three female patients underwent operation. The mean age of the patients was 60.1 years old. Two male patients died of recurred disease of oral squamous cell carcinoma. The mean dose of radiation was 70.5 Gy. All fibular free flaps were survived. Five patients could eat normal diet after operation; however, three patients could eat only soft diet due to loss of teeth. Five patients reported no change of speech after operation, two reported worse speech ability, and one patient reported improved speech after operation. The ipsilateral side of the fibular flap was used when intraoral soft tissue defect with proximal side of the vascular pedicle is required. The contralateral side of the fibular flap was used when extraoral skin defect with proximal side of the vascular pedicle is required. CONCLUSIONS: Osteonecrosis of the jaw is hard to treat because of poor healing process and lack of vascularity. Free fibular flap is the choice of the surgery for jaw bone reconstruction and soft tissue fistula repair. The design and selection of the right or left fibular is dependent on the available vascular pedicle and soft tissue defect sites. PMID- 27995120 TI - Tonsillectomy as prevention and treatment of sleep-disordered breathing: a report of 23 cases. AB - BACKGROUND: The paradigm of tonsillectomy has shifted from a treatment of recurrent throat infection to one of multi-discipline management modalities of sleep-disordered breathing (SDB). While tonsillectomy as a treatment for throat problems has been performed almost exclusively by otorhinolaryngologists, tonsillectomy as a part of the armamentarium for the multifactorial, multidisciplinary therapy of sleep-disordered breathing needs a new introduction to those involved in treating SDB patients. This study has its purpose in sharing a series of tonsillectomies performed at the Seoul National University Dental Hospital for the treatment and prevention of SDB in adult patients. METHODS: Total of 78 patients underwent tonsillectomy at the Seoul National University Dental Hospital from 1996 to 2015, and 23 of them who were operated by a single surgeon (Prof. Jin-Young Choi) were included in the study. Through retrospective chart review, the purpose of tonsillectomy, concomitant procedures, grade of tonsillar hypertrophy, surgical outcome, and complications were evaluated. RESULTS: Twenty-one patients diagnosed with SDB received multiple surgical procedures (uvulopalatal flap, uvulopalatopharyngoplasty, genioglossus advancement genioplasty, tongue base reduction, etc.) along with tonsillectomy. Two patients received mandibular setback orthognathic surgery with concomitant tonsillectomy in anticipation of postoperative airway compromise. All patients showed improvement in symptoms such as snoring and apneic events during sleep. CONCLUSIONS: When only throat infections were considered, tonsillectomy was a procedure rather unfamiliar to oral and maxillofacial surgeons. With a shift of primary indication from recurrent throat infections to SDB and emerging technological and procedural breakthroughs, simpler and safer tonsillectomy has become a major tool in the multidisciplinary treatment modality for SDB. PMID- 27995121 TI - Effect of low-level laser therapy on bisphosphonate-treated osteoblasts. AB - BACKGROUND: This study investigates the effect of alendronate-treated osteoblasts, as well as the effect of low-level laser therapy (LLLT) on the alendronate-treated osteoblasts. Bisphosphonate decreases the osteoblastic activity. Various treatment modalities are used to enhance the bisphosphonate treated osteoblasts; however, there were no cell culture studies conducted using a low-level laser. METHODS: Human fetal osteoblastic (hFOB 1.19) cells were treated with 50 MUM alendronate. Then, they were irradiated with a 1.2 J/cm2 low level Ga-Al-As laser (lambda = 808 +/- 3 nm, 80 mW, and 80 mA; spot size, 1 cm2; NDLux, Seoul, Korea). The cell survivability was measured with the MTT assay. The three cytokines of osteoblasts, receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF) were analyzed. RESULTS: In the cells treated with alendronate at concentrations of 50 MUM and higher, cell survivability significantly decreased after 48 h (p < 0.05). After the applications of low-level laser on alendronate treated cells, cell survivability significantly increased at 72 h (p < 0.05). The expressions of OPG, RANKL, and M-CSF have decreased via the alendronate. The RANKL and M-CSF expressions have increased, but the OPG was not significantly affected by the LLLT. CONCLUSIONS: The LLLT does not affect the OPG expression in the hFOB cell line, but it may increase the RANKL and M-CSF expressions, thereby resulting in positive effects on osteoclastogenesis and bone remodeling. PMID- 27995122 TI - Three-dimensional morphometric analysis of mandibule in coronal plane after bimaxillary rotational surgery. AB - BACKGROUND: The aim of this report is to present a new reference for aesthetic mandible surgery using three-dimensional cone-beam computed tomography-based treatment planning for orthognathic surgery which can be implemented in surgical planning and perioperative procedure. METHODS: To make an objective standard for evaluating aesthetic mandibular outline, we make an aesthetic scoring criteria with consideration of asymmetry, broad mandibular border line, and prominent mandibular angle. Two maxillofacial surgeons and two orthodontists rated their aesthetical evaluation from 1 to 5. Experimental group consisting of 47 female and 38 male patients who had rotational orthognathic two-jaw surgery from 2010 to 2011 were chosen according to aesthetic scoring done by two maxillofacial surgeons and two orthodontists. A high aesthetic score (>=16) means the facial contour is symmetric, with no broad and narrow aesthetic mandible frontal profiles. Control A group consisted of ten female and ten male patients who had no orthognathic surgery experience and low aesthetic score (<=10). Control B group consisted of ten female and ten male patients who had no orthognathic surgery experience and had anaesthetic mandibular frontal profile and a high aesthetic score (>=16). The three-dimensional image of the patient was taken from dental cone-beam CT (DCT) scanning (experimental group and control A group: 6 months DCT after surgery, control B group: 1st visit DCT). Each DCT was reformatted to reorient the 3D image using 3D analyzing program (OnDemand3D, cybermed Inc, CA, USA). After selection of 12 landmarks and the construction of reoriented horizontal, vertical, and coronal reference lines, 15 measurements were taken in 3D analysis of frontal mandibular morphology. Afterwards, horizontal and vertical linear measurements and angular measurements, linear ratio were obtained. RESULTS: Mean Go'Rt-Me'-Go'Lt angular measurement was 100.74 +/- 2.14 in female patients and 105.37 +/- 3.62 in male patients. These showed significant difference with control A group in both genders. Ratio of Go'Rt,Go'Lt Me' length to some linear measurements (ratio of Me'-Cd'RtCd'Lt to Me' Go'RtGo'Lt, ratio of Me'-Go' to Me'-Go'RtGo'Lt, ratio of Go'Rt-Go'Lt to Me' Go'RtGo'Lt) showed significant difference with control A group in both genders. CONCLUSION: This study was intended to find some standard measurement of mandible frontal view in 3D analysis of aesthetic patient. So, these potential measurement value may be helpful for orthognathic treatment planning to have more aesthetic and perspective outcomes. PMID- 27995124 TI - Selecting manuscript for publication. PMID- 27995123 TI - Evaluation of clinical outcomes of implants placed into the maxillary sinus with a perforated sinus membrane: a retrospective study. AB - BACKGROUND: The aim of this study was to evaluate the clinical outcomes of implants that were placed within the maxillary sinus that has a perforated sinus membrane by the lateral window approach. METHODS: We examined the medical records of the patients who had implants placed within the maxillary sinus that has a perforated sinus membrane by the lateral approach at the Department of Oral and Maxillofacial Surgery of Chonnam National University Dental Hospital from January 2009 to December 2015. There were 41 patients (male:female = 28:13). The mean age of patients was 57.2 +/- 7.2 years at the time of operation (range, 20-76 years). The mean follow-up duration was 2.1 years (range, 0.5-5 years) after implant placement. Regarding the method of sinus elevation, only the lateral approach was included in this study. RESULTS: Ninety-nine implants were placed in 41 patients whose sinus membranes were perforated during lateral approach. The perforated sinus membranes were repaired with a resorbable collagen membrane. Simultaneous implant placements with sinus bone grafting were performed in 37 patients, whereas delayed placements were done in four patients. The average residual bone height was 3.4 +/- 2.0 mm in cases of simultaneous implant placement and 0.6 +/- 0.9 mm in cases of delayed placement. Maxillary bone graft with implant placement, performed on the patients with a perforated maxillary sinus membrane did not fail, and the cumulative implant survival rate was 100%. CONCLUSIONS: In patients with perforations of the sinus mucosa, sinus elevation and implant placement are possible regardless of the location and size of membrane perforation. Repair using resorbable collagen membrane is a predictable and reliable technique. PMID- 27995125 TI - Probing the Interaction between Nanoparticles and Lipid Membranes by Quartz Crystal Microbalance with Dissipation Monitoring. AB - There is increasing interest in using quartz crystal microbalance with dissipation monitoring (QCM-D) to investigate the interaction of nanoparticles (NPs) with model surfaces. The high sensitivity, ease of use and the ability to monitor interactions in real-time has made it a popular technique for colloid chemists, biologists, bioengineers, and biophysicists. QCM-D has been recently used to probe the interaction of NPs with supported lipid bilayers (SLBs) as model cell membranes. The interaction of NPs with SLBs is highly influenced by the quality of the lipid bilayers. Unlike many surface sensitive techniques, by using QCM-D, the quality of SLBs can be assessed in real-time, hence QCM-D studies on SLB-NP interactions are less prone to the artifacts arising from bilayers that are not well formed. The ease of use and commercial availability of a wide range of sensor surfaces also have made QCM-D a versatile tool for studying NP interactions with lipid bilayers. In this review, we summarize the state-of-the-art on QCM-D based techniques for probing the interactions of NPs with lipid bilayers. PMID- 27995126 TI - Discriminability of Single and Multichannel Intracortical Microstimulation within Somatosensory Cortex. AB - The addition of tactile and proprioceptive feedback to neuroprosthetic limbs is expected to significantly improve the control of these devices. Intracortical microstimulation (ICMS) of somatosensory cortex is a promising method of delivering this sensory feedback. To date, the main focus of somatosensory ICMS studies has been to deliver discriminable signals, corresponding to varying intensity, to a single location in cortex. However, multiple independent and simultaneous streams of sensory information will need to be encoded by ICMS to provide functionally relevant feedback for a neuroprosthetic limb (e.g., encoding contact events and pressure on multiple digits). In this study, we evaluated the ability of an awake, behaving non-human primate (Macaca mulatta) to discriminate ICMS stimuli delivered on multiple electrodes spaced within somatosensory cortex. We delivered serial stimulation on single electrodes to evaluate the discriminability of sensations corresponding to ICMS of distinct cortical locations. Additionally, we delivered trains of multichannel stimulation, derived from a tactile sensor, synchronously across multiple electrodes. Our results indicate that discrimination of multiple ICMS stimuli is a challenging task, but that discriminable sensory percepts can be elicited by both single and multichannel ICMS on electrodes spaced within somatosensory cortex. PMID- 27995129 TI - Biometric monitoring in silicosis to detect early disease and monitor lung injury: not quite there. AB - Biomonitoring of artificial stone-exposed workers http://ow.ly/Ut4J304amUr. PMID- 27995128 TI - Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy. AB - RATIONALE: Barriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features. METHODS: Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1 4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal-Wallis test. RESULTS: No adverse events were noted. TPM concentration-time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20-30 MUg/mL) at 30 min post-dose. CONCLUSION: This study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people. PMID- 27995127 TI - Stereotactic Laser Ablation for Medically Intractable Epilepsy: The Next Generation of Minimally Invasive Epilepsy Surgery. AB - Epilepsy is a common, disabling illness that is refractory to medical treatment in approximately one-third of patients, particularly among those with mesial temporal lobe epilepsy. While standard open mesial temporal resection is effective, achieving seizure freedom in most patients, efforts to develop safer, minimally invasive techniques have been underway for over half a century. Stereotactic ablative techniques, in particular, radiofrequency (RF) ablation, were first developed in the 1960s, with refinements in the 1990s with the advent of modern computed tomography and magnetic resonance-based imaging. In the past 5 years, the most recent techniques have used MRI-guided laser interstitial thermotherapy (LITT), the development of which began in the 1980s, saw refinements in MRI thermal imaging through the 1990s, and was initially used primarily for the treatment of intracranial and extracranial tumors. The present review describes the original stereotactic ablation trials, followed by modern imaging-guided RF ablation series for mesial temporal lobe epilepsy. The developments of LITT and MRI thermometry are then discussed. Finally, the two currently available MRI-guided LITT systems are reviewed for their role in the treatment of mesial temporal lobe and other medically refractory epilepsies. PMID- 27995130 TI - Biometric monitoring in silicosis to detect early disease and monitor lung injury: not quite there. AB - Biometric monitoring in exposure to silica dust http://ow.ly/qRrB303lMDg. PMID- 27995131 TI - Total particulate matter concentration skews cigarette smoke's gene expression profile. AB - Exposure of small animals to cigarette smoke is widely used as a model to study the pathogenesis of chronic obstructive pulmonary disease. However, protocols and exposure systems utilised vary substantially and it is unclear how these different systems compare. We analysed the gene expression profile of six publically available murine datasets from different cigarette smoke-exposure systems and related the gene signatures to three clinical cohorts. 234 genes significantly regulated by cigarette smoke in at least one model were used to construct a 55-gene network containing 17 clusters. Increasing numbers of differentially regulated clusters were associated with higher total particulate matter concentrations in the different datasets. Low total particulate matter induced genes mainly related to xenobiotic/detoxification responses, while higher total particulate matter activated immune/inflammatory processes in addition to xenobiotic/detoxification responses. To translate these observations to the clinic, we analysed the regulation of the revealed network in three human cohorts. Similar to mice, we observed marked differences in the number of regulated clusters between the cohorts. These differences were not determined by pack-year. Although none of the experimental models exhibited a complete alignment with any of the human cohorts, some exposure systems showed higher resemblance. Thus, depending on the cohort, clinically observed changes in gene expression may be mirrored more closely by specific cigarette smoke exposure systems. This study emphasises the need for careful validation of animal models. PMID- 27995133 TI - Comparison of the Lag Screw Placements for the Treatment of Stable and Unstable Intertrochanteric Femoral Fractures regarding Trabecular Bone Failure. AB - Background. In this study, the cut-out risk of Dynamic Hip Screw (DHS) was investigated in nine different positions of the lag screw for two fracture types by using Finite Element Analysis (FEA). Methods. Two types of fractures (31-A1.1 and A2.1 in AO classification) were generated in the femur model obtained from Computerized Tomography images. The DHS model was placed into the fractured femur model in nine different positions. Tip-Apex Distances were measured using SolidWorks. In FEA, the force applied to the femoral head was determined according to the maximum value being observed during walking. Results. The highest volume percentage exceeding the yield strength of trabecular bone was obtained in posterior-inferior region in both fracture types. The best placement region for the lag screw was found in the middle of both fracture types. There are compatible results between Tip-Apex Distances and the cut-out risk except for posterior-superior and superior region of 31-A2.1 fracture type. Conclusion. The position of the lag screw affects the risk of cut-out significantly. Also, Tip Apex Distance is a good predictor of the cut-out risk. All in all, we can supposedly say that the density distribution of the trabecular bone is a more efficient factor compared to the positions of lag screw in the cut-out risk. PMID- 27995134 TI - Comparative Analysis of Nutritional and Bioactive Properties of Aerial Parts of Snake Gourd (Trichosanthes cucumerina Linn.). AB - The present investigation was carried out to determine the nutritional and functional properties of T. cucumerina. Water extracts of freeze dried flowers, fruits, and leaves of T. cucumerina were evaluated for their total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity, alpha-amylase inhibitory activity, and fiber and mineral contents. Antioxidant activity, TPC, and TFC were significantly higher (P <= 0.05) in leaves than in flowers and fruits. A significant linear correlation was observed between the TPC, TFC, and antioxidant activities of plant extracts. Although, leaves and flower samples showed a significantly higher (P <= 0.05) amylase inhibitory activity than the fruit samples, the overall amylase inhibition was low in all three parts of T. cucumerina. Soluble and insoluble dietary fiber contents were significantly higher (P <= 0.05) in fruits than in flowers and leaves. Ca and K contents were significantly higher (P <= 0.05) in leaf followed by fruit and flower and Mg, Fe, and Zn contents were significantly higher (P <= 0.05) in leaves followed by flowers and fruits. In conclusion, T. cucumerina can be considered as a nourishing food commodity which possesses high nutritional and functional benefits for human health. PMID- 27995132 TI - Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers. AB - Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5-20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5-20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5-20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-alpha (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD. PMID- 27995135 TI - TRIM25 Identification in the Chinese Goose: Gene Structure, Tissue Expression Profiles, and Antiviral Immune Responses In Vivo and In Vitro. AB - The retinoic acid-inducible gene I (RIG-I) and the RIG-I-like receptor (RLR) protein play a critical role in the interferon (IFN) response during RNA virus infection. The tripartite motif containing 25 proteins (TRIM25) was reported to modify caspase activation and RIG-I recruitment domains (CARDs) via ubiquitin. These modifications allow TRIM25 to interact with mitochondrial antiviral signaling molecules (MAVs) and form CARD-CARD tetramers. Goose TRIM25 was cloned from gosling lungs, which possess a 1662 bp open reading flame (ORF). This ORF encodes a predicted 554 amino acid protein consisting of a B-box domain, a coiled coil domain, and a PRY/SPRY domain. The protein sequence has 89.25% sequence identity with Anas platyrhynchos TRIM25, 78.57% with Gallus gallus TRIM25, and 46.92% with Homo sapiens TRIM25. TRIM25 is expressed in all gosling and adult goose tissues examined. QRT-PCR revealed that goose TRIM25 transcription could be induced by goose IFN-alpha, goose IFN-gamma, and goose IFN-lambda, as well as a35 s polyinosinic-polycytidylic acid (poly(I:C)), oligodeoxynucleotides 2006 (ODN 2006), and resiquimod (R848) in vitro; however, it is inhibited in H9N2 infected goslings for unknown reasons. These data suggest that goose TRIM25 might play a positive role in the regulation of the antiviral immune response. PMID- 27995136 TI - Sagittal and Vertical Craniofacial Growth Pattern and Timing of Circumpubertal Skeletal Maturation: A Multiple Regression Study. AB - The knowledge of the associations between the timing of skeletal maturation and craniofacial growth is of primary importance when planning a functional treatment for most of the skeletal malocclusions. This cross-sectional study was thus aimed at evaluating whether sagittal and vertical craniofacial growth has an association with the timing of circumpubertal skeletal maturation. A total of 320 subjects (160 females and 160 males) were included in the study (mean age, 12.3 +/- 1.7 years; range, 7.6-16.7 years). These subjects were equally distributed in the circumpubertal cervical vertebral maturation (CVM) stages 2 to 5. Each CVM stage group also had equal number of females and males. Multiple regression models were run for each CVM stage group to assess the significance of the association of cephalometric parameters (ANB, SN/MP, and NSBa angles) with age of attainment of the corresponding CVM stage (in months). Significant associations were seen only for stage 3, where the SN/MP angle was negatively associated with age (beta coefficient, -0.7). These results show that hyperdivergent and hypodivergent subjects may have an anticipated and delayed attainment of the pubertal CVM stage 3, respectively. However, such association remains of little entity and it would become clinically relevant only in extreme cases. PMID- 27995137 TI - Biomechanical Consequences of the Elastic Properties of Dental Implant Alloys on the Supporting Bone: Finite Element Analysis. AB - The objective of the present study is to evaluate how the elastic properties of the fabrication material of dental implants influence peri-implant bone load transfer in terms of the magnitude and distribution of stress and deformation. A three-dimensional (3D) finite element analysis was performed; the model used was a section of mandibular bone with a single implant containing a cemented ceramic metal crown on a titanium abutment. The following three alloys were compared: rigid (Y-TZP), conventional (Ti-6Al-4V), and hyperelastic (Ti-Nb-Zr). A 150-N static load was tested on the central fossa at 6 degrees relative to the axial axis of the implant. The results showed no differences in the distribution of stress and deformation of the bone for any of the three types of alloys studied, mainly being concentrated at the peri-implant cortical layer. However, there were differences found in the magnitude of the stress transferred to the supporting bone, with the most rigid alloy (Y-TZP) transferring the least stress and deformation to cortical bone. We conclude that there is an effect of the fabrication material of dental implants on the magnitude of the stress and deformation transferred to peri-implant bone. PMID- 27995138 TI - Functional Genomics, Genetics, and Bioinformatics 2016. PMID- 27995139 TI - Carious Exposure versus Mechanical Exposure for MTA Pulpotomy in Primary Teeth. AB - Introduction. The etiology of exposure determines pulpal response, making it crucial to distinguish between mechanical and carious exposure. This study clinically and radiographically evaluated the success of MTA pulpotomies conducted to treat carious and mechanical pulp exposure. Materials and Methods. This study was conducted with 50 mandibular primary molar teeth. Teeth were divided into 2 groups according to status of the exposure site, with teeth surrounded by carious dentin placed in a carious exposure group and those surrounded by sound dentin in a mechanical exposure group. MTA pulpotomies were performed for both groups. Treatment was followed up clinically and radiographically for 18 months. Results. Clinical and radiographic success rates at 18 months were 100% for both groups. Success rates did not vary significantly between the groups (p = 1.000). Pulp canal obliteration was only seen in the carious exposure group, observed in 2 teeth (8.3%). Conclusion. The long term success rates achieved in this study indicate that MTA can be used as a vital pulpotomy material for the long term success in primary teeth with either mechanical or carious exposure. The findings of the present study highlight the fact that treatment prognosis is dependent upon diagnosis and selection of the appropriate materials for treatment. PMID- 27995140 TI - Rapid Retrieval of Lung Nodule CT Images Based on Hashing and Pruning Methods. AB - The similarity-based retrieval of lung nodule computed tomography (CT) images is an important task in the computer-aided diagnosis of lung lesions. It can provide similar clinical cases for physicians and help them make reliable clinical diagnostic decisions. However, when handling large-scale lung images with a general-purpose computer, traditional image retrieval methods may not be efficient. In this paper, a new retrieval framework based on a hashing method for lung nodule CT images is proposed. This method can translate high-dimensional image features into a compact hash code, so the retrieval time and required memory space can be reduced greatly. Moreover, a pruning algorithm is presented to further improve the retrieval speed, and a pruning-based decision rule is presented to improve the retrieval precision. Finally, the proposed retrieval method is validated on 2,450 lung nodule CT images selected from the public Lung Image Database Consortium (LIDC) database. The experimental results show that the proposed pruning algorithm effectively reduces the retrieval time of lung nodule CT images and improves the retrieval precision. In addition, the retrieval framework is evaluated by differentiating benign and malignant nodules, and the classification accuracy can reach 86.62%, outperforming other commonly used classification methods. PMID- 27995141 TI - Impact of Training on Three-Dimensional versus Two-Dimensional Laparoscopic Systems on Acquisition of Laparoscopic Skills in Novices: A Prospective Comparative Pilot Study. AB - In this prospective educational study, 10 medical students (novices) were randomized to practice two basic laparoscopic tasks from the MISTELS program, namely, Pegboard Transfer (PT) and Intracorporeal Knot Tying (IKT) tasks, using either a 2D or a 3D laparoscopic platform. There was no significant difference between both groups in the baseline assessments (PT task: 130.8 +/- 18.7 versus 151.5 +/- 33.4; p = 0.35) (IKT task: 123.9 +/- 41.0 versus 122.9 +/- 44.9; p = 0.986). Following two training sessions, there was a significant increase in the scores of PT task for the 2D (130.8 +/- 18.7 versus 222.6 +/- 7.0; p = 0.0004) and the 3D groups (151.5 +/- 33.4 versus 211.7 +/- 16.2; p = 0.0001). Similarly, there was a significant increase in the scores of IKT task for the 2D (123.9 +/- 41.0 versus 373.3 +/- 47.2; p = 0.003) and the 3D groups (122.9 +/- 44.9 versus 338.8 +/- 28.6; p = 0.0005). However, there was no significant difference in the final assessment scores between 2D and 3D groups for both tasks (p > 0.05). Therefore, 3D laparoscopic systems do not provide an advantage over 2D systems for training novices in basic laparoscopic skills. PMID- 27995143 TI - Combined Overlap Extension PCR Method for Improved Site Directed Mutagenesis. AB - The combined overlap extension PCR (COE-PCR) method developed in this work combines the strengths of the overlap extension PCR (OE-PCR) method with the speed and ease of the asymmetrical overlap extension (AOE-PCR) method. This combined method allows up to 6 base pairs to be mutated at a time and requires a total of 40-45 PCR cycles. A total of eight mutagenesis experiments were successfully carried out, with each experiment mutating between two to six base pairs. Up to four adjacent codons were changed in a single experiment. This method is especially useful for codon optimization, where doublet or triplet rare codons can be changed using a single mutagenic primer set, in a single experiment. PMID- 27995142 TI - The Costs and Their Determinant of Cesarean Section and Vaginal Delivery: An Exploratory Study in Chongqing Municipality, China. AB - Objectives. This study aims to analyze the cesarean section (CS) rates and vaginal delivery rates in tertiary hospitals of China, explore the costs of two different deliveries, and examine the relative influencing factors of the costs in both CS and vaginal deliveries. Methods. 30,168 anonymized obstetric medical cases were selected from three sample tertiary hospitals in Chongqing Municipality from 2011 to 2013. Chi-square test was used to compare the distributions of CS and vaginal deliveries under different indicators. Mann Whitney test and Kruskal-Wallis test were adopted to analyze the differences under different items. Multiple linear regression was used to determine the influencing factors of the costs of different delivery modes. Results. (1) The rates of CS were 69%, 65.5%, and 59.2% in the three sample tertiary hospitals in Chongqing from 2011 to 2013. (2) The costs and the length of stay of CS were greater than those of vaginal delivery, which had significant differences (P < 0.005). (3) The areas, length of stay, age, medical insurance, and modes of delivery were the influencing factors of both CS and vaginal delivery costs. Discussion. The high CS rates in China must be paid significant attention. The indicators of two modes of delivery should be regulated strictly. CS rate reduction and saving medical resources will be the benefits if vaginal delivery is chosen by pregnant women. PMID- 27995144 TI - Structural Femoral Shaft Allografts for Anterior Spinal Column Reconstruction in Osteoporotic Spines. AB - This study was to investigate the clinical and radiographical outcomes of anterior spinal column reconstruction using structural femoral shaft allografts in osteoporotic patients. Retrospective analyses of medical records, radiographic parameters, and postoperative complications were performed in twenty-one patients who underwent anterior spinal column reconstruction surgery for osteoporotic vertebral collapse or nonunion. Surgical invasiveness, clinical outcomes, postoperative complications, and radiographic outcomes were evaluated. Ambulatory status and back pain significantly improved. The Cobb's angle of segmental kyphosis significantly improved immediately after surgery with slight progression at the final follow-up. There were two cases of failed reconstruction with marked progression of kyphosis; both were related to loosening of screws rather than subsidence of the graft. Anterior spinal column reconstruction using femoral shaft allografts improved kyphosis and resulted in minimal subsidence and therefore is recommended as an effective treatment option for dealing with osteoporotic vertebral collapse and kyphotic deformity. PMID- 27995145 TI - A First Insight into the Genetic Diversity and Drug Susceptibility Pattern of Mycobacterium tuberculosis Complex in Zhejiang, China. AB - In this study, our aim was to determine the predominant genotypes among the Mycobacterium tuberculosis (MTB) strains circulating in Zhejiang Province. In addition, we also sought to determine the potential associations between MTB genotypes and susceptibility to first-line drugs. Out of these isolates, 673 (71.6%) were classified into the Beijing genotype, while the other 267 (28.4%) were from non-Beijing families. The highest proportion of Beijing genotype was found in Huzhou (80.0%) and the lowest in Lishui (48.3%). Statistical analysis revealed that there was a significant difference in the prevalence of Beijing genotype among different regions (chi2 = 17.57, P = 0.04). In addition, the overall proportions of drug resistance to INH, RIF, SM, and EMB were 13.2% (124/940), 21.8% (75/940), 3.4% (32/940), and 5.9% (55/940) in Zhejiang, respectively. Further comparison revealed that there was no significant difference in drug susceptibility profiles between Beijing and non-Beijing strains (P > 0.05). In conclusion, we describe the genetic diversity and drug susceptibility pattern of MTB in Zhejiang for the first time. Our data demonstrate that Beijing genotype is the predominant lineage in Zhejiang, while the distribution of Beijing-genotype strains shows geographic diversity. In addition, no correlation is observed between Beijing genotype and anti-TB drug resistance. PMID- 27995146 TI - Comparison of Experimental Diabetic Periodontitis Induced by Porphyromonas gingivalis in Mice. AB - Periodontitis is one of the severe complications in diabetic patients and gingival epithelium plays an initial role on the onset and progression of this disease. However the potential mechanism is yet sufficiently understood. Meanwhile, the research on the correlational experimental animal models was also insufficient. Here, we established periodontitis with type 2 diabetes in db/db and Tallyho/JngJ (TH) mice and periodontitis with type 1 diabetes in streptozotocin induced diabetes C57BL/6J (STZ-C57) mice by oral infection of periodontal pathogen Porphyromonas gingivalis W50. We demonstrated that periodontal infected mice with high blood glucose levels showed dramatically more alveolar bone loss than their counterparts, in which infected db/db mice exhibited the most bone defects. No contrary impact could be observed between this periodontal infection and onset and severity of diabetes. The expressions of PTPN2 were inhibited whereas the expression of JAK1, STAT1, and STAT3 increased dramatically in gingival epithelia and the serum TNF-alpha also significantly increased in the mice with diabetic periodontitis. Our results indicated that the variations of inflammation-related protein expressions in gingival epithelia might lead to the phenotype differences in the mice with diabetic periodontitis. PMID- 27995147 TI - Effect of Demographic Status and Lifestyle Habits on Glycaemic Levels in Apparently Healthy Subjects: A Cross-Sectional Study. AB - Aim. To identify the effects of sociodemographic status, family history, and lifestyle habits on fasting blood glucose (FBG) and fasting serum insulin (FSI) levels in apparently healthy subjects. Methods. Information was gathered using an interviewer-administered questionnaire from 227 apparently healthy nondiabetic subjects residing in a suburban area in Sri Lanka. Venous blood samples were collected after an overnight fast for FBG and FSI analysis. Correlations and differences were analyzed using SPSS (ver. 17) software. Results. The majority of the subjects were females, having secondary or tertiary education, monthly income >=Rs. 25,000 (USD 175), and a positive family history of diabetes. Among the subjects, 10.1% were identified as prediabetics and the majority had familial diabetes with monthly income >=Rs. 25,000 (USD 175). Subjects with high income had significantly higher mean FBG. In addition FBG had a significant correlation with age. Males and subjects with less than 6 hours/day sleeping duration at night had significantly higher FBG. Subjects with less vigorous physical activity and longer sitting duration had significantly higher FSI levels. Conclusions. Increasing age, higher income, positive familial history of diabetes, sedentary lifestyle, and short sleep at night have positive impact on glycaemic status in apparently healthy subjects. PMID- 27995148 TI - Investigation of the Effects and Mechanisms of Mai Tong Formula on Lower Limb Macroangiopathy in a Spontaneous Diabetic Rat Model. AB - A new Chinese herbal formula called Mai Tong Formulae (MTF) has recently been used to treat lower limb macroangiopathy in type 2 diabetes mellitus (T2DM) patients. In this study, we investigated the effect of MTF on lower limb macroangiopathy in a spontaneous diabetic rat model (GK rats). We found that MTF treatment significantly reduced serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), IL6, and VEGF and increased serum insulin in this model. Histological and ultrastructural observations showed that MTF treatment significantly reduced vascular endothelial cell shedding and improved endothelium injuries. We further detect proteome alteration following MTF treatment. 25 differential proteins (DPs) abnormally expressed in GK rats were normalized by MTF treatment. These DPs significantly are enriched in biological processes and pathways that regulate muscle contraction and cGMP-PKG signaling pathway and so on. Additional protein-protein interaction (PPI) network analyses of the DPs showed that Fasn and Prkar2a are involved in the AMPK signaling pathway, and Gnas, Myh11, and Myh6 are involved in vascular smooth muscle contraction; these 5 DPs were validated by Western blotting. These results indicate that MTF treatment effectively treats lower limb macroangiopathy by regulating key proteins involved in AMPK signaling pathway and vascular smooth muscle contraction. PMID- 27995149 TI - Psychometric Evaluation of the Revised Michigan Diabetes Knowledge Test (V.2016) in Arabic: Translation and Validation. AB - Objective. To translate the revised Michigan Diabetes Knowledge Test into the Arabic language and examine its psychometric properties. Setting. Of the 139 participants recruited through King Fahad Medical City in Riyadh, Saudi Arabia, 34 agreed to the second-round sample for retesting purposes. Methods. The translation process followed the World Health Organization's guidelines for the translation and adaptation of instruments. All translations were examined for their validity and reliability. Results. The translation process revealed excellent results throughout all stages. The Arabic version received 0.75 for internal consistency via Cronbach's alpha test and excellent outcomes in terms of the test-retest reliability of the instrument with a mean of 0.90 infraclass correlation coefficient. It also received positive content validity index scores. The item-level content validity index for all instrument scales fell between 0.83 and 1 with a mean scale-level index of 0.96. Conclusion. The Arabic version is proven to be a reliable and valid measure of patient's knowledge that is ready to be used in clinical practices. PMID- 27995151 TI - Burns resulting from spontaneous combustion of electronic cigarettes: a case series. AB - BACKGROUND: Electronic cigarette (e-cigarette) sales have grown rapidly in recent years, coinciding with a public perception that they are a safer alternative to traditional cigarettes. However, there have been numerous media reports of fires associated with e-cigarette spontaneous combustion. CASE PRESENTATION: Three severe burns caused by spontaneous combustion of e-cigarettes within a 6-month period were treated at the Santa Clara Valley Medical Center Burn Unit. Patients sustained partial and full-thickness burns. Two required hospitalization and surgical treatment. CONCLUSIONS: E-cigarettes are dangerous devices and have the potential to cause significant burns. Consumers and the general public should be made aware of these life-threatening devices. PMID- 27995150 TI - Risk Factors for the Requirement of Antenatal Insulin Treatment in Gestational Diabetes Mellitus. AB - Poor maternal glycemic control increases maternal and fetal risk for adverse outcomes, and strict management of gestational diabetes mellitus (GDM) is recommended to prevent neonatal and maternal complications. However, risk factors for the requirement of antenatal insulin treatment (AIT) are not well investigated in the pregnant women with GDM. We enrolled 37 pregnant women with GDM and investigated the risk for AIT by comparing the patients with AIT (AIT group; n = 10) and without insulin therapy (Diet group; n = 27). The 1-h and 2-h plasma glucose levels and the number of abnormal values in 75 g OGTT were significantly higher in AIT group compared with Diet group. By logistic regression analysis, plasma glucose level at 1-h was significant predictor for AIT and the odds ratios were 1.115 (1.004-1.239) using forward selection method and 1.192 (1.006-1.413) using backward elimination method. There were no significant differences in obstetrical outcomes and neonatal complications. 1-h plasma glucose levels in 75 g OGTT are useful parameters in predicting the requirement for AIT in GDM. Both maternal and neonatal complications are comparable in GDM patients with and without insulin therapy. PMID- 27995152 TI - Combination effects of sorafenib with PI3K inhibitors under hypoxia in colorectal cancer. AB - AIM: This study reports the influence of hypoxia on response of colorectal cancer cells to anticancer effects of sorafenib in combination with PI3K inhibitors GDC 0941 and BEZ-235. MATERIALS AND METHODS: All hypoxic exposures were carried out at 1% O2/5% CO2. Antiproliferation activity was evaluated by 48 hours propidium iodide and 14 days clonogenic assay. Protein levels were evaluated by fluorescence ELISA. Metabolites lactate and glucose were evaluated biochemically. RESULTS: In the 48-hour proliferation assay, sorafenib acted synergistically with GDC-0941 but not with BEZ-235. In long-term colony-forming assays, both GDC-0941 and BEZ-235 were shown to potentiate the antiproliferative activity of sorafenib. At the molecular level, the synergism is mediated through inhibition of pAKT, pS6, p4EBP1, pERK, cyclin D1, and Bcl-2. No change in hypoxia-inducible factor 1alpha (HIF-1alpha) levels was observed in cells treated with the combination of compounds under hypoxia. A significant reduction in glucose uptake and lactate release was observed in cells treated with the combination of compounds under normoxia and hypoxia. CONCLUSION: Combinations of sorafenib with PI3K inhibitors BEZ-235 and GDC-0941 are efficacious under hypoxia. Thus, these anticancer combinations have a potential to overcome the hypoxia-mediated resistance mechanisms to antiproliferative agents in cancer therapy. PMID- 27995153 TI - Data on eNOS T786 and G894T polymorphisms and peripheral blood eNOS mRNA levels in Sickle Cell Disease. AB - In this article, we present data on endothelial Nitric Oxide Synthase (eNOS) gene T786C and G894T polymorphisms in Greek steady-state Sickle Cell Disease patients in comparison to healthy controls. Moreover, eNOS mRNA levels were determined in peripheral blood samples from 18 patients and 9 controls. This article complements our recently published article named "Prognostic value of eNOS T786C and G894T polymorphisms in Sickle Cell Disease" (I. Armenis, V. Kalotychou, R. Tzanetea, Z. Kontogeorgiou, D. Anastasopoulou, M. Mantzourani, M. Samarkos, K. Pantos, K. Konstantopoulos, I. Rombos, 2016) [1]. PMID- 27995154 TI - Difference distance map data of alternative crystal forms of UlaA. AB - We introduce the value of information obtained by comparing alternative crystal forms of the same sub-state (of outward open UlaA, our example protein), which is found in the same lattice configuration but different space groups. We compare instability estimates obtained using this new method (alternative crystal forms) with temperature factors. Using a transport assay result, we correlate observations for two homologous secondary structure elements, and show that the alternative states method for obtaining instability estimates provide differentiating information about an important and immobilized mid-TMS region. The data presented in this article are related to the article entitled "The V motifs facilitate the substrate capturing step of the PTS elevator mechanism" (A. Vastermark, A. Driker, J. Weng, X. Li, J. Wang, M.H. Saier Jr., 2016). PMID- 27995155 TI - Engineered HA hydrogel for stem cell transplantation in the brain: Biocompatibility data using a design of experiment approach. AB - This article presents data related to the research article "Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain" (P. Moshayedi, L.R. Nih, I.L. Llorente, A.R. Berg, J. Cinkornpumin, W.E. Lowry et al., 2016) [1] and focuses on the biocompatibility aspects of the hydrogel, including its stiffness and the inflammatory response of the transplanted organ. We have developed an injectable hyaluronic acid (HA)-based hydrogel for stem cell culture and transplantation, to promote brain tissue repair after stroke. This 3D biomaterial was engineered to bind bioactive signals such as adhesive motifs, as well as releasing growth factors while supporting cell growth and tissue infiltration. We used a Design of Experiment approach to create a complex matrix environment in vitro by keeping the hydrogel platform and cell type constant across conditions while systematically varying peptide motifs and growth factors. The optimized HA hydrogel promoted survival of encapsulated human induced pluripotent stem cell derived-neural progenitor cells (iPS-NPCs) after transplantation into the stroke cavity and differentially tuned transplanted cell fate through the promotion of glial, neuronal or immature/progenitor states. The highlights of this article include: (1) Data of cell and bioactive signals addition on the hydrogel mechanical properties and growth factor diffusion, (2) the use of a design of Experiment (DOE) approach (M.W. 2 Weible and T. Chan-Ling, 2007) [2] to select multi-factorial experimental conditions, and (3) Inflammatory response and cell survival after transplantation. PMID- 27995156 TI - Subjective and objective evaluation of 10-30% dose reduced coronary artery phantom scans reconstructed with Forward projected model-based Iterative Reconstruction SoluTion (FIRST). AB - The data presented in this articles are related to the research article entitled "The feasibility of Forward-projected model-based Iterative Reconstruction SoluTion (FIRST) for coronary 320-row computed tomography angiography: a pilot study" (E. Maeda, N. Tomizawa, S. Kanno, K. Yasaka, T. Kubo, K. Ino, R. Torigoe, K. Ohtomo, 2016) [1]. This article describes subjective and objective evaluations of 2 mm-4 mm coronary artery phantom scanned with 100% dose and reconstructed with hybrid iterative reconstruction, and 90%, 80% and 70% dose reconstructed with full iterative reconstruction. PMID- 27995157 TI - Dataset on elemental concentration and group identification of ancient potteries from Tamil Nadu, India. AB - The dataset contains concentration of major and trace elements of ancient potteries from Tamilnadu and grouping different potteries from the statistical techniques of factor and cluster analysis (Figs. 2, 3 and 4). The major and trace elemental concentration data generated using energy dispersive X-ray fluorescence technique (EDXRF) and factor and cluster analysis data obtained using STATISTICA (10.0 version) software. The concentration of major and trace elements determines the type of clay minerals (Calcareous/Non-Calcareous and either low or high refractory) and firing atmosphere adopted by the artisans at the time of manufacture. The statistical tool examined graphically the grouping pattern of the samples in terms of chemical composition and extract information about their provenance. The compilation of this data provides a resource for the wider research community in archeology. PMID- 27995158 TI - Data on the effect of boiling on the organosulfides and the hydrogen sulfide releasing activity of garlic. AB - This article contains experimental data on the identification and quantification of the organosulfides on boiled garlic extracts. Data included are related to the research article "Boiling enriches the linear polysulfides and the hydrogen sulfide-releasing activity of garlic" (R. Tocmo, Y. Wu, D. Liang, V. Fogliano, D. Huang, 2016) [1]. Characterization was carried out by GC-MS and HPLC. Dose response curves obtained from the cell-based H2S-releasing capacity assay of allicin transformation products, namely vinyl dithiins and ajoene are also included. DATS-E values were calculated from these dose-response curves to quantify the contribution of the individual polysulfides to the H2S-releasing capacity of boiled extracts. PMID- 27995159 TI - Dataset of urinary metabolites measured by 1H NMR analysis of normal human urine. AB - The data in this article are related to the research entitled, "Assessment of 1H NMR-based metabolomics analysis for normalization of urinary metals against creatinine" (M. Cassiede, S. Nair, M. Dueck, J. Mino, R. McKay, P. Mercier, B. Quemerais, P. Lacy, 2016) [1]. This article describes the analysis of urinary metabolites in normal, healthy individuals by 1H NMR-based metabolomics. NMR spectra of urine samples typically contain hundreds of peaks that must be carefully screened for reproducibility and detectability. An important requirement in the screening of appropriate urinary metabolites is to ensure that they are reproducibly detected. In our study, we applied the peak profiles of 151 known urinary metabolites to 10 normal human urine samples and found that 50 metabolites were reproducibly measured between 600 and 700 MHz magnets in the same samples. The data set has been made publicly available to enable critical or extended analysis. PMID- 27995160 TI - Dataset of Trans-Resveratrol on diabetes-induced abnormal spermatogenesis, poly (ADP-ribose) polymerase-1 (PARP1) expression in intra-testicular blood vessels, and stage-dependent expression of PARP1 and Sirtuin 1 in the rat testis. AB - This article contains data related to the article "Effects of Trans-Resveratrol on hyperglycemia-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase signaling in rat testis" (A. Abdelali, M. Al-Bader, N. Kilarkaje, 2016) [1]. The data are related to Resveratrol on diabetes-induced changes in blood glucose levels, body weights of rats, sperm count and motility, expression of poly (ADP-ribose) polymerase-1 (PARP1) in Leydig cells and in intratesticular blood vessels, and stage-dependent expression of PARP1 and Sirtuin 1 (SirT1) in the rat testis. In this experiment, the data were obtained from control, Resveratrol-treated, diabetic and Resveratrol-treated diabetic rats on day 42 after the induction of diabetes. Resveratrol treatment for a group each of normal and diabetic rats started on day 22 and extended up to day 42. The sperm parameters were conducted in samples obtained from the epididymis. The expression of proteins was evaluated by immunohistochemistry by using specific primary antibodies. The data are presented in the form of figures and significance of them has been given in the research article [1]. PMID- 27995161 TI - Circulating adipokines data associated with insulin secretagogue use in breast cancer patients. AB - Oral drugs stimulating endogenous insulin production (insulin secretagogues) may have detrimental effects on breast cancer outcomes. The data presented shows the relationship between pre-existing insulin secretagogues use, adipokine profiles at the time of breast cancer (BC) diagnosis and subsequent cancer outcomes in women diagnosed with BC and type 2 diabetes mellitus (T2DM). The Pearson correlation analysis evaluating the relationship between adipokines stratified by T2DM pharmacotherapy and controls is also provided. This information is the extension of the data presented and discussed in "Insulin use, adipokine profiles and breast cancer prognosis" (Wintrob et al., in press) [1]. PMID- 27995162 TI - Dataset of proteins mapped on HepG2 cells and those differentially abundant after expression of the dengue non-structural 1 protein. AB - The data supplied in this article are related to the research article entitled "The effect of the dengue non-structural 1 protein expression over the HepG2 cell proteins in a proteomic approach" (K. Rabelo, M.R. Trugillo, S.M. Costa, B.A. Pereira, O.C. Moreira, A.T. Ferreira et al., 2016) [1]. The present article provides the inventory of peptides and proteins mapped in a hepatocyte cell line (HepG2) by mass spectrometry in the presence of the non-structural protein 1 (NS1) of Dengue 2 virus (DENV2). Cells were transfected with pcENS1 plasmid, which encodes the DENV2 NS1 protein, or the controls pcDNA3 (negative control) or pMAXGFP, encoding the green fluorescent protein (GFP), a protein unrelated to dengue. Differentially abundant protein lists were obtained by comparing cells transfected with pcENS1 and controls. PMID- 27995163 TI - Retrospective life course data from European countries on how early life experiences determine health in old age and possible mid-life mediators. AB - The data presented in this article is related to the research paper entitled "The long arm of childhood circumstances on health in old age: Evidence from SHARELIFE" (E. Pakpahan, R. Hoffmann, H. Kroger, 2016) [1]. It presents the distribution of socioeconomic status (SES) and health from childhood until old age in thirteen European countries. In order to capture the characteristics of longitudinal data, which resembles life course data, we divide the data into three schematic periods: childhood (up to 15 years old), adulthood (30 to 60 years old), and old age (61 to 90 years old). This data set contains respondents' life histories, ranging from childhood conditions (such as housing and health) to detailed questions on education, adult SES (working history, income, and wealth) and old age health. The data can be used not only to understand on how early life experiences determine health in old age, but also to recognise the importance of possible mid-life mediators. PMID- 27995164 TI - Biomarker of exposure level data set in smokers switching from conventional cigarettes to Tobacco Heating System 2.2, continuing smoking or abstaining from smoking for 5 days. AB - Levels of biomarkers of exposure to selected harmful and potentially harmful smoke constituents found in cigarette smoke, in addition to nicotine were measured in 160 smokers randomized for 5 days to continuing smoking conventional cigarettes (41 participants), switching to Tobacco Heating System 2.2 (THS 2.2) (80 participants), or abstaining from smoking (39 participants). The data reported here are descriptive statistics of the levels of each biomarker of exposure expressed as concentrations adjusted to creatinine; at baseline, and at the end of the study, and their relative change from baseline. Reductions in the levels of biomarkers of exposure when expressed as quantity excreted, are also reported. Detailed descriptions of bioanalytical assays used are also provided. The data presented here are related to the article entitled "Evaluation of the Tobacco Heating System 2.2. Part 8: 5-Day randomized reduced exposure clinical study in Poland" (Haziza et al., 2016) [1]. PMID- 27995165 TI - Characterizing the ?3 boundaries in a cold deformed and annealed pure iron. AB - This article contains the experimental data for the characterization of ?3 boundaries in a cold deformed and annealed pure iron. Mentioned data are relevant to the research article " The inter-connections of ?3 boundaries in pure iron" (Weiguo Wang, Song Chen, Gregory S. Rohrer, Wenzhe Chen, 2017) [1]. The characterization of ?3 boundaries was performed through an integrated method including electron backscatter diffraction, stereology based five parameter analysis and crystallographic analysis. This method as formulated can determine the inter-connections of any type grain boundaries with fixed misorientation. PMID- 27995166 TI - Quantitative data describing the impact of the flavonol rutin on in-vivo blood glucose and fluid-intake profiles, and survival of human-amylin transgenic mice. AB - Here we provide data describing the time-course of blood-glucose and fluid-intake profiles of diabetic hemizygous human-amylin (hA) transgenic mice orally treated with rutin, and matched control mice treated with water. We employed "parametric change-point regression analysis" for investigation of differences in time-course profiles between the control and rutin-treatment groups to extract, for each animal, baseline levels of blood glucose and fluid-intake, the change-point time at which blood glucose (diabetes-onset) and fluid-intake (polydipsia-onset) accelerated away from baseline, and the rate of this acceleration. The parametric change-point regression approach applied here allowed a much more accurate determination of the exact time of onset of diabetes than do the standard diagnostic criteria. These data are related to the article entitled "Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro, and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice" (J.F. Aitken, K.M. Loomes, I. Riba-Garcia, R.D. Unwin, G. Prijic, A.S. Phillips, A.R.J. Phillips, D. Wu, S.D. Poppitt, K. Ding, P.E. Barran, A.W. Dowsey, G.J.S. Cooper. 2016) [1]. PMID- 27995167 TI - Theoretical and analyzed data related to thermal degradation kinetics of poly (L lactic acid)/chitosan-grafted-oligo L-lactic acid (PLA/CH-g-OLLA) bionanocomposite films. AB - The theoretical and analyzed data incorporated in this article are related to the recently published research article entitled "Thermal degradation behaviour of nanoamphiphilic chitosan dispersed poly (lactic acid) bionanocomposite films" (http://dx.doi.org/10.1016/j.ijbiomac.2016.11.024) (A.K. Pal, V. Katiyar, 2016) [1]. Supplementary information and data (both raw and analyzed) are related to thermal degradation kinetics and explains various model fitting and is conversional methods, which are used in this research work to enhance the knowledge about degradation behaviour of PLA/CH-g-OLLA bionanocomposite system. Non-isothermal degradation kinetics of such polymeric system was proposed using Kissinger, Kissinger-Akahira-Sunose, Flynn-Wall-Ozawa and Augis and Bennett models to estimate the activation energies (Ea ) and R2 values. PMID- 27995168 TI - Data on the effect of pro-fibrotic cytokine TGF-beta on hepatic stellate cell autophagy. AB - Our data describe autophagic flux in primary rat hepatic stellate cells (rHSCs) treated with pro-fibrotic growth factor, transforming growth factor beta (TGF beta). An autophagy flux experiment determines the rate of synthesis and degradation of the autophagosome marker, LC3-II in the presence and absence of the lysosomal inhibitor bafilomcyin, which blocks LC3-II degradation in lysosomes. The effects of a test agent on LC3-II flux through the autophagic pathway is determined immunochemically by its relative amounts detected in lysates of cells treated with and without bafilomycin. This measurement helps to validate whether exposure to an agent affects the biogenesis or the degradation of autophagosomes during autophagy, a major macromolecular degrading mechanism in eukaryotic cells. ("Rev-erb Agonist and TGF-beta Similarly Affect Autophagy but Differentially Regulate Hepatic Stellate Cell Fibrogenic Phenotype" (Thomes et al., in press) [1]. PMID- 27995169 TI - Complementary pharmacological and toxicological characterization data on the pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1-piperidinyl) acetamide. AB - This text presents complementary data corresponding to pharmacological and toxicological characterization of N-(2,6-dichlorophenyl)-2-(4-methyl-1 piperidinyl)acetamide (LIA) compound. These data support our research article entitled "Pharmacological profile of N-(2,6-dichlorophenyl)-2-(4-methyl-1 piperidinyl)acetamide, a novel analog of lidocaine" Deciga-Campos M., Navarrete Vazquez G., Lopez-Munoz F.J., Librowski T., Sanchez-Recillas A., Yanez-Perez V., Ortiz-Andrade R. (2016) [1]. Toxicity was predicted through the ACD/ToxSuite software and evaluated in vivo using brine shrimp larvae (Artemia salina L.) and mice. Also, we used the micronucleus assay to determine genotoxicity. We used the platform admetSAR to predict absorption properties of LIA and lidocaine. PMID- 27995170 TI - Proteome data on the microbial microbiome of grasshopper feces. AB - We present proteome data from the microbiota (feces) after a diet shift from a natural diverse to a monocultural meadow with Dactylis glomerata. The abundant grasshopper species, Chorthippus dorsatus, was taken from the wild and kept in captivity and were fed with Dactylis glomerata for five days. For phytophagous insects, the efficiency of utilization of hemicellulose and cellulose depends on the gut microbiota. Shifts in environmental and management conditions alter the presence and abundance of plant species which may induce adaptations in the diversity of gut microbiota. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD005126. PMID- 27995171 TI - MicroRNA expression analysis in the liver of high fat diet-induced obese mice. AB - A previous study indicated a causal link between certain miRNAs induced by obesity and the development of hepatic insulin resistance and type 2 diabetes. Here we provide accompanying data collected using Affymetrix GeneChip miRNAs microarrays to identify the changes in miRNAs expression in the liver of mice fed a high fat diet (HFD). Differentially expressed microRNA analyses in the liver of the HFD-fed mice revealed a range of upregulated (>1.5-fold) or downregulated (<0.5-fold) miRNAs. Among those upregulated miRNAs, in silico target analysis, such as TargetScan, PicTar, and miRWalk, identified miRNAs with the putative binding sites on the 3'UTRs of INSR and/or IRS-1. Interpretation of the data and further extensive insights into the implication of miRNAs, particularly miR-15b, in hepatic insulin resistance can be found in "Obesity-induced miR-15b is linked causally to the development of insulin resistance through the repression of the insulin receptor in hepatocytes." (W.M. Yang, H.J. Jeong, S.W. Park, W. Lee, 2015)[1]. PMID- 27995172 TI - Flawed external validation study of the ADNEX model to diagnose ovarian cancer. PMID- 27995173 TI - Response to letter to the editor concerning validation of IOTA ADNEX model. PMID- 27995174 TI - RE: Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery. PMID- 27995175 TI - Response to the letter of Fagotti et al. regarding the manuscript: "Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery". PMID- 27995176 TI - Epithelial ovarian cancer inherent resistance: May the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role? AB - *Cancer cells may have inherent chemoresistance which allows an indefinite expansion.*Transformed ovarian epithelial cells may undergo an immunoediting process.*Immunoedited ovarian cancer drug-resistant cells escape first-line chemotherapy. PMID- 27995177 TI - Response to comment from Brasky et al. PMID- 27995179 TI - A Review of Research Conducted with Probiotic E. coli Marketed as Symbioflor. AB - This review article summarizes the scientific literature that is currently available about a probiotic E. coli that is known under the name Symbioflor E. coli. The probiotic is marketed for human use and has been subjected to over 20 years of scientific research. As is presented here, the available literature not only contains multiple works to investigate and analyse the probiotic activity of this E. coli, but also describes a variety of other research experiments, dealing with a surprising and interesting range of subjects. By compiling all these works into one review article, more insights into this interesting probiotic E. coli were obtained. PMID- 27995178 TI - Association of individual and community factors with C-reactive protein and 25 hydroxyvitamin D: Evidence from the National Health and Nutrition Examination Survey (NHANES). AB - Many individual and community/neighborhood factors may contribute to inflammation and vitamin D deficiency leading to the development of chronic diseases. This study examined the associations of serum C-reactive protein (CRP) and 25 hydroxyvitamin D [25(OH)D] levels with individual and community/neighborhood (tract-level or county-level) factors using a nationally representative sample from 2001-2006 National Health and Nutrition Examination Survey (NHANES). Data from the 2001-2006 waves of the continuous NHANES was merged with the 2000 census and other neighborhood data sources constructed using geographic information system. Associations between multilevel factors and biomarker levels were assessed using multilevel random-intercept regression models. 6643 participants aged 19-65 (3402 men and 3241 women) were included in the analysis. Family income to-needs ratio was inversely associated with CRP (P=0.002) and positively associated with 25(OH)D levels (P=0.0003). County crime rates were positively associated with CRP (P=0.007) and inversely associated with 25(OH)D levels (P=0.0002). The associations with income-to-needs ratio were significant in men [CRP; P=0.005; 25(OH)D, P=0.005] but not in women. For county crime rates, the association was only significant in women for CRP (P=0.004) and was significant in both men (P=0.01) and women (P=0.001) for 25(OH)D. Additionally, overall CRP was positively associated with age (P<0.0001), female sex (P<0.0001), Hispanic race/ethnicity (P=0.0001), current smokers (P<0.0001), body mass index (BMI, P<0.0001), and participants who were US-born (P=0.02). Non-Hispanic black (P<0.0001) and Hispanic race/ethnicity (P<0.0001), current smoker (P=0.047), and higher BMI (P<0.0001) were associated with lower serum 25(OH)D levels. No significant associations were observed between other community/neighborhood variables and serum CRP and 25(OH)D levels. The current results suggest that family income-to-needs ratio and county crime rate may be important contributors to chronic inflammation and vitamin D status. PMID- 27995181 TI - Do molecular tests really differentiate malignant IPMNS from benign? PMID- 27995180 TI - Endoscopic ultrasound-guided fine-needle aspiration plus KRAS and GNAS mutation in malignant intraductal papillary mucinous neoplasm of the pancreas. AB - Background:KRAS and GNAS mutations are common in intraductal papillary mucinous neoplasia of the pancreas (IPMN). The aims of this study were to assess the role of pre-therapeutic cytopathology combined with KRAS and GNAS mutation assays within cystic fluid sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to predict malignancy of IPMN. Patients and methods: We prospectively included 37 IPMN patients with clinical and/or imaging predictors of malignancy (men: 24; mean age: 69.5 years). Cytopathology (performed on cystic fluid and/or IPMN nodules), KRAS (Exon 2, codon 12) and GNAS (Exon 8, codon 201) mutations assays (using TaqMan(r) allelic discrimination) were performed on EUS FNA material. The final diagnosis was obtained from IPMN resections (n = 18); surgical biopsies, EUS-FNA analyses, and follow-up (n = 19): 10 and 27 IPMN were benign and malignant, respectively. Results: Sensitivity, specificity, positive and negative predictive values, and accuracy of cytopathology alone to diagnose IPMN malignancy were 55 %, 100 %, 100 %, 45 %, and 66 %, respectively. When KRAS mutation analysis was combined with cytopathology these values were 92 %, 50 %, 83 %, 71 %, and 81 %, respectively. GNAS assays did not improve the performances of cytopathology alone or those of cytopathology plus a KRAS assay. Conclusions: In patients with a likelihood of malignant IPMN at pre-therapeutic investigation, testing for KRAS mutations in cystic fluid sampling by EUS-FNA improved the results of cytopathology for the diagnosis of malignancy whereas GNAS mutation assay did not. PMID- 27995182 TI - Automatic and unbiased assessment of competence in colonoscopy: exploring validity of the Colonoscopy Progression Score (CoPS). AB - : Background and aims: Colonoscopy is a difficult procedure to master. Increasing demands for colonoscopy, due to screening and surveillance programs, have highlighted the need for competent performers. Valid methods for assessing technical skills are pivotal for training and assessment. This study is the first clinical descriptive report of a novel colonoscopy assessment tool based on Magnetic Endoscopic Imaging (MEI) data and the aim was to gather validity evidence based on the data collected using the "Colonoscopy Progression Score" (CoPS). Methods: We recorded 137 colonoscopy procedures performed by 31 endoscopists at three university hospitals. The participants performed more than two procedures each (range 2 - 12) and had an experience of 0 - 10 000 colonoscopies. The CoPS was calculated for each recording and validity was explored using a widely accepted contemporary framework. The following sources of validity evidence were explored: response process (data collection), internal structure (reliability), relationship to other variables (i. e. operator experience), and consequences of testing (pass/fail). Results: Identical set-ups at all three locations ensured uniform data collection. The Generalizability coefficient (G-coefficient) was 0.80, and a Decision-study (D-study) revealed that four recordings were sufficient to ensure a G-coefficient above 0.80. We showed a positive correlation between CoPS and experience with Pearson's r of 0.61 (P < 0.001). A pass/fail standard of 107 points was established using the contrasting group method to explore the consequences of testing. Conclusion: This study provides evidence supporting the validity of the CoPS for use in assessing technical colonoscopy performance in the clinical setting. STUDY REGISTRATION: NCT01997177. PMID- 27995183 TI - Life-threatening bleeding of a duodenal gastrointestinal stromal tumor in a teenager: a rare case report. AB - Duodenal gastrointestinal stromal tumors (GIST) are per se infrequent and are exceptional in children or young adults. So far, only 2 cases of pediatric duodenal GISTs have been published. Here we report on the case of a 19-year-old female patient who was admitted in hemorrhagic shock due to arterial bleeding of a duodenal GIST located in immediate proximity to the major duodenal papilla. After several attempts of endoscopic hemostasis failed, the tumor bleeding was controlled with a second coil embolization of the pancreaticoduodenal arcades. PMID- 27995184 TI - Semi-solid feeds may reduce the risk of aspiration pneumonia and shorten postoperative length of stay after percutaneous endoscopic gastrostomy (PEG). AB - Background and study aims: Feeding-related adverse events after percutaneous endoscopic gastrostomy (PEG) such as aspiration pneumonia may result in prolonged hospitalization and postoperative mortality. This study evaluated the efficacy of using semi-solid feeds to reduce feeding-related adverse events and improve clinical outcomes. Patients and methods: Patients who received PEG for enteral nutrition at our hospital between January 2014 and December 2015 were allocated to a postoperative feeding protocol that used either liquid feed or semi-solid feed. Baseline characteristics, postoperative feeding-related adverse events and clinical outcomes in the 2 groups were prospectively analysed and compared. Results: One hundred and seventeen PEG patients (age range: 59 - 97 years, male: 53) were enrolled with 72 patients given liquid feed and 45 patients receiving semi-solid feed. Baseline characteristics were similar in both groups. The semi solid feed group experienced fewer incidence of feeding-related aspiration pneumonia (2.2 % vs. 22.2 %, P < 0.005) and shorter postoperative hospital length of stay (12.7 days vs. 18.8 days, P < 0.01). Significant differences were not observed in the frequency of peristomal infection (11.1 % vs. 12.5 %, P = 0.82), feeding-related diarrhea (2.2 % vs. 12.5 %, P = 0.09) and 30-day mortality rates (2.2 % vs. 8.3 %, P = 0.25). Conclusions: Semi-solid feeding may reduce the risk of aspiration pneumonia and shorten postoperative hospital length of stay after PEG. Semi-solid feeds are safe to use and can be employed either as a first line feeding protocol or an alternative when liquid feeding is unsuccessful. PMID- 27995185 TI - The efficacy of training insertion skill on a physical model colonoscopy simulator. AB - Background and study aims: Prior research supports the validity of performance measures derived from the use of a physical model colonoscopy simulator - the Kyoto Kagaku Colonoscope Training Model (Kyoto Kagaku Co. Ltd., Kyoto, Japan) - for assessing insertion skill. However, its use as a training tool has received little research attention. We assessed the efficacy of a brief structured program to develop basic colonoscope insertion skill through unsupervised practice on the model. Participants and methods: This was a training study with pretesting and post-testing. Thirty-two colonoscopy novices completed an 11-hour training regime in which they practiced cases on the model in a colonoscopy simulation research laboratory. They also attempted a series of test cases before and after training. For each outcome measure (completion rates, time to cecum and peak force applied to the model), we compared trainees' post-test performance with the untrained novices and experienced colonoscopists from a previously-reported validation study. Results: Compared with untrained novices, trained novices had higher completion rates and shorter times to cecum overall (Ps < .001), but were out performed by the experienced colono-scopists on these metrics (Ps < .001). Nevertheless, their performance was generally closer to that of the experienced group. Overall, trained novices did not differ from either experience-level comparison group in the peak forces they applied (P > .05). We also present the results broken down by case. Conclusions: The program can be used to teach trainees basic insertion skill in a more or less self-directed way. Individuals who have completed the program (or similar training on the model) are better prepared to progress to supervised live cases. PMID- 27995186 TI - Comparing endoscopic intervention against fully covered self-expanding metal stent placement for post-endoscopic sphincterotomy bleed (CEASE Study). AB - Background and study aims: Limited data exist for the use of fully covered self expanding metal stent (FCSEMS) as an intervention for immediate bleeds post endoscopic sphincterotomy (ES) after primary endoscopic intervention failure or to reduce the number of delayed bleeding events in patient with increased risk of bleeding post-ES. Patients and methods: We evaluated a retrospective cohort of individuals who had ES performed from 2011 to 2014. A total of 700 patients were identified with 67 patients having post-ES bleeding. The FCSEMS treatment group included 23 patients and the non-FCSEMS treatment group included 44 patients. The primary end point was rate of change of Hgb at 72 hours after ES in the FCSEMS group and the primary endoscopic intervention-only group. A comparison also was made between the FCSEMS and non-FCSEMS group with regards to proportion of coagulopathy and number of delayed bleeding events. Results: The FCSEMS treatment group had a lower bleeding rate at 72 hours (0.66 g/dL vs 1.98 g/dL P < 0.001), increased proportion of patients at high risk of bleeding (40 % vs 9 % P value 0.008), and increased frequency of bleeding events that were moderately severe (52 % vs 9 % P = 0.0002) compared to the non-FCSEMS treatment group. The FCSEMS group included 9 patients at increased risk of bleeding and no patients with delayed bleed compared to the non-FCSEMS group, in which all 4 patients at increased risk of bleeding developed a delayed bleed. Conclusion: FCSEMS can provide homeostasis after primary endoscopic intervention failure, thus reducing the need for high-risk procedures. FCSEMS can reduce delayed bleeding events in patients at high risk of post-ES bleeding. PMID- 27995187 TI - Metal stent for refractory post-ES bleeding: Is this the ultimate treatment modality? PMID- 27995188 TI - Does carbon dioxide insufflation impact adenoma detection rate? A single-center retrospective analysis. AB - Background and study aims: Carbon dioxide (CO2) has been associated with reduced post-procedural pain and improved patient satisfaction when compared to air insufflation (AI). The effect of CO2 insufflation (CO2I) on the adenoma detection rate (ADR) remains unclear. The aims of this study are to compare ADR in patients undergoing screening colonoscopy with AI vs. CO2I and identify predictors of ADR. Patients and methods: Single-center retrospective cohort study of 2,107 patients undergoing screening colonoscopy at the University of Florida Hospital between November 2011 and June 2015. Patient demographics, procedural parameters, and histology results were retrospectively obtained from a prospectively maintained colonoscopy database. Univariate and multivariate analysis were performed to identify predictors of ADR. Results: A total of 2107 colonoscopies (644 with AI and 1463 with CO2I) were analyzed. Overall ADR was 27.8 %. There was no significant difference in ADR between AI (27.6 %) vs. CO2I (27.8 %) (P = 0.93). Method of insufflation (AI vs. CO2I) was not significantly associated with ADR (OR 0.9; 95 % CI:0.7 - 1.2). Older age (OR: 1.02; 95 % CI: 1.001 - 1.03 per year increase), male gender (OR 1.48; 95 % CI: 1.17 - 1.87), and longer scope withdraw time (OR 1.13; 95 % CI: 1.1 - 1.16 per minute) were associated with a higher ADR. Fellow involvement was negatively associated with ADR (OR 0.60; 95 % CI: 0.47 - 0.77). Conclusion: ADR was similar between patients who underwent screening colonoscopy with AI vs. CO2I. While CO2I has been associated with improved patient comfort and post-procedural recovery time, there is no definitive evidence to suggest that this method of luminal distention enhances ADR. PMID- 27995189 TI - Evaluation of microvascular findings of deeply invasive colorectal cancer by endocytoscopy with narrow-band imaging. AB - : Background and study aims: Magnifying narrow-band imaging (NBI) is useful for examination of colorectal lesions, and endocytoscopy (EC) allows diagnostic evaluation of structural atypia, nuclear atypia, and vascular structures of colorectal tumors. The aim of this study was to examine surface microvessels in deep invasive colorectal cancer using EC with a new NBI video processor system. Patients and methods: We retrospectively assessed 132 colorectal neoplastic lesions: 81 adenomas, 18 intramucosal cancers, 4 submucosal slightly invasive cancers, and 29 submucosal deep invasive cancers. Detailed vascular findings commonly seen in submucosal deep invasive carcinomas included > 2-fold vasodilatation seen in adenomas, abnormal tortuosity and branching, loss of the micro-network pattern, caliber change in > 2 places in a single blood vessel, and blood vessels not visible in a line because they appear like a string of beads (beaded sign). Results: Univariate analysis revealed 4 vascular findings that were strongly predictive of submucosal deep invasion: vasodilatation (odds ratio [OR] 9.31; 95 % confidence interval [CI] 3.57 - 24.30), loss of the micro-network pattern (OR 61.60; 95 % CI 17.87 - 212.29), caliber change (OR 35.7; 95 % CI 9.16 - 139.14), and the beaded sign (OR 45.90; 95 % CI 5.50 - 382.73). Conclusions: Detailed assessment of ultra-magnified microvessels could improve the diagnostic performance for submucosal deep invasive cancer. STUDY REGISTRATION: UMIN CTR000014033. PMID- 27995190 TI - Learning curve for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic lesions in a novel ex-vivo simulation model. AB - Background: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is essential in the management of digestive cancers. However, teaching and learning this technique remain challenging due to the lack of cost-effective models. Material and methods: This was a prospective experimental study using a complete porcine upper gastrointestinal ex-vivo organ package, placed in an Erlangen Active Simulator for Interventional Endoscopy (EASIE-R), and prepared with one cyst and two solid masses (2 cm). Five fellows inexperienced in EUS-FNA were enrolled, performing 10 procedures on each lesion, alternatively. The total time, number of attempts for success, of needle view losses, and of scope handling were recorded, associated with an independent skills rating by procedure. We compared the first 15 procedures with the last 15 for each fellow. Results: The fellows successfully performed all procedures in 2 to 40 minutes, requiring 1 to 6 attempts. All (5/5) improved their total time taken (P < 0.001), number of times when the EUS view of the needle was lost (P < 0.05), scope handling (P < 0.005), and skills rating (P < 0.001), whereas 4/5 (80 %) improved their number of attempts. The overall evaluation showed a significant decrease (P < 0.001) in the total time taken (11.2 +/- 7.8 vs 4.3 +/- 2.2 minutes), number of attempts (2.6 +/- 1.2 vs 1.2 +/- 0.7), number of times when the EUS view of the needle was lost (2.3 +/- 2 vs 0.5 +/- 0.7), and need for scope handling (1.1 +/- 1.7 vs 0.1 +/- 0.2). We also observed an improvement in skills rating (5 +/- 1.9 vs. 7.7 +/- 1.1). Conclusion: This newly designed ex-vivo model seems to be an effective way to improve the initial learning of EUS-FNA, by performing 30 procedures. PMID- 27995191 TI - Non-radical, stepwise complete endoscopic resection of Barrett's epithelium in short segment Barrett's esophagus has a low stricture rate. AB - Background and aims: Radical endoscopic excision of Barrett's epithelium performing 4 - 6 endoscopic resections during the same endoscopic session results in complete Barrett's eradication but has a high stricture rate (40 - 80 %). Therefore radiofrequency ablation is preferred after endoscopic mucosal resection (EMR) of visible nodules. We investigated the clinical outcome of non-radical, stepwise endoscopic mucosal resection with a maximum of two endoscopic resections per endoscopic session. Methods: We analysed our prospectively maintained database of patients undergoing esophageal EMR for early neoplasia in Barrett's esophagus from 2009 to 2014. EMR was performed using a maximum of two band ligation mucosectomies per endoscopic session; thereafter, follow-up was 3 monthly and EMR was repeated as required for Barrett's eradication. Results: In total, 118 patients underwent staging EMR for early Barrett's neoplasia. Subsequently, 27 patients underwent surgery/chemotherapy due to deep submucosal or more advanced tumor stages or were managed conservatively. The remaining 91 patients with high grade dysplasia (48), intramucosal (38) or submucosal cancer (5) in the resected nodule underwent further endoscopic therapy with a mean follow-up of 24 months. Remission of dysplasia/neoplasia was achieved in 95.6 % after 12 months treatment. Stepwise endoscopic Barrett's resection resulted in complete Barrett's eradication in 36/91 patients (39.6 %) in a mean of four sessions; 40/91 patients (44.0 %) had a short circumferential Barrett's segment (< 3 cm). In this group, repeated EMR achieved complete Barrett's excision in 85.0 %. One patient developed a stricture (1.1 %), one a delayed bleeding, and there were no perforations. Conclusion: In patients with a short Barrett's segment, non-radical endoscopic Barrett's resection at the time of scheduled endoscopy follow-up allows complete Barrett's eradication with very low stricture rate. PMID- 27995192 TI - A basic study of the effect of the shielding method with polyglycolic acid fabric and fibrin glue after endoscopic submucosal dissection. AB - Background and study aims: Recently, the shielding method with polyglycolic acid (PGA) fabric and fibrin glue (P-F method) has been reported to prevent serious complications after endoscopic submucosal dissection (ESD). However, the effectiveness and mechanism to prevent complications by this method remain unclear and the corresponding basic research has not been fully conducted. Methods and results: We examined the effectiveness and mechanism of the P-F method, using a surgical ESD model of canine stomach and in vitro experiments. In the model experiment treated by P-F method or no treatment (control), ulcer perforation or penetration occurred only in the control group, but not in the P-F group. Microscopically, the P-F group showed less damages of the ulcer lesion than that of the control group, showing thicker granulation tissues including PGA fibers on the third day and excellent mucosal regeneration on the fourteenth day. In vitro culture experiments showed that fibroblasts proliferated at a significantly higher rate on PGA than on fibrin or a complex thereof. However, under hydrochloric acid treatment, fibroblasts were protected by fibrin, followed by the complex of both, and PGA. Conclusion: The P-F method exhibited a protective effect against gastric juice by fibrin glue to reduce tissue damages and a scaffold function of PGA fabric to induce better granulation formation at the earlier phase, resulting in excellent long-term tissue repair, on ulcer lesion following ESD, although the results were based on basic experiments. PMID- 27995193 TI - Chromoendoscopy in combination with random biopsies does not improve detection of gastric cancer foci in CDH1 mutation positive patients. AB - Background and study aims: Hereditary diffuse gastric cancer (HGGC), an autosomal dominant tumor-syndrome, accounts for 1 % to 3 % of gastric cancers worldwide. Presumably 30 % to 40 % of all patients fulfilling the clinical guidelines for HDGC are carriers of a pathogenic mutation in the CDH1 gene. Patients often show multiple foci of signet ring cell carcinoma at early age and are advised to undergo prophylactic total gastrectomy (PTG). Our aim was to improve the endoscopic detection of HDGC by using an enhanced endoscopic protocol. Patient and methods: Patients with a proven CDH1 germline mutation identified in our institute were prospectively included. Patients were advised to undergo PTG and offered a baseline endoscopic examination prior surgery. Examination was performed by using high-resolution white-light endoscopy and pan-gastric chromoendoscopy with indigo carmine as dye combined with targeted and multiple random biopsies assessed by an expert histopathologist. Postoperative histopathology was compared with results from endoscopic biopsies. Results: Between September 2012 and November 2014 8 patients with a proven CDH1 germline mutation were included. We conducted 44 targeted (6.3/patient) and 225 random (32.1/patient) biopsies in 7 patients. We detected 1 gastric cancer by random biopsy (14 %). All other examinations showed no signs of cancer. Histopathology of gastrectomy specimen revealed multiple foci of gastric carcinoma in 6 patients (86 %) with a total number of 27 cancer foci. Conclusions: Examination with targeted and random biopsies combined with chromoendoscopy is not able to detect small foci of gastric cancer in CDH1 mutation carriers. Therefore PTG is advocated in these patients. PMID- 27995194 TI - Early diagnosis of hereditary diffuse gastric cancer: (not only) an endoscopic challenge! PMID- 27995195 TI - Does ampullary adenoma size predict invasion on EUS? Does invasion on EUS predict presence of malignancy? AB - Background and study aims: It is common practice to perform ampullectomy without endoscopic ultrasound (EUS) for ampullary lesions < 1 cm but no data exists to support it. No studies have explored whether EUS findings of invasion correlate with malignancy or high-grade dysplasia (HGD) on pathology. We explored the association between adenoma size, pathology results, and invasion on EUS. Patients and methods: This was a single-center retrospective cohort study at a large tertiary care academic hospital. Chart review was performed for 161 patients with benign ampullary lesions on endoscopic biopsy (identified by pathology records). The primary outcomes were mean size (mm) of adenomas and pathology findings with and without intraductal and/or duodenal wall invasion on EUS. Results: Invasion was identified by EUS in 41 (34.1 %) of 120 patients who underwent EUS. The mean size of the lesion in these patients was 20.9 mm (+/- 11.6 mm) compared to 13.9 mm (+/- 11.3 mm, P = 0.0001) in patients without invasion. A receiver operating characteristic (ROC) curve (AUC 0.73, 95 % CI 0.63 - 0.83) revealed 100 % sensitivity for absence of invasion on EUS in lesions less than 6.5 mm. Invasion on EUS had sensitivity of 63.0 % (95 % CI 47.0 % - 77.0 %) and specificity 88.0 % (95 % CI 78.0 % - 95.0 %) for presence of malignancy, HGD or invasion on pathology. Conclusions: EUS should be considered for ampullary lesions > 6.5 mm. This study provides evidence to support the practice of ampullectomy without EUS for smaller adenomas. EUS evidence of invasion is highly specific for pathologic malignancy, HGD, or invasion (which preclude endoscopic ampullectomy). PMID- 27995196 TI - EUS and ampullary adenoma: Why? When? PMID- 27995197 TI - EUS-guided biliary drainage or enteroscopy-assisted ERCP in patients with surgical anatomy and biliary obstruction: an international comparative study. AB - Background and study aims: How enteroscopy-assisted ERCP (e-ERCP) and endoscopic ultrasound-guided biliary drainage (EUS-BD) compare in patients with surgically altered upper gastrointestinal anatomy is currently unknown. The aims of this study were to compare efficacy and safety of both techniques and study predictors of these outcomes. Patients and methods: This was an international, multicenter comparative cohort study at 10 tertiary centers. Outcomes data included technical success (biliary access with cholangiography and stent placement [when indicated]), clinical success (resolution of biliary obstruction) and adverse events (AEs) (graded according to the ASGE lexicon). Results: A total of 98 patients underwent EUS-BD (n = 49) or e-ERCP (n = 49). Technical success was achieved in 48 (98 %) patients in the EUS-BD group as compared to 32 (65.3 %) patients in the e-ERCP group (OR 12.48, P = 0.001). Clinical success was attained in 88 % of patients in EUS-BD group as compared to 59.1 % in the e-ERCP group (OR 2.83, P = 0.03). Procedural time was significantly shorter in the EUS-BD group (55 min vs 95 min, P < 0.0001). AEs occurred more commonly in the EUS-BD group (20 % vs. 4 %, P = 0.01). However, the majority (90 %) of AEs were mild/moderate. Length of stay was significantly longer in the EUS-BD group (6.6 d vs. 2.4 d, P < 0.0001). Conclusions: EUS-BD can be performed with a higher degree of clinical efficacy and shorter procedure time than e-ERCP in patients with surgically altered upper gastrointestinal anatomy. Whether or not this approach should be first-line therapy in this patient population is highly dependent on the indication for the procedure, the patient's anatomy, and local practice and expertise. PMID- 27995198 TI - Biliary drainage in case of surgically altered anatomy: How to select the first line approach? PMID- 27995199 TI - Reply to Xavier S and colleague: "Hemospray use in upper gastrointestinal bleeding from tumor - is it the answer?" PMID- 27995200 TI - Hemospray use in upper gastrointestinal bleeding from tumor: Is it the answer? PMID- 27995201 TI - Effects of a sweetpotato protein digest on lipid metabolism in mice administered a high-fat diet. AB - Sweetpotato peptide (SPP) was prepared by enzyme digestion of sweetpotato protein from starch wastewater. Animal experiments assessed the effect of SPP on body weight, abdominal adipose tissue mass, serum lipids and adipocytokines. Body and liver weight and epididymal and mesenteric fat of mice fed a high-fat diet containing 0.5% or 5% SPP for 28 days were significantly lower than control mice. Triglyceride and cholesterol in VLDL and LDL and leptin levels were significantly lower in the serum of SPP-administered mice compared to control mice. Biomarker arrays showed that adiponectin, melanocyte-stimulating-hormone-alpha and neuromedin U were more than 1.5 times higher, while TNF-alpha was about 1.5 times lower in the livers of SPP-administered mice compared to control mice. These results suggest SPP mitigated leptin resistance in mice administered a high-fat diet, and maintained anorexigenic peptide levels. SPP administration may suppress lipogenesis by increasing adiponectin levels and decreasing TNF-alpha levels in adipocytes. PMID- 27995202 TI - A novel bilateral lower extremity mirror therapy intervention for individuals with stroke. AB - Despite improvements made in stroke rehabilitation, motor impairment and gait deficits persist at discharge. New interventions are needed. Mirror therapy has promise as one element of a rehabilitation program. The primary objectives were to 1) describe a bilateral, lower extremity mirror therapy (LE-MT) device and training protocol and 2) investigate the feasibility of LE-MT. A LE-MT device was constructed to train bilateral LE movements for 30 min, 3 times/week for 4 weeks, as an adjunct to physiotherapy in three individuals post-stroke. Sessions were digitally recorded and reviewed to extract feasibility measures; repetitions, rests and session duration. Pre and post measures of gait and motor impairment were taken. Two participants completed 100% of the sessions and a third completed 83% due to a recurrence of pre-existing back pain. Repetitions increased and session duration was maintained. Number of rests decreased for two participants and increased for one participant. Participants reported fatigue and mild muscle soreness but also that the intervention was tolerable. Positive gait changes included increased velocity and decreased variability. LE motor impairment also improved. A bilateral LE-MT adjunct intervention for stroke is feasible and may have positive effects. A history of low back pain should be a precaution. PMID- 27995203 TI - BaroFuse, a novel pressure-driven, adjustable-throughput perfusion system for tissue maintenance and assessment. AB - OBJECTIVES: Microfluidic perfusion systems are used for assessing cell and tissue function while assuring cellular viability. Low perfusate flow rates, desired both for conserving reagents and for extending the number of channels and duration of experiments, conventionally depend on peristaltic pumps to maintain flow yet such pumps are unwieldy and scale poorly for high-throughput applications requiring 16 or more channels. The goal of the study was to develop a scalable multichannel microfluidics system capable of maintaining and assessing kinetic responses of small amounts of tissue to drugs or changes in test conditions. METHODS: Here we describe the BaroFuse, a novel, multichannel microfluidics device fabricated using 3D-printing technology that uses gas pressure to drive large numbers of parallel perfusion experiments. The system is versatile with respect to endpoints due to the translucence of the walls of the perifusion chambers, enabling optical methods for interrogating the tissue status. The system was validated by the incorporation of an oxygen detection system that enabled continuous measurement of oxygen consumption rate (OCR). RESULTS: Stable and low flow rates (1-20 MUL/min/channel) were finely controlled by a single pressure regulator (0.5-2 psi). Control of flow in 0.2 MUL/min increments was achieved. Low flow rates allowed for changes in OCR in response to glucose to be well resolved with very small numbers of islets (1-10 islets/channel). Effects of acetaminophen on OCR by precision-cut liver slices of were dose dependent and similar to previously published values that used more tissue and peristaltic-pump driven flow. CONCLUSIONS: The very low flow rates and simplicity of design and operation of the BaroFuse device allow for the efficient generation of large number of kinetic profiles in OCR and other endpoints lasting from hours to days. The use of flow enhances the ability to make measurements on primary tissue where some elements of native three-dimensional structure are preserved. We offer the BaroFuse as a powerful tool for physiological studies and for pharmaceutical assessment of drug effects as well as personalized medicine. PMID- 27995204 TI - The evaluation of the audit of Fresh-Frozen Plasma (FFP) usage in emergency department. AB - OBJECTIVES: In our study, the aim is to evaluate the use of Fresh-Frozen Plasma (FFP) in our emergency department and to assess its audit for transfusion. METHODS: All the patients aged 18 and over who received FFP transfusion in the emergency department between March 1, 2013 and March 1, 2016 were included into the study. The audit of FFP use was evaluated by according to 'British Committee for Standards in Hematology Guideline-2004'. RESULTS: Total 141 patients were identified to receive FFP transfusion in our emergency department. When the audit of FFP use was evaluated, 59.6% of all the practices were regarded as improper use. We identified that while the rate of improper use was 40.2% in patients with bleeding, it rose to 90.7% in patients without active bleeding or in those who used FFP with the aim of bleeding prophylaxis. CONCLUSION: We have determined that FFP transfusions were conducted with improper indications at high rate in our emergency department. Preparing an up-to-date transfusion guideline for the practices in emergency departments in our country and training and supervising the medical staff at regular intervals may help prevent the shortcomings in FFP practices. PMID- 27995205 TI - The ED use and non-urgent visits of elderly patients. AB - OBJECTIVE: To evaluate the use of the emergency department (ED) by elderly patients, their non-urgent visits and the prevalence of main disease for ED visits. METHODS: This cross-sectional study was conducted on patients aged 65 years and over who visited the ED of a tertiary care university hospital in Turkey between January 2015 and January 2016 retrospectively. RESULTS: A total of 36,369 elderly patients who visited the ED were included in the study. The rate of ED visits by elderly patients was higher than their representation within the general population (p < 0.001). While the rate of elderly patients visiting polyclinics was 15.8%, the rate of elderly patients visiting the ED was 24.3% (p < 0.001). For both genders, the rates of ED visits for patients between 65 and 74 years old was higher than for other elderly age groups (p < 0.001). The prevalence of upper respiratory tract infection (URTI) was the highest within the elderly population (17.5%, CI: 17.1-17.9). The proportion of ED visits for non urgent conditions was 23.4%. Most of the ED visits were during the non-business hours (51.1%), and they were highest in the winter season (25.9%) and in January (10.2%). The hospitalization rate was 9.4%, and 37.9% of hospitalized patients were admitted to intensive care units. CONCLUSION: The proportion of ED visits by elderly patients was higher than their representation within the general population. Elderly patients often visited the ED instead of a polyclinic. The rate of inappropriate ED use by elderly patients in this hospital was higher than in other countries. PMID- 27995206 TI - Accuracy of SOFA score in prediction of 30-day outcome of critically ill patients. AB - OBJECTIVES: Researchers have attempted to design various scoring systems to determine the severity and predict the outcome of critically ill patients. The present study aimed to evaluate the accuracy of SOFA score in predicting 1-month outcome of these patients in emergency department. METHODS: The present study is a prospective cross-sectional study of >18 year old non-trauma critically ill patients presented to EDs of 3 hospitals, Tehran, Iran, during October 2014 to October 2015. Baseline characteristics, SOFA score variables, and 1-month outcome of patients were recorded and screening performance characteristics of the score were calculated using STATA 11 software. RESULTS: 140 patients with the mean age of 68.36 +/- 18.62 years (18-95) were included (53.5% male). The most common complaints were decrease in level of consciousness (76.43%) and sepsis (60.0%), were the most frequent final diagnoses. Mean SOFA score of the patients was 7.13 +/- 2.36 (minimum 2 and maximum 16). 72 (51.43%) patients died during the following 30 days and 16 (11.43%) patients were affected with multiple organ failure. Area under the ROC curve of SOFA score in predicting mortality of studied patients was 0.73 (95%CI: 0.65-0.81) (Fig. 2). Table 2 depicts screening performance characteristics of this scale in prediction of 1-month mortality in the best cut-off point of >=7. At this cut-off point, sensitivity and specificity of SOFA in predicting 1-month mortality were 75% and 63.23%, respectively. CONCLUSION: Findings of the present study showed that SOFA scoring system has fair accuracy in predicting 1-month mortality of critically ill patients. However, until a more reliable scoring system is developed, SOFA might be useful for narrative prediction of patient outcome considering its acceptable likelihood ratios. PMID- 27995207 TI - Electrocardiographic changes in patients with tramadol-induced idiosyncratic seizures. AB - OBJECTIVES: To assess ECG changes in patients with tramadol-induced seizure(s) and compare these changes in lower and higher than 500 mg tramadol doses as a main goal. MATERIAL AND METHODS: In an analytical-cross sectional manner over 1 year, 170 patients with idiosyncratic seizure(s) after using tramadol, were studied. Full data were recorded for each patient. ECGs were taken from all the patients on admission and 1 h later and were assessed for findings. RESULTS: 70 of 170 patients (41.2%) had used lower than 500 mg doses of tramadol while 90 patients (52.9%) were included in the high dose group. Rate of female patients in the high dose group was significantly higher. The average age of patients in the high dose group was significantly lower (22.04 vs 25.76). The high dose group had significantly higher heart rates. There was no history of cardiovascular diseases; two patients had previous history of seizure. No significant difference was shown between low dose and high dose groups from the point of ECG changes. DISCUSSION AND CONCLUSION: Using doses higher than 500 mg is more frequently seen in women, young people and those who have not experienced previous use of tramadol. Terminal S wave, sinus tachycardia, and terminal R wave in the lead aVR are among the most common ECG changes in tramadol users. PMID- 27995209 TI - Respiratuvar depression after accidental nasal ingestion of brimonidine eye drops in infant. AB - OBJECTIVES: Brimonidine tartrate is an alpha-2 agonist used for glaucoma treatment. It can lead to serious poisoning symptoms when misused by children. CASE REPORT: In this case report, 3 months-old male patient with severe central nervous system depression and respiratory arrest as a result of accidentally nasal instillation of 1 cc brimonidine tartrate that benefited from mechanic ventilation and naloxone treatment was presented. CONCLUSION: This case report suggested, that misuse of nasal brimonidine eye drop could result in serious respiratory distress and central nervous system depression. Mechanical ventilation and naloxone administration can be useful for these patients. PMID- 27995210 TI - Sudden bilateral hearing loss after organophosphate inhalation. AB - Sudden bilateral hearing loss are seen rarely and the toxic substance exposure constitutes a small part of etiology. A Fifty-eight-year-old woman admitted to our clinic with sudden bilateral hearing loss shortly after chlorpyrifos-ethyl exposure. Otolaryngologic examination findings were normal. The patient had 40 dB sensorineural hearing loss (SNHL) on the right ear and 48 dB SNHL on the left ear. Additional diagnostic tests were normal. The conventional treatment for sudden hearing loss was performed. On the second week following organophosphate (OP) exposure the patient's hearing loss almost completely resolved. OP's are heavily used in agriculture and should be taken into consideration as an etiologic factor in sudden hearing loss. PMID- 27995211 TI - Fungal endocarditis presenting with right lumbar pain and femoral artery ischemia - An unusual case report. AB - Fungal endocarditis is a rare entity which has a poor outcome. Our case reports an atypical presentation of similar pathology now presenting with femoral artery ischemia in an immune competent individual. A 62-year Asian male presented with sudden onset of right sided lumbar pain. Initial clinical exam was consistent with right sided renal colic. Intravenous analgesia did not relieve the pain. Repeat clinical examination revealed absent right femoral artery pulsation. The patient underwent a Computerized tomography angiography of right lower extremity. Echocardiogram revealed valvular vegetations that were later revealed to be because of Aspergillus Terreus. This case highlights the atypical presentation of a rare fungal endocarditis in an immune competent individual presenting with right sided lumbar pain. This case is of particular interest for emergency physicians who are at the forefront and may require to deal with such presentations. PMID- 27995208 TI - A systematic and technical guide on how to reduce a shoulder dislocation. AB - OBJECTIVES: Our objective is to provide a systematic and technical guide on how to reduce a shoulder dislocation, based on techniques that have been described in literature for patients with anterior and posterior shoulder instability. MATERIALS AND METHODS: A PubMed and EMBASE query was performed, screening all relevant literature on the closed reduction techniques. Studies regarding open reduction techniques and studies with fracture dislocations were excluded. RESULTS: In this study we give an overview of 23 different techniques for closed reduction and 17 modifications of these techniques. DISCUSSION: In this review article we present a complete overview of the techniques, that have been described in the literature for closed reduction for shoulder dislocations. This manuscript can be regarded as a clinical guide how to perform a closed reduction maneuver, including several technical tips and tricks to optimize the success rate and to avoid complications. CONCLUSION: There are 23 different reduction techniques with 17 modifications of these techniques. Knowledge of the different techniques is highly important for a good reduction. PMID- 27995212 TI - Is this a simple drug eruption to be discharged? AB - 'Erythema Multiforme associated with Phenytoin And Cranial radiation Therapy' (EMPACT) is a very rare clinic situation and classified in EM-like drug reactions. It can be easily misdiagnosed as acute urticaria or drug eruption in ED. Initial symptoms may resemble a simple skin problem, but diagnosing and early hospitalization of the patients can be lifesaving. Here, we present a man with renal cell cancer and brain metastases who admitted to ED due to fever and generalized rash. His skin lesions beginning from his head and spreading through the torso appeared four days after the end of radiotherapy (11 days after the initial dose of both radiation and oral phenytoin). Inspection showed erythematous lesions on the scalp, neck, torso and arms. These lesions had desquomative character on the scalp. Erythematous maculopapular lesions with the tendency of fusion were also visible on the chest, abdomen, back, on the flexor areas of the arm, forearm and femoral region. Laboratory studies showed normal complete blood counts, high creatinine kinase, creatinine kinase-MB, gamma glutamyl transpeptidase, aspartate aminotransferase, lactate dehydrogenase, albumin and total protein. After discontinuation of phenytoin and giving H1, H2 receptor blockers and steroid intravenously, he was discharged two weeks later with full recovery. PMID- 27995213 TI - Robotic surgery an evolution of future direction. PMID- 27995214 TI - Past, present, and future of laparoscopic renal surgery. AB - Although laparoscopic renal surgery dates to almost 30 years ago, in which the first laparoscopic nephrectomy was performed in 1990, the history of laparoscopy extends back over 100 years, when laparoscopy was first performed on dogs. Over the last 30 years, laparoscopic renal surgery has seen many advancements in technology and technique. With the introduction of robotics and new instruments, renal surgery is becoming increasingly less invasive, and patients are having improved operative outcomes. As new technology develops, the envelope will continue to be pushed by urologists with the hope of improvement of patient outcomes and satisfaction. PMID- 27995215 TI - Proctorship and mentoring: Its backbone and application in robotic surgery. AB - In pursuit of continuing medical education in robotic surgery, several forms of training have been implemented. This variable application of curriculum has brought acquisition of skills in a heterogeneous and unstandardized fashion from different parts of the world. Recently, efforts have been made to provide cost effective and well-structured curricula with the aim of bridging the gap between formal fellowship training and short courses. Proctorship training has been implicated on some curriculum to provide excellent progression during the learning curve while ensuring patient safety. PMID- 27995216 TI - Current status of robotic partial nephrectomy in Japan. AB - The safety and efficacy of robot-assisted partial nephrectomy (RAPN) has been reported in Western countries. However, there are no similar reported studies of RAPN in Japan. Although common medical services are covered by public health insurance in Japan, RAPN had not been approved as a listed treatment for public insurance. We conducted a prospective clinical trial to confirm the efficacy and safety of RAPN in Japan. The aim of the present review article is to describe current status of RAPN in Japan and to introduce a part of clinical results obtained from the clinical trial. Based on the favorable results obtained in this clinical trial, RAPN was approved in April 2016 by the Japanese Ministry of Health, Labour and Welfare to be covered by public health insurance. This change allows access to RAPN to everyone in Japan, regardless of wealth. The RAPN techniques used in Japan are also reviewed. PMID- 27995217 TI - Robotic assisted adrenalectomy: Is it ready for prime time? AB - Adrenal surgery is undergoing continuous evolution and minimally invasive surgery is increasingly being used for the surgical management of adrenal masses. With robotic-assisted surgery being a widely accepted surgical treatment for many urological conditions such as prostate carcinoma and renal cell carcinoma, the use of the robot has been expanded to include robotic-assisted adrenalectomy, offering an alternative minimally invasive platform for adrenal surgery. We performed a literature review on robotic-assisted adrenalectomy, reviewing the current surgical techniques and perioperative outcomes. PMID- 27995218 TI - Updates of prostate cancer staging: Prostate-specific membrane antigen. AB - The ability to accurately stage prostate cancer in both the primary and secondary staging setting can have a major impact on management. Until recently radiological staging has relied on computer tomography, magnetic resonance imaging, and nuclear bone scans to evaluate the extent of disease. However, the utility of these imaging technologies has been limited by their sensitivity and specificity especially in detecting early recurrence. Functional imaging using positron-emission tomography with a radiolabeled ligand targeted to prostate specific membrane antigen has transformed the prostate cancer imaging landscape. Initial results suggest that it is a substantial improvement over conventional imaging in the setting of recurrence following primary therapy by having a superior ability to detect disease and to do so at an earlier stage. Additionally, it appears that the benefits seen in the secondary staging setting may also exist in the primary staging setting. PMID- 27995220 TI - Standardized 4-step technique of bladder neck dissection during robot-assisted radical prostatectomy. AB - Bladder neck (BN) dissection is considered one of the most challenging steps during robot-assisted radical prostatectomy. Better understanding of the BN anatomy, coupled with a standardized approach may facilitate dissection while minimizing complications. We describe in this article the 4 anatomic spaces during standardized BN dissection, as well other technical maneuvers of managing difficult scenarios including treatment of a large median lobe or patients with previous transurethral resection of the prostate. The first step involves the proper identification of the BN followed by slow horizontal dissection of the first layer (the dorsal venous complex and perivesicle fat). The second step proceeds with reconfirming the location of the BN followed by midline dissection of the second anatomical layer (the anterior bladder muscle and mucosa) using the tip of the monopolar scissor until the catheter is identified. The deflated catheter is then grasped by the assistant to apply upward traction on the prostate from 2 directions along with downward traction on the posterior bladder wall by the tip of the suction instrument. This triangulation allows easier, and safer visual, layer by layer, dissection of the third BN layer (the posterior bladder mucosa and muscle wall). The forth step is next performed by blunt puncture of the fourth layer (the retrotrigonal fascia) aiming to enter into the previously dissected seminal vesical space. Finally, both vas deferens and seminal vesicles are pulled through the open BN and handed to the assistant for upper traction to initiate Denovillier's dissection and prostate pedicle/neurovascular bundle control. PMID- 27995222 TI - Editorial. PMID- 27995219 TI - Current technique and results for extended pelvic lymph node dissection during robot-assisted radical prostatectomy. AB - The practice of extended pelvic lymph node dissection (ePLND) remains one of the most controversial topics in the management of clinically localized prostate cancer. Although most urologists agree on its benefit for staging and prognostication, the role of the ePLND in cancer control continues to be debated. The increased perioperative morbidity makes it unpalatable, especially in patients with low likelihood of lymph node disease. With the advent of robotic assisted laparoscopic prostatectomy, many surgeons were slow to adopt ePLND in the robotic setting. In this study, we summarize the evidence for the prognostic and therapeutic roles of ePLND, review the clinical tools used for lymph node metastasis prediction and survey the numerous experiences of ePLND compiled by robotic urologic surgeons over the years. PMID- 27995223 TI - Three Basic Steps for Applying Digital Images ?to Oral and Facial Surgery. AB - In this paper, the authors discuss three basic steps related to the application of digital technology to reconstructive oral and maxillofacial surgery (OMFS), in an effort to improve surgical outcomes. These steps include acquiring digital images, processing images in order to build three-dimentional structures, and mapping images to patient anatomy for guided surgery. For each step mentionioned, available technologies and barriers that need to be overcome are discussed. Digital technology is still under development and it has begun to merge into surgical care. Surgeons and computer scientists are required to work together to find solutions when facing such challenges. PMID- 27995221 TI - Nerve-sparing techniques and results in robot-assisted radical prostatectomy. AB - Nerve-sparing techniques in robot-assisted radical prostatectomy (RARP) have advanced with the developments defining the prostate anatomy and robotic surgery in recent years. In this review we discussed the surgical anatomy, current nerve sparing techniques and results of these operations. It is important to define the right and key anatomic landmarks for nerve-sparing in RARP which can demonstrate individual variations. The patients' risk assessment before the operation and intraoperative anatomic variations may affect the nerve-sparing technique, nerve sparing degree and the approach. There is lack of randomized control trials for different nerve-sparing techniques and approaches in RARP, therefore accurate preoperative and intraoperative assessment of the patient is crucial. Current data shows that, performing the maximum possible nerve-sparing using athermal techniques have better functional outcomes. PMID- 27995224 TI - Comparison of Oral Health Status in Asia: Results for Eight Emerging and Five High Income Countries or Regions and Implications. AB - OBJECTIVE: To review the burden of oral disease by investigating the current situation of oral health status in selected countries within the regions of South, East and South-East Asia, with a view to determining which countries are performing better than others and why. METHODS: The study is descriptive and observational in nature and the material is derived from existing databases. As this is a cross-sectional investigation, it offers evidence about relationships and influencing factors. If available, the longitudinal data is integrated. RESULTS: Amongst the emerging countries, the Chinese enjoy a relatively favourable dental health status and amongst the high income countries, the South Koreans exhibit the best dental health status by comparison. In contrast to the above-mentioned perception, caries levels are relatively low and occur in the early stages in most of the emerging Asian countries investigated, even though, for the most part, caries and periodontitis remain untreated. The hypothesis that, when countries climb the socioeconomic development ladder, caries levels increase and worsen if left untreated, leading to edentulousness, cannot be confirmed for most of the developing Asian countries under investigation. Probable reasons for this surprising finding is discussed and found to be in line with current knowledge in cariology. Interestingly, the high income Asian countries under investigation perform better than many Western European countries. CONCLUSION: Under the specific circumstances prevailing in the Asian countries under investigation, a preventive and tooth preserving dental strategy for the entire population should offer emerging countries great opportunities to maintain a relatively low level of caries. Utilising a strategy of this ilk, these countries could achieve improved dental health across the population with comparatively low resources. PMID- 27995225 TI - Oral Health Status and Oral Health Care Model in China. AB - OBJECTIVE: To review the current oral health status and oral health care models in China in an effort to provide recommendations for the future implementation of these models. METHODS: A systematic literature review was conducted. The Medline, EMBASE, CNKI and Wanfang databases were searched for English and Chinese articles reporting relevant data from 1949 to the present. Data from three national oral health epidemiology surveys, Chinese government reports and national statistics yearbooks from 2011 to 2015 were also included. RESULTS: The oral health status of preschool children were significantly improved over the past 10 years, while caries experience among 35 to 45-year-old and 65 to 74-year-old groups showed an increase in 2005. The status of poor oral hygiene was observed for both adolescent and elderly groups. The ratio of dentist-to-population in China was reported as 1:10,000 in 2009, which was much lower than that of developed countries. The workforce of the dental service is distributed unevenly and remains insufficient for such a highly populated country. Although the need for dental treatment was perceived as high, the true demand for dental service in China was relatively low and not seen as critical. This situation clearly did not reflect so well with true oral disease conditions. There are several basic social medical insurance systems available in China, which covered most of the population's need for medical attention, but seldom covered dental treatment. CONCLUSION: National oral health policy in China should emphasise oral health promotion, especially in school education for children and young adults, to further strengthen daily toothbrushing, use of fluoride toothpaste and dental floss, and actively promote annual oral health examination. Oral health management should focus on cost-effective primary and secondary prevention with the long-term goal of maintaining oral health. PMID- 27995226 TI - Effect of Stiffness of Cement on Stress Distribution ?in Ceramic Crowns. AB - OBJECTIVE: To analyse the stress distribution in monolithic- and bilayer structured ceramic crowns by means of the finite element method (FEM), as a function of elastic modulus of the core ceramic, Ecor, and that of the cement used to lute the crown, Ecem, with a view to identifying an ideal stiffness for the cement. METHODS: A two-dimensional axisymmetric FEM model was created to represent tooth structure with a cemented ceramic crown in place. The value of Ecor was set at 70, 100, 150 and 200 GPa representative of the range of commercially available materials. For the veneer, Even, it was set at 70 GPa, while that of the cement, Ecem, was varied from 0.2 to 200 GPa, in a 1-2-5 sequence. The tensile stress along the x-direction was calculated as an indication of the local sensitivity of the model to failure at a given load. RESULTS: The stiffness of both the core ceramic and of the cement strongly affected the tensile stress distribution. With an increase in Ecor, the stress was increased for low Ecem. Also, the stress in the cement tended to increase with an increase in Ecem. However, the stress in the dentine varied little over the ranges studied here. For Ecor > Ecem, the stress in the core for low Ecem was higher than for high Ecem. CONCLUSION: It is suggested that the modulus of elasticity for the cement used to lute the ceramic crown plays a critical role in improving the fracture resistance of ceramic restorations. PMID- 27995227 TI - Education Status of Oral Genetics at the Fourth Military Medical University and other Chinese Dental Schools. AB - OBJECTIVE: To investigate the current state of genetics education at the Fourth Military Medical University (FMMU) and compare it with other dental schools of China. METHODS: Detailed information about the history and current education status of Oral Genetics in the FMMU were collected and questionnaires were completed to acquire the feedback of twenty-seven students on the course. In the other thirty-five dental schools including the capitals of twenty-five provinces and four municipalities in China, information about the oral genetic course were collected by a telephone survey. The contents of survey included whether or not the Oral Genetic course is offered and some basic information about the curriculum (such as the content, hours, teachers' background and teaching methods). RESULTS: Among a total of thirty-six dental schools investigated, six of them (16.7%) offered the Oral Genetic course or related lectures/seminars. The length and contents of the curriculum vary among these schools. The FMMU offered the oral genetic curriculum both to undergraduates and graduated students. Their teachers had a broad range of backgrounds, such as dentistry, biology, genetics, and biochemistry. The students considered the Oral Genetics course to be helpful for their future professional careers. CONCLUSION: Genetic education in dentistry in China is still at a preliminary stage. More effort must be paid to spread the knowledge of Oral Genetics in China. In addition, domestic and international communications and networks for Oral Genetics should be set up in the near future. PMID- 27995229 TI - All-inorganic large-area low-cost and durable flexible perovskite solar cells using copper foil as a substrate. AB - Here, a low-cost perovskite solar cell using CuI and ZnO as the respective inorganic hole and electron transport layers is introduced. Copper foil is chosen as a cheap and low-weight conductive substrate which has a similar work function to ITO. Besides, copper foil is an interesting copper atom source for the growth of the upper cuprous iodide layer on copper foil. A spray coating of a transparent silver nanowire electrode is used as a top contact. The prepared device shows a maximum power conversion efficiency of 12.80% and long-term durability providing an environmentally and market friendly perovskite solar cell. PMID- 27995228 TI - A Novel Approach Using 15% Natural Chitosan Gel ?in the Management of Intrabony Defects: A Pilot Study. AB - OBJECTIVE: To evaluate the effectiveness of 15% chitosan in gel form as a periodontal regenerative material in the periodontal intrabony defects. METHODS: A pilot study split-mouth design of 10 patients within the age group of 30 to 55 years with bilateral intrabony defects >= 3mm and clinical attachment levels (CAL) >= 5mm were selected. The test site received open flap debridement with 15% Chitosan gel as a regenerative material and the controlateral side that acted as a control received only open flap debridement. Clinical and radiographic measurements were recorded at baseline, and 3, 6 and 9 months after the treatment. RESULTS: Data revealed that there was a significant improvement in both clinical and radiographic parameters when intragroup comparison was performed. When intergroup comparison was done, there was a mean difference in CAL (5.8 +/- 1.398 mm) and the depth of the intrabony defect (3.41 +/- 1.17 mm) at 9 months when compared to baseline. CONCLUSION: Within the limitations of the study, it can be concluded that a 15% concentration of chitosan gel is a promising aid and could be used as an effective material in periodontal regeneration. PMID- 27995231 TI - Interface control of electronic and optical properties in IV-VI and II-VI core/shell colloidal quantum dots: a review. AB - Semiconductor colloidal quantum dots (CQDs) have attracted vast scientific and technological interest throughout the past three decades, due to the unique tuneability of their optoelectronic properties by variation of size and composition. However, the nanoscale size brings about a large surface-to-bulk volume ratio, where exterior surfaces have a pronounced influence on the chemical stability and on the physical properties of the semiconductor. Therefore, numerous approaches have been developed to gain efficient surface passivation, including a coverage by organic or inorganic molecular surfactants as well as the formation of core/shell heterostructures (a semiconductor core epitaxially covered by another semiconductor shell). This review focuses on special designs of core/shell heterostructures from the IV-VI and II-VI semiconductor compounds, and on synthetic approaches and characterization of the optical properties. Experimental observations revealed the formation of core/shell structures with type-I or quasi-type-II band alignment between the core and shell constituents. Theoretical calculations of the electronic band structures, which were also confirmed by experimental work, exposed surplus electronic tuning (beyond the radial diameter) with adaptation of the composition and control of the interface properties. The studies also considered strain effects that are created between two different semiconductors. It was disclosed experimentally and theoretically that the strain can be released via the formation of alloys at the core-shell interface. Overall, the core/shell and core/alloyed-shell heterostructures showed enhancement in luminescence quantum efficiency with respect to that of pure cores, extended lifetime, uniformity in size and in many cases good chemical sustainability under ambient conditions. PMID- 27995230 TI - Tumor-cell targeting polydiacetylene micelles encapsulated with an antitumor drug for the treatment of ovarian cancer. AB - Peptide functionalized polydiacetylene (PDA) micelles encapsulated with camptothecin (CPT) kill ovarian cancer cells by the lysosome release of anticancer drug CPT. Moreover, the sub-30 nm PDA micelles penetrate efficiently into a tumor for enhanced therapeutic efficacy. PMID- 27995232 TI - Diacenaphthylene-fused benzo[1,2-b:4,5-b']dithiophenes: polycyclic heteroacenes containing full-carbon five-membered aromatic rings. AB - We herein report on an efficient synthesis of diacenaphthylene-fused benzo[1,2 b:4,5-b']dithiophenes and demonstrate that their packing structure in the solid state depends on the substituent groups. These compounds form dimers with their radical cations in high concentration solution and exhibit good field-effect mobility. PMID- 27995233 TI - Charge ordering and scattering pre-peaks in ionic liquids and alcohols. AB - The structural properties of ionic liquids and alcohols are viewed under the charge ordering process as a common basis to explain the peculiarity of their radiation scattering properties, namely the presence, or absence, of a scattering pre-peak. Through the analysis of models, it is shown that the presence, or absence, of a radiation scattering pre-peak is principally related to the symmetry breaking, or not, of the global charge order, induced by the peculiarities of the molecular shapes. This symmetry breaking is achieved, in practice, by the emergence of specific types of clusters, which manifests how the global charge order has changed into a local form. Various atom-atom correlations witness the symmetry breaking induced by this re organization, and this is manifested into a pre-peak in the structure factor. This approach explains why associated liquids such as water do not show a scattering pre-peak. It also explains under which conditions core-soft models can mimic associating liquids. PMID- 27995234 TI - New insights into the stability and structural evolution of some gold nanoclusters. AB - Revealing the stability and structural patterns is important for precisely synthesizing or assembling ligand protected nanoclusters, and even their applications as functional nanomaterials. Investigations on structural evolutional patterns and structural stability are very challenging, because structures change with the nanocluster size and the structural stability depends on both the electron structures of cores and ligand type. Herein, we propose a hybrid superatom network (hSAN) model to understand the stability of some gold nanoclusters with different kinds of ligands. In this model, 4c-2e superatom Au4 can form conjugated superatom networks by vertex sharing, and ligands further connect the conjugated superatom networks together to form a bigger complex network, i.e. a hSAN. The stability of the clusters, including [Au24(C[triple bond, length as m-dash]CPh)14(PPh3)4]2+, Au28(S-c-C6H11)20, Au36(SCH2Ph tBu)8Cl20, Au40(O-MBT)24 and Au52(TBBT)32 can be explained uniformly by the hSAN model. Beyond that, a new heuristic structural pattern named the Au13 topological rule is proposed. In the light of this heuristic rule, every Au7 bi-tetrahedral kernel is included in an Au13 structure with quasi-Oh symmetry, i.e. as long as the Au7 bi-tetrahedral kernel is formed, it will be surrounded by six Au atoms to form an Au13 structure topologically. According to this understanding, a new nanocluster [Au44(C[triple bond, length as m-dash]CH3)26(PCH3)4]2+ and a new nanowire with the structural evolutional formula [Au(20n+4)(C[triple bond, length as m-dash]CH3)(12n+2)(PCH3)4]2+ (n = 1, 2, 3, 4, ...) are predicted. Both the understanding of the stability and the structure rule are free from the type of ligand, and will be useful for the structural predictions and determinations of ligand protected gold nanoclusters. PMID- 27995235 TI - Liquid-capped encoded microcapsules for multiplex assays. AB - Although droplet microfludics is a promising technology for handling a number of liquids of a single type of analyte, it has limitations in handling thousands of different types of analytes for multiplex assay. Here, we present a novel "liquid capped encoded microcapsule", which is applicable to various liquid format assays. Various liquid drops can be graphically encoded and arrayed without repeated dispensing processes, evaporation, and the risk of cross-contamination. Millions of nanoliter-scale liquids are encapsulated within encoded microcapsules and self-assembled in microwells in a single dispensing process. The graphical code on the microcapsule enables identification of randomly assembled microcapsules in each microwell. We conducted various liquid phase assays including enzyme inhibitor screening, virus transduction, and drug-induced apoptosis tests. The results showed that our liquid handling technology can be utilized widely for various solution phase assays. PMID- 27995236 TI - A protecting-group-free synthesis of (+)-nephrosteranic, (+)-protolichesterinic, (+)-nephrosterinic, (+)-phaseolinic, (+)-rocellaric acids and (+) methylenolactocin. AB - A collective synthesis of a gamma-butyrolactone class of paraconic acids such as (+)-methylenolactocin, (+)-phaseolinic acid, (+)-nephrosteranic acid, (+) nephrosterinic acid, (+)-rocellaric acid and (+)-protolichesterinic acid is described. The strategy adopted is protecting-group-free based on efficient Pd catalyzed Suzuki-Miyaura coupling and Ru-catalyzed Sharpless oxidation to construct the core beta-CO2H-gamma-butyrolactone unit to accomplish the synthesis of various paraconic acids. PMID- 27995239 TI - Tuning the hybridization properties of modified oligonucleotides: from flexible to conformationally constrained phosphonate internucleotide linkages. AB - The concept of conformational restriction leading to the preorganization of modified strands has proven to be successful and has afforded nucleic acid analogues with many interesting properties suitable for various biochemical applications. We utilized this concept to prepare a set of constrained oligonucleotides derived from 1,4-dioxane and 1,3-dioxolane-locked nucleoside phosphonates and evaluated their hybridization affinities towards their complementary RNA strands. With an increase of DeltaTm per modification up to +5.2 degrees C, the hybridization experiments revealed the (S)-2',3'-O phosphonomethylidene internucleotide linkage as one of the most Tm-increasing modifications reported to date. Moreover, we introduced a novel prediction tool for the pre-selection of potentially interesting chemical modifications of oligonucleotides. PMID- 27995240 TI - Systematic synthetic and biophysical development of mixed sequence DNA binding agents. AB - It is now well established that, although only about 5% of the human genome codes for protein, most of the DNA has some function, such as synthesis of specific, functional RNAs and/or control of gene expression. These functional sequences open immense possibilities in both biotechnology and therapeutics for the use of cell-permeable, small molecules that can bind mixed-base pair sequences of DNA for regulation of genomic functions. Unfortunately very few types of modules have been designed to recognize mixed DNA sequences and for progress in targeting specific genes, it is essential to have additional classes of compounds. Compounds that can be rationally designed from established modules and which can bind strongly to mixed base pair DNA sequences are especially attractive. Based on extensive experience in design of minor-groove agents for AT recognition, a small library of compounds with two AT specific binding modules, connected through linkers which can recognize the G.C base pairs, were prepared. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that some pyridyl-linked compounds bind with the target sequence with sub-nanomolar KD, with very slow dissociation kinetics and 200 times selectivity over the related sequence without a G.C base pair. Interestingly, a set of compounds with AT module connected by different linkers shows cooperative dimer recognition of related sequences. This type of design approach can be expanded to additional modules for recognition of a wide variety of sequences. PMID- 27995242 TI - Surface acoustic wave enabled pipette on a chip. AB - Mono-disperse droplet formation in microfluidic devices allows the rapid production of thousands of identical droplets and has enabled a wide range of chemical and biological studies through repeat tests performed at pico-to nanoliter volume samples. However, it is exactly this efficiency of production which has hindered the ability to carefully control the location and quantity of the distribution of various samples on a chip - the key requirement for replicating micro well plate based high throughput screening in vastly reduced volumetric scales. To address this need, here, we present a programmable microfluidic chip capable of pipetting samples from mobile droplets with high accuracy using a non-contact approach. Pipette on a chip (PoaCH) system selectively ejects (pipettes) part of a droplet into a customizable reaction chamber using surface acoustic waves (SAWs). Droplet pipetting is shown to range from as low as 150 pL up to 850 pL with precision down to tens of picoliters. PoaCH offers ease of integration with existing lab on a chip systems as well as a robust and contamination-free droplet manipulation technique in closed microchannels enabling potential implementation in screening and other studies. PMID- 27995243 TI - Nano-layered magnesium fluoride reservoirs on biomaterial surfaces strengthen polymorphonuclear leukocyte resistance to bacterial pathogens. AB - Biomaterial-related bacterial infections cause patient suffering, mortality and extended periods of hospitalization, imposing a substantial burden on medical systems. In this context, understanding of nanomaterials-bacteria-cells interactions is of both fundamental and clinical significance. Herein, nano-MgF2 films were deposited on titanium substrate via magnetron sputtering. Using this platform, the antibacterial behavior and mechanism of the nano-MgF2 films were investigated in vitro and in vivo. It was found that, for S. aureus (CA-MRSA, USA300) and S. epidermidis (RP62A), the nano-MgF2 films possessed excellent anti biofilm activity, but poor anti-planktonic bacteria activity in vitro. Nevertheless, both the traditional SD rat osteomyelitis model and the novel stably luminescent mouse infection model demonstrated that nano-MgF2 films exerted superior anti-infection effect in vivo, which cannot be completely explained by the antibacterial activity of the nanomaterial itself. Further, using polymorphonuclear leukocytes (PMNs), the critical immune cells of innate immunity, a complementary investigation of MgF2-bacteria-PMNs co-culturing revealed that the nano-MgF2 films improved the antibacterial effect of PMNs through enhancing their phagocytosis and stability. To our knowledge, this is the first time of exploring the antimicrobial mechanism of nano-MgF2 from the perspective of innate immunity both in vitro and in vivo. Based on the research results, a plausible mechanism is put forward for the predominant antibacterial effect of nano-MgF2in vivo, which may originate from the indirect immune enhancement effect of nano-MgF2 films. In summary, this study of surface antibacterial design using MgF2 nanolayer is a meaningful attempt, which can promote the host innate immune response to bacterial pathogens. This may give us a new understanding towards the antibacterial behavior and mechanism of nano-MgF2 films and pave the way towards their clinical applications. PMID- 27995247 TI - Designing ordered mesoporous aluminosilicates under acidic conditions via an intrinsic hydrolysis method. AB - Acid-mediated synthesis of ordered mesoporous aluminosilicates (OMAS) with medium to-strong Bronsted acid sites and trivalent aluminium exclusively in a tetrahedral framework structure is realized by a newly devised intrinsic hydrolysis method. In this way, we have synthesized a series of well-ordered OMAS, e.g., H-AlSBA-15 and H-AlIITM-56, which are otherwise difficult to distinguish under acidic conditions owing to very different hydrolysis rates of both silicon and aluminium sources used for preparation as well as easy dissociation of thus formed Al-O-Si bonds. This novel intrinsic hydrolysis approach, however, relies mainly on similar hydrolysis rates of constituent inorganic species leading to efficient condensation. Thus, the innovative methodology using tetraethyl orthosilicate and aluminium citrate, respectively, as tetravalent silicon and trivalent aluminium as precursors facilitates the formation of high quality OMAS with a narrow pore size distribution, thicker walls, and trivalent aluminium in a tetrahedral framework structure with a high aluminium content, as evidenced by a battery of characterization techniques, viz., XRD, XRF, SEM, TEM and BET. The resulting materials, in turn, generate Bronsted acid sites in the aluminosilicate matrix, with the absence of the usually encountered Lewis acid sites, viz., extra-framework and/or non-framework species, as confirmed by both 27Al MAS-NMR and NH3-TPD studies. All the prepared catalysts exhibit excellent activity towards the tertiary butylation of phenol, and the high activity of the catalysts is attributed to the unique and exclusive presence of medium-to-strong acid sites in the OMAS matrix. PMID- 27995244 TI - Nanoporous carbon derived from a functionalized metal-organic framework as a highly efficient oxygen reduction electrocatalyst. AB - High levels of iron-nitrogen doped porous carbon materials are obtained from MOF 253 using a step-by-step post-synthetic modification strategy. MOF-253 possessing open 2,2'-bipyridine nitrogen sites not only serves as a precursor but also provides chelate bonding sites for Fe2+. Followed by further impregnation of 1,10 phenanthroline, high surface area porous carbon materials are obtained. For comparison, when iron-1,10-phenanthroline species as a whole are incorporated into MOF-253, carbon materials with less active sites and low surface area are obtained. The porous carbon materials derived from MOF-253 by using a step-by step post-synthetic modification strategy demonstrate excellent ORR activity, high selectivity (direct 4e- reduction of oxygen to water) and stability under both alkaline and acidic conditions. The onset potential of the porous carbon material under alkaline conditions (980 mV) is the same as that of Pt/C (20 wt%) (980 mV) and the half-wave potential (E1/2) is 840 mV, which is 20 mV more than that of Pt/C (20 wt%). Under acidic conditions, the onset potential and the half wave potential are only 20 mV and 30 mV less than those of Pt/C (20 wt%). The developed step-by-step post-synthetic modification route of MOFs has expanded the ways to prepare functionalized porous carbon for energy related applications. PMID- 27995248 TI - Phase transition and aggregation behaviour of an UCST-type copolymer poly(acrylamide-co-acrylonitrile) in water: effect of acrylonitrile content, concentration in solution, copolymer chain length and presence of electrolyte. AB - An UCST-type copolymer of acrylamide (AAm) and acrylonitrile (AN) (poly(AAm-co AN)) was prepared by reversible addition fragmentation chain transfer (RAFT) polymerization and its temperature-induced phase transition and aggregation behaviour studied by turbidimetry, static and dynamic light scattering, small angle neutron scattering (SANS) and cryo-transmission electron microscopy (cryo TEM) measurements. The phase transition temperature was found to increase with increasing AN content in the copolymer, concentration of the solutions and copolymer chain length. A significant effect was observed onto the phase transition temperature by addition of different electrolytes into the copolymer solution. The copolymer chains were aggregated below the phase transition temperature and disaggregated above it. The size of the aggregates increases with increasing AN contents and concentration of the copolymer solutions below the phase transition temperature. The copolymer chains were expanded and weekly associated in solution above the phase transition temperature. A model is proposed to explain such association-aggregation behaviour of poly(AAm-co-AN) copolymers depending on AN contents and concentration of the copolymer solutions as a function of temperature. PMID- 27995249 TI - Isolation, structure and magnetic properties of two novel core-shell 3d-4f heterometallic nanoscale clusters. AB - Two novel core-shell Ni-Ln nanosized clusters, Na4(H3O)4[Nd38Ni42.5(IDA)42(OAc)4(CH3CH2OH)2(CO3)18(MU3-OH)62(MU3 O)6(H2O)12]Cl6.26H2O (1) and Na[Pr42Ni38(MU3-OH)71(MU3 O)4(IDA)38(NH2CH2COO)2(OAc)2(CH3CH2OH)2(CO3)16(H2O)6Cl7]Cl3.37H2O (2) (IDA = iminodiacetate), were successfully prepared using the Cl- anion and the flexible ligand iminodiacetic acid. Structural analysis indicates that the discrete dumbbell-shaped 3d-4f heterometallic cluster in 1 is constructed from two {Nd19Ni21} clusters connected by one {NiO6} unit, whereas the bowknot-shaped nanosized cluster is composed of two {Pr19Ni19} clusters ligated by two {Pr2} units and CO32- anions. The formation of both compounds indicates that Cl- ions play important roles and act not only as balance anions but also as template and bridging ligands. The magnetic properties of compounds 1 and 2 were investigated, and it was revealed that they display dominant antiferromagnetic exchange. PMID- 27995250 TI - Discovery of new dual binding TNKS inhibitors of Wnt signaling inhibition by pharmacophore modeling, molecular docking and bioassay. AB - Tankyrases (TNKS), key transmitters in the Wnt signaling pathway which is very conservative in evolution, are vital targets as they are overexpressed widely in many cancers. In this work, 5 inhibitors with novel structures have been discovered and validated using the ligand-based (pharmacophore) virtual screening, docking study, and Luciferase reporter assays for Wnt signaling. Among them, PYL-1, in particular, was the most potent inhibitor with an IC50 value of 9.56 MUM against Wnt signaling. The analysis of binding modes was performed to further understand the vital interactions between inhibitors and TNKS 2, and the five hits belong to dual site inhibitors. This work could be helpful for the design and development of novel dual binders as TNKS inhibitors. PMID- 27995251 TI - A flexible transparent colorimetric wrist strap sensor. AB - A flexible, transparent, and portable wrist strap sensor device has been well developed from a hierarchical polydiacetylene/MoS2 nanocomposite (PDA/MoS2) film. MoS2 with a nanoflake structure and chelation ability acts as a supporter for PDA films to enhance the porosity as well as the transparency of films, which increases the sensitivity, selectivity, and application potential of a PDA sensor. The PDA/MoS2 film sensor shows a linear detection range for N,N dimethylformamide (DMF) vapor from 0.01% to 4% with a visible blue to red color change detected by the naked eye, which is more sensitive than other organic vapors. Exploiting the high transparency, vivid color change, remarkable flexibility and reliability, a wearable wrist strap sensor device with visible DMF sensing ability is fabricated based on PDA/MoS2 films, indicating their great potential for smart wearable devices. PMID- 27995252 TI - Tracking the formation of supramolecular G-quadruplexes via self-assembly enhanced emission. AB - We report the synthesis and self-assembly of two lipophilic 2'-deoxyguanosine (G) derivatives whose fluorescence intensity is modulated by self-assembly into supramolecular G-quadruplexes (SGQs). Whereas both derivatives self-assemble isostructurally, one shows up to 100% emission enhancement while the other shows an initial enhancement, followed by 10% quenching. Thus, the rotational restrictions resulting from self-assembly are enough to induce significant changes in emission, but it is critical to consider the specific interactions between fluorophores since they will determine the ultimate emission signature. These findings could open the door to the development of luminescent supramolecular sensors and probes. PMID- 27995253 TI - The correlations of the electronic structure and film growth of 2,7 diocty[1]benzothieno[3,2-b]benzothiophene (C8-BTBT) on SiO2. AB - Combining ultraviolet photoemission spectroscopy (UPS), X-ray photoemission spectroscopy (XPS), atomic force microscopy (AFM) and small angle X-ray diffraction (SAXD) measurements, we perform a systematic investigation on the correlations of the electronic structure, film growth and molecular orientation of 2,7-diocty[1]benzothieno[3,2-b]benzothiophene (C8-BTBT) on silicon oxide (SiO2). AFM analysis reveals a phase transition of disorderedly oriented molecules in clusters in thinner films to highly ordered standing-up molecules in islands in thicker films. SAXD peaks consistently support the standing-up configuration in islands. The increasing ordering of the molecular orientation with film thickness contributes to the changing of the shape and lowering of the leading edge of the highest occupied molecular orbital (HOMO). The end methyl of the highly ordered standing molecules forms an outward pointing dipole layer which makes the work function (WF) decrease with increasing thickness. The downward shift of the HOMO and a decrease of WF result in unconventional downward band bending and decreased ionization potential (IP). The correlations of the orientation ordering of molecules, film growth and interface electronic structures provide a useful design strategy to improve the performance of C8-BTBT thin film based field effect transistors. PMID- 27995254 TI - Primary vs. secondary H-atom abstraction in the Cl-atom reaction with n-pentane. AB - Velocity map imaging (VMI) measurements and quasi-classical trajectory (QCT) calculations on a newly developed, global potential energy surface (PES) combine to reveal the detailed mechanisms of reaction of Cl atoms with n-pentane. Images of the HCl (v = 0, J = 1, 2 and 3) products of reaction at a mean collision energy of 33.5 kJ mol-1 determine the centre-of-mass frame angular scattering and kinetic energy release distributions. The HCl products form with relative populations of J = 0-5 levels that fit to a rotational temperature of 138 +/- 13 K. Product kinetic energy release distributions agree well with those derived from a previous VMI study of the pentyl radical co-product [Estillore et al., J. Chem. Phys. 2010, 132, 164313], but the angular distributions show more pronounced forward scattering. The QCT calculations reproduce many of the experimental observations, and allow comparison of the site-specific dynamics of abstraction of primary and secondary H-atoms. They also quantify the relative reactivity towards Cl atoms of the three different H-atom environments in n pentane. PMID- 27995255 TI - Surface enhanced spectroscopic investigations of adsorption of cations on electrochemical interfaces. AB - The adsorption of alkali and tetraalkylammonium cations on Pt is investigated using surface enhanced infrared absorption spectroscopy and carbon monoxide as a probe molecule. Alkali cations exhibit a stronger adsorption than organic cations, with potassium showing the strongest effect, followed by sodium and lithium. PMID- 27995256 TI - Theoretical study on substituent and solvent effects for nanocubes formed with gear-shaped amphiphile molecules. AB - Gear-shaped amphiphile molecules (1) recently synthesized by Hiraoka et al. self assemble into a hexameric structure, nanocubes (16), in 25% aqueous methanol due to a solvophobic effect. Here we have carried out molecular dynamic simulations to elucidate the stability of these hexameric capsules (16 and 26) in water, 25% aqueous methanol, and methanol. In all solvents, the 16 nanocubes are maintained for all trajectories. On the other hand, 26 was found to collapse for one trajectory in water and seven trajectories in 25% aqueous methanol. In a pure methanol solvent, 26 was found to collapse for all trajectories. The number of collapsed trajectories of 26 increased with the amount of methanol in the solvent. We therefore focused on the structure of the pi-pi stacking between pyridyl groups and the CH-pi interactions between the methyl and pyridyl groups within the nanocube. Our study clearly shows the role played by the methanol solvent molecules in the assembly of the nanocube in terms of the substituent and solvent effects at the molecular level, and that these substituent and solvent effects are important for the self-assembly of the nanocubes. PMID- 27995257 TI - Supramolecular organization of perfluorinated 1H-indazoles in the solid state using X-ray crystallography, SSNMR and sensitive (VCD) and non sensitive (MIR, FIR and Raman) to chirality vibrational spectroscopies. AB - 1H-Indazole derivatives exhibit a remarkable property since some of them form chiral supramolecular structures starting from achiral monomers. The present work deals with the study of three perfluorinated 1H-indazoles that resolve spontaneously as conglomerates. These conglomerates can contain either a pure enantiomer (one helix) or a mixture of both enantiomers (both helices) with an enantiomeric excess (e.e.) of one of them. The difficulty of the structural analysis of these types of compounds is thus clear. We outline a complete strategy to determine the structures and configurations (M or P helices) of the enantiomers (helices) forming the conglomerates of these perfluorinated 1H indazoles based on X-ray crystallography, solid state NMR spectroscopy and different solid state vibrational spectroscopies that are either sensitive (VCD) or not (FarIR, IR and Raman) to chirality, together with quantum chemical calculations (DFT). PMID- 27995258 TI - Polaron dynamics with off-diagonal coupling: beyond the Ehrenfest approximation. AB - Treated traditionally by the Ehrenfest approximation, the dynamics of a one dimensional molecular crystal model with off-diagonal exciton-phonon coupling is investigated in this work using the Dirac-Frenkel time-dependent variational principle with the multi-D2Ansatz. It is shown that the Ehrenfest method is equivalent to our variational method with the single D2Ansatz, and with the multi D2Ansatz, the accuracy of our simulated dynamics is significantly enhanced in comparison with the semi-classical Ehrenfest dynamics. The multi-D2Ansatz is able to capture numerically accurate exciton momentum probability and help clarify the relation between the exciton momentum redistribution and the exciton energy relaxation. The results demonstrate that the exciton momentum distributions in the steady state are determined by a combination of the transfer integral and the off-diagonal coupling strength, independent of the excitonic initial conditions. We also probe the effect of the transfer integral and the off-diagonal coupling on exciton transport in both real and reciprocal space representations. Finally, the variational method with importance sampling is employed to investigate temperature effects on exciton transport using the multi-D2Ansatz, and it is demonstrated that the variational approach is valid in both low and high temperature regimes. PMID- 27995259 TI - On the accuracy of the general, state-specific polarizable-continuum model for the description of correlated ground- and excited states in solution. AB - Equilibrium and non-equilibrium formulations of the state-specific polarizable continuum model (SS-PCM) are evaluated in combination with correlated ground- and excited-state densities provided by the algebraic-diagrammatic construction method (ADC) for the polarization propagator via the computationally efficient intermediate-state representation (ISR) formalism. Since the influence of the SS PCM onto quantum-chemical method is naturally limited to the presence of the apparent surface charges in the one-electron Hamiltonian and hence fully contained in the polarized MOs, the herein presented solvent model can be combined with all implemented orders and variants of ADC. Employing ADC/SS-PCM, the symmetric, ionized dimers of neon, ethene and nitromethane are investigated. Their broken-symmetry wavefunctions exhibit a low-lying charge-transfer state that is symmetry-equivalent to the ground state. This curious though ultimately artificial feature is convenient as it allows for a direct comparison of ADC/SS PCM for the CT state to the Moller-Plesset/PCM description of the ground state. The agreement down to 0.02 eV for a wide range of dielectric constants validates the ADC/SS-PCM approach. Eventually, the relaxed potential-energy surfaces of the ground and lowest excited states of 4-(N,N)-dimethylaminobenzonitrile in cyclohexane and acetonitrile are computed, and it is demonstrated that the ADC(2)/SS-PCM approach affords excellent agreement with experimental fluorescence data. Only at the ADC(3) level of theory, however, the experimentally observed solvent-dependent dual fluorescence can be explained. PMID- 27995260 TI - Generalized Born implicit solvent models for small molecule hydration free energies. AB - Hydration free energy estimation of small molecules from all-atom simulations was widely investigated in recent years, as it provides an essential test of molecular force fields and our understanding of solvation effects. While explicit solvent representations result in highly accurate models, they also require extensive sampling due to the high number of solvent degrees of freedom. Implicit solvent models, such as those based on the generalized Born model for electrostatic solvation effects and a solvent accessible surface area term for nonpolar contributions (GBSA), significantly reduce the number of degrees of freedom and the computational cost to estimate hydration free energies. However, a recent survey revealed a gap in the accuracy between explicit TIP3P solvent estimates and those computed with many common GBSA models. Here we address this shortcoming by providing a thorough comparison of the performance of three implicit solvent models with different nonpolar contributions and a generalized Born term to estimate experimental hydration free energies. Starting with a minimal set of only ten atom types, we demonstrate that a nonpolar term with atom type dependent surface tension coefficients in combination with an accurate generalized Born term and fully optimized parameters performs best in estimating hydration free energies, even yielding comparable results to the explicit TIP3P water model. Analysis of our results provides evidence that the asymmetric behavior of water around oppositely charged atoms is one of the main sources of error for two of the three implicit solvent models. Explicitly accounting for this effect in the parameterization reduces the corresponding errors, suggesting this as a general strategy for improving implicit solvent models. The findings presented here will help to improve the existing generalized Born based implicit solvent models implemented in state-of-the-art molecular simulation packages. PMID- 27995261 TI - Interval increase in the prevalence of symptomatic cholelithiasis-associated non alcoholic fatty liver disease over a ten-year period in an Asian population. AB - INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is frequently associated with cholelithiasis. The prevalence of NAFLD in Asia has been on the rise, but the magnitude of this increase had not been studied previously. METHODS: A retrospective cohort study was conducted on consecutive patients who underwent laparoscopic or open cholecystectomy from November 2001 to November 2004 (Cohort 1) and from November 2011 to November 2014 (Cohort 2) at Singapore General Hospital. Preoperative diagnostic scans (e.g. ultrasonography, computed tomography and magnetic resonance imaging) and clinical data were reviewed for the presence of fatty liver. Statistical analysis was performed. RESULTS: In Cohorts 1 and 2, 127 patients and 99 patients were operated on, respectively. Cohort 2 had significantly higher proportions of patients with NAFLD (56.6% vs. 40.2%; p < 0.015) and hyperlipidaemia (45.5% vs. 18.9%; p < 0.001) as compared to Cohort 1. Binary logistic regression analysis showed that hypertension (odds ratio [OR] 2.558; p < 0.004) and Indian ethnicity (OR 5.448; p < 0.043) were significantly associated with NAFLD. CONCLUSION: Similar to other international studies, we found a significant increase in the prevalence of patients with NAFLD presenting symptomatically for cholecystectomy over an interval of ten years in Singapore. Hypertension and Indian ethnicity were significantly associated with NAFLD in both time periods. This trend supports the need for concerted public health intervention to stem the increasing incidence of NAFLD and prevent its progression to more advanced liver disease. PMID- 27995262 TI - Anti-apoptotic and myocardial protective effects of ethyl pyruvate after regional ischaemia/reperfusion myocardial damage in an in vivo rat model. AB - INTRODUCTION: The integration of reactive oxygen species is strongly associated with important pathophysiological mechanisms that mediate myocardial ischaemia/reperfusion (I/R) damage. Pyruvate is an efficacious scavenger of reactive oxygen species and a previous study has shown that ethyl pyruvate (EP) has a myocardial protective effect against regional I/R damage in an in vivo rat model. The purpose of this study was to determine whether the myocardial protective effect of EP is associated with anti-apoptosis. METHODS: Rats were allocated to receive EP dissolved in lactated Ringer's solution or lactated Ringer's solution alone, via intraperitoneal infusion one hour before ischaemia. They were exposed to 30 minutes of ischaemia followed by reperfusion of the left coronary artery territory over two hours. Anti-apoptotic effects were checked using several biochemical parameters after two hours of reperfusion. Apoptosis was analysed using measured caspase-3 activity, Western blotting of B-cell lymphoma 2 (Bcl-2) family protein cleaved by caspase-3, and assessment of DNA laddering patterns and the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining test. RESULTS: In ischaemic myocardium, EP increased Bcl-2 expression, but reduced Bcl-2-associated X protein and cleaved caspase-3 expressions. EP reduced the expression of DNA laddering and the number of myocardial I/R-damaged TUNEL-positive cells. CONCLUSION: This study demonstrated that EP has an anti-apoptotic effect after regional I/R damage in an in vivo rat heart model. The myocardial protective effect of EP may be related to its anti apoptotic effect. PMID- 27995263 TI - Outpatient management of transient ischaemic attack. AB - Stroke is a significant cause of death and disability in Singapore; in 2014, it was the fourth most common cause of death. Transient ischaemic attack (TIA) is defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischaemia without evidence of acute infarction. The diagnosis of TIA/acute stroke needs to be considered in all patients who present with sudden focal neurological dysfunction. Prompt referral for assessment, neuroimaging and intervention provides the best chance for neurological recovery and/or minimising further neurological damage. Primary care physicians have a crucial role in TIA/stroke prevention and management. This includes referring patients with suspected acute TIA/stroke to hospitals with stroke treatment facilities immediately; managing the modifiable risk factors of cerebral ischaemia; continuing prescription of antiplatelet agents and/or anticoagulation where indicated; and teaching patients to recognise and respond to suspected cerebral ischaemia using the FAST (face, arm, speech, time) acronym. PMID- 27995264 TI - Clinics in diagnostic imaging (172). Colocolic intussusception with a lipoma as the lead point. AB - A 50-year-old Chinese man presented with abdominal pain associated with bloody mucoid stools, loss of appetite and weight loss. Contrast-enhanced computed tomography of the abdomen and pelvis revealed a colocolic intussusception secondary to a lipoma. The patient subsequently underwent a left hemicolectomy. Clinical and imaging findings of intussusception in adults are discussed in this article. PMID- 27995265 TI - A case of adult submersion injury with clinical and radiological evidence of severe brain and lung injury, and subsequent complete clinical recovery. PMID- 27995267 TI - [Implementation of alternative treatment models for refugees in Germany : What can and what should we learn from Afghanistan?] PMID- 27995266 TI - Cardiac computed tomography : A new player in the imaging portfolio for myocardial fibrosis. PMID- 27995268 TI - [Psychiatric and psychotherapeutic care of refugees : Challenges and perspectives]. PMID- 27995269 TI - [New legal regulations for palliative care with implications for politics and practice]. AB - In December 2015 two different laws were adopted. Both are of importance for palliative care. One of the laws criminalizes commercial, "business-like" assisted suicide (S 217 German Criminal Code), the other one aims to improve hospice and palliative care in Germany. Through the latter far-reaching changes in Social Code Books V and XI, as well as of the Hospital Finance Act have been made. This new Act to Improve Hospice and Palliative Care (HPG) focuses, amongst others, on: (a) Better funding of hospice services, by raising the minimum grant for patients in inpatient hospices paid per day by the health insurance funds by about 28.5%, and for outpatient hospice services by about 18%; (b) further development of general outpatient nursing and medical palliative care, and the networking of different service providers; (c) introduction of an arbitration procedure for service provider agreements to be concluded between the health insurance funds and the teams providing specialized home palliative care (SAPV); (d) the right to individual advice and support by the health insurance funds; (e) care homes may offer their residents advance care planning programs to be funded by the statutory health insurers; (f) palliative care units in hospitals can be remunerated outside the DRG system by per diem rates; (g) separate funding and criteria for multi-professional palliative care services within a hospital.While little concrete impact on hospice and palliative care can be expected following the new S 217 German Criminal Code, the HPG provides a good basis to improve care. For this purpose, however, which complementary and more concrete agreements are made to put the new legal regulations into practice will be crucial. PMID- 27995270 TI - ? AB - On February 5th, 2016 an expert meeting on rapid diagnostic tests (RDT) for sexually transmitted infections (STI) was held in Berlin at the Robert-Koch Institute. The aim of the conference was to update a former evaluation of RDTs for diagnosis of HIV, HBV, HCV, T. pallidum, C. trachomatis and N. gonorrhoeae in low-threshold counseling services for STI that had been published after the previous meeting in 2012. According to the strategy to control HIV, hepatitis B and C and other STI, recently adopted by the German Government, there is a lack of test capabilities and a demand for more testing services as well as improved access to testing. Using RDTs as low-threshold test services in counseling centers or even for testing at home may provide an important option to lower the barrier of testing. Based on performance data evaluated in clinical trials some RDTs for HIV, HCV and syphilis are quite well suited as a point-of-care Test (POCT). In contrast, sufficient diagnostic accuracy for detection of C. trachomatis and N. gonorrhoeae can only be achieved by PCR-based POCTs. In Germany the use of POCTs is subjected to legal stipulations of IfSG and MPG. Of importance, it is not allowed to deliver HIV tests to private persons for home testing (S 11, MPG). Furthermore, both assessment and communication of infectious diseases are reserved to the physician and must not happen as remote diagnostics (S 24, IfSG). In addition, like all laboratory tests, RDTs are subject to quality assessment according to guidelines of the German Medical Association. PMID- 27995271 TI - [Functional electrostimulation for drop foot treatment : Clinical outcome]. AB - INTRODUCTION: Neurologic paralysis of the foot due to damage to the central nervous system is primarily caused by a cerebral insult. The ankle-foot orthosis (AFO), which is the classical conservative treatment option, is associated with drawbacks, e.g., increased contractures, limited mobilization from the sitting position, and cosmetic aspects. METHODS: Functional external electrostimulation (FES) is an suitable treatment method for patients with a central lesion and intact peroneal nerve. Based on this method, the neuroprosthesis is a dynamic therapy option in the form of an implantable nerve stimulator (ActiGait(r) system, Otto Bock, Duderstadt, Germany) which is placed directly on the motor branch of the peroneus nerve and results in active foot lifting. The aim of the present study is to evaluate the clinical effect of the ActiGait(r) system with regard to its suitability for everyday use by means of gait tests with an emphasis on time-distance parameters and to compare it with the current literature. RESULTS AND CONCLUSION: In this retrospective study, the clinical results after implantation of the ActiGait(r) system are presented and evaluated. In summary, the implantation of a neuroprosthesis in patients with stroke-related drop foot represents a sensible and promising therapy option. PMID- 27995272 TI - [Mastocytosis : Clinical aspects, diagnostics, therapy]. AB - Mastocytosis is a rare, almost exclusively sporadically occurring disease involving an increase in clonal tissue mast cells. The disease spectrum is heterogenous, ranging from isolated skin lesions with a normal life expectancy to rare, aggressive forms with very poor prognosis. Children are often affected. But whereas these almost invariantly display solely a cutaneous mastocytosis with polymorphous skin lesions, in adults the lesions are small and maculopapular and in over 80% of cases accompanied by involvement of bone marrow and the D816V activating mutation of the gene for the c-Kit receptor. There are many symptoms for the disease. Patients suffer frequently from pruritus, diarrhea, abdominal cramp, palpitations and flush. Osteoporosis is often present, with osteolysis with pathological fractures frequently involved in more aggressive forms. Patients are especially at risk to severe anaphylaxis caused by hymenoptera stings. Therapy is symptomatic, with cytoreductive therapy reserved for resistant and aggressive forms. PMID- 27995273 TI - [Partial response of solar urticaria to omalizumab therapy]. AB - The treatment of solar urticaria is regarded as difficult. In some cases good responses to the anti-IgE antibody omalizumab (Xolair(r)), approved for treatment of chronic spontaneous urticaria, have been reported. We report on a 50-year-old Caucasian woman who for the last 5 years has developed localized itching and stinging erythemas following exposure to sunlight accompanied sometimes by anaphylactic reactions. Oral antihistamines in three- to four-fold doses and a topical sun screen had been only partially effective in long-term use. Positive immediate-type reactions with whealing appeared in phototesting with low doses of UVB and UVA. Three weeks after s. c. injection of 300 mg omalizumab, the minimal urticarial dose (MUD) for UVB was increased at least 20-fold (from <0.001 to 0.02 J/cm2) and for UVA four-fold (from 0.1 to 0.4 J/cm2) and the patient reported no itching at the test area. On the other hand, MUD for UVA1 remained unchanged (5.0 J/cm2). The weekly urticarial activity score (UAS7) was reduced from 30 points before omalizumab administration to 14 points in weeks two and three. Overall, a partial response of solar urticaria to omalizumab therapy could be observed in the present case. PMID- 27995274 TI - Emergence of Life on Earth: A Physicochemical Jigsaw Puzzle. AB - We review physicochemical factors and processes that describe how cellular life can emerge from prebiotic chemical matter; they are: (1) prebiotic Earth is a multicomponent and multiphase reservoir of chemical compounds, to which (2) Earth Moon rotations deliver two kinds of regular cycling energies: diurnal electromagnetic radiation and seawater tides. (3) Emerging colloidal phases cyclically nucleate and agglomerate in seawater and consolidate as geochemical sediments in tidal zones, creating a matrix of microspaces. (4) Some microspaces persist and retain memory from past cycles, and others re-dissolve and re disperse back into the Earth's chemical reservoir. (5) Proto-metabolites and proto-biopolymers coevolve with and within persisting microspaces, where (6) Macromolecular crowding and other non-covalent molecular forces govern the evolution of hydrophilic, hydrophobic, and charged molecular surfaces. (7) The matrices of microspaces evolve into proto-biofilms of progenotes with rudimentary but evolving replication, transcription, and translation, enclosed in unstable cell envelopes. (8) Stabilization of cell envelopes 'crystallizes' bacteria-like genetics and metabolism with low horizontal gene transfer-life 'as we know it.' These factors and processes constitute the 'working pieces' of the jigsaw puzzle of life's emergence. They extend the concept of progenotes as the first proto cellular life, connected backward in time to the cycling chemistries of the Earth Moon planetary system, and forward to the ancient cell cycle of first bacteria like organisms. Supra-macromolecular models of 'compartments first' are preferred: they facilitate macromolecular crowding-a key abiotic/biotic transition toward living states. Evolutionary models of metabolism or genetics 'first' could not have evolved in unconfined and uncrowded environments because of the diffusional drift to disorder mandated by the second law of thermodynamics. PMID- 27995275 TI - Genome-wide mapping and prediction suggests presence of local epistasis in a vast elite winter wheat populations adapted to Central Europe. AB - KEY MESSAGE: Genome-wide association mapping as well as marker- and haplotype based genome-wide selection unraveled a complex genetic architecture of grain yield with absence of large effect QTL and presence of local epistatic effects. The genetic architecture of grain yield determines to a large extent the optimum design of genomic-assisted wheat breeding programs. The main goal of our study was to examine the potential and limitations to dissect the genetic architecture of grain yield in wheat using a large experimental data set. Our study was based on phenotypic information and genomic data of 13,901 SNPs of a diverse set of 3816 elite wheat lines adapted to Central Europe. We applied genome-wide association mapping based on experimental and simulated data sets and performed marker- and haplotype-based genomic prediction. Computer simulations revealed for our mapping population a high power to detect QTL, even if they individually explained only 2.5% of the genetic variation. Despite this, we found no stable marker-trait associations when validating in independent subsets. A two dimensional scan for marker-marker interactions indicated presence of local epistasis which was further supported by improved prediction abilities when shifting from marker- to haplotype-based genome-wide prediction approaches. We observed that marker effects estimated using genome-wide prediction approaches strongly varied across years albeit resulting in high prediction abilities. Thus, our results suggested that the prediction accuracy of genomic selection in wheat is mainly driven by relatedness rather than by exploiting knowledge of the genetic architecture. PMID- 27995277 TI - [Cochlear implant treatment of patients with single-sided deafness or asymmetric hearing loss. German version]. AB - BACKGROUND: The rehabilitation of patients with single-sided deafness (SSD) or asymmetric hearing loss can be achieved with conventional (bilateral) contralateral routing of signals ((Bi)CROS) hearing aids ((Bi)CROS-HA, (Bi)CROS), bone-anchored hearing systems (BAHS) or cochlear implants (CI). To date, only small case series have been published on treatment outcomes in SSD patients after CI surgery and there are only a few comparative studies evaluating rehabilitation outcomes. OBJECTIVE: The aim of this study was to provide evidence of successful treatment of SSD and asymmetric hearing loss with a CI compared to the untreated monaural hearing condition and the BAHS and (Bi)CROS treatment options in a large number of patients. MATERIALS AND METHODS: In a single-centre study, 45 patients with SSD and 40 patients with asymmetric hearing loss were treated with a CI after careful evaluation for CI candidacy. Monaural speech comprehension in noise and localisation ability were examined with (Bi)CROS-HA and BAHS devices (on a test rod) both preoperatively and at 12 months after CI switch-on. At the same intervals, subjective evaluation of hearing ability was conducted using the Speech, Spatial and Qualities of Hearing Scale (SSQ). RESULTS: This report presents the first evidence of successful binaural rehabilitation with CI in a relatively large patient cohort and the advantages over (Bi)CROS and BAHS in smaller subgroups, thus confirming the indication for CI treatment. Moreover, patients with long-term acquired deafness (>10 years) show a benefit from the CI comparable to that observed in patients with shorter-term deafness. PMID- 27995276 TI - Seasonal differences of tympanogram and middle ear findings in children. AB - BACKGROUND: It is a known fact that bacterial or viral acute otitis media occurs more frequently in the winter months. Only a few older studies on seasonal differences in middle ear findings are available. These studies are based solely on tympanography, without correlation to intraoperative middle ear findings. This study addresses the question of whether seasonal differences can be found in the preoperative tympanogram and in the corresponding intraoperative findings in children with chronic middle ear problems. PATIENTS AND METHODS: This retrospective study included patients who had undergone myringotomy with or without tympanostomy tube insertion at the Charite-Universitatsmedizin Berlin between January and December 2011. Corresponding to the catarrhal phases, winter months were defined as those from November to April; summer months from May to October. The preoperative tympanogram and the documented intraoperative middle ear finding were statistically analyzed for seasonal differences. RESULTS: A total of 654 ears from 206 male and 127 female patients with mean age 3.7 +/- 2.5 years were analyzed. In the majority of cases, a type B tympanogram was found (n = 376; 57.5%), whereas the middle ear was filled with air in 19.1% of cases. No significant seasonal differences were found for either the intraoperative middle ear findings or the preoperative tympanograms (p > 0.05). CONCLUSION: For children with a typical history of chronic otitis media without effusion and chronic tube ventilation dysfunction, myringotomy with or without tympanostomy tube insertion is indicated independently of the season. The results indicate that a wait-and-see approach with hope of improvement during the summer months is not rational. PMID- 27995278 TI - Modulation of PKA, PKC, CAMKII, ERK 1/2 pathways is involved in the acute antidepressant-like effect of (octylseleno)-xylofuranoside (OSX) in mice. AB - RATIONALE: (Octylseleno)-xylofuranoside (OSX) is an organoselenium compound from the class of alkylseleno carbohydrates possessing a C8 alkyl chain. Members of this class of organoselenium compounds have promising pharmacological activities, among them are antioxidant and acute antidepressant-like activities with the involvement of monoaminergic system, as previously presented by our research group. OBJECTIVE: The objective of the study was to investigate the possible involvement of cellular signalling pathways in the antidepressant-like effect caused by OSX (0.01 mg/kg, oral route (p.o.) by gavage) in the tail suspension test (TST) in mice. METHODS: Mice were treated by intracerebroventricular (i.c.v.) injection either with vehicle or with H-89 (1 MUg/site i.c.v., an inhibitor of protein kinase A-PKA), KN-62 (1 MUg/site i.c.v., an inhibitor of Ca2+/calmodulin-dependent protein kinase II-CAMKII), chelerythrine (1 MUg/site i.c.v., an inhibitor of protein kinase C-PKC) or PD098059 (5 MUg/site i.c.v., an inhibitor of extracellular-regulated protein kinase 1/2-ERK1/2). Fifteen minutes after, vehicle or OSX was injected, and 30 min later, the TST and open field tests (OFT) were carried out. RESULTS: The antidepressant-like effect of orally administered OSX was blocked by treatment of the mice with H-89, KN-62, chelerythrine and PD098059; all inhibitors of signalling proteins involved with neurotrophic signalling pathways. The number of crossings in the OFT was not altered by treatment with OSX and/or signalling antagonists. CONCLUSIONS: The results demonstrated that OSX showed an antidepressant-like effect in the TST in mice through the activation of protein kinases PKA, PKC, CAMKII and ERK1/2 that are involved in intracellular signalling pathways. PMID- 27995280 TI - Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD). AB - Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients. PMID- 27995281 TI - The use of stable and unstable green fluorescent proteins for studies in two bacterial models: Agrobacterium tumefaciens and Xanthomonas campestris pv. campestris. AB - Fluorescent proteins have been used to track plant pathogens to understand their host interactions. To be useful, the transgenic pathogens must present similar behaviour than the wild-type isolates. Herein, a GFP marker was used to transform two plant pathogenic bacteria, Agrobacterium and Xanthomonas, to localize and track the bacteria during infection. The transgenic bacteria were evaluated to determine whether they showed the same fitness than the wild-type strains or whether the expression of the GFP protein interfered in the bacterial activity. In Agrobacterium, the plasmid used for transformation was stable in the bacteria and the strain kept the virulence, while Xanthomonas was not able to conserve the plasmid and transformed strains showed virulence variations compared to wild-type strains. Although marking bacteria with GFP to track infection in plants is a common issue, works to validate the transgenic strains and corroborate their fitness are not usual. Results, presented here, confirm the importance of proper fitness tests on the marked strains before performing localization assays, to avoid underestimation of the microbe population or possible artificial effects in its interaction with the plant. PMID- 27995279 TI - From bench to bedside: mGluR2 positive allosteric modulators as medications to treat substance use disorders. AB - OBJECTIVE: This paper provides an overview of the role of type 2 metabotropic glutamate receptors (mGluR2) in addiction and behaviors reflecting addictive processes. RESULTS: AZD8529, an mGluR2 positive allosteric modulator (PAM), failed to separate from placebo in a phase II schizophrenia trial. The demonstration by Athina Markou's laboratory that AZD8529 attenuated both nicotine self-administration and cue-induced reinstatement was a key factor in the decision to move this compound into a smoking cessation study. CONCLUSION: Here, we highlight Markou laboratory's contribution to this project, as well as several innovative features of the phase II clinical trial that has already completed enrollment with top line results expected in early 2017. PMID- 27995282 TI - [ASA classification : Transition in the course of time and depiction in the literature]. AB - The American Society of Anesthesiologists classification of physical status (ASA PS) is a widely used system for categorizing the preoperative status of patients. The ASA class is a good independent predictor of perioperative morbidity and mortality. The definitions of the ASA classes have been amended several times since 1941, resulting in inconsistent and confusing usage in the current literature. Conflicting definitions of ASA PS exist, particularly for classes III, IV and V. The high variability of individual classifications by different anesthesiologist, however, can be explained by the previous lack of examples for diagnoses. In 2014, the ASA has added a catalogue of examples for a simplified definition for classification of the ASA PS. This has so far received limited attention in German-speaking countries. This article describes the transition of the ASA classification over the past 75 years und summarizes the currently valid definitions. PMID- 27995283 TI - Pedicle screw augmentation in osteoporotic spine: indications, limitations and technical aspects. AB - PURPOSE: The need for spinal instrumented fusion in osteoporotic patients is rising. In this review, we try to give an overview of the current spectrum of pedicle screw augmentation techniques, safety aspects and indications. METHODS: Review of literature and discussion of indications, limitations and technical aspects. RESULTS: Various studies have shown higher failure rates in osteoporotic patients, most probably due to reduced bone quality and a poor bone-screw interface. Augmentation of pedicle screws with bone cement, such as polymethylmethacrylate or calcium based cements, is one valid option to enhance fixation if required. CONCLUSIONS: Crucial factors for success in the use of augmented screws are careful patient selection, a proper technique and choice of the ideal cement augmentation option. PMID- 27995284 TI - An overview on severe infections in Europe. PMID- 27995285 TI - Pace-on-T phenomenon: the wrong spike at the wrong time. PMID- 27995286 TI - Revision surgery in anterior cruciate ligament reconstruction: a cohort study of 17,682 patients from the Swedish National Knee Ligament Register. AB - PURPOSE: To investigate the association between surgical variables and the risk of revision surgery after ACL reconstruction in the Swedish National Knee Ligament Register. METHODS: This cohort study was based on data from the Swedish National Knee Ligament Register. Patients who underwent primary single-bundle ACL reconstruction with hamstring tendon were included. Follow-up started with primary ACL reconstruction and ended with ACL revision surgery or on 31 December, 2014, whichever occurred first. Details on surgical technique were collected using an online questionnaire. All group comparisons were made in relation to an "anatomic" reference group, comprised of essential AARSC items, defined as utilization of accessory medial portal drilling, anatomic tunnel placement, visualization of insertion sites and pertinent landmarks. Study end-point was revision surgery. RESULTS: A total of 108 surgeons (61.7%) replied to the questionnaire. A total of 17,682 patients were included [n = 10,013 males (56.6%) and 7669 females (43.4%)]. The overall revision rate was 3.1%. Older age as well as cartilage injury evident at index surgery was associated with a decreased risk of revision surgery. The group using transtibial drilling and non-anatomic bone tunnel placement was associated with a lower risk of revision surgery [HR 0.694 (95% CI 0.490-0.984); P = 0.041] compared with the anatomic reference group. The anatomic reference group showed no difference in risk of revision surgery compared with the transtibial drilling groups with partial anatomic [HR 0.759 (95% CI 0.548-1.051), n.s.] and anatomic tunnel placement [HR 0.944 (95% CI 0.718 1.241), n.s.]. The anatomic reference group showed a decreased risk of revision surgery compared with the transportal drilling group with anatomic placement [HR 1.310 (95% CI 1.047-1.640); P = 0.018]. CONCLUSION: Non-anatomic bone tunnel placement via transtibial drilling resulted in the lowest risk of revision surgery after ACL reconstruction. The risk of revision surgery increased when using transportal drilling. Performing anatomic ACL reconstruction utilizing eight selected essential items from the AARSC lowered the risk of revision surgery associated with transportal drilling and anatomic bone tunnel placement. Detailed knowledge of surgical technique using the AARSC predicts the risk of ACL revision surgery. LEVEL OF EVIDENCE: III. PMID- 27995287 TI - [Noninfectious differential diagnoses of pneumonia]. AB - BACKGROUND: In patients with a clinical suspicion of pneumonia, typical clinical and laboratory features along with the detection of infiltrates on chest X-ray are as a rule considered diagnostic and therapy is immediately initiated; however, studies have shown that in up to 5% of patients with an initial suspicion of pneumonia, another noninfectious pulmonary disease was the underlying cause. Early recognition and differentiation of diseases mimicking pneumonia are prerequisites for an adequate therapy. OBJECTIVE: The aim of this review is to present the important noninfectious differential diagnoses of pneumonia and to provide the reader with tools for a systematic diagnostic approach. MATERIAL AND METHOD: A literature search was carried out. RESULTS: As alterations in the lungs often result in similar imaging appearances and a differentiation between transudates, exsudates, blood and cells is not feasible by chest X-ray or CT, a systematic approach is essential to make an appropriate diagnosis. Hence, consideration of the temporal course, predominant pattern, distribution of findings, additional findings and clinical presentation are indispensable. PMID- 27995288 TI - Nadolol for Treatment of Supraventricular Tachycardia in Infants and Young Children. AB - Supraventricular tachycardia (SVT) is a common infant arrhythmia, for which beta blockers are frequently chosen as therapy. Propranolol is a common choice though it is dosed every 6-8 h. We reviewed the clinical results of treating infant SVT with an extemporaneous preparation of nadolol. Retrospective cohort study of patients under 2 years old receiving nadolol for SVT at a single center. Patients were ascertained by patient and pharmacy databases. Twenty-eight infants received nadolol, of whom 25 had regular narrow complex tachycardia, 2 atrial flutter, and 1 focal atrial tachycardia. Patient age at initiation was a median 54 days (range 10-720). The final dose was 1 mg/kg/day in 22/28 patients (range 0.5-2). Once daily dosing was used in 20 patients (71.4%); dosing was BID in 7, TID in 1. Among regular narrow complex tachycardia patients, 18/25 received nadolol monotherapy and 7 required additional agents; flecainide in 6, digoxin in 1. The median age of tachyarrhythmia onset was 18 days (range 1-180) with a median age of nadolol initiation of 30 days (range 11-390). Of the 20 regular narrow complex tachycardia patients initiated on nadolol monotherapy, 85% had no recurrences as of 1-year follow-up. Side effects were suspected in 3 of 28 (10.7%), including wheezing (n = 1, 3.5%), irritability and diarrhea (n = 1, 3.5%), and bradycardia (n = 1, 3.5%). Oral nadolol suspension was a successful treatment for SVT in 85% of patients with minimal adverse effects. Single daily dosing was used in the majority of patients. PMID- 27995289 TI - The Fetus with Ectopia Cordis: Experience and Expectations from Two Centers. AB - Ectopia cordis (EC) is a rare congenital anomaly often associated with congenital heart disease (CHD). There is a lack of contemporary information on EC diagnosed prenatally. We sought to combine the experiences of two regional referral centers in order to evaluate current outcomes for EC. Clinical, echocardiographic features and perinatal outcomes of fetuses with EC managed at two large cardiac centers from 1995 to 2014 were retrospectively reviewed. Seventeen fetuses with EC were diagnosed at a median gestational age of 23 weeks (range 17-36). There were 6 thoracic EC and 11 thoracoabdominal. Fifteen had associated CHD: 10 conotruncal defects, 2 tricuspid atresia, 1 aortic stenosis, 1 atrial septal defect, and 1 atrioventricular septal defect. There were 2 terminations of pregnancy, 2 fetal deaths, 2 lost to follow-up, and 11 live born. Mean gestational age at birth was 36.4 weeks (range 26-39). Three patients died shortly after birth with comfort care, and 8 were actively managed. Six patients underwent postnatal cardiac intervention and are currently alive with a mean follow-up of 7.3 years (range 1.4-11.4), 2 of them with chronic dependency on ventilatory support. Two patients without CHD died after attempted chest closure. When diagnosed in utero, a high proportion of pregnancy termination or fetal demise is expected. In our cohort, conotruncal anomalies were the most common associated CHD. Though mortality in actively managed patients was not as high as previously reported, and cardiac surgical intervention may be achieved, EC is still associated with high mortality and significant long-term morbidity. PMID- 27995290 TI - Transposition of Great Arteries with Complex Coronary Artery Variants: Time Related Events Following Arterial Switch Operation. AB - Coronary artery anatomy represents a challenging and, often, determining predictor of outcome in an arterial switch operation (ASO). Impact of specific coronary artery variants, such as single, intramural and inverted, on time related events following ASO, is, yet, to be determined. We sought to compare early and late outcomes within the group of nonstandard coronary artery variants. Patients who underwent ASO from January 1995 to October 2010 were reviewed. Patients with coronary artery variants other than L1Cx1R2 ("standard" by Leiden classification) were included. Patients with single, intramural and inverted coronary artery variants incorporated in group A. All other nonstandard coronary variants incorporated in group B. Demographics, perioperative variables, early and late outcomes were assessed. Of the 123 ASO, 24 patients (19.5%) with nonstandard coronary variant were studied. Thirteen were in group A and 11 in group B. There were two early deaths (1 in group A and 1 in group B) (p > 0.05). There is one death early after hospital discharge (group A). Mean follow-up was 59.4 +/- 55.1 months. There was no structural coronary artery failure after hospital discharge following ASO. Freedom from any reintervention at 8 years was (78.3 +/- 9.6%) (p 0.55) with no late neo-aortic or mitral valve intervention. ASO with single, intramural or inverted coronary artery course carries no added longitudinal risk for structural or flow impairment within the group of nonstandard coronary artery variants. There is an early hazard period with no late survival attrition. Aortic arch repair as part of staged strategy prior to ASO might influence early and late outcome. PMID- 27995291 TI - Assessing Myocardial Function in Infants with Pulmonary Hypertension: The Role of Tissue Doppler Imaging and Tricuspid Annular Plane Systolic Excursion. AB - Transthoracic echocardiography is the most common noninvasive method of evaluating pulmonary hypertension (PH) in infants. Identification of reliable, quantitative indices of myocardial function may enhance the diagnostic value of echocardiography in this population. We hypothesized that pulsed wave tissue Doppler imaging (TDI) and tricuspid annular plane systolic excursion (TAPSE) would be reproducible measurements and would suggest decreased ventricular function, in infants with PH. This retrospective case-control study involved subjects diagnosed clinically and echocardiographically with PH at <12 months of age, matched with controls by age and gestational age (GA). TAPSE was measured by M-mode in the apical 4-chamber view. TDI velocities were averaged from three consecutive cardiac cycles. Observers were blinded to patient identity and clinical status. Fifty-seven subjects, including 35 term or near-term infants >=35 weeks GA [mean GA 39 weeks (+/-1.7), median age 1 day (range 0-2)] and 22 preterm infants [median GA 25.4 weeks (24.1-26.6), age 66 days (4-128)], were matched with 57 controls. Subjects with PH had lower TAPSE (term p < 0.001, preterm p = 0.03) and TAPSE indexed to body surface area (term p < 0.001, preterm p = 0.005). Mitral annular, septal, and tricuspid annular systolic (S') and early diastolic (E') TDI velocities were also decreased compared to controls (all p < 0.05). Intraclass correlation demonstrated 84-99% agreement between observers in measuring TDI and 92% for TAPSE. Intraobserver reliability for these measures was 98-99% and 96%, respectively. We concluded that TDI and TAPSE are reproducible indices of myocardial function and may serve as useful adjuncts to standard echocardiographic measures in infants with PH. PMID- 27995292 TI - Initial Experience with Elective Perventricular Melody Valve Placement in Small Patients. AB - Perventricular Melody valve placement has been described as a bailout approach or alternative RVOT approach in patients >30 kg. We present three patients <20 kg and two patients with limited venous access, where we electively performed the perventricular approach. Retrospective analysis of patients <30 kg and vascular access limitation undergoing elective hybrid pulmonary valve replacement were reviewed. The subcostal approach was performed without sternotomy with the sheath introduced through the diaphragmatic surface of the right ventricle. Diagnoses included tetralogy of Fallot (n = 3) and truncus arteriosus (n = 2). Mean weight was 16.2 kg (range 4.7-28.1 kg). Four patients had RV-PA conduits (size: 14-21 mm), and the fifth patient had a transannular patch. All patients met criteria for surgical valve replacement. Technical success was 100%. In two patients with absent pulmonary valve, the stent migrated during advancement of the delivery sheath. These stents were anchored in the distal main pulmonary artery (n = 1) or branch pulmonary artery (n = 1) without sequela. Tricuspid valve chordal injury occurred in one patient, where transesophageal echocardiogram (TEE) was not utilized. No patient required conversion to cardiopulmonary bypass. One patient with absent pulmonary valve died on follow-up as a consequence of severe airway compromise. Our initial experience demonstrates that the perventricular valve can be placed safely in small-sized patients. Advancement of the melody ensemble may be difficult and may cause stent migration. We conclude that the technique is feasible in small-sized patients and that prevention of complications includes placement of the stent at the time of the valve and TEE assistance in reducing tricuspid valve injury. PMID- 27995293 TI - Comparative Analysis of Transcriptional Profile Changes in Larval Zebrafish Exposed to Zinc Oxide Nanoparticles and Zinc Sulfate. AB - Many studies of the toxic effects of zinc oxide nanoparticles (ZnO NPs) in aquatic organisms have been performed because of increasing ZnO NP use. However, the toxicological pathways are not understood. In this study, ZnO NPs were found to be more toxic than ZnSO4 to zebrafish larvae, but ZnO NP toxicity did not involve transcript alterations. Biological processes affected by ZnO NPs and ZnSO4 were investigated by performing ingenuity pathway analysis on differently expressed genes in larvae exposed to sub-lethal ZnO NP and ZnSO4 concentrations. We identified upregulated and downregulated differently expressed genes in fish exposed to ZnO NPs and ZnSO4, and found that ZnO NPs slightly induced cell differentiation and pathways associated with the immune system and activated several key genes involved in cancer cell signaling. The results may be key to predicting and elucidating the mechanisms involved in ZnO NP and ZnSO4 toxicity in zebrafish larvae. PMID- 27995294 TI - Laboratory Measured Emission Losses of Methyl Isothiocyanate at Pacific Northwest Soil Surface Fumigation Temperatures. AB - Temperature is a major environmental factor influencing land surface volatilization at the time of agricultural field fumigation. Cooler fumigation soil temperatures relevant to Pacific Northwest (PNW) application practices with metam sodium/potassium should result in appreciably reduced methyl isothiocyanate (MITC) emission rates, thus minimizing off target movement and bystander inhalation exposure. Herein, a series of laboratory controlled flow-through soil column assessments were performed evaluating MITC emissions over the range of cooler temperatures (2-13 degrees C). Assessments were also conducted at the maximum allowed label application temperature of 32 degrees C. All assessments were conducted at registration label-specified field moisture capacity, and no more than 50% cumulative MITC loss was observed over the 2-day post-fumigation timeframe. Three-fold reductions in MITC peak fluxes at cooler PNW application temperatures were observed compared to the label maximum temperature. This study supports current EPA metam sodium/potassium label language that indicates surface fumigations during warmer soil conditions should be discouraged. PMID- 27995295 TI - Spatial Distribution of Elemental Concentrations in Street Dust of Hanoi, Vietnam. AB - Street dust samples were collected at 163 locations across four different zones of Hanoi, Vietnam, covering different traffic and population densities. Samples were sieved into three fractions of different particle sizes and analyzed for elemental concentrations (K, Ca, Mn, Fe, Zn, Pb) using an X-ray fluorescence (XRF) instrument. The metal concentrations in street dust were compared among different sampling zones and with samples from background to evaluate the degree of pollution. The smallest size particle fraction (diameter <75 MUm) contained higher concentrations of metals than the coarser ones (diameters = 75-180 and >180 MUm). While concentrations of metals like Ca and Fe are spatially similar, concentrations of Pb and Zn in street dust varied between different zones, with the highest concentrations observed in dust from the downtown area, and lowest levels in the new suburb areas. Overall, compared to studies from cities in other countries, the mean concentration of Pb in street dust in Hanoi was relatively low, suggesting a lower risk to human health due to inhalation or ingestion of Pb containing dust particles than in cities where Pb concentrations were several times higher. PMID- 27995296 TI - [Current trends in oncological esophageal surgery : A worldwide survey]. PMID- 27995297 TI - [Quality of dying processes after commencement of the German Living Will Act : Experiences of a surgical intensive care unit]. AB - BACKGROUND: There is so far no information on how the third act on amendment of the German guardianship law from 29 July 2009 has affected dying processes of critically ill patients. METHODS: This retrospective study analyzed the patterns of dying processes in postoperative critically ill patients treated from 2009 to 2012 (period II after the commencement of the German Living Will Act) and 10 years before (period I, 1999-2002). Independent associations were calculated by logistic regression. RESULTS: In the observation period II (n = 137 dying patients) time until death significantly decreased to 19.3 days (95% CI 14.8 23.8, p = 0.008) vs. 29.2 days (95% CI 23.7-34.6) in period I (n = 163). In period II respect of the patient's will preceded death in 42.3% of the dying patients (period I: 8.6%, p < 0.001). Simultaneously, the frequency of patients with a severe preoperative comorbidity (failure of more than one organ) increased (26.8% of dying patients vs. 5.5% in period I, p = 0.001). The treatment during period II was, in addition to high age and a severe comorbidity, a significant independent predictor for the possibility that respect of the patient's will preceded death (odds ratio 7.42; 95% CI 3.77-14.60). CONCLUSION: Independent of various covariables, treatment after the commencement of the German Living Will Act was associated with a broader and earlier respect of the patient's will, thereby shortening the time until death. PMID- 27995298 TI - [Trust and reliability in surgery]. AB - Social interactions are hardly possible without trust. Medical and in particular surgical actions can change the lives of people directly and indirectly existentially. Thus, the relationship between doctor and patient is a special form of social interaction, and will be hard to find anywhere else. The nature of the doctor-patient relationship also determines the success of a treatment. The core and the importance of trust, as a central part of this relationship, will be reconstructed in the present paper. The increasing possibilities of information acquisition in modern societies, and the ever-present need for transparency, impact more and more on the doctor-patient relationship. At first glance, concepts of trust seem to be of secondary importance. The current developments regarding the remuneration of services in the medical system likewise bear the risk to increasingly determine the importance of trust in the doctor-patient relationship. However, it is necessary to delineate reliability from trust. Due to the conditions which are constitutive for the operational disciplines, a climate of trust, even in a modern information society, is more necessary than ever. PMID- 27995299 TI - [Colovesical fistulas : An interdisciplinary challenge]. AB - BACKGROUND: The aim of treatment of patients with colovesical fistulas should be prompt elimination of the infection and the social burden. We focused on the question whether a minimally invasive surgical approach as a cooperation between surgeons and urologists is possible. This requires effective diagnostics prior to the operation. METHODS: Since 2007 a total of 32 patients with the clinical suspicion of colovesical fistula have undergone extensive preoperative diagnostics. Operative treatment aimed primarily for a minimally invasive approach. In particular, the validity of preoperative diagnostics was analyzed and surgical results were characterized by clinical success, complications and long-term effects. RESULTS: The medical history significant for colovesical fistula and detected urinary infection provided the best evidence for the specific diagnosis. Cystoscopy, computed tomography (CT) scan and colonoscopy were only partially effective for predicting a fistula as subsequently diagnosed by histopathological investigations. Fistulas due to diverticulitis of the sigmoid colon occurred in 28 cases, while in 3 subjects there was a gynecological and inflammatory cause (malignant tumor growth, n = 1). A laparoscopic approach achieving repair and healing of the fistula was possible in 29 cases including conversion in 3 subjects because of intraoperative complications. The remaining patients underwent conventional treatment. The disease-related complication rate as revealed during follow-up was 10%. DISCUSSION: Laparoscopic repair and healing of a colovesical fistula is possible in the majority of cases by the recommended preoperative ureteral stenting. As part of diagnostic measures, the medical history significant for a fistula and detection of urinary infections are the most reliable aspects. In the case of this combination together with a further diagnostic measure, a laparoscopic approach is always recommended. The recurrency rate is 0%. PMID- 27995300 TI - Homophilic replicator equations. AB - Tags are conspicuous attributes of organisms that affect the behaviour of other organisms toward the holder, and have previously been used to explore group formation and altruism. Homophilic imitation, a form of tag-based selection, occurs when organisms imitate those with similar tags. Here we further explore the use of tag-based selection by developing homophilic replicator equations to model homophilic imitation dynamics. We assume that replicators have both tags (sometimes called traits) and strategies. Fitnesses are determined by the strategy profile of the population, and imitation is based upon the strategy profile, fitness differences, and similarity in tag space. We show the characteristics of resulting fixed manifolds and conditions for stability. We discuss the phenomenon of coat-tailing (where tags associated with successful strategies increase in abundance, even though the tags are not inherently beneficial) and its implications for population diversity. We extend our model to incorporate recurrent mutations and invasions to explore their implications upon tag and strategy diversity. We find that homophilic imitation based upon tags significantly affects the diversity of the population, although not the ESS. We classify two different types of invasion scenarios by the strategy and tag compositions of the invaders and invaded. In one scenario, we find that novel tags introduced by invaders become more readily established with homophilic imitation than without it. In the other, diversity decreases. Lastly, we find a negative correlation between homophily and the rate of convergence. PMID- 27995301 TI - Borrelia miyamotoi and Co-Infection with Borrelia afzelii in Ixodes ricinus Ticks and Rodents from Slovakia. AB - Borrelia miyamotoi causes relapsing fever in humans. The occurrence of this spirochete has been reported in Ixodes ricinus and wildlife, but there are still gaps in the knowledge of its eco-epidemiology and public health impact. In the current study, questing I. ricinus (nymphs and adults) and skin biopsies from rodents captured in Slovakia were screened for the presence of B. miyamotoi and Borrelia burgdorferi s.l. DNA. The prevalence of B. miyamotoi and B. burgdorferi s.l. in questing ticks was 1.7 and 16.9%, respectively. B. miyamotoi was detected in Apodemus flavicollis (9.3%) and Myodes glareolus (4.4%). In contrast, B. burgdorferi s.l. was identified in 11.9% of rodents, with the highest prevalence in Microtus arvalis (68.4%) and a lower prevalence in Apodemus spp. (8.4%) and M. glareolus (12.4%). Borrelia afzelii was the prevailing genospecies infecting questing I. ricinus (37.9%) and rodents (72.2%). Co-infections of B. miyamotoi and B. burgdorferi s.l. were found in 24.1 and 9.3% of the questing ticks and rodents, respectively, whereas the proportion of ticks and rodents co-infected with B. miyamotoi and B. afzelii was 6.9 and 7.0%, respectively. The results suggest that B. miyamotoi and B. afzelii share amplifying hosts. The sequences of the B. miyamotoi glpQ gene fragment from our study showed a high degree of identity with sequences of the gene amplified from ticks and human patients in Europe. The results seem to suggest that humans in Slovakia are at risk of contracting tick-borne relapsing fever, and in some cases together with Lyme borreliosis. PMID- 27995302 TI - A double-blind, placebo-controlled randomized clinical trial to evaluate the efficacy of tranexamic acid in irrigant solution on blood loss during percutaneous nephrolithotomy: a pilot study from tertiary care center of North India. AB - PURPOSE: To evaluate the efficacy and safety of 0.1% tranexamic acid in irrigant fluid in reducing blood loss during PCNL. MATERIALS AND METHODS: The study involved 400 patients who were planned for PCNL and were prospectively randomized into two equal groups. In tranexamic group, 0.1% tranexamic acid was given in irrigant fluid, while in placebo group, distilled water was added to irrigant fluid during surgery. Operative data were recorded which included fall in hemoglobin, total blood loss, operative time, irrigation fluid, length of stay in hospital, requirement of blood transfusion, complications related to PCNL and adverse events of tranexamic acid. RESULTS: Baseline parameters were comparable between two groups. The fall in hemoglobin and total blood loss in the tranexamic group was significantly lower than placebo group (1.71 vs. 2.67 gm/dL, 154.55 vs. 212.61 mL, respectively, p < 0.0001). Operative time, amount of irrigation fluid used and hospital stay of tranexamic group were significantly less compared to placebo (p < 0.05). Complete stone clearance rate was 88% in tranexamic group versus 82% in placebo (p = 0.12). The blood transfusion requirement was significantly lower in the tranexamic group versus placebo (5 vs. 12.5%, p = 0.012), as was the complication rate (19 vs. 28%, p = 0.044). The requirement of angioembolization in the tranexamic group was significantly less as compared to placebo (0.5 vs. 4%, p = 0.03). No adverse events related to administration of tranexamic acid were noted. CONCLUSIONS: 0.1% tranexamic acid in irrigant fluid is safe and significantly reduces perioperative blood loss and requirement of blood transfusion during percutaneous nephrolithotomy. It is associated with lower perioperative complication rates. PMID- 27995303 TI - Integration of MRI to clinical nomogram for predicting pathological stage before radical prostatectomy. AB - BACKGROUND: Debate persists regarding whether MRI should be used routinely for preoperative evaluation of prostate cancer. OBJECTIVE: The aim is to assess the role of prostatic magnetic resonance imaging (MRI) and other preoperative data in extra-prostatic extension (EPE) evaluation. PATIENTS AND METHODS: From 2000 to 2013, 1743 patients operated for radical prostatectomy had a preoperative MRI. Age, clinical stage with digital rectal exam (DRE), PSA, prostate weight, biopsy, MRI and pathological findings of the surgical specimen were noticed. A multiparametric score of the variables independently associated with EPE was built with or without MRI on a random sample test population and internally validated. RESULTS: With mean age of 62.9 years and mean PSA of 9.6 ng/ml, the population was distributed as follows: 1424 DRE T1, 254 T2, 32 T3; on biopsy 990 Gleason score = 6 and 717 >= 7; on MRI 1322 iT2, 290 iT3A and 131 iT3B; on prostatectomy 15 pT0, 998 pT2, 548 pT3A, 181 pT3B and 1 pT4A. In multivariate analysis, DRE, PSA, Gleason score, prostate weight and MRI were independently associated with EPE and integrated in a score with an area under curve (AUC) of 0.74 [95% CI 0.71-0.77] (0.72 without MRI, p < 0.01) a positive predictive value of 61% and a negative predictive value of 74%, internally validated. The Hosmer Lemeshow goodness-of-fit test showed good accuracy (p = 0.77). CONCLUSIONS: Integration of MRI with clinical data for predicting pathological stage before radical prostatectomy permits to exclude accurately EPE in 74% of cases. PMID- 27995305 TI - Stubborn Disease in Iran: Diversity of Spiroplasma citri Strains in Circulifer haematoceps Leafhoppers Collected in Sesame Fields in Fars Province. AB - Spiroplasma citri is a bacterial pathogen responsible for the economically important citrus stubborn disease. Sesame and citrus seeds serve as hosts for both S. citri and its leafhopper vector Circulifer haematoceps. To evaluate whether sesame could act as a reservoir for citrus-infecting strains or not, the genetic diversity among S. citri strains found in leafhoppers collected in citrus and citrus-free sesame fields was investigated. Among 26 periwinkle plants exposed to the collected C. haematoceps leafhoppers, 12 plants developed typical stubborn symptoms. All symptomatic periwinkles were polymerase chain reaction positive using S. citri-specific primer pairs targeting the spiralin and P89 genes. Phylogenetic trees based on spiralin gene sequence analysis indicated that the novel field-collected strains clustered with those belonging to two formerly defined S. citri groups (groups 6 and 1). In addition, our results strongly suggest that group 1 strains could be transmitted from sesame-infected plants to citrus trees by C. haematoceps, while group 6 strains may not infect citrus trees. PMID- 27995306 TI - T cell receptor gene recombinations in human tumor specimen exome files: detection of T cell receptor-beta VDJ recombinations associates with a favorable oncologic outcome for bladder cancer. AB - Understanding tumor-resident T cells is important for cancer prognosis and treatment options. Conventional, solid tumor specimen exome files can be searched directly for recombined T cell receptor (TcR)-alpha segments; RNASeq files can include TcR-beta VDJ recombinations. To learn whether there are medically relevant uses of exome-based detection of TcR V(D)J recombinations in the tumor microenvironment, we searched cancer genome atlas and Moffitt Cancer Center, tumor specimen exome files for TcR-beta, TcR-gamma, and TcR-delta recombinations, for bladder and stomach cancer. We found that bladder cancer exomes with productive TcR-beta recombinations had a significant association with No Subsequent Tumors and a positive response to drug treatments, with p < 0.004, p < 0.05, and p < 0.004, depending on the sample sets examined. We also discovered the opportunity to detect productive TcR-gamma and TcR-delta recombinations in the tumor microenvironment, via the tumor specimen exome files. PMID- 27995304 TI - Patient specific instrumentation versus conventional knee arthroplasty: comparative study. AB - BACKGROUND: The key to a successful knee replacement is restoring normal kinematics with a neutral alignment, thus a hip-knee-ankle (HKA) angle of 180 degrees (within 3 degrees limits). Conventional TKR is proven to have excellent results but relies in extensive visual referencing of bony landmarks. Customised cutting blocks provide accurate bone cuts, also lowering the risk of fat embolism, blood loss and operating time. METHOD: We share our experience comparing two different TKA techniques using patient specific instrumentation (PSI) with the Visionaire knee and conventional instrumentation (CVI) from the same system (Genesis II Smith&Nephew). A total number of 80 knees were divided into two equal groups, 40 PSI and 40 CVI respectively, operated between April 2013 and August 2014. One female patient had bilateral TKR during this period, at six months interval, both with the PSI. RESULTS: All operated knees had varus deformity, with a mean HKA of 168 degrees (PSI) vs 163 degrees (CVI). We used tranexamic acid (double-dose scheme) and suction drains for 48 hours, with a mean blood drainage in the PSI group of 185 ml and Hb levels of 11.2 g/dl at three days post, compared to 260 ml and 10.7 g/dl in the CVI. Mean blood loss was 3.5 g/dl in PSI, and 4.2 g/dl in the CVI. On the long leg standing radiograph at six weeks, all knees were aligned in frontal plane, with simillar HKA values (178.9 degrees PSI vs 178.6 degrees CVI). Bone cuts measured intraoperatively proved to be accurate within a 1 mm limit. CONCLUSIONS: We cannot recommend PSI-TKR for a better outcome. It is an alternative to conventional and computer-assisted TKR, but further studies are needed to evaluate weather surgical or economic benefits may be achieved by choosing customised instruments. PMID- 27995307 TI - Phase I study of nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small cell lung cancer. AB - BACKGROUND: The aim of our study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of nanoparticle albumin-bound paclitaxel (nab paclitaxel) plus carboplatin in combination with thoracic radiotherapy for patients with locally advanced stage III non-small cell lung cancer (NSCLC). METHODS: Weekly nab-paclitaxel plus carboplatin was administered intravenously for 6 weeks. Doses of each drug were planned as follows: level 1, 40/2; level 2, 60/2; level 3, 80/2 (nab-paclitaxel [mg/m2]/carboplatin [area under the plasma concentration time curve mg/ml/min]). Concurrent thoracic radiotherapy was administered in 2-Gy fractions 5 times weekly, to a total dose of 60 Gy. RESULTS: Fourteen patients were enrolled in the present study. Eleven (78%) patients received full cycles (6 cycles) of chemotherapy, and 12 (86%) patients received 60 Gy of thoracic radiotherapy. At level 1, none of 3 patients experienced a dose limiting toxicity (DLT). At level 2, 2 of 7 patients developed grade 3 diarrhea, grade 3 hyponatremia, grade 3 fatigue, and grade 3 esophagitis. Therefore, 4 patients were started at dose level 3 and none developed a DLT. No pulmonary toxicities, such as interstitial pneumonitis and treatment-related deaths, were observed at either level. Therefore, level 3 was considered the MTD and level 3 was defined as the RD. An objective response was observed in 71.4% of all patients. CONCLUSIONS: This regimen is feasible and well tolerated for the treatment of patients with unresectable locally advanced NSCLC. PMID- 27995308 TI - Efficient CRISPR/Cas9-based gene knockout in watermelon. AB - KEY MESSAGE: CRISPR/Cas9 system can precisely edit genomic sequence and effectively create knockout mutations in T0 generation watermelon plants. Genome editing offers great advantage to reveal gene function and generate agronomically important mutations to crops. Recently, RNA-guided genome editing system using the type II clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) has been applied to several plant species, achieving successful targeted mutagenesis. Here, we report the genome of watermelon, an important fruit crop, can also be precisely edited by CRISPR/Cas9 system. ClPDS, phytoene desaturase in watermelon, was selected as the target gene because its mutant bears evident albino phenotype. CRISPR/Cas9 system performed genome editing, such as insertions or deletions at the expected position, in transfected watermelon protoplast cells. More importantly, all transgenic watermelon plants harbored ClPDS mutations and showed clear or mosaic albino phenotype, indicating that CRISPR/Cas9 system has technically 100% of genome editing efficiency in transgenic watermelon lines. Furthermore, there were very likely no off-target mutations, indicated by examining regions that were highly homologous to sgRNA sequences. Our results show that CRISPR/Cas9 system is a powerful tool to effectively create knockout mutations in watermelon. PMID- 27995310 TI - Production of the immunosuppressant cyclosporin A by a new soil isolate, Aspergillus fumigatus, in submerged culture. AB - Cyclosporin A (CyA) has received meticulous attention owing to its immunosuppressive and biological activities. In this study, a soil isolate, capable of producing CyA, was named Zag1 strain and identified as Aspergillus fumigatus based on macroscopic and microscopic characteristics, 18S rDNA sequence, and phylogenetic characteristic analysis. To maximize the production of CyA, the fungal culture was grown under various fermentation conditions including selection of the cultivation medium, agitation rate, fermentation time, incubation temperature, pH value, inoculum nature, and medium volume. A simple medium (pH 5.0) containing 5% maltose as a carbon source and 2% potassium nitrate as a nitrogen source favored the highest CyA production when the fermentation process was maintained at 120 rpm for 9 days and at 30 degrees C using 3% standard inoculum of 5-day-old. The final CyA titer under these conditions was intensified to 2.23-3.31-fold, as compared with the amount obtained with seven types of basal media. A. fumigatus Zag1 appears to possess a good biotechnological potential for CyA production under favorable culture conditions. PMID- 27995311 TI - Comparison of lipases and glycoside hydrolases as catalysts in synthesis reactions. AB - Lipases and glycoside hydrolases have large similarities concerning reaction mechanisms. Acyl-enzyme intermediates are formed during lipase-catalyzed reactions and in an analogous way, retaining glycoside hydrolases form glycosyl enzyme intermediates during catalysis. In both cases, the covalent enzyme intermediates can react with water or other nucleophiles containing hydroxyl groups. Simple alcohols are accepted as nucleophiles by both types of enzymes. Lipases are used very successfully in synthesis applications due to their efficiency in catalyzing reversed hydrolysis and transesterification reactions. On the other hand, synthesis applications of glycoside hydrolases are much less developed. Here, important similarities and differences between the enzyme groups are reviewed and approaches to reach high synthesis yields are discussed. Useful strategies include the use of low-water media, high nucleophile concentrations, as well as protein engineering to modify the selectivity of the enzymes. The transglycosylases, hydrolases which naturally catalyze mainly transfer reactions, are of special interest and might be useful guides for engineering of other hydrolases. PMID- 27995312 TI - Prognostic impact of tumour burden measured by quantitative real-time PCR from sentinel lymph nodes of melanoma patients: data from 10-year follow-up. AB - BACKGROUND: Sentinel node (SN) biopsy is regarded as standard of care for patients (pts) with cutaneous melanoma >=1.0 mm of thickness. In the recent AJCC classification, findings in the SN are simply classified as positive or negative. In our analyses, we were interested whether quantitative real-time PCR (qRT-PCR) is able to predict disease-free survival (DFS) and overall survival (OS) depending on tumour burden in the SN. METHODS: One hundred and forty-five pts were analysed using qRT-PCR for tyrosinase. Results were analysed using accelerated failure time survival model and cox proportional hazards models using the R statistics framework. RESULTS: Forty-one pts (28%) were positive according to qRT-PCR. In total, 12 of 41 pts showed tumour deposits in the SN using S100 and/or HMB-45-labelled immunohistochemistry as well. One patient had micrometastases detected by immunohistochemistry staining but failed in the qRT PCR. After 10 years of follow-up, 34 patients recurred and 27 patients died. Significant differences for DFS and OS were detected for sex, increasing tumour thickness, ulceration of the primary tumour, and metastatic spread in the SN determined by histology as well as qRT-PCR. CONCLUSION: Quantitative analyses showed a logarithmic correlation between tumour burden and prognosis. However, as multivariate analyses reveal qRT-PCR was not superior compared to classical histology or immunohistology. PMID- 27995309 TI - Characterization of three pyranose dehydrogenase isoforms from the litter decomposing basidiomycete Leucoagaricus meleagris (syn. Agaricus meleagris). AB - Multigenicity is commonly found in fungal enzyme systems, with the purpose of functional compensation upon deficiency of one of its members or leading to enzyme isoforms with new functionalities through gene diversification. Three genes of the flavin-dependent glucose-methanol-choline (GMC) oxidoreductase pyranose dehydrogenase (AmPDH) were previously identified in the litter-degrading fungus Agaricus (Leucoagaricus) meleagris, of which only AmPDH1 was successfully expressed and characterized. The aim of this work was to study the biophysical and biochemical properties of AmPDH2 and AmPDH3 and compare them with those of AmPDH1. AmPDH1, AmPDH2 and AmPDH3 showed negligible oxygen reactivity and possess a covalently tethered FAD cofactor. All three isoforms can oxidise a range of different monosaccarides and oligosaccharides including glucose, mannose, galactose and xylose, which are the main constituent sugars of cellulose and hemicelluloses, and judging from the apparent steady-state kinetics determined for these sugars, the three isoforms do not show significant differences pertaining to their reaction with sugar substrates. They oxidize glucose both at C2 and C3 and upon prolonged reaction C2 and C3 double-oxidized glucose is obtained, confirming that the A. meleagris genes pdh2 (AY753308.1) and pdh3 (DQ117577.1) indeed encode CAZy class AA3_2 pyranose dehydrogenases. While reactivity with electron donor substrates was comparable for the three AmPDH isoforms, their kinetic properties differed significantly for the model electron acceptor substrates tested, a radical (the 2,2'-azino-bis[3-ethylbenzothiazoline 6-sulphonic acid] cation radical), a quinone (benzoquinone) and a complexed iron ion (the ferricenium ion). Thus, a possible explanation for this PDH multiplicity in A. meleagris could be that different isoforms react preferentially with structurally different electron acceptors in vivo. PMID- 27995313 TI - Accumulation of proanthocyanidins and/or lignin deposition in buff-pigmented soybean seed coats may lead to frequent defective cracking. AB - MAIN CONCLUSION: Defective cracking frequently occurs in buff-pigmented soybean seed coats, where proanthocyanidins accumulate and lignin is deposited, suggesting that proanthocyanidins and/or lignin may change physical properties and lead to defective cracking. In the seed production of many yellow soybean (Glycine max) cultivars, very low percentages of self-pigmented seeds are commonly found. This phenomenon is derived from a recessive mutation of the I gene inhibiting seed coat pigmentation. In Japan, most of these self-pigmented seeds are buff-colored, and frequently show multiple defective cracks in the seed coat. However, it is not known why cracking occurs specifically in buff seed coats. In this study, quantitative analysis was performed between yellow and buff soybean seed coats. Compared with yellow soybeans, in which defective cracking rarely occurs, contents of proanthocyanidins (PAs) and lignin were significantly higher in buff seed coats. Histochemical data of PAs and lignin in the seed coats strongly supported this result. Measurements of the physical properties of seed coats using a texture analyzer showed that a hardness value was significantly decreased in the buff seed coats. These results suggest that PA accumulation and/or lignin deposition may affect the physical properties of buff seed coats and lead to the defective cracking. This work contributes to understanding of the mechanism of defective cracking, which decreases the seed quality of soybean and related legumes. PMID- 27995314 TI - Acclimation of Pistacia integerrima trees to frost in semi-arid environments depends on autumn's drought. AB - Main conclusion Cold acclimation is revealed through induced stem respiration during pre-winter frost of native Pistacia integerrima trees in continental semi arid environments. Semi-arid environments challenge vegetation by simultaneous abiotic stresses. In this study, we examine the combined effects of water stress and frost on the physiology of Pistacia integerrima stems. This species is native to semi-arid environments where drought and frost frequently co-occur. We quantified carbohydrates and proline in P. integerrima stems responding to frost and experiencing water potentials between -0.2 and -1.8 MPa. We report that dehydrated trees (i.e., Psistem <=-1 MPa) had more soluble sugars and proline than the well-watered trees (-0.2 MPa). The dehydrated trees also froze at lower temperatures and were less damaged by freezing. Interestingly, we observed a significant increase in stem CO2 efflux at near-freezing temperatures that could be linked to frost protection. This novel finding challenges current paradigm of plant respiration-kinetics which predicts, according to Arrhenius equation, lower respiration rates during frost. Our results support the notion that drought and frost are analogous stresses that can independently activate corresponding physiological processes in trees and amplify protection. This inevitable stress response 'collaboration' may be the key to understanding how non-dormant perennial plants survive the highly variable weather patterns of early winters in semi-arid environments. PMID- 27995316 TI - Absolute versus relative measures of plasma fatty acids and health outcomes: example of phospholipid omega-3 and omega-6 fatty acids and all-cause mortality in women. AB - PURPOSE: In a well-characterised community-based prospective study, we aimed to systematically assess the differences in associations of plasma omega-3 and omega 6 fatty acid (FA) status with all-cause mortality when plasma FA status is expressed in absolute concentrations versus relative levels. METHODS: In a community sample of 564 women aged 25-75 years in Queensland, Australia, baseline plasma phospholipid FA levels were measured using gas chromatography. Specific FAs analysed were eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, total long-chain omega-3 FAs, linoleic acid, arachidonic acid, and total omega-6 FAs. Levels of each FA were expressed in absolute amounts (ug/mL) and relative levels (% of total FAs) and divided into thirds. Deaths were monitored for 17 years and hazard ratios and 95% confidence intervals calculated to assess risk of death according to absolute versus relative plasma FA levels. RESULT: In total 81 (14%) women died during follow-up. Agreement between absolute and relative measures of plasma FAs was higher in omega-3 than omega-6 FAs. The results of multivariate analyses for risk of all-cause mortality were generally similar with risk tending to inverse associations with plasma phospholipid omega 3 FAs and no association with omega-6 FAs. Sensitivity analyses examining effects of age and presence of serious medical conditions on risk of mortality did not alter findings. CONCLUSIONS: The directions and magnitude of associations with mortality of absolute versus relative FA levels were comparable. However, plasma FA expressed as absolute concentrations may be preferred for ease of comparison and since relative units can be deduced from absolute units. PMID- 27995317 TI - No common understanding of profession terms utilized in health services research : An add-on qualitative study in the context of the QUALICOPC project in Austria. AB - BACKGROUND: Health services research, especially in primary care, is challenging because the systems differ widely between countries. This study aimed to explore the different understanding of the terminology used, particularly, regarding the professions nursing and medical secretaries. METHODS: The study was an add-on study to the Quality and Costs in Primary Care (QUALICOPC) project in Austria and designed as qualitative research. The qualitative phase was conducted by using semi-structured telephone interviews with general practitioners (GP). and17 GPs participated in the study. RESULTS: No uniform meaning of the terms commonly utilized for the abovementioned health professions could be found among Austrian GPs. For example, under the profession term practice assistants, nurses as well as literal medical secretaries with and without special education and related work competencies and responsibilities were subsumed. CONCLUSIONS: Our study results show that no uniform meaning of the terms commonly utilized for above described health profession could be found even within one country by GPs. These findings are highly relevant, especially, when trying to compare results with similar data from other countries or negotiating about workforce issues. Our findings implicate several action points for health services research and health policy. We propose the development of a harmonized terminology in Europe for the health profession based on standards of undergraduate and postgraduate education, competencies and continuous education commitments. This would not only benefit comparative health system research but also patient safety across Europe. PMID- 27995315 TI - A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus. AB - The majority of tinnitus patients are affected by chronic idiopathic tinnitus, and almost 60 different treatment modalities have been reported. The present study is a multidisciplinary systematic analysis of the evidence for the different forms of treatment for chronic tinnitus. The results are used to form the basis of an S3 guideline. A systematic search was carried out in PubMed and the Cochrane Library. The basis for presenting the level of evidence was the evidence classification of the Oxford Centre of Evidence-based Medicine. Whenever available, randomised controlled trials were given preference for discussing therapeutic issues. All systematic reviews and meta-analyses were assessed for their methodological quality, and effect size was taken into account. As the need for patient counselling is self-evident, specific tinnitus counselling should be performed. Due to the high level of evidence, validated tinnitus-specific, cognitive behavioural therapy is strongly recommended. In addition, auditory therapeutic measures can be recommended for the treatment of concomitant hearing loss and comorbidities; those should also be treated with drugs whenever appropriate. In particular, depression should be treated, with pharmacological support if necessary. If needed, psychiatric treatment should also be given on a case-by-case basis. With simultaneous deafness or hearing loss bordering on deafness, a CI can also be indicated. For auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation. PMID- 27995318 TI - Nausea and disturbed sleep as predictors of cancer-related fatigue in breast cancer patients: a multicenter NCORP study. AB - PURPOSE: Cancer-related fatigue (CRF) is a prevalent and distressing side effect of cancer and its treatment that remains inadequately understood and poorly managed. A better understanding of the factors contributing to CRF could result in more effective strategies for the prevention and treatment of CRF. The objectives of this study were to examine the prevalence, severity, and potential predictors for the early onset of CRF after chemotherapy cycle 1 in breast cancer patients. METHODS: We report on a secondary data analysis of 548 female breast cancer patients from a phase III multi-center randomized controlled trial examining antiemetic efficacy. CRF was assessed by the Brief Fatigue Inventory at pre- and post-chemotherapy cycle 1 as well as by the four-day diary. RESULTS: The prevalence of clinically relevant post-CRF was 75%. Linear regression showed that pre-treatment CRF, greater nausea, disturbed sleep, and younger age were significant risk factors for post-CRF (adjusted R2 = 0.39; P < 0.0001). Path modeling showed that nausea severity influenced post-CRF both directly and indirectly by influencing disturbed sleep. Similarly, pre-treatment CRF influenced post-CRF directly as well as indirectly through both nausea severity and disturbed sleep. Pearson correlations showed that changes in CRF over time were significantly correlated with concurrent changes in nausea severity (r = 0.41; P < 0.0001) and in disturbed sleep (r = 0.20; P < 0.0001). CONCLUSION: This study showed a high prevalence (75%) of clinically relevant CRF in breast cancer patients following their initial chemotherapy, and that nausea severity, disturbed sleep, pre-treatment CRF, and age were significant predictors of symptom. PMID- 27995319 TI - Prediction of biogeographical ancestry from genotype: a comparison of classifiers. AB - DNA can provide forensic intelligence regarding a donor's biogeographical ancestry (BGA) and other externally visible characteristics (EVCs). A number of algorithms have been proposed to assign individual human genotypes to a BGA using ancestry informative marker (AIM) panels. This study compares the BGA assignment accuracy of the population clustering program STRUCTURE and three generic classification approaches including a Bayesian algorithm, genetic distance, and multinomial logistic regression (MLR). A selection of 142 ancestry informative single nucleotide polymorphisms (SNPs) were chosen from existing marker panels (SNPforID 34-plex, Eurasiaplex, Seldin, and Kidd's AIM panels) to assess BGA classification at the continental level for Africans, Europeans, East Asians, and Amerindians. A training set of 1093 individuals with self-declared BGA from the 1000 Genomes phase 1 database was used by each classifier to predict BGA in a test set of 516 individuals from the HGDP-CEPH (Stanford) cell line panel. Tests were repeated with 0, 10, 50, 70, and 90% of the genotypes missing. Comparison of the area under the receiver operating characteristic curves (AUROCs) showed high accuracy in STRUCTURE and the generic Bayesian approach. The latter algorithm offers a computationally simpler alternative to STRUCTURE with little loss in accuracy and is suitable for phenotype prediction while STRUCTURE is not. PMID- 27995320 TI - Thrombosis of TAVI prosthesis-cause for concern or innocent bystander? A comment and review of currently available data. PMID- 27995322 TI - What drives cold-related excess mortality in a south Asian tropical monsoon climate-season vs. temperatures and diurnal temperature changes. AB - Despite the tropical climate which is characterized by generally high temperatures and persistent mild temperatures during the winter season, Bangladesh, along with many other tropical countries, experiences strong winter and cold-related excess mortality. The objective of this paper was to analyse the nature of these cold effects and understand the role of season vs. temperature and diurnal changes in temperature. For approaching these questions, we applied different Poisson regression models. Temperature as well as diurnal temperature range (DTR) were considered as predictor variables. Different approaches to seasonality adjustment were evaluated and special consideration was given to seasonal differences in atmospheric effects. Our findings show that while seasonality adjustment affected the magnitude of cold effects, cold-related mortality persisted regardless the adjustment approach. Strongest effects of low temperatures were observed at the same day (lag 1) with an increase of 1.7% (95% CI = 0.86-2.54%) per 1 degrees C decrease in temperature during the winter season. Diurnal temperature affected mortality with increasing levels at higher ranges. Mortality increased with 0.97% (95% CI = 0.17-1.75%) when looking at the entire season, but effects of DTR were not significant during winter when running a seasonal model. Different from effects observed in the mid-latitudes, cold effects in Bangladesh occurred on a very short time scale highlighting the role of temperature versus season. Insufficient adaptation with regard to housing and clothing might lead to such cold-related increases in mortality despite rather moderate temperature values. Although the study did not demonstrate an effect of DTR during the cold season, the strong correlation with (minimum) temperature might cause a multicollinearity problem and effects are difficult to attribute to one driver. PMID- 27995321 TI - Expression dynamics of HSP70 during chronic heat stress in Tharparkar cattle. AB - Six male Tharparkar cattle aged 2-3 years were selected for the study. The animals were acclimatized in the psychrometric chamber at thermoneutral zone (TNZ) for 15 days and then exposed to 42 degrees C temperature up to 23 days followed by 12 days of recovery period. Physiological responses were estimated, and peripheral blood mononuclear cells (PBMCs) were isolated at TNZ on day 1, day 5, and day 12; after 6 h of heat stress exposure on day 16 to day 20, day 25, day 30, day 32, day 34, day 36, and day 38; and a recovery period on day 45 and day 50. The PBMCs were cultured to study the effect of thermal challenge on HSP70 messenger RNA (mRNA) expression pattern at different temperature-time combinations. The mRNA and protein expression of HSP70 in PBMCs along with serum extracellular HSP70 (eHSP70) was increased (P < 0.05) and showed two peaks on day 17 and day 32 (2nd and 17th days of thermal challenge, respectively). The HSP70 mRNA expression was increased (P < 0.05) in a temperature- and time-dependent manner in heat stress challenge treatment as compared to control in cultured PBMCs. HSP70 expression was found to be higher (P < 0.05) after 10 days of heat exposure (corresponds to chronic heat stress) as compared to the first 5 days of heat stress (corresponds to short-term heat stress) and control period at TNZ. The present findings indicate that HSP70 is possibly involved in heat stress adaptive response in Tharparkar cattle and the biphasic expression pattern may be providing a second window of protection during chronic heat stress. PMID- 27995323 TI - Mucosa-associated lymphoid tissue (MALT) variant of primary rectal lymphoma: a review of the English literature. AB - PURPOSE: Primary rectal lymphoma (PRL) is the third most common cause of rectal cancer following adenocarcinoma (90-95 %) and carcinoid (5 %). The most common variant of PRL is the mucosa-associated lymphoid tissue (MALT) type. To date, no study has been able to recommend an optimal treatment algorithm for this rare disease. The aim of our study was to review the English literature on primary rectal MALT lymphoma. METHODS: A review of the English literature was conducted to identify articles describing the MALT variant of PRL. RESULTS: Fifty-one cases were identified. A complete response was achieved in 12 of 19 cases treated with Helicobacter pylori eradication therapy, 5 of 6 with radiation, 2 of 4 cases with chemotherapy, 2 of 4 with endoscopic resection, 6 of 8 cases with surgical resection, and all 8 with combination therapies. Cases failing initial therapies were responsive to various second-line treatments. Two cases spontaneously regressed with observation alone. CONCLUSION: Complete regression of primary rectal MALT lymphoma was achieved using various therapeutic strategies, although the numbers of different treatment modalities are too small to draw definitive conclusions. PMID- 27995324 TI - HLA epitope matching in pediatric renal transplantation. AB - Chronic graft loss due to antibody-mediated rejection (AMR) and the difficulty of re-transplanting highly sensitized patients are two of the major long-term challenges in pediatric renal transplantation. Treatments for AMR are often ineffective and desensitization protocols can be a high risk, making prevention a highly appealing strategy. Insights into the structural determinants of humoral alloantigenicity present an exciting opportunity to reassess our current paradigm of tissue matching and potentially preventing these complications. We review the theory behind human leukocyte antigen (HLA) B cell epitopes and the various systems that have been proposed to define them, including eplets. There is a growing body of clinical evidence suggesting that epitope-based tissue matching may be superior to traditional HLA antigen matching at predicting a range of clinical outcomes. However, additional studies are required to better understand the biological relevance of these systems of defining epitopes and their role in pediatric transplantation. PMID- 27995325 TI - [Histology of the living eye : Noninvasive microscopic structure and functional analysis of the retina with adaptive optics]. AB - Equipping an ophthalmoscope with adaptive optics (AO) offers access to the living human retina with unprecedented spatial resolution. With AO, cellular structures such as the nerve fiber layer, the microvasculature of the smallest retinal capillaries, rod and cone photoreceptors and the mosaic of the retinal pigment epithelium are directly observable. A large number of studies in the normal and diseased retina have already shown that this level of detail offers new insights into disease mechanisms and progression, and promises to identify early disease markers. In conjunction with functional testing of single photoreceptors that is possible with AO microstimulation, a structure-function relationship on the cellular scale is within reach. These technological advances offer new avenues for clinical ophthalmology, interventional efforts, and basic research of the function and dysfunction of vision. PMID- 27995326 TI - Using a novel PV-Cre rat model to characterize pallidonigral cells and their terminations. AB - In the present study, we generated a novel parvalbumin (PV)-Cre rat model and conducted detailed morphological and electrophysiological investigations of axons from PV neurons in globus pallidus (GP). The GP is considered as a relay nucleus in the indirect pathway of the basal ganglia (BG). Previous studies have used molecular profiling and projection patterns to demonstrate cellular heterogeneity in the GP; for example, PV-expressing neurons are known to comprise approximately 50% of GP neurons and represent majority of prototypic neurons that project to the subthalamic nucleus and/or output nuclei of BG, entopeduncular nucleus and substantia nigra (SN). The present study aimed to identify the characteristic projection patterns of PV neurons in the GP (PV-GP neurons) and determine whether these neurons target dopaminergic or GABAergic neurons in SN pars compacta (SNc) or reticulata (SNr), respectively. We initially found that (1) 57% of PV neurons co-expressed Lim-homeobox 6, (2) the PV-GP terminals were preferentially distributed in the ventral part of dorsal tier of SNc, (3) PV-GP neurons formed basket-like appositions with the somata of tyrosine hydroxylase, PV, calretinin and cholecystokinin immunoreactive neurons in the SN, and (4) in vitro whole-cell recording during optogenetic photo-stimulation of PV-GP terminals in SNc demonstrated that PV-GP neurons strongly inhibited dopamine neurons via GABAA receptors. These results suggest that dopamine neurons receive direct focal inputs from PV-GP prototypic neurons. The identification of high-contrast inhibitory systems on dopamine neurons might represent a key step toward understanding the BG function. PMID- 27995327 TI - Quantitative diagnosis of chronic pancreatitis using EUS elastography. AB - BACKGROUND: It is difficult to diagnose chronic pancreatitis (CP) objectively because of a lack of standard diagnostic criteria. Endoscopic ultrasonography (EUS) has been used to assess the severity of CP, but the diagnosis of CP using EUS depends on an endosnonographer. The aim of this study was to establish an objective diagnostic method for CP using EUS elastography (EUS-EG). METHODS: A retrospective study was designed and 96 patients underwent EUS-EG for follow-up of known CP, or who were clinically suspected as having CP. CP patients were categorized CP patients as 4 stages using the Rosemont classification (RC). EUS EG was performed and the "Mean value", which was negatively correlated with pancreatic fibrosis, was calculated using histogram analysis. RESULTS: The "Mean value" of each RC stage (normal, indeterminate for CP, suggestive of CP, and consistent with CP) was 90.1 +/- 19.3, 73.2 +/- 10.6, 63.7 +/- 14.2, and 56.1 +/- 13.6, respectively, and showed significant differences for each stage (p < 0.001). There was a significant negative correlation between the "Mean value" and the number of EUS features (r s = -0.59, p < 0.001). Multiple linear regression analysis was used to assess the diagnostic finding of the "Mean value" and showed that hyperechoic foci with shadowing and lobularity with honeycombing maintained their independent diagnostic findings. CONCLUSIONS: EUS-EG was an objective diagnostic apparatus for CP and provided objective information to support EUS features. PMID- 27995328 TI - New surgical scoring system to predict postoperative mortality. AB - PURPOSE: There is still no easy and highly useful method to comprehensively assess both preoperative and intraoperative patient statuses to predict postoperative outcomes. We attempted to develop a new scoring system that would enable a comprehensive assessment of preoperative and intraoperative patient statuses instantly at the end of anesthesia, predicting postoperative mortality. METHODS: The study included 32,555 patients who underwent surgery under general or regional anesthesia from 2008 to 2012. From the anesthesia records, extracted factors, including patient characteristics and American Society of Anesthesiologists physical status classification (ASA-PS), and three intraoperative indexes (the lowest heart rate, lowest mean arterial pressure, and estimated volume of blood loss) are used to calculate the surgical Apgar score (sAs). The sAs and ASA-PS, and surgical Apgar score combined with American Society of Anesthesiologists physical status classification (SASA), which combines the sAs and ASA-PS into a single adjusted scale, were compared and analyzed with postoperative 30-day mortality. RESULTS: Increased severity of the sAs, ASA-PS and SASA was correlated with significantly higher mortality. The risk of death was elevated by 3.65 for every 2-point decrease in the sAs, by 6.4 for every 1-point increase in the ASA-PS, and by 9.56 for every 4-point decrease in the SASA. The ROC curves of the sAs and ASA-PS alone also individually demonstrated high validity (AUC = 0.81 for sAs and 0.79 for ASA-PS, P < 0.001). The SASA was even more valid (AUC = 0.87, P < 0.001). CONCLUSIONS: The sAs and ASA-PS were shown to be extremely useful for predicting 30-day mortality after surgery. An even higher predictive ability was demonstrated by the SASA, which combines these simple and effective scoring systems. PMID- 27995330 TI - Piceatannol attenuates homocysteine-induced endoplasmic reticulum stress and endothelial cell damage via heme oxygenase-1 expression. AB - A growing body of evidence implicates endoplasmic reticulum (ER)-induced cellular dysfunction and apoptosis as important factors to a variety of diseases. In endothelial cells (ECs), the sulfur-containing amino acid homocysteine (Hcy) causes EC apoptosis and reactive oxygen species (ROS) generation through induction of ER stress. Here, we have investigated whether piceatannol (Pic), a resveratrol analog, could protect ECs against Hcy-induced apoptosis, oxidative stress and ER stress, with specific emphasis on heme oxygenase-1 (HO-1). In human ECs, we determined the effects of Hcy and Pic on annexin V positivity, glucose regulated protein 78 kDa (GRP78) and C/EBP homologous protein (CHOP) expression, X-box binding protein 1 (Xbp-1) mRNA slicing, and ROS-sensitive dihydroethidium (DHE) oxidation. Hcy increased annexin V-positive cells, DHE oxidation, GRP78 and CHOP expression and Xbp-1 mRNA splicing, indicating that Hcy induces apoptosis, oxidative stress and ER stress. Pretreatment of ECs with Pic significantly inhibited Hcy-induced apoptosis, ROS generation and ER stress. Pic also increased HO-1 expression via activation of nuclear factor-E2-related factor 2 (Nrf2). Interestingly, the inhibitory effects of Pic on Hcy-induced apoptosis, ROS generation and ER stress were abolished by down-regulation of HO-1 expression, while mimicked by treatment of ECs with the HO-1 inducer hemin. Overall, these results suggest that Pic may protect ECs against Hcy-induced apoptosis, oxidative stress and ER stress via Nrf2-dependent HO-1 expression. PMID- 27995329 TI - Stress hormones and posttraumatic stress symptoms following paediatric critical illness: an exploratory study. AB - In this exploratory case-control study, we investigated basal cortisol regulation in 5-16-year-old children, 3-6 months following PICU (paediatric intensive care) admission. This was nested within a study of child psychological and cognitive function; 47 children were assessed alongside 56 healthy controls. Saliva samples were collected three times per day (immediately after waking, waking +30 min, and waking +12 h) over two consecutive weekdays. In addition, data on posttraumatic stress symptoms were ascertained from 33 PICU admitted children using the Impact of Events Scale-8 (IES-8). Primary analysis revealed no significant differences in basal cortisol concentrations between PICU discharged children and healthy controls (p > 0.05). Secondary analysis in the PICU group identified a significant positive association between posttraumatic stress symptoms and evening (waking +12 h) cortisol concentrations (p = 0.004). However, when subject to multivariate analysis, evening cortisol was a modest independent predictor of IES-8 scores, relative to the presence of septic illness and poor pre-morbid health. We conclude that paediatric critical illness does not appear to result in marked perturbations to basal cortisol at 3-6 month following discharge. There was evidence of a link between evening cortisol and symptoms of PTSD, but this was not a robust effect and requires further elucidation. PMID- 27995331 TI - ERF73/HRE1 is involved in H2O2 production via hypoxia-inducible Rboh gene expression in hypoxia signaling. AB - Hypoxia deprives cells of energy and induces severe physical damage in embryophytes. Under hypoxia, the equilibrium between ethylene and H2O2 affects the response of the transcription factor AtERF73/HRE1. To evaluate the role of AtERF73/HRE1 during hypoxia signaling, we used three independent AtERF73/HRE1 knockout lines to detect H2O2 accumulation. The results revealed that under hypoxia, H2O2 accumulation in the AtERF73/HRE1 knockout lines decreased, indicating that AtERF73/HRE1 uses a negative feedback regulation mechanism to influence the production of H2O2 induced through hypoxia signal transduction. Quantitative RT-PCR analyses showed that oxygen deficiency had different effects on the expression of the hypoxia-induced genes Rboh B, D, G, and I in the AtERF73/HRE1 knockout lines. In particular, Rboh B and D expression were increased, whereas Rboh G expression was decreased. The expression of Rboh I was increased at 1 h but decreased at 3 h during hypoxia treatment in the AtERF73/HRE1 knockout lines. Similarly, the transcript levels of antioxidant and hypoxia-induced/ethylene response genes in the AtERF73/HRE1 knockout lines were affected by hypoxic stress, indicating that AtERF73/HRE1 is essential to hypoxia signal transduction in embryophytes. Additionally, in histochemical analysis, AtERF73/HRE1 promoter-induced GUS expression was detected in various plant parts throughout the plant growth process (e.g., leaves, inflorescences, siliques), particularly in the edges of mature leaves and guard cells. Taken together, our results confirm that AtERF73/HRE1 plays a role in H2O2 production by affecting the hypoxia-induced expression of Rboh genes in hypoxia signal transduction. PMID- 27995333 TI - Graphene nanoflakes on transparent glass electrode sensor for electrochemical sensing of anti-diabetic drug. AB - Metformin (Mf) plays a major role in controlling insulin level of individuals at risk of developing diabetes mellitus. Overdose of Mf can cause lactic acidosis, diarrhoea, cough, or hoarseness, etc. These particulars point out the identification for selective and sensitive methods of Mf determination. In the present work, graphene nanoflakes-polymethylene blue (GNF-PMB) nano-composites were developed onto fluorine-doped tin oxide (SnO2/F) coated glass substrates for electrochemical sensing of Mf using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The developed sensor shows quick response time (10 s), linearity as 10-103 uM, LOD (0.1 nM), and good shelf life (10 weeks). Attempts have been made to utilize this electrode for estimation of Mf in urine samples. Configured as a highly responsive, reproducible Mf sensor, it combines the electrical properties of GNF and stable electron transfer of PMB. The newly developed Mf sensor presents a promising candidate in point-of-care diagnosis. PMID- 27995334 TI - Strategies on process engineering of chondrocyte culture for cartilage tissue regeneration. AB - The current work is an attempt to study the strategies for cartilage tissue regeneration using porous scaffold in wavy walled airlift bioreactor (ALBR). Novel chitosan, poly (L-lactide) and hyaluronic acid based composite scaffold were prepared. The scaffolds were cross-linked with 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide, N-hydroxysuccinimide and chondroitin sulfate to obtain interconnected 3D microstructure showing excellent biocompatibility, higher cellular differentiation and increased stability. The surface morphology and porosity of the scaffolds were analyzed using scanning electron microscopy (SEM) and mercury intrusion porosimeter and optimized for chondrocyte regeneration. The study shows that the scaffolds were highly porous with pore size ranging from 48 to 180 um and the porosities in the range 80-92%. Swelling and in vitro degradation studies were performed for the composite scaffolds; by increasing the chitosan: HA ratio in the composite scaffolds, the swelling property increases and stabilizes after 24 h. There was controlled degradation of composite scaffolds for 4 weeks. The uniform chondrocyte distribution in the scaffold using various growth modes in the shake flask and ALBR was studied by glycosaminoglycans (GAG) quantification, MTT assay and mixing time evaluation. The cell culture studies demonstrated that efficient designing of ALBR increases the cartilage regeneration as compared to using a shake flask. The free chondrocyte microscopy and cell attachment were performed by inverted microscope and SEM, and from the study it was confirmed that the cells uniformly attached to the scaffold. This study focuses on optimizing strategies for the culture of chondrocyte using suitable scaffold for improved cartilage tissue regeneration. PMID- 27995332 TI - Synthesis of Ni(II) complexes bearing indole-based thiosemicarbazone ligands for interaction with biomolecules and some biological applications. AB - A series of new Ni(II) complexes containing indole-based thiosemicarbazone ligands was synthesized and characterized by elemental analyses, and UV-visible, FT-IR, 1H & 13C NMR and mass spectroscopic techniques. The Ni(II) complexes (1-4) bear the general formula [Ni{C10H9N2NHCSNH(R)}2] where R = hydrogen (1), 4-methyl (2), 4-phenyl (3) and 4-cyclohexyl (4). Molecular structure of ligands (L3 and L4) and complexes (2, 3 and 4) was confirmed by single crystal X-ray crystallography. Four coordinated Ni(II) complexes showed square planar geometry. The interaction of the Ni(II) complexes with calf thymus DNA (CT-DNA) has been evaluated by absorption spectroscopic and ethidium bromide (EB) competitive binding studies, which revealed the intercalative interaction of the complexes with CT-DNA. Gel electrophoresis experiments showed the cleavage of DNA by the complexes without any external agent. Further, the interaction of the complexes with bovine serum albumin (BSA) was investigated using UV-visible, fluorescence and synchronous fluorescence spectroscopic methods, which showed that the complexes could bind strongly with BSA. Molecular docking was employed to understand the binding of the Ni(II) complexes with the molecular target B-DNA, human DNA topoisomerase I and BSA. All the Ni(II) complexes possess high antioxidant activity against 2-2-diphenyl-1-picrylhydrazyl (DPPH) radical and antihaemolytic activity. In addition, in vitro cytotoxicity of the Ni(II) complexes against lung cancer (A549), human breast cancer (MCF7) and mouse embryonic fibroblasts (L929) cell lines was investigated. Complex 4 has high cytotoxicity. The mode of cell death effected by complex 4 has been explored using Hoechst 33258 staining. Nickel(II) complexes of thiosemicarbazone ligands were synthesized and their DNA/protein binding, DNA cleavage and cytotoxicity abilities were studied. PMID- 27995335 TI - Differential expression of the epithelial mesenchymal transition factors Snail, Slug, Twist, TGF-beta, and E-cadherin in ameloblastoma. AB - Epithelial mesenchymal transition (EMT), the transition of epithelial cells into motile mesenchymal cells, plays an important role in embryogenesis, cancer invasion, and metastasis. Ameloblastomas are common epithelial odontogenic tumors, occurring exclusively in the mandible with locally invasive growth. Thirty-seven ameloblastoma cases were evaluated for the involvement of EMT by immunohistochemical staining and western blotting using antibodies against Slug, Snail, Twist, TGF-beta, and E-cadherin. Double immunostaining was also performed. Slug and TGF-beta were expressed in the nuclei of peripheral and stellate reticulum cells of ameloblastoma nests. Twenty cases of Snail, 36 of Slug, 8 of Twist, and 19 of TGF-beta showed strong expression in tumor cells in follicular and plexiform patterns. Expression of Slug and TGF-beta increased in regions where the expression of E-cadherin was reduced. EMT was found to be associated with the local invasive growth of ameloblastoma. These data suggest that reduced expression of E-cadherin and over-expression of Slug, Snail, and TGF-beta induce EMT. Given that ameloblastomas are characterized by local invasiveness, EMT might be related to their development. Thus, strong expression of Slug and TGF-beta and reduced expression of E-cadherin might be related to the local invasiveness of ameloblastoma. PMID- 27995336 TI - Characterization and complete genome sequence of a panicovirus from Bermuda grass by high-throughput sequencing. AB - Bermuda grass samples were examined by transmission electron microscopy and 28-30 nm spherical virus particles were observed. Total RNA from these plants was subjected to high-throughput sequencing (HTS). The nearly full genome sequence of a panicovirus was identified from one HTS scaffold. Sanger sequencing was used to confirm the HTS results and complete the genome sequence of 4404 nt. This virus was provisionally named Bermuda grass latent virus (BGLV). Its predicted open reading frames follow the typical arrangement of the genus Panicovirus. Based on sequence comparisons and phylogenetic analyses BGLV differs from other viruses and therefore taxonomically it is a new member of the genus Panicovirus, family Tombusviridae. PMID- 27995338 TI - Erratum to: The need for differentiating diabetes-specific mortality from total mortality when comparing metformin with insulin regarding cancer survival. PMID- 27995337 TI - Functional characterization of recombinant major envelope protein (rB2L) of orf virus. AB - Orf, or contagious ecthyma, a highly contagious transboundary disease of sheep and goats, is caused by a double-stranded DNA virus (ORFV) belonging to the genus Parapoxvirus of the family Poxviridae. The ORFV genome encodes the major envelope proteins B2L and F1L, which have been found to be highly immunogenic and have multiple functional characteristics. In order to investigate the functional properties of the B2L protein, in this study, the B2L gene of ORFV strain 59/05, encoding recombinant mature B2L (aa 1M-D334), was produced as a fusion protein in Escherichia coli. The functional characteristics of purified rB2L fusion protein (~60 kDa) were evaluated in vivo and in vitro, showing that this protein had lipase and immunomodulatory activities. Immunization trials involving laboratory animals (mice, rabbits and guinea pigs) using either constant or graded doses of rB2L fusion protein with or without adjuvants (FCA, alum) as well as co administration with candidate rErns-Ag protein of classical swine fever virus (CSFV) indicated that the rB2L protein is immunogenic and has immunomodulatory properties. This study shows the potential utility of the rB2L protein as a safe and novel adjuvant in veterinary vaccine formulations. PMID- 27995339 TI - Cardiovascular complications of type 1 diabetes: update on the renal link. AB - AIMS: Despite recent findings of increased life expectancy among individuals with type 1 diabetes, mortality remains greatly increased compared to the general population. As this is largely the result of cardiovascular and renal complications, we aimed to review recent findings surrounding these diseases in type 1 diabetes. METHODS: We reviewed published findings concerning the cardiovascular complications of type 1 diabetes, with a particular focus on links with renal disease. RESULTS: The cardiovascular and renal complications of type 1 diabetes share many features including insulin resistance, oxidative damage, and genetic associations with the Haptoglobin genotype, and both are strongly affected by glycemic control. CONCLUSIONS: Although current knowledge on predictors of type 1 diabetes cardiovascular and renal complications has increased, further investigation is required to understand the mechanisms leading to cardio-renal complications in this population. PMID- 27995342 TI - Insect Immunity to Entomopathogenic Nematodes and Their Mutualistic Bacteria. AB - Entomopathogenic nematodes are important organisms for the biological control of insect pests and excellent models for dissecting the molecular basis of the insect immune response against both the nematode parasites and their mutualistic bacteria. Previous research involving the use of various insects has found distinct differences in the number and nature of immune mechanisms that are activated in response to entomopathogenic nematode parasites containing or lacking their associated bacteria. Recent studies using model insects have started to reveal the identity of certain molecules with potential anti-nematode or antibacterial activity as well as the molecular components that nematodes and their bacteria employ to evade or defeat the insect immune system. Identification and characterization of the genes that regulate the insect immune response to nematode-bacteria complexes will contribute significantly to the development of improved practices to control insects of agricultural and medical importance, and potentially nematode parasites that infect mammals, perhaps even humans. PMID- 27995340 TI - New single-nucleotide polymorphisms associated with differences in platelet reactivity and their influence on survival in patients with type 2 diabetes treated with acetylsalicylic acid: an observational study. AB - AIMS: Genetic polymorphisms may contribute to platelet reactivity in diabetic patients; however, the information on their influence on long-term antiplatelet therapy is lacking. Our aim was to evaluate the role of previously described genetic variants and platelet reactivity on risk of all-cause mortality and cardiovascular events. METHODS: Blood samples were obtained from 303 Caucasian patients. Genome-wide genotyping was performed using Illumina Human Omni 2.5-Quad microarrays, and individual genotyping of selected SNPs was performed using a custom Sequenom iPLEX assay in conjunction with the Mass ARRAY platform. Platelet reactivity was measured with VerifyNow Aspirin Assay and PFA-100 Assay. Univariate and multivariate Cox regression analyses were performed to determine the impact of genetic variants and platelets reactivity on risk of all-cause mortality and cardiovascular events. RESULTS: Among the 237 patients included in the follow-up, death from any cause occurred in 34 (14.3%) patients and cardiovascular events occurred in 51 (21.5%) patients within a median observation time of 71 months (5.9 years). In univariate analyses, significant association in the presence of minor alleles in TXBA2R (rs1131882) with primary (HR 2.54, 95% CI 1.15-5.60, p = 0.021) and secondary endpoint (HR 2.06, 95% CI 1.06-4.04, p = 0.034) was observed. In addition, multivariate analyses revealed the impact of this polymorphism on primary (HR 2.34, 95% CI 1.09-5.00, p = 0.029) and secondary endpoint (HR 1.89, 95% CI 1.00-3.57, p = 0.048). CONCLUSIONS: Results of the study demonstrate for the first time an association between genetic polymorphism within TXBA2R gene encoding platelet's surface receptor and long-term survival of diabetic patients treated with ASA. PMID- 27995341 TI - Cervical spine meniscoids: an update on their morphological characteristics and potential clinical significance. AB - PURPOSE: Cervical spine meniscoids are intra-articular folds of synovial membrane that have been theorised to have potential clinical significance in neck pain. Recent anatomical and clinical research has re-visited the pathoanatomical capacity of these structures. The purpose of this review is to discuss cervical spine meniscoid morphology in light of recently published work, to provide an update on the plausible relevance of these structures to clinical practice. METHODS: Narrative review critically discussing basic science and clinical research regarding cervical spine meniscoids, with focus upon implications for clinical practice. RESULTS: Basic science research indicates that cervical spine meniscoids can be innervated and appear to vary in morphology in the presence of articular degeneration. In a clinical population, associations have been observed between cervical spine meniscoid morphology and presence of cervical spine symptoms. CONCLUSIONS: Recent studies regarding cervical spine meniscoid morphology provide further evidence of pathoanatomical capacity of these structures. Further research is required, however, in clinical populations to empirically investigate specific theorised mechanisms of cervical spine meniscoid involvement in neck pain. PMID- 27995344 TI - Health and Disease in Translocated Wild Animals. PMID- 27995343 TI - Pre-procedural renal resistive index accurately predicts contrast-induced acute kidney injury in patients with preserved renal function submitted to coronary angiography. AB - The study aimed to evaluate the clinical utility of ultrasonographic intra-renal blood flow parameters, together with the wide range of different risk factors, for the prediction of contrast-induced acute kidney injury (CI-AKI) in patients with preserved renal function, referred for coronary angiography or percutaneous coronary interventions (CA/PCI). This prospective study covered 95 consecutive patients (69.5% men; median age 65 years) subject to elective or urgent CA/PCI. Data regarding 128 peri-procedural variables were collected. Ultrasonographic intra-renal blood flow parameters, including renal resistive index (RRI) and pulsatility index (RPI), were acquired directly before the procedure. CI-AKI was defined as >=50% relative or >=0.3 mg/dL absolute increase of serum creatinine 48 h after procedure. CI-AKI was confirmed in nine patients (9.5%). Patients with CI AKI had higher SYNTAX score (p = 0.0002), higher rate of left main disease (p < 0.00001), peripheral artery disease (PAD; p = 0.02), coronary artery anomaly (p = 0.017), more frequently underwent surgical revascularization (p = 0.0003), 'had greater...' intima-(p = 0.004) and extra-medial thickness (p = 0.001), and received higher contrast media dose (p = 0.049), more often overused non steroidal anti-inflammatory drugs (p = 0.001), and had substantially higher pre procedural RRI (0.69 vs. 0.62; p = 0.005) and RPI values (1.54 vs. 1.36; p = 0.017). Logistic regression confirmed age, SYNTAX score, presence of PAD, diabetes mellitus, and pre-procedural RRI independently predicted CI-AKI onset (AUC = 0.95; p < 0.0001). Pre-procedural RRI > 0.69 had 78% sensitivity and 81% specificity in CI-AKI prediction. High pre-procedural RRI seems to be a useful novel risk factor for CI-AKI in patients with preserved renal function. Coronary, peripheral and renal vascular pathology contribute to the development of CI-AKI following CA/PCI. PMID- 27995345 TI - Interpretation of the Elecsys Toxo IgG avidity results for very low and very high index: study on 741 sera with a determined date of toxoplasmosis. AB - Initial results with the Elecsys Toxo IgG Avidity assay showed some potential for interpretation of a very low or very high index result. We aimed to examine these new insights into interpretation using a large panel of serum samples and to define the optimal thresholds. A total of 741 patient serum samples with known date of infection (from a few weeks to more than 9 months after infection), were analysed with the Elecsys Toxo IgG Avidity assay. Values >=80% (threshold defined by the manufacturer) were reported in 289 sera; 288 sera were sampled more than 4 months after infection. Thus, avidity values >=80% excluded an infection less than 4 months. Avidity values >=90% were reported in 112 sera sampled more than 9 months after infection. Thus, avidity values >=90% excluded infection less than 9 months. Moreover avidity values <=15% were reported in the 62 sera sampled less than 3 months after infection. Thus avidity values <=15% excluded infection more than 3 months. PMID- 27995346 TI - The role of deep breathing on stress. AB - The objective of this study was to verify, in a sample of university students, whether a relaxing technique called deep breathing (stress Intervention Functional IFA) is capable to improve the mood and to reduce the levels of stress. Thirty-eight adult healthy subjects (aged between 18 and 28 years) volunteered the study. They were randomly divided in two groups, the Experimental Group (N = 19) and the Control Group (N = 19). The subjects of the Experimental Group were submitted, once per week, to 10 treatment's sessions of Anti-stress Protocol, each lasting 90 min, whereas subjects of the Control Group sat ten times for 90 min, once per week, without practicing any treatment. The psychological state of mood and stress was evaluated using Measurement of Psychological Stress (MSP) and Profile of Mood State (POMS), while the biological profile of the stress was detected by measuring the heart rate and the salivary cortisol. The results obtained from the present research support the possibility that deep breathing technique is capable to induce an effective improvement in mood and stress both in terms of self-reported evaluations (MPS and POMS) and of objective parameters, such as heart rate and salivary cortisol levels. No statistically significant difference was found between men and women. PMID- 27995347 TI - The cholinomimetic morantel as an open channel blocker of the Ascaris suum ACR-16 nAChR. AB - Nematode parasite infections pose a significant threat in human and veterinary medicine. At least a third of the world's population is at risk from nematode parasite infections. These infections not only cause health problems, but also cause loss of livestock production and hence, economic losses. Anthelmintic drugs are the mainstay by which control of nematode parasite infections is achieved. Many of the currently available anthelmintics act on nicotinic acetylcholine receptors (nAChRs). However, the detailed mode of action (MOA) of these anthelmintics is not clearly understood. Elucidation of the MOA of anthelmintics is highly desirable; an in-depth knowledge of the MOA will better inform on mechanisms of resistance development and on ways to slow down or overcome resistance. The cholinomimetic anthelmintic, morantel, has a complex MOA involving the activation and block of levamisole-sensitive single nAChR channels (L-type nAChR or L-nAChR). More recently, morantel has been demonstrated to activate Haemonchus contortus and Parascaris equorum ACR-26/ACR-27 nAChRs expressed in Xenopus laevis oocytes. Previous studies in our laboratory, however, have shown morantel does not activate the nicotine-sensitive nAChR (N-type nAChR or N-nAChR), Ascaris suum ACR-16 (Asu-ACR-16). In this study, we used two electrode voltage-clamp (TEVC) electrophysiology to investigate the inhibitory effects of morantel, on expressed Asu-ACR-16 nAChRs in X. laevis oocytes. Our results show that morantel acts as a non-competitive antagonist on Asu-ACR-16. This non-competitive antagonism by morantel was further demonstrated to be voltage-sensitive. We conclude based on our findings that morantel is a non competitive voltage-sensitive open channel blocker of Asu-ACR-16. PMID- 27995348 TI - Mitochondrial genome of Pteronotus personatus (Chiroptera: Mormoopidae): comparison with selected bats and phylogenetic considerations. AB - We described the complete mitochondrial genome (mitogenome) of the Wagner's mustached bat, Pteronotus personatus, a species belonging to the family Mormoopidae, and compared it with other published mitogenomes of bats (Chiroptera). The mitogenome of P. personatus was 16,570 bp long and contained a typically conserved structure including 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and one control region (D-loop). Most of the genes were encoded on the H-strand, except for eight tRNA and the ND6 genes. The order of protein-coding and rRNA genes was highly conserved in all mitogenomes. All protein-coding genes started with an ATG codon, except for ND2, ND3, and ND5, which initiated with ATA, and terminated with the typical stop codon TAA/TAG or the codon AGA. Phylogenetic trees constructed using Maximum Parsimony, Maximum Likelihood, and Bayesian inference methods showed an identical topology and indicated the monophyly of different families of bats (Mormoopidae, Phyllostomidae, Vespertilionidae, Rhinolophidae, and Pteropopidae) and the existence of two major clades corresponding to the suborders Yangochiroptera and Yinpterochiroptera. The mitogenome sequence provided here will be useful for further phylogenetic analyses and population genetic studies in mormoopid bats. PMID- 27995349 TI - The essential Drosophila CLAMP protein differentially regulates non-coding roX RNAs in male and females. AB - Heterogametic species require chromosome-wide gene regulation to compensate for differences in sex chromosome gene dosage. In Drosophila melanogaster, transcriptional output from the single male X-chromosome is equalized to that of XX females by recruitment of the male-specific lethal (MSL) complex, which increases transcript levels of active genes 2-fold. The MSL complex contains several protein components and two non-coding RNA on the X ( roX) RNAs that are transcriptionally activated by the MSL complex. We previously discovered that targeting of the MSL complex to the X-chromosome is dependent on the chromatin linked adapter for MSL proteins (CLAMP) zinc finger protein. To better understand CLAMP function, we used the CRISPR/Cas9 genome editing system to generate a frameshift mutation in the clamp gene that eliminates expression of the CLAMP protein. We found that clamp null females die at the third instar larval stage, while almost all clamp null males die at earlier developmental stages. Moreover, we found that in clamp null females roX gene expression is activated, whereas in clamp null males roX gene expression is reduced. Therefore, CLAMP regulates roX abundance in a sex-specific manner. Our results provide new insights into sex specific gene regulation by an essential transcription factor. PMID- 27995350 TI - Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model. AB - Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment. PMID- 27995351 TI - Short-term and long-term survival of interval breast cancers taking into account prognostic features. AB - PURPOSE: The aim of this population-based study was to estimate short-term and long-term survival of interval breast cancers and to compare them to clinically detected cancers, taking into account prognostic features. METHODS: This study included all interval cancers and clinically detected cancers diagnosed in the Loire-Atlantique population-based cancer registry from 2000 to 2010 in women aged 50-76 years. We used the Pohar-Perme method to estimate 5- and 10 year net survival rates and a flexible parametric model to compare interval cancer and clinically detected cancer prognosis with and without adjustment for the main prognostic factors (age, stage, histological grade, and phenotype). RESULTS: This study included 813 interval cancers and 1,354 clinically detected cancers. Interval cancers were diagnosed at a significantly less advanced stage than clinically detected cancers, but more often with a triple-negative phenotype. Interval cancer age-standardised net survival was 88.0% at 5 years (95% CI 84.9 91.2) and 81.7% at 10 years (95% CI 76.9-86.9), whereas clinically detected cancer age-standardised net survival was 77.8% (95% CI 75.1-80.6) and 64.6% (95% CI 60.7-68.7), respectively. After adjustment for covariates, survival no longer differed between interval cancers and clinically detected cancers at 5 and 10 years. CONCLUSION: Although the interval cancer net survival rate was higher, interval cancers had a similar short-term and long-term prognosis than clinically detected cancers after taking into account the main prognostic factors. PMID- 27995352 TI - Diabetes and breast cancer mortality in Black women. AB - PURPOSE: Breast cancer mortality is higher in Black women than in White women. The prevalence of type 2 diabetes mellitus is also higher, yet data on whether diabetes affects breast cancer mortality in this population are lacking. We investigated the relation of diabetes at the time of breast cancer diagnosis to breast cancer mortality in the Black Women's Health Study, a prospective cohort study. METHODS: 1,621 Black women with invasive breast cancer diagnosed in 1995 2013 were followed by mailed questionnaires and searches of the National Death Index. Multivariable Cox regression analysis was used to compute hazard ratios (HRs) for diabetes in relation to breast cancer mortality and all-cause mortality, with adjustment for age, stage, treatment modality, estrogen receptor (ER) status, and body mass index. RESULTS: There were 368 deaths during follow up, of which 273 were due to breast cancer. Breast cancer mortality was significantly increased in women who had been diagnosed with diabetes at least 5 years before breast cancer occurrence, HR 1.86 (95% CI 1.20-2.89), with elevations observed for both ER+ and ER- breast cancer. All-cause mortality was also higher in diabetics, with HRs of 1.54 (95% CI 1.12-2.07) overall and 2.26 (95% CI 1.62-3.15) for >=5-year duration of diabetes relative to non-diabetics. CONCLUSIONS: Our results present the first solid evidence of a positive association of type 2 diabetes with breast cancer mortality in Black women. Given the higher prevalence and earlier onset of type 2 diabetes in Black women, it is likely that diabetes contributes to racial disparities in breast cancer mortality. PMID- 27995353 TI - Soil sampling strategies for site assessments in petroleum-contaminated areas. AB - Environmental site assessments are frequently executed for monitoring and remediation performance evaluation purposes, especially in total petroleum hydrocarbon (TPH)-contaminated areas, such as gas stations. As a key issue, reproducibility of the assessment results must be ensured, especially if attempts are made to compare results between different institutions. Although it is widely known that uncertainties associated with soil sampling are much higher than those with chemical analyses, field guides or protocols to deal with these uncertainties are not stipulated in detail in the relevant regulations, causing serious errors and distortion of the reliability of environmental site assessments. In this research, uncertainties associated with soil sampling and sample reduction for chemical analysis were quantified using laboratory-scale experiments and the theory of sampling. The research results showed that the TPH mass assessed by sampling tends to be overestimated and sampling errors are high, especially for the low range of TPH concentrations. Homogenization of soil was found to be an efficient method to suppress uncertainty, but high-resolution sampling could be an essential way to minimize this. PMID- 27995354 TI - Estimation of the daily soil/dust (SD) ingestion rate of children from Gansu Province, China via hand-to-mouth contact using tracer elements. AB - A total of 60 children (31 males and 29 females) between the ages of 3 and 12 years were randomly selected from Lanzhou City in Gansu Province, northwest China. Hand (soil/dust) SD samples from these children were collected using hand wipes. We determined the approximate amounts of hand SD and the concentrations of three tracer soil elements (Ce, Y, and V) in these samples. The approximate amounts of hand SD ranged from 42.28 to 173.76 mg, with a median value of 85.42 mg. In addition, the mean amounts of hand SD estimated using the concentrations of Ce, Y, and V in the samples were 4.63, 3.43, and 3.42 mg, respectively. The amount of hand SD varied greatly among the age groups: primary school children had more hand SD than kindergarten children, males had more hand SD than females, and children from rural areas had more hand SD than those from urban areas. The rates of daily ingestion of hand SD for kindergarten and primary school children were estimated to be 7.73 and 6.61 mg/day, respectively. PMID- 27995355 TI - Cytotoxicity and cellular response mechanisms of water-soluble platinum(II) complexes of lidocaine and phenylcyanamide derivatives. AB - Three new platinum(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pt(3,5-(NO2)2pcyd)2(LC)], 1, K[Pt(3,5-(CF3)2pcyd)2(LC)], 2, K[Pt(3,5-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 3,5-(NO2)2pcyd: 3,5-dinitro phenylcyanamide, 3,5-(CF3)2pcyd: 3,5-bis(trifluoromethyl) phenylcyanamide, 3,5 Cl2pcyd: 3,5-dichloro phenylcyanamide) have been synthesized and fully characterized. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. The complexes 1-3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines. All the complexes are more active than cisplatin and follow the trend 1 > 2 > 3. Mechanistic studies showed that the trend in cytotoxicity of the Pt(II) complexes is mainly consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which consequently results in the loss of mitochondrial membrane potential and apoptosis induction. The complex 1 caused to approximately 80-fold higher DNA platination level with respect to cisplatin. The complexes 1-3 can considerably stimulate the production of hydrogen peroxide in a time-dependent manner. Also, the complexes 1-3 induced an increase in reactive oxygen species (ROS) production that was superior to that induced by antimycin. The complex 1 had the most effect on ROS production in comparison with other complexes. PMID- 27995356 TI - Tripartite Motif 8 (TRIM8) Positively Regulates Pro-inflammatory Responses in Pseudomonas aeruginosa-Induced Keratitis Through Promoting K63-Linked Polyubiquitination of TAK1 Protein. AB - Pseudomonas aeruginosa (PA)-induced keratitis is a rapidly progressive ocular infectious disease that often leads to inflammatory epithelial edema, stromal infiltration, tissue destruction, corneal ulceration, and vision loss. In this study, we investigate the role of tripartite motif 8 (TRIM8) in regulating the inflammatory process of PA-induced keratitis. The expression of TRIM8 was increased in mouse corneas and in vitro-cultured macrophages after PA infection. Knockdown of the expression of TRIM8 significantly inhibited the activation of NF kappaB signaling and decreased the production of pro-inflammatory cytokines both in vivo and in vitro after infected with PA. Furthermore, we investigated the potential mechanism and we found after PA infection that TRIM8 could promote K63 linked polyubiquitination of transforming growth factor beta-activated kinase 1 (TAK1), leading to the activation of TAK1 and enhanced inflammatory responses. Taken together, we demonstrated that TRIM8 has pro-inflammatory effect on PA induced keratitis and suggest TRIM8 as a potential therapeutic target for keratitis. PMID- 27995357 TI - Bone Morphogenetic Protein-Modulator BMPER Regulates Endothelial Barrier Function. AB - The endothelium serves as a selective barrier and controls the exchange of nutrients, hormones, and leukocytes between blood and tissues. Molecular mechanisms contributing to the pathogenesis of endothelial barrier dysfunction remain incompletely understood. Accumulating evidence implicates bone morphogenetic protein (BMP)-modulator BMPER as a key regulator in endothelial biology. Herein, we analyze the impact of BMPER in the control of endothelial barrier function. To assess the role of BMPER in vascular barrier function in mice, we measured the leakage of Evans blue dye from blood into interstitial lung tissue. BMPER+/- mice exhibited a significantly higher degree of vascular leak compared with wild-type siblings. In accordance with our in vivo observation, siRNA-based BMPER knockdown in human umbilical endothelial cells increased endothelial permeability measured by FITC-dextran passage in transwell assays. Mechanistically, BMPER knockdown reduced the expression of VE-cadherin, a pivotal component of endothelial adherens junctions. Conversely, recombinant human BMPER protein upregulated VE-cadherin protein levels and improved endothelial barrier function in transwell assays. The effects of BMPER knockdown on VE-cadherin expression and endothelial permeability were induced by enhanced BMP activity. Supporting this notion, activation of BMP4-Smad-Id1 signaling reduced VE-cadherin levels and impaired endothelial barrier function in vitro. In vivo, Evans blue dye accumulation was higher in the lungs of BMP4-treated C57BL/6 mice compared to controls indicating that BMP4 increased vascular permeability. High levels of BMPER antagonized BMP4-Smad5-Id1 signaling and prevented BMP4-induced downregulation of VE-cadherin and endothelial leakage, suggesting that BMPER exerts anti-BMP effects and restores endothelial barrier function. Taken together, this data demonstrates that BMPER-modulated BMP pathway activity regulates VE-cadherin expression and vascular barrier function. PMID- 27995358 TI - Ecological Momentary Assessment of Affective and Interpersonal Instability in Adolescent Non-Suicidal Self-Injury. AB - Affective and interpersonal instability, both core features of Borderline Personality Disorder (BPD), have been suggested to underlie non-suicidal self injury (NSSI). Ecological momentary assessment (EMA) is the method of choice when investigating dynamic processes. Previously no study addressed affective and interpersonal instability in daily life of adolescents engaging in NSSI. Female adolescents with NSSI (n = 26) and age- and sex-matched healthy controls (n = 20) carried e-diaries on 2 consecutive weekends and were prompted in hourly intervals to rate their momentary affective state and feelings of attachment towards their mother and best friend. The majority of participants in the NSSI group also fulfilled diagnostic criteria for BPD (73%). Squared successive differences were calculated to quantify instability. Adolescents with NSSI reported less positive affect, t (44) = 6.94, p < 0.01, lower levels of attachment to the mother, t (44) = 5.53, p < 0.01, and best friend, t (44) = 4.36, p < 0.01. Both affective, t (44) = -5.55, p < 0.01, and interpersonal instability, mother: t (44) = -4.10, p < 0.01; best friend: t (44) = -4.57, p < 0.01, were significantly greater in adolescents engaging in NSSI. In the NSSI group, the number of BPD criteria met was positively correlated with affective instability, r = 0.40, p < 0.05, and instability of attachment to the best friend, r = 0.42, p < 0.05, but not instability of attachment towards the mother, r = 0.06, p = 0.79. In line with previous work in adults, NSSI is associated with affective and interpersonal instability assessed by EMA in adolescents. Preliminary findings highlight the association of affective and interpersonal instability with diagnostic criteria for BPD. Clinical implications and avenues for further research are discussed. PMID- 27995359 TI - Associations between Disorder-Specific Symptoms of Anxiety and Error-Monitoring Brain Activity in Young Children. AB - Anxiety disorders are among the earliest emerging disorders and most common mental health problem across the lifespan. A common characteristic of individuals with anxiety is poor attentional and cognitive control. Therefore, researchers are interested in how cognitive functioning relates to anxiety in young children. In particular, research has demonstrated associations between anxiety and electrophysiological markers of cognitive control skills such as the error related negativity (ERN). The nature of the anxiety-ERN relationship is not well understood, however. The purpose of the present study was to examine: 1) the association between the ERN and diagnostically-defined symptoms of different anxiety disorders; and 2) the extent to which disorder-specific symptoms of anxiety moderated the association between ERN and behavioral performance on a Go/No-Go task in a sample of 139 children 5-8 years of age (70 females and 69 males). Results suggest that more separation anxiety disorder (SAD) symptoms are associated with a smaller DeltaERN, even after controlling for other anxiety disorder symptoms. Children with more SAD symptoms showed higher error rates and failed to exhibit the expected association between DeltaERN and behavioral performance, suggesting ineffective error-monitoring in young children with SAD problems. PMID- 27995360 TI - A European Society of Paediatric and Neonatal Intensive Care (ESPNIC) survey of European critical care management of young people. AB - : Adolescents have specific healthcare needs distinct from adults or younger children secondary to anatomical, physiological and socio-behavioural differences. Healthcare providers have been slow to address this, leading the UK Department of Health (2011) to publish 'You're Welcome' quality criteria for services for young people. (In the UK, the term young people is preferred to adolescent.) These generic criteria poorly fit the critical care environment, omitting key issues whilst insisting upon irrelevant standards. But as young people are infrequent patients for any individual unit, the research base to guide optimal management is poor and we could find no international or national guidance. Together with the hospital's young people's group, our intensive care team identified six areas important for critically ill young people, which are the 6Ps: privacy, permission, deep vein thrombosis (DVT) prophylaxis, personal life, puberty and practical issues. We then surveyed practice across Europe regarding these themes. Fifty-four hospitals from 16 countries participated, demonstrating disparate practice and widely differing policies to meet the requirements of critically ill young people. CONCLUSION: There is little consistency of practice in some areas such as pregnancy testing, DVT prophylaxis or partner visiting, whereas in others, such as involving young people in healthcare decisions where possible, practice is consistently good. Further research should focus on the young people's experience of critical care to refine healthcare policy. What is Known: * Adolescents have distinct health and psychosocial needs that are often poorly catered for in contemporary healthcare settings, including critical care. * As adolescents are infrequent patients for any intensive care unit, there is a poor research base and essentially no guidance, regarding optimal care. What is New: * We developed a mnemonic with adolescents and ICU staff to improve healthcare delivery to young people in critical care, the 6Ps: privacy, permission, DVT prophylaxis, personal life, puberty and practical issues. * Delivery of the adolescents' critical care varies greatly both between and within countries; the 6Ps offers a method of standardising and improving this across different countries. PMID- 27995361 TI - Bladder and bowel dysfunctions in 1748 children referred to pelvic physiotherapy: clinical characteristics and locomotor problems in primary, secondary, and tertiary healthcare settings. AB - : The aims of this study are to evaluate in a pragmatic cross-sectional study, the clinical characteristics of childhood bladder and/or bowel dysfunctions (CBBD) and locomotor problems in the primary through tertiary health care setting. It was hypothesized that problems would increase, going from primary to tertiary healthcare. Data were retrieved from patient-records of children (1-16 years) presenting with CBBD and visiting pelvic physiotherapists. Prevalence's of dysfunctions were compared between healthcare settings and gender using ANOVA and chi-square test. Agreement between physicians' diagnoses and parent-reported symptoms was evaluated (Cohen's Kappa). One thousand seventy hundred forty-eight children (mean age 7.7 years [SD 2.9], 48.9% boys) were included. Daytime urinary incontinence (P = 0.039) and enuresis (P < 0.001) were more diagnosed in primary healthcare, whereas constipation (P < 0.001) and abdominal pain (P = 0.009) increased from primary to tertiary healthcare. All parent-reported symptoms occurred more frequently than indicated by the physicians. Poor agreement between physicians' diagnoses and parent-reported symptoms was found (k = 0.16). Locomotor problems prevailed in all healthcare settings, motor skills (P = 0.041) and core stability (P = 0.015) significantly more in tertiary healthcare. CONCLUSIONS: Constipation and abdominal pain (physicians' diagnoses) and the parent-reported symptoms hard stools and bloating increased from primary to tertiary healthcare. Discrepancies exist between the prevalence's of physicians' diagnoses and parent-reported symptoms. Locomotor problems predominate in all healthcare settings. What is Known: * Childhood bladder and/or bowel dysfunctions (CCBD) are common. * Particularly tertiary healthcare characteristics of CBBD are available What is New: * Characteristics of CBBD referred to pelvic physiotherapy are comparable in primary, secondary, and tertiary healthcare settings. * Concomitant CBBD appeared to be more prevalent than earlier reported. * Discrepancies exist between referring physicians' diagnoses and parent-reported symptoms. PMID- 27995362 TI - (Pro)renin and (pro)renin receptor expression during kidney development in neonates. AB - : Although a recent study demonstrated that the (pro)renin receptor ((P)RR) was highly expressed in the developing kidney during the mouse embryonic development, the mechanism by which (P)RR supports renal development in humans is not fully understood. In this study, we examined the plasma levels of (pro)renin and soluble (P)RR (s(P)RR) in cord blood and neonates as well as (P)RR expression in human kidney tissues. Samples were collected from 57 preterm and 67 full-term human neonates. (Pro)renin and s(P)RR levels were measured using enzyme-linked immunosorbent assays. Additionally, we performed an immunohistochemical (IHC) analysis of kidney tissues from neonates and minor glomerular abnormalities in order to assess (P)RR expression in the kidney. Plasma (pro)renin and s(P)RR levels in cord blood were significantly higher in preterm neonates than in full term neonates. Four weeks after birth, these differences were no longer evident for either plasma (pro)renin or s(P)RR levels between the two groups. Importantly, plasma (pro)renin and s(P)RR levels in cord blood were inversely correlated with gestational age. Furthermore, IHC indicated that renal expression levels of (P)RR in neonates were stronger than those in minor glomerular abnormalities. CONCLUSION: (P)RR may play a pivotal role in prenatal renal development in humans. What is Known: * Renal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in pediatric renal disease. * Renal RAS activation plays a key role of renal development during gestation. What is New : * Plasma (pro)renin and soluble (pro)renin receptor (s(P)RR) levels in cord blood were significantly higher in preterm neonates than in full-term neonates. * Immunohistochemical analysis of kidney tissue indicated that renal expression levels of (P)RR in neonates were stronger than in minor glomerular abnormalities. PMID- 27995363 TI - Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore. AB - Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the first minutes of reperfusion. AZP-531 is an optimized analog of unacylated ghrelin currently in clinical development in several metabolic diseases. We investigated a potential cardioprotective effect of AZP-531 in ischemia/reperfusion (IR) and the molecular underlying mechanism(s) involved in this protection. In vivo postconditioning with AZP-531 in C57BL6 mouse IR model decreased infarct size. Western blot analysis on areas at risk from the different mouse groups showed that AZP-531 activates Akt, ERK1-2 as well as S6 and 4EBP1, mTORC1 effectors. We also showed an inhibition of caspase 3 cleavage and Bax translocation to the mitochondria. AZP-531 also stimulated the expression of antioxidants and was capable of decreasing mitochondrial H2O2 production, contributing to the reduction of ROS accumulation. AZP-531 exhibits cardioprotective effect when administrated for postconditioning in C57BL6 mouse IR model. Treatment with AZP-531 rescued the myocardium from cell death at early reperfusion by stimulating protein synthesis, inhibiting Bax/caspase 3-induced apoptosis as well as ROS accumulation and oxidative stress-induced necrosis. AZP-531 may prove useful in the treatment of IR injury. PMID- 27995364 TI - Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease. AB - In microvessels of patients with coronary artery disease (CAD), flow-mediated dilation (FMD) is largely dependent upon the endothelium-derived hyperpolarizing factor H2O2. The goal of this study is to examine the influence of age and presence or absence of disease on the mechanism of FMD. Human coronary or adipose arterioles (~150 um diameter) were prepared for videomicroscopy. The effect of inhibiting COX [indomethacin (Indo) or NOS (L-NAME), eliminating H2O2 (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E (mtVitamin E); phenylboronic acid (mtPBA)] was determined in children aged 0-18 years; young adults 19-55 years; older adults >55 years without CAD, and similarly aged adults with CAD. Indo eliminated FMD in children and reduced FMD in younger adults. This response was mediated mainly by PGI2, as the prostacyclin-synthase-inhibitor trans-2-phenyl cyclopropylamine reduced FMD in children and young adults. L-NAME attenuated dilation in children and younger adults and eliminated FMD in older adults without CAD, but had no effect on vessels from those with CAD, where mitochondria-derived H2O2 was the primary mediator. The magnitude of dilation was reduced in older compared to younger adults independent of CAD. Exogenous treatment with a sub-dilator dose of NO blocked FMD in vessels from subjects with CAD, while prolonged inhibition of NOS in young adults resulted in a phenotype similar to that observed in disease. The mediator of coronary arteriolar FMD evolves throughout life from prostacyclin in youth, to NO in adulthood. With the onset of CAD, NO-inhibitable release of H2O2 emerges as the exclusive mediator of FMD. These findings have implications for use of pharmacological agents, such as nonsteroidal anti-inflammatory agents in children and the role of microvascular endothelium in cardiovascular health. PMID- 27995365 TI - Evidence that Cerambycid Beetles Mimic Vespid Wasps in Odor as well as Appearance. AB - We present evidence that cerambycid species that are supposed mimics of vespid wasps also mimic their model's odor by producing spiroacetals, common constituents of vespid alarm pheromones. Adults of the North American cerambycids Megacyllene caryae (Gahan) and Megacyllene robiniae (Forster) are conspicuously patterned yellow and black, and are believed to be mimics of aculeate Hymenoptera, such as species of Vespula and Polistes. Adult males of M. caryae produce an aggregation-sex pheromone, but both sexes produce a pungent odor when handled, which has been assumed to be a defensive response. Headspace aerations of agitated females of M. caryae contained 16 compounds with mass spectra characteristic of spiroacetals of eight distinct chemical structures, with the dominant compound being (7E,2E)-7-ethyl-2-methyl-1,6-dioxaspiro[4.5]decane. Headspace samples of agitated males of M. caryae contained five of the same components, with the same dominant compound. Females of M. robiniae produced six different spiroacetals, one of which was not produced by M. caryae, (2E,7E)-2 ethyl-7-methyl-1,6-dioxaspiro[4.5]decane, and five that were shared with M. caryae, including the dominant (2E,8E)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane. The latter compound is the sole spiroacetal produced by both males and females of a South American cerambycid species, Callisphyris apicicornis (Fairmaire & Germain), which is also thought to be a wasp mimic. Preliminary work also identified spiroacetals of similar or identical structure released by vespid wasps that co-occur with the Megacyllene species. PMID- 27995366 TI - Psychometric evaluation of the Condom Barriers and Motivations Scale (CBMS). AB - The Condom Barriers and Motivations Scale (CBMS) was developed to measure four distinct categories of barriers and motives to condom use, including: risk reduction motivations, pleasure reduction barriers, intimacy interference barriers, and partner pressure barriers. The CBMS is a 16-item scale with four items that correspond to each of these subscales. The CBMS was tested in two samples of gay and bisexual men. Results support the reliability and validity of the scale and its structure. Results also indicate that CBMS subscales are distinct from general measures of sexual wellbeing, personality factors, or relationship quality (i.e., discriminant validity) and are associated with self reported condom use with different partner types (i.e., construct validity). The CBMS can be helpful in better understanding the dynamics of condom use in the context of pre-exposure prophylaxis decision-making, and can shed light on innovative approaches to enhance condom use as part of comprehensive HIV prevention and sexual health goals. PMID- 27995367 TI - Paracoccidioides brasiliensis induces cytokine secretion in epithelial cells in a protease-activated receptor-dependent (PAR) manner. AB - Paracoccidioides brasiliensis is one of the etiological agents of the human systemic mycosis paracoccidioidomycosis. Protease-activated receptors (PARs) are expressed in many cell types and comprise a family of G protein-coupled receptors (PAR-1, PAR-2, and PAR-4), which may be activated by proteases secreted by several pathogens. In the present study, we showed that the pathogenic fungus P. brasiliensis secretes components that promote interleukin (IL)-6 and IL-8 secretion by the lung epithelial cell line A549. Cytokine secretion was reduced by antagonistic peptides for PAR-1 and PAR-2, but not for PAR-4. P. brasiliensis proteases were isolated from fungal culture supernatants in a p aminomethylbenzamidine-Sepharose column. The obtained fractions were tested for enzymatic activity against fluorescence resonance energy transfer (FRET) peptides derived from sequences that spanned the activation sites of human PARs. The eluted fraction, termed PbP, contained protease activities that were able to hydrolyze the FRET peptides. PbP also induced IL-6 and IL-8 secretion in A549 epithelial cells, which was reduced upon heat inactivation of PbP, incubation with antagonistic peptides for PAR-1 and PAR-2, and the protease inhibitors aprotinin, leupeptin, and E-64. Together, these results show for the first time that P. brasiliensis yeasts secrete proteases that activate PARs in lung epithelial cells, leading to cytokine secretion. PMID- 27995368 TI - Cost of informal care for patients with cardiovascular disease or diabetes: current evidence and research challenges. AB - PURPOSE: Patients with cardiovascular disease (CVD) or diabetes often require informal care. The burden of informal care, however, was not fully integrated into economic evaluation. We conducted a literature review to summarize the current evidence on economic burden associated with informal care imposed by CVD or diabetes. METHODS: We searched EconLit, EMBASE, and PubMed for publications in English during the period of 1995-2015. Keywords for the search were informal care cost, costs of informal care, informal care, and economic burden. We excluded studies that (1) did not estimate monetary values, (2) examined methods or factors affecting informal care, or (3) did not address CVD or diabetes. RESULTS: Our search identified 141 potential abstracts, and 10 of the articles met our criteria. Although little research has been conducted, studies used different methods without much consensus, estimates suffered from recall bias, and study samples were small, the costs of informal care have been found high. In 2014 US dollars, estimated additional annual costs of informal care per patient ranged from $1563 to $7532 for stroke, $860 for heart failure, and $1162 to $5082 for diabetes. The total cost of informal care ranged from $5560 to $143,033 for stoke, $12,270 to $20,319 for heart failure, and $1192 to $1321 for diabetes. CONCLUSIONS: The costs of informal care are substantial, and excluding them from economic evaluation would underestimate economic benefits of interventions for the prevention of CVD and diabetes. PMID- 27995369 TI - Responsiveness of SF-36 Health Survey and Patient Generated Index in people with chronic knee pain commenced on oral analgesia: analysis of data from a randomised controlled clinical trial. AB - PURPOSE: (1) To assess the responsiveness of the Short Form 36 Health Survey (SF 36) and Patient Generated Index (PGI) in people with knee pain who were given oral analgesics; and (2) to perform content analysis of the SF-36 and PGI aiming to identify differences between the instruments and causes of different responsiveness. METHODS: An observational study nested within a randomised controlled trial comparing oral paracetamol, ibuprofen or a combination of the two in 884 community-derived people with chronic knee pain. Each participant was given the SF-36 and PGI questionnaires to fill out at baseline, day 10, week 7 and week 13 after commencement on analgesia. Responsiveness was measured as a standardised response mean from baseline, and contents of the instruments were analysed. RESULTS: The PGI showed the greater responsiveness to analgesics than the SF-36 throughout the study period. Only the Bodily Pain Score of the SF-36 showed comparable responsiveness to the PGI. The standardised response mean of the PGI at 13 weeks was 0.61 (95% CI 0.51-0.72), and that of the Bodily Pain Score of the SF-36 was 0.49 (95% CI 0.39-0.58). Content analysis of the PGI identified multiple areas which are not represented in the SF-36 which may help explain its performance. CONCLUSIONS: Overall the PGI is more responsive than the SF-36 to commonly used oral analgesics taken for knee pain. The PGI is able to elicit areas of individualised health-related quality of life which are not captured by the SF-36. PMID- 27995371 TI - Therapeutic effect of acupuncture on the outcomes of in vitro fertilization: a systematic review and meta-analysis. AB - PURPOSE: Controversial results have been reported concerning the effect of acupuncture on in vitro fertilization (IVF) outcomes. The current review was conducted to systematically review published studies of the effects of acupuncture on IVF outcomes. METHODS: Women undergoing IVF in randomized controlled trials (RCTs) were evaluated for the effects of acupuncture on IVF outcomes. The treatment groups involved traditional, electrical, laser, auricular, and other acupuncture techniques. The control groups consisted of no, sham, and placebo acupuncture. The PubMed, Embase, and Web of Science databases were searched. The pregnancy outcomes data are expressed as odds ratios (ORs) with 95% confidence intervals (CIs) based on a fixed model or random model depending on the heterogeneity determined by the Q test and I2 statistic. The major outcomes were biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), live birth rate (LBR), and ongoing pregnancy rate (OPR). Heterogeneity of the therapeutic effect was evaluated by a forest plot analysis, and publication bias was assessed by a funnel plot analysis. RESULTS: Thirty trials (a total of 6344 participants) were included in this review. CPR data showed a significant difference between the acupuncture and control groups (OR 1.26, 95% CI 1.06-1.50, p = 0.01), but there was significant statistical heterogeneity among the studies (p = 0.0002). When the studies were restricted to Asian or non-Asian area trials with a sensitivity analysis, the results significantly benefited the CPR in Asian group (OR 1.51, 95% CI 1.04-2.20, p = 0.03). Based on the area subgroup analysis, we found that in the Asian group, the IVF outcomes from the EA groups were all significantly higher than those from the control groups (CPR: OR 1.81, 95% CI 1.20-2.72, p = 0.005; BPR: OR 1.84, 95% CI 1.12-3.02, p = 0.02; LBR: OR 2.36, 95% CI 1.44-3.88, p = 0.0007; OPR: OR 1.94, 95% CI 1.03-3.64, p = 0.04). Meanwhile, compared with other acupuncture time, the IVF outcome results were significantly superior in the acupuncture group when acupuncture was conducted during controlled ovarian hyperstimulation (COH) (CPR: OR 1.71, 95% CI 1.27-2.29, p = 0.0004; LBR: OR 2.41, 95% CI 1.54-3.78, p = 0.0001; BPR: OR 1.50, 95% CI 1.02 2.20, p = 0.04; OPR: OR 1.88, 95% CI 1.06-3.34, p = 0.03). However, when acupuncture was conducted at the time of embryo transfer, the BPR and OPR from the acupuncture groups were significantly lower than those of the controls in the Asian group (BPR: OR 0.67, 95% CI 0.48-0.92, p = 0.01; OPR: OR 0.68, 95% CI 0.49 0.96, p = 0.03). CONCLUSIONS: Based on an analysis of the studies, acupuncture improves the CPR among women undergoing IVF. When the studies were restricted to Asian or non-Asian area patients, compared with traditional acupuncture and other methods, electrical acupuncture yielded better IVF outcomes. Optimal positive effects could be expected using acupuncture in IVF during COH, especially in Asian area. However, as a limitation of this review, most of the included studies did not mention the number of embryos transferred. PMID- 27995370 TI - The impact of ultra-radical surgery in the management of patients with stage IIIC and IV epithelial ovarian, fallopian tube, and peritoneal cancer. AB - OBJECTIVE: The aim of this study is to estimate the percentage of patients with metastatic ovarian, fallopian tube, and primary peritoneal cancer requiring ultra radical surgery to achieve cytoreduction to less than 1 cm (optimal) or no macroscopic residual disease (complete). METHODS: Perioperative data were collected prospectively on consecutive patients undergoing elective cytoreductive surgery for metastatic epithelial ovarian, fallopian tube, or primary peritoneal cancer at the Norfolk and Norwich University Hospital, a tertiary referral cancer centre in the United Kingdom from November 2012 to June 2016. RESULTS: Over a 42 month period, 135 consecutive patients underwent cytoreductive surgery for stage IIIC and IV ovarian, fallopian tube, or primary peritoneal cancer. The median age of the patients was 69 years. 47.4% of the patients underwent diaphragmatic peritonectomy and/or resection, 20% underwent splenectomy, 14.1% had excision of disease from porta hepatis and celiac axis, and 5.2% of the patients had gastrectomy. Cytoreduction to no macroscopic visible disease (complete) and to disease with greater tumour diameter of less than 1 cm (optimal) was achieved in 54.1 and 34.1% of the cases, respectively. Without incorporating surgical procedures in the upper abdomen ('ultra-radical'), the combined rate of complete and optimal cytoreduction would be only 33.3%. CONCLUSIONS: Up to 50.4% of the patients in this study required at least one surgical procedure classified as ultra-radical, emphasizing the importance of cytoreductive surgery in the upper abdomen in management of women with stage IIIC and IV ovarian, fallopian tube, and primary peritoneal cancer. PMID- 27995372 TI - Prognostic value of MMP-2 for patients with ovarian epithelial carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: The reported roles of matrix metalloproteinase 2 (MMP-2) on the prognosis of patients with epithelial ovarian cancers (EOCs) are inconsistent. OBJECTIVE: This meta-analysis was performed to evaluate the prognostic significance of MMP-2 for patients with EOCs by analyzing 11 studies. METHODS: We systematically searched articles in the Cochrane Library, Pubmed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Biological Medical (CBM) Database, updated to February 1st 2015, with the following search terms: ovarian neoplasm OR ovarian tumor OR ovarian carcinoma OR ovarian malignance OR ovarian cancer AND matrix metalloproteinase-2 OR MMP-2. RESULTS: A total of 11 studies involving 1058 patients with EOCs were in accordance with the inclusion criteria. The pooled HR was 1.09 (95% CI 0.32-1.86, p = 0.006) in patients with overexpression of stromal MMP-2 with significant heterogeneity (I 2 = 53.1%, p = 0.074) between studies. For patients with MMP-2 overexpression in tumor cells, the pooled HR was 1.42 (95% CI 1.14-1.70, p = 0.000) with no significant heterogeneity (I 2 = 43.4%, p = 0.078) between studies. Sensitivity analyses were stable. CONCLUSIONS: MMP-2 overexpression in tumor cells rather than stroma was significantly associated with poor prognosis in patient with endothelial ovarian cancer; however, the result remains to be confirmed with additional high-quality studies. PMID- 27995374 TI - Nuclear migration during karyogamy in rice zygotes is mediated by continuous convergence of actin meshwork toward the egg nucleus. AB - Fertilization is comprised of two sequential fusion processes; plasmogamy and karyogamy. Karyogamy completes with migration and fusion of the male and female nuclei in the fused cell. In animals, microtubules organized by the centrosome control female/male pronuclei migration. In contrast, the nuclear migration in fused gametes of angiosperms is controlled by actin filaments, but the mechanism that regulates actin filament-dependent nuclear migration is not clear. In this study, we prepared fused rice (Oryza sativa L.) gametes/zygotes using in vitro fertilization and observed the spatial and temporal movements of actin filaments and sperm nuclei. Our results show that actin filaments in egg cells form a meshwork structure surrounding the nuclei. Quantitative analysis of the actin meshwork dynamics suggests that actin meshwork converges toward the egg nucleus. In egg cells fused with sperm cells, actin filaments appeared to interact with a portion of the sperm nuclear membrane. The velocity of the actin filaments was positively correlated with the velocity of the sperm nucleus during karyogamy. These results suggest that sperm nuclear membrane and actin filaments physically interact with each other during karyogamy, and that the sperm nucleus migrates toward the egg nucleus through the convergence of the actin meshwork. Interestingly, actin filament velocity increased promptly after gamete fusion and was further elevated during nuclear fusion. In addition to the migration of gamete nuclei, convergence of actin meshwork may also be critical during early zygotic developments. PMID- 27995373 TI - Treatment of reno-ureteral colic by twelfth intercostal nerve block with lidocaine versus intramuscular diclofenac. AB - INTRODUCTION AND OBJECTIVE: Renal colic is one of the most intense pains known to humans. Standard treatment usually consists of nonsteroidal anti-inflammatory drugs and opiates, but they do not always provide optimum efficacy and speed in relieving the pain. For more than 25 years, our hospital has been employing twelfth subcostal nerve block. The objective of the present study was to compare the efficacy of subcostal nerve block with lidocaine versus intramuscular diclofenac in renal colic management. METHODS: Sixty patients of both sexes, above the age of 18 years, and presenting with renal colic were randomly selected for the study. The visual analog scale was applied prior to the treatment and at minutes 1, 3, 5, 30, and 45 after the application of the twelfth nerve block or the intramuscular administration of diclofenac. RESULTS: A total of 60 patients, 35 women and 25 men, were included in the study. There were statistically significant differences in the mean scores for pain from minute 1 to minute 45. There were no adverse effects. CONCLUSIONS: Twelfth Subcostal nerve block with lidocaine is an efficacious, safe, inexpensive, and very fast-acting medication for pain control related to renal colic. These characteristics make it superior to diclofenac. PMID- 27995375 TI - Leaf structure affects a plant's appearance: combined multiple-mechanisms intensify remarkable foliar variegation. AB - The presence of foliar variegation challenges perceptions of leaf form and functioning. But variegation is often incorrectly identified and misinterpreted. The striking variegation found in juvenile Blastus cochinchinensis (Melastomataceae) provides an instructive case study of mechanisms and their ecophysiological implications. Variegated (white and green areas, vw and vg) and non-variegated leaves (normal green leaves, ng) of seedlings of Blastus were compared structurally with microtechniques, and characterized for chlorophyll content and fluorescence. More limited study of Sonerila heterostemon (Melastomataceae) and Kaempferia pulchra (Zingiberaceae) tested the generality of the findings. Variegation in Blastus combines five mechanisms: epidermal, air space, upper mesophyll, chloroplast and crystal, the latter two being new mechanisms. All mesophyll cells (vw, vg, ng) have functional chloroplasts with dense thylakoids. The vw areas are distinguished by flatter adaxial epidermal cells and central trichomes containing crystals, the presence of air spaces between the adaxial epidermis and a colorless spongy-like upper mesophyll containing smaller and fewer chloroplasts. The vw area is further distinguished by having the largest spongy-tissue chloroplasts and fewer stomata. Both leaf types have similar total chlorophyll content and similar F v/F m (maximum quantum yield of PSII), but vg has significantly higher F v/F m than ng. Variegation in Sonerila and Kaempferia is also caused by combined mechanisms, including the crystal type in Kaempferia. This finding of combined mechanisms in three different species suggests that combined mechanisms may occur more commonly in nature than current understanding. The combined mechanisms in Blastus variegated leaves represent intricate structural modifications that may compensate for and minimize photosynthetic loss, and reflect changing plant needs. PMID- 27995376 TI - Double-stranded RNA-binding protein DRB3 negatively regulates anthocyanin biosynthesis by modulating PAP1 expression in Arabidopsis thaliana. AB - The model plant Arabidopsis thaliana has five double-stranded RNA-binding proteins (DRB1-DRB5), two of which, DRB1 and DRB4, are well characterized. In contrast, the functions of DRB2, DRB3 and DRB5 have yet to be elucidated. In this study, we tried to uncover their functions using drb mutants and DRB-over expressed lines. In over-expressed lines of all five DRB genes, the over expression of DRB2 or DRB3 (DRB2ox or DRB3ox) conferred a downward-curled leaf phenotype, but the expression profiles of ten small RNAs were similar to that of the wild-type (WT) plant. Phenotypes were examined in response to abiotic stresses. Both DRB2ox and DRB3ox plants exhibited salt-tolerance. When these plants were exposed to cold stress, drb2 and drb3 over-accumulated anthocyanin but DRB2ox and DRB3ox did not. Therefore, the over-expression of DRB2 or DRB3 had pleiotropic effects on host plants. Microarray and deep-sequencing analyses indicated that several genes encoding key enzymes for anthocyanin biosynthesis, including chalcone synthase (CHS), dihydroflavonol reductase (DFR) and anthocyanidin synthase (ANS), were down-regulated in DRB3ox plants. When DRB3ox was crossed with the pap1-D line, which is an activation-tagged transgenic line that over-expresses the key transcription factor PAP1 (Production of anthocyanin pigmentation1) for anthocyanin biosynthesis, over-expression of DRB3 suppressed the expression of PAP1, CHS, DFR and ANS genes. DRB3 negatively regulates anthocyanin biosynthesis by modulating the level of PAP1 transcript. Since two different small RNAs regulate PAP1 gene expression, a possible function of DRB3 for small RNA biogenesis is discussed. PMID- 27995377 TI - Novel insights into the molecular mechanism of sperm-egg fusion via IZUMO1. AB - When a spermatozoon fertilizes an oocyte in mammals, there must be an extremely precise regulation system for successful gamete fusion to occur, which is the final step of fertilization. Using gene-modified animals, IZUMO1 on the sperm side and its receptor, JUNO, on the ovum side, have been unveiled as indispensable factors for triggering membrane fusion. We recently analyzed the detailed molecular machinery of the IZUMO1-JUNO recognition system and clarified the tertiary architecture of the IZUMO1-JUNO complex based on the crystal structure. Over the past 2 years, important discoveries have successively emerged, presenting a new perspective on fertilization. In this mini-review, I will initially explain the historical background of the molecular mechanism study of gamete fusion, and go on to describe our latest study data. PMID- 27995378 TI - Curcumin, a Compound from Natural Sources, a True Scientific Challenge - A Review. AB - Curcumin, a plant-derived polyphenolic compound, naturally present in turmeric (Curcuma longa), has been the subject of intensive investigations on account of its various activities. The implementation of safe, beneficial and highly functional compounds from natural sources in human nutrition/prevention/therapy requires some modifications in order to achieve their multi-functionality, improve their bioavailability and delivery strategies, with the main aim to enhance their effectiveness. The low aqueous solubility of curcumin, its rapid metabolism and elimination from the body, and consequently, poor bioavailability, constitute major obstacles to its application. The main objectives of this review are related to reported strategies to overcome these limitations and, thereby, improve the solubility, stability and bioavailability of curcumin. The effectiveness of curcumin could be greatly improved by using nanoparticle-based carriers. The significance of the quality of a substance delivery system is reflected in the fact that carrying curcumin as a food additive/nutrition also means carrying the active biological product/drug. This review summarizes the state of the art, and highlights some examples and the most significant advances in the field of curcumin research. PMID- 27995379 TI - Yeast for Mathematicians: A Ferment of Discovery and Model Competition to Describe Data. AB - In addition to the memorization, algorithmic skills and vocabulary which are the default focus in many mathematics classrooms, professional mathematicians are expected to creatively apply known techniques, construct new mathematical approaches and communicate with and about mathematics. We propose that students can learn these professional, higher-level skills through Laboratory Experiences in Mathematical Biology which put students in the role of mathematics researcher creating mathematics to describe and understand biological data. Here we introduce a laboratory experience centered on yeast (Saccharomyces cerevisiae) growing in a small capped flask with a jar to collect carbon dioxide created during yeast growth and respiration. The lab requires no specialized equipment and can easily be run in the context of a college math class. Students collect data and develop mathematical models to explain the data. To help place instructors in the role of mentor/collaborator (as opposed to jury/judge), we facilitate the lab using model competition judged via Bayesian Information Criterion. This article includes details about the class activity conducted, student examples and pedagogical strategies for success. PMID- 27995380 TI - A Discrete Velocity Kinetic Model with Food Metric: Chemotaxis Traveling Waves. AB - We introduce a mesoscopic scale chemotaxis model for traveling wave phenomena which is induced by food metric. The organisms of this simplified kinetic model have two discrete velocity modes, [Formula: see text] and a constant tumbling rate. The main feature of the model is that the speed of organisms is constant [Formula: see text] with respect to the food metric, not the Euclidean metric. The uniqueness and the existence of the traveling wave solution of the model are obtained. Unlike the classical logarithmic model case there exist traveling waves under super-linear consumption rates and infinite population pulse-type traveling waves are obtained. Numerical simulations are also provided. PMID- 27995381 TI - The Behavioral Avoidance Task with Anxious Youth: A Review of Procedures, Properties, and Criticisms. AB - The measurement of avoidance behavior in youth with anxiety and related disorders is essential. Historically, the behavioral avoidance task (BAT) has been used as a measure of avoidance that can be tailored to a youth's particular fear. Although in use for over 90 years, there has yet to be a systematic review of its use, properties, etc. Here we examine the use of the BAT with youth as a measure of avoidance over the past 30 years. Studies have used the BAT as a measure of treatment outcome, to explore theories related to avoidance, and provide evidence for the psychometric properties of phobia questionnaires. Specifically, we compare the results of these studies, the purposes of the BAT, and the types of data collected. Results indicated that the BAT might be particularly sensitive to treatment effects. Furthermore, youth with specific phobias can be expected to complete an average of 30% of the BAT at pre-treatment and 60% at post-treatment. These affects have generally been maintained at 6-month follow-ups. Measures of subjective units of distress (SUDS) proved more consistent than steps completed, but more resistant to treatment effects; researchers can expect a SUDS rating of approximately 55% at pre-treatment and 40% at post-treatment. We review the properties and procedures that are used within these studies and provide a critical review. Overall, the BAT is in need of a standardized procedure to allow for psychometric studies to provide evidence of the task's reliability and validity. PMID- 27995383 TI - Ultrasound resistive index, power Doppler, and clinical parameters in established rheumatoid arthritis. AB - Ultrasonography (US) is a useful tool for the evaluation of sinovial vascularization and proliferation in rheumatoid arthritis (RA). Accordingly, resistive index (RI) on spectral Doppler (sD) US provides a quantitative analysis of vascular inflammation, but its utility in the evaluation of RA activity has not been established. Our objective was to determine the association of RI with other US parameters of synovitis and with clinical disease activity in established RA. Patients with positive power Doppler (pD) were included in a prospective cross-sectional study. Disease activity and disability were evaluated using the Disease Activity Score in 28-joints (DAS28) and Health Assessment Questionnaire (HAQ), respectively. Gray scale (GS) synovitis, pD, and sD analyses were performed by one of two examiners in wrists and the second and third metacarpophalangeal and proximal interphalangeal joints. The 10-joint GS and 10 joint pD scores and mean RI were then calculated. Weighted kappa (WK) values were employed to assess interobserver reability, and correlations were tested using the Spearman coefficient. Ninety-five RA patients (median duration of disease of 7 years and mean DAS28 of 4.32 +/- 1.66) were included. WK values in real-time US were 0.77 for synovitis, 0.87 for pD, and 0.68 for RI. There were no significant correlations of RI with 10-joint GS, 10-joint pD, DAS28, joint counts, or HAQ (P > 0.10 for all tests). Patients in remission had a mean RI similar to those with high disease activity (0.62 +/- 0.10, n = 15 versus 0.63 +/- 0.13, n = 34, respectively). The addition of the RI score did not seem to improve US performance in patients with established RA. PMID- 27995385 TI - Effect of shorter pulse duration in cochlear neural activation with an 810-nm near-infrared laser. AB - Optical neural stimulation in the cochlea has been presented as an alternative technique to the electrical stimulation due to its potential in spatially selectivity enhancement. So far, few studies have selected the near-infrared (NIR) laser in cochlear neural stimulation and limited optical parameter space has been examined. This paper focused on investigating the optical parameter effect on NIR stimulation of auditory neurons, especially under shorter pulse durations. The spiral ganglion neurons in the cochlea of deafened guinea pigs were stimulated with a pulsed 810-nm NIR laser in vivo. The laser radiation was delivered by an optical fiber and irradiated towards the modiolus. Optically evoked auditory brainstem responses (OABRs) with various optical parameters were recorded and investigated. The OABRs could be elicited with the cochlear deafened animals by using the 810-nm laser in a wide pulse duration ranged from 20 to 1000 MUs. Results showed that the OABR intensity increased along with the increasing laser radiant exposure of limited range at each specific pulse duration. In addition, for the pulse durations from 20 to 300 MUs, the OABR intensity increased monotonically along with the pulse duration broadening. While for pulse durations above 300 MUs, the OABR intensity basically kept stable with the increasing pulse duration. The 810-nm NIR laser could be an effective stimulus in evoking the cochlear neuron response. Our experimental data provided evidence to optimize the pulse duration range, and the results suggested that the pulse durations from 20 to 300 MUs could be the optimized range in cochlear neural activation with the 810-nm-wavelength laser. PMID- 27995382 TI - Latitude gradient influences the age of onset of rheumatoid arthritis: a worldwide survey. AB - The age of onset of rheumatoid arthritis (RA) is an important outcome predictor. Northern countries report an age of RA onset of around 50 years, but apparently, variability exists across different geographical regions. The objective of the present study is to assess whether the age of onset of RA varies across latitudes worldwide. In a proof-of-concept cross-sectional worldwide survey, rheumatologists from preselected cities interviewed 20 consecutive RA patients regarding the date of RA onset (RAO, when the patient first noted a swollen joint). Other studied variables included location of each city, rheumatologist settings, latitudes (10 degrees increments, south to north), longitudes (three regions), intracountry consistency, and countries' Inequality-adjusted Human Development Index (IHDI). Data from 2481 patients (82% females) were obtained from 126 rheumatologists in 77 cities of 41 countries. Worldwide mean age of RAO was 44 +/- 14 years (95% CI 44-45). In 28% of patients, RA began before age 36 years and before age 46 years in 50% of patients. RAO was 8 years earlier around the Tropic of Cancer when compared with northern latitudes (p < 0.001, 95% CI 3.5 13). Multivariate analysis showed that females, western cities, and latitudes around the Tropic of Cancer are associated with younger age of RAO (R 2 0.045, p < 0.001). A positive correlation was found between the age of RAO and IHDI (r = 0.7, p < 0.01, R 2 0.5). RA often begins at an early age and onset varies across latitudes worldwide. We postulate that countries' developmental status and their geographical and geomagnetic location influence the age of RAO. PMID- 27995386 TI - The Roles of Mitochondrial Cation Channels Under Physiological Conditions and in Cancer. AB - Bioenergetics has become central to our understanding of pathological mechanisms as well as the development of new therapeutic strategies and as a tool for gauging disease progression in neurodegeneration, diabetes, cancer, and cardiovascular disease. The view is emerging that inner mitochondrial membrane (IMM) cation channels have a profound effect on mitochondrial function and, consequently, on the metabolic state and survival of the whole cell. Since disruption of the sustained integrity of mitochondria is strongly linked to human disease, pharmacological intervention offers a new perspective concerning neurodegenerative and cardiovascular diseases as well as cancer. This review summarizes our current knowledge regarding IMM cation channels and their roles under physiological conditions as well as in cancer, with special emphasis on potassium channels and the mammalian mitochondrial calcium uniporter. PMID- 27995384 TI - Quantitative imaging by pixel-based contrast-enhanced ultrasound reveals a linear relationship between synovial vascular perfusion and the recruitment of pathogenic IL-17A-F+IL-23+ CD161+ CD4+ T helper cells in psoriatic arthritis joints. AB - To develop quantitative imaging biomarkers of synovial tissue perfusion by pixel based contrast-enhanced ultrasound (CEUS), we studied the relationship between CEUS synovial vascular perfusion and the frequencies of pathogenic T helper (Th) 17 cells in psoriatic arthritis (PsA) joints. Eight consecutive patients with PsA were enrolled in this study. Gray scale CEUS evaluation was performed on the same joint immediately after joint aspiration, by automatic assessment perfusion data, using a new quantification approach of pixel-based analysis and the gamma-variate model. The set of perfusional parameters considered by the time intensity curve includes the maximum value (peak) of the signal intensity curve, the blood volume index or area under the curve, (BVI, AUC) and the contrast mean transit time (MTT). The direct ex vivo analysis of the frequencies of SF IL17A-F+CD161+IL23+ CD4+ T cells subsets were quantified by fluorescence-activated cell sorter (FACS). In cross-sectional analyses, when tested for multiple comparison setting, a false discovery rate at 10%, a common pattern of correlations between CEUS Peak, AUC (BVI) and MTT parameters with the IL17A-F+IL23+ - IL17A-F+CD161+ - and IL17A-F+CD161+IL23+ CD4+ T cells subsets, as well as lack of correlation between both peak and AUC values and both CD4+T and CD4+IL23+ T cells, was observed. The pixel-based CEUS assessment is a truly measure synovial inflammation, as a useful tool to develop quantitative imaging biomarker for monitoring target therapeutics in PsA. PMID- 27995387 TI - Noncoding RNAs in Heart Failure. AB - Heart failure is a major contributor to the healthcare burden and mortality worldwide. Current treatment strategies are able to slow down the transition of healthy heart into the failing one; nevertheless better understanding of the complex genetic regulation of maladaptive remodeling in the failing heart is essential for new drug discovery. Noncoding RNAs are key epigenetic regulators of cardiac gene expression and thus significantly influence cardiac homeostasis and functions.In this chapter we will discuss characteristics of noncoding RNAs, especially miRNAs, long noncoding RNAs, and circular RNAs, and review recent evidences proving their profound involvement during different stages of heart failure progression. Several open questions still prevent the extensive use of noncoding RNA-modulating therapies in clinics; yet they are becoming an attractive target to define novel regulatory mechanisms in the heart. In-depth study of their interaction with gene networks will refine our current view of heart failure and revolutionize the drug development in coming years. PMID- 27995388 TI - Structural Insights into Sigma1 Function. AB - Sigma1 (also known as this sigma-1 receptor) is an unusual and enigmatic transmembrane protein implicated in a diverse array of biological processes ranging from neurodegenerative disease to cancer. Despite decades of research, the molecular architecture of Sigma1 is only beginning to become clear. Recent work has established that Sigma1 is an oligomer, and crystallographic studies have now offered the first high-resolution views of its molecular structure. For the first time, these results provide a detailed framework to understand mutagenesis data and the molecular pharmacology of Sigma1 ligands. Structural data also raise new questions surrounding the mechanisms of ligand activity and the molecular basis for interactions between Sigma1 and other proteins. As Sigma1 research enters the structural era, the field is poised for new discoveries and reevaluation of old data and old models. PMID- 27995389 TI - Equipping Physiologists with an Informatics Tool Chest: Toward an Integerated Mitochondrial Phenome. AB - Understanding the complex involvement of mitochondrial biology in disease development often requires the acquisition, analysis, and integration of large scale molecular and phenotypic data. An increasing number of bioinformatics tools are currently employed to aid in mitochondrial investigations, most notably in predicting or corroborating the spatial and temporal dynamics of mitochondrial molecules, in retrieving structural data of mitochondrial components, and in aggregating as well as transforming mitochondrial centric biomedical knowledge. With the increasing prevalence of complex Big Data from omics experiments and clinical cohorts, informatics tools have become indispensable in our quest to understand mitochondrial physiology and pathology. Here we present an overview of the various informatics resources that are helping researchers explore this vital organelle and gain insights into its form, function, and dynamics. PMID- 27995390 TI - The Three-Decade Long Journey in Heart Failure Drug Development. AB - Heart failure is a global disease with increasing prevalence due to an aging worldwide population with increasing co-morbidities. Despite several therapeutic options available to treat HFrEF, morbidity and mortality remain high. Importantly, no approved therapies are available to treat HFpEF. This paper will briefly summarize the burden of disease, HF classification and definitions and the landmark clinical trials in both HFrEF and HFpEF. Given the increasing incidence and prevalence of HF and the high morbidity and mortality associated with this disease, continued development efforts are essential to address the unmet needs of these patients. PMID- 27995391 TI - Irritable Bowel Syndrome: Pathophysiology and Current Therapeutic Approaches. AB - Irritable bowel syndrome (IBS) is a prevalent condition affecting 10-20% of adults in most countries; IBS results in significant morbidity and health care costs. IBS is a disorder of the brain-gut axis, and recent insights into the pathophysiological mechanisms include altered bile acid metabolism, neurohormonal regulation, immune dysfunction, alterations in the epithelial barrier, and secretory properties of the gut. There remains a significant unmet need for effective treatments, particularly for the pain component of IBS, although the introduction of drugs directed at secretion, motility, and a nonabsorbable antibiotic provides an option for the bowel dysfunction in IBS. PMID- 27995392 TI - Abnormal Barrier Function in Gastrointestinal Disorders. AB - There is increasing concern in identifying the mechanisms underlying the intimate control of the intestinal barrier, as deregulation of its function is strongly associated with digestive (organic and functional) and a number of non-digestive (schizophrenia, diabetes, sepsis, among others) disorders. The intestinal barrier is a complex and effective defensive functional system that operates to limit luminal antigen access to the internal milieu while maintaining nutrient and electrolyte absorption. Intestinal permeability to substances is mainly determined by the physicochemical properties of the barrier, with the epithelium, mucosal immunity, and neural activity playing a major role. In functional gastrointestinal disorders (FGIDs), the absence of structural or biochemical abnormalities that explain chronic symptoms is probably close to its end, as recent research is providing evidence of structural gut alterations, at least in certain subsets, mainly in functional dyspepsia (FD) and irritable bowel syndrome (IBS). These alterations are associated with increased permeability, which seems to reflect mucosal inflammation and neural activation. The participation of each anatomical and functional component of barrier function in homeostasis and intestinal dysfunction is described, with a special focus on FGIDs. PMID- 27995393 TI - Genetic determinants of serum vitamin B12 and their relation to body mass index. AB - Lower serum vitamin B12 levels have been related to adverse metabolic health profiles, including adiposity. We used a Mendelian randomization design to test whether this relation might be causal. We included two Danish population-based studies (ntotal = 9311). Linear regression was used to test for associations between (1) serum vitamin B12 levels and body mass index (BMI), (2) genetic variants and serum vitamin B12 levels, and (3) genetic variants and BMI. The effect of a genetically determined decrease in serum vitamin B12 on BMI was estimated by instrumental variable regression. Decreased serum vitamin B12 associated with increased BMI (P < 1 * 10-4). A genetic risk score based on eight vitamin B12 associated variants associated strongly with serum vitamin B12 (P < 2 * 10-43), but not with BMI (P = 0.91). Instrumental variable regression showed that a 20% decrease in serum vitamin B12 was associated with a 0.09 kg/m2 (95% CI 0.05; 0.13) increase in BMI (P = 3 * 10-5), whereas a genetically induced 20% decrease in serum vitamin B12 had no effect on BMI [-0.03 (95% CI -0.22; 0.16) kg/m2] (P = 0.74). Nevertheless, the strongest serum vitamin B12 variant, FUT2 rs602662, which was excluded from the B12 genetic risk score due to potential pleiotropic effects, showed a per allele effect of 0.15 kg/m2 (95% CI 0.01; 0.32) on BMI (P = 0.03). This association was accentuated including two German cohorts (ntotal = 5050), with a combined effect of 0.19 kg/m2 (95% CI 0.08; 0.30) (P = 4 * 10-4). We found no support for a causal role of decreased serum vitamin B12 levels in obesity. However, our study suggests that FUT2, through its regulation of the cross-talk between gut microbes and the human host, might explain a part of the observational association between serum vitamin B12 and BMI. PMID- 27995395 TI - Mitral Valve Chordae Tendineae: Topological and Geometrical Characterization. AB - Mitral valve (MV) closure depends upon the proper function of each component of the valve apparatus, which includes the annulus, leaflets, and chordae tendineae (CT). Geometry plays a major role in MV mechanics and thus highly impacts the accuracy of computational models simulating MV function and repair. While the physiological geometry of the leaflets and annulus have been previously investigated, little effort has been made to quantitatively and objectively describe CT geometry. The CT constitute a fibrous tendon-like structure projecting from the papillary muscles (PMs) to the leaflets, thereby evenly distributing the loads placed on the MV during closure. Because CT play a major role in determining the shape and stress state of the MV as a whole, their geometry must be well characterized. In the present work, a novel and comprehensive investigation of MV CT geometry was performed to more fully quantify CT anatomy. In vitro micro-tomography 3D images of ovine MVs were acquired, segmented, then analyzed using a curve-skeleton transform. The resulting data was used to construct B-spline geometric representations of the CT structures, enriched with a continuous field of cross-sectional area (CSA) data. Next, Reeb graph models were developed to analyze overall topological patterns, along with dimensional attributes such as segment lengths, 3D orientations, and CSA. Reeb graph results revealed that the topology of ovine MV CT followed a full binary tree structure. Moreover, individual chords are mostly planar geometries that together form a 3D load-bearing support for the MV leaflets. We further demonstrated that, unlike flow-based branching patterns, while individual CT branches became thinner as they propagated further away from the PM heads towards the leaflets, the total CSA almost doubled. Overall, our findings indicate a certain level of regularity in structure, and suggest that population-based MV CT geometric models can be generated to improve current MV repair procedures. PMID- 27995394 TI - The MRC National Survey of Health and Development reaches age 70: maintaining participation at older ages in a birth cohort study. AB - A life course approach to ageing relies on maintaining participation rates in national birth cohorts and other long-term longitudinal studies. This reduces the risk of selective attrition biasing associations between lifetime risk factors and health outcomes in later life and ensures the studies remain as representative as possible of the original population. We report the participation patterns for a postal questionnaire and home visit at 68-69 years of study members in the MRC National Survey of Health and Development, the oldest and longest-running British birth cohort study. We investigated how participation varied by lifetime and recent contact, health status, previous clinical feedback and study engagement, taking account of prior socioeconomic and cognitive characteristics. Overall participation and home visit participation remained high (94 and 80%, respectively) and there were no gender differences. Participation was higher in those with higher levels of prior contact and lower in those with the poorest health status. Having previously received clinical feedback on actionable blood results was associated with reduced home visit participation but other forms of clinical feedback were not associated with subsequent participation. Activities that fostered study engagement were associated with increased home visit participation. These findings inform strategies to maintain participation in life course studies. PMID- 27995396 TI - Vibration Testing Procedures for Bone Stiffness Assessment in Fractures Treated with External Fixation. AB - A bone healing assessment is crucial for the successful treatment of fractures, particularly in terms of the timing of support devices. However, in clinical practice, this assessment is only made qualitatively through bone manipulation and X-rays, and hence cannot be repeated as often as might be required. The present study reconsiders the quantitative method of frequency response analysis for healing assessments, and specifically for fractures treated with an external fixator. The novelty consists in the fact that bone excitation and response are achieved through fixator pins, thus overcoming the problem of transmission through soft-tissues and their damping effect. The main objective was to develop and validate a test procedure in order to characterize the treated bone. More than 80 tests were performed on a tibia phantom alone, a phantom with pins, and a phantom with a complete fixator. Different excitation techniques and input-output combinations were compared. The results demonstrated the effectiveness of a procedure based on impact tests using a micro-hammer. Pins and fixator were demonstrated to influence the frequency response of the phantom by increasing the number of resonant frequencies. This procedure will be applied in future studies to monitor healing both in in vitro and in vivo conditions. PMID- 27995397 TI - Uterine Tissue Engineering and the Future of Uterus Transplantation. AB - The recent successful births following live donor uterus transplantation are proof-of-concept that absolute uterine factor infertility is a treatable condition which affects several hundred thousand infertile women world-wide due to a dysfunctional uterus. This strategy also provides an alternative to gestational surrogate motherhood which is not practiced in most countries due to ethical, religious or legal reasons. The live donor surgery involved in uterus transplantation takes more than 10 h and is then followed by years of immunosuppressive medication to prevent uterine rejection. Immunosuppression is associated with significant adverse side effects, including nephrotoxicity, increased risk of serious infections, and diabetes. Thus, the development of alternative approaches to treat absolute uterine factor infertility would be desirable. This review discusses tissue engineering principles in general, but also details strategies on how to create a bioengineered uterus that could be used for transplantation, without risky donor surgery and any need for immunosuppression. We discuss scaffolds derived from decellularized organs/tissues which may be recellularized using various types of autologous somatic/stem cells, in particular for uterine tissue engineering. It further highlights the hurdles that lay ahead in developing an alternative to an allogeneic source for uterus transplantation. PMID- 27995399 TI - Low Yield and High Cost of Gastric and Duodenal Biopsies for Investigation of Symptoms of Abdominal Pain During Routine Esophagogastroduodenoscopy. AB - BACKGROUND: Esophagogastroduodenoscopy (EGD) referrals for symptoms of abdominal pain are common. Current guidelines for dyspepsia recommend biopsies of gastric mucosa for Helicobacter pylori in all patients referred for EGD. Our study aimed to determine the clinical yield and cost-effectiveness of gastric and duodenal biopsy in EGDs performed for abdominal pain. METHODS: Three hundred and ninety one outpatient EGDs performed at a single academic tertiary care center were studied. For each procedure, endoscopic as well as pathologic findings from the stomach and duodenum were then recorded. Charge of biopsy was calculated using the increased charges for professional fees, forceps, and pathology fees when a biopsy was performed. RESULTS: Gastric biopsies were obtained on 304 EGDs performed with 13 (4.2%) patients diagnosed with H. pylori. In patients with abnormal gastric mucosa on EGD, 11 of 167 (6.5%) were positive for H. pylori compared to 2 of 137 (1.4%) with normal appearing mucosa (p = 0.02). Charge per diagnosis of H. pylori for normal mucosa was calculated to be $43,073. Duodenal biopsies were performed in 263 cases. Celiac disease was diagnosed in 4 of 263 cases (1.5%). Of patients with abnormal duodenal mucosa on EGD, 1 of 36 (2.7%) were positive for celiac disease compared to 3 of 227 (1.3%) with normal mucosa (p = 0.57). Charge per diagnosis of celiac disease for normal mucosa was calculated to be $47,580. CONCLUSION: Routine biopsy during EGD for symptoms of abdominal pain has low yield with high costs. Practice of routine biopsies of normal appearing tissue and the present guidelines should be reconsidered in the investigation of abdominal pain with EGD. PMID- 27995398 TI - A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. AB - SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G; c.338G>C; p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome, possibly via reduced activity of the manganese-dependent enzymes beta-galactosyltransferase and mitochondrial manganese superoxide dismutase. PMID- 27995400 TI - Adalimumab Maintenance Treatment in Ulcerative Colitis: Outcomes by Prior Anti TNF Use and Efficacy of Dose Escalation. AB - BACKGROUND: The impact of prior anti-TNF use on "real-life" outcomes of adalimumab therapy in ulcerative colitis (UC) is not well known. AIM: To compare the influence of prior anti-TNF use on the outcomes of adalimumab maintenance treatment in UC patients. We also assessed the effectiveness of adalimumab dose escalation. METHODS: This retrospective multicenter cohort study included consecutive UC who advanced to an adalimumab maintenance regimen. Patients in whom adalimumab was discontinued prior to week eight of treatment were excluded. The co-primary efficacy endpoints were the cumulative probabilities of adalimumab failure-free survival and colectomy-free survival. We also assessed the need for and the effectiveness of adalimumab dose escalation. RESULTS: Of 184 UC on maintenance treatment with adalimumab, 116 (63%) had previous anti-TNF use. After a median follow-up of 23 months (interquartile range 13-49), 112 patients (60%) maintained corticosteroid-free clinical response. Sixty-nine patients (37%) had adalimumab failure, and 22 (12%) needed colectomy. Anti-TNF-naive patients had significantly lower adjusted rates of adalimumab failure (hazard ratio [HR] 0.65; p < 0.001), adalimumab dose escalation (HR 0.35; p = 0.002), and need for colectomy (HR 0.26; p < 0.004). Seventy-six patients (41%) needed dose escalation after secondary loss of response, and 47% of these regained response after escalation. Short-term response after escalation was identified as a significant predictor of colectomy avoidance (HR 0.53; p = 0.007). CONCLUSIONS: In this "real life" cohort of UC patients on maintenance treatment with adalimumab, anti-TNF naive patients had significantly better long-term outcomes. Adalimumab dose escalation enabled recovery of response in nearly half of patients. PMID- 27995401 TI - Shiftwork Is Not Associated with Increased Risk of NAFLD: Findings from the National Health and Nutrition Examination Survey. AB - AIMS: There is increased focus on the metabolic impact of shiftwork, especially given the significant number of employees who work nighttime or rotating shifts. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. We conducted a cross-sectional study to examine the association between shiftwork and the risk of NAFLD. METHODS: We used aggregated data from the 2005-2006, 2007-2008, and 2009-2010 cycles of the National Health and Nutrition Examination Survey (NHANES). We defined NAFLD by elevated serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (males: AST > 40 or ALT > 37; females: AST > 31 or ALT > 31) in the absence of excessive alcohol use and viral hepatitis. We defined shiftworkers as participants who self reported currently working regular night shifts or rotating shifts. We calculated adjusted odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression. RESULTS: Overall, 8159 participants aged 20-79 years reported working at a job or business using the NHANES Occupation Questionnaire and were included in the analysis. Of these, 11.1% were classified as shiftworkers. Compared to non-shiftworkers, shiftworkers were younger, were less likely to be non-Hispanic White, and have health insurance or health care. The overall prevalence of NAFLD was 15.7%. NAFLD occurred more frequently in shiftworkers (17.0%) than non-shiftworkers (15.5%). However, in the overall multivariable analysis, shiftwork was not associated with the risk of NAFLD (OR 1.11, 95% CI 0.87-1.43). CONCLUSIONS: The findings from this NHANES-based cross sectional study do not support an association between shiftwork and increased risk of NAFLD. PMID- 27995403 TI - A Remembrance of Procedures Past: Late Hepatic Artery Thrombosis. PMID- 27995402 TI - Does the Ileal Brake Contribute to Delayed Gastric Emptying After Pancreatoduodenectomy? AB - Delayed gastric emptying (DGE) represents a significant cause for morbidity following pancreatoduodenectomy (PD). At a time when no specific and universally effective therapy exists to treat these patients, elucidating other potential (preventable or treatable) mechanisms for DGE is important. The aim of the manuscript was to test the hypothesis that ileal brake contributes to DGE in PD patients receiving jejunal tube feeding by systematically reviewing experimental and clinical literature. A series of clinically relevant questions were framed related to the potential role of the ileal brake in development of DGE post-PD and formed the basis of targeted literature searches. A comprehensive search of major reference databases from January 1980 to June 2015 was carried out which included human and animal studies. The ileal brake is a feedback loop neurally mediated by the vagus and sympatho-adrenergic pathways and hormonally by gut peptides including glucagon-like peptide-1, peptide YY (PYY), and neurotensin. The most potent stimulus for this inhibitory reflex is intra-ileal fat. There is evidence to indicate the role of an inhibitory reflex (on gastric emptying) mediated by PYY and CCK which, in turn, are stimulated by nutrient delivery into the distal small intestine providing indirect support to the role of ileal brake in post-PD DGE. The ileal brake is a likely factor contributing to DGE post-PD. While there has been no study to directly test this hypothesis, there is compelling indirect evidence to support it. Designing a trial that would answer such a question appears to be the most appropriate way forward. PMID- 27995404 TI - Circulating Zonulin Correlates with Density of Enteroviruses and Tolerogenic Dendritic Cells in the Small Bowel Mucosa of Celiac Disease Patients. AB - BACKGROUND: Impaired intestinal integrity, including increased permeability of the small bowel mucosa, has been shown in patients with celiac disease (CD) as well as with type 1 diabetes (T1D). Zonulin (ZO, pre-haptoglobin), a tight junction regulator, plays a particular role in the regulation of intestinal barrier function and in the pathogenesis of the above-mentioned diseases. AIM: To investigate whether enteroviruses (EVs) and immunoregulatory cells are associated with intestinal permeability in patients with CD alone and with coexistent T1D. MATERIALS AND METHODS: Altogether 80 patients (mean age 10.68 +/- 6.69 years) who had undergone small bowel biopsy were studied. Forty patients with functional dyspepsia and normal small bowel mucosa formed the control group. The circulating ZO level in sera was evaluated using ELISA. The densities of EV, FOXP3+ regulatory T cells (Tregs), indoleamine 2,3-dioxygenase (IDO+) dendritic cells (DCs) and glutamic acid dexarboxylase (GAD)65+ cells in small bowel mucosa were investigated by immunohistochemistry. The expression analysis of FOXP3, tight junction protein 1 (TJP1), gap junction (GJA1), IDO and CD103 genes was evaluated by real-time PCR. RESULTS: The ZO level was higher in CD patients compared to subjects with a normal small bowel mucosa, particularly in those with Marsh IIIc atrophy (p = 0.01), and correlated with the density of EV (r = 0.63; p = 0.0003) and IDO+ DCs (r = 0.58; p = 0.01) in the small bowel mucosa. The density of GAD65+ epithelial cells was correlated with the density of EV (r = 0.59; p = 0.03) and IDO+ DCs (r = 0.78; p = 0.004) in CD patients. The relative expression of FOXP3 mRNA in the small bowel mucosa tissue was significantly higher in patients with CD, compared to subjects with a normal mucosa, and correlated with the density of EV (r = 0.62; p = 0.017) as well as with the relative expression of IDO mRNA (r = 0.54; p = 0.019). CONCLUSIONS: The CD is associated with elevation of the circulating ZO level, the value of which correlates with the density of EV in CD patients with severe atrophic changes in the small bowel mucosa, particularly in cases of concomitant T1D. The CD is also characterized by the close relationship of the density of GAD65+ epithelial cells with the EV, ZO level and IDO+ DCs. PMID- 27995405 TI - Comparison of Colonoscopy Quality Measures Across Various Practice Settings and the Impact of Performance Scorecards. AB - BACKGROUND: Quality performance measures for screening colonoscopy vary among endoscopists. The impact of practice setting is unknown. AIMS: We aimed to (1) compare screening colonoscopy performance measures among three different US practice settings; (2) evaluate factors associated with adenoma detection; and (3) assess a scorecard intervention on performance metrics. METHODS: This multi center prospective study compared patient, endoscopist, and colonoscopy characteristics performed at a tertiary care hospital (TCH), community-based hospital (CBH), and private practice group (PPG). Withdrawal times (WT), cecal intubation, and adenoma detection rates (ADR) were compared by site at baseline and 12 weeks following scorecard distribution. Generalized linear mixed models identified factors associated with adenoma detection. RESULTS: Twenty-eight endoscopists performed colonoscopies on 1987 asymptomatic, average-risk individuals >=50 years. Endoscopist and patient characteristics were similar across sites. The PPG screened more men (TCH: 42.8%, CBH: 45.0%, PPG: 54.2%; p < 0.0001). Preparation quality varied with good/excellent results in 70.6, 88.3, and 92% of TCH, CBH, and PPG cases, respectively (p < 0.0001). Male ADRs, cecal intubation, and WT exceeded recommended benchmarks despite variable results at each site; female ADRs were <15% at the PPG which screened the fewest females. Performance remained unchanged following scorecard distribution. Adenoma detection was associated with increasing patient age, male gender, WT, adequate preparation, but not practice setting. CONCLUSIONS: Each practice performed high quality screening colonoscopy. Scorecards did not improve performance metrics. Preparation quality varies among practice settings and can be modified to improve adenoma detection. PMID- 27995406 TI - Effects of Ex Vivo Infection with ETEC on Jejunal Barrier Properties and Cytokine Expression in Probiotic-Supplemented Pigs. AB - BACKGROUND AND AIM: Enterotoxigenic Escherichia coli (ETEC) strains are involved in piglet post-weaning diarrhea. Prophylactic measures including probiotics have been examined in infection experiments with live piglets. In the present study, we have tested whether the early effects of ETEC infection can also be evoked and studied in a model in which ETEC is added to whole mucosal tissues ex vivo, and whether this response can be modulated by prior supplementation of the piglets with probiotics. METHODS: Jejunal barrier and transport properties of Enterococcus faecium-supplemented or control piglets were assessed in Ussing chambers. Part of the epithelia was challenged with an ETEC strain at the mucosal side. Fluxes of fluorescein as a marker of paracellular permeability, and the expression of selected tight junction (TJ) proteins and of proinflammatory cytokines were measured. RESULTS: The addition of ETEC ex vivo induced an increase in transepithelial resistance peaking in the first 2 h with a concomitant reduction in fluorescein fluxes, indicating tightening effects on barrier function. The response of short-circuit current after stimulation with PGE2 or glucose was reduced in epithelia treated with ETEC. ETEC induced a decrease in the TJ protein claudin-4 in the control diet group after 280 min and an increase in the mRNA expression of the proinflammatory cytokines interleukin-8 and TNF-alpha in both groups after 180 min. CONCLUSIONS: The addition of ETEC ex vivo affected barrier function and transport properties of the jejunal tissues and enhanced cytokine expression. The differences in claudin-4 expression in the jejunum might indicate a beneficial effect of E. faecium prefeeding. PMID- 27995407 TI - The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis. AB - BACKGROUND: Ulcerative colitis (UC) is strongly associated with inflammation and intestinal barrier disorder. The nonselective cannabinoid receptor agonist HU210 has been shown to ameliorate inflamed colon in colitis, but its effects on intestinal barrier function and extraintestinal inflammation are unclear. AIMS: To investigate the effects and the underlying mechanism of HU210 action on the UC in relation to a role of TLR4 and MAP kinase signaling. METHODS: Wild-type (WT) and TLR4 knockout (Tlr4 -/-) mice were exposed to 4% dextran sulfate sodium (DSS) for 7 days. The effects of HU210 on inflammation and intestinal barrier were explored. RESULTS: Upon DSS challenge, mice suffered from bloody stool, colon shortening, intestinal mucosa edema, pro-inflammatory cytokine increase and intestinal barrier destruction with goblet cell depletion, increased intestinal microflora accompanied with elevated plasma lipopolysaccharide, reduced mRNA expression of the intestinal tight junction proteins, and abnormal ratio of CD4+/CD8+ T cells in the intestinal Peyer's patches. Pro-inflammatory cytokines in the plasma and the lung, as well as pulmonary myeloperoxidase activity, indicators of extraintestinal inflammation were increased. Protein expression of p38alpha and pp38 was up-regulated in the colon of WT mice. Tlr4 -/- mice showed milder colitis. HU210 reversed the intestinal barrier changes in both strains of mice, but alleviated inflammation only in WT mice. CONCLUSIONS: Our study indicates that in experimental colitis, HU210 displays a protective effect on the intestinal barrier function independently of the TLR4 signaling pathway; however, in the extraintestinal tissues, the anti-inflammatory action seems through affecting TLR4-mediated p38 mitogen-activated protein kinase pathway. PMID- 27995409 TI - The Hydra regeneration assay reveals ecological risks in running waters: a new proposal to detect environmental teratogenic threats. AB - The regenerative ability of Hydra vulgaris was tested as potential biomarker for the development of a new eco-toxicological index. The test is based on the regeneration rate and the aberration frequency of the columna (body and adhesive foot) after separation from head and tentacles by a bistoury. Particularly, 45 columnae were submerged in the rearing solution (that is Hydra medium) to have control, and 285 in potential contaminated waters to have treatments, collected from 19 sites along 10 rivers in central Italy. ANCOVA and chi-square tests were used to compare values from each site to a laboratory control. Subsequently the values on regeneration rate and aberration frequency were inserted in a double entry matrix, where the match of the two entries in the matrix provides the score of the proposed Teratogenic Risk Index (TRI). Each score corresponded to one of the 5 teratogenic risk classes, to which a risk level was associated: from 1 (no risk) to 5 (very high risk). On the whole, 32% of the studied sites were classified as no teratogenic risk while the remaining showed a variable risk level from low to very high. This study proposed for the first time an early warning system to detect the presence of teratogens in running waters, providing a rapid and cost-effective evaluation method. Therefore, TRI may contribute to initiate adequate measures to manage riverine habitats, and to monitor the running water teratogenic status. Specifically, this index may provide the opportunity to identify the disturbance sources and then to drive the decisions, together with competent authorities, on the catchment and landscape management and on the possible use of waters for urban, agricultural, and industrial activities, since they may show significant effects on the human health. PMID- 27995408 TI - High Expression of BCCIP beta Can Promote Proliferation of Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: BCCIP was originally identified as a BRCA2 interacting protein in humans and Ustilago maydis. It had low expression in some human cancer tissues. However, recent research indicated that many caretaker genes are also necessary for cell viability and their expression could contribute to tumor progression. AIM: To characterize whether BCCIP is a caretaker gene in esophageal squamous cell carcinoma (ESCC). METHODS: Western blotting and immunohistochemistry were used to measure the expression of BCCIP beta. In vitro studies were used to verify the effects of BCCIP beta in Eca109 cells. RESULTS: Expression of BCCIP beta was notably higher in tumor tissues of ESCC and Eca 109 cells. Meanwhile, the immunohistochemistry stain revealed that BCCIP beta was positively correlated with clinical pathologic variables such as tumor size and tumor grade, as well as Ki-67, and prompted poor prognosis. In vitro studies such as starvation and refeeding assay along with BCCIP beta-shRNA transfection assay demonstrated that BCCIP beta expression promoted proliferation of ESCC cells. In addition, BCCIP beta downregulation by silencing RNA significantly decreased the rate of colony formation, alleviated cellular apoptosis and increased the chemosensitivity of cisplatin. CONCLUSIONS: This research first put forward that BCCIP beta is an oncogene in human ESCC and contributes to the poor outcome of the deadly disease. PMID- 27995410 TI - Temporal trends in mercury concentrations in raptor flight feathers stored in an environmental specimen bank in Galicia (NW Spain) between 2000 and 2013. AB - Temporal trends in Hg concentrations were investigated in primary flight feathers from 319 specimens of three birds of prey: P7 in the northern goshawk (Accipiter gentilis), P6 in the common buzzard (Buteo buteo) and P5 in the tawny owl (Strix aluco). The samples were stored in a regional environmental specimen bank and belonged to specimens which died between 2000 and 2013 in Galicia (NW Spain). We would expect to see a decline in Hg concentrations across the study period, as data of atmospheric emissions show a gradual reduction of this pollutant in Europe in the last two decades. The study did not reveal any temporal pattern in Hg concentrations of feathers in any of the three species for the study period, may be due to the persistence of Hg in the environment, but showed a low level of contamination by this metal in the study area. In addition, the results show high intra-specific, as well as, inter-annual and inter-specific variability in data, mainly attributed to the level of exposure of the raptors to this pollutant and to the biomagnification process of Hg through food chains. These findings indicate that the high variability can be a limiting factor in the use of raptors for biomonitoring temporal patterns of Hg, but nevertheless, the technique provides qualitative information about the amount of Hg that reach the top of the terrestrial food chains. PMID- 27995411 TI - Depression During Pregnancy and Adverse Birth Outcomes Among Predominantly Puerto Rican Women. AB - Objectives To examine associations between depression and preterm birth and small for gestational age (SGA) among women of predominantly Puerto Rican descent, a population who experiences disparities in adverse birth outcomes and one of the highest infant mortality rates in the United States. Methods Proyecto Buena Salud (PBS) was a prospective cohort study conducted from 2006 to 2011 at a large tertiary care center in Western Massachusetts. Caribbean Islander (i.e., Puerto Rican and Dominican Republic) women were interviewed in early, mid and late pregnancy. Among 1262 participants, associations between depression, assessed using the Edinburgh Postnatal Depression Scale, and risk of preterm birth and small-for-gestational age (SGA) were evaluated. Results Women with at least probable minor depression [odds ratio (OR) = 1.77 (95% confidence interval (CI) = 1.02, 3.07)] or probable major depression [OR = 1.82 (95% CI = 1.01, 3.25)] in mid-pregnancy had an increased risk of SGA compared to non-depressed women in adjusted analyses. Borderline significant associations were observed between increasing levels of depressive symptom scores in early and mid-pregnancy [OR = 1.05 (95% CI = 1.00, 1.11) and OR = 1.04 (95% CI = 1.00, 1.09), respectively] and each additional trimester of exposure to probable major depression across mid- to late pregnancy [OR = 1.66 (95% CI = 1.00, 2.74)] and SGA. Late pregnancy depression was not associated with SGA; depression during pregnancy was not associated with preterm birth. Conclusions for Practice In this population of predominantly Puerto Rican women, mid-pregnancy depression increased risk for SGA. Findings can inform culturally appropriate, targeted interventions to identify and treat pregnant women with depression. PMID- 27995412 TI - HuCOP1 contributes to the regulation of DNA repair in keratinocytes. AB - We have previously demonstrated that the E3 ligase Human Constitutive Photomorphogenic Protein (huCOP1) is expressed in human keratinocytes and negatively regulates p53. The MutS homolog 2 (MSH2) protein plays a central role in DNA MMR mechanism and is implicated in the cellular response to anticancer agents, such as cisplatin. Our aim was to clarify whether huCOP1 plays a role in DNA MMR by affecting MSH2 protein level in human keratinocytes. To define the role of huCOP1 in DNA mismatch repair, we determined whether huCOP1 affects MSH2 abundance. MSH2 protein level was detected by immunocytochemical staining using a keratinocyte cell line in which the expression level of huCOP1 was stably decreased (siCOP1). To investigate whether huCOP1 silencing influences cisplatin induced cell death, control and siCOP1 keratinocyte cells were treated with increasing concentrations of cisplatin and cell viability was recorded after 48 and 96 h. Stable silencing of huCOP1 in human keratinocytes resulted in a reduced level of MSH2 protein. huCOP1 silencing also sensitized keratinocytes to the interstrand crosslinking inducer cisplatin. Our results indicate that decreased huCOP1 correlates with lower MSH2 levels. These protein level changes lead to increased sensitivity toward cisplatin treatment, implicating that huCOP1 plays a positive role in maintaining genome integrity in human keratinocytes. PMID- 27995413 TI - Is cytochrome P450 3A4 regulated by menstrual cycle hormones in control endometrium and endometriosis? AB - The estrogen-metabolizing activities of cytochrome P450 (CYP) enzymes have been implicated in endometriosis. However, their regulation in various sources of endometrial tissue under different hormonal conditions has not been clarified. Our objective was to study the hormone regulation of a specific CYP enzyme, namely CYP3A4, in control (n = 15) and endometriosis patients (n = 42). To this end, we evaluated mRNA expression (using real-time PCR) of CYP3A4 in tissue samples classified according to the phase of menstrual cycle at which they were obtained as confirmed by the related circulating hormone levels. Protein expression was also evaluated by Western Blot. In order to further investigate the hormonal regulation of CYP3A4, stromal cells from ovarian endometriotic lesions were cultured with the prevailing hormones of the distinct phases of the menstrual cycle. We observed that all control and endometriosis tissues express CYP3A4. Nevertheless, changes in CYP3A4 gene expression related to cycle phase were only seen in the control eutopic endometrium and not in samples from endometriosis patients, with an increase in the luteal phase. Stromal cells isolated from ovarian endometriotic lesions expressed CYP3A4 and their exposure to luteal phase-mimicking hormones (estradiol + progesterone) reduced CYP3A4 mRNA in parallel with a diminished expression of the corresponding receptors, estrogen receptor alpha and progesterone receptor. Our findings suggest that steroid hormones are able to regulate CYP3A4 mRNA expression, although the circulating levels of these hormones can only regulate control endometrium and not endometriosis tissues, probably because of dysregulated local steroid concentration in these latter samples. PMID- 27995414 TI - Na+/H+ exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous beta-globin knockout thalassemic mice. AB - Recent investigation has shown that the liver-derived iron-regulating hormone, hepcidin, can potentiate intestinal calcium absorption in hemizygous beta-globin knockout thalassemic (BKO) mice. Since the upregulation of Fe2+ and H+ cotransporter, divalent metal transporter (DMT)-1, has been shown to correlate with thalassemia-induced intestinal calcium absorption impairment, the inhibition of the apical Na+/H+ exchanger (NHE)-3 that is essential for cytoplasmic pH regulation and transepithelial sodium absorption was hypothesized to negatively affect hepcidin action. Herein, the positive effect of hepcidin on the duodenal calcium transport was evaluated using Ussing chamber technique. The results showed that BKO mice had lower absorptive surface area and duodenal calcium transport than wild-type mice. Besides, paracellular transport of zinc in BKO mice was compromised. Hepcidin administration completely restored calcium transport. Since this hepcidin action was totally abolished by inhibitors of the basolateral calcium transporters, Na+/Ca2+ exchanger (NCX1) and plasma membrane Ca2+-ATPase (PMCA1b), the enhanced calcium flux potentially occurred through the transcellular pathway rather than paracellular pathway. Interestingly, the selective NHE3 inhibitor, 100 nM tenapanor, markedly inhibited hepcidin-enhanced calcium transport. Accordingly, hepcidin is one of the promising therapeutic agents for calcium malabsorption in beta-thalassemia. It mainly stimulates the transcellular calcium transport across the duodenal epithelium in an NHE3 dependent manner. PMID- 27995415 TI - Regulation of PPARgamma and CIDEC expression by adenovirus 36 in adipocyte differentiation. AB - This study is to investigate the role of adenovirus 36 (Ad36) in regulating expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and cell death-inducing DFFA-like effector c (CIDEC) in Ad36-induced adipocyte differentiation. Human adipose-derived mesenchymal stem cells (hAMSCs) were isolated and cultured, and then infected with Ad36. Ad36-induced adipocytes were identified using quantitative real-time PCR and Oil red O staining. The expression levels of PPARgamma and CIDEC in Ad36-induced adipocytes were determined by quantitative real-time PCR and Western blot analysis. Glucose uptake and intracellular triglyceride content were also determined in these induced cells. Our results from the Oil red O staining showed that Ad36 induced the differentiation of hAMSCs into human adipocytes in vitro. Moreover, the medium glucose concentration was significantly decreased, while the intracellular triglyceride content was significantly increased, in the Ad36-induced adipocytes, compared with the control group. Furthermore, our results showed that, the mRNA and protein expression levels of PPARgamma and CIDEC were significantly upregulated in Ad36-induced adipocytes, in a time-dependent manner. On the other hand, compared with the control group, the CIDEC expression was downregulated when the Ad36-induced adipocytes were treated with the PPARgamma inhibitor, GW9662. Ad36 could upregulate the expression level of CIDEC through increasing PPARgamma expression during the adipocyte differentiation process. PMID- 27995416 TI - Synergistic action of cisplatin and echistatin in MDA-MB-231 breast cancer cells. AB - The aim of our study was to determine whether the use of cisplatin in the presence echistatin in MDA-MB-231 breast cancer cells leads to a reduction of toxic effects associated with the use of cisplatin. The expression of beta1 integrin and insulin-like growth factor 1 receptor (IGF-IR), signaling pathway protein expression: protein kinase B (AKT), mitogen-activated protein kinases (ERK1/ERK2), nuclear factor kappa B (NFkappaB), and caspase-3 and -9 activity was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The viability of MDA-MB-231 breast cancer cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Annexin V-FITC/propidium iodide staining assay was performed to detect the induction of apoptosis. Inhibition DNA biosynthesis was determined by [3H]thymidine incorporation into DNA. The expression of of beta1-integrin, IGF-IR, AKT, ERK1/ERK2, NFkappaB, caspase-3 and -9 was evaluated using Western blot. The results suggest that treatment of MDA-MB-231 breast cancer cells for 24 h cisplatin plus echistatin severely inhibits cell growth and activates apoptosis by upregulation of caspase-3 and -9 expressions. The effect was stronger than treatment cisplatin and echistatin alone. In this study, we have found that cisplatin plus echistatin treatment decreases collagen biosynthesis in MDA-MB-231 breast cancer cells stronger than the individual compounds. The inhibition was found to be dependent on the beta1-integrin and IGF receptor activation. A significant reduction of ERK1/ERK2, AKT expression in cancer cells after cisplatin plus echistatin treatment was also found. The cancer cells treated by echistatin, cisplatin, and in particular the combination of both compounds drastically increased expression of NFkappaB transcription factor. Our results suggest that combined therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin. This mechanism probably is due to downregulation of expression of beta1-integrin and IGF-IR receptors, and the signaling pathway proteins induced by these receptors. Our results suggest that therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin. PMID- 27995417 TI - High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling. AB - Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content. Using western blotting, we identified that piHDL profoundly upregulated the expression of scavenger receptor CD36 and suppressed the expression of ABCG1 and SRB1 in macrophages, thereby facilitating cholesterol influx capacity of macrophages. We then identified that CD36 did not act alone, indeed it was activated in macrophages along with ERK/MAPK, in response to piHDL, which in turn led to lipid accumulation as well as proinflammatory response via activation of NFkB and subsequent release of proinflammatory markers-TNF-alpha and MMP-9. These effects were confirmed using pharmacological inhibitors for either CD36 or ERK/MAPK. Furthermore, piHDL treatment moderately activated PPAR-gamma and Nrf2, the known regulators of CD36 in macrophages, suggesting that the two forms of HDL differentially regulate CD36 expression. Taken together, the results demonstrate that a novel CD36-ERK/MAPK dependent mechanism is involved in macrophage lipid accumulation by piHDL, there by revealing the importance of functional deficiency in HDL and its potential link to atherogenesis. PMID- 27995418 TI - The effects of sildenafil citrate on urinary podocin and nephrin mRNA expression in an L-NAME model of pre-eclampsia. AB - We investigated the effects of sildenafil citrate (SC) on podocyturia in N omega nitro-L-arginine methyl ester hydrochloride (L-NAME) model of pre-eclampsia (PE). One hundred and twenty Sprague-Dawley rats (SDR) were divided into five groups like pregnant control (PC), early-onset PE (EOPE), late-onset PE(LOPE), early and late-onset PE with SC-treated groups [EOPE (SC); LOPE (SC)]. PE was induced in SDR by oral administration of L-NAME in drinking water for 4-8 days for EOPE and 8-14 day for LOPE. The blood pressure, urine volume and total urine protein were increased in EOPE and LOPE groups when compared to PC, and all the above parameters decreased in EOPE (SC) and LOPE (SC) groups when compared to EOPE and LOPE groups, respectively. The EOPE and LOPE groups showed an increase in urinary nephrin mRNA and podocin mRNA levels compared to PC group. Increases in serum and renal soluble fms-like tyrosine kinase-1 (sFlt-1) expression levels and decreases in renal vascular endothelial growth factor (VEGF) expression and serum placenta growth factor (PlGF) levels were observed in EOPE and LOPE groups when compared to PC group. In addition, decreases in serum and renal sFlt-1 expression levels and increases in renal VEGF expression and serum PlGF levels were observed in EOPE (SC) and LOPE (SC) groups when compared to EOPE and LOPE groups, respectively. The light microscopy showed that the renal tissue of L-NAME-treated rats had extensive glomerular damage, tubular damage and infiltration by mononuclear cells when compared to PC group. Therefore, SC ameliorated podocyturia through its effects on the antiangiogenic/angiogenic status in this animal model. PMID- 27995420 TI - Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling. AB - Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFNgamma and IL4 productions from NKT cells, and more profound influence on IFNgamma was observed. By adjusting the pH of culture medium we further showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin (mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger (PLZF). Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls. PMID- 27995419 TI - T-cell Lymphoma Epidemiology: the Known and Unknown. AB - T-cell lymphoma, a collection of subtypes of Non-Hodgkin lymphoma, is a rare malignancy. The low prevalence of this disease has made it challenging to identify subtype-specific risk factors. Potential risk factors could enable us to identify high-risk patients and predict patient outcomes. Here, we report on the current epidemiologic and prognostic factors data associated with the individual subtypes both of peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) found in large cohort and case studies. Additionally, with recent findings, as well as updates in the new World Health Organization (WHO) classification of lymphoid neoplasms, we consider what this could do to change our approach to this group of diseases. PMID- 27995421 TI - Characterization of two monoclonal antibodies, 38F10 and 44D11, against the major envelope fusion protein of Helicoverpa armigera nucleopolyhedrovirus. AB - The envelope fusion protein F of baculoviruses is a class I viral fusion protein which play a significant role during virus entry into insect cells. F is initially synthesized as a precursor (F0) and then cleaved into a disulfide linked F1 and F2 subunits during the process of protein maturation and secretion. To facilitate further investigation into the structure and function of F protein during virus infection, monoclonal antibodies (mAbs) against the F2 subunit of Helicoverpa armigera nucleopolyhedrovirus (HearNPV) (HaF) were generated. Two kinds of mAbs were obtained according to their different recognition epitopes: one kind of mAbs, as represented by 38F10, recognizes amino acid (aa) 85 to 123 of F2 and the other kind, represented by 44D11, recognizes aa 148 to 173 of F2. Western blot and immunofluorescence assay confirmed that both of the mAbs recognized the F protein expressed in HearNPV infected cells, however, only 44D11 could neutralize HearNPV infection. The results further showed that 44D11 may not interact with a receptor binding epitope, rather it was demonstrated to inhibit syncytium formation in cells expressing the HaF protein. The results imply that the monoclonal antibody 44D11 recognizes a region within HaF2 that may be involved in the F-mediated membrane fusion process. PMID- 27995422 TI - Entry of severe fever with thrombocytopenia syndrome virus. AB - Severe fever with thrombocytopenia syndrome virus (SFTSV) is a globe-shaped virus covered by a dense icosahedral array of glycoproteins Gn/Gc that mediate the attachment of the virus to host cells and the fusion of viral and cellular membranes. Several membrane factors are involved in virus entry, including C-type lectins and nonmuscle myosin heavy chain IIA. The post-fusion crystal structure of the Gc protein suggests that it is a class II membrane fusion protein, similar to the E/E1 protein of flaviviruses and alphaviruses. The virus particles are internalized into host cell endosomes through the clathrin-dependent pathway, where the low pH activates the fusion of the virus with the cell membrane. With information from studies on other bunyaviruses, herein we will review our knowledge of the entry process of SFTSV. PMID- 27995423 TI - A simple web-based risk calculator (www.anastomoticleak.com) is superior to the surgeon's estimate of anastomotic leak after colon cancer resection. AB - BACKGROUND: Anastomotic leak can be a devastating complication, and early prediction is difficult. The aim of this study is to prospectively validate a simple anastomotic leak risk calculator and compare its predictive value with the estimate of the primary operating surgeon. METHODS: Consecutive patients undergoing elective or emergency colon cancer surgery with a primary anastomosis over a 1-year period were prospectively included. A recently published anastomotic leak risk nomogram was converted to an online calculator ( www.anastomoticleak.com ). The calculator-derived risk of anastomotic leak and the risk estimated by the primary operating surgeon were recorded at the completion of surgery. The primary outcome was anastomotic leak within 90 days as defined by previously published criteria. Area under receiver operating characteristic curve analysis (AUROC) was performed for both risk estimates. RESULTS: A total of 105 patients were screened for inclusion during the study period, of whom 83 met the inclusion criteria. The overall anastomotic leak rate was 9.6%. The anastomotic leak calculator was highly predictive of anastomotic leak (AUROC 0.84, P = 0.002), whereas the surgeon estimate was not predictive (AUROC 0.40, P = 0.243). CONCLUSIONS: A simple anastomotic leak risk calculator is significantly better at predicting anastomotic leak than the estimate of the primary surgeon. Further external validation on a larger data set is required. PMID- 27995424 TI - Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency. AB - Fragile X premutation carriers have 55-200 CGG repeats in the 5' untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI. PMID- 27995425 TI - Prophylactic mesh to prevent parastomal hernia after end colostomy: a meta analysis and trial sequential analysis. AB - PURPOSE: Prevention of parastomal hernia (PSH) formation is crucial, given the high prevalence and difficulties in the surgical repair of PSH. To investigate the effect of a preventive mesh in PSH formation after an end colostomy, we aimed to meta-analyze all relevant randomized controlled trials (RCTs). METHODS: We searched five databases. For each trial, we extracted risk ratios (RRs) of the effects of mesh or no mesh. The primary outcome was incidence of PSH with a minimum follow-up of 12 months with a clinical and/or computed tomography diagnosis. RRs were combined using the random-effect model (Mantel-Haenszel). To control the risk of type I error, we performed a trial sequential analysis (TSA). RESULTS: Seven RCTs with low risk of bias (451 patients) were included. Meta analysis for primary outcome showed a significant reduction of the incidence of PSH using a mesh (RR 0.43, 95% CI 0.26-0.71; P = 0.0009). Regarding TSA calculation for the primary outcome, the accrued information size (451) was 187.1% of the estimated required information size (RIS) (241). Wound infection showed no statistical differences between groups (RR 0.77, 95% CI 0.39-1.54; P = 0.46). PSH repair rate showed a significant reduction in the mesh group (RR 0.28 (95% CI 0.10-0.78; P = 0.01). CONCLUSIONS: PSH prevention with mesh when creating an end colostomy reduces the incidence of PSH, the risk for subsequent PSH repair and does not increase wound infections. TSA shows that the RIS is reached for the primary outcome. Additional RCTs in the previous context are not needed. PMID- 27995428 TI - Epiploic Appendagitis: A Benign Process at Risk of Unnecessary Hospitalization and Interventions. PMID- 27995426 TI - Who Gets Testosterone? Patient Characteristics Associated with Testosterone Prescribing in the Veteran Affairs System: a Cross-Sectional Study. AB - BACKGROUND: There has been concern about the growing off-label use of testosterone. Understanding the context within which testosterone is prescribed may contribute to interventions to improve prescribing. OBJECTIVE: To evaluate patient characteristics associated with receipt of testosterone. DESIGN: Cross sectional. SETTING: A national cohort of male patients, who had received at least one outpatient prescription within the Veterans Affairs (VA) system during Fiscal Year 2008- Fiscal Year 2012. PARTICIPANTS: The study sample consisted of 682,915 non-HIV male patients, of whom 132,764 had received testosterone and a random 10% sample, 550,151, had not. MAIN MEASURES: Conditions and medications associated with testosterone prescription. KEY RESULTS: Only 6.3% of men who received testosterone from the VA during the study period had a disorder of the testis, pituitary or hypothalamus associated with male hypogonadism. Among patients without a diagnosed disorder of hypogonadism, the use of opioids and obesity were the strongest predictors of testosterone prescription. Patients receiving >100 mg/equivalents of oral morphine daily (adjusted odds ratio = 5.75, p < 0.001) and those with body mass index (BMI) >40 kg/m2 (adjusted odds ratio = 3.01, p < 0.001) were more likely to receive testosterone than non-opioid users and men with BMI <25 kg/m2. Certain demographics (age 40-54, White race), comorbid conditions (sleep apnea, depression, and diabetes), and medications (antidepressants, systemic corticosteroids) also predicted a higher likelihood of testosterone receipt, all with an adjusted odds ratio less than 2 (p < 0.001). CONCLUSIONS: In the VA, 93.7% of men receiving testosterone did not have a diagnosed condition of the testes, pituitary, or hypothalamus. The strongest predictors of testosterone receipt (e.g., obesity, receipt of opioids), which though are associated with unapproved, off-label use, may be valid reasons for therapy. Interventions should aim to increase the proportion of testosterone recipients who have a valid indication. PMID- 27995429 TI - The Clinical Pharmacy Specialist: Part of the Solution. PMID- 27995427 TI - Primary care providers' cancer genetic testing-related knowledge, attitudes, and communication behaviors: A systematic review and research agenda. AB - BACKGROUND: Primary care providers (PCPs) can play a critical role in helping patients receive the preventive health benefits of cancer genetic risk information. Thus, the objective of this systematic review was to identify studies of US PCPs' knowledge, attitudes, and communication-related behaviors regarding genetic tests that could inform risk-stratification approaches for breast, colorectal, and prostate cancer screening in order to describe current findings and research gaps. METHODS: We conducted a systematic search of six electronic databases to identify peer-reviewed empirical articles relating to US PCPs and genetic testing for breast, colorectal, or prostate cancer published in English from 2008 to 2016. We reviewed these data and used narrative synthesis methods to integrate findings into a descriptive summary and identify research needs. RESULTS: We identified 27 relevant articles. Most focused on genetic testing for breast cancer (23/27) and colorectal cancer risk (12/27); only one study examined testing for prostate cancer risk. Most articles addressed descriptive research questions (24/27). Many studies (24/27) documented PCPs' knowledge, often concluding that providers' knowledge was incomplete. Studies commonly (11/27) examined PCPs' attitudes. Across studies, PCPs expressed some concerns about ethical, legal, and social implications of testing. Attitudes about the utility of clinical genetic testing, including for targeted cancer screening, were generally favorable; PCPs were more skeptical of direct-to consumer testing. Relatively fewer studies (9/27) examined PCPs' communication practices regarding cancer genetic testing. DISCUSSION: This review indicates a need for investigators to move beyond descriptive research questions related to PCPs' knowledge and attitudes about cancer genetic testing. Research is needed to address important gaps regarding the development, testing, and implementation of innovative interventions and educational programs that can improve PCPs' genetic testing knowledge, assuage concerns about the appropriateness of cancer genetic testing, and promote open and effective patient-provider communication about genetic risk and genetic testing. PMID- 27995430 TI - EEG artifacts reduction by multivariate empirical mode decomposition and multiscale entropy for monitoring depth of anaesthesia during surgery. AB - Electroencephalography (EEG) has been widely utilized to measure the depth of anaesthesia (DOA) during operation. However, the EEG signals are usually contaminated by artifacts which have a consequence on the measured DOA accuracy. In this study, an effective and useful filtering algorithm based on multivariate empirical mode decomposition and multiscale entropy (MSE) is proposed to measure DOA. Mean entropy of MSE is used as an index to find artifacts-free intrinsic mode functions. The effect of different levels of artifacts on the performances of the proposed filtering is analysed using simulated data. Furthermore, 21 patients' EEG signals are collected and analysed using sample entropy to calculate the complexity for monitoring DOA. The correlation coefficients of entropy and bispectral index (BIS) results show 0.14 +/- 0.30 and 0.63 +/- 0.09 before and after filtering, respectively. Artificial neural network (ANN) model is used for range mapping in order to correlate the measurements with BIS. The ANN method results show strong correlation coefficient (0.75 +/- 0.08). The results in this paper verify that entropy values and BIS have a strong correlation for the purpose of DOA monitoring and the proposed filtering method can effectively filter artifacts from EEG signals. The proposed method performs better than the commonly used wavelet denoising method. This study provides a fully adaptive and automated filter for EEG to measure DOA more accuracy and thus reduce risk related to maintenance of anaesthetic agents. PMID- 27995432 TI - Investigation of Image Reconstruction Parameters of the Mediso nanoScan PC Small Animal PET/CT Scanner for Two Different Positron Emitters Under NEMA NU 4-2008 Standards. AB - PURPOSE: The Tera-Tomo 3D image reconstruction algorithm (a version of OSEM), provided with the Mediso nanoScan(r) PC (PET8/2) small-animal positron emission tomograph (PET)/x-ray computed tomography (CT) scanner, has various parameter options such as total level of regularization, subsets, and iterations. Also, the acquisition time in PET plays an important role. This study aims to assess the performance of this new small-animal PET/CT scanner for different acquisition times and reconstruction parameters, for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and Ga-68, under the NEMA NU 4-2008 standards. PROCEDURES: Various image quality metrics were calculated for different realizations of [18F]FDG and Ga-68 filled image quality (IQ) phantoms. RESULTS: [18F]FDG imaging produced improved images over Ga-68. The best compromise for the optimization of all image quality factors is achieved for at least 30 min acquisition and image reconstruction with 52 iteration updates combined with a high regularization level. CONCLUSION: A high regularization level at 52 iteration updates and 30 min acquisition time were found to optimize most of the figures of merit investigated. PMID- 27995431 TI - Prototype Willingness Model Drinking Cognitions Mediate Personalized Normative Feedback Efficacy. AB - Personalized normative feedback (PNF) interventions have been shown to be efficacious at reducing college student drinking. Because descriptive norms have been shown to mediate PNF efficacy, the current study focused on examining additional prototype willingness model social reaction cognitions, namely, prototypes and willingness, as mediators of intervention efficacy. We expected the PNF interventions to be associated with increased prototype favorability of students who do not drink, which would in turn be associated with decreased willingness to drink and subsequently, less drinking. The current study included 622 college students (53.2% women; 62% Caucasian) who reported one or more heavy drinking episodes in the past month and completed baseline and three-month follow up assessments. As posited by the framework of the prototype willingness model, sequential mediation analyses were conducted to evaluate increases in abstainer prototype favorability on willingness on drinking, and subsequently willingness to drink on drinking behavior. Mediation results revealed significant indirect effects of PNF on three-month drinking through three-month prototypes and willingness, indicating that the social reaction pathway of the prototype willingness model was supported. Findings have important implications for PNF interventions aiming to reduce high-risk drinking among college students. Study findings suggest that we should consider looking at additional socially-based mediators of PNF efficacy in addition to perceived descriptive norms. PMID- 27995434 TI - Predictors of HIV Risk Behaviors Among a National Sample of Russian Men Who Have Sex with Men. AB - Russia has one of the fastest growing HIV epidemics in the world and is at the point of transitioning from injection drug use to sexual transmissions. We sought to identify factors associated with unprotected sex among men who have sex with men (MSM) in Russia, separately for Moscow, St. Petersburg and the rest of the country. Multivariable data from a national cross-sectional study (n = 5035) demonstrate that significant correlates of unprotected anal intercourse (UAI) with a non-steady partner across all areas were visiting sex-related venues (AOR range 1.35-1.96) and access to condoms (AOR range 0.37-0.52). In Moscow and St. Petersburg, being HIV-positive was correlated with UAI (AOR 2.13 and 2.69). The dynamics of the HIV epidemic among MSM in Russia appear to be both similar, and different, across various areas and factors associated with unprotected sex should be seen as part of an environment of exogenous factors impacting MSM's sexual behaviors. PMID- 27995433 TI - Direct Percutaneous Endoscopic Jejunostomy (DPEJ) Tube Placement: A Single Institution Experience and Outcomes to 30 Days and Beyond. AB - INTRODUCTION: Patients with prior foregut surgery requiring long-term enteral access typically undergo operative jejunostomy tube placement; however, direct percutaneous endoscopic jejunostomy (DPEJ) is a viable alternative. METHODS: All de novo DPEJ procedures performed by surgical and advanced endoscopists from May 2003 to June 2015 were retrospectively reviewed following approval by the Institutional Review Board. There were 59 cases identified. RESULTS: Our cohort had a mean age of 50.3 +/- 16.9 years and 35 (59.3%) were female. All but two patients previously had foregut surgery including 19 patients (34.5%) with prior bariatric surgery. The composite of malnutrition and dehydration was the indication for DPEJ in 29 patients (49.1%) and was the initial enteral access placed in 47 patients (79.7%). Moderate sedation was used in 32 cases (54.2%), and 29 procedures (49.2%) were performed in the operating room. Within 30 days, there were six complications in five patients, giving a peri-procedural complication rate of 12.5%. Beyond 30 days, the most common complications were peri-tube leakage and dislodgement (each 16.9%). The median time to complication was 197 days. CONCLUSIONS: In patients with surgically altered foregut anatomy, DPEJ offers a less invasive alternative to operative jejunostomy tube placement. DPEJ can be placed in the endoscopy suite or operating room with an acceptable risk of perioperative complications. PMID- 27995435 TI - Beliefs in Antiretroviral Treatment and Self-Efficacy in HIV Management are Associated with Distinctive HIV Treatment Trajectories. AB - An online survey was conducted among people living with HIV (PLHIV) in Australia to discern key factors associated with distinctive ART use patterns. The sample (N = 358), was further divided into three groups: those on ART continuously since initiation (n = 208, 58.1%); those on ART intermittently (n = 117, 32.7%); and those not on ART at the time of survey (n = 33, 9.2%). ART non-users were the most likely to hold serious concerns about ART that outweighed perceived necessities (benefits) from ART (AOR = 0.13; 95% CI 0.06-0.29; p < 0.001). They were also the least self-efficacious in HIV disease management (AOR = 0.29; 95% CI 0.09-0.87; p = 0.028). Intermittent ART users were more likely to receive their HIV diagnosis prior to 2003 (AOR = 0.38; 95% CI 0.28-0.53; p < 0.001) and perceive lower HIV management self-efficacy (AOR = 0.50, 95% CI 0.28-0.87; p = 0.015) than continuous users. ART-related beliefs and perceived self-efficacy in HIV self-management play an important role in achieving universal treatment uptake and sustained high levels of adherence. PMID- 27995436 TI - Obstructive sleep apnea is the triggering factor for massive hemoptysis : Obstructive sleep apnea and hemoptysis. AB - PURPOSE: The purpose of this study was to investigate the prevalence of obstructive sleep apnea (OSA) in patients with hemoptysis. METHODS: Files of patients who had undergone bronchial arterial embolization due to hemoptysis between 1 December 2009 and 2015 were evaluated and interviews of patients were conducted until 1 June 2016. Pittsburgh Sleep Quality Index (PSQI), STOP and STOP BANG surveys were administered. OSA risk was determined with Berlin Questionnaire. RESULTS: Study group consisted of 53 patients and 58 control subjects. Mean age was 46.94 +/- 14.36 and 41.97 +/- 12.92 in patient and control group, respectively. Of these patients, seven had re-embolization procedure because of recurrence of hemoptysis. High OSA risk was more common among patients with hemoptysis (24.5%, n = 13) than the control group (8.6%, n = 5) (p = 0.023). Percentage of high risk OSA patients with massive hemoptysis, nonmassive hemoptysis, and control subjects was 29.7% (n = 11), 12.5% (n = 2), and 8.6% (n = 5), respectively (p = 0.022). There were more high OSA risk subjects among patients with idiopathic hemoptysis 44.4% (four out of nine), while 20.5% (nine out of 53) patients with a known etiology had high risk (p = 0.127). The number of patients with high OSA risk was also higher in patients who required a second embolization procedure (four out of seven, 57.1%), while 19.6% of patients without need for re-embolization had high risk (p = 0.031). CONCLUSIONS: OSA is found to be a risk factor for hemoptysis and also may provoke massive hemoptysis. It seems reasonable to consider OSA as an underlying condition in idiopathic hemoptysis. OSA may contribute to embolization failure. PMID- 27995437 TI - Toward Personalized Targeted Therapeutics: An Overview. AB - In neuro-oncology, there has been a movement towards personalized medicine, or tailoring treatment to the individual patient. Ideally, tumor and patient evaluations would lead to the selection of the best treatment (based on tumor characterization) and the right dosing schedule (based on patient characterization). The recent advances in the molecular analysis of glioblastoma have created optimism that personalized targeted therapy is within reach. Although our understanding of the molecular complexity of glioblastoma has increased over the years, the path to developing effective targeted therapeutic strategies is wrought with many challenges, as described in this review. These challenges include disease heterogeneity, clinical and genomic patient variability, limited number of effective treatments, clinical trial inefficiency, drug delivery, and clinical trial support and accrual. To confront these challenges, it will be imperative to devise innovative and adaptive clinical trials in order to accelerate our efforts in improving the outcomes for our patients who have been in desperate need. PMID- 27995438 TI - Urate as a Marker of Risk and Progression of Neurodegenerative Disease. AB - Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration. PMID- 27995439 TI - Immuno-Oncology: The Third Paradigm in Early Drug Development. AB - Clinical researchers in oncology face the difficulty of developing new drugs for treating cancer patients. This challenge nowadays extends towards new horizons since a high number of drugs are developed in each of the three paradigms: classical cytotoxics, new targeted agents, and emergent immunotherapeutic approaches. Over the last decade, there has been an unstoppable progress in this third paradigm, to the extent that in 2013 immunotherapy was granted the scientific breakthrough of the year. However, the novel mechanisms of action of these immunotherapeutic agents entail a whole new series of concepts, resulting in a number of unresolved questions to which clarification is crucial for their success: establishment of accurate preclinical models able to predict human toxicities, better selection of candidate populations, finding and validation of predictive biomarkers, definition of suitable endpoints, improvements in first-in human study designs, proposal of more accurate radiological response criteria, management of novel immune-related toxicities and development of combinations based on a biological rationale. In this article, we review the major challenges to overcome in forthcoming years. The final role of immunotherapy in cancer will be determined by our capacity to shed some light on some of these key points. PMID- 27995441 TI - Integral Health Status-Based Cluster Analysis in Moderate-Severe COPD Patients Identifies Three Clinical Phenotypes: Relevant for Treatment As Usual and Pulmonary Rehabilitation. AB - PURPOSE: The purposes of the study are to identify clinical phenotypes that reflect the level of adaptation to the disease and to examine whether these clinical phenotypes respond differently to treatment as usual (TAU) and pulmonary rehabilitation (PR), the latter with its strong emphasis on improving adaptation. METHODS: Clusters were identified by a cluster analysis using data on many subdomains of the four domains of health status (HS) (physiological functioning, functional impairment, symptoms and quality of life) in 160 outpatients with chronic obstructive pulmonary disease (COPD) receiving TAU. By discriminant analysis in the TAU sample, all 459 PR patients could be assigned to one of the identified clusters. The effect of TAU and PR on HS was examined with paired t tests. RESULTS: Three distinct phenotypes were identified in the TAU sample. Two types were labelled adapted: phenotype 1 (moderate COPD-low impact on HS, n = 53) and phenotype 3 (severe COPD-moderate impact on HS, n = 73). One type was labelled non-adapted: phenotype 2 (moderate COPD-high impact on HS, n = 34). After 1-year TAU, the integral health status of all patients did not improve in any subdomain. In contrast, at the end of PR, significant improvements in HS were found in all three phenotypes especially the non-adapted. CONCLUSIONS: Different phenotypes exist in COPD that are based on behavioural aspects (i.e. the level of adaptation to the disease). Non-adapted patient responds better to treatments with a strong emphasis on improving adaptation by learning the patient better self-management skills. Knowing to which clinical phenotype a patient belongs helps to optimize patient-tailored treatment. PMID- 27995440 TI - The hologenome concept: we need to incorporate function. AB - Are we in the midst of a paradigm change in biology and have animals and plants lost their individuality, i.e., are even so-called 'typical' organisms no longer organisms in their own right? Is the study of the holobiont-host plus its symbiotic microorganisms-no longer optional, but rather an obligatory path that must be taken for a comprehensive understanding of the ecology and evolution of the individual components that make up a holobiont? Or are associated microbes merely a component of their host's environment, and the holobiont concept is just a beautiful idea that does not add much or anything to our understanding of evolution? This article explores different aspects of the concept of the holobiont. We focus on the aspect of functional integration, a central holobiont property, which is only rarely considered thoroughly. We conclude that the holobiont comes in degrees, i.e., we regard the property of being a holobiont as a continuous trait that we term holobiontness, and that holobiontness is differentiated in several dimensions. Although the holobiont represents yet another level of selection (different from classical individual or group selection because it acts on a system that is composed of multiple species), it depends on the grade of functional integration whether or not the holobiont concept helps to cast light on the various degrees of interactions between symbiotic partners. PMID- 27995442 TI - Religion, Alcohol Use and Risk Drinking Among Canadian Adults Living in Ontario. AB - This research examines (1) the association between risk drinking and religious affiliation and (2) differences between religions for risk drinking among adults living in Ontario, Canada, for Christians, Buddhists, Sikhs, Muslims, Hindus, Jews, other religious groups and the non-religious. Data are based on telephone interviews with 16,596 respondents and are derived from multiple cycles (2005 2011) of the Centre for Addiction and Mental Health's (CAMH) Monitor survey, an ongoing cross-sectional survey of adults in Ontario, Canada, aged 18 years and older. Data were analysed using bivariate cross-tabulations, Mann-Whitney U nonparametric test and logistic regression. Alcohol use and risk drinking occur among members of all religious groups; however, the rate of drinking ranges widely. Risk drinking is significantly associated with religion. When compared to the No religion/Atheist group, several religious groups (Baptist, Christian, Hindu, Jehovah's Witness, Jewish, Muslim/Islam, Non-denominational, Pentecostal, Sikh and Other religion) in our sample have significantly lower odds of risk drinking. Risk drinkers also attended significantly fewer services among several religions. Results suggest that there are differences in the risk drinking rates among Canadian adults, living in Ontario, by religion. It appears that religious traditions of prohibition and abstention do hold sway among Canadian adults for some religious groups. PMID- 27995444 TI - E-Government Attempts in Small Island Developing States: The Rate of Corruption with Virtualization. AB - In recent years, many Small Island Developing State (SIDS) governments have worked to increase openness and transparency of their transactions as a means to enhance efficiency and reduce corruption in their economies. In order to achieve a cost-effective and efficient strategy to implement a transparent government, Information Communication Technologies offer an opportunity of virtualization by deploying e-government services to promote transparency, accountability and consistency in the public sector and to minimize corruption. This paper explores the potential impact of government virtualization by SIDS and against corruption by comparing the corruption perception index (CPI) rates of 15 SIDS countries. The CPI relates to the degree by which corruption is perceived to exist among public officials and politicians by business people and country analysts. In order to reveal the long-term impact of virtual deployment and its consequences on corruption, an in-depth case analysis based on the CPI index rates was conducted on the deployment of the e-government system in Cyprus. PMID- 27995443 TI - Pseudohypoparathyroidism: one gene, several syndromes. AB - Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several sites. GNAS encodes the alpha-subunit of the stimulatory G protein (Gsalpha) and several splice variants thereof. Heterozygous inactivating mutations involving the maternal GNAS exons 1-13 cause PHP type Ia (PHP1A). Because of much reduced paternal Gsalpha expression in certain tissues, such as the proximal renal tubules, thyroid, and pituitary, there is little or no Gsalpha protein in the presence of maternal GNAS mutations, thus leading to PTH-resistant hypocalcemia and hyperphosphatemia. When located on the paternal allele, the same or similar GNAS mutations are the cause of PPHP. Besides biochemical abnormalities, patients affected by PHP1A show developmental abnormalities, referred to as Albrights hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylated GNAS exons. LOM at exon A/B and the resulting biallelic expression of A/B transcripts reduces Gsalpha expression, thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, the most frequent disease variant, which remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q). PMID- 27995445 TI - Promoting Virtue or Punishing Fraud: Mapping Contrasts in the Language of 'Scientific Integrity'. AB - Even though integrity is widely considered to be an essential aspect of research, there is an ongoing debate on what actually constitutes research integrity. The understanding of integrity ranges from the minimal, only considering falsification, fabrication and plagiarism, to the maximum, blending into science ethics. Underneath these obvious contrasts, there are more subtle differences that are not as immediately evident. The debate about integrity is usually presented as a single, universal discussion, with shared concerns for researchers, policymakers and 'the public'. In this article, we show that it is not. There are substantial differences between the language of research integrity in the scientific arena and in the public domain. Notably, scientists and policymakers adopt different approaches to research integrity. Scientists tend to present integrity as a virtue that must be kindled, while policy documents and newspapers stress norm enforcement. Rather than performing a conceptual analysis through philosophical reasoning and discussion, we aimed to clarify the discourse of 'scientific integrity' by studying its usage in written documents. To this end, large numbers of scientific publications, policy documents and newspaper articles were analysed by means of scientometric and content analysis techniques. The texts were analysed on their usage of the term 'integrity' and of frequently co-occurring terms and concepts. A comparison was made between the usage in the various media, as well as between different periods in which they were published through co-word analysis, mapping co-occurrence networks of significant terms and themes. PMID- 27995446 TI - Public Perceptions of Ethical, Legal and Social Implications of Pre-implantation Genetic Diagnosis (PGD) in Malaysia. AB - Pre-implantation genetic diagnosis (PGD) became well known in Malaysia after the birth of the first Malaysian 'designer baby', Yau Tak in 2004. Two years later, the Malaysian Medical Council implemented the first and only regulation on the use of Pre-implantation Genetic Diagnosis in this country. The birth of Yau Tak triggered a public outcry because PGD was used for non-medical sex selection thus, raising concerns about PGD and its implications for the society. This study aims to explore participants' perceptions of the future implications of PGD for the Malaysian society. We conducted in-depth interviews with 21 participants over a period of one year, using a semi-structured questionnaire. Findings reveal that responses varied substantially among the participants; there was a broad acceptance as well as rejection of PGD. Contentious ethical, legal and social issues of PGD were raised during the discussions, including intolerance to and discrimination against people with genetic disabilities; societal pressure and the 'slippery slope' of PGD were raised during the discussions. This study also highlights participants' legal standpoint, and major issues regarding PGD in relation to the accuracy of diagnosis. At the social policy level, considerations are given to access as well as the impact of this technology on families, women and physicians. Given these different perceptions of the use of PGD, and its implications and conflicts, policies and regulations of the use of PGD have to be dealt with on a case-by-case basis while taking into consideration of the risk benefit balance, since its application will impact the lives of so many people in the society. PMID- 27995447 TI - Ethics, Nanobiosensors and Elite Sport: The Need for a New Governance Framework. AB - Individual athletes, coaches and sports teams seek continuously for ways to improve performance and accomplishment in elite competition. New techniques of performance analysis are a crucial part of the drive for athletic perfection. This paper discusses the ethical importance of one aspect of the future potential of performance analysis in sport, combining the field of biomedicine, sports engineering and nanotechnology in the form of 'Nanobiosensors'. This innovative technology has the potential to revolutionise sport, enabling real time biological data to be collected from athletes that can be electronically distributed. Enabling precise real time performance analysis is not without ethical problems. Arguments concerning (1) data ownership and privacy; (2) data confidentiality; and (3) athlete welfare are presented alongside a discussion of the use of the Precautionary Principle in making ethical evaluations. We conclude, that although the future potential use of Nanobiosensors in sports analysis offers many potential benefits, there is also a fear that it could be abused at a sporting system level. Hence, it is essential for sporting bodies to consider the development of a robust ethically informed governance framework in advance of their proliferated use. PMID- 27995448 TI - Functional characterization of human equilibrative nucleoside transporter 1. AB - Equilibrative nucleoside transporters (ENTs), which facilitate cross-membrane transport of nucleosides and nucleoside-derived drugs, play an important role in the salvage pathways of nucleotide synthesis, cancer chemotherapy, and treatment for virus infections. Functional characterization of ENTs at the molecular level remains technically challenging and hence scant. In this study, we report successful purification and biochemical characterization of human equilibrative nucleoside transporter 1 (hENT1) in vitro. The HEK293F-derived, recombinant hENT1 is homogenous and functionally active in proteoliposome-based counter flow assays. hENT1 transports the substrate adenosine with a Km of 215 +/- 34 umol/L and a Vmax of 578 +/- 23.4 nmol mg-1 min-1. Adenosine uptake by hENT1 is competitively inhibited by nitrobenzylmercaptopurine ribonucleoside (NBMPR), nucleosides, deoxynucleosides, and nucleoside-derived anti-cancer and anti-viral drugs. Binding of hENT1 to adenosine, deoxyadenosine, and adenine by isothermal titration calorimetry is in general agreement with results of the competitive inhibition assays. These results validate hENT1 as a bona fide target for potential drug target and serve as a useful basis for future biophysical and structural studies. PMID- 27995449 TI - Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Adolescent and Young Adults with Peritoneal Metastases. AB - BACKGROUND: Several studies suggest that young patients may derive less oncologic benefit from surgical resection of cancers compared with older patients. We hypothesized that young patients may have worse outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) for peritoneal metastases. METHODS: Perioperative and oncologic outcomes in adolescent and young adults (AYA), defined as younger than age 40 years (n = 135), undergoing CRS/HIPEC between 2001 and 2015 were reviewed and compared with middle-aged adults, defined as aged 40-65 years (n = 684). RESULTS: The two groups were similar with regards to perioperative characteristics except that AYA were more likely to be symptomatic at presentation (65.2 vs. 50.9%, p = 0.003), had lower Charleson comorbidity index (median 6 vs. 8, p < 0.001), were less likely to receive neoadjuvant chemotherapy (32.8 vs. 42.5%, p = 0.042), and had longer operative times (median 543 vs. 493 min, p = 0.010). Postoperative Clavien Dindo grade 3-4 morbidity was lower in AYA (17 vs. 26%, p = 0.029), and they required fewer reoperations for complications (3.7 vs. 10.4%, p = 0.014). AYA had longer median overall survival (103.6 vs. 73.2 months, p = 0.053). In a multivariate Cox regression analysis, age was an independent predictor of improved overall survival [hazard ratio 0.705; 0.516-0.963, p = 0.028]. CONCLUSIONS: Young patients with peritoneal metastases derive similar benefits from CRS/HIPEC as middle-aged patients. Young age should not be a deterrent to consideration of CRS/HIPEC for peritoneal metastases. PMID- 27995450 TI - Prognostic Factors and Significance of Gastrointestinal Leak After Cytoreductive Surgery (CRS) with Heated Intraperitoneal Chemotherapy (HIPEC). AB - BACKGROUND: Gastrointestinal leak (GIL) after cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) is associated with significant morbidity and mortality. This study aimed to identify GIL prognostic factors and its impact on overall survival. METHODS: A retrospective analysis of a prospectively maintained database comprising 1270 CRS/HIPEC procedures was performed. Type of GIL, functional and resection status, morbidity, mortality, and survival were reviewed. RESULTS: Gastrointestinal leaks were identified in 8.7% (110/1270) of CRS/HIPEC procedures, including 53 anastomotic leaks (4.2%), 53 hollow viscus perforations (4.2%), and four leaks at unknown sites. The multivariate predictors of leak were Eastern Cooperative Oncology Group (ECOG) functional status (ECOG 1 vs. 0: odds ratio [OR] 2.12, p = 0.009; ECOG 2 vs. 0: OR 2.90, p = 0.004), and number of anastomoses (OR 5.34; p < 0.0001). The in-hospital mortality rate for the GIL cohort was 21.8% (24/110), with a 72% (80/110) reoperation rate. The leak cohort had a higher major morbidity rate (88.3 vs. 23.3%; p < 0.0001), a longer hospital stay (39.0 vs. 9.9 days; p < 0.0001), and a longer intensive care unit (ICU) stay (7.7 vs. 1.7 days; p = 0.0003). After surgical mortality was excluded, the overall survival periods for the leak and no-leak patients with complete cytoreduction were respectively 1.5 and 4.98 years (p = 0.0001). Clinically significant decreases in survival were observed for all primary malignancies. CONCLUSIONS: Gastrointestinal leak after CRS/HIPEC is a source of significant mortality, with a decrease in overall survival even after complete CRS. Preoperative functional status and number of anastomoses are predictors of leak for CRS/HIPEC patients. PMID- 27995451 TI - Survival and Prognostic Factors for Metachronous Peritoneal Metastasis in Patients with Colon Cancer. AB - BACKGROUND: The clinical course of metachronous peritoneal metastasis of colorectal origin is poorly understood. In this retrospective study, we aimed to elucidate survival and prognostic factors for metachronous peritoneal metastasis. METHODS: Patients with metachronous peritoneal metastasis after curative resection for stage I-III colon cancer were retrospectively reviewed, and the incidence and prognosis of metachronous peritoneal metastasis were investigated. Prognostic factors were identified by univariate and multivariate analyses. RESULTS: Among 1582 surgically resected stage I-III colon cancer patients, 65 developed metachronous peritoneal metastasis. The 5-year cumulative incidence rate was 4.5%, and the median survival after diagnosis of peritoneal metastasis was 29.6 months. None of the patients underwent peritonectomy or intraperitoneal chemotherapy. Independent prognostic factors included right colon cancer [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.26-5.64; p = 0.011], time to metachronous peritoneal metastasis of <1 year (HR 2.02, 95% CI 1.04-3.87; p = 0.040), Peritoneal Cancer Index (PCI) >10 (HR 3.68, 95% CI 1.37-8.99; p = 0.012), concurrent metastases (HR 4.09, 95% CI 2.02-8.23; p < 0.001), and peritoneal nodule resection (HR 0.31, 95% CI 0.13-0.65; p = 0.002). CONCLUSIONS: A proportion of colon cancer patients with metachronous peritoneal metastasis may benefit from combined peritoneal nodule resection and systemic chemotherapy. Right colon cancer, early peritoneal metastasis, a high PCI, and concurrent metastases negatively affected prognosis in patients with metachronous peritoneal metastasis. PMID- 27995452 TI - An Optimal Approach for Laparoscopic D3 Lymphadenectomy Plus Complete Mesocolic Excision (D3+CME) for Right-Sided Colon Cancer. AB - BACKGROUND: It is common knowledge that high ligation of blood vessels at the D3 level and complete mesocolic excision (CME) are two critical points of right hemicolectomy for right colon cancer (RCC). 1-5 To date, a safe strategy for completing these two procedures under laparoscopic surgery has not been extensively described. The authors provide a video to demonstrate laparoscopic right hemicolectomy (D3 + CME) with an optimal mesentery-defined approach. By identifying three "tri-junctions," this approach facilitates dissection of the entire mesocolon along the embryologic planes as far centrally as possible and enables the high tie of feeding vessels at bifurcation. The authors propose that this approach is safe, decreases blood loss, and is a secure method for right colon cancer intervention. METHODS: Between June 2014 and June 2015, the study recruited 36 patients with informed consent, and these patients underwent laparoscopic D3+CME for right colon cancer by a single surgeon. All the participants provided informed written consent to participate in the study. This study was approved by the Tongji Hospital Ethics Committee. The patients' demographics, oncologic charac- teristics, postoperative outcomes within 30 days, and follow-up data were collected. The perioperative outcomes included blood lost, number of retrieved lymph nodes, postoperative hospital length of stay, and morbidity. The postoperative 30-day morbidity included cardiovascular, pulmonary, and urinary complications, as well as wound infection, anastomotic leakage, and postoperative ileus. The complications were diagnosed and categorized based on relevant clinical manifestations. For this procedure, all patients are placed in the Trendelenburg position, with five trocars inserted. Carbon dioxide (CO2) is inflated through the intraumbilical trocar, maintaining steady intraabdominal pressure. The operating surgeon stands between the patient's legs, with the camera holder on the left and the assistant on the right. The operation table will be rotated left side up to redistribute the small bowels. The standard surgical procedures shown in the video are as follows. First, the surgeon identifies the first "tri-junction" (TJ1) in the ileocolic area (TJ1 is the fusion point of the mesocolon, the visceral peritoneum, and the intestinal mesentery). The surgeon then incises along the fusion fascia and separates the loose connective tissues with an ultrasonically activated device. Mobilization is continued to the origins of the ileocolic vessels, which are clipped and cut. The posterior mesocolic fascia is bluntly separated from the inferior mesentery bed, which is formed by duodenum, Gerota's fascia, and nearby structures. The second part of duodenum and the head of pancreas are exposed. Next, the surgeon mobilizes along the superior mesentery vein (SMV) and superior mesentery artery (SMA), with blunt dissection of the covering fascia and loose connective tissue to preserve the entire mesocolon completely and as far centrally as possible. Careful dissection is continued until the middle colic vessels (middle colic vein and middle colic artery) are reached. Afterward, the superior right colic vein of Henle's trunk is exposed and divided at the root. One pack of gauze is inserted beneath the mobilized mesocolon. Second, the surgeon divides the greater omentum. Entrance to the omental bursa is established after the second "tri-junction" (TJ2) is identified (TJ2 is the fusion point of the transverse mesocolon, the mesogastrium and the greater omentum). The fusion plane is bluntly separated between the transverse mesocolon (TM) and the right gastroepiploic mesentery (RGEM) until the previously placed gauze is exposed. Finally, the third "tri junction" (TJ3) is identified (TJ3 is the fusion point of the retroperitoneum, the mesocolon, and the lateral peritoneum) at the inferior attachments of cecum. The ascending colon is freed up with mobilization of the lateral retroperitoneal attachments from the cecum to the hepatic flexture. Special attention should be paid to avoid breaking the fascia renalis. The tumor carrying the colon is exteriorized through an abdominal incision with a wound protector. Continuity of the digestive tract is performed extracorporeally with side-to-side ileotransverse colon anastomosis using a linear stapler. All the treatments follow standardized recovery protocols. RESULTS: This study recruited 20 males and 16 females. The median age was 56.5 years, and the median body mass index (BMI) was 22.1 kg/m2. Twelve patients had experienced previous abdominal surgery. No intraoperative complications occurred. The tumor was located in the ileocecus of 14 patients and in the hepatic flexture of 22 patients (Supplemental Table 1). The median number of retrieved lymph nodes was 20 (interquartile range [IQR], 14.8-27 (Supplemental Table 2). The median volume of blood lost was 5 ml (IQR 5 10 ml). The median postoperative hospital stay was 10 days (IQR 9-12.3 days). One patient received treatments from the intensive care unit (ICU). One patient underwent reoperation for incision dehiscence. Seven patients had a postoperative complication diagnosed within 30 days (Supplemental Table 3). The median follow up period was 12 months (IQR 3-20) months. All the patients received adjuvant chemotherapy, with no case of recurrence (Supplemental Table 4). CONCLUSION: An optimal mesentery-defined approach for laparoscopic D3 + CME allows for ligation of feeding vessels at their bifurcation and for CME to be performed simultaneously with technical efficiency. This procedure is safe and strongly practical for advanced right colon cancer intervention. PMID- 27995453 TI - Laparoscopic Glissonean Pedicle Transection (Takasaki) for Negative Fluorescent Counterstaining of Segment 6. AB - BACKGROUND: The portal pedicles are wrapped in connective tissue known as the Walaeus sheath, which abut Laennec's capsule covering the liver parenchyma. Precise knowledge of this anatomic relationship allows for dissection of this interspace and early control of the segmental portal pedicle (Glissonean pedicle transection method [GPTM], Takasaki approach). 1,2 Subsequent systemic administration of indocyanine green (ICG) leads to negative counterstaining of the segment to be resected. PATIENT: The patient was a 60-year-old healthy woman with invasive lobular breast cancer, grade 2, which was estrogen receptor positive (ER +), progesterone receptor-positive (PR +), human epidermal growth factor-negative (HER2-), Ki-67 80%, and cT2N0M1. A synchronous solitary liver metastasis between segments 6 and 7 was diagnosed. After treatment with letrozole and palbociclib for 1 year had achieved stable disease, the patient was considered for liver metastasectomy. 3,4 METHODS: After an intraoperative ultrasound, the patient was placed in the French position, 5 and the gallbladder was disconnected from the cystic duct for exposure of the hepatoduodenal ligament. The hilar plate was lowered, and the portal pedicle of segment 6 was dissected out using the GPTM approach. After test-clamping, an appropriate demarcation was observed, and ICG was administered systemically. This led to negative counterstaining of segment 6 and allowed for precise anatomic dissection under near-infrared vision. CONCLUSIONS: Laparoscopic application of GPTM facilitates anatomically precise liver resection through early pedicle control. Negative counterstaining using ICG under near-infrared vision leads to visual enhancement of the anatomically precise borders. They typically do not follow straight lines and are therefore difficult to dissect precisely. Counterstaining with ICG shows patient-specific anatomic variations that would be a challenge to determine, especially laparoscopically. PMID- 27995454 TI - Neoadjuvant Chemotherapy Increases R0 Cytoreduction Rate But Does Not Improve Final Outcome in Advanced Epithelial Ovarian Cancer. AB - BACKGROUND: Most epithelial ovarian cancers present in advanced stages. Traditional management is maximum cytoreductive effort followed by platinum taxane-based chemotherapy. We hypothesized that providing all chemotherapy before surgery will increase the R0 cytoreductive rate and improve prognosis. METHODS: Patients with advanced epithelial ovarian carcinoma [International Federation of Gynecology and Obstetrics (FIGO) stages IIIC and IV without parenchymal metastasis] were included in a comparative study. Group A underwent cytoreductive surgery followed by six cycles of chemotherapy, and group B completed six cycles of preoperative systemic therapy followed by cytoreduction. Demographic, clinical, surgical and pathologic variables were recorded and analyzed. Main outcome end points were progression-free survival (PFS) and overall survival (OS). Complete cytoreduction (R0) was defined as absence of macroscopic disease. Kaplan-Meier curves were constructed for survival analysis and univariate and multivariate analysis was performed. Significance was considered at p < 0.05. RESULTS: One hundred five patients were included: 42 in group A and 63 in group B. Mean patient age was 56 years (range 32-85 years). There were no significant differences between groups regarding demographic, clinical, surgical or pathologic variables. Surgical morbidity was low and not different between groups and there was no surgical mortality. R0 cytoreduction was obtained in 35.5 versus 64.5% in groups A and B, respectively. Median PFS and OS for the entire cohort were 16.17 and 38 months, respectively. Median PFS were 14.71 and 17.52 months for groups A and B, respectively (p = NS), and OS were 33.59 and 56.4 months for groups A and B, respectively (p = 0.08). Factors significantly associated with decreased survival on multivariate analysis were non-R0 resection (p < 0.001), anemia (Hb < 12 g/dL; p = 0.004) and comorbidities (Charlson score > 2; p = 0.007). CONCLUSIONS: In spite of nearly doubling the rate of complete cytoreduction and reduce severe surgical complications, preoperative chemotherapy does not improve long-term outcome in advanced epithelial ovarian carcinoma. PMID- 27995455 TI - Clinical Translation of the National Institutes of Health's Investments in Nanodrug Products and Devices. AB - The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting biomedical research. The NIH's mission is to seek fundamental knowledge about the nature and behavior of living systems and to apply that knowledge to enhance health, lengthen life, and reduce illness and disability. In support of this mission, NIH has invested about $4.4 billion since 2001 in nanotechnology (NT) research. This investment is leading to fundamental changes in understanding biological processes in health and disease, as well as enabling novel diagnostics and interventions for treating disease. NIH scientists are developing molecular agents and methods for earlier and more accurate diagnosis and therapies aimed directly and selectively at diseased cells, and are exploring root causes of common and rare diseases at the nanoscale. Work is also underway to move these research tools and devices into clinical practice. This particular investigative review examines the NIH NT portfolio linked to clinical trials from FY2008 to FY2015 to assess the progress of clinical translation. Among the subset of trials identified, 70% target drug or combination drug-device products used in treating cancer, AIDS, and other various diseases. The review also provides insight into trends observed from studying the clinical research portfolio. PMID- 27995456 TI - Current treatment strategies in relapsed/refractory mantle cell lymphoma: where are we now? AB - The management of relapsed/refractory mantle cell lymphoma remains challenging. Patients with relapsed mantle cell lymphoma have been treated with multi-agent salvage chemotherapies; however, outcomes are poor. Although there have been studies in the relapse/refractory setting, current data indicate that autologous hematopoietic stem cell transplantation may be an especially useful approach in the front line setting in patients in first complete or partial remission following induction chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only curative option, although reduced intensity conditioning in chemo-sensitive relapse or refractory mantle cell lymphoma provides better survival rates. In addition, bortezomib, lenalidomide, temsirolimus, and ibrutinib have opened a new therapeutic era. More randomized trials should be conducted to evaluate the appropriate use of these new molecules. In this review, I discuss autologous and allo-transplant options as well as the data regarding recently approved novel agents in the relapse/refractory setting in patients with MCL. PMID- 27995458 TI - A Community-Based Outreach Navigator Approach to Establishing Partnerships for a Safety Net Mammography Screening Center. AB - Washington, DC, has one of the highest incidence and mortality rates for breast cancer in the USA. Patient navigation coupled with informational and community resources are important strategies that assist patients' access and help them understand the complex world of cancer care. The Georgetown Lombardi Comprehensive Cancer Center's Capital Breast Care Center (CBCC) is a safety net mammography screening center that utilizes a community-based navigation program. In addition to providing assistance with coordination of clinical services, navigators at CBCC are integral in establishing intra-community partnerships to educate members of the community about breast cancer screening. The aim of this study was to detail the role of patient navigation at the CBCC, with an emphasis on community engagement and community-based partnerships. We describe the process by which CBCC established partnerships with multiple community organizations between 2004 and 2015 and analyzed data of women screened in relationship to the evolution of the patient navigation services. Application of the CBCC navigation model that integrates individual patient outreach with community engagement has yielded viable and lasting community partnerships that have resulted in an increase in mammography uptake, especially among medically underserved minority women. PMID- 27995457 TI - Detection of chromosomal abnormalities by G-banding and prognostic impact in follicular lymphoma in the rituximab era. AB - Disease-specific cytogenetic abnormalities involving BCL2 gene rearrangement frequently co-exist with other cytogenetic abnormalities, contributing to disease progression in follicular lymphoma (FL). In the present study, we retrospectively investigated the prognostic impact of BCL2-unrelated cytogenetic abnormalities in FL. Of 139 consecutively diagnosed patients with FL at two independent institutes, metaphase spreads of tumor cells were obtained for use in G-banding analysis in 77 patients. The recurrent additional cytogenetic abnormalities included chromosome gains +5 (n = 8), +7 (n = 16), +12 (n = 10), and +X (n = 12), and losses -8 (n = 7), -13 (n = 12) -15 (n = 7), and 6q- (n = 7). While -15 was associated with shorter progression-free survival (PFS) in all 77 analyzed patients with evaluable G-banding results (p = 0.04), this negative impact was not evident in 42 patients treated using an R-CHOP-like regimen as first-line treatment. By contrast, 6q- was predictive for shorter PFS in patients who were initially treated with R-CHOP-like regimens without maintenance therapy (p < 0.01), while this negative impact was not evident in all 77 patients with evaluable G-banding results. These results suggest the presence of a molecular region in chromosome 6q that is responsible for the shorter PFS following R-CHOP like chemotherapy. PMID- 27995460 TI - Coumarin Based Highly Selective "off-on-off" Type Novel Fluorescent Sensor for Cu2+ and S2- in Aqueous Solution. AB - Solvent free synthesis of 6,7-dihydroxy-3-(3-chlorophenyl) coumarin (CFHC) was designed and obtained by the interaction of 2-(2,4,5-trimethoxyphenyl)-1-(3 chlorophenyl)acrylonitrile with pyridinium hydrochloride in the presence of silica gel by using microwave irradiation. The characterization of CFHC was confirmed by FT-IR, 1H, 13C, 13C-APT and 2D HETCOR spectroscopy methods. The optical behavior of CFHC towards metal ions was investigated by UV-visible and fluorescence spectroscopy. CFHC showed "on-off" type fluorescence response towards Cu2+ with high selectivity in aqueous solution (CH3CN/H2O, 9/1, v/v). Once binding with Cu2+, CFHC-Cu2+ complex also displayed high selectivity for sulfide, resulting in "off-on" type sensing of sulfide anion. Graphical abstract Visual fluorescence changes upon addition of various metal ions (5.0 eq.) to CFHC in CH3CN/H2O (90:10, v/v) under UV excitation (365 nm). PMID- 27995461 TI - Determination of mTG Activity in Low-Fat Semi-Hard Cheese Using Fluorescent Labelling. AB - A method to directly determine enzyme activity in cheese has not been published yet despite the fact that mTG mediated gel strength or hardness modification may be unpredictable and unfavorable during ripening and/or storage. The present study was performed to determine enzyme activity of semi-fat semi-hard Hungarian Trappist cheese. The widely known hydroxamate method was not suitable to even detect enzyme treatment, because of the disturbing effect of milk proteins. However incorporation of a dansylated glutamine dipeptide into milk protein contributed to monitoring the enzyme activity. The fluorescent measurement reflected mTG activity by increasing fluorescence intensity at 532 nm in a 5-min continuously running assay. The presented dipeptide assay allows the determination of enzyme activity after 2 min measurement by the manufacturing stage: cutting and up-heating. This assay can be used to monitor mTG activity during manufacture of low-fat semi-hard cheese type, in case if it was produced according to general recommendation of enzyme preparation providers (enzyme dosage: 0.1%, v/w). According to the preliminary calibration this assay can define mTG activity in the range of 0.05-0.3 U/g. PMID- 27995459 TI - Epac activation inhibits IL-6-induced cardiac myocyte dysfunction. AB - Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA) mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca2+ concentration and contractility in response to isoproterenol, most likely through inhibition of the Jak-STAT pathway via SOCS3, with subsequent changes in inducible nitric oxide synthase expression. These findings suggest a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia. PMID- 27995462 TI - Highly Selective and Sensitive Colorimetric and Fluorescent Chemosensor for Rapid Detection of Ag+, Cu2+ and Hg2+ Based on a Simple Schiff Base. AB - A new reversible colorimetric and fluorescent chemosensor MMIP based on a simple Schiff base has been successfully synthesized. MMIP exhibited high selectivity and sensitivity towards Ag+, Cu2+ and Hg2+ ions with a short response time in DMSO/H2O (1/1, v/v) solution among various metal ions, and the results could be monitored directly by naked eyes. The binding stoichiometry between MMIP and Ag+/Hg2+/Cu2+ has been determined to be 1:2 by Job's plot and FT-IR analysis. MMIP could effectively detect Ag+, Cu2+ and Hg2+ over a wide pH range of 3-10. The good linear correlations were obtained in the concentration ranges of 0-20 MUM for Ag+, Cu2+ and Hg2+. Thus sensor MMIP could be potentially used for the quantification of Ag+, Cu2+ and Hg2+ in aqueous solution. PMID- 27995463 TI - Effect of Formulation and Process Parameters on Chitosan Microparticles Prepared by an Emulsion Crosslinking Technique. AB - There are many studies about the synthesis of chitosan microparticles; however, most of them have very low production rate, have wide size distribution, are difficult to reproduce, and use harsh crosslinking agents. Uniform microparticles are necessary to obtain repeatable drug release behavior. The main focus of this investigation was to study the effect of the process and formulation parameters during the preparation of chitosan microparticles in order to produce particles with narrow size distribution. The technique evaluated during this study was emulsion crosslinking technique. Chitosan is a biocompatible and biodegradable material but lacks good mechanical properties; for that reason, chitosan was ionically crosslinked with sodium tripolyphosphate (TPP) at three different ratios (32, 64, and 100%). The model drug used was acetylsalicylic acid (ASA). During the preparation of the microparticles, chitosan was first mixed with ASA and then dispersed in oil containing an emulsifier. The evaporation of the solvents hardened the hydrophilic droplets forming microparticles with spherical shape. The process and formulation parameters were varied, and the microparticles were characterized by their morphology, particle size, drug loading efficiency, and drug release behavior. The higher drug loading efficiency was achieved by using 32% mass ratio of TPP to chitosan. The average microparticle size was 18.7 MUm. The optimum formulation conditions to prepare uniform spherical microparticles were determined and represented by a region in a triangular phase diagram. The drug release analyses were evaluated in phosphate buffer solution at pH 7.4 and were mainly completed at 24 h. PMID- 27995464 TI - PAT-Based Control of Fluid Bed Coating Process Using NIR Spectroscopy to Monitor the Cellulose Coating on Pharmaceutical Pellets. AB - Current endeavor was aimed towards monitoring percent weight build-up during functional coating process on drug-layered pellets. Near-infrared (NIR) spectroscopy is an emerging process analytical technology (PAT) tool which was employed here within quality by design (QbD) framework. Samples were withdrawn after spraying every 15-Kg cellulosic coating material during Wurster coating process of drug-loaded pellets. NIR spectra of these samples were acquired using cup spinner assembly of Thermoscientific Antaris II, followed by multivariate analysis using partial least squares (PLS) calibration model. PLS model was built by selecting various absorption regions of NIR spectra for Ethyl cellulose, drug and correlating the absorption values with actual percent weight build up determined by HPLC. The spectral regions of 8971.04 to 8250.77 cm-1, 7515.24 to 7108.33 cm-1, and 5257.00 to 5098.87 cm-1 were found to be specific to cellulose, where as the spectral region of 6004.45 to 5844.14 cm-1was found to be specific to drug. The final model gave superb correlation co-efficient value of 0.9994 for calibration and 0.9984 for validation with low root mean square of error (RMSE) values of 0.147 for calibration and 0.371 for validation using 6 factors. The developed correlation between the NIR spectra and cellulose content is useful in precise at-line prediction of functional coat value and can be used for monitoring the Wurster coating process. PMID- 27995465 TI - Microwave-Assisted Development of Orally Disintegrating Tablets by Direct Compression. AB - Orally disintegrating tablets (ODTs) are challenged by the need for simple technology to ensure good mechanical strength coupled with rapid disintegration. The objective of this work was to evaluate microwave-assisted development of ODTs based on simple direct compression tableting technology. Placebo ODTs comprising directly compressible mannitol and lactose as diluents, super disintegrants, and lubricants were prepared by direct compression followed by exposure to >97% relative humidity and then microwave irradiation for 5 min at 490 W. Placebo ODTs with hardness (>5 kg/cm2) and disintegration time (<60 s) were optimized. Palatable ODTs of Lamotrigine (LMG), which exhibited rapid dissolution of LMG, were then developed. The stability of LMG to microwave irradiation (MWI) was confirmed. Solubilization was achieved by complexation with beta-cyclodextrin (beta-CD). LMG ODTs with optimal hardness and disintegration time (DT) were optimized by a 23 factorial design using Design Expert software. Taste masking using sweeteners and flavors was confirmed using a potentiometric multisensor based electronic tongue, coupled with principal component analysis. Placebo ODTs with crospovidone as a superdisintegrant revealed a significant increase in hardness from ~3 to ~5 kg/cm2 and a decrease in disintegration time (<60 s) following microwave irradiation. LMG ODTs had hardness >5 kg/cm2, DT < 30s, and rapid dissolution of LMG, and good stability was optimized by DOE and the design space derived. While beta-CD complexation enabled rapid dissolution and moderate taste masking, palatability, which was achieved including flavors, was confirmed using an electronic tongue. A simple step of humidification enabled MWI facilitated development of ODTs by direct compression presenting a practical and scalable advancement in ODT technology. PMID- 27995466 TI - Preparation and Evaluation of Diosgenin Nanocrystals to Improve Oral Bioavailability. AB - Diosgenin (DSG), a well-known steroid sapogenin derived from Dioscorea nipponica Makino and Dioscorea zingiberensis Wright, has a variety of bioactivities. However, it shows low oral bioavailability due to poor aqueous solubility and strong hydrophobicity. The present study aimed to develop DSG nanocrystals to increase the dissolution and then improve the oral bioavailability and biopharmaceutical properties of DSG. DSG nanocrystals were prepared by the media milling method using a combination of pluronic F127 and sodium dodecyl sulfate as surface stabilizers. The physicochemical properties of the optimal DSG nanocrystals were characterized using their particle size distribution, morphology, differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy data, and solubility and dissolution test results. Pharmacokinetic studies of the DSG coarse suspension and its nanocrystals were performed in rats. The particle size and polydispersity index of DSG nanocrystals were 229.0 +/- 3.7 nm and 0.163 +/- 0.064, respectively. DSG retained its original crystalline state during the manufacturing process, and its chemical structure was not compromised by the nanonizing process. The dissolution rate of the freeze-dried DSG nanocrystals was significantly improved in comparison with the original DSG. The pharmacokinetic studies showed that the AUC0-72h and C max of DSG nanocrystals increased markedly (p < 0.01) in comparison with the DSG coarse suspension by about 2.55- and 2.01-fold, respectively. The use of optimized nanocrystals is a good and efficient strategy for oral administration of DSG due to the increased dissolution rate and oral bioavailability of DSG nanocrystals. PMID- 27995467 TI - A case of gastrojejunocolic fistula with steatohepatitis. AB - A man in his 30s, who had undergone retrocolic Billroth II reconstruction for perforated duodenal ulcer, presented with watery diarrhea for 2 years and suspected fatty liver. He was referred to our hospital for management of chronic diarrhea, weight loss, hepatopathy and hypoalbuminemia. Initial upper and lower gastrointestinal endoscopies were negative. Since a small bowel lesion was suspected, peroral single-balloon enteroscopy was performed, which identified feces-like residue near the Billroth II anastomotic site and a connection to the colon separate from the afferent and efferent loops. Transanal single-balloon enteroscopy identified a fistula between the gastrojejunal anastomosis and transverse colon, with the scope reaching the stomach transanally. Barium enema confirmed flow of contrast medium from the transverse colon through the fistula to the anastomotic site, allowing the diagnosis of gastrojejunocolic fistula. Liver biopsy showed relatively severe steatohepatitis (Brunt's classification: stage 2-3, grade 3). Resection of the anastomotic site and partial transverse colectomy were performed to remove the fistula, followed by Roux-en-Y reconstruction. Postoperatively, watery diarrhea resolved and the stools became normal. Hepatopathy and hypoproteinemia improved. One year later, liver biopsy showed marked improvement of steatosis. This case demonstrated marked improvement of both diarrhea/nutritional status and steatohepatitis after treatment of gastrojejunocolic fistula, suggesting that the fistula caused non-alcoholic steatohepatitis. PMID- 27995468 TI - Alpha-fetoprotein-producing esophageal adenocarcinoma: a mimicker of hepatocellular carcinoma. AB - Alpha-fetoprotein (AFP)-producing esophageal adenocarcinoma (EAC) is a rare occurrence. Elevation of serum AFP is commonly associated with hepatocellular carcinoma and yolk sac tumors, but rarely with esophageal carcinoma. Here, we report a rare case of AFP-producing EAC. A 51-year-old man presented with two weeks of acid reflux and a 35-lb weight loss. Laboratory data were notable for transaminitis and AFP was 2524 ng/mL. Computed tomography of the abdomen revealed abnormal thickening of the esophagus and multiple metastatic masses throughout the liver. Biopsy of one of the masses revealed adenocarcinoma of gastrointestinal origin. Subsequent upper endoscopy revealed an esophageal mass with biopsy notable for ulcerated dysplastic glandular mucosa with likely underlying malignancy. The patient underwent palliative esophageal stent placement but died two months later. Elevated AFP levels are an unusual occurrence in EAC. Prognosis is poor given its advanced presenting stage and high metastatic potential. Most cases are unsuccessfully treated with surgery and chemotherapy. Serial measurement of serum AFP may be useful for monitoring clinical status and treatment response. Clinicians should consider AFP-producing EAC in their differential diagnosis in the work-up of a liver mass in the setting of elevated AFP or liver function impairment, especially in the absence of chronic liver disease. PMID- 27995469 TI - A case of liver hemangioma with markedly reduced tumor size after metformin treatment: a case report. AB - A 52-year-old man with a 9-year history of hepatic hemangioma was treated with the anti-diabetic drug metformin, resulting in complete remission of the tumor. In 2006, a hemangioma with diameter of 20 * 25 mm was detected incidentally in the liver. The results of imaging studies including ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) were all compatible with that of hepatic hemangioma. The patient consequently underwent imaging annually from 2006 to 2015. The tumor size increased slightly, to 30 * 35 mm in 2012; however, the general tumor characteristics in imaging were not changed. Beginning May 2012, metformin (750 mg/day) was administered because of an increase in blood sugar and hemoglobin A1c levels. After the start of metformin treatment, the tumor size on US gradually decreased. Finally, in October 2015, the tumor was no longer detected. Dynamic CT study also demonstrated markedly reduced tumor size, with a decrease of 2-3 mm in diameter. These results indicate that metformin treatment strongly suppressed cell proliferation in liver hemangioma. The anti angiogenic effect of metformin was indicated as a possible cause of the reduction in tumor size. PMID- 27995470 TI - A quick glance at selected topics in this issue. AB - "A quick glance at selected topics in this issue" aims to highlight few randomly selected articles and provide a quick review to the readers. PMID- 27995471 TI - Percutaneous closure of a left atrial appendage with relevant suture dehiscence. AB - Atrial fibrillation is a widespread disease and highly relevant as it carries an extended risk for ischaemic stroke. Surgical closure of the left atrial appendage is routinely performed during open heart surgery in patients with atrial fibrillation with the aim of thromboembolic protection. In this report we present a successful percutaneous closure of a left atrial appendage, which showed clinically relevant suture dehiscence several years after surgical closure. PMID- 27995482 TI - Comparison of long-term outcomes of endoscopic submucosal dissection and surgery for esophagogastric junction adenocarcinoma. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has become accepted as the standard treatment for early gastric cancer. However, comparative outcomes of ESD and surgery have not been evaluated for adenocarcinoma in the esophagogastric junction (EGJ). We investigated the long-term outcomes of ESD compared with those of surgery for adenocarcinoma in the EGJ. METHODS: Patients who underwent ESD or surgery for Siewert type II adenocarcinoma between 2005 and 2010 and who met the absolute and expanded criteria for endoscopic resection were eligible. Clinical features and treatment outcomes were retrospectively reviewed using medical records. RESULTS: Of the 79 patients included, 40 underwent ESD and 39 underwent surgery. During the median follow-up period of 60.9 months (range, 13.1-125.4 months), the 5-year overall survival rates were 93.9% and 97.3% for the ESD and surgery groups, respectively (p = 0.376). There were no gastric cancer-related deaths in either group. Adverse events occurred in 11 patients (13.9%) overall, and the incidence of treatment-related adverse events was similar between the two groups (10.0% vs. 17.9%, p = 0.308). CONCLUSIONS: ESD may be an effective alternative to surgery for the treatment of early gastric cancer in the EGJ based on the comparable long-term outcomes. PMID- 27995484 TI - Metal Hypersensitivity Reactions to Orthopedic Implants. AB - Total hip and knee replacement surgery using metal alloy devices is common. Type IV allergic reactions to these implants occur, though infrequently. While uncommon, peri-implant metal allergic reactions may cause significant morbidity for the affected individual-including aseptic loosening, pseudotumor formation and frank device failure. It is challenging to predict who will have these reactions, even in those with established pre-implant metal allergy. At this time, the scientific literature clearly supports few conclusions. Despite this, we believe several conclusions can be made: routine pre-implant testing in asymptomatic individuals is not indicated; listen to patient's concerns about metal allergy if the concern arises; patch testing is probably the best pre- and post-implant screening test; post-implantation testing is controversial and even positive LTT or patch test does not definitively diagnose morbidity from a metal allergy; and complete recovery following revision placement of an immunologically inert device is diagnostic. More research is needed to scientifically approach this issue. PMID- 27995483 TI - Assessing tumor vascularization as a potential biomarker of imatinib resistance in gastrointestinal stromal tumors by dynamic contrast-enhanced magnetic resonance imaging. AB - BACKGROUND: Most metastatic gastrointestinal stromal tumors (GISTs) develop resistance to the first-line imatinib treatment. Recently, increased vessel density and angiogenic markers were reported in GISTs with a poor prognosis, suggesting that angiogenesis is implicated in GIST tumor progression and resistance. The purpose of this study was to investigate the relationship between tumor vasculature and imatinib resistance in different GIST mouse models using a noninvasive magnetic resonance imaging (MRI) functional approach. METHODS: Immunodeficient mice (n = 8 for each cell line) were grafted with imatinib sensitive (GIST882 and GIST-T1) and imatinib-resistant (GIST430) human cell lines. Dynamic contrast-enhanced MRI (DCE-MRI) was performed on GIST xenografts to quantify tumor vessel permeability (K trans) and vascular volume fraction (v p). Microvessel density (MVD), permeability (mean dextran density, MDD), and angiogenic markers were evaluated by immunofluorescence and western blot assays. RESULTS: Dynamic contrast-enhanced magnetic resonance imaging showed significantly increased vessel density (P < 0.0001) and permeability (P = 0.0002) in imatinib-resistant tumors compared to imatinib-sensitive ones. Strong positive correlations were observed between MRI estimates, K trans and v p, and their related ex vivo values, MVD (r = 0.78 for K trans and r = 0.82 for v p) and MDD (r = 0.77 for K trans and r = 0.94 for v p). In addition, higher expression of vascular endothelial growth factor receptors (VEGFR2 and VEFGR3) was seen in GIST430. CONCLUSIONS: Dynamic contrast-enhanced magnetic resonance imaging highlighted marked differences in tumor vasculature and microenvironment properties between imatinib-resistant and imatinib-sensitive GISTs, as also confirmed by ex vivo assays. These results provide new insights into the role that DCE-MRI could play in GIST characterization and response to GIST treatment. Validation studies are needed to confirm these findings. PMID- 27995485 TI - Efficacy and Safety of 5-Fluorouracil 0.5%/Salicylic Acid 10% in the Field Directed Treatment of Actinic Keratosis: A Phase III, Randomized, Double-Blind, Vehicle-Controlled Trial. AB - INTRODUCTION: Due to the high prevalence of actinic keratosis (AK) and potential for lesions to become cancerous, clinical guidelines recommend that all are treated. The objective of this study was to evaluate the efficacy and safety of 5 fluorouracil (5-FU) 0.5%/salicylic acid 10% as field-directed treatment of AK lesions. METHODS: This multicenter, double-blind, vehicle-controlled study (NCT02289768) randomized adults, with a 25 cm2 area of skin on their face, bald scalp, or forehead covering 4-10 clinically confirmed AK lesions (grade I/II), 2:1 to treatment or vehicle applied topically once daily for 12 weeks. The primary endpoint was the proportion of patients with complete clinical clearance (CCC) of lesions in the treatment field 8 weeks after the end of treatment. Secondary endpoints included partial clearance (PC; >=75% reduction) of lesions. Safety outcomes were assessed. RESULTS: Of 166 patients randomized, 111 received 5-FU 0.5%/salicylic acid 10% and 55 received vehicle. At 8 weeks after the end of treatment, CCC was significantly higher with 5-FU 0.5%/salicylic acid 10% than with vehicle [49.5% vs. 18.2%, respectively; odds ratio (OR) 3.9 (95% CI) 1.7, 8.7; P = 0.0006]. Significantly more patients achieved PC of lesions with treatment than with vehicle [69.5% vs. 34.6%, respectively; OR 4.9 (95% CI 2.3, 10.5); P < 0.0001]. Treatment-emergent adverse events, predominantly related to application- and administration-site reactions, were more common with 5-FU 0.5%/salicylic acid 10% than with vehicle (99.1% vs. 83.6%). CONCLUSIONS: Compared with vehicle, field-directed treatment of AK lesions with 5-FU 0.5%/salicylic acid 10% was effective in terms of CCC. Safety outcomes were consistent with the known and predictable safety profile. TRIAL REGISTRATION: NCT02289768. FUNDING: Almirall S.A. PMID- 27995487 TI - The potential roles of dopamine in malignant glioma. AB - Despite the numerous promising discoveries in contemporary cancer research and the emerging innovative cancer treatment strategies, the global burden of malignant glioma is expected to increase, partially due to its poor prognosis and human aging. Dopamine, a monoamine catecholamine neurotransmitter, is currently regarded as an important endogenous regulator of tumor growth. Dopamine may be an important treatment for brain tumors and could impact the pathogenesis of glioma by regulating tumor angiogenesis and vasculogenesis. Additionally, dopamine might exert an anti-glioma, cytotoxic effect by modulating apoptosis and autophagy. Dopamine and its receptors are also known to influence the immune system, as it is related to the pathogenesis of glioma. Dopamine may also increase the efficacy of anti-cancer drugs. Here, we review the potential roles of dopamine in malignant glioma and further identify the previously unknown function of dopamine as a potent regulator in the pathogenesis of glioma. Currently, the precise mechanisms regarding the protective effect of dopamine on glioma are poorly understood. However, our experimental results strongly emphasize the importance of this topic in future investigations. PMID- 27995486 TI - Clostridium difficile infection: Updates in management. AB - Clostridium difficile was first identified in 1978 as a diarrhea-causing bacterium in humans. In the last three decades, C. difficile infection (CDI) has reached an epidemic state, both in health care and community settings worldwide. There has been substantial progress in the field of CDI, including identification of novel risk factors, presence of CDI in individuals not considered at risk previously, and treatment options including new drugs, monoclonal antibodies, and fecal microbiota transplantation. This review discusses epidemiology, novel and traditional risk factors, and updates in management for CDI. PMID- 27995488 TI - Impact of somatic severity on long-term mortality in anorexia nervosa. AB - PURPOSE: Anorexia nervosa (AN) is a severe pathology on account of the high levels of associated morbidity and mortality. This study aimed to assess whether time in somatic intensive care unit, justified by a patient's somatic condition in the course of hospital care, has any relationship with patient outcome in terms of mortality in the long term. METHODS: 195 patients were hospitalised for AN between April 1996 and May 2002, 97 were re-assessed 9 years later on average. RESULTS: Out of 195 patients hospitalised for AN between April 1996 and May 2002, 29 had required transfer to intensive care. Mortality at 9 years was 20 times higher in the group having been transferred to intensive care, irrespective of the duration of follow-up. CONCLUSION: The clinical seriousness of the somatic condition during hospitalisation for AN is a risk factor for excess mortality in the medium term. PMID- 27995489 TI - The comorbidity of personality disorders in eating disorders: a meta-analysis. AB - PURPOSE: The present meta-analysis summarized the proportion of comorbid personality disorders (PDs) in patients with anorexia (AN) and bulimia nervosa (BN), respectively, and examined possible moderating variables. METHODS: A search of the databases PsychINFO, Embase, and Medline for the period 1980-2016 identified 87 studies from 18 different countries. RESULTS: The mean proportion of PDs among patients with any type of eating disorder (ED) was .52 compared to .09 in healthy controls. There were no statistically significant differences between AN (.49) and BN (.54) in proportions of any PD or PD clusters except for obsessive-compulsive PD (.23 vs .12 in AN and BN, respectively). CONCLUSIONS: Both ED diagnoses had a similar comorbidity profile with a high prevalence of borderline and avoidant PDs. Moderator analyses conducted for any ED and any PD yielded significant differences for diagnostic systems with respect to EDs, method for assessing PD as well as patient weight and age. PMID- 27995490 TI - Hydrogel tissue expanders for stomatology. Part I. Methacrylate-based polymers. AB - In order to create a soft tissue surplus, implantable volume expanders are often utilized in dental surgery. Implanted tissue expanders should gradually increase their volume, exerting a constant pressure on the surrounding tissue for weeks. Current tissue expanders are based predominantly on externally inflatable balloons or on osmotically active tissue expanders that use soft hydrogels wrapped in perforated plastic coatings, which limit fluid entry and swelling. We have designed and examined tissue expanders based on the controlled rate expansive hydrogels synthesized from copolymers of selected methacrylates and N vinylpyrrolidone, cross-linked with a combination of non-degradable (glycol dimethacrylates) and hydrolytically degradable (N,O-dimethacryloylhydroxylamine) cross-linkers. These copolymers have close-to-linear volume expansion rates (up to 6-9 times their original volume) and exert an increasing swelling pressure in vitro. The anesthetic benzocaine has been incorporated into the hydrogels, and kinetic release experiments have shown that most of the drug (90%) was released within 48 h. Our proposed hydrogel expanders are homogeneous and have suitable mechanical properties, thus simplifying the surgical manipulations required. Further studies will be needed to completely evaluate their biocompatibility and tissue response to the implants. PMID- 27995491 TI - Preparation and characterization of laser-melted Mg-Sn-Zn alloys for biomedical application. AB - The rapid degradation rate of Magnesium (Mg) alloy limits its biomedical application even though it possesses outstanding biological performance and biomechanical compatibility. In this study, a combined method of laser rapid melting and alloying Zinc (Zn) was proposed to decrease the degradation rate of Mg-Sn alloy. The microstructure, degradation behaviors and mechanical properties of the laser-melted Mg-5Sn-xZn (x = 0, 2, 4, 6 and 8 wt.%) alloys were investigated. The results indicated that the grain size of the alloys decreased with increasing Zn content, due to the increased number of nucleation particles formed in the process of solidification. Moreover, the laser-melted Mg-Sn alloys possessed finer grains compared with traditional as-cast and as-rolled Mg-Sn alloys. The degradation rate of the alloys decreased with increasing Zn content (0-4 wt.%), which was ascribed to the grain refinement and the formation of Zn(OH)2 protective layer. However, the degradation rate increased as the Zn content further increased (4-8 wt.%), which was caused by the galvanic corrosion between the Mg matrix and the generated Mg7Zn3 phase. Besides, Zn also increased the hardness of the alloys owing to the grain refinement strengthening and solid solution strengthening. PMID- 27995492 TI - Synthesis and characterization of PLGA/collagen composite scaffolds as skin substitute produced by electrospinning through two different approaches. AB - Skin damage can occur for many reasons, including burns and injuries, which in extreme cases can even lead to death. Different methods such as electrospinning are used to produce scaffolds used in skin tissue engineering. Natural and synthetic polymers were used in this method. It was observed that the use of both natural and synthetic polymers gives better results for cell culturing rather than using of each material solely. In this study, scaffolds of poly(lactic-co glycolic acid) and collagen were prepared using coating and common solvent methods. The characteristics of samples were evaluated through scanning electron microscopy, porosimetry, mechanical testing, degradation behavior, and in vitro assays. The mechanical and biocompatibility test results of the scaffold prepared by coating method were better than the other one. However, the degradation rate of the common solvent was nearly five times more than coating sample that leads to cytotoxicity in contact with the skin cells. PMID- 27995493 TI - Expression of CD68 positive macrophages in the use of different barrier materials to prevent peritoneal adhesions-an animal study. AB - In preventing postoperative adhesion formation the optimal barrier material has still not been found. It is therefore imperative to assess the biocompatibility of potential barrier devices. Macrophages play a decisive role in the regulation of wound healing, tissue regeneration and foreign body reaction. Since the number of CD68-positive macrophages represents an important parameter within biomaterial testing, in the present study it was analysed whether a correlation exists between the total number of CD68-positive macrophages and the extent of fibrosis or inflammation in peritoneal adhesion prevention using biomaterials. After standardized peritoneal wounding, Wistar rats were treated with five adhesion barriers or remained untreated as a control. After 14 days, animals were sacrificed and the treated areas were evaluated histomorphologically and immunohistologically. A heterogeneous pattern of macrophage count in relation to fibrosis or inflammation was found. While some groups described a moderate macrophage infiltration without fibrosis, others showed similar numbers of macrophages, but accompanied by moderate fibrosis. Moreover, a minimal number of macrophages was associated with minimal fibrosis. Mild inflammation was seen both with minimal and moderate macrophage infiltration. Altogether, no correlation could be established between the tissue response and the count of CD68-positive macrophages. With a view to macrophage heterogeneity further studies are required to determine the different macrophage subpopulations and clarify the role of these in the tissue responses to barrier materials. PMID- 27995494 TI - Effects of (-)-Sesamin on Chronic Stress-Induced Anxiety Disorders in Mice. AB - This study investigated the effects of (-)-sesamin on chronic electric footshock (EF) stress-induced anxiety disorders in mice. Mice were treated with (-)-sesamin (25 and 50 mg/kg) orally once a day for 21 days prior to exposure to EF stress (0.6 mA, 1 s every 5 s, 3 min). Mice treated with (-)-sesamin (25 and 50 mg/kg) exhibited less severe decreases in the number of open arm entries and time spent on open arms in the elevated plus-maze test and the distance traveled in the open field test following exposure to chronic EF stress. Similarly, mice treated with (-)-sesamin exhibited significantly less severe decreases in brain levels of dopamine, norepinephrine, and serotonin following exposure to chronic EF stress. Increases in serum levels of corticosterone and expression of c-Fos were also less pronounced in mice treated with (-)-sesamin (25 and 50 mg/kg). These results suggest that (-)-sesamin may protect against the effects of chronic EF stress induced anxiety disorders by modulating dopamine, norepinephrine, and serotonin levels, c-Fos expression, and corticosterone levels. PMID- 27995495 TI - Downregulation of Oxytocin Receptor Decreases the Length of Projections Stimulated by Retinoic Acid in the U-87MG Cells. AB - Oxytocin is a neuropeptide widely expressed in the brain. Oxytocin plays a role in both proliferation and differentiation of various cells. Previous studies have suggested that oxytocin could affect the morphology of neuronal cells, therefore the objective of the present study was to test whether (1) oxytocin receptor stimulation/inhibition by specific ligands may change cell morphology and gene expression of selected cytoskeletal proteins (2) oxytocin receptor silencing/knockdown may decrease the length of cell projections (3) oxytocin receptor knockdown may affect human glioblastoma U-87MG cell survival. We confirmed the stimulatory effect of retinoic acid (10 uM) and oxytocin (1 uM) on projection growth. The combination of retinoic acid (10 uM) and oxytocin receptor antagonist (L-371,257, 1 uM) decreased projections length. Contrary to our assumptions, oxytocin receptor silencing did not prevent stimulation of length of projection by retinoic acid. Retinoic acid's and oxytocin's stimulation of projections length was significantly blunted in U-87MG cells with oxytocin receptor knockdown. Cell viability was significantly decreased in U-87MG cells with oxytocin receptor knockdown. Significantly higher levels of mRNA for cytoskeletal proteins drebrin and vimentin were observed in response to oxytocin incubation for 48 h. The data obtained in the present study clearly show that oxytocin induces formation and elongation of cell projections in astrocyte-like U 87MG cells. The effect is mediated by oxytocin receptors and it is accompanied by an increase in gene expression of drebrin and vimentin. Thus, oxytocin receptor signaling, particularly in the glial cells, may play an important role in native cell life, differentiation processes, and tumor progression, as well. PMID- 27995496 TI - Neuroprotective Effect of Erythropoietin on Phenylhydrazine-Induced Hemolytic Hyperbilirubinemia in Neonatal Rats. AB - Neonatal unconjugated hyperbilirubinemia might cause severe bilirubin neurotoxicity in especially hemolytic conditions. The study aimed to elucidate the potential neuroprotective effects of erythropoietin (EPO) in hemolysis induced hyperbilirubinemia. In newborn rats, hyperbilirubinemia secondary to hemolysis was induced by injecting with phenylhydrazine hydrochloride (PHZ) and rats were injected with either vehicle or EPO. At 54th hour of the PHZ injection, rats were decapitated. Serum levels of TNF-alpha, IL-1beta, IL-10, brain-derived neurotrophic factor (BDNF) and S100-B and brain malondialdehyde, glutathione levels and myeloperoxidase activities were measured. TUNEL staining and NF-kappaB expression were evaluated. As compared to control pups, in vehicle-treated PHZ group, TNF-alpha and IL-1beta levels, malondialdehyde level and myeloperoxidase activity were increased with concomitant decreases in IL-10 and glutathione. All EPO regimens reversed PHZ-induced alterations in IL-10, TNF-alpha, malondialdehyde and glutathione levels. Three-day-treatment abolished increases in myeloperoxidase activity and IL-1beta levels, while BDNF and S100-B were elevated. Increased TUNEL (+) cells and NF-kappaB expressions in the brain of PHZ group were reduced in the 3-day-treated group. EPO exerted anti-inflammatory effects on PHZ-induced neural damage in newborn rats, while the neuroprotection was more obvious when the treatments were repeated successively. The results suggest that EPO treatment may have a therapeutic potential in supporting neuroplasticity in the hyperbilirubinemic neonates. PMID- 27995498 TI - ACE inhibitors and the risk of fractures: a meta-analysis of observational studies. AB - A meta-analysis was conducted to evaluate the effect of treatment with angiotensin-converting enzyme inhibitors on the risk of fractures. All the included articleswere retrieved from MEDLINE, EMBASE and the Cochrane Database. Trial eligibility and methodological quality were assessed before data extraction. Relative risk (RR) with corresponding 95% confidence intervals (95% CI) were used to assess the effect. Six case-control studies with11,387,668 participants met the inclusion criteria and were included in the meta-analysis. A small but significant risk effect on fractures was shown in the overall analysis of angiotensin-converting enzyme inhibitor users compared with nonusers (Pooled RR 1.27; 95% CI 1.01-1.60), although a relatively high heterogeneity was found across studies. In the stratified analysis, therewas no statistically significant association in the subgroups of hip fracture (Pooled RR 1.14; 95% CI 0.73-1.76) and the study quality (Pooled RR 1.13; 95% CI 0.89-1.44), while the over 65-year old angiotensin-converting enzyme inhibitor users showed a stronger risk effect on fractures (Pooled RR 2.06; 95% CI 1.53-3.17). Moreover, age was found to be contributed a large part of the high heterogeneity across the included studies. This study demonstrated that the use of angiotensin-converting enzyme inhibitors might have a small but significant risk effect on fractures, especially for the over 65-year-old users. These results should be interpreted with caution as the relatively high heterogeneity across studies. Additional multiple observational studies and high quality data from randomized controlled trials are needed to confirm these findings. PMID- 27995497 TI - Induction of G1 Cell Cycle Arrest in Human Glioma Cells by Salinomycin Through Triggering ROS-Mediated DNA Damage In Vitro and In Vivo. AB - Chemotherapy has always been one of the most effective ways in combating human glioma. However, the high metastatic potential and resistance toward standard chemotherapy severely hindered the chemotherapy outcomes. Hence, searching effective chemotherapy drugs and clarifying its mechanism are of great significance. Salinomycin an antibiotic shows novel anticancer potential against several human tumors, including human glioma, but its mechanism against human glioma cells has not been fully elucidated. In the present study, we demonstrated that salinomycin treatment time- and dose-dependently inhibited U251 and U87 cells growth. Mechanically, salinomycin-induced cell growth inhibition against human glioma was mainly achieved by induction of G1-phase arrest via triggering reactive oxide species (ROS)-mediated DNA damage, as convinced by the activation of histone, p53, p21 and p27. Furthermore, inhibition of ROS accumulation effectively attenuated salinomycin-induced DNA damage and G1 cell cycle arrest, and eventually reversed salinomycin-induced cytotoxicity. Importantly, salinomycin treatment also significantly inhibited the U251 tumor xenograft growth in vivo through triggering DNA damage-mediated cell cycle arrest with involvement of inhibiting cell proliferation and angiogenesis. The results above validated the potential of salinomycin-based chemotherapy against human glioma. PMID- 27995499 TI - Idiopathic hypophosphatemic osteomalacia: recurrent pseudofracture of the proximal femur in a 65-year-old man. PMID- 27995500 TI - Adrenal crises: perspectives and research directions. AB - Adrenal crises are life-threatening complications of adrenal insufficiency. These events have an estimated incidence of between 5 and 10 adrenal crises/100 patient years and are responsible for some of the increased morbidity and excess mortality experienced by patients with adrenal insufficiency. Treatment involves urgent administration of IV/IM hydrocortisone and IV fluids. Patient education regarding preventive measures, such as increasing the dose of replacement therapy ("stress dosing") when sick, using parenteral hydrocortisone as necessary and accessing medical assistance promptly, is still considered the best approach to averting the onset of an adrenal crisis at times of physiological stress, most commonly an infection. However, recent evidence has demonstrated that patient education does not prevent many adrenal crisis events and the reasons for this are not fully understood. Furthermore, there is no widely accepted definition of an adrenal crisis. Without a validated adrenal crisis definition it is difficult to interpret variations in the incidence of adrenal crises and determine the effectiveness of preventive measures. This article aims to review the clinical aspects of adrenal crisis events, to explore the epidemiology, and to offer a definition of an adrenal crisis and to offer a perspective on future directions for research into adrenal crisis prevention. PMID- 27995501 TI - Investigation and Applications of In-Source Oxidation in Liquid Sampling Atmospheric Pressure Afterglow Microplasma Ionization (LS-APAG) Source. AB - A liquid sampling-atmospheric pressure afterglow microplasma ionization (LS-APAG) source is presented for the first time, which is embedded with both electrospray ionization (ESI) and atmospheric pressure afterglow microplasma ionization (APAG) techniques. This ion source is capable of analyzing compounds with diverse molecule weights and polarities. An unseparated mixture sample was detected as a proof-of-concept, giving complementary information (both polarities and non polarities) with the two ionization modes. It should also be noted that molecular mass can be quickly identified by ESI with clean and simple spectra, while the structure can be directly studied using APAG with in-source oxidation. The ionization/oxidation mechanism and applications of the LS-APAG source have been further explored in the analysis of nonpolar alkanes and unsaturated fatty acids/esters. A unique [M + O - 3H]+ was observed in the case of individual alkanes (C5-C19) and complex hydrocarbons mixture under optimized conditions. Moreover, branched alkanes generated significant in-source fragments, which could be further applied to the discrimination of isomeric alkanes. The technique also facilitates facile determination of double bond positions in unsaturated fatty acids/esters due to diagnostic fragments (the acid/ester-containing aldehyde and acid oxidation products) generated by on-line ozonolysis in APAG mode. Finally, some examples of in situ APAG analysis by gas sampling and surface sampling were given as well. Graphical Abstract ?. PMID- 27995502 TI - Clusters of Monoisotopic Elements for Calibration in (TOF) Mass Spectrometry. AB - Precise calibration in TOF MS requires suitable and reliable standards, which are not always available for high masses. We evaluated inorganic clusters of the monoisotopic elements gold and phosphorus (Au n+/Au n- and P n+/P n-) as an alternative to peptides or proteins for the external and internal calibration of mass spectra in various experimental and instrumental scenarios. Monoisotopic gold or phosphorus clusters can be easily generated in situ from suitable precursors by laser desorption/ionization (LDI) or matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Their use offers numerous advantages, including simplicity of preparation, biological inertness, and exact mass determination even at lower mass resolution. We used citrate-stabilized gold nanoparticles to generate gold calibration clusters, and red phosphorus powder to generate phosphorus clusters. Both elements can be added to samples to perform internal calibration up to mass-to-charge (m/z) 10-15,000 without significantly interfering with the analyte. We demonstrated the use of the gold and phosphorous clusters in the MS analysis of complex biological samples, including microbial standards and total extracts of mouse embryonic fibroblasts. We believe that clusters of monoisotopic elements could be used as generally applicable calibrants for complex biological samples. Graphical Abstract ?. PMID- 27995503 TI - Improvement of anti-nutritional effect resulting from beta-glucanase specific expression in the parotid gland of transgenic pigs. AB - beta-Glucan is the predominant anti-nutritional factors in monogastric animal feed. Although beta-glucanase supplementation in diet can help to eliminate the adverse effects, enzyme stability is substantially modified during the feed manufacturing process. To determine whether the expression of endogenous beta glucanase gene (GLU) in vivo can improve digestibility of dietary beta-glucan and absorption of nutrients, we successfully produced transgenic pigs via nuclear transfer which express the GLU from Paenibacillus polymyxa CP7 in the parotid gland. In three live transgenic founders, beta-glucanase activities in the saliva were 3.2, 0.07 and 0.03 U/mL, respectively, and interestingly the enzyme activities increased in the pigs from 178 days old to 789 days old. From the feed the amount of gross energy, crude protein and crude fat absorbed by the transgenic pigs was significantly higher than the non-transgenic pigs. Meanwhile the moisture content of the feces was significantly reduced in transgenic pigs compared with the non-transgenic pigs. Furthermore, in all positive G1 pigs, beta glucanase activity was detectable and the highest enzyme activity reached 3.5 U/mL in saliva. Also, crude protein digestion was significantly higher in G1 transgenic pigs than in control pigs. Taken together, our data showed that the transgenic beta-glucanase exerted its biological catalytic function in vivo in the saliva, and the improved performance of the transgenic pigs could be accurately passed on to the offspring, indicating a promising alternative approach to improving nutrient availability was established to improve utilization of livestock feed through transgenic animals. PMID- 27995504 TI - Phenylpropanoids are key players in the antioxidant defense to ozone of European ash, Fraxinus excelsior. AB - Physiological and biochemical responses to ozone (O3) (150 ppb, 8 h day-1, 35 consecutive days) of two Italian provenances (Piedmont and Tuscany) of Fraxinus excelsior L. were evaluated, with special attention to the role of phenylpropanoids. Our results indicate (i) the high O3 sensitivity especially of Piedmont provenance (in terms of visible injury, water status, and photosynthetic apparatus); (ii) although the intra-specific sensitivity to O3 between provenances differs (mainly due to different stomatal behaviors since only Tuscany plants partially avoided the uptake of the pollutant gas), both provenances showed detoxification and defense mechanisms; (iii) the crucial participation of phenylpropanoids, with a key role played by flavonoids (especially quercitrin): among this class of metabolites, isoquercitrin is the principal player in the lower O3 sensitivity of Tuscany plants, together with lignins; (iv) although coumarins (typical compounds of Fraxinus) were severely depressed by O3, isofraxidin was triggered suggesting a key role in reactive oxygen species (ROS) detoxification, as well as trans-chalcone. Furthermore, the different behavior of verbascoside and oleuropein among provenances lead us to speculate on their influence in the tentatively repair or acclimation shown by Piedmont plants at the end of the exposure. Finally, the intra-specific O3 sensitivity may be also due to de novo peaks triggered by O3 not yet associated to some chemicals. PMID- 27995505 TI - Cd inhibition and pH improvement via a nano-submicron mineral-based soil conditioner. AB - Cd contamination of rice in recent years has aroused a nationwide concern on the potential health risk to people in China. A significant increase of soil acidification in major Chinese croplands improves available Cd content by crops, and this further pushes a heavier burden on controlling Cd contamination. Therefore, it is urgent to find a workable and green way to control Cd contamination, i.e., decrease Cd content in rice, for people's health in China, as other countries in the world. From chemical and economic points, stabilizing/solidifying Cd may be a feasible way except in-situ ways such as removing it by the absorption of special plants and ex-situ ones such as removing the contaminated soil and treating it by special equipment. Then, it is very important how to choose a green solidifying agent. By simulating a rock weathering process, a nano-submicron mineral-based soil conditioner (NSC) was prepared through environmentally friendly hydrothermal reaction. The application of NSC not only decreased Cd content in rice, i.e., inhibited Cd absorption, and increased pH of the soil, but also improved the content of healthy nutrients such as organic matter, available Ca, available K, available P, and available Si in the soil. The mechanism why NSC showed such good performance was also discussed in this study. PMID- 27995506 TI - Production of methyl ester from two microalgae by two-step transesterification and direct transesterification. AB - The efficiency of oil extraction from Chlorella sp. and Scenedesmus sp. using different cell disruption and solvent system was investigated. The ultrasound cell disruption method showed the maximum oil extraction in both algae. Oil extraction with hexane resulted in maximum oil yield for both algae. The kinetic parameters were studied and the extraction followed the first-order kinetics. The activation energy and thermodynamic activation parameters were calculated for both microalgae and the results suggested that the extraction was endothermic, irreversible and spontaneous. The methyl ester yields by two-step transesterification and direct transesterification were 95 and 96% for Scenedesmus sp. and 89 and 92% for Chlorella sp. respectively. Both methods had similar net energy consumption suitable for industrial application. The methyl ester properties were analysed in comparison with those of American Society for Testing and Materials (ASTM) D6751 standards. PMID- 27995507 TI - Isolation and purification of antialgal compounds from the red alga Gracilaria lemaneiformis for activity against common harmful red tide microalgae. AB - Seven antialgal compounds (1-7) were successfully isolated from the red alga Gracilaria lemaneiformis through a combination of silica gel column chromatography and repeated preparative thin-layer chromatography. On the basis of the spectral data, the compounds were identified as gossonorol (1), 7,10-epoxy ar-bisabol-11-ol (2), glycerol monopalmitate (3), stigmasterol (4), 15 hydroxymethyl-2, 6, 10, 18, 22, 26, 30-heptamethyl-14-methylene-17-hentriacontene (5), 4-hydroxyphenethyl alcohol (6), and margaric acid (7). These seven compounds were isolated from G. lemaneiformis for the first time, while the compounds 4, 6, and 7 were isolated from marine macroalgae for the first time. Furthermore, a quantitative relationship between the inhibition of algal growth and the concentration of each antialgal compound was determined and important parameters for future practical HAB control, e.g., EC50-96h, were also obtained. The results indicated that isolated compounds 1-7 possess selective antialgal activity against the growth of several red tide microalgae (including Amphidinium carterae, Heterosigma akashiwo, Karenia mikimitoi, Phaeocystis globsa, Prorocentrum donghaiense, and Skeletonema costatum). Their antialgal activity against test red tide microalgae has not been previously reported. Furthermore, the EC50-96h of one or more of the compounds towards the tested red microalgae was not only significantly less than 10 MUg/mL but also was smaller than that of the characteristic antialgal agent potassium dichromate. The study demonstrates that compounds 1-7 possess significant application potential as antialgal agents against several harmful red tide microalgae. PMID- 27995508 TI - Spatio-temporal variability of fluorescent dissolved organic matter in the Rhone River delta and the Fos-Marseille marine area (NW Mediterranean Sea, France). AB - The spatio-temporal variability of fluorescent dissolved organic matter (FDOM) and its relationships with physical (temperature, salinity) and chemical (nutrients, chlorophyll a, dissolved and particulate organic carbon, nitrogen and phosphorus) parameters were investigated in inland waters of the Rhone River delta and the Fos-Marseille marine area (northwestern Mediterranean, France). Samples were taken approximately twice per month in two inland sites and three marine sites from February 2011 to January 2012. FDOM was analysed using fluorescence excitation-emission matrices (EEMs) coupled with parallel factor analysis (PARAFAC). In inland waters, humic-like components C1 (lambdaEx/lambdaEm: 250 (330)/394 nm) and C3 (lambdaEx/lambdaEm: 250 (350)/454 nm) dominated over one tryptophan-like component C2 (lambdaEx/lambdaEm: 230 (280)/340 nm), reflecting a background contribution of terrigenous material (~67% of total fluorescence intensity, in quinine sulphate unit (QSU)) throughout the year. In marine waters, protein-like material, with tyrosine-like C4 (lambdaEx/lambdaEm: <220 (275)/<300 nm) and tryptophan-like C5 (lambdaEx/lambdaEm: 230 (280)/342 nm), dominated (~71% of total fluorescence intensity, in QSU) over a single humic-like component C6 (lambdaEx/lambdaEm: 245 (300)/450 nm). In inland waters of the Rhone River delta, humic-like components C1 and C3 were more abundant in autumn-winter, very likely due to inputs of terrestrial organic matter from rainfalls, runoffs and wind-induced sediment resuspension. In marine sites, intrusions of the Berre Lagoon and Rhone River waters had a significant impact on the local biogeochemistry, leading to higher fluorescence intensities of humic- and protein-like components in spring-summer. On average, the fluorescence intensities of FDOM components C4, C5 and C6 increased by 33-81% under lower salinity. This work highlights the complex dynamics of FDOM in coastal waters and confirms the link between marine FDOM and the Rhone River freshwater intrusions on larger spatial and temporal scales in the Fos-Marseille marine area. PMID- 27995509 TI - The evaluation of growth and phytoextraction potential of Miscanthus x giganteus and Sida hermaphrodita on soil contaminated simultaneously with Cd, Cu, Ni, Pb, and Zn. AB - One of the cheapest, environmentally friendly methods for cleaning an environment polluted by heavy metals is phytoextraction. It builds on the uptake of pollutants from the soil by the plants, which are able to grow under conditions of high concentrations of toxic metals. The aim of this work was to assess the possibility of growing and phytoextraction potential of Miscanthus x giganteus and Sida hermaphrodita cultivated on two different soils contaminated with five heavy metals simultaneously: Cd, Cu, Ni, Pb, and Zn. A 3-year microplot experiment with two perennial energy crops, M. x giganteus and S. hermaphrodita, was conducted in the experimental station of IUNG-PIB in Poland (5 degrees 25' N, 21 degrees 58 'E), in the years of 2008-2010. Miscanthus was found more tolerant to concomitant soil contamination with heavy metals and produced almost double biomass than Sida in all three tested years, independent of soil type. Miscanthus collected greater amount of heavy metals (except for cadmium) in the biomass than Sida. Both energy crops absorb high levels of zinc, lower levels of lead, copper, and nickel, and absorbed cadmium at least, generally more metals were taken from the sandy soil, where plants also yielded better. Photosynthesis net rate of Miscanthus was on average 40% higher compared to Sida. Obtained results indicate that M. x giganteus and S. hermaphrodita can successfully be grown on moderately contaminated soil with heavy metals. PMID- 27995511 TI - Zika Virus Disease for the Neurointensivist. AB - Zika virus (ZIKV) is a mosquito-borne and sexually transmitted flavivirus currently spreading throughout the Pacific and Western Hemisphere. ZIKV infection is often either asymptomatic or causes a self-limiting illness with symptoms such as rash, fever, myalgia, arthralgia, headache, or conjunctivitis. Rarely, ZIKV infection has been associated with conditions such as severe thrombocytopenia, microcephaly and other developmental abnormalities, acute polyneuropathy/Guillain Barre syndrome, myelitis, meningoencephalitis, transient encephalopathy, provoked seizures, and various ophthalmologic conditions. Optimal treatment of these ZIKV associated conditions is currently unclear and is largely guided by expert opinion or case reports/series. Further studies are needed to establish best treatment practices. This review concentrates on caring by neurointensivists for the patient affected with Zika virus-expected to flare up again in the summer. PMID- 27995510 TI - Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage. AB - A growing body of clinical literature emphasizes the impact of cerebral edema in early brain injury following aneurysmal subarachnoid hemorrhage (aSAH). Aneurysm rupture itself initiates global cerebral edema in up to two thirds of cases. Although cerebral edema is not a universal feature of aSAH, it portends a poor clinical course, with quantitative analysis revealing a direct correlation between cerebral edema and poor outcome, including mortality and cognitive deficits. Mechanistically, global cerebral edema has been linked to global ischemia at the time of aneurysm rupture, dysfunction of autoregulation, blood breakdown products, neuroinflammation, and hyponatremia/endocrine abnormalities. At a molecular level, several culprits have been identified, including aquaporin 4, matrix metalloproteinase-9, SUR1-TRPM4 cation channels, vascular endothelial growth factor, bradykinin, and others. Here, we review these cellular and molecular mechanisms of global cerebral edema formation in aSAH. Given the importance of edema to the outcome of patients with aSAH and its status as a highly modifiable pathological process, a better understanding of cerebral edema in aSAH promises to hasten the development of medical therapies to improve outcomes in this frequently devastating disease. PMID- 27995512 TI - Clevidipine Versus Nicardipine for Acute Blood Pressure Reduction in a Neuroscience Intensive Care Population. AB - BACKGROUND: Currently, a lack of published literature exists regarding the use of clevidipine in the neuroscience population. This agent may be preferred in some patients because of its short half-life, potentially leading to more narrow blood pressure (BP) control in comparison with other agents. The purpose of this study was to compare the difference in time to achieve target systolic blood pressure (SBP) goals with clevidipine versus nicardipine infusions in patients admitted to the neuroscience intensive care unit (NSICU) at our institution. METHODS: A retrospective review was performed on patients receiving clevidipine or nicardipine infusions while in the NSICU between July 1, 2011 and June 30, 2014. Patients were matched based on indication for BP lowering and target SBP. Primary endpoints included time to target SBP and percentage of time within target BP range. RESULTS: Of the 57 patients included in the study, the median time to target SBP was 30 min in the clevidipine group and 46 min in the nicardipine group (p = 0.13). The percentage of time spent within target BP range was 79 versus 78% (p = 0.64). Clevidipine administration resulted in significantly less volume administered per patient versus nicardipine (530 vs. 1254 mL, p = 0.02). CONCLUSIONS: There were no statistically significant differences in acute BP management between the two agents; however, there was a trend toward shorter time to target and significantly less volume administered in the clevidipine group. Either agent should be considered a viable option in a NSICU population. PMID- 27995513 TI - Progesterone Provides the Pleiotropic Neuroprotective Effect on Traumatic Brain Injury Through the Nrf2/ARE Signaling Pathway. AB - OBJECTIVE: This study was to investigate the role of Nrf2/ARE signaling pathway in the pleiotropic neuroprotective effect of progesterone (PROG) on traumatic brain injury (TBI). METHODS: The Nrf2-knockout (Nrf2-/-) and C57 mice were respectively subjected to a lateral cortical impact injury caused by a free falling object and randomly divided into three groups: sham-operated, trauma, and trauma + PROG treatment group. The PROG treatment group was given PROG (32 mg/kg of body weight, intraperitoneal injection) immediately after injury. For all groups, a series of brain samples were obtained after trauma at 24 and 72 h, respectively. The cerebral edema was evaluated; the expression of IL-1beta, IL-6, and TNF-alpha was measured using ELISA array, and the apoptosis index was detected by TUNEL. Flow cytometry was used to detect the intracellular calcium concentration. RESULTS: The water content, the apoptosis index, the levels of inflammatory cytokine, and the intracellular calcium ion were significantly decreased with the PROG treatment in C57 mice with TBI model. However, the effect of PROG on TBI was not found in the Nrf2-/- mouse model of TBI. CONCLUSIONS: PROG reduced cerebral edema, apoptosis, inflammatory reaction, and intracellular calcium ion overload effects after TBI. These beneficial effects were not seen in the Nrf2-/- mouse model of TBI. The results from this study suggested that the Nrf2/ARE signal pathway may be involved in the pleiotropic neuroprotective effect of PROG on TBI. PMID- 27995514 TI - The need for scientific software engineering in the pharmaceutical industry. AB - Scientific software engineering is a distinct discipline from both computational chemistry project support and research informatics. A scientific software engineer not only has a deep understanding of the science of drug discovery but also the desire, skills and time to apply good software engineering practices. A good team of scientific software engineers can create a software foundation that is maintainable, validated and robust. If done correctly, this foundation enable the organization to investigate new and novel computational ideas with a very high level of efficiency. PMID- 27995515 TI - Computational chemistry at Janssen. AB - Computer-aided drug discovery activities at Janssen are carried out by scientists in the Computational Chemistry group of the Discovery Sciences organization. This perspective gives an overview of the organizational and operational structure, the science, internal and external collaborations, and the impact of the group on Drug Discovery at Janssen. PMID- 27995516 TI - Roux-en-Y Gastric Bypass Versus Sleeve Gastrectomy as Revisional Procedures after Adjustable Gastric Band: 5-Year Outcomes. AB - INTRODUCTION: In 2013, a worldwide bariatric surgery survey showed that laparoscopic adjustable gastric banding (LAGB) has been abandoned in favor of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-y gastric bypass (LRYGBP). PURPOSE: The aim of this study was to compare results of LRYGBP and LSG performed as a revisional procedure after LAGB. MATERIALS AND METHODS: All patients converted from LAGB to LSG or to LRYGBP from January 2007 to December 2011 were included in the study. Clinical data collected were age, gender, indications for revision, complications, body mass index (BMI), and body weight at revisional procedures. Weight loss was calculated at 1, 3, and 5 years after conversion. RESULTS: Fifty-one patients were included in this study, 43 females and 8 males. Twenty-four patients were converted to LRYGBP (LRYGBP group) and 27 to LSG (LSG group). Indication for conversion was weight loss failure in 34 (67%) patients and band complications in 17 (33%) patients. No significant difference in age, BMI, and body weight in the two groups was found at the time of revision. One patient converted to LRYGBP had an internal hernia; one patient initially scheduled for LSG was intraoperatively converted to LRYGBP due to staple line leak. No other major perioperative complication was observed. Follow-up rate at 5 years was 84.3% (43 patients out of 51 patients) Delta-BMI and percentage of excess weight loss (%EWL) were not significantly different in the two groups at 1, 3, and 5 years (p > 0.05). CONCLUSION: LRYGBP or LSG are feasible and effective surgical options after LAGB. Satisfactory weight loss was achieved after both procedures. PMID- 27995517 TI - Weight Loss Analysis According to Different Formulas after Sleeve Gastrectomy With or Without Antral Preservation: a Randomised Study. AB - BACKGROUND: The measurement of weight loss after bariatric surgery is under constant review in order to obtain the ideal standard for reporting weight loss. Several formulas have been proposed for this purpose. Our goal is to analyse weight loss after sleeve gastrectomy, with or without antrum preservation through different measurement formulas. METHODS: A prospective randomised study of 60 patients (30 patients with initial section at 3 cm from pylorus and 30 patients at 8 cm from the pylorus). We calculate the following variables at 3, 6 and 12 months from surgery: BMI, excess weight loss (%EWL), percentage of excess of BMI loss (%PEBMIL), expected BMI, % PEBMIL corrected by EBMI and percentage of total weight loss (%TWL). RESULTS: Weight evolution is similar in both groups, reaching a mean BMI of 33.62 +/- 4.35 and 34.48 +/- 4.23 kg/m2 respectively 12 months after surgery, closer to expected BMI. TWL follows the same trend, with losses exceeding 30%, although 3 cm group is above the tables of percentiles made with our series. Regarding PEBMIL, the 3 cm group reaches 67.8% classified as excellent, while 8 cm group reaches 62.8% classified as a good result. EWL situates the best results for 3 cm group. CONCLUSIONS: Group 3 cm obtained a lower percentage of suboptimal results using EWL. %TWL places the 3 cm group in higher percentile than 8 cm group. Through EBMI, both groups are equally effective. It is necessary to have standardised dynamic tables for each surgical technique, becoming essential elements to measure weight loss after surgery. PMID- 27995518 TI - Erratum to: Effects of Neighborhood Walkability on Physical Activity and Sedentary Behavior Long-Term Post-Bariatric Surgery. PMID- 27995519 TI - Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study. AB - INTRODUCTION AND AIMS: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several episodes of hepatic cyst infection, all during lanreotide treatment. We describe these events and provide a review of the literature. METHODS: The DIPAK-1 Study is an ongoing investigator driven, randomized, controlled, open-label multicenter trial. Patients (ADPKD, ages 18-60 years, estimated glomerular filtration rate 30-60 mL/min/1.73 m2) were randomized 1:1 to receive lanreotide 120 mg subcutaneously every 28 days or standard care during 120 weeks. Hepatic cyst infection was diagnosed by local physicians. RESULTS: We included 309 ADPKD patients of which seven (median age 53 years [interquartile range: 48-55], 71% female, median estimated glomerular filtration rate 42 mL/min/1.73 m2 [interquartile range: 41-58]) developed eight episodes of hepatic cyst infection during 342 patient-years of lanreotide use (0.23 cases per 10 patient-years). These events were limited to patients receiving lanreotide (p < 0.001 vs. standard care). Baseline characteristics were similar between subjects who did or did not develop a hepatic cyst infection during lanreotide use, except for a history of hepatic cyst infection (29 vs. 0.7%, p < 0.001). Previous studies with somatostatin analogs reported cyst infections, but did not identify a causal relationship. CONCLUSIONS: These data suggest an increased risk for hepatic cyst infection during use of somatostatin analogs, especially in ADPKD patients with a history of hepatic cyst infection. The main results are still awaited to fully appreciate the risk-benefit ratio. CLINICALTRIALS. GOV IDENTIFIER: NCT 01616927. PMID- 27995520 TI - Effect of Medications for Gastric Acid-Related Symptoms on Total Motile Sperm Count and Concentration: A Case-Control Study in Men of Subfertile Couples from the Netherlands. AB - INTRODUCTION: Gastric acid-related symptoms are highly prevalent in the general population (21-40%), and more than 11% of individuals use medication for the treatment of these symptoms. The uptake of micronutrients is dependent on the gastrointestinal potential of hydrogen (pH). OBJECTIVE: We hypothesized that medication affecting gastrointestinal pH reduces the availability of B vitamins, thereby deranging one-carbon metabolism and detrimentally affecting spermatogenesis. METHODS: This explorative nested case-control study in men of subfertile couples investigated associations between medication used for gastric acid-related symptoms and semen parameters. We included 40 men using medication for gastric acid-related symptoms and 843 men not using medication. Semen analyses were performed between 70 days before and 21 days after the visit. RESULTS: The use of medication was associated with a twofold higher risk of a low total motile sperm count [TMSC <1 * 106, odds ratio (OR) 2.090, p = 0.049] and negatively with sperm concentration (beta -0.320, p = 0.028). Red blood cell folate was positively associated with TMSC (beta 0.257, p = 0.026), sperm count (beta 1.679, p = 0.013) and ejaculate volume (beta 0.120, p = 0.023), and total homocysteine (tHcy) was negatively associated with sperm count (beta -0.077, p = 0.021). CONCLUSION: Here we delineate associations between the use of medication for gastric acid-related symptoms and poor semen quality in men of subfertile couples. The use of medication for gastric acid-related symptoms is associated with a twofold higher risk of a low TMSC and a decreased sperm concentration. Although these findings warrant further research on causality, the associations between folate, tHcy and semen quality emphasize the importance of preconception counselling in male subfertility. PMID- 27995522 TI - A Random Forest Approach for Counting Silicone Oil Droplets and Protein Particles in Antibody Formulations Using Flow Microscopy. AB - PURPOSE: To evaluate a random forest model that counts silicone oil droplets and non-silicone oil particles in protein formulations with large class imbalance. METHODS: In this work, we present a novel approach for automated image analysis of flow microscopy data based on random forest classification enabling rapid analysis of large data sets. The random forest approach overcomes many of the limitations of traditional classification schemes derived from simple filters or regression models. In particular, the approach does not require a priori selection of important morphology parameters. RESULTS: We analyzed silicone oil droplets and non-silicone oil particles observed in four model systems with protein concentrations of 20, 50 and 125 mg/mL. Filters based on random forests achieve higher classification accuracies when compared to regression based filters. Additionally, we showcase a procedure that allows for accurate counting of particles >=1 MUm. CONCLUSIONS: Our method is generally applicable for classification and counting of different classes of particles as long as class morphologies are differentially expressed. PMID- 27995521 TI - Efficacy and Safety of Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam Compared with Betamethasone 17-Valerate-Medicated Plaster for the Treatment of Psoriasis. AB - BACKGROUND: Fixed combination calcipotriol as hydrate (Cal) 50 ug/g plus betamethasone as dipropionate (BD) 0.5 mg/g aerosol foam is an alcohol-free treatment for psoriasis. Betamethasone 17-valerate 2.25 mg (BV)-medicated plasters are recommended for treating psoriasis plaques localized in difficult-to treat (DTT; elbow, knee, anterior face of the tibia) areas. OBJECTIVE: The aim of this study was to compare the efficacy of Cal/BD foam with BV-medicated plaster in patients with plaque psoriasis. METHODS: In this phase IIa, randomized, single center, investigator-blinded, 4-week study, both Cal/BD foam and BV-medicated plaster were applied once daily to six test sites (three for each treatment). The primary efficacy endpoint was absolute change in total clinical score (TCS; sum of erythema, scaling, and infiltration); secondary endpoints were changes from baseline in each individual clinical score, ultrasonographic changes (total skin and echo-poor band thickness), and safety; and post hoc analysis was change from baseline in TCS on DTT areas. RESULTS: Thirty-five patients were included. Least squares mean change in TCS from baseline was significantly greater for Cal/BD foam (-5.8) than BV-medicated plaster (-3.7; difference -2.2; 95% confidence interval -2.6 to -1.8; p < 0.001); greater changes for Cal/BD foam were observed from day 8 for each clinical sign. Absolute total skin and echo-poor band thickness change was significantly greater for Cal/BD foam than for BV-medicated plaster (both p < 0.001). Post hoc analyses showed that Cal/BD foam was significantly more effective than BV-medicated plaster on DTT areas after 4 weeks (p < 0.001), and both treatments were well tolerated. CONCLUSION: Cal/BD foam demonstrated superior efficacy versus BV-medicated plasters, including on DTT areas, in patients with plaque psoriasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT02518048. PMID- 27995524 TI - Intra- and Extracellular Biosynthesis and Characterization of Iron Nanoparticles from Prokaryotic Microorganisms with Anticoagulant Activity. AB - BACKGROUND: The use of microorganisms for the synthesis of nanoparticles (NPs) is relatively new in basic research and technology areas. PURPOSE: This work was conducted to optimized the biosynthesis of iron NPs intra- and extracellular by Escherichia coli or Pseudomonas aeruginosa and to evaluate their anticoagulant activity. STUDY DESIGN/METHODS: The structures and properties of the iron NPs were investigated by Ultraviolet-visible (UV-vis) spectroscopy, Zeta potential, Dynamic light scattering (DLS), Field emission scanning electron microscope (FESEM)/ Energy dispersive X-ray (EDX) and transmission electron microscopy (TEM). Anticoagulant activity was determined by conducting trials of Thrombin Time (TT), Activated Partial Prothrombin Time (APTT) and Prothrombin Time (PT). RESULTS: UV-vis spectrum of the aqueous medium containing iron NPs showed a peak at 275 nm. The forming of iron NPs was confirmed by FESEM/ EDX, and TEM. The morphology was spherical shapes mostly with low polydispersity and the average particle diameter was 23 +/- 1 nm. Iron NPs showed anticoagulant activity by the activation of extrinsic pathway. CONCLUSION: The eco-friendly process of biosynthesis of iron NPs employing prokaryotic microorganisms presents a good anticoagulant activity. This could be explored as promising candidates for a variety of biomedical and pharmaceutical applications. PMID- 27995523 TI - In Vitro Modulation of TrkB Receptor Signaling upon Sequential Delivery of Curcumin-DHA Loaded Carriers Towards Promoting Neuronal Survival. AB - PURPOSE: To in vitro investigate the capacity of carrier-free and lipid nanoparticle (NP)-encapsulated phytochemical compounds to prevent neuronal damage through neurotrophin potentiating activities. Delivery of molecules promoting the neurotrophin receptor signaling in the central nervous system (CNS) present ongoing interest for combination therapy development. METHODS: Super-resolution Stimulated Emission Depletion (STED) microscopy imaging and flow cytometry analysis were employed to study the expression of the neurotrophin TrkB receptor in a neuronal cell model, which is highly responsive to binding of brain-derived neurotrophic factor (BDNF). Dual drug-loaded nanoparticle formulations, prepared by self-assembly of lyotropic lipids and PEGylated amphiphile derivatives, were delivered to differentiated human neuroblastoma SH-SY5Y cells subjected to degenerative conditions. RESULTS: The expression of BDNF in the intra and extracellular domains was quantified by ELISA and flow cytometry after sequential treatment of the degenerating SH-SY5Y cells by neurotherapeutic formulations. Flow cytometry was also used to assess the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in the intracellular domain as a result of the treatment by nanoformulations. CONCLUSION: Over time, dual drug formulations (curcumin and docosahexaenoic acid (DHA)) promoted the neuronal survival and repair processes through enhanced BDNF secretion and increased phosphorylation of CREB as compared to untreated degenerating cells. PMID- 27995526 TI - Chitosan-Based Matrices Prepared by Gamma Irradiation for Tissue Regeneration: Structural Properties vs. Preparation Method. AB - In the last decade, new generations of biopolymer-based materials have attracted attention, aiming its application as scaffolds for tissue engineering. These engineered three-dimensional scaffolds are designed to improve or replace damaged, missing, or otherwise compromised tissues or organs. Despite the number of promising methods that can be used to generate 3D cell-instructive matrices, the innovative nature of the present work relies on the application of ionizing radiation technology to form and modify surfaces and matrices with advantage over more conventional technologies (room temperature reaction, absence of harmful initiators or solvents, high penetration through the bulk materials, etc.), and the possibility of preparation and sterilization in one single step. The current chapter summarizes the work done by the authors in the gamma radiation processing of biocompatible and biodegradable chitosan-based matrices for skin regeneration. Particular attention is given to the correlation between the different preparation conditions and the final polymeric matrices' properties. We therefore expect to demonstrate that instructive matrices produced and improved by radiation technology bring to the field of skin regenerative medicine a supplemental advantage over more conservative techniques. PMID- 27995525 TI - Pharmacokinetics and Biodistribution of GDC-0449 Loaded Micelles in Normal and Liver Fibrotic Mice. AB - PURPOSES: To determine the pharmacokinetic parameters and biodistribution of GDC 0449 loaded polymeric micelles after systemic administration into common bile duct ligation (CBDL) induced liver fibrotic mice. METHODS: We used GDC-0449 encapsulated methoxy poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl propylene carbonate)-graft-dodecanol (PEG-PCD) non-targeted polymeric micelles for GDC-0449 delivery to normal and liver fibrotic mice. To maximize GDC-0449 delivery to hepatic stellate cells (HSCs), mixed micelles formulations with 10, 20 and 30% w/w mannose-6-phosphate (M6P)-conjugated micelles were administered to normal and liver fibrotic mice for targeting M6P/IGF-IIR overexpressed on activated HSCs and biodistribution of GDC-0449 was determined at 30 and 120 min post systemic administration. RESULTS: GDC-0449 distributed to all major organs after systemic administration of drug loaded micelles, with higher accumulation in the liver of both normal and fibrotic mice. The plasma concentration versus time profiles suggest rapid clearance of GDC-0449 after systemic administration of drug loaded micelles in both normal and fibrotic mice, with similar plasma clearance (CL), area under the curve (AUCint) and volume of distribution at steady state (Vss). However, there is significant increase in GDC-0449 accumulation in the liver when M6P-conjugated mixed micelles were injected, with the highest GDC-0449 concentration in the liver with mixed micelles carrying 30% M6P-conjugated polymer. HSCs accounted for 14.19% of GDC-0449 accumulation for M6P-targeted micelles in fibrotic mice compared to 5.62% of non-targeted micelles in the liver uptake study. CONCLUSION: M6P-conjugated GDC-0449 loaded mixed micelles may be used as a potential drug delivery vehicle for treating liver fibrosis. PMID- 27995527 TI - Unilateral lower limb strength assessed using the Nintendo Wii Balance Board: a simple and reliable method. AB - BACKGROUND: Lower limb weakness is an important risk factor for fall accidents and a predictor for all-cause mortality among older adults. Unilateral whole lower limb strength may be a better measure of fall risk than the bilateral measure. In addition, a number of clinical conditions affect only one leg, and thus this type of assessment is relevant in clinical settings. AIM: To explore the intra-rater reproducibility of the Nintendo Wii Balance Board (WBB) to measure unilateral whole-lower limb strength and to compare the method with stationary isometric muscle apparatus (SID). METHOD: Intra-rater test-retest design with 1 week between sessions. Thirty community-dwelling older adults (69 +/- 4.2 years) were enrolled and examined for maximum lower limb strength in their dominant and non-dominant leg. Intraclass correlation coefficient (ICC) was calculated to describe relative reproducibility, while standard error of measurement (SEM), limits of agreement (LOA) and smallest real difference (SRD) were calculated to describe absolute reproducibility between test sessions. Concurrent validity with the SID was explored using the Pearson product-moment correlation coefficient (PCC). RESULTS: No systematic difference was observed between test sessions. ICC was 0.919-0.950 and SEM, LOA and SRD was 2.9-4.1 kg, 24.1-28.3 kg and 7.6-11.3 kg, respectively. Further, the PCC was 0.755 and 0.730 for the dominant limb and the non-dominant limb, respectively. CONCLUSION: A high relative and an acceptable absolute reproducibility was seen when using the Nintendo Wii Balance Board for testing unilateral lower limb strength in community-dwelling older adults. The WBB correlated strongly with the SID. PMID- 27995528 TI - Population Pharmacokinetic Approach Applied to Positron Emission Tomography: Computed Tomography for Tumor Tissue Identification in Patients with Glioma. AB - BACKGROUND AND AIMS: 18F-fluoro-ethyl-tyrosine (FET) is a radiopharmaceutical used in positron emission tomography (PET)-computed tomography in patients with glioma. We propose an original approach combining a radiotracer-pharmacokinetic exploration performed at the voxel level (three-dimensional pixel) and voxel classification to identify tumor tissue. Our methodology was validated using the standard FET-PET approach and magnetic resonance imaging (MRI) data acquired according to the current clinical practices. METHODS: FET-PET and MRI data were retrospectively analyzed in ten patients presenting with progressive high-grade glioma. For FET-PET exploration, radioactivity acquisition started 15 min after radiotracer injection, and was measured each 5 min during 40 min. The tissue segmentation relies on population pharmacokinetic modeling with dependent individuals (voxels). This model can be approximated by a linear mixed-effects model. The tumor volumes estimated by our approach were compared with those determined with the current clinical techniques, FET-PET standard approach (i.e., a cumulated value of FET signal is computed during a time interval) and MRI sequences (T1 and T2/fluid-attenuated inversion recovery [FLAIR]), used as references. The T1 sequence is useful to identify highly vascular tumor and necrotic tissues, while the T2/FLAIR sequence is useful to isolate infiltration and edema tissue located around the tumor. RESULTS: With our kinetic approach, the volumes of tumor tissue were larger than the tissues identified by the standard FET-PET and MRI T1, while they were smaller than those determined with MRI T2/FLAIR. CONCLUSION: Our results revealed the presence of suspected tumor voxels not identified by the standard PET approach. PMID- 27995529 TI - CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients. AB - OBJECTIVE: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients. METHODS: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc). RESULTS: CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median +/- standard deviation: 0.28 +/- 0.08, 0.18 +/- 0.06 and 0.22 +/- 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 +/- 0.66 vs. 1.45 +/ 0.74 [P < 0.05] and 1.36 +/- 0.98 MUg/mL [P < 0.05], respectively). CONCLUSIONS: CYP2C8 genotype significantly alters imatinib metabolism in patients through gain and loss-of-function mechanisms. PMID- 27995530 TI - A Phase I Pharmacokinetic Study of Trastuzumab Emtansine (T-DM1) in Patients with Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer and Normal or Reduced Hepatic Function. AB - OBJECTIVE: The aim of this study was to evaluate the pharmacokinetics (PK) of trastuzumab emtansine (T-DM1) and relevant analytes in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and hepatic impairment. METHODS: Patients were enrolled in three independent parallel cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment, and moderate hepatic impairment. Patients received T-DM1 3.6 mg/kg intravenously every 3 weeks. PK samples were collected during cycles 1 and 3, and the PK of T-DM1 and relevant analytes were characterized and compared across cohorts. RESULTS: Compared with patients with normal hepatic function (n = 10), T-DM1 clearance at cycle 1 was 1.8- and 4.0 fold faster in the mild (n = 10) and moderate (n = 8) cohorts, respectively. The trend of faster clearance was less apparent in cycle 3, with similar T-DM1 clearance across cohorts (mean +/- standard deviation 8.16 +/- 3.27 [n = 9], 9.74 +/- 3.62 [n = 7], and 8.99 and 10.2 [individual values, n = 2] mL/day/kg for the normal, mild, and moderate cohorts, respectively). T-DM1 clearance at cycle 1 correlated significantly with baseline albumin, aspartate aminotransferase, and HER2 extracellular domain concentrations (p < 0.05). Plasma concentrations of DM1 and DM1-containing catabolites were low and were comparable across cohorts. CONCLUSIONS: No increase in systemic DM1 concentration was observed in patients with mild or moderate hepatic impairment versus those with normal hepatic function. The faster T-DM1 clearance observed at cycle 1 in patients with hepatic impairment appeared to be transient. After repeated dosing (three cycles), T-DM1 exposure in patients with mild and moderate hepatic impairment was within the range seen in those with normal hepatic function. PMID- 27995531 TI - Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial. AB - INTRODUCTION: Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-beta) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. OBJECTIVES: We investigated whether a combination of estroprogestins and IFN-beta can improve cognition in women with MS. METHODS: Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-beta-1a (Rebif(r), Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-beta-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon(r), MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-beta-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial(r), Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao's Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined 'cognitive impairment'. RESULTS: At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). CONCLUSIONS: This study suggests that the combination of high-dose estroprogestins and IFN-beta may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised. Protocol Number NCT00151801, registered in ClinicalTrials.gov. PMID- 27995532 TI - Safety Profile Based on Concordance of Nonclinical Toxicity and Clinical Adverse Drug Reactions for Blood Cancer Drugs Approved in Japan. AB - BACKGROUND: In drug development, animal toxicology data are very important for the evaluation of clinical safety. We quantitatively assessed the safety profiles of blood cancer drugs approved in Japan from category I (high) to V (low). We examined the ratios of drug exposure in animals at the no observed adverse effect level to those in humans at the expected therapeutic dose. In addition, qualitative analysis of the relationship between toxicological findings and adverse drug reactions (ADRs) is one of the primary approaches for determining the risk-benefit profile of a pharmaceutical. This study thus aimed to evaluate the potential of nonclinical safety assessments for predicting ADRs in humans. METHODS: We examined toxicological findings at the lowest observed adverse effect level and ADRs in pivotal clinical studies. We calculated concordance rates as the ratio of the number of concordant ADRs to all ADRs. RESULTS: Twenty-seven drugs were eligible for analysis. Concordance rates ranged from 0 to 84.8%. No significant differences were observed in concordance rates between antibodies (median 14.3%) and small molecules (median 18.5%). There was a significant correlation between concordance rates and quantitative safety profiles (p = 0.047), suggesting that some drugs with low safety profiles (categories III, IV, or V) have high concordance rates. CONCLUSION: The results suggested that ADRs in clinical trials could be predicted based on toxicity data obtained in animal tests, especially for some drugs with a low quantitative safety profile. PMID- 27995533 TI - Advancing Leadership in Sport: Time to 'Actually' Take the Blinkers Off? PMID- 27995534 TI - Authors' Reply to Mills and Boardley: "Advancing Leadership in Sport: Time To Take Off the Blinkers?" PMID- 27995535 TI - Comment on: "A Review of the Acute Effects and Long-Term Adaptations of Single- and Multi-Joint Exercises During Resistance Training". PMID- 27995536 TI - Authors' Reply to Ribeiro et al.: "A Review of the Acute Effects and Long-Term Adaptations of Single- and Multi-Joint Exercises During Resistance Training". PMID- 27995537 TI - Self-Reported Outcome Measures of the Impact of Injury and Illness on Athlete Performance: A Systematic Review. AB - BACKGROUND: Self-reported outcome measures of athlete health, wellbeing and performance add information to that obtained from clinical measures. However valid, universally accepted outcome measures are required. OBJECTIVE: To determine which athlete-reported outcome measures of performance have been used to measure the impact of injury and illness on performance in sport and assess evidence to support their validity. METHODS: The authors searched Ovid MEDLINE, Ovid EMBASE, CINAHL Plus, SPORTDiscus with Full Text and Cochrane library to January 2016. Predefined inclusion and exclusion criteria were applied and papers included if an outcome measure of performance, assessed in relation to illness, injury or a related intervention, was reported by an elite, adult, able-bodied athlete. A checklist was used to assess eligible outcome measures for aspects of validity. Reporting of this study was guided by PRISMA guidelines for systematic reviews. RESULTS: Twenty athlete-reported outcome measures in 21 papers were identified. Of these 20, only four cited validation. Of these four, three reported evidence to support validity in elite athlete groups as defined by the predetermined checklist. Fifteen patient-reported outcome measures were identified, of which four demonstrated validity in young athletic populations. CONCLUSIONS: Most athlete-reported outcome measures of performance have been designed for individual studies with no reported assessment of validity. Despite some limitations, the Oslo Sports Trauma Centre overuse injury questionnaire demonstrates validity and potential utility to investigate the self-reported impact of pre-defined conditions on athletic performance across different sports. PMID- 27995539 TI - Use of Electronic Resources for Psychiatry Clerkship Learning: A Medical Student Survey. AB - OBJECTIVE: The primary aim of this study is to examine medical students' use patterns, preferences, and perceptions of electronic educational resources available for psychiatry clerkship learning. METHODS: Eligible participants included medical students who had completed the psychiatry clerkship during a 24 month period. An internet-based questionnaire was used to collect information regarding the outcomes described above. RESULTS: A total of 68 medical students responded to the survey. Most respondents reported high utilization of electronic resources on an array of devices for psychiatry clerkship learning and indicated a preference for electronic over print resources. The most commonly endorsed barriers to the use of electronic resources were that the source contained irrelevant and non-specific content, access was associated with a financial cost, and faculty guidance on recommended resources was insufficient. Respondents indicated a wish for more psychiatry-specific electronic learning resources. CONCLUSION: The authors' results suggest that a demand exists for high-quality electronic and portable learning tools that are relevant to medical student education in psychiatry. Psychiatry educators are usefully positioned to be involved in the development of such resources. PMID- 27995538 TI - Promoting Optimal Native Outcomes (PONO) by Understanding Women's Stress Experiences. AB - A growing body of evidence links stress with mental illness and chronic disease. Existing scales of women's stress fail to capture the daily stressors of low income, rural women. We explored the psychosocial stressors of local women residing in a rural Hawaii community with a large Native Hawaiian and Other Pacific Islander population. We recruited women, aged 18-35 years, at a community health center. We convened four focus groups to elicit information about women's stress. We identified key themes from the focus group data to generate questions that target concerns raised by participants. These were corroborated by additional focus groups. Thirty-six women participated in the study. Seven stressor themes emerged: intimate relationships-limited partner assistance, gender stereotype; family and home life-feeling like an outsider, lack of respect; childrearing-quality and affordable childcare, conflicting discipline styles; time for self-never-ending duties, being too tired to relax; neighborhood environment-safety concerns, not feeling part of the community; workplace workload and transportation obstacles; and finances-making ends meet and arguments about money. Women in this study articulated a broad range of daily stressors. Sociocultural factors leading to feeling like an outsider within their own family, intercultural marriage conflicts, and perceptions of community discrimination are not included in other published scales. Our focus group investigations thus provided critical knowledge for developing a community relevant scale. This is a prerequisite for developing and testing innovative intervention strategies designed to reduce stress in this population. We believe that reducing stress is necessary to mitigate the negative effects of stressors on physical and mental health among women in this rural community. PMID- 27995540 TI - High-mobility group box-1 and receptor for advanced glycation end products in preterm infants with brain injury. AB - BACKGROUND: High-mobility group box-1 (HMGB1) protein acts as an important pro infl ammatory mediator, which is capable of activating inflammation and tissue repair. HMGB1 can bind to its receptor such as advanced glycation end products (RAGE). RAGE, in turn, can promote the production of pro-inflammatory cytokines. Soluble RAGE (sRAGE) is a truncated form of the receptor comprising the extracellular domain of RAGE and can inhibit RAGE-activation. The objective of this study was to investigate whether HMGB1 and RAGE are involved in the development of brain injury in preterm infants. METHODS: In total, 108 infants <=34 weeks gestation at birth were divided into 3 groups according to cranial altrasound scan: mild brain damage (n=33), severe brain damage (n=8) and no brain damage (n=67). All the placentas were submitted for pathologic evaluation. Histological chorioamnionitis (HCA) was defined as neutrophil infi ltration of amniotic membranes, umbilical cord or chorionic plate. Expressions of HMGB1 and RAGE proteins were assessed by immunohistochemical analysis. The concentration of HMGB1 and sRAGE in umbilical cord blood were measured by enzyme-linked immunosorbent assay. RESULTS: The frequency of HCA was 30.12%. HCA was associated with elevated concentrations of HMGB1 and decreased sRAGE in umbilical cord blood. The severe brain injury group demonstrated higher cord blood HMGB1 concentrations (P<0.001) and lower sRAGE concentrations (P<0.001) than both other groups. Brain injury in the premature infants was linked to intense staining for HMGB1/RAGE, particularly in infl ammatory cells. CONCLUSIONS: Changes of cord blood HMGB1 and sRAGE of premature infants had direct relationship with the degree of infl ammation and severity of brain damage. Monitoring sRAGE and HMGB1 levels may be helpful to predict intrauterine infection and brain injury in premature infants. PMID- 27995541 TI - Aging affects the balance between goal-guided and habitual spatial attention. AB - Visual clutter imposes significant challenges to older adults in everyday tasks and often calls on selective processing of relevant information. Previous research has shown that both visual search habits and task goals influence older adults' allocation of spatial attention, but has not examined the relative impact of these two sources of attention when they compete. To examine how aging affects the balance between goal-driven and habitual attention, and to inform our understanding of different attentional subsystems, we tested young and older adults in an adapted visual search task involving a display laid flat on a desk. To induce habitual attention, unbeknownst to participants, the target was more often placed in one quadrant than in the others. All participants rapidly acquired habitual attention toward the high-probability quadrant. We then informed participants where the high-probability quadrant was and instructed them to search that screen location first-but pitted their habit-based, viewer centered search against this instruction by requiring participants to change their physical position relative to the desk. Both groups prioritized search in the instructed location, but this effect was stronger in young adults than in older adults. In contrast, age did not influence viewer-centered search habits: the two groups showed similar attentional preference for the visual field where the target was most often found before. Aging disrupted goal-guided but not habitual attention. Product, work, and home design for people of all ages--but especially for older individuals--should take into account the strong viewer centered nature of habitual attention. PMID- 27995542 TI - Bone scan index of the jaw: a new approach for evaluating early-stage anti resorptive agents-related osteonecrosis. AB - OBJECTIVE: A computer-aided diagnosis of bone scintigraphy using a bone scan index (BSI) has not been applied to a diagnosis of anti-resorptive agents-related osteonecrosis of the jaw (ARONJ). The aim of this study was to validate a diagnostic ability of BSI for early-stage ARONJ. METHODS: A total of 44 cancer patients treated with anti-resorptive drugs were evaluated retrospectively. All patients underwent bone scintigraphy and the tracer uptakes were analyzed by BSI. The software BONENAVI (FUJIFILM RI Pharma; EXINIbone, EXINI Diagnostics) could automatically detect abnormal intensities and calculate each regional BSI (rBSI). Among the rBSIs, the largest one in the jaw was manually selected and defined as maximum BSI of the jaw (BSIJmax). Uptake ratio (UR) between the maximum jaw count to-average forehead count was also calculated. Screening accuracy of ARONJ based on 2 parameters was compared. Receiver operating characteristic analysis and Fisher's exact test were performed. RESULTS: The BSIJmax was significantly higher in patients who developed ARONJ than in those who did not, 3 months before the diagnosis of stage 2 ARONJ (p < 0.0001 and p = 0.02 in the maxilla and mandible, respectively). Using the cutoff values of 0.09% in the maxilla and 0.06% in the mandible, BSIJmax for predicting stage 2 ARONJ showed sensitivity and specificity of 88 and 96%, respectively, in the maxilla and 64 and 89%, respectively, in the mandible at 3 months before the diagnosis. The BSIJmax >0.09% and BSIJmax >0.06% in the maxilla and mandible, respectively, were much more frequently observed in patients who subsequently developed stage 2 ARONJ 3 months after the bone scintigraphy than in those who did not (p < 0.0001 and odds ratio = 182 in the maxilla and p < 0.005 and odds ratio = 14 in the mandible). The UR showed comparable diagnostic ability. CONCLUSION: The BSIJ provided a new index for evaluating ARONJ. For predicting occurrence of ARONJ, the thresholds of BSIJmax = 0.09 and 0.06% in the maxilla and mandible, respectively, may be used in patients treated with anti-resorptive drugs, and a differential diagnosis including ARONJ is recommended. PMID- 27995543 TI - Salvage robotic prostatectomy following whole gland high-intensity focused ultrasound with a Sonablate 500 device: technical feasibility and safety. AB - High-intensity focused ultrasound (HIFU) has been used to treat localized prostate cancers. Similar to all forms of ablation, including radiation and cryoablation, there is a local persistence rate. Salvage robotic prostatectomy has been utilized but published series are multi-institutional, multi-surgeon, and do not segregate the different HIFU devices. The results are also grouped with other forms of ablation. This series describes the technical results of a single surgeon performing salvage robotic prostatectomy on only HIFU patients, and only after whole gland ablation on a Sonablate 500 device. A retrospective hospital and office chart review was performed of nine consecutive patients. Results of the surgical cases reveal an acceptable mean OR time of 130 min, mean estimated blood loss of 125 cc with no intraoperative or post-operative transfusions, and mean length of hospital stay of 2.4 days. Urinary catheters were removed after 7-10 days. All patients were pad free no longer than 35 days later. There was no surgical field or systemic complications in any patient. Intraoperative findings include diffuse fibrosis of the periprostatic tissues including the endopelvic and lateral pelvic fascia. The thermal changes make the surgery more tedious, particularly for nerve sparing. These cases support the stance that robotic salvage prostatectomy can be safely performed in this patient cohort with immediate surgical results similar to non-salvage cases. PMID- 27995544 TI - Transoral robotic resection of a combined laryngocele. AB - This case report describes the use of trans-oral robotic surgery (TORS) for the excision of a combined laryngocele. Mixed or combined laryngoceles extend from the supraglottic larynx through the thyrohyoid membrane into the neck. Surgical excision for these benign lesions often requires combined external (transcervical) and internal (transoral endoscopic) approaches which carry significant morbidity. We present the case of a 37-year-old male who was diagnosed with a large laryngopyocele and was subsequently managed with a transoral excision using the da Vinci Si surgical robot system. The procedure was without complications and the patient was discharged on the second post-operative day on a full liquid diet supplemented with a naso-gastric feeding tube. Postoperative stroboscopy performed 1 month later demonstrated a well-healed hemilarynx and a normal voice. The patient is on a regular diet and now over three years removed from surgery with no evidence of recurrence. We conclude that TORS is an effective tool in the management of benign laryngeal pathology including combined laryngoceles, resulting in reduced morbidity. PMID- 27995545 TI - Validation of the Australian diagnostic reference levels for paediatric multi detector computed tomography: a comparison of RANZCR QUDI data and subsequent NDRLS data from 2012 to 2015. AB - The national diagnostic reference level service (NDRLS), was launched in 2011, however no paediatric data were submitted during the first calendar year of operation. As such, Australian national diagnostic reference levels (DRLs), for paediatric multi detector computed tomography (MDCT), were established using data obtained from a Royal Australian and New Zealand College of Radiologists (RANZCR), Quality Use of Diagnostic Imaging (QUDI), study. Paediatric data were submitted to the NDRLS in 2012 through 2015. An analysis has been made of the NDRLS paediatric data using the same method as was used to analyse the QUDI data to establish the Australian national paediatric DRLs for MDCT. An analysis of the paediatric NDRLS data has also been made using the method used to calculate the Australian national adult DRLs for MDCT. A comparison between the QUDI data and subsequent NDRLS data shows the NDRLS data to be lower on average for the Head and AbdoPelvis protocol and similar for the chest protocol. Using an average of NDRLS data submitted between 2012 and 2015 implications for updated paediatric DRLS are considered. PMID- 27995547 TI - A Comparison of Deceptive and Non-Deceptive Placebo Analgesia: Efficacy and Ethical Consequences. AB - BACKGROUND: Research has demonstrated the efficacy of analgesic placebos. The manner in which they are usually delivered deceptively raises questions about their impact on recipients. However, there has been little empirical investigation into the potential harms of analgesic placebo. Moreover, the role of deception in determining the magnitude of analgesic placebo response remains poorly understood. PURPOSE: This study aimed to investigate the consequences of deceptive placebo analgesia in terms of ethical/psychological effects and efficacy. METHODS: Healthy adults (N = 75) were randomized to a control group, deceptive placebo manipulation, or non-deceptive placebo manipulation. All participants underwent repeated pain testing using a thermal stimulus. Placebo manipulation groups underwent placebo conditioning involving a cream that was described as being either analgesic or inert. State-specific negative mood and attitudes toward research and pain treatment were assessed before and after placebo conditioning. RESULTS: Deceptive and non-deceptive placebo manipulations yielded pain ratings that did not differ significantly from one another but did differ from those of the control group, which experienced a pain sensitization response across trials. Results thus indicated that both deceptive and non deceptive placebo manipulations prevented pain sensitization. Across groups, the participants reported improved depression, anxiety, frustration, and fear. The use of placebo did not negatively impact participants' attitudes and beliefs about research or pain treatments. The participants tended to rate several parameters related to research participation more positively after participating in our study. CONCLUSIONS: Our results indicate that the placebo manipulation groups experienced an anti-sensitization effect. The use of analgesic placebo did not result in any detrimental ethical or psychological effects. PMID- 27995546 TI - Preliminary experience of the concurrent use of radiosurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer. AB - This is preliminary study assessing the efficacy and safety of concurrent use of radiation therapy (RT) and T-DM1 for the treatment of brain metastases (BM) in patients with HER2-positive metastatic breast cancer (BC). We retrospectively studied 12 patients treated for BM at the Institut Curie in 2014-2015 with T-DM1 and concurrent (4) or sequential (8) radiosurgery with or without whole brain irradiation. The following variables were studied: local control, clinical and radiological response as well as early and late side effects. The mean age of the population was 38 years at the time of diagnosis of BC and 46 years at of BM. All patients were with good PS. The response rate of the concurrent treatment group was 75 % with 1 complete response, 1 partial response, one stable disease and 1 progression. Comparatively, the response rate in the sequential group was as follows: two complete responses, two partial responses, six cases of stable disease and two cases of local progression. No patient experienced interruption of irradiation because of side effects. About 50 % of patients were asymptomatic after treatment. Radiation necrosis was observed in 50 % of patients in the concurrent group and 28.6 % of patients in the sequential group with a similar rate of oedema in the two groups. We found that the combination of T-DM1 and radiosurgery was feasible but can increase the incidence of radiation necrosis. Larger prospective studies with longer follow-up are needed to more clearly evaluate this association. PMID- 27995548 TI - Gender Differences in Relations among Perceived Family Characteristics and Risky Health Behaviors in Urban Adolescents. AB - BACKGROUND: Research regarding the role of gender in relations between family characteristics and health risk behaviors has been limited. PURPOSE: This study aims to investigate gender differences in associations between family processes and risk-taking in adolescents. METHODS: Adolescents (N = 249; mean age = 14.5 years) starting their first year at an urban high school in the northeastern USA completed self-report measures that assessed family characteristics (i.e., parental monitoring, family social support, family conflict) and health behaviors (i.e., tobacco use, alcohol use, marijuana use, sex initiation) as part of a prospective, community-based study. Multivariate logistic regression models were used to investigate gender differences in associations between the family characteristics and health behaviors. RESULTS: Among males, higher levels of perceived parental monitoring were associated with lower odds of using tobacco and having ever engaged in sex. Among females, higher levels of perceived parental monitoring were associated with lower odds of marijuana use, alcohol use, and having ever engaged in sex. However, in contrast to males, among females (a) higher levels of perceived family social support were associated with lower odds of alcohol use and having ever engaged in sex and (b) higher levels of perceived family conflict were associated with higher odds of marijuana use and having ever engaged in sex. CONCLUSION: Family processes were more strongly related to health behaviors among adolescent females than adolescent males. Interventions that increase parental monitoring and family social support as well as decrease family conflict may help to protect against adolescent risk taking, especially for females. PMID- 27995551 TI - Shark recreational fisheries: Status, challenges, and research needs. AB - For centuries, the primary manner in which humans have interacted with sharks has been fishing. A combination of their slow-growing nature and high use-values have resulted in population declines for many species around the world, and to date the vast majority of fisheries-related work on sharks has focused on the commercial sector. Shark recreational fishing remains an overlooked area of research despite the fact that these practices are popular globally and could present challenges to their populations. Here we provide a topical overview of shark recreational fisheries, highlighting their history and current status. While recreational fishing can provide conservation benefits under certain circumstances, we focus our discourse on the relatively understudied, potentially detrimental impacts these activities may have on shark physiology, behavior, and fitness. We took this angle given the realized but potentially underestimated significance of recreational fishing for shark conservation management plans and stock assessments, in hopes of creating a dialogue around sustainability. We also present a series of broad and focused research questions and underpin areas of future research need to assist with the development of this emergent area of research. PMID- 27995552 TI - The Sociocultural Determination of Planned Behaviour. AB - Goochani, Ghanian, Baradaran & Azadi's (2017) study provides support for an extension of the theory of planned behaviour through inclusion of the variables of Trust and Perceived Benefits in the determination of attitudes. Considering the fact that the only other direct effect observed in this study is exercised by Subjective Norms, we argue that this new model provides support for the sociocultural determination of attitudes and, by extension, planned behaviour. We argue that understanding behavioural intentions for cultivating Bt rice requires an understanding of the social representations concerning this technology and its regulation in Iran. We further argue that due concern is required regarding the evolution of these representations over time. We conclude by proposing different avenues for future research. PMID- 27995549 TI - Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic cancer in Spain. AB - The management of patients with pancreatic cancer has advanced over the last few years. We convey a multidisciplinary group of experts in an attempt to stablish practical guidelines for the diagnoses, staging and management of these patients. This paper summarizes the main conclusions of the working group. Patients with suspected pancreatic ductal adenocarcinoma should be rapidly evaluated and referred to high-volume centers. Multidisciplinary supervision is critical for proper diagnoses, staging and to frame a treatment plan. Surgical resection together with chemotherapy offers the highest chance for cure in early stage disease. Patients with advanced disease should be classified in treatment groups to guide systemic treatment. New chemotherapeutic regimens have resulted in improved survival. Symptomatic management is critical in this disease. Enrollment in a clinical trial is, in general, recommended. PMID- 27995550 TI - Somatic Mutations in Prostate Cancer: Closer to Personalized Medicine. AB - The molecular cause of prostate cancer (PCa) is still unclear; however, its progression involves androgen, PI3K/Akt, and PTEN signaling, as cycle and apoptotic pathways. Alterations in oncogenes and tumor suppressor genes as PIK3CA, BRAF, KRAS and TP53 are not very common. Recently, somatic mutations have been discovered in relation to cancer progression mainly in genes such as PIK3CA; however, little data has been described in PCa. Nowadays genetic tools allow us to investigate multiple details about the biological heterogeneity of PCa, to better understand the mechanisms of disease progression and treatment resistance. Therefore, if the most relevant somatic mutations were included during screening, we could identify the best treatment for the right patient, bringing us closer to personalized medicine. The main objective of this article is to provide a review of the principal somatic mutations that appear to have a relevant role in hormonal cancers, like prostate cancer. PMID- 27995553 TI - Role of neutrophil to lymphocyte and monocyte to lymphocyte ratios in the diagnosis of bacterial infection in patients with fever. AB - PURPOSE: To study the role of the neutrophil:lymphocyte ratio (NLR) and monocyte:lymphocyte ratio (MLR) in discriminating between different patient groups hospitalized for fever due to infection and those without infection. METHODS: For 299 patients admitted to hospital for fever with unknown cause, a number of characteristics including NLR and MLR were recorded. These characteristics were used in a multiple multinomial regression analysis to estimate the probability of a final diagnostic group of bacterial, viral, clinically confirmed, or no infection. RESULTS: Both NLR and MLR significantly predicted final diagnostic group. Being highly correlated, however, both variables could not be retained in the same model. Both variables also interacted significantly with duration of fever. Generally, higher values of NLR and MLR indicated larger probabilities for bacterial infection and low probabilities for viral infection. Patients with septicemia had significantly higher NLR compared to patients with other bacterial infections with fever for less than one week. White blood cell counts, neutrophil counts, and C-reactive proteins did not differ significantly between septicemia and the other bacterial infection groups. CONCLUSIONS: NLR is a more useful diagnostic tool to identify patients with septicemia than other more commonly used diagnostic blood tests. NLR and MLR may be useful in the diagnosis of bacterial infection among patients hospitalized for fever. PMID- 27995554 TI - A Randomized Trial to Assess the Contribution of a Novel Thorax Support Vest (Corset) in Preventing Mechanical Complications of Median Sternotomy. AB - OBJECTIVES: Mechanical complications of median sternotomy may cause significant morbidity and mortality in cardiac surgical patients. This study was aimed at assessing the role of Posthorax support vest (Epple, Inc., Vienna, Austria) in the prevention of sternal complications and the improvement of anatomical healing in patients at high risk for mechanical sternal dehiscence after cardiac surgery by mean of median sternotomy. METHODS: A prospective, randomized, study was performed and 310 patients with predisposing factors for sternal dehiscence after sternotomy for cardiac surgery were included. The patients were divided into two groups: patients who received the Posthorax support vest after surgery, and patients who did not. Primary variables assessed included the incidence of mechanical sternal complications, the quality of sternal healing, the rate of re operation, the duration of hospitalization, rate and duration of hospital, re admission for sternal complications. Secondary variables assessed were the post operative pain, the number of requests for supplemental analgesia and the quality of life measured by means of the EQ-5D format. RESULTS: Patients using vest demonstrated a lower incidence of mechanical sternal complications, a better anatomical sternum healing, lower hospital stay, no re-operations for sternal dehiscence before discharge and lower re-admissions for mechanical sternal complication. In addition, patients using a vest reported a better quality of life with better freedom from limitations in mobility, self-care, and pain. CONCLUSIONS: Our findings demonstrate that the use of the Posthorax vest reduces post-sternotomy mechanical complications and improves the healing of the sternotomy, the clinical course, and the post-operative quality of life. PMID- 27995555 TI - CORR Insights(r): Perioperative Risk Adjustment for Total Shoulder Arthroplasty: Are Simple Clinically Driven Models Sufficient? PMID- 27995556 TI - CORR Insights(r): No Decrease in Knee Survivorship or Outcomes Scores for Patients With HIV Infection Who Undergo TKA. PMID- 27995557 TI - Cochrane in CORR (r): Intramedullary Nailing for Tibial Shaft Fractures in Adults (Review). PMID- 27995558 TI - Is There Benefit to Free Over Pedicled Vascularized Grafts in Augmenting Tibial Intercalary Allograft Constructs? AB - BACKGROUND: Intercalary reconstruction of tibial sarcomas with vascularized fibula autografts and massive bone allografts is reliable with predictable long term results. However, inadequate data exist comparing free and pedicled vascularized fibula autografts in combination with a massive bone allograft in patients undergoing intercalary tibia reconstructions. QUESTIONS/PURPOSES: Among patients undergoing large-segment intercalary allografting, we sought to compare supplemental free vascularized fibular autografts with supplemental pedicled vascularized fibular autografts, in terms of (1) oncologic results, (2) complications associated with surgery, (3) Musculoskeletal Tumor Society (MSTS) scores, and (4) surgical time. METHODS: Between 1994 and 2013, we treated 320 patients, younger than 40 years, with tibial sarcomas. Thirty-five patients (11%) underwent amputations. One hundred ninety-five patients (61%) were treated with intraarticular resection of the tibia, which constituted 104 tumor endoprostheses, 63 proximal tibia allograft prosthetic composites, 21 osteoarticular allografts, and seven arthrodeses with allografts. Ninety patients (28%) underwent joint-sparing intercalary reconstruction. Forty-one (13%) of these 90 patients were treated with allografts alone, two (1%) with vascularized fibula grafts, and 47 (15%) with intercalary allografts supplemented by autografts (free fibular autografts, 22 patients, 7%; pedicled fibular autografts, 25 patients, 8%). During the study period, we used free vascularized fibular autografts in association with massive bone allograft for a resection longer than 12 cm with a very small periarticular residual segment. The choice for using a pedicled fibula harvested in the ipsilateral leg initially was for patients having only diaphyseal resections and the indication was later extended to intraepiphyseal osteotomies with a small periarticular residual segment. The goals of this study are to present the long-term results in this group of patients and compare their results based on the type of vascularized fibula harvest. There were 33 male and 14 female patients with mean age of 14 +/- 6 years. The median followup was 84 months (range, 7-231 months). No patients were lost to followup before 1 year. Four patients died and were not available for followup after 18 months. The mean tibia resection length was 15 +/- 4 cm and mean length of the harvested vascularized fibula was 18 +/- 4 cm. RESULTS: Overall 5- and 10-year oncologic survival rates in this study were 87% +/- 5% and 83% +/- 6% respectively. With the numbers available, we observed no difference in survivorship free from death from disease between the study groups (85% +/- 8% [95% CI, 174-232 months] of the free vascularized group versus 82% +/- 8% [95% CI, 148-206 months] of the pedicled fibula graft group; p = 0.741). At last followup, 40 patients had no evidence of disease and seven had died of disease. Local recurrence was observed in two patients in the supplemental free vascularized fibula group and three patients in the supplemental pedicled vascularized fibula group, whereas metastases was observed in eight patients. With the numbers available, we observed no difference in the proportion of patients experiencing surgical complications between those treated with free vascularized fibula grafts and those treated with pedicled grafts (eight of 22 [36%] versus nine of 25 [36%] respectively; p = 0.605). With the numbers available, we observed no difference in mean MSTS scores between patients treated with free vascularized fibula grafts and those treated with pedicled grafts (24 +/- 9 versus 25 +/- 8; mean difference, 0.48; 95% CI, 0.54-4.6; p = 0.858). Mean surgical time was longer in the free vascularized fibula and massive bone allograft group at 9.4 +/- 1.7 hours compared with that of the pedicled vascularized fibula and massive bone allograft group at 5.7 +/- 1.3 hours (mean difference, 3.73 hours; 95% CI, 2.8-4.6 hours; p <= 0.001). CONCLUSIONS: Intercalary reconstruction of tibia sarcomas with massive bone allografts supplemented with vascularized fibula grafts provide predictable results. Complications occur as expected in a biologic reconstruction, but are salvageable, preserving the original construct. The pedicled fibula can be an alternative to a free contralateral fibula for intraepiphyseal resections. Comparative technical ease, shorter surgical time, avoidance of additional microvascular anastomosis, and avoidance of surgery on the contralateral leg are notable advantages of pedicled vascularized fibula over free fibula grafts to supplement allografts when indicated in intercalary tibia resections. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 27995559 TI - Value-based Healthcare: Person-centered Measurement: Focusing on the Three C's. PMID- 27995560 TI - Racial Disparities in Above-knee Amputations After TKA: A National Database Study. AB - BACKGROUND: Above-knee amputation (AKA) is a rare but devastating complication of TKA. Although racial disparities have been previously reported in the utilization of TKA, it is unclear whether disparities exist in the rates of AKA after TKA. QUESTIONS/PURPOSES: (1) Which gender-racial group has the highest rate of AKA from septic and aseptic complications of TKA? (2) Which age groups have higher rates of AKA from septic and aseptic complications of TKA? METHODS: Using National Inpatient Sample data from 2000 to 2011, AKAs resulting from complications of TKA were identified using a combination of International Classification of Diseases, 9th Revision procedure and diagnosis codes. Of the 341,954 AKAs identified, 9733 AKAs were the result of complications of TKA (septic complications = 8104, aseptic complications = 1629). Standardized AKA rates were calculated for different age and gender- racial groups by dividing the number of AKAs in each group with the corresponding number of TKAs. Standardized rate ratios were calculated after adjusting for demographics and comorbidities. RESULTS: After adjusting for age and comorbidities, black men had the highest rate of AKA after TKA (adjusted rate in black men = 578 AKAs per 100,000 TKAs, standardized rate ratio [SRR] = 4.32 [confidence interval {CI}, 3.87-4.82], p < 0.001). Black men also had the highest rate of AKA after septic complications of TKA (p < 0.001). The adjusted rates of AKA were higher in patients younger than 50 years (adjusted rate = 473, SRR = 3.14 [CI, 2.94-3.36], p < 0.001) and older than 80 years (adjusted rate = 297, SRR = 1.85 [CI, 1.76-1.95], p < 0.001). CONCLUSIONS: The rising demand for TKA has led to an increase in the number of AKAs performed for complications of TKA in the United States. Although we did not find an increase in the rate of AKA during the study period, certain populations, including black men and patients older than 80 years and younger than 50 years, had higher rates of AKA. Further studies are required to understand the reasons for these disparities and measures should be undertaken to eliminate these disparities. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 27995561 TI - CORR Insights(r): Periacetabular Osteotomy Provides Higher Survivorship Than Rim Trimming for Acetabular Retroversion. PMID- 27995562 TI - CORR Insights(r): Can We Estimate Short- and Intermediate-term Survival in Patients Undergoing Surgery for Metastatic Bone Disease? PMID- 27995563 TI - Feeling Hot and Cold: Thermal Sensation in Drosophila. AB - Sensing environmental temperature is crucial for animal life. The model animal, Drosophila melanogaster, can be investigated with a large number of genetic tools, which have greatly facilitated studies of the cellular and molecular mechanisms of thermal sensing. At the molecular level, a group of proteins, including Transient Receptor Potential channels and ionotropic receptors, have been characterized as potential thermal sensors in both larval and adult Drosophila. At the cellular and circuit levels, peripheral and central thermosensory neurons have been identified. More interestingly, thermal information has been found to be specifically encoded by specific central neurons. In this short review, we mainly survey the progress in understanding the molecular mechanisms of thermosensation and the neuronal mechanisms of thermal information processing in the brain of Drosophila. Other recent temperature related findings such as its impact on neurosecretion and thermotactic behavior in Drosophila are also introduced. PMID- 27995566 TI - Glial Activation, A Common Mechanism Underlying Spinal Synaptic Plasticity? PMID- 27995564 TI - A Review of the Functional and Anatomical Default Mode Network in Schizophrenia. AB - Schizophrenia is a severe mental disorder characterized by impaired perception, delusions, thought disorder, abnormal emotion regulation, altered motor function, and impaired drive. The default mode network (DMN), since it was first proposed in 2001, has become a central research theme in neuropsychiatric disorders, including schizophrenia. In this review, first we define the DMN and describe its functional activity, functional and anatomical connectivity, heritability, and inverse correlation with the task positive network. Second, we review empirical studies of the anatomical and functional DMN, and anti-correlation between DMN and the task positive network in schizophrenia. Finally, we review preliminary evidence about the relationship between antipsychotic medications and regulation of the DMN, review the role of DMN as a treatment biomarker for this disease, and consider the DMN effects of individualized therapies for schizophrenia. PMID- 27995565 TI - A New Perspective for Parkinson's Disease: Circadian Rhythm. AB - Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options. PMID- 27995567 TI - Associations Between PPP1R1B Gene Polymorphisms and Anxiety Levels in the Chinese Population. PMID- 27995568 TI - Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development. AB - Abnormal expression and dysfunction of methyl-CpG binding protein 2 (MeCP2) cause Rett syndrome (RTT). The diverse phosphorylation modifications modulate MeCP2 function in neural cells. Using western blot and immunohistochemistry, we examined the expression patterns of MeCP2 and three phospho-MeCP2s (pMeCP2s) in the developing rat brain. The expression of MeCP2 and phospho-S80 (pS80) MeCP2 increased while pS421 MeCP2 and pS292 MeCP2 decreased with brain maturation. In contrast to the nuclear localization of MeCP2 and pS80 MeCP2, pS421 MeCP2 and pS292 MeCP2 were mainly expressed in the cytoplasmic compartment. Apart from their distribution in neurons, they were also detected at a low level in astrocytes. Postnatally-initiated MeCP2 deficiency affected cerebellar neural cell development, as determined by the abnormal expression of GFAP, DCX, Tuj1, MAP-2, and calbindin-D28k. Together, these results demonstrate that MeCP2 and diverse pMeCP2s have distinct features of spatio-temporal expression in the rat brain, and that the precise levels of MeCP2 in the postnatal period are vital to cerebellar neural cell development. PMID- 27995569 TI - Fourier Transform Infrared Spectroscopic Imaging-Derived Collagen Content and Maturity Correlates with Stress in the Aortic Wall of Abdominal Aortic Aneurysm Patients. AB - Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta characterized by severe disruption of the structural integrity of the aortic wall and its major molecular constituents. From the early stages of disease, elastin in the aorta becomes highly degraded and is replaced by collagen. Questions persist as to the contribution of collagen content, quality and maturity to the potential for rupture. Here, using our recently developed Fourier transform infrared imaging spectroscopy (FT-IRIS) method, we quantified collagen content and maturity in the wall of AAA tissues in pairs of specimens with different wall stresses. CT scans of AAAs from 12 patients were used to create finite element models to estimate stress in different regions of tissue. Each patient underwent elective repair of the AAA, and two segments of the AAA tissues from anatomic regions more proximal or distal with different wall stresses were evaluated by histology and FT-IRIS after excision. For each patient, collagen content was generally greater in the tissue location with lower wall stress, which corresponded to the more distal anatomic regions. The wall stress/collagen ratio was greater in the higher stress region compared to the lower stress region (1.01 +/- 1.09 vs. 0.55 +/- 0.084, p = 0.02). The higher stress region also corresponded to the location with reduced intraluminal thrombus thickness. Further, collagen maturity tended to decrease with increased collagen content (p = 0.068, R = 0.38). Together, these results suggest that an increase in less mature collagen content in AAA patients does not effectively compensate for the loss of elastin in the aortic wall, and results in a reduced capability to endure wall stresses. PMID- 27995570 TI - Hydrodynamic Assessment of Aortic Valves Prepared from Porcine Small Intestinal Submucosa. AB - Infants and children born with severe cardiac valve lesions have no effective long term treatment options since currently available tissue or mechanical prosthetic valves have sizing limitations and no avenue to accommodate the growth of the pediatric patient. Tissue engineered heart valves (TEHVs) which could provide for growth, self-repair, infection resistance, and long-term replacement could be an ideal solution. Porcine small intestinal submucosa (PSIS) has recently emerged as a potentially attractive bioscaffold for TEHVs. PSIS may possess the ability to recruit endogenous cardiovascular cells, leading to phenotypically-matched replacement tissue when the scaffold has completely degraded. Our group has successfully implanted custom-made PSIS valves in 4 infants with critical valve defects in whom standard bioprosthetic or mechanical valves were not an option. Short term clinical follow-up has been promising. However, no hydrodynamic data has been reported to date on these valves. The purpose of this study was to assess the functional effectiveness of tri-leaflet PSIS bioscaffolds in the aortic position compared to standard tri-leaflet porcine bioprosthetic valves. Hydrodynamic evaluation of acute PSIS function was conducted using a left heart simulator in our laboratory. Our results demonstrated similar flow and pressure profiles (p > 0.05) between the PSIS valves and the control valves. However, forward flow energy losses were found to be significantly greater (p < 0.05) in the PSIS valves compared to the controls possibly as a result of stiffer material properties of PSIS relative to glutaraldehyde-fixed porcine valve tissue. Our findings suggest that optimization of valve dimensions and shape may be important in accelerating de novo valve tissue growth and avoidance of long-term complications associated with higher energy losses (e.g. left ventricular hypertrophy). Furthermore, long term animal and clinical studies will be needed in order to conclusively address somatic growth potential of PSIS valves. PMID- 27995571 TI - Evaluating the Feasibility of DNA Methylation Analyses Using Long-Term Archived Brain Formalin-Fixed Paraffin-Embedded Samples. AB - We here characterize the usability of archival formalin-fixed paraffin-embedded (FFPE) brain tissue as a resource for genetic and DNA methylation analyses with potential relevance for brain-manifested diseases. We analyzed FFPE samples from The Brain Collection, Aarhus University Hospital Risskov, Denmark (AUBC), constituting 9479 formalin-fixated brains making it one of the largest collections worldwide. DNA extracted from brain FFPE tissue blocks was interrogated for quality and usability in genetic and DNA methylation analyses by different molecular techniques. Overall, we found that DNA quality was inversely correlated with storage time and DNA quality was insufficient for Illumina methylation arrays; data from methylated DNA immunoprecipitation, clonal bisulfite sequencing, and pyrosequencing of BDNF and ST6GALNAC1 suggested that the original methylation pattern is indeed preserved. Proof-of-principle experiments predicting sex based on the methylation status of the X-inactivated SLC9A7 gene, or genotype differences of the Y and X chromosomes, showed consistency between predicted and actual sex for a subset of FFPE samples. In conclusion, even though DNA from FFPE samples is of low quality and technically challenging, it is likely that a subset of samples can provide reliable data given that the methodology used is designed for small DNA fragments. We propose that simple PCR-based quality control experiments at the genetic and DNA methylation level, carried out at the beginning of any given project, can be used to enrich for the best-performing FFPE samples. The apparent preservation of genetic and DNA methylation patterns in archival FFPE samples may bring along new perspectives for the identification of genetic and epigenetic changes associated with brain-manifested diseases. PMID- 27995572 TI - Intramuscular Delivery of scAAV9-hIGF1 Prolongs Survival in the hSOD1G93A ALS Mouse Model via Upregulation of D-Amino Acid Oxidase. AB - Self-complementary adeno-associated viral vector 9 (scAAV9) has been confirmed to be an efficient AAV serotype for gene transfer to the central nervous system (CNS). Neurotrophic factors have been considered to be therapeutic targets for amyotrophic lateral sclerosis (ALS). In the present study, we intramuscularly injected scAAV9 encoding human insulin-like growth factor 1 (hIGF1) into an hSOD1G93A ALS mouse model. We observed that scAAV9-hIGF1 significantly reduced the loss of motor neurons of the anterior horn in the lumbar spinal cord and delayed muscle atrophy in ALS mice. Importantly, IGF1 significantly delayed disease onset and prolonged the life span of ALS mice. In addition, scAAV9-hIGF1 protected motor neurons from apoptosis through upregulation of D-amino acid oxidase (DAO), which controls the level of D-serine. Moreover, to further verify these results, we used CRISPR-Cas9 system to target the central nervous system knockdown of IGF1. This experiment supported the continued investigation of neurotrophic factor gene therapies targeting the central nervous system as a potential treatment for ALS. PMID- 27995574 TI - Metabolite Variation in Lean and Obese Streptozotocin (STZ)-Induced Diabetic Rats via 1H NMR-Based Metabolomics Approach. AB - Diabetes mellitus (DM) is considered as a complex metabolic disease because it affects the metabolism of glucose and other metabolites. Although many diabetes studies have been conducted in animal models throughout the years, the pathogenesis of this disease, especially between lean diabetes (ND + STZ) and obese diabetes (OB + STZ), is still not fully understood. In this study, the urine from ND + STZ, OB + STZ, lean/control (ND), and OB + STZ rats were collected and compared by using 1H NMR metabolomics. The results from multivariate data analysis (MVDA) showed that the diabetic groups (ND + STZ and OB + STZ) have similarities and dissimilarities for a certain level of metabolites. Differences between ND + STZ and OB + STZ were particularly noticeable in the synthesis of ketone bodies, branched-chain amino acid (BCAA), and sensitivity towards the oral T2DM diabetes drug metformin. This finding suggests that the ND + STZ group was more similar to the T1DM model and OB + STZ to the T2DM model. In addition, we also managed to identify several pathways and metabolism aspects shared by obese (OB) and OB + STZ. The results from this study are useful in developing drug target-based research as they can increase understanding regarding the cause and effect of DM. PMID- 27995573 TI - Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons. AB - Abnormally hyperphosphorylated tau is the major protein constituent of neurofibrillary tangles (NFTs) in the brain of Alzheimer disease (AD) patients. Cell cycle reactivation is considered an important neuropathological feature of AD, and re-expression and activation of cell cycle regulators are known to occur in neurons containing NFTs. The aim of the present study was to investigate cell cycle reactivation during tau hyperphosphorylation in primary hippocampal neurons. We used forskolin, a specific activator of PKA, to induce tau hyperphosphorylation in cultured primary hippocampal neurons, and then measured levels of cyclin D1 and cyclin B1. We found that forskolin induced hyperphosphorylation of tau at Ser214, Ser396, and Ser202/Thr205 sites, attaining peak levels at 6, 12, and 12 h, respectively, while returning to normal levels at 24 h. Forskolin also induced a sustained cAMP elevation and PKA activation, which peaked at 6 h, in association with activation and overexpression of protein phosphatase-2A (PP-2A) at 24 h. The tau hyperphosphorylation was accompanied by increases in cyclin D1 and cyclin B1 levels; immunostaining showed overlapping distribution of hyperphosphorylated tau and cyclin D1 and cyclin B1 in primary hippocampal neurons. Forskolin induced hyperphosphorylation of tau and increased cyclin D1 and cyclin B1 protein levels in HEK293/tau441 cells, but not in the HEK293/vector cells, whereas the PKA inhibitor H89 inhibited the effects of forskolin on tau hyperphosphorylation and cyclin D1 and cyclin B1 protein levels. These findings suggest that forskolin induces tau hyperphosphorylation, which is itself necessary for the subsequent increases of cyclin D1 and cyclin B1 levels. PMID- 27995577 TI - Patient dumping, outlier payments, and optimal healthcare payment policy under asymmetric information. AB - We analyze a rationale for official authorization of patient dumping in the prospective payment policy framework. We show that when the insurer designs the healthcare payment policy to let hospitals dump high-cost patients, there is a trade-off between the disutility of dumped patients (changes in hospitals' rent extraction due to low-severity patients) and the shift in the level of cost reduction efforts for high-severity patients. We also clarify the welfare improving conditions by allowing hospitals to dump high-severity patients. Finally, we show that if the efficiency of the cost reduction efforts varies extensively and the healthcare payment cost is substantial, or if there are many private hospitals, the patient dumping policy can improve social welfare in a wider environment. PMID- 27995578 TI - Erratum to: From 2000 to 2016: Which Second-Line Treatment in Advanced Non-Small Cell Lung Cancer? PMID- 27995576 TI - Serine residues at positions 162 and 166 of the rabies virus phosphoprotein are critical for the induction of oxidative stress in rabies virus infection. AB - Our previous work in a mouse model of experimental rabies showed neuronal process (dendrites and axons) degeneration in association with severe clinical disease. Cultured adult rodent dorsal root ganglion (DRG) neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus (RABV) showed axonal swellings and reduced axonal growth with evidence of oxidative stress. We have shown that CVS infection alters a variety of mitochondrial parameters and increases mitochondrial complex I activity and reactive oxygen species (ROS) production. Expression of a peptide from amino acid 139-172 of the CVS phosphoprotein (P) increased complex I activity and ROS generation similar to expression of the entire P. Site-directed mutational analyses illustrated the importance of the 145-151 and 157-169 regions of P and that serine residues at 162 and 166 are important single amino acid sites. Two CVS recombinant viruses with serine to alanine mutations at positions 162 (A162r) and 166 (A166r) did not increase complex I activity or ROS generation and also did not induce axonal swellings or inhibit axonal growth in DRG neurons. RABV infection is a mitochondrial disorder initiated by interaction of the RABV P and complex I; S162 and S166 are critical sites in the P for this interaction. The resulting mitochondrial dysfunction produces oxidative stress in neurons causing acute degenerative changes affecting neuronal processes resulting in a severe and fatal clinical disease. This information will be important for the future development of novel therapies for rabies. PMID- 27995575 TI - Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV infected individuals in Rakai, Uganda. AB - In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/MUL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM CSF), TNF-alpha, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium binding protein B (S100B) and lower levels of amyloid beta42. Individuals with CD4 351-500 cells/MUL (N = 40) had significantly higher CSF levels of interleukin (IL)-1beta, amyloid beta42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-gamma were associated with increased odds of mild neurocognitive impairment or HIV associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND. PMID- 27995580 TI - Olaratumab: First Global Approval. AB - Olaratumab (LartruvoTM) is a fully human IgG1 monoclonal antibody targeted against the human platelet-derived growth factor (PDGF) receptor alpha (PDGFRalpha). It was developed by Eli Lilly and Co. (previously ImClone Systems) after PDGFRalpha was identified as a potential therapeutic target in a variety of cancers. Olaratumab acts by selectively binding PDGFRalpha, thereby blocking PDGF ligand binding and inhibiting PDGFRalpha activation and downstream signalling. In October 2016, olaratumab received its first global approval, in the USA, for use in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma. The approval was granted by the US FDA under its Accelerated Approval Program based on the results of the JGDG phase II trial (NCT01185964). In addition, the EMA granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program. An international, confirmatory phase III trial in patients with soft tissue sarcoma is ongoing (ANNOUNCE; NCT02451943). Olaratumab has also been investigated in phase II trials in several other cancers. This article summarizes the milestones in the development of olaratumab leading to this first approval, for use in combination with doxorubicin for the treatment of soft tissue sarcoma in adults. PMID- 27995579 TI - Recent Advances in the Medical Treatment of Recurrent or Metastatic Renal Cell Cancer. AB - Renal cell carcinoma (RCC) historically has had limited treatment options in the metastatic setting but in the last decade, a significant arsenal of new therapies has emerged. Specifically, targeted anti-angiogenic therapies through vascular endothelial growth factor (VEGF) inhibition and immunotherapy through PD-1 inhibition have become the foundation of metastatic RCC treatment increasing not only progression-free survival but also an improved overall survival with improved toxicity profiles compared with older therapies such as IL-2 and interferon. With the development of these newer medications, the optimal sequence and pairing of treatments is not yet well understood but important studies are ongoing as this information will allow for more effective and safe treatment of patients. PMID- 27995581 TI - Bone Health in Classic Galactosemia: Systematic Review and Meta-Analysis. AB - INTRODUCTION: Previous studies have reported an association between classic galactosemia (CG) and decreased bone mass. The primary objective of this systematic review with meta-analysis was to determine the extent of bone mineral density (BMD) Z-score reduction. Low BMD was defined as a Z-score <=-2 standard deviations (SD). The secondary objective was to evaluate other indicators of bone status through a descriptive analysis. METHODS: Systematic search strategies were developed by an experienced clinical librarian. Selection of relevant manuscripts, risk of bias assessment, and data extraction were performed independently by two investigators. RESULTS: Four studies were included in the meta-analysis. BMD Z-scores in children and adults with CG measured at the lumbar spine (LBMD; 4 studies; n = 112), total hip (HBMD; 2 studies; n = 58), and femoral neck (FBMD; 2 studies; n = 73) were assessed. Mean BMD Z-scores in the CG population were LBMD -0.70 (95% CI: -0.88, -0.52); HBMD -0.89 (95% CI: -1.14, 0.64); and FBMD -0.63 (95% CI -1.29, 0.02). Results from studies included in the descriptive analysis (n = 7) show that vitamin D levels were frequently in the low reference range, whereas serum calcium levels were within reference range. CONCLUSION: The mean BMD Z-score in the CG population is -0.7, which is lower than in the general population, though still within two SD of the reference mean of zero. This indicates that bone health is mildly affected in CG and that more patients, compared to the general population, are at risk for a BMD Z-score <=-2 SD. In conclusion, clinicians should ensure appropriate preventive and therapeutic measures for CG patients. PMID- 27995582 TI - Denudation of human amniotic membrane by a novel process and its characterisations for biomedical applications. AB - This study was aimed to investigate the suitability of a modified method to get decellularised human amniotic membrane (DHAM). The obtained membrane was subjected to physico-chemical and biological evaluations to validate its potential for biomedical applications. The human amniotic membrane was processed with detergent and alkali followed by enzymatic treatments. Hematoxylin and eosin (H&E) and Masson's trichrome staining of membrane were in accordance with conjectures: the decellularised membrane stained for extracellular matrix is rich in collagen. Scanning electron micrograph also showed the denudation in the processed membrane with the cellular impressions on the basement membrane. Physical characteristics namely the differential scanning calorimetric, tensile, shrinkage behaviour and the Fourier transform infrared spectra of decellularised membrane showed its stability and intact structure similar to the unprocessed membrane. In the visible range of light, the membrane was found to be transparent from 90 to 98 %. Proliferation rate of fibroblasts, keratinocytes, myoblasts and hepatocytes were significantly upregulated compared to the control. The cell morphologies were normal and differentiation of myoblasts into myotubes were more pronounced in decellularised membrane. Proliferation of corneal limbal cells on decellularised membrane showed 92-100 % confluency on day 21 and the migrated cells displayed a spindle shape and changing later to a more cuboidal appearance. PMID- 27995583 TI - Recent progress on magnetic nanoparticles for magnetic hyperthermia. AB - Recent advances in nanomaterials science contributed to develop new micro- and nano-devices as potential diagnostic and therapeutic tools in the field of oncology. The synthesis of superparamagnetic nanoparticles (SPMNPs) has been intensively studied, and the use of these particles in magnetic hyperthermia therapy has demonstrated successes in treatment of cancer. However, some physical limitations have been found to impact the heating efficiency required to kill cancer cells. Moreover, the bio-safety of NPs remains largely unexplored. The primary goals of this review are to summarize the recent progress in the development of magnetic nanoparticles (MNPs) for hyperthermia, and discuss the limitations and advances in the synthesis of these particles. Based on this knowledge, new perspectives on development of new biocompatible and biofunctional nanomaterials for magnetic hyperthermia are discussed. PMID- 27995584 TI - The effect of simulating body fluid on the structural properties of hydroxyapatite synthesized in the presence of citric acid. AB - In present work, the effect of citric acid (CA) addition in different amounts (0, 1, 5 and 10 ml) on the structure of hydroxyapatite (HAp) was investigated using X ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) spectroscopy techniques. The crystallite dimensions, lattice parameters, unit cell volume, crystallinity percentage and Ca/P molar ratio were found to be affected by the CA content. To investigate the influence of CA on the bioactive properties of the HAp samples and to determine the optimum amount of CA, in vitro soaking tests in simulated body fluid (SBF) were performed. Although the samples' morphology was found to be affected by neither the amount of CA nor the soaking time in SBF, the soaking results revealed that the maximum changes in the Ca/P ratio were found for the HAp samples prepared in the presence of the highest amounts of CA, which pointed out to the highest bioactivity of these samples. PMID- 27995585 TI - Physical and mechanical characterization of PLLA interference screws produced by two stage injection molding method. AB - The purpose of this study was to produce and evaluate different mechanical, physical and in vitro cell culture characteristics of poly(L-lactic) acid (PLLA) interference screws. This work will focus on evaluating the effect of two important parameters on operation of these screws, first the tunnel diameter which is one of the most important parameters during the operation and second the thermal behavior, the main effective characteristic in production process. In this work, PLLA screws were produced by a two-stage injection molding machine. For mechanical assessment of the produced screws, Polyurethane rigid foam was used as cancellous bone and polypropylene rope as synthetic graft to simulate bone and ligament in real situation. Different tunnel diameters including 7-10 mm were evaluated for fixation strength. When the tunnel diameter was changed from 10 to 9 mm, the pull-out force has increased to about 12 %, which is probably due to the aforementioned frictional forces, however, by reducing the tunnel diameter to 8 and 7 mm, the pull-out force reduced to 16 and 50 % for 8 and 7 mm tunnel diameter, respectively. The minimum and maximum pull-out force was obtained 160.57 and 506.86 N for 7 and 9 mm tunnel diameters, respectively. For physicochemical assay, Fourier transform infrared spectroscopy (FTIR), degradation test and differential scanning calorimetry (DSC) were carried out. The crystallinity (Xc) of samples were decreased considerably from 64.3 % before injection to 32.95 % after injection with two different crystallographic forms alpha' and alpha. probably due to the fast cooling rate at room temperature. In addition, MTT and cell attachment assays were utilized by MG63 osteoblast cell line, to evaluate the cytotoxicity of the produced screws. The results revealed no cytotoxicity effect. PMID- 27995586 TI - Characterization of Bombyx mori and Antheraea pernyi silk fibroins and their blends as potential biomaterials. AB - Fibroin proteins isolated from the cocoons of certain silk-producing insects have been widely investigated as biomaterials for tissue engineering applications. In this study, fibroins were isolated from cocoons of domesticated Bombyx mori (BM) and wild Antheraea pernyi (AP) silkworms following a degumming process. The object of this study was to obtain an assessment on certain properties of these fibroins in order that a concept might be had regarding the feasibility of using their blends as biomaterials. Membranes, 10-20 MUm thick, which are water insoluble, flexible and transparent, were prepared from pure fibroins and from their blends, and subjected to water vapor annealing in vacuum, with the aim of providing materials sufficiently strong for manipulation. The resulting materials were characterized by electrophoretic analysis and infrared spectrometry. The tensile properties of the membranes were measured and correlated with the results of infrared analysis. At low concentrations of any of the two fibroins, the mechanical characteristics of the membranes appeared to be adequate for surgical manipulation, as the modulus and strength surpassed those of BM silk fibroin alone. It was noticed that high concentrations of AP silk fibroin led to a significant reduction in the elasticity of membranes. PMID- 27995587 TI - Roll-designed 3D nanofibrous scaffold suitable for the regeneration of load bearing bone defects. AB - In this work, an innovative and easy method for the fabrication of 3D scaffold from 2D electrospun structures is introduced. For this aim, coral microparticles were fixed inside the nanofibrous PCL/Gelatin mat and the obtained structure was post assembled into a cylindrical design. Scaffold fabrication procedure is described in detail and morphological properties, physical and mechanical characteristics and in vitro assessments of the prepared scaffold are reported. Presences of coral microparticles in the structure led to the formation of empty spaces (3D pores) between nanofibrous layers which in turn prevent the compact accumulation of nanofibers. Post-assembly of the obtained nanofibrous coral loaded structures makes it possible to prepare a scaffold with any desired dimension (diameter and height). Existence of coral particles within the nanofibrous mats resulted in distant placement of layers toward each other in the assembling step, which in turn create vacancy in the structure for cellular migration and fluid and nutrients exchange of the scaffold with the surrounding environment. Cell morphology within the scaffolds is investigated and cytotoxicity and cytocompatibility of the structure is evaluated using Alamar blue assay. Enhancement in mineralization of the seeded cells within the prepared coral-loaded scaffolds is demonstrated by the use of SEM-EDX. Performed compression mechanical test revealed excellent modulus and stiffness values for the cylindrical samples which are comparable to those of natural bone tissue. PMID- 27995588 TI - Fabrication and characterization of biosilver nanoparticles loaded calcium pectinate nano-micro dual-porous antibacterial wound dressings. AB - Development of materials for medical applications using biologically derived materials by green approaches is emerging as an important focus in the present healthcare scenario. Herein the first time, we report the plant extract mediated ultra-rapid biosynthesis of silver nanoparticles using whole plant extracts of Biophytum sensitivum. Synthesized nanoparticles were immobilized in nano-micro dual-porous calcium pectinate scaffolds for wound dressing application. Pectinate wound dressings containing silver nanoparticles have shown excellent antibacterial property and exudate uptake capacity while being biocompatible to the human cells. PMID- 27995589 TI - Comparative of fibroblast and osteoblast cells adhesion on surface modified nanofibrous substrates based on polycaprolactone. AB - One of the determinant factors for successful bioengineering is to achieve appropriate nano-topography and three-dimensional substrate. In this research, polycaprolactone (PCL) nano-fibrous mat with different roughness modified with O2 plasma was fabricated via electrospinning. The purpose of this study was to evaluate the effect of plasma modification along with surface nano-topography of mats on the quality of human fibroblast (HDFs) and osteoblast cells (OSTs) substrate interaction. Surface properties were studied using scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle, Fourier transformation infrared spectroscopy. We evaluated mechanical properties of fabricated mats by tensile test. The viability and proliferation of HDFs and OSTs on the substrates were followed by 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide (MTT). Mineralization of the substrate was determined by alizarin red staining method and calcium content of OSTs was determined by calcium content kit. Cells morphology was studied by SEM analysis. The results revealed that the plasma-treated electrospun nano-fibrous substrate with higher roughness was an excellent designed substrate. A bioactive topography for stimulating proliferation of HDFs and OSTs is to accelerate the latter's differentiation time. Therefore, the PCL substrate with high density and major nano-topography were considered as a bio-functional and elegant bio-substrate for tissue regeneration applications. PMID- 27995590 TI - Behavioral Comparisons of Ingestion and Excretion by Selected Species of Pentatomids: Evidence of Feeding on Different Food Sources Supports Pest Status. AB - Laboratory studies were conducted on food ingestion and excretion by selected species of pentatomids on different food sources to support their pest status. We compared the frequency and time of feeding on vegetative (stem) and reproductive (seed) structures of soybean, Glycine max (L.) Merrill and of maize, Zea mays L. by Piezodorus guildinii (Westwood), Dichelops melacanthus (Dallas), and Edessa meditabunda (F.); in addition, the amount of excreta (feces) produced were compared for D. melacanthus feeding on seed of soybean and stem of maize seedling. The feeding behavior of E. meditabunda and P. guildinii on soybean, and of D. melacanthus on maize was recorded using the electropenetrography (EPG) technique. Excretion was estimated using water sensitive paper recording number and area of fecal drops. Results indicated that E. meditabunda on soybean stem repeated events of ingestion (both xylem and phloem sap) over four times per bug during the 8 h of recording for ca. 53 min per event. Dichelops melacanthus on maize seedling repeated each ingestion event over three times per bug for ca. 24 min per event. Piezodorus guildinii feeding on soybean stem repeated each ingestion 1.2 times per bug for ca. 40 min per event; on seed endosperm, it fed for a longer time, ca. 80 min per event, each event repeated only 0.5 times per bug. Number of excretory drops was higher (9.9 drops per bug) when D. melacanthus fed on maize seedling than on soybean seed (1.4 drops per bug). A larger amount of saliva/regurgitate liquid food was expelled when bugs fed on the former than on the later food. PMID- 27995592 TI - Clinical protein science developments for patient monitoring in hospital central laboratories. AB - Patient care relies heavily on standardized tests performed in hospital laboratories, typically including clinical chemistry, pathology and microbiology. With the introduction of personalized medicine tremendous efforts have been made to identify new biomarkers of disease with various omics technologies, often including mass spectrometry. In order to validate new biomarkers and perform clinical studies high quality biobank samples are of key importance. In this editorial different aspects of mass spectrometry in future personalized medicine are discussed. PMID- 27995593 TI - Exenatide Add-on to Continuous Subcutaneous Insulin Infusion Therapy Reduces Bolus Insulin Doses in Patients with Type 2 Diabetes: A Randomized, Controlled, Open-Label Trial. AB - INTRODUCTION: The objective of this study was to investigate the effect of adding exenatide to continuous subcutaneous insulin infusion (CSII) therapy on the precise insulin doses required by type 2 diabetic patients to maintain glycemic control. METHODS: This was a single-center, randomized, controlled, open-label trial. Uncontrolled T2D patients were recruited between March 2010 and November 2011 at Nanjing First Hospital, China. Subjects were randomly assigned (1:1) to either an exenatide add-on to CSII group or a CSII therapy only (i.e., control) group (n = 18, respectively) for 5 weeks. Patients were subjected to 3 days of continuous glucose monitoring (CGM) during the screening period and after therapy. The precise insulin doses, the times taken by the patients to achieve euglycemic control, and the mean amplitude of glycemic excursion (MAGE) at the endpoint were compared between the two groups. The primary endpoint was precise insulin dose differences between groups from baseline to the endpoint. RESULTS: A total of 36 subjects were admitted as inpatients. Patients in the exenatide add on therapy group needed less insulin titration time to achieve glycemic control (3.67 +/- 1.33 vs. 4.78 +/- 1.00 days, P = 0.028) and significantly lower bolus insulin doses than the control group at the endpoint (total bolus, 0.13 +/- 0.03 vs. 0.17 +/- 0.04 U/kg, P = 0.02, breakfast bolus, 0.05 +/- 0.01 vs. 0.06 +/- 0.01 U/kg, P = 0.01, lunch bolus, 0.04 +/- 0.01 vs. 0.06 +/- 0.01 U/kg, P = 0.01, dinner bolus, 0.04 +/- 0.01 vs. 0.05 +/- 0.01 U/kg, P = 0.01, respectively). Moreover, the CGM data showed that patients in the exenatide add-on therapy group exhibited a significant reduction in MAGE as compared to the control group (2.96 +/- 1.14 vs. 4.21 +/- 1.39 mmol/L, P = 0.012). CONCLUSION: Our data suggest that adding exenatide therapy to CSII therapy leads to an improvement in glycemic excursions and the use of smaller bolus insulin doses. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier, ChiCTR-PPR-15007045. PMID- 27995594 TI - Liraglutide Versus SGLT-2 Inhibitors in People with Type 2 Diabetes: A Network Meta-Analysis. AB - INTRODUCTION: For people with type 2 diabetes (T2DM) inadequately controlled with oral antidiabetic drugs (OADs), evidence from both randomized controlled trials (RCTs) and real-world studies has demonstrated that treatment intensification with liraglutide offers effective glycemic control, weight reduction, and a lower risk of hypoglycemia compared to treatment intensification with insulin or additional OADs. Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a new class of OADs that have also been shown to be effective in T2DM patients inadequately controlled with OADs. Currently there are no head-to-head RCTs comparing these to liraglutide. METHODS: We aimed to evaluate the relative efficacy, using network meta-analysis (NMA), of treatment intensification with liraglutide and SGLT-2 inhibitors people with T2DM who have been treated with metformin (alone or in combination with SU, DPP-4, and TZD). We performed a systematic literature review to identify relevant RCTs comparing liraglutide (1.2 and 1.8 mg), canagliflozin (100 and 300 mg), empagliflozin (10 and 25 mg), or dapagliflozin (5 and 10 mg) to placebo. To strengthen the indirect evidence base, we also included non-placebo RCTs where sitagliptin (100 mg) was the active comparator. Bayesian NMA was performed on the following outcomes to assess the relative efficacy and safety of interventions: reduction (change) in HbA1c, weight, and fasting plasma glucose (FPG) as well as proportion reaching target HbA1c (<7%), and risk of hypoglycemia. Doses for each intervention were considered separately. RESULTS: A total of 16 RCTs were identified. All trials were similar with respect to important baseline characteristics and study design. Both doses of liraglutide were generally statistically significantly superior to the SGLT-2s with respect to change from baseline in HbA1c and FPG as well as odds of reaching target HbA1c <7%. For weight, canagliflozin 300 mg was superior to liraglutide 1.2 mg, and SGLT-2s were generally associated with larger change from baseline in weight. For risk of major or minor hypoglycemia, no differences were found between treatments. CONCLUSIONS: Compared to SGLT-2 inhibitors, liraglutide offers improvement in HbA1c and FPG. Reductions in weight are likely comparable between liraglutide and SGLT-2s. Liraglutide did not differ from SGLT-2s in terms of risk of hypoglycemia. Given the lack of head-to-head evidence, this analysis provides valuable insight into the comparative outcomes of liraglutide versus SGLT-2 inhibitors. PMID- 27995595 TI - Fear of Self-Injecting and Self-Testing and the Related Risk Factors in Adolescents with Type 1 Diabetes: A Cross-Sectional Study. AB - INTRODUCTION: This study was conducted to investigate the fear of self-injecting and self-testing and its related risk factors among adolescents with type 1 diabetes mellitus (T1DM). METHODS: From December 2015 to April 2016, a cross sectional study was performed at the Diabetes Treatment Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia on 142 registered T1DM patients between 13 and 19 years of age. Selection of the respondents was done deliberately and carefully, and the suitable patients were given specific identification numbers. A trained interviewer administered the short Diabetes Fear of Injecting and Self-testing Questionnaire to each patient. It included two subscales estimating the fear of self-injection (FSI) and fear of self-testing (FST). Each patient's age, gender, weight, height, adjusted body mass index (BMI), duration of the diabetic condition, treatment modality, insulin dosage, and glycosylated hemoglobin (HbA1c) were recorded. RESULTS: The study found that the overall mean score of FSI was 2.44 +/- 0.96, whereas that of FST was 2.25 +/- 1.04. Adolescents above 16 years of age, treated with multiple daily insulin (MDI), on higher insulin doses, having poor glycemic control, and fewer finger pricks were observed to show significant risk factors for fear of self-injection of insulin, whereas in those patients having a long duration of T1DM, MDI treated, on higher insulin doses, with poor glycemic control, and fewer finger pricks showed significant risk factors for fear of self-testing of blood glucose. From the regression analysis it was evident that the variables of higher age, MDI treatment, and fewer finger pricks were independent risk factors for fear of self injection of the insulin, whereas a fewer number of finger pricks was an independent risk factor for fear of self-testing the blood glucose. CONCLUSION: Fear of self-injecting and fear of self-testing are common among adolescents with T1DM. Therefore, it is essential to ensure comprehensive multidisciplinary diabetes education to lower the risk factor of fear of injections. PMID- 27995596 TI - Development of biological tools to assess the role of TMPRSS4 and identification of novel tumor types with high expression of this prometastatic protein. AB - Metastatic spread is responsible for the majority of cancer deaths and identification of metastasis-related therapeutic targets is compulsory. TMPRSS4 is a pro-metastatic druggable transmembrane type II serine protease whose expression has been associated with the development of several cancer types and poor prognosis. To study the role and expression of this protease in cancer, we have developed molecular tools (active recombinant proteins and a polyclonal antibody) that can be used for diagnostic purposes and for testing anti-TMPRSS4 drugs. In addition, we have evaluated TMPRSS4 protein expression in several cancer tissue microarrays (TMAs). Full length and truncated TMPRSS4 recombinant proteins maintained the catalytic activity in two different expression systems (baculovirus and E. coli). Sensitivity of the rabbit polyclonal antisera against TMPRSS4 (ING-pAb) outperformed the antibody most commonly used in clinical settings. Analysis by immunohistochemistry in the different TMAs identified a subset of adenocarcinomas, squamous carcinomas, large cell carcinomas and carcinoids of the lung, which may define aggressive tumors. In conclusion, our biological tools will help the characterization of TMPRSS4 activity and protein expression, as well as the evaluation of anti-TMRSS4 drugs. Future studies should determine the clinical value of assessing TMPRSS4 levels in different types of lung cancer. PMID- 27995597 TI - Acute heart failure in patients admitted to the emergency department with acute myocardial infarction. AB - BACKGROUND: Acute heart failure (AHF), occurring as a complication of ongoing acute myocardial infarction (AMI), is a common predictor of worse clinical outcome. Much less is known about the unique subpopulation of patients who present these two life-threatening conditions in the emergency department (ED). AIM: The aim of the study was to establish the prevalence of coexistence of AHF with AMI in the ED, to identify clinical factors associated with the higher prevalence of AHF at very early onset of AMI, and to assess the prognostic impact of the presence of AHF with AMI. METHODS: A prospective study of 289 consecutive patients (mean age: 68 +/- 11 years, 61% men) admitted to our institution (via the ED) with the diagnosis of AMI between May and October 2012 and followed-up for 2.5 years. RESULTS: Acute heart failure was diagnosed in 13% of patients in the ED. In multivariable analysis, female sex, chronic obstruc-tive pulmonary disease, and chronic kidney disease significantly increased the risk of developing AHF together with AMI (all p < 0.05). Patients with AHF were hospitalised for longer (9.2 +/- 6.1 vs. 6.3 +/- 4.5 days, p < 0.001), had higher in-hospital cardiovascular mortality (8% vs. 0%, p < 0.001), and all-cause (34% vs. 15%, p = 0.004) and cardiovascular mortality (26% vs. 9%, p = 0.002) during long-term follow-up. CONCLUSIONS: Despite good logistic- and evidence-based treatment, AHF is present in one in eight patients with AMI at the time of admission to the ED. Particularly poor outcomes characterise critically ill patients; therefore, great effort should be undertaken to improve their care. PMID- 27995598 TI - Risk factors of immunoglobulin resistance and coronary complications in children with Kawasaki disease. AB - BACKGROUND: The risk of immunoglobulin resistance is still likely to occur in Kawasaki disease (KD) despite adequate treatment. The Kobayashi score (KS) is used to predict unresponsiveness to treatment although the usefulness of the score in populations other than Asian seems to be debatable. AIM: The analysis of clinical and laboratory parameters predisposing to immunoglobulin resistance and coronary complica-tions in children hospitalised due to KD. METHODS: The data of children hospitalised due to KD between 2003 and 2016 underwent analysis. Clinical and laboratory parameters were analysed, including all parameters present in KS in relation to the risk of intravenous immunoglobulin (IVIG) resistance and the occurrence of coronary complications in the form of aneurysms and dilatations. RESULTS: Seventy-three children (51 boys; aged 1.5-135 months) with KD were hospitalised. In eight (11%) patients IVIG re-sistance was observed. We reported aneurysms or coronary dilatations in 13 (17.8%) children. The criterion for increased risk of IVIG resistance based on KS (>= 4 points) was fulfilled by 21 (29%) children. Resistance to IVIG and coronary complications were observed in four (19.1%) and two (9.5%) children with the score >= 4 points, respectively, and four (7.7%) and 11 (21.6%) from the group < 4 points in KS, respectively. The prevalence of IVIG resistance and coronary artery complications was not different between the group with >= 4 and the group with < 4 points (p = 0.22, p = 0.32, respectively). A higher risk of IVIG resistance was confirmed in children with a longer duration of fever (13.0 days with IVIG resistance vs. 9.2 days with a good response to IVIG, p = 0.04). For the prediction of the occurrence of coronary artery aneurysms the following were of great importance: the day of diagnosis (which was usually the day of the beginning of treatment), the number of symptoms, and the maximal platelet count (p = 0.001; p = 0.019 and p = 0.026, respectively). CONCLUSIONS: In our study population we did not demonstrate the usefulness of KS to predict IVIG resistance or the risk of the occurrence of coronary artery aneurysms. However, prolonged fever, late diagnosis, poorly symptomatic course of the disease, and a high platelet count at the time of the follow-up remain independent risk factors. PMID- 27995599 TI - Knowledge of cardiovascular disease risk factors and the risk of death in middle aged residents of Krakow. AB - BACKGROUND: Providing knowledge of cardiovascular disease (CVD) risk factors is the main component of prevention pro-grammes, which aim to reduce the exposure to these factors and decrease CVD incidence and mortality. However, evidence linking knowledge of CVD risk factors and the risk of death is scarce. AIM: The aim of the study was to assess the relation between knowledge of CVD risk factors and the risk of death from all causes in middle-aged residents of Krakow and to assess whether this relation depends on the level of education. METHODS: The study sample included 1756 men and 1788 women selected from a population of Krakow residents at age 45-64 years. Knowledge of CVD risk factors was assessed for every risk factor separately using a standard questionnaire. Results were summarised by calculating the "knowledge index" (from -15 to 15 points). Information on deaths was obtained from the registry of Krakow residents. Cox proportional hazards model was used to assess the relation between knowledge of CVD risk factors and all-cause mortality. RESULTS: At baseline examination the participation rate was 66% in men and 65% in women. The proportion of participants with secondary or higher education was 61% in men and 66% in women. Distribution of knowledge index was right skewed, and the median was 11 (interquartile range: 9-13) in both sexes. Median time of follow-up was 14.35 years (interquartile range: 14.30-14.39). There were 307 deaths in men and in women. Men with a low level of knowledge of risk factors had a higher risk of death. However, adjustment for education attenuated the association. After stratification by the level of education, in men with secondary education or higher, an inverse relation between the knowledge of CVD risk factors and the risk of death was found. In this group, men with a low level of knowledge of CVD risk factors had about a 60% higher risk of death, compared to men with high knowledge. In men with low education and in women the risk of death was not associated with knowledge of risk factors. CONCLUSIONS: In a Krakow population characterised by a high proportion of residents with secondary or higher education, the association between knowledge of CVD risk factors and the risk of death depended on sex and the level of education. A lower level of knowledge of risk factors was associated with a higher risk of death only in men with secondary or higher education. PMID- 27995600 TI - Emergency medical system response time does not affect incidence of return of spontaneous circulation after prehospital resuscitation in one million central European agglomeration residents. AB - BACKGROUND: The survival of out-of-hospital sudden cardiac arrest (OHSCA) in Europe still remains low. The State Medical Rescue System is composed of several elements. The efficacy of each of these elements may have an influence on the victim's survival. Until now, the incidence of return of spontaneous circulation (ROSC) and its correlation with rescue services time in the city of Poznan has not been determined. AIM: The main purpose of this study was to assess incidents of OHSCA and prehospital frequency of ROSC after OHSCA in Poznan city and district. We also wanted to analyse whether ROSC depends on Emergency Medical System (EMS) reaction time. METHODS: Retrospective analysis based on medical documentation conducted in 2015 in Poznan EMS. RESULTS: Return of spontaneous circulation was achieved in 68.88% of cases. It was most frequent when OHSCA occurred in public places (p = 0.000, contingency factor = 0.233) and victims were younger (p = 0.042, contingency factor = 0.129). 63.17% of patients were male, but sex did not affect the incidence of ROSC. The median time of system response was 8.53 min, while time from ambulance departure to arrival was 5.42 min. We did not find any statistically significant difference between the number of deaths and those parameters (p = 0.723, p = 0.891). However, longer team response time correlated with the highest mortality (p = 0.042, contingency factor = 0.126). In the group where ROSC was achieved the median time of EMS response was 8.18 min, while among the group of deceased the median was 8.63 min. CONCLUSIONS: The incidence of OHSCA in our region is similar to other Polish and European cities. EMS response time does not affect the frequency of ROSC. ROSC was achieved more often if OHSCA occurred in public and the victim was younger. PMID- 27995601 TI - The associations between atrial fibrillation and parameters of nutritional status assessment in the general hospital population - a cross-sectional analysis of medical documentation. AB - BACKGROUND: Atrial fibrillation (AF) and nutrition status abnormalities are two of the most significant epidemics in current health care. AIM: The aim of this study was to determine the relationship between the prevalence and outcome of AF, and the parameters of nutritional status among consecutive, real-life patients hospitalised in a university hospital. METHODS: Analysis of the medical documentation of 4930 consecutive patients aged >= 18 years hospitalised for more than one day with diagnoses of cardiovascular disorders. RESULTS: Patients admitted with a diagnosis of AF (n = 512) compared to their counterparts without AF less frequently had an NRS-2002 score >= 3, normal range of body mass index (BMI), higher blood haemoglobin, and lower low density lipoprotein cholesterol (LDL-C) concentration. In logistic regression analysis, the risk of a hospitalisation due to AF was negatively related to BMI, NRS-2002 score, and the value of the difference between ideal and actual body mass. Urgent admission and having an NRS-2002 score >= 3 remained the only significant variables determining the risk of in-hospital death. Blood concentration of LDL-C and urgent admission were the only significant variables determining risk of 30-day rehospitalisation in the studied population. CONCLUSIONS: Inpatients with AF had a lower prevalence of normal body mass. Patients with an AF diagnosis had different risk factors for in-hospital death and 30-day rehospitalisation than their counterparts with diagnosis of cardiovascular diseases but without AF; however, the parameters of nutritional status played an important role in both patient groups. The obesity and cholesterol paradoxes were also observed. PMID- 27995602 TI - Hospitalisation length and prognosis in heart failure patients. AB - BACKGROUND: Heart failure (HF) is a chronic disease with poor prognosis, being the final stage of many cardiovascular conditions and often requiring hospitalisation. AIM: The aim of the study was to evaluate the effect of hospitalisation length on prognosis in patients with HF. METHODS: Between February 2012 and January 2013, in 32 cardiology centres in Poland, 1126 HF patients were included in the EURObservational Research Programme on Heart Failure Registry. A total of 765 persons were hospitalised. A follow-up (FU) of 414 +/- 121 days was conducted. RESULTS: The median length of hospitalisation was seven days (interquartiles 25th-75th; 4-11), also for new onset (14.5% of patients) and chronic HF (seven days, 5-11 and 4-11, respectively). Patients who died during FU (16.5%) and those who survived were hospitalised for a median of eight days (6-12) and seven days (4-10), respectively (p < 0.001). Patients hospitalised for 8-21 and 22 or more days had an increased risk of death after discharge (hazard ratio [HR] 1.70; 95% confidence interval [CI] 1.16-2.49 and HR 2.20; 95% CI 1.04-4.67, respectively) than those hospitalised for up to seven days. Predictors of death in the FU period in multivariate analysis included age (1.02; 95% CI 1.01-1.04), history of chronic kidney disease (CKD) (HR 1.55; 95% CI 1.05-2.30), and New York Heart Association (NYHA) class III (HR 2.52; 95% CI 1.22-5.18) and IV (HR 4.77; 95% CI 2.32-9.82) at admission. Patients hospitalised for 22 or more days were more often male (77%), and with a history of CKD (34%). At admission they had lower systolic (118 +/- 25 mm Hg) and diastolic (72 +/- 12 mm Hg) blood pressure, higher NT-proBNP (9191 +/- 8776 pg/mL), lower serum sodium level (137 +/- 5 mmol/l), as well as lower ejection fraction before and during hospital stay (30 +/- 12% and 34 +/- 14%, respectively; p < 0.05 for all factors). Factors that influenced the length of hospital stay included history of CKD (p < 0.001), current malignancy (p = 0.026), and infection at admission (p < 0.001). Most of the admitted patients presented NYHA class III (45%). The poorer the NYHA class at admission, the longer the patient's hospital stay (p < 0.001). 54% patients were re-admitted to the hospital during FU. Patients re-admitted and not re-admitted during the one-year FU had the same median duration of the index hospitalisation (seven days; 4-10 and 4-11, respectively; p = 0.957). CONCLUSIONS: Patients with HF hospitalised for 22 or more days, in comparison to patients hospitalised for less than eight days, had double the risk of death during FU. We believe that prolonged hospitalisation might be regarded as a marker of poor prognosis in patients with acute HF. PMID- 27995604 TI - Exercise therapy for chronic fatigue syndrome. AB - BACKGROUND: Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory. CFS presents as a common, debilitating and serious health problem. Treatment may include physical interventions, such as exercise therapy, which was last reviewed in 2004. OBJECTIVES: The objective of this review was to determine the effects of exercise therapy (ET) for patients with CFS as compared with any other intervention or control.* Exercise therapy versus 'passive control' (e.g. treatment as usual, waiting-list control, relaxation, flexibility).* Exercise therapy versus other active treatment (e.g. cognitive-behavioural therapy (CBT), cognitive treatment, supportive therapy, pacing, pharmacological therapy such as antidepressants).* Exercise therapy in combination with other specified treatment strategies versus other specified treatment strategies (e.g. exercise combined with pharmacological treatment vs pharmacological treatment alone). SEARCH METHODS: We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL) and SPORTDiscus up to May 2014 using a comprehensive list of free-text terms for CFS and exercise. We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014). We screened reference lists of retrieved articles and contacted experts in the field for additional studies SELECTION CRITERIA: Randomised controlled trials involving adults with a primary diagnosis of CFS who were able to participate in exercise therapy. Studies had to compare exercise therapy with passive control, psychological therapies, adaptive pacing therapy or pharmacological therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) and standardised mean differences (SMDs). We combined serious adverse reactions and drop-outs using risk ratios (RRs). We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome. MAIN RESULTS: We have included eight randomised controlled studies and have reported data from 1518 participants in this review. Three studies diagnosed individuals with CFS using the 1994 criteria of the Centers for Disease Control and Prevention (CDC); five used the Oxford criteria. Exercise therapy lasted from 12 to 26 weeks. Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise. Control groups consisted of passive control (eight studies; e.g. treatment as usual, relaxation, flexibility) or CBT (two studies), cognitive therapy (one study), supportive listening (one study), pacing (one study), pharmacological treatment (one study) and combination treatment (one study). Risk of bias varied across studies, but within each study, little variation was found in the risk of bias across our primary and secondary outcome measures.Investigators compared exercise therapy with 'passive' control in eight trials, which enrolled 971 participants. Seven studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems: an 11-item scale with a scoring system of 0 to 11 points (MD -6.06, 95% CI -6.95 to -5.17; one study, 148 participants; low-quality evidence); the same 11-item scale with a scoring system of 0 to 33 points (MD -2.82, 95% CI -4.07 to -1.57; three studies, 540 participants; moderate-quality evidence); and a 14-item scale with a scoring system of 0 to 42 points (MD -6.80, 95% CI -10.31 to -3.28; three studies, 152 participants; moderate-quality evidence). Serious adverse reactions were rare in both groups (RR 0.99, 95% CI 0.14 to 6.97; one study, 319 participants; moderate quality evidence), but sparse data made it impossible for review authors to draw conclusions. Study authors reported a positive effect of exercise therapy at end of treatment with respect to sleep (MD -1.49, 95% CI -2.95 to -0.02; two studies, 323 participants), physical functioning (MD 13.10, 95% CI 1.98 to 24.22; five studies, 725 participants) and self-perceived changes in overall health (RR 1.83, 95% CI 1.39 to 2.40; four studies, 489 participants). It was not possible for review authors to draw conclusions regarding the remaining outcomes.Investigators compared exercise therapy with CBT in two trials (351 participants). One trial (298 participants) reported little or no difference in fatigue at end of treatment between the two groups using an 11-item scale with a scoring system of 0 to 33 points (MD 0.20, 95% CI -1.49 to 1.89). Both studies measured differences in fatigue at follow-up, but neither found differences between the two groups using an 11-item fatigue scale with a scoring system of 0 to 33 points (MD 0.30, 95% CI -1.45 to 2.05) and a nine-item Fatigue Severity Scale with a scoring system of 1 to 7 points (MD 0.40, 95% CI -0.34 to 1.14). Serious adverse reactions were rare in both groups (RR 0.67, 95% CI 0.11 to 3.96). We observed little or no difference in physical functioning, depression, anxiety and sleep, and we were not able to draw any conclusions with regard to pain, self-perceived changes in overall health, use of health service resources and drop-out rate.With regard to other comparisons, one study (320 participants) suggested a general benefit of exercise over adaptive pacing, and another study (183 participants) a benefit of exercise over supportive listening. The available evidence was too sparse to draw conclusions about the effect of pharmaceutical interventions. AUTHORS' CONCLUSIONS: Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed, but no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible. The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention. PMID- 27995605 TI - Eczema and educational attainment: a systematic review. PMID- 27995603 TI - Role of interferon-gamma and inflammatory monocytes in driving colonic inflammation during acute Clostridium difficile infection in mice. AB - The inflammatory response to the colonic pathogen Clostridium difficile is characterized by the induction of inflammatory cytokines including Interleukin-23 (IL-23) and interferon-gamma (IFN-gamma) and the recruitment of myeloid cells including Ly6CHigh monocytes. IL-23 knockout mice showed reduced expression of the monocyte chemokines Ccl4 and Ccl7, but not Ccl2, as well as reduced Ly6CHigh Ly6GMid monocyte recruitment to the colon in response to C. difficile colitis. Clostridium difficile-infected CCR2-/- (CCR2 KO) mice showed a significant defect in Ly6CHigh Ly6GMid monocyte recruitment to the colon in response to C. difficile. Although there was no decrease in expression of the inflammatory cytokines Il1b, Il6 or Tnf or reduction in the severity of colonic histopathology associated with ablation of monocyte recruitment, Slpi and Inos expression was significantly reduced in the colons of these animals. Additionally, neutralization of IFN-gamma through the administration of anti-IFN-gamma monoclonal antibody resulted in a significant reduction in the expression of the IFN-gamma-inducible chemokines Cxcl9 and Cxcl10, but not a reduction in the neutrophil chemokines Cxcl1, Cxcl2 and Ccl3 or the monocyte chemokine Ccl2. Consistently, monocyte and neutrophil recruitment were unchanged following anti IFN-gamma treatment. Additionally, Inos and Slpi expression were unchanged following anti-IFN-gamma treatment, suggesting that Inos and Slpi regulation is independent of IFN-gamma during C. difficile colitis. Taken together, these data strongly suggest that IL-23 and CCR2 signalling are required for monocyte recruitment during C. difficile colitis. Additionally, these studies also suggest that monocytes, but not IFN-gamma, are necessary for full expression of Inos and Slpi in the colon. PMID- 27995606 TI - Differential requirement for N-ethylmaleimide-sensitive factor in endosomal trafficking of transferrin receptor from anterograde trafficking of vesicular stomatitis virus glycoprotein G. AB - N-ethylmaleimide-sensitive fusion factor (NSF) is an ATPase that plays a crucial role in vesicular transport. Here, we examined the effects of NSF knockdown on Golgi structure and different vesicle trafficking pathways in mammalian cells. NSF knockdown caused Golgi fragmentation and abolished transferrin receptor exocytosis, defects that were rescued by RNAi-resistant NSF. Strikingly, NSF deficiency in HeLa cells barely affected cell viability, anterograde trafficking of vesicular stomatitis virus glycoprotein G and transferrin endocytosis. These results confirm the central role of NSF in Golgi structure and reveal differential requirement of NSF for exocytic recycling and constitutive trafficking pathways. PMID- 27995607 TI - Longchain polyunsaturated fatty acid supplementation in preterm infants. AB - BACKGROUND: Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants because they may not be able to synthesise sufficient amounts of LCPUFA to meet the needs of the developing brain and retina. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is safe and of benefit to preterm infants. The main areas of interest were the effects of supplementation on the visual function, development and growth of preterm infants. SEARCH METHODS: Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 28 February 2016), MEDLINE Ovid (1966 to 28 February 2016), Embase Ovid (1980 to 28 February 2016), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1980 to 28 February 2016), MEDLINE In Process & Other Non-indexed Citations (1966 to 28 February 2016) and by checking reference lists of articles and conference proceedings. We also searched ClinicalTrials.gov (13 April 2016). No language restrictions were applied. SELECTION CRITERIA: All randomised trials evaluating the effect of LCPUFA supplemented formula in enterally-fed preterm infants (compared with standard formula) on visual development, neurodevelopment and physical growth. Trials reporting only biochemical outcomes were not included. DATA COLLECTION AND ANALYSIS: All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information. MAIN RESULTS: Seventeen trials involving 2260 preterm infants were included in the review. The risk of bias varied across the included trials with 10 studies having low risk of bias in a majority of the domains. The median gestational age (GA) in the included trials was 30 weeks and median birth weight (BW) was 1300 g. The median concentration of docosahexaenoic acid (DHA) was 0.33% (range: 0.15% to 1%) and arachidonic acid (AA) 0.37% (range: 0.02% to 0.84%). Visual acuity Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by visual evoked potential (VEP) in six studies and by electroretinogram (ERG) in two studies. Most studies found no significant differences in visual acuity between supplemented and control infants. The form of data presentation and the varying assessment methods precluded the use of meta analysis. A GRADE analysis for this outcome indicated that the overall quality of evidence was low. Neurodevelopment Three out of seven studies reported some benefit of LCPUFA on neurodevelopment at different postnatal ages. Meta-analysis of four studies evaluating Bayley Scales of Infant Development at 12 months (N = 364) showed no significant effect of supplementation (Mental Development Index (MDI): MD 0.96, 95% CI -1.42 to 3.34; P = 0.43; I2 = 71% - Psychomotor DeveIopment Index (PDI): MD 0.23, 95% CI -2.77 to 3.22; P = 0.88; I2 = 81%). Furthermore, three studies at 18 months (N = 494) also revealed no significant effect of LCPUFA on neurodevelopment (MDI: MD 2.40, 95% CI -0.33 to 5.12; P = 0.08; I2 = 0% - PDI: MD 0.74, 95% CI -1.90 to 3.37; P = 0.58; I2 = 54%). A GRADE analysis for these outcomes indicated that the overall quality of evidence was low. Physical growth Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postmenstrual ages (PMAs), whereas two trials suggested that LCPUFA-supplemented infants grow less well. One trial reported mild reductions in length and weight z scores at 18 months. Meta analysis of five studies (N = 297) showed increased weight and length at two months post-term in supplemented infants (Weight: MD 0.21, 95% CI 0.08 to 0.33; P = 0.0010; I2 = 69% - Length: MD 0.47, 95% CI 0.00 to 0.94; P = 0.05; I2 = 0%). Meta-analysis of four studies at a corrected age of 12 months (N = 271) showed no significant effect of supplementation on growth outcomes (Weight: MD -0.10, 95% CI -0.31 to 0.12; P = 0.34; I2 = 65% - Length: MD 0.25; 95% CI -0.33 to 0.84; P = 0.40; I2 = 71% - Head circumference: MD -0.15, 95% CI -0.53 to 0.23; P = 0.45; I2 = 0%). No significant effect of LCPUFA on weight, length or head circumference was observed on meta-analysis of two studies (n = 396 infants) at 18 months (Weight: MD -0.14, 95% CI -0.39 to 0.10; P = 0.26; I2 = 66% - Length: MD -0.28, 95% CI -0.91 to 0.35; P = 0.38; I2 = 90% - Head circumference: MD -0.18, 95% CI 0.53 to 0.18; P = 0.32; I2 = 0%). A GRADE analysis for this outcome indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula. PMID- 27995608 TI - Conversion of an instantaneous activating K+ channel into a slow activating inward rectifier. AB - The miniature channel, Kcv, is a structural equivalent of the pore of all K+ channels. Here, we follow up on a previous observation that a largely voltage insensitive channel can be converted into a slow activating inward rectifier after extending the outer transmembrane domain by one Ala. This gain of rectification can be rationalized by dynamic salt bridges at the cytosolic entrance to the channel; opening is favored by voltage-sensitive formation of salt bridges and counteracted by their disruption. Such latent voltage sensitivity in the pore could be relevant for the understanding of voltage gating in complex Kv channels. PMID- 27995609 TI - Factors influencing suicidal ideation among Chinese patients with stomach cancer: qualitative study. AB - AIM: The aim of this qualitative descriptive study was to explore the influencing factors of suicidal ideation in Chinese patients diagnosed with stomach cancer. INTRODUCTION: More recently, links have been made between suicide and cancer. For inpatients with cancer, nurses are at the front line to cope with suicidal issues in clinical settings. METHOD: This study was part of a larger study that investigated psychological strains and related factors associated with suicidal ideation. Thirty-two patients with stomach cancer participated in a face-to-face interview. Thematic analysis was used to analyse the qualitative data. FINDINGS: Four themes were identified as protective factors against suicidal ideation: suicidal denial and fears of stigmatization; positive coping skills; family connectedness; and desire to live well and longer. DISCUSSION: Consistent with previous research, these four protective factors may encourage participants to think more positively about life and cancer. CONCLUSION: Our findings suggest four protective factors for targeted suicide prevention, which may play an important role in future suicide-prevention programmes for Chinese patients diagnosed with stomach cancer. IMPLICATIONS FOR NURSING: Nurses may help reduce patients' risk for suicidal ideation more effectively by discussing beliefs, family and meaning in life perspectives, as well as offering health education about positive coping skills. IMPLICATIONS FOR HEALTHY POLICY: Clinical nurses, hospitals and the government should work collaboratively with each other. It is suggested that Chinese national guidelines for working with the high-risk suicide populations should be considered within a future mental health working plan. PMID- 27995610 TI - Growth rate and resource imbalance interactively control biomass stoichiometry and elemental quotas of aquatic bacteria. AB - The effects of resource stoichiometry and growth rate on the elemental composition of biomass have been examined in a wide variety of organisms, but the interaction among these effects is often overlooked. To determine how growth rate and resource imbalance affect bacterial carbon (C): nitrogen (N): phosphorus (P) stoichiometry and elemental content, we cultured two strains of aquatic heterotrophic bacteria in chemostats at a range of dilution rates and P supply levels (C:P of 100:1 to 10,000:1). When growing below 50% of their maximum growth rate, P availability and dilution rate had strong interactive effects on biomass C:N:P, elemental quotas, cell size, respiration rate, and growth efficiency. In contrast, at faster growth rates, biomass stoichiometry was strongly homeostatic in both strains (C:N:P of 70:13:1 and 73:14:1) and elemental quotas of C, N, and P were tightly coupled (but not constant). Respiration and cell size increased with both growth rate and P limitation, and P limitation induced C accumulation and excess respiration. These results show that bacterial biomass stoichiometry is relatively constrained when all resources are abundant and growth rates are high, but at low growth rates resource imbalance is relatively more important than growth rate in controlling bacterial biomass composition. PMID- 27995611 TI - Disruptive Potential of the Internet to Transform Illicit Drug Markets and Impact on Future Patterns of Drug Consumption. AB - The internet facilitates rapid and covert communication, knowledge transfer, and has the potential to disrupt and transform drug market models and associated consumption patterns. Innovation and new trends diffuse rapidly through this medium and new operational models are emerging. Although the online drug markets currently only account for a small share of all drug transactions, the potential of the surface and deep web to provide a new platform for drug sale and exchanges is considerable. PMID- 27995612 TI - "Inflamm-aging" influences immune cell survival factors in human bone marrow. AB - The bone marrow (BM) plays a key role in the long-term maintenance of immunological memory. However, the impact of aging on the production of survival factors for effector/memory T cells and plasma cells in the human BM has not been studied. We now show that the expression of molecules involved in the maintenance of immunological memory in the human BM changes with age. While IL-15, which protects potentially harmful CD8+ CD28- senescent T cells, increases, IL-7 decreases. IL-6, which may synergize with IL-15, is also overexpressed. In contrast, a proliferation-inducing ligand, a plasma cell survival factor, is reduced. IFN-y, TNF, and ROS accumulate in the BM in old age. IL-15 and IL-6 expression are stimulated by IFN-y and correlate with ROS levels in BM mononuclear cells. Both cytokines are reduced by incubation with the ROS scavengers N-acetylcysteine and vitamin C. IL-15 and IL-6 are also overexpressed in the BM of superoxide dismutase 1 knockout mice compared to their WT counterparts. In summary, our results demonstrate the role of inflammation and oxidative stress in age-related changes of immune cell survival factors in the BM, suggesting that antioxidants may be beneficial in counteracting immunosenescence by improving immunological memory in old age. PMID- 27995613 TI - Methylation-independent adaptation in chemotaxis of Escherichia coli involves acetylation-dependent speed adaptation. AB - Chemoreceptor methylation and demethylation has been shown to be at the core of the adaptation mechanism in Escherichia coli chemotaxis. Nevertheless, mutants lacking the methylation machinery can adapt to some extent. Here we carried out an extensive quantitative analysis of chemotactic and chemokinetic methylation independent adaptation. We show that partial or complete adaptation of the direction of flagellar rotation and the swimming speed in the absence of the methylation machinery each occurs in a small fraction of cells. Furthermore, deletion of the main enzyme responsible for acetylation of the signaling molecule CheY prevented speed adaptation but not adaptation of the direction of rotation. These results suggest that methylation-independent adaptation in bacterial chemotaxis involves chemokinetic adaptation, which is dependent on CheY acetylation. PMID- 27995614 TI - Influenza and dengue virus co-infection impairs monocyte recruitment to the lung, increases dengue virus titers, and exacerbates pneumonia. AB - Co-infections of influenza virus and bacteria are known to cause severe disease, but little information exists on co-infections with other acute viruses. Seasonal influenza and dengue viruses (DENV) regularly co-circulate in tropical regions. The pandemic spread of influenza virus H1N1 (hereafter H1N1) in 2009 led to additional severe disease cases that were co-infected with DENV. Here, we investigated the impact of co-infection on immune responses and pathogenesis in a new mouse model. Co-infection of otherwise sublethal doses of a Nicaraguan clinical H1N1 isolate and two days later with a virulent DENV2 strain increased systemic DENV titers and caused 90% lethality. Lungs of co-infected mice carried both viruses, developed severe pneumonia, and expressed a unique pattern of host mRNAs, resembling only partial responses against infection with either virus alone. A large number of monocytes were recruited to DENV-infected but not to co infected lungs, and depletion and adoptive transfer experiments revealed a beneficial role of monocytes. Our study shows that co-infection with influenza and DENV impairs host responses, which fail to control DENV titers and instead, induce severe lung damage. Further, our findings identify key inflammatory pathways and monocyte function as targets for future therapies that may limit immunopathology in co-infected patients. PMID- 27995615 TI - Afternoon Napping and Cognition in Chinese Older Adults: Findings from the China Health and Retirement Longitudinal Study Baseline Assessment. AB - OBJECTIVES: To examine the cross-sectional associations between self-reported postlunch napping and structured cognitive assessments in Chinese older adults. DESIGN: Cross-sectional cohort study. SETTING: China. PARTICIPANTS: Individuals aged 65 and older from the baseline national wave of the China Health and Retirement Longitudinal Study (CHARLS) (N = 2,974). MEASUREMENTS: Interview-based cognitive assessments of orientation and attention, episodic memory, visuospatial abilities, and a combined global cognition score incorporating these assessments. Other self-reported or interview-based assessments included postlunch napping duration, nighttime sleep duration, demographic characteristics, health habits, comorbidities, functional status and social activities. According to reported napping duration, older adults were categorized as non-nappers (0 minutes), short nappers (<30 minutes), moderate nappers (30-90 minutes), and extended nappers (>90 minutes). RESULTS: Postlunch napping was reporting in 57.7% of participants for a mean of 63 minutes. Cognitive function was significantly associated with napping (P < .001). Between-group comparisons showed that moderate nappers had better overall cognition than nonnappers (P < .001) or extended nappers (P = .01). Nonnappers also had significantly poorer cognition than short nappers (P = .03). In multiple regression analysis, moderate napping was significantly associated with better cognition than non- (P = .004), short (P = .04), and extended napping (P = .002), after controlling for demographic characteristics, body mass index, depression, instrumental activities of daily living, social activities, and nighttime sleep duration. CONCLUSION: A cross-sectional association was found between moderate postlunch napping and better cognition in Chinese older adults. The cross-sectional design and self-reported measures of sleep limited the findings. Longitudinal studies with objective napping measures are needed to further test this hypothesis. PMID- 27995616 TI - B cell subsets are modulated during allergic airway inflammation but are not required for the development of respiratory tolerance in a murine model. AB - Allergic asthma is a widespread chronic inflammatory disease of the airways. The role of different B cell subsets in developing asthma and respiratory tolerance is not well known. Especially regulatory B (Breg) cells are proposed to be important in asthma regulation. Using wild-type (WT) and B cell-deficient (MUMT) mice we investigated how B cells are affected by induction of allergic airway inflammation and respiratory tolerance and whether they are necessary to develop these conditions. WT mice with an asthma-like phenotype, characterized by increased airway hyper reactivity, eosinophilic airway inflammation, mucus hypersecretion and elevated Th2 cytokines, exhibited increased MHCII and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen, which contributed to allergen-specific T cell proliferation in vitro. Germinal center B cell numbers were elevated and associated with increased production of allergen-specific immunoglobulins especially in bLN. In contrast, respiratory tolerance clearly attenuated these B cell alterations and directly enhanced marginal zone precursor B cells, which induced regulatory T cells in vitro. However, MUMT mice developed asthma-like and tolerized phenotypes like WT mice. Our data indicate that although B cell subsets are affected by asthma-like and respiratory tolerant phenotypes, B cells are not required for tolerance induction. PMID- 27995617 TI - Prevalence of alexithymia in patients with psoriasis and its association with disease burden: a multicentre observational study. AB - BACKGROUND: Single-centre studies show that alexithymia, defined as difficulty in recognizing and describing emotions, is more prevalent among patients with psoriasis than in the general population. However, its prevalence and the consequences of the association between alexithymia and psoriasis are unclear. OBJECTIVES: The primary objective of this study was to determine the prevalence of alexithymia, as defined by a score >= 61 in the 20-item Toronto Alexithymia Scale, in a large sample of patients who had plaque psoriasis for <= 10 years and were eligible for phototherapy or systemic treatment. The secondary objectives were to investigate the relationship between alexithymia and the clinical and psychological aspects of psoriasis. METHODS: Data were collected in the framework of an observational, multicentre, international study, the EPidemiological Study In Patients With Recently DiagnosEd PSOriasis (EPIDEPSO), aiming at investigating the prevalence of alexithymia and other psychosocial comorbidities in patients with psoriasis of <= 10 years' disease duration. RESULTS: The prevalence of alexithymia within a cohort of 670 patients was 24.8% (95% confidence interval 21.7-28.2). Patients with alexithymia had a higher burden of psoriasis, including significant impairment of quality of life, higher levels of anxiety and depression, a higher risk of alcohol dependency and impairment of work productivity, compared with patients without alexithymia. CONCLUSIONS: It is important to identify alexithymic patients with psoriasis in clinical practice as they experience a higher disease burden and have a lower ability to express their feelings. PMID- 27995619 TI - Idiopathic linear IgA bullous dermatosis: prognostic factors based on a case series of 72 adults. AB - BACKGROUND: Linear IgA bullous dermatosis (LABD) is a clinically and immunologically heterogeneous, subepidermal, autoimmune bullous disease (AIBD), for which the long-term evolution is poorly described. OBJECTIVES: To investigate the clinical and immunological characteristics, follow-up and prognostic factors of adult idiopathic LABD. METHODS: This retrospective study, conducted in our AIBD referral centre, included adults, diagnosed between 1995 and 2012, with idiopathic LABD, defined as pure or predominant IgA deposits by direct immunofluorescence. Clinical, histological and immunological findings were collected from charts. Standard histology was systematically reviewed, and indirect immunofluorescence (IIF) on salt-split skin (SSS) and immunoblots (IBs) on amniotic membrane extracts using anti-IgA secondary antibodies were performed, when biopsies and sera obtained at diagnosis were available. Prognostic factors for complete remission (CR) were identified using univariate and multivariate analyses. RESULTS: Of the 72 patients included (median age 54 years), 60% had mucous membrane (MM) involvement. IgA IIF on SSS was positive for 21 of 35 patients tested; 15 had epidermal and dermal labellings. Immunoelectron microscopy performed on the biopsies of 31 patients labelled lamina lucida (LL) (26%), lamina densa (23%), anchoring-fibril zone (AFz) (19%) and LL+AFz (23%). Of the 34 IgA IBs, 22 were positive, mostly for LAD-1/LABD97 (44%) and full-length BP180 (33%). The median follow-up was 39 months. Overall, 24 patients (36%) achieved sustained CR, 19 (29%) relapsed and 35% had chronic disease. CR was significantly associated with age > 70 years or no MM involvement. No prognostic immunological factor was identified. CONCLUSIONS: Patients with LABD who are < 70 years old and have MM involvement are at risk for chronic evolution. PMID- 27995620 TI - Inner ear development in cetaceans. AB - Cetaceans face the challenge of maintaining equilibrium underwater and obtaining sensory input within a dense, low-visibility medium. The cetacean ear represents a key innovation that marked their evolution from terrestrial artiodactyls to among the most fully aquatic mammals in existence. Using micro-CT and histological data, we document shape and size changes in the cetacean inner ear during ontogeny, and demonstrate that, as a proportion of gestation time, the cetacean inner ear is precocial in its growth compared with that of suid artiodactyls. Cetacean inner ears begin ossifying and reach near-adult shape as early as at 32% of the gestation period, and near-adult dimensions as early as at 27% newborn total length. Our earliest embryos with measurable inner ears (13% newborn length) exhibit a flattened cochlea (i.e. smaller distance from cochlear apex to round window) compared with later and adult stages. Inner ears of Sus scrofa have neither begun ossifying nor reached near-adult dimensions at 55% of the gestation period, but have an adult-like ratio of cochlear diameters to each other, suggesting an adult-like shape. The precocial development of the cetacean inner ear complements previous work demonstrating precocial development of other cetacean anatomical features such as the locomotor muscles to facilitate swimming at the moment of birth. PMID- 27995618 TI - Foxd3 suppresses interleukin-10 expression in B cells. AB - Interleukin-10-positive (IL-10+ ) regulatory B (Breg) cells play an important role in restraining excessive inflammatory responses by secreting IL-10. However, it is still unclear what key transcription factors determine Breg cell differentiation. Hence, we explore what transcription factor plays a key role in the expression of IL-10, a pivotal cytokine in Breg cells. We used two types of web-based prediction software to predict transcription factors binding the IL-10 promoter and found that IL-10 promoter had many binding sites for Foxd3. Chromatin immunoprecipitation PCR assay demonstrated that Foxd3 directly binds the predicted binding sites around the start codon upstream by -1400 bp. Further, we found that Foxd3 suppressed the activation of IL-10 promoter by using an IL-10 promoter report system. Finally, knocking out Foxd3 effectively promotes Breg cell production by up-regulating IL-10 expression. Conversely, up-regulated Foxd3 expression was negatively associated with IL-10+ Breg cells in lupus-prone MRL/lpr mice. Hence, our data suggest that Foxd3 suppresses the production of IL 10+ Breg cells by directly binding the IL-10 promoter. This study demonstrates the mechanism for Breg cell production and its application to the treatment of autoimmune diseases by regulating Foxd3 expression. PMID- 27995622 TI - Lower cognitive functioning as a predictor of weight gain in bipolar disorder: a 12-month study. AB - OBJECTIVE: In cross-sectional studies, elevated body mass index (BMI) is associated with cognitive impairment in bipolar disorder (BD). We investigated the direction of this association by prospectively examining changes in BMI and cognition. METHOD: We measured BMI and performance in six cognitive domains over 12 months in 80 adolescent and young adult BD patients and 46 healthy comparison subjects (HS). Ninety-three percent of patients received pharmacotherapy and 84% were euthymic. We used repeated-measures ancova and longitudinal mixed models to investigate whether (i) higher BMI and increasing BMI over time predicted lower subsequent cognitive functioning, and (ii) lower cognitive functioning and changes in cognition predicted increasing BMI. RESULTS: Neither baseline BMI nor BMI change predicted lower cognitive functioning. Lower baseline scores in attention, verbal memory, working memory, and a composite measure of global cognition predicted increasing BMI in patients and HS. In patients, lower cognitive functioning remained associated with increasing BMI when clinical and treatment variables were adjusted for. Improvement in working memory predicted a smaller subsequent BMI increase in patients. CONCLUSION: Lower cognitive functioning in specific domains predicts increasing BMI in patients with BD and healthy young adults. Targeting cognition may be important for minimizing weight gain in BD. PMID- 27995621 TI - Annexin A1 promotes timely resolution of inflammation in murine gout. AB - Gout is a self-limited inflammatory disease caused by deposition of monosodium urate (MSU) crystals in the joints. Resolution of inflammation is an active process leading to restoration of tissue homeostasis. Here, we studied the role of Annexin A1 (AnxA1), a glucocorticoid-regulated protein that has anti inflammatory and proresolving actions, in resolution of acute gouty inflammation. Injection of MSU crystals in the knee joint of mice induced inflammation that was associated with expression of AnxA1 during the resolving phase of inflammation. Neutralization of AnxA1 with antiserum or blockade of its receptor with BOC-1 (nonselective) or WRW4 (selective) prevented the spontaneous resolution of gout. There was greater neutrophil infiltration after challenge with MSU crystals in AnxA1 knockout mice (AnxA1-/- ) and delayed resolution associated to decreased neutrophil apoptosis and efferocytosis. Pretreatment of mice with AnxA1-active N terminal peptide (Ac2-26 ) decreased neutrophil influx, IL-1beta, and CXCL1 production in periarticular joint. Posttreatment with Ac2-26 decreased neutrophil accumulation, IL-1beta, and hypernociception, and improved the articular histopathological score. Importantly, the therapeutic effects of Ac2-26 were associated with increased neutrophils apoptosis and shortened resolution intervals. In conclusion, AnxA1 plays a crucial role in the context of acute gouty inflammation by promoting timely resolution of inflammation. PMID- 27995623 TI - Organizational politics, nurses' stress, burnout levels, turnover intention and job satisfaction. AB - AIM: This is a research report examining the influence of organizational politics perceptions on nurses' work outcomes (job satisfaction, work stress, job burnout and turnover intention). BACKGROUND: Organizational politics is a phenomenon common in almost all institutions and is linked with undesirable consequences in employees. INTRODUCTION: Despite the plethora of research around the world on this topic, studies describing organizational politics in nursing remain underexplored. METHODS: A cross-sectional research design was utilized in this study. One hundred sixty-six (166) nurses participated. Five standardized tools were used: the Job Satisfaction Index, the Job Stress Scale, the Burnout Measure Scale, the Turnover Intention Inventory Scale and the Perception of Organizational Politics Scale. RESULTS: Nurses employed both in private and government-owned hospitals perceived moderate levels of organizational politics. Positive correlations were identified between perceived organizational politics and job stress, turnover intention and job burnout. Negative correlations were found between perceived organizational politics and job satisfaction. DISCUSSION: Perceptions of workplace politics in Filipino nurses were lower when compared to findings in other international studies. A strong link was found between organizational politics perceptions and the four job outcomes (stress and burnout levels, turnover intention and job satisfaction). LIMITATIONS: Use of a self reporting questionnaire and exclusion of nurses from other provinces. CONCLUSION: Perceived organizational politics predicted nurses' stress and burnout levels, turnover intention and job satisfaction. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: The findings of this study may provide a valuable perspective of this organizational issue and could assist policymakers and nurse administrators in formulating interventions that could minimize the effect of workplace politics. PMID- 27995624 TI - Diagnosing liver fibrosis: a narrative review of current literature for dermatologists. AB - Chronic liver disease is a growing problem worldwide due to obesity, alcohol related liver disease and viral hepatitis. Liver fibrosis is generally asymptomatic and patients may not present until they have advanced cirrhosis, when the scope for reversibility is limited. Identification of asymptomatic individuals at an early stage is fundamental to reversing the rising toll of liver-related morbidity and mortality. Awareness of liver disease and the techniques for diagnosis is important for dermatologists, not only due to the burden of disease in the general population but also because some dermatology cohorts may have an elevated risk. For example, there is an increased prevalence of metabolic syndrome and excess alcohol use in those with psoriasis and hidradenitis suppurativa. In isolation, standard liver function tests lack sensitivity to detect advanced fibrosis and cirrhosis and are of limited value. Traditionally diagnosis has relied on liver biopsy, which remains the gold standard but is both costly and invasive. There have been several recent advances in the development of noninvasive alternatives. These include scoring systems combining clinical and conventional laboratory parameters for use as screening tools, direct serum biomarkers of fibrogenesis and tissue elastography using both ultrasound (Fibroscan) and magnetic resonance. This review summarizes current and future noninvasive diagnostic techniques for evaluation of liver fibrosis. PMID- 27995625 TI - In-training assessments: 'The difficulty is trying to balance reality and really tell the truth'. AB - BACKGROUND: In-training assessments (ITA) aim to evaluate trainees' progress and give valuable feedback on their performance. Many factors can affect supervisors during their completion of assessments and these can influence the final results recorded. METHODS: This is the second part of a study of supervisors of the Australasian College of Dermatologists (ACD) and presents the qualitative data on their opinions of the ACD ITA process and the influences on their ITA ratings. RESULTS: Supervisors noted the benefits of this assessment tool, together with many limitations. Potential influences upon supervisor ratings included the relationship between the supervisor and trainee and the level of honesty in completing and delivery of the assessment. CONCLUSIONS: Many factors influence supervisors in the completion of the ITA. These include the impact of interpersonal relationships and concerns about the consequences of delivering a negative assessment, which sometimes lead supervisors to modify the assessment they deliver to the trainee. Further research is needed into honesty in assessment judgements. PMID- 27995626 TI - Difficult tracheal tube passage and subglottic airway injury during intubation with the GlideScope(r) videolaryngoscope: a randomised, controlled comparison of three tracheal tubes. AB - Difficulty during placement of the tracheal tube is a known problem when intubating with the GlideScope(r) , which may lead to subglottic airway injury. This randomised, controlled clinical trial was designed to compare the resistance to passage of PVC (polyvinyl chloride), reinforced or BlockBuster tracheal tubes during intubation with the GlideScope. Secondary outcomes included the time taken to intubate and assessment of subglottic airway injury. One-hundred and seventy seven patients were included in the data analysis. There was difficult tracheal tube passage (moderate or severe resistance) in 15 (21.4%) patients using the PVC tube compared with 4 (7.4%) and 1 (1.9%) using the reinforced and BlockBuster tubes, respectively (p = 0.003 for PVC vs. BlockBuster). The median (IQR [range]) time taken to intubate was 35 (27-45 [15-115]) s, 25 (20-27 [15-110]) s and 25 (22-30 [16-90]) s, respectively, (p < 0.001 for PVC vs. reinforced as well as PVC vs. BlockBuster). Subglottic airway injury, assessed using a fibreoptic bronchoscope after extubation, was higher with the PVC tube (p < 0.001) and the reinforced tube (p = 0.012) compared with the BlockBuster tube. We conclude that the BlockBuster tracheal tube is a better choice for orotracheal intubation with the GlideScope than PVC or reinforced tubes. PMID- 27995627 TI - Exposure to violence, a risk for suicide in youths and young adults. A meta analysis of longitudinal studies. AB - OBJECTIVE: To assess the association and magnitude of the effect of early exposure to different types of interpersonal violence (IPV) with suicide attempt and suicide death in youths and young adults. METHOD: We searched six databases until June 2015. Inclusion criteria were as follows: (1) assessment of any type of IPV as risk factor of suicide attempt or suicide: (i) child maltreatment [childhood physical, sexual, emotional abuse, neglect], (ii) bullying, (iii) dating violence, and (iv) community violence; (2) population-based case-control or cohort studies; and (3) subjects aged 12-26 years. Random models were used for meta-analyses (Reg: CRD42013005775). RESULTS: From 23 682 articles, 29 articles with 143 730 subjects for meta-analyses were included. For victims of any IPV, OR of subsequent suicide attempt was 1.99 (95% CI: 1.73-2.28); for child maltreatment, 2.25 (95% CI: 1.85-2.73); for bullying, 2.39 (95% CI: 1.89-3.01); for dating violence, 1.65 (95% CI: 1.40-1.94); and for community violence, 1.48 (95% CI: 1.16-1.87). Young victims of IPV had an OR of suicide death of 10.57 (95% CI: 4.46-25.07). CONCLUSION: Early exposure to IPV confers a risk of suicide attempts and particularly suicide death in youths and young adults. Future research should address the effectiveness of preventing and detecting early any type of IPV exposure in early ages. PMID- 27995628 TI - Determination of the minimal erythema dose for ultraviolet A1 radiation. AB - BACKGROUND: There is limited knowledge of the potential of ultraviolet A1 (UVA1) radiation to induce erythema. OBJECTIVES: To investigate the minimal erythema dose (MED) for UVA1 in a German and Austrian population and to determine UVA1 dose-response curves for erythema and pigmentation. METHODS: We determined the UVA1-MED in 59 participants using a geometric increase in the dose. Visual readings of erythema and pigmentation were performed at 10 min, 2 h and 24 h after the UVA1 irradiation. Colorimetric measurements were taken to determine erythema (a* value) and pigmentation (L* value) objectively. RESULTS: More than 30% (18 of 59) of the participants had a high-dose UVA1-MED (> 70-130 J cm-2 ); 56% (33) had no detectable UVA1-MED after 24 h and eight (14%) had a medium-dose UVA1-MED (20-70 J cm-2 ). We observed a stepwise decrease of the a* value measured at the UVA1-MED skin site from 10 min to 2 h and 24 h (P < 0.001). In contrast, there was a stepwise increase of the L* value measured at the UVA1-MED skin site from 10 min to 2 h and 24 h (P < 0.001). CONCLUSIONS: Most participants had no measurable UVA1-MED even after commencing high doses such as 130 J cm-2 . Only a minority of participants (14%) may develop UVA1-induced erythema in the low- and medium-dose region. Hence, it appears to be safe to start UVA1 phototherapy with 20 J cm-2 of UVA1 and continue with subsequent daily dose increments of 10 J cm-2 , up to the desired maximum dose. PMID- 27995630 TI - Editorial - Journal of Anatomy January 2017. PMID- 27995631 TI - A multilevel framework to reconstruct anatomical 3D models of the hepatic vasculature in rat livers. AB - The intricate (micro)vascular architecture of the liver has not yet been fully unravelled. Although current models are often idealized simplifications of the complex anatomical reality, correct morphological information is instrumental for scientific and clinical purposes. Previously, both vascular corrosion casting (VCC) and immunohistochemistry (IHC) have been separately used to study the hepatic vasculature. Nevertheless, these techniques still face a number of challenges such as dual casting in VCC and limited imaging depths for IHC. We have optimized both techniques and combined their complementary strengths to develop a framework for multilevel reconstruction of the hepatic circulation in the rat. The VCC and micro-CT scanning protocol was improved by enabling dual casting, optimizing the contrast agent concentration, and adjusting the viscosity of the resin (PU4ii). IHC was improved with an optimized clearing technique (CUBIC) that extended the imaging depth for confocal microscopy more than five fold. Using in-house developed software (DeLiver), the vascular network - in both VCC and IHC datasets - was automatically segmented and/or morphologically analysed. Our methodological framework allows 3D reconstruction and quantification of the hepatic circulation, ranging from the major blood vessels down to the intertwined and interconnected sinusoids. We believe that the presented framework will have value beyond studies of the liver, and will facilitate a better understanding of various parenchymal organs in general, in physiological and pathological circumstances. PMID- 27995632 TI - Reply to Vitule et al. (2017): Comment on 'Fish biodiversity and conservation in South America by Reis et al. (2016)'. PMID- 27995633 TI - Infliximab vs. adalimumab in Crohn's disease: results from 327 patients in an Australian and New Zealand observational cohort study. AB - BACKGROUND: Maintenance anti-tumour necrosis factor-alpha (anti-TNFalpha) treatment for Crohn's disease is the standard of care for patients with an inadequate response to corticosteroids and immunomodulators. AIM: To compare the efficacy and safety of infliximab and adalimumab in clinical practice and assess the value of concomitant immunomodulator therapy. METHODS: We performed an observational cohort study in consecutive patients with Crohn's disease qualifying for anti-TNFalpha treatment in Australia and New Zealand between 2007 and 2011. Demographic and clinical data were prospectively recorded to identify independent factors associated with induction and maintenance of response to infliximab or adalimumab, or to either anti-TNFalpha therapy. RESULTS: Three hundred and twenty-seven patients (183 infliximab, 144 adalimumab) successfully applied for treatment. Eighty-nine percent responded in all groups and median maintenance of response was similar for the two agents. Concomitant immunomodulator with infliximab, but not adalimumab, demonstrated a significantly longer response overall (P = 0.002), and significantly fewer disease and treatment-related complications (P = 0.017). Corticosteroids at baseline, and/or in the preceding 12 months, were associated with a 9-13 times greater risk of disease flare during maintenance treatment as compared to no corticosteroids (P < 0.0001). Maintenance of response was similar in the anti-TNF naive and anti-TNF experienced subgroups. CONCLUSIONS: In this large, real-life study, we demonstrate infliximab and adalimumab to have similar response characteristics. However, infliximab requires concomitant immunomodulator to achieve optimal maintenance of response comparable to adalimumab monotherapy. The results of this study will assist clinicians in further optimising patient care in their day-to day clinical practice. PMID- 27995634 TI - Comment on 'Fish biodiversity and conservation in South America by Reis et al. (2016)'. PMID- 27995635 TI - Modulation of CycD3;1-CDK complexes by phytohormones and sucrose during maize germination. AB - Maize CycD3;1 associates to CDKA or CDKB1;1 proteins during germination and the complexes formed develop kinase activity. These complexes appear to vary in size as germination proceeds, suggesting association to different sets of proteins. CycD3;1 and associated CDK proteins respond to phytohormones and sucrose. Results revealed a reduction in the CycD3;1 protein amount along germination in the presence of indoleacetic acid (IAA) or abscisic acid (ABA), although in the latter protein levels recover at the end of germination. While the levels of CDKA increase with IAA, they decrease with ABA. Both phytohormones, IAA and ABA, increase levels of CDKB1;1 only during the early germination times. CycD3;1 associated kinase activity is only reduced by both phytohormones towards the end of the germination period. On the other hand, lack of sucrose in the imbibition medium strongly reduces CycD3;1 protein levels without affecting the levels of neither CDKA nor CDKB1;1. The corresponding CycD3;1 associated kinase activity is also severely decreased. The presence of sucrose in the medium appears to stabilize the CycD3;1 protein levels. PMID- 27995636 TI - Managing the Rising Costs and High Drug Expenditures in Critical Care Pharmacy Practice. AB - Pharmaceutical costs for patients in the intensive care unit (ICU) constitute a large portion of hospital drug budgets. Unfortunately, prices for medications commonly used in the ICU are on the rise for a variety of reasons. In particular, the U.S. Food and Drug Administration's Unapproved Drugs Initiative, generic manufacturers cornering the marketplace, drug shortages, and regulatory device changes are major drivers of pharmaceutical price escalation affecting costs in the ICU. Furthermore, traditional high acquisition cost items still pose challenges to controlling costs. To offer strategies to mitigate the rising costs of pharmaceuticals in the ICU setting, we searched the PubMed/Medline and International Pharmaceutical Abstracts databases and other related sources to identify published cost-saving protocols concerning specific medications that are affected by rising prices or have traditional high acquisition costs. In the absence of specific protocols, we offer possible cost-saving initiatives based on published literature regarding specific agents or based on our own diverse set of experiences. Finally, we review suggested clinical and operational activities at an institutional level to address these rising drug costs in the ICU setting. PMID- 27995637 TI - Active Atrial Function and Atrial Scar Burden After Multiple Catheter Ablations of Persistent Atrial Fibrillation. AB - BACKGROUND: Extensive and repeated substrate modification (SM) is frequently performed as an ablation strategy in persistent atrial fibrillation (persAF). The effect of these extended ablation strategies on atrial function has not been investigated sufficiently so far. The purpose was to assess atrial function by cardiac magnetic resonance (CMR) and its association with left atrial (LA) scar burden by electroanatomical voltage-mapping after multiple persAF ablation procedures. METHODS: We included 16 persAF patients who had >=2 SM procedures and a control group (CG) of 21 persAF patients without prior ablation. CMR was performed in sinus rhythm at least 4 weeks after the last cardioversion. Active left and right (RA) atrial emptying fractions (AEF) as well as peak active left atrial appendage (LAA) emptying velocities were obtained by CMR flow measurements. Furthermore, LA scar burden was quantified on electroanatomical voltage maps by the portion of points with local voltage amplitude <0.2 mV. RESULTS: We found median LA-AEF to be lower (13 [9-22] vs 32 [26-36] %, P < 0.001) and median LA scar burden to be higher (40 [20-68] vs nine [3-18] %, P < 0.05) in the SM group compared with the CG. Furthermore, a significant correlation was found between mean LA voltage and LA-AEF (r2 = 0.62, P < 0.001). No significant differences were detected with respect to median RA-AEF (41 [28 48] vs 47 [35-50] %, P = 0.43) and median peak LAA emptying velocities (30 [16 40] vs 17 [13-28] cm/s, P = 0.07). CONCLUSIONS: Active LA function is preserved but significantly impaired and associated with ablation-related LA scar burden after multiple extensive persAF ablations. PMID- 27995638 TI - In vitro and in vivo studies of the native isolates of nematophagous fungi from China against the larvae of trichostrongylides. AB - To screen potential nematophagous fungi candidates for the biological control of parasitic nematodes in livestock, in vitro and in vivo studies of the native isolates of nematophagous fungi against the larvae of trichostrongylides were conducted. The in vitro predatory activity of 16 native nematophagous fungal isolates on the larvae of trichostrongylides in sheep feces was assessed. In the ten isolates of Duddingtonia flagrans, the reduction percentage for the infective larvae (L3) of Trichostrongylus colubriformis ranged from 57.21 to 99.83%, and that of Haemonchus contortus ranged from 62.12 to 99.88%. The analysis of the same assay on five isolates of Arthrobotrys superba and one isolate of A. cookedickinson (Monacrosporium cystosporum) showed comparable results with those for D. flagrans. To determine the excretion time of fungal isolates in feces after oral administration, D. flagrans (SDH035) were studied in vivo in sheep and rabbits. Results showed that the tested fungal isolates existed in sheep feces from 12 to 72 h after fungal treatment, and the fungal excretion in rabbit feces occurred at 4 h, reached a peak at 10 h, and declined gradually 18 h after oral administration. All the native fungal isolates were assessed after passing through the gastrointestinal tract of sheep. Treatment with isolates of D. flagrans significantly reduced the number of developing larvae in the feces, and the efficacies ranged from 55.15 to 98.82%. One out of the five isolates of A. superba and A. cookedickinson (BS002) survived after passing through the gastrointestinal tract, and the L3 reduction rates were 83.79 and 81.33%, respectively. Results of the present study provide information about the in vitro predatory activity of nematophagous fungi from China on the L3 of trichostrongylides and their ability to pass through the gastrointestinal tract before administering them for biocontrol. PMID- 27995639 TI - Glucose-rich diet aggravates monocrotophos-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans. AB - The present study aimed to obtain insights into the mechanism(s) by which glucose rich diet aggravates monocrotophos (MCP)-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans. In this study, we exposed three different strains of worms (wild-type N2, CB1112 (cat-2(e1112)II, tyrosine hydroxylase deficient mutant, catecholamine absent) and the transgenic BZ555 (egls1-dat 1p::green fluorescent protein [GFP]) (in which bright GFP is tagged to the dopamine neuronal soma and processes) grown and maintained in normal nematode growth medium or 2% glucose enriched-nematode growth medium to MCP (0.75 mm) for 48 h. After the exposure, dopamine-mediated behaviors such as repulsion to nonanone, chemotaxis index and basal slowing response were determined in worms. Dopamine, 3,4-dihydroxy phenyl acetic acid and homovanillic acid content were quantified in N2 worms. The extent of neurodegeneration was visualized and quantified in dat-1::GFP worms. Basal slowing response study clearly indicated that cat-2 worms exposed to MCP and glucose were less affected compared to N2 of the same treatment. Learning and memory were affected by MCP and glucose. While MCP-treated worms showed lesser repulsion to nonanone compared to control worms, MCP-treated, glucose-fed worms showed a greater reduction in repulsion to nonanone. Further, MCP-treated, glucose-fed worms exhibited a marked reduction in dopamine content and an increase in 3,4-dihydroxy phenyl acetic acid and homovanillic acid levels compared to that in control. Dat-1::GFP showed a significant degeneration of dopaminergic neurons when exposed to glucose and MCP. Thus, our results clearly demonstrate that glucose-rich diet aggravates the dopaminergic neuronal dysfunction induced by MCP in C. elegans. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27995641 TI - Two sides to the story: Adolescent and parent views on harmful intention in defining school bullying. AB - Bullying is defined as repeated negative actions involving a power differential, and intention to harm. There is limited research on harmful intention as a definitional component. This study explored the role of the perpetrator's harmful intention and the target's perception of harmful intention. Some 209 students (M = 14.5 years; 66.5% female) and 447 parents (M = 46.4 years; 86.4% female) were randomly assigned in an online survey. Participants assessed the likelihood of bullying in five hypothetical scenarios (physical, verbal, rumor, exclusion, and cyber) across five intention conditions, that also involved repetition and a power differential. The five intention conditions were: 1) harm intended by perpetrator (I) and perceived as intended to harm by target (I) [II condition]; 2) harm not intended by perpetrator (N) but perceived as intended to harm by target (I) [NI condition]; 3) harm intended by perpetrator (I) but not perceived as intended to harm by target (N) [IN condition]; 4) harm not intended by perpetrator (N) and not perceived as intended to harm by target N [NN condition]; and 5) a control which did not state any actual or perceived harmful intention [C condition]. For students and parents, the perpetrator's harmful intention and the target's perception of harmful intention were important when considering whether a peer interaction constituted bullying. These findings confirm the applicability of the three-part definition of bullying, and highlight the importance of assessing these two dimensions of harmful intention when determining whether a problematic peer interaction should be regarded as bullying. Aggr. Behav. 43:352 363, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27995640 TI - Genotoxic risk of ethyl-paraben could be related to telomere shortening. AB - The ability of parabens to promote the appearance of multiple cancer hallmarks in breast epithelium cells provides grounds for regulatory review of the implication of the presence of parabens in human breast tissue. It is well documented that telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer. In the present study, we evaluated the genotoxic effect of ethyl 4-hydroxybenzoate (ethyl-paraben), with and without metabolic activation (S9), in studies following OECD guidelines. We observed a significant increase in genotoxic damage using the Mouse Lymphoma Assay and in vitro micronucleus (MN) tests in the L5178Y cell line in the presence of S9 only after a short exposure. A high frequency of MN was observed in the TK6 cells after a short exposure (3 h) in the presence of S9 and a long exposure (26 h) without S9. We found significant increases in the MN frequency and induced chromosomal aberrations in the lymphocytes of only one donor after ethyl-paraben exposure in the presence of S9 after a short exposure. Cytogenetic characterization of the paraben-treated cells demonstrated telomere shortening associated with telomere loss and telomere deletions in L5178Y and TK6 cells and lymphocytes of the paraben sensitive-donor. In a control cohort of 68 human lymphocytes, telomere length and telomere aberrations were age-dependent and showed high inter-individual variation. This study is the first to link telomere shortening and the genotoxic effect of ethyl paraben in the presence of S9 and raises the possibility that telomere shortening may be a proxy for underlying inter-individual sensitivity to ethyl-paraben. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27995642 TI - Health-related quality of life in adult dermatitis patients stratified by filaggrin genotype. AB - BACKGROUND: Information concerning health-related quality of life (HRQoL) and comorbidities of adult dermatitis patients stratified by loss-of-function mutations in the filaggrin gene (FLG) is limited. OBJECTIVE: To investigate HRQoL, skin symptoms and comorbidities in adult FLG mutation carriers. METHODS: This cross-sectional study included patients diagnosed with atopic dermatitis and/or hand eczema (n = 520). Patients completed questionnaires about dermatitis, skin symptoms, HRQoL, and comorbidities, including actinic keratosis, and atopic and mental disorders. RESULTS: FLG mutations (R501X, 2282del4, and R2447X) were identified in 16.9% of patients, and were significantly associated not only with atopic dermatitis, but also independently with skin fissures on the fingers and heels, and self-reported actinic keratosis. Although FLG mutations were significantly associated with reduced HRQoL, as measured by use of the Dermatology Life Quality Index (DLQI), no association with self-reported anxiety or depression was identified. Notably, the highest median DLQI score, reflecting greater impairment, was reported by patients with both FLG mutations and atopic dermatitis. Overall, 19.7% of patients with both atopic dermatitis and FLG mutations reported a 'large or extremely large' impact on their lives; this represents twice the prevalence seen in patients with atopic dermatitis and wild type FLG (9.6%). CONCLUSION: Patients with both atopic dermatitis and common FLG mutations are more frequently affected by reduced HRQoL. PMID- 27995643 TI - Loperamide Trends in Abuse and Misuse Over 13 Years: 2002-2015. AB - STUDY OBJECTIVE: With the increasing amount of information available on the Internet describing techniques for using loperamide either for self-treatment of opioid withdrawal syndromes or for recreational use (so-called legal highs), the objective was to describe a statewide poison control system's experience with loperamide misuse and abuse, with specific interest in cases of cardiotoxicity, and to determine if reported loperamide misuse or abuse cases have recently increased. DESIGN: Retrospective review. DATA SOURCE: Statewide poison control system electronic database. PATIENTS: A total of 224 adults who presented or were referred to a health care facility between January 1, 2002, and November 10, 2015, for intentional ingestions of loperamide, and whose cases were reported to the poison control system by either physicians or nurses at the bedside. MEASUREMENTS AND MAIN RESULTS: Between 2002 and 2013, the number of yearly calls to the poison control system regarding loperamide cases ranged from 12-19 (mean 16.4, median 17.5 calls). In 2014, a sharp increase to 41 calls was noted. On completion of the study (November 10, 2015), 27 calls had been recorded. Medical outcomes of loperamide exposure for each patient were classified in accordance with the American Association of Poison Control Center's classification system as minor, moderate, or severe. For those patients with known outcomes, 3 resulted in death, 9 had major effects, 49 had moderate effects, and 36 had minor effects. We identified nine reports of patients who developed cardiotoxicity, with eight of them occurring between 2012 and 2015. A spike in the number of cases of loperamide toxicity reported in 2014 and 2015 coincided with an abundance of online instructions on how to abuse this drug. Almost all cases of recorded cardiotoxicity occurred over the last 3 years. Cardiotoxicity from loperamide abuse has only recently been recognized as a potential complication during the last few years, so earlier cases of cardiotoxicity resulting from loperamide abuse were likely missed. CONCLUSION: Our data suggest that loperamide may be increasing in popularity as a drug of abuse and for treatment of opioid withdrawal symptoms. Given the potential for significant toxicity with loperamide exposure, including life-threatening cardiac dysrhythmias, clinicians should consider obtaining a screening electrocardiogram for patients presenting after acute or chronic high-dose ingestions of loperamide. In addition, increased control over the availability of loperamide may be warranted. PMID- 27995644 TI - Excellent Pace Maps Recorded from Two Remote Sites Inside and Outside the Scar in a Patient with Ischemic VT: What Is the Mechanism? PMID- 27995645 TI - In vivo deep two-photon imaging of neural circuits with the fluorescent Ca2+ indicator Cal-590. AB - In vivo two-photon Ca2+ imaging has become an effective approach for the functional analysis of neuronal populations, individual neurons and subcellular neuronal compartments in the intact brain. When imaging individually labelled neurons, depth penetration can often reach up to 1 mm below the cortical surface. However, for densely labelled neuronal populations, imaging with single-cell resolution is largely restricted to the upper cortical layers in the mouse brain. Here, we review recent advances of deep two-photon Ca2+ imaging and the use of red-shifted fluorescent Ca2+ indicators as a promising strategy to increase the imaging depth, which takes advantage of reduced photon scattering at their long excitation and emission wavelengths. We describe results showing that the newly introduced fluorescent Ca2+ -sensitive dye Cal-590 can be used to record in vivo neuronal activity in isolated cortical neurons and in neurons within populations in depths of up to 900 MUm below the pial surface. Thus, the new approach allows the comprehensive functional mapping of all six cortical layers of the mouse brain. Specific features of Cal-590-based in vivo Ca2+ two-photon imaging include a good signal-to-noise ratio, fast kinetics and a linear dependence of the Ca2+ transients on the number of action potentials. Another area of application is dual-colour imaging by combining Cal-590 with other, shorter wavelength Ca2+ indicators such as OGB-1. Overall, Cal-590-based two-photon microscopy emerges as a promising tool for the recording of neuronal activity at depths that were previously inaccessible to functional imaging of neuronal circuits. PMID- 27995647 TI - Temporal development of the barley leaf metabolic response to Pi limitation. AB - The response of plants to Pi limitation involves interplay between root uptake of Pi , adjustment of resource allocation to different plant organs and increased metabolic Pi use efficiency. To identify potentially novel, early-responding, metabolic hallmarks of Pi limitation in crop plants, we studied the metabolic response of barley leaves over the first 7 d of Pi stress, and the relationship of primary metabolites with leaf Pi levels and leaf biomass. The abundance of leaf Pi , Tyr and shikimate were significantly different between low Pi and control plants 1 h after transfer of the plants to low Pi . Combining these data with 15 N metabolic labelling, we show that over the first 48 h of Pi limitation, metabolic flux through the N assimilation and aromatic amino acid pathways is increased. We propose that together with a shift in amino acid metabolism in the chloroplast a transient restoration of the energetic and redox state of the leaf is achieved. Correlation analysis of metabolite abundances revealed a central role for major amino acids in Pi stress, appearing to modulate partitioning of soluble sugars between amino acid and carboxylate synthesis, thereby limiting leaf biomass accumulation when external Pi is low. PMID- 27995648 TI - Pharmacotherapy: Cover Story and Updates. PMID- 27995646 TI - Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium. AB - KEY POINTS: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3- concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO3- . Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO3- concentrations is to minimize the secretion of Cl- ions. These findings help to clarify the mechanism responsible for pancreatic HCO3- secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. ABSTRACT: A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3- ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP-stimulated secretion were well replicated by increasing the activities of the basolateral Na+ -HCO3- cotransporter (NBC1) and apical Cl- /HCO3- exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl- and HCO3- permeabilities (CFTR), and reducing the activity of the basolateral Cl- /HCO3- exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ~140 mm HCO3- at a rate of ~3 nl min-1 mm-2 , which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl- /HCO3- exchange via SLC26A6 at the apical membrane were able to support a HCO3- -rich secretion. Raising the HCO3- /Cl- permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO3- concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ~80% was essential in minimizing the intracellular Cl- concentration following cAMP stimulation and thereby maximizing the secreted HCO3- concentration. The addition of a basolateral Na+ -K+ -2Cl- cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl- and resulted in a lower secreted HCO3- concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl- secretion is the main requirement for secreting 140 mm HCO3- . PMID- 27995650 TI - Socio-cultural issues in medical school: we don't know enough! PMID- 27995649 TI - Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants. AB - AIMS: The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. METHODS: Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2 h, 4 h or 6 h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. RESULTS: A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P < 0.001). Total, renal and nonrenal clearances of theophylline were 0.50 +/- 0.29 ml kg-1 min-1 , 0.16 +/- 0.06 ml kg-1 min-1 and 0.34 +/- 0.28 ml kg-1 min-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CONCLUSIONS: CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants. PMID- 27995651 TI - 'Trust' versus 'competency' in the workplace. PMID- 27995652 TI - Correlates of sun protection behaviors among Hispanic children residing in a high UVR environment. AB - BACKGROUND/PURPOSE: Rates of melanoma are rising in Hispanics in the United States. Excessive sun exposure in childhood increases the risk of melanoma in adulthood, and little is known about the factors motivating sun protection behaviors among Hispanic youth. METHODS: Correlates of sun protection were examined among Hispanic children residing in Los Angeles, California (N = 1891). Associations between multiple constructs (psychosocial, familial, and cultural) and sun protection outcomes (use of sunscreen, protective clothing, and shade seeking/sun avoidance) were examined. RESULTS: Family variables were associated with more frequent sun protection among Hispanic children across outcomes, as were perceived peer norms, perceived self-efficacy, and fewer sun protection barriers. Skin cancer risk factors such as lighter skin and sunburn experience, and level of acculturation were not associated with greater sun protection. CONCLUSION: Family sun protection habits are instrumental to Hispanic children's sun safe behaviors, and interventions that engage the family may be most effective. Increasing risk communication to high-risk subgroups of Hispanic children (those with lighter, more sun reactive skin) is important when developing intervention strategies. However, there is overlap between Hispanic children's sun protection correlates and those observed among non-Hispanic white children, suggesting that interventions to improve sun protection may generalize across cultural contexts. PMID- 27995653 TI - Influence of misfit on the occurrence of veneering porcelain fractures (chipping) in implant-supported metal-ceramic fixed dental prostheses: an in vitro pilot trial. AB - OBJECTIVE: Technical complications such as veneer fractures are more common in implant-supported than tooth-supported restorations. The underlying causes have not been fully identified. The aim of this study was to evaluate whether misfit between the restoration and the implant may affect the risk of veneer fractures. MATERIALS AND METHODS: Twenty standardized five-unit implant-supported metal ceramic fixed dental prostheses (FDP)s were manufactured and fixed in acrylic blocks. The test group consisted of ten FDPs fixed with a 150-MUm misfit at the distal abutment. The remaining ten FDPs were fixed without misfit and acted as a control group. All FDPS underwent cyclic loading for a total of 100,000 cycles at 30-300 N. The FDPs were checked for cracks or chip-off fractures regularly. After cyclic load, the retorque value of all abutment screws was checked. RESULTS: Cracks within the veneering porcelain were noted in nine FDPs in the test group and one FDP in the control group. This difference was statistically significant (P < 0.001). Fractures of the veneering porcelain occurred in three FDPs in the test group. No fractures occurred in the control group. This difference was not statistically significant. There were no significant differences in retorque values neither between the groups nor between different abutment positions in the FDPs. CONCLUSIONS: Within the limitations of this in vitro pilot trial, it is suggested that misfit between a restoration and the supporting implant may increase the risk of cracking and/or chipping of the veneering porcelain for metal-ceramic FDPs. PMID- 27995654 TI - Simultaneous detection of sulfoxaflor and its metabolites, X11719474 and X11721061, in lettuce using a modified QuEChERS extraction method and liquid chromatography-tandem mass spectrometry. AB - An analytical method has been developed to quantify the residual levels of sulfoxaflor and its metabolites (X11719474 and X11721061) in/on cultivated lettuce grown under greenhouse conditions. Samples were extracted and purified using a quick, easy, cheap, effective, rugged, and safe 'QuEChERS' method (original version) following systematic method optimization and were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Good linearity with coefficient of determination >=0.9930 was obtained and the limits of detection (LOD) and quantification (LOQ) were in the ranges of 0.003-0.006 and 0.01-0.02 mg/kg, respectively. The recovery rates of both the parent compound and its metabolites (fortified at 10 and 50* the LOQ) estimated from six replicates ranged between 81.9 and 115.5% with a relative standard deviation <12%. The validated method was applied to field-incurred samples (collected over 7 days) sprayed once or twice with a water-dispersible granule formulation. Notably, a substantial reduction in rate was observed after 3 days and the half-life was short, only 1.5 days. The developed method is simple and versatile and can be used for various leafy vegetables. PMID- 27995655 TI - Phenotypic assays for analyses of pluripotent stem cell-derived cardiomyocytes. AB - Stem cell-derived cardiomyocytes (CMs) hold great hopes for myocardium regeneration because of their ability to produce functional cardiac cells in large quantities. They also hold promise in dissecting the molecular principles involved in heart diseases and also in drug development, owing to their ability to model the diseases using patient-specific human pluripotent stem cell (hPSC) derived CMs. The CM properties essential for the desired applications are frequently evaluated through morphologic and genotypic screenings. Even though these characterizations are necessary, they cannot in principle guarantee the CM functionality and their drug response. The CM functional characteristics can be quantified by phenotype assays, including electrophysiological, optical, and/or mechanical approaches implemented in the past decades, especially when used to investigate responses of the CMs to known stimuli (eg, adrenergic stimulation). Such methods can be used to indirectly determine the electrochemomechanics of the cardiac excitation-contraction coupling, which determines important functional properties of the hPSC-derived CMs, such as their differentiation efficacy, their maturation level, and their functionality. In this work, we aim to systematically review the techniques and methodologies implemented in the phenotype characterization of hPSC-derived CMs. Further, we introduce a novel approach combining atomic force microscopy, fluorescent microscopy, and external electrophysiology through microelectrode arrays. We demonstrate that this novel method can be used to gain unique information on the complex excitation contraction coupling dynamics of the hPSC-derived CMs. PMID- 27995657 TI - Protective effects of Aloe sterols against UVB-induced photoaging in hairless mice. AB - BACKGROUND: Aloe vera is a traditional medical plant whose gel has been widely used in skin care. Previously, we have identified Aloe sterols from Aloe vera as active ingredients. This study investigated the protective effects of Aloe sterols without polysaccharides, against ultraviolet B (UVB)-induced skin photoaging in mice using Aloe vera gel extract (AVGE) obtained by supercritical fluid extraction. METHODS: Aloe vera gel extract was supplemented in the diet (12 or 120 ppm), and HR-1 hairless mice were exposed to UVB irradiation for 7 weeks. Skin measurements and histological and analytical studies were performed. RESULTS: Repeated UVB irradiation induced rough wrinkling of skin with water content reduction and hyperkeratosis. AVGE administration resulted in the significant improvement of UVB-induced skin dryness, epidermal thickness, and wrinkle formation. The AVGE group also suppressed the degenerations of dermal collagen fibers and the appearance of cutaneous apoptosis cells induced by UVB. Furthermore, AVGE administration reduced the excess elevation of pro-inflammatory cytokines (IL-1beta and TNF-alpha) and matrix metalloproteinases (MMP-2, MMP-9, MMP-12, and MMP-13) in UVB-exposed skin. CONCLUSION: The dietary ingestion of Aloe sterols protected against chronic UVB damage in mouse skin, and our results suggest that Aloe sterols may prevent skin photoaging through the anti inflammation and MMP regulation. PMID- 27995658 TI - Microvascular proliferation of brain metastases mimics glioblastomas in squash cytology. AB - OBJECTIVE: Although microvascular proliferation is a key feature in the diagnosis of high-grade glioma, the characteristics of metastatic tumour vessels in smear preparations have not been documented. In this study, the vascular changes in metastatic brain tumours, using squash cytology to examine the vascular patterns in brain metastases, were reviewed. METHODS: One hundred and forty-three squash smears of brain tissue, including 25 normal or reactive tissue, 23 malignant lymphomas, 8 grade I glioma (pilocytic astrocytoma), 23 grade II glioma (diffuse astrocytoma and oligodendroglioma), 42 grade IV glioma (glioblastoma), and 22 metastasis, were assessed. Two vascular patterns were assessed: thick and branching, and glomeruloid. The vessel density, nuclear layer and the number of vessel branches were compared. Furthermore, tumour vessels of brain metastases were analysed by histology and for immunohistochemical expression of CD34, alpha smooth muscle actin (SMA) and high-molecular-weight caldesmon (h-CD). RESULTS: Among 22 metastatic tumours, thick and branching vessels were found in 17 (77%) and glomeruloid vessels in 13 (59%). These incidences of microvascular proliferation patterns were similar to those of glioblastomas or pilocytic astrocytomas. Vessel density, nuclear layer and vessel wall branches were significantly higher in metastatic tumours than malignant lymphomas, grade II gliomas or normal brain tissues. Glomeruloid vessels consisted of CD34-positive cells and alpha-SMA-positive cells, and alpha-SMA-positive cells had a low h-CD expression. These immunohistochemical patterns were similar to those of high grade gliomas. CONCLUSIONS: The vascular features of metastatic brain tumours are similar to those of glioblastomas, suggesting that these microvascular proliferations contribute to the progression of metastatic tumours. PMID- 27995661 TI - Science-in-brief: Equine viral hepatitis. PMID- 27995662 TI - Effects of preference heterogeneity among landowners on spatial conservation prioritization. AB - The participation of private landowners in conservation is crucial to efficient biodiversity conservation. This is especially the case in settings where the share of private ownership is large and the economic costs associated with land acquisition are high. We used probit regression analysis and historical participation data to examine the likelihood of participation of Danish forest owners in a voluntary conservation program. We used the results to spatially predict the likelihood of participation of all forest owners in Denmark. We merged spatial data on the presence of forest, cadastral information on participation contracts, and individual-level socioeconomic information about the forest owners and their households. We included predicted participation in a probability model for species survival. Uninformed and informed (included land owner characteristics) models were then incorporated into a spatial prioritization for conservation of unmanaged forests. The choice models are based on sociodemographic data on the entire population of Danish forest owners and historical data on their participation in conservation schemes. Inclusion in the model of information on private landowners' willingness to supply land for conservation yielded at intermediate budget levels up to 30% more expected species coverage than the uninformed prioritization scheme. Our landowner-choice model provides an example of moving toward more implementable conservation planning. PMID- 27995660 TI - A new paradigm for clinical communication: critical review of literature in cancer care. AB - OBJECTIVES: To: (i) identify key assumptions of the scientific 'paradigm' that shapes clinical communication research and education in cancer care; (ii) show that, as general rules, these do not match patients' own priorities for communication; and (iii) suggest how the paradigm might change to reflect evidence better and thereby serve patients better. METHODS: A critical review, focusing on cancer care. We identified assumptions about patients' and clinicians' roles in recent position and policy statements. We examined these in light of research evidence, focusing on inductive research that has not itself been constrained by those assumptions, and considering the institutionalised interests that the assumptions might serve. RESULTS: The current paradigm constructs patients simultaneously as needy (requiring clinicians' explicit emotional support) and robust (seeking information and autonomy in decision making). Evidence indicates, however, that patients generally value clinicians who emphasise expert clinical care rather than counselling, and who lead decision making. In denoting communication as a technical skill, the paradigm constructs clinicians as technicians; however, communication cannot be reduced to technical skills, and teaching clinicians 'communication skills' has not clearly benefited patients. The current paradigm is therefore defined by assumptions that that have not arisen from evidence. A paradigm for clinical communication that makes its starting point the roles that mortal illness gives patients and clinicians would emphasise patients' vulnerability and clinicians' goal-directed expertise. Attachment theory provides a knowledge base to inform both research and education. CONCLUSIONS: Researchers will need to be alert to political interests that seek to mould patients into 'consumers', and to professional interests that seek to add explicit psychological dimensions to clinicians' roles. New approaches to education will be needed to support clinicians' curiosity and goal directed judgement in applying this knowledge. The test for the new paradigm will be whether the research and education it promotes benefit patients. PMID- 27995663 TI - Phytoelectrochemical analysis of Zanthoxylum chiloperone. AB - INTRODUCTION: An innovative application of the voltammetry of microparticles methodology to characterize the phytochemical composition of extracts of different parts of Zanthoxylum chiloperone var. angustifolium Engl. is described. OBJECTIVE: Characterize the phytochemical composition of extracts of different parts of plants by electrochemical methodologies. METHODS: The voltammetry of microparticles methodology was applied to alcoholic extracts from leaves, seeds, fruits, roots and stem bark of Zanthoxylum chiloperone. RESULTS: In contact with aqueous phosphate buffer, characteristic cathodic signals of its main natural products (canthin-6-one, 5-methoxycanthin-6-one and trans-avicennol) were recorded. The study of the voltammograns allows the estimation of the relative amounts of canthin-6-one, 5-methoxycanthin-6-one and trans-avicennol from the different parts of Zanthoxylum chiloperone. CONCLUSION: The voltammetric responses of alcoholic extracts from different parts of Zanthoxylum chiloperone var. angustifolium allows their phytochemical characterization without need of sample pretreatment thus illustrating the capabilities of the voltammetry of microparticles methodology to increase the tools applied to phytochemical analysis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27995664 TI - AraQTL - workbench and archive for systems genetics in Arabidopsis thaliana. AB - Genetical genomics studies uncover genome-wide genetic interactions between genes and their transcriptional regulators. High-throughput measurement of gene expression in recombinant inbred line populations has enabled investigation of the genetic architecture of variation in gene expression. This has the potential to enrich our understanding of the molecular mechanisms affected by and underlying natural variation. Moreover, it contributes to the systems biology of natural variation, as a substantial number of experiments have resulted in a valuable amount of interconnectable phenotypic, molecular and genotypic data. A number of genetical genomics studies have been published for Arabidopsis thaliana, uncovering many expression quantitative trait loci (eQTLs). However, these complex data are not easily accessible to the plant research community, leaving most of the valuable genetic interactions unexplored as cross-analysis of these studies is a major effort. We address this problem with AraQTL (http://www.bioinformatics.nl/Ara QTL/), an easily accessible workbench and database for comparative analysis and meta-analysis of all published Arabidopsis eQTL datasets. AraQTL provides a workbench for comparing, re-using and extending upon the results of these experiments. For example, one can easily screen a physical region for specific local eQTLs that could harbour candidate genes for phenotypic QTLs, or detect gene-by-environment interactions by comparing eQTLs under different conditions. PMID- 27995665 TI - Changes in sleep duration and recreational screen time among Canadians, 1998 2010. AB - It is commonly claimed that sleep duration has declined in recent years - over a period coinciding with a marked increase in personal electronics and communications use. The aim of this study was to assess change in sleep duration among Canadians from 1998 to 2010, and examine any associations with non-work related screen time. The analysis uses population-representative data from Statistics Canada's General Social Survey cycles of 1998 and 2010; the respective samples numbered 10 749 and 15 390 individuals. Response rates were 80% in 1998 and 55% in 2010. Respondents were aged 15 years and older, residing in private households in the 10 Canadian provinces. The General Social Survey is administered by computer-assisted telephone interviewing. Data on sleep duration (excluding naps outside essential sleep time) and recreational screen time were obtained using a 24-h time-use diary. Survey weights were applied to adjust for non-response and non-landline households. Frequencies (respondent characteristics) and averages (time-use variables) were estimated by age group and sex. Sleep duration was examined by weighted quartile of screen time. Confidence intervals (95%) were calculated around estimates. Average sleep duration increased from 8.1 h in 1998 to 8.3 h in 2010. Average screen time increased from 140 min in 1998 to 154 min in 2010. Sleep duration and screen time were positively related in both years. The percentage of people averaging less than 6 h sleep decreased from 9.6% in 1998 to 8.6% in 2010. Between 1998 and 2010, increases in screen time did not occur at the expense of sleep duration. PMID- 27995666 TI - Hypermethylation of ATP-binding cassette B1 (ABCB1) multidrug resistance 1 (MDR1) is associated with cisplatin resistance in the A549 lung adenocarcinoma cell line. AB - Development of multiple drug resistance has been attributed to the overexpression of the ATP-binding cassette B1 (ABCB1) gene. In this study, the major purpose was to assess the expression and methylation levels of ABCB1 in human lung adenocarcinoma and to reveal the relationship between these processes and acquisition of cisplatin (DDP) resistance in the human cancer cell line A549. Methylation and expression levels of the ABCB1 gene ABCB1 in clinical human lung tissue were assessed using bisulphite sequencing, reverse transcription real-time PCR (RT2 -PCR) and Western blot methods. Cell viability, DDP resistance and apoptosis of A549 cells were evaluated using the Cell Counting Kit-8 and fluorescence-activated cell sorter analysis. Our results showed that the onset of resistance to the cisplatin analogue, DDP, was associated with hypermethylation of the ABCB1 gene. Expression of the ABCB1 gene was enhanced at both mRNA and protein levels. Treatment with 5-Aza-C contributed to the hypomethylation of the ABCB1 gene and decreased ABCB1 protein expression in A549 cells. In conclusion, this in vitro and human tissue study of lung adenocarcinoma cells demonstrated that hypermethylation of the ABCB1 gene correlated with increased gene expression and was associated with the acquisition of resistance to the cisplatin analogue, DDP in human lung adenocarcinoma cells. Taken together, our study highlighted the connection between increased ABCB1 methylation level and upregulated expression of the gene in lung cancer. Moreover, the abnormally high expression of ABCB1 in A549 cells contributed to the development of the DDP resistance. PMID- 27995667 TI - Liver dysfunction in women with pregnancy-induced antithrombin deficiency. AB - AIM: The aim of this study was to determine whether women with pregnancy-induced antithrombin deficiency (PIATD) had higher risk of liver dysfunction in the absence of thrombocytopenia. METHODS: We carried out a retrospective observational study at five centers in all 129 women with incidentally found PIATD among 5249 maternities and 129 control women without PIATD matched for number of fetuses and gestational week at delivery. PIATD was diagnosed in women with antenatal antithrombin (AT) activities of <=75% followed by a further decrease to <=65% peripartum. Liver dysfunction was defined as serum aspartate aminotransferase > 45 IU/L concomitant with lactate dehydrogenase > 400 IU/L. Thrombocytopenia was defined as platelet count < 120 * 109 /L. RESULTS: Thrombocytopenia (22% [28/129] vs 5.4% [7/129], P = 0.0001) and liver dysfunction (16% [20/129] vs 0.0% [0/129], P = 0.0000) occurred significantly more often in PIATD than in control women. Of the 20 women with liver dysfunction, 15 (75%) had PIATD, but not thrombocytopenia. Thus, even in the absence of thrombocytopenia, liver dysfunction occurred significantly more often in PIATD than in control women (15% [15/101] vs 0.0% [0/122], respectively, P = 0.0000). The relative risk (95% confidence interval) of liver dysfunction was 28.6 (1.64-500) for women with AT activity of 60-65% and 52.4 (3.17-865) for women with AT activity of <60%, compared to women with AT activity >=66%. CONCLUSION: PIATD can occur in the absence of thrombocytopenia and PIATD women had higher risk of liver dysfunction even in the absence of thrombocytopenia. PMID- 27995668 TI - Erratum: Plasma neurofilament heavy chain is not a useful biomarker in Charcot Marie-Tooth disease. PMID- 27995669 TI - PERCH: A Unified Framework for Disease Gene Prioritization. AB - To interpret genetic variants discovered from next-generation sequencing, integration of heterogeneous information is vital for success. This article describes a framework named PERCH (Polymorphism Evaluation, Ranking, and Classification for a Heritable trait), available at http://BJFengLab.org/. It can prioritize disease genes by quantitatively unifying a new deleteriousness measure called BayesDel, an improved assessment of the biological relevance of genes to the disease, a modified linkage analysis, a novel rare-variant association test, and a converted variant call quality score. It supports data that contain various combinations of extended pedigrees, trios, and case-controls, and allows for a reduced penetrance, an elevated phenocopy rate, liability classes, and covariates. BayesDel is more accurate than PolyPhen2, SIFT, FATHMM, LRT, Mutation Taster, Mutation Assessor, PhyloP, GERP++, SiPhy, CADD, MetaLR, and MetaSVM. The overall approach is faster and more powerful than the existing quantitative method pVAAST, as shown by the simulations of challenging situations in finding the missing heritability of a complex disease. This framework can also classify variants of unknown significance (variants of uncertain significance) by quantitatively integrating allele frequencies, deleteriousness, association, and co-segregation. PERCH is a versatile tool for gene prioritization in gene discovery research and variant classification in clinical genetic testing. PMID- 27995670 TI - The tomato I gene for Fusarium wilt resistance encodes an atypical leucine-rich repeat receptor-like protein whose function is nevertheless dependent on SOBIR1 and SERK3/BAK1. AB - We have identified the tomato I gene for resistance to the Fusarium wilt fungus Fusarium oxysporum f. sp. lycopersici (Fol) and show that it encodes a membrane anchored leucine-rich repeat receptor-like protein (LRR-RLP). Unlike most other LRR-RLP genes involved in plant defence, the I gene is not a member of a gene cluster and contains introns in its coding sequence. The I gene encodes a loopout domain larger than those in most other LRR-RLPs, with a distinct composition rich in serine and threonine residues. The I protein also lacks a basic cytosolic domain. Instead, this domain is rich in aromatic residues that could form a second transmembrane domain. The I protein recognises the Fol Avr1 effector protein, but, unlike many other LRR-RLPs, recognition specificity is determined in the C-terminal half of the protein by polymorphic amino acid residues in the LRRs just preceding the loopout domain and in the loopout domain itself. Despite these differences, we show that I/Avr1-dependent necrosis in Nicotiana benthamiana depends on the LRR receptor-like kinases (RLKs) SERK3/BAK1 and SOBIR1. Sequence comparisons revealed that the I protein and other LRR-RLPs involved in plant defence all carry residues in their last LRR and C-terminal LRR capping domain that are conserved with SERK3/BAK1-interacting residues in the same relative positions in the LRR-RLKs BRI1 and PSKR1. Tyrosine mutations of two of these conserved residues, Q922 and T925, abolished I/Avr1-dependent necrosis in N. benthamiana, consistent with similar mutations in BRI1 and PSKR1 preventing their interaction with SERK3/BAK1. PMID- 27995671 TI - The control of flowering time by environmental factors. AB - The timing of flowering is determined by endogenous genetic components as well as various environmental factors, such as day length, temperature, and stress. The genetic elements and molecular mechanisms that rule this process have been examined in the long-day-flowering plant Arabidopsis thaliana and short-day flowering rice (Oryza sativa). However, reviews of research on the role of those factors are limited. Here, we focused on how flowering time is influenced by nutrients, ambient temperature, drought, salinity, exogenously applied hormones and chemicals, and pathogenic microbes. In response to such stresses or stimuli, plants either begin flowering to produce seeds for the next generation or else delay flowering by slowing their metabolism. These responses vary depending upon the dose of the stimulus, the plant developmental stage, or even the cultivar that is used. Our review provides insight into how crops might be managed to increase productivity under various environmental challenges. PMID- 27995672 TI - Biofilms for Monitoring Presence of Microsporidia in Environmental Water. AB - The development of molecular methodologies for targeting pathogens such as the Microsporidia has greatly improved our monitoring capabilities and initiatives. This study analyzed samples collected from five locations in Pensacola, Florida, USA for the presence of Microsporidian pathogens. To circumvent various impediments associated with water collection and filtration, we utilized biofilms as sentinels for detection of Microsporidia. We implemented membrane-dissolution and sample purification in a single confined step followed by real-time PCR to confirm pathogen presence. The results of this study demonstrate that microsporidia are present in environmental water sites in the Florida panhandle and that biofilms may serve as another alternative mode to circumvent filtration methods for their detection. PMID- 27995673 TI - How to confirm or deny high-risk thyroid carcinoma is a challenge for pathologists. PMID- 27995674 TI - Cognitive Analytic Therapy for Bipolar Disorder: A Pilot Randomized Controlled Trial. AB - : The evidence base for treatment of bipolar affective disorder (BD) demands the evaluation of new psychotherapies in order to broaden patient choice. This study reports on the feasibility, safety, helpfulness and effectiveness of cognitive analytic therapy (CAT). In a pilot randomized controlled trial, BD patients in remission were randomized to either receiving 24 sessions of CAT (n = 9) or treatment as usual (n = 9) and were assessed in terms of symptoms, functioning and service usage over time. In the CAT arm no adverse events occurred, 8/9 completed treatment, 5/8 attended all 24 sessions and 2/8 were categorized as recovered. The most common helpful event during CAT was recognition of patterns in mood variability, with helpfulness themes changing according to phase of therapy. No major differences were found when comparing the arms over time in terms of service usage or psychometric outcomes. The study suggests that conducting further research into the effectiveness of CAT in treating BD is warranted and guidance regarding future trials is provided. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Treating BD with CAT appears feasible and safe. Retaining fidelity to the reformulation, recognition and revision structure of CAT appears useful. Participants stated that across the phases of CAT, focussing on patterns of mood variability was consistently helpful. PMID- 27995675 TI - GLUT1: A novel tool reflecting proliferative activity of lung neuroendocrine tumors? AB - Lung neuroendocrine tumors (LNT) represents approximately 20% of all lung cancers. The classification of LNT relies upon morphology. Recently, in the World Health Organization (WHO) classification, Ki-67 rate has been proposed for classification. It is, however, known that Ki-67 count has a poor interlaboratory reproducibly. For that reason, our team has looked for a new biomarker. GLUT1 protein a facilitative glucose transporter protein which has ubiquitous expression in mammalian. GLUT1 is overexpressed in many human cancers. But, no study has evaluated the GLUT1 staining as an aid diagnosis in LNT. Our team have assessed the GLUT1 immunohistochemical staining in 36 LNT and to assess its diagnostic value. GLUT1 staining was higher in neuroendocrine carcinoma than in carcinoid tumor. A positive predictive value in a priori and posteriori testing for diagnosis of LNT is demonstrated. GLUT1 staining could aid in the diagnosis and should be validated in a large prospective cohort. PMID- 27995677 TI - Plasma products do not solve the inhibitor problem. PMID- 27995676 TI - Double Core-Shell Si@C@SiO2 for Anode Material of Lithium-Ion Batteries with Excellent Cycling Stability. AB - Lithium-ion batteries (LIBs) composed of silicon (Si) anodes suffer from severe capacity decay because of the volume expansion deriving from the formation of Li15 Si4 alloy. In this study, we prepared a double core-shell Si@C@SiO2 nanostructure by the modified Stober method. In the process of Si lithiation, the carbon layer alleviates the large pressure slightly then the silica shell restricts the lithiation degree of Si. The combination of carbon interlayer and silica shell guarantees structural integrity and avoids further decay of capacity because of the formation of stable solid-electrolyte interphase (SEI) films. The resultant Si@C@SiO2 presents remarkable cycling stability with capacity decay of averagely 0.03 % per cycle over 305 cycles at 200 mA g-1 , an improvement on Si@C (0.22 %) by more than a factor of 7. This encouraging result demonstrates that the designation involved in this work is effective for mitigating the capacity decay of Si-based anodes for LIBs. PMID- 27995656 TI - The effects of aminosalicylates or thiopurines on the risk of colorectal cancer in inflammatory bowel disease. AB - BACKGROUND: Whether aminosalicylates or thiopurines reduce the risk of colorectal cancer (CRC) in inflammatory bowel (IBD) disease is controversial. AIM: To assess simultaneously the chemopreventive effect of aminosalicylates or thiopurines in a case-control study nested in the CESAME observational cohort that enrolled consecutive patients with IBD between May 2004 and June 2005. Patients were followed up to December 2007. METHODS: Study population comprised 144 case patients who developed CRC from the diagnosis of IBD (65 and 79 cases diagnosed, respectively, before and from 2004, starting year of the prospective observational period of CESAME) and 286 controls matched for gender, age, IBD subtype and year of diagnosis, and cumulative extent of colitis. Exposure to aminosalicylates or thiopurines was defined by an exposure to the treatment during the year of the diagnosis of cancer. The propensity of receiving 5-ASA and thiopurines was quantified by a composite score taking into account patient and IBD characteristics. The role of aminosalicylates or thiopurines was assessed by multivariate analysis. Propensity scores and the history of primary sclerosing cholangitis were entered into the multivariate model for adjustment. RESULTS: By multivariate analysis adjusted for propensity, a significant protective effect of exposure to drugs during the year of cancer was found for aminosalicylates (OR = 0.587, 95% CI: 0.367-0.937, P = 0.0257), but not for thiopurines (OR = 0.762, 95% CI: 0.432-1.343, P = 0.3468). CONCLUSION: In a case-control study nested in the CESAME cohort, a significant decrease in the risk of colorectal cancer in IBD was associated with exposure to aminosalicylates, not to thiopurines. PMID- 27995678 TI - Nursing home manager's knowledge, attitudes and beliefs about advance care planning for people with dementia in long-term care settings: a cross-sectional survey. AB - AIMS AND OBJECTIVES: To examine nursing home managers' knowledge, attitudes, beliefs and current practice regarding advance care planning for people with dementia in long-term care settings informed by the theory of planned behaviour. BACKGROUND: Internationally, advance care planning is advocated for people with dementia. However, evidence suggests that discussions with people with dementia are rare, particularly in long-term care settings. Whilst nursing home managers can be considered central to implementation in this setting, there is a dearth of research that has examined their perspective. This study reports on their role with regard to advance care planning and the perceived factors which influence this. DESIGN: A cross-sectional postal survey was carried out as part of a larger scale sequential explanatory mixed-methods study between January-March 2015. SETTING AND PARTICIPANTS: Nursing home managers in a region in the UK (n = 178). RESULTS: A response rate of 66% (n = 116) was achieved. Nursing home managers demonstrated a lack of knowledge of advance care planning, with negative attitudes underpinned by concerns regarding the capacity and lack of perceived benefits to the person with dementia. Currently, they do not view advance care planning as part of their role, with lack of ownership impacting upon current practice behaviours. CONCLUSIONS: Whilst nursing home managers recognise the potential benefits of advance care planning, barriers and challenges create a reluctance to facilitate. Targeted training to address the knowledge deficit is required, with the wider components of advance care planning promoted. There is a need for greater role clarification to ensure nurses in long-term care settings identify with the process in the future. A gap between rhetoric and reality of implementation is evident; therefore, long-term care settings must critically examine system, organisational and individual factors for failure to implement advance care planning for people with dementia. RELEVANCE TO CLINICAL PRACTICE: Increased cognisance of the context in which advance care planning takes place is vital for improved implementation in this context. In addition strong nursing leadership is imperative to facilitate initiation, engagement and re-evaluation of the process of advance care planning. PMID- 27995679 TI - Some PWID communities are ready for PrEP, so what's next? PMID- 27995680 TI - BAY 81-8973, a full-length recombinant factor VIII: manufacturing processes and product characteristics. AB - BAY 81-8973 (Kovaltry(r) , Bayer, Berkeley, CA, USA) is an unmodified, full length recombinant human factor VIII (FVIII) approved for prophylaxis and on demand treatment of bleeding episodes in patients with haemophilia A. The BAY 81 8973 manufacturing process is based on the process used for sucrose-formulated recombinant FVIII (rFVIII-FS), with changes and enhancements made to improve production efficiency, further augment pathogen safety, and eliminate animal- and human-derived raw materials from the production processes. The baby hamster kidney cell line used for BAY 81-8973 was developed by introducing the gene for human heat shock protein 70 into the rFVIII-FS cell line, a change that improved cell line robustness and productivity. Pathogen safety was enhanced by including a 20-nm filtration step, which can remove viruses, transmissible spongiform encephalopathy agents and potential protein aggregates. No human- or animal derived proteins are added to the cell culture process, purification or final formulation. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of sialylation of N-linked glycans on the molecular surface. The innovative manufacturing techniques used for BAY 81-8973 yield an effective rFVIII product with a favourable safety profile for treatment of haemophilia A. PMID- 27995681 TI - On-Surface Dual-Response Structural Transformations of Guanine Molecules and Fe Atoms. AB - Structural transformation of metal-organic nanostructures holds great promise for structural diversity and flexibility and opens the way towards an adaptive and evolutive chemistry owing to the dynamic characteristic of coordination bonds. It is thus generally interesting and also challenging to develop systems showing reversible structural transformations which involve multiple metal-organic motifs on surfaces. Here, we have successfully constructed a system that presents structural transformations on a solid surface, in which controllable formation of multiple metal-organic nanostructures (with different coordination binding modes by use of distinct binding sites) in response to both metal atoms and molecules is achieved at room temperature (RT) under ultrahigh vacuum (UHV) conditions. The key to making these interconversions successful is the intrinsic dynamic characteristic of coordination bonds together with the coordination priority and diversity. PMID- 27995682 TI - Divergent Iron-Catalyzed Coupling of O-Acyloximes with Silyl Enol Ethers. AB - An iron-catalyzed coupling reaction of O-acyloximes and O-benzoyl amidoximes with silyl enol ethers is reported. The protocol provides access to functionalized pyrroles, 1,6-ketonitriles, pyrrolines and imidazolines via carbon-centered radicals generated from an initially formed iminyl radical. The intramolecular cyclization and ring-opening processes of the iminyl radical take place preferentially over reactions that proceed through a 1,3-hydrogen transfer, providing insights into iron-catalyzed reactions with oxime derivatives. The cheap and environmentally friendly iron catalyst, the broad substrate scope and the functional group compatibility make this protocol useful for synthesis of valuable nitrogen-containing products. PMID- 27995683 TI - Letter to the editor regarding cardiac arrest with vagal stimulation during intraoperative nerve monitoring. PMID- 27995684 TI - Comparing QT interval variability of semiautomated and high-precision ECG methodologies in seven thorough QT studies-implications for the power of studies intended for definitive evaluation of a drug's QT effect. AB - BACKGROUND: In studies of drug effects on electrocardiographic parameters, the level of precision in measuring QTc interval changes will influence a study's ability to detect small effects. METHODS: Variability data from investigational, placebo and moxifloxacin treatments from seven thorough QT studies performed by the same sponsor were analyzed with the objective to compare the performance of two commonly used approaches for ECG interval measurements: semiautomated (SA) and the high-precision QT (HPQT) analysis. Five studies were crossover and two parallel. Harmonized procedures were implemented to ensure similar experimental conditions across studies. ECG replicates were extracted serially from continuous 12-lead recordings at predefined time points from subjects supinely resting. The variability estimates were based on the time-point analysis of change-from baseline QTcF as the dependent variable for the standard primary analysis of previous thorough QT studies. The residual variances were extracted for each study and ECG technique. RESULTS: High-precision QT resulted in a substantial reduction in ?QTc variability as compared to SA. A reduction in residual variability or approximately 50% was achieved in both crossover and parallel studies, both for the active comparison (drug vs. placebo) and for assay sensitivity (moxifloxacin vs. placebo) data. CONCLUSIONS: High-precision QT technique significantly reduces QT interval variability and thereby the number of subjects needed to exclude small effects in QT studies. Based on this assessment, the sample size required to exclude a QTc effect >10 ms with 90% power is reduced from 35 with SA to 18 with HPQT, if a 3 ms underlying drug effect is assumed. PMID- 27995685 TI - TaADF4, an actin-depolymerizing factor from wheat, is required for resistance to the stripe rust pathogen Puccinia striiformis f. sp. tritici. AB - Actin filament assembly in plants is a dynamic process, requiring the activity of more than 75 actin-binding proteins. Central to the regulation of filament assembly and stability is the activity of a conserved family of actin depolymerizing factors (ADFs), whose primarily function is to regulate the severing and depolymerization of actin filaments. In recent years, the activity of ADF proteins has been linked to a variety of cellular processes, including those associated with response to stress. Herein, a wheat ADF gene, TaADF4, was identified and characterized. TaADF4 encodes a 139-amino-acid protein containing five F-actin-binding sites and two G-actin-binding sites, and interacts with wheat (Triticum aestivum) Actin1 (TaACT1), in planta. Following treatment of wheat, separately, with jasmonic acid, abscisic acid or with the avirulent race, CYR23, of the stripe rust pathogen Puccinia striiformis f. sp. tritici, we observed a rapid induction in accumulation of TaADF4 mRNA. Interestingly, accumulation of TaADF4 mRNA was diminished in response to inoculation with a virulent race, CYR31. Silencing of TaADF4 resulted in enhanced susceptibility to CYR23, demonstrating a role for TaADF4 in defense signaling. Using a pharmacological-based approach, coupled with an analysis of host response to pathogen infection, we observed that treatment of plants with the actin-modifying agent latrunculin B enhanced resistance to CYR23, including increased production of reactive oxygen species and enhancement of localized hypersensitive cell death. Taken together, these data support the hypothesis that TaADF4 positively modulates plant immunity in wheat via the modulation of actin cytoskeletal organization. PMID- 27995686 TI - Reply to letter to the editor regarding cardiac arrest after vagal stimulation in intraoperative neuromonitoring. PMID- 27995687 TI - Pathological findings of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. PMID- 27995688 TI - Self-administered medications in the postpartum wards: A study on satisfaction and perceptions. AB - OBJECTIVE: The objective of this study was to describe women's satisfaction and perceptions on the postpartum self-administered medication (SAM) program at our institution and on pain relief. Also, we aimed at describing maternal and breastfed infants' adverse events with the use of the postpartum SAM program. METHOD: This prospective 1-group mixed methods survey conducted in a mother-and child tertiary center included women enrolled in the postpartum SAM program who had a live newborn, understood French or English, and were at least 18 years old. Newborns included cohabited with their mother during their hospitalization and had received breast milk at least once. Data were collected through direct interviews using a questionnaire and through medical charts. RESULTS: We included 314 mothers and 263 breastfed newborns in the study. Ninety-seven percent of all users appreciated the SAM. The self-reported median overall improvement of pain was 80% (interquartile range, 70%-90%). However, 18% of users who delivered vaginally and 32% who delivered through caesarean would have preferred traditional drug dispensing by the nurse (P = .009). Drugs used in the SAM program were generally well tolerated. There were no worrisome adverse drug events reported in newborns' medical charts. CONCLUSION: Results show a 97% rate of satisfaction of the SAM program and a high self-reported pain improvement in a cohort of 314 women using our SAM program. The results suggest that the SAM program should remain a standard practice in our institution. Some recommendations will be drawn to better tailor the SAM program to the needs expressed by the users. PMID- 27995689 TI - An indoleacetic acid-producing Ochrobactrum sp. MGJ11 counteracts cadmium effect on soybean by promoting plant growth. AB - AIMS: To analyse whether some indoleacetic acid (IAA)-secreting plant growth promoting bacteria can alleviate cadmium (Cd) stress, the role of an Ochrobactrum sp. MGJ11 from rhizosphere of soybean in promoting plant growth, and to evaluate the counteracting Cd effects on soybean. METHODS AND RESULTS: Ochrobactrum sp. MGJ11 produced 121.2 mg l-1 of IAA. MGJ11 increased soybean root length, shoot length and biomass by 30.1, 30.8 and 13.4% respectively. In liquid medium, no IAA production was detected in Cd concentration of 100 mg l-1 . In soil with 20-80 mg kg-1 Cd, MGJ11 promoted soybean root elongation (29.4-161.4%) and increased the shoot length (up to 52.7%) and biomass (up to 87.2%). After growing for 38 days, Cd concentrations in the roots of inoculated soybean were lower than in those of noninoculated plants. Only a little Cd (2.6-16.9 MUg g-1 ) was translocated from the root to shoot. CONCLUSIONS: Ochrobactrum sp. MGJ11 secretes IAA and shows tolerance against Cd. MGJ11 inoculation improves the root length, shoot length and biomass of soybean in both vermiculite and Cd vermiculite, and decreases Cd concentration of soybean root. The characteristics of MGJ11 suggest that it could be used for promoting soybean growth and lowering bioavailability of soil Cd for soybean root. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we isolated a plant growth-promoting Ochrobactrum with the activity of mitigating Cd toxicity to plant roots. The Ochrobactrum can be considered as a potential bioaugmentation agent that promotes plant growth, especially in some agricultural systems, or that helps in the phytoremediation of Cd-contaminated soil. PMID- 27995691 TI - Hidden authority study data have come to light: besides narcolepsy, the swine influenza vaccine Pandemrix caused type 1 diabetes. PMID- 27995690 TI - An investigation of mental imagery in bipolar disorder: Exploring "the mind's eye". AB - OBJECTIVES: Mental imagery abnormalities occur across psychopathologies and are hypothesized to drive emotional difficulties in bipolar disorder (BD). A comprehensive assessment of mental imagery in BD is lacking. We aimed to test whether (i) mental imagery abnormalities (abnormalities in cognitive stages and subjective domains) occur in BD relative to non-clinical controls; and (ii) to determine the specificity of any abnormalities in BD relative to depression and anxiety disorders. METHODS: Participants included 54 subjects in the BD group (depressed/euthymic; n=27 in each subgroup), subjects with unipolar depression (n=26), subjects with anxiety disorders (n=25), and non-clinical controls (n=27) matched for age, gender, ethnicity, education, and premorbid IQ. Experimental tasks assessed cognitive (non-emotional) measures of mental imagery (cognitive stages). Questionnaires, experimental tasks, and a phenomenological interview assessed subjective domains including spontaneous imagery use, interpretation bias, and emotional mental imagery. RESULTS: (i) Compared to non-clinical controls, the BD combined group reported a greater impact of intrusive prospective imagery in daily life, more vivid and "real" negative images (prospective imagery task), and higher self-involvement (picture-word task). The BD combined group showed no clear abnormalities in cognitive stages of mental imagery. (ii) When depressed individuals with BD were compared to the depressed or anxious clinical control groups, no significant differences remained-across all groups, imagery differences were associated with affective lability and anxiety. CONCLUSIONS: Compared to non-clinical controls, BD is characterized by abnormalities in aspects of emotional mental imagery within the context of otherwise normal cognitive aspects. When matched for depression and anxiety, these abnormalities are not specific to BD-rather, imagery may reflect a transdiagnostic marker of emotional psychopathology. PMID- 27995692 TI - C-peptide and the pathophysiology of microvascular complications of diabetes. PMID- 27995693 TI - Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. PMID- 27995694 TI - Response to letter from Lars Andersson. PMID- 27995695 TI - Analysis of plant hormone profiles in response to moderate dehydration stress. AB - Plant responses to dehydration stress are mediated by highly complex molecular systems involving hormone signaling and metabolism, particularly the major stress hormone abscisic acid (ABA) and ABA-dependent gene expression. To understand the roles of plant hormones and their interactions during dehydration, we analyzed the plant hormone profiles with respect to dehydration responses in Arabidopsis thaliana wild-type (WT) plants and ABA biosynthesis mutants (nced3-2). We developed a procedure for moderate dehydration stress, and then investigated temporal changes in the profiles of ABA, jasmonic acid isoleucine (JA-Ile), salicylic acid (SA), cytokinin (trans-zeatin, tZ), auxin (indole-acetic acid, IAA), and gibberellin (GA4 ), along with temporal changes in the expression of key genes involved in hormone biosynthesis. ABA levels increased in a bi-phasic pattern (at the early and late phases) in response to moderate dehydration stress. JA-Ile levels increased slightly in WT plants and strongly increased in nced3-2 mutant plants at 72 h after the onset of dehydration. The expression profiles of dehydration-inducible genes displayed temporal responses in an ABA dependent manner. The early phase of ABA accumulation correlated with the expression of touch-inducible genes and was independent of factors involved in the major ABA regulatory pathway, including the ABA-responsive element-binding (AREB/ABF) transcription factor. JA-Ile, SA, and tZ were negatively regulated during the late dehydration response phase. Transcriptome analysis revealed important roles for hormone-related genes in metabolism and signaling during dehydration-induced plant responses. PMID- 27995697 TI - Language development, delay and intervention-the views of parents from communities that speech and language therapy managers in England consider to be under-served. AB - BACKGROUND: Evidence-based practice includes research evidence, clinical expertise and stakeholder perspectives. Stakeholder perspectives are important and include parental ethno-theories, which embrace views about many aspects of speech, language and communication, language development, and interventions. The Developmental Niche Framework provides a useful theory to understand parental beliefs. Ethnotheories, including those about language development, delay and interventions, may vary cross culturally and are less well understood in relation to families who may be considered 'under-served' or 'hard-to-reach' by speech and language therapy services. Who is considered to be under-served and the reasons why some families are under-served are complex. AIM: To describe beliefs and reported practices, in relation to speech and language development, delay and intervention, of parents and carers from a small number of groups in England who were perceived to be under-served in relation to SLT services. METHODS & PROCEDURES: As part of a wider National Institute for Health Research (NIHR) funded study (Child Talk), seven focus groups (with a total of 52 participants) were held with parents from three communities in England. Topics addressed included beliefs about language development, language delay and parents' reported responses to language delay. Data were transcribed and analysed using adapted framework analysis, which also drew on directed content analysis. OUTCOMES & RESULTS: Four themes resulted that broadly matched the topics addressed in the focus groups: language development and the environment; causes and signs of speech and language delay; responses to concerns about speech, language and communication; and improving SLT. These produced some previously unreported ideas, e.g., about how language develops and the causes of delay. CONCLUSIONS & IMPLICATIONS: The findings are discussed in relation to previous literature and the Developmental Niche Framework. Clinical implications include ideas about issues for SLTs to discuss with families and the need to recognize that parents may see themselves as competent facilitators of language. Suggestions are made for future research, including: expanded investigation of a wider range of under served groups, an exploration of who parents consult when concerned about their child's language, and how key community figures advise parents in relation to language delay. PMID- 27995696 TI - Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. AB - AIMS: Heart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long-term preventive application of the phosphodiesterase-5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy associated HFpEF. METHODS AND RESULTS: Zucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro-oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro-oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro-oxidative stress, myocardial hypertrophy and fibrotic remodelling. CONCLUSIONS: We report that vardenafil successfully prevented the development of diabetes mellitus-associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus. PMID- 27995698 TI - Dibora[2]ferrocenophane: A Carbene-Stabilized Diborene in a Strained cis Configuration. AB - Unsaturated bridges that link the two cyclopentadienyl ligands together in strained ansa metallocenes are rare and limited to carbon-carbon double bonds. The synthesis and isolation of a strained ferrocenophane containing an unsaturated two-boron bridge, isoelectronic with a C=C double bond, was achieved by reduction of a carbene-stabilized 1,1'-bis(dihaloboryl)ferrocene. A combination of spectroscopic and electrochemical measurements as well as density functional theory (DFT) calculations was used to assess the influence of the unprecedented strained cis configuration on the optical and electrochemical properties of the carbene-stabilized diborene unit. Initial reactivity studies show that the dibora[2]ferrocenophane is prone to boron-boron double bond cleavage reactions. PMID- 27995699 TI - Conformational Analysis of a High-Mannose-Type Oligosaccharide Displaying Glucosyl Determinant Recognised by Molecular Chaperones Using NMR-Validated Molecular Dynamics Simulation. AB - Exploration of the conformational spaces of flexible oligosaccharides is essential to gain deeper insights into their functional mechanisms. Here we characterised dynamic conformation of a high-mannose-type dodecasaccharide with a terminal glucose residue, a critical determinant recognised by molecular chaperones. The dodecasaccharide was prepared by our developed chemoenzymatic technique, which uses 13 C labelling and lanthanide tagging to detect conformation-dependent paramagnetic effects by NMR spectroscopy. The NMR validated molecular dynamics simulation produced the dynamic conformational ensemble of the dodecasaccharide. This determined its spatial distribution as well as the glycosidic linkage conformation of the terminal glucose determinant. Moreover, comparison of our results with previously reported crystallographic data indicates that the chaperone binding to its target oligosaccharides involves an induced-fit mechanism. PMID- 27995700 TI - SHOT conference report 2016: serious hazards of transfusion - human factors continue to cause most transfusion-related incidents. AB - The Annual SHOT Report for incidents reported in 2015 was published on 7 July at the SHOT symposium. Once again, the majority of reports (77.7%) were associated with mistakes ('human factors'). Pressures and stress in the hospital environment contributed to several error reports. There were 26 deaths where transfusion played a part, one due to haemolysis from anti-Wra (units issued electronically). The incidence of haemolysis due to this antibody has increased in recent years. Transfusion-associated circulatory overload is the most common contributor to death and major morbidity. Reports of delays to transfusion have increased, some caused by the failure of correct patient identification. There were seven ABO incompatible red cell transfusions (one death) with an additional six to allogeneic stem cell transplant recipients. Near-miss reporting and analysis is useful and demonstrated nearly 300 instances of wrong blood in tube, which could have resulted in ABO-incompatible transfusion had the error not been detected. Errors with anti-D immunoglobulin continue, and preliminary data from the new survey of new anti-D found in pregnancy has shown that sensitisation occurs in some women even with apparently 'ideal' care. For the first time, the SHOT report now incorporates a chapter on donor events. PMID- 27995701 TI - Abstracts from the SHOT Symposium 7th July 2016. PMID- 27995703 TI - Shade tolerance and herbivory are associated with RGR of tree species via different functional traits. AB - Relative growth rate (RGR) plays an important role in plant adaptation to the light environment through the growth potential/survival trade-off. RGR is a complex trait with physiological and biomass allocation components. It has been argued that herbivory may influence the evolution of plant strategies to cope with the light environment, but little is known about the relation between susceptibility to herbivores and growth-related functional traits. Here, we examined in 11 evergreen tree species from a temperate rainforest the association between growth-related functional traits and (i) species' shade-tolerance, and (ii) herbivory rate in the field. We aimed at elucidating the differential linkage of shade and herbivory with RGR via growth-related functional traits. We found that RGR was associated negatively with shade-tolerance and positively with herbivory rate. However, herbivory rate and shade-tolerance were not significantly related. RGR was determined mainly by photosynthetic rate (Amax ) and specific leaf area (SLA). Results suggest that shade tolerance and herbivore resistance do not covary with the same functional traits. Whereas shade-tolerance was strongly related to Amax and to a lesser extent to leaf mass ratio (LMR) and dark respiration (Rd ), herbivory rate was closely related to allocation traits (SLA and LMR) and slightly associated with protein content. The effects of low light on RGR would be mediated by Amax , while the effects of herbivory on RGR would be mediated by SLA. Our findings suggest that shade and herbivores may differentially contribute to shape RGR of tree species through their effects on different resource-uptake functional traits. PMID- 27995704 TI - Treatment of intractable chronic cluster headache by occipital nerve stimulation: a cohort of 51 patients. AB - BACKGROUND AND PURPOSE: Chronic cluster headache is a rare, highly disabling primary headache condition. When medically intractable, occipital nerve stimulation can offer effective treatment. Open-label series have provided data on small cohorts only. METHODS: We analyzed 51 subjects to evaluate the long-term outcomes of highly intractable chronic cluster headache with occipital nerve stimulation. Patients with intractable chronic cluster headache were implanted with occipital nerve stimulators during the period 2007-2014. The primary endpoint was improvement in daily attack frequency. Secondary endpoints included attack severity, attack duration, quality-of-life measures, headache disability scores and adverse events. RESULTS: We studied 51 patients [35 males; mean age at implant 47.78 (range 31-70) years; mean follow-up 39.17 (range 2-81) months]. Nineteen patients had other chronic headache types in addition in chronic cluster headache. At final follow-up, there was a 46.1% improvement in attack frequency (P < 0001) across all patients, 49.5% (P < 0.001) in those with cluster headache alone and 40.3% (P = 0.036) in those with multiple phenotypes. There were no significant differences in response in those with or without multiple headache types. The overall response rate (defined as at least a 50% improvement in attack frequency) was 52.9%. Significant reductions were also seen in attack duration and severity. Improvements were noted in headache disability scores and quality of-life measures. Triptan use of responders dropped by 62.56%, resulting in significant cost savings. Adverse event rates were highly favorable. CONCLUSION: Occipital nerve stimulation appears to be a safe and efficacious treatment for highly intractable chronic cluster headache even after a mean follow-up of over 3 years. PMID- 27995705 TI - More Than Money: Motivating Physician Behavior Change in Accountable Care Organizations. PMID- 27995706 TI - Prescription Drug Pricing Is Not Just an Election Issue. PMID- 27995708 TI - How Helpful Are Hospital Rankings and Ratings for the Public's Health? PMID- 27995709 TI - Hard to Avoid but Difficult to Sustain: Scotland's Innovative Health Tax on Large Retailers Selling Tobacco and Alcohol. PMID- 27995710 TI - Violent Injury as a Preventable Condition. PMID- 27995712 TI - A Very Long Journey: A Decade's Quest for Quarantine Regulations. PMID- 27995713 TI - Winning the War on Tobacco-and Public Cynicism, Too. PMID- 27995711 TI - Instruments Measuring Integrated Care: A Systematic Review of Measurement Properties. AB - : Policy Points: Investigations on systematic methodologies for measuring integrated care should coincide with the growing interest in this field of research. A systematic review of instruments provides insights into integrated care measurement, including setting the research agenda for validating available instruments and informing the decision to develop new ones. This study is the first systematic review of instruments measuring integrated care with an evidence synthesis of the measurement properties. We found 209 index instruments measuring different constructs related to integrated care; the strength of evidence on the adequacy of the majority of their measurement properties remained largely unassessed. CONTEXT: Integrated care is an important strategy for increasing health system performance. Despite its growing significance, detailed evidence on the measurement properties of integrated care instruments remains vague and limited. Our systematic review aims to provide evidence on the state of the art in measuring integrated care. METHODS: Our comprehensive systematic review framework builds on the Rainbow Model for Integrated Care (RMIC). We searched MEDLINE/PubMed for published articles on the measurement properties of instruments measuring integrated care and identified eligible articles using a standard set of selection criteria. We assessed the methodological quality of every validation study reported using the COSMIN checklist and extracted data on study and instrument characteristics. We also evaluated the measurement properties of each examined instrument per validation study and provided a best evidence synthesis on the adequacy of measurement properties of the index instruments. FINDINGS: From the 300 eligible articles, we assessed the methodological quality of 379 validation studies from which we identified 209 index instruments measuring integrated care constructs. The majority of studies reported on instruments measuring constructs related to care integration (33%) and patient-centered care (49%); fewer studies measured care continuity/comprehensive care (15%) and care coordination/case management (3%). We mapped 84% of the measured constructs to the clinical integration domain of the RMIC, with fewer constructs related to the domains of professional (3.7%), organizational (3.4%), and functional (0.5%) integration. Only 8% of the instruments were mapped to a combination of domains; none were mapped exclusively to the system or normative integration domains. The majority of instruments were administered to either patients (60%) or health care providers (20%). Of the measurement properties, responsiveness (4%), measurement error (7%), and criterion (12%) and cross-cultural validity (14%) were less commonly reported. We found <50% of the validation studies to be of good or excellent quality for any of the measurement properties. Only a minority of index instruments showed strong evidence of positive findings for internal consistency (15%), content validity (19%), and structural validity (7%); with moderate evidence of positive findings for internal consistency (14%) and construct validity (14%). CONCLUSIONS: Our results suggest that the quality of measurement properties of instruments measuring integrated care is in need of improvement with the less-studied constructs and domains to become part of newly developed instruments. PMID- 27995714 TI - Might Oral Health Be the Next Big Thing? PMID- 27995716 TI - Neglected. PMID- 27995715 TI - The Evolving Dynamics of Employer-Sponsored Health Insurance: Implications for Workers, Employers, and the Affordable Care Act. PMID- 27995718 TI - When Old Is New: Medicaid's EPSDT Benefit at Fifty, and the Future of Child Health Policy. PMID- 27995717 TI - Spanish-Speaking Immigrants' Access to Safety Net Providers and Translation Services Across Traditional and Emerging US Destinations. PMID- 27995720 TI - Webs of Denial: Climate Change and the Challenge to Public Health. PMID- 27995721 TI - Dermatology 2016: old problems - new challenges: editor's pick of the year 2016. PMID- 27995722 TI - Comparative study of surgical knots using a domestically produced Chinese surgical robot, laparoscope, or barehanded approach. AB - BACKGROUND: We conducted a comparative analysis of the first domestically produced Chinese surgical robot, 'MicroHand', laparoscopic, and barehanded approaches in tying surgical knots. METHODS: Four surgeons performed square or triple knots individually using the three approaches and documented the operational time, circumference, the bearable tension and action trajectory for each knot. RESULTS: MicroHand took more time than the barehanded method but nearly the same as with the laparoscope. The barehanded method generated the smallest knots among the three approaches and MicroHand produced smaller square knots than those by laparoscope. MicroHand and barehanded methods produced square knots displaying higher bearable tension than those produced by the laparoscope. For the action trajectory, MicroHand operated in a smaller space than that needed by the laparoscope. CONCLUSIONS: The square knots produced by MicroHand were tighter and more solid than those by laparoscope, although the triple knots generated by the two methods were similar. Also MicroHand required a smaller operational space than the laparoscope. PMID- 27995723 TI - MasterOnline Periodontology and Implant Therapy-revisited after seven years: A case study of the structures and outcomes in a blended learning CPD. AB - INTRODUCTION: There is a great need for postgraduate training and continuing professional development (CPD), specifically in the field of periodontology. Despite the plenty of periodontal CPDs, there is a lack of information about the performance of CPDs in a blended learning setting. This study is a case study of the structures and outcomes in a blended learning CPD programme in periodontology, the MasterOnline Periodontology and Implant Therapy hosted by the University of Freiburg's Dental School. MATERIAL AND METHODS: The structures of the blended learning CPD were analysed with the aims to (i) make explicit how various innovative educational methods and ICT tools can be successfully applied to a Web-supported postgraduate periodontology training programme, (ii) identify the programme's impact on learning transfer in students' dental practices and (iii) identify other outcomes, synergies and any changes required during the existence. Using qualitative interviewing, the various types of learning transfer and elements of the study programme that foster transfer could be exemplified. RESULTS: A period of 7 years was analysed. In this duration, 50 students successfully graduated to a master of science. Qualitative interviews were performed with six students and four teachers affirming the learning transfer in a blended learning setting. CONCLUSIONS: This case study shows that blended learning can be a successful approach for CPD in dentistry. PMID- 27995724 TI - Canagliflozin versus placebo for post-bariatric surgery patients with persistent type II diabetes: A randomized controlled trial (CARAT). PMID- 27995725 TI - The dysregulated brain: consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis. AB - Increasingly, evidence has been accumulating emphasizing the importance of looking at bipolar disorder (BD) from a neurodevelopmental and transdimensional perspective to better understand its origins and its course. In this overview article, the problems facing pathophysiological psychiatric research in BD are addressed and interpreted in the light of brain complexity. Brain complexity can be split into spatial complexity, which constitutes the physiological levels of the central nervous system (i.e., the genetic, molecular, cellular, neuronal circuit and phenomenological levels), and temporal complexity, that is, neurodevelopment. The consequences of this consideration are discussed and suggestions for clinical practice and pathophysiological psychiatric research are made. PMID- 27995726 TI - Glycemic control indicator levels at diagnosis of neonatal diabetes mellitus: Comparison with other types of insulin-dependent diabetes mellitus. AB - BACKGROUND: Neonatal diabetes mellitus (NDM) is a monogenic insulin-dependent diabetes that develops within 6 months of age. The progression of hyperglycemia until diagnosis is unknown. Glycemic control indicators at diagnosis are useful to estimate the extent and duration of hyperglycemia. We recently established that age-adjusted glycated albumin (GA) is a useful indicator of glycemic control, regardless of age. OBJECTIVE: To compare the levels of various glycemic control indicators at diagnosis between NDM and other types of insulin-dependent diabetes mellitus. PATIENTS AND METHODS: We included 8 patients with NDM, 8 with fulminant type 1 diabetes (FT1D), and 24 with acute-onset autoimmune type 1 diabetes (T1AD). Plasma glucose, glycated hemoglobin (HbA1c), GA, and age adjusted GA (calculated as previously reported) were measured and compared. RESULTS: There were no significant differences in the plasma glucose levels of the group of patients with NDM and those with FT1D or T1AD. HbA1c and GA levels in the NDM group were not significantly different from those in the FT1D group, and both indicators were lower than those in the T1AD group. Age-adjusted GA levels in the NDM group did not differ significantly from those in the T1AD group, but were higher than those in the FT1D group. CONCLUSIONS: These findings suggest that the time-course of plasma glucose elevation in NDM until diagnosis is similar to that in T1AD. In addition, the high age-adjusted GA value at diagnosis of NDM indicates that this test is useful for assessing chronic hyperglycemia in NDM. PMID- 27995727 TI - Kinetic analysis and binding studies of a new recombinant human factor VIIa for treatment of haemophilia. AB - INTRODUCTION/AIM: LR769 is a new second-generation recombinant human Factor VIIa (rhFVIIa) developed for haemophilia treatment. We determined enzymatic properties of LR769 and its interaction with antithrombin, tissue factor, platelets and endothelial protein C receptor (EPCR), compared with NovoSevenRT. METHODS: Kinetic enzyme assays and active site titration were used for enzymatic studies. Surface Plasmon Resonance (SPR) was used for determination of binding constants. Cellular binding was determined for platelets and cultured human umbilical vein endothelial cells (HUVEC). RESULTS: The dissociation constant (Kd ) for activated platelet binding was in the 1 MUm range for both products. At saturation, more LR769 than NovoSevenRT was bound to the platelets. Binding to HUVEC was 25-50% higher for LR769 than for NovoSevenRT. Protein C, soluble EPCR, and anti-EPCR antibody all reduced the binding, indicating specificity for EPCR. LR769 was similar to NovoSevenRT in all kinetic assays. Active site titration demonstrated 0.7 mole of active site/mole of protein. The kcat /Km values for activation of FX and FIX with purified recombinant tissue factor and phospholipids were 10.5 s-1 /0.32 MUm and 3.3 s-1 /0.44 MUm respectively. The apparent second-order rate constant for inactivation by human plasma AT was 5.9 +/- 0.4 * 103 m-1 s-1 . The Kd values for binding of LR769 to soluble tissue factor and full-length tissue factor were 8.1 nm and 0.9 nm, respectively, and the Kd for binding to soluble EPCR was 41 nm. CONCLUSION: Overall, LR769 exhibited characteristics similar to NovoSevenRT, but bound EPCR on HUVEC with somewhat higher affinity than NovoSevenRT. PMID- 27995728 TI - Do dental undergraduates think that Thiel-embalmed cadavers are a more realistic model for teaching exodontia? AB - INTRODUCTION: Teaching exodontia to novice undergraduates requires a realistic model. Thiel-embalmed cadavers retain the flexibility of the soft tissues and could be used to teach exodontia. OBJECTIVE: The objective was to determine whether Thiel-embalmed cadavers were perceived to be a more realistic model by undergraduates in comparison with mannequins. MATERIALS AND METHODS: Over a period of 4 years (2011-2014), students were randomly assigned into two groups: those taught exodontia on mannequins only (NT) and those who also experienced cadaveric teaching (T). This was followed by an assessment. RESULTS: There were 174 students in the T group and 108 in the NT group. Sixty-five per cent of the T group and 69% of the NT group provided feedback. Ninety-eight per cent (98%) felt that they had been advantaged by being included in the group compared with 95% in the NT who felt disadvantaged. The majority (98%) thought that using the cadavers was advantageous and gave a realistic feel for soft tissue management (89%) and that it was similar to managing a patient (81%). Self-reported confidence in undertaking an extraction was not different between the two groups (P=.078), and performance in the extraction assessment was not significantly different between the two groups over the 4 years (P=.8). CONCLUSION: The Thiel-embalmed cadavers were well received by the students who found it a more realistic model for exodontia than a mannequin, even though this did not impact on their performance in a following assessment. Future work on these cadavers may be expanded to include surgical procedures. PMID- 27995730 TI - Dental students' perceptions on the contribution and impact role of a clinical teacher. AB - OBJECTIVES: This study was conducted in University of Malaya to evaluate student perceptions on the contribution and role of an effective clinical teacher based on the cognitive apprenticeship model in clinical practice. METHODS: Self administered questionnaires were distributed to 233 undergraduate dental students involved with clinical teaching. This modified and validated questionnaire focusing on students' learning environment was used in order to gain relevant information related to dental clinical teaching. Six domains with different criteria applicable to clinical teaching in dentistry were selected consisting of modelling (four criteria), coaching (four criteria), scaffolding (four criteria), articulation (four criteria), reflection (two criteria) and general learning environment (six criteria). Data analyses were performed using IBM SPSS Statistics 20. RESULTS: Majority of the students expressed positive perceptions on their clinical learning experience towards the clinical teachers in the Faculty of Dentistry, University of Malaya, in all criteria of the domains. Few negative feedbacks concerning the general learning environment were reported. CONCLUSION: Further improvement in the delivery of clinical teaching preferably by using wide variety of teaching-learning activities can be taken into account through students' feedback on their learning experience. PMID- 27995729 TI - Is serum level of nestin useful in detecting epithelial ovarian cancer? AB - AIM: The aim of the present study was to evaluate the usefulness of nestin as a discriminative marker between benign and malignant ovarian tumors. METHODS: During the 1 year from January 2015 through December 2015, a nonconsecutive series of 80 patients (40 malignant, 40 benign) who underwent surgery for an adnexal mass were enrolled in the study. Intraoperative frozen section evaluation was performed if there was a suspicion in diagnosis. Statistical analyses were performed using spss ver. 16.0, while clinicopathological variables, including the categorical data, were analyzed using the chi2 -test or Fisher's exact test. A P-value < 0.05 was defined as statistically significant. RESULTS: Preoperative serum carbohydrate antigen (CA)-125, CA-15-3, and nestin levels were significantly higher in the malignant group compared to patients with benign ovarian tumors (P < 0.001, respectively). Serum nestin levels did not differ significantly on the basis of histologic subtypes. Serum nestin levels had specificity of 89.7%, which demonstrates nestin's sufficiency to distinguish benign from malignant epithelial ovarian tumors. The positive likelihood ratio of nestin was found to be superior to that of CA-125 and CA-15-3. CONCLUSION: The results obtained from our study suggest that measurement of nestin level, alongside physical examination, transvaginal ultrasound, and serum CA-125 and CA 15-3 levels, can help differentiate benign ovarian tumors from malignant epithelial ovarian tumors. The findings of our study need to be supported with additional studies. PMID- 27995731 TI - Treatment of prednisolone-induced hyperglycaemia in hospitalized patients: Insights from a randomized, controlled study. AB - AIM: Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine-based basal-bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized patients. MATERIALS AND METHODS: Fifty inpatients prescribed >=20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) >=15 mmol/L or (2) BGLs >=10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system. RESULTS: On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% +/- 5.5% vs 50.0% +/- 5.7%, P = .28), mean daily glucose (10.2 +/- 0.7 vs 10.8 +/- 0.8 mmol/L, P = .57) or glucose <4 mmol/L (2.2% +/- 1.1% vs 2.0% +/- 1.3%, P = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced ( P = .02) and the insulin dose was increased over time ( P = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time ( P = .45) or between groups ( P = .24). CONCLUSIONS: There were no differences in the efficacy or safety of the isophane and glargine-based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre-prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone-induced hyperglycaemia. PMID- 27995732 TI - oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca2+ /K+ channel flow. AB - oxLDL peptide vaccine and its antibody adoptive transferring have shown a significantly preventive or therapeutic effect in atherosclerotic animal model. The molecular mechanism behind this is obscure. Here, we report that oxLDL induces MCP-1 release in monocytes/macrophages through their TLR-4 (Toll-like receptor 4) and ERK MAPK pathway and is calcium/potassium channel-dependent. Using blocking antibodies against CD36, TLR-4, SR-AI and LOX-1, only TLR-4 antibody was found to have an inhibitory effect and ERK MAPK-specific inhibitor (PD98059) was found to have a dramatic inhibitory effect compared to inhibitors of other MAPK group members (p38 and JNK MAPKs) on oxLDL-induced MCP-1 release. The release of cytokines and chemokines needs influx of extracellular calcium and imbalance of efflux of potassium. Nifedipine, a voltage-dependent calcium channel (VDCC) inhibitor, and glyburide, an ATP-regulated potassium channel (K+ATP ) inhibitor, inhibit oxLDL-induced MCP-1 release. Potassium efflux and influx counterbalance maintains the negative potential of macrophages to open calcium channels, and our results suggest that oxLDL actually induces the closing of potassium influx channel - inward rectifier channel (Kir ) and ensuing the opening of calcium channel. ERK MAPK inhibitor PD98059 inhibits oxLDL-induced Ca2+ /Kir channel alterations. The interfering of oxLDL-induced MCP-1 release by its monoclonal antibody is through its FcgammaRIIB (CD32). Using blocking antibodies against FcgammaRI (CD64), FcgammaRIIB (CD32) and FcgammaRIII (CD16), only CD32 blocking antibody was found to reverse the inhibitory effect of oxLDL antibody on oxLDL-induced MCP-1 release. Interestingly, oxLDL antibody specifically inhibits oxLDL-induced ERK MAPK activation and ensuing Ca2+ /Kir channel alterations, and MCP-1 release. Thus, we found a molecular mechanism of oxLDL antibody on inhibition of oxLDL-induced ERK MAPK pathway and consequent MCP 1 release. PMID- 27995733 TI - Dentate gyrus-cornu ammonis (CA) 4 volume is decreased and associated with depressive episodes and lipid peroxidation in bipolar II disorder: Longitudinal and cross-sectional analyses. AB - OBJECTIVES: Reduced dentate gyrus volume and increased oxidative stress have emerged as potential pathophysiological mechanisms in bipolar disorder. However, the relationship between dentate gyrus volume and peripheral oxidative stress markers remains unknown. Here, we examined dentate gyrus-cornu ammonis (CA) 4 volume longitudinally in patients with bipolar II disorder (BD-II) and healthy controls and investigated whether BD-II is associated with elevated peripheral levels of oxidative stress. METHODS: We acquired high-resolution structural 3T magnetic resonance imaging (MRI) images and quantified hippocampal subfield volumes using an automated segmentation algorithm in individuals with BD-II (n=29) and controls (n=33). The participants were scanned twice, at study inclusion and on average 2.4 years later. In addition, we measured peripheral levels of two lipid peroxidation markers (4-hydroxy-2-nonenal [4-HNE] and lipid hydroperoxides [LPH]). RESULTS: First, we demonstrated that the automated hippocampal subfield segmentation technique employed in this work reliably measured dentate gyrus-CA4 volume. Second, we found a decreased left dentate gyrus-CA4 volume in patients and that a larger number of depressive episodes between T1 and T2 predicted greater volume decline. Finally, we showed that 4-HNE was elevated in BD-II and that 4-HNE was negatively associated with left and right dentate gyrus-CA4 volumes in patients. CONCLUSIONS: These results are consistent with a role for the dentate gyrus in the pathophysiology of bipolar disorder and suggest that depressive episodes and elevated oxidative stress might contribute to hippocampal volume decreases. In addition, these findings provide further support for the hypothesis that peripheral lipid peroxidation markers may reflect brain alterations in bipolar disorders. PMID- 27995735 TI - Midsagittal corpus callosum area and conversion to multiple sclerosis after clinically isolated syndrome: A multicentre Australian cohort study. AB - INTRODUCTION: Patients presenting with clinically isolated syndrome (CIS) may proceed to clinically definite multiple sclerosis (CDMS). Midsagittal corpus callosum area (CCA) is a surrogate marker for callosal atrophy, and can be obtained from a standard MRI study. This study explores the relationship between CCA measured at CIS presentation (baseline) and at 5 years post presentation, with conversion from CIS to CDMS. The association between CCA and markers of disability progression is explored. METHODS: Corpus callosum area was measured on MRI scans at presentation and 5-year review following diagnosis of a first demyelinating event, or evidence of progressive MS, in 143 participants in the Ausimmune/AusLong Study. Relationships between CCA (at baseline and follow-up) and clinical outcomes were assessed. RESULTS: Mean CCA at baseline study was 6.63 cm2 (SD 1.01). Patients who converted to MS by 5-year review (n = 100) had a significantly smaller mean CCA at follow-up (6.22 vs. 6.74, P = 0.007). Greater CCA reduction was associated with higher annualized relapse rate over follow-up. CONCLUSION: Baseline CCA obtained from standard MRI protocols may be compared with subsequent MRI examinations as a surrogate for neurodegeneration and cerebral atrophy in patients with MS. This study demonstrates an association between CCA and disability in individuals presenting with CIS who convert to MS. PMID- 27995734 TI - The X-linked juvenile retinoschisis protein retinoschisin is a novel regulator of mitogen-activated protein kinase signalling and apoptosis in the retina. AB - X-linked juvenile retinoschisis (XLRS) is a hereditary retinal dystrophy in young males, caused by mutations in the RS1 gene. The function of the encoded protein, termed retinoschisin, and the molecular mechanisms underlying XLRS pathogenesis are still unresolved, although a direct interaction partner of the secreted retinoschisin, the retinal Na/K-ATPase, was recently identified. Earlier gene expression studies in retinoschisin-deficient (Rs1h-/Y ) mice provided a first indication of pathological up-regulation of mitogen-activated protein (MAP) kinase signalling in disease pathogenesis. To further investigate the role for retinoschisin in MAP kinase regulation, we exposed Y-79 cells and murine Rs1h-/Y retinae to recombinant retinoschisin and the XLRS-associated mutant RS1-C59S. Although normal retinoschisin stably bound to retinal cells, RS1-C59S exhibited a strongly reduced binding affinity. Simultaneously, exposure to normal retinoschisin significantly reduced phosphorylation of C-RAF and MAP kinases ERK1/2 in Y-79 cells and murine Rs1h-/Y retinae. Expression of MAP kinase target genes C-FOS and EGR1 was also down-regulated in both model systems. Finally, retinoschisin treatment decreased pro-apoptotic BAX-2 transcript levels in Y-79 cells and Rs1h-/Y retinae. Upon retinoschisin treatment, these cells showed increased resistance against apoptosis, reflected by decreased caspase-3 activity (in Y-79 cells) and increased photoreceptor survival (in Rs1h-/Y retinal explants). RS1-C59S did not influence C-RAF or ERK1/2 activation, C-FOS or EGR1 expression, or apoptosis. Our data imply that retinoschisin is a novel regulator of MAP kinase signalling and exerts an anti-apoptotic effect on retinal cells. We therefore discuss that disturbances of MAP kinase signalling by retinoschisin deficiency could be an initial step in XLRS pathogenesis. PMID- 27995736 TI - pH-Modulating Poly(ethylene glycol)/Alginate Hydrogel Dressings for the Treatment of Chronic Wounds. AB - The development of chronic wounds has been frequently associated with alkaline pH values. The application of pH-modulating wound dressings can, therefore, be a promising treatment option to promote normal wound healing. This study reports on the development and characterization of acidic hydrogel dressings based on interpenetrating poly(ethylene glycol) diacrylate/acrylic acid/alginate networks. The incorporation of ionizable carboxylic acid groups results in high liquid uptake up to 500%. The combination of two separate polymer networks significantly improves the tensile and compressive stability. In a 2D cell migration assay, the application of hydrogels (0% to 1.5% acrylic acid) results in complete "wound" closure; hydrogels with 0.25% acrylic acid significantly increase the cell migration velocity to 19.8 +/- 1.9 um h-1 . The most promising formulation (hydrogels with 0.25% acrylic acid) is tested on 3D human skin constructs, increasing keratinocyte ingrowth into the wound by 164%. PMID- 27995737 TI - Splice site mutation in factor X gene manifesting as severe intracranial haemorrhage in neonatal period with a challenging treatment course. PMID- 27995738 TI - Novel approach to determine ghrelin analogs by liquid chromatography with mass spectrometry using a monolithic column. AB - In our project, ghrelin analogs possessing enhanced stability and potential to significantly increase food intake were used. Three newly synthesized ghrelin analogs with fatty acid residues consisting of 8, 10, and 14 carbon atoms were studied. The main goal of this work was to develop a suitable analytical method for the determination of the stability of the novel ghrelin analogs in plasma. An appropriate liquid chromatography-mass spectrometry method was developed and optimized. The results obtained were compared with the data measured by using a commercial enzyme-linked immunosorbent assay kit, and a good correlation was found. A preparation strategy for plasma samples was optimized and consisted of simple dilution of the plasma samples followed by direct injection onto a very short monolithic column in combination with mass spectrometric detection. The developed analytical method was utilized for the determination of the stability of the prepared lipopeptides in plasma and for the quantification of the lipopeptides in a preliminary pharmacokinetic study. The feasibility of the developed separation method was clearly demonstrated. Accuracy and precision were within 80-120% and +/-20% limits, respectively. Calibration curves were constructed in the range of 1-250 MUg/mL. PMID- 27995739 TI - Survival in patients with Child-Pugh class C cirrhosis: Analysis of the liver transplant registry in Japan. AB - AIM: To clarify the survival and prognostic factors in patients with Child Turcotte-Pugh class C (CTP-C) cirrhosis. METHODS: From all candidates for deceased donor liver transplantation in Japan between 2007 and 2015, 1014 adult patients with CTP-C cirrhosis were retrospectively enrolled in this study. The hazard ratio (HR) of factors associated with mortality was estimated by the Cox proportional hazard model. The survival probabilities were evaluated by Kaplan Meier analysis and the log-rank test. RESULTS: Median survival time of the entire cohort was 475 days. Univariate analysis identified age, CTP, Model for End-Stage Liver Disease (MELD) score, and primary biliary cholangitis (PBC) as significant variables associated with mortality and hepatitis B virus (HBV) infection as a close-to-significant variable. Multivariate analysis revealed that age-adjusted mortality risk increased by 59% and 12% per 1 score step up in CTP and MELD scores, respectively. The HRs for HBV infection and PBC were significant after adjustment for age and CTP score, and they showed a 26% lower risk and an 83% higher risk than hepatitis C virus (HCV) infection, respectively. After adjustment for age and MELD score, the HR was also significant for HBV infection, but lost statistical significance for PBC. The survival curves were well stratified by both CTP or MELD score and revealed significant difference in both HBV infection and PBC as compared to HCV infection. CONCLUSIONS: In patients with CTP-C cirrhosis, CTP and MELD scores could well stratify the patients' survival, and HBV infection and PBC as etiologies have an impact on survival. PMID- 27995740 TI - Understanding the Genomic Structure of Copy-Number Variation of the Low-Affinity Fcgamma Receptor Region Allows Confirmation of the Association of FCGR3B Deletion with Rheumatoid Arthritis. AB - Fcgamma receptors are a family of cell-surface receptors that are expressed by a host of different innate and adaptive immune cells, and mediate inflammatory responses by binding the Fc portion of immunoglobulin G. In humans, five low affinity receptors are encoded by the genes FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B, which are located in an 82.5-kb segmental tandem duplication on chromosome 1q23.3, which shows extensive copy-number variation (CNV). Deletions of FCGR3B have been suggested to increase the risk of inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA). In this study, we identify the deletion breakpoints of FCGR3B deletion alleles in the UK population and endogamous native American population, and show that some but not all alleles are likely to be identical-by-descent. We also localize a duplication breakpoint, confirming that the mechanism of CNV generation is nonallelic homologous recombination, and identify several alleles with gene conversion events using fosmid sequencing data. We use information on the structure of the deletion alleles to distinguish FCGR3B deletions from FCGR3A deletions in whole-genome array comparative genomic hybridization (aCGH) data. Reanalysis of published aCGH data using this approach supports association of FCGR3B deletion with increased risk of RA in a large cohort of 1,982 cases and 3,271 controls (odds ratio 1.61, P = 2.9*10-3 ). PMID- 27995742 TI - Tracking the amphibian pathogens Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans using a highly specific monoclonal antibody and lateral-flow technology. AB - The fungus Batrachochytrium dendrobatidis (Bd) causes chytridiomycosis, a lethal epizootic disease of amphibians. Rapid identification of the pathogen and biosecurity is essential to prevent its spread, but current laboratory-based tests are time-consuming and require specialist equipment. Here, we describe the generation of an IgM monoclonal antibody (mAb), 5C4, specific to Bd as well as the related salamander and newt pathogen Batrachochytrium salamandrivorans (Bsal). The mAb, which binds to a glycoprotein antigen present on the surface of zoospores, sporangia and zoosporangia, was used to develop a lateral-flow assay (LFA) for rapid (15 min) detection of the pathogens. The LFA detects known lineages of Bd and also Bsal, as well as the closely related fungus Homolaphlyctis polyrhiza, but does not detect a wide range of related and unrelated fungi and oomycetes likely to be present in amphibian habitats. When combined with a simple swabbing procedure, the LFA was 100% accurate in detecting the water-soluble 5C4 antigen present in skin, foot and pelvic samples from frogs, newts and salamanders naturally infected with Bd or Bsal. Our results demonstrate the potential of the portable LFA as a rapid qualitative assay for tracking these amphibian pathogens and as an adjunct test to nucleic acid-based detection methods. PMID- 27995741 TI - Intermittent calorie restriction largely counteracts the adverse health effects of a moderate-fat diet in aging C57BL/6J mice. AB - SCOPE: Calorie restriction (CR) has been shown to extend life- and health-span in model species. For most humans, a life-long CR diet is too arduous to adhere to. The aim of this study was to explore whether weekly intermittent CR can (1) provide long-term beneficial effects and (2) counteract diet-induced obesity in male aging mice. METHODS AND RESULTS: In this study, we have exposed C57Bl/6J mice for 24 months to an intermittent (INT) diet, alternating weekly between CR of a control diet and ad libitum moderate-fat (MF) feeding. This weekly intermittent CR significantly counteracted the adverse effects of the MF diet on mortality, body weight, and liver health markers in 24-month-old male mice. Hepatic gene expression profiles of INT-exposed animals appeared much more comparable to CR- than to MF-exposed mice. At 12 months of age, a subgroup of MF exposed mice was transferred to the INT diet. Gene expression profiles in the liver of the 24-month-old diet switch mice were highly similar to the INT-exposed mice. However, a small subset of genes was consistently changed by the MF diet during the first phase of life. CONCLUSION: Weekly intermittent CR largely, but not completely, reversed adverse effects caused by a MF diet. PMID- 27995743 TI - Anticholinergic Exposure in a Cohort of Adults Aged 80 years and Over: Associations of the MARANTE Scale with Mortality and Hospitalization. AB - Anticholinergics are frequently prescribed for older adults and can lead to adverse drug events. The novel MARANTE (Muscarinic Acetylcholinergic Receptor ANTagonist Exposure) scale measures the anticholinergic exposure by incorporating potency and dosages of each medication into its calculations. The aims were to assess prevalence and intensity of the anticholinergic exposure in a longitudinal cohort study of community-dwelling patients aged 80 years and over (n = 503) and to study the impact on mortality and hospitalization. Chronic medication use at baseline (November 2008-September 2009) was entered and codified with the Anatomical Therapeutic Chemical classification. Time-to-event analysis until first hospitalization or death was performed at 18 months after inclusion, using Kaplan-Meier curves. Cox regression was performed to control for covariates. Mean age was 84 years (range 80-102), and mean number of medications was 5 (range 0 16). Prevalence of anticholinergic use was 31.8%, with 9% taking >=2 anticholinergics (range 0-4). Main indications for anticholinergics were depression, pain and gastric dysfunction. Female gender, the level of multi morbidity and the number of medications were associated with anticholinergic use. Mortality and hospitalization rate were 8.9% and 31.0%, respectively. After adjustment for the level of multi-morbidity and medication intake, multi-variable analysis showed increased risks of mortality (HR 2.3, 95% CI: 1.07-4.78) and hospitalization (HR 1.7; 95% CI: 1.13-2.59) in those with high anticholinergic exposure. The longitudinal study among Belgian community-dwelling oldest old demonstrated great anticholinergic exposure, which was associated with increased risk of mortality and hospitalization after 18 months. PMID- 27995744 TI - Online Hemodiafiltration Reduces Bisphenol A Levels. AB - Several uremic toxins have been identified and related to higher rates of morbidity and mortality in dialysis patients. Bisphenol A (BPA) accumulates in patients with chronic kidney disease. The aim of this study is to demonstrate the usefulness of online hemodiafiltration (OL-HDF) in reducing BPA levels. Thirty stable hemodialysis patients were selected to participate in this paired study. During three periods of 3 weeks each, patients were switched from high-flux hemodialysis (HF-HD) to OL-HDF, and back to HF-HD. BPA levels were measured in the last session of each period (pre- and post-dialysis) using ELISA and HPLC. Twenty-two patients (mean age 73 +/- 14 years; 86.4% males) were included. Measurements of BPA levels by HPLC and ELISA assays showed a weak but significant correlation (r = 0.218, P = 0.012). BPA levels decreased in the OL-HDF period of hemodialysis, in contrast to the HF-HD period when they remained stable (P = 0.002). In conclusion, OL-HDF reduced BPA levels in dialysis patients. PMID- 27995745 TI - Towards an integrated understanding of cardiac arrhythmogenesis - Growing roles of experimental pathology. AB - Cardiac arrhythmias have long been regarded as derangement of electrical impulse initiation and conduction within the heart. However, underlying mechanisms for arrhythmogenesis are not fully understood solely from the electrophysiological viewpoint. This review article discusses pathogenesis of arrhythmias from non electrical aspects, which were elucidated by spatiotemporal imaging of functional molecules in combination with morphological analysis of living heart tissues. Intracellular Ca2+ ([Ca2+ ]i ) overload, caused by myocardial injury, provokes Ca2+ waves that could lead to abnormal excitations, i.e., triggered arrhythmias. Depressed Ca2+ release from the sarcoplasmic reticulum, caused by ischemia, heart failure, or T-tubular remodeling, results in spatiotemporally inhomogeneous [Ca2+ ]i dynamics that could disturb impulse conduction, leading to reentrant tachyarrhythmias. Impairment of the gap junction-mediated intercellular communications, which provokes derangement of impulse propagation of the myocardium, also leads to reentrant arrhythmias. Interpositions of non cardiomyocytes, especially fibroblasts, in the myocardium could also contribute to arrhythmogenesis via heterocellular gap-junctional coupling with cardiomyocytes. Furthermore, alterations in myocardial histology, e.g., density and arrangements of myocytes in association with gap-junctional distributions, could constitute important pathologic bases of atrial fibrillation. Integration of these molecular, functional, and morphological features of the myocardium, unveiled by experimental pathological approaches, would pave a new way for understanding pathogenesis of cardiac arrhythmias. PMID- 27995746 TI - A Simplified Fe-Based PhotoATRP Using Only Monomers and Solvent. AB - A photoinduced atom transfer radical polymerization (photoATRP) of methacrylates is investigated using air-stable FeBr3 as catalyst in the absence of conventional ATRP initiators, additional ligands, reducing agents, and/or radical initiators. The ATRP alkyl halide initiator is formed in situ via photoreduction of FeBr3 by methacrylate monomers. The kinetics of the polymerization display a linear semilogarithmic plot after several hours of induction period. The molecular weight can be modulated by additions of different amounts of FeBr3 , and polymers have narrow molecular weight distributions. Thus, FeBr3 acts as deactivator, as well as a source of activator FeBr2 and initiator. This method features a temporal control, and can provide various polymethacrylates with high chain end functionality. PMID- 27995747 TI - New 3-alkylpyridine marine alkaloid analogues as promising antitumor agents against the CD44+/high /CD24-/low subset of triple-negative breast cancer cell line. AB - Triple-negative breast cancer (TNBC) is one of the most aggressive cancers in women. Additionally, presence of residual cancer stem cells (CSC) in TNBC has challenged the efficacy of chemotherapy. Thus, the development of new molecules with potential action against CSC is fundamental. In this study, six synthetic analogues of theonelladin C, a 3-alkylpyridine marine alkaloid, were tested for cytotoxic activity against human TNBC cell line (BT-549) and tumorspheres derived from BT-549. Cytotoxicity assay was performed by sulforhodamine B (SRB). BT-549 and tumorspheres were examined for CD44+/high /CD24-/low markers, indicative of CSC profile, by flow cytometry. Clonogenic assay was performed to verify inhibiting growth of tumorspheres by the synthetic analogues. Cell death by apoptosis was investigated employing annexin V assay. SRB assay on BT-549 cells revealed that compounds 1c and 2c were the most active of the series, with IC50 values of 18.66 and 9.8 MUm, respectively. Compounds 1c and 2c were able to reduce both CSC-like population (CD44+/high /CD24-/low ) and non-CSC population (CD44+/high /CD24+/high ) in tumorsphere model. Clonogenic and annexin V assays confirmed the ability of 1c and 2c to induce growth inhibition and apoptosis in BT-549 cells and tumorspheres. These preliminary data indicate that these compounds are a promising class for development of anticancer agents. PMID- 27995748 TI - WRKY transcription factors in plant responses to stresses. AB - The WRKY gene family is among the largest families of transcription factors (TFs) in higher plants. By regulating the plant hormone signal transduction pathway, these TFs play critical roles in some plant processes in response to biotic and abiotic stress. Various bodies of research have demonstrated the important biological functions of WRKY TFs in plant response to different kinds of biotic and abiotic stresses and working mechanisms. However, very little summarization has been done to review their research progress. Not just important TFs function in plant response to biotic and abiotic stresses, WRKY also participates in carbohydrate synthesis, senescence, development, and secondary metabolites synthesis. WRKY proteins can bind to W-box (TGACC (A/T)) in the promoter of its target genes and activate or repress the expression of downstream genes to regulate their stress response. Moreover, WRKY proteins can interact with other TFs to regulate plant defensive responses. In the present review, we focus on the structural characteristics of WRKY TFs and the research progress on their functions in plant responses to a variety of stresses. PMID- 27995749 TI - Evaluation of sample injection precision in respect to sensitivity in capillary electrophoresis using various injection modes. AB - A comparative study was conducted to assess the injection precision in capillary electrophoresis for cationic analytes (arecoline, codeine, papaverine). The precision was measured in respect to methods sensitivity in various injection modes in capillary electrophoresis: standard hydrodynamic injection (3.45 kPa for 6 s), large volume sample stacking (3.45 kPa for 40 s), and field-amplified sample injection (10 kV for 65 s). All measurements were conducted for aqueous solutions of standards to minimize the errors linked to the sample preparation step. The methods were submitted to precision assessment at three concentration levels: at the limit of quantification, three-fold and ten-fold of limit of quantification. The results were compared to those from high-performance liquid chromatography as a reference technique. The field-amplified sample injection method was shown to provide greatest sensitivity (quantification limits down to 4 ng/mL for all three tested compounds) but the lowest precision. High-performance liquid chromatography was established as the most reliable technique (coefficient of variation in all intraday experiments was below 1%). It was also shown that with a use of large volume sample injection technique, similar sensitivity as in high-performance liquid chromatography can be easily reached. PMID- 27995750 TI - Keloid progression: a stiffness gap hypothesis. AB - Keloids are fibroproliferative skin disorders characterised clinically by continuous horizontal progression and post-surgical recurrence and histologically by the accumulation of collagen and fibroblast ingredients. Till now, their aetiology remains clear, which may cover genetic, environmental and metabolic factors. Evidence in the involvement of local mechanics (e.g. predilection site and typical shape) and the progress in mechanobiology have incubated our stiffness gap hypotheses in illustrating the chronic but constant development in keloid. We put forward that the enlarged gap between extracellular matrix (ECM) stiffness and cellular stiffness potentiates keloid progression. Matrix stiffness itself provides organisational guidance cues to regulate the mechanosensitive resident cells (e.g. proliferation, migration and apoptosis). During this dynamic process, the ECM stiffness and cell stiffness are not well balanced, and the continuously enlarged stiffness gap between them potentiates keloid progression. The cushion factors, such as prestress for cell stiffness and topology for ECM stiffness, serve as compensations, the decompensation of which aggravates keloid development. It can well explain the typical shape of keloids, their progression in a horizontal but not vertical direction and the post-surgical recurrence, which were evidenced by our clinical cases. Such a stiffness gap hypothesis might be bridged to mechanotherapeutic approaches for keloid progression. PMID- 27995752 TI - Ultrasound image based visual servoing for moving target ablation by high intensity focused ultrasound. AB - BACKGROUND: Although high intensity focused ultrasound (HIFU) is a promising technology for tumor treatment, a moving abdominal target is still a challenge in current HIFU systems. In particular, respiratory-induced organ motion can reduce the treatment efficiency and negatively influence the treatment result. In this research, we present: (1) a methodology for integration of ultrasound (US) image based visual servoing in a HIFU system; and (2) the experimental results obtained using the developed system. MATERIALS AND METHODS: In the visual servoing system, target motion is monitored by biplane US imaging and tracked in real time (40 Hz) by registration with a preoperative 3D model. The distance between the target and the current HIFU focal position is calculated in every US frame and a three-axis robot physically compensates for differences. Because simultaneous HIFU irradiation disturbs US target imaging, a sophisticated interlacing strategy was constructed. RESULTS: In the experiments, respiratory-induced organ motion was simulated in a water tank with a linear actuator and kidney-shaped phantom model. Motion compensation with HIFU irradiation was applied to the moving phantom model. Based on the experimental results, visual servoing exhibited a motion compensation accuracy of 1.7 mm (RMS) on average. Moreover, the integrated system could make a spherical HIFU-ablated lesion in the desired position of the respiratory-moving phantom model. CONCLUSIONS: We have demonstrated the feasibility of our US image based visual servoing technique in a HIFU system for moving target treatment. PMID- 27995753 TI - Differential proteomic analysis of white adipose tissues from T2D KKAy mice by LC ESI-QTOF. AB - Type 2 diabetes (T2D) has become a worldwide increasingly social health burden for its high morbidity and heightened prevalence. As one of the main tissues involved in uptake of glucose under the stimulation of insulin, WAT plays very important role in metabolic and homeostasis regulation. We performed a differential proteomics study to investigate alterations in epididymis fat pad of high fat diet fed T2D KKAy mice compared to normal fed C57BL/6J mice, by 18 O labeling relative quantitative technique. Among 329 confidently identified proteins, 121 proteins showed significant changes with CV <= 20% (fold changes of >2 or <0.5 as threshold). According to GO classification, we found that altered proteins contained members of biological processes of metabolic process, oxidative stress, ion homeostasis, apoptosis and cell division. In metabolic, proteins assigned to fatty acid biosynthesis (FAS etc.) were decreased, the key enzyme (ACOX3) in beta-oxidation process was increased. Increased glycolysis enzymes (ENOB etc.) and decreased TCA cycle related enzymes (SCOT1 etc.) suggested that glucose metabolism in mitochondria of T2D mice might be impaired. Elevated oxidative stress was observed with alterations of a series of oxidordeuctase (QSOX1 etc.). Besides, alterations of ion homeostasis (AT2C1 etc.) proteins were also observed. The enhancement of cell proliferation associated proteins (ELYS etc.) and inhibition of apoptosis associated proteins (RASF6 etc.) in WAT might contributed to the fat pad and body weight gain. Overall, these changes in WAT may serve as a reference for understanding the functional mechanism of T2D. PMID- 27995754 TI - Contribution of proteomics to our understanding of periodontal inflammation. AB - Periodontal diseases entail the inflammatory destruction of the tooth supporting (periodontal) tissues and may eventually lead tooth loss. Severe periodontal disease (or periodontitis) affects approximately 10% of the global population. Periodontitis not only severely deteriorates people's quality of life by impairing the dentition but also adversely affects systemic health. The present review paper highlights the advancements made in our understanding of inflammatory periodontal diseases by the use of proteomic technologies. The novel information comes from both clinical and in vitro studies, the former investigating samples of saliva and gingival crevicular fluid in patients with periodontal disease, whereas the latter utilizing host cell/tissue bacteria/biofilm interaction models of relevance to periodontal disease. A broad range of information on protein profiles can be obtained, which is useful, however needs to be individually validated by golden-standard sensitive antibody based methods. The development of the employed proteomic platform technologies will help complete in breadth and in depth the protein profiles of periodontal disease. The so-far collected data highlights the importance of moving away from the concept of a handful of proteins being responsible for the pathogenesis of the disease, and start to accept that there are "signatures" of proteins and associated pathways that lead to this. PMID- 27995751 TI - 3D Bioprinting for Organ Regeneration. AB - Regenerative medicine holds the promise of engineering functional tissues or organs to heal or replace abnormal and necrotic tissues/organs, offering hope for filling the gap between organ shortage and transplantation needs. Three dimensional (3D) bioprinting is evolving into an unparalleled biomanufacturing technology due to its high-integration potential for patient-specific designs, precise and rapid manufacturing capabilities with high resolution, and unprecedented versatility. It enables precise control over multiple compositions, spatial distributions, and architectural accuracy/complexity, therefore achieving effective recapitulation of microstructure, architecture, mechanical properties, and biological functions of target tissues and organs. Here we provide an overview of recent advances in 3D bioprinting technology, as well as design concepts of bioinks suitable for the bioprinting process. We focus on the applications of this technology for engineering living organs, focusing more specifically on vasculature, neural networks, the heart and liver. We conclude with current challenges and the technical perspective for further development of 3D organ bioprinting. PMID- 27995755 TI - Application of phage peptide display technology for the study of food allergen epitopes. AB - Phage peptide display technology has been used to identify IgE-binding mimotopes (mimics of natural epitopes) that mimic conformational epitopes. This approach is effective in the characterization of those epitopes that are important for eliciting IgE-mediated allergic responses by food allergens and those that are responsible for cross-reactivity among allergenic food proteins. Application of this technology will increase our understanding of the mechanisms whereby food allergens elicit allergic reactions, will facilitate the discovery of diagnostic reagents and may lead to mimotope-based immunotherapy. PMID- 27995757 TI - Protective effects of beta-sheet breaker alpha/beta-hybrid peptide against amyloid beta-induced neuronal apoptosis in vitro. AB - Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-beta oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-beta (Abeta). Increased production of Abeta invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a beta-sheet breaker alpha/beta-hybrid peptide (BSBHp) and the underlying mechanisms against Abeta40 -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with the peptide Abeta40 to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca2+ , and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Abeta40 -induced toxicity by retaining cell viability, suppressing generation of ROS, Ca2+ levels, and effectively protects neuronal apoptosis by suppressing pro apoptotic protein Bax and up-regulating antiapoptotic protein Bcl-2. These results suggest that alpha/beta-hybrid peptide has neuroprotective effects against Abeta40 -induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases. PMID- 27995756 TI - Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor-recipient age-mismatch in transplants. AB - To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12-92 years before transplants and in 11 biopsies after transplants with high donor-recipient age-mismatch. We also assessed liver function in 36 age-mismatched recipients. The major findings were the following: (i) miR-31-5p, miR-141-3p, and miR-200c-3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT-qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR-31-5p and miR-200c-3p, and both its mRNA (RT-qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR-31-5p, miR-141-3p and miR-200c-3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor-recipient extreme age mismatch; (v) the analysis of recipients plasma by N-glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age-mismatch, and recipients apparently 'rejuvenated' according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor recipient age-mismatches in transplantation, and offered positive evidence for the use of organs from old donors. PMID- 27995758 TI - Cellulose Biorefinery Based on a Combined Catalytic and Biotechnological Approach for Production of 5-HMF and Ethanol. AB - In this study, a combination of catalytic and biotechnological processes was proposed for the first time for application in a cellulose biorefinery for the production of 5-hydroxymethylfurfural (5-HMF) and bioethanol. Hydrolytic dehydration of the mechanically activated microcrystalline cellulose over a carbon-based mesoporous Sibunt-4 catalyst resulted in moderate yields of glucose and 5-HMF (21.1-25.1 and 6.6-9.4 %). 5-HMF was extracted from the resulting mixture with isobutanol and subjected to ethanol fermentation. A number of yeast strains were isolated that also revealed high thermotolerance (up to 50 degrees C) and resistance to inhibitors found in the hydrolysates. The strains Kluyveromyces marxianus C1 and Ogataea polymorpha CBS4732 were capable of producing ethanol from processed catalytic hydrolysates of cellulose at 42 degrees C, with yields of 72.0+/-5.7 and 75.2+/-4.3 % from the maximum theoretical yield of ethanol, respectively. PMID- 27995759 TI - Hydrogel Functionalized Janus Membrane for Skin Regeneration. AB - In this study, a hydrogel functionalized Janus membrane is developed and its capacity is examined as a wound dressing biomaterial. A hydrophobic fluoropolymer, poly(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate) (PHFDMA), is uniformly coated onto macroporous polyester membrane through initiated chemical vapor deposition process on both sides. PHFDMA-coated macroporous membrane exhibits antibacterial property, allows air permeation, and inhibits water penetration. Janus membrane property is obtained by exposing one side of PHFDMA coated membrane with 1 m KOH solution, which allows PHFDMA cleavage resulting in carboxylic acid residue. This carboxylic acid residue is then further functionalized with gelatin methacrylate-based photocrosslinkable hydrogel for moisture retention and growth factor release. When applied to full thickness dorsal skin defect model, functionalized hydrogel allows moisture retention and hydrophobic surface prevents exudate leaks via water repellence. Furthermore, hydrogel functionalized Janus membrane enhances the wound healing rate and induces thick epidermal layer formation. In conclusion, the multifunctional Janus membrane with hydrophobic outer surface and immobilized hydrogel on the other surface is fabricated for an innovative strategy for wound healing. PMID- 27995760 TI - ENRI: A tool for selecting structure-based virtual screening target conformations. AB - Finding pharmaceutically relevant target conformations from an arbitrary set of protein conformations remains a challenge in structure-based virtual screening (SBVS). The growth in the number of available conformations, either experimentally determined or computationally derived, obscures the situation further. While the inflated conformation space potentially contains viable druggable targets, the increase of conformational complexity, as a consequence, poses a selection problem. To address this challenge, we took advantage of machine learning methods, namely an over-sampling and a binary classification procedure, and present a novel method to select druggable receptor conformations. Specifically, we trained a binary classifier on a set of nuclear receptor conformations, wherein each conformation was labeled with an enrichment measure for a corresponding SBVS. The classifier enabled us to formulate suggestions and identify enriching SBVS targets for six of seven nuclear receptors. Further, the classifier can be extended to other proteins of interest simply by feeding new training data sets to the classifier. Our work, thus, provides a methodology to identify pharmaceutically interesting receptor conformations for nuclear receptors and other drug targets. PMID- 27995761 TI - An ultrasensitive electrochemiluminescent sensor based on a pencil graphite electrode modified with CdS nanorods for detection of chlorogenic acid in honeysuckle. AB - In this paper, a novel and ultrasensitive electrochemiluminescent sensor employing a solvothermal-synthesized CdS nanorod-modified pencil graphite electrode (CdS/PGE) for the determination of chlorogenic acid (CA) is fabricated. In the first step, the PGE surface is modified using CdS nanorods. In the next step, the developed electrode is used to detect CA using a electrochemiluminescent (ECL) technique, in which potassium persulfate (K2 S2 O8 ) served as a co-reactant. The possible ECL mechanism is investigated, and the influences of pH and cyclic voltammetric scanning rate on the signal response are studied. The ECL intensity decreases quantitatively in relation to the concentration of the target molecule. Under optimized conditions, the linear correlation between the quenched ECL intensity and the logarithm of CA concentration is observed in the range from 2 * 10-9 to 8 * 10-7 mol L-1 with a limit of detection of 1 * 10-9 mol L-1 . This proposed method is applied to the analysis of CA in honeysuckle flower, giving recoveries of 99-107%. The experimental results demonstrate that this ECL sensor shows good stability and reproducibility. PMID- 27995762 TI - Encapsulation of Insulin-Secreting Cells Expressing a Genetically Encoded Fluorescent Calcium Indicator for Cell-Based Sensing In Vivo. AB - The development of cell-based biosensors that give insight into cell and tissue function in vivo is an attractive technology for biomedical research. Here, the development of a cell line expressing a fluorescent calcium sensor for the study of beta-cell function in vivo is reported. The bioresponsive cell model is based on INS-1E pancreatic beta-cells, stably expressing the genetically encoded cameleon-based fluorescent sensor YC3.6cyto . Following single-cell selection and expansion, functional testing and in vitro encapsulation experiments are used to identify a suitable clone of INS-1E cells expressing the calcium sensor. This clone is transplanted subcutaneous in mouse using a cell macroencapsulation system based on flat sheet porous membranes. Cells in the implanted capsules are able to respond to glucose in vivo by secreting insulin and thereby contributing to the regulation of glycaemia in the mice. Furthermore, fluorescence imaging of explanted devices shows that encapsulated cells maintain high level expression of YC3.6cyto in vivo. In conclusion, these data show that encapsulated INS-1E cells stably expressing a genetically encoded calcium sensor can be successfully implanted in vivo, and therefore serve as biosensing element or in vivo model to longitudinally monitor the function of pancreatic beta-cells. PMID- 27995763 TI - Stable Di- and Tri-coordinated Carbon(II) Supported by an Electron-Rich beta Diketiminate Ligand. AB - Complexes of the ubiquitous beta-diketiminates (NacNac) ligands have been reported with most elements of the periodic table, including Group 14 Si, Ge, Sn, and Pb. The striking absence of carbon representatives has been attributed to the extreme electrophilicity of the putative C-NacNac adducts. An electron enriched 2,4-(dimethylamino)diketiminato backbone is described, which allowed for the synthesis and isolation of such stable pyrimidin-1,3-diium and pyrimidinium-2 ylidene salts. Structural and preliminary reactivity studies are reported, including an air-stable gold complex. An unforeseen original class of stable N heterocyclic carbenes and, more generally, the potential of electron-rich NacNac patterns for taming highly electrophilic centers are showcased. PMID- 27995764 TI - Frequency-tuned contactless conductivity detector for the electrophoretic separation of clinical samples in capillaries with very small internal dimensions. AB - An axial design of a capacitively coupled contactless conductivity detector was tested in combination with fused-silica capillaries with internal diameters of 10, 15, and 25 MUm, which are used for high-efficiency electrophoretic separation. The transmission of the signal in the detection probe dependent on the specific conductivity of the solution in the capillary in the range 0-278 mS.m-1 has a complex character and a minimum appears on the curve at very low conductivities. The position of the minimum of the calibration dependence gradually shifts with decreasing frequency of the exciting signal from 1.0 to 0.25 MHz toward lower specific conductivity values. The presence of a minimum on the calibration curves is a natural property of the axial design of contactless conductivity detector, demonstrated by solution of the equivalent electrical circuit of the detection probe, and is specifically caused by the use of shielding foil. The behavior of contactless conductivity detector in the vicinity of the minimum was documented for practical separations of amino acids in solutions of 3.2 M acetic acid with addition of 0-50% v/v methanol. PMID- 27995766 TI - Antidepressant treatment response in bipolar II disorder. PMID- 27995765 TI - Shockwaves prevent from heart failure after acute myocardial ischaemia via RNA/protein complexes. AB - Shock wave treatment (SWT) was shown to induce regeneration of ischaemic myocardium via Toll-like receptor 3 (TLR3). The antimicrobial peptide LL37 gets released by mechanical stress and is known to form complexes with nucleic acids thus activating Toll-like receptors. We suggested that SWT in the acute setting prevents from the development of heart failure via RNA/protein release. Myocardial infarction in mice was induced followed by subsequent SWT. Heart function was assessed 4 weeks later via transthoracic echocardiography and pressure-volume measurements. Human umbilical vein endothelial cells (HUVECs) were treated with SWT in the presence of RNase and proteinase and analysed for proliferation, tube formation and LL37 expression. RNA release and uptake after SWT was evaluated. We found significantly improved cardiac function after SWT. SWT resulted in significantly higher numbers of capillaries and arterioles and less left ventricular fibrosis. Supernatants of treated cells activated TLR3 reporter cells. Analysis of the supernatant revealed increased RNA levels. The effect could not be abolished by pre-treatment of the supernatant with RNase, but only by a sequential digestion with proteinase and RNase hinting strongly towards the involvement of RNA/protein complexes. Indeed, LL37 expression as well as cellular RNA uptake were significantly increased after SWT. We show for the first time that SWT prevents from left ventricular remodelling and cardiac dysfunction via RNA/protein complex release and subsequent induction of angiogenesis. It might therefore develop a potent regenerative treatment alternative for ischaemic heart disease. PMID- 27995767 TI - Mannoside recognition and degradation by bacteria. AB - Mannosides constitute a vast group of glycans widely distributed in nature. Produced by almost all organisms, these carbohydrates are involved in numerous cellular processes, such as cell structuration, protein maturation and signalling, mediation of protein-protein interactions and cell recognition. The ubiquitous presence of mannosides in the environment means they are a reliable source of carbon and energy for bacteria, which have developed complex strategies to harvest them. This review focuses on the various mannosides that can be found in nature and details their structure. It underlines their involvement in cellular interactions and finally describes the latest discoveries regarding the catalytic machinery and metabolic pathways that bacteria have developed to metabolize them. PMID- 27995768 TI - Substrate Stress-Relaxation Regulates Scaffold Remodeling and Bone Formation In Vivo. AB - The rate of stress relaxation of adhesion substrates potently regulates cell fate and function in vitro, and in this study the authors test whether it can regulate bone formation in vivo by implanting alginate gels with differing rates of stress relaxation carrying human mesenchymal stem cells into rat calvarial defects. After three months, the rats that received fast-relaxing hydrogels (t1/2 ~ 50 s) show significantly more new bone growth than those that received slow-relaxing, stiffness-matched hydrogels. Strikingly, substantial bone regeneration results from rapidly relaxing hydrogels even in the absence of transplanted cells. Histological analysis reveals that the new bone formed with rapidly relaxing hydrogels is mature and accompanied by extensive matrix remodeling and hydrogel disappearance. This tissue invasion is found to be prominent after just two weeks and the ability of stress relaxation to modulate cell invasion is confirmed with in vitro analysis. These results suggest that substrate stress relaxation can mediate scaffold remodeling and thus tissue formation, giving tissue engineers a new parameter for optimizing bone regeneration. PMID- 27995769 TI - TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. AB - Multiple loss-of-function mutations in TRIAD3 (a.k.a. RNF216) have recently been identified in patients suffering from Gordon Holmes syndrome (GHS), characterized by cognitive decline, dementia, and movement disorders. TRIAD3A is an E3 ubiquitin ligase that recognizes and facilitates the ubiquitination of its target for degradation by the ubiquitin-proteasome system (UPS). Here, we demonstrate that two of these missense substitutions in TRIAD3 (R660C and R694C) could not regulate the degradation of their neuronal target, activity-regulated cytoskeletal-associated protein (Arc/Arg 3.1), whose expression is critical for synaptic plasticity and memory. The synaptic deficits due to the loss of endogenous TRIAD3A could not be rescued by TRIAD3A harboring GHS-associated missense mutations. Moreover, we demonstrate that the loss of endogenous TRIAD3A in the mouse hippocampal CA1 region led to deficits in spatial learning and memory. Finally, we show that these missense mutations abolished the interaction of TRIAD3A with Arc, disrupting Arc ubiquitination, and consequently Arc degradation. Our current findings of Arc misregulation by TRIAD3A variants suggest that loss-of-function mutations in TRIAD3A may contribute to dementia observed in patients with GHS driven by dysfunctional UPS components, leading to cognitive impairments through the synaptic protein Arc. PMID- 27995771 TI - One-Pot Anchoring of Pd Nanoparticles on Nitrogen-Doped Carbon through Dopamine Self-Polymerization and Activity in the Electrocatalytic Methanol Oxidation Reaction. AB - Exploration of advanced electrocatalysts to promote the sluggish methanol oxidation reaction (MOR) is of vital importance for developing high efficiency and low-cost direct methanol fuel cells. Highly dispersed palladium nanoparticles (Pd NPs) anchored on a nitrogen-doped carbon support were fabricated using a facile one-pot dopamine self-polymerization mediated redox strategy, in which dopamine not only acted as a moderate reductant to induce the formation of Pd NPs during self-polymerization but was also the precursor of the nitrogen-doped carbon support for Pd. The synthesized hybrid features the following characteristics: 1) High dispersity of Pd NPs, which exposed a high abundance of active surfaces and sites for heterogeneous electrocatalysis; 2) metal-support interactions, which may affect the surface chemistry and electron distribution of active Pd NPs; 3) the Pd NPs were partially imbedded or encapsulated into the support, thus reducing the possible agglomeration of Pd NPs during cyclic measurements. The electrocatalyst with such favorable features provided higher mass activity (2.2 times that of commercial Pd/C) and better durability (reduced loss of activity during simulated frequent startup-shutdown operations) for the MOR in alkaline media. PMID- 27995770 TI - Consensus statements on the imaging of axial spondyloarthritis in Australia and New Zealand. PMID- 27995773 TI - New ways to teach new doctors about older people. PMID- 27995772 TI - A novel tomato SUMO E3 ligase, SlSIZ1, confers drought tolerance in transgenic tobacco. AB - SUMOylation is an important post-translational modification process that regulates different cellular functions in eukaryotes. SIZ/PIAS-type SAP and Miz1 (SIZ1) proteins exhibit SUMO E3 ligase activity, which modulates SUMOylation. However, SIZ1 in tomato has been rarely investigated. In this study, a tomato SIZ1 gene (SlSIZ1) was isolated and its molecular characteristics and role in tolerance to drought stress are described. SlSIZ1 was up-regulated by cold, sodium chloride (NaCl), polyethylene glycol (PEG), hydrogen peroxide (H2 O2 ) and abscisic acid (ABA), and the corresponding proteins were localized in the nucleus. The expression of SlSIZ1 in Arabidopsis thaliana (Arabidopsis) siz1-2 mutants partially complemented the phenotypes of dwarf, cold sensitivity and ABA hypersensitivity. SlSIZ1 also exhibited the activity of SUMO E3 ligase to promote the accumulation of SUMO conjugates. Under drought stress, the ectopic expression of SlSIZ1 in transgenic tobacco lines enhanced seed germination and reduced the accumulation of reactive oxygen species. SlSIZ1 overexpression conferred the plants with improved growth, high free proline content, minimal malondialdehyde accumulation and increased accumulation of SUMO conjugates. SlSIZ1 is a functional homolog of Arabidopsis SIZ1 with SUMO E3 ligase activity. Therefore, overexpression of SlSIZ1 enhanced the tolerance of transgenic tobacco to drought stress. PMID- 27995775 TI - The FEBS Journal past ... and present. PMID- 27995774 TI - Occult primary pulmonary synovial sarcoma presenting as recurrent spontaneous pneumothorax and explosive progression. AB - Primary pulmonary synovial sarcoma (PPSS) is a relatively rare neoplasm with highly progressive potential. We present an extremely rare case of PPSS presenting as recurrent pneumothorax with bullous lesions. Bullectomy was performed at the local hospital. Unfortunately, the patient was initially misdiagnosed as atypical carcinoid. Although a negative resection margin was obtained during the first surgery and a remedial operation and chemotherapy followed, the patient developed severe disease progression and died soon after. This report demonstrates that PPSS can easily be misdiagnosed and should be seriously considered in the differential diagnosis of pneumothorax. PMID- 27995777 TI - A return to the pore - dissecting Bacillus thuringiensis toxin mode of action via voltage clamp experiments. AB - Pore-forming toxins from Bacillus thuringiensis are increasingly used in crop protection, but evolution of resistance in crop pests threatens their continued deployment. A study by Tanaka et al. shows how voltage clamp experiments that quantify pore formation can be used to dissect toxin mode of action, thereby revealing unexpected complexities that could be exploited to counter resistance. PMID- 27995778 TI - [Upper G. I. cancer]. PMID- 27995779 TI - [Head and Neck Tumor: HPV-Positive Oropharynx Cancer]. PMID- 27995780 TI - [Head and Neck Tumor: Pathology]. PMID- 27995781 TI - Index, Volume 91, 2016, Nos. 1-52. PMID- 27995783 TI - Review of global influenza activity, October 2015-October 2016. PMID- 27995782 TI - Index, Volume 91, 2016, Nos. 1-52. PMID- 27995785 TI - Dearomatizing Radical Cyclizations and Cyclization Cascades Triggered by Electron Transfer Reduction of Amide-Type Carbonyls. AB - Highly selective dearomatizing radical cyclizations and cyclization cascades, triggered by single electron transfer to amide-type carbonyls by SmI2-H2O-LiBr, provide efficient access to unprecedented spirocyclic scaffolds containing up to five stereocenters with high diastereocontrol. The first dearomatizing radical cyclizations involving radicals derived from amide carbonyls by single electron transfer take place under mild conditions and engage a range of aromatic and heteroaromatic systems present in the barbiturate substrates. The radical cyclizations deliver new polycyclic hemiaminals or enamines selectively, depending on the conditions employed, that are based on a medicinally proven scaffold and can be readily manipulated. PMID- 27995784 TI - Malaria control improves for vulnerable in Africa, but global progress off-track. PMID- 27995786 TI - Cellulose Nanofibers Prepared Using the TEMPO/Laccase/O2 System. AB - The 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/laccase/O2 system was used to prepare cellulose nanofibers from wood cellulose without requiring any chlorine containing oxidant. Laccase was degraded by oxidized TEMPO (TEMPO+) formed by laccase-mediated oxidation with O2, which competed with the oxidation of wood cellulose. Thus, large amounts of laccase and TEMPO and a long reaction time were needed to introduce ~0.6 mmol g-1 of C6-carboxylate groups onto wood cellulose. The TEMPO/laccase/O2 system underwent one-way reaction from TEMPO to reduced TEMPO through TEMPO+. When the oxidation was applied again to the oxidized wood cellulose following isolation and purification, the C6-carboxylate groups increased to ~1.1 mmol g-1, which was sufficient to convert the sample to cellulose nanofibers by sonication in water. However, the higher the carboxylate content of the oxidized celluloses, the lower their degree of polymerization. PMID- 27995787 TI - Dynamic Heterogeneity and Flexibility of the Alkyl Chain in Pyridinium-Based Ionic Liquids. AB - Changing the number of carbon atoms in the substituents of ionic liquids (ILs) is a way to shift the balance between Coulomb and van der Waals forces and, thus, to tune physicochemical properties. Here we address this topic on the microscopic level by employing quasielastic neutron scattering (QENS) and provide information about the stochastic ionic motions in the N-alkylpyridinium based ILs in a relatively expanded time range, from short time (subpicosecond) particle rattling to long time diffusive regime (hundreds of picoseconds). We have systematically investigated the effect of the alkyl chain length on the picosecond dynamics by employing partial deuteration of the samples and varying the number of carbon atoms in the alkyl substituent. The localized dynamics of the side groups have appeared to be enhanced for bulkier cations, which is opposite to the trend observed for the translational motion. This result highlights the role of the conformational flexibility of the alkyl group on the dynamical properties of ILs. PMID- 27995788 TI - Glycan OH Exchange Rate Determination in Aqueous Solution: Seeking Evidence for Transient Hydrogen Bonds. AB - Hydrogen bonds (Hbonds) are important stabilizing forces in biomolecules. However, for glycans in aqueous solution, direct NMR detection of Hbonds is elusive because of their transient nature. Here, we present Isotope-based Natural abundance TOtal correlation eXchange SpectroscopY (INTOXSY), a new 1H-13C heteronuclear single quantum coherence-total correlation spectroscopy based method, to extract OH groups' exchange rate constants (kex) for molecules in natural 13C abundance and show that OH Hbonds can be inferred from "slower" H/D kex. We evaluate kex measured with INTOXSY in light of those extracted with line shape analysis. Subsequently, we use a set of common glycans to establish a kex reference basis set and to infer the existence of transient Hbonds involving OH donor groups. Then, we report kex values for a series of mono- and disaccharides, as well as for oligosaccharides sialyl Lewis X and beta-cyclodextrin, and compare the results with those from the reference set to extract Hbond information. Finally, we utilize NMR experimental data in conjunction with molecular dynamics simulations to establish donor and acceptor Hbond pairs. Our exchange rate measurements indicate that OH/OD exchange rates, kHD, values <10 s-1 are consistent with transient Hbond OH groups and potential acceptor groups can be uncovered through MD simulations. PMID- 27995789 TI - Solution-Processed Nb:SnO2 Electron Transport Layer for Efficient Planar Perovskite Solar Cells. AB - Electron transport layer (ETL), facilitating charge carrier separation and electron extraction, is a key component in planar perovskite solar cells (PSCs). We developed an effective ETL using low-temperature solution-processed Nb-doped SnO2 (Nb:SnO2). Compared to the pristine SnO2, the power conversion efficiency of PSCs based on Nb:SnO2 ETL is raised to 17.57% from 15.13%. The splendid performance is attributed to the excellent optical and electronic properties of the Nb:SnO2 material, such as smooth surface, high electron mobility, appropriate electrical conductivity, therefore making a better growth platform for a high quality perovskite absorber layer. Experimental analyses reveal that the Nb:SnO2 ETL significantly enhances the electron extraction and effectively suppresses charge recombination, leading to improved solar cell performance. PMID- 27995790 TI - Physiological Responses of Salinity-Stressed Vibrio sp. and the Effect on the Biofilm Formation on a Nanofiltration Membrane. AB - This study evaluated the effects of salinity on the physiological characteristics of Vibrio sp. B2 and biofilm formation on nanofiltration (NF) membrane coupons used in the high recovery seawater desalination process. The test conditions were at 0.6, 1.2, and 2.4 M sodium chloride (NaCl), equivalent to salinity of seawater, brine at 50% and 75% water recovery, respectively. High salinity inhibited the cell growth rate but increased the viability and bacterial membrane integrity. In addition, protein and eDNA concentrations of salinity-stressed bacteria were increased at 1.2 and 2.4 M NaCl. In particular, protein concentration was linearly correlated with the NaCl concentration. Similarly, less biofilm formation on the NF membrane coupon (without permeation flux) was observed by the salinity-stressed bacteria; however, the production of extracellular polymeric substances (EPS) was significantly increased as compared to control, and protein was an influential factor for biofilm formation. This study shows that salinity-stressed bacteria have a high potential to cause biofouling on membrane surface as the bacteria still maintain the cell activity and overproduce EPS. The potential of biofilm formation by the salinity-stressed bacteria has not been reported. Therefore, the findings are important to understand the mechanisms of membrane biofouling in a high salinity environment. PMID- 27995791 TI - Observation of Ultrathin Precursor Film Formation during Ge-Si Liquid-Phase Epitaxy from an Undersaturated Solution. AB - Our in situ X-ray study shows that a silicon substrate in contact with an undersaturated In(Ge) solution is wetted by an approximately 1 nm thin germanium film, which does not grow any thicker. The results can be understood by the use of thickness-dependent correlated interfacial energies. This near-equilibrium heterogeneous interface structure marks the initial stage of crystal growth before the formation of bulk material, which can only form under conditions of supersaturation. This finding uncovers a fundamental aspect of the thermodynamics at solid-liquid interfaces relevant for understanding the transition from equilibrium to supersaturation and is of importance for nanoscale solution growth methods. PMID- 27995792 TI - pH-Dependent Fluorescent Probe That Can Be Tuned for Cysteine or Homocysteine. AB - The very close structural similarities between cysteine and homocysteine present a great challenge to achieve their selective detection using regular fluorescent probes, limiting the biological and pathological studies of these two amino thiols. A coumarin-based fluorescent probe was designed featuring pH-promoted distinct turn-on followed by ratiometric fluorescence responses for Cys and turn on fluorescence response for Hcy through two different reaction paths. These specific responses demonstrate the activity differences between Cys and Hcy qualitatively for the first time. The probe could also be used for Cys and Hcy imaging in living cells. PMID- 27995793 TI - Experimental Determination of Isotope Enrichment Factors - Bias from Mass Removal by Repetitive Sampling. AB - Application of compound-specific stable isotope approaches often involves comparisons of isotope enrichment factors (epsilon). Experimental determination of epsilon-values is based on the Rayleigh equation, which relates the change in measured isotope ratios to the decreasing substrate fractions and is valid for closed systems. Even in well-controlled batch experiments, however, this requirement is not necessarily fulfilled, since repetitive sampling can remove a significant fraction of the analyte. For volatile compounds the need for appropriate corrections is most evident, and various methods have been proposed to account for mass removal and for volatilization into the headspace. In this study we use both synthetic and experimental data to demonstrate that the determination of epsilon-values according to current correction methods is prone to considerable systematic errors even in well-designed experimental setups. Application of inappropriate methods may lead to incorrect and inconsistent epsilon-values entailing misinterpretations regarding the processes underlying isotope fractionation. In fact, our results suggest that artifacts arising from inappropriate data evaluation might contribute to the variability of published epsilon-values. In response, we present novel, adequate methods to eliminate systematic errors in data evaluation. A model-based sensitivity analysis serves to reveal the most crucial experimental parameters and can be used for future experimental design to obtain correct epsilon-values allowing mechanistic interpretations. PMID- 27995794 TI - Enantioselective alpha-Arylation of O-Carbamates via Sparteine-Mediated Lithiation and Negishi Cross-Coupling. AB - A general and highly enantioselective arylation of carbamates derived from primary alcohols was developed by combining Hoppe's sparteine-mediated asymmetric lithiation with Negishi cross-coupling. Coupled with Aggarwal's lithiation borylation sequence, the current method provides a short and divergent access to a variety of enantioenriched secondary and tertiary benzylic alcohols. PMID- 27995796 TI - Tracking Nanoparticle Diffusion and Interaction during Self-Assembly in a Liquid Cell. AB - Nanoparticle self-assembly has been well studied theoretically, but it remains challenging to directly observe and quantify individual nanoparticle interactions. With our custom image analysis method, we track the trajectories of nanoparticle movement with high precision from a stack of relatively noisy images obtained using liquid cell transmission electron microscopy. In a time frame of minutes, Pt-Fe nanoparticles self-assembled into a loosely packed hcp lattice. The energetics and stability of the dynamic assembly were studied quantitatively. From velocity and diffusion measurements, we experimentally determined the magnitude of forces between single particles and the related physical properties. The results illustrate that long-range anisotropic forces drive the formation of chains, which then clump and fold to maximize close range van der Waals interactions. PMID- 27995797 TI - A Facile Electrochemical Reduction Method for Improving Photocatalytic Performance of alpha-Fe2O3 Photoanode for Solar Water Splitting. AB - Electrochemical reduction method is used for the first time to significantly improve the photo-electrochemical performance of alpha-Fe2O3 photoanode prepared on fluorine-doped tin oxide substrates by spin-coating aqueous solution of Fe(NO3)3 followed by thermal annealing in air. Photocurrent density of alpha Fe2O3 thin film photoanode can be enhanced 25 times by partially reducing the oxide film to form more conductive Fe3O4 (magnetite). Fe3O4 helps facilitate efficient charge transport and collection from the top alpha-Fe2O3 layer upon light absorption and charge separation to yield enhanced photocurrent density. The optimal enhancement can be obtained for <50 nm films because of the short charge transport distance for the alpha-Fe2O3 layer. Thick alpha-Fe2O3 films require more charge and overpotential than thinner films to achieve limited enhancement because of the sluggish charge transport over a longer distance to oxidize water. Electrochemical reduction of alpha-Fe2O3 in unbuffered pH-neutral solution yields much higher but unstable photocurrent enhancement because of the increase in local pH value accompanied by proton reduction at a hematite surface. PMID- 27995795 TI - Quantitative Proteomics Based on Optimized Data-Independent Acquisition in Plasma Analysis. AB - The advent of high-resolution and frequency mass spectrometry has ushered in an era of data-independent acquisition (DIA). This approach affords enormous multiplexing capacity and is particularly suitable for clinical biomarker studies. However, DIA-based quantification of clinical plasma samples is a daunting task due to the high complexity of clinical plasma samples, the diversity of peptides within the samples, and the high biologic dynamic range of plasma proteins. Here we applied DIA methodology, including a highly reproducible sample preparation and LC-MS/MS analysis, and assessed its utility for clinical plasma biomarker detection. A pancreatic cancer-relevant plasma spectral library was constructed consisting of over 14 000 confidently identified peptides derived from over 2300 plasma proteins. Using a nonhuman protein as the internal standard, various empirical parameters were explored to maximize the reliability and reproducibility of the DIA quantification. The DIA parameters were optimized based on the quantification cycle times and fragmentation profile complexity. Higher analytical and biological reproducibility was recorded for the tryptic peptides without labile residues and missed cleavages. Quantification reliability was developed for the peptides identified within a consistent retention time and signal intensity. Linear analytical dynamic range and the lower limit of quantification were assessed, suggesting the critical role of sample complexity in optimizing DIA settings. Technical validation of the assay using a cohort of clinical plasma indicated the robustness and unique advantage for targeted analysis of clinical plasma samples in the context of biomarker development. PMID- 27995798 TI - [3 + 2] Cycloaddition of Oxazol-5-(4H)-ones with Nitrones for Diastereoselective Synthesis of Isoxazolidin-5-ones. AB - In the presence of TMSCl, the [3 + 2] cycloaddition of oxazol-5-(4H)-ones with nitrones proceeded smoothly and furnished the desired isoxazolidin-5-ones with high diastereoselectivities in reasonable chemical yields. The chemical structure of the title compounds was firmly confirmed by X-ray single-crystal structure analysis. PMID- 27995799 TI - Electric-Field-Induced Energy Tuning of On-Demand Entangled-Photon Emission from Self-Assembled Quantum Dots. AB - We explore a method to achieve electrical control over the energy of on-demand entangled-photon emission from self-assembled quantum dots (QDs). The device used in our work consists of an electrically tunable diode-like membrane integrated onto a piezoactuator, which is capable of exerting a uniaxial stress on QDs. We theoretically reveal that, through application of the quantum-confined Stark effect to QDs by a vertical electric field, the critical uniaxial stress used to eliminate the fine structure splitting of QDs can be linearly tuned. This feature allows experimental realization of a triggered source of energy-tunable entangled photon emission. Our demonstration represents an important step toward realization of a solid-state quantum repeater using indistinguishable entangled photons in Bell state measurements. PMID- 27995801 TI - Molecular Dynamics Study of Nitrogen-Pyramidalized Bicyclic beta-Proline Oligomers: Length-Dependent Convergence to Organized Structures. AB - In this study, the solution structures of the homooligomers of a conformationally constrained bicyclic proline-type beta-amino acid were studied by means of molecular dynamics (MD) calculations in explicit methanol and water using the umbrella sampling method. The ratio of trans-amide and cis-amide was estimated by NMR and the rotational barrier of the amide of acetylated bicyclic amino acid monomer was estimated by two-dimensional (2D) exchange spectroscopy (EXSY) or line-shape analysis. A bias potential was introduced with respect to the amide torsion angle omega to enhance conformational exchange including isomerization of amide bonds by lowering the rotation energy barrier. After determination of reweighting parameters to best reproduce the experimental results of the monomer amide, the free energy profile around the amide torsion angle omega was obtained from the MD trajectory by reweighting of the biased probability density. The MD simulation results support the existence of invertomers of nitrogen-pyramidalized amide. Furthermore, extended structures with a high fraction of trans-amide conformation appear to be increasingly stabilized as the oligomer is elongated, both in methanol and in water. Our conformational analysis of natural and non natural tertiary-amide-based peptide oligomers indicates that these oligomers preferentially adopt a limited number of conformations. PMID- 27995802 TI - The Methylerythritol Phosphate Pathway to Isoprenoids. AB - Isoprenoids constitute one of the most diverse classes of natural products. As a compound class, they are essential to basic metabolic processes including cell wall biosynthesis, post-translational protein modifications, and signaling. In addition, isoprenoid secondary metabolites are highly valuable natural products with a wide range of biotechnological applications. The biosynthesis of their two universal building blocks, isopentenyl diphosphate and dimethylallyl diphosphate, was thought to proceed exclusively by way of mevalonate as a key intermediate until a novel pathway involving methylerithritol phosphate (MEP) was discovered in the early 1990s. In this review, we describe the seven enzymes of the MEP pathway, along with their discoveries, three-dimensional structures, and mechanisms. The latter include examples of remarkable enzyme catalysis including an unusual cytidilation reaction and the use of iron-sulfur cluster cofactors in reductive ring opening and hydroxy-group elimination. Furthermore, isoprenoid biosynthesis shows a characteristic species distribution. A brief overview highlights the MEP pathway's potential as a selective drug target, which is absent in humans but essential to the survival of many important bacterial and apicomplexan pathogens. PMID- 27995800 TI - Reactive Center Loop Insertion in alpha-1-Antitrypsin Captured by Accelerated Molecular Dynamics Simulation. AB - Protease inhibition by metastable serine protease inhibitors (serpins) is mediated by one of the largest functional intradomain conformational changes known in biology. In this extensive structural rearrangement, protease-serpin complex formation triggers cleavage of the serpin reactive center loop (RCL), its subsequent insertion into central beta-sheet A, and covalent trapping of the target protease. In this study, we present the first detailed accelerated molecular dynamics simulation of the insertion of the fully cleaved RCL in alpha 1-antitrypsin (alpha1AT), the archetypal member of the family of human serpins. Our results reveal internal water pathways that allow the initial incorporation of side chains of RCL residues into the protein interior. We observed structural plasticity of the helix F (hF) element that blocks the RCL path in the native state, which is in excellent agreement with previous experimental reports. Furthermore, the simulation suggested a novel role of hF and the connected turn (thFs3A) as chaperones that support the insertion process by reducing the conformational space available to the RCL. Transient electrostatic interactions of RCL residues potentially fine-tune the serpin inhibitory activity. On the basis of our simulation, we generated the alpha1AT mutants K168E, E346K, and K168E/E346K and analyzed their inhibitory activity along with their intrinsic stability and heat-induced polymerization. Remarkably, the E346K mutation exhibited enhanced inhibitory activity along with an increased rate of premature structural collapse (polymerization), suggesting a significant role of E346 in the gatekeeping of the strain in the metastable native state. PMID- 27995803 TI - Optimization of Acquisition and Data-Processing Parameters for Improved Proteomic Quantification by Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectrometry. AB - Proteomic analysis with data-independent acquisition (DIA) approaches represented by the sequential window acquisition of all theoretical fragment ion spectra (SWATH) technique has gained intense interest in recent years because DIA is able to overcome the intrinsic weakness of conventional data-dependent acquisition (DDA) methods and afford higher throughout and reproducibility for proteome-wide quantification. Although the raw mass spectrometry (MS) data quality and the data mining workflow conceivably influence the throughput, accuracy and consistency of SWATH-based proteomic quantification, there lacks a systematic evaluation and optimization of the acquisition and data-processing parameters for SWATH MS analysis. Herein, we evaluated the impact of major acquisition parameters such as the precursor mass range, isolation window width and accumulation time as well as the data-processing variables including peak extraction criteria and spectra library selection on SWATH performance. Fine tuning these interdependent parameters can further improve the throughput and accuracy of SWATH quantification compared to the original setting adopted in most SWATH proteomic studies. Furthermore, we compared the effectiveness of two widely used peak extraction software PeakView and Spectronaut in discovery of differentially expressed proteins in a biological context. Our work is believed to contribute to a deeper understanding of the critical factors in SWATH MS experiments and help researchers optimize their SWATH parameters and workflows depending on the sample type, available instrument and software. PMID- 27995804 TI - Arsenate and Selenate Scavenging by Basaluminite: Insights into the Reactivity of Aluminum Phases in Acid Mine Drainage. AB - Basaluminite precipitation may play an important role in the behavior of trace elements in water and sediments affected by acid mine drainage and acid sulfate soils. In this study, the affinity of basaluminite and schwertmannite for arsenate and selenate is compared, and the coordination geometries of these oxyanions in both structures are reported. Batch isotherm experiments were conducted to examine the sorption capacity of synthetic schwertmannite and basaluminite and the potential competitive effect of sulfate. In addition, synchrotron-based techniques such as differential pair distribution function (d PDF) analysis and extended X-ray absorption fine structure (EXAFS) were used to determine the local structure of As(V) and Se(VI) complexes. The results show that oxyanion exchange with structural sulfate was the main mechanism for removal of selenate, whereas arsenate was removed by a combination of surface complexes and oxyanion exchange. The arsenate adsorption capacity of basaluminite was 2 times higher than that of schwertmannite and 3 times higher than that of selenate in both phases. The sulfate:arsenate and sulfate:selenate exchange ratios were 1:2 and 1:1, respectively. High sulfate concentrations in the solutions did not show a competitive effect on arsenate sorption capacity but had a strong impact on selenate uptake, suggesting some kind of specific interaction for arsenate. Both d-PDF and EXAFS results indicated that the bidentate binuclear inner sphere was the most probable type of ligand for arsenate on both phases and for selenate on schwertmannite, whereas selenate forms outer-sphere complexes in the aluminum octahedral interlayer of basaluminite. Overall, these results show a strong affinity of poorly crystalline aluminum phases such as basaluminite for As(V) and Se(VI) oxyanions, with adsorption capacities on the same order of magnitude as those of iron oxides. The results obtained in this study are relevant to the understanding of trace element behavior in environments affected by acid water, potentially opening new research lines focused on remediation by natural attenuation processes or engineered water treatment systems. PMID- 27995805 TI - Reactive oxygen species and Ca2+ are involved in cadmium-induced cell killing in yeast cells. AB - Cadmium (Cd) is one of the most toxic heavy metals. It is of great environmental concern and its toxicity has been investigated in a variety of cells. In this study, we elucidated the toxic effects of Cd in cells of yeast (Saccharomyces cerevisiae). Our results showed that Cd2+ (0.05-5.0 mmol.L-1) significantly inhibited yeast cell growth, and the inhibitory effect was positively correlated with Cd2+ concentrations. Cd2+ caused loss of yeast cell viability in a concentration- and duration-dependent manner. Intracellular reactive oxygen species (ROS) and Ca2+ levels increased in yeast cells after exposure to 5.0 mmol.L-1 Cd for 6 h. Cd2+-caused cell viability loss was blocked by antioxidants (0.5 mmol.L-1 ascorbic acid or 500 U.mL-1 catalase) or Ca2+ antagonists (0.5 mmol.L-1 ethylene glycol tetraacetic acid or 0.5 mmol.L-1 LaCl3). Moreover, a collapse of mitochondrial membrane potential (DeltaPsim) was observed in Cd2+ treated yeast cells. These results indicate that Cd-induced yeast cell killing was associated with the elevation of intracellular ROS and Ca2+ levels and also the loss of DeltaPsim. PMID- 27995806 TI - Aetiologies of internal carotid artery pseudo-occlusions in acute stroke patients: what neurointerventionalists can expect. AB - In cases of acute stroke, differentiation between an occluded and a patent internal carotid artery (ICA) is crucial for diagnosis and management. Although CT angiography (CTA) can be highly accurate in defining high-grade stenosis and ICA occlusions, misleading ICA occlusion patterns are not rare in patients with acute stroke. We investigated the underlying causes of ICA pseudo-occlusions with CTA with respect to digital subtraction angiography. 11 out of 72 patients had pseudo-occlusion on CTA. Of these, there were three cases of tandem occlusions accompanying high-grade ICA stenosis, five cases of Distal ICA bifurcation occlusion as a result of atrial fibrillation, two cases of cervical ICA dissection and one acute thrombosis of the stent. Consideration of the aforementioned aetiologies by interventionists is warranted, as it may change the planning of endovascular intervention and treatment of acute stroke. PMID- 27995807 TI - Optimal scan timing for artery-vein separation at whole-brain CT angiography using a 320-row MDCT volume scanner. AB - OBJECTIVE: A 320-row multidetector CT (MDCT) is expected for a good artery-vein separation in terms of temporal resolution. However, a shortened scan duration may lead to insufficient vascular enhancement. We assessed the optimal scan timing for the artery-vein separation at whole-brain CT angiography (CTA) when bolus tracking was used at 320-row MDCT. METHODS: We analyzed 60 patients, who underwent whole-brain four-dimensional CTA. Difference in CT attenuation between the internal carotid artery (ICA) and the superior sagittal sinus (Datt) was calculated in each phase. Using a visual evaluation score for the depiction of arteries and veins, we calculated the difference between the mean score for the intracranial arteries and the mean score for the veins (Dscore). We assessed the time at which the maximum Datt and Dscore were simultaneously observed. RESULTS: The maximum Datt was observed at 6.0 s and 8.0 s in the arterial-dominant phase and at 16.0 s and 18.0 s in the venous-dominant phase after the contrast media arrival time at the ICA (Taa). The maximum Dscore was observed at 6.0 s and 8.0 s in the arterial-dominant phase and at 16.0 s in the venous-dominant phase after the Taa. There were no statistically significant differences in Datt (p = 0.375) or Dscore (p = 0.139) between these scan timings. CONCLUSION: The optimal scan timing for artery-vein separation at whole-brain CTA was 6.0 s or 8.0 s for the arteries and 16.0 s for the veins after the Taa. Advances in knowledge: Optimal scan timing allowed us to visualize intracranial arteries or veins with minimal superimposition. PMID- 27995808 TI - Quercetin and derivatives: useful tools in inflammation and pain management. AB - Inflammation represents a very frequent condition in humans; it is often underestimated, making the problem an increasingly alarming phenomenon. For these reasons, conventional therapies are losing their effectiveness, leaving room for innovative therapies. In this field, natural products showed their efficacy in various diseases; and flavonoids, in particular quercetin, is known for its broad range of activities. In this review, we have highlighted its efficacy in various models of inflammation, focusing also on the activity of its semisynthetic derivatives, and those naturally present in plant extracts. Finally, the analgesic property of quercetin, intrinsically linked to its anti-inflammatory action, has been also evaluated, to investigate about an innovative approach to this interesting natural compound, such as analgesic remedial. PMID- 27995809 TI - Correlations between the enantio- and regio-selective metabolisms of warfarin. AB - AIM: To clarify whether the activities of multiple CYPs associated with warfarin metabolism would be correlated with each other. METHODS: Oral clearances (CLpo) of warfarin enantiomers were estimated in 378 Chinese, Caucasians and African Americans. The partial metabolic clearances (CLm) for 7-hydroxywarfarin enantiomers were also measured. In addition, CLpo and CLm were determined in a patient on warfarin and rifampicin. RESULTS: Correlations between CLpo for warfarin enantiomers existed across the three populations. In addition, there was a significant correlation between the CLm for 7-hydroxylation of warfarin enantiomers. Under induced conditions by rifampicin, there were significant correlations between the enantio- and regio-selective metabolisms of warfarin. CONCLUSION: Metabolic activities of CYP2C9, CYP1A2 and CYP3A4 may be regulated by common transcriptional mechanism(s). PMID- 27995810 TI - A comprehensive look of poly(ADP-ribose) polymerase inhibition strategies and future directions for cancer therapy. AB - The finding of promising drugs represents a huge challenge in cancer therapeutics, therefore it is important to seek out novel approaches and elucidate essential cellular processes in order to identify potential drug targets. Studies on DNA repair pathway suggested that an enzyme, PARP, which plays a significant role in DNA repair responses, could be targeted in cancer therapy. Hence, the efficacy of PARP inhibitors in cancer therapy has been investigated and has progressed from the laboratory to clinics, with olaparib having already been approved by the US FDA for ovarian cancer treatment. Here, we have discussed the development of PARP inhibitors, strategies to improve their selectivity and efficacy, including innovative combinational and synthetic lethality approaches to identify effective PARP inhibitors in cancer treatment. PMID- 27995811 TI - Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach. AB - AIM: Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2 targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments. MATERIALS & METHODS: A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation. RESULTS: A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound 3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src. CONCLUSION: This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents. PMID- 27995812 TI - Social support buffers the effect of interpersonal life stress on suicidal ideation and self-injury during adolescence. AB - BACKGROUND: The effect of life stress on suicidal symptoms during adolescence is well documented. Stressful life events can trigger suicidality, but most adolescents are resilient and it is unclear which factors protect against the deleterious impact of stress. Social support is thought to be one such factor. Therefore, we investigated the buffering effect of specific sources of social support (parental and peer) on life stress (interpersonal and non-interpersonal) in predicting suicidal symptoms during adolescence. In order to test the specificity of this stress buffering, we also examined it with regard to dysphoric mood. METHOD: Data come from the Adolescent Development of Emotions and Personality Traits (ADEPT) Project, a cohort of 550 adolescent females aged 13.5 15.5 recruited from Long Island. Self-reported social support, suicidality, and dysphoria were assessed at baseline and suicidality and dysphoria were assessed again at 9-month follow-up. Life stress was assessed by interview at the follow up. RESULTS: High levels of parental support protected adolescent girls from developing suicidal symptoms following a stressor. This effect was less pronounced for peer support. Also, social support did not buffer the pathogenic effects of non-interpersonal stress. Finally, social support did not buffer the effect of life stress on dysphoric symptoms. CONCLUSIONS: Altogether, our results highlight a distinct developmental pathway for the development of suicidal symptoms involving parental support that differs from the development of dysphoria, and signifies the importance and specificity of social support in protecting against suicidality in adolescent girls. PMID- 27995813 TI - The predictors of persistent DSM-IV disorders in 3-year follow-ups of the British Child and Adolescent Mental Health Surveys 1999 and 2004. AB - BACKGROUND: The identification of the factors that influence the persistence of psychiatric disorder may assist practitioners to focus on young people who are particularly prone to poor outcomes, but population-based samples of sufficient size are rare. METHOD: This secondary analysis combined data from two large, population-based cross-sectional surveys in Great Britain (1999 and 2004) and their respective follow-ups (2002 and 2007), to study homotypic persistence among the 998 school-age children with psychiatric disorder at baseline. Psychiatric disorder was measured using the Development and Well-Being Assessment applying DSM-IV criteria. Factors relating to the child, family, and the severity and type of psychopathology at baseline were analysed using logistic regression. RESULTS: Approximately 50% of children with at least one psychiatric disorder were assigned the same diagnostic grouping at 3-year follow-up. Persistent attention deficit/hyperactivity disorder and anxiety were predicted by poor peer relationship scores. Persistent conduct disorder was predicted by intellectual disability, rented housing, large family size, poor family function and by severer baseline psychopathology scores. CONCLUSIONS: Homotypic persistence was predicted by different factors for different groups of psychiatric disorders. Experimental research in clinical samples should explore whether these factors also influence response to interventions. PMID- 27995814 TI - A Comparison of Administrative Data Versus Surveillance Data for Hospital Associated Methicillin-Resistant Staphylococcus aureus Infections in Canadian Hospitals. AB - BACKGROUND In Canadian hospitals, clinical information is coded according to national coding standards and is routinely collected as administrative data. Administrative data may complement active surveillance programs by providing in hospital MRSA infection data in a standardized and efficient manner, but only if infections are accurately captured. OBJECTIVE To assess the accuracy of administrative data regarding in-hospital bloodstream infections (BSIs) and all body-site infections due to MRSA. METHODS A retrospective study of all (adult and pediatric) in-hospital MRSA infections was conducted by comparing administrative data against surveillance data from 217 acute Canadian hospitals (124 in Ontario, 93 in Alberta) over a 12-month period. Hospital-associated MRSA BSI cases in Ontario, and for all-body-site MRSA infections in Alberta were identified. Pearson correlation coefficients were used to compare the number of hospital level MRSA cases within administrative versus surveillance datasets. The correlation of all-body-site MRSA infections versus MRSA BSIs was also assessed using the Ontario administrative data. RESULTS Strong correlations between hospital-level MRSA cases in administrative and surveillance datasets were identified for Ontario (r=0.79; 95% CI, 0.72-0.85) and Alberta (r=0.92; 95% CI, 0.88-0.94). A strong correlation between all-body-site and bloodstream-only MRSA infection rates was identified across Ontario hospitals (r=0.95; P<.0001; 95% CI, 0.93-0.96). CONCLUSIONS This study provides good evidence of the comparability of administrative and surveillance datasets in identifying in-hospital MRSA infections. With standard definitions, administrative data can provide estimates of in-hospital infections for monitoring and/or comparisons across hospitals. Infect Control Hosp Epidemiol 2017;38:436-443. PMID- 27995816 TI - Breaking cycles of risk: The mitigating role of maternal working memory in associations among socioeconomic status, early caregiving, and children's working memory. AB - Previous research has documented socioeconomic-related disparities in children's working memory; however, the putative proximal caregiving mechanisms that underlie these effects are less known. The present study sought to examine whether the effects of early family socioeconomic status on children's working memory were mediated through experiences of caregiving, specifically maternal harsh discipline and responsiveness. Utilizing a psychobiological framework of parenting, the present study also tested whether maternal working memory moderated the initial paths between the family socioeconomic context and maternal harsh discipline and responsiveness in the mediation model. The sample included 185 socioeconomically diverse mother-child dyads assessed when children were 3.5 and 5 years old. Results demonstrated that maternal harsh discipline was a unique mediator of the relation between early experiences of family socioeconomic adversity and lower working memory outcomes in children. Individual differences in maternal working memory emerged as a potent individual difference factor that specifically moderated the mediating influence of harsh discipline within low socioeconomic contexts. The findings have implications for early risk processes underlying deficits in child working memory outcomes and potential targets for parent-child interventions. PMID- 27995818 TI - Acquisition of nouns and verbs in Italian pre-school children. AB - Noun and verb acquisition was investigated in three- and five-year-old Italian children by means of picture naming of objects and actions, selected from Druks and Masterson (2000). The aim was to examine the previously reported advantage of nouns compared to verbs. Older children were faster than younger children, and naming latencies were faster for object pictures than for action pictures. For errors, the advantage of objects over actions was greater for younger children. A qualitative analysis of errors was carried out according to a classification derived by Masterson, Druks, and Gallienne (2008). Overall, 25% of the errors reflected a complete lack of knowledge of the names or of the meanings of the pictures. Most errors, however, were likely to be due to a not yet fully developed knowledge of the meaning of words labelling the pictures, or to an incomplete conceptual representation, and this pattern was more marked for action concepts. PMID- 27995815 TI - The role of parental marital discord in the etiology of externalizing problems during childhood and adolescence. AB - Previous research has established that parental marital discord is associated with higher levels of offspring externalizing behaviors, but it is unclear how parental relationship functioning is associated with the genetic and environmental variance on a factor of externalizing problems. Thus, the current study assessed how parental marital discord moderates genetic and environmental variance on offspring externalizing problems at two different ages: childhood and late adolescence. That is, the magnitude of genetic and environmental influences on offspring externalizing at ages 11 and 17 was examined as a function of parental marital discord. Consistent with a diathesis-stress model of psychopathology, it was hypothesized that with increasing marital discord, genetic influences on externalizing would be more pronounced. Rather, results indicated that for the 11-year-old sample, nonshared environmental influences were greater when parental marital discord was low, and comparatively, shared environmental influences contributed more to the variance in externalizing problems when parental marital discord was high. No moderation was found for the 17-year-old cohort. In contrast to studies that do not find an effect of the shared environment, these results provide evidence that the common rearing environment has an impact on externalizing problems in preadolescent children. PMID- 27995817 TI - Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci. AB - BACKGROUND: Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. METHOD: We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome sequenced at 11* depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential. RESULTS: Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. CONCLUSIONS: The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk. PMID- 27995819 TI - Cochrane Review Summary: Interventions for improving outcomes in patients with multimorbidity in primary care and community settings. PMID- 27995820 TI - Household food insecurity in black-slaves descendant communities in Brazil: has the legacy of slavery truly ended? AB - OBJECTIVE: To identify the factors associated with food insecurity among Quilombolas communities in Brazil. DESIGN: An analysis of secondary data assessed in the 2011 Quilombolas Census was performed. The Brazilian Food Insecurity Measurement Scale (Escala Brasileira de Inseguranca Alimentar, EBIA) was used to assess household food security status. Sociodemographic conditions and access to social programmes and benefits were also evaluated. SETTING: National survey census from recognized Quilombolas Brazilian territories. SUBJECTS: Quilombolas households (n 8846). RESULTS: About half (47.8 %) of the Quilombolas lived in severely food-insecure households, with the North and Northeast regions facing the most critical situation. Households located in North Brazil, whose head of the family had less than 4 years of education, with a monthly per capita income below $US 44, without adequate sanitation and without adequate water supply had the greatest chance of experiencing moderate or severe food insecurity. Households that had access to a water supply programme for dry regions (Programa Cisternas) and an agricultural harvest subsidy programme (Programa Garantia Safra) had less chance of experiencing moderate and severe food insecurity. Households that did not have access to health care (Programa Saude da Familia) had greater chance of suffering from moderate or severe food insecurity. CONCLUSIONS: Interventions are urgently needed to strengthen and promote public policies aimed to improve living conditions and food security in Quilombolas communities. PMID- 27995821 TI - Modes of relating to contingency: An exploration of experiences in advanced cancer patients. AB - OBJECTIVE: Throughout their lives, people are confronted with unexpected life events, which can be difficult to incorporate into their life narratives. Such a confrontation can result in an experience of contingency. Different ways of relating to contingency have been described by Wuchterl: denying, acknowledging, and "encounter with the Other." In the present article, we aim to trace these theoretical distinctions in real-life experiences of patients. METHOD: We analyzed 45 interviews using the constant comparative method with a directed content analysis approach in the Atlas.ti coding program. The interviews originated from a randomized controlled trial evaluating an assisted reflection on life events and ultimate life goals. Seven spiritual counselors from six hospitals in the Netherlands conducted the interviews from July of 2014 to March of 2016. All 45 patients had advanced cancer. RESULTS: We found four different modes into which relating to contingency can be classified: denying, acknowledging, accepting, and receiving. With denying, patients did not mention any impact of the life event on their lives. In acknowledging, the impact was recognized and a start was made to incorporate the event into their life. In accepting, patients went through a process of reinterpretation of the event. In receiving, patients talked about receiving insights from their illness and living a more conscious life. SIGNIFICANCE OF RESULTS: Our study is the first to investigate the different ways of relating to contingency in clinical practice. The defined modes will improve our understanding of the various ways in which cancer patients relate to their disease, allowing caregivers to better target and shape individual care. PMID- 27995822 TI - Factors to consider for motor neurone disease carer intervention research: A narrative literature review. AB - OBJECTIVE: The experience of caregiving in the context of motor neurone disease (MND) is extremely challenging. Over the past 15 years, quantitative and qualitative studies have delineated the psychosocial aspects of this experience, exploring its impact on caregivers' quality of life, rates of depression, distress, anxiety, and burden. Our paper aimed to provide an overview of the lived experience of MND caregivers, identifying the variables that can influence MND caregiver functioning that are relevant to the development of an intervention. METHOD: A narrative review was conducted, synthesizing the findings of literature retrieved from 2000 to early 2016. RESULTS: A total of 37 articles were included in the review. The articles varied considerably in terms of methodology and quality. The main influential aspects reported and identified were factors pertaining to the patient, factors intrinsic to the caregiver, relationship factors, and social support factors. SIGNIFICANCE OF RESULTS: There is evidence to support the fact that caregivers have poorer outcomes when they care for patients with a more severe clinical profile, poorer emotional health or neurobehavioral concerns, or when the caregivers themselves struggle with adaptive problem-solving and coping skills. The availability and use of social support are also likely to be important for caregiver psychosocial outcomes. Further investigation is required to clarify the influence of changes in the relationship with the patient. Significant factors affecting the caregiver experience are considered in relation to their amenability to psychosocial intervention. Recommendations are made regarding the optimal features of future psychosocial intervention research. PMID- 27995823 TI - Improving Compliance With Antibiotic Stewardship: What Is the Role of Initial Microscopy on the Management of Mechanically Ventilated Patients? PMID- 27995824 TI - Not all dietary diversity scores can legitimately be interpreted as proxies of diet quality. PMID- 27995825 TI - Treatment initiation in paediatric pulmonary hypertension: insights from a multinational registry. AB - Different treatment options for pulmonary hypertension have emerged in recent years, and evidence-based management strategies have improved quality of life and survival in adults. In children with pulmonary vascular disease, therapeutic algorithms are not so clearly defined; this study determined current treatment initiation in children with pulmonary hypertension in participating centres of a registry. Through the multinational Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension registry, patient demographics, diagnosis, and treatment as judged and executed by the local physician were collected. Inclusion criteria were >3 months and <18 years of age and diagnostic cardiac catheterisation consistent with pulmonary hypertension (mean pulmonary arterial pressure ?25 mmHg, pulmonary vascular resistance index ?3 Wood units*m2, and mean pulmonary capillary wedge pressure ?12 mmHg). At diagnostic catheterisation, 217/244 patients (88.9%) were treatment naive for pulmonary hypertension-targeted therapy. Targeted therapy was initiated after catheterisation in 170 (78.3%) treatment-naive patients. A total of 19 patients received supportive therapy, 28 patients were not started on therapy, and 26 patients (10.7%) were on targeted treatment before catheterisation. Among treatment-naive subjects, treatment was initiated with one targeted drug (n=112, 51.6%), dual therapy (n=39, 18%) or triple-therapy (n=5, 2.3%), and calcium channel blockers with one targeted medication in one patient (0.5%). Phosphodiesterase inhibitors type 5 were used frequently; some patients with pulmonary hypertension related to lung disease received targeted therapy. There is a diverse therapeutic approach for children with pulmonary hypertension with a need of better-defined treatment algorithms based on paediatric consensus for different aetiologies including the best possible diagnostic workup. PMID- 27995826 TI - Patient, staff, and clinician perspectives on implementing electronic communications in an interdisciplinary rural family health practice. AB - : Aim To conduct an environmental scan of a rural primary care clinic to assess the feasibility of implementing an e-communications system between patients and clinic staff. BACKGROUND: Increasing demands on healthcare require greater efficiencies in communications and services, particularly in rural areas. E communications may improve clinic efficiency and delivery of healthcare but raises concerns about patient privacy and data security. METHODS: We conducted an environmental scan at one family health team clinic, a high-volume interdisciplinary primary care practice in rural southwestern Ontario, Canada, to determine the feasibility of implementing an e-communications system between its patients and staff. A total of 28 qualitative interviews were conducted (with six physicians, four phone nurses, four physicians' nurses, five receptionists, one business office attendant, five patients, and three pharmacists who provide care to the clinic's patients) along with quantitative surveys of 131 clinic patients. Findings Patients reported using the internet regularly for multiple purposes. Patients indicated they would use email to communicate with their family doctor for prescription refills (65% of respondents), appointment booking (63%), obtaining lab results (60%), and education (50%). Clinic staff expressed concerns about patient confidentiality and data security, the timeliness, complexity and responsibility of responses, and increased workload. CONCLUSION: Clinic staff members are willing to use an e-communications system but clear guidelines are needed for successful adoption and to maintain privacy of patient health data. E communications might improve access to and quality of care in rural primary care practices. PMID- 27995827 TI - Prevalence of current anxiety disorders in people with bipolar disorder during euthymia: a meta-analysis. AB - BACKGROUND: Anxiety disorders are highly prevalent in people with bipolar disorder, but it is not clear how many have anxiety disorders even at times when they are free of major mood episodes. We aimed to establish what proportion of euthymic individuals with bipolar disorder meet diagnostic criteria for anxiety disorders. METHOD: We performed a random-effects meta-analysis of prevalence rates of current DSM-III- and DSM-IV-defined anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and anxiety disorder not otherwise specified) in euthymic adults with bipolar disorder in studies published by 31 December 2015. RESULTS: Across 10 samples with 2120 individuals with bipolar disorder, 34.7% met diagnostic criteria for one or more anxiety disorders during euthymia [95% confidence interval (CI) 23.9 45.5%]. Direct comparison of 189 euthymic individuals with bipolar disorder and 17 109 population controls across three studies showed a 4.6-fold increase (risk ratio 4.60, 95% CI 2.37-8.92, p < 0.001) in prevalence of anxiety disorders in those with bipolar disorder. CONCLUSIONS: These findings suggest that anxiety disorders are common in people with bipolar disorder even when their mood is adequately controlled. Euthymic people with bipolar disorder should be routinely assessed for anxiety disorders and anxiety-focused treatment should be initiated if indicated. PMID- 27995828 TI - Single dose intratympanic mesna application inhibits propylene glycol induced cholesteatoma formation. AB - OBJECTIVE: Mesna (i.e. sodium 2-mercaptoethanesulfonate; C2H5NaO3S2) has been used in otological surgery such as cholesteatoma dissection and tympanic membrane lateralisation in atelectatic ears. However, this study aimed to investigate its effect on cholesteatoma formation. METHODS: A total of 20 Wistar rats were divided into two groups of 10 animals. The right and left ears of control animals were treated with saline (saline control group; n = 10 ears) and propylene glycol plus saline (propylene glycol control group; n = 10 ears), respectively. In the mesna group, both ears were treated with propylene glycol plus mesna (n = 20 ears). On days 1, 8 and 15, the saline control group had intratympanic injections of 0.2 ml saline and the propylene glycol control and mesna groups had intratympanic injections of 0.2 ml 100 per cent propylene glycol. On day 22, the propylene glycol control group had a single intratympanic injection of 0.2 ml saline and the mesna group had a single intratympanic injection of 10 per cent mesna. Animals were killed 12 weeks after the last injection and the temporal bones were sent for histopathological evaluation. RESULTS: The cholesteatoma formation rate was 88 per cent in the propylene glycol control group, but was significantly lower in the mesna group (p = 0.01). There were no significant differences in granulation tissue formation (p = 0.498), cyst formation in the bulla (p = 0.381), fibrosis (p = 0.072) and epithelial hyperplasia (p = 0.081) among experimental groups. CONCLUSION: Intratympanic propylene glycol administration is an effective method of promoting experimental cholesteatoma formation. Administration of a single dose of intratympanic mesna inhibited cholesteatoma formation in an animal model. PMID- 27995829 TI - Microwave Frequency Comb from a Semiconductor in a Scanning Tunneling Microscope. AB - Quasi-periodic excitation of the tunneling junction in a scanning tunneling microscope, by a mode-locked ultrafast laser, superimposes a regular sequence of 15 fs pulses on the DC tunneling current. In the frequency domain, this is a frequency comb with harmonics at integer multiples of the laser pulse repetition frequency. With a gold sample the 200th harmonic at 14.85 GHz has a signal-to noise ratio of 25 dB, and the power at each harmonic varies inversely with the square of the frequency. Now we report the first measurements with a semiconductor where the laser photon energy must be less than the bandgap energy of the semiconductor; the microwave frequency comb must be measured within 200 MUm of the tunneling junction; and the microwave power is 25 dB below that with a metal sample and falls off more rapidly at the higher harmonics. Our results suggest that the measured attenuation of the microwave harmonics is sensitive to the semiconductor spreading resistance within 1 nm of the tunneling junction. This approach may enable sub-nanometer carrier profiling of semiconductors without requiring the diamond nanoprobes in scanning spreading resistance microscopy. PMID- 27995830 TI - Mechanisms responsible for the hypocholesterolaemic effect of regular consumption of probiotics. AB - CVD affect a large proportion of the world's population, with dyslipidaemia as the major risk factor. The regular consumption of both probiotic bacteria and yeast has been associated with improvement in the serum lipid profile. Thus, the present review aims to describe and discuss the potential mechanisms responsible for the hypocholesterolaemic effect of regular consumption of probiotic bacteria and yeast. Regarding the hypocholesterolaemic effect of probiotic bacteria, the potential mechanisms responsible include: deconjugation of bile salts; modulation of lipid metabolism; and decreased absorption of intestinal cholesterol through co-precipitation of intestinal cholesterol with the deconjugated bile salts, incorporation and assimilation of cholesterol in the cell membrane of the probiotics, intestinal conversion of cholesterol in coprostanol, and inhibition of the expression of the intestinal cholesterol transporter Niemann-Pick C1 like 1 (NPC1L1) in the enterocytes. The potential mechanisms responsible for the hypocholesterolaemic effect of probiotic yeasts include: deconjugation of bile salts; co-precipitation of intestinal cholesterol with the deconjugated bile salts; incorporation and assimilation of cholesterol in the cell membrane; and inhibition of hepatic cholesterol synthesis. The regular consumption of probiotic bacteria and yeast, as a non-pharmaceutical approach to help manage cardiovascular risk, holds promise, according to the beneficial hypocholesterolaemic effects described herein. However, the hypocholesterolaemic effects vary according to the strains used, the physiological state of the host, and the type of diet to which the probiotics are added. Further studies are necessary to fill the gaps with regard to the knowledge related to this topic. PMID- 27995831 TI - Associations between physical home environmental factors and vegetable consumption among Norwegian 3-5-year-olds: the BRA-study. AB - OBJECTIVE: First, to explore item pools developed to measure the physical home environment of pre-school children and assess the psychometric properties of these item pools; second, to explore associations between this environment and vegetable consumption among Norwegian 3-5-year-olds. DESIGN: Data were collected in three steps: (i) a parental web-based questionnaire assessing the child's vegetable intake and factors potentially influencing the child's vegetable consumption; (ii) direct observation of the children's fruit, berry and vegetable intakes at two meals in one day in the kindergarten; and (iii) a parental web based 24 h recall. SETTING: The target group for this study was pre-school children born in 2010 and 2011, attending public or private kindergartens in the counties of Vestfold and Buskerud, Norway. SUBJECTS: A total of 633 children participated. RESULTS: Principal component analysis on the thirteen-item pool assessing availability/accessibility resulted in two factors labelled 'availability at home' and 'accessibility at home', while the eight-item pool assessing barriers resulted in two factors labelled 'serving barriers' and 'purchase barriers'. The psychometric properties of these factors were satisfactory. Linear regression of the associations between vegetable intake and the factors showed generally positive associations with 'availability at home' and 'accessibility at home' and negative associations with 'serving barriers'. CONCLUSIONS: This age group has so far been understudied and there is a need for comparable studies. Our findings highlight the importance of targeting the physical home environment of pre-school children in future interventions as there are important modifiable factors that both promote and hinder vegetable consumption in this environment. PMID- 27995832 TI - Importance of mental performance in parental choice of food for children aged 4 10 years: a study in four European countries. AB - OBJECTIVE: Typically, attention focuses on how nutrition affects physical health. The present study investigated the importance that parents attach to the impact of diet on mental performance when choosing food for their child. DESIGN: Questionnaire. SETTING: Four European countries. SUBJECTS: Parents of children aged 4-10 years (n 1574): England (n 397), Germany (n 389), Hungary (n 398) and Spain (n 390). RESULTS: Most parents (80-85 %) considered the effect of food on four elements of mental performance (child's ability to learn, attention, behaviour, mood) to be moderately, very, extremely (v. slightly, not at all) important in food choices; over 90 % considered healthiness of food and making food appealing to their child important; 79.8 % cost; 76.8 % convenience. Belief that food affects mental performance was 57.4 % (ability to learn), 60.5 % (attention); less than 40 % of parents agreed they were aware which foods had an effect. Parents with lower general interest in healthy eating were less likely to consider the effect of food on mental performance elements as important. Respondents from Germany were more likely to rate mental performance as important (except behaviour); those in Hungary less likely. The most important influence on parents' decisions about feeding their child was their own experience, except Spain, where family/friends/health professionals were more important. CONCLUSIONS: Nutrition affects brain development and cognitive functioning. Low prioritisation of the effect of food on mental performance indicates potential for educating parents. PMID- 27995834 TI - Environmental and genetic factors influence the vitamin D content of cows' milk. AB - Vitamin D is obtained by cattle from the diet and from skin production via UVB exposure from sunlight. The vitamin D status of the cow impacts the vitamin D content of the milk produced, much like human breast milk, with seasonal variation in the vitamin D content of milk well documented. Factors such as changes in husbandry practices therefore have the potential to impact the vitamin D content of milk. For example, a shift to year-round housing from traditional practices of cattle being out to graze during the summer months and housed during the winter only, minimises exposure to the sun and has been shown to negatively influence the vitamin D content of the milk produced. Other practices such as changing dietary sources of vitamin D may also influence the vitamin D content of milk, and evidence exists to suggest genetic factors such as breed can cause variation in the concentrations of vitamin D in the milk produced. The present review aims to provide an overview of the current understanding of how genetic and environmental factors influence the vitamin D content of the milk produced by dairy cattle. A number of environmental and genetic factors have previously been identified as having influence on the nutritional content of the milk produced. The present review highlights a need for further research to fully elucidate how farmers could manipulate the factors identified to their advantage with respect to increasing the vitamin D content of milk and standardising it across the year. PMID- 27995835 TI - An update on the status of front-of-package labelling regulations in Latin America. PMID- 27995836 TI - GEOSPATIAL ASSESSMENT BASED ON FERTILITY AND MORTALITY DIFFERENTIAL INDICES OF NATURAL SELECTION IN NORTH-WEST AND EASTERN HIMALAYAN POPULATIONS. AB - There is contradictory evidence of having fewer live births and higher embryonic mortality among high-altitude populations than their counterparts at lower altitude. This study explores the geospatial differences in selection intensities among human populations living in different ecological settings. Reproductive data from post-menopausal women were collected from 75 women from near Shimla, Himachal Pradesh, at an altitude of 2150 m above sea level and 100 women from Jind, Haryana, at an altitude of 227 m. Secondary data were taken from 85 women from the Kinnaur district of Himachal Pradesh at an average altitude of 3420 m. A comparison of the study data was made with similar data from different populations living in the western and eastern Himalayas. The total selection intensity index based on Johnston and Kensinger's index was highest in Shimla and lowest in Kinnaur. The fertility selection component was highest in Shimla and lowest in Kinnaur. The prenatal mortality contribution to the total selection was highest in Shimla (30.76%) and lowest in Kinnaur (2.14%), while the contributions of normalized postnatal mortality were 16.39% and 57.80% in Shimla and Kinnaur, respectively. The fertility component of selection was higher than the mortality component in Shimla, while in the other two places the reverse was observed. Hypoxic conditions at high altitude seem to have little effect on the fertility and embryonic mortality rates of indigenous people. The geospatial differences in the selection intensities may be due to differences in ethnic, behavioural ecology, environmental, cultural and socioeconomic factors. PMID- 27995837 TI - Antiseptic Effect of Conventional Povidone-Iodine Scrub, Chlorhexidine Scrub, and Waterless Hand Rub in a Surgical Room: A Randomized Controlled Trial. AB - OBJECTIVE Effective perioperative hand antisepsis is crucial for the safety of patients and medical staff in surgical rooms. The antimicrobial effectiveness of different antiseptic methods, including conventional hand scrubs and waterless hand rubs, has not been well evaluated. DESIGN, SETTING, AND PARTICIPANTS A randomized controlled trial was conducted to investigate the effectiveness of the 3 antiseptic methods among surgical staff of Taipei Medical University-Shuang Ho Hospital. For each method used, a group of 80 participants was enrolled. INTERVENTION Surgical hand cleansing with conventional 10% povidone-iodine scrub, conventional 4% chlorhexidine scrub, or waterless hand rub (1% chlorhexidine gluconate and 61% ethyl alcohol). RESULTS Colony-forming unit (CFU) counts were collected using the hand imprinting method before and after disinfection and after surgery. After surgical hand disinfection, the mean CFU counts of the conventional chlorhexidine (0.5+/-0.2, P<0.01) and waterless hand rub groups (1.4+/-0.7, P<0.05) were significantly lower than that of the conventional povidone group (4.3+/-1.3). No significant difference was observed in the mean CFU count among the groups after surgery. Similar results were obtained when preexisting differences before disinfection were considered in the analysis of covariance. Furthermore, multivariate regression indicated that the antiseptic method (P=.0036), but not other variables, predicted the mean CFU count. CONCLUSIONS Conventional chlorhexidine scrub and waterless hand rub were superior to a conventional povidone-iodine product in bacterial inhibition. We recommend using conventional chlorhexidine scrub as a standard method for perioperative hand antisepsis. Waterless hand rub may be used if the higher cost is affordable. Infect Control Hosp Epidemiol 2017;38:417-422. PMID- 27995838 TI - Mental Hospitals in India in the 21st century: transformation and relevance. AB - Mental hospitals in India, as elsewhere in the world, have played an important role in the care of persons with mental illness. Since their inception, they have both been decried for gross violations of human rights and dignity as well as lauded as places of refuge and care for persons turned away by the communities. In a country where community interventions for mental health care are still fragmentary, the mental hospital still continues to be a relevant and legitimate locus of care along with other limited resources available for the care of persons with mental illness outside of the family. In India, positive changes in the infrastructure and resourcing of mental hospitals, reductions in involuntary admissions and improvements in facilities have largely occurred through judicial interventions. Recent pilot interventions for rehabilitation of long-stay patients point towards the need to develop rehabilitation and community facilities for persons with severe mental illness. PMID- 27995839 TI - Experience With a Novel, Global, Open-Access Template for Major Incidents: Qualitative Feasibility Study. AB - OBJECTIVE: The transfer of experiences gained after prehospital medical responses to major incidents has largely been nonsystematic, and better-structured reporting methods have been advocated. A consensus-based template was recently created and implemented as an open-access website. This qualitative study assessed the feasibility of using the template and reporting site. METHODS: Informants who had used or who had been asked to use the template were interviewed. The semi-structured interviews were transcribed verbatim, and the transcripts were analyzed by using an inductive approach based on grounded theory methodology. RESULTS: The major theme identified was a need for "defining purpose" as explained by the minor themes "relevance," "scope," "resources," and "usefulness." Informants reported that the template content needed to be revised and that the scope and rationale behind each question should be conveyed to the user. Resources necessary for reporting and clarity regarding the aim and outcome also need to be communicated to users and policy-makers. The interface between informants and the template is critical. CONCLUSIONS: Informants considered the template and website useful but reported that the workload exceeded their expectations. Despite pilot testing of the template before implementation, early revision of the template is recommended. (Disaster Med Public Health Preparedness. 2017;11:403-406). PMID- 27995840 TI - Storm Impact and Depression Among Older Adults Living in Hurricane Sandy-Affected Areas. AB - OBJECTIVE: Research on the impact of natural disasters on the mental health of older adults finds both vulnerabilities and resilience. We report on the rates of clinically significant depression among older adults (aged >=60 years) living in areas affected by Hurricane Sandy in 2012 and the factors associated with mental health need. METHODS: The Sandy Mobilization, Assessment, Referral and Treatment for Mental Health (SMART-MH) program integrates community outreach and needs assessments to identify older adults with mental health and aging service needs. Older adults with significant anxiety or depressive symptoms were offered short term psychotherapy. Social service referrals were made directly to community agencies. All SMART-MH activities were offered in Spanish, Russian, Mandarin/Cantonese, and English. RESULTS: Across the full sample, 14% of participants screened positive for depression. Hurricane Sandy stressors predicted increased odds of depression, including storm injury, post-storm crime, and the total count of stressors. Outcomes varied significantly by age group, such that all Sandy-related variables remained significant for younger-old adults (aged 60-74 years), whereas only the loss of access to medical care was significant for older-old adults (aged >=75 years). CONCLUSIONS: Storm-affected communities show higher rates of depressive symptoms than seen in the general population, with storm stressors affecting mental health needs differentially by age group. (Disaster Med Public Health Preparedness. 2017;11:97-109). PMID- 27995841 TI - Relationship between copper and lipids and atherogenic indices soon after birth in Japanese preterm infants of 32-35 weeks. AB - Several studies have reported association of altered levels of lipids and some trace elements with risk factors for cardiovascular disease development in adulthood. Accordingly, the present study aimed to determine the relationship among the serum levels of copper (Cu), zinc (Zn), lipids, lipoproteins and apolipoproteins in preterm infants through an assessment of atherogenic indices shortly after birth. Blood samples were collected within 20 min of birth from 45 preterm infants with gestational ages ranging from 32 to 35 weeks. Serum Cu, Zn, total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), apolipoprotein-A1 (apoA1) and apolipoprotein-B (apoB) levels were measured, and the TC/HDLc, LDLc/HDLc and apoB/apoA1 ratios were calculated. Upon determining the correlation between the levels of Cu, Zn and these indices of lipid metabolism, triglyceride (TG) and Cu were found to correlate negatively with birth weight (BW) and the standard deviation (s.d.) score for body weight. Furthermore, Cu levels correlated positively with the TG level and TC/HDLc, LDLc/HDLc and apoB/apoA1 ratios and negatively with the HDLc level and HDLc/apoA1 ratios. However, a stepwise multiple regression analysis indicated that the s.d. score for BW and TG level were significant independent determinants of the Cu level. In contrast, Zn did not correlate with any of these indices. In conclusion, intrauterine growth restriction and the TG level at birth influence Cu levels in preterm infants, whereas atherogenic indices do not affect this parameter. PMID- 27995842 TI - Maternal depression and trajectories of child internalizing and externalizing problems: the roles of child decision making and working memory. AB - BACKGROUND: Maternal depression may affect the emotional/behavioural outcomes of children with normal neurocognitive functioning less severely than it does those without. To guide prevention and intervention efforts, research must specify which aspects of a child's cognitive functioning both moderate the effect of maternal depression and are amenable to change. Working memory and decision making may be amenable to change and are so far unexplored as moderators of this effect. METHOD: Our sample was 17 160 Millennium Cohort Study children. We analysed trajectories of externalizing (conduct and hyperactivity) and internalizing (emotional and peer) problems, measured with the Strengths and Difficulties Questionnaire at the ages 3, 5, 7 and 11 years, using growth curve models. We characterized maternal depression, also time-varying at these ages, by a high score on the K6. Working memory was measured with the Cambridge Neuropsychological Test Automated Battery Spatial Working Memory Task, and decision making (risk taking and quality of decision making) with the Cambridge Gambling Task, both at age 11 years. RESULTS: Maternal depression predicted both the level and the growth of problems. Risk taking and poor-quality decision making were related positively to externalizing and non-significantly to internalizing problems. Poor working memory was related to both problem types. Neither decision making nor working memory explained the effect of maternal depression on child internalizing/externalizing problems. Importantly, risk taking amplified the effect of maternal depression on internalizing problems, and poor working memory that on internalizing and conduct problems. CONCLUSIONS: Impaired decision making and working memory in children amplify the adverse effect of maternal depression on, particularly, internalizing problems. PMID- 27995844 TI - Next steps for meeting the needs of people with severe mental illness in low- and middle-income countries. AB - The explicit inclusion of mental health within the Sustainable Development Goals is a welcome development, borne out of powerful advocacy using public health, economic and human rights arguments. As funding comes on line for scale-up of evidence-based mental health care by task-sharing with primary care, it is time to take stock about care for people affected by severe mental illness (SMI). The existing evidence base for task shared care for SMI provides an imperative to get started, but is skewed towards relatively more affluent and urban populations in middle-income countries where specialist mental health professionals provide most of the care. Randomised, controlled trials and rigorous implementation research on task shared service models are underway which will go some way to improving understanding of the quality, safety, effectiveness and acceptability of more widely generalisable care for people with SMI. A sub-group of people with SMI have more complex and long-term needs for care, with a high risk of homelessness, imprisonment and human rights violations as family and social supports become overwhelmed. Case studies from non-governmental organisations provide examples of holistic approaches to rehabilitation, recovery and empowerment of people with SMI, but rigorous comparative studies are needed to identify the most efficient, effective and scalable approaches to care. Health system constraints are emerging as the over-riding barriers to successful task-sharing, highlighting a need to develop and evaluate chronic care models for people with SMI that succeed in reducing premature mortality, improving wellbeing and achieving better social outcomes. Addressing these evidence gaps is essential if task-sharing mental health care is going to deliver on its promise of promoting recovery for the full range of people affected by SMI. PMID- 27995845 TI - Management of Small Renal Masses: Can Registries Answer Some Essential Questions? PMID- 27995843 TI - Effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose insulin dynamics in young adult horses. AB - In several species, adult metabolic phenotype is influenced by the intrauterine environment, often in a sex-linked manner. In horses, there is also a window of susceptibility to programming immediately after birth but whether adult glucose insulin dynamics are altered by neonatal conditions remains unknown. Thus, this study investigated the effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose-insulin dynamics of young adult horses. For the first 5 days after birth, term foals were treated with saline as a control or ACTH to raise cortisol levels to those of stressed neonates. At 1 and 2 years of age, insulin secretion and sensitivity were measured by exogenous glucose administration and hyperinsulinaemic-euglycaemic clamp, respectively. Glucose stimulated insulin secretion was less in males than females at both ages, although there were no sex-linked differences in glucose tolerance. Insulin sensitivity was greater in females than males at 1 year but not 2 years of age. Birth weight was inversely related to the area under the glucose curve and positively correlated to insulin sensitivity at 2 years but not 1 year of age. In contrast, neonatal glucocorticoid overexposure induced by adrenocorticotropic hormone (ACTH) treatment had no effect on whole body glucose tolerance, insulin secretion or insulin sensitivity at either age, although this treatment altered insulin receptor abundance in specific skeletal muscles of the 2-year-old horses. These findings show that glucose-insulin dynamics in young adult horses are sexually dimorphic and determined by a combination of genetic and environmental factors acting during early life. PMID- 27995846 TI - Legends in Urology. PMID- 27995847 TI - Legends in Urology: In Memorium. PMID- 27995848 TI - Patient reported outcomes among treatment modalities for prostate cancer. AB - INTRODUCTION: To characterize patient reported outcomes for urinary and sexual function using International Prostate Symptom Score (IPSS) and Sexual Health Inventory for Men (SHIM) comparing intensity modulated radiation therapy (IMRT), low dose rate brachytherapy (LDR), post-prostatectomy IMRT (PPRT), and radical prostatectomy (RP). MATERIALS AND METHODS: Patients treated for prostate cancer from 2001-2012 completed self-reported SHIM and IPSS surveys. Subgroups were created by baseline score. Mean change from baseline was determined at each time point for the cohort and subgroups. Statistical analysis was performed with generalized estimating equation method. Incontinence was not captured in the questionnaires. RESULTS: A total of 14,523 IPSS surveys from 3,515 men were evaluated. Patients treated with IMRT experienced a minimal decrease in IPSS score from baseline. PPRT scores did not differ from IMRT at any time point (range: +/- 3 points from baseline in IPSS score over 50 months). LDR had an initial IPSS rise (between 5-10 points on the IPSS over 1-9 months) versus IMRT but returned to comparable levels at 34 months. RP was associated with a lower IPSS versus IMRT. LDR had the largest rise from baseline, with return toward baseline. A total of 2,624 SHIM surveys from 857 men were evaluated. LDR and PPRT did not differ from IMRT at any time point (range: +/- 5 points from baseline in SHIM score for 36 months). RP experienced the largest decline from baseline (up to -7 points on SHIM score), at 3 to 7 months; RP had a larger early decrease in SHIM score versus IMRT between 3 and 22 months, after which there was no difference. CONCLUSIONS: IPSS and SHIM score patterns differed among treatment modalities. These data can be used to predict changes in urinary and sexual function over time based on modality and baseline score. PMID- 27995849 TI - Physical therapy for chronic scrotal content pain with associated pelvic floor pain on digital rectal exam. AB - INTRODUCTION: Chronic scrotal content pain (CSCP) is a common condition that can be challenging to manage definitively. A cohort of patients with CSCP have referred pain from myofascial abnormalities of the pelvic floor and therefore require treatment modalities that specifically address the pelvic floor such as pelvic floor physical therapy (PFPT). MATERIALS AND METHODS: Retrospective chart review of all men with a pelvic floor component of CSCP presenting to our tertiary care medical center and undergoing PFPT from 2011-2014. Patients with CSCP and pain/tightness on pelvic floor evaluation with 360 degrees digital rectal exam (DRE) were referred to a physiotherapist for PFPT. CSCP was defined as primary unilateral or bilateral pain of the testicle, epididymis and/or spermatic cord that was constant or intermittent, lasted greater than 3 months, and significantly interfered with daily activities. Long term follow up was conducted by office visit and physical therapy chart review. RESULTS: Thirty patients, mean age of 42 years (range 18-75), were followed for a median of 13 months (range 3-48). Median pre-PFPT pain score was 6/10 (range 2-10). After a mean of 12 PFPT sessions (IQR 6-16), pain improved in 50.0% of patients, median decrease in pain was 4.5/10 (range 1-10). Complete resolution of pain occurred in 13.3%, 44.0% had none to minor residual pain. Following PFPT, fewer subjects required pain medication compared with prior to PFPT (44.0% versus 73.3%, p = 0.03). CONCLUSIONS: For men with CSCP and a positive pelvic floor exam with DRE, we recommend a trial of PFPT as an effective and non-operative treatment modality. PMID- 27995850 TI - Prostate cancer polar localization on core biopsy predicts pathologic stage. AB - INTRODUCTION: This study investigated the polar sub-localization of prostate cancer on needle core biopsy ('polar' defined as tumor = 1 mm from the tissue polar edge) as a predictor of extraprostatic extension. MATERIALS AND METHODS: Histologic sections from 58 patients who underwent preoperative prostate biopsy and radical prostatectomy at the University of Kentucky from 2006 to 2013 were evaluated. Patients were retrospectively case matched based on pathologic stage (pT2 versus pT3/4) using biopsy Gleason grade and prostate-specific antigen. Histologic sections of needle core biopsies were analyzed for polar involvement. The location of polar involvement was correlated to the presence of extraprostatic extension on final prostatectomy pathology. RESULTS: Average percentage of total polar cores was predictive of extraprostatic extension on final prostatectomy, particularly in the prostatic apex and base (p = 0.029 and 0.006, respectively). Higher grade tumors were identified at the pole in the high stage cohort (p = 0.032). Total percent polar involvement had the greatest sensitivity and specificity for predicting extraprostatic extension when directly compared to previously described histologic parameters (percent greatest involvement of a single core, length of greatest involvement of a single core, presence of perineural invasion, presence of bilateral gland involvement, and percent total positive core involvement). The location of polar involvement on needle core biopsy was also predictive of the precise location of extraprostatic extension on final prostatectomy pathology (Chi-square p < .001, negative predictive value > 70% in all prostate sextants). CONCLUSIONS: These data suggest the use of biopsy polar core involvement as a valuable histologic predictor of increased pathologic stage. PMID- 27995851 TI - The impact of training on the perioperative and intermediate functional outcomes after holmium laser enucleation of the prostate. AB - INTRODUCTION: To systemically measure the impact of trainees' participation on the perioperative and functional outcomes after holmium laser enucleation of the prostate (HoLEP). MATERIALS AND METHODS: Benign prostatic hyperplasia patients who underwent HoLEP at our department between January 2007 and January 2013 were classified based on trainee's level. Perioperative outcomes and complications were collected. Functional outcomes were assessed using the Sexual Health Inventory for Men (SHIM), International Prostate Symptom Score (IPSS), and International Continence Society-Short Form (ICSmaleSF) questionnaires. Voiding and incontinence domains of ICSmaleSF were assessed separately. Patients were divided into group 1 if no trainee participated in the operation, group 2 if a senior trainee performed the operation, and group 3 if a junior trainee participated in the operation. The patient's baseline characteristics, complications, and perioperative outcomes were compared. RESULTS: There were no differences in the baseline characteristics. There were significant differences in overall operative and enucleation time (p = 0.0186, p = 0.0047, respectively) with shorter times noticed with more experienced operators. There were no differences in resected tissue weight, hemoglobin change, and transfusion rates. Postoperatively, all patients had a similar length of stay and catheterization. Complications (graded by Clavien grading system) were not different. All patients were followed up at regular intervals starting at 6 weeks, 3 months , 6 months, 1 year, and every year after that and there were no differences in flow rates or post void residual volumes at any time point. There were no differences in SHIM, IPSS, and ICSmale voiding scale among the groups. However, ICSmale continence scale was significantly different where the highest score seen in group 2. CONCLUSION: Trainee participation in HoLEP in a controlled training environment does not compromise the safety of the procedure. PMID- 27995852 TI - Does endorectal coil MRI increase the accuracy of preoperative prostate cancer staging? AB - INTRODUCTION: We sought to investigate the association of preprostatectomy magnetic resonance imaging (MRI) and surgical pathologic findings in patients with prostate cancer. MATERIALS AND METHODS: All patients with prostate cancer and preprostatectomy MRI available between 2002 and 2015 were included. Age, prostate-specific antigen at diagnosis, Gleason score at biopsy, MRI technique, radiology report suggestive of prostate cancer, extraprostatic invasion and seminal vesicle involvement, lymphadenopathy and final pathology report were retrospectively reviewed. Data was analyzed for sensitivity, specificity, positive and negative predictive values of MRI findings for predicting T3 disease. Consistency of MRI findings with pathology report was compared between MRIs with or without endorectal coil (ERC). RESULTS: A cohort of 83 patients was identified. Eighty-seven percent of the patients had MRI findings suggestive of prostate cancer. MRI was performed with and without ERC in 21 (25.3%) and 62 (74.3%) patients respectively. Eighty-five percent of patients with ERC and 88.7% of those without ERC had MRI findings suggestive of prostate cancer (p = 0.659). MRI correlated with final surgical pathology stage T3 in 53 patients (64%). MRI findings were consistent with final pathology report in 70% of ERC group and 61.3% of non ERC group (p = 0.482). In terms of extra prostatic invasion or seminal vesicle involvement, MRI had specificity, sensitivity, positive and negative predictive values of 84.44%, 37.84%, 66.67% and 62.3% respectively. CONCLUSIONS: MRI was specific but not sensitive in determining extraprostatic or seminal vesicle invasion. MRI was not accurate for lymph node involvement. In addition, using an ERC did not increase the accuracy of prostate MRI in this small cohort. PMID- 27995854 TI - Postoperative radiotherapy after prostatectomy: whom to treat. Finally light at the end of the tunnel? PMID- 27995853 TI - Prognostic implications of immediate PSA response to early salvage radiotherapy. AB - INTRODUCTION: Up to 25% of men with prostate cancer who undergo radical prostatectomy will recur. In this setting, salvage radiotherapy may cure patients with local recurrence, but is unable to cure those with occult metastatic disease. The objective of this study is to examine how prostate-specific antigen (PSA) response to radiotherapy predicts subsequent disease progression and survival. MATERIALS AND METHODS: Using a prospectively populated database of 3089 men who underwent open radical prostatectomy, 212 patients (7%) were identified who received early salvage radiotherapy for biochemical recurrence. The main outcome was time to disease progression after salvage radiotherapy. Patients were stratified by PSA response after radiotherapy: 1) PSA < 0.1 ng/mL, 2) persistently detectable PSA, and 3) rising PSA. RESULTS: Patients received salvage radiotherapy at a median PSA of 0.20 ng/mL (IQR 0.10-0.30 ng/mL). At a median follow up of 47.3 months, a total of 52 (25%) patients experienced disease progression. On multivariable analysis, both persistent PSA (HR 5.12; 95% CI 1.98 13.23) and rising PSA (HR 16.55; 95% CI 6.61-41.48) were associated with increased risk of disease progression compared to those with PSA < 0.1 ng/mL after adjusting for pre-radiotherapy PSA, Gleason score, margin status, stage, and time to radiotherapy. Only rising PSA was associated with an increased risk of cancer-specific and all-cause mortality. CONCLUSIONS: PSA response is associated with the risk of disease progression following salvage radiotherapy. This information can be used to counsel patients on the potential need for additional therapy and identify those at greatest risk for progression and cancer related mortality. PMID- 27995855 TI - Recurrent nephrolithiasis associated with keratinizing desquamative squamous metaplasia. AB - Keratinizing desquamative squamous metaplasia (KDSM) in the renal pelvis is a rare condition with unclear malignant potential. Recent reports suggest it is likely benign and favor endoscopic treatment approaches. Medical record review was completed on two cases at our center to obtain history, physical examination, radiographic findings, and management. A literature review was completed to identify all published cases of KDSM. Both patients at our center suffered recurrent urolithiasis, hypothesized to be secondary to KDSM. Both were managed with a percutaneous approach to ensure complete stone and KDSM plaque removal. Our cases highlight that percutaneous surgery is an excellent management option for stone and KDSM eradication from the collecting system. This approach also allows adequate oncologic surveillance of the underlying urothelium. PMID- 27995856 TI - Spermatic cord dedifferentiated liposarcoma presenting as a recurrent inguinal hernia. AB - Paratesticular sarcomas are a rare entity and provide a unique clinical challenge due to their slow growing, often painless natural course. Adding to this challenge is the complex anatomy of the scrotum that allows these masses to mimic other conditions, including inguinal hernia, cysts, or fluid collections. We report such a case and our approach to an 83-year-old male with dedifferentiated liposarcoma of the spermatic cord with a history of inguinal hernia. In doing so, we highlight the need for thorough evaluation of scrotal masses and the management of these rare, though well-described, tumors. PMID- 27995857 TI - Malignant mesothelioma of the tunica vaginalis: a rare case report and description of multimodal treatment. AB - Malignant mesothelioma is an uncommon neoplasm that develops from serous surfaces, and rarely from the tunica vaginalis. Although atypical in any location, paratesticular presentation is exceedingly infrequent as only 0.3% to 1.4% of mesothelioma cases arise from the tunica vaginalis. Fewer than 300 cases have been reported with very few descriptions of long term follow up and multimodal therapy. Here we describe a patient with 2 years of follow up for metastatic mesothelioma treated with orchiectomy, chemotherapy and robot-assisted laparoscopic retroperitoneal lymph node dissection. PMID- 27995858 TI - How I do it: Aquablation of the prostate using the AQUABEAM system. AB - Benign prostatic hyperplasia (BPH) represents one of the most common conditions encountered in urological practice. For many years, transurethral resection of the prostate (TURP) has been considered the gold standard for surgical management of symptoms in prostates of 30 cc-80 cc. Although TURP provides excellent functional outcomes, there is significant morbidity associated with the procedure, particularly with regards to bleeding, electrolyte imbalance and sexual dysfunction. Emerging technologies aim to maintain the excellent functional results of TURP whilst decreasing the adverse events experienced by the patient. Aquablation is a novel therapy using a high-velocity waterjet and real-time ultrasound imaging with robotic assistance for targeted removal of prostate tissue. We present our experiences with this new technique, the equipment required and steps involved. PMID- 27995859 TI - Management of acute scrotum in children: a 25-year single center experience on 558 pediatric patients. AB - INTRODUCTION: The aim of this study was to analyze management and outcomes of treatment in patients with acute scrotum. MATERIAL AND METHODS: From January 1990 until January 2015 case records of 558 patients who underwent surgery for acute scrotum were retrospectively reviewed. Mean age was 12 years old. Each patient was analyzed for following parameters: history data, localization of pain, physical examination, operating results and the results of follow up, age, etiology, and the time from initial symptoms to surgery. RESULTS: Scrotal explorations revealed 142 cases (25%) of spermatic cord torsion, 344 (62%) torsion of the testicular appendage, 54 (10%) epididymitis, 10 (2%) testicular trauma and 8 cases (1%) of other conditions. Two peaks of incidence of spermatic cord torsion were found, the first during first year of life and the second between 13 and 15 years of life. In patients with spermatic cord torsion, median duration of symptoms in the group of salvaged testes was 6 hours; while in the group of patients who underwent orchiectomy was 46 hours. Of the total number of patients with spermatic cord torsion 40 patients (28%) underwent orchiectomy while 102 testicles (72%) were saved. There were no major complications. Acute scrotum is significantly more common in the winter. Torsion of the testis has the highest incidence in January and August. CONCLUSION: Early scrotal exploration based on careful physical examination decreases the risk of misdiagnosis of spermatic cord torsion. It is of great importance that the patient seeks immediate medical attention. If the patient arrived within 6 hours the testicle can be saved. PMID- 27995860 TI - Testis torsion: recent lessons. PMID- 27995861 TI - Paenibacillus aceris sp. nov., isolated from the rhizosphere of Acer okamotoanum, a plant native to Ulleungdo Island, Republic of Korea. AB - Strain KUDC4121T was isolated from the rhizosphere of Acer okamotoanum, a plant native to the Korean island of Ulleungdo. The strain was a Gram-stain-positive, non-spore-forming, non-motile, rod-shaped bacterium that can grow at 18-37 degrees C and pH 6.0-7.5, with optimum growth at 30 degrees C and pH 7.0. It grew on tryptic soy agar containing less than 0.5 % (w/v) NaCl and in R2A broth. Cell length ranged from 2.0 to 2.5 um. Strain KUDC4121T was oxidase- and catalase positive and did not hydrolyse starch or casein. The genomic G+C content was 48.8 mol%. The major fatty acids were anteiso-C15 : 0 and iso-C16 : 0. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain KUDC4121T belongs to the genus Paenibacillus. The closest type strain was Paenibacillus chondroitinus DSM 5051T, with 97.8 % similarity, followed by Paenibacillus alginolyticus DSM 5050T (97.6 %), Paenibacillus ferrarius CY1T (97.5 %), Paenibacillus pocheonensis Gsoil 1138T (97.5 %), Paenibacillus frigoriresistens YIM 016T (97.5 %), Paenibacillus pectinilyticus RCB-08T (97.2 %) and Paenibacillus aestuarii CJ25T (96.9 %). Based on its phenotypic properties and phylogenetic and genetic data, strain KUDC4121T should be considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus aceris sp. nov. is proposed. The type strain is KUDC4121T (=KCTC 13870T=DSM 24950T). PMID- 27995862 TI - International Committee on Systematics of Prokaryotes Subcommittee on the taxonomy of Chlamydiae. Minutes of the closed meeting, 4 July 2012, Amsterdam, Netherlands. PMID- 27995863 TI - Discovery of a novel accessory protein NS7a encoded by porcine deltacoronavirus. AB - Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus. Bioinformatics predicts that PDCoV encodes two accessory proteins (NS6 and NS7), the species-specific proteins for coronavirus. In this study, four mAbs against the predicted NS7 were prepared by using the purified recombinant NS7 protein. Indirect immunofluorescence assay demonstrated that all mAbs recognized cells transfected with an NS7 expression construct or infected with PDCoV. Western blot showed that NS7-specific mAbs recognized an additional protein band of about 12 kDa from PDCoV-infected cell lysates but not from cells with the ectopic expression of NS7. Detailed analysis suggested that this additional protein band represented a novel accessory protein, termed NS7a, a 100 amino acid polypeptide identical to the 3' end of NS7. Moreover, NS7a is encoded by a separate subgenomic mRNA with a non-canonical transcription regulatory sequence. In summary, our results identified a third accessory protein encoded by PDCoV, which will enhance our understanding of PDCoV. PMID- 27995864 TI - Detection of mycobacteria by volatile organic compound analysis of invitro cultures using differential ion mobility spectrometry. AB - PURPOSE: Differential ion mobility spectrometry (DMS) is an analytical technique used to detect volatile organic compounds (VOCs) in gaseous samples at very low concentration ranges from ppb to ppt. The aim of this study was to investigate whether VOC analysis by DMS is capable of detecting Mycobacterium avium subsp. paratuberculosis (MAP). METHODOLOGY: Headspaces of in vitro cultures of two different MAP strains at 1, 2, 3, 4 and 6 weeks after inoculation (each at two dilutions) were analysed with DMS in comparison to control samples without viable bacteria [(i) blank medium, (ii) medium inoculated with heat-inactivated MAP and (iii) sterile-filtered MAP culture broth]. Furthermore, VOC patterns in the headspace over cultures of six non-tuberculous mycobacterial species were compared to MAP-derived VOC patterns. Data analysis included peak detection, cluster analysis, identification of discriminating VOC features (Mann-Whitney U test) and different cross-validated discriminant analyses. RESULTS: VOC analysis resulted in up to 127 clusters and revealed highly significant differences between MAP strains and controls at all time points. In addition, few clusters allowed differentiation between MAP and other non-tuberculous mycobacteria and even between different MAP strains. Compounds have not been characterized. VOC analysis by DMS was able to identify MAP-positive samples after 1 week of in vitro growth. CONCLUSIONS: This study provides strong evidence that VOC analysis of headspace over mycobacterial cultures in combination with appropriate data analysis has the potential to become a valuable method to identify positive samples much earlier than with current standard procedures. PMID- 27995866 TI - Thermodesulfobium acidiphilum sp. nov., a thermoacidophilic, sulfate-reducing, chemoautotrophic bacterium from a thermal site. AB - An obligately anaerobic, sulfate-reducing micro-organism, strain 3127-1T, was isolated from geothermally heated soil (Oil Site, Uzon Caldera, Kamchatka, Russia). The new isolate was a moderately thermoacidophilic anaerobe able to grow with H2 or formate by respiration of sulfate or thiosulfate. The pH range for growth was 3.7-6.5, with an optimum at 4.8-5.0. The temperature range for growth was 37-65 degrees C, with an optimum at 55 degrees C. The G+C content of the genomic DNA was 33.7 mol%. The genome of strain 3127-1T contained two almost identical 16S rRNA genes, differing by a single nucleotide substitution. The closest 16S rRNA gene sequence of a validly published species belonged to Thermodesulfobium narugense Na82T (99.5 % similarity). However, the average nucleotide identity of the genomes of strain 3127-1T and T. narugense Na82T and the predicted DNA-DNA hybridization value (GGDC 2.1 blast+, formula 2) were as low as 86 and 32.5+/-2.5 %, respectively. This, together with phenotypic data, showed the new isolate to belong to a novel species, for which the name Thermodesulfobium acidiphilum sp. nov. is proposed. The type strain is 3127-1T (=DSM 102892T=VKM B-3043T). PMID- 27995867 TI - Poly(A) polymerase I participates in the indole regulatory pathway of Pantoea agglomerans YS19. AB - Pantoea agglomerans YS19 is a preponderant endophytic bacterium isolated from rice. It is characterized by the formation of symplasmata, a type of multicellular aggregate structure, contributing to a strong stress resistance and specific adaptation of YS19 in endophyte-host associations. Indole is an important signal molecule in intra- or interspecies relationships, regulating a variety of bacterial behaviours such as cell aggregation and stress resistance; however, the regulatory mechanism remains an ongoing area of investigation. This study selected YS19 as a model strain to construct a mutant library, utilizing the mTn5 transposon mutagenesis method, thus obtaining a positive mutant with an indole-inhibited mutation gene. Via thermal asymmetric interlaced PCR, the mutational site was identified as the gene of pcnB, which encodes the poly(A) polymerase I to catalyse the polyadenylation of RNAs. The full length of the pcnB sequence was 1332 bp, and phylogenetic analysis revealed that pcnB is extremely conserved among strains of P. agglomerans. The expression of the gene was significantly inhibited (by 36.6 % as detected via quantitative PCR) by indole (0.5 mM). Many physiological behaviours of YS19 were affected by this mutation: the cell decay rate in the post-stationary growth phase was promoted, symplasmata formation and motility were inhibited in the late stationary growth phase and the colonization ability and growth-promoting effect of YS19 on the host plant were also inhibited. This study discusses the indole regulatory pathways from the point of RNA post-transcriptional modification, thus enriching our knowledge of polyadenylation and expanding current research ideas of indole regulation. PMID- 27995869 TI - Evaluation of Xpert MRSA Gen 3 and BD MAX MRSA XT for meticillin-resistant Staphylococcusaureus screening in a routine diagnostic setting in a low prevalence area. AB - Screening and pre-emptive isolation of at-risk patients are important aspects of the Danish approach to the prevention of meticillin-resistant Staphylococcusaureus (MRSA) infection, but screening with conventional culture can take up to 3 days for results to become available with attendant costs and disadvantages of prolonged isolation. We sought to evaluate the accuracy, time to availability of results and potential economic benefits of two next-generation MRSA screening assays, Xpert MRSA Gen 3 (GX MRSA) and BD MAX MRSA XT, in a setting of a consolidated laboratory serving a number of hospitals with a low prevalence of MRSA and using enrichment culture as a reference method. Four hundred and forty-seven screening samples together with 49 previously positive MRSA samples were evaluated. Xpert MRSA Gen 3 demonstrated sensitivity, specificity, positive predictive value and negative predictive value of 88.2, 97.9, 62.5 and 99.5 %, respectively, and for BD MAX MRSA XT, they were 88.2, 97.4, 57.7 and 99.5 %, respectively. Hands-on time was 8.8 and 21.6 min, respectively, for the Xpert MRSA Gen 3 and BD MAX MRSA XT PCR assays when five samples were handled simultaneously. The mean laboratory turnaround time was 2.9 (1-6) hours for the Xpert MRSA Gen 3 assay, 6.5 (2-46) hours for BD MAX MRSA XT and 49.6 (42-122) hours for enriched culture. Despite laboratory costs being higher for the rapid PCR assays, when the costs of isolation are taken into account, the assays offer the potential for significant cost savings. PMID- 27995870 TI - Noviherbaspirillum agri sp. nov., isolated from reclaimed grassland soil, and reclassification of Herbaspirillum massiliense (Lagier et al., 2014) as Noviherbaspirillum massiliense comb. nov. AB - A straw-coloured, Gram-staining-negative, aerobic, motile and rod-shaped bacterium, designated strain K-1-15T, was isolated from reclaimed grassland soil from Biratnagar, Morang, Nepal. This strain was non-spore-forming, catalase negative and oxidase-positive. It was able to grow at 10-45 degrees C, pH 6.5 9.5 and 0-1.5 % (w/v) NaCl concentration. This strain was taxonomically characterized by a polyphasic approach. Based on the results of 16S rRNA gene sequence analysis, K-1-15T formed a distinct lineage within the family Oxalobacteraceae and was most closely related to members of the genera Herbaspirillum(96.99-95.34 % sequence similarity), Noviherbaspirillum(96.72-95.45 % sequence similarity) and Paraherbaspirillum (95.85 % sequence similarity). The only respiratory quinone was ubiquinone-8. The polar lipid profile revealed the presence of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The major fatty acids of K-1 15T were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C10 : 0 3-OH, and iso C16 : 0. The genomic DNA G+C content of this novel strain was 65.2 mol %. The DNA DNA relatedness between K-1-15T and Herbaspirillum massiliense DSM 25712T and Noviherbaspirillum soli LMG 26149T were 18.3 and 13.7 % repectively. On the basis of the results of morphological, physiological, chemotaxonomic and phylogenetic analyses, K-1-15T represents a novel species of the genus Noviherbaspirillum in the family Oxalobacteraceae, for which the name Noviherbaspirillum agri sp. nov. is proposed. The type strain is K-1-15T (=KEMB 9005-422T=KACC 18909T=JCM 31463T). Based on new data obtained in this study, we also propose the reclassification of Herbaspirillum massiliense as Noviherbaspirillum massiliense comb. nov. (type strain JC206T=CSUR P159T=DSM 25712T). PMID- 27995871 TI - International Committee on Systematics of Prokaryotes Subcommittee on the taxonomy of Chlamydiae. Minutes of the closed meeting, 31 March 2015, New Orleans, USA. PMID- 27995868 TI - Pedobacter jamesrossensis sp. nov., Pedobacter lithocola sp. nov., Pedobacter mendelii sp. nov. and Pedobacter petrophilus sp. nov., isolated from the Antarctic environment. AB - A taxonomic study performed on 17 Gram-stain-negative rod-shaped bacterial strains originating from the Antarctic environment is described. Initial phylogenetic analysis using 16S rRNA gene sequencing differentiated the strains into four groups belonging to the genus Pedobacter but they were separated from all hitherto described Pedobacter species. Group I (n=8) was closest to Pedobacter aquatilis (97.8 % 16S rRNA gene sequence similarity). Group II (n=2) and group III (n=4) were closely related (98.8 % 16S rRNA gene sequence similarity) and had Pedobacter jejuensis as their common nearest neighbour. Group IV (n=3) was distantly delineated from the remaining Pedobacter species. Differentiation of the analysed strains into four clusters was further confirmed by repetitive sequence-based PCR fingerprinting, ribotyping, DNA-DNA hybridization and phenotypic traits. Common to representative strains for the four groups were the presence of major menaquinone MK-7, sym-homospermidine as the major polyamine, phosphatidylethanolamine, two unidentified lipids (L2, L5) and an unidentified aminolipid (AL2) as the major polar lipids, presence of an alkali-stable lipid, and C16:1omega7c/C16:1omega6c (summed feature 3), iso-C15:0 and iso-C 17:0 3-OH as the major fatty acids, which corresponded to characteristics of the genus Pedobacter. The obtained results showed that the strains analysed represent four novel species of the genus Pedobacter, for which the names Pedobacter jamesrossensis sp. nov. (type strain CCM 8689T=LMG 29684T), Pedobacter lithocola sp. nov. (CCM 8691T=LMG 29685T), Pedobacter mendelii sp. nov. (CCM 8685T=LMG 29688T) and Pedobacter petrophilus sp. nov. (CCM 8687T=LMG 29686T) are proposed. PMID- 27995872 TI - International Committee on Systematics of Prokaryotes Subcommittee on the taxonomy of Chlamydiae. Minutes of the closed meeting, 21 March 2013, San Antonio, Texas, USA. PMID- 27995874 TI - Brevundimonas balnearis sp. nov., isolated from the well water of a thermal bath. AB - A novel alphaproteobacterium was isolated from the well water of a thermal bath at Budapest, Hungary. Phylogenetic analysis of the novel strain showed that this bacterium belongs to a distinct lineage among the genus Brevundimonas. Based on the 16S rRNA gene sequence strain FDRGB2bT showed the highest sequence similarity values to Brevundimonas naejangsanensis BIO-TAS2-2T (97.35 %), Brevundimonas viscosa F3T (97.28 %), Brevundimonas vesicularis LMG 2350T (97.27 %), Brevundimonas nasdae GTC 1043T (97.14 %), Brevundimonas vancanneytii LMG 2337T (97.13 %) and Brevundimonas aurantiaca DSM 4731T (97.13 %). The newly isolated bacterium was strictly aerobic, and its optimum growth occurred at 20-30 degrees C, between pH 8-9 and without NaCl. Movement was with a single polar flagellum, but the cells could also produce stalks. The major isoprenoid quinone of strain FDRGB2bT was Q-10, the major cellular fatty acids were C18 : 1omega7c and C16 : 0, and the polar lipid profile contained phosphatidylglycerol, diphosphatidylglycerol, two unknown phospholipids and four unknown glycolipids. The characteristic diamino acid in its cell wall is meso-diaminopimelic acid. The G+C content of DNA of the type strain was 69.8 mol%. Strain FDRGB2bT (=DSM 29841T=NCAIM B.02621T) is proposed as the type strain of a novel species with the proposed name Brevundimonas balnearis sp. nov. PMID- 27995875 TI - [Patient reported outcome of tyrosine kinase inhibitor related side effects and their impact on daily life in Chinese patients with chronic myeloid leukemia in the chronic phase]. AB - Objective: To explore the impact of patient reported outcome of tyrosine kinase inhibitor (TKI) related side effects on daily life in Chinese patients with chronic myeloid leukemia (CML) in the chronic phase (CP). Methods: From May to November in 2014, anonymous questionnaires were distributed to adult CML patients who were receiving TKI treatment in China. The impact of TKI-related side effects on daily life were assessed by the score of 1 (no impact) to 5 (high impact) from patient self-report. Results: Data from 731 respondents in the CP who reported the score of the impact of TKI-related side effects on daily life were collected. 407 (56%) were male. The median age was 41 years (range, 18 to 88 years). 560 (77%) started TKI treatment within 1 year after diagnosis. With a median treatment duration of 3 years (range, <1 to 13 years), 549 (75% ) respondents achieved a complete cytogenetic response (CCyR) and 301 (41%) achieved a complete molecular response (CMR). The most common TKI-related adverse effects were edema (n=323, 44% ), fatigue (n=277, 38% ), gastrointestinal disorders (n=235, 32% ), skin color changes (n=142, 19% ), muscle cramps (n=137, 19% ), rash (n=105, 14% ), hepatic function abnormalities (n=91, 12%), weight gain (n=86, 12%), and cytopenia (n=59, 8%). Multivariate analyses showed that TKI treatment duration <4 years was the factor associated with fatigue; Edema was more observed in female, >=40 years old and use of 1st generation TKI; Gastrointestinal disorders in use of 1st generation TKI; Hepatic function abnormalities and rash in use of 2nd generation TKI; Weight gain in female; Muscle cramps in long-term interval from diagnosis to therapy and use of 1st generation TKI; Low blood counts in use of generic TKI. There was no impact of TKI-related side effects on daily life in 218 (30%)respondents (1 score). 375 (51%)respondents reported their daily life were slightly or moderately decreased (2 or 3 score), while 138 (19%) significantly decreased (4 or 5 score). Multivariate analyses showed that female, >=40 years old, use of generic TKI, TKI treatment duration <4 years were factors associated with negative effect on their daily life. When taking TKI related side-effects into considderation, secondary school and below, use of generic TKI, TKI treatment duration <4 years, edema, fatigue, gastrointestinal disorders, skin color changes, rash and hepatic function abnormalities, were factors associated with negative effect on their daily life. Conclusion: Edema, fatigue, gastrointestinal disorders, rash, skin color changes and hepatic function abnormalities were common TKI-related side effects and influenced CML patients' daily life in China. In addition, female, older age, lower education level, use of generic TKI and shorter TKI treatment duration were associated with negative impact on quality of life. PMID- 27995876 TI - [EVI1 expression, clinical and cytogenetical characteristics in 447 patients with acute myeloid leukemia]. AB - Objective: To investigate EVI1 expression and its associated clinical and cytogenetic characteristics in 447 acute myeloid leukemia (AML) patients. Methods: EVI1 expressions were measured in 447 AML cases from Jan. 2007 to Apr. 2015 to couple with clinical, cytogenetic and mutations' characteristics to summarize the features of AMLs with high EVI1 expression. Results: 17.9% of AML were high EVI1 expression (EVI1 +), and the remainder low EVI1 expression (EVI1 ). No significant differences between the two groups in terms of age, sex, hemoglobin level, white blood cell count and platelet count were observed. More M0, M5 and M6 subtypes were observed in EVI1+ group (P= 0.027, 0.004 and 0.011, respectively). Cytogenetic abnormalities of 11q15, 11q23/MLL, 3q26, -7/7q- and t (9;11) were observed more frequently in EVI1 + group (P<0.001, <0.001, <0.001, <0.001, =0.014, respectively). Normal karyotype, inv (16), t (8;21) were observed more frequent in EVI1- group (P=0.001, 0.009, 0.002, respectively). EVI1 + was more observed in high risk cytogenetics. Mutation of NPM1 was more observed in EVI1- group (P <0.001). Remission rate in EVI1 + group was significantly lower than EVI1- group (P<0.001). Leukemia-free survival was improved in EVI1 + AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo HSCT). Conclusions: High EVI1 expression was more observed in FAB subgroup M5, harbored more cytogenetic abnormalities of 11p15, 11q23/MLL, 3q26 rearrangement, 7/7q- and t (9;11). Remission rate of high EVI1 expression AML was lower, which could be improved by allo-HSCT. PMID- 27995877 TI - [The diagnostic and prognostic values of serum free light chain in patients with primary light chain amyloidosis]. AB - Objective: To investigate the diagnostic and prognostic values of serum free light chain (sFLC) in patients with primary light chain amyloidosis (pAL). Methods: Patients diagnosed with pAL between January 2009 and June 2015 at Peking Union Medical College Hospital were included in this study to retrospectively evaluate the clinical data, sFLC, treatment and survival. Results: In total, 126 newly diagnosed pAL patients with complete sFLC data were included in this study. The median age was 57 years old (range, 37-81 years) and male to female ratio was 1.57. Eighty patients (63.5%) had lambda type light chain. Renal and cardiac involvements occurred in 87 cases (69% ) and 79 cases (62.7% ), respectively. The median value of difference between involved and uninvolved serum immunoglobulin free light chain levels (dFLC) was 99 mg/L (range, 1-4 263 mg/L). The positive rate of serum protein electrophoresis, serum immune fixation electrophoresis, urine immunofixation electrophoresis and abnormal sFLC ratio to detect monoclonal immunoglobulin were 34.9%(44 cases), 63.5%(80 cases), 77.0%(97 cases) and 81.0% (102 cases), respectively. The sensitivity for identifying monoclonal immunoglobulin could be increased to 98.4%(124 cases) by using the above mentioned four methods. The median follow-up was 16 months, 37 patients were dead at the last follow-up. The median overall survival of all patients were not reached. Multivariate analysis showed that dFLC>=130 mg/L was independently associated with inferior survival (HR=3.272, 95%CI 1.384-7.739, P=0.007). Conclusions: Serum FLC measurement combined with other methods could improve the sensitivity of detection of monoclonal immunoglobulin in patients with pAL. The high level of dFLC was an independent prognostic factor for survival. PMID- 27995878 TI - [Treatment of transfusion-dependent nonsevere aplastic anemia with cyclosporine A plus ATG/ALG versus cyclosporine A plus androgens: a retrospective single center study]. AB - Objective: To determine whether cyclosporine A (CsA) plus androgens was as effective as the current standard immunosuppressive therapy (IST) for transfusion dependent nonsevere aplastic anemia (TD-NSAA). Methods: The records of 125 consecutive TD-NSAA patients who were treated between Aug. 2007 and Sept. 2014, with either CsA plus androgen or ALG/ATG plus CsA regimen were reviewed. The 3 month and 6-month hematologic responses and survival were evaluated. Results: There were 125 TD-NSAA patients (70 were male and 55 female, 1.25?1). Median age was 27 (6-66) years. There was no significant difference in early mortality between 48 treated by ATG/ALG plus CsA and 77 by CsA plus androgen patients (1/48 vs 0/77, P=0.384). Both the total hematologic response and the better hematological response rates at 3-month (70.8% vs 45.5%, P=0.006 and 27.1% vs 10.4%, P=0.015, respectively) and 6-month (75.0% vs 55.8%, P=0.031 and 41.7% vs 22.1% P =0.020, respectively) after treatment were much higher in the standard IST group than that in CsA plus androgen group. The median time to transfusion independent of 36.5 (0-149) days in the standard IST group was significantly shorter than 98 (14-180) days in CsA plus androgen group (P<0.001). Survival was comparable between the two groups (97.9% vs 100.0%, P=0.227). It was superior (71.2% vs 59.5%) but not significantly (P=0.227) in event-free survival in standard IST group. Conclusions: CsA plus androgen was inferior to the standard IST of ATG/ALG and CsA regimen in treating TD-NSAA in terms of the hematologic response and the quality of response, despite of comparable short-term survival. PMID- 27995879 TI - [Comparison of allogeneic or autologous hematopoietic stem cell transplant for high-risk peripheral T cell lymphomas]. AB - Objective: To evaluate the efficacy of auto-HSCT and allo-HSCT in the treatment of high risk peripheral T cell lymphoma (PTCL). Methods: From July 2007 to July 2014, 60 cases of high risk PTCL were analyzed retrospectively. Results: All 60 patients were at high risk group (carried with IPI>=3), with a median age of 31 (12-58) years old. Of the 60 cases, 22 were PTCL-not otherwise specified (PTCL NOS), 22 ALK negative anaplastic large cell lymphoma (ALK-negative ALCL) and 16 angioimmunoblastic T-cell lymphoma (AITL). Twenty-one patients (21/60) received allo-HSCT, and thirty-nine (39/60) auto-HSCT. Before receiving transplantation, 40/60 patients were in complete remission (CR), 2/60 patients partial remission (PR) and 18/60 patients not remission (NR). In the 40 CR patients before transplant, 10 patients received allo-HSCT and 30 patients auto-HSCT, respectively. In the 20 PR/NR patients before transplant, 11 patients received allo-HSCT and 9 patients auto-HSCT, respectively. After a median follow-up of 39 (range 1-96) months, the K-M analysis showed that the 5-year PFS by auto-HSCT and allo-HSCT were 61% and 60% (P=0.724) , respectively. The 5-year OS by auto-HSCT and allo-HSCT were 62% and 61% (P=0.724) , respectively. There were no statistically significant differences between auto-HSCT and allo-HSCT. And the cumulative TRM of auto-HSCT and allo-HSCT were 22.7% and 41.8% (P=0.250) , respectively within 5-years after transplantation. At the end of the last follow up, 7 and 2 patients relapsed in auto-HSCT and allo-HSCT groups respectively, the 5-year cumulative recurrence rates of auto-HSCT and allo-HSCT transplantation were 37.2% and 10.1% (P=0.298), respectively. Conclusion: There was no significant difference in the long-term survival between auto-HSCT and allo-HSCT for high risk PTCL patients. Outcome by allo-HSCT may be better for NR patients. PMID- 27995880 TI - [Pharmacokinetics of generic dasatinib in the management of chronic myeloid leukemia in the choronie phase]. AB - Objective: To evaluate the pharmacokinetics and bioequivalence of generic dasatinib in patients with chronic myeloid leukemia in the choronie phase (CML CP). Methods: Using randomized, parallel, overlapping, self-control designed study, a 100 mg dose of the reference or test tablet was given to 12 CML-CP patients who were resistant or intolerant to Imatinib and Nilotinib in a randomized two-way crossover design, and the plasma concentration of the medicine was assayed by HPLC-MS-MS. The main pharmacokinetic parameters and bioequivalence of the two formulations were evaluated. Results: The major pharmacokinetic parameters were as follows: Cmax (209.01+/-58.69) MUg/L and (223.07+/-79.51) MUg/L, Tmax (1.1+/-0.8) h and (1.1+/-0.8) h, T1/2 (5.10+/-1.34) h and (4.39+/ 0.74) h, AUC0-tau (646.65+/-185.67) h.MUg/L and (695.84+/-273.40) h.MUg/L (all P>0.05); AUC0-? (668.11+/-186.00) h.MUg/L and (712.42+/-278.08) h.MUg/L, MRT (5.32 +/- 1.70) h and (4.68 +/- 1.53) h (all P>0.05). Conclusion: The two formulations were bioequivalent. PMID- 27995881 TI - [Establishment and assessment of a nomogram for predicting the differentiation syndrome of acute promyelocytic leukemia]. AB - Objective: By analyzing the risk factors for occurrence of differentiation syndrome (DS) during induction therapy in newly-diagnosed acute promyelocytic leukemia (APL) patients, a prediction nomogram for DS was established and the accuracy of this nomogram was validated. Methods: The modeling group was made up of 130 classical APL patients during the period of 1st January 2011 to 31st December 2013. After single factor screening of clinical variables, the logistic regression model was used to identify the final model variables. A nomogram subsequently established by R software was validated by Bootstrap resampling as internal validation. Concordance index (C-index) was used for the accuracy evaluation of the nomogram, and calibration curves were painted to test the actual observation and the nomogram-prediction of occurrence rate of DS. Results: Occurrence rate of DS in 130 APL patients was 30.0%; In multivariate analysis, body mass index (BMI) >=24 kg/m2 and without using steroids for prevention of DS were identified as independent risk factors. The C-index of the nomogram for predicting DS was 0.818 (95% CI 0.741-0.895). The calibration curves showed good concordance of occurrence rate of DS between nomogram-prediction and actual observation. Conclusion: The nomogram was successfully established as a more accurate and visible tool for predicting the occurrence rate of DS in APL patients. PMID- 27995882 TI - [Gene diagnosis of four patients with protein C deficiency]. AB - Objective: To investigate the molecular etiology of protein C (PC) deficiency. Methods: Routine diagnosis and genetic analysis were performed on four probands with PC deficiency. Results: 1Case 1, female, 40 years old, diagnosed of deep vein thrombosis in left lower limb. PC activity (PC?C) was 48%, PS activity (PS?C) was 26.3%, AT activity (AT?C) was 75.6%. Genetic analysis discovered heterozygous mutation C5156T on promoter of PC gene, together with heterozygous mutation A6578T on Exon2 of PC gene. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. 2Case 2, female, 32 years old, diagnosed of deep vein thrombosis in both lower limb, ischemia in both lower and upper limb, and skin infection in both lower limb. PC?C 27%, PS?C 22.9%, AT?C 86.7%. Genetic analysis identified heterozygous mutation C5156T, together with heterozygous mutation A5045T on promoter of PC gene. After anticoagulant and anti-infection therapy, the patient died of respiratory failure, septic shock and DIC. 3Case 3, female, 28 years old, diagnosed of vein thrombosis in right iliac and femoral vein. PC?C 58%, PS?C 57.3% , AT?C 80.8%. Genetic analysis disclosed heterozygous mutation C4867T on promoter of PC gene, AGA 12702-12704del or 12705-12707del on Exon7, the latter one lead to Arg192 or 193del. Heterozygous mutation G15240A on Exon9 was also found. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. 4Case 4, male, 30 years old, diagnosed of vein thrombosis in right iliac and femoral vein. PC?C 50%, PS?C 75.0%, AT?C 89.1%. Genetic analysis found homozygous mutation C4867T and G4880A on promoter of PC gene, heterozygous mutation A5045T on promoter and heterozygous mutation T6589C on Exon2. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. 5 Polymorphism analysis revealed that heterozygous mutation C4867T, homozygous mutation G4880A, and heterozygous mutation C5156T were polymorphism sites of PC gene. Conclusions: Polymorphism sites (G4880A, C4867T, C5156T), missense mutation A5045T, A6578T, G15240A, and deletion mutation AGA12702-12704del, 12705-12707del may be related to deficiency of PC. Missense mutation A5045T, A6578T, G15240A, and deletion mutation AGA12702 12704, 12705-12707del were first reported worldwide. PMID- 27995883 TI - [Construction of the pIRES2-ZsGreen1 eukaryotic expression vector of Factor IX gene and expression in HEK-293 cells]. AB - Objective: To construct pIRES2-ZsGreen1/F IX expression vector, using the pcDNA/FIX plasmid containing FIX cDNA as template, and express in HEK-293 cells. Methods: The total ORF of F IX gene was amplified from pcDNA/F IX plasmid, then the amplified fragment was clonded into the pIRES2-ZsGreen1 vector using the Infusion enzyme. The positive clones of eukaryotic expression vector of pIRES2 ZsGreen1/F IX were screened and expanded after transfection, then were constructed and confirmed by PCR and sequencing. Transient expression experiments were performed using HEK-293 cells transfected with the expression vectors and observed the expression of ZsGreen1 protein by confocal laser microscope. The relative expression levels of FIX mRNA, protein and FIX activity (FIX?C) were detected by real time PCR (RT-PCR), immunofluorescence microscopy, One-Stage method, respectively. Results: The expression vector, pIRES2-ZsGreen1/F IX, was successfully constructed and expressed in HEK-293 cells. RT-PCR detected the expression of F IX mRNA in HEK-293 cells and the immunofluorescence microscopy showed FIX protein distributed in the surrounding of nucleus. FIX?C of cell lysates and cell culture fluid transfected with the expression vectors were (92.03 +/- 0.29)% and (86.89 +/- 8.78)%, respectively; while both F IX?C of cell lysates and cell culture fluid transfected with or without the expression vectors were 0. Conclusion: The experimental results showed the expression vector, pIRES2 ZsGreen1/FIX, was successfully constructed , which provided experiment basement for the follow study on the location, function and molecular pathology of hemophilia B. PMID- 27995884 TI - [Study of the effects in vitro of berberine combined with bortezomib on multiple myeloma cell line U266 cells]. AB - Objective: To investigate the effects of berberine in combination with bortezomib on proliferation and apoptosis of multiple myeloma (MM) cell line. Methods: MM cell line U266 cells were treated with berberine and/or bortezomib. The effects of berberine and/or bortezomib on proliferation of cells were measured by methylthiazolyl tetrazolium bromide (MTT). Flow cytometric Annexin V/PI double staining method was used to detect effect of either drug alone or in combination on apoptosis of MM cell line U266. ELISA was used to measure the expression of casepase-3,-8,-9 affected by the two drugs. Western blot was used to detect the expression of the apoptosis-related protein TRADD and FADD. King formula was used to determine if there was a synergistic effect of berberine in combination with bortezomib. Results: 1 Both berberine and bortezomib as single agent had dose- and time-dependent effects of proliferation inhibition on U266 cells. Berberine (20 MUmol/L) and bortezomib (5 nmol/L) had a synergistic effect of proliferation inhibition (Q value: 1.31-1.65). 2 The proportion of early stage apoptosis in both single agent groups and combination group significantly increased compared to control group (P< 0.05). Berberine and bortezomib had a synergistic effect on cell apoptosis (Q value after 6 h and 12 h were 0.896 and 1.197, respectively). 3 Berberine in combination with bortezomib significantly upregulated expressions of caspase-3, -8 and -9, which were statistically significant (P<0.05). 4Berberine in combination with bortezomib significantly upregulated expressions of TRADD (0.91+/-0.01, 0.70+/-0.01) and FADD (0.98+/-0.01, 0.98+/-0.01) compared with control group (both P<0.05). Conclusion: Berberine in combination with bortezomib had synergistic effects on proliferation inhibition and apoptosis, which were mediated by up-regulated levels of TRADD and FADD. PMID- 27995885 TI - [Targeted suppression of miRNA-21 inhibit K562 cells growth through PTEN-PI3K/AKT signaling pathway]. AB - Objective: To investigate the K562 cells biological function and related molecular changes in PTEN-PI3K/AKT signaling pathway of leukemia K562 cells by inhibiting the miRNA-21 expression to explore its pathogenesis of leukemia. Methods: The chemical synthetic miRNA-21 inhibitor was transfered into K562 cells by electrotransfection. RT-PCR was used to detect the miRNA-21 expression changes. Cell proliferation and apoptosis were determined by using MTT and flow cytometry. Western-blot were used to detect the protein expression changes of PTEN, PI3K and p-AKT respectively. Results: The relative expression of miRNA-21 in experimental group was (8.070 +/- 5.138)% at 24 hours, which was lower than control groups (P<0.05). The apoptotic rate of (13.370+/-0.250)% at 24 hours in experimental group was obviously higher than control groups. The cellular proliferation were significantly different at 24 hours. The proliferation inhibition rate was (8.1+/-0.9)% at 24 hours, which was up to (43.1+/-2.1)% at 60 hours, but the control groups showed no difference. K562 cell proliferation significantly decreased, while cell apoptosis markedly increased by inhibiting miRNA-21 expression (P<0.01). Western-blot analysis revealed up-regulation of PTEN and down-regulation of PI3K and p-AKT protein expressions after successfully suppressed miRNA-21 expression (P<0.01). Conclusion: Inhibiting miRNA-21 expression in K562 cell could suppress the PI3K/AKT pathway by up-regulation of PTEN expression and promote cell antiproliferative and pro-apoptosis effects. PMID- 27995886 TI - [miR-202 contributes to sensitizing MM cells to drug significantly via activing JNK/SAPK signaling pathway]. AB - Objective: To explore the role of miR-202 in multiple myeloma (MM) cells, and study the regulation of miR-202 on drug sensitivity of MM cells. Methods: miR-202 and BAFF mRNA levels were detected by real-time PCR. U266 cells were transfected with miR-202-mimics, miR-202-inhibitor, siBAFF and their negative controls. After above treatments, protein levels of Bcl-2 family and MAPK signaling pathway were detected by Western blot analysis, and the proliferation and apoptosis ability of MM cells were examined by WST-1, Annexin V-FLUOS assay, respectively. Results: The results showed that the expression of miR-202 in CD138+ MM cells (0.304+/ 0.354) and U266 cells (0.052+/- 0.009) were lower than in normal controls (3.550 +/- 1.126) (P<0.001, P=0.009), whereas BAFF mRNA levels (5.700 +/- 0.734, 9.576 +/- 2.887) were higher than in normal controls (1.819 +/- 0.853) (P<0.001, P= 0.006). The proliferation ability of U266 cells transfected with miR-202 mimics was significantly inhibited than in control group [(56.04+/-0.021)% vs (18.89+/ 0.32)%, P=0.002]. The result of Western blot showed that the expression of Bcl-2 decreased by about 24%, and the expression of Bax increased by about 124% in cells transfected with miR-202 mimics. The apoptosis rate in cells transfected with miR-202 mimics was significantly more than in control group [(49.60+/-4.89)% vs (26.20+/-1.28)%, P=0.029]. The apoptosis rate in miR-202 mimics combined with Bort group (51.23+/-5.41)% was higher as compared with Bort treatment alone (31.70+/-4.40)% or miR-202 mimics control combined with Bort group (27.94+/ 4.04)%, (P=0.047, P= 0.028), whereas the apoptosis rate in miR-202 mimics combined with Thal or Dex had no significant difference compared with miR-202 mimics control [(11.66+/-1.91)% vs (10.63+/-1.74)%, P=0.700; (16.35+/- 1.32)% vs (17.43 +/- 1.95)%, P=0.400]. The inhibitory rate of cell growth in miR-202 mimics combined with Bort group was higher as compared with Bort treatment alone [(36.93+/-5.98)% vs (18.18+/-4.10)%, P= 0.029]. The expressions of p-JNK protein decreased in U266 cells transfected with miR-202 mimics and treated with Bort. Conclusion: miR-202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNK/SAPK signaling pathway. PMID- 27995887 TI - [A pilot study of ten-day decitabine regimen as initial therapy for newly diagnosed elderly patients with acute myeloid leukemia]. PMID- 27995888 TI - [The genetics and prognostic analysis of 60 patients with chronic lymphocytic leukemia in Xinjiang]. PMID- 27995889 TI - [EBV related post-transplantation lymphoproliferative diseases in patients with severe aplastic anemia after allogeneic hematopoietic stem cell transplantation: five cases report and literatures review]. PMID- 27995890 TI - [The study of one case of APL with rare cryptic PML-RARalpha fusion gene and the literatures review]. PMID- 27995891 TI - [Modification of DNA methylation in leukemia development]. PMID- 27995892 TI - [Advances of therapeutic strategies in hematological malignancies]. PMID- 27995893 TI - [Recent progresses of autoimmune hemolytic anemia]. PMID- 27995894 TI - Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury. AB - Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection. PMID- 27995895 TI - Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease. AB - The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At <2 and 6 months of age autonomous STN activity was impaired due to activation of KATP channels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or the break down of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons had been lost, as in HD. Together, these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course. PMID- 27995896 TI - Publication bias and the canonization of false facts. AB - Science is facing a "replication crisis" in which many experimental findings cannot be replicated and are likely to be false. Does this imply that many scientific facts are false as well? To find out, we explore the process by which a claim becomes fact. We model the community's confidence in a claim as a Markov process with successive published results shifting the degree of belief. Publication bias in favor of positive findings influences the distribution of published results. We find that unless a sufficient fraction of negative results are published, false claims frequently can become canonized as fact. Data dredging, p-hacking, and similar behaviors exacerbate the problem. Should negative results become easier to publish as a claim approaches acceptance as a fact, however, true and false claims would be more readily distinguished. To the degree that the model reflects the real world, there may be serious concerns about the validity of purported facts in some disciplines. PMID- 27995899 TI - Passive mechanism of pitch recoil in flapping insect wings. AB - The high torsional flexibility of insect wings allows for elastic recoil after the rotation of the wing during stroke reversal. However, the underlying mechanism of this recoil remains unclear because of the dynamic process of transitioning from the wing rotation during stroke reversal to the maintenance of a high angle of attack during the middle of each half-stroke, when the inertial, elastic, and aerodynamic effects all have a significant impact. Therefore, the interaction between the flapping wing and the surrounding air was directly simulated by simultaneously solving the incompressible Navier-Stokes equations, the equation of motion for an elastic body, and the fluid-structure interface conditions using the three-dimensional finite element method. This direct numerical simulation controlling the aerodynamic effect revealed that the recoil is the residual of the free pitch vibration induced by the flapping acceleration during stroke reversal in the transient response very close to critical damping due to the dynamic pressure resistance of the surrounding air. This understanding will enable the control of the leading-edge vortex and lift generation, the reduction of the work performed by flapping wings, and the interpretation of the underlying necessity for the kinematic characteristics of the flapping motion. PMID- 27995897 TI - Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. AB - Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 A TREM2 crystal structure revealed that mutations found in Nasu Hakola disease are buried whereas Alzheimer's disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer's risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer's risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders. PMID- 27995898 TI - IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact. AB - IRBIT is a molecule that interacts with the inositol 1,4,5-trisphosphate (IP3) binding pocket of the IP3 receptor (IP3R), whereas the antiapoptotic protein, Bcl2l10, binds to another part of the IP3-binding domain. Here we show that Bcl2l10 and IRBIT interact and exert an additive inhibition of IP3R in the physiological state. Moreover, we found that these proteins associate in a complex in mitochondria-associated membranes (MAMs) and that their interplay is involved in apoptosis regulation. MAMs are a hotspot for Ca2+ transfer between endoplasmic reticulum (ER) and mitochondria, and massive Ca2+ release through IP3R in mitochondria induces cell death. We found that upon apoptotic stress, IRBIT is dephosphorylated, becoming an inhibitor of Bcl2l10. Moreover, IRBIT promotes ER mitochondria contact. Our results suggest that by inhibiting Bcl2l10 activity and promoting contact between ER and mitochondria, IRBIT facilitates massive Ca2+ transfer to mitochondria and promotes apoptosis. This work then describes IRBIT as a new regulator of cell death. PMID- 27995901 TI - Human-in-the-loop active electrosense. AB - Active electrosense is a non-visual, short range sensing system used by weakly electric fish, enabling such fish to locate and identify objects in total darkness. Here we report initial findings from the use of active electrosense for object localization during underwater teleoperation with a virtual reality (VR) head-mounted display (HMD). The advantage of electrolocating with a VR system is that it naturally allows for aspects of the task that are difficult for a person to perform to be allocated to the computer. However, interpreting weak and incomplete patterns in the incoming data is something that people are typically far better at than computers. To achieve human-computer synergy, we integrated an active electrosense underwater robot with the Oculus Rift HMD. The virtual environment contains a visualization of the electric images of the objects surrounding the robot as well as various virtual fixtures that guide users to regions of higher information value. Initial user testing shows that these fixtures significantly reduce the time taken to localize an object, but may not increase the accuracy of the position estimate. Our results highlight the advantages of translating the unintuitive physics of electrolocation to an intuitive visual representation for accomplishing tasks in environments where imaging systems fail, such as in dark or turbid water. PMID- 27995900 TI - Effects of f-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior. AB - Histotripsy is an ultrasound ablation method that depends on the initiation of a cavitation bubble cloud to fractionate soft tissue. Although previous work has provided significant insight into the process of intrinsic threshold histotripsy, the majority of these studies have used highly focused (i.e. f-number < 0.6) transducers. In this study, we investigate the effects of f-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior using a 500 kHz array transducer, with the effective f-number of the transducer varied from 0.51 to 0.89. The intrinsic threshold did not significantly change with f-number, with the threshold remaining ~27-30 MPa for all conditions. The predictability of intrinsic threshold histotripsy was further demonstrated by experiments comparing the predicted and experimentally measured bubble cloud dimensions, with results showing close agreement for all f-numbers. Finally, the effects of f-number on 'bubble density' and tissue fractionation efficiency were investigated, with results supporting the hypothesis that the density of the bubbles within the bubble cloud significantly decreases at higher f-numbers, resulting in decreased fractionation efficiency. Overall, this study provides significant insight into the effects of f-number on intrinsic threshold histotripsy that will help to guide the development of histotripsy for specific clinical applications. PMID- 27995902 TI - Plant-inspired adaptive structures and materials for morphing and actuation: a review. AB - Plants exhibit a variety of reversible motions, from the slow opening of pine cones to the impulsive closing of Venus flytrap leaves. These motions are achieved without muscles and they have inspired a wide spectrum of engineered materials and structures. This review summarizes the recent developments of plant inspired adaptive structures and materials for morphing and actuation. We begin with a brief overview of the actuation strategies and physiological features associated to these plant movements, showing that different combinations of these strategies and features can lead to motions with different deformation characteristics and response speeds. Then we offer a comprehensive survey of the plant-inspired morphing and actuation systems, including pressurized cellular structures, osmotic actuation, anisotropic hygroscopic materials, and bistable systems for rapid movements. Although these engineered systems are vastly different in terms of their size scales and intended applications, their working principles are all related to the actuation strategies and physiological features in plants. This review is to promote future cross-disciplinary studies between plant biology and engineering, which can foster new solutions for many applications such as morphing airframes, soft robotics and kinetic architectures. PMID- 27995903 TI - Experimental study of laminar and turbulent boundary layer separation control of shark skin. AB - The Shortfin Mako shark (Isurus oxyrinchus) is a fast swimmer and has incredible turning agility, and has flexible scales known to bristle up to 50 degrees in the flank regions. It is purported that this bristling capability of the scales may result in a unique pass flow control method to control flow separation and reduce drag. It appears that the scales have evolved to be only actuated when the flow over the body is reversed; thereby inducing a method of inhibiting flow reversal close to the surface. In addition, bristled scales form cavities which could induce boundary layer mixing and further assist in delaying flow separation. To substantiate the hypothesis, samples of skin from the flank region of the mako have been tested in a water tunnel facility under various strengths of adverse pressure gradient (APG). Laminar and turbulent separation over the skin was studied experimentally using time-resolved digital particle image velocimetry, where the APG was generated and varied using a rotating cylinder. Shark skin results were compared with that of a smooth plate data for a given amount of APG. Both the instantaneous and time-averaged results reveal that shark skin is capable of controlling laminar as well as turbulent separation. Under laminar conditions, the shark skin also induces an early transition to turbulence and reduces the degree of laminar separation. For turbulent separation, the presence of the shark skin reduces the amount of backflow and size of the separation region. Under both flow conditions, the shark skin also delayed the point of separation as compared to a smooth wall. PMID- 27995904 TI - NanOx, a new model to predict cell survival in the context of particle therapy. AB - Particle therapy is increasingly attractive for the treatment of tumors and the number of facilities offering it is rising worldwide. Due to the well-known enhanced effectiveness of ions, it is of utmost importance to plan treatments with great care to ensure tumor killing and healthy tissues sparing. Hence, the accurate quantification of the relative biological effectiveness (RBE) of ions, used in the calculation of the biological dose, is critical. Nevertheless, the RBE is a complex function of many parameters and its determination requires modeling. The approaches currently used have allowed particle therapy to thrive, but still show some shortcomings. We present herein a short description of a new theoretical framework, NanOx, to calculate cell survival in the context of particle therapy. It gathers principles from existing approaches, while addressing some of their weaknesses. NanOx is a multiscale model that takes the stochastic nature of radiation at nanometric and micrometric scales fully into account, integrating also the chemical aspects of radiation-matter interaction. The latter are included in the model by means of a chemical specific energy, determined from the production of reactive chemical species induced by irradiation. Such a production represents the accumulation of oxidative stress and sublethal damage in the cell, potentially generating non-local lethal events in NanOx. The complementary local lethal events occur in a very localized region and can, alone, lead to cell death. Both these classes of events contribute to cell death. The comparison between experimental data and model predictions for the V79 cell line show a good agreement. In particular, the dependence of the typical shoulders of cell survival curves on linear energy transfer are well described, but also the effectiveness of different ions, including the overkill effect. These results required the adjustment of a number of parameters compatible with the application of the model in a clinical scenario thereby showing the potential of NanOx. Said parameters are discussed in detail in this paper. PMID- 27995905 TI - Lymphocytic division clocked up by Myc. PMID- 27995906 TI - ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. AB - Clinicians are required to assess abnormal liver chemistries on a daily basis. The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin. These tests should be termed liver chemistries or liver tests. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels. Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin and an elevated conjugated bilirubin implies hepatocellular disease or cholestasis. Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality. A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed. The degree of elevation of ALT and or AST in the clinical setting helps guide the evaluation. The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency. In addition, a history of prescribed and over-the-counter medicines should be sought. For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken. Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible. PMID- 27995907 TI - Regulatory T cells in cancer immunotherapy. AB - FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity. One strategy for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3+ T cells, because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions. For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. It is hoped that combination of Treg-cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine or immune checkpoint blockade) will make the current cancer immunotherapy more effective. PMID- 27995909 TI - Chirality-driven orbital magnetic moments as a new probe for topological magnetic structures. AB - When electrons are driven through unconventional magnetic structures, such as skyrmions, they experience emergent electromagnetic fields that originate several Hall effects. Independently, ground-state emergent magnetic fields can also lead to orbital magnetism, even without the spin-orbit interaction. The close parallel between the geometric theories of the Hall effects and of the orbital magnetization raises the question: does a skyrmion display topological orbital magnetism? Here we first address the smallest systems with nonvanishing emergent magnetic field, trimers, characterizing the orbital magnetic properties from first-principles. Armed with this understanding, we study the orbital magnetism of skyrmions and demonstrate that the contribution driven by the emergent magnetic field is topological. This means that the topological contribution to the orbital moment does not change under continuous deformations of the magnetic structure. Furthermore, we use it to propose a new experimental protocol for the identification of topological magnetic structures, by soft X-ray spectroscopy. PMID- 27995910 TI - A portrait of cadmium. PMID- 27995908 TI - Structural insights into ribosomal rescue by Dom34 and Hbs1 at near-atomic resolution. AB - The surveillance of mRNA translation is imperative for homeostasis. Monitoring the integrity of the message is essential, as the translation of aberrant mRNAs leads to stalling of the translational machinery. During ribosomal rescue, arrested ribosomes are specifically recognized by the conserved eukaryotic proteins Dom34 and Hbs1, to initiate their recycling. Here we solve the structure of Dom34 and Hbs1 bound to a yeast ribosome programmed with a nonstop mRNA at 3.3 A resolution using cryo-electron microscopy. The structure shows that Domain N of Dom34 is inserted into the upstream mRNA-binding groove via direct stacking interactions with conserved nucleotides of 18S rRNA. It senses the absence of mRNA at the A-site and part of the mRNA entry channel by direct competition. Thus, our analysis establishes the structural foundation for the recognition of aberrantly stalled 80S ribosomes by the Dom34.Hbs1.GTP complex during Dom34 mediated mRNA surveillance pathways. PMID- 27995911 TI - Homochiral polymerization-driven selective growth of graphene nanoribbons. AB - The surface-assisted bottom-up fabrication of graphene nanoribbons (GNRs), which consists of the radical polymerization of precursors followed by dehydrogenation, has attracted attention because of the method's ability to control the edges and widths of the resulting ribbon. Although these reactions on a metal surface are believed to be catalytic, the mechanism has remained unknown. Here, we demonstrate 'conformation-controlled surface catalysis': the two-zone chemical vapour deposition of a 'Z-bar-linkage' precursor, which represents two terphenyl units linked in a 'Z' shape, results in the efficient formation of acene-type GNRs with a width of 1.45 nm through optimized cascade reactions. These precursors exhibit flexibility that allows them to adopt chiral conformations with height asymmetry on a Au(111) surface, which enables the production of self assembled homochiral polymers in a chain with a planar conformation, followed by dehydrogenation via a conformation-controlled mechanism. This is conceptually analogous to enzymatic catalysis and will be useful for the fabrication of new nanocarbon materials. PMID- 27995913 TI - Chemists boldly go. PMID- 27995912 TI - Conformer-specific hydrogen atom tunnelling in trifluoromethylhydroxycarbene. AB - Conformational control of organic reactions is at the heart of the biomolecular sciences. To achieve a particular reactivity, one of many conformers may be selected, for instance, by a (bio)catalyst, as the geometrically most suited and appropriately reactive species. The equilibration of energetically close-lying conformers is typically assumed to be facile and less energetically taxing than the reaction under consideration itself: this is termed the 'Curtin-Hammett principle'. Here, we show that the trans conformer of trifluoromethylhydroxycarbene preferentially rearranges through a facile quantum mechanical hydrogen tunnelling pathway, while its cis conformer is entirely unreactive. Hence, this presents the first example of a conformer-specific hydrogen tunnelling reaction. The Curtin-Hammett principle is not applicable, due to the high barrier between the two conformers. PMID- 27995914 TI - Breaking scaling relations to achieve low-temperature ammonia synthesis through LiH-mediated nitrogen transfer and hydrogenation. AB - Ammonia synthesis under mild conditions is a goal that has been long sought after. Previous investigations have shown that adsorption and transition-state energies of intermediates in this process on transition metals (TMs) scale with each other. This prevents the independent optimization of these energies that would result in the ideal catalyst: one that activates reactants well, but binds intermediates relatively weakly. Here we demonstrate that these scaling relations can be broken by intervening in the TM-mediated catalysis with a second catalytic site, LiH. The negatively charged hydrogen atoms of LiH act as strong reducing agents, which remove activated nitrogen atoms from the TM or its nitride (TMN), and as an immediate source of hydrogen, which binds nitrogen atoms to form LiNH2. LiNH2 further splits H2 heterolytically to give off NH3 and regenerate LiH. This synergy between TM (or TMN) and LiH creates a favourable pathway that allows both early and late 3d TM-LiH composites to exhibit unprecedented lower-temperature catalytic activities. PMID- 27995915 TI - An infrared spectroscopy approach to follow beta-sheet formation in peptide amyloid assemblies. AB - Amyloidogenic peptides and proteins play a crucial role in a variety of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These proteins undergo a spontaneous transition from a soluble, often partially folded form, into insoluble amyloid fibrils that are rich in beta-sheets. Increasing evidence suggests that highly dynamic, polydisperse folding intermediates, which occur during fibril formation, are the toxic species in the amyloid-related diseases. Traditional condensed-phase methods are of limited use for characterizing these states because they typically only provide ensemble averages rather than information about individual oligomers. Here we report the first direct secondary-structure analysis of individual amyloid intermediates using a combination of ion mobility spectrometry-mass spectrometry and gas-phase infrared spectroscopy. Our data reveal that oligomers of the fibril-forming peptide segments VEALYL and YVEALL, which consist of 4-9 peptide strands, can contain a significant amount of beta-sheet. In addition, our data show that the more extended variants of each oligomer generally exhibit increased beta-sheet content. PMID- 27995916 TI - Emergence of a catalytic tetrad during evolution of a highly active artificial aldolase. AB - Designing catalysts that achieve the rates and selectivities of natural enzymes is a long-standing goal in protein chemistry. Here, we show that an ultrahigh throughput droplet-based microfluidic screening platform can be used to improve a previously optimized artificial aldolase by an additional factor of 30 to give a >109 rate enhancement that rivals the efficiency of class I aldolases. The resulting enzyme catalyses a reversible aldol reaction with high stereoselectivity and tolerates a broad range of substrates. Biochemical and structural studies show that catalysis depends on a Lys-Tyr-Asn-Tyr tetrad that emerged adjacent to a computationally designed hydrophobic pocket during directed evolution. This constellation of residues is poised to activate the substrate by Schiff base formation, promote mechanistically important proton transfers and stabilize multiple transition states along a complex reaction coordinate. The emergence of such a sophisticated catalytic centre shows that there is nothing magical about the catalytic activities or mechanisms of naturally occurring enzymes, or the evolutionary process that gave rise to them. PMID- 27995917 TI - Bioinorganic chemistry: Nitrate NO more. PMID- 27995918 TI - Multistep nucleation of nanocrystals in aqueous solution. AB - The nucleation and growth of solids from solutions impacts many natural processes and is fundamental to applications in materials engineering and medicine. For a crystalline solid, the nucleus is a nanoscale cluster of ordered atoms that forms through mechanisms still poorly understood. In particular, it is unclear whether a nucleus forms spontaneously from solution via a single- or multiple-step process. Here, using in situ electron microscopy, we show how gold and silver nanocrystals nucleate from supersaturated aqueous solutions in three distinct steps: spinodal decomposition into solute-rich and solute-poor liquid phases, nucleation of amorphous nanoclusters within the metal-rich liquid phase, followed by crystallization of these amorphous clusters. Our ab initio calculations on gold nucleation suggest that these steps might be associated with strong gold gold atom coupling and water-mediated metastable gold complexes. The understanding of intermediate steps in nuclei formation has important implications for the formation and growth of both crystalline and amorphous materials. PMID- 27995919 TI - C-H activation: Complex peptides made simple. PMID- 27995920 TI - Interplay between defects, disorder and flexibility in metal-organic frameworks. AB - Metal-organic frameworks are a novel family of chemically diverse materials, which are of interest across engineering, physics, chemistry, biology and medicine-based disciplines. Since the development of the field in its current form more than two decades ago, priority has been placed on the synthesis of new structures. However, more recently, a clear trend has emerged in shifting the emphasis from material design to exploring the chemical and physical properties of structures already known. In particular, although such nanoporous materials were traditionally seen as rigid crystalline structures, there is growing evidence that large-scale flexibility, the presence of defects and long-range disorder are not the exception in metal-organic frameworks, but the rule. Here we offer some perspective into how these concepts are perhaps inescapably intertwined, highlight recent advances in our understanding and discuss how a consideration of the interfaces between them may lead to enhancements of the materials' functionalities. PMID- 27995921 TI - Reticular synthesis of porous molecular 1D nanotubes and 3D networks. AB - Synthetic control over pore size and pore connectivity is the crowning achievement for porous metal-organic frameworks (MOFs). The same level of control has not been achieved for molecular crystals, which are not defined by strong, directional intermolecular coordination bonds. Hence, molecular crystallization is inherently less controllable than framework crystallization, and there are fewer examples of 'reticular synthesis', in which multiple building blocks can be assembled according to a common assembly motif. Here we apply a chiral recognition strategy to a new family of tubular covalent cages to create both 1D porous nanotubes and 3D diamondoid pillared porous networks. The diamondoid networks are analogous to MOFs prepared from tetrahedral metal nodes and linear ditopic organic linkers. The crystal structures can be rationalized by computational lattice-energy searches, which provide an in silico screening method to evaluate candidate molecular building blocks. These results are a blueprint for applying the 'node and strut' principles of reticular synthesis to molecular crystals. PMID- 27995922 TI - Lack of evidence for phase-only control of retinal photoisomerization in the strict one-photon limit. AB - The concept of shaping electric fields to steer light-induced processes coherently has fascinated scientists for decades. Despite early theoretical considerations that ruled out one-photon coherent control (CC), several experimental studies reported that molecular responses are sensitive to the shape of the excitation field in the weak-field limit. These observations were largely attributed to the presence of rapid-decay channels, but experimental verification is lacking. Here, we test this hypothesis by investigating the degree of achievable control over the photoisomerization of the retinal protonated Schiff base in bacteriorhodopsin, isorhodopsin and rhodopsin, all of which exhibit similar chromophores but different isomerization yields and excited-state lifetimes. Irrespective of the system studied, we find no evidence for dissipation-dependent behaviour, nor for any CC in the strict one-photon limit. Our results question the extent to which a photochemical process at ambient conditions can be controlled at the amplitude level, and how the underlying molecular potential-energy surfaces and dynamics may influence this controllability. PMID- 27995923 TI - Bridging the gaps in 18F PET tracer development. PMID- 27995924 TI - Structure prediction: Encoding evolution of porous solids. PMID- 27995925 TI - Fusing tetrapyrroles to graphene edges by surface-assisted covalent coupling. AB - Surface-assisted covalent linking of precursor molecules enables the fabrication of low-dimensional nanostructures, which include graphene nanoribbons. One approach to building functional multicomponent systems involves the lateral anchoring of organic heteromolecules to graphene. Here we demonstrate the dehydrogenative coupling of single porphines to graphene edges on the same metal substrate as used for graphene synthesis. The covalent linkages are visualized by scanning probe techniques with submolecular resolution, which directly reveals bonding motifs and electronic features. Distinct configurations are identified that can be steered towards entities predominantly fused to graphene edges through two pyrrole rings by thermal annealing. Furthermore, we succeeded in the concomitant metallation of the macrocycle with substrate atoms and the axial ligation of adducts. Such processes combined with graphene-nanostructure synthesis has the potential to create complex materials systems with tunable functionalities. PMID- 27995926 TI - Suppression of Kasha's rule as a mechanism for fluorescent molecular rotors and aggregation-induced emission. AB - Although there are some proposed explanations for aggregation-induced emission, a phenomenon with applications that range from biosensors to organic light-emitting diodes, current understanding of the quantum-mechanical origin of this photophysical behaviour is limited. To address this issue, we assessed the emission properties of a series of BF2-hydrazone-based dyes as a function of solvent viscosity. These molecules turned out to be highly efficient fluorescent molecular rotors. This property, in addition to them being aggregation-induced emission luminogens, enabled us to probe deeper into their emission mechanism. Time-dependent density functional theory calculations and experimental results showed that the emission is not from the S1 state, as predicted from Kasha's rule, but from a higher energy (>S1) state. Furthermore, we found that suppression of internal conversion to the dark S1 state by restricting the rotor rotation enhances fluorescence, which leads to the proposal that suppression of Kasha's rule is the photophysical mechanism responsible for emission in both viscous solution and the solid state. PMID- 27995927 TI - Mechanism of O2 diffusion and reduction in FeFe hydrogenases. AB - FeFe hydrogenases are the most efficient H2-producing enzymes. However, inactivation by O2 remains an obstacle that prevents them being used in many biotechnological devices. Here, we combine electrochemistry, site-directed mutagenesis, molecular dynamics and quantum chemical calculations to uncover the molecular mechanism of O2 diffusion within the enzyme and its reactions at the active site. We propose that the partial reversibility of the reaction with O2 results from the four-electron reduction of O2 to water. The third electron/proton transfer step is the bottleneck for water production, competing with formation of a highly reactive OH radical and hydroxylated cysteine. The rapid delivery of electrons and protons to the active site is therefore crucial to prevent the accumulation of these aggressive species during prolonged O2 exposure. These findings should provide important clues for the design of hydrogenase mutants with increased resistance to oxidative damage. PMID- 27995928 TI - Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity. AB - Comprehensive knowledge of immunoglobulin genetics is required to advance our understanding of B cell biology. Validated immunoglobulin variable (V) gene databases are close to completion only for human and mouse. We present a novel computational approach, IgDiscover, that identifies germline V genes from expressed repertoires to a specificity of 100%. IgDiscover uses a cluster identification process to produce candidate sequences that, once filtered, results in individualized germline V gene databases. IgDiscover was tested in multiple species, validated by genomic cloning and cross library comparisons and produces comprehensive gene databases even where limited genomic sequence is available. IgDiscover analysis of the allelic content of the Indian and Chinese origin rhesus macaques reveals high levels of immunoglobulin gene diversity in this species. Further, we describe a novel human IGHV3-21 allele and confirm significant gene differences between Balb/c and C57BL6 mouse strains, demonstrating the power of IgDiscover as a germline V gene discovery tool. PMID- 27995930 TI - The interactive microbial ocean. PMID- 27995931 TI - Bacterial pathogenesis: Remodelling recurrent infection. PMID- 27995929 TI - The biomechanical properties of an epithelial tissue determine the location of its vasculature. AB - An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor 'empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue. PMID- 27995933 TI - An interesting year. PMID- 27995935 TI - Prostate cancer: Do the maths - modelling tumour growth. PMID- 27995936 TI - Infection: Dapivirine ring reduces HIV acquisition. PMID- 27995934 TI - Extending standard testing period in honeybees to predict lifespan impacts of pesticides and heavy metals using dynamic energy budget modelling. AB - Concern over reported honeybee (Apis mellifera spp.) losses has highlighted chemical exposure as a risk. Current laboratory oral toxicity tests in A. mellifera spp. use short-term, maximum 96 hour, exposures which may not necessarily account for chronic and cumulative toxicity. Here, we use extended 240 hour (10 day) exposures to examine seven agrochemicals and trace environmental pollutant toxicities for adult honeybees. Data were used to parameterise a dynamic energy budget model (DEBtox) to further examine potential survival effects up to 30 day and 90 day summer and winter worker lifespans. Honeybees were most sensitive to insecticides (clothianidin > dimethoate ? tau fluvalinate), then trace metals/metalloids (cadmium, arsenic), followed by the fungicide propiconazole and herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). LC50s calculated from DEBtox parameters indicated a 27 fold change comparing exposure from 48 to 720 hours (summer worker lifespan) for cadmium, as the most time-dependent chemical as driven by slow toxicokinetics. Clothianidin and dimethoate exhibited more rapid toxicokinetics with 48 to 720 hour LC50s changes of <4 fold. As effects from long-term exposure may exceed those measured in short term tests, future regulatory tests should extend to 96 hours as standard, with extension to 240 hour exposures further improving realism. PMID- 27995937 TI - The effect of the USPSTF PSA screening recommendation on prostate cancer incidence patterns in the USA. AB - Guidelines regarding recommendations for PSA screening for early detection of prostate cancer are conflicting. In 2012, the United States Preventive Services Task Force (USPSTF) assigned a grade of D (recommending against screening) for men aged >=75 years in 2008 and for men of all ages in 2012. Understanding temporal trends in rates of screening before and after the 2012 recommendation in terms of usage patterns in PSA screening, changes in prostate cancer incidence and biopsy patterns, and how the recommendation has influenced physician's and men's attitudes about PSA screening and subsequent ordering of other screening tests is essential within the scope of prostate cancer screening policy. Since the 2012 recommendation, rates of PSA screening decreased by 3-10% in all age groups and across most geographical regions of the USA. Rates of prostate biopsy and prostate cancer incidence have declined in unison, with a shift towards tumours being of higher grade and stage upon detection. Despite the recommendation, some physicians report ongoing willingness to screen appropriately selected men, and many men report intending to continue to ask for the PSA test from their physician. In the coming years, we expect to have an improved understanding of whether these decreased rates of screening will affect prostate cancer metastasis and mortality. PMID- 27995938 TI - A radiographic evaluation of facet sagittal angle in cervical spinal cord injury without major fracture or dislocation. AB - STUDY DESIGN: A retrospective radiographic study with a minimum 2-year follow-up. OBJECTIVE: To evaluate the relationships between the cervical articular facets' morphology and the incidence of traumatic cervical spinal cord injury (CSCI) without major fracture or dislocation. SETTING: Spinal Injuries Center, Japan. METHODS: This study included 113 patients with traumatic CSCI without major fracture or dislocation. Eighty-four healthy volunteers without neurological deficits or cervical cord pathology on magnetic resonance imaging (MRI) were defined as control subjects. We used a plain sagittal radiograph to measure the facet sagittal angles (FSA) at four cervical segments in all the CSCI patients and controls. We defined the FSA as the angle between the inferior margin of the superior cervical spinal body and the inferior articular process of the superior vertebra. RESULTS: Most frequent incidence of CSCI was seen at C3-4 segment (54%). With respect to CSCI at C3-4 segment, 55.7% of the subjects showed smallest FSA at C3-4 segment. CONCLUSION: Most of the traumatic CSCI at C3-4 segment showed raised cervical articular facets at C3-4 segment. On the basis of our results, we hypothesized that the raised cervical articular facets might have an important role in the etiology of traumatic CSCI. The cervical spinal cord at the C3-4 segment might receive the highest load during acute hyperextension of the cervical spine because of the C3-4 articular facets' morphology. PMID- 27995932 TI - Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates. AB - The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects. PMID- 27995939 TI - Telephone-based management of pressure ulcers in people with spinal cord injury in low- and middle-income countries: a randomised controlled trial. AB - STUDY DESIGN: A multicentre, prospective, assessor-blinded, parallel randomised controlled trial. OBJECTIVES: The objective of the trial was to determine the effectiveness of telephone-based management of pressure ulcers in people with spinal cord injury (SCI) in low- and middle-income countries. METHODS: One hundred and twenty people with SCI living in the community were recruited through three hospitals in India and Bangladesh between November 2013 and March 2016. Participants had sustained an SCI >3 months prior and had a pressure ulcer. Participants were randomly allocated (1:1) to a control or intervention group. Participants in the control group received no intervention. Participants in the intervention group received weekly advice by telephone for 12 weeks about the management of their pressure ulcers from a trained health-care professional. Outcomes were measured by a blinded assessor at baseline and 12 weeks. There was one primary outcome, namely, the size of the pressure ulcer and 13 secondary outcomes. RESULTS: The mean between-group difference for the size of the pressure ulcer at 12 weeks was 2.3 cm2 (95% confidence interval -0.3 to 4.9; favouring the intervention group). Eight of the 13 secondary outcomes were statistically significant. CONCLUSION: The results of our primary outcome (that is, size of pressure ulcer) do not provide conclusive evidence that people with SCI can be supported at home to manage their pressure ulcers through regular telephone-based advice. However, the results from the secondary outcomes are sufficiently positive to provide hope that this simple intervention may provide some relief from this insidious problem in the future. PMID- 27995940 TI - Precision of dual-energy X-ray absorptiometry of the knee and heel: methodology and implications for research to reduce bone mineral loss after spinal cord injury. AB - STUDY DESIGN: Methodological validation of dual-energy x-ray absorptiometry (DXA) based measures of leg bone mineral density (BMD) based on the guidelines of the International Society for Clinical Densitometry. OBJECTIVES: The primary objective of this study was to determine the precision of BMD estimates at the knee and heel using the manufacturer provided DXA acquisition algorithm. The secondary objective was to determine the smallest change in DXA-based measurement of BMD that should be surpassed (least significant change (LSC)) before suggesting that a biological change has occurred in the distal femur, proximal tibia and calcaneus. SETTING: Academic Research Centre, Canada. METHODS: Ten people with motor-complete SCI of at least 2 years duration and 10 people from the general population volunteered to have four DXA-based measurements taken of their femur, tibia and calcaneus. BMDs for seven regions of interest (RIs) were calculated, as were short-term precision (root-mean-square (RMS) standard deviation (g cm-2), RMS-coefficient of variation (RMS-CV, %)) and LSC. RESULTS: Overall, RMS-CV values were similar between SCI (3.63-10.20%, mean=5.3%) and able bodied (1.85-5.73%, mean=4%) cohorts, despite lower absolute BMD values at each RIs in those with SCI (35%, heel to 54%, knee; P<0.0001). Precision was highest at the calcaneus and lowest at the femur. Except at the femur, RMS-CV values were under 6%. CONCLUSIONS: For DXA-based estimates of BMD at the distal femur, proximal tibia and calcaneus, these precision values suggest that LSC values >10% are needed to detect differences between treated and untreated groups in studies aimed at reducing bone mineral loss after SCI. PMID- 27995941 TI - Outcome of bloodstream infections among spinal cord injury patients and impact of multidrug-resistant organisms. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Our study aimed to describe the outcome of bloodstream infection (BSI) in spinal cord injury (SCI) patients and their associated risk factors for severity and mortality. SETTING: A French University Hospital. METHODS: We conducted a retrospective cohort study of all BSIs occurring in hospitalized SCI patients. We analyzed their outcome and risk factors especially the impact of multidrug-resistant organisms (MDROs). RESULTS: Overall, 318 BSIs occurring among 256 patients were included in the analysis. Mean age was 50.8 years and gender ratio (M/F) was 2.70, with a mean injury duration of 11.6 years.Severity and 30-day mortality of BSI episodes were, respectively, 43.4% and 7.9%. BSI severity was significantly more frequent when caused by respiratory tract infections (RTIs) (odds ratio (OR)=1.38; 95% confidence interval (CI): 1.13-1.44) and significantly lower when caused by urinary tract infections (UTIs) (OR=0.47; 95% CI: 0.28-0.76). BSI mortality was significantly higher when caused by RTIs (OR=3.08; 95% CI: 1.05-8.99), catheter related bloodstream infections (OR=3.54; 95% CI: 1.36-9.18) or Pseudomonas aeruginosa infections (OR=3.79; 95% CI: 1.14-12.55).MDROs were responsible for 41.2% of all BSI. They have no impact on severity and mortality, whichever be the primary site of infection.In multivariate analysis, mortality was higher when BSI episodes were due to RTIs (OR=3.26; 95% CI: 1.29-8.22) and Pseudomonas aeruginosa infections (OR=3.53; 95% CI: 1.06-11.70), or when associated with immunosuppressive therapy (OR=2.57; 95% CI: 1.14-5.78) or initial severity signs (OR=1.68; 95% CI: 1.01-2.81). CONCLUSION: BSI occurring in SCI population were often severe but mortality remained low. MDROs were frequent but not associated with severity or mortality of BSI episodes. Risk factors associated with mortality were initial severe presentation, RTI, immunosuppressive therapy and BSI due to Pseudomonas aeruginosa. PMID- 27995942 TI - Improvement in detrusor-sphincter dyssynergia by bladder-wall injection of replication-defective herpes simplex virus vector-mediated gene delivery of kynurenine aminotransferase II in spinal cord injury rats. AB - STUDY DESIGN: An experimental study. OBJECTIVES: To investigate the effect of replication-defective herpes simplex virus (HSV) vectors encoding the kynurenine aminotransferase II (HSVrd-KATII) gene on detrusor-sphincter dyssynergia (DSD) in spinal cord injury (SCI) rats. SETTING: Beijing, China. METHODS: Sprague-Dawley rats (240-265 g) were spinalized with complete transaction at the T10 level of the spinal cord. The rats were randomly divided into the following three groups: sham group (n=12, with normal saline); HSVrd group (n=12, with HSVrd) and HSVrd KATII group (n=12, with HSVrd-KATII). One week after spinalization normal saline, HSVrd or HSVrd-KATII was injected into the bladder walls of the three groups, respectively. Three weeks after virus injection, the urethral pressure profile (UPP) and continuous cystometry were performed under awake conditions and gene expression was evaluated in all of the SCI rats. RESULTS: In the HSVrd-KATII group, the maximum urethral closure pressure (Pclo.max), maximum voiding pressure (MVP), and the number and amplitude of non-voiding contraction (NVCs) were significantly decreased (34.7-39.1%, 46.7-56.2% and 31.5-32.5%, respectively), along with an increase in voiding efficiency (49.1-52.1%) compared with the sham and HSVrd groups. In addition, the levels of KATII protein and mRNA were significantly increased in the L6-S1 dorsal root ganglia (DRG) and L6-S1 spinal cord segments in the HSVrd-KATII group compared with the HSVrd group. CONCLUSIONS: HSVrd vector encoding the KATII gene effectively improved DSD and detrusor overactivity by bladder-wall injection, perhaps by blocking N-methyl-d aspartate receptors in the L6-S1 dorsal root ganglion and L6-S1 spinal cord. PMID- 27995943 TI - The corticomotor projection to liminally-contractable forearm muscles in chronic spinal cord injury: a transcranial magnetic stimulation study. AB - STUDY DESIGN: A cross-sectional study in chronic spinal cord injury with cervical lesions (cSCI). OBJECTIVE: To determine the corticomotor projection and motor cortex organization of paralyzed forearm muscles that presented only liminal voluntary activation. SETTING: Burke Medical Research Institute, White Plains, NY, USA. METHODS: We identified ten people with chronic SCI who had a wrist flexor or extensor muscle with a motor power (MP) of 1 over 5. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) over the primary motor cortex of the hemisphere contralateral to the target muscle. We measured resting motor threshold (RMT), corticomotor latency (LTY), MEP amplitude (AMP) and performed cortical motor mapping to determine the optimal site (OPT) and map area (AREA). Results were compared with the data from 18 controls. RESULTS: A MEP in the target muscle was observed for all cSCI cases. LTY was normal, while corticomotor excitability (as determined by RMT and AMP) was reduced in about half of the group. The OPT site of the motor maps was within control range for all cSCI cases, while AREA was reduced in three cases. CONCLUSIONS: Corticomotor conduction and cortical topography were appreciably normal despite only liminal activation of the target muscle with voluntary effort. Muscles with these characteristics may benefit from a targeted rehabilitation program even in the chronic phase after SCI. PMID- 27995944 TI - Subacute posttraumatic ascending myelopathy: a literature review. AB - STUDY DESIGN: A literature review. OBJECTIVES: Our aim was to summarise the history, epidemiology, aetiological mechanism, pathological study, clinical and radiological evaluation, treatment and prognosis of subacute posttraumatic ascending myelopathy (SPAM). METHODS: Medical literature on SPAM were searched in the PubMed, Medline, Ovid and Embase databases. The cases of SPAM reported in literature were analysed, and the history, epidemiology, aetiological mechanism, pathological study, clinical and radiological evaluation, treatment and prognosis of SPAM were summarised. RESULTS: SPAM remains a relatively rare disorder occurring within the first few weeks after spinal cord injury (SCI). The incidence rate ranges from 0.42% to 1% among all SCI. SPAM is likely to occur in young and middle-aged male patients. Risk factors of SPAM include complete injury, low blood pressure, early postoperative mobilisation and nonsurgical treatment. CONCLUSIONS: SPAM is well recognised according to typical clinical manifestation and magnetic resonance imaging characteristics. There is no effective therapy for this neurological deterioration. The prognosis of SPAM is poor. There is usually a slight improvement of one or more level(s) below the maximal level of deterioration. The mortality rate is approximately 10%. PMID- 27995946 TI - RECIST - learning from the past to build the future. AB - Response Evaluation Criteria In Solid Tumours (RECIST) remain an integral part of the assessment of tumour burden in many clinical trials in oncology; these criteria are used to evaluate the activity and efficacy of new cancer therapeutics in solid tumours. We aim to define the purpose of RECIST, and reflect on the level of documentation needed to enable changes for these criteria to develop a new RECIST. Maintaining the applicability of RECIST as a standard evaluation approach is associated with many challenges, in particular with maintaining a balance between the specificity and generalizability, continued validation and innovation, and use of RECIST in early phase versus late-phase drug development, as well as its relevance in clinical trials versus clinical practice. Key questions relate to different modes of actions of new classes of treatments and new imaging modalities; thus, the RECIST Working Group remains committed to maintain RECIST as a standard for the oncology community. PMID- 27995947 TI - Haematological cancer: TP53 mutations sensitize to decitabine. PMID- 27995945 TI - The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood. AB - STUDY DESIGN: Review study. OBJECTIVES: The identification of prognostic biomarkers of spinal cord injury (SCI) will help to assign SCI patients to the correct treatment and rehabilitation regimes. Further, the detection of biomarkers that predict permanent neurological outcome would aid in appropriate recruitment of patients into clinical trials. The objective of this review is to evaluate the current state-of-play in this developing field. SETTING: Studies from multiple countries were included. METHODS: We have completed a comprehensive review of studies that have investigated prognostic biomarkers in either the blood or cerebrospinal fluid (CSF) of animals and humans following SCI. RESULTS: Targeted and unbiased approaches have identified several prognostic biomarkers in CSF and blood. These proteins associate with cellular damage following SCI and include components from neurons, oligodendrocytes and reactive astrocytes, that is, neurofilament proteins, glial fibrillary acidic protein, Tau and S100 calcium binding protein beta. Unbiased approaches have also identified microRNAs that are specific to SCI, as well as other cell damage-associated proteins. CONCLUSIONS: The discovery and validation of stable, specific, sensitive and reproducible biomarkers of SCI is a rapidly expanding field of research. So far, few studies have utilised unbiased approaches aimed at the discovery of biomarkers within the CSF or blood in this field; however, some targeted approaches have been successfully used. Several studies using various animal models and some with small human patient cohorts have begun to pinpoint biomarkers in the CSF and blood with putative prognostic value. An increased sample size will be required to validate these biomarkers in the heterogeneous clinical setting. PMID- 27995948 TI - Liver cancer: Regorafenib - a new RESORCE in HCC. PMID- 27995950 TI - In the news: From ENA 2016. PMID- 27995951 TI - Ti/Au Cathode for Electronic transport material-free organic-inorganic hybrid perovskite solar cells. AB - We have fabricated organic-inorganic hybrid perovskite solar cell that uses a Ti/Au multilayer as cathode and does not use electron transport materials, and achieved the highest power conversion efficiency close to 13% with high reproducibility and hysteresis-free photocurrent curves. Our cell has a Schottky planar heterojunction structure (ITO/PEDOT:PSS/perovskite/Ti/Au), in which the Ti insertion layer isolate the perovskite and Au layers, thus proving good contact between the Au and perovskite and increasing the cells' shunt resistance greatly. Moreover, the Ti/Au cathode in direct contact with hybrid perovskite showed no reaction for a long-term exposure to the air, and can provide sufficient protection and avoid the perovskite and PEDOT:PSS layers contact with moisture. Hence, the Ti/Au based devices retain about 70% of their original efficiency after 300 h storage in the ambient environment. PMID- 27995952 TI - Photon Entanglement Through Brain Tissue. AB - Photon entanglement, the cornerstone of quantum correlations, provides a level of coherence that is not present in classical correlations. Harnessing it by study of its passage through organic matter may offer new possibilities for medical diagnosis technique. In this work, we study the preservation of photon entanglement in polarization, created by spontaneous parametric down-conversion, after one entangled photon propagates through multiphoton-scattering brain tissue slices with different thickness. The Tangle-Entropy (TS) plots show the strong preservation of entanglement of photons propagating in brain tissue. By spatially filtering the ballistic scattering of an entangled photon, we find that its polarization entanglement is preserved and non-locally correlated with its twin in the TS plots. The degree of entanglement correlates better with structure and water content than with sample thickness. PMID- 27995949 TI - Surveillance after curative treatment for colorectal cancer. AB - Treatments for colorectal cancer (CRC) of all stages have evolved considerably over the past two decades, resulting in improved long-term outcomes. After curative treatment, however, 30% of patients with stage I-III and up to 65% of patients with stage IV CRC develop recurrent disease. Thus, patients are routinely offered surveillance in order to detect disease recurrence at an early, asymptomatic stage, with the intention of improving survival. Nevertheless, controversy continues to surround the optimal surveillance protocols. For patients with stage I-III CRC, more-intensive surveillance improves overall survival compared with less-intensive or no surveillance, probably owing to improved outcomes after cancer recurrence, as well as proactive treatment of other conditions detected opportunistically. The benefit of surveillance after curative treatment of stage IV CRC is more controversial, but might be justified because repeat resection can improve overall survival and 20% of these patients are eligible for such treatment with curative intent. No trials have assessed the optimal follow-up approach after curative resection of metastatic CRC, and similarly to surveillance of patients with stage I-III disease, most programmes are more intensive during the first 3 years than at later time points. Herein, we provide a comprehensive overview of surveillance strategies for patients with CRC, and discuss the future development of patient-centred programmes. PMID- 27995953 TI - Anthropogenic- and natural sources of dust in peatland during the Anthropocene. AB - As human impact have been increasing strongly over the last decades, it is crucial to distinguish human-induced dust sources from natural ones in order to define the boundary of a newly proposed epoch - the Anthropocene. Here, we track anthropogenic signatures and natural geochemical anomalies in the Mukhrino peatland, Western Siberia. Human activity was recorded there from cal AD 1958 (+/ 6). Anthropogenic spheroidal aluminosilicates clearly identify the beginning of industrial development and are proposed as a new indicator of the Anthropocene. In cal AD 1963 (+/-5), greatly elevated dust deposition and an increase in REE serve to show that the geochemistry of elements in the peat can be evidence of nuclear weapon testing; such constituted an enormous force blowing soil dust into the atmosphere. Among the natural dust sources, minor signals of dryness and of the Tunguska cosmic body (TCB) impact were noted. The TCB impact was indirectly confirmed by an unusual occurrence of mullite in the peat. PMID- 27995954 TI - A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers. AB - Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide and is etiologically linked to several cancers, including cervical and genital cancers. NKG2D, an activating receptor expressed by NK cells, plays an important role in cancer immune-surveillance. We analyzed the impact of a NKG2D gene variant, rs1049174, on the incidence of HPV-related cancers in Vietnamese patients and utilized various molecular approaches to elucidate the mechanisms of NKG2D receptor regulation by rs1049174. In a group of 123 patients with HPV+ anogenital cancers, the low cytotoxicity allele LNK was significantly associated with increased cancer susceptibility (p = 0.016). Similar results were also observed in a group of 153 women with cervical cancer (p = 0.05). In functional studies, NK cells from individuals with LNK genotype showed a lower NKG2D expression and displayed less efficient NKG2D-mediated functions than NK cells with HNK genotype. Notably, the rs1049174 variant occurs within a targeting site for miR-1245, a negative regulator of NKG2D expression. Compared with the higher cytotoxicity allele HNK, the LNK allele was more efficiently targeted by miR-1245 and thus determined lower NKG2D expression in NK cells with the LNK genotype. The NKG2D variants may influence cancer immunosurveillance and thus determine susceptibility to various malignancies, including HPV-induced cancers. PMID- 27995955 TI - Evidences for Piperine inhibiting cancer by targeting human G-quadruplex DNA sequences. AB - Piperine, a naturally occurring alkaloid, is well known as anti-oxidant, anti mutagenic, anti-tumor and anti-proliferative agent. Piperine exerts such pharmacological activities by binding or interacting with various cellular targets. Recently, the first report for Piperine interaction with duplex DNA has been published last year but its interaction with G-quadruplex structures has not been studied yet. Herein, we report for the first time the interaction of Piperine with various DNA G-quadruplex structures. Comprehensive biophysical techniques were employed to determine the basis of interaction for the complex formed between Piperine and G-quadruplex DNA sequences. Piperine showed specificity for G-quadruplex DNA over double stranded DNA, with highest affinity for G-quadruplex structure formed at c-myc promoter region. Further, in-vitro studies show that Piperine causes apoptosis-mediated cell death that further emphasizes the potential of this natural product, Piperine, as a promising candidate for targeting G-quadruplex structure and thus, acts as a potent anti cancer agent. PMID- 27995956 TI - Nanofocusing of the free-space optical energy with plasmonic Tamm states. AB - To achieve extreme electromagnetic enhancement, we propose a plasmonic Tamm states (PTSs) configuration based on the metal-insulator-metal Bragg reflector, which is realized by periodically modulating the width of the insulator. Both the thick (2D) and thin (3D) structures are discussed. Through optimization performed by the impedance-based transfer matrix method and the finite difference time domain method, we find that both the electric field and magnetic field intensities can be increased by three orders of magnitude. The field-enhancement inside the PTSs configuration is not limited to extremely sharp waveguide terminal, which can greatly reduce processing difficulties. PMID- 27995957 TI - Arbitrary Inequality in Reputation Systems. AB - Trust is an essential condition for exchange. Large societies must substitute the trust traditionally provided through kinship and sanctions in small groups to make exchange possible. The rise of internet-supported reputation systems has been celebrated for providing trust at a global scale, enabling the massive volumes of transactions between distant strangers that are characteristic of modern human societies. Here we problematize an overlooked side-effect of reputation systems: Equally trustworthy individuals may realize highly unequal exchange volumes. We report the results of a laboratory experiment that shows emergent differentiation between ex ante equivalent individuals when information on performance in past exchanges is shared. This arbitrary inequality results from cumulative advantage in the reputation-building process: Random initial distinctions grow as parties of good repute are chosen over those lacking a reputation. We conjecture that reputation systems produce artificial concentration in a wide range of markets and leave superior but untried exchange alternatives unexploited. PMID- 27995958 TI - Horses discriminate between facial expressions of conspecifics. AB - In humans, facial expressions are rich sources of social information and have an important role in regulating social interactions. However, the extent to which this is true in non-human animals, and particularly in non-primates, remains largely unknown. Therefore we tested whether domestic horses (Equus caballus) could discriminate between facial expressions of their conspecifics captured in different contexts, and whether viewing these expressions elicited functionally relevant reactions. Horses were more likely to approach photographic stimuli displaying facial expressions associated with positive attention and relaxation, and to avoid stimuli displaying an expression associated with aggression. Moreover, differing patterns of heart rate changes were observed in response to viewing the positive anticipation and agonistic facial expressions. These results indicate that horses spontaneously discriminate between photographs of unknown conspecifics portraying different facial expressions, showing appropriate behavioural and physiological responses. Thus horses, an animal far-removed from the primate lineage, also have the ability to use facial expressions as a means of gaining social information and potentially regulating social interactions. PMID- 27995959 TI - A nationwide cross-sectional survey on prevalence, management and pharmacoepidemiology patterns on hypertension in Chinese patients with chronic kidney disease. AB - Limited data are available on epidemiology and drug use in Chinese hypertensive patients with chronic kidney disease (CKD). We determined the prevalence; awareness, treatment, and control rates of hypertension; anti-hypertensive use, expenditure pattern; and factors associated with hypertension prevalence and control in Chinese patients with CKD. This was one of the largest cross-sectional surveys that enrolled 6079 CKD participants (mean age, 51.0 +/- 16.37 years) with or without hypertension from 22 centres across China. The prevalence, awareness, and treatment rates were 71.2%, 95.4%, and 93.7%, respectively. Control rates 1 and 2 (Blood pressure, BP <140/90 and <130/80 mmHg) were 41.1% and 15.0%, respectively. Patients were treated mostly with monotherapy (37.7%) or 2-drug anti-hypertensive combination (38.7%). Factors associated with prevalence of hypertension included age; smoking; body mass index; physical exercise; family history of hypertension; hyperuricaemia; and CKD. Control rate was associated with CKD stage, BP monitoring at home, and use of drug combinations. Despite high rates of awareness and treatment, the control rates are low. CKD stages 4 and 5 adversely affect the control rate. The results suggest the immediate need of comprehensive controlling measures to improve the control of hypertension in Chinese patients with CKD. PMID- 27995960 TI - Effect of Positive Psychological Intervention on Posttraumatic Growth among Primary Healthcare Workers in China: A Preliminary Prospective Study. AB - Posttraumatic growth (PTG) is defined as positive psychological change in the wake of highly challenging circumstances. Healthcare workers in particular are more vulnerable to stressors and trauma than the general population. The current study examined the use and effectiveness of a novel positive psychological intervention based on Chinese traditional culture to improve PTG in hospital healthcare workers. The intervention was provided to 579 healthcare workers at hospitals in Guilin, Shenzhen and Xiangtan. Scores on the Posttraumatic Growth Inventory (PTGI) and its subscales were significantly higher after intervention than before (p < 0.001). Of the five aspects of PTG, the aspect of "new possibilities" benefited the most from intervention (Cohen's d = 0.45). PTG in women, nurses and college graduates increased to a greater extent than other participants after intervention. It was concluded that our novel intervention is effective at improving PTG in medical staff. PMID- 27995961 TI - Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay. AB - We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 MUM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 MUM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with DeltaGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors. PMID- 27995962 TI - Engineering the surface properties of a human monoclonal antibody prevents self association and rapid clearance in vivo. AB - Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins. PMID- 27995963 TI - Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. AB - Hemorrhagic cystitis is an inflammatory and ulcerative bladder condition associated with systemic chemotherapeutics, like cyclophosphomide. Earlier, we reported reactive oxygen species resulting from cyclophosphamide metabolite, acrolein, causes global methylation followed by silencing of DNA damage repair genes. Ogg1 (8-oxoguanine DNA glycosylase) is one such silenced base excision repair enzyme that can restore DNA integrity. The accumulation of DNA damage results in subsequent inflammation associated with pyroptotic death of bladder smooth muscle cells. We hypothesized that reversing inflammasome-induced imprinting in the bladder smooth muscle could prevent the inflammatory phenotype. Elevated recruitment of Dnmt1 and Dnmt3b to the Ogg1 promoter in acrolein treated bladder muscle cells was validated by the pattern of CpG methylation revealed by bisulfite sequencing. Knockout of Ogg1 in detrusor cells resulted in accumulation of reactive oxygen mediated 8-Oxo-dG and spontaneous pyroptotic signaling. Histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), restored Ogg1 expression in cells treated with acrolein and mice treated with cyclophosphamide superior to the standard of care, mesna or nicotinamide-induced DNA demethylation. SAHA restored cyclophosphamide-induced bladder pathology to that of untreated control mice. The observed epigenetic imprinting induced by inflammation suggests a new therapeutic target for the treatment of hemorrhagic cystitis. PMID- 27995964 TI - An Unbiased Analysis of Candidate Mechanisms for the Regulation of Drosophila Wing Disc Growth. AB - The control of organ size presents a fundamental open problem in biology. A declining growth rate is observed in all studied higher animals, and the growth limiting mechanism may therefore be evolutionary conserved. Most studies of organ growth control have been carried out in Drosophila imaginal discs. We have previously shown that the area growth rate in the Drosophila eye primordium declines inversely proportional to the increase in its area, which is consistent with a dilution mechanism for growth control. Here, we show that a dilution mechanism cannot explain growth control in the Drosophila wing disc. We computationally evaluate a range of alternative candidate mechanisms and show that the experimental data can be best explained by a biphasic growth law. However, also logistic growth and an exponentially declining growth rate fit the data very well. The three growth laws correspond to fundamentally different growth mechanisms that we discuss. Since, as we show, a fit to the available experimental growth kinetics is insufficient to define the underlying mechanism of growth control, future experimental studies must focus on the molecular mechanisms to define the mechanism of growth control. PMID- 27995965 TI - Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia. AB - The aim of this study was to describe a new pathogenic variant in the mutational hot spot exon ORF15 of retinitis pigmentosa GTPase regulator (RPGR) gene within an Italian family with X-linked retinitis pigmentosa (RP), detailing its distinctive genotype-phenotype correlation with pathologic myopia (PM). All members of this RP-PM family underwent a complete ophthalmic examination. The entire open reading frames of RPGR and retinitis pigmentosa 2 genes were analyzed by Sanger sequencing. A novel frame-shift mutation in exon ORF15 of RPGR gene (c.2091_2092insA; p.A697fs) was identified as hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibited symmetrical PM in both eyes. The c.2091_2092insA mutation coherently co-segregated with the observed phenotypes. These findings expand the spectrum of X-linked RP variants. Interestingly, focusing on Caucasian ethnicity, just three RPGR mutations are hitherto reported in RP-PM families: one of these is located in exon ORF15, but none appears to be characterized by a high penetrance of PM trait as observed in the present, relatively small, pedigree. The geno-phenotypic attributes of this heterozygosity suggest that gain-of function mechanism could give rise to PM via a degenerative cell-cell remodeling of the retinal structures. PMID- 27995966 TI - Identification of an evolutionary conserved structural loop that is required for the enzymatic and biological function of tryptophan 2,3-dioxygenase. AB - The enzyme TDO (tryptophan 2,3-dioxygenase; TDO-2 in Caenorhabditis elegans) is a potential therapeutic target to cancer but is also thought to regulate proteotoxic events seen in the progression of neurodegenerative diseases. To better understand its function and develop specific compounds that target TDO we need to understand the structure of this molecule. In C. elegans we compared multiple different CRISPR/Cas9-induced tdo-2 deletion mutants and identified a motif of three amino acids (PLD) that is required for the enzymatic conversion of tryptophan to N-formylkynurenine. Loss of TDO-2's enzymatic activity in PDL deletion mutants was accompanied by an increase in motility during aging and a prolonged lifespan, which is in line with the previously observed phenotypes induced by a knockdown of the full enzyme. Comparison of sequence structures suggests that blocking this motif might interfere with haem binding, which is essential for the enzyme's activity. The fact that these three residues are situated in an evolutionary conserved structural loop of the enzyme suggests that the findings can be translated to humans. The identification of this specific loop region in TDO-2-essential for its catalytic function-will aid in the design of novel inhibitors to treat diseases in which the TDO enzyme is overexpressed or hyperactive. PMID- 27995967 TI - A Balanced Mixture of Antagonistic Pressures Promotes the Evolution of Parallel Movement. AB - A common hypothesis about the origins of collective behaviour suggests that animals might live and move in groups to increase their chances of surviving predator attacks. This hypothesis is supported by several studies that use computational models to simulate natural evolution. These studies, however, either tune an ad-hoc model to 'reproduce' collective behaviour, or concentrate on a single type of predation pressure, or infer the emergence of collective behaviour from an increase in prey density. In nature, prey are often targeted by multiple predator species simultaneously and this might have played a pivotal role in the evolution of collective behaviour. We expand on previous research by using an evolutionary rule-based system to simulate the evolution of prey behaviour when prey are subject to multiple simultaneous predation pressures. We analyse the evolved behaviour via prey density, polarization, and angular momentum. Our results suggest that a mixture of antagonistic external pressures that simultaneously steer prey towards grouping and dispersing might be required for prey individuals to evolve dynamic parallel movement. PMID- 27995968 TI - Preliminary effectiveness of breast cancer screening among 1.22 million Chinese females and different cancer patterns between urban and rural women. AB - To determine the preliminary effectiveness of breast cancer screening among Chinese females, 1226714 women aged 35-69 years first received clinical breast examinations. Urban women with suspected cancer received mammography followed by breast ultrasound (BUS), while rural suspected women underwent BUS followed by mammography. After one-year follow-up, 223 and 431 breast cancers were detected among urban and rural women (respectively), with overall detection rates of 0.56/1000 and 0.52/1000. Higher detection rates were significantly associated with older age at screening for both urban and rural women; additionally, urban women were at significantly higher risk if they had no job, no insurance, or were obese; additional risk factors specific to rural women included Han nationality, higher income, being unmarried, and having a family history of cancer (all P values < 0.05). Among screening-detected breast cancers in urban vs. rural women, 46.2% and 38.8% (respectively) were early stage, 62.5% and 66.3% were <=2 centimeters, 38.0% and 47.3% included lymph-node involvement, and 14.0% and 6.0% were identified as carcinoma in situ. All abovementioned cancer characteristics were significantly better than clinic-detected cancers (all P values < 0.001). In conclusion, several important differences were found between urban and rural women in screening effectiveness and patterns of cancer distribution. PMID- 27995970 TI - Yields and Nutritional of Greenhouse Tomato in Response to Different Soil Aeration Volume at two depths of Subsurface drip irrigation. AB - This study investigated the effects of 4 aeration levels (varied by injection of air to the soil through subsurface irrigation lines) at two subsurface irrigation line depths (15 and 40 cm) on plant growth, yield and nutritional quality of greenhouse tomato. In all experiments, fruit number, width and length, yield, vitamin C, lycopene and sugar/acid ratio of tomato markedly increased in response to the aeration treatments. Vitamin C, lycopene, and sugar/acid ratio increased by 41%, 2%, and 43%, respectively, in the 1.5 times standard aeration volume compared with the no-aeration treatment. An interaction between aeration level and depth of irrigation line was also observed with yield, fruit number, fruit length, vitamin C and sugar/acid ratio of greenhouse tomato increasing at each aeration level when irrigation lines were placed at 40 cm depth. However, when the irrigation lines were 15 cm deep, the trend of total fruit yields, fruit width, fruit length and sugar/acid ratio first increased and then decreased with increasing aeration level. Total soluble solids and titrable acid decreased with increasing aeration level both at 15 and 40 cm irrigation line placement. When all of the quality factors, yields and economic benefit are considered together, the combination of 40 cm line depth and "standard" aeration level was the optimum combination. PMID- 27995969 TI - Biliary Phospholipids Sustain Enterocyte Proliferation and Intestinal Tumor Progression via Nuclear Receptor Lrh1 in mice. AB - The proliferative-crypt compartment of the intestinal epithelium is enriched in phospholipids and accumulation of phospholipids has been described in colorectal tumors. Here we hypothesize that biliary phospholipid flow could directly contribute to the proliferative power of normal and dysplastic enterocytes. We used Abcb4-/- mice which lack biliary phospholipid secretion. We first show that Abcb4-/- mice are protected against intestinal tumorigenesis. At the molecular level, the transcriptional activity of the nuclear receptor Liver Receptor Homolog-1 (Lrh1) is reduced in Abcb4-/- mice and its re-activation re-establishes a tumor burden comparable to control mice. Feeding Abcb4-/- mice a diet supplemented with phospholipids completely overcomes the intestinal tumor protective phenotype, thus corroborating the hypothesis that the absence of biliary phospholipids and not lack of Abcb4 gene per se is responsible for the protection. In turn, phospholipids cannot re-establish intestinal tumorigenesis in Abcb4-/- mice crossed with mice with intestinal specific ablation of Lrh1, a nuclear hormone receptor that is activates by phospholipids. Our data identify the key role of biliary phospholipids in sustaining intestinal mucosa proliferation and tumor progression through the activation of nuclear receptor Lrh1. PMID- 27995971 TI - Prognostic value of pulmonary congestion assessed by lung ultrasound imaging during heart failure hospitalisation: A two-centre cohort study. AB - Pulmonary congestion assessed at discharge by lung ultrasonography predicts poor prognosis in heart failure (HF) patients. We investigated the association of B lines with indices of hemodynamic congestion [BNP, E/e', pulmonary systolic arterial pressure (PAPs)] in HF patients, and their prognostic value overall and according to concomitant atrial fibrillation (AF), reduced (<=40%) ejection fraction (EF), and timing of quantification during hospitalisation for heart failure (HHF). In 110 HHF patients, B-lines were highly discriminative of BNP >400 pg/ml (AUC >= 0.80 for all), and moderately discriminative of PAPs >50 mmHg (AUC = 0.68, 0.56 to 0.80); conversely, B-lines poorly discriminated average E/e' >= 15, except at discharge. B-line count significantly predicted mid-term recurrent HHF or death (overall and in subgroups), regardless of AF status, EF, and timing of quantification during HHF (all p for interaction >0.10). regardless, B-lines >=30 at discharge were most predictive of outcome (HR = 7.11, 2.06-24.48; p = 0.002) while B-lines >=45 early during HHF were most predictive of outcome (HR = 9.20, 1.82-46.61; p = 0.007). Lung ultrasound was able to identify patients with high BNP levels, but not with increased E/e', also showing a prognostic role regardless of AF status, EF or timing of quantification; best B line cut-off appears to vary according to the timing of quantification during hospitalization. PMID- 27995972 TI - Difference in evolutionary patterns of strongly or weakly selected characters among ant populations. AB - Despite being a central issue in evolutionary biology, few studies have examined the stasis of characters in populations with no gene flow. A possible mechanism of such stasis is stabilizing selection with similar peaks in each population. This study examined the evolutionary patterns of morphological characters with and without strong selection in ant populations. We show that compared to a character that seems to be less important, characters that are more important were less variable within and among populations. Microsatellite analyses showed significant genetic differences between populations, implying limited gene flow between them. The observed levels of genetic differentiation cannot be attributed to recent population separations. Thus, the observed differences in morphological variance seem to reflect the degree of selection on each character. The less important character changed proportionately with time, but such a pattern was not observed in more important characters. These results suggest that stabilizing selection maintains morphological stasis between populations of the same species with minimal gene flow independent of divergence times. PMID- 27995973 TI - The Angiogenic Secretome in VEGF overexpressing Breast Cancer Xenografts. AB - The plasticity of cancer cells and the fluidity of the tumor microenvironment continue to present major challenges in the comprehensive understanding of cancer that is essential to design effective treatments. The tumor interstitial fluid (TIF) encompasses the secretome and holds the key to several of the phenotypic characteristics of cancer. Difficulties in sampling this fluid have resulted in limited characterization of its components. Here we have sampled TIF from triple negative and estrogen receptor (ER)-positive human breast tumor xenografts with or without VEGF overexpression. Angiogenesis-related factors were characterized in the TIF and plasma, to understand the relationship between the TIF and plasma secretomes. Clear differences were observed between the TIF and plasma angiogenic secretomes in triple negative MDA-MB-231 breast cancer xenografts compared to ER positive MCF-7 xenografts with or without VEGF overexpression that provide new insights into TIF components and the role of VEGF in modifying the angiogenic secretome. PMID- 27995974 TI - Polarization shaping of high-order harmonics in laser-aligned molecules. AB - The present work reports on the generation of short-pulse coherent extreme ultraviolet radiation of controlled polarization. The proposed strategy is based on high-order harmonics generated in pre-aligned molecules. Field-free molecular alignment produced by a short linearly-polarized infrared laser pulse is used to break the isotropy of a gas medium. Driving the aligned molecules by a circularly polarized infrared pulse allows to transfer the anisotropy of the medium to the polarization of the generated harmonic light. The ellipticity of the latter is controlled by adjusting the angular distribution of the molecules at the time they interact with the driving pulse. Extreme ultraviolet radiation produced with high degree of ellipticity (close to circular) is demonstrated. PMID- 27995975 TI - RNA activation of haploinsufficient Foxg1 gene in murine neocortex. AB - More than one hundred distinct gene hemizygosities are specifically linked to epilepsy, mental retardation, autism, schizophrenia and neuro-degeneration. Radical repair of these gene deficits via genome engineering is hardly feasible. The same applies to therapeutic stimulation of the spared allele by artificial transactivators. Small activating RNAs (saRNAs) offer an alternative, appealing approach. As a proof-of-principle, here we tested this approach on the Rett syndrome-linked, haploinsufficient, Foxg1 brain patterning gene. We selected a set of artificial small activating RNAs (saRNAs) upregulating it in neocortical precursors and their derivatives. Expression of these effectors achieved a robust biological outcome. saRNA-driven activation (RNAa) was limited to neural cells which normally express Foxg1 and did not hide endogenous gene tuning. saRNAs recognized target chromatin through a ncRNA stemming from it. Gene upregulation required Ago1 and was associated to RNApolII enrichment throughout the Foxg1 locus. Finally, saRNA delivery to murine neonatal brain replicated Foxg1-RNAa in vivo. PMID- 27995976 TI - In vivo MEMRI characterization of brain metastases using a 3D Look-Locker T1 mapping sequence. AB - Although MEMRI (Manganese Enhanced MRI) informations were obtained on primary tumors in small animals, MEMRI data on metastases are lacking. Thus, our goal was to determine if 3D Look-Locker T1 mapping was an efficient method to evaluate Mn ions transport in brain metastases in vivo. The high spatial resolution in 3D (156 * 156 * 218 MUm) of the sequence enabled to detect metastases of 0.3 mm3. In parallel, the T1 quantitation enabled to distinguish three populations of MDA-MB 231 derived brain metastases after MnCl2 intravenous injection: one with a healthy blood-tumor barrier that did not internalize Mn2+ ions, and two others, which T1 shortened drastically by 54.2% or 24%. Subsequent scans of the mice, enabled by the fast acquisition (23 min), demonstrated that these T1 reached back their pre-injection values in 24 h. Contrarily to metastases, the T1 of U87-MG glioma remained 26.2% shorter for one week. In vitro results supported the involvement of the Transient Receptor Potential channels and the Calcium-Sensing Receptor in the uptake and efflux of Mn2+ ions, respectively. This study highlights the ability of the 3D Look-Locker T1 mapping sequence to study heterogeneities (i) amongst brain metastases and (ii) between metastases and glioma regarding Mn transport. PMID- 27995977 TI - Biodegradation of 3-methyldiphenylether (MDE) by Hydrogenophaga atypical strain QY7-2 and cloning of the methy-oxidation gene mdeABCD. AB - 3-Methyldiphenylether (MDE) is an important alkyl-substituted diphenyl ether compound that is widely used as an intermediate in the synthesis of pyrethroid insecticides. An efficient MDE-degrading strain QY7-2, identified as Hydrogenophaga atypical, was isolated from activated sludge for the first time. Strain QY7-2 can utilize MDE as the sole carbon and energy source and completely mineralize MDE. The degradation pathway of MDE was proposed in the strain through metabolites identification. A gene cluster involving in methy-oxidation of MDE was cloned from QY7-2 and expressed in Escherichia coli BL21 (DE3), and the products were purified by SDS-PAGE. The specific activities of the recombinant enzymes MdeAB, MdeC and MdeD were 113.8 +/- 3.5, 274.5 +/- 6.2 and 673.4 +/- 8.7 nmol min-1 mg-1, respectively. These results provide the biochemical and genetic foundation of microbial degradation pathway of MDE and benefit the bioremediation of MDE-contaminated environments. PMID- 27995978 TI - Three-dimensional ultrastructural analysis of cells in the periodontal ligament using focused ion beam/scanning electron microscope tomography. AB - The accurate comprehension of normal tissue provides essential data to analyse abnormalities such as disease and regenerative processes. In addition, understanding the proper structure of the target tissue and its microenvironment may facilitate successful novel treatment strategies. Many studies have examined the nature and structure of periodontal ligaments (PDLs); however, the three dimensional (3D) structure of cells in normal PDLs remains poorly understood. In this study, we used focused ion beam/scanning electron microscope tomography to investigate the whole 3D ultrastructure of PDL cells along with quantitatively analysing their structural properties and ascertaining their orientation to the direction of the collagen fibre. PDL cells were shown to be in contact with each other, forming a widespread mesh-like network between the cementum and the alveolar bone. The volume of the cells in the horizontal fibre area was significantly larger than in other areas, whereas the anisotropy of these cells was lower than in other areas. Furthermore, the orientation of cells to the PDL fibres was not parallel to the PDL fibres in each area. As similar evaluations are recognized as being challenging using conventional two-dimensional methods, these novel 3D findings may contribute necessary knowledge for the comprehensive understanding and analysis of PDLs. PMID- 27995979 TI - Purified Lesser weever fish venom (Trachinus vipera) induces eryptosis, apoptosis and cell cycle arrest. AB - Accidents caused by the sting of Trachinus vipera (known as Lesser weever fish) are relatively common in shallow waters of the Mediterranean. Symptoms after the sting vary from severe pain to edema or even tissue necrosis in some cases. Here we show that purified Lesser weever fish venom induces eryptosis, the suicidal erythrocyte death, and apoptosis of human colon carcinoma cells. The venom leads to erythrocyte shrinkage, phosphatidylserine translocation and increased intracellular Ca2+, events typical for eryptosis. According to mitochondrial staining cancer cells dyed after the activation of the intrinsic apoptotic pathway. Trachinus vipera venom further causes cell cycle arrest. PMID- 27995980 TI - Fractal aggregation kinetics contributions to thermal conductivity of nano suspensions in unsteady thermal convection. AB - Nano-suspensions (NS) exhibit unusual thermophysical behaviors once interparticle aggregations and the shear flows are imposed, which occur ubiquitously in applications but remain poorly understood, because existing theories have not paid these attentions but focused mainly on stationary NS. Here we report the critical role of time-dependent fractal aggregation in the unsteady thermal convection of NS systematically. Interestingly, a time ratio lambda = tp/tm (tp is the aggregate characteristic time, tm the mean convection time) is introduced to characterize the slow and fast aggregations, which affect distinctly the thermal convection process over time. The increase of fractal dimension reduces both momentum and thermal boundary layers, meanwhile extends the time duration for the full development of thermal convection. We find a nonlinear growth relation of the momentum layer, but a linear one of the thermal layer, with the increase of primary volume fraction of nanoparticles for different fractal dimensions. We present two global fractal scaling formulas to describe these two distinct relations properly, respectively. Our theories and methods in this study provide new evidence for understanding shear-flow and anomalous heat transfer of NS associated non-equilibrium aggregation processes by fractal laws, moreover, applications in modern micro-flow technology in nanodevices. PMID- 27995981 TI - Iron arsenides with three-dimensional FeAs layer networks: Can(n+1)/2(Fe1 xPtx)(2+3n)Ptn(n-1)/2As(n+1)(n+2)/2 (n = 2, 3). AB - We report the comprehensive studies between synchrotron X-ray diffraction, electrical resistivity and magnetic susceptibility experiments for the iron arsenides Can(n+1)/2(Fe1-xPtx)(2+3n)Ptn(n-1)/2As(n+1)(n+2)/2 for n = 2 and 3. Both structures crystallize in the monoclinic space group P21/m (#11) with three dimensional FeAs structures. The horizontal FeAs layers are bridged by inclined FeAs planes through edge-sharing FeAs5 square pyramids, resulting in triangular tunneling structures rather than the simple layered structures found in conventional iron arsenides. n = 3 system shows a sign of superconductivity with a small volume fraction. Our first-principles calculations of these systems clearly indicate that the Fermi surfaces originate from strong Fe-3d characters and the three-dimensional nature of the electric structures for both systems, thus offering the playgrounds to study the effects of dimensionality on high Tc superconductivity. PMID- 27995982 TI - Crosstalk between Activated Microglia and Neurons in the Spinal Dorsal Horn Contributes to Stress-induced Hyperalgesia. AB - Stress has been shown to enhance pain sensitivity resulting in stress-induced hyperalgesia. However, the underlying mechanisms have yet to be elucidated. Using single-prolonged stress combined with Complete Freund's Adjuvant injection model, we explored the reciprocal regulatory relationship between neurons and microglia, which is critical for the maintenance of posttraumatic stress disorder (PTSD) induced hyperalgesia. In our assay, significant mechanical allodynia was observed. Additionally, activated neurons in spinal dorsal horn were observed by analysis of Fos expression. And, microglia were also significantly activated with the presence of increased Iba-1 expression. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or minocycline (a specific microglia inhibitor) attenuated mechanical allodynia. Moreover, intrathecal administration of c-fos ASO significantly suppressed the activation of neurons and microglia. Interestingly, inhibition of microglia activation by minocycline significantly suppressed the activation of both neurons and microglia in spinal dorsal horn. P38 inhibitor SB203580 suppressed IL-6 production, and inhibition of IL-6 receptor (IL-6R) activation by tocilizumab suppressed Fos expression. Together, our data suggest that the presence of a "crosstalk" between activated microglia and neurons in the spinal dorsal horn, which might contribute to the stress induced hyperactivated state, leading to an increased pain sensitivity. PMID- 27995983 TI - Cognitive control activity is modulated by the magnitude of interference and pre activation of monitoring mechanisms. AB - The Simon task is used to study interference from irrelevant spatial information. Interference is manifested by longer reaction times when the required response based on non-spatial features- is spatially incompatible with stimulus position. Interference is greater when incompatible trials are preceded by compatible trials (compatible-incompatible sequence) than when they are preceded by incompatible trials (incompatible-incompatible sequence). However, the relationships between spatial attention, interference and cognitive control have not been investigated. In the present study, we distinguished three experimental conditions according to sequential effects: same mappings (SM, compatible compatible/incompatible-incompatible sequences: low interference), opposite mappings (OM, compatible-incompatible/incompatible-compatible sequences: high interference) and unrelated mappings (UM, central-compatible/central-incompatible sequences: intermediate interference). The negativity central contralateral (N2cc, a correlate of prevention of spatial response tendencies) was larger in OM than in SM, indicating greater cognitive control for greater interference. Furthermore, N2cc was larger in UM than in SM/OM, indicating lower neural efficiency for suppressing spatial tendencies of the response after central trials. Attentional processes (negativity posterior contralateral) were also delayed in UM relative to SM/OM, suggesting attentional facilitation by similar sets of attentional shifts in successive trials. Overall, the present findings showed that cognitive control is modulated by the magnitude of interference and pre-activation of monitoring mechanisms. PMID- 27995984 TI - Nutrient enrichment alters impacts of Hydrocotyle vulgaris invasion on native plant communities. AB - Nutrients may affect the invasiveness of alien plants and the invasibility of native plant communities. We performed a greenhouse experiment to investigate the interactive effect of invasion by a clonal herb Hydrocotyle vulgaris and nutrient enrichment on biomass and evenness of native plant communities. We established three types of plant communities (H. vulgaris alone, native plant communities without or with H. vulgaris) under low and high levels of nutrients. Native communities consisted of eight native, terrestrial species of three functional groups, i.e. four grasses, two legumes, and two forbs. Invasion of H. vulgaris had no effect on biomass of the native community, the functional groups, or the individual species. High nutrients increased biomass of grasses, but reduced evenness of the community. High nutrients also decreased the competitive effect, and the relative dominance index of H. vulgaris. Therefore, high nutrients reduced the competitive ability of H. vulgaris and enhanced the resistance of the native community to invasion. The results provide a basis for management strategies to control the invasion and spread of H. vulgaris by manipulating resource availability to support native communities. PMID- 27995986 TI - Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation. AB - The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55?NS mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55?NS mice after M. tuberculosis challenge. Defective expressions of CD44 and INFgamma attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection. PMID- 27995985 TI - De novo transcriptome assembly, development of EST-SSR markers and population genetic analyses for the desert biomass willow, Salix psammophila. AB - Salix psammophila, a sandy shrub known as desert willow, is regarded as a potential biomass feedstock and plays an important role in maintaining local ecosystems. However, a lack of genomic data and efficient molecular markers limit the study of its population evolution and genetic breeding. In this study, chromosome counts, flow cytometry and SSR analyses indicated that S. psammophila is tetraploid. A total of 6,346 EST-SSRs were detected based on 71,458 de novo assembled unigenes from transcriptome data. Twenty-seven EST-SSR markers were developed to evaluate the genetic diversity and population structure of S. psammophila from eight natural populations in Northern China. High levels of genetic diversity (mean 10.63 alleles per locus; mean HE 0.689) were dectected in S. psammophila. The weak population structure and little genetic differentiation (pairwise FST = 0.006-0.016) were found among Population 1-Population 7 (Pop1 Pop7; Inner Mongolia and Shaanxi), but Pop8 (Ningxia) was clearly separated from Pop1-Pop7 and moderate differentiation (pairwise FST = 0.045-0.055) was detected between them, which may be influenced by local habitat conditions. Molecular variance analyses indicated that most of the genetic variation (94.27%) existed within populations. These results provide valuable genetic informations for natural resource conservation and breeding programme optimisation of S. psammophila. PMID- 27995987 TI - Intrinsic Photosensitivity Enhances Motility of T Lymphocytes. AB - Sunlight has important biological effects in human skin. Ultraviolet (UV) light striking the epidermis catalyzes the synthesis of Vitamin D and triggers melanin production. Although a causative element in skin cancers, sunlight is also associated with positive health outcomes including reduced incidences of autoimmune diseases and cancers. The mechanisms, however, by which light affects immune function remain unclear. Here we describe direct photon sensing in human and mouse T lymphocytes, a cell-type highly abundant in skin. Blue light irradiation at low doses (<300 mJ cm-2) triggers synthesis of hydrogen peroxide (H2O2) in T cells revealed by the genetically encoded reporter HyPerRed. In turn, H2O2 activates a Src kinase/phospholipase C-gamma1 (PLC-gamma1) signaling pathway and Ca2+ mobilization. Pharmacologic inhibition or genetic disruption of Lck kinase, PLC-gamma1 or the T cell receptor complex inhibits light-evoked Ca2+ transients. Notably, both light and H2O2 enhance T-cell motility in a Lck dependent manner. Thus, T lymphocytes possess intrinsic photosensitivity and this property may enhance their motility in skin. PMID- 27995988 TI - The neural representation of competence traits: An fMRI study. AB - Previous neuroimaging studies have revealed that a trait code is mainly represented in the ventral medial prefrontal cortex (vmPFC). However, those studies only investigated the neural code of warmth traits. According to the 'Big Two' model of impression formation, competence traits are the other major dimension when we judge others. The current study explored the neural representation of competence traits by using an fMRI repetition suppression paradigm, which is a rapid reduction of neuronal responses upon repeated presentation of the same implied trait. Participants had to infer an agent's trait from brief behavioral descriptions that implied a competence trait. In each trial, the critical target sentence was preceded by a prime sentence that implied the same or opposite competence-related trait, or no trait. The results revealed robust repetition suppression from prime to target in the vmPFC and precuneus during trait conditions. Critically, the suppression effect was much stronger after being primed with a similar and opposite competence trait compared with a trait-irrelevant prime. This suppression pattern was found nowhere else in the brain. Consistent with previous fMRI studies, we suggest that the neural code of competence traits is represented in these two brain areas with different levels of abstraction. PMID- 27995990 TI - Long-Term Acclimation to Different Thermal Regimes Affects Molecular Responses to Heat Stress in a Freshwater Clam Corbicula Fluminea. AB - Global climate change (GCC) can negatively affect freshwater ecosystems. However, the degree to which freshwater populations can acclimate to long-term warming and the underlying molecular mechanisms are not yet fully understood. We used the cooling water discharge (CWD) area of a power plant as a model for long-term warming. Survival and molecular stress responses (expression of molecular chaperones, antioxidants, bioenergetic and protein synthesis biomarkers) to experimental warming (20-41 degrees C, +1.5 degrees C per day) were assessed in invasive clams Corbicula fluminea from two pristine populations and a CWD population. CWD clams had considerably higher (by ~8-12 degrees C) lethal temperature thresholds than clams from the pristine areas. High thermal tolerance of CWD clams was associated with overexpression of heat shock proteins HSP70, HSP90 and HSP60 and activation of protein synthesis at 38 degrees C. Heat shock response was prioritized over the oxidative stress response resulting in accumulation of oxidative lesions and ubiquitinated proteins during heat stress in CWD clams. Future studies should determine whether the increase in thermal tolerance in CWD clams are due to genetic adaptation and/or phenotypic plasticity. Overall, our findings indicate that C. fluminea has potential to survive and increase its invasive range during warming such as expected during GCC. PMID- 27995989 TI - Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies. AB - The main treatment for advanced gastric cancer is fluoropyrimidine and platinum based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0.3, P=0.0025), whereas ENOSF1 rs2612091 G/G was nominally associated with OS after adjustment for TYMS 3 R/3 R (hazard ratio (HR) 1.5, P=0.041). In a subgroup analysis of patients with locally advanced disease (n=33), ENOSF1 rs2612091 was strongly associated with OS (HR 6.5, P=0.001). CYP3A4*22/CYP3A5*3 genotype was nominally associated with grade 3/4 toxicity in patients receiving docetaxel-containing chemotherapy (P=0.0175). This is the first study suggesting that ENOSF1 rs2612091 is prognostic or predictive of OS in gastric cancer. This finding requires prospective validation. PMID- 27995991 TI - Development and deployment of a high-density linkage map identified quantitative trait loci for plant height in peanut (Arachis hypogaea L.). AB - Plant height is one of the most important architecture traits in crop plants. In peanut, the genetic basis of plant height remains ambiguous. In this context, we genotyped a recombinant inbred line (RIL) population with 140 individuals developed from a cross between two peanut varieties varying in plant height, Zhonghua 10 and ICG 12625. Genotyping data was generated for 1,175 SSR and 42 transposon polymorphic markers and a high-density genetic linkage map was constructed with 1,219 mapped loci covering total map length of 2,038.75 cM i.e., accounted for nearly 80% of the peanut genome. Quantitative trait locus (QTL) analysis using genotyping and phenotyping data for three environments identified 8 negative-effect QTLs and 10 positive-effect QTLs for plant height. Among these QTLs, 8 QTLs had a large contribution to plant height that explained >=10% phenotypic variation. Two major-effect consensus QTLs namely cqPHA4a and cqPHA4b were identified with stable performance across three environments. Further, the allelic recombination of detected QTLs proved the existence of the phenomenon of transgressive segregation for plant height in the RIL population. Therefore, this study not only successfully reported a high-density genetic linkage map of peanut and identified genomic region controlling plant height but also opens opportunities for further gene discovery and molecular breeding for plant height in peanut. PMID- 27995992 TI - Enabling Ultrasensitive Photo-detection Through Control of Interface Properties in Molybdenum Disulfide Atomic Layers. AB - The interfaces in devices made of two-dimensional materials such as MoS2 can effectively control their optoelectronic performance. However, the extent and nature of these deterministic interactions are not fully understood. Here, we investigate the role of substrate interfaces on the photodetector properties of MoS2 devices by studying its photocurrent properties on both SiO2 and self assembled monolayer-modified substrates. Results indicate that while the photoresponsivity of the devices can be enhanced through control of device interfaces, response times are moderately compromised. We attribute this trade off to the changes in the electrical contact resistance at the device metal semiconductor interface. We demonstrate that the formation of charge carrier traps at the interface can dominate the device photoresponse properties. The capture and emission rates of deeply trapped charge carriers in the substrate semiconductor-metal regions are strongly influenced by exposure to light and can dynamically dope the contact regions and thus perturb the photodetector properties. As a result, interface-modified photodetectors have significantly lower dark-currents and higher on-currents. Through appropriate interfacial design, a record high device responsivity of 4.5 * 103 A/W at 7 V is achieved, indicative of the large signal gain in the devices and exemplifying an important design strategy that enables highly responsive two-dimensional photodetectors. PMID- 27995993 TI - PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma. AB - Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E cadherin axis could serve as a potential therapeutic target. PMID- 27995994 TI - Counteracting bone fragility with human amniotic mesenchymal stem cells. AB - The impaired maturation of bone-forming osteoblasts results in reduced bone formation and subsequent bone weakening, which leads to a number of conditions such as osteogenesis imperfecta (OI). Transplantation of human fetal mesenchymal stem cells has been proposed as skeletal anabolic therapy to enhance bone formation, but the mechanisms underlying the contribution of the donor cells to bone health are poorly understood and require further elucidation. Here, we show that intraperitoneal injection of human amniotic mesenchymal stem cells (AFSCs) into a mouse model of OI (oim mice) reduced fracture susceptibility, increased bone strength, improved bone quality and micro-architecture, normalised bone remodelling and reduced TNFalpha and TGFbeta sigalling. Donor cells engrafted into bones and differentiated into osteoblasts but importantly, also promoted endogenous osteogenesis and the maturation of resident osteoblasts. Together, these findings identify AFSC transplantation as a countermeasure to bone fragility. These data have wider implications for bone health and fracture reduction. PMID- 27995995 TI - Ascorbic Acid Protects against Hypertension through Downregulation of ACE1 Gene Expression Mediated by Histone Deacetylation in Prenatal Inflammation-Induced Offspring. AB - Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Prenatal exposure to lipopolysaccharide (LPS) leads to hypertension in a rat offspring. However, the mechanism is still unclear. This study unraveled epigenetic mechanism for this and explored the protective effects of ascorbic acid against hypertension on prenatal inflammation-induced offspring. Prenatal LPS exposure resulted in an increase of intrarenal oxidative stress and enhanced angiotensin-converting enzyme 1 (ACE1) gene expression at the mRNA and protein levels in 6- and 12-week-old offspring, correlating with the augmentation of histone H3 acetylation (H3AC) on the ACE1 promoter. However, the prenatal ascorbic acid treatment decreased the LPS-induced expression of ACE1, protected against intrarenal oxidative stress, and reversed the altered histone modification on the ACE1 promoter, showing the protective effect in offspring of prenatal LPS stimulation. Our study demonstrates that ascorbic acid is able to prevent hypertension in offspring from prenatal inflammation exposure. Thus, ascorbic acid can be a new approach towards the prevention of fetal programming hypertension. PMID- 27995996 TI - The Quantum Biology of Reactive Oxygen Species Partitioning Impacts Cellular Bioenergetics. AB - Quantum biology is the study of quantum effects on biochemical mechanisms and biological function. We show that the biological production of reactive oxygen species (ROS) in live cells can be influenced by coherent electron spin dynamics, providing a new example of quantum biology in cellular regulation. ROS partitioning appears to be mediated during the activation of molecular oxygen (O2) by reduced flavoenzymes, forming spin-correlated radical pairs (RPs). We find that oscillating magnetic fields at Zeeman resonance alter relative yields of cellular superoxide (O2*-) and hydrogen peroxide (H2O2) ROS products, indicating coherent singlet-triplet mixing at the point of ROS formation. Furthermore, the orientation-dependence of magnetic stimulation, which leads to specific changes in ROS levels, increases either mitochondrial respiration and glycolysis rates. Our results reveal quantum effects in live cell cultures that bridge atomic and cellular levels by connecting ROS partitioning to cellular bioenergetics. PMID- 27995997 TI - TIARP attenuates autoantibody-mediated arthritis via the suppression of neutrophil migration by reducing CXCL2/CXCR2 and IL-6 expression. AB - TNFalpha-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP-/-) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP-/- mice. Arthritis in TIARP-/- mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP /- mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP-/ neutrophils. Neutrophils of TIARP-/- mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo. Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP-/- TNFalpha-stimulated FLS. Blockade of IL-6R significantly attenuated serum transferred TIARP-/- arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints. PMID- 27995998 TI - A novel FIKK kinase regulates the development of mosquito and liver stages of the malaria. AB - Protein phosphorylation is the most important post-translational event in the regulation of various essential signaling pathways in a cell. Here, we show the functional characterization of a FIKK family protein kinase of the rodent malaria parasite (PbMLFK), which is expressed only in mosquito and liver stages and contains two functional C-terminal PEXEL motifs. We demonstrate that this protein plays a role in mosquito and liver stages of parasite growth. The oocysts of PbMLFK-deficient parasites produced 4-fold fewer sporozoites. In the liver of infected mice, PbMLFK-deficient parasites grew 100-fold less than did wild type parasites. We also show that the C-terminal domain of this protein has a functional serine-threonine kinase and that its activity was inhibited by a known PKA inhibitor. Transcriptome analysis of infected host cells suggests that in absence of this protein expression of the 288 host mRNAs are perturbed which are primarily associated with the immune system, cell cycle and metabolism. PMID- 27995999 TI - Tissue specific transcript profiling of wheat phosphate transporter genes and its association with phosphate allocation in grains. AB - Approaches enabling efficient phosphorus utilization in crops are of great importance. In cereal crop like wheat, utilization of inorganic phosphate (Pi) is high and mature grains are the major sink for Pi utilization and storage. Research that addresses the importance of the Pi homeostasis in developing grains is limited. In an attempt to understand the Pi homeostasis in developing wheat grains, we identified twelve new phosphate transporters (PHT), these are phyologentically well distributed along with the members reported from Arabidopsis and rice. Enhanced expression of PHT1-subfamily genes was observed in roots subjected to the Pi starvation suggesting their active role in Pi homeostasis. Differential expression patterns of all the PHT genes during grain filling stages suggested their importance in the filial tissues. Additionally, high accumulation of Pi and total P in aleurone correlates well with the expression of TaPHTs and other phosphate starvation related genes. Tissue specific transcript accumulation of TaPHT1.1, TaPHT1.2, TaPHT1.4 in aleurone; TaPHT3.1 in embryo and TaPHT4.2 in the endosperm was observed. Furthermore, their transcript abundance was affected in low phytate wheat grains. Altogether, this study helps in expanding the knowledge and prioritize the candidate wheat Pi transporters to modulate the Pi homeostasis in cereal grains. PMID- 27996000 TI - Central Role of CD169+ Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01. AB - Saponins represent a promising class of vaccine adjuvant. Together with the TLR4 ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169+ resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T-cell and antibody responses to co-administered antigens. DCs rather than lymph node resident macrophages were directly involved in T-cell priming by QS-21, as revealed by the decrease in antigen-specific T-cell response in Batf3-/- mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans. PMID- 27996003 TI - Bacterial secretion: A new front for intermicrobial wars. PMID- 27996001 TI - A Biomimetic Silk Fibroin/Sodium Alginate Composite Scaffold for Soft Tissue Engineering. AB - A cytocompatible porous scaffold mimicking the properties of extracellular matrices (ECMs) has great potential in promoting cellular attachment and proliferation for tissue regeneration. A biomimetic scaffold was prepared using silk fibroin (SF)/sodium alginate (SA) in which regular and uniform pore morphology can be formed through a facile freeze-dried method. The scanning electron microscopy (SEM) studies showed the presence of interconnected pores, mostly spread over the entire scaffold with pore diameter around 54~532 MUm and porosity 66~94%. With significantly better water stability and high swelling ratios, the blend scaffolds crosslinked by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) provided sufficient time for the formation of neo-tissue and ECMs during tissue regeneration. Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) results confirmed random coil structure and silk I conformation were maintained in the blend scaffolds. What's more, FI-TR spectra demonstrated crosslinking reactions occurred actually among EDC, SF and SA macromolecules, which kept integrity of the scaffolds under physiological environment. The suitable pore structure and improved equilibrium swelling capacity of this scaffold could imitate biochemical cues of natural skin ECMs for guiding spatial organization and proliferation of cells in vitro, indicating its potential candidate material for soft tissue engineering. PMID- 27996002 TI - Tunable molecular separation by nanoporous membranes. AB - Metal-organic frameworks offer tremendous potential for efficient separation of molecular mixtures. Different pore sizes and suitable functionalizations of the framework allow for an adjustment of the static selectivity. Here we report membranes which offer dynamic control of the selectivity by remote signals, thus enabling a continuous adjustment of the permeate flux. This is realized by assembling linkers containing photoresponsive azobenzene-side-groups into monolithic, crystalline membranes of metal-organic frameworks. The azobenzene moieties can be switched from the trans to the cis configuration and vice versa by irradiation with ultraviolet or visible light, resulting in a substantial modification of the membrane permeability and separation factor. The precise control of the cis:trans azobenzene ratio, for example, by controlled irradiation times or by simultaneous irradiation with ultraviolet and visible light, enables the continuous tuning of the separation. For hydrogen:carbon-dioxide, the separation factor of this smart membrane can be steplessly adjusted between 3 and 8. PMID- 27996005 TI - Twinned growth behaviour of two-dimensional materials. AB - Twinned growth behaviour in the rapidly emerging area of two-dimensional nanomaterials still remains unexplored although it could be exploited to fabricate heterostructure and superlattice materials. Here we demonstrate how one can utilize the twinned growth relationship between two two-dimensional materials to construct vertically stacked heterostructures. As a demonstration, we achieve 100% overlap of the two transition metal dichalcogenide layers constituting a ReS2/WS2 vertical heterostructure. Moreover, the crystal size of the stacked structure is an order of magnitude larger than previous reports. Such twinned transition metal dichalcogenides vertical heterostructures exhibit great potential for use in optical, electronic and catalytic applications. The simplicity of the twinned growth can be utilized to expand the fabrication of other heterostructures or two-dimensional material superlattice and this strategy can be considered as an enabling technology for research in the emerging field of two-dimensional van der Waals heterostructures. PMID- 27996004 TI - MicroRNA-182 targets SMAD7 to potentiate TGFbeta-induced epithelial-mesenchymal transition and metastasis of cancer cells. AB - The transforming growth factor beta (TGFbeta) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) and metastasis. SMAD7 is both a transcriptional target and a negative regulator of TGFbeta signalling, thus mediating a negative feedback loop that may potentially restrain TGFbeta responses of cancer cells. Here, however, we show that TGFbeta treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGFbeta activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGFbeta treatment and prevents TGFbeta-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGFbeta-induced osteoclastogenesis for bone metastasis. Furthermore, miR-182 expression inversely correlates with SMAD7 protein in human tumour samples. Therefore, our data reveal the miR-182-mediated disruption of TGFbeta self restraint and provide a mechanism to explain the unleashed TGFbeta responses in metastatic cancer cells. PMID- 27996006 TI - Astrocytes gate Hebbian synaptic plasticity in the striatum. AB - Astrocytes, via excitatory amino-acid transporter type-2 (EAAT2), are the major sink for released glutamate and contribute to set the strength and timing of synaptic inputs. The conditions required for the emergence of Hebbian plasticity from distributed neural activity remain elusive. Here, we investigate the role of EAAT2 in the expression of a major physiologically relevant form of Hebbian learning, spike timing-dependent plasticity (STDP). We find that a transient blockade of EAAT2 disrupts the temporal contingency required for Hebbian synaptic plasticity. Indeed, STDP is replaced by aberrant non-timing-dependent plasticity occurring for uncorrelated events. Conversely, EAAT2 overexpression impairs the detection of correlated activity and precludes STDP expression. Our findings demonstrate that EAAT2 sets the appropriate glutamate dynamics for the optimal temporal contingency between pre- and postsynaptic activity required for STDP emergence, and highlight the role of astrocytes as gatekeepers for Hebbian synaptic plasticity. PMID- 27996007 TI - Molecular and electronic structure of terminal and alkali metal-capped uranium(V) nitride complexes. AB - Determining the electronic structure of actinide complexes is intrinsically challenging because inter-electronic repulsion, crystal field, and spin-orbit coupling effects can be of similar magnitude. Moreover, such efforts have been hampered by the lack of structurally analogous families of complexes to study. Here we report an improved method to U=N triple bonds, and assemble a family of uranium(V) nitrides. Along with an isoelectronic oxo, we quantify the electronic structure of this 5f1 family by magnetometry, optical and electron paramagnetic resonance (EPR) spectroscopies and modelling. Thus, we define the relative importance of the spin-orbit and crystal field interactions, and explain the experimentally observed different ground states. We find optical absorption linewidths give a potential tool to identify spin-orbit coupled states, and show measurement of UV...UV super-exchange coupling in dimers by EPR. We show that observed slow magnetic relaxation occurs via two-phonon processes, with no obvious correlation to the crystal field. PMID- 27996008 TI - Unusual marine unicellular symbiosis with the nitrogen-fixing cyanobacterium UCYN A. AB - Nitrogen fixation - the reduction of dinitrogen (N2) gas to biologically available nitrogen (N) - is an important source of N for terrestrial and aquatic ecosystems. In terrestrial environments, N2-fixing symbioses involve multicellular plants, but in the marine environment these symbioses occur with unicellular planktonic algae. An unusual symbiosis between an uncultivated unicellular cyanobacterium (UCYN-A) and a haptophyte picoplankton alga was recently discovered in oligotrophic oceans. UCYN-A has a highly reduced genome, and exchanges fixed N for fixed carbon with its host. This symbiosis bears some resemblance to symbioses found in freshwater ecosystems. UCYN-A shares many core genes with the 'spheroid bodies' of Epithemia turgida and the endosymbionts of the amoeba Paulinella chromatophora. UCYN-A is widely distributed, and has diversified into a number of sublineages that could be ecotypes. Many questions remain regarding the physical and genetic mechanisms of the association, but UCYN A is an intriguing model for contemplating the evolution of N2-fixing organelles. PMID- 27996009 TI - Energy dissipation from a correlated system driven out of equilibrium. AB - In complex materials various interactions have important roles in determining electronic properties. Angle-resolved photoelectron spectroscopy (ARPES) is used to study these processes by resolving the complex single-particle self-energy and quantifying how quantum interactions modify bare electronic states. However, ambiguities in the measurement of the real part of the self-energy and an intrinsic inability to disentangle various contributions to the imaginary part of the self-energy can leave the implications of such measurements open to debate. Here we employ a combined theoretical and experimental treatment of femtosecond time-resolved ARPES (tr-ARPES) show how population dynamics measured using tr ARPES can be used to separate electron-boson interactions from electron-electron interactions. We demonstrate a quantitative analysis of a well-defined electron boson interaction in the unoccupied spectrum of the cuprate Bi2Sr2CaCu2O8+x characterized by an excited population decay time that maps directly to a discrete component of the equilibrium self-energy not readily isolated by static ARPES experiments. PMID- 27996011 TI - Bacterial physiology: Life without an essential coenzyme. PMID- 27996010 TI - Super-resolution imaging of light-matter interactions near single semiconductor nanowires. AB - Nanophotonics is becoming invaluable for an expanding range of applications, from controlling the spontaneous emission rate and the directionality of quantum emitters, to reducing material requirements of solar cells by an order of magnitude. These effects are highly dependent on the near field of the nanostructure, which constitutes the evanescent fields from propagating and resonant localized modes. Although the interactions between quantum emitters and nanophotonic structures are increasingly well understood theoretically, directly imaging these interactions experimentally remains challenging. Here we demonstrate a photoactivated localization microscopy-based technique to image emitter-nanostructure interactions. For a 75 nm diameter silicon nanowire, we directly observe a confluence of emission rate enhancement, directivity modification and guided mode excitation, with strong interaction at scales up to 13 times the nanowire diameter. Furthermore, through analytical modelling we distinguish the relative contribution of these effects, as well as their dependence on emitter orientation. PMID- 27996012 TI - Emergent order in the kagome Ising magnet Dy3Mg2Sb3O14. AB - The Ising model-in which degrees of freedom (spins) are binary valued (up/down) is a cornerstone of statistical physics that shows rich behaviour when spins occupy a highly frustrated lattice such as kagome. Here we show that the layered Ising magnet Dy3Mg2Sb3O14 hosts an emergent order predicted theoretically for individual kagome layers of in-plane Ising spins. Neutron-scattering and bulk thermomagnetic measurements reveal a phase transition at ~0.3 K from a disordered spin-ice-like regime to an emergent charge ordered state, in which emergent magnetic charge degrees of freedom exhibit three-dimensional order while spins remain partially disordered. Monte Carlo simulations show that an interplay of inter-layer interactions, spin canting and chemical disorder stabilizes this state. Our results establish Dy3Mg2Sb3O14 as a tuneable system to study interacting emergent charges arising from kagome Ising frustration. PMID- 27996013 TI - A user-friendly modified pore-solid fractal model. AB - The primary objective of this study was to evaluate a range of calculation points on water retention curves (WRC) instead of the singularity point at air-entry suction in the pore-solid fractal (PSF) model, which additionally considered the hysteresis effect based on the PSF theory. The modified pore-solid fractal (M PSF) model was tested using 26 soil samples from Yangling on the Loess Plateau in China and 54 soil samples from the Unsaturated Soil Hydraulic Database. The derivation results showed that the M-PSF model is user-friendly and flexible for a wide range of calculation point options. This model theoretically describes the primary differences between the soil moisture desorption and the adsorption processes by the fractal dimensions. The M-PSF model demonstrated good performance particularly at the calculation points corresponding to the suctions from 100 cm to 1000 cm. Furthermore, the M-PSF model, used the fractal dimension of the particle size distribution, exhibited an accepted performance of WRC predictions for different textured soils when the suction values were >=100 cm. To fully understand the function of hysteresis in the PSF theory, the role of allowable and accessible pores must be examined. PMID- 27996014 TI - Photon pair generation in hydrogenated amorphous silicon microring resonators. AB - We generate photon pairs in a-Si:H microrings using a CW pump, and find the Kerr coefficient of a-Si:H to be 3.73 +/- 0.25 * 10-17m2/W. By measuring the Q factor with coupled power we find that the loss in the a-Si:H micro-rings scales linearly with power, and therefore cannot originate from two photon absorption. Theoretically comparing a-Si:H and c-Si micro-ring pair sources, we show that the high Kerr coefficient of this sample of a-Si:H is best utilized for microrings with Q factors below 103, but that for higher Q factor devices the photon pair rate is greatly suppressed due to the first order loss. PMID- 27996015 TI - Passive exposure to speech sounds induces long-term memory representations in the auditory cortex of adult rats. AB - Experience-induced changes in the functioning of the auditory cortex are prominent in early life, especially during a critical period. Although auditory perceptual learning takes place automatically during this critical period, it is thought to require active training in later life. Previous studies demonstrated rapid changes in single-cell responses of anesthetized adult animals while exposed to sounds presented in a statistical learning paradigm. However, whether passive exposure to sounds can form long-term memory representations remains to be demonstrated. To investigate this issue, we first exposed adult rats to human speech sounds for 3 consecutive days, 12 h/d. Two groups of rats exposed to either spectrotemporal or tonal changes in speech sounds served as controls for each other. Then, electrophysiological brain responses from the auditory cortex were recorded to the same stimuli. In both the exposure and test phase statistical learning paradigm, was applied. The exposure effect was found for the spectrotemporal sounds, but not for the tonal sounds. Only the animals exposed to spectrotemporal sounds differentiated subtle changes in these stimuli as indexed by the mismatch negativity response. The results point to the occurrence of long term memory traces for the speech sounds due to passive exposure in adult animals. PMID- 27996016 TI - Quantum Zeno-type effect and non-Markovianity in a three-level system. AB - We study the coexistence of the quantum Zeno-type effect and non-Markovianity for a system decaying in a structured bosonic environment and subject to a control field. The interaction with the environment induces decay from the excited to the ground level, which, in turn, is coherently coupled to another meta-stable state. The control of the strength of the coherent coupling between the stable levels allows the engineering of both the dissipation and of the memory effects, without modifying neither the system-reservoir interaction, nor environmental properties. We use this framework in two different parameter regimes corresponding to fast (bad cavity limit) and slow dissipation (good cavity limit) in the original and un-controlled qubit system. Our results show a non-monotonic behavior of memory effects when increasing the effectiveness of the Zeno-like freezing. Moreover, we identify a new source of memory effects which allows the persistence of non Markovianity for long times while the excited state has already been depleted. PMID- 27996017 TI - Do invasive quagga mussels alter CO2 dynamics in the Laurentian Great Lakes? AB - The Laurentian Great Lakes have experienced unprecedented ecological and environmental changes, especially after the introduction of invasive quagga mussel (Dreissena rostriformis bugensis). While impacts on ecological functions have been widely recognized, the response of carbon dynamics to invasive species remains largely unknown. We report new CO2 data showing significant increases in pCO2 (up to 800 MUatm in Lake Michigan) and CO2 emission fluxes in most of the Great Lakes compared to those prior to or during the early stage of the colonization of invasive quagga mussels. The increased CO2 supersaturation is most prominent in Lakes Huron and Michigan, followed by Lakes Ontario and Erie, but no evident change was observed in Lake Superior. This trend mirrors the infestation extent of invasive quagga mussels in the Great Lakes and is consistent with the decline in primary production and increase in water clarity observed pre- and post-Dreissena introduction, revealing a close linkage between invasive species and carbon dynamics. The Great Lakes have become a significant CO2 source to the atmosphere, emitting >7.7 +/- 1.0 Tg-C annually, which is higher than the organic carbon burial rate in global inland-seas and attesting to the significant role of the Laurentian Great Lakes in regional/global CO2 budget and cycling. PMID- 27996018 TI - Survival strategies of citrus rootstocks subjected to drought. AB - Two citrus rootstocks, Rangpur lime (RL) and Sunki Maravilha mandarin (SM), were analyzed either ungrafted or grafted with their reciprocal graft combinations or with shoot scions of two commercial citrus varieties: Valencia orange (VO) and Tahiti acid lime (TAL). All graft combinations were subjected to distinct watering regimes: well-watered, severe drought and rehydration. Growth and water relation parameters, gas exchange as well as sugar and hormone profiles were determined. Data indicated that RL adopted a dehydration avoidance strategy and maintained growth, whereas SM adopted a dehydration tolerance strategy focused on plant survival. Compared with RL, the leaves and roots of SM exhibited higher concentrations of abscisic acid and salicylic acid, which induced drought tolerance, and accumulation of carbohydrates such as trehalose and raffinose, which are important reactive oxygen species scavengers. SM rootstocks were able to transfer their survival strategy to the grafted shoot scions (RL, VO, TAL). Because of their contrasting survival strategies, RL reached the permanent wilting point more quickly than SM whereas SM recovered from prolonged droughts more efficiently than RL. This is one of the most complete studies of drought tolerance mechanisms in citrus crops and is the first to use reciprocal grafting to clarify scion/rootstock interactions. PMID- 27996019 TI - Intragenic CFTR Duplication and 5T/12TG Variant in a Patient with Non-Classic Cystic Fibrosis. AB - Cystic fibrosis (CF) is an autosomal recessive disorder characterized by the accumulation of sticky and heavy mucus that can damage several organs. CF shows variable expressivity in affected individuals, but it typically causes respiratory and digestive complications as well as congenital bilateral absence of the vas deferens in males. Individuals with classic CF usually have variants that produce a defective protein from both alleles of the CFTR gene. Individuals with other variants may present with classic, non-classic, or milder forms of CF due to lower levels of functional CFTR protein. This article reports the genetic analysis of a female with features of asthma and mild or non-classic CF. CFTR sequencing demonstrated that she is a carrier for a maternally derived 5T/12TG variant. Deletion/duplication analysis by multiplex ligation-dependent probe amplification (MLPA) showed the presence of an intragenic paternally derived duplication involving exons 7-11 of the CFTR gene. This duplication is predicted to result in the production of a truncated CFTR protein lacking the terminal part of the nucleotide-binding domain 1 (NBD1) and thus is likely to be a non functioning allele. The combination of this large intragenic duplication and 5T/12TG is the probable cause of the mild or non-classic CF features in this individual. PMID- 27996020 TI - Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion. AB - The gene separation anxiety (san) encodes Naa50/San, a N-terminal acetyltransferase required for chromosome segregation during mitosis. Although highly conserved among higher eukaryotes, the mitotic function of this enzyme is still poorly understood. Naa50/San was originally proposed to be required for centromeric sister chromatid cohesion in Drosophila and human cells, yet, more recently, it was also suggested to be a negative regulator of microtubule polymerization through internal acetylation of beta Tubulin. We used genetic and biochemical approaches to clarify the function of Naa50/San during development. Our work suggests that Naa50/San is required during tissue proliferation for the correct interaction between the cohesin subunits Scc1 and Smc3. Our results also suggest a working model where Naa50/San N-terminally acetylates the nascent Scc1 polypeptide, and that this co-translational modification is subsequently required for the establishment and/or maintenance of sister chromatid cohesion. PMID- 27996021 TI - tCRISPRi: tunable and reversible, one-step control of gene expression. AB - The ability to control the level of gene expression is a major quest in biology. A widely used approach employs deletion of a nonessential gene of interest (knockout), or multi-step recombineering to move a gene of interest under a repressible promoter (knockdown). However, these genetic methods are laborious, and limited for quantitative study. Here, we report a tunable CRISPR-cas system, "tCRISPRi", for precise and continuous titration of gene expression by more than 30-fold. Our tCRISPRi system employs various previous advancements into a single strain: (1) We constructed a new strain containing a tunable arabinose operon promoter PBAD to quantitatively control the expression of CRISPR-(d)Cas protein over two orders of magnitude in a plasmid-free system. (2) tCRISPRi is reversible, and gene expression is repressed under knockdown conditions. (3) tCRISPRi shows significantly less than 10% leaky expression. (4) Most important from a practical perspective, construction of tCRISPRi to target a new gene requires only one-step of oligo recombineering. Our results show that tCRISPRi, in combination with recombineering, provides a simple and easy-to-implement tool for gene expression control, and is ideally suited for construction of both individual strains and high-throughput tunable knockdown libraries. PMID- 27996022 TI - Perceptual learning to discriminate the intensity and spatial location of nociceptive stimuli. AB - Accurate discrimination of the intensity and spatial location of nociceptive stimuli is essential to guide appropriate behaviour. The ability to discriminate the attributes of sensory stimuli is continuously refined by practice, even throughout adulthood - a phenomenon called perceptual learning. In the visual domain, perceptual learning to discriminate one of the features that define a visual stimulus (e.g., its orientation) can transfer to a different feature of the same stimulus (e.g., its contrast). Here, we performed two experiments on 48 volunteers to characterize perceptual learning in nociception, which has been rarely studied. We investigated whether learning to discriminate either the intensity or the location of nociceptive stimuli (1) occurs during practice and is subsequently maintained, (2) requires feedback on performance, and (3) transfers to the other, unpractised stimulus feature. First, we found clear evidence that perceptual learning in discriminating both the intensity and the location of nociceptive stimuli occurs, and is maintained for at least 3 hours after practice. Second, learning occurs only when feedback is provided during practice. Finally, learning is largely confined to the feature for which feedback was provided. We discuss these effects in a predictive coding framework, and consider implications for future studies. PMID- 27996023 TI - Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams. AB - High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40-55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction. PMID- 27996025 TI - In vitro synthesis of a Major Facilitator Transporter for specific active transport across Droplet Interface Bilayers. AB - Nature encapsulates reactions within membrane-bound compartments, affording sequential and spatial control over biochemical reactions. Droplet Interface Bilayers are evolving into a valuable platform to mimic this key biological feature in artificial systems. A major issue is manipulating flow across synthetic bilayers. Droplet Interface Bilayers must be functionalised, with seminal work using membrane-inserting toxins, ion channels and pumps illustrating the potential. Specific transport of biomolecules, and notably transport against a concentration gradient, across these bilayers has yet to be demonstrated. Here, we successfully incorporate the archetypal Major Facilitator Superfamily transporter, lactose permease, into Droplet Interface Bilayers and demonstrate both passive and active, uphill transport. This paves the way for controllable transport of sugars, metabolites and other essential biomolecular substrates of this ubiquitous transporter superfamily in DIB networks. Furthermore, cell-free synthesis of lactose permease during DIB formation also results in active transport across the interface bilayer. This adds a specific disaccharide transporter to the small list of integral membrane proteins that can be synthesised via in vitro transcription/translation for applications of DIB-based artificial cell systems. The introduction of a means to promote specific transport of molecules across Droplet Interface Bilayers against a concentration gradient gives a new facet to droplet networks. PMID- 27996024 TI - A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate. AB - Acrophobia, an abnormal fear of heights, is a specific phobia characterized as apprehension cued by the occurrence or anticipation of elevated spaces. It is considered a complex trait with onset influenced by both genetic and environmental factors. Identification of genetic risk variants would provide novel insight into the genetic basis of the fear of heights phenotype and contribute to the molecular-level understanding of its aetiology. Genetic isolates may facilitate identification of susceptibility alleles due to reduced genetic heterogeneity. We took advantage of an internal genetic isolate in Finland in which a distinct acrophobia phenotype appears to be segregating in pedigrees originally ascertained for schizophrenia. We conducted parametric, nonparametric, joint linkage and linkage disequilibrium analyses using a microsatellite marker panel, genotyped in families to search for chromosomal regions correlated with acrophobia. Our results implicated a few regions with suggestive evidence for linkage on chromosomes 4q28 (LOD = 2.17), 8q24 (LOD = 2.09) and 13q21-q22 (LOD = 2.22). We observed no risk haplotypes shared between different families. These results suggest that genetic predisposition to acrophobia in this genetic isolate is unlikely to be mediated by a small number of shared high-risk alleles, but rather has a complex genetic architecture. PMID- 27996027 TI - Localisation and origin of the bacteriochlorophyll-derived photosensitizer in the retina of the deep-sea dragon fish Malacosteus niger. AB - Most deep-sea fish have a single visual pigment maximally sensitive at short wavelengths, approximately matching the spectrum of both downwelling sunlight and bioluminescence. However, Malcosteus niger produces far-red bioluminescence and its longwave retinal sensitivity is enhanced by red-shifted visual pigments, a longwave reflecting tapetum and, uniquely, a bacteriochlorophyll-derived photosensitizer. The origin of the photosensitizer, however, remains unclear. We investigated whether the bacteriochlorophyll was produced by endosymbiotic bacteria within unusual structures adjacent to the photoreceptors that had previously been described in this species. However, microscopy, elemental analysis and SYTOX green staining provided no evidence for such localised retinal bacteria, instead the photosensitizer was shown to be distributed throughout the retina. Furthermore, comparison of mRNA from the retina of Malacosteus to that of the closely related Pachystomias microdon (which does not contain a bacterichlorophyll-derived photosensitzer) revealed no genes of bacterial origin that were specifically up-regulated in Malacosteus. Instead up-regulated Malacosteus genes were associated with photosensitivity and may relate to its unique visual ecology and the chlorophyll-based visual system. We also suggest that the unusual longwave-reflecting, astaxanthin-based, tapetum of Malacosteus may protect the retina from the potential cytotoxicity of such a system. PMID- 27996028 TI - High resolution 3D imaging of living cells with sub-optical wavelength phonons. AB - Label-free imaging of living cells below the optical diffraction limit poses great challenges for optical microscopy. Biologically relevant structural information remains below the Rayleigh limit and beyond the reach of conventional microscopes. Super-resolution techniques are typically based on the non-linear and stochastic response of fluorescent labels which can be toxic and interfere with cell function. In this paper we present, for the first time, imaging of live cells using sub-optical wavelength phonons. The axial imaging resolution of our system is determined by the acoustic wavelength (lambdaa = lambdaprobe/2n) and not on the NA of the optics allowing sub-optical wavelength acoustic sectioning of samples using the time of flight. The transverse resolution is currently limited to the optical spot size. The contrast mechanism is significantly determined by the mechanical properties of the cells and requires no additional contrast agent, stain or label to image the cell structure. The ability to breach the optical diffraction limit to image living cells acoustically promises to bring a new suite of imaging technologies to bear in answering exigent questions in cell biology and biomedicine. PMID- 27996026 TI - Public reporting as a prescriptions quality improvement measure in primary care settings in China: variations in effects associated with diagnoses. AB - The overprovision and irrational use of antibiotics and injections are a major public health concern. Public reporting has been adopted as a strategy to encourage good prescribing practices. This study evaluated the effects of public reporting on antibiotic and injection prescriptions in urban and rural primary care settings in Hubei province, China. A randomized control trial was conducted, with 10 primary care institutions being subject to public reporting and another 10 serving as controls. Prescription indicators were publicly reported monthly over a one-year period. Prescriptions for bronchitis, gastritis and hypertension before and after the intervention were collected. Difference-in-difference tests were performed to estimate the effect size of the intervention on five prescription indicators: percentage of prescriptions containing antibiotics; percentage of prescriptions containing two or more antibiotics; percentage of prescriptions containing injections; percentage of prescriptions containing antibiotic injections; and average prescription cost. Public reporting had varied effects on prescriptions for different diagnoses. It reduced antibiotic prescribing for gastritis. Prescriptions containing injections, especially antibiotic injections, also declined, but only for gastritis. A reduction of prescription costs was noted for bronchitis and gastritis. Public reporting has the potential to encourage good prescribing practices. Its effects vary with different disease conditions. PMID- 27996029 TI - Structure of Crenezumab Complex with Abeta Shows Loss of beta-Hairpin. AB - Accumulation of amyloid-beta (Abeta) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of Abeta remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Abeta monoclonal IgG4 that binds multiple forms of Abeta, with higher affinity for aggregated forms, and that blocks Abeta aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with Abeta. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab's versatile binding profile. We find interactions consistent with high affinity for multiple forms of Abeta, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Abeta and breaks an essential salt-bridge characteristic of the beta-hairpin conformation, eliminating features characteristic of the basic organization in Abeta oligomers and fibrils, and explains crenezumab's inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumab's unique mechanism of action, particularly regarding Abeta oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy. PMID- 27996030 TI - SLINGER: large-scale learning for predicting gene expression. AB - Recent studies have established that single nucleotide polymorphisms are sufficient to build accurate predictive models of gene expression. Gamazon, et al., found that gene expression values predicted from cis neighborhood SNPs show statistical association with disease status. In this work, we remove the cis neighborhood constraint during the learning process, and propose a novel predictive approach called SLINGER. We demonstrate that models drawing from a genome-wide set of SNPs are able to predict expression for more genes than the ones built on cis neighborhood only. Results indicate that these new models significantly improve accuracy for a large number of genes. Thanks to a penalized linear model, we also show that the number of features used in our models remains comparable to the cis-only models. Finally, SLINGER application on seven Wellcome Trust Case-Control Consortium genome-wide association studies demonstrate that compared to a cis-only approach, our models lead to associations with greater fidelity to actual gene expression values. PMID- 27996031 TI - Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity. AB - Severe intrauterine ischemia is detrimental to the developing brain. The impact of mild intrauterine hypoperfusion on neurological development, however, is still unclear. We induced mild intrauterine hypoperfusion in rats on embryonic day 17 via arterial stenosis with metal microcoils wrapped around the uterine and ovarian arteries. All pups were born with significantly decreased birth weights. Decreased gray and white matter areas were observed without obvious tissue damage. Pups presented delayed newborn reflexes, muscle weakness, and altered spontaneous activity. The levels of proteins indicative of inflammation and stress in the vasculature, i.e., RANTES, vWF, VEGF, and adiponectin, were upregulated in the placenta. The levels of mRNA for proteins associated with axon and astrocyte development were downregulated in fetal brains. The present study demonstrates that even mild intrauterine hypoperfusion can alter neurological development, which mimics the clinical signs and symptoms of children with neurodevelopmental disorders born prematurely or with intrauterine growth restriction. PMID- 27996034 TI - Specific arrangements of species dominance can be more influential than evenness in maintaining ecosystem process and function. AB - The ecological consequences of species loss are widely studied, but represent an end point of environmental forcing that is not always realised. Changes in species evenness and the rank order of dominant species are more widespread responses to directional forcing. However, despite the repercussions for ecosystem functioning such changes have received little attention. Here, we experimentally assess how the rearrangement of species dominance structure within specific levels of evenness, rather than changes in species richness and composition, affect invertebrate particle reworking and burrow ventilation behaviour - important moderators of microbial-mediated remineralisation processes in benthic environments - and associated levels of sediment nutrient release. We find that the most dominant species exert a disproportionate influence on functioning at low levels of evenness, but that changes in biomass distribution and a change in emphasis in species-environmental interactions become more important in governing system functionality as evenness increases. Our study highlights the need to consider the functional significance of alterations to community attributes, rather than to solely focus on the attainment of particular levels of diversity when safeguarding biodiversity and ecosystems that provide essential services to society. PMID- 27996033 TI - The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy. AB - Autophagy and the unfolded protein response (UPR) both promote activation of hepatic stellate cells (HSC), however the link between the two stimuli remains unclear. Here we have explored the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways and sought to establish the interdependence between autophagy and the UPR during HSC activation. XBP1 induction accompanied both culture-based HSC activation and ER stress induced by tunicamycin. Ectopic overexpression of XBP1 induced collagen 1-alpha expression in HSCs, which was inhibited by knockdown of ATG7, a critical autophagy mediator. Genome-wide transcriptomic profiling indicated an upregulation of collagen synthesis pathways, but not of the transforming growth factor (TGF)-b pathway, a canonical fibrogenic driver, suggesting that XBP1 activates a specific subset of fibrogenesis pathways independent of TGF-beta1. XBP1 target gene signatures were significantly induced in rodent liver fibrosis models (n = 3-5) and in human samples of non-alcoholic fatty liver disease (NAFLD) (n = 72-135). Thus, XBP1 mediated UPR contributes to fibrogenic HSC activation and is functionally linked to cellular autophagy. PMID- 27996032 TI - Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury. AB - Classical antimicrobial drugs target proliferation and therefore place microbes under extreme selective pressure to evolve resistance. Alternative drugs that target bacterial virulence without impacting survival directly offer an attractive solution to this problem, but to date few such molecules have been discovered. We previously discovered a widespread group of bacterial adhesins, termed Multivalent Adhesion Molecules (MAMs) that are essential for initial binding of bacteria to host tissues and virulence. Thus, targeting MAM-based adherence is a promising strategy for displacing pathogens from host tissues and inhibiting infection. Here, we show that topical application of polymeric microbeads functionalized with the adhesin MAM7 to a burn infected with multidrug resistant Pseudomonas aeruginosa substantially decreased bacterial loads in the wound and prevented the spread of the infection into adjacent tissues. As a consequence, the application of this adhesion inhibitor allowed for vascularization and wound healing, and maintained local and systemic inflammatory responses to the burn. We propose that MAM7-functionalized microbeads can be used as a topical treatment, to reduce bacterial attachment and hence prevent bacterial colonization and infection of wounds. As adhesion is not required for microbial survival, this anti-infective strategy has the potential to treat multidrug-resistant infections and limit the emergence of drug-resistant pathogens. PMID- 27996035 TI - Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity. AB - Tumor microenvironment has been recognized as a key determinant of tumor formation and metastasis, but how tumor microenvironment is affected by nanomaterials is essentially unknown. Here, we investigated whether carbon nanotubes (CNTs), a widely used nanomaterial with known carcinogenic potential, can affect cancer-associated fibroblasts (CAFs), which are a key component of tumor microenvironment that provides necessary support for tumor growth. We show for the first time that single-walled CNT and to a lesser extent multi-walled and its COOH-functionalized form induced CAF-like cells, which are non-tumorigenic in animals, but promote tumor growth of human lung carcinoma and CNT-transformed lung epithelial cells. The mechanism by which CNT-induced CAF-like cells promote tumor growth involved the acquisition of cancer stem cells (CSCs) in cancer population. Gene knockdown experiments showed that an expression of podoplanin on CAF-like cells is essential for their effects, indicating the functional role of CAF-like cells and podoplanin in CNT tumorigenic process. Our findings unveil a novel mechanism of CNT-induced carcinogenesis through the induction of CAF-like cells that support CSCs and drive tumor formation. Our results also suggest the potential utility of podoplanin as a mechanism-based biomarker for rapid screening of carcinogenicity of CNTs and related nanomaterials for their safer design. PMID- 27996036 TI - Conformation-driven quantum interference effects mediated by through-space conjugation in self-assembled monolayers. AB - Tunnelling currents through tunnelling junctions comprising molecules with cross conjugation are markedly lower than for their linearly conjugated analogues. This effect has been shown experimentally and theoretically to arise from destructive quantum interference, which is understood to be an intrinsic, electronic property of molecules. Here we show experimental evidence of conformation-driven interference effects by examining through-space conjugation in which pi conjugated fragments are arranged face-on or edge-on in sufficiently close proximity to interact through space. Observing these effects in the latter requires trapping molecules in a non-equilibrium conformation closely resembling the X-ray crystal structure, which we accomplish using self-assembled monolayers to construct bottom-up, large-area tunnelling junctions. In contrast, interference effects are completely absent in zero-bias simulations on the equilibrium, gas-phase conformation, establishing through-space conjugation as both of fundamental interest and as a potential tool for tuning tunnelling charge transport in large-area, solid-state molecular-electronic devices. PMID- 27996037 TI - Estrogen-induced SDF-1alpha production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment. AB - Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF 1alpha) by cancer-associated fibroblasts (CAFs) to promote the progression of ER negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1alpha and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1alpha by CAFs extracted from BC patients. Recombinant SDF-1alpha could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1alpha/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF 1alpha, which can recruit MDSCs to the tumor microenvironment to exert tumor promoting effects. PMID- 27996038 TI - Metabolic engineering of Corynebacterium crenatium for enhancing production of higher alcohols. AB - Biosynthesis approaches for the production of higher alcohols as a source of alternative fossil fuels have garnered increasing interest recently. However, there is little information available in the literature about using undirected whole-cell mutagenesis (UWCM) in vivo to improve higher alcohols production. In this study, for the first time, we approached this question from two aspects: first preferentially improving the capacity of expression host, and subsequently optimizing metabolic pathways using multiple genetic mutations to shift metabolic flux toward the biosynthetic pathway of target products to convert intermediate 2 keto acid compounds into diversified C4~C5 higher alcohols using UWCM in vivo, with the aim of improving the production. The results demonstrated the production of higher alcohols including isobutanol, 2-methyl-1-butanol, 3-methyl-1-butanol from glucose and duckweed under simultaneous saccharification and fermentation (SSF) scheme were higher based on the two aspects compared with only the use of wild-type stain as expression host. These findings showed that the improvement via UWCM in vivo in the two aspects for expression host and metabolic flux can facilitate the increase of higher alcohols production before using gene editing technology. Our work demonstrates that a multi-faceted approach for the engineering of novel synthetic pathways in microorganisms for improving biofuel production is feasible. PMID- 27996039 TI - Loss of miR-140 is a key risk factor for radiation-induced lung fibrosis through reprogramming fibroblasts and macrophages. AB - Radiation-induced lung fibrosis (RILF) is a common side effect for patients with thoracic cancer receiving radiation therapy. RILF is characterized by excessive collagen deposition mediated by TGF-beta1 and its downstream factor SMAD3, but the exact molecular mechanism leading to fibrosis is yet to be determined. The present study investigated the impact of miR-140 on RILF development. Herein, we first found that loss of miR-140 is a marker of fibrotic lung tissue in vivo one year post-radiation treatment. We showed that miR-140 knockout primary lung fibroblasts have a higher percentage of myofibroblasts compared to wild type primary lung fibroblasts, and that loss of miR-140 expression leads to increased activation of TGF-beta1 signaling as well as increased myofibroblast differentiation. We also identified fibronectin as a novel miR-140 target gene in lung fibroblasts. Finally, we have shown that miR-140 deficiency promotes accumulation of M2 macrophages in irradiated lung tissues. These data suggest that miR-140 is a key protective molecule against RILF through inhibiting myofibroblast differentiation and inflammation. PMID- 27996040 TI - Compound to Extract to Formulation: a knowledge-transmitting approach for metabolites identification of Gegen-Qinlian Decoction, a traditional Chinese medicine formula. AB - Herbal medicines usually contain a large group of chemical components, which may be transformed into more complex metabolites in vivo. In this study, we proposed a knowledge-transmitting strategy for metabolites identification of compound formulas. Gegen-Qinlian Decoction (GQD) is a classical formula in traditional Chinese medicine (TCM). It is widely used to treat diarrhea and diabetes in clinical practice. However, only tens of metabolites could be detected using conventional approaches. To comprehensively identify the metabolites of GQD, a "compound to extract to formulation" strategy was established in this study. The metabolic pathways of single representative constituents in GQD were studied, and the metabolic rules were transmitted to chemically similar compounds in herbal extracts. After screening diversified metabolites from herb extracts, the knowledge was summarized to identify the metabolites of GQD. Tandem mass spectrometry (MSn), fragment-based scan (NL, PRE), and selected reaction monitoring (SRM) were employed to identify, screen, and monitor the metabolites, respectively. Using this strategy, we detected 131 GQD metabolites (85 were newly generated) in rats biofluids. Among them, 112 metabolites could be detected when GQD was orally administered at a clinical dosage (12.5 g/kg). This strategy could be used for systematic metabolites identification of complex Chinese medicine formulas. PMID- 27996041 TI - Leptospira surface adhesin (Lsa21) induces Toll like receptor 2 and 4 mediated inflammatory responses in macrophages. AB - Leptospirosis is zoonotic and emerging infectious disease of global importance. Little is understood about Leptospira pathogenesis and host immune response. In the present work we have investigated how Leptospira modulates the host innate immune response mediated by Toll-like receptors (TLRs) via surface exposed proteins. We screened Leptospira outer membrane/surface proteins for their ability to activate/inhibit TLR2/4 signaling in HEK293 cell lines. Of these the 21 kDa Leptospira surface adhesin, Lsa21 had strong TLR2 and TLR4 activity leading to production of proinflammatory cytokines and expression of costimulatory molecules in mouse macrophages. This activity of Lsa21 on innate response was dependent on activation of mitogen activated protein kinases (MAPKs) via stimulating the rapid phosphorylation of p38, JNK and activation of transcription factor NF-kappaB. Additionally, neutralizing antibodies against TLR2 and TLR4 significantly inhibited cytokine secretion and attenuated Lsa21 induced phosphorylation of p38 and JNK. Furthermore, Lsa21 induced cytokine levels were significantly lower in TLR2-/- and TLR4-/- than in wild type mouse macrophage cell lines. Confocal microscopy and molecular docking confirmed that Lsa21 interacted with both TLR2 and TLR4. These results indicate that Lsa21 is a potent TLR2 and TLR4 agonist that induces strong innate response and may play important role in Leptospira pathogenesis. PMID- 27996042 TI - Photochemical solution processing of films of metastable phases for flexible devices: the beta-Bi2O3 polymorph. AB - The potential of UV-light for the photochemical synthesis and stabilization of non-equilibrium crystalline phases in thin films is demonstrated for the beta Bi2O3 polymorph. The pure beta-Bi2O3 phase is thermodynamically stable at high temperature (450-667 degrees C), which limits its applications in devices. Here, a tailored UV-absorbing bismuth(III)-N-methyldiethanolamine complex is selected as an ideal precursor for this phase, in order to induce under UV-light the formation of a -Bi-O-Bi- continuous network in the deposited layers and the further conversion into the beta-Bi2O3 polymorph at a temperature as low as 250 degrees C. The stabilization of the beta-Bi2O3 films is confirmed by their conductivity behavior and a thorough characterization of their crystal structure. This is also supported by their remarkable photocatalytic activity. Besides, this processing method has allowed us for the first time the preparation of beta-Bi2O3 films on flexible plastic substrates, which opens new opportunities for using these materials in potential applications not available until now (e.g., flexible photocatalytic reactors, self-cleaning surfaces or wearable antimicrobial fabrics). Therefore, photochemical solution deposition (PCSD) demonstrates to be not only an efficient approach for the low temperature processing of oxide films, but also an excellent alternative for the stabilization of metastable phases. PMID- 27996043 TI - Probabilistic Assessment of Above Zone Pressure Predictions at a Geologic Carbon Storage Site. AB - Carbon dioxide (CO2) storage into geological formations is regarded as an important mitigation strategy for anthropogenic CO2 emissions to the atmosphere. This study first simulates the leakage of CO2 and brine from a storage reservoir through the caprock. Then, we estimate the resulting pressure changes at the zone overlying the caprock also known as Above Zone Monitoring Interval (AZMI). A data driven approach of arbitrary Polynomial Chaos (aPC) Expansion is then used to quantify the uncertainty in the above zone pressure prediction based on the uncertainties in different geologic parameters. Finally, a global sensitivity analysis is performed with Sobol indices based on the aPC technique to determine the relative importance of different parameters on pressure prediction. The results indicate that there can be uncertainty in pressure prediction locally around the leakage zones. The degree of such uncertainty in prediction depends on the quality of site specific information available for analysis. The scientific results from this study provide substantial insight that there is a need for site specific data for efficient predictions of risks associated with storage activities. The presented approach can provide a basis of optimized pressure based monitoring network design at carbon storage sites. PMID- 27996044 TI - Translational regulation of APOBEC3G mRNA by Vif requires its 5'UTR and contributes to restoring HIV-1 infectivity. AB - The essential HIV-1 viral infectivity factor (Vif) allows productive infection of non-permissive cells expressing cytidine deaminases APOBEC3G (A3G) and A3F by decreasing their cellular level, and preventing their incorporation into virions. Unlike the Vif-induced degradation of A3G, the functional role of the inhibition of A3G translation by Vif remained unclear. Here, we show that two stem-loop structures within the 5'-untranslated region of A3G mRNA are crucial for translation inhibition by Vif in cells, and most Vif alleles neutralize A3G translation efficiently. Interestingly, K26R mutation in Vif abolishes degradation of A3G by the proteasome but has no effect at the translational level, indicating these two pathways are independent. These two mechanisms, proteasomal degradation and translational inhibition, similarly contribute to decrease the cellular level of A3G by Vif and to prevent its incorporation into virions. Importantly, inhibition of A3G translation is sufficient to partially restore viral infectivity in the absence of proteosomal degradation. These findings demonstrate that HIV-1 has evolved redundant mechanisms to specifically inhibit the potent antiviral activity of A3G. PMID- 27996045 TI - PI16 is a shear stress and inflammation-regulated inhibitor of MMP2. AB - Raised endothelial shear stress is protective against atherosclerosis but such protection may be lost at sites of inflammation. We found that four splice variants of the peptidase inhibitor 16 (PI16) mRNA are among the most highly shear stress regulated transcripts in human coronary artery endothelial cells (HCAECs), in vitro but that expression is reduced by inflammatory mediators TNFalpha and IL-1beta. Immunohistochemistry demonstrated that PI16 is expressed in human coronary endothelium and in a subset of neointimal cells and medial smooth muscle cells. Adenovirus-mediated PI16 overexpression inhibits HCAEC migration and secreted matrix metalloproteinase (MMP) activity. Moreover, PI16 inhibits MMP2 in part by binding an exposed peptide loop above the active site. Our results imply that, at high endothelial shear stress, PI16 contributes to inhibition of protease activity; protection that can be reversed during inflammation. PMID- 27996046 TI - Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. AB - Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. A total of 8.7% of TGCT families carry rare disruptive mutations in the cilia-microtubule genes (CMG) as compared with 0.5% of controls (P=2.1 * 10-8). The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers. DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1hu255h(+/-) zebrafish model, which has a 94% risk of TGCT. Our data implicate cilia-microtubule inactivation as a cause of TGCT and provide evidence for CMGs as cancer susceptibility genes. PMID- 27996047 TI - A genome-scale Escherichia coli kinetic metabolic model k-ecoli457 satisfying flux data for multiple mutant strains. AB - Kinetic models of metabolism at a genome scale that faithfully recapitulate the effect of multiple genetic interventions would be transformative in our ability to reliably design novel overproducing microbial strains. Here, we introduce k ecoli457, a genome-scale kinetic model of Escherichia coli metabolism that satisfies fluxomic data for wild-type and 25 mutant strains under different substrates and growth conditions. The k-ecoli457 model contains 457 model reactions, 337 metabolites and 295 substrate-level regulatory interactions. Parameterization is carried out using a genetic algorithm by simultaneously imposing all available fluxomic data (about 30 measured fluxes per mutant). The Pearson correlation coefficient between experimental data and predicted product yields for 320 engineered strains spanning 24 product metabolites is 0.84. This is substantially higher than that using flux balance analysis, minimization of metabolic adjustment or maximization of product yield exhibiting systematic errors with correlation coefficients of, respectively, 0.18, 0.37 and 0.47 (k ecoli457 is available for download at http://www.maranasgroup.com). PMID- 27996048 TI - High expression of GFAT1 predicts poor prognosis in patients with pancreatic cancer. AB - Pancreatic cancer is one of the most lethal of all types of cancer, with the 5 year survival rate ranging only at 6-7%. The aberrant glucose metabolism is one of the hallmarks of cancer cells, and as a branch of glucose metabolism, hexosamine biosynthesis pathway (HBP) has been reported to play a critical role in the insulin resistance and progression of cancer. Glutamine:fructose-6 phosphate amidotransferase (GFAT1) is the rate-limiting enzyme of the HBP; nevertheless, the prognostic value of GFAT1 in pancreatic cancer remains elusive. In this study, we found that the expression of GFAT1 was increased in pancreatic cancer samples compared to peri-tumor tissues. High expression of GFAT1 was positively associated with lymph node metastasis, pTNM stage and shorter overall survival (OS) in pancreatic cancer patients. GFAT1 was identified as an independent prognosticator for OS, and combining GFAT1 expression with pTNM stage generated a predictive nomogram, which showed better prognostic efficiency for OS in patients with pancreatic cancer. In summary, high GFAT1 expression is identified as an independent predictor of adverse clinical outcome in our small number of pancreatic cancer patients, and the practical prognostic nomogram model may help clinicians in decision making and the design of clinical studies. PMID- 27996049 TI - Intelligence and eeg measures of information flow: efficiency and homeostatic neuroplasticity. AB - The purpose of this study was to explore the relationship between the magnitude of EEG information flow and intelligence. The electroencephalogram (EEG) was recorded from 19 scalp locations from 371 subjects ranging in age from 5 years to 17.6 years. The Wechler Intelligence Scale for Children (WISC-R) was administered for individuals between 5 years of age and 16 years and the Weschler Adult Intelligence Scale revised (WAIS-R) was administered to subjects older than 16 years to estimate I.Q. The phase slope index estimated the magnitude of information flow between all electrode combinations for difference frequency bands. Discriminant analyses were performed between high I.Q. (>120) and low I.Q. groups (<90). The magnitude of information flow was inversely related to I.Q. especially in the alpha and beta frequency bands. Long distance inter-electrode distances exhibited greater information flow than short inter-electrode distances. Frontal-parietal correlations were the most significant. It is concluded that higher I.Q. is related to increased efficiency of local information processing and reduced long distance compensatory dynamics that supports a small-world model of intelligence. PMID- 27996051 TI - Engineered metabarrier as shield from seismic surface waves. AB - Resonant metamaterials have been proposed to reflect or redirect elastic waves at different length scales, ranging from thermal vibrations to seismic excitation. However, for seismic excitation, where energy is mostly carried by surface waves, energy reflection and redirection might lead to harming surrounding regions. Here, we propose a seismic metabarrier able to convert seismic Rayleigh waves into shear bulk waves that propagate away from the soil surface. The metabarrier is realized by burying sub-wavelength resonant structures under the soil surface. Each resonant structure consists of a cylindrical mass suspended by elastomeric springs within a concrete case and can be tuned to the resonance frequency of interest. The design allows controlling seismic waves with wavelengths from 10-to 100 m with meter-sized resonant structures. We develop an analytical model based on effective medium theory able to capture the mode conversion mechanism. The model is used to guide the design of metabarriers for varying soil conditions and validated using finite-element simulations. We investigate the shielding performance of a metabarrier in a scaled experimental model and demonstrate that surface ground motion can be reduced up to 50% in frequency regions below 10 Hz, relevant for the protection of buildings and civil infrastructures. PMID- 27996050 TI - Liver Enzymes and Risk of Ischemic Heart Disease and Type 2 Diabetes Mellitus: A Mendelian Randomization Study. AB - We used Mendelian randomization to estimate the causal effects of the liver enzymes, alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT), on diabetes and cardiovascular disease, using genetic variants predicting these liver enzymes at genome wide significance applied to extensively genotyped case-control studies of diabetes (DIAGRAM) and coronary artery disease (CAD)/myocardial infarction (MI) (CARDIoGRAMplusC4D 1000 Genomes). Genetically higher ALT was associated with higher risk of diabetes, odds ratio (OR) 2.99 per 100% change in concentration (95% confidence interval (CI) 1.62 to 5.52) but ALP OR 0.92 (95% CI 0.71 to 1.19) and GGT OR 0.88 (95% CI 0.75 to 1.04) were not. Genetically predicted ALT, ALP and GGT were not clearly associated with CAD/MI (ALT OR 0.74, 95% CI 0.54 to 1.01, ALP OR 0.86, 95% CI 0.64 to 1.16 and GGT OR 1.08, 95% CI 0.97 to 1.19). We confirm observations of ALT increasing the risk of diabetes, but cannot exclude the possibility that higher ALT may protect against CAD/MI. We also cannot exclude the possibility that GGT increases the risk of CAD/MI and reduces the risk of diabetes. Informative explanations for these potentially contradictory associations should be sought. PMID- 27996053 TI - Anisotropic magnetic coupling with a two-dimensional characteristic in noncentrosymmetric Cr11Ge19. AB - In this work, we successfully synthesize the single crystal Cr11Ge19. The magnetism of the noncentrosymmetric Cr11Ge19 with itinerant ferromagnetic ground state is thoroughly investigated on the single crystal. Based on the variation measurements including the angular rotation, temperature, and magnetic field dependence of magnetization, we find that this material exhibits strong magnetic anisotropy along the c-axis. To clearly reveal the magnetic interactions, the critical behavior is studied using the modified Arrott plot, the Kouvel-Fisher method, and the critical isotherm technique. Combining these different methods, three main critical exponents (beta, gamma, and delta) are obtained. The critical exponent beta is close to the theoretical prediction of a three-dimensional XY model with spin-dimensionality n = 2, indicating two-dimensional magnetic coupling. Meanwhile, the critical exponent gamma suggests that the magnetic interaction is of long-range type with magnetic exchange distance decaying as J(r) ~ r-4.61. We propose that the ferromagnetic ground state of Cr11Ge19 is formed by the polarized magnetic moments along the c-axis, while the long-range magnetic coupling is established within the ab plane. PMID- 27996052 TI - Distinct roles of short and long thymic stromal lymphopoietin isoforms in house dust mite-induced asthmatic airway epithelial barrier disruption. AB - Loss of airway epithelial integrity contributes significantly to asthma pathogenesis. Thymic stromal lymphopoietin (TSLP) may have dual immunoregulatory roles. In inflammatory disorders of the bowel, the long isoform of TSLP (lfTSLP) promotes inflammation while the short isoform (sfTSLP) inhibits inflammation. We hypothesize that lfTSLP contributes to house dust mite (HDM)-induced airway epithelial barrier dysfunction and that synthetic sfTSLP can prevent these effects. In vitro, airway epithelial barrier function was assessed by monitoring transepithelial electrical resistance, fluorescent-dextran permeability, and distribution of E-cadherin and beta-catenin. In vivo, BALB/c mice were exposed to HDM by nasal inhalation for 5 consecutive days per week to establish an asthma model. sfTSLP and 1alpha,25-Dihydroxyvitamin D3 (1,25D3) were administered 1 h before HDM exposure. After 8 weeks, animal lung function tests and pathological staining were performed to evaluate asthma progression. We found that HDM and lfTSLP impaired barrier function. Treatment with sfTSLP and 1,25D3 prevented HDM induced airway epithelial barrier disruption. Moreover, sfTSLP and 1,25D3 treatment ameliorated HDM-induced asthma in mice. Our data emphasize the importance of the different expression patterns and biological properties of sfTSLP and lfTSLP. Moreover, our results indicate that sfTSLP and 1,25D3 may serve as novel therapeutic agents for individualized treatment of asthma. PMID- 27996054 TI - Size-dependent and tunable crystallization of GeSbTe phase-change nanoparticles. AB - Chalcogenide-based nanostructured phase-change materials (PCMs) are considered promising building blocks for non-volatile memory due to their high write and read speeds, high data-storage density, and low power consumption. Top-down fabrication of PCM nanoparticles (NPs), however, often results in damage and deterioration of their useful properties. Gas-phase condensation based on magnetron sputtering offers an attractive and straightforward solution to continuously down-scale the PCMs into sub-lithographic sizes. Here we unprecedentedly present the size dependence of crystallization for Ge2Sb2Te5 (GST) NPs, whose production is currently highly challenging for chemical synthesis or top-down fabrication. Both amorphous and crystalline NPs have been produced with excellent size and composition control with average diameters varying between 8 and 17 nm. The size-dependent crystallization of these NPs was carefully analyzed through in-situ heating in a transmission electron microscope, where the crystallization temperatures (Tc) decrease when the NPs become smaller. Moreover, methane incorporation has been observed as an effective method to enhance the amorphous phase stability of the NPs. This work therefore elucidates that GST NPs synthesized by gas-phase condensation with tailored properties are promising alternatives in designing phase-change memories constrained by optical lithography limitations. PMID- 27996055 TI - Experimental test of genuine multipartite nonlocality under the no-signalling principle. AB - Genuine multipartite nonlocality (GMN) has been recognized as the strongest form of multipartite quantum correlation. However, there exist states that cannot violate the Svetlichny inequality derived from the standard definition of GMN, even though they possess GMN properties. The reason is that the standard definition of GMN allows correlations that permit signalling among parties, which is inconsistent with an operational definition. Here, for the first time, we present an experimental test of GMN in the no-signalling scenario, with a three photon pure state |psis> and a noisy W state. The experimental results show that these states cannot violate the Svetlichny inequality. However, our results also demonstrate that they do violate a new inequality derived from the definition of GMN based on the no-signalling principle, i.e., these states can exhibit GMN under the requirement of no-signalling. Our results will be useful for the study and applications of GMN in quantum communications and quantum computation. PMID- 27996056 TI - The hydrogen-bond collective dynamics in liquid methanol. AB - The relatively simple molecular structure of hydrogen-bonded (HB) systems is often belied by their exceptionally complex thermodynamic and microscopic behaviour. For this reason, after a thorough experimental, computational and theoretical scrutiny, the dynamics of molecules in HB systems still eludes a comprehensive understanding. Aiming at shedding some insight into this topic, we jointly used neutron Brillouin scattering and molecular dynamics simulations to probe the dynamics of a prototypical hydrogen-bonded alcohol, liquid methanol. The comparison with the most thoroughly investigated HB system, liquid water, pinpoints common behaviours of their THz microscopic dynamics, thereby providing additional information on the role of HB dynamics in these two systems. This study demonstrates that the dynamic behaviour of methanol is much richer than what so far known, and prompts us to establish striking analogies with the features of liquid and supercooled water. In particular, based on the strong differences between the structural properties of the two systems, our results suggest that the assignment of some dynamical properties to the tetrahedral character of water structure should be questioned. We finally highlight the similarities between the characteristic decay times of the time correlation function, as obtained from our data and the mean lifetime of hydrogen bond known in literature. PMID- 27996057 TI - Associations between dairy food consumption and chronic kidney disease in older adults. AB - We aimed to assess the association between dairy product consumption and calcium intake with the prevalence and 10-year incidence of chronic kidney disease (CKD). 1185 participants aged >=50 years at baseline were examined between 1992-4 and 2002-4. Dietary data were collected using a food frequency questionnaire, and servings of dairy food consumption were calculated. Baseline biochemistry including serum creatinine was measured. CKD was defined as Modification of Diet in Renal Disease Study estimated glomerular filtration rate <60 mL.min-1.1.73 m 2. Cross-sectional analysis showed that older adults in the highest quintile compared to the lowest quintile (reference group) of low/reduced fat dairy food consumption had reduced odds of CKD, multivariable-adjusted odds ratio, OR, 0.64 (95% confidence intervals, CI, 0.43-0.96). Increasing total intake of dietary calcium was associated with reduced odds of CKD (P-trend = 0.02); comparing highest versus lowest quintile: OR 0.62 (95% CI 0.42-0.92). Participants in the second versus first quintile of low/reduced fat dairy food consumption at baseline had 49% reduced risk of CKD 10 years later, OR 0.51 (95% CI 0.29-0.89). Higher consumption of low/reduced fat dairy foods was independently associated with lower risk of CKD. Additional population-based studies are warranted to confirm these findings. PMID- 27996058 TI - Bend it like Beckham! The Ethics of Genetically Testing Children for Athletic Potential. AB - The recent boom of direct-to-consumer (DTC) genetic tests, aimed at measuring children's athletic potential, is the latest wave in the 'pre professionalization' of children that has characterized, especially but not exclusively, the USA in the last 15 years or so. In this paper, I analyse the use of DTC genetic tests, sometimes coupled with more traditional methods of 'talent scouting', to assess a child's predisposition to athletic performance. I first discuss the scientific evidence at the basis of these tests, and the parental decision in terms of education, and of investing in the children's future, taken on the basis of the results of the tests. I then discuss how these parental practices impact on the children's right to an open future, and on their developing sense of autonomy. I also consider the meaning and role of sports in childhood, and conclude that the use of DTC genetic tests to measure children's athletic potential should be seen as a 'wake up' call for other problematic parental attitudes aimed at scouting and developing children's talent. PMID- 27996059 TI - The effect of perceived stress on life satisfaction : The mediating effect of self-efficacy. AB - Lazarus and Folkman's theory of cognitive appraisal of coping inspired the present study to test a mediation model examining the effects of self-efficacy on the relationship between perceived stress and life satisfaction. A total of 282 Korean undergraduate students participated in the present study. Perceived Stress Scale, the Satisfaction with Life Scale, and the Self Efficacy Scale were used for this study. A series of hierarchical regressions investigated the mediating effect of self-efficacy on the relationship between perceived stress and life satisfaction. Results indicated that there was a partial mediation effect of self efficacy on the relation between perceived stress and life satisfaction. The results supported the mediation of secondary cognitive appraisal (i.e., self efficacy) on the relationship between primary cognitive appraisal (i.e., perceived stress) and life satisfaction among South Korean college students. Implications of the present study and future research suggestions are discussed. PMID- 27996061 TI - Treating patients on new anticoagulant drugs. PMID- 27996062 TI - Embodied innovation and regulation of medical technoscience: transformations in cancer patienthood. AB - Biomedical advances are transforming the diagnosis and treatment of disease. Patienthood is also transforming, as patients actively participate in research, innovation and regulation of novel technologies and therapies. In this paper we explore the new kinds of practices that patients are performing in their roles as research subject, co-researchers, donors, campaigners, representatives and consumers of novel stratified therapies. We outline their embodied contributions to clinical trials, biobanks and stratified therapies prior to, during and after having cancer. Exploring how patienthood involves donating more than tissue or data to these developments, we consider their emotional and identity work which informs and shapes the novel diagnostics and therapies being developed. We also consider how this kind of work is stratified according to the social and biological location of participants, and end by reflecting on the implications of our analysis for the organisation and regulation of biomedicine. PMID- 27996060 TI - Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice. AB - Background: Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all mutant embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve.Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates. PMID- 27996063 TI - Securitization, alterity, and the state Human (in)security on an Amazonian frontier. AB - Focusing on the region surrounding the Maroni River, which forms the border between Suriname and French Guiana, we examine how relations between different state and non-state social groups are articulated in terms of security. The region is characterised by multiple "borders" and frontiers of various kinds, the state boundary having the features of an interface or contact zone. Several key collectivities meet in this border zone: native Amazonians, tribal Maroon peoples, migrant Brazilian gold prospectors, and metropolitan French state functionaries. We explore the relationships between these different sets of actors and describe how their mutual encounters center on discourses of human and state security, thus challenging the commonly held view of the region as a stateless zone and showing that the "human security" of citizens from the perspective of the state may compete with locally salient ideas or experiences of well-being. PMID- 27996065 TI - Highly efficient electrochemiluminescence labels comprising iridium(iii) complexes. AB - Improving the performance of labeling agents is crucial to the further development of electrochemiluminescence (ECL) related technologies. Although a large number of ECL luminophores beyond ruthenium complexes have been reported so far, there is still a scarcity of studies involving novel ECL labeling agents. Herein, five novel iridium ECL labels and one control label comprising a ruthenium complex have been rationally designed and thoroughly characterized using photophysical techniques, theoretical calculations and electrochemical characterization to assess the ECL properties in this work. Both in coreactant assisted potential scan experiments and through an annihilation approach, most of these novel iridium labels exhibit equivalent or even-stronger ECL signals than tri-2,2'-bipyridylruthenium(ii) [abbreviated as Ru(bpy)32+] under the same experimental conditions. Most importantly, using the same labeling protocol, bovine serum albumin (BSA) labeled with an iridium label (label 3 in this work) exhibits a much more intense ECL signal (1.9 times) than the same amount labeled with a traditional ruthenium complex (Ru-based Label in this work) in ProCell buffer solution. In addition to the advantage of exhibiting various emission colors, the novel iridium labels reported in this work may offer insight for the further development of ECL-based analytical technology. PMID- 27996064 TI - Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis. AB - Background A major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS. Methods We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry. Results There was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta haemoglobin, respectively. The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10-12) in patients with secondary progressive multiple sclerosis. Conclusions An underlying low-grade chronic intravascular haemolysis is a potential source of the iron whose deposition along blood vessels in multiple sclerosis plaques contributes to the neurodegeneration and consequent brain atrophy seen in progressive disease. Chelators of free serum iron will be ineffective in preventing this neurodegeneration, because the iron (Fe2+) is chelated by haemoglobin. PMID- 27996066 TI - Trapping of Au nanoparticles in a microfluidic device using dielectrophoresis for surface enhanced Raman spectroscopy. AB - Dielectrophoresis (DEP) is the electrokinetic movement of non-charged particles when they are subjected to a non-uniform electric field. This is a growing area of research, which can be used for trapping, concentrating and separating different particles. Some work has been reported with the intention of trapping metal particles to optimize the surface enhanced Raman spectroscopy (SERS) effect. In this paper, we use DEP with insulating structures (iDEP) to generate a non-uniform electric field for trapping gold nanoparticles (AuNP). The system was coupled to a Raman spectrometer for the detection of Crystal Violet by utilizing the SERS effect. PMID- 27996067 TI - Dinuclear oxidative addition reactions using an isostructural series of Ni2, Co2, and Fe2 complexes. AB - A family of low-valent Ni2, Co2, and Fe2 naphthyridine-diimine (NDI) complexes is presented. Ligand-based pi* orbitals are sufficiently low-lying to fall within the metal 3d manifold, resulting in electronic structures that are highly delocalized across the conjugated [NDI]M2 system. This feature confers stability to metal-metal interactions during two-electron redox reactions, as demonstrated in a prototypical oxidative addition of allyl chloride. PMID- 27996068 TI - Synthesis and reactivity of tantalum corrole complexes. AB - Reaction of the free base corrole (Mes2(p-OMePh)corrole)H3 with tantalum trialkyl precursors TaMe3Cl2 and TaBn3NtBu resulted in the formation of the tantalum dichloride (1) and tantalum imido (4) corrole complexes via alkane elimination. The X-ray crystal structures of these two compounds have been determined and the structural parameters are discussed. The Ta centre of 1 was found to sit out of the plane of the corrole ring by 0.903 A and is cis-ligated, similarly to what has been reported for group 4 porphyrin complexes. From complex 1 we synthesized the dimethyl derivative (2), the reactivity of which is compared to an analogous tantalum dimethyl porphyrin cation. The imido complex 4 reacted with triphenylmethanol and 4-methylbenzyl alcohol, resulting in different extents of protonation of the imido group. PMID- 27996077 TI - Hybrid Rigid-Deformable Model for Prediction of Neighboring Intervertebral Disk Loads During Flexion Movement After Lumbar Interbody Fusion at L3-4 Level. AB - Knowledge of spinal loads in neighboring disks after interbody fusion plays an important role in the clinical decision of this treatment as well as in the elucidation of its effect. However, controversial findings are still noted in the literature. Moreover, there are no existing models for efficient prediction of intervertebral disk stresses within annulus fibrosus (AF) and nucleus pulposus (NP) regions. In this present study, a new hybrid rigid-deformable modeling workflow was established to quantify the mechanical stress behaviors within AF and NP regions of the L1-2, L2-3, and L4-5 disks after interbody fusion at L3-4 level. The changes in spinal loads were compared with results of the intact model without interbody fusion. The fusion outcomes revealed maximal stress changes (10%) in AF region of L1-2 disk and in NP region of L2-3 disk. The minimal stress change (1%) is noted at the NP region of the L1-2 disk. The validation of simulation outcomes of fused and intact lumbar spine models against those of other computational models and in vivo measurements showed good agreements. Thus, this present study may be used as a novel design guideline for a specific implant and surgical scenario of the lumbar spine disorders. PMID- 27996078 TI - Physically Realizable Three-Dimensional Bone Prosthesis Design With Interpolated Microstructures. AB - We present a new approach to designing three-dimensional, physically realizable porous femoral implants with spatially varying microstructures and effective material properties. We optimize over a simplified design domain to reduce shear stress at the bone-prosthetic interface with a constraint on the bone resorption measured using strain energy. This combination of objective and constraint aims to reduce implant failure and allows a detailed study of the implant designs obtained with a range of microstructure sets and parameters. The microstructure sets are either specified directly or constructed using shape interpolation between a finite number of microstructures optimized for multifunctional characteristics. We demonstrate that designs using varying microstructures outperform designs with a homogeneous microstructure for this femoral implant problem. Further, the choice of microstructure set has an impact on the objective values achieved and on the optimized implant designs. A proof-of-concept metal prototype fabricated via selective laser melting (SLM) demonstrates the manufacturability of designs obtained with our approach. PMID- 27996079 TI - Parasite transmission among relatives halts Red Queen dynamics. AB - The theory that coevolving hosts and parasites create a fluctuating selective environment for one another (i.e., produce Red Queen dynamics) has deep roots in evolutionary biology; yet empirical evidence for Red Queen dynamics remains scarce. Fluctuating coevolutionary dynamics underpin the Red Queen hypothesis for the evolution of sex, as well as hypotheses explaining the persistence of genetic variation under sexual selection, local parasite adaptation, the evolution of mutation rate, and the evolution of nonrandom mating. Coevolutionary models that exhibit Red Queen dynamics typically assume that hosts and parasites encounter one another randomly. However, if related individuals aggregate into family groups or are clustered spatially, related hosts will be more likely to encounter parasites transmitted by genetically similar individuals. Using a model that incorporates familial parasite transmission, we show that a slight degree of familial parasite transmission is sufficient to halt coevolutionary fluctuations. Our results predict that evidence for Red Queen dynamics, and its evolutionary consequences, are most likely to be found in biological systems in which hosts and parasites mix mainly at random, and are less likely to be found in systems with familial aggregation. This presents a challenge to the Red Queen hypothesis and other hypotheses that depend on coevolutionary cycling. PMID- 27996080 TI - Digest: On the temporal evolution of reproductive isolation. PMID- 27996081 TI - Tolerogenic probiotics: potential immunoregulators in Systemic Lupus Erythematosus. AB - Probiotics are commensal or nonpathogenic microbes that colonize the gastrointestinal tract and confer beneficial effects on the host through several mechanisms such as competitive exclusion, anti-bacterial effects, and modulation of immune responses. There is growing evidence supporting the immunomodulatory ability of some probiotics. Several experimental and clinical studies have been shown beneficial effect of some probiotic bacteria, particularly Lactobacillus and Bifidobacteria strains, on inflammatory and autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease that is mainly characterized by immune intolerance towards self-antigens. Some immunomodulatory probiotics have been found to regulate immune responses via tolerogenic mechanisms. Dendritic and T regulatory (Treg) cells, IL-6, IFN-gamma, IL-17, and IL-23 can be considered as the most determinant dysregulated mediators in tolerogenic status. As demonstrated by documented experimental and clinical trials on inflammatory and autoimmune diseases, a number of probiotic bacterial strains can restore tolerance in host through modification of such dysregulated mediators. Since there are limited reports regarding to impact of probiotic supplementation in SLE patients, the preset review was aimed to suggest a number of probiotics bacteria, mainly from Bifidobacteria and Lactobacillus strains that are able to ameliorate immune responses. The aim was followed through literature survey on immunoregulatory probiotics that can restore tolerance and also modulate the important dysregulated pro/anti-inflammatory cytokines contributing to the pathogenesis of SLE. PMID- 27996082 TI - Activin-SMAD signaling is required for maintenance of porcine iPS cell self renewal through upregulation of NANOG and OCT4 expression. AB - Porcine induced pluripotent stem cells (piPSCs) retain the enormous potential for farm animal reproduction and translational medicine, and have been reported by many laboratories worldwide. Some piPSC lines were bFGF-dependence and showed mouse EpiSC-like morphology; other lines were LIF-dependence and showed mouse ESC like morphology. Metastable state of piPSC line that required both LIF and bFGF was also reported. Because bona fide pig embryonic stem cells were not available, uncovering piPSC state-specific regulatory circuitries was the most important task. In this study, we explored the function of Activin-SMAD signaling pathway and its downstream activated target genes in piPSCs. Transcriptome analysis showed that genes involved in Activin-SMAD signaling pathway were evidently activated during porcine somatic cell reprogramming, regardless piPSCs were LIF- or bFGF-dependent. Addition of Activin A and overexpression of SMAD2/3 significantly promoted expressions of porcine NANOG and OCT4, whereas inhibition of Activin-SMAD signaling by SB431542 and SMAD7 reduced NANOG and OCT4 expressions, and induced piPSCs differentiation exiting from pluripotent state. Our data demonstrate that activation of Activin-SMAD signaling pathway by addition of Activin A in culture medium is necessary for maintenance of self renewal in porcine pluripotent stem cells. PMID- 27996084 TI - Distance stability analysis in multidimensional scaling using the jackknife method. AB - Stability or sensitivity analysis is an important topic in data analysis that has received little attention in the application of multidimensional scaling (MDS), for which the only available approaches are given in terms of a coordinate-based analytical jackknife methodology. Although in MDS the prime interest is in assessing the stability of the points in the configuration, this methodology may be influenced by imprecisions resulting from the inherently necessary Procrustes method. This paper proposes an analytical distance-based jackknife procedure to study stability and cross-validation in MDS in terms of the jackknife distances, which is not influenced by the Procrustes method. For each object, the corresponding jackknife estimated points are considered as naturally clustered points, and stability and cross-validation are analysed in terms of the MDS distances arising from the jackknife procedure, on the basis of a weighted cluster-MDS algorithm. A jackknife-relevant configuration is also proposed for cross-validation in terms of coordinates, in a cluster-MDS framework. PMID- 27996083 TI - Dressings for the prevention of surgical site infection. AB - BACKGROUND: Surgical wounds (incisions) heal by primary intention when the wound edges are brought together and secured, often with sutures, staples, or clips. Wound dressings applied after wound closure may provide physical support, protection and absorb exudate. There are many different types of wound dressings available and wounds can also be left uncovered (exposed). Surgical site infection (SSI) is a common complication of wounds and this may be associated with using (or not using) dressings, or different types of dressing. OBJECTIVES: To assess the effects of wound dressings compared with no wound dressings, and the effects of alternative wound dressings, in preventing SSIs in surgical wounds healing by primary intention. SEARCH METHODS: We searched the following databases: the Cochrane Wounds Specialised Register (searched 19 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2016, Issue 8); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations, MEDLINE Daily and Epub Ahead of Print; 1946 to 19 September 2016); Ovid Embase (1974 to 19 September 2016); EBSCO CINAHL Plus (1937 to 19 September 2016).There were no restrictions based on language, date of publication or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing wound dressings with wound exposure (no dressing) or alternative wound dressings for the postoperative management of surgical wounds healing by primary intention. DATA COLLECTION AND ANALYSIS: Two review authors performed study selection, 'Risk of bias' assessment and data extraction independently. MAIN RESULTS: We included 29 trials (5718 participants). All studies except one were at an unclear or high risk of bias. Studies were small, reported low numbers of SSI events and were often not clearly reported. There were 16 trials that included people with wounds resulting from surgical procedures with a 'clean' classification, five trials that included people undergoing what was considered 'clean/contaminated' surgery, with the remaining studies including people undergoing a variety of surgical procedures with different contamination classifications. Four trials compared wound dressings with no wound dressing (wound exposure); the remaining 25 studies compared alternative dressing types, with the majority comparing a basic wound contact dressing with film dressings, silver dressings or hydrocolloid dressings. The review contains 11 comparisons in total. PRIMARY OUTCOME: SSIIt is uncertain whether wound exposure or any dressing reduces or increases the risk of SSI compared with alternative options investigated: we assessed the certainty of evidence as very low for most comparisons (and low for others), with downgrading (according to GRADE criteria) largely due to risk of bias and imprecision. We summarise the results of comparisons with meta-analysed data below:- film dressings compared with basic wound contact dressings following clean surgery (RR 1.34, 95% CI 0.70 to 2.55), very low certainty evidence downgraded once for risk of bias and twice for imprecision.- hydrocolloid dressings compared with basic wound contact dressings following clean surgery (RR 0.91, 95% CI 0.30 to 2.78), very low certainty evidence downgraded once for risk of bias and twice for imprecision.- hydrocolloid dressings compared with basic wound contact dressings following potentially contaminated surgery (RR 0.57, 95% CI 0.22 to 1.51), very low certainty evidence downgraded twice for risk of bias and twice for imprecision.- silver-containing dressings compared with basic wound contact dressings following clean surgery (RR 1.11, 95% CI 0.47 to 2.62), very low certainty evidence downgraded once for risk of bias and twice for imprecision.- silver-containing dressings compared with basic wound contact dressings following potentially contaminated surgery (RR 0.83, 95% CI 0.51 to 1.37), very low certainty evidence downgraded twice for risk of bias and twice for imprecision. Secondary outcomesThere was limited and low or very low certainty evidence on secondary outcomes such as scarring, acceptability of dressing and ease of removal, and uncertainty whether wound dressings influenced these outcomes. AUTHORS' CONCLUSIONS: It is uncertain whether covering surgical wounds healing by primary intention with wound dressings reduces the risk of SSI, or whether any particular wound dressing is more effective than others in reducing the risk of SSI, improving scarring, reducing pain, improving acceptability to patients, or is easier to remove. Most studies in this review were small and at a high or unclear risk of bias. Based on the current evidence, decision makers may wish to base decisions about how to dress a wound following surgery on dressing costs as well as patient preference. PMID- 27996085 TI - Supportive interventions for enhancing dietary intake in malnourished or nutritionally at-risk adults. AB - BACKGROUND: Supportive interventions such as serving meals in a dining room environment or the use of assistants to feed patients are frequently recommended for the management of nutritionally vulnerable groups. Such interventions are included in many policy and guideline documents and have implications for staff time but may incur additional costs, yet there appears to be a lack of evidence for their efficacy. OBJECTIVES: To assess the effects of supportive interventions for enhancing dietary intake in malnourished or nutritionally at-risk adults. SEARCH METHODS: We identified publications from comprehensive searches of the Cochrane Library, MEDLINE, Embase, AMED, British Nursing Index, CINAHL, SCOPUS, ISI Web of Science databases, scrutiny of the reference lists of included trials and related systematic reviews and handsearching the abstracts of relevant meetings. The date of the last search for all databases was 31 March 2013. Additional searches of CENTRAL, MEDLINE, ClinicalTrials.gov and WHO ICTRP were undertaken to September 2016. The date of the last search for these databases was 14 September 2016. SELECTION CRITERIA: Randomised controlled trials of supportive interventions given with the aim of enhancing dietary intake in nutritionally vulnerable adults compared with usual care. DATA COLLECTION AND ANALYSIS: Three review authors and for the final search, the editor, selected trials from titles and abstracts and independently assessed eligibility of selected trials. Two review authors independently extracted data and assessed risk of bias, as well as evaluating overall quality of the evidence utilising the GRADE instrument, and then agreed as they entered data into the review. The likelihood of clinical heterogeneity amongst trials was judged to be high as trials were in populations with widely different clinical backgrounds, conducted in different healthcare settings and despite some grouping of similar interventions, involved interventions that varied considerably. We were only able, therefore, to conduct meta-analyses for the outcome measures, 'all-cause mortality', 'hospitalisation' and 'nutritional status (weight change)'. MAIN RESULTS: Forty-one trials (10,681 participants) met the inclusion criteria. Trials were grouped according to similar interventions (changes to organisation of nutritional care (N = 13; 3456 participants), changes to the feeding environment (N = 5; 351 participants), modification of meal profile or pattern (N = 12; 649 participants), additional supplementation of meals (N = 10; 6022 participants) and home meal delivery systems (N = 1; 203 participants). Follow-up ranged from 'duration of hospital stay' to 12 months.The overall quality of evidence was moderate to very low, with the majority of trials judged to be at an unclear risk of bias in several risk of bias domains. The risk ratio (RR) for all-cause mortality was 0.78 (95% confidence interval (CI) 0.66 to 0.92); P = 0.004; 12 trials; 6683 participants; moderate-quality evidence. This translates into 26 (95% CI 9 to 41) fewer cases of death per 1000 participants in favour of supportive interventions. The RR for number of participants with any medical complication ranged from 1.42 in favour of control compared with 0.59 in favour of supportive interventions (very low quality evidence). Only five trials (4451 participants) investigated health related quality of life showing no substantial differences between intervention and comparator groups. Information on patient satisfaction was unreliable. The effects of supportive interventions versus comparators on hospitalisation showed a mean difference (MD) of -0.5 days (95% CI -2.6 to 1.6); P = 0.65; 5 trials; 667 participants; very low-quality evidence. Only three of 41 included trials (4108 participants; very low-quality evidence) reported on adverse events, describing intolerance to the supplement (diarrhoea, vomiting; 5/34 participants) and discontinuation of oral nutritional supplements because of refusal or dislike of taste (567/2017 participants). Meta-analysis across 17 trials with adequate data on weight change revealed an overall improvement in weight in favour of supportive interventions versus control: MD 0.6 kg (95% CI 0.21 to 1.02); 2024 participants; moderate-quality evidence. A total of 27 trials investigated nutritional intake with a majority of trials not finding marked differences in energy intake between intervention and comparator groups. Only three trials (1152 participants) reported some data on economic costs but did not use accepted health economic methods (very low-quality evidence). AUTHORS' CONCLUSIONS: There is evidence of moderate to very low quality to suggest that supportive interventions to improve nutritional care results in minimal weight gain. Most of the evidence for the lower risk of all-cause mortality for supportive interventions comes from hospital-based trials and more research is needed to confirm this effect. There is very low-quality evidence regarding adverse effects; therefore whilst some of these interventions are advocated at a national level clinicians should recognise the lack of clear evidence to support their role. This review highlights the importance of assessing patient-important outcomes in future research. PMID- 27996086 TI - International consensus statement on the peri-operative management of anaemia and iron deficiency. AB - Despite current recommendations on the management of pre-operative anaemia, there is no pragmatic guidance for the diagnosis and management of anaemia and iron deficiency in surgical patients. A number of experienced researchers and clinicians took part in an expert workshop and developed the following consensus statement. After presentation of our own research data and local policies and procedures, appropriate relevant literature was reviewed and discussed. We developed a series of best-practice and evidence-based statements to advise on patient care with respect to anaemia and iron deficiency in the peri-operative period. These statements include: a diagnostic approach for anaemia and iron deficiency in surgical patients; identification of patients appropriate for treatment; and advice on practical management and follow-up. We urge anaesthetists and peri-operative physicians to embrace these recommendations, and hospital administrators to enable implementation of these concepts by allocating adequate resources. PMID- 27996087 TI - Gene therapy for haemophilia. AB - BACKGROUND: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy has recently been prompted as a curative treatment modality. This is an update of a published Cochrane Review. OBJECTIVES: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of last search: 18 August 2016. SELECTION CRITERIA: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX. DATA COLLECTION AND ANALYSIS: No trials of gene therapy for haemophilia were found. MAIN RESULTS: No trials of gene therapy for haemophilia were identified. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in its nascent stages and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia. PMID- 27996089 TI - Regulation of mitotic spindle orientation during epidermal stratification. AB - The epidermis is a stratified epithelium that serves as a barrier to infection from environmental pathogens and prevents water loss. Epidermal stratification is tightly controlled during embryogenesis. Progenitor cells in the developing epidermis undergo both symmetric and asymmetric cell divisions to balance the growth of the skin surface area against the generation of differentiated cell layers. Therefore, understanding the relationship between oriented divisions of progenitor cells and the development and stratification of the epidermis is of paramount importance in the field of skin biology and pathology. We provide here an integrated view of recent studies implicating that improper orientation of the mitotic spindle contributes to disorders associated with abnormal epidermal stratification and suggesting that spindle orientation could serve as a potential therapeutic target in skin diseases. PMID- 27996090 TI - Eco-friendly biorefractory films of gelatin and TEMPO-oxidized cellulose ester for food packaging application. AB - BACKGROUND: In recent years, many types of food-packaging films and composites have been prepared using gelatin because of its good film-forming ability, non toxic nature and cost-effectiveness. However, the relatively weak thermal stability, poor mechanical properties and easily-degradable quality limit the potential application of gelatin as a practical material. Microcrystalline cellulose (MCC), which comprises one of the most abundant biomass resources, has been regarded as a safe and reliable food additive because it has the same ingredients as the cellulose in people's daily intake. Food-packaging films with the excellent properties provided by gelatin and oxidized-cellulose represent a topic of great interest. RESULTS: MCC was modified by 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation and chosen as the base of the macromolecule cross-linker (TMN). After modification of gelatin film by TMN, the minimum amount of free -NH2 in solution was 4.8 * 10-4 mol g-1 ). The thermal property obviously increased (from 322.31 o C to 352.63 o C) and was crucial for usage in the food industry. The highest water contact value 123.09 degrees (eta = 25%) indicated a better surface hydrophobicity. The higher Eab (58.88%) and lower Em (77.16%) demonstrated that a more flexible and shatter proof material was obtained. Water vapor uptake studies suggested increased moisture absorption and greater swelling ability. CONCLUSION: The film material obtained in the present study was safe, stable, eco-friendly and biorefractory and could also be decomposed completely by the environment after disposal as a result of the properties of the ingredients gelatin and cellulose. The incorporation of a cellulosic cross-linker to gelatin-based films was an ideal choice with respect to developing a packaging for the food industry. (c) 2016 Society of Chemical Industry. PMID- 27996091 TI - Finding Home: A Qualitative Approach to Understanding Adolescent Mothers' Housing Instability. AB - Many low-income Latina adolescent mothers face instability in their housing circumstances, which has implications for their long-term prospects and that of their children. This study used longitudinal, ethnographic data from Welfare, Children, and Families: A Three-City Study to explore experiences of low-income, Latina adolescent mothers (N = 15) with unstable housing who primarily rely on their families or the families of their significant others for housing support. Results of analysis employing grounded theory and narrative approaches suggested two types of instability: "Horizontal moves" between family homes and "vertical moves" between family homes and independent living. Although family support often was fundamental in allowing for participants' pursuit of independent housing (i.e., vertical moves), it also was associated with greater residential mobility (i.e., horizontal moves), most often in the context of intrafamilial conflict and family instability. These results are discussed with respect to inconsistencies in policies to address this vulnerable population. PMID- 27996092 TI - Maxillofacial injuries among National Collegiate Athletic Association athletes: 2004-2014. AB - OBJECTIVE: Participation in National Collegiate Athletic Association (NCAA) sports increases annually, yet the risk of maxillofacial injuries among these athletes is unknown. We report the incidence and trends in maxillofacial injuries among NCAA athletes. STUDY DESIGN: Retrospective study of the NCAA Injury Surveillance System (ISS) representing athletes from seven men's and eight women's sports across Divisions 1, 2, and 3. Incidence of maxillofacial injuries by sport, gender, anatomic location, and injuries requiring surgery were measured. METHODS: Athlete exposure data from 2004 to 2005 through 2013 to 2014 were analyzed, along with maxillofacial injuries recorded in the NCAA-ISS. RESULTS: There were 2,017 injuries recorded, which projects to 41,204 injuries from 202,087,229 athlete events, or 2.04 injuries per 10,000 athlete events (95% confidence interval [CI], 1.68 to 2.40). Women had higher injury rates, 2.06 versus 2.03 (P = 0.016 [95% CI 0.22 to 2.09]). Highest rates were noted in men's wrestling 7.02 (95% CI, 2.84 to 11.19) and men's basketball 4.80 (95% CI, 3.57 to 6.02), and were lowest in women's ice hockey 0.61 (95% CI, 0.17 to 1.06) and women's volleyball 0.43 (95% CI, 0.20 to 0.66). No gender differences in fractures or need for surgery, but men sustained more operative fractures, 27.85% versus 17.04% (P = 0.035 [95% CI, 0.79 to 20.82]). Men's football, women's ice hockey, women's volleyball, and women's gymnastics had consistently low fracture rates. CONCLUSION: Maxillofacial injuries represent approximately 3.4% of all injuries sustained by NCAA athletes. Women had a higher injury rate, whereas men had a higher rate of operative facial fractures. Awareness and improved facial protection, especially among noncontact sports, will be crucial in reducing the incidence of these injuries. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1296-1301, 2017. PMID- 27996088 TI - Oral zinc for treating diarrhoea in children. AB - BACKGROUND: In developing countries, diarrhoea causes around 500,000 child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF). OBJECTIVES: To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library 2016, Issue 5), MEDLINE, Embase, LILACS, CINAHL, mRCT, and reference lists up to 30 September 2016. We also contacted researchers. SELECTION CRITERIA: Randomized controlled trials (RCTs) that compared oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery. DATA COLLECTION AND ANALYSIS: Both review authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. The primary outcomes were diarrhoea duration and severity. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using either a fixed-effect or random-effects model) and assessed heterogeneity.We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Thirty-three trials that included 10,841 children met our inclusion criteria. Most included trials were conducted in Asian countries that were at high risk of zinc deficiency. Acute diarrhoeaThere is currently not enough evidence from well-conducted RCTs to be able to say whether zinc supplementation during acute diarrhoea reduces death or number of children hospitalized (very low certainty evidence).In children older than six months of age, zinc supplementation may shorten the average duration of diarrhoea by around half a day (MD -11.46 hours, 95% CI -19.72 to -3.19; 2581 children, 9 trials, low certainty evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, 6 trials, moderate certainty evidence). In children with signs of malnutrition the effect appears greater, reducing the duration of diarrhoea by around a day (MD -26.39 hours, 95% CI -36.54 to -16.23; 419 children, 5 trials, high certainty evidence).Conversely, in children younger than six months of age, the available evidence suggests zinc supplementation may have no effect on the mean duration of diarrhoea (MD 5.23 hours, 95% CI -4.00 to 14.45; 1334 children, 2 trials, moderate certainty evidence), or the number of children who still have diarrhoea on day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, 1 trial, moderate certainty evidence).None of the included trials reported serious adverse events. However, zinc supplementation increased the risk of vomiting in both age groups (children greater than six months of age: RR 1.57, 95% CI 1.32 to 1.86; 2605 children, 6 trials, moderate certainty evidence; children less than six months of age: RR 1.54, 95% CI 1.05 to 2.24; 1334 children, 2 trials, moderate certainty evidence). Persistent diarrhoeaIn children with persistent diarrhoea, zinc supplementation probably shortens the average duration of diarrhoea by around 16 hours (MD -15.84 hours, 95% CI -25.43 to -6.24; 529 children, 5 trials, moderate certainty evidence). AUTHORS' CONCLUSIONS: In areas where the prevalence of zinc deficiency or the prevalence of malnutrition is high, zinc may be of benefit in children aged six months or more. The current evidence does not support the use of zinc supplementation in children less six months of age, in well-nourished children, and in settings where children are at low risk of zinc deficiency. PMID- 27996093 TI - Dlx3 and GCM-1 functionally coordinate the regulation of placental growth factor in human trophoblast-derived cells. AB - Placental growth factor (PGF) is abundantly expressed by trophoblast cells within human placentae and is important for trophoblast development and placental vascularization. Circulating maternal serum levels of PGF are dynamically upregulated across gestation in normal pregnancies, whereas low circulating levels and placental production of PGF have been implicated in the pathogenesis of preeclampsia and other gestational diseases. However, the underlying molecular mechanism of regulating PGF expression in the human placenta remains poorly understood. In this study, we demonstrated that transcription factors Distal-less 3 (DLX3) and Glial cell missing-1 (GCM1) were both sufficient and required for PGF expression in human trophoblast-derived cells by overexpression and knockdown approaches. Surprisingly, while DLX3 and GCM1 were both positive regulators of PGF, co-overexpression of DLX3 and GCM1 led to an antagonist effect on PGF expression on the endogenous gene and a luciferase reporter. Further, deletion and site-directed mutagenesis studies identified a novel regulatory element on the PGF promoter mediating both DLX3- and GCM1-dependent PGF expression. This regulatory region was also found to be essential for the basal activity of the PGF promoter. Finally, Chromatin-immunoprecipitation (ChIP) assays revealed colocalization of DLX3 and GCM1 at the identified regulatory region on the PGF promoter. Taken together, our studies provide important insights into intrinsic regulation of human placental PGF expression through the functional coordination of DLX3 and GCM1, and are likely to further the understanding of pathogenesis of PGF dysregulation in preeclampsia and other disease conditions. PMID- 27996094 TI - Living Conditions and Psychological Distress in Latino Migrant Day Laborers: The Role of Cultural and Community Protective Factors. AB - The purpose of this study was to examine the relationship between typically difficult living conditions and psychological distress in Latino migrant day laborers (LMDLs), with attention to the potentially protective roles of contact with family in country of origin (i.e., communication, sending money, etc.), availability of local culture (i.e., food, music, people from one's country of origin), and utilization of community resources perceived to be culturally competent (i.e., services that are respectful, able to serve Latinos, able to solve problems, in Spanish, etc.). Participants were 344 LMDLs surveyed in the San Francisco Bay Area. As hypothesized: (a) difficult living conditions were related to depression, anxiety, and desesperacion [desperation], the latter a popular Latino idiom of psychological distress recently validated on LMDLs; (b) contact with family moderated the relation between difficult living conditions and depression and desesperacion but not anxiety and (c) access to local culture, and utilization of community resources, mediated the relation between difficult living conditions and depression and desesperacion but not anxiety. Implications for intervening at local and larger levels in order to provide some protection against distress built into the LMDL experience in the United States are discussed. PMID- 27996095 TI - Biological and pharmacological evaluation of dimethoxycurcumin: A metabolically stable curcumin analogue with a promising therapeutic potential. AB - Dimethoxycurcumin (DiMC) is a synthetic analog of curcumin with superior inter related pro-oxidant and anti-cancer activity, and metabolic stability. Numerous studies have shown that DiMC reserves the biologically beneficial features, including anti-inflammatory, anti-carcinogenic, and cytoprotective properties, almost to the same extent as curcumin exhibits. DiMC lacks the phenolic-OH groups as opposed to curcumin, dimethoxycurcumin, and bis-demethoxycurcumin that all vary in the number of methoxy groups per molecule, and has drawn the attentions of researchers who attempted to discover the structure-activity relationship (SAR) of curcumin. In this regard, tetrahydrocurcumin (THC), the reduced and biologically inert metabolite of curcumin, denotes the significance of the conjugated alpha,beta diketone moiety for the curcumin activity. DiMC exerts unique molecular activities compared to curcumin, including induction of androgen receptor (AR) degradation and suppression of the transcription factor activator protein-1 (AP-1). The enhanced AR degradation on DiMC treatment suggests it as a novel anticancer agent against resistant tumors with androgenic etiology. Further, DiMC might be a potential treatment for acne vulgaris. DiMC induces epigenetic alteration more effectively than curcumin, although both showed no direct DNA hypomethylating activity. Given the metabolic stability, nanoparticulation of DiMC is more promising for in vivo effectiveness. However, studies in this regard are still in its infancy. In the current review, we portray the various molecular and biological functions of DiMC reported so far. Whenever possible, the efficiency is compared with curcumin and the reasons for DiMC being more metabolically stable are elaborated. We also provide future perspective investigations with respect to varying DiMC-nanoparticles. PMID- 27996097 TI - Prevention of Cardiac Implantable Electronic Device Infections: Single Operator Technique with Use of Povidone-Iodine, Double Gloving, Meticulous Aseptic/Antiseptic Measures and Antibiotic Prophylaxis. AB - BACKGROUND: Cardiac implantable electronic device (CIED) implantation is complicated by infection still at a worrisome rate of 2-5%. Since early on during device implantation procedures, we have adopted an infection-preventive technique which has hitherto resulted in effective prevention of infections. Herein we present our results of applying this technique by a single operator in a prospective series of 762 consecutive patients undergoing device implantation. METHODS: A meticulous search for and treatment of active, occult, or smoldering infection was undertaken preoperatively. An aseptic/antiseptic technique was used for implantation of each device. Skin preparation is thorough with initial cleansing performed with alcohol followed by povidone-iodine 10% solution, which is also used in the wound and inside the pocket. In addition, we routinely use double gloving, and IV antibiotic prophylaxis 1 hour before and for 48 hours afterwards followed by oral antibiotic for 2-3 days after discharge. The skin is closed with absorbable sutures. The study includes 382 patients having a new pacemaker (n = 333) or battery change, system upgrade or lead revision (n = 49), and 380 patients having a new implantable cardioverter-defibrillator (ICD) (n = 296) or device replacement/upgrade/lead revision (n = 84). RESULTS: The pacemaker group, aged 70.2 +/- 16.5 years, includes 18% VVI, 49% DDD, 29% VDD, and 4% cardiac resynchronization therapy (CRT) devices. The ICD group, aged 61.3 +/- 13.0 years, with a mean ejection fraction of 36 +/- 13%, includes 325 ICD and 55 CRT implants. Over 26.6 +/- 33.4 months for the pacemaker group and 36.6 +/- 38.3 months for the ICD group, infection occurred in one patient in each group (0.26%) having a device replacement. CONCLUSION: A consistent and strict approach of aseptic/antiseptic technique with the use of double gloving and povidone-iodine solution within the pocket plus a 4-day regimen of antibiotic prophylaxis minimizes infections in CIED implants. PMID- 27996096 TI - Super-resolution structure of DNA significantly differs in buccal cells of controls and Alzheimer's patients. AB - The advent of super-resolution microscopy allowed for new insights into cellular and physiological processes of normal and diseased cells. In this study, we report for the first time on the super-resolved DNA structure of buccal cells from patients with Alzheimer's disease (AD) versus age- and gender-matched healthy, non-caregiver controls. In this super-resolution study cohort of 74 participants, buccal cells were collected and their spatial DNA organization in the nucleus examined by 3D Structured Illumination Microscopy (3D-SIM). Quantitation of the super-resolution DNA structure revealed that the nuclear super-resolution DNA structure of individuals with AD significantly differs from that of their controls (p < 0.05) with an overall increase in the measured DNA free/poor spaces. This represents a significant increase in the interchromatin compartment. We also find that the DNA structure of AD significantly differs in mild, moderate, and severe disease with respect to the DNA-containing and DNA free/poor spaces. We conclude that whole genome remodeling is a feature of buccal cells in AD. PMID- 27996098 TI - Corn silage replacement with barley silage in dairy cows' diet does not change milk quality, cheese quality and yield. AB - BACKGROUND: Considering that water availability for agricultural needs is being restricted, an alternative to corn in animal nutrition should be explored in the Po Valley. The present study aimed to evaluate the effects of either a partial (Trial I) or a total (Trial II) corn silage substitution with barley silage in dairy cows' diet on milk yield and composition, its coagulation properties, cheese yield and the sensorial profile of 16-month-aged Grana Padano cheese. RESULTS: A partial or a total substitution of corn silage with barley silage had no effect on milk yield. Milk fat content in Trial I and milk urea content in both trials were higher with barley silage based diets than in corn silage based diets. No effects were observed concerning the lactodinamographic profile for milk aptitude to cheese-making, cheese yield and its organoleptic traits between feed treatments in Trials I and II. In both trials, hardness, friability and solubility scores were generally lower than reference values, whereas deformability, elasticity and stickiness scores were generally higher than reference values. CONCLUSION: A partial or a total substitution of corn silage with barley silage in diets for dairy cows did not induce any negative effects on animal performance, nor on milk-quality traits, cheese quality and yield. (c) 2016 Society of Chemical Industry. PMID- 27996100 TI - Complications with the MICRA TPS Pacemaker System: Persistent Complete Heart Block and Late Capture Failure. AB - A Medtronic MICRA transcatheter pacing system (Medtronic, Minneapolis, MN, USA) was implanted in an 86-year-old patient with sick sinus syndrome and left bundle branch block after transfemoral aortic valve implantation. During implantation she developed a persistent complete heart block due to manipulation with the large-bore delivery catheter. Two weeks later, acute pacemaker dysfunction occurred due to massive increase of pacing threshold and impedance without obvious pacemaker dislocation or myocardial perforation. Recurrent capture failure was seen with pacing output set at 5 V/1.0 ms. Hence, microdislocation or fixation of the tines in the right ventricular trabeculae has to be assumed. PMID- 27996099 TI - Preliminary study of a novel transfection modality for in vivo siRNA delivery to vocal fold fibroblasts. AB - OBJECTIVE: An obstacle to clinical use of RNA-based gene suppression is instability and inefficiency of current delivery modalities. Nanoparticle delivery likely holds great promise, but the kinetics and transfection conditions must be optimized prior to in vivo utility. We investigated a RNA nanoparticle complex incorporating a lipitoid transfection reagent in comparison to a commercially available reagent. STUDY DESIGN: In vitro. METHODS: We investigated which variables influence transfection efficiency of lipitoid oligomers and a commercially available reagent across species, in vitro. These variables included duration, dose, and number of administrations, as well as serum and media conditions. The target gene was Smad3, a signaling protein in the transforming growth factor-beta cascade implicated in fibroplasia in the vocal folds and other tissues. RESULTS: The two reagents suppressed Smad3 mRNA for up to 96 hours; lipitoid performed favorably and comparably. Both compounds yielded 60% to 80% mRNA knockdown in rat, rabbit, and human vocal fold fibroblasts (P < 0.05 relative to control). Dose and number of administrations played a significant role in gene suppression (P < 0.05). Suppression was more dose-sensitive with lipitoid. At a constant siRNA concentration, a 50% decrease in gene expression was observed in response to a five-fold increase in lipitoid concentration. Increased number of administrations enhanced gene suppression, ~45% decrease between one and four administrations. Neither serum nor media type altered efficiency. CONCLUSION: Lipitoid effectively knocked down Smad3 expression across multiple transfection conditions. These preliminary data are encouraging, and lipitoid warrants further investigation with the goal of clinical utility. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:E231-E237, 2017. PMID- 27996102 TI - Current sights for mechanisms of deoxynivalenol-induced hepatotoxicity and prospective views for future scientific research: A mini review. AB - Deoxynivalenol (DON) belongs to the group B trichothecenes, which are the most common mycotoxins in cereal commodities. It is very stable within the temperature range 170-350 degrees C, showing no reduction in its concentration after 30 min at 170 degrees C. This chemical property is a very dangerous factor for human and animal health. Liver is also responsible for the detoxification and formation of DON-glucuronide in both human and animals. Some studies already demonstrated that DON could induce liver damage remarkably through DON altering expressions of p53, caspase-3, caspase-7, caspase-8 and Bax in different cell lines. At the same time, other publications illustrated some opposite results. At present, a full and systematic discussion of the hepatic toxicity of DON is still lacking. Therefore, the aim of the present review is to summarize and update the prominent evidence, regarding DON effects on liver tissues and cell lines. Moreover, based on the current studies we outline some of the identified molecule targets or pathways involved in DON-induced hepatotoxicity, and put forward our opinions and suggest an hypothesis for future research. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27996101 TI - The Neutrophil-to-Lymphocyte Ratio Predicts All-Cause Mortality in Patients with Implantable Cardioverter Defibrillators. AB - BACKGROUND: The relationship between the neutrophil-to-lymphocyte ratio (NLR) and outcome in patients with implantable cardioverter-defibrillators (ICDs) is unclear. METHODS AND RESULTS: Consecutive patients with cardiomyopathy who had received an ICD (n = 120, mean age 64 +/- 11 years) were prospectively enrolled. Blood samples were obtained on the morning of the day of implantation. Patients were followed for a median period of 61.2 months, to an endpoint of all-cause mortality or appropriate ICD shock, which occurred in 35 (29%) and 28 (23%) patients, respectively. Multivariate Cox analysis revealed that secondary prevention was only associated with appropriate ICD shocks. The NLR, brain natriuretic peptide level, and estimated glomerular filtration rate were independent predictors of all-cause mortality but not of appropriate ICD shocks. Subgroup analysis revealed that a high NLR (>=2.1) was valuable for anticipating all-cause mortality among patients who had received ICDs for primary or secondary prevention. A high NLR was also associated with death prior to appropriate ICD shock. CONCLUSION: Evaluating the NLR may be useful for predicting outcomes in patients with cardiomyopathy who have received ICDs. PMID- 27996103 TI - Validation of the Chinese Version of Montreal Cognitive Assessment Basic for Screening Mild Cognitive Impairment. AB - OBJECTIVES: To evaluate the effectiveness of the Chinese version of the Montreal Cognitive Assessment Basic (MoCA-BC) as a screening tool for detecting mild cognitive impairment (MCI) in Chinese elderly adults. DESIGN: Cross-sectional. SETTING: Huashan Hospital, Shanghai, China. PARTICIPANTS: Individuals with MCI (n = 264) and mild Alzheimer's disease (AD) (n = 160) were recruited from the Memory Clinic, Huashan Hospital; cognitively normal controls were recruited from Jinshan Community, Shanghai, China (n = 280). MEASUREMENTS: MoCA-BC scores. RESULTS: The MoCA-BC had good criterion-related validity (Pearson correlation coefficient MoCA BC vs MMSE = 0.787) and reliable internal consistency (Cronbach alpha = 0.807). The optimal cutoff scores for MCI screening were 19 for individuals with no more than 6 years of education, 22 for individuals with 7 to 12 years of education, and 24 for individuals with more than 12 years of education. The MoCA-BC was superior to the MMSE for detecting MCI, with optimal sensitivity and specificity across all education groups using the above cutoff scores. CONCLUSION: The MoCA BC is a reliable cognitive screening test across all education levels in Chinese elderly adults, with high acceptance and good reliability. PMID- 27996104 TI - Serum Parathyroid Hormone but Not Vitamin D Is Associated with Impaired Gait in Community-Dwelling Older Adults. PMID- 27996105 TI - A Cluster of Group A Streptococcal Infections in a Skilled Nursing Facility-the Potential Role of Healthcare Worker Presenteeism. AB - OBJECTIVES: To determine the extent of a group A streptococcus (GAS) cluster (2 residents with invasive GAS (invasive case-patients), 2 carriers) caused by a single strain (T antigen type 2 and M protein gene subtype 2.0 (T2, emm 2.0)), evaluate factors contributing to transmission, and provide recommendations for disease control. DESIGN: Cross-sectional analysis and retrospective review. SETTING: Skilled nursing facility (SNF). PARTICIPANTS: SNF residents and staff. MEASUREMENTS: The initial cluster was identified through laboratory notification and screening of SNF residents with wounds. Laboratory and SNF administrative records were subsequently reviewed to identify additional residents with GAS, oropharyngeal and wound (if present) swabs were collected from SNF staff and residents to examine GAS colonization, staff were surveyed to assess infection control practices and risk factors for GAS colonization, epidemiologic links between case-patients and persons colonized with GAS were determined, and facility infection control practices were assessed. RESULTS: No additional invasive case-patients were identified. Oropharyngeal swabs obtained from all 167 SNF residents were negative; one wound swab grew GAS that was the same as the outbreak strain (T2, emm 2.0). The outbreak strain was not identified in any of the 162 staff members. One of six staff members diagnosed with GAS pharyngitis worked while ill and had direct contact with invasive case-patients within a few weeks before their onset of symptoms. Additional minor breaches in infection control were noted. CONCLUSION: Sick healthcare workers may have introduced GAS into the SNF, with propagation by infection control lapses. "Presenteeism," or working while ill, may introduce and transmit GAS to vulnerable in SNF populations. Identification of an invasive GAS case-patient should trigger a prompt response by facilities to prevent further transmission and workplace culture, and policies should be in place to discourage presenteeism in healthcare settings. PMID- 27996106 TI - Drug Therapy for Gender Transitions and Health Screenings in Transgender Older Adults. AB - Transgender medicine is a relatively new field in health care, with only a small amount of evidence-based literature available for reference. This is especially true for the older adult population, for whom most information must be extrapolated from younger adults. Be it a newly transitioned older adult or a transgendered individual who has been undergoing hormonal therapy for many years, it is important that healthcare professionals be aware of the significant effects that transgender pharmacotherapy can have on older adults. Healthcare providers must also recommend appropriate preventative screenings to transgendered persons. PMID- 27996107 TI - Identifying Consistent and Coherent Dimensions of Nursing Home Quality: Exploratory Factor Analysis of Quality Indicators. AB - BACKGROUND: There is a general belief that the markers of nursing home quality do not aggregate easily. Identifying consistent and coherent dimensions of quality that usefully summarize the multiplicity of nursing home quality measures is an important goal. It would simplify interpretation and help consumers, their families and advocates to choose nursing facilities. OBJECTIVES: This study uses quality indicators (QIs) from a state nursing home report card to explore the dimensionality of quality in nursing homes and to determine whether aggregation at the resident versus facility level yields the same underlying dimensions. DESIGN: Cross-sectional study. SETTING: 382 Medicare- and/or Medicaid-certified nursing homes in Minnesota. PARTICIPANTS: Residents admitted to the nursing homes during 2011-2012. MEASUREMENTS: 16 QIs obtained from the Minimum Data Set 3.0 assessment instrument between 2011 and 2012 were used in the exploratory factor analysis. RESULTS: Factor analysis results suggest four main factors or dimensions to characterize facility performance: continence care (including 4 QIs), restraints and behavioral symptoms (including 3 QIs), care for specific conditions (including 6 QIs), and physical functioning (including 3 QIs). The resident-level and facility-level results generally agreed for 11 QIs. CONCLUSION: Nursing home quality of care can be captured in summary measures, which can be used by consumers, providers and researchers. Reporting at the resident or facility level will depend on the purpose. These summary measures can be used by policy-makers to identify and reward high-performing facilities and by families to choose nursing facilities for care. PMID- 27996110 TI - Geriatric Cardiology Mini-Focus Issue: Call for Papers. PMID- 27996109 TI - Reliability and Validity of a Simplified Comprehensive Assessment Tool for Feeding Support: Kuchi-Kara Taberu Index. AB - OBJECTIVES: To verify the reliability and validity and develop an English version of an instrument (Kuchi-Kara Taberu Index (KT Index)) to comprehensively assess and intervene in problems with eating and swallowing. DESIGN: Multicenter cross sectional study. SETTING: Nursing homes. PARTICIPANTS: Individuals aged 65 and older (mean age 88.3 +/- 6.8; 80.0% female) who had lived in a nursing home for longer than 1 month (N = 115). MEASUREMENTS: The KT index consisted of 13 items: desire to eat, overall condition, respiratory condition, oral condition, cognitive function while eating, oral preparatory and propulsive phases, dysphagia severity, position and endurance while eating, eating, daily life, food intake level, food modification, and nutrition. Weighted kappa coefficients, Cronbach alpha, and Spearman rank correlation coefficients were determined. RESULTS: Weighted kappa values in the inter- and intrarater reliability tests ranged from 0.54 to 0.96 and 0.68 to 0.98, respectively. Cronbach alpha was 0.892. Spearman rank correlation coefficients (r) between the total KT index and external criteria were determined (Functional Oral Intake Scale, r = 0.790; Barthel Index, r = 0.830; Mini Nutritional Assessment Short Form, r = 0.582; Cognitive Performance Scale, r = -0.673; all P < .001). Similar correlations were observed when some items related to each external criterion were removed from the total KT index. Translation-retranslation procedures were conducted to develop an English version of the KT index. CONCLUSION: The study provided evidence of the reliability and validity of the KT index and developed an English version. Future studies regarding validation of health-related quality of life indices and their effect on clinical courses of eating and swallowing conditions are needed. PMID- 27996111 TI - Growing Old or Just Growing. PMID- 27996112 TI - Erratum. PMID- 27996108 TI - Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. AB - OBJECTIVES: To investigate the association between reproductive history indicators of hormonal exposure, including reproductive period, pregnancy, and use of hormonal contraceptives, and mid- and late-life cognition in postmenopausal women. DESIGN: Analysis of baseline data from two randomized clinical trials: the Women's Isoflavone Soy Health and the Early vs Late Intervention Trial of Estradiol. SETTING: University academic research center. PARTICIPANTS: Naturally menopausal women (N = 830). MEASUREMENTS: Participants were uniformly evaluated using a cognitive battery and a structured reproductive history questionnaire. Outcomes were composite scores for verbal episodic memory, executive function, and global cognition. Reproductive variables included ages at pregnancies, menarche, and menopause; reproductive period; number of pregnancies; and use of hormones for contraception and menopausal symptoms. Multivariable linear regression was used to evaluate associations between cognitive scores (dependent variable) and reproductive factors (independent variables), adjusting for age, race and ethnicity, income, and education. RESULTS: On multivariable modeling, age at menarche of 13 and older was inversely associated with global cognition (P = .05). Last pregnancy after age 35 was positively associated with verbal memory (P = .03). Use of hormonal contraceptives was positively associated with global cognition (P trend = .04), and verbal memory (P trend = .007). The association between hormonal contraceptive use and verbal memory and executive function was strongest for more than 10 years of use. Reproductive period was positively associated with global cognition (P = .04) and executive function (P = .04). CONCLUSION: In this sample of healthy postmenopausal women, reproductive life events related to sex hormones, including earlier age at menarche, later age at last pregnancy, longer reproductive period, and use of oral contraceptives are positively related to aspects of cognition in later life. PMID- 27996113 TI - Age Is Not a Relative Contraindication for Surgical Treatment of Infected Aortic and Iliac Aneurysms. PMID- 27996115 TI - Characterizing Potentially Inappropriate Prescribing of Proton Pump Inhibitors in Older People in Primary Care in Ireland from 1997 to 2012. AB - OBJECTIVES: To characterize prescribing of proton pump inhibitors (PPIs) and medicines that increase gastrointestinal bleeding risk (ulcerogenic) in older people from 1997 to 2012 and assess factors associated with maximal-dose prescribing in long-term PPI users. DESIGN: Repeated cross-sectional study of pharmacy claims data. SETTING: Eastern Health Board region of Ireland. PARTICIPANTS: Individuals aged 65 and older from a means-tested health plan in 1997, 2002, 2007, and 2012 (range 78,489-133,884 individuals). MEASUREMENTS: PPI prescribing prevalence was determined per study year, categorized according to duration (<=8 or >8 weeks), dosage (maximal or maintenance), and co-prescribed drugs. Logistic regression in long-term PPI users was used to determine whether age, sex, polypharmacy, and ulcerogenic medicine use were associated with being prescribed a maximal dose rather than a maintenance dose. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are presented. RESULTS: Half of this older population received a PPI in 2007 and 2012. Long-term use (>8 weeks) of maximal doses rose from 0.8% of individuals in 1997 to 23.6% in 2012. Although some ulcerogenic medicines and polypharmacy were significantly associated with maximal PPI doses, any nonsteroidal anti-inflammatory drug use was significantly associated with lower odds of maximal PPI dose (adjusted OR = 0.87, 95% CI = 0.85 0.89), as were aspirin use and older age. Adjusting for medication and demographic factors, odds of being prescribed a maximal PPI dose were significantly higher in 2012 than in 1997 (adjusted OR = 6.30, 95% CI = 5.76 6.88). CONCLUSIONS: Long-term maximal-dose PPI prescribing is highly prevalent in older adults and is not consistently associated with gastrointestinal bleeding risk factors. Interventions involving prescribers and patients may promote appropriate PPI use, reducing costs and adverse effects of PPI overprescribing. PMID- 27996116 TI - Fragile Warriors. PMID- 27996114 TI - Mexican-American Dementia Nomogram: Development of a Dementia Risk Index for Mexican-American Older Adults. AB - OBJECTIVES: To create a risk index (Mexican American Dementia Nomogram (MADeN)) that predicts dementia over a 10-year period for Mexican Americans aged 65 and older. DESIGN: Retrospective cohort study with longitudinal analysis. SETTING: Texas, New Mexico, Colorado, Arizona, and California. PARTICIPANTS: Hispanic Established Populations for the Epidemiologic Study of the Elderly (H-EPESE) participants (n = 1,739). MEASUREMENTS: Dementia was defined as a decline of three or more points per year on the Mini-Mental State Examination and inability to perform one or more daily activities. Candidate risk factors included demographic characteristics, measures of social engagement, self-reported health conditions, ability to perform daily activities, and physical activity. RESULTS: The MADeN comprised the following risk factors: age, sex, education, not having friends to count on, not attending community events, diabetes mellitus, feeling the blues, pain, impairment in instrumental activities of daily living, and unable to walk a half-mile. The area under the receiver operating characteristic curve was 0.74 (95% confidence interval (CI) = 0.70-0.78) and a score of 16 points or higher had a sensitivity of 0.65 (95% CI = 0.59-0.72) and specificity of 0.70 (95% CI = 0.67-0.73) in predicting dementia. CONCLUSION: The MADeN was able to predict dementia in a population of older Mexican-American adults with moderate accuracy. It has the potential to identify older Mexican-American adults who may benefit from interventions to reduce dementia risk and to educate this population about risk factors for dementia. PMID- 27996117 TI - Pilot Randomized Controlled Trial of Spinal Versus General Anesthesia for Hip Fracture Surgery. PMID- 27996119 TI - Bevacizumab chemotherapy for management of pulmonary and laryngotracheal papillomatosis in a child. AB - Recurrent laryngeal papillomatosis (RRP) can be a devastating condition for a child to endure, and pulmonary involvement may have terminal consequences. Adjuvant therapies have been trialed and reported over the years; however, these chemotherapy options have not been successful. Bevacizumab (Avastin, Genetech Inc., South San Francisco, CA) is a vascular endothelial factor (VEGF) inhibitor that has shown promise in the management of papillomatosis. Most research has focused on intralesional injections of this antiangiogenic drug. The systemic use of bevacizumab is not as well described. This is a case report of a 12-year-old female diagnosed with severe laryngotracheal papillomatosis near birth who underwent a tracheostomy tube placement at 1 year of age. She required weekly debridements to prevent tracheal obstruction. When lung involvement was diagnosed at 1 year of age, cidofovir was started intravenously. Over the course of the past 10 years, the patient was managed with celecoxib (Celebrex, Pfizer, New York, NY), anti-reflux medications, zithromycin, propranolol, Gardasil (Merck and Co., Kenilworth, NJ), and a 7-year course of interferon-alpha. Intravenous bevacizumab was started when the patient's pulmonary status deteriorated. There was remarkable improvement in her laryngotracheal disease within 6 weeks of therapy. Following 3 months of bevacizumab, the patient's disease was completely resolved at the laryngeal level and nearly gone in the trachea, and she was decannulated. A computed scan was performed following 5 months of intravenous bevacizumab, and the pulmonary RRP nodules completely resolved. The patient had no major or minor complication from the chemotherapy to date. Systemic Bevacizumab is a promising modality of adjuvant therapy for significant papillomatosis. Laryngoscope, 127:1538-1542, 2017. PMID- 27996120 TI - Electrochemotherapy - yet another innovative application. PMID- 27996121 TI - A promising new strategy for monitoring erythropoietic protoporphyria therapy. PMID- 27996122 TI - Is DRESS syndrome a single entity or within a spectrum of adverse reactions to drug? PMID- 27996124 TI - Skin cancer in the end-stage renal disease population: unique risk factors for patients on dialysis. PMID- 27996125 TI - A sting in the tail: filler nodules after monoclonal antibody treatment. PMID- 27996126 TI - Dermoscopy in Europe: coming of age. PMID- 27996127 TI - Laser tattoo removal: is there light at the end of the tunnel or is it just the light of an oncoming train? PMID- 27996128 TI - Psoriasin (S100A7): a novel mediator of angiogenesis. PMID- 27996129 TI - Programmed cell death protein-1 inhibitors for immunotherapy of advanced nonmelanoma skin cancer: showing early promise. PMID- 27996130 TI - Statin exposure and the risk for herpes zoster: implications for public health. PMID- 27996132 TI - Can you have your cake and eat it too? The sunlight D-lema. PMID- 27996133 TI - The SCAR (Scar Cosmesis Assessment and Rating) scale: new evaluation method for postoperative scars. PMID- 27996134 TI - Image Gallery: Syphilitic chancre of the palm. PMID- 27996135 TI - Cover Image: Detection of hair follicle-associated Merkel cell polyomavirus in an immunocompromised host with follicular spicules and alopecia. PMID- 27996137 TI - Are patients capable and comfortable using mobile teledermoscopy? PMID- 27996136 TI - Routine usage of sentinel node biopsy in melanoma management must cease. PMID- 27996139 TI - Plain language summaries. PMID- 27996138 TI - Antihistamine updosing in chronic urticaria - is there enough evidence? PMID- 27996140 TI - Image Gallery: A case of unilateral laterothoracic exanthem. PMID- 27996142 TI - Optical coherence tomography for diagnosis of basal cell carcinoma: essentials and perspectives. PMID- 27996143 TI - Image Gallery: Periorbital and temporal dermal melanocytosis of hypohidrotic ectodermal dysplasia. PMID- 27996144 TI - JNK-ERK signalling in melanoma: rewired or entangled? PMID- 27996146 TI - Plain language summaries in Simplified Chinese. PMID- 27996145 TI - Integrating clinical information, dermoscopy and reflectance confocal microscopy to improve the diagnostic accuracy and confidence of amelanotic and lightly pigmented melanomas. PMID- 27996147 TI - Corrigendum. PMID- 27996148 TI - Image Gallery: Lichen amyloidosis on the external auditory canal. PMID- 27996149 TI - Fatal attractions? Correlations of CXCL12-CXCR4-CXCR7 expression with disease progression in melanoma and Kaposi sarcoma. PMID- 27996150 TI - Epidermal growth factor receptor inhibitor-associated rash prevented by oral tetracyclines. PMID- 27996151 TI - Expanding genetics and phenotypic spectrum of epidermodysplasia verruciformis. PMID- 27996153 TI - Antibiotics and acne: an emerging iceberg of antibiotic resistance? PMID- 27996152 TI - Image Gallery: Vasculo-Behcet disease. PMID- 27996154 TI - Assessing Climate Change Impacts on Wildfire Exposure in Mediterranean Areas. AB - We used simulation modeling to assess potential climate change impacts on wildfire exposure in Italy and Corsica (France). Weather data were obtained from a regional climate model for the period 1981-2070 using the IPCC A1B emissions scenario. Wildfire simulations were performed with the minimum travel time fire spread algorithm using predicted fuel moisture, wind speed, and wind direction to simulate expected changes in weather for three climatic periods (1981-2010, 2011 2040, and 2041-2070). Overall, the wildfire simulations showed very slight changes in flame length, while other outputs such as burn probability and fire size increased significantly in the second future period (2041-2070), especially in the southern portion of the study area. The projected changes fuel moisture could result in a lengthening of the fire season for the entire study area. This work represents the first application in Europe of a methodology based on high resolution (250 m) landscape wildfire modeling to assess potential impacts of climate changes on wildfire exposure at a national scale. The findings can provide information and support in wildfire management planning and fire risk mitigation activities. PMID- 27996155 TI - The Origin and Role of Trust in Local Policy Elites' Perceptions of High-Voltage Power Line Installations in the State of Arkansas. AB - The debate over an installation of high-voltage power lines (HVPLs) has been intense, particularly in northwest Arkansas. Detractors claim that the installation will negatively affect both the natural environment and the local economy, which contains a large tourism component. By contrast, those in favor of installing HVPLs claim that the installation is necessary in order to reliably support the increasing demand for electric power. Using original data collected from a recent statewide Internet survey of 420 local policy elites in Arkansas, this article focuses on two key aspects. First, we examine how local policy elites' perceptions of risks versus benefits of HVPL installation in their communities are influenced by their levels of trust toward information provided by various sources (e.g., energy industry, environmental groups, and government). Second, we utilize cultural theory to explain how the cultural worldviews of policy elites--specifically, egalitarianism, individualism, hierarchism, and fatalism--shape these levels of trust and HVPL benefit-risk perceptions, while controlling for other factors claimed by previous literature, including levels of knowledge on energy-related issues and demographic characteristics. In general, our analysis indicates that policy elites' value-oriented formation of HVPL benefit-risk perceptions is partially due to the influence cultural values have on trust in information sources. We conclude this article by discussing broader implications for the origin and role of trust in policy elites' decisions throughout the policy-making process. PMID- 27996156 TI - alpha-enolase promotes tumorigenesis and metastasis via regulating AMPK/mTOR pathway in colorectal cancer. AB - The alpha-enolase (ENO1) plays pivotal roles in several types of cancer, but its clinical significance, functional role, and possible mechanism in colorectal cancer (CRC) have remained unclear. Expression level of ENO1 in CRC tissues was examined by qRT-PCR, Western blot, and immunohistochemistry. The effects of ENO1 on cell growth were investigated by MTT, colony formation, flow cytometry assays, and in vivo tumorigenic capacity analysis. The impacts of ENO1 on cell migration and invasion were also explored by scratch-healing, Transwell or Matrigel chamber assays, and in vivo metastatic capacity analysis. Our results showed that the expression level of ENO1 was significantly elevated in CRC tissues. High expression level of ENO1 was associated with disease progression in CRC patients. Overexpression of ENO1 in HCT116 cell line promoted cell proliferation, migration, and invasion in vitro as well as tumorigenesis and metastasis in vivo. In other hand, ablation of ENO1 in HCT116 cells led to totally reverse effects. Mechanistically, we revealed ENO1 could regulate AMPK/mTOR signaling pathway. AMPK pathway activation or mTOR pathway suppression blocked these ENO1 induced alterations. Together, our results demonstrated that ENO1 is a potent promoter of CRC genesis and metastasis at least in part though regulating AMPK/mTOR pathway. These findings also suggested that ENO1 may be a promising therapeutic target in CRC patients. PMID- 27996158 TI - Chemopreventive potential of in vitro fermented nuts in LT97 colon adenoma and primary epithelial colon cells. AB - Due to their beneficial nutritional profile the consumption of nuts contributes to a healthy diet and might reduce colon cancer risk. To get closer insights into potential mechanisms, the chemopreventive potential of different in vitro fermented nut varieties regarding the modulation of genes involved in detoxification (CAT, SOD2, GSTP1, GPx1) and cell cycle (p21, cyclin D2) as well as proliferation and apoptosis was examined in LT97 colon adenoma and primary epithelial colon cells. Fermentation supernatants (FS) of nuts significantly induced mRNA expression of CAT (up to 4.0-fold), SOD2 (up to 2.5-fold), and GSTP1 (up to 2.3-fold), while GPx1 expression was significantly reduced by all nut FS (0.8 fold on average). Levels of p21 mRNA were significantly enhanced (up to 2.6 fold), whereas all nut FS significantly decreased cyclin D2 expression (0.4-fold on average). In primary epithelial cells, expression of CAT (up to 3.5-fold), GSTP1 (up to 3.0-fold), and GPx1 (up to 3.9-fold) was increased, whereas p21 and cyclin D2 levels were not influenced. Nut FS significantly inhibited growth of LT97 cells and increased levels of early apoptotic cells (8.4% on average) and caspase 3 activity (4.6-fold on average), whereas caspase 3 activity was not modulated in primary colon cells. The differential modulation of genes involved in detoxification and cell cycle together with an inhibition of proliferation and induction of apoptosis in adenoma cells might contribute to chemopreventive effects of nuts regarding colon cancer. PMID- 27996160 TI - Response to: Comment on "Cryptosporidium Infection Risk: Results of New Dose Response Modeling"--Discussion of Underlying Assumption and Their Implications. PMID- 27996157 TI - High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study. AB - Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n = 142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P < 0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P < 0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels <=16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P = 0.03), CpG3 (chr10:131,265,810; P = 0.05), and the mean across CpGs measured in the MGMT promoter (P = 0.03) among applicators >59 years and reduced LINE-1 DNAm (P = 0.05) among applicators with <=16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1. The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer. Environ. Mol. Mutagen. 58:19-29, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27996159 TI - Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen-induced cell transformation. AB - Identification of aberrant histone H3 phosphorylation during chemical carcinogenesis will lead to a better understanding of the substantial roles of histone modifications in cancer development. To explore whether aberrant H3 phosphorylation contributes to chemical carcinogenesis, we examined the dynamic changes of H3 phosphorylation at various residues in chemical carcinogen-induced transformed human cells and human cancers. We found that histone H3 phosphorylation at Ser10 (p-H3S10) and Ser28 (p-H3S28) was upregulated by 1.5-4.8 folds and 2.1-4.3 folds, respectively in aflatoxin B1 -transformed hepatocytes L02 cells (L02RT-AFB1 ), benzo(a)pyrene-transformed HBE cells (HBERT-BaP), and coke oven emissions-transformed HBE cells (HBERT-COE). The ectopic expression of histone H3 mutant (H3S10A or H3S28A) in L02 cells led to the suppression of an anchorage-independent cell growth as well as tumor formation in immunodeficient mice. In addition, an enhanced p-H3S10 was found in 70.6% (24/34) of hepatocellular carcinoma (HCC), and 70.0% (21/30) of primary lung cancer, respectively. Notably, we found that expression of H3 carrying a mutant H3S10A or H3S28A conferred to cells the ability to maintain a denser chromatin and resistance to induction of DNA damage and carcinogen-induced cell transformation. Particularly, we showed that introduction of a mutant H3S10A abolished the bindings of p-H3S10 to the promoter of DNA repair genes, PARP1 and MLH1 upon AFB1 treatment. Furthermore, we revealed that PP2A was responsible for dephosphorylation of p-H3S10. Taken together, these results reveal a key role of persistent H3S10 or H3S28 phosphorylation in chemical carcinogenesis through regulating gene transcription of DNA damage response (DDR) genes. PMID- 27996161 TI - Medium-term assessment of cardiac function in pediatric cancer survivors. Comparison of different echocardiographic methods, cardiac MRI and cardiac biomarker testing in adolescent cancer survivors. AB - PURPOSE: To evaluate the feasibility and correlation of 3D echocardiography (echo) and cardiac biomarkers with cardiac MRI, in surveillance of cardiac function for cancer survivors. METHODS: Subjects >=10 years of age who have survived >2 years after completion of cancer treatment from a single center were enrolled. Cardiac MRI and 3D echo images were obtained on the same day when routine echo was obtained. On the same day, along with annual routine blood test, cardiac biomarkers N-terminal pro-B-type natriuretic peptide levels (NT-proBNP) and troponin-I levels were also measured. RESULTS: Cardiac MRI was feasible in all 50 subjects. Three-dimensional echo and 2D echo images were of poor quality in four subjects. With a median duration of remission of 10 years, there were four subjects with mild LV dysfunction (cardiac MRI LV EF of<53%). None had MRI EF <50%, and nine subjects had LVEF <55%. M-mode echo overestimated EF more than 2D and 3D echo. Two-dimensional and 3D echo methods had much tighter limits of agreement for LV EF. For measurement of LVEF, 3D echo had a lower % error than 2D echo or M-mode echo. One subject had an abnormal troponin-I level and another one had an elevated NT-proBNP. CONCLUSIONS: Three-dimensional echo can be performed in most adolescent cancer survivors, and it correlates well with MRI. Further large-scale research is required in assessing utility of cardiac biomarkers in pediatric cancer survivors. PMID- 27996162 TI - Effect of NR5A2 inhibition on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers. AB - NR5A2 (aka LRH-1) has been identified as a pancreatic cancer susceptibility gene with missing biological link. This study aims to demonstrate expression and potential role of NR5A2 in pancreatic cancer. NR5A2 expression was quantified in resected pancreatic ductal adenocarcinomas and the normal adjacent tissues of 134 patients by immunohistochemistry. The intensity and extent of NR5A2 staining was quantified and analyzed in association with overall survival (OS). The impact of NR5A2 knockdown on pancreatic cancer stem cell (CSC) properties and epithelial mesenchymal transition (EMT) markers was examined in cancer cells using RT-PCR and Western Blot. NR5A2 was overexpressed in pancreatic tumors, the IHC-staining H score (mean +/- SE) was 96.4 +/- 8.3 in normal versus 137.9 +/- 8.2 in tumor tissues (P < 0.0001). Patients with a higher NR5A2 expression had a median survival time 18.4 months compared to 23.7 months for those with low IHC H scores (P = 0.019). The hazard ratio of death (95% confidence interval) was 1.60 (1.07 2.41) after adjusting for disease stage and tumor grade (P = 0.023). NR5A2 was highly expressed in pancreatic cancer sphere forming cells. NR5A2-inhibition by siRNA was associated with reduced sphere formation and decreased levels of CSCs markers NANOG, OCT4, LIN28B, and NOTCH1. NR5A2 knockdown also resulted in reduced expression of FGB, MMP2, MMP3, MMMP9, SNAIL, and TWIST, increased expression of epithelial markers E-cadherin and beta-catenin, and a lower expression of mesenchymal marker Vimentin. Taken together, our findings suggest that NR5A2 could play a role in CSC stemness and EMT in pancreatic cancer, which may contribute to the worse clinical outcome. PMID- 27996163 TI - Study of IL4-590C/T and IL6-174G/C Gene Polymorphisms in Type 2 Diabetic Patients With Chronic Kidney Disease in North Indian Population. AB - To explore the associations between potential functional promoter polymorphisms in pro-inflammatory and anti-inflammatory (IL-4(-590C/T) and IL-6(-174G/C) cytokine genes, and kidney dysfunction in North Indian type 2 diabetic subjects with chronic kidney disease. A total of 150 subjects aged 25-75 year were included in this study. The glomerular filtration rate (GFR) and serum creatinine were estimated. PCR was performed to analyse genotype distribution in IL-4 ( 590T/C) and IL-6 (-174G/C) among healthy, type 2 diabetic patients with or without CKD. The genotype distributions were determined by Hardy-Weinberg equilibrium. CKD patients showed lower GFR (59.36 +/- 1.33 ml/min/1.73 m2 ) and higher serum creatinine (1.93 +/- 0.99% mg) level in comparison to diabetic patients without CKD and healthy subjects. Genotypic distribution of the different genotypes among the study groups in IL-4 gene was genotype CC = 30, TC = 12, and TT = 8 in CKD patients. In type 2 diabetic patients without CKD, genotype distribution was CC = 38, TC = 10, and TT = 2. In healthy subjects, distribution of genotype was CC = 35, TC = 14, and TT = 1. The distribution of different genotype among the study groups for IL-6 gene was GG = 27, GC = 20, and CC = 3 in healthy subjects; GG = 28, GC = 19, and CC = 3 in diabetic patients without CKD and GG = 38, GC = 11, and CC = 1 in diabetic patients with CKD. There was no significant difference in the distribution of genotype frequencies between healthy subjects and diabetic patients without CKD but a significant difference was found in diabetic patients with CKD. The functional promoter polymorphisms IL4-590C/T and IL6-174G/C, which affect the IL-4 and IL-6 levels in north Indian subjects, were associated with kidney dysfunction and CKD. J. Cell. Biochem. 118: 1803-1809, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27996165 TI - Mimicking Classical Conditioning Based on a Single Flexible Memristor. AB - The mimicking of classical conditioning, including acquisition, extinction, recovery, and generalization, can be efficiently achieved by using a single flexible memristor. In particular, the experiment of Pavlov's dog is successfully demonstrated. This demonstration paves the way for reproducing advanced neural processes and provides a frontier approach to the design of artificial intelligence systems with dramatically reduced complexity. PMID- 27996164 TI - Neoalbaconol inhibits angiogenesis and tumor growth by suppressing EGFR-mediated VEGF production. AB - Neoalbaconol, derived from Albatrellus confluens, shows anti-cancer activities in the previously study, but its role in angiogenesis is unknown. Here, we determined whether neoalbaconol could attenuate angiogenesis and how does it occur. Data demonstrated that neoalbaconol could inhibit the proliferation of breast cancer cells and induce apoptosis. Also, neoalbaconol suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. VEGF receptor activation and the downstream signal transduction cascades activation were inhibited by neoalbaconol. Additionally, neoalbaconol blocked EGFR-mediated VEGF production. EGFR overexpression reversed the neoalbaconol-induced VEGF reduction, confirming the importance of the EGFR inhibition in anti-angiogenesis of neoalbaconol. Furthermore, neoalbaconol inhibited tumor growth and tumor angiogenesis in a breast cancer xenograft model in vivo. Taken together, these results indicate that neoalbaconol could inhibit tumor angiogenesis and growth through direct suppression effects on vascular endothelial cells and reduction of proangiogenic factors in cancer cells. PMID- 27996166 TI - A Stochastic Model to Assess the Effect of Meat Inspection Practices on the Contamination of the Pig Carcasses. AB - The objective of meat inspection is to promote animal and public health by preventing, detecting, and controlling hazards originating from animals. With the improvements of sanitary level in pig herds, the hazards profile has shifted and the inspection procedures no longer target major foodborne pathogens (i.e., not risk based). Additionally, carcass manipulations performed when searching for macroscopic lesions can lead to cross-contamination. We therefore developed a stochastic model to quantitatively describe cross-contamination when consecutive carcasses are submitted to classic inspection procedures. The microbial hazard used to illustrate the model was Salmonella, the data set was obtained from Brazilian slaughterhouses, and some simplifying assumptions were made. The model predicted that due to cross-contamination during inspection, the prevalence of contaminated carcass surfaces increased from 1.2% to 95.7%, whereas the mean contamination on contaminated surfaces decreased from 1 logCFU/cm2 to -0.87 logCFU/cm2, and the standard deviations decreased from 0.65 to 0.19. These results are explained by the fact that, due to carcass manipulations with hands, knives, and hooks, including the cutting of contaminated lymph nodes, Salmonella is transferred to previously uncontaminated carcasses, but in small quantities. These small quantities can easily go undetected during sampling. Sensitivity analyses gave insight into the model performance and showed that the touching and cutting of lymph nodes during inspection can be an important source of carcass contamination. The model can serve as a tool to support discussions on the modernization of pig carcass inspection. PMID- 27996167 TI - Intracellular Chloride Concentration Changes Modulate IL-1beta Expression and Secretion in Human Bronchial Epithelial Cultured Cells. AB - Cystic fibrosis (CF) is caused by mutations in the CFTR gene, which encodes a cAMP-regulated chloride channel. Several cellular functions are altered in CF cells. However, it is not clear how the CFTR failure induces those alterations. We have found previously several genes differentially expressed in CF cells, including c-Src, MUC1, MTND4, and CISD1 (CFTR-dependent genes). Recently, we also reported the existence of several chloride-dependent genes, among them GLRX5 and RPS27. Here, varying the intracellular chloride concentration [Cl- ]i of IB3-1 CF bronchial epithelial cells, we show that IL-1beta mRNA expression and secretion are also under Cl- modulation. The response to Cl- is biphasic, with maximal effects at 75 mM Cl- . The regulation of the IL-1beta mRNA expression involves an IL-1beta autocrine effect, since in the presence of the IL-1beta receptor antagonist IL1RN or anti-IL-1beta blocking antibody, the mRNA response to Cl- disappeared. Similar effects were obtained with the JNK inhibitor SP600125, the c Src inhibitor PP2 and the IKK inhibitor III (BMS-345541). On the other hand, the IL-1beta secretion is still modulated by Cl- in the presence of IL-1RN, IL-1beta blocking antibody, or cycloheximide, suggesting that Cl- is affecting the IL 1beta maturation/secretion, which in turn starts an autocrine positive feedback loop. In conclusion, the Cl- anion acts as a second messenger for CFTR, modulating the IL-1beta maturation/secretion. The results also imply that, depending on its intracellular concentration, Cl- could be a pro-inflammatory mediator. J. Cell. Biochem. 118: 2131-2140, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27996168 TI - Follicle-Stimulating Hormone beta-Subunit Potentiates Bone Morphogenetic Protein 9-Induced Osteogenic Differentiation in Mouse Embryonic Fibroblasts. AB - Postmenopausal osteoporosis (PMOP)-related fractures usually result in morbidity and mortality in aging women, so it remains a global public health concern, and new effective safe treatments are urgently needed recently. Efficient osteogenesis from mesenchymal stem cells (MSCs) would have the clinical application potential in treating multiple osteal disorders. Follicle-stimulating hormone (FSH), a pituitary glycoprotein hormone highly associated with menopausal bone turnover, whose peculiar part of receptor binding is follicle-stimulating hormone beta-subunit (FSHbeta). Bone morphogenetic protein 9 (BMP9), a potent osteogenic factor, can up-regulate FSHbeta in mouse embryonic fibroblasts (MEFs). However, it is unclear, whether extrapituitary FSHbeta affects BMP9-induced osteogenesis in MEFs. In this study, we investigated the role of FSHbeta in BMP9 induced osteogenesis in MEFs. We found that exogenous expression of FSHbeta significantly increased BMP9-induced alkaline phosphatase activity (ALP), the expression of osteogenic transcriptional factors, Runx2 and Osx, and the established late osteogenic markers, osteopontin (OPN) and osteocalcin (OCN), so does the ectopic bone formation. Mechanistically, FSHbeta dramatically enhanced BMP9-induced BMP/Smad signal transduction, presenting the augment phosphorylation of Smad1/5/8, whereas treatment with anti-FSHbeta antibodies suppressed these effects. An adenylate cyclase inhibitor obviously suppressed ALP and BMP/Smad signal transduction induced by BMP9 or the combination of BMP9 and FSHbeta in MEFs. Collectively, our findings suggested that FSHbeta may promote BMP9-induced activation of BMP/Smad signaling through a FSH/FSH receptor (FSHR)/cAMP dependent pathway in MEFs partly. J. Cell. Biochem. 118: 1792-1802, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27996169 TI - Palladium-Catalyzed Asymmetric Allylic Allylation of Racemic Morita-Baylis Hillman Adducts. AB - A palladium-catalyzed asymmetric allyl-allyl cross-coupling of acetates of racemic Morita-Baylis-Hillman adducts and allylB(pin) has been developed using a spiroketal-based bis(phosphine) as the chiral ligand, thus affording a series of chiral 1,5-dienes bearing a vinylic ester functionality in good yields, high branched regioselectivities, and uniformly excellent enantioselectivities (95-99 % ee). Further synthetic manipulations of the allylation products provided novel ways for rapid access to a range of chiral polycyclic lactones and polycyclic lactams, as well as the antidepressant drug (-)-Paroxetine, in high optical purities. PMID- 27996171 TI - Rhodium-Catalyzed Synthesis and Optical Properties of Silicon-Bridged Arylpyridines. AB - A convergent and regioselective synthesis of silicon-bridged 4-arylpyridines has been developed through a rhodium-catalyzed [2+2+2] cycloaddition of silicon containing diynes with nitriles. The absorption and emission properties of these compounds have been examined and could be tuned by varying the substituent on the benzene ring, as well as through the protonation or alkylation of the nitrogen atom on the pyridine ring. A catalytic asymmetric synthesis of silicon-centered axially chiral spirocyclic derivatives has also been achieved with high enantioselectivity by using a newly modified MeO-MOP (MeO-MOP=2 (diphenylphosphino)-2'-methoxy-1,1'-binaphthyl) derivative as the chiral ligand. These spirocyclic compounds were found to be CPL-active (CPL=circularly polarized luminescence), representing the first CPL-active compounds based on the chirality at silicon. PMID- 27996170 TI - Association between patterns of jaw motor activity during sleep and clinical signs and symptoms of sleep bruxism. AB - The aim of this study was to investigate the association between patterns of jaw motor activity during sleep and clinical signs and symptoms of sleep bruxism. A total of 35 university students and staff members participated in this study after providing informed consent. All participants were divided into either a sleep bruxism group (n = 21) or a control group (n = 14), based on the following clinical diagnostic criteria: (1) reports of tooth-grinding sounds for at least two nights a week during the preceding 6 months by their sleep partner; (2) presence of tooth attrition with exposed dentin; (3) reports of morning masticatory muscle fatigue or tenderness; and (4) presence of masseter muscle hypertrophy. Video-polysomnography was performed in the sleep laboratory for two nights. Sleep bruxism episodes were measured using masseter electromyography, visually inspected and then categorized into phasic or tonic episodes. Phasic episodes were categorized further into episodes with or without grinding sounds as evaluated by audio signals. Sleep bruxism subjects with reported grinding sounds had a significantly higher total number of phasic episodes with grinding sounds than subjects without reported grinding sounds or controls (Kruskal Wallis/Steel-Dwass tests; P < 0.05). Similarly, sleep bruxism subjects with tooth attrition exhibited significantly longer phasic burst durations than those without or controls (Kruskal-Wallis/Steel-Dwass tests; P < 0.05). Furthermore, sleep bruxism subjects with morning masticatory muscle fatigue or tenderness exhibited significantly longer tonic burst durations than those without or controls (Kruskal-Wallis/Steel-Dwass tests; P < 0.05). These results suggest that each clinical sign and symptom of sleep bruxism represents different aspects of jaw motor activity during sleep. PMID- 27996172 TI - The protein interacting with carboxyl terminus-1 codon 389 polymorphism impairs protein interacting with carboxyl terminus-1 function and is a risk factor for uterine cervical cancer. AB - PICT-1 is a nucleolar protein with various tumor suppressor functions. Recently, PICT-1 expression was reported to be dramatically reduced in several cancers. To investigate the role of PICT-1 in uterine cervical carcinogenesis, we examined its gene mutations, protein expression, cellular localization, and effect on p53 stabilization. PCR-SSCP analysis of the entire coding region of PICT-1 showed that a polymorphism at codon 389 may increase the risk of uterine cervical cancers, and also identified a novel missense mutation. Expression of wild-type PICT-1 inhibited the degradation of p53 in the presence or absence of HPV 18 E6 viral protein in vitro, while the expression of codon 389 polymorphic PICT-1 had a diminished inhibitory effect on p53 degradation. Moreover, we observed that PICT-1 degradation was induced both independently and cooperatively by E6 and E7 proteins from high-risk HPVs, but only marginal degradation was observed with proteins from low-risk HPV. Immunohistochemical staining of tumor samples revealed that lower levels of PICT-1 were observed in samples from CIN III and cervical cancer tissues, compared to normal cervical epithelium and CIN I, II tissues (P < 0.05). The reduction of PICT-1 may therefore be an early event in uterine cervical tumorigenesis. Our results indicated that PICT-1 counteracts HPV induced p53 degradation and that aberrant PICT-1 function may contribute towards inactivating p53. Therefore, PICT-1 may play a critical role during the pathogenesis of uterine cervical cancers. PMID- 27996173 TI - The Set of Structural DNA-Nuclear Matrix Interactions in Neurons Is Cell-Type Specific and Rather Independent of Functional Constraints. AB - In metazoans, nuclear DNA is organized during the interphase in negatively supercoiled loops anchored to a compartment or substructure known as the nuclear matrix. The interactions between DNA and the nuclear matrix (NM) are of higher affinity than those between DNA and chromatin proteins since the last ones do not resist the procedures for extracting the NM. The structural interactions DNA-NM constitute a set of topological relationships that define a nuclear higher order structure (NHOS) although there are further higher order levels of organization within the nucleus. So far, the evidence derived from studies with primary hepatocytes and naive B lymphocytes indicates that the NHOS is cell-type specific at the local and at the large-scale level, and so it has been suggested that such NHOS is primary determined by structural and thermodynamic constraints. We carried out a comparative characterization of the NHOS of postmitotic cortical neurons with that of hepatocytes and naive B lymphocytes. Our results indicate that the NHOS of neurons is completely different at the large scale and at the local level from that one observed in hepatocytes or in naive B lymphocytes, confirming on the one hand that the set of structural DNA-NM interactions is cell type specific and supporting, on the other hand the notion that structural constraints that impinge on chromosomal DNA and the NM are more important for determining this NHOS than functional constraints related to replication and/or transcription. J. Cell. Biochem. 118: 2151-2160, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27996174 TI - Engineered Graphene Materials: Synthesis and Applications for Polymer Electrolyte Membrane Fuel Cells. AB - Engineered graphene materials (EGMs) with unique structures and properties have been incorporated into various components of polymer electrolyte membrane fuel cells (PEMFCs) such as electrode, membrane, and bipolar plates to achieve enhanced performances in terms of electrical conductivity, mechanical durability, corrosion resistance, and electrochemical surface area. This research news article provides an overview of the recent development in EGMs and EGM-based PEMFCs with a focus on the effects of EGMs on PEMFC performance when they are incorporated into different components of PEMFCs. The challenges of EGMs for practical PEMFC applications in terms of production scale, stability, conductivity, and coupling capability with other materials are also discussed and the corresponding measures and future research trends to overcome such challenges are proposed. PMID- 27996175 TI - Homogeneous and Heterogeneous Anion Sensing by a Molecular Cobalt-Vanadium Oxide. AB - Spectroscopic anion sensing is a vital non-invasive tool in chemistry and biology. Here, a molecular cobalt-vanadium-oxide cluster was shown to be capable of selectively binding and detecting various mono-anions in solution and immobilized on a solid support. The cluster anion [Co(X)V4 O12 ]3- (X=mono-anion, for example, halide, pseudohalide, carboxylate, etc.) was formed spontaneously upon anion addition by self-assembly in solution. The cluster showed distinct spectral changes upon anion binding that could be followed spectroscopically and visually owing to a significant change of the solution color. DFT computations showed that the anion binding observed experimentally was correlated to the relative cluster stabilities. Competitive-binding studies showed that selective anion binding was possible from a mixture of anions. Immobilization of the anion sensor on silica strips provided access to single-use dip-stick sensors for the facile detection of anions in solution. The system presented enables the development of homogeneous or heterogeneous molecular anion sensors with possible applications in chemistry, bio-medical scenarios, and under harsh environmental conditions. PMID- 27996176 TI - A Free-Standing Molecular Spin-Charge Converter for Ubiquitous Magnetic-Energy Harvesting and Sensing. AB - Magnetic-energy harvesting in a centimeter-sized free-standing (BEDT-TTF)C60 charge-transfer single crystal is demonstrated. The crystal shows sensitive magnetic-, thermal-, and mechanical-sensing ability, with an excellent piezoresistance coefficient of -5.1 * 10-6 Pa-1 . The self-powered sensing performance, together with its solution processability and flexibility, endow it with the capability of driving a new generation of noncontact magnetic-energy harvesting and sensing technologies. PMID- 27996177 TI - Peroxisome proliferator-activated receptor-beta/delta inhibits human neuroblastoma cell tumorigenesis by inducing p53- and SOX2-mediated cell differentiation. AB - Neuroblastoma is a common childhood cancer typically treated by inducing differentiation with retinoic acid (RA). Peroxisome proliferator-activated receptor-beta/delta, (PPARbeta/delta) is known to promote terminal differentiation of many cell types. In the present study, PPARbeta/delta was over expressed in three human neuroblastoma cell lines, NGP, SK-N-BE(2), and IMR-32, that exhibit high, medium, and low sensitivity, respectively, to retinoic acid induced differentiation to determine if PPARbeta/delta and retinoic acid receptors (RARs) could be jointly targeted to increase the efficacy of treatment. All-trans-RA (atRA) decreased expression of SRY (sex determining region Y)-box 2 (SOX2), a stem cell regulator and marker of de-differentiation, in NGP and SK-N BE(2) cells with inactive or mutant tumor suppressor p53, respectively. However, atRA did not suppress SOX2 expression in IMR-32 cells carrying wild-type p53. Over-expression and/or ligand activation of PPARbeta/delta reduced the average volume and weight of ectopic tumor xenografts from NGP, SK-N-BE(2), or IMR-32 cells compared to controls. Compared with that found with atRA, PPARbeta/delta suppressed SOX2 expression in NGP and SK-N-BE(2) cells and ectopic xenografts, and was also effective in suppressing SOX2 expression in IMR-32 cells that exhibit higher p53 expression compared to the former cell lines. Combined, these observations demonstrate that activating or over-expressing PPARbeta/delta induces cell differentiation through p53- and SOX2-dependent signaling pathways in neuroblastoma cells and tumors. This suggests that combinatorial activation of both RARalpha and PPARbeta/delta may be suitable as an alternative therapeutic approach for RA-resistant neuroblastoma patients. PMID- 27996179 TI - Crestal Bone Loss Around Adjacent Dental Implants Restored with Splinted and Nonsplinted Fixed Restorations: A Systematic Literature Review. AB - PURPOSE: The aim of this systematic review was to compare the crestal bone loss around splinted and nonsplinted adjacent implants. MATERIALS AND METHODS: To address the focused question, "Is crestal bone loss around adjacent implants different with splinted from that with nonsplinted restorations?," indexed databases were searched from 1965 up to and including May 2016 using various combinations of the following keywords: "implant," "splinted," "nonsplinted," "unsplinted," "connected," "unconnected," "nonconnected," and "bone loss." Letters to the editor, commentaries, historic reviews, case reports, case series, animal studies, and studies on full-arch rehabilitation were excluded. RESULTS: Six studies were included with titanium implants ranging from 114 to 1187 implants. All studies had nonsplinted and splinted restorations that ranged from 20 to 234 restorations and from 60 to 970 restorations, respectively. In all the studies, the follow-up period after the restoration placement ranged between 1 and 22 years, with a mean follow-up ranging between 3 and 10.18 +/- 3.18 years. In all studies, the mean crestal bone loss for implants restored with nonsplinted restorations ranged between 0.30 +/- 0.65 and 1.3 +/- 0.2 mm, whereas the mean crestal bone loss for implants restored with splinted restorations ranged between 0.50 +/- 0.8 and 1.22 +/- 0.95 mm. CONCLUSION: Within the limitations of this review it is concluded that adjacent implants restored with splinted and nonsplinted fixed restorations did not exhibit a difference in crestal bone loss. The evidence from this systematic review suggests further investigation. PMID- 27996178 TI - Quantitative Analysis of Extracranial Arterial Tortuosity in Patients with Sickle Cell Disease. AB - PURPOSE: Compared to the intracranial vasculature in sickle cell disease (SCD) patients, the morphologic changes of the extracranial vasculature in SCD patients are less well understood. The purpose of this study was to evaluate the tortuosity of the extracranial carotid and vertebral arteries in patients with SCD compared to age-matched controls. METHODS: Following Institution Review Board approval, between January 2004 and December 2013, Magnetic resonance angiogram neck examinations were retrospectively reviewed on 56 patients with SCD and 56 age-matched controls. Vessel tortuosity was measured as curved vector lengths in the common carotid, extracranial internal carotid, and vertebral arteries bilaterally. Correlation of vessel tortuosity with age and hematocrit level was assessed. Paired and unpaired Student's t-tests were performed to determine within and between group differences. RESULTS: Greater tortuosity in extracranial carotid and vertebral arteries were noted in patients with SCD as compared to age matched control patients (P < .001). Greater differences in tortuosity between carotid and vertebral arteries were noted in SCD patients as compared to differences in control patients. Incidence of infarction was significantly associated with greater tortuosity of right carotid (P = .002), right (P = .004), and left (P = .020) vertebral arteries. CONCLUSIONS: Extracranial carotid and vertebral arterial tortuosity is increased in SCD patients. This could be related to aberrations in hemodynamics from nonlaminar flow in these vessels. These increases in extracranial vascular tortuosity could potentially lead to alterations in intracranial vascular tortuosity and may be an independent risk factor for cerebral infarct. PMID- 27996180 TI - Nonlethal laparoscopic detection of intersex (testicular oocytes) in largemouth bass (Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). AB - Intersex in wild fish populations has received considerable attention in the scientific literature and public media. Conventional detection of testicular oocytes, the presence of immature oocytes within testis of male fish, commonly employs transverse sectioning of excised testis and is lethal. The present study used a nonlethal laparoscopic technique to collect biopsies of testis from black bass, entering the body cavity via the genital pore. Detection of testicular oocytes was compared between biopsy and conventional methods using 79 smallmouth bass (Micropterus dolomieu) from 8 sites and 68 largemouth bass (Micropterus salmoides) from 4 sites. The 2 methods performed similarly at sites where testicular oocyte severity was moderate or high (6 of 8 smallmouth bass sites), whereas transverse sectioning resulted in superior testicular oocyte detection at sites where severity was low (2 of 8 smallmouth bass sites and all 4 largemouth bass sites). In smallmouth bass, testicular oocyte prevalence by transverse and biopsy methods was strongly correlated across sites (r2 = 0.81) and severity reported by enumeration of testicular oocytes was moderately correlated across sites (r2 = 0.59). Survival of a subset of largemouth bass (n = 20) to 28 d after laparoscopic surgery was 90%. The present research indicates that laparoscopy may be useful for monitoring the prevalence and severity of testicular oocytes in Micropterus species, particularly when lethal sampling is precluded. Environ Toxicol Chem 2017;36:1924-1933. (c) 2016 SETAC. PMID- 27996181 TI - Graphene Substrate for van der Waals Epitaxy of Layer-Structured Bismuth Antimony Telluride Thermoelectric Film. AB - Graphene as a substrate for the van der Waals epitaxy of 2D layered materials is utilized for the epitaxial growth of a layer-structured thermoelectric film. Van der Waals epitaxial Bi0.5 Sb1.5 Te3 film on graphene synthesized via a simple and scalable fabrication method exhibits good crystallinity and high thermoelectric transport properties comparable to single crystals. PMID- 27996182 TI - Intrafibrillar mineralization of polyacrylic acid-bound collagen fibrils using a two-dimensional collagen model and Portland cement-based resins. AB - The biomimetic remineralization of apatite-depleted dentin is a potential method for enhancing the durability of resin-dentin bonding. To advance this strategy from its initial proof-of-concept design, we sought to investigate the characteristics of polyacrylic acid (PAA) adsorption to desorption from type I collagen and to test the mineralization ability of PAA-bound collagen. Portland cement and beta-tricalcium phosphate (beta-TCP) were homogenized with a hydrophilic resin blend to produce experimental resins. The collagen fibrils reconstituted on nickel (Ni) grids were mineralized using different methods: (i) group I consisted of collagen treated with Portland cement-based resin in simulated body fluid (SBF); (ii) group II consisted of PAA-bound collagen treated with Portland cement-based resin in SBF; and (iii) group III consisted of PAA bound collagen treated with beta-TCP-doped Portland cement-based resin in deionized water. Intrafibrillar mineralization was evaluated using transmission electron microscopy. We found that a carbonyl-associated peak at pH 3.0 increased as adsorption time increased, whereas a hydrogen bond-associated peak increased as desorption time increased. The experimental resins maintained an alkaline pH and the continuous release of calcium ions. Apatite was detected within PAA-bound collagen in groups II and III. Our results suggest that PAA-bound type I collagen fibrils can be mineralized using Portland cement-based resins. PMID- 27996183 TI - Relationship Between ABCB1 Polymorphisms and Cold Pain Sensitivity Among Healthy Opioid-naive Malay Males. AB - BACKGROUND: Endogenous and exogenous opioids are substrates of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Genetic polymorphisms of ABCB1 may contribute to interindividual differences in pain modulation and analgesic responses. We investigated the relationship between ABCB1 polymorphisms and cold pain sensitivity among healthy males. METHODS: Cold pain responses, including pain threshold and pain tolerance, were measured using the cold-pressor test (CPT). DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms, including c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642), using the allelic discrimination real-time polymerase chain reaction. RESULTS: A total of 152 participants were recruited in this observational study. Frequencies of mutated allele for c.1236C>T, c.2677G>T/A, and c.3435C>T polymorphisms were 56.6%, 49.7%, and 43.4%, respectively. Our results revealed an association of the CGC/CGC diplotype (c.1236C>T, c.2677G>T/A, and c.3435C>T) with cold pain sensitivity. Participants with the CGC/CGC diplotype had 90% and 72% higher cold pain thresholds (87.62 seconds vs. 46.19 seconds, P = 0.010) and cold pain tolerances (97.24 seconds vs. 56.54 seconds, P = 0.021), respectively, when compared with those without the diplotype. CONCLUSION: The CGC/CGC diplotype of ABCB1 polymorphisms was associated with variability in cold pain threshold and pain tolerance in healthy males. PMID- 27996184 TI - Anastomotic stenosis after coloanal, colorectal and ileoanal anastomosis: what is the best management? AB - AIM: To assess the results of treatment for colorectal (CRA), coloanal (CAA) or ileal pouch-anal (IPAA) anastomotic stenosis (AS). METHOD: All patients operated on for AS from 1995 to 2014 were included. Success was defined as the absence of an additional surgical procedure for AS during 12 months after the last procedure and the absence of a stoma at the end of follow-up. RESULTS: Fifty consecutive patients presenting with AS after CRA (n = 16, 32%), CAA (n = 18, 36%) or IPAA (n = 16, 32%), performed for colorectal cancer (n = 28, 56%), familial adenomatous polyposis (n = 5, 10%), inflammatory bowel disease (n = 8, 16%), diverticulitis (n = 4, 8%), benign colorectal neoplasia (n = 3, 6%) or other (n = 2, 4%) underwent a total of 99 procedures including digital (n = 14, 14%), instrumental (n = 38, 38%) or endoscopic dilatation (n = 5, 5%), transanal AS stricturoplasty (n = 9, 10%), transanal circular stapler resection (n = 11, 11%) or transabdominal redo-anastomosis (n = 22, 22%). Overall the per-procedure success rate was 53% (52/99). Success rates were 36% (5/14) for digital dilatation, 40% (15/38) for instrumental dilatation, 20% (1/5) for endoscopic dilatation, 64% (7/11) for circular stapler resection, 89% (8/9) for stricturoplasty and 73% (16/22) for transabdominal redo-anastomosis. After a mean follow-up of 46 months, 42/50 (84%) patients had treatment that was considered successful. Multivariate analysis identified redo-anastomosis [OR = 5.1 (95% CI: 1.4-18.7), P = 0.003] as the only independent prognostic factor for success. CONCLUSION: AS should be managed according to a step-up strategy. Conservative procedures are associated with acceptable success rates. If these fail, transabdominal redo-anastomosis is associated with the highest probability of success. PMID- 27996185 TI - Chiral Lithium Amides: Tuning Asymmetric Synthesis on the Basis of Structural Parameters. AB - An overview on the structural arrangements adopted by Chiral Lithium Amides (CLAs), alone or in mixed complexes, is presented. These species are important reagents for asymmetric synthesis and understanding their organization is essential to improve their design and the reaction conditions. PMID- 27996186 TI - N-Heterocyclic Carbene Stabilized Boryl Radicals. AB - The reaction of the 2-(trimethylsilyl)imidazolium triflate 9 with diarylboron halides (4-R-C6 H4 )2 BX (R=H, X=Br; R=CH3 , X=Cl; R=CF3 , X=Cl) afforded the NHC stabilized borenium cations 10 a-c. Cyclic voltammetry revealed a linear correlation between the Hammett parameter sigmap of the para substituent and the half-wave potential. Chemical reduction with decamethylcobaltocene, [(C5 Me5 )2 Co], furnished the corresponding radicals 11 a-c; their characterization by EPR spectroscopy confirmed the paramagnetic character of 11 a-c, with large hyperfine coupling constants to the boron isotopes 11 B and 10 B, while delocalization of the unpaired electron into the NHC is negligible. DFT calculations of the percentage of spin density distribution between the carbene (NHC) and the boryl fragments (BR2 ) revealed for 11 a-c a spin density ratio (BR2 /NHC) of ca. 9:1, which underlines their distinct boryl radical character. The molecular structure of the most stable species 11 c was established by X-ray diffraction analysis. PMID- 27996188 TI - Quenching of electronically excited N2 molecules and Tb3+ /Eu3+ ions by polyatomic sulfur-containing gases upon triboluminescence of inorganic lanthanide salts. AB - The triboluminescence of Eu2 (SO4 )3 .8H2 O and Tb2 (SO4 )3 .8H2 O crystals in an atmosphere of sulfur dioxide (SO2 ) or sulfur hexafluoride (SF6 ) was studied. Quenching of the gaseous (emitter N2 ) and solid-state (emitter Ln3+ ) components of the triboluminescence (TL) emission spectrum was seen when compared with the TL spectra of the crystals in air. One reason for the quenching is a reduction in the effective charge both on the crystal surface and in micro-cracks under an SO2 or SF6 atmosphere, leading to a decrease in the probability of electrical breakdown and a reduction in electric field strength responsible for the electroluminescence excitation of lanthanide ions in TL. In an SO2 atmosphere, there is an additional mode of quenching, as confirmed by quenching of the crystal photoluminescence (emitter Ln3+ ). It is supposed that this quenching is due to an exchange of energy on electronic excitation of the lanthanide ions to the vibrational sublevels of the SO2 molecules adsorbed on the crystal surface. Another additional channel of TL quenching originates from non-radiative transfer of excitation energy during collisions between the *N2 and SO2 molecules in the gaseous phase. PMID- 27996189 TI - 'Canaries in the mine'. Parents of adult children with schizophrenia: An integrative review of the literature. AB - The purpose of this integrative review was to evaluate the current state of knowledge of parents who have adult children diagnosed with schizophrenia and their relationship with mental health professionals. Findings indicated that parents (primarily mothers) believed they intuitively knew when their adult children were becoming unwell and that they doggedly pursued connections with mental health care providers. Five themes were evident in the literature: trusting your instincts, feeling dismissed and devalued, making connections and making concessions, living with distress and sorrow, and becoming your own health care provider. The implications of the findings on mental health nursing practice indicate that professional family relationships were not ideal, and that parents wanted to improve these relationships. Parents wanted health-care professionals to respond to their requests for help for both their children and for themselves, and wanted to be able to help the mental health team to help their adult children. PMID- 27996187 TI - Gasserian Ganglion and Retrobulbar Nerve Block in the Treatment of Ophthalmic Postherpetic Neuralgia: A Case Report. AB - OBJECTIVES: Varicella zoster virus reactivation can cause permanent histological changes in the central and peripheral nervous system. Neural inflammatory changes or damage to the dorsal root ganglia sensory nerve fibers during reactivation can lead to postherpetic neuralgia (PHN). For PHN of the first division of the fifth cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence of inflammatory change in the ganglion and adjacent ocular neural structures. First division trigeminal nerve PHN can prove to be difficult and sometimes even impossible to manage despite the use of a wide range of conservative measures, including anticonvulsant and antidepressant medication. Steroids have been shown to play an important role by suppressing neural inflammatory processes. We therefore chose the trigeminal ganglion as an interventional target for an 88 year-old woman with severe ophthalmic division PHN after she failed to respond to conservative treatment. METHODS: Under fluoroscopic guidance, a trigeminal ganglion nerve block was performed with lidocaine combined with dexamethasone. A retrobulbar block with lidocaine and triamcinolone settled residual oculodynia. RESULTS: At 1-year follow-up, the patient remained pain free and did not require analgesic medication. CONCLUSION: To our knowledge, this is the first reported case of ophthalmic division PHN successfully treated with a combination of trigeminal ganglion and retrobulbar nerve block using a local anesthetic agent and steroid for central and peripheral neural inflammatory processes. PMID- 27996190 TI - Brute Force Orientation of Matrix-Isolated Molecules: Reversible Reorientation of Formaldehyde in an Argon Matrix toward Perfect Alignment. AB - Brute force orientation by an electric field is a promising way of controlling the orientation of polar molecules in the gas phase, but its application to condensed-phase molecules has been very limited. We studied the reorientation of formaldehyde molecules in a solid Ar matrix under the influence of a strong electric field using reflection absorption infrared spectroscopy. Asymptotically perfect alignment of the formaldehyde molecules along the field was achieved at field strengths exceeding 1*108 V m-1 . The vibrational bands of the aligned molecules exhibited a unidirectional Stark shift proportional to the field strength. The reorientation of the molecules was reversible despite the cryogenic solid environment of the system. PMID- 27996191 TI - Validation of the Greek Version of the Fibromyalgia Rapid Screening Tool. AB - BACKGROUND AND AIM: The Fibromyalgia Rapid Screening Tool (FiRST) is a brief, simple, and straightforward self-administered questionnaire that was developed by Perrot et al. for the detection of fibromyalgia syndrome in patients with diffuse chronic pain. The aim of our study was to develop and validate the Greek version of FiRST. METHODS: The study was set up as a prospective observational study. The original French version of FiRST was adapted into Greek using forward and backward translation. Patients with chronic diffuse pain with a clinical diagnosis of fibromyalgia and osteoarthritis based on the criteria of the American College of Rheumatology were invited to participate to the study. RESULTS: Of the 101 patients who met our inclusion criteria, 42 were diagnosed with fibromyalgia and 59 with osteoarthritis. The 2 groups did not differ significantly regarding gender and pain characteristics (duration, intensity). Cronbach's alpha coefficient was 0.79. Receiver operating characteristic analysis showed an area under the curve of 89% (95% confidence interval = 83 to 95%; SE: 0.032, P < 0.001). At a cutoff score of >= 5, FiRST showed a sensitivity of 86%, a specificity of 83%, a positive predictive value of 78%, and a negative predictive value of 89%. The intraclass coefficient for the test-retest reliability was 0.96. CONCLUSION: The Greek version of FiRST is a valid screening tool for fibromyalgia in daily practice. PMID- 27996193 TI - Gold(I)/Chiral N,N'-Dioxide-Nickel(II) Relay Catalysis for Asymmetric Tandem Intermolecular Hydroalkoxylation/Claisen Rearrangement. AB - A highly efficient asymmetric cascade reaction between alkynyl esters and allylic alcohols has been realized. Key to success was the combination of a hydroalkoxylation reaction catalyzed by a pi-acidic gold(I) complex with a Claisen rearrangement catalyzed by a chiral Lewis acidic N,N'-dioxide-nickel(II) complex. A range of acyclic alpha-allyl beta-keto esters were synthesized in high yields (up to 99 %) with good diastereoselectivities (up to 97:3) and excellent enantioselectivities (up to 99 % ee) under mild reaction conditions. These products can be easily transformed into optically active beta-hydroxy esters, beta-hydroxy acids, or 1,3-diols. PMID- 27996192 TI - Copper/P(tBu)3 -Mediated Regiospecific Synthesis of Fused Furans and Naphthofurans. AB - A novel [3+2] cycloaddition between a variety of cyclic ketones and diverse olefins or alkynes can be effectively promoted by copper in combination with the tri-tert-butylphosphine [P(tBu)3 ] ligand. This protocol exhibits excellent selectivity and provides an exemplary set of fused heterocycles in good to excellent yields. Present strategy also represents an extremely simple and atom economic way to construct substituted fused furans and naphthofurans from readily available starting materials under mild reaction conditions. The utility of the method is further demonstrated by the synthesis of chiral furans from (R)-(-) carvone and (S)-(+)-carvone. A plausible mechanism involving the oxidative radical cyclization has been suggested based on experimental observations. PMID- 27996194 TI - Photoactivatable Substrates: A Material-Based Approach for Dissecting Cell Migration. AB - Photoactivatable substrates, which show changes in surface cell adhesiveness in response to photoirradiation, are promising platforms for cell manipulation with high spatiotemporal resolution. In addition to having applications in cell and tissue engineering, these materials are unique tools for basic biological sciences research, and they complement conventional genetic engineering technologies. One of the most useful applications is in the study of cell migration, which occurs in various physiological and pathological processes. In this personal account, I provide a brief overview of the development of photoactivatable substrates and their applications, highlighting in particular the contributions of our research group to collective cell migration studies. This material-based approach is useful for dissecting the molecular biological and mechanobiological aspects of the regulatory mechanisms in the cellular social activities. PMID- 27996195 TI - Histological and clinical evaluation of the hard palate mucous membrane graft for treatment of lower eyelid retraction. AB - PURPOSE: To evaluate the histological appearances of the epithelial cells and the clinical effect of the hard palate mucous membrane (HPM) graft for the treatment of lower eyelid retraction (LER). METHODS: This was a follow-up study involving 15 patients, with a total of 16 eyes operated. Five patients had LER as a result of Graves' ophthalmopathy and/or inferior rectus recession, six patients because of wearing an eye prosthesis, two patients because of previous tumour excision, one patient because of proptosis due to sphenoid wing meningioma and one patient because of previous lower eyelid blepharoplasty. Three imprint biopsies were taken from each patient, one from the tarsal conjunctiva in the healthy eye, one from the graft in the operated eye and one from unoperated hard palate. The inferior scleral show was measured on pre- and postoperative photographs and related to the horizontal corneal diameter. RESULTS: Median follow-up time was 21.2 [range 4.5-87.9] months. Imprints from the graft and the hard palate showed equally large epithelial cells; imprints from conjunctiva showed small epithelial cells. The mean (+/-SD) scleral show was 0.12 +/- 0.09 cornea diameter before surgery and 0.0003 +/- 0.08 cornea diameter at invited follow-up (p < 0.001, paired t-test). Corrected for direction of gaze, the mean improvement in scleral show was 0.12 +/- 0.08 cornea diameter. Thirteen of 14 patients were satisfied with the final result. CONCLUSION: A HPM graft for LER maintains its native epithelial morphology and gives a lasting improvement in most patients. PMID- 27996197 TI - CO Adsorption on GaPd-Unravelling the Chemical Bonding in Real Space. AB - The electron localizability indicator-an efficient quantum chemical tool for analysis of chemical bonding-is applied to unveil the chemical bonding behind the CO adsorption on the (1? 1? 1? ) surface of the highly selective semi hydrogenation catalyst GaPd. Refining the commonly applied Blyholder model, the obtained results are in excellent agreement with previous experimental and theoretical findings. The clean GaPd(1? 1? 1? ) surface presents unshielded negatively charged Pd centers and positively charged Ga species partially shielded by dangling bonds. The CO molecule adsorbs on-top of the Pd centers perperdicular to the surface, while no CO-Ga interaction is observed. The chemical bonding analysis results in deep understanding, thus enabling a cost efficient route to innovative materials by reverse engineering. PMID- 27996196 TI - Reverse Translational Study of Fenofibrate's Observed Effects in Diabetes Associated Retinopathy. AB - Clinical trials suggest that fenofibrate reduces the progression of retinopathies in patients with type 2 diabetes. Furthermore, patients with retinopathies have elevated levels of inflammatory chemokines and dysfunctional retinal angiogenesis. Therefore, we investigated the effects of fenofibrate on the production of inflammatory chemokines and genes associated with angiogenesis. Retinal pigment epithelial cells (RPECs) were cultured with IL-1beta and fenofibrate ranging from 1-50 MUM. ENA-78, IL-8, and RANTES were measured in cell culture by ELISA. ENA-78, ABCA1, and ABCG1 gene expression were tested by RT-PCR. IL-1beta significantly induced the production of ENA-78, IL-8, and RANTES. Fenofibrate at concentrations of 25-50 uM blunted the IL-1beta induced production of ENA-78 (p < 0.05) with no significant effects on RANTES and IL-8. Fenofibrate also reduced the expression of the ENA-78 gene as well as ABCA1 and ABCG1, which are genes involved in angiogenesis. Fenofibrate decreases ENA-78 production and ABCA1/ABCG1 gene expression in RPECs. PMID- 27996198 TI - The Key Role of Sulfation and Branching on Fucoidan Antitumor Activity. AB - There is an urgent need for antitumor bioactive agents with minimal or no side effects over normal adjacent cells. Fucoidan is a marine-origin polymer with known antitumor activity. However, there are still some concerns about its application due to the inconsistent experimental results, specifically its toxicity over normal cells and the mechanism behind its action. Herein, three fucoidan extracts (FEs) have been tested over normal and breast cancer cell lines. From cytotoxicity results, only one of the extracts shows selective antitumor behavior (at 0.2 mg mL-1 ), despite similarities in sulfation degree and carbohydrates composition. Although the three FEs present different molecular weights, depolymerization of selected samples discarded Mw as the key factor in the antitumor activity. Significant differences in sulfates position and branching are observed, presenting FE 2 the higher branching degree. Based on all these experimental data, it is believed that these last two properties are the ones that influence the cytotoxic effects of fucoidan extracts. PMID- 27996199 TI - Chronic Postsurgical Pain Outcomes in Breast Reconstruction Patients Receiving Perioperative Transversus Abdominis Plane Catheters at the Donor Site: A Prospective Cohort Follow-up Study. AB - BACKGROUND: Chronic postsurgical pain (CPSP) is a debilitating and costly condition. Risk factors for CPSP after autologous breast reconstruction have not been clearly established. Previously, we demonstrated that transversus abdominis plane (TAP) catheters delivering intermittent local anesthetic reduced postoperative morphine consumption. This prospective follow-up study aimed to (1) compare the incidence of CPSP after autologous breast reconstruction between patients who received postoperative intermittent TAP catheters with bupivacaine or saline boluses and (2) assess the factors that contribute to the development and maintenance of CPSP in this study cohort. METHODS: Ninety-three patients who underwent deep inferior epigastric artery perforator or muscle-sparing transverse rectus abdominis breast reconstruction were randomized to receive TAP catheters with bupivacaine or saline postoperatively. Subsequently, patients were followed for a year to assess persistent pain, pain severity, quality of life scores, and functional disability at 6 and 12 months after surgery. RESULTS: Twenty-four percent and 23% of patients reported CPSP at 6 and 12 months, respectively. There were no significant differences between groups (bupivacaine vs. placebo) on pain related variables, including incidence of CPSP. Patients who reported greater variability in pain scores at rest over the first 48 hours postoperatively were more likely to have CPSP 6 months, but not 12 months, later. CONCLUSIONS: Acute postoperative pain variability may contribute to the development of CPSP up to 6 months after autologous breast reconstruction surgery. Neither postoperative use of bupivacaine vs. saline in the TAP catheters nor acute pain severity influenced the 6- or 12-month incidence of CPSP. PMID- 27996200 TI - PPI-G4 Glycodendrimers Upregulate TRAIL-Induced Apoptosis in Chronic Lymphocytic Leukemia Cells. AB - Although chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western world, it remains incurable with conventional chemotherapeutic agents. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an antitumor candidate in cancer therapy. This study examines the proapoptotic effects of poly(propylene imine) (PPI) glycodendrimers modified with the maltotriose residues (PPI-G4-OS-Mal-III and PPI-G4-DS-Mal-III) on the TNF family in CLL cells. The combination of an understanding of the signaling pathways associated with CLL and the development of a molecular profiling is a key issue for the design of personalized approaches to therapy. Gene expression is determined with two-color microarray 8 * 60K. The findings indicate that PPI-G4 OS/DS-Mal-III affect gene expression from the TRAIL apoptotic pathway and exert a strong effect on CLL cells comparable with fludarabine. Dendrimer-targeted technology may well prove to bridge the gap between the ineffective treatment of today and the effective personalized therapy of the future. PMID- 27996201 TI - AIE Polymers: Synthesis, Properties, and Biological Applications. AB - Aggregation-caused quenching (ACQ) is a general phenomenon that is faced by traditional fluorescent polymers. Aggregation-induced emission (AIE) is exactly opposite to ACQ. AIE molecules are almost nonemissive in their molecularly dissolved state, but they can be induced to show high fluorescence in the aggregated or solid state. Incorporation of AIE phenomenon into polymer design has yielded various polymers with AIE characteristics. In this review, the recent progress of AIE polymers for biological applications is summarized. PMID- 27996202 TI - Long-term evolution of superficial optic disc drusen. AB - PURPOSE: Optic disc drusen (ODD) is hyaline deposits in the optic nerve head seen in 1-2% of the population. Long-term evolution of ODD anatomy and visual field defects in ODD patients is a key factor for learning more about pathophysiology and prognosis of the condition. With a median follow-up period of 56 years, this is the first study that evaluates superficial optic disc anatomy and visual fields in patients with ODD over a life span. METHODS: Observational case series investigating progression of superficial optic disc anatomy and visual fields in ODD patients. Eight patients with hereditary ODD were included. RESULTS: Mean age at initial and follow-up examination was, respectively, 16.8 and 73.3 years. The median follow-up time was 56 years. A minimal or non-existing change in superficial ODD anatomy (size and number) was seen in 10 of 12 eyes. There was a tendency towards more anatomical change in subjects younger at first examination. A 27% decrease in Goldmann perimetric visual field area (cm2 ) was found between initial and follow-up examinations. CONCLUSION: Minimal or no change in superficial optic disc anatomy and visual fields in ODD patients oldest at the initial examination suggests that anatomical progression of ODD in patients with hereditary ODD happens primarily before adulthood. PMID- 27996204 TI - Postoperative Pain Control Following Craniotomy: A Systematic Review of Recent Clinical Literature. AB - BACKGROUND: Pain intensity after craniotomy is considered to be moderate to severe during the first 2 postoperative days. The ideal pain treatment to facilitate a rapid postoperative recovery and optimize outcome is unknown. OBJECTIVES: This systematic review aims to report current clinical evidence related to pharmacological and adjuvant analgesic modalities for postcraniotomy pain control. DESIGN: Systematic review of randomized controlled trials (RCTs). DATA SOURCES: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (January 2011 to April 2016). ELIGIBILITY CRITERIA: Original research involving the use of any analgesic drug, analgesic method, or nonpharmacological intervention for postcraniotomy pain relief, as assessed by pain scores up to 48 hours postoperatively, supplemental analgesic requirements, or occurence of adverse events. RESULTS: Nineteen RCTs enrolling a total of 1,805 patients were included. Most of the retrieved studies were of moderate-to-good methodological quality. Systemic pharmacological intervention was assessed in 14 RCTs. Opioids (5 RCTs) provided superior pain relief to other analgesics with no significant side effects, but the quality of studies was low. Diclofenac (3 RCTs) presented adequate craniotomy pain control without any adverse effects, while the use of parecoxib is not supported. Dexmedetomidine (3 RCTs) provided adequate transitional analgesia, but further research is needed. Data on the analgesic efficacy of gabapentin, pregabalin, and intravenous lidocaine are very limited (1 RCT for each). Scalp infiltration/block (3 RCTs) provided adequate analgesia in the early postoperative period, while more studies are needed to verify the analgesic benefit obtained from nonpharmacological interventions, such as multipoint electro-acupuncture, in craniotomy surgery (2 RCTs). CONCLUSIONS: No definite recommendations can be made based on this systematic review of pharamacological interventions following craniotomy due to significant divergence in the methodology of available studies. Limited evidence on scalp infiltration/block suggests an adequate analgesic effect in the early postoperative period. Analgesic efficacy of dexmedetomidine and multipoint electro-acupuncture needs further evaluation. PMID- 27996203 TI - Sialotranscriptome sequencing and analysis of Anopheles sinensis and comparison with Psorophora albipes sialotranscriptome (Diptera: Culicidae). AB - Most of adult female mosquitoes secrete saliva to facilitate blood sucking, digestion and nutrition, and mosquito-borne disease prevention. The knowledge of classification and characteristics of sialotranscriptome genes are still quite limited. Anopheles sinensis is a major malaria vector in China and southeast Asian countries. In this study, the An. sinensis sialotranscriptome was sequenced using Illumina sequencing technique with a total of 10 907 unigenes to be obtained and annotated in biological functions and pathways, and 10 470 unigenes were mapped to An. sinensis reference genome with 70.46% of genes having 90%-100% genome mapping through bioinformatics analysis. These mapped genes were classified into four categories: housekeeping (6632 genes), secreted (1177), protein-coding genes with function-unknown (2646) and transposable element (15). The housekeeping genes were divided into 27 classes, and the secreted genes were divided into 11 classes and 96 families. The classification, characteristics and evolution of these classes/families of secreted genes are further described and discussed. The comparison of the 1177 secreted genes in An. sinensis in the Anophelinae subfamily with 811 in Psorophora albipes in the Culicinae subfamily show that six classes/subclasses have the gene number more than twice and two classes (uniquely found in anophelines, and Orphan proteins of unique standing) are unique in the former compared with the latter, whereas four classes/subclasses are much expanded and uniquely found in the Aedes class and is unique in the later. The An. sinensis sialotranscriptome sequence data is the most complete in mosquitoes to date, and the analyses provide a comprehensive information frame for further research of mosquito sialotranscriptome. PMID- 27996205 TI - NIR-Responsive Polycationic Gatekeeper-Cloaked Hetero-Nanoparticles for Multimodal Imaging-Guided Triple-Combination Therapy of Cancer. AB - Responsive multifunctional organic/inorganic nanohybrids are promising for effective and precise imaging-guided therapy of cancer. In this work, a near infrared (NIR)-triggered multifunctional nanoplatform comprising Au nanorods (Au NRs), mesoporous silica, quantum dots (QDs), and two-armed ethanolamine-modified poly(glycidyl methacrylate) with cyclodextrin cores (denoted as CD-PGEA) has been successfully fabricated for multimodal imaging-guided triple-combination treatment of cancer. A hierarchical hetero-structure is first constructed via integration of Au NRs with QDs through a mesoporous silica intermediate layer. The X-ray opacity and photoacoustic (PA) property of Au NRs are utilized for tomography (CT) and PA imaging, and the imaging sensitivity is further enhanced by the fluorescent QDs. The mesoporous feature of silica allows the loading of a typical antitumor drug, doxorubicin (DOX), which are sealed by the polycationic gatekeepers, low toxic hydroxyl-rich CD-PGEA/pDNA complexes, realizing the co delivery of drug and gene. The photothermal effect of Au NRs is utilized for photothermal therapy (PTT). More interestingly, such photothermal effect also induces a cascade of NIR-triggered release of DOX through the facilitated detachment of CD-PGEA gatekeepers for controlled chemotherapy. The resultant chemotherapy and gene therapy for glioma tumors are complementary for the efficiency of PTT. This work presents a novel responsive multifunctional imaging guided therapy platform, which combines fluorescent/PA/CT imaging and gene/chemo/photothermal therapy into one nanostructure. PMID- 27996206 TI - Factors Influencing the Performance of Pd/C Catalysts in the Green Production of Hydrogen from Formic Acid. AB - Formic acid derived from biomass is known to be used for hydrogen production over Pd catalysts. The effects of preparation variables, structure of the carbon support, surface functional composition on the state of Pd, and catalytic properties of the samples in the vapor-phase decomposition of formic acid were studied. In all catalysts derived from Pd acetate, metal particles visible by conventional TEM had similar sizes, but the adsorption capacity towards CO responded strongly to N-doping of the carbon surface. Moreover, a decrease in the CO/Pd values was accompanied by a significant increase in the reaction rate. Taking account of X-ray photoelectron spectroscopy (XPS) and atomic resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF/STEM) data, the trends observed were assigned to a larger fraction of single electron-deficient Pd atoms in the N-doped samples, which do not adsorb CO but interact with formic acid to produce hydrogen. This was confirmed by extended DFT studies. The obtained results are valuable for the development of Pd catalysts on carbon supports for different processes. PMID- 27996207 TI - Complete Regression of Psoriatic Arthritis After Belatacept Conversion in a Highly HLA-Sensitized Kidney Transplant Patient. AB - Costimulatory inhibitors (i.e. abatacept and belatacept) effectively abrogate T lymphocyte activation and proliferation and have been shown to be effective for disease control in certain autoimmune disorders as well as in preventing allograft rejection in kidney transplantation. Whether such immunomodulatory agents may be useful for the control of autoimmune flares and allograft acceptance, while avoiding the need of additional strong immunosuppressants, has not been shown. Here, we report the first case of a 47-year-old man affected by a serious debilitating form of psoriatic arthritis that presented during the course of a third, high immunological-risk kidney transplantation. Three years after transplantation, the patient benefited by switching from tacrolimus- to belatacept-based therapy, without additional immunosuppression, by showing complete regression of the arthritic symptoms as well as no progression of severe radiological lesions, which leaded to the recovery of disability and functional impairment. Remarkably, the treatment with belatacept in association with mycophenolate mofetil and steroids also provided a stable normal allograft function over time and abrogated the development of de novo circulating donor specific alloantibodies after 4 years of follow-up. PMID- 27996208 TI - Disparity in neural and subjective responses to food images in women with obesity and normal-weight women. AB - OBJECTIVE: Self-reports tend to differ from objective measurements of food intake, particularly in adults with obesity; however, no studies have examined how neural responses to food (an objective measure) and subjective ratings of food differ by BMI status. This study tested normal-weight women (NWW) and women with obesity (OBW) for group differences in neural indices of attention towards food pictures, subjective ratings of these pictures, and the disparity between objective and subjective measurements. METHODS: Twenty-two NWW (21.8 +/- 1.7 kg/m2 ) and 22 OBW (37.0 +/- 5.7 kg/m2 ) viewed food and flower pictures while late positive potential amplitude, an event-related potential, was recorded. Participants rated pictures for arousal and valence. RESULTS: Late positive potential amplitude was larger toward food than flower pictures. OBW self reported flower pictures as more pleasant than food; NWW showed no difference for pleasantness. There were no significant main effects or interactions for arousal. Standardized scores showed that only on subjective, but not objective, measures did OBW compared with NWW disproportionately indicate food pictures as less pleasant than flowers. CONCLUSIONS: Compared with NWW, OBW showed larger discrepancies between neural and subjective reports of attention towards food. Inaccurate self-reports of attention towards food may reduce the efficiency of health interventions. PMID- 27996209 TI - Induced Europium Circularly Polarized Luminescence Monitors Reversible Drug Binding to Native alpha1 -Acid Glycoprotein. AB - Alpha-1-acid glycoprotein (alpha1 -AGP) is an important blood plasma glycoprotein. Following an acute-phase reaction such as stress, inflammation, burn, or infection, the bloodstream concentration of alpha1 -AGP can increase up to 400 % of its normal concentration. A wide range of drugs is known to bind alpha1 -AGP. Increased binding of pharmacologically active compounds to alpha1 AGP moderates their clinical effect by decreasing the amount of unbound drug in the bloodstream. This has important clinical ramifications for such applications as the duration of anesthesia and in determining dosage for drug therapy. In this study, the competitive binding to alpha1 -AGP of a dynamically racemic europium(III) complex with seven pharmacologically active drugs absorbing in the range lambda 250-290 nm was monitored by following changes in europium total emission and in induced circularly polarized luminescence (CPL). Binding affinities corresponding to Kd values in the range 0.5-100 MUm were measured, in good agreement with published data. PMID- 27996210 TI - Aggregation kinetics of human mesenchymal stem cells under wave motion. AB - Human mesenchymal stem cells (hMSCs) are primary candidates in cell therapy and regenerative medicine but preserving their therapeutic potency following culture expansion is a significant challenge. hMSCs can spontaneously assemble into three dimensional (3D) aggregates that enhance their regenerative properties. The present study investigated the impact of hydrodynamics conditions on hMSC aggregation kinetics under controlled rocking motion. While various laboratory methods have been developed for hMSC aggregate production, the rocking platform provides gentle mixing and can be scaled up using large bags as in wave motion bioreactors. The results show that the hMSC aggregation is mediated by cell adhesion molecules and that aggregate size distribution is influenced by seeding density, culture time, and hydrodynamic conditions. The analysis of fluid shear stress by COMSOL indicated that aggregate size distribution is inversely correlated with shear stress and that the rocking angle had a more pronounced effect on aggregate size distribution than the rocking speed due to its impact on shear stress. hMSC aggregates obtained from the bioreactor exhibit increased stemness, migratory properties, and expression of angiogenic factors. The results demonstrate the potential of the rocking platform to produce hMSC aggregates with controlled size distribution for therapeutic application. PMID- 27996211 TI - GSK-3beta Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia. AB - INTRODUCTION: Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function. AIMS: To investigate the physical interaction and functional modulation between D1R and GSK-3beta. RESULTS: D1R and GSK-3beta physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C-terminus of D1R. Inhibition of GSK-3beta impaired D1R activation along with a decrease in D1R GSK-3beta interaction. GSK-3beta inhibition reduced agonist-stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of beta-arrestin-2. Similarly, inhibition of GSK-3beta in rat PFC also resulted in impaired D1R activation and association with GSK-3beta. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK-3beta activity and D1R-GSK-3beta association and decreased D1R activation in the PFC. CONCLUSIONS: The present work identified GSK 3beta as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK-3beta-regulated D1R function which may underlie D1R dysfunction in schizophrenia. PMID- 27996214 TI - p-Quaterphenylene as an Aggregation-Induced Emission Fluorogen in Supramolecular Organogels and Fluorescent Sensors. AB - Two dumbbell-shaped organogelators with a p-quaterphenylene core were synthesized, and their self-assembly properties were investigated. These low molecular-weight gelators could form self-supporting gels in many apolar organic solvents with an H-type aggregation form through a synergic effect of pi-pi stacking, intermolecular translation-related hydrogen bonding, and van der Waals forces. In comparison to the p-terphenylene-cored gelator, the extended pi conjugated segment improved the gelation efficiency significantly with enhanced gelation rate. Additionally, these p-quaterphenylene-centered gelators exhibited strong fluorescence emission induced by aggregation, which not only provided an in situ method to optically monitor the gelation process, but also endowed these self-assemblies with substantial applications in sensing explosives. PMID- 27996212 TI - Ectodermal-Neural Cortex 1 Isoforms Have Contrasting Effects on MC3T3-E1 Osteoblast Mineralization and Gene Expression. AB - The importance of Wnt pathway signaling in development of bone has been well established. Here we investigated the role of a known Wnt target, ENC1 (ectodermal-neural cortex 1; NRP/B), in osteoblast differentiation. Enc1 expression was detected in mouse osteoblasts, chondrocytes, and osteocytes by in situ hybridization, and osteoblastic expression was verified in differentiating primary cultures and MC3T3-E1 pre-osteoblast cells, with 57 kDa and 67 kDa ENC1 protein isoforms detected throughout differentiation. Induced knockdown of both ENC1 isoforms reduced alkaline phosphatase staining and virtually abolished MC3T3 E1 mineralization. At culture confluence, Alpl (alkaline phosphatase liver/bone/kidney) expression was markedly reduced compared with control cells, and there was significant and coordinated alteration of other genes involved in cellular phosphate biochemistry. In contrast, with 67 kDa-selective knockdown mineralized nodule formation was enhanced and there was a two-fold increase in Alpl expression at confluence. There was enhanced expression of Wnt/beta-catenin target genes with knockdown of both isoforms at this time-point and a five-fold increase in Frzb (Frizzled related protein) with 67 kDa-selective knockdown at mineralization, indicating possible ENC1 interactions with Wnt signaling in osteoblasts. These results are the first to demonstrate a role for ENC1 in the control of osteoblast differentiation. Additionally, the contrasting mineralization phenotypes and transcriptional patterns seen with coordinate knockdown of both ENC1 isoforms vs selective knockdown of 67 kDa ENC1 suggest opposing roles for the isoforms in regulation of osteoblastic differentiation, through effects on Alpl expression and phosphate cellular biochemistry. This study is the first to report differential roles for the ENC1 isoforms in any cell lineage. J. Cell. Biochem. 118: 2141-2150, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27996213 TI - Versatile Homoallylic Boronates by Chemo-, SN 2'-, Diastereo- and Enantioselective Catalytic Sequence of Cu-H Addition to Vinyl-B(pin)/Allylic Substitution. AB - A highly chemo-, diastereo- and enantioselective catalytic method that efficiently combines a silyl hydride, vinyl-B(pin) (pin=pinacolato) and (E)-1,2 disubstituted allylic phosphates is introduced. Reactions, best promoted by a Cu based complex with a chiral sulfonate-containing N-heterocyclic carbene, are broadly applicable. Aryl-, heteroaryl-, alkenyl-, alkynyl- and alkyl-substituted allylic phosphates may thus be converted to the corresponding homoallylic boronates and then alcohols (after C-B bond oxidation) in 46-91 % yield and in up to >98 % SN 2':SN 2 ratio, 96:4 diastereomeric ratio and 98:2 enantiomeric ratio. The reasons why an NHC-Cu catalyst is uniquely effective (vs. the corresponding phosphine systems) and the basis for different trends in stereoselectivity are provided with the aid of DFT calculations. PMID- 27996215 TI - Prognostic impact of the length of the longitudinal resection margin in colon cancer. AB - AIM: Although several guidelines recommend a longitudinal resection margin (LRM) of at least 5 cm, the impact of the LRM on survival is still unknown. The study assessed the prognostic significance of the LRM in patients with colon cancer. METHOD: We retrospectively reviewed 1343 primary colon cancer patients without distant metastasis who underwent curative resection between January 2004 and December 2012. Patients were classified into three groups: LRM < 3 cm (n = 186), LRM >= 3 and <5 cm (n = 376) and LRM >=5 cm (n = 781). Clinicopathological characteristics and the oncological outcome in the three groups were compared. RESULTS: The median LRM length was 5.0 cm (range 0.5-26.0 cm). With increasing LRM, the number of retrieved lymph nodes (LNs) tended to increase (19.5 +/- 12.0, 22.1 +/- 12.8 and 30.0 +/- 16.2; P < 0.001). After a median follow-up period of 45 (1-128) months, 3-year disease-free survival (DFS) (89.2%, 89.0% and 87.0%; P = 0.629) and 5-year overall survival (OS) (89.0%, 92.1% and 91.8%; P = 0.679) were not significantly different between the three groups. When confounders were adjusted, LRM was not significantly associated with either DFS or OS, but the number of retrieved LNs (< 12) was an independent risk factor for both DFS (hazard ratio 1.748, 95% confidence interval 1.048-2.917) and OS (hazard ratio 1.929, 95% confidence interval 1.046-3.559). CONCLUSION: LRM was not associated with oncological outcome, but care should be taken to obtain an adequate number of LNs for better survival. PMID- 27996216 TI - Decomposition of Imidazolium-Based Ionic Liquids in Contact with Lithium Metal. AB - Ionic liquids (ILs) are considered to be suitable electrolyte components for lithium-metal batteries. Imidazolium cation based ILs were previously found to be applicable for battery systems with a lithium-metal negative electrode. However, herein it is shown that, in contrast to the well-known IL N-butyl-N methylpyrrolidinium bis[(trifluoromethyl)sulfonyl]imide ([Pyr14 ][TFSI]), 1-ethyl 3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([C2MIm][TFSI]) and 1 butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([C4MIm][TFSI]) are chemically unstable versus metallic lithium. A lithium-metal sheet was immersed in pure imidazolium-based IL samples and aged at 60 degrees C for 28 days. Afterwards, the aged IL samples were investigated to deduce possible decomposition products of the imidazolium cation. The chemical instability of the ILs in contact with lithium metal and a possible decomposition starting point are shown for the first time. Furthermore, the investigated imidazolium-based ILs can be utilized for lithium-metal batteries through the addition of the solid electrolyte interphase (SEI) film-forming additive fluoroethylene carbonate. PMID- 27996217 TI - Supervised exercise training improves exercise cardiovascular function in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease associated with cardiovascular impairments which compromise exercise tolerance and worsen prognosis. AIM: To examine the effect of participating in supervised exercise training (ET) program on cardiovascular function in patients with IPF. DESIGN: A randomized controlled study. SETTING: Outpatient hospital. POPULATION: Thirty-two IPF patients (68+/-8 years). METHODS: An ET group (N.=15) participated in a 12-week twice a week 60-minute supervised exercise program while a control group (N.=17) received usual care. At baseline and after the 12-week intervention all patients underwent resting echocardiography, cardiopulmonary exercise testing and N-terminal pro-brain natriuretic peptide (NT-proBNP) assessments. RESULTS: The ET group significantly improved peak values of exercise cardiovascular indexes while the control group showed a trend of deterioration in the outcomes. The mean difference between the groups (95% CI) for circulatory power was 638 mLO2/kg/min/mmHg (95% CI: 197-1080) (P=0.006), cardiac power output 0.3 W (95% CI: 0.1 to 0.6) (P=0.041), and stroke work 312 mL/beat/mmHg (95% CI: 52-573) (P=0.02). No significant differences between groups were detected in most echocardiography measures and NT-proBNP. Changes in exercise cardiovascular indexes showed significant correlation with improvements in functional capacity, dyspnea and quality of life among ET group. CONCLUSIONS: Participation in supervised ET program can improve exercise cardiovascular function in patients with IPF, however resting cardiac evaluations seem to be less sensitive to detect such changes. CLINICAL REHABILITATION IMPACT: These findings underscore the utility of supervised ET for cardiovascular enhancement which may also be clinically beneficial in reducing the cardiovascular morbidity and mortality in IPF patients. PMID- 27996218 TI - Association of early physical activity time with pain, activities of daily living, and progression of vertebral body collapse in patients with vertebral compression fractures. AB - BACKGROUND: Physical activity can reduce pain and improve the ability to perform daily activities in patients with acute low back pain (LBP) due to various non specific causes. The association between physical activity during the early phase of acute vertebral compression fractures (VCFs) and rehabilitation outcomes is unknown. AIM: The aim of this study was to investigate the effects of early physical activity time (EPAT) on pain following acute VCFs, recovery of the ability to perform activities of daily living (ADLs), and progression of fractured vertebral body collapse. DESIGN: Observational study. SETTING: Inpatient clinic. POPULATION: Sixty-nine patients with acute VCFs being treated conservatively at Nagasaki Memorial Hospital. METHODS: Physical activity was evaluated as the activity time corresponding to 1.8-8.3 metabolic equivalent activities measured by a motion-sensor during the first week after admission; it was defined as EPAT. The verbal rating scale (VRS) (0-4) at rest and during standing and walking and motor functional independence measure (mFIM) were assessed at weeks 0 (baseline), 2, and 4. Loss of vertebral height was measured in week 4. Mini-mental state examinations, trail making test part-A (TMT-A), and geriatric depression scale-15 were administered at baseline. Patients were divided into active (N.=35) and sedentary (N.=34) groups according to their median EPAT value during the first week. RESULTS: The completion times for TMT-A and mFIM scores at baseline as well as the relative functional gains of mFIM from baseline to week 2 or 4 were significantly associated with EPAT. VRS at rest and during standing and walking were not significantly different between the groups at week 2 and 4. Loss of vertebral height was not significantly different between the groups. CONCLUSIONS: EPAT in patients with acute VCF is associated with the recovery of the ability to perform ADLs. However, EPAT is associated with neither pain reduction nor progression of fractured vertebral body collapse. CLINICAL REHABILITATION IMPACT: This observational study indicates that physical activity in the early acute phase of VCF is associated with better recovery from acute VCF and would be an important factor for short-term recovery. PMID- 27996219 TI - Self-management and self-efficacy in stroke survivors: validation of the Italian version of the Stroke Self-Efficacy Questionnaire. AB - BACKGROUND: Self-efficacy is an important mediator of the adaptation process after stroke. However, few studies have attempted to measure self-efficacy in a stroke population. The most recently developed scale is the Stroke Self-Efficacy Questionnaire that measures self-efficacy ratings in specific domains of functioning relevant for a stroke survivor. AIM: The aim of this study was to validate the Italian version of Stroke Self-efficacy Questionnaire in stroke survivors. DESIGN: Cross-sectional study. SETTING: Three Physical Medicine and Rehabilitation Units located in public hospitals. POPULATION: 149 adult patients recruited after their first stroke. METHODS: Patients were assessed using the Self-efficacy in stroke survivors questionnaire, the Modified Barthel Index, the Geriatric Depression Scale and the Short Form Health Survey. RESULTS: Patients (38.3% female, mean age 69.3 years) completed the Self-efficacy in stroke survivors questionnaire with the help of an interviewer. Using confirmatory factor analysis two factors were identified (activity and self-management). The factor score 'activity' was significantly associated with the Modified Barthel Index and with the physical component of the Short Form Health Survey, but uncorrelated with the mental component of the Short Form Health Survey and with the Geriatric Depression Scale, supporting the convergent/discriminant validity of the instrument. The 'self-management' factor was weakly associated with the Modified Barthel Index, the physical and mental components of the Short Form Health Survey and uncorrelated with the Geriatric Depression Scale, suggesting that it measures a different construct. When we categorized patients according to their walking status, we found that the walking group had significantly higher scores on the activity factor than the non-walking group, while no significant differences were found concerning the self-management factor. CONCLUSIONS: The findings supported the validity of the Italian version of the Stroke Self efficacy questionnaire . It measures two dimensions of self-efficacy, activity and self-management, strongly related to independence and recovery after stroke and therefore it represents a useful tool to assess self-efficacy. CLINICAL REHABILITATION IMPACT: The Italian version of the Stroke Self-efficacy questionnaire is a valid and reliable measure of self-efficacy. Clinicians can use this instrument to target rehabilitation interventions according to patients' individual confidence in their functional and self-management capacity and in order to set realistic goals. PMID- 27996220 TI - Understanding community-based rehabilitation and the role of physical and rehabilitation medicine. AB - Community-based rehabilitation (CBR) is an accepted model to improve the delivery of rehabilitation in the community. It includes the access to health care, education, labor and accessible environments. The role of Specialists in Physical and Rehabilitation Medicine in this strategy (SPRM) is not very well defined. On the occasion of the international consultation for the WHO Action Plan for persons with disabilities, a discussion about the meaning of CBR and the role of SPRM on CBR has occurred among the International Society of Physical and Rehabilitation Medicine (ISPRM) members. The following major questions were identified; what is CBR? What is the role of Specialists in Physical and Rehabilitation Medicine (SPMR) in CBR? A review of the literature and a discussion among experts was held to answer these questions. It is of major importance to distinguish between the two concepts of CBR: The first one is the policy or management strategy of CBR that was developed by WHO about 30 years ago. The second one is the provision of basic rehabilitation services offered at the community level. CBR strategy must also addresses the need for optimal access to specialized rehabilitation services and will have a key role in the design and building of so-called "Basic Rehabilitation Services." The authors proposed a scheme, which integrates all relevant aspects surrounding the concept of CBR; levels of care rehabilitation services and the roles proposed for SPRM. In addition, the convention for the rights of persons with disabilities and the conceptual framework of the ICF was taken into account. PMID- 27996222 TI - [HPV-Related Oropharyngeal Cancer--Epidemiology and Diagnosis]. PMID- 27996221 TI - The practice of physical activity and cryotherapy in rheumatoid arthritis: systematic review. AB - INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune, chronic and inflammatory disease, which the affected patients present a higher cardiovascular mortality rate. Physical activities have been identified as the most important strategy to prevent cardiovascular diseases. However, the articular damage and the chronic pain caused by RA challenges its regular practice. Moreover, persons with RA tend to avoid PA due to the fear of exacerbating the inflammatory potential and pain. One alternative to avoid the collateral effects of the PA could be the cryotherapy. Therefore, this study aimed to review studies focused on the use of both PA and cryotherapy in RA patients and to identify evidences that both therapies could be combined in order to optimize the symptomatic treatment. EVIDENCE ACQUISITION: Four databases (MEDLINE, CINAHL, Elsevier and PEDro) were searched to identify publications regarding RA patients, PA and cryotherapy intervention by the terms and operators (rheumatoid arthritis AND exercise OR physical activity OR activity OR training OR reconditioning OR cryotherapy OR cold OR immersion). The selected studies should at least present one measure of the aerobic capacity, disease activity or pain relief. Among 19 studies with RA patients identified, only 4 studies used PA combined with cryotherapy. The other 13 studies used physical activities and 2 studies used cryotherapy intervention. EVIDENCE SYNTHESIS: The results of the physical activities combined with cryotherapy studies showed an improvement in the disease activity and pain relief, however without details of the physical activities intervention and an aerobic capacity. Among the physical activities studies, evidence was found suggesting that aerobic exercises and multiactivity exercises with high intensity are the more effective for improve the aerobic capacity. CONCLUSIONS: Even if few studies on cryotherapy were found, there are enough evidences in the literature that demonstrate the benefits of this intervention on pain relief and disease activity. In summary, neither study found associated physical activities to improve aerobic capacity with cryotherapy to improve disease activity and pain relief. This may be an innovative therapeutic strategy to improve the aerobic capacity in arthritis patients and consequently reduce their cardiovascular risk while minimizing pain and disease activity. PMID- 27996223 TI - [Treatment of Oropharyngeal Cancer Human Papillomavirus Positive]. PMID- 27996224 TI - [Thorax/Lung and Mediastinum, Pleura: Cancer T Factor in Lung Adenocarcinoma]. PMID- 27996225 TI - [Revision of TNM Classification for Lung Cancer by Staging and Prognostic Factors Committee of LASLC (International Association for the Study of Lung Cancer)]. PMID- 27996226 TI - [Imaging Characteristics and Clinical Significance of Pulmonary Pure GGNs]. PMID- 27996228 TI - [New Japanese Classification of Esophageal Cancer (11th Edition)]. PMID- 27996227 TI - [Clinical Treatment of Pure Ground-Glass Nodule on Chest Computed Tomography]. PMID- 27996229 TI - [Photodynamic Therapy for Local Recurrence of Esophageal Cancer after Chemoradiotherapy]. PMID- 27996230 TI - Improved Surface Stability of C+MxOy@Na3V2(PO4)3 Prepared by Ultrasonic Method as Cathode for Sodium-Ion Batteries. AB - Coated C+MxOy@Na3V2(PO4)3 samples containing 1.5% or 3.5% wt. of MxOy (Al2O3, MgO or ZnO) have been synthesized by a two-step method including first a citric based sol-gel method for preparing the active material and second an ultrasonic stirring technique to deposit MxOy. The presence of the metal oxides properly coating the surface of the active material is evidenced by XPS and electron microscopy. Galvanostatic cycling of sodium half-cells reveals a significant capacity enhancement for samples coated with 1.5% of metal oxides and an exceptional cycling stability as evidenced by Coulombic efficiencies as high as 95.9% for ZnO@ Na3V2(PO4)3. It is correlated to their low surface layer and charge transfer resistance values. The formation of metal fluorides that remove traces of corrosive HF from the electrolyte is checked by XPS spectroscopy. The feasibility of sodium-ion batteries assembled with C+MxOy@Na3V2(PO4)3 is further verified by evaluating the electrochemical performance of full cells. Particularly, a Graphite//Al2O3@ Na3V2(PO4)3 battery delivers an energy density as high as 260 W h kg-1 and exhibits a Coulombic efficiency of 89.3% after 115 cycles. PMID- 27996231 TI - Coupling Molecularly Ultrathin Sheets of NiFe-Layered Double Hydroxide on NiCo2O4 Nanowire Arrays for Highly Efficient Overall Water-Splitting Activity. AB - Developing efficient but nonprecious bifunctional electrocatalysts for overall water splitting in basic media has been the subject of intensive research focus with the increasing demand for clean and regenerated energy. Herein, we report on the synthesis of a novel hierarchical hybrid electrode, NiFe-layered double hydroxide molecularly ultrathin sheets grown on NiCo2O4 nanowire arrays assembled from thin platelets with nickel foam as the scaffold support, in which the catalytic metal sites are more accessible and active and most importantly strong chemical coupling exists at the interface, enabling superior catalytic power toward both oxygen evolution reaction (OER) and additionally hydrogen evolution reaction (HER) in the same alkaline KOH electrolyte. The behavior ranks top-class compared with documented non-noble HER and OER electrocatalysts and even comparable to state-of-the-art noble-metal electrocatalysts, Pt and RuO2. When fabricated as an integrated alkaline water electrolyzer, the designed electrode can deliver a current density of 10 mA cm-2 at a fairly low cell voltage of 1.60 V, promising the material as efficient bifunctional catalysts toward whole cell water splitting. PMID- 27996232 TI - Shape-Dependent Defect Structures of Monolayer MoS2 Crystals Grown by Chemical Vapor Deposition. AB - Monolayer MoS2 crystals with tailored morphologies have been shown to exhibit shape-dependent properties and thus have potential applications in building nanodevices. However, a deep understanding of the relationship between the shape and defect structures in monolayer MoS2 is yet elusive. Monolayer MoS2 crystals in polygonal shapes, including triangle, tetragon, pentagon, and hexagon, are grown using the chemical vapor deposition technique. Compared with other shapes, the hexagon MoS2 crystal contains more electron-donor defects that are mainly due to sulfur vacancies. In the triangular shapes, the defects are mainly distributed at the vertices of the shapes while they are located at the center of hexagonal shapes. On the basis of the Coulomb interaction of exciton and trion, quantitative calculations demonstrate a high electron density (~1012/cm2) and high Fermi level (EC - EF = 15 meV) for hexagonal shape at room temperature, compared to triangular shapes (~1011/cm2, EC - EF ~ 30 meV). These findings verify that a much higher number of donor-like sulfur vacancies are formed in hexagonal MoS2 shapes. This property allows more electrons or trions to localize in such sites through the physical/chemical adsorption of O2/H2O, which results in a strong enhancement of the light emission efficiency in the hexagonal crystal. The findings provide a better understanding of the formation of shape dependent defect structures of monolayer MoS2 crystals and are inspiring for applications in fabricating nanoelectronic and optoelectronic devices through defect engineering. PMID- 27996233 TI - Tuning Bandgap of p-Type Cu2Zn(Sn, Ge)(S, Se)4 Semiconductor Thin Films via Aqueous Polymer-Assisted Deposition. AB - Bandgap engineering of kesterite Cu2Zn(Sn, Ge)(S, Se)4 with well-controlled stoichiometric composition plays a critical role in sustainable inorganic photovoltaics. Herein, a cost-effective and reproducible aqueous solution-based polymer-assisted deposition approach is developed to grow p-type Cu2Zn(Sn, Ge)(S, Se)4 thin films with tunable bandgap. The bandgap of Cu2Zn(Sn, Ge)(S, Se)4 thin films can be tuned within the range 1.05-1.95 eV using the aqueous polymer assisted deposition by accurately controlling the elemental compositions. One of the as-grown Cu2Zn(Sn, Ge)(S, Se)4 thin films exhibits a hall coefficient of +137 cm3/C. The resistivity, concentration and carrier mobility of the Cu2ZnSn(S, Se)4 thin film are 3.17 ohm.cm, 4.5 * 1016 cm-3, and 43 cm2/(V.S) at room temperature, respectively. Moreover, the Cu2ZnSn(S, Se)4 thin film when used as an active layer in a solar cell leads to a power conversion efficiency of 3.55%. The facile growth of Cu2Zn(Sn, Ge)(S, Se)4 thin films in an aqueous system, instead of organic solvents, provides great promise as an environmental-friendly platform to fabricate a variety of single/multi metal chalcogenides for the thin film industry and solution-processed photovoltaic devices. PMID- 27996234 TI - Highly Stretchable, Hysteresis-Free Ionic Liquid-Based Strain Sensor for Precise Human Motion Monitoring. AB - A highly stretchable, low-cost strain sensor was successfully prepared using an extremely cost-effective ionic liquid of ethylene glycol/sodium chloride. The hysteresis performance of the ionic-liquid-based sensor was able to be improved by introducing a wavy-shaped fluidic channel diminishing the hysteresis by the viscoelastic relaxation of elastomers. From the simulations on visco-hyperelastic behavior of the elastomeric channel, we demonstrated that the wavy structure can offer lower energy dissipation compared to a flat structure under a given deformation. The resistance response of the ionic-liquid-based wavy (ILBW) sensor was fairly deterministic with no hysteresis, and it was well-matched to the theoretically estimated curves. The ILBW sensors exhibited a low degree of hysteresis (0.15% at 250%), low overshoot (1.7% at 150% strain), and outstanding durability (3000 cycles at 300% strain). The ILBW sensor has excellent potential for use in precise and quantitative strain detections in various areas, such as human motion monitoring, healthcare, virtual reality, and smart clothes. PMID- 27996235 TI - Increasing Stability of Biotin Functionalized Electrospun Fibers for Biosensor Applications. AB - This paper describes the effects of both solvent and copolymer block lengths on the stability of electrospun poly(lactic acid)/poly(lactic acid)-b-poly(ethylene glycol) (PLA/PLA-b-PEG) and PLA/PLA-b-PEG-Biotin fibers in water. By tailoring the block length of copolymers PLA-b-PEG, water stability of electrospun fibers is improved over fibers reported previously. The solvent used also influenced the stability and hydrophilicity of resulting fibers. Fibers formed using 1,1,1,3,3,3 hexafluoro-2-propanol (HFIP) have greater water stability, but less PEG at the surface of fibers than fibers spun from dimethylformamide (DMF). Attaching biotin to the end of PLA(3600)-b-PEG(2000) and spinning from DMF resulted, initially, in 7.6% of the total biotin incorporated into the fiber, assuming every PEG terminal had one biotin attached (1.1 mg of biotin per gram of fiber) available at the fibers' surface. In addition, PLA/PLA(3600)-b-PEG(2000)-Biotin spun from DMF hindered biotin migration to the aqueous phase, leaving 2% of the incorporated biotin remaining at the surface of fibers after 7 days of water exposure. The water wicking ability of DMF spun fibers also increased significantly with the biotin attachment to the PEG terminal. While HFIP spun fibers lost little biotin from fibers, there was no detectable surface available biotin, indicating biotin was at the interior. With biotin and PEG at the interior of the fibers spun from HFIP, the water wicking remained the same for PLA/PLA(3600)-b-PEG(2000) spun samples and decreased for PLA/PLA(5700)-b-PEG(1000). The dissimilarities observed in water wicking for HFIP spun samples are primarily the result of differences in fiber morphology. PMID- 27996236 TI - Controlling the Thickness of Thermally Expanded Films of Graphene Oxide. AB - "Paper-like" film material made from stacked and overlapping graphene oxide sheets can be exfoliated (expanded) through rapid heating, and this has until now been done with no control of the final geometry of the expanded graphene oxide material, i.e., the expansion has been physically unconstrained. (As a consequence of the heating and exfoliation, the graphene oxide is "reduced", i.e., the graphene oxide platelets are deoxygenated to a degree.) We have used a confined space to constrain the expanding films to a controllable and uniform thickness. By changing the gap above the film, the final thickness of expanded films prepared from, e.g., a 10 MUm-thick graphene oxide film, could be controlled to values such as 20, 30, 50, or 100 MUm. When the expansion of the films was unconstrained, the final film was broken into pieces or had many cracks. In contrast, when the expansion was constrained, it never cracked or broke. Hot pressing the expanded reduced graphene oxide films at 1000 degrees C yielded a highly compact structure and promoted graphitization. Such thickness controlled expansion of graphene oxide films up to tens or hundreds of times the original film thickness was used to emboss patterns on the films to produce areas with different thicknesses that remain connected "in plane". In another set of experiments, we treated the original graphene oxide film with NaOH before its controlled expansion resulted in a different structure featuring uniformly distributed pores and interconnected layers as well as simultaneous activation of the carbon. PMID- 27996237 TI - Targeted Synthesis of Unique Nickel Sulfide (NiS, NiS2) Microarchitectures and the Applications for the Enhanced Water Splitting System. AB - Water splitting is one of the ideal technologies to meet the ever increasing demands of energy. Many materials have aroused great attention in this field. The family of nickel-based sulfides is one of the examples that possesses interesting properties in water-splitting fields. In this paper, a controllable and simple strategy to synthesize nickel sulfides was proposed. First, we fabricated NiS2 hollow microspheres via a hydrothermal process. After a precise heat control in a specific atmosphere, NiS porous hollow microspheres were prepared. NiS2 was applied in hydrogen evolution reaction (HER) and shows a marvelous performance both in acid medium (an overpotential of 174 mV to achieve a current density of 10 mA/cm2 and the Tafel slope is only 63 mV/dec) and in alkaline medium (an overpotential of 148 mV to afford a current density of 10 mA/cm2 and the Tafel slope is 79 mV/dec). NiS was used in oxygen evolution reaction (OER) showing a low overpotential of 320 mV to deliver a current density of 10 mA/cm2, which is meritorious. These results enlighten us to make an efficient water-splitting system, including NiS2 as HER catalyst in a cathode and NiS as OER catalyst in an anode. The system shows high activity and good stabilization. Specifically, it displays a stable current density of 10 mA/cm2 with the applying voltage of 1.58 V, which is a considerable electrolyzer for water splitting. PMID- 27996238 TI - Latitudinal and Seasonal Distribution of Particulate MSA over the Atlantic using a Validated Quantification Method with HR-ToF-AMS. AB - Methanesulfonic acid (MSA) has been widely used as a proxy for marine biogenic sources, but it is still a challenge to provide an accurate MSA mass concentration with high time resolution. This study offers an improved MSA quantification method using high resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). Particularly, the method was validated based on an excellent agreement with parallel offline measurements (slope = 0.88, R2 = 0.89). This comparison is much better than those using previously reported methods, resulting in underestimations of 31-54% of MSA concentration. With this new method, MSA mass concentrations were obtained during 4 North/South Atlantic cruises in spring and autumn of 2011 and 2012. The seasonal and spatial variation of the particulate MSA mass concentration as well as the MSA to non-sea-salt sulfate ratio (MSA:nssSO4) over the North/South Atlantic Ocean were determined for the first time. Seasonal variation of the MSA mass concentration was observed, with higher values in spring (0.03 MUg m-3) than in autumn (0.01 MUg m 3). The investigation of MSA:nssSO4 suggests a ubiquitous and significant influence of anthropogenic sources on aerosols in the marine boundary layer. PMID- 27996239 TI - Cancer Cell Specific Delivery of Photosystem I Through Integrin Targeted Liposome Shows Significant Anticancer Activity. AB - Many anticancer drugs are developed for the treatment of cancer from natural sources. Photosystem I (PSI), a protein complex present in the chloroplast, is involved in photosynthesis and generates reactive oxygen species (ROS) in plant. Here, we used the ROS generation property of PSI for cancer therapy. We show that PSI can enter into different kinds of cancer cell like human lung carcinoma (A549) and mouse melanoma (B16F10) cell lines and generate ROS inside the cells. It inhibits the proliferation of cancer cell and causes apoptotic death of cancer cells. We also show that PSI induces apoptosis through mitochondria-dependent internal pathway, induces caspase3, causes DNA fragmentation, and arrests cell cycle at SubG0 phase. We also prepared, using C16-LDV lipopeptide [C16 long chain attached on the N-terminal of the tripeptide containing amino acids leucine (L), aspartic acid (D), and valine (V) abbreviated as NH2-LDV-COOH], alpha4beta1 integrin targeted liposomal formulation of PSI, which specifically kills the cancer cell without affecting normal cells, and it is found to be more potent compared to clinically used drug doxorubicin. Finally, we found that LDV liposomal formulation of PSI inhibits the growth of tumor in C57BL/6J mice model. PMID- 27996240 TI - Cation-Inhibited Transport of Graphene Oxide Nanomaterials in Saturated Porous Media: The Hofmeister Effects. AB - Transport of negatively charged nanoparticles in porous media is largely affected by cations. To date, little is known about how cations of the same valence may affect nanoparticle transport differently. We observed that the effects of cations on the transport of graphene oxide (GO) and sulfide-reduced GO (RGO) in saturated quartz sand obeyed the Hofmeister series; that is, transport-inhibition effects of alkali metal ions followed the order of Na+ < K+ < Cs+, and those of alkaline earth metal ions followed the order of Mg2+ < Ca2+ < Ba2+. With batch adsorption experiments and microscopic data, we verified that cations having large ionic radii (and thus being weakly hydrated) interacted with quartz sand and GO and RGO more strongly than did cations of small ionic radii. In particular, the monovalent Cs+ and divalent Ca2+ and Ba2+, which can form inner sphere complexes, resulted in very significant deposition of GO and RGO via cation bridging between quartz sand and GO and RGO, and possibly via enhanced straining, due to the enhanced aggregation of GO and RGO from cation bridging. The existence of the Hofmeister effects was further corroborated with the interesting observation that cation bridging was more significant for RGO, which contained greater amounts of carboxyl and phenolic groups (i.e., metal-complexing moieties) than did GO. The findings further demonstrate that transport of nanoparticles is controlled by the complex interplay between nanoparticle surface functionalities and solution chemistry constituents. PMID- 27996241 TI - Silver Leakage from Ag/AgCl Reference Electrodes as a Potential Cause of Interference in the Electrocatalytic Hydrogen Evolution Reaction. AB - The electrocatalytic hydrogen evolution reaction (HER) is of considerable interest for the production of H2 from sustainable sources. Herein, we show that under conditions commonly employed in identifying new electrocatalysts for this reaction (using Ag/AgCl reference electrodes in 1 M H2SO4), silver ions can leak from the reference electrode into solution and then deposit on the working electrode as Ag(0), giving current densities for the HER of over 5 mA cm-2 at ~500 mV overpotential. This is well within the activity range reported for many electrocatalysts of the HER and calls into question the validity of any reports using Ag/AgCl reference electrodes which either fail to explicitly exclude silver as a cause of the electrocatalytic activity or else cannot demonstrate significantly superior activity to this baseline. PMID- 27996242 TI - Coupled Hydro-Biogeochemical Processes Controlling Cr Reductive Immobilization in Columbia River Hyporheic Zone. AB - An experiment and modeling study was conducted to investigate coupled hydro biogeochemical processes controlling reductive immobilization of groundwater Cr in the hyporheic zone (HZ) at the U.S. Department of Energy's Hanford Site, where dynamic surface water-groundwater exchange occurs on a daily basis. Experiments were performed to calibrate kinetic models, and the calibrated models were incorporated into a multicomponent reactive transport model to simulate Cr redox transformation and immobilization under field hydrological conditions. The results revealed that the rates of Cr(VI) reduction, Cr(III) accumulation, and Cr(VI) release to the river are mostly affected by dynamic sediment redox conditions represented by Fe(II) reactivity, which is controlled by its cyclic interaction with O2 carried by river water, microbial activities, and the supply and bioavailability of organic carbon (OC) that is present in the HZ and/or carried by transport. In addition, the HZ geophysical properties including hydraulic conductivity and the thickness of the top alluvial layer have a significant influence on Cr reactive transport and immobilization by controlling residence times for reactions and the supply rates of O2, Cr, and OC into the HZ. The results provide important insights into the dynamic redox environments in the HZ that can reductively immobilize contaminants. PMID- 27996243 TI - Rational Construction of Multivoids-Assembled Hybrid Nanospheres Based on VPO4 Encapsulated in Porous Carbon with Superior Lithium Storage Performance. AB - The design of a new nanostructured anode material with high tap density while still keeping the common advantages of the hollow structure is a great challenge for future lithium-ion batteries (LIBs). Here, multivoids-assembled hierarchically meso-macroporous nanospheres based on VPO4 encapsulated in porous carbon (MVHP-VPO4@C NSs) were designed and fabricated. This unique structure can evidently decrease the excessive interior space in hollow spheres or multishelled hollow spheres to gain high volumetric energy density and at the same time can alleviate the large mechanical strain during the cycling process. As expected, MVHP-VPO4@C NSs show good lithium storage behavior with gravimetric discharge capacity of 628 mAh g-1 after 100 cycles at a current density of 100 mA g-1. Furthermore, the full cell (LiFePO4 cathode//MVHP-VPO4@C NSs anode) also exhibits outstanding lithium storage performance. The insight obtained from this structure may provide guidance for the design of other electrode materials experiencing large volume variation during the lithiation-delithiation process. PMID- 27996244 TI - In Vivo Detoxification of Lipopolysaccharide by Antimicrobial Peptides. AB - Abundant lipopolysaccharide (LPS) can result in sepsis and septic shock, indicating a serious Gram-negative bacterial contamination. We have developed a novel strategy based on dendritic antimicrobial peptides that can detoxify LPS. The dendritic antimicrobial peptides bind to LPS at the surface of Gram-negative bacteria, killing the bacteria but removing the LPS from the cell wall of dead Gram-negative bacteria, hence detoxifying pathogenic bacteria in its host cells and effectively improving survival of animals infected with Pseudomonas aeruginosa. Our findings provide a way to detoxify bacterial contamination. PMID- 27996245 TI - Ultra-Sensitive Colorimetric Assay System Based on the Hybridization Chain Reaction-Triggered Enzyme Cascade Amplification. AB - A versatile and ultrasensitive colorimetric detection platform has been developed based on the hybridization chain reaction (HCR)-triggered enzyme cascade amplification in this work. The proposal involves the preparation of two different hairpin DNA strands consisting of the H1, modified with glucose oxidase (GOx-H1) and H2, modified with horseradish peroxidase (HRP-H2). The H1 and H2 were composed of complementary sequence of nucleic acid target (T) and interlaced complementary stem-loop sequences. In the nucleic acid detection, the hybridization of T and its complementary sequence induces the autonomous assembly of GOx-H1 and HRP-H2 through the predictable HCR, accompanied by the formation of GOx/HRP enzyme pairs with a multiple enzymatic cascade. In contrast to the crude mixture of free GOx-H1 and HRP-H2, the catalytic performance of enzyme cascade reaction has been significantly enhanced, which can be determined by monitoring the absorbance change of 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS2-), a typical substrate with hydrogen peroxide for the HRP. Furthermore, this platform can be utilized in the assay of biological substances by the introduction of corresponding aptamer (Apt), complementary strands (Com), and an assistant hairpin DNA strand (HAssist). In view of the signal amplification of HCR and the enhanced catalytic performance of cascaded enzymes, our colorimetric assay system exhibits excellent sensitivity, and the detection limits have been calculated to be 5.2 fM and 0.8 pM for the nucleic acid target (T as a model) and biological substances (ATP as a model), respectively. PMID- 27996246 TI - Classification of the Electronic Properties of Chelating Ligands in cis [LL'Rh(CO)2] Complexes. AB - By analogy to the Tolman electronic parameter, a ligand electronic parameter, referred to as L2EP, is introduced here for estimating the donating ability of chelating ligands, featuring two coordinating extremities. It is based on the average of the computed infrared stretching frequencies of CO in a series of isostructural rhodium(I)-dicarbonyl complexes, that is linearly correlated to the number x of N-heterocyclic carbene coordinating ends (x = 0, 1, or 2). The L2EP values allow the design of an unified scale for the classification of the electron donation of chelating ligands, based on an ortho-phenylene bridge substituted by two coordinating extremities, which may have a different donating character. Strengths and limitations of the L2EP scale are illustrated for a large diversity of bidentate chelating ligands with coordinating ends ranging from extremely electron-rich phosphonium yldiides to extremely electron-poor amidiniophosphonites. PMID- 27996247 TI - Self-Assembling Molecular Capsules Based on alpha,gamma-Cyclic Peptides. AB - A new capsule based on a beta-sheet self-assembling cyclic peptide with the ability to recognize and release several guests is described. The host structure is composed of two self-complementary alpha,gamma-cyclic peptides bearing a Zn porphyrin cap that is used for the selective recognition of the guest. The two components are linked through two dynamic covalent bonds. The combination of binding forces, including hydrogen bonding, metal coordination, and dynamic hydrazone bonds, allows the reversible recognition of long bipyridine guests. The affinity for these ligands showed a strong dependence on the guest length. Delivery of the encapsulated ligand can be achieved by hydrolysis of hydrazones to disrupt the sandwich complex structure. PMID- 27996248 TI - Na2Ti3O7 Nanoplatelets and Nanosheets Derived from a Modified Exfoliation Process for Use as a High-Capacity Sodium-Ion Negative Electrode. AB - The increasing interest in Na-ion batteries (NIBs) can be traced to sodium abundance, its low cost compared to lithium, and its intercalation chemistry being similar to that of lithium. We report that the electrochemical properties of a promising negative electrode material, Na2Ti3O7, are improved by exfoliating its layered structure and forming 2D nanoscale morphologies, nanoplatelets, and nanosheets. Exfoliation of Na2Ti3O7 was carried out by controlling the amount of proton exchange for Na+ and then proceeding with the intercalation of larger cations such as methylammonium and propylammonium. An optimized mixture of nanoplatelets and nanosheets exhibited the best electrochemical performance in terms of high capacities in the range of 100-150 mA h g-1 at high rates with stable cycling over several hundred cycles. These properties far exceed those of the corresponding bulk material, which is characterized by slow charge-storage kinetics and poor long-term stability. The results reported in this study demonstrate that charge-storage processes directed at 2D morphologies of surfaces and few layers of sheets are an exciting direction for improving the energy and power density of electrode materials for NIBs. PMID- 27996249 TI - Selective Visualization of the Endogenous Peroxynitrite in an Inflamed Mouse Model by a Mitochondria-Targetable Two-Photon Ratiometric Fluorescent Probe. AB - Peroxynitrite (ONOO-) is a kind of reactive oxygen species (ROS) with super activity of oxidization and nitration, and overproduction of ONOO- is associated with pathogenesis of many diseases. Thus, accurate detection of ONOO- with high sensitivity and selectivity is imperative for elucidating its functions in health or disease states. Herein we for the first time present a new two-photon ratiometric fluorescent ONOO- probe (MITO-CC) based on FRET mechanism by combining rational design strategy and dye-screening approach. MITO-CC, with fast response rate (within 20 s), excellent sensitivity (detection limit = 11.30 nM) and outstanding selectivity toward ONOO-, was successfully applied to ratiometric detection of endogenous ONOO- produced by HepG2/RAW264.7 cells and further employed for imaging oxidative stress in an inflamed mouse model. Therefore, probe MITO-CC could be a potential biological tool to explore the roles of ONOO- under different physiological and pathological settings. PMID- 27996250 TI - Hybrids of Cobalt/Iron Phosphides Derived from Bimetal-Organic Frameworks as Highly Efficient Electrocatalysts for Oxygen Evolution Reaction. AB - The electrochemical splitting of water, as an efficient and large-scale method to produce H2, is still hindered by the sluggish kinetics of the oxygen evolution reaction (OER) at the anode. Considering the synergetic effect of the different metal sites with coordination on the surface of electrocatalysts, the hybrids of Co/Fe phosphides (denoted as Co-Fe-P) is prepared by one-step phosphorization of CoFe metal-organic frameworks for the first time as highly efficient electrocatalysts for OER. Benefiting from the synergistic effect of Co and Fe, the high valence of Co ions induced by strongly electronegative P and N and the large electrochemical active surface area (ECSA) originated from exposed nanowires on the surface of Co/Fe phosphides, the resultant Co-Fe-P-1.7 exhibits remarkable electrocatalytic performances for OER in 1.0 M KOH, affording an overpotential as low as 244 mV at a current density of 10 mA/cm2, a small Tafel slope of 58 mV/dec, and good stability, which is superior to that of the state-of the-art OER electrocatalysts. In addition, the two-electrode cell with Co-Fe-P 1.7 modified Ni foam as anode and cathode in an alkaline electrolyte, respectively, exhibits the decomposition potential of ca. 1.60 V at a current density of 10 mA/cm2 and excellent stability. PMID- 27996251 TI - Introducing the 4-Phenyl-1,2,3-Triazole Moiety as a Versatile Scaffold for the Development of Cytotoxic Ruthenium(II) and Osmium(II) Arene Cyclometalates. AB - Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general form [(eta6-p-cym)RuCl(kappa2-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure-activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC50 values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium(II) counterparts. The IC50 values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIalpha. Still, the most cytotoxic representatives 2b and 3b showed pronounced effects on cell cycle distribution. PMID- 27996252 TI - Formation and Occurrence of N-Chloro-2,2-dichloroacetamide, a Previously Overlooked Nitrogenous Disinfection Byproduct in Chlorinated Drinking Waters. AB - Haloacetamides (HAMs) are a class of newly identified nitrogenous disinfection byproducts (N-DBPs) whose occurrence in drinking waters has recently been reported in several DBP surveys. As the most prominent HAM species, it is commonly acknowledged that 2,2-dichloroacetamide (DCAM) is mainly generated from dichloroacetonitrile (DCAN) hydrolysis because the concentrations of these two compounds are often well correlated. Instead of DCAM, a previously unreported N DBP, N-chloro-2,2-dichloroacetamide (N-Cl-DCAM), was confirmed in this study as the actual DCAN degradation product in chlorinated drinking waters. It is suspected that N-Cl-DCAM has been erroneously identified as DCAM, because its nitrogen-bound chlorine is readily reduced by most commonly used quenching agents. This hypothesis is supported by kinetic studies that indicate almost instantaneous N-chlorination of DCAM even at low chlorine residuals. Therefore, it is unlikely that DCAM can persist as a long-lived DCAN decomposition product in systems using free chlorine as a residual disinfectant. Instead, chlorination of DCAM will lead to the formation of an equal amount of N-Cl-DCAM by forming a hydrogen bond between hypochlorite oxygen and amino hydrogen. Alternatively, N-Cl DCAM can be produced directly from DCAN chlorination via nucleophilic addition of hypochlorite on the nitrile carbon. Due to its relatively low pKa value, N-Cl DCAM tends to deprotonate under typical drinking water pH conditions, and the anionic form of N-Cl-DCAM was found to be very stable in the absence of chlorine. N-Cl-DCAM can, however, undergo acid-catalyzed decomposition to form the corresponding dichloroacetic acid (DCAA) when chlorine is present, although those acidic conditions that favor N-Cl-DCAM degradation are generally atypical for finished drinking waters. For these reasons, N-Cl-DCAM is predicted to have very long half-lives in most distribution systems that use free chlorine. Furthermore, an analytical method using ultra performance liquid chromatography (UPLC)/negative electrospray ionization (ESI-)/quadrupole time-of-flight mass spectrometry (qTOF) was developed for the detection of a family of seven N-chloro haloacetamides (N-Cl-HAMs). Combined with solid phase extraction (SPE), the occurrence of N-Cl-DCAM and its two brominated analogues (i.e., N-chloro-2,2 bromochloroacetamide and N-chloro-2,2-dibromoacetamide) was quantitatively determined for the first time in 11 real tap water samples. The discovery of N-Cl DCAM or, more broadly speaking, N-Cl-HAMs in chlorinated drinking waters is of significance because they are organic chloramines, a family of compounds that is perceived to be more toxicologically potent than halonitriles (e.g., DCAN) and haloamides (e.g., DCAM), and therefore they may pose greater risks to drinking water consumers given their widespread occurrence and high stability. PMID- 27996253 TI - Efficient Approximation of Ligand Rotational and Translational Entropy Changes upon Binding for Use in MM-PBSA Calculations. AB - A major uncertainty in binding free energy estimates for protein-ligand complexes by methods such as MM-PB(GB)SA or docking scores results from neglecting or approximating changes in the configurational entropies (DeltaSconfig.) of the solutes. In MM/PB(GB)SA-type calculations, DeltaSconfig. has usually been estimated in the rigid rotor, harmonic oscillator approximation. Here, we present the development of a computationally efficient method (termed BEERT) to approximate DeltaSconfig. in terms of the reduction in translational and rotational freedom of the ligand upon protein-ligand binding (DeltaSR/T), starting from the flexible molecule approach. We test the method successfully in binding affinity computations in connection with MM-PBSA effective energies describing changes in gas-phase interactions and solvation free energies. Compared to related work by Ruvinsky and co-workers, clustering bound ligand poses based on interactions with the protein rather than structural similarity of the poses, and an appropriate averaging over single entropies associated with an individual well of the energy landscape of the protein-ligand complex, were found to be crucial. Employing three data sets of protein-ligand complexes of pharmacologically relevant targets for validation, with up to 20, in part related ligands per data set, spanning binding free energies over a range of <=7 kcal mol 1, reliable and predictive linear models to estimate binding affinities are obtained in all three cases (R2 = 0.54-0.72, p < 0.001, root mean squared error S = 0.78-1.44 kcal mol-1; q2 = 0.34-0.67, p < 0.05, root mean squared error sPRESS = 1.07-1.36 kcal mol-1). These models are markedly improved compared to considering MM-PBSA effective energies alone, scoring functions, and combinations with DeltaSconfig. estimates based on the number of rotatable bonds, rigid rotor, harmonic oscillator approximation, or interaction entropy method. As a limitation, our method currently requires a target-specific training data set to identify appropriate scaling coefficients for the MM-PBSA effective energies and BEERT DeltaSR/T. Still, our results suggest that the approach is a valuable, computationally more efficient complement to existing rigorous methods for estimating changes in binding free energy across structurally (weakly) related series of ligands binding to one target. PMID- 27996254 TI - Correction to alpha-Glucosidase Inhibitors from Brickellia cavanillesii. PMID- 27996255 TI - Different Ways of Hydrogen Bonding in Water - Why Does Warm Water Freeze Faster than Cold Water? AB - The properties of liquid water are intimately related to the H-bond network among the individual water molecules. Utilizing vibrational spectroscopy and modeling water with DFT-optimized water clusters (6-mers and 50-mers), 16 out of a possible 36 different types of H-bonds are identified and ordered according to their intrinsic strength. The strongest H-bonds are obtained as a result of a concerted push-pull effect of four peripheral water molecules, which polarize the electron density in a way that supports charge transfer and partial covalent character of the targeted H-bond. For water molecules with tetra- and pentacoordinated O atoms, H-bonding is often associated with a geometrically unfavorable positioning of the acceptor lone pair and donor sigma*(OH) orbitals so that electrostatic rather than covalent interactions increasingly dominate H bonding. There is a striking linear dependence between the intrinsic strength of H-bonding as measured by the local H-bond stretching force constant and the delocalization energy associated with charge transfer. Molecular dynamics simulations for 1000-mers reveal that with increasing temperature weak, preferentially electrostatic H-bonds are broken, whereas the number of strong H bonds increases. An explanation for the question why warm water freezes faster than cold water is given on a molecular basis. PMID- 27996256 TI - Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity. AB - The most exploited strategy to develop potent zinc-metalloprotease inhibitors relies on a core zinc chelator and a peptidic or nonpeptidic scaffold that provides supplementary interactions for optimized potency and selectivity. Applied to matrix metalloproteases (MMPs) with highly conserved catalytic domains, this strategy failed to identify inhibitors with the desired selectivity profiles. To question the precise role of the zinc-binding group (ZBG), we have carried out a study on MMP-12 inhibitors with a common peptidic core but different ZBGs. We find that exchanging the ZBG modifies inhibitor positioning and affects its dynamics and selectivity. The binding properties of these compounds were compared through biochemical, structural, and calorimetric studies, showing a complex interplay between cooperative interactions and dynamics dictated by the ZBG. Improving selectivity will require expanding the ZBG repertoire within inhibitor libraries, since relying on a single ZBG significantly decreases our chance to identify effective inhibitors. PMID- 27996257 TI - Correction to Cantharimide and Its Derivatives from the Blister Beetle Mylabris phalerata Palla. PMID- 27996258 TI - Reference Determinant Dependence of the Random Phase Approximation in 3d Transition Metal Chemistry. AB - Without extensive fitting, accurate prediction of transition metal chemistry is a challenge for semilocal and hybrid density funcitonals. The Random Phase Approximation (RPA) has been shown to yield superior results to semilocal functionals for main group thermochemistry, but much less is known about its performance for transition metals. We have therefore analyzed the behavior of reaction energies, barrier heights, and ligand dissociation energies obtained with RPA and compare our results to several semilocal and hybrid functionals. Particular attention is paid to the reference determinant dependence of RPA. We find that typically the results do not vary much between semilocal or hybrid functionals as a reference, as long as the fraction of exact exchange (EXX) mixing in the hybrid functional is small. For large fractions of EXX mixing, however, the Hartree-Fock-like nature of the determinant can severely degrade the performance. Overall, RPA systematically reduces the errors of semilocal functionals and delivers excellent performance from a single reference determinant for inherently multireference reactions. The behavior of dual hybrids that combine RPA correlation with a hybrid exchange energy was also explored, but ultimately did not lead to a systematic improvement compared to traditional RPA for these systems. We rationalize this conclusion by decomposing the contributions to the reaction energies, and briefly discuss the possible implications for double-hybrid functionals based on RPA. The correlation between EXX mixing and spin-symmetry breaking is also discussed. PMID- 27996259 TI - Spiro Meroterpenoids from Ganoderma applanatum. AB - Spiroapplanatumines A-Q (1-12, 14-16, 18, and 20), new spiro meroterpenoids respectively bearing a 6/5/7 or 6/5/5 ring system, along with three known compounds, spirolingzhines A, B, and D, were isolated from the fruiting bodies of the fungus Ganoderma applanatum. Their structures including absolute configurations were assigned by using spectroscopic methods, ECD and 13C NMR calculations, and single-crystal X-ray diffraction analysis. Biological evaluation of all the compounds disclosed that compounds 7 and 8 inhibited JAK3 kinase with IC50 values of 7.0 +/- 3.2 and 34.8 +/- 21.1 MUM, respectively. PMID- 27996260 TI - Optimal Path Search for Recurrence Relation in Cartesian Gaussian Integrals. AB - In quantum chemistry applications the computation of analytical integrals with Gaussian basis functions such as electron repulsion integrals is often the rate determining step. In this work we developed a general search algorithm to find the optimal path for the recurrence relations in the integral evaluation. This optimal path uses the least amount of intermediate integrals for building the recurrence relations to improve the computational efficiency. We also developed a redundant integral removal technique, and an efficient hybrid scheme to compute incomplete Gamma functions. A software implementation of these algorithms is able to generate efficient integral code for electron repulsion integrals and other types of integrals used in quantum chemistry. Because the algorithms are independent of the details of the recurrence relations, the software can be easily modified to generate new types of analytical integrals. PMID- 27996261 TI - Imaging Excited-State Dynamics of Doped He Nanodroplets in Real-Time. AB - The real-time dynamics of excited alkali metal atoms (Rb) attached to quantum fluid He nanodroplets is investigated using femtosecond imaging spectroscopy and time-dependent density functional theory. We disentangle the competing dynamics of desorption of excited Rb atoms off the He droplet surface and solvation inside the droplet interior as the Rb atom is ionized. For Rb excited to the 5p and 6p states, desorption occurs on starkly differing time scales (~100 versus ~1 ps, respectively). The comparison between theory and experiment indicates that desorption proceeds either impulsively (6p) or in a transition regime between impulsive dissociation and complex desorption (5p). PMID- 27996263 TI - Determining Rate Constants and Mechanisms for Sequential Reactions of Fe+ with Ozone at 500 K. AB - We present rate constants and product branching ratios for the reactions of FeOx+ (x = 0-4) with ozone at 500 K. Fe+ is observed to react with ozone at the collision rate to produce FeO+ + O2. The FeO+ in turn reacts with ozone at the collision rate to yield both Fe+ and FeO2+ product channels. Ions up to FeO4+ display similar reactivity patterns. Three-body clustering reactions with O2 prevent us from measuring accurate rate constants at 300 K although the data do suggest that the efficiency is also high. Therefore, it is probable that little to no temperature dependence exists over this range. Implications of our measurements to the regulation of atmospheric iron and ozone are discussed. Density functional calculations on the reaction of Fe+ with ozone show no substantial kinetic barriers to make the FeO+ + O2 product channel, which is consistent with the reaction's efficiency. While a pathway to make FeO2+ + O is also found to be barrierless, our experiments indicate no primary FeO2+ formation for this reaction. PMID- 27996264 TI - Characterizing Structural Complexity in Disordered Carbons: From the Slit Pore to Atomistic Models. AB - The reliable characterization of nanoporous carbons is critical to the design and optimization of their numerous applications; however, the vast majority of carbons in industrial use are highly disordered, with complex structures whose understanding has long challenged researchers. The idealized slit pore model represents the most commonly used approximation to a carbon nanopore; nevertheless, it has been only partially successful in predicting adsorption isotherms and fails significantly in predicting transport properties because of its inability to capture structural disorder and its effect on fluid accessibility. Atomistic modeling of the structure has much potential for overcoming this limitation, and among such approaches, hybrid reverse Monte Carlo simulation has emerged as the most attractive. This method reconstructs the structure of a carbon based on the fitting of its experimentally measured pair distribution function and appropriate properties such as porosity while minimizing the energy. The method is shown to be best implemented using a multistage strategy, with the first stage used to attain a deep minimum of the energy and subsequent stages to refine the structure based on the fitting of specific properties. Methods to determine the accessibility of gases based on the atomistic structure are outlined, and it is shown that energy barriers are very sensitive to small differences in the sizes of constrictions and pore entries. The ability to accurately predict macroscopic transport coefficients of adsorbates in nanoporous carbons appears to be the greatest limitation of such models. Overcoming this will require the fitting of properties more sensitive to long-range disorder than the currently used pair distribution and the use of a suitable multiscaling strategy, which is suggested as a future direction for advancing atomistic models. The inclusion of heteroatoms in the structure is also an important area requiring further attention, particularly in the development of computationally efficient force fields incorporating their interactions. PMID- 27996262 TI - Distance-Guided Forward and Backward Chain-Growth Monte Carlo Method for Conformational Sampling and Structural Prediction of Antibody CDR-H3 Loops. AB - Antibodies recognize antigens through the complementary determining regions (CDR) formed by six-loop hypervariable regions crucial for the diversity of antigen specificities. Among the six CDR loops, the H3 loop is the most challenging to predict because of its much higher variation in sequence length and identity, resulting in much larger and complex structural space, compared to the other five loops. We developed a novel method based on a chain-growth sequential Monte Carlo method, called distance-guided sequential chain-growth Monte Carlo for H3 loops (DiSGro-H3). The new method samples protein chains in both forward and backward directions. It can efficiently generate low energy, near-native H3 loop structures using the conformation types predicted from the sequences of H3 loops. DiSGro-H3 performs significantly better than another ab initio method, RosettaAntibody, in both sampling and prediction, while taking less computational time. It performs comparably to template-based methods. As an ab initio method, DiSGro-H3 offers satisfactory accuracy while being able to predict any H3 loops without templates. PMID- 27996265 TI - Improved Cycling Performance of a Si Nanoparticle Anode Utilizing Citric Acid as a Surface-Modifying Agent. AB - Citric acid and its analogues have been investigated as surface-modifying agents for Si nanoparticle anodes using electrochemical cycling, attenuated total reflectance infrared (ATR IR), and X-ray photoelectron spectroscopy (XPS). A Si nanoparticle anode prepared with citric acid (CA) has better capacity retention than one containing 1,2,3,4-butanetetracarboxylic acid (BA), but both electrodes outperform Si-PVDF. The Si-CA anode has an initial specific capacity of 3530 mA h/g and a first cycle efficiency of 82%. Surprisingly, the Si-CA electrode maintains a high specific capacity of ~2200 mA h/g after 250 cycles, corresponding to 64% capacity retention, which is similar to the Si prepared with long-chain poly(acrylic acid) (PAA). On the contrary, the silicon electrode prepared with PVDF has a fast capacity fade and retains only 980 mA h/g after 50 cycles. The IR and XPS data show that the Si-CA electrode has an SEI composed primarily of lithium citrate during the first 50 cycles, resulting from the electrochemical reduction of citric acid. Only low concentrations of electrolyte reduction products are observed. The lithium citrate layer derived from CA stabilizes the silicon surface and suppresses electrolyte reduction, which likely contributes to the enhanced cycling performance of the Si nanoparticle anode. PMID- 27996266 TI - Blueberry Anthocyanin-Enriched Extracts Attenuate Fine Particulate Matter (PM2.5) Induced Cardiovascular Dysfunction. AB - Blueberry anthocyanin-enriched extracts (BAE) at three doses (0.5, 1.0, and 2.0 g/kg) were administered by oral gavage to rats exposed to 10 mg/kg fine particulate matter (PM2.5) three times a week. A positive control group was exposed to PM2.5 without BAE treatment. We analyzed heart rate (HR), electrocardiogram (ECG), and histopathology, and biomarkers of cardiovascular system injuries, systemic inflammation, oxidative stress, endothelial function, and apoptosis. Results indicated that BAE, particularly at 1.0 g/kg, improved ECG and decreased cytokine levels in PM2.5-exposed rats. These changes were accompanied by an increase in interleukin 10 levels and superoxide dismutase activity in heart tissue and Bcl-2 protein expression, as well as a decrease in interleukin 6, malondialdehyde, endothelin 1, and angiotensin II levels and a reduction in Bax protein expression. This study demonstrates that BAE at certain doses can protect the cardiovascular system from PM2.5-induced damage. PMID- 27996268 TI - Phase Behavior and Dynamics of Binary and Multicomponent Thioester Liquid Crystal Mixtures. AB - The results of studies conducted by means of complementary methods, differential scanning calorimetry, transmitted light intensity measurements, polarized optical microscopy, the electro-optical method, as well as dielectric relaxation spectroscopy of two new liquid crystal mixtures are presented. The first mixture is an equimolecular binary mixture consisting of two ferroelectric chiral liquid crystals from the homologous series, abbreviated as (S)-MHOBSn. The second mixture is a multicomponent mixture and consists of four mesogens from the homologous series of nOS5 as the base of the mixture, abbreviated as 610712 and chiral MHOBS8. The binary MHOBS4 + MHOBS7 mixture has an enantiotropic phase sequence, as follows: Cr, SmG*, SmI*, SmC*, N*. The second mixture has the same phase sequence but a much wider temperature range of ferroelectric SmC* phase. The switching time changes from 50 to 90 MUs in the SmC* phase of the binary MHOBS4 + MHOBS7 mixture, whereas in 610712 + MHOBS8, the change is more than an order of magnitude higher, ranging from 500 to 3500 MUs. Numerical analysis of the dielectric spectra results point toward the complex dynamics of the MHOBS4 + MHOBS7 and 610712 + MHOBS8 mixtures. The relaxation processes in the crystalline, SmC*, SmI*, and SmG* subphases have been observed and described. The relaxation processes have been detected up to 12 degrees C. There is a very low intensity Goldstone mode in SmC* and a low-frequency noncancellation mode in the SmI* and SmG* phases. PMID- 27996269 TI - Novel Glycoprotein VI Antagonists as Antithrombotics: Synthesis, Biological Evaluation, and Molecular Modeling Studies on 2,3-Disubstituted Tetrahydropyrido(3,4-b)indoles. AB - The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50 = 28.36 MUmol/kg po in mice) showed improved inhibition for collagen (IC50 = 6.7 MUM), CRP-XL (IC50 = 53.5 MUM), and convulxin (CVX) (IC50 = 5.7 MUM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50 = 10.4 MUM; CRP-XL, IC50 = 158 MUM; CVX, IC50 = 11 MUM) than any of its enantiomers S (6c) (collagen, IC50 = 25.3 MUM; CRP-XL, IC50 = 181.4 MUM; CVX, IC50 = 9 MUM) and R (6d) (collagen, IC50 = 126.3 MUM; CRP-XL, IC50 > 500 MUM; CVX, IC50 = 86.8 MUM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies. PMID- 27996270 TI - Upconversion-Triggered Charge Separation in Polymer Semiconductors. AB - Upconversion is a unique optical property that is driven by a sequential photon pumping and generation of higher energy photons in a consecutive manner. The efficiency improvement in photovoltaic devices can be achieved when upconverters are integrated since upconverters contribute to the generation of extra photons. Despite numerous experimental studies confirming the relationship, fundamental explanations for a real contribution of upconversion to photovoltaic efficiency are still in demand. In this respect, we suggest a new approach to visualize the upconversion event in terms of surface photovoltage (SPV) by virtue of Kelvin probe force microscopy (KPFM). One of the most conventional polymer semiconductors, poly(3-hexyl thiophene) (P3HT), is employed as a sensitizer to generate charge carriers by upconverted light. KPFM measurements reveal that the light upconversion enabled the formation of charge carriers in P3HT, resulting in large SPV of -54.9 mV. It confirms that the energy transfer from upconverters to P3HT can positively impact the device performance in organic solar cells (OSCs). PMID- 27996271 TI - Nanostructuring of Au(111) during the Adsorption of an Aromatic Isocyanide from Solution. AB - We present a combined vibrational and morphological characterization of the self assembly of 1,4-phenylene-diisocyanide (PDI) on Au(111) from methanol solution. Vibrational sum frequency generation (vSFG) and scanning tunneling microscopy (STM) have been applied to determine the adsorption geometry of the PDI-Au adatom complexes as well as the morphological transformations of the Au(111) substrate upon SAM formation from solutions with PDI concentrations in the MUM to mM range. At low concentration/coverage, PDI adsorbs in flat adsorption geometry, with both isocyanide groups attached to Au adatoms on the Au(111) surface. Transformation to a standing-up phase is observed with increasing concentration/coverage. In contrast to findings for PDI adsorbed in ultrahigh vacuum, PDI does not form a long-range-ordered monolayer phase when adsorbed from solution. In addition, the Au(111) surface is subjected to structural modifications. Au vacancy islands and ad-islands, which are typical substrate defects formed during the self-assembly of aromatic thiols on Au(111), are also created during PDI adsorption from solution. At low PDI concentration, the Au vacancy islands and ad-islands are found at specific sites mediated by the herringbone reconstruction of the Au(111) surface, giving rise to long-range-ordered structures. These structures do not form during UHV adsorption of PDI on Au(111) nor has a similar ordering effect been observed for any related thiol-SAM system investigated so far. PMID- 27996272 TI - IL-6 Linkage to Exercise-Induced Shifts in Lipid-Related Metabolites: A Metabolomics-Based Analysis. AB - Metabolomics profiling and bioinformatics technologies were used to determine the relationship between exercise-induced increases in IL-6 and lipid-related metabolites. Twenty-four male runners (age 36.5 +/- 1.8 y) ran on treadmills to exhaustion (2.26 +/- 0.01 h, 24.9 +/- 1.3 km, 69.7 +/- 1.9% VO2max). Vastus lateralis muscle biopsy and blood samples were collected before and immediately after running and showed a 33.7 +/- 4.2% decrease in muscle glycogen, 39.0 +/- 8.8-, 2.4 +/- 0.3-, and 1.4 +/- 0.1-fold increases in plasma IL-6, IL-8, and MCP 1, respectively, and 95.0 +/- 18.9 and 158 +/- 20.6% increases in cortisol and epinephrine, respectively (all, P < 0.001). The metabolomics analysis revealed changes in 209 metabolites, especially long- and medium-chain fatty acids, fatty acid oxidation products (dicarboxylate and monohydroxy fatty acids, acylcarnitines), and ketone bodies. OPLS-DA modeling supported a strong separation in pre- and post-exercise samples (R2Y = 0.964, Q2Y = 0.902). OPLSR analysis failed to produce a viable model for the relationship between IL-6 and all lipid-related metabolites (R2Y = 0.76, Q2Y = -0.0748). Multiple structure equation models were evaluated based on IL-6, with the best-fit pathway model showing a linkage of exercise time to IL-6, then carnitine, and 13-methylmyristic acid (a marker for adipose tissue lipolysis) and sebacate. These metabolomics based data indicate that the increase in plasma IL-6 after long endurance running has a minor relationship to increases in lipid-related metabolites. PMID- 27996273 TI - Ion-Specific Effects on the Elongation Dynamics of a Nanosized Water Droplet in Applied Electric Fields. AB - We report an all-atom molecular dynamics study of the structures and dynamics of salty water droplets on a silicon surface under the influence of applied electric field. Our simulation results support ion-specific effects on the elongation dynamics of salty nanodroplets, induced by the field. This feature has not been explored up to now in monovalent salts. Nevertheless, the importance of ion specific effects is widely confirmed in biological and colloidal systems. In particular, the increase of salt concentration enhances the effect of the nature of ions on the wetting properties of droplets. In the presence of electric field (0.05 V A-1), a complete spreading is implemented in a short time for different droplets at a concentration of 1 M, and the droplet morphology is stable, observed at long time scales. However, a higher salt concentration of 4 M considerably suppresses the spreading process owing to the increase of surface tension. It was found that the NaCl droplet shows deformation oscillations along the external field, but cannot fully wet the substrate surface. By contrast, the CsCl droplet reaches complete elongation rapidly and adopts a steady strip shape. The KCl droplet undergoes frequent transitions between breakup and connection. Additionally, the droplets can be elongated only when the electric field strength exceeds a threshold value. The dipole orientation of interfacial water and the ionic diffusion exhibit ion-specific dependences, but the hydrogen bond network is scarcely disturbed, excluding a concentration-dependent effect. PMID- 27996267 TI - Covalent Modifiers: A Chemical Perspective on the Reactivity of alpha,beta Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions. AB - Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on alpha,beta-unsaturated carbonyls given their preponderance in bioactive natural products. PMID- 27996274 TI - Relay Visible-Light Photoredox Catalysis: Synthesis of Pyrazole Derivatives via Formal [4 + 1] Annulation and Aromatization. AB - A relay visible-light photoredox catalysis strategy has been accomplished. Three successive photoredox cycles (one oxidative quenching cycle and two reductive quenching cycles) are engaged in a single reaction with one photocatalyst. This strategy enables formal [4 + 1] annulation of hydrazones with 2-bromo-1,3 dicarbonyl compounds, which functionalizes three C-H bonds of hydrazones. This method affords rapid access to a complex and biologically important pyrazole scaffold in a step-economical manner with high efficiency under mild conditions. PMID- 27996275 TI - Diastereoselective Michael-Claisen Cyclizations of gamma-Oxa-alpha,beta unsaturated Ketones en Route to 5-Oxatetracyclines. AB - 5-Oxatetracyclines were synthesized from d-arabinose using sequential Michael Claisen cyclization reactions via a 5-oxa-AB enone substrate. The 5 oxatetracyclines were found to have poor stability in aqueous buffer (pH 7.4, 37 degrees C) and showed little to no inhibition of bacterial growth (S. aureus, E. coli). PMID- 27996276 TI - Diastereoselective Synthesis of gamma-Substituted 2-Butenolides via (CDC)-Rh Catalyzed Intermolecular Hydroalkylation of Dienes with Silyloxyfurans. AB - Catalytic intermolecular hydroalkylation of dienes with silyloxyfuran nucleophiles is reported. Reactions are catalyzed by 5 mol % of a (CDC)-Rh complex and proceed in up to 87% yield and 6:1 dr (syn/anti) to provide allylic butenolides bearing vicinal stereocenters. Reactions proceed with terminal aryl and alkyl dienes and with modified silyl enol ether nucleophiles including a thiophenone variant. Utility of the products is demonstrated in the synthesis of a polypropionate anti,syn-stereotriad. PMID- 27996277 TI - Esterase Activated Carbonyl Sulfide/Hydrogen Sulfide (H2S) Donors. AB - Hydrogen sulfide (H2S) is a mediator of a number of cellular processes, and modulating cellular levels of this gas has emerged as an important therapeutic area. Localized generation of H2S is thus very useful but highly challenging. Here, we report pivaloyloxymethyl-based carbonothioates and carbamothioates that are activated by the enzyme, esterase, to generate carbonyl sulfide (COS), which is hydrolyzed to H2S. PMID- 27996278 TI - Fully Reversible Quantitative Phase Transfer of Gold Nanoparticles Using Bifunctional PNIPAM Ligands. AB - Ligand exchange with end-functionalized polymers is often applied to render nanoparticles with enhanced colloidal stability, to change the solubility in various environments, and/or to introduce new functionalities. Here we show that exchange of citrate molecules with alpha-trithiocarbonate-omega-carboxyl terminated poly(N-isopropylacrylamide) can successfully stabilize spherical gold particles of different diameters ranging from 15 to 53 nm. This is verified by transmission electron microscopy, dynamic light scattering, and extinction spectroscopy. We show that the polymer-decorated nanoparticles respond to temperature and pH allowing access to control interparticle interactions. In a range of pH slightly below the pKa of the terminal carboxyl groups, phase transfer of the particles from water to chloroform can be mediated by increasing the dispersion temperature above the lower critical solution temperature of poly(N-isopropylacrylamide). Upon cooling, fully reversible phase transfer to the water phase is observed. Extinction spectroscopy reveals phase transfer efficiencies close to 100% for every system under investigation. PMID- 27996280 TI - A comparative pilot study of the efficacy and safety of nebulized magnesium sulfate and intravenous magnesium sulfate in children with severe acute asthma. AB - INTRODUCTION: Severe asthma attacks are life-threatening, and require serious medical attention. Intravenous MgSO4 is an efficient medication, proven to improve outcomes. To date, most research has focused on administration of nebulized MgSO4 in adults with critical asthma. However, its benefits for treating childhood asthma has been little investigated. This study compared the clinical efficacy and adverse effects of nebulized MgSO4 and intravenous MgSO4 in the treatment of children with severe acute asthma. METHOD: A prospective, open label, randomized, controlled pilot study was conducted in children with severe asthma exacerbation admitted at the Queen Sirikit National Institute of Child Health. Twenty-eight patients were randomized to receive three intermittent doses of nebulized or intravenous MgSO4. The Modified Wood's Clinical Asthma Score was determined prior to, and at 20, 40, 60, 120, 180 and 240 minutes after treatment administration. The length of hospital stay was also recorded. RESULTS: Fifteen patients received nebulized isotonic MgSO4 and 13 were administered intravenous MgSO4. There were no differences in the baseline characteristics of the two groups, including their initial asthma severity scores (4.87 +/- 0.92 vs. 5.0 +0.82; p = 0.69). No statistically significant differences between the two groups were identified at 60 minutes (2.47 +/- 0.83 vs. 2.77 +/- 0.93; p = 0.37) until 240 minutes. The length of hospital stay for both groups was also similar (4.0 +/ 1.2 vs. 4.54 +/- 2.7; p = 0.51). No adverse effects from MgSO4 administration were observed among the participants. CONCLUSIONS: In this small sample size we demonstrated that nebulized MgSO4 and intravenous MgSO4 are both clinically beneficial and safe for Thai children suffering from severe asthma exacerbation. PMID- 27996279 TI - Association between sleep duration and the prevalence of atopic dermatitis and asthma in young adults. AB - BACKGROUND: Sleep duration affects allergic diseases; however, this association requires further investigation. OBJECTIVE: To evaluate the association between sleep duration and the prevalence of atopic dermatitis and asthma in young Korean adults. METHOD: We analyzed data of 10,148 subjects (4,239 men; 5,909 women) aged 19-39 years from the Korean National Health and Nutrition Examination Survey 2008 2010. Self-reported sleep duration was categorized into five groups: <=5h, 6h, 7h, 8h, and >=9h. The prevalence of atopic dermatitis and asthma was examined based on a questionnaire and compared between participants from five sleep duration groups after adjusting for potential confounding factors, including model 1 [age], model 2 [model 1 + BMI, current smoking, current alcohol use, regular physical activity, household income, and serum 25(OH)D level], and model 3 [model 2 + stress levels]. RESULTS: In female participants, a higher risk of atopic dermatitis was associated with sleep duration <=5 hours [odds ratio (OR): 1.665, 95% confidence interval (CI): 1.004-2.762; model 1], and >=9 hours (OR, 1.746, 95% CI, 1.145-2.661; model 3), compared to a 7-hour sleep duration. Similarly, a higher risk of asthma was associated with sleep duration <=5 hours and >=9 hours (OR, 1.553, 95% CI, 1.023-2.359 and OR, 1.569, 95% CI, 1.048-2.349, respectively; model 3). In male participants, there was no significant association between sleep duration and the prevalence of atopic dermatitis or asthma. CONCLUSIONS: Sleep duration <=5 and >=9 hours may be a risk factor for atopic dermatitis and asthma in young female adults. PMID- 27996282 TI - A novel mutation of WAS gene in a boy with Mycobacterium bovis infection in spleen. AB - Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by mutations of the gene encoding WAS protein (WASp). A scoring system has been used to grade severity of the disease. However, the phenotype of the disease may progress over time, especially in children younger than 2 years of age. Here, we report a male child who presented with X-linked thrombocytopenia (XLT). Mutation analysis revealed a novel hemizygous 13-bp deletion (c.181_193delGCTGAGCACTGGA) on exon 2 of the WAS gene. This frameshift mutation resulted in a premature terminating codon at position 71 (p.A61fsX10). Molecular analysis of maternal DNA revealed a heterozygosity of the same mutation. The disease progressed to classic WAS within 8 months. Later, gastric varices as a consequence of Mycobacterium bovis infection in the spleen was detected. The rapid worsening of the disease may be due to the severe genotype of this patient. PMID- 27996281 TI - IL12Rbeta1 defect presenting with massive intra-abdominal lymphadenopathy due to Mycobacterium intracellulare infection. AB - Infections due to non-tuberculous mycobacteria species are problematic for immunodeficient individuals. Mendelian susceptibility to mycobacterial diseases (MSMD) defines a group of genetic defects affecting cellular interactions and the interferon (IFN)-gamma pathway. Patients with MSMD may present with a disseminated infection resulting from the Bacillus Calmette-Guerin vaccine, Mycobacterium tuberculosis complex, environmental nontuberculous mycobacteria or Salmonella species. Atypical mycobacterial infections and deficient granuloma or giant cell formation are important indicators for MSMD, especially in patients with a family history of parental consanguineous marriage. Herein we report the case of a boy with an IL-12Rbeta1 defect who presented with massive intraabdominal lymphadenopathy due to Mycobacterium intracellulare infection. The patient was born to consanguineous parents, both heterozygous for the IL-12Rbeta1 defect mutation. Debulking surgery was planned in order to decrease the abdominal mass, but could not be performed due to a high risk of fatal outcomes. He has been receiving linezolid, levofloxacin, azithromycin, rifabutin and IFN-gamma therapy for the past 14 months. At follow-up, the patient showed significant clinical improvement and weight gain. PMID- 27996283 TI - Evaluation of serum interleukin- 35 level in children with persistent asthma. AB - BACKGROUND: IL-35 is a novel cytokine suppressing the immune response through the expansion of regulatory T cells and suppression of Th17 cell development. Few studies have been done on the effect of this cytokine in a different disease. Asthma is a complex disease that many inflammatory cells and cytokines play a role in. OBJECTIVE: We decide to determine the difference between serum level of IL-35 in childhood asthma & healthy children. METHOD: We obtained serum samples from 44 asthmatic children between 2 and 15 years as a case group and from healthy children as a control group. IL-35 serum concentration was determined by ELISA method in both groups. RESULTS: Mean serum level is 30.9 pg/ml in the case group and 30.2 pg/ml in the control group. There is no significant difference between serum level of IL-35 in asthmatic & healthy children. CONCLUSIONS: Our data reveal no relation between childhood asthma and serum level of IL35. So, further study will be needed to clarify effects of this cytokine in human allergic diseases. PMID- 27996284 TI - Allergic sensitization in kidney transplanted patients - Is it a result of immunosuppressive agents or the sensitization of living donor? AB - BACKGROUND: Allergic sensitization has been reported increasingly in organ transplant recipients. However, the pathogenesis of this sensitization has still not been clearly understood. OBJECTIVE: The aim of this study was to evaluate allergic sensitization in kidney transplanted children and adolescents under immunosuppressive treatment. METHODS: Twenty seven kidney-transplanted subjects were studied by standardized interviews from the International Study of Asthma and Allergies in Childhood criteria, skin prick test (SPT) and measurement of specific immunoglobulin E (s-IgE). Patients were considered to have allergic sensitization when presenting a positive SPT and/or s-IgE >0.35 kUA/l to at least one of the tested allergens. Patients with a history of allergic diseases accompanied by sensitization were accepted as allergic. We also performed SPT on the living donors of the allergic groups. RESULTS: Seven patients (25.9%) were found to be sensitized to >=1 common inhalant and 3 subjects (11.1%) additionally reported a corresponding present history of allergic diseases. All of the living donors' sensitized patients were allergic. New-onset post-transplantation food allergy was not documented in any patients. CONCLUSIONS: This study supports the concept that not only immunosuppressant agents but also sensitization of living donors could be a significant contributor to allergic sensitization in kidney recipients. PMID- 27996285 TI - BCAP 31 expression and promoter demethylation in psoriasis. AB - BACKGROUND: Psoriasis is the disease of abnormal keratinocyte differentiation and apoptosis. Alterations in DNA methylation leading to keratinocyte hyperproliferation is one of the proposed pathogenic mechanisms of psoriasis. B cell receptor associated protein (BCAP31) has been reported to be involved in the proliferation and apoptosis of keratinocytes. Up-regulation and changing in BCAP31 promoter methylation has been reported to be associated with some cancers. To date, there has been no study of psoriasis. OBJECTIVE: We investigated BCAP31 protein expression and the status of BCAP31 promoter methylation in psoriasis. METHODS: Ten patients with psoriasis and 10 healthy subjects were enrolled. The immunohistochemistry was performed on paraffin-embedded tissue section to detect BCAP31 protein expression and compared between psoriasis and normal skin. The laser capture micro-dissected keratinocyte were analyzed using bisulfite PCR method and cloning and sequencing. RESULTS: Increased BCAP31 protein expression was observed in psoriatic epidermis compared with normal epidermis. Interestingly the methylation level of the BCAP31 promoter was significantly lower in patients with psoriasis compared with healthy subjects (p < 0.001, % psoriasis vs. normal skin methylation = 14.94 vs. 60.61). CONCLUSION: The present study demonstrated increase expression of BCAP31 protein related to BCAP31 DNA demethylation in psoriasis. Future study is needed to indicate the mechanism of BCAP31 promoter demethylation and its potential use as a novel treatment for psoriasis in the future. PMID- 27996286 TI - Safety and efficacy of ant rush immunotherapy in children. AB - BACKGROUND: The Rush Immunotherapy (RIT) protocol is a valid alternative in order to reach the maintenance phase early. However, there are scarce studies in the literature that have evaluated the safety and the efficacy of an ant RIT process in children. OBJECTIVE: To evaluate the safety and the efficacy of an ant RIT protocol and to identify the risk factors for systemic reactions (SRs) during an RIT procedure in children. METHOD: A retrospective review was conducted for those children who were receiving an ant RIT procedure. The 3-day RIT protocol consisted of hourly subcutaneous injections in order to achieve a 0.5 ml maintenance dose of a 1:100 weight/ volume (wt/vol) of the Solenopsis invicta whole body extract. The safety for an RIT procedure was monitored by using the World Allergy Organization Subcutaneous Immunology Systemic Reaction Grading System. The efficacy was assessed by the reactions after a field ant re-sting. RESULT: A total of 20 children who were receiving an ant RIT therapy were reviewed. The mean age was 9.5+/-3.07 years. There were 6 systemic reactions (SRs) from 324 injections during the RIT procedure (1.85%). All of the systemic reactions were Grade 1-2. There were no associations of SRs regarding age, gender, an atopic history, or the levels of immunoglobulin E (IgE) sensitization to the ants. Among the 14 patients who experienced a field ant re-sting, 4 (28.5%) patients developed Grade 3 SRs. These Grade 3 reactions were resolved after an increase of the maintenance dose to 0.5 ml of a 1:50 wt/vol. There was a significant difference in the mean age of those children who had ant re-sting systemic reactions and those who had no reactions (6.75+/-0.95 year vs. 10.8+/ 3.29, p=0.036). CONCLUSION: Rush immunotherapy with ant in children is safe and it has a low occurrence of severe systemic reactions. It is an alternative treatment for those patients requiring a rapid protection. PMID- 27996287 TI - Association of indoor air quality and preschool children's respiratory symptoms. AB - BACKGROUND: This study aimed to assess the association between exposure to indoor air pollution in DCCs (Child Day Care Centers) and the respiratory symptoms of children under 6 years old. METHODS: Air quality data were collected three times regarding to seasonal variation. Pollutants measured in 11 DCCs included PM10, CO, NO2, SO2, O3, benzene, bacteria, fungi, and dust mite. The frequencyof respiratory symptoms including coughing, rhinitis, and dyspnea were recorded via teacher and parent-report questionnaires. Fractional exhaled nitric oxide (FENO) levels were measured to assess airway inflammation. RESULTS: 436 children participated in the study. 83% completed data collection in all 3 seasons. The frequency of rhinitis correlated with PM10 (IRR=70.3, 95%CI=12.4-399.7, p<0.001), CO (IRR=3.2, 95%CI=2.4-4.2, p<0.001), benzene (IRR=2.3, 95%CI=1.8-3.2, p<0.001) and D.Pteronyssinus level (IRR=2.1, 95%CI=1.7-2.7, p<0.001). The frequency of coughingcorrelated with levels of PM10 (IRR=15.2, 95%CI=3.0-78.2, p<0.001), CO (IRR=2.8, 95%CI=2.1-3.7, p<0.001), benzene (IRR=1.4, 95%CI=1.1-1.9, p=0.02). The frequency of dyspnea correlated with D.Pteronyssinus level (IRR=3.9, 95%CI=1.7 9.1, p=0.001). FENO levels associated with high benzene levels (OR=5.9, 95%CI=1.5 22.9, p=0.01). The majority of DCCs had at least one PM10 measurement above the standard level, and these high levels were noted in all 3 seasons. Three DCCs had PM10 levels above the standard level in all seasons. 64% of the DCCs had indoor bacterial counts above the standard level in all seasons. CONCLUSIONS: PM10 and bacterial count is a significant problem in Bangkok metropolitan DCCs. The respiratory symptoms of children positively associated with PM10, CO, benzene and dust mite levels. PMID- 27996288 TI - The natural history of atopic dermatitis and its association with Atopic March. AB - BACKGROUND: Atopic dermatitis (AD) is the first manifestation of Atopic March. The natural history of AD and predictive factors for Atopic March have not been widely studied in Asia. OBJECTIVE: To study the natural history and associated factors of disease remission and risk of respiratory allergy in Thai children with AD. METHODS: Medical records of AD patients attending Allergy clinic at Siriraj hospital from 2004-2014 were reviewed. Patients were further followed-up to obtain current symptoms and treatment. RESULTS: One hundred and two AD patients (60.8% female) were followed for 10.2+/-4.7 years. The median age at diagnosis was 1.5 (0.1-12.0) years. The most common allergen sensitization was Dermatophagoides pteronyssinus and Dermatophagoides farinae. Forty-four percent of patients had complete remission at the median age of 6.3 (2.0-15.0) years. Forty-seven percent of early AD patients (onset < 2 years) had concomitant food allergy which egg and cow's milk were leading causes. The remission rate of AD was higher in early AD than later onset AD (p=0.02). Allergic rhinitis (AR) and asthma were diagnosed in 61.8% and 29.4% of the patients at the median age of 4.6 and 3.8 years, respectively. Early AD and food allergies were significantly associated with early asthma (onset < 3years) (OR=10.80, p< 0.01 and OR=8.70, p=0.01). CONCLUSION: Almost half of AD children had complete remission at school age with a better prognosis in early AD. At preschool age, two-thirds and one third developed AR and asthma, respectively. Early AD and food allergy were risk factors of early asthma. PMID- 27996289 TI - Cardiac involvement in DRESS syndrome. AB - OBJECTIVE: Cardiac involvement in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome varies considerably between 4% and 21%. Here we present our case and review literatures for its diagnosis and management. An algorithm for diagnosis of cardiac involvement in DRESS syndrome is proposed in this article. DATA SOURCES: Data regarding DRESS-associated myocarditis and eosinophilic myocarditis were gather primarily from MEDLINE database. RESULTS: DRESS syndrome is a hypersensitivity reaction which is due to massive T cell stimulation resulting in cytotoxicity and eosinophil activation and recruitment. It is characterized by fever, morbilliform rash, and various systemic symptoms, in particular hepatitis. Hypersensitivity myocarditis (acute eosinophilic myocarditis) which is typically related to a drug reaction can lead to acute necrotizing eosinophilic myocarditis, cardiac thrombosis and fibrotic stage. Cardiac symptoms range from no symptoms to cardiogenic shock. Diagnosis is based on history, clinical findings, cardiac biomarkers and cardiac imaging techniques. Endomyocardial biopsy is done in a minority of patients for definite diagnosis. If suspected, drug discontinuation and suppression of immune reactions are the first therapies. Corticosteroids are the cornerstone of systemic treatments and should be initiated at the time of diagnosis of DRESS syndrome. Additional therapy and ventricular assist devices could be considered in refractory cases. CONCLUSIONS: According to its high morbidity and mortality, patients with DRESS syndrome should be carefully monitored or screened for cardiac involvement. Multidisciplinary care is important for a successful treatment outcome. PMID- 27996290 TI - Determination of fractional exhaled nitric oxide (FENO) reference values in healthy Thai population. AB - BACKGROUND: Fractional exhaled nitric oxide (FENO) level is directly correlated with airway inflammation in asthma patients. The objective of this study was to define normal FENO levels in healthy Thai volunteers. METHODS: This prospective cohort study was conducted in healthy Thai volunteers aged >=5 years. Demographic and clinical data were recorded and pulmonary function test (PFT) was performed. FENO was measured using a chemiluminescence nitric oxide analyzer. RESULTS: Seventy-nine healthy Thai volunteers with normal lung function test were included. Mean age of participants was 13 (6-47) years and 58.2% were female. All subjects had no history of allergic respiratory diseases. Mean FENO level increased with age, and the differences between age groups were statistically significant (p=0.001). The highest mean FENO level was 13.6 ppb in the 11-15 year age group, and then the FENO level gradually declined with age. The highest mean FENO level was found in the 18-24.9 body mass index (BMI) group. Significant differences were observed for FENO levels between different height groups (p=0.005) but not between different BMI groups (p=0.46). Fair correlations between FENO levels and body weight, height, FEV1, and FVC were observed. A fair correlation between FENO level and age, FENO level and FEF25%-75% was found only in volunteers <=15 years of age. CONCLUSION: FENO level in healthy Thais increased with age until reaching maximum level (mean FENO 13.6 ppb) in the 11-15 year age group. Significant differences were observed for FENO levels between different age groups and different height groups. PMID- 27996291 TI - Is the prevalence of atopic dermatitis in Korean children decreasing? : National Database 2009-2014. AB - BACKGROUND: The prevalence of atopic dermatitis (AD) in children is increasing in many developing countries. OBJECTIVE: This study aimed to explore trends in the prevalence of AD in Korean children. METHODS: We analyzed data from the Korean National Health Insurance Service (NHIS) from 2009 to 2014. Data for the estimated populations were collected from the Statistics Korea. The annual prevalence of AD was obtained by dividing the number of patients by the estimated population each year. We analyzed the prevalence of AD in 2014 and evaluated the change in the annual prevalence of AD from 2009 through 2014. RESULTS: The estimated population of children aged 18 years or younger was 9,992,581 in 2014, and the number of children with AD was 578,678 with the prevalence of 5.8%. The prevalence was 17.2% in infants aged 12-23 months, which decreased substantially to 7.3%, 3.2% and 2.4% at 5, 12 and 18 years of age, respectively. In the pediatric age group, the prevalence of AD slightly decreased from 6.5% to 5.8% from 2009 through 2014. Notably, in infants aged less than 24 months, the prevalence decreased from 20.8% to 15.4%. CONCLUSIONS: Based on the Korean NHIS database, the prevalence of AD in Korean children aged 18 years or younger appears to be decreasing, especially in infants. Although the reason is not clear, an increase in breast milk feeding, vaginal delivery or consumption of probiotics might be involved. Further studies are needed to confirm this trend and to explain the possible mechanisms. PMID- 27996292 TI - Activation of dengue virus-specific T cells modulates vascular endothelial growth factor receptor 2 expression. AB - BACKGROUND: The pathogenic mechanisms underlying the increased vascular permeability in dengue hemorrhagic fever (DHF) are not well understood. Enhanced cellular immune activation, especially activation of serotype-cross reactive T cells, has been implicated in plasma leakage in DHF. Changes in several biological markers and mediators including cytokines, chemokines, angiogenic factors and their receptors have been shown to correlate with disease severity. A decline in plasma levels of a soluble form of vascular endothelial growth factor receptor 2 (VEGFR2), a receptor of vascular endothelial growth factor (VEGF), has been associated with plasma leakage in dengue patients. OBJECTIVE: We aimed to investigate the effect of dengue virus (DV)-specific CD8+ T cells on the expression of VEGFR2 on endothelial cells. METHODS: An in vitro model was developed in which dengue virus-specific CD8+ T cells generated from peripheral blood mononuclear cells (PBMCs) of DHF patients were co-cultured with antigen presenting cells, human umbilical vein endothelial cells (HUVECs) and activated with DV non-structural protein 3 (NS3) peptides. The expression of VEGFR2 by endothelial cells was measured. RESULTS: DV-specific CD8+ T cells were serotype cross-reactive. Activation of DV-specific CD8+ T cells resulted in down regulation of soluble VEGFR2 production and an up-regulation of cell-associated VEGFR2. CONCLUSIONS: Our findings indicate that activation of DV-specific T cell is associated with modulation of VEGFR2 expression that may contribute to increased VEGF responsiveness and vascular permeability. PMID- 27996293 TI - How dietary intake has been assessed in African countries? A systematic review. AB - BACKGROUND: Dietary patterns are often considered as one of the main causes of non-communicable diseases worldwide. It is of utmost importance to study dietary habits in developing countries since this work is scarce. OBJECTIVE: To summarize the most recent research conducted in this field in African countries, namely the most used methodologies and tools. METHODS: A systematic review was conducted on MEDLINE(r)/PubMed, aiming to identify scientific publications focused on studies of dietary intake of different African populations, in a ten-year period. Papers not written in English/Portuguese/Spanish, studies developed among African people but not developed in African countries, studies aiming to assess a particular nutrient/specific food/food toxin and studies that assessed dietary intake among children were excluded. FINDINGS: Out of 99 included studies, the 24-hour recall and the food-frequency questionnaire were the most used dietary intake assessment tools, used to assess diet at an individual level. It was also observed that often country-unspecific food composition databases are used, and the methodologies employed are poorly validated and standardized. CONCLUSIONS: There is an emergent need to improve the existing food databases by updating food data and to develop suitable country-specific databases for those that do not have their own food composition table. PMID- 27996294 TI - Visualization of CombiHIVvac Vaccine Particles Using Electron Microscopy. PMID- 27996295 TI - Medicinal Plants for Management of Gastroesophageal Reflux Disease: A Review of Animal and Human Studies. AB - OBJECTIVES: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disease that causes troublesome symptoms and/or complications. The major therapeutic strategy for GERD focuses mainly on symptom alleviation using proton pump inhibitors (PPIs), which does not produce a perfect response in all patients. An approach with new therapeutic agents for GERD seems to be essential. The aim of this study was to review animal and human studies investigating the effect of medicinal plants in GERD as well as mechanisms underlying their therapeutic effects. METHODS: Medline, Scopus, and Cochrane Central Register of Controlled Trials were searched for animal or human studies. The data collected covered January 1966-October 2015. RESULTS: A total of 22 studies were included in this review, of which nine were animal studies and 13 were human studies. Ceratonia siliqua as a medicinal plant and rikkunshito as a multicomponent herbal preparation were the most frequently studied herbal medicines in GERD. Antioxidant and anti-inflammatory activities were the main mechanisms demonstrated in animal studies for ameliorating the effects of medicinal plants in GERD. Other mechanisms include downregulation of genes encoding inflammatory proteins, improvement of barrier function and gastric mucus, a decrease in gastric acid, and induction of tonic contractions of the lower esophageal sphincter. All herbal preparations used in human studies have led to the alleviation of symptoms related to GERD. Myrtus communis and Cydonia oblonga showed marked reduction in GERD symptoms comparable to omeprazole. The therapeutic effect of Cydonia oblonga persisted after discontinuation of the drug. Tongjlang and rikkunshito showed therapeutic effects for non-erosive reflux disease (NERD) where PPIs failed to show a promising effect. Studies on Ceratonia siliqua have been solely focused on regurgitation in infants, and a remarkable decrease in the number of regurgitations was demonstrated. CONCLUSION: The multiple mechanisms of action of medicinal plants in GERD other than anti secretory properties appear to provide more efficient treatment and helped to manage the histopathological changes associated with this disorder. Further studies are needed to understand the effects of medicinal plants on GERD better. PMID- 27996296 TI - The Academy of Breastfeeding Medicine's Leadership Team for 2017. PMID- 27996297 TI - The Cleft Aesthetic Rating Scale for 18-Year-Old Unilateral Cleft Lip and Palate Patients: A Tool for Nasolabial Aesthetics Assessment. AB - OBJECTIVE: To develop a reliable and easy-to-use method to assess the nasolabial appearance of 18-year-old patients with unilateral cleft lip and palate (CLP). DESIGN: Retrospective analysis of nasolabial aesthetics using a 5-point ordinal scale and newly developed photographic reference scale: the Cleft Aesthetic Rating Scale (CARS). Three cleft surgeons and 20 medical students scored the nasolabial appearance on standardized frontal photographs. SETTING: VU University Medical Center, Amsterdam. PATIENTS: Inclusion criteria: 18-year-old patients, unilateral cleft lip and palate, available photograph of the frontal view. EXCLUSION CRITERIA: history of facial trauma, congenital syndromes affecting facial appearance. Eighty photographs were available for scoring. MAIN OUTCOME MEASURES: The interobserver and intraobserver reliability of the CARS for 18-year old patients when used by cleft surgeons and medical students. RESULTS: The interobserver reliability for the nose and lip together was 0.64 for the cleft surgeons and 0.61 for the medical students. There was an intraobserver reliability of 0.75 and 0.78 from the surgeons and students, respectively, on the nose and lip together. No significant difference was found between the cleft surgeons and medical students in the way they scored the nose ( P = 0.22) and lip ( P = 0.72). CONCLUSIONS: The Cleft Aesthetic Rating Scale for 18-year-old patients has a substantial overall estimated reliability when the average score is taken from three or more cleft surgeons or medical students assessing the nasolabial aesthetics of CLP patients. PMID- 27996298 TI - Genetic Interactions in Nonsyndromic Orofacial Clefts in Europe-EUROCRAN Study. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (nsCL+/-P) and nonsyndromic cleft palate (nsCP) are caused by a combination of genetic and environmental risk factors. We investigated gene-environment and gene-gene joint effects in a large multicenter study of case-parent triads. METHODS: The nsCL+/-P or nsCP triads were recruited in 11 European countries between 2001 and 2005. We collected DNA samples from infants and from their mothers and fathers, and mothers completed a questionnaire on exposures, including smoking and folic acid supplement use during pregnancy. We used log-linear regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between nsCL+/-P or nsCP and variants in MTHFR, MTHFD1, TGFA, SATB2, and MSX1, stratifying by environmental or genetic factors. RESULTS: We obtained genotype and exposure data for 728 nsCL+/-P triads and 292 nsCP triads. In male infants, there was no association between the mother's homozygous MSX1 p(CA) *4/*4 genotype and nsCL+/-P (RR, 0.98; 95% CI, 0.63-1.54), but this maternal genotype resulted in a doubling of risk for female infants (RR, 2.21; 95% CI, 1.13-4.34). There was evidence suggestive of gene-gene joint-effects between MTHFR-TGFA for nsCP but not for nsCL+/-P. CONCLUSION: Although we chose the genes and their variants and putative joint effects based on associations previously reported in the literature, we replicated few associations. These results do not provide evidence supporting associations between these genes and oral clefts in European populations, although gene-environment and gene-gene interactions could play a role in oral cleft etiology. PMID- 27996300 TI - Phytoextraction of soil trace elements by willow during a phytoremediation trial in Southern Quebec, Canada. AB - The phytoextraction of the trace elements (TEs) As, Cd, Cu, Ni, Pb, and Zn by willow cultivars (Fish Creek, SV1 and SX67) was measured during a 3-year field trial in a mildly contaminated soil. Biomass ranged from 2.8 to 4.4 Mg/ha/year at 30,000 plants/ha. Shoots (62%) were the main component followed by leaves (23%) and roots (15%). Biomass was positively linked to soluble soil dissolved organic carbon, K, and Mg, while TEs, not Cd and Zn, had a negative effect. The TE concentration ranking was: Zn > Cu > Cd > Ni, Pb > As, and distribution patterns were: (i) minima in shoots (As, Ni), (ii) maxima in leaves (Cd, Zn), or (iii) maxima in roots (Cu, Pb). Correlations between soil and plant TE were significant for the six TEs in roots. The amounts extracted were at a maximum for Zn, whereas Fish Creek and SV1 extracted more TE than SX67. More than 60% (91-94% for Cd and Zn) of the total TE was in the aboveground parts. Uptake increased with time because of higher biomass. Fertilization, the selection of cultivars, and the use of complementary plants are required to improve productivity and Cd and Zn uptake. PMID- 27996299 TI - DNA recovery from microhymenoptera using six non-destructive methodologies with considerations for subsequent preparation of museum slides. AB - Because of the tiny size of microhymenoptera, successful morphological identification typically requires specific mounting protocols that require time, skills, and experience. Molecular taxonomic identification is an alternative, but many DNA extraction protocols call for maceration of the whole specimen, which is not compatible with preserving museum vouchers. Thus, non-destructive DNA isolation methods are attractive alternatives for obtaining DNA without damaging sample individuals. However, their performance needs to be assessed in microhymenopterans. We evaluated six non-destructive methods: (A) DNeasy(r) Blood & Tissue Kit; (B) DNeasy(r) Blood & Tissue Kit, modified; (C) Protocol with CaCl2 buffer; (D) Protocol with CaCl2 buffer, modified; (E) HotSHOT; and (F) Direct PCR. The performance of each DNA extraction method was tested across several microhymenopteran species by attempting to amplify the mitochondrial gene COI from insect specimens of varying ages: 1 day, 4 months, 3 years, 12 years, and 23 years. Methods B and D allowed COI amplification in all insects, while methods A, C, and E were successful in DNA amplification from insects up to 12 years old. Method F, the fastest, was useful in insects up to 4 months old. Finally, we adapted permanent slide preparation in Canada balsam for every technique. The results reported allow for combining morphological and molecular methodologies for taxonomic studies. PMID- 27996301 TI - Factor Structure of Sizing Me Up, a Self-Reported Weight-Related Quality of Life Instrument, in Community Children across Weight Status. AB - BACKGROUND: To further understand the psychometric properties of the Sizing Me Up a newly developed quality of life (QoL) instrument related to weight status. We extended the target population to a community sample, including obese, overweight, normal-weight, and underweight children. METHODS: Based on the data of 497 students in third to sixth grades, we used the following approaches: analysis of variance to detect the QoL scores among groups; confirmatory factor analysis (CFA) to examine the original structure; and Rasch analysis to test the misfit items, disordered response descriptors, and differential item functioning (DIF) items. RESULTS: Obese children had the lowest QoL total score; overweight children had lower QoL total score than normal-weight children; and underweight children had lower QoL in social avoidance than normal-weight children (all p < 0.01). CFA suggested that the factor structure is acceptable. Rasch corroborated that there were no misfit items; however, 10 items showed disordered thresholds in response descriptors and 6 items displayed significant DIF. CONCLUSIONS: Sizing Me Up can be applied to underweight children in the community and it can yield valid and reliable scores. Future studies are needed to explore the issues of disordered response descriptors and DIF items. Additional revisions for the Sizing Me Up may be warranted. PMID- 27996302 TI - Determination of Interference During In Vitro Pyrogen Detection: Development and Characterization of a Cell-Based Assay. AB - Contamination of pharmaceutical products and medical devices with pyrogens such as endotoxins is the most common cause of systemic inflammation and, in worst cases, of septic shock. Thus, quantification of pyrogens is crucial. The limulus amebocyte lysate (LAL)-based assays are the reference tests for in vitro endotoxin detection, in association with the in vivo rabbit pyrogen test (RPT), according to European Pharmacopoeia (EP 2.6.14), and U.S. Pharmacopoeia (USP <85>). However, several substances interfere with LAL assay, while RPT is not accurate, not quantitative, and raises ethical limits. Biological assays, as monocyte activation tests, have been developed and included in European Pharmacopoeia (EP 7.0; 04/2010:20630) guidelines as an alternative to RPT and proved relevant to the febrile reaction in vivo. Because this reaction is carried out by endogenous mediators under the transcriptional control of nuclear factor kappaB (NF-kappaB), we sought to determine whether a NF-kappaB reporter-gene assay, based on MonoMac-6 (MM6) cells, could reconcile the basic mechanism of innate immune response with the relevance of monocytoid cell lines to the organism reaction to endotoxins. This article describes both optimization and characterization of the reporter cells-based assay, which overall proved the linearity, accuracy, and precision of the test, and demonstrated the sensitivity of the assay to 0.24 EU/mL endotoxin, close to the pyrogenic threshold in humans. Moreover, the assay was experimentally compared to the LAL test in the evaluation of selected interfering samples. The good performance of the MM6 reporter test demonstrates the suitability of this assay to evaluate interfering or false positive samples. PMID- 27996303 TI - Re: "Increased Cardiometabolic Risk and Worsening Hypoxemia at High Altitude" by Miele et al. PMID- 27996304 TI - Corneal Thickness in Highlanders. AB - : Patyal, Sagarika, Amit Arora, Arun Yadav, and Vijay K. Sharma. Corneal thickness in highlanders. High Alt Med Biol. 18:56-60, 2017. BACKGROUND: Corneal thickness is an important parameter with diagnostic and therapeutic implications. Various studies have highlighted increase in corneal thickness in lowlanders on ascending to high altitude. However, there are no studies in the published literature pertaining to corneal thickness of the highlanders who are inhabitants of such altitudes. Hence, study was carried out with objective to determine the corneal thickness of highlanders living at heights of more than 11,000 feet and compare it with corneal thickness of lowlanders. MATERIALS AND METHODS: The highlander participants of the study consisted of inhabitants of Ladakh region of India at an altitude of 11,000 feet or more and lowlander participants consisted of inhabitants at an altitude of 1500 feet. A total of 254 highlanders and 212 lowlanders participated. A mean of 25 measurements of central corneal thickness (CCT) of every participant was obtained for each eye using ultrasonic pachymeter. RESULTS: The mean age of the participants was 41.8 (15.9) and 47.7 (17.7) years among lowlanders and highlanders, respectively. The highlanders had 11.95 MUm lower mean CCT reading compared to lowlanders after adjusting for age and sex (p value <0.001). There was no statistically significant difference in mean CCT readings of right eye and left eye in either lowlanders or highlanders. Age also had a significant effect after adjustment for location and gender (p = 0.001). CCT decreased by 0.31 MUm with every year increase in the age. Gender had no statistically significant effect. CONCLUSION: This study found statistically significant difference in CCT measurements between highlanders and lowlanders. The thinner corneas of highlanders may have a bearing on diagnosis and treatment of glaucoma, refractive surgery, contact lens fitting implantation of Intacs, and astigmatic keratectomy done on such patients. The study also opens the scope of further research in the area. PMID- 27996305 TI - Infection control and patient discomfort with an alternative plastic barrier in intraoral digital radiography. AB - OBJECTIVES: (1) To compare the efficacy of a commercially available hygienic sheath and an alternative plastic bag in preventing contamination of the imaging plate during intraoral radiography and (2) to compare patient discomfort when using the hygienic sheath and the plastic bag. METHODS: 60 sterilized Size 2 imaging plates covered with either the hygienic sheath (n = 30) or the plastic bag (n = 30) were used to simulate digital periapical radiographic examination in 30 volunteer patients. After disinfection, each plate was swabbed. The swabbed medium was then plated on trypticase soy agar and incubated. Bacterial colonies were counted. Patient discomfort was assessed using a visual analogue scale (VAS) score. The comparison of the number of bacterial colonies and VAS scores between the two groups was tested by paired t-test at p < 0.05. RESULTS: There was no significant difference in the number of bacterial colonies between the two groups (p = 0.745). Of all the plates, 10% plates yielded bacterial colonies. The mean count of bacterial colonies for both groups was 10-20 CFU ml-1. However, there was a significant difference between VAS scores for the two systems (p = 0.000). The mean VAS scores (range 0-10) for patient discomfort for the hygienic sheath group and the plastic bag group were 3.03 and 5.33, respectively. CONCLUSIONS: Based on the design of this study, the alternative barrier provided similar results to those commercially available. Regarding the type of barrier envelope, the hygienic sheath induced less discomfort than the plastic bag. PMID- 27996306 TI - Mapping QTLs associated with agronomic and physiological traits under terminal drought and heat stress conditions in wheat (Triticum aestivum L.). AB - Wheat crops frequently experience a combination of abiotic stresses in the field, but most quantitative trait loci (QTL) studies have focused on the identification of QTLs for traits under single stress field conditions. A recombinant inbred line (RIL) population derived from SeriM82 * Babax was used to map QTLs under well-irrigated, heat, drought, and a combination of heat and drought stress conditions in two years. A total of 477 DNA markers were used to construct linkage groups that covered 1619.6 cM of the genome, with an average distance of 3.39 cM between adjacent markers. Moderate to relatively high heritability estimates (0.60-0.70) were observed for plant height (PHE), grain yield (YLD), and grain per square meter (GM2). The most important QTLs for days to heading (DHE), thousand grain weight (TGW), and YLD were detected on chromosomes 1B, 1D a, and 7D-b. The prominent QTLs related to canopy temperature were on 3B. Results showed that common QTLs for DHE, YLD, and TGW on 7D-b were validated in heat and drought trials. Three QTLs for chlorophyll content in SPAD unit (on 1A/6B), leaf rolling (ROL) (on 3B/4A), and GM2 (on 1B/7D-b) showed significant epistasis * environment interaction. Six heat- or drought-specific QTLs (linked to 7D-acc/cat 10, 1B-agc/cta-9, 1A-aag/cta-8, 4A-acg/cta-3, 1B-aca/caa-3, and 1B-agc/cta-9 for day to maturity (DMA), SPAD, spikelet compactness (SCOM), TGW, GM2, and GM2, respectively) were stable and validated over two years. The major DHE QTL linked to 7D-acc/cat-10, with no QTL * environment (QE) interaction increased TGW and YLD. This QTL (5.68 <= LOD <= 10.5) explained up to 19.6% variation in YLD in drought, heat, and combined stress trials. This marker as a candidate could be used for verification in other populations and identifying superior allelic variations in wheat cultivars or its wild progenitors to increase the efficiency of selection of high yielding lines adapted to end-season heat and drought stress conditions. PMID- 27996307 TI - Clock genes associate with white matter integrity in depressed bipolar patients. AB - Human genetic studies have implicated specific genes that constitute the molecular clock in the manifestation of bipolar disorder (BD). Among the clock genes involved in the control system of circadian rhythms, CLOCK 3111 T/C and Period3 (PER3) influence core psychopathological features of mood disorders, such as patterns of sleep, rest, and activity, diurnal preference, cognitive performances after sleep loss, age at the onset of the illness, and response to antidepressant treatment. Furthermore, several studies pointed out that bipolar symptomatology is associated with dysfunctions in white matter (WM) integrity, suggesting these structural alterations as a possible biomarker of the disorder. We hypothesise that CLOCK and PER3 polymorphisms could be potential factors affecting WM microstructure integrity in bipolar patients. The relationship between these clock genes and DTI measures of WM integrity in a sample of 140 (53 M; 87 F) patients affected by BD type I was studied. Tract-based spatial statistics analyses on DTI measures of WM integrity were performed for each clock gene polymorphism, between the genetic groups. We accounted for the effect of nuisance covariates known to influence WM microstructure: age, sex, lithium treatment, age at the onset of the illness, and the number of illness episodes. We found that compared to T homozygotes, CLOCK C carriers showed a widespread increase of the mean diffusivity in several WM tracts. Compared with PER35/5 homozygotes, PER34/4 homozygotes showed significantly increased radial diffusivity and reduced fractional anisotropy in several brain WM tracts. No significant difference was observed between heterozygotes and the other subgroups. Altogether, this pattern of results suggests WM disruption in CLOCK C carrier and in PER34 homozygotes. Sleep promotes myelination and oligodendrocyte precursor cell proliferation and associates with higher expression of genes coding for phospholipid synthesis and myelination in oligodendrocytes. These clock genes play a pivotal role in maintaining circadian rhythms and the sleep wake cycle. Thus, it may be suggested that CLOCK rs1801260*C and PER34/4 influence myelination processes by regulating sleep quality and quantity. PMID- 27996308 TI - Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies. AB - Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer. PMID- 27996309 TI - The association between artificial light at night and prostate cancer in Gwangju City and South Jeolla Province of South Korea. AB - ABSRACT Exposure to artificial light at night (ALAN) has been reported to be associated with various pathological changes including sleep deprivation, circadian rhythm disruption, and melatonin suppression with increase in various cancers such as breast or prostate cancers. In this study, we sought to elucidate the association between ALAN and prostate cancer in 27 districts within Gwangju City and urban and rural areas from South Jeolla Province in South Korea. We analyzed the correlation between ALAN and the incidence of a range of cancers by Poisson regression analysis, after adjustment for confounding risk factors, such as smoking, drinking, obesity, stress, air pollution (particulate matter <10 MUm in diameter), urbanization (proportion of urbanized area), and the cancer screening rate. Interestingly, the incidence of prostate cancer was significantly associated with ALAN (risk ratio = 1.02, p = 0.0369) and urbanization (risk ratio = 1.06, p = 0.0055). In particular, comparing the prostate cancer incidence at 25% and 75% level of ALAN, the risk ratio was 1.726 (12.6 over 7.3, respectively). No significant association was observed between ALAN and other cancers, including stomach, esophageal, liver, pancreatic, laryngeal, lung and tracheal, bladder, and brain and central nervous system cancers, as well as lymphoma and multiple myeloma. In conclusion, this study shows that a high incidence of prostate cancer may be independently associated with light pollution and urbanization, which represent significant factors in the rapid process of industrialization of South Korea. PMID- 27996311 TI - Evaluating the Application of Tissue-Specific Dose Kernels Instead of Water Dose Kernels in Internal Dosimetry: A Monte Carlo Study. AB - PURPOSE: The aim of this work is to evaluate the application of tissue-specific dose kernels instead of water dose kernels to improve the accuracy of patient specific dosimetry by taking tissue heterogeneities into consideration. MATERIALS AND METHODS: Tissue-specific dose point kernels (DPKs) and dose voxel kernels (DVKs) for yttrium-90 (90Y), lutetium-177 (177Lu), and phosphorus-32 (32P) are calculated using the Monte Carlo (MC) simulation code GATE (version 7). The calculated DPKs for bone, lung, adipose, breast, heart, intestine, kidney, liver, and spleen are compared with those of water. The dose distribution in normal and tumorous tissues in lung, liver, and bone of a Zubal phantom is calculated using tissue-specific DVKs instead of those of water in conventional methods. For a tumor defined in a heterogeneous region in the Zubal phantom, the absorbed dose is calculated using a proposed algorithm, taking tissue heterogeneity into account. The algorithm is validated against full MC simulations. RESULTS: The simulation results indicate that the highest differences between water and other tissue DPKs occur in bone for 90Y (12.2% +/- 0.6%), 32P (18.8% +/- 1.3%), and 177Lu (16.9% +/- 1.3%). The second highest discrepancy corresponds to the lung for 90Y (6.3% +/- 0.2%), 32P (8.9% +/- 0.4%), and 177Lu (7.7% +/- 0.3%). For 90Y, the mean absorbed dose in tumorous and normal tissues is calculated using tissue specific DVKs in lung, liver, and bone. The results are compared with doses calculated considering the Zubal phantom water equivalent and the relative differences are 4.50%, 0.73%, and 12.23%, respectively. For the tumor in the heterogeneous region of the Zubal phantom that includes lung, liver, and bone, the relative difference between mean calculated dose in tumorous and normal tissues based on the proposed algorithm and the values obtained from full MC dosimetry is 5.18%. CONCLUSIONS: A novel technique is proposed considering tissue specific dose kernels in the dose calculation algorithm. This algorithm potentially enables patient-specific dosimetry and improves estimation of the average absorbed dose of 90Y in a tumor located in lung, bone, and soft tissue interface by 6.98% compared with the conventional methods. PMID- 27996312 TI - Overexpression of TSPAN8 Promotes Tumor Cell Viability and Proliferation in Nonsmall Cell Lung Cancer. AB - BACKGROUND: Overexpression of TSPAN8 has been involved in several epithelial cancers and TSPAN8 can form a complex with a variety of proteins to participate in several import cellular functions. However, the effects of TSPAN8 in nonsmall cell lung cancer (NSCLC) remain unclear. MATERIALS AND METHODS: In this study, the authors determined the expression of TSPAN in several NSCLC cell lines (95C, A549, H1299, and 95D) and human bronchial epithelial (HBE) cells. Furthermore, the authors investigated the biological function of TSPAN8 in NSCLC cell lines using gain-of-function and loss-of-function assays, as well as the underlying mechanisms. RESULTS: TSPAN8 was found to be overexpressed in NSCLC cells compared with normal HBE cells, of which the expression in H1299 is the highest and, in 95C, it is relatively lowest. Functional assays indicated that knockdown of TSPAN8 in H1299 remarkably reduced cell viability and proliferation, while overexpression of TSPAN8 in 95C dramatically enhanced cell viability and proliferation. In addition, TSPAN8 knockdown led to G1 phase arrest and apoptosis by downregulating CDK2, CDK4, and Cyclin D1 and upregulating Bax and PARP. CONCLUSIONS: These results provide evidence that TSPAN8 may contribute to the pathogenesis of lung cancer by promoting cell viability and proliferation. TSPAN8 silencing may provide a potential therapeutic intervention for the treatment of NSCLC. PMID- 27996314 TI - The Problem of Missed Mental Health Care Appointments. AB - Missed appointments are a problem in all types of outpatient clinics including those providing mental health care. A review of literature was conducted to explore the problem of missed appointments in mental health and identify methods that have been used to improve attendance. Study results demonstrate that patients miss appointments for many reasons. Common reasons for missed appointments in the articles reviewed were the interval between scheduling and appointment day, forgetting, being discharged against medical advice, and problems with substance abuse. Effective in reducing no shows was contact via phone, mail, or text messaging. No articles were found related to the use of positive reinforcement in reducing no shows, which is an area to consider for further research. Clinicians may identify techniques from this review applicable to their particular clinical setting to improve clinic attendance. PMID- 27996310 TI - Severity of alcohol dependence is negatively related to hypothalamic and prefrontal cortical gray matter density in heavy drinking smokers. AB - BACKGROUND: While research has examined brain structure in individuals who use alcohol or nicotine, heavy drinking smokers comprise a unique subpopulation of substance users for whom less is known about the relationship between alcohol or nicotine use and structural brain abnormalities. OBJECTIVES: The present study examined gray matter morphometry in a sample of 39 heavy drinking smokers (24 males, 15 females) in relation to alcohol and nicotine dependence and quantity of use. METHODS: Traditional voxel-based morphometry techniques were employed for preprocessing of imaging data. One multiple regression analysis for alcohol and nicotine dependence severity and another for alcohol and nicotine quantity of use were conducted, while controlling for age, gender, and total intracranial volume (ICV). RESULTS: Alcohol dependence severity was significantly negatively associated with gray matter density in the hypothalamus (p < 0.001, uncorrected) and the right superior frontal gyrus (p < 0.001, uncorrected), while controlling for nicotine dependence severity, age, gender, and ICV. There were no significant relationships observed with respect to nicotine dependence severity, the quantity of alcohol use, or the quantity of nicotine use variables and gray matter density. CONCLUSIONS: These findings suggest that within heavy drinking smokers, alcohol dependence severity is significantly related to alterations in brain structure, while this effect is not seen for the quantity of alcohol or nicotine use, or severity of nicotine dependence. The current findings help clarify the contribution of alcohol and nicotine effects on brain structure, which could aid in understanding their neurocognitive consequences in heavy drinking smokers. PMID- 27996313 TI - Prognostic Importance of Bone Marrow Uptake on Baseline 18F-FDG Positron Emission Tomography in Diffuse Large B Cell Lymphoma. AB - AIM: To define the role of 18F-flourodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the detection of bone marrow (BM) involvement in patients with diffuse large B cell lymphoma (DLBCL). MATERIALS AND METHODS: Fifty-four (mean age: 55.5 +/- 18.3 years, 20 female and 34 male) DLBCL patients who underwent pretreatment 18F-FDG PET/CT were included to the study. Focal or diffuse BM 18F-FDG uptake that is higher than mediastinal blood pool uptake was accepted as positive. After staging of disease by CT and 18F-FDG PET/CT, all the patients received R-CHOP treatment after diagnostic blinded bone marrow biopsy (BMB). Presence of positive BM uptake in 18F-FDG PET/CT and histopathological examination results of BMBs were analyzed by Chi-square test. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of 18F-FDG PET/CT in the detection of BM involvement were calculated. Prognostic importance of the presence of BM 18F-FDG uptake was analyzed by Kaplan-Meier analysis. RESULTS: BM 18F-FDG uptake was detected in 8 patients. Histopathological examination of BMB revealed BM involvement in 6 out of 8 patients. BMB was negative in all patients who have no 18F-FDG uptake in the evaluation of PET/CT images. Sensitivity, specificity, accuracy, PPV, and NPV of 18F-FDG PET/CT in the detection of BM involvement were calculated as 100%, 96%, 96%, 75%, and 100%, respectively. In the Kaplan-Meier analysis, we found that presence of pretreatment 18F-FDG uptake in BM has a prognostic importance. Whereas mean time to progression (TTP) in patients with BM uptake was 32.25 +/- 10.9 months and mean TTP in those without was 51.69 +/- 3.6 months (p = 0.013). CONCLUSIONS: BM uptake in pretreatment 18F-FDG PET/CT is an important prognostic factor in DLBCL patients. Moreover, in consideration of high NPV, 18F-FDG PET/CT could eliminate unnecessary BMB in FDG-negative patients. PMID- 27996315 TI - Unusual psychotic presentation after discontinuation of treatment in a patient with Wilson's disease: a case report. AB - Psychiatric manifestations are common in patients with Wilson's Disease(WD), and they are usually correlated with neurological symptoms. However, psychotic presentation without neurological symptoms has rarely been reported. We present a case of WD involving a 34-year-old gentleman who was diagnosed at the age of 22, but due to lack of medication for approximately 5 months was admitted in a psychiatric ward with delusional thoughts of grandeur and persecution, echopraxia and echolalia. No neurological impairment, ophthalmic manifestations or liver abnormalities were identified. Through this report, we aim to discuss the pathophysiology and the treatment of psychosis in WD, and its association with neurological, liver and ophthalmic manifestations. PMID- 27996316 TI - Developmental Coordination Disorder Plus Oculomotor and Visuospatial Impairment as Neurodevelopmental Heralds of Psychosis Proneness. AB - Aiming at preventing transitions to more severe psychopathology and boosted by the availability of operational criteria to identify help-seeking subjects at increased risk for psychosis, research into the early prodromal phases of psychosis is attracting a growing clinical interest. Furthermore, the focus of early detection is gradually shifting from prodromal syndromes to the premorbid period. Although mainly driven by clinical-pragatic aims, such a shift is coherent with the neurodevelopmental hypothesis of schizophrenia that might offer a unifying, developmentally informed conceptual framework for early detection. Psychotic experiences, indeed, while overtly manifested in adolescence/early adulthood, are often antedated by subtle expressions of biological vulnerability already presenting in the early years of life and indexing a putatively altered neurodevelopmental process. Concretely, unspecific premorbid symptoms that may be present since infancy and childhood may lead to early clinical consultancy in child-adolescent mental health services, which could be considered the primary clinical setting to implement early detection. We herewith present a clinical vignette of a child with severe Developmental Coordination Disorder presenting an Attenuated Psychosis Syndrome. The vignette illustrates the intertwining between possible early neurodevelopmental disorders and clinical psychosis proneness in childhood. PMID- 27996317 TI - Cardiac Arrest with Clozapine and Olanzapine: Revealing Long QT Syndrome. AB - The authors describe a rare case of "concealed" congenital Long QT Syndrome (LQTS) Type 3 in a patient with treatment resistant schizophrenia and no known personal or family history of cardiac disease. The patient in this Case Report had a hidden genetic condition revealed only following the essential administration of antipsychotics. As a result, this patient experienced an aborted cardiac arrest and a total of five episodes of ventricular tachycardia (VT) requiring cardioversion. Successful control of the VT occurred with an Automatic Internal Defibrillator (AID), judicious use of antipsychotic medications, and anti-arrhythmic medications. Risk factors for this rare anomaly include history of syncopy, unexplained ventricular arrhythmias, history of sudden cardiac death in a young family member, unusual reaction to initial dosages of medication known to prolong QTc which includes antipsychotics (particularly in combination). The work-up for those with risk factors would be a thorough family history of sudden cardiac death, baseline ECG, electrolytes, cardiology and electrophysiological consultation, and when indicated a genetic analysis for the Long QT Syndrome (LQTS). Monitoring includes ongoing patient assessment for symptoms, ECGs and electrolytes when indicated such as when medication and dosages are adjusted, AID interviewing, and cardiac and electrophysiological follow-up. PMID- 27996318 TI - Brain natriuretic peptide as a biomarker of asymptomatic clozapine-related heart dysfunction: a criterion for a more cautious administration. AB - Clozapine-related pericarditis is a rare side effect of the drug. We reported the clinical cases of two women, aged 22 and 28 years, affected by schizophrenia with pericarditis symptoms related to clozapine treatment of 200 mg/day. Clozapine was discontinued in both patients, resulting in normalization of the ECG changes, and echocardiography confirmed the progressive disappearance of the pericardial effusion. Interestingly, while inflammatory indices and pro-brain natriuretic peptide (pro-BNP) plasma levels were high in both patients, only one of them showed tachycardia, subjective chest pain, shortness of breath and dyspnea, with a clinical symptomatology suggesting a cardiac involvement. BNP is a vasoactive peptide synthetized by the ventricular myocardium which splits in two fragments: BNP and the N-terminal (pro-BNP). Both are considered valuable biomarkers in clinical practice for the prediction of disease state and prognosis in patients with suspected heart failure. Pro-BNP acts as a key regulator in the homeostasis of water and salt excretion and in the maintenance of blood pressure, mainly by inhibiting the renin-angiotensin-aldosterone axis and blocking the sympathetic nervous activity. In our cases, pro-BNP plasma levels proved to be a profitable way to identify subjects with asymptomatic cardiac impairment who could benefit from a therapy preventing progression to heart failure. PMID- 27996319 TI - Hypoglycemia in Older Adults with Type 1 Diabetes. AB - BACKGROUND: Hypoglycemia is a major concern in older adults with type 1 diabetes (T1D) and there is limited knowledge in this population. We examined data from 199 adults, >=60 years of age, who participated in a T1D Exchange study assessing factors associated with severe hypoglycemia (SH) in older adults with T1D: 100 with SH in the prior year and 99 with no SH in prior 3 years (mean age 68; mean diabetes duration 40 years; 47% female; 92% non-Hispanic white). Hypoglycemia was assessed with up to 14 days of blinded continuous glucose monitoring (CGM). Linear regression models were performed to assess the association between biochemical hypoglycemia [defined as percentage of time below specific cutoffs (<70/60/50 mg/dL)] and various factors. RESULTS: Overall, participants had CGM values <70 mg/dL for a median of 91 min per day. On 53% of days, glucose levels continuously were <70 mg/dL for >=20 min. Hypoglycemia was found to be strongly associated with glucose variability (r = 0.76; P < 0.001). Time spent in hypoglycemia was greater in those who were younger (P = 0.004), had shorter diabetes duration (P = 0.008), lower HbA1c (P < 0.001), and undetectable C peptide (P = 0.001), but did not differ by insulin method, education level, number of blood glucose checks per day, cognition, activities of daily living, or fear of hypoglycemia. INNOVATION: This study adds valuable data on the frequency of hypoglycemia in older adults with T1D. CONCLUSION: Future studies need to focus on how to prevent hypoglycemia in this vulnerable population of older adults with long-standing T1D. PMID- 27996321 TI - Measures of Glycemic Variability in Type 1 Diabetes and the Effect of Real-Time Continuous Glucose Monitoring. AB - OBJECTIVE: To report the impact of continuous glucose monitoring (CGM) on glycemic variability (GV) indices, factors predictive of change, and to correlate variability with conventional markers of glycemia. METHODS: Data from the JDRF study of CGM in participants with type 1 diabetes were used. Participants were randomized to CGM or self-monitored blood glucose (SMBG). GV indices at baseline, at 26 weeks in both groups, and at 52 weeks in the control group were analyzed. The associations of demographic and clinical factors with change in GV indices from baseline to 26 weeks were evaluated. RESULTS: Baseline data were available for 448 subjects. GV indices were all outside normative ranges (P < 0.001). Intercorrelation between GV indices was common and, apart from coefficient of variation (CV), low blood glucose index (LBGI), and percentage of glycemic risk assessment diabetes equation score attributable to hypoglycemia (%GRADEhypoglycemia), all indices correlate positively with HbA1c. There was strong correlation between time spent in hypoglycemia, and CV, LBGI, and %GRADEhypoglycemia, but not with HbA1c. A significant reduction in all GV indices, except lability index and mean absolute glucose change per unit time (MAG), was demonstrated in the intervention group at 26 weeks compared with the control group. Baseline factors predicting a change in GV with CGM include baseline HbA1c, baseline GV, frequency of daily SMBG, and insulin pump use. CONCLUSIONS: CGM reduces most GV indices compared with SMBG in people with type 1 diabetes. The strong correlation between time spent in hypoglycemia and CV, LBGI, and %GRADEhypoglycemia highlights the value of these metrics in assessing hypoglycemia as an adjunct to HbA1c in the overall assessment of glycemia. PMID- 27996320 TI - Mitigating Reductions in Glucose During Exercise on Closed-Loop Insulin Delivery: The Ex-Snacks Study. AB - OBJECTIVE: To assess whether snacking could be used with closed-loop (CL) insulin delivery to avoid exercise-induced reductions in plasma glucose (PG), as well as elevations in PG at the end of exercise. RESEARCH DESIGN AND METHODS: Twelve type 1 diabetes (T1D) subjects (age 13-36 years, duration 10.7 +/- 8.4 years, A1c 7.4% +/- 0.8% [57 +/- 8.7 mmol/mol]) underwent two 105-min exercise studies while under CL control: CL alone and CL+snack. Exercise, commenced at 3 PM, consisted of four 15-min periods of brisk treadmill walking to 65%-70% HRmax (separated by three 5-min rest periods), followed by a 30-min recovery period. Fifteen to 30 g carbohydrate (Gatorade) was provided on snacking visits just before and midway through the exercise period. PG and insulin were measured every 15-20 min during the exercise studies. RESULTS: Baseline PG levels were similar for CL alone (164 +/- 16 mg/dL) versus CL+snack (172 +/- 11 mg/dL). During exercise, PG levels fell by 53 +/- 10 mg/dL without snacking versus a modest 10 +/- 13 mg/dL increase in PG with snacking (P = 0.0005); similar differences in the change in PG levels were observed at the end of recovery period. Hypoglycemia requiring rescue treatment (PG <=60 mg/dL) during exercise occurred in three nonsnacking visits versus none with snacking. During the 75-min exercise period, insulin delivered was 1.8 +/- 0.4 U for the CL+snack admission compared to 0.7 +/- 0.1 U during CL alone (P = 0.002). CONCLUSION: These results support the use of a simple snacking strategy to avoid exercise-induced lowering of PG while on CL insulin delivery. Persistent insulin infusion during exercise with snacking also appears to be effective in limiting increases in PG at the end of exercise. PMID- 27996322 TI - Minimally Disruptive Diabetes Care for the Elderly. PMID- 27996323 TI - "It's just so bloody hard": recommendations for improving health interventions and maternity support services for disabled women. AB - PURPOSE: Little is known about the barriers and facilitators to pregnancy, birth and motherhood for disabled women within the New Zealand context. Our study explored this deficit with the aim of improving health care interventions and support for disabled mothers. METHODS: This paper reports on the third phase of a mixed-methods study. The first two phases used semi-structured individual and focus group interviews with disabled women, and health professionals, involved in maternity and postnatal care and has been reported elsewhere. Phase 3 utilised a modified Delphi technique with both groups of participants to seek consensus on the prioritisation of recommendations from the study. This article focuses on the disabled women's recommendations. RESULTS: In all, 20 disabled women took part in the Delphi phase of the study (28% of the cohort from Phase 1). In total, 11 key recommendations were identified by the disabled women, with the top seven discussed in detail here. CONCLUSIONS: Health professionals and health systems could, and arguably should, utilise a matrix of these recommendations to facilitate a review of service responsiveness to disabled women. Implications for Rehabilitation Becoming a mother is a potentially relevant and important rehabilitation issue for women of childbearing age who come into contact with rehabilitation services. Disabled women encounter a range of economic, attitudinal and knowledge barriers in relation to becoming mothers. Centralised sites/sources of information have potential to provide accessible and useful information for disabled women and health professionals. PMID- 27996326 TI - Outcomes of repetitive facilitation exercises in convalescent patients after stroke with impaired health status. AB - OBJECTIVE: To investigate the impact of stroke on health status and the effects of repetitive facilitation exercises (RFEs) for convalescent patients after stroke. METHODS: The study was a prospective observational study of patients enrolled in an RFE programme. Between April 2008 and March 2012, 468 patients with stroke were enrolled in an intensive, comprehensive RFE programme. Patients participated in this interdisciplinary programme for 12 weeks, for an average of 5 hours per week. Before and immediately after the programme, several measures of rehabilitation outcomes and health-related quality-of-life were evaluated. RESULTS: At baseline, most patients (95.4%) had modified Rankin scale scores of 3 5. Their health-related quality-of-life was significantly impaired, with physical and mental component summary scores on the Short Form 36-item questionnaire (SF 36) of 30.7 and 35.8, respectively. After the RFE programme, all outcome measures improved significantly. CONCLUSIONS: The results demonstrate that convalescent patients after stroke may benefit substantially from RFE programmes in stroke rehabilitation centres, even when patients have impaired health status or high levels of healthcare utilization. Thus, an RFE programme is a simple yet highly effective means to improve rehabilitation outcomes and health-related quality-of life, with a relatively low dropout rate. PMID- 27996327 TI - New vignettes for the experimental manipulation of injury cause in prospective mild traumatic brain injury research. AB - PURPOSE: This study developed standardized vignettes that depict a mild traumatic brain injury (TBI) from one of several causes and subjected them to formal expert review. METHOD: A base vignette was developed using the World Health Organization operational criteria for mild TBI. Eight specific causes (e.g. sport vs assault) were examined. A convenience sample of mild TBI experts with a discipline background of Neuropsychology from North America, Australasia and Europe (n = 21) used an online survey to evaluate the vignettes and rated the role of cause on outcome. RESULTS: The vignette suite was rated as fitting the mild TBI WHO operational diagnostic criteria at least moderately well. When compared to other factors, cause was not rated as significantly contributing to outcome. When evaluated in isolation, approximately half of the sample rated cause as important or very important and at least two of three clinical outcomes were associated with a different cause. DISCUSSION: The vignettes may be useful in experimental mild TBI research. They enable the injury parameters to be controlled so that the effects of cause can be isolated and examined empirically. Such studies should advance understanding of the role of this factor in mild TBI outcome. PMID- 27996328 TI - Reproducibility in measuring physical activity in children and adolescents with an acquired brain injury. AB - AIM: To examine the reproducibility in measurement of physical activity performance using the ActiGraph(r) GT3X+ accelerometer in children aged 8-16 years with Acquired Brain Injury (ABI). METHODS: Reproducibility of standardized tasks: Thirty-two children with ABI (12 years 1 month, SD = 2 years 4 months; 20 males; Gross Motor Function Classification System I = 17, II = 15) performed the following activities on 2 consecutive days while wearing an accelerometer and a heart rate monitor: quiet sitting, slow walking (SW), moderate walking (MW), fast walking (FW) and rapid stepping on/off a block (STEP). Intra-class correlation coefficients (ICC) were calculated. Performance variability: Fifty-one participants (12 years 1 month, SD = 2 years 5 months; 27 males; GMFCS I = 26, II = 25) wore an accelerometer for 4 days in the community and reliability coefficients were calculated using standardized 12-hour time spent in moderate-to vigorous physical activity (MVPA). RESULTS: Test-re-test reproducibility was excellent for all activities (SW, ICC = 0.90; MW, ICC = 0.83; FW, ICC = 0.91; STEP, ICC = 0.89). Three days of monitoring produced excellent variability estimates of MVPA (R = 0.78). CONCLUSION: Therapists can confidently use accelerometry as a reproducible measure of physical activity under standardized walking and stepping conditions, as well as in the community for children with ABI. PMID- 27996329 TI - Inhibitory control and traumatic brain injury: The association between executive control processes and social communication deficits. AB - PRIMARY OBJECTIVE: To further examine the proposed relationship between executive impairments in inhibitory control and social communication difficulties reflecting poor inhibition following TBI. METHOD: Inhibitory control was assessed in 14 adults with TBI on the Hayling Sentence Completion Test (HSCT). Errors on Part B (failed inhibition) and Part B-Part A response latencies (delayed inhibition) were examined. A relative, friend or frequent communication partner of each participant with TBI completed the La Trobe Communication Questionnaire (LCQ) on the communication difficulties of the person with TBI. The Inhibitory Control Factor (ICF) score of the LCQ based on seven items relating to poor inhibition was specifically analysed against performance on the HSCT. RESULTS: Multiple regression analysis indicated that 58% (51% adjusted) of the variance in LCQ ICF scores was accounted for by measures on the HSCT. Only B-A response latencies on the HSCT explained a significant proportion of the variability in LCQ ICF scores. CONCLUSIONS: Reduced inhibition speed may more strongly contribute to disinhibited communication behaviours than failures in inhibition. These findings contribute to understanding of the cognitive processes underlying social communication and have the potential to support and inform the use and development of management practices for individuals following TBI. PMID- 27996330 TI - Suicide in professional American football players in the past 95 years. AB - OBJECTIVE: To examine publicly-available information on all identified cases of suicide in active or former American professional football players between 1920 and the spring of 2015. DESIGN: Retrospective cohort study. SETTING: Professional American Football in the US. PARTICIPANTS: A cohort of 26 702 athletes who had died, retired or were currently playing in the NFL from nfl.com since 1920 was identified. MAIN OUTCOME MEASURES: Internet queries identifying 26 professional football players who completed suicide. Obituaries and news reports were reviewed. The primary outcome measures included mortality, demographic characteristics and life circumstances in professional American football players completing suicide. RESULTS: From 1920-2015, the median age of the 26 men who completed suicide was 39.5 years (range = 23-85). The median number of years after retirement was 6.5 (range = 0-63). Most of the deaths since 1920 have occurred in the past 15 years (58.7%) and a large percentage have occurred since 2009 (42.3%). Most of the men suffered from multiple life stressors prior to their deaths, such as retirement from sport, loss of steady income, divorce, failed business ventures, estrangement from family members and medical, psychiatric and/or substance abuse problems. CONCLUSIONS: A disproportionate number of completed suicides in current and former professional football players have occurred since 2009 (42.3%). It is well established in the literature that the causes of depression and suicidality are diverse, often multifactorial and treatable. Providing at-risk retired athletes with mental health treatment will likely reduce their suffering and improve their quality-of-life. PMID- 27996331 TI - Volumetric and morphometric MRI findings in patients with mild traumatic brain injury. AB - OBJECTIVE: This study compared cortical and sub-cortical volumes between patients with complicated (i.e. presence of intracranial abnormality on the day-of-injury CT) and uncomplicated (i.e. absence of intracranial abnormality) mild traumatic brain injury (MTBI) 4 weeks post-injury. The study hypothesized regionally decreased brain volumes and reduced cortical thickness in patients with complicated MTBIs compared with uncomplicated MTBI. METHODS: This study was part of a larger 2 years cohort study on MTBI. Baseline clinical and magnetic resonance imaging (MRI) data were compared for those with complicated and uncomplicated MTBI. It identified 168 patients with MTBI (90 uncomplicated and 78 complicated), aged 16-65 years. 3T MRI-system (Signa HDxt, GE Medical Systems, Milwaukee, WI) and cortical reconstruction and volumetric segmentation by FreeSurfer software have been used. RESULTS: No significant differences between uncomplicated and complicated MTBIs were found in neuroanatomic volumes and cortical thickness after controlling for age, gender and education. The complicated MTBI group showed larger ventricles compared with the uncomplicated group, but this effect diluted when adjusting for potential confounders. CONCLUSION: The study findings suggest that the classification of complicated and uncomplicated MTBI may be too broad to differentiate volumetric and morphometric effects of injury in the early post-injury phase. PMID- 27996333 TI - Intimate Partner Violence: The Lived Experience of Single Women. AB - Research in intimate partner violence has focused on married, cohabiting, adolescents, or college aged women. The experience of intimate partner violence by single women has not been studied separately from other groups of women. An interpretive phenomenological approach was used with feminist inquiry to gain insight into the experience of intimate partner violence by single women. The overarching theme was control and manipulation by the abuser. Subthemes included not feeling safe, poor communication skills, and caretaking. Nurses need to be aware of the occurrence of intimate partner violence in male and female partnered relationships to provide comprehensive and nonjudgmental care. PMID- 27996332 TI - DTaP5-IPV-Hib-HepB, a hexavalent vaccine for infants and toddlers. AB - INTRODUCTION: Combination vaccines reduce the 'shot burden' and simplify the childhood immunization schedule. Only 5-valent DTaP-based vaccines are licensed in the U.S. Areas covered: A new combination vaccine - DTaP5-IPV-Hib-HepB - is described, which induces antibody responses in infants (given in different schedules, including a 2, 4, and 6-month schedule) that are similar to the respective component vaccines. The vaccine appears to be safe and would be expected to protect against six diseases: diphtheria, tetanus, pertussis, hepatitis B, H influenzae type b, and polio. Administration is associated with higher rates of mild fever, but without significant safety signals. Expert commentary: Incorporation of this hexavalent vaccine into the U.S. schedule could improve coverage rates and timeliness, and addition to the E.U. market would add depth to the available repertoire of combination vaccines. PMID- 27996335 TI - Laparoscopy-assisted endoscopic full-thickness resection for gastric subepithelial tumors originated from the muscularis propria layer: a pilot study with literature review. AB - OBJECTIVE: Laparoscopy-assisted endoscopic full-thickness resection (LAEFTR) has been suggested as an alternative to laparoscopic wedge resection in the treatment of gastric subepithelial tumors (SETs). It is expected to minimize the resection of the tissue surrounding the tumors and maintain the function of the remnant stomach. Here, we performed a prospective pilot study to evaluate the efficacy of laparoscopy-assisted endoscopic full-thickness resection (LAEFTR) for patients with gastric SETs. MATERIAL AND METHODS: We enrolled twelve patients who were diagnosed with gastric SETs with an intraluminal growth pattern or which is located in the gastric antrum between October 2011 and September 2013. LAEFTR was performed endoscopically using an endoscopic knife to make an incision half way around the tumor circumference and a laparoscopic resection around the remaining tumor circumference, followed by its laparoscopic removal. The feasibility, safety, and effectiveness of LAEFTR for gastric SETs were evaluated. RESULTS: The median size of the tumors in twelve patients was 22 mm (21-33). Of the 12 patients, 8 received LAEFTR, while the others underwent conventional laparoscopic wedge resection, since their tumor outlines were clearly visible in laparoscopic view. In 8 patients who underwent LAEFTR, the mean total operation time (endoscopic procedure time/laparoscopic procedure time) were 117 (37/41) min. The tumors were completely resected with clear margin, and there was no perioperative and postoperative complications. CONCLUSIONS: LAEFTR currently seems to be the ideal treatment modality of intraluminal gastric SETs where their resection margins are difficult to define under laparoscopic guidance alone. PMID- 27996334 TI - Postnatal Growth and Retinopathy of Prematurity Study: Rationale, Design, and Subject Characteristics. AB - PURPOSE: Postnatal-growth-based predictive models demonstrate strong potential for improving the low specificity of retinopathy of prematurity (ROP) screening. Prior studies are limited by inadequate sample size. We sought to study a sufficiently large cohort of at-risk infants to enable development of a model with highly precise estimates of sensitivity for severe ROP. METHODS: The Postnatal Growth and ROP (G-ROP) Study was a multicenter retrospective cohort study of infants at 30 North American hospitals during 2006-2012. A total of 65 G ROP-certified abstractors submitted data to a secure, web-based database. Data included ROP examination findings, treatments, complications, daily weight measurements, daily oxygen supplementation, maternal/infant demographics, medical comorbidities, surgical events, and weekly nutrition. Data quality was monitored with system validation rules, data audits, and discrepancy algorithms. RESULTS: Of 11,261 screened infants, 8334 were enrolled, and 2927 had insufficient data due to transfer, discharge, or death. Of the enrolled infants, 90% (7483) had a known ROP outcome and were included in the study. Median birth weight was 1070 g (range 310-3000g) and mean gestational age 28 weeks (range 22-35 weeks). Severe ROP (Early Treatment of Retinopathy type 1 or 2) developed in 931 infants (12.5%). CONCLUSION: Successful incorporation of a predictive model into ROP screening requires confidence that it will capture cases of severe ROP. This dataset provides power to estimate sensitivity with half-confidence interval width of less than 0.5%, determined by the high number of severe ROP cases. The G ROP Study represents a large, diverse cohort of at-risk infants undergoing ROP screening. It will facilitate evaluation of growth-based algorithms to improve efficiency of ROP screening. PMID- 27996336 TI - Participation and occupation in occupational therapy models of practice: A discussion of possibilities and challenges. AB - BACKGROUND: Occupation has been the focus in occupational therapy practice to greater or lesser degrees from a historical viewpoint. This evokes a need to discuss whether concepts that are added to our field will enhance or blur our focus on occupation. AIM: To explore how the concept of participation in the International Classification of Functioning, Disability and Health (ICF) is related to the concept of occupation by reviewing and comparing its use in three models of practice within occupational therapy. The aim was also to generate discussion on possibilities and challenges concerning the relationship of participation and occupation. METHOD: The models reviewed were The Model of Human Occupation (MOHO), the Canadian Model of Occupational Performance and Engagement (CMOP-E) and the Occupational Therapy Intervention Process Model (OTIPM). RESULTS: The concept of participation was related to occupation in different ways in these models. Based on the review some challenges and considerations for occupational therapy were generated. CONCLUSION: Relating the concept of participation from the ICF to the concept of occupation in models of practice can be challenging. At the same time, relating the concepts can be a resource to develop occupational therapy and the understanding of occupational issues in society. PMID- 27996337 TI - Steady-state energy balance in animal models of obesity and weight loss. AB - OBJECTIVE: We wanted to exam the steady-state energy balance by using high-fat diet-induced obese (DIO) rats and mice as models for positive energy balance, and gastric bypassed (GB) rats and gene knockout of muscarinic acetylcholine M3 receptor (M3KO) mice as models for negative energy balance. METHODS: One hundred and thirty-two rats and mice were used. Energy balance was measured by a comprehensive laboratory animal monitoring system. Gene expression was analysed by in situ hybridisation in M3KO mice. RESULTS: DIO rats reached the plateau of body weight 28 weeks after starting high-fat diet (25% heavier than controls), whereas DIO mice reached the plateau after 6 weeks (23% heavier than controls). At the plateau, DIO rats had higher calorie intake during the light phase but not during the dark phase, while mice had the same calorie intake per day as controls. DIO rats and mice had lower energy expenditure (EE) and respiratory exchange ratio (RER) than controls. GB-rats reached the plateau (15% weight loss) 2 weeks after surgery and had the same calorie intake as sham-operated controls. EE, but not RER, was higher in GB rats than controls during the dark phase. The lean M3KO mice (25% lighter than wild-type (WT) mice at the plateau between 6 and 15 months of age) had the same calorie intake but higher EE, RER and hypothalamic mRNA expression of NPY, AgRP and leptin receptor than WT mice. CONCLUSION: When body weight gain or loss reached a plateau, the steady-state energy balance was mainly maintained by EE and/or RER rather than calorie intake. PMID- 27996338 TI - Distribution, Risks, and Responses to Parkinson's Disease. PMID- 27996339 TI - Efficacy of Bowen Theory on Marital Conflict in the Family Nursing Practice: A Randomized Controlled Trial. AB - Family plays an important role in health and illness, and preparing the nurses to assess and improve the family functioning and relationship based on a theoretical framework is of critical importance. This randomized controlled trial was performed to evaluate the effectiveness of Bowen system theory on marital conflict in the family nursing practice. A total of 42 couples referring to the family court of Shiraz, Iran were randomly assigned to either the intervention (receiving eight 90-minute sessions of Bowen systemic family therapy) or the control group (receiving no interventions). Outcomes were measured before, after and after one month of the follow up by marital conflict questionnaire and analyzed using repeated measure ANOVAs and t-test. The study results revealed no statistically significant differences between the study groups regarding the total marital conflict scores (t = 2.8, p = .935) or any of the seven subscales of conflict before the intervention (p > .05). However, a significant difference was observed between the two groups in this regard immediately and one month after the intervention (p < .05). The results demonstrated a significant difference between the intervention and control groups regarding the conflict scores and its subscales during the three study periods and groups (F = 79.43, p < .001). This study highlighted the importance of applying Bowen systemic family therapy by nurses in decreasing marital conflicts. Similar studies with larger sample sizes and longer follow-ups are recommended to be conducted on the issue. PMID- 27996340 TI - Geographic variation as a risk factor for digital ulcers in systemic sclerosis patients: a multicentre registry. AB - OBJECTIVE: To evaluate the influence of geographic variation on the risk of digital ulcer (DU) development in systemic sclerosis (SSc) patients. METHODS: This cross-sectional, multicentre study evaluated patients with SSc from centres located in different geographic regions of Brazil (subtropical and tropical climate zones). Demographic and clinical data were collected. RESULTS: The study included 141 patients with SSc (26 from the subtropical and 115 from the tropical zone). In total, 43 DUs were observed in 23 (16%) of the patients. By a simple logistic regression model, the presence of DUs was associated with a higher modified Rodnan skin score, previous necrosis or amputation of the extremities, flexion contracture of the fingers, active smoking, higher avascular score on capillaroscopy, higher severity of Raynaud's phenomenon, a higher Health Assessment Questionnaire Disability Index (HAQ-DI) score, a higher visual analogue scale score for Raynaud's phenomenon and overall disease, and the subtropical climate zone. Using multiple logistic regression, the presence of DUs was significantly associated with patients living in the subtropical climate zone [odds ratio (OR) = 5.4, p = 0.002], necrosis or amputation (OR = 5.2, p = 0.011), and a higher HAQ-DI score (OR = 2.6, p = 0.021). CONCLUSION: In this multicentre study in a continental country with different climates, patients with SSc living in a subtropical climate region had a 5.4 times higher risk of developing DUs than patients living in a warmer region (tropical climate), suggesting a more severe course of peripheral vasculopathy among patients living in geographic regions with relatively cold weather. PMID- 27996341 TI - Platelet extracellular vesicles as biomarkers for arterial thrombosis. AB - Arterial thrombosis is a major and global cause of human death and disability. Considering the socioeconomic costs of arterial thrombosis, identification of biomarkers to predict and detect arterial thrombosis at an early stage is an important public health goal. Platelet extracellular vesicles (PEV) are a new candidate biomarker of arterial thrombosis. PEV can be measured in biorepositories, thereby offering the possibility to validate PEV in multicenter clinical trials. PEV analysis has been hitherto hampered by lack of standardized methodology, but substantial technological improvements of PEV detection techniques have been achieved recently. However, before PEV emerge from research tools to clinical applications, a number of issues should be clarified. To facilitate validation of PEV as biomarkers of thrombosis, we discuss (i) whether PEV are useful as biomarkers of thrombosis, (ii) why previous conclusions on PEV concentrations, composition and functions require re-evaluation, and (iii) which questions have to be answered before PEV become clinically useful. PMID- 27996343 TI - Meta-Ethnography of Qualitative Research on the Experience of Being a Partner to an Individual with Schizophrenia Spectrum Disorder. AB - Several qualitative studies explore the experience of being a partner to an individual with schizophrenia spectrum disorder, but these studies remain isolated "islands of knowledge." This meta-ethnography aimed to synthesize current qualitative studies using Noblit and Hare's method. Thirteen studies were identified for inclusion. Three overarching themes were revealed: unmet expectations of relationship, renegotiating relationship roles, and separation versus togetherness. Themes interacted as a cycle with separation versus togetherness as temporal endpoints. Partners also renegotiated relationships with mental health professionals to accommodate unmet expectations. Leverage points for intervention were identified. PMID- 27996342 TI - Sick leave in Sweden before and after total joint replacement in hip and knee osteoarthritis patients. AB - Background and purpose - Little is know about patterns of sick leave in connection with total hip and knee joint replacement (THR and TKR) in patients with osteoarthritis (OA). Patients and methods - Using registers from southern Sweden, we identified hip and knee OA patients aged 40-59 years who had a THR or TKR in the period 2004-2012. Patients who died or started on disability pension were excluded. We included 1,307 patients with THR (46% women) and 996 patients with TKR (56% women). For the period 1 year before until 2 years after the surgery, we linked individual-level data on sick leave from the Swedish Social Insurance Agency. We created a matched reference cohort from the general population by age, birth year, and area of residence (THR: n = 4,604; TKR: n = 3,425). The mean number of days on sick leave and the proportion (%) on sick leave 12 and 24 months before and after surgery were calculated. Results - The month after surgery, about 90% of patients in both cohorts were on sick leave. At the two-year follow-up, sick leave was lower for both cohorts than 1 year before surgery, except for men with THR, but about 9% of the THR patients and 12-17% of the TKR patients were still sick-listed. In the matched reference cohorts, sick leave was constant at around 4-7% during the entire study period. Interpretation A long period of sick leave is common after total joint replacement, especially after TKR. There is a need for better knowledge on how workplace adjustments and rehabilitation can facilitate the return to work and can postpone surgery. PMID- 27996344 TI - Association of methylenetetrahydrofolate reductase gene-gene interaction and haplotype with susceptibility to acute lymphoblastic leukemia in Chinese children. AB - The aim of this study was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and additional gene gene interaction with acute lymphoblastic leukemia (ALL) risk. Logistic regression was performed to investigate the association between two single nucleotide polymorphisms (SNPs) within MTHFR gene and ALL risk and additional gene-gene interaction between rs1801133 and rs1801131. The minor allele of rs1801133 and rs1801131 is associated with decreased ALL risk, OR (95% CI) were 0.61 (0.38-0.89), and 0.68 (0.50-0.96), respectively. We also found a significantly interaction between the two SNPs, participants with rs1801133 - CT or TT and rs1801131 - AC or CC genotype have the lowest ALL risk, compared with participants with rs1801133 - CC and rs1801131 - AA genotype, OR (95% CI) was 0.32 (0.12-0.63). We did not find any haplotype between the rs1801133 and rs1801131 associated with ALL risk. rs1801133 and rs1801131 within MTHFR gene and their interaction were both associated with ALL risk in Chinese children. PMID- 27996346 TI - Journal of Cosmetic and Laser Therapy. PMID- 27996345 TI - Editorial. PMID- 27996347 TI - Oxcarbazepine-induced cytotoxicity and genotoxicity in human lymphocyte cultures with or without metabolic activation. AB - There has been considerable debate about the relationship between epilepsy and cancer. Oxcarbazepine (OXC) is used for treating certain types of seizures in patients with epilepsy. There have been no detailed investigations about genotoxicity of OXC and its metabolites. Therefore, the aim of this study is to investigate the cytotoxic and genotoxic effects of OXC and its metabolites on cultured human lymphocytes. The cytotoxicity and genotoxicity of OXC on human peripheral blood lymphocytes were examined in vitro by sister chromatid exchange (SCE), chromosomal aberration (CA) and micronucleus (MN) tests. Cultures were treated with 125, 250 and 500 MUg/ml of OXC in the presence (3 h treatment) and absence (24 h and 48 h treatment) of a metabolic activator (S9 mix). Dimethyl sulfoxide (DMSO) was used as a solvent control. OXC showed cytotoxic activities due to significant decreases in mitotic index (MI), proliferation index (PI) and nuclear division index (NDI) in the absence of S9 mix when compared with solvent control. Metabolites of OXC also significantly reduced MI and PI in cultures with S9 mix. OXC significantly increased the CAs, aberrant cells, SCE and MN values in the presence and absence of S9 mix. Our results indicated that both OXC and its metabolites have cytotoxic, cytostatic and genotoxic potential on human peripheral blood lymphocyte cultures under the experimental conditions. Further studies are necessary to elucidate the relationship between cytotoxic, cytostatic and genotoxic effects, and to make a possible risk assessment in patients receiving therapy with this drug. PMID- 27996348 TI - Involvement of the activation of Nrf2/HO-1, p38 MAPK signaling pathways and endoplasmic reticulum stress in furazolidone induced cytotoxicity and S phase arrest in human hepatocyte L02 cells: modulation of curcumin. AB - Furazolidone (FZD) is extensively used as the antiprotozoal and antibacterial drug in clinic. The previous study has shown that curcumin pretreatment could improve FZD induced cytotoxicity by inhibiting oxidative stress and mitochondrial apoptotic pathway. The current study aimed to investigate the potential roles of endoplasmic reticulum (ER) stress, p38 mitogen-activated protein kinases (p38 MAPK) signaling pathway in curcumin against FZD cytotoxicity by using human hepatocyte L02 cells. The results showed that curcumin could markedly attenuate FZD induced cytotoxicity. Compared with FZD alone group, curcumin pretreatment significantly reduced the expression of phospho (p)-p38, cyclin D1, p-checkpoint kinase 1 (ChK1) and breast cancer associated gene 1 (BRCA1) protein, followed to attenuate S phase arrest. Meanwhile, curcumin pretreatment prevented FZD induced ER stress, evidenced by the inhibition of glucose-regulated protein 78 and DNA damage inducible gene 153/C/EBP-homologous protein (GADD153/CHOP) protein expression. Moreover, compared with the control, FZD exposure activated the protein and mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), which were further activated by curcumin treatment. These results reveal that curcumin could prevent FZD induced cytotoxicity and S phase arrest, which may involve the activation of Nrf2/HO-1 pathway and the inhibition of p38 MAPK pathway and ER stress. PMID- 27996349 TI - Similar migration in computer-assisted and conventional total knee arthroplasty. AB - Background and purpose - Computer-assisted surgery (CAS) in total knee arthroplasty (TKA) has been used in recent years in the hope of improving the alignment and positioning of the implant, thereby achieving a better functional outcome and durability. However, the role of computer navigation in TKA is still under debate. We used radiostereometric analysis (RSA) in a randomized controlled trial (RCT) to determine whether there are any differences in migration of the tibial component between CAS- and conventionally (CONV-) operated TKA. Patients and methods - 54 patients (CAS, n = 26; CONV, n = 28) with a mean age of 67 (56 78) years and with osteoarthritis or arthritic disease of the knee were recruited from 4 hospitals during the period 2009-2011. To estimate the mechanical stability of the tibial component, the patients were examined with RSA up to 24 months after operation. The following parameters representing tibial component micromotion were measured: 3-D vector of the prosthetic marker that moved the most, representing the magnitude of migration (maximum total point motion, MTPM); the largest negative value for y-translation (subsidence); the largest positive y translation (lift-off); and prosthetic rotations. The precision of the RSA measurements was evaluated and migration in the 2 groups was compared. Results - Both groups had most migration within the first 3 months, but there was no statistically significant difference in the magnitude of the migration between the CAS group and the CONV group. From 3 to 24 months, the MTPM (in mm) was 0.058 and 0.103 (p = 0.1) for the CAS and CON groups, respectively, and the subsidence (in mm) was 0.005 and 0.011 (p = 0.3). Interpretation - Mean MTPM, subsidence, lift-off, and rotational movement of tibial trays were similar in CAS- and CONV operated knees. PMID- 27996351 TI - Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia. AB - OBJECTIVES: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment. METHODS: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10 mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals' locomotor activity was also studied. RESULTS: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p < 0.05). During the acquisition phase of the Morris water maze pregabalin-treated memory-impaired mice performed the test with longer escape latencies than the vehicle-treated mice (significant at p < 0.05 on Day 5, and at p < 0.001 on Day 6). There were no differences in this parameter between the scopolamine-treated control group and pregabalin-treated memory-impaired mice, which indicated that pregabalin had no influence on spatial learning in this task. During the probe trial a significant difference (p < 0.05) was observed in terms of the mean number of target crossings between vehicle-treated mice and pregabalin-treated memory-impaired mice but there was no difference between the scopolamine-treated control group and mice treated with pregabalin + scopolamine. Pregabalin did not influence locomotor activity increased by scopolamine. DISCUSSION: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain). PMID- 27996352 TI - Lessons learned developing and piloting interprofessional handover simulations for paramedic, nursing, and physiotherapy students. AB - Interprofessional education is an important element in the preparation of healthcare students who can communicate effectively and work collaboratively. A grant from Health Workforce Australia funded a shared nursing, paramedicine, and physiotherapy simulation suite and a staff member dedicated to interprofessional simulation, with the aim of increasing high fidelity simulation within and across the three professions. This article describes the development process and pilot testing of four purpose-designed interprofessional handover scenarios for paramedic, nursing, and physiotherapy students. The scenarios tracked an elderly patient (manikin) with a fractured neck of femur from pre-hospital to postoperative assessment and handover. The National League of Nursing Simulation Design Scale was used to evaluate the scenarios. Students' feedback indicated they considered the simulations to be relevant to their practice, with a high level of fidelity. This study re-emphasises the importance of pilot testing simulations before use in large-scale studies. PMID- 27996350 TI - Longitudinal Changes in Depression Symptoms and Survival Among Patients With Lung Cancer: A National Cohort Assessment. AB - Purpose Depression symptoms are common among patients with lung cancer; however, longitudinal changes and their impact on survival are understudied. Methods This was a prospective, observational study from the Cancer Care Outcomes Research and Surveillance Consortium from five US geographically defined regions from September 2003 through December 2005. Patients enrolled within 3 months of their lung cancer diagnosis were eligible. The eight-item Center for Epidemiologic Studies Depression scale was administered at diagnosis and 12 months' follow-up. The main outcome was survival, which was evaluated using Kaplan-Meyer curves and adjusted Cox proportional hazards modeling. Results Among 1,790 participants, 681 (38%) had depression symptoms at baseline and an additional 105 (14%) developed new-onset depression symptoms during treatment. At baseline, depression symptoms were associated with increased mortality (hazard ratio [HR], 1.17; 95% CI, 1.03 to 1.32; P = .01). Participants were classified into the following four groups based on longitudinal changes in depression symptoms from baseline to follow-up: never depression symptoms (n = 640), new-onset depression symptoms (n = 105), depression symptom remission (n = 156), and persistent depression symptoms (n = 254) and HRs were calculated. Using the never-depression symptoms group as a reference group, HRs were as follows: new-onset depression symptoms, 1.50 (95% CI, 1.12 to 2.01; P = .006); depression symptom remission, 1.02 (95% CI, 0.79 to 1.31; P = .89), and persistent depression symptoms, 1.42 (95% CI, 1.15 to 1.75; P = .001). At baseline, depression symptoms were associated with increased mortality among participants with early-stage disease (stages I and II; HR, 1.61; 95% CI, 1.26 to 2.04), but not late-stage disease (stages III and IV; HR, 1.05; 95% CI, 0.91 to 1.22). At follow-up, depression symptoms were associated with increased mortality among participants with early-stage disease (HR, 1.71; 95% CI, 1.27 to 2.31) and those with late-stage disease (HR, 1.32; 95% CI, 1.04 to 1.69). Conclusion Among patients with lung cancer, longitudinal changes in depression symptoms are associated with differences in mortality, particularly among patients with early-stage disease. Symptom remission is associated with a similar mortality rate as never having had depression. PMID- 27996353 TI - Cross-cultural adaptation of the professional version of the Readiness for Interprofessional Learning Scale (RIPLS) in Japanese. AB - Interprofessional education (IPE) for healthcare professionals is important in Japan because of its rapidly aging population and increasingly complex healthcare needs. However, no tools have been validated in the Japanese context to evaluate healthcare professionals' attitudes towards, or readiness for, IPE. The professional version of the Readiness for Interprofessional Learning Scale (RIPLS) with 23 items was selected for cross-cultural adaptation because it has been widely used internationally and a Japanese edition of the student version has already been developed. We followed a guideline for cross-cultural adaptation and subsequently conducted factor analysis with 368 responses from over 16 professions. Face and content validity was confirmed through the translation process. We obtained four factors with good internal consistency (Cronbach's alpha > 0.7). These results were similar to those of the original UK study, apart from one factor being divided into two different factors in this study. Studies are required to further confirm the rigor and generalisability of the results; however, the Japanese RIPLS can be used to evaluate healthcare professionals' attitudes towards IPE, which can eventually lead to a better IPE development for healthcare professionals in Japan. PMID- 27996354 TI - Different perceptions of interprofessional collaboration and factors influencing the one-stop service for sexual assault victims in Taiwan. AB - The purpose of interprofessional collaboration is to bring better services for sexual assault victims. In order to avoid secondary victimisation and improve the quality of forensic examination and prosecution rate, a one-stop service has been developed recently in Taiwan. However, whether the collaboration is successful may depend on participants' professional backgrounds and personal experiences and can be influenced by a number of factors. This study used the Index of Interdisciplinary Collaboration to examine the different perceptions of collaboration in team members and the related influences on collaboration. Surveys were conducted in 140 team members including social workers, doctors, nurses, and police officers. The result indicated that collaboration was perceived differently in different professionals and significantly lower by social workers in the domain of interdependence and reflection on process. Factors such as professional roles, structural characteristics, personal characteristics, and history of collaboration were positively associated with the overall perception of collaboration. Only structural and personal characteristics predicted the type of profession. This study highlights the importance to acknowledge different experiences. Additional efforts and investments for improving mutual help and trust by the organisations are recommended. PMID- 27996355 TI - Assessing faculty attitudes after participation in an interprofessional teaching scholars programme. AB - Promoting interprofessional education (IPE) and practice is a priority in academic health centres; however, implementation of IPE can be challenging. Recognizing the need for faculty development in teaching, and specifically IPE, the University of California, Davis Schools of Health launched the Interprofessional Teaching Scholars Program (ITSP) in 2014. Two cohorts of 11 faculty scholars each completed the nine-month programme and participated in this longitudinal comparative study in which pre- and post-assessments using a validated survey instrument were administered to measure changes in faculty attitudes towards IPE and collaborative practice. There was a statistically significant increase in the summated scores on all three of the subscales: Attitudes Towards Interprofessional Health Care Teams, Attitudes Towards IPE, and Attitudes Towards Interprofessional Learning in the Academic Setting. The results suggest that the ITSP was associated with positive changes in faculty attitudes related to interprofessional collaboration and teamwork. PMID- 27996357 TI - Corrigendum. PMID- 27996356 TI - The Prato Statement on cost and value in professional and interprofessional education. PMID- 27996358 TI - Expanding pharmacy roles and the interprofessional experience in primary healthcare: A qualitative study. AB - The pharmacist role is undergoing significant changes which are reshaping the way primary healthcare is delivered throughout England. Due to increased physician workload and focus on primary healthcare, the pharmacist role has expanded to provide enhanced patient services, integrating into general practice (GP) settings and working more closely as a member of the healthcare team. However, the experiences of pharmacists and team members are yet to be explored. The proposed study aims to explore the experiences, thoughts, and perceptions of a purposive sample of pharmacists, physicians, and nurses working in 10 GP clinics throughout the southeast of England. Interprofessional relationships, power dynamics, changing professional roles, and barriers and facilitators to the integration of the pharmacist role will be explored. An exploratory multiple case study design will be used to investigate interprofessional experiences within and between clinics. In-depth interviews will be completed with each participant. A thematic analysis will identify themes and patterns from the interview data. Results are expected to produce recommendations to help facilitate the integration of pharmacists in their new role and will have implications for interprofessional collaboration and interprofessional education which are important for delivering safe and effective care. PMID- 27996359 TI - How do we develop health educators for the future using an interprofessional approach? PMID- 27996360 TI - Liver Transplantation for Hepatocellular Carcinoma in Young Adults: A United Network for Organ Sharing Study. AB - PURPOSE: Orthotopic liver transplantation (OLT) is curative for hepatocellular carcinoma (HCC). HCC is typically a disease of older adults (OAs); therefore, characteristics and outcomes of OLT for young adults (YAs) (ages 18-40) are not described. The objective of this study was to assess the characteristics and outcomes of YAs with HCC receiving OLT and compare these to OAs (ages >40 years). METHODS: YAs with HCC who had OLT from the United Network for Organ Sharing (UNOS) database were included in this study. As a comparison group, OAs with HCC were matched 4:1 to the YA group. Descriptive statistics of demographics, comorbidities, and outcomes were generated. Kaplan-Meier product limit estimates were used to assess patient and graft survival. Conditional logistic regression and Cox proportional hazards frailty models were used to compare the groups. RESULTS: A total of 464 YAs received OLT for HCC. The most common underlying liver diseases were hepatitis C virus (21.3%), hepatitis B virus (HBV, 15.5%), and autoimmune/cholestatic disease (12.3%). An increased number of YAs received OLT for HCC after implementation of model for end-stage liver disease scoring. One thousand two hundred eighty OAs served as the comparison group. Post transplant 5-year survival was 73.1% in YAs with a retransplantation rate of 7.8%. In OAs, survival and retransplantation rates were lower (68.6% p = 0.093; 4.3% p = 0.001). CONCLUSION: Four hundred sixty-four YAs with HCC received OLT in the UNOS database. Compared to the older population, survival and retransplantation rates were higher. HBV, which is vaccine preventable, is a frequent contributor to HCC in YAs. PMID- 27996361 TI - Insight into the molecular mechanism of P-glycoprotein mediated drug toxicity induced by bioflavonoids: an integrated computational approach. AB - In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein-ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein-ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb-drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future. PMID- 27996362 TI - The effects of di 2-ethyl hexyl phthalate (DEHP) on cellular lipid accumulation in HepG2 cells and its potential mechanisms in the molecular level. AB - Diethylhexyl phthalate (DEHP) is suspected to be an inevitable factor related to metabolic disease. Our previous study demonstrated that excess DEHP could exacerbate non-alcoholic fatty liver disease (NAFLD) in SD rats. Addressing the terra incognita in DEHP-induced metabolic dysfunction, this study used HepG2 cells to investigate the potential mechanisms involved in DEHP-induced toxicity in vitro. The cells were established lipid overload model with oleic acid and BSA, then exposed to different concentrations (5, 10, 25, 50, 100 MUmol/l DEHP) of DEHP for further analysis. The Oil Red O staining results showed that DEHP could promote lipid accumulation in cells. The level of superoxide dismutase (SOD) and malondialdehyde (MDA) changed suggested the balance of oxidative stress was disrupted. Additionally, western blot analysis showed that DEHP could promote the expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and sterol regulatory element-binding protein 1c (SREBP-1c). By quantifying the expressions of the two proteins, it is of interest to determine that DEHP could promote lipid accumulation in hepatocytes via activating the SREBP-1c and PPARalpha-signaling pathway. PMID- 27996364 TI - Subcutaneous Lidocaine Infusion for Pain in Patients with Cancer. AB - BACKGROUND: Intravenous lidocaine is effective in treating pain. Limited studies have assessed the effectiveness and safety of subcutaneous lidocaine infusions. METHODS: We conducted a retrospective review of patients with cancer who received subcutaneous lidocaine infusions for pain. Patient characteristics, pain scores and opioid doses before and after lidocaine, and details of infusions were recorded. We identified three time periods of interest. T0 is defined as the 24 hour period immediately before commencing lidocaine treatment. T1 is defined as the 24-hour period before lidocaine was ceased. T2 is defined as the first 24 hour period after lidocaine was ceased. In addition, the overall impression of the effectiveness of lidocaine was subjectively evaluated by the authors. RESULTS: Twenty patients (13M;7F) received lidocaine. Two patients received it twice, totaling 22 episodes. The median lidocaine dose was 0.67 mg/kg/h with the median duration being 5.5 days. The median worst pain score at T0 and T1 was 8.5 and 5.5, respectively. The difference in the mean pain scores was 3.2 95% CI (2.1, 4.4; p < 0.001). In 15/22 episodes (68%), patients experienced a decrease in pain scores of more than 2. The median morphine oral equivalent (MOE) daily doses at T0, T1, and T2 were 425, 362.5, and 275 mg, respectively. The difference in the mean MOE between T0 and T1 was -126 (95% CI [-281, 28]; p = 0.13). The difference in the mean MOE between T0 and T2 was -207 (95% CI [-370, -44]; p = 0.025). Lidocaine was subjectively deemed effective in 10/22 episodes (45%). There were no documented adverse events attributed to lidocaine. Univariate analyses did not identify any subgroups likely to benefit from lidocaine. CONCLUSION: Subcutaneous lidocaine infusions may be used safely in cancer pain management and is effective in some patients. PMID- 27996363 TI - Randomized, double-blind, multi-center, phase III clinical trial to evaluate the immunogenicity and safety of MG1109 (egg-based pre-pandemic influenza A/H5N1 vaccine) in healthy adults. AB - Considering the pandemic potential of avian influenza A/H5N1, development of an effective and well-tolerated vaccine is an essential part of pandemic preparedness plans. This phase III, randomized, double-blind study was conducted to assess the immunogenicity and safety profile of an alum-adjuvanted, whole virion, pre-pandemic influenza A/H5N1 vaccine (MG1109). Healthy individuals were randomly assigned, in a 3:1 ratio, to receive two doses of either MG1109 or placebo containing alum gel. Immunogenicity was determined by hemagglutination inhibition (HI) and microneutralization (MN) assays. Solicited and unsolicited adverse events were assessed after vaccination. Among 420 enrolled subjects, 418 were available for safety analysis, and 298 MG1109 recipients were available for per-protocol immunogenicity analyses. According to the HI assays, after two vaccine doses, all three of the Committee for Medicinal Products for Human Use (CHMP) criteria were met against the vaccine strain for all age groups: seroprotection rate = 74.8% (95% CI: 69.9 - 79.8), seroconversion rate = 67.8% (95% CI: 62.5-73.1), and geometric mean titer ratio (GMTR) = 5.9 (95% CI: 5.4 - 6.4). According to the MN assays, the GMTR was 2.4 (95% CI: 2.1 - 2.7) and 7.0 (95% CI: 6.3 - 7.9) three weeks after the first and second vaccine doses, respectively. Solicited local and systemic adverse events were mostly mild to moderate and were not significantly different between MG1109 and placebo recipients. In conclusion, two-dose administration of alum-adjuvanted H5N1 pre pandemic influenza vaccine (MG1109) was highly immunogenic and tolerable in adults. PMID- 27996365 TI - Laparoscopic Management of Mirizzi Syndrome Without Dissection of Calot's Triangle. AB - BACKGROUND: Mirizzi syndrome (MS) is a rare complication of cholecystolithiasis that causes compacted gallstones and is often accompanied by severe inflammation of Calot's triangle. This study compared the use of laparoscopic surgery for MS without dissection of Calot's triangle with routine laparoscopic cholecystectomy (LC). METHODS: A total of 411 consecutive patients underwent laparoscopic surgery for benign gallbladder (GB) disease between January 2013 and December 2014. Five patients underwent laparoscopic surgery for MS (MS group) while 406 underwent routine LC (LC group). The preoperative diagnosis was accurate in all patients in the MS group. RESULTS: The LC and MS groups did not differ significantly in the operation time, blood loss, length of hospital stay, or incidence of GB carcinoma. In addition, conversion, bile duct injury, and bile leak rate were not different between the two groups. CONCLUSIONS: This study demonstrates the safety of laparoscopic partial cholecystectomy without dissection of Calot's triangle for MS. In addition, an accurate preoperative diagnosis is critical in surgical decision making to avoid injury to the bile duct. PMID- 27996366 TI - Vitamin E supplementation modulates the biological effects of omega-3 fatty acids in naturally aged rats. AB - Omega-3 fatty acids are well-known class of nutraceuticals with established health benefits. Recently, the oxidation products of these fatty acids are gaining attention, as they are likely to disturb body redox balance. Therefore, the efficacy of omega-3 fats under conditions of diminished antioxidant status, such as aging, is always a concern. Present study assessed the effects of omega-3 fats (DHA and EPA) together with or without vitamin-E in naturally aged rats. It was found that in omega-3 fats alone consumed rats the lipid profile was improved, while in omega-3 fat with vitamin-E-consumed group (OMVE), the hepato protective and antioxidant properties were pronounced, especially the redox status of brain tissue. It is possible that vitamin-E might have reduced the peroxidation of omega-3 fats, thereby allowing their synergistic effects. Hence, the use of vitamin-E along with omega-3 fat may be beneficial under aged conditions. PMID- 27996367 TI - Video-Assisted Thoracoscopic Lobectomy Is the Preferred Approach Following Induction Chemotherapy. AB - OBJECTIVE: A video-assisted thoracoscopic surgical (VATS) resection, after induction chemotherapy, has long been considered a relative contraindication. We report our experience with VATS lobectomy after induction chemotherapy for patients with nonsmall cell lung cancer (NSCLC), with propensity-matched group of patients, who underwent an open approach, to determine safety and oncological outcome. METHODS: A retrospective review of a prospective database (2002-2014) was performed to identify patients undergoing potentially curative lobectomy for NSCLC after induction therapy. Propensity score matching (age, gender, and clinical stage) was performed (1:2) to obtain a balanced cohort of patients undergoing VATS resection and thoracotomy. RESULTS: A total of 285 patients underwent lobectomy after induction therapy, 114 were propensity matched (VATS, n = 40, thoracotomy, n = 74). There were no differences in the clinicopathological factors or type of induction therapy (conventional versus targeted) between VATS and thoracotomy groups. Similarly, no differences were found in the number of lymph nodes resected (12 versus 15, P = .94), the number of stations sampled (4 for each, P = .68), or in the rate of R0 resection (95% versus 96%, P = .81) between VATS and thoracotomy groups. Five VATS cases were converted to an open approach because of adhesions. VATS resection was associated with less estimated blood loss (EBL), shorter length of stay (LOS), and a trend toward fewer postoperative complications. There was no difference in 5 years disease-free survival (DFS) between VATS and thoracotomy groups (73% versus 48%, P = .09). Similarly, for patients who presented with cN2, there were no differences between thoracotomy and VATS groups in DFS (P = .37). On multi-variable analysis (MVA), only the clinical N1/2 status [Hazard ratio (HR): 4.86, P < .001] independently predicted poor DFS. CONCLUSIONS: A VATS lobectomy is a feasible, safe, and oncologically sound approach after induction therapy for NSCLC. When compared with thoracotomy, VATS lobectomy is associated with lower EBL, shorter LOS, and a trend toward fewer postoperative complications. PMID- 27996368 TI - Optimization of an acidic digestion method for the determination of total Pb concentration and its isotope ratios in human blood using ICP-QMS. AB - Adverse effects of lead (Pb) on human health are observed even at levels below 5 MUg/dL, affecting principally the children population and suggesting that there is not a safe exposure level. The determination of Pb isotopic ratios (LIRs) in biological and environmental samples, is an appropriate tool to track and control the exposure sources, because LIRs constitutes the pollutant's isotopic signature and hence can be used to identify sources of Pb emission. This study proposes the optimization of a method in order to significantly reduce the biological samples' matrix interferences, and improves precision and accuracy in the measurements of LIRs. Four total blood digestion methods were evaluated and the results were subjected to statistical methods (ANOVA) determining the combination of HNO3:H2O2 (2:1 v v-1)/g from a sample on a hot plate as the best of them. For the method's validation, detection and quantification limits, linearity range, intermediate precision and recovery were evaluated. The total Pb (PbT) and LIRs were performed by ICP-QMS, defining the optimal value of detector dead time (DT), and correcting mass bias and instrumental drift for this matrix. LIRs based on 206Pb, 207Pb and 208Pb were determined at high precision (%RSD 0.03-0.49%), than those involving 204Pb (%RSD > 0.8). The optimized methodology can be used to identify pollution sources in blood and environmental samples using LIRs (206Pb/207Pb, 207Pb/208Pb, 208Pb/206Pb, etc.) in a trustworthy and simple way, with accurate results. PMID- 27996369 TI - Advanced Imaging Techniques in Gastrointestinal Endoscopy. AB - The fundamental approach to endoscopy is to identify concerning and potentially premalignant lesions in the gastrointestinal tract, sample or resect the area of interest, await histologic results, and subsequently formulate a treatment and/or surveillance strategy. Detecting subtle lesions and deciding whether they are clinically significant are challenges that rely on the endoscopist's observation skills and experience. Enhanced imaging technologies have been developed to aid in lesion identification and classification, enabling better visualization of the lumen from a wide-field view while also enabling real-time near-field, including cellular level, imaging of the tissue. These innovations can potentially help reduce the rate of missed lesions, the need for extensive surveillance biopsies, and the frequency of surveillance. Several of these advanced imaging technologies are discussed in this review. PMID- 27996370 TI - Lost in translation? Microchimersim detection in experimental and clinical transplantation. AB - The importance of further elucidating the properties surrounding microchimerism in various experi- mental models and clinical transplantation are limited by current techniques and the sensitivity of available platforms. Development of reliable methods and use routine use of microchimerism detection in clinical practice could guide clinical decision making regarding rejection, stable function, and tolerance. PMID- 27996371 TI - The Simple and Multidimensional Method of Pain Reduction After Laparoscopic Cholecystectomy: A Randomized Prospective Controlled Trial. AB - BACKGROUND: Herein, we evaluate the effect of pain relief after laparoscopic cholecystectomy (LC) of various intraoperative maneuvers through a prospective randomized study and identify the synergistic effects of combined maneuvers compared with a single maneuver that was shown to be useful in a previous report. METHODS: Fifty-one patients who were scheduled for elective LC were randomly allocated to group A (26 patients, on whom were performed the combined maneuver) or group B (25 patients, no maneuvers). In group A, the patient underwent several maneuvers concomitantly during LC: injection of local anesthesia at the incision site, low-pressure pneumoperitoneum, active gas suction (AGS), and pulmonary recruitment. Pain after LC was assessed using the visual analog scale (VAS) and the measurement of analgesic consumption. RESULTS: Four cases of postoperative morbidity relevant to the analgesic supplements developed (one case, 3.8%, in group A, and the others, 12%, in group B, P = .350) The mean analgesic consumption of group A was significantly lower than that of group B (48.1 +/- 46.3 mg versus 106.7 +/- 83.3 mg, P = .000), and VAS was also lower in group A at postoperative 6, 12, and 24 hours (3.7 +/- 1.2 versus 4.8 +/- 1.7, 1.5 +/- 0.6 versus 3.3 +/- 1.3, and 1.0 +/- 0.6 versus 3.0 +/- 1.7, respectively; P = .016, .000, and .000). Group A showed lower VAS than did a group in our previous study given AGS alone. CONCLUSIONS: Our combined maneuvers, comprising of various simple methods during LC, could be effective and feasible means of reducing the convoluted pain that occurs after LC, and also reduce the demand for analgesics. PMID- 27996372 TI - Laparoscopic Pediatric Inguinal Hernia Repair: A Pilot Study in a Novel Guinea Pig Animal Model. AB - BACKGROUND: The purpose of this study was to compare different techniques for pediatric laparoscopic inguinal hernia repair. We hypothesize that the amount of dissection performed at the internal ring, with or without division of the peritoneum, will impact healing and thus long-term success of the repair. METHODS: Following the Institution's Animal Care and Use Committee approval (708024-4), 20 Hartley guinea pigs underwent laparoscopic repair of their natural open internal rings. The guinea pigs were divided equally into four surgical groups: intracorporeal suture repair (IS), hernia dissection and division with intracorporeal suture (DDIS) repair, subcutaneous endoscopically assisted ligation (SEAL), and Yueng (HOOK) repair. After a 6-week survival period, a necropsy was performed. Repairs were evaluated and tested under pressures up to 30 mmHg. The suture was then removed to assess primary healing. Experimental data were analyzed using chi-square test. RESULTS: There were no perioperative or postoperative complications. On initial evaluation, before suture removal, repair integrity was as follows: 5/10 IS, 10/10 DDIS, 7/10 SEAL, and 7/10 HOOK (P = .09). After suture removal, repair integrity was as follows: 3/10 IS, 10/10 DDIS, 5/10 SEAL, and 6/10 HOOK (P = .01). CONCLUSION: Overall, dissecting and dividing the sac with intracorporeal suture (DDIS) closure had the best outcome. This method appears to best replicate standard open high ligation. PMID- 27996373 TI - Helicobacter pylori Primary Antibiotic Resistance in 2015 in Morocco: A Phenotypic and Genotypic Prospective and Multicenter Study. AB - Knowledge of local antibiotic resistance is crucial to adaption of the choice of effective empirical first-line treatment for Helicobacter pylori infection. The aim of this study was to evaluate, for the first time in Morocco, the prevalence of the primary resistance of H. pylori to clarithromycin, metronidazole, amoxicillin, levofloxacin, tetracycline, and rifamycin. We conducted a 1-year prospective study (2015), including 255 Moroccan patients referred for gastro duodenal endoscopy to two hospitals of Rabat (Morocco) and never previously treated for H. pylori infection. Three gastric biopsies were collected: one for histology, one for culture, and one for molecular detection of H. pylori and the mutations in 23S rRNA genes that confer resistance to clarithromycin. Antimicrobial susceptibility testing was performed on isolated strains by Etest and disk diffusion methods. One hundred seventy-seven patients were infected (69.4%). The prevalence of primary resistances of H. pylori to clarithromycin was 29%, 40% to metronidazole, 0% to amoxicillin, tetracycline, and rifamycin, and 11% to levofloxacin. Only four isolates (2%) were resistant to both clarithromycin and metronidazole. The high level of primary clarithromycin resistance in the H. pylori strains infecting the Moroccan population leads us to recommend the abandonment of the standard clarithromycin-based triple therapy as a first-line treatment in Morocco and to prefer a concomitant quadruple therapy. PMID- 27996374 TI - Image-Based Quantification of Plant Immunity and Disease. AB - Measuring the extent and severity of disease is a critical component of plant pathology research and crop breeding. Unfortunately, existing visual scoring systems are qualitative, subjective, and the results are difficult to transfer between research groups, while existing quantitative methods can be quite laborious. Here, we present plant immunity and disease image-based quantification (PIDIQ), a quantitative, semi-automated system to rapidly and objectively measure disease symptoms in a biologically relevant context. PIDIQ applies an ImageJ based macro to plant photos in order to distinguish healthy tissue from tissue that has yellowed due to disease. It can process a directory of images in an automated manner and report the relative ratios of healthy to diseased leaf area, thereby providing a quantitative measure of plant health that can be statistically compared with appropriate controls. We used the Arabidopsis thaliana-Pseudomonas syringae model system to show that PIDIQ is able to identify both enhanced plant health associated with effector-triggered immunity as well as elevated disease symptoms associated with effector-triggered susceptibility. Finally, we show that the quantitative results provided by PIDIQ correspond to those obtained via traditional in planta pathogen growth assays. PIDIQ provides a simple and effective means to nondestructively quantify disease from whole plants and we believe it will be equally effective for monitoring disease on excised leaves and stems. PMID- 27996376 TI - Sexual Orientation Disclosure in Primary Care Settings by Gay, Bisexual, and Other Men Who Have Sex with Men in a Canadian City. AB - PURPOSE: Sexual orientation affects individuals' health histories and is fundamental to providers' understanding of patients as a whole. Gay, bisexual, and other men who have sex with men (GB-MSM) are vulnerable to certain health conditions, including HIV. The aim of this exploratory analysis was to examine factors associated with sexual orientation disclosure and communication with providers about GB-MSM health issues and to discuss implications. METHODS: We conducted a cross-sectional internet survey of GB-MSM (n = 202) in London Middlesex, Ontario, Canada; analyses were limited to those with a regular primary care provider (n = 173). Blockwise regression models explored demographic, psychosocial, and healthcare-related factors associated with sexual orientation disclosure and physician-patient communication about GB-MSM-related health. RESULTS: Just over seventy-one percent (71.1%) of participants reported that their primary care provider (PCP) knew their sexual orientation, and 44.5% had talked to them about GB-MSM health. Overt negative comments or being refused care based on sexual orientation occurred infrequently, although 26.6% reported their provider had assumed they were heterosexual. Being married to or living common law with another man, more frequent experiences of homosexual prejudice, and higher quality assessment of provider's communication skills were associated with the PCP knowing respondents' sexual orientation. Greater internalized homonegativity was associated with not talking to a PCP about GB-MSM-related health issues. More frequent experiences of homosexual prejudice, higher assessment of provider communication, and having prior negative experiences with a PCP were significantly associated with talking to a PCP about GB-MSM health. CONCLUSION: The majority of our sample disclosed their sexual orientation; however, not all patients voluntarily disclose. Medical training and education in Canada, where specific rights protections exist for sexual orientation minority populations, should emphasize awareness of essential patient health information. Training should include information about GB-MSM health and building a foundation on how to speak with GB-MSM patients nonjudgmentally. PMID- 27996377 TI - A Comparison of Endoloop Ligatures and Nonabsorbable Polymeric Clips for the Closure of the Appendicular Stump During Laparoscopic Appendectomy in Children. AB - BACKGROUND: The aim of this prospective trial was to evaluate the clinical outcomes of nonabsorbable polymeric clips in laparoscopic appendix stump closure in children by comparing the endoloop ligature. PATIENTS AND METHODS: From June 2011 to June 2016, 277 children who underwent laparoscopic appendectomy were included in the study. The patients were divided into two groups based on the technique used for appendiceal stump closure: there were 101 patients in the polymeric clips group and 176 in the endoloop group. The risk of intraoperative and postoperative complications was investigated for two different techniques to close the appendiceal stump. RESULTS: Among the 277 patients who underwent laparoscopic appendectomy, no intraoperative complications and 17 (6.1%) postoperative complications were recorded. There were no significant differences between the groups with respect to the postoperative complications (P = .546). The median length of the operation was 10 minutes shorter when the polymeric clips were used (P < .001). The median hospital stay was also shorter in the polymeric clips group (P = .008). Costs of polymeric clip were significantly lower (? 17.64) compared to endoloop (? 34.16). CONCLUSIONS: Closure of the appendix stump with polymeric nonabsorbable clips in laparoscopic appendectomy reduces operative time and may be a cost-effective and simpler alternative to widely used endoloops. PMID- 27996375 TI - Trimeric gp120-specific bovine monoclonal antibodies require cysteine and aromatic residues in CDRH3 for high affinity binding to HIV Env. AB - We isolated HIV-1 Envelope (Env)-specific memory B cells from a cow that had developed high titer polyclonal immunoglobulin G (IgG) with broad neutralizing activity after a long duration vaccination with HIV-1AD8 Env gp140 trimers. We cloned the bovine IgG matched heavy (H) and light (L) chain variable (V) genes from these memory B cells and constructed IgG monoclonal antibodies (mAbs) with either a human constant (C)-region/bovine V-region chimeric or fully bovine C and V regions. Among 42 selected Ig+ memory B cells, two mAbs (6A and 8C) showed high affinity binding to gp140 Env. Characterization of both the fully bovine and human chimeric isoforms of these two mAbs revealed them as highly type-specific and capable of binding only to soluble AD8 uncleaved gp140 trimers and covalently stabilized AD8 SOSIP gp140 cleaved trimers, but not monomeric gp120. Genomic sequence analysis of the V genes showed the third heavy complementarity determining region (CDRH3) of 6A mAb was 21 amino acids in length while 8C CDRH3 was 14 amino acids long. The entire V heavy (VH) region was 27% and 25% diverged for 6A and 8C, respectively, from the best matched germline V genes available, and the CDRH3 regions of 6A and 8C were 47.62% and 78.57% somatically mutated, respectively, suggesting a high level of somatic hypermutation compared with CDRH3 of other species. Alanine mutagenesis of the VH genes of 6A and 8C, showed that CDRH3 cysteine and tryptophan amino acids were crucial for antigen binding. Therefore, these bovine vaccine-induced anti-HIV antibodies shared some of the notable structural features of elite human broadly neutralizing antibodies, such as CDRH3 size and somatic mutation during affinity-maturation. However, while the 6A and 8C mAbs inhibited soluble CD4 binding to gp140 Env, they did not recapitulate the neutralizing activity of the polyclonal antibodies against HIV infection. PMID- 27996378 TI - Fast Early Recovery After Transabdominal Preperitoneal Repair in Athletes with Sportsman's Groin: A Prospective Clinical Cohort Study. AB - BACKGROUND: Current literature on chronic groin pain suggests that laparoscopic mesh repair on athletes enables a faster recovery and subsequent return to unrestricted athletic activities. The aim of this study was to evaluate the role of transabdominal preperitoneal (TAPP) mesh repair in athletes resistant to conservative therapy. METHODS: A multidisciplinary approach with tailored physiotherapy. Thirty-nine professional athletes with chronic groin pain were referred to surgery at a single clinic. A full assessment was carried out on each, including medical history, physical examination, dynamic ultrasound, and pelvic magnetic resonance imaging. TAPP repair was performed using a polypropylene mesh and fibrin glue fixation on 30 athletes who had exhibited typical symptoms, shown resistance to conservative therapy, not benefited from accompanying physiotherapy, and had ceased training in the 3 to 6 months prior. The outcome measures were early postoperative recovery of 6 weeks and full resumption of athletic activities. RESULTS: Mean duration of symptoms from onset to surgical repair was 7 months. Conservative treatment had improved symptoms temporarily or to some extent in 7 athletes, while 2 ceased competing altogether. Twenty-three athletes exhibited unilateral and 16 bilateral groin pain. Laparoscopy confirmed posterior wall deficiency in 24 and true inguinal hernia in 6 athletes. Mild scrotal hematoma occurred in 2 athletes postoperatively; all were discharged within 24 hours of surgery. Twenty-one (70%) returned to sports activities after 6 weeks of convalescence. Persistent mild pain was experienced by 5 athletes postoperatively for up to 1 year, yet did not interfere with normal daily activity. Twenty-five participants (85%) reported full satisfaction with the procedure 1 year after treatment; all returned to the same or even higher level of athletic performance. CONCLUSION: The study confirms that the endoscopic placement of retropubic mesh is an efficient, safe, and minimally invasive treatment that enables fast early recovery. PMID- 27996379 TI - The Affordable Care Act and Health Insurance Coverage for Lesbian, Gay, and Bisexual Adults: Analysis of the Behavioral Risk Factor Surveillance System. AB - PURPOSE: This study compares uninsurance rates for lesbian, gay, and bisexual (LGB) adults by state Medicaid expansion decisions under the Affordable Care Act. METHODS: Data come from nonelderly adults in the 2014 Behavioral Risk Factor Surveillance System. Prevalence estimates and logistic regression models identified LGB adults most likely to be uninsured. RESULTS: Approximately 15.7% of LGB adults lack health insurance, but the uninsurance rate is lower among LGB adults in Medicaid expansion states (12.5%) compared with LGB adults in nonexpansion states (20.0%). CONCLUSIONS: Expanding Medicaid in states that have not yet done so should increase coverage and lead to improved health for vulnerable LGB adults. PMID- 27996585 TI - Transnasal Endoscopy Removal of Dislodged Dental Implant: A Case Report. AB - Displacement of dental implants into the maxillary sinus is a rare complication. This article presents a case of displaced dental implant into maxillary sinus. Retrieval of the dental implant from left maxillary sinus was performed via endoscopic sinus surgery. This case highlighted a delayed referral of a 53-year old male by a general dental practitioner for management of a dislodged dental implant into the left maxillary antrum. The implant was dislodged during placement of a healing abutment 4 months after implant insertion to replace missing 25. Cone beam computerized tomography revealed the displaced implant was located at the ostium of the left nose. A sudden change in sinonasal pressure when the patient took a deep breath during the procedure may have created a negative pressure and suction effect causing the implant to be dislodged and embedded at the ostium. In view of its position, a referral to an otorhinolaryngologist was made for endoscopic removal of the displaced implant. This case also highlighted the need for inter disciplinary cooperation in the management of such a complication for the best interest of the patients. PMID- 27996380 TI - A reflection on invasive pneumococcal disease and pneumococcal conjugate vaccination coverage in children in Southern Europe (2009-2016). AB - Higher-valent pneumococcal conjugate vaccines (PCVs) were licensed from 2009 in Europe; similar worldwide clinical effectiveness was observed for PCVs in routine use. Despite a proven medical need, PCV vaccination in Southern Europe remained suboptimal until 2015/16. We searched PubMed for manuscripts published between 2009 and mid-2016. Included manuscripts had to contain data about invasive pneumococcal disease (IPD) incidence, or vaccination coverage with higher-valent PCVs. This review represents the first analysis of vaccination coverage and impact of higher-valent PCVs on overall IPD in Southern European countries (Portugal, Spain, Italy, Greece, Cyprus). Vaccination coverage in the Portuguese private market peaked around 2008 at 75% (children <= 2 years) but declined to 63% in 2012. In Madrid, coverage was 95% (2007-2012) but dropped to 67% (2013/14; children <= 2 years) after funding termination in May 2012. PCVs were recently introduced in the national immunisation program (NIP) of Portugal (2015) and Spain (2015/16). In Italy, coverage for the complete PCV schedule (children <= 2 years) was 88% in 2013, although highly variable between regions (45-99%). In Greece, in 2013, 82.3% had received 3 PCV doses by 12 months, while 62.3% received the fourth dose by 24 months. Overall IPD (net benefit: effect on vaccine types, vaccine-related types, and non-vaccine types) has decreased; in Greece, pneumococcal meningitis incidence remained stable. Continued IPD surveillance or national registers using ICD-10 codes of clinically suspected IPD are necessary, with timely publicly available reports and adequate national vaccination registers to assess trends in vaccination coverage, allowing evaluation of PCVs in NIPs. PMID- 27996634 TI - A comparison of CH4, N2O and CO2 emissions from three different cover types in a municipal solid waste landfill. AB - : High-density polyethylene (HDPE) membranes are commonly used as a cover component in sanitary landfills, although only limited evaluations of its effect on greenhouse gas (GHG) emissions have been completed. In this study, field GHG emission were investigated at the Dongbu landfill, using three different cover systems: HDPE covering; no covering, on the working face; and a novel material Oreezyme Waste Cover (OWC) material as a trial material. Results showed that the HDPE membrane achieved a high CH4 retention, 99.8% (CH4 mean flux of 12 mg C m-2 h-1) compared with the air-permeable OWC surface (CH4 mean flux of 5933 mg C m-2 h-1) of the same landfill age. Fresh waste at the working face emitted a large fraction of N2O, with average fluxes of 10 mg N m-2 h-2, while N2O emissions were small at both the HDPE and the OWC sections. At the OWC section, CH4 emissions were elevated under high air temperatures but decreased as landfill age increased. N2O emissions from the working face had a significant negative correlation with air temperature, with peak values in winter. A massive presence of CO2 was observed at both the working face and the OWC sections. Most importantly, the annual GHG emissions were 4.9 Gg yr-1 in CO2 equivalents for the landfill site, of which the OWC-covered section contributed the most CH4 (41.9%), while the working face contributed the most N2O (97.2%). HDPE membrane is therefore, a recommended cover material for GHG control. IMPLICATIONS: Monitoring of GHG emissions at three different cover types in a municipal solid waste landfill during a 1-year period showed that the working face was a hotspot of N2O, which should draw attention. High CH4 fluxes occurred on the permeable surface covering a 1- to 2-year-old landfill. In contrast, the high-density polyethylene (HDPE) membrane achieved high CH4 retention, and therefore is a recommended cover material for GHG control. PMID- 27996635 TI - Disengagement from tasks as a function of cognitive load and depressive symptom severity. AB - INTRODUCTION: Depression is associated with impairment in cognition and everyday functioning. Mechanisms of cognitive dysfunction in depression and the factors that influence strategic deployment of cognitive abilities in complex environments remain elusive. In this study we investigated whether depression symptom severity is associated with disengagement from a working memory task (Paced Auditory Serial Addition Task; PASAT) with parametric adjustment of task difficulty. METHODS: 235 participants completed the Beck Depression Inventory, low and high cognitive load conditions of the PASAT, and quality of life. Cognitive disengagement was the sum of consecutive items in which participants did not proffer a response to the trial. RESULTS: Individuals with higher depression severity showed more cognitive disengagement on the high but not low cognitive load trial of the PASAT; they did not differ in number of correct responses. Increased disengagement from the low to high cognitive load was associated with more impaired quality of life. CONCLUSIONS: Depression severity is associated with increased disengagement from tasks as difficulty increases. These findings suggest the importance of measuring how cognitive skills are avoided in complex environments in addition to considering performance accuracy. Individuals with depressive symptoms might preferentially avoid cognitive tasks that are perceived as more complex in spite of intact ability. PMID- 27996692 TI - Three Reviews Highlight Different Aspects of the Host Response to Viral Infection. PMID- 27996693 TI - Assessment of semi-automated nucleic acid testing programme in a Regional Blood Transfusion Centre. AB - BACKGROUND: Detection of human immunodeficiency virus type-1 (HIV-1), hepatitis-C (HCV) and hepatitis-B virus (HBV) in the blood donors is crucial. An efficient form of detection is nucleic acid testing (NAT) in blood screening. We assessed the suitability of commercial NAT testing in a developing country, focusing on the Altona RealStar assay and the method of Sacace Biotechnologies. METHODS: We have standardised and validated commercially available NAT kits with a semi automated system for detection of HBV, HCV and HIV-1 in blood donations. The MP NAT (mini-pool) assay consists of pooling of sample, virus extraction, amplification and detection with commercially available NAT kits. An internal control (IC) is incorporated in the assay to monitor the extraction, target amplification and detection process. RESULTS: The sensitivity of the Altona RealStar assay at 10-MP for each viral target was evaluated, HBV showed amplification in all diluted positive samples of 100, 50, 25, 10 and 5 IU/ml. HIV and HCV infected samples showed amplification in all diluted positive samples of 500, 100, 50 and 30 IU/ml. For HIV, out of six diluted samples of 30 IU/ml, five were amplified. A total of 14,170 seronegative blood samples were tested by RealStar PCR kit in 10-MP and 6 (0.042%) samples/pools were positive. A total of 65,362 seronegative blood donations were also tested by kits of Sacace Biotechnologies, in 10-MP and 45 (0.075%) pools were positive. The prevalence of combined NAT yield cases among routine donors was 1 in 1559 donations tested for all the 3 viruses. CONCLUSION: The semi-automated combined system for NAT screening assays is robust, sensitive, reproducible, and this gives an additional layer of safety with affordable cost. PMID- 27996636 TI - Immunogenicity Evaluation of Modified Adenovirus Vaccines Expressing Porcine Circovirus Type 2 Capsid Protein in Pigs. AB - Porcine circovirus type 2 (PCV2) adenovirus vaccine has been reported, but strong immune responses induced by adenovirus vector can decrease vaccine efficacy. To reduce the immunogenicity of adenovirus proteins, in previous study, we constructed the PCV2 adenovirus vaccine either modified with human cytomegalovirus first intron (Intron A) and woodchuck hepatitis virus post transcriptional regulatory element (WPRE) to increase the expression of Cap, or coexpressed porcine tumor necrosis factor-related activate protein (CD40L) and granulocyte macrophage colony-stimulating factor (GMCSF) to improve the immunogenicity of PCV2 Cap adenovirus vaccine. All these vaccines were evaluated in mice. In the present study, the protective immune responses of Intron A/WPRE modified recombinant adenovirus Ad-A-C-W and CD40L/GMCSF-modified recombinant adenovirus Ad-CD40L-Cap-GMCSF were evaluated in pigs. Enzyme-linked immunosorbent assay and virus neutralization assay showed that both Ad-A-C-W and Ad-CD40L-Cap GMCSF could induce a higher specific antibody and neutralizing antibody than Ad Cap (p < 0.05). Lymphocyte proliferation assay and cytokine release assay showed that Ad-A-C-W and Ad-CD40L-Cap-GMCSF induced a stronger cellular immune response than Ad-Cap. The PCV2 challenge experiment showed that viral loads of Ad-A-C-W vaccinated group and Ad-CD40L-Cap-GMCSF-vaccinated group were lower than Ad-Cap vaccinated group (p < 0.05) after pigs were oronasally challenged with 5 * 105 TCID50 PCV2. Autopsy and histopathological examination showed that no obvious clinical and microscopic lesions were observed in groups Ad-Cap, Ad-A-C-W, and Ad CD40L-Cap-GMCSF. Taken together, the results demonstrated that two modified recombinant adenovirus vaccines (Ad-A-C-W and Ad-CD40L-Cap-GMCSF) induced stronger humoral and cellular immune responses and provided better protection than unmodified adenovirus Ad-Cap. Therefore, Ad-A-C-W and Ad-CD40L-Cap-GMCSF would be used as potential vaccines for prevention and control of PCV2 infection. PMID- 27996694 TI - No effect of acute and chronic supramaximal exercise on circulating levels of the myokine SPARC. AB - Myokines may play a role in the health benefits of regular physical activity. Secreted protein acidic rich in cysteine (SPARC) is a pleiotropic myokine that has been shown to be released into the bloodstream by skeletal muscle in response to aerobic exercise. As there is evidence suggesting that SPARC release may be linked to glycogen breakdown and activation of 5' adenosine monophosphate activated protein kinase, we hypothesised that brief supramaximal exercise may also be associated with increased serum SPARC levels. In the present study, 10 participants (3 women; mean +/- SD age: 21 +/- 3 y, body mass index (BMI): 22 +/- 3 kg m-2, and VO2max: 39 +/- 6 mL kg-1 min-1) performed an acute bout of supramaximal cycle exercise (20-s Wingate sprint against 7.5% of body mass, with a 1-min warm-up and a 3-min cool-down consisting of unloaded cycling). Serum SPARC levels were determined pre-exercise as well as 0, 15, and 60 min post exercise and corrected for plasma volume change. To determine whether regular exercise affected the acute SPARC response, participants repeated the acute exercise protocol three times per week for four weeks, and serum SPARC response to supramaximal exercise was reassessed after this period. Acute supramaximal exercise significantly decreased plasma volume (-10%; p < .001), but was not associated with a significant change in serum SPARC levels at either the pre training or post-training testing sessions. In conclusion, in contrast to aerobic exercise, a single brief supramaximal cycle sprint is not associated with an increase in serum SPARC levels, suggesting that SPARC release is not related to skeletal muscle glycogen breakdown. PMID- 27996695 TI - Reduced combustion mechanism for C1-C4 hydrocarbons and its application in computational fluid dynamics flare modeling. AB - : Emissions from flares constitute unburned hydrocarbons, carbon monoxide (CO), soot, and other partially burned and altered hydrocarbons along with carbon dioxide (CO2) and water. Soot or visible smoke is of particular concern for flare operators/regulatory agencies. The goal of the study is to develop a computational fluid dynamics (CFD) model capable of predicting flare combustion efficiency (CE) and soot emission. Since detailed combustion mechanisms are too complicated for (CFD) application, a 50-species reduced mechanism, LU 3.0.1, was developed. LU 3.0.1 is capable of handling C4 hydrocarbons and soot precursor species (C2H2, C2H4, C6H6). The new reduced mechanism LU 3.0.1 was first validated against experimental performance indicators: laminar flame speed, adiabatic flame temperature, and ignition delay. Further, CFD simulations using LU 3.0.1 were run to predict soot emission and CE of air-assisted flare tests conducted in 2010 in Tulsa, Oklahoma, using ANSYS Fluent software. Results of non premixed probability density function (PDF) model and eddy dissipation concept (EDC) model are discussed. It is also noteworthy that when used in conjunction with the EDC turbulence-chemistry model, LU 3.0.1 can reasonably predict volatile organic compound (VOC) emissions as well. IMPLICATIONS: A reduced combustion mechanism containing 50 C1-C4 species and soot precursors has been developed and validated against experimental data. The combustion mechanism is then employed in the computational fluid dynamics (CFD) of modeling of soot emission and combustion efficiency (CE) of controlled flares for which experimental soot and CE data are available. The validated CFD modeling tools are useful for oil, gas, and chemical industries to comply with U.S. Environmental Protection Agency's (EPA) mandate to achieve smokeless flaring with a high CE. PMID- 27996889 TI - Correlation of MRI features and pathohistological prognostic factors in invasive ductal breast carcinoma. AB - OBJECTIVE: The aim of this study was to correlate magnetic resonance imaging (MRI) features of invasive ductal carcinomas (IDC) with pathohistological prognostic factors. Such an association, if present, could have significant translational implications for early identification of aggressive types of breast cancer. MATERIALS AND METHODS: One hundred and fourteen consecutive women with IDC who underwent breast MRI within one month prior to surgery were included in this retrospective study. MRI features were analyzed and then interpreted with a Gottingen score (GS) that included morphological (shape, margins, and pattern of enhancement) and kinetic characteristics (initial signal increase and post initial behavior of the time-signal intensity curve). Histological specimens were analyzed for tumor size, axillary lymph node status, histological grade, estrogen receptors (ER), progesterone receptors (PR), HER2, and Ki-67. RESULTS: By multivariate analysis, a smooth margin was a significant, independent predictor of a larger tumor size (p = 0.041), lymph node invasion (p = 0.013), and lower expression of ER (p = 0.022). High GS was a significant, independent predictor of a higher histological grade (p = 0.022) while round or oval shape of lesion was independent predictor of a higher PR expression (p = 0.027). CONCLUSION: A smooth margin of breast cancer on breast MRI was able to predict positive axillary lymph nodes, larger tumor size, and lower expression of ER. Except for a higher histological grade, GS was not able to predict other unfavorable prognostic factors, probably due to the fact that smooth margins were assigned fewer points than spiculated margins. PMID- 27996890 TI - The effect of 1, 25(OH)2 D3 (calcitriol) alone and in combination with all-trans retinoic acid on ROR-gammat, IL-17, TGF-beta, and FOXP3 gene expression in experimental autoimmune encephalomyelitis. AB - OBJECTIVES: It has been shown that calcitriol and all-trans retinoic acid (ATRA) have modulatory effects on the immune system. The present study investigates the synergistic effects of combination treatment of calcitriol and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: The mice were allocated to four preventive groups, each consisting of eight animals, ATRA (250 MUg/mouse), calcitriol (100 ng/mouse), combination of ATRA and calcitriol (125 MUg/mouse and 50 ng/mouse) and vehicle groups. EAE was induced by MOG35-55 peptide in female C57BL/6 mice. Treatments were initiated at day 1 before immunization and continued every other day throughout the study until the day 21 post-immunization. Splenocytes were isolated from EAE-induced mice and the expression of retinoic acid receptor related orphan receptor gamma t (ROR-gammat), Interleukin-17 (IL-17), transforming growth factor beta (TGF-beta), and forkhead box P3 (FOXP3) genes was measured using real-time polymerase chain reaction. RESULTS: The expression of FOXP3 and TGF-beta genes in the splenocytes of combination-treated and calcitriol alone-treated mice was significantly increased compared to vehicle group (P < 0.05). The expression of ROR-gammat and IL-17 genes in the splenocytes of ATRA, calcitriol and combination- treated mice was significantly reduced compared to those of vehicle- treated mice (P < 0.05). The relative expression level of ROR gammat was significantly (P < 0.05) lower in the combination group than in the mice treated by ATRA or calcitriol alone. DISCUSSION: This study demonstrated that treatment with combination of calcitriol and ATRA can be considered as a new strategy for MS prevention and treatment. PMID- 27996891 TI - Mapping air quality zones for coastal urban centers. AB - : This study presents a new method that incorporates modern air dispersion models allowing local terrain and land-sea breeze effects to be considered along with political and natural boundaries for more accurate mapping of air quality zones (AQZs) for coastal urban centers. This method uses local coastal wind patterns and key urban air pollution sources in each zone to more accurately calculate air pollutant concentration statistics. The new approach distributes virtual air pollution sources within each small grid cell of an area of interest and analyzes a puff dispersion model for a full year's worth of 1-hr prognostic weather data. The difference of wind patterns in coastal and inland areas creates significantly different skewness (S) and kurtosis (K) statistics for the annually averaged pollutant concentrations at ground level receptor points for each grid cell. Plotting the S-K data highlights grouping of sources predominantly impacted by coastal winds versus inland winds. The application of the new method is demonstrated through a case study for the nation of Kuwait by developing new AQZs to support local air management programs. The zone boundaries established by the S-K method were validated by comparing MM5 and WRF prognostic meteorological weather data used in the air dispersion modeling, a support vector machine classifier was trained to compare results with the graphical classification method, and final zones were compared with data collected from Earth observation satellites to confirm locations of high-exposure-risk areas. The resulting AQZs are more accurate and support efficient management strategies for air quality compliance targets effected by local coastal microclimates. IMPLICATIONS: A novel method to determine air quality zones in coastal urban areas is introduced using skewness (S) and kurtosis (K) statistics calculated from grid concentrations results of air dispersion models. The method identifies land-sea breeze effects that can be used to manage local air quality in areas of similar microclimates. PMID- 27996892 TI - The influence of a real job on upper limb performance in motor skill tests: which abilities are transferred? AB - To investigate whether the specificities of real jobs create distinctions in the performance of workers in different motor tests for the upper limbs, 24 participants were divided into two groups according to their specific job: fine and repetitive tasks and general tasks. Both groups reproduced tasks related to aiming movements, handling and strength of the upper limbs. There were no significant differences between groups in the dexterity and performance of aiming movements. However, the general tasks group had higher grip strength than the repetitive tasks group, demonstrating differences according to job specificity. The results suggest that a particular motor skill in a specific job cannot improve performance in other tasks with the same motor requirements. The transfer of the fine and gross motor skills from previous experience in a job-specific task is the basis for allocating training and guidance to workers. PMID- 27996894 TI - Motivation, expectations, and usability of a driven gait orthosis in stroke patients and their therapists. AB - BACKGROUND: In the development of efficacious driven gait orthoses (DGO), it is an added value to consider patients' and therapists' perspectives concerning robot-assisted gait training (RAGT). A better understanding of these issues may improve the process of care and outcome. OBJECTIVES: This study aimed to examine stroke patients' motivation and expectations of RAGT, and therapists' expectations and perspectives on the usability of RAGT. Additionally, the differences in expectations between stroke patients and their therapists were analyzed. METHODS: A cross sectional, multi-center, three-group trial was conducted. Included were (1) stroke patients who have experience with RAGT (i.e. the stroke user group), (2) stroke patients who have no experience with RAGT (i.e. the stroke non-user group), and (3) therapists who have experience with RAGT (i.e. the therapist user group). The Intrinsic Motivation Inventory (IMI), Credibility/Expectancy Questionnaire (CEQ), and Usefulness, Satisfaction and Ease of Use Questionnaire (USE) were used. Descriptive statistics and non-parametric Kruskal-Wallis tests were conducted. RESULTS: In total, 46 subjects were assessed (stroke user group: n = 23, stroke non-user group: n = 14, therapist user group: n = 9). IMI subscale scores ranged from 42 to 88%. Mean credibility and expectancy ranged from 80 to 85% and 57 to 72%, respectively, with no significant differences between groups. USE subscale scores ranged from 61 to 72%. CONCLUSIONS: Stroke user group patients seem quite motivated to train with the DGO and both patients and therapists reasonably believe that this training could improve gait functioning. Therapists are moderately satisfied with the usability of the DGO, but there is room for improvement with respect to usefulness and ease of use. PMID- 27996895 TI - Dr. Pangloss's Clinic: Prenatal Whole Genome Sequencing and a Return to Reality. PMID- 27996896 TI - Concerns About Justification for Fetal Genome Sequencing. PMID- 27996897 TI - Collegiate Sports: Professionals All But in Name Raise Unique Bioethics Concerns in the Collection of Biometric Data. PMID- 27996898 TI - The Legality of Biometric Screening of Professional Athletes. PMID- 27996899 TI - Biometrics and Antidoping Enforcement in Professional Sport. PMID- 27996900 TI - TBI and NFL Culture: Can Players Autonomously Refuse Biometric Monitoring? PMID- 27996901 TI - Breaking the Sounds of Silence: Respecting People With Disabilities and Reproductive Decision Making. PMID- 27996902 TI - C-Section and Referential Opacity. PMID- 27996903 TI - Wearable Biometric Technologies and Public Health. PMID- 27996904 TI - Resisting Paternalism in Prenatal Whole-Genome Sequencing. PMID- 27996905 TI - Uncertainty, Humility, and Engagement in Pregnancy Care. PMID- 27996906 TI - Athletic Performance Monitoring, Pseudo Science and Metaphysics Meet Ethics. PMID- 27996907 TI - Resuscitation Decisions of Extremely Premature Infants at the Limits of Viability: Defining Best Interests. PMID- 27996908 TI - Modern Pregnancies and (Im)Perfect Babies. PMID- 27996909 TI - Wearable Technologies in Collegiate Sports: The Ethics of Collecting Biometric Data From Student-Athletes. PMID- 27996910 TI - A Brave New World of Bespoke Babies? PMID- 27996911 TI - Response to Open Peer Commentaries on "A Framework for Unrestricted Prenatal Whole-Genome Sequencing: Respecting and Enhancing the Autonomy of Prospective Parents". PMID- 27996912 TI - Noninvasive Prenatal Whole-Genome Sequencing: A Solution in Search of a Problem. PMID- 27996913 TI - Comfort Care Request for Preterm Infant: Prescriptive Analysis. PMID- 27996914 TI - Response to Open Peer Commentaries on "Governance of Transnational Global Health Research Consortia and Health Equity". PMID- 27996915 TI - Permissibility or Priority? Testing or Screening? Essential Distinctions in the Ethics of Prenatal Testing. PMID- 27996916 TI - Resolving Perceived Maternal-Fetal Conflicts Through Active Patient-Physician Collaboration. PMID- 27996917 TI - Beneficence In Utero: A Framework for Restricted Prenatal Whole-Genome Sequencing to Respect and Enhance the Well-Being of Children. PMID- 27996918 TI - Tracking U.S. Professional Athletes: The Ethics of Biometric Technologies. AB - Professional sport in the United States has widely adopted biometric technologies, dramatically expanding the monitoring of players' biodata. These technologies have the potential to prevent injuries, improve performance, and extend athletes' careers; they also risk compromising players' privacy and autonomy, the confidentiality of their data, and their careers. The use of these technologies in professional sport and the consumer sector remains largely unregulated and unexamined. We seek to provide guidance for their adoption by examining five areas of concern: (1) validity and interpretation of data; (2) increased surveillance and threats to privacy; (3) risks to confidentiality and concerns regarding data security; (4) conflicts of interest; and (5) coercion. Our analysis uses professional sport as a case study; however, these concerns extend to other domains where their use is expanding, including the consumer sector, collegiate and high school sport, the military, and commercial sectors where monitoring employees is viewed as useful for safety or to maximize labor potential. PMID- 27996919 TI - Decision Zone at the Margins of Life and Good Health: The Role of Medical Staff Guidelines for the Care of Extremely Early Gestation Pregnancies and Premature Infants. PMID- 27996921 TI - Prenatal Whole Genome Sequencing: An Argument for Professional Self-Regulation. PMID- 27996922 TI - Preemptive C-Section Refusal Based on Religious Beliefs. PMID- 27996923 TI - A Framework for Unrestricted Prenatal Whole-Genome Sequencing: Respecting and Enhancing the Autonomy of Prospective Parents. AB - Noninvasive, prenatal whole genome sequencing (NIPW) may be a technological reality in the near future, making available a vast array of genetic information early in pregnancy at no risk to the fetus or mother. Many worry that the timing, safety, and ease of the test will lead to informational overload and reproductive consumerism. The prevailing response among commentators has been to restrict conditions eligible for testing based on medical severity, which imposes disputed value judgments and devalues those living with eligible conditions. To avoid these difficulties, we propose an unrestricted testing policy, under which prospective parents could obtain information on any variant of known significance after a careful informed consent process that uses an interactive decision aid to deliver a mandatory presentation on the purposes, techniques, and limitations of genomic testing, as well as optional resources for reflection and consultation. This process would encourage thoughtful, informed deliberation by prospective parents before deciding whether or how to use NIPW. PMID- 27996924 TI - Mandating Moral Reflection? PMID- 27996925 TI - Providing Unrestricted Access to Prenatal Testing Does Not Translate to Enhanced Autonomy. PMID- 27996926 TI - Comfort Care Request for Preterm Infant. PMID- 27996927 TI - Biometric Tracking From Professional Athletes to Consumers. PMID- 27996928 TI - Corrigendum. PMID- 27996929 TI - When Trust in God Means Preemptive Refusal of C-Section. PMID- 27996930 TI - "I Felt Like a Lab Rat": The Importance of Power and Context in Understanding Biometric Technologies. PMID- 27996932 TI - Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2010-2014. AB - Objectives-This report identifies the specific drugs most frequently involved in drug overdose deaths in the United States from 2010 through 2014. Methods-The 2010-2014 National Vital Statistics System mortality files were linked to electronic files containing literal text information from death certificates. Drug overdose was defined using the International Classification of Diseases, Tenth Revision underlying cause-of-death codes X40-X44 (unintentional), X60-X64 (suicide), X85 (homicide), and Y10-Y14 (undetermined intent). Among deaths with an underlying cause of death of drug overdose, the literal text in three fields of the death certificate (i.e., the cause of death from Part I, significant conditions contributing to death from Part II, and a description of how the injury occurred from Box 43) were searched to identify drug mentions. Search term lists were developed using existing drug classification systems as well as from manual review of the literal text. The search term list was then used to identify the specific drugs involved in overdose deaths. Descriptive statistics were reported for drug overdose deaths involving the 10 most frequently mentioned drugs on death certificates. Tables and figures presenting information on the specific drugs involved in deaths are based on deaths with mention of at least one specific drug on the death certificate. Results-From 2010 through 2014, the number of drug overdose deaths per year increased 23%, from 38,329 in 2010 to 47,055 in 2014. During this time period, the percentage of drug overdose deaths involving at least one specific drug increased, from 67% in 2010 to 78% in 2014. Among drug overdose deaths with at least one drug specified on the death certificate, the 10 drugs most frequently involved in overdose deaths included the following opioids: heroin, oxycodone, methadone, morphine, hydrocodone, and fentanyl; the following benzodiazepines: alprazolam and diazepam; and the following stimulants: cocaine and methamphetamine. During this 5-year period, the age-adjusted rate of drug overdose deaths involving heroin more than tripled, and the rate of drug overdose deaths involving methamphetamine more than doubled. The rate of drug overdose deaths involving fentanyl more than doubled in a single year (from 2013 to 2014). In 2014, of the 36,667 drug overdose deaths involving at least one specific drug, 52% of these deaths specified one drug, 38% specified two or three drugs, and 11% specified four or more drugs. Conclusions-Analysis of the literal text from death certificates can be used to identify patterns in the specific drugs most frequently involved in drug overdose deaths. From 2010 through 2014, the top 10 drugs involved were the same, but the relative ranking and age-adjusted rates for deaths involving these drugs changed. Literal text analysis also revealed that many drug overdose deaths involved multiple drugs. Findings should be interpreted in light of the improvement in the quality of the data that resulted from better reporting of specific drugs on death certificates from 2010 through 2014. Relative increases in the death rates involving specific drugs and the rankings of these drugs may be affected by improvements in reporting, real increases in the numbers of death, or both. PMID- 27996934 TI - Confidentiality Concerns and Sexual and Reproductive Health Care Among Adolescents and Young Adults Aged 15-25. AB - KEY FINDINGS: Data from the National Survey of Family Growth *About 7% of persons aged 15-25 would not seek sexual or reproductive health care because of concerns that their parents might find out about it. *For females aged 15-17 and 18-25, those who had confidentiality concerns were less likely to receive sexual and reproductive health services in the past year compared with those without these concerns. *Less than one-half of teenagers aged 15-17 (38.1%) spent some time alone in the past year during a visit with a doctor or other health care provider without a parent, relative, or guardian in the room. *Teenagers aged 15-17 who spent some time alone during a visit with a health care provider were more likely to have received sexual or reproductive health services in the past year compared with those who had not. Confidentiality concerns can impact adolescent and young adults' access to sexual and reproductive health services (1-4). Young people who are covered by their parents' private health insurance may be deterred from obtaining these services due to concerns that their parents might find out about it (2). Similarly, confidentiality concerns may arise because youth seeking such services may not have time alone during a visit with a health care provider (4). This report describes two measures related to confidentiality concerns and sexual and reproductive health care. PMID- 27996933 TI - Using Literal Text From the Death Certificate to Enhance Mortality Statistics: Characterizing Drug Involvement in Deaths. AB - Objectives-This report describes the development and use of a method for analyzing the literal text from death certificates to enhance national mortality statistics on drug-involved deaths. Drug-involved deaths include drug overdose deaths as well as other deaths where, according to death certificate literal text, drugs were associated with or contributed to the death. Methods-The method uses final National Vital Statistics System-Mortality files linked to electronic files containing literal text information from death certificates. Software programs were designed to search the literal text from three fields of the death certificate (the cause of death from Part I, significant conditions contributing to the death from Part II, and a description of how the injury occurred from Box 43) to identify drug mentions as well as contextual information. The list of drug search terms was developed from existing drug classification systems as well as from manual review of the literal text. Literal text surrounding the identified drug search terms was analyzed to ascertain the context. Drugs mentioned in the death certificate literal text were assumed to be involved in the death unless contextual information suggested otherwise (e.g., "METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS INFECTION"). The literal text analysis method was assessed by comparing the results from application of the method with results based on ICD 10 codes, and by conducting a manual review of a sample of records. PMID- 27996935 TI - The mother of all actins? AB - New insights into the structure of filaments made of crenactin, a homolog of actin found in archaea, shed light on how the cytoskeleton might have evolved. PMID- 27996936 TI - Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development. AB - Kidney formation involves patterning events that induce renal progenitors to form nephrons with an intricate composition of multiple segments. Here, we performed a chemical genetic screen using zebrafish and discovered that prostaglandins, lipid mediators involved in many physiological functions, influenced pronephros segmentation. Modulating levels of prostaglandin E2 (PGE2) or PGB2 restricted distal segment formation and expanded a proximal segment lineage. Perturbation of prostaglandin synthesis by manipulating Cox1 or Cox2 activity altered distal segment formation and was rescued by exogenous PGE2. Disruption of the PGE2 receptors Ptger2a and Ptger4a similarly affected the distal segments. Further, changes in Cox activity or PGE2 levels affected expression of the transcription factors irx3b and sim1a that mitigate pronephros segment patterning. These findings show for the first time that PGE2 is a regulator of nephron formation in the zebrafish embryonic kidney, thus revealing that prostaglandin signaling may have implications for renal birth defects and other diseases. PMID- 27996937 TI - Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling. AB - The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1alpha uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling beta catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the beta catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems. PMID- 27996938 TI - CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory. AB - Although the role of CCR5 in immunity and in HIV infection has been studied widely, its role in neuronal plasticity, learning and memory is not understood. Here, we report that decreasing the function of CCR5 increases MAPK/CREB signaling, long-term potentiation (LTP), and hippocampus-dependent memory in mice, while neuronal CCR5 overexpression caused memory deficits. Decreasing CCR5 function in mouse barrel cortex also resulted in enhanced spike timing dependent plasticity and consequently, dramatically accelerated experience-dependent plasticity. These results suggest that CCR5 is a powerful suppressor for plasticity and memory, and CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits. Consistent with this hypothesis, the HIV V3 peptide caused LTP, signaling and memory deficits that were prevented by Ccr5 knockout or knockdown. Overall, our results demonstrate that CCR5 plays an important role in neuroplasticity, learning and memory, and indicate that CCR5 has a role in the cognitive deficits caused by HIV. PMID- 27996940 TI - Allergic Fungal Airway Disease. AB - Fungi are ubiquitous and form their own kingdom. Up to 80 genera of fungi have been linked to type I allergic disease, and yet, commercial reagents to test for sensitization are available for relatively few species. In terms of asthma, it is important to distinguish between species unable to grow at body temperature and those that can (thermotolerant) and thereby have the potential to colonize the respiratory tract. The former, which include the commonly studied Alternaria and Cladosporium genera, can act as aeroallergens whose clinical effects are predictably related to exposure levels. In contrast, thermotolerant species, which include fungi from the Candida, Aspergillus, and Penicillium genera, can cause a persistent allergenic stimulus independent of their airborne concentrations. Moreover, their ability to germinate in the airways provides a more diverse allergenic stimulus, and may result in noninvasive infection, which enhances inflammation. The close association between IgE sensitization to thermotolerant filamentous fungi and fixed airflow obstruction, bronchiectasis, and lung fibrosis suggests a much more tissue-damaging process than that seen with aeroallergens. This review provides an overview of fungal allergens and the patterns of clinical disease associated with exposure. It clarifies the various terminologies associated with fungal allergy in asthma and makes the case for a new term (allergic fungal airway disease) to include all people with asthma at risk of developing lung damage as a result of their fungal allergy. Lastly, it discusses the management of fungirelated asthma. PMID- 27996941 TI - IgE-Api m 4 Is Useful for Identifying a Particular Phenotype of Bee Venom Allergy. AB - BACKGROUND AND OBJECTIVE: Different clinical behaviors have been identified in patients allergic to bee venom. Compound-resolved diagnosis could be an appropriate tool for investigating these differences. The aims of this study were to analyze whether specific IgE to Api m 4 (sIgE-Api m 4) can identify a particular kind of bee venom allergy and to describe response to bee venom immunotherapy (bVIT). METHODS: Prospective study of 31 patients allergic to bee venom who were assigned to phenotype group A (sIgE-Api m 4 <0.98 kU/L), treated with native aqueous (NA) extract, or phenotype group B (sIgE-Api m 4 >=0.98 kU/L), treated with purified aqueous (PA) extract. Sex, age, cardiovascular risk, severity of preceding sting reaction, exposure to beekeeping, and immunological data (intradermal test, sIgE/sIgG4-Apis-nApi m 1, and sIgE-rApi m 2-Api m 4 were analyzed. Systemic reactions (SRs) during bVIT build-up were analyzed. Immunological and sting challenge outcomes were evaluated in each group after 1 and 2 years of bVIT. RESULTS: Phenotype B patients had more severe reactions (P=.049) and higher skin sensitivity (P=.011), baseline sIgE-Apis (P=.0004), sIgE nApi m 1 (P=.0004), and sIgG4-Apis (P=.027) than phenotype A patients. Furthermore, 41% of patients in group B experienced SRs during the build-up phase with NA; the sting challenge success rate in this group was 82%. There were no significant reductions in serial intradermal test results, but an intense reduction in sIgE-nApi m 1 (P=.013) and sIgE-Api m 4 (P=.004) was observed after the first year of bVIT. CONCLUSION: Use of IgE-Api m 4 as the only discrimination criterion demonstrated differences in bee venom allergy. Further investigation with larger populations is necessary. PMID- 27996939 TI - Sam68/KHDRBS1-dependent NF-kappaB activation confers radioprotection to the colon epithelium in gamma-irradiated mice. AB - Previously we reported that Src-associated-substrate-during-mitosis-of-68kDa (Sam68/KHDRBS1) is pivotal for DNA damage-stimulated NF-kappaB transactivation of anti-apoptotic genes (Fu et al., 2016). Here we show that Sam68 is critical for genotoxic stress-induced NF-kappaB activation in the gamma-irradiated colon and animal and that Sam68-dependent NF-kappaB activation provides radioprotection to colon epithelium in vivo. Sam68 deletion diminishes gamma-irradiation-triggered PAR synthesis and NF-kappaB activation in colon epithelial cells (CECs), thus hampering the expression of anti-apoptotic molecules in situ and facilitating CECs to undergo apoptosis in mice post whole-body gamma-irradiation (WBIR). Sam68 knockout mice suffer more severe damage in the colon and succumb more rapidly from acute radiotoxicity than the control mice following WBIR. Our results underscore the critical role of Sam68 in orchestrating genotoxic stress-initiated NF-kappaB activation signaling in the colon tissue and whole animal and reveal the pathophysiological relevance of Sam68-dependent NF-kappaB activation in colonic cell survival and recovery from extrinsic DNA damage. PMID- 27996942 TI - IgE Reactivity to Polcalcins Varies According to Pollen Source. AB - BACKGROUND: Polcalcins are highly cross-reactive pollen panallergens. Less than 10% of allergic patients are sensitized to polcalcins. All pollen species are considered able to sensitize patients to this panallergen. OBJECTIVE: We aimed to assess the presence of polcalcins in various pollen extracts used in allergen immunotherapy. METHODS: ELISA inhibition experiments were performed with sera from patients sensitized to polcalcin and rPhl p 7 and rBet v 4. Recombinant polcalcin was used as the substrate and freshly prepared pollen extracts as inhibitors. RESULTS: All pollen extracts induced significant inhibition of IgE reactivity to rBet v 4, whereas only grass pollen extract induced marked inhibition of IgE reactivity to rPhl p 7. CONCLUSION: Grass polcalcin probably contains more epitopes than polcalcins from other pollen sources. Grass pollen could be responsible for sensitization to polcalcins, and grass pollen immunotherapy is likely to be an option for polcalcin-hypersensitive patients. PMID- 27996943 TI - Insect Venom Immunotherapy: Analysis of the Safety and Tolerance of 3 Buildup Protocols Frequently Used in Spain. AB - INTRODUCTION: Hymenoptera venom immunotherapy (VIT) is an effective treatment but not one devoid of risk, as both local and systemic adverse reactions may occur, especially in the initial phases. We compared the tolerance to 3 VIT buildup protocols and analyzed risk factors associated with adverse reactions during this phase. MATERIALS AND METHODS: We enrolled 165 patients divided into 3 groups based on the buildup protocol used (3, 4, and 9 weeks). The severity of systemic reactions was evaluated according to the World Allergy Organization model. Results were analyzed using exploratory descriptive statistics, and variables were compared using analysis of variance. RESULTS: Adverse reactions were recorded in 53 patients (32%) (43 local and 10 systemic). Local reactions were immediate in 27 patients (63%) and delayed in 16 (37%). The severity of the local reaction was slight/moderate in 15 patients and severe in 13. Systemic reactions were grade 1-2. No significant association was found between the treatment modality and the onset of local or systemic adverse reactions or the type of local reaction. We only found a statistically significant association between severity of the local reaction and female gender. As for the risk factors associated with systemic reactions during the buildup phase, we found no significant differences in values depending on the protocol used or the insect responsible. CONCLUSIONS: The buildup protocols compared proved to be safe and did not differ significantly from one another. In the population studied, patients undergoing the 9-week schedule presented no systemic reactions. Therefore, this protocol can be considered the safest approach. PMID- 27996944 TI - Broad Bean-Induced Anaphylaxis: A Case Report. PMID- 27996945 TI - Linseed Allergy Due to LTP: Another Food for LTP Syndrome. PMID- 27996946 TI - Accelerated-type Reactions to High Parenteral Doses of Metamizole in Patients Who Tolerated Therapeutic Doses of Oral Metamizole and Other NSAIDs. PMID- 27996948 TI - Allergy to Blue Dye. PMID- 27996947 TI - Serious Adverse Reaction to Timolol Eye Drops in a 7-Year-Old Boy With Glaucoma and Asthma. PMID- 27996950 TI - Fungal Allergens in a Saxophonist Who Had Never Smoked With Allergic Bronchopulmonary Aspergillosis Previously Diagnosed as COPD. PMID- 27996949 TI - Triggers and Prodromal Symptoms of Angioedema Attacks in Patients With Hereditary Angioedema. PMID- 27996951 TI - Vaginal Capsules: An Unsuspected Probable Source of Exposure to alpha-Gal. PMID- 27996952 TI - A Bronchovascular Anomaly in a Patient With 22q11.2 Deletion Syndrome. PMID- 27996953 TI - Successful Desensitization to Vitamin D in a Patient With Vitamin D Deficiency. PMID- 27996954 TI - Anaphylaxis Due to the Excipient Polysorbate 80. PMID- 27996955 TI - Component-Resolved Diagnosis: Impact on Indications for Therapy in Patients With Respiratory Allergy and Sensitization to Multiple Pollens in Catalonia, Spain. PMID- 27996956 TI - IgE-Mediated Anaphylaxis Induced by Macrogol 6000. PMID- 27996957 TI - Analysis of Allergy Alerts Registered in a Hospital Electronic Health Record System. PMID- 27996958 TI - Is Allergic Sensitization to Siberian Hamster Preventable in High-Risk Individuals Who Are Already Sensitized or Exposed to Furry Animals? PMID- 27996959 TI - Reply to Liccardi et al. PMID- 27996960 TI - Recombinant vascular endothelial growth factor 121 injection for the prevention of fetal growth restriction in a preeclampsia mouse model. AB - AIM: To discover the potential role of recombinant VEGF121 (rVEGF121) injection for the prevention of fetal growth restriction in a preeclampsia (PE) mouse model (Mus musculus). SUBJECTS AND METHODS: This is an experimental study of 30 pregnant mice that were randomly divided into three groups: normal, PE, and PE with rVEGF121 injection. The PE mouse model was created by injecting anti Qa-2 10 ng iv, which is deleterious to Qa-2 expression (homologous to HLA-G), from the first to the fourth day of gestation. PE was validated by measuring serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor(PIGF) and also by kidney histopathology. Recombinant VEGF121 was given on the ninth day until the 11th day of pregnancy; mice were terminated on the 16th day. Fetal weights were acquired with a Denver analytical balance. Serum levels of sFlt-1 and PlGF were measured using enzyme-linked immunosorbent assay (ELISA). The data were statistically analyzed via analysis of variance (ANOVA). RESULTS: On average, fetal birth weight was 0.7150 g in the normal group, 0.4936 g in the PE group, and 0.6768 g in the PE with rVEGF121 injection group. ANOVA showed significant growth restriction in the PE group (P=0.006), confirming the use of anti Qa-2 as a suitable PE model. Kidney histopathology results, sFlt-1 levels, and PlGF levels also demonstrated that anti Qa-2 consistently conferred hallmarks of PE in mice. Vascular endothelial growth factor (VEGF) injection prevented fetal growth restriction; comparable fetal weights were observed between the PE model with VEGF treatment and the normal group (P=0.610) but differed from the untreated PE group (P=0.021). CONCLUSIONS: Injection of rVEGF121 has the potential to prevent fetal growth restriction in a newly proposed PE mouse model. PMID- 27996961 TI - Quasiparticle interference in unconventional 2D systems. AB - At present, research of 2D systems mainly focuses on two kinds of materials: graphene-like materials and transition-metal dichalcogenides (TMDs). Both of them host unconventional 2D electronic properties: pseudospin and the associated chirality of electrons in graphene-like materials, and spin-valley-coupled electronic structures in the TMDs. These exotic electronic properties have attracted tremendous interest for possible applications in nanodevices in the future. Investigation on the quasiparticle interference (QPI) in 2D systems is an effective way to uncover these properties. In this review, we will begin with a brief introduction to 2D systems, including their atomic structures and electronic bands. Then, we will discuss the formation of Friedel oscillation due to QPI in constant energy contours of electron bands, and show the basic concept of Fourier-transform scanning tunneling microscopy/spectroscopy (FT-STM/STS), which can resolve Friedel oscillation patterns in real space and consequently obtain the QPI patterns in reciprocal space. In the next two parts, we will summarize some pivotal results in the investigation of QPI in graphene and silicene, in which systems the low-energy quasiparticles are described by the massless Dirac equation. The FT-STM experiments show there are two different interference channels (intervalley and intravalley scattering) and backscattering suppression, which associate with the Dirac cones and the chirality of quasiparticles. The monolayer and bilayer graphene on different substrates (SiC and metal surfaces), and the monolayer and multilayer silicene on a Ag(1 1 1) surface will be addressed. The fifth part will introduce the FT-STM research on QPI in TMDs (monolayer and bilayer of WSe2), which allow us to infer the spin texture of both conduction and valence bands, and present spin-valley coupling by tracking allowed and forbidden scattering channels. PMID- 27996962 TI - An atlas of transcriptional, chromatin accessibility, and surface marker changes in human mesoderm development. AB - Mesoderm is the developmental precursor to myriad human tissues including bone, heart, and skeletal muscle. Unravelling the molecular events through which these lineages become diversified from one another is integral to developmental biology and understanding changes in cellular fate. To this end, we developed an in vitro system to differentiate human pluripotent stem cells through primitive streak intermediates into paraxial mesoderm and its derivatives (somites, sclerotome, dermomyotome) and separately, into lateral mesoderm and its derivatives (cardiac mesoderm). Whole-population and single-cell analyses of these purified populations of human mesoderm lineages through RNA-seq, ATAC-seq, and high throughput surface marker screens illustrated how transcriptional changes co occur with changes in open chromatin and surface marker landscapes throughout human mesoderm development. This molecular atlas will facilitate study of human mesoderm development (which cannot be interrogated in vivo due to restrictions on human embryo studies) and provides a broad resource for the study of gene regulation in development at the single-cell level, knowledge that might one day be exploited for regenerative medicine. PMID- 27996963 TI - Genome resequencing and comparative variome analysis in a Brassica rapa and Brassica oleracea collection. AB - The closely related species Brassica rapa and B. oleracea encompass a wide range of vegetable, fodder and oil crops. The release of their reference genomes has facilitated resequencing collections of B. rapa and B. oleracea aiming to build their variome datasets. These data can be used to investigate the evolutionary relationships between and within the different species and the domestication of the crops, hereafter named morphotypes. These data can also be used in genetic studies aiming at the identification of genes that influence agronomic traits. We selected and resequenced 199 B. rapa and 119 B. oleracea accessions representing 12 and nine morphotypes, respectively. Based on these resequencing data, we obtained 2,249,473 and 3,852,169 high quality SNPs (single-nucleotide polymorphisms), as well as 303,617 and 417,004 InDels for the B. rapa and B. oleracea populations, respectively. The variome datasets of B. rapa and B. oleracea represent valuable resources to researchers working on evolution, domestication or breeding of Brassica vegetable crops. PMID- 27996964 TI - Multi-echo fMRI replication sample of autobiographical memory, prospection and theory of mind reasoning tasks. AB - The default network is involved in self-generated thought, a class of cognition that includes autobiographical memory, prospection, and reasoning about the mental states of others. We collected a replication sample of Spreng and Grady (J Cogn. Neurosci. 22, 1112-1123, 2010), confirming that the default network differentially supports each of these forms of self-generated thought. Here we describe this dataset of multi-echo fMRI data in 31 young adults during autobiographical remembering, imagining, and mentalizing; we also provide an additional resting-state scan for each subject. In this new sample, the findings from the original report are successfully replicated using the same analysis. Physiological measures were additionally collected and allow for interrogation of the impact of multi-echo independent components preprocessing both in task and rest. Future work on this dataset may provide insight into evoked brain response for cued self-generated thought, International Affective Picture System viewing, resting state dynamics, preprocessing procedures, and more. The dataset is accompanied by experimental code for independent behavioral data collection. PMID- 27996965 TI - Rapid tuning shifts in human auditory cortex enhance speech intelligibility. AB - Experience shapes our perception of the world on a moment-to-moment basis. This robust perceptual effect of experience parallels a change in the neural representation of stimulus features, though the nature of this representation and its plasticity are not well-understood. Spectrotemporal receptive field (STRF) mapping describes the neural response to acoustic features, and has been used to study contextual effects on auditory receptive fields in animal models. We performed a STRF plasticity analysis on electrophysiological data from recordings obtained directly from the human auditory cortex. Here, we report rapid, automatic plasticity of the spectrotemporal response of recorded neural ensembles, driven by previous experience with acoustic and linguistic information, and with a neurophysiological effect in the sub-second range. This plasticity reflects increased sensitivity to spectrotemporal features, enhancing the extraction of more speech-like features from a degraded stimulus and providing the physiological basis for the observed 'perceptual enhancement' in understanding speech. PMID- 27996966 TI - Adenovirus-mediated Foxp3 expression in lung epithelial cells ameliorates acute radiation-induced pneumonitis in mice. AB - Forkhead transcription factor 3 (Foxp3) has a critical role in regulatory T cells (Treg). There are an increasing number of researches concerning the functions of Foxp3 in other cells, including lung epithelial cells besides Treg. However, the roles of Foxp3 in lung epithelial cells remain poorly understood. To examine the potential therapeutic benefits of Foxp3 for lung inflammation, this study investigates the effect of adenovirus-mediated Foxp3 overexpression in a radiation-induced lung damage model. Foxp3-EGFP expressing adenovirus was administered by intratracheal injection three times over 14 days after focal X ray irradiation. To evaluate effects of Foxp3 overexpression in radiation-induced lung inflammation, immune cell profiles of bronchoalveolar lavage (BAL) fluid were analyzed. Foxp3 gene-delivered mice showed significant inhibition of immune cell infiltration, such as eosinophils, lymphocytes, macrophages and neutrophils in BAL fluid. Histopathological analysis also showed that Foxp3 overexpression inhibits inflammatory cell recruitment and collagen deposition in lung tissues. In addition, expression of inflammatory and fibrosis-related genes was decreased in the Foxp3 expression adenovirus-infected group. These results suggest that Foxp3 expression in lungs holds considerable therapeutic potential for attenuating inflammation and fibrosis in radiation-induced lung injury. PMID- 27996967 TI - Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. AB - We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3 4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na+] and [Cl-] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery. PMID- 27996968 TI - RNA sequencing analysis of the developing chicken retina. AB - RNA sequencing transcriptome analysis using massively parallel next generation sequencing technology provides the capability to understand global changes in gene expression throughout a range of tissue samples. Development of the vertebrate retina requires complex temporal orchestration of transcriptional activation and repression. The chicken embryo (Gallus gallus) is a classic model system for studying developmental biology and retinogenesis. Existing retinal transcriptome projects have been critical to the vision research community for studying aspects of murine and human retinogenesis, however, there are currently no publicly available data sets describing the developing chicken retinal transcriptome. Here we used Illumina RNA sequencing (RNA-seq) analysis to characterize the mRNA transcriptome of the developing chicken retina in an effort to identify genes critical for retinal development in this important model organism. These data will be valuable to the vision research community for characterizing global changes in gene expression between ocular tissues and critical developmental time points during retinogenesis in the chicken retina. PMID- 27996969 TI - The nature of prosociality in chimpanzees. AB - An important debate centres around the nature of prosociality in nonhuman primates. Chimpanzees help other individuals in some experimental settings, yet they do not readily share food. One solution to this paradox is that they are motivated to help others provided there are no competing interests. However, benefits to recipients could arise as by-products of testing. Here we report two studies that separate by-product from intended helping in chimpanzees using a GO/NO-GO paradigm. Actors in one group could help a recipient by releasing a food box, but the same action for another group prevented a recipient from being able to get food. We find no evidence for helping-chimpanzees engaged in the test regardless of the effects on their partners. Illusory prosocial behaviour could arise as a by-product of task design. PMID- 27996971 TI - Transcriptome characterisation and simple sequence repeat marker discovery in the seagrass Posidonia oceanica. AB - Posidonia oceanica is an endemic seagrass in the Mediterranean Sea, where it provides important ecosystem services and sustains a rich and diverse ecosystem. P. oceanica meadows extend from the surface to 40 meters depth. With the aim of boosting research in this iconic species, we generated a comprehensive RNA-Seq data set for P. oceanica by sequencing specimens collected at two depths and two times during the day. With this approach we attempted to capture the transcriptional diversity associated with change in light and other depth-related environmental factors. Using this extensive data set we generated gene predictions and identified an extensive catalogue of potential Simple Sequence Repeats (SSR) markers. The data generated here will open new avenues for the analysis of population genetic features and functional variation in P. oceanica. In total, 79,235 contigs were obtained by the assembly of 70,453,120 paired end reads. 43,711 contigs were successfully annotated. A total of 17,436 SSR were identified within 13,912 contigs. PMID- 27996970 TI - A new mouse model of ADHD for medication development. AB - ADHD is a major societal problem with increasing incidence and a stagnant track record for treatment advances. A lack of appropriate animal models has partly contributed to the incremental advance of this field. Hence, our goal was to generate a novel mouse model that could be useful for ADHD medication development. We reasoned that hyperactivity is a core feature of ADHD that could easily be bred into a population, but to what extent other hallmark features of ADHD would appear as correlated responses was unknown. Hence, starting from a heterogeneous population, we applied within-family selection over 16 generations to produce a High-Active line, while simultaneously maintaining an unselected line to serve as the Control. We discovered that the High-Active line demonstrated motor impulsivity in two different versions of the Go/No-go test, which was ameliorated with a low dose of amphetamine, and further displayed hypoactivation of the prefrontal cortex and dysregulated cerebellar vermal activation as indexed by c-Fos immunohistochemical staining. We conclude that the High-Active line represents a valid model for the Hyperactive-Impulsive subtype of ADHD and therefore may be used in future studies to advance our understanding of the etiology of ADHD and screen novel compounds for its treatment. PMID- 27996972 TI - Corrigendum: Australian sea-floor survey data, with images and expert annotations. PMID- 27996974 TI - Remotely sensed high resolution irrigated area mapping in India for 2000 to 2015. AB - India is among the countries that uses a significant fraction of available water for irrigation. Irrigated area in India has increased substantially after the Green revolution and both surface and groundwater have been extensively used. Under warming climate projections, irrigation frequency may increase leading to increased irrigation water demands. Water resources planning and management in agriculture need spatially-explicit irrigated area information for different crops and different crop growing seasons. However, annual, high-resolution irrigated area maps for India for an extended historical record that can be used for water resources planning and management are unavailable. Using 250 m normalized difference vegetation index (NDVI) data from Moderate Resolution Imaging Spectroradiometer (MODIS) and 56 m land use/land cover data, high resolution irrigated area maps are developed for all the agroecological zones in India for the period of 2000-2015. The irrigated area maps were evaluated using the agricultural statistics data from ground surveys and were compared with the previously developed irrigation maps. High resolution (250 m) irrigated area maps showed satisfactory accuracy (R2=0.95) and can be used to understand interannual variability in irrigated area at various spatial scales. PMID- 27996973 TI - Perceptual restoration of masked speech in human cortex. AB - Humans are adept at understanding speech despite the fact that our natural listening environment is often filled with interference. An example of this capacity is phoneme restoration, in which part of a word is completely replaced by noise, yet listeners report hearing the whole word. The neurological basis for this unconscious fill-in phenomenon is unknown, despite being a fundamental characteristic of human hearing. Here, using direct cortical recordings in humans, we demonstrate that missing speech is restored at the acoustic-phonetic level in bilateral auditory cortex, in real-time. This restoration is preceded by specific neural activity patterns in a separate language area, left frontal cortex, which predicts the word that participants later report hearing. These results demonstrate that during speech perception, missing acoustic content is synthesized online from the integration of incoming sensory cues and the internal neural dynamics that bias word-level expectation and prediction. PMID- 27996975 TI - Gene expression profiles and physiological data from mice fed resveratrol enriched rice DJ526. AB - The molecular mechanism underlying lifespan extension by resveratrol remains widely discussed. To help study this mechanism, we previously created resveratrol enriched rice, DJ526, by transferring the resveratrol biosynthesis gene into Dongjin rice. DJ526 accumulates 1.4-1.9 MUg g-1 of resveratrol in its grain and can ameliorates age-related deterioration in mice, as compared to control animals, based on assessments of motor coordination, physical strength and cutaneous tissue aging. Here, we present raw data sets, deposited in public repositories, from microarray analysis and physiological data of mice fed with DJ526 and Dongjin rice and treated with resveratrol. We also provide a method to analyze blood serum at micron levels. These data sets may help other researchers find new clues regarding the etiology of the anti-aging process and signaling pathways induced by resveratrol, rice, or DJ526. PMID- 27996976 TI - Magmas near the critical degassing pressure drive volcanic unrest towards a critical state. AB - During the reawaking of a volcano, magmas migrating through the shallow crust have to pass through hydrothermal fluids and rocks. The resulting magma hydrothermal interactions are still poorly understood, which impairs the ability to interpret volcano monitoring signals and perform hazard assessments. Here we use the results of physical and volatile saturation models to demonstrate that magmatic volatiles released by decompressing magmas at a critical degassing pressure (CDP) can drive volcanic unrest towards a critical state. We show that, at the CDP, the abrupt and voluminous release of H2O-rich magmatic gases can heat hydrothermal fluids and rocks, triggering an accelerating deformation that can ultimately culminate in rock failure and eruption. We propose that magma could be approaching the CDP at Campi Flegrei, a volcano in the metropolitan area of Naples, one of the most densely inhabited areas in the world, and where accelerating deformation and heating are currently being observed. PMID- 27996977 TI - Insect mimicry of plants dates back to the Permian. AB - In response to predation pressure, some insects have developed spectacular plant mimicry strategies (homomorphy), involving important changes in their morphology. The fossil record of plant mimicry provides clues to the importance of predation pressure in the deep past. Surprisingly, to date, the oldest confirmed records of insect leaf mimicry are Mesozoic. Here we document a crucial step in the story of adaptive responses to predation by describing a leaf-mimicking katydid from the Middle Permian. Our morphometric analysis demonstrates that leaf-mimicking wings of katydids can be morphologically characterized in a non-arbitrary manner and shows that the new genus and species Permotettigonia gallica developed a mimicking pattern of forewings very similar to those of the modern leaf-like katydids. Our finding suggests that predation pressure was already high enough during the Permian to favour investment in leaf mimicry. PMID- 27996978 TI - Experimental warming reveals positive feedbacks to climate change in the Eurasian Steppe. AB - Identifying soil microbial feedbacks to increasing temperatures and moisture alterations is critical for predicting how terrestrial ecosystems will respond to climate change. We performed a 5-year field experiment manipulating warming, watering and their combination in a semiarid temperate steppe in northern China. Warming stimulated the abundance of genes responsible for degrading recalcitrant soil organic matter (SOM) and reduced SOM content by 13%. Watering, and warming plus watering also increased the abundance of recalcitrant SOM catabolism pathways, but concurrently promoted plant growth and increased labile SOM content, which somewhat offset SOM loss. The treatments also increased microbial biomass, community complexity and metabolic potential for nitrogen and sulfur assimilation. Both microbial and plant community composition shifted with the treatment conditions, and the sample-to-sample compositional variations of the two communities (pairwise beta-diversity distances) were significantly correlated. In particular, microbial community composition was substantially correlated with the dominant plant species (~0.54 Spearman correlation coefficient), much more than with measured soil indices, affirming a tight coupling between both biological communities. Collectively, our study revealed the direction and underlying mechanisms of microbial feedbacks to warming and suggested that semiarid regions of northern steppes could act as a net carbon source under increased temperatures, unless precipitation increases concurrently. PMID- 27996979 TI - Modeling of soil nitrification responses to temperature reveals thermodynamic differences between ammonia-oxidizing activity of archaea and bacteria. AB - Soil nitrification potential (NP) activities of ammonia-oxidizing archaea and bacteria (AOA and AOB, respectively) were evaluated across a temperature gradient (4-42 degrees C) imposed upon eight soils from four different sites in Oregon and modeled with both the macromolecular rate theory and the square root growth models to quantify the thermodynamic responses. There were significant differences in response by the dominant AOA and AOB contributing to the NPs. The optimal temperatures (Topt) for AOA- and AOB-supported NPs were significantly different (P<0.001), with AOA having Topt>12 degrees C greater than AOB. The change in heat capacity associated with the temperature dependence of nitrification (DeltaCP?) was correlated with Topt across the eight soils, and the DeltaCP? of AOB activity was significantly more negative than that of AOA activity (P<0.01). Model results predicted, and confirmatory experiments showed, a significantly lower minimum temperature (Tmin) and different, albeit very similar, maximum temperature (Tmax) values for AOB than for AOA activity. The results also suggested that there may be different forms of AOA AMO that are active over different temperature ranges with different Tmin, but no evidence of multiple Tmin values within the AOB. Fundamental differences in temperature influenced properties of nitrification driven by AOA and AOB provides support for the idea that the biochemical processes associated with NH3 oxidation in AOA and AOB differ thermodynamically from each other, and that also might account for the difficulties encountered in attempting to model the response of nitrification to temperature change in soil environments. PMID- 27996981 TI - [Future Psychiatry: a "Think Tank" for the Italian Psychiatry]. AB - The Future Psychiatry Project was founded with the goal to address the critical ratio of research/training / clinic. In
a series of regular meetings, each devoted to a specific clinical topic, data and more advanced models for the clinical area in question
will be analyzed in an integrated and multidisciplinary approach and the real possibility of extension of development and
prospects of scientific advances to the clinic and therapy will be evaluated.The primary methodological objective of the Future
Psychiatry meetings is the training method to overcome the common type of teacher/learner classroom teaching, albeit divided
into the various possibilities offered by different types of educational meetings.The structure is informal, with features of intensive
seminars and suggested modes for better interaction.The objective is the "Think Tank", a common space for study and exchange
of knowledge, experiences, opinions and expectations, aimed at producing an integrated and shared dynamic result, that
can provide a real reference point for participants and for all researchers and clinicians engaged in improving their level of updating
and best clinical activity.The first Future Psychiatry meeting was held in Sermoneta (Latina) in the halls of the Castello Caetani
on September 16th to 18th 2010.The chosen topic was "The Future of Depression: the development of knowledge, the evolution
of therapies". The currently most advanced data of research were discussed and developed in their potential to reach a
shared model taking into account the etiological complexity of Depression and to be a real reference to the possibility of application
to real clinical experience.The main guidelines of the current research and major prospects for development of this in the
field Depression have been outlined, also in relation to the ongoing evolution and the future outlook of the models and tools of
therapy. Psychiatrists' clinical needs and expectations in front of the development of scientific knowledge were analyzed in relation
to the translational prospect of a better application of these in the clinical practice of present and future care of Depression. PMID- 27996980 TI - Regional synchrony in full-scale activated sludge bioreactors due to deterministic microbial community assembly. AB - Seasonal community structure and regionally synchronous population dynamics have been observed in natural microbial ecosystems, but have not been well documented in wastewater treatment bioreactors. Few studies of community dynamics in full scale activated sludge systems facing similar meteorological conditions have been done to compare the importance of deterministic and neutral community assembly mechanisms. We subjected weekly activated sludge samples from six regional full scale bioreactors at four wastewater treatment plants obtained over 1 year to Illumina sequencing of 16S ribosomal RNA genes, resulting in a library of over 17 million sequences. All samples derived from reactors treating primarily municipal wastewater. Despite variation in operational characteristics and location, communities displayed temporal synchrony at the individual operational taxonomic unit (OTU), broad phylogenetic affiliation and community-wide scale. Bioreactor communities were dominated by 134 abundant and highly regionally synchronized OTU populations that accounted for over 50% of the total reads. Non-core OTUs displayed abundance-dependent population synchrony. Alpha diversity varied by reactor, but showed a highly reproducible and synchronous seasonal fluctuation. Community similarity was dominated by seasonal changes, but individual reactors maintained minor stable differences after 1 year. Finally, the impacts of mass migration driven by direct biomass transfers between reactors was investigated, but had no significant effect on community similarity or diversity in the sink community. Our results show that population dynamics in activated sludge bioreactors are consistent with niche-driven assembly guided by seasonal temperature fluctuations. PMID- 27996982 TI - [Vortioxetine in the treatment of major depression]. AB - Notwithstanding the high prevalence, functional burden, negative consequences and risk of chronicity of major depressive disorder, few innovative medications have been developed in recent years for the treatment of this heterogeneous disease. Vortioxetine is a multi-modal antidepressant that functions both as serotonin transporter (SERT) inhibitor and as 5-HT3, 5-HT7 and 5-HT1D receptors antagonist, 5-HT1A receptor agonist and 5-HT1B receptor partial agonist. A recent meta analysis of 11 randomized, double-blind, placebo controlled, acute (6-8 weeks) treatment studies has demonstrated the efficacy of vortioxetine 5-20 mg/day in the treatment of depression, with an increasing effect associated with increasing dose. Additionally, vortioxetine 5-20 mg/day has shown efficacy on the whole range of depression symptoms (as demonstrated by the improvement of all single item MADRS scores). Vortioxetine has also been shown effective in the treatment of severe depression and depression with inadequate response to a previous SSRI or SNRI treatment, as well as in the prevention of relapse. In studies designed to assess cognition in depression, vortioxetine showed evidence of improving cognitive performance in patients with acute major depressive disorder. Vortioxetine appears well-tolerated, with very limited effects on weight gain and sexual functioning. The most commonly occurring adverse event (nausea) was generally transitory. PMID- 27996983 TI - [Complicated Grief in DSM-5 era]. AB - An increasing number of data has been recently focused on recognizing pathological grief reactions and on the distinction from physiological processes. Particularly, several studies have supported Complicated Grief (CG) as an independent disorder, in order to define the failure of spontaneous physiological mourning resolution. Upon these studies, the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) with the name of "Persistent Complex Bereavement Disorder". This article aims at retracing the history of clinical research about the physiological and psychopathological processes related to grief and aims at presenting the main scientific studies that have described the features of the CG defining it as a distinct disorder. Similarities and distinctions among CG and Depression, Posttraumatic Stress Disorder and Adjustment Disorder were also reported. PMID- 27996984 TI - [Consensus document: a model of integrated management of patients with psycomotor agitation]. AB - Psychomotor agitation (PMA) is a heterogeneous clinical syndrome associated with a widenumber of pathological conditions. The currently available recommendations and guidelines on PMA correct assessment and management are significantly dishomogeneous and suffer from a lack of standardization, especially regarding pharmacological interventions. Based on this deficiency, and on multidisciplinary nature of PMA, that includes factors shared by different health professionals other than pharmacoeconomic and risk management aspects, we started a project aimed to elaborate a shared model of integrated management for PMA patients. The model, developed by a scientific board and a multidisciplinary panel using the consensus Delphi-RAND method, aims to give indications of good clinical practice for the management of these patients. The present document reports the results of this consensus process, whose main principles are the centrality of the patient, as an active and collaborating subject, the importance of prompt and not coercive interventions able to block the escalation to violence and to allow a correct diagnostic and therapeutic workup, the appropriate use of pharmacological interventions based on the severity of symptoms and the importance of an integrated and harmonized approach by the different professionals involved in PMA management. PMID- 27996985 TI - [Parental Stress and psychopathological traits in children and adolescents. A controlled study]. AB - AIM: Since parental stress and family empowerment were shown to influence children's and adolescents' outcome, especially in the case of psychotherapeutic treatments, the present study aims to deeply explore factors that are likely to impact on stress and empowerment in parents of children with a psychiatric diagnosis. METHODS: Parenting stress and empowerment have been compared between 45 parents of children with a psychiatric disorder and 96 parents of children without psychiatric disorders. RESULTS: Parenting stress appeared to be higher in patients' parents and it varied according to disorder severity, while socio demographic variables seemed to influence the stress levels only to a slight extent. Moreover parental stress and empowerment influenced each other within the parental couple. CONCLUSIONS: Developing interventions aimed to support parenting and to involve fathers in the parent-child relationship, focused on increasing parents empowerment and self-efficacy, could contribute to decrease stress and positively influence children's psychopathology. PMID- 27996986 TI - [Effectiveness of a postnatal psychological treatment for women who had screened positive for depression]. AB - AIM: This study evaluates the effectiveness of a psychological intervention based on a brief cognitive behavioural and psycho-educational treatment for women suffering from post partum depression. METHOD: The sample was recruited within a programme of screening and early intervention for post partum depression risk. 1558 women were screened between the 6th and 12th week after birth. 110 (7.1%) of them resulted positive to the Edinburgh Postnatal Depression Scale (score >=12) and 81 accepted a thorough clinical diagnostic examination through the administration of the Mini International Neuropsychiatric Interview and the self assessment instruments Beck Depression Inventory, State-Trait Anxiety Inventory, Psychological Well-being Scales, Short-Form Health Survey and Positivity Scale. Women who had been confirmed with the diagnosis of major depression episode (N=65; 80.2%) were offered to follow the treatment (10 weekly sessions) and to fill in again the instruments at the end of the treatment and after six months. Out of the 81, 63 women accepted and begun the treatment. RESULTS: 56 (88.9%) women completed treatment and filled in the instruments. Most of them (N=43) completed the instruments even after 6 months. At the end of treatment and after 6 months significant improvements were found in all scores of the instruments used. Furthermore, up to 70% of women who had been treated showed a clinically significant improvement in one or more evaluated outcomes. Such improvements were persistent in women evaluated 6 months after the treatment. CONCLUSION: The results of the study are consistent with studies that in other Countries evaluated, even experimentally, the same intervention or similar interventions with postnatal women and based on cognitive behavioural techniques. Such brief and structured interventions are most likely effective and easily accepted by women who suffer from post partum depression even in the routine practice of Italian health care services. PMID- 27996987 TI - Equine-Assisted Intervention in a child diagnosed with autism spectrum disorder: a case report. AB - An increasing number of studies have shown the beneficial effects of both recreational and therapeutic interventions assistedby animals for children with Autism Spectrum Disorders (ASD). The observed effects are believed to be mainly due to the ability of some animals to positively engage people, thus potentially counteracting the social withdrawal characterizing these subjects. Here we report the case of a child with high-functioning autism who has been included in an Equine-Assisted Intervention (EAI) program for 2 years. In particular, the relationship with the animal was used to encourage child's narrative abilities as a primary means of improving cognition and communication. This case represents a first attempt to theorize the role of human-animal interaction as an adjunct to classic therapeutic strategies in ASD. During the intervention, the child appeared to gradually abandon his attitude to avoid the contact with the present and to hide in imaginative past and future. We propose animal-assisted interventions as complementary approaches capable to facilitate the verbalization of the patient's internal states and to promote psychological well-being through the development of a bond with the animal. PMID- 27996988 TI - ? PMID- 27996990 TI - [The ABSORB III study]. PMID- 27996991 TI - [Aspirin use for the primary prevention of cardiovascular disease and cancer: reflections on the 2016 U.S. Preventive Services Task Force recommendation statement]. PMID- 27996992 TI - [Ten questions awaiting for a definitive answer on the use of non-vitamin K oral anticoagulants in atrial fibrillation]. AB - After more than 3 years from the appearance in Italy of the non-vitamin K antagonist oral anticoagulants (NOACs), their use for the prevention of thromboembolism in atrial fibrillation is still limited, with wide differences in prescriptions across regions. When NOACs became available for clinical practice, several doubts arose about their practical management in the "real world". This article analyses the 10 more frequent questions asked by clinicians dealing with NOACs in their daily activity with atrial fibrillation patients. The answers are synthetic and schematic with pragmatic suggestions that could help clinicians in their doubts. PMID- 27996993 TI - [Referral to cardiac rehabilitation of patients with left ventricular assist devices in Italy]. AB - In recent years, the lack of heart donors caused an increase in the proportion of patients undergoing left ventricular assist device (LVAD) implantation. The clinical complexity of these devices requires a multidisciplinary approach to be extended after hospital discharge. The lack of shared care pathways for these patients may result in an impairment of both of short- and long-term results. Available data show that cardiac rehabilitation (CR) improves physical performance and quality of life. Notwithstanding this, there is a lack of information about its effects on mortality, hospitalizations and major complications. This article is a survey focus on the referral to CR facilities and the number and types of LVAD implanted in Italy. Among the 24 Italian cardiac surgery centers that have been contacted, 22 provided their data: from 2012 to 2014, 260 patients underwent LVAD implantation with an in-hospital post-surgical mortality of 10%, and 77% of patients were admitted to CR facilities. For patients with LVAD, a referral to an inpatient rehabilitation unit may be considered appropriate. PMID- 27996994 TI - [Sudden cardiac arrest in Italian sports facilities in 2015: epidemiological implications of the so-called "Balduzzi decree"]. AB - Under the Italian Law "Legge Balduzzi", which was issued after the sudden cardiac death of professional athletes Pier Mario Morosini and Vigor Bovolenta in 2012, the presence of an automated external defibrillator (AED) and personnel trained to perform cardiopulmonary resuscitation must be available in every Italian sports facility from 2016. In 2015 the national and local press reported 123 cases of sudden cardiac arrests (SCA) occurring in Italian sport facilities, corresponding to an estimated ~0.2-0.4% of all SCA and to ~0.6-1.2% of SCA in public places. The majority of SCA victims were males (93%) and >35 years old (88%, median age 50 years). On the basis of the report of the event on the press, the rate of return of spontaneous circulation was 62% when an AED was used before emergency medical system arrival versus 9% when no bystander cardiopulmonary resuscitation or AED use by lay rescuers was mentioned. These data demonstrated that the Law has the potential to increase the survival to SCA in athletes; however, limiting the obligation of the presence of an AED only to sports facilities is not enough to decrease significantly the incidence of SCA in the general population. PMID- 27996995 TI - [Acute aortic dissection type A: from the past to the present]. AB - Acute aortic dissection type A (AADA) is a disease that has a catastrophic impact on a patient's life. Although refinements in perioperative and surgical care have translated into improved outcomes for patients affected by AADA, hospital mortality after surgery still remains very high, ranging from 15% to 30%. The management of AADA is complex and dictated by the modality of presentation, extent and location of the disease. Attempts to formulate consensus statements and relevant guidelines have identified significant gaps in the AADA knowledge with reference to pathogenesis, appropriate management and configuration for clinical services. Several international registries have been created to generate an evidence base that can address current and future management. In this context, the extensive use of surgical/hybrid approaches in treating AADA should be encouraged as well as more extensive interventions to replace the entire dissected aortic root and aortic arch tissues. In addition, the excellent outcome results recently achieved by high-volume surgical centers with focused expertise in AADA pointed out the need for regionalized super-centers offering specific multidisciplinary aortic surgery programs with dedicated high-specialized surgeons. PMID- 27996996 TI - [ECG for non-competitive sports in childhood: strengths and disputes]. AB - BACKGROUND: Sport is very important for health promotion and conservation. Active lifestyle and regular exercise reduce cardiovascular disease incidence. The Italian Ministry of Health issued the Law Decree no. 243 (10/18/2014) concerning "guidelines for certification about non-competitive sports" to promote safety in sports. This regulation defines the activities for which a certificate is required, the professional actors involved and the clinical exams to be performed according to the patient's health status. In particular, the Law Decree recommends to perform an electrocardiogram (ECG) "at least once in a lifetime", introducing much greater news into pediatric practice. METHODS: We proposed a survey evaluating frequency of ECG implementation for non-competitive sports and cardiovascular diseases incidence was administered to 7 Ligurian pediatricians. RESULTS: The number of ECG/year for pediatrician increased from 10 ECG/year to 50 ECG/year with an indication of suitability to non-competitive sports. One case of QT prolongation and 2 cases of type 1 Brugada ECG pattern were diagnosed. In addition, 3 patients had an atrial septal defect and 3 children had a ventricular septal defect. Forty-three percent of the pediatricians considered useful performing the ECG. CONCLUSIONS: ECG in children has enhanced the positive effects on the community health. However, it remains to be defined in agreement with scientific societies the age at which to perform ECG, the sports for which ECG is required and the cost-benefit ratio for the National Health System and families. PMID- 27996997 TI - [The eye of ECG]. PMID- 27996998 TI - [Management of thromboembolic risk in patients with atrial fibrillation in Italy: follow-up data from the PREFER in AF European Registry]. AB - BACKGROUND: Baseline data of the PREFER in AF (PREvention oF thromboembolic events - European Registry in Atrial Fibrillation) Registry have shown undertreatment of patients with atrial fibrillation (AF), particularly in Italy, where greater difficulties in the management of antithrombotic drugs compared with other European countries were also observed. The aim of the follow-up evaluation was to verify the trends of examined variables after 1 year. METHODS: Clinical features, patterns of prescriptions and patient adherence to guidelines, quality-of-life and treatment satisfaction variables were evaluated at follow-up, similarly to baseline. RESULTS: In Italy, 88% of patients originally enrolled completed the 1-year follow-up. The incidence of major cardiovascular events was lower than at baseline (12.6 vs 30.8%, p<0.0001), but was higher compared with the European mean (12.6 vs 10.4%, p=0.0006). In particular, the incidence of heart failure (5.1 vs 3.6%, p=0.0003) and transient ischemic attacks (1.4 vs 0.7%, p<0.0001) were more frequent in Italy; on the other hand, the incidence of major bleeding was lower in Italy compared with the European mean (1.6 vs 2.4, p=0.0168). Patients with a high thromboembolic risk (CHA 2DS2-VASc >=2) were >80%, similarly to baseline, with a mean CHA2DS2-VASc score of 3.3. However, about one fourth of high-risk patients continued not to be treated with anticoagulant drugs, and treated patients at follow-up were fewer than at baseline (65.1 vs 72.6%, p<0.0001). The percentage of patients treated with non vitamin K antagonist oral anticoagulants (NOACs) was increased at follow-up compared with baseline (3.3 vs 0.3%, p<0.0001), although lower than the European mean (12.6 vs 6.1%, p<0.0001). The number of INR measurements was higher and related to a higher time in therapeutic range (TTR), compared with baseline, and exceeded the European mean TTR. However, similarly to baseline, a higher difficulty in managing anticoagulant therapy and a lower level of satisfaction for treatment was reported in Italian patients compared with the rest of Europe. CONCLUSIONS: The Italian data of the PREFER in AF Registry at 1-year follow-up continue to demonstrate undertreatment of patients with AF at increased risk of stroke and a high grade of unsatisfaction for anticoagulant treatment. The low percentage of patients treated with NOACs did not allow the evaluation of their impact on clinical events and acceptance of therapy. PMID- 27997000 TI - [Psychological evaluation and support in patients with left ventricular assist devices: preliminary data at 6-month follow-up]. AB - BACKGROUND: Heart disease has an impact on patient's identity and self perception. Taking into account the wide literature about psychological aspects before and after heart transplant, it clearly emerges that there is a lack of data and results for patients up to implantation of ventricular assist devices (VAD). The aim of the present study was to explore quality of life and factors correlated with psychological adjustment in patients supported with VAD. METHODS: From February 2013 to August 2014, 18 patients (17 male, mean age 57 years) under clinical evaluation before and after VAD implantation were enrolled. During interviews, patients were assessed with EuroQoL-5D questionnaire to monitor improvement of quality of life before implantation and at 3 and 6 months; critical issues, needs and point of views of patients have been described. RESULTS: A significant improvement in the quality of life score was observed at 3 (score 38 [interquartile range 30-40] vs 75 [60-80], p<0.05) and 6 months (38 [30 40] vs 70 [60-80], p<0.05). Overall, patients' psychological state investigated by the test showed a clear and positive trend. All patients need to empower through complete information about the device, related risks and life expectancy. Interdisciplinary approach improved compliance with therapy. CONCLUSIONS: Successful treatment and efficient psychological care are closely related to assessment and continuous clinical support. This approach ensures a better selection of patients and improves their compliance. Further data are needed to support our preliminary observations and to explore long-term quality of life. PMID- 27996999 TI - [Real life clinical management of nonvalvular atrial fibrillation: results from the Italian epidemiological survey eXperience on the use of rivaroxaban]. AB - BACKGROUND: Atrial fibrillation-related stroke prevention with anticoagulant drugs is currently evolving towards the introduction into clinical practice of the new oral anticoagulants, including rivaroxaban. Our aim was to evaluate in a real-life setting the characteristics and management of patients with nonvalvular atrial fibrillation to whom Italian doctors decided to prescribe rivaroxaban. METHODS: Between January and February 2014, a group of 95 physicians collected aggregate retrospective data, through an online questionnaire, on 1127 patients with nonvalvular atrial fibrillation receiving rivaroxaban. Descriptive statistics were performed based on the data collected. RESULTS: Mean age of patients was 76 years; 20% of patients suffered a previous transient ischemic attack and 16% a previous stroke; 16% was anemic or at risk of bleeding. Over 40% of patients was unable to have a good control of the previous antithrombotic therapy, 22% was also taking antiplatelet drugs or nonsteroidal anti-inflammatory drugs, and 85% had been on a previous stroke prevention therapy; among the latter the main causes for switching to rivaroxaban were patient choice (30%), problems in maintaining the prothromin time-international normalized ratio (PT-INR) within the therapeutic range (27%), and logistic problems in attending the PT-INR follow up visits (20%). Rivaroxaban was prescribed at a dosage of 15 mg in 37.8% of patients and 20 mg in 62.2%; the 15 mg dose was prescribed to 264 of 354 patients with creatinine clearance <50 ml/h (74.6%) and in older patients with more comorbidities. CONCLUSIONS: In this real-life analysis, patient characteristics were similar to those of patients enrolled in large randomized trials, whereas differences in dose prescriptions were observed. PMID- 27997002 TI - ? PMID- 27997001 TI - [A rare cardiomegaly]. AB - We present the case of a patient who came to our attention for enlargement of the cardiac silhouette on chest X-ray. Echocardiography showed moderate diastolic overload of both ventricles with enhanced cardiac output without valvular disease or cardiac shunt that could account for this cardiomegaly. A subsequent abdominal echocardiographic exploration showed an angiomatous transformation of the liver due to diffuse lacunar enlargement of hepatic portal vein branches and arterial venous shunts. Computed tomography and magnetic resonance imaging confirmed the echocardiographic findings. The imaging findings coupled with cutaneous and nasopharyngeal lesions were suggestive of hereditary hemorrhagic telangiectasia (HHT) and the diagnosis was confirmed after the identification of a mutation in the ACVRL1 gene on chromosome 12. HHT is a rare but underestimated vascular disease that can affect different organs, in particular the liver, leading to organ failure requiring transplantation as occurred in our patient. Echocardiography is a useful imaging tool to exclude cardiac abnormalities as a cause of cardiomegaly and to guide the correct diagnosis of a peripheral origin of high cardiac output. PMID- 27997003 TI - [Unpleaseant news.] AB - An impressive amount of new drugs and new indications is arriving in the cancer arena. Financial affordability of so much innovation is difficult everywhere. In Europe, the access to new drugs is not uniform and particularly the patients of Eastern countries frequently cannot receive effective drugs. In the United States financial distress is acknowledged to be a side effect of new expensive drugs. However, we surprisingly found that financial problems are associated with worse cancer patients outcomes also in Italy, where a public health system exists and pays anticancer drugs. Namely, we found that patients with baseline financial problems have a 35% higher risk of worsening their quality of life after treatment and that patients who develop or worsen financial problems during treatment (so-called financial toxicity) have a 20% higher death risk. Financial problems and their potential impact on the outcome of cancer patients should be matter of attention also outside the United States. PMID- 27997004 TI - [Reliability of biomedical research.] AB - In the last century, use of statistics became widespread in biomedical research, making medicine more scientific. However, the misuse of statistical methods may have a negative impact on the reproducibility of experiments, which instead should be at the core of scientific method. The consequence is the so called "replicability crisis", which can affect the reliability of scientific results: if one cannot replicate a published finding, she would hardly trust it. In this paper, firstly, we will provide a short review of the replicability crisis. Indeed, this issue has recently drawn the attention of the entire scientific community. Secondly, we will try to figure out some potential explanation for this phenomenon. Finally, we will show how this problem deeply affects also the reliability of randomized clinical trial, which is fundamental for the medical and regulatory decision-making. PMID- 27997005 TI - [Urgent hospitalization of the cancer patient: problems and opportunity.] AB - Cancer patients are frequently subject to non programmed access to the emergency department or to the oncological services. The main underlying needs are disease related symptoms, treatment-related toxicity and end-of-life issues. Sudden events frequently change the trajectory of the disease and ask for rapid changes of cancer care. Hospital admission is frequently an unavoidable step in clinical history, especially in the last months of life. While an improvement in symptoms management and a tighter patients' control could prevent from the unexpected worsening of clinical conditions, oncologists and emergency physicians are called to a strict cooperation. Clinical informations availability, prompt symptom control, appropriate hospital admission or referral to a palliative care pathway are the key elements of a progress in the care of patients accessing the emergency departments. PMID- 27997006 TI - [Nivolumab in second-line treatment of squamous non-small cell lung cancer.] AB - The treatment of non-small cell lung cancer (NSCLC) is changing dramatically in the last period, considering both non-squamous and squamous disease. In the last five years, the identification of different molecular predictive biomarker (e.g., EGFR, ALK e ROS1) and the utilize of new chemotherapy agents associated or not with antiangiogenics agents (e.g., bevacizumab and nintedanib), allowed the improvement of survival and related responses to these treatments. However, these advances, did not allow an improvement of the same endpoints in the management of NSCLC with squamous cell histology (SCC), where until very recently, docetaxel in monotherapy remained as a corner stone treatment for the second line, although associated with an unfavorable toxicity profile. In recent years, the improvement knowledge of mechanisms of immune response in patients suffering from solid tumors, and especially lung cancer, allowed the identification of different anti PD1 and anti-PDL1 monoclonal antibodies (e.g., atezolizumab, avelumab, nivolumab, pembrolizumab) able to improved survival and response when used in second-line setting. In this review, we report the evidences of nivolumab in NSCLC with squamous histology, through the discussion of data related to phase I, II and III published and searchable via Medline/PubMed. PMID- 27997007 TI - [New perspectives in second-line treatment in non-squamous non-small cell lung cancer]. AB - The treatment options for patients with non-squamous non-small cell lung cancer (NSCLC) in second-line have been limited for a long time. Docetaxel, pemetrexed and erlotinib are the standard second-line treatment. Docetaxel is frequently used although it is associated with an unfavorable safety profile. Recently, the results from the trial CheckMate 057 with nivolumab, an anti-PD-1 inhibitor, has increased the therapeutic options for patients with non-squamous NSCLC in the second-line setting. The results of this randomized phase III trial comparing nivolumab vs docetaxel have deeply changed our current clinical practice. This review explores the recent findings about nivolumab in this setting by analyzing the results of CheckMate 057 trial findings and discussing their implications in clinical practice. Particular attention has been given to efficacy, patients selection, toxicity profile, and quality of life. PMID- 27997008 TI - [Aflibercept: focus on tolerability.] AB - Aflibercept, a potent antiangiogenic agent that exhibits a broad spectrum of antitumor activity, is currently administered in combination with FOLFIRI for the second-line treatment of metastatic colorectal cancer. Here, practical measures to minimize the risk of toxicity in real-world patients are suggested. PMID- 27997009 TI - [Genomics of lung adenocarcinoma: pathogenetic significance and clinical applications.] AB - Diagnostic and therapeutic approaches to non small cell lung cancer (NSCLC), especially adenocarcinoma, have recently undergone dramatic evolution according to the tremendous amount of molecular data collected on this cancer. In fact, the application of oncogenomics has identified novel molecular subtypes of NSCLC and led the way to diagnostic criteria based on the expression of specific genetic alterations that can provide prognostic and specific indications to the molecular targeted therapies. In NSCLC, several genes show "driver" molecular alterations that confer oncogenic potential to progenitor cells through the enrollment of metabolic pathways critical for cell proliferation and tumor development. On the other hand, clinical management of NSCLC with small molecules has undoubtedly provided optimistic results with both a significant increase in overall survival and reduction in therapy-related toxicity including relative complications. Thus, pharmacogenomics, as the newest tool for using the targeted therapy represents the most innovative approach for treatment of this cancer once the molecular aberrations are identified. In particular, the relative mutational status of several driver genes including EGFR, ALK, ROS1 and others, is directly correlated to a better response to thyrosin-kinase inhibitors. Furthermore, other therapeutic strategies with inhibitors of angiogenic receptors, PARP, histone deacetylase, PI3K and HSP90, are intensively studied in pre-clinical models as well as in clinical trials for a potential adoption in clinical practice. The introduction of more advanced techniques for molecular profiling also allows to identify pathogenic variants of many other genes involved in the progression of lung adenocarcinoma with the aim to develop novel molecular targets for pharmacological research. In this review, we will revisit the current applications of oncogenomics in the diagnosis and treatment of this tumor. PMID- 27997010 TI - Sacrum colon-rectal cancer metastasis: microwave ablation for palliative pain treatment. AB - Local treatment of bone metastasis (BM) remains controversial in colon-rectum carcinoma for pain control. A patient developed a sacrum BM 4years after a left colectomy for an adenocarcinoma. Metastasis was treated in one session of CT guided microwave ablation showing good pain control immediately after and on follow-up at four months. PMID- 27997011 TI - ? PMID- 27997016 TI - Optimizing light delivery through fiber bundle in photoacoustic imaging with clinical ultrasound system: Monte Carlo simulation and experimental validation. AB - Translating photoacoustic (PA) imaging into clinical setup is a challenge. We report an integrated PA and ultrasound imaging system by combining the light delivery to the tissue with the ultrasound probe. First, Monte Carlo simulations were run to study the variation in absorbance within tissue for different angles of illumination, fiber-to-probe distance (FPD), and fiber-to-tissue distance (FTD). This is followed by simulation for different depths of the embedded sphere (object of interest). Several probe holders were designed for different light launching angles. Phantoms were developed to mimic a sentinel lymph node imaging scenario. It was observed that, for shallower imaging depths, the variation in signal-to-noise ratio (SNR) values could be as high as 100% depending on the angle of illumination at a fixed FPD and FTD. Results confirm that different light illumination angles are required for different imaging depths to get the highest SNR PA images. The results also validate that one can use Monte Carlo simulation as a tool to optimize the probe holder design depending on the imaging needs. This eliminates a trial-and-error approach generally used for designing a probe holder. PMID- 27997017 TI - Ferric plasmonic nanoparticles, aptamers, and magnetofluidic chips: toward the development of diagnostic surface-enhanced Raman spectroscopy assays. AB - Conjugation of aptamers and their corresponding analytes onto plasmonic nanoparticles mediates the formation of nanoparticle assemblies: molecularly bound nanoclusters that cause a measurable change in the colloid's optical properties. The optimization of a surface-enhanced Raman spectroscopy (SERS) competitive binding assay utilizing plasmonic "target" and magnetic "probe" nanoparticles for the detection of the toxin bisphenol-A (BPA) is presented. These assay nanoclusters were housed inside three types of optofluidic chips patterned with magnetically activated nickel pads, in either a straight or array pattern. Both Fe 2 O 3 and Fe 2 CoO 4 were compared as potential magnetic cores for the silver-coated probe nanoparticles. We found that the Ag @ Fe 2 O 3 particles were, on average, more uniform in size and more stable than Ag @ Fe 2 CoO 4 , whereas the addition of cobalt significantly improved the collection time of particles. Using Raman mapping of the assay housed within the magnetofluidic chips, it was determined that a 1 * 5 array of 50 ?? ? m square nickel pads provided the most uniform SERS enhancement of the assay (coefficient of variation ? 25 % ) within the magnetofluidic chip. Additionally, the packaged assay demonstrated the desired response to BPA, verifying the technology's potential to translate magnetic nanoparticle assays into a user-free optical analysis. PMID- 27997018 TI - Biomedical optics centers: forty years of multidisciplinary clinical translation for improving human health. AB - Despite widespread government and public interest, there are significant barriers to translating basic science discoveries into clinical practice. Biophotonics and biomedical optics technologies can be used to overcome many of these hurdles, due, in part, to offering new portable, bedside, and accessible devices. The current JBO special issue highlights promising activities and examples of translational biophotonics from leading laboratories around the world. We identify common essential features of successful clinical translation by examining the origins and activities of three major international academic affiliated centers with beginnings traceable to the mid-late 1970s: The Wellman Center for Photomedicine (Mass General Hospital, USA), the Beckman Laser Institute and Medical Clinic (University of California, Irvine, USA), and the Medical Laser Center Lubeck at the University of Lubeck, Germany. Major factors driving the success of these programs include visionary founders and leadership, multidisciplinary research and training activities in light-based therapies and diagnostics, diverse funding portfolios, and a thriving entrepreneurial culture that tolerates risk. We provide a brief review of how these three programs emerged and highlight critical phases and lessons learned. Based on these observations, we identify pathways for encouraging the growth and formation of similar programs in order to more rapidly and effectively expand the impact of biophotonics and biomedical optics on human health. PMID- 27997019 TI - Deep imaging in scattering media with selective plane illumination microscopy. AB - In most biological tissues, light scattering due to small differences in refractive index limits the depth of optical imaging systems. Two-photon microscopy (2PM), which significantly reduces the scattering of the excitation light, has emerged as the most common method to image deep within scattering biological tissue. This technique, however, requires high-power pulsed lasers that are both expensive and difficult to integrate into compact portable systems. Using a combination of theoretical and experimental techniques, we show that if the excitation path length can be minimized, selective plane illumination microscopy (SPIM) can image nearly as deep as 2PM without the need for a high powered pulsed laser. Compared to other single-photon imaging techniques like epifluorescence and confocal microscopy, SPIM can image more than twice as deep in scattering media ( ? 10 times the mean scattering length). These results suggest that SPIM has the potential to provide deep imaging in scattering media in situations in which 2PM systems would be too large or costly. PMID- 27997020 TI - [Non-invasive diagnostics in stable coronary artery disease]. PMID- 27997021 TI - [New care model for prevention after acute coronary artery disease]. PMID- 27997022 TI - [Patient organizations in ethical review--a perilous slap in the air]. PMID- 27997023 TI - [Now there are guidelines for patients' participation in clinical teaching]. PMID- 27997024 TI - [Stop grants to researchers whose research can not be reproduced]. PMID- 27997025 TI - [What effect does the full moon have on the physician's on call burden?]. PMID- 27997026 TI - [All physicians must master the language of cell biology and biochemistry]. PMID- 27997027 TI - ["Half-time" for standardized care courses in cancer care]. PMID- 27997029 TI - Reply. PMID- 27997030 TI - Experimental investigation on the accuracy of plastic scintillators and of the spectrum discrimination method in small photon fields. AB - PURPOSE: To investigate the accuracy of output factor measurements using a commercial (Exradin W1, SI) and a prototype, "in-house" developed, plastic scintillation dosimeter (PSD) in small photon fields. METHODS: Repetitive detector-specific output factor OFdet measurements were performed in water (parallel to the CAX) using two W1 PSDs (SI), a PTW microLion, a PTW microDiamond and an unshielded diode D1V (SI) to which Monte Carlo calculated corrections factors were applied. Four sets of repetitive measurements were performed with the W1 PSD positioned parallel and perpendicular to the CAX, each set on a different day, and with analytically calculated volume averaging corrections applied. The W1 OFdet measurements were compared to measurements using an "in house" developed PSD in water (CHUQ) and both were validated against a previously commissioned Monte Carlo beam model in small photon fields. The performance of the spectrum discrimination calibration procedure was evaluated under different fiber orientations and wavelength threshold choices and the impact on the respective OFdet was reported. RESULTS: For all detectors in the study an excellent agreement was observed down to a field size of 1 * 1 cm2 . For the smallest field size of 0.5 * 0.5 cm2 , the W1 PSDs presented OFdet readings higher by 3.8 to 5.0% relative to the mean corrected OFdet of the rest of the detectors and by 5.8 to 6.1% relative to the CHUQ PSD. The repetitive W1 OFdet measurements in water (parallel CAX) were higher by 3.9% relative to the OFdet measurements in Solid WaterTM (perpendicular CAX) even after volume averaging corrections were applied, indicating a potential fiber orientation dependency in small fields. Uncertainties in jaw and detector repositioning as well as source variations with time were estimated to be less than 0.9% (1 sigma) for the W1 under both orientations. The CHUQ PSD agreed with the MC dose calculations in water, for the smallest field size, within 1.1-1.7% before any corrections and within 0.3-0.8% after volume averaging corrections. The spectrum discrimination method provided reproducible Cherenkov spectra under the different calibration set-ups with noisier spectra extracted if the calibration is performed in water and parallel to the CAX. The impact of fiber orientation and wavelength threshold during calibration on OFdet was in general minimal. CONCLUSIONS: Clinically relevant differences were observed between similar scintillator dosimeters in photon fields smaller than 1 * 1 cm2 . Further research on PSDs is needed that can explain the origin of these differences especially related to the Cherenkov spectrum dependencies on the optical fiber technical characteristics. PMID- 27997028 TI - Differential Sensitivity to Ethanol-Induced Circadian Rhythm Disruption in Adolescent and Adult Mice. AB - BACKGROUND: Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus, a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol [EtOH]) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether EtOH has similar effects on circadian regulation during adolescence. METHODS: General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12-hour light, 12-hour dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of EtOH (1.5 g/kg, i.p.) or equal volume saline 15 minutes prior to a 30-minute light pulse at Zeitgeber Time 14 (2 hours into the dark phase) and then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age-group received injections but no light pulse prior to DD. RESULTS: While adults showed the expected decrease in photic phase delays induced by acute EtOH, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. CONCLUSIONS: Collectively, our results indicate that adolescent mice are less sensitive to the effect of EtOH on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults. PMID- 27997032 TI - K27M midline gliomas display malignant progression by imaging and histology. PMID- 27997031 TI - PREDICTORS OF INFANT AND TODDLER BLACK BOYS' EARLY LEARNING: SEIZING OPPORTUNITIES AND MINIMIZING RISKS. AB - Using the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) data set (U.S. Department of Education Institute of Education Sciences, National Center for Education Statistics, 2001), this study examined child, family, and community factors in the early years (infant and toddler years) to predict the cognitive and language outcomes for preschool-age Black boys in relation to Black girls and White boys. Findings indicate that Black children face many challenges, with Black boys experiencing less sensitive parenting as compared to their peers. We live in a highly complex, racialized environment. While there are universal indicators that predict children's preschool outcomes such as strong social positioning and positive parenting, there are, in addition, some indicators that are more beneficial for Black boys' early development, including a stable, less urban home environment with parents engaging in "tough love." PMID- 27997033 TI - Brain mechanisms of abnormal temperature perception in cold allodynia induced by ciguatoxin. AB - OBJECTIVE: Cold allodynia occurs as a major symptom of neuropathic pain states. It remains poorly treated with current analgesics. Ciguatoxins (CTXs), ichthyosarcotoxins that cause ciguatera, produce a large peripheral sensitization to dynamic cold stimuli in Adelta-fibers by activating sodium channels without producing heat or mechanical allodynia. We used CTXs as a surrogate model of cold allodynia to dissect the framework of cold allodynia-activated central pain pathways. METHODS: Reversible cold allodynia was induced in healthy male volunteers by shallow intracutaneous injection of low millimolar concentrations of CTX into the dorsal skin of the forefoot. Cold and warm stimuli were delivered to the treated and the control site using a Peltier-driven thermotest device. Functional magnetic resonance imaging (fMRI) scans were acquired with a 3T MRI scanner using a blood oxygen level-dependent (BOLD) protocol. RESULTS: The CTX induced substantial peripheral sensitization to cooling stimuli in Adelta-fibers is particularly retrieved in BOLD changes due to dynamic temperature changes and less during constant cooling. Brain areas that responded during cold allodynia were almost always located bilaterally and appeared in the medial insula, medial cingulate cortex, secondary somatosensory cortex, frontal areas, and cerebellum. Whereas these areas also produced changes in BOLD signal during the dynamic warming stimulus on the control site, they remained silent during the warming stimuli on the injected site. INTERPRETATION: We describe the defining feature of the cold allodynia pain percept in the human brain and illustrate why ciguatera sufferers often report a perceptual temperature reversal. ANN NEUROL 2017;81:104 116. PMID- 27997035 TI - Regarding "Eteplirsen for the treatment of Duchenne muscular dystrophy". PMID- 27997034 TI - Changes in turnover rather than production regulate biomass of ectomycorrhizal fungal mycelium across a Pinus sylvestris chronosequence. AB - In boreal forest soils, ectomycorrhizal fungi are fundamentally important for carbon (C) dynamics and nutrient cycling. Although their extraradical mycelium (ERM) is pivotal for processes such as soil organic matter build-up and nitrogen cycling, very little is known about its dynamics and regulation. In this study, we quantified ERM production and turnover, and examined how these two processes together regulated standing ERM biomass in seven sites forming a chronosequence of 12- to 100-yr-old managed Pinus sylvestris forests. This was done by determining ERM biomass, using ergosterol as a proxy, in sequentially harvested in-growth mesh bags and by applying mathematical models. Although ERM production declined with increasing forest age from 1.2 to 0.5 kg ha-1 d-1 , the standing biomass increased from 50 to 112 kg ha-1 . This was explained by a drastic decline in mycelial turnover from seven times to one time per year with increasing forest age, corresponding to mean residence times from 25 d up to 1 yr. Our results demonstrate that ERM turnover is the main factor regulating biomass across differently aged forest stands. Explicit inclusion of ERM parameters in forest ecosystem C models may significantly improve their capacity to predict responses of mycorrhiza-mediated processes to management and environmental changes. PMID- 27997036 TI - Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies. AB - OBJECTIVE: Recent studies have shown that positron emission tomography (PET) tracer AV-1451 exhibits high binding affinity for paired helical filament (PHF) tau pathology in Alzheimer's brains. However, the ability of this ligand to bind to tau lesions in other tauopathies remains controversial. Our goal was to examine the correlation of in vivo and postmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimer tauopathy cases. METHODS: We quantified in vivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451 binding assays, and quantitative tau measurements in postmortem brain samples from two progressive supranuclear palsy (PSP) cases and a MAPT P301L mutation carrier. They all underwent [F-18]-AV-1451 PET imaging before death. RESULTS: The three subjects exhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia and midbrain. Neuropathological examination confirmed the PSP diagnosis in the first two subjects; the MAPT P301L mutation carrier had an atypical tauopathy characterized by grain-like tau-containing neurites in gray and white matter with heaviest burden in basal ganglia. In all three cases, autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined, with the exception of entorhinal cortex (reflecting incidental age related neurofibrillary tangles) and neuromelanin-containing neurons in the substantia nigra (off-target binding). The lack of a consistent significant correlation between in vivo [F-18]-AV-1541 retention and postmortem in vitro binding and tau measures in these cases suggests that this ligand has low affinity for tau lesions primarily made of straight tau filaments. INTERPRETATION: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in these non-Alzheimer tauopathies. ANN NEUROL 2017;81:117-128. PMID- 27997038 TI - Inflammation of peripheral tissues and injury to peripheral nerves induce differing effects in the expression of the calcium-sensitive N arachydonoylethanolamine-synthesizing enzyme and related molecules in rat primary sensory neurons. AB - Elevation of intracellular Ca2+ concentration induces the synthesis of N arachydonoylethanolamine (anandamide) in a subpopulation of primary sensory neurons. N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is the only known enzyme that synthesizes anandamide in a Ca2+ -dependent manner. NAPE-PLD mRNA as well as anandamide's main targets, the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1), the inhibitory cannabinoid type 1 (CB1) receptor, and the main anandamide-hydrolyzing enzyme fatty acid amide hydrolase (FAAH), are all expressed by subpopulations of nociceptive primary sensory neurons. Thus, NAPE-PLD, TRPV1, the CB1 receptor, and FAAH could form an autocrine signaling system that could shape the activity of a major subpopulation of nociceptive primary sensory neurons, contributing to the development of pain. Although the expression patterns of TRPV1, the CB1 receptor, and FAAH have been comprehensively elucidated, little is known about NAPE-PLD expression in primary sensory neurons under physiological and pathological conditions. This study shows that NAPE-PLD is expressed by about one-third of primary sensory neurons, the overwhelming majority of which also express nociceptive markers as well as the CB1 receptor, TRPV1, and FAAH. Inflammation of peripheral tissues and injury to peripheral nerves induce differing but concerted changes in the expression pattern of NAPE-PLD, the CB1 receptor, TRPV1, and FAAH. Together these data indicate the existence of the anatomical basis for an autocrine signaling system in a major proportion of nociceptive primary sensory neurons and that alterations in that autocrine signaling by peripheral pathologies could contribute to the development of both inflammatory and neuropathic pain. PMID- 27997037 TI - Descending projections from the basal forebrain to the orexin neurons in mice. AB - The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic sleepiness and cataplexy. The orexin neurons excite wake-promoting neurons in the basal forebrain (BF), and a reciprocal projection from the BF back to the orexin neurons may help promote arousal and motivation. The BF contains at least three different cell types (cholinergic, glutamatergic, and gamma aminobutyric acid (GABA)ergic neurons) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata). Given the neurochemical and anatomical heterogeneity of the BF, we mapped the pattern of BF projections to the orexin neurons across multiple BF regions and neuronal types. We performed conditional anterograde tracing using mice that express Cre recombinase only in neurons producing acetylcholine, glutamate, or GABA. We found that the orexin neurons are heavily apposed by axon terminals of glutamatergic and GABAergic neurons of the substantia innominata (SI) and magnocellular preoptic area, but there was no innervation by the cholinergic neurons. Channelrhodopsin-assisted circuit mapping (CRACM) demonstrated that glutamatergic SI neurons frequently form functional synapses with the orexin neurons, but, surprisingly, functional synapses from SI GABAergic neurons were rare. Considering their strong reciprocal connections, BF and orexin neurons likely work in concert to promote arousal, motivation, and other behaviors. J. Comp. Neurol. 525:1668-1684, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27997039 TI - Euglossine bees mediate only limited long-distance gene flow in a tropical vine. AB - Euglossine bees (Apidae: Euglossini) have long been hypothesized to act as long distance pollinators of many low-density tropical plants. We tested this hypothesis by the analysis of gene flow and genetic structure within and among populations of the euglossine bee-pollinated vine Dalechampia scandens. Using microsatellite markers, we assessed historical gene flow by the quantification of regional-scale genetic structure and isolation by distance among 18 populations, and contemporary gene flow by the estimation of recent migration rates among populations. To assess bee-mediated pollen dispersal on a smaller scale, we conducted paternity analyses within a focal population, and quantified within population spatial genetic structure in four populations. Gene flow was limited to certain nearby populations within continuous forest blocks, whereas drift appeared to dominate on larger scales. Limited long-distance gene flow was supported by within-population patterns; gene flow was biased towards nearby plants, and significant small-scale spatial genetic structure was detected within populations. These findings suggest that, although female euglossine bees might be effective at moving pollen within populations, and perhaps within forest blocks, their contribution to gene flow on the regional scale seems too limited to counteract genetic drift in patchily distributed tropical plants. Among population gene flow might have been reduced following habitat fragmentation. PMID- 27997040 TI - Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. PMID- 27997042 TI - What do we know about the inflammasome in humans? AB - The inflammasome complex is part of the innate immune system, which serves to protect the host against harm from pathogens and damaged cells. It is a term first proposed by Tschopp's group in 2002, with numerous original research articles and reviews published on the topic since. There have been many types of inflammasome identified, but all result in the common pathway of activation of caspases and interleukin 1beta along with possible cell death called pyroptosis. Despite a growing body of research investigating the structure and function of the inflammasome in animal models, there is still limited evidence identifying inflammasome components in human physiology and disease. In this review, we explore the molecular structure and mechanism of activation of the inflammasome with a particular focus on inflammasome complexes expressed in humans. Inflammasome components have been identified in several human peripheral and brain tissues using both in vivo and ex vivo work, and the inflammasome complex has been shown to be associated with several genetic and acquired inflammatory and neoplastic disorders. We discuss the strengths and weaknesses of the information available on the inflammasome with an emphasis on the importance of prioritizing work on human tissue. There is a huge demand for more effective treatments for a number of inflammatory and neurodegenerative diseases. Modulation of the inflammasome has been proposed as a novel treatment for several of these diseases and there are currently clinical trials ongoing to test this theory. PMID- 27997043 TI - Habitat continuity and stepping-stone oceanographic distances explain population genetic connectivity of the brown alga Cystoseira amentacea. AB - Effective predictive and management approaches for species occurring in a metapopulation structure require good understanding of interpopulation connectivity. In this study, we ask whether population genetic structure of marine species with fragmented distributions can be predicted by stepping-stone oceanographic transport and habitat continuity, using as model an ecosystem structuring brown alga, Cystoseira amentacea var. stricta. To answer this question, we analysed the genetic structure and estimated the connectivity of populations along discontinuous rocky habitat patches in southern Italy, using microsatellite markers at multiple scales. In addition, we modelled the effect of rocky habitat continuity and ocean circulation on gene flow by simulating Lagrangian particle dispersal based on ocean surface currents allowing multigenerational stepping-stone dynamics. Populations were highly differentiated, at scales from few metres up to thousands of kilometres. The best possible model fit to explain the genetic results combined current direction, rocky habitat extension and distance along the coast among rocky sites. We conclude that a combination of variable suitable habitat and oceanographic transport is a useful predictor of genetic structure. This relationship provides insight into the mechanisms of dispersal and the role of life-history traits. Our results highlight the importance of spatially explicit modelling of stepping stone dynamics and oceanographic directional transport coupled with habitat suitability, to better describe and predict marine population structure and differentiation. This study also suggests the appropriate spatial scales for the conservation, restoration and management of species that are increasingly affected by habitat modifications. PMID- 27997044 TI - Major host transitions are modulated through transcriptome-wide reprogramming events in Schistocephalus solidus, a threespine stickleback parasite. AB - Parasites with complex life cycles have developed numerous phenotypic strategies, closely associated with developmental events, to enable the exploitation of different ecological niches and facilitate transmission between hosts. How these environmental shifts are regulated from a metabolic and physiological standpoint, however, still remain to be fully elucidated. We examined the transcriptomic response of Schistocephalus solidus, a trophically transmitted parasite with a complex life cycle, over the course of its development in an intermediate host, the threespine stickleback, and the final avian host. Results from our differential gene expression analysis show major reprogramming events among developmental stages. The final host stage is characterized by a strong activation of reproductive pathways and redox homoeostasis. The attainment of infectivity in the fish intermediate host-which precedes sexual maturation in the final host and is associated with host behaviour changes-is marked by transcription of genes involved in neural pathways and sensory perception. Our results suggest that un-annotated and S. solidus-specific genes could play a determinant role in host-parasite molecular interactions required to complete the parasite's life cycle. Our results permit future comparative analyses to help disentangle species-specific patterns of infection from conserved mechanisms, ultimately leading to a better understanding of the molecular control and evolution of complex life cycles. PMID- 27997041 TI - Genetic variation at 16q24.2 is associated with small vessel stroke. AB - OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 * 10-9 ). The lead single nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 * 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 * 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 * 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394. PMID- 27997045 TI - Dynamics of Escherichia coli type I-E CRISPR spacers over 42 000 years. AB - CRISPR-Cas are nucleic acid-based prokaryotic immune systems. CRISPR arrays accumulate spacers from foreign DNA and provide resistance to mobile genetic elements containing identical or similar sequences. Thus, the set of spacers present in a given bacterium can be regarded as a record of encounters of its ancestors with genetic invaders. Such records should be specific for different lineages and change with time, as earlier acquired spacers get obsolete and are lost. Here, we studied type I-E CRISPR spacers of Escherichia coli from extinct pachyderm. We find that many spacers recovered from intestines of a 42 000-year old mammoth match spacers of present-day E. coli. Present-day CRISPR arrays can be reconstructed from palaeo sequences, indicating that the order of spacers has also been preserved. The results suggest that E. coli CRISPR arrays were not subject to intensive change through adaptive acquisition during this time. PMID- 27997046 TI - The on-again, off-again relationship between mitochondrial genomes and species boundaries. AB - The study of reproductive isolation and species barriers frequently focuses on mitochondrial genomes and has produced two alternative and almost diametrically opposed narratives. On one hand, mtDNA may be at the forefront of speciation events, with co-evolved mitonuclear interactions responsible for some of the earliest genetic incompatibilities arising among isolated populations. On the other hand, there are numerous cases of introgression of mtDNA across species boundaries even when nuclear gene flow is restricted. We argue that these seemingly contradictory patterns can result from a single underlying cause. Specifically, the accumulation of deleterious mutations in mtDNA creates a problem with two alternative evolutionary solutions. In some cases, compensatory or epistatic changes in the nuclear genome may ameliorate the effects of mitochondrial mutations, thereby establishing coadapted mitonuclear genotypes within populations and forming the basis of reproductive incompatibilities between populations. Alternatively, populations with high mitochondrial mutation loads may be rescued by replacement with a more fit, foreign mitochondrial haplotype. Coupled with many nonadaptive mechanisms of introgression that can preferentially affect cytoplasmic genomes, this form of adaptive introgression may contribute to the widespread discordance between mitochondrial and nuclear genealogies. Here, we review recent advances related to mitochondrial introgression and mitonuclear incompatibilities, including the potential for cointrogression of mtDNA and interacting nuclear genes. We also address an emerging controversy over the classic assumption that selection on mitochondrial genomes is inefficient and discuss the mechanisms that lead lineages down alternative evolutionary paths in response to mitochondrial mutation accumulation. PMID- 27997047 TI - No evidence for homosubtypic immunity of influenza H3 in Mallards following vaccination in a natural experimental system. AB - The Mallard (Anas platyrhynchos) is an important reservoir species for influenza A viruses (IAV), and in this host, prevalence and virus diversity are high. Studies have demonstrated the presence of homosubtypic immunity, where individuals are unlikely to be reinfected with the same subtype within an autumn season. Further, evidence for heterosubtypic immunity exists, whereby immune responses specific for one subtype offer partial or complete protection against related HA subtypes. We utilized a natural experimental system to determine whether homo- or heterospecific immunity could be induced following experimental vaccination. Thirty Mallards were vaccinated with an inactivated H3, H6 or a sham vaccine and after seroconversion were exposed to naturally infected wild conspecifics. All ducks were infected within 2 days and had both primary and secondary infections. Overall, there was no observable difference between groups; all individuals were infected with H3 and H10 IAV. At the cessation of the experiment, most individuals had anti-NP antibodies and neutralizing antibodies against H10. Not all individuals had H3 neutralizing antibodies. The isolated H3 IAVs revealed genetic dissimilarity to the H3 vaccine strain, specifically substitutions in the vicinity of the receptor-binding site. There was no evidence of vaccine-induced homosubtypic immunity to H3, a likely result of both a poor H3 immune response in the ducks and H3 immune escape. Likewise, there was no observed heterosubtypic protection related to H6 vaccination. This study highlights the need for experimental approaches to assess how exposure to pathogens and resulting immune processes translates to individual and population disease dynamics. PMID- 27997049 TI - Advances in ecological genomics in forest trees and applications to genetic resources conservation and breeding. AB - Forest trees are an unparalleled group of organisms in their combined ecological, economic and societal importance. With widespread distributions, predominantly random mating systems and large population sizes, most tree species harbour extensive genetic variation both within and among populations. At the same time, demographic processes associated with Pleistocene climate oscillations and land use change have affected contemporary range-wide diversity and may impinge on the potential for future adaptation. Understanding how these adaptive and neutral processes have shaped the genomes of trees species is therefore central to their management and conservation. As for many other taxa, the advent of high throughput sequencing methods is expected to yield an understanding of the interplay between the genome and environment at a level of detail and depth not possible only a few years ago. An international conference entitled 'Genomics and Forest Tree Genetics' was held in May 2016, in Arcachon (France), and brought together forest geneticists with a wide range of research interests to disseminate recent efforts that leverage contemporary genomic tools to probe the population, quantitative and evolutionary genomics of trees. An important goal of the conference was to discuss how such data can be applied to both genome-enabled breeding and the conservation of forest genetic resources under land use and climate change. Here, we report discoveries presented at the meeting and discuss how the ecological genomic toolkit can be used to address both basic and applied questions in tree biology. PMID- 27997048 TI - The opsin genes of amazonian cichlids. AB - Vision is a critical sense for organismal survival with visual sensitivities strongly shaped by the environment. Some freshwater fishes with a Gondwanan origin are distributed in both South American rivers including the Amazon and African rivers and lakes. These different habitats likely required adaptations to murky and clear environments. In this study, we compare the molecular basis of Amazonian and African cichlid fishes' visual systems. We used next-generation sequencing of genomes and retinal transcriptomes to examine three Amazonian cichlid species. Genome assemblies revealed six cone opsin classes (SWS1, SWS2B, SWS2A, RH2B, RH2A and LWS) and rod opsin (RH1). However, the functionality of these genes varies across species with different pseudogenes found in different species. Our results support evidence of an RH2A gene duplication event that is shared across both cichlid groups, but which was probably followed by gene conversion. Transcriptome analyses show that Amazonian species mainly express three opsin classes (SWS2A, RH2A and LWS), which likely are a good match to the long-wavelength-oriented light environment of the Amazon basin. Furthermore, analysis of amino acid sequences suggests that the short-wavelength-sensitive genes (SWS2B, SWS2A) may be under selective pressures to shift their spectral properties to a longer-wavelength visual palette. Our results agree with the 'sensitivity hypothesis' where the light environment causes visual adaptation. Amazonian cichlid visual systems are likely adapting through gene expression, gene loss and possibly spectral tuning of opsin sequences. Such mechanisms may be shared across the Amazonian fish fauna. PMID- 27997050 TI - Why UV vision and red vision are important for damselfish (Pomacentridae): structural and expression variation in opsin genes. AB - Coral reefs belong to the most diverse ecosystems on our planet. The diversity in coloration and lifestyles of coral reef fishes makes them a particularly promising system to study the role of visual communication and adaptation. Here, we investigated the evolution of visual pigment genes (opsins) in damselfish (Pomacentridae) and examined whether structural and expression variation of opsins can be linked to ecology. Using DNA sequence data of a phylogenetically representative set of 31 damselfish species, we show that all but one visual opsin are evolving under positive selection. In addition, selection on opsin tuning sites, including cases of divergent, parallel, convergent and reversed evolution, has been strong throughout the radiation of damselfish, emphasizing the importance of visual tuning for this group. The highest functional variation in opsin protein sequences was observed in the short- followed by the long wavelength end of the visual spectrum. Comparative gene expression analyses of a subset of the same species revealed that with SWS1, RH2B and RH2A always being expressed, damselfish use an overall short-wavelength shifted expression profile. Interestingly, not only did all species express SWS1 - a UV-sensitive opsin - and possess UV-transmitting lenses, most species also feature UV-reflective body parts. This suggests that damsels might benefit from a close-range UV-based 'private' communication channel, which is likely to be hidden from 'UV-blind' predators. Finally, we found that LWS expression is highly correlated to feeding strategy in damsels with herbivorous feeders having an increased LWS expression, possibly enhancing the detection of benthic algae. PMID- 27997051 TI - Association of adipocyte enhancer-binding protein 1 with Alzheimer's disease pathology in human hippocampi. AB - Adipocyte enhancer binding protein 1 (AEBP1) activates inflammatory responses via the NF-kappaB pathway in macrophages and regulates adipogenesis in preadipocytes. Up-regulation of AEBP1 in the hippocampi of patients with Alzheimer's disease (AD) has been revealed by microarray analyses of autopsied brains from the Japanese general population (the Hisayama study). In this study, we compared the expression patterns of AEBP1 in normal and AD brains, including in the hippocampus, using immunohistochemistry. The subjects were 24 AD cases and 52 non AD cases. Brain specimens were immunostained with antibodies against AEBP1, tau protein, amyloid beta protein, NF-kappaB, GFAP and Iba-1. In normal brains, AEBP1 immunoreactivity mainly localized to the perikarya of hippocampal pyramidal neurons, and its expression was elevated in the pyramidal neurons and some astrocytes in AD hippocampi. Although AEBP1 immunoreactivity was almost absent in neurons containing neurofibrillary tangles, AEBP1 was highly expressed in neurons with pretangles and in the tau-immunopositive, dystrophic neurites of senile plaques. Nuclear localization of NF-kappaB was also observed in certain AEBP1 positive neurons in AD cases. Comparison of AD and non-AD cases suggested a positive correlation between the expression level of AEBP1 and the degree of amyloid beta pathology. These findings imply that AEBP1 protein has a role in the progression of AD pathology. PMID- 27997052 TI - Coexisting true umbilical cord knot and nuchal cord: possible cumulative increased risk of adverse perinatal outcome. PMID- 27997053 TI - Cervical length screening for prevention of preterm birth in singleton pregnancy with threatened preterm labor: systematic review and meta-analysis of randomized controlled trials using individual patient-level data. AB - OBJECTIVE: Cervical length screening by transvaginal sonography (TVS) has been shown to be a good predictive test for spontaneous preterm birth (PTB) in symptomatic singleton pregnancy with threatened preterm labor (PTL). The aim of this review and meta-analysis of individual participant data was to evaluate the effect of knowledge of the TVS cervical length (CL) in preventing PTB in singleton pregnancies presenting with threatened PTL. METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register and the Cochrane Complementary Medicine Field's Trials Register (May 2016) and reference lists of retrieved studies. Selection criteria included randomized controlled trials of singleton gestations with threatened PTL randomized to management based mainly on CL screening (intervention group), or CL screening with no knowledge of results or no CL screening (control group). Participants included women with singleton gestations at 23 + 0 to 36 + 6 weeks with threatened PTL. We contacted corresponding authors of included trials to request access to the data and perform a meta-analysis of individual participant data. Data provided by the investigators were merged into a master database constructed specifically for the review. The primary outcome was PTB < 37 weeks. Summary measures were reported as relative risk (RR) or as mean difference (MD) with 95% CI. RESULTS: Three trials including a total of 287 singleton gestations with threatened PTL between 24 + 0 and 35 + 6 weeks were included in the meta-analysis, of which 145 were randomized to CL screening with knowledge of results and 142 to no knowledge of CL. Compared with the control group, women who were randomized to the known CL group had a significantly lower rate of PTB < 37 weeks (22.1% vs 34.5%; RR, 0.64 (95% CI, 0.44-0.94); three trials; 287 participants) and a later gestational age at delivery (MD, 0.64 (95% CI, 0.03-1.25) weeks; MD, 4.48 (95% CI, 1.18-8.98) days; three trials; 287 participants). All other outcomes for which there were available data were similar in the two groups. CONCLUSIONS: There is a significant association between knowledge of TVS CL and lower incidence of PTB and later gestational age at delivery in symptomatic singleton gestations with threatened PTL. Given that in the meta-analysis we found a significant 36% reduction in the primary outcome, but other outcomes were mostly statistically similar, further study needs to be undertaken to understand better whether the predictive characteristics of CL screening by TVS can be translated into better clinical management and therefore better outcomes and under what circumstances. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. CRIBADO MEDIANTE LA LONGITUD CERVICAL PARA LA PREVENCION DEL PARTO PRETERMINO EN EMBARAZOS CON FETO UNICO Y RIESGO DE PARTO PREMATURO: REVISION SISTEMATICA Y METAANALISIS DE ENSAYOS CONTROLADOS ALEATORIZADOS HACIENDO USO DE LOS DATOS INDIVIDUALES DE LAS PACIENTES: RESUMEN OBJETIVO: El cribado mediante la longitud cervical obtenida con ecografia transvaginal (ETV) ha demostrado ser una buena prueba para la prediccion del parto pretermino espontaneo (PPTE) en embarazos con feto unico sintomaticos debido a la amenaza de parto pretermino (PPT). El objetivo de esta revision y metaanalisis de los datos de participantes individuales fue evaluar el efecto de medir la longitud cervical (LC) mediante ETV con el fin de prevenir el parto prematuro en embarazos unicos con amenaza de PPT. METODOS: Se realizaron busquedas en los ficheros de ensayos de Cochrane Pregnancy and Childbirth Group y Complementary Medicine Field (mayo de 2016), y en las listas de referencias de los estudios encontrados. Los criterios de seleccion incluyeron ensayos controlados aleatorizados de embarazos con feto unico y riesgo de PPT con aleatorizacion de la paciente basada principalmente en el cribado mediante la LC (grupo de intervencion), el cribado mediante la LC sin conocimiento de los resultados, o sin cribado de LC (grupo de control). Las participantes fueron mujeres embarazadas con feto unico desde las 23 + 0 hasta las 36 + 6 semanas y con riesgo de PPT. Se establecio contacto con los autores de los ensayos incluidos para solicitar el acceso a los datos y llevar a cabo un metaanalisis de los datos de las participantes individualmente. Los datos proporcionados por los investigadores se agregaron a una base de datos maestra creada especificamente para esta revision. El resultado primario fue el PPTE < 37 semanas. Las medidas resumen se reportaron como riesgo relativo (RR) o como diferencia de medias (DM) con IC del 95%. RESULTADOS: En el metaanalisis se incluyeron tres ensayos con un total de 287 embarazos con feto unico y riesgo de PPT entre 24 + 0 y 35 + 6 semanas, de los cuales 145 fueron asignados al azar a un cribado mediante la LC con conocimiento de los resultados y 142 a aquellos para los que se desconocia la LC. En comparacion con el grupo control, las mujeres que fueron asignadas aleatoriamente al grupo en el que se conocia la LC tuvieron una tasa de parto prematuro a < 37 semanas significativamente menor (22,1% vs. 34,5%; RR 0,64 (IC 95%, 0,44-0,94); 3 ensayos; 287 participantes ) y una edad gestacional al momento del parto mas tardia (DM 0,64 (IC 95%, 0.03-1.25) semanas; DM 4,48 (IC 95%, 1,18 8,98) dias; 3 ensayos; 287 participantes). El resto de los resultados para los cuales habia datos disponibles fueron similares en ambos grupos. CONCLUSIONES: Existe una asociacion significativa entre el conocimiento de la LC obtenida mediante ETV y una menor incidencia de PPTE y edad gestacional mas tardia en el momento del parto en embarazos con feto unico sintomaticos debido al riesgo de parto pretermino (PPT). Teniendo en cuenta que en el metaanalisis se encontro una reduccion significativa del 36% en el resultado primario, pero que los otros resultados fueron estadisticamente similares en su mayoria, seran necesarios mas estudios para entender mejor si las propiedades predictivas del cribado mediante la LC obtenida con ETV se pueden traducir en una mejor atencion clinica y por lo tanto mejores resultados dependiendo de las circunstancias. :META: : ,(preterm labor,PTL),(transvaginal sonography,TVS)(spontaneous preterm birth,PTB)?metaPTL,TVS(cervical length,CL)PTB? : CochraneCochrane(20165)?PTL,CL()CLCL()?23 + 036+6PTL?,,meta??37PTB?(relative risk,RR)95%CI(mean difference,MD)? : meta3,28724 + 035+6PTL,145CL,142CL?,CL37PTB[22.1%34.5%;RR,0.64(95% CI,0.44 ~ 0.94);3;287],[MD,0.64(95% CI,0.03 ~ 1.25);MD,4.48(95% CI,1.18 ~ 8.98);3;287]?2,? : PTL,TVS CLPTB?meta36%,,,TVSCL,?. PMID- 27997056 TI - Computational Investigation of the Role Played by Rhodium(V) in the Rhodium(III) Catalyzed ortho-Bromination of Arenes. AB - In this study, M11-L was used to evaluate the feasibility of the formation of rhodium(V) species using the rhodium(III)-catalyzed ortho-bromination of arenes as a model reaction. In most cases for these types of reactions, DFT calculations reveal that the bromination step involves a Br transfer from N-bromosuccinimide to the reacting arylrhodium to form a bromonium intermediate, followed by a Br shift to generate a new C-Br bond, which is more favorable than the previously proposed RhIII /RhV catalytic cycle. The rhodium catalyst remains in its +3 oxidation state throughout. The substituent effects of the reacting arene were studied, and computational results showed that the introduction of electron donating groups on the reacting arene was favorable for this pathway. In contrast, the inclusion of a strong electron-withdrawing group on the aromatic ring would hinder the formation of a bromonium intermediate. Therefore, the RhIII /RhV catalytic cycle is favorable in cases that involve a RhV intermediate, which is generated by oxidative addition with NBS. In this pathway, the C-Br bond is formed by reductive elimination from the RhV intermediate. Additionally, a distortion-interaction analysis model along the reaction pathway was used to explain the directing-group effects. The results showed that the interaction energy controlled the reactivity because of the difference in electronic nature of various directing groups. PMID- 27997055 TI - Role of immediate recurrent laryngeal nerve reconstruction in surgery for thyroid cancers with fixed vocal cords. AB - BACKGROUND: Quality of voice after immediate recurrent laryngeal nerve (RLN) reconstruction in thyroid cancers has not been thoroughly studied. METHODS: Thirteen patients with fixed vocal cords (fixed vocal cord group) and 8 patients with intact or impaired mobile vocal cords (mobile vocal cord group) who had immediate RLN reconstruction simultaneously with total thyroidectomy, and patients who had arytenoid adduction and thyroplasty for vocal cord paralysis caused by previous surgery (arytenoid adduction thyroplasty group) were enrolled in this study. RESULTS: Preoperative phonation efficiency index was significantly lower (p = .008) in the fixed vocal cord group than in the mobile vocal cord group. One year after surgery, all voice parameters of the patients in the fixed vocal cord group had improved, compared with their preoperative data. The fixed vocal cord group had attained satisfactory voice qualities equivalent to those of the mobile vocal cord group in terms of various voice parameters. CONCLUSION: The present results support the idea that immediate RLN reconstruction at the time of surgery for thyroid cancers may spare the need for subsequent arytenoid adduction thyroplasty even in the patients with preoperatively fixed vocal cords. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 427-431, 2017. PMID- 27997054 TI - Stereotactic body radiotherapy for recurrent head and neck cancer: A critical review. AB - The management of patients with recurrent head and neck cancers remains a challenging clinical dilemma. Concerns over toxicity with re-irradiation have limited its use in the clinical setting. Stereotactic Body Radiation Therapy (SBRT) has emerged as a highly conformal and precise type of radiotherapy and has the advantage of sparing normal tissue. Although SBRT is an attractive treatment modality, its use in the clinic is limited, given the technically challenging nature of the procedure. In this review, we attempt to provide a comprehensive overview of the role of re-irradiation in patients with recurrent head and neck cancers, with particular attention to the advent of SBRT and its use with systemic therapies such as cetuximab. In the second portion of this review, we present our systematic review of published experiences with SBRT in recurrent head and neck cancers in an attempt to provide data on response rates (RR), overall survival and toxicity. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 595 601, 2017. PMID- 27997057 TI - Evidence for microbial local adaptation in nature. AB - Local adaptation is an outcome of divergent selection on microbial populations and has been linked to the immense genetic diversity of microbes observed in nature. Because it is difficult to study microbes in their natural habitats, most tests of microbial local adaptation have been performed in model laboratory systems; as a result, microbiologists have limited understanding of local adaptation among natural microbial populations. In this review, we summarize the evidence for microbial local adaptation in nature. Local adaptation has been most frequently studied, and most frequently found, in host-pathogen systems. We argue that more research is needed to understand the prevalence of local adaptation in free-living microbial populations. However, researchers will need to overcome a variety of logistical and conceptual challenges when studying natural microbial local adaptation, including a lack of solid understanding of many microbes' natural histories. We propose strategies to facilitate future natural history research on divergent selection. We also summarize laboratory experimental work investigating the ecological and evolutionary processes leading to local adaptation. Microbiologists' ongoing challenge is to integrate the valuable knowledge gained from laboratory experiments into well-designed field experiments. Such integration will help us understand the prevalence of, and circumstances leading to, local adaptation among microorganisms. PMID- 27997058 TI - Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). AB - The aptly named inflammasomes are powerful signaling complexes that sense inflammatory signals under a myriad of conditions, including those from infections and endogenous sources. The inflammasomes promote inflammation by maturation and release of the pro-inflammatory cytokines, IL-1beta and IL-18. Several inflammasomes have been identified so far, but this review focuses mainly on the NLRP3 inflammasome. By still ill-defined activation mechanisms, a sensor molecule, NLRP3 (NACHT, LRR and PYD domains-containing protein 3), responds to danger signals and rapidly recruits ASC (apoptosis-associated speck-like protein containing a CARD) and pro-caspase-1 to form a large oligomeric signaling platform-the inflammasome. Involvement of the NLRP3 inflammasome in infections, metabolic disorders, autoinflammation, and autoimmunity, underscores its position as a central player in sensing microbial and damage signals and coordinating pro inflammatory immune responses. Indeed, evidence in patients with multiple sclerosis (MS) suggests inflammasome activation occurs during disease. Experiments with the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), specifically describe the NLRP3 inflammasome as critical and necessary to disease development. This review discusses recent studies in EAE and MS which describe associations of inflammasome activation with promotion of T cell pathogenicity, infiltration of cells into the central nervous system (CNS) and direct neurodegeneration during EAE and MS. PMID- 27997059 TI - A brain in flame; do inflammasomes and pyroptosis influence stroke pathology? AB - Stroke is one of the leading causes of death and disability worldwide. Inflammation plays a key role across the time course of stroke, from onset to the post-injury reparative phase days to months later. Several regulatory molecules are implicated in inflammation, but the most established inflammatory mediator of acute brain injury is the cytokine interleukin-1. Interleukin-1 is regulated by large, macromolecular complexes called inflammasomes, which play a central role in cytokine release and cell death. In this review we highlight recent advances in inflammasome research and propose key roles for inflammasome components in the progression of stroke damage. PMID- 27997060 TI - Comparison of Left Atrial Bipolar Voltage and Scar Using Multielectrode Fast Automated Mapping versus Point-by-Point Contact Electroanatomic Mapping in Patients With Atrial Fibrillation Undergoing Repeat Ablation. AB - INTRODUCTION: Bipolar voltage criteria to delineate left atrial (LA) scar have been derived using point-by-point (PBP) contact electroanatomical mapping. It remains unclear how PBP-derived LA scar correlates with multielectrode fast automated mapping (ME-FAM) derived scar. We aimed to correlate scar and bipolar voltages from LA maps created using PBP versus ME-FAM. METHODS AND RESULTS: In consecutive patients undergoing repeat AF ablation, 2 separate LA maps were created using PBP and ME-FAM during sinus rhythm before ablation. Contiguous areas in the LA with a bipolar voltage cutoff of <=0.2 mV represented dense scar; LA scar percentage was calculated for each map. Each LA shell was divided into 9 regions and each region further subdivided into 4 quadrants for additional analysis; mean voltages of all points obtained using PBP versus ME-FAM in each region were compared. Forty maps (20 PBP: mean 228.5 +/- 95.6 points; 20 ME-FAM: 923.0 +/- 382.6 points) were created in 20 patients. Mapping time with ME-FAM was shorter compared with PBP (13.3 +/- 5.3 vs. 34.4 +/- 13.1 minutes; P < 0.001). Mean LA scar percentage was higher with PBP compared with ME-FAM (15.5 +/- 17.1% vs. 12.8 +/- 17.6%; P = 0.04). Mean PBP voltage distribution was lower (compared with ME-FAM) in the septum (0.95 +/- 0.73 vs. 1.46 +/- 0.99 mV; P = 0.009), posterior wall (0.84 +/- 0.42 vs. 1.40 +/- 0.83 mV; P = 0.0008), roof (0.78 +/- 0.80 vs. 1.39 +/- 1.09 mV; P = 0.0003), and right PV-LA junction (0.34 +/- 0.25 vs. 0.59 +/- 0.50 mV; P = 0.01) regions, while voltages were similar in all other LA regions (all P > 0.05). CONCLUSIONS: In AF patients undergoing repeat ablation, bipolar voltage is greater in certain LA segments with ME-FAM compared with PBP mapping. PMID- 27997061 TI - Use of pretreatment serum uric acid level to predict metastasis in locally advanced nasopharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to determine the predictive value of pretreatment serum uric acid (SUA) for metastasis in locally advanced nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy. METHODS: This retrospective study examined 1063 patients with locally advanced NPC. Multivariate survival analysis was used. RESULTS: High pretreatment SUA level (>353.4 MUmol/L) independently predicted distant metastasis-free survival (p = .013) and was associated with high white blood cell (p = .005), lymphocyte counts (p < .001), and male sex (p < 0.001). In addition, SUA levels were significantly elevated in patients with T1 to T3 classification (p = .042). For patients with subsequent lung metastases after treatment, markedly higher pretreatment SUA levels were detected compared with patients who had other distant metastases (p =.012) and patients without distant metastasis (p = .024). CONCLUSION: Pretreatment SUA may be a useful biomarker for evaluating treatment options for patients with locally advanced NPC. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 492-497, 2017. PMID- 27997062 TI - Surgical anatomy, radiological features, and molecular biology of the lumbar intervertebral discs. AB - The intervertebral disc (IVD) is a joint unique in structure and functions. Lying between adjacent vertebrae, it provides both the primary support and the elasticity required for the spine to move stably. Various aspects of the IVD have long been studied by researchers seeking a better understanding of its dynamics, aging, and subsequent disorders. In this article, we review the surgical anatomy, imaging modalities, and molecular biology of the lumbar IVD. Clin. Anat. 30:251 266, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27997063 TI - Investigation of arguments against properly indicated extracapsular dissection in the parotid gland. AB - BACKGROUND: The ideal extent of surgical intervention for benign parotid tumors remains a matter of controversy. The purpose of this study was to examine the existing arguments against extracapsular dissection and present our experience over the last 16 years. METHODS: A retrospective evaluation was carried out on the records of all patients who underwent extracapsular dissection for benign parotid tumors at a tertiary referral center between 2000 and 2015. RESULTS: A total of 1359 cases were included in the study. Temporary postoperative facial palsy was detected in 68 cases (5%), permanent facial palsy in 5 cases (0.37%), and postoperative Frey's syndrome in 31 cases (2.3%). Recurrences of pleomorphic adenomas were shown in 4 cases (0.87%). CONCLUSION: Our analysis could not justify the arguments against correctly indicated implementation of extracapsular dissection and showed that increased performance of this modality was associated with excellent oncologic and functional outcomes. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 498-502, 2017. PMID- 27997064 TI - Nintedanib in Japanese patients with idiopathic pulmonary fibrosis: A subgroup analysis of the INPULSIS(r) randomized trials. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia. Nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo in patients with IPF in two replicate trials (INPULSIS(r)). We examined the efficacy and safety of nintedanib in Japanese patients. METHODS: We conducted pre-specified subgroup analyses of the annual rate of decline in FVC, time to first acute exacerbation (AE), change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and safety using pooled data from the INPULSIS(r) trials for Japanese patients. RESULTS: In the overall population, 76 of 638 and 50 of 423 patients in the nintedanib and placebo groups, respectively, were Japanese. Results in Japanese patients were consistent with those in the overall population. In Japanese patients, the adjusted annual rate of decline in FVC was -135.9 mL/year in the nintedanib group and -267.7 mL/year in the placebo group (difference (95% CI): 131.9 (50.7, 213.1) mL/year); the hazard ratio for the time to first AE was 0.25 (0.06, 1.02); and the adjusted mean change from baseline in SGRQ total score at week 52 was 5.81 in the nintedanib group and 9.68 in the placebo group (difference: -3.87 (-8.51, 0.76)). Diarrhoea and liver-related adverse events were the most common events in the nintedanib group, but were reversible following dose reduction, drug interruption or symptomatic therapy. CONCLUSION: The present results indicate that the efficacy and safety of nintedanib in Japanese patients are comparable with those in the overall population. PMID- 27997065 TI - Depression and severity of substance dependence among heroin dependent patients with ADHD symptoms. AB - BACKGROUND AND OBJECTIVES: Comorbid attention deficit hyperactivity disorder (ADHD) symptoms are highly prevalent among heroin-dependent patients. We aim to investigate differences in dependence severity, depression, and quality of life between heroin-dependent patients with and without ADHD-screened positive. METHODS: Heroin-dependent participants (n = 447) entering methadone maintenance treatment were divided into ADHD-screened positive (ADHD-P) and ADHD-screened negative (ADHD-N) groups according to scores of Adult ADHD Self-Report Scale (ASRS). Mini-International Neuropsychiatric Interview was used to identify current and lifetime depressive episodes and suicidality. Substance use disorder, depression, family support, and quality of life in two groups were also assessed. RESULTS: About 7.8% (n = 35) scored 24 or higher of ASRS indicating highly likely Adult ADHD. More heroin-dependent patients of ADHD-P had a current depressive episode (p = .02). They had higher Center for Epidemiological Studies Depression (CESD) scores (p = .003), and more severe heroin dependence (p = .006). Poorer family support and quality of life in physical, and psychological domains were found in patients of ADHD-P compared to ADHD-N. DISCUSSION AND CONCLUSIONS: Heroin-dependent patients of ADHD-P represent a vulnerable minority. They were comorbid with regard to depression, greater substance dependence severity, and poorer quality of life. SCIENTIFIC SIGNIFICANCE: Assessment for ADHD symptoms in heroin-dependent patients may be indicated for the effective management of the complex problems of these patients. (Am J Addict 2017;26:26-33). PMID- 27997066 TI - Historical processes and contemporary ocean currents drive genetic structure in the seagrass Thalassia hemprichii in the Indo-Australian Archipelago. AB - Understanding spatial patterns of gene flow and genetic structure is essential for the conservation of marine ecosystems. Contemporary ocean currents and historical isolation due to Pleistocene sea level fluctuations have been predicted to influence the genetic structure in marine populations. In the Indo Australian Archipelago (IAA), the world's hotspot of marine biodiversity, seagrasses are a vital component but population genetic information is very limited. Here, we reconstructed the phylogeography of the seagrass Thalassia hemprichii in the IAA based on single nucleotide polymorphisms (SNPs) and then characterized the genetic structure based on a panel of 16 microsatellite markers. We further examined the relative importance of historical isolation and contemporary ocean currents in driving the patterns of genetic structure. Results from SNPs revealed three population groups: eastern Indonesia, western Indonesia (Sunda Shelf) and Indian Ocean; while the microsatellites supported five population groups (eastern Indonesia, Sunda Shelf, Lesser Sunda, Western Australia and Indian Ocean). Both SNPs and microsatellites showed asymmetrical gene flow among population groups with a trend of southwestward migration from eastern Indonesia. Genetic diversity was generally higher in eastern Indonesia and decreased southwestward. The pattern of genetic structure and connectivity is attributed partly to the Pleistocene sea level fluctuations modified to a smaller level by contemporary ocean currents. PMID- 27997067 TI - Rotenone and elevated extracellular potassium concentration induce cell-specific fibrillation of alpha-synuclein in axons of cholinergic enteric neurons in the guinea-pig ileum. AB - BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder that results in the widespread loss of select classes of neurons throughout the nervous system. The pathological hallmarks of Parkinson's disease are Lewy bodies and neurites, of which alpha-synuclein fibrils are the major component. alpha Synuclein aggregation has been reported in the gut of Parkinson's disease patients, even up to a decade before motor symptoms, and similar observations have been made in animal models of disease. However, unlike the central nervous system, the nature of alpha-synuclein species that form these aggregates and the classes of neurons affected in the gut are unclear. We have previously reported selective expression of alpha-synuclein in cholinergic neurons in the gut (J Comp Neurol. 2013; 521:657), suggesting they may be particularly vulnerable to degeneration in Parkinson's disease. METHODS: In this study, we used immunohistochemistry to detect alpha-synuclein oligomers and fibrils via conformation-specific antibodies after rotenone treatment or prolonged exposure to high [K+ ] in ex vivo segments of guinea-pig ileum maintained in organotypic culture. KEY RESULTS: Rotenone and prolonged raising of [K+ ] caused accumulation of alpha-synuclein fibrils in the axons of cholinergic enteric neurons. This took place in a time- and, in the case of rotenone, concentration-dependent manner. Rotenone also caused selective necrosis, indicated by increased cellular autofluorescence, of cholinergic enteric neurons, labeled by ChAT immunoreactivity, also in a concentration-dependent manner. CONCLUSIONS & INFERENCES: To our knowledge, this is the first report of rotenone causing selective loss of a neurochemical class in the enteric nervous system. Cholinergic enteric neurons may be particularly susceptible to Lewy pathology and degeneration in Parkinson's disease. PMID- 27997068 TI - A response to 'Trends in tropical tree growth: reanalysis confirms earlier findings'. AB - We recently demonstrated that growth trends from tree rings from Van Der Sleen et al. (Nature Geoscience, 8, 2015, 24) and Groenendijk et al. (Global Change Biology, 21, 2015, 3762) are affected by demographic biases. In particular, clustered age distributions led to a negative bias in their growth trends. In a response, they challenge our analysis and present an alternative correction approach. We here show that their arguments are incorrect and based on misunderstanding of our analysis and that their alternative approach does not work. PMID- 27997069 TI - Urbanization drives community shifts towards thermophilic and dispersive species at local and landscape scales. AB - The increasing conversion of agricultural and natural areas to human-dominated urban landscapes is predicted to lead to a major decline in biodiversity worldwide. Two conditions that typically differ between urban environments and the surrounding landscape are increased temperature, and high patch isolation and habitat turnover rates. However, the extent and spatial scale at which these altered conditions shape biotic communities through selection and/or filtering on species traits are currently poorly understood. We sampled carabid beetles at 81 sites in Belgium using a hierarchically nested sampling design wherein three local-scale (200 * 200 m) urbanization levels were repeatedly sampled across three landscape-scale (3 * 3 km) urbanization levels. First, we showed that communities sampled in the most urbanized locations and landscapes displayed a distinct species composition at both local and landscape scale. Second, we related community means of species-specific thermal preferences and dispersal capacity (based on European distribution and wing morphology, respectively) to the urbanization gradients. We showed that urban communities consisted on average of species with a preference for higher temperatures and with better dispersal capacities compared to rural communities. These shifts were caused by an increased number of species tolerating higher temperatures, a decreased richness of species with low thermal preference, and an almost complete depletion of species with very low-dispersal capacity in the most urbanized localities. Effects of urbanization were most clearly detected at the local scale, although more subtle effects could also be found at the scale of entire landscapes. Our results demonstrate that urbanization may fundamentally and consistently alter species composition by exerting a strong filtering effect on species dispersal characteristics and favouring replacement by warm-dwelling species. PMID- 27997070 TI - A fresh look at IBS-opportunities for systems medicine approaches. AB - NeuroGUT is a EU-funded initial training network (ITN) of 14 research projects in neurogastroenterology that have employed an equal number of early-stage researchers. Neurogut trainees have-among other activities-attended an international conference on irritable bowel syndrome (IBS) in Bologna in 2016 and were asked to critically review and evaluate the current knowledge on IBS for their respective research activities, and to state what they were missing. Most appreciated were the topics brain imaging of gut activity, the role of the gut microbiota, the pharmacology of gut functions, the IBS-IBD interrelation, the new Rome IV criteria, the role of gas, and the placebo response in functional disorders. Missed were more detailed coverage of high-resolution manometry, functional brain imaging, advanced "systems medicine" approaches and bioinformatics technology, better sub-classification of IBS patients, and the development of disease biomarkers, extended at the molecular (genetic/epigenetic, proteonomic) level. They summarize that despite excellent specialized research, there is a gap open that should be filled with systems medicine. For this, it would be necessary that medical research learns even more from the data sciences and other basic disciplines, for example, information technology and system biology, and also welcomes a change in paradigm that enhances open sharing of data, information, and resources. PMID- 27997071 TI - Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference. AB - Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end-stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence-based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision-making process were considered. This report summarizes the group's deliberations. PMID- 27997072 TI - Structural and performance characteristics of representative anion exchange resins used for weak partitioning chromatography. AB - Weak partitioning chromatography (WPC) has been proposed for the purification of monoclonal antibodies using an anion exchange (AEX) resin to simultaneously remove both acidic and basic protein impurities. Despite potential advantages, the relationship between resin structure and WPC performance has not been evaluated systematically. In this work, we determine the structure of representative AEX resins (Fractogel(r) EMD TMAE HiCap, Q Sepharose FF, and POROS 50 HQ) using transmission electron microscopy and inverse size exclusion chromatography and characterize protein interactions while operating these resins under WPC conditions using two mAb monomers, a mAb dimer, mAb multimers, and BSA as model products and impurities. We determine the isocratic elution behavior of the weakly bound monomer and dimer species and the adsorptive and mass transfer properties of the strongly bound multimers and BSA by confocal laser scanning microscopy. The results show that for each resin, using the product Kp value as guidance, salt, and pH conditions can be found where mAb multimers and BSA are simultaneously removed. Isocratic elution and adsorption mechanisms are, however, different for each resin and for the different components. Under WPC conditions, the Fractogel resin exhibited very slow diffusion of both mAb monomer and dimer species but fast adsorption for both mAb multimers and BSA with high capacity for BSA, while the Sepharose resin, because of its small pore size, was unable to effectively remove mAb multimers. The POROS resin was instead able to bind both multimers and BSA effectively, while exhibiting a greater resolution of mAb monomer and dimer species. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:425-434, 2017. PMID- 27997073 TI - Effects of Growth on Muscle, Tendon, and Aponeurosis Tissues in Rabbit Shank Musculature. AB - There exist several studies using morphological analyses of skeletal muscles to obtain a better understanding of muscle structure. The structural information obtained are primarily determined from single muscle components using individual animals of discrete ages. Further, little is known about changing dimensions of the aponeurosis, which is an important load-transferring interface in muscle mechanics. Thus, the aim of the present study was to determine how the muscle, tendon, and particularly the aponeurosis geometry of the rabbit shank musculature (M. soleus, M. extensor digitorum longus, and M. plantaris) change during growth. In doing so, morphological studies on muscles of eighty-nine female rabbits aged between 18 and 108 days were conducted. We found an almost linear increase over time in all of the geometrical parameters observed. The aponeurosis of the muscles exhibited lower growth rates in width than in length. The distal and proximal aponeurosis areas were nearly identical. The ratio of aponeurosis area to the physiological cross-sectional area was 2.54, 2.54, and 1.88 for M. soleus, M. extensor digitorum longus, and M. plantaris, respectively. M. extensor digitorum longus and M. soleus exhibited a nearly similar tendon-muscle fascicle length ratio during growth, increasing from 2.86 to 5.30 and 3.48 to 6.16, respectively. Interestingly, the tendon-muscle fascicle length ratio of the M. plantaris started initially with a much higher value (~8) and increased to ~18. Taken together, these results provide insight into the structure of the muscle tendon complex and thus, a general understanding of muscle growth. Anat Rec, 300:1123-1136, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27997074 TI - Production of 8,11-dihydroxy and 8-hydroxy unsaturated fatty acids from unsaturated fatty acids by recombinant Escherichia coli expressing 8,11-linoleate diol synthase from Penicillium chrysogenum. AB - Hydroxy unsaturated fatty acids can be used as antimicrobial surfactants. 8,11 Linoleate diol synthase (8,11-LDS) catalyzes the conversion of unsaturated fatty acid to 8-hydroperoxy unsaturated fatty acid, and it is subsequently isomerized to 8,11-dihydroxy unsaturated fatty acid by the enzyme. The optimal reaction conditions of recombinant Escherichia coli expressing Penicillium chrysogenum 8,11-LDS for the production of 8,11-dihydroxy-9,12(Z,Z)-octadecadienoic acid (8,11-DiHODE), 8,11-dihydroxy-9,12,15(Z,Z,Z)-octadecatrienoic acid (8,11 DiHOTrE), 8-hydroxy-9(Z)-hexadecenoic acid (8-HHME), and 8-hydroxy-9(Z) octadecenoic acid (8-HOME) were pH 7.0, 25 degrees C, 10 g/L linoleic acid, and 20 g/L cells; pH 6.0, 25 degrees C, 6 g/L alpha-linolenic acid, and 60 g/L cells; pH 7.0, 25 degrees C, 8 g/L palmitoleic acid, and 25 g/L cells; and pH 8.5, 30 degrees C, 6 g/L oleic acid, and 25 g/L cells, respectively. Under these optimized conditions, the recombinant cells produced 6.0 g/L 8,11-DiHODE for 60 min, with a conversion of 60% (w/w) and a productivity of 6.0 g/L/h; 4.3 g/L 8,11 DiHOTrE for 60 min, with a conversion of 72% (w/w) and a productivity of 4.3 g/L/h; 4.3 g/L 8-HHME acid for 60 min, with a conversion of 54% (w/w) and a productivity of 4.3 g/L/h; and 0.9 g/L 8-HOME for 30 min, with a conversion of 15% (w/w) and a productivity of 1.8 g/L/h. To best of our knowledge, this is the first report on the biotechnological production of 8,11-DiHODE, 8,11-DiHOTrE, 8 HHME, and 8-HOME. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:390-396, 2017. PMID- 27997075 TI - Vascular Canals in Permanent Hyaline Cartilage: Development, Corrosion of Nonmineralized Cartilage Matrix, and Removal of Matrix Degradation Products. AB - Core areas in voluminous pieces of permanent cartilage are metabolically supplied via vascular canals (VCs). We studied cartilage corrosion and removal of matrix degradation products during the development of VCs in nose and rib cartilage of piglets. Conventional staining methods were used for glycosaminoglycans, immunohistochemistry was performed to demonstrate collagens types I and II, laminin, Ki-67, von Willebrand factor, VEGF, macrophage marker MAC387, S-100 protein, MMPs -2,-9,-13,-14, and their inhibitors TIMP1 and TIMP2. VCs derived from connective tissue buds that bulged into cartilage matrix ("perichondrial papillae", PPs). Matrix was corroded at the tips of PPs or resulting VCs. Connective tissue stromata in PPs and VCs comprised an axial afferent blood vessel, peripherally located wide capillaries, fibroblasts, newly synthesized matrix, and residues of corroded cartilage matrix (collagen type II, acidic proteoglycans). Multinucleated chondroclasts were absent, and monocytes/macrophages were not seen outside the blood vessels. Vanishing acidity characterized areas of extracellular matrix degradation ("preresorptive layers"), from where the dismantled matrix components diffused out. Leached-out material stained in an identical manner to intact cartilage matrix. It was detected in the stroma and inside capillaries and associated downstream veins. We conclude that the delicate VCs are excavated by endothelial sprouts and fibroblasts, whilst chondroclasts are specialized to remove high volumes of mineralized cartilage. VCs leading into permanent cartilage can be formed by corrosion or inclusion, but most VCs comprise segments that have developed in either of these ways. Anat Rec, 300:1067-1082, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27997076 TI - Biological pretreatment of corn stover with Phlebia brevispora NRRL-13108 for enhanced enzymatic hydrolysis and efficient ethanol production. AB - Biological pretreatment of lignocellulosic biomass by white-rot fungus can represent a low-cost and eco-friendly alternative to harsh physical, chemical, or physico-chemical pretreatment methods to facilitate enzymatic hydrolysis. In this work, solid-state cultivation of corn stover with Phlebia brevispora NRRL-13018 was optimized with respect to duration, moisture content and inoculum size. Changes in composition of pretreated corn stover and its susceptibility to enzymatic hydrolysis were analyzed. About 84% moisture and 42 days incubation at 28 degrees C were found to be optimal for pretreatment with respect to enzymatic saccharification. Inoculum size had little effect compared to moisture level. Ergosterol data shows continued growth of the fungus studied up to 57 days. No furfural and hydroxymethyl furfural were produced. The total sugar yield was 442 +/- 5 mg/g of pretreated corn stover. About 36 +/- 0.6 g ethanol was produced from 150 g pretreated stover per L by fed-batch simultaneous saccharification and fermentation (SSF) using mixed sugar utilizing ethanologenic recombinant Eschericia coli FBR5 strain. The ethanol yields were 32.0 +/- 0.2 and 38.0 +/- 0.2 g from 200 g pretreated corn stover per L by fed-batch SSF using Saccharomyces cerevisiae D5A and xylose utilizing recombinant S. cerevisiae YRH400 strain, respectively. This research demonstrates that P. brevispora NRRL 13018 has potential to be used for biological pretreatment of lignocellulosic biomass. This is the first report on the production of ethanol from P. brevispora pretreated corn stover. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:365-374, 2017. PMID- 27997077 TI - Bone Microstructure of Pareiasaurs (Parareptilia) from the Karoo Basin, South Africa: Implications for Growth Strategies and Lifestyle Habits. AB - Numerous morphological studies have been carried out on pareiasaurs; yet their taxonomy and biology remain incompletely understood. Earlier works have suggested that these herbivorous parareptiles had a short juvenile period as compared to the duration of adulthood. Several studies further suggested an (semi-) aquatic lifestyle for these animals, but more recent investigations have proposed a rather terrestrial habitat. Bone paleohistology is regarded as a powerful tool to assess aspects of tetrapod paleobiology, but few studies have been conducted on pareiasaurs. The present study assesses intra and inter-specific histovariability of pareiasaurs and provides fresh insights into their paleobiology, thereby permitting a re-evaluation of earlier hypotheses. Our sample comprises various skeletal elements and several specimens covering most of the taxonomic and stratigraphic spectrum of South African pareiasaurs, including large and basal forms from the Middle Permian, as well as smaller and more derived forms from the Late Permian. Our results concerning size of elements and histological tissues show that for pareiasaurs, element size is not a good indicator of ontogenetic age, and furthermore, suggest that the specific diversity of the Middle Permian pareiasaurs may have been underestimated. The bone histology of these animals shows that they experienced a relatively rapid growth early in ontogeny. Periosteal growth later slowed down, but seems to have been protracted for several years during adulthood. Pareiasaur bone microanatomy is unusual for continental tetrapods, in having spongious stylopod diaphyses and thin compact cortices. Rigorous paleoecological interpretations are thus limited since no modern analogue exists for these animals. Anat Rec, 300:1039-1066, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27997078 TI - Hiding in Plain Sight: A Case of Ornithine Transcarbamylase Deficiency Unmasked Post-Liver Transplantation. AB - Ornithine transcarbamylase deficiency represents the most common inherited defect of the urea cycle. This enzyme, predominantly found in the liver, plays a crucial role in recycling free ammonia, with deficiencies often leading to fatal complications. Here, we present the case of a 63-year-old man with alcoholic cirrhosis who underwent orthotopic liver transplantation, gradual worsening of his mental status, and progressive elevation of ammonia levels. Liver allograft function was deemed normal, raising concern for a donor-derived metabolic disorder of the urea cycle. Evaluation of the donor patient's blood revealed that the donor was heterozygous for the OTC gene. Posttransplantation changes in mental status should prompt a clinician to consider the most likely causes; however, once these have been ruled out, it is important to consider the less common causes of metabolic derangements. The rarity of these disorders makes expertise of diagnosis, standardization of evaluation, and treatment strategies challenging. PMID- 27997079 TI - Optimization of enzymatic hydrolysis and fermentation conditions for improved bioethanol production from potato peel residues. AB - The aim of this work was the optimization of the enzyme hydrolysis of potato peel residues (PPR) for bioethanol production. The process included a pretreatment step followed by an enzyme hydrolysis using crude enzyme system composed of cellulase, amylase and hemicellulase, produced by a mixed culture of Aspergillus niger and Trichoderma reesei. Hydrothermal, alkali and acid pretreatments were considered with regards to the enhancement of enzyme hydrolysis of potato peel residues. The obtained results showed that hydrothermal pretreatment lead to a higher enzyme hydrolysis yield compared to both acid and alkali pretreatments. Enzyme hydrolysis was also optimized for parameters such as temperature, pH, substrate loading and surfactant loading using a response surface methodology. Under optimized conditions, 77 g L-1 of reducing sugars were obtained. Yeast fermentation of the released reducing sugars led to an ethanol titer of 30 g L-1 after supplementation of the culture medium with ammonium sulfate. Moreover, a comparative study between acid and enzyme hydrolysis of potato peel residues was investigated. Results showed that enzyme hydrolysis offers higher yield of bioethanol production than acid hydrolysis. These results highlight the potential of second generation bioethanol production from potato peel residues treated with onsite produced hydrolytic enzymes. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:397-406, 2017. PMID- 27997080 TI - Prevention of Allograft Rejection by Use of Regulatory T Cells With an MHC Specific Chimeric Antigen Receptor. AB - CD4+ CD25high FOXP3+ regulatory T cells (Tregs) are involved in graft-specific tolerance after solid organ transplantation. However, adoptive transfer of polyspecific Tregs alone is insufficient to prevent graft rejection even in rodent models, indicating that graft-specific Tregs are required. We developed a highly specific chimeric antigen receptor that recognizes the HLA molecule A*02 (referred to as A2-CAR). Transduction into natural regulatory T cells (nTregs) changes the specificity of the nTregs without alteration of their regulatory phenotype and epigenetic stability. Activation of nTregs via the A2-CAR induced proliferation and enhanced the suppressor function of modified nTregs. Compared with nTregs, A2-CAR Tregs exhibited superior control of strong allospecific immune responses in vitro and in humanized mouse models. A2-CAR Tregs completely prevented rejection of allogeneic target cells and tissues in immune reconstituted humanized mice in the absence of any immunosuppression. Therefore, these modified cells have great potential for incorporation into clinical trials of Treg-supported weaning after allogeneic transplantation. PMID- 27997081 TI - Uterine focal adhesion dynamics during pregnancy in a marsupial (Sminthopsis crassicaudata; Dasyuridae). AB - Alterations to the basal attachment points between the epithelium of the uterus and the underlying tissue in early pregnancy affect how easily the epithelium can be invaded by the implanting embryo. Attachment points- focal adhesions- disassemble to facilitate highly invasive implantation in rats, but species with less invasive implantation, including marsupials, may require different basal alterations for successful pregnancy. Here we used immunofluorescence microscopy and Western blotting to conduct the first study of basal plasma membrane dynamics in the uterus during marsupial pregnancy. We describe localisation patterns of two key anchoring molecules, talin and paxillin, throughout pregnancy in the fat tailed dunnart (Sminthopsis crassicaudata; Dasyuridae). Basal staining of both molecules occurs in early pregnancy, as it does in the rat. However, unlike rats, there is strong basal localisation of talin and paxillin just before implantation in S. crassicaudata, indicating that focal adhesions do not disassemble during pregnancy in this species, and that molecular reinforcement of the epithelium may be a maternal strategy to regulate invasion. Additionally, talin and paxillin do not co-localise at all stages of pregnancy as they do in the rat. Different localisation patterns among mammalian species demonstrate that not all early pregnancy changes are ubiquitous in mammalian pregnancy, as changes to the basal plasma membrane of the epithelium, in particular, may instead be dependent on mode of implantation. Anat Rec, 300:1150-1159, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27997082 TI - Genetic effects of landscape, habitat preference and demography on three co occurring turtle species. AB - Expanding the scope of landscape genetics beyond the level of single species can help to reveal how species traits influence responses to environmental change. Multispecies studies are particularly valuable in highly threatened taxa, such as turtles, in which the impacts of anthropogenic change are strongly influenced by interspecific differences in life history strategies, habitat preferences and mobility. We sampled approximately 1500 individuals of three co-occurring turtle species across a gradient of habitat change (including varying loss of wetlands and agricultural conversion of upland habitats) in the Midwestern USA. We used genetic clustering and multiple regression methods to identify associations between genetic structure and permanent landscape features, past landscape composition and landscape change in each species. Two aquatic generalists (the painted turtle, Chrysemys picta, and the snapping turtle Chelydra serpentina) both exhibited population genetic structure consistent with isolation by distance, modulated by aquatic landscape features. Genetic divergence for the more terrestrial Blanding's turtle (Emydoidea blandingii), on the other hand, was not strongly associated with geographic distance or aquatic features, and Bayesian clustering analysis indicated that many Emydoidea populations were genetically isolated. Despite long generation times, all three species exhibited associations between genetic structure and postsettlement habitat change, indicating that long generation times may not be sufficient to delay genetic drift resulting from recent habitat fragmentation. The concordances in genetic structure observed between aquatic species, as well as isolation in the endangered, long-lived Emydoidea, reinforce the need to consider both landscape composition and demographic factors in assessing differential responses to habitat change in co-occurring species. PMID- 27997083 TI - Acute sacral nerve stimulation reduces visceral mechanosensitivity in a cross organ sensitization model. AB - BACKGROUND: Sacral nerve stimulation (SNS) is a surgical treatment of fecal and urinary incontinence that consists of inserting a stimulating electrode into one of the s3 or s4 sacral holes. In addition to the benefit of SNS in the treatment of incontinence, recent studies showed that SNS is effective in the treatment of irritable bowel syndrome as well as bladder pain syndrome. The aim of this study was to evaluate the effect of SNS on visceral mechanosensitivity in a cross-organ sensitization rat model. METHODS: Hypersensitive model was obtained by instillation of acetic acid into the bladder of rats during 5 minutes, 30 minutes before the start of the experiments. Visceral sensitivity was assessed by monitoring the change in mean arterial pressure in response to graded isobaric colorectal distension series. To decipher the mechanisms underlying SNS effect, rats were administered intravenously either a nonselective opioid receptor antagonist (naloxone) or a nitric oxide synthesis antagonist (L-NAME). Neuronal activation in the dorsal horn of the sacral spinal cord was measured by counting c-fos immunoreactive cells in response to colorectal distension and NMS. KEY RESULTS: Intravesical acetic acid instillation increased mean arterial pressure variation in response to colorectal distension when compared to saline group. SNS reduced the variation in arterial pressure. Colorectal distension induced a rise in c-fos immunoreactive cells in the dorsal horn of the spinal cord. This effect was reduced by SNS. CONCLUSIONS & INFERENCES: SNS reduces visceral mechanosensitivity in a cross-organ sensitization model. PMID- 27997084 TI - Electrodialytic separation of levulinic acid catalytically synthesized from woody biomass for use in microbial conversion. AB - Levulinic acid (LA) is produced by the catalytic conversion of a variety of woody biomass. To investigate the potential use of desalting electrodialysis (ED) for LA purification, electrodialytic separation of levulinate from both reagent and cedar-derived LA solution (40-160 g L-1 ) was demonstrated. When using reagent LA solution with pH5.0-6.0, the recovery rates of levulinate ranged from 68 to 99%, and the energy consumption for recovery of 1 kg of levulinate ranged from 0.18 to 0.27 kWh kg-1 . With cedar-derived LA solution (pH6.0), good agreement in levulinate recovery (88-99%), and energy consumption (0.18-0.22 kWh kg-1 ) were observed in comparison to the reagent LA solutions, although a longer operation time was required due to some impurities. The application of desalting ED was favorable for promoting microbial utilization of cedar-derived LA. From 0.5 mol L 1 of the ED-concentrated sodium levulinate solution, 95.6% of levulinate was recovered as LA calcium salt dihydrate by crystallization. This is the first report on ED application for LA recovery using more than 20 g L-1 LA solutions (40-160 g L-1 ). (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:448-453, 2017. PMID- 27997086 TI - [Current Status and Future Views of Gastric Cancer Treatment in Elderly Patients]. PMID- 27997085 TI - Effect of guanidine and arginine on protein-ligand interactions in multimodal cation-exchange chromatography. AB - The addition of fluid phase modifiers provides significant opportunities for increasing the selectivity of multimodal chromatography. In order to optimize this selectivity, it is important to understand the fundamental interactions between proteins and these modifiers. To this end, molecular dynamics (MD) simulations were first performed to study the interactions of guanidine and arginine with three proteins. The simulation results showed that both guanidine and arginine interacted primarily with the negatively charged regions on the proteins and that these regions could be readily predicted using electrostatic potential maps. Protein surface characterization was then carried out using computationally efficient coarse-grained techniques for a broader set of proteins which exhibited interesting chromatographic retention behavior upon the addition of these modifiers. It was shown that proteins exhibiting an increased retention in the presence of guanidine possessed hydrophobic regions adjacent to negatively charged regions on their surfaces. In contrast, proteins which exhibited a decreased binding in the presence of guanidine did not have hydrophobic regions adjacent to negatively charged patches. These results indicated that the effect of guanidine could be described as a combination of competitive binding, charge neutralization and increased hydrophobic interactions for certain proteins. In contrast, arginine resulted in a significant decrease in protein retention times primarily due to competition for the resin and steric effects, with minimal accompanying increase in hydrophobic interactions. The approach presented in this paper which employs MD simulations to guide the application of coarse-grained approaches is expected to be extremely useful for methods development in downstream bioprocesses. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:435-447, 2017. PMID- 27997087 TI - [Molecular Targeted Therapy for Gastric Cancer]. PMID- 27997103 TI - Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase. AB - Phenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l methionine (SAM)-dependent conversion of norepinephrine to epinephrine. Epinephrine has been associated with critical processes in humans including the control of respiration and blood pressure. Additionally, PNMT activity has been suggested to play a role in hypertension and Alzheimer's disease. In the current study, labeled SAM substrates were used to measure primary methyl-14C and 36S and secondary methyl-3H, 5'-3H, and 5'-14C intrinsic kinetic isotope effects for human PNMT. The transition state of human PNMT was modeled by matching kinetic isotope effects predicted via quantum chemical calculations to intrinsic values. The model provides information on the geometry and electrostatics of the human PNMT transition state structure and indicates that human PNMT catalyzes the formation of epinephrine through an early SN2 transition state in which methyl transfer is rate-limiting. PMID- 27997104 TI - Direct-Write Fabrication of 4D Active Shape-Changing Structures Based on a Shape Memory Polymer and Its Nanocomposite. AB - Four-dimensional (4D) active shape-changing structures based on shape memory polymers (SMPs) and shape memory nanocomposites (SMNCs) are able to be controlled in both space and time and have attracted increasing attention worldwide. However, conventional processing approaches have restricted the design space of such smart structures. Herein, 4D active shape-changing architectures in custom defined geometries exhibiting thermally and remotely actuated behaviors are achieved by direct-write printing of ultraviolet (UV) cross-linking poly(lactic acid)-based inks. The results reveal that, by the introduction of a UV cross linking agent, the printed objects present excellent shape memory behavior, which enables three-dimensional (3D)-one-dimensional (1D)-3D, 3D-two-dimensional (2D) 3D, and 3D-3D-3D configuration transformations. More importantly, the addition of iron oxide successfully integrates 4D shape-changing objects with fast remotely actuated and magnetically guidable properties. This research realizes the printing of both SMPs and SMNCs, which present an effective strategy to design 4D active shape-changing architectures with multifunctional properties. This paves the way for the further development of 4D printing, soft robotics, flexible electronics, minimally invasive medicine, etc. PMID- 27997105 TI - Cyclohexane-Coupled Bipolar Host Materials with High Triplet Energies for Organic Light-Emitting Diodes Based on Thermally Activated Delayed Fluorescence. AB - Thermally activated delayed fluorescence-based organic light-emitting diodes (TADF-OLEDs) have recently attracted tremendous research interest as next generation optoelectronic devices. However, there are a limited number of host materials with an appropriately high lowest-excited triplet energy (ET) and bipolar charge transport properties for high-efficiency TADF-OLEDs. Moreover, these host materials should have high thermal and morphological stabilities. In this study, we develop novel bipolar host materials consisting of an electron donating 9-phenylcarbazole unit and an electron-accepting triphenylphosphine oxide, triphenylphosphine sulfide, or 2,4,6-triphenyl-1,3,5-triazine unit linked by a nonconjugated cyclohexane core. These bipolar host materials possess high glass-transition temperatures of over 100 degrees C and high ET values of approximately 3.0 eV. TADF-OLEDs employing these bipolar host materials could achieve high external electroluminescence quantum efficiencies of up to 21.7% together with reduced efficiency roll-off characteristics, because of expansion of the charge-recombination zone within the emission layer arising from the bipolar charge transport ability of these host materials. PMID- 27997106 TI - Correction to Opportunities and Limitations for Nanophotonic Structures To Exceed the Shockley-Queisser Limit. PMID- 27997107 TI - Protein-Directed Synthesis of Bifunctional Adsorbent-Catalytic Hemin-Graphene Nanosheets for Highly Efficient Removal of Dye Pollutants via Synergistic Adsorption and Degradation. AB - Herein, for the first time, we report a "green", one-pot reduction/decoration method for the synthesis of bifunctional adsorbent-catalytic hemin-graphene nanosheets by using a common available protein (bovine serum albumin, BSA) as both a reductant and a stabilizer. Our prepared nanosheets are highly stable and possess intrinsic peroxidase-like catalytic activity due to the decoration of BSA and hemin. Furthermore, benefiting from the combined advantages of graphene and BSA, these nanosheets are able to efficiently adsorb dye pollutants from aqueous solution. More importantly, due to their adsorption and catalytic ability, these adsorbent-catalytic nanosheets can be applied to highly efficient dye removal via synergistic adsorption and degradation. Specifically, our catalysts can easily bring organic dyes to their surface by adsorption, and then activate H2O2 to generate hydroxyl radicals, leading to the degradation of the dyes. Such catalytic mechanism of our as-prepared nanosheets was analogous to that of natural enzymes, in which the extremely high catalytic efficiency is largely dependent upon their ability to bring substrates in close proximity to the active sites of enzymes. Our finding may open new potential applications of hemin graphene hybrid nanosheets in environmental chemistry, biotechnology, and medicine. PMID- 27997109 TI - Strain Effects in Epitaxial VO2 Thin Films on Columnar Buffer-Layer TiO2/Al2O3 Virtual Substrates. AB - Epitaxial VO2/TiO2 thin film heterostructures were grown on (100) (m-cut) Al2O3 substrates via pulsed laser deposition. We have demonstrated the ability to reduce the semiconductor-metal transition (SMT) temperature of VO2 to ~44 degrees C while retaining a 4 order of magnitude SMT using the TiO2 buffer layer. A combination of electrical transport and X-ray diffraction reciprocal space mapping studies help examine the specific strain states of VO2/TiO2/Al2O3 heterostructures as a function of TiO2 film growth temperatures. Atomic force microscopy and transmission electron microscopy analyses show that the columnar microstructure present in TiO2 buffer films is responsible for the partially strained VO2 film behavior and subsequently favorable transport characteristics with a lower SMT temperature. Such findings are of crucial importance for both the technological implementation of the VO2 system, where reduction of its SMT temperature is widely sought, as well as the broader complex oxide community, where greater understanding of the evolution of microstructure, strain, and functional properties is a high priority. PMID- 27997110 TI - Size Dependence of Nanoscale Wear of Silicon Carbide. AB - Nanoscale, single-asperity wear of single-crystal silicon carbide (sc-SiC) and nanocrystalline silicon carbide (nc-SiC) is investigated using single-crystal diamond nanoindenter tips and nanocrystalline diamond atomic force microscopy (AFM) tips under dry conditions, and the wear behavior is compared to that of single-crystal silicon with both thin and thick native oxide layers. We discovered a transition in the relative wear resistance of the SiC samples compared to that of Si as a function of contact size. With larger nanoindenter tips (tip radius ~ 370 nm), the wear resistances of both sc-SiC and nc-SiC are higher than that of Si. This result is expected from the Archard's equation because SiC is harder than Si. However, with the smaller AFM tips (tip radius ~ 20 nm), the wear resistances of sc-SiC and nc-SiC are lower than that of Si, despite the fact that the contact pressures are comparable to those applied with the nanoindenter tips, and the plastic zones are well-developed in both sets of wear experiments. We attribute the decrease in the relative wear resistance of SiC compared to that of Si to a transition from a wear regime dominated by the materials' resistance to plastic deformation (i.e., hardness) to a regime dominated by the materials' resistance to interfacial shear. This conclusion is supported by our AFM studies of wearless friction, which reveal that the interfacial shear strength of SiC is higher than that of Si. The contributions of surface roughness and surface chemistry to differences in interfacial shear strength are also discussed. PMID- 27997108 TI - In Vivo Systems Response Profiling and Multivariate Classification of CNS Active Compounds: A Structured Tool for CNS Drug Discovery. AB - This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose-response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery. PMID- 27997111 TI - Cellulose Nanofibrils from Nonderivatizing Urea-Based Deep Eutectic Solvent Pretreatments. AB - Deep eutectic solvents (DESs) are a fairly new class of green solvents applied in various fields. This study investigates urea-based DES systems as novel pretreatments for cellulose nanofibril production. In the experiments, deep eutectic systems having urea and ammonium thiocyanate or guanidine hydrochloride as a second component were formed at 100 degrees C and then applied to disintegrate wood-derived cellulose fibers. The DES-pretreated fibers were nanofibrillated into three different levels of mechanical treatments with a microfluidizer, and their properties were analyzed. Moreover, nanofibril films were fabricated by solvent casting method. Both DES systems were able to loosen and swell the cellulose fiber structure as indicated by the increase in the lateral dimension of the fibers. Nonpretreated birch cellulose fibers had difficulties in mechanical nanofibrillation as clogging of the chamber occurred often. However, cellulose nanofibrils with widths ranging from 13.0 to 19.3 nm were successfully fabricated from DES-pretreated fibers with both systems. Translucent nanofibril films generated from DES-pretreated cellulose nanofibrils had good thermal stability and mechanical properties, with tensile strengths of approximately 135-189 MPa and elastic modulus of 6.4-7.7 GPa. Consequently, both urea-based DESs showed a high potential as environmentally friendly solvents in the manufacture of cellulose nanofibrils. PMID- 27997112 TI - Progressive Assessment on the Decomposition Reaction of Na Superionic Conducting Ceramics. AB - The successful analysis on the microstructure of Hong-type Na superionic conducting (NASICON) ceramics revealed that it consists of several heterogeneous phases: NASICON grains with rectangular shapes, monoclinic round ZrO2 particles, grain boundaries, a SiO2-rich vitrified phase, Na-rich amorphous particles, and pores. A dramatic microstructural evolution of NASICON ceramics was demonstrated via an in situ analysis, which showed that NASICON grains sequentially lost their original morphology and were transformed into comminuted particles (as indicated by the immersion of bulk NASICON samples into seawater at a temperature of 80 degrees C). The consecutive X-ray diffraction analysis represented that the significant shear stress inside NASICON ceramics caused their structural decomposition, during which H3O+ ions occupied ceramic Na+ sites (predominantly along the (111) and (133) planes), while the original Na+ cations came out in the (020) plane of the NASICON ceramic crystalline structure. The results of time-of flight secondary-ion mass spectrometry analysis confirmed that large concentrations of Cl- and Na+ ions were distributed across the surface of NASICON ceramics, leading to local densification of a 20 MUm thick surface layer after treatment within seawater solution at a temperature of 80 degrees C. PMID- 27997113 TI - Tunable Azacrown-Embedded Graphene Nanomeshes for Ion Sensing and Separation. AB - Remarkable selectivity with which crown ethers served as macrocyclic hosts for various guest species has led to numerous investigations on structure-specific interactions. Successful fabrication of graphene nanomeshes has opened up a plethora of avenues for sensing and separation applications. Embedding crown ether backbones in graphene frameworks can therefore be an interesting strategy for exploring the advantages offered by crown ether backbones, yet having the properties of graphene-based materials. Motivated by the recent success in fabrication of crown ether-based graphene nanopores, herein we investigate their performance toward ion sensing and separation using electronic structure methods. The effect of topology and electronic properties of the nanopore are probed by considering a series of oxygen-based and nitrogen-based graphene crown ethers (crown-n; n = 1-6). Our computations have revealed the excellent alkali ion binding properties of azacrown-based graphene nanomeshes over conventional oxygen crown-based graphene nanomeshes and normal crown ethers. Selectivity in ion transmission through the nanomeshes is demonstrated by employing graphene crown ethers [crown-n (n = 4-6)]. To the best of our knowledge, this article is the first report on azacrown-based graphene nanomeshes and their possible applications in ion sensing and separation, an aspect that we hope will be demonstrated in experiments soon. PMID- 27997114 TI - Low-Molecular-Weight Hydrogels as New Supramolecular Materials for Bioelectrochemical Interfaces. AB - Controlling the interface between biological tissues and electrodes remains an important challenge for the development of implantable devices in terms of electroactivity, biocompatibility, and long-term stability. To engineer such a biocompatible interface a low molecular weight gel (LMWG) based on a glycosylated nucleoside fluorocarbon amphiphile (GNF) was employed for the first time to wrap gold electrodes via a noncovalent anchoring strategy, that is, self-assembly of GNF at the electrode surface. Scanning electron microscopy (SEM) studies indicate that the gold surface is coated with the GNF hydrogels. Electrochemical measurements using cyclic voltammetry (CV) clearly show that the electrode properties are not affected by the presence of the hydrogel. This coating layer of 1 to 2 MUm does not significantly slow down the mass transport through the hydrogel. Voltammetry experiments with gel coated macroporous enzyme electrodes reveal that during continuous use their current is improved by 100% compared to the noncoated electrode. This demonstrates that the supramolecular hydrogel dramatically increases the stability of the bioelectrochemical interface. Therefore, such hybrid electrodes are promising candidates that will both offer the biocompatibility and stability needed for the development of more efficient biosensors and biofuel cells. PMID- 27997115 TI - SIRT7 Is an RNA-Activated Protein Lysine Deacylase. AB - Mammalian SIRT7 is a member of the sirtuin family that regulates multiple biological processes including genome stability, metabolic pathways, stress responses, and tumorigenesis. SIRT7 has been shown to be important for ribosome biogenesis and transcriptional regulation. SIRT7 knockout mice exhibit complications associated with fatty liver and increased aging in hematopoietic stem cells. However, the molecular basis for its biological function remains unclear, in part due to the lack of efficient enzymatic activity in vitro. Previously, we have demonstrated that double-stranded DNA could activate SIRT7's deacetylase activity in vitro, allowing it to deacetylate H3K18 in the context of chromatin. Here, we show that RNA can increase the catalytic efficiency of SIRT7 even better and that SIRT7 can remove long chain fatty acyl groups more efficiently than removing acetyl groups. Truncation and mutagenesis studies revealed residues at both the amino and carboxyl termini of SIRT7 that are involved in RNA-binding and important for activity. RNA immunoprecipitation sequencing (RIP-seq) identified ribosomal RNA (rRNA) as the predominant RNA binding partner of SIRT7. The associated RNA was able to effectively activate the deacetylase and defatty-acylase activities of SIRT7. Knockdown of SIRT7 increased the lysine fatty acylation of several nuclear proteins based on metabolic labeling with an alkyne-tagged fatty acid analog, supporting that the defatty acylase activity of SIRT7 is physiologically relevant. These findings provide important insights into the biological functions of SIRT7, as well as an improved platform to develop SIRT7 modulators. PMID- 27997117 TI - Engineering High Affinity Protein-Protein Interactions Using a High-Throughput Microcapillary Array Platform. AB - Affinity maturation of protein-protein interactions requires iterative rounds of protein library generation and high-throughput screening to identify variants that bind with increased affinity to a target of interest. We recently developed a multipurpose protein engineering platform, termed MUSCALE (Microcapillary Single Cell Analysis and Laser Extraction). This technology enables high throughput screening of libraries of millions of cell-expressing protein variants based on their binding properties or functional activity. Here, we demonstrate the first use of the MUSCALE platform for affinity maturation of a protein protein binding interaction. In this proof-of-concept study, we engineered an extracellular domain of the Axl receptor tyrosine kinase to bind tighter to its ligand Gas6. Within 2 weeks, two iterative rounds of library generation and screening resulted in engineered Axl variants with a 50-fold decrease in kinetic dissociation rate, highlighting the use of MUSCALE as a new tool for directed evolution. PMID- 27997116 TI - Cross-Linked Fluorescent Supramolecular Nanoparticles as Finite Tattoo Pigments with Controllable Intradermal Retention Times. AB - Tattooing has been utilized by the medical community for precisely demarcating anatomic landmarks. This practice is especially important for identifying biopsy sites of nonmelanoma skin cancer (NMSC) due to the long interval (i.e., up to 3 months) between the initial diagnostic biopsy and surgical treatment. Commercially available tattoo pigments possess several issues, which include causing poor cosmesis, being mistaken for a melanocytic lesion, requiring additional removal procedures when no longer desired, and potentially inducing inflammatory responses. The ideal tattoo pigment for labeling of skin biopsy sites for NMSC requires (i) invisibility under ambient light, (ii) fluorescence under a selective light source, (iii) a finite intradermal retention time (ca. 3 months), and (iv) biocompatibility. Herein, we introduce cross-linked fluorescent supramolecular nanoparticles (c-FSNPs) as a "finite tattoo" pigment, with optimized photophysical properties and intradermal retention time to achieve successful in vivo finite tattooing. Fluorescent supramolecular nanoparticles encapsulate a fluorescent conjugated polymer, poly[5-methoxy-2-(3-sulfopropoxy) 1,4-phenylenevinylene] (MPS-PPV), into a core via a supramolecular synthetic approach. FSNPs which possess fluorescent properties superior to those of the free MPS-PPV are obtained through a combinatorial screening process. Covalent cross-linking of FSNPs results in micrometer-sized c-FSNPs, which exhibit a size dependent intradermal retention. The 1456 nm sized c-FSNPs display an ideal intradermal retention time (ca. 3 months) for NMSC lesion labeling, as observed in an in vivo tattoo study. In addition, the c-FSNPs induce undetectable inflammatory responses after tattooing. We believe that the c-FSNPs can serve as a "finite tattoo" pigment to label potential malignant NMSC lesions. PMID- 27997118 TI - Composite Pillars with a Tunable Interface for Adhesion to Rough Substrates. AB - The benefits of synthetic fibrillar dry adhesives for temporary and reversible attachment to hard objects with smooth surfaces have been successfully demonstrated in previous studies. However, surface roughness induces a dramatic reduction in pull-off stresses and necessarily requires revised design concepts. Toward this aim, we introduce cylindrical two-phase single pillars, which are composed of a mechanically stiff stalk and a soft tip layer. Adhesion to smooth and rough substrates is shown to exceed that of conventional pillar structures. The adhesion characteristics can be tuned by varying the thickness of the soft tip layer, the ratio of the Young's moduli and the curvature of the interface between the two phases. For rough substrates, adhesion values similar to those obtained on smooth substrates were achieved. Our concept of composite pillars overcomes current practical limitations caused by surface roughness and opens up fields of application where roughness is omnipresent. PMID- 27997119 TI - Anisotropic Self-Assembly of Hairy Inorganic Nanoparticles. AB - Current interest in functional assemblies of inorganic nanoparticles (NPs) stems from their collective properties and diverse applications ranging from nanomedicines to optically active metamaterials. Coating the surface of NPs with polymers allows for tailoring of the interactions between NPs to assemble them into hybrid nanocomposites with targeted architectures. This class of building blocks is termed "hairy" inorganic NPs (HINPs). Regiospecific attachment of polymers has been used to achieve directional interactions for HINP assembly. However, to date anisotropic surface functionalization of NPs still remains a challenge. This Account provides a review of the recent progress in the self assembly of isotropically functionalized HINPs in both the condensed state and aqueous solution as well as the applications of assembled structures in such areas as biomedical imaging and therapy. It aims to provide fundamental mechanistic insights into the correlation between structural characteristics and self-assembly behaviors of HINPs, with an emphasis on HINPs made from NPs grafted with linear block copolymer (BCP) brushes. The key to the anisotropic self assembly of these HINPs is the generation of directional interactions between HINPs by designing the surrounding medium (e.g., polymer matrix) or engineering the surface chemistry of the HINPs. First, HINPs can self-assemble into a variety of 1D, 2D, or 3D nanostructures with a nonisotropic local arrangement of NPs in films. Although a template is not always required, a polymer matrix (BCPs or supramolecules) can be used to assist the assembly of HINPs to form hybrid architectures. The interactions between brushes of neighboring HINPs or between HINPs and the polymer matrix can be modulated by varying the grafting density and length of one or multiple types of polymers on the surface of the NPs. Second, the rational design of deformable brushes of BCP or mixed homopolymer tethers on HINPs enables the anisotropic assembly of HINPs (in analogy to molecular self assembly) into complex functional structures in selective solvents. It is evidenced that the directional interactions between BCP-grafted NPs arise from the redistribution and conformation change of the long, flexible polymer tethers, while the lateral phase separation of brushes on NP surfaces is responsible for the assembly of HINPs carrying binary immiscible homopolymers. For HINPs decorated with amphiphilic BCP brushes, their self-assembly can produce a variety of hybrid structures, such as vesicles with a monolayer of densely packed NPs in the membranes and with controlled sizes, shapes (e.g., spherical, hemispherical, disklike), and morphologies (e.g., patchy, Janus-like). This strategy allows fine tuning of the NP organization and collective properties of HINP assemblies, thus facilitating their application in effective cancer imaging, therapy, and drug delivery. We expect that the design and assembly of such HINPs with isotropic functionalization is likely to open up new avenues for the fabrication of new functional nanocomposites and devices because of its simplicity, low cost, and ease of scale-up. PMID- 27997120 TI - Elemental Mercury Oxidation over Fe-Ti-Mn Spinel: Performance, Mechanism, and Reaction Kinetics. AB - The design of a high-performance catalyst for Hg0 oxidation and predicting the extent of Hg0 oxidation are both extremely limited due to the uncertainties of the reaction mechanism and the reaction kinetics. In this work, Fe-Ti-Mn spinel was developed as a high-performance catalyst for Hg0 oxidation, and the reaction mechanism and the reaction kinetics of Hg0 oxidation over Fe-Ti-Mn spinel were studied. The reaction orders of Hg0 oxidation over Fe-Ti-Mn spinel with respect to gaseous Hg0 concentration and gaseous HCl concentration were approximately 1 and 0, respectively. Therefore, Hg0 oxidation over Fe-Ti-Mn spinel mainly followed the Eley-Rideal mechanism (i.e., the reaction of gaseous Hg0 with adsorbed HCl), and the rate of Hg0 oxidation mainly depended on Cl* concentration on the surface. As H2O, SO2, and NO not only inhibited Cl* formation on the surface but also interfered with the interface reaction between gaseous Hg0 and Cl* on the surface, Hg0 oxidation over Fe-Ti-Mn spinel was obviously inhibited in the presence of H2O, SO2, and NO. Furthermore, the extent of Hg0 oxidation over Fe-Ti-Mn spinel can be predicted according to the kinetic parameter kE-R, and the predicted result was consistent with the experimental result. PMID- 27997121 TI - Direct Exchange Mechanism for Interlayer Ions in Non-Swelling Clays. AB - The mobility of radiocesium in the environment is largely mediated by cation exchange in micaceous clays, in particular Illite-a non-swelling clay mineral that naturally contains interlayer K+ and has high affinity for Cs+. Although exchange of interlayer K+ for Cs+ is nearly thermodynamically nonselective, recent experiments show that direct, anhydrous Cs+-K+ exchange is kinetically viable and leads to the formation of phase-separated interlayers through a mechanism that remains unclear. Here, using classical atomistic simulations and density functional theory calculations, we identify a molecular-scale positive feedback mechanism in which exchange of the larger Cs+ for the smaller K+ significantly lowers the migration barrier of neighboring K+, allowing exchange to propagate rapidly once initiated at the clay edge. Barrier lowering upon slight increase in layer spacing (~0.7 A) during Cs+ exchange is an example of "chemical-mechanical coupling" that likely explains the observed sharp exchange fronts leading to interstratification. Interestingly, we find that these features are thermodynamically favored even in the absence of a heterogeneous layer charge distribution. PMID- 27997122 TI - Climate Change Increasing Calcium and Magnesium Leaching from Granitic Alpine Catchments. AB - Climate change can reverse trends of decreasing calcium and magnesium [Ca + Mg] leaching to surface waters in granitic alpine regions recovering from acidification. Despite decreasing concentrations of strong acid anions (-1.4 MUeq L-1 yr-1) during 2004-2016 in nonacidic alpine lakes in the Tatra Mountains (Central Europe), the average [Ca + Mg] concentrations increased (2.5 MUeq L-1 yr 1), together with elevated terrestrial export of bicarbonate (HCO3-; 3.6 MUeq L-1 yr-1). The percent increase in [Ca + Mg] concentrations in nonacidic lakes (0.3 3.2% yr-1) was significantly and positively correlated with scree proportion in the catchment area and negatively correlated with the extent of soil cover. Leaching experiments with freshly crushed granodiorite, the dominant bedrock, showed that accessory calcite and (to a lesser extent) apatite were important sources of Ca. We hypothesize that elevated terrestrial export of [Ca + Mg] and HCO3- resulted from increased weathering caused by accelerated physical erosion of rocks due to elevated climate-related mechanical forces (an increasing frequency of days with high precipitation amounts and air temperatures fluctuating around 0 degrees C) during the last 2-3 decades. These climatic effects on water chemistry are especially strong in catchments where fragmented rocks are more exposed to weathering, and their position is less stable than in soil. PMID- 27997123 TI - Environmental Populism. PMID- 27997125 TI - Secretagogin Is a Redox-Responsive Ca2+ Sensor. AB - Secretagogin (SCGN), a multifunctional, Ca2+ binding, regulatory protein, known to regulate insulin release, has recently been implicated in the control of stress-related corticotropin-releasing hormone (CRH) secretion. Localization of SCGN to multiple intracellular (such as cytosol, nucleus, and endoplasmic reticulum) and extracellular sites appears to provide multifunctional capabilities; however, the structural elements conferring such a widespread cellular distribution to SCGN remain unidentified. We report that the spatial and functional attributes of SCGN plausibly originate from the interplay between Ca2+ and its redox state. The mutation of selective Cys residues provides further insights into the origin and mode of redox responsiveness. In the reducing milieu, SCGN exhibits a higher affinity for Ca2+, and more stability than in the oxidizing environment, suggesting it is a redox-responsive Ca2+ sensor protein, which is further supported by its response to dithiothreitol (reducing stress) in MIN6 cells. Our data provide a biophysical and biochemical explanation for the diverse localization of SCGN in the cellular scenario and beyond the cell. PMID- 27997124 TI - Differential Membrane Binding Mechanics of Synaptotagmin Isoforms Observed in Atomic Detail. AB - Synaptotagmin (Syt) is a membrane-associated protein involved in vesicle fusion through the SNARE complex that is found throughout the human body in 17 different isoforms. These isoforms have two membrane-binding C2 domains, which sense Ca2+ and thereby promote anionic membrane binding and lead to vesicle fusion. Through molecular dynamics simulations using the highly mobile membrane mimetic acclerated bilayer model, we have investigated how small protein sequence changes in the Ca2+-binding loops of the C2 domains may give rise to the experimentally determined difference in binding kinetics between Syt-1 and Syt-7 isoforms. Syt-7 C2 domains are found to form more close contacts with anionic phospholipid headgroups, particularly in loop 1, where an additional positive charge in Syt-7 draws the loop closer to the membrane and causes the anchoring residue F167 to insert deeper into the bilayer than the corresponding methionine in Syt-1 (M173). By performing additional replica exchange umbrella sampling calculations, we demonstrate that these additional contacts increase the energetic cost of unbinding the Syt-7 C2 domains from the bilayer, causing them to unbind more slowly than their counterparts in Syt-1. PMID- 27997126 TI - Efficient Tumor Accumulation, Penetration and Tumor Growth Inhibition Achieved by Polymer Therapeutics: The Effect of Polymer Architectures. AB - To obtain high tumor-specific accumulation, strong tumor penetration and low off target uptake, we developed a series of polymer therapeutics with different architectures, including random, block, and brush-like structure, based on the classic N-(2-hydroxypropyl) methacrylamide polymers. The influence of polymer architecture on biological properties such as cellular uptake, blood clearance, and biodistribution have been investigated. Besides small micelles whose sizes were determined by polymer architectures, large aggregates formed by micelle aggregation could also be observed. Although they had different architectures, the drug release rate, endocytic pathways and cellular uptake level of various conjugates have been proved to be identical. The polymer architecture of various conjugates lay great impact on the blood clearance, biodistribution and tumor growth inhibition. We assumed that the differences in in vivo biological properties were coordinately caused by the different size of the small aggregates and the formation and stability of large aggregates for different conjugates. Even though the reason was still unclear, the results inspired us that only by diblock conjugates with improved cellular uptake can we realize tumor specific accumulation, deep penetration, and efficient tumor inhibition. PMID- 27997127 TI - Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor. AB - A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound's efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch-migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin. PMID- 27997128 TI - Spatial and Temporal Trends of Polyhalogenated Carbazoles in Sediments of Upper Great Lakes: Insights into Their Origin. AB - Polyhalogenated carbazoles (PHCZs) have been increasingly detected in the environment. Their similarities in chemical structure with legacy pollutants and their potential toxicity have caused increasing concern. In this work, 112 Ponar grab and 28 core sediment samples were collected from Lakes Michigan, Superior, and Huron, and a total of 26 PHCZs were analyzed along with unsubstituted carbazole using gas chromatography coupled with single- or triple-quadrupole mass spectrometry. Our results show that the total accumulation of PHCZs in the sediments of the upper Great Lakes is >3000 tonnes, orders of magnitude greater than those of polychlorinated biphenyls (PCBs) and decabromodiphenyl ether (BDE209). The 27 individual analytes differ in spatial distribution and temporal trend. Our results showed that PHCZs with substitution patterns of -Br2-5, -Cl1 2Br2-4, or having iodine, were more abundant in sediment of Lake Michigan deposited before 1900 than those deposited more recently, implying a natural origin. Some "emerging" PHCZs have been increasingly deposited into the sediment in recent decades, and deserve further environmental monitoring and research. Other PHCZs with low halogen substitution may form from in situ dehalogenation of PHCZs having more halogens. Anthropogenic sources of PHCZs may exist, particularly for the emerging and low molecular mass congeners. PMID- 27997129 TI - Alkali Metal CO2 Sorbents and the Resulting Metal Carbonates: Potential for Process Intensification of Sorption-Enhanced Steam Reforming. AB - Sorption-enhanced steam reforming (SESR) is an energy and cost efficient approach to produce hydrogen with high purity. SESR makes it economically feasible to use a wide range of feedstocks for hydrogen production such as methane, ethanol, and biomass. Selection of catalysts and sorbents plays a vital role in SESR. This article reviews the recent research aimed at process intensification by the integration of catalysis and chemisorption functions into a single material. Alkali metal ceramic powders, including Li2ZrO3, Li4SiO4 and Na2ZrO3 display characteristics suitable for capturing CO2 at low concentrations (<15% CO2) and high temperatures (>500 degrees C), and thus are applicable to precombustion technologies such as SESR, as well as postcombustion capture of CO2 from flue gases. This paper reviews the progress made in improving the operational performance of alkali metal ceramics under conditions that simulate power plant and SESR operation, by adopting new methods of sorbent synthesis and doping with additional elements. The paper also discusses the role of carbonates formed after in situ CO2 chemisorption during a steam reforming process in respect of catalysts for tar cracking. PMID- 27997130 TI - Development of a Transcription Factor-Based Lactam Biosensor. AB - Lactams are an important class of commodity chemicals used in the manufacture of nylons, with millions of tons produced every year. Biological production of lactams could be greatly improved by high-throughput sensors for lactam biosynthesis. To identify biosensors of lactams, we applied a chemoinformatic approach inspired by small molecule drug discovery. We define this approach as analogue generation toward catabolizable chemicals or AGTC. We discovered a lactam biosensor based on the ChnR/Pb transcription factor-promoter pair. The microbial biosensor is capable of sensing epsilon-caprolactam, delta valerolactam, and butyrolactam in a dose-dependent manner. The biosensor has sufficient specificity to discriminate against lactam biosynthetic intermediates and therefore could potentially be applied for high-throughput metabolic engineering for industrially important high titer lactam biosynthesis. PMID- 27997131 TI - Autoinduced AND Gate Controls Metabolic Pathway Dynamically in Response to Microbial Communities and Cell Physiological State. AB - Quorum sensing (QS) systems have been widely applied in biotechnology and synthetic biology that require coordinated, community-level behaviors. Meanwhile, the cell physiological state is another key parameter that affects metabolic pathway regulation. Here, we designed an autoinduced AND gate that responds to both microbial communities and the cell physiological state. A series of tunable QS systems in response to different cell densities were obtained through random mutagenesis of LuxR and optimization of the luxRI promoter; the corresponding suitable stationary phase sensing system was selected after monitoring the fluorescence process during cell growth. The application of the final synthetic device was demonstrated using the polyhydroxybutyrate (PHB) production system. The AND gate system increased PHB production by 1-2-fold in Escherichia coli. This synthetic logic gate is a tool for developing a general dynamic regulation system in metabolic engineering in response to complex signals, without using a specific sensor. PMID- 27997132 TI - Chemical Characterization of Water-Soluble Organic Aerosol in Contrasting Rural and Urban Environments in the Southeastern United States. AB - We developed a novel system for direct and online characterization of water solubility of organic aerosol (OA) by coupling a Particle Into Liquid Sampler (PILS) to a High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF AMS). We showed that approximately 88% and 77% of OA are water-soluble in rural Centreville, Alabama and urban Atlanta, Georgia, respectively. The water solubility of OA factors, resolved with Positive Matrix Factorization analysis of AMS data, is directly investigated for the first time. Above 80% of isoprene derived OA is water-soluble and its water-soluble fraction has the least variability among all OA factors. This is consistent with that the majority of this factor represents OA formed through the aqueous-phase reaction of isoprene epoxydiols. More-oxidized oxygenated OA is dominantly water-soluble, consistent with this factor representing highly oxidized compounds. Less-oxidized oxygenated OA has the lowest water-solubility among all secondary OA factors, which agrees with the hypothesis that this factor in the southeastern U.S. includes contributions from organic nitrates. While hydrocarbon-like OA is largely water insoluble, biomass burning OA and cooking OA have the largest range of water soluble fraction. This study on the water-solubility of OA factors provides insights for interpretation of OA factors and improves understanding of the complex OA sources in the atmosphere. PMID- 27997133 TI - Injectable, Guest-Host Assembled Polyethylenimine Hydrogel for siRNA Delivery. AB - While siRNA has tremendous potential for therapeutic applications, advancement is limited by poor delivery systems. Systemically, siRNAs are rapidly degraded, may have off-target silencing, and necessitate high working concentrations. To overcome this, we developed an injectable, guest-host assembled hydrogel between polyethylenimine (PEI) and polyethylene glycol (PEG) for local siRNA delivery. Guest-host modified polymers assembled with siRNAs to form polyplexes that had improved transfection and viability compared to PEI. At higher concentrations, these polymers assembled into shear-thinning hydrogels that rapidly self-healed. With siRNA encapsulation, the assemblies eroded as polyplexes which were active and transfected cells, observed by Cy3-siRNA uptake or GFP silencing in vitro. When injected into rat myocardium, the hydrogels localized polyplex release, observed by uptake of Cy5.5-siRNA and silencing of GFP for 1 week in a GFP expressing rat. These results illustrate the potential for this system to be applied for therapeutic siRNA delivery, such as in cardiac pathologies. PMID- 27997134 TI - Native Mass Spectrometry Analysis of Oligomerization States of Fluorescence Recovery Protein and Orange Carotenoid Protein: Two Proteins Involved in the Cyanobacterial Photoprotection Cycle. AB - The orange carotenoid protein (OCP) and fluorescence recovery protein (FRP) are present in many cyanobacteria and regulate an essential photoprotection cycle in an antagonistic manner as a function of light intensity. We characterized the oligomerization states of OCP and FRP by using native mass spectrometry, a technique that has the capability of studying native proteins under a wide range of protein concentrations and molecular masses. We found that dimeric FRP is the predominant state at protein concentrations ranging from 3 to 180 MUM and that higher-order oligomers gradually form at protein concentrations above this range. The OCP, however, demonstrates significantly different oligomerization behavior. Monomeric OCP (mOCP) dominates at low protein concentrations, with an observable population of dimeric OCP (dOCP). The ratio of dOCP to mOCP, however, increases proportionally with protein concentration. Higher-order OCP oligomers form at protein concentrations beyond 10 MUM. Additionally, native mass spectrometry coupled with ion mobility allowed us to measure protein collisional cross sections and interrogate the unfolding of different FRP and OCP oligomers. We found that monomeric FRP exhibits a one-stage unfolding process, which could be correlated with its C-terminal bent crystal structure. The structural domain compositions of FRP and OCP are compared and discussed. PMID- 27997135 TI - Subinhibitory Concentrations of Disinfectants Promote the Horizontal Transfer of Multidrug Resistance Genes within and across Genera. AB - The greater abundances of antibiotic resistance genes (ARGs) in point-of-use tap and reclaimed water than that in freshly treated water raise the question whether residual disinfectants in distribution systems facilitate the spread of ARGs. This study investigated three widely used disinfectants (free chlorine, chloramine, and hydrogen peroxide) on promoting ARGs transfer within Escherichia coli strains and across genera from Escherichia coli to Salmonella typhimurium. The results demonstrated that subinhibitory concentrations (lower than minimum inhibitory concentrations [MICs]) of these disinfectants, namely 0.1-1 mg/L Cl2 for free chlorine, 0.1-1 mg/L Cl2 for chloramine, and 0.24-3 mg/L H2O2, led to concentration-dependent increases in intragenera conjugative transfer by 3.4-6.4, 1.9-7.5, and 1.4-5.4 folds compared with controls, respectively. By comparison, the intergenera conjugative frequencies were slightly increased by approximately 1.4-2.3 folds compared with controls. However, exposure to disinfectants concentrations higher than MICs significantly suppressed conjugative transfer. This study provided evidence and insights into possible underlying mechanisms for enhanced conjugative transfer, which involved intracellular reactive oxygen species formation, SOS response, increased cell membrane permeability, and altered expressions of conjugation-relevant genes. The results suggest that certain oxidative chemicals, such as disinfectants, accelerate ARGs transfer and therefore justify motivations in evaluating disinfection alternatives for controlling antibiotic resistance. This study also triggers questions regarding the potential role of environmental chemicals in the global spread of antibiotic resistance. PMID- 27997136 TI - Size-Dependent Protein-Nanoparticle Interactions in Citrate-Stabilized Gold Nanoparticles: The Emergence of the Protein Corona. AB - Surface modifications of highly monodisperse citrate-stabilized gold nanoparticles (AuNPs) with sizes ranging from 3.5 to 150 nm after their exposure to cell culture media supplemented with fetal bovine serum were studied and characterized by the combined use of UV-vis spectroscopy, dynamic light scattering, and zeta potential measurements. In all the tested AuNPs, a dynamic process of protein adsorption was observed, evolving toward the formation of an irreversible hard protein coating known as Protein Corona. Interestingly, the thickness and density of this protein coating were strongly dependent on the particle size, making it possible to identify different transition regimes as the size of the particles increased: (i) NP-protein complexes (or incomplete corona), (ii) the formation of a near-single dense protein corona layer, and (iii) the formation of a multilayer corona. In addition, the different temporal patterns in the evolution of the protein coating came about more quickly for small particles than for the larger ones, further revealing the significant role that size plays in the kinetics of this process. Since the biological identity of the NPs is ultimately determined by the protein corona and different NP-biological interactions take place at different time scales, these results are relevant to biological and toxicological studies. PMID- 27997137 TI - Versatile Synthesis of Amino Acid Functional Polymers without Protection Group Chemistry. AB - The copolymerization of N-isopropylacrylamide (NiPAm) with aldehyde functional monomers facilitates postpolymerization functionalization with amino acids via reductive amination, negating the need for protecting groups. In reductive amination, the imine formed from the condensation reaction between an amine and an aldehyde is reduced to an amine. In this work, we categorize amino acids into four classes based on the functionality of their side chains (acidic, polar neutral, neutral, and basic) and use their amine groups in condensation reactions with aldehyde functional polymers. The dynamic nature of the imine as well as the versatility of reductive amination to functionalize a polymer with a range of amino acids is highlighted. In this manner, amino acid functional polymers are synthesized without the use of protecting groups with high yields, demonstrating the high functional group tolerance of carbonyl condensation chemistry and the subsequent reduction of the imine. Prior to the reduction of the imine bond, transimination reactions are used to demonstrate dynamic polymers that shuffle from a glycine- to a histidine-functional polymer. PMID- 27997138 TI - Analysis of Hydroxyl Radicals and Inactivation Mechanisms of Bacteriophage MS2 in Response to a Simultaneous Application of UV and Chlorine. AB - The simultaneous application of UV and chlorine (expressed as UV/Cl2) as a water treatment method may be a good disinfection option for UV-resistant microorganisms, such as human adenoviruses (HAdVs). In this study, we developed two approaches using UV/Cl2: one to quantitate the OH* radicals based on the degradation of the probe compound para-chlorobenzoic acid (pCBA) and the other to use bacteriophage MS2 to understand the virus inactivation mechanisms in response to UV, chlorine and UV/Cl2 disinfection using reverse-transcription quantitative polymerase chain reaction (RT-qPCR), attachment and genome penetration assays. The results revealed that OH* radicals were produced at a concentration of 2.70 * 10-14 M in the UV/Cl2 treatment with a practical chlorine dose of 1 mg/L and with a minimum UV254 fluence of approximately 10 mJ/cm2, whereas UV or chlorine alone did not produce OH* radicals. In the UV/Cl2 treatment, synergistic effects on viral genome damage were observed, but were not directly due to OH* radicals. The ability of MS2 to penetrate the genome of the host bacteria was impaired, but its ability to attach to the host was not affected by the treatment. We concluded that the major cause of virus inactivation in response to UV/Cl2 was the damage to the viral genome caused by combination actions of chlorine species and OH* radicals. PMID- 27997139 TI - Isotope Dilution nanoLC/ESI+-HRMS3 Quantitation of Urinary N7-(1-Hydroxy-3-buten 2-yl) Guanine Adducts in Humans and Their Use as Biomarkers of Exposure to 1,3 Butadiene. AB - 1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a known human carcinogen. Occupational exposure to BD in the polymer and monomer industries is associated with an increased incidence of lymphoma. BD is present in automobile exhaust, cigarette smoke, and forest fires, raising concern about potential exposure of the general population to this carcinogen. Following inhalation exposure, BD is bioactivated to 3,4-epoxy-1 butene (EB). If not detoxified, EB is capable of modifying guanine and adenine bases of DNA to form nucleobase adducts, which interfere with accurate DNA replication and cause cancer-initiating mutations. We have developed a nanoLC/ESI+-HRMS3 methodology for N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts in human urine (limit of detection: 0.25 fmol/mL urine; limit of quantitation: 1.0 fmol/mL urine). This new method was successfully used to quantify EB-GII in urine of F344 rats treated with 0-200 ppm of BD, occupationally exposed workers, and smokers belonging to two different ethnic groups. EB-GII amounts increased in a dose-dependent manner in urine of laboratory rats exposed to 0, 62.5, or 200 ppm of BD. Urinary EB-GII levels were significantly increased in workers occupationally exposed to 0.1-2.2 ppm of BD (1.25 +/- 0.51 pg/mg of creatinine) as compared to administrative controls exposed to <0.01 ppm of BD (0.22 +/- 0.08 and pg/mg of creatinine) (p = 0.0024), validating the use of EB-GII as a biomarker of human exposure to BD. EB-GII was also detected in smokers' urine with European American smokers excreting significantly higher amounts of EB-GII than African American smokers (0.48 +/- 0.09 vs 0.12 +/- 0.02 pg/mg of creatinine, p = 3.1 * 10-7). Interestingly, small amounts of EB-GII were observed in animals and humans with no known exposure to BD, providing preliminary evidence for its endogenous formation. Urinary EB-GII adduct levels and urinary mercapturic acids of BD (MHBMA, DHBMA) were compared in a genotyped multiethnic smoker cohort. PMID- 27997140 TI - In-Silico Analysis and Implementation of a Multicellular Feedback Control Strategy in a Synthetic Bacterial Consortium. AB - Living organisms employ endogenous negative feedback loops to maintain homeostasis despite environmental fluctuations. A pressing open challenge in Synthetic Biology is to design and implement synthetic circuits to control host cells' behavior, in order to regulate and maintain desired conditions. To cope with the high degree of circuit complexity required to accomplish this task and the intrinsic modularity of classical control schemes, we suggest the implementation of synthetic endogenous feedback loops across more than one cell population. The distribution of the sensing, computation, and actuation functions required to achieve regulation across different cell populations within a consortium allows the genetic engineering in a particular cell to be reduced, increases the robustness, and makes it possible to reuse the synthesized modules for different control applications. Here, we analyze, in-silico, the design of a synthetic feedback controller implemented across two cell populations in a consortium. We study the effects of distributing the various functions required to build a control system across two populations, prove the robustness and modularity of the strategy described, and provide a computational proof-of concept of its feasibility. PMID- 27997142 TI - Thiosulfate Conversion to Sulfide by a Haloalkaliphilic Microbial Community in a Bioreactor Fed with H2 Gas. AB - In industrial gas biodesulfurization systems, where haloalkaline conditions prevail, a thiosulfate containing bleed stream is produced. This bleed stream can be treated in a separate bioreactor by reducing thiosulfate to sulfide and recycling it. By performing treatment and recycling of the bleed stream, its disposal decreases and less caustics are required to maintain the high pH. In this study, anaerobic microbial thiosulfate conversion to sulfide in a H2/CO2 fed bioreactor operated at haloalkaline conditions was investigated. Thiosulfate was converted by reduction to sulfide as well as disproportionation to sulfide and sulfate. Formate production from H2/CO2 was observed as an important reaction in the bioreactor. Formate, rather than H2, might have been used as the main electron donor by thiosulfate/sulfate-reducing bacteria. The microbial community was dominated by bacteria belonging to the family Clostridiaceae most closely related to Tindallia texcoconensis. Bacteria phylogenetically related to known haloalkaline sulfate and thiosulfate reducers, thiosulfate-disproportionating bacteria, and remarkably sulfur-oxidizing bacteria were also detected. On the basis of the results, two approaches to treat the biodesulfurization waste stream are proposed: (i) addition of electron donor to reduce thiosulfate to sulfide and (ii) thiosulfate disproportionation without the need for an electron donor. The concept of application of solely thiosulfate disproportionation is discussed. PMID- 27997141 TI - Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure. AB - Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in Gomez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure. PMID- 27997143 TI - Desorption of SVOCs from Heated Surfaces in the Form of Ultrafine Particles. AB - Ultrafine particles (UFP) produced by electric heating of stoves and metal cooking pans, absent food, have been hypothesized to be created from a surface film of semivolatile organic compounds (SVOCs) sorbed from the surrounding air. This study tests that hypothesis by size-resolved measurements extending the lower range of the UFP studied from 10 to 2.3 nm, and including other surfaces (glass, aluminum, and porcelain). Heating glass Petri dishes or squares of aluminum foil to about 350-400 degrees C for 4-6 min removed all sorbed organic substances completely. Subsequent exposure of these "clean" Petri dishes and foil squares to indoor air in two different residences for successively longer periods (1 h to 281 days), followed by heating the materials for 4-6 min, indicated a strong relationship of the number, size distribution, and mass of the UFP to the time exposed. Estimates of the accumulation rate of SVOCs on surfaces were similar to those in studies of organic film buildup on indoor windows. Transfer of skin oils by touching the glass or foil surfaces, or after washing the glass surface with detergent and bare hands, was also observed, with measured particle production comparable with that produced by long-term exposure to indoor air. PMID- 27997144 TI - Iron-Anode Enhanced Sand Filter for Arsenic Removal from Tube Well Water. AB - Sand filters are widely used for well water purification in endemic arsenicosis areas, but arsenic (As) removal is difficult at low intrinsic iron concentrations. This work developed an enhanced sand filter by electrochemically generated Fe(II) from an iron anode. The efficiency of As removal was tested in an arsenic burdened region in the Jianghan Plain, central China. By controlling a current of 0.6 A and a flow rate of about 12 L/h, the filter removed total As in the tube well water from 196 to 472 MUg/L to below 10 MUg/L, whereas the residual As was about 110 MUg/L without electricity. Adsorption and subsequent oxidation on the surface of Fe(III) precipitates are the main processes controlling the removals of As and Fe. During a 30-day intermittent operation, both effluent As concentration and electrical energy consumption decreased progressively. Although filter clogging was observed, it can be alleviated by replacing the top layer of sand. Our findings suggest that dosing Fe(II) by an iron anode is an effective means to enhance As removal in a sand filter. PMID- 27997145 TI - Detecting Microbially Induced Calcite Precipitation in a Model Well-Bore Using Downhole Low-Field NMR. AB - Microbially induced calcite precipitation (MICP) has been widely researched recently due to its relevance for subsurface engineering applications including sealing leakage pathways and permeability modification. These applications of MICP are inherently difficult to monitor nondestructively in time and space. Nuclear magnetic resonance (NMR) can characterize the pore size distributions, porosity, and permeability of subsurface formations. This investigation used a low-field NMR well-logging probe to monitor MICP in a sand-filled bioreactor, measuring NMR signal amplitude and T2 relaxation over an 8 day experimental period. Following inoculation with the ureolytic bacteria, Sporosarcina pasteurii, and pulsed injections of urea and calcium substrate, the NMR measured water content in the reactor decreased to 76% of its initial value. T2 relaxation distributions bifurcated from a single mode centered about approximately 650 ms into a fast decaying population (T2 less than 10 ms) and a larger population with T2 greater than 1000 ms. The combination of changes in pore volume and surface minerology accounts for the changes in the T2 distributions. Destructive sampling confirmed final porosity was approximately 88% of the original value. These results indicate the low-field NMR well-logging probe is sensitive to the physical and chemical changes caused by MICP in a laboratory bioreactor. PMID- 27997146 TI - Silver Sink Effect of Humic Acid on Bacterial Surface Colonization in the Presence of Silver Ions and Nanoparticles. AB - Silver nanoparticles (AgNPs) released from consumer products may enter the environment and possibly harm microbial communities. Prior research showed that surface-adherent AgNPs inhibit bacterial surface colonization, a precursor to biofilm formation, only when planktonic bacterial inoculum concentrations are less than a threshold level ( Wirth and co-workers, J. Colloid Interface Sci. 2016 , 467 , 17 - 27 ). This inoculum effect is due to a decrease in free silver ion concentration associated with sublethal binding to bacteria. Natural organic matter can be an additional silver sink in environmental systems. Using Pseudomonas fluorescens as a model biofilm-forming bacterium, we find significant increases in minimum bactericidal concentrations for AgNP suspensions and Ag+ in solution when adding humic acid (HA) to bacterial suspensions. When HA is present, planktonic bacteria survive and colonize AgNP-laden glass surfaces at lower bacterial inoculum concentrations than were needed for survival and colonization in its absence. This occurs despite the observed tendency of HA to inhibit colonization on bare glass surfaces when silver is absent. Results are interpreted through equilibrium Ag+ binding isotherms to HA and suspended bacteria. These results indicate that silver ion sinks may lessen AgNP impacts on natural microbial ecology relative to the disruption observed in pristine laboratory conditions. PMID- 27997148 TI - Pyridine-Catalyzed Radical Borylation of Aryl Halides. AB - A pyridine-catalyzed transition-metal-free borylation reaction of haloarenes has been developed based on the selective cross-coupling of an aryl radical and a pyridine-stabilized boryl radical. Arylboronates were produced from haloarenes under mild conditions. This borylation reaction features a broad substrate scope, operational simplicity, and gram-scale synthetic ability. PMID- 27997147 TI - Field Measurements of Black Carbon Yields from Gas Flaring. AB - Black carbon (BC) emissions from gas flaring in the oil and gas industry are postulated to have critical impacts on climate and public health, but actual emission rates remain poorly characterized. This paper presents in situ field measurements of BC emission rates and flare gas volume-specific BC yields for a diverse range of flares. Measurements were performed during a series of field campaigns in Mexico and Ecuador using the sky-LOSA optical measurement technique, in concert with comprehensive Monte Carlo-based uncertainty analyses. Parallel on site measurements of flare gas flow rate and composition were successfully performed at a subset of locations enabling direct measurements of fuel-specific BC yields from flares under field conditions. Quantified BC emission rates from individual flares spanned more than 4 orders of magnitude (up to 53.7 g/s). In addition, emissions during one notable ~24-h flaring event (during which the plume transmissivity dropped to zero) would have been even larger than this maximum rate, which was measured as this event was ending. This highlights the likely importance of superemitters to global emission inventories. Flare gas volume-specific BC yields were shown to be strongly correlated with flare gas heating value. A newly derived correlation fitting current field data and previous lab data suggests that, in the context of recent studies investigating transport of flare-generated BC in the Arctic and globally, impacts of flaring in the energy industry may in fact be underestimated. PMID- 27997149 TI - Separation and Selective Formation of Fullerene Adducts within an M(II)(8)L(6) Cage. AB - The self-assembly of 4-fold-symmetric porphyrins with FeII or ZnII gave a new cubic MII8L6 cage framework with electron-deficient walls. This cage bound C60 indene or C60-anthracene bisadducts selectively, whereas unfunctionalized fullerenes and monoadducts were not encapsulated. The FeII8L6 cage also enabled the reaction of C60 and anthracene to yield the bisadducts selectively under conditions where no reaction was observed in the absence of the cage. These findings have relevance in the context of polymer solar cells, where C60 bisadducts have found use as electron acceptors, because these adducts currently require laborious and time-consuming syntheses and purification. PMID- 27997150 TI - Nutrient Recovery and Emissions of Ammonia, Nitrous Oxide, and Methane from Animal Manure in Europe: Effects of Manure Treatment Technologies. AB - Animal manure contributes considerably to ammonia (NH3) and greenhouse gas (GHG) emissions in Europe. Various treatment technologies have been implemented to reduce emissions and to facilitate its use as fertilizer, but a systematic analysis of these technologies has not yet been carried out. This study presents an integrated assessment of manure treatment effects on NH3, nitrous oxide (N2O) and methane (CH4) emissions from manure management chains in all countries of EU 27 in 2010 using the MITERRA-Europe model. Effects of implementing 12 treatment technologies on emissions and nutrient recovery were further explored through scenario analyses; the level of implementation corresponded to levels currently achieved by forerunner countries. Manure treatment decreased GHG emissions from manures in EU countries by 0-17% in 2010, with the largest contribution from anaerobic digestion; the effects on NH3 emissions were small. Scenario analyses indicate that increased use of slurry acidification, thermal drying, incineration and pyrolysis may decrease NH3 (9-11%) and GHG (11-18%) emissions; nitrification denitrification treatment decreased NH3 emissions, but increased GHG emissions. The nitrogen recovery (% of nitrogen excreted in housings that is applied to land) would increase from a mean of 57% (in 2010) to 61% by acidification, but would decrease to 48% by incineration. Promoting optimized manure treatment technologies can greatly contribute to achieving NH3 and GHG emission targets set in EU environmental policies. PMID- 27997151 TI - Changing Ce3+ Content and Codoping Mn2+ Induced Tunable Emission and Energy Transfer in Ca2.5Sr0.5Al2O6:Ce3+,Mn2. AB - A series of color-tunable Ce3+ single-doped and Ce3+, Mn2+ codoped Ca2.5Sr0.5Al2O6 phosphors were synthesized by a high-temperature solid-state reaction. The crystal structure, luminescent properties, and energy transfer were studied. For Ca2.5Sr0.5Al2O6:Ce3+ phosphors obtained with Al(OH)3 as the raw material, three emission profiles were observed. The peak of photoluminescence (PL) spectra excited at ~360 nm shifts from 470 to 420 nm, while that of the PL spectra excited at 305 nm stays unchanged at 470 nm with the increase of Ce3+ content. Furthermore, the peak of PL spectra is situated at 500 nm under excitation at ~400 nm. The relationship between the luminescent properties and crystal structure was studied in detail. Ce3+, Mn2+ codoped Ca2.5Sr0.5Al2O6 phosphors also showed interesting luminescent properties when focused on the PL spectra excited at 365 nm. Obvious different decreasing trends of blue and cyan emission components were observed in Ca2.5Sr0.5Al2O6:0.11Ce3+,xMn2+ phosphors with the increase in Mn2+ content, suggesting different energy transfer efficiencies from blue- and cyan-emitting Ce3+ to Mn2+. Phosphors with high color rendering index (CRI) values are realized by adjusting the doping content of both Ce3+ and Mn2+. Studies suggest that the Ca2.5Sr0.5Al2O6:Ce3+,Mn2+ phosphor is a promising candidate for near UV-excited w-LEDs. PMID- 27997152 TI - Electrocatalytic Z -> E Isomerization of Azobenzenes. AB - A variety of azobenzenes were synthesized to study the behavior of their E and Z isomers upon electrochemical reduction. Our results show that the radical anion of the Z isomer is able to rapidly isomerize to the corresponding E configured counterpart with a dramatically enhanced rate as compared to the neutral species. Due to a subsequent electron transfer from the formed E radical anion to the neutral Z starting material the overall transformation is catalytic in electrons; i.e., a substoichiometric amount of reduced species can isomerize the entire mixture. This pathway greatly increases the efficiency of (photo)switching while also allowing one to reach photostationary state compositions that are not restricted to the spectral separation of the individual azobenzene isomers and their quantum yields. In addition, activating this radical isomerization pathway with photoelectron transfer agents allows us to override the intrinsic properties of an azobenzene species by triggering the reverse isomerization direction (Z -> E) by the same wavelength of light, which normally triggers E -> Z isomerization. The behavior we report appears to be general, implying that the metastable isomer of a photoswitch can be isomerized to the more stable one catalytically upon reduction, permitting the optimization of azobenzene switching in new as well as indirect ways. PMID- 27997153 TI - Self-Assembly of Discrete RuII8 Molecular Cages and Their in Vitro Anticancer Activity. AB - Four new octanuclear Ru(II) cages (OC-1-OC-4) were synthesized from dinuclear p cymene ruthenium(II) acceptors [Ru2(MU-eta4-C2O4)(CH3OH)2(eta6-p cymene)2](O3SCF3)2 (A1), [Ru2(MU-eta4-C6H2O4)(CH3OH)2(eta6-p-cymene)2](O3SCF3)2 (A2), [Ru2(dhnq)(H2O)2(eta6-p-cymene)2](O3SCF3)2 (A3), and [Ru2(dhtq)(H2O)2(eta6 p-cymene)2](O3SCF3)2 (A4) separately with a tetradentate pyridyl ligand (L1) in methanol using coordination-driven self-assembly [L1= N,N,N',N'-tetra(pyridin-4 yl)benzene-1,4-diamine]. The octanuclear cages are fully characterized by various spectroscopic techniques including single-crystal X-ray diffraction analysis of OC-4. The self-assembled cages show strong in vitro anticancer activity against human lung adenocarcinoma A549 and human cervical cancer HeLa cell lines as observed from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Of all the octanuclear cages, OC-3 exhibits remarkable anticancer activity against both cancer cell lines and is more active than that reported for cisplatin. The excellent anticancer activity of OC-3 and OC-4 highlights the importance of the synergistic effects of the spacer component of the dinuclear p cymene Ru(II) acceptor clips. PMID- 27997155 TI - UV and IR Spectroscopy of Cryogenically Cooled, Lanthanide-Containing Ions in the Gas Phase. AB - We measure UV and IR spectra in the gas phase for EuOH+, EuCl+, and TbO+ ions, which are produced by an electrospray ionization source and cooled to ~10 K in a cold, 22-pole ion trap. The UV photodissociation (UVPD) spectra of these ions show a number of sharp, well-resolved bands in the 30000-38000 cm-1 region, although a definite assignment of the spectra is difficult because of a high degree of congestion. We also measure an IR spectrum of the EuOH+ ion in the 3500 3800 cm-1 region by IR-UV double-resonance spectroscopy, which reveals an OH stretching band at 3732 cm-1. We perform density functional theory (DFT) and time dependent DFT (TD-DFT) calculations of these ions in order to examine the nature of the transitions. The DFT results indicate that the states of highest-spin multiplicity (octet for EuOH+ and EuCl+ and septet for TbO+) are substantially more stable than other states of lower-spin multiplicity. The TD-DFT calculations suggest that UV absorption of the EuOH+ and EuCl+ ions arises from Eu(4f) -> Eu(5d,6p) transitions, whereas electronic transitions of the TbO+ ion are mainly due to the electron promotion of O(2p) -> Tb(4f,6s). The UVPD results of the lanthanide-containing ions in this study suggest the possibility of using lanthanide ions as "conformation reporters" for gas-phase spectroscopy for large molecules. PMID- 27997154 TI - Combining Electrospun Fiber Mats and Bioactive Coatings for Vascular Graft Prostheses. AB - The patency of small-diameter (<6 mm) synthetic vascular grafts (VGs) is still limited by the absence of a confluent, blood flow-resistant monolayer of endothelial cells (ECs) on the lumen and of vascular smooth muscle cell (VSMC) growth into the media layer. In this research, electrospinning has been combined with bioactive coatings based on chondroitin sulfate (CS) to create scaffolds that possess optimal morphological and bioactive properties for subsequent cell seeding. We fabricated random and aligned electrospun poly(ethylene terephthalate), ePET, mats with small pores (3.2 +/- 0.5 or 3.9 +/- 0.3 MUm) and then investigated the effects of topography and bioactive coatings on EC adhesion, growth, and resistance to shear stress. Bioactive coatings were found to dominate the cell behavior, which enabled creation of a near-confluent EC monolayer that resisted physiological shear-flow conditions. CS is particularly interesting since it prevents platelet adhesion, a key issue to avoid blood clot formation in case of an incomplete EC monolayer or partial cell detachment. Regarding the media layer, circumferentially oriented nanofibers with larger pores (6.3 +/- 0.5 MUm) allowed growth, survival, and inward penetration of VSMCs, especially when the CS was further coated with tethered, oriented epithelial growth factor (EGF). In summary, the techniques developed here can lead to adequate scaffolds for the luminal and media layers of small-diameter synthetic VGs. PMID- 27997156 TI - Structure-Band Gap Relationships in Hexagonal Polytypes and Low-Dimensional Structures of Hybrid Tin Iodide Perovskites. AB - The present study deals with the structural characterization and classification of the novel compounds 1-8 into perovskite subclasses and proceeds in extracting the structure-band gap relationships between them. The compounds were obtained from the employment of small, 3-5-atom-wide organic ammonium ions seeking to discover new perovskite-like compounds. The compounds reported here adopt unique or rare structure types akin to the prototype structure perovskite. When trimethylammonium (TMA) was employed, we obtained TMASnI3 (1), which is our reference compound for a "perovskitoid" structure of face-sharing octahedra. The compounds EASnI3 (2b), GASnI3 (3a), ACASnI3 (4), and IMSnI3 (5) obtained from the use of ethylammonium (EA), guanidinium (GA), acetamidinium (ACA), and imidazolium (IM) cations, respectively, represent the first entries of the so-called "hexagonal perovskite polytypes" in the hybrid halide perovskite library. The hexagonal perovskites define a new family of hybrid halide perovskites with a crystal structure that emerges from a blend of corner- and face-sharing octahedral connections in various proportions. The small organic cations can also stabilize a second structural type characterized by a crystal lattice with reduced dimensionality. These compounds include the two-dimensional (2D) perovskites GA2SnI4 (3b) and IPA3Sn2I7 (6b) and the one-dimensional (1D) perovskite IPA3SnI5 (6a). The known 2D perovskite BA2MASn2I7 (7) and the related all-inorganic 1D perovskite "RbSnF2I" (8) have also been synthesized. All compounds have been identified as medium-to-wide-band-gap semiconductors in the range of Eg = 1.90-2.40 eV, with the band gap progressively decreasing with increased corner-sharing functionality and increased torsion angle in the octahedral connectivity. PMID- 27997157 TI - Reaction Parameters Influencing Cobalt Hydride Formation Kinetics: Implications for Benchmarking H(2)-Evolution Catalysts. AB - The need for benchmarking hydrogen evolution catalysts has increasingly been recognized. The influence of acid choice on activity is often reduced to the overpotential for catalysis. Through the study of a stable cobalt hydride complex, we demonstrate the influence of acid choice, beyond pKa, on the kinetics of hydride formation. A linear free energy relationship between acid pKa and second-order rate constants is observed for weaker acids. For stronger acids, however, further increases in pKa do not correlate to increases in rate constants. Further, steric bulk around the acidic proton is shown to influence rate constants dramatically. Together, these observations reveal the complex factors dictating catalyst performance. PMID- 27997158 TI - Chaperone-like Activity of Calnuc Prevents Amyloid Aggregation. AB - Calnuc is a ubiquitously expressed protein of the EF-hand Ca2+-binding superfamily. Previous studies have implicated it in Ca2+-sensitive physiological processes, whereas details of its function and involvement in human diseases are lacking. Drawing upon the sequence homology of calnuc with calreticulin, we propose it functions as a molecular chaperone-like protein. In cells under thermal, chemical [urea and guanidinium chloride (GdmCl)], and acidic stress, calnuc exhibits properties similar to those of established chaperone-like proteins (GRP78, spectrin, and alpha-crystallin), effectively demonstrated by its ability to suppress aggregation of malate dehydrogenase (MDH), alcohol dehydrogenase, and catalase. Calnuc aids in refolding of MDH with retention of 80% of its enzymatic activity. In HEK293 cells subjected to heat shock, calnuc chaperones luciferase, protecting its activity. Our in vitro and cell culture results establish the ability of calnuc to inhibit fibrillation of insulin and lysozyme and validate its neuroprotective role in cells treated with amyloid fibrils. Calnuc also rescues cells from fibrillar toxicity (caused by misfolded or aggregated proteins), providing a plausible explanation for the previous observation of its low level of expression in brains affected by Alzheimer's disease. We propose that calnuc is possibly involved in controlling protein unfolding diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), prion disease, and type II diabetes. PMID- 27997159 TI - The Formation Time of Ti-O* and Ti-O*-Ti Radicals at the n-SrTiO3/Aqueous Interface during Photocatalytic Water Oxidation. AB - The initial step of photocatalytic water oxidation reaction at the metal oxide/aqueous interface involves intermediates formed by trapping photogenerated, valence band holes on different reactive sites of the oxide surface. In SrTiO3, these one-electron intermediates are radicals located in Ti-O* (oxyl) and Ti-O* Ti (bridge) groups arranged perpendicular and parallel to the surface respectively, and form electronic states in the band gap of SrTiO3. Using an ultrafast sub band gap probe of 400 nm and white light, we excited transitions between these radical states and the conduction band. By measuring the time evolution of surface reflectivity following the pump pulse of 266 nm light, we determined an initial radical formation time of 1.3 +/- 0.2 ps, which is identical to the time to populate the surface with titanium oxyl (Ti-O*) radicals. The oxyl was separately observed by a subsurface vibration near 800 cm 1 from Ti-O located in the plane right below Ti-O*. Second, a polarized transition optical dipole allows us to assign the 1.3 ps time constant to the production of both O-site radicals. After a 4.5 ps delay, another distinct surface species forms with a time constant of 36 +/- 10 ps with a yet undetermined structure. As would be expected, the radicals' decay, specifically probed by the oxyl's subsurface vibration, parallels that of the photocurrent. Our results led us to propose a nonadiabatic kinetic mechanism for generating radicals of the type Ti-O* and Ti-O*-Ti from valence band holes based on their solvation at aqueous interfaces. PMID- 27997160 TI - Cobalt N-Heterocyclic Phosphenium Complexes Stabilized by a Chelating Framework: Synthesis and Redox Properties. AB - Two cobalt complexes containing coordinated N-heterocyclic phosphenium (NHP+) ligands are synthesized using a bidentate NHP+/phosphine chelating ligand, [PP]+. Treatment of Na[Co(CO)4] with the chlorophosphine precursor [PP]Cl (1) affords [PP]Co(CO)2 (2), which features a planar geometry at the NHP+ phosphorus center and a short Co-P distance [1.9922(4) A] indicative of a Co?P double bond. The more electron-rich complex [PP]Co(PMe3)2 (3), which is synthesized in a one-pot reduction procedure with 1, CoCl2, PMe3, and KC8, has an even shorter Co-P bond [1.9455(6) A] owing to stronger metal-to-phosphorus back-donation. The redox properties of 2 and 3 were explored using cyclic voltammetry, and oxidation of 3 was achieved to afford [[PP]Co(PMe3)2]+ (4). The electron paramagnetic resonance spectrum of complex 4 features hyperfine coupling to both 59Co and 31P, suggesting strong delocalization of the unpaired electron density in this complex. Density functional theory calculations are used to further explore the bonding and redox behavior of complexes 2-4, shedding light on the potential for redox noninnocent behavior of NHP+ ligands. PMID- 27997161 TI - Bacteriochlorins with a Twist: Discovery of a Unique Mechanism to Red-Shift the Optical Spectra of Bacteriochlorins. AB - Owing to their intense near infrared absorption and emission properties, to the ability to photogenerate singlet oxygen, or to act as photoacoustic imaging agents within the optical window of tissue, bacteriochlorins (2,3,12,13 tetrahydroporphyrins) promise to be of utility in many biomedical and technical applications. The ability to fine-tune the electronic properties of synthetic bacteriochlorins is important for these purposes. In this vein, we report the synthesis, structure determination, optical properties, and theoretical analysis of the electronic structure of a family of expanded bacteriochlorin analogues. The stepwise expansion of both pyrroline moieties in near-planar meso tetraarylbacteriochlorins to morpholine moieties yields ruffled mono- and bismorpholinobacteriochlorins with broadened and up to 90 nm bathochromically shifted bacteriochlorin-like optical spectra. Intramolecular ring-closure reactions of the morpholine moiety with the flanking meso-aryl groups leads to a sharpened, blue-shifted wavelength lambdamax band, bucking the general red shifting trend expected for such linkages. A conformational origin of the optical modulations was previously proposed, but discrepancies between the solid state conformations and the corresponding solution state optical spectra defy simple structure-optical property correlations. Using density functional theory and excited state methods, we derive the molecular origins of the spectral modulations. About half of the modulation is due to ruffling of the bacteriochlorin chromophore. Surprisingly, the other half originates in the localized twisting of the Cbeta-Calpha-Calpha-Cbeta dihedral angle within the morpholine moieties. Our calculations suggest a predictable and large spectral shift (2.0 nm/deg twist) for morpholine deformations within these fairly flexible moieties. This morpholine moiety deformation can take place largely independently from the overall macrocycle conformation. The morpholinobacteriochlorins are thus excellent models for localized bacteriochlorin chromophore deformations that are suggested to also be responsible for the optical modulation of naturally occurring bacteriochlorophylls. We propose the use of morpholinobacteriochlorins as mechanochromic dyes in engineering and materials science applications. PMID- 27997162 TI - Carbohydrate-Neuroactive Hybrid Strategy for Metabolic Glycan Engineering of the Central Nervous System in Vivo. AB - Sialic acids are abundant in the central nervous system (CNS) and are essential for brain development, learning, and memory. Dysregulation in biosynthesis of sialo-glycoconjugates is known to be associated with neurological disorders, CNS injury, and brain cancer. Metabolic glycan engineering (MGE) and bioorthogonal ligation have enabled study of biological roles of glycans in vivo; however, direct investigations of sialoglycans in brain have been intractable. We report a simple strategy utilizing carbohydrate-neuroactive hybrid (CNH) molecules, which exploit carrier-mediated transport systems available at the blood-brain barrier, to access brain via tail vein injection in mice. Peracetylated N-azidoacetyl-d mannosamine (Ac4ManNAz) conjugated with neuroactive carriers, namely, nicotinic acid, valproic acid, theophylline-7-acetic acid, and choline, were synthesized and evaluated in SH-SY5Y (human neuroblastoma) cells for MGE. Intravenous administration of CNH molecules in mice (C57BL/6J and BALB/cByJ) resulted in robust expression of N-azidoacetyl-neuraminic acid (NeuAz)-carrying glycoproteins in both brain and heart, while the nonhybrid molecule Ac4ManNAz showed NeuAz expression in heart but not in brain. Successful neuroactive carriers were then conjugated with N-butanoyl-d-mannosamine (ManNBut) with a goal to achieve modulation of polysialic acid (polySia) on neural cell adhesion molecules (NCAM). PolySia levels on NCAM in adult mice were reduced significantly upon administration of Ac3ManNBut-nicotinate hybrid, but not with Ac4ManNBut. This novel application of MGE not only offers a noninvasive tool for investigating brain glycosylation, which could be developed in to brain mapping applications, but also serves as a potential drug by which modulation of neural glycan biosynthesis and thus function can be achieved in vivo. PMID- 27997163 TI - Origin of High Regio-, Diastereo-, and Enantioselectivities in 1,6-Addition of Azlactones to Dienyl N-Acylpyrroles: A Computational Study. AB - Chiral P-spiro triaminoiminophosphorane (1) was developed to promote the highly regio-, diastereo-, and enantioselective 1,6- and 1,8-additions of azlactones (2.H) to dienyl and trienyl N-acylpyrroles (3 and 4). DFT calculations enabled us to gain deep insight into the whole reaction mechanism as well as the origin of the high regio- and stereoselectivities. The present reaction consists of three steps: (1) formation of the phosphonium-enolate ion-pair complex by deprotonation of 2.H with 1, (2) C-C bond formation of 2 with 3 and 4, and (3) protonation of the resulting enolate anion. The C-C bond formation is irreversible, and the rate and stereodetermining step. The Calpha-protonation preferentially proceeds rather than the thermodynamically and kinetically disfavored O- and Cgamma protonation, respectively. The high regio- and enantioselectivities are mainly attributed to the steric and electronic features of 1.H and 3/4. The hydrogen bonds (NH-O and CH-O) and the attractive CH-pi interaction between 1.H and 2 and 3 play a key role in achieving high stereocontrol. The high regioselectivity is mainly controlled by the structural distortion of 1.H and the disruption of the pi-conjugated system of 3 (1,4-system) and 4 (1,4- and 1,6-systems). PMID- 27997164 TI - Synthesis of Novel c(AmpRGD)-Sunitinib Dual Conjugates as Molecular Tools Targeting the alphavbeta3 Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis. AB - On the basis of a previously discovered anti-alphaVbeta3 integrin peptidomimetic (c(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds 1-3), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward alphaVbeta3 (using both isolated receptors and alphaVbeta3-overexpressing endothelial progenitor EP cells) and the kinase inhibitory activity (toward both isolated kinases and EPCs) remained almost untouched and comparable to the activity of the single active units. Compounds 1-3 showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate 3 strongly inhibited in vivo angiogenesis in Matrigel plug assays in FVB mice. These results offer proof-of-concept of how the covalent conjugation of two angiogenesis-related small modules may result in novel and stable molecules, which impair tumor related angiogenesis with equal or even superior ability as compared to the single modules or their simple combinations. PMID- 27997166 TI - Operative Mechanism of Hole-Assisted Negative Charge Motion in Ground States of Radical-Anion Molecular Wires. AB - Charge transfer/transport in molecular wires over varying distances is a subject of great interest. The feasible transport mechanisms have been generally accounted for on the basis of tunneling or superexchange charge transfer operating over small distances which progressively gives way to hopping transport over larger distances. The underlying molecular sequential steps that likely take place during hopping and the operative mechanism occurring at intermediate distances have received much less attention given the difficulty in assessing detailed molecular-level information. We describe here the operating mechanisms for unimolecular electron transfer/transport in the ground state of radical-anion mixed-valence derivatives occurring between their terminal perchlorotriphenylmethyl/ide groups through thiophene-vinylene oligomers that act as conjugated wires of increasing length up to 53 A. The unique finding here is that the net transport of the electron in the larger molecular wires is initiated by an electron-hole dissociation intermediated by hole delocalization (conformationally assisted and thermally dependent) forming transient mobile polaronic states in the bridge that terminate by an electron-hole recombination at the other wire extreme. On the contrary, for the shorter radical-anions our results suggest that a flickering resonance mechanism which is intermediate between hopping and superexchange is the operative one. We support these mechanistic interpretations by applying the pertinent biased kinetic models of the charge/spin exchange rates determined by electron paramagnetic resonance and by molecular structural level information obtained from UV-vis and Raman spectroscopies and by quantum chemical modeling. PMID- 27997165 TI - Aromatic-Aromatic Interactions Enable alpha-Helix to beta-Sheet Transition of Peptides to Form Supramolecular Hydrogels. AB - Isolated short peptides usually are unable to maintain their original secondary structures due to the lack of the restriction from proteins. Here we show that two complementary pentapeptides from a beta-sheet motif of a protein, being connected to an aromatic motif (i.e., pyrene) at their C-terminal, self-assemble to form beta-sheet like structures upon mixing. Besides enabling the self assembly to result in supramolecular hydrogels upon mixing, aromatic-aromatic interactions promote the pentapeptides transform from alpha-helix to beta-sheet conformation. As the first example of using aromatic-aromatic interactions to mimic the conformational restriction in a protein, this work illustrates a bioinspired way to generate peptide nanofibers with predefined secondary structures of the peptides by a rational design using protein structures as the blueprint. PMID- 27997168 TI - Cooking Has Variable Effects on the Fermentability in the Large Intestine of the Fraction of Meats, Grain Legumes, and Insects That Is Resistant to Digestion in the Small Intestine in an in Vitro Model of the Pig's Gastrointestinal Tract. AB - This study aimed to evaluate the fermentation in the large intestine of indigestible dietary protein sources from animal, insect, and plant origin using an in vitro model of the pig's gastrointestinal tract. Protein sources were used raw and after a cooking treatment. Results showed that the category of the ingredient (meats, insects, or grain legumes) exerts a stronger impact on enzymatic digestibility, fermentation patterns, and bacterial metabolites such as short-chain fatty acids (SCFA) and hydrogen sulfide (H2S) than the cooking treatment. The digestibility and the fermentation characteristics of insects were more affected by the cooking procedure than the other categories. Per gram of consumed food, ingredients from animal origin, namely, meats and insects, were associated with fewer fermentation end-products (gas, H2S, SCFA) than ingredients from plant origin, which is related to their higher small intestinal digestibility. PMID- 27997169 TI - Rapid, Accurate, Precise, and Reliable Relative Free Energy Prediction Using Ensemble Based Thermodynamic Integration. AB - The accurate prediction of the binding affinities of ligands to proteins is a major goal in drug discovery and personalized medicine. The time taken to make such predictions is of similar importance to their accuracy, precision, and reliability. In the past few years, an ensemble based molecular dynamics approach has been proposed that provides a route to reliable predictions of free energies based on the molecular mechanics Poisson-Boltzmann surface area method which meets the requirements of speed, accuracy, precision, and reliability. Here, we describe an equivalent methodology based on thermodynamic integration to substantially improve the speed, accuracy, precision, and reliability of calculated relative binding free energies. We report the performance of the method when applied to a diverse set of protein targets and ligands. The results are in very good agreement with experimental data (90% of calculations agree to within 1 kcal/mol), while the method is reproducible by construction. Statistical uncertainties of the order of 0.5 kcal/mol or less are achieved. We present a systematic account of how the uncertainty in the predictions may be estimated. PMID- 27997167 TI - Three-Dimensional Structure Determination of Surface Sites. AB - The spatial arrangement of atoms is directly linked to chemical function. A fundamental challenge in surface chemistry and catalysis relates to the determination of three-dimensional structures with atomic-level precision. Here we determine the three-dimensional structure of an organometallic complex on an amorphous silica surface using solid-state NMR measurements, enabled through a dynamic nuclear polarization surface enhanced NMR spectroscopy approach that induces a 200-fold increase in the NMR sensitivity for the surface species. The result, in combination with EXAFS, is a detailed structure for the surface complex determined with a precision of 0.7 A. We observe a single well-defined conformation that is folded toward the surface in such a way as to include an interaction between the platinum metal center and the surface oxygen atoms. PMID- 27997170 TI - Comprehensive Insights into the Multi-Antioxidative Mechanisms of Melanin Nanoparticles and Their Application To Protect Brain from Injury in Ischemic Stroke. AB - Nanotechnology-mediated antioxidative therapy is emerging as a novel strategy for treating a myriad of important diseases through scavenging excessive reactive oxygen and nitrogen species (RONS), a mechanism critical in disease development and progression. However, similar to antioxidative enzymes, currently studied nanoantioxidants have demonstrated scavenging activity to specific RONS, and sufficient antioxidative effects against multiple RONS generated in diseases remain elusive. Here we propose to develop bioinspired melanin nanoparticles (MeNPs) for more potent and safer antioxidative therapy. While melanin is known to function as a potential radical scavenger, its antioxidative mechanisms are far from clear, and its applications for the treatment of RONS-associated diseases have yet to be well-explored. In this study, we provide for the first time exhaustive characterization of the activities of MeNPs against multiple RONS including O2*-, H2O2, *OH, *NO, and ONOO-, the main toxic RONS generated in diseases. The potential of MeNPs for antioxidative therapy has also been evaluated in vitro and in a rat model of ischemic stroke. In addition to the broad defense against these RONS, MeNPs can also attenuate the RONS-triggered inflammatory responses through suppressing the expression of inflammatory mediators and cytokines. In vivo results further demonstrate that these unique multi-antioxidative, anti-inflammatory, and biocompatible features of MeNPs contribute to their effective protection of ischemic brains with negligible side effects. PMID- 27997171 TI - Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain. AB - The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 +/- 1.3 to 1.6 +/- 0.3 MUM) and CME (IC50(CME) = 65.9 +/- 7.7 to 3.7 +/- 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors. PMID- 27997173 TI - Rapid Prediction of Fatty Acid Content in Marine Oil Omega-3 Dietary Supplements Using a Portable Fourier Transform Infrared (FTIR) Device and Partial Least Squares Regression (PLSR) Analysis. AB - Using a portable field device, a Fourier transform infrared spectroscopy (FTIR) and partial least-squares regression (PLSR) method was developed for the rapid (<5 min) prediction of major and minor fatty acid (FA) concentrations in marine oil omega-3 dietary supplements. Calibration models were developed with 174 gravimetrically prepared samples. These models were tested using an independent validation set of dietary supplements. FAs analyzed included eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); the sums of saturated, branched-chain, and monounsaturated FAs; and n-6, n-4, n-3, n-1, and trans polyunsaturated FA. The spectral ranges 650-1500 or 650-1500 and 2800-3050 cm-1 provided reliable predictions for FA components in 34 neat oil products: standard error of prediction, 0.73-1.58%; residual predictive deviation, 6.41-12.6. This simple, nondestructive quantitative method is a rapid screening tool and a time and cost saving alternative to gas chromatography for verifying label declarations and in quality control. PMID- 27997172 TI - Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality. AB - A growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor. PMID- 27997175 TI - alpha-Phenyl-N-cyclohexyl Nitrones: Preparation and Use as Spin-Traps. AB - Two bifunctional alpha-phenyl-N-cyclohexyl nitrones were synthesized with the expectation that the cyclohexyl ring will impart lipophilicity to the molecule, high reactivity to the nitronyl group, and stability to the spin adducts formed. The synthesis of the acid nitrone 4 and its corresponding tert-butyl ester 3 was initiated by a Michael reaction to introduce the cyclohexyl ring. A Zn/AcOH mediated reduction of the nitro functionality followed by condensation onto benzaldehyde generated the nitronyl function. In agreement with their high lipophilicity values, nitrone 3 was insoluble in water, while nitrone 4 exhibited a poor water solubility. It was determined that the presence of the cyclohexyl ring did not affect either the reduction or oxidation potentials of the nitronyl group in comparison to the classical alpha-phenyl-N-tert-butylnitrone (PBN). The spin trapping ability of 3 and 4 was investigated by EPR for oxygen- and carbon centered radicals. In most cases, the nitrones gave rise to a standard six-line EPR spectrum whose values were in agreement with the literature, accompanied by a minor second species. In DMSO, the half-lives of nitrone 3 and 4-OOH adducts were double that of PBN, suggesting that the stabilization comes from the cyclohexyl ring and/or the electronic effect of the carboxylic acid. PMID- 27997174 TI - Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries. AB - Lithium enolates derived from carboxylic acids are ubiquitous intermediates in organic synthesis. Asymmetric transformations with these intermediates, a central goal of organic synthesis, are typically carried out with covalently attached chiral auxiliaries. An alternative approach is to utilize chiral reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as noncovalent, or traceless, chiral auxiliaries. Lithium amides are an obvious choice for such reagents as they are known to form mixed aggregates with lithium enolates. We demonstrate here that mixed aggregates can effect highly enantioselective transformations of lithium enolates in several classes of reactions, most notably in transformations forming tetrasubstituted and quaternary carbon centers. Easy recovery of the chiral reagent by aqueous extraction is another practical advantage of this one-step protocol. Crystallographic, spectroscopic, and computational studies of the central reactive aggregate, which provide insight into the origins of selectivity, are also reported. PMID- 27997176 TI - Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes. AB - Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a "detergent-like" mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies. PMID- 27997177 TI - Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects. AB - Novel azo-bis-ebselen compounds 7 were prepared by reduction of 7-nitro-2-aryl 1,2-benzisoselenazol-3(2H)-ones 3 and 6 with sodium benzenetellurolate, NaTeC6H5, and by reaction of 2-bromo-3-nitrobenzamides with Na2Se2. The X-ray structure of 7b showed that the molecule, due to strong intramolecular secondary Se...N interactions, is completely planar. Azo-compounds 7 upon further reaction with NaTeC6H5 were reductively cleaved to provide 2 equiv of the corresponding aromatic amine. The weak Se-N bond was not stable enough to survive the reaction conditions, and diselenides 8 were isolated after workup. Whereas azo-bis ebselens 7 were poor mimics of the glutathione peroxidase (GPx)-enzymes, nitroebselens 3, 6, and 11b and diselenides 8 were 3-6-fold more active than ebselen. Based on 77Se NMR spectroscopy, a catalytic cycle for diselenide 8b, involving aminoebselen 14, was proposed. As assessed by chemiluminescence measurements, the good GPx-mimics could reduce production of reactive oxygen species (ROS) in stimulated human mononuclear cells more efficiently than Trolox. No toxic effects of the compounds were seen in MC3T3-cells at 25 MUM. PMID- 27997178 TI - Electrocatalytic Alcohol Oxidation with Ruthenium Transfer Hydrogenation Catalysts. AB - Octahedral ruthenium complexes [RuX(CNN)(dppb)] (1, X = Cl; 2, X = H; CNN = 2 aminomethyl-6-tolylpyridine, dppb = 1,4-bis(diphenylphosphino)butane) are highly active for the transfer hydrogenation of ketones with isopropanol under ambient conditions. Turnover frequencies of 0.88 and 0.89 s-1 are achieved at 25 degrees C using 0.1 mol % of 1 or 2, respectively, in the presence of 20 equiv of potassium t-butoxide relative to catalyst. Electrochemical studies reveal that the Ru-hydride 2 is oxidized at low potential (-0.80 V versus ferrocene/ferrocenium, Fc0/+) via a chemically irreversible process with concomitant formation of dihydrogen. Complexes 1 and 2 are active for the electrooxidation of isopropanol in the presence of strong base (potassium t butoxide) with an onset potential near -1 V versus Fc0/+. By cyclic voltammetry, fast turnover frequencies of 3.2 and 4.8 s-1 for isopropanol oxidation are achieved with 1 and 2, respectively. Controlled potential electrolysis studies confirm that the product of isopropanol electrooxidation is acetone, generated with a Faradaic efficiency of 94 +/- 5%. PMID- 27997179 TI - The Suzuki-Miyaura Cross-Coupling Reaction of Halogenated Aminopyrazoles: Method Development, Scope, and Mechanism of Dehalogenation Side Reaction. AB - The efficient Suzuki-Miyaura cross-coupling reaction of halogenated aminopyrazoles and their amides or ureas with a range of aryl, heteroaryl, and styryl boronic acids or esters has been developed. The method allowed incorporation of problematic substrates: aminopyrazoles bearing protected or unprotected pyrazole NH, as well as the free amino or N-amide group. Direct comparison of the chloro, bromo, and iodopyrazoles in the Suzuki-Miyaura reaction revealed that Br and Cl derivatives were superior to iodopyrazoles, as a result of reduced propensity to dehalogenation. Moreover, the mechanism and factors affecting the undesired dehalogenation side reaction were revealed. PMID- 27997181 TI - Oxidative C-C Bond Formation Reactivity of Organometallic Ni(II), Ni(III), and Ni(IV) Complexes. AB - The use of the tridentate ligand 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3tacn) and the cyclic alkyl/aryl C-donor ligand -CH2CMe2-o-C6H4- (cycloneophyl) allows for the synthesis of isolable organometallic NiII, NiIII, and NiIV complexes. Surprisingly, the five-coordinate NiIII complex is stable both in solution and the solid state, and exhibits limited C-C bond formation reactivity. Oxidation by one electron of this NiIII species generates a six coordinate NiIV complex, with an acetonitrile molecule bound to Ni. Interestingly, illumination of the NiIV complex with blue LEDs results in rapid formation of the cyclic C-C product at room temperature. This reactivity has important implications for the recently developed dual Ni/photoredox catalytic systems proposed to involve high-valent organometallic Ni intermediates. Additional reactivity studies show the corresponding NiII species undergoes oxidative addition with alkyl halides, as well as rapid oxidation by O2, to generate detectable NiIII and/or NiIV intermediates and followed by C-C bond formation. PMID- 27997180 TI - Antroquinonol, a Ubiquinone Derivative from the Mushroom Antrodia camphorata, Inhibits Colon Cancer Stem Cell-like Properties: Insights into the Molecular Mechanism and Inhibitory Targets. AB - Antroquinonol (ANQ) is a ubiquinone derivative from the unique mushroom Antrodia camphorata, which exhibits broad-spectrum bioactivities. The effects of ANQ on cancer stem cell-like properties in colon cancer, however, remain unclear. In this study, we found that ANQ inhibited growth of colon cancer cells. The 50% growth inhibitions (GI50) of ANQ on HCT15 and LoVo were 34.8 +/- 0.07 and 17.9 +/ 0.07 MUM. Moreover, ANQ exhibited inhibitory activities toward migration/invasion and tumorsphere formation of colon cancer cells. Mechanistically, ANQ inhibited pluripotent and cancer stem cell-related genes and down-regulated beta-catenin/T-cell factor (TCF) signaling. Moreover, activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/beta-catenin signaling axis was identified to be crucial for regulating the expressions of pluripotent genes, whereas suppression of PI3K/AKT by ANQ inhibited expressions of beta-catenin and downstream targets. Molecular docking identified the potential interaction of ANQ with PI3K. Our data show for the first time that the bioactive component of A. camphorata, ANQ, suppresses stem cell-like properties via targeting PI3K/AKT/beta catenin signaling. ANQ could be a promising cancer prevention agent for colon cancer. PMID- 27997182 TI - Kinetic Energy and Angular Distributions of He and Ar Atoms Evaporating from Liquid Dodecane. AB - We report both kinetic energy and angular distributions for He and Ar atoms evaporating from C12H26. All results were obtained by performing molecular dynamics simulations of liquid C12H26 with around 10-20 noble gas atoms dissolved in the liquid and by subsequently following the trajectories of the noble gas atoms after evaporation from the liquid. Whereas He evaporates with a kinetic energy distribution of (1.05 +/- 0.03) * 2RT (corrected for the geometry used in experiments: (1.08 +/- 0.03) * 2RT, experimentally obtained value: (1.14 +/- 0.01) * 2RT), Ar displays a kinetic energy distribution that better matches a Maxwell-Boltzmann distribution at the temperature of the liquid ((0.99 +/- 0.04) * 2RT). This behavior is also reflected in the angular distributions, which are close to a cosine distribution for Ar but slightly narrower, especially for faster atoms, in the case of He. This behavior of He is most likely due to the weak interaction potential between He and the liquid hydrocarbon. PMID- 27997183 TI - Hydrogen-Bond Donicity in DMSO and Gas Phase and Its Dependence on Bronsted Acidity. AB - The hydrogen-bond (HB) donicity of various HB donors, expressed as standard Gibbs free energy of HB formation with chloride ion, was studied experimentally in dimethyl sulfoxide (DMSO) and computationally in DMSO and the gas phase. Acidity and HB donicity data in the gas phase and DMSO have been obtained for 77 HB donors from different compound families. Applicability of two computational methods (SMD and COSMO-RS) for calculation of solvation contribution to reaction free energy in DMSO was evaluated and discussed. The quality of calculated Gibbs free energies of solvation was assessed using the correlation between HB strengths in solvent and in the gas phase. The investigation of the relationships between HB donicity and Bronsted acidity showed that in the gas phase the correlation is good, and within structurally uniform compound groups both acidity and donicity are described well by substituent constants. The same correlation in DMSO is less distinct. Bidentate HB donors are characterized by higher HB donicity than could be expected from their acidity in both media, and therefore, these HB donors have an important advantage in anion binding applications, e.g., in catalysis. PMID- 27997185 TI - Alkyl(C16, C18, C22)trimethylammonium-Based Herbicidal Ionic Liquids. AB - In the framework of this study a synthesis methodology and characterization of long alkyl herbicidal ionic liquids (HILs) based on four commonly used herbicides (2,4-D, MCPA, MCPP, and dicamba) are presented. New HILs were obtained with high efficiency (>95%) using an acid-base reaction between herbicidal acids and hexadecyltrimethylammonium, octadecyltrimethylammonium, and behenyltrimethylammonium hydroxides in alcoholic medium. Among all synthesized salts, only three compounds comprising the MCPP anion were liquids at room temperature. Subsequently, the influence of both the alkyl chain length and the anion structure on their physicochemical properties (thermal decomposition profiles, solubility in 10 representative solvents, surface activity, density, viscosity, and refractive index) was determined. All HILs exhibited high thermal stability as well as surface activity; however, their solubility notably depended on both the length of the carbon chain and the structure of the anion. The herbicidal efficacy of the obtained salts was tested in greenhouse and field experiments. Greenhouse testing performed on common lambsquarters (Chenopodium album L.) and flixweed (Descurainia sophia L.) as test plants indicated that HILs were characterized by similar or higher efficacy compared to commercial herbicides. The results of field trials confirmed the high activity of HILs, particularly those containing phenoxyacids as anions (MCPA, 2,4-D, and MCPP). PMID- 27997186 TI - Graphenes as Metal-Free Catalysts with Engineered Active Sites. AB - This Perspective article highlights how recent discoveries on the activity of defective graphene to promote different organic reactions as metal-free catalysts has led to propose certain substructures present on these defective graphenes as active sites. The sustainability of using as catalysts graphenes obtained from biomass and the possibility to generate active sites by introducing defects on the sheet are the two main characteristics triggering research in this area. Emphasis is made in the need to gain understanding on the nature of the active sites and how this understanding requires the combination of conventional kinetic experiments as well as advanced characterization tools. The relationship between catalysis by graphene and that by organocatalysis has also been remarked. PMID- 27997184 TI - Investigation of the Effect of Bilayer Composition on PKCalpha-C2 Domain Docking Using Molecular Dynamics Simulations. AB - The protein kinase Calpha (PKCalpha) enzyme is a member of a broad family of serine/threonine kinases, which are involved in varied cellular signaling pathways. The initial step of PKCalpha activation involves the C2 subunit docking with the cell membrane, which is followed by interactions of the C1 domains with diacylglycerol (DAG) in the membrane. Notably, the molecular mechanisms of these interactions remain poorly understood, especially what effects, if any, DAG may have on the initial C2 docking. To further understand this process, we have performed a series of conventional molecular dynamics simulations to systematically investigate the interaction between PKCalpha-C2 domains and lipid bilayers with different compositions to examine the effects of POPS, PIP2, and 1 palmitoyl-2-oleoyl-sn-glycerol (POG) on domain docking. Our results show that the PKCalpha-C2 domain does not interact with the bilayer surface in the absence of POPS and PIP2. In contrast, the inclusion of POPS and PIP2 to the bilayer resulted in strong domain docking in both perpendicular and parallel orientations, whereas the further inclusion of POG resulted in only parallel domain docking. In addition, lysine residues in the C2 domain formed hydrogen bonds with PIP2 molecule bilayers containing POG. These effects were further explored with umbrella sampling calculations to estimate the free energy of domain docking to the lipid bilayer in the presence of one or two PIP2 molecules. The results show that the binding of one or two PIP2 molecules is thermodynamically favorable, although stronger in bilayers lacking POG. However, in POG-containing bilayers, the binding mode of the C2 domain appears to be more flexible, which may have implications for activation of full-length PKCalpha. Together, our results shed new insights into the process of C2 bilayer binding and suggest new mechanisms for the roles of different phospholipids in the activation process of PKCalpha. PMID- 27997187 TI - Understanding of Cyclic Volatile Methyl Siloxane Fate in a High Latitude Lake Is Constrained by Uncertainty in Organic Carbon-Water Partitioning. AB - Cyclic volatile methyl siloxanes (cVMS) are emitted to aquatic environments with wastewater effluents. Here, we evaluate the environmental behavior of three cVMS compounds (octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5) and dodecamethylcyclohexasiloxane (D6)) in a high latitude lake (Storvannet, 70 degrees N 23 degrees E), experiencing intermittent wastewater emissions and high latitude environmental conditions (low temperatures and seasonal ice cover). Measured cVMS concentrations in lake water were below detection limits in both March and June 2014. However, mean concentrations in sediments were 207 +/- 30, 3775 +/- 973 and 848 +/- 211 ng g-1 organic carbon for D4, D5 and D6, respectively. To rationalize measurements, a fugacity-based model for lakes (QWASI) was parametrized for Storvannet. The key removal process for cVMS from the lake was predicted to be advection due to the low hydraulic retention time of the lake, followed by volatilization. Predicted cVMS behavior was highly sensitive to the partition coefficient between organic carbon and water (KOC) and its temperature dependence. Predictions indicated lower overall persistence with decreasing temperature due to enhanced partitioning from sediments to water. Inverse modeling to predict steady-state emissions from cVMS concentrations in sediment provided unrealistically high emissions, when evaluated against measured concentrations in sewage. However, high concentrations of cVMS in sediment and low concentrations in water could be explained via a hypothetical dynamic emission scenario consistent with combined sewer overflows. The study illustrates the importance of considering compound-specific behavior of emerging contaminants that may differ from legacy organic contaminants. PMID- 27997189 TI - Influence of Radical Bridges on Electron Spin Coupling. AB - Increasing interactions between spin centers in molecules and molecular materials is a desirable goal for applications such as single-molecule magnets for information storage or magnetic metal-organic frameworks for adsorptive separation and targeted drug delivery and release. To maximize these interactions, introducing unpaired spins on bridging ligands is a concept used in several areas where such interactions are otherwise quite weak, in particular, lanthanide-based molecular magnets and magnetic metal-organic frameworks. Here, we use Kohn-Sham density functional theory to study how much the ground spin state is stabilized relative to other low-lying spin states by creating an additional spin center on the bridge for a series of simple model compounds. The di- and triradical structures consist of nitronyl nitroxide (NNO) and semiquinone (SQ) radicals attached to a meta-phenylene(R) bridge (where R = -NH*/-NH2, O*/OH, -CH2*/CH2). These model compounds are based on a fully characterized SQ meta-phenylene-NNO diradical with moderately strong antiferromagnetic coupling. Replacing closed-shell substituents CH3 and NH2 with their radical counterparts CH2* and NH* leads to an increase in stabilization of the ground state with respect to other low-lying spin states by a factor of 3-6, depending on the exchange-correlation functional. For OH compared with O* substituents, no conclusions can be drawn as the spin state energetics depend strongly on the functional. This could provide a basis for constructing sensitive test systems for benchmarking theoretical methods for spin state energy splittings. Reassuringly, the stabilization found for a potentially synthesizable complex (up to a factor of 3.5) is in line with the simple model systems (where a stabilization of up to a factor of 6.2 was found). Absolute spin state energy splittings are considerably smaller for the potentially stable system than those for the model complexes, which points to a dependence on the spin delocalization from the radical substituent on the bridge. PMID- 27997190 TI - Approximate Force Constants from Uncoupled Self-Consistent Field Perturbation Theory Using Nonhybrid Density Functional Theory. AB - Second derivatives of the molecular energy with respect to the nuclear coordinates (the nuclear Hessian or force constant matrix) are important for predicting infrared and Raman spectra, for calculating thermodynamic properties, for characterizing stationary states, and for guiding geometry optimization. However, their calculation for larger systems scales with molecular size one power higher than the calculation of the energy and the forces. The step responsible for the steep scaling of the nuclear Hessian is the coupled-perturbed self-consistent field (CP-SCF) iteration. This is omitted in the uncoupled SCF (UC-SCF) approximation. We have found that, though UC-SCF performs rather poorly at the Hartree-Fock and hybrid DFT levels, its performance for "pure" (non hybrid) DFT is remarkably good. This is valid also for imaginary frequencies that characterize transition states. UC-SCF vibrational frequencies and normal modes are compared with coupled calculations for various exchange-correlation functionals including Hartree-Fock, and with basis sets ranging from simple to large for a variety of organic and some organometallic molecules. Their unexpectedly good performance makes them good candidates for calculating thermodynamic properties and for guiding difficult geometry optimizations, including the determination of transition states. PMID- 27997188 TI - Natural Variability of Allergen Levels in Conventional Soybeans: Assessing Variation across North and South America from Five Production Years. AB - Soybean (Glycine max L. Merrill) is one of eight major allergenic foods with endogenous proteins identified as allergens. To better understand the natural variability of five soybean allergens (Gly m 4, Gly m 5, Gly m 6, Gly m Bd 28k, and Gly m Bd 30k), validated enzyme-linked immunosorbent assays (ELISAs) were developed. These ELISAs measured allergens in 604 soybean samples collected from locations in North and South America over five growing seasons (2009-2013/2014) and including 37 conventional varieties. Levels of these five allergens varied 5 19-fold. Multivariate statistical analyses and pairwise comparisons show that environmental factors have a larger effect on allergen levels than genetic factors. Therefore, from year to year, consumers are exposed to highly variable levels of allergens in soy-based foods, bringing into question whether quantitative comparison of endogenous allergen levels of new genetically modified soybean adds meaningful information to their overall safety risk assessment. PMID- 27997191 TI - Products of the Propargyl Self-Reaction at High Temperatures Investigated by IR/UV Ion Dip Spectroscopy. AB - The propargyl radical is considered to be of key importance in the formation of the first aromatic ring in combustion processes. Here we study the bimolecular (self-) reactions of propargyl in a high-temperature pyrolysis flow reactor. The aromatic reaction products are identified by IR/UV ion dip spectroscopy, using the free electron laser FELIX as mid-infrared source. This technique combines mass selectivity with structural sensitivity. We identified several aromatic reaction products based on their infrared spectra, among them benzene, naphthalene, phenanthrene, indene, biphenyl, and surprisingly a number of aromatic compounds with acetylenic (ethynyl) side chains. The observation of benzene confirms that propargyl is involved in the formation of the first aromatic ring. The observation of compounds with acetylenic side chains shows that, in addition to a propargyl- and phenyl-based mechanism, the HACA (hydrogen abstraction C2H2 addition) mechanism of polycyclic aromatic hydrocarbons formation is present, although no acetylene was used as a reactant. On the basis of the experimental results we suggest a mechanism that connects the two pathways. PMID- 27997192 TI - Stabilization and Antifouling of Polymer Films on a Planar Surface by CO2 Pressurization. AB - In this article, we study the dewetting phenomenon of a polymer and carbon dioxide (CO2) mixture on a planar surface by combining density functional theory and the string method. It is found that dewetting is a first-order discontinuous phase transition. When the pressure is lower than the completely dewetting pressure (Pd), CO2 stabilizes the polymer films. The density fluctuation of the polymer decreases significantly with the inclusion of CO2. When the pressure is above Pd, the polymer film is depleted far away from the surface, leaving a thick layer of pure CO2 in the region near the surface. Pd is proportional to the surface energy strength. The CO2 molecules enhance the density fluctuation of the polymer during the dewetting process. The polymer-rich phase at the triple point dewets to a CO2-rich vapor film, as the CO2-rich liquid film near the surface is metastable. These results have promising application in the industry of fabricating polymer films and antifouling polymers on attractive surfaces. PMID- 27997193 TI - Asymmetric One-Pot Synthesis of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A Key Component of Current HIV Protease Inhibitors. AB - A concise and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, a key building block for several clinical and experimental HIV protease inhibitors including the highly important drug darunavir, was achieved via a one pot procedure using furan and Cbz-protected glycol aldehyde as starting materials. A [2+2]-photocycloaddition between both reactants which can be prepared from wood-based starting materials according to the principles of xylochemistry, followed by hydrogenation and lipase-catalyzed kinetic resolution afforded the target compound in high yield and up to 99% ee. PMID- 27997194 TI - Crystalline WS2 via Room Temperature, Solution-Phase Synthesis. AB - Crystalline tungsten disulfide (WS2) has been prepared from the reaction of bis(cyclopentadienyl)tungsten dihydride with sulfur at room temperature and ambient pressure in organic solvents. WS2 was characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, resonance Raman spectroscopy, transmission electron microscopy, and X-ray absorption spectroscopy, and the resulting WS2 is highly crystalline by X-ray diffraction. The low-temperature synthesis is hypothesized to be a result of highly mobile surface W-Cp groups that are able to facilitate crystallization. PMID- 27997195 TI - Free Energy Based Equation of State for Pentaerythritol Tetranitrate. AB - An equation of state for the energetic molecular crystal pentaerythritol tetranitrate (PETN) has been developed from a parametrized model for its Helmholtz free energy. The ion motion contribution to the free energy is represented by a sum of Debye models for the vibrational modes of mainly lattice phonon and intramolecular character. The dependence of the frequencies of the normal modes on density is captured using the quasi-harmonic approximation whereby the Debye temperatures for both populations of modes depend explicitly on specific volume. The dependence of the Debye temperatures on specific volume was parametrized to normal-mode frequencies computed from solid state dispersion corrected density functional theory. The model provides a good description of the thermophysical properties of PETN. The equation of state has been applied to the calculation of thermodynamic states along the principal Hugoniot of single crystal PETN. PMID- 27997196 TI - Molecular Simulation of Gas Solubility in Nitrile Butadiene Rubber. AB - Molecular simulation is used to compute the solubility of small gases in nitrile butadiene rubber (NBR) with a Widom particle-insertion technique biased by local free volume. The convergence of the method is examined as a function of the number of snapshots upon which the insertions are performed and the number of insertions per snapshot and is compared to the convergence of the unbiased Widom insertion technique. The effect of varying the definition of local free volume is also investigated. The acrylonitrile content of the polymer is altered to examine its influence on the solubility of helium, CO2, and H2O, and the solubilities of polar gases are found to be enhanced relative to those of nonpolar gases, in qualitative agreement with experiment. To probe this phenomenon further, the solubilities are decomposed into contributions from the neighborhoods of different atoms, using a Voronoi cell construction, and a strong bias is found for CO2 and H2O in particular to be situated near nitrogen sites in the elastomer. Temperature is shown to suppress the solubility of CO2 and H2O but to increase that of helium. Increasing pressure is found to suppress the solubility of all gases but at different rates, according to a balance between their molecular sizes and electrostatic interactions with the polymer. These results are relevant to the use of NBR seals at elevated temperatures and pressures, such as in oil and gas wells. PMID- 27997197 TI - Computational Investigation on the Role of Disilene Substituents Toward N2O Activation. AB - The effect of substituents in disilene mediated N2O activation was studied at the M06-2X/QZVP//omegaB97xD/TZVP level of theory. The relationship between structural diversity and the corresponding reactivity of six disilenes (IA-Ft) in the presence of four different substituents (-NMe2, -Cl, -Me, -SiMe3) is addressed in this investigation. We primarily propose two plausible mechanistic routes: Pathway I featuring disilene -> silylene decomposition followed by N2O coordination and Pathway II constituting the N2O attack without Si-Si bond cleavage. Depending on the fashion of N2O approach the latter route was further differentiated into Pathway IIa and Pathway IIb detailing the "end-on" and "side on" attack to the disilene scaffold. Interestingly, the lone pair containing substituents (-NMe2, -Cl,) facilitates disilene -> silylene dissociation; on the contrary it reduces the electrophilicity at Si center in silylene, a feature manifested with higher activation barrier during N2O attack. In the absence of any lone-pair influence from substituents (-Me, -SiMe3), the decomposition of disilenes is considerably endothermic. Therefore, Pathway I appears to be the less preferred route for both types of substituents. In Pathway IIa, the N2O moiety uniformly approaches via O-end to both the silicon centers in disilenes. However, the calculations reveal that Pathway IIa, although not operational for all disilenes, is unlikely to be a viable route due to the predominantly higher transition barrier (ca. 36 kcal/mol). The most feasible route in this current study accompanying moderately low activation barriers (~19-26 kcal/mol) is Pathway IIb, which involves successive addition of two N2O units proceeding via terminal N, O toward the Si centers and is applicable for all disilenes. The reactivity of substituted disilenes can be estimated in terms of the first activation barrier of N2O attack. Surprisingly, in Pathway IIb, the initial activation barrier and hence the reactivity shows negligible correlation with Si Si bond strength, indicating toward the versatility of the reaction route. PMID- 27997198 TI - In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma. AB - Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol and their short-term safety and antitumor effects were also evaluated. In this open, prospective, nonrandomized multicenter study, LIPDOX (n = 13) or DEBDOX (n = 12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p < 0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX. PMID- 27997199 TI - Hyaluronic Acid Coated Albumin Nanoparticles for Targeted Peptide Delivery to the Retina. AB - Recent studies have shown that Connexin43 mimetic peptide (Cx43 MP) can prevent secondary damage following several retinal ischemic and inflammatory disorders by blocking the pathological opening of gap junction hemichannels. However, the poor stability of peptides and the presence of various intraocular barriers limit efficient retinal delivery in the clinical setting. The present study aimed to prolong the bioactivity of Cx43 MP and achieve targeted delivery to the retina by loading the peptide into hyaluronic acid (HA) coated human serum albumin nanoparticles (HSA NPs). Two different loading methods, adsorption and incorporation, were used with the peptide released slowly over a period of up to four months. Compared to uncoated particles, HA coated HSA NPs exhibited enhanced in vitro cellular uptake and ex vivo retinal penetration via HA-CD44 receptor mediated interactions. Furthermore, cell viability and Cx43 MP functionality assays showed that NPs protected Cx43 MP from degradation, sustained its release, and thus prolonged its bioactivity without reducing cell viability at concentrations used for Cx43 hemichannel blocking. Therefore, HA coated HSA NPs could have great potential for sustained and targeted delivery of Cx43 MP to treat various retinal inflammatory conditions. PMID- 27997200 TI - Effects of Co-solvents on Reactions Run under Micellar Catalysis Conditions. AB - The impact of varying percentages of an organic solvent added to reactions run in aqueous nanomicelles as the reaction medium has been investigated. Issues such as rates of reaction, percent conversion, and yield, as well as various practical aspects (e.g., effect on stirring, etc.), are discussed, leading to an operationally simple method for the general improvement of potentially problematic systems across a broad range of reaction types, in particular for reactions run at scale. PMID- 27997201 TI - A Palladium-Catalyzed Asymmetric Allylic Alkylation Approach to alpha-Quaternary gamma-Butyrolactones. AB - The Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) of enol carbonates derived from gamma-butyrolactones is reported, affording the corresponding enantioenriched alpha,alpha'-disubstituted gamma-butyrolactones in both high yields and high enantioselectivities (up to 94% ee). This method was eventually applied to the synthesis of chiral spirocyclic compounds. PMID- 27997202 TI - Peptigram: A Web-Based Application for Peptidomics Data Visualization. AB - Tandem mass spectrometry (MS/MS) techniques, developed for protein identification, are increasingly being applied in the field of peptidomics. Using this approach, the set of protein fragments observed in a sample of interest can be determined to gain insights into important biological processes such as signaling and other bioactivities. As the peptidomics era progresses, there is a need for robust and convenient methods to inspect and analyze MS/MS derived data. Here, we present Peptigram, a novel tool dedicated to the visualization and comparison of peptides detected by MS/MS. The principal advantage of Peptigram is that it provides visualizations at both the protein and peptide level, allowing users to simultaneously visualize the peptide distributions of one or more samples of interest, mapped to their parent proteins. In this way rapid comparisons between samples can be made in terms of their peptide coverage and abundance. Moreover, Peptigram integrates and displays key sequence features from external databases and links with peptide analysis tools to offer the user a comprehensive peptide discovery resource. Here, we illustrate the use of Peptigram on a data set of milk hydrolysates. For convenience, Peptigram is implemented as a web application, and is freely available for academic use at http://bioware.ucd.ie/peptigram . PMID- 27997203 TI - Platinum-Catalyzed alpha,beta-Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal. AB - Formal syntheses of tetracyclic terpenoids frondosin B and liphagal are described. Both synthetic routes rely on the use of platinum-catalyzed alpha,beta unsaturated carbene formation for the key C-C bond forming transformations. The successful route toward frondosin B utilizes a formal (4 + 3) cycloaddition, while the liphagal synthesis features the vinylogous addition of an enol nucleophile as a key step. Both synthetic routes are discussed, revealing insights into structural requirements in the catalytic alpha,beta-unsaturated carbene reaction manifold. PMID- 27997204 TI - Molecular Structure and Dynamics of Ionic Liquids in a Rigid-Rod Polyanion-Based Ion Gel. AB - The recent fabrication of liquid crystalline ion gels featuring rigid-rod polyanions aligned within room-temperature ionic liquids (RTILs) opens up exciting new avenues for engineering ion conducting materials. These gels exhibit an unusual combination of properties including high ionic conductivity, distinct transport anisotropy, and widely tunable elastic modulus. Using molecular simulations, we study the structure and dynamics of the ions in an ion gel consisting of rigid-rod polyanions and [C2mim][TfO] RTILs. We show that the ion distribution in the interstitial space between polymer rods exhibits the hallmarks of the RTIL structure near charged surfaces; i.e., cations (C2mim+) and anions (TfO-) form alternating layers around the polymer rods and the charge on the rod is overscreened by the ionic layer surrounding it. The distinct ordering of ions suggests the formation of a long-range "electrostatic network" in the ion gel, which may contribute to its mechanical cohesion and high modulus. The dynamics of both C2mim+ and TfO- ions slow down due to the fact that some C2mim+ ions become associated with the sulfonate groups of the polymer rod on nanosecond time scales, which hinders the dynamics of all ions in the gel. C2mim+ and TfO- ion diffusion in the gel are only 2-10 times slower than in bulk RTILs, which is still much faster than, e.g., Li ions in typical ion conducting polymers. This fast ion transport combined with strong mechanical cohesion open up exciting opportunities for application of these gels in electrochemical devices including Li-metal batteries. PMID- 27997205 TI - Interaction of Droplets Separated by an Elastic Film. AB - The Laplace pressure of a droplet placed on one side of an elastic thin film can cause significant deformation in the form of a bulge on its opposite side. Here, we show that this deformation can be detected by other droplets suspended on the opposite side of the film, leading to interaction between droplets separated by the solid (but deformable) film. The interaction is repulsive when the drops have a large overlap and attractive when they have a small overlap. Thus, if two identical droplets are placed right on top of each other (one on either side of the thin film), they tend to repel each other, eventually reaching an equilibrium configuration where there is a small overlap. This observation can be explained by analyzing the energy landscape of the droplets interacting via an elastically deformed film. We further demonstrate this idea by designing a pattern comprising a big central drop with satellite droplets. This phenomenon can lead to techniques for directed motion of droplets confined to one side of a thin elastic membrane by manipulations on the other side. PMID- 27997207 TI - Palladium/Copper Co-catalyzed Oxidative C-H/C-H Carbonylation of Diphenylamines: A Way To Access Acridones. AB - An efficient palladium/copper co-catalyzed oxidative double C(sp2)-H functionalization/carbonylation of diphenylamines for synthesis of acridones has been developed. This method utilizes readily available starting materials and mild reaction conditions. The protocol provides a simple, efficient, and atom economic way to access acridones. Notably, the present protocol has excellent functional group tolerance and application value. PMID- 27997206 TI - Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure-Activity Relationships. AB - Inspired by the discovery of the antimalarial drug artemisinin from a traditional Chinese medicine (TCM), a natural product library of 44 lindenane-type sesquiterpenoids was assessed for activities against the Dd2 chloroquine resistant strain of the malaria parasite Plasmodium falciparum. These compounds were mainly isolated from plants of the Chloranthus genus, many species of which are named "Sikuaiwa" in TCM and have long been used to treat malaria. The compounds consisted of 41 sesquiterpenoid dimers and three monomers, including the 12 new dimers 1-12 isolated from Chloranthus fortunei. The results showed that 16 dimers exhibited potent antiplasmodial activities (<100 nM); in particular, compounds 1, 14, and 19 exhibited low nanomolar activities with IC50 values ranging from 1 to 7 nM, which is comparable to the potency of artemisinin, and selectivity index values toward mammalian cells greater than 500. A comprehensive structure-activity relationship study indicated that three functional groups are essential and two motifs can be modified. PMID- 27997208 TI - Alternative Route to Silicene Synthesis via Surface Reconstruction on h-MoSi2 Crystallites. AB - Silicene is a two-dimensional material with a Dirac-type band structure and it is particularly attractive due to its potential for integration with Si-based technology. The primary focus has been to grow single silicene layers and understand how the electronic structure is affected by the substrate and the phase transition between low- and high-buckling configurations. Typically, silicene is synthesized by depositing monolayer amounts of silicon onto a heated Ag(111) surface; however, other growth substrates such as Ir(111) and ZrB2 have been studied recently. We present a novel route for silicene synthesis via a high temperature surface reconstruction of hexagonal-MoSi2 nanocrystallites. The h MoSi2 crystallites are formed by annealing of thin Mo-layers on Si(100)-(2 * 1) and their crystallographic orientation is controlled via an epitaxial relation with the Si-substrate. The (0001) plane of h-MoSi2 is comprised of Si-hexagons with a Mo atom residing in the center. Annealing above approximately 650 degrees C causes the (0001) plane to undergo a surface reconstruction process leaving a honeycomb pattern on the surface of these crystallites as shown by scanning tunneling microscopy. We define this surface layer as a silicene-like reconstruction (SLR), and a detailed geometric analysis of our structure yields a perfect match with the (?3 * ?3)R30 degrees silicene superstructure in a low buckled configuration (ABA). Scanning tunneling spectroscopy data of the SLR, Si(001)-(2 * 1) and h-MoSi2 surfaces agree with this interpretation. The formation of this structure on a transition metal silicide opens up the opportunity for integration into Si-based devices without the necessity for a transfer scheme. PMID- 27997209 TI - GeSe Thin-Film Solar Cells Fabricated by Self-Regulated Rapid Thermal Sublimation. AB - GeSe has recently emerged as a promising photovoltaic absorber material due to its attractive optical and electrical properties as well as earth-abundant and low-toxic constituent elements. However, no photovoltaic device has been reported based on this material so far, which could be attributed to the inevitable coexistence of phase impurities Ge and GeSe2, leading to detrimental recombination-center defects and seriously degrading the device performance. Here we overcome this issue by introducing a simple and fast (4.8 MUm min-1) rapid thermal sublimation (RTS) process designed according to the sublimation feature of the layered structured GeSe. This new method offers a compelling combination of assisting raw material purification to suppress deleterious phase impurities and preventing the formation of detrimental point defects through congruent sublimation of GeSe, thus providing an in situ self-regulated process to fabricate high quality polycrystalline GeSe films. Solar cells fabricated following this process show a power conversion efficiency of 1.48% with good stability. This preliminary efficiency and high stability, combined with the self regulated RTS process (also extended to the fabrication of other binary IV-VI chalcogenide films, i.e., GeS), demonstrates the great potential of GeSe for thin film photovoltaic applications. PMID- 27997211 TI - Double Chiral Induction Enables a Stereoselective Carbonyl Allylation with Simple Alkenes under the Sequential Catalysis of Palladium Complex and Chiral Phosphoric Acid. AB - An enantioselective carbonyl allylation of aldehydes with simple alkenes has been achieved via a one-pot protocol consisting of a Pd-catalyzed allylic C-H borylation with bis(pinanediolato)diboron and a chiral Bronsted acid catalyzed asymmetric allylborylation, delivering homoallylic alcohols in high yields and with excellent diastereo- and enantioselectivities. The double chiral induction of chiral allylic borate and chiral phosphoric acid allows the reaction to give excellent stereoselectivities. PMID- 27997210 TI - Procedure for Transferable Coarse-Grained Models of Aqueous Polysaccharides. AB - We present a procedure to obtain Coarse-Grained (CG) models for aqueous polysaccharide solutions that are transferable over different degrees of polymerization and different polysaccharide concentrations based on atomistic Molecular Dynamics (MD) simulations. This is achieved by a hybrid procedure combining Boltzmann Inversion (BI) and the Multiscale Coarse-Graining (MS-CG) method. In order to overcome problems that have been previously reported with this approach, namely differences in the aggregation behavior and the end to end distance between the atomistic reference simulation and the coarse-grained simulation, we employ a separation-ansatz and explicit 1-3 and 1-4 nonbonded intramolecular interactions. This allows the use of the model for long polysaccharides. We demonstrate the transferability over both concentration and degrees of polymerization, evaluate the scope for which the coarse-grained model can be applied, and then present a scheme to extend the concentration transferability. In addition, we show that the procedure can be applied to generate a transferable implicit solvent model and demonstrate that it can be used for different atomistic force fields (FFs) as well. The procedure is then applied to derive a coarse-grained model of different hemicellulose polysaccharides. The resulting model is used to demonstrate that branching with monomer side-chains significantly increases the water uptake capacity of the molecules in comparison to linear polysaccharides which is consistent with experimental results. PMID- 27997212 TI - Edge-Controlled Growth and Etching of Two-Dimensional GaSe Monolayers. AB - Understanding the atomistic mechanisms governing the growth of two-dimensional (2D) materials is of great importance in guiding the synthesis of wafer-sized, single-crystalline, high-quality 2D crystals and heterostructures. Etching, in many cases regarded as the reverse process of material growth, has been used to study the growth kinetics of graphene. In this work, we explore a growth-etching regrowth process of monolayer GaSe crystals, including single-crystalline triangles and irregularly shaped domains formed by merged triangles. We show that the etching begins at a slow rate, creating triangular, truncated triangular, or hexagonally shaped holes that eventually evolve to exclusively triangles that are rotated 60 degrees with respect to the crystalline orientation of the monolayer triangular crystals. The regrowth occurs much faster than etching, reversibly filling the etched holes and then enlarging the size of the monolayer crystals. A theoretical model developed based on kinetic Wulff construction (KWC) theory and density functional theory (DFT) calculations accurately describe the observed morphology evolution of the monolayer GaSe crystals and etched holes during the growth and etching processes, showing that they are governed by the probability of atom attachment/detachment to/from different types of edges with different formation energies of nucleus/dents mediated by chemical potential difference DeltaMU between Ga and Se. Our growth-etching-regrowth study provides not only guidance to understand the growth mechanisms of 2D binary crystals but also a potential method for the synthesis of large, shape-controllable, high-quality single-crystalline 2D crystals and their lateral heterostructures. PMID- 27997213 TI - The Solvation Structure of Lithium Ions in an Ether Based Electrolyte Solution from First-Principles Molecular Dynamics. AB - The solvation and desolvation of the Li ion play a crucial role in the electrolytes of Li based secondary batteries, and their understanding at the microscopic level is of great importance. Oligoether (glyme) based electrolytes have attracted much attention as electrolytes used in Li based secondary batteries, such as Li-ion, Li-S, and Li-O2 batteries. However, the solvation structure of the Li ion in glyme based electrolytes has not been fully clarified yet. We present a computational study on the solvation structure of lithium ions in the mixture of triglyme and lithium bis(trifluoromethylsulfonyl)-amide (LiTFSA) by means of molecular orbital and molecular dynamics calculations based on density functional theory. We found that, in the electrolyte solution composed of the equimolar mixture of triglyme and LiTFSA, lithium ions are solvated mainly by crown-ether-like curled triglyme molecules and in direct contact with an TFSA anion. We also found the aggregate formed with Li ion and TFSA anions and/or triglyme molecule(s) is equally stable, which has not been reported in the previous classical molecular dynamics simulations, suggesting that in reality a small fraction of Li ions form aggregates and they might have a significant impact on the Li ion transport. Our results demonstrate the importance of performing electronic structure based molecular dynamics of electrolyte solution to clarify the detailed solvation structure of the Li ion. PMID- 27997214 TI - Visible-Light-Induced Direct Difluoroalkylation of Uracils, Pyridinones, and Coumarins. AB - An efficient and general method for the synthesis of difluoroalkylated uracils, pyridinones, and coumarins through visible-light-induced reaction with commercial materials is developed. The strategy proceeds with high efficiency under mild reaction conditions and shows excellent functional group compatibility, even toward bromide and hydroxyl group, thus demonstrates high potent application in a late-stage fluoroalkylation. Moreover, the difluoroalkylated products can be further transformed to a diverse variety of difluoroalkylated heterocycles, including molecules of potential biological activity. PMID- 27997215 TI - Room Temperature O-band DFB Laser Array Directly Grown on (001) Silicon. AB - Several approaches for growing III-V lasers on silicon were recently demonstrated. Most are not compatible with further integration, however, and rely on thick buffer layers and require special substrates. Recently, we demonstrated a novel approach for growing high quality InP without buffer on standard 001 silicon substrates using a selective growth process compatible with integration. Here we show high quality InGaAs layers can be grown on these InP-templates. High resolution TEM analysis shows these layers are free of optically active defects. Contrary to InP, the InGaAs material exhibits strong photoluminescence for wavelengths relevant for integration with silicon photonics integrated circuits. Distributed feedback lasers were defined by etching a first order grating in the top surface of the device. Clear laser operation at a single wavelength with strong suppression of side modes was demonstrated. Compared to the previously demonstrated InP lasers 65% threshold reduction is observed. Demonstration of laser arrays with linearly increasing wavelength prove the control of the process and the high quality of the material. This is an important result toward realizing fully integrated photonic ICs on silicon substrates. PMID- 27997217 TI - Investigating Hypoglycemic Confidence in Type 1 and Type 2 Diabetes. AB - BACKGROUND: While research designed to understand the concerns about hypoglycemia among patients with diabetes has been primarily focused on the investigation of fear and anxiety, recent evidence suggests a potentially important and conceptually distinct element-hypoglycemic confidence. To investigate this dimension, we developed the Hypoglycemic Confidence Scale (HCS); herein, we describe the construction and validation of the HCS and examine how key patient factors are associated with hypoglycemic confidence. METHODS: Items were developed from interviews with six type 1 diabetes (T1D) adults, six insulin using type 2 diabetes (T2D) adults, and seven diabetes healthcare professionals, resulting in nine self-report items. Separate exploratory factor analyses (EFAs) were conducted with T1D adults (N = 326), with T2D adults using both basal and prandial insulins (T2D-BP, N = 145) and with T2D adults using only basal insulin (T2D-BO, N = 82). Construct validity for the HCS was established with overall well-being (World Health Organization-5), diabetes distress (Diabetes Distress Scale), global anxiety (Generalized Anxiety Disorder), hypoglycemic fear (Hypoglycemic Fear Survey-II), and glycemic control (self-reported A1C). Hierarchical regression analyses examined the unique contribution of HCS scores, independent of hypoglycemic fear, on key psychosocial constructs and A1C. RESULTS: EFAs of the nine HCS items yielded a single factor solution for each of the three subject samples, accounting for 50.8%, 65.1%, and 73.7% of the variance for the T1D, T2D-BP, and T2D-BO groups, respectively. Construct validity was established by significant correlations with criterion variables. The HCS was associated with well-being and diabetes distress in the T1D (in both cases, P < 0.001) and T2D-BP groups (in both cases, P < .05) and for self-reported A1C in the T2D-BP group (P < .05) independent of hypoglycemic fear. CONCLUSIONS: Hypoglycemic confidence is a unique dimension of patient experience, different from hypoglycemic fear, and is deserving of further study. The HCS is a reliable valid measure of hypoglycemic confidence for adults with T1D and insulin-using T2D. PMID- 27997216 TI - Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes. AB - RATIONALE: Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown. OBJECTIVES: To identify mycobacterial genetic markers associated with increased transmissibility and to examine whether these markers lead to altered in vitro immune responses. METHODS: Using a comprehensive tuberculosis registry (n = 10,389) and strain collection in the Netherlands, we identified a set of 100 M. tuberculosis strains either least or most likely to be transmitted after controlling for host factors. We subjected these strains to whole-genome sequencing and evolutionary convergence analysis, and we repeated this analysis in an independent validation cohort. We then performed immunological experiments to measure in vitro cytokine production and neutrophil responses to a subset of the original strains with or without the identified mutations associated with increased transmissibility. MEASUREMENTS AND MAIN RESULTS: We identified the loci espE, PE-PGRS56, Rv0197, Rv2813-2814c, and Rv2815-2816c as targets of convergent evolution among transmissible strains. We validated four of these regions in an independent set of strains, and we demonstrated that mutations in these targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis. CONCLUSIONS: In this study, we identified genetic markers in convergent evolution of M. tuberculosis toward enhanced transmissibility in vivo that are associated with altered immune responses in vitro. PMID- 27997219 TI - Real-world cost-effectiveness of infliximab for moderate-to-severe rheumatoid arthritis in a medium-sized city of China. AB - AIM: To assess the cost-effectiveness of infliximab-containing therapy (ICT) for moderate-to-severe rheumatoid arthritis (RA) in a medium-sized Chinese city. METHODS: A Chinese prospective cohort study comparing ICT (25 patients) versus conventional disease-modified antirheumatic drugs (24 patients) for RA was used to assess the cost-effectiveness of ICT. RESULTS: The cohort study observed significantly reduced disease activity score of 28 joints (coefficient -2.718, p < 0.001), improved EQ-5D (coefficient 0.453, p < 0.001) and increased medical costs (coefficient 1.289, p < 0.001) associated with ICT. The incremental cost effectiveness ratio per gained quality-adjusted life year for ICT versus disease modified antirheumatic drugs was 1.897-times of the local gross domestic product per capita. CONCLUSION: Infliximab was a favorable cost-effective alternative option for moderate-to-severe RA in a medium-sized city of China. PMID- 27997218 TI - Inhibition of the gut enzyme intestinal alkaline phosphatase may explain how aspartame promotes glucose intolerance and obesity in mice. AB - Diet soda consumption has not been associated with tangible weight loss. Aspartame (ASP) commonly substitutes sugar and one of its breakdown products is phenylalanine (PHE), a known inhibitor of intestinal alkaline phosphatase (IAP), a gut enzyme shown to prevent metabolic syndrome in mice. We hypothesized that ASP consumption might contribute to the development of metabolic syndrome based on PHE's inhibition of endogenous IAP. The design of the study was such that for the in vitro model, IAP was added to diet and regular soda, and IAP activity was measured. For the acute model, a closed bowel loop was created in mice. ASP or water was instilled into it and IAP activity was measured. For the chronic model, mice were fed chow or high-fat diet (HFD) with/without ASP in the drinking water for 18 weeks. The results were that for the in vitro study, IAP activity was lower (p < 0.05) in solutions containing ASP compared with controls. For the acute model, endogenous IAP activity was reduced by 50% in the ASP group compared with controls (0.2 +/- 0.03 vs 0.4 +/- 0.24) (p = 0.02). For the chronic model, mice in the HFD + ASP group gained more weight compared with the HFD + water group (48.1 +/- 1.6 vs 42.4 +/- 3.1, p = 0.0001). Significant difference in glucose intolerance between the HFD +/- ASP groups (53 913 +/- 4000.58 (mg.min)/dL vs 42 003.75 +/- 5331.61 (mg.min)/dL, respectively, p = 0.02). Fasting glucose and serum tumor necrosis factor-alpha levels were significantly higher in the HFD + ASP group (1.23- and 0.87-fold increases, respectively, p = 0.006 and p = 0.01). In conclusion, endogenous IAP's protective effects in regard to the metabolic syndrome may be inhibited by PHE, a metabolite of ASP, perhaps explaining the lack of expected weight loss and metabolic improvements associated with diet drinks. PMID- 27997220 TI - Identifying determinants of medication adherence following myocardial infarction using the Theoretical Domains Framework and the Health Action Process Approach. AB - BACKGROUND: Despite evidence-based recommendations, adherence with secondary prevention medications post-myocardial infarction (MI) remains low. Taking medication requires behaviour change, and using behavioural theories to identify what factors determine adherence could help to develop novel adherence interventions. OBJECTIVE: Compare the utility of different behaviour theory-based approaches for identifying modifiable determinants of medication adherence post MI that could be targeted by interventions. METHODS: Two studies were conducted with patients 0-2, 3-12, 13-24 or 25-36 weeks post-MI. Study 1: 24 patients were interviewed about barriers and facilitators to medication adherence. Interviews were conducted and coded using the Theoretical Domains Framework. Study 2: 201 patients answered a telephone questionnaire assessing Health Action Process Approach constructs to predict intention and medication adherence (MMAS-8). RESULTS: Study 1: domains identified: Beliefs about Consequences, Memory/Attention/Decision Processes, Behavioural Regulation, Social Influences and Social Identity. Study 2: 64, 59, 42 and 58% reported high adherence at 0-2, 3-12, 13-24 and 25-36 weeks. Social Support and Action Planning predicted adherence at all time points, though the relationship between Action Planning and adherence decreased over time. CONCLUSIONS: Using two behaviour theory-based approaches provided complimentary findings and identified modifiable factors that could be targeted to help translate Intention into action to improve medication adherence post-MI. PMID- 27997221 TI - Design and Validation of a New MLPA-Based Assay for the Detection of RS1 Gene Deletions and Application in a Large Family with X-Linked Juvenile Retinoschisis. AB - AIMS: X-linked juvenile retinoschisis (XLRS) is a severe ocular disorder that can evolve to blindness. More than 200 different disease-causing mutations have been reported in the RS1 gene and approximately 10% of these are deletions. Since transmission is X-linked, males are always affected and females are usually carriers. The identification of female carriers is always important and poses a technical challenge. Therefore, we sought to develop a multiplex ligation dependent probe amplification (MLPA)-based method to identify deletions or duplications in this gene. We then used our assay to study a large XLRS family. METHODS: We designed six probes specific for each RS1 exon and then optimized and validated our method using control samples with known gene deletions. In the XLRS family, RS1 gene copy number variation was assessed by "home-made" MLPA analysis and by single nucleotide polymorphism (SNP) array analysis using the CytoScan HD Array. Direct sequencing was used for deletion breakpoint mapping. RESULTS: Our assay detected all deletions in control samples. All affected males of the family were positive for a deletion of exon 2 of the RS1 gene (RS1:NM_000330:c.53 ?_78+?del). Carrier females were also identified. CONCLUSION: Our method is easily replicated, reliable, and inexpensive and allows female carriers to be detected. This is the first report of deep characterization of a whole exon deletion in the RS1 gene. PMID- 27997222 TI - Empathy in Medical Students Is Moderated by Openness to Spirituality. AB - THEORY: Empathy is one component of medical student education that may be important to nurture, but there are many potential psychological barriers to empathy, such as student depression, burnout, and low quality of life or wellness behaviors. However, few studies have addressed how positive behaviors such as wellness and spirituality, in combination with these barriers, might affect empathy. HYPOTHESES: We hypothesized a negative relationship between psychological distress and empathy, and a positive relationship between empathy and wellness behaviors. We also hypothesized that openness to others' spirituality would moderate the effects of psychological distress on empathy in medical students. METHOD: This cross-sectional study included 106 medical students in a public medical school in the U.S. Midwest. Mailed questionnaires collected student information on specialty choice and sociodemographics, empathy, spirituality openness, religiosity, wellness, burnout, depression, anxiety, and stress. Hierarchical multiple regression analysis was conducted, with empathy as the dependent variable, psychological distress and all wellness behaviors as predictors, and spirituality openness as a moderator. RESULTS: Specialty choice, burnout, wellness behaviors, spirituality openness, and religiosity were significant independent predictors of empathy. In addition, when added singly, one interaction was significant: Spirituality Openness * Depression. Spirituality openness was related to empathy only in nondepressed students. Empathy of students with higher levels of depression was generally lower and not affected by spirituality openness. CONCLUSIONS: Nondepressed students who reported lower openness to spirituality might benefit most from empathy training, because these students reported the lowest empathy. Highly depressed or disengaged students may require interventions before empathy can be addressed. In addition, burnout was related to lower levels of empathy and wellness was related to higher levels. These provide potential points of intervention for medical schools developing tools to increase medical trainees' empathy levels. PMID- 27997223 TI - Estimating Incremental Validity Under Missing Data. AB - A common form of missing data is caused by selection on an observed variable (e.g., Z). If the selection variable was measured and is available, the data are regarded as missing at random (MAR). Selection biases correlation, reliability, and effect size estimates when these estimates are computed on listwise deleted (LD) data sets. On the other hand, maximum likelihood (ML) estimates are generally unbiased and outperform LD in most situations, at least when the data are MAR. The exception is when we estimate the partial correlation. In this situation, LD estimates are unbiased when the cause of missingness is partialled out. In other words, there is no advantage of ML estimates over LD estimates in this situation. We demonstrate that under a MAR condition, even ML estimates may become biased, depending on how partial correlations are computed. Finally, we conclude with recommendations about how future researchers might estimate partial correlations even when the cause of missingness is unknown and, perhaps, unknowable. PMID- 27997224 TI - Implementing Peer Learning in Clinical Education: A Framework to Address Challenges In the "Real World". AB - : Phenomenon: Peer learning has many benefits and can assist students in gaining the educational skills required in future years when they become teachers themselves. Peer learning may be particularly useful in clinical learning environments, where students report feeling marginalized, overwhelmed, and unsupported. Educational interventions often fail in the workplace environment, as they are often conceived in the "ideal" rather than the complex, messy real world. This work sought to explore barriers and facilitators to implementing peer learning activities in a clinical curriculum. APPROACH: Previous peer learning research results and a matrix of empirically derived peer learning activities were presented to local clinical education experts to generate discussion around the realities of implementing such activities. Potential barriers and limitations of and strategies for implementing peer learning in clinical education were the focus of the individual interviews. FINDINGS: Thematic analysis of the data identified three key considerations for real-world implementation of peer learning: culture, epistemic authority, and the primacy of patient-centered care. Strategies for peer learning implementation were also developed from themes within the data, focusing on developing a culture of safety in which peer learning could be undertaken, engaging both educators and students, and establishing expectations for the use of peer learning. Insights: This study identified considerations and strategies for the implementation of peer learning activities, which took into account both educator and student roles. Reported challenges were reflective of those identified within the literature. The resultant framework may aid others in anticipating implementation challenges. Further work is required to test the framework's application in other contexts and its effect on learner outcomes. PMID- 27997225 TI - Use of the Personality Assessment Inventory in Fitness-for-Duty Evaluations of Physicians. AB - This study provides normative data regarding the use of the Personality Assessment Inventory (PAI) in physician fitness-for-duty evaluations. Information was derived from a sample of 371 physicians who took the PAI as part of a comprehensive fitness-for-duty evaluation. A multidisciplinary evaluation team, not blinded to psychological testing results, recommended whether or not each physician was fit to practice, allowing for the differentiation of results by this finding. The majority of PAI protocols were valid and interpretively useful. Descriptive statistics are presented for validity, clinical, treatment, interpersonal, and subscale scores. Mean differences for those found fit versus unfit to practice are also presented. Significant elevations for clinical scales are rare in physicians referred for fitness-for-duty evaluations. Although mean differences were small between the fit and unfit groups, there were significant mean differences found. Guidance is offered for interpreting the PAI in this population. PMID- 27997226 TI - Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the major threat to human health, and disruption of circadian clock genes is implicated in hepatocarcinogenesis. This study examined the dysregulation of metallothioneins and circadian genes in achieved human HCC (n = 24), peri-HCC tissues (n = 24) as compared with normal human livers (n = 36). Total RNA was extracted and reverse transcribed. Real-time RT-qPCR was performed to determine the expression of genes of interest. The results demonstrated the downregulation of metallothionein-1 (MT-1), MT-2, and metal transcription factor-1 (MFT-1) in human HCC as compared with Peri-HCC and normal tissues. MTs are a biomarker for HCC and have typical circadian rhythms; the expression of major circadian clock genes was also determined. HCC produced a dramatic decrease in the expression of core clock genes, circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein 1 (Bmal1), and decreased the expression of the clock feedback control genes, Periods (Per1, Per2) and Cryptochromes (Cry1, Cry2). On the other hand, the expression of clock target genes nuclear orphan receptor factor protein (Nr1d1) and D-box-binding protein (Dbp) was upregulated as compared with Peri-HCC and normal livers. Peri HCC also had mild alterations in these gene expressions. In summary, the present study clearly demonstrated the dysregulation of MTs and circadian clock genes in human HCC, which could provide the information of targeting MT and circadian clock in HCC management. PMID- 27997227 TI - Aggressive Drive Derivatives in the Rorschachs of Maltreated Children and Adolescents: Latent Structure and Clinical Correlates. AB - Psychological assessment can play an important role in informing the intervention process with child and adolescent victims of maltreatment. This study investigated the validity of the Rorschach in assessing aggressive drive derivatives using a profile-based approach, with a sample of 108 children and adolescents in foster care. Aggression indicators were derived from the work of Gacono and Meloy ( 1994 ). Latent class analysis yielded a 4-class model including gender and age as covariates. The first 2 classes were characterized by low prevalence rates across all indicators of aggression, and were distinguished primarily on the basis of participant's age. The 3rd class was characterized by the presence of Aggressive Vulnerability (AgV) responses, whereas the 4th showed higher occurrence of all markers except AgV. Modest associations were found between characteristics of abuse, select classes, and behavior problems. The 4th class showed the strongest link with behavior problems, albeit only in the presence of ego impairment. These findings support a contextualized, developmentally informed use of aggression markers on the Rorschach in the context of child maltreatment. PMID- 27997228 TI - Comprehensive HIV Prevention for Transgender Persons. AB - Transgender persons are at high risk for HIV infection, but prevention efforts specifically targeting these people have been minimal. Part of the challenge of HIV prevention for transgender populations is that numerous individual, interpersonal, social, and structural factors contribute to their risk. By combining HIV prevention services with complementary medical, legal, and psychosocial services, transgender persons' HIV risk behaviors, risk determinants, and overall health can be affected simultaneously. For maximum health impact, comprehensive HIV prevention for transgender persons warrants efforts targeted to various impact levels-socioeconomic factors, decision-making contexts, long-lasting protections, clinical interventions, and counseling and education. We present current HIV prevention efforts that reach transgender persons and present others for future consideration. PMID- 27997229 TI - Incidence of Mental Health Diagnoses in Veterans of Operations Iraqi Freedom, Enduring Freedom, and New Dawn, 2001-2014. AB - OBJECTIVES: To evaluate gender, age, and race/ethnicity as predictors of incident mental health diagnoses among Operations Iraqi Freedom, Enduring Freedom, and New Dawn veterans. METHODS: We used US Veterans Health Administration (VHA) electronic health records from 2001 to 2014 to examine incidence rates and sociodemographic risk factors for mental health diagnoses among 888 142 veterans. RESULTS: Posttraumatic stress disorder (PTSD) was the most frequently diagnosed mental health condition across gender and age groups. Incidence rates for all mental health diagnoses were highest at ages 18 to 29 years and declined thereafter, with the exceptions of major depressive disorder (MDD) in both genders, and PTSD among women. Risk of incident bipolar disorder and MDD diagnoses were greater among women; risk of incident schizophrenia, and alcohol- and drug-use disorders diagnoses were greater in men. Compared with Whites, risk incident PTSD, MDD, and alcohol-use disorder diagnoses were lower at ages 18 to 29 years and higher at ages 45 to 64 years for both Hispanics and African Americans. CONCLUSIONS: Differentiating high-risk demographic and gender groups can lead to improved diagnosis and treatment of mental health diagnoses among veterans and other high-risk groups. PMID- 27997230 TI - Racial/Ethnic Disparities in the Use of Lethal Force by US Police, 2010-2014. AB - OBJECTIVES: To update previous examinations of racial/ethnic disparities in the use of lethal force by US police. METHODS: I examined online national vital statistics data for deaths assigned an underlying cause of "legal intervention" (International Classification of Diseases, 10th Revision, external-cause-of injury codes Y35.0-Y35.7, excluding Y35.5 [legal execution]) for the 5-year period 2010 to 2014. RESULTS: Death certificates identified 2285 legal intervention deaths (1.5 per million population per year) from 2010 to 2014. Among males aged 10 years or older, who represented 96% of these deaths, the mortality rate among non-Hispanic Black and Hispanic individuals was 2.8 and 1.7 times higher, respectively, than that among White individuals. CONCLUSIONS: Substantial racial/ethnic disparities in legal intervention deaths remain an ongoing problem in the United States. PMID- 27997231 TI - Transgender Health: New Zealand's Innovative Statistical Standard for Gender Identity. AB - The implementation of the New Zealand government's recently developed statistical standard for gender identity has led to, and will stimulate further, collection of gender identity data in administrative records, population surveys, and perhaps the census. This will provide important information about the demographics, health service use, and health outcomes of transgender populations to allow evidence-based policy development and service planning. However, the standard does not promote the two-question method, risking misclassification and undercounts; does promote the use of the ambiguous response category "gender diverse" in standard questions; and is not intersex inclusive. Nevertheless, the statistical standard provides a first model for other countries and international organizations, including United Nations agencies, interested in policy tools for improving transgender people's health. PMID- 27997232 TI - Human Trafficking of Minors and Childhood Adversity in Florida. AB - OBJECTIVES: To examine the link between human trafficking of minors and childhood adversity. METHODS: We compared the prevalence of adverse childhood experiences (ACEs) and cumulative childhood adversity (ACE score) among a sample of 913 juvenile justice-involved boys and girls in Florida for whom the Florida child abuse hotline accepted human trafficking abuse reports between 2009 and 2015 with those of a matched sample. RESULTS: ACE composite scores were higher and 6 ACEs indicative of child maltreatment were more prevalent among youths who had human trafficking abuse reports. Sexual abuse was the strongest predictor of human trafficking: the odds of human trafficking was 2.52 times greater for girls who experienced sexual abuse, and there was a 8.21 times greater risk for boys who had histories of sexual abuse. CONCLUSIONS: Maltreated youths are more susceptible to exploitation in human trafficking. Sexual abuse in connection with high ACE scores may serve as a key predictor of exploitation in human trafficking for both boys and girls. PMID- 27997233 TI - The Contagious Spread of Violence Among US Adolescents Through Social Networks. AB - OBJECTIVES: To test the hypothesis that violence among US adolescents spreads like a contagious disease through social networks. METHODS: Participants were a nationally representative sample of 90 118 US students aged 12 to 18 years who were involved in the National Longitudinal Study of Adolescent Health. Violence was assessed by having participants report the number of times in the preceding 12 months they had been involved in a serious physical fight, had hurt someone badly, and had pulled a weapon on someone. RESULTS: Participants were 48% more likely to have been involved in a serious fight, 183% more likely to have hurt someone badly, and 140% more likely to have pulled a weapon on someone if a friend had engaged in the same behavior. The influence spread up to 4 degrees of separation (i.e., friend of friend of friend of friend) for serious fights, 2 degrees for hurting someone badly, and 3 degrees for pulling a weapon on someone. CONCLUSIONS: Adolescents were more likely to engage in violent behavior if their friends did the same, and contagion of violence extended beyond immediate friends to friends of friends. PMID- 27997234 TI - The Association of a Large-Scale Television Campaign With Exclusive Breastfeeding Prevalence in Vietnam. AB - OBJECTIVES: To examine the association between exposure to breastfeeding television spots and exclusive breastfeeding (EBF). METHODS: We performed face-to face interviews with 11 722 mothers of infants younger than 6 months using 5 cross-sectional surveys 6 or more months apart between 2011 and 2014 in Vietnam. Sample sizes were 2065 to 2593, and approximately 50% of participants lived in areas with (Alive & Thrive [A&T]-intensive [I]) and approximately 50% without (A&T-nonintensive [NI]) facilities offering counseling services. We analyzed data at individual and commune levels separately for A&T-I and A&T-NI areas. RESULTS: Exposure to television spots was associated with higher EBF in A&T-I (odds ratio [OR] = 3.33; 95% confidence interval [CI] = 2.70, 4.12) and A&T-NI (OR = 1.31; 95% CI = 1.03, 1.67) areas. In A&T-I areas, mothers who could recall at least 1 message were more likely to report EBF. In A&T-NI areas, only recall of at least 3 messages was associated with higher EBF. In communes, 1 message recalled (mean score range = 0.3-2.4) corresponded to 17 (P = .005) and 8 (P = .1) percentage points higher EBF prevalence in A&T-I and A&T-NI communes, respectively. CONCLUSIONS: Mass media should be part of comprehensive programs to promote EBF. PMID- 27997235 TI - Familial Factors, Victimization, and Psychological Health Among Sexual Minority Adolescents in Sweden. AB - OBJECTIVES: To determine the influences of victimization experience and familial factors on the association between sexual minority status and psychological health outcomes among adolescents. METHODS: We used data from the Child and Adolescent Twin Study in Sweden, a prospective, population-based study of all twins born in Sweden since 1992. Cross-sectional analyses included individuals who completed assessments at age 18 years (n = 4898) from 2000 to 2013. We also compared psychological health among sexual minority adolescents and their nonminority co-twins. RESULTS: Sexual minority adolescents were more likely than were unrelated nonminority adolescents to report victimization experiences, including emotional abuse, physical abuse or neglect, and sexual abuse. Sexual minority adolescents also reported significantly more symptoms of anxiety, depression, attention-deficit/hyperactivity disorder, disordered eating, and substance misuse in addition to increased parent-reported behavior problems. Victimization experience partially mediated these associations. However, when controlling for unmeasured familial confounding factors by comparing sexual minority adolescents to their same-sex, nonminority co-twins, the effect of sexual minority status on psychological health was almost entirely attenuated. CONCLUSIONS: Familial factors-common genetic or environmental influences-may explain decreased psychological adjustment among sexual minority adolescents. PMID- 27997236 TI - Impact of a Text-Messaging Program on Adolescent Reproductive Health: A Cluster Randomized Trial in Ghana. AB - OBJECTIVES: To evaluate whether text-messaging programs can improve reproductive health among adolescent girls in low- and middle-income countries. METHODS: We conducted a cluster-randomized controlled trial among 756 female students aged 14 to 24 years in Accra, Ghana, in 2014. We randomized 38 schools to unidirectional intervention (n = 12), interactive intervention (n = 12), and control (n = 14). The unidirectional intervention sent participants text messages with reproductive health information. The interactive intervention engaged adolescents in text messaging reproductive health quizzes. The primary study outcome was reproductive health knowledge at 3 and 15 months. Additional outcomes included self-reported pregnancy and sexual behavior. Analysis was by intent-to-treat. RESULTS: From baseline to 3 months, the unidirectional intervention increased knowledge by 11 percentage points (95% confidence interval [CI] = 7, 15) and the interactive intervention by 24 percentage points (95% CI = 19, 28), from a control baseline of 26%. Although we found no changes in reproductive health outcomes overall, both unidirectional (odds ratio [OR] = 0.14; 95% CI = 0.03, 0.71) and interactive interventions (OR = 0.15; 95% CI = 0.03, 0.86) lowered odds of self-reported pregnancy for sexually active participants. CONCLUSIONS: Text-messaging programs can lead to large improvements in reproductive health knowledge and have the potential to lower pregnancy risk for sexually active adolescent girls. PMID- 27997237 TI - Lost in E-Cigarette Clouds: A Culture on the Rise. PMID- 27997238 TI - The Progress of US Hospitals in Addressing Community Health Needs. AB - OBJECTIVES: To identify how US tax-exempt hospitals are progressing in regard to community health needs assessment (CHNA) implementation following the Patient Protection and Affordable Care Act. METHODS: We analyzed data on more than 1500 tax-exempt hospitals in 2013 to assess patterns in CHNA implementation and to determine whether a hospital's institutional and community characteristics are associated with greater progress. RESULTS: Our findings show wide variation among hospitals in CHNA implementation. Hospitals operating as part of a health system as well as hospitals participating in a Medicare accountable care organization showed greater progress in CHNA implementation whereas hospitals serving a greater proportion of uninsured showed less progress. We also found that hospitals reporting the highest level of CHNA implementation progress spent more on community health improvement. CONCLUSIONS: Hospitals widely embraced the regulations to perform a CHNA. Less is known about how hospitals are moving forward to improve population health through the implementation of programs to meet identified community needs. PMID- 27997239 TI - Transgender Demographics: A Household Probability Sample of US Adults, 2014. AB - OBJECTIVES: To estimate the proportion of US adults who identify as transgender and to compare the demographics of the transgender and nontransgender populations. METHODS: We conducted a secondary analysis of data from states and territories in the 2014 Behavioral Risk Factor Surveillance System that asked about transgender status. The proportion of adults identified as transgender was calculated from affirmative and negative responses (n = 151 456). We analyzed data with a design-adjusted chi2 test. We also explored differences between male to-female and nontransgender females and female-to-male and nontransgender males. RESULTS: Transgender individuals made up 0.53% (95% confidence interval = 0.46, 0.61) of the population and were more likely to be non-White (40.0% vs 27.3%) and below the poverty line (26.0% vs 15.5%); as likely to be married (50.5% vs 47.7%), living in a rural area (28.7% vs 22.6%), and employed (54.3% vs 57.7%); and less likely to attend college (35.6% vs 56.6%) compared with nontransgender individuals. CONCLUSIONS: Our findings suggest that the transgender population is a racially diverse population present across US communities. Inequalities in the education and socioeconomic status have negative implications for the health of the transgender population. PMID- 27997240 TI - Lifetime Prevalence of Investigating Child Maltreatment Among US Children. AB - OBJECTIVES: To estimate the lifetime prevalence of official investigations for child maltreatment among children in the United States. METHODS: We used the National Child Abuse and Neglect Data System Child Files (2003-2014) and Census data to develop synthetic cohort life tables to estimate the cumulative prevalence of reported childhood maltreatment. We extend previous work, which explored only confirmed rates of maltreatment, and we add new estimations of maltreatment by subtype, age, and ethnicity. RESULTS: We estimate that 37.4% of all children experience a child protective services investigation by age 18 years. Consistent with previous literature, we found a higher rate for African American children (53.0%) and the lowest rate for Asians/Pacific Islanders (10.2%). CONCLUSIONS: Child maltreatment investigations are more common than is generally recognized when viewed across the lifespan. Building on other recent work, our data suggest a critical need for increased preventative and treatment resources in the area of child maltreatment. PMID- 27997241 TI - Trends in Walking and Cycling Safety: Recent Evidence From High-Income Countries, With a Focus on the United States and Germany. AB - OBJECTIVES: To examine changes in pedestrian and cyclist fatalities per capita (1990-2014) and per kilometer (2000-2010) in selected high-income countries, and in fatalities and serious injuries per kilometer by age in the United States and Germany (2001-2009). METHODS: We used Organisation for Economic Cooperation and Development data to estimate 5-year annual averages of per-capita fatalities relative to the 1990-1994 average. To control for exposure, we divided fatalities and serious injuries by kilometers of walking or cycling per year for countries with comparable data from national household travel surveys. RESULTS: Most countries have reduced pedestrian and cyclist fatality rates per capita and per kilometer. The serious injuries data show smaller declines or even increases in rates per kilometer. There are large differences by age group in fatality and serious injury rates per kilometer, with seniors having the highest rates. The United States has much higher fatality and serious injury rates per kilometer than the other countries examined, and has made the least progress in reducing per-capita fatality rates. CONCLUSIONS: The United States must greatly improve walking and cycling conditions. All countries should focus safety programs on seniors and children. PMID- 27997243 TI - Introduction to a Reprint of Emilia Lombardi's "Enhancing Transgender Health Care". PMID- 27997242 TI - Incarceration Rates and Traits of Sexual Minorities in the United States: National Inmate Survey, 2011-2012. AB - OBJECTIVES: To report characteristics of sexual minority US inmates. METHODS: We drew our data from the National Inmate Survey, 2011-2012, a probability sample of inmates in US prisons and jails. We determined weighted proportions and odds ratios with 95% confidence intervals to estimate differences between sexual minority and heterosexual inmates. RESULTS: Sexual minorities (those who self identify as lesbian, gay, or bisexual or report a same-sex sexual experience before arrival at the facility) were disproportionately incarcerated: 9.3% of men in prison, 6.2% of men in jail, 42.1% of women in prison, and 35.7% of women in jail were sexual minorities. The incarceration rate of self-identified lesbian, gay, or bisexual persons was 1882 per 100 000, more than 3 times that of the US adult population. Compared with straight inmates, sexual minorities were more likely to have been sexually victimized as children, to have been sexually victimized while incarcerated, to have experienced solitary confinement and other sanctions, and to report current psychological distress. CONCLUSIONS: There is disproportionate incarceration, mistreatment, harsh punishment, and sexual victimization of sexual minority inmates, which calls for special public policy and health interventions. PMID- 27997244 TI - Effect of Medicaid Expansion on Workforce Participation for People With Disabilities. AB - OBJECTIVES: To use data from the Health Reform Monitoring Survey (HRMS) to examine differences in employment among community-living, working-age adults (aged 18-64 years) with disabilities who live in Medicaid expansion states and nonexpansion states. METHODS: Analyses used difference-in-differences to compare trends in pooled, cross-sectional estimates of employment by state expansion status for 2740 HRMS respondents reporting a disability, adjusting for individual and state characteristics. RESULTS: After the Affordable Care Act (ACA), respondents in expansion states were significantly more likely to be employed compared with those in nonexpansion states (38.0% vs 31.9%; P = .011). CONCLUSIONS: Prior to the ACA, many people with disabilities were required to live in poverty to maintain their Medicaid eligibility. With Medicaid expansion, they can now enter the workforce, increase earnings, and maintain coverage. Public Health Implications. Medicaid expansion may improve employment for people with disabilities. PMID- 27997245 TI - US Traffic Fatalities, 1985-2014, and Their Relationship to Medical Marijuana Laws. AB - OBJECTIVES: To determine the association of medical marijuana laws (MMLs) with traffic fatality rates. METHODS: Using data from the 1985-2014 Fatality Analysis Reporting System, we examined the association between MMLs and traffic fatalities in multilevel regression models while controlling for contemporaneous secular trends. We examined this association separately for each state enacting MMLs. We also evaluated the association between marijuana dispensaries and traffic fatalities. RESULTS: On average, MML states had lower traffic fatality rates than non-MML states. Medical marijuana laws were associated with immediate reductions in traffic fatalities in those aged 15 to 24 and 25 to 44 years, and with additional yearly gradual reductions in those aged 25 to 44 years. However, state specific results showed that only 7 states experienced post-MML reductions. Dispensaries were also associated with traffic fatality reductions in those aged 25 to 44 years. CONCLUSIONS: Both MMLs and dispensaries were associated with reductions in traffic fatalities, especially among those aged 25 to 44 years. State-specific analysis showed heterogeneity of the MML-traffic fatalities association, suggesting moderation by other local factors. These findings could influence policy decisions on the enactment or repealing of MMLs and how they are implemented. PMID- 27997247 TI - Welcome to volume 12 of the journal Future Microbiology. PMID- 27997246 TI - Anabolic Steroid Misuse Among US Adolescent Boys: Disparities by Sexual Orientation and Race/Ethnicity. AB - OBJECTIVES: To examine the prevalence of anabolic steroid misuse among US adolescent boys as a function of sexual orientation and race/ethnicity. METHODS: We analyzed boys from the 2015 Youth Risk Behavior Survey (n = 6248; mean age = 16), a representative sample of US high school students. Lifetime prevalence of anabolic steroid misuse was dichotomized as never versus 1 or more times. RESULTS: Sexual minority boys reported elevated misuse compared with heterosexual boys, within each level of race/ethnicity. Black, Hispanic, and White sexual minority boys reported misuse at approximately 25%, 20%, and 9%, respectively. CONCLUSIONS: Sexual orientation health disparities in anabolic steroid misuse disproportionally affect Black and Hispanic sexual minority adolescent boys, but more research is needed to understand the mechanisms driving these disparities. PMID- 27997248 TI - Next-Generation Molecular Diagnostics Provide Evidence Suggestive of a Role for Nontraditional Bacterial Pathogens in Osteoarthritis of the Knee. PMID- 27997250 TI - Association of Tear Film Stability and Corneal Surface Temperature in Pudong Patients. AB - OBJECTIVE: To investigate the association between corneal temperature on ocular surface and stability of tear film, and define the normal reference range of corneal surface temperature in the population of Pudong New Area, Shanghai, China. METHODS: Temperature of cornea (TOC) and tear film break-up time (BUT) were measured among 515 volunteers with or without dry eye. The association between TOC and tear film stability was analyzed, and the normal reference range of TOC was determined. RESULTS: TOC was 32.6 +/- 0.97 degrees C among the 318 subjects without dry eye including 147 males (TOC = 32.6 +/- 0.70 degrees C) and 171 females (TOC = 32.64 +/- 1.16 degrees C). Significant differences existed in TOC on ocular surface among three separated groups according to BUT measurement. Age was positively related to TOC, whereas BUT was negatively correlated with TOC. CONCLUSION: It is recommended to consider 32.6 +/- 0.70 degrees C as the normal reference value for human central corneal temperature. Instability of tear film is concomitant with elevated TOC in the population of Pudong New Area, Shanghai. PMID- 27997249 TI - Dosage of Sex Chromosomal Genes in Blood Deposited on Filter Paper for Neonatal Screening of Sex Chromosome Aneuploidy. AB - AIMS: In this study, we examined the doses of the stature homeobox (SHOX), vesicle-associated membrane protein 7 (VAMP7), and SRY genes to establish a protocol for using peripheral blood samples deposited on filter paper for the screening of sex chromosome aneuploidy in neonates. We also measured correlations with karyotypes to assess this method as a neonatal screening strategy. MATERIALS AND METHODS: This was an observational, descriptive, comparative blind study. Thirty-two healthy young adults (17 women, 15 men; age, >=18 years), four patients with known sex chromosome aneuploidy (positive control group), and 1000 healthy newborns were included. Gene dosages were determined using quantitative real-time polymerase chain reaction (RT-PCR). Values with standard deviations (SDs) of three or more were considered abnormal. RESULTS: Men and women differed in the gene dosage of the SRY gene. Cases with Turner syndrome showed values below 3 SDs for SHOX and VAMP7 genes, and cases with Klinefelter syndrome showed values above 3 SDs for SHOX and VAMP7 genes. Two suspected cases of sex chromosome aneuploidy were diagnosed using our neonatal screening strategy; these cases were confirmed as Turner syndrome and 47,XYY syndrome by karyotyping. CONCLUSIONS: Our data establish a basis for the determination of chromosomal sex and neonatal screening of sex chromosome aneuploidy using RT-PCR. PMID- 27997251 TI - Changes of Respiratory Mechanics in COPD Patients from Stable State to Acute Exacerbations with Respiratory Failure. AB - Symptoms, clinical course, functional and biological data during an exacerbation of chronic obstructive pulmonary disease (EXCOPD) have been investigated, but data on physiological changes of respiratory mechanics during a severe exacerbation with respiratory acidosis requiring noninvasive mechanical ventilation (NIMV) are scant. The aim of this study was to evaluate changes of respiratory mechanics in COPD patients comparing data observed during EXCOPD with those observed during stable state in the recovery phase. In 18 COPD patients having severe EXCOPD requiring NIMV for global respiratory failure, we measured respiratory mechanics during both EXCOPD (T0) and once the patients achieved a stable state (T1). The diaphragm and inspiratory muscles effort was significantly increased under relapse, as well as the pressure-time product of the diaphragm and the inspiratory muscle (PTPdi and PTPes). The resistive loads to breathe (i.e., PEEPi,dyn, compliance and inspiratory resistances) were also markedly increased, while the maximal pressures generated by the diaphragm and the inspiratory muscles, together with forced expired volumes were decreased. All these indices statistically improved but with a great intrasubject variability in stable condition. Moreover, tension-time index (TTdi) significantly improved from the EXCOPD state to the condition of clinical stability (0.156 +/- 0.04 at T0 vs. 0.082 +/- 0.02 at T1 p < 0.001). During an EXCOPD, the load/capacity of the respiratory pump is impaired, and although the patients exhibit a rapid shallow breathing pattern, this does not necessarily correlate with a TTdi >= 0.15. These changes are reverted once they recover from the EXCOPD, despite a large variability between patients. PMID- 27997252 TI - Outcomes of Pulmonary Rehabilitation for COPD in Older Patients: A Comparative Study. AB - Pulmonary rehabilitation (PR) is established as an effective intervention in optimising function and quality of life in patients with chronic obstructive pulmonary disease (COPD). However, there are very limited data on the effectiveness of PR in older patients with COPD. We reviewed all patients attending an 8-week outpatient programme. Patients were divided into two groups; Group A (n = 202), below 70 years, and Group B (n = 122), above 70 years of age. Outcomes in both patient subgroups were compared using FEV1, Incremental Shuttle Walk Test (ISWT), Endurance Shuttle Walk Test (ESWT), Grip Strength, St. George's Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Score (HADS), and COPD Assessment Test (CAT) score. Statistical analysis was conducted using Mann-Whitney non-parametric testing and chi-square testing for comparison of clinically relevant improvements between groups. There was no significant difference in PR outcomes between Group A and Group B using absolute values. Mean changes in ISWT for Groups A and B 39.7 m vs. 32.8 m (p = 0.63), respectively, SGRQ -2.5 vs. -2.8 (p = 0.95), HADS anxiety score -0.83 vs. -0.57 (p = 0.43) and HADS depression score -0.69 vs. -0.39 (p = 0.48), respectively. There was no difference in the proportion of patients who achieved the minimal clinically significant improvement in Group A versus Group B for parameters ISWT (38.6% vs 42.7%), SGRQ (27.8% vs 21.3%), and HADS total score (20.5% vs 28.1%). These data suggest that benefits of PR in COPD are not age dependent. Age should not be a barrier to enrolling patients with COPD in PR programmes. PMID- 27997253 TI - The progress and potential of proteomic biomarkers for type 1 diabetes in children. AB - INTRODUCTION: Although it is possible to identify the genetic risk for type 1 diabetes (T1D), it is not possible to predict who will develop the disease. New biomarkers are needed that would help understand the mechanisms of disease onset and when to administer targeted therapies and interventions. Areas covered: An overview is presented of international study efforts towards understanding the cause of T1D, including the collection of several extensive temporal sample series that follow the development of T1D in at risk children. The results of the proteomics analysis of these materials are presented, which have included bodily fluids, such as serum or plasma and urine, as well as tissue samples from the pancreas. Expert commentary: Promising recent reports have indicated detection of early proteomic changes in the serum of patients prior to diagnosis, potentially providing new measures for risk assessment. Similarly, there has been evidence that post-translational modification (PTM) may result in the recognition of islet cell proteins as autoantigens; modified proteins could thus be used as targets for immunomodulation to overcome the threat of the autoimmune response. PMID- 27997254 TI - An International Study of Adherence to Guidelines for Patients Hospitalised with a COPD Exacerbation. AB - Guideline adherence rates for the treatment of chronic obstructive pulmonary disease (COPD) exacerbation are low. The aim of this study is to perform an importance-performance analysis as an approach for prioritisation of interventions by linking guidelines adherence rates to expert consensus rates for the in-hospital management of COPD exacerbation. We illustrate the relevance of such approach by describing variation in guideline adherence across indicators and hospitals. A secondary data analysis of patients with an acute COPD exacerbation admitted to Belgian, Italian and Portuguese hospitals was performed. Twenty-one process indicators were used to describe adherence to guidelines from patient record reviews. Expert consensus on the importance for follow-up of these 21 indicators was derived from a previous Delphi study. Three of the twenty-one indicators had high level of expert consensus and a high level of adherence. Eleven of the twenty-one indicators had high level of expert consensus but a low level of adherence. For none of the 378 patients included in this study were all process indicators adhered to, patients received 41.0% of the recommended care on average, and only 34.1% of the patients received 50% or more of the care they should receive. There was also a large variation within and between hospitals regarding the care received. This study confirms the findings of previous studies, indicating that COPD exacerbations are largely undertreated. Importance performance analysis provides a decision-making tool for prioritising indicators. All hospitals in this study would benefit from having in place a quality framework for systematic follow-up of these indicators. PMID- 27997255 TI - Emphysema on Thoracic CT and Exercise Ventilatory Inefficiency in Mild-to Moderate COPD. AB - There is growing evidence that emphysema on thoracic computed tomography (CT) is associated with poor exercise tolerance in COPD patients with only mild-to moderate airflow obstruction. We hypothesized that an excessive ventilatory response to exercise (ventilatory inefficiency) would underlie these abnormalities. In a prospective study, 19 patients (FEV1 = 82 +/- 13%, 12 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1) and 26 controls underwent an incremental exercise test. Ventilatory inefficiency was assessed by the ventilation ([Formula: see text]E)/CO2 output ([Formula: see text]CO2) nadir. Pulmonary blood flow (PBF) in a submaximal test was calculated by inert gas rebreathing. Emphysema was quantified as % of attenuation areas below 950 HU. Patients typically presented with centrilobular emphysema (76.8 +/- 10.1% of total emphysema) in the upper lobes (upper/total lung ratio = 0.82 +/- 0.04). They had lower peak oxygen uptake ([Formula: see text]O2), higher [Formula: see text]E/[Formula: see text]CO2 nadir, and greater dyspnea scores than controls (p < 0.05). Lower peak [Formula: see text]O2 and worse dyspnea were found in patients with higher [Formula: see text]E/[Formula: see text]CO2 nadirs (>=30). Patients had blunted increases in PBF from rest to iso-[Formula: see text]O2 exercise (p < 0.05). Higher [Formula: see text]E/[Formula: see text]CO2 nadir in COPD was associated with emphysema severity (r = 0.63) which, in turn, was related to reduced lung diffusing capacity (r = -0.72) and blunted changes in PBF from rest to exercise (r = -0.69) (p < 0.01). Ventilation "wasted" in emphysematous areas is associated with impaired exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (DLCO) to a key clinical outcome (poor exercise tolerance) in COPD patients with only modest spirometric abnormalities. PMID- 27997256 TI - Ultrasound functional evaluation of fetuses with myelomeningocele: study of the interpretation of results. AB - OBJECTIVE: To assess the reliability of the interpretation of a new technique for the ultrasound evaluation of the level of neurological lesion in fetuses with myelomeningocele. METHODS: Observational study including myelomeningocele fetuses, referred to our center for the sonographic assessment of the fetal lower limb movements, made and recorded by an expert in Maternal-fetal medicine and a specialist in Rehabilitation. Two observers, with different levels of expertise and blinded to each other's results, interpreted each recorded scan two different times. The agreement for the segmental levels assigned between the observers and the gold standard, the inter-observer and intra-observer reproducibility were tested using the weighed Kappa (wkappa) index. RESULTS: Twenty-eight scans were recorded and evaluated. The agreement between the observers and the gold standard remained constant for the expert observer (wkappa = 0.82) and increased (wkappa = 0.66-wkappa = 0.72) for the other one. The inter-observer and the intra-observer variability for the expert observer were wkappa = 0.72 and wkappa = 0.94, respectively. DISCUSSION: The agreement for the prenatal evaluation of the segmental neurological level was excellent, after a short training period, for observers with different degrees of expertise. The interpretation of this technique is reproducible enough and this supports its value for the prediction of postnatal motor function in myelomeningocele fetuses. PMID- 27997257 TI - Solid, Gel, and Liquid Carbohydrate Format Effects on Gut Comfort and Performance. AB - Carbohydrate sports drinks produce worthwhile benefits to endurance performance compared with noncaloric controls. However, athletes now consume carbohydrate in a range of formats, including gels and bars, but the comparable performance outcomes are unknown. Therefore, the aim of this study was to establish the relative effects of drink, gel, bar, and mixed carbohydrate formats on intense cycling performance. In a treatmentapparent randomized crossover design, 12 well trained male cyclists completed 4 trials comprising a 140-min race simulation, followed by a double-blind slow-ramp to exhaustion (0.333 W.s-1). Carbohydrate comprising fructose and maltodextrin was ingested every 20 min via commercial drink, gel, bar, or mix of all 3, providing 80 g carbohydrate.h-1. Fluid ingestion was 705 ml.h-1. Exertion, fatigue, and gastrointestinal discomfort were measured with VAS. Performance peak power (SD) was 370 (41), 376 (37), 362 (51) and 368 W (54) for drink, gels, bars, and mix respectively. The reduction in power (-3.9%; 90%CI +/-4.3) following bar ingestion vs. gel was likely substantial (likelihood harm 81.2%; benefit 0.8%), but no clear differences between drinks, gels, and the mix were evident. Bars also produced small-moderate standardized increases in nausea, stomach fullness, abdominal cramps, and perceived exertion, relative to gels (likelihood harm 95-99.5%; benefit <0.01%) and drink (75-95%; <0.01%); mix also increased nausea relative to gels (95%; <0.01%). Relative to a gel, carbohydrate bar ingestion reduced peak power, gut comfort, and ease of exertion; furthermore, no clear difference relative to drink suggests bars alone are the less favorable exogenous-carbohydrate energy source for intense endurance performance. PMID- 27997258 TI - A Swedish cross-cultural adaptation and validation of the Tinnitus Functional Index. AB - OBJECTIVE: The Tinnitus Functional Index (TFI) is a recent self-report instrument for tinnitus with potential advantages over other existing instruments, including a demonstrated high responsiveness. The objectives of this study were to translate and cross-culturally adapt the TFI into Swedish and to investigate its validity and reliability. DESIGN: The development of the Swedish version (TFI-SE) followed published guidelines on cross-cultural adaptation of health questionnaires. Validity and reliability was investigated by correlating responses on the TFI-SE with other tinnitus measures [Tinnitus Handicap Inventory (THI) and visual analogue scale (VAS)] and a scale measuring anxiety and depression (HADS). STUDY SAMPLE: Consecutively recruited tinnitus patients (n = 100) from four Swedish clinics completed the questionnaires. The mean age of the sample was 51 years (SD =17). RESULTS: The internal consistency of the TFI-SE was good (alpha = 0.95) and the test-retest reliability was high (ICC =0.93). Our results supported the eight-factor structure proposed for the original TFI, and a high correlation between the TFI-SE and the THI (r = 0.8; p < 0.01) and lower correlations between the TFI-SE and the HADS-D (r = 0.60; p < 0.01) and HADS-A (r = 0.59; p < 0.01) confirmed satisfactory convergent and discriminant validity. CONCLUSIONS: We found that the Swedish translation and cross-cultural adaptation of the TFI is valid and reliable for use with adult tinnitus patients. PMID- 27997259 TI - A new comprehensive model for Continuous Professional Development. AB - BACKGROUND: It is generally agreed that continuing professional development (CPD) for GPs is important for quality of care. Internationally, however, different approaches to identify the learning objectives and the CPD content have been chosen. OBJECTIVES: To improve GPs' CPD in Denmark we explore how general practitioners' (GPs) self-experienced learning needs can be combined with learning needs experienced from a societal perspective and still make sense for GPs. METHODS: We performed a multi-dimensional learning needs analysis with a modified Delphi method in a participatory action research set-up. Twenty practice based small learning groups and a group appointed by the Danish public health service were asked to identify learning needs with the Danish family medicine curriculum as reference. Then we asked a group of GP researchers and hospital consultants, a group of GPs with interests in narrative, person-centred medicine and a group of GP educators, and administrative staff, to triangulate the initial findings. RESULTS: We identified educational themes through a defined collaborative consensus oriented process. Examples of themes are the diagnostic challenge, care for patients with multi-morbidity, elderly patients and children. Due to variation in requested learning objectives, the identified themes do not cover all relevant areas for CPD training. The identified themes will only make sense if seen as supplementary to other CPD activities based on GPs individual needs analyses. CONCLUSION: It is possible to identify prioritized educational themes for GPs through a process involving the majority of stakeholders. Nevertheless, CPD should also include activities based on individual needs analysis. [Box: see text]. PMID- 27997260 TI - Acoustic wave therapy for cellulite, body shaping and fat reduction. AB - BACKGROUND: Cellulite is a common aesthetic condition that affects almost every woman. OBJECTIVE: To evaluate the efficacy of acoustic wave therapy (AWT) for cellulite and body shaping. METHODS: In this open-label, single-centre trial, 30 women presenting moderate or severe cellulite underwent 12 sessions of AWT on the gluteus and back of the thighs, over six weeks. The following assessments were performed at baseline, and up to 12 weeks after treatment: Cellulite Severity Scale (CSS), body circumference measurements, subcutaneous fat thickness by magnetic resonance imaging (MRI), quality of life related by Celluqol(r) and a satisfaction questionnaire. RESULTS: The treatment reduced cellulite severity from baseline up to 12 weeks after the last treatment session (subjects presenting severe cellulite: 60% to 38%). The mean CSS shifted from 11.1 to 9.5 (p < 0.001). Hips circumferences reduced from 99.7 and 103.2 cm to 96.2 and 100.3 cm (respectively, p < 0.001). The average thickness of the subcutaneous fat tissue also decreased (28.3 +/- 6.5 mm to 26.7 +/- 6.1mm; p < 0.001). The treatment also improved quality of life. More than 90% of the subjects would undergo the treatment again and 89% were satisfied with the results. No serious adverse events were reported. CONCLUSIONS: AWT is a safe treatment to improve cellulite appearance and reduce body circumferences. PMID- 27997261 TI - Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students. AB - We investigated the effects of aerobic exercise intensity on oxidative nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100beta; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 +/- 1.7 mM) compared with that after LI (2.8 +/- 1.4 mM) exercise (p < .05). At 60MAE, ROS concentration was higher following HI (2.5 +/- 1.2 mM) than after LI (1.5 +/- 0.5 mM) and MI (1.4 +/- 0.3 mM) conditions (p < .05). Plasma NO IAE increased significantly after MI and HI exercise (p < .05). Serum BDNF, NGF, and S-100b levels were significantly higher IAE following MI and HI exercise (p < .05). BDNF and S-100b were higher IAE following MI (29.6 +/- 3.4 ng/mL and 87.1 +/- 22.8 ng/L, respectively) and HI (31.4 +/- 3.8 ng/mL and 100.6 +/- 21.2 ng/L, respectively) than following LI (26.5 +/- 3.0 ng/mL and 64.8 +/- 19.2 ng/L, respectively) exercise (p < .05). 60MAE, S-100b was higher following HI (71.1 +/- 14.5 ng/L) than LI (56.2 +/- 14.7 ng/L) exercise (p < .05). NSE levels were not significantly different among all intensity conditions and time points (p > .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability. PMID- 27997262 TI - A 10-year evaluation on adolescents with anxiety disorders: are they at risk of bipolarity? AB - OBJECTIVE: Anxiety disorders are the most frequent disorders comorbid with bipolar disorder (BD) often preceding the BD onset. The presence of comorbid anxiety in patients diagnosed with BD is associated with worsening of their BD symptoms, increased risky behaviour, decreased response to pharmacological treatment and deterioration in their quality of life and global functioning. The aim of this study was to investigate if anxiety disorders in adolescence could be considered as predictors of BD. METHODS: Adolescents with a primary anxiety disorder were recruited consecutively from the Mood and Anxiety Disorders Unit, Department of Neuroscience, University of Turin. Subjects were evaluated for Axis I psychiatric disorders, family history and global functioning, and followed up on average 10 years later. RESULTS: A total of 29 patients (59.2%) were male and the mean age at the onset of anxiety disorder was 16.3 (+/-0.8). Ten years following recruitment, 11 (22.4%) patients fulfilled the criteria for BD. Of them, 10 (90.9%) had a family history of BD and four (36.4%) presented a comorbid substance use disorder. CONCLUSIONS: Our study shows that both family history of BD and substance use disorder, in adolescent patients with a primary anxiety disorder, should be considered as potential predictors of BD onset. PMID- 27997263 TI - Dietary Nitrate Fails to Improve 1 and 4 km Cycling Performance in Highly Trained Cyclists. AB - We aimed to compare the effects of two different dosing durations of dietary nitrate (NO3-) supplementation on 1 and 4 km cycling time-trial performance in highly trained cyclists. In a double-blind crossover-design, nine highly trained cyclists ingested 140ml of NO3- -rich beetroot juice containing ~8.0mmol [NO3-], or placebo, for seven days. Participants completed a range of laboratory-based trials to quantify physiological and perceptual responses and cycling performance: time-trials on day 3 and 6 (4km) and on day 4 and 7 (1km) of the supplementation period. Relative to placebo, effects following 3- and 4-days of NO3- supplementation were unclear for 4 (-0.8; 95% CL, +/- 2.8%, p = .54) and likely harmful for 1km (-1.9; +/- 2.5% CL, p = .17) time-trial mean power. Effects following 6- and 7-days of NO3- supplementation resulted in unclear effects for 4 (0.1; +/- 2.2% CL, p = .93) and 1km (-0.9; +/- 2.6%CL, p = .51) time-trial mean power. Relative to placebo, effects for 40, 50, and 60% peak power output were unclear for economy at days 3 and 6 of NO3- supplementation (p > .05). Dietary NO3- supplementation appears to be detrimental to 1km time-trial performance in highly trained cyclists after 4-days. While, extending NO3- dosing to >= 6-days reduced the magnitude of harm in both distances, overall performance in short duration cycling time-trials did not improve relative to placebo. PMID- 27997264 TI - Decrease in Ionized and Total Magnesium Blood Concentrations in Endurance Athletes Following an Exercise Bout Restores within Hours-Potential Consequences for Monitoring and Supplementation. AB - Magnesium is essential for optimal sport performance, generating an interest to monitor its status in athletes. However, before measuring magnesium status in blood could become routine, more insight into its diurnal fluctuations and effects of exercise itself is necessary. Therefore, we measured the effect of an acute bout of exercise on ionized (iMg) and total plasma magnesium (tMg) in blood obtained from 18 healthy well-trained endurance athletes (age, 31.1 +/- 8.1 yr.; VO2max, 50.9 +/- 7.5 ml/kg/min) at multiple time points, and compared this with a resting situation. At both days, 7 blood samples were taken at set time points (8:30 fasted, 11:00, 12:30, 13:30, 15:00, 16:00, 18:30). The control day was included to correct for a putative diurnal fluctuation of magnesium. During the exercise day, athletes performed a 90 min bicycle ergometer test (70% VO2max) between 11:00 and 12:30. Whole blood samples were analyzed for iMg and plasma for tMg concentrations. Both concentrations decreased significantly after exercise (0.52 +/- 0.04-0.45 +/- 0.03 mmol/L and 0.81 +/- 0.07-0.73 +/- 0.06 mmol/L, respectively, p < .001) while no significant decline was observed during that time-interval on control days. Both, iMg and tMg, returned to baseline, on average, 2.5 hr after exercise. These findings suggest that timing of blood sampling to analyze Mg status is important. Additional research is needed to establish the recovery time after different types of exercise to come to a general advice regarding the timing of magnesium status assessment in practice. PMID- 27997265 TI - Plasma lactoferrin levels in newborn preterm infants with sepsis. AB - INTRODUCTION: Lactoferrin (Lf) is one of the major proteins of all exocrine secretions with a role in the antinfective process. Our aim was to evaluate how plasma Fl levels may change in response to infection in newborn preterm infants. METHODS: A total of 15 (8 females, 7 males) newborn preterm infants with a postnatal age >72 h of life, underwent to blood culture and others markers of infection, for suspected sepsis, were enrolled in the study. RESULTS: We found that Lf serum concentration was significantly lowest in four neonates (26.7%) with confirmed sepsis than in 11 (73.3%) with clinical sepsis. The AUC was 0.90 (95%CI: 0.63-0.99). The optimal cutoff for Lf was <1.2 MUg/ml with a sensibility of 100% and a specificity of 81.8%. Lf serum concentration was positively correlated with WBC or neutrophil (Spearman rho = 0.69 and 0.49, respectively). CONCLUSIONS: Serum Lf could prove a promising, sensitive and specific marker in the diagnostic approach to infants with suspected sepsis, thanks to its role in defense mechanisms and physiological functions of the immune system. Low levels of Lf in sepsis may suggest an immature response due to suboptimal leukocites activity in newborn preterm infants. PMID- 27997266 TI - Obesity as an independent risk factor for group B streptococcal colonization. AB - OBJECTIVE: Approximately 25% of women are colonized with group B streptococcus (GBS). We assessed whether body mass index (BMI) is an independent risk factor for GBS colonization. STUDY DESIGN: We performed a retrospective cohort study using a previously collected database of women who delivered singleton gestations at term. Individual patient medical record review was undertaken to add GBS related information to the database. Univariable logistic regression was used to assess the relationship between GBS colonization and BMI. Multivariable logistic regression was used to adjust for confounders. RESULTS: A total of 2045 patients met enrollment criteria. The prevalence of GBS colonization was 29%. In the unadjusted analysis, there was a statistically significant increase in GBS colonization per unit increase in BMI (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.04). This relationship remained significant after adjusting for confounders (race, marital status, payer, chronic hypertension, concomitant genital infections) (OR 1.01, 95% CI 1.00-1.03; p = 0.04). By BMI category, there were no differences in antibiotic susceptibilities or mode of ascertainment of GBS colonization. CONCLUSION: Obesity is an independent risk factor for GBS colonization; however, this association is weak. PMID- 27997267 TI - Non-ablative radiofrequency associated or not with low-level laser therapy on the treatment of facial wrinkles in adult women: A randomized single-blind clinical trial. AB - OBJECTIVES: The objective of this study was to evaluate the effects of Non ablative Radiofrequency (RF) associated or not with low-level laser therapy (LLLT) on aspect of facial wrinkles among adult women. METHODS: Forty-six participants were randomized into three groups: Control Group (CG, n = 15), RF Group (RG, n = 16), and RF and LLLT Group (RLG, n = 15). Every participant was evaluated on baseline (T0), after eight weeks (T8) and eight weeks after the completion of treatment (follow-up). They were photographed in order to classify nasolabial folds and periorbital wrinkles (Modified Fitzpatrick Wrinkle Scale and Fitzpatrick Wrinkle Classification System, respectively) and improvement on appearance (Global Aesthetic Improvement Scale). Photograph analyses were performed by 3 blinded evaluators. RESULTS: Classification of nasolabial and periorbital wrinkles did not show any significant difference between groups. Aesthetic appearance indicated a significant improvement for nasolabial folds on the right side of face immediately after treatment (p = 0.018) and follow-up (p = 0.029) comparison. RG presented better results than CG on T8 (p = 0.041, ES = 0.49) and on follow-up (p = 0.041, ES = -0.49) and better than RLG on T8 (p = 0.041, ES = -0.49). RLG presented better results than CG on follow-up (p = 0.007, ES = -0.37). CONCLUSION: Nasolabial folds and periorbital wrinkles did not change throughout the study; however, some aesthetic improvement was observed. LLLT did not potentiate RF treatment. PMID- 27997268 TI - Impaired ApoB-Lipoprotein and Triglyceride Metabolism in Obese Adolescents With Polycystic Ovary Syndrome. AB - Context: Adolescents with polycystic ovary syndrome (PCOS) have atherogenic dyslipidemia and increased cardiovascular disease (CVD) risk, and this is exacerbated in obesity. Objective: To determine and compare fasting and nonfasting lipid and apolipoprotein (Apo)B-lipoprotein metabolism in 3 groups of adolescent girls: healthy-weight controls, obese without PCOS (obese-control), and obese with PCOS (obese-PCOS). Design, setting, and participants: Participants aged 12 to 17 years were recruited for this cross-sectional study from a pediatric weight management clinic and the local community in Alberta, Canada. Main Outcome Measures: Plasma lipids and ApoB lipoproteins, including triglycerides (TGs) and ApoB100- and ApoB48-lipoproteins, were measured in the fasted and postprandial state following a high-fat meal. Results: Obese-control (n = 12) and obese-PCOS (n = 18) groups had twofold higher concentrations of fasting plasma TG and ApoB100- and ApoB48-lipoprotein remnants compared to healthy-weight controls (n = 10) (ApoB48-lipoproteins: 19.32 +/- 2.10, 24.02 +/- 4.28, and 8.95 +/- 1.05 MUg/mL, respectively; P < 0.001). The obese-PCOS group had 50% higher fasting plasma TG level compared to the obese-control group. The postprandial response was higher in both obese-controls and obese-PCOS subjects compared with healthy-weight controls in plasma TG area under the curve (AUC) (1028.0 +/- 83.67, 1587.01 +/- 259.6, and 615.42 +/- 76.42 MUg/mL?h, respectively; P < 0.01) and ApoB48(AUC) (191.30 +/- 19.06, 238.8 +/- 37.73, and 96.58 +/- 9.17 MUg/mL?h, respectively; P < 0.0001). Nonfasting plasma TG(AUC) and ApoB48(AUC) were positively correlated with free testosterone (r = 0.38; P < 0.001 and r = 0.33; P < 0.05, respectively), and these relationships were highly associated with insulin and body mass index. Conclusions: Adolescent girls with obesity and PCOS have elevated fasting and postprandial plasma TG and ApoB lipoprotein remnants, providing evidence of early subclinical CVD risk, and these indices are highly associated with impaired insulin metabolism and hyperandrogenemia. PMID- 27997270 TI - Molecular interactions of dioxins and DLCs with the ketosteroid receptors: an in silico risk assessment approach. AB - Dioxins and dioxin-like compounds (DLCs) are the ones with poor water solubility and low volatility, resistant to physical, chemical and biological processes, persistent in the environment even under extreme conditions. Due to lipophilic nature, they get adhered to the fatty material and concentrate through biomagnification and bioaccumulation, thereby easily getting incorporated into food chains, paving the way to endocrine disruption via modulation of various human receptors. This in turn leads to certain adverse health effects. In the present study, a total of 100 dioxins and DLCs were taken and their binding pattern was assessed with the ketosteroid receptors, i.e. androgen (hAR), glucocorticoid (hGR), progesterone (hPR) and mineralocorticoid (hMR) in comparison to the corresponding natural steroids and a known endocrine disrupting xenobiotic, Bisphenol A (BPA). Most of the DLCs, particularly those bearing hydroxyl (-OH) group showed considerable affinities with ketosteroid receptors. On comparing D scores of all the dioxins and DLCs against all four receptors, compound 8-hydroxy-3,4-dichlorodibenzofuran(8-OH-DCDF) exhibited least D score of -9.549 kcal mol-1 against hAR. 3,8-Dihydroxy-2-chlorodibenzofuran(3,8-DiOH-CDF), 4'-hydroxy-2,3,4,5-tetrachlorobiphenyl (4'-OH-TCB) and 4-hydroxy-2,2',5' trichlorobiphenyl(4-OH-TCB) also showed comparable molecular interactions with the ketosteroid receptors. These interactions mainly include H-bonding, pi-pi stacking, hydrophobic, polar and van der Waals' interactions. In contrast, BPA and some natural ligands tested in this study showed lower binding affinities with these receptors than certain DLCs reported herein, i.e. certain DLCs might be more toxic than the proven toxic agent, BPA. Such studies play a pivotal role in the risk assessment of exposure to dioxins and DLCs on human health. PMID- 27997269 TI - The effects of endoplasmic reticulum stress inducer thapsigargin on the toxicity of ZnO or TiO2 nanoparticles to human endothelial cells. AB - It was recently shown that ZnO nanoparticles (NPs) could induce endoplasmic reticulum (ER) stress in human umbilical vein endothelial cells (HUVECs). If ER stress is associated the toxicity of ZnO NPs, the presence of ER stress inducer thapsigargin (TG) should alter the response of HUVECs to ZnO NP exposure. In this study, we addressed this issue by assessing cytotoxicity, oxidative stress and inflammatory responses in ZnO NP exposed HUVECs with or without the presence of TG. Moreover, TiO2 NPs were used to compare the effects. Exposure to 32 MUg/mL ZnO NPs (p < 0.05), but not TiO2 NPs (p > 0.05), significantly induced cytotoxicity as assessed by WST-1 and neutral red uptake assay, as well as intracellular ROS. ZnO NPs dose-dependently increased the accumulation of intracellular Zn ions, and ZnSO4 induced similar cytotoxic effects as ZnO NPs, which indicated a role of Zn ions. The release of inflammatory proteins tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) or the adhesion of THP 1 monocytes to HUVECs was not significantly affected by ZnO or TiO2 NP exposure (p > 0.05). The presence of 250 nM TG significantly induced cytotoxicity, release of IL-6 and THP-1 monocyte adhesion (p < 0.01), but did not significantly affect intracellular ROS or release of TNFalpha (p > 0.05). ANOVA analysis indicated no interaction between exposure to ZnO NPs and the presence of TG on almost all the endpoints (p > 0.05) except neutral red uptake assay (p < 0.01). We concluded ER stress is probably not associated with ZnO NP exposure induced oxidative stress and inflammatory responses in HUVECs. PMID- 27997271 TI - Improvement in Physical Activity in Persons With Obstructive Sleep Apnea Treated With Continuous Positive Airway Pressure. AB - BACKGROUND: Exercise improves sleep quality, yet people with untreated obstructive sleep apnea (OSA) may engage in less physical activity (PA) due to fatigue and daytime sleepiness. We examined changes in PA and sleep quality before and after treatment with continuous positive airway pressure (CPAP) in OSA patients. METHODS: In this prospective longitudinal study, persons with a primary diagnosis of OSA were enrolled at a community-based hospital in New York City. At 3 time intervals pre- and post-CPAP (3-8 months), we measured sleep quality using validated questionnaires, perceived PA using the International Physical Activity Questionnaire (IPAQ), and actual PA using pedometer steps per day. We sought to investigate how CPAP use and changes in sleep quality impacted the number of steps taken, as recorded in pedometer steps. RESULTS: In total, 62 patients were enrolled in the study from March 2012 to July 2014. In all, patients averaged 53 years of age, and 26 patients (42%) were female. Among all participants, 86% of persons had moderate to severe sleep apnea (AHI >=15). Approximately 73% of participants were compliant with CPAP use. Poor sleep quality correlated with lower actual PA (P = .004) at baseline. At 3 and 7 months, there was significant improvement in sleep quality (Delta -2.63 +/- 3.4 and Delta -3.5 +/- 3.8; P < .001) and actual PA (Delta 840 +/- 1313 and Delta 1431 +/- 1419 steps/day, P < .001) compared with baseline. On multivariate analyses, participants with a higher waist circumference had a significantly greater increase in actual PA (P = .018). CONCLUSION: Treatment of OSA with CPAP had a progressive incremental improvement in sleep quality and actual PA. PMID- 27997273 TI - On the mechanism of genotoxicity of ethephon on embryonic fibroblast cells. AB - Ethephon is one of the most widely used plant growth regulator in agriculture that its application has been increased in recent years. Many reports have raised concern over the safety of this organophosphorus compound. The aim of the current study was to assess the potential genotoxic effect of ethephon on murine embryonic fibroblast (MEF) cell line, using two genotoxicity endpoints: gammaH2AX expression and comet assay. gammaH2AX served as an early and sensitive biomarker of genotoxic damage. Oxidative stress biomarkers, including reactive oxygen species (ROS), lipid peroxidation (LPO) and total antioxidant capacity were also examined. The results showed a significant increase in cell proliferation, 24 h post-treatment with 10, 40,160 MUg/ml ethephon, while at the higher concentrations cytotoxic effect was observed. The gammaH2AX expression and gammaH2AX foci count per cell were significantly increased at non-cytotoxic concentrations of ethephon, accompanied with increased DNA damage as illustrated by comet assay. LPO and ROS levels were elevated only at 160 MUg/ml and higher doses. The results interestingly showed that low non-cytotoxic doses of ethephon promoted DNA damage inducing cell proliferation, raising the possibility of ethephon mutagenicity. The genotoxic effect of ethephon at low doses might not relate to oxidative damage and that increased in the level of ROS and LPO generation at higher doses could account for the cytotoxic effect of ethephon. Taken together, our study provides strong in vitro evidence on potential genotoxicity of ethephon at low doses. More precise studies are needed to clarify the mutagenic effect of chronic exposure to ethephon. PMID- 27997274 TI - The efficacy of psychoeducation on recurrent depression: a randomized trial with a 2-year follow-up. AB - BACKGROUND: The efficacy of psychoeducation is well documented in the treatment of relapse prevention of schizophrenia, and recently also in bipolar disorder; however, for recurrent depression only few controlled studies focusing on the efficacy of psychoeducation have been conducted. AIMS: This randomized study tests the efficacy of treatment-as-usual supplemented with a psychoeducative programme for patients with recurrent depression, treated at Community Mental Health Centres (CMHC) in Denmark. The primary outcome measurements concern was decline in consumption of psychiatric inpatient services and decline in Beck's Depression Inventory (BDI). METHODS: Eighty patients were randomized, either to the psychoeducative programme (consisting of eight sessions, each of 2 hours duration) and 2-year outpatient follow-up (42 cases), or only to 2-year outpatient follow-up (38 controls). The patients were monitored during 2 years after randomization. Data were collected from interviews including BDI, drug treatment and social measurements, and register data concerning use of psychiatric services. RESULTS: At 2-year follow-up, a significant reduction in the consumption of psychiatric inpatient services and in BDI was found; however, it was uniform for case and control patients. Drop-out/non-compliance was significantly more frequent among patients randomized to the control group. Furthermore, during follow-up the case group got a significant stronger attachment to the Labour market than the control group. CONCLUSIONS: The primary hypothesis could not be confirmed. Secondary outcome measurements concerning drop out/non-compliance and attachment to the Labour market were significantly in favour of cases. PMID- 27997276 TI - One-year Stability of Objectively Measured Physical Activity in Young Brazilian Adults. AB - BACKGROUND: To evaluate the 1-year stability of objectively measured physical activity among young adults living in South Brazil, as well as assessing the influences of temperature, humidity and precipitation on physical activity. METHODS: A longitudinal study was conducted over 12 consecutive months (October 2012 to September 2013). Sixteen participants (8 men) used GT3X+ accelerometers 1 week per month for the entire year. Climate variables were obtained from an official climate information provider. RESULTS: Physical activity was remarkably stable over the year-the proportion of the day spent in moderate-to-vigorous intensity physical activity (MVPA) was around 5% in every month. Average temperature (rho = -0.64; P = .007), humidity (rho = -0.68; P = .004) and rain (rho = -0.67; P = .004) were inversely correlated to MVPA in the Summer. Rain was also inversely correlated to MVPA in the Spring (rho = -0.54; P = .03). CONCLUSIONS: Objectively measured physical activity was stable over a 1-year period. Climate variables consistently influenced physical activity practice in the Summer, but not in the other seasons. PMID- 27997275 TI - Influences of parents, close friends and classmates on four co-existing oral health practices in Saudi male teenagers. AB - OBJECTIVE: The objective of this study is to investigate the association between oral health practices and similar practices adopted by parents, close friends and classmates in a group of Saudi male teenagers. MATERIAL AND METHODS: A cross sectional study was conducted in Dammam, Saudi Arabia, in 2016 including 12-14 year-old intermediate school students (n = 478). A questionnaire assessed socioeconomic background, whether participants, their parents, close friends and classmates brushed twice daily, used tobacco, snacked on sugary foods or sugary drinks and perceiving a supportive classroom environment. Univariate and multivariate logistic regression models assessed the association of parents', close friends', classmates' practices and classroom support with participants' four practices, controlling for socioeconomic factors. RESULTS: The response rate was 93.9%. In multivariate regression, close friends' practices had a strong significant association with teenagers' tooth brushing (OR = 4.45; 95%CI = 1.09, 18.12), tobacco use (OR = 5.63; 95%CI = 3.44, 7.88), snacking on sugary foods (OR = 14.42; 95%CI = 7.89, 21.89) and sugary drinks (OR = 7.05; 95%CI = 5.97, 9.20). The percentages of classmates perceived to brush their teeth and use tobacco were significantly associated with the respective practices in teenagers (OR = 1.03 and 1.02). Fathers' snacking on sugary drinks was significantly associated with that of the teenagers (OR = 4.04; 95%CI= 1.03, 15.85). CONCLUSIONS: In early adolescence, four oral health practices of Saudi males were associated with those perceived to be adopted by their close friends. Fathers' use of sugary drinks was also significantly associated with that of teenagers. PMID- 27997277 TI - Opposite brain laterality in analogous auditory and visual tests. AB - Laterality for language processing can be assessed by auditory and visual tasks. Typically, a right ear/right visual half-field (VHF) advantage is observed, reflecting left-hemispheric lateralization for language. Historically, auditory tasks have shown more consistent and reliable results when compared to VHF tasks. While few studies have compared analogous tasks applied to both sensory modalities for the same participants, one such study by Voyer and Boudreau [(2003). Cross-modal correlation of auditory and visual language laterality tasks: a serendipitous finding. Brain Cogn, 53(2), 393-397] found opposite laterality for visual and auditory language tasks. We adapted an experimental paradigm based on a dichotic listening and VHF approach, and applied the combined language paradigm in two separate experiments, including fMRI in the second experiment to measure brain activation in addition to behavioural data. The first experiment showed a right-ear advantage for the auditory task, but a left half field advantage for the visual task. The second experiment, confirmed the findings, with opposite laterality effects for the visual and auditory tasks. In conclusion, we replicate the finding by Voyer and Boudreau (2003) and support their interpretation that these visual and auditory language tasks measure different cognitive processes. PMID- 27997279 TI - Palliative Uses of Botulinum Neurotoxin #324. PMID- 27997278 TI - The Appropriate Provision of Primary versus Specialist Palliative Care to Cancer Patients: Oncologists' Perspectives. AB - BACKGROUND: Many cancer patients do not receive recommended palliative care (PC). Oncologists' perspectives about PC have not been adequately described qualitatively and may explain some of the gaps in the delivery of PC. OBJECTIVE: To characterize U.S. oncologists' perceptions of: primary and specialist PC; experiences interacting with PC specialists; and the optimal interface of PC and oncology in providing PC. DESIGN: In-depth interviews with practicing oncologists. SETTING/SUBJECTS: Oncologists working in: the general community, academic medical centers (AMC), and Veterans Health Administration. MEASUREMENTS: Semistructured telephone interviews with 31 oncologists analyzed using matrix and thematic approaches. RESULTS: Seven major themes emerged: PC was perceived as appropriate throughout the disease trajectory but due to resource constraints was largely provided at end of life; oncologists had three schools of thought on primary versus specialist PC; there was an under-availability of outpatient PC; poor communication about prognosis and care plans created tension between providers; PC was perceived as a "team of outsiders"; PC had too narrow a focus of care; and AMC-based PC evidence did not generalize to community practices. Oncologists noted three ways to improve the interface between oncologists and PC providers: a clear division of responsibility, in-person collaboration, and sharing of nonphysician palliative team members. CONCLUSIONS: Oncologists in our sample were supportive of PC, but they reported obstacles related to care coordination and inpatient PC. Inpatient PC posed some unique challenges with respect to conflicting prognoses and care practices that would be mitigated through the increased availability and use of outpatient PC. PMID- 27997280 TI - Betel Nut Chewing in Iron Age Vietnam? Detection of Areca catechu Alkaloids in Dental Enamel. AB - The betel quid is one of the most commonly consumed psychoactive substances in the world. By archaeological evidence like the occurrence of areca nuts in archaeological sites, the typical overall reddish-brown staining on prehistoric human teeth or specific artifacts linked with the habit, it is assumed that this tradition reaches back to prehistoric times. Since this kind of evidence is indirect, it is frequently doubted. The present study provides the earliest direct analytical indication of betel nut chewing in human history. A typical stained tooth from an Iron Age skeleton (site Go O Chua in Southern Vietnam, 400 100 BC) was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-high-resolution mass spectrometry (LC-HR-ToF-MS) and the alkaloid arecoline which is specific for Areca catechu L. (Arecaceae) was detected. PMID- 27997281 TI - Use of Compounded Dextromethorphan-Quinidine Suspension for Pseudobulbar Affect in Hospice Patients. AB - BACKGROUND: Pseudobulbar affect (PBA) consists of unprovoked and uncontrollable episodes of laughing and/or crying. In end-of-life situations, PBA symptoms can be especially distressing to family and friends during an already heightened emotional time. Although a commercial product combining dextromethorphan and quinidine (DMQ) is FDA approved for use in PBA, many hospice patients are unable to swallow any solids or semisolids. An alternative formulation for these patients is needed. OBJECTIVE: We present here two cases in which we used a compounded DMQ suspension successfully to treat PBA symptoms in the weeks before the patients' death. DESIGN: A retrospective chart review was completed on the two cases where the DMQ suspension was used. A description of the DMQ suspension formula is described. SETTING/SUBJECTS: Both patients were under the care of a hospice program; one in home care and one in a skilled nursing facility. MEASUREMENTS: Episodes of PBA symptoms were summarized in a narrative of the patients' symptom relief. RESULTS: Both patients tolerated the administration of the DMQ suspension and there were noted improvements in PBA symptoms. CONCLUSIONS: DMQ suspension is an effective alternative for PBA symptoms in patients who cannot swallow oral solid medication. PMID- 27997282 TI - Effectiveness of a Community-Based Physical Activity and Nutrition Behavior Intervention on Features of the Metabolic Syndrome: A Cluster-Randomized Controlled Trial. AB - BACKGROUND: Metabolic syndrome (MetS) and its subclinical diseases are now public health problems in Vietnam. This study aimed at determining the effectiveness of a physical activity and nutrition program for reducing MetS proportion and its components among adults with MetS in Hanam province, Vietnam. METHODS: A total of 417 volunteers aged 50-65 years with MetS were recruited from 10 communes. The communes were randomly allocated to an intervention group (five communes, n = 214) and a control group (five communes, n = 203). The participants in the intervention group received a nutrition and physical activity program for 6 months, whereas participants in the control group received standard diet and physical activity advice on only one occasion. Anthropometry, lipid profiles, glycemic status, and blood pressure were measured at baseline and at 6 months to evaluate program effectiveness. RESULTS: In total, 175 intervention (81.8%) and 162 control (79.8%) participants completed the post-program evaluation. After controlling for the effects of clustering and confounding factors, the intervention group showed significant improvements in high-density lipoprotein cholesterol (+0.42 mM, P < 0.001), waist circumference (-1.63 cm, P < 0.001), waist-to-hip ratio (-0.024, P < 0.001), weight (-1.44 kg, P < 0.001), and body mass index (-0.59 kg/m2, P < 0.001) when compared with the control group. A reduction in the MetS proportion was found in both intervention and control groups (P < 0.001), decreasing to 56.0% and 75.9%, respectively, but the post program proportion was significantly lower among the intervention participants (P < 0.001). Furthermore, the mean number of MetS components exhibited by individuals decreased significantly in the intervention group (P < 0.001). CONCLUSIONS: The community-based physical activity and nutrition program reduced MetS proportion, with significant improvements in several metabolic and anthropometric parameters for Vietnamese adults with MetS. PMID- 27997284 TI - Empowering Older Adults to Make Medical Decisions: Two Solutions & A Problem. PMID- 27997283 TI - Overall Survival among Cancer Patients Undergoing Opioid Rotation to Methadone Compared to Other Opioids. AB - BACKGROUND: Methadone has been associated with lower overall survival (OS) in patients with chronic pain. There are no data available on the association of methadone with OS in cancer patients. OBJECTIVE: Our aim was to compare the OS in cancer outpatients undergoing opioid rotation (OR) to methadone and other strong opioids. DESIGN: Demographics, symptoms, and morphine equivalent daily dose (MEDD) were collected in patients who underwent OR from strong opioids to either methadone or other strong opioids and returned for a follow-up within six weeks. SETTING/SUBJECTS: Nine hundred thirty-eight consecutive outpatients to the supportive care center of a tertiary cancer center were reviewed. MEASUREMENTS: Kaplan-Meier curves were used to evaluate survival. RESULTS: Of a total of 164 eligible patients, 54/76 patients who underwent OR to methadone and 48/88 patients who underwent OR to other opioids returned for a follow-up visit. The median age was 56 years, 54% were male, and 87% had advanced cancer. There were no significant differences between the two groups in patient characteristics, performance status, MEDD, and pain scores. The Kaplan-Meier curves revealed no significant difference in median OS between all patients undergoing OR to methadone and other opioids [3.75 months (95% confidence interval, CI, 2.30-6.46) vs. 2.62 months (95% CI 1.74-4.33); p = 0.35] and also among those who returned for a follow-up following an OR to methadone and other opioids [5.15 months (95% CI 3.64-7.41) vs. 5.90 months (95% CI 2.62-9.28); p = 0.89]. CONCLUSIONS: We observed no significant difference in OS in cancer patients in methadone group compared to other opioids. PMID- 27997285 TI - Short and Sweet: The Persuasive Effects of Message Framing and Temporal Context in Antismoking Warning Labels. AB - Current warning labels on cigarette packages are generally focused on long-term losses that can be incurred if one continues smoking. This study compares the effects of these labels against warning labels that stress short-term losses of smoking as well as labels that stress short- and long-term benefits that can be obtained when one quits smoking. A 2 (message frame: gain vs. loss) * 2 (temporal context: short vs. long term) between-subjects experiment was conducted among 132 smokers, with attitude toward quitting smoking and intention to quit smoking, as well as information-seeking behavior and message recall, as the dependent variables. Findings were in line with theory regarding message framing and temporal discounting, showing enhanced effects of gain over loss frames and short term over long-term consequences on warning labels for attitudes and intentions. In addition, an interaction between message frame and temporal context was found. Especially, gain-framed messages showed stronger effects on intentions to quit smoking than loss-framed messages when warning labels concerned short-term outcomes. Findings suggest that current warning labels, with an emphasis on long term negative health outcomes, should be reconsidered. PMID- 27997286 TI - Kounis syndrome following canned tuna fish ingestion. AB - Kounis syndrome (KS) is a complex of cardiovascular symptoms and signs following either allergy or hypersensitivity and anaphylactic or anaphylactoid insults. We report the case of 57-year-old man, with hypertension and history of allergy, referred for facial rash and palpitations appeared after consumption of canned tuna fish. Suddenly, the patient collapsed: electrocardiogram showed ST-elevation in inferior leads. The patient was transferred from the spoke emergency room for coronary angio, which did not show any sign of coronary atherosclerosis. A transient coronary spasm was therefore hypothesized and the final diagnosis was KS. To the best of our knowledge, this is one of the first cases of KS following the ingestion of tuna fish. KS secondary to food allergy has also been reported, and shellfish ingestion has been considered as one of the most active KS inducer foods. Canned tuna fish too is well known as an allergy inducer. Tuna fish allergy should be considered, however, within the context of scombroid food poisoning, also called histamine fish poisoning. Fish with high levels of free histidine, the enzyme substrate converted to histamine by bacterial histidine decarboxylase, are those most often implicated in scombroid poisoning. Inflammatory mediators such as histamine constitute the pathophysiologic basis of Kounis hypersensitivity-associated acute coronary syndrome. Patients with coronary risk factors, allergic reaction after food ingestion, and suspected scombroid poisoning should be therefore carefully monitored for a prompt diagnosis of possible coronary complications. PMID- 27997287 TI - Acute dissociative reaction to spontaneous delivery in a case of total denial of pregnancy: Diagnostic and forensic aspects. AB - This article presents the history of a 21-year-old female college student with total denial of pregnancy who experienced an acute dissociative reaction during the spontaneous delivery at home without medical assistance where the newborn died immediately. Psychiatric examination, self-report questionnaires, legal documents, and witness reports have been reviewed in evaluation of the case. Evidence pointed to total denial of pregnancy, that is, until delivery. The diagnoses of an acute dissociative reaction to stress (remitted) and a subsequent PTSD were established in a follow-up examination conducted 7 months after the delivery. Notwithstanding the inherently dissociative nature of total denial of pregnancy, no other evidence has been found about pre-existing psychopathology. For causing the newborn's death, the patient faced charges for "aggravated murder," which were later on reduced into "involuntary manslaughter." Given the physical incapacity to perform voluntary acts due to the loss of control over her actions during the delivery, and the presence of an acute dissociative reaction to unexpected delivery, the legal case represents an intricate overlap between "insanity" and "incapacitation" defenses. The rather broad severity spectrum of acute dissociative conditions requires evaluation of the limits and conditions of appropriate legal defenses by mental health experts and lawyers. Denial of pregnancy as a source of potential stress has attracted little interest in psychiatric literature although solid research exists which documented that it is not infrequent. Arguments are presented to introduce this condition as a diagnostic category of female reproductive psychiatry with a more neutral label: "unperceived pregnancy." PMID- 27997288 TI - Associations of Perceived Parental Psychopathology with Mental Health Burden and Lifetime Drug Use in Gay, Bisexual, and other YMSM: The P18 Cohort Study. AB - Parental mental health may be a critical component in understanding the overlapping health burdens of mental health symptomatology and drug use in young men who have sex with men (YMSM), yet studies of YMSM have not fully examined these associations. To understand these relationships, data drawn from a study of gay, bisexual, and other YMSM were used to examine associations between perceived parental psychopathology and the health of YMSM. Findings suggest that YMSM reporting at least one parent with perceived depression, manic depression, schizophrenia, or antisocial behavior anytime during their childhoods were more likely to report higher levels of both depressive symptomatology and post traumatic stress disorder (PTSD) than those reporting no perception of any of these psychopathologies in their parents. Number of different drugs used in one's life were higher among participants who perceived at least one parent as depressed. Mediation analyses indicated that the relationship between perceived parental depression and lifetime drug use of YMSM was mediated both by YMSM depression and YMSM PTSD. These results suggest that parental psychopathology plays an important role in the health of sexual minority men, a population with elevated levels of mental health burden and drug use across the lifespan. PMID- 27997289 TI - Comparison of muscle activity between subjects with or without lip competence: Electromyographic activity of lips, supra- and infrahyoid muscles. AB - AIM: This study compares the electromyographic (EMG) activity of the muscles from the lips and hyoid bone in subjects with or without lip competence. METHODOLOGY: Two groups of 20 subjects each, with or without lip competence were studied. EMG activity of the superior orbicularis oris (SOO), inferior orbicularis oris (IOO), suprahyoid (SH) and infrahyoid (IH) muscles was recorded with the subject seated in the upright position during the following tasks: (1) at rest; (2) speaking; (3) swallowing; (4) forced deep breathing; (5) maximal voluntary clenching; and (6) chewing. RESULTS: EMG activity was significantly higher in subjects without competent lips than with competent lips in the SOO and IOO muscles during tasks 3 and 4, SOO during task 2 and IOO during task 6. EMG activity was similar in the SOO and IOO muscles during tasks 1 and 5, SOO during task 6 and IOO during task 2. Activity of the SH and IH muscles was similar in both groups for all tasks. CONCLUSIONS: Higher activity in subjects without competent lips implies a higher muscular effort due to the requirement of lip sealing during functional activities. Hyoid muscular activity was not modified by the presence or absence of lip competence. PMID- 27997291 TI - Framing Child Sexual Abuse: A Longitudinal Content Analysis of Newspaper and Television Coverage, 2002-2012. AB - The way in which the news media frame child sexual abuse can influence public perception. This content analysis of the child sexual abuse coverage of eight national news organizations in the United States from 2002 to 2012 includes the two dominant events of the Catholic Church and Pennsylvania State University child sexual abuse scandals. Census and systematic stratified sampling techniques were applied to articles obtained from the Lexis/Nexis Academic database, resulting in a sample of 503 articles. Intercoder reliability was ensured by double coding a randomly selected sample. Study findings indicate a shift in the attribution of responsibility of child sexual abuse among news organizations over the past decade from an individual-level problem with individual-level solutions to a societal-level problem with institutional culpability. Nevertheless, individual-level solutions continue to be framed as the best possible solution. PMID- 27997290 TI - Exploring Emotion Regulation in Juveniles Who Have Sexually Offended: An fMRI Study. AB - This exploratory study compared juveniles who sexually offend to nonoffending juveniles in their capacities to behaviorally and neurologically regulate, or reappraise, negative emotions. Participants were 39 juvenile males, including 10 healthy, nonoffending control subjects and 29 juveniles who sexually offend, comprising 12 juveniles who sexually offend with history of child sexual abuse. Participants completed a clinical assessment and a reappraisal task during functional magnetic resonance imaging. Difficulties in Emotional Regulation Scale results showed significantly less difficulties in emotion regulation among controls compared to juveniles who sexually offend, but when self-rating reappraisal abilities during the functional magnetic resonance imaging, all groups obtained comparable results. The imaging results showed no significant differences in fronto-temporal regions between controls and juveniles who sexually offend. Differences were found in other regions indicated in cognitive control, working memory, and emotional processing between controls and juveniles who sexually offend as well as between juveniles who sexually offend and those without history of child sexual abuse. Findings suggest that juveniles who sexually offend are capable of emotion regulation. PMID- 27997293 TI - Gerontological Social Workers are Key to a Sustainable Long-Term Services and Supports System. PMID- 27997292 TI - Intergenerational Care Perceptions of Older Women and Middle Adolescents in a Resource-Constrained Community in South Africa. AB - This study describes intergenerational care perceptions in a resource-challenged community. Ten women (aged 60+) and eight middle adolescents (3 boys and 5 girls) participated in the Mmogo-method(r), a visual data-collection method. Textual data were analysed thematically, and visual data by applying Roos and Redelinghuys (2016) proposed steps. Both groups provided physical and instrumental care to the other. Older women cared for adolescents by teaching and disciplining them, while the adolescents cared for them by obtaining an education and by showing respect. Older women felt being cared for when adolescents helped them, obeyed and complied with instructions and discipline, while the youngsters expressed it when their basic needs were addressed and school attendance was enabled. Older women's expressions of caring about were vague, while the younger people detected, act and elicited reactions from the elders. The adopted care approach informed care perceptions. Joint intergenerational activities are proposed to discover care currencies and contributions of generational members. PMID- 27997294 TI - Afterthoughts on an Exciting Summer. PMID- 27997295 TI - Dementia Caregivers and Live Discharge from Hospice: What Happens When Hospice Leaves? AB - Hospice offers holistic support for individuals living with terminal illness and their caregivers. Some individuals receiving hospice services experience a slower decline in health as than expected, resulting in a 'live discharge' from hospice. A live discharge affects both patient and caregiver(s).The current study (N=24) explored the experiences of caregivers of adults with dementia who experienced a live discharge from hospice. Findings emphasize the comprehensive services covered under the Medicare Hospice benefit and those lost after a live discharge. Implications for social workers supporting caregivers are discussed, including the need to view the patient-caregiver unit during a live discharge. PMID- 27997297 TI - Predicting Tests Ordered in Hospital Laboratories using Generalized Linear Modeling. AB - Laboratory services in healthcare systems play a vital role in inpatient care. Most hospital laboratories are facing the challenge of reducing cost and improving service quality. The author focuses on identifying test order patterns in a laboratory for a large urban hospital. The data collected from this facility consists of all tests ordered over a three-month time frame and contains test orders for approximately 17,500 patients. Poisson and negative binomial regression models are used to determine how well patient characteristics (patient length of stay and the medical units in which patients are placed) will predict the number of tests being ordered. The test order prediction model developed in this study will aid the management and phlebotomists in the hospital laboratory in securing methods to satisfy the test order demand. By implementing the recommendations of this study, hospital laboratories should see significant improvements in phlebotomist productivity and resource utilization, implementation of which could result in cost savings. PMID- 27997298 TI - An Interview with Christine Kovner Mathy Mezey Professor of Geriatric Nursing, Rory Meyers College of Nursing, New York University, New York, New York, USA. PMID- 27997299 TI - Study on Hospital Administrators' Beliefs and Attitudes toward the Practice of Evidence-Based Management. AB - The authors' purpose was to explore hospital administrators' beliefs and attitudes toward the practice of evidence-based management (EBMgt) and to identify the needs for EBMgt training programs. A cross-sectional, nonexperimental design was utilized. Survey data were analyzed using descriptive statistics and Spearman's correlation. The results showed that hospital administrators had positive attitudes toward the practice of EBMgt. There was a significant correlation between attitudes and percentage of healthcare management decisions made using an evidence-based practice approach (p < .01). The study findings suggest EBMgt educational training programs would likely help hospital administrators adopt evidence-based practice in management decision-making. PMID- 27997300 TI - The Importance of a Role-Specific, In-Hospital Ward Clerk Education Program. AB - Ward clerks are essential members of the healthcare team, providing administrative and organizational support to acute care units and clinics. This role influences such matters as nurses' direct patient-care time, timeliness of patient discharges, and patient safety. To support ward clerks in the varying responsibilities and complex scope of this role, a formal orientation and ongoing education program is imperative. Whereas corporate orientation informs new employees of overall organizational processes, a ward clerk-specific workplace education program prepares individuals for the demands of the position, ultimately supporting the healthcare team and patient safety. PMID- 27997301 TI - Treatment Burden of Medicare Beneficiaries With Stage I Non-Small-Cell Lung Cancer. AB - PURPOSE: To quantify the burden and complexity associated with treatment of Medicare beneficiaries with stage I non-small-cell lung cancer (NSCLC). METHODS: Using the SEER-Medicare database, we conducted a retrospective cohort study of Medicare beneficiaries who were diagnosed with stage I NSCLC from 2007 to 2011 and who were treated with surgery, stereotactic body radiation therapy, or external beam radiation therapy. Main outcome measures were the number of days a patient was in contact with the health care system (encounter days), the number of physicians involved in a patient's care, and the number of medications prescribed. Logistic regression modeled the association between patient characteristics, treatment type, and high treatment burden (defined as >= 66 encounter days). RESULTS: On average, 7,955 patients spent 1 in 3 days interacting with the health care system during the initial 60 days of treatment. Patients experienced a median of 44 encounter days with high variability (interquartile range [IQR], 29 to 66) in the 12 months after treatment initiation. The median number of physicians involved was 20 (IQR, 14 to 28), and the median number of medications prescribed was 12 (IQR, 8 to 17). Patients who were treated with surgery had high treatment burden (predicted probability, 21.6%; 95% CI, 20.2 to 23.1) compared with patients who were treated with stereotactic body radiation therapy (predicted probability, 16.1%; 95% CI, 12.9 to 19.3), whereas patients who were treated with external beam radiation therapy had the highest burden (predicted probability, 46.8%; 95% CI, 43.3 to 50.2). CONCLUSION: The treatment burden imposed on patients with early-stage NSCLC was substantial in terms of the number of encounters, physicians involved, and medications prescribed. Because treatment burden varied markedly across patients and treatment types, future work should identify opportunities to understand and ameliorate this burden. PMID- 27997302 TI - Rosai-Dorfman Disease Manifesting as a Pancreatic Head Mass Diagnosed Nonoperatively. PMID- 27997303 TI - Curing Early-Stage Lung Cancer: Is There an Easy Way Out? PMID- 27997304 TI - Supporting the Supporters: What Family Caregivers Need to Care for a Loved One With Cancer. AB - Patients with cancer who live at home often require help with activities of daily living, basic medical care (eg, injections), social needs, and patient advocacy. Most of that support comes from intimate caregivers, typically members of the patient's family. These family caregivers themselves require support so that they can be effective and maintain their own well-being while caring for the patient with cancer. Research shows that support for caregivers contributes to achieving these goals. We propose a four-part framework for supporting family caregivers: (1) assess caregivers' needs using formal measures, just as the cancer patient's own needs are assessed, (2) educate caregivers for their caregiving roles, most notably, with training in the low-level medical support that cancer patients require at home, (3) empower caregivers to become full-fledged members of the patient's cancer team, all working toward common goals, and (4) assist caregivers proactively in their duties, so that they retain a sense of control and self efficacy rather than having to react to imminent medical crises without sufficient resources at their disposal. Funding support for family caregivers requires refocusing on the overall well-being of the patient-caregiver dyad rather than just on the patient. It will necessitate a paradigm shift in reimbursement that recognizes the need for holistic cancer care. PMID- 27997305 TI - Unwanted Variation in Cancer Care: It Is Time to Innovate and Change. PMID- 27997306 TI - Ergonomic assessment of selected workstations on a merchant ship. AB - This study describes some key ergonomic factors within the engine room, navigation bridge and other locations of a merchant ship. Ergonomic assessments were carried out on a crew of a merchant ship. The study examines the importance of factors such as noise, vibration, heat radiation (in machinery areas), psychological stress and ergonomics of the physical arrangement of the navigation bridge. It also addresses the effect of working in confined areas for a long duration and the need to process large amounts of data, decision-making and the influence of specific operating conditions in different areas of a ship. This study includes analysis of workstations, working methods and the burden of environmental factors as well as a discussion of specific marine environmental conditions such as confined working and leisure spaces, long-term family and sociocultural separation, frequent changes in climate and time zones, and temporary physical overload and long-term psychological burdens. PMID- 27997307 TI - CAERvest(r) - a novel endothermic hypothermic device for core temperature cooling: safety and efficacy testing. AB - INTRODUCTION: Cooling of the body is used to treat hyperthermic individuals with heatstroke or to depress core temperature below normal for neuroprotection. A novel, chemically activated, unpowered cooling device, CAERvest(r), was investigated for safety and efficacy. METHODS: Eight healthy male participants (body mass 79.9 +/- 1.9 kg and body fat percentage 16.1 +/- 3.8%) visited the laboratory (20 degrees C, 40% relative humidity) on four occasions. Following 30 min rest, physiological and perceptual measures were recorded. Participants were then fitted with the CAERvest(r) proof of concept (PoC) or prototype 1 (P1), 2 (P2) or 3 (P3) for 60 min. Temperature, cardiovascular and perceptual measures were recorded every 5 min. After cooling, the CAERvest(r) was removed and the torso checked for cold-related injuries. RESULTS: Temperature measures significantly (p < 0.05) reduced pre to post in all trials. Larger reductions in core and skin temperatures were observed for PoC (-0.36 +/- 0.18 and -1.55 +/- 0.97 degrees C) and P3 (-0.36 +/- 0.22 and -2.47 +/- 0.82 degrees C), compared with P1 and P2. No signs of cold-related injury were observed at any stage. CONCLUSION: This study demonstrates that the CAERvest(r) is an effective device for reducing body temperature in healthy normothermic individuals without presence of cold injury. Further research in healthy and clinical populations is warranted. PMID- 27997308 TI - Short-Term Impact of a Multimedia Communication Campaign on Children's Physical Activity Beliefs and Behavior. AB - To examine the short-term impact of the WIXX multimedia communication campaign on children's physical activity (PA) beliefs and behaviors, 3 repeated cross sectional telephone surveys were conducted before, 9 months after, and 21 months after the launch of the campaign. A random-digit dialing procedure was used to recruit children ages 9 to 13 years. Children's PA beliefs, behaviors, and recall of the WIXX ads were self-reported. Logistic regression models showed that girls exposed to the WIXX ads were more likely to believe that PA would help to make new friends (odds ratio [OR] = 1.4, 95% confidence interval [CI] [1.0, 1.9]) and that they can be active even if too busy (OR = 1.4, 95% CI [1.0, 1.8]) compared to girls not exposed. Boys exposed were more likely to believe that PA would help to spend time with friends (OR = 1.4, 95% CI [1.1, 1.9]). Boys (OR = 1.5, 95% CI [1.1, 2.0.]) and girls (OR = 1.4, 95% CI [1.1, 1.8]) exposed were more likely to report having tried new PAs. No significant impact of the campaign was observed on overall PA after we controlled for confounders. Recall of the WIXX ads was associated with a significant, albeit modest, impact on some PA beliefs and intermediate PA behaviors. PMID- 27997309 TI - Monitoring and evaluation of sport-based HIV/AIDS awareness programmes: Strengthening outcome indicators. AB - There are number of Non-Governmental Organisations (NGOs) in South Africa that use sport as a tool to respond to Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), however, little is reported about the outcomes and impact of these programmes. The aim of this study is to contribute to a generic monitoring and evaluation framework by improving the options for the use of outcome indicators of sport-based HIV/AIDS awareness programmes of selected NGOs in South Africa. A qualitative method study was carried out with seven employees of five selected NGOs that integrate sport to deliver HIV/AIDS programmes in South Africa. The study further involved six specialists/experts involved in the field of HIV/AIDS and an official from Sport Recreation South Africa (SRSA). Multiple data collection instruments including desktop review, narrative systematic review, document analysis, one-on-one interviews and focus group interview were used to collect information on outcomes and indicators for sport-based HIV/AIDS awareness programmes. The information was classified according to the determinants of HIV/AIDS. The overall findings revealed that the sport-based HIV/AIDS awareness programmes of five selected NGOs examined in this study focus on similar HIV prevention messages within the key priorities highlighted in the current National Strategic Plan for HIV/AIDS, STIs and TB of South Africa. However, monitoring and evaluating outcomes of sport-based HIV/AIDS programmes of the selected NGOs remains a challenge. A need exists for the improvement of the outcome statements and indicators for their sport-based HIV/AIDS awareness programmes. This study proposed a total of 51 generic outcome indicators focusing on measuring change in the knowledge of HIV/AIDS and change in attitude and intention towards HIV risk behaviours. In addition, this study further proposed a total of eight generic outcome indicators to measure predictors of HIV risk behaviour. The selected NGOs can adapt the proposed generic outcomes and indicators based on the settings of their programmes. A collaborative approach by all stakeholders is required, from international organisations, funders, governments, NGOs and communities to strengthening monitoring and evaluation of sport-based HIV/AIDS awareness programmes including other development programmes. This will assist the NGOs that use sport for development to be able to reflect accurately the information about their HIV/AIDS activities and also be able to contribute to on-going monitoring activities at a national and global level as well as to the Sustainable Development Goals. PMID- 27997312 TI - Lymphedema in Head and Neck Cancer. PMID- 27997310 TI - ? PMID- 27997313 TI - They Survived, We Can Help Them Thrive: Older Adult Refugees in the United States. PMID- 27997318 TI - Mobile Applications for Mental Health Providers. AB - Mobile devices such as smartphones and tablets have fundamentally changed the ways in which we interact with information. Far more than communication devices, smartphones and tablets are now indispensable tools in the pocket of healthcare providers. Mobile mental health applications (apps) provide instant access to up to-date information on prevention, assessment and treatment. Self-help apps allow patients to take greater ownership of their own health and well-being. The past decade has seen an extraordinarily rapid proliferation of mobile medical apps. Though thousands of apps now exist, the challenge for healthcare providers and consumers alike has become sorting through mobile apps for those which provide accurate content delivered in the most user-friendly format. This article will review six mobile apps that can assist healthcare providers and consumers interested in enhancing mental health. PMID- 27997322 TI - Time, Focus, Relationship, and Trauma: A Contemporary Object Relations Approach to Brief Therapy. PMID- 27997325 TI - Books for Psychotherapy and the Psychotherapist. PMID- 27997324 TI - An Evaluation of the Buffering Effects of Types and Sources of Support on Depressive Symptoms Among Natural Disaster-Exposed Chinese Adults. AB - OBJECTIVE: Social support is a key protective factor for people exposed to natural disasters. The effect of type and source of this support is not well documented. Investigations are needed to identify the specific modifying role of received and perceived support from family and friends on the association between disaster exposure and depressive symptoms. METHODS: Face-to-face household interviews were conducted in 2014 with a random sample of 751 adults recruited from Yuexiu and Tianhe districts in Guangzhou, China. Sampling was accomplished through spatial epidemiological methods. Participants' exposure to disaster, depressive symptoms, and social support networks was recorded on tablet devices. Multiple regression analysis was used to test the potential moderating role of social support on depression symptoms. RESULTS: A total of 30.24% reported natural disaster exposure. Disaster exposure and received family support were significantly and positively related to depressive symptoms. In contrast, perceived family support moderated the relationship between disaster exposure and depressive symptoms. No association was found between support from friends and depressive severity. CONCLUSION: Perceived family support buffered the effect of disaster exposure in this sample, while received family support was associated with increased depression. Perceived family support is an important resource among those who experience disaster exposure and actual provision of family support may be harmful or miscarried. Natural disasters are becoming increasingly prevalent in Asia. According to the Economic and Social Commission for Asia and the Pacific (ESCAP, 2015a), a total of 119 disaster events, accounting for more than half of the total number of disasters occurred in the world, took place in Asia in 2014, affecting 79.6 million people, among whom 6050 died. The Chinese Mainland experienced several major natural disasters, including the earthquake in Wechuan, Sichuan Province, in 2008 and natural disasters affected more than 500,000 people causing 0.4% of GDP loss (roughly US$3 trillion; ESCAP, 2015b). The current study investigated the effect of social resources on mental health following natural disaster exposure. PMID- 27997326 TI - Posttraumatic Growth and Shattered World Assumptions Among Ex-POWs: The Role of Dissociation. AB - OBJECTIVE: The controversy regarding the nature of posttraumatic growth (PTG) includes two main competing claims: one which argues that PTG reflects authentic positive changes and the other which argues that PTG reflects illusionary defenses. The former also suggests that PTG evolves from shattered world assumptions (WAs) and that the co-occurrence of high PTG and negative WAs among trauma survivors reflects reconstruction of an integrative belief system. The present study aimed to test these claims by investigating, for the first time, the mediating role of dissociation in the relation between PTG and WAs. METHOD: Former prisoners of war (ex-POWs; n = 158) and comparable controls (n = 106) were assessed 38 years after the Yom Kippur War. RESULTS: Ex-POWs endorsed more negative WAs and higher PTG and dissociation compared to controls. Ex-POWs with posttraumatic stress disorder (PTSD) endorsed negative WAs and a higher magnitude of PTG and dissociation, compared to both ex-POWs without PTSD and controls. WAs were negatively correlated with dissociation and positively correlated with PTG. PTG was positively correlated with dissociation. Moreover, dissociation fully mediated the association between WAs and PTG. CONCLUSION: These findings imply that PTG might reflect illusory defenses and raise questions regarding the integration between the co-occurrence of high PTG and negative WAs among trauma survivors. PMID- 27997328 TI - Pathological Jealousy: An Interactive Condition. AB - OBJECTIVE: The aim of this review is to describe the psychopathology, antecedents, and current management of pathological jealousy from an interpersonal perspective. METHOD: The Google Scholar database was searched with the following terms: delusional jealousy; morbid jealousy; paranoid jealousy; pathological jealousy; Othello syndrome; delusional disorder-jealous type; conjugal paranoia. From a total of 600 articles, 40 were selected based on their currency and pertinence to the interpersonal aspects of jealousy. RESULTS: Findings were that delusional jealousy is equally prevalent among men and women, with a greater prevalence in the elderly. Antecedents to this condition can be neurologic, drug related, and/or psychological, most often preceded by low self esteem and excessive dependence on a romantic partner. Pathological jealousy can be triggered by the behavior of the partner and maintained by reasoning biases and by the psychological benefits that it initially bestows on the relationship. In the long run, however, it poses dangerous risks to the patient, the partner, and the imagined rival so that involuntary hospitalization is sometimes required. Treatment recommendations include couple therapy, a strong cognitive focus, antipsychotic medication, and interventions which enhance self-esteem of both partners and which address the solidarity of the existing relationship. CONCLUSION: Treatment effectiveness does not yet have a firm evidence base. PMID- 27997327 TI - Sexual Problems Predict PTSD and Depression Symptom Change Among Male OEF/OIF Veterans Completing Exposure Therapy. AB - OBJECTIVE: A growing literature documents frequent sexual problems among Operations Enduring/Iraqi Freedom (OEF/OIF) veterans with post-traumatic stress disorder (PTSD). However, there has been no examination of how (1) sexual problems may be affected by evidenced-based psychotherapy for PTSD or (2) how the presence of sexual problems might impact effectiveness of evidenced-based psychotherapy for PTSD. As such, the present study investigated associations among symptoms of PTSD, depression, and problems with sexual desire and arousal among 45 male OEF/OIF veterans receiving behavioral activation and therapeutic exposure (BA-TE), an evidence-based behavior therapy targeting co-occurring symptoms of PTSD and depression. METHOD: Participants completed clinical interviews and several questionnaires including measures of sexual arousal, sexual desire, PTSD symptoms, and depression symptoms at baseline and after completion of 8 sessions of BA-TE treatment. A records review was also conducted to assess for relevant medication use. RESULTS: Overall, sexual desire and sexual arousal problems did not improve during the course of treatment. Moreover, veterans with co-occurring sexual problems at baseline evidenced significantly less improvement in symptoms of PTSD and depression across treatment as compared to veterans without sexual problems. CONCLUSIONS: These findings suggest that veterans with co-occurring symptoms of PTSD and sexual problems may require additional assessment and treatment considerations in order to improve their treatment outcomes for both primary psychiatric symptoms as well as sexual problems. Future research on combination treatments of medication for sexual problems and psychotherapy for PTSD is needed. PMID- 27997329 TI - Female Fire-Setters: Gender-Associated Psychological and Psychopathological Features. AB - OBJECTIVE: Female fire-setters are reported to commit nearly one-third of deliberately set fires, yet there are limited studies examining the characteristics that distinguish them from suitable comparison groups. The aim of this study is to compare incarcerated female fire-setters with incarcerated male fire-setters and female offender controls on psychopathological and psychological features that could be targeted via therapeutic interventions. METHOD: We recruited 65 female fire-setters, 128 male fire-setters, and 63 female offenders from the prison estate. Participants completed a battery of validated tools assessing psychiatric traits and psychological characteristics (i.e., inappropriate fire interest, emotion/self-regulation, social competence, self concept, offense-supportive attitudes, and boredom proneness) highlighted in the existing literature. RESULTS: Major depression and an internal locus of control distinguished female fire-setters from male fire-setters. Alcohol dependence, serious/problematic fire interest, and more effective anger regulation distinguished female fire-setters from the female offender control group. CONCLUSIONS: This is the first study to examine differences between female fire setters, male fire-setters, and female control offenders on both psychopathological features and psychological traits. These findings highlight the gender-specific and offense-specific needs of female fire-setters that clinicians need to consider when implementing programs that ensure client responsivity. PMID- 27997330 TI - Severe Thrombocytopenia after Zika Virus Infection, Guadeloupe, 2016. AB - Severe thrombocytopenia during or after the course of Zika virus infection has been rarely reported. We report 7 cases of severe thrombocytopenia and hemorrhagic signs and symptoms in Guadeloupe after infection with this virus. Clinical course and laboratory findings strongly suggest a causal link between Zika virus infection and immune-mediated thrombocytopenia. PMID- 27997331 TI - Detection of Multiple Parallel Transmission Outbreak of Streptococcus suis Human Infection by Use of Genome Epidemiology, China, 2005. AB - Streptococcus suis sequence type 7 emerged and caused 2 of the largest human infection outbreaks in China in 1998 and 2005. To determine the major risk factors and source of the infections, we analyzed whole genomes of 95 outbreak associated isolates, identified 160 single nucleotide polymorphisms, and classified them into 6 clades. Molecular clock analysis revealed that clade 1 (responsible for the 1998 outbreak) emerged in October 1997. Clades 2-6 (responsible for the 2005 outbreak) emerged separately during February 2002 August 2004. A total of 41 lineages of S. suis emerged by the end of 2004 and rapidly expanded to 68 genome types through single base mutations when the outbreak occurred in June 2005. We identified 32 identical isolates and classified them into 8 groups, which were distributed in a large geographic area with no transmission link. These findings suggest that persons were infected in parallel in respective geographic sites. PMID- 27997332 TI - Delivering on Antimicrobial Resistance Agenda Not Possible without Improving Fungal Diagnostic Capabilities. AB - Antimicrobial resistance, a major public health concern, largely arises from excess use of antibiotic and antifungal drugs. Lack of routine diagnostic testing for fungal diseases exacerbates the problem of antimicrobial drug empiricism, both antibiotic and antifungal. In support of this contention, we cite 4 common clinical situations that illustrate this problem: 1) inaccurate diagnosis of fungal sepsis in hospitals and intensive care units, resulting in inappropriate use of broad-spectrum antibacterial drugs in patients with invasive candidiasis; 2) failure to diagnose chronic pulmonary aspergillosis in patients with smear negative pulmonary tuberculosis; 3) misdiagnosis of fungal asthma, resulting in unnecessary treatment with antibacterial drugs instead of antifungal drugs and missed diagnoses of life-threatening invasive aspergillosis in patients with chronic obstructive pulmonary disease; and 4) overtreatment and undertreatment of Pneumocystis pneumonia in HIV-positive patients. All communities should have access to nonculture fungal diagnostics, which can substantially benefit clinical outcome, antimicrobial stewardship, and control of antimicrobial resistance. PMID- 27997333 TI - Presence and Persistence of Zika Virus RNA in Semen, United Kingdom, 2016. AB - Zika virus RNA has been detected in semen collected several months after onset of symptoms of infection. Given the potential for sexual transmission of Zika virus and for serious fetal abnormalities resulting from infection during pregnancy, information regarding the persistence of Zika virus in semen is critical for advancing our understanding of potential risks. We tested serial semen samples from symptomatic male patients in the United Kingdom who had a diagnosis of imported Zika virus infection. Among the initial semen samples from 23 patients, Zika virus RNA was detected at high levels in 13 (56.5%) and was not detected in 9 (39.1%); detection was indeterminate in 1 sample (4.4%). After symptomatic infection, a substantial proportion of men have detectable Zika virus RNA at high copy numbers in semen during early convalescence, suggesting high risk for sexual transmission. Viral RNA clearance times are not consistent and can be prolonged. PMID- 27997334 TI - Ontogeny of clock and KiSS-1 metastasis-suppressor (Kiss1) gene expression in the prepubertal mouse hypothalamus. AB - Kisspeptin is crucial for the generation of the circadian-gated preovulatory gonadotrophin-releasing hormone (GnRH)-LH surge in female rodents, with expression in the anteroventral periventricular nucleus (AVPV) peaking in the late afternoon of pro-oestrus. Given kisspeptin expression is established before puberty, the aim of the present study was to investigate kisspeptin and clock gene rhythms during the neonatal period. Anterior and posterior hypothalami were collected from C57BL/6J mice on Postnatal Days (P) 5, 15 and 25, at six time points across 24h, for analysis of gene expression by reverse transcription quantitative polymerase chain reaction. Expression of aryl hydrocarbon receptor nuclear translocator-like gene (Bmal1) and nuclear receptor subfamily 1, group D, member 2 (Rev-erbalpha) in the anterior hypothalamus (containing the suprachiasmatic nucleus) was not rhythmic at P5 or P15, but Bmal1 expression exhibited rhythmicity in P25 females, whereas Rev-erbalpha expression was rhythmic in P25 males. KiSS-1 metastasis-suppressor (Kiss1) expression did not exhibit time-of-day variation in the anterior (containing the AVPV) or posterior (containing the arcuate nucleus) hypothalami in female and male mice at P5, P15 or P25. The data indicate that the kisspeptin circadian peak in expression observed in the AVPV of pro-oestrous females does not manifest at P5, P15 or P25, likely due to inadequate oestrogenic stimuli, as well as incomplete development of clock gene rhythmicity before puberty. PMID- 27997335 TI - Intrafollicular oestradiol production, expression of the LH receptor (LHR) gene and its isoforms, and early follicular deviation in Bos indicus. AB - The aim of the present study was to characterise the roles of intrafollicular oestradiol production and granulosa cell (GC) expression of the LH receptor (LHR) gene and its isoforms during follicular deviation in Bos indicus. Follicular wave emergence was synchronised in heifers from a Bos taurus dairy (Holstein; n=10) and a B. indicus dairy breed (Gir; n=10). Follicles were aspirated individually at sizes corresponding to the periods of predeviation, deviation and postdeviation. Intrafollicular oestradiol (IF-E2) and progesterone (IF-P4) concentrations were determined in the follicular fluid (FF) by radioimmunoassay, and relative expression of P450 aromatase (CYP19A1) and LHR forms was evaluated in GC using real-time quantitative-polymerase chain reaction. Despite differences in the size of the dominant follicle at deviation, changes in CYP19A1 expression and IF-E2 concentrations were similar in follicles of the same diameter in both breeds. A peak in total LHR expression occurred after follicular deviation in association with low expression of LHR isoforms. The results suggest that regulation of LHR function by sequential changes in the expression pattern of LHR isoforms may play a role in the early deviation of the dominant follicle, as observed in B. indicus breeds. PMID- 27997337 TI - Correction: TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. PMID- 27997336 TI - Transcriptional signatures of somatic neoblasts and germline cells in Macrostomum lignano. AB - The regeneration-capable flatworm Macrostomum lignano is a powerful model organism to study the biology of stem cells in vivo. As a flatworm amenable to transgenesis, it complements the historically used planarian flatworm models, such as Schmidtea mediterranea. However, information on the transcriptome and markers of stem cells in M. lignano is limited. We generated a de novo transcriptome assembly and performed the first comprehensive characterization of gene expression in the proliferating cells of M. lignano, represented by somatic stem cells, called neoblasts, and germline cells. Knockdown of a selected set of neoblast genes, including Mlig-ddx39, Mlig-rrm1, Mlig-rpa3, Mlig-cdk1, and Mlig h2a, confirmed their crucial role for the functionality of somatic neoblasts during homeostasis and regeneration. The generated M. lignano transcriptome assembly and gene expression signatures of somatic neoblasts and germline cells will be a valuable resource for future molecular studies in M. lignano. PMID- 27997338 TI - The EB66(r) cell line as a valuable cell substrate for MVA-based vaccines production. AB - The selection of a cell substrate is a critical step for the development and manufacturing of a viral vaccine candidate. Several parameters such as cell susceptibility and permissiveness to the viral pathogens but also performance in terms of viral antigens quality and production yields are important considerations when identifying the ideal match between a viral vaccine and cell substrate. The modified vaccinia virus Ankara (MVA) is a replication-deficient viral vector that holds great promise as a vaccine platform, however only limited cell substrates have been tested or are available for industrialization. Here we evaluate the duck embryo-derived EB66(r) cell line as potential cell substrate for MVA production. To this end, we used two recombinant MVA constructs and demonstrated that EB66(r) cells are propagating the tested MVA viruses very efficiently, while preserving viral attenuation and transgene expression for up to 20 serial passages. Furthermore we developed upstream and downstream processes that enable industrialization of the virus production. In conclusion, we showed that EB66(r) cells can be used as potent cell substrate for MVA-based vaccines and represent therefore an attractive alternative for vaccine production. PMID- 27997339 TI - Toll-like receptor 3 adjuvant in combination with virus-like particles elicit a humoral response against HIV. AB - Human Immunodeficiency Virus (HIV) Virus-Like Particles (VLPs) composed of HIVIIIB Gag and HIVBaL gp120/gp41 envelope are a pseudovirion vaccine capable of presenting antigens in their native conformations. To enhance the immunogenicity of the HIV Env antigen, VLPs were coupled to VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV) containing one of four toll-like-receptor (TLR) ligands, each activating a receptor with distinct cellular localization and downstream pathways. C57BL/6 mice were vaccinated by intranasal prime followed by two sub cheek boosts and their sera immunoglobulin and neutralizing potency were measured over a duration of 3months after vaccination. PBS control, VLPs alone, CALV+VLPs, and VLPs complexed with CALV and ligands for TLR2 (PAM3CAG), TLR3 (dsRNA), TLR4 (MPLA), or TLR7/8 (resiquimod) were evaluated based on antibody titer, IgG1 and IgG2c class switching, germinal center formation, T follicular cells and potency of neutralizing antibodies. Consistently, the TLR3 ligand dsRNA complexed to CALV and in combination with VLPs (CALV(dsRNA)+VLPs) induced the strongest response. CALV(dsRNA)+VLPs induced the highest titers against the recombinant vaccine antigens clade B Bal gp120 and pr55 Gag. Additionally, CALV(dsRNA)+VLPs induced cross-clade antibodies, represented by high titers of antibody to clade c 96ZM651 gp120. CALV(dsRNA)+VLPs induced predominantly IgG2c over IgG1, a response associated with T helper type 1 (Th1)-like cytokines. In turn, CALV(dsRNA)+VLP immunized mice generated the most potent neutralizing antibodies against HIV strain MN.3. Finally, at time of sacrifice, a significant increase in germinal center B cells and T follicular cells was detected in mice which received CALV(dsRNA)+VLPs compared to PBS. Our results indicate that CALV(dsRNA) is a superior adjuvant for HIV VLPs in generating a Th1-like immunoglobulin profile, while prolonging lymph node germinal centers, T follicular cells and generating neutralizing antibodies to a highly sensitive tier 1A variant of HIV. PMID- 27997340 TI - Specific memory B cell response and participation of CD4+ central and effector memory T cells in mice immunized with liposome encapsulated recombinant NE protein based Hepatitis E vaccine candidate. AB - BACKGROUND: Liposome encapsulated neutralizing epitope protein of Hepatitis E virus (HEV), rNEp, our Hepatitis E vaccine candidate, was shown to be immunogenic and safe in pregnant and non-pregnant mice and yielded sterilizing immunity in rhesus monkeys. METHODS: The current study in Balb/c mice assessed the levels and persistence of anti-HEV IgG antibodies by ELISA, frequencies of B, memory B, T and memory T cells by flow cytometry and HEV-specific IgG secreting memory B cells by ELISPOT till 420days post immunization (PI) with 5?g rNEp encapsulated in liposome based adjuvant (2 doses, 4weeks apart). Mice immunized with a lower dose (1?g) were assessed only for anamnestic response post booster dose. RESULTS: Vaccine candidate immunized mice (5?g dose) elicited strong anti-HEV IgG response that was estimated to persist for lifetime. At day 120 PI, frequency of memory B cells was higher in immunized mice than those receiving adjuvant alone. Anti-HEV IgG titers were lower in mice immunized with 1?g dose. A booster dose yielded a heightened antibody response in mice with both high (>800GMT, 5?g) and low (?100GMT, 1?g) anti-HEV IgG titers. At day 6th post booster dose, HEV-specific antibody secreting plasma cells (ASCs) were detected in 100% and 50% of mice with high and low anti-HEV IgG titers, respectively, whereas the frequencies of CD4+ central and effector memory T cells were high in mice with high anti-HEV IgG titers only. CONCLUSIONS: Taken together, the vaccine candidate effectively generates persistent and anamnestic antibody response, elicits participation of CD4+ memory T cells and triggers memory B cells to differentiate into ASCs upon boosting. This approach of assessing the immunogenicity of vaccine candidate could be useful to explore the longevity of HEV-specific memory response in future HEV vaccine trials in human. PMID- 27997341 TI - Mumps, measles and rubella vaccination in children with PFAPA syndrome. AB - : There is no published data regarding immunologic response to vaccinations in children with PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis). The aim of this study was to evaluate mumps, measles and rubella immunity in children with PFAPA. 31 children with PFAPA syndrome and 22 healthy children (control group - CG) were recruited to the study. All children were previously vaccinated with one dose of MMR vaccine according to the Polish obligatory vaccination schedule. The patients from both groups were evaluated for anti-measles, anti-mumps and anti-rubella IgG antibodies concentrations (ELISA tests; the reference values for protective antibody levels were 150IU/L, 16RU/L and 11IU/ml respectively). The percentage of patients with protective antibodies levels was as follows: measles - 93.55% of PFAPA and 95.45% of CG patients (p=0.77); mumps - 74.19% of PFAPA and 95.45% of CG patients (p=0.02); rubella - 80.65% of PFAPA and 90.9% of CG patients (p=0.30). CONCLUSIONS: Children with PFAPA syndrome present a good response to the measles and rubella component of the MMR vaccine, however immunity against mumps after one dose of MMR may not be sufficient. Further investigation concerning immunity against vaccine-preventable diseases and the safety of vaccinations in children with periodic fever syndromes is required. PMID- 27997342 TI - Evaluation of a candidate live attenuated influenza vaccine prepared in Changchun BCHT (China) for safety and efficacy in ferrets. AB - We evaluated the safety and efficacy of a live attenuated influenza vaccine (LAIV) product in ferrets. The BCHT LAIV product was significantly less virulent than wild-type H1N1 virus, when evaluated by comparing virus shedding and histopathologic lesions. The data indicated strong evidence for an attenuated phenotype of LAIV. Furthermore, the vaccine induced robust humoral immune responses in seronegative ferrets, and protected ferrets against development of fever, weight loss and turbinate inflammatory lesions after challenging with H3N2 wide-type influenza virus. Thus, the BCHT LAIV product was safe in healthy seronegative ferrets and protected ferrets against infection of H3N2 influenza virus. PMID- 27997343 TI - Rabies pre-exposure prophylaxis elicits long-lasting immunity in humans. AB - Despite the availability of safe and effective human vaccines, rabies remains a global threat, with an estimated 60,000 human deaths annually attributed to rabies. Pre-exposure prophylaxis against rabies infection is recommended for travelers to countries where rabies is endemic, and also for those with a higher risk of exposure. In this study, the rabies-specific neutralising antibody responses in a cohort of rabies-vaccinated recipients over a period of twenty years have been assessed. In particular, the antibody response to primary vaccinations and boosters, and the waning of antibody post primary vaccination and post booster were investigated. The significance of gender, age at vaccination, vaccine manufacturer and vaccination intervals were also evaluated. These data confirm that rabies vaccination can elicit a neutralising antibody response that can remain at detectable levels for a number of years, without additional booster vaccinations. The antibody response following both primary vaccination and booster was significantly influenced by the gender of the subject (p=0.002 and 0.03 respectively), with supportive data that suggests an effect by the make of vaccine administered following primary vaccination, with significantly higher VNA titres observed for one vaccine manufactured prior to 2006 (p<0.001) in a small subset of recipients (n=5). Additionally, the decay rate was demonstrated through the overall decline in antibody titre for all individuals, which was a 37% and 27% reduction per 2-fold change in time following primary and booster vaccination respectively. Individuals within older age groups demonstrated a significantly faster decline in antibody titre following the primary vaccination course (p=0.012). Rate of decline in antibody titre was also significantly influenced by the vaccine make following primary course (p<0.001). The assessment of neutralising antibody titre decline has also provided an insight into the most appropriate timing for booster administration, and enabled the prediction of long term titres from post-vaccination antibody titres. PMID- 27997344 TI - Host immunity to Mycobacterium tuberculosis and risk of tuberculosis: A longitudinal study among Greenlanders. AB - BACKGROUND: Human immune responses to latent Mycobacterium tuberculosis (Mtb) infection (LTBI) may enable individuals to control Mtb infection and halt progression to tuberculosis (TB), a hypothesis applied in several novel TB vaccines. We aimed to evaluate whether immune responses to selected LTBI antigens were associated with subsequent reduced risk of progression to TB. METHODS: We conducted a population-based cohort study in East Greenland (2012-2014) including individuals aged 5-31years. A personal identifier allowed follow-up in national registers including the TB notification register. Mtb infection was defined by a positive Quantiferon test. Immune responses to LTBI antigens were assessed by whole blood antigen stimulation and interferon gamma measurement. RESULTS: Among 978 participants, 67 previously had TB. LTBI antigen (Rv1284, Rv2659, Rv2660c) immune response prevalence was 18%, 50%, 2% among Mtb-infected and 7%, 40%, 4% among non-infected (Quantiferon negative) participants. Among 911 participants without prior notified TB, 31 were notified with TB during study follow-up. Immune responses to LTBI antigens were not associated with reduced risk of subsequent TB; Rv1284 HR 0.92 (95%CI 0.28-3.04), Rv2659 HR 1.05 (95%CI 0.51 2.13), Rv2660c HR 3.06 (95%CI 0.70-13.37). CONCLUSION: In this large population based study, human immune responses to selected LTBI antigens were not found to be strongly associated with reduced risk of subsequent TB. PMID- 27997345 TI - Mitofusin 2 attenuates the histone acetylation at collagen IV promoter in diabetic nephropathy. AB - Extracellular matrix (ECM) increase in diabetic nephropathy (DN) is closely related to mitochondrial dysfunction. The mechanism of protective function of mitofusin 2 (Mfn2) for mitochondria remains largely unknown. In this study, the molecular mechanisms for the effect of Mfn2 on mitochondria and subsequent collagen IV expression in DN were investigated. Ras-binding-deficient mitofusin 2 (Mfn2-Ras(Delta)) were overexpressed in rat glomerular mesangial cells, and then the cells were detected for mitochondrial morphology, cellular reactive oxygen species (ROS), mRNA and protein expression of collagen IV with advanced glycation end-product (AGE) stimulation. Preliminary results reveal that the mitochondrial dysfunction and the increased synthesis of collagen IV after AGE stimulation were reverted by Mfn2-Ras(Delta) overexpression. Bioinformatical computations were performed to search transcriptional factor motifs in the promoter region of collagen IV. Three specific regions for TFAP2A binding were identified, followed by validation with chromatin immunoprecipitation experiments. Knocking down TFAP2A significantly decreased the TF binding in the first two regions and the gene expression of collagen IV. Furthermore, results reveal that Mfn2-Ras(Delta) overexpression significantly mitigated TFAP2A binding and also reverted the histone acetylation at Regions 1 and 2 after AGE stimulation. In streptozotocin induced diabetic rats, Mfn2-Ras(Delta) overexpression also ameliorated glomerular mesangial lesions with decreased collagen IV expression, accompanied by decreased acetylation and TFAP2A binding at Region 1. In conclusion, this study highlights the pathway by which mitochondria affect the histone acetylation of gene promoter and provides a new potential therapy approach for DN. PMID- 27997347 TI - Mirolysin, a LysargiNase from Tannerella forsythia, proteolytically inactivates the human cathelicidin, LL-37. AB - Tannerella forsythia is a periodontal pathogen expressing six secretory proteolytic enzymes with a unique multidomain structure referred to as KLIKK proteases. Two of these proteases, karilysin and mirolysin, were previously shown to protect the bacterium against complement-mediated bactericidal activity. The latter metalloprotease, however, was not characterized at the protein level. Therefore, we purified recombinant mirolysin and subjected it to detailed biochemical characterization. Mirolysin was obtained as a 66 kDa zymogen, which autoproteolytically processed itself into a 31 kDa active form via truncations at both the N- and C-termini. Further autodegradation was prevented by calcium. Substrate specificity was determined by the S1' subsite of the substrate-binding pocket, which shows strong preference for Arg and Lys at the carbonyl side of a scissile peptide bond (P1' residue). The protease cleaved an array of host proteins, including human fibronectin, fibrinogen, complement proteins C3, C4, and C5, and the antimicrobial peptide, LL-37. Degradation of LL-37 abolished not only the bactericidal activity of the peptide, but also its ability to bind lipopolysaccharide (LPS), thus quenching the endotoxin proinflammatory activity. Taken together, these results indicate that, through cleavage of LL-37 and complement proteins, mirolysin might be involved in evasion of the host immune response. PMID- 27997348 TI - Relationship between plasma and salivary melatonin and cortisol investigated by LC-MS/MS. AB - BACKGROUND: Disturbance of the circadian rhythm has been associated with disease states, such as metabolic disorders, depression and cancer. Quantification of the circadian markers such as melatonin and cortisol critically depend on reliable and reproducible analytical methods. Previously, melatonin and cortisol were primarily analyzed separately, mainly using immunoassays. METHODS: Here we describe the validation and application of a high-throughput liquid chromatography in combination with mass spectrometry (LC-MS/MS) method for the combined analysis of melatonin and cortisol in plasma and saliva. The LC-MS/MS method was validated according to international validation guidelines. We used this method to analyze total plasma, free plasma (as obtained by equilibrium dialysis) and saliva melatonin and cortisol in healthy adults. RESULTS: Validation results for plasma and saliva melatonin and cortisol were well within the international validation criteria. We observed no difference between saliva collected by passive drooling or Salivette. Moreover, we noted a significant difference in saliva vs. free plasma melatonin. We observed on average 36% (95% CI: 4%-60%) higher salivary melatonin levels in comparison to free plasma melatonin, suggestive of local production of melatonin in the salivary glands. CONCLUSIONS: The novel outcome of this study is probably due to the high precision of our LC-MS/MS assay. These outcomes illustrate the added value of accurate and sensitive mass spectrometry based methods for the quantification of neuroendocrine biomarkers. PMID- 27997346 TI - Efficiency of treatment with non-steroidal anti-inflammatory drugs according to current recommendations in patients with radiographic and non-radiographic axial spondyloarthritis. AB - OBJECTIVE: NSAIDs are first-line therapy in axial SpA (axSpA). The proportion of patients responding to NSAIDs and differences between AS and non-radiographic axSpA (nr-axSpA) in this regard have not been studied in detail to date. The aim of this study was to examine the proportion of patients with AS and nr-axSpA responding to NSAIDs according to current treatment recommendations. METHODS: Consecutive anti-TNF-naive patients with nr-axSpA and AS (n = 50 each) were included if their BASDAI score was ?4 without having received maximal NSAID doses. In case of a BASDAI score ?4 1 week later, another NSAID was prescribed. For the next 3 weeks, continuous intake of maximal doses was recommended but patients could reduce doses in case of intolerance or improvement. MRI of the SI joints was performed at baseline and week 4. RESULTS: All outcomes except for CRP and MRI scores improved significantly after 4 weeks of NSAIDs, with no difference between axSpA subgroups. An Assessment of SpondyloArthritis international Society 40% (ASAS40) response and partial remission rates were 35 and 16% at week 4, respectively. At the same time point, a BASDAI score ?4 was still present in 44% of patients, 30% of which had reduced NSAID doses, partly due to intolerance (38%). Only 13% of all patients had continuously taken NSAIDs at the maximal dosage, but there was no difference in the efficacy outcome compared with those who had taken reduced doses. CONCLUSION: AS and nr-axSpA patients had similar response rates to NSAIDs while objective signs of inflammation did not change over 4 weeks. Only a minority of patients was willing to take maximal doses of NSAIDs, and ?40% patients remained candidates for TNF blockers. These results may influence future trial designs. PMID- 27997349 TI - Evaluation of a chemiluminescent immunoassay for urinary aldosterone on the DiaSorin LIAISON automated platform against RIA and LC-MS/MS. PMID- 27997350 TI - A low dose (6.5 mg) of intravaginal DHEA permits a strictly local action while maintaining all serum estrogens or androgens as well as their metabolites within normal values. AB - OBJECTIVE: Serum concentrations of estradiol (E2) and testosterone (testo) measured by mass spectrometry-based assays should remain below the 95th centile measured at 9.3 pg/mL for E2 and 0.26 ng/mL for testo in normal postmenopausal women in order to avoid the risk of non-physiological systemic exposure to elevated serum concentrations of these two sex steroids. METHODS: Serum E2 and testo, as well as dehydroepiandrosterone (DHEA) and nine of its other metabolites, were measured at 10 time intervals over 24 h on the first and seventh days of daily intravaginal administration of 0.50% (6.5 mg) DHEA by validated mass spectrometry-based assays. RESULTS: No biologically significant change in the individual serum concentrations of E2, testo or DHEA was observed. Most importantly, estrone sulfate (E1-S) and the glucuronidated androgen metabolites also remained within normal values, thus confirming the absence of biologically significant systemic exposure in line with intracrinology. Using data from the literature, comparison is made with serum E2 above normal postmenopausal values following administration of 10-MUg E2 tablets. CONCLUSION: While the clinical program on vulvovaginal atrophy has shown the efficacy and safety of intravaginal 6.5 mg of DHEA (prasterone), the present data illustrate in detail the serum levels of the individual sex steroids and their metabolites derived from DHEA. The data obtained are in line with the physiology of intracrinology and confirm an action limited to the vagina as the serum concentrations of all sex steroids are maintained within the normal values of menopause, thus protecting the uterus and most likely other tissues. PMID- 27997351 TI - The prevalence of dyslipidemia and associated factors in children and adolescents with type 1 diabetes. AB - BACKGROUND: Dyslipidemia increases the frequency and severity of micro and macrovascular complications of type 1 diabetes (T1D). The present study aims to determine the prevalence of dyslipidemia and its association with clinical and laboratory findings in diabetic children and adolescents. METHODS: The study included 202 children and adolescents with T1D. Demographic data and laboratory findings were obtained from patients files. RESULTS: Dyslipidemia prevalence was found to be 26.2%. Hypercholesterolemia (15.8%) and hyperglyceridemia (12.9%) were most common findings. Age, body mass index (BMI), hemoglobin A1c (A1C) and poor metabolic control were significantly higher in cases with dyslipidemia. Smoking rate was 14.1% in the pubertal group. Poor metabolic control and dyslipidemia was found higher among smokers (p<0.05). CONCLUSIONS: Blood lipid levels should be monitored regularly and nutrition education should be repeated periodically to prevent and control dyslipidemia in patients with T1D. Smoking related risks should be a part of patient education in the pubertal period. PMID- 27997352 TI - Transdermal testosterone gel for induction and continuation of puberty in adolescent boys with hepatic dysfunction. AB - Treatment to induce puberty in boys is indicated in those who do not undergo spontaneous development at a normal age. Stimulating development of the secondary sex characteristics is possible using gradually increasing doses of testosterone esters (TEs) via intramuscular (IM) administration, which is the most widely used method of testosterone (T) supplementation. When TEs are administered as monthly injection, serum T levels exhibit large fluctuations with supraphysiologic levels seen immediately after the injection followed by a decrease into the low range. Transdermal T (TT) has also been used for replacement therapy in adult males with hypogonadism and this provides steadier serum T levels. We report three adolescent boys with delayed puberty who were treated with TT gel for pubertal induction/continuation. This route was chosen as an alternative therapy due to their hepatic dysfunction, as is known that TT avoids the hepatic first-pass metabolism. PMID- 27997353 TI - Vitamin D status in Egyptian children with type 1 diabetes and the role of vitamin D replacement in glycemic control. AB - BACKGROUND: The association of low serum 25 hydroxy cholecalciferol (25OHD) levels with high glucose level and diminished insulin sensitivity suggests that vitamin D (VD) may modulate insulin metabolism. The aim of the study was to screen for vitamin D deficiency (VDD) in pediatric patients with type 1 diabetes (T1D) and study the effect of VD supplementation on their glycemic control and insulin requirements. METHODS: A prospective cohort study including 50 patients with T1D. VD level was assessed initially and after 3 months of VD supplementation (in those with VDD). HbA1c and insulin requirements were studied at 0, 3 and 6 months of supplementation. RESULTS: Fifty patients with T1D were included with mean diabetes duration of 4.11+/-2.34 years. VD level ranged from 0.2 to 33 ng/mL. VD status correlated significantly with daily insulin dose (p=0.030, r=0.306) and HbA1c (p<0.001, r=0.243). Thirty-five patients (70%) had VDD and were allocated for VD supplementation for 3 months. The mean HbA1c improved significantly after supplementation (p=0.003), followed by a significant deterioration at 6 months with no change in their insulin requirements at 3 or 6 months. CONCLUSIONS: VD was highly prevalent in Egyptian T1D patients. VD supplementation improved glycemic control at 3 months after therapy with no reduction in insulin requirements. PMID- 27997354 TI - Applications of transcranial direct current stimulation in children and pediatrics. AB - Transcranial direct current stimulation (tDCS) is a neuromodulatory noninvasive brain stimulation tool with potential to increase or reduce regional and remote cortical excitability. Numerous studies have shown the ability of this technique to induce neuroplasticity and to modulate cognition and behavior in adults. Clinical studies have also demonstrated the ability of tDCS to induce therapeutic effects in several central nervous system disorders. However, knowledge about its ability to modulate brain functions in children or induce clinical improvements in pediatrics is limited. The objective of this review is to describe relevant data of some recent studies that may help to understand the potential of this technique in children with specific regard to effective and safe treatment of different developmental disorders in pediatrics. Overall, the results show that standard protocols of tDCS are well tolerated by children and have promising clinical effects. Nevertheless, treatment effects seem to be partially heterogeneous, and a case of a seizure in a child with previous history of infantile spasms and diagnosed epilepsy treated with tDCS for spasticity was reported. Further research is needed to determine safety criteria for tDCS use in children and to elucidate the particular neurophysiological changes induced by this neuromodulatory technique when it is applied in the developing brain. PMID- 27997355 TI - Role of ABC transporters in the pathology of Alzheimer's disease. AB - The ATP-binding cassette (ABC) transporter superfamily is a large family of proteins that transport specific molecules across membranes. These proteins are associated with both cholesterol metabolism and Alzheimer's disease (AD). Cholesterol homeostasis has a key role in AD, and ABC transporters are important mediators of lipid transportation. Emerging evidence suggests that decreased expression and hypofunction of ABC transporters are crucial to the occurrence and development of AD. In the present article, we review the current knowledge regarding ABC transporters and speculate on their role in the pathogenesis of AD. PMID- 27997356 TI - Termiglaucescin, a new polyhydroxy triterpene glucoside from Terminalia glaucescens with antioxidant and anti-inflammatory potential. AB - Termiglaucescin (1), a new triterpene glucoside, has been isolated from the ethyl acetate extract of the root bark of Terminalia glaucescens Planch. ex Benth, together with 11 known compounds, beta-D-glucopyranosyl 2alpha,3beta,6beta trihydroxy-23-galloylolean-12-en-28-oate (2), arjunglucoside I (3), sericoside (4), arjungenin (5), sericic acid (6), arjunetin (7), chebuloside II (8), 3,3',4 tri-O-methylelagic acid (9), 3,3'-di-O-methylelagic acid (10), beta-sitosterol (11) and stigmasterol (12). Compounds 2, 3, 7, 8 and 9 are reported from the plant for the first time. The structures of the isolated compounds were characterized by spectroscopic data interpretations, especially 1D and 2D NMR. The triterpenic isolates showed potent antioxidant and anti-inflammatory activities. PMID- 27997357 TI - Effect of the micronutrient iodine in thyroid carcinoma angiogenesis. AB - Iodide is a micronutrient essential for thyroid hormone production. The uptake and metabolism of iodide by thyrocytes is crucial to proper thyroid function. Iodide ions are drawn into the thyroid follicular cell via the sodium-iodide symporter (NIS) in the cell membrane and become integrated into tyrosyl residues to ultimately form thyroid hormones. We sought to learn how an abnormal concentration of iodide within thyrocyte can have significant effects on the thyroid, specifically the surrounding vascular network. Insufficient levels of iodide can lead to increased expression or activity of several pathways, including vascular endothelial growth factor (VEGF). The VEGF protein fuel vessel growth (angiogenesis) and therefore enhances the nutrients available to surrounding cells. Alternatively, normal/surplus iodide levels can have inhibitory effects on angiogenesis. Varying levels of iodide in the thyroid can influence thyroid carcinoma cell proliferation and angiogenesis via regulation of the hypoxia inducible factor-1 (HIF-1) and VEGF-dependent pathway. We have reviewed a number of studies to investigate how the effect of iodide on angiogenic and oxidative stress regulation can affect the viability of thyroid carcinoma cells. The various studies outlined give key insights to the role of iodide in thyroid follicles function and vascular growth, generally highlighting that insufficient levels of iodide stimulate pathways resulting in vascular growth, and viceversa normal/surplus iodide levels inhibit such pathways. Intriguingly, TSH and iodine levels differentially regulate the expression levels of angiogenic factors. All cells, including carcinoma cells, increase uptake of blood nutrients, meaning the vascular profile is influential to tumor growth and progression. Importantly, variation in the iodine concentrations also influence BRAFV600E-mediated oncogenic activity and might deregulate tumor proliferation. Although the mechanisms are not well eluted, iodine concentrations and metabolism might have a crucial influence on thyroid carcinoma cell viability via regulation of different molecular pathways, including angiogenesis regulatory autocrine and microenvironment-mediated signals. PMID- 27997358 TI - Dosimetric evaluation of the skin-sparing effects of 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy for left breast cancer. AB - The purpose of this study was to evaluate the skin-sparing effects of 3 dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in patients with early left-sided breast cancer. Twenty left breast cancer patients treated with whole breast radiotherapy following breast-conserving surgery were enrolled in this study, and the 3D-CRT and IMRT plans were generated for each patient. To evaluate the dose delivered to the skin, 2 mm thickness skin (2-mm skin) and 3 mm thickness skin (3-mm skin) were contoured and a dosimetric comparison between the 2 plans was performed. The target volume coverage was better in IMRT than in 3D-CRT. The mean dose was 50.8 Gy for 3D-CRT and 51.1 Gy for IMRT. V40Gy was 99.4% for 3D-CRT and 99.9% for IMRT. In the case of skin, the mean dose was higher in 3D-CRT than in IMRT (mean dose of 2-mm skin: 32.8 Gy and 24.2 Gy; mean dose of 3-mm skin: 37.2 Gy and 27.8 Gy, for 3D-CRT and IMRT, respectively). These results indicated that the skin-sparing effect is more prominent in IMRT compared to 3D-CRT without compromising the target volume coverage. PMID- 27997359 TI - Naked mole-rats maintain healthy skeletal muscle and Complex IV mitochondrial enzyme function into old age. AB - The naked mole-rat (NMR) Heterocephalus glaber is an exceptionally long-lived rodent, living up to 32 years in captivity. This extended lifespan is accompanied by a phenotype of negligible senescence, a phenomenon of very slow changes in the expected physiological characteristics with age. One of the many consequences of normal aging in mammals is the devastating and progressive loss of skeletal muscle, termed sarcopenia, caused in part by respiratory enzyme dysfunction within the mitochondria of skeletal muscle fibers. Here we report that NMRs avoid sarcopenia for decades. Muscle fiber integrity and mitochondrial ultrastructure are largely maintained in aged animals. While mitochondrial Complex IV expression and activity remains stable, Complex I expression is significantly decreased. We show that aged naked mole-rat skeletal muscle tissue contains some mitochondrial DNA rearrangements, although the common mitochondrial DNA deletions associated with aging in human and other rodent skeletal muscles are not present. Interestingly, NMR skeletal muscle fibers demonstrate a significant increase in mitochondrial DNA copy number. These results have intriguing implications for the role of mitochondria in aging, suggesting Complex IV, but not Complex I, function is maintained in the long-lived naked mole rat, where sarcopenia is avoided and healthy muscle function is maintained for decades. PMID- 27997360 TI - Salvia miltiorrhiza bunge increases estrogen level without side effects on reproductive tissues in immature/ovariectomized mice. AB - Salvia miltiorrhiza bunge(SM) is a popular herb for alleviating menopausal symptoms, although the scientific evidence of applying SM to estrogen replacement therapy is limited. In this study, we characterized the estrogenic activity of SM using in vivo models of immature and ovariectomized (OVX) mice and performed in vitro studies focusing on the estrogen receptor (ER) pathway for further molecular characterizations. SM treatments demonstrated significant estrogenic activity by promoting the development of uterus and vagina in immature mice, restoring the estrus cycle and reversing the atrophy of reproductive tissues in OVX mice, as well as increasing the expressions of ERalpha and ERbeta at protein and mRNA level in the reproductive tissues. Meanwhile, SM significantly increased estradiol in serum, and decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the circulation of immature and OVX mice. SM could stimulate the binding effect of ERalpha and ERbeta, and significantly induce ERalpha/beta-estrogen response element (ERE) luciferase reporter gene expression. All these activities were inhibited by the ER antagonist ICI182, 780. This study demonstrates SM exerts estrogenic effects by stimulating biosynthesis of estrogen and increasing ERs in target tissues without side effects on reproductive tissues and through ER-ERE-dependent pathway. PMID- 27997362 TI - Elucidating the relationship between crystallo-chemistry and optical properties of CIGS nanocrystals. AB - The performance of solar cells fabricated using Cu(In,Ga)(S,Se)2 nanocrystal (NC) inks synthesized using the hot injection method has yielded efficiencies up to 12% recently. The efficiency of these devices is highly dependent on the chemical composition and crystallographic quality of the NCs. The former has been extensively discussed as it can be easily correlated to the optical properties of the film, but detailed crystallographic structure of these NCs has scarcely been discussed and it can influence both the optical and electrical properties. Hence both chemical composition and crystal structure should be explored for these NCs in order for this material to be further developed for application in thin film solar cells. In this work, a thorough investigation of the composition and crystal structure of CuIn x Ga1-x Se2 NCs synthesized using the hot injection method over the entire composition range (0 <= x <= 1) has been conducted. Raman spectroscopy of the NCs complements the information derived from x-ray diffraction (XRD) and electron probe microanalysis (EPMA). EPMA, which was carried out for the first time, indicates good controllability of the NC Ga/(In + Ga) ratio using this synthesis method. Raman spectroscopy reveals that CuInSe2 NCs are a mixture of chalcopyrite and sphalerite with disordered cations, whereas CuGaSe2 NCs are purely chalcopyrite. The lattice parameters determined from XRD were found to deviate from those calculated using Vegard's law for all compositions. Hence, it can be deduced that the lattice is distorted in the crystal. The optical and electrochemical band gap of CuIn x Ga1-x Se2 NCs increases as the Ga content increases. The energy band gap deviates from the theoretical values, which could be related to the contribution from cation disordering and strain. These results help to tailor the opto-electrical properties of semiconductors, which inherently depend on the crystalline quality, strain and composition. PMID- 27997363 TI - A plant-inspired robot with soft differential bending capabilities. AB - We present the design and development of a plant-inspired robot, named Plantoid, with sensorized robotic roots. Natural roots have a multi-sensing capability and show a soft bending behaviour to follow or escape from various environmental parameters (i.e., tropisms). Analogously, we implement soft bending capabilities in our robotic roots by designing and integrating soft spring-based actuation (SSBA) systems using helical springs to transmit the motor power in a compliant manner. Each robotic tip integrates four different sensors, including customised flexible touch and innovative humidity sensors together with commercial gravity and temperature sensors. We show how the embedded sensing capabilities together with a root-inspired control algorithm lead to the implementation of tropic behaviours. Future applications for such plant-inspired technologies include soil monitoring and exploration, useful for agriculture and environmental fields. PMID- 27997364 TI - Synthesis and photocatalytic activity of Pt-ZnO hybrid nanocomposite by solution plasma technology. AB - In this paper, Pt-ZnO hybrid nanocomposites were prepared by solution plasma technology. X-ray diffraction (XRD) and energy dispersive x-ray analysis (EDX) were used to verify their chemical composition. The size and morphology of the Pt ZnO hybrid nanocomposites were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These results indicate that about 2-3 nm Pt nanoparticles (NPs) were synthesized and dispersed on the pyramid like ZnO (20-60 nm) surface. Photodegradation of Rhodamine B (RhB) demonstrates that the Pt (5 wt%)-ZnO hybrid nanocomposite has better photocatalytic activity than commercial P25 because Pt NPs restrain the photogenerated electron/hole recombination and increase the catalyst activity. PMID- 27997361 TI - Association of neovascular age-related macular degeneration with month and season of birth in Italy. AB - In order to investigate the influence of season and month of birth on the risk of neovascular age-related macular degeneration (n-AMD) in Italy, we evaluated the month birth and sex of all patients, recorded in the anti-vascular endothelial growth factor (VEGF) monitoring registry of the Italian Medicines Agency, born between 1925-1944, who received intravitreal anti-VEGF injections for n-AMD between January 1, 2013 and July 29, 2015. The numbers of all births in Italy in the same years, extracted from the Italian National Institute of Statistics, were used to calculate the expected number of n-AMD cases. Overall, 45,845 patients (19,207 men, 26,638 women) received intravitreal anti-VEGF for n-AMD; in the same years, 20,140,426 people (10,334,262 male, 9,806,164 female) were born in Italy. Comparing the observed number of n-AMD cases with the expected number of n- AMD cases in each season, we found that the season-specific risk for n-AMD was 2.5% higher for those born in summer (OR=1.03, Bonferroni-corrected P=0.008) and 3% lower for those born in winter (OR=0.96, Bonferroni-corrected P=0.0004). When considering the month of birth, the risk of n-AMD was 5.9% lower for people born in January (OR=0.93, Bonferroni-corrected P=0.0012). The factors causing such differences should be determined. PMID- 27997365 TI - Recent advances in exploitation of nanomaterial for arsenic removal from water: a review. AB - Recently, increasing research efforts have been made to exploit the enormous potential of nanotechnology and nanomaterial in the application of arsenic removal from water. As a result, there are myriad of types of nanomaterials being developed and studied for their arsenic removal capabilities. Nevertheless, challenges such as having a complete understanding of the material properties and removal mechanism make it difficult for researchers to engineer nanomaterials that are best suited for specific water treatment applications. In this review paper, a comprehensive review will be conducted on several selected categories of nanomaterials that possess promising prospects in arsenic removal application. The synthesis process, material properties, as well as arsenic removal performance and removal mechanisms of each of these nanomaterials will be discussed in detail. Fe-based nanomaterials, particularly iron oxide nanoparticles, have displayed advantages in arsenic removal due to their super paramagnetic property. On the other hand, TiO2-based nanomaterials are the best candidates as photocatalytic arsenic removal agents, having been reported to have more than 200-fold increase in adsorption capacity under UV light irradiation. Zr based nanomaterials have among the largest BET active area for adsorption-up to 630 m2 g-1-and it has been reported that amorphous ZrO2 performs better than crystalline ZrO2 nanoparticles, having about 1.77 times higher As(III) adsorption capacity. Although Cu-based nanomaterials are relatively uncommon as nano adsorbents for arsenic in water, recent studies have demonstrated their potential in arsenic removal. CuO nanoparticles synthesized by Martinson et al were reported to have adsorption capacities up to 22.6 mg g-1 and 26.9 mg g-1 for As(V) and As(III) respectively. Among the nanomaterials that have been reviewed in this study, Mg-based nanomaterials were reported to have the highest maximum adsorption capacities for As(V) and As(III), at 378.79 mg g-1 and 643.84 mg g-1 respectively. By combining desired properties of different nanomaterials, composite nanomaterials can be made that have superior potential as efficient arsenic removal agents. Particularly, magnetic composite nanomaterials are interesting because the super-paramagnetic property, which allows efficient separation of nano-adsorbents in water, and high adsorption capacities, could be achieved simultaneously. For instance, Fe-Mn binary oxide nanowires have shown promising As(III) adsorption capacity at 171 mg g-1. Generally, nanomaterials used for arsenic removal face severe degradation in performance in the presence of competing ions in water, especially phosphate ions. This study will contribute to future research in developing nanomaterials used for arsenic removal that are highly efficient, environmentally friendly and cost-effective by providing a thorough, structured and detailed review on various nanomaterial candidates that have promising potential. PMID- 27997366 TI - SPR platform based on image acquisition for HER2 antigen detection. AB - HER2 antigen is a marker used for breast cancer diagnosis and prevention. Its determination has great importance since breast cancer is one of the most insidious types of cancer in women. HER2 antigen assessment in human serum is traditionally achieved by enzyme-linked immunosorbent assay (ELISA method), but it has some disadvantages, such as suppressing the thermodynamic-kinetic studies regarding the antibody-antigen interaction, and the use of labeled molecules that can promote false positive responses. Biosensors based on surface plasmon resonance (SPR) are sensitive optical techniques widely applied on bioassays. The plasmonic devices do not operate with labeled molecules, overcoming conventional immunoassay limitations, and enabling a direct detection of target analytes. In this way, a new SPR biosensor to assess HER2 antigen has been proposed, using nanohole arrays on a gold thin film by signal transduction of transmitted light measurements from array image acquisitions. These metallic nanostructures may couple the light directly on surface plasmons using a simple collinear arrangement. The proposed device reached an average sensitivity for refractive index (RI) variation on a metal surface of 4146 intensity units/RIU (RIU = RI units). The device feasibility on biomolecular assessment was evaluated. For this, 3 ng ml-1 known HER2 antigen concentration was efficiently flowed (using a microfluidic system) and detected from aqueous solutions. This outcome shows that the device may be a powerful apparatus for bioassays, particularly toward breast cancer diagnosis and prognosis. PMID- 27997367 TI - Ga crystallization dynamics during annealing of self-assisted GaAs nanowires. AB - In As atmosphere, we analyzed the crystallization dynamics during post-growth annealing of Ga droplets residing at the top of self-assisted GaAs nanowires grown by molecular beam epitaxy. The final crystallization steps, fundamental to determining the top facet nanowire morphology, proceeded via a balance of Ga crystallization via vapor-liquid-solid and layer-by-layer growth around the droplet, promoted by Ga diffusion out of the droplet perimeter, As desorption, and diffusion dynamics. By controlling As flux and substrate temperature the transformation of Ga droplets into nanowire segments with a top surface flat and parallel to the substrate was achieved, thus opening the possibility to realize atomically sharp vertical heterostructures in III-As self-assisted nanowires through group III exchange. PMID- 27997369 TI - Effect of argon implantation on solid-state dewetting: control of size and surface density of silicon nanocrystals. AB - Thermally induced solid-state dewetting of ultra-thin films on insulators is a process of prime interest, since it is capable of easily forming nanocrystals. If no particular treatment is performed to the film prior to the solid-state dewetting, it is already known that the size, the shape and the density of nanocrystals is governed by the initial film thickness. In this paper, we report a novel approach to control the size and the surface density of silicon nanocrystals based on an argon-implantation preliminary surface treatment. Using 7.5 nm thin layers of silicon, we show that increasing the implantation dose tends to form smaller silicon nanocrystals with diameter and height lower than 50 nm and 30 nm, respectively. Concomitantly, the surface density is increased by a factor greater than 20, going from 5 MUm-2 to values over 100 MUm-2. PMID- 27997370 TI - Investigation of electrically active defects in InGaAs quantum wire intermediate band solar cells using deep-level transient spectroscopy technique. AB - InGaAs quantum wire (QWr) intermediate-band solar cell-based nanostructures grown by molecular beam epitaxy are studied. The electrical and interface properties of these solar cell devices, as determined by current-voltage (I-V) and capacitance voltage (C-V) techniques, were found to change with temperature over a wide range of 20-340 K. The electron and hole traps present in these devices have been investigated using deep-level transient spectroscopy (DLTS). The DLTS results showed that the traps detected in the QWr-doped devices are directly or indirectly related to the insertion of the Si delta-layer used to dope the wires. In addition, in the QWr-doped devices, the decrease of the solar conversion efficiencies at low temperatures and the associated decrease of the integrated external quantum efficiency through InGaAs could be attributed to detected traps E1QWR_D, E2QWR_D, and E3QWR_D with activation energies of 0.0037, 0.0053, and 0.041 eV, respectively. PMID- 27997371 TI - First-principles study of thermal transport in nitrogenated holey graphene. AB - Nitrogenated holey graphene (NHG), a new two-dimensional graphene variant with a large fundamental direct band gap, has recently been successfully synthesized via a simple wet-chemical reaction. Motivated by its unique geometry and novel properties, we investigated the phonon transport properties of the material by combining first-principle calculations and the phonon Boltzmann transport equation. The lattice thermal conductivity of NHG at room temperature is predicted to be about 82.22 W mK-1, which is almost two orders of magnitude lower than that of graphene (about 3500 W mK-1). Deviating from the traditional understanding that thermal transport is usually largely contributed by the acoustic phonon modes for most suspended 2D materials, both out-of-plane flexural acoustic (ZA) and optical phonon modes make a more or less equal contribution, and their combination abnormally dominates the overall thermal transport in NHG. The major three-phonon process in NHG is further analyzed and the scattering between the acoustic and optical phonon modes like [Formula: see text] is the main phonon process channel. Meanwhile, the mean free path distribution of different phonon modes is calculated for the purpose of the thermal management of NHG-based devices. Our results elucidate the unusual thermal transport properties of NHG as compared with the representative case of graphene, and underpin its potential application for use by the thermal management community. PMID- 27997372 TI - Magnetization and ferromagnetic resonance in a Fe/Gd multilayer: experiment and modelling. AB - Static and dynamic magnetic properties of a [Fe(35 A)/Gd(50 A)]12 superlattice are investigated experimentally in the temperature range 5-295 K using SQUID magnetometery and the ferromagnetic resonance (FMR) technique at frequencies 7-38 GHz. The obtained magnetization curves and FMR spectra are analysed theoretically using numerical simulation on the basis of the effective field model. At every given temperature, both static and resonance experimental data can be approximated well within the proposed model. However, a considerable temperature dependence of the effective field parameter in gadolinium layers has to be taken into account to achieve reasonable agreement with the experimental data in the entire temperature range studied. To describe the peculiarities of experimental FMR spectra, a non-local diffusion-type absorption term in Landau-Lifshitz equations is considered in addition to the Gilbert damping term. Possible reasons for the observed effects are discussed. PMID- 27997373 TI - Depinning and nonequilibrium dynamic phases of particle assemblies driven over random and ordered substrates: a review. AB - We review the depinning and nonequilibrium phases of collectively interacting particle systems driven over random or periodic substrates. This type of system is relevant to vortices in type-II superconductors, sliding charge density waves, electron crystals, colloids, stripe and pattern forming systems, and skyrmions, and could also have connections to jamming, glassy behaviors, and active matter. These systems are also ideal for exploring the broader issues of characterizing transient and steady state nonequilibrium flow phases as well as nonequilibrium phase transitions between distinct dynamical phases, analogous to phase transitions between different equilibrium states. We discuss the differences between elastic and plastic depinning on random substrates and the different types of nonequilibrium phases which are associated with specific features in the velocity-force curves, fluctuation spectra, scaling relations, and local or global particle ordering. We describe how these quantities can change depending on the dimension, anisotropy, disorder strength, and the presence of hysteresis. Within the moving phase we discuss how there can be a transition from a liquid like state to dynamically ordered moving crystal, smectic, or nematic states. Systems with periodic or quasiperiodic substrates can have multiple nonequilibrium second or first order transitions in the moving state between chaotic and coherent phases, and can exhibit hysteresis. We also discuss systems with competing repulsive and attractive interactions, which undergo dynamical transitions into stripes and other complex morphologies when driven over random substrates. Throughout this work we highlight open issues and future directions such as absorbing phase transitions, nonequilibrium work relations, inertia, the role of non-dissipative dynamics such as Magnus effects, and how these results could be extended to the broader issues of plasticity in crystals, amorphous solids, and jamming phenomena. PMID- 27997374 TI - Stable phantom materials for ultrasound and optical imaging. AB - Phantoms mimicking the specific properties of biological tissues are essential to fully characterize medical devices. Water-based materials are commonly used to manufacture phantoms for ultrasound and optical imaging techniques. However, these materials have disadvantages, such as easy degradation and low temporal stability. In this study, we propose an oil-based new tissue-mimicking material for ultrasound and optical imaging, with the advantage of presenting low temporal degradation. A styrene-ethylene/butylene-styrene (SEBS) copolymer in mineral oil samples was made varying the SEBS concentration between 5%-15%, and low-density polyethylene (LDPE) between 0%-9%. Acoustic properties, such as the speed of sound and the attenuation coefficient, were obtained using frequencies ranging from 1-10 MHz, and were consistent with that of soft tissues. These properties were controlled varying SEBS and LDPE concentration. To characterize the optical properties of the samples, the diffuse reflectance and transmittance were measured. Scattering and absorption coefficients ranging from 400 nm-1200 nm were calculated for each compound. SEBS gels are a translucent material presenting low optical absorption and scattering coefficients in the visible region of the spectrum, but the presence of LDPE increased the turbidity. Adding LDPE increased the absorption and scattering of the phantom materials. Ultrasound and photoacoustic images of a heterogeneous phantom made of LDPE/SEBS containing a spherical inclusion were obtained. Annatto dye was added to the inclusion to enhance the optical absorbance. The results suggest that copolymer gels are promising for ultrasound and optical imaging, making them also potentially useful for photoacoustic imaging. PMID- 27997376 TI - Voxel-based dose prediction with multi-patient atlas selection for automated radiotherapy treatment planning. AB - Automating the radiotherapy treatment planning process is a technically challenging problem. The majority of automated approaches have focused on customizing and inferring dose volume objectives to be used in plan optimization. In this work we outline a multi-patient atlas-based dose prediction approach that learns to predict the dose-per-voxel for a novel patient directly from the computed tomography planning scan without the requirement of specifying any objectives. Our method learns to automatically select the most effective atlases for a novel patient, and then map the dose from those atlases onto the novel patient. We extend our previous work to include a conditional random field for the optimization of a joint distribution prior that matches the complementary goals of an accurately spatially distributed dose distribution while still adhering to the desired dose volume histograms. The resulting distribution can then be used for inverse-planning with a new spatial dose objective, or to create typical dose volume objectives for the canonical optimization pipeline. We investigated six treatment sites (633 patients for training and 113 patients for testing) and evaluated the mean absolute difference in all DVHs for the clinical and predicted dose distribution. The results on average are favorable in comparison to our previous approach (1.91 versus 2.57). Comparing our method with and without atlas-selection further validates that atlas-selection improved dose prediction on average in whole breast (0.64 versus 1.59), prostate (2.13 versus 4.07), and rectum (1.46 versus 3.29) while it is less important in breast cavity (0.79 versus 0.92) and lung (1.33 versus 1.27) for which there is high conformity and minimal dose shaping. In CNS brain, atlas-selection has the potential to be impactful (3.65 versus 5.09), but selecting the ideal atlas is the most challenging. PMID- 27997375 TI - Impact of motion and partial volume effects correction on PET myocardial perfusion imaging using simultaneous PET-MR. AB - PET is an established modality for myocardial perfusion imaging (MPI) which enables quantification of absolute myocardial blood flow (MBF) using dynamic imaging and kinetic modeling. However, heart motion and partial volume effects (PVE) significantly limit the spatial resolution and quantitative accuracy of PET MPI. Simultaneous PET-MR offers a solution to the motion problem in PET by enabling MR-based motion correction of PET data. The aim of this study was to develop a motion and PVE correction methodology for PET MPI using simultaneous PET-MR, and to assess its impact on both static and dynamic PET MPI using 18F Flurpiridaz, a novel 18F-labeled perfusion tracer. Two dynamic 18F-Flurpiridaz MPI scans were performed on healthy pigs using a PET-MR scanner. Cardiac motion was tracked using a dedicated tagged-MRI (tMR) sequence. Motion fields were estimated using non-rigid registration of tMR images and used to calculate motion dependent attenuation maps. Motion correction of PET data was achieved by incorporating tMR-based motion fields and motion-dependent attenuation coefficients into image reconstruction. Dynamic and static PET datasets were created for each scan. Each dataset was reconstructed as (i) Ungated, (ii) Gated (end-diastolic phase), and (iii) Motion-Corrected (MoCo), each without and with point spread function (PSF) modeling for PVE correction. Myocardium-to-blood concentration ratios (MBR) and apparent wall thickness were calculated to assess image quality for static MPI. For dynamic MPI, segment- and voxel-wise MBF values were estimated by non-linear fitting of a 2-tissue compartment model to tissue time-activity-curves. MoCo and Gating respectively decreased mean apparent wall thickness by 15.1% and 14.4% and increased MBR by 20.3% and 13.6% compared to Ungated images (P < 0.01). Combined motion and PSF correction (MoCo-PSF) yielded 30.9% (15.7%) lower wall thickness and 82.2% (20.5%) higher MBR compared to Ungated data reconstructed without (with) PSF modeling (P < 0.01). For dynamic PET, mean MBF across all segments were comparable for MoCo (0.72 +/- 0.21 ml/min/ml) and Gating (0.69 +/- 0.18 ml/min/ml). Ungated data yielded significantly lower mean MBF (0.59 +/- 0.16 ml/min/ml). Mean MBF for MoCo-PSF was 0.80 +/- 0.22 ml/min/ml, which was 37.9% (25.0%) higher than that obtained from Ungated data without (with) PSF correction (P < 0.01). The developed methodology holds promise to improve the image quality and sensitivity of PET MPI studies performed using PET-MR. PMID- 27997377 TI - Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams. AB - We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry. PMID- 27997378 TI - Impacts of gantry angle dependent scanning beam properties on proton PBS treatment. AB - While proton beam models in treatment planning systems are generally assumed invariant with respect to the beam deliveries at different gantry angles. Physical properties of scanning pencil beams can change. The gantry angle dependent properties include the delivered charge to the monitor unit chamber, the spot position and the spot shape. The aim of this study is to investigate the extent of the changes and their dosimetric impacts using historical pencil beam scanning (PBS) treatment data. Online beam delivery records at the time of the patient-specific qualify assurance were retrospectively collected for a total of 34 PBS fields from 28 patients treated at our institution. For each field, proton beam properties at two different gantry angles (the planned and zero gantry angles) were extracted by a newly-developed machine log analysis method and used to reconstruct the delivered dose distributions in the cubic water phantom geometry. The reconstructed doses at the two different angles and a planar dose measurement by a 2D ion-chamber array were compared and the dosimetric impacts of the gantry angle dependency were accessed by a 3D gamma-index analysis. In addition, the pencil beam spot size was independently characterized as a function of the gantry angle and the beam energy. The dosimetric effects of the perturbed beam shape were also investigated. Comparisons of spot-by-spot beam positions between both gantry angles show a mean deviation of 0.4 and 0.7 mm and a standard deviation of 0.3 and 0.6 mm for x and y directions, respectively. The delivered giga-protons per spot show a percent mean difference and a standard deviation of 0.01% and 0.3%, respectively, from each planned spot weight. These small deviations lead to an excellent agreement in dose comparisons with an average gamma passing rate of 99.1%. When each calculation for both planned and zero gantry angles was compared to the measurement, a high correlation in gamma values was also observed, also indicating the dosimetric differences are small when a field is delivered at different gantry angles. Utilizing the online beam delivery records, the gantry angle dependencies of the PBS beam delivery were assessed and quantified. The study confirms the variations of the physical properties to be sufficiently small within the clinical tolerances without taking into account the gantry angle variation. PMID- 27997379 TI - The impact of intraocular pressure on elastic wave velocity estimates in the crystalline lens. AB - Intraocular pressure (IOP) is believed to influence the mechanical properties of ocular tissues including cornea and sclera. The elastic properties of the crystalline lens have been mainly investigated with regard to presbyopia, the age related loss of accommodation power of the eye. However, the relationship between the elastic properties of the lens and IOP remains to be established. The objective of this study is to measure the elastic wave velocity, which represents the mechanical properties of tissue, in the crystalline lens ex vivo in response to changes in IOP. The elastic wave velocities in the cornea and lens from seven enucleated bovine globe samples were estimated using ultrasound shear wave elasticity imaging. To generate and then image the elastic wave propagation, an ultrasound imaging system was used to transmit a 600 us pushing pulse at 4.5 MHz center frequency and to acquire ultrasound tracking frames at 6 kHz frame rate. The pushing beams were separately applied to the cornea and lens. IOP in the eyeballs was varied from 5 to 50 mmHg. The results indicate that while the elastic wave velocity in the cornea increased from 0.96 +/- 0.30 m s-1 to 6.27 +/- 0.75 m s-1 as IOP was elevated from 5 to 50 mmHg, there were insignificant changes in the elastic wave velocity in the crystalline lens with the minimum and the maximum speeds of 1.44 +/- 0.27 m s-1 and 2.03 +/- 0.46 m s-1, respectively. This study shows that ultrasound shear wave elasticity imaging can be used to assess the biomechanical properties of the crystalline lens noninvasively. Also, it was observed that the dependency of the crystalline lens stiffness on the IOP was significantly lower in comparison with that of cornea. PMID- 27997380 TI - Developing a new case based computer-aided detection scheme and an adaptive cueing method to improve performance in detecting mammographic lesions. AB - The purpose of this study is to evaluate a new method to improve performance of computer-aided detection (CAD) schemes of screening mammograms with two approaches. In the first approach, we developed a new case based CAD scheme using a set of optimally selected global mammographic density, texture, spiculation, and structural similarity features computed from all four full-field digital mammography images of the craniocaudal (CC) and mediolateral oblique (MLO) views by using a modified fast and accurate sequential floating forward selection feature selection algorithm. Selected features were then applied to a 'scoring fusion' artificial neural network classification scheme to produce a final case based risk score. In the second approach, we combined the case based risk score with the conventional lesion based scores of a conventional lesion based CAD scheme using a new adaptive cueing method that is integrated with the case based risk scores. We evaluated our methods using a ten-fold cross-validation scheme on 924 cases (476 cancer and 448 recalled or negative), whereby each case had all four images from the CC and MLO views. The area under the receiver operating characteristic curve was AUC = 0.793 +/- 0.015 and the odds ratio monotonically increased from 1 to 37.21 as CAD-generated case based detection scores increased. Using the new adaptive cueing method, the region based and case based sensitivities of the conventional CAD scheme at a false positive rate of 0.71 per image increased by 2.4% and 0.8%, respectively. The study demonstrated that supplementary information can be derived by computing global mammographic density image features to improve CAD-cueing performance on the suspicious mammographic lesions. PMID- 27997382 TI - Investigation of undersampling and reconstruction algorithm dependence on respiratory correlated 4D-MRI for online MR-guided radiation therapy. AB - The purpose of this work is to investigate the effects of undersampling and reconstruction algorithm on the total processing time and image quality of respiratory phase-resolved 4D MRI data. Specifically, the goal is to obtain quality 4D-MRI data with a combined acquisition and reconstruction time of five minutes or less, which we reasoned would be satisfactory for pre-treatment 4D-MRI in online MRI-gRT. A 3D stack-of-stars, self-navigated, 4D-MRI acquisition was used to scan three healthy volunteers at three image resolutions and two scan durations. The NUFFT, CG-SENSE, SPIRiT, and XD-GRASP reconstruction algorithms were used to reconstruct each dataset on a high performance reconstruction computer. The overall image quality, reconstruction time, artifact prevalence, and motion estimates were compared. The CG-SENSE and XD-GRASP reconstructions provided superior image quality over the other algorithms. The combination of a 3D SoS sequence and parallelized reconstruction algorithms using computing hardware more advanced than those typically seen on product MRI scanners, can result in acquisition and reconstruction of high quality respiratory correlated 4D-MRI images in less than five minutes. PMID- 27997381 TI - Generalized paired-agent kinetic model for in vivo quantification of cancer cell surface receptors under receptor saturation conditions. AB - New precision medicine drugs oftentimes act through binding to specific cell surface cancer receptors, and thus their efficacy is highly dependent on the availability of those receptors and the receptor concentration per cell. Paired agent molecular imaging can provide quantitative information on receptor status in vivo, especially in tumor tissue; however, to date, published approaches to paired-agent quantitative imaging require that only 'trace' levels of imaging agent exist compared to receptor concentration. This strict requirement may limit applicability, particularly in drug binding studies, which seek to report on a biological effect in response to saturating receptors with a drug moiety. To extend the regime over which paired-agent imaging may be used, this work presents a generalized simplified reference tissue model (GSRTM) for paired-agent imaging developed to approximate receptor concentration in both non-receptor-saturated and receptor-saturated conditions. Extensive simulation studies show that tumor receptor concentration estimates recovered using the GSRTM are more accurate in receptor-saturation conditions than the standard simple reference tissue model (SRTM) (% error (mean +/- sd): GSRTM 0 +/- 1 and SRTM 50 +/- 1) and match the SRTM accuracy in non-saturated conditions (% error (mean +/- sd): GSRTM 5 +/- 5 and SRTM 0 +/- 5). To further test the approach, GSRTM-estimated receptor concentration was compared to SRTM-estimated values extracted from tumor xenograft in vivo mouse model data. The GSRTM estimates were observed to deviate from the SRTM in tumors with low receptor saturation (which are likely in a saturated regime). Finally, a general 'rule-of-thumb' algorithm is presented to estimate the expected level of receptor saturation that would be achieved in a given tissue provided dose and pharmacokinetic information about the drug or imaging agent being used, and physiological information about the tissue. These studies suggest that the GSRTM is necessary when receptor saturation exceeds 20% and highlight the potential for GSRTM to accurately measure receptor concentrations under saturation conditions, such as might be required during high dose drug studies, or for imaging applications where high concentrations of imaging agent are required to optimize signal-to-noise conditions. This model can also be applied to PET and SPECT imaging studies that tend to suffer from noisier data, but require one less parameter to fit if images are converted to imaging agent concentration (quantitative PET/SPECT). PMID- 27997384 TI - Rectal perforation during defecography: extraluminal barium impaction removed by TEM (Transanal Endoscopic Microsurgery). AB - AIM: Defecography is the standard diagnostic technique for the diagnosis of functional disorders of the posterior pelvic compartment. However it has some limits as radiation exposure, low-contrast resolution, some degrees of embarrassment and discomfort for the patients. Furthermore it often fails to directly visualize the changes that affect the pararectal space. Here we present a never described case of rectal perforation after defecography with barium impaction removed by TEM (Transanal Endoscopic Microsurgery). CASE REPORT: We present a case of a 50 years old woman with extraluminal barium impaction due to perforation occurred during defecography. Both pelvic MR and endoanal ultrasound confirmed the presence of the extramural rectal mass below rectal mucosa. It was completely and safely removed using transanal endoscopic microsurgery (TEM). RESULTS: The barium impaction has been radically removed using transanal endoscopic microsurgery. The post-operative period was uneventful and the patient was discharged 3 days after the operation. She is asymptomatic after 6 months from surgery. CONCLUSION: Defecography is not completely safe and its use must be indicated only in selected cases. When a patient has complications during or after this investigation he must be referred to a specialistic centre where a tailored treatment can be performed. It is mandatory that the indication for defecography and other diagnostic functional investigations is given by a colorectal specialist KEY WORD: Barium Impaction, Defecography, Rectal Perforation, TEM (Transanal Endoscopic Microsurgery). PMID- 27997383 TI - Laparoscopic resection of tailgut cysts: the size is not the issue. AB - INTRODUCTION: Tailgut cysts are rare retrorectal cystic lesions usually treated by surgical resection, even where asymptomatic, due to the risk of malignancy and recurrence. In the last 20 years, the laparoscopic abdominal approach has been gaining consensus for its better visualization of pelvic structures and minimal invasiveness. CASE REPORT: We present the case of the biggest tailgut cysts managed laparoscopically reported so far. DISCUSSION: Mostly asymptomatic, diagnosis of tailgut cysts is often fortuitous during routine examination. Their malignant transformation is estimated being 14.1% of cases. MRI is particularly indicated to lead the surgical approach, given its superior resolution in soft tissues and assessment of local invasion. Surgical resection is the therapy of choice, performed with different approaches: the laparoscopic abdominal technique, performed by surgeons with expertise in pelvic laparoscopic surgery, allows the best visualization of pelvic viscera with lesser morbidity. Due to rupture and seeding risks, the laparoscopic approach should not be performed if there is any suspicion of malignancy. CONCLUSION: Our case substantiates safety and feasibility of laparoscopic tailgut cysts management, even of large-size cysts. Preoperative imaging is crucial to assess the possible malignancy of the lesion and, in that case, to perform a laparotomic approach. KEY WORDS: Laparoscopy, Retrorectal space, Tailgut Cyst. PMID- 27997385 TI - Comparative experimental study on fouling mechanisms in nano-porous membrane: cheese whey ultrafiltration as a case study. AB - Determination of fouling mechanisms and accurate quantitative prediction of nano porous membrane behavior are of great interest in membrane processes. This work has focused on a comprehensive comparison of two classical and new fouling models. Different operational conditions were tested to analyze the level of agreement of these models with experimental observation. Whey solutions of 8, 0.8 and 0.5 g/L were ultrafiltered in transmembrane pressures (TMPs) of 300 and 500 KPa through a synthesized polyethersulfone/copolymer blend membrane. Fouling mechanisms and the effect of different combinations of TMPs and protein concentrations were determined and analyzed by fitting the experimental data to different models. Based on the results obtained from classical models, it was found that the predictions of the cake layer formation model were quite acceptable, followed by the intermediate blocking model. The new combined pore blockage-cake filtration model, however, was found to be very successful in predicting the flux decline over time for every operational condition tested, with all relative errors of prediction less than 5%. The latter also showed a good performance in the transition from the pore blockage mechanism to cake layer formation. PMID- 27997386 TI - Single and competitive adsorption of Cd(II) and Pb(II) from aqueous solution by activated carbon prepared with Salix matsudana Kiodz. AB - In this study, Salix matsudana activated carbon (SAC) was prepared by phosphoric acid activation, and the adsorption characteristics of Cd(II) and Pb(II) on SAC in single- and double-component solutions were investigated. In both systems, the adsorption capacities of both ions on SAC increased with the increasing initial pH value and temperature in the solutions, and the adsorption equilibrium was approached at 10 min. The adsorption process was spontaneous, endothermic, and depicted well by the pseudo-second-order adsorption model, and the equilibrium adsorption fitted reasonably well with the Langmuir isotherm. The maximum adsorption capacity (Qm) of Cd(II) and Pb(II) was 58.48 and 59.01 mg/g, respectively, in the single-element systems. However, it reduced to 25.32 and 31.09 mg/g, respectively, in the double-element system. The physicochemical property analysis showed that the specific surface area, total pore volume, and average pore diameter of SAC was 435.65 m2/g, 35.68 mL/g, and 3.86 nm, respectively. The SAC contained groups of -OH, C = O, and P = O. Results suggest that SAC had a good performance for the adsorption of Cd(II) and Pb(II) from solution, and the adsorption selectivity sequence was Pb(II) > Cd(II). PMID- 27997387 TI - Magnetized manganese oxide nanocomposite for effective decontamination of Cd(II) from wastewaters. AB - In this study, a composite with magnetic properties has been successfully synthesized by a novel and environmentally friendly route and is applied to Cd(II) adsorption for water decontamination. The quantification of the phases obtained by Rietveld refinement has shown the presence of 84% of Mn3O4 and 16% of Fe3O4. Transmission electron microscopy image shows an aggregate of Mn3O4 nanoparticles without specific orientation and the predominance of octahedral morphology with nanoparticles size estimated around 25-30 nm. The Cd(II) adsorption isotherm is fitted using the Langmuir-Freundlich model. The estimated maximum adsorption capacities of Cd(II) at pH 6 and 7 are similar (0.28 +/- 0.02 and 0.31 +/- 0.02 mg/m2, respectively). The kinetic results show that the studied system follows the pseudo-second-order model. The Raman results indicate that Cd is being specifically adsorbed by the Mn3O4 in the composite. The hysteresis curve of the composite Mn3O4/Fe3O4 has changed when compared to the pure magnetite; however, the coercive field after the addition of manganese oxide remains unaltered and does not change with a value around 158 Oe. The turbidity tests showed that the magnetic sedimentation was efficient and promising for wastewater treatment in large scale. These materials can be conveniently recovered by magnetic separation, avoiding the filtration steps, which will make easier the solid-liquid separation operation that follows the adsorption process. PMID- 27997388 TI - Notable increases in nutrient concentrations in a shallow lake during seasonal ice growth. AB - Nutrients may be eliminated from ice when liquid water is freezing, resulting in enhanced concentrations in the unfrozen water. The nutrients diluted from the ice may contribute to accumulated concentrations in sediment during winter and an increased risk of algae blooms during the following spring and summer. The objective of this study was to evaluate the influence of ice cover on nitrogen (N) and phosphorus (P) concentrations in the water and sediment of a shallow lake, through an examination of Ulansuhai Lake, northern China, from the period of open water to ice season in 2011-2013. The N and P concentrations were between two and five times higher, and between two and eight times higher, than in unfrozen lakes, respectively. As the ice thickness grew, contents of total N and total P showed C-shaped profiles in the ice, and were lower in the middle layer and higher in the bottom and surface layers. Most of the nutrients were released from the ice to liquid water. The results confirm that ice can cause the nutrient concentrations in water and sediment during winter to increase dramatically, thereby significantly impacting on processes in the water environment of shallow lakes. PMID- 27997389 TI - Dinitrogen oxide (N2O) emission in the treatment of urban wastewater via nitrite: influence of liquid kinetic rates. AB - N2O emission was studied in a continuous process via nitrite for real urban wastewater treatment. The relationship between the gaseous forms and the liquid kinetic rates of nitritation and denitritation was investigated. N2O mass load and global nitrogen mass balance were quantified. The emission factor of the N2O (gN2Oemitted/kg mixed liquor volatile suspended solids [MLVSS]/d) was calculated. Incrementing the nitritation rate permits the reduction of N2O emission by 78%. Instead, an N2O decrease of 93% was observed by increasing the denitritation velocity. The determinant role of the anoxic phase in the production of dinitrogen oxide was identified. The contribution of N2O emission from the anoxic phase (4.8 gN2O-N/kgMLVSS/d) was enhanced under limiting denitritation conditions (kd lower than 0.08 kgNOx-N/kgMLVSS/d). N2O production increased by five times with the accumulation of nitrites in the solution up to 200 mg/L. Strict correlation between free ammonia concentration and nitritation rate was found as a possible signal of further ammonia oxidizing bacteria selection. PMID- 27997390 TI - Effect of filter media thickness on the performance of sand drying beds used for faecal sludge management. AB - The effect of sand filter media thickness on the performance of faecal sludge (FS) drying beds was determined in terms of: dewatering time, contaminant load removal efficiency, solids generation rate, nutrient content and helminth eggs viability in the dried sludge. A mixture of ventilated improved pit latrine sludge and septage in the ratio 1:2 was dewatered using three pilot-scale sludge drying beds with sand media thicknesses of 150, 250 and 350 mm. Five dewatering cycles were conducted and monitored for each drying bed. Although the 150 mm filter had the shortest average dewatering time of 3.65 days followed by 250 mm and 350 mm filters with 3.83 and 4.02 days, respectively, there was no significant difference (p > 0.05) attributable to filter media thickness configurations. However, there was a significant difference for the percolate contaminant loads in the removal and recovery efficiency of suspended solids, total solids, total volatile solids, nitrogen species, total phosphorus, chemical oxygen demand, dissolved chemical oxygen demand and biochemical oxygen demand, with the highest removal efficiency for each parameter achieved by the 350 mm filter. There were also significant differences in the nutrient content (NPK) and helminth eggs viability of the solids generated by the tested filters. Filtering media configurations similar to 350 mm have the greatest potential for optimising nutrient recovery from FS. PMID- 27997391 TI - Poly(sodium methacrylate)/eggshell particles hydrogel composites as dye sorbent. AB - Eggshell (ES) particles as an available and low-cost waste material were utilized to prepare novel hydrogel composites for dye adsorbing application. For this purpose, solution polymerization of sodium methacrylate was carried out in the presence of ES particles with various size ranges. Results showed that incorporation of ES particles resulted in heterogeneous pores and cavities in the structure of the poly(sodium methacrylate) (PNaMA) matrix. Hydrogel composites with lower content (20 wt%) and smaller size (<75 MUm) of ES particles presented higher water absorption capacity. The equilibrium water absorption values in distilled water were higher than phosphate buffered saline medium. ES particles showed low methylene blue (MB) and crystal violet (CV) adsorption capacities due to electrostatic repulsion of the positively charged species on the surface of ES particles and dye molecules. In contrast, hydrogel composites depicted fast and considerable dye adsorbability. The combination of 60 wt% ES particles within PNaMA provided a cost-effective adsorbent with similar CV adsorption capacity compared with the unfilled matrix, while MB removal was slightly decreased. The dye adsorption by either ES particles or hydrogel composites followed the pseudo second-order kinetics, indicating that chemical sorption is the rate-limiting step for both of them. PMID- 27997392 TI - Adsorption performance of coconut shell activated carbon for the removal of chlorate from chlor-alkali brine stream. AB - Activated carbon from coconut shell was used to investigate the adsorption of chlorate from a chlor-alkali plant's brine stream. The effect of pH, flowrate, chlorate and chloride concentration on the breakthrough curves were studied in small-scale column trials. The results obtained show enhanced adsorption at low flowrates, higher chlorate concentrations, and at a pH of 10. These studies show that introducing an activated carbon adsorption column just before the saturator would remove sufficient quantities of chlorate to allow more of the chlor-alkali plant's brine stream to be reused. From column dynamic studies, the Thomas model showed close approximation when the chlorate in the effluent was higher than breakthrough concentrations and there was close correlation at high influent concentration. The qo (maximum adsorption capacity) values were close to those obtained experimentally, indicating close representation of the breakthrough curve by the Thomas model. PMID- 27997393 TI - Environmental fate and behavior of acesulfame in laboratory experiments. AB - Acesulfame is a widely used artificial sweetener. It can be discharged into surface water by domestic wastewater due to its incomplete retention during wastewater treatment. Concentrations may reach up to 10 MUg/L for smaller rivers. State-of-the-art analysis allows the determination of acesulfame traces (0.01 MUg/L) and thus a potential tracking of the presence of wastewater in riverbank filtrate. To evaluate the behavior of acesulfame in the aquatic environment, biodegradation and sorption of acesulfame were tested. Batch experiments yielded low sorption for several soils (estimated solid-water distribution coefficient of acesulfame <0.1 L/kg). Biodegradation in a fixed-bed reactor was not observed at environmental concentrations of 9 MUg/L in aqueous compost and soil extract (observation period 56 days). Only in diluted effluent of a wastewater treatment plant did biodegradation start, after 17 days of operation, and acesulfame completely fade, within 28 days. Flow-through column experiments indicated conservative behavior of acesulfame (recovery >83%) and long-term observations at different concentration levels yielded no biodegradation. Overall, laboratory experiments demonstrated a conservative behavior of acesulfame under conditions typical for riverbank filtration. However, there are hints for certain settings which favor an adaptation of the microbial community and facilitate a rapid biodegradation of acesulfame. PMID- 27997394 TI - Characteristics and sources analysis of riverine chromophoric dissolved organic matter in Liaohe River, China. AB - Chromophoric dissolved organic matter (CDOM) in riverine systems can be affected by environmental conditions and land-use, and thus could provide important information regarding human activities in surrounding landscapes. The optical properties of water samples collected at 42 locations across the Liaohe River (LHR, China) watershed were examined using UV-Vis and fluorescence spectroscopy to determine CDOM characteristics, composition and sources. Total nitrogen (TN) and total phosphorus (TP) concentrations at all sampling sites exceeded the GB3838-2002 (national quality standards for surface waters, China) standard for Class V waters of 2.0 mg N/L and 0.4 mg P/L respectively, while trophic state index (TSIM) indicated that all the sites investigated were mesotrophic, 64% of which were eutrophic at the same time. Redundancy analysis showed that total suspended matter (TSM), dissolved organic carbon (DOC), and turbidity had a strong correlation with CDOM, while the other parameters (Chl a, TN, TP and TSIM) exhibited weak correlations with CDOM absorption. High spectral slope values and low SUVA254 (the specific UV absorption) values indicated that CDOM in the LHR was primarily comprised of low molecular weight organic substances. Analysis of excitation-emission matrices contour plots showed that CDOM in water samples collected from upstream locations exhibited fulvic-acid-like characteristics whereas protein-like substances were most likely predominant in samples collected in estuarine areas and downstream from large cities. These patterns were interpreted as indicative of water pollution from urban and industrial activities in several downstream sections of the LHR watershed. PMID- 27997395 TI - Alkaline fermentation of waste activated sludge stimulated by saponin: volatile fatty acid production, mechanisms and pilot-scale application. AB - Volatile fatty acid (VFA) production stimulated by saponin (SP), an environmentally friendly bio-surfactant, was investigated during sludge alkaline fermentation in laboratory studies and pilot applications. The combined use of SP and pH 9 condition significantly enhanced VFA production to approximately 425 mg COD/g VSS, which was 4.7-fold of raw sludge and 1.5-fold of sole pH 10 adjustment (the optimum pH for alkaline fermentation). Further results indicated that SP & pH 9 condition provided sufficient substrates for acidification and decreased the consumption of VFAs through methanogenesis. Moreover, SP accompanied by moderate alkaline condition (i.e. pH 9) showed weaker inhibitory effects on key enzyme activities and metabolic potential of acidification microorganisms than sole pH 10 adjustment. On this basis, a pilot-scale system involving anaerobic fermentation and anaerobic-anoxic-aerobic step-feed bioreaction tanks was established to study the potential of VFAs as supplementary carbon sources for wastewater treatment. The influent of the pilot system was sanitary wastewater characterized by low C/N ratios from a scenic rural area. After flocculation and nutrient precipitation, the fermentation supernatant was mixed with the influent at a volume ratio of 1:30. With this approach, nitrogen and phosphorus concentrations in effluent fulfilled the first-A wastewater discharge standard in China. PMID- 27997396 TI - Nitrous oxide emissions from one-step partial nitritation/anammox processes. AB - Measurements of nitrous oxide were made at pilot- and full-scale plants to evaluate greenhouse gas emissions from one-step partial nitritation/anammox processes applied in moving bed biofilm reactors treating reject water. It was found that 0.51-1.29% and 0.35-1.33% of the total nitrogen loads in the pilot- and full-scale reactor, respectively, were emitted as nitrous oxide. Between 80 and 90% of nitrous oxide emissions were in gaseous form and the rest amount was found in the reactor effluent; over 90% of nitrous oxide emissions occurred in the aerated period and less than 8% in the non-aerated period in the full-scale study. Nitrous oxide productions/consumptions were closely related to aeration and the nitrogen loads applied in the system. PMID- 27997397 TI - Phenanthrene removal from liquid medium with emphasis on production of biosurfactant. AB - In the current study, there are some considerable issues which focused on: (1) the production of biosurfactant, (2) its correlation with the initial bacterial inoculum in the liquid phase and (3) its effect on polycyclic hydrocarbon (PAH) bioremediation performance. Therefore, two strains Pseudomonas facilis and Pseudomonas spp. were able to form a large clear zone diameter on the oil surface. Phenanthrene (PHE) was also utilized as a sole substrate. Furthermore, biosurfactant production (BP) was detected by methylene blue analysis procedure and surface tension (ST) lowering. The capacity of these two strains to lower the aqueous ST was 29 and 30.7 from 72 mN m-1 by 6 days for P. facilis and Pseudomonas spp., respectively. Higher initial bacterial inoculation led to an improvement in PHE removal (P < 0.0001). But there was no significant correlation between either PHE solubility or BP and the initial bacterial inoculation. The removal efficiency of 88.44% within 21 days confirms that the inoculation of P. facilis led to the considerable BP for removal of PAHs from contaminated water. PMID- 27997399 TI - Structural improvements on hydrodynamic separators: a computational fluid dynamics approach. AB - Hydrodynamic separators (HDSs) have been used extensively to reduce stormwater pollutants from urbanized areas before entering the receiving water bodies. They primarily remove particulates and associated pollutants using gravity settling. Two types of HDSs with different structural configurations of the inner vortex inducing components were presented in this study. One configuration consisted of a dip cylindrical plate with a center shaft while the other one has a hollow screen inside. With the help of computational fluid dynamics, the performance of these different types of HDSs have been evaluated and comparatively analyzed. The results showed that the particle removal efficiency was better with the cylindrical plate type HDSs than the screen type HDSs because of the larger swirling flow regime formed inside the device. Plate type HDSs were found more effective in removing fine particles (~50 MUm) than the screen type HDSs that were only efficient in removing large particles (>=250 MUm). Structural improvements in a HDS such as increase in diameter and angle of the inlet pipe can enhance the removal efficiencies by up to 20% for plate type HDS while increase in the screen diameter can increase removal efficiencies of the screen type HDS. PMID- 27997398 TI - Toxicity and biofilm-based selection for methyl tert-butyl ether bioremediation technology. AB - Extractive membrane biofilm reactor (EMBFR) technology offers productive solutions for volatile and semi-volatile compound removal from water bodies. In this study, the bacterial strains Paenibacillus etheri SH7T (CECT 8558), Agrobacterium sp. MS2 (CECT 8557) and Rhodococcus ruber strains A5 (CECT 8556), EE6 (CECT 8612) and EE1 (CECT 8555), previously isolated from fuel-contaminated sites, were tested for adherence on tubular semipermeable membranes in laboratory scale systems designed for methyl tert-butyl ether (MTBE) bioremediation. Biofilm formation on the membrane surface was evaluated through observation by field emission scanning electron microscope (FESEM) as well as the acute toxicity (as EC50) of the bacterial growth media. Moreover, extracellular polymeric substance (EPS) production for each strain under different MTBE concentrations was measured. Strains A5 and MS2 were biofilm producers and their adherence increased when the MTBE flowed through the inner tubular semipermeable membrane. No biofilm was formed by Paenibacillus etheri SH7T, nevertheless, the latter and strain MS2 exhibited the lowest toxicity after growth on the EMBFR. The results obtained from FESEM and toxicity analysis demonstrate that bacterial strains R. ruber EE6, A5, P. etheri SH7T and Agrobacterium sp. MS2 could be excellent candidates to be used as selective inocula in EMBFR technology for MTBE bioremediation. PMID- 27997400 TI - The application of moving bed biofilm reactor to denitrification process after trickling filters. AB - The paper presents research of a prototype moving bed biofilm reactor (MBBR). The device was used for the post-denitrification process and was installed at the end of a technological system consisting of a septic tank and two trickling filters. The concentrations of suspended biomass and biomass attached on the EvU Perl moving bed surface were determined. The impact of the external organic carbon concentration on the denitrification rate and efficiency of total nitrogen removal was also examined. The study showed that the greater part of the biomass was in the suspended form and only 6% of the total biomass was attached to the surface of the moving bed. Abrasion forces between carriers of the moving bed caused the fast stripping of attached microorganisms and formation of flocs. Thanks to immobilization of a small amount of biomass, the MBBR was less prone to leaching of the biomass and the occurrence of scum and swelling sludge. It was revealed that the maximum rate of denitrification was an average of 0.73 gN NO3/gDM.d (DM: dry matter), and was achieved when the reactor was maintained in external organic carbon concentration exceeding 300 mgO2/dm3 chemical oxygen demand. The reactor proved to be an effective device enabling the increase of total nitrogen removal from 53.5% to 86.0%. PMID- 27997401 TI - Modeling on-site wastewater treatment system performance fragility to hydroclimate stressors. AB - Increasing variability of climate-related factors, especially precipitation and temperature, poses special risks to on-site wastewater treatment systems (OWTS), which depend on subsurface saturation conditions for treatment and dispersion of wastewater. We assess OWTS fragility - the degree to which a system loses functionality - as a step to characterizing the resilience of residential wastewater treatment systems. We used the frequency and indexed severity of OWTS failures and resulting repairs to quantify fragility as a function of hydroclimate variables, including precipitation, temperature and stream flow. The frequency of each category of repair (minor, moderate and major) for 225 OWTS obtained from Boulder County public health records was modeled as a function of climate factors using a generalized linear model with a Poisson distribution link function. The results show that prolonged precipitation patterns, with monthly rainfall >10.16 cm, influence OWTS fragility, and complete loss of OWTS functionality, requiring replacement, is impacted by high temperatures, frequency of wetter-than-normal months, and the magnitude of peak stream flow in the watershed. Weather-related covariates explained 70% of the variability in OWTS major repair data between 1979 and 2006. These results indicate that fragility arising from climate factors, and associated costs to owners, environmental and health impacts, should be considered in planning, design and operation of OWTS. PMID- 27997402 TI - The elimination of siloxanes from the biogas of a wastewater treatment plant by means of an adsorption process. AB - Siloxanes present in the biogas produced during anaerobic digestion in wastewater treatment plants (WWTPs) can damage the mechanism of cogeneration heat engines and obstruct the process of energy valorization. The objective of this research is to detect the presence of siloxanes in the biogas and evaluate a procedure for their elimination. A breakthrough curve of a synthetic decamethylcyclopentasiloxane on an experimental bed of activated carbon was modeled and the theoretical mathematical model of the adsorption process was adjusted. As a result, the constants of the model were obtained: the mass transfer constant, Henry's equilibrium constant, and the Eddy diffusion. The procedure developed allows the adsorption equilibrium of siloxanes on activated carbon to be predicted, and makes it possible to lay the basis for the design of an appropriate activated carbon module for the elimination of siloxanes in a WWTP. PMID- 27997403 TI - A comprehensive approach for diagnosing opportunities for improving the performance of a WWTP. AB - High quality services of wastewater treatment require a continuous assessment and improvement of the technical, environmental and economic performance. This paper demonstrates a comprehensive approach for benchmarking wastewater treatment plants (WWTPs), using performance indicators (PIs) and indices (PXs), in a 'plan do-check-act' cycle routine driven by objectives. The performance objectives herein illustrated were to diagnose the effectiveness and energy performance of an oxidation ditch WWTP. The PI and PX results demonstrated an effective and reliable oxidation ditch (good-excellent performance), and a non-reliable UV disinfection (unsatisfactory-excellent performance) related with influent transmittance and total suspended solids. The energy performance increased with the treated wastewater volume and was unsatisfactory below 50% of plant capacity utilization. The oxidation ditch aeration performed unsatisfactorily and represented 38% of the plant energy consumption. The results allowed diagnosing opportunities for improving the energy and economic performance considering the influent flows, temperature and concentrations, and for levering the WWTP performance to acceptable-good effectiveness, reliability and energy efficiency. Regarding the plant reliability for fecal coliforms, improvement of UV lamp maintenance and optimization of the UV dose applied and microscreen recommissioning were suggested. PMID- 27997404 TI - Removal of Hg(II) from aqueous solution using sodium humate as heavy metal capturing agent. AB - An environmental friendly and economic natural biopolymer-sodium humate (HA-Na) was used to capture Hg(II) from aqueous solutions, and the trapped Hg(II) (HA-Na Hg) was then removed by aluminium coagulation. The best Hg(II) capturing performance (90.60%) was observed under the following conditions: initial pH of 7.0, coagulation pH of 6.0, HA-Na dosage of 5.0 g L-1, Al2(SO4)3.18H2O dosage of 4.0 g L-1, initial Hg(II) concentration of 50 mg L-1 and capturing time of 30 min. The HA-Na compositions with the molecular weight beyond 70 kDa showed the most intense affinity toward Hg(II). The results showed that the reaction equilibrium was achieved within 10 min (pH 7.0), and could be well fitted by the pseudo-second-order kinetics model. The capturing process could be well described by the Langmuir isotherm model and the maximum capturing capacity of Hg(II) was high up to 9.80 mg g-1 at 298 K (pH 7.0). The Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis showed that the redox reaction between Hg(II) and HA-Na and the coordination reaction of carboxyl and hydroxy groups of HA-Na with Hg(II) were responsible for Hg(II) removal. The successive regeneration experiment showed that the capturing efficiency of humates for Hg(II) was maintained at about 51% after five capture regeneration recycles. PMID- 27997405 TI - Hurdles in the investigation of influent fractionation for measurement campaigns under diluted wastewater conditions. AB - Evaluating the performance of a wastewater treatment plant (WWTP) requires a good characterization of the biodegradable substrate entering the plant. As is generally acknowledged, the wastewater characteristics under rain or storm weather conditions vary significantly from dry weather conditions but this is rarely accounted for in modelling exercises. In order to address this defect, a measurement campaign was set up and samples were analysed using respirometric assays. In this paper, some hurdles regarding measurement campaigns under dilute wastewater conditions and a better exploration of the impact of using respirometric assays are described and discussed. The dependence of the heterotrophic yield on different substrates severely hampers the evaluation of the respirograms under dilute wastewater conditions. In addition, the low load conditions limit the application of the assays due to insufficient sensitivity of the experiment and uncontrolled oxygen inputs. The results clearly demonstrate the need for further research in order to allow for a proper evaluation of WWTP performance under rain and storm weather conditions. PMID- 27997406 TI - Ammonia removal from landfill leachate by struvite formation: an alarming concentration of phosphorus in the treated effluent. AB - This study examined the removal of ammonia nitrogen from the leachate of a landfill site using the chemical precipitation of struvite (MgNH4PO4.6H2O). This procedure achieved a reduction in the ammonia concentration that was higher than 99% when the molar ratio of 1.8:1.0:1.4 for Mg2+:NH4+:PO43- was adopted. The metal concentration found in the precipitate formed was lower than the limits set by Brazilian and American regulations (CONAMA 375/2006 and US EPA, 40 CFR 503.1993). This demonstrates the potential use for this practice in agriculture. However, the effluent obtained from the tests presented a phosphorus concentration higher than the one in the raw leachate. This shows that removing this compound from the effluent must be further studied. Otherwise, adopting the chemical precipitation of ammonia by the formation of struvite may become unfeasible. PMID- 27997407 TI - A black-box model for generation of site-specific WWTP influent quality data based on plant routine data. AB - This paper presents a simple method for the generation of continuous influent quality datasets for wastewater treatment plants (WWTPs) that is based on incomplete available routine data, only, without referring to any further measurement. In the approach, Weibull-distributed random data are fitted to the available routine data, such that the resulting distribution of influent quality data shows the identical statistical characteristics. Beside the description of the method, this paper contains a comprehensive analysis of robustness and universality of the approach. It is shown that incomplete datasets with only 10% remaining influent quality data can be filled with this method with nearly the same statistical parameters as the original data. In addition, the use with datasets of different WWTP plants sizes results always in a good agreement between original and filled datasets. PMID- 27997408 TI - Effective methods for extracting extracellular polymeric substances from Shewanella oneidensis MR-1. AB - Extracellular polymeric substances (EPS) play crucial roles in bio-aggregate formation and survival of bacterial cells. To develop an effective but harmless method for EPS extraction from Shewanella oneidensis MR-1, five extraction methods, i.e. centrifugation (control), heating (40, 45, 50, and 60 degrees C), and treatments with H2SO4, ethylenediaminetetraacetic acid (EDTA) and NaOH, were examined, respectively. Results from scanning electron microscope and flow cytometric analyses indicate that MR-1 cells were severely broken by H2SO4, NaOH and heating temperature >=45 degrees C. Proteins and polysaccharides in EPS extracted by heating at 40 degrees C were 7.12 and 1.60 mg g-1 dry cell, respectively. Although EDTA treatment had a relatively lower yield of EPS (proteins and polysaccharides yields of 5.15 and 1.30 mg g-1 dry cell, respectively), cell lysis was barely found after EPS extraction. Three peaks were identified from the three-dimensional excitation-emission matrix spectrum of each EPS sample, suggesting the presence of protein-like substances. Furthermore, the peak intensity was in good accordance with protein concentration measured by the chemical analysis. In short, heating (40 degrees C) and EDTA treatments were found the most suitable methods for EPS extraction considering the cell lysis and EPS content, composition and functional groups together. PMID- 27997409 TI - Eight Leadership Emergency Codes Worth Calling. AB - Hospitals have a contemporary opportunity to change themselves before attempting to transform the larger US health care system. However, actually implementing change is much more easily described than accomplished in practice. This article calls out 8 dysfunctional behaviors that compromise professional standards at the ground level of the hospital. The construct of calling a code when one witnesses such behaviors is intended to make it safe for leaders to "See something, say something" and confront them in real time. The coordinated continuum of services that health care reform seeks to attain will not emerge until individual hospital organizations prepare themselves to operate better in their own spaces and the ones that immediately surround them. PMID- 27997410 TI - Influence of nutrition therapy on the intestinal microbiome. AB - PURPOSE OF REVIEW: This review describes the relationship between nutritional therapies and the intestinal microbiome of critically ill patients. RECENT FINDINGS: The intestinal microbiome of the critically ill displays a near complete loss of health-promoting microbiota with overgrowth of virulent healthcare-associated pathogens. Early enteral nutrition within 24 h of admission to the ICU has been advocated in medical and surgical patients to avoid derangements of the intestinal epithelium and the microbiome associated with starvation. Contrary to previous dogma, permissive enteral underfeeding has recently been shown to have similar outcomes to full feeding in the critically ill, whereas overfeeding has been shown to be deleterious in those patients who are not malnourished at baseline. Randomized clinical trials suggest that peripheral nutrition can be used safely either as the sole or supplemental source of nutrition even during the early phases of critical care. The use of probiotics has been associated with a significant reduction in infectious complications in the critically ill without a notable mortality benefit. SUMMARY: Focus of research is shifting toward strategies that augment the intestinal environment to facilitate growth of beneficial microorganisms, strengthen colonization resistance, and maintain immune homeostasis. PMID- 27997411 TI - Research Priorities for Optimal Use of Patient-reported Outcomes in Quality and Outcome Improvement for Total Knee Arthroplasty. AB - The national Functional and Outcomes Research for Comparative Effectiveness in Total Joint Replacement program routinely collects pre- and postoperative patient reported outcomes for clinicians to use when making individual patient treatment decisions and monitoring aggregate quality of care and outcomes. When the pre post gains in pain or function at one site vary from the national norms, the next question is, "how do we improve?" This paper will use the traditional quality management's framework of inputs (patients), processes (clinical care), and outcomes to outline priority research questions to learn how clinicians, hospital managers, and patients can interpret patient-reported outcomes to improve total knee arthroplasty care and outcomes. In summary, research should identify best practices to minimize variation in a patient's health status before surgery, tailor peri-total knee arthroplasty care pathways to match individual patient risks to optimize safe care, and implement patient-reported measures to document optimal outcomes. PMID- 27997412 TI - How Can We Use Computational Modeling to Improve Total Knee Arthroplasty? Modeling Stability and Mobility in the Implanted Knee. AB - Validated computational models promise a virtual platform to create optimal articular surfaces that best achieve desired implant characteristics. Today, designers can parametrically define the primary geometric features of an implant, and automatically modify design variables until stability/mobility performance objectives are best achieved. This preclinical, virtual design iteration minimizes the development cycle compared with testing physical prototypes and, by evaluating a broader scope of design concepts, likely improves the clinical performance of the final product. However, the scenario described is not without shortcomings and requires thorough understanding of the capabilities and the limitations of the models used. Although models typically represent the articular interface well, the interaction with the patient and the surgical process includes significant variability and increase in complexity. We present current modeling capabilities for the estimation of implant stability/mobility, with further suggestions for answering the difficult question of how an implant might perform throughout the population. PMID- 27997413 TI - Joint Stability in Total Knee Arthroplasty: What Is the Target for a Stable Knee? AB - Instability remains a common cause of failure in total knee arthroplasty. Although approaches for surgical treatment of instability exist, the target for initial stability remains elusive, increasing the likelihood that failures will persist because adequate stability is not restored when performing the primary arthroplasty. Although the mechanisms that stabilize the knee joint-contact between the articular surfaces, ligamentous constraints, and muscle forces-are well-defined, their relative importance and the interplay among them throughout functions of daily living are poorly understood. The problem is exacerbated by the complex multiplanar motions that occur across the joint and the large variations in these motions across the population, suggesting that stability targets may need to be patient-specific. PMID- 27997414 TI - Biologic prosthetic aortic malfunction: is there a role for percutaneous treatment (transcatheter aortic valve implantation)? PMID- 27997415 TI - High-intensity focused ultrasound for focal therapy: reality or pitfall? AB - PURPOSE OF REVIEW: Progress in imaging, fusion software, and ablative modalities has fostered growth of the latest image-guided generation of high-intensity focused ultrasound (HIFU) for focal treatment of prostate cancer. Although early reports are encouraging, important questions remain regarding candidate selection, treatment, and outcomes. We review contemporary considerations for the use of HIFU for focal treatment of primary and radio-recurrent prostate cancer. RECENT FINDINGS: HIFU has been used to treat prostate cancer for over two decades. More recently, stage migration from screening and improvements in pelvic imaging and fusion technology has resulted in wider clinical application of focal HIFU as a first-line treatment for localized prostate cancer. Advanced imaging has also improved targeting for focal salvage therapy of radio-recurrent disease. Proponents point to the minimally invasive nature, limited morbidity profile, and ability to perform retreatments in the future. Critics emphasize positive post treatment biopsies, nonuniform treatment protocols, and absence of long-term follow-up. Thus, a review of clinical considerations and recently published data is warranted. SUMMARY: Recent advances have strengthened support for the use of focal HIFU. Although HIFU has great potential, it must be applied judiciously, maintaining appropriate oncologic principles in the setting of standardized trials to determine its true clinical value. PMID- 27997416 TI - Are Anemia and Hypotension Causally Related to Perioperative Ischemic Optic Neuropathy? PMID- 27997417 TI - 68Ga-DOTA Ubiquicidin PET/CT in an Infected Implant. AB - We describe the case of a 55-year-old man who presented with history of fever for 3 months that began 2 months after he had undergone open reduction and internal fixation of left humerus fracture. Implant infection was suspected, but conventional imaging remained unyielding. Ga-DOTA ubiquicidin PET/CT showed increased tracer uptake along the entire length of the implant in the left humerus. Implant removal and temporary external fixation were done. In 24 hours, the patient became afebrile, and blood culture on the fourth day was sterile. PMID- 27997418 TI - Unsuspected Metastatic Ovarian Cancer Revealed by 18F-NaF PET/CT Performed to Evaluate Lower-Back Pain. AB - A 59-year-old woman with back pain underwent an F-NaF PET/CT bone scan. Unexpectedly, multiple foci of increased tracer uptake were present in the abdomen and pelvis, which corresponded to the calcified soft tissue masses. The subsequent F-FDG PET/CT not only confirmed increased FDG activity in these partially calcified mass but also revealed abnormal activity in noncalcified lesions. The pathological examination demonstrated that the patient had ovarian cancer. PMID- 27997419 TI - Re: Radio-Guided Lymph Node Mapping in Bladder Cancer Using SPECT/CT and Intraoperative gamma-Probe Methods. PMID- 27997420 TI - Collar Osteophytes Mimicking Osteonecrosis in Planar Bone Scintigraphy and Usefulness of SPECT/CT Images. AB - The use of prednisolone is one major risk factor for osteonecrosis in patients with systemic lupus erythematosus. Bone scintigraphy can be a diagnostic tool for early diagnosis. We present a case who had collar osteophytes at the bilateral femoral heads, which mimicked osteonecrosis in the planar bone scintigram. An SPECT/CT scan avoided this pitfall and increased the diagnostic accuracy for osteonecrosis. PMID- 27997421 TI - Incidental Detection of Retiform Hemangioendothelioma by 68Ga DOTATOC PET/CT. AB - A 52-year-old man underwent Ga DOTATOC PET/CT scan for postsurgical staging of a neuroendocrine tumor of the lung. The PET images showed a single focus of increased activity in a soft tissue nodule located posteriorly to a cervical vertebra. Surgical removal of the lesion led to the histological diagnosis of retiform hemangioendothelioma. PMID- 27997422 TI - PSMA Expression in Tumor Neovasculature Endothelial Cells of Follicular Thyroid Adenoma as Identified by Molecular Imaging Using 68Ga-PSMA Ligand PET/CT. AB - The prostate-specific membrane antigen (PSMA) is expressed by both prostate cancer and other neoplasms. We report the case of a 65-year-old man with castration-resistant metastatic prostate cancer who underwent Ga-PSMA ligand PET/CT for restaging of disease. Ga-PSMA ligand accumulation was noted in a thyroid lesion, suspicious for thyroid malignancy on complementary ultrasound. Subsequent resection and histopathological analysis showed follicular thyroid adenoma with PSMA expression in tumor neovasculature endothelial cells, but not in thyroid epithelial cells. It is important to be aware that both malignant and benign thyroid neoplasms may show PSMA expression to avoid misinterpretation. PMID- 27997423 TI - Strong PSMA Radioligand Uptake by Rectal Carcinoma: Who Put the "S" in PSMA? AB - We present a case of a 71-year-old patient with newly diagnosed rectal adenocarcinoma and hepatic metastases. Restaging after chemotherapy revealed a good response of the rectal primary while liver metastases were progressive. As the patient also had a history of prostate cancer, a Ga-PSMA-HBED-CC PET/CT scan was performed to noninvasively further assess hepatic metastases. However, a definite differentiation between tumor entities was not possible because not only the liver metastases but also the rectal primary showed radioligand uptake (moderate and strong, respectively). Consecutive liver biopsy revealed a poorly differentiated adenocarcinoma of intestinal origin. PMID- 27997424 TI - Gastric Visualization in Dacryoscintigraphy: An Unequivocal Sign of Patent Nasolacrimal Duct. AB - We reported a 6-year-old girl with a history of left-eye epiphora since 2 years ago who was referred to our nuclear medicine center for dacryoscintigraphy imaging. The scan showed obstruction in the proximal portion of the nasolacrimal duct in the left eye. Imaging also showed patent nasolacrimal duct of the right eye. Tc pertechnetate activity was seen in the esophagus and stomach owing to swallowing of the excreted tracer in the nasal cavity. This was an unequivocal sign of patent lacrimal apparatus. PMID- 27997425 TI - Elevated MIBG Activity at the Site of Erythema of Unknown Etiology. AB - A 6-year-old boy underwent I-MIBG therapy for recurrent neuroblastoma. On posttherapy scan, there were new foci of increased MIBG activity in the anterior abdomen, which were not seen on pretherapy I-MIBG scan. Physical examination demonstrated that these new foci of activity corresponded to the sites of asymptomatic erythema, which had of unknown etiology and was spontaneously resolved without treatment. PMID- 27997426 TI - Subacute Cortical Infarct Showing Uptake on 68Ga-PSMA PET/CT. AB - Ga prostate-specific membrane antigen (PSMA) PET/CT is increasingly used to evaluate extent of disease in prostate carcinoma. We present a case of subacute cortical cerebral infarct showing focal uptake on PSMA PET/CT. It is an important potential cause of false-positive uptake in this imaging cohort. The patient is an 85-year-old man with a background of nonbacterial thrombotic endocarditis and previous cerebrovascular events. He was referred for PSMA PET/CT for staging of high-risk prostate cancer. PMID- 27997427 TI - Cat-Scratch Disease: A Pitfall for Lymphoma Evaluation by FDG-PET/CT. AB - FDG-PET/CT is a standard of care in staging and response assessment of Hodgkin lymphoma. Hence, it is important to recognize pitfalls owing to the potential therapeutic impact. We report a case of a 29-year-old woman affected by stage III bulky Hodgkin lymphoma. The interim FDG-PET/CT showed a complete metabolic response. After three new cycles of chemotherapy, the patient showed fever and lymphadenopathy at clinic examination, PET/CT revealed several FDG uptakes at lymph nodes in inguinal and iliac region. Pathologic analyses, after biopsy and serologic examinations, led to the diagnosis of cat-scratch disease. PMID- 27997428 TI - Quality and Safety in Health Care, Part XXI: PSOs and the Vascular Quality Initiative. AB - Congress provided for the formation of patient safety organizations (PSOs) so that physicians and other providers would come forward to improve the safety and quality of health care. Important legal safeguards for the providers and patients were put in place for PSOs. The Society for Vascular Surgery (SVS) PSO operates the Vascular Quality Initiative. The latter gathers information from certain commonly done vascular procedures. First, information is collected so a risk adjustment determination of each individual patient can be done. Then the details of every procedure are recorded for later analysis of the processes of the patient's care. In addition, outcome analysis from all procedures is carried out. This registry is an important source of data for research improving health care safety and quality. PMID- 27997429 TI - Combined 18F-FDG PET/CT and 68Ga DOTATATE PET/CT "Superscan" in Metastatic Pancreatic Neuroendocrine Tumor. AB - Metastatic neureoendocrine tumor to bone is well recognized. Typically, this has an appearance of multiple focal lesions. We present an example of diffuse skeletal involvement on both F-FDG PET/CT and Ga DOTATATE PET/CT with a pattern similar to the superscan appearance described on skeletal scintigraphy. PMID- 27997430 TI - FDG PET/CT in Carcinoma of the Tongue With Bilateral Adrenal Metastases. AB - Squamous cell carcinoma is the most common malignant neoplasm of the oral cavity, and it contributes approximately 90% of all oral malignancies. We present a case of a squamous cell carcinoma of the tongue with rare site of bilateral adrenal metastases on F-FDG PET/CT with response evaluation after chemotherapy. PMID- 27997432 TI - The Efficacy of Assisted Reproduction in Women with Inflammatory Bowel Disease and the Impact of Surgery-A Nationwide Cohort Study. AB - BACKGROUND: In this study, we analyze the chance of a live birth and the impact of inflammatory bowel disease surgery in women with Crohn's disease (CD) or ulcerative colitis (UC) who have undergone assisted reproductive technology (ART) treatments. METHODS: This is a nationwide cohort study based on the Danish health registries. We compare all women with and without CD or UC who received a first time ART treatment from January 1, 1994 to June 30, 2012 with follow-up until December 31, 2013. Our outcome was live birth per woman within 18 months after the first ART treatment. We adjusted for multiple covariates and looked specifically at CD and UC surgeries before ART. RESULTS: In all, 381 women with UC, 158 women with CD, and 50,321 women without inflammatory bowel disease received first time ART treatments. In women with UC, the adjusted odds ratio (OR) of a live birth was 0.82 (95% confidence interval [CI], 0.57-1.17). In women with CD, the adjusted OR of a live birth was 0.58 (95% CI, 0.32-1.03). In women with CD having previous CD surgery versus no CD surgery, the adjusted OR of a live birth was significantly decreased (0.29, 95% CI, 0.13-0.65). In women with UC with previous UC surgery, the similar OR was 0.81 (95% CI, 0.47-1.40). CONCLUSIONS: In women with CD surgery, the chance of a live birth within 18 months after initiation of ART treatment was significantly decreased. This knowledge should help patients make decisions regarding pregnancy planning. PMID- 27997431 TI - Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas. AB - Epigenetic modification of DNA, namely covalent changes of cytosine residues, plays a key role in the maintenance of inactive chromatin regions, both in health and in disease. In the vast majority of malignant melanomas, the most notable known epigenetic abnormality is the attenuation of 5-hydroxymethylcytosine (5 hmC) residues. However, it remains unknown whether a decrease in 5-hmC represents a primary defect of melanoma cancer epigenome or whether it is secondary to the loss of 5-methylcytosine (5-mC), a chemical substrate for 5-hmC. Here, we evaluated 5-mC levels in a spectrum of melanocytic proliferations. To study the epigenetic features of melanocytic nuclei, we began by measuring 5-mC levels in histologic specimens semiquantitatively by immunohistochemistry. We next treated established melanoma cell lines with S-adenosyl methionine (SAM), a universal methyl group donor, in an effort to cause changes in 5-mC levels. We detected a marked reduction in 5-mC levels in both primary and metastatic melanomas compared with 5-mC levels in benign melanocytic nevi. We also empirically induced changes in 5-mC in melanoma cell lines by incubation with SAM. To our surprise, we observed a significant cytoreductive effect of SAM on all melanoma cell lines examined. At subcytotoxic levels, SAM treatment is accompanied by a genome-wide increase in 5-mC. Moreover, we recorded a dose-dependent increase in genome-wide 5-mC levels in melanoma cell lines following SAM treatment. Taken together, we report that genome-wide attenuation of 5-mC is a hallmark of malignant melanomas. We propose that genome-wide attenuation of 5-mC is not merely an epiphenomenon as it is required for melanoma cell growth, albeit by an as of yet undetermined mechanism. Given its potential benefit in slowing down the growth of melanoma cells, SAM should be studied further to determine its role in epigenome modulation. PMID- 27997433 TI - Tuberculosis Screening and Reactivation Among a National Cohort of Patients with Inflammatory Bowel Disease Treated with Tumor Necrosis Factor Alpha Antagonists. AB - BACKGROUND: Tumor necrosis factor antagonists (anti-TNFs) are effective in treating inflammatory bowel disease (IBD) but may cause reactivation of tuberculosis (TB). TB screening rates and related outcomes are not well described among patients with IBD. This study aims to evaluate the prevalence and determinants of TB screening before anti-TNF initiation and related outcomes among patients with IBD. METHODS: We identified patients with IBD with filled prescriptions for anti-TNFs using the National Veterans Affairs administrative data sets. Determinants of TB screening were identified by univariate and multivariate analyses. Patients with TB reactivation were identified by ICD9 codes or prescriptions for isoniazid, and confirmed by chart review. RESULTS: A total of 3357 patients with IBD were identified with filled anti-TNF prescriptions. Approximately 72% to 86% of patients received TB screening. In multivariate analyses, patients in rural areas were less likely to be screened for TB compared with those in urban areas (odds ratio 0.72, 95% confidence ratio 0.54-0.95). Patients who received care at academically affiliated facilities were more likely to have received screening for TB (odds ratio 1.49, 95% confidence ratio 1.31-1.95). In 7210 patient-years of follow-up on anti-TNF, TB reactivation was confirmed in 2 patients, both of whom had a history and treatment of latent TB before anti-TNF initiation. CONCLUSIONS: TB screening before anti-TNF is estimated to be between 72% and 86%. Receipt of care at urban, academic affiliated, high-volume IBD facilities is associated with higher rates of screening. Reactivation of TB in a highly screened cohort is estimated to be 2.8 per 10,000 patient-years. PMID- 27997434 TI - The Crohn's and Colitis Foundation of America Survey of Inflammatory Bowel Disease Patient Health Care Access. AB - BACKGROUND: Despite anecdotal information about unaffordable care for patients with inflammatory bowel disease (IBD), there are no data regarding access to health care resources and expert care for patients with IBD. Our study was designed to assess IBD patients' ability to access and use care, as well as the timeliness, affordability, and financial stressors related to care. METHODS: We modified the Centers for Disease Control National Health Interview Survey for IBD. The resultant 59-question survey was electronically mailed to the entire Crohn's and Colitis Foundation of America (CCFA) mailing list. Three thousand six hundred eight adult U.S. respondents completed the survey. Statistical analysis was performed. RESULTS: Respondents who had insurance coverage were 96.1%, but 66.3% reported health care-related financial worry. Of the 452 patients who tried to obtain new insurance coverage in the year prior, 60.1% (n = 270) reported difficulty finding sufficient coverage. We found that 25.4% (n = 897) of patients reported delays in medical care, and 48.0% (n = 431) of those respondents reported that the delay was due to cost concerns. Respondents who were denied coverage by an insurance company were 55.3%. Risk factors for emergency department utilization included Crohn's disease, younger age, female sex, lower income, non-White race, and steroid therapy. CONCLUSIONS: Our assessment of patient health care access suggests that many patients have health care-related financial worry and have forgone a variety of medical services because of cost, lack of prompt access to care, denial by insurance carriers, and worry over medical coverage. We also identify risk factors for emergency department utilization. These data inform additional studies and interventions to improve access for patients with IBD. PMID- 27997435 TI - Risk of Surgery and Mortality in Elderly-onset Inflammatory Bowel Disease: A Population-based Cohort Study. AB - BACKGROUND: As the prevalence of inflammatory bowel disease (IBD) increases in the elderly population, we sought to characterize IBD-related outcomes in this population. METHODS: We identified incident IBD cases in Ontario, Canada between 1999 and 2008 and categorized subjects by age at diagnosis as young adults (18-40 yr); middle-age adults (41-64 yr); and elderly (>=65 yr) from within population based health administrative data. We determined the risk of IBD-related surgery and mortality in those with elderly-onset IBD compared with other age groups. RESULTS: Of 21,218 persons with IBD, there were 1749 cases of elderly-onset ulcerative colitis (UC) and 725 cases elderly-onset Crohn's disease (CD). Elderly UC had higher rates of IBD-related surgery than those with young-adult UC (adjusted hazard ratio, 1.34; 95% CI, 1.16-1.55), although there was no difference in surgical rates between age groups in CD. IBD-specific mortality was higher in elderly-onset CD (33.1/10,000 person-year) compared with that in middle age CD (5.6/10,000 person-year, P < 0.0001) and young adult CD (1.0/10,000 person year) but was not different by age in UC. The leading cause of death in elderly UC and CD was solid malignancies accounting for 22.9% and 26.4% of deaths, respectively, whereas IBD was third most frequent cause of death accounting for 6.3% and 9.1% of deaths, respectively. CONCLUSIONS: Elderly-onset patients with UC were more likely to undergo surgery while elderly-onset patients with CD exhibited higher IBD-specific mortality than those with younger-onset disease. These findings should prompt more optimized disease management in elderly IBD. PMID- 27997436 TI - Dihydromyricetin reverses MRP2-mediated MDR and enhances anticancer activity induced by oxaliplatin in colorectal cancer cells. AB - Dihydromyricetin (DMY), extracted from the Chinese herbal medicine Ampelopsis grossedentata, possesses antitumor potential in different types of human cancer cells. Hence, its effects on drug resistance and molecular mechanisms in colorectal cancer (CRC) are still unknown. In our present study, we observed that DMY enhanced the chemosensitivity to oxaliplatin (OXA). DMY increased OXA-induced apoptosis and reduced 5(6)-carboxy-2',7'-dichlorofluorescein accumulation in OXA resistant CRC HCT116/L-OHP cells. Our mechanistic study suggested that DMY treatment inhibited multidrug resistance protein 2 (MRP2) expression levels and promoter activity, indicating that DMY reduced not only MRP2 transcriptional and translational levels but also its function. Additional experiments indicated that the nuclear translocation of nuclear factor-erythroid 2 p45 related factor 2, a MRP2 regulator, was also inhibited by DMY. In summary, our study provided the first direct evidence that the inhibitory effects of DMY on MRP2 expression in OXA-resistant CRC cells were closely associated with the inhibition of nuclear factor-erythroid 2 p45 related factor 2 signaling. DMY could be a potential candidate for CRC chemotherapy. PMID- 27997437 TI - Association between adjuvant docetaxel-based chemotherapy and breast cancer related lymphedema. AB - Docetaxel-based chemotherapy can lead to fluid retention and secondary peripheral edema of the extremities, but its association with lymphedema remains unclear. In this study, we retrospectively investigated the relationship between adjuvant docetaxel-based chemotherapy and breast cancer-related lymphedema. Patients with stage II/III breast cancer who received adjuvant chemotherapy were evaluated for lymphedema on the basis of arm circumference measurements. The incidence and risk factors of lymphedema were determined by Kaplan-Meier and Cox proportional hazard analyses. A total of 320 patients were included. Specifically, 182 patients received docetaxel and 138 patients did not receive docetaxel. Compared with docetaxel-free chemotherapy, docetaxel-based chemotherapy significantly increased the 2.5-year cumulative incidence of all-grade lymphedema (19.91 vs. 32.09%; P=0.011), which was further verified in grade 1-2 (P=0.012), but not in grade 3 lymphedema (P=0.448). Similar results were found in a comparison between docetaxel and nontaxane, but not in a comparison between docetaxel and other taxanes. Multivariate analysis showed that docetaxel-based chemotherapy is an independent risk factor for both all-grade (hazard ratio=1.73; P=0.017) and grade 1-2 lymphedema (hazard ratio=1.87; P=0.022). In conclusion, adjuvant docetaxel based chemotherapy significantly increased the risk of breast cancer-related lymphedema. PMID- 27997438 TI - Diffusion-Weighted Imaging for Differentiating Uterine Leiomyosarcoma From Degenerated Leiomyoma. AB - PURPOSE: The study aimed to investigate magnetic resonance diffusion-weighted imaging (DWI) in the differentiation of uterine leiomyosarcoma (ULMS) from degenerated leiomyoma (DLM). METHODS: Sixteen patients with ULMSs and 26 patients with DLMs confirmed by surgery and pathology underwent conventional magnetic resonance imaging and DWI. The mean apparent diffusion coefficient (ADC) values of the 2 groups' tumors were measured and compared using an independent-sample t test (b = 0.1000 s/mm [ADC1]; b = 0.800 s/mm [ADC2], respectively). A receiver operating characteristic curve was used to evaluate the diagnostic performance of DWI in the differentiation of ULMS from DLM. Intraobserver and interobserver agreements were evaluated using an intraclass correlation coefficient and Bland Altman analysis. RESULTS: The mean ADC value in ULMSs (0.81 +/- 0.14 * 10mm/s [ADC1], 0.90 +/- 0.11 * 10mm/s [ADC2]) was significantly lower than that in DLMs (1.22 +/- 0.22 * 10mm/s [ADC1], 1.50 +/- 0.22 * 10mm/s [ADC2]) (P < 0.001, <0.001, respectively). The sensitivity, specificity, accuracy, and positive and negative predictive values for characterizing ULMS were 100%, 90%, 93%, and 83% and 100% [ADC1] and 100%, 93%, 96%, and 90% and 100% [ADC2]; respectively. Intraobserver and interobserver reproducibilities were excellent (intraclass correlation coefficient = 0.967-0.988; small variability and 95% limits of agreement). CONCLUSIONS: Diffusion-weighted imaging is helpful in differentiating ULMS from DLM. PMID- 27997439 TI - Structural and Functional Correlates of Myocardial T1 Mapping in 321 Patients With Hypertrophic Cardiomyopathy. AB - OBJECTIVE: The aim of this study was to evaluate the structural and functional correlates of T1 mapping in 321 patients with hypertrophic cardiomyopathy (HCM). METHODS: Three hundred twenty-one patients with HCM who underwent cardiac magnetic resonance from 2003 to 2013 were retrospectively identified from our institution's HCM registry. Left ventricular volume, function, late gadolinium enhancement (LGE), and Look-Locker T1 time were quantified. T1 time was normalized to blood pool to calculate T1 ratio. Correlations between LGE%, T1 ratio, and structural and functional features were performed using Pearson correlation coefficient. RESULTS: Late gadolinium enhancement showed stronger correlation with left ventricular mass index (r = 0.41, P < 0.001) compared with T1 ratio (r = -0.17, P = 0.004). Both LGE% and T1 ratio correlated with ejection fraction (r = -0.18 and P = 0.002 vs r = 0.21 and P < 0.001, respectively). E/e' showed correlation with LGE% but not with T1 ratio. CONCLUSIONS: Late gadolinium enhancement was more strongly correlated with the phenotypic expression of HCM compared with T1 ratio. PMID- 27997440 TI - Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging of Cervical Cancer With Different b-Values. AB - OBJECTIVE: The aims of this study were to evaluate the dependence of diffusion parameters on the b values adopted for intravoxel incoherent motion diffusion weighted magnetic resonance imaging and to investigate the application value of multiple diffusion parameters obtained from monoexponential and biexponential models in subjects with a normal cervix and in cervical cancer patients. METHODS: A total of 120 female patients with cervical cancer and 21 female control subjects with a normal cervix underwent diffusion-weighted magnetic resonance imaging with 13 b values (0-2000 s/mm) at 3 T. The standard apparent diffusion coefficient (Dst), diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were calculated by fitting with monoexponential and biexponential models at 2 different ranges of b values: 0 to 1000 and 0 to 2000 s/mm. A univariate analysis was performed to identify factors that could distinguish cervical carcinoma from normal cervical tissue. Parameters that correlated with the pathological grade and stage of cervical cancer were also evaluated. Receiver operating characteristic curves were used to evaluate the diagnostic efficiency of every parameter. RESULTS: All the tested parameters, except the D* of the 2 different ranges of b value groups, significantly differed between the patients with cervical carcinoma and control subjects (P < 0.01). D2000, Dst2000, and D1000 showed comparable diagnostic value, with an area under the curve of 0.923, 0.909, and 0.907, respectively. Dst2000, D2000, Dst1000, and D1000 differed significantly among the 3 degrees of cervical stromal infiltration depth (P < 0.05). CONCLUSIONS: D2000 and Dst2000 tended to outperform D1000 in terms of diagnostic efficiency, but there was no significant difference in their ability to differentiate cervical carcinoma from normal cervix. Cervical cancers with lower Dst and D values tended to have greater infiltration depth. PMID- 27997441 TI - Fatal Congenital Retroperitoneal Neuroblastoma Diagnosed by Fetal Magnetic Resonance Imaging. AB - Congenital extra-adrenal neuroblastoma is a rare condition, which typically has a favorable prognosis. We present a unique case of extra-adrenal retroperitoneal neuroblastoma diagnosed by fetal magnetic resonance imaging, which ultimately leads to fetal hydrops and neonatal death. PMID- 27997442 TI - Intrasession and Intersession Repeatability of Diffusion Tensor Imaging in Healthy Human Liver. AB - OBJECTIVE: The aim of this study was to evaluate the effect of signal to noise ratio (SNR) and number of gradient directions (NGD) on intra- and intersession repeatability of liver diffusion tensor imaging (DTI) metrics. METHODS: At each of 3 liver DTI scan sessions, liver diffusion was assessed in 5 healthy volunteers using a 6-direction DTI scan performed 9 separate times (ie, number of signal averages [NSA]). In addition, 4 combinations of NSA and NGD were acquired (NSA/NGD = 1/30, 3/10, 3/12, and 5/6) to determine the combined effect to DTI metrics, which was based on intersubject variability and intrasession (Vintra) and intersession (Vinter) repeatability. RESULTS: Intersubject variability was less than 20%, whereas Vintra and Vinter repeatability were less than 5% and less than 10%, respectfully. Vinter was not affected by the NGD used. Decreases in Vinter(FA), Vinter(lambda1), Vinter(RD), and Vinter(MD) were observed with increasing NSA, and hence SNR. CONCLUSION: Increased SNR may improve intrasession and intersession repeatability of liver DTI metrics. Scan repeatability was not influenced by NGD. PMID- 27997444 TI - Foreign Body Inside the Concha Bullosa. PMID- 27997443 TI - Automated Infarct Core Volumetry Within the Hypoperfused Tissue: Technical Implementation and Evaluation. AB - OBJECTIVE: The aim of this study was to develop a rapid and fully automatic infarct core and tissue at risk volumetry approach in acute ischemic stroke. METHODS: We evaluated an algorithm in which segmentation was restricted to 1 hemisphere and the potential lesion characterized on the basis of the perfusion parameter Tmax with a region-wise comparison of local histograms to its mirrored counterpart. RESULTS: We applied the "Tmax inside" method to 30 cases of a public data set with ground-truth segmentations for diffusion-weighted and perfusion magnetic resonance imaging. Lesions were robustly identified with significantly higher dice coefficients (apparent diffusion coefficient, 0.83 +/- 0.22; Tmax, 0.80 +/- 0.05, compared with 0.53 +/- 0.27 and 0.56 +/- 0.18) than for a global thresholding approach. CONCLUSIONS: The proposed "Tmax inside" method is superior to the commonly used global thresholding approach. Furthermore, the method allows evaluating changes in cerebral blood volume and blood flow by taking the counterpart in the healthy hemisphere as a patient-individual reference. PMID- 27997445 TI - Pyogenic Granuloma on the Upper Lip: A Rare Location. PMID- 27997446 TI - Single Z-Plasty Versus Double-Opposing Z-Plasty: A Cadaveric Study of Palatal Lengthening. AB - OBJECTIVE: The double-opposing Z-plasty is an effective method of repairing the cleft palate due to its reorientation of the palatal musculature and lengthening of the soft palate. A technique for lengthening the palate with a single oral Z plasty has also been described. The authors hypothesize that these 2 techniques have equivalent effects on palate length. METHODS: A cadaver study was performed. Ten fresh adult cadaver heads were used.All palates were divided in the midline. In 5 specimens, a modified double-opposing Z-plasty technique was used; 5 other specimens underwent an oral Z-plasty with a straight-line repair of the nasal mucosa. In both groups, the levator veli palatini muscles were separately dissected and reapproximated with an intravelar veloplasty. The velar length, defined in this study as the distance from the posterior nasal spine to the tip of uvula, was measured before and after the surgical procedure. RESULTS: The double-opposing Z-plasty produced a mean increase of 1.0 +/- 0.6 cm in velar length (P = 0.023). The single Z-plasty repair resulted in a mean gain of 1.1 +/- 0.3 cm (P = 0.001). There was no difference in change in palate length between the 2 procedures (P = 0.941), and no difference in the percentage of soft palate lengthening (24% vs 29%, respectively; P = 0.565). CONCLUSIONS: A single oral Z plasty provides palatal lengthening equivalent to that of a double-opposing Z plasty procedure. PMID- 27997447 TI - Combined Counterclockwise Maxillomandibular Advancement and Uvulopalatopharyngoplasty Surgeries for Severe Obstructive Sleep Apnea. AB - As the most effective surgical technique maxillomandibular advancement (MMA) has been used to treat severe obstructive sleep apnea (OSA) in adults, particularly for those who are intolerant of continuous positive airway pressure. Yet for large-scale advancement, it is faced with esthetic problems with marked skeletal protrusion especially for people with convex facial profile. In this study, the authors performed counterclockwise MMA combined with quantified uvulopalatopharyngoplasty (UPPP) surgeries on Chinese adult patients with severe OSA, in order to initially explore the efficacy of these procedures on Chinese populations and provide evidence for esthetic advantages. As the primary procedure counterclockwise MMA was applied on 10 patients, achieving a forward distance of the mandible and the maxilla for 10.6 and 6.7 mm, respectively, and the occlusion plane rotated counterclockwise of 6.2 degrees . After a follow-up of beyond 12 months, polysomnography results showed the apnea-hypopnea index (AHI) significantly decreased from 64.3 to 11.0 per hour, achieving surgical success of 90%. Upper airway measurements demonstrated that the retropalatal and retrolingual spaces got enlarged greatly, resulting in significant AHI reduction and oxygen saturation elevation. More importantly, cephalometric analysis revealed that SNA and SNB were enlarged but in well control without visual abnormalities. Follow-up results showed large-scale advancement of the maxilla and mandible were stable in treating severe OSA. Quantified UPPP surgeries guaranteed no functional insufficiency in pronouncing and swallowing and played auxiliary role in enlarging the upper airway. Thus, procedures of counterclockwise MMA combined with quantified UPPP surgeries might find more application especially in patients with severe OSA with convex facial profile in future. PMID- 27997448 TI - The Retroauricular Approach to the Facial Nerve Trunk. AB - BACKGROUND: Exposure of the common trunk of the facial nerve has traditionally been approached based on principles of parotidectomy, which is associated with high rates of facial nerve palsy and landmarks that may be unreliable. On the basis of experience gained with vascularized composite allotransplantation of the face, the authors propose a retroauricular approach that may be more time effective and safe. METHODS: In the proposed retroauricular facial nerve approach, an incision is made posterior to the ear in the retroauricular sulcus, and dissection proceeds anteriorly to the mastoid fascia to the base of the conchal bowl. The anteroinferior edge of the external auditory canal is followed as a reference structure to locate the facial nerve trunk (FNT), coursing between the stylomastoid foramen (posteromedially) and entering the parotid gland (anteriorly). Twelve unilateral FNT dissections were performed in 6 fresh human cadaver heads. Six dissections were performed for illustration and proof of concept using full facial transplant, conventional, and limited retroauricular exposures; 6 additional dissections were performed by trainees to assess reliability and replicability of technique. RESULTS: The FNT was successfully identified in all 12 dissections. Trainees tended toward being more time efficient in exploring the anatomy when using the limited retroauricular technique than with the conventional approach, 7.8 +/- 0.78 minutes versus 13.0 +/- 3.3 minutes (P = 0.089). No intraoperative injury to any critical structure was noted with either technique. CONCLUSION: A retroauricular approach to the FNT based on liberating anterior tissues from the auditory canal provides expedient and aesthetic exposure of the FNT. PMID- 27997449 TI - A Novel Method of Mild to Moderate Parry-Romberg Syndrome Reconstruction: Computer-Assisted Surgery With Mandibular Outer Cortex and Fat Grafting. AB - BACKGROUND: In patients with mild to moderate Parry-Romberg syndrome (PRS), plastic surgeons have mainly focused on the restoration of soft tissue deficiencies. While, bone deficits are easily overlooked. This study developed a new method combines the autologous mandibular outer cortex (MOC) grafting with fat grafting in mild to moderate patients with PRS, and apply computer-assisted techniques to improve the surgical outcomes and accuracy. METHODS: Seven patients with mild to moderate PRS were prospectively enrolled in the study. Preoperative and 7 days and 6 months postoperative computed tomography (CT) and photographs were performed. Computer-aided design was done based on preoperative CT data. Surgical templates for MOC harvesting and grafting were designed and printed out. The topographic map of fat grafting was generated. The accuracy of MOC bone grafting was evaluated by the MOC thickness relative error, the MOC thickness accuracy at the preop most severe bone atrophy point (preop MSBAP), and the MOC volume accuracy. The percentage volume maintenance of the fat grafting surgery was assessed. RESULTS: All 7 patients had ideal clinical outcomes with significant improvement in facial symmetry and no major complications happened. The average MOC thickness relative error is 2.85 +/- 0.50%. The average MOC thickness accuracy at the preop MSBAP is 3.36 +/- 1.13%. The average MOC volume accuracy is 3.41 +/- 1.37%. The average percentage volume maintenance of fat grafting is 62.79 +/- 5.73%. CONCLUSIONS: The combination of MOC grafting with fat grafting can be an excellent choice in reconstruction of mild to moderate patients with PRS. Applying computer-assisted techniques offers a reliable and accurate outcome. PMID- 27997450 TI - Acellular Dermal Matrix as an Adjunct Material in Cleft Le Fort I Osteotomies. AB - PURPOSE: To evaluate the use of acellular dermal matrix in the management of nasal lining deficiency at the time of Le Fort I osteotomy. METHODS: This was a retrospective cohort study of patients with residual/recurrent oronasal fistulae who underwent Le Fort I osteotomy. In instances where there was an inadequate volume of nasal mucosa for tension-free closure or for defects >1 cm in width, the acellular dermal matrix was used for augmentation. Demographic and cleft related factors were recorded. Complications (recurrent fistula, infection, seroma, and wound dehiscence) were recorded. RESULTS: Over the 3-year period, the authors used acellular dermal matrix to augment nasal lining in 8 subjects. The sample's mean age was 18.7 +/- 3.1 years; 5 subjects were male. Six patients had bilateral cleft defects. The mean follow-up time was 20.2 +/- 3.2 years. There were no episodes of infection, seroma, wound dehiscence, or recurrent fistula. CONCLUSION: Acellular dermal matrix is a useful adjunct for managing nasal liningdeficiency at the time of Le Fort I osteotomy. There were no episodes of bone graft extrusion, infection, tooth loss, or bone graft loss. The Enemark scores improved significantly across both subsets (P <0.001). There was 1 recurrent fistula in the allograft bone alone group.Residual alveolar clefts and oronasal fistulae can be successfully managed at the time of Le Fort I osteotomy using allograft bone and acellular dermal matrix. PMID- 27997451 TI - Effect of Submucosal Mesna Application on Mucoperichondrial Elevation in Septoplasty. AB - OBJECTIVE: It was revealed that the thiol compound named mesna chemically softens the connective tissue with submucosal injection, and facilitates the endoscopic submucosal dissection. The authors aimed to investigate the effect of mesna injection on mucoperichondrial elevation during septoplasty operation. METHODS: This study was planned as a patient-control study and performed. Fifty-six patients who had septoplasty operation were divided into 2 groups that are submucosal mesna (group 1) and submucosal saline (group 2) applied ones. In both groups, the measurement was initiated by a timer during the start of septal incision and elevation processes. After bilateral subperichondrial and subperiostal elevation were finished, timer was stopped and time was recorded. After that, mucosal integrity was reviewed and mucosal damage status was recorded. The difficulty of mucoperichondrial elevation for the surgeon was recorded for each patient. RESULTS: Twenty-five (44.7%) of the patients who participated in our study were females while 31 (55.3%) were males. The average elevation periods were 201.4 +/- 74.3 seconds in group 1 and 260.2 +/- 84.1 seconds in group 2. In mesna applied patients, elevation period was statistically and significantly shorter (P = 0.009). Impairment in mucosal integrity was observed as 33.3% in group 1 and 58.8% in group 2. In mesna applied patients, significantly less impairment in mucosal integrity was observed (P = 0.031). The average mucoperichondrial elevation difficulty for the surgeon is observed as 4.83 +/- 2.47 in group 1 and 6.5 +/- 1.9 in group 2. Mesna applied patients were defined as significantly easier patients for the surgeon (P = 0.006). CONCLUSION: Submucosal mesna application is an approach that provides a convenient, fast, and effective mucoperichondrial elevation in septoplasty and protects the mucosal integrity. PMID- 27997453 TI - Editorial: no health without cognitive health. PMID- 27997452 TI - Effect of Tapentadol on Splenic Cytokine Production in Mice. AB - BACKGROUND: Opioid drugs affect immunity, but not all opioid drugs share the same immunomodulatory properties. Tapentadol is an analgesic drug with a dual synergistic mechanism of action: u-opioid receptor agonism and noradrenaline reuptake inhibition. Weaker u-opioid receptor agonism combined with noradrenaline reuptake inhibition results in potent analgesia with reduced opioid side effects. We evaluated the impact of tapentadol on splenic cytokine in normal and in hyperalgesia/allodynia mice, comparing it with morphine and reboxetine, a noradrenaline reuptake inhibitor. METHODS: Tapentadol, reboxetine, and morphine were injected subcutaneously into naive and mice that underwent sciatic nerve chronic constriction injury, and their effect on splenic cytokines (interferon gamma [IFN-gamma], interleukin [IL]-2, IL-10, and IL-4) was measured by enzyme linked immunosorbent assay after acute or chronic treatment. Nociceptive thresholds, thermal hyperalgesia, and allodynia also were assessed. Data were analyzed with 2-way analysis of variance (behavior) or 1-way analysis of variance (cytokines) followed by Bonferroni post hoc test. RESULTS: Primary outcomes of our study were the effects of drugs on splenic cytokines. Our data indicate that acute tapentadol did not modify cytokine production in comparison with animals that received saline, whereas morphine suppressed all the cytokines: saline versus morphine 10 mg/kg (mean difference [MD], 95% confidence interval [CI]: IFN gamma = 12,400 [7760, 17,040], P < .001; IL-2 = 216.2 [47.69, 384.7], P < .01; IL 10 = 868 [523.7, 1212], P < .001; and IL-4 = 17.26 [10.32, 24.20], P < .001). A significant difference also was present between morphine and tapentadol (morphine 10 mg/kg versus tapentadol 20 mg/kg: MD [95% CI]: IFN-gamma = -11,600 [-16,240, 6960], P < .001; IL-2 = -334.2 [-502.7, -165.7], P < .001; IL-10 = -959 [-1303, 614.7], P < .001; IL-4 = -18.66 [-25.60, -11.72], P < .001). When chronically injected for 7 days, tapentadol and reboxetine did not significantly affect cytokines when compared with saline-treated animals. The immunoprofile of tapentadol was different from that of morphine also in mice that were in a condition of neuropathic pain. All cytokines appeared significantly decreased in mice that received a chronic constriction injury in comparison with sham animals but, after 7 days of treatment, with a similar antihyperalgesic profile, IL-10 and IL-4 were significantly increased in tapentadol and reboxetine animals in comparison with morphine mice (morphine versus tapentadol: MD [95% CI], IL-10 = 926.4 [-1664, -188.5], P < .01; IL-4 = -8.15 [-12.46, -3.84], P < .001). CONCLUSIONS: Acute and chronic tapentadol seem to be protective of splenic cytokines in contrast with morphine, which exerts a generalized suppression on all cytokines. PMID- 27997454 TI - 'Dementia-friendly communities' and being dementia friendly in healthcare settings. AB - PURPOSE OF REVIEW: This review discusses the concept of 'dementia-friendly communities' and summarizes the latest research and practice around such communities. This review also highlights important topic areas to be considered to promote dementia friendliness in healthcare settings. RECENT FINDINGS: Definitions of 'dementia-friendly communities' reflect the contemporary thinking of living with dementia (e.g., dementia as a disability, equal human rights, a sense of meaning). Existing research has covered a wide range of topic areas relevant to 'dementia-friendly communities'. However, these studies remain qualitative and exploratory by nature and do not evaluate how dementia-friendly communities impact health and quality of life of people living with dementia and their caregivers. In healthcare settings, being dementia friendly can mean the inclusion of people with dementia in treatment discussion and decision-making, as well as the provision of first, adequate and appropriate service to people with dementia at an equivalent standard of any patient, second, person-centered care, and third, a physical environment following dementia-friendly design guidelines. SUMMARY: Research incorporating more robust study designs to evaluate dementia friendly communities is needed. Being dementia-friendly in healthcare settings requires improvement in multiple areas - some may be achieved by environmental modifications while others may be improved by staff education. PMID- 27997456 TI - Accelerating Research Impact in a Learning Health Care System: VA's Quality Enhancement Research Initiative in the Choice Act Era. AB - BACKGROUND: Since 1998, the Veterans Health Administration (VHA) Quality Enhancement Research Initiative (QUERI) has supported more rapid implementation of research into clinical practice. OBJECTIVES: With the passage of the Veterans Access, Choice and Accountability Act of 2014 (Choice Act), QUERI further evolved to support VHA's transformation into a Learning Health Care System by aligning science with clinical priority goals based on a strategic planning process and alignment of funding priorities with updated VHA priority goals in response to the Choice Act. DESIGN: QUERI updated its strategic goals in response to independent assessments mandated by the Choice Act that recommended VHA reduce variation in care by providing a clear path to implement best practices. Specifically, QUERI updated its application process to ensure its centers (Programs) focus on cross-cutting VHA priorities and specify roadmaps for implementation of research-informed practices across different settings. QUERI also increased funding for scientific evaluations of the Choice Act and other policies in response to Commission on Care recommendations. RESULTS: QUERI's national network of Programs deploys effective practices using implementation strategies across different settings. QUERI Choice Act evaluations informed the law's further implementation, setting the stage for additional rigorous national evaluations of other VHA programs and policies including community provider networks. CONCLUSIONS: Grounded in implementation science and evidence-based policy, QUERI serves as an example of how to operationalize core components of a Learning Health Care System, notably through rigorous evaluation and scientific testing of implementation strategies to ultimately reduce variation in quality and improve overall population health. PMID- 27997457 TI - Outcomes From the First 6 Years of Operation of the Central Portugal Pharmacovigilance Unit. AB - OBJECTIVES: The aim of this study was to analyze and characterize the outcomes of the Central Portugal Regional Pharmacovigilance Unit over a 6-year period. METHODS: Spontaneous reports received between January 2009 and December 2014 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, reporting professional, pharmacotherapeutic groups of the suspected drugs, and type of adverse drug reactions most frequently reported. RESULTS: The Pharmacovigilance Unit received 1277 reports that contained 3222 adverse events. In 2014, the reporting rate was estimated at 124 reports per million inhabitants. Sixty-five percent of the reports were assessed as serious. Seventy-three percent of the cases were assessed as being at least possibly related with the suspected drug. Physicians reported 49% of the cases. The suspected drugs most frequently reported were "anti-infectives for systemic use" (n = 494, 38%). The most frequently reported adverse events were "general disorders and administration site conditions" (n = 667, 21%). CONCLUSIONS: Despite the continuous efforts carried out by the Central Portugal Regional Pharmacovigilance Unit in promoting spontaneous reports of suspected adverse drug reactions, the results, although representing a contribution to the postmarketing safety monitoring of drugs, are still modest illustrating the need to promote the adherence of health-care professionals to the pharmacovigilance system and to increase their reporting rates of suspected ADRs. PMID- 27997455 TI - Cervical Cancer Screening With Human Papillomavirus DNA and Cytology in Japan. AB - OBJECTIVE: The aim of this study was to determine the value of human papillomavirus (HPV) testing for primary cervical cancer screening in Japan. METHODS: In total, 5065 women who underwent primary screening with cytology and HPV between January 2005 and December 2006 were enrolled. In the baseline phase, these women were stratified by age, and the rates of HPV-positive and abnormal cytology were compared between women younger than and older than 30 years. In the follow-up phase, women aged 20 to 69 years and cytology negative for intraepithelial lesions or malignancy at baseline were followed up until December 2011 (n = 2383). Progression to grade 2/3 cervical intraepithelial neoplasia or worse (CIN2+/CIN3+) was compared between the HPV-positive and HPV-negative groups. RESULTS: In the baseline phase, HPV-positive rates were significantly higher in women younger than 30 years at 20.7% (95% confidence interval [CI], 18.4-22.9; 255/1234) compared with women 30 years or older at 7.2% (95% CI, 6.4% 8.0%; 275/3831; P < 0.001). However, there was no statistical difference for high grade squamous intraepithelial lesion or worse rates between them, at 2.7% (95% CI, 1.8%-3.6%; 33/1234) and 2.4% (95% CI, 1.9%-2.9%; 91/3831), respectively, P = 0.55. In the follow-up phase, the rate of progression to CIN2+/CIN3+ was significantly higher in the HPV-positive group than in the HPV-negative group (P < 0.001). Moreover, relative risk of progression to CIN2+ was 15.9 times higher in the HPV-positive group, and that of progression to CIN3+ was 16.1 times higher in the HPV-positive group. CONCLUSIONS: Human papillomavirus testing is a useful test for predicting progression to CIN and is recommended as a primary screening tool. However, screening with cytology alone is still appropriate for younger women, younger than 30 years, because HPV testing yields more false-positive results in younger women. PMID- 27997458 TI - ACUTE RETINAL NECROSIS AFTER ADMINISTRATION OF ADALIMUMAB, A SYSTEMIC ANTITUMOR NECROSIS FACTOR ANTIBODY. AB - PURPOSE: To report a case of acute retinal necrosis in a patient on anti-tumor necrosis factor alpha immunosuppressive therapy. METHODS: Case report. RESULTS: A 47-year-old man with psoriasis presented with blurred vision and floaters in the left eye 4 days after receiving his fourth dose of adalimumab, a tumor necrosis factor alpha antagonist. He was diagnosed with acute retinal necrosis and was treated with intravenous acyclovir as well as prophylactic laser barricade. Seven years later, he is 20/20 with no history of a retinal detachment. CONCLUSION: Physicians prescribing tumor necrosis factor alpha antagonist immunosuppressive therapy should be aware of the potential of developing acute retinal necrosis. PMID- 27997460 TI - RETINAL CASES & BRIEF REPORTS 2016 Scientific Reviewers. PMID- 27997459 TI - SHORT-TERM FINDINGS ON OPTICAL COHERENCE TOMOGRAPHY AND MICROPERIMETRY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY PATIENTS TREATED WITH HALF-DOSE PHOTODYNAMIC THERAPY. AB - PURPOSE: To assess the short-term outcome of and possible temporary vision loss after half-dose verteporfin photodynamic therapy (PDT) in patients with chronic central serous chorioretinopathy (cCSC). METHODS: In this prospective study, 14 eyes of 13 cCSC patients who underwent half-dose PDT were included. Patients received spectral-domain optical coherence tomography (OCT) imaging and microperimetry before PDT on the day of treatment and 1 week after treatment. RESULTS: Five patients (38%) reported worsening of visual complaints in the week after half-dose PDT. No significant changes in both central foveal thickness, height of subretinal fluid, and choroidal thickness on optical coherence tomography imaging and retinal sensitivity on microperimetry were observed, neither in the patients who did not experience worsening of visual symptoms, nor in those who did. CONCLUSION: Worsening of visual complaints can occur in a noteworthy number of cCSC patients in the first week after half-dose verteporfin PDT. Despite the fact that no significant short-term changes on both optical coherence tomography and microperimetry have been detected in this study, the assessment could be of importance for the long-term outcome of treatment and needs further investigation. PMID- 27997462 TI - Customized Minimally Invasive Orbital Decompression Surgery Improves Lower Eyelid Retraction and Contour in Thyroid Eye Disease. AB - PURPOSE: To investigate the outcome of a customized approach with targeted zygomatic basin bone removal orbital decompression in lower eyelid retraction and contour of patients with thyroid eye disease. METHODS: In a comparative case series, clinical charts and photos of a consecutive sample of 92 patients with thyroid eye disease submitted to different types orbital decompression were studied. Exophthalmos, midpupil to lower eyelid margin distances (MRD2) at 11 meridians, and globe position were measured and compared according to the types of decompression. Each eyelid was also labeled as within or outside normal limits regarding both contour pattern analysis and MRD2 compared with a control normal range. Eyelid contour and globe position from patients with orbital decompression with zygomatic basin removal were compared with those without basin removal. RESULTS: A total of 105 orbits from 57 patients met the study inclusion criteria. Ninety-eight orbits had lateral orbital wall decompression and in 53% of these cases, bone in the zygomatic basin was removed. Removal of the zygomatic basin did not significantly enhance decrease in proptosis, but significantly induced vertical globe descent and improved MRD2 (p < 0.05). Preoperatively, 37% of the eyelids were in the normal MRD2 range and 18% within the normal contour range. Preoperatively, 77% had normal MRD2 and 55% normal contour range. CONCLUSIONS: Our study findings support the practical utility of incorporating a customized approach to orbital decompression, and suggest that an individualized approach with targeted bone removal may obviate the need for additional surgeries such as lower eyelid retraction repair. PMID- 27997461 TI - Proboscis Lateralis. PMID- 27997463 TI - Outcomes of Endoscopic Dacryocystorhinostomy in Secondary Acquired Nasolacrimal Duct Obstruction: A Case-Control Study. AB - INTRODUCTION: Secondary acquired nasolacrimal duct obstruction (SANDO), where the obstruction is caused by a known process, is becoming more commonly treated by endoscopic dacryocystorhinostomy (endoDCR). This study evaluates outcomes of endoDCR for cases of SANDO in comparison to endoDCR outcomes treating primary acquired nasolacrimal duct obstruction (PANDO). METHODS: All patients undergoing endoDCR from 2006 to 2015 at a tertiary referral center were reviewed for etiology of nasolacrimal duct obstruction (NLDO) and success of procedure. Inclusion criteria were preoperative determination of NLDO via probing and irrigation, greater than 60-day follow up with assessment of duct patency via probing and irrigation after silicone tube removal, and postoperative survey for recurrent epiphora. Exclusion criteria were cases treating partial NLDO, patients undergoing concurrent conjunctivodacryocystorhinostomy, and patients lost to follow up or with incomplete records. Preanalysis stratification was performed for the following preexisting conditions: PANDO, granulomatosis with polyangiitis, sarcoidosis, midfacial radiotherapy, radioactive iodine therapy, severe prolonged sinusitis, prior failed DCR, and midface trauma. The primary outcome was postoperative anatomical patency of the nasolacrimal system with resolution of epiphora. Fisher-Freeman-Halton exact tests were performed comparing each SANDO group to the PANDO group with statistical significance set at p < 0.05. RESULTS: Fifty-nine cases of NLDO underwent endoDCR in this series, 21 of which had a diagnosis consistent with SANDO. All patients treated with the aggressive perioperative management protocol the authors describe achieved anatomical patency. Patients with history of radioactive iodine therapy and radiotherapy had statistically worse outcomes compared with patients with PANDO, p = 0.011, p = 0.045, respectively. Stratified groups with increased intranasal sinus inflammation trended toward worse outcomes, but were not statistically different. CONCLUSIONS: EndoDCR is a viable approach for the treatment of SANDO. In patients with history of radiotherapy or radioactive iodine therapy, however, endoDCR demonstrated decreased success rates as compared with patients with PANDO. Modifications of operative and postoperative management based on underlying etiology of NLDO may improve outcomes of endoDCR in SANDO cases. The authors describe an aggressive protocol for perioperative management of patients with pathologic nasal inflammation undergoing endoDCR. PMID- 27997464 TI - Evaluation of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) Fellowship Program Website Content and Quality. AB - PURPOSE: The qualities that applicants value in the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) fellowship programs have been studied, but the availability of this information on program websites has not yet been reviewed. The authors evaluated the availability of resident-valued ASOPRS fellowship program information on the Internet. METHODS: The authors performed an Internet search of the 53 ASOPRS fellowship program websites and evaluated websites for 20 characteristics of interest to ASOPRS fellowship applicants such as teaching faculty, program description, rotation schedule, operative cases, and interview information. RESULTS: Of the 53 ASOPRS fellowship programs, 43 (81.1%) had a fellowship program-dedicated website. The fellowship websites contained a mean 7.6 characteristics (38.1%, range 0-15). Faculty listing, program description, and case diversity were the most commonly included data (74.4%, 72.1%, and 69.8%, respectively). Fellow selection process, interview information, and graduate job placement were least commonly included (7.0%, 2.3%, and 0.0%, respectively). There was no significant difference in website inclusiveness based on fellowship region or faculty number. Programs affiliated with an ophthalmology residency were more complete than those that were not (40.3% vs. 20.0%, p = 0.0098). CONCLUSIONS: This review found that most programs had websites and contained a reasonable number of characteristics. However, applicant-valued information regarding surgical volume, procedure variety, application information, and postgraduate employment history were often missing. American Society of Ophthalmic Plastic and Reconstructive Surgery fellowship programs may improve match outcomes by providing and enhancing program websites with details that their applicants seek. PMID- 27997465 TI - Does Lumbopelvic Fixation Add Stability? A Cadaveric Biomechanical Analysis of an Unstable Pelvic Fracture Model. AB - OBJECTIVE: We sought to determine the role of lumbopelvic fixation (LPF) in the treatment of zone II sacral fractures with varying levels of sacral comminution combined with anterior pelvic ring (PR) instability. We also sought to determine the proximal extent of LPF necessary for adequate stabilization and the role of LPF in complex sacral fractures when only 1 transiliac-transsacral (TI-TS) screw is feasible. MATERIALS AND METHODS: Fifteen L4 to pelvis fresh-frozen cadaveric specimens were tested intact in flexion-extension (FE) and axial rotation (AR) in a bilateral stance gliding hip model. Two comminution severities were simulated through the sacral foramen using an oscillating saw, with either a single vertical fracture (small gap, 1 mm) or 2 vertical fractures 10 mm apart with the intermediary bone removed (large gap). We assessed sacral fracture zone (SZ), PR, and total lumbopelvic (TL) stability during FE and AR. The following variables were tested: (1) presence of transverse cross-connector, (2) presence of anterior plate, (3) extent of LPF (L4 vs. L5), (4) fracture gap size (small vs. large), (5) number of TI-TS screws (1 vs. 2). RESULTS: The transverse cross-connector and anterior plate significantly increased PR stability during AR (P = 0.02 and P = 0.01, respectively). Increased sacral comminution significantly affected SZ stability during FE (P = 0.01). Two versus 1 TI-TS screw in a large-gap model significantly affected TL stability (P = 0.04) and trended toward increased SZ stabilization during FE (P = 0.08). Addition of LPF (L4 and L5) significantly improved SZ and TL stability during AR and FE (P < 0.05). LPF in combination with TI-TS screws resulted in the least amount of motion across all 3 zones (SZ, PR, and TL) compared with all other constructs in both small-gap and large-gap models. CONCLUSIONS: The role of LPF in the treatment of complex sacral fractures is supported, especially in the setting of sacral comminution. LPF with proximal fixation at L4 in a hybrid approach might be needed in highly comminuted cases and when only 1 TI-TS screw is feasible to obtain maximum biomechanical support across the fracture zone. PMID- 27997466 TI - Prevalence of Depression and Posttraumatic Stress Disorder After Acute Orthopaedic Trauma: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This study aims to systematically assess the existing literature and to derive a pooled estimate of the prevalence of depression and posttraumatic stress disorder (PTSD) in adult patients after acute orthopaedic trauma. DATA SOURCES: A comprehensive search of databases, including MEDLINE, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials databases was conducted through June 2015. STUDY SELECTION: We included studies that assessed the prevalence of depression or PTSD in patients who experienced acute orthopaedic trauma to the appendicular skeleton or pelvis. Studies with a sample size of <=10 were excluded. DATA EXTRACTION: Two authors independently extracted data from the selected studies and the data collected were compared with verify agreement. DATA SYNTHESIS: Twenty-seven studies and 7109 subjects were included in the analysis. Using a random-effects model, the weighted pooled prevalence of depression was 32.6% (95% CI, 25.0%-41.2%) and the weighted pooled prevalence of PTSD was 26.6% (95% CI, 19.0%-35.9%). Six studies evaluated the prevalence of both depression and PTSD in patients with acute orthopaedic injuries. The weighted pooled prevalence of both depression and PTSD for those patients was 16.8% (95% CI, 9.0%-29.4%). CONCLUSIONS: Nearly one-third of patients suffer from depression and more than one-quarter of patients suffer from PTSD after an acute orthopaedic injury suggesting that strategies to address both the mental and physical rehabilitation after an orthopaedic injury should be considered to optimize patient recovery. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27997467 TI - Functional Outcomes of Operative Management of Scapula Fractures in a Geriatric Cohort. AB - OBJECTIVES: To analyze functional outcomes, motion, and strength in patients 65 years of age and older who underwent operative management of a scapula fracture. DESIGN: Retrospective review of prospective database. SETTING: A single level-1 teaching trauma center. PATIENTS/PARTICIPANTS: Two hundred fifty patients with scapula fractures were operated between January 2002 and March 2014. A review identified 16 geriatric patients 65 years of age and older. INTERVENTION: All patients underwent operative treatment of a scapular fracture. MAIN OUTCOME MEASUREMENTS: Disabilities of the Arm, Shoulder, and Hand (DASH), Short-Form Health Survey versions 1 and 2 (SF-36), Range of Motion (ROM), and Strength assessment at final follow-up 1 year or greater. RESULTS: Outcomes were attained on 15/16 patients at a mean follow-up of 40 months (range = 12-114). All fractures were united. Three patients experienced minor perioperative complications (temporary delirium in 2 patients, urinary tract infection in 1). One patient required subsequent removal of an intraarticular screw, and 1 patient required resection of heterotopic ossification and requested implant removal. The mean ROM expressed as a percent of contralateral ROM ranged from 78% to 96%. The mean strength expressed as a percent of contralateral strength ranged from 76% to 92%. The mean DASH score was 8.4. SF-36 scores were comparable with the normal population. All patients returned to activities. CONCLUSIONS: Operative treatment for displaced fractures in patients 65 years of age and older is safe and can yield good functional results and return to function. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27997468 TI - Locking Compression Pilon Plate for Fixation of Comminuted Posterior Wall Acetabular Fractures: A Novel Technique. AB - Posterior wall acetabular fractures involving a large portion the wall's width and with extensive comminution are difficult fractures to manage operatively. Cortical substitution with a pelvic reconstruction plate and supplemental spring plates has been the traditional means of fixation for these fractures. This option, however, requires the use of multiple, unlinked plates and provides no reliable option for peripheral fixation in comminuted fragments. We describe a novel technique for operative fixation of large, comminuted posterior wall fractures using a single distal tibia pilon plate with the option for peripheral locking screw fixation and report on a series of 20 consecutive patients treated with this method. PMID- 27997469 TI - Imaging of the Postsurgical Thoracic Aorta: A State-of-the-Art Review. AB - Techniques for repair of the aorta currently include open and endovascular methods, hybrid approaches, minimally-invasive techniques, and aortic branch vessel reimplantation or bypass. Collaboration among radiologists and vascular and cardiothoracic surgeons is essential. An awareness of the various surgical techniques, expected postoperative appearance, and potential complications is essential for radiologists. This review will cover the postoperative appearance of the thoracic aorta with a focus on the ascending aorta. The value of three dimensional image evaluation will also be emphasized. PMID- 27997470 TI - Oncological Outcomes After Robotic Proctectomy for Rectal Cancer: Analysis of a Prospective Database. AB - OBJECTIVE: The aim of this study is to evaluate the oncological outcomes of robotic total mesorectal excision (TME) at an NCI designated cancer center. SUMMARY BACKGROUND DATA: The effectiveness of laparoscopic TME could not be established, but the robotic-assisted approach may hold some promise, with improved visualization and ergonomics for pelvic dissection. Oncological outcome data is presently lacking. METHODS: Patients who underwent total mesorectal excision or tumor-specific mesorectal excision for rectal cancer between April 2009 and April 2016 via a robotic approach were identified from a prospective single-institution database. The circumferential resection margin (CRM), distal resection margin, and TME completeness rates were determined. Kaplan-Meier analysis of disease-free survival and overall survival was performed for all patients treated with curative intent. RESULTS: A total of 276 patients underwent robotic proctectomy during the study period. Robotic surgery was performed initially by 1 surgeon with 3 additional surgeons progressively transitioning from open to robotic during the study period with annual increase in the total number of cases performed robotically. Seven patients had involved circumferential resection margins (2.5%), and there were no positive distal or proximal resection margins. One hundred eighty-six patients had TME quality assessed, and only 1 patient (0.5%) had an incomplete TME. Eighty-three patients were followed up for a minimum of 3 years, with a local recurrence rate of 2.4%, and a distant recurrence rate of 16.9%. Five-year disease-free survival on Kaplan Meier analysis was 82%, and 5-year overall survival was 87%. CONCLUSIONS: Robotic proctectomy for rectal cancer can be performed with good short and medium term oncological outcomes in selected patients. PMID- 27997471 TI - Rate of Acute Hospital Admissions Before and After Roux-en-Y Gastric Bypass Surgery: A Population-based Cohort Study. AB - OBJECTIVE: To examine rates of acute inpatient hospital admissions patients undergoing Roux-en-Y gastric bypass (RYGB) surgery and a matched population-based comparison cohort. SUMMARY BACKGROUND DATA: Little is known about the admission rates before and after RYGB. METHODS: Nationwide population-based cohort study, including all 9985 patients undergoing RYGB in Denmark during 2006 to 2010, and 247,375 matched general population comparisons. We calculated cumulative incidence of surgical complications after RYGB and incidence rate ratios (RRs) of hospital admission in RYGB patients versus comparisons before and after RYGB. RESULTS: Admissions for surgical complications occurred in 3.3% (n = 328) of RYGB patients <30 days after surgery and in 23.9% (n = 2367) during entire follow-up (median 4.2 yrs). Fifteen percent (n = 1486) were admitted with abdominal pain, 5.2% (n = 518) with intestinal obstruction during follow-up. Overall admission rates in RYGB patients versus comparisons were 11.5 versus 5.9 per 100 person years before RYGB [RR = 1.95 (95% confidence interval (CI): 1.89-2.01)], increasing to 24.9 versus 7.1 per 100 person-years after RYGB [RR = 3.38 (95% CI; 3.30, 3.47)]. RRs of cardiovascular and chronic pulmonary disease admissions decreased considerably. RRs increased for alcohol abuse [0.59 (95% CI; 0.39-0.88) to 2.17 (95% CI; 1.72-2.72)], self-harm (suicide attempts, medication overuse) [1.72 (95% CI; 1.32-2.25) to 3.61 (95% CI; 2.88-4.52)], anemia [0.84 (95% CI; 0.39-1.78) to 17.92 (95% CI; 14.94-21.48)], and osteoporosis [1.19 (95% CI; 0.93 1.53) to 1.65 (95% CI; 1.35-2.02)]. CONCLUSIONS: Short-term surgical complications occurred in 3% and long-term complications in one-fourth of RYGB patients. Compared with the general population, the RR for any inpatient admission increased after RYGB. PMID- 27997472 TI - Ensuring Early Mobilization Within an Enhanced Recovery Program for Colorectal Surgery: A Randomized Controlled Trial. AB - OBJECTIVE: To estimate the extent to which the addition of staff-directed facilitation of early mobilization to an Enhanced Recovery Program (ERP) impacts recovery after colorectal surgery, compared with usual care. SUMMARY BACKGROUND DATA: Early mobilization is considered an important component of ERPs but, despite guidelines recommendations, adherence remains quite low. The value of dedicating specific resources (eg, staff time) to increase early mobilization is unknown. METHODS: This randomized trial involved 99 colorectal surgery patients in an established ERP (median age 63, 57% male, 80% laparoscopic) randomized 1:1 to usual care (including preoperative education about early mobilization with postoperative daily targets) or facilitated mobilization [staff dedicated to assist transfers and walking from postoperative days (PODs) 0-3]. Primary outcome was the proportion of patients returning to preoperative functional walking capacity (6-min walk test) at 4 weeks after surgery. We also explored the association of the intervention with in-hospital mobilization, time to achieve discharge criteria, time to recover gastrointestinal function, 30-day comprehensive complication index, and patient-reported outcome measures. RESULTS: In the facilitated mobilization group, adherence to mobilization targets was greater on POD0 [OR 4.7 (95% CI 1.8-11.9)], POD1 [OR 6.5 (95% CI 2.3-18.3)], and POD2 [OR 3.7 (95% CI 1.2-11.3)]. Step count was at least 2-fold greater on POD1 [mean difference 843.3 steps (95% CI 219.5-1467.1)] and POD2 [mean difference 1099.4 steps (95% CI 282.7-1916.1)] There was no between-group difference in recovery of walking capacity at 4 weeks after surgery [OR 0.77 (95% CI 0.30 1.97)]. Other outcome measures were also not different between groups. CONCLUSIONS: In an ERP for colorectal surgery, staff-directed facilitation of early mobilization increased out-of-bed activities during hospital stay but did not improve outcomes. This study does not support the value of allocating additional resources to ensure early mobilization in ERPs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02131844. PMID- 27997473 TI - Impact of State Legislation on Hospital Breastfeeding Support in New York. AB - OBJECTIVE: The purpose of this study was to evaluate whether 2 state mandates, both implemented in 2010, had an impact on NY hospitals providing maternity care. Specifically, we measured changes in hospital staff's awareness, attitudes, and promotion of breastfeeding (BF), maternity care practices, and hospital breastfeeding policies and tested whether they were related to implementation of the Breastfeeding Mothers' Bill of Rights or the mandate for public reporting of hospital-specific BF measures. DESIGN: In 2009 and 2011, written hospital BF policies were collected and evaluated using a 28-item review tool and hospital BF surveys were conducted. The surveys assessed hospital culture and staff attitudes associated with BF promotion and support and recommended maternity care practices. SETTING AND PARTICIPANTS: NY hospitals providing maternity care services and hospital staff. MAIN OUTCOMES MEASURE: Changes over time in hospital BF policies (BF policy score) and implementation of recommended maternity care practices (9 of Ten Steps to Successful BF) were evaluated. The relationships and correlations between these changes in staff awareness, hospital culture, and BF promotion were determined. RESULTS: Between 2009 and 2011, there were increases in BF policy scores, maternity care practices implemented, and lactation staff (P < .001). Greater awareness by hospital administrators of BF measures was associated with more emphasis in promoting BF (P = .02). Hospitals reporting much more emphasis in promoting BF or reporting large changes in organizational culture had greater increases in BF policy scores and the recommended maternity care practices implemented (P < .05). CONCLUSION: These findings suggest that state mandates requiring key BF policies and support in hospitals and public reporting of BF rates may have led to increased emphasis and promotion of BF, improvement in hospital BF policies, and increased implementation of maternity care practices supporting BF. Implementation of similar policies by other states, combined with rigorous evaluation, is needed to replicate these findings and assess the long-term impact on maternal and infant health outcomes. PMID- 27997474 TI - The Effects of a Park Awareness Campaign on Rural Park Use and Physical Activity. AB - To examine the effects of a park awareness campaign on park use in 6 community parks. One-group pretest-posttest design. Six community parks located in a South Carolina county. Children, adolescents, and adults observed in community parks. A 1-month awareness campaign that culminated in single 1.5-hour events at 6 parks in April 2011 and May 2011. The System for Observing Play and Recreation in Communities was used to objectively measure park use in May 2010 (baseline) and May 2011 (postcampaign). Zero-inflated Poisson models tested whether the number of total park users and the number of park users engaged in sedentary, walking, and vigorous activities differed by observation date. Park use was significantly greater at baseline than postcampaign (97 vs 84 users, respectively; chi = 4.69, P = .03). There were no significant differences in the number of park users engaged in sedentary (chi = 2.45, P = .12), walking (chi = 0.29, P = .59), and vigorous (chi = 0.20, P = .65) activities between baseline and postcampaign. Although only 97 and 84 people were observed across all parks at baseline and postcampaign, a total of 629 people were observed during the 6 separate 1.5-hour campaign park events. This suggests that there is potential for greater park utilization in these communities, and important questions remain on how to conduct effective awareness campaigns and how to harness interest in park events for the purpose of contributing to future community-wide physical activity and health promotion efforts. PMID- 27997475 TI - Diabetes Among People With Tuberculosis, HIV Infection, Viral Hepatitis B and C, and STDs in New York City, 2006-2010. AB - Matching infectious disease surveillance data has become a routine activity for many health departments. With the increasing focus on chronic disease, it is also useful to explore opportunities to match infectious and chronic disease surveillance data. To understand the burden of diabetes in New York City (NYC), adults with select infectious diseases (tuberculosis, HIV infection, hepatitis B, hepatitis C, chlamydial infection, gonorrhea, and syphilis) reported between 2006 and 2010 were matched with hemoglobin A1c results reported in the same period. Persons were considered to have diabetes with 2 or more hemoglobin A1c test results of 6.5% or higher. The analysis was restricted to persons who were 18 years or older at the time of first report, either A1c or infectious disease. Overall age-adjusted diabetes prevalence was 8.1%, and diabetes prevalence was associated with increasing age; among NYC residents, prevalence ranged from 0.6% among 18- to 29-year-olds to 22.4% among those 65 years and older. This association was also observed in each infectious disease. Diabetes prevalence was significantly higher among persons with tuberculosis born in Mexico, Jamaica, Honduras, Guyana, Bangladesh, Dominican Republic, the Philippines, and Haiti compared with those born in the United States after adjusting for age and sex. Hepatitis C virus-infected women had higher age-adjusted prevalence of diabetes compared with the NYC population as a whole. Recognizing associations between diabetes and infectious diseases can assist early diagnosis and management of these conditions. Matching chronic disease and infectious disease surveillance data has important implications for local health departments and large health system practices, including increasing opportunities for integrated work both internal to systems and with the local community. Large health systems may consider opportunities for increased collaboration across infectious and chronic disease programs facilitated through data linkages of routinely collected surveillance data. PMID- 27997476 TI - Facilitating Community Health Improvement Capacity Through Nongovernmental Public Health Partners. AB - The purpose of this study was to evaluate the effectiveness of the Facilitating the Community Health Improvement Process training in increasing the capacity of nongovernmental public health partners to serve as facilitators and supporters of community health improvement coalitions. Ten members of WellCare Advocacy and Community-Based Program teams (CommUnity Advocates) serving communities across the country were identified to participate in the pilot training group. They completed pre- and posttraining surveys to evaluate knowledge of community health improvement process models and facilitation techniques, as well as qualitative interviews to assess use of training material 6 months after the training. Results of the project revealed successful use of content from the training, which enhanced the impact of nongovernmental public health partners as facilitators of community health improvement planning and implementation. PMID- 27997477 TI - An Examination of the Self-directed Online Leadership Learning Choices of Public Health Professionals: The Maternal and Child Health Public Health Leadership Institute Experience. AB - OBJECTIVES: To assess the self-selected asynchronous leadership module-based learning choices of public health professionals participating in the Maternal and Child Health Public Health Leadership Institute (MCH PHLI). METHODS: Online module completion and evaluation data were used to determine the topics most utilized by the Fellows; whether the topics and mode of training were acceptable, relevant, and practical; and whether participant characteristics explained any usage patterns. PARTICIPANTS: A total of 109 enrolled Fellows in the MCH PHLI program. MAIN OUTCOME MEASURES: Module frequency of selection by Fellows; Fellows' rating scores in regard to relevance, practicality, and acceptability of module topics. RESULTS: All program titles were highly rated. The 5 most frequently selected module topics were employee engagement (87.2%), talent acquisition strategies (84.4%), employee motivation (79.8%), emotional intelligence (78.9%), and workforce development strategies (68.8%). The least accessed topics focused on cultural competence (15.6%), social marketing (25.7%), effective communication and advocacy (25.7%), family partnerships (25.9%), and creating learning organizations (31.2%). All module topics provided were rated as relevant, practical, and acceptable to these public health leaders. CONCLUSION: Self-directed computer-based learning was rated strongly by the MCH public health leaders in this study. Such an approach can be used to customize training to individual needs and interests. These findings suggest that inclusion of skills that enable public health leaders to effectively work with and through others was of core interest in the MCH PHLI. The finding of higher usage of topics related to workforce management can provide guidance for those developing leadership development programs for maternal and child health professionals. In addition, leadership needs and interests should be assessed regularly to ensure that competency-based leadership development guidelines are adapting to the evolving and complex challenges faced by leaders. While these results were tested in MCH professionals, they may be generalizable to other disciplines within the field of public health. PMID- 27997478 TI - Establishing a Baseline: Community Benefit Spending by Not-for-Profit Hospitals Prior to Implementation of the Affordable Care Act. AB - CONTEXT: Community Benefit spending by not-for-profit hospitals has served as a critical, formalized part of the nation's safety net for almost 50 years. This has occurred mostly through charity care. This article examines how not-for profit hospitals spent Community Benefit dollars prior to full implementation of the Affordable Care Act (ACA). METHODS: Using data from 2009 to 2012 hospital tax and other governmental filings, we constructed national, hospital-referral region, and facility-level estimates of Community Benefit spending. Data were collected in 2015 and analyzed in 2015 and 2016. Data were matched at the facility level for a non-profit hospital's IRS tax filings (Form 990, Schedule H) and CMS Hospital Cost Report Information System and Provider of Service data sets. RESULTS: During 2009, hospitals spent about 8% of total operating expenses on Community Benefit. This increased to between 8.3% and 8.5% in 2012. The majority of spending (>80%) went toward charity care, unreimbursed Medicaid, and subsidized health services, with approximately 6% going toward both community health improvement and health professionals' education. By 2012, national spending on Community Benefit likely exceeded $60 billion. The largest hospital systems spent the vast majority of the nation's Community Benefit; the top 25% of systems spent more than 80 cents of every Community Benefit dollar. DISCUSSION: Community Benefit spending has remained relatively steady as a proportion of total operating expenses and so has increased over time-although charity care remains the major focus of Community Benefit spending overall. IMPLICATIONS: More than $60 billion was spent on Community Benefit prior to implementation of the ACA. New reporting and spending requirements from the IRS, alongside changes by the ACA, are changing incentives for hospitals in how they spend Community Benefit dollars. In the short term, and especially the long term, hospital systems would do well to partner with public health, other social services, and even competing hospitals to invest in population-based activities. The mandated community health needs assessment process is a logical home for these sorts of collaborations. Relatively modest investments can improve the baseline level of health in their communities and make it easier to improve population health. Aside from a population health justification for a partnership model, a business case is necessary for widespread adoption of this approach. Because of their authorities, responsibilities, and centuries of expertise in community health, public health agencies are in a position to help hospitals form concrete, sustainable collaborations for the improvement of population health. CONCLUSION: The ACA will likely change the delivery of uncompensated and charity care in the United States in the years to come. How hospitals choose to spend those dollars may be influenced greatly by the financial and political environments, as well as the strength of community partnerships. PMID- 27997479 TI - Potential for Pharmacy-Public Health Collaborations Using Pharmacy-Based Point-of Care Testing Services for Infectious Diseases. AB - CONTEXT: Health care professionals must continually identify collaborative ways to combat antibiotic resistance while improving community health and health care delivery. Clinical Laboratory Improvement Amendments of 1988 (CLIA)-waived point of-care (POC) testing (POCT) services for infectious disease conducted in community pharmacies provide a means for pharmacists to collaborate with prescribers and/or public health officials combating antibiotic resistance while improving community health and health care delivery. OBJECTIVE: To provide a comprehensive literature review that explores the potential for pharmacists to collaborate with public health professionals and prescribers using pharmacy-based CLIA-waived POCT services for infectious diseases. DESIGN: Comprehensive literature review. SETTING: PubMed and Google Scholar were searched for manuscripts and meeting abstracts for the following key words: infectious disease, community pharmacy, rapid diagnostic tests, rapid assay, and POC tests. INTERVENTION: All relevant manuscripts and meeting abstracts utilizing POCT in community pharmacies for infectious disease were reviewed. OUTCOME MEASURE: Information regarding the most contemporary evidence regarding CLIA-waived POC infectious diseases tests for infectious diseases and their use in community pharmacies was synthesized to highlight and identify opportunities to develop future collaborations using community pharmacy-based models for such services. RESULTS: Evidence demonstrates that pharmacists in collaboration with other health care professionals can leverage their knowledge and accessibility to provide CLIA-waived POCT services for infectious diseases. Testing for influenza may augment health departments' surveillance efforts, help promote rationale antiviral use, and avoid unnecessary antimicrobial therapy. Services for human immunodeficiency virus infection raise infection status awareness, increase access to health care, and facilitate linkage to appropriate care. Testing for group A streptococcal pharyngitis may curb inappropriate outpatient antibiotic prescribing. However, variance in pharmacy practice statues and the application of CLIA across states stifle collaboration. CONCLUSION: CLIA-waived POCT services for infectious diseases are a means for pharmacists, public health professionals, and prescribers to collaboratively combat antibiotic resistance and improve community health. PMID- 27997481 TI - State-Level Surveillance of Underinsurance and Health Care-Related Financial Burden. AB - BACKGROUND: The Affordable Care Act (ACA) has reduced uninsurance, but underinsurance, health care-related financial burden, and dental uninsurance may not follow suit. Underinsurance is associated with reduced access to care, household debt, and bankruptcy but has been difficult to track without economic data. METHODS: We used readily available state-level survey data to build a model that states can adopt to implement surveillance over underinsurance and health care-related financial burden, as well as assess related disparities and health profiles. RESULTS: The state prevalence of underinsurance and dental uninsurance did not change in the first year of the ACA's individual mandate. Underinsurance was associated with poorer health-related quality-of-life measures: compared with the fully insured, underinsured adults had an adjusted odds ratio of 2.40 (95% CI, 1.71-3.38) of fair or poor general health. CONCLUSION: Tracking underinsurance and medical debt can help public health and health care access stakeholders evaluate which mechanisms (deductibles, co-pays, uncovered services, or is proportionately priced health care services and products) are barriers to care and improved health outcomes. PMID- 27997480 TI - Health Care Provider Knowledge and Attitudes Regarding Reporting Diseases and Events to Public Health Authorities in Tennessee. AB - CONTEXT: In the United States, state laws require health care providers to report specific diseases and events to public health authorities, a fundamental facet of disease surveillance. However, reporting by providers is often inconsistent, infrequent, and delayed. OBJECTIVE: To examine knowledge, attitudes, and practices regarding provider disease reporting and to understand current barriers to provider disease reporting. DESIGN: A cross-sectional study was conducted via an anonymous, standardized electronic survey. SETTING: The survey was conducted at Vanderbilt University Medical Center, a large, tertiary academic medical center in Nashville, Tennessee. PARTICIPANTS: Health care providers in 4 specialties (internal medicine, pediatrics, obstetrics-gynecology, and emergency medicine). MAIN OUTCOME MEASURE(S): Knowledge of and attitudes regarding provider reporting of diseases to public health authorities in Tennessee. RESULTS: The majority of providers acknowledged they cared for patients with reportable diseases (362/435, 83.2%) and believed that it was their responsibility to report to public health authorities (429/436, 98.4%); however, less than half had ever reported a case (206/436, 47.2%). The median percent correct on the knowledge assessment of Tennessee reportable diseases and conditions was 81.3% (interquartile range = 68.8-87.5). Providers cited a lack of knowledge of which diseases are reportable (186/429, 43.3%) and the logistics of reporting (153/429, 35.7%) as the primary barriers for compliance. CONCLUSION: Most providers acknowledged they cared for patients with reportable diseases and believed they had an obligation to report to public health authorities. However, a lack of knowledge about reporting was frequently described as a limitation to report effectively. Many knowledge deficits were significantly greater among residents than other providers.The policy and practice implications of these findings include a demonstrated need for education of providers about disease reporting as well as development of more convenient reporting mechanisms. Fundamental knowledge of reportable disease requirements and procedures is critical for participation in the broader public health system. PMID- 27997482 TI - Bringing Healthy Aging to Scale: A Randomized Trial of a Quality Improvement Intervention to Increase Adoption of Evidence-Based Health Promotion Programs by Community Partners. AB - OBJECTIVE: To evaluate the effectiveness of a quality improvement intervention to increase delivery of 2 evidence-based health promotion workshops, Stepping On and Chronic Disease Self-Management Program (CDSMP), in rural communities. DESIGN: A cluster-randomized wait-list control group design. SETTING: Rural Wisconsin counties with trained workshop leaders but no workshops in the prior year were eligible to participate. INTERVENTION: Sixteen counties were randomized to receive the NIATx intervention or wait-list control. The 1-year intervention consisted of training and coaching county aging unit staff to apply NIATx methods to increase and sustain the number of Stepping On or CDSMP workshops in their community. MAIN OUTCOMES: Mann-Whitney tests examined effect on workshops held, participants, and workshop completers. The paired Wilcoxon signed rank test explored change in participants' health behaviors and health care utilization. RESULTS: Counties receiving the NIATx intervention significantly increased the number of workshops per county per year as compared with baseline (1.5 vs 0.19, P < .001) and sustained improvements during the year following the intervention. Stepping On participants, during the 6 months postintervention, had reduced falls risk behaviors (P < .001), 0.43 fewer falls (P < .01), and 0.028 fewer medical record-verified emergency department visits for falls-related injuries (P < .05) compared with the 6 months before the intervention. CDSMP participants had reduced social isolation (P = .018) and improved physician communication skills (P = .005). IMPLICATIONS: Our study demonstrates that coaching rural service organizations in use of the quality improvement process, NIATx, may increase implementation reach of evidence-based health promotion/disease prevention programs. Initiative findings indicate that this approach may be a new and potentially important strategy to increase reach of health promotion programs for older adults in community settings. CONCLUSION: A quality improvement approach effectively increases and sustains delivery of evidence-based health promotion/workshops for older adults in rural communities. Counties or states struggling to engage older adults in evidence-based health promotion workshops could integrate quality improvement into policies and practices to increase workshop availability. Once engaged, older adults experience improved health behaviors from both programs and reduced falls and emergency department utilization from Stepping On. PMID- 27997483 TI - Familial Creutzfeldt-Jakob Disease Cluster Among an African American Family. AB - Familial Creutzfeldt-Jakob disease (fCJD) results from inheritance of mutations in the prion protein gene. Confirming fCJD diagnosis is essential for informing persons of their potential hereditary risk and for genetic counseling to support personal decisions for genetic testing and family planning. We describe a case of fCJD that was linked to a large cluster of African Americans with fCJD identified through a public health investigation, including 8 confirmed cases and 13 suspected cases involving 7 generations in 1 family. Genetic counseling is an important component of fCJD management for families coping with genetic prion diseases. PMID- 27997484 TI - What's Up With the App?: Inconsistencies Within the ASRA Coags Regional Smartphone App Leave Practitioners Guessing. PMID- 27997485 TI - Reply to Drs Weisman and Gebhard. PMID- 27997486 TI - Nerve Roots of the Brachial Plexus: Further Refining the "Stoplight" Sign. PMID- 27997487 TI - The Ultrasound Images of the Proximal Interscalene Space: A Reply to Dr Gabriel and Dr Sandhu. PMID- 27997488 TI - "Stop at the Stoplight: " Seeking Alternative Targets in Ultrasound-Guided Brachial Plexus Block for Regional Anesthesia of the Shoulder. PMID- 27997489 TI - When the Light Switches to Green, Proceed With Caution: A Reply to Dr Malhas and Dr Chin. PMID- 27997490 TI - Optimizing the Combined Suprascapular and Axillary Nerve (SSAX) Block. PMID- 27997491 TI - Reply to Dr Price. PMID- 27997492 TI - Similarities Between the Retrolaminar and Erector Spinae Plane Blocks. PMID- 27997493 TI - Consideration of Block Nomenclature: Erector Spinae Plane Block or Retrolaminar Block? PMID- 27997494 TI - Reply to Dr Ueshima and Dr Murouchi. PMID- 27997495 TI - Single-shot Quadratus Lumborum Block for Postoperative Analgesia After Minimally Invasive Hip Arthroplasty: A New Alternative to Continuous Lumbar Plexus Block? PMID- 27997496 TI - Safety and Subepineural Injections. PMID- 27997497 TI - Safety and Subepineural Injections: A Reply to Dr Bigeleisen. PMID- 27997498 TI - Quadratus Lumborum Block: Conundrums and Questions. PMID- 27997499 TI - Reply to Drs La Colla and Ben-David. PMID- 27997500 TI - Catheter Taping Methods-Single-Layer Versus Reinforced Double-Layer Technique: A Volunteer-Simulated Study. PMID- 27997502 TI - Mitotic Index Determined by Phosphohistone H3 Immunohistochemistry for Precise Grading in Follicular Lymphoma. AB - The World Health Organization classification recommends follicular lymphoma (FL) grading (G1-3) by considering centroblast number, while also suggesting its influence on disease outcome. As centroblast counting and other proliferation markers have limitations, we looked for more specific measures of cellular activity in FL. Phosphorylated histone H3 (pHH3) was widely applied for the objective detection of mitotic activity in different tumors. The aim was to evaluate the utility of pHH3 protein in FL grading and compare its value with the classical features of cell proliferation. Representative samples from 48 FL patients and 9 samples with follicular hyperplasia were examined. Hematoxylin eosin-based mitosis index (HE-MI), number of mitotic figures based on anti-pHH3 immunohistochemical staining (pHH3-MI), and percentage of Ki-67-positive cells [proliferation index (PI)] were determined and compared with centroblast-based histologic grade. PHH3-MI showed significant correlation with HE-MI (r=0.85, P<0.0001) and PI (r=0.84, P<0.0001). All 3 cell proliferation parameters showed significant correlation with histologic grade: HE-MI versus grade, r=0.85 (P<0.0001); PI versus grade, r=0.74 (P<0.0001); pHH3-MI versus grade, r=0.80 (P<0.0001). PHH3-MI showed continuous increase with the histologic grade. The pHH3-MI value was distinctive between the G2 and the G1 FL groups (P<0.0001) and was increased in G3 FL compared with that in the G2 FL group (P=0.0020). In conclusion, easy-to-perform mitotic counting following phosphohistone H3 immunohistochemistry (pHH3-MI) correlates well with centroblast-based grading. PHH3 immunohistochemistry offers a reliable quantification tool supporting lymphoma grading and can be recommended as an additional parameter for the precise subcategorization of FL cases. PMID- 27997503 TI - Dose-dependent Nerve Inflammatory Response to rhBMP-2 in a Rodent Spinal Nerve Model. AB - STUDY DESIGN: We developed a spinal nerve root wrapping rodent model to evaluate the relationship between recombinant human bone morphogenetic protein 2 (rhBMP-2) dosage and the degree of inflammation. OBJECTIVE: To investigate the direct effects of recombinant human bone morphogenetic protein 2 (rhBMP-2) dosage and the degree of inflammation in rodent spinal nerve roots. SUMMARY OF BACKGROUND DATA: rhBMP-2 is commonly used in clinical practice to augment spinal fusion. However, complications such as postoperative leg pain, and a higher rate of postoperative neurologic deficits have been reported. These may be attributable to the exposure of adjacent nerve roots to high doses of rhBMP-2. METHODS: Eighteen rats were randomized into three groups as follows: Group 1: absorbable collagen sponge (ACS) + 10 MUg rhBMP-2, Group 2: ACS + 1 MUg rhBMP-2, and Group 3 ACS with 20 MUL saline. The ACS containing rhBMP-2 or saline were then wrapped around the L5 nerve root and secured loosely with nonabsorbable sutures. At 1 week postoperation, the rats were sacrificed, and the L5 nerve root and dorsal root ganglion harvested for reverse transcription polymerase chain reaction (RT PCR), histology and immunohistochemical staining. RESULTS: In our study, 10 MUg rhBMP-2 induced a 10-fold increase in seroma compared with 1 MUg group. Using RT PCR, macrophage markers MIP3-alpha, and CD-68 were upregulated by 8- and 2-fold respectively in comparison with the saline group. Haematoxylin and eosin (H&E) images demonstrated disruption of nerve structures in the high dose 10 MUg rhBMP 2, but not at 1 MUg rhBMP-2 and with saline. CONCLUSION: High doses of rhBMP-2 induced neuroinflammation in a dose dependent manner, resulting in higher seroma volume, macrophage marker gene expressions, and higher proportions of immunohistochemically stained TNF-alpha and more macrophage infiltration. LEVEL OF EVIDENCE: 2. PMID- 27997504 TI - Surgical Treatment of Primary Osteosarcoma of the Sacrum: A Case Series of 26 Patients. AB - STUDY DESIGN: Twenty-six patients were treated surgically for sacral osteosarcomas in our center. The oncological and functional results are analyzed. OBJECTIVE: To describe the general characteristics and evaluate the outcome of surgical treatment of primary osteosarcoma of the sacrum. SUMMARY OF BACKGROUND DATA: A very few reports have addressed the technique and outcome of surgical treatment of primary sacral osteosarcoma. The survival rate of such cases is low. METHODS: The clinical data of 26 patients treated surgically for sacral osteosarcomas from June 2000 to December 2013 at our hospital were retrospectively reviewed. RESULTS: There were 15 males and 11 females with a median age of 28 years (range, 12-68 years). Distal metastasis occurred in 13 patients (50%), and local recurrence occurred in 10 patients (38.5%, including 6 patients with additional distal metastasis). The 1-year and 5-year survival rates were 92.3% and 38.7%, respectively. Adequate and inadequate surgical margins were obtained in 16 and 10 cases, respectively. Patients with adequate margins had a significantly lower recurrence rate (P = 0.015) and higher event-free survival rate (P = 0.04) than those with inadequate margins. However, the overall survival rate did not differ significantly between patients with adequate and inadequate margins (P = 0.22). Only seven cases showed a good response based on necrosis rate (>90%). Patients with a better response to chemotherapy had better event free and overall survival rates. CONCLUSION: Adequate surgical margins are achievable in most cases of sacral osteosarcomas. Adequate margins can significantly improve the recurrence rate and event-free survival rate compared with inadequate margins. However, sacrectomy is still a challenging surgical technique. Adequate margins are also difficult to obtain in sacrectomy. In addition, only a few patients had a good response to chemotherapy. These reasons lead to a low 5-year survival rate in primary sacral osteosarcoma patients. LEVEL OF EVIDENCE: 4. PMID- 27997505 TI - Characterization and Predictive Value of Segmental Curve Flexibility in Adolescent Idiopathic Scoliosis Patients. AB - STUDY DESIGN: A prospective radiographic analysis of adolescent idiopathic scoliosis (AIS) patients managed with alternate-level pedicle screw fixation was performed. OBJECTIVE: The objective of this study was to characterize segmental curve flexibility and to determine its predictive value in curve correction in AIS patients. SUMMARY OF BACKGROUND DATA: Little is known regarding the distinct segmental curve characteristics and their ability to predict curve correction in patients with AIS. METHODS: The segmental Cobb angle was measured on posteroanterior standing radiographs and on fulcrum bending radiographs. Radiographs were analyzed preoperatively and at 2 years postoperatively and the curve was divided into upper, mid, and lower segments based on predefined criteria. The segmental flexibility and the segmental fulcrum bending correction index (FBCI) were calculated. RESULTS: Eighty patients were included with mean age of 15 years. Preoperative mean segmental Cobb angles were 18, 31, and 17 degrees in the upper, mid, and lower segments, respectively. Segmental bending Cobb angles were 6, 13, and 4 degrees, respectively, corresponding to segmental flexibilities of 50%, 47%, and 83% in the upper, mid, and lower segments, respectively (P < 0.001). At 2-year follow up, the mean segmental FBCI were 155%, 131%, and 100% in the upper, mid, and lower segments, respectively (P < 0.001), which suggested that the lower segment of the curve was more flexible than the other segments and that higher correction was noted in the upper segments. A significant, positive correlation was noted between the segmental bending Cobb angle and the segmental FBCI (P < 0.05), whereby the strength of the correlation varied based on the curve segment. CONCLUSION: This is the first study to demonstrate the segmental variations in curve flexibility using the fulcrum bending radiograph in AIS patients. Curve flexibility is not uniform throughout the curve and different segments exhibit greater flexibility/correctibility than others. Segmental flexibility should be considered in assessing AIS patients and in the clinical decision-making strategy to optimize curve correction outcomes. LEVEL OF EVIDENCE: 03. PMID- 27997507 TI - Prevalence and Risk Factors of Iliac Screw Loosening After Adult Spinal Deformity Surgery. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: We investigated the prevalence of iliac screw loosening and determined risk factors after adult spinal deformity surgery. SUMMARY OF BACKGROUND DATA: Lumbosacral fixation is crucial to maintain optimal sagittal alignment. Iliac screws are commonly placed to provide protection for sacral pedicle screws. Radiolucent areas around the screws indicate fixation loss and pseudarthrosis. METHODS: Seventy-two patients with adult spinal deformity (13 men, 59 women; mean age, 69.0 yr) who underwent spinal deformity surgeries using bilateral iliac screws with at least 2 years follow-up were studied. Iliac and S1 screw loosening were assessed by postoperative radiograph. The period of loosening appearance and the relations between loosening and the following items were investigated: (1) upper instrumented vertebra, (2) L5/S interbody fusion, (3) iliac screw placement, (4) spinopelvic parameters (T1 pelvic angle, sagittal vertical axis, pelvic tilt, pelvic incidence-lumbar lordosis [LL]). Oswestry Disability Index scores were obtained preoperatively and 2 years postoperatively. RESULTS: Iliac and S1 screw loosening was found in 20 (27.8%) and 7 patients (9.7%), respectively. Iliac screw loosening appeared at 5.2 months (range, 3-12) on average. Compared with nonloosening, loosening had significantly higher upper thoracic fusion rates (above T6), lower L5/S interbody fusion rate, higher misplacement rate, and higher insufficient correction rate (PI-LL >10 degrees ). Oswestry Disability Index significantly improved in nonloosening, whereas no significant difference was observed in loosening. Multiple regression analysis showed that misplacement (odds ratio = 10.8) and insufficient correction (odds ratio = 7.5) affected loosening. CONCLUSION: Iliac screw loosening indicated instability of the lumbosacral junction, resulting in sagittal malalignment and poor outcomes. Accurate screw insertion and restoration of optimal LL were necessary to prevent complications. LEVEL OF EVIDENCE: 4. PMID- 27997508 TI - Cost Variation of Anterior Cervical Fusions in Elderly Medicare Beneficiaries. AB - STUDY DESIGN: Retrospective database review. OBJECTIVE: To determine how demographics and comorbid diagnoses influence hospital costs during admission for anterior cervical fusions (ACFs) in the elderly Medicare population. SUMMARY OF BACKGROUND DATA: Elective ACFs to treat degenerative cervical pathology are extremely common within the elderly population. Although it is well known that every patient has a significantly different medical profile that guides treatment and postoperative care, little information is available regarding how hospital costs vary from patient to patient. METHODS: Medicare records from the PearlDiver database (2011-2012) were retrospectively queried to select all 65- to 84-year old patients who underwent primary, 1 to 2 level ACF (International Classification of Diseases, Ninth Revision, Clinical Modification: 81.02) for either cervical spondylosis or cervical disc disease. All patients with corpectomies, posterior cervical fusions, and all other same-day spine fusion surgeries were excluded. The primary outcome of this study was Medicare reimbursement from the full inpatient stay as associated with the selected International Classification of Diseases, Ninth Revision procedure code. The relative contributions of year, age, sex, region, myelopathy diagnosis, and various comorbidities to the total cost were determined with both univariate statistics and multivariate analysis. For all analyses, P < 0.001 was determined to be significant. RESULTS: In total, 21,853 patients were selected for analysis. The average reimbursement for the full cohort was $13,648 +/- $7306. On multivariate analysis, advanced age ($1083), diagnosis of myelopathy ($2150), diabetes mellitus ($1019), obesity ($651), congestive heart failure ($1523), chronic kidney disease ($1962), and chronic pulmonary disease ($489) were all factors that increased costs. Of note, sex, smoking history, and prior liver disease were not associated with changes in cost. CONCLUSION: Medicare reimbursements provide a value means by which determinants of cost can be elucidated. Although multiple comorbidities, older age, and myelopathy diagnosis could be theorized to contribute to increased costs, there is still some uncertainty regarding their relative costs. These data are informative to practicing physicians as health care as a whole transitions to a more value-based approach. LEVEL OF EVIDENCE: 4. PMID- 27997509 TI - Minimally Invasive Placement of Spinal Cord Stimulator Paddle Electrodes Is Associated With Improved Perioperative and Long-Term Experience Among Neuropathic Pain Patients. AB - STUDY DESIGN: Prospective, observational cohort study. OBJECTIVE: This study compared in-hospital and long-term outcomes among spinal cord stimulation (SCS) patients undergoing paddle insertion by open or minimally invasive surgery (MIS) approaches. SUMMARY OF BACKGROUND DATA: Patients with treatment-refractory extremity neuropathic pain may benefit from SCS. Conventional placement of surgical paddles for an external neurostimulation trial is through open laminectomy, but MIS techniques may offer advantages. METHODS: Twenty SCS patients were prospectively assessed. Open patients underwent caudal thoracic laminectomy for multicolumnar electrode paddle placement. MIS patients underwent paddle placement through interlaminar flavectomy using tubular retractors. Demographic data included age, sex, underlying diagnosis, and preoperative visual analog scale (VAS) extremity scores. Intraoperative data included operative duration, blood loss, and number of device passages to achieve final position. Perioperative data included VAS back pain scores; trial data included time-to trial and time-to-decision. Postoperative data included 1 month VAS back pain scores and 1 year follow-up device complications. RESULTS: No demographic differences were observed among surgical cohorts. MIS procedures had shorter operative duration (P = 0.03), less blood loss (P < 0.001), and similar median number of device passages (2 vs 1.5, P = 0.71). MIS patients reported less perioperative surgical back pain (P < 0.05). External neurostimulation trials began sooner among MIS patients who also made sooner decision whether to implant the SCS device (2.8 +/- 1.4 vs 4.3 +/- 1.0 days, P = 0.013). Similar 1 month back pain scores were reported between surgical cohorts (P = 0.08). CONCLUSION: MIS techniques for SCS surgical paddle implantation is associated with less perioperative morbidity and surgical site back pain, shorter external neurostimulator trial duration, and long-term device stability benefits. LEVEL OF EVIDENCE: 2. PMID- 27997510 TI - A Whole Exome Study Identifies Novel Candidate Genes for Vertebral Bone Marrow Signal Changes (Modic Changes). AB - STUDY DESIGN: A family-based study. OBJECTIVE: The aim of this study was to identify rare genetic factors predisposing to Modic changes (MCs). SUMMARY OF BACKGROUND DATA: Lumbar disc degeneration (LDD) is one of the contributing factors behind low back pain (LBP). Lumbar MC visualized as bone marrow signal intensity changes on magnetic resonance imaging (MRI) represent a specific phenotype of LDD, which has a stronger association with LBP than LDD without MC. METHODS: The study set consisted of two Finnish families: Family I included seven affected and four unaffected individuals and Family II eight affected and seven unaffected individuals. MCs were evaluated in 26 individuals using MRI. Whole exome sequencing was used to identify alleles cosegregating with MC. Annotate variation was used to carry out functional annotation of alleles and their frequencies were evaluated using 1000Genomes, Sequencing Initiative Suomi (SISu), and the Exome Aggregation Consortium (ExAC) databases. RESULTS: We identified predisposing genetic alleles for MC in two Finnish families. In each family, only single allele cosegregated with MC. In Family I, the observed allele was an insertion and deletion in the HSPG2 gene, resulting in a premature termination codon. In Family II, a single nucleotide polymorphism (rs61753465) in the MAML1 gene was identified in all affected family members. CONCLUSION: We have identified two novel candidate genes, MAML1 and HSPG2, associating with MC. These genes are important in cartilage structure and joint cartilage maintenance. Our findings are novel among lumbar spine degenerative phenotypes. LEVEL OF EVIDENCE: N/A. PMID- 27997511 TI - CLINICAL OUTCOMES OF INTRAVITREAL BEVACIZUMAB VERSUS PHOTODYNAMIC THERAPY WITH OR WITHOUT BEVACIZUMAB FOR MYOPIC CHOROIDAL NEOVASCULARIZATION: A 7-Year Follow-up Study. AB - PURPOSE: To compare the long-term visual outcomes of intravitreal bevacizumab (IVB) with those of photodynamic therapy (PDT) for myopic choroidal neovascularization over a 7-year period. METHODS: Eyes treated with IVB (17 eyes) or PDT (20 eyes) that were followed up for at least 7 years were included in this retrospective study. Myopic maculopathy was classified according to the international photographic classification before treatment. The best-corrected visual acuity (BCVA) and the chorioretinal atrophy (CRA) size were measured before and after treatment over a 7-year period. RESULTS: The mean change in BCVA at 7 years was greater in the IVB group than in the PDT group (P = 0.044). While BCVA improved from baseline throughout the 7-year period in the IVB group (P = 0.029), there was no improvement in the PDT group (P = 0.266). In subgroup analysis for 18 eyes with preoperative tessellated fundi (Category 1), there was no difference in BCVA improvement (P = 0.166) and CRA size between the 2 groups at 7 years. However, for 17 eyes with preoperative diffuse CRA (Category 2), BCVA remained unchanged in the IVB group and decreased in the PDT group (P = 0.030) at 7 years. CONCLUSION: IVB resulted in superior long-term functional and anatomical outcomes compared with PDT. In particular, PDT resulted in a greater BCVA decrease and CRA increase compared with IVB in eyes with preoperative diffuse CRA. However, the clinical outcomes were not different in eyes with preoperative tessellated fundi. PMID- 27997512 TI - VARIABILITY IN FOVEAL AVASCULAR ZONE AND CAPILLARY DENSITY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY MACHINES IN HEALTHY EYES. AB - PURPOSE: To evaluate the variability in foveal avascular zone (FAZ) and capillary density measurements on optical coherence tomography angiography using Optovue RTVue XR Avanti (OA) (Optovue) and Zeiss Cirrus HD-OCT 5000 (ZC) (Carl Zeiss Meditec). METHODS: In this prospective, comparative case series, parafoveal (3 * 3 mm) optical coherence tomography angiography scans were obtained on healthy volunteers using both the Avanti and Cirrus. The FAZ area and capillary density at the level of both the superficial and deep capillary plexus were measured automatically using the built-in ReVue software (Optovue) with the Avanti as well as manually using ImageJ (National Institutes of Health) with both machines. RESULTS: There were 50 eyes in 25 healthy volunteers included in the analysis. Mean subject age was 33 years and there were 14 women (56%). On optical coherence tomography, mean central macular thickness was significantly greater on OA (259.1 MUm) than ZC (257.6 MUm, P = 0.0228). On optical coherence tomography angiography, mean superficial and deep plexus FAZ measured 0.2855 mm and 0.3465 mm on Avanti automated (A-A), 0.2739 mm and 0.3637 mm on Avanti manual (A-M), and 0.2657 mm and 0.3993 mm on Cirrus manual (C-M), respectively. There were no statistically significant differences in superficial plexus FAZ measurements between the A-A and A-M (P = 0.4019) or A-A and C-M (P = 0.1336). The A-M measured significantly larger than C-M (P = 0.0396). Deep plexus FAZ measurements were similar on A-A and A-M (P = 0.6299), but both were significantly less compared with C-M (P < 0.0001 for A-A vs. C-M, P = 0.0184 for A-M vs. C-M). Mean superficial and deep plexus capillary densities were 53.6% and 59.3% on A-A, 48.1% and 47.7% on A-M, and 52.5% and 48.1% on C-M, respectively. Superficial plexus capillary density measurements were statistically similar on A-A and C-M (P = 0.0623), but both were significantly higher than A-M (P < 0.0001 for A-A vs. A-M, P < 0.0001 for A-M vs. C-M). However, deep plexus capillary density measurements on A-A were significantly higher than A-M (P < 0.0001) and C-M (P < 0.0001), but A-M and C-M measurements were similar (P = 0.5986). There was no significant difference in all parameters measured in both eyes of one subject using any of the three measuring techniques. CONCLUSION: While measurements taken with the same machine and technique are consistent and reliable between fellow eyes, significant variability exists in FAZ and capillary density measurements among different machines and techniques. Comparison of measurements across machines and techniques should be considered with caution. PMID- 27997513 TI - SEMIAUTOMATED QUANTITATIVE APPROACH TO CHARACTERIZE TREATMENT RESPONSE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Real-World Study. AB - PURPOSE: To perform a quantitative study of the vascular microstructure in actively treated choroidal neovascularization by optical coherence tomographic angiography. METHODS: Patients undergoing individualized anti-vascular endothelial growth factor therapy of minimum 12 months duration were included in this cross-sectional observational study and imaged using optical coherence tomographic angiography. En face optical coherence tomographic angiography images were analyzed for quantitative features, such as junction density, vessel length, and lacunarity using validated software (Angiotool). Patients were divided into 2 groups depending on their individualized treatment interval: "good responders, treated less frequently than 6 weeks" versus "poor responders, treated every 6 weeks or more frequently." Nonparametric testing was used to assess differences between these groups. RESULTS: Twenty-five eyes of 23 consecutive patients with a median 58-month history of choroidal neovascularization, treated by median of 34 anti-vascular endothelial growth factor injections, were included in the analysis. There was no significant difference between any of the microvascular choroidal neovascularization features between the 2 groups (P > 0.05). CONCLUSION: The semiautomated vessel segmentation software provides an objective and quantitative approach for choroidal neovascularization characterization. The consistently nonsignificant outcomes between the groups may provide evidence to support the "normalization hypothesis." This would suggest that regardless of treatment interval, individualized therapy in these eyes established vessel stability. PMID- 27997514 TI - Serotypes not Included in 13-Valent Pneumococcal Vaccine as Causes of Acute Otitis Media with Spontaneous Tympanic Membrane Perforation in a Geographic Area with High Vaccination Coverage. AB - In 177 children living in an area with high 13-valent pneumococcal conjugate vaccine 13 coverage, who had acute otitis media complicated with spontaneous tympanic membrane perforation, Streptococcus pneumoniae was identified in the middle ear fluid of 48 (27.1%) subjects, with 37 (77.1%) cases caused by nonpneumococcal conjugate vaccine 13 serotypes. PMID- 27997518 TI - Burden of Childhood Rotavirus Disease in the Outpatient Setting of the Russian Federation. AB - BACKGROUND: This is a prospective, multicentered study conducted in 9 large urban areas in Russia, in order to determine the burden of rotavirus gastroenteritis in children <5 years of age and the genotypes circulating during 1 rotavirus season. METHODS: From November 2012 to May 2013, surveillance was conducted in Moscow, Saint-Petersburg, Vologda, Krasnodar, Krasnoyarsk, Novosibirsk, Yaroslavl, Khanty Mansiysk and Vladivostok. Children <5 years of age presenting at outpatient clinics with acute gastroenteritis (AGE) of less than 72 hours duration were enrolled in the study. Stool samples were tested for rotavirus and positive samples were P- and G-typed. Clinical symptoms were captured by physicians and parents on Day 1. Symptom severity was analyzed by Vesikari scoring system. The direct expenses of parents caused by AGE were obtained from questionnaires provided to parents by phone. RESULTS: A total of 501 were children enrolled. Stool samples were analyzed for 487 (97%) children, and 151 (31%) of those were rotavirus positive. Rotavirus gastroenteritis was associated with more severe clinical course (Vesikari score 11.4 +/- 2.2) versus non-rotavirus gastroenteritis (Vesikari score 9 +/- 3). The identified serotypes were G4P[8] 38.9%, G1P[8] 34.2%, G3P[8] 6%, G9P[8] 6%, G2P[4] 2% and G4P[4] 0.7%. The mean overall expenses of parents caused by rotavirus and non-rotavirus gastroenteritis were 143.7 USD and 128.8 USD, respectively. CONCLUSIONS: Rotavirus accounted for 31% of all AGE-related outpatient visits. The major rotavirus genotypes were G1P[8] and G4P[8]. Rotavirus gastroenteritis was associated with significantly more severe clinical symptoms than non-rotavirus gastroenteritis. The average costs of rotavirus cases for parents of children were elevated against the same indications for non-rotavirus. These findings underscore the need for a safe and effective rotavirus vaccine in Russia. PMID- 27997521 TI - Laboratory Diagnosis of Breakthrough Varicella in Children. AB - BACKGROUND: Breakthrough varicella (BV) develops in vaccinated persons as a result of infection by wild-type varicella-zoster virus more than 42 days after varicella vaccination. The clinical symptoms are atypical, and clinical diagnosis can be difficult. We investigated laboratory-based diagnostic methods that are relatively simple and highly precise to conduct accurate surveillance. SUBJECTS AND METHODS: We enrolled 42 patients with suspected BV at 2 pediatric hospitals and performed a real-time polymerase chain reaction (PCR) on the skin lesions to confirm the BV diagnosis. We performed PCR on saliva and blood collected during the acute phase, as well as direct fluorescent antibody (DFA) imaging on lesions, and measured varicella-zoster virus immunoglobulin (Ig) G and IgM during the acute and convalescent phases. RESULTS: We confirmed the BV diagnosis in 31 of 42 enrolled patients. The sensitivity of DFA imaging of the lesion, and PCR of saliva and blood were 93.5%, 87.1% and 61.3%, respectively. IgM was detected in 12.9% of patients during the acute phase and in 65.5% during the convalescent phase. IgG increased more than 4-fold in 86.2% of patients between the acute and convalescent phases. The sensitivity and specificity of the assay were 83.9% and 81.8%, respectively, when the diagnostic criteria for IgG were set to greater than 20 during the acute phase. CONCLUSIONS: The gold standard of laboratory based diagnosis of BV has been the PCR of samples taken from lesions. However, DFA of the lesion showed equivalent sensitivity when compared with PCR. PCR using saliva samples is an effective, noninvasive method of diagnosis. We found that high values of IgG during the acute phase can aid in the diagnosis of BV. PMID- 27997519 TI - Epidemiology and Clinical Features of Kawasaki Disease in South Korea, 2012-2014. AB - BACKGROUND: To reveal the recent epidemiologic features of Kawasaki disease (KD) in South Korea based on data from a nationwide survey. METHODS: We collected data between 2012 and 2014 regarding the incidence, symptoms and signs, treatment trends and coronary complications associated with acute KD by sending questionnaires to 97 hospitals with pediatric residency programs as well as 19 community hospitals without residency training. RESULTS: We received full and partial data from 97 and 13 hospitals, respectively (response rate: 94.8%). A total of 14,916 cases of KD were reported by these 110 hospitals (4588 in 2012, 5183 in 2013 and 5145 in 2014). The male-to-female ratio was 1.4:1, and the median age at diagnosis was 29 months. The incidence of KD per 100,000 children younger than 5 years of age were 170.9, 194.9 and 194.7 in 2012, 2013 and 2014, respectively. The recurrence rate was 4.7%. KD occurred more frequently during summer (especially June and July) and winter (December and January) seasons. Intravenous immunoglobulin was administered to 95.4% of the patients, and the nonresponder rate for the first intravenous immunoglobulin was 11.8%. Coronary aneurysm occurred in 1.7% of the patients, and giant aneurysm developed in 19 patients (0.16%) during the 3 years. One patient had myocardial infarction and 1 patient died of suspected coronary aneurysm rupture. CONCLUSIONS: The incidence of KD in South Korea increased to 194.7 per 100,000 children younger than 5 years in 2014; meanwhile, the coronary aneurysm rate decreased to 1.7%. PMID- 27997524 TI - Digital Anatomical Measurement for Anterolateral Fixation of Middle and Lower Thoracic Vertebrae. AB - : BACKGROUND The key to its successful application is to determine the best entry point for the vertebral screw(s). This study aimed to provide a reference for clinical anterolateral fixation through digital measurement of computed tomography (CT) data to identify relevant anatomical positions in the middle and lower thoracic vertebrae (T4-T12) of 30 adults. MATERIAL AND METHODS We performed digital measurement of anatomical positions in the middle and lower thoracic vertebrae (T4-T12) of 30 adults. ABBREVIATIONS: Left height of vertebral body, LHV; Right height of vertebral body, RHV; Anterior height of vertebral body, AHV; Middle height of vertebral body, MHV; Posterior height of vertebral body, PHV; Superior sagittal diameter of vertebral body, SSDV; Superior transverse diameter of vertebral body, STDV; inferior sagittal diameter of vertebral body, ISDV; Inferior transverse diameter of vertebral body, ITDV; (1) Left (right) height of vertebral body, [L(R)HV]; Anterior (middle, posterior) height of vertebral body [A(M,P)HV]; Superior (inferior) sagittal diameter of vertebral body, [S(I)SDV]; Superior (inferior) transverse diameter of vertebral body, [S(I)TDV]. RESULTS The transverse diameters of vertebral bodies were always larger than the sagittal diameter for 3~4 mm. The distance between 2 vertebrae (interval of 1 vertebra) range were (52-56) mm for T4-T7 and (44-48) mm for T8-T12, and the surgeons could collate these data to choose a suitable stick length. CONCLUSIONS Bone graft should prune into laterigrade cuboid, it can recover A-P and bilateral physiological functions load, and the height of the vertebral body increased from T4 to T12. PMID- 27997525 TI - Reply: Comment on 'MicroRNA-214 suppresses growth, migration and invasion through a novel target, high mobility group AT-hook 1, in human cervical and colorectal cancer cells'. PMID- 27997526 TI - Organ preservation with local excision or active surveillance following chemoradiotherapy for rectal cancer. AB - BACKGROUND: Organ preservation has been proposed as an alternative to radical surgery for rectal cancer to reduce morbidity and mortality, and to improve functional outcome. METHODS: Locally advanced non-metastatic rectal cancers were identified from a prospective database. Patients staged ?T3 or any stage N+ were referred for neoadjuvant chemoradiotherapy (CRT) (50-54 Gy and 5-fluorouracil), and were reassessed 6-8 weeks post treatment. An active surveillance programme ('watch and wait') was offered to patients who were found to have a complete endoluminal response. Transanal excision was performed in patients who were found to have an objective clinical response and in whom a residual ulcer measured ?3 cm. Patients were followed up clinically, endoscopically and radiologically to assess for local recurrence or disease progression. RESULTS: Of 785 patients with rectal cancer between 2005 and 2015, 362 had non-metastatic locally advanced tumours treated with neoadjuvant CRT. Sixty out of three hundred and sixty-two (16.5%) patients were treated with organ-preserving strategies - 10 with 'watch and wait' and 50 by transanal excision. Fifteen patients were referred for salvage total mesorectal excision post local excision owing to adverse pathological findings. There was no significant difference in overall survival (85.6% vs 93.3%, P=0.414) or disease-free survival rate (78.3% vs 80%, P=0.846) when the outcomes of radical surgery were compared with organ preservation. Tumour regrowth occurred in 4 out of 45 (8.9%) patients who had organ preservation. CONCLUSIONS: Organ preservation for locally advanced rectal cancer is feasible for selected patients who achieve an objective endoluminal response to neoadjuvant CRT. Transanal excision defines the pathological response and refines decision-making. PMID- 27997527 TI - Comment on 'MicroRNA-214 suppresses growth, migration and invasion through a novel target, high mobility group AT-hook 1, in human cervical and colorectal cancer cells'. PMID- 27997528 TI - Losartan attenuates the coronary perivasculitis through its local and systemic anti-inflammatory properties in a murine model of Kawasaki disease. AB - BACKGROUND: Kawasaki disease is a common systemic vasculitis that leads to coronary artery lesions. Besides its antihypertensive effects, losartan can modulate inflammation in cardiovascular disease. We examined whether losartan can attenuate coronary inflammation in a murine model of Kawasaki disease. METHODS AND RESULTS: Five-wk-old C57/BL6J male mice were intraperitoneally injected with Lactobacillus casei cell wall extract to induce coronary inflammation and divided into four groups: placebo, intravenous immunoglobulin (IVIG), losartan, and IVIG+losartan. After 2 wk, mice were harvested. The coronary perivasculitis was significantly attenuated by losartan but not by IVIG alone, and further dramatic attenuation by IVIG+losartan was observed. The frequency of Lactobacillus casei cell wall extract-induced myocarditis (80%) was markedly lowered by losartan (22%) and IVIG+losartan (0%). Furthermore, interleukin (IL)-6 mRNA was markedly attenuated by IVIG+losartan. Serum levels of IL-6, TNF-alpha, MCP-1, and IL-10 after Lactobacillus casei cell wall extract injection were slightly decreased by IVIG or losartan. Moreover, IL-1beta, IL-10, and MCP-1 levels were significantly decreased by IVIG+losartan. CONCLUSION: The addition of losartan to IVIG strongly attenuated the severity of coronary perivasculitis and the incidence of myocarditis, along with suppressing systemic/local cytokines as well as the activated macrophage infiltration. Therefore, losartan may be a potentially useful additive drug for the acute phase of Kawasaki disease to minimize coronary artery lesions. PMID- 27997529 TI - Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternal creatine supplementation during pregnancy. AB - BACKGROUND: Acute kidney injury affects ~70% of asphyxiated newborns, and increases their risk of developing chronic kidney disease later in life. Acute kidney injury is driven by renal oxygen deprivation during asphyxia, thus we hypothesized that creatine administered antenatally would protect the kidney from the long-term effects of birth asphyxia. METHODS: Pregnant spiny mice were fed standard chow or chow supplemented with 5% creatine from 20-d gestation (midgestation). One day prior to term (37-d gestation), pups were delivered by caesarean or subjected to intrauterine asphyxia. Litters were allocated to one of two time-points. Kidneys were collected at 1 mo of age to estimate nephron number (stereology). Renal function (excretory profile and glomerular filtration rate) was measured at 3 mo of age, and kidneys then collected for assessment of glomerulosclerosis. RESULTS: Compared with controls, at 1 mo of age male (but not female) birth-asphyxia offspring had 20% fewer nephrons (P < 0.05). At 3 mo of age male birth-asphyxia offspring had 31% lower glomerular filtration rate (P < 0.05) and greater glomerular collagen IV content (P < 0.01). Antenatal creatine prevented these renal injuries arising from birth asphyxia. CONCLUSION: Maternal creatine supplementation during pregnancy may be an effective prophylactic to prevent birth asphyxia induced acute kidney injury and the emergence of chronic kidney disease. PMID- 27997530 TI - Utility of cytokines to predict neonatal sepsis. AB - BACKGROUND: Sepsis is an important cause of neonatal morbidity and mortality worldwide. Diagnosis and treatment of neonatal sepsis relies on clinical judgment and interpretation of nonspecific laboratory tests. In a prospective cohort, we measured inflammatory cytokines as a potential biomarker for neonatal sepsis. METHODS: Serum inflammatory cytokine levels were evaluated in the early stage of neonatal sepsis and after antimicrobial treatment. Receiver operating characteristic curves assessed the diagnostic value of cytokines. We performed multiple logistic regression analysis to characterize the role of each cytokine independently for infants with culture proven sepsis. RESULTS: C-reactive protein, interleukin (IL)-6, IL-10 and IL-6/IL-10 levels were significantly elevated in neonatal sepsis when compared with the control group and there were 1.4 (95% confidence interval (CI): 1.2-1.5), 4.9 (95% CI: 4.6-5.1), 5.1 (95% CI: 4.5-5.6), and 10.2 (95% CI: 9.2-11.1) fold greater odds, respectively, to predict neonatal sepsis when increased. After effective treatment, median IL-6 (pretreatment value: 263.0 pg/ml and post-treatment value: 7.4 pg/ml) and IL-6/IL 10 levels (pretreatment value: 16.6 and post-treatment value: 1.4) significantly decreased. The areas under the curve for IL-6, IL-10, IL-6/IL-10 and C-reactive protein for differential diagnosis were 0.98, 0.82, 0.90, and 0.88, respectively. CONCLUSION: IL-6 and IL-6/IL-10 outperformed C-reactive protein to diagnose neonatal sepsis. Of the cytokines studied, IL-6 was the most sensitive, whereas IL-6/IL-10 was the most specific predictor of neonatal sepsis. PMID- 27997531 TI - Redefining short bowel syndrome in the 21st century. AB - In 1968, Wilmore and Dudrick reported an infant sustained by parenteral nutrition (PN) providing a potential for survival for children with significant intestinal resections. Increasing usage of TPN over time led to some patients developing Intestinal Failure Associated Liver Disease (IFALD), a leading cause of death and indication for liver/intestinal transplant. Over time, multidisciplinary teams called Intestinal Rehabilitation Programs (IRPs) began providing meticulous and innovative management. Usage of alternative lipid emulsions and lipid minimization strategies have resulted in the decline of IFALD and an increase in long-term and transplant-free survival, even in the setting of ultrashort bowel (< 20 cm). Autologous bowel reconstructive surgeries, such as the serial tapering enteroplasty procedure, have increased the likelihood of achieving enteral autonomy. Since 2007, the number of pediatric intestinal transplants performed has sharply declined and likely attributed to the newer innovations healthcare. Recent data support the need for changes in the listing criteria for intestinal transplantation given the overall improvement in outcomes. Over the last 50 y, the diagnosis of short bowel syndrome has changed from a death sentence to one of hope with a vast improvement of quality of life and survival. PMID- 27997532 TI - Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia. AB - Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated alpha tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of alpha-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of alpha-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration. PMID- 27997533 TI - Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study. AB - BACKGROUND: Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). METHODS AND FINDINGS: We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at >=20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, p = 0.008). Conversely, a decrease in TP53MAF of <=60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. CONCLUSIONS: In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of <=60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment. PMID- 27997534 TI - DNA Methylation Signatures of the Plant Chromomethyltransferases. AB - DNA methylation in plants is traditionally partitioned into CG, CHG and CHH contexts (with H any nucleotide but G). By investigating DNA methylation patterns in trinucleotide contexts in four angiosperm species, we show that such a representation hides spatial and functional partitioning of different methylation pathways and is incomplete. CG methylation (mCG) is largely context-independent whereas, at CHG motifs, there is under-representation of mCCG in pericentric regions of A. thaliana and tomato and throughout the chromosomes of maize and rice. In A. thaliana the biased representation of mCCG in heterochromatin is related to specificities of H3K9 methyltransferase SUVH family members. At CHH motifs there is an over-representation of different variant forms of mCHH that, similarly to mCCG hypomethylation, is partitioned into the pericentric regions of the two dicots but dispersed in the monocot chromosomes. The over-represented mCHH motifs in A. thaliana associate with specific types of transposon including both class I and II elements. At mCHH the contextual bias is due to the involvement of various chromomethyltransferases whereas the context-independent CHH methylation in A. thaliana and tomato is mediated by the RNA-directed DNA methylation process that is most active in the gene-rich euchromatin. This analysis therefore reveals that the sequence context of the methylome of plant genomes is informative about the mechanisms associated with maintenance of methylation and the overlying chromatin structure. PMID- 27997535 TI - Selection for Mitochondrial Quality Drives Evolution of the Germline. AB - The origin of the germline-soma distinction is a fundamental unsolved question. Plants and basal metazoans do not have a germline but generate gametes from pluripotent stem cells in somatic tissues (somatic gametogenesis). In contrast, most bilaterians sequester a dedicated germline early in development. We develop an evolutionary model which shows that selection for mitochondrial quality drives germline evolution. In organisms with low mitochondrial replication error rates, segregation of mutations over multiple cell divisions generates variation, allowing selection to optimize gamete quality through somatic gametogenesis. Higher mutation rates promote early germline sequestration. We also consider how oogamy (a large female gamete packed with mitochondria) alters selection on the germline. Oogamy is beneficial as it reduces mitochondrial segregation in early development, improving adult fitness by restricting variation between tissues. But it also limits variation between early-sequestered oocytes, undermining gamete quality. Oocyte variation is restored through proliferation of germline cells, producing more germ cells than strictly needed, explaining the random culling (atresia) of precursor cells in bilaterians. Unlike other models of germline evolution, selection for mitochondrial quality can explain the stability of somatic gametogenesis in plants and basal metazoans, the evolution of oogamy in all plants and animals with tissue differentiation, and the mutational forces driving early germline sequestration in active bilaterians. The origins of predation in motile bilaterians in the Cambrian explosion is likely to have increased rates of tissue turnover and mitochondrial replication errors, in turn driving germline evolution and the emergence of complex developmental processes. PMID- 27997536 TI - Putting Temperature and Oxygen Thresholds of Marine Animals in Context of Environmental Change: A Regional Perspective for the Scotian Shelf and Gulf of St. Lawrence. AB - We conducted a literature review of reported temperature, salinity, pH, depth and oxygen preferences and thresholds of important marine species found in the Gulf of St. Lawrence and Scotian Shelf region. We classified 54 identified fishes and macroinvertebrates as important either because they support a commercial fishery, have threatened or at risk status, or meet one of the following criteria: bycatch, baitfish, invasive, vagrant, important for ecosystem energy transfer, or predators or prey of the above species. The compiled data allow an assessment of species-level impacts including physiological stress and mortality given predictions of future ocean physical and biogeochemical conditions. If an observed, multi-decadal oxygen trend on the central Scotian Shelf continues, a number of species will lose favorable oxygen conditions, experience oxygen stress, or disappear due to insufficient oxygen in the coming half-century. Projected regional trends and natural variability are both large, and natural variability will act to alternately amplify and dampen anthropogenic changes. When estimates of variability are included with the trend, species encounter unfavourable oxygen conditions decades sooner. Finally, temperature and oxygen thresholds of adult Atlantic wolffish (Anarhichas lupus) and adult Atlantic cod (Gadus morhua) are assessed in the context of a potential future scenario derived from high-resolution ocean models for the central Scotian Shelf. PMID- 27997538 TI - Overcoming Steroid Resistance in T Cell Acute Lymphoblastic Leukemia. AB - In a Perspective, Pieter Van Vlierberghe and Steven Goossens discuss Meijerink and colleagues' findings on steroid resistance in pediatric T cell acute lymphoblastic leukemia. PMID- 27997537 TI - Patterns and Determinants of Care-Seeking for Antepartum and Intrapartum Complications in Rural Bangladesh: Results from a Cohort Study. AB - BACKGROUND: The burden of maternal complications during antepartum and intrapartum periods is high and care seeking from a trained provider is low, particularly in low middle income countries of sub-Saharan Africa and South Asia. Identification of barriers to access to trained care and development of strategies to address them will contribute to improvements in maternal health. Using data from a community-based cohort of pregnant women, this study identified the prevalence of antepartum and intrapartum complications and determinants of care-seeking for these complications in rural Bangladesh. METHODS: The study was conducted in 24,274 pregnant women between June 2011 and December 2013 in rural Sylhet district of Bangladesh. Women were interviewed during pregnancy to collect data on demographic and socioeconomic characteristics; prior miscarriages, stillbirths, live births, and neonatal deaths; as well as data on their ability to make decision to go to health center alone. They were interviewed within the first 7 days of child birth to collect data on self-reported antepartum and intrapartum complications and care seeking for those complications. Bivariate analysis was conducted to explore association between predisposing (socio demographic), enabling (economic), perceived need, and service related factors with care-seeking for self-reported antepartum and intrapartum complications. Multivariable multinomial logistic regression was performed to examine the association of selected factors with care-seeking for self-reported antepartum and intrapartum complications adjusting for co-variates. RESULTS: Self-reported antepartum and intrapartum complications among women were 14.8% and 20.9% respectively. Among women with any antepartum complication, 58.9% sought care and of these 46.5% received care from a trained provider. Of the women with intrapartum complications, 61.4% sought care and of them 46.5% did so from a trained provider. Care-seeking for both antepartum and intrapartum complications from a trained provider was significantly higher for women with higher household wealth status, higher literacy level of both women and their husbands, and for those living close to a health facility (<10 km). Women's decision making ability to go to health centre alone was associated with untrained care only for antepartum complications, but was associated with both trained and untrained care for intrapartum complications. CONCLUSIONS: Nearly 40.0% of the women who experienced either an antepartum or intrapartum complications did not seek care from any provider and 11.5% -14.9% received care from untrained providers, primarily because of economic and geographic barriers to access. Development and evaluation of context specific, cost-effective, and sustainable strategies that will address these barriers to access to care for the maternal complications will enhance care seeking from trained health care providers and improve maternal health. PMID- 27997539 TI - The Impact of Virtual Reality on Chronic Pain. AB - The treatment of chronic pain could benefit from additional non-opioid interventions. Virtual reality (VR) has been shown to be effective in decreasing pain for procedural or acute pain but to date there have been few studies on its use in chronic pain. The present study was an investigation of the impact of a virtual reality application for chronic pain. Thirty (30) participants with various chronic pain conditions were offered a five-minute session using a virtual reality application called Cool! Participants were asked about their pain using a 0-10 visual analog scale rating before the VR session, during the session and immediately after the session. They were also asked about immersion into the VR world and about possible side effects. Pain was reduced from pre-session to post-session by 33%. Pain was reduced from pre-session during the VR session by 60%. These changes were both statistically significant at the p < .001 level. Three participants (10%) reported no change between pre and post pain ratings. Ten participants (33%) reported complete pain relief while doing the virtual reality session. All participants (100%) reported a decrease in pain to some degree between pre-session pain and during-session pain. The virtual reality experience was found here to provide a significant amount of pain relief. A head mounted display (HMD) was used with all subjects and no discomfort was experienced. Only one participant noted any side effects. VR seems to have promise as a non-opioid treatment for chronic pain and further investigation is warranted. PMID- 27997540 TI - IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. AB - BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment. METHODS AND FINDINGS: We performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild-type and mutant IL7R signaling molecules in two steroid-sensitive T-ALL cell lines (SUPT1 and P12 Ichikawa cells) using inducible lentiviral expression constructs. We found that expressing mutant IL7R, JAK1, or NRAS, or wild-type NRAS or AKT, specifically induced steroid resistance without affecting sensitivity to vincristine or L-asparaginase. In contrast, wild-type IL7R, JAK1, and JAK3, as well as mutant JAK3 and mutant AKT, had no effect. We then performed a functional study to examine the mechanisms underlying steroid resistance and found that, rather than changing the steroid receptor's ability to activate downstream targets, steroid resistance was associated with strong activation of MEK-ERK and AKT, downstream components of the IL7R signaling pathway, thereby inducing a robust antiapoptotic response by upregulating MCL1 and BCLXL expression. Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM. Importantly, treating our cell lines with IL7R signaling inhibitors restored steroid sensitivity. To address clinical relevance, we treated primary T-ALL cells obtained from 11 patients with steroids either alone or in combination with IL7R signaling inhibitors; we found that including a MEK, AKT, mTOR, or dual PI3K/mTOR inhibitor strongly increased steroid-induced cell death. Therefore, combining these inhibitors with steroid treatment may enhance steroid sensitivity in patients with ALL. The main limitation of our study was the modest cohort size, owing to the very low incidence of T-ALL. CONCLUSIONS: Using an unbiased sequencing approach, we found that specific mutations in IL7R signaling molecules underlie steroid resistance in T-ALL. Future prospective clinical studies should test the ability of inhibitors of MEK, AKT, mTOR, or PI3K/mTOR to restore or enhance steroid sensitivity and improve clinical outcome. PMID- 27997541 TI - Suppression of Dopamine Neurons Mediates Reward. AB - Massive activation of dopamine neurons is critical for natural reward and drug abuse. In contrast, the significance of their spontaneous activity remains elusive. In Drosophila melanogaster, depolarization of the protocerebral anterior medial (PAM) cluster dopamine neurons en masse signals reward to the mushroom body (MB) and drives appetitive memory. Focusing on the functional heterogeneity of PAM cluster neurons, we identified that a single class of PAM neurons, PAM gamma3, mediates sugar reward by suppressing their own activity. PAM-gamma3 is selectively required for appetitive olfactory learning, while activation of these neurons in turn induces aversive memory. Ongoing activity of PAM-gamma3 gets suppressed upon sugar ingestion. Strikingly, transient inactivation of basal PAM gamma3 activity can substitute for reward and induces appetitive memory. Furthermore, we identified the satiety-signaling neuropeptide Allatostatin A (AstA) as a key mediator that conveys inhibitory input onto PAM-gamma3. Our results suggest the significance of basal dopamine release in reward signaling and reveal a circuit mechanism for negative regulation. PMID- 27997542 TI - Systematic Approximations to Susceptible-Infectious-Susceptible Dynamics on Networks. AB - Network-based infectious disease models have been highly effective in elucidating the role of contact structure in the spread of infection. As such, pair- and neighbourhood-based approximation models have played a key role in linking findings from network simulations to standard (random-mixing) results. Recently, for SIR-type infections (that produce one epidemic in a closed population) on locally tree-like networks, these approximations have been shown to be exact. However, network models are ideally suited for Sexually Transmitted Infections (STIs) due to the greater level of detail available for sexual contact networks, and these diseases often possess SIS-type dynamics. Here, we consider the accuracy of three systematic approximations that can be applied to arbitrary disease dynamics, including SIS behaviour. We focus in particular on low degree networks, in which the small number of neighbours causes build-up of local correlations between the state of adjacent nodes that are challenging to capture. By examining how and when these approximation models converge to simulation results, we generate insights into the role of network structure in the infection dynamics of SIS-type infections. PMID- 27997544 TI - Zipf's Law Arises Naturally When There Are Underlying, Unobserved Variables. AB - Zipf's law, which states that the probability of an observation is inversely proportional to its rank, has been observed in many domains. While there are models that explain Zipf's law in each of them, those explanations are typically domain specific. Recently, methods from statistical physics were used to show that a fairly broad class of models does provide a general explanation of Zipf's law. This explanation rests on the observation that real world data is often generated from underlying causes, known as latent variables. Those latent variables mix together multiple models that do not obey Zipf's law, giving a model that does. Here we extend that work both theoretically and empirically. Theoretically, we provide a far simpler and more intuitive explanation of Zipf's law, which at the same time considerably extends the class of models to which this explanation can apply. Furthermore, we also give methods for verifying whether this explanation applies to a particular dataset. Empirically, these advances allowed us extend this explanation to important classes of data, including word frequencies (the first domain in which Zipf's law was discovered), data with variable sequence length, and multi-neuron spiking activity. PMID- 27997543 TI - Cell Cycle Constraints and Environmental Control of Local DNA Hypomethylation in alpha-Proteobacteria. AB - Heritable DNA methylation imprints are ubiquitous and underlie genetic variability from bacteria to humans. In microbial genomes, DNA methylation has been implicated in gene transcription, DNA replication and repair, nucleoid segregation, transposition and virulence of pathogenic strains. Despite the importance of local (hypo)methylation at specific loci, how and when these patterns are established during the cell cycle remains poorly characterized. Taking advantage of the small genomes and the synchronizability of alpha proteobacteria, we discovered that conserved determinants of the cell cycle transcriptional circuitry establish specific hypomethylation patterns in the cell cycle model system Caulobacter crescentus. We used genome-wide methyl-N6-adenine (m6A-) analyses by restriction-enzyme-cleavage sequencing (REC-Seq) and single molecule real-time (SMRT) sequencing to show that MucR, a transcriptional regulator that represses virulence and cell cycle genes in S-phase but no longer in G1-phase, occludes 5'-GANTC-3' sequence motifs that are methylated by the DNA adenine methyltransferase CcrM. Constitutive expression of CcrM or heterologous methylases in at least two different alpha-proteobacteria homogenizes m6A patterns even when MucR is present and affects promoter activity. Environmental stress (phosphate limitation) can override and reconfigure local hypomethylation patterns imposed by the cell cycle circuitry that dictate when and where local hypomethylation is instated. PMID- 27997545 TI - A General Method for Targeted Quantitative Cross-Linking Mass Spectrometry. AB - Chemical cross-linking mass spectrometry (XL-MS) provides protein structural information by identifying covalently linked proximal amino acid residues on protein surfaces. The information gained by this technique is complementary to other structural biology methods such as x-ray crystallography, NMR and cryo electron microscopy[1]. The extension of traditional quantitative proteomics methods with chemical cross-linking can provide information on the structural dynamics of protein structures and protein complexes. The identification and quantitation of cross-linked peptides remains challenging for the general community, requiring specialized expertise ultimately limiting more widespread adoption of the technique. We describe a general method for targeted quantitative mass spectrometric analysis of cross-linked peptide pairs. We report the adaptation of the widely used, open source software package Skyline, for the analysis of quantitative XL-MS data as a means for data analysis and sharing of methods. We demonstrate the utility and robustness of the method with a cross laboratory study and present data that is supported by and validates previously published data on quantified cross-linked peptide pairs. This advance provides an easy to use resource so that any lab with access to a LC-MS system capable of performing targeted quantitative analysis can quickly and accurately measure dynamic changes in protein structure and protein interactions. PMID- 27997546 TI - The Eatwell Guide: Modelling the Health Implications of Incorporating New Sugar and Fibre Guidelines. AB - OBJECTIVE: To model population health impacts of dietary changes associated with the redevelopment of the UK food-based dietary guidelines (the 'Eatwell Guide'). METHOD: Using multi-state lifetable methods, we modelled the impact of dietary changes on cardiovascular disease, diabetes and cancers over the lifetime of the current UK population. From this model, we determined change in life expectancy and disability-adjusted life years (DALYs) that could be averted. RESULTS: Changing the average diet to that recommended in the new Eatwell Guide, without increasing total energy intake, could increase average life expectancy by 5.4 months (95% uncertainty interval: 4.7 to 6.2) for men and 4.0 months (3.4 to 4.6) for women; and avert 17.9 million (17.6 to 18.2) DALYs over the lifetime of the current population. A large proportion of the health benefits are from prevention of type 2 diabetes, with 440,000 (400,000 to 480,000) new cases prevented in men and 340,000 (310,000 to 370,000) new cases prevented in women, over the next ten years. Prevention of cardiovascular diseases and colorectal cancer is also large. However, if the diet recommended in the new Eatwell Guide is achieved with an accompanying increase in energy intake (and thus an increase in body mass index), around half the potential improvements in population health will not be realised. CONCLUSIONS: The dietary changes required to meet recommendations in the Eatwell Guide, which include eating more fruits and vegetables and less red and processed meats and dairy products, are large. However, the potential population health benefits are substantial. PMID- 27997547 TI - Prevalence of Antibodies to Zika Virus in Mothers from Hawaii Who Delivered Babies with and without Microcephaly between 2009-2012. AB - Zika virus (ZIKV) is an emerging mosquito-borne pathogen. ZIKV infection is linked to the development of severe fetal abnormalities that include spontaneous abortion, stillbirth, hydranencephaly, and microcephaly. ZIKV outbreaks have been recorded in the United States. We recently demonstrated the first congenital ZIKV infection in the United States. In this study, we investigated archived blood samples from six mothers who gave birth to babies with microcephaly and 12 mothers who gave birth to healthy babies in Hawaii between 2009 and 2012. We tested maternal blood for the presence of ZIKV IgM and IgG antibodies using commercially available human ZIKV IgM and IgG ELISA kits. Blood from one mother who delivered babies with microcephaly tested positive for ZIKV IgM antibody (16.6%) and blood from three mothers tested positive for ZIKV IgG antibody (50%). ZIKV showed a trend toward significance with microcephaly. ZIKV IgG antibody positive mothers were more likely to deliver babies with microcephaly than mothers who were negative for ZIKV IgG antibodies (Odds ratio [OR] = 11.0, 95% confidence interval [CI] = 0.8-147.9, p = 0.083). Similarly, ZIKV IgM antibody positive mothers were also more likely to deliver babies with microcephaly than mothers who were negative for ZIKV IgM antibody (OR = 6.8, 95% CI = 0.2-195.1). These data provide further evidence of a link between ZIKV infection and microcephaly and suggests presence of ZIKV positive cases and associated microcephaly in the United States as early as 2009. PMID- 27997548 TI - Using Diffusion Tensor Imaging to Evaluate Microstructural Changes and Outcomes after Radiofrequency Rhizotomy of Trigeminal Nerves in Patients with Trigeminal Neuralgia. AB - Trigeminal neuralgia is characterized by facial pain that may be sudden, intense, and recurrent. Our aim was to investigate microstructural tissue changes of the trigeminal nerve in patients with trigeminal neuralgia resulting from neurovascular compression by diffusion tensor imaging, and to test the predictive value of diffusion tensor imaging for determining outcomes after radiofrequency rhizotomy. Forty-three patients with trigeminal neuralgia were recruited, and diffusion tensor imaging was performed before radiofrequency rhizotomy. By selecting the cisternal segment of the trigeminal nerve manually, we measured the volume of trigeminal nerve, fractional anisotropy, apparent diffusion coefficient, axial diffusivity, and radial diffusivity. The apparent diffusion coefficient and mean value of fractional anisotropy, axial diffusivity, and radial diffusivity were compared between the affected and normal side in the same patient, and were correlated with pre-rhizotomy and post-rhizotomy visual analogue scale pain scores. The results showed the affected side had significantly decreased fractional anisotropy, increased apparent diffusion coefficient and radial diffusivity, and no significant change of axial diffusivity. The volume of the trigeminal nerve on affected side was also significantly smaller. There was a trend of fractional anisotropy reduction and visual analogue scale pain score reduction (P = 0.072). The results suggest that demyelination without axonal injury, and decreased size of the trigeminal nerve, are the microstructural abnormalities of the trigeminal nerve in patients with trigeminal neuralgia caused by neurovascular compression. The application of diffusion tensor imaging in understanding the pathophysiology of trigeminal neuralgia, and predicting the treatment effect has potential and warrants further study. PMID- 27997550 TI - Correction: Brucellosis Seropositivity in Animals and Humans in Ethiopia: A Meta analysis. AB - [This corrects the article DOI: 10.1371/journal.pntd.0005006.]. PMID- 27997549 TI - Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome. AB - Neuroblastoma is characterized by a relative paucity of recurrent somatic mutations at diagnosis. However, recent studies have shown that the mutational burden increases at relapse, likely as a result of clonal evolution of mutation carrying cells during primary treatment. To inform the development of personalized therapies, we sought to further define the frequency of potentially actionable mutations in neuroblastoma, both at diagnosis and after chemotherapy. We performed a retrospective study to determine mutation frequency, the only inclusion criterion being availability of cancer gene panel sequencing data from Foundation Medicine. We analyzed 151 neuroblastoma tumor samples: 44 obtained at diagnosis, 42 at second look surgery or biopsy for stable disease after chemotherapy, and 59 at relapse (6 were obtained at unknown time points). Nine patients had multiple tumor biopsies. ALK was the most commonly mutated gene in this cohort, and we observed a higher frequency of suspected oncogenic ALK mutations in relapsed disease than at diagnosis. Patients with relapsed disease had, on average, a greater number of mutations reported to be recurrent in cancer, and a greater number of mutations in genes that are potentially targetable with available therapeutics. We also observed an enrichment of reported recurrent RAS/MAPK pathway mutations in tumors obtained after chemotherapy. Our data support recent evidence suggesting that neuroblastomas undergo substantial mutational evolution during therapy, and that relapsed disease is more likely to be driven by a targetable oncogenic pathway, highlighting that it is critical to base treatment decisions on the molecular profile of the tumor at the time of treatment. However, it will be necessary to conduct prospective clinical trials that match sequencing results to targeted therapeutic intervention to determine if cancer genomic profiling improves patient outcomes. PMID- 27997551 TI - The Prevalence and Symptoms Characteristic of Functional Constipation Using Rome III Diagnostic Criteria among Tertiary Education Students. AB - BACKGROUND AND AIMS: Functional constipation is very common with heterogeneous symptoms that have substantial impact on patient quality of life as well as medical resources which are rarely reported as life-threatening. The aim of this study is to examine the prevalence and symptoms characteristic of functional constipation (FC) by using Rome III diagnostic criteria among tertiary education students with an intention to introduce treatment in the future. METHODS: Demographic, socio-economics characteristics and symptoms of FC using the Rome III criteria were sought using a questionnaire administered to Malaysian students in a tertiary education setting. Other data obtained were the general health status, lifestyle factors and anthropometric measurements. Using a simple random sampling method, a total of 1662 students were recruited in the study with a response rate of 95.0%. Sampled data are presented as frequency and percentage and stratified accordingly into categories for Chi-square analysis. RESULTS: The prevalence of functional constipation among the students was 16.2%, with a significantly higher prevalence among women (17.4%) than men (12.5%). Hard or lumpy stool, incomplete evacuation, anorectal obstruction and straining were reported as the commonest symptoms experienced. Type 3 was the most frequent stool consistency experienced among the constipated individuals (35.2%). Only 4.4% of individuals reported having less than three defecations per week. Using univariable analysis, FC was significantly associated with sex (odds ratio: 1.48, 95% CI: 1.06-2.06) and age group (odds ratio: 1.34, 95% CI: 1.01-1.79) with P value < 0.05 significance level. In multivariate logistic regression analysis, only sex was found significantly associated with FC (adjusted odds ratio: 1.53, 95% CI: 1.08-2.17, P < 0.05). CONCLUSIONS: Based on the prevalence rate, constipation is a common problem among tertiary education students (16.2%), with significantly more prevalence among the female respondents. Early detection of symptoms and further intervention studies focusing on treatment recommendation in improving the symptoms are essential. PMID- 27997552 TI - Hypothalamic L-Histidine Decarboxylase Is Up-Regulated During Chronic REM Sleep Deprivation of Rats. AB - A competition of neurobehavioral drives of sleep and wakefulness occurs during sleep deprivation. When enforced chronically, subjects must remain awake. This study examines histaminergic neurons of the tuberomammillary nucleus of the posterior hypothalamus in response to enforced wakefulness in rats. We tested the hypothesis that the rate-limiting enzyme for histamine biosynthesis, L-histidine decarboxylase (HDC), would be up-regulated during chronic rapid eye movement sleep deprivation (REM-SD) because histamine plays a major role in maintaining wakefulness. Archived brain tissues of male Sprague Dawley rats from a previous study were used. Rats had been subjected to REM-SD by the flowerpot paradigm for 5, 10, or 15 days. For immunocytochemistry, rats were transcardially perfused with acrolein-paraformaldehyde for immunodetection of L-HDC; separate controls used carbodiimide-paraformaldehyde for immunodetection of histamine. Immunolocalization of histamine within the tuberomammillary nucleus was validated using carbodiimide. Because HDC antiserum has cross-reactivity with other decarboxylases at high antibody concentrations, titrations localized L-HDC to only tuberomammillary nucleus at a dilution of >= 1:300,000. REM-SD increased immunoreactive HDC by day 5 and it remained elevated in both dorsal and ventral aspects of the tuberomammillary complex. Our results suggest that up-regulation of L-HDC within the tuberomammillary complex during chronic REM-SD may be responsible for maintaining wakefulness. PMID- 27997553 TI - Solar-Aligned Pictographs at the Paleoindian Site of Painel do Pilao along the Lower Amazon River at Monte Alegre, Brazil. AB - The archaeological sites near Monte Alegre, along Brazil's lower Amazon River, provide new information on the little-known activities and symbolism of South American Paleoindians toward the end of the Ice Age. While paleoindian sites like Monte Verde in Chile, or Guitarrero Cave in Peru, are located near the pacific coast, Monte Alegre lies much further inland, 680 km upriver from the mouth of the Amazon River and the Atlantic Coast. With excavated wood charcoal radiocarbon dated as early as 13,200 calibrated years ago, the hill-as a source of sandstone and quartz lithics-supplied early pioneers with adequate tools needed for colonizing the interior of the continent. Once there, they painted rock art on the landscape, which bears a record of the sun's horizon positions throughout the year. At just 2 degrees south of the equator, Monte Alegre shows no overt seasonal changes beyond fluctuating rainfall amounts, unlike at higher latitudes where temperature, amount of daylight, foliage, and forms of precipitation markedly change. Near the equator, solar and stellar horizon sightings most visibly track the passage of time and seasonal cycles. However, horizons are often hidden behind high forest canopy throughout much of the Amazon Rainforest; but in the Monte Alegre hill ridges looming above the river, paleoindians could hike above the canopy to peer at the horizon, more effectively synchronizing their activities to ecological cycles. This research suggests that Monte Alegre paleoindians delimited the azimuthal range of the sun in a solar year with notational pictographs aligned to horizon sightings at Painel do Pilao, and leaving a painted grid of tally marks that might have served as a rudimentary early calendar. The broad-reaching implication for early Americans is that through the strategic placement of rock art, these ancient artists fostered predictive archaeorecording from which resources could be optimally extracted, ceremonial activities could be consistently scheduled, and gatherings for social and economic exchange could be more efficiently coordinated. PMID- 27997554 TI - Drug Resistance and Virological Failure among HIV-Infected Patients after a Decade of Antiretroviral Treatment Expansion in Eight Provinces of China. AB - BACKGROUND: China's National Free Antiretroviral Treatment Program (NFATP) has substantially increased the survival rate since 2002. However, the emergence of HIV drug resistance (HIVDR) limits the durability and effectiveness of antiretroviral treatment (ART) in at risk patients. METHOD: A cross-sectional survey was conducted among patients having received a median of 13.9 months of ART in eight provinces in China. Demographic and clinical information was collected, and venous blood was sampled for CD4 cell counts, measurement of the HIV viral load (VL), and HIV drug resistance (HIVDR) genotyping. Possible risk factors for HIVDR were analyzed by the logistic regression model. RESULTS: The study included 765 patients. Among them, 65 patients (8.5%) had virological failure (VLF) defined as >=1,000 copies/ml. Among the individuals with VLF, 64 were successful genotyped, and of these, 33 had one or more HIVDR mutations. The prevalence of HIVDR mutations among patients receiving first-line ART was 4.3% (33/765). All of the patients with HIVDR mutations were resistant to non nucleoside transcriptase inhibitors, 81.8% were resistant to nucleoside reverse transcriptase inhibitors, and only 3% had mutations that caused resistance to protease inhibitors. Having lower ratios of drug intake in the past month and dwelling in two southwestern provinces were factors independently associated with the emergence of HIVDR. CONCLUSION: Most patients receiving first-line ART treatment achieved sound virological and immunological outcomes. However, poor adherence is still a key problem, which has led to the high rate of HIVDR. It was notable that the proportion of drug resistance widely varied among the provinces. More studies are needed to focus on adherence. PMID- 27997556 TI - Self-Organizing Global Gene Expression Regulated through Criticality: Mechanism of the Cell-Fate Change. AB - BACKGROUND: A fundamental issue in bioscience is to understand the mechanism that underlies the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome to regulate the change in cell fate. We address this issue by elucidating a physically motivated mechanism of self-organization. PRINCIPAL FINDINGS: Building upon transcriptome experimental data for seven distinct cell fates, including early embryonic development, we demonstrate that self-organized criticality (SOC) plays an essential role in the dynamic control of global gene expression regulation at both the population and single-cell levels. The novel findings are as follows: i) Mechanism of cell-fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). A cell-fate change occurs by means of a dissipative pulse-like global perturbation in self organization through the erasure of initial-state critical behaviors (criticality). Most notably, the reprogramming of early embryo cells destroys the zygote SOC control to initiate self-organization in the new embryonal genome, which passes through a stochastic overall expression pattern. ii) Mechanism of perturbation of SOC controls: Global perturbations in self-organization involve the temporal regulation of critical states. Quantitative evaluation of this perturbation in terminal cell fates reveals that dynamic interactions between critical states determine the critical-state coherent regulation. The occurrence of a temporal change in criticality perturbs this between-states interaction, which directly affects the entire genomic system. Surprisingly, a sub-critical state, corresponding to an ensemble of genes that shows only marginal changes in expression and consequently are considered to be devoid of any interest, plays an essential role in generating a global perturbation in self-organization directed toward the cell-fate change. CONCLUSION AND SIGNIFICANCE: 'Whole-genome' regulation of gene expression through self-regulatory SOC control complements gene-by-gene fine tuning and represents a still largely unexplored non equilibrium statistical mechanism that is responsible for the massive reprogramming of genome expression. PMID- 27997557 TI - Evidence Based Weighing Policy during the First Week to Prevent Neonatal Hypernatremic Dehydration while Breastfeeding. AB - BACKGROUND: Neonatal hypernatremic dehydration is prevented by daily neonatal weight monitoring. We aim to provide evidence-based support of this universally promoted weighing policy and to establish the most crucial days of weighing. METHODS: Weight measurements of 2,359 healthy newborns and of 271 newborns with clinical hypernatremic dehydration were used within the first seven days of life to simulate various weighting policies to prevent hypernatremic dehydration; its sensitivity, specificity and positive predictive value (PPV) of these policies were calculated. Various referral criteria were also evaluated. RESULTS: A policy of daily weighing with a cut-off value of -2.5 Standard Deviation Score (SDS) on the growth chart for weight loss, had a 97.6% sensitivity, 97.6% specificity and a PPV of 2.80%. Weighing at birth and only at days two, four and seven with the same -2.5 SDS cut-off, resulted in 97.3% sensitivity, 98.5% specificity and a PPV of 4.43%. CONCLUSION: A weighing policy with measurements restricted to birth and day two, four and seven applying the -2.5 SDS cut-off seems an optimal policy to detect hypernatremic dehydration. Therefore we recommend to preferably weigh newborns at least on day two (i.e. ~48h), four and seven, and refer them to clinical pediatric care if their weight loss increases below -2.5 SDS. We also suggest lactation support for the mother, full clinical assessment of the infant and weighing again the following day in all newborns reaching a weight loss below -2.0 SDS. PMID- 27997555 TI - Exploration of Serum Proteomic Profiling and Diagnostic Model That Differentiate Crohn's Disease and Intestinal Tuberculosis. AB - AIM: To explore the diagnostic models of Crohn's disease (CD), Intestinal tuberculosis (ITB) and the differential diagnostic model between CD and ITB by analyzing serum proteome profiles. METHODS: Serum proteome profiles from 30 CD patients, 21 ITB patients and 30 healthy controls (HCs) were analyzed by using weak cationic magnetic beads combined with MALDI-TOF-MS technique to detect the differentially expressed proteins of serum samples. Three groups were made and compared accordingly: group of CD patients and HCs, group of ITB patients and HCs, group of CD patients and ITB patients. Wilcoxon rank sum test was used to screen the ten most differentiated protein peaks (P < 0.05). Genetic algorithm combining with support vector machine (SVM) was utilized to establish the optimal diagnostic models for CD, ITB and the optimal differential diagnostic model between CD and ITB. The predictive effects of these models were evaluated by Leave one out (LOO) cross validation method. RESULTS: There were 236 protein peaks differently expressed between group of CD patients and HCs, 305 protein peaks differently expressed between group of ITB patients and HCs, 332 protein peaks differently expressed between group of CD patients and ITB patients. Ten most differentially expressed peaks were screened out between three groups respectively (P < 0.05) to establish diagnostic models and differential diagnostic model. A diagnostic model comprising of four protein peaks (M/Z 4964, 3029, 2833, 2900) can well distinguish CD patients and HCs, with a specificity and sensitivity of 96.7% and 96.7% respectively. A diagnostic model comprising four protein peaks (M/Z 3030, 2105, 2545, 4210) can well distinguish ITB patients and HCs, with a specificity and sensitivity of 93.3% and 95.2% respectively. A differential diagnostic model comprising three potential biomarkers protein peaks (M/Z 4267, 4223, 1541) can well distinguish CD patients and ITB patients, with a specificity and sensitivity of 76.2% and 80.0% respectively. Among the eleven protein peaks from the diagnostic models and differential diagnostic model, two have been successfully purified and identified, Those two peaks were M/Z 2900 from the diagnostic model between CD and HCs and M/Z 1541 from the differential diagnostic model between CD and ITB. M/Z 2900 was identified as appetite peptide, M/Z 1541 was identified as Lysyl oxidase-like 2 (LOXL-2). CONCLUSION: The differently expressed protein peaks analyzed by serum proteome with weak cationic magnetic beads combined MALDI-TOF-MS technique can effectively distinguish CD patients and HCs, ITB patients and HCs, CD patients and ITB patients. The diagnostic model between CD patients and HCs consisting of four protein peaks (M/Z 4964, 3029, 2833, 2900), the diagnostic model between ITB patients and HCs comprising four protein peaks (M/Z 3030, 2105, 2545, 4210) and the differential diagnostic model between CD patients and ITB patients comprising three protein peaks (M/Z 4267, 4223, 1541) had high specificity and sensitivity and can contribute to diagnoses of CD, ITB and the differential diagnosis between CD and ITB. Two proteins from the diagnostic model of CD and the differential diagnostic model between CD and ITB were identified. Further experiments are required using a larger cohort of samples. PMID- 27997558 TI - Beyond Synchrony: Joint Action in a Complex Production Task Reveals Beneficial Effects of Decreased Interpersonal Synchrony. AB - A variety of joint action studies show that people tend to fall into synchronous behavior with others participating in the same task, and that such synchronization is beneficial, leading to greater rapport, satisfaction, and performance. It has been noted that many of these task environments require simple interactions that involve little planning of action coordination toward a shared goal. The present study utilized a complex joint construction task in which dyads were instructed to build model cars while their hand movements and heart rates were measured. Participants built these models under varying conditions, delimiting how freely they could divide labor during a build session. While hand movement synchrony was sensitive to the different tasks and outcomes, the heart rate measure did not show any effects of interpersonal synchrony. Results for hand movements show that the more participants were constrained by a particular building strategy, the greater their behavioral synchrony. Within the different conditions, the degree of synchrony was predictive of subjective satisfaction and objective product outcomes. However, in contrast to many previous findings, synchrony was negatively associated with superior products, and, depending on the constraints on the interaction, positively or negatively correlated with higher subjective satisfaction. These results show that the task context critically shapes the role of synchronization during joint action, and that in more complex tasks, not synchronization of behavior, but rather complementary types of behavior may be associated with superior task outcomes. PMID- 27997559 TI - Optimizing Surveillance Performance of Alpha-Fetoprotein by Selection of Proper Target Population in Chronic Hepatitis B. AB - Although alpha-fetoprotein (AFP) is the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance, disease activity may also increase AFP levels in chronic hepatitis B (CHB). Since nucleos(t)ide analog (NA) therapy may reduce not only HBV viral loads and transaminase levels but also the falsely elevated AFP levels in CHB, we tried to determine whether exposure to NA therapy influences AFP performance and whether selective application can optimize the performance of AFP testing in CHB during HCC surveillance. A retrospective cohort of 6,453 CHB patients who received HCC surveillance was constructed from the electronic clinical data warehouse. Covariates of AFP elevation were determined from 53,137 AFP measurements, and covariate-specific receiver operating characteristics regression analysis revealed that albumin levels and exposure to NA therapy were independent determinants of AFP performance. C statistics were largest in patients with albumin levels >= 3.7 g/dL who were followed without NA therapy during study period, whereas AFP performance was poorest when tested in patients with NA therapy during study and albumin levels were < 3.7 g/dL (difference in C statics = 0.35, p < 0.0001). Contrary to expectation, CHB patients with current or recent exposure to NA therapy showed poorer performance of AFP during HCC surveillance. Combination of concomitant albumin levels and status of NA therapy can identify subgroup of CHB patients who will show optimized AFP performance. PMID- 27997560 TI - Activation of Human Salivary Aldehyde Dehydrogenase by Sulforaphane: Mechanism and Significance. AB - Cruciferous vegetables contain the bio-active compound sulforaphane (SF) which has been reported to protect individuals against various diseases by a number of mechanisms, including activation of the phase II detoxification enzymes. In this study, we show that the extracts of five cruciferous vegetables that we commonly consume and SF activate human salivary aldehyde dehydrogenase (hsALDH), which is a very important detoxifying enzyme in the mouth. Maximum activation was observed at 1 MUg/ml of cabbage extract with 2.6 fold increase in the activity. There was a ~1.9 fold increase in the activity of hsALDH at SF concentration of >= 100 nM. The concentration of SF at half the maximum response (EC50 value) was determined to be 52 +/- 2 nM. There was an increase in the Vmax and a decrease in the Km of the enzyme in the presence of SF. Hence, SF interacts with the enzyme and increases its affinity for the substrate. UV absorbance, fluorescence and CD studies revealed that SF binds to hsALDH and does not disrupt its native structure. SF binds with the enzyme with a binding constant of 1.23 x 107 M-1. There is one binding site on hsALDH for SF, and the thermodynamic parameters indicate the formation of a spontaneous strong complex between the two. Molecular docking analysis depicted that SF fits into the active site of ALDH3A1, and facilitates the catalytic mechanism of the enzyme. SF being an antioxidant, is very likely to protect the catalytic Cys 243 residue from oxidation, which leads to the increase in the catalytic efficiency and hence the activation of the enzyme. Further, hsALDH which is virtually inactive towards acetaldehyde exhibited significant activity towards it in the presence of SF. It is therefore very likely that consumption of large quantities of cruciferous vegetables or SF supplements, through their activating effect on hsALDH can protect individuals who are alcohol intolerant against acetaldehyde toxicity and also lower the risk of oral cancer development. PMID- 27997561 TI - On Emulation of Flueric Devices in Excitable Chemical Medium. AB - Flueric devices are fluidic devices without moving parts. Fluidic devices use fluid as a medium for information transfer and computation. A Belousov Zhabotinsky (BZ) medium is a thin-layer spatially extended excitable chemical medium which exhibits travelling excitation wave-fronts. The excitation wave fronts transfer information. Flueric devices compute via jets interaction. BZ devices compute via excitation wave-fronts interaction. In numerical model of BZ medium we show that functions of key flueric devices are implemented in the excitable chemical system: signal generator, and, xor, not and nor Boolean gates, delay elements, diodes and sensors. Flueric devices have been widely used in industry since late 1960s and are still employed in automotive and aircraft technologies. Implementation of analog of the flueric devices in the excitable chemical systems opens doors to further applications of excitation wave-based unconventional computing in soft robotics, embedded organic electronics and living technologies. PMID- 27997562 TI - Genome-Wide Association Study Reveals the PLAG1 Gene for Knuckle, Biceps and Shank Weight in Simmental Beef Cattle. AB - Carcass traits of beef cattle have been genetically improved to increase yield of high quality meat. Genome-wide association study (GWAS) is a powerful method to identify genetic variants associated with carcass traits. For the 770K genotyped SNPs from 1141 Chinese Simmental cattle, we used the compressed mixed linear model (CMLM) to perform a genome-wide association study for knuckle, biceps and shank of beef carcass traits. Seventeen significantly associated SNPs were found, which are located on BTA6, BTA14 and BTA15. Interestingly, one pleiotropic quantitative trait nucleotide (QTN), named BovineHD1400007259 (p < 10-8) within the well-known gene region PLAG1-CHCHD7 on BTA14, was found to govern variation of the knuckle, biceps and shank traits. The QTN accounted for 8.6% of phenotypic variance for biceps. In addition, 16 more SNPs distributed on BTA14 were detected as being associated with the carcass traits. PMID- 27997563 TI - DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment. AB - BACKGROUND: Novel direct-acting antivirals (DAAs) have completely changed the panorama of hepatitis C due to their high efficacy and optimal safety profile. Unfortunately, an unexpectedly high rate of early recurrence of hepatocellular carcinoma has been reported within weeks of starting treatment, but the mechanism is not known. METHODS: We monitored the serum level of vascular endothelial growth factor (VEGF) and changes in the pattern of circulating interleukins in 103 chronic hepatitis C patients during antiviral treatment with DAA-regimens. VEGF, epidermal growth factor (EGF), and several interleukins were assessed at baseline, during treatment, and after treatment. The biological effect of DAA treated patient serum on human umbilical vein endothelial cell (HUVEC) proliferation was also confirmed. RESULTS: After 4 weeks of therapy, VEGF increased approximately 4-fold compared to baseline, remained elevated up to the end of treatment, and returned to the pre-treatment level after the end of therapy. In contrast, interleukin-10 and tumor necrosis factor-alpha significantly decreased during therapy, which was coincident with HCV clearance. The levels of both remained low after treatment. The addition of serum from patients collected during therapy induced HUVEC proliferation; however, this disappeared after the end of therapy. CONCLUSIONS: DAA administration induces an early increase in serum VEGF and a change in the inflammatory pattern, coinciding with HCV clearance. This may alter the balance between inflammatory and anti inflammatory processes and modify the antitumor surveillance of the host. Fortunately, such modifications return reverse to normal after the end of treatment. PMID- 27997564 TI - Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize Type I Interferon Production. AB - Type I interferons (IFN-alpha/beta) play a key role in antiviral defense, and porcine reproductive and respiratory syndrome virus (PRRSV) is known to down regulate the IFN response in virus-infected cells and pigs. In this study, we showed that the overexpression of nsp11 of PRRSV induced a strong suppression of IFN production. Nsp11 suppressed both IRF3 and NF-kappaB activities when stimulated with a dsRNA analogue and TNF-alpha, respectively. This suppression was RLR dependent, since the transcripts and proteins of MAVS and RIG-I, two critical factors in RLR-mediated pathway, were both found to be reduced in the presence of overexpressed nsp11. Since nsp11 is an endoribonuclease (EndoU), the structure function relationship was examined using a series of nsp11 EndoU mutant plasmids. The mutants that impaired the EndoU activity failed to suppress IFN and led to the normal expression of MAVS. Seven single amino acid substitutions (4 in subdomain A and 3 in subdomain B) plus one insertion (frame-shift in nsp11) were then introduced into PRRSV infectious cDNA clones to generate nsp11 mutant viruses. Unfortunately, all EndoU knock-out nsp11 mutant viruses appeared replication-defective and no progenies were produced. Three mutations in EndoU subdomain A expressed the N and nsp2/3 proteins but their infectivity diminished after 2 passages. Taken together, our data show that PRRSV nsp11 endoribonuclease activity is critical for both viral replication and IFN antagonism. More importantly, the endoribonuclease activity of nsp11 demonstrates the substrate specificity towards MAVS and RIG-I (transcripts and proteins) over p65 and IRF3 in the context of gene transfection and overexpression. This is likely a mechanism of nsp11 suppression of type I IFN production. PMID- 27997565 TI - In Vivo, Non-Invasive Characterization of Human Bone by Hybrid Broadband (600 1200 nm) Diffuse Optical and Correlation Spectroscopies. AB - Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600-1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care. PMID- 27997566 TI - Autonomous Vehicles: Disengagements, Accidents and Reaction Times. AB - Autonomous vehicles are being viewed with scepticism in their ability to improve safety and the driving experience. A critical issue with automated driving at this stage of its development is that it is not yet reliable and safe. When automated driving fails, or is limited, the autonomous mode disengages and the drivers are expected to resume manual driving. For this transition to occur safely, it is imperative that drivers react in an appropriate and timely manner. Recent data released from the California trials provide compelling insights into the current factors influencing disengagements of autonomous mode. Here we show that the number of accidents observed has a significantly high correlation with the autonomous miles travelled. The reaction times to take control of the vehicle in the event of a disengagement was found to have a stable distribution across different companies at 0.83 seconds on average. However, there were differences observed in reaction times based on the type of disengagements, type of roadway and autonomous miles travelled. Lack of trust caused by the exposure to automated disengagements was found to increase the likelihood to take control of the vehicle manually. Further, with increased vehicle miles travelled the reaction times were found to increase, which suggests an increased level of trust with more vehicle miles travelled. We believe that this research would provide insurers, planners, traffic management officials and engineers fundamental insights into trust and reaction times that would help them design and engineer their systems. PMID- 27997567 TI - Red and Green Fluorescence from Oral Biofilms. AB - Red and green autofluorescence have been observed from dental plaque after excitation by blue light. It has been suggested that this red fluorescence is related to caries and the cariogenic potential of dental plaque. Recently, it was suggested that red fluorescence may be related to gingivitis. Little is known about green fluorescence from biofilms. Therefore, we assessed the dynamics of red and green fluorescence in real-time during biofilm formation. In addition, the fluorescence patterns of biofilm formed from saliva of eight different donors are described under simulated gingivitis and caries conditions. Biofilm formation was analysed for 12 hours under flow conditions in a microfluidic BioFlux flow system with high performance microscopy using a camera to allow live cell imaging. For fluorescence images dedicated excitation and emission filters were used. Both green and red fluorescence were linearly related with the total biomass of the biofilms. All biofilms displayed to some extent green and red fluorescence, with higher red and green fluorescence intensities from biofilms grown in the presence of serum (gingivitis simulation) as compared to the sucrose grown biofilms (cariogenic simulation). Remarkably, cocci with long chain lengths, presumably streptococci, were observed in the biofilms. Green and red fluorescence were not found homogeneously distributed within the biofilms: highly fluorescent spots (both green and red) were visible throughout the biomass. An increase in red fluorescence from the in vitro biofilms appeared to be related to the clinical inflammatory response of the respective saliva donors, which was previously assessed during an in vivo period of performing no-oral hygiene. The BioFlux model proved to be a reliable model to assess biofilm fluorescence. With this model, a prediction can be made whether a patient will be prone to the development of gingivitis or caries. PMID- 27997568 TI - Longipin: An Amyloid Antimicrobial Peptide from the Harvestman Acutisoma longipes (Arachnida: Opiliones) with Preferential Affinity for Anionic Vesicles. AB - In contrast to vertebrate immune systems, invertebrates lack an adaptive response and rely solely on innate immunity in which antimicrobial peptides (AMPs) play an essential role. Most of them are membrane active molecules that are typically unstructured in solution and adopt secondary/tertiary structures upon binding to phospholipid bilayers. This work presents the first characterization of a constitutive AMP from the hemolymph of an Opiliones order animal: the harvestman Acutisoma longipes. This peptide was named longipin. It presents 18 aminoacid residues (SGYLPGKEYVYKYKGKVF) and a positive net charge at neutral pH. No similarity with other AMPs was observed. However, high sequence similarity with heme-lipoproteins from ticks suggested that longipin might be a protein fragment. The synthetic peptide showed enhanced antifungal activity against Candida guilliermondii and C. tropicalis yeasts (MIC: 3.8-7.5 MUM) and did not interfered with VERO cells line viability at all concentrations tested (200-0.1 MUM). This selectivity against microbial cells is related to the highest affinity of longipin for anionic charged vesicles (POPG:POPC) compared to zwitterionic ones (POPC), once microbial plasma membrane are generally more negatively charged compared to mammalian cells membrane. Dye leakage from carboxyfluorescein-loaded POPG:POPC vesicles suggested that longipin is a membrane active antimicrobial peptide and FT-IR spectroscopy showed that the peptide chain is mainly unstructured in solution or in the presence of POPC vesicles. However, upon binding to POPG:POPC vesicles, the FT-IR spectrum showed bands related to beta sheet and amyloid-like fibril conformations in agreement with thioflavin-T binding assays, indicating that longipin is an amyloid antimicrobial peptide. PMID- 27997569 TI - Three-Dimensional Arrangement of Human Bone Marrow Microvessels Revealed by Immunohistology in Undecalcified Sections. AB - The arrangement of microvessels in human bone marrow is so far unknown. We combined monoclonal antibodies against CD34 and against CD141 to visualise all microvessel endothelia in 21 serial sections of about 1 cm2 size derived from a human iliac crest. The specimen was not decalcified and embedded in Technovit(r) 9100. In different regions of interest, the microvasculature was reconstructed in three dimensions using automatic methods. The three-dimensional models were subject to a rigid semiautomatic and manual quality control. In iliac crest bone marrow, the adipose tissue harbours irregularly distributed haematopoietic areas. These are fed by networks of large sinuses, which are loosely connected to networks of small capillaries prevailing in areas of pure adipose tissue. Our findings are compatible with the hypothesis that capillaries and sinuses in human iliac crest bone marrow are partially arranged in parallel. PMID- 27997570 TI - The Study on Biological Function of Keratin 26, a Novel Member of Liaoning Cashmere Goat Keratin Gene Family. AB - In our research, we explored the relationship between Keratin 26 and the regulation of fine hair, BMP signaling pathway, MT, FGF5, and IGF-I. The result of hybridization in situ revealed that Keratin 26 was specially expressed in cortex of skin hair follicles; the result of immunohistochemistry indicated that Keratin 26 was expressed in internal root sheath, external root sheath. Then, Real-time quantitative PCR results showed that relative expressive quantity of Keratin 26 was 1.08 or 3.3 * greater in secondary follicle than primary follicle during anagen or catagen; the difference during anagen was not remarkable (p>0.05), however, that of catagen was extremely significant (p<0.01). Relative expressive quantity of Keratin 26 increased during telogen; the difference was extremely significant (p<0.01). Moreover, after Noggin expression interference using RNAi technology, we found that relative expressive quantity of Keratin 26 extremely remarkably declined (p<0.01); after K26 overexpression, we found that relative expressive quantity of Noggin extremely remarkably increased (p<0.01). We detected expressive quantity change of Keratin 26 and Keratin 26 using Real time quantitative PCR and immunofluorescence technologies after fibroblasts were treated with MT, FGF5 or IGF-I; the results indicated that MT and FGF5 played a positive role in Keratin 26 and Keratin 26 expression, IGF-I played a negative role in Keratin 26 expression, positive role in Keratin 26 expression. The results above showed that Keratin 26 could inhibit cashmere growth, and was related to entering to catagen and telogen of hair follicles; Keratin 26 and BMP signaling pathway were two antagonistic pathways each other which could inhibit growth and development of cashmere; MT, FGF5 and IGF-I could affect expression of Keratin 26 and Keratin 26, and Keratin 26 was one of the important pathways that MT induced cashmere production in advance, FGF5 regulated cashmere growth and IGF I promoted cashmere growth and development. PMID- 27997571 TI - Assessing the Impact of U.S. Food Assistance Delivery Policies on Child Mortality in Northern Kenya. AB - The U.S. is the main country in the world that delivers its food assistance primarily via transoceanic shipments of commodity-based in-kind food. This approach is costlier and less timely than cash-based assistance, which includes cash transfers, food vouchers, and local and regional procurement, where food is bought in or nearby the recipient country. The U.S.'s approach is exacerbated by a requirement that half of its transoceanic food shipments need to be sent on U.S.-flag vessels. We estimate the effect of these U.S. food assistance distribution policies on child mortality in northern Kenya by formulating and optimizing a supply chain model. In our model, monthly orders of transoceanic shipments and cash-based interventions are chosen to minimize child mortality subject to an annual budget constraint and to policy constraints on the allowable proportions of cash-based interventions and non-US-flag shipments. By varying the restrictiveness of these policy constraints, we assess the impact of possible changes in U.S. food aid policies on child mortality. The model includes an existing regression model that uses household survey data and geospatial data to forecast the mean mid-upper-arm circumference Z scores among children in a community, and allows food assistance to increase Z scores, and Z scores to influence mortality rates. We find that cash-based interventions are a much more powerful policy lever than the U.S.-flag vessel requirement: switching to cash based interventions reduces child mortality from 4.4% to 3.7% (a 16.2% relative reduction) in our model, whereas eliminating the U.S.-flag vessel restriction without increasing the use of cash-based interventions generates a relative reduction in child mortality of only 1.1%. The great majority of the gains achieved by cash-based interventions are due to their reduced cost, not their reduced delivery lead times; i.e., the reduction of shipping expenses allows for more food to be delivered, which reduces child mortality. PMID- 27997572 TI - The Impact of Deoxynivalenol on Pigeon Health: Occurrence in Feed, Toxicokinetics and Interaction with Salmonellosis. AB - Seed-based pigeon diets could be expected to result in exposure of pigeons to mycotoxins such as deoxynivalenol (DON). Ingestion of low to moderate contamination levels of DON may impair intestinal health, immune function and/or pathogen fitness, resulting in altered host-pathogen interactions and thus different outcome of infections. Here we demonstrate that DON was one of the most frequently detected mycotoxins in seed-based racing pigeons feed, contaminating 5 out of 10 samples (range 177-1,466 MUg/kg). Subsequently, a toxicokinetic analysis revealed a low absolute oral bioavailability (F) of DON in pigeons (30.4%), which is comparable to other avian species. Furthermore, semi quantitative analysis using high-resolution mass spectrometry revealed that DON 3alpha-sulphate is the major metabolite of DON in pigeons after intravenous as well as oral administration. Following ingestion of DON contaminated feed, the intestinal epithelial cells are exposed to significant DON concentrations which eventually may affect intestinal translocation and colonization of bacteria. Feeding pigeons a DON contaminated diet resulted in an increased percentage of pigeons shedding Salmonella compared to birds fed control diet, 87 +/- 17% versus 74 +/- 13%, respectively. However, no impact of DON was observed on the Salmonella induced disease signs, organ lesions, faecal and organ Salmonella counts. The presented risk assessment indicates that pigeons are frequently exposed to mycotoxins such as DON, which can affect the outcome of a Salmonella infection. The increasing number of pigeons shedding Salmonella suggests that DON can promote the spread of the bacterium within pigeon populations. PMID- 27997573 TI - Genetic Characterization of Circulating 2015 A(H1N1)pdm09 Influenza Viruses from Eastern India. AB - In 2015, the swine derived A(H1N1)pdm09 pandemic strain outbreak became widespread throughout the different states of India. The reported cases and deaths in 2015 surpassed the previous years with more than 39000 laboratory confirmed cases and a death toll of more than 2500 people. There are relatively limited complete genetic sequences available for this virus from Asian countries. In this study, we describe the full genome analysis of influenza 2015 A(H1N1)pdm09 viruses isolated from West Bengal between January through December 2015. The phylogenetic analysis of the haemagglutinin sequence revealed clustering with globally circulating strains of genogroup 6B. This was further confirmed by the constructed concatenated tree using all eight complete gene segments of Kolkata A(H1N1)pdm09 isolates with the other strains from different timeline and lineages. A study from Massachusetts Institute of Technology (MIT) in 2015 reported novel mutations T200A and D225N in haemagglutinin gene of a 2014 Indian strain (A/India/6427/2014). However, in all the pandemic strains of 2014 2015 reported from India, so far including A(H1N1)pdm09 strains from Kolkata, D225N mutation was not observed, though the T200A mutation was found to be conserved. Neuraminidase gene of the analyzed strains did not show any oseltamivir resistant mutation H275Y suggesting continuation of Tamiflu(r) as drug of choice. The amino acid sequences of the all gene segments from 2015 A(H1N1)pdm09 isolates identified several new mutations compared to the 2009 A(H1N1)pdm09 strains, which may have contributed towards enhanced virulence, compared to 2009 A(H1N1)pdm09 strains. PMID- 27997574 TI - Rheumatoid Arthritis Was Negatively Associated with Alzheimer's Disease: A Population-Based Case-Control Study. AB - Some of the prior literature investigated the potential association between rheumatoid arthritis (RA) and Alzheimer's disease (AD) because these two diseases may share similar inflammatory mechanisms. Nevertheless, to date, findings of the previous literature are still controversial, and some methodological limitations were observed in those studies. The aim of this case-control study was to investigate the relationship between prior RA and AD using a large population based dataset. This study used the Taiwan Longitudinal Health Insurance Database 2005. We included 2271 patients with AD who had received prescriptions for acetylcholinesterase inhibitors (AChEIs) as cases and 6813 patients without AD as controls in this study. In addition, we performed a conditional logistic regression to examine the odds ratio (OR) and 95% confidence interval (CI) for prior RA between cases and controls. The study found that 330 (3.63%) of the total sampled patients had an RA diagnosis before the index date. Additionally, prior RA was found in 60 (2.64%) cases and in 270 (3.96%) controls. The conditional logistic regression analysis showed that the crude OR of prior RA for cases was 0.66 (95% confidence interval (CI): 0.49~0.87) compared to controls. After adjusting for patients' geographic location, urbanization level, and comorbidities, the adjusted OR of prior RA for patients with AD was 0.73 (95% CI: 0.55~0.98) compared to those without AD. We concluded that there was an inverse association between prior RA and AD even after adjusting for potential confounders. PMID- 27997575 TI - The Heat Shock Transcription Factor HSF1 Induces Ovarian Cancer Epithelial Mesenchymal Transition in a 3D Spheroid Growth Model. AB - Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. The proteotoxic stress-responsive transcription factor HSF1 is frequently overexpressed in a variety of cancers and is vital to cellular proliferation and invasion in some cancers. Upon analysis of various patient data sets, we find that HSF1 is frequently overexpressed in ovarian tumor samples. In order to determine the role of HSF1 in ovarian cancer, inducible HSF1 knockdown cell lines were created. Knockdown of HSF1 in SKOV3 and HEY ovarian cancer cell lines attenuates the epithelial-to-mesenchymal transition (EMT) in cells treated with TGFbeta, as determined by western blot and quantitative RT-PCR analysis of multiple EMT markers. To further explore the role of HSF1 in ovarian cancer EMT, we cultured multicellular spheroids in a non-adherent environment to simulate early avascular tumors. In the spheroid model, cells more readily undergo EMT; however, EMT inhibition by HSF1 becomes more pronounced in the spheroid model. These findings suggest that HSF1 is important in the ovarian cancer TGFbeta response and in EMT. PMID- 27997576 TI - Reconciling Mining with the Conservation of Cave Biodiversity: A Quantitative Baseline to Help Establish Conservation Priorities. AB - Caves pose significant challenges for mining projects, since they harbor many endemic and threatened species, and must therefore be protected. Recent discussions between academia, environmental protection agencies, and industry partners, have highlighted problems with the current Brazilian legislation for the protection of caves. While the licensing process is long, complex and cumbersome, the criteria used to assign caves into conservation relevance categories are often subjective, with relevance being mainly determined by the presence of obligate cave dwellers (troglobites) and their presumed rarity. However, the rarity of these troglobitic species is questionable, as most remain unidentified to the species level and their habitats and distribution ranges are poorly known. Using data from 844 iron caves retrieved from different speleology reports for the Carajas region (South-Eastern Amazon, Brazil), one of the world's largest deposits of high-grade iron ore, we assess the influence of different cave characteristics on four biodiversity proxies (species richness, presence of troglobites, presence of rare troglobites, and presence of resident bat populations). We then examine how the current relevance classification scheme ranks caves with different biodiversity indicators. Large caves were found to be important reservoirs of biodiversity, so they should be prioritized in conservation programs. Our results also reveal spatial autocorrelation in all the biodiversity proxies assessed, indicating that iron caves should be treated as components of a cave network immersed in the karst landscape. Finally, we show that by prioritizing the conservation of rare troglobites, the current relevance classification scheme is undermining overall cave biodiversity and leaving ecologically important caves unprotected. We argue that conservation efforts should target subterranean habitats as a whole and propose an alternative relevance ranking scheme, which could help simplify the assessment process and channel more resources to the effective protection of overall cave biodiversity. PMID- 27997577 TI - Spatial Accessibility to Health Care Services: Identifying under-Serviced Neighbourhoods in Canadian Urban Areas. AB - BACKGROUND: Urban environments can influence many aspects of health and well being and access to health care is one of them. Access to primary health care (PHC) in urban settings is a pressing research and policy issue in Canada. Most research on access to healthcare is focused on national and provincial levels in Canada; there is a need to advance current understanding to local scales such as neighbourhoods. METHODS: This study examines spatial accessibility to family physicians using the Three-Step Floating Catchment Area (3SFCA) method to identify neighbourhoods with poor geographical access to PHC services and their spatial patterning across 14 Canadian urban settings. An index of spatial access to PHC services, representing an accessibility score (physicians-per-1000 population), was calculated for neighborhoods using a 3km road network distance. Information about primary health care providers (this definition does not include mobile services such as health buses or nurse practitioners or less distributed services such as emergency rooms) used in this research was gathered from publicly available and routinely updated sources (i.e. provincial colleges of physicians and surgeons). An integrated geocoding approach was used to establish PHC locations. RESULTS: The results found that the three methods, Simple Ratio, Neighbourhood Simple Ratio, and 3SFCA that produce City level access scores are positively correlated with each other. Comparative analyses were performed both within and across urban settings to examine disparities in distributions of PHC services. It is found that neighbourhoods with poor accessibility scores in the main urban settings across Canada have further disadvantages in relation to population high health care needs. CONCLUSIONS: The results of this study show substantial variations in geographical accessibility to PHC services both within and among urban areas. This research enhances our understanding of spatial accessibility to health care services at the neighbourhood level. In particular, the results show that the low access neighbourhoods tend to be clustered in the neighbourhoods at the urban periphery and immediately surrounding the downtown area. PMID- 27997578 TI - Identification and Characterisation of a Novel Protein FIP-sch3 from Stachybotrys chartarum. AB - In this study, a novel FIP named FIP-sch3 has been identified and characterised. FIP-sch3 was identified in the ascomycete Stachybotrys chartarum, making it the second FIP to be identified outside the order of Basidiomycota. Recombinant FIP sch3 (rFIP-shc3) was produced in Escherichia coli and purified using GST-affinity magnetic beads. The bioactive characteristics of FIP-sch3 were compared to those of well-known FIPs LZ-8 from Ganoderma lucidum and FIP-fve from Flammulina velutipes, which were produced and purified using the same method. The purified rFIP-sch3 exhibited a broad spectrum of anti-tumour activity in several types of tumour cells but had no cytotoxicity in normal human embryonic kidney 293 cells. Assays that were implemented to study these properties indicated that rFIP-sch3 significantly suppressed cell proliferation, induced apoptosis and inhibited cell migration in human lung adenocarcinoma A549 cells. The anti-tumour effects of rFIP-sch3 in A549 cells were comparable to those of rLZ-8, but they were significantly greater than those of rFIP-fve. Molecular assays that were built on real-time PCR further revealed potential mechanisms related to apoptosis and migration and that underlie phenotypic effects. These results indicate that FIP shc3 has a unique anti-tumour bioactive profile, as do other FIPs, which provide a foundation for further studies on anti-tumour mechanisms. Importantly, this study also had convenient access to FIP-sch3 with potential human therapeutic applications. PMID- 27997579 TI - The C-Terminal SynMuv/DdDUF926 Domain Regulates the Function of the N-Terminal Domain of DdNKAP. AB - NKAP (NF-kappaB activating protein) is a highly conserved SR (serine/arginine rich) protein involved in transcriptional control and splicing in mammals. We identified DdNKAP, the Dictyostelium discoideum ortholog of mammalian NKAP, as interacting partner of the nuclear envelope protein SUN-1. DdNKAP harbors a number of basic RDR/RDRS repeats in its N-terminal domain and the SynMuv/DUF926 domain at its C-terminus. We describe a novel and direct interaction between DdNKAP and Prp19 (Pre mRNA processing factor 19) which might be relevant for the observed DdNKAP ubiquitination. Genome wide analysis using cross-linking immunoprecipitation-high-throughput sequencing (CLIP-seq) revealed DdNKAP association with intergenic regions, exons, introns and non-coding RNAs. Ectopic expression of DdNKAP and its domains affects several developmental aspects like stream formation, aggregation, and chemotaxis. We conclude that DdNKAP is a multifunctional protein, which might influence Dictyostelium development through its interaction with RNA and RNA binding proteins. Mutants overexpressing full length DdNKAP and the N-terminal domain alone (DdN-NKAP) showed opposite phenotypes in development and opposite expression profiles of several genes and rRNAs. The observed interaction between DdN-NKAP and the DdDUF926 domain indicates that the DdDUF926 domain acts as negative regulator of the N-terminus. PMID- 27997580 TI - Natalizumab-Related Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis: Findings from an Italian Independent Registry. AB - BACKGROUND: The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). OBJECTIVE: To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. METHODS: An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. RESULTS: Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01). CONCLUSION: Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients. PMID- 27997582 TI - (GT)n Repeat Polymorphism in Heme Oxygenase-1 (HO-1) Correlates with Clinical Outcome after Myeloablative or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation. AB - Allogeneic hematopoietic cell transplantation (HCT) is a treatment for various hematologic diseases where efficacy of treatment is in part based on the graft versus tumour (GVT) activity of cells in the transplant. The cytoprotective enzyme heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation and it has been shown to exert anti-inflammatory functions. In humans a (GT)n repeat polymorphism regulates the expression of HO-1. We conducted fragment length analyses of the (GT)n repeat in the promotor region of the gene for HO-1 in DNA from donors and recipients receiving allogeneic myeloablative- (MA) (n = 110) or nonmyeloablative- (NMA-) (n = 250) HCT. Subsequently, we compared the length of the (GT)n repeat with clinical outcome after HCT. We demonstrated that transplants from a HO-1high donor after MA-conditioning (n = 13) is associated with higher relapse incidence at 3 years (p = 0.01, n = 110). In the NMA conditioning setting transplantation of HO-1low donor cells into HO-1low recipients correlated significantly with decreased relapse related mortality (RRM) and longer progression free survival (PFS) (p = 0.03 and p = 0.008, respectively). Overall, our findings suggest that HO-1 may play a role for the induction of GVT effect after allogeneic HCT. PMID- 27997581 TI - Identification of Polycystic Ovary Syndrome (PCOS) Specific Genes in Cumulus and Mural Granulosa Cells. AB - Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder which affects women of reproductive age with prevalence of 8-18%. The oocyte within the follicle is surrounded by cumulus cells (CCs), which connect with mural granulosa cells (MGCs) that are responsible for secreting steroid hormones. The main aim of this study is comparing gene expression profiles of MGCs and CCs in PCOS and control samples to identify PCOS-specific differentially expressed genes (DEGs). In this study, two microarray databases were searched for mRNA expression microarray studies performed with CCs and MGCs obtained from PCOS patients and control samples. Three independent studies were selected to be integrated with naive meta-analysis since raw meta-data from these studies were found to be highly correlated. DEGs in these somatic cells were identified for PCOS and control groups. This study enabled us to reveal dysregulation in MAPK (mitogen activated protein kinase), insulin and Wnt signaling pathways between CCs and MGCs in PCOS. The meta-analysis results together with qRT-PCR validations provide evidence that molecular signaling is dysregulated through MGCs and CCs in PCOS, which is important for follicle and oocyte maturation and may contribute to the pathogenesis of the syndrome. PMID- 27997583 TI - Rapid Generation of Marker-Free P. falciparum Fluorescent Reporter Lines Using Modified CRISPR/Cas9 Constructs and Selection Protocol. AB - The CRISPR/Cas9 system is a powerful genome editing technique employed in a wide variety of organisms including recently the human malaria parasite, P. falciparum. Here we report on further improvements to the CRISPR/Cas9 transfection constructs and selection protocol to more rapidly modify the P. falciparum genome and to introduce transgenes into the parasite genome without the inclusion of drug-selectable marker genes. This method was used to stably integrate the gene encoding GFP into the P. falciparum genome under the control of promoters of three different Plasmodium genes (calmodulin, gapdh and hsp70). These genes were selected as they are highly transcribed in blood stages. We show that the three reporter parasite lines generated in this study (GFP@cam, GFP@gapdh and GFP@hsp70) have in vitro blood stage growth kinetics and drug sensitivity profiles comparable to the parental P. falciparum (NF54) wild-type line. Both asexual and sexual blood stages of the three reporter lines expressed GFP-fluorescence with GFP@hsp70 having the highest fluorescent intensity in schizont stages as shown by flow cytometry analysis of GFP-fluorescence intensity. The improved CRISPR/Cas9 constructs/protocol will aid in the rapid generation of transgenic and modified P. falciparum parasites, including those expressing different reporters proteins under different (stage specific) promoters. PMID- 27997584 TI - Prediction of Possible Biomarkers and Novel Pathways Conferring Risk to Post Traumatic Stress Disorder. AB - Post-traumatic stress disorder is one of the common mental ailments that is triggered by exposure to traumatic events. Till date, the molecular factors conferring risk to the development of PTSD is not well understood. In this study, we have conducted a meta-analysis followed by hierarchical clustering and functional enrichment, to uncover the potential molecular networks and critical genes which play an important role in PTSD. Two datasets of expression profiles from Peripheral Blood Mononuclear Cells from 62 control samples and 63 PTSD samples were included in our study. In PTSD samples of GSE860 dataset, we identified 26 genes informative when compared with Post-deploy PTSD condition and 58 genes informative when compared with Pre-deploy and Post-deploy PTSD of GSE63878 dataset. We conducted the meta-analysis using Fisher, roP, Stouffer, AW, SR, PR and RP methods in MetaDE package. Results from the rOP method of MetaDE package showed that among these genes, the following showed significant changes including, OR2B6, SOX21, MOBP, IL15, PTPRK, PPBPP2 and SEC14L5. Gene ontology analysis revealed enrichment of these significant PTSD-related genes for cell proliferation, DNA damage and repair (p-value <= 0.05). Furthermore, interaction network analysis was performed on these 7 significant genes. This analysis revealed highly connected functional interaction networks with two candidate genes, IL15 and SEC14L5 highly enriched in networks. Overall, from these results, we concluded that these genes can be recommended as some of the potential targets for PTSD. PMID- 27997585 TI - Essential Genes Embody Increased Mutational Robustness to Compensate for the Lack of Backup Genetic Redundancy. AB - Genetic robustness is a hallmark of cells, occurring through many mechanisms and at many levels. Essential genes lack the common robustness mechanism of genetic redundancy (i.e., existing alongside other genes with the same function), and thus appear at first glance to leave cells highly vulnerable to genetic or environmental perturbations. Here we explore a hypothesis that cells might protect against essential gene loss through mechanisms that occur at various cellular levels aside from the level of the gene. Using Escherichia coli and Saccharomyces cerevisiae as models, we find that essential genes are enriched over non-essential genes for properties we call "coding efficiency" and "coding robustness", denoting respectively a gene's efficiency of translation and robustness to non-synonymous mutations. The coding efficiency levels of essential genes are highly positively correlated with their evolutionary conservation levels, suggesting that this feature plays a key role in protecting conserved, evolutionarily important genes. We then extend our hypothesis into the realm of metabolic networks, showing that essential metabolic reactions are encoded by more "robust" genes than non-essential reactions, and that essential metabolites are produced by more reactions than non-essential metabolites. Taken together, these results testify that robustness at the gene-loss level and at the mutation level (and more generally, at two cellular levels that are usually treated separately) are not decoupled, but rather, that cellular vulnerability exposed due to complete gene loss is compensated by increased mutational robustness. Why some genes are backed up primarily against loss and others against mutations still remains an open question. PMID- 27997586 TI - Determination of Normal Ranges of Shock Index and Other Haemodynamic Variables in the Immediate Postpartum Period: A Cohort Study. AB - OBJECTIVE: To determine the normal ranges of vital signs, including blood pressure (BP), mean arterial pressure (MAP), heart rate (HR) and shock index (SI) (HR/systolic BP), in the immediate postpartum period to inform the development of robust obstetric early warning scores. STUDY DESIGN: We conducted a secondary analysis of a prospective observational cohort study evaluating vital signs collected within one hour following delivery in women with estimated blood loss (EBL) <500ml (316 women) delivering at a UK tertiary centre over a one-year period. Simple and multiple linear regression were used to explore associations of demographic and obstetric factors with SI. RESULTS: Median (90% reference range) was 120 (100-145) for systolic BP, 75 (58-90) for diastolic BP, 90 (73 108) for MAP, 81 (61-102) for HR, and 0.66 (0.52-0.89) for SI. Third stage Syntometrine(r) administration was associated with a 0.03 decrease in SI (p = 0.035) and epidural use with a 0.05 increase (p = 0.003). No other demographic or obstetric factors were associated with a change in shock index in this cohort. CONCLUSION: This is the first study to determine normal ranges of maternal BP, MAP, HR and SI within one hour of birth, a time of considerable haemodynamic adjustment, with minimal effect of demographic and obstetric factors demonstrated. The lower 90% reference point for systolic BP and upper 90% reference point for HR correspond to triggers used to recognise shock in obstetric practice, as do the upper 90% reference points for systolic and diastolic BP for obstetric hypertensive triggers. The SI upper limit of 0.89 in well postpartum women supports current literature suggesting a threshold of 0.9 as indicating increased risk of adverse outcomes. PMID- 27997587 TI - COX7A2L/SCAFI and Pre-Complex III Modify Respiratory Chain Supercomplex Formation in Different Mouse Strains with a Bcs1l Mutation. AB - The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BL/6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2l/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research. In contradiction, another recent study suggested that supercomplex formation is independent of SCAFI isoforms. We investigated whether SCAFI isoform status affected the disease severity and supercomplex formation in the liver of Bcs1lc.232A>G knock-in mice with incomplete complex III assembly. In homozygotes (Bcs1lG/G) of mixed (C57BL/6:129/Sv) genetic background, the lifespan was similar in mice with wild-type SCAFI allele and in those homozygous (SCAFIshort/short) for the deleted SCAF1 variant (34+/-3 days; n = 6 vs. 32+/-2 days; n = 7, respectively). SCAFI heterozygosity (SCAFIlong/short) resulted in decreased SCAFI protein but respirasome assembly was unaffected. Congenic (C57BL/6) mice were of the genotype SCAFIshort/short and had no detectable SCAFI protein. In their liver mitochondria, respirasome composition was altered as compared to mixed background mice. Complex IV was mainly present as monomers and dimers, and only low amounts were found in combination with complex I and complex III or with precomplex III. The main supercomplex in the liver mitochondria of C57BL/6 mice comprised only complexes I and III. In conclusion, in liver mitochondria of C57BL/6 mice, supercomplexes had markedly reduced amount of, but were not completely depleted of, complex IV, supporting a role for COX7A2L/SCAFI in supercomplex assembly. However, the disease progression of the Bcs1l mutant mice was unrelated to SCAFI isoforms and supercomplex composition, suggesting that other genetic factors contribute to the different survival in the different genetic backgrounds. PMID- 27997588 TI - Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats. AB - Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model. PMID- 27997589 TI - Ganglioside Profiling of the Human Retina: Comparison with Other Ocular Structures, Brain and Plasma Reveals Tissue Specificities. AB - Gangliosides make a wide family of glycosphingolipids, highly heterogeneous in both the ceramide moiety and the oligosaccharide chain. While ubiquitously expressed in mammalian tissues, they are particularly abundant in the brain and the peripheral nervous system. Gangliosides are known to play a crucial role in the development, maintenance and functional integrity of the nervous system. However, the expression and roles of gangliosides in the retina, although often considered as a window on the brain, has been far less studied. We performed an in-depth analysis of gangliosides of the human retina, especially using powerful LC/MS methods. We compared the pattern of ganglioside classes and ceramide molecular species of this tissue with other ocular structures and with brain and plasma in elderly human individuals. About a hundred of ganglioside molecular species among 15 distinct classes were detected illustrating the huge structural diversity of these compounds. The retina exhibited a very diverse ganglioside profile and shared several common features with the brain (prominence of tetraosylgangliosides, abundance of d20:1 long chain base and 18:0 fatty acid...). However, the retina stood out with the specific expression of GD3, GT3 and AcGT3, which further presented a peculiar molecular species distribution. The unique ganglioside pattern we observed in the human retina suggests that these ganglioside species play a specific role in the structure and function of this tissue. This lipidomic study, by highlighting retina specific ganglioside species, opens up novel research directions for a better understanding of the biological role of gangliosides in the retina. PMID- 27997591 TI - The Role of Glucose Metabolism on Porcine Oocyte Cytoplasmic Maturation and Its Possible Mechanisms. AB - In the present study, we investigated the potential role of glucose and pyruvate in the cytoplasmic maturation of porcine oocytes by investigating the effect of glucose and/or pyruvate supplementation, in the presence or absence of 10% porcine follicular fluid (PFF), on meiotic maturation and subsequent embryo development. In the absence of 10% PFF, without exogenous addition of glucose and pyruvate, the medium seemed unable to support maturation. In the presence of 10% PFF, the addition of 5.6 mM glucose and/or 2 mM pyruvate during in vitro maturation of cumulus enclosed oocytes increased MII oocyte and blastocyst rates. In contrast, oocytes denuded of cumulus cells were not able to take full advantage of the glucose in the medium, as only pyruvate was able to increase the MII rate and the subsequent early embryo developmental ability. Treatment of cumulus enclosed oocytes undergoing maturation with 200 MUM dehydroepiandrosterone (DHEA), a pentose phosphate pathway inhibitor, or 2 MUM iodoacetate (IA), a glycolysis inhibitor, significantly reduced GHS, intra-oocyte ATP, maternal gene expression, and MPF activity levels. DHEA was also able to increase ROS and reduce the levels of NADPH. Moreover, blastocysts of the DHEA- or IA-treated groups presented higher apoptosis rates and markedly lower cell proliferation cell rates than those of the non-treated group. In conclusion, our results suggest that oocytes maturing in the presence of 10% PFF can make full use of energy sources through glucose metabolism only when they are accompanied by cumulus cells, and that pentose phosphate pathway (PPP) and glycolysis promote porcine oocyte cytoplasmic maturation by supplying energy, regulating maternal gene expression, and controlling MPF activity. PMID- 27997590 TI - Anti-Inflammatory Properties of the Enaminone E121 in the Dextran Sulfate Sodium (DSS) Colitis Model. AB - BACKGROUND: Enaminones are synthetic compounds with an established role in the prevention of various forms of seizures. Recent evidence suggests potent anti tussive, bronchodilation and anti-inflammatory properties. Pre-treatment with particularly E121 compound resulted in a decrease in leukocyte recruitment in the ovalbumin induced-model of asthma, immune cell proliferation and cytokine release in vitro. We hypothesize that E121 might serve as a therapeutic potential in intestinal inflammation through modulating immune cell functions. METHODS: Colitis was induced by daily dextran sulfate sodium (DSS) administration for 5 days, and its severity was determined by gross and histological assessments. The plasma level of various cytokines was measured using flow cytometry-based assay. The colonic expression/ phosphorylation level of various molecules was determined by immunofluorescence and western blotting. The effects of E121 treatment on in vitro neutrophil chemotaxis (under-agarose assay), superoxide release (luminol oxidation assay) and apoptosis (annexin V/7AAD) were also determined. RESULTS: DSS-induced colitis in mice was significantly reduced by daily E121 treatment (30 100 mg/kg) at gross and histological levels. This effect was due to modulated plasma levels of interleukin (IL-2) and colonic expression levels of various signaling molecules and proteins involved in apoptosis. In vitro neutrophil survival, chemotaxis, and superoxide release were also reduced by E121 treatment. CONCLUSION: Our results indicate important anti-inflammatory actions of E121 in the pathogenesis of IBD. PMID- 27997592 TI - Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy. AB - We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer. PMID- 27997593 TI - Predictors of Information Technology Integration in Secondary Schools: Evidence from a Large Scale Study of More than 30,000 Students. AB - The present study examined the predictors of information technology (IT) integration in secondary school mathematics lessons. The predictors pertained to IT resource availability in schools, school contextual/institutional variables, accountability pressure faced by schools, subject culture in mathematics, and mathematics teachers' pedagogical beliefs and practices. Data from 32,256 secondary school students from 2,519 schools in 16 developed economies who participated in the Program for International Student Assessment (PISA) 2012 were analyzed using hierarchical linear modeling (HLM). Results showed that after controlling for student-level (gender, prior academic achievement and socioeconomic status) and school-level (class size, number of mathematics teachers) variables, students in schools with more computers per student, with more IT resources, with higher levels of IT curricular expectations, with an explicit policy on the use of IT in mathematics, whose teachers believed in student-centered teaching-learning, and whose teachers provided more problem solving activities in class reported higher levels of IT integration. On the other hand, students who studied in schools with more positive teacher-related school learning climate, and with more academically demanding parents reported lower levels of IT integration. Student-related school learning climate, principal leadership behaviors, schools' public posting of achievement data, tracking of school's achievement data by administrative authorities, and pedagogical and curricular differentiation in mathematics lessons were not related to levels of IT integration. Put together, the predictors explained a total of 15.90% of the school-level variance in levels of IT integration. In particular, school IT resource availability, and mathematics teachers' pedagogical beliefs and practices stood out as the most important determinants of IT integration in mathematics lessons. PMID- 27997595 TI - Seedborne Pathogenic Fungi in Common Bean (Phaseolus vulgaris cv. INTA Rojo) in Nicaragua. AB - Common bean (Phaseolus vulgaris L.) is an important legume with high nutritional value. In Nicaragua, certified healthy seeds of local bean varieties are not available, and seedborne fungi have gained little attention. Here, were surveyed seedborne pathogenic fungi in an important local bean cultivar, 'INTA Rojo'. Beans grown in the four main production areas in Nicaragua (Boaco, Carazo, Esteli, Matagalpa) for future use as seed stock were sampled from four seed storehouses and six seed lots. A total of 133 fungal strains were isolated from surface-sterilized beans and inoculated to healthy lima beans (Phaseolus lunatus) under controlled conditions. Eighty-seven isolates caused symptoms of varying severity in the seedlings, including discoloration, necrotic lesions, cankers, rot, and lethal necrosis. Pathogenic isolates were divided into eight phenotypically distinguishable groups based on morphology and growth characteristics on artificial growth medium, and further identified by analysis of the internal transcribed spacer sequences (ITS1 and ITS2) of the ribosomal RNA genes. The pathogenic isolates belonged to eight genera. Fusarium spp. (F. chlamydosporum, F. equiseti, F. incarnatum), Lasiodiplodia theobromae, Macrophomina phaseolina, and Penicillium citrinum were the most damaging and common fungi found in the seed lots. Furthermore, Corynespora cassiicola, Colletotrichum capsisi, Colletotrichum gloeosporioides, Aspergillus flavus, and Diaporthe sp. (Phomopsis) were seedborne in cultivar 'INTA Rojo' and found to be pathogenic to bean seedlings. This study reveals, for the first time, many seedborne pathogenic fungi in beans in Nicaragua; furthermore, prior to this study, little information was available concerning F. equiseti, F. incarnatum, L. theobromae, C. cassiicola, and Diaporthe spp. as seedborne pathogens of common bean. Our results lay the basis for developing diagnostic tools for seed health inspection and for further study of the epidemiology, ecology, and control of the pathogenic fungi of common beans in the field. PMID- 27997594 TI - Weight Change and Risk of Venous Thromboembolism: The Tromso Study. AB - BACKGROUND: Obesity is a major risk factor for venous thromboembolism (VTE), but it is unknown to what extent weight change over time affects VTE risk. AIMS: To investigate the association between weight change and risk of incident VTE in a population-based cohort with repeated measurements. METHODS: Participant data were collected from the Tromso 3 (1986-87), 4 (1994-95), 5 (2000-01) and 6 (2007 08) surveys. Subjects who attended two subsequent or more surveys were included (n = 17802), and weight change between the surveys was calculated. Person-time at risk was accrued from the second of two subsequent vists until the next survey, the date of an incident VTE, migration, death or study end (December 31st 2012), whichever came first. Cox regression models were used to calculate risk of VTE according to change in body weight. RESULTS: There were 302 incident VTE events during a median of 6.0 years of follow-up. Subjects who gained most weight (7.5 40.0 kg weight gain) had a 1.9-fold higher risk of VTE compared to those with no or a moderate (0-7.4 kg) weight gain (HR 1.92; 95% CI 1.38-2.68). The VTE risk by >=7.5 kgs over no or moderate (0-7.4 kg) weight gain was highest (HR 3.75; 95% 1.83-7.68) in subjects with baseline body mass index (BMI) >=30 kg/m2. There was a joint effect of weight gain and baseline BMI on VTE risk. Those with BMI >=30 who gained >=7.5 kgs had a 6.6-fold increased risk (HR 6.64; 95% CI 3.61-12.22) compared to subjects with BMI <25 and no or moderate (0-7.4 kg) weight gain. CONCLUSIONS: Our findings imply that further weight gain is a considerable risk factor for VTE, particularly in obese individuals. PMID- 27997596 TI - A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next Generation Sequencing. AB - Enlarged vestibular aqueduct (EVA) is one of the most common congenital inner ear malformations and accounts for 1-12% of sensorineural deafness in children and adolescents. Multiple genetic defects contribute to EVA; therefore, early molecular diagnosis is critical for EVA patients to ensure that the most effective treatment strategies are employed. This study explored a new genetic diagnosis method for EVA and applied it to clinic diagnoses of EVA patients. Using next-generation sequencing technology, we set up a multiple polymerase chain reaction enrichment system for target regions of EVA pathogenic genes (SLC26A4, FOXI1, and KCNJ10). Forty-six EVA samples were sequenced by this system. Variants were detected in 87.0% (40/46) of cases, including three novel variants (SLC26A4 c.923_929del, c.1002-8C>G, and FOXI1 c.519C>A). Biallelic potential pathogenic variants were detected in 27/46 patient samples, leading to a purported diagnostic rate of 59%. All results were verified by Sanger sequencing. Our target region capture system was validated to amplify and measure SLC26A4, FOXI1, and KCNJ10 in one reaction system. The result supplemented the mutation spectrum of EVA. Thus, this strategy is an economic, rapid, accurate, and reliable method with many useful applications in the clinical diagnosis of EVA patients. PMID- 27997597 TI - Immunogenicity and Protective Efficacy of the DAR-901 Booster Vaccine in a Murine Model of Tuberculosis. AB - BACKGROUND: The development of a novel tuberculosis vaccine is a leading global health priority. SRL172, an inactivated, whole-cell mycobacterial vaccine, was safe, immunogenic and reduced the incidence of culture-confirmed tuberculosis in a phase III trial in HIV-infected and BCG immunized adults in Tanzania. Here we describe the immunogenicity and protective efficacy of DAR-901, a booster vaccine against tuberculosis manufactured from the same seed strain using a new scalable method. METHODS: We evaluated IFN-gamma responses by ELISpot and antibody responses by enzyme linked immunosorbent assay in C57BL/6 and BALB/c mice after three doses of DAR-901. In an aerosol challenge model, we evaluated the protective efficacy of the DAR-901 booster in C57BL/6 mice primed with BCG and boosted with two doses of DAR-901 at 4 dosage levels in comparison with homologous BCG boost. RESULTS: DAR-901 vaccination elicited IFN-gamma responses to mycobacterial antigen preparations derived from both DAR-901 and Mycobacterium tuberculosis. DAR-901 immunization enhanced antibody responses to DAR-901 but not Mycobacterium tuberculosis lysate or purified protein derivative. Among animals primed with BCG, boosting with DAR-901 at 1 mg provided greater protection against aerosol challenge than a homologous BCG boost (lungs P = 0.036, spleen P = 0.028). CONCLUSIONS: DAR-901 induces cellular and humoral immunity and boosts protection from M. tuberculosis compared to a homologous BCG boost. PMID- 27997599 TI - Beyond Academia - Interrogating Research Impact in the Research Excellence Framework. AB - Big changes to the way in which research funding is allocated to UK universities were brought about in the Research Excellence Framework (REF), overseen by the Higher Education Funding Council, England. Replacing the earlier Research Assessment Exercise, the purpose of the REF was to assess the quality and reach of research in UK universities-and allocate funding accordingly. For the first time, this included an assessment of research 'impact', accounting for 20% of the funding allocation. In this article we use a text mining technique to investigate the interpretations of impact put forward via impact case studies in the REF process. We find that institutions have developed a diverse interpretation of impact, ranging from commercial applications to public and cultural engagement activities. These interpretations of impact vary from discipline to discipline and between institutions, with more broad-based institutions depicting a greater variety of impacts. Comparing the interpretations with the score given by REF, we found no evidence of one particular interpretation being more highly rewarded than another. Importantly, we also found a positive correlation between impact score and [overall research] quality score, suggesting that impact is not being achieved at the expense of research excellence. PMID- 27997598 TI - Use of Proton Pump Inhibitors and the Risk of Hospitalization for Infectious Gastroenteritis. AB - INTRODUCTION: To quantify the association between PPI use, type and dose and infectious gastroenteritis hospitalization in a population-based cohort of middle aged and older adults. METHODS: Prospective study of 38,019 concession card holders followed up over 6 years in the Sax Institute's 45 and Up Study. Data from the baseline questionnaire were linked to prescription medication, hospitalization, notifiable disease, cancer registry and death datasets from 2006 2012. Associations between PPI use and gastroenteritis hospitalization were examined using Cox regressions with age as the underlying time variable. RESULTS: Among 38,019 participants, the median age was 69.7 years, and 57.3% were women. Compared to non-users, current PPI users were more likely to be older, and have a higher BMI. During follow-up there were 1,982 incident gastroenteritis hospitalizations (crude rate: 12.9 per 1000 person-years, 95% CI: 12.3-13.5). PPI use was significantly associated with infectious gastroenteritis hospitalization (aHR 1.4, 95% CI: 1.2-1.5). Among current users, a dose-response relationship was observed between the average daily dose (DDD) dispensed per day and infectious gastroenteritis hospitalization (Ptrend<0.001). We also observed higher rates of infectious gastroenteritis hospitalization and greater PPI use among participants with a history of chronic bowel problems (aHR 2.2, 95% CI: 1.9-2.5). There was no difference in risk by type of PPI. Recent use of H2 receptors was not associated with gastroenteritis hospitalization. CONCLUSION: PPI use is associated with an increased risk of infectious gastroenteritis hospitalization. Clinicians should be aware of this risk when considering PPI therapy. PMID- 27997600 TI - Exploring Identity-By-Descent Segments and Putative Functions Using Different Foundation Parents in Maize. AB - Maize foundation parents (FPs) play no-alternative roles in hybrid breeding because they were widely used in the development of new lines and hybrids. The combination of different identity-by-descent (IBD) segments and genes could account for the formation patterns of different FPs, and knowledge of these IBD regions would provide an extensive foundation for the development of new candidate FP lines in future maize breeding. In this paper, a panel of 304 elite lines derived from FPs, i.e., B73, 207, Mo17, and Huangzaosi (HZS), was collected and analyzed using 43,252 single nucleotide polymorphism (SNP) markers. Most IBD segments specific to particular FP groups were identified, including 116 IBD segments in B73, 105 in Mo17, 111 in 207, and 190 in HZS. In these regions, 423 quantitative trait nucleotides (QTNs) associated with 15 agronomic traits and 804 candidate genes were identified. Some known adaptation-related genes, e.g., dwarf8 and vgt1 in HZS, zcn8 and epc in Mo17, and ZmCCT in 207, were validated as being tightly linked to particular IBD segments. In addition, numerous new candidate genes were also identified. For example, GRMZM2G154278 in HZS, which belongs to the cell cycle control family, was closely linked to a QTN of the ear height/plant height (EH/PH) trait; GRMZM2G051943 in 207, which encodes an endochitinase precursor (EP) chitinase, was closely linked to a QTN for kernel density; and GRMZM2G170586 in Mo17 was closely linked to a QTN for ear diameter. Complex correlations among these genes were also found. Many IBD segments and genes were included in the formation of FP lines, and complex regulatory networks exist among them. These results provide new insights on the genetic basis of complex traits and provide new candidate IBD regions or genes for the improvement of special traits in maize production. PMID- 27997601 TI - Physical Activity, Sedentary Behavior, Cardiorespiratory Fitness and Metabolic Syndrome in Adolescents: Systematic Review and Meta-Analysis of Observational Evidence. AB - BACKGROUND: Metabolic syndrome (MetS) has been diagnosed in adolescents and among the associated factors are low levels of physical activity, sedentary behavior over long periods and low cardiorespiratory fitness. However, specifically in adolescents, studies present conflicting results. The aim of the present study was to conduct a systematic review and meta-analysis of observational studies, in order to map the association between physical activity, sedentary behavior, cardiorespiratory fitness and MetS in adolescents. METHODS: A search was performed in the databases PubMed, SPORTDiscus, LILACS and the Cochrane Library. For the meta-analysis, the odds ratio (OR) was calculated together with the respective confidence intervals (95% CI), in which the measures of effect were analyzed by dichotomous data (exposure variables) with MetS used as events. RESULTS: Eighteen studies were included in the meta-analysis. Primary analysis demonstrated that low levels of physical activity (OR = 1.35 [1.03 to 1.79]; p = 0.03) and low cardiorespiratory fitness (OR = 4.05 [2.09 to 7.87]; p < 0.01) were significantly associated with the development of MetS, while for sedentary behavior, represented by screen time > 2 hours/day, a significant association was not identified (OR = 1.20 [0.91 to 1.59]; p = 0.20). Subgroup analyses demonstrated that the association between low physical activity and MetS was dependent on the use of the accelerometry technique (OR = 2.93 [1.56 to 5.47]; p < 0.01). Screen time > 2 hours/day was significantly associated with MetS only on weekends (OR = 2.05 [1.13 to 3.73]; p = 0.02). With respect to cardiorespiratory fitness, a significant association with MetS was found independent of the maximal oxygen uptake (VO2max) measurement method. CONCLUSIONS: Low levels of physical activity, low indices of cardiorespiratory fitness and sedentary behavior, represented by screen time > 2 hours/day on weekends, were significantly associated with the development of MetS in adolescence. PMID- 27997602 TI - Influenza like Illness among Medical Residents Anticipates Influenza Diffusion in General Population: Data from a National Survey among Italian Medical Residents. AB - The aim of this multicentre study was to assess incidence of influenza like illness (ILI) among Italian medical residents (MRs) during 2011-2012 influenza season, to detect variables associated with ILI and to compare estimated ILI incidence among MRs and general population. A cross-sectional survey was carried out throughout an anonymous questionnaire administered to all MRs attending the post-graduate medical schools of 18 Italian Universities. At the same time an analysis of the ILI incidence in the Italian general population was conducted through the Italian Influenza Surveillance Network. Of a total of 2,506 MRs, 1,191 (47.5%) reported at least one ILI episode. A higher proportion of ILIs was reported by MRs of Central (25.0% with ILI vs 20.2% without ILI) and Southern Italy (40.2% with ILI vs. 36.4 without ILI) compared to Northern Italy (34.8% with ILI vs. 43.4% without ILI) (p<0.001). Italian MRs had a higher cumulative incidence of ILIs (546.7 episodes per 1,000 vs. 75.9 episodes per 1,000) and an earlier peak (January 2012 vs. February 2012), compared to general population due to higher number of contacts in hospital setting. MRs reported a high rate of ILI infection probably in association with their working activities. These data suggest the need to offer an earlier influenza vaccination to HCWs than general population with the aim to both prevent ILI and its transmission to patients. PMID- 27997603 TI - Socio-Ecological Variables Associated with Context-Specific Sitting Time in Belgian Older Adults: A One-Year Follow-Up Study. AB - INTRODUCTION: Knowledge about variables associated with context-specific sitting time in older adults is limited. Therefore, this study explored cross-sectional and longitudinal associations of socio-demographic, social-cognitive, physical environmental and health-related variables with sitting during TV viewing, computer use and motorized transport in older adults. METHODS: A sample of Belgian older adults completed structured interviews on context-specific sitting time and associated variables using a longitudinal study design. Objective measurements of grip strength and physical performance were also completed. Complete baseline data were available of 258 participants (73.98+/-6.16 years) of which 229 participants remained in the study at one year follow-up (retention rate: 91.60%). Cross-sectional correlates (baseline data) and longitudinal predictors (change-scores in relation with change in sitting time) were explored through multiple linear regression analyses. RESULTS: Per context-specific sitting time, most of the cross-sectional correlates differed from the longitudinal predictors. Increases over time in enjoyment of watching TV (+one unit), encouragement of partner to watch less TV (+one unit) and TV time of partner (+30.0 min/day) were associated with respectively 9.1 min/day (p<0.001), 16.0 min/day (p<0.001) and 12.0 min/day (p<0.001) more sitting during TV viewing at follow-up. Increases over time in enjoyment of using a computer (+one unit), the number of smartphones and tablets (+1) and computer use of the partner (+30.0 min/day) were associated with respectively 5.5 min/day (p < .01), 10.4 min/day (p < .05) and 3.0 min/day (p < .05) more sitting during computer use at follow-up. An increase over time in self-efficacy regarding taking a bicycle or walking was associated with 2.9 min/day (p < .05) less sitting during motorized transport at follow-up. CONCLUSIONS: The results stressed the importance of looking at separate contexts of sitting. Further, the results highlighted the importance of longitudinal research in order to reveal which changes in particular variables predicted changes in context-specific sitting time. Variables at the social cognitive level were most frequently related to context-specific sitting. PMID- 27997604 TI - Physical Activity in Community Dwelling Older People: A Systematic Review of Reviews of Interventions and Context. AB - BACKGROUND: The promotion and maintenance of higher physical activity (PA) levels in the older population is an imperative for cognitive and healthy ageing but it is unclear what approaches are best suited to achieve this for the increasing number of older people living in the community. Effective policies should be informed by robust, multi-disciplinary and multi-dimensional evidence, which not only seeks what works, but in 'what context? In addition to evidence on the efficacy and effectiveness of PA for maintaining cognitive health, social contexts such as 'how do we actually get older people to partake in PA?' and 'how do we sustain that activity long-term?' also need highlighting. This review is part of a comprehensive evidence synthesis of preventive interventions in older age, with a focus on healthy behaviours to identify evidence gaps and inform policy relating to ageing well and cognitive health. An overview of systematic reviews of PA was conducted to explore three topics: (1) PA efficacy or effectiveness for primary prevention of cognitive decline in 55+; (2) Interventions efficacious or effective for increasing PA uptake and maintenance in 55+; (3) barriers and facilitators to PA in 55+. METHODS: Multiple databases were searched for studies in English from OECD countries between 2000 and 2016. Quality of included reviews in questions (1) and (2) were assessed using AMSTAR. Review protocols were registered on PROSPERO (CRD42014015554, 42014015584, CRD42014015557) and reviews follow PRISMA guideline. FINDINGS: Overall, 40 systematic reviews were included. Question 1 (n = 14). 8,360 participants. Evidence suggests that PA confer mild positive effects on cognition in older adults with and without previous cognitive impairment. However, there is insufficient evidence of a dose-response relationship. Evidence on the effects of PA on delay of dementia onset is inconclusive. Question 2 (n = 17). 79,650 participants. Evidence supports the effectiveness of a variety of interventions, including group delivered, centre-based and cognitive approaches on short-term uptake of PA behaviour. Question 3 (n = 9). 22,413 participants. Barriers include health status, previous PA habits and experiences, and cultural sensitivity, while facilitators include enjoyable activities and convenient scheduling. CONCLUSION: PA can offer small benefits to brain health, but evidence on how much activity is required to produce this effect is lacking. Evidence on the effectiveness of PA for preventing dementia and cognitive decline is lacking. Behavioural (walking, exercise) and cognitive (counselling and motivational interviews) interventions are effective for short-term uptake of physical activity in older people. In order to maintain long-term participation in PA, individualised interventions modelled using behavioural theories may be required. Public health messages should be aimed at promoting acceptable levels of PA above normal daily activities in older people. Policy and strategies aimed at increasing PA in older people should be encouraged while considering barriers and facilitators to behaviour change. PMID- 27997606 TI - Correction: Persistence of Neighborhood Demographic Influences over Long Phylogenetic Distances May Help Drive Post-Speciation Adaptation in Tropical Forests. AB - [This corrects the article DOI: 10.1371/journal.pone.0156913.]. PMID- 27997605 TI - Role of Myeloperoxidase Oxidants in the Modulation of Cellular Lysosomal Enzyme Function: A Contributing Factor to Macrophage Dysfunction in Atherosclerosis? AB - Low-density lipoprotein (LDL) is the major source of lipid within atherosclerotic lesions. Myeloperoxidase (MPO) is present in lesions and forms the reactive oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). These oxidants modify LDL and have been strongly linked with the development of atherosclerosis. In this study, we examined the effect of HOCl, HOSCN and LDL pre treated with these oxidants on the function of lysosomal enzymes responsible for protein catabolism and lipid hydrolysis in murine macrophage-like J774A.1 cells. In each case, the cells were exposed to HOCl or HOSCN or LDL pre-treated with these oxidants. Lysosomal cathepsin (B, L and D) and acid lipase activities were quantified, with cathepsin and LAMP-1 protein levels determined by Western blotting. Exposure of J774A.1 cells to HOCl or HOSCN resulted in a significant decrease in the activity of the Cys-dependent cathepsins B and L, but not the Asp dependent cathepsin D. Cathepsins B and L were also inhibited in macrophages exposed to HOSCN-modified, and to a lesser extent, HOCl-modified LDL. No change was seen in cathepsin D activity or the expression of the cathepsin proteins or lysosomal marker protein LAMP-1. The activity of lysosomal acid lipase was also decreased on treatment of macrophages with each modified LDL. Taken together, these results suggest that HOCl, HOSCN and LDL modified by these oxidants could contribute to lysosomal dysfunction and thus perturb the cellular processing of LDL, which could be important during the development of atherosclerosis. PMID- 27997607 TI - Correction: Dual Energy X-Ray Absorptiometry Compared with Anthropometry in Relation to Cardio-Metabolic Risk Factors in a Young Adult Population: Is the 'Gold Standard' Tarnished? AB - [This corrects the article DOI: 10.1371/journal.pone.0162164.]. PMID- 27997609 TI - Statistical Downscaling of General Circulation Model Outputs to Precipitation Accounting for Non-Stationarities in Predictor-Predictand Relationships. AB - This paper presents a novel approach to incorporate the non-stationarities characterised in the GCM outputs, into the Predictor-Predictand Relationships (PPRs) in statistical downscaling models. In this approach, a series of 42 PPRs based on multi-linear regression (MLR) technique were determined for each calendar month using a 20-year moving window moved at a 1-year time step on the predictor data obtained from the NCEP/NCAR reanalysis data archive and observations of precipitation at 3 stations located in Victoria, Australia, for the period 1950-2010. Then the relationships between the constants and coefficients in the PPRs and the statistics of reanalysis data of predictors were determined for the period 1950-2010, for each calendar month. Thereafter, using these relationships with the statistics of the past data of HadCM3 GCM pertaining to the predictors, new PPRs were derived for the periods 1950-69, 1970-89 and 1990-99 for each station. This process yielded a non-stationary downscaling model consisting of a PPR per calendar month for each of the above three periods for each station. The non-stationarities in the climate are characterised by the long term changes in the statistics of the climate variables and above process enabled relating the non-stationarities in the climate to the PPRs. These new PPRs were then used with the past data of HadCM3, to reproduce the observed precipitation. It was found that the non-stationary MLR based downscaling model was able to produce more accurate simulations of observed precipitation more often than conventional stationary downscaling models developed with MLR and Genetic Programming (GP). PMID- 27997608 TI - Effect of Peripheral Electrical Stimulation (PES) on Nocturnal Blood Glucose in Type 2 Diabetes: A Randomized Crossover Pilot Study. AB - BACKGROUND: Regulation of hepatic glucose production has been a target for antidiabetic drug development, due to its major contribution to glucose homeostasis. Previous pre-clinical study demonstrated that peripheral electrical stimulation (PES) may stimulate glucose utilization and improve hepatic insulin sensitivity. The aim of the present study was to evaluate safety, tolerability, and the glucose-lowering effect of this approach in patients with type 2 diabetes (T2DM). METHODS: Twelve patients with T2DM were recruited for an open label, interventional, randomized trial. Eleven patients underwent, in a crossover design, an active, and a no-intervention control periods, separated with a two week washout phase. During the active period, the patients received a daily lower extremity PES treatment (1.33Hz/16Hz burst mode), for 14 days. Study endpoints included changes in glucose levels, number of hypoglycemic episodes, and other potential side effects. Endpoints were analyzed based on continuous glucose meter readings, and laboratory evaluation. RESULTS: We found that during the active period, the most significant effect was on nocturnal glucose control (P < 0.0004), as well as on pre-meal mean glucose levels (P < 0.02). The mean daily glucose levels were also decreased although it did not reach clinical significance (P = 0.07). A reduction in serum cortisol (P < 0.01) but not in insulin was also detected after 2 weeks of treatment. No adverse events were recorded. CONCLUSIONS: These results indicate that repeated PES treatment, even for a very short duration, can improve blood glucose control, possibly by suppressing hepatic glucose production. This effect may be mediated via hypothalamic-pituitary-adrenal axis modulation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02727790. PMID- 27997611 TI - Short-Term Effects of Changing Precipitation Patterns on Shrub-Steppe Grasslands: Seasonal Watering Is More Important than Frequency of Watering Events. AB - Climate change is expected to alter precipitation patterns. Droughts may become longer and more frequent, and the timing and intensity of precipitation may change. We tested how shifting precipitation patterns, both seasonally and by frequency of events, affects soil nitrogen availability, plant biomass and diversity in a shrub-steppe temperate grassland along a natural productivity gradient in Lac du Bois Grasslands Protected Area near Kamloops, British Columbia, Canada. We manipulated seasonal watering patterns by either exclusively watering in the spring or the fall. To simulate spring precipitation we restricted precipitation inputs in the fall, then added 50% more water than the long term average in the spring, and vice-versa for the fall precipitation treatment. Overall, the amount of precipitation remained roughly the same. We manipulated the frequency of rainfall events by either applying water weekly (frequent) or monthly (intensive). After 2 years, changes in the seasonality of watering had greater effects on plant biomass and diversity than changes in the frequency of watering. Fall watering reduced biomass and increased species diversity, while spring watering had little effect. The reduction in biomass in fall watered treatments was due to a decline in grasses, but not forbs. Plant available N, measured by Plant Root Simulator (PRS)-probes, increased from spring to summer to fall, and was higher in fall watered treatments compared to spring watered treatments when measured in the fall. The only effect observed due to frequency of watering events was greater extractable soil N in monthly applied treatments compared to weekly watering treatments. Understanding the effects of changing precipitation patterns on grasslands will allow improved grassland conservation and management in the face of global climatic change, and here we show that if precipitation is more abundant in the fall, compared to the spring, grassland primary productivity will likely be negatively affected. PMID- 27997610 TI - Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines. AB - CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses. Vaccination by the subcutaneous or the intranasal route stimulated systemic and mucosal CTL memory respectively. However, only CTL memory induced by intranasal vaccination was protective against influenza viral challenge, and correlated with an enhancement of memory CTLs in the airways and CD103+ CD69+ CXCR3+ resident memory-like CTLs in the lungs. Mechanistically, Myd88-deficient mice mounted primary CTL responses to Adjuplex vaccines that were similar in magnitude to wild-type mice, but exhibited altered differentiation of effector cell subsets. Immune potentiating effects of Adjuplex entailed alterations in the frequency of antigen-presenting cell subsets in vaccine draining lymph nodes, and in the lungs and airways following intranasal vaccination. Further, Adjuplex enhanced the ability of dendritic cells to promote antigen-induced proliferation of naive CD8 T cells by modulating antigen uptake, its intracellular localization, and rate of processing. Taken together, we have identified an adjuvant that elicits both systemic and mucosal CTL memory to non-replicating antigens, and engenders protective CTL-based heterosubtypic immunity to influenza A virus in the respiratory tract. Further, findings presented in this manuscript have provided key insights into the mechanisms and factors that govern the induction and programming of systemic and protective memory CTLs in the respiratory tract. PMID- 27997612 TI - Signatures of Crested Ibis MHC Revealed by Recombination Screening and Short Reads Assembly Strategy. AB - Whole-genome shotgun (WGS) sequencing has become a routine method in genome research over the past decade. However, the assembly of highly polymorphic regions in WGS projects remains a challenge, especially for large genomes. Employing BAC library constructing, PCR screening and Sanger sequencing, traditional strategy is laborious and expensive, which hampers research on polymorphic genomic regions. As one of the most highly polymorphic regions, the major histocompatibility complex (MHC) plays a central role in the adaptive immunity of all jawed vertebrates. In this study, we introduced an efficient procedure based on recombination screening and short-reads assembly. With this procedure, we constructed a high quality 488-kb region of crested ibis MHC that consists of 3 superscaffolds and contains 50 genes. Our sequence showed comparable quality (97.29% identity) to traditional Sanger assembly, while the workload was reduced almost 7 times. Comparative study revealed distinctive features of crested ibis by exhibiting the COL11A2-BLA-BLB-BRD2 cluster and presenting both ADPRH and odorant receptor (OR) gene in the MHC region. Furthermore, the conservation of the BF-TAP1-TAP2 structure in crested ibis and other vertebrate lineages is interesting in light of the hypothesis that coevolution of functionally related genes in the primordial MHC is responsible for the appearance of the antigen presentation pathways at the birth of the adaptive immune system. PMID- 27997613 TI - Spatiotemporal Dynamics of Virus Infection Spreading in Tissues. AB - Virus spreading in tissues is determined by virus transport, virus multiplication in host cells and the virus-induced immune response. Cytotoxic T cells remove infected cells with a rate determined by the infection level. The intensity of the immune response has a bell-shaped dependence on the concentration of virus, i.e., it increases at low and decays at high infection levels. A combination of these effects and a time delay in the immune response determine the development of virus infection in tissues like spleen or lymph nodes. The mathematical model described in this work consists of reaction-diffusion equations with a delay. It shows that the different regimes of infection spreading like the establishment of a low level infection, a high level infection or a transition between both are determined by the initial virus load and by the intensity of the immune response. The dynamics of the model solutions include simple and composed waves, and periodic and aperiodic oscillations. The results of analytical and numerical studies of the model provide a systematic basis for a quantitative understanding and interpretation of the determinants of the infection process in target organs and tissues from the image-derived data as well as of the spatiotemporal mechanisms of viral disease pathogenesis, and have direct implications for a biopsy-based medical testing of the chronic infection processes caused by viruses, e.g. HIV, HCV and HBV. PMID- 27997615 TI - Correction: Vaccine Strain-Specificity of Protective HLA-Restricted Class 1 P. falciparum Epitopes. AB - [This corrects the article DOI: 10.1371/journal.pone.0163026.]. PMID- 27997614 TI - Effectiveness of Teriparatide on Fracture Healing: A Systematic Review and Meta Analysis. AB - PURPOSE: Nowadays, the efficacy of teriparatide in treating osteoporosis was widely accepted, but the discussion about using teriparatide to enhance fracture healing hasn't come to an agreement. This meta-analysis was conducted to evaluate the effectiveness of teriparatide for fracture healing. METHODS: We searched PubMed, the Cochrane Library, and Embase in August 2016 for randomized controlled trials (RCTs) which concerned the treatment of teriparatide for fracture healing. RESULTS: Finally, a total of 380 patients were randomly assigned in the 5 trials included in this meta-analysis. There was a significant effectiveness with regards to function improvement in patients following fracture, however, there was no significant effectiveness with regards to time of radiographic fracture healing, fracture healing rate and reduction in pain. CONCLUSIONS: This analysis showed that administration of teriparatide following fracture lacked the effectiveness for fracture healing. Moreover, teriparatide administration had no apparent adverse effects. These results should be interpreted with caution because of some clear limitations. If we want to confirm whether teriparatide improves fracture healing, more high-quality randomized controlled trials are needed. PMID- 27997616 TI - Structure Elucidation of a Polysaccharide from Umbilicaria esculenta and Its Immunostimulatory Activity. AB - Umbilicaria esculenta has been used as a tonic food in China for several centuries owing to its pleasant flavor and health benefits. In this study, a water soluble polysaccharide, which we designated as UP2, with an average molecular weight of 3.33 * 105 Da, was isolated from U. esculenta cultivated in the Huangshan Mountain, by consecutive hot water extraction and anion-exchange chromatography. Gas chromatography analysis indicated that UP2 contained three kinds of monosaccharides, including mannose, glucose, and galactose at a molar ratio of 1.7:1.0:1.2. Linkage analysis of UP2 revealed the presence of (1 -> 6) linked glucosyl, (1 -> 3,6)-linked glucosyl, t-linked galactosyl, (1 -> 6)-linked galactosyl and (1 -> 6)-linked mannosyl at a molar ratio of 0.7:4.6:4.1:2.2:9.1. Structural analysis determined that UP2 possessed a backbone consisting of (1 -> 6)-linked beta-D-glucopyranosyl and (1 -> 6)-linked alpha-D-mannopyranosyl residues, which substituted at the O-3 position of (1 -> 6)-linked beta-D glucopyranosyl residues by branches of (1 -> 6)-linked alpha-D-galactopyranosyl and 1-linked beta-D-galactopyranosyl residues. Immunostimulatory activity analysis showed that UP2 could stimulate the proliferation of RAW264.7 cells in a dose-dependent manner, and all the samples (20-500 MUg/mL) were found to enhance nitric oxide production. The highest phagocytic activity of UP2 was observed at 200 MUg/mL. Thus, UP2 may be a potential source of biological and pharmacological agents. PMID- 27997617 TI - The Influence of Community Members on Participation by Youth in an HIV Vaccine Trial in Tanzania. AB - In sub-Saharan Africa, the burden of HIV is high among young people and it is of the utmost importance that they be recruited into vaccination trials. Since community members influence the willingness of young people to participate in the vaccination trials, ascertaining their opinions is essential to overcoming barriers to such participation. Here, in seven focus group discussions we explored the views of 44 community members identified as someone they felt close by youth in Tanzania. The transcripts of these discussions were examined using content analysis. Our participants expressed that community members would be directly involved in the decisions of young people about whether or not to participate in an HIV vaccine trial. In general, they felt that community members would provide social support for youth during the trial and perceived that youth might have misconceptions concerning the vaccine and trial process. The participants pointed out structural factors such as substance use, poverty, stigma and unemployment that are barriers to participation. In conclusion, involvement of community members could be an integral part of the recruitment and retention of young people in HIV vaccine trials in Tanzania. PMID- 27997618 TI - Evaluation of a Commercial Multiplex PCR Assay for Detection of Pathogen DNA in Blood from Patients with Suspected Sepsis. AB - The Magicplex Sepsis Real-time Test (MST) is a commercial multiplex PCR that can detect more than 90 different pathogens in blood, with an analysis time of six hours. The aim of the present study was to evaluate this method for the detection of bloodstream infection (BSI). An EDTA whole blood sample for MST was collected together with blood cultures (BC) from patients with suspected sepsis at the Emergency Department of a university hospital. Among 696 study patients, 322 (46%) patients were positive with at least one method; 128 (18%) were BC positive and 268 (38%) were MST positive. Considering BC to be the gold standard, MST had an overall sensitivity of 47%, specificity of 66%, positive predictive value (PPV) of 23%, and a negative predictive value of 87%. Among the MST positive samples with a negative BC, coagulase-negative staphylococci (CoNS) and species that rarely cause community-acquired BSI were frequently noted. However, the quantification cycle (Cq) values of the MST+/BC- results were often high. We thus hypothesized that the performance of the MST test could be improved if the Cq cut off level was adjusted downwards. With a lower Cq cut-off value, i.e. 6.0 for Staphylococcus species and 9.0 for all other species, the number of MST positive cases decreased to 83 (12%) and the overall sensitivity decreased to 38%. However, the PPV increased to 59% and the specificity increased to 96%, as many MST positive results for CoNS and bacteria that rarely cause community-acquired BSI turned MST negative. In conclusion, our study shows that with a lower Cq cut off value, the MST will detect less contaminants and findings with unclear relevance, but to the cost of a lower sensitivity. Consequently, we consider that a positive MST results with a Cq value above the adjusted cut-off should be interpreted with caution, as the result might be clinically irrelevant. In a correspondent way, quantitative results could probably be useful in the interpretation of positive results from other molecular assays for the detection of BSI. PMID- 27997619 TI - Intranasal Chromium Induces Acute Brain and Lung Injuries in Rats: Assessment of Different Potential Hazardous Effects of Environmental and Occupational Exposure to Chromium and Introduction of a Novel Pharmacological and Toxicological Animal Model. AB - Chromium (Cr) is used in many industries and it is widely distributed in the environment. Exposure to Cr dust has been reported among workers at these industries. Beside its hazardous effects on the lungs, brain injury could be induced, as the absorption of substances through the nasal membrane has been found to provide them a direct delivery to the brain. We investigated the distribution and the effects of Cr in both brain and lung following the intranasal instillation of potassium dichromate (inPDC) in rats. Simultaneously, we used the common intraperitoneal (ipPDC) rat model of acute Cr-toxicity for comparison. Thirty male Wistar rats were randomly allocated into five groups (n = 6); each received a single dose of saline, ipPDC (15 mg/kg), or inPDC in three dose levels: 0.5, 1, or 2 mg/kg. Locomotor activity was assessed before and 24 h after PDC administration, then, the lungs and brain were collected for biochemical, histopathological, and immunohistochemical investigations. Treatment of rats with ipPDC resulted in a recognition of 36% and 31% of the injected dose of Cr in the brain and lung tissues, respectively. In inPDC-treated rats, targeting the brain by Cr was increased in a dose-dependent manner to reach 46% of the instilled dose in the group treated with the highest dose. Moreover, only this high dose of inPDC resulted in a delivery of a significant concentration of Cr, which represented 42% of the instilled dose, to the lungs. The uppermost alteration in the rats locomotor activity as well as in the brain and lung histopathological features and contents of oxidative stress biomarkers, interleukin-1beta (IL-1beta), phosphorylated protein kinase B (PKB), and cyclooxygenase 2 (COX-2) were observed in the rats treated with inPDC (2 mg/kg). The findings revealed that these toxic manifestations were directly proportional to the delivered concentration of Cr to the tissue. In conclusion, the study showed that a comparably higher concentrations of Cr and more elevated levels of oxidative stress and inflammatory markers were observed in brain and lung tissues of rats subjected to inPDC in a dose that is just 0.13 that of ipPDC dose commonly used in Cr-induced toxicity studies. Therefore, the study suggests a high risk of brain-targeting injury among individuals environmentally or occupationally exposed to Cr dust, even in low doses, and an additional risk of lung injury with higher Cr concentrations. Moreover, the study introduces inPDC (2 mg/kg)-instillation as a new experimental animal model suitable to study the acute brain and lung toxicities induced by intranasal exposure to Cr compounds. PMID- 27997620 TI - Molecular and Serological Survey of Selected Viruses in Free-Ranging Wild Ruminants in Iran. AB - A molecular and serological survey of selected viruses in free-ranging wild ruminants was conducted in 13 different districts in Iran. Samples were collected from 64 small wild ruminants belonging to four different species including 25 Mouflon (Ovis orientalis), 22 wild goat (Capra aegagrus), nine Indian gazelle (Gazella bennettii) and eight Goitered gazelle (Gazella subgutturosa) during the national survey for wildlife diseases in Iran. Serum samples were evaluated using serologic antibody tests for Peste de petits ruminants virus (PPRV), Pestiviruses [Border Disease virus (BVD) and Bovine Viral Diarrhoea virus (BVDV)], Bluetongue virus (BTV), Bovine herpesvirus type 1 (BHV-1), and Parainfluenza type 3 (PI3). Sera were also ELISA tested for Pestivirus antigen. Tissue samples including spleen, liver, lung, tonsils, mesenteric and mediastinal lymph nodes and white blood cells (WBCs) were tested using polymerase chain reaction (PCR) for PPRV, Foot and Mouth Disease virus (FMDV), Pestivirus, BTV, Ovine herpesvirus type 2 (OvHV-2) and BHV-1. Serologic tests were positive for antibodies against PPRV (17%), Pestiviruses (2%) and BTV (2%). No antibodies were detected for BHV-1 or PI3, and no Pestivirus antigen was detected. PCR results were positive for PPRV (7.8%), FMDV (11%), BTV (3%), OvHV-2 (31%) and BHV-1 (1.5%). None of the samples were positive for Pestiviruses. PMID- 27997621 TI - Tolerance to Gamma Radiation in the Marine Heterotardigrade, Echiniscoides sigismundi. AB - Tardigrades belong to the most radiation tolerant animals on Earth, as documented by a number of studies using both low-LET and high-LET ionizing radiation. Previous studies have focused on semi-terrestrial species, which are also very tolerant to desiccation. The predominant view on the reason for the high radiation tolerance among these semi-terrestrial species is that it relies on molecular mechanisms that evolved as adaptations for surviving dehydration. In this study we report the first study on radiation tolerance in a marine tardigrade, Echiniscoides sigismundi. Adult specimens in the hydrated active state were exposed to doses of gamma radiation from 100 to 5000 Gy. The results showed little effect of radiation at 100 and 500 Gy but a clear decline in activity at 1000 Gy and higher. The highest dose survived was 4000 Gy, at which ca. 8% of the tardigrades were active 7 days after irradiation. LD50 in the first 7 days after irradiation was in the range of 1100-1600 Gy. Compared to previous studies on radiation tolerance in semi-terrestrial and limnic tardigrades, Echiniscoides sigismundi seems to have a lower tolerance. However, the species still fits into the category of tardigrades that have high tolerance to both desiccation and radiation, supporting the hypothesis that radiation tolerance is a by-product of adaptive mechanisms to survive desiccation. More studies on radiation tolerance in tardigrade species adapted to permanently wet conditions, both marine and freshwater, are needed to obtain a more comprehensive picture of the patterns of radiation tolerance. PMID- 27997622 TI - Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling. AB - BACKGROUND: Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. METHODS: We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children's Oncology Group (COG) induction therapy from 2014-2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. RESULTS: In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. CONCLUSIONS: Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance. PMID- 27997624 TI - Two-Photon Laser Scanning Stereomicroscopy for Fast Volumetric Imaging. AB - Bessel beams have been successfully used in two-photon laser scanning fluorescence microscopy to extend the depth of field (EDF), which makes it possible to observe fast events volumetrically. However, the depth information is lost due to integration of fluorescence signals along the propagation direction. We describe the design and implementation of two-photon lasers scanning stereomicroscopy, which allows viewing dynamic processes in three-dimensional (3D) space stereoscopically in real-time with shutter glasses at the speed of 1.4 volumes per second. The depth information can be appreciated by human visual system or be recovered with correspondence algorithms for some cases. PMID- 27997623 TI - The Coupling of Peripheral Blood Pressure and Ventilatory Responses during Exercise in Young Adults with Cystic Fibrosis. AB - PURPOSE: Cystic fibrosis (CF) is commonly recognized as a pulmonary disease associated with reduced airway function. Another primary symptom of CF is low exercise capacity where ventilation and gas-exchange are exacerbated. However, an independent link between pathophysiology of the pulmonary system and abnormal ventilatory and gas-exchange responses during cardiopulmonary exercise testing (CPET) has not been established in CF. Complicating this understanding, accumulating evidence suggests CF demonstrate abnormal peripheral vascular function; although, the clinical implications are unclear. We hypothesized that compared to controls, relative to total work performed (WorkTOT), CF would demonstrate increased ventilation accompanied by augmented systolic blood pressure (SBP) during CPET. METHODS: 16 CF and 23 controls (age: 23+/-4 vs. 27+/ 4 years, P = 0.11; FEV1%predicted: 73+/-14 vs. 96+/-5, P<0.01) participated in CPET. Breath-by-breath oxygen uptake ([Formula: see text]), ventilation ([Formula: see text]), and carbon dioxide output ([Formula: see text]) were measured continuously during incremental 3-min stage step-wise cycle ergometry CPET. SBP was measured via manual sphygmomanometry. Linear regression was used to calculate [Formula: see text] slope from rest to peak-exercise. RESULTS: Compared to controls, CF performed less WorkTOT during CPET (90+/-19 vs. 43+/-14 kJ, respectively, P<0.01). With WorkTOT as a covariate, peak [Formula: see text] (62+/-8 vs. 90+/-4 L/min, P = 0.76), [Formula: see text] (1.8+/-0.3 vs. 2.7+/-0.1 L/min, P = 0.40), and SBP (144+/-13 vs. 152+/-6 mmHg, P = 0.88) were similar between CF and controls, respectively; whereas CF demonstrated increased [Formula: see text] slope (38+/-4 vs. 28+/-2, P = 0.02) but lower peak [Formula: see text] versus controls (22+/-5 vs. 33+/-4 mL/kg/min, P<0.01). There were modest-to-moderate correlations between peak SBP with [Formula: see text] (r = 0.30), [Formula: see text] (r = 0.70), and [Formula: see text] (r = 0.62) in CF. CONCLUSIONS: These data suggest that relative to WorkTOT, young adults with mild to-moderate severity CF demonstrate augmented [Formula: see text] slope accompanied by increased SBP during CPET. Although the underlying mechanisms remain unclear, the coupling of ventilatory inefficiency with increased blood pressure suggest important contributions from peripheral pathophysiology to low exercise capacity in CF. PMID- 27997625 TI - What Constitutes a Phrase in Sound-Based Music? A Mixed-Methods Investigation of Perception and Acoustics. AB - Phrasing facilitates the organization of auditory information and is central to speech and music. Not surprisingly, aspects of changing intensity, rhythm, and pitch are key determinants of musical phrases and their boundaries in instrumental note-based music. Different kinds of speech (such as tone- vs. stress-languages) share these features in different proportions and form an instructive comparison. However, little is known about whether or how musical phrasing is perceived in sound-based music, where the basic musical unit from which a piece is created is commonly non-instrumental continuous sounds, rather than instrumental discontinuous notes. This issue forms the target of the present paper. Twenty participants (17 untrained in music) were presented with six stimuli derived from sound-based music, note-based music, and environmental sound. Their task was to indicate each occurrence of a perceived phrase and qualitatively describe key characteristics of the stimulus associated with each phrase response. It was hypothesized that sound-based music does elicit phrase perception, and that this is primarily associated with temporal changes in intensity and timbre, rather than rhythm and pitch. Results supported this hypothesis. Qualitative analysis of participant descriptions showed that for sound-based music, the majority of perceived phrases were associated with intensity or timbral change. For the note-based piano piece, rhythm was the main theme associated with perceived musical phrasing. We modeled the occurrence in time of perceived musical phrases with recurrent event 'hazard' analyses using time-series data representing acoustic predictors associated with intensity, spectral flatness, and rhythmic density. Acoustic intensity and timbre (represented here by spectral flatness) were strong predictors of perceived musical phrasing in sound-based music, and rhythm was only predictive for the piano piece. A further analysis including five additional spectral measures linked to timbre strengthened the models. Overall, results show that even when little of the pitch and rhythm information important for phrasing in note-based music is available, phrasing is still perceived, primarily in response to changes of intensity and timbre. Implications for electroacoustic music composition and music recommender systems are discussed. PMID- 27997626 TI - Bioactive Volatiles from an Endophytic Daldinia cf. concentrica Isolate Affect the Viability of the Plant Parasitic Nematode Meloidogyne javanica. AB - Plant-parasitic nematodes form one of the largest sources of biotic stress imposed on plants, and are very difficult to control; among them are the obligate parasites, the sedentary root-knot nematodes (RKNs)-Meloidogyne spp.-which are extremely polyphagous and exploit a very wide range of hosts. Endophytic fungi are organisms that spend most of their life cycle within plant tissue without causing visible damage to the host plant. Many endophytes secrete specialized metabolites and/or emit volatile organic compounds (VOCs) that exhibit biological activity. Recently, we demonstrated that the endophytic fungus Daldinia cf. concentrica secrets biologically active VOCs. Here we examined the ability of the fungus and its VOCs to control the RKN M. javanica both in vitro and greenhouse experiments. The D. cf. concentrica VOCs showed bionematicidal activity against the second-stage juveniles (J2s) of M. javanica. We found that exposure of J2s to fungal volatiles caused 67% reduction in viability, and that application of a synthetic volatile mixture (SVM), comprising 3-methyl-1-butanol, (+/-)-2-methyl-1 butanol, 4-heptanone, and isoamyl acetate, in volumetric ratio of 1:1:2:1 further reduced J2s viability by 99%. We demonstrated that, although each of the four VOCs significantly reduced the viability of J2s relative to the control, only 4 heptanone elicited the same effect as the whole mixture, with nematicidal activity of 90% reduction in viability of the J2s. Study of the effect of the SVM on egg hatching demonstrated that it decreased eggs hatching by 87%. Finally, application of the SVM to soil inoculated with M. javanica eggs or J2s prior to planting susceptible tomato plants resulted in a significantly reduced galling index and fewer eggs produced on each root system, with no effect on root weight. Thus, D. cf. concentrica and/or SVM based on fungal VOCs may be considered as a novel alternative approach to controlling the RKN M. javanica. PMID- 27997631 TI - Correction: Continuous and simultaneous measurement of the biophysical properties of blood in a microfluidic environment. AB - Correction for 'Continuous and simultaneous measurement of the biophysical properties of blood in a microfluidic environment' by Yang Jun Kang, Analyst, 2016, 141, 6583-6597. PMID- 27997627 TI - Comparative Analysis of Volatile Defensive Secretions of Three Species of Pyrrhocoridae (Insecta: Heteroptera) by Gas Chromatography-Mass Spectrometric Method. AB - The true bugs (Hemiptera: Heteroptera) have evolved a system of well-developed scent glands that produce diverse and frequently strongly odorous compounds that act mainly as chemical protection against predators. A new method of non-lethal sampling with subsequent separation using gas chromatography with mass spectrometric detection was proposed for analysis of these volatile defensive secretions. Separation was performed on Rtx-200 column containing fluorinated polysiloxane stationary phase. Various mechanical irritation methods (ultrasonics, shaking, pressing bugs with plunger of syringe) were tested for secretion sampling with a special focus on non-lethal irritation. The preconcentration step was performed by sorption on solid phase microextraction (SPME) fibers with different polarity. For optimization of sampling procedure, Pyrrhocoris apterus was selected. The entire multi-parameter optimization procedure of secretion sampling was performed using response surface methodology. The irritation of bugs by pressing them with a plunger of syringe was shown to be the most suitable. The developed method was applied to analysis of secretions produced by adult males and females of Pyrrhocoris apterus, Pyrrhocoris tibialis and Scantius aegyptius (all Heteroptera: Pyrrhocoridae). The chemical composition of secretion, particularly that of alcohols, aldehydes and esters, is species specific in all three pyrrhocorid species studied. The sexual dimorphism in occurrence of particular compounds is largely limited to alcohols and suggests their epigamic intraspecific function. The phenetic overall similarities in composition of secretion do not reflect either relationship of species or similarities in antipredatory color pattern. The similarities of secretions may be linked with antipredatory strategies. The proposed method requires only a few individuals which remain alive after the procedure. Thus secretions of a number of species including even the rare ones can be analyzed and broadly conceived comparative studies can be carried out. PMID- 27997632 TI - Photoacoustic tomography using orthogonal Fabry-Perot sensors. AB - Fabry-Perot sensors have been used to produce in-vivo photoacoustic images of exquisite quality. However, for ease of construction and interrogation, they are produced in a planar form. Planar arrays suffer from a limited detection aperture, which leads to artifacts in the reconstruction of the initial pressure distribution. Here, an L-shaped detection geometry is described that allows a greater field of view by placing a second planar array orthogonal to the first. This captures data from the deeper lying regions of interest and mitigates the limited view, thus reducing artifacts in the reconstructed initial pressure distribution. PMID- 27997633 TI - Quantitative evaluation of atherosclerotic plaques using cross-polarization optical coherence tomography, nonlinear, and atomic force microscopy. AB - A combination of approaches to the image analysis in cross-polarization optical coherence tomography (CP OCT) and high-resolution imaging by nonlinear microscopy and atomic force microscopy (AFM) at the different stages of atherosclerotic plaque development is studied. This combination allowed us to qualitatively and quantitatively assess the disorganization of collagen in the atherosclerotic arterial tissue (reduction and increase of CP backscatter), at the fiber (change of the geometric distribution of fibers in the second-harmonic generation microscopy images) and fibrillar (violation of packing and different nature of a basket-weave network of fibrils in the AFM images) organization levels. The calculated CP channel-related parameters are shown to have a statistically significant difference between stable and unstable (also called vulnerable) plaques, and hence, CP OCT could be a potentially powerful, minimally invasive method for vulnerable plaques detection. PMID- 27997634 TI - Screening for Genital Herpes: What Is Not to Be Done. PMID- 27997635 TI - "Healing" Objets d'art Shine in Minerals in Medicine. PMID- 27997636 TI - A Recommendation Against Serologic Screening for Genital Herpes Infection-What Now? PMID- 27997637 TI - Physical Activity or Rest After Concussion in Youth: Questions About Timing and Potential Benefit. PMID- 27997639 TI - Progress for Soft Tissue Sarcoma. PMID- 27997638 TI - Heater-Cooler Cautions Updated. PMID- 27997640 TI - Shot in the Arm for Rare Diseases. PMID- 27997641 TI - Duration of Antibiotic Therapy for Community-Acquired Pneumonia in the Era of Personalized Medicine. PMID- 27997643 TI - Partnering With Nurses to Transform Primary Care. PMID- 27997644 TI - The Relationship Between Herpes Zoster, Syphilis and Chickenpox. PMID- 27997645 TI - Reducing Sodium Intake in the Population. PMID- 27997646 TI - Screening for Social Determinants of Health. PMID- 27997647 TI - Screening for Social Determinants of Health. PMID- 27997648 TI - Evaluating a Value-Driven Outcomes Program. PMID- 27997649 TI - Reducing Sodium Intake in the Population-Reply. PMID- 27997650 TI - Screening for Social Determinants of Health-Reply. PMID- 27997651 TI - Evaluating a Value-Driven Outcomes Program-Reply. PMID- 27997652 TI - Association Between Early Participation in Physical Activity Following Acute Concussion and Persistent Postconcussive Symptoms in Children and Adolescents. AB - Importance: Although concussion treatment guidelines advocate rest in the immediate postinjury period until symptoms resolve, no clear evidence has determined that avoiding physical activity expedites recovery. Objective: To investigate the association between participation in physical activity within 7 days postinjury and incidence of persistent postconcussive symptoms (PPCS). Design, Setting, and Participants: Prospective, multicenter cohort study (August 2013-June 2015) of 3063 children and adolescents aged 5.00-17.99 years with acute concussion from 9 Pediatric Emergency Research Canada network emergency departments (EDs). Exposures: Early physical activity participation within 7 days postinjury. Main Outcomes and Measures: Physical activity participation and postconcussive symptom severity were rated using standardized questionnaires in the ED and at days 7 and 28 postinjury. PPCS (>=3 new or worsening symptoms on the Post-Concussion Symptom Inventory) was assessed at 28 days postenrollment. Early physical activity and PPCS relationships were examined by unadjusted analysis, 1:1 propensity score matching, and inverse probability of treatment weighting (IPTW). Sensitivity analyses examined patients (>=3 symptoms) at day 7. Results: Among 2413 participants who completed the primary outcome and exposure, (mean [SD] age, 11.77 [3.35] years; 1205 [39.3%] females), PPCS at 28 days occurred in 733 (30.4%); 1677 (69.5%) participated in early physical activity including light aerobic exercise (n = 795 [32.9%]), sport-specific exercise (n = 214 [8.9%]), noncontact drills (n = 143 [5.9%]), full-contact practice (n = 106 [4.4%]), or full competition (n = 419 [17.4%]), whereas 736 (30.5%) had no physical activity. On unadjusted analysis, early physical activity participants had lower risk of PPCS than those with no physical activity (24.6% vs 43.5%; Absolute risk difference [ARD], 18.9% [95% CI,14.7%-23.0%]). Early physical activity was associated with lower PPCS risk on propensity score matching (n = 1108 [28.7% for early physical activity vs 40.1% for no physical activity]; ARD, 11.4% [95% CI, 5.8%-16.9%]) and on inverse probability of treatment weighting analysis (n = 2099; relative risk [RR], 0.74 [95% CI, 0.65-0.84]; ARD, 9.7% [95% CI, 5.7%-13.7%]). Among only patients symptomatic at day 7 (n = 803) compared with those who reported no physical activity (n = 584; PPCS, 52.9%), PPCS rates were lower for participants of light aerobic activity (n = 494 [46.4%]; ARD, 6.5% [95% CI, 5.7%-12.5%]), moderate activity (n = 176 [38.6%]; ARD, 14.3% [95% CI, 5.9%-22.2%]), and full-contact activity (n = 133 [36.1%]; ARD, 16.8% [95% CI, 7.5%-25.5%]). No significant group difference was observed on propensity-matched analysis of this subgroup (n = 776 [47.2% vs 51.5%]; ARD, 4.4% [95% CI, -2.6% to 11.3%]). Conclusions and Relevance: Among participants aged 5 to 18 years with acute concussion, physical activity within 7 days of acute injury compared with no physical activity was associated with reduced risk of PPCS at 28 days. A well designed randomized clinical trial is needed to determine the benefits of early physical activity following concussion. PMID- 27997653 TI - Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences: A Randomized Clinical Trial. AB - Importance: Current therapy of herpes infections relies on nucleoside analogues. Pritelivir is a well-tolerated novel herpes simplex virus (HSV) helicase-primase inhibitor that reduced genital shedding and lesions. Objective: To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. Design, Setting, and Participants: A phase 2, randomized, double blind, crossover clinical trial at clinical research centers in 4 US cities (October 2012-July 2013) compared daily oral doses of 100 mg of pritelivir with 500 mg of valacyclovir. The planned sample size was 98 adults, allowing for detection of a 50% reduction in viral shedding between the study treatments. Healthy adults with 4 to 9 annual genital HSV-2 recurrences were eligible. 45 participants were randomized to receive pritelivir [corrected] and 46 to receive valacyclovir first when the US Food and Drug Administration placed the trial on clinical hold based on findings in a concurrent nonclinical toxicity study, and the sponsor terminated the study. Interventions: Participants took the first drug for 28 days followed by 28 days of washout before taking the second drug for 28 days. Throughout treatment, the participants collected genital swabs 4 times daily for testing by HSV polymerase chain reaction assays. Main Outcomes and Measures: The primary end point was within-participant genital HSV shedding while receiving pritelivir compared with valacyclovir. Secondary end points included the quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes. Results: Of the 91 randomized participants (median age, 48 years; 57 women [63%]), 56 had completed both treatment periods at the time of the study's termination. In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valacyclovir treatment (relative risk [RR], 0.42 [corrected]; 95% CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95% CI, -0.6 to 0.5; P = .83). Genital lesions were present on 1.9% of days in the pritelivir group vs 3.9% in the valacyclovir group (RR, 0.40; 95% CI, 0.17-0.96; P = .04). The frequency of shedding episodes did not differ by group, with 1.3 per person-month for pritelivir and 1.6 per person-month for valacyclovir (RR, 0.80; 95% CI, 0.52 to 1.22; P = .29). Treatment-emergent adverse events occurred in 62.3% of participants in the pritelivir group and 69.2% of participants in the valacyclovir group. Conclusions and Relevance: Among adults with frequently recurring genital HSV-2, the use of pritelivir compared with valacyclovir resulted in a lower percentage of swabs with HSV detection over 28 days. Further research is needed to assess longer-term efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT01658826. PMID- 27997654 TI - Association Between the Birth of an Infant With Major Congenital Anomalies and Subsequent Risk of Mortality in Their Mothers. AB - Importance: Giving birth to a child with a major birth defect is a serious life event for a woman, yet little is known about the long-term health consequences for the mother. Objective: To assess whether birth of an infant born with a major congenital anomaly was associated with higher maternal risk of mortality. Design, Setting, and Participants: This population-based cohort study (n = 455 250 women) used individual-level linked Danish registry data for mothers who gave birth to an infant with a major congenital anomaly (41 508) between 1979 and 2010, with follow-up until December 31, 2014. A comparison cohort (413 742) was constructed by randomly sampling, for each mother with an affected infant, up to 10 mothers matched on maternal age, parity, and year of infant's birth. Exposure: Live birth of an infant with a major congenital anomaly as defined by the European Surveillance of Congenital Anomalies classification system. Main Outcomes and Measures: Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality. Hazard ratios (HRs) were adjusted for marital status, immigration status, income quartile (since 1980), educational level (since 1981), diabetes mellitus, modified Charlson comorbidity index score, hypertension, depression, history of alcohol-related disease, previous spontaneous abortion, pregnancy complications, smoking (since 1991), and body mass index (since 2004). Results: Mothers in both groups were a mean (SD) age of 28.9 (5.1) years at delivery. After a median (IQR) follow-up of 21 (12-28) years, there were 1275 deaths (1.60 per 1000 person-years) among 41 508 mothers of a child with a major congenital anomaly vs 10 112 deaths (1.27 per 1000 person-years) among 413 742 mothers in the comparison cohort, corresponding to an absolute mortality rate difference of 0.33 per 1000 person-years (95% CI, 0.24-0.42), an unadjusted HR of 1.27 (95% CI, 1.20-1.35), and an adjusted HR of 1.22 (95% CI, 1.15-1.29). Mothers with affected infants were more likely to die of cardiovascular disease (rate difference, 0.05 per 1000 person-years [95% CI, 0.02-0.08]; adjusted HR, 1.26 [95% CI, 1.04-1.53]), respiratory disease (rate difference, 0.02 per 1000 person years [95% CI, 0.00-0.04]; adjusted HR, 1.45 [95% CI, 1.01-2.08]), and other natural causes (rate difference, 0.11 per 1000 person-years [95% CI, 0.07-0.15]; adjusted HR, 1.50 [95% CI, 1.27-1.76]). Conclusions and Relevance: In Denmark, having a child with a major congenital anomaly was associated with a small but statistically significantly increased mortality risk in the mother compared with women without an affected child. However, the clinical importance of this association is uncertain. PMID- 27997655 TI - JAMA patient page: Screening for Genital Herpes. PMID- 27997657 TI - A piece of my mind: Healing Physicians. PMID- 27997659 TI - Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Recommendation Statement. AB - Importance: Genital herpes is a prevalent sexually transmitted infection in the United States, occurring in almost 1 in 6 persons aged 14 to 49 years. Infection is caused by 2 subtypes of the herpes simplex virus (HSV), HSV-1 and HSV-2. Antiviral medications may provide symptomatic relief from outbreaks but do not cure HSV infection. Neonatal herpes infection, while uncommon, can result in substantial morbidity and mortality. Objective: To update the 2005 US Preventive Services Task Force (USPSTF) recommendation on screening for genital herpes. Evidence Review: The USPSTF reviewed the evidence on the accuracy, benefits, and harms of serologic screening for HSV-2 infection in asymptomatic persons, including those who are pregnant, as well as the effectiveness and harms of preventive medications and behavioral counseling interventions to reduce future symptomatic episodes and transmission to others. Findings: Based on the natural history of HSV infection, its epidemiology, and the available evidence on the accuracy of serologic screening tests, the USPSTF concluded that the harms outweigh the benefits of serologic screening for genital HSV infection in asymptomatic adolescents and adults, including those who are pregnant. Conclusions and Recommendation: The USPSTF recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including those who are pregnant. (D recommendation). PMID- 27997661 TI - The Evolving Taxonomy of Health in Older Persons. PMID- 27997660 TI - Serologic Screening for Genital Herpes: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Genital herpes simplex virus (HSV) infection is a prevalent sexually transmitted infection. Vertical transmission of HSV can lead to fetal morbidity and mortality. Objective: To assess the evidence on serologic screening and preventive interventions for genital HSV infection in asymptomatic adults and adolescents to support the US Preventive Services Task Force for an updated recommendation statement. Data Sources: MEDLINE, Cochrane Library, EMBASE, and trial registries through March 31, 2016. Surveillance for new evidence in targeted publications was conducted through October 31, 2016. Study Selection: English-language randomized clinical trials (RCTs) comparing screening with no screening in persons without past or current symptoms of genital herpes; studies evaluating accuracy and harms of serologic screening tests for HSV-2; RCTs assessing preventive interventions in asymptomatic persons seropositive for HSV 2. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; pooled sensitivities and specificities of screening tests using a hierarchical summary receiver operating characteristic curve analysis when at least 3 similar studies were available. Main Outcomes and Measures: Accuracy of screening tests, benefits of screening, harms of screening, reduction in genital herpes outbreaks. Results: A total of 17 studies (n = 9736 participants; range, 24-3290) in 19 publications were included. No RCTs compared screening with no screening. Most studies of the accuracy of screening tests were from populations with high HSV-2 prevalence (greater than 40% based on Western blot). Pooled estimates of sensitivity and specificity of the most commonly used test at the manufacturer's cutpoint were 99% (95% CI, 97%-100%) and 81% (95% CI, 68%-90%), respectively (10 studies; n = 6537). At higher cutpoints, pooled estimates were 95% (95% CI, 91%-97%) and 89% (95% CI, 82%-93%), respectively (7 studies; n = 5516). Use of this test at the manufacturer's cutpoint in a population of 100 000 with a prevalence of HSV-2 of 16% (the seroprevalence in US adults with unknown symptom status) would result in 15 840 true-positive results and 15 960 false-positive results (positive predictive value, 50%). Serologic screening for genital herpes was associated with psychosocial harms, including distress and anxiety related to positive test results. Four RCTs compared preventive medications with placebo, 2 in nonpregnant asymptomatic adults who were HSV-2 seropositive and 2 in HSV-2-serodiscordant couples. Results in both populations were heterogeneous and inconsistent. Conclusions and Relevance: Serologic screening for genital herpes is associated with a high rate of false positive test results and potential psychosocial harms. Evidence from RCTs does not establish whether preventive antiviral medication for asymptomatic HSV-2 infection has benefit. PMID- 27997662 TI - Creating Local Learning Health Systems: Think Globally, Act Locally. PMID- 27997664 TI - Industrial Pollution Threatens Millions in Developing World. PMID- 27997663 TI - Learning by Listening-Improving Health Care in the Era of Yelp. PMID- 27997665 TI - Sub-Saharan Mortality Hotspots for Children Younger Than 5 Years. PMID- 27997666 TI - Boosting Breastfeeding Practices in Vietnam and Bangladesh. PMID- 27997668 TI - Coping with tinnitus. AB - This narrative article on coping with tinnitus has four primary objectives. First, theoretical perspectives about defining and categorizing coping are discussed. Second, an overview of the empirical research on coping with tinnitus is provided, focusing on how coping with tinnitus has been measured and on the trends that were found in research on coping with tinnitus. Third, the problems related to the current state of research on coping with tinnitus are highlighted. Fourth, suggestions are provided on ways that researchers can improve research on coping with tinnitus. PMID- 27997667 TI - Intelligibility and Clarity of Reverberant Speech: Effects of Wide Dynamic Range Compression Release Time and Working Memory. AB - Purpose: The purpose of this study was to examine the effects of varying wide dynamic range compression (WDRC) release time on intelligibility and clarity of reverberant speech. The study also considered the role of individual working memory. Method: Thirty older listeners with mild to moderately-severe sloping sensorineural hearing loss participated. Individuals were divided into high and low working memory groups on the basis of the results of a reading span test. Participants listened binaurally to sentence stimuli simulated at a range of reverberation conditions and WDRC release times using a high compression ratio. Outcome measures included objective intelligibility and subjective clarity ratings. Results: Speech intelligibility and clarity ratings both decreased as a function of reverberation. The low working memory group demonstrated a greater decrease in intelligibility with increasing amounts of reverberation than the high working memory group. Both groups, regardless of working memory, had higher speech intelligibility and clarity ratings with longer WDRC release times. WDRC release time had a larger effect on speech intelligibility under more reverberant conditions. Conclusions: Reverberation significantly affects speech intelligibility, particularly for individuals with lower working memory. In addition, longer release times in hearing aids may improve listener speech intelligibility and clarity in reverberant environments. PMID- 27997669 TI - Prosthesis management of residual-limb perspiration with subatmospheric vacuum pressure. AB - For the ambulatory person with lower-limb amputation, insufficient management of perspiration can result in inadequate prosthesis adherence, reduced mobility, and discomfort. This study compared a dynamic air exchange (DAE) prosthesis designed to expel accumulated perspiration with a total surface bearing suction socket (Suction) that cannot. Five people with unilateral transtibial amputation participated in a randomized, crossover experiment. All subjects were given a 1 wk acclimation to each study prosthesis while we measured their step activity levels. A rest-walk-rest protocol, including a 30 min treadmill walk at a self selected speed while wearing thermally insulative garments, was then used to observe residual-limb skin temperatures and perspiration. Afterward, subject opinions about the prostheses were assessed with questionnaires. During the week long acclimation period, no statistical difference in step activity levels were detected between prostheses (p = 0.22), but this may have been due to self reported behavioral modifications. During the rest-walk-rest protocol, no differences in skin temperatures were observed (p = 0.37). The DAE prosthesis accumulated 1.09 +/- 0.90 g and expelled 0.67 +/- 0.38 g of perspiration, while the Suction prosthesis accumulated 0.97 +/- 0.75 g. The questionnaire results suggest that participants were receptive to both prostheses. The DAE prosthesis was able to expel more than a third of the total perspiration, suggesting it may enable longer uninterrupted periods of perspiration-inducing activity. PMID- 27997670 TI - Perceived health, caregiver burden, and quality of life in women partners providing care to Veterans with traumatic brain injury. AB - Families of Veterans with traumatic brain injury (TBI) are often faced with providing long-term informal care to their loved one. However, little is known about how their perceived health and caregiving burden contribute to their quality of life (QOL). The purpose of this descriptive study was to describe perceived health, somatic symptoms, caregiver burden, and perceived QOL and to identify the extent to which these variables are associated with QOL in female partners/spouses of Veterans with TBI. Participants completed a written questionnaire including the Patient Health Questionnaire-15, Caregiver Reaction Assessment, Quality of Life Index, and the general health subscale of the 12-Item Short Form Survey version 2. Caregivers reported moderate levels of QOL, and over a quarter of the sample reported high levels of somatic symptoms, particularly fatigue and sleep disturbance. Age, perceived general health, somatic symptoms, the five subscales of caregiver burden (self-esteem, disrupted schedule, effect on finances, lack of family support, and effect on health) predicted QOL and explained 64% of its variance (adjusted r2 = 0.64, F(8,31) = 9.59). However, only somatic symptoms and the caregiver burden subscales of self-esteem and effect on finances were significant predictors in the model. These findings have implications for development of family-centered interventions to enhance the QOL of informal caregivers of Veterans with TBI. PMID- 27997673 TI - Functional performance differences between the Genium and C-Leg prosthetic knees and intact knees. AB - Microprocessor prosthetic knees (MPKs) have advanced technologically, offering new features to decrease impairment and activity limitations for persons with transfemoral amputation (TFA). The Genium knee is functionally untested, and functional differences between it and intact knees are unknown. This study sought to determine whether Genium use improves functional performance compared with the C-Leg. A randomized experimental crossover design was used, with a cross-section of five nonamputee controls for comparison to normal. Twenty community-ambulating persons with TFA were trained and tested for accommodation with study components. All subjects (n = 25) were assessed using the Continuous-Scale Physical Functional Performance-10 (CS-PFP10) assessment. Subjects with TFA used both MPK systems. Genium use improved upper-body flexibility, balance, and endurance domain scores (7.0%-8.4%, p 2 mm) retina. We conclude that the fovea is dominated by midget and parasol cells, but outside the fovea the ganglion cell diversity in marmoset is likely as great as that reported for nonprimate retinas. Taken together, the ganglion cell types in marmoset retina resemble those described previously in macaque retina with respect to morphology, stratification, and change in proportion across the retina. PMID- 27997692 TI - Effects of Airflow Induced by Rainfall on Shallow Groundwater Table Fluctuations. AB - An investigation of groundwater table fluctuations induced by rainfall should consider interactions between the liquid and gas phases in soils. In this study, a water-air two-phase flow model was initially verified by simulating an infiltration experiment. It was then employed to model the interactions between liquid and gas phases regarding actions of airflow on the groundwater table and the fluctuations of the phreatic level and water level in the well induced by rainfall. The effects of airflo7w caused by rainfall on phreatic level fluctuations were also studied quantitatively by comparing the results obtained using the proposed model with those obtained from a water single-phase flow model. The simulation results show that in addition to actual recharge, compressed airflow in unsaturated zones causes the phreatic level to increase, but the rise in the phreatic level is lower than that in the pore-air pressure head in unsaturated zones due to the mitigation of capillary fringe. The existence of airflow enhances the phreatic level rise during and after rainfall. In addition, the water level in the well, pushed by the phreatic level fluctuations, varies similarly to the phreatic level, but it experiences somewhat delayed and slightly attenuated. The Lisse effect precisely reflects the phreatic level fluctuations before actual recharge. Furthermore, the fluctuations in the phreatic level and water level in the well and the contributions of airflow to phreatic level fluctuations are affected by many factors: rain intensity, initial moisture, overlying aquitard, groundwater table depths, and screen depths of the well. PMID- 27997693 TI - Genetic ablation of P65 subunit of NF-kappaB in mdx mice to improve muscle physiological function. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genetic muscle disease characterized by dystrophin deficiency. Beyond gene replacement, the question of whether ablation of the p65 gene of nuclear factor-kappa B (NF-kappaB) in DMD can improve muscle physiology function is unknown. In this study, we investigated muscle physiological improvement in mdx mice (DMD model) with a genetic reduction of NF-kappaB. METHODS: Muscle physiological function and histology were studied in 2-month-old mdx/p65+/- , wild-type, mdx, and human minidystrophin gene transgenic mdx (TghDeltaDys/mdx) mice. RESULTS: Improved muscle physiological function was found in mdx/p65+/- mice when compared with mdx mice; however, it was similar to TghDeltaDys/mdx mice. The results indicate that genetic reduction of p65 levels diminished chronic inflammation in dystrophic muscle, thus leading to amelioration of muscle pathology and improved muscle physiological function. CONCLUSIONS: The results show that inhibition of NF-kappaB may be a promising therapy when combined with gene therapy for DMD. Muscle Nerve 56: 759-767, 2017. PMID- 27997694 TI - Spatial patterning of excitatory and inhibitory neuropil territories during spinal circuit development. AB - To generate rhythmic motor behaviors, both single neurons and neural circuits require a balance between excitatory inputs that trigger action potentials and inhibitory inputs that promote a stable resting potential (E/I balance). Previous studies have focused on individual neurons and have shown that, over a short spatial scale, excitatory and inhibitory (E/I) synapses tend to form structured territories with inhibitory inputs enriched on cell bodies and proximal dendrites and excitatory inputs on distal dendrites. However, systems-level E/I patterns, at spatial scales larger than single neurons, are largely uncharted. We used immunostaining for PSD-95 and gephyrin postsynaptic scaffolding proteins as proxies for excitatory and inhibitory synapses, respectively, to quantify the numbers and map the distributions of E/I synapses in zebrafish spinal cord at both an embryonic stage and a larval stage. At the embryonic stage, we found that PSD-95 puncta outnumber gephyrin puncta, with the number of gephyrin puncta increasing to match that of PSD-95 puncta at the larval stage. At both stages, PSD-95 puncta are enriched in the most lateral neuropil corresponding to distal dendrites while gephyrin puncta are enriched on neuronal somata and in the medial neuropil. Significantly, similar to synaptic puncta, neuronal processes also exhibit medial-lateral territories at both developmental stages with enrichment of glutamatergic (excitatory) processes laterally and glycinergic (inhibitory) processes medially. This establishment of neuropil excitatory-inhibitory structure largely precedes dendritic arborization of primary motor neurons, suggesting that the structured neuropil could provide a framework for the development of E/I balance at the cellular level. J. Comp. Neurol. 525:1649-1667, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27997695 TI - Timing isn't everything: Influenza vaccination in cancer patients. PMID- 27997698 TI - Specific joint angle dependency of voluntary activation during eccentric knee extensions. AB - INTRODUCTION: This study compared voluntary activation during isometric, concentric, and eccentric maximal knee extensions at different joint angles. METHODS: Fifteen participants performed isometric, concentric, and eccentric protocols (9 contractions each). For each protocol, the central activation ratio (CAR) was randomly measured at 50 degrees , 75 degrees , or 100 degrees of knee joint angle (0 degrees = full knee extension) using superimposed supramaximal paired nerve stimulations during contractions. RESULTS: CAR increased between 50 degrees and 100 degrees during isometric (93.6 +/- 3.1 vs. 98.5 +/- 1.4%), concentric (92.4 +/- 5.4 vs. 99.2 +/- 1.2%), and eccentric (93.0 +/- 3.5 vs. 96.6 +/- 3.8%) contractions. CAR was lower during eccentric than both isometric and concentric contractions at 75 degrees and 100 degrees , but similar between contraction types at 50 degrees . CONCLUSIONS: The ability to activate muscle maximally is impaired during eccentric contractions compared with other contraction types at 75 degrees and 100 degrees , but not at 50 degrees . Muscle Nerve 56: 750-758, 2017. PMID- 27997697 TI - Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration. AB - Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. ofCS is absent in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA-specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy. PMID- 27997696 TI - The organization of frequency and binaural cues in the gerbil inferior colliculus. AB - The inferior colliculus (IC) is the common target of separate pathways that transmit different types of auditory information. Beyond tonotopy, little is known about the organization of response properties within the 3-dimensional layout of the auditory midbrain in most species. Through study of interaural time difference (ITD) processing, the functional properties of neurons can be readily characterized and related to specific pathways. To characterize the representation of ITDs relative to the frequency and hodological organization of the IC, the properties of neurons were recorded and the sites recovered histologically. Subdivisions of the IC were identified based on cytochrome oxidase (CO) histochemistry. The results were plotted within a framework formed by an MRI atlas of the gerbil brain. The central nucleus was composed of two parts, and lateral and dorsal cortical areas were identified. The lateral part of the central nucleus had the highest CO activity in the IC and a high proportion of neurons sensitive to ITDs. The medial portion had lower CO activity and fewer ITD-sensitive neurons. A common tonotopy with a dorsolateral to ventromedial gradient of low to high frequencies spanned the two regions. The distribution of physiological responses was in close agreement with known patterns of ascending inputs. An understanding of the 3-dimensional organization of the IC is needed to specify how the single tonotopic representation in the IC central nucleus leads to the multiple tonotopic representations in core areas of the auditory cortex. PMID- 27997699 TI - Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma. AB - In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low grade, non-ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE-positive endometrioid endometrial carcinomas (EECs). We performed exome-sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling-related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA-repair-related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co-occurrence (RAD50-KMT2D and RAD50-SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches. PMID- 27997700 TI - Evolution of bird genomes-a transposon's-eye view. AB - Birds, the most species-rich monophyletic group of land vertebrates, have been subject to some of the most intense sequencing efforts to date, making them an ideal case study for recent developments in genomics research. Here, we review how our understanding of bird genomes has changed with the recent sequencing of more than 75 species from all major avian taxa. We illuminate avian genome evolution from a previously neglected perspective: their repetitive genomic parasites, transposable elements (TEs) and endogenous viral elements (EVEs). We show that (1) birds are unique among vertebrates in terms of their genome organization; (2) information about the diversity of avian TEs and EVEs is changing rapidly; (3) flying birds have smaller genomes yet more TEs than flightless birds; (4) current second-generation genome assemblies fail to capture the variation in avian chromosome number and genome size determined with cytogenetics; (5) the genomic microcosm of bird-TE "arms races" has yet to be explored; and (6) upcoming third-generation genome assemblies suggest that birds exhibit stability in gene-rich regions and instability in TE-rich regions. We emphasize that integration of cytogenetics and single-molecule technologies with repeat-resolved genome assemblies is essential for understanding the evolution of (bird) genomes. PMID- 27997701 TI - River Seepage Conductance in Large-Scale Regional Studies. AB - Flow exchange between surface and groundwater is of great importance be it for beneficial allocation and use of water resources or for the proper exercise of water rights. In large-scale regional studies, most numerical models use coarse grid sizes, which make it difficult to provide an accurate depiction of the phenomenon. In particular, a somewhat arbitrary leakance coefficient in a third type (i.e., Cauchy, General Head) boundary condition is used to calculate the seepage discharge as a function of the difference of head in the river and in the aquifer, whose value is often found by calibration. A different approach is presented to analytically estimate that leakance coefficient. It is shown that a simple equivalence can be deduced from the analytical solution for the empirical coefficient, so that it provides the accuracy of the analytical solution while the model maintains a very coarse grid, treating the water-table aquifer as a single calculation layer. Relating the empirical leakance coefficient to the exact conductance, derived from physical principles, provides a physical basis for the leakance coefficient. Factors such as normalized wetted perimeter, degree of penetration of the river, presence of a clogging layer, and anisotropy can be included with little computational demand. In addition the river coefficient in models such as MODFLOW, for example, can be easily modified when grid size is changed without need for recalibration. PMID- 27997702 TI - Impulse control disorder, lysosomal malfunction and ATP13A2 insufficiency in Parkinsonism. AB - Lysosomal transport of cargos in neurons is essential for neuronal proteostasis, transmission and functional motors and behaviours. Lysosomal malfunction including storage disorders is involved in the pathogenesis of Parkinson's disease (PD). Given the unclear molecular mechanisms of diverse defects in PD phenotypes, especially behavioural deficits, this mini review explores the cellular contexts of PD impulse control disorders and the molecular aspects of lysosomal cross-membrane transports. Focuses are paid to trace metal involvements in alpha-synuclein assembly in Lewy bodies, the functions and molecular interactions of ATP13A2 as ATPase transporters in lysosomal membranes for cross membrane trafficking and lysosomal homeostasis, and our current understandings of the neural circuits in ICD. Erroneously polarized distributions of cargos such as metals and lipids on each side of lysosomal membranes triggered by gene mutations and deregulated expression of ATP13A2 may thus instigate sensing protein structural changes such as aggregations, organelle degeneration, and specific neuronal ageing and death in Parkinsonism. PMID- 27997704 TI - Two-Year Follow-up Outcomes in Emotionally Focused Couple Therapy: An Investigation of Relationship Satisfaction and Attachment Trajectories. AB - Emotionally Focused Couple Therapy (EFT; The practice of emotionally focused couple therapy: Creating connection. New York, NY: Brunner-Routledge) is an evidence-based couple therapy that aims to create lasting change for couples (Clinical Psychology: Science and Practice, 6(1), 67-79). Although studies have demonstrated strong results in follow-up (Journal of Marital and Family Therapy, 28(4), 391-398), less is known about relationship functioning across time after therapy has ended. We modelled change in relationship satisfaction and attachment from pre-therapy through 24 months follow-up in 32 couples. HLM results confirmed a significant growth pattern demonstrating increases in relationship satisfaction and secure base behaviour and decreases in relationship specific attachment anxiety over the course of therapy and across follow-up at a decelerated rate. These findings support the theoretical assumption that EFT helps couples engaged in therapy create lasting relationship satisfaction and attachment change. PMID- 27997703 TI - Optimal timing of influenza vaccination during 3-week cytotoxic chemotherapy cycles. AB - BACKGROUND: Cytopenia occurs frequently during cytotoxic chemotherapy. Little is known about the optimal timing of influenza vaccination for patients receiving chemotherapy. This study compared the immunogenicity of an influenza vaccine administered concurrently with chemotherapy (day 1) and within the cytopenic period (day 11) during 3-week cytotoxic chemotherapy cycles. METHODS: Adult patients with solid cancer undergoing scheduled 3-week cytotoxic chemotherapy were randomly assigned to receive the 2014-2015 seasonal influenza vaccine on day 1 or 11 during the chemotherapy cycle. Patients were stratified by their age (<60 and >=60 years) and previous influenza vaccination status. Antibody responses to influenza vaccine strains H1N1, H3N2, and B were measured before and 21 to 28 days after vaccination with a hemagglutination inhibition antibody assay. RESULTS: Ninety-seven patients were randomized into a day 1 group (n = 43) or a day 11 group (n = 54). Eighty-three patients were included in the final analysis. The mean age was 54 (+/- 11) years. Cancer types included breast (61%) and lung cancer (30%). Baseline characteristics were not significantly different between the groups. Seroprotection rates after vaccination were also not significantly different for the day 1 and 11 groups (strain H1N1, 67% vs 75% [P = .403]; strain H3N2, 77% vs 80% [P = .772]; strain B, 21% vs 27% [P = .472]). Seroconversion rates and postvaccination geometric mean titers were also similar for the groups. Vaccine-related adverse events were more common in the day 11 group (13% vs. 32%; P = .040). CONCLUSIONS: The antibody responses to influenza vaccination on days 1 and 11 during a 3-week cytotoxic chemotherapy cycle were comparable. Influenza vaccination can be performed concurrently with cytotoxic chemotherapy or during the cytopenic period. Cancer 2017;123:841-48. (c) 2016 American Cancer Society. PMID- 27997705 TI - MAGNETIC RESONANCE IMAGING FEATURES OF INTRAVENTRICULAR EPENDYMOMAS IN Five CATS. AB - Intraventricular ependymoma is a rare type of feline intracranial neoplasia and published information on magnetic resonance imaging (MRI) characteristics is currently lacking. The purpose of this retrospective case series study was to describe the clinical and MRI characteristics of histopathologically confirmed intraventricular ependymomas in a group of cats. Five cats met inclusion criteria. In relation to normal gray matter, ependymomas appeared hyperintense on T2W, T2W-FLAIR, PD, and DW-EPI images; isointense on ADC images; and had subtle to strong contrast enhancement. Some variability was seen on T2*GRE and on T1W images with masses being isointense to hyperintense. Four ependymomas were small and homogeneous, and one was centrally cavitated. All cats had obstructive hydrocephalus, transtentorial herniation, and foramen magnum herniation. Perilesional edema was identified in most cats but was questionable in one. Intraventricular ependymoma should be considered as a differential diagnosis for cats with this combination of MRI signs. PMID- 27997707 TI - Two regulatory RNA elements affect TisB-dependent depolarization and persister formation. AB - Bacterial survival strategies involve phenotypic diversity which is generated by regulatory factors and noisy expression of effector proteins. The question of how bacteria exploit regulatory RNAs to make decisions between phenotypes is central to a general understanding of these universal regulators. We investigated the TisB/IstR-1 toxin-antitoxin system of Escherichia coli to appreciate the role of the RNA antitoxin IstR-1 in TisB-dependent depolarization of the inner membrane and persister formation. Persisters are phenotypic variants that have become transiently drug-tolerant by arresting growth. The RNA antitoxin IstR-1 sets a threshold for TisB-dependent depolarization under DNA-damaging conditions, resulting in two sub-populations: polarized and depolarized cells. Furthermore, our data indicate that an inhibitory 5' UTR structure in the tisB mRNA serves as a regulatory RNA element that delays TisB translation to avoid inappropriate depolarization when DNA damage is low. Investigation of the persister sub population further revealed that both regulatory RNA elements affect persister levels as well as persistence time. This work provides an intriguing example of how bacteria exploit regulatory RNAs to control phenotypic heterogeneity. PMID- 27997706 TI - Exploring the potential of boronic acids as inhibitors of OXA-24/40 beta lactamase. AB - beta-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to beta-lactams is the expression of beta-lactamase enzymes. To overcome beta-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for beta-lactamases also contain the characteristic beta-lactam ring, making them susceptible to resistance mechanisms employed by bacteria. This presents a critical need for novel, non-beta-lactam inhibitors that can circumvent these resistance mechanisms. The carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are of particular concern, given that they efficiently hydrolyze potent carbapenem antibiotics. Unfortunately, these enzymes are not inhibited by clinically available beta-lactamase inhibitors, nor are they effectively inhibited by the newest, non-beta-lactam inhibitor, avibactam. Boronic acids are known transition state analog inhibitors of class A and C beta lactamases, and are not extensively characterized as inhibitors of class D beta lactamases. Importantly, boronic acids provide a novel way to potentially inhibit class D beta-lactamases. Sixteen boronic acids were selected and tested for inhibition of the CHDL OXA-24/40. Several compounds were identified as effective inhibitors of OXA-24/40, with Ki values as low as 5 MUM. The X-ray crystal structures of OXA-24/40 in complex with BA3, BA4, BA8, and BA16 were determined and revealed the importance of interactions with hydrophobic residues Tyr112 and Trp115. These boronic acids serve as progenitors in optimization efforts of a novel series of inhibitors for class D beta-lactamases. PMID- 27997708 TI - Modular toxin from the lynx spider Oxyopes takobius: Structure of spiderine domains in solution and membrane-mimicking environment. AB - We have recently demonstrated that a common phenomenon in evolution of spider venom composition is the emergence of so-called modular toxins consisting of two domains, each corresponding to a "usual" single-domain toxin. In this article, we describe the structure of two domains that build up a modular toxin named spiderine or OtTx1a from the venom of Oxyopes takobius. Both domains were investigated by solution NMR in water and detergent micelles used to mimic membrane environment. The N-terminal spiderine domain OtTx1a-AMP (41 amino acid residues) contains no cysteines. It is disordered in aqueous solution but in micelles, it assumes a stable amphiphilic structure consisting of two alpha helices separated by a flexible linker. On the contrary, the C-terminal domain OtTx1a-ICK (59 residues) is a disulfide-rich polypeptide reticulated by five S-S bridges. It presents a stable structure in water and its core is the inhibitor cystine knot (ICK) or knottin motif that is common among single-domain neurotoxins. OtTx1a-ICK structure is the first knottin with five disulfide bridges and it represents a good reference for the whole oxytoxin family. The affinity of both domains to membranes was measured with NMR using titration by liposome suspensions. In agreement with biological tests, OtTx1a-AMP was found to show high membrane affinity explaining its potent antimicrobial properties. PMID- 27997709 TI - The role of allogenic keratin-derived dressing in wound healing in a mouse model. AB - Keratin is an interesting protein needed for wound healing and tissue recovery. We have recently proposed a new, simple and inexpensive method to obtain fur and hair keratin-derived biomaterials suitable for medical application. The aim of the study was to evaluate the role of the fur keratin-derived protein (FKDP) dressing in the allogenic full-thickness surgical skin wound model. The data obtained using scanning electron microscopy showed that employed processed biomaterial had higher surface porosity compared with control raw material. From the MTS test, it was found keratin biomaterial is not only toxic to the NIH/3T3 cell line (p < 0.05), but also enhances cell proliferation compared with the control. In vivo studies have shown keratin dressings are tissue biocompatible, accelerate wound closure and epithelialization to the statistically significant differences on day 5 (p < 0.05) in comparison to control wounds. Histological examination revealed, that in FKDP-treated wounds the inflammatory response contained predominantly macrophages whilst their morphological untreated variants showed mixed cell infiltrates rich in neutrophils. Predominant macrophages based response creates more favorable environment for healing. In FKDP-dressed wounds the number of microhemorrhages was also significantly decreased (p < 0.05) as compared with undressed wounds. Applied keratin dressing favors reconstruction of a more regular skin structure and assures better cosmetic effect in terms of scar formation and appearance. In conclusion, fur keratin-derived protein dressings significantly accelerated wound healing in the mouse model. Further studies are needed to determine the molecular mechanisms involved in the multilayer wound healing process and to assess the possible use of these dressings for medical purposes. PMID- 27997710 TI - The presence of non-native helical structure in the unfolding of a beta-sheet protein MPT63. AB - MPT63, a major secreted protein from Mycobacterium tuberculosis, has been shown to have immunogenic properties and has been implicated in virulence. MPT63 is a beta-sandwich protein containing 11 beta strands and a very short stretch of 310 helix. The detailed experimental and computational study reported here investigates the equilibrium unfolding transition of MPT63. It is shown that in spite of being a complete beta-sheet protein, MPT63 has a strong propensity toward helix structures in its early intermediates. Far UV-CD and FTIR spectra clearly suggest that the low-pH intermediate of MTP63 has enhanced helical content, while fluorescence correlation spectroscopy suggests a significant contraction. Molecular dynamics simulation complements the experimental results indicating that the unfolded state of MPT63 traverses through intermediate forms with increased helical characteristics. It is found that this early intermediate contains exposed hydrophobic surface, and is aggregation prone. Although MPT63 is a complete beta-sheet protein in its native form, the present findings suggest that the secondary structure preferences of the local interactions in early folding pathway may not always follow the native conformation. Furthermore, the Gly25Ala mutant supports the proposed hypothesis by increasing the non-native helical propensity of the protein structure. PMID- 27997711 TI - Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA-binding protein 43 inclusions) in missense progranulin mutation Cys139Arg. AB - Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau-negative frontotemporal lobar degeneration with TAR DNA-binding protein 43-positive inclusions (FTLD-TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late-onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Abeta-amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD-TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD-TDP. PMID- 27997712 TI - Effect of acrylodan conjugation and forced oxidation on the structural integrity, conformational stability, and binding activity of a glucose binding protein SM4 used in a prototype continuous glucose monitor. AB - Continuous glucose monitoring (CGM) devices offer diabetes patients a convenient approach to assist in controlling blood glucose levels. A prototype CGM has been developed that uses the emission profile of a polarity-sensitive fluorophore (acrylodan) conjugated to a glucose/galactose-binding protein (SM4-AC) to measure the concentration of glucose in vivo. During development, a decrease in the devices signal intensity was observed in vivo over time, which was postulated to be result of oxidative degradation of SM4-AC. A comprehensive physicochemical analysis of SM4-AC was pursued to identify potential mechanisms of signal intensity loss in this CGM during in vitro forced oxidation studies. An assessment of the structural integrity and conformational stability of SM4-AC indicated a relatively decreased polarity and lower tertiary structure stability compared to unconjugated protein (SM4). The stability and polarity of SM4-AC was also altered in the presence of H2 O2 . Furthermore, a time-dependent loss in the fluorescence signal of SM4-AC was observed when incubated with H2 O2 . An LC-MS peptide mapping analysis of these protein samples indicated that primarily two Met residues in SM4-AC were susceptible to oxidation. When these two residues were genetically altered to an amino acid not prone to oxidation, the glucose binding ability of the protein was retained and no loss of acrylodan fluorescence was observed in the presence of H2 O2 . Genetic alteration of these two residues is proposed as an effective approach to increase the long-term stability of SM4 AC within this prototype CGM in vivo. PMID- 27997713 TI - Effects of unilatral- and bilateral inhibition of rostral ventral tegmental area and central nucleus of amygdala on morphine-induced place conditioning in male Wistar rat. AB - The rostral ventral tegmental area (VTAR) and central nucleus of amygdala (CeA) are considered the main regions for induction of psychological dependence on abused drugs, such as morphine. The main aim of this study was to investigate the transient inhibition of each right and left side as well as both sides of the VTAR and the CeA by lidocaine (2%) on morphine reward properties using the conditioned place preference (CPP) method. Male Wistar rats (250+/-20 g) 7 days after recovery from surgery and cannulation were conditioned to morphine (7.5 mg/kg) in CPP apparatus. Five minutes before morphine injection in conditioning phase, lidocaine was administered either uni- or bilaterally into the VTAR (0.25 MUL/site) or CeA (0.5 MUL/site). The results revealed that lidocaine administration into the left side, but not the right side of the VTAR and the CeA reduced morphine CPP significantly. The reduction was potentiated when lidocaine was injected into both sides of the VTAR and the CeA. The number of compartment crossings was reduced when lidocaine was injected into both sides of the VTAR and the CeA as well as the left side. Rearing was reduced when lidocaine was injected into the right, but not the left side of the VTAR. Sniffing and rearing increased when animals received lidocaine in the right side and reduced in the group that received lidocaine in the left side of the CeA. It was concluded that the right and the left side of VTAR and the CeA play different roles in morphine-induced activity and reward. PMID- 27997714 TI - Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib-resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single-nucleotide variants and copy-number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin-dependent kinase activity. Some variants in the resistant samples were traced back to the drug-sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre-existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. (c) 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc. PMID- 27997715 TI - Structural mechanism for bacterial oxidation of oceanic trimethylamine into trimethylamine N-oxide. AB - Trimethylamine (TMA) and trimethylamine N-oxide (TMAO) are widespread in the ocean and are important nitrogen source for bacteria. TMA monooxygenase (Tmm), a bacterial flavin-containing monooxygenase (FMO), is found widespread in marine bacteria and is responsible for converting TMA to TMAO. However, the molecular mechanism of TMA oxygenation by Tmm has not been explained. Here, we determined the crystal structures of two reaction intermediates of a marine bacterial Tmm (RnTmm) and elucidated the catalytic mechanism of TMA oxidation by RnTmm. The catalytic process of Tmm consists of a reductive half-reaction and an oxidative half-reaction. In the reductive half-reaction, FAD is reduced and a C4a hydroperoxyflavin intermediate forms. In the oxidative half-reaction, this intermediate attracts TMA through electronic interactions. After TMA binding, NADP+ bends and interacts with D317, shutting off the entrance to create a protected micro-environment for catalysis and exposing C4a-hydroperoxyflavin to TMA for oxidation. Sequence analysis suggests that the proposed catalytic mechanism is common for bacterial Tmms. These findings reveal the catalytic process of TMA oxidation by marine bacterial Tmm and first show that NADP+ undergoes a conformational change in the oxidative half-reaction of FMOs. PMID- 27997717 TI - Sequential analysis of 18 genes in polycythemia vera and essential thrombocythemia reveals an association between mutational status and clinical outcome. AB - Philadelphia-negative classical myeloproliferative neoplasms (MPN) are clonal diseases characterized by driver mutations of JAK2, MPL, or CALR. Additional mutations may occur in epigenetic regulators, signaling, or splicing genes that may be useful in the prognostic assessment of MPN patients. In primary myelofibrosis, molecular-based prognostic scoring systems have been recently proposed, but few data are available to date for polycythemia vera (PV) and essential thrombocythemia (ET). In this study, we used a next generation sequencing-based 18-gene panel in 50 JAK2V617F positive PV and JAK2V617F positive ET patients from an institutional cohort investigated at diagnosis and at 3-year follow-up (3y). Disease progression at 3y was defined by a composite criterion. Patients (28 PV and 22 ET) were included according to their clinical status, with or without disease progression. At diagnosis, we found 28 additional mutations in 21 of the 50 patients. Patients with disease progression were more likely to have at least one additional mutation. There was no difference between PV and ET. All patients with two or more additional mutations exhibited disease progression at 3y. No novel mutations appeared at 3y. The allele burden increase by at least one mutation at 3y was more frequent in patients with disease progression. Our data suggest that screening for additional mutations in PV and ET could identify patients at a higher risk of disease progression. (c) 2017 Wiley Periodicals, Inc. PMID- 27997718 TI - Dynamics of the peptidoglycan biosynthetic machinery in the stalked budding bacterium Hyphomonas neptunium. AB - Most commonly studied bacteria grow symmetrically and divide by binary fission, generating two siblings of equal morphology. An exception to this rule are budding bacteria, in which new offspring emerges de novo from a morphologically invariant mother cell. Although this mode of proliferation is widespread in diverse bacterial lineages, the underlying mechanisms are still incompletely understood. Here, we report the first molecular-level analysis of growth and morphogenesis in the stalked budding alphaproteobacterium Hyphomonas neptunium. Peptidoglycan labeling shows that, in this species, buds originate from a stalk like extension of the mother cell whose terminal segment is gradually remodeled into a new cell compartment. As a first step toward identifying the machinery mediating the budding process, we performed comprehensive mutational and localization studies of predicted peptidoglycan biosynthetic proteins in H. neptunium. These analyses identify factors that localize to distinct zones of dispersed and zonal growth, and they suggest a critical role of the MreB controlled elongasome in cell morphogenesis. Collectively, our work shows that the mechanism of growth in H. neptunium is distinct from that in related, polarly growing members of the order Rhizobiales, setting the stage for in-depth analyses of the molecular principles regulating the fascinating developmental cycle of this species. PMID- 27997720 TI - Prediction of chemical composition and peroxide value in unground pet foods by near-infrared spectroscopy. AB - The massive development of the pet food industry in recent years has lead to the formulation of hundreds of canine and feline complete extruded foods with the objective of meeting both the needs of the animals and numerous demands from pet owners. In the meantime, highly variable raw material compositions and the industry's new production techniques oblige manufacturers to monitor all phases of the extrusion process closely in order to ensure the targeted composition and quality of the products. This study aimed at evaluating the potential of infrared technology (visible and near-infrared spectrophotometer; 570-1842 nm) in predicting the chemical composition and peroxide value (PV) of unground commercial extruded dog foods. Six hundred and forty-nine commercial extruded dog foods were collected. For each product, an unground aliquot was analysed by infrared instrument while a second aliquot was sent to a laboratory for proximate analysis and PV quantification. The wide range of extruded dog food typologies included in the study was responsible for the wide variability observed within each nutritional trait, especially crude fibre and ash. The mean value of the 208 pet foods sampled for PV quantification was 17.49 mEq O2 /kg fat (min 2.2 and max 94.10 mEq O2 /kg fat). The coefficients of determination in cross-validation of NIRS prediction models were 0.77, 0.97, 0.83, 0.86, 0.78 and 0.94 for moisture, crude protein, crude fat, crude fibre, ash and nitrogen-free extract (NFE) respectively. PV prediction was less precise, as demonstrated by the coefficient of determination in cross-validation (0.66). The results demonstrated the potential of NIRS in predicting chemical composition in unground samples, with lower accuracy for moisture and ash, while PV prediction models suggest use for screening purposes only. PMID- 27997719 TI - Insulation and wiring specificity of BceR-like response regulators and their target promoters in Bacillus subtilis. AB - BceRS and PsdRS are paralogous two-component systems in Bacillus subtilis controlling the response to antimicrobial peptides. In the presence of extracellular bacitracin and nisin, respectively, the two response regulators (RRs) bind their target promoters, PbceA or PpsdA , resulting in a strong up regulation of target gene expression and ultimately antibiotic resistance. Despite high sequence similarity between the RRs BceR and PsdR and their known binding sites, no cross-regulation has been observed between them. We therefore investigated the specificity determinants of PbceA and PpsdA that ensure the insulation of these two paralogous pathways at the RR-promoter interface. In vivo and in vitro analyses demonstrate that the regulatory regions within these two promoters contain three important elements: in addition to the known (main) binding site, we identified a linker region and a secondary binding site that are crucial for functionality. Initial binding to the high-affinity, low-specificity main binding site is a prerequisite for the subsequent highly specific binding of a second RR dimer to the low-affinity secondary binding site. In addition to this hierarchical cooperative binding, discrimination requires a competition of the two RRs for their respective binding site mediated by only slight differences in binding affinities. PMID- 27997716 TI - Collagen-like proteins of pathogenic streptococci. AB - The collagen domain, which is defined by the presence of the Gly-X-Y triplet repeats, is amongst the most versatile and widespread known structures found in proteins from organisms representing all three domains of life. The streptococcal collagen-like (Scl) proteins are widely present in pathogenic streptococci, including Streptococcus pyogenes, S. agalactiae, S. pneumoniae, and S. equi. Experiments and bioinformatic analyses support the hypothesis that all Scl proteins are homotrimeric and cell wall-anchored. These proteins contain the rod shaped collagenous domain proximal to cell surface, as well as a variety of outermost non-collagenous domains that generally lack predicted functions but can be grouped into one of six clusters based on sequence similarity. The well characterized Scl1 proteins of S. pyogenes show a dichotomous switch in ligand binding between human tissue and blood environments. In tissue, Scl1 adhesin specifically recognizes the wound microenvironment, promotes adhesion and biofilm formation, decreases bacterial killing by neutrophil extracellular traps, and modulates S. pyogenes virulence. In blood, ligands include components of complement and coagulation-fibrinolytic systems, as well as plasma lipoproteins. In all, the Scl proteins signify a large family of structurally related surface proteins, which contribute to the ability of streptococci to colonize and cause diseases in humans and animals. PMID- 27997721 TI - Metabolic adaptation of Chlamydia trachomatis to mammalian host cells. AB - Metabolic adaptation is a key feature for the virulence of pathogenic intracellular bacteria. Nevertheless, little is known about the pathways in adapting the bacterial metabolism to multiple carbon sources available from the host cell. To analyze the metabolic adaptation of the obligate intracellular human pathogen Chlamydia trachomatis, we labeled infected HeLa or Caco-2 cells with 13 C-marked glucose, glutamine, malate or a mix of amino acids as tracers. Comparative GC-MS-based isotopologue analysis of protein-derived amino acids from the host cell and the bacterial fraction showed that C. trachomatis efficiently imported amino acids from the host cell for protein biosynthesis. FT-ICR-MS analyses also demonstrated that label from exogenous 13 C-glucose was efficiently shuffled into chlamydial lipopolysaccharide probably via glucose 6-phosphate of the host cell. Minor fractions of bacterial Ala, Asp, and Glu were made de novo probably using dicarboxylates from the citrate cycle of the host cell. Indeed, exogenous 13 C-malate was efficiently taken up by C. trachomatis and metabolized into fumarate and succinate when the bacteria were kept in axenic medium containing the malate tracer. Together, the data indicate co-substrate usage of intracellular C. trachomatis in a stream-lined bipartite metabolism with host cell-supplied amino acids for protein biosynthesis, host cell-provided glucose 6 phosphate for cell wall biosynthesis, and, to some extent, one or more host cell derived dicarboxylates, e.g. malate, feeding the partial TCA cycle of the bacterium. The latter flux could also support the biosynthesis of meso-2,6 diaminopimelate required for the formation of chlamydial peptidoglycan. PMID- 27997722 TI - Pitavastatin suppresses hyperglycaemia-induced podocyte injury via bone morphogenetic protein-7 preservation. AB - Podocytes form the essential components of the glomerular filtration barrier and play a critical role in diabetic nephropathy. Recent evidence suggests that HMG CoA reductase inhibitors (statins) exert renoprotective effects. We investigated whether pitavastatin directly suppresses hyperglycaemia-induced podocyte injury using cultured podocytes and, if so, the mechanism of the beneficial effects. Cultured podocytes were exposed to media containing normal (NG; 5 mmol/L) or high (HG; 25 mmol/L) glucose for 1 week. HG increased the lethal injury of podocytes and disruption of F-actin fibers, and reduced the mRNA expression of novel podocyte markers, synaptopodin and Wilms tumor-1 (WT-1), in association with decreased bone morphogenetic protein-7 (BMP-7) expression. Pitavastatin (100 nmol/L) reduced podocyte injury and restored the mRNA expression of synaptopodin and WT1; however, these protective effects were abolished by BMP-7 siRNA. Additionally, pitavastatin suppressed HG-induced Rho kinase activation, as assessed by the phosphorylation level of myosin phosphatase targeting subunit 1 (MYTP1), and C3 exotoxin, a Rho inhibitor, mimicked the effect of pitavastatin on BMP-7 preservation. Pitavastatin attenuates hyperglycaemia-induced podocyte injury via Rho-Rho kinase-dependent BMP-7 preservation. PMID- 27997723 TI - Covered versus uncovered metal stents for malignant gastric outlet obstruction: Systematic review and meta-analysis. AB - BACKGROUND AND AIM: Self-expandable metal stents (SEMS) are used for non resectable malignant gastric outlet obstruction (GOO). Studies of covered versus uncovered SEMS have yielded inconsistent results as a result of heterogeneity in design and patient population. We carried out a meta-analysis to compare covered and uncovered gastroduodenal SEMS. METHODS: Using MEDLINE, Embase, and the Cochrane database, we identified 1624 patients from 13 prospective and retrospective studies that evaluated covered and uncovered SEMS for malignant GOO and were published until October 2016. We pooled data on SEMS dysfunction, technical and clinical success, and adverse events using the fixed-effect or random-effects model. RESULTS: Compared with uncovered SEMS, covered SEMS did not show any significant difference in stent dysfunction risk (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.79-1.32). A subgroup analysis of five randomized trials suggested a trend toward a lower dysfunction risk in covered SEMS (RR, 0.63; 95% CI, 0.45-0.88). Covered SEMS were associated with a lower occlusion risk (RR, 0.44; 95% CI, 0.28-0.68), but with a higher migration risk (RR, 4.28; 95% CI, 2.89-6.34). Technical and clinical success rates were comparable between the groups. Overall adverse events tended to be more frequent in covered SEMS (RR, 1.75; 95% CI, 1.09-2.83). CONCLUSIONS: Outcomes of covered and uncovered gastroduodenal SEMS were comparable, although the lower dysfunction rate of covered SEMS observed in the analysis of randomized trials needs further investigation. Antimigration mechanisms for covered SEMS and identification of patients who can achieve longer patency from uncovered SEMS would help improve the outcomes of gastroduodenal SEMS. PMID- 27997724 TI - Anti-neutrophil cytoplasmic antibody-associated vasculitis resembling esophageal cancer. PMID- 27997725 TI - Efficacy of an emollient cream in the treatment of xerosis in diabetic foot: a double-blind, randomized, vehicle-controlled clinical trial. AB - BACKGROUND: Peripheral neuronal impairment compromises foot health in patients with diabetes. Clinically, xerosis is the most common mild complication, but it should not be underestimated. An effective treatment must be able to restore the cutaneous barrier and prevent water loss, to maintain adequate hydration and protection. OBJECTIVE: This study aimed to assess the efficacy of an emollient cream on foot xerosis in patients with diabetes. METHODS: This is a prospective, multicenter, randomized, double-blind contralateral vehicle-controlled study in 57 patients with diabetes. Patients were treated twice daily for 27 +/- 2 days with the study emollient containing glycerol 15%, liquid and soft paraffin 10%, glycerol monostearate, stearic acid, polydimethylcyclosiloxane, silicone oil, macrogol 600, trolamine, propyl parahydroxybenzoate and purified water (Dexeryl(r) ; Pierre Fabre Medicament, Boulogne, France) or its vehicle (glycerol monostearate, stearic acid, polydimethylcyclosiloxane, silicone oil, macrogol 600, trolamine, propyl parahydroxybenzoate and purified water). Efficacy was assessed after a 28-day treatment period using a validated score [Xerosis Assessment Scale (XAS) score], instrumental measurements and subjective assessment. RESULTS: The XAS score decreased to 3.2 +/- 2.6 points with the emollient and 4.1 +/- 2.3 with the vehicle (P = 0.001). Improvement was observed from day 14 (P = 0.012). Compared with the vehicle, the emollient also significantly improved the overall skin score, hydration index, D-Squame(r) (CuDerm Corporation, Dallas, TX, USA) test, skin roughness and patients' opinions. CONCLUSION: Treatment with an emollient is effective for improving foot xerosis in patients with diabetes. PMID- 27997726 TI - Functional relatedness in the Inv/Mxi-Spa type III secretion system family. AB - Type III Secretion Systems (T3SSs) are structurally conserved nanomachines that span the inner and outer bacterial membranes, and via a protruding needle complex contact host cell membranes and deliver type III effector proteins. T3SS are phylogenetically divided into several families based on structural basal body components. Here we have studied the evolutionary and functional conservation of four T3SS proteins from the Inv/Mxi-Spa family: a cytosolic chaperone, two hydrophobic translocators that form a plasma membrane-integral pore, and the hydrophilic 'tip complex' translocator that connects the T3SS needle to the translocon pore. Salmonella enterica serovar Typhimurium (S. Typhimurium), a common cause of food-borne gastroenteritis, possesses two T3SSs, one belonging to the Inv/Mxi-Spa family. We used invasion-deficient S. Typhimurium mutants as surrogates for expression of translocator orthologs identified from an extensive phylogenetic analysis, and type III effector translocation and host cell invasion as a readout for complementation efficiency, and identified several Inv/Mxi-Spa orthologs that can functionally substitute for the S. Typhimurium chaperone and translocator proteins. Functional complementation correlates with amino acid sequence identity between orthologs, but varies considerably between the four proteins. This is the first in-depth survey of the functional interchangeability of Inv/Mxi-Spa T3SS proteins acting directly at the host-pathogen interface. PMID- 27997728 TI - Azathioprine-induced rosacea. PMID- 27997727 TI - Intramolecular Diaza-Diels-Alder Protocol: A New Diastereoselective and Modular One-Step Synthesis of Constrained Polycyclic Frameworks. AB - Phenotype-based screening of diverse compound collections generated by privileged substructure-based diversity-oriented synthesis (pDOS) is considered one of the prominent approaches in the discovery of novel drug leads. However, one key challenge that remains is the development of efficient and modular synthetic routes toward the facile access of privileged small-molecule libraries with skeletal and stereochemical complexity and drug-like properties. In this regard, a novel and diverse one-pot procedure for the diastereoselective synthesis of privileged polycyclic benzopyrans and benzoxepines is described herein. These unexplored chemotypes were accessed by utilizing an acid-mediated diaza-Diels Alder reaction of 2-allyloxy- and/or homoallyloxy benzaldehyde with 2-aminoazine building blocks. Profiling of representative analogues against blood-stage Plasmodium falciparum parasites identified three lead candidates with low micromolar antimalarial activity. PMID- 27997729 TI - Clinical and dermoscopic features of common warts. PMID- 27997730 TI - Inhibitors of oxidative and hydrolytic endocannabinoid degradation do not enhance depolarization-induced suppression of excitation on dorsal cochlear nucleus glycinergic neurons. AB - Neurons from the dorsal cochlear nucleus (DCN) present endocannabinoid (EC) dependent short-term synaptic plasticity in the form of depolarization-induced suppression of excitation (DSE). Postsynaptic calcium influx promotes EC synthesis and depression of neurotransmission. ECs can be degraded by a hydrolytic and an oxidative pathway, the latter via the enzyme cyclooxygenase 2 (COX-2). Hyperactivity in the DCN is related to the development of tinnitus, which can be induced by high doses of salicylate, a COX-2 inhibitor. Since EC dependent plasticity in the DCN can affect its excitation-inhibition balance, we investigated the impact of inhibitors of both oxidative and hydrolytic EC metabolism on the DSE from the synapses between the parallel fibers and cartwheel neurons (PF-CW) in the DCN. We found that inhibitors of COX-2 (ibuprofen and indomethacin) did not alter DSE at the PF-CW synapse. Salicylate also did not alter DSE. However, we found that inhibitors of the hydrolytic pathway did not affect DSE magnitude, but surprisingly speeded DSE decay. We conclude that oxidative EC degradation in the PF-CW synapse is not relevant for termination of DSE and are probably not important for controlling this form of synaptic plasticity in the DCN PF-CW synapse. The lack of effect on DSE of high doses of salicylate also suggests that it is not acting by increasing DSE in the PF-CWC synapse. However, the counter intuitive effect of the hydrolytic inhibitors shows that increasing EC on this synapse have more complex effects on DSE. PMID- 27997731 TI - The Effect of Inadequate Presample Blood Volume Withdrawal from Intravenous Catheter and Extension Sets on Measured Circulating L-Blood Lactate Concentration in Horses Receiving Lactated Ringer's Solution. AB - BACKGROUND: Circulating l-lactate concentration is commonly measured in hospitalized horses by sampling from indwelling intravenous (IV) catheters. However, there are no published evidence-based recommendations to prevent contamination by lactated Ringer's solution (LRS). HYPOTHESIS: Withdrawing 10 mL of blood from the LRS-containing extension set connected to the IV catheter before obtaining the sample for analysis should be adequate to obtain accurate measurement of blood lactate concentration (BLC). ANIMALS: Thirty-three adult hospitalized horses receiving constant rate infusion of LRS. METHODS: Immediately after disconnecting the LRS, 5 sequential 5 mL blood samples were obtained by aspiration from an extension set connected to an indwelling IV catheter, followed by 3 samples collected by direct venipuncture of the contralateral jugular vein. Samples were analyzed with 1 portable blood lactate analyzer. A linear mixed model was used to examine differences in lactate concentrations among samples collected from the catheter and by direct venipuncture. RESULTS: After considering differences in age, breed, sex, and reason for hospitalization, BLCs were higher (P < .001) in the first and second 5 mL samples collected through the extension set/catheter than in all other extension set/catheter samples or the direct venipuncture samples. The largest difference observed between the third and subsequent catheter or venipuncture samples was 0.34 mmol/L with an upper 95% CI of 1.12 mmol/L. CONCLUSIONS AND CLINICAL IMPORTANCE: Withdrawing 15 mL of blood from a LRS-containing extension set connected to an IV catheter (5.9 mL total volume capacity) before obtaining the sample for blood lactate analysis is suggested to optimize accuracy of BLC measurements. PMID- 27997733 TI - Global identification of alternative splicing via comparative analysis of SMRT- and Illumina-based RNA-seq in strawberry. AB - Alternative splicing (AS) is a key post-transcriptional regulatory mechanism, yet little information is known about its roles in fruit crops. Here, AS was globally analyzed in the wild strawberry Fragaria vesca genome with RNA-seq data derived from different stages of fruit development. The AS landscape was characterized and compared between the single-molecule, real-time (SMRT) and Illumina RNA-seq platform. While SMRT has a lower sequencing depth, it identifies more genes undergoing AS (57.67% of detected multiexon genes) when it is compared with Illumina (33.48%), illustrating the efficacy of SMRT in AS identification. We investigated different modes of AS in the context of fruit development; the percentage of intron retention (IR) is markedly reduced whereas that of alternative acceptor sites (AA) is significantly increased post-fertilization when compared with pre-fertilization. When all the identified transcripts were combined, a total of 66.43% detected multiexon genes in strawberry undergo AS, some of which lead to a gain or loss of conserved domains in the gene products. The work demonstrates that SMRT sequencing is highly powerful in AS discovery and provides a rich data resource for later functional studies of different isoforms. Further, shifting AS modes may contribute to rapid changes of gene expression during fruit set. PMID- 27997732 TI - The metalloprotease SepA governs processing of accumulation-associated protein and shapes intercellular adhesive surface properties in Staphylococcus epidermidis. AB - The otherwise harmless skin inhabitant Staphylococcus epidermidis is a major cause of healthcare-associated medical device infections. The species' selective pathogenic potential depends on its production of surface adherent biofilms. The Cell wall-anchored protein Aap promotes biofilm formation in S. epidermidis, independently from the polysaccharide intercellular adhesin PIA. Aap requires proteolytic cleavage to act as an intercellular adhesin. Whether and which staphylococcal proteases account for Aap processing is yet unknown. Here, evidence is provided that in PIA-negative S. epidermidis 1457Deltaica, the metalloprotease SepA is required for Aap-dependent S. epidermidis biofilm formation in static and dynamic biofilm models. qRT-PCR and protease activity assays demonstrated that under standard growth conditions, sepA is repressed by the global regulator SarA. Inactivation of sarA increased SepA production, and in turn augmented biofilm formation. Genetic and biochemical analyses demonstrated that SepA-related induction of biofilm accumulation resulted from enhanced Aap processing. Studies using recombinant proteins demonstrated that SepA is able to cleave the A domain of Aap at residue 335 and between the A and B domains at residue 601. This study identifies the mechanism behind Aap-mediated biofilm maturation, and also demonstrates a novel role for a secreted staphylococcal protease as a requirement for the development of a biofilm. PMID- 27997734 TI - Effect of botulinum toxin A on vasoconstriction and sympathetic neurotransmitters in a murine random pattern skin flap model. AB - Blood supply is the most important factor determining the survival of a skin flap. Botulinum toxin-A (Botox-A) is used as pharmacologic agent not only for aesthetic purposes, but also for its vasomotor actions. This study was conducted to establish whether local application of Botox-A increased survival of random pattern skin flaps in rats by changing the expression of neurotransmitters. Forty adult Sprague-Dawley rats with a caudally-based random pattern skin flap were divided into two groups: Botox-A group and saline group. Surviving flap area and cutaneous blood flow in the flap were evaluated on postoperative days 3 and 7. After injection of Botox-A, changes in vessels were analyzed using immunohistochemical staining. Levels of norepinephrine, neuropeptide-Y, nitric oxide, and endothelial nitric oxide synthase were analyzed quantitatively by high performance liquid chromatography, Western blot, and colorimetric assay. The survived area in the Botox-A group was significantly higher than that in the control group on postoperative days 3 and 7. Blood flow in the Botox-A group was significantly high in the proximal and middle areas immediately after the operation. The number of CD31-positive vessels in the Botox-A group was significant greater than that in the control group. Norepinephrine level in the Botox-A group decreased significantly immediately after flap elevation and at postoperative day 3. There were no significant differences in neuropeptide-Y level between the two groups. Nitric oxide level did not change significantly in either group despite the increase in endothelial nitric oxide synthase immediately after flap elevation and at 3 days postoperatively. In conclusion, Botox-A increased vascular blood flow and viable flap area in rats by reducing norepinephrine level. In contrast, neuropeptide-Y, another vasoconstrictor, was not affected by Botox-A. Nitric oxide, a vasodilator, was also not affected by Botox-A, despite the significant increase in endothelial nitric oxide synthase expression in the flaps. PMID- 27997735 TI - Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats. AB - Curcuma is a natural compound that has shown neuroprotective properties, and has been reported to prevent aging and improve memory. While the mechanism(s) underlying these effects are unclear, they may be related to increases in neural plasticity. Morphological changes have been reported in neuronal dendrites in the limbic system in animals and elderly humans with cognitive impairment. In this regard, there is a need to use alternative therapies that delay the onset of morphologies and behavioral characteristics of aging. Therefore, the objective of this study was to evaluate the effect of curcuma on cognitive processes and dendritic morphology of neurons in the prefrontal cortex (PFC), the CA1 and CA3 regions of the dorsal hippocampus, the dentate gyrus, and the basolateral amygdala (BLA) of aged rats. 18-month-old rats were administered curcuma (100 mg/kg) daily for 60 days. After treatment, recognition memory was assessed using the novel object recognition test. Curcuma-treated rats showed a significant increase in the exploration quotient. Dendritic morphology was assessed by Golgi Cox staining and followed by Sholl analysis. Curcuma-treated rats showed a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC, the CA1 and CA3, and the BLA. The preservation of dendritic morphology was positively correlated with cognitive improvements. Our results suggest that curcuma induces modification of dendritic morphology in the aforementioned regions. These changes may explain how curcuma slows the aging process that has already begun in these animals, preventing deterioration in neuronal morphology of the limbic system and recognition memory. PMID- 27997736 TI - Commentary on Pharmacometrics for Immunotherapy. AB - This commentary provides an overview of recent examples of pharmacometrics applied during the clinical development of two antagonists of the programmed death-1 (PD-1) cell surface receptor, pembrolizumab and nivolumab. Despite the remarkable achievements obtained in predicting the correct dosing schedule from different quantitative approaches, data indicated a great degree of heterogeneity in tumor response. To achieve therapeutic goals the search for predictive biomarkers associated with a lack of response and mechanism-based combination studies are warranted. PMID- 27997737 TI - Distribution of type I corticotropin-releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala. AB - The neuropeptide corticotropin-releasing factor (CRF) plays a critical role in mediating anxiety-like responses to stressors, and dysfunction of the CRF system has been linked to the etiology of several psychiatric disorders. Extra hypothalamic CRF can also modulate learning and memory formation, including amygdala-dependent learning. The basolateral nucleus of the amygdala (BLA) contains dense concentrations of CRF receptors, yet the distribution of these receptors on specific neuronal subtypes within the BLA has not been characterized. Here, we quantified the expression of CRF receptors on three nonoverlapping classes of GABAergic interneurons: those containing the calcium binding protein parvalbumin (PV), and those expressing the neuropeptides somatostatin (SOM) or cholecystokinin (CCK). While the majority of PV+ neurons and roughly half of CCK+ neurons expressed CRF receptors, they were expressed to a much lesser extent on SOM+ interneurons. Knowledge of the distribution of CRF receptors within the BLA can provide insight into how manipulations of the CRF system modulate fear and anxiety-like behaviors. PMID- 27997738 TI - Full Blood Count - Internal QC Protocol: a review by the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) Pty Ltd - Haematology. AB - INTRODUCTION: The RCPAQAP (Royal College of Pathologists of Australasia Quality Assurance Program) Haematology has undertaken an exercise to review the internal quality control protocol for full blood count (FBC) instrumentation as well as review the action taken by laboratories when nonconforming results are evident in the RCPAQAP proficiency testing reports. METHOD: A questionnaire was sent to laboratories enrolled in the RCPAQAP FBC module. Laboratories were asked to provide information with regard to the type of control measures used within their testing environment that would trigger alerts for nonconforming events. The questionnaire also reviewed the action taken by laboratories in response to nonconforming test results in their external QA reports. RESULTS: A total of 253 of the 850 laboratories enrolled in the FBC module returned a response to the questionnaire, which identified variation in the QC protocol used to identify nonconforming events on the FBC analyser, including the type of controls, control levels processed and the frequency of use. CONCLUSION: This questionnaire identified variation in the internal QC protocol used by laboratories, including the types of control measures used and the rules applied to identify nonconforming events. However, the majority of laboratories appear to follow the most favourable choice of actions supplied when reviewing results of external QA data. PMID- 27997740 TI - Model-Based Estimates of Tumor Growth Inhibition Metrics Are Time-Independent: A Reply to Mistry. PMID- 27997739 TI - Is oxygen saturation variable of simplified pulmonary embolism severity index reliable for identification of patients, suitable for outpatient treatment. AB - INTRODUCTION: The pulmonary embolism severity index (PESI) or simplified version (sPESI) are widely validated risk scores for the identification of eligible patients for outpatient treatment. Saturation is one of these criteria. For this metric, saturation of 90% or greater is assigned zero points. However, 90% saturation does not always exclude hypoxemic respiratory failure. OBJECTIVE: The aims of this study were first was to define corresponding partial arterial oxygen pressure (PaO2 ) values according to saturation in pulmonary embolism (PE) patients, and the second was to define a target saturation that can exclude hypoxemic respiratory failure and enable secure discharge of PE patients from emergency departments. METHODS: This is a retrospective study. To determine the optimal saturation value by which to detect hypoxemic respiratory failure, we generated receiver operating characteristic (ROC) curves and calculated the negative predictive value. RESULTS: Total of 65 patients were included in this study. Mean PaO2 levels from SaO2 89% to SaO2 93% were 52.8, 57.1, 57.3, 61, and 63.8 mmHg, respectively. ROC curve analysis revealed SaO2 level of 91.5% to be optimal target saturation for excluding respiratory failure with 84.6% specificity and 89.7% sensitivity; area under the curve was 0.885 (95% CI 0.796 0.975). The negative predictive value was 80% for SaO2 level of 92%. CONCLUSION: Patients with PE may be in respiratory failure despite an oxyhemoglobin saturation of >=90%. Although saturation is likely more important than precise PaO2 in tissue oxygenation, clinicians should be aware of the physiological effects of hypoxemia and take this into account before making outpatient treatment decisions. PMID- 27997741 TI - Advances in pleuroscopy. AB - OBJECTIVES: To describe the technique of pleuroscopy, its clinical uses such as diagnosis of exudative pleural effusion, treatment of pleural infection, treatment of pneumothorax, and diagnosis and pleurodesis of malignant pleural mesothelioma. Also to describe the newer techniques developed such as minothoracoscopy, semirigid thoracoscopy, narrow band imaging pleuroscopy, infrared pleuroscopy, autofluorescence pleuroscopy. DATA SOURCE: We searched the pubmed the last decade for publications with the key words pleuroscopy, medical thoracoscopy, pneumothorax and pleuroscopy, malignant pleural mesothelioma, minothoracoscopy, semirigid thoracoscopy, autofluorescence pleuroscopy. CONCLUSION: Medical thoracoscopy is the method of choice for investigation of the undiagnosed exudative pleural effusions. Newer techniques, such as narrow band imaging thoracoscopy, infrared thoracoscopy, autofluorescence thoracoscopy are offering a promising future for medical thoracoscopy. PMID- 27997742 TI - Reconstructing the plant mitochondrial genome for marker discovery: a case study using Pinus. AB - Whole-genome-shotgun (WGS) sequencing of total genomic DNA was used to recover ~1 Mbp of novel mitochondrial (mtDNA) sequence from Pinus sylvestris (L.) and three members of the closely related Pinus mugo species complex. DNA was extracted from megagametophyte tissue from six mother trees from locations across Europe, and 100-bp paired-end sequencing was performed on the Illumina HiSeq platform. Candidate mtDNA sequences were identified by their size and coverage characteristics, and by comparison with published plant mitochondrial genomes. Novel variants were identified, and primers targeting these loci were trialled on a set of 28 individuals from across Europe. In total, 31 SNP loci were successfully resequenced, characterizing 15 unique haplotypes. This approach offers a cost-effective means of developing marker resources for mitochondrial genomes in other plant species where reference sequences are unavailable. PMID- 27997743 TI - Metal NHC Complexes with Naphthalimide Ligands as DNA-Interacting Antiproliferative Agents. AB - Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5 cyclooctadiene)(NHC)RhCl)] (4 a-c), [(p-cymene)(NHC)RuCl2 )] (5 a-c), and [(NHC)CuBr] (6 a-c) were synthesized and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which is a DNA-intercalating moiety. Regarding the metal center, the highest activities were observed with the rhodium complexes, and cytotoxic activity was significantly lower for the ruthenium derivatives. The stable coordination of the NHC ligands of selected complexes 4 b and 5 b in solution was confirmed, and their DNA binding properties were studied by UV/Vis spectroscopy, mass spectrometry, and circular dichroism. Stable intercalative binding into the DNA for all selected naphthalimide-based complexes is indicated by high DNA binding constants. Particularly efficient binding was observed in the case of the rhodium complex 4 b. More detailed biological studies on 4 b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4 b-induced apoptosis. PMID- 27997744 TI - A comparative outcomes analysis evaluating clinical effectiveness in two different human placental membrane products for wound management. AB - Advances in tissue preservation have led to the commercialization of human placental membranes for the purposes of wound management with each product being characterized by different compositions and properties. The a priori specification of the research question in this investigator-initiated study focused on the clinical outcomes in two nonrandomized, however statistically equal and homogenous patient cohorts receiving either a viable intact cryopreserved human placental membrane (vCPM) or a dehydrated human amnion/chorion membrane (dHACM), for the management of wounds at a single center. A total of 79 patients with 101 wounds were analyzed: 40 patients with 46 wounds received vCPM and 39 patients with 55 wounds received dHACM. The proportion of wounds achieving complete wound closure was 63.0% (29/46) for vCPM and 18.2% (10/55) for dHACM (p < 0.0001) for all treated wounds combined. This is the first comparative effectiveness study to report on the clinical outcomes associated with the use of different placental wound care products once broadly implemented in the clinical setting. PMID- 27997745 TI - Impact of treatment on progression to castration-resistance, metastases, and death in men with localized high-grade prostate cancer. AB - Men with high-grade prostate cancer (HGPC) are at greatest risk of disease progression. Clinical risk factors associated with castration-resistant prostate cancer (CRPC), metastases, and prostate cancer-specific mortality (PCSM) were identified in a contemporary HGPC cohort. Clinical data was collected from men diagnosed with Gleason sum (GS) >=8 at the Greater Los Angeles Veterans Affairs (GLA-VA) Healthcare System between 2000 and 2013. Multivariable competing risks regression analyses assessed progression to CRPC, metastases, and PCSM within three treatment strata. The cumulative incidence of disease progression was calculated at 2, 5, and 10-year time points. Review of 2149 prostate cancer cases yielded 322 with HGPC. Median survival times for cancer-specific and overall mortality were significantly shorter in men treated with primary androgen deprivation therapy (ADT) (P = 0.0002 and P < 0.0001). Multivariable analyses revealed that clinical stage N1, GS 10, and treatment with primary ADT were significantly associated with increased risk of CRPC, metastases, and PCSM. Significant differences in these outcomes were not observed in men treated with radical prostatectomy (RP) when compared to those treated with radiation therapy combined with short-term ADT (XRT-ADT). Ten-year event rates of progression to CRPC, metastases, and PCSM, for men treated with primary ADT, were 45.5%, 25.4%, and 25.1%, respectively. In conclusion, GS 10 and lymph node involvement, as well as primary ADT treatment in men with HGPC was associated with increased risk of CRPC, metastases, and PCSM. Curative-intent treatment with RP or XRT-ADT is associated with reduced progression rates and death in men with HGPC. PMID- 27997747 TI - Dynamics of the sealing zone in cultured osteoclasts. AB - Bone resorption by osteoclasts (OCs) depends on the formation and stability of the sealing zone (SZ), a peripheral belt of actin and integrin-based podosomes. Recent studies demonstrated that the SZ is a highly dynamic structure, undergoing cycles of assembly and disassembly. In this study, we explored the mechanisms underlying the regulation of SZ stability and reorganization in OCs cultured on glass slides, and forming an SZ-like podosome belt (SZL). By monitoring this belt in cultured RAW264.7 cells expressing GFP-tagged actin, we show here that SZL stability is usually locally regulated, and its dissociation, occurring mostly in concave segments, is manifested in the loss of both podosome coherence, and actin belt continuity. Double labeling of cells for actin and tubulin indicated that microtubules (MTs) are mostly confined by the inner aspect of the stable SZL associated actin belt. However, in unstable regions of the SZL, MTs tend to extend radially, across the SZL, toward the cell edge. Disruption of MTs by nocodazole induces SZ disassembly, without affecting individual podosome stability. Inspection of the MT network indicates that it is enriched along stable SZL regions, while bypassing disorganized regions. These results suggest that the SZL is stabilized by MTs flanking its inner aspect, while disruption or misalignment of MTs leads to SZL destabilization. We further demonstrate that the MT-associated protein dynamin2 is involved in the regulation of SZL stability, and dynamin2 knockdown or inactivation cause SZL destabilization. PMID- 27997748 TI - Genesis of the Special Issues on Mass Cytometry. PMID- 27997746 TI - Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion-associated cardiac arrhythmias. AB - Oxidative stress placed on tissues that involved in pathogenesis of a disease activates compensatory metabolic changes, such as DNA damage repair that in turn causes intracellular accumulation of detritus and 'proteotoxic stress', leading to emergence of 'senescent' cellular phenotypes, which express high levels of inflammatory mediators, resulting in degradation of tissue function. Proteotoxic stress resulting from hyperactive inflammation following reperfusion of ischaemic tissue causes accumulation of proteinaceous debris in cells of the heart in ways that cause potentially fatal arrhythmias, in particular ventricular fibrillation (VF). An adaptive response to VF is occurrence of autophagy, an intracellular bulk degradation of damaged macromolecules and organelles that may restore cellular and tissue homoeostasis, improving chances for recovery. Nevertheless, depending on the type and intensity of stressors and inflammatory responses, autophagy may become pathological, resulting in excessive cell death. The present review examines the multilayered defences that cells have evolved to reduce proteotoxic stress by degradation of potentially toxic material beginning with endoplasmic reticulum-associated degradation, and the unfolded protein response, which are mechanisms for removal from the endoplasmic reticulum of misfolded proteins, and then progressing through the stages of autophagy, including descriptions of autophagosomes and related vesicular structures which process material for degradation and autophagy-associated proteins including Beclin-1 and regulatory complexes. The physiological roles of each mode of proteotoxic defence will be examined along with consideration of how emerging understanding of autophagy, along with a newly discovered regulatory cell type called telocytes, may be used to augment existing strategies for the prevention and management of cardiovascular disease. PMID- 27997749 TI - Inhibition of platelet aggregation and thrombosis by indole alkaloids isolated from the edible insect Protaetia brevitarsis seulensis (Kolbe). AB - Protaetia brevitarsis seulensis (Kolbe) has been temporarily registered as a food material by the Ministry of Food and Drug Safety of Korea (MFDS). The current study aimed to discover small antithrombotic molecules from this edible insect. Five indole alkaloids, 5-hydroxyindolin-2-one (1), (1R,3S)-1-methyl-1,2,3,4 tetrahydro-beta-carboline-3-carboxylic acid (2), (1S,3S)-1-methyl-1,2,3,4 tetrahydro-beta-carboline-3-carboxylic acid (3), (3S)-1,2,3,4-tetrahydro-beta carboline-3-carboxylic acid (4) and L-tryptophan (5), were isolated from the insect. Among them, compounds 1 and 2 prolonged aPTT and PT and impaired thrombin and FXa generation on HUVEC surface. Moreover, these compounds inhibited platelet aggregation. Antithrombotic effects of compounds 1 and 2 were further confirmed in pre-clinical models of pulmonary embolism and arterial thrombosis. Collectively, these results demonstrated that compounds 1 and 2 could be effective antithrombotic agents and serve as new scaffolds for the development of antithrombotic drug. PMID- 27997750 TI - Bactericidal mechanism of glutaraldehyde-didecyldimethylammonium bromide as a disinfectant against Escherichia coli. AB - AIMS: This study focuses on the bactericidal mechanism of the new combination of disinfectant glutaraldehyde-didecyldimethylammonium bromide (GA-DDAB) against Escherichia coli. METHODS AND RESULTS: Escherichia coli were exposed to GA-DDAB, and assays for cell morphology, K+ and Ca2+ leakage, H+ -ATPase activity and DNA degradation were performed. GA-DDAB damaged the cell wall and disrupted cell membrane integrity. Leakage of K+ and Ca2+ increased, resulting in significantly lower intracellular concentrations within 60 min of treatment. In addition, H+ ATPase was inactivated and DNA was degraded. CONCLUSIONS: Leakage of intracellular components indicated that GA-DDAB damaged the cell membrane of E. coli. This may have caused the observed disruption in equilibria of metal ions, inactivation of H+ -ATPase, and DNA damage. SIGNIFICANCE AND IMPACT OF THE STUDY: Using a low concentration of GA and DDAB, a new combination disinfectant was developed. GA-DDAB displayed higher antimicrobial activity than treatment with GA or DDAB alone. Therefore, GA-DDAB may be a more cost-effective and efficient antimicrobial agent than others in use today. Furthermore, this study provided a paradigm for developing high-efficiency disinfectant to help address the growing problem of bacterial resistance. PMID- 27997751 TI - Identifying the plant-associated microbiome across aquatic and terrestrial environments: the effects of amplification method on taxa discovery. AB - Plants in terrestrial and aquatic environments contain a diverse microbiome. Yet, the chloroplast and mitochondria organelles of the plant eukaryotic cell originate from free-living cyanobacteria and Rickettsiales. This represents a challenge for sequencing the plant microbiome with universal primers, as ~99% of 16S rRNA sequences may consist of chloroplast and mitochondrial sequences. Peptide nucleic acid clamps offer a potential solution by blocking amplification of host-associated sequences. We assessed the efficacy of chloroplast and mitochondria-blocking clamps against a range of microbial taxa from soil, freshwater and marine environments. While we found that the mitochondrial blocking clamps appear to be a robust method for assessing animal-associated microbiota, Proteobacterial 16S rRNA binds to the chloroplast-blocking clamp, resulting in a strong sequencing bias against this group. We attribute this bias to a conserved 14-bp sequence in the Proteobacteria that matches the 17-bp chloroplast-blocking clamp sequence. By scanning the Greengenes database, we provide a reference list of nearly 1500 taxa that contain this 14-bp sequence, including 48 families such as the Rhodobacteraceae, Phyllobacteriaceae, Rhizobiaceae, Kiloniellaceae and Caulobacteraceae. To determine where these taxa are found in nature, we mapped this taxa reference list against the Earth Microbiome Project database. These taxa are abundant in a variety of environments, particularly aquatic and semiaquatic freshwater and marine habitats. To facilitate informed decisions on effective use of organelle-blocking clamps, we provide a searchable database of microbial taxa in the Greengenes and Silva databases matching various n-mer oligonucleotides of each PNA sequence. PMID- 27997752 TI - Review of the NICE guidelines for multiple myeloma. AB - In February 2016, the National Institute for Health and Care Excellence (NICE) published guidelines on multiple myeloma. NICE have published numerous guidelines relating to haematology, but this was the first guideline focusing on a single haematological malignancy. The purpose of this review was to highlight the recommendations made in the guideline and the implications for the management of patients in the UK and also internationally. In addition, we review the NICE process and highlight issues around current guideline development. PMID- 27997753 TI - Characterization of a novel beta-globin gene cluster deletion causing (A gammadeltabeta)0 -thalassemia by next-generation sequencing. PMID- 27997754 TI - Uncovering the spatial heterogeneity of Ediacaran carbon cycling. AB - Records of the Ediacaran carbon cycle (635-541 million years ago) include the Shuram excursion (SE), the largest negative carbonate carbon isotope excursion in Earth history (down to -120/00). The nature of this excursion remains enigmatic given the difficulties of interpreting a perceived extreme global decrease in the delta13 C of seawater dissolved inorganic carbon. Here, we present carbonate and organic carbon isotope (delta13 Ccarb and delta13 Corg ) records from the Ediacaran Doushantuo Formation along a proximal-to-distal transect across the Yangtze Platform of South China as a test of the spatial variation of the SE. Contrary to expectations, our results show that the magnitude and morphology of this excursion and its relationship with coexisting delta13 Corg are highly heterogeneous across the platform. Integrated geochemical, mineralogical, petrographic, and stratigraphic evidence indicates that the SE is a primary marine signature. Data compilations demonstrate that the SE was also accompanied globally by parallel negative shifts of delta34 S of carbonate-associated sulfate (CAS) and increased 87 Sr/86 Sr ratio and coastal CAS concentration, suggesting elevated continental weathering and coastal marine sulfate concentration during the SE. In light of these observations, we propose a heterogeneous oxidation model to explain the high spatial heterogeneity of the SE and coexisting delta13 Corg records of the Doushantuo, with likely relevance to the SE in other regions. In this model, we infer continued marine redox stratification through the SE but with increased availability of oxidants (e.g., O2 and sulfate) limited to marginal near-surface marine environments. Oxidation of limited spatiotemporal extent provides a mechanism to drive heterogeneous oxidation of subsurface reduced carbon mostly in shelf areas. Regardless of the mechanism driving the SE, future models must consider the evidence for spatial heterogeneity in delta13 C presented in this study. PMID- 27997755 TI - Chemical Traits of Hemiparasitism in Odontites luteus. AB - The study of the monoterpene glycosides content of Odontites luteus has shown the presence of a total of fifteen iridoid glucosides. The presence of compounds 1 - 5 and 7 - 10 is perfectly on-line with both the biogenetic pathway for iridoids biosynthesis in Lamiales and the current botanical classification of the species. On the other side, the presence of compounds like agnuside (6), adoxosidic acid (11), monotropein (12), 6,7-dihydromonotropein (13), methyl oleoside (14) and methyl glucooleoside (15) is of high interest because, first of all, they have never been reported before in Lamiales. In second instance, the majority of the last compounds are formally derived from a different biogenetic pathway which involves deoxyloganic acid/loganin and led to the formation of decarboxylated iridoid showing the 8beta-configuration. Furthermore, a second abnormality was found during our study and this regards compounds 14 and 15 which are seco iriodids and thus not typical for this family. The presence of these unusual compounds, biogenetically not related to species belonging to Lamiales, is a clear evidence of the metabolites transfer from the hosts. In fact, the collection area is also populated by species belonging to Oleaceae and Ericaceae which could be the possible hosts since the biosynthesis of seco-iridoids and or iridoids related to deoxyloganic acid/loganin pathway, with the 8beta configuration, is well documented in these species. PMID- 27997756 TI - Evidence of molybdenum association with particulate organic matter under sulfidic conditions. AB - The geochemical behavior of molybdenum (Mo) in the oceans is closely linked to the presence of sulfide species in anoxic environments, where Fe availability may play a key role in the Mo scavenging. Here, we show that Mo(VI) is reduced in the presence of particulate organic matter (represented by sulfate-reducing bacteria). Molybdenum was immobilized at the surface of both living cells and dead/lysed cells, but not in cell-free control experiments. Experiments were carried out at four different Mo concentrations (0.1 to 2 mm) to yield cell associated Mo precipitates with little or no Fe, consisting of mainly Mo(IV) sulfide compounds with molecular structures similar to Mo enzymes and to those found in natural euxinic sediments. Therefore, we propose that Mo removal in natural sulfidic waters can proceed via a non-Fe-assisted pathway that requires particulate organic matter (dead or living sulfate-reducing bacteria). This pathway has implications for global marine Mo cycling and the current use of Mo based proxies for paleo-environmental investigations. PMID- 27997757 TI - Hairy cell leukemia-variant without typical morphology and with near-tetraploid DNA content. PMID- 27997758 TI - Comprehensive Mass Cytometry Analysis of Cell Cycle, Activation, and Coinhibitory Receptors Expression in CD4 T Cells from Healthy and HIV-Infected Individuals. AB - RATIONALE: Mass cytometry allows large multiplex analysis of cell cycle stages together with differentiation, activation, and exhaustion markers, allowing further assessment of the quiescence status of resting CD4 T cells. METHODS: Peripheral blood CD4 T lymphocytes from 8 individuals, 4 healthy donors, and 4 HIV-infected on antiretroviral treatment (T) were stained with the same 26 monoclonal antibodies and dyes targeting surface and intracellular markers of differentiation, activation, exhaustion, and cell cycle stages. Samples were run on a CYTOF-2. RESULTS: Patterns of naive [TN] CD4 T cells strongly differed from all other memory subsets central-memory (CM), transitional-memory (TM), effector memory (EM), and terminally differentiated RA-expressing (TEMRA) subsets, while stem-cell memory (SCM) and T follicular-helper cells (TfH) were close to CM and TM cells with the highest percentages in cell cycle. EM and TEMRA were the most altered by HIV infection, with an increased frequency of activated and cycling cells. Activation markers and coinhibitory receptor expression differed among cell cycle stages, with HLA-DR fitting better than CD25 or CD38 with cycle, and opposite PD-1 gradients along differentiation and cell cycle. "Resting" DR-CD25- CD4+ T cells contained similar amounts of cells in G1 than the activated DR +/- CD25+/- ones but three fold lower cells in S-G2-M. CONCLUSION: This broad multiplex mass cytometry analysis demonstrates some subsets of the so-called "resting" CD25-DR- CD4+ T cells contain noticeable amounts of cells into cycle or expressing coinhibitory receptors, opening new avenues for a redefinition of resting peripheral blood CD4 T cells harboring the HIV reservoirs. (c) 2016 International Clinical Cytometry Society. PMID- 27997759 TI - Down-regulation of cladofulvin biosynthesis is required for biotrophic growth of Cladosporium fulvum on tomato. AB - Fungal biotrophy is associated with a reduced capacity to produce potentially toxic secondary metabolites (SMs). Yet, the genome of the biotrophic plant pathogen Cladosporium fulvum contains many SM biosynthetic gene clusters, with several related to toxin production. These gene clusters are, however, poorly expressed during the colonization of tomato. The sole detectable SM produced by C. fulvum during in vitro growth is the anthraquinone cladofulvin. Although this pigment is not detected in infected leaves, cladofulvin biosynthetic genes are expressed throughout the pre-penetration phase and during conidiation at the end of the infection cycle, but are repressed during the biotrophic phase of tomato colonization. It has been suggested that the tight regulation of SM gene clusters is required for C. fulvum to behave as a biotrophic pathogen, whilst retaining potential fitness determinants for growth and survival outside its host. To address this hypothesis, we analysed the disease symptoms caused by mutant C. fulvum strains that do not produce or over-produce cladofulvin during the biotrophic growth phase. Non-producers infected tomato in a similar manner to the wild-type, suggesting that cladofulvin is not a virulence factor. In contrast, the cladofulvin over-producers caused strong necrosis and desiccation of tomato leaves, which, in turn, arrested conidiation. Consistent with the role of pigments in survival against abiotic stresses, cladofulvin protects conidia against UV light and low-temperature stress. Overall, this study demonstrates that the repression of cladofulvin production is required for C. fulvum to sustain its biotrophic lifestyle in tomato, whereas its production is important for survival outside its host. PMID- 27997760 TI - Biodegradable nanocomplex from hyaluronic acid and arginine based poly(ester amide)s as the delivery vehicles for improved photodynamic therapy of multidrug resistant tumor cells: An in vitro study of the performance of chlorin e6 photosensitizer. AB - Photodynamic therapy (PDT), which enables the localized therapeutic effect by light irradiation, provides an alternative and complementary modality for the treatment of tumor. However, the aggregation of photosensitizers in acidic microenvironment of tumor and the non-targeted distribution of photosensitizers in normal tissues significantly affect the PDT efficiency. In this study, we developed a biodegradable nanocomplex HA-Arg-PEA from hyaluronic acid (HA) and arginine based poly(ester amide)s (Arg-PEA) as the nanocarrier for chlorin e6 (Ce6). HA enhanced the tumor-specific endocytosis mediated by the overexpression of CD44 receptor. Arg-PEA not only provide electrostatic interaction with HA to form self-assembled nanostructure, but also improve the monomerization of Ce6 at physiological pH as well as mildly acidic pH. The biodegradable characteristic of HA-Arg-PEA nanocomplex enabled the intracellular delivery of Ce6, in which its release and generation of singlet oxygen can be accelerated by enzymatic degradation of the carrier. The in vitro PDT efficiency of Ce6-loaded HA-Arg-PEA nanocomplex was examined in CD44 positive MDA-MB-435/MDR multidrug resistant melanoma cells. CD44-mediated uptake of Ce6-loaded HA-Arg-PEA nanocomplex significantly improved Ce6 level in MDA-MB-435/MDR cells within short incubation time, and the PDT efficiency in inhibiting multidrug resistant tumor cells was also enhanced at higher Ce6 concentrations. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1487-1499, 2017. PMID- 27997761 TI - The enemy within: phloem-limited pathogens. AB - The growing impact of phloem-limited pathogens on high-value crops has led to a renewed interest in understanding how they cause disease. Although these pathogens cause substantial crop losses, many are poorly characterized. In this review, we present examples of phloem-limited pathogens that include intracellular bacteria with and without cell walls, and viruses. Phloem-limited pathogens have small genomes and lack many genes required for core metabolic processes, which is, in part, an adaptation to the unique phloem environment. For each pathogen class, we present multiple case studies to highlight aspects of disease caused by phloem-limited pathogens. The pathogens presented include Candidatus Liberibacter asiaticus (citrus greening), Arsenophonus bacteria, Serratia marcescens (cucurbit yellow vine disease), Candidatus Phytoplasma asteris (Aster Yellows Witches' Broom), Spiroplasma kunkelii, Potato leafroll virus and Citrus tristeza virus. We focus on commonalities in the virulence strategies of these pathogens, and aim to stimulate new discussions in the hope that widely applicable disease management strategies can be found. PMID- 27997762 TI - Acquired TET2 mutation in one patient with familial platelet disorder with predisposition to AML led to the development of pre-leukaemic clone resulting in T2-ALL and AML-M0. AB - Familial platelet disorder with predisposition to acute myeloid leukaemia (FPD/AML) is characterized by germline RUNX1 mutations, thrombocytopaenia, platelet dysfunction and a risk of developing acute myeloid and in rare cases lymphoid T leukaemia. Here, we focus on a case of a man with a familial history of RUNX1R174Q mutation who developed at the age of 42 years a T2-ALL and, 2 years after remission, an AML-M0. Both AML-M0 and T2-ALL blast populations demonstrated a loss of 1p36.32-23 and 17q11.2 regions as well as other small deletions, clonal rearrangements of both TCRgamma and TCRdelta and a presence of 18 variants at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. Next generation sequencing (NGS) performed on peripheral blood-derived CD34+ cells 5 years prior to T2-ALL development revealed only the missense TET2P1962T mutation at a frequency of 1%, which increases to more than 40% in fully transformed leukaemic T2-ALL and AML-M0 clones. This result suggests that TET2P1962T mutation in association with germline RUNX1R174Q mutation leads to amplification of a haematopoietic clone susceptible to acquire other transforming alterations. PMID- 27997763 TI - The stem cell growth factor receptor KIT is not expressed on interstitial cells in bladder. AB - The mast/stem cell growth factor receptor KIT has long been assumed to be a specific marker for interstitial cells of Cajal (ICC) in the bladder, with possible druggable perspectives. However, several authors have challenged the presence of KIT+ ICC in recent years. The aim of this study was therefore to attempt to clarify the conflicting reports on KIT expression in the bladder of human beings, rat, mouse and guinea pig and to elucidate the possible role of antibody-related issues and interspecies differences in this matter. Fresh samples were obtained from human, rat, mouse and guinea pig cystectomies and processed for single/double immunohistochemistry/immunofluorescence. Specific antibodies against KIT, mast cell tryptase (MCT), anoctamin-1 (ANO1) and vimentin were used to characterize the cell types expressing KIT. Gut (jejunum) tissue was used as an external antibody control. Our results revealed KIT expression on mast cells but not on ICC in human, rat, mouse and guinea pig bladder. Parallel immunohistochemistry showed KIT expression on ICC in human, rat, mouse and guinea pig gut, which confirmed the selectivity of the KIT antibody clones. In conclusion, we have shown that KIT+ cells in human, rat, mouse and guinea pig bladder are mast cells and not ICC. The present report is important as it opposes the idea that KIT+ ICC are present in bladder. In this perspective, functional concepts of KIT+ ICC being involved in sensory and/or motor aspects of bladder physiology should be revised. PMID- 27997765 TI - Intracellular CHO Cell Metabolite Profiling Reveals Steady-State Dependent Metabolic Fingerprints in Perfusion Culture. AB - Perfusion cell culture processes allow the steady-state culture of mammalian cells at high viable cell density, which is beneficial for overall product yields and homogeneity of product quality in the manufacturing of therapeutic proteins. In this study, the extent of metabolic steady state and the change of the metabolite profile between different steady states of an industrial Chinese hamster ovary (CHO) cell line producing a monoclonal antibody (mAb) was investigated in stirred tank perfusion bioreactors. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) of daily cell extracts revealed more than a hundred peaks, among which 76 metabolites were identified by tandem MS (MS/MS) and high resolution Fourier transform ion cyclotron resonance (FT-ICR) MS. Nucleotide ratios (Uridine (U)-ratio, nucleotide triphosphate (NTP)-ratio and energy charge (EC)) and multivariate analysis of all features indicated a consistent metabolite profile for a stable culture performed at 40 * 106 cells/mL over 26 days of culture. Conversely, the reactor was operated continuously so as to reach three distinct steady states one after the other at 20, 60, and 40 * 106 cells/mL. In each case, a stable metabolite profile was achieved after an initial transient phase of approximately three days at constant cell density when varying between these set points. Clear clustering according to cell density was observed by principal component analysis, indicating steady-state dependent metabolite profiles. In particular, varying levels of nucleotides, nucleotide sugar, and lipid precursors explained most of the variance between the different cell density set points. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:879-890, 2017. PMID- 27997764 TI - A method comparison study between two hemoglobinometer models (Hemocue Hb 301 and Hb 201+) to measure hemoglobin concentrations and estimate anemia prevalence among women in Preah Vihear, Cambodia. AB - INTRODUCTION: Hemoglobin (Hb) concentration is often measured in global health and nutrition surveys to determine anemia prevalence using a portable hemoglobinometer such as the Hemocue(r) Hb 201+. More recently, a newer model was released (Hemocue Hb 301) utilizing slightly different methods to measure Hb as compared to the older model. The objective was to measure bias and concordance between Hb concentrations using the Hemocue Hb 301 and Hb 201+ models in a rural field setting. METHODS: Hemoglobin (Hb) concentration was measured using one finger prick of blood (approximately 10 MUL) from 175 Cambodian women (18-49 years) using three Hemocue Hb 201+ and three Hb 301 machines. Bias and concordance were measured and plotted. RESULTS: Overall, mean +/- SD Hb concentration was 116 +/- 13 g/L using the Hb 201+ and 118 +/- 12 g/L using the Hb 301; and anemia prevalence (Hb < 120 g/L) was 58% (n = 102) and 58% (n = 101), respectively. Overall bias +/- SD was 2.0 +/- 10.5 g/L and concordance (95% CI) was 0.63 (0.54, 0.72). Despite the 2 g/L bias detected between models, anemia prevalence was very similar in both models. CONCLUSIONS: The two models measured anemia prevalence comparably in this population of women in rural Cambodia. PMID- 27997766 TI - MR-FLIP: a new method that combines a functional lumen imaging probe with anatomical information for spatial compliance assessment of the anal sphincter muscles. AB - AIM: Continence results from a complex interplay between anal canal (AC) muscles and sensorimotor feedback mechanisms. The passive ability of the AC to withstand opening pressure - its compliance - has recently been shown to correlate with continence. A functional lumen imaging probe (FLIP) is used to assess AC compliance, although it provides no anatomical information. Therefore, assessment of the compliance specific anatomical structures has not been possible, and the anatomical position of critical functional zones remains unknown. In addition, the FLIP technique assumes a circular orifice cross-section, which has not been shown for the AC. To address these shortcomings, a technique combining FLIP with a medical imaging modality is needed. METHOD: We implemented a new research method (MR-FLIP) that combines FLIP with MR imaging. Twenty healthy volunteers underwent MR-FLIP and conventional FLIP assessment. MR-FLIP was validated by comparison with FLIP results. Anatomical markers were identified, and the cross sectional shape of the orifice was investigated. RESULTS: MR-FLIP provides compliance measurements identical to those obtained by conventional FLIP. Anatomical analysis revealed that the least compliant AC zone was located at the proximal end of the external anal sphincter (EAS). The cross-sectional shape of the AC was found to deviate only slightly from circularity in healthy volunteers. CONCLUSION: The proposed method is equivalent to classical FLIP. It establishes for the first time direct mapping between local tissue compliance and anatomical structure, which is key to gaining novel insights into (in)continence. In addition, MR-FLIP provides a tool for better understanding conventional FLIP measurements in the AC by quantifying its limitations and assumptions. PMID- 27997767 TI - Characterization of silencing suppressor p24 of Grapevine leafroll-associated virus 2. AB - Grapevine leafroll-associated virus 2 (GLRaV-2) p24 has been reported to be an RNA silencing suppressor (RSS). However, the mechanisms underlying p24's suppression of RNA silencing are unknown. Using Agrobacterium infiltration mediated RNA silencing assays, we showed that GLRaV-2 p24 is a strong RSS triggered by positive-sense green fluorescent protein (GFP) RNA, and that silencing suppression by p24 effectively blocks the accumulation of small interfering RNAs. Deletion analyses showed that the region of amino acids 1-188, which contains all predicted alpha-helices and beta-strands, is required for the RSS activity of p24. Hydrophobic residues I35/F38/V85/V89/W149 and V162/L169/L170, previously shown to be critical for p24 self-interaction, are also crucial for silencing suppression, and western blotting results suggested that a lack of self-interaction ability results in decreased p24 accumulation in plants. The mutants showed greatly weakened or a lack of RSS activity. Substitution with two basic residues at positions 2 or 86, putatively involved in RNA binding, totally abolished the RSS activity of p24, suggesting that p24 uses an RNA-binding strategy to suppress RNA silencing. Our results also showed that W54 in the WG/GW-like motif (W54/G55) is crucial for the RSS activity of p24, whereas p24 does not physically interact with AGO1 of Nicotiana benthamiana. Furthermore, p24 did not promote AGO1 degradation, but significantly up-regulated AGO1 mRNA expression, and this effect was correlated with the RSS activity of p24, indicating that p24 may interfere with microRNA-directed processes. The presented results contribute to our understanding of viral suppression of RNA silencing and the molecular mechanisms underlying GLRaV-2 infection. PMID- 27997768 TI - Repair of Bicuspid Aortic Valve Syndrome with Anomalous Right Coronary Artery in Osteogenesis Imperfecta. AB - Osteogenesis imperfecta (OI) is an inherited connective tissue disorder caused by the defective synthesis of type I collagen. The clinical phenotype is dominated by bone fragility, but cardiovascular tissue involvement has also been reported. Here, the case is described of a 37-year-old man with OI who presented with aortic insufficiency, bicuspid aortic valve, dilated aortic root, and anomalous right coronary artery. The patient was treated successfully with a mechanical valved conduit aortic root replacement and anomalous coronary artery unroofing and reimplantation. This case highlights the feasibility of complex surgical repairs in this population, as well as challenges surrounding the choice of valve prosthesis given the congenital bone fragility and predilection for fractures. PMID- 27997770 TI - A Rare Aortic Valve Congenital Abnormality in Association with Coarctation of the Aorta. AB - The case is reported of a 25-year-old woman who presented with an episode of syncope on minimal exertion. She had undergone a repair of coarctation of the aorta at one year of age. Transesophageal echocardiography showed a unicuspid aortic valve (UAV) with critical stenosis. The patient underwent aortic valve replacement (AVR) with a bioprosthetic porcine valve. Although UAV is associated with other congenital cardiac abnormalities, its association with coarctation of the aorta is very rare. The currently available literature and treatment options are discussed. It appears that there is an association of UAV with coarctation, and the diagnosis of one condition should lead to an evaluation of the other. PMID- 27997769 TI - Aortic Valve Replacement in Redo-Scenarios: A Comparison Between Traditional Aortic Valve Replacement (TAVR) and Transapical-TAVR from Two Real-World Multicenter Registries. AB - BACKGROUND: The study aim was to compare the outcome of transapical transcatheter aortic valve replacement (TaTAVR) and traditional aortic valve replacement (AVR) in redo from two real-world registries. METHODS: The 30-day and follow up outcome of 462 patients enrolled in two multicenter redo registries, treated with redo AVR (RAVR; n = 292 patients) or TaTAVR (n = 170 patients), were analyzed according to VARC-2 criteria, stratified also by propensity-matching analysis. RESULTS: TaTAVR-patients were older and sicker than RAVR patients, and reported a higher all-cause 30-day mortality (p <0.01), a higher risk for all-cause mortality (p = 0.006) and cardiovascular mortality (p = 0.05) at follow up, but similar 30-day cardiovascular mortality (p = 0.12). Prolonged intubation (p <0.01) and Acute Kidney Injury Network (AKIN) 2/3 p = 0.02) prevailed in RAVR. TaTAVR patients reported a higher level of major/life-threatening/disabling bleeding (p <0.01) and 'early safety-events' (ES) (p = 0.04). Thirty-day acute myocardial infarction (AMI), stroke, and follow up freedom from acute heart failure (AHF), from stroke and from reinterventions were similar (p = NS). The NYHA class was better after RAVR (p <0.01). The intermediate-to-high risk (Logistic EuroSCORE RAVR 17.1 +/- 8.5; TaTAVR 16.0 +/- 17.0) propensity-matched population demonstrated comparable 30-day and follow up all-cause and cardiovascular mortality, ES, AMI, stroke, prolonged intubation, follow up freedom from AHF, from stroke and from reinterventions and NYHA class. TaTAVR still reported lower levels of AKIN 2/3 (2.2% versus 15.6%, p = 0.03) and shorter hospitalization (9.5 +/- 3.4 days versus 12.0 +/- 7.0 days, p = 0.03). CONCLUSIONS: Outcome differences between RAVR and TaTAVR in redo-scenarios reflect methodological differences and different baseline risk profiles. Propensity-matched patients showed a better renal outcome after TaTAVR. *Drs. Onorati and D'Onofrio contributed equally to this article and should both be considered as first authors. PMID- 27997771 TI - Bicuspid Aortic Valve and Aortic Root Morphology in Hispanic Patients. AB - BACKGROUND: The study aim was to evaluate the aortic valve and aortic root morphology in Hispanic patients with a bicuspid aortic valve (BAV). BAV disease is one of the most common congenital anomaly of the heart, and is associated with abnormalities of the aorta. Interracial differences have been described between Caucasian and African-American patients with BAV, which may have clinical and therapeutic implications. The clinical and anatomical spectrum of BAV disease in Hispanic patients has not been well established. METHODS: A retrospective review was conducted of all heart operations performed at the authors' institution between April 2008 and June 2013. Patients with BAV who underwent aortic valve replacement (AVR) were identified. All echocardiograms available were reviewed in order to compare cusp morphology, valvular function, and ascending aorta dimensions between Hispanic and non-Hispanic individuals. RESULTS: A total of 291 patients (159 Hispanic, 132 non-Hispanic) with a mean age of 62 +/- 13 years were identified. The baseline characteristics were similar between the two groups. In both Hispanics and non-Hispanics, the most prevalent cusp morphology was fusion of the right and left coronary cusps (82% for both groups). The most common indication for surgery was aortic stenosis. Hispanic patients had a larger aortic annulus diameter (2.58 +/- 0.32 cm versus 2.39 +/- 0.39 cm, p = 0.04). However, this difference was not significant after adjusting for age, gender, body surface area, and the presence of moderate-to-severe aortic insufficiency. Ascending aortopathy was present in 42.7% of the total study population. Regardless of ethnicity, the most common pattern of aortopathy involved the tubular ascending aorta with mild to moderate root enlargement (type 1). CONCLUSIONS: Compared with other ethnic groups, Hispanics with BAVs have similar aortic valve morphology and function, as well as comparable aortopathy. PMID- 27997772 TI - TAVI and Bicuspid Aortic Valve: Check the Inter-Commissural Space! AB - Transcatheter aortic valve implantation (TAVI) in cases of bicuspid aortic valve (BAV) with a large aortic annulus remains challenging and is rarely performed due to the risk of residual paravalvular aortic leakage. A SAPIEN 3 prosthesis was successfully implanted in two BAV patients each with a relatively large aortic annulus. The New SAPIEN 3 design, coupled with good sealing at the level of the inter-commissural space of the bicuspid valve, seems to account for the efficiency of TAVI for BAV with a large annulus. PMID- 27997773 TI - Right Anterior Mini-Thoracotomy: A 'New Gold Standard' for Aortic Valve Replacement? AB - BACKGROUND: Details are provided of the authors' four-year experience with minimally invasive aortic valve replacement (AVR) through a right mini thoracotomy, using totally central cannulation. METHODS: Between November 2011 and October 2014, a total of 248 patients (143 males, 105 females; mean age 72.6 +/- 11.5 years; range: 29-93 years) underwent isolated AVR through a right anterior mini-thoracotomy with total arterial and venous central cannulation. RESULTS: AVR was performed through a 4- to 6-cm skin incision at the third intercostal space. The overall cardiopulmonary bypass time was 60.4 +/- 16.7 min, and the aortic cross-clamp time 47.5 +/- 14.1 min. A biological prosthesis was implanted in 242 patients (97.6%), using running sutures. The median intensive care unit and hospital stays were 40.5 h (IQR 24.6) and six days (IQR 6.0), respectively. In-hospital mortality was 1.2% (3/248); among 86 patients operated on during 2014 the hospital mortality was zero. CONCLUSIONS: AVR performed via a right mini-thoracotomy with total central cannulation provided encouraging results. Adequate surgeon experience, in addition to technical expedience, are of utmost importance as demonstrated by the progressive and steady reduction in operating times. This approach may become highly competitive to a standard full sternotomy, and could become the 'new gold standard' for aortic valve surgery in the near future. PMID- 27997774 TI - Assessment of the Relationship Between Serum Vascular Adhesion Protein-1 (VAP-1) and Severity of Calcific Aortic Valve Stenosis. AB - BACKGROUND: Vascular adhesion protein-1 (VAP-1), a dual-function glycoprotein, is secreted by endothelial cells, adipocytes, and kidney and vascular smooth muscle cells. It has been reported to participate in the development of atherosclerosis as an adhesion molecule and a pro-inflammatory enzyme. Increased VAP-1 levels are related to type 2 diabetes mellitus, atherosclerosis, stroke and chronic renal failure. The study aim was to investigate serum VAP-1 levels in patients with calcific aortic stenosis (AS) and the possible relationship between VAP-1 and severity of calcific AS. METHODS: A total of 168 patients was categorized as having mild (n = 54), moderate (n = 58), or severe (n = 56) AS. Serum VAP-1 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: The mean serum VAP-1 level was significantly higher in patients with AS compared to healthy controls (244.3 +/- 50.1 ng/ml versus 149.8 +/- 27.5 ng/ml, p <0.001), and in the severe AS group compared to the moderate and mild AS groups (288.3 +/- 30.1 ng/ml, 243.1 +/- 31.8 ng/ml, and 200.8 +/- 43.2 ng/ml, respectively, p <0.001). The VAP-1 level was positively related to the maximum aortic gradient, mean aortic gradient, and maximum aortic jet velocity (r = 0.649, p <0.001; r = 0.660, p <0.001; r = 0.655, p <0.001, respectively) and negatively related to the aortic valve area (r = -0.683, p <0.001). CONCLUSIONS: The present study was the first to demonstrate a significant relationship between increased serum VAP-1 levels and the severity of calcific AS. VAP-1 might be a useful biomarker for the evaluation of AS and the follow up of its severity. PMID- 27997775 TI - Downward Displacement of the Aortic Annulus: Case Report and Literature Review. AB - Downward displacement of the aortic annulus is a very rare cardiac malformation, the etiology of which is not fully understood, while the surgical methods used for its correction are inconsistent. Herein is described a case of downward displacement of the aortic annulus, together with a review of the current relevant literature on the subject. PMID- 27997776 TI - An Extreme Case of CoreValve Bioprosthesis Embolization into the Abdominal Aorta and of the Delivery Catheter Cone into the Right Internal Iliac Artery. AB - Transcatheter aortic valve implantation (TAVI) is a new and hopefully therapeutic option in patients with symptomatic severe calcific aortic valve stenosis and multiple comorbidities who are not eligible for open-heart surgery due to unacceptable conventional surgical risks. Herein is reported the case of a patient who underwent TAVI in whom an unusual CoreValve bioprosthesis embolization occurred into the abdominal aorta. While attempting to retrieve the whole system, the conical tip of the catheter delivery system also became embolized into the right iliac artery. Importantly, this case demonstrated a rare complication of CoreValve bioprosthesis embolization which was managed without surgical intervention. Video 1: Peripheral angiography demonstrating the embolized CoreValve bioprosthesis. Video 2: Fluoroscopy demonstrating completely opened CoreValve bioprosthesis at a level above the iliac artery bifurcation and the mobile conical tip in the valve system. Video 3: Peripheral angiography demonstrating prosthetic valve without any flow limitation and embolized conical tip into the right internal iliac artery. Video 4: Peripheral angiography demonstrating prosthetic valve without any flow limitation and embolized conical tip into the right internal iliac artery. Video 5: Aortography demonstrating the successfully implanted second CoreValve bioprosthesis in an optimal aortic position, with no paravalvular leak. Video 6: Peripheral angiography demonstrating the embolized conical tip into the right iliac artery with a normal external iliac artery flow. Video 7: Peripheral angiography demonstrating the embolized conical tip into the right iliac artery with a normal external iliac artery flow. PMID- 27997777 TI - Bicuspid Aortic Valve-Associated Ascending Thoracic Aortic Aneurysm: Patient Specific Finite Element Analysis. AB - BACKGROUND: Elective repair of bicuspid aortic valve (BAV)-associated ascending thoracic aortic aneurysm (aTAA) is recommended at lower size limits than tricuspid aortic valve (TAV)-associated aTAA. Rupture/dissection can occur when wall stress exceeds wall strength. Previously, a validated computational method was developed for determining aTAA wall stress, but to date this method has not applied to a patient-specific BAV aTAA. The study aim was to develop a patient specific BAV aTAA computational model to determine regional wall stress, using the required zero-pressure geometry, wall thickness, material properties, and residual stress. METHODS: A BAV aTAA specimen was excised intact during elective repair, and zero-pressure geometry generated using micro-computed tomography. Residual stress was determined from the aTAA opening angle. aTAA material properties determined using biaxial stretch testing were incorporated into an Ogden hyperelastic model. Finite element analyses (FEAs) were performed in LS DYNA to determine wall stress distribution and magnitudes at systemic pressure. RESULTS: The left aTAA region had the highest stiffness, followed by the right, and then anterior/posterior walls, suggesting regional variability in mechanical properties. During systole, the mean principal wall stresses were 108.8 kPa (circumferential) and 59.9 kPa (longitudinal), while peak wall stresses were 789.4 kPa (circumferential) and 618.8 kPa (longitudinal). Elevated wall stress pockets were seen in anatomic left aTAA regions. CONCLUSIONS: To the present authors' knowledge, this was the first patient-specific BAV aTAA model based on surgical specimens to be developed. Surgical specimens serve as the 'gold standard' for determining wall stress to validate models based on in-vivo imaging data alone. Regions of maximal wall stress may indicate sites most prone to rupture, and are crucial for evaluating rupture risk based on the wall stress/strength relationship. PMID- 27997778 TI - Subcoronary Stentless Aortic Valves are Not Superior to Supra-Annular Stented Valves Regarding Turbulent Stress. AB - BACKGROUND: Regions of turbulence downstream of bioprosthetic heart valves may cause damage to blood components, vessel walls, and also to aortic valve leaflets. Stentless aortic heart valves are known to possess several hemodynamic benefits such as a larger effective orifice area and a lower aortic transvalvular pressure difference compared to their stented counterparts. To date, turbulence analysis downstream of a stentless valve prosthesis has been investigated exclusively indirectly, using magnetic resonance imaging or in animal settings only. The study aim was to investigate turbulence using direct Doppler ultrasonography measurements in subcoronary stentless and stented valves in human subjects. METHODS: Either stented pericardial valve prostheses (Mitroflow) or stentless valve prostheses (Solo) were implanted in 15 patients in a randomized fashion. Following surgery, blood velocity was measured in the cross-sectional area downstream of the valves using 10 MHz ultrasonic probes connected to dedicated pulsed Doppler equipment. As a measure of turbulence, Reynolds normal stress (RNS) values were calculated, as well as two-dimensional maps of the turbulence distribution. Preoperative and perioperative data were collected prospectively, and postoperative data retrospectively, from hospital records. RESULTS: The median follow up was 1,624 days. No differences were found in perioperative or postoperative clinical data. Implantation of the Mitroflow valve was significantly faster than that of the Solo valve (p <0.05). Neither was any difference found in the mean or max RNS between the two valve groups. However, the turbulence profiles showed a large variation in the Solo valve compared to the more uniform profiles of the Mitroflow valve. CONCLUSIONS: Comparable turbulent flow values were found between the two valve types, although the Solo group exhibited a large variation in turbulence profiles. As no clear clinical advantages were shown to exist for stentless valves, a normal stented valve should be the first choice in most cases. PMID- 27997779 TI - Effects of Mitral Balloon Valvuloplasty on Coronary Blood Flow and Flow Reserve. AB - BACKGROUND: While the effects of percutaneous mitral balloon valvuloplasty (PMBV) on left ventricular, right ventricular, left atrial and right atrial functions have been well demonstrated, the effects on coronary flow velocity remain unclear. The study aim was to evaluate the effects of PMBV on coronary flow velocity and flow velocity reserve in patients with mitral stenosis (MS). METHODS: A total of 32 symptomatic patients (22 females, 10 males; mean age 41.2 years) with moderate or severe isolated rheumatic MS (valve area <1.5 cm2) detected by planimetric methods was included in the study. The left anterior descending (LAD) artery flows were evaluated by coronary presets and pulsed-wave Doppler echocardiography. Hyperemic diastolic coronary flow velocities were evaluated under basal conditions and after intravenous dipyridamole, and the coronary flow velocity reserve was calculated. At seven days after PMBV the coronary flow velocity and flow velocity reserve were re-evaluated, and values obtained pre- and post-PMBV were compared. RESULTS: The pre- and post-PMBV basal diastolic flow velocities were 22.6 +/- 5.1 cm/s and 33.0 +/- 7.9 cm/s, respectively (p = 0.030), while hyperemic diastolic flow velocities were 45.8 +/- 10.0 cm/s and 53.7 +/- 11.5 cm/s, respectively (p = 0.003). The systolic and diastolic peak flow velocities were significantly increased compared to the pre PMBV values, whereas there was no significant change in diastolic coronary flow velocity reserve (2.04 +/- 0.55 versus 1.83 +/- 0.28, p = 0.265). CONCLUSIONS: PMBV increases coronary flow in isolated MS without affecting coronary flow reserves. The low coronary flow velocities may be a reason for the subclinical left ventricular dysfunction that occurs in isolated MS. PMID- 27997780 TI - Mitral Valve Surgery in The Elderly: Should We Treat Atrial Fibrillation Too? AB - BACKGROUND: The study aim was to examine whether concomitant atrial fibrillation (AF) surgery at the time of mitral valve surgery in the elderly results in increased operative mortality (OM). METHODS: Medicare beneficiaries aged >=65 years undergoing primary mitral valve repair or replacement between 2004 and 2006 were included. The cohort was divided into three groups: Group 1, AF- (n = 2,705); group 2, AF+AF surgery- (n = 2,119), and group 3, AF+AF surgery+ (n = 1,832). The primary outcomes were OM and long-term survival. A secondary outcome was the association between hospital annual mitral procedure volume and OM. RESULTS: The unadjusted OM was 6.4% for group 1 (AF-), 10.3% for group 2 (AF+AF surgery-), and 7.1% for group 3 (AF+AF surgery+) (p = 0.0001). Adjusted OM for AF+AF surgery+ patients was not significantly different from that of AF- patients (OR 1.16, 95% CI 0.90-1.48), or from AF+AF surgery patients (OR 0.83, 95% CI 0.66 1.06). When comparisons were adjusted for differences in baseline characteristics, AF+AF surgery- patients were more likely to experience long-term mortality than AF- patients (HR 1.30, 95% CI 1.17-1.45), as well as AF+AF surgery+ patients (HR 1.17, 95% CI 1.05-1.31). An annual average mitral procedure volume <=40 was independently predictive of OM (OR 1.42, 95% CI 1.13-1.78). The effect of institutional volume on mortality was strongest in those who received AF surgery (AF+AF surgery+) (HR 1.75, 95% CI 1.15-2.65), compared to those who did not undergo surgery (AF+AF surgery-) (OR 1.20, 95% CI 0.86-1.67). CONCLUSIONS: Elderly patients undergoing mitral valve surgery do not appear to have an increased mortality when clinical judgment favored the performance of concomitant AF surgery. PMID- 27997781 TI - Annuloplasty Ring Size Determines Exercise-Induced Mitral Stenosis Severity after Valve Repair. AB - BACKGROUND: Patients are occasionally encountered with high mitral pressure gradients after mitral valve repair for degenerative mitral regurgitation (MR), despite the use of a 'truesized' ring based on the anterior leaflet dimension. The study aim was to assess these patients at rest and during exercise, using echocardiography. METHODS: Sixty-seven patients who underwent mitral repair for degenerative disease using a semi-rigid, complete annuloplasty ring were assessed. A truesized ring was always selected for the annuloplasty. Of these patients, 20 were enrolled for exercise stress echocardiography. The indexed ring orifice area (iROA) was calculated by dividing the geometric orifice area of the annuloplasty ring by the patient's body surface area (BSA). Postoperatively, the patients were in sinus rhythm and had less than moderate MR. RESULTS: During peak exercise, seven patients were considered to have severe mitral stenosis (MS), with a mean pressure gradient (mPG) >15 mmHg. The annuloplasty rings used in these seven patients were significantly smaller than those used in the other 13 patients (28.6 +/- 1.9 mm versus 33.1 +/- 3.1 mm; p = 0.003). The mPG at peak exercise was strongly correlated with the iROA (r = -0.767, p <0.001). CONCLUSIONS: Mitral repair, even following the use of a true-sized ring, may be associated with severe MS when the ring size is relatively small for the patient's BSA. This association was shown to become more prominent during exercise. PMID- 27997782 TI - Surgical Treatment of Posterior Mitral Valve Prolapse: Towards 100% Repair. AB - BACKGROUND: The study aim was to evaluate the immediate and long-term results of surgical treatment of isolated posterior mitral valve leaflet prolapse (PLP), focusing on survival and freedom from recurrent mitral regurgitation (MR). METHODS: Between January 1998 and December 2012, a total of 492 consecutive patients (375 males, 117 females; mean age 61.8 +/- 12.1 years; range: 13-86 years) with isolated PLP [304 (61.8%) with myxomatous degeneration; 188 (38.2%) with fibroelastic deficiency] were treated at the authors' institution. Of these patients, 202 (41.1%) were in NYHA class III-IV, and atrial fibrillation was present in 104 (21.1%). Mitral valve repair was achieved in 484 patients (98.4%), resection was performed in 419 (85.2%), and prosthetic ring annuloplasty was used in 436 (88.6%). Concomitant procedures were performed in 153 patients (31.1%), including tricuspid valve repair in 50 (10.2%), aortic valve surgery in 34 (6.9%), and coronary artery bypass grafting (CABG) in 64 (13%). RESULTS: The hospital mortality rate was 0.2%, and the mean follow up was 7.1 +/- 3.9 years. There were 71 late deaths (14.4%), and overall survival at five, 10 and 15 years was 91.7 +/- 1.3%, 82.1 +/- 2.3% and 64.7 +/- 6.1%, respectively. There was no significant difference in long-term survival compared with the age- and gender matched general population (p = 0.146). Multivariate Cox-proportional hazard analysis showed older age (HR 1.03 per annum), left ventricular dysfunction (HR 2.44), atrial fibrillation (HR 1.96), left ventricular end-diastolic dimension (HR 1.05 per mm) and non-use of prosthetic ring (HR 3.03) as significant predictors of late mortality. Recurrence of moderate or severe MR occurred in 31 patients, six of whom underwent mitral valve reoperation. Predictors of late recurrence of MR were fibroelastic deficiency (HR 2.38), mitral calcification (HR 5.26), posterior leaflet plication (HR 3.58), absence of complete ring annuloplasty (HR 3.84) and systolic pulmonary artery pressure at discharge (HR 1.10 per mmHg). Freedom from mitral valve reoperation at 15 years was 97.4 +/- 1.1% CONCLUSIONS: Mitral valve repair in isolated PLP can be achieved in virtually all cases with a very low operative risk and a high durability of repair. Atrial fibrillation or large left ventricles are associated with a poor prognosis. Failure to use a complete ring annuloplasty carries a risk not only for the return of MR but also for survival. PMID- 27997783 TI - Clinical impact of a new bioprosthetic aortic valve: the St. Jude Medical TrifectaATM. AB - BACKGROUND: The St. Jude Medical (SJM) TrifectaTM aortic valve was designed to face common issues such as high transvalvular pressure gradients and low effective orifice areas (EOAs), which lead to prosthesis-patient mismatch after implanting small valve sizes. To reduce the obstruction of the left ventricular outflow tract, the TrifectaTM was designed as a stented valve for supraannular placement. The aim of this study was to evaluate the early hemodynamic performance of this new valve. METHODS: Between September 2010 and February 2013, 380 patients underwent an aortic valve replacement (AVR) using the SJM TrifectaTM. Patients were subsequently followed up for two years and data records were analyzed retrospectively. Mean patient age was 73 years (range 33-93 years), 58% were male. The average mean preoperative pressure gradient was 45mmHg, with an EOA of 0,73cm2. The majority of patients (62%) were in NYHA class III. Indication for AVR was valve stenosis or insufficiency in 95%, presence of endocarditis caused the AVR in 5%. RESULTS: The 30-day-mortality was 4% (n=16; mean log EuroSCORE 20.9%), including two intraoperative non-valve-related cardiac deaths (0.52%) and one valve-related death due to lethal aortotomy bleedings (0.26%). 25 patients died during the follow-up period, 9 of them in a valve related manner. At discharge, no valve thromboses or prosthesis failures could be identified. The average EOA and mean pressure gradient at discharge was 1.36cm2 and 11mmHg for 19mm valves and 2.1cm2 and 7mmHg for 25mm valves. CONCLUSIONS: The new SJM TrifectaTM demonstrates excellent early hemodynamics over all valve sizes. In particular, large EOAs and low gradients in small valves attest a satisfying outcome after implantation. Further data is needed to investigate the stableness of these results over long-term follow up. PMID- 27997784 TI - The Usefulness of Magnetic Resonance Imaging in the Diagnosis of Infectious Endocarditis. AB - BACKGROUND: Whilst echocardiography is currently the 'gold standard' for the diagnosis of infective endocarditis (IE), it has certain limitations and alternative imaging methods are being sought. The study aim was assess the usefulness of cardiac magnetic resonance (CMR) imaging when diagnosing IE. METHODS: Twenty consecutive patients with diagnosed IE were included in the study. All patients underwent CMR and transthoracic echocardiography, and 16 (80%) underwent also transesophageal echocardiography. RESULTS: CMR revealed vegetations in 15 patients (75%). Following echocardiography, vegetations were identified in 19 patients (95%) and valve perforation was suspected in seven (35%); vegetations were identified by CMR in six (30%) of these patients. Echocardiography identified two patients suspected of perivalvular abscess; in one patient the abscess was diagnosed also by CMR and intraoperatively, but in the second patient neither CMR nor intraoperative examination confirmed this diagnosis. Late gadolinium enhancement (LGE) was reported at CMR in eight patients (40%), associated with an extension of the inflammatory process and myocardium infiltration. The valve insufficiency fraction allowed the degree of insufficiency of the valves affected by inflammatory processes to be estimated. A positive correlation was found between the degree of valve insufficiency assessed with CMR and echocardiography. CONCLUSIONS: CMR may serve as a useful method for diagnosing perivalvular complications in IE patients, although vegetation visualization is limited by the low spatial resolution of the method. CMR may prove superior to echocardiography in evaluating the degree of inflammatory process involvement in the myocardium. The degree of valve insufficiency and its hemodynamic significance can also be assessed. PMID- 27997785 TI - Multiple Fibroelastoma: Search and You Will Find. AB - Fibroelastoma is a rare cardiac tumor. Even more rare is multilocalization of these tumors as well as their residence inside the cardiac chambers. Here, the case is reported of a 46-year-old male with three fibroelastomas of which only two were diagnosed preoperatively. The third tumor was discovered during surgery on the endocardium of the left ventricular wall, 2 cm away from the base of the anterolateral papillary muscle after a thorough examination of the ventricle had been instituted. Emphasis must be placed on the importance of performing such an examination during the excision of fibroelastomas, as a failure to address multiple lesions - although their existence is rare - might expose the patient to dangers of future embolization or reoperation. PMID- 27997786 TI - Pasteurella multocida Infective Endocarditis. AB - Pasteurella multocida, a Gram-negative facultative anaerobic coccobacillus, is a common oral flora of dogs and cats. P. multocida often causes infection in humans after animal bites and scratches, and human pasteurellosis is generally a locoregional infection. Systemic complications, particularly endocarditis, are very rare, except in immunodeficient patients. Endocarditis caused by P. multocida can have severe outcomes; hence, surgical treatment is often required. Here, a case is described of endocarditis caused by P. multocida in a previously healthy patient with no history of animal injury, which was successfully treated with surgery. PMID- 27997787 TI - Surgical Thrombectomy of Mechanical Valve Thrombosis. AB - BACKGROUND: The study aim was to review the authors' experience with the surgical thrombectomy of mechanical valve thrombosis at the Heart Institute of the Medical School of Sao Paulo University, Brazil. METHODS: Between January 1993 and March 2014, a total of 21 patients (16 females, five males; mean age 48.2 years) with mechanical valve thrombosis was treated surgically. Of these patients, 70% were in NYHA class IV, including two in cardiogenic shock; 71% of the patients had inadequate anticoagulation levels. The median period between the initial valve replacement and valve thrombosis was 105 months. Thrombosis occurred in the mitral position in 12 patients (57%) and in the aortic position in nine (43%). Clinical and surgical data were collected from hospital records. RESULTS: The major surgical finding was thrombus (57.1%), and pannus formation was found in 42.9% of patients. The mean cardiopulmonary bypass time was 90 min, and aortic cross-clamp time 63 min. Operative complications occurred in three patients (14%): two patients required revisions for bleeding and one patient needed ventricular assistance and hemodialysis. The operative mortality rate was 19% (n = 4). Two of these deaths occurred in patients who had been transferred to the operating room with cardiopulmonary resuscitation, one death was due to prolonged mechanical ventilator support and sepsis, and one was due to cardiac tamponade. The 11-year actuarial survival rate was 69.3 +/- 12.9%, and the actuarial rate freedom from reintervention was 85.7 +/- 13.2% during an 11-year follow up period. CONCLUSIONS: Early surgical intervention is a safe and effective treatment in patients with mechanical valve thrombosis. PMID- 27997788 TI - Adverse effect of excess body weight on survival in cervical cancer patients after surgery and radiotherapy. AB - PURPOSE: This study aimed to assess the effects of body mass index (BMI) on survival in cervical cancer patients who had undergone surgery and radiotherapy (RT). MATERIALS AND METHODS: We retrospectively reviewed the medical records of 70 cervical cancer patients who underwent surgery and RT from 2007 to 2012. Among them, 40 patients (57.1%) had pelvic lymph node metastases at the time of diagnosis. Sixty-seven patients (95.7%) had received chemotherapy. All patients had undergone surgery and postoperative RT. Median BMI of patients was 22.8 kg/m2 (range, 17.7 to 35.9 kg/m2). RESULTS: The median duration of follow-up was 52.3 months (range, 16 to 107 months). Twenty-four patients (34.3%) showed recurrence. Local failure, regional lymph nodal failure, and distant failure occurred in 4 (5.7%), 6 (8.6%), and 17 (24.3%) patients, respectively. The 5-year actuarial pelvic control rate was 83.4%. The 5-year cancer-specific survival (CSS) and disease-free survival (DFS) rates were 85.1% and 65.0%, respectively. The presence of pelvic lymph node metastases (n = 30) and being overweight or obese (n = 34, BMI >= 23 kg/m2) were poor prognostic factors for CSS (p = 0.003 and p = 0.045, respectively). Of these, pelvic lymph node metastasis was an independent prognostic factor (p = 0.030) for CSS. CONCLUSION: Overweight or obese cervical cancer patients showed poorer survival outcomes than normal weight or underweight patients. Weight control seems to be important in cervical cancer patients to improve clinical outcomes. PMID- 27997789 TI - Nano Secondary Ion Mass Spectrometry Imaging of Dopamine Distribution Across Nanometer Vesicles. AB - We report an approach to spatially resolve the content across nanometer neuroendocrine vesicles in nerve-like cells by correlating super high-resolution mass spectrometry imaging, NanoSIMS, with transmission electron microscopy (TEM). Furthermore, intracellular electrochemical cytometry at nanotip electrodes is used to count the number of molecules in individual vesicles to compare to imaged amounts in vesicles. Correlation between the NanoSIMS and TEM provides nanometer resolution of the inner structure of these organelles. Moreover, correlation with electrochemical methods provides a means to quantify and relate vesicle neurotransmitter content and release, which is used to explain the slow transfer of dopamine between vesicular compartments. These nanoanalytical tools reveal that dopamine loading/unloading between vesicular compartments, dense core and halo solution, is a kinetically limited process. The combination of NanoSIMS and TEM has been used to show the distribution profile of newly synthesized dopamine across individual vesicles. Our findings suggest that the vesicle inner morphology might regulate the neurotransmitter release event during open and closed exocytosis from dense core vesicles with hours of equilibrium needed to move significant amounts of catecholamine from the protein dense core despite its nanometer size. PMID- 27997790 TI - Probing Molecular Mechanisms of Self-Assembly in Metal-Organic Frameworks. AB - Metal-organic framework materials (MOFs) are a class of nanoporous materials, important to many applications (e.g., gas storage, separation), and their synthesis has received considerable attention. Yet, very little is known about the mechanisms of self-assembly of MOFs. Here, we provide molecular-level insights into the previously unexplored behavior of the self-assembly process, through molecular dynamics simulations, for an archetypal Zn-carboxylate MOF system exhibiting complex vertex topologies (e.g., paddle-wheel clusters). A key finding of this study is the characterization of a stochastic and multistage ordering process intrinsic to self-assembly of the Zn-carboxylate MOF system. A variety of transient intermediate structures consisting of various types of Zn ion clusters and carboxylate-ligand coordination, and featuring a range of geometric arrangements, are observed during structural evolution. The general features deduced here for the mechanism of the self-assembly of this archetypal MOF system expose the complexities of the various molecular-level events that can occur during the early stages of this process spanning time scales of nano- to microseconds. More generally, we provide fundamental insights that elucidate key aspects of the early stages of the self-assembly mechanism for an important class of nanoporous materials, and of experimental studies exploring nucleation and growth processes in such materials. PMID- 27997791 TI - Neural-Network-Biased Genetic Algorithms for Materials Design: Evolutionary Algorithms That Learn. AB - Machine learning has the potential to dramatically accelerate high-throughput approaches to materials design, as demonstrated by successes in biomolecular design and hard materials design. However, in the search for new soft materials exhibiting properties and performance beyond those previously achieved, machine learning approaches are frequently limited by two shortcomings. First, because they are intrinsically interpolative, they are better suited to the optimization of properties within the known range of accessible behavior than to the discovery of new materials with extremal behavior. Second, they require large pre-existing data sets, which are frequently unavailable and prohibitively expensive to produce. Here we describe a new strategy, the neural-network-biased genetic algorithm (NBGA), for combining genetic algorithms, machine learning, and high throughput computation or experiment to discover materials with extremal properties in the absence of pre-existing data. Within this strategy, predictions from a progressively constructed artificial neural network are employed to bias the evolution of a genetic algorithm, with fitness evaluations performed via direct simulation or experiment. In effect, this strategy gives the evolutionary algorithm the ability to "learn" and draw inferences from its experience to accelerate the evolutionary process. We test this algorithm against several standard optimization problems and polymer design problems and demonstrate that it matches and typically exceeds the efficiency and reproducibility of standard approaches including a direct-evaluation genetic algorithm and a neural-network evaluated genetic algorithm. The success of this algorithm in a range of test problems indicates that the NBGA provides a robust strategy for employing informatics-accelerated high-throughput methods to accelerate materials design in the absence of pre-existing data. PMID- 27997793 TI - Three-Dimensional Carbon Nanotubes Forest/Carbon Cloth as an Efficient Electrode for Lithium-Polysulfide Batteries. AB - The development of a three-dimensionally flexible, large-surface area, high conductivity electrode is important to improve the low conductivity and utilization of active materials and restrict the shuttle of long-chain polysulfides in Li-polysulfide batteries. Herein, we constructed an integrated three-dimensional carbon nanotube forest/carbon cloth electrode with heteroatom doping and high electrical conductivity. The as-constructed electrode provides strong trapping on the polysulfide species and fast charge transfer. Therefore, the Li-polysulfide batteries with as-constructed electrodes achieved high specific capacities of ~1200 and ~800 mA h g-1 at 0.1 and 1 C, respectively. After 300 cycles at 0.5 C, a specific capacity of 623 mA h g-1 was retained. PMID- 27997792 TI - Tethering an N-Glycosylation Sequon-Containing Peptide Creates a Catalytically Competent Oligosaccharyltransferase Complex. AB - Oligosaccharyltransferase (OST) transfers an oligosaccharide chain to the Asn residue in the Asn-X-Ser/Thr sequon in proteins, where X is not proline. A sequon was tethered to an archaeal OST enzyme via a disulfide bond. The positions of the cysteine residues in the OST protein and the sequon-containing acceptor peptide were selected by reference to the eubacterial OST structure in a noncovalent complex with an acceptor peptide. We determined the crystal structure of the cross-linked OST-sequon complex. The Ser/Thr-binding pocket recognizes the Thr residue in the sequon, and the catalytic structure termed the "carboxylate dyad" interacted with the Asn residue. Thus, the recognition and the catalytic mechanism of the sequon are conserved between the archaeal and eubacterial OSTs. We found that the tethered peptides in the complex were efficiently glycosylated in the presence of the oligosaccharide donor. The stringent requirements are greatly relaxed in the cross-linked state. The two conserved acidic residues in the catalytic structure were each dispensable, although the double mutation abolished the activity. A Gln residue at the Asn position in the sequon functioned as an acceptor, and the hydroxy group at position +2 was not required. In the standard assay using short free peptides, strong amino acid preferences were observed at the X position, but the preferences, except for Pro, completely disappeared in the cross-linked state. By skipping the initial binding process and stabilizing the complex state, the catalytically competent cross-linked complex offers a unique system for studying the oligosaccharyl transfer reaction. PMID- 27997794 TI - Reaction-Based Semiconducting Polymer Nanoprobes for Photoacoustic Imaging of Protein Sulfenic Acids. AB - Protein sulfenic acids play a key role in oxidative signal transduction of many biological and pathological processes; however, current chemical tools rely on visible fluorescence signals, limiting their utility to in vitro assays. We herein report reaction-based semiconducting polymer nanoprobes (rSPNs) with near infrared absorption for in vivo photoacoustic (PA) imaging of protein sulfenic acids. rSPNs comprise an optically active semiconducting polymer as the core shielded with inert silica and poly(ethylene glycol) corona. The sulfenic acid reactive group (1,3-cyclohexanedione) is efficiently conjugated to the surface of nanoparticles via click chemistry. Such a nanostructure enables the specific recognition reaction between rSPNs and protein sulfenic acids without compromising the fluorescence and PA properties. In addition to in vitro tracking of the production of protein sulfenic acids in cancer cells under oxidative stress, rSPNs permit real-time PA and fluorescence imaging of protein sulfenic acids in tumors of living mice. This study thus not only demonstrates the first reaction-based PA probes with submolecular level recognition ability but also highlights the opportunities provided by hybrid nanoparticles for advanced molecular imaging. PMID- 27997795 TI - Formal Total Synthesis of l-Ossamine via Decarboxylative Functionalization Using Visible-Light-Mediated Photoredox Catalysis in a Flow System. AB - A formal total synthesis of l-ossamine was achieved. The key feature of the synthesis was the decarboxylative functionalization of a threonine derivative using visible-light-mediated photoredox catalysis. This reaction was implemented in a flow reactor, allowing for the efficient conversion to the desired product. PMID- 27997796 TI - Synergetic Effect of Blended Alkylamines for Copper Complex Ink To Form Conductive Copper Films. AB - Cu(II) complex ink consisting of copper formate (Cuf) and a primary alkylamine could yield highly conductive copper films at low heating temperatures without a reducing atmosphere. A synergetic effect of the blended alkylamines on the formation of conductive films was observed. It was found that blending two types of amines with different alkyl chain lengths as ligands could improve the conductivity of copper films, compared with using one of these amines alone. The decomposition mechanism of the Cuf-amine complex and the role of amines with different alkyl chain lengths were investigated. It was found that the decrease in the decomposition temperature and the formation of copper films were attributed to the activating effect and capping effect of the amine, and these two effects were dependent on the alkyl chain length. The relative intensity of the dual effects determined the decomposition rate of the complex and the nucleation and growth of particles. The use of blended amines with different alkyl chain lengths as ligands could balance the two effects and lead to appropriate nucleation and growth rates, so that densely packed copper films with low resistivity could be obtained at low heating temperature in a short time. The Cuf-butylamine-octylamine (Cuf-butyl-octyl) ink with 1:1 molar ratio of the amines showed the best performance. The understanding of the synergetic effect could provide guidance to the design of copper complex inks to control the morphology of the films. PMID- 27997797 TI - Infrared Thermography Investigation of an Evaporating Water/Oil Meniscus in Confined Geometry. AB - To simulate the heat and mass transfer in real heterogeneous systems, such as metal-production processes and lubrication, the point-contact condition with the formation of narrowly confined liquid film and its surrounding meniscus was constructed to study the classical microchannel boiling problem in this work. Specifically, the evaporation and diffusion of the superheated water meniscus and water/oil droplet in the point-contact geometry were investigated. The emphasis is put on the influence of the contact-line transport behaviors on nucleation and bubble dynamics in the confined meniscus. The observations suggested that superheat is the necessary condition for bubble formation, and enough vapor supply is the necessary condition for bubble growth in the confined liquid. The oil film could significantly inhibit the evaporation and diffusion of water molecules in the superheat geometry. The water/oil droplet can exist for a long time even in the hot contact region, which could have sustained damages to the mechanical system suffering from water pollution. This work is of great significance to better understand the damage mechanism of water pollution to the mechanical system. PMID- 27997798 TI - Label-Free Imaging of Single Microtubule Dynamics Using Spatial Light Interference Microscopy. AB - Due to their diameter, of only 24 nm, single microtubules are extremely challenging to image without the use of extrinsic contrast agents. As a result, fluorescence tagging is the common method to visualize their motility. However, such investigation is limited by photobleaching and phototoxicity. We experimentally demonstrate the capability of combining label-free spatial light interference microscopy (SLIM) with numerical processing for imaging single microtubules in a gliding assay. SLIM combines four different intensity images to obtain the optical path length map associated with the sample. Because of the use of broadband fields, the sensitivity to path length is better than 1 nm without (temporal) averaging and better than 0.1 nm upon averaging. Our results indicate that SLIM can image the dynamics of microtubules in a full field of view, of 200 * 200 MUm2, over many hours. Modeling the microtubule transport via the diffusion advection equation, we found that the dispersion relation yields the standard deviation of the velocity distribution, without the need for tracking individual tubes. Interestingly, during a 2 h window, the microtubules begin to decelerate, at 100 pm/s2 over a 20 min period. Thus, SLIM is likely to serve as a useful tool for understanding molecular motor activity, especially over large time scales, where fluorescence methods are of limited utility. PMID- 27997799 TI - Sc(OTf)3 Catalyzed [4 + 2]-Annulation Reaction between Electron-Rich Phenols and Donor-Acceptor Cyclopropanes: Synthesis of Polysubstituted Dihydronaphthols. AB - On the basis of the Lewis acid-catalyzed Friedel-Crafts alkylation between 1-acyl 2-arylcyclopropanecarboxylate esters and electron-rich phenols, a Sc(OTf)3 catalyzed cascade [4 + 2]-annulation reaction was developed for the direct synthesis of polysubstituted dihydronaphthols from phenols. In this reaction, the structure of products is dominated by the directing effect of the substituent groups on phenols. Meanwhile, a one-pot Friedel-Crafts alkylation/oxidative cyclization reaction was also developed for the synthesis of spiro-fused 2,5 cyclohexadienones. PMID- 27997800 TI - Design and Function of Supramolecular Recognition Systems Based on Guest Targeting Probe-Modified Cyclodextrin Receptors for ATP. AB - In this study, we have developed a rational design strategy to obtain highly selective supramolecular recognition systems of cyclodextrins (CyDs) on the basis of the lock and key principle. We designed and synthesized dipicolylamine (dpa) modified gamma-CyD-Cu2+ complexes possessing an azobenzene unit (Cu.1-gamma-CyD) and examined how they recognized phosphoric acid derivatives in water. The results revealed that Cu.1-gamma-CyD recognized ATP with high selectivity over other phosphoric acid derivatives. The significant blue shift in the UV-vis spectra and 1H NMR analysis suggested that the selective ATP recognition was based on the multipoint interactions between the adenine moiety of ATP and both the CyD cavity and the azobenzene unit in addition to the recognition of phosphoric moieties by the Cu-dpa complex site. Our unique receptor made it capable of distinguishing ATP from AMP and ADP, revealing the discrimination of even a length of one phosphoric group. This study demonstrates that, compared to conventional recognition systems of CyDs, this multipoint recognition system confers a higher degree of selectivity for certain organic molecules, such as ATP, over their similar derivatives. PMID- 27997801 TI - Detailed Mechanistic Studies on Palladium-Catalyzed Selective C-H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling. AB - Directing group-assisted regioselective C-H olefination with electronically biased olefins is well studied. However, the incorporation of unactivated olefins has remained largely unsuccessful. A proper mechanistic understanding of olefination involving unactivated alkenes is therefore essential for enhancing their usage in future. In this Article, detailed experimental and computational mechanistic studies on palladium catalyzed C-H olefination with unactivated, aliphatic alkenes are described. The isolation of Pd(II) intermediates is shown to be effective for elucidating the elementary steps involved in catalytic olefination. Reaction rate and order determination, control experiments, isotopic labeling studies, and Hammett analysis have been used to understand the reaction mechanism. The results from these experimental studies implicate beta-hydride elimination as the rate-determining step and that a mechanistic switch occurs between cationic and neutral pathway. Computational studies support this interpretation of the experimental evidence and are used to uncover the origins of selectivity. PMID- 27997802 TI - Influence of Fluorination on the Solubilities of Carbon Dioxide, Ethane, and Nitrogen in 1-n-Fluoro-alkyl-3-methylimidazolium Bis(n-fluoroalkylsulfonyl)amide Ionic Liquids. AB - The effect on gas solubilities of adding partially fluorinated alkyl side chains either on imidazolium-based cations or on bis(perfluoroalkylsulfonyl)amide anions was studied. The aim was to gain knowledge of the mechanisms of dissolution of gases in fluorinated ionic liquids and, if possible, to improve physical absorption of carbon dioxide in ionic liquids. We have determined experimentally, in the temperature range of 298-343 K and at pressures close to atmospheric pressure, the solubility and thermodynamics of solvation of carbon dioxide, ethane, and nitrogen in the ionic liquids 1-octyl-3-methylimidazolium bis[trifluoromethylsulfonyl]amide ([C8mim][NTf2]), 1-octyl-3-methylimidazolium bis[pentafluoroethylsulfonyl]amide ([C8mim][BETI]), 1-(3,3,4,4,5,5,6,6,7,7,8,8,8 tridecafluorooctyl)-3-methylimidazolium bis[trifluoromethylsulfonyl]amide ([C8H4F13mim][NTf2]), and 1-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-3 methylimidazolium bis[pentafluoroethylsulfonyl]amide ([C8H4F13mim][BETI]). Ionic liquids with partial fluorination on the cation were found to exhibit higher carbon dioxide and nitrogen mole fraction solubilities but lower ethane solubilities, compared to those of their hydrogenated counterparts. Molecular simulation provided insights about the mechanisms of solvation of the different gases in the ionic liquids. PMID- 27997803 TI - Mesoscale Particle-Based Model of Electrophoretic Deposition. AB - We present and evaluate a semiempirical particle-based model of electrophoretic deposition using extensive mesoscale simulations. We analyze particle configurations in order to observe how colloids accumulate at the electrode and arrange into deposits. In agreement with existing continuum models, the thickness of the deposit increases linearly in time during deposition. Resulting colloidal deposits exhibit a transition between highly ordered and bulk disordered regions that can give rise to an appreciable density gradient under certain simulated conditions. The overall volume fraction increases and falls within a narrow range as the driving force due to the electric field increases and repulsive intercolloidal interactions decrease. We postulate ordering and stacking within the initial layer(s) dramatically impacts the microstructure of the deposits. We find a combination of parameters, i.e., electric field and suspension properties, whose interplay enhances colloidal ordering beyond the commonly known approach of only reducing the driving force. PMID- 27997804 TI - A Modular Access to (+/-)-Tubocurine and (+/-)-Curine - Formal Total Synthesis of Tubocurarine. AB - Two consecutive Cu-catalyzed Ullmann-type C-O couplings permitted the first successful entry toward the curare alkaloids (+/-)-tubocurine and (+/-)-curine. Starting from vanillin, the synthetic sequence comprises 15 linear steps and includes a total of 24 transformations. In addition, the total synthesis of tubocurine represents a formal total synthesis of the famous arrow poison alkaloid tubocurarine. PMID- 27997805 TI - Physiologic Effects of High-Flow Nasal Cannula in Acute Hypoxemic Respiratory Failure. AB - RATIONALE: High-flow nasal cannula (HFNC) improves the clinical outcomes of nonintubated patients with acute hypoxemic respiratory failure (AHRF). OBJECTIVES: To assess the effects of HFNC on gas exchange, inspiratory effort, minute ventilation, end-expiratory lung volume, dynamic compliance, and ventilation homogeneity in patients with AHRF. METHODS: This was a prospective randomized crossover study in nonintubated patients with AHRF with PaO2/setFiO2 less than or equal to 300 mm Hg admitted to the intensive care unit. We randomly applied HFNC set at 40 L/min compared with a standard nonocclusive facial mask at the same clinically set FiO2 (20 min/step). MEASUREMENTS AND MAIN RESULTS: Toward the end of each phase, we measured arterial blood gases, inspiratory effort, and work of breathing by esophageal pressure swings (DeltaPes) and pressure time product, and we estimated changes in lung volumes and ventilation homogeneity by electrical impedance tomography. We enrolled 15 patients aged 60 +/- 14 years old with PaO2/setFiO2 130 +/- 35 mm Hg. Seven (47%) had bilateral lung infiltrates. Compared with the facial mask, HFNC significantly improved oxygenation (P < 0.001) and lowered respiratory rate (P < 0.01), DeltaPes (P < 0.01), and pressure time product (P < 0.001). During HFNC, minute ventilation was reduced (P < 0.001) at constant arterial CO2 tension and pH (P = 0.27 and P = 0.23, respectively); end-expiratory lung volume increased (P < 0.001), and tidal volume did not change (P = 0.44); the ratio of tidal volume to DeltaPes (an estimate of dynamic lung compliance) increased (P < 0.05); finally, ventilation distribution was more homogeneous (P < 0.01). CONCLUSIONS: In patients with AHRF, HFNC exerts multiple physiologic effects including less inspiratory effort and improved lung volume and compliance. These benefits might underlie the clinical efficacy of HFNC. PMID- 27997806 TI - Discontinued drug therapies to treat diabetes in 2015. AB - INTRODUCTION: This manuscript describes 21 drug targets in the area of diabetes and related conditions that were discontinued in 2015. Areas covered: The material for this paper was obtained by contacting biopharmaceutical companies, reviewing their pipelines, press releases and annual reports. Additionally, the authors searched clinicaltrials.gov, PubMed and general Internet search engines. Majority of the compounds were in early stages of the development. Expert opinion: Business reasons for termination of the drug projects emerge more and more frequently over the years. Safety signals usually appear early in the development and are often associated with novel drugs. 2015 medicines with inadequate efficacy were unable to compete with existing approved members of the class they represented. PMID- 27997807 TI - Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells. AB - Roflumilast is an orally active phosphodiesterase 4 inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has a demonstrated antiinflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on beta2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation. RNO (0.001-1,000 nM) alone had no effect on AMP production from ASM cells, and significant potentiation of the long-acting beta2-agonist formoterol induced cAMP could only be achieved at the highest concentration of RNO tested (1,000 nM). At this concentration, RNO exerted a small, but not significantly different, potentiation of formoterol-induced expression of antiinflammatory mitogen-activated protein kinase phosphatase 1. Consequently, tumor necrosis factor-induced IL-8 secretion was unaffected by RNO in combination with formoterol. However, because there was the potential for phosphodiesterase 4 inhibitors and long-acting beta2-agonists to interact with corticosteroids to achieve superior antiinflammatory efficacy, we examined whether RNO, alone or in combination with formoterol, enhanced the antiinflammatory effect of dexamethasone by measuring the impact on IL-8 secretion. Although RNO alone did not significantly enhance the cytokine repression achieved with steroids, RNO in combination with formoterol significantly enhanced the antiinflammatory effect of dexamethasone in ASM cells. This was linked to increased mitogen-activated protein kinase phosphatase 1 expression in ASM cells, suggesting that a molecular mechanism is responsible for augmented antiinflammatory actions of combination therapeutic approaches that include RNO. PMID- 27997808 TI - Clinical Momentum in the Intensive Care Unit. A Latent Contributor to Unwanted Care. AB - Many older adults in the United States receive invasive medical care near the end of life, often in an intensive care unit (ICU). However, most older adults report preferences to avoid this type of medical care and to prioritize comfort and quality of life near death. We propose a novel term, "clinical momentum," to describe a system-level, latent, previously unrecognized property of clinical care that may contribute to the provision of unwanted care in the ICU. The example of chronic critical illness illustrates how clinical momentum is generated and propagated during the care of patients with prolonged illness. The ICU is an environment that is generally permissive of intervention, and clinical practice norms and patterns of usual care can promote the accumulation of multiple interventions over time. Existing models of medical decision-making in the ICU describe how individual signs, symptoms, or diagnoses automatically lead to intervention, bypassing opportunities to deliberate about the value of an intervention in the context of a patient's likely outcome or treatment preferences. We hypothesize that clinical momentum influences patients, families, and physicians to accept or tolerate ongoing interventions without consideration of likely outcomes, eventually leading to the delivery of unwanted care near the end of life. In the future, a mixed-methods research program could refine the conceptual model of clinical momentum, measure its impact on clinical practice, and interrupt its influence on unwanted care near the end of life. PMID- 27997809 TI - Brexpiprazole for the treatment of schizophrenia. AB - INTRODUCTION: Limited efficacy on negative and cognitive symptoms and adverse effects of current antipsychotics raise the need of developing new antipsychotics. Brexpiprazole, a new antipsychotic drug approved by the U.S. Food and Drug Administration in July 2015 for the treatment of schizophrenia, is a novel serotonin-dopamine receptor modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors. Areas covered: We reviewed brexpiprazole related in vitro and in vivo studies, including phase II and phase III clinical trials in this article. Brexpiprazole showed significant improvement of psychotic symptoms for patients with schizophrenia in clinical trials. Most of the clinical trials demonstrated the antipsychotic effect of brexpiprazole using Positive and Negative Syndrome Scale (PANSS) in acute schizophrenia patients, and found that higher doses (2-4 mg daily) of brexpiprazole had better outcomes. In short-term trials, brexpiprazole did not show benefit for cognitive function in 6 weeks. Insomnia, akathisia, headache, and agitation were the most frequently recorded adverse events. Expert commentary: Brexpiprazole showed better efficacy than placebo in acute phase of schizophrenia. Long-term studies are needed to investigate the efficacy of brexpiprazole for cognitive function as well as the strength and weakness of brexpiprazole among current antipsychotic drugs. PMID- 27997811 TI - Macromolecular target prediction by self-organizing feature maps. AB - INTRODUCTION: Rational drug discovery would greatly benefit from a more nuanced appreciation of the activity of pharmacologically active compounds against a diverse panel of macromolecular targets. Already, computational target-prediction models assist medicinal chemists in library screening, de novo molecular design, optimization of active chemical agents, drug re-purposing, in the spotting of potential undesired off-target activities, and in the 'de-orphaning' of phenotypic screening hits. The self-organizing map (SOM) algorithm has been employed successfully for these and other purposes. Areas covered: The authors recapitulate contemporary artificial neural network methods for macromolecular target prediction, and present the basic SOM algorithm at a conceptual level. Specifically, they highlight consensus target-scoring by the employment of multiple SOMs, and discuss the opportunities and limitations of this technique. Expert opinion: Self-organizing feature maps represent a straightforward approach to ligand clustering and classification. Some of the appeal lies in their conceptual simplicity and broad applicability domain. Despite known algorithmic shortcomings, this computational target prediction concept has been proven to work in prospective settings with high success rates. It represents a prototypic technique for future advances in the in silico identification of the modes of action and macromolecular targets of bioactive molecules. PMID- 27997812 TI - Why EMA should provide clearer guidance on the authorization of NBCDs in generic and hybrid applications. PMID- 27997810 TI - Glucose Transporter 1-Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis. AB - Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)-induced glycolysis regulates age-dependent fibrogenesis of the lung. Mouse and human lung tissues were analyzed for GLUT1 and glycolytic markers using immunoblotting. Glycolytic function was measured using a Seahorse apparatus. To study the effect of GLUT1, genetic inhibition of GLUT1 was performed by short hairpin RNA transduction, and phloretin was used for pharmacologic inhibition of GLUT1. GLUT1-dependent glycolysis is activated in aged lung. Genetic and pharmacologic inhibition of GLUT1 suppressed the protein expression of alpha-smooth muscle actin, a key cytoskeletal component of activated fibroblasts, in mouse primary lung fibroblast cells. Moreover, we demonstrated that the activation of AMP-activated protein kinase, which is regulated by GLUT1-dependent glycolysis, represents a critical metabolic pathway for fibroblast activation. Furthermore, we demonstrated that phloretin, a potent inhibitor of GLUT1, significantly inhibited bleomycin-induced lung fibrosis in vivo. These results suggest that GLUT1-dependent glycolysis regulates fibrogenesis in aged lung and that inhibition of GLUT1 provides a potential target of therapy of age-related lung fibrosis. PMID- 27997813 TI - Quality criteria for medical device registries: best practice approaches for improving patient safety - a systematic review of international experiences. AB - INTRODUCTION: As the benefit of medical device registries (MDRs) depends on their content and quality, it is important to ensure that MDRs have a robust and adequate structure to fulfill their objectives. However, no requirements are specified for the design and content of MDRs. The aim of this work is to analyze different MDRs in the field of implants and to give best practice recommendations for quality criteria regarding their design and development. Areas covered: A systematic literature search performed in databases (Medline, Cochrane Library, Scopus, Embase, CRD York), selected journals and websites identified 66 articles describing either a general MDR structure or the development process of specific registries. Extracted information about MDRs served as the basis for recommendations: MDRs should deliver a minimal data set and report information about the geographical area, data collection, numbers of patients enrolled, registry staff, and security and confidentiality of data. Expert commentary: Well structured registries are a cornerstone of the regulatory process of medical devices and a major tool for decision makers. A future goal is to establish agreed minimal data sets for different devices - overcoming national borders. By establishing clear guidelines, the outcomes as well as registry comparability can be fundamentally improved. PMID- 27997814 TI - Proteomics in cardiovascular disease: recent progress and clinical implication and implementation. AB - INTRODUCTION: Although multiple efforts have been initiated to shed light into the molecular mechanisms underlying cardiovascular disease, it still remains one of the major causes of death worldwide. Proteomic approaches are unequivocally powerful tools that may provide deeper understanding into the molecular mechanisms associated with cardiovascular disease and improve its management. Areas covered: Cardiovascular proteomics is an emerging field and significant progress has been made during the past few years with the aim of defining novel candidate biomarkers and obtaining insight into molecular pathophysiology. To summarize the recent progress in the field, a literature search was conducted in PubMed and Web of Science. As a result, 704 studies from PubMed and 320 studies from Web of Science were retrieved. Findings from original research articles using proteomics technologies for the discovery of biomarkers for cardiovascular disease in human are summarized in this review. Expert commentary: Proteins associated with cardiovascular disease represent pathways in inflammation, wound healing and coagulation, proteolysis and extracellular matrix organization, handling of cholesterol and LDL. Future research in the field should target to increase proteome coverage as well as integrate proteomics with other omics data to facilitate both drug development as well as clinical implementation of findings. PMID- 27997815 TI - Annular pustular psoriasis in a 14-month-old girl: a therapeutic challenge. AB - Annular pustular psoriasis (annular PP) is a rare but severe variant of psoriasis, which may even occur in early childhood. At this age, therapeutic options are limited and medication issues can be challenging. We report clinical features, diagnostic findings and treatment of an 11-month-old girl with annular PP. Oral acitretin therapy was initiated at 0.9 mg/kg/d and gradually tapered after complete resolution in the subsequent 10 months without relapse. Acitretin proved to be a highly effective therapeutic option in an infant with annular PP. PMID- 27997816 TI - Recent early clinical drug development for acute kidney injury. AB - INTRODUCTION: Despite significant need and historical trials, there are no effective drugs in use for the prevention or treatment of acute kidney injury (AKI). There are several promising agents in early clinical development for AKI and two trials have recently been terminated. There are also exciting new findings in pre-clinical AKI research. There is a need to take stock of current progress in the field to guide future drug development for AKI. Areas covered: The main clinical trial registries, PubMed and pharmaceutical company website searches were used to extract the most recent clinical trials for sterile, transplant and sepsis-associated AKI. We summarise the development of the agents recently in clinical trial, update on their trial progress, consider reasons for failed efficacy of two agents, and discuss new paradigms in pre-clinical targets for AKI. Agents covered include- QPI-1002, THR-184, BB-3, heme arginate, human recombinant alkaline phosphatase (recAP), ciclosporin A, AB103, levosimendan, AC607 and ABT-719. Expert opinion: Due to the heterogenous nature of AKI, agents with the widest pleiotropic effects on multiple pathophysiological pathways are likely to be most effective. Linking preclinical models to clinical indication and improving AKI definition and diagnosis are key areas for improvement in future clinical trials. PMID- 27997817 TI - On the Reportability of Nontuberculous Mycobacterial Disease to Public Health Authorities. AB - Nontuberculous mycobacteria (NTM) are environmental pathogens that are an increasingly common cause of pulmonary and extrapulmonary disease. Electronic laboratory-based reporting is a straightforward mechanism for identifying NTM infections and for monitoring trends in disease. Oregon was the first state to make NTM reportable, although at this time the reporting requirement is limited to extrapulmonary infection. This has assisted authorities in detecting outbreaks and healthcare-related infections. However, further consideration should be given to the reportability of pulmonary NTM disease. Pulmonary NTM disease is more common than tuberculosis in the United States and is of emerging public health concern. Although the direct public health action that would be triggered by a pulmonary NTM disease report is not clear, without surveillance, public health is missing an opportunity to better understand pulmonary NTM disease trends and reasons for its increasing recognition within our population. We believe state health authorities should conduct surveillance for pulmonary NTM, either by mandating reporting of laboratory isolates or by other mechanisms as we have done in Oregon. PMID- 27997818 TI - Hox Service Warranty Extends to Adult Bone Repair. AB - Hox genes are key developmental regulators. In this issue of Developmental Cell, Rux et al. (2016) uncover an adult role for Hox11 genes in regionalized bone repair. This function relies on Hox activity in bone marrow multipotent mesenchymal stem progenitor cells, which promotes skeletal cell differentiation. PMID- 27997819 TI - Robo-Enabled Tumor Cell Extrusion. AB - How aberrant cells are removed from a tissue to prevent tumor formation is a key question in cancer biology. Reporting in this issue of Developmental Cell, Vaughen and Igaki (2016) show that a pathway with an important role in neural guidance also directs extrusion of tumor cells from epithelial tissues. PMID- 27997820 TI - Germ Cells Get by with a Little Cannibalistic Help from Their Friends. AB - During development, primordial germ cells (PGCs) navigate a complex journey to generate the germline. In a recent paper in Nature Cell Biology, Nance and colleagues (Abdu et al., 2016) have discovered an unexpected step along the way: PGCs get cut in half by endodermal cells. PMID- 27997821 TI - Macrophages Tell the Non-Professionals What to Do. AB - Phagocytosis by professional and non-professional phagocytes plays a critical role in tissue homeostasis and the immune response. Using an airway inflammation model, Han et al. (2016) report in Nature that macrophages secrete IGF-1 to signal epithelial cells to stop ingesting apoptotic cells while increasing the uptake of anti-inflammatory macrophage-derived microvesicles. PMID- 27997822 TI - Hippo Wades into Cancer Immunology. AB - The Hippo pathway limits organ size and suppresses tumors. Reporting in Cell, Moroishi et al. (2016), show that, paradoxically, Hippo pathway inactivation can repress tumor growth by modulating tumor immunogenicity. This could explain the rarity of pathway mutations in cancers and suggests Hippo pathway repression as a cancer immunotherapy modality. PMID- 27997824 TI - Generic Theoretical Models to Predict Division Patterns of Cleaving Embryos. AB - Life for all animals starts with a precise 3D choreography of reductive divisions of the fertilized egg, known as cleavage patterns. These patterns exhibit conserved geometrical features and striking interspecies invariance within certain animal classes. To identify the generic rules that may govern these morphogenetic events, we developed a 3D-modeling framework that iteratively infers blastomere division positions and orientations, and consequent multicellular arrangements. From a minimal set of parameters, our model predicts detailed features of cleavage patterns in the embryos of fishes, amphibians, echinoderms, and ascidians, as well as the genetic and physical perturbations that alter these patterns. This framework demonstrates that a geometrical system based on length-dependent microtubule forces that probe blastomere shape and yolk gradients, biased by cortical polarity domains, may dictate division patterns and overall embryo morphogenesis. These studies thus unravel the default self organization rules governing early embryogenesis and how they are altered by deterministic regulatory layers. PMID- 27997823 TI - Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression. AB - Errors in chromosome segregation during mitosis have been recognized as a hallmark of tumor cells since the late 1800s, resulting in the long-standing hypothesis that mitotic abnormalities drive tumorigenesis. Recent work has shown that mitotic defects can promote tumors, suppress them, or do neither, depending on the rate of chromosome missegregation. Here we discuss the causes of chromosome missegregation, their effects on tumor initiation and progression, and the evidence that increasing the rate of chromosome missegregation may be an effective chemotherapeutic strategy. PMID- 27997826 TI - Repulsive Epithelial Cues Direct Glial Migration along the Nerve. AB - Most glial cells show pronounced migratory abilities and generally follow axonal trajectories to reach their final destination. However, the molecular cues controlling their directional migration are largely unknown. To address this, we established glial migration onto the developing Drosophila leg imaginal disc as a model. Here, CNS-derived glial cells move along nerves containing motoaxons and sensory axons. Along their path, glial cells encounter at least three choice points where directional decisions are needed. Subsequent genetic analyses allowed uncovering mechanisms that escaped previous studies. Most strikingly, we found that glial cells require the expression of the repulsive guidance receptors PlexinA/B and Robo2 to prevent breaking away from the nerve. Interestingly, the repulsive ligands are presented by the underlying leg imaginal disc epithelium, which appears to push glial cells toward the axon fascicle. In conclusion, nerve formation not only requires neuron-glia interaction but also depends on glial epithelial communication. PMID- 27997825 TI - Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia. AB - Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers. PMID- 27997827 TI - Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation. AB - While gene regulatory networks involved in cardiogenesis have been characterized, the role of bioenergetics remains less studied. Here we show that until midgestation, myocardial metabolism is compartmentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1alpha regulation mirrors this pattern, with expression predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1alpha and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1alpha hyperactivation, blocking the midgestational metabolic shift and impairing cardiac maturation and function. Moreover, the altered glycolytic signature induced by HIF1 trabecular activation precludes regulation of genes essential for establishment of the cardiac conduction system. Our findings reveal VHL-HIF-mediated metabolic compartmentalization in the developing heart and the connection between metabolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricular myocardium specialization and its potential relevance to congenital heart disease. PMID- 27997828 TI - A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis. AB - While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop between replication intermediates and an M phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis-licensed by unrestrained CDK1 activity during S phase-requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation. PMID- 27997829 TI - Redox Regulation by Pitx2 and Pitx3 Is Critical for Fetal Myogenesis. PMID- 27997830 TI - Fifty years of illumination about the natural levels of adaptation. AB - A visionary Darwinian ahead of his time, George C. Williams developed in his 1966 book Adaptation and Natural Selection the essentials of a unifying theory of adaptation that remains robust today and has inspired immense progress in understanding how natural selection works. PMID- 27997831 TI - Flaviviruses. AB - What do Zika, Dengue and West Nile viruses have in common? All are members of a family of viruses called the Flaviviruses. Here, Sonja Best lays out the essentials of this group of significant human pathogens. PMID- 27997832 TI - Thirst. AB - Our bodies are mostly water, and this water is constantly being lost through evaporative and other means. Thus the evolution of robust mechanisms for finding and consuming water has been critical for the survival of most animals. In this Primer, we discuss how the brain monitors the water content of the body and then transforms that physical information into the motivation to drink. PMID- 27997833 TI - A magnetic compass that might help coral reef fish larvae return to their natal reef. AB - Many coral reef fish larvae spend days to months in the open ocean before settlement on coral reefs [1]. Early in development, larvae have limited swimming capabilities and will therefore be greatly affected by currents. This can potentially result in dispersal distances of tens of kilometers [2]. Nevertheless, up to 60 % of surviving larvae have been shown to return to their natal reefs [2]. To home, the larvae must develop strong swimming capabilities and appropriate orientation mechanisms. Most late-stage larval reef fish can, after being passively drifted for days to weeks, swim strongly [3], and Ostorhinchus doederleini larvae have been shown to use chemotaxis to identify their natal reef once in its vicinity [2] and a sun compass for longer distance orientation [4] during the day. But how do they orient at night? Here, we show that newly settled fish caught at One Tree Island (OTI) at the Capricorn Bunker Reef Group (Great Barrier Reef) can use geomagnetic compass information to keep a south-east heading. This behavior might help them return to their natal reef in the absence of any celestial cues at night. PMID- 27997834 TI - Association of deep-sea incirrate octopods with manganese crusts and nodule fields in the Pacific Ocean. AB - Incirrate octopods (those without fins) are among the larger megafauna inhabiting the benthic environments of all oceans, commonly in water depths down to about 3,000 m. They are known to protect and brood their eggs until the juveniles hatch, but to date there is little published information on octopod deep-sea life cycles and distribution. For this study, three manganese-crust and nodule abundant regions of the deep Pacific were examined by remote operated-vehicle and towed camera surveys carried out between 2011 and 2016. Here, we report that the depth range of incirrate octopods can now be extended to at least 4,290 m. Octopods (twenty-nine individuals from two distinct species) were observed on the deep Ka'ena and Necker Ridges of the Hawaiian Archipelago, and in a nodule abundant region of the Peru Basin. Two octopods were observed to be brooding clutches of eggs that were laid on stalks of dead sponges attached to nodules at depths exceeding 4,000 m. This is the first time such a specific mineral-biota association has been observed for incirrate octopods. Both broods consisted of approximately 30 large (2.0-2.7 cm) eggs. Given the low annual water temperature of 1.5oC, it is likely that egg development, and hence brooding, takes years [1]. Stalked-sponge fauna in the Peru Basin require the presence of manganese nodules as a substrate, and near total collapse of such sponge populations was observed following the experimental removal of nodules within the DISCOL (DISturbance and COLonisation) area of the Peru Basin [2]. Stalked fauna are also abundant on the hard substrates of the Hawaiian archipelago. The brooding behavior of the octopods we observed suggests that, like the sponges, they may also be susceptible to habitat loss following the removal of nodule fields and crusts by commercial exploitation. PMID- 27997835 TI - Synthetic rainfall vibrations evoke toad emergence. AB - Toads occupy underground refugia during periods of daily or seasonal inactivity, emerging only during rainfall [1]. We test the hypothesis that rainfall-induced vibrations in soil are the cues that trigger the emergence of toads from underground. Using playback experiments in the absence of natural rainfall in native habitats, we observed that two Iberian toad species (Pelobates cultripes and Bufo calamita) emerged significantly earlier than controls when exposed to low-frequency soil vibrations that closely mimic those of rainfall. Our results suggest that detection of abiotic seismic events are biologically relevant and widespread in arid-zone anurans. These findings provide insights into the evolutionary role played by the two low-frequency-tuned inner-ear organs in anuran amphibians - the amphibian papilla and sacculus, both detectors of weak environmental vibrational cues. PMID- 27997836 TI - Cell Division: Flipping the Mitotic Switches. AB - Alternation between DNA replication in the mother cell (S phase) and equal partitioning of the replicated chromosomes to the daughter cells (M phase) during eukaryotic cell division is governed by switches that flip protein kinases on and off. New work reveals that the M-phase promoting kinase is opposed by a phosphatase that also participates in a bistable switching mechanism. PMID- 27997837 TI - Photomorphogenesis: Plants Feel Blue in the Shade. AB - Plants integrate multiple environmental signals to detect and avoid shading from neighbouring vegetation. Two new studies highlight the importance of blue light in the regulation of stem elongation and bending during shade escape. PMID- 27997838 TI - Ecology and Fisheries: Dark Carbon on Your Dinner Plate. AB - Chemosynthetic primary production by symbiotic microbes powers entire ecosystems in the remote deep sea. New research shows that in shallow waters chemosynthetic symbioses can contribute substantially to a vital economic resource - lobster fisheries in the Caribbean Sea. PMID- 27997839 TI - Phagocytosis: How Macrophages Tune Their Non-professional Counterparts. AB - Foreign particles and apoptotic cells are engulfed by professional phagocytes (e.g. macrophages) and non-professional phagocytes (e.g. epithelial cells). These phagocyte populations exchange information to coordinate and prioritise their activities, but the nature of these messages was unknown. Recently, IGF-1 and microvesicles were identified as means of communication between macrophages and epithelia. PMID- 27997840 TI - Plant Evolution: Repeated Loss of Floral Scent - A Path of Least Resistance? AB - Two independent studies converge on similar causes for olfactory loss-of-function mutants in evolutionary transitions to scentless flowers. This molecular deja vu may reflect selection to minimize negative pleiotropy in a complex biosynthetic pathway. PMID- 27997842 TI - Cell Biology: Microtubule Collisions to the Rescue. AB - The proper regulation of microtubule lengths is fundamental to their cellular function. New work now reports that the collision of a growing microtubule end with another object, such as a microtubule, can contribute to the regulation of microtubule lengths by leaving behind damage that ultimately acts to stabilize the microtubule network. PMID- 27997841 TI - RNA Transport: From Head to Toe in Radial Glial Cells. AB - Intracellular mRNA localization critically contributes to proper brain development and function. A recent study demonstrates that mRNAs are actively transported in radial glial cells from the soma to the distal basal endfeet, where they are locally translated. PMID- 27997843 TI - Evolution: Plumbing the Depths of Diplonemid Diversity. AB - Environmental molecular sequence surveys have opened a window on the hidden riches of the microbial biosphere. Recent genetic 'barcoding' and single-cell genomics studies have provided a snapshot of the biology of diplonemids - abundant, diverse, marine heterotrophic protists whose ecological roles are becoming clearer. PMID- 27997844 TI - Cell Biology: Kinesin-14 Backsteps to Organize Polymerizing Microtubules. AB - Microtubules nucleated from an organizing center grow radially in all directions. A new study shows that, to organize those microtubules into arrays of parallel bundles, the kinesin-14 Cik1-Kar3 guides growing microtubule tips along pre existing microtubules. PMID- 27997845 TI - Evolutionary Genetics: Smells like a Pseudo-pseudogene. AB - A new study reports the presence of a chemosensory pseudogene in Drosophila sechellia, which in spite of carrying a premature stop-codon nevertheless encodes a fully functional and full-length protein. Such 'pseudo-pseudogenes' might well be a widespread phenomenon. PMID- 27997846 TI - Micelle-vesicle-micelle transition in aqueous solution of anionic surfactant and cationic imidazolium surfactants: Alteration of the location of different fluorophores. AB - The presence of different surfactants can alter the physicochemical behaviors of aqueous organized assemblies. In this article, we have investigated the location of hydrophobic molecule (Coumarin 153, C153) and hydrophilic molecule (Rhodamine 6G perchlorate, R6G) during micelle-vesicle-micelle transition in aqueous medium in presence of anionic surfactant, sodium dodecylbenzenesulfonate (SDBS) and cationic imidazolium-based surfactant, 1-alkyl-3-methylimidazolium chloride (CnmimCl; n=12, 16). Initially, the physicochemical properties of anionic micellar solution of SDBS has been investigated in presence of imidazolium-based surfactant, CnmimCl (n=12, 16) in aqueous medium by visual observation, turbidity measurement, zeta potential (zeta), dynamics light scattering (DLS), and transmission electron microscopy (TEM). Zeta potential (zeta) measurement clearly indicates that the incorporation efficiency of C16mimCl in SDBS micelle is better than the other one due to the involvement of strong hydrophobic as well as electrostatic interaction between the two associated molecules. Turbidity and DLS measurements clearly suggest the formation of vesicles over a wide range of concentration. Finally, the rotational motion of C153 and R6G has also been monitored at different mole fractions of CnmimCl in SDBS-CnmimCl (n=12, 16) solution mixtures. The hydrophobic C153 molecules preferentially located in the bilayer region of vesicle, whereas hydrophilic R6G can be solubilized at surface of the bilayer, inner water pool or outer surface of vesicles. It is observed that rotational motion of R6G is altered significantly in SDBS-CnmimCl solution mixtures in presence of different mole fractions of CnmimCl. Additionally, the translational diffusion motion of R6G is monitored using fluorescence correlation spectroscopy (FCS) techniques to get a complete scenario about the location and translational diffusion of R6G. PMID- 27997847 TI - Anatase TiO2 sheet-assisted synthesis of Ti3+ self-doped mixed phase TiO2 sheet with superior visible-light photocatalytic performance: Roles of anatase TiO2 sheet. AB - On the basis of measurements, such as field emission scanning electron microscope, UV-Vis diffuse reflectance spectra, X-ray diffraction, electron paramagnetic resonance, photoluminescence spectra, and photocurrent measurements, the roles of anatase TiO2 sheet on synthesizing Ti3+ self-doped mixed phase TiO2 nanosheets (doped TiO2 (A/R, TiO2 (A))) and on improving the performance for photocatalytic CO2 reduction were explored systematically. High surface area anatase TiO2 nanosheets (TiO2 (A)) as a substrate, structure directing agent, and inhibitor, mediated the synthesis of Ti3+ self-doped mixed phase TiO2 nanosheets. Addition of TiO2 (A) significantly improved not only visible light absorption of doped TiO2 (A/R, TiO2 (A)), but also the efficiency of photo-excited charges separations due to the existence of interfacial regions of anatase-rutile TiO2 junctions. Finally, a possible mechanism for interfacial charge transfer at the anatase-rutile TiO2 interface and for photocatalytic CO2 reduction over Pt loaded doped TiO2 (A/R, TiO2 (A)) were proposed. PMID- 27997848 TI - Noble metal-titania hybrid nanoparticle clusters and the interaction to proteins for photo-catalysis in aqueous environments. AB - We report a systematic study of the controlled synthesis of new hybrid spherical TiO2 nanoparticle cluster (TiO2-NPC) homogeneously decorated with noble metal nanoparticles (NPs) by gas-phase evaporation-induced self-assembly. Silver NP (AgNP) was used as the representative noble metal NP. The degradation of methyl blue (MB) in the aqueous solution was chosen as the representative system for the study of photocatalysis, which were tested and evaluated with respect to irradiation conditions and the presence of bovine serum albumin (BSA). The results show that particle size and chemical composition of the hybrid nanostructure were tunable by choosing the suitable concentration of precursors. The photocatalytic activity of AgNP-decorated TiO2-NPC was strongly affected by the light irradiation and the ligand-nanoparticle interfacial interaction. The presence of BSA influenced molecular conjugation to the surface of the hybrid nanostructure. Under conditions of simultaneous competitive adsorption of MB and BSA, the combination of AgNPs improved the photocatalytic activity of the TiO2 NPC-based catalysts. Our work describes a prototype methodology to fabricate TiO2 NPC homogeneously decorated with noble metal NPs with well-controlled material properties. The mechanistic understanding developed in this study can be useful for the future optimization of material properties of hybrid nanostructures versus interfacial interactions with the surrounding molecules. PMID- 27997850 TI - Hierarchically porous fluorine-doped graphene nanosheets as efficient metal-free electrocatalyst for oxygen reduction in gas diffusion electrode. AB - Here a simple yet cost-effective strategy is developed to fabricate fluorine doped graphene nanosheets, we successfully, prepared fluorine doped graphene via thermal treatment of graphene oxide and NaF (sodium fluoride) in H2SO4 solution phase. Importantly, the electrocatalytic activity for oxygen reduction reaction (ORR) is carefully evaluated for fluorographene (FG). None-metal graphene electro catalysts for the ORR are attractive for their high activity and economic advantages. A significant research effort is also directed to the so-called "metal-free" ORR on heteroatom-doped graphene surfaces. The electrochemical activity of F-RGO in the ORR is investigated by cyclic voltammetry (CV) and linear sweep voltammetry (LSV) using rotating disk electrode (RDE) measurements on glassy carbon and on gas diffusion electrode (GDE) based carbon paper in oxygen saturated alkaline aqueous solutions. PMID- 27997849 TI - BiOBr/BiOF composites for efficient degradation of rhodamine B and nitrobenzene under visible light irradiation. AB - BiOBr/BiOF (BF) composites were successfully synthesized via a facile one-step hydrothermal method for the first time. The structures, morphologies and photocatalytic performances of BF composites were characterized by X-ray diffraction, scanning electron microscopy, high-resolution transmission electron microscopy, UV-vis absorption spectroscopy, X-ray photoelectron spectroscopy, photoluminescence spectroscopy and electrochemical impedance spectroscopy respectively. The results show that the BF composites exhibit enhanced photocatalytic performances in the degradation of RhB and nitrobenzene with maximum degradation rates of 100% (25min) and 94% (300min) under visible light irradiation, respectively. The improved photocatalytic performance is mainly ascribed to the small crystalline size and the reduced electron-hole pair recombination with the presence of BiOF in the composites. Furthermore, the photodegradation mechanism was investigated and the h+ and OH radicals are suggested to be the main active species for photocatalytic degradation of RhB and nitrobenzene. PMID- 27997852 TI - The roles of oncogenic miRNAs and their therapeutic importance in breast cancer. AB - Since the discovery of tumour suppressive miRNA in 2002, the dysregulation of miRNAs was implicated in many cancers, exhibiting both tumour suppressive and oncogenic roles. Dysregulation of miRNAs was found to be involved in the initiation of oncogenesis, as well as the progression, invasion and metastasis of cancers. While normal miRNA inhibitory functions help regulate gene expression in the cell, oncogenic miRNA, when dysregulated can lead to suppression of critical pathways that control apoptosis, cell cycle progression, growth and proliferation. This suppression allows for the upregulation of pro-oncogenic factors that drive cell survival, growth and proliferation. Due to emerging discoveries, oncogenic miRNAs are proving to be a critical component in cancers, such as breast cancer, and may provide novel avenues for cancer treatment. In this article, we discuss the roles of the most studied oncogenic miRNAs in breast cancer including clusters and families involved as well as the less studied and recently discovered oncogenic miRNAs. These miRNAs provide valuable information into the complexity of regulatory elements affected by their overexpression and the overall impact in the progression of breast cancer. Also, identifying miRNAs causing or leading to resistance or sensitivity to current anti-cancer drugs prior to treatment may lead to an improvement in treatment selection and overall patient response. This review summarizes known and recently discovered miRNAs in literature found to have oncogenic roles in breast cancer initiation and the progression, invasion and metastasis of the disease. PMID- 27997851 TI - Depressed adolescents' positive and negative use of social media. AB - This qualitative study examined descriptions of social media use among 23 adolescents (18 female, 5 male) who were diagnosed with depression to explore how social media use may influence and be influenced by psychological distress. Adolescents described both positive and negative use of social media. Positive use included searching for positive content (i.e. for entertainment, humor, content creation) or for social connection. Negative use included sharing risky behaviors, cyberbullying, and for making self-denigrating comparisons with others. Adolescents described three types of use in further detail including "oversharing" (sharing updates at a high frequency or too much personal information), "stressed posting" (sharing negative updates with a social network), and encountering "triggering posts." In the context of treatment, these adolescents shifted their social media use patterns from what they perceived as negative to more positive use. Implications for clinicians counseling depressed adolescents on social media use are discussed. PMID- 27997853 TI - Spin polarisation with electron Bessel beams. AB - The theoretical possibility to use an electron microscope as a spin polarizer is studied. It turns out that a Bessel beam passing a standard magnetic objective lens is intrinsically spin polarized when post-selected on-axis. In the limit of infinitely small detectors, the spin polarisation tends to 100%. Increasing the detector size, the polarisation decreases rapidly, dropping below 10-4 for standard settings of medium voltage microscopes. For extremely low voltages, the Figure of Merit increases by two orders of magnitude, approaching that of existing Mott detectors. Our findings may lead to new desings of spin filters, an attractive option in view of its inherent combination with the electron microscope, especially at low voltage. PMID- 27997854 TI - The emerging metabolic view of Clostridium difficile pathogenesis. AB - It is widely accepted that Clostridium difficile exploits dysbiosis and leverages inflammation to thrive in the gut environment, where it can asymptomatically colonize humans or cause a toxin-mediated disease ranging in severity from frequent watery diarrhea to pseudomembranous colitis or toxic megacolon. Here, we synthesize recent findings from the gut microbiota and enteric pathogenesis fields to inform the next steps toward a better understanding of C. difficile infection (CDI). In this review, we present a model in which the lifestyle of C. difficile is dictated by the metabolic state of the distal gut ecosystem. Contributions by C. difficile (specifically the production and action of the large glycosylating toxins TcdA and TcdB), the microbiota, and the host dictate whether the gut environment is supportive to the pathogen. Mechanistic, metabolic pathway-focused approaches encompassing the roles of all of these players are helping to elucidate the molecular ecology of the distal gut underlying a diseased or healthy ecosystem. A new generation of therapeutic strategies that are more targeted (and palatable) than fecal microbiota transplants or broad spectrum antibiotics will be fueled by insight into the interspecies (host microbe and microbe-microbe) interactions that differentiate healthy from pathogen-infested microbiotas. PMID- 27997855 TI - Actin-based motility and cell-to-cell spread of bacterial pathogens. AB - Subversion of the host actin cytoskeleton is a critical virulence mechanism used by a variety of intracellular bacterial pathogens during their infectious life cycles. These pathogens manipulate host actin to promote actin-based motility and coordinate motility with cell-to-cell spread. Growing evidence suggests that the tactics employed by pathogens are surprisingly diverse. Here, we review recent advances suggesting that bacterial surface proteins exhibit divergent biochemical mechanisms of actin polymerization and recruit distinct host protein networks to drive motility, and that bacteria deploy secreted effector proteins that alter host cell mechanotransduction pathways to enable spread. Further investigation into the divergent strategies used by bacterial pathogens to mobilize actin will reveal new insights into pathogenesis and cytoskeleton regulation. PMID- 27997856 TI - New silver complexes with bioactive glycine and nicotinamide molecules - Characterization, DNA binding, antimicrobial and anticancer evaluation. AB - This study introduces a pair of newly synthesized silver complexes, [Ag2(HGly)2]n(NO3)2n (1) and [Ag(Nam)2]NO3.H2O (2) (Gly - glycine, Nam - nicotinamide), that were prepared and characterized by relevant methods in solid state (elemental, spectral, thermal and structural analysis) and their stability in solution was verified by 1H NMR measurements. Moreover, suitable reaction conditions were observed by potentiometry depending on pH in case of binary system Ag-Gly. X-ray analysis confirmed argentophilic interactions in complex 1 with an Ag1-Ag2 distance of 2.8018(6) A. Antimicrobial testing indicates higher growth inhibition effect of complex 1 than complex 2. Moreover the effectivity of both complexes against bacteria (Staphylococcus aureus and Escherichia coli) is superior (or similar) to that of the commercially available Ag(I) sulfadiazine, AgSD (used, for example, in Dermazine cream). The binding of the Ag(I) complexes to calf thymus DNA was investigated using electronic absorption, fluorescence and circular dichroism spectrophotometry. The Stern-Volmer quenching constants obtained from the linear quenching plot were estimated in the range from 2.01*103 to 20.34*103M-1. The results of topoisomerase I and topoisomerase II (Topo I and Topo II) inhibition assay suggested that complex 2 inhibits the enzyme activity of both enzymes at a concentration of 2MUM. The cytotoxicity of both complexes on L1210 leukemia cells was revealed to be approximately three times higher than that of cisplatin. Moreover, the new Ag(I) complexes also induced apoptosis of the leukemia cells. The high DNA binding activity of these complexes is considered to be responsible for their cytotoxic effects. PMID- 27997858 TI - Psychological ownership: The implicit association between self and already-owned versus newly-owned objects. AB - Evidence from explicit measures (e.g. favourability ratings, valuations) has led to the prevalent hypothesis that owned objects become cognitively associated with self-concept. Using a novel version of the Implicit Association Test (self-object IAT), wherein participants categorized objects by colour, we evaluated implicit cognitive associations involving self with already-owned and newly-owned objects. We observed faster responses when self-related words required the same response key as the colour that incidentally corresponded to self-owned objects, irrespective of length of ownership. These findings suggest that participants efficiently form cognitive associations between self and self-owned objects within mere minutes of ownership induction and inspire questions about the extent to which length of ownership drives the strength of this association. PMID- 27997857 TI - Silver complexes of ligands derived from adamantylamines: Water-soluble silver donating compounds with antibacterial properties. AB - Two new silver(I) complexes, namely [Ag(qyAm)2](CF3SO3) (1) and [Ag(qyTAm)2](CF3SO3) (2), (qyAm=2-(quinonyl)iminoadamantane, qyTAm=2 (quinonyl)iminotriazaadamantane) have been synthesized and characterized by elemental analyses, 1H NMR, IR, electronic absorption spectroscopy, and X-ray diffraction. The coordination geometry of the silver center in both complexes is distorted tetrahedral where their respective qyAm and qyTAm ligand bind in a bidentate fashion using the imine and quinoline nitrogen atoms. Complex 2 is soluble in water and exhibits strong antimicrobial actions on both Gram-negative (E. coli, and P. aeruginosa) and Gram-positive (S. aureus) bacteria. The minimal inhibitory concentration (MIC) values for complex 2 (4, 4, and 8 MUg for E. coli, P. aeruginosa, and S. aureus, respectively) are comparable to MIC values of silver nitrate and silver sulfadiazine. PMID- 27997859 TI - Interleukin-1beta as a driver of renal NGAL production. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is increasingly regarded as a biomarker of acute kidney injury, or kidney injury in general, but the stimuli responsible for its production are incompletely understood. This study tested the relationship between the pro-inflammatory cytokine interleukin-1beta (IL-1beta) and both circulating and renal NGAL, using chronic subcutaneous infusion of IL 1beta in mice and tissue culture of renal cell lines. Following a 14-day subcutaneous infusion of vehicle or IL-1beta (10ng/h) in male C57Bl/6 mice, a striking positive correlation (r2=0.94; P<0.01) was observed between plasma IL 1beta and NGAL concentrations. NGAL was markedly increased in the kidneys of IL 1beta-infused mice compared with vehicle-treated mice, both at the protein and mRNA level, indicating increased local as well as systemic production of NGAL. Immunohistochemical staining revealed prominent increases of NGAL in the proximal tubular epithelium of IL-1beta infused mice. These effects occurred in the absence of overt renal injury, with plasma creatinine concentration not significantly different between groups. Further showing that IL-1beta has a direct effect on NGAL production by tubular epithelial cells, exposure of a proximal tubular cell line (HK-2 cells) and a cortical collecting duct principal cell line (mpkCCD cells) to IL-1beta for 24h produced a significant increase of NGAL mRNA levels (>30-fold). These data indicate IL-1beta serves as a powerful stimulus for renal production of NGAL. PMID- 27997861 TI - Comparative fly species composition on indoor and outdoor forensic cases in Malaysia. AB - Forensic entomology refers to the science of collection and analysis of insect evidence in order to determine the minimum time period since death. This study aimed to investigate the occurrence of forensically important flies on 34 human remains referred to Universiti Kebangsaan Malaysia Medical Centre over a period of three years. Entomological specimens were collected at the death scenes and/or during autopsies. Live specimens were reared into adults while preserved specimens were processed for species identification. Five families, seven genera and nine species of flies were identified from human remains. The results of the study showed Chrysomya megacephala (Calliphoridae) maggots occurred on corpses with the highest frequency (70.6%), followed by Ch. rufifacies (Calliphoridae) (44.1%), sarcophagid fly (Sarcophagidae) (38.2%), Synthesiomya nudiseta (Muscidae) (20.6%), Megaselia scalaris (Phoridae) (14.7%), Lucilia cuprina (Calliphoridae) (5.9%), Ch. nigripes (Calliphoridae) (5.9%), Eristalis spp. (Syrphidae) (5.9%) and Hydrotaea spinigera (Muscidae) (2.9%). The greatest fly diversity occurred on remains recovered indoors (eight species) compared to outdoors (three species). Whilst, single and double infestations were common for both indoor and outdoor cases, multiple infestation of up to six species was observed in one of the indoor cases. Although large numbers of fly species were found on human remains, the predominant species were still those of Chrysomya, while S. nudiseta was found only on human remains recovered from indoors. The present study provides additional knowledge in the context of Malaysian forensic entomology and the distribution of forensically important flies which is of relevance to forensic science. PMID- 27997860 TI - VEGF gene therapy cooperatively recruits molecules from the immune system and stimulates cell homing and angiogenesis in refractory angina. AB - BACKGROUND: New vessels are formed in response to stimuli from angiogenic factors, a process in which paracrine signaling is fundamental. OBJECTIVE: To investigate the cooperative paracrine signaling profile in response to Vascular Endothelial Growth Factor (VEGF) gene therapy in patients with coronary artery disease (CAD) and refractory angina. METHOD: A cohort study was conducted in which plasma was collected from patients who underwent gene therapy with a plasmid expressing VEGF 165 (10) and from surgical procedure controls (4). Blood samples were collected from both groups prior to baseline and on days 3, 9 and 27 after the interventions and subjected to systemic analysis of protein expression (Interleukin-6, IL-6; Tumor Necrosis Factor-alpha, TNF-alpha; Interleukin-10, IL 10; Stromal Derived Factor-1 alpha, SDF-1alpha; VEGF; Angiopoietin-1, ANGPT-1; and Endothelin-1, ET-1) using the enzyme-linked immunosorbent assay (ELISA). RESULTS: Analysis showed an increase in proinflammatory IL-6 (p=0.02) and ET-1 (p=0.05) on day 3 after gene therapy and in VEGF (p=0.02) on day 9. A strong positive correlation was found between mobilization of endothelial progenitor cells and TNF-alpha on day 9 (r=0.71; p=0.03). Furthermore, a strong correlation between beta-blockers, antiplatelets, and vasodilators with SDF-1alpha baseline in the group undergoing gene therapy was verified (r=0.74; p=0.004). CONCLUSION: Analysis of cooperative paracrine signaling after VEGF gene therapy suggests that the immune system cell and angiogenic molecule expression as well as the endothelial progenitor cell mobilization are time-dependent, influenced by chronic inflammatory process and continuous pharmacological treatment. PMID- 27997862 TI - The association of pulse pressure with metabolic syndrome in Korean elderly: A nationwide population-based study. AB - AIMS: Metabolic syndrome (MetS) is one of the most important issues in elderly people because of its association with ensuing cardiovascular disease (CVD). The components of MetS play a key role in the pathogenesis of arterial thickness and stiffness. Pulse pressure (PP), an easily accessible parameter in a basic health evaluation, has been documented as a marker of arterial stiffness and widespread atherosclerosis. The aim of our study was to assess the association between PP and MetS in Korean elderly people. METHODS: A nationwide cross-sectional study was conducted to examine the relationship between PP and MetS among 6187 participants (2687 men and 3500 women) aged 60years older Korean people using the Korean National Health and Nutrition Examination Survey. The odds ratios (ORs) and 95% confidence intervals (CIs) for MetS were calculated across PP quartiles using multiple logistic regression analyses. RESULTS: There was a positive relationship between PP and MetS in a dose-response manner. The prevalence of MetS significantly increased with increasing PP quartile in both men and women (p<0.001). Compared with the lowest PP quartile group, the ORs (95% CIs) for MetS of the highest PP quartile was 2.60 (1.91-3.52) for men and 1.97 (1.48-2.59) for women after adjusting for age, cigarette smoking, alcohol intake, regular exercise and mean arterial blood pressure. These associations remained valid after additionally adjusting for hypertension and diabetes medications. CONCLUSION: We found a positive relationship between PP and MetS among Korean elderly men and women. PMID- 27997863 TI - Low testosterone and clinical outcomes in Chinese men with type 2 diabetes mellitus - Hong Kong Diabetes Registry. AB - AIMS: To assess the implications of low testosterone on cardiovascular risk factors, metabolic syndrome (MES) and clinical outcomes in Chinese men with Type 2 Diabetes (T2D). METHODS: A prospective cohort study carried out in a university hospital involving a consecutive cohort of 1239 Chinese men with T2D and a median disease duration of 9years followed up for 4.8years. Clinical characteristics, frequency of MES, serum total testosterone and clinical events were analyzed. Multivariate logistic regression was performed to examine the independent association of low testosterone with MES after adjustment for confounding covariates. Cox proportional hazards regression analysis was used to derive hazard ratio for clinical outcomes. RESULTS: More men with low testosterone had cardiovascular-renal disease and MES than those with normal testosterone. The adjusted odds ratio (OR) of low testosterone for MES was 2.63 (95% Confidence Interval [CI] 1.56-4.61). After a median follow-up of 4.8years, the hazard ratio (HR) of low testosterone was 2.22 (95% CI 1.23-4.01) for incident non-prostate cancer. In a multivariate Cox-regression model, the HRs were attenuated but remained significant with adjustment for MES and renal parameters. CONCLUSIONS: Chinese men with low testosterone had high prevalence of cardiovascular disease and MES with high incidence non-prostate cancer. PMID- 27997864 TI - Does contextual unemployment matter for health status across the life course? A longitudinal multilevel study exploring the link between neighbourhood unemployment and functional somatic symptoms. AB - This study examines whether neighbourhood unemployment is related to functional somatic symptoms, independently of the individual employment, across the life course and at four specific life course periods (age 16, 21, 30 and 42). Self reported questioner data was used from a 26-year prospective Swedish cohort (n=1010) with complementary neighbourhood register data. A longitudinal and a set of age-specific cross-sectional hierarchal linear regressions was carried out. The results suggest that living in a neighbourhood with high unemployment has implications for residents' level of functional somatic symptoms, regardless of their own unemployment across time, particularly at age 30. PMID- 27997865 TI - Multicolor imaging of hydrogen peroxide level in living and apoptotic cells by a single fluorescent probe. AB - To understand the entangled relationship between reactive oxygen species (ROS) and apoptosis, there is urgent need for simultaneous dynamic monitoring of these two important biological events. In this study, we have developed a fluorescent probe, pep4-NP1, which can simultaneously detect H2O2 and caspase 3, the respective markers of ROS and apoptosis. The probe contains a H2O2 fluorescence reporter (NP1) and Cy5 fluorescent chromophore connected by a caspase 3 specific recognition peptide. The detecting strategy was realized through a controllable fluorescence resonance energy transfer (FRET) process between NP1 and Cy5 of pep4 NP1, after reaction with H2O2, which was verified by molecular calculation and in vitro spectral studies. In the absent of caspase 3, the accumulation of H2O2 induces red fluorescence of pep4-NP1 centered at 663nm in living cells due to the existence of FRET. In contrast, FRET is inhibited in apoptotic cells due to cleavage of the peptide spacer of pep4-NP1 by over-expressed caspase 3. Consequently, green fluorescence (555nm) predominated when labelling production of H2O2 in apoptotic cells. Moreover, Pep4-NP1 shows excellent selectivity towards H2O2 and caspase 3 on their respective reaction sites. Therefore, pep4 NP1 can distinguish endogenously generated H2O2 between living cells and apoptotic cells with different fluorescence wavelengths, providing additional information on the ROS production pathways. PMID- 27997866 TI - Catalytic depolymerization of the hydrolyzed lignin over mesoporous catalysts. AB - In this work, the mesoporous SBA-15 and a series of modified catalysts based on it, such as Al-SBA-15 and Ni/Al-SBA-15, were synthesized and used for eliminating the char formation during the depolymerization of hydrolyzed lignin. The temperature, time and solvent effects on the lignin depolymerization were also investigated. Results showed that the repolymerization was effectively suppressed over SBA-15 due to its well-ordered pore structure and large pore size. The addition of Al and Ni elements in SBA-15 could improve the lignin depolymerization performance and saturate the instable intermediates. Ethanol was found to be more effective in suppressing repolymerization than other solvents. 81.4% liquefaction degree and 21.90wt% monomer yield was achieved, and no obvious char was observed after the depolymerization of hydrolyzed lignin in ethanol solvent at 300 degrees C for 4h over Ni/Al-SBA-15(20) catalyst. PMID- 27997867 TI - Multivariate analysis of fatty acid and biochemical constitutes of seaweeds to characterize their potential as bioresource for biofuel and fine chemicals. AB - In the present study bio prospecting of thirty seaweeds from Indian coasts was analyzed for their biochemical components including pigments, fatty acid and ash content. Multivariate analysis of biochemical components and fatty acids was done using Principal Component Analysis (PCA) and Agglomerative hierarchical clustering (AHC) to manifest chemotaxonomic relationship among various seaweeds. The overall analysis suggests that these seaweeds have multi-functional properties and can be utilized as promising bioresource for proteins, lipids, pigments and carbohydrates for the food/feed and biofuel industry. PMID- 27997868 TI - One-step ethanolysis of lignin into small-molecular aromatic hydrocarbons over nano-SiC catalyst. AB - Catalytic depolymerization of lignin for preparation of aromatic hydrocarbons without external hydrogen was first carried out over nano-SiC catalyst in supercritical ethanol. Mixture of the catalyst and lignin was innovatively suspended in a closed reactor and small-molecular aromatic hydrocarbons were successfully achieved at 500 degrees C. Results revealed that not only did conversion of lignin increase sharply under the nano-SiC catalyst, but also phenols were not detected. The increase of residence time under the Fe-SiC catalyst did not change distribution of the liquid products besides the yield improvement, suggesting that the catalyst was suitable and selective towards formation of small-molecular benzenes, especially C6-C8 benzenes. Preliminary studies found that lignin depolymerization and deoxygenation were successfully fulfilled during the reactions, which provided a very effective route to conversion of lignin into high added-value molecules as transportation fuel additives. PMID- 27997869 TI - Effect of extended famine conditions on aerobic granular sludge stability in the treatment of brewery wastewater. AB - Results obtained from three aerobic granular sludge reactors treating brewery wastewater are presented. Reactors were operated for 60d days in each of the two periods under different cycle duration: (Period I) short 6h cycle, and (Period II) long 12h cycle. Organic loading rates (OLR) varying from 0.7kgCODm-3d-1 to 4.1kgCODm-3d-1 were tested. During Period I, granules successfully developed in all reactors, however, results revealed that the feast and famine periods were not balanced and the granular structure deteriorated and became irregular. During Period II at decreased 12h cycle time, granules were observed to develop again with superior structural stability compared to the short 6h cycle time, suggesting that a longer starvation phase enhanced production of proteinaceous EPS. Overall, the extended famine conditions encouraged granule stability, likely because long starvation period favours bacteria capable of storage of energy compounds. PMID- 27997870 TI - Effect of gradual transition of substrate on performance of flat-panel air cathode microbial fuel cells to treat domestic wastewater. AB - In order to confirm the effects of the low conductivity and biodegradability of wastewater, flat-panel air-cathode microbial fuel cells (FA-MFCs) were operated by supplying substrates with different volume ratios of domestic wastewater mixed with an artificial medium: the artificial medium only, 25% wastewater, 50% wastewater, 75% wastewater, 100% of wastewater with 500mg-COD/L by adding acetate, and raw domestic wastewater (230mg-COD/L). With the increase of wastewater ratio, the maximum power density and organic removal efficiency decreased from 187 to 60W/m3 and 51.5 to 37.4%, respectively, but the Coulombic efficiency was maintained in the range of 18.0-18.9%. The FA-MFCs could maintain their low internal resistances and overcome the decreasing conductivity. The acetate concentration was more important than the total organics for power production. This study suggests that the FA-MFC configuration has great applicability for practical applications when supplied by domestic wastewater with low conductivity and biodegradability. PMID- 27997871 TI - The effect of anode potential on bioelectrochemical and electrochemical tetrathionate degradation. AB - The effect of poised anode potential on electricity production and tetrathionate degradation was studied in two-chamber flow-through electrochemical (ES) and bioelectrochemical systems (BES). The minimum anode potential (vs. Ag/AgCl) for positive current generation was 0.3V in BES and 0.5V in the abiotic ES. The anode potential required to obtain average current density above 70mAm-2 was 0.4V in BES and above 0.7V in ES. ES provided higher coulombic efficiency, but the average tetrathionate degradation rate remained significantly higher in BES (above 110mgL-1d-1) than in the abiotic ES (below 35mgL-1d-1). This study shows that at anode potentials below 0.7V, the electrochemical tetrathionate degradation is only efficient with microbial catalyst and that significantly higher tetrathionate degradation rates can be obtained with bioelectrochemical systems than with electrochemical systems at the tested anode potentials. PMID- 27997872 TI - Efficient methanogenic degradation of alcohol ethoxylates and microbial community acclimation in treatment of municipal wastewater using a submerged anaerobic membrane bioreactor. AB - The effect of alcohol ethoxylates on the treatment of municipal wastewater by a submerged anaerobic membrane bioreactor was investigated by a 400days operation including the treatment efficiency, methanogenic activity of sludge and microbial community structure. The results indicated that alcohol ethoxylates (5.0-200mg/L) was efficiently degraded and converted into methane due to the similar COD removal 95.5-98.8% and rising biogas production rate (2.30-4.25L/d) compared with control (96.8% and 2.55L/d). The microbes in sludge could copy with the presence of alcohol ethoxylates in wastewater by releasing more SMP and EPS, which caused a higher membrane fouling rate. Moreover, via long term acclimation, the specific methanogenic activity of sludge was greatly enhanced due to the changes of microbial community structure. Hence, the sludge self-acclimation to alcohol ethoxylates was responsible to the efficient methane recovery in treatment of municipal wastewater. PMID- 27997873 TI - Effect of precursors combined with bacteria communities on the formation of humic substances during different materials composting. AB - The aim of this work was to put forward a method to improve HS amount by studying the formation regularity of HS. Five precursors have been detected and few researches combined them with bacteria to study HS formation. During composting, the polyphenols, carboxyl and amino acids concentration decreased by 75.8%, 63.2% and 68.3% on average, respectively. However, the polysaccharides, reducing sugars and HS concentration increased by 61.2%, 47.1% and 37.33% on average. Relationships between precursors and HS concentration showed that the HS formation were significantly affected (p<0.05). The key bacteria community and physical-chemical parameters which affected HS formation have also been identified by redundancy analysis. Twelve key bacteria communities have been selected, which were significantly affected by physical-chemical parameters (p<0.05). Accordingly, we proposed an adjusting method to promote HS amount during composting based on the relationship between the key bacteria communities and the precursors as well as physical-chemical parameters. PMID- 27997874 TI - Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients. AB - BACKGROUND: O(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer (mCRC) with selection based on methyl-specific PCR (MSP) testing with modest results. We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment. PATIENTS AND METHODS: Formalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS). RESULTS: One hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p < 0.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p < 0.001) and a 77% in the hazard for death (p = 0.001). CONCLUSION: In mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting. PMID- 27997875 TI - The impact of social marketing campaigns on reducing mental health stigma: Results from the 2009-2014 Time to Change programme. AB - BACKGROUND: In England, during 2009-2014 the 'Time to Change' anti-stigma programme has included a social marketing campaign (SMC) using mass media channels, social media and social contact events but the efficacy of such approach has not been evaluated yet. METHODS: The target population included people aged between mid-twenties/mid-forties, from middle-income groups. Participants were recruited through an online market research panel, before and after each burst of the campaign (with a mean number of unique participants per each burst: 956.9+/-170.2). Participants completed an online questionnaire evaluating knowledge [Mental Health Knowledge Schedule (MAKS)]; attitudes [Community Attitudes toward Mental Illness (CAMI)]; and behaviours [Reported and Intended Behaviour Scale (RIBS)]. Socio-demographic data and level of awareness of the SMC were also collected. RESULTS: A total of 10,526 people were interviewed. An increasing usage of the SMC-media channels as well as of the level of awareness of SMC was found (P<0.001). Being aware of the SMC was found to be associated with higher score at MAKS (OR=0.95, CI=0.68 to 1.21; P<0.001), at 'tolerance and support' CAMI subscale (OR=0.12, CI=0.09 to 0.16; P<0.001), and at RIBS (OR=0.71, CI=0.51 to 0.92; P<0.001), controlling for confounders. CONCLUSION: The SMC represents an important way to effectively reduce stigma. Taking into account these positive findings, further population-based campaigns using social media may represent an effective strategy to challenge stigma. PMID- 27997876 TI - Diagnostic conversion to bipolar disorder in unipolar depressed patients participating in trials on antidepressants. AB - OBJECTIVE: In unipolar depressed patients participating in trials on antidepressants, we investigated if illness characteristics at baseline could predict conversion to bipolar disorder. METHOD: A long-term register-based follow up study of 290 unipolar depressed patients with a mean age of 50.8 years (SD=11.9) participating in three randomized trials on antidepressants conducted in the period 1985-1994. The independent effects of explanatory variables were examined by applying Cox regression analyses. RESULTS: The overall risk of conversion was 20.7%, with a mean follow-up time of 15.2 years per patient. The risk of conversion was associated with an increasing number of previous depressive episodes at baseline, [HR 1.18, 95% CI (1.10-1.26)]. No association with gender, age, age at first depressive episode, duration of baseline episode, subtype of depression or any of the investigated HAM-D subscales included was found. LIMITATIONS: The patients were followed-up through the Danish Psychiatric Central Research Register, which resulted in inherent limitations such as possible misclassification of outcome. CONCLUSION: In a sample of middle-aged hospitalized unipolar depressed patients participating in trials on antidepressants, the risk of conversion was associated with the number of previous depressive episodes. Therefore, this study emphasizes that unipolar depressed patients experiencing a relatively high number of recurrences should be followed more closely, or at least be informed about the possible increased risk of conversion. PMID- 27997877 TI - Effects of low-dose atrial natriuretic peptide infusion on cardiac surgery associated acute kidney injury: A multicenter randomized controlled trial. AB - PURPOSE: To evaluate the effects of atrial natriuretic peptide (ANP) on renal function and medical costs in patients with acute kidney injury (AKI) associated with cardiac surgery. MATERIALS AND METHODS: The Japanese trial for AKI in Post cardiovascular surgery patients by ANP (JAPAN) was a prospective, multicenter, randomized, double-blind, placebo-controlled study conducted in 11 hospitals in Japan. Acute kidney injury was defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours. The patients were randomly assigned to receive ANP (0.02 MUg kg-1 min-1) or placebo. The primary end point was a change in renal function. The secondary end points were a need for renal replacement therapy, the lengths of intensive care unit and hospital stays, and medical costs incurred over the 90-day follow-up. RESULTS: Of the 77 randomized patients, 37 were in the ANP group and 40 were in the placebo group. Although ANP significantly (P = .018) increased urine output, it did not significantly improve renal function compared with placebo. There were no significant differences between the groups in the renal replacement therapy rate, the lengths of the intensive care unit and hospital stays, or medical costs. CONCLUSION: Atrial natriuretic peptide infusion did not show a renoprotective effect or cost-saving effect in the treatment of cardiac surgery-associated AKI. PMID- 27997878 TI - Design and synthesis of novel 2-substituted 11-keto-boswellic acid heterocyclic derivatives as anti-prostate cancer agents with Pin1 inhibition ability. AB - A series of novel acetyl-11-keto-beta-boswellic acid (AKBA) derivatives with a different electron-withdrawing group on ring A and a nitrogen heterocycle at C-24 were designed and synthesized. These semi-synthetic compounds showed improved anti-proliferative activity against prostate cancer cells over AKBA. Compound 8f bearing 2-cyano-3,11-dioxo moiety and piperazine was the most potent to inhibit growth of prostate cancer PC-3 (IC50 = 0.04 MUM) and LNCaP (IC50 = 0.27 MUM) cell lines. 8f caused cell cycle arrest in G2/M and induced apoptosis. 8f decreased the protein levels of anti-apoptosis protein Mcl-1, c-FLIP and cell cycle regulating protein cyclin D1. 8f inhibited the activity of Pin1, a peptidyl prolyl cis-trans isomerase to stabilize cyclin D1. 8f represented a compound with improved anti-proliferative effects for prostate cancer therapy working through new mechanisms. PMID- 27997879 TI - Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase. AB - Aberrant cellular metabolism drives cancer proliferation and metastasis. ATP citrate lyase (ACL) plays a critical role in generating cytosolic acetyl CoA, a key building block for de novo fatty acid and cholesterol biosynthesis. ACL is overexpressed in cancer cells, and siRNA knockdown of ACL limits cancer cell proliferation and reduces cancer stemness. We characterized a new class of ACL inhibitors bearing the key structural feature of the natural product emodin. Structure-activity relationship (SAR) study led to the identification of 1d as a potent lead that demonstrated dose-dependent inhibition of proliferation and cancer stemness of the A549 lung cancer cell line. Computational modeling indicates this class of inhibitors occupies an allosteric binding site and blocks the entrance of the substrate citrate to its binding site. PMID- 27997880 TI - Synthesis and antimicrobial evaluation of novel analogues of dehydroabietic acid prepared by CH-Activation. AB - Dehydroabietic acid (DHAA) plays an important role in drug discovery. Its modification at chemically reactive positions has been exploited to a large extent over the last decades, generating a wide range of analogues. In contrast, introduction of substituents at chemically inert positions remains a sizeable challenge. Hereby we wish to report the synthesis of a first series of C-19 arylated DHAA-analogues by application of a simple CH activation protocol, as well as their antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA). PMID- 27997881 TI - Mapping cross-border collaboration and communication in cardiovascular research from 1992 to 2012. AB - Aims: The growing burden of cardiovascular disease requires growth in research and innovation. We examine world-wide participation and citation impact across the cardiovascular research landscape from 1992 to 2012; we investigate cross fertilization between countries and examine whether cross-border collaboration affects impact. Methods and Results: State-of-the-art bibliometric methods and indicators are used to identify cardiovascular publications from the Web of Science, and to map trends over time in output, citation impact, and collaboration. The publication output in cardiovascular research has grown steadily from 1992 to 2012 with increased participation worldwide. China has the highest growth as relative share. The USA share initially predominated yet has reduced steadily. Over time, the EU-27 supra-national region has increased its participation above the USA, though on average it has not had greater citation impact than the USA. However, a number of European countries, as well as Australia and Canada, have improved their absolute and relative citation impact above that of the USA by 2006-2012. Europe is a hub of cross-fertilization with strengthening collaborations and strong citation links; the UK, Germany, and France remain central in this network. The USA has the highest number of strong citation links with other countries. All countries, but especially smaller, highly collaborative countries, have higher citation impact for their internationally collaborative research when compared with their domestic publications. Conclusion: Participation in cardiovascular research is growing but growth and impact show wide variability between countries. Cross-border collaboration is increasing, in particular within the EU, and is associated with greater citation impact. PMID- 27997882 TI - Mutations in Genes Coding for Synaptonemal Complex Proteins and Their Impact on Human Fertility. AB - Human infertility is often classified as idiopathic in both males and females. Meiotic errors may account for at least part of these cases. As the synaptonemal complex (SC, a meiosis-specific protein scaffold) is essential for successful meiosis progression, in this paper, we analyzed the mutations in genes coding for SC components described in infertile patients to assess to what extent alterations in the SC can be related to human infertility. So far, mutations in SYCP3 and SYCE1 genes have been reported. While most SYCP3 mutations are heterozygous mutations with dominant-negative effect on the region encoding the C terminal coiled coil of the protein, SYCE1 mutations are homozygous, which is consistent with a recessive inheritance. Similarities and differences between males and females as well as between mice and humans have been found and are discussed herein. The results suggest that a low percentage of human infertility cases may be explained by mutations in genes coding for SC components. The characterization of these mutations, together with available information from the study of knockout mice, will enable a deeper understanding of the underlying molecular bases for some of the cases of idiopathic infertility. PMID- 27997883 TI - Human Immunodeficiency Virus Lymphadenitis Patterns on Fine-Needle Aspiration Cytology. AB - OBJECTIVE: The aim of this work was to study the microscopic patterns of human immunodeficiency virus (HIV) lymphadenitis on fine-needle aspiration cytology (FNAC) and correlate them with cluster of differentiation 4 (CD4) counts. STUDY DESIGN: A retrospective study of known HIV-positive patients who underwent lymph node FNAC over a period of 5 years (2009-2013) was undertaken. The cytology slides were retrieved and reviewed. Out of 317 cases, 38 (11.7%) were diagnosed as HIV lymphadenitis. We analysed the cytomorphological patterns of HIV lymphadenitis and correlated them with the CD4 cell counts. RESULTS: Smears of HIV lymphadenitis were classified akin to histology patterns (A, B, and C) depending on cellularity, number of tingible body macrophages, mitosis, apoptotic bodies, plasma cells, Warthin-Finkeldey giant cells, and proliferating blood vessels. Thirty-one cases showed pattern A, 3 showed pattern B, and 4 were of pattern C. Pattern A had the highest CD4 cell count. CONCLUSION: Histologic patterns of HIV lymphadenitis are recognisable on FNAC smears. These can offer a clue to the diagnosis and guide further workup, even in the absence of history. The changes can mimic those of the infective lymphadenitis, Castleman disease, and lymphoma. Hence, the clinical history, serological correlation, and awareness of cytomorphology can aid the correct diagnosis. PMID- 27997885 TI - Streptozotocin Inhibits Electrophysiological Determinants of Excitatory and Inhibitory Synaptic Transmission in CA1 Pyramidal Neurons of Rat Hippocampal Slices: Reduction of These Effects by Edaravone. AB - BACKGROUND: Streptozotocin (STZ) has served as an agent to generate an Alzheimer's disease (AD) model in rats, while edaravone (EDA), a novel free radical scavenger, has recently emerged as an effective treatment for use in vivo and vitro AD models. However, to date, these beneficial effects of EDA have only been clearly demonstrated within STZ-induced animal models of AD and in cell models of AD. A better understanding of the mechanisms of EDA may provide the opportunity for their clinical application in the treatment of AD. Therefore, the purpose of this study was to investigate the underlying mechanisms of STZ and EDA as assessed upon electrophysiological alterations in CA1 pyramidal neurons of rat hippocampal slices. METHODS: Through measures of evoked excitatory postsynaptic currents (eEPSCs), AMPAR-mediated eEPSCs (eEPSCsAMPA), evoked inhibitory postsynaptic currents (eIPSCs), evoked excitatory postsynaptic current paired pulse ratio (eEPSC PPR) and evoked inhibitory postsynaptic current paired pulse ratio (eIPSC PPR), it was possible to investigate mechanisms as related to the neurotoxicity of STZ and reductions in these effects by EDA. RESULTS: Our results showed that STZ (1000 uM) significantly inhibited peak amplitudes of eEPSCs, eEPSCsAMPA and eIPSCs, while EDA (1000 uM) attenuated these STZ-induced changes at holding potentials ranging from -60mV to +40 mV for EPSCs and -60mV to +20 mV for IPSCs. Our work also indicated that mean eEPSC PPR were substantially altered by STZ, effects which were partially restored by EDA. In contrast, no significant effects upon eIPSC PPR were obtained in response to STZ and EDA. CONCLUSION: Our data suggest that STZ inhibits glutamatergic transmission involving pre-synaptic mechanisms and AMPAR, and that STZ inhibits GABAergic transmission by post synaptic mechanisms within CA1 pyramidal neurons. These effects are attenuated by EDA. PMID- 27997886 TI - The Clinicopathological Significance of Epigenetic Silencing of VHL Promoter and Renal Cell Carcinoma: A Meta-Analysis. AB - BACKGROUND/AIMS: Von Hippel-Lindau gene (VHL) has been reported as a tumor suppressor gene in some cancers. However, the association between VHL promoter hypermethylation and renal cell carcinoma (RCC) remains to be clarified. We are the first to systematically integrate published papers to assess the role of hypermethylated VHL in RCC. METHODS: The potential relevant papers were searched via PubMed, Embase, EBSCO, CNKI, and Wanfang databases. The overall odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to evaluate the relationship between VHL promoter hypermethylation and RCC. RESULTS: Finally, a total of 1,998 RCC patients and 294 controls from 13 eligible articles were included in this meta-analysis. Under the fixed-effects model, the pooled OR from seven studies including 596 RCC and 294 nonmalignant samples showed that VHL promoter hypermethylation was significantly higher in cancer than in controls (OR = 7.93, 95% CI = 2.84- 22.15, P < 0.001). Subgroup analysis based on ethnic population and testing method revealed that hypermethylated VHL had a significantly similar OR value in different races and detection methodologies. No significant association was found between hypermethylated VHL and tumor grade, tumor stage, tumor size, histological types, and lymph node status in cancer (all P > 0.05). In the current study, there was no evidence of publication bias as determined by Egger's test (all P > 0.05). CONCLUSIONS: In the investigated patients, VHL promoter hypermethylation, which may play an important role in carcinogenesis of RCC, is significantly associated with an increased risk of RCC. However, VHL promoter hypermethylation is not correlated with specific clinicopathological characteristics. Additional future studies are needed to confirm our results. PMID- 27997884 TI - The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels. AB - BACKGROUND/AIMS: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. METHODS: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. RESULTS: We show that currents carried by Kv7.1 (EC50 = 1.48 MUM), Kv7.1/KCNE1 (EC50 = 4.9 MUM), and Kv7.4 (EC50 = 0.148 MUM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1. CONCLUSION: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug. PMID- 27997887 TI - Bleomycin Suppresses the Proliferation and the Mobility of Human Gastric Cancer Cells Through the Smad Signaling Pathway. AB - BACKGROUND/AIMS: Extensive studies have demonstrated that Bleomycin (BLM) is a glycopeptide antibiotic that has been used as an anticancer chemotherapeutic reagent. It can induce both single- and double-strand DNA damage, inhibit synthesis of DNA, suppress proliferation, and induce apoptosis in cancer cells. Smad signaling transducers are considered as important molecules in tumor development and progression, and may closely be related to the biological behaviors of some malignant carcinomas, including gastric cancer. METHODS: The effects of different concentrations of BLM on the proliferation, cell cycle, apoptosis, migration, and invasion on gastric cancer cell lines MKN45 and AGS were assayed by using CCK-8 assay, Annexin V/PI double staining, PI staining, and transwell assay. Western blot and Immunohistochemistry were applied to analyze the potential mechanism(s). RESULTS: BLM treatment resulted in a low proliferation, high apoptosis, low migration and invasion in MKN45 and AGS cells. Furthermore, the possible mechanisms underlying that Smad3 activity could be changed after binding with BLM, and subsequently the Smad signaling pathway had a cascade response. CONCLUSION: These results highlight BLM as an exciting theme for gastric cancer treatment, which may represent an effective clinical therapeutic reagent for gastric cancer patients. PMID- 27997888 TI - RASD1 Knockdown Results in Failure of Oocyte Maturation. AB - BACKGROUND: Ras dexamethasone-induced protein (RASD1) is a member of Ras superfamily of small GTPases. RASD1 regulates various signaling pathways involved in iron homeostasis, growth hormone secretion, and circadian rhythm. However, RASD1 function in oocyte remains unknown. METHODS: Using immunohistochemistry, immunofluorescence, and quantitative real-time RT-PCR, RASD1 expression in mouse ovary and RASD1 role in oocyte maturation-related gene expression, spindle formation, and chromosome alignment were analyzed. RNAi microinjection and time lapse video microscopy were used to examine the effect of Rasd1 knockdown on oocyte maturation. RESULTS: RASD1 was highly detected in oocytes transitioning from primordial to secondary follicles. Rasd1 was highly expressed in germinal vesicle (GV), during GV breakdown, and in metaphase I (MI) stage as oocytes mature, and its expression was significantly downregulated in MII stage. With knockdown of Rasd1, maturation in GV oocytes was arrested at MI stage, showing disrupted meiotic spindling and chromosomal misalignment. In addition, Obox4 and Arp2/3, engaged in MI-MII transition and cytokinesis, respectively, were misregulated in GV oocytes by Rasd1 knockdown. CONCLUSION: These findings suggest that RASD1 is a novel factor in MI-MII oocyte transition and may be involved in regulating the progression of cytokinesis and spindle formation, controlling related signaling pathways during oocyte maturation. PMID- 27997889 TI - MiR-22 may Suppress Fibrogenesis by Targeting TGFbetaR I in Cardiac Fibroblasts. AB - BACKGROUND/AIMS: Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure, but the mechanisms undelying cardiac fibrosis remained unknown. microRNAs (miRNAs) are novel mechanisms leading to fibrotic diseases, including cardiac fibrosis. Previous studies revealed that miR-22 might be a potential target. However, the roles and mechanisms of miR-22 in cardiac fibrosis remained ill defined. The present study thus addressed the impact of miR-22 in cardiac fibrosis. METHODS: After seven days following coronary artery occlusion in mice, tissues used for histology were collected and processed for Masson's Trichrome staining. In addition, cardiac fibroblasts were transfected with mimics and inhibitors of miR 22 using Lipofectamin 2000, and luciferase activity was measured in cell lysates using a luciferase assay kit. Western blotting was used to detect the expression of collagen1, alpha-SMA and TGFbetaRI proteins levels, and real time-PCR was employed to measure the Col1alpha1, Col3alpha1, miR-22 and TGFbetaRI mRNA levels. RESULTS: In this study, we found that miR-22 was dynamically downregulated following MI induced by permanent ligation of the left anterior descending coronary artery for 7 days, an effect paralleled by significant collagen deposition. Inhibition of miR-22 with AMO-22 resulted in increased expression of Col1alpha1, Col3alpha1 and fibrogenesis in cultured cardiac fibroblasts. Conversely, overexpression of miR-22 in cultured cardiac fibroblasts significantly abrogated angiotensin II-induced collagen formation and fibrogenesis. Furthermore, we found that TGFbetaRI is a direct target for miR-22, and downregulation of TGFbetaR may have mediated the antifibrotic effect of miR 22. CONCLUSION: Our data clearly demonstrate that miR-22 acts as a novel negative regulator of angiotensin II-induced cardiac fibrosis by suppressing the expression of TGFbetaRI in the heart and may represent a new potential therapeutic target for treating cardiac fibrosis. PMID- 27997890 TI - Potential Links between Cytoskeletal Disturbances and Electroneurophysiological Dysfunctions Induced in the Central Nervous System by Inorganic Nanoparticles. AB - Inorganic nanomaterials have been widely applied in biomedicine. However, several studies have noted that inorganic nanoparticles can enter the brain and induce cytoskeletal remodeling, as well as electrophysiological alterations, which are related to neurodevelopmental disorders and neurodegenerative diseases. The toxic effects of inorganic nanomaterials on the cytoskeleton and electrophysiology are summarized in this review. The relationships between inorganic NPs-induced cytoskeletal and electrophysiological alterations in the central nervous system remain obscure. We propose several potential relationships, including those involving N-methyl-D-aspartate receptor function, ion channels, transient receptor potential channels, and the Rho pathway. PMID- 27997891 TI - Endothelin Receptor Down-Regulation Mediated Ligand Regulation Mechanisms Protect Against Cellular Hypoxia Injury in Rat Vascular Endothelial Cells. AB - OBJECTIVE: Investigation of the effect of endothelin receptor A (ETaR)-targeting small interfering RNA (siRNA) on rat vascular endothelial cellular hypoxia injury, as well as its underlying mechanism. METHODS: An in vitro rat vascular smooth muscle cells - endothelial cells co-culture model was established and transfected with ETaR siRNA before hypoxia treatment. Cell culture supernatant, cellular protein and RNA were collected and examined at 0.5hrs, 1hrs, 2hrs, 4hrs, 8hrs, 16hrs, 24hrs and 48hrs of hypoxia with 1% oxygen. The time point at which the best silencing effect was achieved was chosen, eNOS inhibitor L-NAME was added, and post hypoxia cell culture supernatant, cellular protein and RNA was collected for further examination. RESULTS: After hypoxic treatment, endothelial 1 (ET-1) and ETaR expression levels gradually increased as oxygen deprivation extended. ET-1 and ETaR expression levels were significantly lower in the ETaR siRNA group compared with the Hypoxia group (P<0.001). Such difference peaked at 4hrs of hypoxia. ELISA examination of cell culture supernatant revealed that the amount of ET-1 and TGF-betain the ETaR siRNA group were significantly lower compared to the Hypoxia group at all times, while the amount of NO and eNOS was higher. After 4 hrs of hypoxia, Smad2, Smad3, HIF-1, TNF-alpha, IFN-gamma, IL-6, MCP-1, NF-kappab, ET-1 and ANG II mRNA expression in endothelial cells and ETaR mRNA expression in A-10 cells of the ETaR siRNA group were lower than those of the Hypoxia siRNA group, while such results were much higher in the L-NAME group. Western Blot results showed lower expression of ETaR in the ETaR siRNA group compared with the hypoxia and negative siRNA groups, as well as significantly higher ETaR expression in the L-NAME group compared with the ETaR siRNA group. PI3K and p-AKT expression levels were mildly elevated after mild oxygen deprivation, and ETaR siRNA was able to enhance such elevation induced by hypoxia. In the L-NAME group, PI3K and p-AKT expression was much higher than the ETaR siRNA group. PKG and sGC expression levels significantly descended after mild oxygen deprivation. While such levels were higher in the ETaR siRNA group, compared with the hypoxia and negative siRNA groups, the L-NAME group had lower levels of PKG and sGC compared with the ETaR siRNA group. CONCLUSION: ETaR siRNA is capable of down-regulating the expression of inflammatory and transcription factors among endothelial cells treated with hypoxia. Down-regulation of ET-1 is triggered by altered nucleus transcription factor activity through the sGC/PKG signal pathway, and results in enhanced eNOS activity through the PI3K/Akt signal pathway. We suspect this to be the mechanism of the protective effect of ETaR siRNA. PMID- 27997892 TI - The Role of TLR4 in M1 Macrophage-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells. AB - BACKGROUND/AIMS: Peritoneal fibrosis is a frequent complication of peritoneal dialysis that follows inflammation. It is recognized that epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs), plays a key role in fibrogenesis. However, the relationship between inflammatory macrophages and PMCs remains elusive. In this study, we investigated the effects of different polarized macrophages on EMT of HMrSV5 PMCs. METHODS: Monocytes were polarized to M1/M2 macrophages before being added to HMrSV5 in direct or indirect contact. Morphological changes of HMrSV5 were observed and toll-like receptors 4 (TLR4) on macrophage surfaces was detected using flow cytometry. EMT markers and intracellular signals of HMrSV5 cells were assessed using real time-PCR and WB. RESULTS: The typical epithelial cell morphology of HMrSV5 disappeared after co culture with M1 macrophages and was accompanied by decreased E-cadherin and increased alpha-SMA, suggesting HMrSV5 undergo EMT. These effects depended on direct contact between the two cells, as indirect contact or co-culture with M2 macrophages had no effect. Intriguingly, we found TLR4 surface receptors were activated on sorted M1 cells in co-culture, and related signal adaptors, such as TRIF, were obviously upregulated. CONCLUSION: Direct contact with M1 macrophages induces EMT of PMCs, during which TRIF-dependent TLR4 signaling pathway was activated. PMID- 27997893 TI - 1alpha,25(OH)2D3 Induces Actin Depolymerization in Endometrial Carcinoma Cells by Targeting RAC1 and PAK1. AB - BACKGROUND: Cell proliferation and motility require actin reorganization, which is under control of various signalling pathways including ras-related C3 botulinum toxin substrate 1 (RAC1), p21 protein-activated kinase 1 (PAK1) and actin related protein 2 (ARP2). Tumour cell proliferation is modified by 1alpha,25-Dihydroxy-Vitamin D3 (1alpha,25(OH)2D3), a steroid hormone predominantly known for its role in calcium and phosphorus metabolism. The present study explored whether 1alpha,25(OH)2D3 modifies actin cytoskeleton in Ishikawa cells, a well differentiated endometrial carcinoma cell line. METHODS: To this end, actin cytoskeleton was visualized by confocal microscopy. Globular over filamentous actin ratio was determined utilizing Western blotting and flow cytometry, transcript levels by qRT-PCR and protein abundance by immunoblotting. RESULTS: A 24 hour treatment with 1alpha,25(OH)2D3 (100 nM) significantly decreased RAC1 and PAK1 transcript levels and activity, decreased ARP2 protein levels and depolymerized actin. The effect of 1alpha,25(OH)2D3 on actin polymerization was mimicked by pharmacological inhibition of RAC1 and PAK1. CONCLUSIONS: 1alpha,25(OH)2D3 leads to disruption of RAC1 and PAK1 activity with subsequent actin depolymerization of endometrial carcinoma cells. PMID- 27997894 TI - Zedoarondiol Inhibits Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cells Proliferation via Regulating AMP-Activated Protein Kinase Signaling Pathway. AB - BACKGROUND/AIMS: Vascular smooth muscle cells (VSMCs) proliferation contributes significantly to atherosclerosis and in-stent restenosis. Platelet-derived growth factor-BB (PDGF-BB) plays a vital role in VSMCs proliferation. Zedoarondiol, a sesquiterpene lactone compound, has an anti-inflammatory activity. However, the role of zedoarondiol in PDGF-BB-mediated VSMCs proliferation remains unclear. In this study, we investigated the effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation and explored the possible mechanisms. METHODS: The inhibitory effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation were evaluated by direct cell counting and the Cell Counting Kit-8 (CCK-8) assay. DNA synthesis was examined by bromodeoxyuridine (BrdU) incorporation assay. Cell cycle was assessed by propidium iodide staining. Western blotting was performed to determine the expression of cyclin-dependent kinase 2 (CDK2), cyclin E, p53, p21, total and phosphorylated adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), mammalian target of rapamycin (mTOR), and p70 ribosomal protein S6 kinase (p70S6K). RESULTS: Zedoarondiol suppressed PDGF-BB-induced VSMCs proliferation and DNA synthesis, and induced cell cycle arrest in G0/G1 phase. In addition, zedoarondiol activated AMPK and ACC, inhibited the phosphorylation of mTOR and p70S6K, increased the expression of p53 and p21, and decreased the expression of CDK2 and cyclin E. Compound C (an AMPK inhibitor) abrogated, whereas 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR, an AMPK activator) enhanced zedoarondiol-mediated inhibition of VSMCs proliferation and DNA synthesis. CONCLUSION: Zedoarondiol inhibits PDGF-BB induced VSMCs proliferation via AMPK-mediated down-regulation of the mTOR/p70S6K pathway and up-regulation of the p53/p21 pathway. These findings suggest that zedoarondiol might be a promising compound against atherosclerosis and in-stent restenosis. PMID- 27997895 TI - Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is the third most common type of cancer worldwide. Sprouty proteins are modulators of mitogeninduced signal transduction processes and therefore can influence the process of cancerogenesis. The encoded protein of Sprouty homolog 4 (SPRY4) is associated with various human cancers. However, its biological role and clinical significance in CRC development and progression are unknown. METHODS: The aim of this study was to evaluate the expression and biological role of SPRY4 in colorectal cancer. qRT-PCR was performed to investigate the expression of SPRY4 in tumor tissues and corresponding non tumor colorectal tissues from 70 patients. The effect of SPRY4 on proliferation was evaluated by MTT and colony formation assays. CRC cells transfected with SPRY4 were injected into nude mice to study the effect of SPRY4 on tumorigenesis in vivo. RESULTS: The lower expression of SPRY4 was remarkably correlated with deep tumor invasion and advanced TNM stage. Multivariate analyses revealed that SPRY4 expression served as an independent predictor for overall survival. Using 5-aza treatment, we also observed that SPRY4 expression can be affected by DNA methylation. Further experiments revealed that overexpressed SPRY4 significantly inhibited CRC cell proliferation both in vitro and in vivo. CONCLUSION: Our study demonstrated that SPRY4 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that SPRY4 may be a potential diagnostic and prognostic target in patients with colorectal cancer. PMID- 27997896 TI - Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis. AB - BACKGROUND/AIMS: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis. METHODS: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared. RESULTS: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC. CONCLUSION: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis. PMID- 27997897 TI - Plasma Gelsolin Promotes Proliferation of Mesangial Cell in IgA Nephropathy. AB - BACKGROUND/AIMS: Plasma gelsolin (pGSN) is an actin-binding protein that plays a critical role in the pathogenesis of rheumatoid arthritis. However, whether pGSN is involved in other immunological diseases remains unknown. This study focused on the relationship between pGSN and immunoglobulin A (IgA) nephropathy (IgAN). METHODS: Two hundred patients with IgAN, 200 patients each with several other types of nephropathy and healthy controls (HCs) who underwent kidney biopsies between 2000 and 2014 were enrolled in the study. The Oxford classification system was used to predict the risk of disease progression. Serum and renal tissue were used to detect pGSN, and the correlations between pGSN and IgA, galactose-deficient IgA1 (Gd-IgA1), transforming growth factor beta1 (TGF-beta1), fibronectin (FN) content, clinical symptoms, and kidney function were analyzed. RESULTS: We found that the pGSN levels were significantly decreased in sera from IgAN patients compared to sera from patients with other forms of glomerular nephritis and HCs. Furthermore, the serum pGSN levels were negatively correlated with the serum IgA1, FN, and TGF-beta1 levels, and positively correlated with the estimated glomerular filtration rate. Conversely, the glomerular pGSN content was significantly elevated in the IgAN patients and was positively correlated with TGF-beta1 and FN levels. In renal tissue, the pGSN levels were significantly higher in IgAN patients with M1 and S1 compared to patients with M0 and S0 (p < 0.05). Meanwhile, pGSN promoted human mesangial cell (HMC) proliferation by facilitating cell mitosis in vitro. pGSN also promoted integrin alpha2beta1 expression in HMCs and enhanced the integrin alpha2beta1-pGSN interaction. CONCLUSION: Our study suggested that pGSN may play an important role in the development of IgAN by promoting the proliferation of mesangial cells and that serum and glomerular pGSN levels may be new markers for predicting IgAN progression and prognosis. PMID- 27997898 TI - Mechanisms of IhERG/IKr Modulation by alpha1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes. AB - BACKGROUND: The rapid delayed rectifier K+ current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. alpha1 adrenoceptors (alpha1-AR) activation reduces IKr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the alpha1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which alpha1-AR stimulation regulates IKr. METHODS: alpha1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP2-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. IKr was recorded in isolated feline cardiac myocytes. RESULTS: Activation of the alpha1-AR reduces the amplitude of IhERG and IKr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the alpha1-AR to the hERG channel in HEK293 cells includes activation of the Galphaq protein, PLC activation and PIP2 hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC mediated IKr channel phosphorylation and subsequent IKr reduction after alpha1-AR stimulation was corroborated in feline cardiac myocytes. CONCLUSIONS: These findings clarify the link between sympathetic nervous system hyperactivity and IKr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation. PMID- 27997899 TI - Bufalin Inhibits hTERT Expression and Colorectal Cancer Cell Growth by Targeting CPSF4. AB - BACKGROUND/AIMS: Bufalin can induce apoptosis in certain human cancer cell lines, but bufalin has not yet been thoroughly evaluated in colorectal cancer cells. Cleavage and polyadenylation specific factor 4 (CPSF4) and human telomerase reverse transcriptase (hTERT) play important roles in colorectal cancer growth. The aim of this study was to investigate the roles and interactions of bufalin, CPSF4 and hTERT and the effects of bufalin in human colorectal cancer. METHODS: We treated LoVo and SW620 cells with bufalin to investigate the effect of bufalin on proliferation, apoptosis and migration. We verified the relationship between CPSF4 and hTERT using pulldown assays, luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. RESULTS: Bufalin inhibited the proliferation and migration of and induced apoptosis in LoVo and SW620 cells. We identified CPSF4 as an hTERT promoter-binding protein in colorectal cancer cells. CONCLUSION: Our study identified bufalin as a potential small molecule inhibitor for cancer therapy. PMID- 27997900 TI - A Difference in the Incidences of Hypersensitivity Reactions to Original and Generic Taxanes. AB - PURPOSE: To compare incidences of hypersensitivity reaction (HSR) between original and generic taxanes including paclitaxel and docetaxel. METHODS: We conducted a prospective study enrolling all patients receiving taxanes at King Chulalongkorn Memorial Hospital. Taxanes were infused accordingly to the step wise rate escalation protocol at this hospital. Active surveillance for HSRs was performed. During the study period, there was only 1 generic brand used for each taxane. We primarily compared the incidences of HSR between original and generic drugs for each taxane. RESULTS: During the period from January 1 to December 31, 2013, a total of 258 consecutive patients receiving taxanes were enrolled; 128 received paclitaxel, i.e. 65 and 63 in the original (Taxol) and generic arms, respectively, and 130 received docetaxel, i.e. 66 and 64 in the original (Taxotere) and generic arms, respectively. Premedication, including antihistamines and dexamethasone, was administered to all patients 30 min before taxane infusion. There were 26 (10.0%) HSR events including 24 grade 2 and 2 grade 3 HSRs. In the paclitaxel group, there were 9 (13.8%) and 7 (11.1%) HSRs in the original and generic arms, respectively (p = 0.791). In the docetaxel group, there were 9 (13.6%) and 1 (1.6%) HSRs in the original and generic arms, respectively (p = 0.017). No life-threatening symptoms or permanent discontinuation of taxanes occurred. CONCLUSIONS: In this prospective study, the incidences of HSR were similar with generic and original paclitaxel but significantly different with generic and original docetaxel. PMID- 27997901 TI - MiR-520b/e Regulates Proliferation and Migration by Simultaneously Targeting EGFR in Gastric Cancer. AB - BACKGROUND: MicroRNAs (miRNAs) have been demonstrated to play a crucial role in tumorigenesis. Previous studies have shown that miR-520b/e acts as a tumor suppressor in several tumors. Other studies indicated that epidermal growth factor receptor (EGFR) is highly expressed in many tumors, and involved in the development of tumors, such as cell proliferation, migration, angiogenesis and apoptosis. However, the correlation of miRNAs and EGFR in gastric cancer (GC) has not been adequately investigated. Our aim was to explore the relationship. METHODS: The expression levels of EGFR and miR-520b/e were examined by RT-PCR and Western blot. We also investigated the relationship between EGFR and miR-520b/e in GC cell lines by relevant experiments. RESULTS: In this study, we found that miR-520b/e inhibits the protein expression of EGFR by directly binding with the 3'-untranslated region (3'-UTR). And it was shown that the down-regulation of miR 520b/e promotes cell proliferation and migration by negative regulation of the EGFR pathway, while over-expression of miR-520b/e inhibits these properties. In addition, the biological function of EGFR in GC cell lines was validated by silencing and over-expression assays respectively. CONCLUSIONS: Taken together, our results demonstrate that miR-520b/e acts as a tumor suppressor by regulating EGFR in GC, and provide a novel marker and insight for the potential therapeutic target of GC. PMID- 27997902 TI - Didymin Alleviates Hepatic Fibrosis Through Inhibiting ERK and PI3K/Akt Pathways via Regulation of Raf Kinase Inhibitor Protein. AB - BACKGROUND: Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined. METHODS: Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP) and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot. RESULTS: Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin. CONCLUSION: Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression. PMID- 27997903 TI - Circular RNA Expression Profile of Pancreatic Ductal Adenocarcinoma Revealed by Microarray. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) are a special novel type of a stable, diverse and conserved noncoding RNA in mammalian cells. Particularly in cancer, circRNAs have been reported to be widely involved in the physiological/pathological process of life. However, it is unclear whether circRNAs are specifically involved in pancreatic ductal adenocarcinoma (PDAC). METHODS: We investigated the expression profile of circRNAs in six PDAC cancer samples and paired adjacent normal tissues using microarray. A high-throughput circRNA microarray was used to identify dysregulated circular RNAs in six PDAC patients. Bioinformatic analyses were applied to study these differentially expressed circRNAs. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm these results. RESULTS: We revealed and confirmed that a number of circRNAs were dysregulated, which suggests a potential role in pancreatic cancer. CONCLUSIONS: this study demonstrates that clusters of circRNAs are aberrantly expressed in PDAC compared with normal samples and provides new potential targets for the future treatment of PDAC and novel insights into PDAC biology. PMID- 27997904 TI - The Relationship of Plasma miR-29a and Oxidized Low Density Lipoprotein with Atherosclerosis. AB - BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory condition associated with a variety of vascular diseases. Previous studies showed that both miR-29a and oxidized low density lipoprotein (ox-LDL) were vital in the development of atherosclerosis. However, the relationship between miR-29a and ox-LDL remains unknown. This study was designed to investigate the association of miR-29a and ox LDL and to test whether circulating miR-29a and ox-LDL levels could predict atherosclerosis. METHODS: In 170 participants, plasma levels of miR-29a were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) while plasma ox-LDL levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. The relationship between miR-29a level and ox-LDL and carotid intima-media thickness (cIMT) was assessed using the Spearman correlation coefficient and multiple liner regression. RESULTS: Compared with the normal cIMT group, the increased cIMT group had higher levels of ox-LDL (0.47 +/- 0.08 vs 0.29 +/- 0.06 ng/ml, p = 0.003) and miR-29a (32.93 +/- 4.26 vs 26.37 +/- 1.04, p < 0.001). A positive correlation was found between ox-LDL and miR-29a (r = 0.695, p < 0.001), and both the ox-LDL (r = 0.857, p < 0.001) and the miR-29a (r = 0.753, p < 0.001) were positively related to cIMT. Furthermore, multiple liner regression indicated that a significant correlation between ox-LDL and cIMT (beta = 0.768, p < 0.001), as well as between miR-29a and cIMT (beta = 0.686, p <0.001). The combination of miR-29a and ox-LDL (AUC = 0.926, p < 0.001) offered a better predictive value for atherosclerosis than either miR-29a (AUC = 0.759, p < 0.001) or ox-LDL (AUC = 0.762, p < 0.001) alone. CONCLUSION: Increased miR-29a and ox-LDL levels were associated with an early stage of atherosclerosis, and the combination of miR-29a and ox-LDL offered better predictive values for atherosclerosis than either alone. PMID- 27997905 TI - Blocking Mammalian Target of Rapamycin (mTOR) Attenuates HIF-1alpha Pathways Engaged-Vascular Endothelial Growth Factor (VEGF) in Diabetic Retinopathy. AB - BACKGROUND/AIMS: Prior studies demonstrate that hypoxia inducible factor subtype 1alpha (HIF-1alpha) in retinal tissues is involved in development of diabetic retinopathy (DR). In this report, we particularly examined the role played by mammalian target of rapamycin (mTOR) in regulating expression of HIF-1alpha and its downstream pathway, namely vascular endothelial growth factor (VEGF). METHODS: Streptozotocin (STZ) was systemically injected to induce hyperglycemia in rats. ELISA and Western Blot analysis were employed to determine the levels of HIF-1alpha and VEGF as well as expression of mTOR pathways in retinal tissues of control rats and STZ rats. RESULTS: Our results show that HIF-1alpha and VEGF as well as VEGF receptor subtype 2 (VEGFR-2) were increased in STZ rats. Also, the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in diabetic retina compared with controls. Blocking mTOR by using rapamycin significantly attenuated activities of HIF-1alpha and VEGF signaling pathways. CONCLUSION: Our data for the first time revealed specific signaling pathways engaged in the development of DR, including the activation of mTOR and HIF-1alpha -VEGF mechanism. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of DR often observed in clinics. PMID- 27997906 TI - Effects of Leptin on Na+/Ca2+ Exchanger in PC12 Cells. AB - BACKGROUND/AIMS: Alzheimer's disease (AD) is known to be related to alterations in neuronal intracellular calcium activity ([Ca2+]i). The present study revealed the distinct role of leptin in Na+/Ca2+-exchanger activity. METHODS: [Ca2+]i was determined utilizing Fura-2 fluorescence. The activity of NCX was measured by removal of extracellular Na+ in the presence of external Ca2+. Na+/Ca2+-exchanger activity was further quantified from whole cell currents following removal of extracellular Na+. Na+/Ca2+-exchanger isoform NCX1 transcript levels and protein abundance were quantified by RT-PCR and Western blotting, respectively. RESULTS: Exposure of PC12 cells to 30 uM amyloid (Abeta42) increased [Ca2+]i, an effect significantly blunted by 6 hours incubation with leptin before Abeta42 treatment. Moreover, leptin treatment significantly increased Na+/Ca2+-exchanger mediated Ca+ transport and current, NCX1 transcript level as well as NCX1 membrane protein abundance. CONCLUSION: We show that leptin blunts Abeta42-evoked [Ca2+]i increase by increasing expression and activity of Na+/Ca2+-exchanger NCX1. PMID- 27997907 TI - Improvement of Huangqi Decoction on Endothelial Dysfunction in 5/6 Nephrectomized Rats. AB - BACKGROUND/AIMS: Endothelial dysfunction is a major factor in the progression of chronic kidney disease, which correlates with oxidative stress and NO deficiency. Huangqi decoction (HQD) is a potential anti-oxidant ingredient in renoprotection. However, the underlying mechanisms remained identified. Therefore, we investigated whether HQD exhibit improvement in endothelial dysfunction in the 5/6 nephrectomy (Nx) rat model. METHODS: Male Wistar rats (180 - 250 g) were divided into sham, Nx and Nx + HQD (0.05, 0.15 and 0.45 g/kg) group, respectively. Renal function and histology were examined with ELISA and Immunohistochemical analysis. Endothelium-dependent relaxation of rat aortas was investigated by isometric tension recordings. Oxidative stress and NO bioavailability were detected by ELISA, DHE-staining, DAF-2 staining and western blotting. RESULTS: Compared with Nx rats, HQD treatment reversed the functional and structural changes of kidney significantly. Besides, endothelium-dependent relaxation of rat aortas was also improved by HQD treatment. NADPH oxidase and ROS generation were inhibited while NO bioavailability was enhanced. CONCLUSION: HQD can act as a potent prescription for the treatment of endothelium related vascular complications. PMID- 27997908 TI - Circulating Long Non-Coding RNAs Act as Biomarkers for Predicting 131I Uptake and Mortality in Papillary Thyroid Cancer Patients with Lung Metastases. AB - PURPOSE: The aims of the current study were to explore plasma lncRNAs as a novel biomarker panel for the diagnosis of non-131I-avid lung metastases of PTC and to investigate the plasma lncRNA expression levels associated with survival in PTC patients with lung metastases. METHODS: The expression of lncRNAs was examined using an lncRNA microarray chip. The lncRNAs with the most significant difference in expression between PTC patients with non-131I-avid lung metastases and PTC patients with 131I-avid lung metastases were verified by quantitative reverse transcription polymerase chain reaction. The Kaplan-Meier method was used to determine whether the plasma lncRNA levels might be indicative of patient prognosis. RESULTS: Compared with 131I-avid lung metastases, we discovered that two lncRNAs (ENST00000462717 andENST00000415582) were upregulated and two (TCONS_00024700 and NR_028494) were downregulated in the non-131I-avid lung metastases of PTC. Receiver operating characteristic curve (ROC) analyses indicated that the use of these four lncRNAs had high diagnostic sensitivity and specificity for predicting non-131I-avid lung metastases of PTC. The merged areas under the curve for ENST00000462717, ENST00000415582, TCONS_00024700,and NR_028494 in the training and validation sets were 0.890, 0.936, 0.975, and 0.918, respectively. Low (ENST00000462717 and ENST00000415582) and high plasma lncRNA levels(TCONS_00024700and NR_028494) were also found to be associated with better prognosis of PTC patients with lung metastases(P<0.001). CONCLUSIONS: ENST00000462717, ENST00000415582, TCONS_00024700, and NR_028494 may be used as novel and minimally invasive markers for the diagnosis and prognostic assessment of non-131I-avid lung metastases from PTC. PMID- 27997909 TI - Eryptosis as an Underlying Mechanism in Systemic Lupus Erythematosus-Related Anemia. AB - BACKGROUND: The progression of systemic lupus erythematosus (SLE) leads to anemia in patients, adversely affecting prognosis. The diverse causes of anemia may include excessive eryptosis or premature suicidal erythrocyte death characterized by cell shrinkage and phosphatidylserine (PS) exposure on the cell surface. The present study explored if SLE enhances eryptosis and the underlying mechanisms. MATERIALS AND METHODS: Eryptosis was assessed using flow cytometry in healthy volunteers (n = 20) and anemic patients hospitalized for SLE (n = 22), for parameters including PS exposure, cell volume, cytosolic calcium ion (Ca2+) levels and reactive oxygen species (ROS) and ceramide abundance. These indicators were measured in erythrocytes of experimental subjects and erythrocytes treated with plasma from healthy volunteers or SLE patients. RESULTS: The hemoglobin and hematocrit levels were significantly lower in anemic SLE patients than in healthy volunteers (***p<0.001, p<0.001, respectively). The percentage of PS-exposing erythrocytes was significantly higher in SLE patients than in healthy volunteers (p<0.001), accompanied by an increase in cytosolic Ca2+ levels, oxidative stress. The measurements of PS and Ca2+ levels were significantly higher in the erythrocytes of healthy volunteers following incubation in plasma of SLE patients than in plasma of healthy volunteers for 24h (***p<0.001, *p<0.05 respectively). CONCLUSION: Eryptosis is enhanced in SLE and may contribute to anemia. The probable underlying mechanisms may be an excessive formation of ROS in erythrocytes. Also, some plasma components may trigger eryptosis by increasing the cytosolic Ca2+ concentration. PMID- 27997910 TI - Effects of CDKN2A (p16INK4A/p14ARF) Over-Expression on Proliferation and Migration of Human Melanoma A375 Cells. AB - OBJECTIVE: This study aims to investigate the effects of CDKN2A (p16INK4A/p14ARF) over-expression on the proliferation and migration of human melanoma A375 cells. METHODS: Melanoma tissues and pigmented nevi tissues were collected. Human melanoma A375 cells were transfected by CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expressing vectors and then assigned into blank, negative control (NC), p16INK4A and p14ARF groups. The expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein was detected by qRT-PCR and Western blotting. CCK-8, flow cytometry and Transwell assays were applied to observe cell proliferation, the cell cycle and apoptosis, and migration and invasion, respectively. The model of subcutaneous xenografts in nude mice was established to measure cell growth in vivo. RESULTS: Compared with pigmented nevi tissues, CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein expression were significantly decreased in melanoma tissues. CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expression inhibited proliferation, migration, invasion and progression from G0/G1 to S phase of A375 cells and xenograft tumor growth, but promoted apoptosis. CONCLUSION: Our study demonstrated that over-expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) suppressed proliferation and migration of human melanoma A375 cells. PMID- 27997912 TI - Analysis of the Indicating Value of Cardiac Troponin I, Tumor Necrosis Factor alpha, Interleukin-18, Mir-1 and Mir-146b for Viral Myocarditis among Children. AB - BACKGROUND/AIMS: The primary objective of this study is to evaluate the diagnosis effect of serum protein factors and microRNAs for children suffering from viral myocarditis (VMC). METHODS: The expression levels of serum cardiac troponin I (cTnI), interleukin-18 (IL-18) and tumor necrosis factor-alpha (TNF-alpha) in both VMC and control groups were examined by using the Elisa Kit. The expression levels of miR-1 and miR-146b were measured through RT-PCR. Subsequently, the Receiver Operating Characteristic (ROC) curves were drawn based on the diagnostic results of VMC. Moreover, the Spearman correlation analysis was carried out to unveil the association between the indicator expression levels and the ultrasonic cardiogram results, including the left ventricular fractional shortening (FS) and left ventricular ejection fraction (EF). RESULTS: It is found that the expression levels between the VMC and control group portrait significant differences with respect to cTnI, IL-18, TNF-alpha, miR-1 and mIR-146b (P < 0.05). The diagnostic thresholds for cTnI, IL-18, TNF-alpha were 160.00 ng/L, 2.26 ng/L and 1.14ng/L, respectively. The diagnostic thresholds for miR-1 and miR-146b were 0.75 and 1.27, respectively. Results from the Spearman correlation analysis showed that levels of the miR-1 were negatively correlated with FS and EF, while levels of the cTnI, IL-18, TNF-alpha and miR-146b were positively correlated with FS and EF. CONCLUSIONS: The expression levels of the TNF-alpha, IL-18 and cTnI and the expression levels of the miR-1 and miR-146b could be used to predict VMC among children and this approach may reinforce the diagnosis of VMC in clinical practices. PMID- 27997911 TI - Inhibition of Glutathione Synthesis Induced by Exhaustive Running Exercise via the Decreased Influx Rate of L-Cysteine in Rat Erythrocytes. AB - BACKGROUND/AIMS: The main purpose of this study was to investigate the effect of exhaustive exercise on L-cysteine uptake and its effect on erythrocyte glutathione (GSH) synthesis and metabolism. METHODS: Rats were divided into three groups: sedentary control (C), exhaustive running exercise (ERE) and moderate running exercise (MRE) (n=12 rats/group). We determined the L-cysteine efflux and influx in vitro in rat erythrocytes and its relationship with GSH synthesis. Total anti-oxidant potential of plasma was measured in terms of the ferric reducing ability of plasma (FRAP) values for each exercise group. In addition, the glucose metabolism enzyme activity of erythrocytes was also measured under in vitro incubation conditions. RESULTS: Biochemical studies confirmed that exhaustive running exercise significantly increased oxidative damage parameters in thiobarbituric acid reactive substances (TBARS) and methemoglobin levels. Pearson correlation analysis suggested that L-cysteine influx was positively correlated with erythrocyte GSH synthesis and FRAP values in both the control and exercise groups. In vitro oxidation incubation significantly decreased the level of glucose metabolism enzyme activity in the control group. CONCLUSION: We presented evidence of the exhaustive exercise-induced inhibition of GSH synthesis due to a dysfunction in L-cysteine transport. In addition, oxidative stress induced changes in glucose metabolism were the driving force underlying decreased L-cysteine uptake in the exhaustive exercise group. PMID- 27997913 TI - The Impact of Diabetes Mellitus on Patients Undergoing Cervical Spondylotic Myelopathy: A Meta-Analysis. AB - AIMS: We conducted a meta-analysis of eligible studies to compare the surgical outcomes between diabetic patients and non-diabetic patients who have undergone cervical spondylotic myelopathy (CSM). METHODS: A systematic literature search of PubMed, Embase, and Web of Science (up to February 10, 2016) was conducted. Eligible studies were case-control or cohort studies that compared the outcomes of cervical surgery between diabetic patients and non-diabetic patients. Weighted mean differences, risk ratios, and 95% CIs were calculated and heterogeneity was assessed with Cochrane Q chi-square test and I2 statistic. RESULTS: Six studies with a total of 38,680 patients were included in this meta-analysis. Pooled estimates showed that diabetic patients had significantly lower Japanese Orthopaedic Association (JOA) score change between pre- and post operation, and recovery rate than patients without diabetes. Moreover, diabetic patients had significantly increased risk of operative wound, epidural/wound hematoma, chronic lung disease, and cardiac complication. Other postoperative complications, including cerebrospinal fluid leakage and C5 radiculopathy, were not significantly different between the 2 groups. CONCLUSION: Diabetes mellitus decreased the JOA score change and recovery rate, as well as increased the risk of postoperative complications in patients undergoing CSM. Controlling diabetes mellitus before cervical spine surgery may lead to better outcomes. PMID- 27997914 TI - Can We Predict the Presence and Severity of Intra-Abdominal Adhesions before Cesarean Delivery. AB - AIMS: The study aimed to investigate whether we can predict the presence and severity of intra-abdominal adhesions before cesarean delivery using patient history, symptoms, and abdominal skin scar characteristics. METHODS: In this prospective study, 143 pregnant women with history of previous abdominal surgery were included and they delivered by cesarean. Preoperative abdominal scar characteristics and symptoms as well as intraoperative abdominal adhesions were evaluated using the Manchester Scar Scale, a symptomatology questionnaire and the More Comprehensive Adhesion Scoring Method, respectively. RESULTS: Patients with adhesions (n = 98) and without adhesions (n = 45) had similar baseline characteristics. In the adhesion group, abdominal scar scoring parameters were significantly increased. However, there was no significant correlation among total scar score, adhesion score, and symptom score. CONCLUSION: Despite the availability of many proposed methods, accurate prediction of the severity of surgery-related adhesions is beyond our current abilities. Therefore, as healthcare providers, obstetricians should avoid unnecessary use of the cesarean approach. This approach is more effective, beneficial, realizable, and reasonable than the prediction of surgery-related adhesions. PMID- 27997915 TI - New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus. AB - The goal of this review is the presentation of the new (Bulat-Klarica-Oreskovic) hypothesis of cerebrospinal fluid (CSF) physiology and the ensuing new concept of hydrocephalus development in light of this hypothesis. The widely accepted classic hypothesis of CSF physiology and the traditional concept of hydrocephalus are contradicted by numerous experimental and clinical data, which consequently results in unsatisfying clinical treatment and patient recovery. Therefore, the newly presented concept of hydrocephalus development and possible future treatments are discussed. A new definition suggests that hydrocephalus is a pathological state in which CSF is excessively accumulated inside the cranial part of the CSF system, predominantly in one or more brain ventricles as a consequence of impaired hydrodynamics of intracranial fluids between CSF, brain, and blood compartments. PMID- 27997916 TI - Circulating miR-181a as a Potential Novel Biomarker for Diagnosis of Acute Myocardial Infarction. AB - BACKGROUND: In this study, we tested the hypothesis that miR-181a levels increase during acute myocardial infarction. We investigated circulating miR-181a as a potential novel biomarker for early diagnosis of acute myocardial infarction (AMI). METHODS: From June 2014 to June 2016, 120 consecutive eligible patients with AMI (n = 60) or unstable angina (UA; n = 60) and 60 control subjects were enrolled. Plasma miR-181a levels were determined by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Circulating miR-181a expression levels detected immediately after admission were higher in the AMI group than in the UA and control groups. Relative miR-181a levels in AMI patients were positively correlated with the concentrations of the creatine kinase-MB fraction and cardiac troponin I. Correlation analysis showed that plasma miR-181a was positively correlated with coronary Gensini score (r = 0.573, P < 0.05) and negatively correlated with left ventricular ejection fraction (r = -0.489, P < 0.05). Receiver operating characteristic curve analyses showed that plasma miR 181a was of significant diagnostic value for AMI (AUC, 0.834; 95% CI, 0.756 0.912, P < 0.05). CONCLUSION: Circulating miR-181a levels in patients with AMI were significantly changed in a time-dependent manner, indicating the value of plasma miR-181a as a novel biomarker for diagnosing AMI. PMID- 27997917 TI - Cerebrospinal Fluid Findings in Neurological Diseases Associated with Sjogren's Syndrome. AB - BACKGROUND: Sjogren's syndrome is a chronic autoimmune-mediated disease that can cause a variety of neurological manifestations. METHODS: This study investigated characteristics of clinical and cerebrospinal fluid (CSF) features in patients with neurological diseases associated with Sjogren's syndrome. Eighty-two patients were examined separately according to the presence of Sjogren's syndrome alone or in combination with other autoimmune diseases. RESULTS: In the 47 patients with primary Sjogren's syndrome, peripheral neuropathy (57%) was found most frequently, followed by the involvement of the central nervous system (CNS; 17%), cranial neuropathy (15%), and myalgia (11%). These patients did not display consistent signs of inflammation in the CSF. Slight pleocytosis of 8-107 cells/uL was found in patients with peripheral neuropathy (9%), cranial neuropathy (20%), and CNS involvement (25%). Oligoclonal bands indicating intrathecal IgG synthesis occurred in 26% of patients with peripheral neuropathy, 20% of patients with cranial neuropathy, and 25% of patients with CNS involvement. CONCLUSIONS: In patients with Sjogren's syndrome and neurological manifestations, inflammatory CSF changes were rarely found and did not show a characteristic pattern irrespective of peripheral or central genesis of neurological deficits. Analysis of the CSF presents therefore an important diagnostic procedure to exclude other autoimmune and infectious diseases. PMID- 27997918 TI - Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients. AB - OBJECTIVE: This paper aims at studying the influence of single-nucleotide polymorphisms (SNPs) on cancer risk, tumor recurrence, and survival in head and neck (H&N) cancer patients. METHODS: A total of 45 SNPs in 41 genes were investigated. A total of 174 Caucasian H&N cancer patients and 245 healthy blood donors were enrolled in the study. RESULTS: Ten SNPs were associated with H&N cancer risk, but the identified SNPs differed among males and females. Some of the SNPs were related to immune response genes. The immune response gene SNPs were also related to survival. In particular, we noted that the tumor necrosis factor alpha (TNFalpha) rs1800629 could have an influence on cancer risk, tumor recurrence as well as survival. CONCLUSION: Genetic variation of the TNFalpha rs1800629 might be useful as a biomarker in clinical decision-making since it was found to be related to cancer risk, tumor recurrence, and survival of H&N cancer patients. PMID- 27997919 TI - Viability of Primary Human Pigment Epithelium Cells and Muller-Glia Cells after Intravitreal Ziv-Aflibercept and Aflibercept. AB - PURPOSE: The aim of this study was to access the safety profiles of 2 fusion proteins with anti-vascular endothelial growth factor action (ziv-aflibercept and aflibercept) on retinal pigment epithelium cells and Muller-Glia cells in culture by assessing cell viability post drug exposure. METHODS: Primary human retinal pigment epithelium cells (pRPE) and Muller-Glia cells (Mio-M1) were exposed to the clinical standardized concentrations of ziv-aflibercept (25 mg/mL) and aflibercept (40 mg/mL). Progressively higher concentrations of NaCl (300, 500, 1,000, 1,500, 2,000, 5,000, and 10,000 mosm/kg) were also applied to cells to assess the possibility of potentiating hyperosmotic cytotoxity effect. The study was applied to measure pRPE and Mio-M1 viability by a tetrazolium dye-reduction assay (XTT). RESULTS: Cell viability of both pRPE and Mio-M1 presented no significant changes after exposure of ziv-aflibercept and aflibercept. Progressive NaCl concentrations did not significantly alter cell viability. The exposure to the negative control of 75 uL/mL of dimethyl sulfoxide showed significant reduction in cell viability. CONCLUSIONS: At clinical doses, neither ziv-aflibercept nor aflibercept caused any significant reduction in cell viability in vitro. Furthermore, injection solutions of NaCl with higher osmolality caused no significant reduction in cell viability. PMID- 27997920 TI - Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids Syndrome: Diagnostic Challenge of the Brainstem Inflammation. PMID- 27997921 TI - One-Year Outcomes of the Treat-and-Extend Approach with Aflibercept in Age Related Macular Degeneration: Effects on Typical Choroidal Neovascularization and Retinal Angiomatous Proliferation. AB - OBJECTIVE: To investigate functional/morphological outcomes of the treat-and extend regimen (TER) with aflibercept in typical choroidal neovascularization (CNV) and retinal angiomatous proliferation (RAP) secondary to exudative age related macular degeneration (AMD). METHODS: This was a retrospective study of 37 eyes treated with 2 mg aflibercept according to a TER protocol. Examinations included best corrected visual acuity (BCVA), numbers of injections, and visits needed. Additionally, quantitative/qualitative analyses with fluorescein angiography and spectral- domain optical coherence tomography were conducted at baseline as well as at 3, 6, and 12 months. RESULTS: BCVA significantly improved from 0.6 +/- 0.27 to 0.4 +/- 0.34 logMAR. The final mean numbers of injections were 8.03 +/- 1.27 and 7.28 +/- 0.75 and the numbers of visits 6.5 +/- 1.09 and 7.14 +/- 1.57 in typical CNV and in RAP or atypical CNV, respectively, and they did not differ between the different subtypes of CNV (p > 0.05). CONCLUSIONS: Aflibercept in TER is effective for all exudative AMD subtypes. The patient's visual gain, the mean number of injections, and the number of visits needed did not depend on the subtype of CNV. PMID- 27997922 TI - Continuous Intraoperative Monitoring of Temporal Lobe Epilepsy Surgery. AB - BACKGROUND/AIMS: The monitoring of interictal epileptiform discharge rates (IEDRs) all along anterior temporal lobe resections (ATLRs) has never been reported. Here the effect of ATLR on continuous IEDR monitoring is described. METHODS: IEDRs computed automatically during entire interventions were recorded in 34 patients (38.2%, 13/34 depth; 61.8%, 21/34 scalp electrodes only). Monitorings were invalidated when burst suppression occurred or if initial IEDRs were <5. RESULTS: Monitoring was successful for 69.2% (9/13) of the patients with depth recordings and for 4.8% (1/21) of the patients with scalp recordings. Burst suppressions precluded it in 30.8% (4/13) of the depth and in 57.1% (12/21) of the scalp recordings. Initial IEDRs were <5 for 38.1% (8/21) of the scalp recordings. Significant IEDR decreases were observed in 8/10 patients with successful monitoring. These decreases started with resection of the superior temporal gyrus. IEDRs decreased further with amygdalohippocampectomy in 3/5 patients. At the 12-month follow-up, all patients with IEDR decreases remained seizure free; both patients without did not. CONCLUSION: IEDR monitoring was possible with depth, but not with scalp electrodes. IEDR decreases started with resection of the superior temporal gyrus. A larger patient cohort is necessary to confirm the high predictive values of IEDR monitoring that could become a tool for surgery customization. PMID- 27997923 TI - The Role of HMGB1 in Pial Arteriole Dilating Reactivity following Subarachnoid Hemorrhage in Rats. AB - High-mobility group box 1 protein (HMGB1) has been implicated in inflammatory responses, and is also associated with cerebral vasospasm after subarachnoid hemorrhage (SAH). However, there are no direct evident links between HMGB1 and cerebral vasospasm. We therefore investigated the effects of HMGB1 on pial arteriole reactivity following SAH in rats. We initially found that SAH induced a significant decrease in pial arteriole dilating responses to sciatic nerve stimulation (SNS), hypercapnia (CO2), and the topical suffusion of acetylcholine (ACh), adenosine (ADO), and s-nitroso-N-acetylpenicillamine (SNAP) over a 7-day period after SAH. The percent change of arteriolar diameter was decreased to the lowest point at 48 h after SAH, in response to dilating stimuli (i.e., it decreased from 41.0 +/- 19.0% in the sham group to 11.00 +/- 0.70% after SNS) (n = 5, p < 0.01). HMGB1 infusion in the lateral ventricle in normal rats for 48 h did not change the pial arteriole dilating response. In addition, inhibitors of HMGB1-receptor for advanced glycation end-product or HMGB1-toll-like receptor 2/4 interaction, or the HMBG1 antagonist did not improve pial arteriole reactivity 48 h after SAH. These findings suggest that HMGB1 may not be a major player in cerebral vascular dilating dysfunction after SAH. PMID- 27997924 TI - Test-Retest Reliability of Scotopic and Mesopic Fundus-Controlled Perimetry Using a Modified MAIA (Macular Integrity Assessment) in Normal Eyes. AB - PURPOSE: To assess the intrasession test-retest reliability of scotopic cyan and scotopic red fundus-controlled perimetry (FCP) in normal subjects using a modified MAIA "microperimeter" (macular integrity assessment) device. METHODS: Forty-seven normal eyes of 30 subjects (aged 33.8 years) underwent duplicate mesopic (achromatic stimuli, 400-800 nm), scotopic cyan (505 nm), and scotopic red (627 nm) FCP, using a grid of 49 stimuli over 14 degrees of the central retina. Test-retest reliability for pointwise sensitivity (PWS), stability of fixation, reaction time and test duration were analyzed using mixed-effects models. RESULTS: PWS test-retest reliability was good among all 3 types of retinal sensitivity assessments (coefficient of repeatability of 4.75 dB for mesopic, 5.26 dB for scotopic cyan, and 4.06 dB for scotopic red testing). While the mean sensitivity decreased with eccentricity for both mesopic and scotopic red testing, it was highest at 7 degrees eccentricity for the scotopic cyan assessment (p < 0.001). CONCLUSIONS: The modified MAIA device allows for reliable scotopic FCP in normal subjects. Our findings suggest that testing of scotopic cyan sensitivity largely reflects rod function. PMID- 27997925 TI - Immunothrombosis in Acute Respiratory Distress Syndrome: Cross Talks between Inflammation and Coagulation. AB - Acute respiratory distress syndrome (ARDS) is defined as a syndrome of acute onset, with bilateral opacities on chest imaging and respiratory failure not caused by cardiac failure, leading to mild, moderate, or severe oxygenation impairment. The syndrome is most commonly a manifestation of sepsis-induced organ dysfunction, characterized by disruption of endothelial barrier integrity and diffuse lung damage. Imbalance between coagulation and inflammation is a predominant characteristic of ARDS, leading to extreme inflammatory response and diffuse fibrin deposition in vascular capillary bed and alveoli. Activated platelets, neutrophils, endothelial cells, neutrophil extracellular traps, microparticles, and coagulation proteases, participate in the complex process of immunothrombosis, which is a key event in ARDS pathophysiology. The present review is focused on the elucidation of immunothrombosis in ARDS and the potential therapeutic implications. PMID- 27997926 TI - Exogenous Hydrogen Sulfide Attenuates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation by Suppressing TLR4/NF-kappaB Pathway in H9c2 Cells. AB - BACKGROUND/AIMS: This study aimed to investigate whether exogenous hydrogen sulfide (H2S) confered cardiac protection against high glucose (HG)-induced injury by inhibiting NLRP3 inflammasome activation via a specific TLR4/NF-kappaB pathway. METHODS: H9c2 cardiac cells were exposed to 33 mM glucose for 24 h to induce HG-induced cytotoxicity. The cells were pretreated with NaHS (a donor of H2S) before exposure to HG. Cell viability, cell apoptosis, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and TLR4, NF-kappaB, NLRP3 inflammasome, IL-1beta, IL-18 and caspase-3 expression were measured by standard methods. RESULTS: H2S attenuated HG-induced cell apoptosis, ROS expression and loss of MMP and reduced the expression of NLRP3, ASC, pro caspase-1, caspase-1, IL-1beta, IL-18 and caspase-3. In addition, H2S inhibited the HG-induced activation of TLR4 and NF-kappaB. Furthermore, NLRP3 inflammasome activation was regulated by the TLR4 and NF-kappaB pathway. CONCLUSION: The present study demonstrated for the first time that H2S appears to suppress HG induced cardiomyocyte inflammation and apoptosis by inhibiting the TLR4/NF-kappaB pathway and its downstream NLRP3 inflammasome activation. Thus H2S might possess potential in the treatment of diabetic cardiomyopathy. PMID- 27997927 TI - Correction: A Prime-Boost Vaccination Strategy in Cattle to Prevent Foot-and Mouth Disease Using a "Single-Cycle" Alphavirus Vector and Empty Capsid Particles. AB - [This corrects the article DOI: 10.1371/journal.pone.0157435.]. PMID- 27997929 TI - Achievable Rate Estimation of IEEE 802.11ad Visual Big-Data Uplink Access in Cloud-Enabled Surveillance Applications. AB - This paper addresses the computation procedures for estimating the impact of interference in 60 GHz IEEE 802.11ad uplink access in order to construct visual big-data database from randomly deployed surveillance camera sensing devices. The acquired large-scale massive visual information from surveillance camera devices will be used for organizing big-data database, i.e., this estimation is essential for constructing centralized cloud-enabled surveillance database. This performance estimation study captures interference impacts on the target cloud access points from multiple interference components generated by the 60 GHz wireless transmissions from nearby surveillance camera devices to their associated cloud access points. With this uplink interference scenario, the interference impacts on the main wireless transmission from a target surveillance camera device to its associated target cloud access point with a number of settings are measured and estimated under the consideration of 60 GHz radiation characteristics and antenna radiation pattern models. PMID- 27997928 TI - Development and Validation of the Motivations for Selection of Medical Study (MSMS) Questionnaire in India. AB - BACKGROUND AND OBJECTIVE: Understanding medical students' motivation to select medical studies is particularly salient to inform practice and policymaking in countries-such as India-where shortage of medical personnel poses crucial and chronical challenges to healthcare systems. This study aims to develop and validate a questionnaire to assess the motivation of medical students to select medical studies. METHODS: A Motivation for Selection of Medical Study (MSMS) questionnaire was developed using extensive literature review followed by Delphi technique. The scale consisted of 12 items, 5 measuring intrinsic dimensions of motivations and 7 measuring extrinsic dimensions. Exploratory factor analysis (EFA), confirmatory factor analysis (CFA), validity, reliability and data quality checks were conducted on a sample of 636 medical students from six medical colleges of three North Indian states. RESULTS: The MSMS questionnaire consisted of 3 factors (subscales) and 8 items. The three principal factors that emerged after EFA were the scientific factor (e.g. research opportunities and the ability to use new cutting edge technologies), the societal factor (e.g. job security) and the humanitarian factor (e.g. desire to help others). The CFA conducted showed goodness-of-fit indices supporting the 3-factor model. CONCLUSION: The three extracted factors cut across the traditional dichotomy between intrinsic and extrinsic motivation and uncover a novel three-faceted motivation construct based on scientific factors, societal expectations and humanitarian needs. This validated instrument can be used to evaluate the motivational factors of medical students to choose medical study in India and similar settings and constitutes a powerful tool for policymakers to design measures able to increase selection of medical curricula. PMID- 27997930 TI - VHDL Descriptions for the FPGA Implementation of PWL-Function-Based Multi-Scroll Chaotic Oscillators. AB - Nowadays, chaos generators are an attractive field for research and the challenge is their realization for the development of engineering applications. From more than three decades ago, chaotic oscillators have been designed using discrete electronic devices, very few with integrated circuit technology, and in this work we propose the use of field-programmable gate arrays (FPGAs) for fast prototyping. FPGA-based applications require that one be expert on programming with very-high-speed integrated circuits hardware description language (VHDL). In this manner, we detail the VHDL descriptions of chaos generators for fast prototyping from high-level programming using Python. The cases of study are three kinds of chaos generators based on piecewise-linear (PWL) functions that can be systematically augmented to generate even and odd number of scrolls. We introduce new algorithms for the VHDL description of PWL functions like saturated functions series, negative slopes and sawtooth. The generated VHDL-code is portable, reusable and open source to be synthesized in an FPGA. Finally, we show experimental results for observing 2, 10 and 30-scroll attractors. PMID- 27997932 TI - Emerging infectious diseases. PMID- 27997931 TI - Modeling Outcomes of First-Line Antiretroviral Therapy and Rate of CD4 Counts Change among a Cohort of HIV/AIDS Patients in Ethiopia: A Retrospective Cohort Study. AB - BACKGROUND: Antiretroviral therapy has shown to be effective in reducing morbidity and mortality in patients infected with HIV for the past couples of decades. However, there remains a need to better understand the characteristics of long-term treatment outcomes in resource poor settings. The main aim of this study was to determine and compare the long-term response of patients on nevirapine and efavirenz based first line antiretroviral therapy regimen in Ethiopia. METHODS: Hospital based retrospective cohort study was conducted from January 2009 to December 2013 at University hospital located in Northwest Ethiopia. Human subject research approval for this study was received from University of Gondar Research Ethics Committee and the medical director of the hospital. Cox-proportional hazards model was used to assess the effect of baseline covariates on composite outcome and a semi-parametric mixed effect model was used to investigate CD4 counts response to treatments. RESULTS: A total of 2386 HIV/AIDS naive patients were included in this study. Nearly one-in-four patients experienced the events, of which death, lost to follow up, treatment substitution and discontinuation of Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTI) accounted: 99 (26.8%), 122 (33.0%), 137 (37.0%) and 12 (3.2%), respectively. The hazard of composite outcome on nevirapine compared with efavirenz was 1.02(95%CI: 0.52-1.99) with p-value = 0.96. Similarly, the hazard of composite outcome on tenofovir and stavudine compared with zidovudine were 1.87 (95%CI: 1.52-2.32), p-value < 0.0001 and 1.72(95% CI: 1.22-2.32), p-value = 0.002, respectively. The rate of CD4 increase in response to treatment was high during the first 10 months and stabilized later. CONCLUSIONS: This study revealed that treatment responses were comparable whether nevirapine or efavirenz was chosen to initiate antiretroviral therapy for HIV/AIDS patients in Ethiopia. There was significant difference on risk of composite outcome between patients who were initiated with Tenofovir containing ART regimen compared with zidovudine after controlling for NNRTI drug combinations. PMID- 27997933 TI - From plague to MERS: coordinating Australia's response to emerging infectious diseases. AB - Rapid international travel times and the arrival of new and unexpected infectious disease threats have demonstrated that, for effective communicable disease control, Australia's response needs to be flexible and coordinated. This paper summarises how our public health and clinical systems would respond to a case of Middle East respiratory syndrome (MERS) coronavirus and our responsibility under the International Health Regulations to notify the World Health Organization (WHO). It also describes the processes undertaken by WHO when it declares that a disease outbreak is a Public Health Emergency of International Concern. Australia has robust communicable disease response systems, tested by new threats for many years, which are under constant review and improvement. PMID- 27997934 TI - Future directions for public health research in emerging infectious diseases. AB - Infectious diseases remain responsible for significant global morbidity and mortality, and diseases emerge and re-emerge in sometimes unpredictable locations and at unpredictable times. Although much is known about how to detect and respond to existing infections, more public health research is needed to predict the likelihood of their emergence and spread, and to improve the precision and timeliness of public health responsiveness. To achieve this, further research is required to develop pathogen genomics from more than just a tool for outbreak investigation to one that will identify and quantify catalysts for emergence within a given population. More research is also needed to develop digital epidemiology techniques to identify syndromic clusters earlier. Beyond human public health, appreciating how animals and the environment affect disease emergence presents us with a new challenge: to develop truly interdisciplinary research that encompasses all aspects of pathogen surveillance and response. This includes understanding why microorganisms cross species to cause diseases (e.g. from animals to humans), factors that drive spread of infections, and systems research that will result in development of joint responses to outbreaks from different professional, government and international groups. Only then will we be better prepared for the next outbreak. PMID- 27997935 TI - Exotic mosquito threats require strategic surveillance and response planning. AB - Mosquito-borne diseases caused by endemic pathogens such as Ross River, Barmah Forest and Murray Valley encephalitis viruses are an annual concern in New South Wales (NSW), Australia. More than a dozen mosquito species have been implicated in the transmission of these pathogens, with each mosquito occupying a specialised ecological niche that influences their habitat associations, host feeding preferences and the environmental drivers of their abundance. The NSW Arbovirus Surveillance and Mosquito Monitoring Program provides an early warning system for potential outbreaks of mosquito-borne disease by tracking annual activity of these mosquitoes and their associated pathogens. Although the program will effectively track changes in local mosquito populations that may increase with a changing climate, urbanisation and wetland rehabilitation, it will be less effective with current surveillance methodologies at detecting or monitoring changes in exotic mosquito threats, where different surveillance strategies need to be used. Exotic container-inhabiting mosquitoes such as Aedes aegypti and Ae. albopictus pose a threat to NSW because they are nuisance-biting pests and vectors of pathogens such as dengue, chikungunya and Zika viruses. International movement of humans and their belongings have spread these mosquitoes to many regions of the world. In recent years, these two mosquitoes have been detected by the Australian Government Department of Agriculture and Water Resources at local airports and seaports. To target the detection of these exotic mosquitoes, new trapping technologies and networks of surveillance locations are required. Additionally, incursions of these mosquitoes into urban areas of the state will require strategic responses to minimise substantial public health and economic burdens to local communities. PMID- 27997936 TI - A review of recommendations on the safe and effective use of topical mosquito repellents. AB - Mosquito-borne disease is an annual problem in Australia, with endemic pathogens such as Ross River virus infecting thousands of people each year. The recent emergence of Zika virus in South America and the Pacific, together with ongoing outbreaks of dengue viruses in Southeast Asia, generated great community interest in the most effective strategies to avoid mosquito bites. Large-scale mosquito control programs are not common in Australia and are limited in New South Wales (NSW). The use of topical insect repellents is a key recommendation by health authorities to prevent mosquito-borne disease. All products sold in Australia purporting to repel mosquitoes must be registered with the Australian Pesticides and Veterinary Medicines Authority. Despite around 100 commercial products registered as repelling mosquitoes, there are relatively few active ingredients used across these formulations. The most common are diethyltoluamide (DEET), picaridin, p-menthane-3,8-diol (PMD) and a range of plant-derived products (e.g. melaleuca, eucalyptus, citronella oils). Research has shown that each of these active ingredients varies in the duration of protection provided against biting mosquitoes. Recommendations by health authorities are informed by this research, but inconsistencies between recommendations and available repellent formulations and their concentration of active ingredients can cause confusion in the community. There are conflicts between the data resulting from scholarly research, marketing promotion by manufacturers and recommendations provided by overseas health authorities. A review was undertaken of NSW Health's current recommendations on choosing and using insect repellents, taking into consideration recent research and currently registered topical repellents. PMID- 27997937 TI - Describing meningococcal disease: understanding, perceptions and feelings of people in a regional area of NSW, Australia. AB - OBJECTIVES: To explore understanding, perceptions and feelings about meningococcal disease in members of higher risk groups. To explore what people say are the most important health messages and communication preferences about invasive meningococcal disease (IMD). METHODS: Three focus groups and two semistructured interviews were conducted with people at higher risk of IMD in Hunter New England Local Health District in New South Wales. RESULTS: Participants generally had a low understanding of IMD, but described intense feelings about the disease and empathy for those who had experienced the disease. Fear of stigma and the impact of stigma were identified. Participants identified reasons for delaying presentation for care as perceptions of invincibility (particularly among young people), the cost of care (for all groups), and racism (particularly for Aboriginal people). These issues were both potential and experienced barriers for participants accessing help when acutely unwell. Factors for effective communication to improve understanding of IMD included the communication being acceptable, accessible and appropriate. CONCLUSIONS: IMD is a serious but uncommon disease that has a range of impacts on people, families and communities. Higher risk groups may benefit from receiving more appropriate and accessible information about early signs and symptoms of IMD. Communication and understanding about the disease could be improved by working with new technologies and partnering with key people in high-risk groups. Use of text messages and social networking for urgent communication could be considered and trialled in public health practice. It is also important to recognise the potential direct or indirect experience of racism and stigma for patients with IMD and their families. Management of IMD could be strengthened by connecting people and families with support groups or services to reduce the impact of the disease. PMID- 27997938 TI - Fall prevention services for older Aboriginal people: investigating availability and acceptability. AB - BACKGROUND: Falls and fall-related injury are emerging issues for older Aboriginal people. Despite this, it is unknown whether older Aboriginal people access available fall prevention programs, or whether these programs are effective or acceptable to this population. OBJECTIVE: To investigate the use of available fall prevention services by older Aboriginal people and identify features that are likely to contribute to program acceptability for Aboriginal communities in New South Wales (NSW), Australia. METHODS: A questionnaire was distributed to Aboriginal and mainstream health and community services across NSW to identify the fall prevention and healthy ageing programs currently used by older Aboriginal people. Services with experience in providing fall prevention interventions for Aboriginal communities, and key Aboriginal health services that delivered programs specifically for older Aboriginal people, were followed up and staff members were nominated from within each service to be interviewed. Service providers offered their suggestions as to how a fall prevention program could be designed and delivered to meet the health and social needs of their older Aboriginal clients. RESULTS: Of the 131 services that completed the questionnaire, four services (3%) had past experience in providing a mainstream fall prevention program to Aboriginal people; however, there were no programs being offered at the time of data collection. From these four services, and from a further five key Aboriginal health services, 10 staff members experienced in working with older Aboriginal people were interviewed. Barriers preventing services from offering appropriate fall prevention programs to their older Aboriginal clients were identified, including limited funding, a lack of available Aboriginal staff, and communication difficulties between health services and sectors. According to the service providers, an effective and acceptable fall prevention intervention would be evidence based, flexible, community-oriented and social, held in a familiar and culturally safe location and delivered free of cost. CONCLUSION: This study identified a gap in the availability of acceptable fall prevention programs designed for, and delivered to, older Aboriginal people in NSW. Further consultation with older Aboriginal people is necessary to determine how an appropriate and effective program can be designed and delivered. Terminology: The authors recognise the two distinctive Indigenous populations of Australia: Aboriginal and Torres Strait Islander people. Because the vast majority of the NSW Aboriginal and Torres Strait Islander population is Aboriginal (95.4%)1, this population will be referred to as 'Aboriginal' in this manuscript. PMID- 27997939 TI - Content analysis of comments posted on Australian online news sites reporting a celebrity admitting smoking while pregnant. AB - OBJECTIVES: More than 12% of Australian women who gave birth in 2012 reported smoking during pregnancy. Smoking during pregnancy may be under-reported as a result of negative societal attitudes towards pregnant women who smoke. This study sought to identify the extent and nature of online news readers' reactions to online news stories reporting Australian celebrity Chrissie Swan's admission of smoking while pregnant, and whether any smoking and pregnancy health information was included. STUDY TYPE: Quantitative media content analysis. METHODS: Readers' comments posted online in response to Australian online news stories and blogs reporting that Chrissie Swan had admitted smoking while pregnant were coded for inclusion in one of two categories: (1) opposing the judgement of Swan or (2) supporting the judgement of Swan. These comments were then grouped into seven frames. Comments that reflected the readers' own experiences of smoking during pregnancy and the inclusion of any helpful health information were also assessed. RESULTS: Comments that were critical of the judgement of Swan were most frequently found. Specific health facts and quit smoking advice rarely featured. Common frames were 'against making moral judgement' and 'smoking in pregnancy is wrong or harmful'. CONCLUSIONS: The lack of comments addressing the misinformation about smoking and quitting during pregnancy suggests a potential role for public health practitioners in future smoking and pregnancy communication programs. The increase in the number of Australians participating in online communities and blogs provides the opportunity for capacity building and resources to enable a proactive and rapid public health response to media opportunities. PMID- 27997940 TI - Australia's response to Ebola Virus disease in West Africa, 2014-15. AB - In March 2016, the World Health Organization declared the 2014-15 Ebola virus disease (EVD) outbreak officially over. With around 29 000 cases and 11 000 deaths in 27 months, this EVD outbreak was more than 60 times larger than any before, and unique in its cross-border spread and involvement of urban centres. Local and international responses were slow and initially inadequate, but establishment of the United Nations Mission for Ebola Emergency Response, 9 months after the outbreak began, allowed a coordinated effort that slowed and eventually controlled the spread of disease. Internationally, there were fears that EVD would spread widely beyond Africa, despite reassurances from public health authorities. However, after nurses in the US became infected, public fear and concern for the safety of healthcare workers led to political intervention and varied, sometimes excessive, border controls, quarantine arrangements and hospital preparations. Altogether, fewer than 30 EVD cases were managed in countries outside Africa, all but three of which were acquired in West Africa. In Australia, the Australian Health Protection Principal Committee led the internal response, including enhanced screening of incoming passengers at international airports and development of public health and laboratory testing protocols by expert subcommittees. States and territories nominated designated hospitals to care for EVD patients. Development of EVD infection prevention and control (IPC) guidelines was initially poorly coordinated within and between jurisdictions, often with significant discrepancies, causing confusion and fear among healthcare workers. The Infection Prevention and Control Expert Advisory Group was established to develop national IPC guidelines. There were no confirmed cases in Australia, but investigation of several people with suspected EVD provided valuable experience in use of protocols and high-level containment facilities. The Australian Government was initially reluctant to send aid workers to West Africa, but later contracted a private company to staff and manage a treatment centre in Sierra Leone, which treated 91 patients with EVD during 4 months of operation. Among the lessons learnt for Australia was the need to increase awareness of routine IPC practices in hospitals, where significant deficiencies were exposed, and to maintain a high enough level of preparedness to protect healthcare workers and the public from the next, inevitable, infectious disease emergency. PMID- 27997941 TI - Continuing to lift the burden: using a continuous quality improvement approach to advance Aboriginal tobacco resistance and control. AB - Smoking remains the most preventable cause of early mortality and ill health in Aboriginal people. The Aboriginal Health & Medical Research Council of New South Wales has developed the Aboriginal Tobacco Resistance and Control (ATRAC) Yarning Tool with a range of key stakeholders, to contribute to reducing the prevalence of smoking in Aboriginal communities. The Yarning Tool was adapted from the ATRAC Framework and aims to promote the meaningful discussion, planning and strengthening of tobacco resistance and control activities using a continuous quality improvement (CQI) approach. CQI provides an opportunity to closer align current health service practice with evidence. The Yarning Tool was piloted using focus group testing across four Aboriginal Community Controlled Health Services (ACCHSs) and three Local Health Districts. Purposive sampling was used to ensure that services engaged were from a diverse range of settings, with representation from metropolitan, regional and rural areas, and services with varying degrees of tobacco control capacity. Overall, feedback on the Yarning Tool and its potential use was positive. Pilot participants consistently reported that the Yarning Tool brought staff from a range of positions together to focus on tackling tobacco for the service and community. The pilot participants agreed that the Yarning Tool could be practical for the planning and reviewing stages of a CQI activity, and recommended that the tool should be completed every 6 months. The Yarning Tool is a simple tool to guide the ATRAC Framework principles into practice, and provides a platform to support Aboriginal community-led efforts, and coordination and integration of tobacco control efforts. The tool shows promise as a mechanism to encourage ACCHSs and other relevant services to use a CQI approach to reduce tobacco use in Aboriginal communities. PMID- 27997942 TI - Zika still a threat for Australia. PMID- 27997943 TI - Senate recommends action on 'Lyme-like illness'. PMID- 27997944 TI - Momentum builds for soft-drink tax in Australia. PMID- 27997945 TI - The Use of One or Three Semantic Associative Primes in Treating Anomia in Aphasia. AB - Purpose: The aims of the study were to investigate the use of semantic associative relationships as primes in treating naming deficits, or anomia, in aphasia and to determine if differential treatment effects would be found if 1 or 3 primes were presented. Method: Ten individuals with varying degrees of anomia participated in the study. A single-subject, A-B treatment design with a cross over component was used. A 1-PRIME condition (use of 1 prime) was compared with a 3-PRIMES condition (use of 3 primes) for each participant. Results: Visual analyses of treatment data revealed improvements in 8 of 10 participants. Meaningful effect sizes were obtained in at least 1 of the conditions for 6 of the 10 participants. Slightly more participants demonstrated meaningful effect sizes in the 3-PRIMES condition than in the 1-PRIME condition. Correlation analyses revealed a positive correlation between the number of teaching episodes and 3-PRIMES probe performance. Conclusions: The results support a protocol that uses semantic associative primes to increase naming accuracy in aphasia. The 3 PRIMES condition was slightly more beneficial than the 1-PRIME condition in terms of improving naming abilities in these participants, but there was no overwhelming advantage in using one or the other condition. PMID- 27997946 TI - Recovering With Acquired Apraxia of Speech: The First 2 Years. AB - Purpose: This study was intended to document speech recovery for 1 person with acquired apraxia of speech quantitatively and on the basis of her lived experience. Method: The second author sustained a traumatic brain injury that resulted in acquired apraxia of speech. Over a 2-year period, she documented her recovery through 22 video-recorded monologues. We analyzed these monologues using a combination of auditory perceptual, acoustic, and qualitative methods. Results: Recovery was evident for all quantitative variables examined. For speech sound production, the recovery was most prominent during the first 3 months, but slower improvement was evident for many months. Measures of speaking rate, fluency, and prosody changed more gradually throughout the entire period. A qualitative analysis of topics addressed in the monologues was consistent with the quantitative speech recovery and indicated a subjective dynamic relationship between accuracy and rate, an observation that several factors made speech sound production variable, and a persisting need for cognitive effort while speaking. Conclusions: Speech features improved over an extended time, but the recovery trajectories differed, indicating dynamic reorganization of the underlying speech production system. The relationship among speech dimensions should be examined in other cases and in population samples. The combination of quantitative and qualitative analysis methods offers advantages for understanding clinically relevant aspects of recovery. PMID- 27997947 TI - The Use of Electropalatography in the Treatment of Acquired Apraxia of Speech. AB - Purpose: This investigation was designed to examine the effects of an articulatory-kinematic treatment in conjunction with visual biofeedback (VBFB) via electropalatography (EPG) on the accuracy of articulation for acquired apraxia of speech (AOS). Method: A multiple-baseline design across participants and behaviors was used with 4 individuals with chronic AOS and aphasia. Accuracy of target speech sounds in treated and untreated phrases in probe sessions served as the dependent variable. Participants received an articulatory-kinematic treatment in combination with VBFB, which was sequentially applied to 3 stimulus sets composed of 2-word phrases with a target speech sound for each set. Results: Positive changes in articulatory accuracy were observed for participants for the majority of treated speech sounds. Also, there was generalization to untreated phrases for most trained speech sounds. Two participants had better long-term maintenance of treated speech sounds in both trained and untrained stimuli. Conclusions: Findings indicate EPG may be a potential treatment tool for AOS. It appears that individuals with AOS can benefit from VBFB via EPG in improving articulatory accuracy. However, further research is needed to determine if VBFB is more advantageous than behavioral treatments that have been proven effective in improving speech production for speakers with AOS. PMID- 27997948 TI - Self-Judgments of Word Production Accuracy in Acquired Apraxia of Speech. AB - Purpose: The ability to recognize one's own speech errors has long been considered a clinical feature of acquired apraxia of speech (AOS) despite limited empirical data supporting this notion. This study was designed to (a) investigate the ability of speakers with AOS to self-judge the accuracy of their own word productions and (b) examine the test-retest stability of a measure to quantify the self-judgments of speakers with AOS. Method: Twenty-four speakers with AOS and aphasia repeated mono- and multisyllabic words. After each word, they indicated whether their production was correct or incorrect. This procedure was repeated 1 week later to examine performance stability. Results: Percentage of incorrect word productions was stable for the group across times. Accuracy of judgments ranged from 64% to 100% at Time 1 and from 56% to 100% at Time 2. Inaccurate judgments of error productions (false positives) occurred much more frequently than inaccurate judgments of correct productions (false negatives). Conclusions: Error production was remarkably stable in our participants. As a group, the participants failed to detect almost one third of words produced erroneously. However, accuracy and stability of judgments over sampling times varied across participants. Findings suggest that error awareness might be a worthwhile target for treatment in some individuals with AOS. PMID- 27997949 TI - Core Outcomes in Aphasia Treatment Research: An e-Delphi Consensus Study of International Aphasia Researchers. AB - Purpose: The purpose of this article is to identify outcome constructs that aphasia researchers consider essential to measure in all aphasia treatment research. Method: Purposively sampled researchers were invited to participate in a 3-round e-Delphi exercise. In Round 1, an open-ended question was used to elicit important outcome constructs; responses were analyzed using inductive content analysis. In Rounds 2 and 3, participants rated the importance of each outcome using a 9-point rating scale. Outcomes reaching predefined consensus criteria were further analyzed using International Classification of Functioning, Disability and Health coding. Results: Eighty researchers commenced Round 1, with 72 completing the entire survey. High response rates (>= 85%) were achieved in subsequent rounds. Consensus was reached on 6 outcomes: (a) language functioning in modalities relevant to study aims, (b) impact of treatment from the perspective of the person with aphasia (PWA), (c) communication-related quality of life, (d) satisfaction with intervention from the perspective of the PWA, (e) satisfaction with ability to communicate from the perspective of the PWA, and (f) satisfaction with participation in activities from the perspective of the PWA. Conclusions: Consensus was reached that it is essential to measure language function and specific patient-reported outcomes in all aphasia treatment research. These results will contribute to the development of a core outcome set. PMID- 27997950 TI - Evaluating Treatment and Generalization Patterns of Two Theoretically Motivated Sentence Comprehension Therapies. AB - Purpose: The current study examined treatment outcomes and generalization patterns following 2 sentence comprehension therapies: object manipulation (OM) and sentence-to-picture matching (SPM). Findings were interpreted within the framework of specific deficit and resource reduction accounts, which were extended in order to examine the nature of generalization following treatment of sentence comprehension deficits in aphasia. Method: Forty-eight individuals with aphasia were enrolled in 1 of 8 potential treatment assignments that varied by task (OM, SPM), complexity of trained sentences (complex, simple), and syntactic movement (noun phrase, wh-movement). Comprehension of trained and untrained sentences was probed before and after treatment using stimuli that differed from the treatment stimuli. Results: Linear mixed-model analyses demonstrated that, although both OM and SPM treatments were effective, OM resulted in greater improvement than SPM. Analyses of covariance revealed main effects of complexity in generalization; generalization from complex to simple linguistically related sentences was observed both across task and across movement. Conclusions: Results are consistent with the complexity account of treatment efficacy, as generalization effects were consistently observed from complex to simpler structures. Furthermore, results provide support for resource reduction accounts that suggest that generalization can extend across linguistic boundaries, such as across movement type. PMID- 27997952 TI - Algorithmic Classification of Five Characteristic Types of Paraphasias. AB - Purpose: This study was intended to evaluate a series of algorithms developed to perform automatic classification of paraphasic errors (formal, semantic, mixed, neologistic, and unrelated errors). Method: We analyzed 7,111 paraphasias from the Moss Aphasia Psycholinguistics Project Database (Mirman et al., 2010) and evaluated the classification accuracy of 3 automated tools. First, we used frequency norms from the SUBTLEXus database (Brysbaert & New, 2009) to differentiate nonword errors and real-word productions. Then we implemented a phonological-similarity algorithm to identify phonologically related real-word errors. Last, we assessed the performance of a semantic-similarity criterion that was based on word2vec (Mikolov, Yih, & Zweig, 2013). Results: Overall, the algorithmic classification replicated human scoring for the major categories of paraphasias studied with high accuracy. The tool that was based on the SUBTLEXus frequency norms was more than 97% accurate in making lexicality judgments. The phonological-similarity criterion was approximately 91% accurate, and the overall classification accuracy of the semantic classifier ranged from 86% to 90%. Conclusion: Overall, the results highlight the potential of tools from the field of natural language processing for the development of highly reliable, cost effective diagnostic tools suitable for collecting high-quality measurement data for research and clinical purposes. PMID- 27997951 TI - Looking for a Location: Dissociated Effects of Event-Related Plausibility and Verb-Argument Information on Predictive Processing in Aphasia. AB - Purpose: This study examined the influence of verb-argument information and event related plausibility on prediction of upcoming event locations in people with aphasia, as well as older and younger, neurotypical adults. It investigated how these types of information interact during anticipatory processing and how the ability to take advantage of the different types of information is affected by aphasia. Method: This study used a modified visual-world task to examine eye movements and offline photo selection. Twelve adults with aphasia (aged 54-82 years) as well as 44 young adults (aged 18-31 years) and 18 older adults (aged 50 71 years) participated. Results: Neurotypical adults used verb argument status and plausibility information to guide both eye gaze (a measure of anticipatory processing) and image selection (a measure of ultimate interpretation). Argument status did not affect the behavior of people with aphasia in either measure. There was only limited evidence of interaction between these 2 factors in eye gaze data. Conclusions: Both event-related plausibility and verb-based argument status contributed to anticipatory processing of upcoming event locations among younger and older neurotypical adults. However, event-related likelihood had a much larger role in the performance of people with aphasia than did verb-based knowledge regarding argument structure. PMID- 27997953 TI - Assessment Fidelity in Aphasia Research. AB - Purpose: In aphasia treatment literature, scarce attention is paid to factors that may reduce a study's validity, including adherence to assessment and treatment procedures (i.e., fidelity). Although guidelines have been established for evaluating and reporting treatment fidelity, none exist for assessment fidelity. Method: We reviewed treatment fidelity guidelines and related literature to identify assessment fidelity components. We then examined 88 aphasia treatment studies published between 2010 and 2015 and report the frequency with which researchers provide information regarding the following assessment fidelity components: assessment instruments, assessor qualifications, assessor or rater training, assessment delivery, assessor or rater reliability, and assessor blinding. Results: We found that 4.5% of studies reported information regarding assessment instruments, 35.2% reported information regarding assessor qualifications, 6.85% reported information regarding assessor or rater training, 37.5% reported information regarding assessor or rater reliability, 27.3% reported on assessor blinding, and no studies reported information regarding assessment delivery. Conclusions: There is a paucity of assessment fidelity information reported in aphasia treatment research. The authors propose a set of guidelines to ensure readers will be able to evaluate assessment fidelity, and thus study validity. PMID- 27997955 TI - Cross-Linguistic Differences in a Picture-Description Task Between Korean- and English-Speaking Individuals With Aphasia. AB - Purpose: The purpose of the study was to examine cross-linguistic differences in a picture-description task between Korean- and English-speaking individuals with Broca's and anomic aphasia to determine whether a variation exists in the use of verbs and nouns across the language and aphasia groups. Method: Forty-eight individuals (male = 29; female = 19) participated in the study (n = 28 for aphasic group and n = 20 healthy controls). Data for English speakers were obtained from the Aphasia Bank Project. We used the picture-description task to obtain connected speech samples and analyzed noun- and verb-related linguistic variables. Results: Korean speakers with aphasia produced more verbs per utterance and a lower noun-to-verb ratio than English speakers with aphasia, whereas English speakers produced more nouns than Korean speakers. The Korean anomic group produced more verbs than Korean speakers with Broca's aphasia, whereas no effects were significant for English speakers with aphasia depending on the type of aphasia. Conclusions: Aphasia symptoms vary as a function of linguistic features of languages that individuals with aphasia used premorbidly. Furthermore, the linguistic characteristics of the individual's language influenced aphasia symptoms more strongly than the type of aphasia. It is theoretically and clinically important that this cross-linguistic study provides different perspectives, and that noun-verb deficits may vary depending on linguistic features. PMID- 27997954 TI - Intensive Language Action Therapy in Chronic Aphasia: A Randomized Clinical Trial Examining Guidance by Constraint. AB - Purpose: Intensive language action therapy (ILAT) can be effective in overcoming learned nonuse in chronic aphasia. It is suggested that all three guiding principles (constraint, communication embedding, massed practice) are essential to ILAT's success. We examined whether one of these, guidance by constraint, is critical. Method: Twenty-four participants with aphasia (PWAs) were assigned to ILAT or a modified version of promoting aphasic communicative effectiveness (PACE) in a randomized block, single-blind, parallel-group treatment study. Blocking was by severity (mild/moderate, moderate to severe, severe). Both groups received intensive treatment in the context of therapeutic language action games. Whereas the ILAT group was guided toward spoken responses, the PACE group could choose any response modality. Results: All participants, whether assigned to ILAT or PACE groups, improved on the primary outcome measure, picture naming. There was a Severity * Treatment interaction, with the largest effects estimated for PWAs with mild/moderate and moderate to severe aphasia. Regardless of severity, the ILAT group outperformed the PACE group on untrained pictures, suggesting some benefit of ILAT to generalization. However, this difference was not statistically significant. Conclusion: Although the groups differed in subtle ways, including better generalization to untrained pictures for ILAT, the study was inconclusive on the influence of guidance by constraint. PMID- 27997956 TI - The Effects of Sentence Repetition-Based Working Memory Treatment on Sentence Comprehension Abilities in Individuals With Aphasia. AB - Purpose: This study investigated whether sentence repetition-based working-memory (SR-WM) treatment increased sentence-repetition abilities and the treatment effects generalized to sentence-comprehension abilities, WM-span tasks, and general language-assessment tasks. Method: Six individuals with aphasia participated in the study. The treatment consisted of 12 sessions of approximately 1 hr per day, 3 times per week. The SR-WM treatment protocol followed components including maintenance and computation of linguistic units by facilitating a chunking strategy. We manipulated the length and syntactic structures of the sentence-repetition stimuli using a limited set of vocabulary. Results: Participants demonstrated significant increased repetition ability in treated and untreated sentences after treatment. Furthermore, they showed generalization effects on the sentence-comprehension task, WM measures, and general language tasks, but with some differential patterns, depending on task demands. Conclusions: The SR-WM treatment approach, by manipulating syntactic structures and minimizing top-down semantic processing, elicited increased performance on sentence repetition as well as other linguistic domains. Results indicated that it is clinically and theoretically important to examine whether WM treatment serves as a potentially underlying treatment approach that facilitates the distributed network associated with language processing. PMID- 27997957 TI - Lexical Ambiguity Resolution Using Discourse Contexts in Persons With and Without Aphasia. AB - Purpose: The purpose of this study was to investigate the ability of persons with aphasia (PWA) to resolve different types of ambiguous words (homophones, metaphors, and metonyms) in discourse contexts. Method: Six PWA and 10 controls listened to short discourses that biased either the dominant (more frequent) or subordinate (less frequent) version of an ambiguous word as well as nonsense (filler) discourses. Participants then indicated whether or not the final sentence, which contained the ambiguity, made sense in the discourse. Data for both accuracy and reaction time were collected. Results: There was no significant Group * Word Type * Frequency interaction in the reaction time data. In the accuracy analysis, there was a significant Group * Frequency * Word Type interaction, which appeared to be driven by the PWA's relative accuracy with subordinate homophones and relative inaccuracy with subordinate metaphors. Conclusions: These results suggest that PWA were able to use discourse contexts to resolve subordinate versions of literal ambiguous words but have difficulty resolving metaphoric ambiguous words. Further investigations should be done to clarify how much context PWA require to successfully resolve lexical ambiguities. PMID- 27997958 TI - Use of tDCS in Aphasia Rehabilitation: A Systematic Review of the Behavioral Interventions Implemented With Noninvasive Brain Stimulation for Language Recovery. AB - Purpose: The purpose of this article is to review the behavioral treatments used in aphasia rehabilitation research that have been combined with transcranial direct current stimulation (tDCS). Although tDCS in aphasia treatment has shown promise, the results have not been conclusive, and their interpretation is further compounded by the heterogeneity of study characteristics. Because implementing a behavioral task during brain stimulation has been shown to be pivotal to the adjuvant effects of tDCS, we analyze the behavioral treatments that have been paired with tDCS. Method: A computerized database search (PubMed) was completed to document and review aphasia treatment studies that combine behavioral treatment with noninvasive brain stimulation in the form of tDCS. Two authors reviewed each aphasia tDCS article published between 2008 and 2015 and evaluated (a) the behavioral interventions for aphasia that have been combined with tDCS, and (b) the methodological variables that may have influenced language outcomes in the tDCS aphasia literature. Conclusions: A review of the behavioral treatments implemented in tDCS aphasia rehabilitation studies highlights several methodological considerations for future investigations. Impairment-focused and pragmatic treatments have been implemented in tDCS aphasia research studies. No one behavioral approach stands out as the best treatment to combine with tDCS for the promotion of language recovery. PMID- 27997959 TI - Parthenolide Modulates Immune Response in Cells from C57BL/6 Mice Induced with Experimental Autoimmune Encephalomyelitis. AB - Multiple sclerosis is a chronic inflammatory and autoimmune disease of the central nervous system that affects more than 2.5 million people worldwide. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. Parthenolide, a natural sesquiterpene lactone found in Tanacetum parthenium L., is known for its strong anti-inflammatory activity. Herein, we have investigated the in vitro immunomodulatory effects of parthenolide on cytokine production and nitric oxide in cultured cells from myelin oligodendrocyte glycoprotein 35-55 amino acid peptide mice. Experimental autoimmune encephalomyelitis was induced in C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide, and parthenolide was isolated from T. parthenium. Splenocytes and peritoneal cells were obtained from experimental autoimmune encephalomyelitis-induced mice and incubated with parthenolide (1, 5, and 20 uM). After in vitro treatment with parthenolide, supernatants were collected, and nitric oxide and cytokines were measured. The results suggested that parthenolide may regulate the activity of Th17 and Th1 cells, mainly by decreasing IL-17, TNF-alpha, and interferon gamma production. This modulation may be related to the lower levels of IL-12p40 and IL-6 after treatment with parthenolide. It was shown, for the first time, that parthenolide presents in vitro immunomodulatory effects on inflammatory mediators produced by cells from experimental autoimmune encephalomyelitis-induced mice. PMID- 27997960 TI - Submucosal tunneling endoscopic resection of a symptomatic leiomyoma in the proximal esophagus. PMID- 27997961 TI - Gastric gastrointestinal stromal tumor presenting with an intraluminal draining abscess and left pleural effusion. PMID- 27997962 TI - Over-the-scope clip placement and endosponge insertion for prevention of pancreatic enzyme-induced duodenal damage after large duodenal endoscopic resection. PMID- 27997963 TI - Efficacy of the CryoBalloon Focal Ablation System for the eradication of dysplastic Barrett's esophagus islands. AB - Background and study aim Cryoablation can be used for the treatment of Barrett's esophagus (BE). A recent dosimetry study, using the CryoBalloon Focal Ablation System (CryoBalloon), demonstrated that 10-second ablations result in complete eradication of BE. However, the efficacy of 10-second ablation in a larger cohort of patients has not been investigated, nor has the potential of precise targeting of specific areas. The aim of the study was to assess the efficacy and performance (i. e. targeting of BE islands) of a 10-second cryoablation using the CryoBalloon. Results A total of 30 patients were enrolled (worst pathology: low grade dysplasia in 14 [47 %], high grade dysplasia in 7 [23 %], early adenocarcinoma in 9 [30 %]). Of the 47 BE islands, 44 (94 %) were adequately targeted. Complete eradication of intestinal metaplasia and dysplasia was observed in 100 % of the completely ablated areas. No stenoses were observed. Conclusion Cryoablation of BE islands using the CryoBalloon is effective. BE islands were effectively targeted. PMID- 27997964 TI - Treatment of biliary strictures with fully covered self-expandable metal stents after pancreaticoduodenectomy. AB - Background and study aims Anastomotic stricture is a late complication after biliary reconstructive surgery, but standard treatments are currently lacking. We selected patients who had undergone pancreaticoduodenectomy and Child's procedure, and aimed to evaluate the safety and efficacy of temporary placement of fully covered self-expandable metal stents (FCSEMSs) to treat postoperative anastomotic stricture. Patients and methods This study retrospectively analyzed 13 patients who underwent treatment with FCSEMSs for anastomotic stricture between June 2011 and March 2016. We evaluated technical and clinical success, complications, duration of patency after FCSEMS removal, and re-stenosis. Results All of the anastomotic strictures were improved by FCSEMS placement and luminal patency was maintained throughout the follow-up period, with no complications. After 2 months, the FCSEMSs were removed endoscopically in nine patients, and in four patients the stent had been expelled spontaneously per rectum. Median duration of follow-up was 225 days (range 30 - 935 days). No re-stenosis occurred in any of the 13 cases following stent removal. Conclusion Deployment of FCSEMSs for anastomotic stricture offers a safe and promising treatment that may replace percutaneous transhepatic biliary drainage and deployment of multiple plastic stents as the first-line treatment. PMID- 27997966 TI - Double-guidewire technique in difficult biliary cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis. AB - Background and study aims Difficult cannulation is a risk factor for pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). The double guidewire technique (DGT) may improve cannulation success and reduce the risk of post-ERCP pancreatitis (PEP) in patients with difficult cannulation. This systematic review compared the DGT with persistent conventional cannulation or other advanced techniques in patients with difficult cannulation. Patients and Methods CENTRAL, MEDLINE, EMBASE, and CINAHL databases and DDW and UEGW abstracts up to March 2016 were searched for randomized controlled trials (RCTs) comparing DGT with persistent conventional cannulation or other advanced techniques (precut, pancreatic duct [PD] stenting). The primary outcome was PEP. Secondary outcomes included severity of PEP, successful cannulation of the common bile duct (CBD) with the randomized technique, overall CBD cannulation success, and ERCP related complications. Results 7 RCTs (577 patients) were included. Use of the DGT significantly increased PEP compared to other endoscopic techniques (risk ratio [RR] 1.98, 95 % confidence interval [95 %CI] 1.14 - 3.42). There was no significant difference in CBD cannulation success with the randomized technique (RR 1.04, 95 %CI 0.87 - 1.24) or in overall cannulation success (RR 1.04, 95 %CI 0.91 - 1.18) between DGT and other techniques. There was also no significant difference in the risk of other ERCP-related complications (bleeding, perforation, cholangitis, and mortality). The results were robust in sensitivity analyses. Conclusions In patients with difficult cannulation, sole use of the DGT appears to increase the risk of PEP without any superiority in achieving biliary cannulation compared to other techniques. PD stenting may reduce the risk of PEP when the DGT is used. The influence of co-intervention in the form of per procedural nonsteroidal anti-inflammatory drug (NSAID) administration is unclear. PMID- 27997967 TI - The Last Hurrah. PMID- 27997965 TI - Improving uptake of flexible sigmoidoscopy screening: a randomized trial of nonparticipant reminders in the English Screening Programme. AB - Background and study aims Uptake of flexible sigmoidoscopy screening in the English Bowel Scope Screening (BSS) Programme is low. The aim of this study was to test the impact of a nonparticipant reminder and theory-based leaflet to promote uptake among former nonresponders (previously did not confirm their appointment) and nonattenders (previously confirmed their appointment but did not attend). Patients and methods Eligible adults were men and women in London who had not attended a BSS appointment within 12 months of their invitation. Individuals were randomized (1:1:1) to receive no reminder (control), a 12-month reminder plus standard information booklet (TMR-SIB), or a 12-month reminder plus bespoke theory-based leaflet (TMR-TBL) designed to address barriers to screening. The primary outcome of the study was the proportion of individuals screened within each group 12 weeks after the delivery of the reminder. Results A total of 1383 men and women were randomized and analyzed as allocated (n = 461 per trial arm). Uptake was 0.2 % (n = 1), 10.4 % (n = 48), and 15.2 % (n = 70) in the control, TMR-SIB, and TMR-TBL groups, respectively. Individuals in the TMR-SIB and TMR-TBL groups were significantly more likely to attend screening than individuals in the control group (adjusted odds ratio [OR] 53.7, 95 % confidence interval [CI] 7.4 - 391.4, P < 0.001 and OR 89.0, 95 %CIs 12.3 - 645.4, P < 0.01, respectively). Individuals in the TMR-TBL group were also significantly more likely to attend screening than individuals in the TMR-SIB group (OR 1.7, 95 %CIs 1.1 - 2.5, P = 0.01). Across all groups, former nonattenders were more likely to participate in screening than former nonresponders (uptake was 14.2 % and 8.0 %, respectively; OR 2.5, 95 %CIs 1.4 - 4.4, P < 0.01). The adenoma detection rate among screened adults was 7.6 %, which is comparable to the rate in initial attenders. Conclusions Reminders targeting former nonparticipants can improve uptake and are effective for both former nonresponders and nonattenders. Theory based information designed to target barriers to screening added significantly to this strategy. PMID- 27997968 TI - The Microbiome and the Liver: The Basics. AB - The relationships between the microbiota and other aspects of normal human biology continue to be explored. Indeed, the volume of information relating to the interplay between the host and the microbiota has grown exponentially especially with the advent of ever-improving techniques for rapidly sequencing and identifying bacterial populations and their functions. The gut is initially sterile at birth and colonization and dynamic changes occur during infancy and early childhood in order to establish a mature microbiome. The mature microbiome has direct and important interactions with host metabolism. Bacterial translocation from the gut microbiome is thought to be a key driver of inflammation in liver disease and changes in tolerance to these bacteria drive inflammation in the liver and elsewhere in the host. As we are better able to describe the composition and functional properties of the microbiome, the range of its impact on the homeostatic functions of the human body and implications for disease continue to be extended. PMID- 27997969 TI - Studying the Microbiome: "Omics" Made Accessible. AB - The term microbiome refers to the collection of microbes or microbial genes in a specified location or clinical sample. Identifying micro-organisms has historically relied upon bacteriological culture, which is time consuming and difficult to effectively implement. The recent adaptation of culture-independent techniques for profiling microbial communities, allied with next-generation massively parallel DNA sequencing, allows clinician scientists to determine the entire microbial content of a specimen to a forensic level of detail within 48 hours. The technology is still young, and the main thrust of current efforts is to identify how changes in the microbiome covary with a variety of syndromes and diseases, and to determine if these changes are causative or consequential. Regardless of the outcome of these investigations, it is already apparent that the gut microbiome is a useful biomarker for intestinal and extraintestinal disease. In this review, the authors summarize the main concepts in microbiome analysis, and prospects for the microbiome's clinical deployment. PMID- 27997970 TI - The Metabolic Role of the Microbiome: Implications for NAFLD and the Metabolic Syndrome. AB - Nonalcoholic fatty liver disease (NAFLD) has rapidly emerged as one of the most prevalent liver diseases worldwide and is set to achieve virtually epidemic proportions if current trends in obesity continue. A considerable volume of data from animal experiments has revealed the magnitude of the metabolic contribution of the gut microbiome and how a disordered microbial population could contribute to the development of obesity and its complications, including NAFLD. Although considerable progress has been made in developing a role for the microbiome in NAFLD and nonalcoholic steatosis (NASH), there are still many issues to be resolved, including the nature and location of the altered microbiome (i.e., small intestine or colon, or both); the specificity of deficits in intestinal integrity to NAFLD/NASH versus liver disease in general; the metabolic pathways, in man, that are key to the influence of the microbiome; and finally, the therapeutic interventions that are likely to be of benefit to our patients.As always, the situation in man is somewhat more complex than in animal models, but the role of the microbiota and of interventions that modulate the microbiome, though not yet ready for clinical practice, continue to be fertile areas for basic and clinical research. PMID- 27997971 TI - Microbiome-Host Immune System Interactions. AB - The intestinal immune system recognizes and responds to the vast diversity of microbes present within the gut. Highly sophisticated cellular and molecular networks are continuously coordinated to tolerate the presence of a large number and diversity of bacteria on mucosal surfaces. Different types of bacteria induce different immune responses, and bacterial metabolism of dietary factors generates metabolites that have significant effects on host immune responses. Dendritic cells, epithelial cells, innate lymphoid cells, T-regulatory cells, effector lymphocytes, natural killer T cells, and B-cell responses can all be influenced by the microbiome. Many of the mechanisms being described are bacterial strain or metabolite-specific. A better understanding of the mechanisms governing microbiome-host immune responses will likely lead to novel therapeutics for inflammatory disorders. PMID- 27997972 TI - Changes in the Microbiome in Cirrhosis and Relationship to Complications: Hepatic Encephalopathy, Spontaneous Bacterial Peritonitis, and Sepsis. AB - Chronic liver disease with progression to decompensated cirrhosis and its associated complications, including hepatic encephalopathy, spontaneous bacterial peritonitis, and sepsis, is a leading cause of mortality and morbidity. The pathophysiology of decompensated cirrhosis, which is being intensively studied, leads to the development of gut microbiome changes causing dysbiosis. This is likely related to altered bile acid composition, with a subsequent increase in the relative abundance of potentially pathogenic bacteria that contributes to hepatic encephalopathy and leads to their translocation and the development of spontaneous bacterial peritonitis and bacteremia. Treatments for these conditions have been found to target the gut microbiome, which has become a vital area of study in the treatment of cirrhosis. PMID- 27997973 TI - Bidirectional Communication between Liver and Gut during Alcoholic Liver Disease. AB - Alcoholic liver disease is a major medical burden. Alcohol abuse is the cause for end-stage liver disease in approximately 50% of all patients with cirrhosis. Chronic alcohol consumption is associated with changes in the composition of the intestinal microbiota and gut barrier dysfunction. The portal vein is the major communication route between the intestine and the liver. Increased intestinal permeability allows microbial components, bacteria, and metabolites to translocate to the liver. The liver communicates with the intestine via mediators in the systemic circulation and the biliary system. In this review, the authors describe the changes that occur in the intestinal microbiota with chronic alcohol consumption. They further review the bilateral communication between the liver and the gut, and discuss how this interaction affects the progression of alcoholic liver disease. PMID- 27997974 TI - The Microbiome and Primary Sclerosing Cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with detrimental sequela. In many patients, PSC progresses to end-stage liver disease and hepatobiliary cancer. There is no medical therapy that is proven to halt or reverse the progression of PSC. Approximately 70 to 80% of PSC patients have inflammatory bowel disease, usually ulcerative colitis. The etiology of PSC is poorly understood. Several lines of evidence suggest that the intestinal microbiota plays an important role in the etiopathogenesis of PSC. Stemming from this theory, several antibiotics have been tried in PSC, some of which had shown promising results. Fecal microbiota transplantation is a novel therapy, and is currently being investigated as a potential therapeutic strategy in PSC along with probiotics. In this article, the authors discuss the current knowledge of the intestinal microbiota in PSC. PMID- 27997975 TI - Primary Biliary Cirrhosis and the Microbiome. AB - Primary biliary cirrhosis is a rather uncommon, slowly progressive, cholestatic liver disease that predominantly affects middle-aged women. Apart from the changes in the gut microbiome that have been described in liver disease in general, little is known of the composition of the microbiome in primary biliary cirrhosis. Nevertheless, epidemiological, clinical, and some experimental evidence points to the possible role of a bacterium (or bacteria) in the initiation of the autoimmune process that leads to the development of this unique clinical phenotype. PMID- 27997976 TI - The Microbiome: What Will the Future Hold? AB - Current research on the human microbiome has opened our eyes to the intimate relationship that we have with the bacteria that populate our gastrointestinal tract and its potential relationship to health and disease. To date, clinical research on the microbiome has identified intriguing associations between an altered microbiome and disease states, but proven therapeutic applications have been very limited. The ingestion of prebiotics, probiotics, and/or synbiotics is appealing to the general public and has significant commercial value, but as yet, solid evidence for clinical efficacy in liver disease has been lacking due, in large part, to the paucity of high-quality clinical trials. On the other hand, the resounding success of fecal microbiota transplantation in Clostridium difficile infection has opened our eyes to the real potential of "pharmabiotics" and may well provide an intriguing template for the development of novel approaches to modulate the microbiome and its interactions with the host and thereby treat and/or prevent disease states. We will attempt to examine the current state of microbiome therapeutics and predict how these approaches might fit into the management of liver diseases in the future. PMID- 27997977 TI - Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin. AB - The processes causing increased hepatic triglycerides (TGs) in mouse models of hepatic steatosis (HS) due to high fat diet (HFD)-induced obesity (DIO), EtOH consumption, or obesity mutations (ob/ob, db/db) are uncertain. This report summarizes two studies. Study 1 focused on regulation by five transcription factors (TFs) (NfKb, Srebp-lc, AMPK, PPARalpha, PPARgamma) of seven, much-studied hepatic long-chain fatty acid (LCFA) transporters (FABPpm, CD36, FATPl, FATP2, FATP4, FATP5, & Caveolin-1 [CAV-1]), and expression of genes for enzymes of LCFA synthesis (SCD-1, FASN) in mice with HS from various causes. Study 2 examined the effects of spexin, a novel adipokine, on obesity, type 2 diabetes mellitus (T2DM), and HS in these mice. Study 1 showed that: (1) processes underlying HS differed in mice with normal leptin signaling (DIO, EtoH-fed) versus those without it (ob/ob, db/db). Increased hepatocellular LCFA uptake was the principal cause of HS in the former, but increased hepatocellular LCFA synthesis predominated in the latter. (2) Expression of individual transporters was variable in the HS models studied, but strong correlations between TF expression and mean expression of four transporter genes across multiple HS models suggested regulatory interaction, and support the postulate that complexes of several different transporters mediate hepatic LCFA uptake. Study 2 indicated (1) that obese DIO mice often also have T2DM and/or nonalcoholic fatty liver disease (NAFLD); (2) confirmed that spexin treatment caused weight loss in DIO mice; (3) in DIO mice with T2DM, spexin also improved glucose tolerance, decreasing insulin resistance and HbAlc. Incubation with spexin directly inhibited LCFA uptake by hepatocytes isolated from DIO mice with HS/NAFLD by <=70%. Spexin treatment in vivo for 4 weeks reduced hepatic lipids by 60%, and reduced serum alanine and aspartate aminotransferases. These studies in mice with DIO, T2DM, and HS/NAFLD suggest spexin may be an effective treatment for all three conditions. PMID- 27997978 TI - Blood pressure-lowering efficacy of reserpine for primary hypertension. AB - BACKGROUND: Many antihypertensive agents exist today for the treatment of primary hypertension (systolic blood pressure >= 140 mmHg or diastolic blood pressure >= 90 mmHg, or both). Randomised controlled trials (RCTs) have been carried out to investigate the evidence for these agents. There is, for example, strong RCT evidence that thiazides reduce mortality and morbidity. Some of those trials used reserpine as a second-line therapy. However, the dose-related blood pressure reduction with this agent is not known. OBJECTIVES: The primary objective of this review was to quantify the dose-related efficacy of reserpine versus placebo or no treatment in reducing systolic blood pressure (SBP) or diastolic blood pressure (DBP), or both.We also aimed to evaluate the dose-related effects of reserpine on mean arterial blood pressure (MAP) and heart rate (HR), as well as the dose-related effects on withdrawals due to adverse events. SEARCH METHODS: We searched the Cochrane Hypertension Group Specialised Register (January 1946 to October 2016), CENTRAL (2016, Issue 10), MEDLINE (January 1946 to October 2016), Embase (January 1974 to October 2016), and ClinicalTrials.gov (all dates to October 2016). We also traced citations in the reference sections of the retrieved studies. SELECTION CRITERIA: Included studies were truly randomised controlled trials (RCTs) comparing reserpine monotherapy to placebo or no treatment in participants with primary hypertension. DATA COLLECTION AND ANALYSIS: We assessed methods of randomisation and concealment. We extracted and analysed data on blood pressure reduction, heart rate, and withdrawal due to adverse effects. MAIN RESULTS: We found four RCTs (with a total of 237 participants) that met the inclusion criteria, none of which we found through the 2016 update search. The overall pooled effect demonstrates a statistically significant systolic blood pressure (SBP) reduction in participants taking reserpine compared with placebo (weighted mean difference (WMD) -7.92, 95% confidence interval (CI) -14.05 to -1.78). Because of significant heterogeneity across the trials, a significant effect in diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) could not be found. A dose of reserpine 0.5 mg/day or greater achieved the SBP effects. However, we could not determine the dose-response pattern because of the small number of trials. We did not combine data from the trial that investigated Rauwiloid against placebo with reserpine data from the remaining three trials. This is because Rauwiloid is a different alkaloid extract of the plant Rauwolfia serpentina, and the dose used is not comparable to reserpine. None of the included trials reported withdrawals due to adverse effects. AUTHORS' CONCLUSIONS: Reserpine is effective in reducing SBP roughly to the same degree as other first-line antihypertensive drugs. However, we could not make definite conclusions regarding the dose-response pattern because of the small number of included trials. More RCTs are needed to assess the effects of reserpine on blood pressure and to determine the dose related safety profile before the role of this drug in the treatment of primary hypertension can be established. PMID- 27997979 TI - Reply. PMID- 27997980 TI - New therapeutic concepts in bile acid transport and signaling for management of cholestasis. AB - The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA-induced gut hormones, fibroblast growth factor 19 and glucagon-like peptide 1, and the BA transport systems, apical sodium-dependent bile acid transporter and Na+ taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393-1404). PMID- 27997981 TI - Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. Implications for tissue specificity and durability of elastic tissue. AB - Polymeric elastin provides the physiologically essential properties of extensibility and elastic recoil to large arteries, heart valves, lungs, skin and other tissues. Although the detailed relationship between sequence, structure and mechanical properties of elastin remains a matter of investigation, data from both the full-length monomer, tropoelastin, and smaller elastin-like polypeptides have demonstrated that variations in protein sequence can affect both polymeric assembly and tensile mechanical properties. Here we model known splice variants of human tropoelastin (hTE), assessing effects on shape, polymeric assembly and mechanical properties. Additionally we investigate effects of known single nucleotide polymorphisms in hTE, some of which have been associated with later onset loss of structural integrity of elastic tissues and others predicted to affect material properties of elastin matrices on the basis of their location in evolutionarily conserved sites in amniote tropoelastins. Results of these studies show that such sequence variations can significantly alter both the assembly of tropoelastin monomers into a polymeric network and the tensile mechanical properties of that network. Such variations could provide a temporal- or tissue specific means to customize material properties of elastic tissues to different functional requirements. Conversely, aberrant splicing inappropriate for a tissue or developmental stage or polymorphisms affecting polymeric assembly could compromise the functionality and durability of elastic tissues. To our knowledge, this is the first example of a study that assesses the consequences of known polymorphisms and domain/splice variants in tropoelastin on assembly and detailed elastomeric properties of polymeric elastin. PMID- 27997982 TI - Influence of tooth bleaching on dental enamel microhardness: a systematic review and meta-analysis. AB - Several studies have investigated the effect of bleaching on dental tissues. The evaluation of the effect of home bleaching with 10% carbamide peroxide is important for assessing alterations in enamel microhardness that may affect dental health in terms of resistance to masticatory forces. This meta-analysis was performed in order to determine scientific evidence regarding the effects of home vital bleaching with 10% carbamide peroxide gel on the microhardness of human dental enamel. A systematic electronic literature search was conducted in the PubMed and Web of Science databases using search terms. Two independent researchers evaluated the information and methodological quality of the studies. Inclusion and exclusion criteria were established for article selection; further, only studies published in English were selected. Thirteen studies that met all of the inclusion and exclusion criteria were selected and underwent statistical analysis. The results of this meta-analysis showed no significant changes in enamel microhardness when using the 10% carbamide peroxide bleaching gel over periods of 7, 14 and 21 days. PMID- 27997983 TI - Validation of International Classification of Disease Ninth Revision codes for atopic dermatitis. AB - BACKGROUND: Evaluation of large-scale data sets is needed to better understand the epidemiology, cost, and burden of atopic dermatitis (AD). We sought to validate the use of ICD-9-CM codes for identifying AD. METHODS: Patients from a large metropolitan quaternary care medical center with a diagnostic code of either 691.8 (AD) or 692.9 (eczema and contact dermatitis) were queried. Medical records were reviewed for demographics, Hanifin & Rajka (H&R) and United Kingdom Working Party (UKWP) criteria. Sensitivity, specificity, and positive predictive values (PPV) of the codes were calculated. RESULTS: Of 43 278 patients identified with associated ICD-9 codes of 691.8 or 692.9, 519 and 253 with 691.8 and 692.9 were randomly selected for chart review. There was extensive overlap: 34.3% had >=1 occurrences of 691.8 and 692.9 and 25.6% had multiple occurrences of both codes. Among patients with >=1 occurrence of 691.8, 29.9% and 30.8% met the H&R and UKWP criteria, respectively. Similarly, among patients with >=1 occurrence of 692.9, 33.7% and 32.2% met the H&R and UKWP criteria. Increased PPV was associated with concomitant diagnoses of asthma, hay fever, and food allergy and increased disease severity. CONCLUSIONS: In the outpatient setting, the ICD-9-CM codes 691.8 and 692.9 alone have poor PPV. Incorporation of diagnoses of asthma, hay fever, and food allergy improves PPV and specificity. In the inpatient setting, a primary discharge diagnosis of 691.8 had excellent PPV. Although ICD 10 has been adopted in Europe and more recently in the USA, the same systematic errors would likely occur unless providers standardize their coding. PMID- 27997984 TI - The relationship between lip-closing force and dental arch morphology in patient with Angle Class I malocclusion. AB - Dental arch morphology and tooth position are affected by lip-closing force (LCF). This study aimed to quantitatively evaluate the relationships between the horizontal or vertical balance of the LCF generated during maximum voluntary pursing-like movements and dental arch length (DAL) or width (DAW) or the lingual inclination of the upper or lower 1st molars (LIUM, LILM) in patients with Angle Class I malocclusion. Sixteen subjects with Angle Class I malocclusion (median age: 23.4 +/- 5.9 years) who had never undergone orthodontic treatment were randomly selected. LCF was measured in eight directions during maximum voluntary pursing-like lip-closing movements. Dental arch models were scanned and analysed to obtain DAW, DAL, LIUM and LILM measurements. Mandibular deviation was measured on posteroanterior cephalograms. A significant negative correlation was detected between maxillary DAL and upper LCF. Maxillary DAL, DAW and the DAL/DAW ratio displayed significant negative correlations with total LCF and upper LCF. However, no significant correlations were detected between any mandibular dental arch morphological parameter and LCF. The difference in the LIUM between the deviation and non-deviation sides exhibited a significant positive correlation with the difference in upper LCF between the deviation and non-deviation sides and was significantly negatively correlated with the difference in lower LCF between the deviation and non-deviation sides. These results suggest that upper LCF is related to maxillary DAL, and the horizontal balance of the LCF of the upper and lower lips is related to the LIUM during pursing-like lip-closing movements in patients with Angle Class I malocclusion. PMID- 27997985 TI - The role of postoperative chemoradiation for oropharyngeal carcinoma: A critical appraisal revisited. PMID- 27997987 TI - Long-term outcome in liver transplantation candidates with portopulmonary hypertension. AB - : Portopulmonary hypertension (PoPH) is diagnosed in 2-6% of liver transplantation (LT) candidates. We studied outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, and within 6 months and beyond 6 months after LT. Forty-nine patients (35 males, 48 +/- 8 years) were analyzed (median Model for End-Stage Liver Disease score 20). At baseline, mean pulmonary artery pressure (mPAP) was 44 +/- 10 mm Hg (range 26-73 mm Hg), cardiac index was 3.5 +/ 0.9 L/min/m2 , and pulmonary vascular resistance was 5.6 +/- 2.8 Wood units. Hemodynamic reassessment performed in 35 patients who were treated with pulmonary arterial hypertension-targeted therapies before LT resulted in significant decreases in both mPAP (36 +/- 7 versus 47 +/- 10 mm Hg, P < 0.0001) and pulmonary vascular resistance (3.0 +/- 1.4 versus 6.1 +/- 3.1 Wood units, P < 0.0001). Fourteen patients (29%) died without having had access to LT. Thirty five patients underwent LT and were followed up for a median of 38 months. Eight patients (23%) died after LT including 5 due to PoPH (after 1 day to 6 months). Among survivors (n = 27), all patients treated with intravenous epoprostenol were weaned off post-LT, and endothelin receptor antagonist or phosphodiesterase type 5 inhibitors were continued in 15/27 patients (55%). At last evaluation, 20/27 patients (74%) had mPAP <35 mm Hg and 8 of them (30%) had mPAP <25 mm Hg. Overall survival estimates after LT were 80%, 77%, and 77% at 6 months, 1 year, and 3 years, respectively. CONCLUSION: Stabilization or reversibility of PoPH seems to be an attainable goal using the combination of pulmonary arterial hypertension targeted therapies and LT in patients who are transplantation candidates. (Hepatology 2017;65:1683-1692). PMID- 27997986 TI - Anatomy and spatial organization of Muller glia in mouse retina. AB - Muller glia, the most abundant glia of vertebrate retina, have an elaborate morphology characterized by a vertical stalk that spans the retina and branches in each retinal layer. Muller glia play diverse, critical roles in retinal homeostasis, which are presumably enabled by their complex anatomy. However, much remains unknown, particularly in mouse, about the anatomical arrangement of Muller cells and their arbors, and how these features arise in development. Here we use membrane-targeted fluorescent proteins to reveal the fine structure of mouse Muller arbors. We find sublayer-specific arbor specializations within the inner plexiform layer (IPL) that occur consistently at defined laminar locations. We then characterize Muller glia spatial patterning, revealing how individual cells collaborate to form a pan-retinal network. Muller cells, unlike neurons, are spread across the retina with homogenous density, and their arbor sizes change little with eccentricity. Using Brainbow methods to label neighboring cells in different colors, we find that Muller glia tile retinal space with minimal overlap. The shape of their arbors is irregular but nonrandom, suggesting that local interactions between neighboring cells determine their territories. Finally, we identify a developmental window at postnatal Days 6 to 9 when Muller arbors first colonize the synaptic layers beginning in stereotyped inner plexiform layer sublaminae. Together, our study defines the anatomical arrangement of mouse Muller glia and their network in the radial and tangential planes of the retina, in development and adulthood. The local precision of Muller glia organization suggests that their morphology is sculpted by specific cell to cell interactions with neurons and each other. PMID- 27997988 TI - Hepatostat: Liver regeneration and normal liver tissue maintenance. AB - In contrast to all other organs, liver-to-body-weight ratio needs to be maintained always at 100% of what is required for body homeostasis. Adjustment of liver size to 100% of what is required for homeostasis has been called "hepatostat." Removal of a portion of any other organ is followed with local regeneration of a limited degree, but it never attempts to reach 100% of the original size. The complex mechanisms involved in this uniquely hepatic process encompass a variety of regenerative pathways that are specific to different types of injury. The most studied form of liver regeneration (LR) is that occurring after loss of hepatocytes in a single acute injury, such as rodent LR after two thirds partial hepatectomy or administration of damaging chemicals (CCl4 , acetaminophen, etc.). Alternative regenerative pathways become activated when normal regeneration is thwarted and trigger the appearance of "progenitor" cells. Chronic loss of hepatocytes is associated with regenerative efforts characterized by continual hepatocyte proliferation and often has adverse consequences (development of cirrhosis or liver cancer). Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood. (Hepatology 2017;65:1384-1392). PMID- 27997990 TI - Blood microbiota as a potential noninvasive diagnostic biomarker for liver fibrosis in severely obese patients: Choose carefully. PMID- 27997989 TI - Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study. AB - : Obesity increases the risk of clinical decompensation in cirrhosis, possibly by increasing portal pressure. Whether weight reduction can be safely achieved through lifestyle (LS) changes (diet and exercise) in overweight/obese patients with cirrhosis, and if weight loss reduces portal pressure in this setting, is unknown. This prospective, multicentric, uncontrolled pilot study enrolled patients with compensated cirrhosis, portal hypertension (hepatic venous pressure gradient [HVPG] >=6 mm Hg), and body mass index (BMI) >=26 kg/m2 in an intensive 16-week LS intervention program (personalized hypocaloric normoproteic diet and 60 min/wk of supervised physical activity). We measured HVPG, body weight (BW) and composition, adipokines, health-related quality of life, and safety data before and after the intervention. Changes in HVPG and BW were predefined as clinically relevant if >=10% and >=5%, respectively. Safety and BW were reassessed after 6 months. 60 patients were included and 50 completed the study (56 +/- 8 years old; 62% male; nonalcoholic steatohepatitis etiology 24%; BMI 33.3 +/- 3.2 kg/m2 ; Child A 92%; HVPG >=10 mm Hg, 72%). LS intervention significantly decreased BW (average, -5.0 +/- 4.0 kg; P < 0.0001), by >=5% in 52% and >=10% in 16%. HVPG also significantly decreased (from 13.9 +/- 5.6 to 12.3 +/ 5.2 mm Hg; P < 0.0001), by >=10% in 42% and >=20% in 24%. A >=10% BW loss was associated with a greater decrease in HVPG (-23.7 +/- 19.9% vs. -8.2 +/- 16.6%; P = 0.024). No episodes of clinical decompensation occurred. Weight loss achieved at 16 weeks was maintained at 6 months; Child and Model for End-Stage Liver Disease scores did not change. CONCLUSION: Sixteen weeks of diet and moderate exercise were safe and reduced BW and portal pressure in overweight/obese patients with cirrhosis and portal hypertension. (Hepatology 2017;65:1293-1305). PMID- 27997991 TI - Decreased frequencies and impaired functions of the CD31+ subpopulation in Treg cells associated with decreased FoxP3 expression and enhanced Treg cell defects in patients with coronary heart disease. AB - Coronary heart disease (CHD) is one of the most common types of organ lesions caused by atherosclerosis, in which CD4+ CD25+ forkhead box protein 3 (FoxP3+ ) regulatory T cells (Treg ) play an atheroprotective role. However, Treg cell numbers are decreased and their functions are impaired in atherosclerosis; the underlying mechanisms remain unclear. CD31 plays an important part in T cell response and contributes to maintaining T cell tolerance. The immunomodulatory effects of CD31 are also implicated in atherosclerosis. In this study, we found that decreased frequencies of the CD31+ subpopulation in Treg cells (CD31+ Tr cells) correlated positively with decreased FoxP3 expression in CHD patients. Cell culture in vitro demonstrated CD31+ Tr cells maintaining stable FoxP3 expression after activation and exhibited enhanced proliferation and immunosuppression compared with the CD31- subpopulation in Treg cells (CD31- Tr cells). We also confirmed impaired secretion of transforming growth factor (TGF) beta1 and interleukin (IL)-10 in CD31+ Tr cells of CHD patients. Further analysis revealed reduced phospho-SHP2 (associated with CD31 activation) and phospho signal transducer and activator of transcription-5 (STAT-5) (associated with FoxP3 transcription) levels in CD31+ Tr cells of CHD patients, suggesting that decreased FoxP3 expression in CD31+ Tr cells might be because of attenuated SHP2 and STAT-5 activation. These data indicate that decreased frequencies and impaired functions of the CD31+ Tr subpopulation associated with decreased FoxP3 expression give rise, at least in part, to Treg cell defects in CHD patients. Our findings emphasize the important role of the CD31+ Tr subpopulation in maintaining Treg cell normal function and may provide a novel explanation for impaired immunoregulation of Treg cells in CHD. PMID- 27997992 TI - Acute moderate exercise improves mnemonic discrimination in young adults. AB - Increasing evidence suggests that regular moderate exercise increases neurogenesis in the dentate gyrus (DG) of the hippocampus and improves memory functions in both humans and animals. The DG is known to play a role in pattern separation, which is the ability to discriminate among similar experiences, a fundamental component of episodic memory. While long-term voluntary exercise improves pattern separation, there is little evidence of alterations in DG function after an acute exercise session. Our previous studies showing acute moderate exercise-enhanced DG activation in rats, and acute moderate exercise enhanced prefrontal activation and executive function in humans, led us to postulate that acute moderate exercise may also activate the hippocampus, including more specifically the DG, thus improving pattern separation. We thus investigated the effects of a 10-min moderate exercise (50% VO2peak ) session, the recommended intensity for health promotion, on mnemonic discrimination (a behavioral index of pattern separation) in young adults. An acute bout of moderate exercise improved mnemonic discrimination performance in high similarity lures. These results support our hypothesis that acute moderate exercise improves DG-mediated pattern separation in humans, proposing a useful human acute-exercise model for analyzing the neuronal substrate underlying acute and regular exercise enhanced episodic memory based on the hippocampus. (c) 2016 Wiley Periodicals, Inc. PMID- 27997994 TI - Deciding what is possible and impossible following hippocampal damage in humans. AB - There is currently much debate about whether the precise role of the hippocampus in scene processing is predominantly constructive, perceptual, or mnemonic. Here, we developed a novel experimental paradigm designed to control for general perceptual and mnemonic demands, thus enabling us to specifically vary the requirement for constructive processing. We tested the ability of patients with selective bilateral hippocampal damage and matched control participants to detect either semantic (e.g., an elephant with butterflies for ears) or constructive (e.g., an endless staircase) violations in realistic images of scenes. Thus, scenes could be semantically or constructively 'possible' or 'impossible'. Importantly, general perceptual and memory requirements were similar for both types of scene. We found that the patients performed comparably to control participants when deciding whether scenes were semantically possible or impossible, but were selectively impaired at judging if scenes were constructively possible or impossible. Post-task debriefing indicated that control participants constructed flexible mental representations of the scenes in order to make constructive judgements, whereas the patients were more constrained and typically focused on specific fragments of the scenes, with little indication of having constructed internal scene models. These results suggest that one contribution the hippocampus makes to scene processing is to construct internal representations of spatially coherent scenes, which may be vital for modelling the world during both perception and memory recall. (c) 2016 The Authors. Hippocampus Published by Wiley Periodicals, Inc. PMID- 27997995 TI - cIMPACT-NOW (the consortium to inform molecular and practical approaches to CNS tumor taxonomy): a new initiative in advancing nervous system tumor classification. PMID- 27997996 TI - Oral health interventions in Australian Aboriginal communities: a review of the literature. AB - Aboriginal Australians experience significant disparities in oral health with even poorer outcomes reported in rural and remote areas. The high rates of preventable dental disease in Aboriginal communities are a serious concern from a social standpoint and in terms of service provision and health care expenditure. In this review, primary research literature was comprehensively reviewed. Papers were selected if they reported designing or implementing an intervention or oral health programme specific to the needs of Aboriginal communities. Twenty-one publications fulfilled the inclusion criteria with 19 different interventions being described. Interventions were categorized using a classification adapted from the work of Whitehead (2002). The review identified interventions that aimed to reduce early childhood caries, increase services to remote communities, develop the role of Aboriginal health workers, improve oral health literacy, establish water fluoridation and provide periodontal therapy. Implementing successful oral health interventions in Aboriginal communities is a challenge that is compounded by the complex interplay between psychosocial and cultural determinants. Even interventions that follow a rigorous and consultative design have a high failure rate in Aboriginal communities if upstream determinants of health are not adequately understood and addressed. PMID- 27997993 TI - Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice. AB - Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer's disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late-stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross-sectional study of histologic markers of tauopathy to determine whether (1) early GluCEST changes are associated with synapse loss before volume loss occurs in the hippocampus, and whether (2) subhippocampal dynamics in GluCEST are associated with histopathologic events related to glutamate alterations in tauopathy. Live imaging of the hippocampus in three serial slices was performed without exogenous contrast agents, and subregions were segmented based on a k-means cluster model. Subregions of the hippocampus were analyzed (cornu ammonis CA1, CA3, dentate gyrus DG, and ventricle) in order to associate local MRI-observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA-NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, P <= 0.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6 months. Volume was not significantly reduced in any subregion until 13 months. Further, a gradient in glutamate levels was observed in vivo along hippocampal axes that became polarized as tauopathy progressed. Dynamics in hippocampal glutamate levels throughout lifetime were most closely correlated with combined changes in synaptophysin and GFAP, indicating that GluCEST imaging may be a surrogate marker of glutamate concentration in glial cells and at the synaptic level. (c) 2016 Wiley Periodicals, Inc. PMID- 27997997 TI - The structure of the mite allergen Blo t 1 explains the limited antibody cross reactivity to Der p 1. AB - The Blomia tropicalis (Blo t) mite species is considered a storage mite in temperate climate zones and an important source of indoor allergens causing allergic asthma and rhinitis in tropical and subtropical regions. Here, we report the crystal structure of one of the allergens from Blo t, recombinant proBlo t 1 (rproBlo t 1), determined at 2.1 A resolution. Overall, the fold of rproBlo t 1 is characteristic for the pro-form of cysteine proteases from the C1A class. Structural comparison of experimentally mapped Der f 1/Der p1 IgG epitopes to the same surface patch on Blo t 1, as well as of sequence identity of surface-exposed residues, suggests limited cross-reactivity between these allergens and Blo t 1. This is in agreement with ELISA inhibition results showing that, although cross reactive human IgE epitopes exist, there are unique IgE epitopes for both Blo t 1 and Der p 1. PMID- 27997998 TI - A novel bispecific DARPin targeting FcgammaRIIB and FcepsilonRI-bound IgE inhibits allergic responses. AB - BACKGROUND: Binding of allergen-specific IgE to its high-affinity receptor FcepsilonRI on basophils and mast cells is a central event in the development of allergies. Exposure of these cells to allergens induces the release of soluble mediators causing allergic symptoms. The inhibitory low-affinity IgG Fc-receptor FcgammaRIIB is co-expressed on allergic effector cells and has been implicated in negative regulation of immediate hypersensitivity responses. In order to harvest the inhibitory function of this receptor, we aimed to select specific binders against FcgammaRIIB and to generate a bispecific molecule simultaneously targeting FcgammaRIIB and FcepsilonRI-bound IgE on the surface of allergic effector cells. METHODS: We selected FcgammaRIIB-specific binding molecules from a library of designed ankyrin repeat proteins using ribosome display technology. The bispecific binding modality was generated by molecular cloning and recombinant protein expression. We determined binding characteristics on molecular and cellular levels using SPR, ELISA, and flow cytometry. The inhibitory potential of the newly described molecules was assessed in different cellular degranulation assays ex vivo and in a mouse model of passive systemic anaphylaxis. RESULTS: We demonstrate that the selected DARPin(r) proteins recognize FcgammaRIIB with high affinity. Furthermore, the bispecific binding protein successfully interferes with allergen-induced cell degranulation and efficiently inhibits systemic anaphylaxis in vivo. Mechanistically, we report that FcgammaRIIB-mediated inhibition of effector cell activation requires direct ligation to an activating FcepsilonRI receptor. CONCLUSION: The described bispecific DARPin protein has the ability to co-ligate FcgammaRIIB with FcepsilonRI-bound IgE on allergic effector cells and represents an efficient dual modality to interfere with allergic hypersensitivity reactions. PMID- 27998000 TI - Severe excessive daytime sleepiness induced by hydroxyurea. AB - Excessive daytime sleepiness (EDS) has been reported with many drugs, either as an extension of a hypnotic effect (e.g. central nervous system depressants) or as an idiosyncratic response of the patient. Here, we report unexpected and severe subjective and objective EDS induced by hydroxyurea therapy, with a favorable outcome after withdrawal. Clinical history, sleep log, polysomnography, and multiple sleep latency tests confirming the absence of other EDS causes are presented. PMID- 27998001 TI - Knocked by the shuttlecock: twelve sight-threatening blunt-eye injuries in Australian badminton players. AB - BACKGROUND: Non-penetrating ocular injuries from badminton shuttlecocks can result in severe damage and life-long complications. This case series highlights the morbidity of such injuries, particularly in regard to post-traumatic glaucoma. METHODS: This is a retrospective case series of 12 patients with shuttlecock-related blunt eye injuries sustained during badminton play without eye protection. By approaching colleagues through conference presentations and networking, the authors have attempted to gather all known cases of shuttlecock ocular injury managed in tertiary ocular emergency departments or private ophthalmological clinics in Victoria and New South Wales, Australia in 2015. RESULTS: This is the first multicentre case series to describe badminton-related ocular injuries in Australia. Our case series demonstrates, in particular, long term glaucoma-related morbidity for patients over a large age range (16 to 77 years), with one patient requiring ongoing management 26 years following their initial injury. The cases reported further add to the literature promoting awareness of badminton-related ocular injury. CONCLUSIONS: We encourage player education and advocacy on badminton-related eye injuries and appropriate use of eye protection to reduce associated morbidity. PMID- 27997999 TI - Behavior-dependent activity patterns of GABAergic long-range projecting neurons in the rat hippocampus. AB - Long-range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O-LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin-labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave-ripples, most projection cells, including a novel SOM+ GABAergic back-projecting cell, increased their activity similar to bistratified cells, but unlike O-LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O-LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior- and network state dependent binding of neuronal assemblies amongst functionally-related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas. (c) 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID- 27998002 TI - BASALIT trial: double-blind placebo-controlled allergen immunotherapy with rBet v 1-FV in birch-related soya allergy. AB - BACKGROUND: Conflicting results exist on the effect of allergen immunotherapy (AIT) on pollen-related food allergy. We aimed to investigate the efficacy of one year AIT with the folding variant (FV) of recombinant (r) Bet v 1 on birch related soya allergy. METHODS: Of 138 subjects with Bet v 1 sensitization, 82 were positive at double-blind placebo-controlled food challenge (DBPCFC) with soya. A total of 56 of 82 were randomized in the ratio of 2:1 (active: placebo). Per-protocol population (PPP) had received >=150 MUg of allergen or placebo preparation. OUTCOME MEASURES: lowest observed adverse effect levels (LOAEL), postinterventional occurrence of objective signs (objS) at any dose level, sIgE/IgG4 against Bet v 1 and Gly m 4. Between-group changes were investigated (ancova, Mann-Whitney U-test, Fisher exact test). RESULTS: Baseline characteristics including LOAELs were comparable in both groups with objS and subjS occurring in 82% and 95% of active (n = 38) vs 78% and 83% of placebo group (n = 18). After AIT, objS occurred in 24% and 47%, respectively. LOAEL group differences showed a beneficial tendency (P = 0.081) for LOAELobjective in PPP (30 active, 15 placebo). sIgG4 raised only in active group (Bet v 1: P = 0.054, Gly m 4: P = 0.037), and no relevant changes occurred for sIgE. Only 56% of the intended sample size was recruited. CONCLUSION: For the first time, we present data on the effect of rBet v 1-FV on birch-related soya allergy. rBet v 1-FV AIT induced significant immunogenic effects. Clinical assessment showed a tendency in favour of the active group but did not reach statistical significance. PMID- 27998003 TI - Vitamin D contributes to mast cell stabilization. AB - BACKGROUND AND AIMS: Mast cells are the major effector cells in allergic disorders and many other informatory disorders. The mechanism of mast cell stabilization is not fully understood. Cumulative reports indicate that vitamin D (VitD) contributes to the homeostasis in the body. This study tests a hypothesis that VitD is required in the maintenance of the stability of mast cells. METHODS: The stability of mast cell lines, HMC1 cells, RBL-2H3 cells, p815 cells, and mouse bone marrow-derived mast cells (BMMC) was tested in the presence or absence of VitD3. RESULTS: Mast cells activated automatically in a VitD-deficient environment. Exposure to calcitriol in the culture increased the expression of VitD receptor (VDR) in mast cells. VDR formed complexes with Lyn in mast cells to inhibit the binding of Lyn to the beta chain of FcepsilonRI and MyD88, which decreased the phosphorylation of Syk, decreased the levels of MAPK and NF-kappaB. VDR bound to the promoter of TNF-alpha to decrease the acetylation of histone H3/H4, RNA polymerase II and OCT1 (a transcription factor of TNF-alpha) at the promoter locus and repressed the expression of TNF-alpha in mast cells. CONCLUSIONS: The data demonstrate that VitD is required to maintain the stability of mast cells. The deficiency of VitD results in mast cell activation. PMID- 27998004 TI - Dexmedetomidine preconditioning for myocardial protection in ischaemia reperfusion injury in rats by downregulation of the high mobility group box 1 toll-like receptor 4-nuclear factor kappaB signalling pathway. AB - Pharmacological preconditioning reduces myocardial infarct size in ischaemia reperfusion (I-R) injury. Dexmedetomidine, a selective alpha2 -adrenoceptor agonist, has a proven cardioprotective effect when administered prior to I-R, although the underlying mechanisms for this effect are not fully understood. We evaluated whether dexmedetomidine preconditioning could induce a myocardio protective effect against I-R injury by inhibiting associated inflammatory processes through downregulation of the high mobility group box 1 (HMGB1)-toll like receptor 4 (TLR4)-nuclear factor kappaB (NF-kappaB) signalling pathway. Seventy rats were randomly assigned to seven groups: a control and six test groups, involving I-R for 30 and 120 minutes, respectively, in isolated rat hearts and different pretreatment protocols with dexmedetomidine (10 nmol/L) as well as yohimbine (1 MUmol/L) and recombinant HMGB1 peptide (rHMGB1; 20 MUg/L), alone or in combination with dexmedetomidine. Cardiac function was recorded; myocardial HMGB1, TLR4, and NF-kappaB activities and levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured as were lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary outflow. Dexmedetomidine preconditioning significantly improved cardiac function (P<.05), downregulated the expression of HMGB1-TLR4-NF-kappaB, reduced levels of TNF-alpha and IL-6 in isolated ventricles during I-R injury, and significantly reduced CK and LDH levels in coronary outflow (P<.05). All of these effects were partially reversed by yohimbine (P<.05) or rHMGB1 (P<.05). Dexmedetomidine preconditioning alleviated myocardial I-R injury in rats through inhibition of inflammatory processes associated with downregulation of the HMGB1-TLR4-NF-kappaB signalling pathway via activation at alpha2 -adrenergic receptors. PMID- 27998005 TI - Sex differences in ischaemia/reperfusion-induced acute kidney injury depends on the degradation of noradrenaline by monoamine oxidase. AB - Ischaemic acute kidney injury (AKI) is a leading killer of both sexes; however, resistance to this injury is higher among women than men. We found that renal venous noradrenaline (NAd) overflow after reperfusion played important roles in the development of ischaemic AKI, and that the attenuation of AKI observed in female rats may be dependent on depressing the renal sympathetic nervous system with endogenous oestrogen. In the present study, we used male and female Sprague Dawley rats to investigate whether sex differences in the pathogenesis of ischaemic AKI are related to the degradation of NAd by monoamine oxidase (MAO) in the kidney. Ischaemic AKI was achieved by clamping the left renal artery and vein for 45 minutes followed by reperfusion 2 weeks after contralateral nephrectomy. Renal injury was more severe in male rats than in female rats and renal venous plasma NAd levels after reperfusion were markedly elevated in males, but not in females. These sex differences were eliminated by a treatment with isatin, a non selective MAO inhibitor, and moclobemide, a selective MAOA inhibitor, but not by selegiline, a selective MAOB inhibitor. Ischaemia decreased the mRNA expression levels of both MAOs in the kidney 1 day after reperfusion; however, MAOA mRNA expression levels were higher in female rats than in male rats. These results suggest that the degradation of NAd by MAOA in the kidney contributes to sex differences in the pathogenesis of ischaemia/reperfusion-induced AKI. PMID- 27998006 TI - Pravastatin attenuates the action of the ETS domain-containing protein ELK1 to prevent atherosclerosis in apolipoprotein E-knockout mice via modulation of extracellular signal-regulated kinase 1/2 signal pathway. AB - Oxidative stress plays an important role in atherosclerosis, a vascular disease with high morbidity and mortality. The ETS domain-containing protein ELK1 is an oxidative stress-sensitive factor modulated by the extracellular signal-regulated kinase (ERK) 1/2 pathway. However, the role of ELK1 in the prevention of atherosclerosis by pravastatin remains unclear. In the present study, male apolipoprotein E-knockout (apoE-/- ) mice fed a diet containing 1.25% cholesterol (w/w) were divided into two groups, one treated with pravastatin (80 mg/kg, 2-2.4 mg/mouse per day) for 8 weeks and the other not. Male C57BL/6J mice fed with a normal diet were used as a control group. Human umbilical vein endothelial cells (HUVEC) were cultured and treated with pravastatin (10 MUmol/L) for 18 hours before testing for the presence or absence of 100 MUmol/L H2 O2 (24 hours). Examination of pathological sections from mice aortas revealed that pravastatin treatment almost prevented atherosclerotic plaque formation. Pravastatin also inhibited increases in serum and aortic levels of oxidized low-density lipoprotein and aortic malondialdehyde levels and decreases in aortic reduced glutathione, and the activities of superoxide dismutase, catalase and glutathione peroxidase. H2 O2 -induced increases in reactive oxygen species in HUVECs were reversed by pravastatin by 48%. Pravastatin blocked the phosphorylation of ELK1 and ERK1/2 proteins and reduced mRNA levels of early growth response 1, a known atherogenic transcription factor upregulated by the ROS/ERK/ELK1 pathway, in mice. In conclusion, pravastatin attenuates the action of ELK1 induced by oxidative stress to prevent atherosclerosis, which is dependent partly on modulation of ERK1/2 signalling. PMID- 27998007 TI - Mandibular movements and bite force in Alzheimer's disease before and after new denture insertion. AB - Chewing impairment has been observed in elders with Alzheimer's disease (AD); however, it is unknown whether oral rehabilitation can improve their masticatory function. This study evaluated the influence of new removable prostheses on chewing function of patients with AD. Participants using removable dentures were divided into two groups: patients with mild AD (77.2 +/- 5.8 years, n = 16) and controls (76.0 +/- 4.4, n = 16). All participants received general dental treatment and new total and/or partial removable prostheses. After 2 months of adaptation to the new dentures, chewing was evaluated by the following parameters: masticatory cycle time (CT), cycle velocity (CV), and opening (OA) and closing mandibular angles (CA), registered by a kinesiographic device. Maximum bite force (MBF) was assessed using a strain sensor. Evaluations were performed at baseline and after insertion of the new prostheses. A mixed model (alpha = 5%) was used for within- and between-subject analyses. After insertion of new prostheses, CT was reduced, and CV and MBF were increased in both groups (P < 0.05). There were no changes in OA or CA (P > 0.05). Compared to controls, elders with AD showed higher CT and reduced MBF and CV both at baseline and after insertion of new prostheses (P < 0.05). However, OA and CA did not differ between groups (P > 0.05). Insertion of new removable prostheses improved masticatory function in elders with and without AD, but patients with mild AD still had reduced chewing parameters compared to controls. PMID- 27998009 TI - Endometriosis-associated infertility: aspects of pathophysiological mechanisms and treatment options. AB - Endometriosis is a common condition in women of reproductive age. In addition to pain, endometriosis may also reduce fertility. The causes of infertility in women with endometriosis may range from anatomical distortions due to adhesions and fibrosis to endocrine abnormalities and immunological disturbances. In some cases, the various pathophysiological disturbances seem to interact through mechanisms so far not fully understood. Whether surgery should be offered as a treatment option in endometriosis-associated infertility has become controversial, partly due to its modest or undocumented effect. Medical or hormonal treatment alone has little or no effect and should only be used in conjunction with assisted reproductive technology (ART). Of the various methods of ART, intrauterine insemination, due to its simplicity, can be recommended in women with minimal or mild peritoneal endometriosis, even though insemination may yield a lower success rate than in women without endometriosis. In vitro fertilization (IVF) is an effective treatment option in less-advanced disease stages, and the success rates are similar to the results in other causes of infertility. However, women with more advanced stages of endometriosis have lower success rates with IVF. PMID- 27998008 TI - Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor-alpha inhibited endothelial nitric oxide synthase expression in endothelial-trophoblast cellular networks. AB - Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-alpha (TNF alpha) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-alpha (0.5 ng/mL) or TNF-alpha plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-alpha on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-alpha and sFlt 1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-alpha, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-alpha or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-alpha. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway. PMID- 27998011 TI - Pleuroparenchymal fibroelastosis with prominent thrombosis. PMID- 27998010 TI - Modulation of the anti-inflammatory effects of phosphatidylserine-containing liposomes by PEGylation. AB - Inhibiting liposome uptake by macrophages using polyethylene glycol (PEG) surface modifications is a widely used approach for extending the half-life of liposomes circulating in the blood. However, the biological effects of PEGylated liposomes on macrophages have not yet been thoroughly investigated. The purpose of this study was to examine the effects of PEGylated phosphatidylserine-containing liposomes (PEG-PSLs) on the expression of two inflammation-associated cytokines, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF beta), in the murine macrophage-like cell line RAW 264.7. Previous studies have demonstrated that PSLs inhibit TNF-alpha secretion and enhance TGF-beta synthesis in macrophages by mimicking apoptotic cells. We found that PEGylation differentially affected the TNF-alpha and TGF-beta levels. The PSL-mediated inhibitory effect on TNF-alpha secretion was enhanced by PEGylation, and PEG-PSLs decreased TGF-beta levels compared with non-PEGylated PSLs. Fluorescence activated cell sorting analysis demonstrated that 1% PEGylation disturbed the incorporation of PSLs into macrophages. The interference of uptake is thought to extend the binding interaction between PS to PS receptors for PSL-mediated inhibition of TNF-alpha expression. Together, these findings indicate that PEG PSLs can prevent TNF-alpha secretion without increasing TGF-beta levels in macrophages, and they support the potential clinical use of PEG-PSLs as anti inflammatory agents with a relatively low potential to induce tissue fibrosis. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1479-1486, 2017. PMID- 27998012 TI - High-resolution mapping of the recombination landscape of the phytopathogen Fusarium graminearum suggests two-speed genome evolution. AB - Recombination is a major evolutionary force, increasing genetic diversity and permitting efficient coevolution of fungal pathogen(s) with their host(s). The ascomycete Fusarium graminearum is a devastating pathogen of cereal crops, and can contaminate food and feed with harmful mycotoxins. Previous studies have suggested a high adaptive potential of this pathogen, illustrated by an increase in pathogenicity and resistance to fungicides. In this study, we provide the first detailed picture of the crossover events occurring during meiosis and discuss the role of recombination in pathogen evolution. An experimental recombinant population (n = 88) was created and genotyped using 1306 polymorphic markers obtained from restriction site-associated DNA sequencing (RAD-seq) and aligned to the reference genome. The construction of a high-density linkage map, anchoring 99% of the total length of the reference genome, allowed the identification of 1451 putative crossovers, positioned at a median resolution of 24 kb. The majority of crossovers (87.2%) occurred in a relatively small portion of the genome (30%). All chromosomes demonstrated recombination-active sections, which had a near 15-fold higher crossover rate than non-active recombinant sections. The recombination rate showed a strong positive correlation with nucleotide diversity, and recombination-active regions were enriched for genes with a putative role in host-pathogen interaction, as well as putative diversifying genes. Our results confirm the preliminary analysis observed in other F. graminearum strains and suggest a conserved 'two-speed' recombination landscape. The consequences with regard to the evolutionary potential of this major fungal pathogen are also discussed. PMID- 27998013 TI - Neuroprotective and Ameliorating Impacts of Omega-3 Against Aspartame-induced Neuronal and Astrocytic Degeneration. AB - Aspartame (ASP) is one of the commonest artificial sweetener used all over the world and considered as an extremely risky compound and raises a lot of controversy. Therefore, this study was designed to investigate cellular damage of the anterior horn cells in the spinal cord of albino male rats and the possibility of hindering these changes by using omega-3 (OM3).Thirty seven adult male albino rats were divided into three groups: Control, ASP-treated and ASP + OM3-treated groups. Spinal cord sections were prepared and stained with Hx&E, caspase-3 and GFAP immunostaining. All data were morphometrically and statistically analyzed. In ASP-treated group, the cell body of some degenerated neurons was swollen and its cytoplasm was vacuolated. Their nuclei were eccentric and pyknotic. Moreover, other neurons were of a heterogeneous pattern in the form of cell body shrinkage, loss of Nissl substance, intensely stained eosinophilic cytoplasm and a small darkly stained nucleus that may eventually fragment. However, the cells were apparently normal in ASP+ OM3-treated group. Strong +ve caspase-3 stained neurons were detected in ASP-treated group. Furthermore, the immunoreaction was faint on treating the rats with both ASP and OM3. Few number of +ve GFAP- stained astrocytes were observed in ASP-treated rats. On the other hand, the immunoreactivity for GFAP was found to be intense in the ASP + OM3 treated group. Additionally, there was a significant decrease in the surface area percentage of the +ve GFAP-stained astrocytes of the ASP-treated group compared to the control and the ASP + OM3-treated groups. Anat Rec, 300:1290-1298, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 27998014 TI - Fetuin-A, serum amyloid A and tumor necrosis factor alpha levels in periodontal health and disease. AB - OBJECTIVES: This study is evaluating fetuin-A, serum amyloid A (SAA) and tumor necrosis factor alpha (TNF-alpha) levels in gingival crevicular fluid (GCF) and serum samples in periodontal health and disease. MATERIAL AND METHODS: Sixty patients were divided into three groups: Group 1 periodontal health (n = 20), Group 2 gingivitis (n = 20) and Group 3 chronic periodontitis (CP) (n = 20). GCF and serum samples were evaluated using enzyme-linked immunosorbent assay kit. RESULTS: SAA and TNF-alpha levels in GCF and serum were significantly higher in patients with gingivitis and CP compared with controls (P < 0.016). Contrarily, fetuin-A levels in GCF and serum were significantly higher in controls than in patients with gingivitis and CP (P < 0.016). In CP group, a significant correlation was observed between GCF-SAA amount and the number of sites with 4 <= PPD <= 5 mm (P < 0.05). There was a significant correlation between GCF-fetuin-A levels and the number of sites with PPD >= 6 mm (P < 0.05). GCF-TNF-alpha was found to have a significant relationship with the number of sites with 4 <= PPD <= 5 mm and PPD >= 6 mm (P < 0.05). CONCLUSIONS: In conclusion, serum and total levels of SAA significantly increased, whereas fetuin-A levels significantly decreased, with increasing severity of PD. PMID- 27998016 TI - Elucidating the role of hyposalivation and autoimmunity in oral candidiasis. AB - INTRODUCTION: Oral candidiasis (OC) is a potential oral complication in Sjogren's syndrome (SS). Some studies indicate that the low stimulated salivary flow and not low unstimulated salivary flow is associated with OC in SS, while others report that the underlying autoimmune disorders contribute to OC, based solely on correlation coefficients. Given the conflicting and limited existing evidence, we purposed to ascertain the role of both salivary gland dysfunction (hyposalivation based on unstimulated and stimulated flow rates) and autoimmunity (SS, other autoimmune disorders) in OC among those with SS, other salivary gland dysfunction, and non-salivary gland dysfunction controls (NSGD). METHODS: A nested case-control study was designed within a larger NIH/NIDCR cohort. Descriptive analyses, nonparametric tests, comparative analyses, and multivariate logistic regression analyses were undertaken. RESULTS: Data on 1526 subjects (701 SS, 247 ISS, 355 Sicca, and 223 NSGD) were obtained from the source cohort of 2046 and analyzed for this study. The median whole unstimulated salivary flow rate (WUS, ml 15 min-1 ) was lower in SS (0.8, interquartile range (IQR) 1.8) compared to ISS (5.5, IQR: 5.2, P < 0.001) and NSGD (3.8, IQR: 3.8, P < 0.001) but comparable with that of Sicca (1.0, IQR: 1.5, P = 0.777) participants. The median total stimulated salivary flow rate (TSS, ml 15 min-1 ) was lowest in SS (7.0, IQR: 12.4, P < 0.001) compared to other groups. Of the 45 OC cases in this cohort, 71.1% (n = 32) were from the SS group. The prevalence of OC was highest in the SS group (4.6%, P = 0.008). SS group had twice the risk of OC than NSGD (OR = 2.2, 95%CI: 1.1-4.2, P = 0.02) and Sicca (OR = 2.2, 95% CI: 1.0-4.8, P = 0.03), adjusting for confounders; hyposalivation [WUS (OR = 5.1, 95%CI: 2.5-10.4, P < 0.001), TSS (OR = 1.9, 95%CI: 1.0-3.5, P = 0.04)], history of other autoimmune disorders (OR = 4.4, 95%CI: 1.7-11.3, P = 0.002), medications for extraglandular manifestations (OR = 2.3, 95%CI: 1.1-4.9, P = 0.03), and diabetes mellitus (4.2, 95%CI: 1.2-15.2, P = 0.02) were independent predictors of OC; females had a lower risk than males (OR = 0.29, 95%CI: 0.13-0.67, P = 0.004). Age, race, anti-SSA/SSB autoantibodies, focus score, other medications, anxiety, fatigue, cigarette smoking, alcohol, and caffeine use were not associated with oral candidiasis. CONCLUSION: Salivary gland dysfunction (hyposalivation with WUS being a stronger predictor than TSS) and autoimmunity (SS, other autoimmune disorders, medications, i.e., DMARDS) are both independent predictors of OC. Diabetes mellitus is an independent predictor of OC among those with salivary gland dysfunction. Our findings suggest that these independent predictors should be considered in the prevention and management of OC in this population. PMID- 27998017 TI - Nanogel-based scaffolds fabricated for bone regeneration with mesoporous bioactive glass and strontium: In vitro and in vivo characterization. AB - The delivery of novel bioactive scaffolds for the repair of bone defects remains a prominent challenge worldwide. Currently osteoporosis, a disease caused by low bone mineral density affects over 200 million people worldwide with up to half of this population experiencing at least one fracture within their lifetime. Recently temperature-sensitive p(N-isopropylacrylamide-co-butyl methylacrylate) nanogel (PIB nanogel) scaffolds have emerged as biomaterial candidate for regenerative therapies. It has the advantage of being injected from syringes as a soluble gel form (capable of delivering growth and/or living progenitor cells) yet hardens once it reaches body temperatures. Although this material demonstrates optimal clinical delivery of scaffolds, its main drawback is its low osteoconductivity and bioactivity. Recently we have demonstrated that mesoporous bioactive glass (MBG) loaded with strontium was able to regenerate osteoporotic defects in vivo and enhance osteoblast differentiation in vitro. The aim of this study was to combine the advantages of these two therapies and prepare PIB nanogel scaffolds containing Sr-MBG and investigate their ability to regenerate femur defects created in ovarectamized rats. The results demonstrate that groups containing Sr-MBG within the nanogel formulation had significantly higher new bone formation when compared with other modalities. We further demonstrate that although nanogel demonstrated poor osteogenic ability, the addition of osteoblasts worked synergistically with Sr-MBG particles to enhance the regeneration of the created femur defects in osteoporotic animals. In conclusion, PIB nanogel scaffolds are a viable treatment modality for bone tissue engineering and may serve as a carrier-scaffold for osteogenic cells and/or bioactive scaffolds such as Sr-MBG. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1175-1183, 2017. PMID- 27998018 TI - Genetic polymorphism of heme oxygenase 1 promoter in the occurrence and severity of chronic obstructive pulmonary disease: a meta-analysis. AB - Heme oxygenase 1 (HMOX1) plays an important role in the development of chronic obstructive pulmonary disease (COPD). However, the association of HMOX1 length polymorphism in promoter region to the risk and severity of COPD has not been well studied. In this study, we searched the databases including PubMed, EMBASE, Cochrane Library and China National Knowledge Infrastructure (CNKI) and extracted the information from related articles. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to study the effect of HMOX1 polymorphism on the risk and severity of COPD. As a result, nine studies were included for this meta-analysis. Higher frequencies of L allele and type I genotype (containing at least one L allele) were found in patients with COPD (for L allele, OR 2.02, 95% CI: 1.32-3.11, P = 0.001; for type I genotype, OR 1.82, 95% CI: 1.28-2.61, P = 0.001), especially in Asian population (for L allele, OR 2.23, 95% CI: 1.68-2.95, P < 0.001; for type I genotype, OR 2.02, 95% CI: 1.51 2.70, P < 0.001). Genotyping method, source of control subjects, literature quality and language also affected the results to some extent. However, there was little difference in HMOX1 genotypes distribution in patients with COPD with different severity. Our study indicated L allele and type I genotype were related to the susceptibility but not the severity of COPD. PMID- 27998015 TI - Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial. AB - We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of <2 years, and immunogenicity until 7 months post-dose 1. Here, we report efficacy and safety results from an event-triggered analysis with ~3 years longer follow-up, and immunogenicity until M24. Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV 16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18 associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6 month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV 16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile. PMID- 27998019 TI - Optimizing acitretin use in patients with plaque psoriasis. AB - Acitretin is one of the systemic agents used for the treatment of psoriasis. Because different acitretin dosages resulted therapeutically successful, there is no general agreement on the optimal dose regimen. To report acitretin efficacy and safety in a real-life setting, wherein patient-tailored dose regimen is usually prescribed, a retrospective analysis evaluating charts of all plaque-type psoriasis patients treated with acitretin from the clinic database was performed. PASI score improvement, as well as PASI 50, 75, 90, and 100 responses were assessed throughout the observational period. Overall, 52% PASI score reduction and a satisfactory safety profile were detected. PASI 50, 75, 90, and 100 response was achieved by 53%, 48%, 28%, and 14%, respectively. Treatment consisted on a mean daily acitretin dose of 25.01 mg. The initial dose was increased (51.2% of cases) or decreased (48.8%) prescribing a mean daily dose of 29.8 mg and 20.02 mg, respectively. This study proposed a dose regimen customized on clinical response and patient's needs, to optimized acitretin benefit. PMID- 27998020 TI - Identification, characterization, and expression of sarcomeric tropomyosin isoforms in zebrafish. AB - Tropomyosin is a component of thin filaments that constitute myofibrils, the contractile apparatus of striated muscles. In vertebrates, except for fish, four TPM genes TPM1, TPM2, TPM3, and TPM4 are known. In zebrafish, there are six TPM genes that include the paralogs of the TPM1 (TPM1-1 and TPM1-2), the paralogs of the TPM4 gene (TPM4-1 and TPM4-2), and the two single copy genes TPM2 and TPM3. In this study, we have identified, cloned, and sequenced the TPM1-1kappa isoform of the TPM1-1 gene and also discovered a new isoform TPM1-2nu of the TPM1-2. Further, we have cloned and sequenced the sarcomeric isoform of the TPM4-2 gene designated as TPM4-2alpha. Using conventional RT-PCR, we have shown the expression of the sarcomeric isoforms of TPM1-1, TPM1-2, TPM2, TPM3, TPM4-1, and TPM4-2 in heart and skeletal muscles. By qRT-PCR using both relative expression as well as the absolute copy number, we have shown that TPM1-1alpha, TPM1-2alpha, and TPM1-2nu are expressed mostly in skeletal muscle; the level of expression of TPM1-1kappa is significantly lower compared to TPM1-1alpha in skeletal muscle. In addition, both TPM4-1alpha and TPM4-2alpha are predominantly expressed in heart. 2D Western blot analyses using anti-TPM antibody followed by Mass Spectrometry of the proteins from the antibody-stained spots show that TPM1-1alpha and TPM3alpha are expressed in skeletal muscle whereas TPM4-1alpha and TPM3alpha are expressed in zebrafish heart. To the best of our knowledge, this is by far the most comprehensive analysis of tropomyosin expression in zebrafish, one of the most popular animal models for gene expression study. PMID- 27998021 TI - Melanocortin receptor agonists MCR1-5 protect photoreceptors from high-glucose damage and restore antioxidant enzymes in primary retinal cell culture. AB - Retinal photoreceptors are particularly vulnerable to local high-glucose concentrations. Oxidative stress is a risk factor for diabetic retinopathy development. Melanocortin receptors represent a family of G-protein-coupled receptors classified in five subtypes and are expressed in retina. Our previous data indicate that subtypes 1 and 5 receptor agonists exert a protective role on experimental diabetic retinopathy. This study focuses on their role in primary retinal cell cultures in high-glucose concentrations. After eye enucleation from wild-type male C57BL/6 mice, retinal cells were isolated, plated in high-glucose concentration and treated with melanocortin receptors 1 and 5 agonists and antagonists. Immunocytochemical and biochemical analysis showed that treatment with melanocortin receptors 1 and 5 agonists reduced anti-inflammatory cytokines and chemokines and enhanced manganese superoxide dismutase and glutathione peroxidase levels, preserving photoreceptor integrity. According with these evidences, we propose a major role of melanocortin receptors 1 and 5 on primary retinal cell response against high glucose or oxidative insults. PMID- 27998023 TI - Clinical Enthesitis in a Prospective Longitudinal Psoriatic Arthritis Cohort: Incidence, Prevalence, Characteristics, and Outcome. AB - OBJECTIVE: To evaluate the incidence, prevalence, characteristics, disease associations, risk factors, and outcome of clinical enthesitis in patients with psoriatic arthritis (PsA). METHODS: The study included patients with PsA followed prospectively. Enthesitis was defined as the presence of at least 1 tender enthesis at 1 of the 18 entheseal sites of the Spondyloarthritis Research Consortium of Canada enthesitis index. RESULTS: Between 2008 and 2014, 281 of 803 patients had enthesitis, providing a prevalence of 35%. A total of 192 patients developed enthesitis during the course of followup, with an annual incidence of 0.9%. Most of the patients had 1 (48.4%) or 2 (32.2%) tender entheseal sites, and the mean +/- SD number of sites per visit was 2.03 +/- 1.6. The 3 most common sites were at the insertions of the Achilles tendon, plantar fascia on the calcaneus, and the lateral epicondyles (24.2%, 20.8%, and 17.2%, respectively). More active disease (higher actively inflamed joint count, tenosynovitis, and dactylitis), more pain, and less clinical damage were associated with enthesitis. Higher body mass index, more actively inflamed joints, and younger age were risk factors for developing this condition. Enthesitis resolved in most patients without changing treatment. CONCLUSION: Clinical enthesitis is common, with a period prevalence of 35% of PsA patients. It usually involves only 1 or 2 sites simultaneously. The most common tender sites are at the insertions of the Achilles tendon, plantar fascia, and the lateral epicondyles. More active disease and more pain are associated with enthesitis. PMID- 27998022 TI - The effects of the DNA methyltranfserases inhibitor 5-Azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells. AB - Human adipose tissue is a great source of adult mesenchymal stem cells (MSCs) which are recognized from their ability to self-renew and differentiation into multiple lineages. MSCs have promised a vast therapeutic potential in treatment many diseases including tissue injury and immune disorders. However, their regenerative potential profoundly depends on patients' age. Age-related deterioration of MSC is associated with cellular senescence mainly caused by increased DNA methylation status, accumulation of oxidative stress factors and mitochondria dysfunction. We found that DNA methyltransferase (DNMT) inhibitor i.e. 5-Azacytidine (5-AZA) reversed the aged phenotype of MSCs. Proliferation rate of cells cultured with 5-AZA was increased while the accumulation of oxidative stress factors and DNA methylation status were decreased. Simultaneously the mRNA levels of TET proteins involved in demethylation process were elevated in those cells. Moreover, cells treated with 5-AZA displayed reduced reactive oxygen species (ROS) accumulation, ameliorated superoxide dismutase activity and increased BCL-2/BAX ratio in comparison to control group. Our results indicates that, treating MSCs with 5-AZA can be justified therapeutic intervention, that can slow-down and even reverse aged- related degenerative changes in those cells. PMID- 27998024 TI - Prevalence of Primary Sjogren's Syndrome in a US Population-Based Cohort. AB - OBJECTIVE: To report the point prevalence of primary Sjogren's syndrome (SS) in the first US population-based study. METHODS: Cases of all potential primary SS patients living in Olmsted County, Minnesota, on January 1, 2015, were retrieved using Rochester Epidemiology Project resources, and ascertained by manual medical records review. Primary SS cases were defined according to physician diagnosis. The use of diagnostic tests was assessed and the performance of classification criteria was evaluated. The number of prevalent cases in 2015 was also projected based on 1976-2005 incidence data from the same source population. RESULTS: A total of 106 patients with primary SS were included in the study: 86% were female, with a mean +/- SD age of 64.6 +/- 15.2 years, and a mean +/- SD disease duration of 10.5 +/- 8.4 years. A majority were anti-SSA positive (75%) and/or anti-SSB positive (58%), but only 22% met American-European Consensus Group or American College of Rheumatology criteria, because the other tests required for disease classification (ocular dryness objective assessment, salivary gland functional or morphologic tests, or salivary gland biopsy) were rarely performed in clinical practice. According to the physician diagnosis, the age- and sex adjusted prevalence of primary SS was 10.3 per 10,000 inhabitants, but according to classification criteria, this prevalence was only 2.2 per 10,000. The analysis based on previous incidence data projected a similar 2015 prevalence rate of 11.0 per 10,000. CONCLUSION: The prevalence of primary SS in this geographically well defined population was estimated to be between 2 and 10 per 10,000 inhabitants. Physicians rarely used tests included in the classification criteria to diagnose the disease in this community setting. PMID- 27998025 TI - Effect of different types of therapeutic trauma on vitiligo lesions. AB - New treatment modalities for vitiligo acting by changing certain cytokines and metalloproteinases are newly emerging. The aim of this work is to To assess the efficacy of trichloroacetic acid (TCA) chemical peel, dermapen, and fractional CO2 laser in treatment of stable non-segmental vitiligo and to detect their effects on IL-17 and MMP-9 levels. Thirty patients with stable vitiligo were recruited in a randomized controlled study. They were randomly categorized into three equal groups. Group 1: TCA peel, Group 2: dermapen machine, and Group 3: Fractional CO2 laser. Skin biopsies were taken from treated areas and from control areas for which MMP-9 and IL-17 tissue levels were measured using ELISA. The 30 vitiligo patients had low basal tissue MMP-9 levels and high baseline IL 17 tissue levels. As regards the three different used modalities, all of them caused rise in MMP-9 as well as IL-17 levels and almost their levels were much more elevated with repetition of the previously mentioned traumatic procedures. TCA 25% peel proved to be the most effective modality both clinically and laboratory and it can be used prior or with other conventional therapies in the treatment of vitiligo. PMID- 27998026 TI - Determinants of Patient-Physician Discordance in Global Assessment in Psoriatic Arthritis: A Multicenter European Study. AB - OBJECTIVE: Patient-physician discordance in global assessment of disease activity concerns one-third of patients, but what does it reflect? We aimed to assess patient-physician discordance in psoriatic arthritis (PsA) and patient-reported domains of health (physical and psychological) associated with discordance. METHODS: We analyzed the PsAID (Psoriatic Arthritis Impact of Disease), a cross sectional, multicenter European study of patients with PsA according to expert opinion. Patient global assessment (PGA) and physician global assessment (PhGA) were rated on a 0-10 numeric rating scale. Discordance was defined as the difference (PGA-PhGA) and as the absolute difference |PGA-PhGA| >=3 points. Determinants of PGA-PhGA were assessed by a stepwise multivariate linear regression among 12 physical and psychological aspects of impact: pain, skin problems, fatigue, ability to work/leisure, functional incapacity, feeling of discomfort, sleep disturbance, anxiety/fear, coping, embarrassment/shame, social participation, and depressive affects. RESULTS: In 460 patients (mean +/- SD age 50.6 +/- 12.9 years, 52.2% female, mean +/- SD disease duration 9.5 +/- 9.5 years, mean +/- SD Disease Activity Index for Psoriatic Arthritis score 30.8 +/- 32.4, and 40.4% undergoing treatment with biologic agents), the mean +/- SD PGA was higher than the mean PhGA, with a mean absolute difference of 1.9 +/- 1.8 points. Discordance defined by |PGA-PhGA| >=3 of 10 concerned 134 patients (29.1%), and 115 patients (85.8% of the patients with discordance) had PGA>PhGA. Higher fatigue (beta = 0.14), lower self-perceived coping (beta = 0.23), and impaired social participation (beta = 0.16) were independently associated with a higher difference (PGA-PhGA). CONCLUSION: Discordance concerned 29.1% of these patient/physician dyads, mainly by PGA>PhGA. Factors associated with discordance were psychological rather than physical domains of health. Discordance was more frequent in patients in remission, indicating more work is needed on the patient perspective regarding disease activity. PMID- 27998027 TI - Education and Employment Participation in Young Adulthood: What Role Does Arthritis Play? AB - OBJECTIVE: To examine the association between arthritis diagnosis and education and employment participation among young adults, and to determine whether findings differ by self-rated health and age. METHODS: Data from the National Health Interview Survey, in the years 2009-2015, were combined and analyzed. The study sample was restricted to those ages 18-29 years, either diagnosed with arthritis (n = 1,393) or not (n = 40,537). The prevalence and correlates of employment and education participation were compared by arthritis status. Demographic characteristics, social role participation restrictions, health factors, and health system use variables were included as covariates. Models were stratified for age (18-23 versus 24-29 years) and self-rated health. Weighted proportions and univariate and multivariate associations were calculated to examine the association between arthritis and education and employment participation. RESULTS: Respondents with arthritis were more likely to be female, married, and report having more social participation restrictions, fair/poor health, and more functional limitations than those without arthritis. In multivariate models, arthritis was significantly associated with lower education (prevalence ratio [PR] 0.75 [95% confidence interval (95% CI) 0.57-0.98]) and higher employment participation (PR 1.07 [95% CI 1.03-1.13]). Additional stratified analyses indicated an association between arthritis diagnosis and greater employment participation in those ages 18-23 years and reporting higher self-rated health. CONCLUSION: Young adults with arthritis may be transitioning into employment at an earlier age than their peers without arthritis. To inform the design of interventions that promote employment participation, future research on the education and employment experiences of young adults with arthritis is needed. PMID- 27998029 TI - Incidence and Prevalence of Cardiovascular Risk Factors Among Patients With Rheumatoid Arthritis, Psoriasis, or Psoriatic Arthritis. AB - OBJECTIVE: To estimate prevalence and incidence of cardiovascular (CV) risk factors of hypertension, diabetes mellitus, hyperlipidemia, and obesity in patients with rheumatoid arthritis (RA), psoriasis, or psoriatic arthritis (PsA). METHODS: Patients with RA, psoriasis, or PsA were identified based on medical and pharmacy claims from the MarketScan claims databases from January 1, 2002 through December 31, 2014. Primary outcomes included age- and sex-standardized prevalence of CV risk factors during the 12 months preceding diagnosis date and incidence rates per 1,000 patient-years, with 95% confidence intervals (95% CIs) during followup. RESULTS: Prevalence for RA, psoriasis, and PsA cohorts for hypertension was 18.6% (95% CI 18.3-18.8), 16.6% (95% CI 16.3-17.0), and 19.9% (95% CI 19.4 20.4), respectively; for diabetes mellitus 6.2% (95% CI 6.1-6.4), 6.3% (95% CI 6.0-6.5), and 7.8% (95% CI 7.4-8.2); for hyperlipidemia 9.9% (95% CI 9.7-10.1), 10.4% (95% CI 10.2-10.7), and 11.6% (95% CI 11.2-12.0); and for obesity 4.4% (95% CI 4.2-4.6), 3.8% (95% CI 3.5-4.0), and 6.0% (95% CI 5.6-6.5). Incidence rates per 1,000 patient-years during followup for RA, psoriasis, and PsA cohorts, respectively, for hypertension were 74.0 (95% CI 72.5-75.5), 68.2 (95% CI 65.9 70.4), and 79.8 (95% CI 76.3-83.3); for diabetes mellitus 10.6 (95% CI 10.1 11.1), 13.0 (95% CI 12.1-13.8), and 14.7 (95% CI 13.5-16.0); for hyperlipidemia 40.3 (95% CI 39.4-41.3), 47.1 (95% CI 45.4-48.7), and 52.0 (95% CI 49.6-54.3); and for obesity 24.4 (95% CI 23.4-25.4), 26.4 (95% CI 25.0-27.8), and 32.9 (95% CI 30.6-35.2). CONCLUSION: Patients with RA, psoriasis, and PsA have high prevalence and incidence of CV risk factors, suggesting the need for risk factor monitoring of these patients. PMID- 27998028 TI - Ectopic expression of specific GA2 oxidase mutants promotes yield and stress tolerance in rice. AB - A major challenge of modern agricultural biotechnology is the optimization of plant architecture for enhanced productivity, stress tolerance and water use efficiency (WUE). To optimize plant height and tillering that directly link to grain yield in cereals and are known to be tightly regulated by gibberellins (GAs), we attenuated the endogenous levels of GAs in rice via its degradation. GA 2-oxidase (GA2ox) is a key enzyme that inactivates endogenous GAs and their precursors. We identified three conserved domains in a unique class of C20 GA2ox, GA2ox6, which is known to regulate the architecture and function of rice plants. We mutated nine specific amino acids in these conserved domains and observed a gradient of effects on plant height. Ectopic expression of some of these GA2ox6 mutants moderately lowered GA levels and reprogrammed transcriptional networks, leading to reduced plant height, more productive tillers, expanded root system, higher WUE and photosynthesis rate, and elevated abiotic and biotic stress tolerance in transgenic rice. Combinations of these beneficial traits conferred not only drought and disease tolerance but also increased grain yield by 10-30% in field trials. Our studies hold the promise of manipulating GA levels to substantially improve plant architecture, stress tolerance and grain yield in rice and possibly in other major crops. PMID- 27998030 TI - Associations Between Five Important Domains of Health and the Patient Acceptable Symptom State in Rheumatoid Arthritis and Psoriatic Arthritis: A Cross-Sectional Study of 977 Patients. AB - OBJECTIVE: To explore the link between a patient acceptable symptom state (PASS) and patient-perceived impact in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: This was a cross-sectional study of unselected patients with definite RA or PsA. Pain, functional capacity, fatigue, coping, and sleep disturbance were assessed using a numeric rating scale (0-10) and compared between patients in PASS or not (Cohen's effect sizes). The domains of health associated with PASS status were assessed by multivariate forward logistic regression, and PASS thresholds were determined using the 75th percentile method and receiver operating characteristic analyses. RESULTS: Among 977 patients (531 with RA, 446 with PsA), the mean +/- SD age was 53.4 +/- 13.2 years, mean +/- SD disease duration was 11.2 +/- 10.0 years, and 637 (65.8%) were women. In all, 595 patients (60.9%) were in PASS; they had lower symptom levels, and all domains of health except sleep disturbance discriminated clearly between patients in PASS or not (effect sizes 0.73-1.45 in RA and 0.82-1.52 in PsA). In multivariate analysis, less pain and better coping were predictive of being in PASS. Odds ratios were: RA pain 0.80 (95% confidence interval [95% CI] 0.67-0.96), PsA pain 0.63 (95% CI 0.52-0.75), RA coping 0.84 (95% CI 0.74-0.96), and PsA coping 0.83 (95% CI 0.71-0.97). The cutoffs of symptom intensity (range 0-10), corresponding to PASS for the 5 domains of health and the 2 diseases were similar, i.e., approximately 4-5. CONCLUSION: In RA and PsA, PASS was associated with the 5 domains of health analyzed, and in particular with less pain and better coping. PMID- 27998031 TI - Could the application of bioactive molecules improve vital pulp therapy success? A systematic review. AB - This study aimed to systematically review the literature of animal studies to evaluate whether bioactive dentin proteins could improve vital pulp therapy success. The review is reported in accordance with the PRISMA Statement. Two reviewers independently conducted a literature search of seven databases: PubMed (Medline), Lilacs, IBECS, BBO, Web of Science, Scopus, and SciELO. Animal experiments in which bioactive dentin proteins were applied directly or indirectly to the pulp tissue were included. Data regarding the characteristics of the proteins evaluated, the delivery systems used and the main findings from each study were tabulated to assess the outcomes of interest (tertiary dentin formation, inflammatory response, intratubular mineralization). After screening, 32 papers were subjected to qualitative analysis. In 75% of the studies, direct pulp capping was performed. Additionally, the most studied proteins were BMP-7, TGF-beta1, and extracted soluble dentin matrix proteins. In conclusion, there is evidence in the literature suggesting that bioactive dentin molecules could enhance tertiary dentin formation with fewer initial inflammatory responses in direct and indirect pulp therapy in animal models. There are potential areas to be explored for novel therapeutic approaches for dental tissue repair and regeneration with bioactive materials. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 941-956, 2017. PMID- 27998032 TI - Altering carbon allocation in hybrid poplar (Populus alba * grandidentata) impacts cell wall growth and development. AB - Galactinol synthase is a pivotal enzyme involved in the synthesis of the raffinose family of oligosaccharides (RFOs) that function as transport carbohydrates in the phloem, as storage compounds in sink tissues and as soluble metabolites that combat both abiotic and biotic stress in several plant species. Hybrid poplar (Populus alba * grandidentata) overexpressing the Arabidopsis thaliana GolS3 (AtGolS3) gene showed clear effects on development; the extreme overexpressing lines were stunted and had cell wall traits characteristic of tension wood, whereas lines with only moderate up-regulation grew normally and had moderately altered secondary cell wall composition and ultrastructure. Stem cross-sections of the developing xylem revealed a significant increase in the number of vessels, as well as the clear presence of a G-layer in the fibres. Furthermore, AtGolS3-OE lines possessed higher cellulose and lower lignin contents, an increase in cellulose crystallinity, and significantly altered hemicellulose-derived carbohydrates, notably manifested by their mannose and xylose contents. In addition, the transgenic plants displayed elevated xylem starch content. Transcriptome interrogation of the transgenic plants showed a significant up-regulation of genes involved in the synthesis of myo-inositol, along with genes involved in sucrose degradation. The results suggest that the overexpression of GolS and its product galactinol may serve as a molecular signal that initiates metabolic changes, culminating in a change in cell wall development and potentially the formation of tension wood. PMID- 27998033 TI - Current Physical Activity Monitors in Hip and Knee Osteoarthritis: A Review. PMID- 27998034 TI - Regulation of gene expression by manipulating transcriptional repressor activity using a novel CoSRI technology. AB - Targeted gene manipulation is a central strategy for studying gene function and identifying related biological processes. However, a methodology for manipulating the regulatory motifs of transcription factors is lacking as these factors commonly possess multiple motifs (e.g. repression and activation motifs) which collaborate with each other to regulate multiple biological processes. We describe a novel approach designated conserved sequence-guided repressor inhibition (CoSRI) that can specifically reduce or abolish the repressive activities of transcription factors in vivo. The technology was evaluated using the chimeric MYB80-EAR transcription factor and subsequently the endogenous WUS transcription factor. The technology was employed to develop a reversible male sterility system applicable to hybrid seed production. In order to determine the capacity of the technology to regulate the activity of endogenous transcription factors, the WUS repressor was chosen. The WUS repression motif could be inhibited in vivo and the transformed plants exhibited the wus-1 phenotype. Consequently, the technology can be used to manipulate the activities of transcriptional repressor motifs regulating beneficial traits in crop plants and other eukaryotic organisms. PMID- 27998035 TI - Metagenomic profiling of gut microbial communities in both wild and artificially reared Bar-headed goose (Anser indicus). AB - Bar-headed goose (Anser indicus), a species endemic to Asia, has become one of the most popular species in recent years for rare bird breeding industries in several provinces of China. There has been no information on the gut metagenome configuration in both wild and artificially reared Bar-headed geese, even though the importance of gut microbiome in vertebrate nutrient and energy metabolism, immune homeostasis and reproduction is widely acknowledged. In this study, metagenomic methods have been used to describe the microbial community structure and composition of functional genes associated with both wild and artificially reared Bar-headed goose. Taxonomic analyses revealed that Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes were the four most abundant phyla in the gut of Bar-headed geese. Bacteroidetes were significantly abundant in the artificially reared group compared to wild group. Through functional profiling, we found that artificially reared Bar-headed geese had higher bacterial gene content related to carbohydrate transport and metabolism, energy metabolism and coenzyme transport, and metabolism. A comprehensive gene catalog of Bar-headed geese metagenome was built, and the metabolism of carbohydrate, amino acid, nucleotide, and energy were found to be the four most abundant categories. These results create a baseline for future Bar-headed goose microbiology research, and make an original contribution to the artificial rearing of this bird. PMID- 27998036 TI - Associations Between Clinical Evidence of Inflammation and Synovitis in Symptomatic Knee Osteoarthritis: A Cross-Sectional Substudy. AB - OBJECTIVE: Painful knee osteoarthritis (KOA) has been associated with joint inflammation. There is, however, little literature correlating signs of localized inflammation with contrast-enhanced (CE) magnetic resonance imaging (MRI) of synovium. This study examined the relationship between clinical and functional markers of localized knee inflammation and CE MRI-based synovial scores. METHODS: Patients with symptomatic KOA were enrolled into the randomized, double-blind, Vitamin D Evaluation in Osteoarthritis (VIDEO) trial. In this cross-sectional substudy, associations between validated MRI-based semiquantitative synovial scores of the knee and the following markers of inflammation were investigated: self-reported pain and stiffness, effusion, warmth, joint line tenderness, erythrocyte sedimentation rate, radiographic severity, and functional ability tests. RESULTS: A total of 107 patients satisfied the inclusion criteria of complete data and were included in the analysis. Significant associations were found between the number of regions affected by synovitis and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, effusion, and joint line tenderness. Each additional region affected by synovitis was associated with an increase in WOMAC pain (1.82 [95% confidence interval (95% CI) 0.05, 3.58], P = 0.04), and the association with extent of medial synovitis was particularly strong (3.21 [95% CI 0.43, 5.99], P = 0.02). Extent of synovitis was positively associated with effusion (odds ratio 1.69 [95% CI 1.37, 2.08], P < 0.01) and negatively associated with joint line tenderness (relative risk 0.87 [95% CI 0.84, 0.90], P < 0.01). CONCLUSION: There is a strong positive association between synovitis and self-reported patient pain and clinically detectable effusion. Nonoperative treatments directed at management of inflammation and future trials targeting the synovial tissue for treating KOA should consider these 2 factors as potential inclusion criteria. PMID- 27998037 TI - Investigation of the microbial communities colonizing prepainted steel used for roofing and walling. AB - Microbial colonization of prepainted steel, commonly used in roofing applications, impacts their aesthetics, durability, and functionality. Understanding the relevant organisms and the mechanisms by which colonization occurs would provide valuable information that can be subsequently used to design fouling prevention strategies. Here, next-generation sequencing and microbial community finger printing (T-RFLP) were used to study the community composition of microbes colonizing prepainted steel roofing materials at Burrawang, Australia and Kapar, Malaysia over a 52-week period. Community diversity was low and was dominated by Bacillus spp., cyanobacteria, actinobacteria, Cladosporium sp., Epicoccum nigrum, and Teratosphaeriaceae sp. Cultivation-based methods isolated approximately 20 different fungi and bacteria, some of which, such as E. nigrum and Cladosporium sp., were represented in the community sequence data. Fluorescence in situ hybridization imaging showed that fungi were the most dominant organisms present. Analysis of the sequence and T-RFLP data indicated that the microbial communities differed significantly between locations and changed significantly over time. The study demonstrates the utility of molecular ecology tools to identify and characterize microbial communities associated with the fouling of painted steel surfaces and ultimately can enable the targeted development of control strategies based on the dominant species responsible for fouling. PMID- 27998039 TI - A randomised comparison of three different immobilisation devices for thoracic and abdominal cancers. AB - INTRODUCTION: Patient immobilisation is critically important for both highly conformal conventionally fractionated radiotherapy and for stereotactic body radiotherapy. Different immobilisation devices are available to maintain patient position for radiotherapy but the most suitable one remains unknown. METHODS: Forty-five patients were randomly allocated to one of three immobilisation devices; the Q fix arm shuttle, BodyFIX without wrap or BodyFIX with wrap. Patients were imaged before and after treatment to ascertain intra-fraction and inter-fraction motion. Bony anatomy was used for matching to determine the positional accuracy of each device. Treatments were timed using a standard method. Patient comfort and staff satisfaction questionnaires were also issued to determine comfort, ease of use and preferences for each device. RESULTS: The BodyFIX without wrap was the more accurate device; however, the differences between the devices were not statistically significant. The BodyFIX with wrap was found to take significantly longer to set up and set down compared to the arm shuttle and the BodyFIX without wrap (all P < 0.001). Patients (37%) marginally preferred the BodyFIX with wrap. Most (81%) staff preferred the BodyFIX without wrap. CONCLUSION: Immobilisation using the BodyFIX without wrap was deemed to be suitable for clinical use. It was a clinically accurate device, the more efficient in terms of set up and set down time, the most preferred by staff and was accepted by patients. PMID- 27998038 TI - Whole-exome sequencing predicted cancer epitope trees of 23 early cervical cancers in Chinese women. AB - Emerging evidence suggest that the heterogeneity of cancer limits the efficacy of immunotherapy. To search for optimal therapeutic targets for enhancing the efficacy, we used whole-exome sequencing data of 23 early cervical tumors from Chinese women to investigate the hierarchical structure of the somatic mutations and the neo-epitopes. The putative neo-epitopes were predicted based on the mutant peptides' strong binding with major histocompatibility complex class I molecules. We found that each tumor carried an average of 117 mutations and 61 putative neo-epitopes. Each patient displayed a unique phylogenetic tree in which almost all subclones harbored neo-epitopes, highlighting the importance of individual neo-epitope tree in determination of immunotherapeutic targets. The alterations in FBXW7 and PIK3CA, or other members of the significantly altered ubiquitin-mediated proteolysis and extracellular matrix receptor interaction related pathways, were proposed as the earliest changes triggering the malignant progression. The neo-epitopes involved in these pathways, and located at the top of the hierarchy tree, might become the optimal candidates for therapeutic targets, possessing the potential to mediate T-cell killing of the descendant cells. These findings expanded our understanding in early stage of cervical carcinogenesis and offered an important approach to assist optimizing the immunotherapeutic target selection. PMID- 27998040 TI - Sleep apnoea in heart failure: To treat or not to treat? AB - Heart failure (HF) and sleep apnoea are common disorders which frequently coexist. Two main types of apnoea occur: one is obstructive which, through recurring episodes of snoring, hypoxaemia, large negative intra-thoracic pressures and arousals from sleep leading to downstream inflammatory and autonomic nervous system changes, is thought to be a causative factor to the development of systemic hypertension and HF. The other type of apnoea, Cheyne Stokes respiration with central sleep apnoea (CSR-CSA), is characterized by an oscillatory pattern of ventilation with a prevailing hyperventilation-induced hypocapnia, often in the absence of significant hypoxaemia and snoring, and is thought to be a consequence of advanced HF-related low cardiac output, high sympathetic nervous system activation and pulmonary congestion. CSR-CSA may be a compensatory response to advanced HF. Rostral fluid shift during sleep may play an important role in the pathogenesis of both obstructive sleep apnoea (OSA) and CSA. Studies of positive airway pressure (PAP) treatment of OSA and CSA in HF have shown short-term improvements in cardiac and autonomic function; however, there is no evidence of improved survival. Loop gain may provide useful marker of continuous PAP (CPAP) responsiveness in patients with central apnoea. A greater understanding of the pathophysiology of the interaction between obstructive and central apnoea and the various types of HF, and the mechanisms of therapies, such as PAP, is required to develop new strategies to overcome the disabling symptoms, and perhaps improve the mortality, that accompany HF with sleep apnoea. PMID- 27998042 TI - Ultrasound Features of the Posterior Tibialis Tendon and Peroneus Brevis Tendon Entheses: Comparison Study Between Healthy Adults and Those With Inflammatory Arthritis. AB - OBJECTIVE: Limited literature exists on the sonographic appearance of the posterior tibialis tendon (PTT) and the peroneus brevis tendon (PBT) entheses. We determined the anatomic features and best imaging techniques of normal PTT and PBT using musculoskeletal ultrasound and compared these findings to subjects with inflammatory arthritis. METHODS: Adult subjects were enrolled as healthy controls (HCs), rheumatoid arthritis (RA) patients, or spondyloarthropathy (SpA) patients. Bilateral PTT and PBT entheses were imaged longitudinally, comparing 2 angles of insonation: perpendicular to the skin surface and 45 degrees cephalad. Images were scored on semiquantitative scales assessing pathology. RESULTS: A total of 78 subjects were enrolled (37 HC, 21 RA, and 20 SpA). Complete enthesis visualization was achieved more frequently in the perpendicular than in the cephalad view for the PBT (76.3% versus 58.7%), but more frequently in the cephalad view for the PTT (58.0% versus 19.6%). RA and SpA subjects had higher rates of PTT fiber disruption (P < 0.001), PTT tenosynovial effusion (P < 0.001), and Doppler signal (P < 0.001) than HCs. No significant differences existed at the PBT enthesis. In multivariate analysis, RA and SpA subjects were found to be 5.1 times (P < 0.001) and 3.6 times (P < 0.001) more likely to exhibit ultrasound detected pathology, respectively, than HCs. CONCLUSION: The perpendicular transducer aim is optimal for imaging the PBT, while the cephalad transducer orientation was more effective for evaluation of the PTT. Unlike distal PBT imaging, PTT imaging distinguished healthy and disease states, with both RA and SpA patients showing features of PTT enthesopathy. Distal PTT imaging is a useful technique for musculoskeletal ultrasound. PMID- 27998041 TI - Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. AB - OBJECTIVE: Immune checkpoint inhibitors (ICIs) are improving prognoses in advanced stage cancers, but they also lead to immune-related adverse events (IRAEs). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAEs have not been well-characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAEs to better understand prevalence and clinical characteristics. METHODS: Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence, and treatment data were extracted and summarized. RESULTS: A total of 1,725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full-text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in preexisting autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged 1-43%, and myalgia was reported in 2-20%. Arthritis was reported in 5 of 33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with preexisting autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis. CONCLUSION: Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs such as inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with preexisting autoimmune disease. PMID- 27998043 TI - Patients' Perceptions of Their Relatives' Risk of Developing Rheumatoid Arthritis and of the Potential for Risk Communication, Prediction, and Modulation. AB - OBJECTIVE: To understand the perspectives of patients with rheumatoid arthritis (RA) about the risk of their relatives developing RA in the future, and about communicating with their relatives concerning risk and its modulation. METHODS: Twenty-one RA patients took part in semistructured interviews. RESULTS: Participants reported willingness to communicate with relatives about their risk of developing RA, but described choosing which relatives to communicate with, on the basis of the relatives' perceived receptivity to such risk information. Participants described the potential for risk information to cause negative emotions. Some participants did not consider RA to be hereditable, and few reported smoking as a risk factor. Patients described a lack of public awareness about the causes of RA and the negative impact that RA has on the quality of life. Awareness of this negative impact was identified as an important driver for predictive and preventive strategies. Participants held positive perceptions of predictive testing for RA, though the results of predictive tests were conceptualized as having a high degree of accuracy. Negative views of predictive testing were associated with an appreciation of the probabilistic nature of risk information. Participants felt that their relatives would prefer lifestyle modification over medication as a risk reduction strategy. CONCLUSION: Information about risk factors for RA, and the potential impact of RA on the quality of life, is needed to support family communication about RA risk. Management of expectations is needed in relation to the probabilistic nature of risk information, and appropriate support should be provided for negative psychological outcomes. PMID- 27998045 TI - How can a vascular surgeon help in kidney transplantation. AB - Kidney transplantation is a surgical procedure involving both vascular and ureteric anastomoses. As a matter of fact, it can be performed either by urologists or vascular surgeons. However, vascular surgeon's expertise can be helpful at different times. In the present paper we describe how can vascular surgeons help at the different stages of kidney transplantation process in modern care: 1) before kidney transplantation for recipient preparation in order to allow subsequent graft implantation, either by performing percutaneous embolization of renal arteries in the setting of polycystic kidney disease or treatment of aneurysmal or occlusive lesions that would contra-indicate graft implantation; 2) at the time of surgery graft back table preparation and repair; and 3) after surgery for long-term follow-up, including transplant renal artery stenosis treatment or transplant nephrectomy. PMID- 27998044 TI - Primary Care Screening and Comorbidity Management in Rheumatoid Arthritis in Ontario, Canada. AB - OBJECTIVE: Quality measurement for rheumatoid arthritis (RA) patients has largely focused on care provided by rheumatologists. Our aim was to develop and assess quality measures related to the screening and management of comorbidity in RA patients in primary care. METHODS: We used the primary care Electronic Medical Record Administrative data Linked Database in Ontario, Canada. We harmonized Canadian general population and RA clinical recommendations to develop and assess screening, process, and outcome measures. For each RA patient, 10 non-RA patients were matched by age and sex. Stratified analyses were performed, comparing patients with RA to those without RA, to assess the performance of quality measures. RESULTS: We compared 1,405 RA patients to 14,050 matched non-RA patients (72.8% female; mean age 62.5 years). Compared to non-RA patients, RA patients more frequently had influenza (44.9% versus 40.0%) and pneumococcal (40.4% versus 34.1%) vaccinations and bone mineral density testing (67.4% versus 58.1%). Herpes zoster vaccinations were less frequent among RA patients (13.8% versus 19.5%), as was screening for cervical cancer (58.6% versus 64.0%). No significant differences were observed between RA and non-RA patients in screenings for breast (70.7% versus 73.8%) or colorectal (31.7% versus 34.5%) cancers. Only a quarter of RA patients had a comprehensive cardiovascular risk assessment. No definitive differences were detected in the management of patients who had co-occurring cardiovascular disease or diabetes mellitus. CONCLUSION: For both RA and non-RA patients, compliance with Canadian recommendations for preventive medical services and screening for comorbid conditions in primary care was less than optimal. This indicates key targets for improvement. PMID- 27998046 TI - Supervised exercise therapy: it does work, but how to set up a program? AB - Intermittent claudication (IC) is a manifestation of peripheral arterial disease. IC has a high prevalence in the older population, is closely associated with other expressions of atherosclerotic disease and often co-exists in multimorbid patients. Treatment of IC should address reduction of cardiovascular risk and improvement of functional capacity and health-related quality of life (QoL). As recommended by contemporary international guidelines, the first-line treatment includes supervised exercise therapy (SET). In several randomized controlled trials and systematic reviews, SET is compared with usual care, placebo, walking advice and endovascular revascularization. The evidence supporting the efficacy of SET programs to alleviate claudication symptoms is robust. SET improves walking distance and health-related QoL and appears to be the most cost-effective treatment for IC. Nevertheless, only few of all newly diagnosed IC patients worldwide receive this safe, efficient and structured treatment. Worldwide implementation of structured SET programs is seriously impeded by outdated arguments favoring an invasive intervention, absence of a network of specialized physical therapists providing standardized SET and lack of awareness and/or knowledge of the importance of SET by referring physicians. Besides, misguiding financial incentives and lack of reimbursement hamper actual use of SET programs. In the Netherlands, a national integrated care network (ClaudicatioNet) was launched in 2011 to combat treatment shortcomings and stimulate cohesion and collaboration between stakeholders. This care intervention has resulted in optimized quality of care for all patients with IC. PMID- 27998047 TI - How to manage hypertension with atherosclerotic renal artery stenosis? AB - The management of atherosclerotic renal artery stenosis (ARAS) in patients with hypertension has been the topic of great controversy. Major contemporary clinical trials such as the Cardiovascular Outcomes for Renal Artery lesions (CORAL) and Angioplasty and Stenting for Renal Atherosclerotic lesions (ASTRAL) have failed to show significant benefit of revascularization over medical management in controlling blood pressure and preserving renal function. We present here the implications and limitations of these trials and formulate recommendations for management of ARAS. PMID- 27998048 TI - Chronic mesenteric ischemia: when and how to intervene on patients with celiac/SMA stenosis. AB - BACKGROUND: Studies that compared open surgical mesenteric artery repair (OSMAR) with percutaneous mesenteric artery stenting (PMAS) in patients with chronic mesenteric ischemia (CMI) are based on merely older studies in which only a minority of patients received PMAS. This does not reflect the current PMAS-first choice treatment paradigm. This article focused on the present opinions and changes in outcomes of OSMAR for CMI in the era of preferred use of PMAS. METHODS: Patients who received OSMAR for CMI from 1997 until 2014 in a tertiary referral centre for chronic mesenteric ischemia were included in this report. Patients were divided into two groups, the historical OSMAR preferred group and present PMAS preferred group. RESULTS: Patient characteristics, SVS comorbidity severity score, clinical presentation and number of diseased mesenteric arteries were not significantly changed after the widespread introduction of PMAS. In the present PMAS first era there were trends of less open surgical mesenteric artery multivessel repair, less antegrade situated bypasses, decreased clinical success but improved survival after OSMAR. CONCLUSIONS: Elective OSMAR should only be used in patients with substantial physiologic reserve and who have unfavourable mesenteric lesions, failed PMAS or multiple recurrences of in-stent stenosis/occlusion. PMAS in CMI patients is evolved from "bridge to surgery" to nowadays first choice treatment and "bridge to repeated PMAS" in almost all patients with CMI. PMID- 27998049 TI - Long-term results of outside "instructions for use" EVAR. AB - INTRODUCTION: Endovascular aneurysm repair (EVAR) has progressively expanded to more complex anatomies, frequently outside manufacturer's instructions for use (IFU). However, the long term results of off-label use of EVAR remain largely undocumented. The aim of this paper is to examine the long term results of outside IFU EVAR. EVIDENCE ACQUISITION: English literature was searched to identify publications on long term results for outside IFU EVAR. A follow-up extending for at least 5 years was the minimum required as inclusion criteria. The outcomes measured were: overall mortality, aneurysm-related mortality (ARM), freedom from postimplant aneurysm rupture, aneurysm sac enlargement, type I endoleaks and secondary interventions. Results were compared to randomized clinical trials (RCTs) with long term results published (EVAR-1, DREAM, OVER and ACE Trial). EVIDENCE SYNTHESIS: Thirteen studies were included. 7 studies described outcomes associated to a specific breached IFU, while 6 studies presented general outside IFU results. In patients outside IFU, 3 to 8 years estimates of overall mortality ranged from 21.5% to 40% (RCTs:13.7-46%) and ARM from 0-11% (RCTs: 1.2-7%). Five-year estimates of sac enlargement was approximately 43%. Type I endoleak rates for outside IFU (follow-up 5-12 years) ranged from 3.8-15%, which is higher than found in RCT-derived data (6.6-6.9%). Comparable results are seen for postimplant rupture and secondary interventions. CONCLUSIONS: The long term results of off-label use of EVAR are scarcely published. Although overall mortality and ARM does not seem to differ significantly at long-term, higher rates of type I endoleaks may be expected, mainly in short necks. However, for patients with severe angulation or high thrombus load in the proximal neck, results of outside IFU EVAR seem to match the results of inside IFU. PMID- 27998050 TI - Evidence overview: anatomical criteria determining patients at high risk for carotid stenting. AB - Carotid artery stenting (CAS) is a complex endovascular procedure that may be an alternative for carotid endarterectomy in selected patients. This paper provides an overview of the anatomical and lesion characteristics that are related to an increase in complications with CAS procedures, in order to provide criteria to select patients that will benefit most from CAS. PMID- 27998052 TI - ULTRASONOGRAPHY: how to raise the impact factor. PMID- 27998051 TI - Follow-up and surveillance of vein grafts: when and how to intervene to prevent complications. AB - Despite advances in endovascular strategies, surgical infrainguinal lower limb revascularization remains the gold standard treatment for critical lower limb ischemia and disabling claudication. Maintaining patency of infrainguinal vein bypass grafts has been a challenging task for vascular surgeons as they are prone to developing stenoses which may precipitate failure of the bypass. Duplex ultrasound scanning has evolved as the investigation of choice to identify vein graft lesions but graft surveillance programs using this technique remain controversial. The rationale for graft surveillance is that intervention in a patent but failing graft results in improved long-term patency and limb salvage rates compared to rescue of an occluded graft. The six-week postoperative Duplex ultrasound scan is important in identifying flow abnormalities that can predict the natural history of a vein graft and the outlook for the limb in the medium term. There are multiple factors influencing vein graft failure, which means guidelines should be flexible in terms of when and which type of intervention to the graft is optimum. Patency and durability favour open surgical revision over endovascular intervention but this must be counter balanced by the increased morbidity associated with surgical revision. PMID- 27998053 TI - Ultrasonographic findings of Kikuchi cervical lymphadenopathy in children. AB - PURPOSE: The purpose of this study was to analyze the ultrasonographic (USG) findings of Kikuchi cervical lymphadenopathy in pediatric patients. METHODS: Between April 2007 and September 2016, 84 children (42 male and 42 female; mean+/ standard deviation age, 12.9+/-3.2 years; range, 5 to 18 years) confirmed with Kikuchi disease were enrolled. Clinical findings and USG findings of Kikuchi cervical lymphadenopathy were retrospectively reviewed. Localized symptoms, systemic symptoms, and laboratory findings including the white blood cell count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analyzed. An analysis of the USG findings included evaluation of the location, size, and presence of intranodal abscess; intranodal calcification; perinodal fat swelling; localized fluid collection; and loss of nodal echogenic hilum. RESULTS: Among the patients, 49 (58%) showed localized tenderness at the cervical lymphadenopathy. Fever was present in 55 (66%), while 27 (32%) had prolonged fever. Of 74 with lab results, 54 (73%) had leukopenia but none had leukocytosis. Among the same 74, there was a high ESR (>50 mm/hr) in 10 (14%) and a high CRP level (>5 mg/dL) in seven (9%). The USG findings of most of the patients (n=72, 86%) showed unilateral neck involvement, especially in the left side neck (45 of 72, 63%). The most common site of Kikuchi lymphadenopathy involvement was the area at cervical lymph node level V, at the posterior triangle (n=77, 92%). Conglomerated nodal distribution (n=57, 68%), preserved central nodal echogenic hilum (n=84, 98%), and perinodal fat swelling (n=55, 65%) were common USG findings in the children with Kikuchi. In addition, multiple cervical lymph nodes showed a relatively even size distribution (n=73, 87%). CONCLUSION: The common USG findings of Kikuchi disease in the pediatric population of our study were multiple conglomerated unilateral cervical lymphadenopathy showing perinodal fat swelling and even size distribution. PMID- 27998054 TI - Nanopatterning of Group V Elements for Tailoring the Electronic Properties of Semiconductors by Monolayer Doping. AB - Control of the electronic properties of semiconductors is primarily achieved through doping. While scaling down the device dimensions to the molecular regime presents an increasing number of difficulties, doping control at the nanoscale is still regarded as one of the major challenges of the electronic industry. Within this context, new techniques such as monolayer doping (MLD) represent a substantial improvement toward surface doping with atomic and specific doping dose control at the nanoscale. Our previous work has explained in detail the atomistic mechanism behind MLD by means of density-functional theory calculations (Chem. Mater. 2016, 28, 1975). Here, we address the key questions that will ultimately allow one to optimize the scalability of the MLD process. First, we show that dopant coverage control cannot be achieved by simultaneous reaction of several group V elements, but stepwise reactions make it possible. Second, using ab initio molecular dynamics, we investigate the thermal decomposition of the molecular precursors, together with the stability of the corresponding binary and ternary dopant oxides, prior to the dopant diffusion into the semiconductor surface. Finally, the effect of the coverage and type of dopant on the electronic properties of the semiconductor is also analyzed. Furthermore, the atomistic characterization of the MLD process raises unexpected questions regarding possible crystal damage effects by dopant exchange with the semiconductor ions or the final distribution of the doping impurities within the crystal structure. By combining all our results, optimization recipes to create ultrashallow doped junctions at the nanoscale are finally proposed. PMID- 27998056 TI - Site-Specific and Stoichiometric Stealth Polymer Conjugates of Therapeutic Peptides and Proteins. AB - As potent and selective therapeutic agents, peptides and proteins are an important class of drugs, but they typically have suboptimal pharmacokinetic profiles. One approach to solve this problem is their conjugation with "stealth" polymers. Conventional methods for conjugation of this class of polymers to peptides and proteins are typically carried out by reactions that have poor yield and provide limited control over the site of conjugation and the stoichiometry of the conjugate. To address these limitations, new chemical and biological approaches have been developed that provide new molecular tools in the bioconjugation toolbox to create stealth polymer conjugates of peptides and proteins with exquisite control over their properties. This review article highlights these recent advances in the synthesis of therapeutic peptide- and protein-stealth polymer conjugates. PMID- 27998055 TI - Pillared Structure Design of MXene with Ultralarge Interlayer Spacing for High Performance Lithium-Ion Capacitors. AB - Two-dimensional transition-metal carbide materials (termed MXene) have attracted huge attention in the field of electrochemical energy storage due to their excellent electrical conductivity, high volumetric capacity, etc. Herein, with inspiration from the interesting structure of pillared interlayered clays, we attempt to fabricate pillared Ti3C2 MXene (CTAB-Sn(IV)@Ti3C2) via a facile liquid phase cetyltrimethylammonium bromide (CTAB) prepillaring and Sn4+ pillaring method. The interlayer spacing of Ti3C2 MXene can be controlled according to the size of the intercalated prepillaring agent (cationic surfactant) and can reach 2.708 nm with 177% increase compared with the original spacing of 0.977 nm, which is currently the maximum value according to our knowledge. Because of the pillar effect, the assembled LIC exhibits a superior energy density of 239.50 Wh kg-1 based on the weight of CTAB-Sn(IV)@Ti3C2 even under higher power density of 10.8 kW kg-1. When CTAB-Sn(IV)@Ti3C2 anode couples with commercial AC cathode, LIC reveals higher energy density and power density compared with conventional MXene materials. PMID- 27998057 TI - Spatial Models of Sewer Pipe Leakage Predict the Occurrence of Wastewater Indicators in Shallow Urban Groundwater. AB - Twentieth century municipal wastewater infrastructure greatly improved U.S. urban public health and water quality. However, sewer pipes deteriorate, and their accumulated structural defects may release untreated wastewater to the environment via acute breaks or insidious exfiltration. Exfiltrated wastewater constitutes a loss of potentially reusable water and delivers a complex and variable mix of contaminants to urban shallow groundwater. Yet, predicting where deteriorated sewers impinge on shallow groundwater has been challenging. Here we develop and test a spatially explicit model of exfiltration probability based on pipe attributes and groundwater elevation without prior knowledge of exfiltrating defect locations. We find that models of exfiltration probability can predict the probable occurrence in underlying shallow groundwater of established wastewater indicators including the artificial sweetener acesulfame, tryptophan-like fluorescent dissolved organic matter, nitrate, and a stable isotope of water (delta18O). The strength of the association between exfiltration probability and indicators of wastewater increased when multiple pipe attributes, distance weighting, and groundwater flow direction were considered in the model. The results prove that available sanitary sewer databases and groundwater digital elevation data can be analyzed to predict where pipes are likely leaking and contaminating groundwater. Such understanding could direct sewer infrastructure reinvestment toward water resource protection. PMID- 27998059 TI - Thermal-Responsive Anisotropic Wetting Microstructures for Manipulation of Fluids in Microfluidics. AB - We show morphology-patterned stripes modified by thermal-responsive polymer for smartly guiding flow motion of fluid in chips. With a two-step modification process, we fabricated PNIPAAm-modified Si stripes on silicon slides, which were employed as substrates for fluid manipulation in microchannels. When the system temperature switches between above and below the lower critical solution temperature (LCST) of PNIPAAm, the wettability of the substrates also switches between strong anisotropy and weak anisotropy, which resulted in anisotropic (even unidirectional) flow and isotropic flow behavior of liquid in microchannels. The thermal-responsive flow motion of fluid in the chip is influenced by the applied pressure, the thickness of PNIPAAm, and dimension of the microchannels. Moreover, we measured the feasible applied pressure scopes under different structure factors. Because of the excellent reversibility and quick switching speed, the chip could be used as a thermal-responsive microvalve. Through tuning the system temperature and adding the assistant gas, we realized successive "valve" function. We believe that the practical and simple chip could be widely utilized in medical detection, immunodetection, protein analysis, and cell cultures. PMID- 27998060 TI - Electron Momentum Spectroscopy Investigation of Molecular Conformations of Ethanol Considering Vibrational Effects. AB - The interpretation of experimental electron momentum distributions (EMDs) of ethanol, one of the simplest molecules having conformers, has confused researchers for years. High-level calculations of Dyson orbital EMDs by thermally averaging the gauche and trans conformers as well as molecular dynamical simulations failed to quantitatively reproduce the experiments for some of the outer valence orbitals. In this work, the valence shell electron binding energy spectrum and EMDs of ethanol are revisited by the high-sensitivity electron momentum spectrometer employing symmetric noncoplanar geometry at an incident energy of 1200 eV plus binding energy, together with a detailed analysis of the influence of vibrational motions on the EMDs for the two conformers employing a harmonic analytical quantum mechanical (HAQM) approach by taking into account all of the vibrational modes. The significant discrepancies between theories and experiments in previous works have now been interpreted quantitatively, indicating that the vibrational effect plays a significant role in reproducing the experimental results, not only through the low-frequency OH and CH3 torsion modes but also through other high-frequency ones. Rational explanation of experimental momentum profiles provides solid evidence that the trans conformer is slightly more stable than the gauche conformer, in accordance with thermodynamic predictions and other experiments. The case of ethanol demonstrates the significance of considering vibrational effects when performing a conformational study on flexible molecules using electron momentum spectroscopy. PMID- 27998061 TI - Load-Induced Frictional Transition at a Well-Defined Alkane Loop Surface. AB - Self-assembled monolayers (SAMs) have attracted considerable attention as a tool to confer desirable properties on material surfaces. So far, molecules used for the SAM formation are generally limited to linear ones and thus chain ends dominate the surface properties. In this study, we have successfully demonstrated unique frictional properties of a SAM composed of alkane loops from cyclic alkanedisulfide on a gold substrate, where both sulfurs are bound to gold. The frictional response was proportional to the load. However, once the load went beyond a threshold value, the frictional response became more dominant. Such a frictional transition was reversible and repeatable and was not discerned for a corresponding SAM composed of n-alkyl chains. The load-induced change in the frictional response from the alkane loops could be associated with the conformational change of the alkane loops. The present results differ from most studies, in which the surface properties are designed on the basis of functional chain end groups. PMID- 27998062 TI - A Call to Action on Mental Illness from the World Health Organization. PMID- 27998058 TI - Label-Free Neuroproteomics of the Hippocampal-Accumbal Circuit Reveals Deficits in Neurotransmitter and Neuropeptide Signaling in Mice Lacking Ethanol-Sensitive Adenosine Transporter. AB - The neural circuit of the dorsal hippocampus (dHip) and nucleus accumbens (NAc) contributes to cue-induced learning and addictive behaviors, as demonstrated by the escalation of ethanol-seeking behaviors observed following deletion of the adenosine equilibrative nucleoside transporter 1 (ENT1-/-) in mice. Here we perform quantitative LC-MS/MS neuroproteomics in the dHip and NAc of ENT1-/- mice. Using Ingenuity Pathway Analysis, we identified proteins associated with increased long-term potentiation, ARP2/3-mediated actin cytoskeleton signaling and protein expression patterns suggesting deficits in glutamate degradation, GABAergic signaling, as well as significant changes in bioenergetics and energy homeostasis (oxidative phosphorylation, TCA cycle, and glycolysis). These pathways are consistent with previously reported behavioral and biochemical phenotypes that typify mice lacking ENT1. Moreover, we validated decreased expression of the SNARE complex protein VAMP1 (synaptobrevin-1) in the dHip as well as decreased expression of pro-dynorphin (PDYN), neuroendocrine convertase (PCSK1), and Leu-Enkephalin (dynorphin-A) in the NAc. Taken together, our proteomic approach provides novel pathways indicating that ENT1-regulated signaling is essential for neurotransmitter release and neuropeptide processing, both of which underlie learning and reward-seeking behaviors. PMID- 27998063 TI - Challenges of Finding Novel Drugs Targeting the K-Cl Cotransporter. AB - Human disease-causing mutations and genetically modified mouse models have established the importance of KCC2 and KCC3 in nervous system physiology. These two proteins mediate the electroneutral cotransport of K+ and Cl- ions across the neuronal membrane. Disruption of KCC2 function affects inhibitory synaptic transmission with consequences for epilepsy, pain perception, and potentially some neuropsychiatric disorders, whereas disruption of KCC3 affects both central and peripheral nervous systems, resulting in psychosis and peripheral neuropathy. Until recently, the KCC field has suffered from an almost complete lack of pharmacological tools with which to probe cotransporter function. The only available tools being the very poorly potent loop diuretics (e.g., furosemide EC50 = 6 * 10-4 M). To address this deficiency, efforts that focused on the discovery of KCC modulators have been undertaken. This work has resulted in the discovery of novel inhibitory compounds that are up to four orders of magnitude more potent (EC50 = 6 * 10-7 M) and with increased specificity. While useful for ex vivo studies, these tools possess poor pharmacokinetic properties, severely limiting their utility in vivo. In addition, only a few agents acting on regulatory molecules have been identified as putative KCC activators. Thus, further research is required to develop tools suitable to advance our understanding of how KCC modulation may be useful for the treatment of disease. PMID- 27998065 TI - Pathway Construction in Corynebacterium glutamicum and Strain Engineering To Produce Rare Sugars from Glycerol. AB - Rare sugars are valuable natural products widely used in pharmaceutical and food industries. In this study, we expected to synthesize rare ketoses from abundant glycerol using dihydroxyacetone phosphate (DHAP)-dependent aldolases. First, a new glycerol assimilation pathway was constructed to synthesize DHAP. The enzymes which convert glycerol to 3-hydroxypropionaldehyde and l-glyceraldehyde were selected, and their corresponding aldehyde synthesis pathways were constructed in vivo. Four aldol pathways based on different aldolases and phosphorylase were gathered. Next, three pathways were assembled and the resulting strains synthesized 5-deoxypsicose, 5-deoxysorbose, and 5-deoxyfructose from glucose and glycerol and produce l-fructose, l-tagatose, l-sorbose, and l-psicose with glycerol as the only carbon source. To achieve higher product titer and yield, the recombinant strains were further engineered and fermentation conditions were optimized. Fed-batch culture of engineered strains obtained 38.1 g/L 5 deoxypsicose with a yield of 0.91 +/- 0.04 mol product per mol of glycerol and synthesized 20.8 g/L l-fructose, 10.3 g/L l-tagatose, 1.2 g/L l-sorbose, and 0.95 g/L l-psicose. PMID- 27998066 TI - Secoisolariciresinol Diglucoside and Cyanogenic Glycosides in Gluten-free Bread Fortified with Flaxseed Meal. AB - Flaxseed (Linum usitatissimum L.) meal contains cyanogenic glycosides (CGs) and the lignan secoisolariciresinol diglucoside (1). Gluten-free (GF) doughs and baked goods were produced with added flaxseed meal (20%, w/w) then 1, and CGs were determined in fortified flour, dough, and bread with storage (0, 1, 2, and 4 weeks) at different temperatures (-18, 4, and 22-23 degrees C). 1 was present in flour, dough, and GF bread after baking. 1 was stable with extensive storage (up to 4 weeks) and was not affected by storage temperature. CGs in flaxseed meal and fortified GF samples were analyzed by 1H NMR of the cyanohydrins. Linamarin and/or linustatin were the primary CGs in both flaxseed meal and fortified flour. CGs decreased with storage in dough fortified with flaxseed meal or GF bread after baking. GF bakery food products fortified with flaxseed meal had reduced CGs but remained a good source of dietary 1. PMID- 27998067 TI - Correction to Characterization and Application of BiLA, a Psychrophilic alpha Amylase from Bifidobacterium longum. PMID- 27998068 TI - Effects of Light Intensity and Color on the Biomass, Extracellular Red Pigment, and Citrinin Production of Monascus ruber. AB - Light is a crucial environmental signal for fungi. In this work, the effects of different light intensities and colors on biomass, Monascus pigments (MPs) and citrinin production of Monascus ruber M7 were investigated. We have demonstrated that low intensity of blue light (500 lx) decreased Monascus biomass, increased MPs accumulation via upregulation of MpigA, MpigB, and MpigJ genes expression, but had no significant influence on citrinin production. High intensity of blue light (1500 lx) decreased citrinin accumulation but had no significant influence on biomass and MPs production after 14 days cultivation. Low intensity of green light (500 lx) stimulated citrinin production via upregulation of pksCT, mrl1, mrl2, and ctnA genes expression. One putative red light photoreceptor and two putative green light photoreceptors were identified in M. ruber M7. These observations will not only guide the practical production of Monascus but also contribute to our understanding light effects on Monascus. PMID- 27998069 TI - Correction to Characterization of a Novel Maltose-Forming alpha-Amylase from Lactobacillus plantarum subsp. plantarum ST-III. PMID- 27998070 TI - Camptothecin-Polysaccharide Co-assembly and Its Controlled Release. AB - beta-Cyclodextrin modified camptothecin (CPT-CD) was synthesized through esterification reaction and "click chemistry" to greatly improve the solubility of CPT in aqueous solution, and then, a supramolecular nanoparticle was constructed by strong noncovalent interaction between beta-cyclodextrin and adamantane and amphiphilic interaction by simply mixing CPT-CD and adamantane modified hyaluronic acid (HA-ADA) together. The obtained nanoparticle had a hydrophilic HA shell, which could target and recognize HA receptors overexpressed on the surface of cancer cells, and a hydrophobic CPT core, which could protect CPT from hydrolyzation. The results of cytotoxicity experiments showed that the nanoparticle we have designed in this work exhibited similar anticancer activities to, but with much lower side effects than, the commercial chemotherapeutic drug CPT in vitro. We believe that this work might provide a strategy for improving the treatment performance of CPT in laboratory and clinical settings. PMID- 27998071 TI - Characterization of the Artemisinin Binding Site for Translationally Controlled Tumor Protein (TCTP) by Bioorthogonal Click Chemistry. AB - Despite the fact that multiple artemisinin-alkylated proteins in Plasmodium falciparum have been identified in recent studies, the alkylation mechanism and accurate binding site of artemisinin-protein interaction have remained elusive. Here, we report the chemical-probe-based enrichment of the artemisinin-binding peptide and characterization of the artemisinin-binding site of P. falciparum translationally controlled tumor protein (TCTP). A peptide fragment within the N terminal region of TCTP was enriched and found to be alkylated by an artemisinin derived probe. MS2 fragments showed that artemisinin could alkylate multiple amino acids from Phe12 to Tyr22 of TCTP, which was supported by labeling experiments upon site-directed mutagenesis and computational modeling studies. Taken together, the "capture-and-release" strategy affords consolidated advantages previously unavailable in artemisinin-protein binding site studies, and our results deepened the understanding of the mechanism of protein alkylation via heme-activated artemisinin. PMID- 27998072 TI - Effect of Several HIV Antigens Simultaneously Loaded with G2-NN16 Carbosilane Dendrimer in the Cell Uptake and Functionality of Human Dendritic Cells. AB - Dendrimers are highly branched, star-shaped, and nanosized polymers that have been proposed as new carriers for specific HIV-1 peptides. Dendritic cells (DCs) are the most-potent antigen-presenting cells that play a major role in the development of cell-mediated immunotherapy due to the generation and regulation of adaptive immune responses against HIV-1. This article reports on the associated behavior of two or three HIV-derived peptides simultaneously (p24/gp160 or p24/gp160/NEF) with cationic carbosilane dendrimer G2-NN16. We have found that (i) immature DCs (iDCs) and mature (mDCs) did not capture efficiently HIV peptides regarding the uptake level when cells were treated with G2-NN16 peptide complex alone; (ii) the ability of DCs to migrate was not depending on the peptides presence; and (iii) with the use of molecular dynamic simulation, a mixture of peptides decreased the cell uptake of the other peptides (in particular, NEF hinders the binding of more peptides and is especially obstructing of the binding of gp160 to G2-NN16). The results suggest that G2-NN16 cannot be considered as an alternative carrier for delivering two or more HIV derived peptides to DCs. PMID- 27998073 TI - Matrix Metalloproteinase Responsive Nanoparticles for Synergistic Treatment of Colorectal Cancer via Simultaneous Anti-Angiogenesis and Chemotherapy. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide, especially in developed countries. Although patients' overall survival has been improved by either conventional chemotherapy or newly developed anti-angiogenesis treatment based on its highly vascularized feature, the relatively low therapeutic efficacy and severe side effects remain big problems in clinical practice. In this study, we describe an easy method to construct a novel matrix metalloproteinase-2 (MMP-2) responsive nanocarrier, which can load hydrophobic agents (camptothecin and sorafenib) with high efficiency to exert synergistic efficacy for CRC treatment. The drug-containing nanoparticles can particularly respond to the MMP-2 and realize the controlled release of payloads at the tumor site. Moreover, both in vitro and in vivo studies have demonstrated that this responsive nanoparticle exhibits much higher therapeutic efficacy than that of single antitumor agents or combined drugs coadministrated in traditional ways. PMID- 27998074 TI - Light-Up "Channel Dyes" for Haloalkane-Based Protein Labeling in Vitro and in Bacterial Cells. AB - We describe a novel molecular strategy for engendering a strong light-up signal in fluorescence tagging of the genetically encoded HaloTag protein domain. We designed a set of haloalkane-derivatized dyes having twisted internal charge transfer (TICT) structures potentially narrow enough to partially fit into the enzyme's haloalkane-binding channel. Testing a range of short chain lengths revealed a number of active dyes, with seven carbons yielding optimum light-up signal. The dimethylaminostilbazolium chloroheptyl dye (1d) yields a 27-fold fluorescence emission enhancement (lambdaex = 535 nm; Em(max) = 616 nm) upon reaction with the protein. The control compound with standard 12-atom linkage shows less efficient signaling, consistent with our channel-binding hypothesis. For emission further to the red, we also prepared a chloroheptyl naphthalene based dye; compound 2 emits at 653 nm with strong fluorescence enhancement upon reaction with the HaloTag domain. The two dyes (1d, 2) were successfully tested in wash-free imaging of protein localization in bacteria, using a HaloTag fusion of the filamenting temperature-sensitive mutant Z (FtsZ) protein in Escherichia coli (E. coli). The new dye conjugates are inexpensive and easily synthesized enzyme substrates with low background and large Stokes shifts, offering substantial benefits over known fluorescent substrates for the HaloTag enzyme. PMID- 27998076 TI - Microwave-Triggered Smart Drug Release from Liposomes Co-encapsulating Doxorubicin and Salt for Local Combined Hyperthermia and Chemotherapy of Cancer. AB - The microwave and temperature sensitive liposomes were fabricated successfully from 1,2-dipalmityol-sn-glycero-3-phosphocholine (DPPC), cholesterol, and 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) with a molar ratio of 4:1:0.26 by co-encapsulating NaCl and doxorubicin (DOX) through the thin-film hydration method to externally manipulate drug release at a predetermined location in the body at a desired time in the right dosage for combination microwave hyperthermia and chemotherapy of cancer to afford a synergistic therapeutic effect. It was found that the confinement of the high concentration of NaCl ions inside the small size of the liposomes led to a more-rapid temperature elevation than the dissociative ions upon microwave treatment. More than 67.6% doxorubicin was released from the DOX and NaCl co loaded liposomes (DOX&NaCl@liposomes) upon microwave irradiation for 2 min. After incubation with 2 mg/mL DOX&NaCl@liposomes for 4 h followed by treatment with microwave for 2 min, the inhibition rate of human breast cancer cell MDA-MB-231 was evaluated as 76.1%, much higher than that for NaCl@liposomes (29.8%) and DOX@liposomes (40.2%). The tumor growth inhibition was evaluated to be 73.4% after intravenous injection of DOX&NaCl@liposomes followed by microwave irradiation, much higher than that with only NaCl@liposomes (41.5%) or DOX@liposomes (45.5%) combined with microwave irradiation. Therefore, DOX&NaCl@liposomes could serve as a promising thermochemotherapy nanomedicine for cancer treatment because of its excellent microwave susceptible property and good biocompatibility. PMID- 27998075 TI - Biotin Decorated Gold Nanoparticles for Targeted Delivery of a Smart-Linked Anticancer Active Copper Complex: In Vitro and In Vivo Studies. AB - The synthesis and anticancer activity of a copper(II) diacetyl-bis(N4 methylthiosemicarbazone) complex and its nanoconjugates are reported. The copper(II) complex is connected to a carboxylic acid group through a cleavable disulfide link to enable smart delivery. The copper complex is tethered to highly water-soluble 20 nm gold nanoparticles (AuNPs), stabilized by amine terminated lipoic acid-polyethylene glycol (PEG). The gold nanoparticle carrier was further decorated with biotin to achieve targeted action. The copper complex and the conjugates with and without biotin, were tested against HeLa and HaCaT cells. They show very good anticancer activity against HeLa cells, a cell line derived from cervical cancer and are less active against HaCaT cells. Slow and sustained release of the complex from conjugates is demonstrated through cleavage of disulfide linker in the presence of glutathione (GSH), a reducing agent intrinsically present in high concentrations within cancer cells. Biotin appended conjugates do not show greater activity than conjugates without biotin against HeLa cells. This is consistent with drug uptake studies, which suggests similar uptake profiles for both conjugates in vitro. However, in vivo studies using a HeLa cell xenograft tumor model shows 3.8-fold reduction in tumor volume for the biotin conjugated nanoparticle compared to the control whereas the conjugate without biotin shows only 2.3-fold reduction in the tumor volume suggesting significant targeting. PMID- 27998077 TI - Investigation of Cellular Uptakes of the In-Tether Chiral-Center-Induced Helical Pentapeptides. AB - We recently reported that a precisely positioned in-tether chiral center can modulate backbone peptides' secondary structures, which provides an unbiased platform to evaluate peptides' biophysical properties solely imposed by secondary structure differences. In this work, we studied the cellular uptake efficiency and mechanism of epimer pairs of a panel of chirality-induced helical peptides (CIH peptides). Although the peptides' cellular uptake is a synergetic result of various factors, our results unambiguously indicate that helical content is an important factor for the cellular uptake of CIH peptides. PMID- 27998078 TI - Emerging Designs of Activatable Photoacoustic Probes for Molecular Imaging. AB - Photoacoustic (PA) imaging as a new hybrid imaging modality holds great promise for real-time in vivo monitoring of biological processes with deep tissue penetration and high spatial resolution. To endow PA imaging with the ability to provide real-time molecular information at disease sites, molecular probes that can change their PA signals responding to the target or event of interest have to be developed. This review focuses on the recent development of smart activatable PA probes for molecular imaging. A brief summary of PA imaging agents is given first, followed by the detailed discussion of the contemporary design approaches toward activatable PA probes for different imaging applications. At last, the current challenges are highlighted. PMID- 27998079 TI - Designing Molecular Probes To Prolong Intracellular Retention: Application to Nitroxide Spin Probes. AB - Targeted delivery of molecular probes into cells enables cellular imaging through optical and magnetic modalities. Probe molecules that are well retained by cells can accumulate to higher intracellular concentrations, and thus increase the signal-to-noise ratio of, and widen the temporal window for, imaging. Here we synthesize a paramagnetic spin probe bearing six ionic functional groups and show that it has long intracellular half-life (>12 h) and exceptional biostability in living cells. We demonstrate that judicious incorporation of ionic substituents on probe molecules systematically increases intracellular retention time, and should therefore be beneficial to imaging experiments. PMID- 27998080 TI - Structure of the Lasso Peptide Isopeptidase Identifies a Topology for Processing Threaded Substrates. AB - Lasso peptides are a class of bioactive ribosomally synthesized and post translationally modified peptides (RiPPs), with a threaded knot structure that is formed by an isopeptide bond attaching the N-terminus of the peptide to a side chain carboxylate. Some lasso peptide biosynthetic clusters harbor an enzyme that specifically hydrolyzes the isopeptide bond to yield the linear peptide. We describe here the 2.4 A resolution structure of a lasso peptide isopeptidase revealing a topologically novel didomain architecture consisting of an open beta propeller appended to an alpha/beta hydrolase domain. The 2.2 A resolution cocrystal structure of an inactive variant in complex with a lasso peptide reveals deformation of the substrate, and reorganization of the enzyme active site, which exposes and orients the isopeptide bond for hydrolysis. Structure based mutational analysis reveals how this enzyme recognizes the lasso peptide substrate by shape complementarity rather than through sequence specificity. The isopeptidase gene can be used to facilitate genome mining, as a network-based mining strategy queried with this sequence identified 87 putative lasso peptide biosynthetic clusters, 65 of which have not been previously described. Lastly, we validate this mining approach by heterologous expression of two clusters encoded within the genome of Asticcaucalis benevestitus, and demonstrate that both clusters produce lasso peptides. PMID- 27998081 TI - Liposomal Texaphyrin Theranostics for Metastatic Liver Cancer. AB - Reported here is a new theranostic agent, 1, which consists of a Gd3+-texaphyrin core conjugated to a doxorubicin prodrug via a disulfide bond. Conjugate 1 was designed to undergo cleavage in the presence of glutathione (GSH), a species typically upregulated in cancer cells. As prepared, conjugate 1 displays no appreciable fluorescence. However, when exposed to excess GSH an increase in the fluorescence intensity at 592 nm is observed that is ascribed to release of free doxorubicin. To improve the solubility and enhance the tumor targeting of 1, it was loaded into folate-receptor-targeted liposomes to produce FL-1 (for folate liposome loaded with 1). As inferred from both fluorescence turn on studies and independent HPLC analyses, FL-1 was found to undergo selective uptake and cleavage to release free Dox in the KB and CT26 cell lines, which express folate receptors on the cell surface, relative to the HepG2 and NIH3T3 cell lines, which show low expression of those receptors. FL-1 was found to produce a greater antiproliferative effect in the case of the KB and CT26 cell lines as compared to that in the HepG2 and NIH3T3 cell lines. FL-1 was also found to provide enhanced magnetic resonance imaging in vivo under conditions of T1 contrast in the early stage of metastatic cancer progression. Finally, time-dependent tumor regrowth studies involving both subcutaneous and metastatic liver cancer mouse models revealed that FL-1 is capable of reducing the tumor burden in vivo. PMID- 27998082 TI - Excited-State Dynamics of Oxyluciferin in Firefly Luciferase. AB - The color variations of light emitted by some natural and mutant luciferases are normally attributed to collective factors referred to as microenvironment effects; however, the exact nature of these interactions between the emitting molecule (oxyluciferin) and the active site remains elusive. Although model studies of noncomplexed oxyluciferin and its variants have greatly advanced the understanding of its photochemistry, extrapolation of the conclusions to the real system requires assumptions about the polarity and proticity of the active site. To decipher the intricate excited-state dynamics, global and target analysis is performed here for the first time on the steady-state and time-resolved spectra of firefly oxyluciferin complexed with luciferase from the Japanese firefly (Luciola cruciata). The experimental steady-state and time-resolved luminescence spectra of the oxyluciferin/luciferase complex in solution are compared with the broadband time-resolved firefly bioluminescence recorded in vivo. The results demonstrate that de-excitation of the luminophore results in a complex cascade of photoinduced proton transfer processes and can be interpreted by the pH dependence of the emitted light. It is confirmed that proton transfer is the central event in the spectrochemistry of this system for which any assignment of the pH-dependent emission to a single chemical species would be an oversimplification. PMID- 27998083 TI - General Space-Confined On-Substrate Fabrication of Thickness-Adjustable Hybrid Perovskite Single-Crystalline Thin Films. AB - Organic-inorganic hybrid perovskite single-crystalline thin films (SCTFs) are promising for enhancing photoelectric device performance due to high carrier mobility, long diffusion length, and carrier lifetime. However, bulk perovskite single crystals available today are not suitable for practical device application due to the unfavorable thickness. Herein, we report a facile space-confined solution-processed strategy to on-substrate grow various hybrid perovskite SCTFs in a size of submillimeter with adjustable thicknesses from nano- to micrometers. These SCTFs exhibit photoelectric properties comparable to bulk single crystals with low defect density and good air stability. The clear thickness-dependent colors allow fast visual selection of SCTFs with a suitable thickness for specific device application. The present substrate-independent growth of perovskite SCTFs opens up opportunities for on-chip fabrication of diverse high performance devices. PMID- 27998084 TI - D2d(23)-C84 versus Sc2C2@D2d(23)-C84: Impact of Endohedral Sc2C2 Doping on Chemical Reactivity in the Photolysis of Diazirine. AB - We compared the chemical reactivity of D2d(23)-C84 and that of Sc2C2@D2d(23)-C84, both having the same carbon cage geometry, in the photolysis of 2-adamantane-2,3' [3H]-diazirine, to clarify metal-atom doping effects on the chemical reactivity of the carbon cage. Experimental and computational studies have revealed that the chemical reactivity of the D2d(23)-C84 carbon cage is altered drastically by endohedral Sc2C2 doping. The reaction of empty D2d(23)-C84 with the diazirine under photoirradiation yields two adamantylidene (Ad) adducts. NMR spectroscopic studies revealed that the major Ad monoadduct (C84(Ad)-A) has a fulleroid structure and that the minor Ad monoadduct (C84(Ad)-B) has a methanofullerene structure. The latter was also characterized using X-ray crystallography. C84(Ad) A is stable under photoirradiation, but it interconverted to C84(Ad)-B by heating at 80 degrees C. In contrast, the reaction of endohedral Sc2C2@D2d(23)-C84 with diazirine under photoirradiation affords four Ad monoadducts (Sc2C2@C84(Ad)-A, Sc2C2@C84(Ad)-B, Sc2C2@C84(Ad)-C, and Sc2C2@C84(Ad)-D). The structure of Sc2C2@C84(Ad)-C was characterized using X-ray crystallography. Thermal interconversion of Sc2C2@C84(Ad)-A and Sc2C2@C84(Ad)-B to Sc2C2@C84(Ad)-C was also observed. The reaction mechanisms of the Ad addition and thermal interconversion were elucidated from theoretical calculations. Calculation results suggest that C84(Ad)-B and Sc2C2@C84(Ad)-C are thermodynamically favorable products. Their different chemical reactivities derive from Sc2C2 doping, which raises the HOMO and LUMO levels of the D2d(23)-C84 carbon cage. PMID- 27998085 TI - Structural Insight into NS5 of Zika Virus Leading to the Discovery of MTase Inhibitors. AB - Zika virus (ZIKV) is an emerging mosquito-borne virus recently linked to intrauterine growth restriction including abnormal fetal brain development. The recent outbreak of ZIKV reached pandemic level resulting in an alarming public health emergency. At present, there is limited understanding of the infectious mechanism and no approved therapy. Nonstructural protein 5 is essential for capping and replication of viral RNA and comprises a methyltransferase (MTase) and RNA dependent RNA polymerase domain. Here we used molecular modeling to obtain the structure of ZIKV MTase and molecular docking to identify the additional hydrophobic region uniquely conserved in flavivirus MTase that can be used as a druggable site. Subsequently, a virtual screening with a library of 28 341 compounds identified 10 best hits showing decisive contacts with the MTase. In vitro efficacy analysis of these compounds against ZIKV, by plaque reduction assay, has confirmed four of the top scored ligands (Life Chemicals ID: F3043 0013, F0922-0796, F1609-0442, and F1750-0048) having EC50 (50% effective concentration) values of 4.8 +/- 2.3, 12.5 +/- 7.4, 17.5 +/- 8.4, and 17.6 +/- 3.1 MUM respectively, identifying lead compounds for anti-ZIKV drug development. PMID- 27998086 TI - DNA-Accelerated Copper Catalysis of Friedel-Crafts Conjugate Addition/Enantioselective Protonation Reactions in Water. AB - DNA-induced rate acceleration has been identified as one of the key elements for the success of the DNA-based catalysis concept. Here we report on a novel DNA based catalytic Friedel-Crafts conjugate addition/enantioselective protonation reaction in water, which represents the first example of a reaction that critically depends on the >700- to 990-fold rate acceleration caused by the presence of a DNA scaffold. The DNA-induced rate acceleration observed is the highest reported due to the environment presented by a biomolecular scaffold for any hybrid catalyst, to date. Based on a combination of kinetics and binding studies, it is proposed that the rate acceleration is in part due to the DNA acting as a pseudophase, analogous to micelles, in which all reaction components are concentrated, resulting in a high effective molarity. The involvement of additional second coordination sphere interactions is suggested by the enantioselectivity of the product. The results presented here show convincingly that the DNA-based catalysis concept, thanks to the DNA-accelerating effect, can be an effective approach to achieving a chemically challenging reaction in water. PMID- 27998088 TI - A pH-Induced Switch in Human Glucagon-like Peptide-1 Aggregation Kinetics. AB - Aggregation and amyloid fibril formation of peptides and proteins is a widespread phenomenon. It has serious implications in a range of areas from biotechnological and pharmaceutical applications to medical disorders. The aim of this study was to develop a better understanding of the mechanism of aggregation and amyloid fibrillation of an important pharmaceutical, human glucagon-like peptide-1 (GLP 1). GLP-1 is a 31-residue hormone peptide that plays an important role regulating blood glucose levels, analogues of which are used for treatment of type 2 diabetes. Amyloid fibril formation of GLP-1 was monitored using thioflavin T fluorescence as a function of peptide concentration between pH 7.5 and 8.2. Results from these studies establish that there is a highly unusual pH-induced switch in GLP-1 aggregation kinetics. At pH 8.2, the kinetics are consistent with a nucleation-polymerization mechanism for fibril formation. However, at pH 7.5, highly unusual kinetics are observed, where the lag time increases with increasing peptide concentration. We attribute this result to the formation of off-pathway species together with an initial slow, unimolecular step where monomer converts to a different monomeric form that forms on-pathway oligomers and ultimately fibrils. Estimation of the pKa values of all the ionizable groups in GLP-1 suggest it is the protonation/deprotonation of the N-terminus that is responsible for the switch with pH. In addition, a range of biophysical techniques were used to characterize (1) the start point of the aggregation reaction and (2) the structure and stability of the fibrils formed. These results show that the off-pathway species form under conditions where GLP-1 is most prone to form oligomers. PMID- 27998089 TI - Evidence for Core Oxygen Dynamics and Exchange in Metal Oxide Nanocrystals from In Situ 17O MAS NMR. AB - Long-term stability of the properties of nanocrystals (NCs) is of paramount importance for any applicative development. However, these are jeopardized by chemical and structural alterations of the NCs induced by the environment and the working conditions. Among the species that alter the NCs properties, water molecules are of tremendous importance. We used 17O solid-state NMR spectroscopy to follow this process and the dynamics of O atoms in metal oxide NCs. Using ZnO as reference material, different chemical environments for the O atoms are characterized and a dynamic exchange process between the NCs and the O atoms from water is evidenced. The exchange does not involve only surface atoms but also ones located deeper inside the ZnO core of the NCs. Finally, a postsynthesis process based on watering/drying cycles is proposed that may greatly improve the long-term stability of metal oxide NCs. PMID- 27998091 TI - Tryptophan Lyase (NosL): A Cornucopia of 5'-Deoxyadenosyl Radical Mediated Transformations. AB - Tryptophan lyase (NosL) is a radical S-adenosyl-l-methionine (SAM) enzyme that catalyzes the formation of 3-methyl-2-indolic acid from l-tryptophan. In this paper, we demonstrate that the 5'-deoxyadenosyl radical is considerably more versatile in its chemistry than previously anticipated: hydrogen atom abstraction from Nalpha-cyclopropyltryptophan occurs at Calpha rather than the amino group with NosL Y90A and replacing the substrate amine with a ketone or an alkene changes the chemistry from hydrogen atom abstraction to double bond addition. In addition, the 5'-deoxyadenosyl radical can add to the [4Fe-4S] cluster and dithionite can be used to trap radicals at the active site. PMID- 27998090 TI - Monitoring Chemical and Biological Electron Transfer Reactions with a Fluorogenic Vitamin K Analogue Probe. AB - We report herein the design, synthesis, and characterization of a two-segment fluorogenic analogue of vitamin K, B-VKQ, prepared by coupling vitamin K3, also known as menadione (a quinone redox center), to a boron-dipyrromethene (BODIPY) fluorophore (a lipophilic reporter segment). Oxidation-reduction reactions, spectroelectrochemical studies, and enzymatic assays conducted in the presence of DT-diaphorase illustrate that the new probe shows reversible redox behavior on par with that of vitamin K, provides a high-sensitivity fluorescence signal, and is compatible with biological conditions, opening the door to monitor remotely (i.e., via imaging) redox processes in real time. In its oxidized form, B-VKQ is non-emissive, while upon reduction to the hydroquinone form, B-VKQH2, BODIPY fluorescence is restored, with emission quantum yield values of ca. 0.54 in toluene. Density functional theory studies validate a photoinduced electron transfer intramolecular switching mechanism, active in the non-emissive quinone form and deactivated upon reduction to the emissive dihydroquinone form. Our results highlight the potential of B-VKQ as a fluorogenic probe to study electron transfer and transport in model systems and biological structures with optimal sensitivity and desirable chemical specificity. Use of such a probe may enable a better understanding of the role that vitamin K plays in biological redox reactions ubiquitous in key cellular processes, and help elucidate the mechanism and pathological significance of these reactions in biological systems. PMID- 27998092 TI - Energy Gap between the Poly-p-phenylene Bridge and Donor Groups Controls the Hole Delocalization in Donor-Bridge-Donor Wires. AB - Poly-p-phenylene wires are critically important as charge-transfer materials in photovoltaics. A comparative analysis of a series of poly-p-phenylene (RPPn) wires, capped with isoalkyl (iAPPn), alkoxy (ROPPn), and dialkylamino (R2NPPn) groups, shows unexpected evolution of oxidation potentials, i.e., decrease (-260 mV) for iAPPn, while increase for ROPPn (+100 mV) and R2NPPn (+350 mV) with increasing number of p-phenylenes. Moreover, redox/optical properties and DFT calculations of R2NPPn/R2NPPn+* further show that the symmetric bell-shaped hole distribution distorts and shifts toward one end of the molecule with only 4 p phenylenes in R2NPPn+*, while shifting of the hole occurs with 6 and 8 p phenylenes in ROPPn+* and iAPPn+*, respectively. Availability of accurate experimental data on highly electron-rich dialkylamino-capped R2NPPn together with ROPPn and iAPPn allowed us to demonstrate, using our recently developed Marcus-based multistate model (MSM), that an increase of oxidation potentials in R2NPPn arises due to an interplay between the electronic coupling (Hab) and energy difference between the end-capped groups and bridging phenylenes (Deltaepsilon). A comparison of the three series of RPPn with varied Deltaepsilon further demonstrates that decrease/increase/no change in oxidation energies of RPPn can be predicted based on the energy gap Deltaepsilon and coupling Hab, i.e., decrease if Deltaepsilon < Hab (i.e., iAPPn), increase if Deltaepsilon > Hab (i.e., R2NPPn), and minimal change if Deltaepsilon ~ Hab (i.e., ROPPn). MSM also reproduces the switching of the nature of electronic transition in higher homologues of R2NPPn+* (n >= 4). These findings will aid in the development of improved models for charge-transfer dynamics in donor-bridge-acceptor systems. PMID- 27998093 TI - Cucurbit[7]uril-Tetramethylrhodamine Conjugate for Direct Sensing and Cellular Imaging. AB - This paper describes the design and synthesis of a conjugate (Q7R) comprising the synthetic host cucurbit[7]uril (Q7) linked to the fluorescent dye tetramethylrhodamine (TMR), and the characterization of its optical and guest binding properties as well as its cellular uptake. Q7R was synthesized in two steps from monofunctionalized azidobutyl-Q7 and NHS-activated TMR. The fluorescence of Q7R is quenched upon guest binding, and this observable was used to determine equilibrium dissociation constant (Kd) values. Unexpectedly, the Kd values for guests binding to Q7R and to unmodified Q7 were essentially identical. Therefore, Q7R can directly report binding to Q7 without an energetic penalty due to the conjugated fluorophore. This result demonstrates a potentially general strategy for the design of single-component host-indicator conjugates that respond sensitively to analytes without perturbing the binding properties of the host. The unique properties of Q7R enabled measurement of Kd values across 3 orders of magnitude and at concentrations as low as 0.7 nM. This result is particularly relevant given the unmatched range of guests and binding affinities demonstrated for Q7. Confocal fluorescence microscopy of live and fixed HT22 neurons revealed the cellular uptake of Q7R and its punctate localization in the cytoplasm. Q7R did not alter cell growth at concentrations up to 2.2 MUM over 4 days. These experiments demonstrate the feasibility of Q7R as a direct sensor for guest binding and as a cell-permeable compound for imaging applications. PMID- 27998094 TI - Transmembrane Fluoride Transport: Direct Measurement and Selectivity Studies. AB - Fluoride has been overlooked as a target in the development of synthetic anion transporters despite natural fluoride transport channels being recently discovered. In this paper we report the direct measurement of fluoride transport across lipid bilayers facilitated by a series of strapped calix[4]pyrroles and show that these compounds facilitate transport via an electrogenic mechanism (determined using valinomycin and monensin coupled transport assays and an additional osmotic response assay). An HPTS transport assay was used to quantify this electrogenic process and assess the interference of naturally occurring fatty acids with the transport process and Cl- over H+/OH- transport selectivity. PMID- 27998095 TI - Controlled Synthesis of Two-Dimensional 1T-TiSe2 with Charge Density Wave Transition by Chemical Vapor Transport. AB - Two-dimensional (2D) metallic transition metal dichalcogenides (TMDCs), such as 1T-TiSe2, are ideal systems for exploring the fundamentals in condensed matter physics. However, controlled synthesis of these ultrathin materials has not been achieved. Here, we explored the synthesis of charge density wave (CDW)-bearing 2D TiSe2 with chemical vapor transport (CVT) by extending this bulk crystal growth approach to the surface growth of TiSe2 by introducing suitable growth substrates and dramatically slowing down the growth rate. Sub-10 nm TiSe2 flakes were successfully obtained, showing comparable quality to the mechanically exfoliated thin flakes. A CDW state with 2 * 2 superstructure was clearly observed on these ultrathin flakes by scanning tunneling microscopy (STM), and the phase transition temperature of these flakes was investigated by transport measurements, confirming the existence of CDW states. Our work opens up a new approach to synthesizing 2D CDW and superconductive TMDCs for exploring new fundamentals and applications in novel electronics. PMID- 27998096 TI - Small-Molecule Uncoupling Protein Mimics: Synthetic Anion Receptors as Fatty Acid Activated Proton Transporters. AB - Uncoupling proteins (UCPs) regulate energy expenditure in living cells by inducing proton leakage across the mitochondrial inner membrane, thereby uncoupling adenosine diphosphate phosphorylation from nutrient oxidation. The proton transport activity of UCP1 and UCP2 requires activation by fatty acids. We report here the first examples of synthetic neutral anion receptors performing this biologically important fatty acid-activated function in phospholipid bilayers. We have shown that a tripodal thiourea possesses poor H+/OH- transport activity without fatty acids, but in the presence of long-chain fatty acids is "switched on" as a proton transporter with an activity close to that of a commonly used protonophore. The fatty acid-enhanced proton transport was also observed for other hydrogen and halogen bond-based synthetic anion transporters. We propose that these compounds induce proton permeability by catalyzing transbilayer movement ("flip-flop") of anionic forms of fatty acids, so allowing the fatty acids to complete a proton transport cycle. Several lines of evidence have been provided to support such a fatty acid cycling mechanism. Our findings open up new applications of anion receptor chemistry and provide important clues for understanding biological activities of synthetic anion transporters and potentially the uncoupling mechanism of naturally occurring membrane proteins. PMID- 27998097 TI - Silica-Supported Cu Nanoparticle Catalysts for Alkyne Semihydrogenation: Effect of Ligands on Rates and Selectivity. AB - Narrowly dispersed, silica-supported Cu nanoparticles (ca. 2 nm) prepared via surface organometallic chemistry from a mesityl complex [Cu5Mes5] are highly active for the hydrogenation of a broad range of alkynes. High-throughput experimentation allows for identifying the optimal ligand and reaction conditions to turn these supported Cu nanoparticles into highly chemo- and stereoselective catalysts for the preparation of Z-olefins (overall, 23 examples). For instance, PCy3-modified Cu nanoparticles semihydrogenate 1-phenyl-1-propyne to cis-beta methylstyrene (20 bar H2, 40 degrees C) with turnover number and turnover frequency of ca. 540 and 1.9 min-1, respectively, and with 94% selectivity at full conversion. PMID- 27998098 TI - Organotetrel Chalcogenide Clusters: Between Strong Second-Harmonic and White Light Continuum Generation. AB - Highly directional white-light generation was recently reported for the organotin sulfide cluster [(StySn)4S6] (Sty = p-styryl). This effect was tentatively attributed to the amorphous nature of the material in combination with the specific combination of an inversion-symmetry-free T/E cluster core (T = tetrel, E = chalcogen) with the attachment of ligands that allow pi delocalization of the electron density. Systematic variation of T and the organic ligand (R) that runs from T = Si through Ge to Sn and from R = methyl through phenyl and p-styryl to 1 naphthyl provides a more comprehensive view. According to powder X-ray data, only [(PhSi)4S6] is single-crystalline among the named combinations. Here we demonstrate the fine-tuneability of the nonlinear response, i.e., changing from white-light generation to second-harmonic generation as well as controlling the white-light properties. These are investigated as a function of T, pi delocalization of the electron density within R, and the order within the molecular solids. PMID- 27998099 TI - Fulleropyrrolidinium Iodide As an Efficient Electron Transport Layer for Air Stable Planar Perovskite Solar Cells. AB - Organic-inorganic halide perovskite solar cells have attracted great attention in recent years. But there are still a lot of unresolved issues related to the perovskite solar cells such as the phenomenon of anomalous hysteresis characteristics and long-term stability of the devices. Here, we developed a simple three-layered efficient perovskite device by replacing the commonly employed PCBM electrical transport layer with an ultrathin fulleropyrrolidinium iodide (C60-bis) in an inverted p-i-n architecture. The devices with an ultrathin C60-bis electronic transport layer yield an average power conversion efficiency of 13.5% and a maximum efficiency of 15.15%. Steady-state photoluminescence (PL) and time-resolved photoluminescence (TRPL) measurements show that the high performance is attributed to the efficient blocking of holes and high extraction efficiency of electrons by C60-bis, due to a favorable energy level alignment between the CH3NH3PbI3 and the Ag electrodes. The hysteresis effect and stability of our perovskite solar cells with C60-bis become better under indoor humidity conditions. PMID- 27998100 TI - Carbon Disulfide Cosolvent Electrolytes for High-Performance Lithium Sulfur Batteries. AB - Development of lithium sulfur (Li-S) batteries with high Coulombic efficiency and long cycle stability remains challenging due to the dissolution and shuttle of polysulfides in electrolyte. Here, a novel additive, carbon disulfide (CS2), to the organic electrolyte is reported to improve the cycling performance of Li-S batteries. The cells with the CS2-additive electrolyte exhibit high Coulombic efficiency and long cycle stability, showing average Coulombic efficiency >99% and a capacity retention of 88% over the entire 300 cycles. The function of the CS2 additive is 2-fold: (1) it inhibits the migration of long-chain polysulfides to the anode by forming complexes with polysulfides and (2) it passivates electrode surfaces by inducing the protective coatings on both the anode and the cathode. PMID- 27998101 TI - Highly Flexible and Porous Nanoparticle-Loaded Films for Dye Removal by Graphene Oxide-Fungus Interaction. AB - Highly flexible and porous films with the ability to load various nanoscale adsorbents are of particular importance in the purification field. Herein, we report the sustainable and large-scale fabrication of a porous and flexible hybrid film based on the graphene oxide/hyphae interaction at a relatively low temperature of 130 degrees C. Under identical conditions, such films cannot be constructed with solely graphene oxide or hyphae. Moreover, through the addition of nanoscale building blocks [e.g., nanoscale poly(m-phenylenediamine) (PmPD) adsorbents] in the interaction process, the nanoparticles can be in situ loaded into the film. According to FTIR and XPS analyses, the film formation mechanisms mainly involve redox and cross-linking reactions between graphene oxide and fungus hyphae. In a proof-of-concept study, a PmPD nanoparticle-loaded hybrid film was used as a superior key component to build a flow-through adsorption device that displayed a promising adsorption performance toward dye pollutants. PMID- 27998102 TI - Three-Dimensional Stiff Graphene Scaffold on Neural Stem Cells Behavior. AB - Physical cues of the scaffolds, elasticity, and stiffness significantly guide adhesion, proliferation, and differentiation of stem cells. In addressable microenvironments constructed by three-dimensional graphene foams (3D-GFs), neural stem cells (NSCs) interact with and respond to the structural geometry and mechanical properties of porous scaffolds. Our studies aim to investigate NSC behavior on the various stiffness of 3D-GFs. Two kinds of 3D-GFs scaffolds present soft and stiff properties with elasticity moduli of 30 and 64 kPa, respectively. Stiff scaffold enhanced NSC attachment and proliferation with vinculin and integrin gene expression were up-regulated by 2.3 and 1.5 folds, respectively, compared with the soft one. Meanwhile, up-regulated Ki67 expression and almost no variation of nestin expression in a group of the stiff scaffold were observed, implying that the stiff substrate fosters NSC growth and keeps the cells in an active stem state. Furthermore, NSCs grown on stiff scaffold exhibited enhanced differentiation to astrocytes. Interestingly, differentiated neurons on stiff scaffold are suppressed since growth associated protein-43 expression was significantly improved by 5.5 folds. PMID- 27998103 TI - Nb2O5 Nanostructure Evolution on Nb Surfaces via Low-Energy He+ Ion Irradiation. AB - We propose low-energy, broad-beam He+ ion irradiation as a novel processing technique for the generation of Nb2O5 surface nanostructures due to its relative simplicity and scalability in a commercial setting. Since there have been relatively few studies involving the interaction of high-fluence, low-energy He+ ion irradiation and Nb (or its oxidized states), this systematic study explores both effects of fluence and sample temperature during irradiation on resulting surface morphology. Detailed normal and cross-sectional scanning electron microscopy (SEM) studies reveal subsurface He bubble formation and elucidate potential driving mechanisms for nanostructure evolution. A combination of specular optical reflectivity and X-ray photoelectron spectroscopy (XPS) is also used to gain additional information on roughness and stoichiometry of irradiated surfaces. Our investigations show significant surface modification for all tested irradiation conditions; the resulting surface structure size and geometry have a strong dependence on both sample temperature during irradiation and total ion fluence. Optical reflectivity measurements on irradiated surfaces demonstrate increased surface roughening with increasing ion fluence, and XPS shows higher oxidation levels for samples irradiated at lower temperatures, suggesting larger surface roughness and porosity. Overall, it was found that low-energy He+ ion irradiation is an efficient processing technique for nanostructure formation, and surface structures are highly tunable by adjusting ion fluence and Nb2O5 sample temperature during irradiation. These findings may have excellent potential applications for solar energy conversion through improved efficiency due to effective light absorption. PMID- 27998104 TI - PPy@MIL-100 Nanoparticles as a pH- and Near-IR-Irradiation-Responsive Drug Carrier for Simultaneous Photothermal Therapy and Chemotherapy of Cancer Cells. AB - A medical nanoplatform with small size, low cost, biocompatibility, good biodegradability, and, in particular, multifunctionality has attracted much attention in the exploration of novel therapeutic methodologies. As an emerging material of self-assembled porous structure, metal-organic frameworks (MOFs) have high expectations because of their special properties compared to traditional porous materials. Therefore, integration of MOFs and functional materials is leading to the creation of new multifunctional composites/hybrids. Photothermal therapy (PTT), using near-IR (NIR) laser-absorbing nanomaterials as PTT agents, has shown encouraging therapeutic effects to photothermally ablate tumors. However, the most of widely used PTT agents are inorganic materials and nonbiodegradable. Herein, uniform polypyrrole (PPy) nanoparticles (NPs) with good biodegradability were synthesized by a microemulsion method. The PPy NPs were further coated with the mesoporous iron-based MOF structure MIL-100 by interaction between PPy NPs and MIL-100 precursors at room temperature. As a multifunctional nanoplatform, an anticancer drug could easily be loaded into the mesopores of the MIL-100 shell. The PPy core, as an organic photothermal agent, is able to photothermally ablate cancer cells and improve the efficacy of chemotherapy under NIR irradiation. The composites showed an outstanding in vivo synergistic anticancer capacity. Our work could encourage further study in the construction of a synergetic system using MOFs and organic PTT agents. PMID- 27998105 TI - Layer-by-Layer Photocatalytic Assembly for Solar Light-Activated Self Decontaminating Textiles. AB - Novel photocatalytic nanomaterials that can be used to functionalize textiles, conferring to them efficient solar-light-activated properties for the decontamination of toxic and lethal agents, are described. Textiles functionalized with one-dimensional (1D) SnS2-based nanomaterials were used for photocatalytic applications for the first time. We showed that 1D SnS2/TiO2 nanocomposites can be easily and strongly affixed onto textiles using the layer by-layer deposition method. Ultrathin SnS2 nanosheets were associated with anatase TiO2 nanofibers to form nano-heterojunctions with a tight interface, considerably increasing the photo-oxidative activity of anatase TiO2 due to the beneficial interfacial transfer of photogenerated charges and increased oxidizing power. Moreover, it is easy to process the material on a larger scale and to regenerate these functionalized textiles. Our findings may aid the development of functionalized clothing with solar light-activated photocatalytic properties that provide a high level of protection against chemical warfare agents. PMID- 27998106 TI - Dithienobenzodithiophene-Based Small Molecule Organic Solar Cells with over 7% Efficiency via Additive- and Thermal-Annealing-Free Processing. AB - Here we introduce a novel small molecule based on dithienobenzodithiophene and rhodanine, DTBDT-Rho, developed to study the effect of the rhodanine substitutuent on small molecule bulk heterojunction (BHJ) solar cells. DTBDT-Rho possesses distinct crystalline characteristics, sufficient solubility in chlorinated solvents, and broad absorption properties. Therefore, solution processed BHJ photovoltaic cells made with DTBDT-Rho:PC71BM blends showed an extremely high power conversion efficiency (PCE; 7.10%); notably, this PCE value was obtained without the use of additives or thermal treatments. To our knowledge, the PCE over 7% is a significantly powerful value among rhodanine based small molecule BHJ solar cells without additives or thermal treatments. PMID- 27998107 TI - Efficient Synthesis of Graphene Nanoscrolls for Fabricating Sulfur-Loaded Cathode and Flexible Hybrid Interlayer toward High-Performance Li-S Batteries. AB - A modified lyophilization approach is developed and used for highly efficient transformation of 2D graphene oxide sheet into 1D graphene nanoscroll (GNS) with high topological transforming efficiency (~94%). Because of the unique open tubular structure and large specific surface area (545 m2 g-1), GNS is utilized for the first time as a porous cathode scaffold for encapsulating sulfur with a high loading (81 wt %), and also as a conductive skeleton for assembling MnO2 nanowires into a flexible free-standing hybrid interlayer, both enabling high rate and long-life Li-S battery. PMID- 27998108 TI - One-Pot Synthesis of Biocompatible Silver Nanoparticle Composites from Cellulose and Keratin: Characterization and Antimicrobial Activity. AB - A novel, simple method was developed to synthesize biocompatible composites containing 50% cellulose (CEL) and 50% keratin (KER) and silver in the form of either ionic (Ag+) or Ag0 nanoparticles (Ag+NPs or Ag0NPs). In this method, butylmethylimmidazolium chloride ([BMIm+Cl-]), a simple ionic liquid, was used as the sole solvent and silver chloride was added to the [BMIm+Cl-] solution of [CEL+KER] during the dissolution process. The silver in the composites can be maintained as ionic silver (Ag+) or completely converted to metallic silver (Ag0) by reducing it with NaBH4. The results of spectroscopy [Fourier transform infrared and X-ray diffraction (XRD)] and imaging [scanning electron microscopy (SEM)] measurements confirm that CEL and KER remain chemically intact and homogeneously distributed in the composites. Powder XRD and SEM results show that the silver in the [CEL+KER+Ag+] and [CEL+KER+Ag0] composites is homogeneously distributed throughout the composites in either Ag+ (in the form of AgClNPs) or Ag0NPs form with sizes of 27 +/- 2 or 9 +/- 1 nm, respectively. Both composites were found to exhibit excellent antibacterial activity against many bacteria including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant Enterococus faecalis (VRE). The antibacterial activity of both composites increases with the Ag+ or Ag0 content in the composites. More importantly, for the same bacteria and the same silver content, the [CEL+KER+AgClNPs] composite is relatively more toxic than [CEL+KER+Ag0NPs] composite. Experimental results confirm that there was hardly any Ag0NPs release from the [CEL+KER+Ag0NPs] composite, and hence its antimicrobial activity and biocompatibility is due not to any released Ag0NPs but rather entirely to the Ag0NPs embedded in the composite. Both AgClNPs and Ag0NPs were found to be toxic to human fibroblasts at higher concentration (>0.72 mmol), and for the same silver content, the [CEL+KER+AgClNPs] composite is relatively more toxic than the [CEL+KER+Ag0NPs] composite. As expected, by lowering the Ag0NPs concentration to 0.48 mmol or less, the [CEL+KER+Ag0NPs] composite can be made biocompatible while still retaining its antimicrobial activity against bacteria such as E. coli, S. aureus, P. aeruginosa, MRSA, and VRE. These results, together with our previous finding that [CEL+KER] composites can be used for the controlled delivery of drugs such as ciprofloxacin, clearly indicate that the [CEL+KER+Ag0NPs] composite possesses all of the required properties for it to be successfully used as a high-performance dressing to treat chronic ulcerous infected wounds. PMID- 27998109 TI - Anticancer Effect of alpha-Tocopheryl Succinate Delivered by Mitochondria Targeted Mesoporous Silica Nanoparticles. AB - Mitochondria targeted mesoporous silica nanoparticles (MSNPs) having an average diameter of 68 nm were fabricated and then loaded with hydrophobic anticancer agent alpha-tocopheryl succinate (alpha-TOS). The property of targeting mitochondria was achieved by the surface functionalization of triphenylphosphonium (TPP) on MSNPs, since TPP is an effective mitochondria targeting ligand. Intracellular uptake and mitochondria targeting of fabricated MSNPs were evaluated in HeLa and HepG2 cancerous cell lines as well as HEK293 normal cell line. In addition, various biological assays were conducted with the aim to investigate the effectiveness of alpha-TOS delivered by the functional MSNPs, including studies of cytotoxicity, mitochondria membrane potential, intracellular adenosine triphosphate (ATP) production, and apoptosis. On the basis of these experiments, high anticancer efficiency of alpha-TOS delivered by mitochondria targeted MSNPs was demonstrated, indicating a promising application potential of MSNP-based platform in mitochondria targeted delivery of anticancer agents. PMID- 27998110 TI - Investigation of SrB4O7:Sm2+ as a Multimode Temperature Sensor with High Sensitivity. AB - Sm2+-doped SrB4O7 was synthesized for high-sensitivity thermometry. A high thermal-sensitive fluorescence intensity ratio and fluorescence lifetime were achieved in a wide temperature range. At 500 K, the relative sensitivity of the temperature sensing was 2.16% K-1 for the fluorescence intensity ratio and 3.36% K-1 for the fluorescence lifetime. Furthermore, the fluorescence color-shifted dramatically from deep red at room temperature to green at 700 K. On the basis of this color change, a visible temperature field was obtained on quartz glass covered with our sample, which made the thermal conduction and distribution visible to the human eye. The temperature of the temperature field was determined using two methods. These outstanding properties, combined with the high sensitivity, multimode for temperature sensing and thermal stability of the sample, make SrB4O7:Sm2+ a promising material for highly sensitive thermometry applications. PMID- 27998111 TI - Carbon-Dot-Coated Alginate Beads as a Smart Stimuli-Responsive Drug Delivery System. AB - In this work, we report a smart stimuli-responsive drug delivery system (DDS) that can release drug depending upon the amount of pathogen (MRSA) present in the target. A greater amount of MRSA in the system will lead to more release of drug and vice versa. Carbon-dot-coated novel alginate beads (CA-CD) exhibiting superior stability was successfully used as smart drug delivery vehicle. Garlic extract (GE), which contains allicin, was taken as model drug system to demonstrate the phenomena. It was observed that GE loading was 19 and 78% with CA and CA-CD, respectively. CA-CD-GE shows pH-dependent controlled drug release, which results in increased therapeutic efficiency. CA-CD-GE is not only stimuli responsive but also a controlled drug release system as it releases drug according to the pathogen concentration (MRSA). All the three factors viz. drug release, MRSA concentration and pH of the medium are interdependent as when the cell divides, it produces secondary metabolites that lead to the decrease in pH of the medium. The drop in the pH value triggers drug release from the beads. And the effect of the drug is reflected by the MRSA cell death. Hence, we demonstrate a smart stimuli responsive DDS. However, such DDS will be useful in cases where increased amount of pathogen in the system will lead to reduction in pH. PMID- 27998112 TI - Edge Charge Neutralization of Clay for Improved Oxygen Gas Barrier in Multilayer Nanobrick Wall Thin Films. AB - Layer-by-layer (LbL) assembled polymer-clay multilayer thin films are known to provide transparent and flexible gas barrier. In an effort to further lower the oxygen transmission rate (OTR) of these nanobrick wall thin films, sodium chloride was introduced into montmorillonite (MMT) suspension as an "indifferent electrolyte". At pH 6.5 the amphoteric edge sites of MMT have a neutral net charge, and a moderate concentration of NaCl effectively shields the charge from neighboring platelets, allowing van der Waals forces to attract the edges to one another. This edge-to-edge bonding creates a much more tortuous path for diffusing oxygen molecules. An eight-bilayer (BL) polyethylenimine (PEI)/MMT multilayer coating (~50 nm thick), assembled with 5 mM NaCl in the aqueous clay suspension, exhibited an order of magnitude reduction in oxygen permeability (~4 * 10-20 cm3.cm/(cm2.Pa.s)) relative to its salt-free counterpart. This result represents the best barrier among polymer-clay bilayer systems, which is also lower than SiOx or AlxOy thin films. At higher NaCl concentration, the strong charge screening causes edge-to-face bonding among MMT nanoplatelets, which leads to misalignment in assembled films and increased OTR. This "salty-clay" strategy provides an efficient way to produce better multilayer oxygen barrier thin films by altering ionic strength of the MMT suspension. This simple modification reduces the number of layers necessary for high gas barrier, potentially making these multilayer films interesting for commercial packaging applications. PMID- 27998113 TI - Surface Roughening of Nickel Cobalt Phosphide Nanowire Arrays/Ni Foam for Enhanced Hydrogen Evolution Activity. AB - Development of earth-abundant, efficient, and stable electrocatalysts for hydrogen evolution reactions (HER) in alkaline or even neutral pH electrolyte is very important for hydrogen production from water splitting. Construction of bimetal phosphides via tuning the bonding strength to hydrogen and increasing effective active sites through nanostructuring and surface engineering should lead to high HER activity. Here, ternary NiCoP nanowires (NWs) decorated by homogeneous nanoparticles have been obtained on Ni foam for a highly efficient HER property via long-term cyclic voltammetric (CV) sweeping. The electron density transfer between the positively charged Ni and Co and negatively charged P atoms, one-dimensional electron transfer channel of the NWs, and abundant active sites supplied by the nanoparticles and NWs endow the catalyst with low overpotentials of 43 and 118 mV to achieve the respective current densities of 10 and 100 mA cm-2 together with long durability for at least 33 h in 1 M KOH. A cycled anodic dissolution-redeposition mechanism is disclosed for the formation of the NiCoP nanoparticles during the CV sweeping process. Such a surface roughening method is found to be adaptable to enhance the HER property of other phosphides, including Ni2P nanoplates/NF, NiCoP nanoparticles/NF, and CoP NW/NF. PMID- 27998114 TI - Low-Voltage and High-Performance Multilayer MoS2 Field-Effect Transistors with Graphene Electrodes. AB - Atomically thin two-dimensional (2D) materials are attractive because they have excellent material properties and channel length scalability. Fabrication of complex structures from these materials is also relatively easy. Accordingly, 2D materials such as molybdenum disulfide (MoS2) have been intensively studied because of their novel properties for advanced electronics and optoelectronics. This study realizes the low-voltage and high-performance field-effect transistors with chemical vapor deposition-grown single layer graphene employed as the thinnest electrode and semiconducting multilayer (ML) MoS2 utilized as a channel material. The two-terminal mobility of graphene-contacted ML MoS2 using 15 nm Al2O3 as the top-gate dielectric layer is 131.2 cm2/(V s) at room temperature, which is higher than that of the previously reported metal/graphene-contacted MoS2. The result demonstrates that van der Waals bonding at the graphene-MoS2 interfaces and high-k dielectric provide an important step toward the realization of high-performance and low-voltage thin-film transistors. PMID- 27998115 TI - A Safe High-Performance All-Solid-State Lithium-Vanadium Battery with a Freestanding V2O5 Nanowire Composite Paper Cathode. AB - The electronic conductivity and structural stability are still challenges for vanadium pentoxide (V2O5) as cathode materials in batteries. Here, we report a V2O5 nanowire-reduced graphene oxide (rGO) composite paper for direct use as a cathode without any additives for high-temperature and high-safety solid polymer electrolyte [PEO-MIL-53(Al)-LiTFSI] lithium-vanadium batteries. The batteries can show a fast and stable lithium-ion-storage performance in a wide voltage window of 1.0-4.0 V versus Li+/Li at 80 degrees C, in which with an average capacity of 329.2 mAh g-1 at 17 mA g-1 and a stable cycling performance over 40 cycles are achieved. The excellent electrochemical performance is mainly ascribed to integration of the electronic conductivity of rGO and interconnected networks of the V2O5 nanowires and solid electrolyte. This is a promising lithium battery for flexible and highly safe energy-storage devices. PMID- 27998116 TI - A Mechanoluminescent ZnS:Cu/Rhodamine/SiO2/PDMS and Piezoresistive CNT/PDMS Hybrid Sensor: Red-Light Emission and a Standardized Strain Quantification. AB - We developed a hybrid strain sensor by combining mechanoluminescent ZnS:Cu/rhodamine/SiO2/PDMS composites and piezoresistive CNT/PDMS for qualitative and quantitative analysis of onsite strain. The former guarantees a qualitative onsite measure of strain with red-light emission via mechanoluminescence (ML) and the latter takes part in accurate quantification of strain through the change in electrical resistance. The PDMS matrix enabled a strain sensing in a wider range of strain, spanning up to several hundred percent in comparison to the conventional rigid matrix composites and ceramic-based ML sensors. Red-light emission would be much more effective for the visualization of strain (or stress) when ML is used as a warning sign in actual applications such as social infrastructure safety diagnosis, emergency guide lighting, and more importantly, in biomedical applications such as in the diagnosis of motility and peristalsis disorders in the gastrointestinal tract. Despite the realization of an efficient red-light-emitting ML in a ZnS:Cu/rhodamine/SiO2/PDMS composite, the quantification and standardization of strain throughout the ML has been far from complete. In this regard, the piezoresistive CNT/PDMS compensated for this demerit of mechanoluminescent ZnS:Cu/rhodamine/SiO2/PDMS composites. PMID- 27998117 TI - Direct Observation of the Thickness-Induced Crystallization and Stress Build-Up during Sputter-Deposition of Nanoscale Silicide Films. AB - The kinetics of phase transitions during formation of small-scale systems are essential for many applications. However, their experimental observation remains challenging, making it difficult to elucidate the underlying fundamental mechanisms. Here, we combine in situ and real-time synchrotron X-ray diffraction (XRD) and X-ray reflectivity (XRR) experiments with substrate curvature measurements during deposition of nanoscale Mo and Mo1-xSix films on amorphous Si (a-Si). The simultaneous measurements provide direct evidence of a spontaneous, thickness-dependent amorphous-to-crystalline (a-c) phase transition, associated with tensile stress build-up and surface roughening. This phase transformation is thermodynamically driven, the metastable amorphous layer being initially stabilized by the contributions of surface and interface energies. A quantitative analysis of the XRD data, complemented by simulations of the transformation kinetics, unveils an interface-controlled crystallization process. This a-c phase transition is also dominating the stress evolution. While stress build-up can significantly limit the performance of devices based on nanostructures and thin films, it can also trigger the formation of these structures. The simultaneous in situ access to the stress signal itself, and to its microstructural origins during structure formation, opens new design routes for tailoring nanoscale devices. PMID- 27998118 TI - Controlled Hybrid-Assembly of HPV16/18 L1 Bi VLPs in Vitro. AB - Based on the helix4-exchanged HPV16 L1 and HPV18 L1, HPV16 L1 Bi and HPV18 L1 Bi, we have successfully realized the controlled hybrid-assembly of HPV16/18 L1 Bi VLPs (bihybrid-VLPs) in vitro. The bihybrid-VLPs were further confirmed by fluorescence resonance energy transfer (FRET) and complex-immunoprecipitation (Co IP) assays. The ratio of 16 L1 Bi and 18 L1 Bi in bihybrid-VLPs was verified to be 3:5 based on a modified magnetic Co-IP procedure, when mixing 1 equiv pentamer in assembly buffer solution, but it changed with conditions. In addition, the bihybrid-VLPs showed identical thermal stability as that of normal VLPs, suggesting high potential in practical applications. The present study is significant because it modified one of the vital steps of virus life cycle at the stage of virus assembly, supplying a new approach not only to deepen structural insights but also a possibility to prepare stable, low-cost, bivalent antivirus vaccine. Furthermore, the controlled hybrid-assembly of bihybrid-VLPs in vitro provides suggestions for the design of effective multivalent hybrid-VLPs, being a potential to develop broad-spectrum vaccines for the prevention of infection with multiple types of HPV. PMID- 27998119 TI - Porous CNTs/Co Composite Derived from Zeolitic Imidazolate Framework: A Lightweight, Ultrathin, and Highly Efficient Electromagnetic Wave Absorber. AB - Porous carbon nanotubes/cobalt nanoparticles (CNTs/Co) composite with dodecahedron morphology was synthesized by in situ pyrolysis of the Co-based zeolitic imidazolate framework in a reducing atmosphere. The morphology and microstructure of the composite can be well tuned by controlling the pyrolysis conditions. At lower pyrolysis temperature, the CNTs/Co composite is composed of well-dispersed Co nanoparticles and short CNT clusters with low graphitic degree. The increase of pyrolysis temperature/time promotes the growth and graphitization of CNTs and leads to the aggregation of Co nanoparticles. The optimized CNTs/Co composite exhibits strong dielectric and magnetic losses as well as a good impedance matching property. Interestingly, the CNTs/Co composite displays extremely strong electromagnetic wave absorption with a maximum reflection loss of -60.4 dB. More importantly, the matching thickness of the absorber is as thin as 1.81 mm, and the filler loading of composite in the matrix is only 20 wt %. The highly efficient absorption is closely related to the well-designed structure and the synergistic effect between CNTs and Co nanoparticles. The excellent absorbing performance together with lightweight and ultrathin thickness endows the CNTs/Co composite with the potential for application in the electromagnetic wave absorbing field. PMID- 27998120 TI - Nano- and Microstructure Engineering: An Effective Method for Creating High Efficiency Magnesium Silicide Based Thermoelectrics. AB - Considering the effect of CO2 emission together with the depletion of fossil fuel resources on future generations, industries in particular the transportation sector are in deep need of a viable solution to follow the environmental regulation to limit the CO2 emission. Thermoelectrics may be a practical choice for recovering the waste heat, provided their conversion energy can be improved. Here, the high temperature thermoelectric properties of high purity Bi doped Mg2(Si,Sn) are presented. The samples Mg2Si1-x-ySnxBiy with x(Sn) >= 0.6 and y(Bi) >= 0.03 exhibited electrical conductivities and Seebeck coefficients of approximately 1000 Omega-1 cm-1 and -200 MUV K-1 at 773 K, respectively, attributable to a combination of band convergence and microstructure engineering through ball mill processing. In addition to the high electrical conductivity and Seebeck coefficient, the thermal conductivity of the solid solutions reached values below 2.5 W m-1 K-1 due to highly efficient phonon scattering from mass fluctuation and grain boundary effects. These properties combined for zT values of 1.4 at 773 K with an average zT of 0.9 between 400 and 773 K. The transport properties were both highly reproducible across several measurement systems and were stable with thermal cycling. PMID- 27998121 TI - Co3O4-CeO2/C as a Highly Active Electrocatalyst for Oxygen Reduction Reaction in Al-Air Batteries. AB - Developing high-performance and low-cost electrocatalysts for oxygen reduction reaction (ORR) is still a great challenge for Al-air batteries. Herein, CeO2, a unique ORR promoter, was incorporated into ketjenblack (KB) supported Co3O4 catalyst. We developed a facile two-step hydrothermal approach to fabricate Co3O4 CeO2/KB as a high-performance ORR catalyst for Al-air batteries. The ORR activity of Co3O4/KB was significantly increased by mixing with CeO2 nanoparticles. In addition, the Co3O4-CeO2/KB showed a better electrocatalytic performance and stability than 20 wt % Pt/C in alkaline electrolytes, making it a good candidate for highly active ORR catalysts. Co3O4-CeO2/KB favored a four-electron pathway in ORR due to the synergistic interactions between CeO2 and Co3O4. In full cell tests, the Co3O4-CeO2/KB exhibited a higher discharge voltage plateau than CeO2/KB and Co3O4/KB when used in cathode in Al-air batteries. PMID- 27998122 TI - Nitrogen Doping in Oxygen-Deficient Ca2Fe2O5: A Strategy for Efficient Oxygen Reduction Oxide Catalysts. AB - Oxygen reduction reaction (ORR) is increasingly being studied in oxide systems due to advantages ranging from cost effectiveness to desirable kinetics. Oxygen deficient oxides like brownmillerites are known to enhance ORR activity by providing oxygen adsorption sites. In parallel, nitrogen and iron doping in carbon materials, and consequent presence of catalytically active complex species like C-Fe-N, is also suggested to be good strategies for designing ORR-active catalysts. A combination of these features in N-doped Fe containing brownmillerite can be envisaged to present synergistic effects to improve the activity. This is conceptualized in this report through enhanced activity of N doped Ca2Fe2O5 brownmillerite when compared to its oxide parents. N doping is demonstrated by neutron diffraction, UV-vis spectroscopy, X-ray photoelectron spectroscopy, and X-ray absorption spectroscopy. Electrical conductivity is also found to be enhanced by N doping, which influences the activity. Electrochemical characterization by cyclic voltammetry, rotating disc electrode, and rotating ring disk electrode (RRDE) indicates an improved oxygen reduction activity in N doped brownmillerite, with a 10 mV positive shift in the onset potential. RRDE measurements show that the compound exhibits 4-electron reduction pathways with lower H2O2 production in the N-doped system; also, the N-doped sample exhibited better stability. The observations will enable better design of ORR catalysts that are stable and cost-effective. PMID- 27998123 TI - Preparation of Transparent Bulk TiO2/PMMA Hybrids with Improved Refractive Indices via an in Situ Polymerization Process Using TiO2 Nanoparticles Bearing PMMA Chains Grown by Surface-Initiated Atom Transfer Radical Polymerization. AB - Transparent TiO2/PMMA hybrids with a thickness of 5 mm and improved refractive indices were prepared by in situ polymerization of methyl methacrylate (MMA) in the presence of TiO2 nanoparticles bearing poly(methyl methacrylate) (PMMA) chains grown using surface-initiated atom transfer radical polymerization (SI ATRP), and the effect of the chain length of modified PMMA on the dispersibility of modified TiO2 nanoparticles in the bulk hybrids was investigated. The surfaces of TiO2 nanoparticles were modified with both m (chloromethyl)phenylmethanoyloxymethylphosphonic acid bearing a terminal ATRP initiator and isodecyl phosphate with a high affinity for common organic solvents, leading to sufficient dispersibility of the surface-modified particles in toluene. Subsequently, SI-ATRP of MMA was achieved from the modified surfaces of the TiO2 nanoparticles without aggregation of the nanoparticles in toluene. The molecular weights of the PMMA chains cleaved from the modified TiO2 nanoparticles increased with increases in the prolonging of the polymerization period, and these exhibited a narrow distribution, indicating chain growth controlled by SI-ATRP. The nanoparticles bearing PMMA chains were well-dispersed in MMA regardless of the polymerization period. Bulk PMMA hybrids containing modified TiO2 nanoparticles with a thickness of 5 mm were prepared by in situ polymerization of the MMA dispersion. The transparency of the hybrids depended significantly on the chain length of the modified PMMA on the nanoparticles, because the modified PMMA of low molecular weight induced aggregation of the TiO2 nanoparticles during the in situ polymerization process. The refractive indices of the bulk hybrids could be controlled by adjusting the TiO2 content and could be increased up to 1.566 for 6.3 vol % TiO2 content (1.492 for pristine PMMA). PMID- 27998124 TI - Defect-Rich Ultrathin Cobalt-Iron Layered Double Hydroxide for Electrochemical Overall Water Splitting. AB - Efficient and durable electrocatalysts from earth-abundant elements play a vital role in the key renewable energy technologies including overall water splitting and hydrogen fuel cells. Here, generally used CoFe based layered double hydroxides (LDHs) were first delaminated and exfoliated in the DMF-ethanol solvent (CoFe LDH-F), with enhancement both in oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). The exfoliation process creates more coordinatively unsaturated metals and improves the intrinsic electronic conductivity, which is important in water electrolyzer reactions. In the basic solution, the CoFe LDH-F catalyst outperforms the commercial iridium dioxide (IrO2) electrocatalyst in activity and stability for OER and approaches the performance of platinum (Pt) for HER. The bifunctional electrocatalysts can be further used for overall water splitting, with a current density of ~10 mA/cm2 at the applied voltage of 1.63 V for long-term electrolysis test, rivalling the performance of Pt and IrO2 combination as benchmarks. Our findings demonstrate the promising catalytic activity of LDHs for scale-up alkaline water splitting. PMID- 27998125 TI - Silicone Oil-Infused Slippery Surfaces Based on Sol-Gel Process-Induced Nanocomposite Coatings: A Facile Approach to Highly Stable Bioinspired Surface for Biofouling Resistance. AB - Slippery liquid-infused surfaces (SLIPS) have aroused widespread attention due to their excellent liquid-repellency properties associated with broad applications in various fields. However, the complicated preparation processes and the vulnerable surface lubricant layers severely restrict the practical applications of SLIPS. In this work, robust transparent slippery hybrid coatings (SHCs) were easily fabricated by the infusion of sol-gel-derived nanocomposite coatings in silicone oils of varying viscosity. The prepared silicone oil-infused surfaces exhibited outstanding long-term slippery stability even under extreme operating conditions such as high shear rate, elevated evaporation, and flowing aqueous immersion. Static bacteria culture tests confirmed that the SHCs could significantly inhibit biofilm formation. In addition, bovine serum albumin adhesion experiments were conducted after lubricant loss tests, showing significantly less protein absorption and a long service life of the SLIPS. The unique ultralow bacterial attachment and remarkably long-term protein-resistant performance render the as-prepared SLIPS as a promising candidate for biomedical applications even under harsh environmental conditions. PMID- 27998126 TI - Design of a Nanoscale, CMOS-Integrable, Thermal-Guiding Structure for Boolean Logic and Neuromorphic Computation. AB - One of the requirements for achieving faster CMOS electronics is to mitigate the unacceptably large chip areas required to steer heat away from or, more recently, toward the critical nodes of state-of-the-art devices. Thermal-guiding (TG) structures can efficiently direct heat by "meta-materials" engineering; however, some key aspects of the behavior of these systems are not fully understood. Here, we demonstrate control of the thermal-diffusion properties of TG structures by using nanometer-scale, CMOS-integrable, graphene-on-silica stacked materials through finite-element-methods simulations. It has been shown that it is possible to implement novel, controllable, thermally based Boolean-logic and spike-timing dependent plasticity operations for advanced (neuromorphic) computing applications using such thermal-guide architectures. PMID- 27998127 TI - Tuning the Perfluorosulfonic Acid Membrane Morphology for Vanadium Redox-Flow Batteries. AB - The microstructure of perfluorinated sulfonic acid proton-exchange membranes such as Nafion significantly affects their transport properties and performance in a vanadium redox-flow battery (VRB). In this work, Nafion membranes with various equivalent weights ranging from 1000 to 1500 are prepared and the morphology property-performance relationship is investigated. NMR and small-angle X-ray scattering studies revealed their composition and morphology variances, which lead to major differences in key transport properties related to proton conduction and vanadium-ion permeation. Their performances are further characterized as VRB membranes. On the basis of this understanding, a new perfluorosulfonic acid membrane is designed with optimal pore geometry and thickness, leading to higher ion selectivity and lower cost compared with the widely used Nafion 115. Excellent VRB single-cell performance (89.3% energy efficiency at 50 mA.cm-2) was achieved along with a stable cyclical capacity over prolonged cycling. PMID- 27998128 TI - Universal Approach for Predicting Crystallography of Heterogeneous Epitaxial Nanocrystals with Multiple Orientation Relationships. AB - Heteroepitaxial nanocrystals are one of the most fundamentally and technologically important classes of materials systems. The correlation between form, dictated by crystallographic features such as growth habit and direction, and function, in terms of the ultimate physio-chemical properties is well established, thus placing an onus on precise synthesis control of nanocrystal morphology. Yet, nanocrystal heteroepitaxy can be a frustrating, time-consuming iterative process, particularly during the initial stages of development. What is desired is a powerful predictive tool that is able to successfully predict not only the interface or habit plane, but also rationalize the occurrence of epitaxial growth complexities such as multiple orientation relationships (MORs) and high-index faceting planes for a diverse range of materials. Here we provide such a powerful approach that is based on an invariant deformation element (IDE) model, and fundamentally founded on the crystallography of diffusional phase transformations. We demonstrate its impact by detailed computations supported by transmission electron microscopy evidence, for an archetypical complex metal oxide nanocrystal system (that has up to five MORs for three differing growth orientations). The method is then applied to successfully explain growth for different materials ranging from metals to metal carbides to transition metal oxides, even in thin film form. Thus, this relatively simple yet powerful predictive guide significantly reduces the systemic inefficiencies of guesswork and blind growth. Ultimately it can be easily integrated with machine learning techniques toward reliable and efficient advanced nanomaterials fabrication. PMID- 27998129 TI - Thiazole-Flanked Diketopyrrolopyrrole Polymeric Semiconductors for Ambipolar Field-Effect Transistors with Balanced Carrier Mobilities. AB - In this paper we report three thiazole-flanked diketopyrrolopyrrole-based donor acceptor alternating copolymers as new ambipolar semiconductors and their field effect transistor devices with balanced hole and electron mobilities. Nitrile groups are introduced into the polymer backbone, and the substituent effect on electronic structures is studied. Different side chains are also involved to tune the interdigitation of the polymers. To probe the structural effects that contribute to the device performances, we provide insight into the thin-film microstructures and morphologies. Top-gate bottom-contact transistors fabricated under ambient conditions exhibit the impressive balanced hole and electron mobilities as high as 1.46 and 1.14 cm2 V-1 s-1, respectively, which are among the highest values reported for ambipolar thiazole-flanked diketopyrrolopyrrole based polymers. Additionally, this class of ambipolar polymers also shows promise for complementary-like inverters with a high gain value of 163. PMID- 27998130 TI - Electrospinning Synthesis of Mesoporous MnCoNiOx@Double-Carbon Nanofibers for Sodium-Ion Battery Anodes with Pseudocapacitive Behavior and Long Cycle Life. AB - In this work, MnCoNiOx (denoted as MCNO) nanocrystals (with a size of less than 30 nm) finely encapsulated in double-carbon (DC, including reduced graphene oxide and amorphous carbon derived by polymer) composite nanofibers (MCNO@DC) were successfully synthesized via an electrospinning method followed by a sintering treatment. The as-obtained MCNO@DC nanofibers present superior sodium storage performance and retain an especially high specific capacity of 230 mAh g-1 with a large capacity retention of about 96% at 0.1 A g-1 after 500 cycles and a specific capacity of 107 mAh g-1 with capacity retention of about 89% at 1 A g-1 after 6500 cycles. The outstanding cycle characteristic is mainly due to the tiny MCNO nanoparticles, which shorten the ion migration distance, and the three dimensional DC framework, which remarkably promotes the electronic transfer and efficiently limits the volume expansion during the progress of insertion and extraction of Na+ ions. Moreover, nitrogen doped in carbon is able to improve the electrochemical capability as well. Finally, kinetic analysis of the redox reactions is used to verify the pseudocapacitive mechanism in charge storage and the feasibility of using MCNO@DC composite nanofibers as an anode for sodium-ion batteries with the above-mentioned behavior. PMID- 27998131 TI - InGaN-Based Light-Emitting Diodes Grown on a Micro/Nanoscale Hybrid Patterned Sapphire Substrate. AB - A hybrid patterned sapphire substrate (hybrid-PSS) was prepared using an anodic aluminum oxide etching mask to transfer nanopatterns onto a conventional patterned sapphire substrate with microscale patterns (bare-PSS). The threading dislocation (TD) suppression of light-emitting diodes (LEDs) grown on a hybrid PSS (HP-LED) exhibits a smaller reverse leakage current compared with that of LEDs grown on a bare-PSS (BP-LED). The strain-free GaN buffer layer and fully strained InGaN active layer were evidenced by cross-sectional Raman spectra and reciprocal space mapping of the X-ray diffraction intensity for both samples. The calculated piezoelectric fields for both samples are close, implying that the quantum-confined Stark effect was not a dominant mechanism influencing the electroluminescence (EL) peak wavelength under a high injection current. The bandgap shrinkage effect of the InGaN well layer was considered to explain the large red-shifted EL peak wavelength under high injection currents. The estimated LED chip temperatures rise from room temperature to 150 degrees C and 75 degrees C for BP-LED and HP-LED, respectively, at a 600-mA injection current. This smaller temperature rise of the LED chip is attributed to the increased contact area between the sapphire and the LED structural layer because of the embedded nanopattern. Although the chip generates more heat at high injection currents, the accumulated heat can be removed to outside the chip effectively. The high diffuse reflection (DR) rate of hybrid-PSS increases the escape probability of photons, resulting in an increase in the viewing angle of the LEDs from 130 degrees to 145 degrees . The efficiency droop was reduced from 46% to 35%, effects which can be attributed to the elimination of TDs and strain relaxation by embedded nanopatterns. In addition, the light output power of HP LED at 360-mA injection currents exhibits a ~ 22.3% enhancement, demonstrating that hybrid-PSSs are beneficial to apply in high-power LEDs. PMID- 27998132 TI - Effect of Hydrofluoroether Cosolvent Addition on Li Solvation in Acetonitrile Based Solvate Electrolytes and Its Influence on S Reduction in a Li-S Battery. AB - Li-S batteries are a promising next-generation battery technology. Due to the formation of soluble polysulfides during cell operation, the electrolyte composition of the cell plays an active role in directing the formation and speciation of the soluble lithium polysulfides. Recently, new classes of electrolytes termed "solvates" that contain stoichiometric quantities of salt and solvent and form a liquid at room temperature have been explored due to their sparingly solvating properties with respect to polysulfides. The viscosity of the solvate electrolytes is understandably high limiting their viability; however, hydrofluoroether cosolvents, thought to be inert to the solvate structure itself, can be introduced to reduce viscosity and enhance diffusion. Nazar and co-workers previously reported that addition of 1,1,2,2-tetrafluoroethyl 2,2,3,3 tetrafluoropropyl ether (TTE) to the LiTFSI in acetonitrile solvate, (MeCN)2 LiTFSI, results in enhanced capacity retention compared to the neat solvate. Here, we evaluate the effect of TTE addition on both the electrochemical behavior of the Li-S cell and the solvation structure of the (MeCN)2-LiTFSI electrolyte. Contrary to previous suggestions, Raman and NMR spectroscopy coupled with ab initio molecular dynamics simulations show that TTE coordinates to Li+ at the expense of MeCN coordination, thereby producing a higher content of free MeCN, a good polysulfide solvent, in the electrolyte. The electrolytes containing a higher free MeCN content facilitate faster polysulfide formation kinetics during the electrochemical reduction of S in a Li-S cell likely as a result of the solvation power of the free MeCN. PMID- 27998133 TI - Impact of Premetallization Surface Preparation on Nickel-based Ohmic Contacts to Germanium Telluride: An X-ray Photoelectron Spectroscopic Study. AB - Surfaces of polycrystalline alpha-GeTe films were studied by X-ray photoelectron spectroscopy (XPS) after different treatments in an effort to understand the effect of premetallization surface treatments on the resistance of Ni-based contacts to GeTe. UV-O3 is often used to remove organic contaminants after lithography and prior to metallization; therefore, UV-O3 treatment was used first for 10 min prior to ex situ treatments, which led to oxidation of both Ge and Te to GeOx (x < 2) and TeO2, respectively. Then the oxides were removed by deionized (DI) H2O, (NH4)2S, and HCl treatments. Additionally, in situ Ar+ ion etching was used to clean the GeTe surface without prior UV-O3 treatment. Ar+ ion etching, H2O, and (NH4)2S treatments create a surface richer in Ge compared to the HCl treatment, after which the surface is Te-rich. However, (NH4)2S also oxidizes Ge and gradually etches the GeTe film. All treated surfaces showed poor stability upon prolonged exposure to air, revealing that even (NH4)2S does not passivate the GeTe surface. The refined transfer length method (RTLM) was used to measure the contact resistance (Rc) of as-deposited Ni-based contacts to GeTe as a function of premetallization surface preparation. HCl-treated samples had the highest Rc (0.036 +/- 0.002 Omega.mm), which was more than twice that of the other surface treatments. This increase in Rc is attributed to formation of the Ni1.29Te phase at the Ni/GeTe interface due to an abundance of Te at the surface after HCl treatment. In general, treatments that resulted in Ge-rich surfaces offered lower Rc. PMID- 27998134 TI - A 14.7% Organic/Silicon Nanoholes Hybrid Solar Cell via Interfacial Engineering by Solution-Processed Inorganic Conformal Layer. AB - We demonstrated a high-performance Si-organic hybrid heterojunction solar cell utilizing low-temperature and liquid-phase-processed TiO2 as an interlayer between poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and Si nanoholes to produce a conformal contact on the surface of the Si nanostructure. The hydrophilic TiO2/Si-nanohole surface enabled the PEDOT:PSS to flow into the spacing of the close-packed nanoholes. Scanning electron microscopy images were used to confirm the PEDOT:PSS nanohole filling induced by the TiO2. With forming gas annealing of the double-sided TiO2, high Voc (0.63 V) and Jsc (35.7 mA/cm2) values were obtained, yielding a high power conversion efficiency of 14.7%. The high Voc was attributed to the surface passivation of Si by annealed TiO2. The X-ray photoelectron spectroscopy investigation at the TiO2/Si interface indicates the TiOx signal decreased and the TiO2 and SiOx signals increased after annealing. The Si-O bonding found in the O 1s study appeared in the form of Si-O-Si bonding to serve surface passivation. The band alignment of the PEDOT:PSS/TiO2/n-Si hetero-interfaces was postulated and plotted. The Vbi in the system after annealing was assumed to be higher because of the reduction of bulk and surface states that yield high Voc. After annealing, the Vbi increased from 0.805 to 0.905 V. The reduction of surface recombination velocity proved the passivation ability of TiO2 after annealing. With proven surface passivation and conformal PEDOT:PSS/Si nanohole interfaces for enhanced contact, this Si-organic hybrid heterojunction solar cell with solution-processed TiO2 interlayers has excellent potential for application as a high-efficiency and low-cost Si solar cell. PMID- 27998135 TI - Luminescent Poly(vinyl alcohol)/Carbon Quantum Dots Composites with Tunable Water Induced Shape Memory Behavior in Different pH and Temperature Environments. AB - Luminescent water-induced shape memory polymer (SMP) composites with tunable shape recovery rate are developed by blending poly(vinyl alcohol) (PVA) and carbon quantum dots (CQDs). The oxygen and active hydrogen-rich CQDs can serve as extra physical cross-linking points in PVA via strong hydrogen bonding interaction, which largely improves the shape memory performances of PVA. At room temperature, water can successfully actuate the shape recovery of deformed PVA/CQDs composite. It is demonstrated that this water-induced shape recovery is mainly attributed to the plasticizing effect of water and its competitive hydrogen bonding. Furthermore, a quantitative bending test suggests that the shape recovery time of this water-induced SMP is tunable by altering the environmental pH value and temperature, and a relatively large shape recovery time window (from 20 to 200 s) can be achieved. In addition, the introduction of CQDs endows the PVA/CQDs SMP composites with excellent luminescent property, which makes the shape change of SMP visible under UV light. It should be noted that the mild stimulus condition and tunable shape recovery performances make the luminescent visible PVA/CQDs SMP feasible for diverse biological applications in smart medical devices, stimuli-responsive drug-release, and intelligent sensors in vivo and in vitro. PMID- 27998136 TI - Synthesis of Nanostructured/Macroscopic Low-Density Copper Foams Based on Metal Coated Polymer Core-Shell Particles. AB - A robust, millimeter-sized low-density Cu foam with ~90% (v/v) porosity, ~30 nm thick walls, and ~1 MUm diameter spherical pores is prepared by the slip-casting of metal-coated polymer core-shell particles followed by a thermal removal of the polymer. In this paper, we report our key findings that enable the development of the low-density Cu foams. First, we need to synthesize polystyrene (PS) particles coated with a very thin Cu layer (in the range of tens of nanometers). A simple reduction in the amount of Cu deposited onto the PS was not sufficient to form such a low-density Cu foams due to issues related to foam collapse and densification upon the subsequent polymer removal step. Precise control over the morphology of the Cu coating on the particles is essential for the synthesis of a lower density of foams. Second, improving the dispersion of PS-Cu particles in a suspension used for the casting as well as careful optimization of a baking condition minimize the formation of irregular large voids, leading to Cu foams with a more uniform packing and a better connectivity of neighboring Cu hollow shells. Finally, we analyzed mechanical properties of the Cu foams with a depth sensing indentation test. The uniform Cu foams show a significant improvement in mechanical properties (~1.5* modulus and ~3* hardness) compared to those of uncontrolled foam samples with a similar foam density but irregular large voids. Higher surface areas and a good electric conductivity of the Cu foams present a great potential to future applications. PMID- 27998137 TI - Solution-Processable Ionic Liquid as an Independent or Modifying Electron Transport Layer for High-Efficiency Perovskite Solar Cells. AB - Inorganic metal oxide, especially TiO2, has been commonly used as an electron transport layer (ETL) in regular-structure (n-i-p) planar heterojunction perovskite solar cells (PHJ-PSCs) but generally suffers from high electron recombination rate and incompatibility with low-temperature solution processability. Herein, by applying an ionic liquid (IL, 1-ethyl-3 methylimidazolium hexafluorophosphate ([EMIM]PF6)) as either a TiO2-modifying interlayer or an independent ETL, we investigated systematically IL interface engineering for PHJ-PSCs. Upon spin-coating [EMIM]PF6-IL onto TiO2 ETL as a modification layer, the average power conversion efficiency (PCE) of CH3NH3PbI3 PHJ-PSC devices reaches 18.42 +/- 0.65%, which dramatically surpasses that based on commonly used TiO2 ETL (14.20 +/- 0.43%), and the highest PCE (19.59%) is almost identical to that of the record PCE for planar CH3NH3PbI3 PSCs (19.62%) reported very recently. On the other hand, by applying [EMIM]PF6-IL as an independent ETL, we achieved an average PCE of 13.25 +/- 0.55%, and the highest PCE (14.39%) approaches that obtained for PHJ-PSCs based on independent TiO2 ETL (14.96%). Both IL interface engineering methods reveal the effective electron transport of [EMIM]PF6-IL. The effects of [EMIM]PF6-IL on the surface morphology, crystallinity, and optical absorption of the perovskite film and the interface between the perovskite layer and substrate were investigated and compared with the case of independent TiO2 ETL, revealing the role of [EMIM]PF6-IL in efficient electron transport. PMID- 27998139 TI - High Mobility Flexible Amorphous IGZO Thin-Film Transistors with a Low Thermal Budget Ultra-Violet Pulsed Light Process. AB - Amorphous, sol-gel processed, indium gallium zinc oxide (IGZO) transistors on plastic substrate with a printable gate dielectric and an electron mobility of 4.5 cm2/(V s), as well as a mobility of 7 cm2/(V s) on solid substrate (Si/SiO2) are reported. These performances are obtained using a low temperature pulsed light annealing technique. Ultraviolet (UV) pulsed light system is an innovative technique compared to conventional (furnace or hot-plate) annealing process that we successfully implemented on sol-gel IGZO thin film transistors (TFTs) made on plastic substrate. The photonic annealing treatment has been optimized to obtain IGZO TFTs with significant electrical properties. Organic gate dielectric layers deposited on this pulsed UV light annealed films have also been optimized. This technique is very promising for the development of amorphous IGZO TFTs on plastic substrates. PMID- 27998138 TI - Differential Protein Adsorption and Cellular Uptake of Silica Nanoparticles Based on Size and Porosity. AB - Slight alterations in nanoparticles' surface properties can significantly influence the corona composition which may alter their interaction with the biological milieu. Size and porosity of silica nanoparticles (SNPs) are known to be predominant factors influencing their dose-dependent toxicity. Little is known however about the extent and type of protein adsorption on SNPs as a function of physicochemical properties and the role this might play on mechanisms of cellular uptake and toxicity. In this work we investigated the influence of size and porosity of SNPs on protein adsorption, cellular uptake, and toxicity in RAW 264.7 macrophages. Toxicity of the SNPs was found to be concentration dependent, and the formation of the protein corona mitigated toxicity for all particles. Detailed analysis of the amount of proteins recovered from each nanoparticle revealed similarities in the protein adsorption profile as a function of size and porosity. The mechanism of uptake was highly dependent on size rather than porosity or the adsorbed proteins. PMID- 27998140 TI - Highly Flexible Superhydrophobic and Fire-Resistant Layered Inorganic Paper. AB - Traditional paper made from plant cellulose fibers is easily destroyed by either liquid or fire. In addition, the paper making industry consumes a large amount of natural trees and thus causes serious environmental problems including excessive deforestation and pollution. In consideration of the intrinsic flammability of organics and minimizing the effects on the environment and creatures, biocompatible ultralong hydroxyapatite nanowires are an ideal building material for inorganic fire-resistant paper. Herein, a new kind of free-standing, highly flexible, superhydrophobic, and fire-resistant layered inorganic paper has been successfully prepared using ultralong hydroxyapatite nanowires as building blocks after the surface modification with sodium oleate. During the vacuum filtration, ultralong hydroxyapatite nanowires assemble into self-roughened setalike microfibers, avoiding the tedious fabrication process to construct the hierarchical structure; the self-roughened microfibers further form the inorganic paper with a nacrelike layered structure. We have demonstrated that the layered structure can significantly improve the resistance to mechanical destruction of the as-prepared superhydrophobic paper. The as-prepared superhydrophobic and fire resistant inorganic paper shows excellent nonflammability, liquid repellency to various commercial drinks, high thermal stability, and self-cleaning property. Moreover, we have explored the potential applications of the superhydrophobic and fire-resistant inorganic paper as a highly effective adsorbent for oil/water separation, fire-shielding protector, and writing paper. PMID- 27998141 TI - Space-Confined Growth of Defect-Rich Molybdenum Disulfide Nanosheets Within Graphene: Application in The Removal of Smoke Particles and Toxic Volatiles. AB - In this work, molybdenum disulfide/reduced graphene oxide (MoS2/RGO) hybrids are synthesized by a spatially confined reaction to insert the growth of defect-rich MoS2 nanosheets within graphene to enable incorporation into the polymer matrix for the application in the removal of smoke particles and toxic volatiles. The steady-state tube furnace result demonstrates that MoS2/RGO hybrid could considerably reduce the yield of CO and smoke particles. The TG-IR coupling technique was utilized to identify species of toxic volatiles including aromatic compounds, CO, and hydrocarbons and to investigate the removal effect of MoS2/RGO hybrids on reducing toxic volatiles. The removal of smoke particles and toxic volatiles was attributed to the adsorption capacity derived from edges sites of MoS2 and the honeycomb lattice of graphene, as well as the inhibition of nanobarrier resulting from two-dimensional structure. The work will offer a strategy for fabricating graphene-based hybrids by the space-confined synthesis and exploiting the application of space-confined graphene-based hybrid. PMID- 27998142 TI - Tunable Luminescence Contrast of Na0.5Bi4.5Ti4O15:Re (Re = Sm, Pr, Er) Photochromics by Controlling the Excitation Energy of Luminescent Centers. AB - High luminescent switching contrast of photochromic materials is extremely important in improving the sensitivity and resolution of optical switches and high-density optical data storage devices. To date, conventional methods, such as tuning absorption and emission bands based on electron or resonance energy transfer mechanisms in well-known organic photochromic molecules or compounds, have routinely been adopted to tune luminescent switching behavior. However, these strategies and mechanisms are not effectively applied to luminescence switching in inorganic materials because their crystal structures differ strongly from those of organic materials. In this paper, we report a new method to significantly tune the luminescent switching contrast by modifying the excitation energy of luminescent centers in a newly synthesized photochromism material: Na0.5Bi4.5Ti4O15:Re (Re = Sm, Pr, Er). A significant enhancement of luminescence switching contrast was achieved when the luminescent centers were excited by low energy photons at a given irradiation wavelength, intensity, and time, compared with high excitation energy photons. The trend "the lower the excitation energy, the higher the luminescence switching contrast" is universal in different rare earth ion-doped Na0.5Bi4.5Ti4O15 ferroelectrics. The changes in the luminescent switching contrast based on excitation energy are ascribed to nonradiative energy transfer from the luminescent center to the color center by dipole-dipole interactions according to Dexter theory. This possible utilization of excitation energy at lower energy levels is usually less destructive to both information recording and the recording material itself during luminescent readout processes while achieving higher luminescence switching contrast. PMID- 27998143 TI - Praseodymium Cuprate Thin Film Cathodes for Intermediate Temperature Solid Oxide Fuel Cells: Roles of Doping, Orientation, and Crystal Structure. AB - Highly textured thin films of undoped, Ce-doped, and Sr-doped Pr2CuO4 were synthesized on single crystal YSZ substrates using pulsed laser deposition to investigate their area-specific resistance (ASR) as cathodes in solid-oxide fuel cells (SOFCs). The effects of T' and T* crystal structures, donor and acceptor doping, and a-axis and c-axis orientation on ASR were systematically studied using electrochemical impedance spectroscopy on half cells. The addition of both Ce and Sr dopants resulted in improvements in ASR in c-axis oriented films, as did the T* crystal structure with the a-axis orientation. Pr1.6Sr0.4CuO4 is identified as a potential cathode material with nearly an order of magnitude faster oxygen reduction reaction kinetics at 600 degrees C compared to thin films of the commonly studied cathode material La0.6Sr0.4Co0.8Fe0.2O3-delta. Orientation control of the cuprate films on YSZ was achieved using seed layers, and the anisotropy in the ASR was found to be less than an order of magnitude. The rare-earth doped cuprate was found to be a versatile system for study of relationships between bulk properties and the oxygen reduction reaction, critical for improving SOFC performance. PMID- 27998144 TI - Electronic Structure and Band Gap of Fullerenes on Tungsten Surfaces: Transition from a Semiconductor to a Metal Triggered by Annealing. AB - The understanding and control of molecule-metal interfaces is critical to the performance of molecular electronics and photovoltaics devices. We present a study of the interface between C60 and W, which is a carbide-forming transition metal. The complex solid-state reaction at the interface can be exploited to adjust the electronic properties of the molecule layer. Scanning tunneling microscopy/spectroscopy measurements demonstrate the progression of this reaction from wide band gap (>2.5 eV) to metallic molecular surface during annealing from 300 to 800 K. Differential conduction maps with 104 scanning tunneling spectra are used to quantify the transition in the density of states and the reduction of the band gap during annealing with nanometer spatial resolution. The electronic transition is spatially homogeneous, and the surface band gap can therefore be adjusted by a targeted annealing step. The modified molecules, which we call nanospheres, are quite resistant to ripening and coalescence, unlike any other metallic nanoparticle of the same size. Densely packed C60 and isolated C60 molecules show the same transition in electronic structure, which confirms that the transformation is controlled by the reaction at the C60-W interface. Density functional theory calculations are used to develop possible reaction pathways in agreement with experimentally observed electronic structure modulation. Control of the band gap by the choice of annealing temperature is a unique route to tailoring molecular-layer electronic properties. PMID- 27998145 TI - Performance Enhancement by Secondary Doping in PEDOT:PSS/Planar-Si Hybrid Solar Cells. AB - Solar cells depend on effectively absorbing light and converting it into electrical current. It is therefore essential to increase conductivity and to limit both reflection and parasitic absorbance to achieve higher photoconversion efficiency. Here, we examine the effect of post-treatment on the absorbance and conductivity of hybrid solar cells comprised of p-type poly(3,4-ethylene dioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) on an n-type silicon substrate. Three sets of cells based on pristine PEDOT:PSS film, cosolvent enhanced PEDOT:PSS film using ethylene glycol as a cosolvent, and post-treated PEDOT:PSS film using a novel 1:1 binary mixture of ethylene glycol and methanol have been studied. Markedly different film conductivities have been found for the pristine (~0.8 S/cm), cosolvent added (637 S/cm), and post-treated films (1334 S/cm). The photoconversion efficiency obtained over a large set of samples (72 cells) was used to evaluate the cosolvent addition and post-treatment. Post treatment is found to reproducibly provide films with not only the highest conductivities but also the highest efficiencies along with higher open-circuit voltage and fill factor but lower short-circuit current density when compared to those of the cosolvent added films. The decrease in the latter is attributed to the increase in absorbance in the PEDOT:PSS film. The present work illustrates the delicate challenge in improving the conductivity and carrier collection efficiency of the cells not at the expense of other properties such as absorption. PMID- 27998146 TI - Approximately 800-nm-Thick Pinhole-Free Perovskite Films via Facile Solvent Retarding Process for Efficient Planar Solar Cells. AB - Device performance of organometal halide perovskite solar cells significantly depends on the quality and thickness of perovskite absorber films. However, conventional deposition methods often generate pinholes within ~300 nm-thick perovskite films, which are detrimental to the large area device manufacture. Here we demonstrated a simple solvent retarding process to deposit uniform pinhole free perovskite films with thicknesses up to ~800 nm. Solvent evaporation during the retarding process facilitated the components separation in the mixed halide perovskite precursors, and hence the final films exhibited pinhole free morphology and large grain sizes. In addition, the increased precursor concentration after solvent-retarding process led to thick perovskite films. Based on the uniform and thick perovskite films prepared by this convenient process, a champion device efficiency up to 16.8% was achieved. We believe that this simple deposition procedure for high quality perovskite films around micrometer thickness has a great potential in the application of large area perovskite solar cells and other optoelectronic devices. PMID- 27998147 TI - Chitosan-Coated Diatom Silica as Hemostatic Agent for Hemorrhage Control. AB - Uncontrolled hemorrhage leads to high death risk both in military and civilian trauma. Current hemostatic agents still have various limitations and side effects. In this study, natural diatom silica obtained from diatomite and diatom culture was purified and developed for hemorrhage control. To improve the biocompatibility and hemostatic performance of diatom silica, a series of chitosan-coated diatom (CS-diatom) was developed. The composition of CS-diatom prepared was optimized by in vitro hemocompatibility and blood coagulation evaluation for that prepared with 0.5%, 1%, 3%, and 5% chitosan. The results demonstrated that the CS-diatom prepared with 1% chitosan exhibited favorable biocompatibility (hemolysis ratio < 5%, no cytotoxicity to MEFs), great fluid absorbility (24.39 +/- 1.53 times the weight of liquid), and desirable hemostasis effect (351 +/- 14.73 s at 5 mg/mL, 248 +/- 32.42s at 10 mg/mL). Further blood coagulation mechanism study indicated that CS-diatom could provide an ideal interface to induce erythrocyte absorption and aggregation, along with activating the intrinsic coagulation pathway and thus accelerated blood coagulation. Benefitting from the multiple hemostatic performances, CS-diatom showed the shortest clotting time (98.34 +/- 26.54 s) and lowest blood loss (0.31 +/- 0.11 g) in rat-tail amputation model compare to diatomite and diatom as well as gauze and commercial QuikClot zeolite. The results evidenced that the CS-diatom was a safe and effective hemostatic agent and provided a new understanding of nonsynthetic mesoporous materials for hemorrhage control. PMID- 27998148 TI - Sb2S3/Spiro-OMeTAD Inorganic-Organic Hybrid p-n Junction Diode for High Performance Self-Powered Photodetector. AB - Organic-inorganic hybrid diodes are very promising for solution processing, low cost, high performance optoelectronic devices. Here, we report a high quality p-n heterojunction diode composed of n-type inorganic Sb2S3 and p-type organic 2,2',7,7'-tetrakis-(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro OMeTAD) with a rectification ratio of ~102 at an applied bias of 1 V. On illumination with visible light (470 nm, 1.82 mW/cm2), the current value in our device becomes 8 * 102 times that of its dark value even at a zero bias condition. The estimated responsivity value at zero bias is 0.087 A/W which is so far the highest reported for any organic-inorganic hybrid photodiode, to the best of our knowledge. It also exhibits a fast photoresponse time of <25 ms (instrumental limit). More importantly, our device can also detect visible light with power density as low as 8 MUW/cm2 with a photocurrent density of 1.2 MUA/cm2 and a photocurrent to dark current ratio of more than 8. We also demonstrate that the values of responsivity, short circuit current, and open circuit voltage of the photodetector can be improved significantly using a thin layer of TiO2 hole blocking layer. These findings suggest Sb2S3/spiro-OMeTAD heterojuncton as a promising candidate for efficient self-powered low visible light photodetector. PMID- 27998149 TI - Ultrathin and Atomically Flat Transition-Metal Oxide: Promising Building Blocks for Metal-Insulator Electronics. AB - We present a new and viable template-assisted thermal synthesis method for preparing amorphous ultrathin transition-metal oxides (TMOs) such as TiO2 and Ta2O5, which are converted from crystalline two-dimensional (2D) transition-metal dichalcogenides (TMDs) down to a few atomic layers. X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and scanning transmission electron microscopy (STEM) were used to characterize the chemical composition and bonding, surface morphology, and atomic structure of these ultrathin amorphous materials to validate the effectiveness of our synthesis approach. Furthermore, we have fabricated metal-insulator-metal (MIM) diodes using the TiO2 and Ta2O5 as ultrathin insulating layers with low potential barrier heights. Our MIM diodes show a clear transition from direct tunneling to Fowler-Nordheim tunneling, which was not observed in previously reported MIM diodes with TiO2 or Ta2O5 as the insulating layer. We attribute the improved performance of our MIM diodes to the excellent flatness and low pinhole/defect densities in our TMO insulting layers converted from 2D TMDs, which enable the low-threshold and controllable electron tunneling transport. We envision that it is possible to use the ultrathin TMOs converted from 2D TMDs as the insulating layer of a wide variety of metal insulator and field-effect electronic devices for various applications ranging from microwave mixing, parametric conversion, infrared photodetection, emissive energy harvesting, to ultrafast electronic switching. PMID- 27998150 TI - Realization of Functional Complete Stateful Boolean Logic in Memristive Crossbar. AB - Nonvolatile stateful logic computing in memristors is a promising paradigm with which to realize the unity of information storage and processing in the same physical location that has shown great feasibility for breaking the von Neumann bottleneck in traditional computing architecture. How to reduce the computational complexity of memristor-based logic functions is a matter of concern. Here, based on a general logic expression, we proposed a method to implement the arbitrary logic of complete 16 Boolean logic in two steps with one memristor in the crossbar architecture. A representative functional complete NAND logic is successfully experimentally demonstrated in the filamentary Ag-AgGeTe-Ta memristors to prove the validity of our method. We believe our work may promote the development of the revolutionary logic in memory architectures. PMID- 27998151 TI - Neutral pH Gel Electrolytes for V2O5.0.5H2O-Based Energy Storage Devices. AB - Gel electrolytes are considered to be promising candidates for the use in supercapacitors. It is worthy to systematically evaluate the internal electrochemical mechanisms with a variety of cations (poly(vinyl alcohol) (PVA) based Li+, Na+, and K+) toward redox-type electrode. Herein, we describe a quasi solid-state PVA-KCl gel electrolyte for V2O5.0.5H2O-based redox-type capacitors, effectively avoiding electrochemical oxidation and structural breakdown of layered V2O5.0.5H2O during 10 000 charge-discharge cycles (98% capacitance retention at 400 mV s-1). With the gel electrolyte, symmetric V2O5.0.5H2O-reduced graphene oxide (V2O5.0.5H2O-rGO) devices exhibited a volumetric capacitance of 136 mF cm-3, which was much higher than that of 68 mF cm-3 for PVA-NaCl and 45 mF cm-3 for PVA-LiCl. Additionally, hybrid full cells of activated carbon cloth//V2O5.0.5H2O-rGO delivered an energy density of 102 MUWh cm-3 and a power density of 73.38 mW cm-3 over a wide potential window of 2 V. The present study provides direct experimental evidence for the contribution of PVA-KCl gel electrolytes toward quick redox reactions for redox-type capacitors, which is also helpful for the development of neutral pH gel electrolytes for energy storage devices. PMID- 27998152 TI - Development of Branched Poly(5-Amino-1-pentanol-co-1,4-butanediol Diacrylate) with High Gene Transfection Potency Across Diverse Cell Types. AB - One of the most significant challenges in the development of polymer materials for gene delivery is to understand how topological structure influences their transfection properties. Poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (C32) has proven to be the top-performing gene delivery vector developed to date. Here, we report the development of branched poly(5-amino-1-pentanol-co-1,4 butanediol diacrylate) (HC32) as a novel gene vector and elucidate how the topological structure affects gene delivery properties. We found that the branched structure has a big impact on gene transfection efficiency resulting in a superior transfection efficiency of HC32 in comparison to C32 with a linear structure. Mechanistic investigations illustrated that the branched structure enhanced DNA binding, leading to the formation of toroidal polyplexes with smaller size and higher cationic charge. Importantly, the branched structure offers HC32 a larger chemical space for terminal functionalization (e.g., guanidinylation) to further enhance the transfection. Moreover, the optimized HC32 is capable of transfecting a diverse range of cell types including cells that are known to be difficult to transfect such as stem cells and astrocytes with high efficiency. Our study provides a new insight into the rational design of poly(beta-amino ester) (PAE) based polymers for gene delivery. PMID- 27998153 TI - Fabrication of Tapered Microtube Arrays and Their Application as a Microalgal Injection Platform. AB - A template-synthesis method that enables fabrication of tapered microtube arrays is reported. Track-etched poly(ethylene terephthalate) membranes are used as the template, with closed-tipped conical pores having length and base diameter of 6.27 +/- 0.28 and 1.21 +/- 0.05 MUm, respectively. A conductive layer of Pt is deposited by atomic layer deposition (ALD) to enable the successive electrodeposition of Ni. By decreasing the Pt precursor pulse duration from 10 to 1 s during the ALD step, the heights of the microtubes are controlled from the maximal full length (~6 MUm) to only a fraction (1-2 MUm) of the template pore. Using a pulsed-current electrodeposition (PCD) method, a smooth and uniform Ni deposit is achieved with a thickness that can be controlled as a function of the PCD cycle. The microtubes' lumen is confirmed to stay open even after 2000 cycles of Ni PCD. A potential application of the prepared array as a microinjection platform is demonstrated via successful injection of 10 nm sized CdZnS/ZnS core/shell quantum dots into Chlamydomonas reinhardtii microalgae cells with intact cell walls. The direct delivery method demonstrated in this paper offers novel opportunities for extending the growing interest in array-based microinjection platform to microalgal systems. PMID- 27998154 TI - Preface: In Focus Issue on Nanoparticle Interfaces. PMID- 27998155 TI - Probed adhesion force of living lung cells with a tip-modified atomic force microscope. AB - The mechanical properties of the extracellular matrix play an important role in bio-microenvironment activities. Herein, atomic force microscope (AFM) was used to measure the interaction between Au and Ag nanoparticle (NP) clusters on the surface of human fetal lung cells. Using (3-mercapto-propyl) triethoxysilane (MPTMS), NP clusters were grafted onto the apex of AFM tip, and then, the adhesion force between the tip and the cell was analyzed. The measured adhesion force increased from 92 pN for AFM tip to 332 pN for that modified with MPTMS. The increase is most probably contributed by the nonspecific interactions between the apex of the modified AFM tip and the surface of the cells. The adhesion forces between the surface of NPs clusters grafted AFM tip and that of lung cells were dramatically reduced as NPs clusters were replaced by MPTMS. For the former, as the Au NPs cluster was applied, the adhesion force reached to 122 pN, whereas it significantly augmented with the addition of the cluster's size and dimension on the AFM tip. For the case of Ag cluster grafted on AFM tip, its adhesion force with the surface of the cells significantly lowered and reduced to 56 pN. Presumably, the electrostatic or van der Waals force between the two surfaces results in the variation of measurements. It is also very likely that the cell surface interactions are probably varied by the nature of the contact surfaces, like the force-distance of attraction. The result is significant for understanding the the nature of the interactions between the surface of NPs and the membrane of lung cells. PMID- 27998156 TI - Reliability and Validity of Kurdish Language Version of Health Promoting Lifestyle Profile II among Kurdish Healthcare Providers Kurdish Version of HPLP II. AB - BACKGROUND: Unhealthy lifestyles pose significant threat to public health. This study aimed to assess the validity and reliability of a Kurdish version of the HPLP-II instrument among Kurdish healthcare providers, whose society and culture differ from that of North America and Spain, where the instrument was developed. METHODS: The instrument was translated into Kurdish, back translated, and pilot tested to ascertain cultural sensitivity. It was then evaluated using a convenience sample of 460 healthcare providers in the Kurdistan region, northern Iraq using a principal components factor analysis. RESULTS: The order of factors was entirely identical to those isolated previously during the psychometric assessment of the English language version. The majority of our study participants were male (55%). In addition, 39.2% of participants were nurses. In addition, 42% of participants had less than five years of working experience. Furthermore, 82.1% of our study population held a high school diploma. The mean (SE) of Physical Activities dimension was low (15.3 +/- 4.8) compared to Spiritual Growth dimension (24.5 +/- 4.4). Moreover, the Cronbach's alpha coefficient for the overall HPLP-II questionnaire was 0.870; however, the nutrition dimension was low (0.622) compared to Physical Activities dimension (0.792). Furthermore, the correlation between items ranged from 0.099 to 0.611. CONCLUSIONS: The Kurdish version of the HPLP-II demonstrated initial reliability and validity. It is a precious tool to evaluate and assess lifestyle and lifestyle interventions built to improve the health of Kurds. PMID- 27998157 TI - Promoting the Medical University's Governance: Content Analysis of Decisions Made by the Medical University's Governing Bodies. AB - BACKGROUND: Decisions made by the governing body of a university would overshadow university governance. This study aimed to analyze the quantity and quality of decisions made by the three governing bodies (Board of trustees, Board of Chancellors and University council) of a medical university in Isfahan, Iran. METHODS: A mixed qualitative and quantitative approach was employed, with the quantitative part in cross-sectional format and the qualitative part in content analysis format. In the quantitative part, the number of meetings and resolutions of the governing bodies were collected through Isfahan University of Medical Sciences. In the qualitative part, the content of 3121 resolutions that were selected using stratified sampling method was analyzed. RESULTS: The results indicated the defensible numbers of meetings and resolutions of the boards of trustees and chancellors. The governing bodies' resolutions were mostly operational in domain, administrative (boards of trustees and chancellors) and educational (university council) in nature, financing (board of trustees) and providing services (board of chancellors and university council) in function with the aim of responsiveness. The share of specific and single-department resolutions was greater compared to others. CONCLUSION: Better monitoring and evaluation of the activity of governing bodies, redirecting the decisions made by governing bodies, reminding the position of the governing bodies and revising their duties and responsibilities are recommended for better governance of the medical university. PMID- 27998158 TI - Prevalence of Dementia and Associated Factors among Older Adults in Iran: National Elderly Health Survey (NEHS). AB - BACKGROUND: The prevalence of cognitive impairment and dementia is increasing in Iran and the world. There is no study available on the prevalence of dementia at the national level in Iran. This study aimed to report the rate of dementia at the national level in Iran. METHODS: The National Elderly Health Survey (NEHS) was a cross-sectional study with multistage cluster random sampling on people aged >= 60 years in Iran. Dementia was diagnosed by trained general practitioners using Brief Cognitive Assessment Tool (BCAT). In this study, the dementia diagnosis rate was considered as the ratio of individuals previously diagnosed with dementia to individuals considered as dementia. Analyses were carried out using survey analysis method. The provincial rates were standardized based on the Iranian population in 2011 and the national rate was standardized based on WHO standard populations. Association between risk factors and dementia was assessed using a multivariable logistic regression model. RESULTS: The overall crude prevalence of dementia among people aged >= 60 years was 7.9% (8.7% in women and 6.9% in men) and age standardized dementia prevalence rate in Iran based on WHO standard population was 8.1% (9.6% in women and 6.5% in men). The prevalence of dementia was observed as 3.7% among people aged 60-64 years, 6.2% in the age group 65-69 years, 10.4% in the age-group 70-74 years, 14.4% in the age-group 75 79 years, and 13.0% in the age-group >= 80 years. West Azerbaijan had the lowest and North Khorasan had the highest age-sex adjusted prevalence rate of dementia. Our results indicated that only 21.2% of subjects with dementia were diagnosed. We observed that diabetes mellitus, depressed mood, illiteracy, and increased age were associated with dementia. CONCLUSION: It seems that dementia is more common in Iran than many other countries. However, the rate of dementia diagnosis is much lower than that in developed countries. PMID- 27998159 TI - Relationship between Cystatin C, Retinol-binding Protein 4 and Framingham Risk Score in Healthy Postmenopausal Women. AB - BACKGROUND: We aimed to examine the relationship between high levels of cystatin C, retinol-binding protein 4 (RBP4) and cardiovascular risk score [determined by Framingham Risk Score (FRS)] in postmenopausal women. METHODS: A total of apparently healthy 129 postmenopausal women (mean age 57.1 +/- 4.6 years) were included. Serum cystatin C, RBP4, glucose, lipid parameters, creatinine, uric acid and high sensitivity C-reactive protein (hsCRP) were determined. Anthropometric parameters and blood pressure were also obtained. FRS was calculated. Multiple linear regression analysis (MLR) was performed to identify independent factors affecting FRS and to estimate the final predictors of its variability. Receiver Operating Characteristic (ROC) curve analysis was used with the purpose of testing discriminatory potential of a group of parameters selected in MLR analysis, with FRS level as dependent variable. RESULTS: We found significantly higher levels of both proteins, cystatin C (P = 0.001) and RBP4 (P = 0.006), in the FRS higher (medium and high) risk groups (FRS >= 10%) compared to low risk FRS group (FRS < 10%). MLR revealed the best model consisting of 4 parameters (e.g., body mass index (BMI) (P < 0.001), triglycerides (TG) (P = 0.004), RBP4 (P = 0.021), and cystatin C (P = 0.046), R2-adjusted = 0.347) for FRS prediction. Construction of a model consisted of those 4 FRS formula independent parameters (BMI, TG, cystatin C and RBP4) using logistic regression analysis showed that new ROC curve had excellent discriminatory capability (area under the curve = 0.820). CONCLUSION: High cystatin C and retinol-binding protein 4 may contribute significantly to cardiovascular risk burden in addition to traditional cardiovascular markers. PMID- 27998160 TI - Risk factors of Multiple sclerosis and their Relation with Disease Severity: A Cross-sectional Study from Iran. AB - BACKGROUND: Many risk factors have been investigated in multiple sclerosis (MS); however, few studies have focused on the association between risk factors and the disease severity. The aim of our study was to evaluate the association between some of these risk factors and MS severity in a population sample of Iranian patients. METHODS: This cross-sectional study was conducted on 660 patients with MS. In addition to demographic variables, many potential risk factors were recorded. To compare the severity, progression index (PI) was calculated. This index is created by current Expanded Disability Status Scale (EDSS) /disease duration. RESULTS: Univariate analysis revealed that active smoking status is related with MS severity. (P-value = 0.012). Furthermore, our findings demonstrated that age at the disease onset [P < 0.001; OR = 1.05 (95% CI: 1.03 1.07)], female gender [P = 0.002; OR = 1.86 (95% CI: 1.24-2.77)] and marital status [P = 0.002; OR = 1.71 (95% CI: 1.21-2.41)] correlated with the severity of MS in the adjusted model. MS severity was observed to be related with high school and academic studies ([P = 0.004; OR = 0.56 (95% CI: 0.38-0.83)], [P = 0.001; OR = 0.52 (95% CI: 0.35-0.78)]) (Primary/secondary school studies are used as reference). Moreover, there was an association between MS severity and occupation (white collar, pink collar) ([P = 0.006; OR = 0.32 (95% CI: 0.14-0.73)], [P = 0.007; OR = 0.47 (95% CI: 0.27-0.81)]) (Student is used as reference). Furthermore, the results showed a significant correlation between vision and motor symptoms as an initial symptom and PI (P = 0.001, P = 0.025). CONCLUSION: Due to high cost of MS care and its moderate to severe disability, identification of factors influencing the MS severity is important. Our results demonstrated that the major modifiable factors related with MS severity in Iranian population, some protective and some promotive, were smoking, education, marital status and occupation. Prospective studies on larger scale are needed for further proof of these results. PMID- 27998161 TI - Fee Splitting among General Practitioners: A Cross-Sectional Study in Iran. AB - BACKGROUND: Fee splitting is a process whereby a physician refers a patient to another physician or a healthcare facility and receives a portion of the charge in return. This survey was conducted to study general practitioners' (GPs) attitudes toward fee splitting as well as the prevalence, causes, and consequences of this process. METHODS: This is a cross-sectional study on 223 general practitioners in 2013. Concerning the causes and consequences of fee splitting, an unpublished qualitative study was conducted by interviewing a number of GPs and specialists and the questionnaire options were the results of the information obtained from this study. RESULTS: Of the total 320 GPs, 247 returned the questionnaires. The response rate was 77.18%. Of the 247 returned questionnaires, 223 fulfilled the inclusion criteria. Among the participants, 69.1% considered fee splitting completely wrong and 23.2% (frequently or rarely) practiced fee splitting. The present study showed that the prevalence of fee splitting among physicians who had positive attitudes toward fee splitting was 4.63 times higher than those who had negative attitudes. In addition, this study showed that, compared to private hospitals, fee splitting is less practiced in public hospitals. The major cause of fee splitting was found to be unrealistic/unfair tariffs and the main consequence of fee splitting was thought to be an increase in the number of unnecessary patient referrals. DISCUSSION: Fee splitting is an unethical act, contradicts the goals of the medical profession, and undermines patient's best interest. In Iran, there is no code of ethics on fee splitting, but in this study, it was found that the majority of GPs considered it unethical. However, among those who had negative attitudes toward fee splitting, there were physicians who did practice fee splitting. The results of the study showed that physicians who had a positive attitude toward fee splitting practiced it more than others. Therefore, if physicians consider fee splitting unethical, its rate will certainly decrease. The study claims that to decrease such practice, the healthcare system has to revise the tariffs. PMID- 27998162 TI - Antibiotic Sensitivity pattern of Bacterial Isolates of Neonatal Septicemia in Peshawar, Pakistan. AB - BACKGROUND: Septicemia plays an important role in neonatal morbidity and mortality, especially in developing countries. OBJECTIVE: To investigate the bacterial pathogens causing neonatal sepsis and their antibiotic susceptibility profile. METHODOLOGY: A total of 2,685 neonates aged 0-28 days were included in the study. Blood from each neonate was cultured and isolates were identified using standard biochemical tests. Antibiotic sensitivity pattern was analyzed using modified Kirby-Bauer disc diffusion method. RESULTS: Blood culture positivity was observed in 1,534 (57.1%) samples. Most of the cases (1089 counts 71%) were of early onset sepsis while 445 (29%) were of late onset sepsis. The incidence of sepsis was higher in males 856 (55.8%) than females 678 (44.2%) with a 1:2 ratio. Similarly, 58.3% of septicemic patients were neonates with low birth weights. Twelve hundred and six (78.6%) isolates were gram negative while 328 (23.4%) were gram positive bacteria. E. coli was the dominant pathogen seen in 811 (52.8%) followed by Staphylococcus aureus 300 (19.5%), Pseudomonas 199 (13%), Klebsiella 102 (6.7%), Proteus 87 (5.7%), Staphylococcus epidermidis 28(1.8%) and Salmonella in 7 (0.5%) samples. All bacterial isolates showed high sensitivity to Imipenem, Enoxacin, Ofloxacin and Ciprofloxacin while low sensitivity was observed for other antibiotics (n = 16). The Proteus species showed high level of multiple resistances to all antibiotics (5.9%). CONCLUSION: Imipenem, Enoxacin, Ofloxacin and Ciprofloxacin can be used as an effective antibiotic regimen for treatment of bacterial sepsis in neonates. PMID- 27998163 TI - Opioid Therapy and its Side Effects: A Review. PMID- 27998164 TI - Photoclinic: Renal Abscess. PMID- 27998165 TI - Neutrophilic Dermatosis of Dorsal Hands and Legs. AB - We present a case of neutrophilic dermatosis of dorsal hands (NDDH), with lesions on the dorsal part of the hands with pustular features and histologic picture of vasculitis.This case highlights the notion that low dose oral steroid can offer a useful first therapeutic option for NDDH. Interstingly, in this case, a few additional lesions were located on the legs, making it different from some previously described cases of NDDH. As with other authors, we believe that this recently described neutrophilic dermatosis is a localized and acral variant of SS. To our knowledge, this is the first case report of NDDH from Iran. PMID- 27998166 TI - World Marrow Donor Day to Honor Stem Cell Donors in Tehran. PMID- 27998167 TI - Severe Outbreaks of Respiratory Syndromes Following Autumn Rainfall in Khuzestan, Iran. PMID- 27998168 TI - A Comment on the Letter. PMID- 27998169 TI - Dr. Mohammad Reza Mohareri, the Pioneering Professor of Pschychiatry at Shiraz School of Medicine. PMID- 27998170 TI - Accuracy of femur reconstruction from sparse geometric data using a statistical shape model. AB - Sparse geometric information from limited field-of-view medical images is often used to reconstruct the femur in biomechanical models of the hip and knee. However, the full femur geometry is needed to establish boundary conditions such as muscle attachment sites and joint axes which define the orientation of joint loads. Statistical shape models have been used to estimate the geometry of the full femur from varying amounts of sparse geometric information. However, the effect that different amounts of sparse data have on reconstruction accuracy has not been systematically assessed. In this study, we compared shape model and linear scaling reconstruction of the full femur surface from varying proportions of proximal and distal partial femur geometry in combination with morphometric and landmark data. We quantified reconstruction error in terms of surface-to surface error as well as deviations in the reconstructed femur's anatomical coordinate system which is important for biomechanical models. Using a partial proximal femur surface, mean shape model-based reconstruction surface error was 1.8 mm with 0.15 degrees or less anatomic axis error, compared to 19.1 mm and 2.7-5.6 degrees for linear scaling. Similar results were found when using a partial distal surface. However, varying amounts of proximal or distal partial surface data had a negligible effect on reconstruction accuracy. Our results show that given an appropriate set of sparse geometric data, a shape model can reconstruct full femur geometry with far greater accuracy than simple scaling. PMID- 27998171 TI - Co-infections of tuberculosis, hepatitis B or C viruses in a cohort of people living with HIV/AIDS in China: predictors and sequelae. AB - The co-infection of viral hepatitis and tuberculosis (TB) among people living with HIV/AIDS (PLWHA) makes the syndemic of HIV even worse as there is higher mortality and morbidity among PLWHA with co-infections compared to people with HIV mono-infection. In the current study, we explored predictors and sequelae among a group of Chinese PLWHA to guide future program strategies and enhance the repertoire of action for both preventative and clinical purposes. Between October 2012 and August 2013, we conducted a cross-sectional study in Guangxi Autonomous Region (Guangxi) of China. With an overall participation rate of 90%, we finally recruited 3002 patients with 2987 (99.5%) completed the survey and were included in the data analysis. We employed both predictive and explanatory modeling strategies to explore predictors and sequelae of co-infections among PLWHA. The overall prevalence of co-infection was 15.6% with 4.4% of HBV, 5.4% of HCV and 4.8% of TB, respectively. Predictors of co-infections included history of injecting drugs or drinking alcohol, sharing needles, having sex with sex workers or casual partners, higher viral loads and lower CD4 counts. Meanwhile, co infections were associated with various physical and psychological problems among PLWHA. As an entangled phenomenon, co-infections among PLWHA produce continuous and shifting scenarios, which add complexity to clinic, epidemiological and political ways of dealing with health risks among PLWHA in China. Exploring predictors and sequelae can help to prevent and manage co-infection comorbidities among PLWHA. PMID- 27998172 TI - Commentary on: Addiction in extreme sports: An exploration of withdrawal states in rock climbers. AB - Individuals can display characteristics of behavioral addictions to nature and the outdoors as well as adventure activities. Research on mental health effects of nature exposure is relevant to research on nature and adventure addictions. PMID- 27998173 TI - Prevention of Internet addiction: A systematic review. AB - Background and aims Out of a large number of studies on Internet addiction, only a few have been published on the prevention of Internet addiction. The aim of this study is provide a systematic review of scientific articles regarding the prevention of Internet addiction and to identify the relevant topics published in this area of interest. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adopted. The EBSCO, ProQuest Central, and PubMed databases were searched for texts published in English and Spanish between January 1995 and April 2016. A total of 179 original texts were obtained. After de-duplication and topic-relevance review, 108 texts were systematically classified and subjected to descriptive analysis and subsequent content analysis. Results The results of the content analysis yielded the following thematic areas: (a) target groups, (b) the improvement of specific skills, (c) program characteristics, and (d) environmental interventions. Discussion and conclusion Literature on the prevention of Internet addiction is scarce. There is an urgent need to introduce and implement new interventions for different at-risk populations, conduct well-designed research, and publish data on the effectiveness of these interventions. Developing prevention interventions should primarily target children and adolescents at risk of Internet addiction but also parents, teachers, peers, and others who are part of the formative environment of children and adolescents at risk of Internet addiction. Newly designed interventions focused on Internet addiction should be rigorously evaluated and the results published. PMID- 27998174 TI - Response to "Nature fix: Addiction to outdoor activities"R. C. Buckley's commentary on Heirene, R. M., Shearer, D., Roderique-Davies, G., & Mellalieu, S. D. (2016). Addiction in extreme sports: An exploration of withdrawal states in rock climbers. Journal of Behavioral Addictions, 5, 332-341. AB - Buckley's commentary on our study of rock climber's withdrawal experiences raises a number of important questions surrounding the concept of extreme or adventure sports addiction. Drawing on the few available investigations of this topic, we respond to Buckley's questions here, though emphasize the need for further studies of extreme sports addiction in order to provide more empirically informed answers. PMID- 27998175 TI - Ureteral Access Sheath Influence on the Ureteral Wall Evaluated by Cyclooxygenase 2 and Tumor Necrosis Factor-alpha in a Porcine Model. AB - OBJECTIVE: To examine the effect of ureteral access sheath (UAS) on the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha) in the ureteral wall. MATERIAL AND METHODS: In 22 pigs an UAS was inserted and removed after 2 minutes on one side and 2 hours on the contralateral side. Postoperatively ureters were excised in vivo, and tissue samples from the distal (2 minutes/2 hours) and proximal ureter (2 minutes/2 hours) were snap-frozen before quantitative polymerase chain reaction analysis of COX-2 and TNF-alpha. Five unmanipulated ureteral units from other pigs served as the control group. RESULTS: Compared to controls COX-2 mRNA was significantly upregulated in all UAS treated ureteral groups. Similarly, TNF alpha mRNA was upregulated in all groups except the 2-minute proximal ureteral group. Both COX-2 and TNF-alpha expression were significantly higher in the distal than in the proximal ureter in the UAS treated ureters. After UAS insertion for 2 minutes, expression levels in the distal ureter were increased 6.5- and 8-fold for COX-2 and TNF-alpha, respectively; and after 2 hours of UAS placement COX-2 and TNF-alpha mRNA expression levels were increased 9- and 9.5 fold, respectively. CONCLUSION: The pro-inflammatory mediators COX-2 and TNF alpha were significantly upregulated in the ureteral wall by the influence of UAS. These findings may have implications for postoperative pain, drainage, and complications. PMID- 27998176 TI - Childhood exposure to emotional abuse and later life stress among Kenyan women: a mediation analysis of cross-sectional data. AB - BACKGROUND AND OBJECTIVE: We explore whether perceived stress among Kenyan mothers is predicted by childhood exposure to emotional abuse - both witnessed among parents and experienced directly. Further, we explore whether this association is mediated by social support, family functioning and polygynous marriage. DESIGN: We used cross-sectional data from a systematic random sample (n = 1974) of mothers in semi-rural Kenya. METHODS: Data were collected using validated scales and trained interviewers. Analyses were conducted using bootstrapped structural equation models and fixed-effects linear regression models, controlling for age and household wealth. RESULTS: Reported experience of emotional abuse - both directly experienced and observed among household adults - was high in the present population (72.5% and 69%, respectively). Perceived stress among women was significantly higher if they were exposed to more emotional abuse during childhood (p < .001). Lower social support, worse family functioning and higher rates of polygynous marriage mediated pathways between emotional abuse exposure during childhood and adult perceived stress. CONCLUSION: Future research should investigate whether social integration, identity formation and self-esteem underlie observed dynamics in sub-Saharan Africa. Efforts to promote social integration and support should target children currently experiencing emotional abuse, and may include child-targeted high quality television programing and adult-targeted media and celebrity campaigns. PMID- 27998177 TI - Intimate partner violence is linked to less HIV testing uptake among high-risk, HIV-negative women in Atlanta. AB - Increased risk of HIV acquisition among intimate partner violence (IPV) survivors underscores the need for regular HIV testing, but IPV-associated shame, stigma, and control may hinder uptake. Between March and November 2014, we conducted a cross-sectional study of 79 HIV-negative, high-risk women aged 18-50 in Atlanta, Georgia, to explore whether IPV experience was associated with less uptake of HIV testing, and fewer motivations and more reported barriers to HIV testing uptake. Psychological and physical and/or sexual abuse was significantly associated with less past-year HIV testing (p = .022 and p = .030, respectively), longer time since last HIV test (r = 0.282, p = .012, and r = 0.282, p = .012, respectively), and more reported barriers to HIV testing (r = 0.406, p = .004, and r = 0.389, p = .006). While requiring further validation, these preliminary findings suggest IPV survivors need additional support to access HIV testing services. PMID- 27998178 TI - Overlapping HIV and sex-work stigma among female sex workers recruited to 14 respondent-driven sampling surveys across Zimbabwe, 2013. AB - HIV stigma can inhibit uptake of HIV testing and antiretroviral therapy as well as negatively affect mental health. Efforts to reduce discrimination against people living with HIV (LWH) have contributed to greater acceptance of the infection. Female sex workers (FSW) LWH may experience overlapping stigma due to both their work and HIV status, although this is poorly understood. We examined HIV and sex-work stigma experienced by FSW LWH in Zimbabwe. Using the SAPPH-IRe cluster-randomised trial baseline survey, we analysed the data from 1039 FSW self reporting HIV. The women were recruited in 14 sites using respondent-driven sampling. We asked five questions to assess internalised and experienced stigma related to working as a sex worker, and the same questions were asked in reference to HIV. Among all FSW, 91% reported some form of sex-work stigma. This was not associated with sociodemographic or sex-work characteristics. Rates of sex-work stigma were higher than those of HIV-related stigma. For example, 38% reported being "talked badly about" for LWH compared with 77% for their involvement in sex work. Those who reported any sex-work stigma also reported experiencing more HIV stigma compared to those who did not report sex-work stigma, suggesting a layering effect. FSW in Zimbabwe experience stigma for their role as "immoral" women and this appears more prevalent than HIV stigma. As HIV stigma attenuates, other forms of social stigma associated with the disease may persist and continue to pose barriers to effective care. PMID- 27998179 TI - Patients' intention to speak up for health care providers' hand hygiene in inpatient diabetic foot wound treatment: a cross-sectional survey in diabetes outpatient centres in Lower Saxony, Germany. AB - Hand hygiene in wound care by health care providers (HCPs) is a key principle in treating hospitalized patients with diabetic foot infections. This study aimed to estimate the extent to which patients with type-2-diabetes (T2D) intend to speak up for HCPs' hand hygiene during inpatient foot treatment, test whether this motivation increases given the hospital would invite patients to speak up, and identify associations with socio-demographics, knowledge of hand hygiene requirements, and diabetes-related factors. A questionnaire-survey was conducted in eight diabetes outpatient centres in Lower Saxony/Germany. Intentions to speak up (without and with institutional encouragement) and knowledge about hand hygiene during foot-care were assessed. Analyses of variance were conducted, partly as repeated measures-models with intention-items as within-subject factor. N = 473 patients participated (response = 77.4%). N = 177 (41%) strongly intended to speak up. Institutional encouragement was associated with an increased rate of strong (54% vs. 41%; p < .001) and higher mean intention (M = 3.9 vs. 3.4 with vs. without encouragement [5-point-scales]; F(1, 434) = 41.5, p < .001). In patients without diabetic foot syndrome, this effect was limited to those with at least medium school education (F(2, 292) = 4.4, p = .013) and knowledge on HCPs' hand hygiene (F(2, 294) = 3.1, p = .047). In conclusion, a majority of T2D patients in diabetes outpatient centres intend to speak for HCPs' hand hygiene in inpatient foot treatment, and are receptive to institutional encouragement. However, this presupposes at least medium education and knowledge about hand hygiene, emphasizing that patient empowerment begins with knowledge. PMID- 27998180 TI - Challenging body weight: evidence from a community-based intervention on weight, behaviour and motivation. AB - The objective of this study was to examine the effectiveness of a 12 week weight loss intervention within a commercial fitness centre on body weight, moderate to vigorous physical activity (MVPA), dietary intake, and behavioural regulations for exercise and healthy eating. Using a quasi-experimental design, the intervention group received weekly coaching sessions and bi-weekly seminars designed to increase MVPA and improve dietary intake. Outcome variables were assessed at three time points over a six month period. Results showed a significant interaction for body weight (p = .04) and dietary changes (p < .05) following the weight loss challenge but were not maintained across the six month period. Changes in behavioural regulations favoured the intervention condition. Results imply that a 12 week weight loss challenge within a commercial fitness centre may be effective at prompting short-term weight loss and support the internalization of behavioural regulations specific to healthy eating and exercise. PMID- 27998181 TI - Perspectives and experiences of patients with type 2 diabetes observing the Ramadan fast. AB - INTRODUCTION: Diabetes is a common chronic disease among Australians. Culturally and linguistically diverse groups are observed to have higher prevalence rates of diabetes. Continuing management needs adherence to medication and diet regimens. Religious practices such as fasting can affect diabetes management and medication use. Pharmacists as medication specialists have a significant role in helping people observing religious practices such as the Ramadan fast, which involves month-long absolute abstinence from food during daylight hours, to maintain good control over their condition. OBJECTIVE: This study investigated the perspective of patients with type 2 diabetes (T2D) who undertake the fast of Ramadan, to understand their experiences, health-related needs and service preferences regarding diabetes management. METHODS: A qualitative, exploratory design was used in this study. Data collection comprised the conduct of semi-structured interviews with a purposive convenient sample of patients in areas of ethnic diversity in Sydney, using a standardised interview guide. Interview data were transcribed verbatim and thematically analysed. RESULTS: Twenty-five semi structured interviews (68% males) among a heterogeneous sample of fasting T2D patients were conducted. Themes emerging from analysis of transcripts included issues relating to sociocultural pressure for T2D patients to fast; lack of awareness about the role of pharmacists and, most importantly, the need to train pharmacists in cultural sensitivity and clinical implications thereof. CONCLUSIONS: Community awareness about the role of the pharmacists in assisting medication use and adjustment during fasting periods should be enhanced. Furthermore, community pharmacists need to be trained about the unique religious and sociocultural issues of patients with diabetes opting to observe spiritual rituals such as the Ramadan fast. Clinical education in this area should up-skill pharmacists to inculcate self-management behaviours in fasting T2D patients. PMID- 27998182 TI - Investigation of transrenal KRAS mutation in late stage NSCLC patients correlates to disease progression. AB - PURPOSE: Using transrenal DNA to detect KRAS mutations in non-small cell lung cancer (NSCLC), the study addressed the clinical impact for longitudinal monitoring and prognostic value for disease outcome. METHODS: Digital droplet PCR was used to detect the mutant DNA. A total of 200 NSCLC patients were recruited with varying molecular profiles. To ascertain the specificity of transrenal DNA to accurately profile the disease, primary tissues were compared. Subsequently, serial samplings were performed at different treatment cycles to gauge the predictive value. RESULTS: Transrenal DNA was successfully detected in all 200 patients. Overall concordance rate for mutant KRAS DNA within urine specimens and primary tissue biopsies was 95% (k = 0.87; 95% CI: 0.82-0.95). Patients with positive results at baseline had lower median overall survival (OS) than the wildtype group. More importantly, longitudinal monitoring of urine specimens showed an increase in the quantity of transrenal DNA, which were highly associated with disease progression and outcome. CONCLUSIONS: Our study showed a highly associative link to the patient's tumor KRAS profile. Monitoring its variations aided in stratifying patients with worse outcome. Urinary specimens that can be extracted non-invasively presents new opportunities to track patients with KRAS mutation undergoing therapy. PMID- 27998183 TI - Systemic therapy for cutaneous T-cell lymphoma: who, when, what, and why? AB - INTRODUCTION: CTCL are rare neoplasms. Optimal care requires integrated use of diagnostic and treatment modalities spanning multiple specialties. Current instruments for patient risk stratification and disease measurement across all anatomical compartments are suboptimal. A common treatment dichotomy between early (Dermatology) and advanced stage (Hematology-Oncology) has hindered accrual of long term outcome data. Thus, important facts about natural history, such as frequency and determinants of stage progression, and the impact of specific treatment modalities on these endpoints, are not known. Areas covered: One of the most important decisions in the management of CTCL is when to start systemic therapy and what agents to use. This review provides background information to understand why systemic therapy is needed and what goals are currently achievable. Expert commentary: Risk-adapted approaches, based on better knowledge of host and tumor biology, and more accurate disease measurement tools are needed to optimize the use of specific systemic therapies. PMID- 27998184 TI - CDC-funded HIV testing, HIV positivity, and linkage to HIV medical care in non health care settings among young men who have sex with men (YMSM) in the United States. AB - In the United States, HIV infection disproportionately affects young gay, bisexual, and other men who have sex with men, aged 13-24 years (collectively referred to as YMSM), specifically black YMSM. Knowledge of HIV status is the first step for timely and essential prevention and treatment services. Because YMSM are disproportionately affected by HIV, the number of CDC-funded HIV testing events, overall and newly diagnosed HIV positivity, and linkage to HIV medical care among YMSM in non-health care settings were examined from 61 health department jurisdictions. Differences by age and race/ethnicity were analyzed. Additionally, trends in number of HIV testing events and newly diagnosed HIV positivity were examined from 2011 to 2015. In 2015, 42,184 testing events were conducted among YMSM in non-health care settings; this represents only 6% of tests in non-health care settings. Overall and newly diagnosed HIV positivity was 2.8% and 2.1%, respectively, with black/African-American YMSM being disproportionately affected (5.6% for overall; 4% for newly diagnosed); 71% of YMSM were linked within 90 days. The newly diagnosed HIV positivity among YMSM decreased from 2.8% in 2011 to 2.4% in 2015, and the number of newly diagnosed YMSM also decreased. Further targeted testing efforts among YMSM are needed to identify undiagnosed YMSM, specifically black YMSM. PMID- 27998185 TI - Professor Jack Fowler and Sir Oliver Scott. PMID- 27998186 TI - Nothing endures but change. PMID- 27998187 TI - Small animal image-guided radiotherapy. PMID- 27998188 TI - Can the surgical tourniquet be used in patients with sickle cell disease or trait? A review of the literature. AB - INTRODUCTION: In patients with sickle cell disease, circulatory stasis, acidosis, and hypoxemia induce red cell deoxygenation and consequent sickling. Tourniquets are an important adjunct in limb surgery to obtain a bloodless field. Many local and systemic effects, due to the inflation and deflation of the tourniquet, can develop. These effects may have severe consequences if comorbidities are present. The use of a tourniquet in sickle cell patients is controversial because it may provoke vaso-occlusive complications. Areas covered:We reviewed the literature to detect reports of the use of tourniquet in sickle cell disease or sickle trait. We found only three case reports and five case series, three of which controlled, none randomized, on the complications of tourniquet. Expert commentary:From what we could find in the literature and contrary to what is suggested by most guidelines it appears that complications are rare. However, caution must be applied and the risk/benefit ratio carefully considered. PMID- 27998190 TI - Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines. AB - INTRODUCTION: The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment. Areas covered: The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA's draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed. Expert commentary: We summarize how 'one size does not fit all' for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines. PMID- 27998189 TI - Letermovir for the management of cytomegalovirus infection. AB - INTRODUCTION: Cytomegalovirus (CMV) is a major cause of morbidity and mortality in immunocompromised patients. Available antivirals are fraught with adverse effects and risk for the development of CMV resistance. Letermovir is a novel antiviral in the late stages of drug development for the treatment and prevention of CMV. Areas covered: A MEDLINE search of the MeSH terms 'letermovir,' 'cytomegalovirus,' 'hematopoietic stem cell transplant,' and 'solid organ transplant,' was last conducted on 15 August 2016. Articles were selected on the basis of their contribution to current knowledge about letermovir. Expert opinion: Letermovir's mechanism of action, pharmacokinetic and pharmacodynamic profile, and favorable efficacy and safety make it an attractive option for both the prevention and treatment of CMV in immunocompromised patients. The lack of cross-resistance with other antivirals and the absence of myelosuppression are two prominent characteristics of letermovir that could support broad use of this product following FDA-approval. One major limitation is its lack of activity against other herpesviruses, which are commonly seen in immunocompromised hosts. We believe that with additional clinical efficacy data, this medication could emerge as a primary option for the prevention and treatment of CMV in the immunocompromised patient population. PMID- 27998191 TI - In vitro potential cytogenetic and oxidative stress effects of roxithromycin. AB - Macrolide antibiotic roxithromycin was evaluated in terms of its genotoxic, cytotoxic and oxidative stress effects. For this purpose; 25, 50, 100 and 200 MUg/mL concentrations of roxithromycin were dissolved in dimethyl sulfoxide and treated to human peripheral blood lymphocytes for two different treatment periods (24 and 48 h). In chromosome aberration (CA) and micronucleus (MN) tests, roxithromycin did not show genotoxic effect. But it induced sister chromatid exchange (SCE) at the highest concentration (200 MUg/mL) for the 24-h treatment period and at all concentrations (except 25 MUg/mL) for the 48-h treatment period. Looking at cytotoxic effect of roxithromycin, statistically insignificant decreases on mitotic index and proliferation index were observed. Roxithromycin decreased nuclear division index (NDI) at highest two concentrations (100 and 200 MUg/mL) for the 24-h treatment period and at all concentrations (expect 25 MUg/mL) for the 48-h treatment period. Total oxidant values, total antioxidant values and oxidative stress index did not change with roxithromycin treatment. Eventually, roxithromycin did not have genotoxic and oxidative stress effects in human-cultured lymphocytes. PMID- 27998192 TI - Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules. AB - The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds. PMID- 27998193 TI - Update on dietary therapy for eosinophilic esophagitis in children and adults. AB - INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic inflammatory esophageal disease triggered predominantly, but not excusively, by food antigens. Elimination diet thus remains the only therapy targeting the cause of the disease. Importantly, EoE is a unique form of non-IgE mediated food allergy, largely dependant upon delayed, cell-mediated hypersensitivity. Areas covered: A comprehensive review of literature to summarize and update the most relevant advances on dietary therapy for pediatric and adult EoE patients is conducted. Expert commentary: None of the currently available food allergy tests adequately predict food triggers for EoE, especially in adults. Elemental diet (exclusive feeding with aminoacid-based formulas) and empiric six-food elimination diet, withdrawing cow's milk, wheat, egg, soy, nuts and fish/seafood for 6 weeks, have consistently shown the best cure rates. However, their high level of restriction and need for multiple endoscopies (top-down approach) have been a deterrent for patients and physicians. Less restrictive empiric schemes, like a four-food (animal milk, gluten-containing cereals, egg, legumes) or a two-food (animal milk and gluten-containing cereals) elimination diet have lately shown encouraging results. Therefore, a novel step-up strategy (2-4-6) may enhance patient uptake and promptly identify most responders to empiric diets with few food triggers, besides saving unnecessary dietary restrictions and endoscopic procedures. PMID- 27998194 TI - Use of monoamine oxidase inhibitors in chronic neurodegeneration. AB - INTRODUCTION: Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of 'selective' monoamine oxidase inhibitors. Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration. Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration. We propose that antidepressant therapy should be initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not achieved, only then they should be supplemented with a further antidepressant. PMID- 27998195 TI - Healthcare utilization and costs in patients with tuberous sclerosiscomplex related renal angiomyolipoma. AB - OBJECTIVE: To quantify healthcare utilization and costs in patients with tuberous sclerosis complex (TSC) and renal angiomyolipoma (AML) in a matched cohort of patients without TSC or AML. METHODS: Administrative data from the MarketScan Research Databases were used to select patients with TSC and renal AML during January 1, 2000-March 31, 2013 from the Commercial database and January 1, 2000 June 30, 2012 from the Medicaid database. Patients were required to have at least 30 days of follow-up from initiation into the study, and were followed until inpatient death, end of insurance coverage, or the end of study. Age, calendar year, and payer-matched controls that had no TSC and no AML were selected. All cause annualized healthcare utilization and costs were calculated by service category. RESULTS: A total of 218 patients under 18 years and 377 patients 18 years and older with TSC-renal AML were selected from the Commercial database, and matched to 654 and 1,131 controls, respectively. Thirty-eight patients under 18 years and 110 patients 18 years or older with TSC-renal AML were selected from the Medicaid database, and matched to 54 and 212 controls, respectively. Within the Commercial cohort, and across both age groups, TSC-renal AML patients utilized more healthcare services than their matched controls. Within the Medicaid cohort, in both age groups, utilization was higher in TSC-renal AML patients vs control patients for inpatient admissions, emergency room visits, physician office visits, and hospital-based outpatient visits. Across age groups and in both the Commercial and Medicaid cohorts, the annual average total costs were significantly higher in TSC-renal AML patients compared to control patients (p < 0.05 for all). Healthcare costs ranged from $29,240-$48,499 for TSC-renal AML patients and from $2,082-$10,864 for control patients. CONCLUSIONS: Compared to controls, TSC-renal AML patients incurred substantially higher annual healthcare utilization and costs. PMID- 27998196 TI - Recent trends in neuropathic pain patents. AB - INTRODUCTION: Neuropathic pain (NP) is one of the most important health problems faced nowadays. NP is a chronic disease that cannot be treated like other pain conditions because it is developed from a nerve injury that evolves into a permanent dysfunction of the central and/or peripheral nervous system. Therefore, it involves the participation of several systems and should be viewed as a multi factorial disease that needs a whole new pharmacological strategy in order to achieve the desired pain relief. Areas covered: The Espacenet site was used as the main source in order to perform the patent research for NP treatment. This review covers the patents with relevant approaches for NP treatment from 2014 until today. Expert opinion: Our patent research has shown that there is not a consensus approach to treat NP in any of its forms. In our opinion, the approach regarding NP needs to be like cancer's approach. As there are different types of cancer and different ways to treat them, the same needs to be done for NP. Currently, there are several promising targets, which corroborates that this is a wide-open research area. For these reasons, neuropathic pain is a therapeutic field full of potential for innovation. PMID- 27998197 TI - Saturated and trans fatty acids content in unpackaged traditional bakery products in Santa Fe city, Argentina: nutrition labeling relevance. AB - Studies have reported the relationship between the excessive intake of saturated fatty acids (SFA) and trans fatty acids (t-FA) and an increased risk of cardiovascular disease. Since 2006, the MERCOSUR countries require that the mandatory nutrition labeling should include information not only about the content of SFA but also about the content of t-FA. This does not apply to fractionated products at the point of retail, such as bakery products. This paper aimed to determine the total fat content and the fatty acid profile in unpackaged traditional bakery products (breads, biscuits and pastries) in Santa Fe, Argentina. Except for French bread, the contribution of t-FA and SFA to the total FA consumption from baked products was high. On the other hand, due to the high variability detected in the FA composition of bakery products between bakeries, it would be necessary to implement regulations making nutrition labeling mandatory in these products. PMID- 27998198 TI - Edema with hypoalbuminemia as a rare manifestation of chronic graft versus host disease after allogeneic hematopoietic cell transplant. PMID- 27998199 TI - Uniqueness of action monitoring in children with autism spectrum disorder: Response types and temporal aspects. AB - BACKGROUND: Action monitoring, the process for evaluating the appropriateness of one's own actions, is reported to be atypical in individuals with autism spectrum disorder (ASD). METHOD: We examined the characteristics of action monitoring in 11 children with ASD and 12 children with typical development (TD), analyzing stimulus-locked and response-locked event-related potential components (i.e., N2; error-related negativity, ERN; and error positivity, Pe) related to execution of a flanker task. RESULTS: We found a smaller N2 amplitude in children with ASD than in those with TD. Children with ASD also had a larger amplitude of ERN for partial error responses (electromyographic activity corresponding to the inappropriate hand side before response execution) than did children with TD. Additionally, the ERN amplitude for the partial error response was correlated with the Autistic Mannerisms of the Social Responsiveness Scale. There were no significant differences in Pe amplitudes between children with ASD and those with TD. CONCLUSION: The results suggest that action monitoring in children with ASD is significantly different both before and after response execution. We hypothesized that the detail-focused processing style of ASD reduces the demands of action monitoring before response execution; however, autistic mannerisms evoke excessive concern regarding trivial mistakes after response execution. PMID- 27998200 TI - Spinal Cord Injury Leads to Hyperoxidation and Nitrosylation of Skeletal Muscle Ryanodine Receptor-1 Associated with Upregulation of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4. AB - Spinal cord injury (SCI) results in marked atrophy and dysfunction of skeletal muscle. There are currently no effective treatments for SCI-induced muscle atrophy or the dysfunction of the remaining muscle tissue. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4 (Nox4) produces reactive oxygen species (ROS) in sarcoplasmic reticulum (SR) and has been identified as an important O2 sensor in skeletal muscle. Ryanodine receptors (RyRs) are calcium (Ca2+) channels that are responsible for Ca2+ release from SR. In skeletal muscle, type1 RyR (RyR1) is predominantly functional. RyR1 is regulated by multiple proteins, including calstabin1, which assures that they close appropriately once contraction has ceased. RyR1 function is also regulated by oxidation and redox dependent cysteine nitrosylation. Excessive oxidation/nitrosylation of RyR1 is associated with dissociation of calstabin1 and reduced muscle force generation. However, whether Nox4 levels in skeletal muscle are elevated or whether RyR1 is oxidized or nitrosylated after SCI has not been determined. In this study, we examined Nox4 expression, oxidation/nitrolysation status, and association of calstabin1 with RyR1 in skeletal muscle derived from rats that were subjected to T4 complete transection (SCI), and observed elevated expression of Nox4 messenger RNA and protein in muscle after SCI associated with enhanced binding of Nox4 to RyR1, increased oxidation and nitrosylation of RyR1, and dissociation of calstabin1 from RyR1 in SCI rat muscle. Our data suggest that RyR1 dysfunction resulting from excessive oxidation/nitrosylation may contribute to reduced specific force after SCI and suggest that Nox4 may be the source of ROS responsible for increased oxidation and nitrosylation of RyR1. PMID- 27998201 TI - Cathepsin B and L inhibitors: a patent review (2010 - present). AB - INTRODUCTION: Cathepsins play an important role in protein degradation and processing. Aberrant cathepsin B or L is closely associated with many serious diseases such as cancer, osteoporosis and autoimmune disorders. Therefore, development of potent and selective cathepsin B and L inhibitors has aroused much attention in recent years. Although several classes of cathepsin inhibitors are presently available, there are still some problems to solve, such as broad spectrum inhibition to protease, specially cysteine proteases, which lead to unpredictable side effects in clinical trials. Therefore, it is very necessary to discovery new scaffolds and new application of cathepsin B and L inhibitors for developing therapeutic agents for treating diseases mediated by cathepsin B or L. Areas covered: This updated review summarizes new patents on cathepsin B and L inhibitors from 2010 to present. Expert opinion: The review gives the latest development in the area of inhibitors of cathepsin B and L, which have been considered key therapeutic targets for the development of drugs treating related diseases. This review puts emphasis on the discovery of novel small molecule inhibitors of cathepsin B and L, as well as their new application as new therapeutic agents. PMID- 27998202 TI - Second cord blood transplantation and interferon-alpha maintenance therapy for relapsed Ph+ acute lymphoblastic leukemia with the T315I mutation. PMID- 27998203 TI - Comment to a BMJ Editorial. PMID- 27998204 TI - Construction and comparison of yeast whole-cell biosensors regulated by two RAD54 promoters capable of detecting genotoxic compounds. AB - Two yeast enhanced green fluorescence protein (yEGFP) yeast reporter vectors, pR1558-yEGFP and pR406-yEGFP, which are regulated by two RAD54 promoters containing 406-bp and 1558-bp DNA sequences, respectively, were constructed using molecular biological techniques and transformed into yeast for the screening of genotoxins. The constructed biosensors were named W303-1A/R1558-yEGFP and W303 1A/R406-yEGFP. To quantify biosensor performance, both transformed yeast cells were exposed to multiple doses of genotoxins including methylmethane sulfonate (MMS; a DNA alkylating agent), 4-nitroquinoline-N-oxide (4-NQO; a DNA cleavage agent), 5-fluorouracil (5-Fu; an inhibitor of polymerases and topoisomerases) and colchicine and canavanine (affecting other biochemical activities). The yeast bioassay performance was analyzed using fluorescence-activated cell sorting (FACS) and Multi-Mode Reader in a 96-well black microplate. The observed W303 1A/R1558-yEGFP dose-effect relationship was more obvious and the maximum inductions were 5.96-fold (MMS), 2.19-fold (4-NQO) and 2.71-fold (5-Fu); the corresponding values for W303-1A/R406-yEGFP were 2.53-, 1.50- and 1.91-fold, respectively. It is suggested that it is best to select the entire RAD54 promoter when constructing recombinant yeast cells for screening mutagens. PMID- 27998205 TI - 2015 ParaPan American Games: Autonomic Function, But Not Physical Activity, Is Associated with Vascular-Cognitive Impairment in Spinal Cord Injury. AB - Autonomic dysfunction and diminished capacity for physical exercise are commonly implicated in the 3- to 4-fold increased risk of cerebrovascular disease after spinal cord injury (SCI). We assessed cerebrovascular function (transcranial Doppler; neurovascular coupling [NVC], and cerebral pressure-flow regulation) in elite national level wheelchair rugby players (n = 23), normally active SCI individuals (n = 12), and able-bodied controls (n = 13). Cognitive (Stroop test) and autonomic function (postural change) also were evaluated. SCI individuals demonstrated reduced posterior cerebral blood flow, as well as impaired cerebrovascular and cognitive function. Autonomic dysfunction but not physical activity was related to impaired NVC and cerebral pressure-flow regulation after SCI. Routine upper-body exercise, as utilized by elite wheelchair rugby athletes, may not elicit beneficial cerebrovascular effects. On the other hand, autonomic dysfunction needs to be considered a key culprit in cerebrovascular diseases after SCI. PMID- 27998206 TI - Determination of a quantitative parameter to evaluate swimming technique based on the maximal tethered swimming test. AB - The aim of this study was to propose a new force parameter, associated with swimmers' technique and performance. Twelve swimmers performed five repetitions of 25 m sprint crawl and a tethered swimming test with maximal effort. The parameters calculated were: the mean swimming velocity for crawl sprint, the mean propulsive force of the tethered swimming test as well as an oscillation parameter calculated from force fluctuation. The oscillation parameter evaluates the force variation around the mean force during the tethered test as a measure of swimming technique. Two parameters showed significant correlations with swimming velocity: the mean force during the tethered swimming (r = 0.85) and the product of the mean force square root and the oscillation (r = 0.86). However, the intercept coefficient was significantly different from zero only for the mean force, suggesting that although the correlation coefficient of the parameters was similar, part of the mean velocity magnitude that was not associated with the mean force was associated with the product of the mean force square root and the oscillation. Thus, force fluctuation during tethered swimming can be used as a quantitative index of swimmers' technique. PMID- 27998207 TI - Application of the Rat Grimace Scale as a Marker of Supraspinal Pain Sensation after Cervical Spinal Cord Injury. AB - Experimental models of neuropathic pain (NP) typically rely on withdrawal responses to assess the presence of pain. Reflexive withdrawal responses to a stimulus are used to evaluate evoked pain and, as such, do not include the assessment of spontaneous NP nor evaluation of the affective and emotional consequences of pain in animal models. Additionally, withdrawal responses can be mediated by spinal cord reflexes and may not accurately indicate supraspinal pain sensation. This is especially true in models of traumatic spinal cord injury (SCI), wherein spastic syndrome, a motor disorder characterized by exaggeration of the stretch reflex that is secondary to hyperexcitability of the spinal reflex, can cause paroxysmal withdrawals not associated with NP sensation. Consequently, the aim of this study was to utilize an assessment of supraspinal pain sensation, the Rat Grimace Scale (RGS), to measure both spontaneous and evoked NP after a contusion SCI at cervical level 5 in adult male rats. Spontaneous and evoked pain were assessed using the RGS to score facial action units before and after the application of a stimulus, respectively. Rodents exhibited significantly higher RGS scores at week 5 post-injury as compared to baseline and laminectomy controls before the application of the stimulus, suggesting the presence of spontaneous NP. Additionally, there was a significant increase in RGS scores after the application of the acetone. These data suggest that the RGS can be used to assess spontaneous NP and determine the presence of evoked supraspinal pain sensation after experimental cervical SCI. PMID- 27998208 TI - Increasing Stem Cell Dose Promotes Posttransplant Immune Reconstitution. AB - Umbilical cord blood (UCB) transplantation can provide a successful therapeutic option for patients that have no suitable related donor. UCB transplantation is often limited by the relatively small hematopoietic stem cell (HSC) numbers in UCB especially for adult recipients. Early neutrophil and platelet engraftment correlates with the stem cell numbers in UCB transplant. Compared to other HSC sources, immune reconstitution following UCB transplant is slower and complicated by increased frequency of opportunistic infections. The effect of HSC numbers in UCB transplant on immune reconstitution was not thoroughly examined. Using immunocompromised mice transplanted with purified UCB CD34+ stem cells, we have demonstrated that increasing the numbers of CD34+ cells in the transplant promotes hematopoietic and immune reconstitution. At early stages posttransplant, high stem cell dose generated relatively more B cells, while lower dose generated more myeloid and T cells. Thus, the size of the stem cell graft appears to modulate the differentiation potential of infused stem cells. In addition, increasing stem cell dose in the transplant improved CD8+ T cell development and delayed late memory T cell skewing in expense of naive T cells highlighting the importance of HSC dose to maintain the pool of naive T cells able to develop strong immune responses. Transplantation of ex vivo expanded CD34+ cells did not promote, but rather delayed immune reconstitution suggesting the loss of primitive lymphoid precursor cells during ex vivo expansion. PMID- 27998209 TI - Immunodepletion and Hypoxia Preconditioning of Mouse Compact Bone Cells as a Novel Protocol to Isolate Highly Immunosuppressive Mesenchymal Stem Cells. AB - Compact bones (CB) are major reservoirs of mouse mesenchymal stem cells (mMSC). Here, we established a protocol to isolate MSC from CB and tested their immunosuppressive potential. Collagenase type II digestion of BM-flushed CB from C57B/6 mice was performed to liberate mMSC precursors from bone surfaces to establish nondepleted mMSC. CB cells were also immunodepleted based on the expression of CD45 (leukocytes) and TER119 (erythroid cells) to eliminate hematopoietic cells. CD45-TER119- CB cells were subsequently used to generate depleted mMSC. CB nondepleted and depleted mMSC progenitors were cultured under hypoxic conditions to establish primary mMSC cultures. CB depleted mMSC compared to nondepleted mMSC showed greater cell numbers at subculturing and had increased functional ability to differentiate into adipocytes and osteoblasts. CB depleted mMSC had high purity and expressed key mMSC markers (>85% Sca-1, CD29, CD90) with no mature hematopoietic contaminating cells (<5% CD45, CD11b) when subcultured to passage 5 (P5). Nondepleted mMSC cultures, however, were less pure and heterogenous with <72% Sca-1+, CD29+, and CD90+ cells at early passages (P1 or P2), along with high percentages of contaminating CD11b+ (35.6%) and CD45+ (39.2%) cells that persisted in culture long term. Depleted and nondepleted mMSC nevertheless exhibited similar potency to suppress total (CD3+), CD4+ and CD8+ T cell proliferation, in a dendritic cell allostimulatory one-way mixed lymphocyte reaction. CB depleted mMSC, pretreated with proinflammatory cytokines IFN-gamma, TNF-alpha, and IL-17A, showed superior suppression of CD8+ T cell, but not CD4+ T cell proliferation, relative to untreated-mMSC. In conclusion, CB depleted mMSC established under hypoxic conditions and treated with selective cytokines represent a novel source of potent immunosuppressive MSC. As these cells have enhanced immune modulatory function, they may represent a superior product for use in clinical allotransplantation. PMID- 27998210 TI - Metabolic Stress Induces Cognitive Disturbances and Inflammation in Aged Mice: Protective Role of Resveratrol. AB - Inflammation and oxidative stress (OS) are key points in age progression. Both processes impact negatively in cognition and in brain functions. Resveratrol (RV) has been postulated as a potent antioxidant natural compound, with rejuvenating properties. Inducing a metabolic stress by high-fat (HF) diet in aged C56/BL6 (24 months) led to cognitive disturbances compared with control age mated and with young mice. These changes were prevented by RV. Molecular determinations demonstrated a significant increase in some inflammatory parameters (TNF-alpha, Cxcl10, IL-1, IL-6, and Ccl3) in old mice, but slight changes in OS machinery. RV mainly induced the recovery of the metabolically stressed animals. The study of key markers involved in senescence and rejuvenation (mitochondrial biogenesis and Sirt1-AMPK-PGC1-alpha) demonstrated that RV is also able to modulate the changes in these cellular metabolic pathways. Moreover, changes of epigenetic marks (methylation and acetylation) that are depending on OS were demonstrated. On the whole, results showed the importance of integrative role of different cellular mechanisms in the deleterious effects of age in cognition and the beneficial role of RV. The work presented in this study showed a wide range of processes modified in old age and by metabolic stress, weighting the importance of each one and the role of RV as a possible strategy for fighting against. PMID- 27998212 TI - Skipping of the very-high-frequency structural particle de () in Chinese reading. AB - How do readers decide whether to skip or fixate a word? Angele and Rayner [2013. Processing the in the parafovea: Are articles skipped automatically? Journal of Experimental Psychology: Learning, Memory, and Cognition, 39, 649-662] showed that English readers base skipping decisions on the parafoveal information available, but not the sentential context. Due to the increased visual density of the language, Chinese readers may be able to process a parafoveal word and integrate it with the sentence context to a greater extent than English readers. Consequently, influences on skipping decisions in Chinese may differ from those in English. In a boundary paradigm experiment, participants read sentences containing a single-character target verb (e.g., meaning get) whose preview was manipulated in three conditions: identity preview; a preview consisting of the syntactically anomalous high-frequency structural particle de (), or a pseudocharacter preview. The results showed that Chinese readers were more likely to skip the target when the preview was de than in either of the other conditions, suggesting that de-skipping is triggered by the parafoveal preview of a highly frequent particle word rather than on the likelihood of the upcoming word given the sentential context.. PMID- 27998211 TI - Axial and appendicular body proportions for evaluation of limb and trunk asymmetry. AB - Background and purpose - When children with irregular body proportions or asymmetric limbs present, it may be unclear where the pathology is located. An improved understanding of the clinical ratio between upper extremity, lower extremity, and spine length may help elucidate whether there is disproportion between the trunk and limbs, and whether there is a reduction deficit of the shorter limb rather than hypertrophy of the longer limb. Patients and methods - We used the Brush Foundation study of child growth and development, which was a prospective, longitudinal study of healthy children between the 1930s and the 1950s, and we collected serial clinical measurements for 290 children at 3,326 visits. Children ranged from 2 to 20 years of age during the study period. Linear and quadratic regression were used to construct nomographs and 95% prediction intervals for anthropometric body proportions. Results - The maximum anterior superior iliac spine height to sitting height ratio occurred at 12.4 years in females and at 14.17 years in males. Overall, the ratio of arm length to sitting height was 0.76 (SD 0.06), the ratio of arm length to anterior superior iliac spine height was 0.76 (SD 0.03), and the ratio of anterior superior iliac spine height to sitting height was 0.98 (SD 0.13). When comparing ratios between arm length, anterior superior iliac spine height, and sitting height, the smallest variance between appendicular proportions was found in the arm length to anterior superior iliac spine height ratio. Interpretation - We recommend comparisons between total arm length and anterior superior iliac spine height to distinguish limb reduction deficits from hemi-hypertrophy, with sitting height being used only if combined upper and lower extremity discrepancy is noted. PMID- 27998214 TI - Fabrication of a Highly Aligned Neural Scaffold via a Table Top Stereolithography 3D Printing and Electrospinning. AB - Three-dimensional (3D) bioprinting is a rapidly emerging technique in the field of tissue engineering to fabricate extremely intricate and complex biomimetic scaffolds in the range of micrometers. Such customized 3D printed constructs can be used for the regeneration of complex tissues such as cartilage, vessels, and nerves. However, the 3D printing techniques often offer limited control over the resolution and compromised mechanical properties due to short selection of printable inks. To address these limitations, we combined stereolithography and electrospinning techniques to fabricate a novel 3D biomimetic neural scaffold with a tunable porous structure and embedded aligned fibers. By employing two different types of biofabrication methods, we successfully utilized both synthetic and natural materials with varying chemical composition as bioink to enhance biocompatibilities and mechanical properties of the scaffold. The resulting microfibers composed of polycaprolactone (PCL) polymer and PCL mixed with gelatin were embedded in 3D printed hydrogel scaffold. Our results showed that 3D printed scaffolds with electrospun fibers significantly improve neural stem cell adhesion when compared to those without the fibers. Furthermore, 3D scaffolds embedded with aligned fibers showed an enhancement in cell proliferation relative to bare control scaffolds. More importantly, confocal microscopy images illustrated that the scaffold with PCL/gelatin fibers greatly increased the average neurite length and directed neurite extension of primary cortical neurons along the fiber. The results of this study demonstrate the potential to create unique 3D neural tissue constructs by combining 3D bioprinting and electrospinning techniques. PMID- 27998213 TI - Mitochondrial Omi/HtrA2 Promotes Caspase Activation Through Cleavage of HAX-1 in Aging Heart. AB - Mitochondrial homeostasis is a key process involved in cellular destiny and organic function. When mitochondrial status is abnormal, it will become a "death motor." Impaired mitochondria lead to the release of cytochrome c, and then trigger mitochondria-induced caspase activation. Omi/HtrA2, a serine protease, locates in mitochondria and involves in mitochondrial homeostasis. Increased Omi/HtrA2 is observed in aging cardiac tissues, and whether this has effects on mitochondrial status has not been reported. In this study, natural Sprague-Dawley rats (22 months) were used. We detected markedly increased proteolytic activity of Omi/HtrA2 and obvious activation of caspase-9 and caspase-3 in their myocardium. Then, we constructed stably transfected mitochondrial Omi/HtrA2 cells, and decreased mitochondrial membrane potential was detected by JC-1 (a probe for mitochondria) and tetramethylrhodamine methyl ester (TMRM) dyeing and significant release of cytochrome c was observed after separation of mitochondrial fraction and cytosolic fraction. Furthermore, ucf-101 (a special inhibitor of Omi/HtrA2) and HAX-1 siRNA could ameliorate those phenomena above. In conclusion, excessive Omi/HtrA2 in mitochondria induced decreased mitochondrial membrane potential by its proteolytic activity, followed by cytochrome c released from mitochondria into cytosol where cytochrome c promoted caspase activation. Also, Omi/HtrA2-HAX-1 chain played a significant role in mitochondrial homeostasis. PMID- 27998215 TI - Psychoeducational Intervention to Reduce Fear of Cancer Recurrence in People at High Risk of Developing Another Primary Melanoma: Results of a Randomized Controlled Trial. AB - Purpose People with a history of melanoma commonly report a fear of cancer recurrence (FCR), yet psychologic support is not routinely offered as part of ongoing melanoma care. This randomized controlled trial examined the efficacy of a psychoeducational intervention to reduce FCR and improve psychologic adjustment in this patient group compared with usual care. Methods The intervention comprised a newly developed psychoeducational resource and three telephone-based psychotherapeutic sessions over a 1-month period timed in accordance with dermatologic appointments. Participants were randomly assigned to intervention (n = 80) or usual care (n = 84). Assessments were completed at baseline, 1 month, and 6 months after dermatologic appointments. Linear mixed models were used to examine differences between treatment and control groups for patient-reported outcomes, including FCR, anxiety, stress, depression, melanoma-related knowledge, health behaviors, satisfaction with melanoma care, unmet needs, and health related quality of life. Results At 6 months, the intervention group reported lower FCR severity, trigger, and distress scores than the control group in the baseline-adjusted models; the between-group mean difference was -1.9 for FCR severity (95% CI, -3.1 to -0.7; P = .002), -2.0 for FCR triggers (95% CI, -3.3 to -0.7; P = .003), and -0.7 for FCR distress (95% CI, -1.3 to -0.1; P = .03). The decrease in FCR severity (but not triggers or distress) remained statistically significant after adjustment for other covariates ( P = .04). At 6 months, the intervention group also reported lower stress (-1.6; 95% CI, -3.1 to -0.2; P = .03) and improved melanoma-related knowledge (1.7; 95% CI, 0.8 to 2.6; P < .001) compared with the control group. No differences were found between groups for other secondary outcomes. Conclusion This newly developed evidence-based psychoeducational intervention was effective in reducing FCR and stress and increasing melanoma-related knowledge in people at high risk for another melanoma. PMID- 27998217 TI - Should the American Society of Clinical Oncology Ask for Peer Review Before Publishing Its Advocacy Research? PMID- 27998216 TI - Biases in Recommendations for and Acceptance of Prostate Biopsy Significantly Affect Assessment of Prostate Cancer Risk Factors: Results From Two Large Randomized Clinical Trials. AB - Purpose To identify factors related to who undergoes a prostate biopsy in a screened population and to estimate the impact of biopsy verification on risk factor-prostate cancer associations. Patients and Methods Men who were screened regularly from the placebo arms of two large prostate cancer prevention trials (Prostate Cancer Prevention Trial [PCPT] and Selenium and Vitamin E Cancer Prevention Trial [SELECT]) were examined to define incident prostate cancer cohorts. Because PCPT had an end-of-study biopsy, prostate cancer cases were categorized by a preceding prostate-specific antigen/digital rectal examination prompt (yes/no) and noncases by biopsy-proven negative status (yes v no). We estimated the association of risk factors (age, ethnicity, family history, body mass index, medication use) with prostate cancer and quantified differences in risk associations across cohorts. Results Men 60 to 69 years of age, those with benign prostatic hyperplasia, and those with a family history of prostate cancer were more likely, and those with a higher body mass index (>= 25), diabetes, or a smoking history were less likely, to undergo biopsy, adjusting for age and longitudinal prostate-specific antigen and digital rectal examination. Medication use, education, and marital status also influenced who underwent biopsy. Some risk factor estimates for prostate cancer varied substantially across cohorts. Black ( v other ethnicities) had odds ratios (ORs) that varied from 1.20 for SELECT (community screening standards, epidemiologic-like cohort) to 1.83 for PCPT (end-of-study biopsy supplemented with imputed end points). Statin use in SELECT provided an OR of 0.65 and statin use in in PCPT provided an OR of 0.99, a relative difference of 34%. Conclusion Among screened men enrolled in prostate cancer prevention trials, differences in risk factor estimates for prostate cancer likely underestimate the magnitude of bias found in other cohorts with varying screening and biopsy recommendations and acceptance. Risk factors for prostate cancer derived from epidemiologic studies not only may be erroneous but may lead to misdirected research efforts. PMID- 27998218 TI - Prevalence and Risk Factors of Early Endocrine Disorders in Childhood Brain Tumor Survivors: A Nationwide, Multicenter Study. AB - Purpose To evaluate the prevalence of, and risk factors for, early endocrine disorders in childhood brain tumor survivors (CBTS). Patients and Methods This nationwide study cohort consisted of 718 CBTS who were diagnosed between 2002 and 2012, and who survived >= 2 years after diagnosis. Patients with craniopharyngeoma or a pituitary gland tumor were excluded. Results of all endocrine investigations, which were performed at diagnosis and during follow-up, were collected from patient charts. Multivariable logistic regression was used to study associations between demographic and tumor- and treatment-related variables and the prevalence of early endocrine disorders. Results After a median follow-up of 6.6 years, 178 CBTS (24.8%) were diagnosed with an endocrine disorder. A total of 159 CBTS (22.1%) presented with at least one endocrine disorder within the first 5 years after diagnosis. The most common endocrine disorders were growth hormone deficiency (12.5%), precocious puberty (12.2%), thyroid-stimulating hormone deficiency (9.2%), and thyroidal hypothyroidism (5.8%). The risk of hypothalamic-pituitary dysfunction (n = 138) was associated with radiotherapy (odds ratio [OR], 15.74; 95% CI, 8.72 to 28.42), younger age at diagnosis (OR, 1.09; 95% CI, 1.04 to 1.14), advanced follow-up time (OR, 1.10; 95% CI, 1.02 to 1.18), hydrocephalus at diagnosis (OR, 1.77; 95% CI, 1.09 to 2.88), and suprasellar (OR, 34.18; 95% CI, 14.74 to 79.29) and infratentorial (OR, 2.65; 95% CI, 1.48 to 4.74) tumor site. Conclusion The prevalence of early endocrine disorders among CBTS is high. The observation that 22.1% of CBTS developed at least one endocrine disorder within the first 5 years after diagnosis stresses the importance of early and regular assessment of endocrine function in CBTS who are at risk for endocrine damage. PMID- 27998219 TI - How to Integrate Elotuzumab and Daratumumab Into Therapy for Multiple Myeloma. AB - Purpose Treatment options and outcomes for patients with multiple myeloma have dramatically improved over the past decade with new agents and drug targets for patients at all stages of disease. Incorporation of newly approved monoclonal antibodies is a clinical challenge because the trials used to gain approval are relatively limited in scope and may be less helpful for patients treated in the United States. This article will review data on the use of elotuzumab and daratumumab and provide a foundation for their use in current clinical practice. Methods We performed a review of current published articles and abstract data from clinical trials as well as data on managing adverse events. Results Single agent activity was seen when using daratumumab in refractory myeloma, and trials for both elotuzumab and daratumumab have demonstrated significant activity when combined with proteasome inhibitors and immunomodulatory agents. Unique antibody related adverse events and challenges are reviewed and discussed. Conclusion These antibodies already have had and will continue to have a dramatic impact on myeloma treatment. Combination therapy likely represents the best approach for their use, and trials that evaluate optimal timing and duration of therapy are in progress as part of induction, salvage, and maintenance therapy. PMID- 27998220 TI - What Have We Got to Lose? PMID- 27998221 TI - Risk Factors for Prostate Cancer: Which Are Truly Predictive of Clinically Significant Disease? PMID- 27998222 TI - Federal 340B Program Payment Scheme for Drugs Designated As Orphan Products: Congressional Clarification Needed to Close the Government-Industry Revolving Door. PMID- 27998223 TI - Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. AB - Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 ug/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 ug/m2/d for the first 7 days, followed by 15 ug/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade >= 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications. PMID- 27998224 TI - Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53 Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months. AB - Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL?min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development. PMID- 27998225 TI - Reply to J.J. Tosoian et al. PMID- 27998226 TI - Picking the Right Patient for Human Epidermal Growth Factor Receptor 3-Targeted Therapy in Platinum-Resistant Ovarian Cancer. PMID- 27998228 TI - Reply to P.B. Bach. PMID- 27998227 TI - Optimizing the Use of Gene Expression Profiling in Early-Stage Breast Cancer. AB - Purpose Gene expression profiling assays are frequently used to guide adjuvant chemotherapy decisions in hormone receptor-positive, lymph node-negative breast cancer. We hypothesized that the clinical value of these new tools would be more fully realized when appropriately integrated with high-quality clinicopathologic data. Hence, we developed a model that uses routine pathologic parameters to estimate Oncotype DX recurrence score (ODX RS) and independently tested its ability to predict ODX RS in clinical samples. Patients and Methods We retrospectively reviewed ordered ODX RS and pathology reports from five institutions (n = 1,113) between 2006 and 2013. We used locally performed histopathologic markers (estrogen receptor, progesterone receptor, Ki-67, human epidermal growth factor receptor 2, and Elston grade) to develop models that predict RS-based risk categories. Ordering patterns at one site were evaluated under an integrated decision-making model incorporating clinical treatment guidelines, immunohistochemistry markers, and ODX. Final locked models were independently tested (n = 472). Results Distribution of RS was similar across sites and to reported clinical practice experience and stable over time. Histopathologic markers alone determined risk category with > 95% confidence in > 55% (616 of 1,113) of cases. Application of the integrated decision model to one site indicated that the frequency of testing would not have changed overall, although ordering patterns would have changed substantially with less testing of estimated clinical risk-high or clinical risk-low cases and more testing of clinical risk-intermediate cases. In the validation set, the model correctly predicted risk category in 52.5% (248 of 472). Conclusion The proposed model accurately predicts high- and low-risk RS categories (> 25 or <= 25) in a majority of cases. Integrating histopathologic and molecular information into the decision-making process allows refocusing the use of new molecular tools to cases with uncertain risk. PMID- 27998229 TI - Active Surveillance of Localized Prostate Cancer: Acknowledging Uncertainty. PMID- 27998230 TI - High-Cost, High-Value Oral Specialty Drugs: More Evidence on the Impact of Cost Sharing in Medicare Part D. PMID- 27998231 TI - Hypothalamic-Pituitary Axis Dysfunction in Survivors of Childhood CNS Tumors: Importance of Systematic Follow-Up and Early Endocrine Consultation. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. An 11-year-old male with a history of metastatic tectal plate low-grade glioma who was diagnosed at age 2.8 years transferred his care to the long-term follow-up clinic. He completed treatment with multiagent chemotherapy-carboplatin, vincristine, temozolomide, procarbazine, lomustine, and thioguanine-at age 4.5 years and did not require radiotherapy. At primary diagnosis, he presented with hydrocephalus that required ventriculoperitoneal shunt placement, with a subsequent shunt revision at age 6 years. Residual metastatic tumors in the third and fourth ventricles and in the suprasellar region remained stable for more than 5 years. The patient achieved normal developmental milestones and was not taking medications. He was offered screening for hypothalamic-pituitary axis (HPA) dysfunction because of his suprasellar lesion. His height was at the 25th percentile for chronological age, with decline from the 50th percentile noted during the preceding 18 months ( Fig 1 , point c). Pubertal stage was Tanner 4 for pubic hair and penile size, which contrasted with small testes (4.5 mL). Pubic hair and voice changes were noticed 2 to 3 years before this visit. Plasma testosterone level was consistent with Tanner 4 (255 ng/dL = 8.9 nmol/L). An x-ray of the left hand revealed a notably advanced bone age of 15.5 years. Plasma free T4, thyroid-stimulating hormone (TSH), and 8 am cortisol levels were normal. The patient was referred to the endocrinology clinic where he was diagnosed with growth hormone deficiency and was started on replacement therapy. He reached his final adult height of 144.1 cm at age 13.3 years ( Fig 1 , point d). PMID- 27998232 TI - Medicare D Subsidies and Racial Disparities in Persistence and Adherence With Hormonal Therapy. AB - Purpose To investigate the role of out-of-pocket cost supports through the Medicare Part D Low-Income Subsidy on disparities in breast cancer hormonal therapy persistence and adherence by race or ethnicity. Methods A nationwide cohort of women age >= 65 years with a breast cancer operation between 2006 and 2007 and at least one prescription filled for oral breast cancer hormonal therapy was identified from all Medicare D enrollees. The association of race or ethnicity with nonpersistence (90 consecutive days with no claims for a hormonal therapy prescription) and nonadherence (medication possession rate < 80%) was examined. Survival analyses were used to account for potential differences in age, comorbidity, or intensity of other treatments. Results Among the 25,111 women in the study sample, 77% of the Hispanic and 70% of the black women received a subsidy compared with 21% of the white women. By 2 years, 69% of black and 70% of Hispanic patients were persistent compared with 61% of white patients. In adjusted analyses, patients in all three unsubsidized race or ethnicity groups had greater discontinuation than subsidized groups (white patients: hazard ratio [HR], 1.83; 95% CI, 1.70 to 1.95; black patients: HR, 2.09; 95% CI, 1.73 to 2.51; Hispanic patients: HR, 3.00; 95% CI, 2.37 to 3.89). Racial or ethnic persistence disparities that were present for unsubsidized patients were not present or reversed among subsidized patients. All three subsidized race or ethnicity groups also had higher adherence than all three unsubsidized groups, although with the smallest difference occurring in black women. Conclusion Receipt of a prescription subsidy was associated with substantially improved persistence to breast cancer hormonal therapy among white, black, and Hispanic women and lack of racial or ethnic disparities in persistence. Given high subsidy enrollment among black and Hispanic women, policies targeted at low-income patients have the potential to also substantially reduce racial and ethnic disparities. PMID- 27998233 TI - Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems. AB - Purpose Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference. Patients and Methods Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement. Results A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and >= 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data. Conclusion Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC. PMID- 27998234 TI - Factors Associated With Tyrosine Kinase Inhibitor Initiation and Adherence Among Medicare Beneficiaries With Chronic Myeloid Leukemia. AB - Purpose There is substantial concern surrounding affordability of orally administered anticancer therapies, particularly for Medicare beneficiaries. We examined rates of initiation and adherence to tyrosine kinase inhibitors (TKIs) among Medicare beneficiaries with chronic myeloid leukemia (CML) with and without cost-sharing subsidies. We selected TKIs given their effectiveness and strong indication for use among patients diagnosed with CML. Patients and Methods Using SEER-Medicare data, we identified individuals diagnosed with CML from 2007 to 2011. We used Cox proportional hazards regression to assess time from diagnosis to TKI initiation. We used generalized estimating equations to examine treatment initiation within 180 days and TKI adherence among initiators. We defined adherence as at least 80% of days covered during the 6 months after TKI initiation. Results Among 393 individuals diagnosed with CML from 2007 to 2011, 68% initiated TKI treatment within 180 days after diagnosis. In multivariate analysis, individuals with cost-sharing subsidies, younger age, lower comorbidity, and later year of diagnosis were significantly more likely to initiate TKIs. Among TKI initiators, 61% were adherent; adherence was lower for individuals age 80 years or older versus 66 to 69 years. Conclusion Only 68% of Medicare beneficiaries with CML initiated TKI therapy within 6 months of diagnosis. Delayed initiation among individuals without cost-sharing subsidies suggests that out-of-pocket costs may be a barrier to timely initiation of therapy among individuals diagnosed with CML. PMID- 27998235 TI - Cancer-Related Fatigue in Patients With and Survivors of Hodgkin Lymphoma: The Impact on Treatment Outcome and Social Reintegration. AB - Purpose Cancer-related fatigue occurs frequently in patients with Hodgkin lymphoma (HL) and has a major impact on their quality of life. We hypothesized that severe fatigue (sFA) might have an impact on patients' treatment outcome and social reintegration. Methods Of 5,306 patients enrolled in the German Hodgkin Study Group's fifth generation of clinical trials in HL (HD13, HD14, and HD15; nonqualified and older [> 60 years] patients excluded), 4,529 provided data on health-related quality of life. We describe sFA (defined as a score >= 50 on the 0 to 100 scale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) before and up to 9 years after therapy and analyze its impact on treatment outcome and social reintegration. Results The proportion of patients reporting sFA was 37% at baseline and ranged from 20% to 24% during follow-up. Baseline sFA was associated with significantly impaired progression-free survival and a trend to impaired overall survival, which can be overcome in patients receiving highly effective HL therapies as applied in our fifth-generation trials. Our analysis revealed a significant negative association of sFA and employment in survivors: 5 years after therapy, 51% and 63% of female and male survivors, respectively, with sFA were working or in professional education, compared with 78% and 90% without sFA, respectively ( P < .001 adjusted for age, sex, stage, baseline employment status, and treatment outcome). sFA was also associated with financial problems and the number of visits to a general practitioner and medical specialists. Conclusion sFA is an important factor preventing survivors from social reintegration during follow-up. This observation underscores the need to address fatigue as a significant diagnosis when treating patients with and survivors of cancer. PMID- 27998237 TI - Paralympic Medicine: The Road to Rio. AB - Over the past 10 years, our team has attended numerous Paralympic games and International Paralympic Committee (IPC)-sanctioned events where we have accumulated the largest data set to date from elite athletes with spinal cord injury (SCI). This empirical evidence has allowed us to address critical questions related to health and athletic performance in these incredibly medically complex individuals. Namely, does autonomic function influence performance? Can we account for this with the present sport classification? How can we prevent the doping practice of self-inducing life-threatening episodes of hypertension to improve performance (termed "boosting")? How does extremely high participation in routine upper-body wheelchair exercise impact cardiovascular and cerebrovascular disease risk? Is it possible to improve the sport classification to level the playing field between athletes with and without autonomic dysfunction? Herein, we will narratively address these questions, and provide our perspective on future directions and recommendations moving forward. Our extensive clinical experience and comprehensive dataset suggest preserved autonomic function is critical for elite performance. We will explore how an easy to-execute test may be able to predict which individuals are most likely to develop autonomic dysfunctions that may negatively affect their health and performance. We also will evaluate the possibility that a level playing field may be even more difficult to establish than once thought, considering the importance of not only voluntary movement to performance, but also autonomic function. Finally, we also will discuss new changes in screening guidelines at Rio to assess the occurrence of boosting, which is a banned practice by the IPC. PMID- 27998238 TI - Response to Alexander and Courtois, "Blood Pressure during Sexual Activity after SCI Inaccurately Portrayed". PMID- 27998236 TI - Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer. AB - Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels. PMID- 27998239 TI - Bone Tissue Engineering Under Xenogeneic-Free Conditions in a Large Animal Model as a Basis for Early Clinical Applicability. AB - For decades, researchers have been developing a range of promising strategies in bone tissue engineering with the aim of producing a significant clinical benefit over existing therapies. However, a major problem concerns the traditional use of xenogeneic substances for the expansion of cells, which complicates direct clinical transfer. The study's aim was to establish a totally autologous sheep model as a basis for further preclinical studies and future clinical application. Ovine mesenchymal stromal cells (MSC) were cultivated in different concentrations (0%, 2%, 5%, 10%, and 25%) of either autologous serum (AS) or fetal calf serum (FCS). With an increase of serum concentration, enhanced metabolic activity and proliferation could be observed. There were minor differences between MSC cultivated in AS or FCS, comparing gene and protein expression of osteogenic and stem cell markers, morphology, and osteogenic differentiation. MSC implanted subcutaneously in the sheep model, together with a nanostructured bone substitute, either in stable block or moldable putty form, induced similar vascularization and remodeling of the bone substitute irrespective of cultivation of MSC in AS or FCS and osteogenic differentiation. The bone substitute in block form together with MSC proved particularly advantageous in the induction of ectopic bone formation compared to the cell-free control and putty form. It could be demonstrated that AS is suitable for replacement of FCS for cultivation of ovine MSC for bone tissue engineering purposes. Substantial progress has been made in the development of a strictly xenogeneic-free preclinical animal model to bring future clinical application of bone tissue engineering strategies within reach. PMID- 27998241 TI - Effects of 24 Weeks of Whole Body Vibration Versus Multicomponent Training on Muscle Strength and Body Composition in Postmenopausal Women: A Randomized Controlled Trial. AB - The purposes of this study were to analyze the impact of 24 weeks of vibratory and multicomponent training (MT) and to determine what type of training creates greater adaptations on body composition and isokinetic strength of the knee and ankle joints in postmenopausal women. Thirty-eight women (60.0 +/- 6.3 years) were randomly assigned to whole body vibration group (WBVG), multicomponent training group (MTG), or a control group. A significant decrease in total fat mass was observed in experimental groups. There were no changes in total lean mass and total bone mineral density in both groups. WBVG and MTG showed significant increases in isokinetic strength for knee extensors at 60 degrees /s and at 270 degrees /s. Regarding the ankle joint, there were significant increments in strength for plantar flexion at 60 degrees /s in WBVG and at 120 degrees /s in the two trainings groups. MTG showed a significant increase in strength for dorsiflexion at 60 degrees /s. With respect to eversion and inversion, WBVG and MTG improved strength at 60 degrees /s. Also, the WBVG showed increased strength in the ankle evertors at 120 degrees /s and both groups showed increased strength in the ankle invertors at 120 degrees /s. Twenty-four weeks of whole body vibration or MTs result in positive modifications in total fat mass. These trainings are effective in improving knee extension and stabilizer muscles of the ankle joint strength. PMID- 27998242 TI - The effect of isolating the paretic limb on weight-bearing distribution and EMG activity during squats in hemiplegic and healthy individuals. AB - BACKGROUND: Neural reorganization for movement therapy after a stroke is thought to be an important mechanism that facilitates motor recovery. However, there is a lack of evidence for the effectiveness of exercise programs in improving the lower limbs. OBJECTIVE: We investigated the immediate effect of isolating the paretic limb using different foot positions ((i) foot parallel; both feet parallel, (ii) foot asymmetry; paretic foot backward by 10 cm, and (iii) foot lifting; nonparetic foot lifting by normalization to 25% of knee height) on weight-bearing distribution and electromyography (EMG) of the thigh muscle during squats. METHODS: In total, 20 patients with hemiplegia and 16 healthy subjects randomly performed three squat conditions in which the knee joint was flexed to 30 degrees . Weight distribution was measured using the BioRescue system. Muscle activity was measured using a surface EMG system. RESULTS: Patients with hemiplegia exhibited significantly decreased weight bearing on the paretic foot at 0 degrees and 30 degrees knee flexion compared with the nondominant foot of a healthy subject. The muscle activity of the quadriceps was significantly lower in patients with hemiplegia compared to healthy subjects. Weight bearing and EMG activity of the quadriceps femoris on the paretic or nondominant side significantly increased during a knee flexion of 30 degrees with under the foot asymmetry and foot lifting positions compared with the parallel foot position. CONCLUSION: Isolating the paretic limb using the asymmetric foot positions and lifting of the foot during squats might help patients with hemiplegia to improve weight-bearing and achieve greater activation of the quadriceps muscle in the paretic limb. PMID- 27998240 TI - Superparamagnetic Iron Oxide Nanoparticles in Musculoskeletal Biology. AB - The use of platelet-rich plasma and mesenchymal stem cells has garnered much attention in orthopedic medicine, focusing on the biological aspects of cell function. However, shortly after systemic delivery, or even a local injection, few of the transplanted stem cells or platelets remain at the target site. Improvement in delivery, and the ability to track and monitor injected cells, would greatly improve clinical translation. Nanoparticles can effectively and quickly label most cells in vitro, and evidence to date suggests such labeling does not compromise the proliferation or differentiation of cells. A specific type of nanoparticle, the superparamagnetic iron oxide nanoparticle (SPION), is already employed as a magnetic resonance imaging (MRI) contrast agent. SPIONs can be coupled with cells or bioactive molecules (antibodies, proteins, drugs, etc.) to form an injectable complex for in vivo use. The biocompatibility, magnetic properties, small size, and custom-made surface coatings also enable SPIONs to be used for delivering and monitoring of small molecules, drugs, and cells, specifically to muscle, bone, or cartilage. Because SPIONs consist of cores made of iron oxides, targeting of SPIONs to a specific muscle, bone, or joint in the body can be enhanced with the help of applied gradient magnetic fields. Moreover, MRI has a high sensitivity to SPIONs and can be used for noninvasive determination of successful delivery and monitoring distribution in vivo. Gaps remain in understanding how the physical and chemical properties of nanomaterials affect biological systems. Nonetheless, SPIONs hold great promise for regenerative medicine, and progress is being made rapidly toward clinical applications in orthopedic medicine. PMID- 27998244 TI - Six open questions about the migration of engineered nano-objects from polymer based food-contact materials: a review. AB - The use of nanomaterials in food-contact applications has created enormous interest in recent years. The potential migration of engineered nano-objects (ENOs) from food-contact materials (FCMs) is one of the most important concerns regarding potential human exposure to ENOs and health risks. Current research focusing on FCMs has often reached inconsistency regarding migration of ENOs. The scope of this critical review is to give a concise overview of the most relevant aspects of the subject, and to identify and discuss the major open questions in relation to migration of ENOs from FCMs. This includes the very fundamental questions whether ENOs can migrate from FCMs at all and what the potential release mechanisms of ENOs could be. The inconsistency of findings from experimental studies is highlighted based on the example of silver nanoparticle migration from polymer-based FCMs. Challenges in the detection and characterisation of ENOs in migration studies and the suitability of the most frequently used analytical techniques are discussed. Further, this review questions the suitability of standard food simulants and migration test conditions for FCMs as well as of conventional mathematical migration models. Considerations regarding the risk for consumers associated with migrating ENOs from FCMs are discussed. PMID- 27998243 TI - Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect. AB - Reconstruction of large bone defects can be complicated by the presence of both infection and local antibiotic administration. This can be addressed through a two-stage reconstructive approach, called the Masquelet technique, that involves the generation of an induced osteogenic membrane over a temporary poly(methyl methacrylate) (PMMA) space maintainer, followed by definitive reconstruction after the induced membrane is formed. Given that infection and antibiotic delivery each have independent effects on local tissue response, the objective of this study is to evaluate the interaction between local clindamycin release and bacterial contamination with regards to infection prevention and the restoration of pro-osteogenic gene expression in the induced membrane. Porous PMMA space maintainers with or without clindamycin were implanted in an 8 mm rat femoral defect model with or without Staphylococcus aureus inoculation for 28 days in a full-factorial study design (four groups, n = 8/group). Culture results demonstrated that 8/8 animals in the inoculated/no antibiotic group were infected at 4 weeks, which was significantly reduced to 1/8 animals in the inoculated/antibiotic group. Quantitative polymerase chain reaction analysis demonstrated that clindamycin treatment restores inflammatory cytokine and growth factor expression to the same levels as the no inoculation/no antibiotic group, demonstrating that clindamycin can ameliorate the negative effects of bacterial inoculation and does not itself negatively impact the expression of important cytokines. Main effect analysis shows that bacterial inoculation and clindamycin treatment have independent and interacting effects on the gene expression profile of the induced membrane, further highlighting that antibiotics play an important role in the regeneration of infected defects apart from their antimicrobial properties. PMID- 27998246 TI - ? PMID- 27998247 TI - ? PMID- 27998245 TI - Generation, Endothelialization, and Microsurgical Suture Anastomosis of Strong 1 mm-Diameter Collagen Tubes. AB - Tissue-engineered vascular grafts that are based on reconstituted extracellular matrices have been plagued by weak mechanical strength that prevents handling or anastomosis to native vessels. In this study, we devise a method for making dense, suturable collagen tubular constructs of diameter <=1 mm for potential microsurgical applications, by dehydrating tubes of native rat tail type I collagen and crosslinking them with 20 mM genipin. Crosslinked dense collagen tubes with 1 mm inner diameter yielded ultimate tensile strength of 342 +/- 15 gF and burst pressure of 1313 +/- 156 mm Hg, comparable to the strength of a rat femoral artery, and supported endothelial cell adhesion and growth. End-to-end anastomosis of 0.5-mm-diameter tubes to explanted arteries displayed anastomotic strength of 82 +/- 21 gF, which is sufficient for surgical applications. In vivo implantation of cell-free tubes as interpositional grafts in the rat femoral circulation yielded stable anastomosis with blood flow for 20 min. Seeded dense collagen tubes represent a promising alternative to venous graft that can potentially be used to bridge between short artery stubs in replantation surgeries. PMID- 27998248 TI - ? PMID- 27998249 TI - ? PMID- 27998250 TI - ? PMID- 27998251 TI - ? PMID- 27998252 TI - ? PMID- 27998253 TI - ? PMID- 27998254 TI - ? PMID- 27998255 TI - ? PMID- 27998256 TI - ? PMID- 27998257 TI - The epidemiology of teaching and training General Practices in England. AB - There is no national picture of teaching and training practices or the communities they serve. We aimed to describe the association between general practices' engagement with education and their characteristics, locality and patients' health-status and satisfaction. This data linkage study of all English practices calculated odds ratios for teaching and training status and practice, locality and patient variables. Teaching and training practices are larger than practices which do neither (mean list size (SD) 7074 (3736), 10112 (4934), and 5327 (3368) respectively, p < 0.001 and have fewer patients per GP (1932 (951), 1838 (544), and 2117 (1585) respectively, p < 0.001). Their localities have a higher proportion of White British residents (77.99% (24.17), 81.66% (20.81), 73.07% (26.91), p < 0.001). Practices with more GPs (OR 1.21 (95%CI 1.18-1.20)), fewer male GPs (0.45 (0.36-0.55)) and a higher proportion of White British people in their locality (1.30 (1.06-1.60)) were more likely to teach. Practices in rural areas (1.68 (1.43-1.98)), with more GPs (1.22 (1.27-1.39)), more full time equivalent GPs (2.68 (1.64-4.40)), fewer male GPs (0.17 (0.13-0.22)) and a higher proportion of White British people in their locality (1.34 (1.02-1.75)) were more likely to train. Teaching and training practices had higher patient satisfaction (0.293 (0.190, 0.397) and (0.563 (0.442, 0.685)) respectively and quality and outcomes framework scores (0.507 (0.211, 0.804)) and (0.996 (0.650, 1.342)) respectively than those which did not. Educationally engaged practices are unrepresentative in serving less ethnically diverse and (for training practices) less urban environments. Investment is needed to increase the proportion of educational practices in diverse urban localities. PMID- 27998260 TI - Globalisation will make our societies more creative and prosperous but also more vulnerable [ [1] ]. PMID- 27998262 TI - Neurocognitive considerations when assessing Theory of Mind in Autism Spectrum Disorder. AB - Autism Spectrum Disorder (ASD) is characterised by poor social competence; and since Theory of Mind (ToM) is a building block for social-communicative skills and successful social integration, these skills are important to assess when preparing and monitoring educational and therapeutic plans. ToM is a complex skill requiring the ability to form mental concepts, to represent complex constructs verbally, to inhibit some mental states in favour of others, and to consider and compare multiple perspectives. It is critical to consider cognitive influences on the ability to develop and convey ToM skills to ensure that deficits in other cognitive domains do not falsely present as ToM deficits. This consideration is particularly vital in ASD populations with known difficulties not only in ToM, but also in intellectual functioning, language, and executive functioning. This article reviews the influence of intellectual ability, language, working memory, and inhibition skills on the presentation of ToM; with particular focus on ToM in ASD. We discuss practical suggestions based on clinical experience in neuropsychological practice and research in South Africa for the successful assessment of ToM ability. PMID- 27998261 TI - Suicidal ideation among suburban adolescents: The influence of school bullying and other mediating risk factors. AB - OBJECTIVE: Prior research has identified multiple factors that influence suicidal ideation (SI) among bullied youth. The effects of school bullying on SI cannot be considered in isolation. In this study, we examined the influence of school bullying on SI, through a constellation of risks, which include depressive and anxiety symptoms, family conflict, and alcohol, tobacco, and other drug (ATOD) use. We also provide recommendations for therapists working with bullied youth. METHOD: Our sample consisted of 488 adolescents (ages 10-18 years) from a northern New Jersey, United States suburban community. Students were recruited through the district's physical education and health classes. Students responded to multiple measures, which included family cohesion/conflict, ATOD use, mental health indicators, SI, and school bullying experiences. Following preliminary analyses, several logistic regression models were used to assess the direct influence of bullying on SI, as well as the unique effects of family conflict, depressive and anxiety symptoms, and substance use. In addition, a parallel multiple mediating model with the PROCESS macro in SPSS was used to further assess mediating effects. RESULTS: Logistic regression results indicated that school bullying increased the odds of SI among males and females and that when mediating variables were added to the model, bullying no longer had a significant influence on SI. Overall, these results display that for both males and females, school bullying was a significant contributor to SI. Results from the parallel multiple mediating model further illustrated the mediating effects that family conflict, depression, and ATOD use had between bullying and SI. Some variation was noted based on gender. CONCLUSION: This study draws attention to the multiple experiences associated with school bullying on SI, and how these results may differ by gender. The results of this study are particularly important for those working directly and indirectly with bullied youth. Therapists that engage bullied youth need to consider the multiple spheres of influence that may increase SI among male and female clients. To holistically and adequately assess SI among bullied youth, therapists must also consider how these mechanisms vary between gender groups. PMID- 27998263 TI - A 12 year chart review of childhood and adolescent onset psychosis at a Nigerian tertiary mental health facility. AB - OBJECTIVES: To review the profile of children and adolescents presenting with psychosis at a specialist mental health facility, and to compare childhood with adolescent onset psychosis. METHOD: Hospital records of all children and adolescents over a 12-year period (1999-2010) were perused to identify those falling under the categories of psychotic disorders. Clinical, socio-demographic, obstetric, and developmental information was extracted. RESULTS: Mean age of the children ((n = 409)) was 15.9 years, with 8.1% aged 12 years or less. The most frequent diagnoses were schizophrenia (40.8%), brief psychotic disorder (25.9%), mood disorder with psychosis (15.2%), and organic psychosis (7.8%). Family history of mental illness was reported among 22.5%. Subjects with childhood onset were significantly less likely than those with adolescent onset to have a family history of mental illness (p = 0.016), more likely to report maternal illness during pregnancy (p = 0.005) and illness during infancy (p = 0.010), and more likely to have a diagnosis of psychotic disorder due to another general medical condition (p < 0.001). CONCLUSION: The study suggests that antenatal/obstetric factors and illness during infancy may be particularly relevant in psychosis of childhood onset. Family history of mental illness may however be of greater relevance in adolescent onset psychosis. PMID- 27998264 TI - Factors associated with readmission in South African adolescents discharged from two inpatient psychosocial rehabilitation units. AB - OBJECTIVE: This study aimed to describe the socio-demographic and clinical factors associated with readmission in an adolescent population discharged from two inpatient psychosocial rehabilitation (PSR) units in Cape Town, South Africa. METHOD: Data were obtained from 97 consecutive patients discharged from two adolescent psychiatric PSR units over a period of one year. Patients were followed up for readmission to hospitals offering specialised psychiatric care in the Western Cape Province over a period of 18 months. RESULTS: 35 patients (36%) were readmitted during the study period. Multivariable analysis showed that previous admission increased readmission rate (Incidence Rate Ratio (IRR): 8.01, p < 0.001). Adolescents who were still schooling (IRR: 0.29, p < 0.001) or had a higher level of education (IRR: 0.45, p = 0.001) were less likely to be readmitted. No association was seen with type of diagnosis and readmission, although 51 adolescents (53%) were diagnosed on the schizophrenia spectrum of disorders. CONCLUSION: Study findings highlight the need for increased collaboration between the Departments of Health and Education. Furthermore, the study illustrates the need for specific post-discharge community follow-up for adolescents. Prospective research in this particular population group is needed to contribute to the literature on factors associated with readmission in South African adolescent patients. PMID- 27998265 TI - Participatory organizational intervention for improved use of assistive devices for patient transfer: study protocol for a single-blinded cluster randomized controlled trial. AB - BACKGROUND: Epidemiological studies have shown that patient transfer is a risk factor for back pain, back injuries and long term sickness absence, whereas consistent use of assistive devices during patient transfer seems to be protective. While classical ergonomic interventions based on education and training in lifting and transferring techniques have not proven to be effective in preventing back pain, participatory ergonomics, that is meant to engage and motivate the involved parties while at the same time making the intervention maximally relevant, may represent a better solution. However, these findings are largely based on uncontrolled studies and thus lack to be confirmed by studies with better study designs. In this article, we present the design of a study which aims to evaluate the effect and process of a participatory organizational intervention for improved use of assistive devices. METHODS: The study was performed as a cluster randomized controlled trial. We recruited 27 departments (clusters) from five hospitals in Denmark to participate in the study. Prior to randomization, interviews, observations and questionnaire answers (baseline questionnaire) were collected to gain knowledge of barriers and potential solutions for better use of assistive devices. In April 2016, the 27 departments were randomly allocated using a random numbers table to a participatory intervention (14 clusters, 324 healthcare workers) or a control group (13 clusters, 318 healthcare workers). The participatory intervention will consist of workshops with leaders and selected healthcare workers of each department. Workshop participants will be asked to discuss the identified barriers, develop solutions for increasing the use of assistive devices and implement them in their department. Use of assistive devices (using digital counters -, primary outcome, and accelerometers and questionnaire - secondary outcome), perceived physical exertion during patient transfer, pain intensity in the lower back, occurrence of work-related back injuries during patient transfer, organizational readiness to change, knowledge on how to perform proper patient transfer, social capital and work ability (secondary outcomes) were assessed at baseline and will also be assessed at 1 year follow-up. Process evaluation will be based on qualitative and quantitative data to assess the implementation, the change process, and the impact of context aspects. DISCUSSION: The study will evaluate the effect and process of a participatory intervention on improving the use of assistive devices for patient transfer among hospital healthcare workers. By using cluster randomization, as well as process- and effect evaluation based on objective measures we will contribute to the evidence base of a promising intervention approach. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02708550 ). March, 2016. PMID- 27998266 TI - Impact of pneumococcal conjugate vaccines on pneumococcal meningitis cases in France between 2001 and 2014: a time series analysis. AB - BACKGROUND: Pneumococcal meningitis (PM) is a major invasive pneumococcal disease. Two pneumococcal conjugate vaccines (PCVs) have been introduced in France: PCV7 was recommended in 2003 and replaced in 2010 by PCV13, which has six additional serotypes. The impact of introducing those vaccines on the evolution of PM case numbers and serotype distributions in France from 2001 to 2014 is assessed herein. METHODS: Data on 5166 Streptococcus pneumoniae strains isolated from cerebrospinal fluid between 2001 and 2014 in the 22 regions of France were obtained from the National Reference Center for Pneumococci. The effects of the different vaccination campaigns were estimated using time series analyses through autoregressive moving-average models with exogenous variables ("flu-like" syndromes incidence) and intervention functions. Intervention functions used 11 dummy variables representing each post vaccine epidemiological period. The evolution of serotype distributions was assessed for the entire population and the two most exposed age groups (<5 and > 64 years old). RESULTS: For the first time since PCV7 introduction in 2003, total PM cases decreased significantly after starting PCV13 use: -7.1 (95% CI, -10.85 to -3.35) cases per month during 2013-2014, and was confirmed in children < 5 years old (-3.5; 95% CI, -4.81 to 2.13) and adults > 64 years old (-2.0; 95% CI, -3.36 to -0.57). During 2012-2014, different non-vaccine serotypes emerged: 12F, 24F in the entire population and children, 6C in the elderly; serotypes 3 and 19F persisted in the entire population. CONCLUSIONS: Unlike other European countries, the total PM cases in France declined only after introduction of PCV13. This suggests that vaccine pressure alone does not explain pneumococcal epidemiological changes and that other factors could play a role. Serotype distribution had changed substantially compared to the pre-vaccine era, as in other European countries, but very differently from the US. A highly reactive surveillance system is thus necessary not only to monitor evolutions due to vaccine pressure and to verify the local serotypic appropriateness of new higher-valent pneumococcal vaccines, but also to recognise and prevent unexpected changes due to other internal or external factors. PMID- 27998267 TI - acdc - Automated Contamination Detection and Confidence estimation for single cell genome data. AB - BACKGROUND: A major obstacle in single-cell sequencing is sample contamination with foreign DNA. To guarantee clean genome assemblies and to prevent the introduction of contamination into public databases, considerable quality control efforts are put into post-sequencing analysis. Contamination screening generally relies on reference-based methods such as database alignment or marker gene search, which limits the set of detectable contaminants to organisms with closely related reference species. As genomic coverage in the tree of life is highly fragmented, there is an urgent need for a reference-free methodology for contaminant identification in sequence data. RESULTS: We present acdc, a tool specifically developed to aid the quality control process of genomic sequence data. By combining supervised and unsupervised methods, it reliably detects both known and de novo contaminants. First, 16S rRNA gene prediction and the inclusion of ultrafast exact alignment techniques allow sequence classification using existing knowledge from databases. Second, reference-free inspection is enabled by the use of state-of-the-art machine learning techniques that include fast, non linear dimensionality reduction of oligonucleotide signatures and subsequent clustering algorithms that automatically estimate the number of clusters. The latter also enables the removal of any contaminant, yielding a clean sample. Furthermore, given the data complexity and the ill-posedness of clustering, acdc employs bootstrapping techniques to provide statistically profound confidence values. Tested on a large number of samples from diverse sequencing projects, our software is able to quickly and accurately identify contamination. Results are displayed in an interactive user interface. Acdc can be run from the web as well as a dedicated command line application, which allows easy integration into large sequencing project analysis workflows. CONCLUSIONS: Acdc can reliably detect contamination in single-cell genome data. In addition to database-driven detection, it complements existing tools by its unsupervised techniques, which allow for the detection of de novo contaminants. Our contribution has the potential to drastically reduce the amount of resources put into these processes, particularly in the context of limited availability of reference species. As single-cell genome data continues to grow rapidly, acdc adds to the toolkit of crucial quality assurance tools. PMID- 27998269 TI - Increased T cell breadth and antibody response elicited in prime-boost regimen by viral vector encoded homologous SIV Gag/Env in outbred CD1 mice. AB - BACKGROUND: A major obstacle for the development of HIV vaccines is the virus' worldwide sequence diversity. Nevertheless, the presence of T cell epitopes within conserved regions of the virus' structural Gag protein and conserved structures in the envelope (env) sequence raises the possibility that cross reactive responses may be induced by vaccination. In this study, the aim was to investigate the importance of antigenic match on immunodominance and breadth of obtainable T cell responses. METHODS: Outbred CD1 mice were immunized with either heterologous (SIVmac239 and HIV-1 clade B consensus) or homologous (SIVmac239) gag sequences using adenovirus (Ad5) and MVA vectors. Env (SIVmac239) was co encoded in the vectors to study the induction of antibodies, which is a primary target of current HIV vaccine designs. All three vaccines were designed as virus encoded virus-like particle vaccines. Antibody responses were analysed by ELISA, avidity ELISA, and neutralization assay. T cell responses were determined by intracellular cytokine staining of splenocytes. RESULTS: The homologous Env/Gag prime-boost regimen induced higher Env binding antibodies, and induced stronger and broader Gag specific CD8+ T cell responses than the homologous Env/heterologous Gag prime-boost regimen. Homologous Env/heterologous Gag immunization resulted in selective boosting of Env specific CD8+ T cell responses and consequently a paradoxical decreased recognition of variant sequences including conserved elements of p24 Gag. CONCLUSIONS: These results contrast with related studies using Env or Gag as the sole antigen and suggest that prime-boost immunizations based on homologous SIVmac239 Gag inserts is an efficient component of genetic VLP vaccines-both for induction of potent antibody responses and cross reactive CD8+ T cell responses. PMID- 27998268 TI - Mapping the membrane proteome of anaerobic gut fungi identifies a wealth of carbohydrate binding proteins and transporters. AB - BACKGROUND: Engineered cell factories that convert biomass into value-added compounds are emerging as a timely alternative to petroleum-based industries. Although often overlooked, integral membrane proteins such as solute transporters are pivotal for engineering efficient microbial chassis. Anaerobic gut fungi, adapted to degrade raw plant biomass in the intestines of herbivores, are a potential source of valuable transporters for biotechnology, yet very little is known about the membrane constituents of these non-conventional organisms. Here, we mined the transcriptome of three recently isolated strains of anaerobic fungi to identify membrane proteins responsible for sensing and transporting biomass hydrolysates within a competitive and rather extreme environment. RESULTS: Using sequence analyses and homology, we identified membrane protein-coding sequences from assembled transcriptomes from three strains of anaerobic gut fungi: Neocallimastix californiae, Anaeromyces robustus, and Piromyces finnis. We identified nearly 2000 transporter components: about half of these are involved in the general secretory pathway and intracellular sorting of proteins; the rest are predicted to be small-solute transporters. Unexpectedly, we found a number of putative sugar binding proteins that are associated with prokaryotic uptake systems; and approximately 100 class C G-protein coupled receptors (GPCRs) with non-canonical putative sugar binding domains. CONCLUSIONS: We report the first comprehensive characterization of the membrane protein machinery of biotechnologically relevant anaerobic gut fungi. Apart from identifying conserved machinery for protein sorting and secretion, we identify a large number of putative solute transporters that are of interest for biotechnological applications. Notably, our data suggests that the fungi display a plethora of carbohydrate binding domains at their surface, perhaps as a means to sense and sequester some of the sugars that their biomass degrading, extracellular enzymes produce. PMID- 27998270 TI - PCR mediated recombination impacts the analysis of hepatitis B Virus covalently closed circular DNA. AB - BACKGROUND: The replication of HBV involves the production of covalently closed circular DNA (cccDNA) from the HBV genome through the repair of virion relaxed circular DNA (rcDNA) in the virion. As cccDNA is the transcription template for HBV genomes, it needs to be eliminated from hepatocytes if the eradication of chronic HBV infection is to be achieved. PCR quantitation of cccDNA copy number is the technique of choice for evaluating the efficiency of treatment regimens. The PCR target commonly used to identify cccDNA spans the gapped region of rcDNA and is considered to accurately distinguish between cccDNA and rcDNA. There is however, a potentially confounding issue in that PCR can generate larger targets from collections of small DNA fragments, a phenomenon known as PCR recombination. RESULTS: The impact of PCR recombination towards the amplification of this cccDNA specific target was explored by mixing three marked, yet overlapping HBV DNA fragments. Thirteen of sixteen possible recombinants were identified by sequencing with frequencies ranging from 0.6 to 23%. To confirm this finding in vivo, HBV positive sera were treated with DNase I and submitted to quantitative real-time PCR. Under these conditions, it was possible to amplify the cccDNA specific segment without difficulty. As the virion contains uniquely rcDNA, amplification of the cccDNA target resulted from PCR recombination. CONCLUSIONS: PCR quantitation of cccDNA may be more difficult than hitherto thought. Current detection protocols need to be investigated so as to help in the management of chronic HBV infection. PMID- 27998271 TI - Whole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplification. AB - BACKGROUND: Translating genomic technologies into healthcare applications for the malaria parasite Plasmodium falciparum has been limited by the technical and logistical difficulties of obtaining high quality clinical samples from the field. Sampling by dried blood spot (DBS) finger-pricks can be performed safely and efficiently with minimal resource and storage requirements compared with venous blood (VB). Here, the use of selective whole genome amplification (sWGA) to sequence the P. falciparum genome from clinical DBS samples was evaluated, and the results compared with current methods that use leucodepleted VB. METHODS: Parasite DNA with high (>95%) human DNA contamination was selectively amplified by Phi29 polymerase using short oligonucleotide probes of 8-12 mers as primers. These primers were selected on the basis of their differential frequency of binding the desired (P. falciparum DNA) and contaminating (human) genomes. RESULTS: Using sWGA method, clinical samples from 156 malaria patients, including 120 paired samples for head-to-head comparison of DBS and leucodepleted VB were sequenced. Greater than 18-fold enrichment of P. falciparum DNA was achieved from DBS extracts. The parasitaemia threshold to achieve >5* coverage for 50% of the genome was 0.03% (40 parasites per 200 white blood cells). Over 99% SNP concordance between VB and DBS samples was achieved after excluding missing calls. CONCLUSION: The sWGA methods described here provide a reliable and scalable way of generating P. falciparum genome sequence data from DBS samples. The current data indicate that it will be possible to get good quality sequence on most if not all drug resistance loci from the majority of symptomatic malaria patients. This technique overcomes a major limiting factor in P. falciparum genome sequencing from field samples, and paves the way for large-scale epidemiological applications. PMID- 27998272 TI - Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. AB - Earlier this year, we described an analysis of mitochondrial DNA (mtDNA) variants in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients and healthy controls. We reported that there was no significant association of haplogroups or singe nucleotide polymorphisms (SNPs) with disease status. Nevertheless, a commentary about our paper appeared (Finsterer and Zarrouk Mahjoub. J Transl Med14:182, 2016) that criticized the association of mtDNA haplogroups with ME/CFS, a conclusion that was absent from our paper. The aforementioned commentary also demanded experiments that were outside of the scope of our study, ones that we had suggested as follow-up studies. Because they failed to consult a published and cited report describing the cohorts we studied, the authors also cast aspersions on the method of selection of cases for inclusion. We reiterate that we observed statistically significant association of mtDNA variants with particular symptoms and their severity, though we observed no association with disease status. PMID- 27998273 TI - LncRNA MALAT1 promotes development of mantle cell lymphoma by associating with EZH2. AB - BACKGROUND: Mantle cell lymphoma (MCL) is considered an aggressive subtype of non Hodgkin's lymphoma with variable treatment responses. There is an urgent need to identify novel markers with prognostic and therapeutic value for MCL. Long non coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a lncRNA located at pathognomonic translocation site of t (11; 14) of MCL. MALAT1 is known to be overexpressed in solid tumors and hematologic malignancies. However, the pathological role and clinical relevance of MALAT1 in MCL are not completely understood. METHODS: We quantified MALAT1 in MCL samples (40) and CD19+ B cells by quantitative real time polymerase chain reaction (qRT-PCR) and correlated levels with clinical outcome. We silenced MALAT1 in MCL cell lines and analyzed cells in tumorigenic assays and formation of transcription complexes. RESULTS: We found that the expression of MALAT1 was elevated in human MCL tumors and cell lines as compared to normal controls, and the elevated levels of MALAT1 correlated with higher MCL international prognostic index (MIPI) and reduced overall survival. MCL with knockdown of MALAT1 showed impaired cell proliferation, facilitated apoptosis and produced fewer clonogenic foci. The increased expression of p21 and p27 upon MALAT1 knockdown was regulated by enhancer of zeste homolog 2 (EZH2). Moreover, decreased phosphorylation of EZH2 at T350 attenuated the binding to MALAT1. CONCLUSIONS: Our findings illuminate the oncogenic role of MALAT1, which may serve as a novel biomarker and as a therapeutic target in MCL. PMID- 27998274 TI - Repressed SIRT1/PGC-1alpha pathway and mitochondrial disintegration in iPSC derived RPE disease model of age-related macular degeneration. AB - BACKGROUND: Study of age related macular degeneration (AMD) has been hampered by lack of human models that represent the complexity of the disease. Here we have developed a human in vitro disease model of AMD to investigate the underlying AMD disease mechanisms. METHODS: Generation of iPSCs from retinal pigment epithelium (RPE) of AMD donors, age-matched normal donors, skin fibroblasts of a dry AMD patient, and differentiation of iPSCs into RPE (AMD RPE-iPSC-RPE, normal RPE-iPSC RPE and AMD Skin-iPSC-RPE, respectively). Immunostaining, cell viability assay and reactive oxygen species (ROS) production under oxidative stress conditions, electron microscopy (EM) imaging, ATP production and glycogen concentration assays, quantitative real time PCR, western blot, karyotyping. RESULTS: The AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE present functional impairment and exhibit distinct disease phenotypes compared to RPE-iPSC-RPE generated from normal donors (Normal RPE-iPSC-RPE). The AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE show increased susceptibility to oxidative stress and produced higher levels of reactive oxygen species (ROS) under stress in accordance with recent reports. The susceptibility to oxidative stress-induced cell death in AMD RPE-iPSC-RPE and Skin-iPSC-RPE was consistent with inability of the AMD RPE-iPSC-RPE and Skin-iPSC-RPE to increase SOD2 expression under oxidative stress. Phenotypic analysis revealed disintegrated mitochondria, accumulation of autophagosomes and lipid droplets in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE. Mitochondrial activity was significantly lower in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE compared to normal cells and glycogen concentration was significantly increased in the diseased cells. Furthermore, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), a regulator of mitochondrial biogenesis and function was repressed, and lower expression levels of NAD-dependent deacetylase sirtuin1 (SIRT1) were found in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE as compared to normal RPE-iPSC RPE. CONCLUSIONS: Our studies suggest SIRT1/PGC-1alpha as underlying pathways contributing to AMD pathophysiology, and open new avenues for development of targeted drugs for treatment of this devastating neurodegenerative disease of the visual system. PMID- 27998275 TI - Efficient randomization of biological networks while preserving functional characterization of individual nodes. AB - BACKGROUND: Networks are popular and powerful tools to describe and model biological processes. Many computational methods have been developed to infer biological networks from literature, high-throughput experiments, and combinations of both. Additionally, a wide range of tools has been developed to map experimental data onto reference biological networks, in order to extract meaningful modules. Many of these methods assess results' significance against null distributions of randomized networks. However, these standard unconstrained randomizations do not preserve the functional characterization of the nodes in the reference networks (i.e. their degrees and connection signs), hence including potential biases in the assessment. RESULTS: Building on our previous work about rewiring bipartite networks, we propose a method for rewiring any type of unweighted networks. In particular we formally demonstrate that the problem of rewiring a signed and directed network preserving its functional connectivity (F rewiring) reduces to the problem of rewiring two induced bipartite networks. Additionally, we reformulate the lower bound to the iterations' number of the switching-algorithm to make it suitable for the F-rewiring of networks of any size. Finally, we present BiRewire3, an open-source Bioconductor package enabling the F-rewiring of any type of unweighted network. We illustrate its application to a case study about the identification of modules from gene expression data mapped on protein interaction networks, and a second one focused on building logic models from more complex signed-directed reference signaling networks and phosphoproteomic data. CONCLUSIONS: BiRewire3 it is freely available at https://www.bioconductor.org/packages/BiRewire/ , and it should have a broad application as it allows an efficient and analytically derived statistical assessment of results from any network biology tool. PMID- 27998276 TI - Methodological challenges to multivariate syndromic surveillance: a case study using Swiss animal health data. AB - BACKGROUND: In an era of ubiquitous electronic collection of animal health data, multivariate surveillance systems (which concurrently monitor several data streams) should have a greater probability of detecting disease events than univariate systems. However, despite their limitations, univariate aberration detection algorithms are used in most active syndromic surveillance (SyS) systems because of their ease of application and interpretation. On the other hand, a stochastic modelling-based approach to multivariate surveillance offers more flexibility, allowing for the retention of historical outbreaks, for overdispersion and for non-stationarity. While such methods are not new, they are yet to be applied to animal health surveillance data. We applied an example of such stochastic model, Held and colleagues' two-component model, to two multivariate animal health datasets from Switzerland. RESULTS: In our first application, multivariate time series of the number of laboratories test requests were derived from Swiss animal diagnostic laboratories. We compare the performance of the two-component model to parallel monitoring using an improved Farrington algorithm and found both methods yield a satisfactorily low false alarm rate. However, the calibration test of the two-component model on the one step ahead predictions proved satisfactory, making such an approach suitable for outbreak prediction. In our second application, the two-component model was applied to the multivariate time series of the number of cattle abortions and the number of test requests for bovine viral diarrhea (a disease that often results in abortions). We found that there is a two days lagged effect from the number of abortions to the number of test requests. We further compared the joint modelling and univariate modelling of the number of laboratory test requests time series. The joint modelling approach showed evidence of superiority in terms of forecasting abilities. CONCLUSIONS: Stochastic modelling approaches offer the potential to address more realistic surveillance scenarios through, for example, the inclusion of times series specific parameters, or of covariates known to have an impact on syndrome counts. Nevertheless, many methodological challenges to multivariate surveillance of animal SyS data still remain. Deciding on the amount of corroboration among data streams that is required to escalate into an alert is not a trivial task given the sparse data on the events under consideration (e.g. disease outbreaks). PMID- 27998277 TI - The PULSAR primary care protocol: a stepped-wedge cluster randomized controlled trial to test a training intervention for general practitioners in recovery oriented practice to optimize personal recovery in adult patients. AB - BACKGROUND: General practitioners (GPs) in Australia play a central role in the delivery of mental health care. This article describes the PULSAR (Principles Unite Local Services Assisting Recovery) Primary Care protocol, a novel mixed methods evaluation of a training intervention for GPs in recovery-oriented practice. The aim of the intervention is to optimize personal recovery in patients consulting study GPs for mental health issues. METHODS: The intervention mixed methods design involves a stepped-wedge cluster randomized controlled trial testing the outcomes of training in recovery-oriented practice, together with an embedded qualitative study to identify the contextual enablers and challenges to implementing recovery-oriented practice. The project is conducted in Victoria, Australia between 2013 and 2017. Eighteen general practices and community health centers are randomly allocated to one of two steps (nine months apart) to start an intervention comprising GP training in the delivery of recovery-oriented practice. Data collection consists of cross-sectional surveys collected from patients of participating GPs at baseline, and again at the end of Steps 1 and 2. The primary outcome is improvement in personal recovery using responses to the Questionnaire about the Process of Recovery. Secondary outcomes are improvements in patient-rated measures of personal recovery and wellbeing, and of the recovery oriented practice they have received, using the INSPIRE questionnaire, the Warwick-Edinburgh Mental Well-being Scale, and the Kessler Psychological Distress Scale. Participant data will be analyzed in the group that the cluster was assigned to at each study time point. Another per-protocol dataset will contain all data time-stamped according to the date of intervention received at each cluster site. Qualitative interviews with GPs and patients at three and nine months post-training will investigate experiences and challenges related to implementing recovery-oriented practice in primary care. DISCUSSION: Recovery oriented practice is gaining increasing prominence in mental health service delivery and the outcomes of such an approach within the primary care sector for the first time will be evaluated in this project. If findings are positive, the intervention has the potential to extend recovery-oriented practice to GPs throughout the community. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ( ACTRN12614001312639 ). Registered: 8 August 2014. PMID- 27998278 TI - Janus kinase inhibition suppresses PKC-induced cytokine release without affecting HIV-1 latency reversal ex vivo. AB - BACKGROUND: Despite the durable viral suppression afforded by antiretroviral therapy, HIV-1 eradication will require strategies to target latently infected cells that persist in infected individuals. Protein kinase C (PKC) activation is a promising strategy to reactivate latent proviruses and allow for subsequent recognition and clearance of infected cells by the immune system. Ingenol derivatives are PKC agonists that induce latency reversal but also lead to T cell activation and the release of pro-inflammatory cytokines, which would be undesirable in vivo. In this work, we sought to identify compounds that would suppress pro-inflammatory cytokine production in the context of PKC activation. DESIGN AND METHODS: We performed an in vitro screen to identify compounds that could dampen pro-inflammatory cytokine release associated with T cell activation, using IL-6 as a model cytokine. We then tested the ability of the most promising screening hit, the FDA-approved Janus Kinase (JAK) inhibitor ruxolitinib, to diminish release of multiple cytokines and its effect on latency reversal using cells from HIV-1-positive, aviremic participants. RESULTS: We demonstrate that co administration of ruxolitinib with ingenol-3,20-dibenzoate significantly reduces pro-inflammatory cytokine release without impairing latency reversal ex vivo. CONCLUSION: The combination of ingenol compounds and JAK inhibition represents a novel strategy for HIV-1 eradication. PMID- 27998279 TI - Mycobacterium tuberculosis infections in cynomolgus monkey transplant recipients and institution of a screening program for the prevention and control of tuberculosis. AB - BACKGROUND: Tuberculosis is a major health concern in not only humans, but also in non-human primates. In this paper, we report recent cases of Mycobacterium tuberculosis in cynomolgus monkeys from Cambodia used in transplantation research in a Korean facility and describe a program instituted to prevent and control subsequent infections. CASE PRESENTATION: All monkeys were antibody negative for tuberculosis during quarantine; however, suspected tuberculosis gross lesions were observed in two cynomolgus monkeys who underwent allograft kidney transplantation. Lung tissue from one monkey was found to be weakly positive by PCR for detection of M. tuberculosis. After PCR confirmation of tuberculosis, we decided to sacrifice the remaining animals and instituted a program for preventing subsequent infections. During necropsy of the remaining monkeys, two additional suspected tuberculosis cases were observed. A total of four monkeys with nodular lesions in the respiratory tract, suspected to be tuberculosis, demonstrated no clinical signs. Acid-fast bacilli were identified on slides from the lung or liver in all four monkeys. Two of four monkeys tested PCR positive. We decided that new monkeys entering from Cambodia should undergo a single gastric aspiration PCR and tuberculin skin testing (TST) every 2 weeks until four consecutive negatives to detect latent tuberculosis are obtained before starting experiments. Monkeys should then undergo a chest X-ray monthly and TST every 6 months. CONCLUSIONS: Detection of latent tuberculosis by an effective preventive screening program before starting experiments is an essential process to reduce the risk of reactivation of tuberculosis, especially in studies using immunosuppressive drugs. It also serves to protect the health of captive non human primates, their caretakers and researchers. PMID- 27998280 TI - Misleading early blood volume changes obtained using ferumoxytol-based magnetic resonance imaging perfusion in high grade glial neoplasms treated with bevacizumab. AB - BACKGROUND: Neovascularization, a distinguishing trait of high-grade glioma, is a target for anti-angiogenic treatment with bevacizumab (BEV). This study sought to use ferumoxytol-based dynamic susceptibility contrast magnetic resonance imaging (MRI) to clarify perfusion and relative blood volume (rCBV) changes in glioma treated with BEV and to determine potential impact on clinical management. METHODS: 16 high grade glioma patients who received BEV following post chemoradiation radiographic or clinical progression were included. Ferumoxytol based MRI perfusion measurements were taken before and after BEV. Lesions were defined at each timepoint by gadolinium-based contrast agent (GBCA)-enhancing area. Lesion volume and rCBV were compared pre and post-BEV in the lesion and rCBV "hot spot" (mean of the highest rCBV in a 1.08 cm2 area in the enhancing volume), as well as hypoperfused and hyperperfused subvolumes within the GBCA enhancing lesion. RESULTS: GBCA-enhancing lesion volumes decreased 39% (P = 0.01) after BEV. Mean rCBV in post-BEV GBCA-enhancing area did not decrease significantly (P = 0.227) but significantly decreased in the hot spot (P = 0.046). Mean and hot spot rCBV decreased (P = 0.039 and 0.007) when post-BEV rCBV was calculated over the pre-BEV GBCA-enhancing area. Hypoperfused pixel count increased from 24% to 38 (P = 0.007) and hyperperfused decreased from 39 to 28% (P = 0.017). Mean rCBV decreased in 7/16 (44%) patients from >1.75 to <1.75, the cutoff for pseudoprogression diagnosis. CONCLUSIONS: Decreased perfusion after BEV significantly alters rCBV measurements when using ferumoxytol. BEV treatment response hinders efforts to differentiate true progression from pseudoprogression using blood volume measurements in malignant glioma, potentially impacting patient diagnosis and management. PMID- 27998281 TI - Interpretation of gene associations with risk of acute respiratory distress syndrome: P values, Bayes factors, positive predictive values, and need for replication. PMID- 27998282 TI - Does therapeutic hypothermia during extracorporeal cardiopulmonary resuscitation preserve cardiac function? AB - BACKGROUND: Extracorporeal cardiopulmonary resuscitation (E-CPR) is increasingly used as a rescue method in the management of cardiac arrest and provides the opportunity to rapidly induce therapeutic hypothermia. The survival after a cardiac arrest is related to post-arrest cardiac function, and the application of therapeutic hypothermia post-arrest is hypothesized to improve cardiac outcome. The present animal study compares normothermic and hypothermic E-CPR considering resuscitation success, post-arrest left ventricular function and magnitude of myocardial injury. METHODS: After a 15-min untreated ventricular fibrillation, the pigs (n = 20) were randomized to either normothermic (38 degrees C) or hypothermic (32-33 degrees C) E-CPR. Defibrillation terminated ventricular fibrillation after 5 min of E-CPR, and extracorporeal support continued for 2 h, followed by warming, weaning and a stabilization period. Magnetic resonance imaging and left ventricle pressure measurements were used to assess left ventricular function pre-arrest and 5 h post-arrest. Myocardial injury was estimated by serum concentrations of cardiac TroponinT and Aspartate transaminase (ASAT). RESULTS: E-CPR resuscitated all animals and the hypothermic strategy induced therapeutic hypothermia within minutes without impairment of the resuscitation success rate. All animals suffered a severe global systolic left ventricular dysfunction post-arrest with 50-70% reductions in stroke volume, ejection fraction, wall thickening, strain and mitral annular plane systolic excursion. Serum concentrations of cardiac TroponinT and ASAT increased considerably post-arrest. No significant differences were found between the two groups. CONCLUSIONS: Two-hour therapeutic hypothermia during E-CPR offers an equal resuscitation success rate, but does not preserve the post-arrest cardiac function nor reduce the magnitude of myocardial injury, compared to normothermic E-CPR. Trial registration FOTS 4611/13 registered 25 October 2012. PMID- 27998283 TI - A genotypic method for determining HIV-2 coreceptor usage enables epidemiological studies and clinical decision support. AB - BACKGROUND: CCR5-coreceptor antagonists can be used for treating HIV-2 infected individuals. Before initiating treatment with coreceptor antagonists, viral coreceptor usage should be determined to ensure that the virus can use only the CCR5 coreceptor (R5) and cannot evade the drug by using the CXCR4 coreceptor (X4 capable). However, until now, no online tool for the genotypic identification of HIV-2 coreceptor usage had been available. Furthermore, there is a lack of knowledge on the determinants of HIV-2 coreceptor usage. Therefore, we developed a data-driven web service for the prediction of HIV-2 coreceptor usage from the V3 loop of the HIV-2 glycoprotein and used the tool to identify novel discriminatory features of X4-capable variants. RESULTS: Using 10 runs of tenfold cross validation, we selected a linear support vector machine (SVM) as the model for geno2pheno[coreceptor-hiv2], because it outperformed the other SVMs with an area under the ROC curve (AUC) of 0.95. We found that SVMs were highly accurate in identifying HIV-2 coreceptor usage, attaining sensitivities of 73.5% and specificities of 96% during tenfold nested cross validation. The predictive performance of SVMs was not significantly different (p value 0.37) from an existing rules-based approach. Moreover, geno2pheno[coreceptor-hiv2] achieved a predictive accuracy of 100% and outperformed the existing approach on an independent data set containing nine new isolates with corresponding phenotypic measurements of coreceptor usage. geno2pheno[coreceptor-hiv2] could not only reproduce the established markers of CXCR4-usage, but also revealed novel markers: the substitutions 27K, 15G, and 8S were significantly predictive of CXCR4 usage. Furthermore, SVMs trained on the amino-acid sequences of the V1 and V2 loops were also quite accurate in predicting coreceptor usage (AUCs of 0.84 and 0.65, respectively). CONCLUSIONS: In this study, we developed geno2pheno[coreceptor-hiv2], the first online tool for the prediction of HIV-2 coreceptor usage from the V3 loop. Using our method, we identified novel amino acid markers of X4-capable variants in the V3 loop and found that HIV-2 coreceptor usage is also influenced by the V1/V2 region. The tool can aid clinicians in deciding whether coreceptor antagonists such as maraviroc are a treatment option and enables epidemiological studies investigating HIV-2 coreceptor usage. geno2pheno[coreceptor-hiv2] is freely available at http://coreceptor-hiv2.geno2pheno.org . PMID- 27998284 TI - The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis. AB - BACKGROUND: Altered tumor cell metabolism is an emerging hallmark of cancer; however, the precise role for glucose in tumor initiation is not known. GLUT1 (SLC2A1) is expressed in breast cancer cells and is likely responsible for avid glucose uptake observed in established tumors. We have shown that GLUT1 was necessary for xenograft tumor formation from primary mammary cells transformed with the polyomavirus middle-T antigen but that it was not necessary for growth after tumors had formed in vivo, suggesting a differential requirement for glucose depending on the stage of tumorigenesis. METHODS: To determine whether GLUT1 is required early during mammary tumorigenesis, we crossed MMTV-NIC mice, which express activated HER2/NEU/ERBB2 and Cre recombinase, to Slc2a1 Flox/Flox (GLUT1Flox/Flox) mice to generate NIC-GLUT1+/+, NIC-GLUT1Flox/+, and NIC GLUT1Flox/Flox mice. In addition, we evaluated effects of glucose restriction or GLUT1 inhibition on transformation in MCF10A-ERBB2 breast epithelial cells in three-dimensional culture. Finally, we utilized global gene expression profiling data of primary human breast tumors to determine the relationship between SLC2A1 and stage of tumorigenesis. RESULTS: All of the NIC-GLUT1+/+ mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1Flox/Flox mouse and 1 NIC-GLUT1Flox/+ mouse developed mammary tumors, even after 18 months. Mammary gland development was not disrupted in NIC mice lacking GLUT1; however, epithelial content of mature glands was reduced compared to NIC-GLUT1Flox/+ mice. In MCF10A-ERBB2 cells, glucose restriction or GLUT1 inhibition blocked transformation induced by activated ERBB2 through reduced cell proliferation. In human breast cancers, SLC2A1 was higher in ductal carcinoma in situ compared to the normal breast, but lower in invasive versus in situ lesions, suggesting the requirement for GLUT1 decreases as tumors progress. CONCLUSIONS: This study demonstrates a strict requirement for GLUT1 in the early stages of mammary tumorigenesis in vitro and in vivo. While metabolic adaptation has emerged as a hallmark of cancer, our data indicate that early tumor cells rely heavily on glucose and highlight the potential for glucose restriction as a breast cancer preventive strategy. PMID- 27998286 TI - Ultrasensitive single-genome sequencing: accurate, targeted, next generation sequencing of HIV-1 RNA. AB - BACKGROUND: Although next generation sequencing (NGS) offers the potential for studying virus populations in unprecedented depth, PCR error, amplification bias and recombination during library construction have limited its use to population sequencing and measurements of unlinked allele frequencies. Here we report a method, termed ultrasensitive Single-Genome Sequencing (uSGS), for NGS library construction and analysis that eliminates PCR errors and recombinants, and generates single-genome sequences of the same quality as the "gold-standard" of HIV-1 single-genome sequencing assay but with more than 100-fold greater depth. RESULTS: Primer ID tagged cDNA was synthesized from mixtures of cloned BH10 wild type and mutant HIV-1 transcripts containing ten drug resistance mutations. First, the resultant cDNA was divided and NGS libraries were generated in parallel using two methods: uSGS and a method applying long PCR primers to attach the NGS adaptors (LP-PCR-1). Second, cDNA was divided and NGS libraries were generated in parallel comparing 3 methods: uSGS and 2 methods adapted from more recent reports using variations of the long PCR primers to attach the adaptors (LP-PCR-2 and LP-PCR-3). Consistently, the uSGS method amplified a greater proportion of cDNAs, averaging 30% compared to 13% for LP-PCR-1, 21% for LP-PCR-2 and 14% for LP-PCR-3. Most importantly, when the uSGS sequences were binned according to their primer IDs, 94% of the bins did not contain PCR recombinant sequences versus only 55, 75 and 65% for LP-PCR-1, 2 and 3, respectively. Finally, when uSGS was applied to plasma samples from HIV-1 infected donors, both frequent and rare variants were detected in each sample and neighbor-joining trees revealed clusters of genomes driven by the linkage of these mutations, showing the lack of PCR recombinants in the datasets. CONCLUSIONS: The uSGS assay can be used for accurate detection of rare variants and for identifying linkage of rare alleles associated with HIV-1 drug resistance. In addition, the method allows accurate in-depth analyses of the complex genetic relationships of viral populations in vivo. PMID- 27998287 TI - The thalamic mGluR1-PLCbeta4 pathway is critical in sleep architecture. AB - The transition from wakefulness to a nonrapid eye movement (NREM) sleep state at the onset of sleep involves a transition from low-voltage, high-frequency irregular electroencephalography (EEG) waveforms to large-amplitude, low frequency EEG waveforms accompanying synchronized oscillatory activity in the thalamocortical circuit. The thalamocortical circuit consists of reciprocal connections between the thalamus and cortex. The cortex sends strong excitatory feedback to the thalamus, however the function of which is unclear. In this study, we investigated the role of the thalamic metabotropic glutamate receptor 1 (mGluR1)-phospholipase C beta4 (PLCbeta4) pathway in sleep control in PLCbeta4 deficient (PLCbeta4-/-) mice. The thalamic mGluR1-PLCbeta4 pathway contains synapses that receive corticothalamic inputs. In PLCbeta4-/- mice, the transition from wakefulness to the NREM sleep state was stimulated, and the NREM sleep state was stabilized, which resulted in increased NREM sleep. The power density of delta (delta) waves increased in parallel with the increased NREM sleep. These sleep phenotypes in PLCbeta4-/- mice were consistent in TC-restricted PLCbeta4 knockdown mice. Moreover, in vitro intrathalamic oscillations were greatly enhanced in the PLCbeta4-/- slices. The results of our study showed that thalamic mGluR1-PLCbeta4 pathway was critical in controlling sleep architecture. PMID- 27998285 TI - Are T cells the only HIV-1 reservoir? AB - Current antiretroviral therapies have improved the duration and quality of life of people living with HIV-1. However, viral reservoirs impede complete eradication of the virus. Although there are many strategies to eliminate infectious virus, the most actively pursued are latency reversing agents in conjunction with immune modulation. This strategy, known as "shock and kill", has been tested primarily against the most widely recognized HIV-1 latent reservoir found in resting memory CD4+ T cells. This is in part because of the dearth of conclusive evidence about the existence of non-T cell reservoirs. Studies of non T cell reservoirs have been difficult to interpret because of technical and biological issues that have hampered a better understanding. This review considers the current knowledge of non-T cell reservoirs, the challenges encountered in a better understanding of these populations, and their implications for HIV-1 cure research. PMID- 27998288 TI - Factors influencing job preferences of health workers providing obstetric care: results from discrete choice experiments in Malawi, Mozambique and Tanzania. AB - BACKGROUND: Task shifting from established health professionals to mid-level providers (MLPs) (professionals who undergo shorter training in specific procedures) is one key strategy for reducing maternal and neonatal deaths. This has resulted in a growth in cadre types providing obstetric care in low and middle-income countries. Little is known about the relative importance of the different factors in determining motivation and retention amongst these cadres. METHODS: This paper presents findings from large sample (1972 respondents) discrete choice experiments to examine the employment preferences of obstetric care workers across three east African countries. RESULTS: The strongest predictors of job choice were access to continuing professional development and the presence of functioning human resources management (transparent, accountable and consistent systems for staff support, supervision and appraisal). Consistent with similar works we find pay and allowances significantly positively related to utility, but financial rewards are not as fundamental a factor underlying employment preferences as many may have previously believed. Location (urban vs rural) had the smallest average effect on utility for job choice in all three countries. CONCLUSIONS: These findings are important in the context where efforts to address the human resources crisis have focused primarily on increasing salaries and incentives, as well as providing allowances to work in rural areas. PMID- 27998289 TI - Effects of low doses of esmolol on cardiac and vascular function in experimental septic shock. AB - BACKGROUND: Administration of a selective beta1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction. Certain experimental data also indicate that esmolol exerts systemic anti-inflammatory and beneficial effects on vascular tone. Thus, the present study aimed to determine whether a non-chronotropic dose of esmolol maintains its protective cardiovascular and anti-inflammatory effects in experimental septic shock. METHODS: Four hours after cecal ligation and puncture (CLP), Wistar male rats were randomly allocated to the following groups (n = 8): CLP, CLP + E-1 (esmolol: 1 mg.kg-1.h-1), CLP + E-5 (esmolol: 5 mg.kg-1.h-1), CLP + E-18 (esmolol: 18 mg.kg-1.h-1). An additional eight rats underwent sham operation. All rats received a continuous infusion of saline, analgesic and antibiotics 4 hours after the surgery. Assessment at 18 hours included in vivo cardiac function assessed by echocardiography and ex vivo vasoreactivity assessed by myography. Circulating cytokine levels (IL-6 and IL-10) were measured by ELISA. Cardiac and vascular protein expressions of p-NF-kappaB, IkappaBalpha, iNOS, p-AKT/AKT and p-eNOS/eNOS were assessed by western blotting. RESULTS: CLP induced tachycardia, hypotension, cardiac output reduction, hyperlactatemia and vascular hypo-responsiveness to vasopressors. Compared to CLP animals, heart rate was unchanged in CLP + E-1 and CLP + E-5 but was reduced in CLP + E-18. Stroke volume, cardiac output, mean arterial pressure and lactatemia were improved in CLP + E-1 and CLP + E-5, while vascular responsiveness to phenylephrine was only improved in CLP + E-5 and CLP + E-18. Plasma IL-6 levels were decreased in all esmolol groups. p-NF-kappaB was decreased in both cardiac and vascular tissues in CLP + E-5 and CLP + E-18. CONCLUSION: In experimental septic shock, low doses of esmolol still improved cardiac function and vasoreactivity. These benefits appear to be associated with a modulation of inflammatory pathways. PMID- 27998291 TI - Skeleton-based cerebrovascular quantitative analysis. AB - BACKGROUND: Cerebrovascular disease is the most common cause of death worldwide, with millions of deaths annually. Interest is increasing toward understanding the geometric factors that influence cerebrovascular diseases, such as stroke. Cerebrovascular shape analyses are essential for the diagnosis and pathological identification of these conditions. The current study aimed to provide a stable and consistent methodology for quantitative Circle of Willis (CoW) analysis and to identify geometric changes in this structure. METHOD: An entire pipeline was designed with emphasis on automating each step. The stochastic segmentation was improved and volumetric data were obtained. The L1 medial axis method was applied to vessel volumetric data, which yielded a discrete skeleton dataset. A B-spline curve was used to fit the skeleton, and geometric values were proposed for a one dimensional skeleton and radius. The calculations used to derive these values were illustrated in detail. RESULT: In one example(No. 47 in the open dataset) all values for different branches of CoW were calculated. The anterior communicating artery(ACo) was the shortest vessel, with a length of 2.6mm. The range of the curvature of all vessels was (0.3, 0.9) +/- (0.1, 1.4). The range of the torsion was (-12.4,0.8) +/- (0, 48.7). The mean radius value range was (3.1, 1.5) +/- (0.1, 0.7) mm, and the mean angle value range was (2.2, 2.9) +/- (0, 0.2) mm. In addition to the torsion variance values in a few vessels, the variance values of all vessel characteristics remained near 1. The distribution of the radii of symmetrical posterior cerebral artery(PCA) and angle values of the symmetrical posterior communicating arteries(PCo) demonstrated a certain correlation between the corresponding values of symmetrical vessels on the CoW. CONCLUSION: The data verified the stability of our methodology. Our method was appropriate for the analysis of large medical image datasets derived from the automated pipeline for populations. This method was applicable to other tubular organs, such as the large intestine and bile duct. PMID- 27998290 TI - Methylome evolution in plants. AB - Despite major progress in dissecting the molecular pathways that control DNA methylation patterns in plants, little is known about the mechanisms that shape plant methylomes over evolutionary time. Drawing on recent intra- and interspecific epigenomic studies, we show that methylome evolution over long timescales is largely a byproduct of genomic changes. By contrast, methylome evolution over short timescales appears to be driven mainly by spontaneous epimutational events. We argue that novel methods based on analyses of the methylation site frequency spectrum (mSFS) of natural populations can provide deeper insights into the evolutionary forces that act at each timescale. PMID- 27998292 TI - Genetic evidence that the Makira region in northeastern Madagascar is a hotspot of malaria transmission. AB - BACKGROUND: Encouraging advances in the control of Plasmodium falciparum malaria have been observed across much of Africa in the past decade. However, regions of high relative prevalence and transmission that remain unaddressed or unrecognized provide a threat to this progress. Difficulties in identifying such localized hotspots include inadequate surveillance, especially in remote regions, and the cost and labor needed to produce direct estimates of transmission. Genetic data can provide a much-needed alternative to such empirical estimates, as the pattern of genetic variation within malaria parasite populations is indicative of the level of local transmission. Here, genetic data were used to provide the first empirical estimates of P. falciparum malaria prevalence and transmission dynamics for the rural, remote Makira region of northeastern Madagascar. METHODS: Longitudinal surveys of a cohort of 698 total individuals (both sexes, 0-74 years of age) were performed in two communities bordering the Makira Natural Park protected area. Rapid diagnostic tests, with confirmation by molecular methods, were used to estimate P. falciparum prevalence at three seasonal time points separated by 4-month intervals. Genomic loci in a panel of polymorphic, putatively neutral markers were genotyped for 94 P. falciparum infections and used to characterize genetic parameters known to correlate with transmission levels. RESULTS: Overall, 27.8% of individuals tested positive for P. falciparum over the 10-month course of the study, a rate approximately sevenfold higher than the countrywide average for Madagascar. Among those P. falciparum infections, a high level of genotypic diversity and a high frequency of polygenomic infections (68.1%) were observed, providing a pattern consistent with high and stable transmission. CONCLUSIONS: Prevalence and genetic diversity data indicate that the Makira region is a hotspot of P. falciparum transmission in Madagascar. This suggests that the area should be highlighted for future interventions and that additional areas of high transmission may be present in ecologically similar regions nearby. PMID- 27998293 TI - Global pharmaceutical regulation: the challenge of integration for developing states. AB - BACKGROUND: This paper has set out to map the state of pharmaceutical regulation in the developing world through the construction of cross-national indices drawing from World Health Organization data. The last two decades have been characterized by deep changes for the pharmaceutical sector, including the complete transformation of intellectual property systems at the behest of the World Trade Organization and the consolidation of global active ingredient suppliers in China and India. Although the rules for ownership of medicine have been set and globally implemented, we know surprisingly little about how the standards for market entrance and regulation of pharmaceutical products have changed at the national level. How standardized are national pharmaceutical market systems? Do we find homogeneity or variation across the developing world? Are their patterns for understanding why some countries have moved closer to one global norm for pharmaceutical regulation and others have developed hybrid models for oversight of this sector? Access to medicine is a core tool in public health. This paper gauges the levels of standards in public and private generics markets for developing countries building on national-level pharmaceutical market surveys for 78 countries to offer three indicators of market oversight: State Regulatory Infrastructure, Monitoring the Private Market and Public Quality Control. Identifying the different variables that affect a state's institutional capacity and current standard level offers new insights to the state of pharmaceuticals in the developing world. It is notable that there are very few (none at the time of this paper) studies that map out the new global terrain for pharmaceutical regulation in the post-TRIPS context. RESULTS: This paper uses item response theory to develop original indicators of pharmaceutical regulation. We find remarkable resistance to the implementation of global pharmaceutical norms for quality standards in developing states and in regulatory infrastructure. Human capacity across many developing countries remains limited. Most notably, variation among states is stark. Countries that have been leaders in establishing global norms do not appear to have influenced their neighbors in establishing regional patterns. Finally, in contrast to traditional theories of international norms diffusion, global standard-setters such as the United States or European Union appear to have surprisingly little influence on standard setting across our survey. CONCLUSIONS: Our research has implications for the framing of technical support on public health initiatives aimed at strengthening local public institutions in medicine and offers a new methodological approach for analyzing drug regulation systems in developing countries. PMID- 27998294 TI - Directed differentiation of human iPSC into insulin producing cells is improved by induced expression of PDX1 and NKX6.1 factors in IPC progenitors. AB - BACKGROUND: Induced pluripotent stem cells (iPSC) possess an enormous potential as both, scientific and therapeutic tools. Their application in the regenerative medicine provides new treatment opportunities for numerous diseases, including type 1 diabetes. In this work we aimed to derive insulin producing cells (IPC) from iPS cells established in defined conditions. METHODS: We optimized iPSC generation protocol and created pluripotent cell lines with stably integrated PDX1 and NKX6.1 transgenes under the transcriptional control of doxycycline inducible promoter. These cells were differentiated using small chemical molecules and recombinant Activin A in the sequential process through the definitive endoderm, pancreatic progenitor cells and insulin producing cells. Efficiency of the procedure was assessed by quantitative gene expression measurements, immunocytochemical stainings and functional assays for insulin secretion. RESULTS: Generated cells displayed molecular markers characteristic for respective steps of the differentiation. The obtained IPC secreted insulin and produced C-peptide with significantly higher hormone release level in case of the combined expression of PDX1 and NKX6.1 induced at the last stage of the differentiation. CONCLUSIONS: Efficiency of differentiation of iPSC to IPC can be increased by concurrent expression of PDX1 and NKX6.1 during progenitor cells maturation. Protocols established in our study allow for iPSC generation and derivation of IPC in chemically defined conditions free from animal-derived components, which is of the utmost importance in the light of their prospective applications in the field of regenerative medicine. PMID- 27998295 TI - A transdiagnostic sleep and circadian treatment to improve severe mental illness outcomes in a community setting: study protocol for a randomized controlled trial. AB - BACKGROUND: Severe mental illness (SMI) is common, chronic and difficult to treat. Sleep and circadian dysfunctions are prominent correlates of SMI, yet have been minimally studied in ways that reflect the complexity of the sleep problems experienced. Prior treatment studies have been disorder-focused-they have treated a specific sleep problem in a specific diagnostic group. However, real life sleep and circadianproblems are not so neatly categorized, particularly in SMI where features of insomnia overlap with hypersomnia, delayed sleep phase and irregular sleep-wake schedules. Accordingly, the aim of this studyprotocol is to test the hypothesis that a Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) will improve functional impairment, disorder-focused symptoms and sleep and circadian functioning. Participants across DSM diagnoses and across common sleep and circadian problems are eligible. The elements of TranS-C are efficacious across SMI in research settings with research-based providers. The next step is to test TranS-C in a community setting. Accordingly, this study is being conducted within Alameda County Behavioral Health Care Services (ACBHCS), the Community Mental Health Centre (CMHC) for Alameda County. METHODS/DESIGN: 120 adults diagnosed with SMI and sleep and circadian dysfunction within ACBHCS will be randomly allocated to TranS-C (n = 60) or 6-months of Usual Care followed by Delayed Treatment with TranS-C (UC-DT; n = 60). TranS-C is modularized and delivered across eight to twelve 50-minute, weekly, individual sessions. All participants will be assessed before and immediately following treatment and again 6 months later. Primary analysis will examine whether TranS-C significantly improves functional impairment, disorder-specific symptoms and sleep and circadian functioning, relative to UC-DT. Exploratory analysis will examine whether improvements in sleep and circadian functioning predict reduction in functional impairment and disorder-specific symptoms, and whether the intervention effects are mediated by improved sleep and circadian functioning and moderated by previously reported risk factors (demographics, symptom severity, medications, psychiatric and medical comorbidity). DISCUSSION: This trial tests an important and understudied mechanism-dysregulated sleep and circadian rhythms in SMI, a novel transdiagnostic treatment approach, in a community setting so as to contribute to the goal of bridging the gap between research and practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02469233 . Registered on 9 June 2015. PMID- 27998296 TI - Primary hyperparathyroidism in pregnancy treated with cinacalcet: a case report and review of the literature. AB - BACKGROUND: The efficacy and safety of various modes of medical treatment for primary hyperparathyroidism in pregnancy are largely unknown. CASE PRESENTATION: We report the case of a 34-year-old white woman with primary hyperparathyroidism symptomatic for nephrolithiasis. Her serum calcium was 3.15 mmol/l and parathyroid hormone was 109.0 ng/L. Neck imaging found no pathological parathyroid tissue. Cinacalcet and cholecalciferol were started. She became pregnant 17 months later. The calcimimetic was stopped. During pregnancy, she was admitted for hydration administered intravenously two to three times per week. In her 24th week of pregnancy, cinacalcet was restarted. In her 32nd week, a cesarean section was carried out as planned. CONCLUSIONS: Only three cases of primary hyperparathyroidism in women on cinacalcet therapy in pregnancy have been published in the literature. In the present case, hydration was useful in controlling serum calcium. Cinacalcet therapy helped to control serum calcium. PMID- 27998297 TI - Difficulties in diagnosis and treatment of severe secondary Raynaud's phenomenon in a Cameroonian woman: a case report. AB - BACKGROUND: Raynaud's phenomenon is a microvascular disorder that results in exaggerated vasoconstriction over vasodilatation secondary to an alteration in autonomic control. Though benign, it can result in severe ulceration and ultimately gangrene associated with disfiguration and permanent deformity. We present a case of severe secondary Raynaud's phenomenon in a black-African patient from a resource-limited setting, with focus on the difficulties encountered in the diagnosis and treatment. CASE PRESENTATION: A 43-year-old female Cameroonian farmer with a 7-year history of episodic paresthesia in her fingers and toes (when exposed to cold) presented to our emergency department with severe pain, ulceration, and "darkening" of her fingertips over a period of 2 days. An examination revealed bilateral ulceration and dry gangrene of her fingers and toes, based on which a diagnosis of secondary Raynaud's phenomenon due to a connective tissue disease was proposed. Results of paraclinical investigations were normal. Lifestyle modification along with a calcium channel blocker and phosphodiesterase type 5 inhibitor provided significant relief. CONCLUSIONS: An early diagnosis and knowledge on appropriate treatment of Raynaud's phenomenon is of vital importance to prevent permanent tissue damage and disability. Relying on biphasic color change for the diagnosis of Raynaud's phenomenon in black Africans can be potentially misleading. PMID- 27998298 TI - Erratum to: Evaluating the PRASE patient safety intervention - a multi-centre, cluster trial with a qualitative process evaluation: study protocol for a randomised controlled trial. PMID- 27998300 TI - Is increased positive end-expiratory pressure the culprit? Autoresuscitation in a 44-year-old man after prolonged cardiopulmonary resuscitation: a case report. AB - BACKGROUND: The phenomenon of autoresuscitation is rare, yet it is known to most emergency physicians. However, the pathophysiology of the delayed return of spontaneous circulation remains enigmatic. Among other causes hyperinflation of the lungs and excessively high positive end-expiratory pressure have been suggested, but reports including cardiopulmonary monitoring during cardiopulmonary resuscitation are scarce to support this hypothesis. CASE PRESENTATION: We report a case of autoresuscitation in a 44-year-old white man after 80 minutes of advanced cardiac life support accompanied by continuous capnometry and repeated evaluation by ultrasound and echocardiography. After prolonged cardiopulmonary resuscitation, refractory electromechanical dissociation on electrocardiogram and ventricular akinesis were recorded. In addition, a precipitous drop in end-tidal partial pressure of carbon dioxide was noted and cardiopulmonary resuscitation was discontinued. Five minutes after withdrawal of all supportive measures his breathing resumed and a perfusing rhythm ensued. CONCLUSIONS: Understanding the underlying pathophysiology of autoresuscitation is hampered by a lack of reports including extensive cardiopulmonary monitoring during cardiopulmonary resuscitation in a preclinical setting. In this case, continuous capnometry was combined with repetitive ultrasound evaluation, which ruled out most assumed causes of autoresuscitation. Our observation of a rapid decline in end-tidal partial pressure of carbon dioxide supports the hypothesis of increased intrathoracic pressure. Continuous capnometry can be performed easily during cardiopulmonary resuscitation, also in a preclinical setting. Knowledge of the pathophysiologic mechanisms may lead to facile interventions to be incorporated into cardiopulmonary resuscitation algorithms. A drop in end-tidal partial pressure of carbon dioxide, for example, might prompt disconnection of the ventilation to allow left ventricular filling. Further reports and research on this topic are encouraged. PMID- 27998299 TI - Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin in the treatment of secondary hemophagocytic lymphohistiocytosis with classical Hodgkin lymphoma: a case report and review of the literature. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis is becoming an increasingly recognized disorder in adults. Classical Hodgkin lymphoma is a relatively uncommon etiology of hemophagocytic lymphohistiocytosis and may complicate treatment options. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin are discussed here as a treatment regimen. CASE PRESENTATION: A 66-year-old Hispanic man previously in good health presented with a 1-month history of recurrent fevers, chills, and night sweats and a 3-week history of new onset jaundice. A bone marrow biopsy revealed a normocellular bone marrow with increased histiocytes with areas of hemophagocytic activity. He met five out of eight criteria for hemophagocytic lymphohistiocytosis diagnosis including fevers, pancytopenia, hemophagocytosis, ferritin of 23,292 ng/mL (>500 ng/mL), and soluble-CD25 of 15,330 pg/mL (>1033 pg/mL). A right cervical lymph node biopsy revealed CD15, CD30, MUM-1, and Epstein-Barr virus-encoded small ribonucleic acid-positive cells with morphologic findings of classical Hodgkin lymphoma, lymphocyte-rich subtype. He completed 2 weeks of hemophagocytic lymphohistiocytosis-directed therapy with etoposide and dexamethasone, but then was switched to rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin due to minimal improvement in his pancytopenia and hepatic impairment. He completed one full cycle of rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin with notable improvement in serial hepatic function panels and had an undetectable Epstein-Barr virus viral load. However, he eventually died due to complications of Enterococcus faecalis bacteremia and colonic microperforation in the setting of persistent pancytopenia. CONCLUSIONS: This case discusses the challenges facing treatment of adult malignancy-associated hemophagocytic lymphohistiocytosis. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin may be a viable option for patients with secondary hemophagocytic lymphohistiocytosis and Hodgkin lymphoma who cannot tolerate standard therapies due to hepatic impairment. Targeted therapy and immunotherapy are promising new areas of developing treatments. PMID- 27998301 TI - Acute polyarthritis in a young patient caused by meningococcal and parvovirus B19 infections: a case report and review of the literature. AB - BACKGROUND: Meningococcal infection is a multifaceted disease including acute polyarthritis. This presentation should be known by clinicians in order to prevent delay in treatment. We report what we believe to be the first case of an association of parvovirus B19 and meningococcal polyarthritis in a young adult. CASE PRESENTATION: A 19-year-old Caucasian woman presented to our hospital with fever, intense leg pain, and a transient rash. A physical examination showed asymmetric polyarthritis and no neurological abnormalities. A parvovirus B19 polymerase chain reaction performed using a blood sample and knee fluid aspirate came back positive, but serology was negative for immunoglobulin M and positive for immunoglobulin G. A blood culture was positive for serotype C meningococcus; a polymerase chain reaction performed for Neisseria meningitidis was positive in joint fluid but negative in blood samples (performed after antibiotic treatment had begun). Our patient was treated with ceftriaxone for 15 days, associated with analgesic therapy. Hydroxychloroquine treatment was introduced 5 months after the onset of polyarthritis because of persisting inflammatory arthralgia. CONCLUSIONS: To the best of our knowledge, this is the first case report of polyarthritis caused by concomitant meningococcal and parvovirus B19 infections. This unusual presentation of meningococcal disease may have resulted from the persistent parvovirus B19 infection. Our experience with this case illustrates the need for a systematic approach to the diagnosis of febrile acute polyarthritis. Only long-term follow-up will reveal if this infectious polyarthritis will evolve towards an autoimmune rheumatism. PMID- 27998302 TI - Immunoglobulin G4-related constrictive pericarditis identified by cytological examination of pericardial effusion: a case report. AB - BACKGROUND: Immunoglobulin G4-related disease is increasingly recognized as a systemic autoimmune disorder characterized by immunoglobulin G4-positive lymphocyte infiltration. Organ biopsy and histopathology are the most important diagnostic methods; however, the significance of a cytological examination in immunoglobulin G4-related disease cases is still unclear. CASE PRESENTATION: A 73 year-old Asian man who was a former tobacco smoker presented with progressive exertional dyspnea, systemic edema, and pericardial effusion. A cytological examination of his pericardial effusion detected three or four plasma cells per high-power field by Giemsa staining. Moreover, immunoglobulin G4-positive plasma cells were detected by immunostaining. Cardiac catheterization after pericardiocentesis revealed that both ventricular pressure traces showed an early diastolic dip and plateau. Positron-emission tomography with 18F fluorodeoxyglucose imaging revealed inflammatory foci in his pericardium. A surgical pericardiectomy was performed and the resultant specimen showed significant immunoglobulin G4-positive plasma cell infiltration and marked fibrous thickening of his pericardium; therefore, a diagnosis of constrictive pericarditis due to immunoglobulin G4-related disease was made. Oral administration of 0.6-mg/kg/day prednisolone resolved his heart failure and he was discharged on foot 1 week later. CONCLUSION: Our experience with this case indicates that cytological examination of pericardial effusion was useful in the diagnosis of immunoglobulin G4-related disease. PMID- 27998303 TI - Spontaneous renal artery dissection presenting as an aortic dissection: a case report. AB - BACKGROUND: Renal artery dissection is a condition that has been associated with traumatic injuries and connective tissue disorders. It has been managed in the past by multiple methods because there is no standard treatment, including vascular intervention with angioplasty and stenting, anticoagulation/antiplatelet therapy, and hypertension management. CASE PRESENTATION: We present a case of a spontaneous renal artery dissection in a 55-year-old white man with no traditional risk factors who presented twice to our emergency department in a 2 day period with different symptoms; on his first presentation he presented with symptoms consistent with renal colic and on the second visit he presented with symptoms consistent with aortic dissection. CONCLUSIONS: Our patient was treated with endovascular stent placement by interventional radiology, heparin infusion, and admission to our medical intensive care unit. Our review here highlights the varied management of this diagnosis for which there is no standard treatment and decisions are made in conjunction with consultants. PMID- 27998304 TI - Foveolar gastric metaplasia presenting as a duodenal tumor with an atypical appearance: a case report. AB - BACKGROUND: Foveolar gastric metaplasia of the duodenum is a frequent but not as yet considered correlate of endoscopically detected duodenal polyps. The majority of foveolar gastric metaplasias associated with polyps presented a typical benign endoscopic appearance and they were diagnosed by biopsy. Here we report a case of a surgical-resected foveolar gastric metaplasia manifesting as a duodenal tumor with an atypical appearance. CASE PRESENTATION: An asymptomatic 56-year-old Asian man who presented with a foveolar gastric metaplasia of atypical appearance and had previously undergone esophagogastroduodenoscopy was referred to our hospital. A biopsy revealed a normal duodenum with an inflamed mucosa. Narrow band imaging with magnifying endoscopy revealed normal microvessels with normal micromucosa, which indicated non-neoplasia. Endoscopic ultrasonography using a miniature probe system (20 MHz) revealed a hypoechoic mass with multiple anechoic lesions (16-mm diameter) located in the mucosal layer. The lesion was excised via laparotomy assisted by endoscopic techniques similar to endoscopic submucosal dissection. The pathology indicated foveolar gastric metaplasia. CONCLUSIONS: Foveolar gastric metaplasia can present as a duodenal tumor. We identified two important clinical issues. First, foveolar gastric metaplasia can present as a duodenal tumor with an atypical benign appearance. Second, both endoscopic ultrasonography and narrow band imaging are useful techniques to increase the diagnostic rate of this condition. PMID- 27998305 TI - Cytotoxicity of Plumbagin, Rapanone and 12 other naturally occurring Quinones from Kenyan Flora towards human carcinoma cells. AB - BACKGROUND: Cancer is a major public health concern globally and chemotherapy remains the principal mode of the treatment of various malignant diseases. METHODS: This study was designed to investigate the cytotoxicity of 14 naturally occurring quinones including; 3 anthraquinones, 1 naphthoquinone and 10 benzoquinones against 6 human carcinoma cell lines and normal CRL2120 fibroblasts. The neutral red uptake (NR) assay was used to evaluate the cytotoxicity of the compounds, whilst caspase-Glo assay was used to detect caspases activation. Cell cycle and mitochondrial membrane potential (MMP) were all analyzed via flow cytometry meanwhile levels of reactive oxygen species (ROS) were measured by spectrophotometry. RESULTS: Anthraquinone: emodin (2), naphthoquinone: plumbagin (4), and benzoquinones: rapanone (9), 2,5-dihydroxy-3 pentadecyl-2,5-cyclohexadiene-1,4-dione (10), 5-O-methylembelin (11), 1,2,4,5 tetraacetate-3-methyl-6-(14-nonadecenyl)-cyclohexadi-2,5-diene (13), as well as doxorubicin displayed interesting activities with IC50 values below 100 MUM in the six tested cancer cell lines. The IC50 values ranged from 37.57 MUM (towards breast adenocarcinoma MCF-7 cells) to 99.31 MUM (towards small cell lung cancer A549 cells) for 2, from 0.06 MUM (MCF-7 cells) to 1.14 MUM (A549 cells) for 4, from 2.27 MUM (mesothelioma SPC212 cells) to 46.62 MUM (colorectal adenocarcinoma DLD-1 cells) for 9, from 8.39 MUM (SPC212 cells) to 48.35 MUM (hepatocarinoma HepG2 cells) for 10, from 22.57 MUM (MCF-7 cells) to 61.28 MUM (HepG2 cells) for 11, from 9.25 MUM (MCF-7 cells) to 47.53 MUM (A549 cells) for 13, and from 0.07 MUM (SPC212 cells) to 1.01 MUM (A549 cells) for doxorubicin. Compounds 4 and 9 induced apoptosis in MCF-7 cells mediated by increased ROS production and MMP loss, respectively. CONCLUSION: The tested natural products and mostly 2, 4, 9, 10, 11 and 13 are potential cytotoxic compounds that deserve more investigations towards developing novel antiproliferative drugs against human carcinoma. PMID- 27998306 TI - Intramammary metastatic melanoma of unknown primary origin in a 58-year old patient: a case report. AB - BACKGROUND: Malignant melanoma metastasis to the breast is a rare disease. CASE PRESENTATION: We present the case of a 58-year-old postmenopausal Caucasian woman with metastatic malignant melanoma of unknown origin of the right breast. She presented with a palpable lump in the inferior quadrant of her right breast. The investigations concluded it was breast metastasis from a malignant melanoma of unknown origin. The treatment consisted of mastectomy and axillary lymph node dissection. Two lymph nodes were positive for tumor cells and one showed extracapsular extension. Our patient did not receive immediate adjuvant therapy. Six weeks after the surgery, our patient presented a relapse in the right axilla (a 6 * 4 cm mass) with positive internal mammary lymph nodes and a single brain metastasis. This relapse motivated an adjuvant treatment with partial regression of the disease. Currently, our patient presents multiple metastases with poor prognosis. CONCLUSIONS: From this experience, we advocate an immediate aggressive handling of melanoma metastasis to the breast. PMID- 27998307 TI - Neuro-Behcet disease presenting as a solitary cerebellar hemorrhagic lesion: a case report and review of the literature. AB - BACKGROUND: Behcet's disease is a heterogeneous, multisystem, inflammatory disorder of unknown etiology. The classic triad of oral and genital ulcerations in conjunction with uveitis was originally described by the Turkish dermatologist Hulusi Behcet in 1937, but associated symptoms of the cardiovascular, central nervous, pulmonary, and gastrointestinal systems were later identified. In fact, Behcet's disease with neurological involvement (neuro-Behcet's disease) is not uncommon. Patients with neuro-Behcet's disease typically exhibit a diverse array of symptoms, most commonly in the brainstem and diencephalic regions. Herein, we report an unusual case of neuro-Behcet's disease in a patient who presented with a solitary cerebellar hemorrhage. CASE PRESENTATION: A 39-year-old Asian woman was admitted to our hospital with complaints of a sudden speech difficulty that had manifested the same morning, and dizziness and mild vomiting experienced over the previous 3 days. Magnetic resonance images revealed target-like hemorrhagic lesions in the right hemisphere of the cerebellum. Risk factors that may result in cerebellar hemorrhage, such as high blood pressure or bleeding diathesis, were ruled out, and subsequent brain angiograms were normal. CONCLUSIONS: These findings suggest that the patient's cerebellar hemorrhage could have been due to intracranial vasculitis in a rare, if not unique, complication of neuro-Behcet's disease. PMID- 27998308 TI - Semilobar holoprosencephaly in a 12-month-old baby boy born to a primigravida patient with type 1 diabetes mellitus: a case report. AB - BACKGROUND: Holoprosencephaly is a rare spectrum of cephalic disorders resulting from a failure or incomplete division of the embryonic forebrain into distinct cerebral hemispheres. It is the most common brain malformation with an incidence of 1:250 during embryogenesis; however, owing to the associated high rates of spontaneous abortion the incidence is 1:16,000 among live deliveries. Pathogenesis of holoprosencephaly is complex and heterogeneous involving genetic abnormalities, teratogenic exposures, and syndromic associations. Among the teratogenic exposures, maternal diabetes is a well-established risk factor associated with a 200-fold increased incidence of holoprosencephaly. CASE PRESENTATION: We report a case of a delayed diagnosis of semilobar holoprosencephaly in a 12-month-old baby boy of African descent who presented to us with a history of global developmental delay, erratic sleep patterns, and poor weight gain. He was born to a type 1 diabetes mellitus mother at 39+ weeks by emergency cesarean section due to fetal distress and breech presentation. The baby weighed 2315 g and had Apgar scores of 6/10 and 8/10 at 1 and 5 minutes respectively. A physical examination done at 12 months of age revealed a small for-age child with a developmental age of 2 months. He had normal facies but a neurological examination revealed hypotonia in all four limbs. The rest of systemic examination was unremarkable. Hematological and biochemical investigations revealed normal findings except for iron deficiency anemia. The child also underwent magnetic resonance imaging of his brain which revealed distinctive features of semilobar holoprosencephaly. He was treated for iron deficiency anemia with Hemovit syrup (ferric ammonium citrate, folic acid, pyridoxine hydrochloride, cyanocobalamin, and zinc sulfate) 10 ml thrice daily, ferrous sulfate 10 mg once daily, folic acid 1 mg once daily, and multivitamin syrup 5 ml once daily. Furthermore, nutritional and genetic counseling was offered to his parents. CONCLUSIONS: In conclusion, although rare, holoprosencephaly is the commonest structural anomaly of the brain with a complex and multifactorial etiopathogenesis. It is prudent to diagnose it prenatally, classify its severity, and forge its prognosis so that parents are counseled early enough to make informed decisions especially where termination of pregnancy may be implicated. PMID- 27998310 TI - Pre-ART nutritional status and its association with mortality in adult patients enrolled on ART at Fiche Hospital in North Shoa, Oromia region, Ethiopia: a retrospective cohort study. AB - BACKGROUND: Human immunodeficiency virus (HIV) compromises the nutritional status of infected individuals and in turn, malnutrition worsens the effects of the infection itself by weakening the immune system consequently accelerating disease progression and death. However, few studies have examined the association between nutritional status at antiretroviral therapy (ART) initiation and early mortality. Therefore, this study assesses pre-ART nutritional status and other baseline characteristics and mortality among adult patients on ART at Fiche Hospital, Ethiopia. METHODS: A retrospective cohort study was conducted among 489 ART enrolled adult patients between August 01, 2006 and September 30, 2013 in Fiche Hospital. Study participants were selected by using systematic random sampling method. Actuarial table was used to estimate survival of patients after ART initiation and log rank test was used to compare the survival curves. Cox proportional-hazard regression was used to determine independent predictors of time to death. RESULTS: Most of the study subjects were females 254 (51.9%). A total of 489 patients were included in the analysis, of whom 87 died during a median study follow-up of 22 months. The estimated mortality among malnourished was 21, 28, 33, and 38% at 5, 10, 15, and 25 months respectively with mortality incidence density of 5.63 deaths per 100 person years. The independent predictors of mortality were: BMI <18.5 kg/m2 (AHR = 5.4 95% CI 3.03-9.58), baseline ambulatory functional status (AHR = 3.84; 95% CI 2.19-6.74), bedridden functional status (AHR = 4.78; 95% CI 2.14-10.65), WHO clinical stage III (AHR 2.21; 95% CI 1.16-4.21), WHO clinical stage IV (AHR 4.05; 95% CI 1.50-10.97) and CD4 count less than 200 cells/MUl (AHR = 2.95; 95% CI 1.48-5.88), two and more opportunistic infections (AHR 2.30; 95% CI 1.11-4.75). CONCLUSIONS: Undernutrition at the time of ART initiation was associated with increased risk of death, particularly during the first 3 months after ART initiation. Interventions to promote earlier HIV diagnosis and treatment and integrating nutrition counseling at all stages of ART implementation may improve ART outcomes in this vulnerable population. PMID- 27998309 TI - A subserosal, pedunculated, multilocular uterine leiomyoma with ovarian tumor like morphology and histological architecture of adenomatoid tumors: a case report and review of the literature. AB - BACKGROUND: Uterine leiomyomas are common uterine tumors, and typical cases of leiomyoma are easily diagnosed by imaging study. However, uterine leiomyomas are often altered by degenerative changes, which can cause difficulty and confusion in their clinical diagnosis. We describe the 17th reported case of a uterine leiomyoma clinically diagnosed as an ovarian tumor; however, the present case shows the most detailed radiological evaluation, including contrast-enhanced magnetic resonance imaging. We first show that a uterine leiomyoma can histologically mimic an adenomatoid tumor. CASE PRESENTATION: A 47-year-old premenopausal, nulliparous Japanese woman with a history of type 2 diabetes mellitus, hypertension, and hyperlipidemia had lower abdominal pain. Ultrasonography confirmed a 6-cm mass in the right-sided space of the pelvic cavity. Magnetic resonance imaging evaluation showed that a multilocular mass was present near the uterus, and a mucinous ovarian tumor was considered. Emergency surgery due to acute abdomen was performed under the diagnosis of pedicle torsion of the ovarian tumor. During surgery, a pedunculated uterine mass without stalk torsion was seen. The mass grossly contained serous and hemorrhagic fluids in the cavities, and pathology examination confirmed that the mass was a leiomyoma with hydropic and cystic degeneration. Anastomosing thin cord-like arrangements of the leiomyoma cells mimicked the architecture of adenomatoid tumors. The tumor cells were positive for the microphthalmia transcription factor but negative for other melanoma markers. Three days postoperatively, she was discharged without sequelae. CONCLUSIONS: Marked intratumoral deposition of fluids may induce the multilocular morphology of a tumor, and the cellular arrangement of the tumor cells with hydropic degeneration mimicked an adenomatoid tumor in this case. Clinicians need to be aware that a subserosal leiomyoma with cystic and hydropic degeneration can mimic an ovarian tumor, and pathologists should be aware that such leiomyomas can mimic adenomatoid tumors. Additionally, perivascular epithelioid cell tumors should not be diagnosed only based on its immunoreactivity for the microphthalmia transcription factor. PMID- 27998311 TI - Disseminated tungiasis in a 78-year-old woman from Tanzania: a case report. AB - BACKGROUND: Tungiasis is one of the neglected tropical diseases; it affects up to 40% of individuals living in societies with poor housing and sanitation standards. In endemic areas, Tunga infestation, which predominantly affects the periungual areas of the lower limbs in humans, is associated with considerable morbidity and poor quality of life. CASE PRESENTATION: A 78-year-old woman of African descent presented with pain, inflammation, suppuration, ulceration, and deformation of digits of all four limbs. She had a total of 1146 embedded sand fleas: 812 in lower limbs and 334 in her hands. She was febrile; her full blood count revealed pancytopenia and blood cultures were positive for Staphylococcus aureus and Streptococcus pyogenes isolates. Furthermore, she had severe hyponatremia. We applied 20% salicylated petroleum jelly followed by the manual removal of embedded sand fleas with a sterile needle. Intravenously administered piperacillin-tazobactam, topical ivermectin, ferrous sulfate, folic acid, tolvaptan, albendazole, multivitamins, and tetanus prophylaxis were instituted. She was discharged home after 16 days of hospitalization. CONCLUSIONS: Tungiasis is a neglected disease of concern in underprivileged societies that is preventable and curable. Early recognition and prompt treatment is crucial to prevent complications in this disease which may potentially mimic other conditions resulting in erroneous management. PMID- 27998312 TI - Rare presentation of subcapsular hepatic steatosis in a woman with uncontrolled diabetes without peritoneal dialysis: a case report. AB - BACKGROUND: Subcapsular hepatic steatosis is a rare atypical pattern of fatty deposition of the liver reported in patients with diabetic nephropathy receiving peritoneal dialysis with intraperitoneal insulin. To date, there has been only one pediatric and zero adult cases of subcapsular hepatic steatosis with no history of continuous ambulatory peritoneal dialysis. We report the first published case of subcapsular hepatic steatosis in an adult diabetic patient without any history of peritoneal dialysis or evidence of chronic renal disease. CASE PRESENTATION: A 46-year-old Caucasian woman with type 2 diabetes mellitus without renal disease presented to our emergency department with vague abdominal symptoms and vomiting. Her blood glucose levels were poorly controlled with a range of 400 to 500 mg/dL. She was diagnosed as having subcapsular hepatic steatosis based on magnetic resonance imaging. Of note, after improved glucose control her subcapsular hepatic steatosis had nearly resolved. CONCLUSIONS: Subcapsular hepatic steatosis has been exclusively described in patients with continuous ambulatory peritoneal dialysis and those on intraperitoneal insulin, except for one pediatric case, which was probably due to incorrect insulin administration. Our case demonstrates that a diagnosis of subcapsular hepatic diagnosis should not be restricted to those getting continuous ambulatory peritoneal dialysis, but rather expanded to all patients with uncontrolled blood glucose levels. PMID- 27998313 TI - Embryonal rhabdomyosarcoma of the perineum in an adult: a case report. AB - BACKGROUND: We report the case of an adult patient with embryonal rhabdomyosarcoma of the perineum admitted to our practice at Joliot Curie Institute in Dakar. It is a rare tumor at this age and has a bad prognosis at this localization. CASE PRESENTATION: We describe the case of a 22-year-old African man admitted for a perineal mass that had evolved over 6 months. He complained of tenesmus, obstinate constipation, and dysuria. A clinical examination revealed perineal swelling spread over his anus, scrotum, penis, testicles, and inguinal lymph nodes. A perineal ultrasound and computed tomography scan showed a large mass driving his testicles forward with regional lymph node metastases. An ultrasound-guided biopsy showed embryonal rhabdomyosarcoma on histology and immunohistochemistry, with strong positivity of neural cell adhesion molecule and myogenin while results for cytokeratin AE1/AE3, cluster of differentiation 45, synaptophysin, and chromogranin were negative. Our patient was classified T2N1M1. Outcome was quickly marked by occlusive syndrome and colostomy. Our patient did not opt for chemotherapy and died after 6 months of follow-up. CONCLUSIONS: The embryonic RMS of the adult is a rare disease. Despite the sensitivity to chemotherapy and surgery. Localization to perineum remains poor prognosis. PMID- 27998315 TI - Acute abdominal pain caused by hematometra in an adolescent female: a case report. AB - BACKGROUND: Hematometra is a pathologic collection of blood in the uterus. It is a rare condition that is most commonly associated with congenital anomalies or prior surgical procedures causing an obstruction of the genitourinary outflow tract. We present an unusual case of hematometra in a healthy and active adolescent female with no prior risk factors. This is a rare and important case report due to the complexity of diagnosis when a young female presents with an acute abdomen. In addition, for a patient who presents with no prior risk factors for hematometra, such as in our patient, the diagnosis and workup may become overly complicated, adding strain to patient care and health care cost. To the best of our knowledge and based on an extensive literature search, there has not been a reported case of hematometra in an adolescent female without any aforementioned risk factors. CASE PRESENTATION: Our patient is a healthy 18 year old white woman with no significant prior medical or surgical history. Her only medication was depot medroxyprogesterone acetate use for contraception. She presented to a local emergency department with acute abdominal pain, accompanied by emesis and nausea. Workup with ultrasonography showed uterine distention most likely caused by hematometra, although no obvious cause was noted. She was treated with dilation and curettage; she was also advised to discontinue depot medroxyprogesterone acetate use. She was symptom free without recurrence of hematometra at 6-month follow-up. CONCLUSIONS: Due to the high prevalence of abdominal pain, this case report has a wide breadth of implications for health care providers ranging from general family practitioners to emergency room physicians and obstetricians/gynecologists. This case report provides potential future advancement in management and differential diagnosis in adolescent females presenting with acute abdominal pain. In addition, the use of depot medroxyprogesterone acetate contributing to or causing hematometra cannot be ruled out in our patient and warrants further investigation. PMID- 27998316 TI - Decompressive craniectomy for malignant middle cerebral artery infarction in a 16 year old boy: a case report. AB - BACKGROUND: Cryptogenic stroke frequently occurs in younger patients and has a high risk of recurrence. Consequently, secondary prevention is often suboptimal as there is no known risk factor to target. This case demonstrates an unexpected finding of middle cerebral artery infarction and extensive malignant transformation in a 16-year-old boy more than a day post-admission. The lack of a proven culprit lesion makes this case even more intriguing and subsequently raises questions of cryptogenic mechanisms in the context of unrelated trauma. CASE PRESENTATION: A 16-year-old white boy had been stabbed in his chest but had a Glasgow Coma Scale score of 15. Over a day later he developed sudden signs and symptoms consistent with a neurological event of unknown etiology. Computed tomography demonstrated significant cerebral edema but was equivocal in its list of differentials. A computed tomography scan of his chest demonstrated no cardiac wall or vascular injury and he was transferred to our neurosurgical unit for intracranial pressure monitoring. A computed tomography angiogram revealed an unexpected finding of malignant middle cerebral artery infarction. Failure to medically manage his intracranial pressure resulted in a decompressive craniectomy less than 12-hours postictus. Despite extensive diagnostic investigations no culprit lesion was identified and no patent foramen ovale found. Since discharge he has returned to full functional status. He was the youngest patient (mean age of 43 years) out of a 10-year institutional retrospective on decompressive craniectomies for malignant middle cerebral artery infarction (n = 40) and had the singularly best Glasgow Outcome Scale score of 5. CONCLUSIONS: This case highlights the preponderance of cryptogenic stroke in younger patients and its etiological elusiveness. It further demonstrates that age is predictive in terms of survival and functional outcome in the context of malignant middle cerebral artery infarction. PMID- 27998314 TI - Resilient microorganisms in dust samples of the International Space Station survival of the adaptation specialists. AB - BACKGROUND: The International Space Station (ISS) represents a unique biotope for the human crew but also for introduced microorganisms. Microbes experience selective pressures such as microgravity, desiccation, poor nutrient-availability due to cleaning, and an increased radiation level. We hypothesized that the microbial community inside the ISS is modified by adapting to these stresses. For this reason, we analyzed 8-12 years old dust samples from Russian ISS modules with major focus on the long-time surviving portion of the microbial community. We consequently assessed the cultivable microbiota of these samples in order to analyze their extremotolerant potential against desiccation, heat-shock, and clinically relevant antibiotics. In addition, we studied the bacterial and archaeal communities from the stored Russian dust samples via molecular methods (next-generation sequencing, NGS) and compared our new data with previously derived information from the US American ISS dust microbiome. RESULTS: We cultivated and identified in total 85 bacterial, non-pathogenic isolates (17 different species) and 1 fungal isolate from the 8-12 year old dust samples collected in the Russian segment of the ISS. Most of these isolates exhibited robust resistance against heat-shock and clinically relevant antibiotics. Microbial 16S rRNA gene and archaeal 16S rRNA gene targeting Next Generation Sequencing showed signatures of human-associated microorganisms (Corynebacterium, Staphylococcus, Coprococcus etc.), but also specifically adapted extremotolerant microorganisms. Besides bacteria, the detection of archaeal signatures in higher abundance was striking. CONCLUSIONS: Our findings reveal (i) the occurrence of living, hardy microorganisms in archived Russian ISS dust samples, (ii) a profound resistance capacity of ISS microorganisms against environmental stresses, and (iii) the presence of archaeal signatures on board. In addition, we found indications that the microbial community in the Russian segment dust samples was different to recently reported US American ISS microbiota. PMID- 27998317 TI - Mycobacterium tuberculosis as a cause of mandibular osteomyelitis in a young woman: a case report. AB - BACKGROUND: Tuberculosis is considered an emerging disease worldwide; in the last 10 years, its incidence has increased to more than 9.6 million cases of active tuberculosis. In 2014, it resulted in 1.5 million patient deaths. However, oral presentation with bone involvement occurs in less than 3% of all reported cases and rarely arouses clinical suspicion on initial presentation. CASE PRESENTATION: A 15-year-old Mexican girl who had a previous diagnosis of neurofibromatosis presented to our hospital with pain and swelling in the region of the left mandibular body since November 2011. A clinical examination revealed pain in the mandibular region, a mass of soft consistency that seemed to involve bone, and a fistula with discharge of intraoral purulent material. Additionally, tachycardia and hyperthermia were observed. The left submental and submandibular regions had a 12-cm-diameter swelling, which was well-delineated and nonerythematous. The final diagnosis was established by real-time polymerase chain reaction. CONCLUSIONS: The final diagnosis of rare cases of tuberculous osteomyelitis in the jaw can be established by deoxyribonucleic acid (DNA) identification of Mycobacterium tuberculosis in the lesion. Simple and fast complementary diagnosis by real-time polymerase chain reaction is a fundamental approach to establishing early and effective pharmacological and surgical treatment. PMID- 27998318 TI - Management of severe dengue hemorrhagic fever and bleeding complications in a primigravida patient: a case report. AB - BACKGROUND: The incidence of dengue hemorrhagic fever is increasing among the adult population living in endemic areas. The disease carries a 0.73% fatality rate for the general population, but what happens when the disease strikes a special subpopulation group, the obstetrics? Perhaps the important question specific to this special subpopulation revolves around the right time and mode of delivery under severe coagulopathy and plasma leakage in conditions of imminent delivery. CASE PRESENTATION: A 24-year-old primigravid Sundanese woman presented to our intensive care unit due to acute pulmonary edema secondary to massive plasma leakage caused by severe dengue. She tested positive for both immunoglobulin G and immunoglobulin M dengue serology indicating she had secondary dengue infection, which placed her at risk for an exaggerated cytokine response as was evident clinically. She had to undergo an emergency cesarean section which was later complicated by rebleeding and hemodynamic instability due to an atypical defervescence period. She was successfully managed by multiple blood transfusions and was discharged from our intensive care unit on day 8 without any negative sequel. CONCLUSIONS: Fever, thrombocytopenia, and hemoconcentration are the classical symptoms of dengue hemorrhagic fever observed in adult, pediatric, and obstetric populations. However, a clinician must be particularly watchful in treating a pregnant dengue-infected patient as physiologic hematology changes provide greater volume compensation and the advent of shock marks significant volume loss. In conclusion, an important principle in the management of dengue hemorrhagic fever in pregnancy is to prioritize maternal well-being prior to addressing fetal issues. PMID- 27998319 TI - Leading indicators of community-based violent events among adults with mental illness. AB - BACKGROUND: The public health, public safety and clinical implications of violent events among adults with mental illness are significant; however, the causes and consequences of violence and victimization among adults with mental illness are complex and not well understood, which limits the effectiveness of clinical interventions and risk management strategies. This study examined interrelationships between violence, victimization, psychiatric symptoms, substance use, homelessness and in-patient treatment over time. METHOD: Available data were integrated from four longitudinal studies of adults with mental illness. Assessments took place at baseline, and at 1, 3, 6, 9, 12, 15, 18, 24, 30 and 36 months, depending on the parent studies' protocol. Data were analysed with the autoregressive cross-lag model. RESULTS: Violence and victimization were leading indicators of each other and affective symptoms were a leading indicator of both. Drug and alcohol use were leading indicators of violence and victimization, respectively. All psychiatric symptom clusters - affective, positive, negative, disorganized cognitive processing - increased the likelihood of experiencing at least one subsequent symptom cluster. Sensitivity analyses identified few group-based differences in the magnitude of effects in this heterogeneous sample. CONCLUSIONS: Violent events demonstrated unique and shared indicators and consequences over time. Findings indicate mechanisms for reducing violent events, including trauma-informed therapy, targeting internalizing and externalizing affective symptoms with cognitive-behavioral and psychopharmacological interventions, and integrating substance use and psychiatric care. Finally, mental illness and violence and victimization research should move beyond demonstrating concomitant relationships and instead focus on lagged effects with improved spatio-temporal contiguity. PMID- 27998320 TI - Prevalence and risk factors for attempted suicide in the elderly: a cross sectional study in Shanghai, China. AB - BACKGROUND: Previous studies have thoroughly investigated the prevalence and risk factors for completed suicide. In marked contrast is the lack of a better understanding of attempted suicide in the elderly. The aim of this study was to estimate the prevalence of attempted suicide in the elderly and examine the associated factors. METHODS: Using a multi-stage cluster sampling approach, a cross-sectional survey of 8,399 elderly house-dwelling residents was conducted in Shanghai, China. RESULTS: The two-week prevalence of attempted suicide in the elderly was 0.75%. In the bivariate analysis, having no caregivers, depressive, anxiety, sad, fear, obsessive-compulsive and anger symptom, and lower scores on the Barthel Index of Activities of Daily Living and the Lawton Instrumental Activities of Daily Living Scale were significantly associated with an increased risk of attempted suicide in the elderly. In the multivariate analysis, sad and fear symptoms were significantly and independently associated with a higher risk of attempted suicide in the elderly. CONCLUSION: The two-week prevalence of attempted suicide in the elderly is relatively high when compared with the annualized or lifetime prevalence reported in China and foreign settings. Elderly individuals with certain mental symptoms should be targeted for suicide prevention and provided with timely mental health support. PMID- 27998321 TI - Rhipicephalus turanicus, a new vector of Hepatozoon canis. AB - The distribution of Hepatozoon canis mainly encompasses areas where its main tick vector, Rhipicephalus sanguineus sensu lato, is present. However, the detection of this pathogen in dogs, foxes and golden jackals well outside the areas inhabited by this tick species reinforced the hypothesis that additional ixodids are involved in the life cycle and transmission of this protozoon. The present study provides, for the first time, data supporting the sporogonic development of H. canis in specimens of Rhipicephalus turanicus collected from a naturally infected fox from southern Italy. The epidemiological role of R. turanicus as a vector of H. canis is discussed, along with information on the potential use of cell cultures for the experimental infection with H. canis sporozoites. The in vitro infection of canine leucocytes by sporozoites from ticks is proposed as a potential tool for future in-depth studies on the biology of H. canis. PMID- 27998322 TI - International Federation for Emergency Medicine Consensus Statement: Sonography in hypotension and cardiac arrest (SHoC): An international consensus on the use of point of care ultrasound for undifferentiated hypotension and during cardiac arrest. AB - : Introduction The International Federation for Emergency Medicine (IFEM) Ultrasound Special Interest Group (USIG) was tasked with development of a hierarchical consensus approach to the use of point of care ultrasound (PoCUS) in patients with hypotension and cardiac arrest. METHODS: The IFEM USIG invited 24 recognized international leaders in PoCUS from emergency medicine and critical care to form an expert panel to develop the sonography in hypotension and cardiac arrest (SHoC) protocol. The panel was provided with reported disease incidence, along with a list of recommended PoCUS views from previously published protocols and guidelines. Using a modified Delphi methodology the panel was tasked with integrating the disease incidence, their clinical experience and their knowledge of the medical literature to evaluate what role each view should play in the proposed SHoC protocol. RESULTS: Consensus on the SHoC protocols for hypotension and cardiac arrest was reached after three rounds of the modified Delphi process. The final SHoC protocol and operator checklist received over 80% consensus approval. The IFEM-approved final protocol, recommend Core, Supplementary, and Additional PoCUS views. SHoC-hypotension core views consist of cardiac, lung, and inferior vena vaca (IVC) views, with supplementary cardiac views, and additional views when clinically indicated. Subxiphoid or parasternal cardiac views, minimizing pauses in chest compressions, are recommended as core views for SHoC cardiac arrest; supplementary views are lung and IVC, with additional views when clinically indicated. Both protocols recommend use of the "4 F" approach: fluid, form, function, filling. CONCLUSION: An international consensus on sonography in hypotension and cardiac arrest is presented. Future prospective validation is required. PMID- 27998323 TI - Short- and Long-Term Reduction of Door-to-Needle Time in Thrombolysis for Acute Stroke. AB - BACKGROUND: More timely administration of tissue plasminogen activator (alteplase) for patients with acute ischemic stroke yields greater clinical benefits. We implemented door-to-needle (DTN) time reduction strategies at our center and evaluated their short- and long-term effects on in-hospital treatment delays and clinical outcomes. METHODS: Strategies, including stroke team prenotification, direct computed tomography transfer, not routinely waiting for laboratory results and alteplase delivery on the computed tomography table, were implemented in June 2013. We included all thrombolysed patients admitted directly to our hospital between January 2012 and March 2015. In-hospital delays and symptomatic intracerebral hemorrhage rates were compared between patients pre- and postmodification, and the latter period was divided into early (first 6 months) and late (beyond 6 months) phases to assess the durability of our modifications. RESULTS: Forty-eight individuals were treated premodification compared with 58 postmodification. The median DTN time was reduced from 75 to 46 minutes (p<0.0001). The median DTN time in the early and late postmodification phases was not significantly different (41 vs 46 minutes, p=0.4085). There was no significant difference in rates of symptomatic intracerebral hemorrhage (4.2 vs 1.7%, p=0.361) or stroke mimics (2.1 ves 5.2%, p=0.625) Conclusions: We were able to decrease our DTN time for acute stroke thrombolysis by implementing relatively simple modifications and these improvements persisted over time. PMID- 27998324 TI - Investigating the current methods of assessing behavioral and psychological symptoms in residential aged care facilities in a metropolitan city. AB - Up to 90% of people with dementia living in residential aged care facilities (RACFs) display behavioral and psychological symptoms of dementia (BPSD), and these are associated with poorer quality of life and increased morbidity and mortality. In order to implement appropriate interventions, it is important to understand the symptoms in more detail. Despite the availability of BPSD assessment tools, it is unknown what the current practice of monitoring of BPSD in RACFs. We sought to investigate the current BPSD assessment tools being used in RACFs and explore different stakeholders' views on current practices. A cross sectional convenience sample of 21 clinicians were identified and administered a questionnaire. Old age psychiatrists, aged psychiatry clinicians, behavior management teams and RACF staff completed the questionnaires. Clinicians reported that objective consistent information about BPSD were important for recommending and implementing pharmacological and non-pharmacological strategies for BPSD; however, the use of validated BPSD assessments in RACFs was not a usual part of clinical practice. RACF staff stated the major barrier to assessment of BPSD was lack of time. Alternate methods of assessing BPSD which consider preferences from clinicians and RACF staff should be further investigated. Modern technology which can allow "real time" assessment may be a solution. PMID- 27998325 TI - Improving the care of people with dementia in general hospitals: evaluation of a whole-system train-the-trainer model. AB - BACKGROUND: There are concerns about the quality of care that people with dementia receive in the general hospital. Staff report a lack of confidence and inadequate training in dementia care. METHODS: A train-the-trainer model was implemented across eight acute hospital trusts in London via a large academic health and science network. Impact was evaluated using mixed methods. Data were collected at (a) individual level: "Sense of Competence in Dementia Care" (SCID), (b) ward level: Person Interaction and Environment (PIE) observations, (c) organization level: use of specific tools, i.e. "This Is Me," (d) systems level: numbers and types of staff trained per trust. Results were analyzed with descriptive statistics and paired t-test with thematic framework analysis for PIE observations. RESULTS: The number of staff trained per trust ranged from 67 to 650 (total 2,020). A total of 1,688 (85%) baseline questionnaires and 456 (27%) three month follow-up questionnaires were completed. Mean SCID score was 43.2 at baseline and 50.7 at follow-up (paired t-test, p < 0.001). All sub-scales showed a small increase in competence, the largest being for "building relationships." Organizational level data suggested increased use of carer's passport, "This Is Me" documentation, dementia information leaflets, delirium screening scales, and pathways. PIE observations demonstrated improved staff-patient interactions but little change in hospital environments. CONCLUSIONS: There was a significant improvement in staffs' sense of competence in dementia care and the quality of interactions with patients. More hospitals adopted person-centered tools and pathways. Work is required to investigate if these changes improve hospital outcomes for people with dementia. PMID- 27998327 TI - Entangled Histories: German Veterinary Medicine, c.1770-1900. AB - Medical historians have recently become interested in the veterinary past, investigating the development of animal health in countries such as France, the Netherlands, the United Kingdom and the United States. An appreciation of the German context, however, is still lacking - a gap in the knowledge that the present article seeks to fill. Providing a critical interpretation of the evolution of the veterinary profession, this investigation explains why veterinary and medical spheres intersected, drifted apart, then came back together; it also accounts for the stark differences in the position of veterinarians in Germany and Britain. Emphasis is placed on how diverse traditions, interests and conceptualisations of animal health shaped the German veterinary profession, conditioned its field of operation, influenced its choice of animals and diseases, and dictated the speed of reform. Due to a state oriented model of professionalisation, veterinarians became more enthusiastic about public service than private practice, perceiving themselves to be alongside doctors and scientists in status, rather than next to animal healers or manual labourers. Building on their expertise in epizootics, veterinarians became involved in zoonoses, following outbreaks of trichinosis. They achieved a dominant position in meat hygiene by refashioning abattoirs into sites for the construction of veterinary knowledge. Later, bovine tuberculosis helped veterinarians cement this position, successfully showcasing their expertise and contribution to society by saving as much meat as possible from diseased livestock. Ultimately, this article shows how veterinarians were heavily 'entangled' with the fields of medicine, food, agriculture and the military. PMID- 27998328 TI - 'Apostles of Continence': Doctors and the Doctrine of Sexual Necessity in Progressive-Era America. AB - In the first decades of the twentieth century, a group of doctors under the banner of the social hygiene movement set out on what seemed an improbable mission: to convince American men that they did not need sex. This was in part a response to venereal disease. Persuading young men to adopt the standard of sexual discipline demanded of women was the key to preserving the health of the nation from the ravages of syphilis and gonorrhoea. But their campaign ran up against the doctrine of male sexual necessity, a doctrine well established in medical thought and an article of faith for many patients. Initially, social hygienists succeeded in rallying much of the medical community. But this success was followed by a series of setbacks. Significant dissent remained within the profession. Even more alarmingly, behavioural studies proved that many men simply were not listening. The attempt to repudiate the doctrine of male sexual necessity showed the ambition of Progressive-era doctors, but also their powerlessness in the face of entrenched beliefs about the linkage in men between sex, health and success. PMID- 27998329 TI - Teaching and Researching the History of Medicine in the Era of (Big) Data: Introduction. PMID- 27998326 TI - Reward-related neural activity and structure predict future substance use in dysregulated youth. AB - BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions. PMID- 27998330 TI - Medical Science Meets 'Development Aid' Transfer and Adaptation of West German Microbiology to Togo, 1960-1980. AB - After losing the importance it had held around 1900 both as a colonial power and in the field of tropical medicine, Germany searched for a new place in international health care during decolonisation. Under the aegis of early government 'development aid', which started in 1956, medical academics from West German universities became involved in several Asian, African and South American countries. The example selected for closer study is the support for the national hygiene institute in Togo, a former German 'model colony' and now a stout ally of the West. Positioned between public health and scientific research, between 'development aid' and academia and between West German and West African interests, the project required multiple arrangements that are analysed for their impact on the co-operation between the two countries. In a country like Togo, where higher education had been neglected under colonial rule, having qualified national staff became the decisive factor for the project. While routine services soon worked well, research required more sustained 'capacity building' and did not lead to joint work on equal terms. In West Germany, the arrangement with the universities was a mutual benefit deal for government officials and medical academics. West German 'development aid' did not have to create permanent jobs at home for the consulting experts it needed; it improved its chances to find sufficiently qualified German staff to work abroad and it profited from the academic renown of its consultants. The medical scientists secured jobs and research opportunities for their postgraduates, received grants for foreign doctoral students, gained additional expertise and enjoyed international prestige. Independence from foreign politics was not an issue for most West German medical academics in the 1960s. PMID- 27998331 TI - Yesterday's Doctors: The Human Aspects of Medical Education in Britain, 1957-93. AB - In the wake of the Second World War there was a movement to counterbalance the apparently increasingly technical nature of medical education. These reforms sought a more holistic model of care and to put people - rather than diseases - back at the centre of medical practice and medical education. This article shows that students often drove the early stages of education reform. Their innovations focused on relationships between doctors and their communities, and often took the form of informal discussions about medical ethics and the social dimensions of primary care. Medical schools began to pursue 'humanistic' education more formally from the 1980s onwards, particularly within the context of general practice curricula and with a focus on individual doctor-patient relationships. Overall from the 1950s to the 1990s there was a broad shift in discussions of the human aspects of medical education: from interest in patient communities to individuals; from social concerns to personal characteristics; and from the relatively abstract to the measurable and instrumental. There was no clear shift from 'less' to 'more' humanistic education, but rather a shift in the perceived goals of integrating human aspects of medical education. The human aspects of medicine show the importance of student activism in driving forward community and ethical medicine, and provide an important backdrop to the rise of competencies within general undergraduate education. PMID- 27998332 TI - 'Electroshock Therapy' in the Third Reich. AB - The history of 'electroshock therapy' (now known as electroconvulsive therapy (ECT)) in Europe in the Third Reich is still a neglected chapter in medical history. Since Thomas Szasz's 'From the Slaughterhouse to the Madhouse', prejudices have hindered a thorough historical analysis of the introduction and early application of electroshock therapy during the period of National Socialism and the Second World War. Contrary to the assumption of a 'dialectics of healing and killing', the introduction of electroshock therapy in the German Reich and occupied territories was neither especially swift nor radical. Electroshock therapy, much like the preceding 'shock therapies', insulin coma therapy and cardiazol convulsive therapy, contradicted the genetic dogma of schizophrenia, in which only one 'treatment' was permissible: primary prevention by sterilisation. However, industrial companies such as Siemens-Reiniger-Werke AG (SRW) embraced the new development in medical technology. Moreover, they knew how to use existing patents on the electrical anaesthesia used for slaughtering to maintain a leading position in the new electroshock therapy market. Only after the end of the official 'euthanasia' murder operation in August 1941, entitled T4, did the psychiatric elite begin to promote electroshock therapy as a modern 'unspecific' treatment in order to reframe psychiatry as an 'honorable' medical discipline. War-related shortages hindered even the then politically supported production of electroshock devices. Research into electroshock therapy remained minimal and was mainly concerned with internationally shared safety concerns regarding its clinical application. However, within the Third Reich, electroshock therapy was not only introduced in psychiatric hospitals, asylums, and in the Auschwitz concentration camp in order to get patients back to work, it was also modified for 'euthanasia' murder. PMID- 27998333 TI - Crossing the Rubicon: Death in 'The Year of the Transplant'. AB - How death should be measured was a subject of intense debate during the late 1960s, and one in which transplant surgeons had a particular interest. Legislation required a doctor to first pronounce 'extinct' the patients from whom 'spare parts' were sought for grafting. But transplant surgeons increasingly argued the moment of death was less important than was the moment of establishing that a patient was beyond the point of no return in dying, at which time she or he should be passed to the transplant team. This raised concerns that people identified as being a potential source of organs might not be adequately cared for in their own right. In 1968 the World Medical Association issued an international statement on death at its meeting in Sydney, Australia following a debate between delegates about how and by whom death should be assessed prior to organ removal. Soon afterwards Australian surgeons performed two of the one hundred and five heart transplants carried out around the world that year, dubbed by the New York Times to be one during which an 'international epidemic' of such grafts were carried out. This essay examines debates about death and transplanting, then analyses the pioneering Australian heart transplants, in the context of the Declaration of Sydney and continuing international discussions about whether these operations were moral and legal. PMID- 27998334 TI - Data, Humanities and the History of Medicine: New Pedagogical Approaches. PMID- 27998362 TI - Seasonal and Morphological Variations of Brown Trout (Salmo trutta f. fario) Kidney Peroxisomes: A Stereological Study. AB - Literature about fish kidney peroxisomes is scarce. To tackle this caveat, a stereological approach on renal peroxisome morphological parameters was performed for the first time in a fish, establishing correlations with maturation stages as it was previously done in brown trout liver. Three-year-old brown trout males and females were collected at the major seasons of their reproductive cycle. Trunk kidney was fixed and processed for catalase cytochemistry. Classical stereological methods were applied to electromicrographs to quantitate morphological parameters. Different seasonal variation patterns were observed between genders, and between renal proximal tubule segments I and II. In males, peroxisomes from proximal tubule segment II had a relatively higher volume and number in May, being individually bigger in February. Females presented similar trends, though with less marked variations. Overall, males and females did not show exactly the same seasonal patterns for most peroxisomal parameters, and no correlations were found between the latter and the gonado-somatic index (GSI). Hence, and despite the variations, the morphology of renal peroxisomes is not strictly correlated with gonad maturation kinetics, therefore suggesting that kidney peroxisome morphology is not seasonally modulated by sex steroids, like estradiol, as it seems to happen in liver peroxisomes. PMID- 27998363 TI - Non-Destructive Micro-Chemical and Micro-Luminescence Characterization of Jadeite. AB - Jadeite was greatly appreciated by pre-Hispanic cultures in Mesoamerica. Despite its importance, knowledge of its mining sources was lost after the Spanish conquest. In the 1950s the only confirmed jadeite deposits in Mesoamerica were found in the Motagua River Fault (MRF), Guatemala. The aim of this study is to present a methodology that is appropriate for the study of archeological jadeite objects using non-destructive spectroscopic and micro-ion beam analysis techniques. This methodology has been applied to perform mineral, elemental, and luminescence characterization of five jadeite samples from the MRF, with white, lilac, and green colors. Fourier-transformed infrared spectroscopy and X-ray diffraction analysis confirmed the presence of jadeite, albite, and omphacite as the main mineral phases in the samples. Elemental maps using particle-induced X ray emission (PIXE) with a nuclear microprobe and elemental concentration analysis from individual mineral grains using micro-PIXE coupled with micro ionoluminescence (IL) allowed the detection of minor feldspar, titanite, and grossular mineral contents. Distinctive features from the mineral, elemental, and luminescence characterization have been found that allow the identification of these five jadeite samples. PMID- 27998364 TI - Bone Healing Following Different Types of Osteotomy: Scanning Electron Microscopy (SEM) and Three-Dimensional SEM Analyses. AB - The aim of the present study was to compare dynamics of the bone healing process after different types of osteotomies. In total, 24 Wistar rats were subjected to different types of osteotomy performed with standard steel bur, piezosurgery, contact, and non-contact Erbium:yttrium-aluminum-garnet (Er:YAG) laser ablation. The animals were randomly divided into four groups, to be euthanized immediately after the procedure, or at 1, 2, or 3 weeks after surgery. The obtained bone samples were analyzed by scanning electron microscopy (SEM). Immediately after surgery, there were significant differences in the appearance of the bone defects, with presence of bone fragments and debris after standard steel bur preparation, compared with the clean smooth walls and relatively sharp edges in all other groups. The initial bone formation in defects prepared by piezosurgery was observed to be the most rapid. After 3 weeks, all bone defects were completely restored; although, differences in the healing pattern were noted, with a modest initial delay in healing after laser preparation. The first stage of the bone healing process was delayed when contact and non-contact Er:YAG laser modes were used and accelerated by piezosurgery; however, the results after 3 weeks demonstrated similar restitution of defects in all tested groups. PMID- 27998365 TI - Histopathological Effects on Gills of Nile Tilapia (Oreochromis niloticus, Linnaeus, 1758) Exposed to Pb and Carbon Nanotubes. AB - The effect of heavy metal in fish has been the focus of extensive research for many years. However, the combined effect of heavy metals and nanomaterials is still a new subject that needs to be studied. The aim of this study was to examine histopathologic alterations in the gills of Nile tilapia (Oreochromis niloticus) to determine possible effects of lead (Pb), carbon nanotubes, and Pb+carbon nanotubes on their histological integrity, and if this biological system can be used as a tool for evaluating water quality in monitoring programs. For this, tilapia were exposed to Pb, carbon nanotubes and Pb+carbon nanotubes for 4 days. The main alterations observed were epithelial structure, hyperplasia and displacement of epithelial cells, and alterations of the structure and occurrence of aneurysms in the secondary lamella. The most severe alterations were related to the Pb+carbon nanotubes. We conclude that the oxidized multi walled carbon nanotubes enhanced the acute lead toxicity in Nile tilapias. This work draws attention to the implications of carbon nanomaterials released in the aquatic environment and their interaction with classical pollutants. PMID- 27998366 TI - Correlative Energy-Dispersive X-Ray Spectroscopic Tomography and Atom Probe Tomography of the Phase Separation in an Alnico 8 Alloy. AB - Alnico alloys have long been used as strong permanent magnets because of their ferromagnetism and high coercivity. Understanding their structural details allows for better prediction of the resulting magnetic properties. However, quantitative three-dimensional characterization of the phase separation in these alloys is still challenged by the spatial quantification of nanoscale phases. Herein, we apply a dual tomography approach, where correlative scanning transmission electron microscopy (STEM) energy-dispersive X-ray spectroscopic (EDS) tomography and atom probe tomography (APT) are used to investigate the initial phase separation process of an alnico 8 alloy upon non-magnetic annealing. STEM-EDS tomography provides information on the morphology and volume fractions of Fe-Co rich and Nui-Al-rich phases after spinodal decomposition in addition to quantitative information of the composition of a nanoscale volume. Subsequent analysis of a portion of the same specimen by APT offers quantitative chemical information of each phase at the sub-nanometer scale. Furthermore, APT reveals small, 2-4 nm Fe-rich alpha 1 phases that are nucleated in the Ni-rich alpha 2 matrix. From this information, we show that phase separation of the alnico 8 alloy consists of both spinodal decomposition and nucleation and growth processes. The complementary benefits and challenges associated with correlative STEM-EDS and APT are discussed. PMID- 27998367 TI - State-of-the-Art Three-Dimensional Chemical Characterization of Solid Oxide Fuel Cell Using Focused Ion Beam Time-of-Flight Secondary Ion Mass Spectrometry Tomography. AB - In this paper the potential of time-of-flight secondary ion mass spectroscopy combined with focused ion beam technology to characterize the composition of a solid oxide fuel cell (SOFC) in three-dimension is demonstrated. The very high sensitivity of this method allows even very small amounts of elements/compounds to be detected and localized. Therefore, interlayer diffusion of elements between porous electrodes and presence of pollutants can be analyzed with a spatial resolution of the order of 100 nm. However, proper element recognition and mass interference still remain important issues. Here, we present a complete elemental analysis of the SOFC as well as techniques that help to validate the reliability of obtained results. A discussion on origins of probable artifacts is provided. PMID- 27998368 TI - Melamine-Formaldehyde Microcapsules: Micro- and Nanostructural Characterization with Electron Microscopy. AB - A systematic study has been carried out to compare the surface morphology, shell thickness, mechanical properties, and binding behavior of melamine-formaldehyde microcapsules of 5-30 MUm diameter size with various amounts of core content by using scanning and transmission electron microscopy including electron tomography, in situ nanomechanical tensile testing, and electron energy-loss spectroscopy. It is found that porosities are present on the outside surface of the capsule shell, but not on the inner surface of the shell. Nanomechanical tensile tests on the capsule shells reveal that Young's modulus of the shell material is higher than that of bulk melamine-formaldehyde and that the shells exhibit a larger fracture strain compared with the bulk. Core-loss elemental analysis of microcapsules embedded in epoxy indicates that during the curing process, the microcapsule-matrix interface remains uniform and the epoxy matrix penetrates into the surface micro-porosities of the capsule shells. PMID- 27998369 TI - A 3-week feed restriction after weaning as an alternative to a medicated diet: effects on growth, health, carcass and meat traits of rabbits of two genotypes. AB - Feed restriction after weaning is widely used in meat rabbit farms to promote health and reduce mortality, but this practice impacts negatively on rabbit growth and slaughter performance. This study compared a 3-week post-weaning feed restriction with ad libitum medicated feeding, evaluating effects on feed intake, growth, health, carcass and meat quality of rabbits of two genotypes: Italian White pure breed and Hycole hybrid*Italian White crossbred. A total of 512 rabbits at 36 days of age, of both sexes and two genotypes, were divided into four homogeneous groups assigned, from 36 to 57 days of age, to different feeding programmes (FP): restricted non-medicated (R-N), ad libitum non-medicated (L-N), restricted medicated (R-M) and ad libitum medicated (L-M). The diets were medicated with oxytetracycline (1540 mg/kg) and colistin sulphate (240 mg/kg). The restriction, performed by giving 70, 80 and 90 g/day of feed for the 1st, 2nd and 3rd week, was followed by ad libitum feeding in the successive 5 weeks, up to slaughter at 92 days of age. Restricted feeds were ingested at a level of 64% of the feed intake recorded in the ad libitum fed rabbits; it was significantly associated, regardless of medication and rabbit genotype, with a lower feed intake (-22 to -24 g dry matter/day) during the entire experiment, compensatory growth and a lower feed conversion ratio in the ad libitum period, and a lower final live weight (-150 g) than ad libitum feeding (P<0.001). During restriction, mortality was lower in the restricted rabbits (6.25%, 5.47% v. 12.5%, 14.8% for R N, R-M, L-N and L-M; P<0.05), whereas in the ad libitum period mortality did not differ among the groups (9.23%, 9.90%, 11.0% and 4.59% for R-N, R-M, L-N and L M). Dressing out percentage was not affected by FP or genotype; heavier carcasses were produced by rabbits fed ad libitum (+100 g; P<0.001) and crossbred rabbits (+122 g; P<0.001). Restriction did not alter meat quality, except for a tendency towards a higher cooking loss and less fat; crossbred meat was higher in L* (+1.3; P<0.01) and b* (+0.51; P<0.05) colour indexes and tenderness (-0.14 kg/cm2; P<0.05) than pure breed meat. Under the conditions of this study, a 3 week restricted feeding after weaning resulted to be a suitable alternative, also for high growth potential genotypes, to the antibiotics to preserve rabbit health. The production of lighter carcasses could be compensated partly by the lower feed conversion ratio showed by restricted rabbits. PMID- 27998370 TI - Understanding delirium trajectory and its importance in care provision for older people. AB - Delirium significantly increases morbidity and mortality in older people, especially those affected by other organic disorders, notably dementia (Siddiqi et al., 2006; Davis et al., 2012; Martins and Fernandes, 2012). Both delirium and dementia are characterized by cognitive decline through disintegration of brain functions, i.e. a "brain failure." Delirium has been described as an acute brain failure, in contrast to dementia being a chronic brain failure (Berrios, 1981). If we consider any other organ failure, for example that of kidneys, delirium superimposed on dementia resembles acute renal exacerbation superimposed on chronic renal failure. The timely recognition and treatment of acute renal failure can reverse its damaging effects, whereas chronic renal failure necessitates long-term and invasive or costly interventions (i.e. dialysis, kidney transplantation). Similarly, recognizing delirium and providing timely interventions can improve its symptoms to recover brain functions, delay cognitive decline, and alleviate distress and disability. PMID- 27998371 TI - The global regulator ANR is essential for Pseudomonas chlororaphis strain PA23 biocontrol. AB - Pseudomonas chlororaphis PA23 is a biocontrol agent capable of protecting canola from stem rot disease caused by the fungus Sclerotinia sclerotiorum. The focus of the current study was to elucidate the role of the transcriptional regulator ANR in the biocontrol capabilities of this bacterium. An anr mutant was created, PA23anr, that was devoid antifungal activity. In other pseudomonads, ANR is essential for regulating HCN production. Characterization of PA23anr revealed that, in addition to HCN, ANR controls phenazine (PHZ), pyrrolnitrin (PRN), protease and autoinducer (AHL) signal molecule production. In gene expression studies, hcnA, phzA, prnA and phzI were found to be downregulated, consistent with our endproduct analysis. Because the phenotype of PA23anr closely resembles that of quorum sensing (QS)-deficient strains, we explored whether there is a connection between ANR and the PhzRI QS system. Both phzI and phzR are positively regulated by ANR, whereas PhzR represses anr transcription. Complementation of PA23anr with pUCP-phzR, C6-HSL or both yielded no change in phenotype. Conversely, PA23phzR harbouring pUCP23-anr exhibited partial-to-full restoration of antifungal activity, HCN, PRN and AHL production together with hcnA, prnA, phzI and rpoS expression. PHZ and protease production remained unchanged indicating that ANR can complement the QS-deficient phenotype with respect to some but not all traits. Our experiments were conducted at atmospheric O2 levels underscoring the fact that ANR has a profound effect on PA23 physiology under aerobic conditions. PMID- 27998372 TI - Improving Accuracy of Home Sleep Apnea Testing. PMID- 27998373 TI - Sleep Quality in an Adult American Indian Community Sample. AB - STUDY OBJECTIVES: Epidemiological studies have found that insufficient sleep (< 7 h/night) is more common among American Indians/Alaska Natives (AI/AN). In this study we sought to identify specific demographic, clinical, and cultural factors that may be associated with reduced sleep quality in an American Indian community sample. METHODS: Information on demography along with personal medical, psychiatric, and drinking history was obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The adult participants (n = 386, 54% women) had a mean +/- standard deviation age of 31.35 +/- 14.4 y. Higher degrees of AI ancestry, but not cultural identification, being older than 30 y, and having a high school diploma all were factors predictive of having a short sleep duration (< 6 h). The global score on the PSQI was significantly higher in those participants with a lifetime diagnosis of substance use disorders, anxiety disorders, and affective disorders. Alcohol use disorders and affective disorders were significant predictors of sleep latency whereas anxiety and affective disorders were correlated with waking more often in the night/early morning. Nicotine dependence was associated with having trouble breathing, and alcohol use disorders and anxiety disorders with bad dreams. CONCLUSIONS: Alcohol use disorders are associated with poorer quality of sleep in this population and substance use disorders were associated with different aspects of sleep than anxiety and depressive disorders. These findings add to the understanding of the interactions between sleep and substance use, anxiety, and affective disorders in an understudied and underserved population. PMID- 27998374 TI - A Four-Year-Old Boy with Unusually Severe Obstructive Sleep Apnea. PMID- 27998375 TI - Sleep Disturbances in OEF/OIF/OND Veterans: Associations with PTSD, Personality, and Coping. AB - STUDY OBJECTIVES: Sleep disturbances are well documented in relation to trauma exposure and posttraumatic stress disorder (PTSD), but correlates of such disturbances remain understudied in veteran populations. We conducted a preliminary study of sleep disturbances in Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (n = 133; mean [standard deviation] age = 29.8 [4.7] y). METHODS: Veterans were assigned to one of three groups based on responses to the Clinician Administered PTSD Scale: control (no trauma-exposure [TE] or PTSD), TE, and PTSD. Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Measures of resilience, trauma load, personality, coping, alcohol use, and mild traumatic brain injury were also assessed via self-report. RESULTS: The PTSD group had significantly more disturbed sleep (PSQI global score mean = 8.94, standard deviation = 3.12) than control (mean = 5.27, standard deviation = 3.23) and TE (mean = 5.34, standard deviation = 3.17) groups, but there were no differences between TE and control. The same pattern emerged across most PSQI subscales. Results of linear regression analyses indicated that current smoking, Army (versus other military branches), neuroticism, and using substances to cope were all significant correlates of higher sleep disturbance, whereas post-deployment social support was associated with less sleep disturbance. However, when combined together into a model with PTSD status, only neuroticism and substance use coping remained significant as predictors of more disturbed sleep. CONCLUSIONS: These initial findings suggest that TE itself may not be an independent risk factor for disturbed sleep in veterans, and that neurotic personality and a tendency to cope by using substances may partially explain sleep disturbance, above and beyond a diagnosis of PTSD. PMID- 27998376 TI - Vitamin D Deficiency in Patients Referred for Evaluation of Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: A recent study reported an association between obstructive sleep apnea (OSA) and low vitamin D levels. In this study, we measured vitamin D levels in patients referred for evaluation of suspected OSA and sought to identify associated risk factors for vitamin D deficiency. Our objective was to determine whether evaluations of patients with suspected OSA should include routine screening for vitamin D deficiency. METHODS: Using a cross-sectional study design, we measured vitamin D levels in consecutively enrolled patients referred for an OSA evaluation to Dr. Lutfi Kirdar Kartal Training and Research Hospital in Istanbul, Turkey. We conducted full-night polysomnography and compared vitamin D levels both between patients with OSA and patients without OSA and across the various severity levels of OSA. We evaluated the association between vitamin D levels and various clinical and demographic characteristics, including the apnea-hypopnea index and body mass index. RESULTS: From April 2014 to June 2015, 195 patients were referred for OSA evaluation. Of these, 181 patients (93%) consented to participate and underwent full polysomnography and measurement of vitamin D levels. The mean +/- standard deviation age was 49 +/- 12 years and body mass index of 31 +/- 6 kg/m2. Polysomnography led to the diagnosis of OSA in 162 of the patients (89.5%): 52 (32%) were categorized as having mild OSA, 38 (23.5%) as having moderate OSA, and 72 (44.5%) as having severe OSA. Vitamin D level was 15.5 +/- 11.6 ng/mL (95% confidence interval; 13 17 ng/mL) and 134 patients (74%) met the criterion for vitamin D deficiency (< 20 ng/mL). Sex, vitamin D levels, and percentage of patients with vitamin D deficiency were similar in patients with and without OSA (P > .05). Vitamin D levels were similar across OSA severity categories (P = .68). We found no association between vitamin D levels and the apnea-hypopnea index or body mass index. CONCLUSION: A large proportion of patients referred for OSA evaluation had vitamin D deficiency. Vitamin D levels did not differ by OSA diagnosis status or severity. Patients referred for polysomnography should undergo routine screening for vitamin D deficiency as well as clinically indicated treatment to prevent associated comorbidities. PMID- 27998377 TI - Relationship of Sleep Duration with Sociodemographic Characteristics, Lifestyle, Mental Health, and Chronic Diseases in a Large Chinese Adult Population. AB - STUDY OBJECTIVES: Pattern of sleep duration and its correlates have rarely been reported in China. This study examined the sleep duration and its relationship with sociodemographic variables, lifestyle, mental health, and chronic diseases in a large Chinese adult population. METHODS: This cross-sectional study used multistage stratified cluster sampling. A total of 17,320 participants from Jilin province were selected and interviewed using standardized assessment tools. Basic socio-demographic and clinical data were collected. Sleep duration was classified as short (< 7 h per day), long (> 9 h per day) and medium sleep (7-9 h per day). RESULTS: The mean age of the sample was 42.60 +/- 10.60 y, with 51.4% being female. The mean sleep duration was 7.31 +/- 1.44 h. Short and long sleepers accounted for 30.9% and 6.9% of the sample, respectively. Multinomial logistic regression analysis revealed that older age, current smoking, irregular meal pattern, lack of physical exercise, poor mental health, and chronic diseases or multimorbidity were positively associated with short sleep. Being married and living in rural areas were, however, negatively associated with short sleep. In addition, living in rural area, current smoking, current alcohol use and lack of physical exercise were positively associated with long sleep, while older age and lower education were negatively associated with long sleep. CONCLUSION: Given the high frequency of short sleep and its negative effect on health, health professionals should pay more attention to sleep patterns in general health care. Nationwide epidemiologic surveys in China are needed to further explore the relationship between sleep duration and health. PMID- 27998378 TI - Validation of Contact-Free Sleep Monitoring Device with Comparison to Polysomnography. AB - STUDY OBJECTIVES: To validate a contact-free system designed to achieve maximal comfort during long-term sleep monitoring, together with high monitoring accuracy. METHODS: We used a contact-free monitoring system (EarlySense, Ltd., Israel), comprising an under-the-mattress piezoelectric sensor and a smartphone application, to collect vital signs and analyze sleep. Heart rate (HR), respiratory rate (RR), body movement, and calculated sleep-related parameters from the EarlySense (ES) sensor were compared to data simultaneously generated by the gold standard, polysomnography (PSG). Subjects in the sleep laboratory underwent overnight technician-attended full PSG, whereas subjects at home were recorded for 1 to 3 nights with portable partial PSG devices. Data were compared epoch by epoch. RESULTS: A total of 63 subjects (85 nights) were recorded under a variety of sleep conditions. Compared to PSG, the contact-free system showed similar values for average total sleep time (TST), % wake, % rapid eye movement, and % non-rapid eye movement sleep, with 96.1% and 93.3% accuracy of continuous measurement of HR and RR, respectively. We found a linear correlation between TST measured by the sensor and TST determined by PSG, with a coefficient of 0.98 (R = 0.87). Epoch-by-epoch comparison with PSG in the sleep laboratory setting revealed that the system showed sleep detection sensitivity, specificity, and accuracy of 92.5%, 80.4%, and 90.5%, respectively. CONCLUSIONS: TST estimates with the contact-free sleep monitoring system were closely correlated with the gold-standard reference. This system shows good sleep staging capability with improved performance over accelerometer-based apps, and collects additional physiological information on heart rate and respiratory rate. PMID- 27998380 TI - The Past Is Prologue: The Future of Sleep Medicine. AB - ABSTRACT: The field of sleep medicine has gone through tremendous growth and development over a short period of time, culminating in recognition of the field as an independent medical subspecialty by the Accreditation Council for Graduate Medical Education (ACGME) and the American Board of Medical Specialties (ABMS). However, the fellowship training requirement that is now mandatory for sleep medicine board certification eligibility has had the unintended consequence of restricting the influx of young physicians to the field. In response to the potential workforce shortage confronting the field of sleep medicine, the American Academy of Sleep Medicine (AASM) board of directors has developed a comprehensive plan to strengthen the field by growing sleep fellowship programs, exploring novel sleep medicine training opportunities, creating and fostering the sleep team (with special emphasis on engagement of primary care providers), embracing the role of consumer sleep technologies, and expanding the reach of sleep specialists through telemedicine. The AASM plans summarized in this special article represent efforts to confront serious workforce challenges and turn them into opportunities that will improve the health of both our patients and our field. PMID- 27998381 TI - Who Needs Oxygen with Positive Airway Pressure Therapy? PMID- 27998382 TI - The PTSD-OSA Paradox: They Are Commonly Associated and They Worsen Outcomes, but Treatment Nonadherence Is Common and the Therapeutic Effect Limited. What Are Clinicians To Do? PMID- 27998383 TI - Efficacy of Gold Nanoparticles against Nephrotoxicity Induced by Schistosoma mansoni Infection in Mice. AB - OBJECTIVE: In this study, the ameliorative effects of gold nanoparticles (gold NP) on the renal tissue damage in Schistosoma mansoni (S. mansoni)-infected mice was investigated. METHODS: High-resolution transmission electron microscopy was used for the characterization of NP. The gold NP at concentrations of 250, 500, and 1000 MUg/kg body weight were inoculated into S. mansoni-infected mice. RESULTS: The parasite caused alterations in the histological architecture. Furthermore, it induced a significant reduction in the renal glutathione levels; however, the levels of nitric oxide and malondialdehyde were significantly elevated. The parasite also managed to downregulate KIM-1, NGAL, MCP-1, and TGF beta mRNA expression in infected animals. Notably, gold NP treatment in mice reduced the extent of histological impairment and renal oxidative damage. Gold NP were able to regulate gene expression impaired by S. Mansoni infection. CONCLUSION: The curative effect of gold NP against renal toxicity in S. mansoni infected mice is associated with their role as free radical scavengers. PMID- 27998379 TI - Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. AB - INTRODUCTION: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults. METHODS: The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). PMID- 27998384 TI - The RAS/PI3K Pathway is Involved in the Impairment of Long-term Potentiation Induced by Acute Aluminum Treatment in Rats. AB - OBJECTIVE: To explore the role of RAS/PI3K pathway in the impairment of long-term potentiation (LTP) induced by acute aluminum (Al) treatment in rats in vivo. METHODS: First, different dosages of aluminum-maltolate complex [Al(mal)3] were given to rats via acute intracerebroventricular (i.c.v.) injection. Following Al exposure, the RAS activity of rat hippocampus were detected by ELISA assay after the hippocampal LTP recording by field potentiation technique in vivo. Second, the antagonism on the aluminum-induced suppression of hippocampal LTP was observed after the treatment of the RAS activator epidermal growth factor (EGF). Finally, the antagonism on the downstream molecules (PKB activity and the phosphorylation of GluR1 S831 and S845) were tested by ELISA and West-blot assays at the same time. RESULTS: With the increasing aluminum dosage, a gradually decreasing in RAS activity of the rat hippocampus was produced after a gradually suppressing on LTP. The aluminum-induced early suppression of hippocampal LTP was antagonized by the RAS activator epidermal growth factor (EGF). And the EGF treatment produced changes similar to those observed for LTP between the groups on PKB activity as well as the phosphorylation of GluR1 S831 and S845. CONCLUSION: The RAS->PI3K/PKB->GluR1 S831 and S845 signal transduction pathway may be involved in the inhibition of hippocampal LTP by aluminum exposure in rats. However, the mechanisms underlying this observation need further investigation. PMID- 27998385 TI - Hepatitis B Immunoprophylactic Failure and Characteristics of the Hepatitis B Virus Gene in Mother-Infant Pairs in Parts of China. AB - OBJECTIVE: To determine the hepatitis B immunoprophylactic failure rate in infants born to hepatitis B virus (HBV) infected mothers and to characterize HBV genes. METHODS: HBV-serological testing was conducted for pregnant women and infants. The complete genomes of 30 HBV isolates were sequenced, and genetic characteristics were analyzed using MEGA 5 software. RESULTS: The immunoprophylactic failure rate for infants who had completed the scheduled hepatitis B vaccination program was 5.76% (32/556). High sequence homology (99.8% 100%) was observed in 8 of the 10 mother-infant pairs. We identified 19 subgenotype C2 strains, 9 subgenotype B2 strains, and 2 subgenotype C1 strains. Three serotypes were detected: adr (19/30), adw (9/30), and ayw (2/30). The frequency of amino acid mutation of the 'a' determinant region was 16.67% (5/30), including that of Q129H, F134Y, S136Y, and G145E. We detected 67 amino acid mutations in the basal core promoter, precore, and core regions of the genome. CONCLUSION: The immunoprophylactic failure rate in infants born to HBV-infected mothers is low in the regions of China examined during this study. Moreover, HBV mutation in the 'a' determinant region could not account for immunoprophylactic failure for all infants. PMID- 27998387 TI - Association of TCF7L2 and GCG Gene Variants with Insulin Secretion, Insulin Resistance, and Obesity in New-onset Diabetes. AB - This cohort study was designed to evaluate the association of transcription factor 7-like 2 (TCF7L2) and proglucagon gene (GCG) variants with disordered glucose metabolism and the incidence of type 2 diabetes mellitus (T2DM) in a rural adult Chinese population. A total of 7,751 non-T2DM participants ?18 years old genotyped at baseline were recruited. The same questionnaire interview and physical and blood biochemical examinations were performed at both baseline and follow-up. During a median 6 years of follow-up, T2DM developed in 227 participants. After adjustment for potential contributory factors, nominally significant associations were seen between TT genotype and the recessive model of TCF7L2 rs7903146 and increased risk of T2DM [hazard ratio (HR)=4.068, 95% confidence interval (CI): 1.270-13.026; HR=4.051, 95% CI: 1.268-12.946, respectively]. The TT genotype of rs7903146 was also significantly associated with higher fasting plasma insulin level and the homeostasis model assessment of insulin resistance in case of new-onset diabetes. In addition, the TCF7L2 rs290487 TT genotype was associated with abdominal obesity and the GCG rs12104705 CC genotype was associated with both general obesity and abdominal obesity in case of new-onset diabetes. PMID- 27998386 TI - Analysis of a Community-based Intervention to Reduce Heat-related Illness during Heat Waves in Licheng, China: a Quasi-experimental Study. AB - OBJECTIVE: To reduce health-related threats of heat waves, interventions have been implemented in many parts of the world. However, there is a lack of higher level evidence concerning the intervention efficacy. This study aimed to determine the efficacy of an intervention to reduce the number of heat-related illnesses. METHODS: A quasi-experimental design was employed by two cross sectional surveys in the year 2014 and 2015, including 2,240 participants and 2,356 participants, respectively. Each survey was designed to include one control group and one intervention group, which conducted in Licheng, China. A representative sample was selected using a multistage sampling method. Data, collected from questionnaires about heat waves in 2014 and 2015, were analyzed using a difference-in-difference analysis and cost effectiveness analysis. Outcomes included changes in the prevalence of heat-related illnesses and cost effectiveness variables. RESULTS: Relative to the control participants, the prevalence of heat-related illness in the intervention participants decreased to a greater extent in rural areas than in urban areas (OR=0.495 vs. OR=1.281). Moreover, the cost-effectiveness ratio in the intervention group was less than that in the control group (US$15.06 vs. US$15.69 per participant). Furthermore, to avoid one additional patient, the incremental cost-effectiveness ratio showed that an additional US$14.47 would be needed for the intervention compared to when no intervention was applied. CONCLUSION: The intervention program may be considered a worthwhile investment for rural areas that are more likely to experience heat waves. Meanwhile, corresponding improving measures should be presented towards urban areas. Future research should examine whether the intervention strategies could be spread out in other domestic or international regions where heat waves are usually experienced. PMID- 27998388 TI - Nail Selenium Level and Diabetes in Older People in Rural China. AB - This cross-sectional study aimed to examine the association between selenium levels and diabetes in an older population with life-long natural exposure to selenium in rural China. A total of 1856 subjects aged 65 years or older from four Chinese rural counties with different environmental selenium levels were evaluated. Analysis of covariance models and logistic regression models were used to examine the relationship between nail selenium levels and serum glucose, serum insulin, insulin resistance [using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)], and the risk of diabetes. The mean nail selenium level was 0.461 MUg/g and the prevalence rate of diabetes was 8.3% in this population. The mean nail selenium level was significantly higher in the group with diabetes than in the group without diabetes (P<0.0001). The adjusted odds ratios for diabetes were 2.65 (95% CI: 1.48 to 4.73), 2.47 (95% CI: 1.37 to 4.45), and 3.30 (95% CI: 1.85 to 5.88) from the second selenium quartile to the fourth quartile, respectively, compared with the first quartile group. The mean serum glucose and HOMA-IR in the higher selenium quartile groups were significantly higher than those of the lowest quartile group. However, no significant differences in insulin were observed among the four quartile groups. A long-term, higher level of exposure to selenium may be associated with a higher risk of diabetes. Future studies are needed to elucidate the association between selenium and insulin resistance. PMID- 27998390 TI - Cut-off Values of Diagnostic Indices to Detect Iron Deficiency in Chinese Breast fed Infants. AB - Iron deficiency anemia is one of the most prevalent nutritional deficiency worldwide. The commonly used cut-off values for identifying iron deficiency are extrapolated from older children and may not be suitable for infants. Therefore, our study aimed to establish appropriate cut-off values for the evaluation of iron status in Chinese infants. Pregnant women who delivered at ?37 gestational weeks with normal iron status were recruited. Later, infants with normal birth weight and who were breastfed in the first 4 months were selected. Blood samples were collected to assess hemoglobin, serum ferritin, soluble transferrin receptor, mean corpuscular volume and free erythrocyte protoporphyrin. Cut-offs of all iron indices were determined as the limit of 95% confidence interval. PMID- 27998389 TI - Toll-like Receptor 1 Polymorphisms Increased the Risk of Pulmonary Tuberculosis in an Iranian Population Sample. AB - A case-control study was carried out that involved 203 individuals diagnosed with pulmonary tuberculosis (PTB) and 203 healthy subjects. Genotyping of TLR1 rs5743551 and rs5743618 polymorphisms was done using polymerase chain reaction restriction fragments length polymorphism assay. We found that TLR1 rs5743551 variant affected the risk of PTB in the codominant (OR=3.28, 95% CI=1.98-5.45, P<0.0001, GA vs. GG; OR=1.86, 95% CI=1.05-3.28, P=0.033, AA vs. GG) and dominant (OR=2.69, 95% CI=1.67-4.34, P<0.0001, GA+AA vs. GG) inheritance models tested. The A allele was associated with a higher risk of PTB than the G allele (OR=1.33, 95% CI=1.01-1.75, P=0.049). The TG genotype of the rs5743618 variant significantly increased the risk of PTB compared to the risk associated with the TT genotype (OR=3.29, 95% CI=1.82-5.97, P<0.0001). The G allele was associated with a higher risk of PTB than the T allele (OR=3.00, 95% CI=1.69-5.31, P=0.0001). Our findings revealed that TLR1 rs5743551 and rs5743618 polymorphisms affected the risk of PTB in an Iranian population sample. Additional studies with larger sample sizes and involving subjects of different ethnicities are required to validate our present findings. PMID- 27998391 TI - Obesity, Body Fat Distribution, and Physical Activity in School-age Children: an Urban and Rural Comparison in Valparaiso, Chile. AB - This study analyze the relation between body composition, physical activity (PA), and sex in Chilean children from rural and urban public educational institutions. The prevalence of obesity (according to BMI) was 30.88% in urban children and 28.93% in rural children. Central obesity presented mainly in the rural girls. Approximately 90% of the participants reported <7 h of PA/week, regardless of residential area. In addition, central fat was strongly associated with rural residence; the children reported lower PA levels, and they presented a higher prevalence of central fat. The results reflect the need to implement programs to improve PA conditions in the child urban-rural population. PMID- 27998392 TI - The Role of Nutrition Education in the Promotion of Iron-Fortified Soy Sauce in China. PMID- 27998393 TI - Extracellular S100A4 negatively regulates osteoblast function by activating the NF-kappaB pathway. AB - Patients with inflammatory bone disease or cancer exhibit an increased risk of fractures and delayed bone healing. The S100A4 protein is a member of the calcium binding S100 protein family, which is abundantly expressed in inflammatory diseases and cancers. We investigated the effects of extracellular S100A4 on osteoblasts, which are cells responsible for bone formation. Treating primary calvarial osteoblasts with recombinant S100A4 resulted in matrix mineralization reductions. The expression of osteoblast marker genes including osteocalcin and osterix was also suppressed. Interestingly, S100A4 stimulated the nuclear factor kappaB (NF-kappaB) signaling pathway in osteoblasts. More importantly, the ex vivo organ culture of mouse calvariae with recombinant S100A4 decreased the expression levels of osteocalcin, supporting the results of our in vitro experiments. This suggests that extracellular S100A4 is important for the regulation of bone formation by activating the NF-kappaB signaling pathway in osteoblasts. [BMB Reports 2017; 50(2): 97-102]. PMID- 27998394 TI - The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamilinduced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen induced cytotoxicity. [BMB Reports 2017; 50(2): 91-96]. PMID- 27998395 TI - Neuropeptide Y-based recombinant peptides ameliorate bone loss in mice by regulating hematopoietic stem/progenitor cell mobilization. AB - Ovariectomy-induced bone loss is related to an increased deposition of osteoclasts on bone surfaces. We reported that the 36-amino-acid-long neuropeptide Y (NPY) could mobilize hematopoietic stem/progenitor cells (HSPCs) from the bone marrow to the peripheral blood by regulating HSPC maintenance factors and that mobilization of HSPCs ameliorated low bone density in an ovariectomy-induced osteoporosis mouse model by reducing the number of osteoclasts. Here, we demonstrated that new NPY peptides, recombined from the cleavage of the full-length NPY, showed better functionality for HSPC mobilization than the full-length peptide. These recombinant peptides mediated HSPC mobilization with greater efficiency by decreasing HSPC maintenance factors. Furthermore, treatment with these peptides reduced the number of osteoclasts and relieved ovariectomy-induced bone loss in mice more effectively than treatment with full-length NPY. Therefore, these results suggest that peptides recombined from full-length NPY can be used to treat osteoporosis. [BMB Reports 2017; 50(3): 138-143]. PMID- 27998396 TI - The worldwide trend of using botanical drugs and strategies for developing global drugs. AB - Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with healthenhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development. [BMB Reports 2017; 50(3): 111-116]. PMID- 27998398 TI - [Status of elderly disability in 7 cities of China]. AB - Objective: This study focused on the proportions of disability in old people of China (rural and urban) and the demographic characteristics of disability. Methods: Random sampling was used that including stratified, multiple-stage, and cluster sampling methods. This research project was conducted in 7 municipalities (north, south) of China, including 6 864 urban and rural people aged 60 and above. Interviewers used unified questionnaire and performed door to door. Basic and related information on disability of the community elderly were gathered. chi2 test was used to compare the differences of rates on the extent of disability among different groups of elderly. Results: Health condition and disability assessment on 6 864 urban and rural elderly living in the communities were analyzed. The overall mean rate of disability in the elderly was 7.0%, with the proportion of disability in women (7.9%) significantly higher than in men (6.0%) (P<0.01). Proportions of disability in rural areas (10.9%) were significantly higher than those in urban areas (4.7%) (P<0.01). Region wise, it was also seen higher in the north (7.6%) than in the south (5.4%) (P<0.01) parts of the country. The rates of disability in cities as Beijing, Chongqing, Haerbin, Chengdu, Xi'an, Changsha, Shanghai were 5.7%, 5.3%, 4.5%, 3.9%, 3.0%, 2.3%, 1.2% (P<0.01) respectively with Beijing being the highest and Shanghai being the lowest, all with statistical significances. Mean disability rates in the age groups of 60-, 65-, 70-, 75- and >=80 were 2.5%, 4.0%, 5.3%, 9.9% and 25.1% (P<0.01) respectively, with the rising rates of disability parallel to the increase of age. Conclusion: In China, the overall rate of disability in the elderly (urban and rural community) was 7.0%. The rates of disability were significantly higher in women than in men, in rural than in urban areas and higher in the north than in the south parts of the country. The rates of disability were increasing along with age of the elderly. PMID- 27998399 TI - [Factors associated with quitting intention among male daily smokers in rural areas]. AB - Objective: To study the intention on quitting smoking and related factors, so as to provide evidence on related important determinants. Methods: A cross-sectional study was conducted in 14 villages in Shandong, China. A total of 1 287 male daily smokers were interviewed, face-to-face. Multiple logistic regression method was used to assess the factors associated with quitting intention among male daily smokers. Dominance analysis was used to assess the relative contribution of determinants on quitting intention which were identified in the multiple logistic regression model. Results: Among 1 287 male daily smokers, 24.7% expressed quitting intention within the next 6 months. Four determinants for quitting intention were identified in the multiple logistic regression model, including previous experience of quitting attempt (OR=1.691, 95% CI:1.458-1.962), lower level of smoking intensity (OR=0.751, 95%CI: 0.639-0.884), extensive knowledge on specific health effects of smoking (OR=1.038, 95% CI: 1.001-1.077) and presence of chronic disease (OR=1.765, 95% CI: 1.013-3.075). Results from the dominance analysis showed that 'previous quitting attempt experience' was the most important determinant regarding quitting intention, followed by low smoking intensity, knowledge of the specific health effects of smoking, and the presence of chronic disease. Conclusion: The rate of quitting intention on cigarette smoking among rural male smokers remained low. Quitting intention was associated with previous quit attempt experience. PMID- 27998397 TI - Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. AB - Most of the cancers are still incurable human diseases. According to recent findings, especially targeting cancer stem cells (CSCs) is the most promising therapeutic strategy. CSCs take charge of a cancer hierarchy, harboring stem cell like properties involving self-renewal and aberrant differentiation potential. Most of all, the presence of CSCs is closely associated with tumorigenesis and therapeutic resistance. Despite the numerous efforts to target CSCs, current anti cancer therapies are still impeded by CSC-derived cancer malignancies; increased metastases, tumor recurrence, and even acquired resistance against the anti-CSC therapies developed in experimental models. One of the most forceful underlying reasons is a "cancer heterogeneity" due to "CSC plasticity". A comprehensive understanding of CSC-derived heterogeneity will provide novel insights into the establishment of efficient targeting strategies to eliminate CSCs. Here, we introduce findings on mechanisms of CSC reprogramming and CSC plasticity, which give rise to phenotypically varied CSCs. Also, we suggest concepts to improve CSC targeted therapy in order to overcome therapeutic resistance caused by CSC plasticity and heterogeneity. [BMB Reports 2017; 50(3): 117-125]. PMID- 27998400 TI - [Factors related to the influence on congenital malformation of body surface in Shaanxi province]. AB - Objective: To investigate the influencing factors on congenital malformation of body surface. Methods: Multi-stage stratified random sampling method was adopted. A questionnaire survey was conducted among the childbearing aged women who experienced more than 28 weeks pregnancy or having definite pregnancy outcomes in Shaanxi, during 2010-2013. Results: Results from the logistic regression model showed that factors as: intrahepatic cholestasis of pregnancy (OR=21.76, 95%CI: 4.46-106.25), histories with abnormal pregnancy or reproduction (OR=11.88, 95%CI: 9.14-15.45), having birth defects in the family (OR=6.15, 95%CI: 2.66-14.23), being twins (OR=5.74, 95% CI: 3.34-9.86), being worker (compared with others, OR=2.47, 95% CI: 1.30-4.68) or farmer (compared with others, OR=1.91, 95%CI: 1.14 3.20), less than 4 times of antenatal care (compared with >7, OR=1.84, 95% CI: 1.28-2.64), occupational exposure to related risks during pregnancy (OR=1.74, 95% CI: 1.26-2.42), mother's hometown was from mid-part of Shaanxi (compared with northern Shaanxi, OR=1.65, 95%CI: 1.20-2.28), mother's native residence was from the rural areas (OR=1.75, 95% CI: 1.13-2.71), drug use (OR=1.64, 95% CI: 1.26 2.13) etc. were risk factors for congenital malformation of body surface. Iron supplement during pregnancy (OR=0.46, 95%CI: 0.21-0.99) appeared as protective factor for congenital malformation of body surface. Conclusion: The following factors seemed to be of risk for congenital malformation of body surface, including: mother's native area was from the middle part of Shaanxi and living in rural area, being worker or farmer, histories of abnormal pregnancy and reproduction, history of birth defects in the family, being twins, with antenatal care less than 4 times, occupational exposure to dangerous materials, drug use, intrahepatic cholestasis during pregnancy etc. PMID- 27998401 TI - [Relationship between domestic violence and posttraumatic stress disorder among women living in the communities of Wuhan city]. AB - Objective: To understand the prevalence of domestic violence and the correlation between domestic violence and posttraumatic stress disorder (PTSD) so as to improve the mental health status of women in Wuhan city of China. Methods: A cross-sectional study was conducted in the community health service center in Wuhan. Participants were women who came to the center for gynecological examination. Data on general condition, social support, injury, epidemiological characteristics of domestic violence and PTSD were gathered. Chi-square, student t and Cochran-Armitage trend tests were employed to compare the distribution of each characteristic variable between PTSD and non-PTSD group. Binary logistic regression was used to analyze the correlation between domestic violence and PTSD. Results: A total of 1 015 women were effectively surveyed. The life-time incidence rates of events related to domestic, psychological, physical and sexual violence were 29.36%, 28.28%, 6.60% and 3.55%, respectively. The overall prevalence rate of PTSD was 4.73%. Women who suffered from domestic violence had higher risk of PTSD (OR=2.11, 95%CI: 1.04-4.29) than those who never experiencing domestic violence. Women who suffered from psychological or physical violence were 5.06 times more likely to suffer from PTSD (OR=5.06, 95% CI: 1.91-13.42). Conclusion: A strong correlation between domestic violence and PTSD was seen. Victims who suffered from domestic violence should be provided with psychological counseling to reduce the risk of PTSD. PMID- 27998402 TI - [Effect of low-dose ionizing radiation on platelet and leukocytes of radiation workers]. AB - Objective: To explore the effect of low-dose ionizing radiation on the platelets and leukocytes of the radiation workers. Methods: We collected data from a total number of 2 055 radiation related workers and with their cumulative doses. Data on platelets and leukocytes was gathered from physical examination of the staff members, from 2013 to 2015 in Chengdu. T test, variance analysis, chi2 test, linear correlation, covariance analysis and multivariate logistic regression analysis were used to analyze the data. Results: Results from the covariance analysis showed that with the increase of cumulative doses, the quantity of platelet and leukocyte appeared a decreasing trend. Multivariate logistic regression analysis showed that, with the increase of BMI levels and the medium cumulative dose and above (>4.333 mSv), the risk of thrombocytopenia became more obvious (trend test as P<0.05). In the group with high-dose exposure radiation (>15.639 mSv) and combined factor as smoking, the risk of developing thrombocytopenia would increase (OR=2.33, 95% CI: 1.23-4.44). Staff with cumulative dose of less than 4.332 mSv and exercised more than 1 time per week, the risk of developing low leukocyte would decrease (OR=0.26, 95% CI: 0.09-0.70). Conclusions: Along with the increase of cumulative doses on exposure to radiation related workers. The quantity of platelet and leukocyte showed a decreasing trend among them. When this high-dose exposure radiation combined with overweight/obesity or cigarette smoking, the risk of developing thrombocytopenia was high. However, physical exercise might have served as protective factor on leukopenia. PMID- 27998403 TI - [Allocation of resources for diseases control and prevention in Beijing, from 2010 to 2015]. AB - Objective: To explore the allocation of resources for diseases control and prevention in Beijing CDC and to put forward related scientific evidence for improvement. Methods: To gather and comparatively analyze the human, financial and material resources of Beijing CDC reported by China Information System, from 2010 to 2015. Results: Research findings showed that on average, 1.43 CDC members served ten thousand people in Beijing in 2015, which was below the set national standard. The proportion of staff with either master/doctor degrees or senior professional titles showed an annual upward trend from 2010 to 2015 (P<0.05), the proportion was higher in the municipal CDC than that in the District CDCs, in 2015 (P<0.05). Fiscal deficit had existed for many years. The average capability for different kinds of testings did not reach the national standard. Numbers of instruments and equipment were higher than that of the national standard. The average space of Beijing CDC was 55.9 square meters/person, again had not met the nationally recommended criteria. Conclusions: The allocation of CDC human resources was significantly imbalanced in Beijing. The structure of CDC human resources should be improved. We suggested that the Full Funding Security Model' should be unified. And the average space of the Beijing CDC should meet the national standard in the years to come. PMID- 27998404 TI - [Selection of peer educators for sex education program-based on data from social network analysis among college freshmen students]. AB - Objective: Through combining the results from social network analysis and willingness of the key actors, peer educators for sex education among freshmen to select peer educators for sex education. Methods: Self-developed questionnaires were used to collect information on related demographics, egocentric social networks and whole class-based unit-network. Descriptive analysis was applied. UCINET 6 was used to conduct social network analysis and to draw the whole networking graphs. Results: Classmates appeared as the most important behavior intimate social network (95.8% claimed they could potentially borrow money from them, and 96.6% often went out with them) and were the most important members who could share privacy information with (91.6%) and consulting for private health information on (89.1%), among freshmen students in college. Finally, 17 freshmen were selected to have become peer educators, with 10 of them as the committee members in the class. Conclusion: Classmates formed the most important social network among freshmen students in college. Social network analysis could be used to help identify the suitable peer educators. PMID- 27998405 TI - [Status of seroepidemiology of hepatitis A, B and C in primary and middle school students in Shufu county, Xinjiang Uygur Autonomous Region of China]. AB - Objective: To explore the status of seroepidemiology on hepatitis A, B and C in primary and middle school students in Shufu county, Xinjiang Uygur Autonomous Region of China (Xinjiang) and to evaluate the effect of related immunization. Methods: Students in four towns and villages were selected by cluster random sampling method. HAV-IgG, HBsAg, HBsAb and HCV-IgG were detected in Feb to May, 2015. Results: The overall HAV-IgG positive rate was 99.75%, among 4 830 primary and middle school students. The positive rates were seen 99.92% in boys and 99.57% in girls, with difference statistically significant (chi2=5.798, P=0.016). The overall HBsAg positive rate appeared as 3.02%, with 3.55% for boys and 2.47% for girls, with difference statistically significant (chi2=4.782, P=0.029). The difference between age specific HBsAg positive rates also showed statistically significant (chi2=71.990,P=0.000). HBsAg positive rate in the students in rural area (3.28%) was higher than that in the students in urban area (1.61%, chi2=6.019, P=0.014). HBsAb positive rate was 38.84%, and the differences between the age specific HBsAb positive rates appeared statistically significant (chi2=837.699, P=0.000). HBsAg positive rate in students from the urban area (42.36%) was higher than those from the rural area (38.20%, chi2=4.598, P=0.032). 2 815 students, accounting for 58.28% of the total students, showed negative on both HBsAg and HBsAb. The overall HCV-IgG positive rate was 0.19%, and all appeared in students from the rural areas, with ethnicity solely as Uygur. Conclusions: The effect of hepatitis A vaccine was satisfactory in primary and middle school students in Shufu county but quiet a number of the students missed the vaccination. The infection rate of hepatitis C was low. Publicity and health education on hepatitis immunization and control should be revved up. Programs regarding primary and supplementary immunization on hepatitis, should be carried out timely for children of school age. PMID- 27998406 TI - [Risk behaviors among newly reported Burmese HIV infection in Dehong, Dai and Jingpo Autonomous Prefectures of Yunnan province, 2015]. AB - Objective: To study the AIDS-related socio-demographic characteristics and high risk behaviors of Burmese HIV-infected individuals, in Dehong prefecture, Yunnan province. Methods: A cross-sectional study with questionnaire interview, was conducted. Results: Features of the 489 HIV-infected individuals appearfed as: 367(75.1%) males, 407(83.2%) illiterate or with primary education, 371(75.9%) from Kachin State or Shan State, 306(62.6%) visited Dehong twice or more per year, 238(48.7%) entered Dehong illegally, 339(69.3%) came to the city looking for jobs or working on cargo transportation, 309(63.2%) of them living in working place/rented house/own house, and 313(64.0%) with the length of stay shorter than six months. Only 36(7.4%) of the interviewees were aware of their HIV sero positive status, with 23.3% of them (113/485) reported having had unprotected sex experiences in Dehong. Results from the multivariate logistic regression model analysis showed that HIV-infected individuals with the following characteristics: having spouses/regular sexual partners (OR=12.98, 95%CI: 6.53-25.83, P<0.001), living in working place (OR=2.88, 95% CI: 1.09-7.61, P=0.033), living in rented houses (OR=5.36, 95% CI: 1.94-14.84, P=0.001). Those living in their own houses (OR=5.14, 95% CI: 1.36-19.35, P=0.016) were more likely to engage in unprotected sex. 32.0% (156/487) of the interviewees clained that they ever used drugs in Dehong, with 9.7% (47/487) of them sharing syringe. Data also showed that HIV infected individuals who had the following feartures as: being male (OR=15.61, 95% CI: 6.47-37.69, P<0.001), illiterate (OR=2.89, 95% CI: 1.44-5.84, P=0.003), coming from Kachin State (OR=3.01, 95% CI: 1.50-6.04, P=0.002) or Shan State (OR=5.30, 95% CI: 2.66-10.58, P<0.001), illegal visiters (OR=1.93, 95% CI: 1.18 3.14, P=0.009), living with friends/relatives (OR=5.78, 95% CI: 2.01-16.61, P=0.001), living in working place (OR=6.67, 95% CI: 3.06-14.53, P<0.001), or in rented houses (OR=11.84, 95% CI: 4.76-29.47, P<0.001). The ones who were living in their own houses (OR=6.77, 95%CI: 1.84-24.85, P=0.004) were more likely to engage in drug use in Dehong. Conclusion: Results from our study showed that the Burmese HIV-infected citizens in Dehong prefecture had the following characteristics: high mobility, low awareness of HIV positive status and high prevalence of AIDS-related risky behaviors. These findings called for greater efforts on HIV/AIDS prevention and management in Dehong city. PMID- 27998407 TI - [Effects of standardized follow-up program among newly diagnosed HIV/AIDS cases in 2010]. AB - Objective: To analyze the effects of a follow-up program among newly diagnosed HIV/AIDS cases in 2010 in China. Methods: Database was downloaded on January, 2016 from both HIV/AIDS Case Reporting and Follow-up Cards. Information related to newly diagnosed HIV/AIDS cases in 2010 was extracted from the database. Information on follow-up intervention programs, CD4 testing, antiretroviral treatment, sexual behavior and mortality from 2010 to 2015 were analyzed. Results: Of the newly diagnosed HIV/AIDS cases in 2010, 70.4% were men and 72.0% with Han ethnicity. Heterosexual transmission accounted for 65.8%. The proportion of having received standardized follow-up increased significantly, with an annually upward trend (trend chi2=3 749.77, P<0.01). The proportions of sexual risk behaviors decreased significantly, with safe sexual behaviors over 90%, and having yearly upward trend (trend chi2=16 971.98, P<0.01). Among those eligible for antiretroviral therapy, the proportion of initiation the therapy increased from 56.5% in 2010 to 83.2% in 2015, with significant upward trend, annually (trend chi2=2 504.86, P<0.01). Over the same period, the proportion of deaths decreased from 12.4% in 2010 to 2.4% in 2015, with significant annual downward trend (trend chi2=4 935.89, P<0.01). Conclusion: The standardized follow-up intervention program included the contents of: CD4 testing; counseling and timely referrals to receive antiretroviral therapy etc., which were correlated to the reduction on both high risk sexual behaviors and deaths. PMID- 27998408 TI - [Surveillance on the epidemiological and etiological characteristics of hand-foot mouth disease during the outbreaks in three cities of Jiangsu province, 2012 2015]. AB - Objective: To analyze the epidemiological and etiological characteristics through monitoring the outbreaks of hand-foot-mouth disease (HFMD), in three cities of Jiangsu province from 2012 to 2015 and to provide evidence for prevention and control of the disease. Methods: Data related to cases of HFMD during the outbreaks was collected through active surveillance programs in three cities of Jiangsu province, under the guidelines of clusters and outbreaks of HFMD (2012 edition HFMD). Features related to clusters and outbreaks of the disease were identified according to the real-time RT-PCR detection. Descriptive analysis was conducted to understand the type/subtype of HFMD virus and time, area, place and extent of the outbreaks. Logistic regression was used to explore the influencing factors. Results: From 2012 to 2015, a total of 1 425 HFMD epidemics, including 1 314 clusters and 111 outbreaks were reported. Two incidence peaks were observed each year, between March and June, as well as between September and December, accounting for 58.18% (829/1 425), 33.68% (480/1 425), respectively. Most HFMD clusters and outbreaks were reported in Wuxi city, accounting for 59.30% (845/1 425) of the total. Most HFMD clusters and outbreaks happened in kindergartens, accounting for 68.63% (978/1 425) of the total. A total of 931 HFMD clusters and outbreaks were confirmed under laboratory findings. The main pathogens were Entervirus type 71 (EV71) in 2013 and Coxsackie A16 (Cox A16) in 2015, respectively, while both EV71 and Cox A16 were predominant in 2012 and 2014. With multivariate backward conditional regression, surrounding environment was identified as important risk factor associated with the attack rate. Health condition of the environment was quite good, with low attack rates (middle vs. bad: OR=0.150, 95% CI: 0.034-0.667; good vs. bad: OR=0.072, 95%CI: 0.016-0.317). Time between the onset of index patient and the reporting of HFMD clusters or outbreaks was important in the control program of HFMD epidemics (4-7 d vs. 1-3 d: OR=3.452, 95%CI: 2.293-5.198; 8 d vs. 1-3 d: OR=12.108, 95%CI: 7.767-18.763). Conclusions: The clusters and outbreaks of HFMD happened in Jiangsu province showed an obvious feature of seasonality. The predominant types or subtypes of the virus varied in different years. Kindergartens were the hard-hit places of HFMD clusters and outbreaks. Timely report of the disease appeared the key point regarding the control of HFMD clusters and outbreaks. PMID- 27998409 TI - [Epidemiologic features of hand-foot-mouth disease in Haikou city from 2008 to 2015]. AB - Objective: To analyze the epidemiologic features of hand-foot-mouth disease (HFMD) in Haikou city from 2008 to 2015. Methods: Descriptive methods on epidemiology and detection on pathogens were conducted in Haikou city from 2008 to 2015. Results: A total of 71 611 patients were diagnosed as HFMD in Haikou city from 2008 to 2015, including 728 severe cases, accounting for 1.02% among all the cases. The average annual incidence was 458.89/100 000. A total of 11 deaths were caused by the disease, with the average annual mortality rate as 0.07/100 000. Two peaks of incidence were seen, from April to July and from September to November. Age of the patients mainly fell in children aged 5 and below, taking up 95.78% of the total cases. Among all the patients, 1-year-olds presented the highest incidence as 12 881.24/100 000. The reported incidence for males was higher than that in females. There were 4 districts in Haikou city that reported the disease. Residential areas of the patients were scattered around, with a percentage of 79.89%. Spectrums of pathogens that causing the prevalence of HFMD were EV71 type, Cox A16 type and other enteroviruses, which prevailing in turns, since 2011. Conclusions: Haikou city had been an area with high incidence of HFMD. The incidence started to show a rising trend recently. It is suggested that programs as surveillance, case management, health education and comprehensive prevention and control of disease on HFMD targeting on key population should be intensively implemented to reduce the mortality of the disease. PMID- 27998410 TI - [Analysis on the consistency and timeliness of death data gathered from different sources in the residents of Beijing]. AB - Objective: To further improve the quality of mortality data for Beijing residents, through describing and analyzing the current death data gathered from different sources in Beijing. Methods: Data on death of the Beijing residents from Beijing Public Security Bureau, Beijing Civil Affairs Bureau and Beijing Centers for Disease Control and Prevention (BJCDC) were collated and compared. Timeliness of related data from the three different sources were described and analyzed. The overall consistency and reported timeliness of data from the three sources appear good, but the consistency on the causes of death needs to be improved. Result: Numbers of deaths from the three different sources were 95 318, 130 906 and 160 779 respectively, with 387 003 in total. Data from the Beijing Public Security Bureau and BJCDC seemed better in terms of integrity and accuracy. Data from the Beijing Public Security Bureau had the highest filling rate of ID card number while data from the Beijing Civil Affairs Bureau had the best timeliness. The most informative source of data was from the BJCDC. Conclusion: The overall quality of the exchanged death data from Beijing Public Security Bureau, Beijing Civil Affairs Bureau and BJCDC appeared good but remained some areas for improvement. PMID- 27998411 TI - [Status and related factors of self-reported pain among working-age population in Inner Mongolia Autonomous Region]. AB - Objective: To describe the status and related factors of self-reported pain among working-age population in Inner Mongolia Autonomous Region (Inner Mongolia). Methods: A cross-sectional study was conducted. Data was from the Inner Mongolia fifth health services survey. SPSS 19.0 software package was used for data analysis and chi2 test was to compare the prevalence of self-reported pain in population with different characteristics. Unconditional logistic regression model was used to analyze the related factors on self-reported pain. Results: A total of 11 480 working-age population was involved in this survey, with prevalence of self-reported pain among working age population as 12.3%. The prevalence rates of moderate and severe pain were 11.6% and 0.7%, respectively. Results from the unconditional logistic regression analysis showed that, in the economically poor population, the risk of self-reported pain was 1.718 times of the relatively rich people (OR=1.718, 95%CI: 1.381-2.831). In the rural areas, the risk of self-reported pain was higher than that in the urban population (OR=2.506, 95%CI: 2.030-3.092) and people with chronic illnesses had 2.880 times higher risk than those who did not have the diseases (OR=2.880, 95% CI: 2.474 3.352). There was an interaction noticed between gender and age. Women at or above 45 years old were more likely to develop self-report pain (OR=1.300, 95% CI: 1.072-1.577). Again, factors as people who were current or former smokers, who were suffering from anxiety or depression, being skinny etc. appeared as independently related to the self-reported pain. Conclusion: In working age population of Inner Mongolia, a high prevalence of self-reported pain was seen. Data showed that people who were poor, age at 45 or older, having history of smoking, with chronic diseases and anxiety/depression were risk factors related to self-reported pain. PMID- 27998412 TI - [Molecular typing of Salmonella isolates from poultry production chains in four cities of Heilongjiang province]. AB - Objective: To study the PFGE type of Salmonella (S.) strains isolated from poultry production chains (hatching, breeding, slaughter, distribution and retail) of four cities in Heilongjiang province. Methods: DNA collected from S. strains in 2012 was digested by XbaI according to the standard PFGE protocol of US CDC. The PFGE patterns were then analyzed by BioNumerics software. Results: The contamination of S. appeared most serious during the process of slaughtering (13.84%). PFGE was used to determine the genetic relationships between these isolates from poultry production chains, 89 pulsotypes from 150 S. enteritidis isolates and 55 pulsotypes from 65 S. indiana isolates showed considerable diversity. The same pulsotypes of S. enteritidis can be found between different food chains and cities. In contrast, no identical pulsotypes of S. indiana were found between different food chain and cities. In these four cities, the above said two kinds of S. were from different sources. The source of S. contamination in HLJ2 city had been traced back to the chain of poultry hatching. Conclusions: The distribution of pulsetypes of the S. enteritidis and S. indiana isolates was from different regions and the dominant bands were also different between the chains of poultry production. Cross contamination existed in slaughterhouses and contamination can be traced back to the poultry hatching. PMID- 27998413 TI - [Correlativity of subtype B viral transmission among elderly HIV-1 infected individuals in Yongding district, Zhangjiajie city, Hunan province]. AB - Objective: To investigate the characteristics of transmission correlativity regarding subtype B among elderly HIV-1 infected individuals in Yongding district, Zhangjiajie city, Hunan province and to explore a method on its traceability. Methods: A total of 43 newly diagnosed elderly HIV-1 Infected individuals in Yongding district were enrolled in this study. Pol area genes were amplified and sequenced by 'In house' method. Methods used to analyze the relationship related to HIV individuals transmission would include Bayesian phylogenetic tree and other epidemiological ones. Results: A total of 42 valid sequences were successfully obtained, with predominant strain as subtype B (80.95%, 34/42). All the 42 sequences were gathered into eight clusters. In each cluster, the genetic distance was significantly shorter than the average from the 34 subtype B strains (0.058 3). The HIV-1 infected individuals in one cluster had the same high-risk behaviors and the significantly patchy distributions were identified at the sites where the high-risk behaviors existed. Our results indicated that the local elderly HIV-infected individuals had high level of homology between geographical position and related behaviors. Conclusions: The patchy distribution between geographical position and behavior was associated among the elderly HIV-1 infected individuals. Guidance related to epidemic precise positioning and effective interventions was provided through the findings of this study. PMID- 27998414 TI - [Application of whole genome sequencing technology in the epidemiology of tuberculosis]. AB - Objective: To delineate the application of whole genome sequencing technology in the epidemiology of tuberculosis. Methods: From 2009 to 2012, nine Mycobacterium tuberculosis that sharing identical variable number of tandem repeats genotype (VNTR) patterns were reported from two TB cases designated hospitals. Both whole genome sequencing analysis (WGS) and epidemiologic investigations were performed to describe the transmission patterns of these Mycobacterium tuberculosis. Results: By WGS analysis, two genomic clusters including 7 and 2 Mycobacterium tuberculosis were noticed, respectively. The cluster of 2 cases possessed more than 15 single nucleotide polymorphisms (SNPs) when compared to the cluster of 7 cases and suggesting that the transmission route was independent. The transmission chain based on the SNPs difference showed the process of the propagation direction and the accumulation of drug resistance mutations in each cluster. Conclusion: Using a WGS-based genomic epidemiologic approach, we were able to reconstruct the tuberculosis transmission network, tracing the putative source of the transmission and determining the transmission direction or the missing links. PMID- 27998415 TI - [Effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization]. AB - Objective: To explore the effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization. Methods: Participants were pathologically diagnosed new cases, including 80 women with normal cervical (NC), 55 patients with low-grade cervical intraepithelial neoplasia (CINI), 55 patients with high-grade cervical intraepithelial neoplasia (CINII/III) and 64 patients with cervical squamous cell carcinoma (SCC). Serum folate levels were detected by microbiological assay method while p16 protein expression levels were measured by Western-blot. In vitro, cervical cancer cell lines C33A (HPV negative) and Caski (HPV16 positive) were treated with different concentrations of folate. Proliferation and apoptosis of cells and the levels of p16 protein expression were measured in groups with different folic acid concentrations. Results: Results showed that the levels of serum folate were (5.96+/-3.93) ng/ml, (5.08+/-3.43) ng/ml, (3.92+/-2.59) ng/ml and (3.18+/-2.71) ng/ml, and the levels of p16 protein were 0.80+/-0.32, 1.33+/-0.52, 1.91+/-0.77, and 2.09+/-0.72 in the group of NC, CINI, CINII/III and SCC, respectively. However, the levels of serum folate decreased (trend chi2=32.71, P<0.001) and p16 protein expression increased (trend chi2=56.06, P<0.001) gradually along with the severity of cervix lesions. An additive interaction was seen between serum folate deficiency and high expression of p16 protein in the CINI, CINII/III and SCC group. Results in vitro showed that, with the increase of folate concentration, the inhibition rate of cell proliferation (C33A: r=0.928, P=0.003; Caski: r=0.962, P=0.001) and the rate on cell apoptosis (C33A: r=0.984, P<0.001; Caski: r=0.986, P<0.001) all increased but the levels of p16 protein expression (C33A: r=-0.817, P=0.025; Caski: r= 0.871, P=0.011) reduced. The proliferation inhibition rate (C33A: r=-0.935, P=0.002; Caski: r=-0.963, P=0.001) and apoptosis rate of cells (C33A: r=-0.844, P=0.017; Caski: r=-0.898, P=0.006) were negatively correlated with the levels of p16 protein expression. Conclusions: Our findings indicated that both serum folate deficiency and high expression of p16 protein could increase the risk of cervical cancer and cervix precancerous lesion, and there was an additive interaction between them. Our findings suggested that folic acid supplementation could reverse the abnormal expression of p16 protein, and effectively promote apoptosis and inhibit proliferation in cervical carcinoma cells. PMID- 27998416 TI - [Association between resting heart rate and metabolic syndrome: a cohort study]. AB - Objective: To investigate the association between resting heart rate (RHR) and subsequent metabolic syndrome (MS). Methods: Under a cluster design, participants age >=18 years old were selected from a rural area of Henan province in China. Interview through questionnaire, physical examination, fasting blood glucose, and lipid profile measurements were done from July to August of 2007 and July to August of 2008. Same methods were implemented in the follow-up examination, during July to August of 2013 and July to October of 2014. Results: During the 6 year follow-up period, cumulative incidence rates of MS for overall, male, and female participants appeared as 21.89%(1 933/8 829), 16.78%(664/3 957) and 26.05%(1 269/4 872), respectively. After controlling for potential confounders and compared with the groups of RHR<60 bpm, 60-69, 70-79, 80-89 and >=90 bpm, the ORs (95%CIs) of MS for overall, male, and female participants became 1.24(0.95 1.60), 1.42(1.10-1.84), 1.63(1.24-2.15) and 1.62(1.16-2.27); 1.12(0.81-1.55), 1.23(0.88-1.71), 1.42 (0.97-2.07) and 1.84(1.09-3.11); 1.46(0.93-2.29), 1.70(1.09 2.65), 1.99(1.25-3.16) and 1.78(1.06-2.98); respectively. Conclusions: The risk on MS appeared higher in females than in males while the risk for MS increased with the elevation of RHR. Intensive intervention programs that targeted adult participants with elevated RHR, especially in females, should be formulated and implemented. PMID- 27998417 TI - [Association between human papillomavirus infection and lung cancer]. AB - Objective: To investigate the association between human papillomavirus (HPV) and lung cancer. Methods: We examined a series of 83 lung cancer patients with HPV DNA in both lung tumor specimens and adjacent normal specimens from Fujian province. Twenty-one of the most clinically relevant HPV types from the highly conserved L1 region of the viral genome were analyzed, using the PCR amplification and were followed by reverse hybridization with specific probes. Chi-square test of paired design was used to test the difference of HPV positive rates between lung cancer specimens and adjacent normal specimens. Chi-square test and Fisher's exact test were used to analyze the differences of HPV positive rate of tumor specimens on factors as gender, age, histological subtype, clinical stage, smoking status and alcohol consumption. Results: HPV was detected in 7 of the 83 tumor specimens and in 6 of the paired normal lung tissues. There was no significant correlation between HPV and lung cancer (P>0.999). Neither demographic characteristics nor clinical features were found with significant differences on HPV in lung cancer tissues (P>0.05). Conclusion: Our data showed that HPV was not significantly associated with the risk of lung cancer in Fujian province. PMID- 27998418 TI - [Economic evaluation on breast cancer screening in mainland China: a systematic review]. AB - Objective: To gather available evidence related to the economic evaluation on breast cancer screening in mainland China and to provide reference for further research. Methods: A systematic review was conducted to identify articles in PubMed and three Chinese databases (CNKI, Wanfang and VIP) during 1995-2015. Data related to descriptive characteristics, rates on participation and detection for population-based studies, methods for model-based studies, types of economic evaluation and results, were extracted. A Consolidated Health Economic Evaluation Reporting Standards (CHEERS) was used to assess the reporting quality of included studies. Results: Of the 356 records searched in the databases, 13 studies (all published between 2012 and 2015) were included in the current paper involving 11 population-based studies and 3 model-based evaluations (1 study using both methods). Age of the participants who started to be engaged in the screening program ranged from 18 to 45 years old, but terminated at the age of 59 years or older. The screening modalities included single-used clinical breast examination, mammography and ultrasound or combined applications. Study persepectives were described in 7 studies, with 5 from the healthcare providers, and 2 from societal angles. Only 5 studies discounted cost or effectiveness. Out of 11 papers, 9 showed the results on cost-effectiveness analysis (CEA) that reporting the cost per breast cancer detection, with median as 145.0 thousand Chinese Yuan (CNY), ranging from 49.7 thousand to 2 293.0 thousand CNY. From 4 papers with results of cost-utility analysis (CUA), the cost per quality adjusted life year (QALY) gained or cost per disability adjusted life year (DALY) averted, were evaluated. The incremental cost-effectiveness ratio (ICER) was from 2.9 thousand to 270.7 thousand CNY (GDP per capita of China was CNY 49.3 thousand in 2015). In 13 studies, the quality of reporting varied, with an average score of 14.5 (range: 9.5-21.0). In the domains of study perspective, discounting, ICER and uncertainty, all the scores of equalities were relatively levels. Conclusions: Currently, evidence on economic evaluation of breast cancer screening in mainland China remained limited and weakly comparable, particularly model-based studies. Comprehensive analysis from societal perspective and QALY or DALY related cost utility analysis should be implemented. PMID- 27998420 TI - [A review on the genetic risk factors of chronic obstructive pulmonary disease]. AB - Chronic obstructive pulmonary disease (COPD) refers to a common complex disease characterized by progressive and incomplete reversible airflow limitation. COPD is one of the leading causes on morbidity and mortality in China. Genetic risk factors play important roles on the occurrence of COPD. However, the genetic risk factors of COPD remain unknown, to some extent. The aim of this review is to provide a comprehensive overview on literature concerning the most promising findings related to genetic risk factors of COPD. PMID- 27998419 TI - [A systematic review and Meta-analysis on influencing factors related to the quality of sleep among community population aged 60 and older, in China]. AB - Objective: To systematically evaluate the influencing factors on quality of sleep among community elderly population aged >=60 years in China. Methods: Literature review was conducted using databases of PubMed, EMbase, CBM, CNKI and Wanfang to collect data regarding influencing factors on quality of sleep. Both qualitative and quantitative analysis were performed to pool the eligible studies. Results: Sixteen cross-sectional studies were included. Data from both qualitative and quantitative analysis showed that the elderly population who had ever married (OR=0.72, 95%CI: 0.52-0.98) or lived with other people (OR=0.78, 95%CI: 0.70 0.87) had better quality of sleep but it was worse when with chronic diseases (OR=2.24, 95%CI: 1.39-3.61). The effects of age and sex on the quality of sleep in the elderly was not yet conclusive. Studies on life style, social support and psychological factors appeared scarce. Conclusion: The protective factors on quality of sleep among community elderly population aged >=60 years in China appeared as: ever had married or lived with others while chronic diseases were risk factors in reducing the quality of sleep. PMID- 27998421 TI - [Integration of spatial epidemiology and molecular epidemiology used for study on tuberculosis]. AB - Spatial epidemiology and molecular epidemiology have been widely used in the studies of tuberculosis (TB), but each with limitations. Integration of the two methods provides new ideas and methods in TB research. All referenced articles are from CNKI, Wan Fang database, PubMed database and Web of Science database. Method of combining spatial epidemiology and molecular epidemiology has been widely used in determining the local epidemic strains of TB genotype, the transmission mechanism, risk factors of TB, drug-resistant TB, as well as evaluating the effectiveness of TB prevention and control measures. Application of the combined methods is of important significance in the studies of TB, thus worthy to be further introduced to researchers and disease prevention and control workers in this country. PMID- 27998422 TI - [Progress of research on azole resistance in Aspergillus fumigatus]. AB - Being an important clinical fungal pathogen, Aspergillus (A.) fumigatus can cause fatal invasive fungal infections. Azoles are the first line drugs in treating various Aspergillus-caused diseases. Worldwidely, reports related to azole resistance in A. fumigatus have been increasing which posing a threat on the effectiveness of clinically used azole and agricultural fungicides. Currently, it has become an important public health issue. In this review, we summarize findings from literature regarding the following areas: the occurrence of azole resistance in A. fumigatus, the molecular mechanisms of resistance, contributing factors for the emergence of azole resistance, evolution of resistant strains and related control and prevention measures. PMID- 27998423 TI - [Therapeutic progress of hepatocellular carcinoma with portal vein tumor thrombus]. PMID- 27998424 TI - [Dose effect relationship of the stilled water with the elimination of the exfoliated cancer cells in the peritoneal cavity during hepatocellular carcinoma resection]. AB - Objective: The aim of the study was to investigate the dose effect relationship of warm distilled water to remove the exfoliated cancer cells (ECC) in peritoneal cavity in 116 cases of hepatocellular carcinoma. Methods: Positive rates of exfoliated cancer cells in 116 patients with hepatocellular carcinoma were detected before and after the removal of the tumor. The 43 to 45 C distilled water was used by 1 500 ml/time before closing the abdomen, and then 37 C sterile normal saline 200 ml was used for peritoneal lavage and collected for exfoliated cancer cell detection. Results: Positive rates of ECC had no significant difference before and after resection in groups with tumor diameter <=10 cm (all P>0.05); positive rates of ECC were significantly increased after tumor resection in groups with tumor diameter>10 cm (<=15 cm, >10 cm, P=0.044; >15 cm, P=0.033). With the increase of tumor volume, ECC positive rates were significantly increased after resection (P<0.001), and the residual rate increased after washing; the residual rates was significantly decreased with the increasing of irrigation times in groups with tumor diameter>10 cm (<=15 cm, >10 cm, P=0.002; >15 cm, P=0.001), and undetectable after four times washing. With the increase of irrigation times, the residual rates were not significantly decreased (all P >0.05) in groups with tumor diameter <=5 cm, but no residue was detected after three times of washing. Conclusion: The volume of irrigation needed to eliminate the ECC in the peritoneal cavity during the operation of hepatocellular carcinoma is significantly correlated with the tumor size. PMID- 27998425 TI - [Prevalence of nonalcoholic fatty liver disease and its correlated risk factors in health population in Guangzhou]. AB - Objective: To investigate the situation and its risk factors of nonalcoholic fatty liver (NAFLD) in health population, and to provide the scientific evidence for this disease control and prevention. Methods: The subjects who had health examination in our hospital from Jan 2014 to Jan 2015 were enrolled in this cross sectional survey study. The medical history, body examination data (height, weight and blood pressure), biochemical data (blood lipid, blood sugar, liver function, etc.) and the ultrasound examination result were recorded. The descriptive analysis method was used to demonstrate the distribution of NALFD, and the single and multi-variable analysis method was conduct to obtain the risk factors of NAFLD. Result: The overall prevalence rate of NAFLD was 16.92%, while the rate of male group was greater than that of female group. Logistic regression showed that BMI, diastolic pressure, ALT, GGT, fasting blood-glucose, TG, HLD and LDL were the independent risk factors of NAFLD (P<0.05). HDL was negatively correlated with NAFLD and other factors were positively. Conclusions: The overall prevalence rate of NAFLD of health population was higher in Guangzhou. The factors correlated with metabolism syndrome were the risk factor of NAFLD. PMID- 27998426 TI - [Value of integrated pancreatic and biliary stents for prevention of post-ERCP pancreatitis]. AB - Objective: To investigate the value of integrated pancreatic and biliary stents for prevention of post-Endoscopic Retrograde Cholangiopancreatography (ERCP) pancreatitis. Methods: The clinical data of patients whom had pancreatic stents for prevention of post-ERCP pancreatitis from December 2013 to October 2015 were retrospectively analyzed. The clinical effect and complication were compared between straight pancreatic stents group and integrated pancreatic and biliary stents group. Results: A total of 214 patients had pancreatic stents for prevention of post-ERCP pancreatitis. Among them, 139 of the patients received a straight pancreatic stents with the average operation time of 62.1+/-9.8 min and 75 patients received the integrated pancreatic and biliary stents with the average operation time of 67.2+/-12.7 min. The average operation time was statistically significantly different (P=0.001). Straight stents group was found to have higher incidence of pancreatic stents proximal migration and spontaneous abscission than integrated pancreatic and biliary stents group (8.6% vs 0, P=0.009; 12.9% vs 1.3%, P=0.004). There was no significant difference in the incidence of acute pancreatitis or hyperamylasemia between the two groups (3.6% vs 2.7%, P=1.000; 5.0% vs 4.0%, P=1.000). A total of 123 patients in the straight stents group received a second ERCP to remove the pancreatic stents in 1 to 8 weeks after ERCP, and 2 patients had acute pancreatitis and 3 patients had high amylase, while there was no complication happened after the remove of integrated pancreatic and biliary stents in one week after ERCP. Conclusion: The clinical effect of integrated pancreatic and biliary stents for the prevention of post ERCP pancreatitis is better than straight pancreatic stents. PMID- 27998427 TI - [The clinical characteristics and surgical treatment strategy of acute gangrenous cholecystitis after biliary tract stenting]. AB - Objective: To analysis of the possible cause and surgical diagnosis and treatment strategies of acute gangrenous cholecystitis (AGC) after biliary stent drainage. Methods: The clinical data of 273 patients who received biliary stent drainage in Beijing Chaoyang Hospital from January 2015 to March 2016 were analyzed retrospectively. Among them, 22 patients who underwent surgical treatment were divided into two groups: 9 cases of AGC group and 13 cases of non-AGC group. The risk factors of AGC and surgical approach were analyzed. Result: All 22 patients underwent laparoscopic surgery. In AGC group, 1 patient with toxic shock died of multiple organ viscera function failure caused by infection, and 1 patient with gallbladder triangle inflammatory adhesion suffered from biliary leakage. The postoperative pathology of 2 patients was acute gangrenous cholecystitis. Non-AGC group had no death, bile duct injury and bleeding, with postoperative pathology of chronic cholecystitis. Patients were followed up for 2 month to restore well, without biliary calculi residual. Operation time, intraoperative blood loss, hospitalization days and hospitalization expenses of AGC group were higher than those of non-AGC group. Conclusion: The advocated AGC after biliary stent drainage should actively surgery after early diagnosis and endoscopic therapy should not be repeated. Laparoscopic surgery is a safe and effective treatment for AGC after carotid stenting. PMID- 27998428 TI - [Mutation analysis for two hypophosphatasia families with targeted next generation sequencing]. AB - Objective: To detect the mutations in alkaline phosphatase (ALPL) gene of two Chinese families with perinatal hypophosphatasia (HPP), in order to explore the mechanism of this condition. Methods: Next-generation sequencing (NGS) of osteology system panel was carried out for exome sequencing in the mothers of 2 HPP fetuses, who visited Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University. Further polymerase chain reaction (PCR) and Sanger sequencing validation was performed in the parents, affected fetuses and 200 unrelated healthy individuals to verify the mutation sites. Results: The mother and father of No.1 family carried ALPL gene c. 333delC (p.Gly112AlafsX10) and c. 568_570delAAC (p.190delAsn) base deletions, respectively. The affected fetus carried compound heterozygotes of the two mutations. Two mutations in ALPL gene known to be associated with hypophosphatasia were found in No.2 family, c. 1250A>G (p.Asn417Ser) in the mother and c. 1166C>A (p.Thr389Asn) in the father, while the fetus was a compound heterozygote carrying both of the two mutations. Both families met the pattern of autosomal recessive inheritance. ALPL gene c. 333delC (p.Gly112AlafsX10) was a novel mutation, and it was not found in the 200 unrelated healthy individuals. Conclusions: The mutations in ALPL gene may be the cause of HPP in the 2 families. NGS technology combined with Sanger sequencing could be an efficient and accurate diagnostic method. PMID- 27998430 TI - [Expression of erythropoietin in neovascular glaucoma and its role in the angiogenesis in vitro]. AB - Objective: To explore the expression of erythropoietin (EPO) in neovascular glaucoma (NVG) and its role in the angiogenesis in vitro. Methods: The levels of EPO in aqueous humor and vitreous body of NVG patients (10 cases) and non-NVG patients (10 cases) were detected by enzyme-linked immunosorbent assay (ELISA). Human umbilical vein endothelial cells (HUVECs) were used as the research object, and were divided into EPO 0.1, 1, 10 U/ml group according to EPO concentration, on the basis of treatment of HUVECs cells with 10 ng/ml vascular endothelial growth factor (VEGF). Effect of different concentrations of recombinant human EPO and VEGF on the proliferation, angiogenesis and the formation of capillary like structures of HUVECs in vitro was explored, meanwhile, protein and mRNA expression of hypoxia inducible factor-1alpha (HIF-1alpha) was detected by Western blot and RT-PCR. Results: In the study, no patients discontinued the trial. EPO level of aqueous humor in non-NVG patients was (29.4+/-0.6) ng/L, while EPO level in aqueous humor of NVG patients reached (307.5+/-7.6) ng/L, and the difference was statistically significant (t=2.186, P=0.039); vitreous EPO levels in non-NVG patients was (16.7+/-1.2) ng/L, while vitreous EPO levels in NVG patients reached (267.5+/-11.4) ng/L, with a statistically significant difference (t=2.517, P=0.019). Compared with control group, 0.1, 1, 10 U/ml EPO and 10 ng/ml VEGF promoted the proliferation of HUVECs, and formation of vascular lumen-like and capillary-like structure in vitro, and up-regulated the protein and mRNA expression of HIF-1alpha (all P<0.05). Conclusion: EPO was highly expressed in the NVG patients, and exogenous EPO could significantly promote the proliferation of HUVEC and formation of vascular lumen-like and capillary-like structure, which may be related to up-regulation of HIF-1 expression. PMID- 27998429 TI - [Effect of sodium thiosulfate on coronary artery calcification in maintenance hemodialysis patients]. AB - Objective: To investigate the factors correlated to coronary artery calcification (CAC)in maintenance hemodialysis (MHD) patients and observe the effect of sodium thiosulfate (STS) on the progression of vascular calcification and its safety. Methods: Thirty-eight subjects from Fuzhou Genernal Hospital who underwent coronary artery CT scan using Philip's spiral CT were enrolled and the calcification degree was evaluated by CAC scores from December 2013 to December 2014. The hemodialysis patients were divided into CAC group (CAC scores>10, 27 cases) and non-CAC group (CAC scores<=10, 11 cases)according to the CT scan results.The differences of age, duration of dialysis, blood pressure and other hematological indices between the two groups were analyzed to investigate the factors correlated to CAC. Next, those with CAC (CAC scores>=50) received intravenous 0.18 g/kg STS (dissolved in 100 ml saline) in 30 minutes after each dialysis for 3 months (n=17, only 15 patients completed STS treatment) or received conventional treatment (n=10). Baseline data between the two groups before treatment had no significant statistical difference. All examination indices were evaluated before and after the treatment course. The changes of vascular calcification imaging, CAC scores, biochemical indices and bone mineral density were compared between two groups before and after the treatment. Besides, adverse reactions were observed during the treatment of STS. This study was approved by the Ethics Committee of Fuzhou General Hospital(2013No1). Results: Twenty-seven out of 38 patients (71.05%) had CAC, and the patients with CAC had significantly higher age, phosphate, the product of calcium and phosphate, intact parathyroid hormone (hPTH), hypersensitive C-reactive protein (hsCRP), and longer duration of dialysis (P=0.017, 0.038, 0.037, 0.012, 0.002, 0.037) and lower serum albumin (P=0.026) than patients without CAC.There was no significant statistical difference in the baseline characteristics. CAC score did not change significantly before and after treatment in the STS treatment group[1 045(47-12 734) vs 797(50-14 094), P=0.053], but increased significantly in the conventional treatment group[221(59-3 843) vs 174(50-3 369), P=0.021]. Difference of CAC score parameters before and after treatment showed statistically significant difference between the two groups[-67.5(-474-8) vs 52(-248-1 361) , P=0.004]. After STS treatment, level of hsCRP and HCO3- decreased (P=0.016 and P=0.020, respectively), and level of serum calcium increased (P=0.005). There was no significant statistical difference observed in iPTH, 25(OH)D, bone alkaline phosphatase (bALP), fibroblast growth factor 23 (FGF23) after STS treatment. Conclusion: STS treatment seems to be feasible, safe and may delay the rate of progression of vascular calcification, reduce inflammation in maintenance hemodialysis patients, but the adverse reactions needs further study. PMID- 27998431 TI - [Expression of long noncoding RNA STCAT3 in gastric cancer tissues and its effect on malignant phenotype of gastric cancer cells]. AB - Objective: To detect the expression of long noncoding RNA(lncRNA)stomach cancer associated transcript-3(STCAT3) in gastric cancer tissues, adjacent tissues, human gastric cancer cell lines and normal gastric epithelial cell lines, and to investigate the relationship between STCAT3 expression and clinicopathological features and malignant phenotype of gastric cancer. Methods: Quantitative fluorescent real-time polymerase chain reaction (qRT-PCR) was applied to detect the lncRNA STCAT3 expression levels in gastric cancer tissues, paired adjacent non-tumorous tissues, in order to explore the relationship between STCAT3 expression and clinicopathological features of gastric cancer. lncRNA STCAT3 low expressing and high-expressing gastric cancer cell lines were transfected with expression plasmid to simulate gain-of-function, or interference plasmid to achieve loss-of-function. Cell proliferation was measured with CCK-8 and colony formation assay, cell migration with scratch assay, and cell invasion with Transwell migration assay. human gastric tumor were also transplanted to nude mice to detect the effect of lncRNA STCAT3 on tumorigenesis. Results: The expression of lncRNA STCAT3 was generally up-regulated in gastric cancer tissues compared with the adjacent tissues(12.55+/-0.16 vs 6.52+/-0.14), with median expression level in gastric cancer tissues being 6.03 higher (P<0.05). Meanwhile, the expression level of lncRNA STCAT3 in gastric cancer tissues was not correlated with age or gender (both P>0.05), while positively correlated with TNM stage (P<0.05). Interference of lncRNA STCAT3 expression in BGC-823 cells was found associated with significantly suppressed colony formation, proliferation, invasion, and migration (all P<0.05). Over-expression of lncRNA STCAT3 in AGS cells were also founded could promote the gastric cancer cells' proliferation, colony formation, migration, and invasion (all P<0.05). Conclusions: lncRNA STCAT3 may participate in the proliferation and invasion of gastric cancer cells, indicating that dysregulation of STCAT3 expression may play a role in occurrence and development of gastric cancer. lncRNA STCAT3 has the potential to be the biomarker of gastric cancer progression and target in treatment. The underlying mechanism is yet to be further studied. PMID- 27998432 TI - [Study on the kidney impairment and expressions of FGF21 from a rat model of vascular calcification]. AB - Objective: To investigate the injury and pathological changes of kidney in a rat model of aortic vascular calcification and to explore the expressions of fibroblast growth factor 21 (FGF21). Methods: A total of 14 Spraugue Dawley (SD) rats were randomly divided into two groups: control group and vitamin D3+ nicotine (VDN) group, with 7 rats in each group.The rats in VDN group received vitamin D3 and nicotine to induce vascular calcification.The content of serum creatinine was determined by sarcosine oxidase method.Alkaline phosphatases (ALP) activity was detected by ALP detection kit.The protein levels of FGF21 were measured by radioimmunoassay (RIA). The structure of kidney was observed by hematoxylin and eosin staining. Results: The serum concentration of creatinine in VDN group was significantly higher than control group[(34.00+/-4.69) vs (27.17+/ 5.38) MUmol/L, P<0.05], and the renal pathological changes in VDN group were more apparent. ALP activity in VDN group was significantly higher than that in control group[(62.59+/-22.62) vs (29.89+/-11.78) U/g, P<0.05]. Expression of FGF21 in VDN group increased obviously, compared with that in control group[(0.583+/-0.340) vs (0.207+/-0.105) ng/mg, P<0.05]. Meanwhile, the elevated levels of FGF21 were positively correlated with up-regulation of ALP in calcified kidneys (r=0.878, P<0.05). Conclusions: Flushing dose of vitamin D3 and nicotine can induce the change of pathology and function of the kidney.Meanwhile, the expression of FGF21 in kidney up-regulated significantly, suggesting that FGF21 may be involved in the occurrence and development of vascular calcification and subsequent kidney injury. PMID- 27998433 TI - [Effects of mTOR-Cdc42 signaling pathway on phagocytosis of alveolar macrophages in chronic obstructive pulmonary disease mice]. AB - Objective: To investigate effects of mammalian target of rapamycin (mTOR)- cell division cycle 42 (Cdc42) signaling pathway on phagocytosis of alveolar macrophages (AMs) in chronic obstructive pulmonary disease (COPD) mice. Methods: Forty mice were randomly divided into control group and model group. Each group contained 20 mice. COPD model group were established by cigarette smoking exposure. AMs were isolated from lung tissue by discontinuous density gradient centrifugation. AMs from control group were divided into health control group and rapamycin control group while AMs from model group were divided into COPD group and rapamycin COPD group. The AMs from rapamycin control group and rapamycin COPD group were incubated with a final concentration of 10 nmol/L rapamycin for 24 hours. Mean fluorescence intensity (MFI) and the positive percent of alveolar macrophage engulfed flurescein isothiocyanate-labeled Escherichina coli (FITC E.coli) AM (AM%) were detected by flow cytometry. Real time PCR (RT-PCR) and Western blot were applied to detect mRNA and protein. The activity of Cdc42 was detected by G-LISA Small GTPase Activation Assays (G-LISA) Cdc42 Kit. The cytoskeleton structure of AM was observed by laser scanning confocal microscopy. Results: MFI and AM% in COPD group were decreased than those in health control group[4 060+/-590 vs 9 190+/-988 and (28.65+/-1.26)% vs (67.50+/-4.56)%]; Compared with COPD group, MFI and AM% in rapamycin COPD group[4 856+/-762, (38.31+/-1.71)%]were increased (all P<0.05). The expression of mRNA, protein and activity of mTOR in COPD group were increased than those in health control group[(2.62+/-0.46, 1.30+/-0.52, 1.46+/-0.43) vs (1.00+/-0.00, 0.48+/-0.27, 0.58+/-0.26)]; compared with COPD group, the expression of mRNA, protein and activity of mTOR in rapamycin COPD group (1.40+/-0.36, 0.90+/-0.66, 0.92+/-0.28) were decreased (all P<0.05). The Cdc42 mRNA, protein and activity in COPD group were higher than those in health control group[(2.56+/-0.50, 1.61+/-0.37, 0.46+/ 0.09) vs (1.00+/-0.00, 0.67+/-0.22, 0.30+/-0.07)](all P<0.01); compared with COPD group, the expression of mRNA, protein and activity of Cdc42 in rapamycin COPD group (1.38+/-0.34, 0.91+/-0.48, 0.36+/-0.06) were decreased (all P<0.01). Filopodia protruding can not be seen in the cytoskeleton of AMs from health control group and rapamycin control group; some filopodia protruding can be seen in AM from COPD group; some long filopodia protruding can be seen in AM from rapamycin COPD group. Negative correlations were existed between the mRNA, protein and activity of mTOR, Cdc42 and MFI in all group. Conclusions: mTOR-Cdc42 signaling pathway is activated and related to phagocytosis deficiency of AM in COPD. It can be inferred that the pathway is involved in the pathogenesis of COPD. PMID- 27998434 TI - [Effect of BCYRN1 on proliferation and migration of airway smooth muscle cells in rat model of asthma]. AB - Objective: To detect the effect of brain cytoplasmic RNA 1 (BCYRN1) on the proliferation and migration of airway smooth muscle cells (ASMCs) in rat model of asthma. Methods: Male SD rats were randomly divided into control group and asthma group (n=10 each). The ovalbumin (OVA) model was constructed in asthma group. Real time-qPCR was performed to detect the level of BCYRN1 in the ASMCs separated from the airway tissue of these rats. Then 2-(4-iodophenyl)-3-(4-nitrophenyl)-5 (2, 4-disulfophenyl)-2H-tetrazolium (WST-1) assay, roche real-time cell analyzer assay and Transwell cell migration assay were performed to detect the viability/proliferation and migration of ASMCs which were transfected with Ad BCYRN1.Platelet-derived growth factor (PDGF)-BB was used to treat ASMCs to induce proliferation and migration, and the level of BCYRN1 was examined.The viability/proliferation and migration of ASMCs treated with PDGF-BB and transfected with si-BCYRN1 were detected. Inspiratory resistance and expiratory resistance were measured in rats with BCYRN1 knockdown.Briefly, rats were randomly divided into four groups: control (group A), sensitization + Ad-GFP (group B), sensitization + AdSM22alpha-siBCYRN1 (group C), control + Ad-SM22alpha siBCYRN1 (group D) (n=10 each). The corresponding adenovirus vectors were sent to lung of group B, group C and group D through nasal spray. The OVA model was constructed in group B and group C. The rats in group A and group D were treated with saline.After 24 h of the last treatment with OVA or saline, rats of each group were given tracheal intubation, connected with breathing machine. Rats were injected with methacholine to measure the inspiratory resistance and expiratory resistance. Results: The level of BCYRN1 in ASMCs separated from rats in asthma group and in ASMCs treated with PDGF-BB was 3.60+/-0.45 and 3.53+/-0.35, respectively, significantly higher than those of the corresponding control (both P<0.01). Ad-BCYRN1 significantly increased the expression of BCYRN1 in ASMCs. The cell viability and proliferation rates of ASMCs transfected with Ad-BCYRN1 increased 1.75-and 1.47-fold compared to those of the control group, respectively (P<0.01); mobility increased 2.42-fold compared to that of the control group (all P<0.01). BCYRN1 knockdown reversed the increasing proliferation and migration of ASMCs induced by PDGF-BB. The cell proliferation rate and cell migration number in the PDGF-BB treatment group were (4.87+/-0.21)% and 80.00+/-5.00, respectively, which were significant higher than those in the si-BCYRN1 transfected group ((3.63+/-0.21)% and 25.33+/-2.52, all P<0.01). BCYRN1 knockdown reduced the inspiratory resistance and expiratory resistance in sensitization + Ad-SM22alpha-siBCYRN1 group. When the concentration of acetylcholine reached 1 mg/kg, the inspiratory resistance in the group A, group B, group C, and group D were 8.27+/-0.21, 25.40+/-0.56, 12.07+/-0.67 and 8.40+/-0.46 cmH2O.s.ml-1, and expiratory resistance were 13.30+/-0.56, 38.37+/-1.33, 16.40+/-0.56 and 13.40+/ 0.46 cmH2O.s.ml-1, respectively (all P<0.01). Conclusion: Overexpression of BCYRN1 promotes the proliferation and migration of ASMCs in rat model of asthma. PMID- 27998435 TI - [Association of sleep quality with hypertension in the elderly of Jino nationality: a multilevel model analysis]. AB - Objective: To evaluate the association of sleep quality with hypertension in the elderly population aged 60 years and older of Jino nationality. Methods: In August 2015, a cross-sectional population-based survey was conducted to investigate the prevalence of hypertension in 805 subjects sampled by multistage stratified and cluster sampling from the elderly population of Jino nationality, the sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI, a poor sleep group was defined as having a global PSQI score>7, a good sleep group was with a score of 7 or less), and the multilevel Logistic regression model was applied to analyze the association of sleep quality with hypertension. Results: A total of 793 eligible participants were available for analysis. Overall, 118 participants (14.9%) were in the poor sleep group, and 675 participants (85.1%) were in the good sleep group. The prevalence of hypertension, prevalence of isolated systolic hypertension, average systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the poor sleep group were significantly high than those of the good sleep group[73.7%, 22.0%, (139.2+/-17.7) and (82.5+/-10.6) mmHg (1 mmHg=0.133 kPa) vs 33.0%, 9.0%, (131.2+/-15.0) and (78.5+/-8.9) mmHg, all P<0.05]. The results of covariate-adjusted multilevel Logistic regression model indicated that subjective sleep quality (OR=2.64, 95% CI: 1.08-6.44), sleep latency (OR=2.98, 95% CI: 1.52-5.86), sleep disturbance (OR=2.93, 95% CI: 1.06 8.10), daytime dysfunction (OR=3.86, 95% CI: 1.74-8.58) and poor sleep (OR=3.98, 95% CI: 2.05-7.73) had the positive correlation with hypertension. Conclusions: The elderly population of Jino nationality with poor sleep have high SBP and DBP. There are positive associations of PSQI and its components with hypertension in the elderly population of Jino nationality. PMID- 27998436 TI - [Advances in research on primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer patients]. AB - Lung cancer is one of the most common cancers worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. Chemotherapy for patients with advanced NSCLC has only marginally improved overall survival; whereas recently developed small-molecule compound epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate strong efficacy in treating advanced NSCLC. However, only a part of patients with NSCLC is sensitive to the treatment of EGFR TKIs if they have certain mutations of EGFR gene in their tumors. Patients without EGFR mutations show innate resistance to EGFR TKIs. Furthermore, approximately 20%-30% of patients with EGFR mutations also do not response to EGFR TKIs. In this review, the mechanisms underlying the primary resistance to EGFR TKIs in advanced NSCLC, especially in those with EGFR sensitive mutations, are summarized. PMID- 27998437 TI - [Effects of tetrahydrobiopterin on the angiogenesis in hepatocellular carcinoma]. AB - Objective: To investigate the effect and mechanism of tetrahydrobiopterin (BH4) on the angiogenesis in hepatocellular carcinoma (HCC). Methods: BALB/c-nu mice were subcutaneously injected with HepG-2 cells and randomly divided into control and BH4 groups. The BH4 group and control group received 20 mg/kg BH4 or saline by intraperitoneal injection daily for two weeks, respectively. The level of BH4 was measured by high performance liquid chromatography (HPLC), the level of nitric oxide (NO) was measured by Griess test array, the transcriptional level of K-ras was measured by quantitative RT-PCR, and the protein expressions of guanosine triphosphate cyclohydrolase I(GTPCH), endothelial nitric oxide synthase (eNOS), phospho-Akt and Akt were determined by Western blot. Results: BH4 level in the tumor tissues of BH4 group was (0.24+/-0.02) MUg/ml, significantly higher than the (0.17+/-0.01) MUg/ml in the control group (P<0.01). The level of NO in the tumor tissues of BH4 group was (51.44+/-2.90) mmol/L, significantly higher than the (24.77+/-0.54) mmol/L in the control group (P<0.01). The tumor volume of BH4 group was (191.05+/-8.70) mm3, significantly higher than the (103.10+/-5.03) mm3 in the control group (P<0.01). The expressions of CD34, K-ras, phospho-eNOS, phospho-Akt and GTPCH were significantly up-regulated in the tumor tissues of BH4 group when compared with those of the control group (P<0.01). Conclusions: BH4 recognized as an essential cofactor of eNOS can increase tumor-produced NO by activating the wild-type Ras-PI3K/Akt pathway, thus induces angiogenesis. This might provide a novel and promising way to control the progression of hepatocellular carcinoma through targeting BH4 synthesis pathway and inhibiting angiogenesis. PMID- 27998438 TI - [Inactivation of PMS2 gene by promoter methylation in nasopharyngeal carcinoma]. AB - Objective: To investigate the inactivation of PMS2 gene mediated by promoter methylation and its regulatory mechanism in nasopharyngeal carcinoma (NPC). Methods: Fifty-four NPC tissues, 16 normal nasopharyngeal epithelia (NNE), 5 NPC cell lines (CNE1, CNE2, TWO3, HNE1 and HONE1) and 1 normal nasopharyngeal epithelial cell line (NP69) were collected.Methylation-specific PCR (MSP) was used to detect the PMS2 promoter methylation, semi-quantitative reverse transcription PCR (qRT-PCR) was applied to determine its mRNA expression, and immunohistochemistry (IHC) was used to detect the protein expression of PMS2. The expressions of PMS2 mRNA in CNE1 and CNE2 cells before and after treated with methyltransferase inhibitor 5-aza-2-deoxycytidine were analyzed by qRT-PCR. The impact of methylation and demethylation on the mRNA expression of PMS2, and the association of mRNA and protein expression of PMS2 with clinicopathological features of nasopharyngeal cancer were analyzed. Results: Methylation of PMS2 gene was detected in all of the five NPC cell lines, but not in normal nasopharyngeal epithelial NP69 cells. The methylation rate of PMS2 gene in NPC tissues was 63% (34/54), significantly higher than that of the normal nasopharyngeal epithelia (0/16, P<0.001). The expression levels of PMS2 mRNA and protein were significantly down-regulated in the 54 NPC tissues when compared with those in the 16 NNE tissues (P<0.001), and were also significantly lower in the 34 methylated NPC tissues than those in the 20 unmethylated NPC tissues (P<0.001). After treatment with 5-aza-2-deoxycytidine, the expression of PMS2 mRNA was restored in the CNE1 and CNE2 cells.However, the expressions of PMS2 mRNA and protein were not significantly correlated with patients' age, gender, TNM stage, histopathologic type or lymph node metastasis (P>0.05 for all). Conclusions: Promoter methylation-mediated inactivation of PMS2 gene participates in carcinogenesis and development of NPC. PMS2 may be a candidate tumor suppressor in the treatment for patients with inactivation of PMS2 promoter methylation. PMID- 27998439 TI - [Expression of Ether a go-go 1 and its molecular mechanism of regulating the malignant phenotype of osteosarcoma]. AB - Objective: To explore the expression of ether a go-go 1 (Eag1) in human osteosarcoma and its molecular mechanisms of regulating the malignant phenotype of osteosarcoma. Methods: The expression levels of Eag1 in osteosarcoma cell lines and human osteosarcoma tissues were detected by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry. The small interfering RNA (siRNA) was used to inhibit the expression of Eag1. The abilities of proliferation and invasion in osteosarcoma cells transfected with Eag1 siRNA were determined by CCK-8, colony formation assay, transwell assay and wound healing assay. The osteosarcoma xenograft model of nude mouse was established and tumor growth curve was drawn. Western blot analysis was performed to detect the expression of vascular endothelial growth factor (VEGF) and signal transducer and activator of transcription 3 (STAT3) in osteosarcoma cells transfected with Eag1 siRNAs. Results: Eag1 was overexpressed in the osteosarcoma cells and tissues. Compared with the scrambled siRNA group, the cell survival rates of Eag1 siRNA1 and Eag1 siRNA2 groups of the two cell lines were significantly lower. [MG-63 cells: scrambled siRNA group (100.0+/ 4.65)%, Eag1 siRNA1 group (63.57+/-3.89)%, and Eag1 siRNA2 group (54.13+/-3.70)%; Saos-2 cells: scrambled siRNA group (100.00+/-5.46)%, Eag1 siRNA1 group (56.70+/ 5.34)%, and Eag1 siRNA2 group (40.27+/-5.28)% (P<0.001 for all)]. Similar results were obtained from colony formation assay. The colony formation rates of MG-63 cells: the scrambled siRNA group was (92.00+/-3.46)%, Eag1 siRNA1 group (60.00+/ 3.06)%, and Eag1 siRNA2 group (53.67+/-2.40)%; the colony formation rates of Saos 2 cells: the scrambled siRNA group was (92.00+/-5.57)%, Eag1 siRNA1 group (52.33+/-5.13)%, and Eag1 siRNA2 group (41.67+/-2.73)%. Compared with the scrambled siRNA group, P<0.001 for all. The tumor volumes of osteosarcoma xenograft in the Eag1 siRNA1 and Eag1 siRNA2 groups were significantly smaller than that in the scrambled siRNA group after 10 days treatment (P<0.01 for all). The invasion assay data showed that MG-63 and Saos-2 cells transfected with Eag1 siRNAs exhibited the ability of cell invasion, when compared with the cells transfected with scrambled siRNA. (Invasive cell number of MG-63 cells: the scrambled siRNA group was 134.00+/-3.61, Eag1 siRNA1 group 105.20+/-2.52, and Eag1 siRNA2 group 91.00+/-3.01; Invasive cell number of Saos-2 cells: the scrambled siRNA group was 132.30+/-3.23, Eag1 siRNA1 group 114.30+/-3.48, and Eag1 siRNA2 group 82.67+/-6.33. Compared with the scrambled siRNA group, P<0.01 for all. The migration rates were (62.48+/-1.83)%, (35.98+/-1.23)% and (32.30+/ 1.20)% in the three groups of MG-63 cells, and (70.15+/-1.42)%, (41.38+/-1.34)% and (32.40+/-1.92)% in the three groups of Saos-2 cells, respectively. Compared with the scrambled siRNA group, P<0.001 for all. Notably, the expression levels of VEGF decreased evidently after Eag1 siRNAs transfection, paralleled with reduction in the expression levels of STAT3. Conclusions: Eag1 may promote osteosarcoma cell proliferation and invasion by targeting STAT3-VEGF pathway and may be a potential therapeutic target for osteosarcoma. PMID- 27998440 TI - [Value of single-source dual-energy CT (ssDECT) in differentiating lipid-poor adrenal adenomas from metastatic lesions]. AB - Objective: To evaluate the value of single-source dual-energy CT (ssDECT) in differentiating lipid-poor adenomas from metastases in adrenal glands. Methods: From August 2011 to Oct 2014, 63 patients with 73 adrenal nodules (53 metastases proven by 5-6 months follow-up, and 20 histopathologically proven adenomas, CT value > 10 HU) underwent ssDECT scanning. The CT values of conventional polychromatic CT and virtual monochromatic images (40-140 keV) , fat-water density images and effective atomic number (eff-Z) were reconstructed on an ADW4.5 workstation and ROC curves were then constructed to evaluate the effectiveness of each parameter. The slope of spectral curve was measured and divided into 3 types: increment curve (K>0.1), straight curve (-0.1<=K<=0.1) and decrement curve (K< -0.1) according to the slope (the value of K) of spectral curve, and the curve patterns in the two groups were compared statistically. Results: There was no statistical difference between the mean CT values of metastases (35.12+/-5.29)HU and lipid-poor adenomas (32.48+/-6.94)HU by conventional polychromatic CT (P>0.05). The range of single-energy CT values of metastases [from (53.00+/-15.12) HU to (33.38+/-5.67) HU] was significantly higher than that of lipid-poor adenomas [from (26.90+/-26.94) HU to (28.77+/ 10.66) HU] at energy levels ranging from 40 to 80 keV (P<0.05). There was no significant difference between the single-energy CT value of metastases and lipid poor adenomas at energy levels ranging from 90 to 140 keV (P>0.05). The median fat-water concentration of metastases was -164.61 MUg/cm3, significantly lower than that of lipid-poor adenomas (114.32 MUg/cm3,P<0.05). The eff-Z of metastases (7.76+/-0.15) was also significantly higher than that of lipid-poor adenomas (7.50+/-0.25, P<0.05). When the threshold of fat-water concentration was -143.89 MUg/cm3, the sensitivity, specificity and accuracy rate of metastasis diagnosis was 70.0%, 66.0%, and 76.7%, respectively. When the threshold of eff-Z was 7.63, the sensitivity, specificity and accuracy rate of metastasis diagnosis was 83.0%, 65.0%, and 80.4%, respectively. The lower the energy, the higher the diagnostic accuracy at energy levels ranging from 40 to 80 keV, and that of 40 keV was the highest. The spectral curves of metastases included 2 (3.8%) ascending curves, 9 (17.0%) straight curves and 42 (79.2%) descending curves, while in the 20 lipid poor adenomas, there were 9 (45.0%) ascending curves, 4 (20.0%) straight curves and 7 (35.0%) descending curves, showing significant differences between the two groups (P<0.05). Conclusions: Single-source dual-energy CT provides an effective multi-parameter approach for differentiating lipid-poor adrenal adenomas from metastases. PMID- 27998441 TI - [Intertumoral heterogeneity of molecular phenotype and analysis of prognosis in multifocal and multicentric breast cancer]. AB - Objective: This study was designed to investigate the prognostic implications of the intertumoral heterogeneity of molecular phenotype in multifocal and multicentric breast cancer (MMBC). Methods: The clinical and follow-up data of 146 patients with MMBC from Jan.2009 to Dec. 2009 treated in Tumor Hospital Affiliated to Zhengzhou University were retrospectively analyzed. We used Kaplan Meier curves to compare the survivals of patients who had tumors with molecular phenotypic heterogeneity and patients who had multifocal homogeneous tumors in molecular phenotype, and the survivals of patients who had heterogeneous tumor type and grade and who had homogeneous tumor type and grade.The corresponding hazard ratio was calculated by Cox proportional-hazards regression. Results: Intertumoral heterogeneity in histological type and grade of multiple breast cancer was detected in 16 of 146 patients (11.0%) and in 10 of 146 patients (6.8%), respectively. Interfocal heterogeneous molecular phenotype of multiple breast cancer was detected in 24 of 146 patients (16.4%). There was no significant difference in 5-year disease-free survival in multifocal cancer patients who had heterogeneous histological type and grade and who had homogeneous type and grade tumors (75.0% vs. 77.3%, P=0.808). Multifocal cancers patients who had heterogeneous tumorsin molecular phenotype compared with those with homogeneous tumors in molecular phenotype had worse 5-year disease-specific survival (78.7% vs. 58.3%, P=0.037), and had a greater risk of recurrence (HR=2.130, 95%CI=1.027-4.420; P=0.042). Phenotyping the additional cancer foci influenced the therapeutic decision in up to 16 patients(11.0%). Conclusions: Multifocal breast cancer patients who had heterogeneous tumors in molecular phenotype have a statistically significantly shorter disease-free survival. Phenotyping the additional cancer foci and managing with proper therapeutic decision may reduce the risk of recurrence or metastasis, and improve the outcomes of the patients. PMID- 27998442 TI - [Poorly differentiated gastric cancer associated with Dieulafoy's lesion: a case report]. PMID- 27998443 TI - [Association of the expression of leptin and leptin receptor with bone metastasis in pulmonary adenocarcinoma]. AB - Objective: To explore the association of expression of leptin and leptin receptor (LR) with bone metastasis of pulmonary adenocarcinoma. Methods: One hundred and sixteen pulmonary adenocarcinoma patients who had complete clinicopathological data and definite pathological diagnosis in our hospital from January 2008 to January 2010 were selected. They were divided into the metastasis (n= 58) and non metastasis (control, n=58) groups. The expressions of leptin and LR were identified by immunohistochemistry. The differences between expressions of leptin and LR in primary pulmonary adenocarcinoma tissues and metastasis, and between the groups with and without bone metastasis were analyzed. We also analyzed the correlation of leptin and LR expressed in primary adenocarcinoma and bone metastatic tissues, and the relationship between their expression levels and bone metastasis free survival (BMFS). Results: Among 58 patients of the metastasis group, the cases of high, moderate and low expressions of leptin were 36, 15 and 7, respectively, and the cases of high, moderate and low expressions of LR were 32, 17 and 9, respectively. Among the 58 patients of control group, the cases of high, moderate and low expressions of leptin were 19, 24 and 15, respectively, and those of LR were 17, 16 and 25, respectively. The expressions of leptin and LR in primary pulmonary adenocarcinoma tissues of metastasis group were significantly different from those of the control group (P=0.006, P=0.002, respectively). The expressions of leptin and LR in primary pulmonary adenocarcinoma tissues of the bone metastasis group were also significantly different from those of the non-bone metastasis group (P=0.029, P=0.032, respectively). The high/moderate expression rates of leptin and LR in the bone metastatic tissues reached 91.4% (32/35) and 88.6% (31/35), respectively. The results showed that the expressions of leptin and LR in primary pulmonary adenocarcinoma tissues were positively related with their expressions in bone metastatic tissue (r = 0.612). The median bone metastasis free survival (BMFS) of the bone metastasis groups with high, moderate and low expressions of leptin were 14, 21 and 47 months, respectively, and the median BMFS of high, moderate and low expressions of LR in the bone metastasis group were 13, 19 and 27 months, respectively. The expressions of leptin and LR in pulmonary adenocarcinoma were significantly associated with BMFS (P<0.001, P=0.006, respectively). Conclusions: The expressions of leptin and LR are significantly up-regulated in primary pulmonary adenocarcinoma tissues and bone metastatic tissues, and are negatively correlated with BMFS. These two molecules may be used as effective predictors of bone metastasis in pulmonary adenocarcinoma. PMID- 27998444 TI - [Clinical and imaging features of abdominal rhabdomyosarcoma of non-organ origin in children]. AB - Objective: To evaluate the clinical and imaging features of abdominal rhabdomyosarcoma of non-organ origin in children. Methods: We retrospectively analyzed the clinical and imaging features of 12 pediatric patients with abdominal rhabdomyosarcoma confirmed by surgery and pathology at our hospital. Results: There were 9 boys and 3 girls, with an average age of (5.47+/-3.92) years old (range, 1 to 15). According to Intergroup Rhabdomyosarcoma Study (IRS) staging system, they were of stage III to stage IV, and most were of embryonal type. Tumors of 7 cases were located in the pelvic cavity, 2 cases in the abdominal cavity, 1 in the retroperitoneal space, 1 in both the abdominal and pelvic cavities and 1 across the retroperitoneal space, and abdominal and pelvic cavities. Gray-scale ultrasound showed moderate inhomogeneous echo structure and color Doppler flow imaging showed rich blood flow signals. CT plain scan showed masses of iso- or low-density, and the contrast-enhanced scan showed lesions with inhomogeneous enhancement. The enhancement in delay scan was more obvious and the peripheral enhancement was more significant than central enhancement. Conclusions: Childhood abdominal rhabdomyosarcoma of non-organ origin may arise from the peritoneum, be commonly seen in boys younger than 10 years old, more likely located in the pelvic cavity, and embryonal rhabdomyosarcoma is the most common histological variant seen in childhood. Ultrasound and CT imaging can provide useful information for diagnosis and differential diagnosis of this tumor. PMID- 27998445 TI - [Progression of vulva intraepithelial neoplasia grade III to vulva cancer: a case report]. PMID- 27998446 TI - [Preliminary evaluation of PET-CT and DWI for the detection of lymphoma bone marrow infiltration]. AB - Objective: To evaluate the clinical value of PET-CT and DWI for the detection of bone marrow infiltration of lymphoma. Methods: The bone marrow samples of 93 untreated patients with pathologically diagnosed lymphoma were retrospectively analyzed. 61 patients underwent PET-CT examination, and other 32 underwent DWI examination. With bone marrow biopsy results as "gold standard" , the rates and sites of bone marrow infiltration of various lymphoma subtypes were analyzed, and the detection rates of the two imaging techniques were compared according to different lymphoma subtypes. Results: 39 patients were diagnosed as bone marrow infiltration based on pathological examination of bone marrow biopsies from routine sampling sites and bone marrow pathological examination of biopsies guided by PET-CT and DWI. The sensitivity, specificity, accuracy, positive and negative predictive values of PET-CT for lymphoma bone marrow infiltration were 80.8%, 88.6%, 85.3%, 84.0% and 86.1%, respectively; for DWI examination, these rates were 84.6%, 89.5%, 87.5%, 84.6% and 89.5%, respectively. The detection rates of the two imaging techniques for aggressive lymphoma were 37.5% (18/48) and 38.1% (8/21), respectively, which were slightly higher than those for the indolent lymphoma [23.1% (3/13) and 27.3% (3/11)], although the differences were not statistically significant (P=0.521, P=0.660). For both aggressive lymphoma and indolent lymphoma, the detection rates of DWI were numerically slightly higher than those of PET-CT(P=0.963, P=1.000). Conclusions: PET-CT and DWI have important and similar diagnostic value for bone marrow infiltration of lymphoma. None of PET-CT and DWI can replace bone marrow biopsy (BMB). However, image guided bone marrow biopsies can improve the detection rate of bone marrow infiltration of lymphoma. PMID- 27998447 TI - [Factors influencing survival and recurrence and potential significance of postoperative radiotherapy and adjuvant chemotherapy for stage IIIA-N2 non-small cell lung cancer]. AB - Objective: To investigate the survival, recurrence patterns and risk factors in patients with stage IIIA-N2 NSCLC treated with curative surgery and adjuvant chemotherapy and to explore the significance of postoperative radiation therapy. Methods: The clinical data of 290 patients with pathologically diagnosed stage IIIA-N2 NSCLC after curative resection and adjuvant chemotherapy from January 2010 to December 2014 at our department were retrospectively analyzed. The survival and recurrence patterns were observed, and the factors affecting locoregional recurrence were analyzed. Results: The median survival time was 31.5 months. The 1-, 3-and 5-year survival rates were 88.3%, 46.0% and 33.2%, respectively. The median locoregional control time was 38.5 months. The 1-, 3-and 5-year locoregional control rates were 78.6%, 55.2% and 41.0%, respectively. The median distant metastasis-free survival was 26.8 months. The 1-, 3-and 5-year distant metastasis-free survival rates were 76.4%, 45.5% and 39.5%, respectively. The median progression-free survival was 19.1 months. The 1-, 3-and 5-year progression-free survival rates were 64.1%, 32.5% and 23.8%, respectively. Univariate analysis showed that clinical N status, histological type, pathological T stage, operation mode, the number of positive N2 lymph nodes and the number of positive N2 lymph node stations had a significant influence on overall survival; clinical N status, histological type, the number of positive N2 lymph nodes and the number of positive N2 lymph node stations had a significant influence on locoregional control. Multivariate analysis demonstrated that the number of N2 positive lymph nodes (P= 0.017) was an independent factor for overall survival of stage IIIA-N2 patients; the number of N2 positive lymph nodes (P=0.009) and histological type (P=0.005) were independent factors for locoregional recurrence. For left-sided lung cancer, the lymph node station failure sites were mostly in 2R, 4R, 5, 6 and 7, and the contralateral mediastinum was frequently involved. For right-sided lung cancer, the lymph node station failure sites were mostly in 2R, 4R, 7, 10R and surgical stump. Conclusions: Clinical N2, squamous cell carcinoma, positive N2 nodes of more than 3 and multiple positive N2 stations are poor prognostic factors for locoregional recurrence. Locoregional recurrence of left lung cancer frequently involves the contralateral mediastinum, while that of the right lung cancer usually locates in the ipsilateral mediastinum. PMID- 27998449 TI - [Long term survival of bone-only metastatic breast cancer benefit from bone window CT: a case report]. PMID- 27998448 TI - [Chinese multicenter randomized trial of customized chemotherapy based on BRCA1 (breast cancer susceptibility gene 1)-RAP80 (receptor-associated protein 80) mRNA expression in advanced non-small cell lung cancer (NSCLC) patients]. AB - Objective: BRCA1 (breast cancer susceptibility gene 1) and RAP80 (receptor associated protein 80) play key roles in predicting chemosensitivity of platinum and taxanes. A randomized trial was carried out to compare non-selected cisplatin based chemotherapy with therapy customized according to BRCA1 and RAP80 expression. Methods: Advanced stage NSCLC patients whose tumor specimen was sufficient for molecular analysis were randomized (1?3) to the control or experimental arm. Patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin (Arm 1), those with intermediate/high RAP80 expression and low/intermediate BRCA1expression received docetaxel/cisplatin (Arm 2), and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone (Arm 3). The primary end point was progression-free survival (PFS). Results: 226 patients were screened and 124 were randomized in this trial. ORR in the four subgroups was 22.6%, 48.4%, 30.3% and 19.2%, respectively (P=0.08); PFS was 4.74, 5.59, 3.78 and 2.73 months, respectively (P=0.55); and OS was 10.82, 14.44, 10.86 and 10.86 months, respectively (P=0.84). The common adverse effects included neutropenia, nausea, anemia and fatigue. Conclusions: No statistically significant difference of ORR, PFS or OS is observed in the experimental arms compared with the control arm. Patients with low RAP80 mRNA levels have a trend of better survival and higher response rate to gemcitabine/cisplatin chemotherapy. PMID- 27998450 TI - [A prospective follow-up study on the association between serum level of C reactive protein and risk of digestive system cancers in Chinese women]. AB - Objective: It has been reported by some prospective studies that C-reactive protein (CRP) is associated with cancer risk. However, the correlation between CRP and digestive system cancers has not been evaluated in Chinese females. We conducted a large population-based cohort study to investigate whether elevated level of CRP in serum is associated with an increased risk of digestive system cancers in Chinese women. Methods: From the Chinese Kailuan Female Cohort, 19, 437 women were enrolled in this study in July 2006, and all of the subjects were followed up through 2014. At the baseline investigation, the serum levels of high sensitivity CRP (hsCRP) were tested for all subjects, and demographic information and risk factor data were collected. Multivariable Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and 95% confidence intervals (95% CI) for the baseline levels of hsCRP after adjusting for age, marital status, smoking, drinking, body mass index (BMI), diabetes and physical activity, and risk of digestive system tumors (including colorectal cancer, stomach cancer, pancreas cancer, liver and gallbladder cancer, and other cancers). Results: By Dec 31, 2014, a total of 100 incident cancer cases were observed, including 47 colorectal cancers, 17 stomach cancers, and altogether 29 pancreas, liver and gallbladder cancers. All the subjects investigated were divided into three groups according to the level of hsCRP (<1 mg/L, 1-3 mg/L and >3 mg/L). The 8-year cumulative incidence of digestive system cancers were 405/100 000, 520/100 000 and 787/100 000 in these 3 groups, respectively (Log rank test chi2 = 8.37, P=0.015). Compared to those with lower hsCRP levels (<1 mg/L), the women with higher hsCRP (>3 mg/L) had a significantly increased risk of pancreas, liver and gallbladder cancers (HR = 2.70, 95% CI = 1.06-6.91; Ptrend = 0.036). Conclusions: Elevated levels of hsCRP at baseline may be associated with increased risk of certain digestive system cancers. PMID- 27998451 TI - [Pay attention to the secondary optic neuropathy and the safe appropriate applications of optic neuroprotection]. AB - Secondary optic neuropathy of optic nerve abnormalities is the leading cause of persistent visual impairment. Previous ocular neuroprotection studies have proved that the nerve growth factor and other agents are of significant in the preservation of optic nerve axon and retinal ganglion cells. However, finding novel safe and effective approach as well as the appropriate applications of optic neuroprotection should be highly emphasized and would be very helpful in the treatment of optic neuropathy.(Chin J Ophthalmol, 2016, 52: 881-884). PMID- 27998452 TI - [Pay attention on optical coherence tomography evaluation for optic nerve diseases]. AB - Optical coherence tomography(OCT) had become the most important imaging technique in ophthalmology. OCT is able to segment the retinal nerve fiber layer and retinal ganglion cell layer accurately. Quantitative analysis can be performed for both layers. OCT is very important to evaluate the neuron and axon loss in optic nerve diseases diagnosis. Meanwhile, OCT has great value for differentiating glaucoma and macular diseases from optic nerve diseases. This review presented OCT application in optic nerve diseases diagnosis, differentiation diagnosis, the key points in use and the features of en face OCT and OCT angiography. It gave us suggestions that it should be pay more attention to OCT examination in diagnosis and treatment of optic nerve diseases. (Chin J Ophthalmol, 2016, 52: 885-888). PMID- 27998453 TI - [Clinical features of neurosyphilis with optic neuritis as an initial finding]. AB - Objective: To study the characteristics of neurosyphilis with optic neuritis as an initial finding. Methods: Retrospective analysis of clinical data and laboratory testing results of 16 cases (27 eyes) with optic neuritis as an initial finding of neurosyphilis from October 2010 to March 2015 in General Hospital of People's Liberation Army was made. Results: Six-teen patients (12 males, 4 females) were collected, the median age of patients was 47 (range 33 to 65) years ,the mean age was (49.63+/-9.05) years. Treponema pallidum particle agglutination assay (TPPA) analysis was positive in all of the patients and rapid plasma reagin (RPR) test was positive in 14 patients (2 patients did not test). Lumbar puncture was requested and performed for all patients. Cerebrospinal fluid (CSF) TPPA analysis was positive in 16 patients and RPR test was positive in 12 patients. The CSF white blood cell counting increased in 9 (56.3%) patients and 10(62.5%)patients presented with increased CSF protein level. Both eyes were involved in 11 patients (68.8%). Relative afferent papillary defect was positive in 11 patients. Twenty-seven eyes were affected in 16 patients, and among them 7 eyes' pupil diameter were 2.5 mm or less. Incipient visual acuity was less than 0.1 in 22 eyes. The slit lamp examination showed vitreous opacity in 12 eyes and visible cells in 6 eyes among 27 eyes. Fundus examination found that 6 eyes had papillary edema and 15 eyes had pallordisc among 27eyes. Electro-retinogram (ERG) was tested in 24 eyes, and 18 eyes were abnormal. Visual evoked potential (VEP) were performed in 26 eyes (flash VEP in 22 eyes, pattern VEP in 4 eyes), and all were abnormal. Fourteen eyes were tested by 30-2 perimetry, and 6 eyes had diffuse visual field defect, 2 eyes had peripheral visual field defect, 4 eyes had quadrant defect and 2 eyes had center scotoma. Fundus fluorescence angiography was done in 16 eyes and choroidal hyper-fluorescent dots were found in posterior pole in 4 eyes. All patients were treated with antibiotic medicines, among them 10 cases in the General Hospital, and 6 cases in the other hospitals. During 15 months follow-up after discharge, visual acuity of 17 eyes recovered to 0.5 and above. Conclusion: Syphilitic optic neuritis is a condition that manifests with severe visual loss and tends to involve both eyes, Some patients have a smaller pupil diameter. Due to the particular infective routes of the disease, patients often conceal their sexual history. The manifestations of ocular syphilis are complicated and easy to misdiagnose or undiagnose. Clinical manifestations combining with the detailed history taking, serum and cerebrospinal fluid examination can guide to an accurate diagnosis and prevent from permanent vision loss. (Chin J Ophthalmol, 2016, 52: 898-904). PMID- 27998455 TI - [Optic nerve subarachnoid space expansion in MR imaging: a etiology study]. AB - Objective: To investigate spectrum of causes in optic nerve subarachnoid space (ONSS) expansion by using Magnetic Resonance Imaging (MRI). Methods: A retrospective study. Twenty-six patients (46 eyes) with ONSS expansion and 20 healthy adults (40 eyes) were recruited in Neuro-ophthalmology Department of Chinese PLA General Hospital from January, 2014 to December, 2015. The diameters were measured on the optic nerve (OND) and optic nerve sheath (ONSD) 2.4 mm behind the globe. ONSS was calculated by the formula of (ONSD-OND)/2. All participants were under went ophthalmologic examinations. The patients' clinical features, MRI and final diagnosis were analyzed. Qualitative data were compared between groups by using chi square test and quantitative data were compared by independent sample t test. Results: There was no statistically significant difference between ONSS group and control group with age, BMI and mean arterial blood pressure (P>0.05). Larger space was found in ONSS group with mean+/ standard deviation (SD) of (1.9+/-0.4) mm comparing to the control group with (1.2+/-0. 2) mm (t=2.879, P<0.01). Bilateral ONSS expansion were found in 20 patients, 15 patients (75%) with cerebral venous sinus thrombosis (CVST), 2 patients (10%) with neurosyphilis, 2 patients (10%) with peri-neuritis and 1 patient (5%) with hydrocephalus. Unilateral ONSS expansion were seen in 6 patients, 4 patients (66.7%) with compressive lesson on anterior visual pathway, 1 patient (16.7%) with fungal infection and 1 patient (16.7%) with peri-neuritis. Conclusions: The CVST patients more frequently presented bilateral ONSS expansion. Unilateral ONSS expansion may indicate compressive lesions located on the anterior visual pathway. (Chin J Ophthalmol, 2016, 52: 911-917). PMID- 27998454 TI - [Study on correlation between retinal vessel morphology or ocular hemodynamic parameter and internal carotid artery stenosis]. AB - Objective: To analyze the correlation between retinal vascular calibers, ocular blood flow parameters and internal carotid artery stenosis and to evaluate the effect of internal carotid artery stenosis on ocular blood vessels comprehensively. Methods: A retrospective case-control study. The clinical data of 141 patients who underwent head-and-neck computed tomography (CT) angiography examinations of the ICA were collected at Beijing Friendship Hospital, Capital Medical University from January 2014 to January 2016. According to diagnostic criteria, the patients were divided into four groups: the non-stenosis group, the mild stenosis group, the moderate stenosis group, and the severe stenosis andocclusion group. The retinal vascular caliber was measured in color fundus photograph by IVAN software. Color Doppler ultrasonography was used to measure the parameters of ocular blood flow, including the peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI) and pulsatility index (PI). The enumeration data were analyzed with chi-square test, the measurement data were analyzed with rank-sum test, and the correlation test was performed with spearman. Results: The gender ratio of the patients without stenosis, mild stenosis, moderate stenosis, severe stenosis and occlusion was 12/7, 31/19, 28/25, 12/7, chi2 test was not statistically significant (chi2= 0.79, P=0.85); There was no statistically significant difference between the different groups (chi2= 0.15, P=0.68), the age of four groups were (64.1+/-8.3), (54.3+/-14.3), (68.9+/-11.8) and (59.1+/-8.0) y, respectively. In the no internal carotid artery stenosis group, the arteries diameter is (164.5+/-15.6) MUm ,the vein diameter is (245.6+/-20.0) MUm and the arteriovenous ratio is 0.7+/-0.1. There is no difference among the mild stenosis group, moderate stenosis group and the severe stenosis (chi2artery caliber=6.92, Partery caliber=0.08; chi2vein diameter=4.16, Pvein diameter=0.25; chi2arteriolar-venular ratio=1.38,Parteriolar-venular ratio=0.71) . The PSV of central retinal artery in the above groups were (14.6+/ 3.6), (34.4+/-13.2), (35.7+/-14.6), (42.3+/-19.0)cm/s respectively, the data were analyzed by rank-sum test and there was a significant difference (chi2=13.44, P< 0.01) ; The PSV of the posterior ciliary artery in the above groups (17.6+/-6.5), (15.0+/-4.6), (13.4+/-4.3) and (11.0+/-3.2)cm/s respectively, the data were analyzed by rank-sum test and there was a significant difference (chi2=22.71, P<0.01) , EDV were (5.90+/-2.2), (5.1+/-2.1), (4.3+/-1.5) and (4.3+/-4.8)cm/s respectively and there was a significant difference (chi2=20.36, P<0.01) .There was a correlation between retinal artery diameter, PSV and EDV of the central retinal artery, PSV and EDV of the posterior ciliary artery and the diameter of the internal carotid artery but without linear correlation. (rartery caliber= 0.23, Partery caliber=0.01; rPSV of central retinal artery= -0.29, PPSV of central retinal artery<0.01; rPSV of posteri or ciliary artery=-0.34, PPSV of posterior ciliary artery<0.01, rEDV of posterior ciliary artery=-0.35, PEDV of posterior ciliary artery<0.01). Conclusions: There was a correlation between retinal artery diameter, PSV and EDV of the central retinal artery, PSV and EDV of the posterior ciliary artery and the diameter of the internal carotid artery. PSV of the central retinal artery, PSV and EDV of the posterior ciliary artery changed significantly when the internal carotid artery stenosis existed. (Chin J Ophthalmol, 2016, 52: 905-910). PMID- 27998456 TI - [Temporal and spatial characteristics of RGC death and axon degeneration in the rat model of nonarteritic anterior ischemic optic neuropathy]. AB - Objective: To investigate the temporal and spatial characteristics of retinal ganglion cell (RGC) death and axon degeneration in the rat model of nonarteritic anterior ischemic optic neuropathy (rNAION). Methods: Experimental study. The model of rNAION was induced by directly illuminating the optic nerve head with laser, after intravenous infusion with the photosensitizing agent rose Bengal. Seventy-one SD rats were randomly divided into five groups: 1-week (n=14), 2-week (n=14), 4-week (n=15) , 8-week (n=16) model group and the normal control group (n=12). Hematoxylin and eosin (H&E) staining and morphometric measurement with FG labeling were performed to assess rNAION-indeced histologic changes in the retina at different time points. RGCs were counted on retinal flat mounts in a masked fashion. Semithin sections stained with toluidine blue and transmission electron microscopy were performed to evaluate axonal degeneration. The differences of RGC density among multiple groups were tested with one-way ANOVA while the survival rate of RGC with kruskal-Wallis. Results: H&E-stained retina sections of rNAION revealed RGC loss. The density of labeled RGC was (2 273+/-219) cells/mm2 in the control group, (2 075+/-120) cells/mm2 in the 1-week group, (1 783+/-143) cells/mm2 in the 2-week group, (1 330+/-169) cells/mm2 in the 4-week group and (869+/-301) cells/mm2 in the 8-week group. There were significant differences between all pairs of groups (F=80.98, P<0.01). The impairment of RGC was aggravatedprogressively, which mainly in the upper quadrant. The survival rate of RGC was 99.9%+/-3.4%, 91.8%+/-2.9%, 72.6%+/-5.7%, 54.4%+/-7.0% and 37.5%+/-13.0%, respectively. There were significant differences between the 1-week and 2-week group(Z=-3.78, P<0.01), the 2-week and 4-week group(Z=-3.89, P<0.01), and the 4 week and 8-week group(Z=-3.23, P<0.01). Toluidine blue staining of the ON revealed significant demyelination 1 week after ischemic damage. Progressive axonal degeneration existed for several weeks, which mainly affected the central region of the optic nerve with extensive reactive gliosis. Ultrastructural study showed axonal edema and collapsed sheaths in the ischemic optic. Four weeks later, there were extensive axonal loss and severe glial scars. Conclusions: rNAION results in regional and later RGC death. The extended period of RGC death after rNAION induction is much more longer than previously recognized. (Chin J Ophthalmol, 2016, 52: 918-923). PMID- 27998457 TI - [The application of ultra-wide-field angiography in the evaluation and management of patients with posterior, and panuveitis]. AB - Objective: To evaluate the clinical application of ultra-wide-field fluorescein angiography in posterior and panuveitis patients. Methods: It's a prospective, observational case series study. A total of 82 eyes of 42 patients conformed to the research criteria of posterior and panuveitis. Clinical examinations, conventional fluorescein angiography and ultra-wide-field fluorescein angiograms were performed for each patient. The main outcome was the detection of peripheral retinal changes by ultra-wide-field fluorescein angiography, and how these changes influenced the evaluation and management of the disease. Results: There were 22 male and 20 female in the 42 patients. The mean age of the patients was (43+/-21) years. Twelve eyes (6 patients) were diagnosed as posterior uveitis, and 70 eyes (36 patients) as panuveitis. Clinical examinations and conventional fluorescein angiography detected active inflammation in 30 eyes (37%), while ultra-wide-field fluorescein angiography identified active inflammation in 48 eyes (59%). In these 18 additional eyes (22%) with active inflammation found by ultra-wide-field fluorescein angiography, non-perfusion area was observed in 4 eyes (5%) and neovascularization was observed in 1 eye (1%). By means of ultra wide-field fluorescein angiography, a larger area of peripheral vessel leakage showed in 10 eyes (12%) which judged as active inflammation by conventional fluorescein angiography. Additional angiographic changes showed in 46%(21/45) of the eyes with clear etiology, while only in 19%(7/37) of the eyes without clear etiology. According to these findings, treatment strategies adjusted for 12 patients. Conclusions: Ultra-wide-field fluorescein angiography detected more peripheral retinal vascular pathology than conventional fluorescein angiography. The changes found in the periphery were important in the management of uveitis. (Chin J Ophthalmol, 2016, 52: 924-928). PMID- 27998459 TI - [The preliminary study of stimulus input temporal changes on the visual cortex of rats at different ages]. AB - Objective: To observe the impact of the input temporal changes on visual cortex of rats cells and the change of the synaptic efficacy, for the study of visual developmental plasticity mechanism. Methods: Experimental research. The brain slice of ten 14d healthy Wistar rats and ten 21d healthy Wistar rats were recorded with whole cell recording technique, using single stimulation and combined stimulate model, to observe the visual cortex of rats neurons changes in synaptic activity. Change the stimulus input sequence, and observe the visual cortex of rats changes of synaptic efficacy. Using the paired t test to compare the change of excitatory postsynaptic potential (EPSC) of visual cortex. Result: The difference between single stimulation and combined stimulate about EPSC was statistically significant, which was decreased (14.3+/-7.4) % (n=15) in single stimulation and (53.4+/-17.5) % (n=20) in combined stimulation for P14 rats which were long-term depression (ts2=3.9, ts1+s2=2.2; P<0.05) , and was increased (27.5+/-11.4) % (n=16) in single stimulation and (34.6+/-10.3) % (n=10) in combined stimulation for P20 rats which were long-term potentiation (ts2=2.3, ts1+s2=3.5; P<0.05) . Rats in different development period have a specific time window for input temporal changes. Combined stimulation patterns produced by the neuron cell reaction were not just an accumulation of simple response caused by single stimulation. For P14 rats, its time window was of about +/-0.5ms. However, for P20 rats, scope of time window reduced to +/-0.1ms. Conclusions: Different development period of rats, change the stimulation pattern can cause the change of the visual cortex synapses reaction, and stimulate the temporal change within a specific time window to producenonlinear results. (Chin J Ophthalmol, 2016, 52: 936-940). PMID- 27998458 TI - [The effects and related risk factors on cataract surgery in Shandong province]. AB - Objective: To explore the efficacy and related risk factors on cataract surgery in Shandong province. Methods: A total of 108 190 cataract surgeries which were reported from 17 cities of Shandong province during January 2013 to December were reviewed. The demographic information, preoperative examination, surgery related information (including date of surgery, surgical methods, and intraoperative complications), and postoperative situations (naked eye visual acuity, curative efficacy after three days, and postoperative complications) were reviewed. Wilcoxon signed-ranks, univariate and orderly multivariate Logistic regression analysis were used according to nature of the data. Results: There were 64 852 female patients (59.9 %) and 43 338 male patients (40.1%) in all 108 190 cases. About 36.5% patients (39 496 cases), the highest proportion, were 71 to 80 years of age, 31.26% patients (33 711 cases) were 61 to 70 years old and 13.6% patients (14 720 cases) were over 81 years old. Visual acuity increased significantly after surgery (Z=165.24, P<0.01). Simple factor Logistic regression analysis showed that preoperative corrected visual acuity less than 0.1 (OR=2.30 95%CI: 0.59 to 1.07), complications (OR=8.50,95% CI: 1.34 to 2.94), congenital cataract (OR=1.69, 95%CI: 0.22 to 0.83), extracapsular cataract extraction (OR=1.99, 95% CI:0.57 to 0.81), postoperative complications in three days (OR=7.46, 95% CI:1.77 to 2.25) were predictors of worse outcome after cataract surgery. Multivariate logistic regression analysis showed that the efficacy of cataract surgery were influenced by history of diabetes (OR=1.79, 95% CI: 0.46 to 0.71), history of hypertension (OR=3.49, 95% CI: 1.07-1.43), postoperative complications in three days (OR=3.91, 95% CI: 1.53 to 1.20) and extracapsular cataract extraction (OR=1.54, 95% CI: 0.20 to 0.66). Young male patients (OR=0.82, 95% CI:-0.28 to 0.12), normal preoperative intraocular pressure (OR=0.79, 95%CI: -0.38 to -0.10) and pupil (OR=0.42, 95% CI:-1.17 to -0.57) were predictors of better outcome. Conclusions: Visual acuity improved significantly after cataract surgery in Shandong province. The efficacy of cataract surgery was influenced by many factors. It is important to control systemic diseases and to choose modern operation method. (Chin J Ophthalmol, 2016, 52: 929-935). PMID- 27998460 TI - [Treatment of idiopathic intracranial hypertension]. AB - Idiopathic intracranial hypertension(IIH) is a kind of diffuse brain swelling disease. Several causes could lead to IIH. Intracranial venous circulatory disturbance is more common. The clinical manifestations include intracranial pressure increased, headache and papilledema. Since IIH usually has serious impact on vision even blindness, the diagnosis and corresponding treatment are especially important. This review is to discuss the new insights on the therapeutic options of IIH, which cover medical treatment, weight-losing therapy, surgical treatment, interventional therapy and supportive treatment.(Chin J Ophthalmol, 2016, 52: 948-951). PMID- 27998461 TI - [Research advances of optic nerve lamina cribrosa structure and its measurement analysis]. AB - The lamina cribrosa (LC) is believed to be site of injury to retina ganglion cell axons in glaucoma. The ability to visualize this structure helps us increase the understanding of pathophysiological process of glaucoma. At the same time, it is helpful in the early detection and treatment of glaucoma. While for many years the researches on the LC were essentially dependent on histology. With the development of optical coherence tomography (OCT) in recent years, it is possible to image the LC in vivo in both animals and human. This review focused on the biomechanics of optic nerve and LC, recent advances in OCT imaging of LC, imaging processing and analysis. All of these will supply the ability to diagnose and monitor glaucoma, as well as to expand our recognition of its pathophysiology. (Chin J Ophthalmol, 2016, 52: 952-956). PMID- 27998462 TI - [Research progress of circulating tumor cells: the way from counting to subtyping]. AB - Although circulating tumor cells(CTCs) have long been identified, it was not until the approval of CellSearch(r) system that CTCs are current lyunder in-depth investigation.The CTCs technology has advanced from simple cell counting into era of molecular subtyping. The development of sequencing technologies and liquid biopsy has made it possible to sequence single cell genomes. In the recent years, how to take advantage of CTCs as a useful tool to clarify the mechanisms of carcinogenesis and cancer development and to predict the patient survival have become a hot issue. PMID- 27998463 TI - [Effects of anti-PD-L1 monoclonal antibody and EGFR-TKI on the expression of PD L1 and function of T lymphocytes in EGFR-mutated lung cancer cells]. AB - Objective: To investigate the effects of anti-PD-L1 monoclonal antibody and EGFR TKI on expression of soluble PD-L1 and function of T lymphocytes in EGFR-mutated lung cancer cells. Methods: Flow cytometry was used to analyze the expression of membrane PD-LI. ELISA was performed to detect the level of sPD-L1 in the supernatant of cultured EGFR-mutated and wild type lung cancer cells before and after erlotinib treatment.After treated with anti-PD-L1 monoclonal antibody alone and in combination with erlotinib, the proliferation of T lymphocytes in co culture system was measured using Cell Counting Kit-8 (CCK-8) assay. The expression levels of PD-LI and IFN-gamma in tumor cells and T lymphocytes treated with erlotinib in co-culture system were analyzed by flow cytometry and ELISA, respectively. Results: PD-L1 was highly expressed in EGFR-mutated lung cancer PC9 cells (78.7+/-3.1)% and HCC827 cells (82.7+/-2.6)%.After treated with erlotinib, the expression rates of membrane PD-L1 in PC9 and HCC827 cells were down regulated (64.7%+/-3.1% and 73.0%+/-2.6%, respectively), significantly lower than that in the two cell lines without erlotinib treatment (P<0.05), and the expression levels of sPD-L1 in the supernatant of PC9 and HCC827 cells were also down-regulated (0.680+/-0.120)ng/ml and (0.903+/-0.047)ng/ml, respectively, significantly lower than that in the two cell lines without erlotinib treatment (P<0.01). However, no significant changes of membrane PD-L1 and sPD-L1 expression were found in EGFR wild type lung cancer cells (H1299 and A549) before and after erlotinib treatment. In the co-culture system composed of T cells and EGFR mutated lung cancer cells, treatment with erlotinib alone promoted the proliferation of T lymphocytes (P<0.05), and combined treatment of anti-PD-L1 monoclonal antibody with erlotinib had a stronger effect (P<0.05). In the co culture system composed of T cells and EGFR wild type cell lines, the proliferation of T cells was not changed after using erlotinib alone or combination of erlotinib and anti-PD-L1 monoclonal antibody (P>0.05). Before and after treatment with erlotinib, the secretion levels of IFN-gamma were (856.0+/ 70.3)pg/ml and (1 697.3+/-161.0)pg/ml, respectively, showing a significant difference (P<0.001). The expression rates of membrane PD-L1 were (76.2+/-0.5)% and (50.9+/-0.9)%, respectively, also showing a significant difference (P<0.001). However, no significant changes in the expression of IFN-gamma and membrane PD-L1 were found in the co-culture system composed of T cells and A549 cells. Conclusions: Anti-PD-L1 monoclonal antibody combined with EGFR-TKI can effectively promote the proliferation and secretion function of T lymphocytes in the microenvironment of EGFR-mutated lung cancer cells. PMID- 27998464 TI - [miR-143 inhibits cell proliferation through targeted regulating the expression of K-ras gene in HeLa cells]. AB - Objective: To explore the effect of microRNA miR-143 on the proliferation of cervical cancer HeLa cells through targeted regulating the expression of K-ras gene. Methods: The luciferase report carrier containing wild type 3'-UTR of K-ras gene (K-ras-wt) or mutated 3'-UTR of the K-ras (K-ras-mut) were co-transfected with iR-143 mimic into the HeLa cells respectively, and the targeting effect of miR-143 in the transfectants was verified by the dual luciferase report system. HeLa cells were also transfected with miR-143 mimic (miR-143 mimic group), mimic control (negative control group), and miR-143 mimic plus K-ras gene (miR-143 mimic+ K-ras group), respectively. The expression of miR-143 in the transfected HeLa cells was detected by real-time PCR (RT-PCR), and the expression of K-ras protein was detected by Western blot. The cell proliferation activity of each group was examined by MTT assay. In addition, human cervical cancer tissue samples (n=5) and cervical intraepithelial neoplasia tissue samples (n=5) were also examined for the expression of miR-143 and K-ras protein by RT-PCR and Western blot, respectively. Results: The luciferase report assay showed that co transfection with miR-143 mimic decreased the luciferase activity of the K-ras-wt significantly, but did not inhibit the luciferase activity of the K-ras-mut. The expression of miR-143 in the HeLa cells transfected with miR-143 mimic was significantly higher than that in the HeLa cells transfected with the mimic control (3.31+/-0.45 vs 0.97+/-0.22, P<0.05). The MTT assay revealed that the cell proliferative activity of the miR-143 mimic group was significantly lower than that of the negative control group (P<0.05), and the cell proliferative activity of the miR-143 mimic+ K-ras group was also significantly lower than the control group (P<0.05) but higher than the miR-143 mimic group significantly (P<0.05). The expression levels of K-ras protein in the miR-143 mimic group, the negative control group and the miR-143 mimic+ K-ras group were lowest, moderate, and highest, respectively (115.27+/-34.08, 521.36+/-41.89, and 706.52+/-89.44, all P<0.05). In the tissue samples, the miR-143 expression in the cervical cancer group was significantly lower than that of the cervical intraepithelial neoplasia group (0.32+/-0.06 vs. 0.93+/-0.17, P<0.05); whereas the K-ras protein expression in the cervical cancer group was significantly higher than that in the cervical intraepithelial neoplasia group (584.39+/-72.34 vs. 114.23+/-25.82, P<0.05). Conclusions: In vitro, miR-143 can inhibit the proliferative activity of HeLa cells through targeted regulating the expression of K-ras gene. In human cervical cancer tissues of a small sample set, the expression of miR-143 is downregulated, and the expression of K-ras is upregulated. PMID- 27998465 TI - [Clinical utility of real-time fluorescent PCR for combined detection of anaplastic lymphoma kinase and c-ros oncogene 1 receptor tyrosine kinase in non small cell lung cancer]. AB - Objective: To investigate the clinical application value of combined detection of ALK fusion gene and c-ros oncogene 1 receptor tyrosine kinase (ROS1) fusion gene in non-small cell lung cancer (NSCLC) using real-time fluorescent PCR. Methods: A kit for combined detection of ALK fusion gene and ROS1 fusion gene based on fluorescent PCR was used to simultaneously detect the two fusion genes in 302 cases of NSCLC specimens. The results were validated through Sanger sequencing. The consistency of the two detection methods was analyzed. Results: All 302 cases of NSCLC specimens were successfully analyzed through fluorescent PCR (302/302). 12 cases (4.0%) were found to contain ALK fusion gene, including 3 cases with ALK M1, 3 with ALK-M2, 3 with ALK-M3, 1 with ALK-M4, and 2 with ALK-M6 fusion gene.12 cases (4.0%) were found to contain ROS1 fusion gene, including 1 case with ROS1 M7, 8 cases with ROS1-M8, 1 case with ROS1-M12, 1 case with ROS1-M14, and 1 case with double-positive ROS1-M3 and ROS1-M8 fusion genes. The total detection rate of ALK fusion gene and ROS1 fusion gene was 7.9% (24/302) and 278 cases showed to be negative for ALK fusion gene and ROS1 fusion gene. The successful detection rates for Sanger DNA sequencing were also 100%. The positive, negative and total coincidence rates obtained by real-time fluorescent PCR and by Sanger DNA sequencing were all 100%. Conclusions: The results of Sanger DNA sequencing demonstrate that the real-time fluorescent PCR assay is equally effective in detecting ALK and ROS1 fusion genes in NSCLC tissues. Furthermore, real-time fluorescent PCR assay can be used to detect trace ALK and ROS1 fusion gene simultaneously in tiny samples, and can save time and avoid repeated sampling. It is worthy of recommendation as a rapid and reliable detection technique. PMID- 27998466 TI - [Clinical significance of FOXM1 and Gli-1 protein expression in high-grade ovarian serous carcinoma]. AB - Objective: To investigate the different expression and prognostic significance of forkhead box M1 (FOXM1) and Gli-l in ovarian high grade serous carcinoma (HGSC). Methods: The expressions of FOXM1 and Gli-1 in 94 cases of HGSC and 20 cases of normal fallopian tube tissues were detected by immunohistochemistry. Kaplan-Meier analysis and Cox multivariate survival analysis were used to assess the relationship of the FOXM1 and Gli-1 levels with age, International Federation of Gynecology and Obstetrics (FIGO) stage, omental metastasis, and residual foci and prognosis of HGSC. Results: The positive rates of FOXM1 and Gli-1 expression in HGSC were 79.8% (75/94) and 77.7% (73/94), respectively, both significantly higher than those of the normal controls (P<0.05). The expressions of FOXM1 and Gli-1 were significantly correlated with FIGO stage, and both of their positive rates in stage III-IVpatients were significantly higher than those in stage I-II cases (P<0.001). The expressions of FOXM1 in HGSC were positively correlated with Gli-1.Kaplan-Meier analysis revealed that the 5-year overall survival rates of FOXM1- and Gli-1-positive groups were 8.0% and 6.8%, significantly lower than 36.8% and 38.1% of the FOXM1- and Gli-1-negative groups, respectively (P<0.05 for both). Cox multivariate survival analysis revealed that FIGO stage and overexpression of FOXM1 protein were independent prognostic factors of HGSC patients (P<0.05 for both). Conclusions: The overexpression of FOXM1 and Gli-1 proteins participate in the carcinogenesis of HGSC, and are significantly associated with FIGO stage. The protein expression of FOXM1 is positively correlated with Gli-1 in HGSC. Expression of FOXM1 protein and FIGO stage are independent prognostic factors of HGSC. PMID- 27998467 TI - [Expression and significance of serum microRNA-135a-5p level in colorectal cancer]. AB - Objective: To explore the expression level of serum miR135a-5p and its diagnostic value in colorectal cancer (CRC). Methods: Serum samples were randomly collected from 60 primary CRC patients, 40 patients with intestinal polyps and 50 healthy controls, and the serum concentrations of miR135a-5p, CEA and CA199 were detected. The relationships between serum miR135a-5p level and clinicopathological parameters were analyzed by Mann-Whitney U test. The correlation of serum miR135a-5p level and serum concentrations of CEA or CA199 was analyzed by Pearson's correlation test.Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to evaluate the diagnostic efficacy of miR135a-5p, CEA and CA199 as diagnostic indicators. Results: The serum level of miR135a-5p in CRC patient was 2.451 (1.107, 4.413), significantly higher than 0.946 (0.401, 1.942) in the patients with intestinal polyps and 0.949 (0.194, 1.415) in the healthy controls (U = 351.0 and U = 313.0, respectively, P<0.001). The serum level of miR135a-5p in CRC patients was associated with both histological differentiation and clinical stage (P<0.05 for both), however, not correlated with the serum concentration of CEA (r2 = 0.023, P = 0.293) or CA199 (r2 = 0.067, P = 0.068). The AUC of serum miR135a-5p level in CRC patients was 0.832 (0.730-0.930) when compared to the patients with intestinal polyps and was 0.875 (0.800-0.950) when compared with the healthy controls. Conclusions: The serum level of miR135a-5p in CRC patients is significantly higher than that in patients with intestinal polyps and healthy controls, and might be an important diagnostic marker of CRC. PMID- 27998468 TI - [Clinicopathological factors affecting the lymph node yield from laparoscopically resected specimens of rectal cancer]. AB - Objective: To identify the clinicopathological factors affecting the number of lymph nodes yielded from specimens obtained by laparoscopic-assissted resection of rectal cancer, and discuss further the possible causes of insufficient lymph nodes retrieval (<12). Methods: The clinicopathological data of 422 consecutive rectal cancer cases, who underwent radical laparoscopic rectal resection (R0) at our department during January to October 2015, were analyzed retrospectively. The correlation between the clinicopathological factors and the number of lymph nodes yielded from the surgical specimens was assessed statistically. Results: Age of the patient, length of specimen, tumor size and operating surgeon were significantly associated with the lymph node yield (all P<0.05). The total number of lymph nodes yielded in 351 patients without neoadjuvant therapy ranged 8-49, with an average of 22.5, and the lymph node metastasis rate was 0-100% with an average of 7.6%.The total number of lymph nodes yielded from the 71 patients receiving neoadjuvant therapy ranged 9-70, with an average of 18.3, and the lymph node metastasis rate was 0-73.0%, with an average of 7.6%. Neoadjuvant therapy decreased the total lymph node yield obviously (P<0.001), but didn't decrease the lymph node metastasis rate (P=0.636). Of all the patients investigated, 19 cases had less than 12 dissected lymph nodes, and 403 cases had at least 12 lymph nodes removed. Gender, tumor size and neoadjvant therapy were independent risk factors for yield of twelve or more lymph nodes (all P<0.05). Conclusions: Age of the patient, length of specimen, tumor size, operating surgeons and neoadjuvant therapy are significantly correlated with the total number of lymph nodes yielded from laparoscopically resected specimens of rectal cancer. Neoadjvant therapy may obviously decrease the number of yielded lymph nodes, while not decreases the lymph node metastasis rate. Male gender, small size of the tumor, and neoadjvant therapy are possible risk factors for harvesting less than 12 lymph nodes. PMID- 27998469 TI - [Epidermal growth factor tyrosine kinase inhibitors used in the treatment of NSCLC patients with leptomeningeal metastasis]. AB - Objective: The aim of this study was to identify the clinical features and prognostic factors of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC) patients undergoing treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Methods: Twenty-five cases of NSCLC with LM, treated in our hospital during January 1, 2003 to October 31, 2013, were enrolled in this study. Medical records were reviewed for clinical features and treatments, and the survival and prognostic factors were analyzed. Results: NSCLC-LM were more common in female patients (64.0%), and most were adenocarcinomas (72.0%). Twenty (80.0%) patients underwent anti-cancer treatment, among them 17 patients underwent EGFR-TKIs treatment.The median overall survival (mOS) after the diagnosis of LM was 4.9 months for the whole group (25 cases). Patients receiving EGFR-TKIs treatment had a longer median survival than patients not receiving EGFR-TKIs (5.3 months vs. 1.2 months, P=0.022). Eleven patients who developed LM before the targeted therapy had a prolonged median survival of 8.1 months after EGFR-TKIs treatment. The univariate analysis showed that female gender and EGFR-TKIs treatment were favorable prognostic factors influencing the survival (P<0.05), while age, LM at the time of initial diagnosis, LM developed during the EGFR-TKIs treatment, whole-brain radiotherapy (WBRT), intrathecal chemotherapy, or systemic cytotoxic chemotherapy were not associated with mOS (P>0.05 for all). The multivariate analysis showed that female gender (P=0.012) and EGFR-TKIs treatment (P=0.008) were significant predictors of a good prognosis. Conclusions: EGFR-TKIs treatment may confer benefit for NSCLC-LM patients. Female patients and EGFR-TKIs treatment are favorable prognostic factors for survival. PMID- 27998470 TI - [Surgical treatment and prognosis of pancreatic neuroendocrine carcinoma]. AB - Objective: Pancreatic neuroendocrine carcinoma (pNEC) is a highly malignant tumor.This study aimed to evaluate the role of surgery and the prognosis for patients with pancreatic neuroendocrine carcinoma (pNEC). Methods: We collected and reviewed all clinical data of patients who underwent radical surgery for pNEC from Jan 2000 through Jan 2016 in our hospital. Cox-regression analysis wasused to evaluate the factors potentially influencing survival. Results: Twenty patients including 11 males and 9 females (median age, 62.5 years) were included in this study. All patients underwent radical surgery and 17 cases received postoperative platinum-based chemotherapy.The median follow-up time was 41 months (range, 1 to 127 months). The 1-, 3-, and 5-year survival rates of the patients were 66.7%, 51.5% and 28.1%, with a median survival time of 75.3 months.The multivariate analysis indicated that tumor size and Ki-67 index were of prognostic significance. Conclusions: Pancreatic neuroendocrine carcinomas are rare but increasing in incidence. Patients with localized nonmetastatic primary tumors seem to benefit from surgery. Early diagnosis and multimodality therapy are key points of an improved survival. PMID- 27998471 TI - [Economic burden of cancer in China during 1996-2014: a systematic review]. AB - Objective: To explore the current status of research on economic burden of cancer in China from 1996 to 2014. Methods: The key words including cancer, economic burden, expenditure, cost were used to retrieve the literatures published in CNKI and Wanfang (the two most commonly used databases for literature in Chinese) and PubMed during 1996-2014. A total of 91 studies were included after several exclusionary procedures. Information on subjects and data source, methodology, main results were structurally abstracted. All the expenditure data were discounted to year of 2013 value using China's health care consumer price indices. Results: More than half of the included studies were published over the past 5 years, 32 of the studies were about lung cancer. Among the 83 individual based surveys, 77 were hospital-based and obtained data via individually medical record abstraction, and most of which only considered the direct medical expenditure. Expenditure per cancer patient and expenditure per diem were the most commonly used outcome indicators. Majority of the findings on expenditure per cancer patient ranged from 10 thousands to 30 thousands Chinese Yuan (CNY), with larger disparity in lung and breast cancer (ranged from 10 thousands to 90 thousands CNY), narrower difference in esophageal and stomach cancer (ranged from 10 thousands to 50 thousands CNY), and most stable trend in cervical cancer (almost all the values less than 20 thousands CNY). Without exception, the expenditures per diem for all the common cancers were increasing over the period from 1996 to 2014 (3-7 fold increase). Only 8 population-level economic burden studies were included and the reported expenditure of cancer at national level ranged from 32.6 billions to 100.7 billions CNY. Conclusions: Evidence on economic burden of cancer in China from 1996 to 2014 are limited and weakly comparable, particularly at a population level, and the reported expenditure per patient may be underestimated. PMID- 27998473 TI - [Gingival metastasis of lung cancer: report of two cases]. PMID- 27998472 TI - [Chinese expert consensus on the diagnosis and treatment of breast carcinoma in situ]. AB - In situ carcinomas of the breast constitute 15% to 30% of all newly diagnosed breast cancer cases. Although the concept of carcinoma in situ has been proposed for a long time, there is still a great controversy regarding the screening, diagnosis and treatment. This article attempts to reach some consensus on the management of ductal carcinoma in situ and lobular carcinoma in situ and provide references for clinicians in the following aspects: definition and classification, natural history and prognosis, diagnosis, local and systemic treatment for primary carcinoma in situ, recurrence risk and treatment approaches for recurrent cancers. PMID- 27998474 TI - [Monophasic synovial sarcoma of the liver: a case report]. PMID- 27998475 TI - [46, XY pure gonadal dysgenesis accompanied with malignant mixed germ cell tumor: a case report]. PMID- 27998476 TI - Idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and/or histological pattern of usual interstitial pneumonia. Its aetiology is unknown, but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition. Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other aetiologies. Its clinical evolution is variable, although the mean survival rate is 2-5 years as of its clinical presentation. Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease's clinical course and prognosis. In the mild-moderate disease, the treatment consists of the administration of anti-fibrotic drugs. In severe disease, the best therapeutic option is pulmonary transplantation. In this paper we review the diagnostic and therapeutic aspects of the disease. PMID- 27998478 TI - Characterization and optimization of low cost microfluidic thread based electroanalytical device for micro flow injection analysis. AB - The micro flow injection analysis (MUFIA) is a powerful technique that uses the principles of traditional flow analysis in a microfluidic device and brings a number of improvements related to the consumption of reagents and samples, speed of analysis and portability. However, the complexity and cost of manufacturing processes, difficulty in integrating micropumps and the limited performance of systems employing passive pumps are challenges that must be overcome. Here, we present the characterization and optimization of a low cost device based on cotton threads as microfluidic channel to perform MUFIA based on passive pumps with good analytical performance in a simple, easy and inexpensive way. The transport of solutions is made through cotton threads by capillary force facilitated by gravity. After studying and optimizing several features related to the device, were obtained a flow rate of 2.2 +/- 0.1 MUL s-1, an analytical frequency of 208 injections per hour, a sample injection volume of 2.0 MUL and a waste volume of approximately 40 MUL per analysis. For chronoamperometric determination of naproxen, a detection limit of 0.29 MUmol L-1 was reached, with a relative standard deviation (RSD) of 1.69% between injections and a RSD of 3.79% with five different devices. Thus, based on the performance presented by proposed microfluidic device, it is possible to overcome some limitations of the MUFIA systems based on passive pumps and allow expansion in the use of this technique. PMID- 27998477 TI - Advanced portrayal of SMIL coating by allying CZE performance with in-capillary topographic and charge-related surface characterization. AB - A successive multiple ionic polymer layer (SMIL) coating composed of four layers improved the capillary electrophoretic separation of a recombinant major birch pollen allergen and closely related variants when poly(acrylamide-co-2-acrylamido 2-methyl-1-propansulfonate) (55% PAMAMPS) replaced dextran sulfate as terminal SMIL layer. 55% PAMAMPS decelerated the electroosmotic flow (EOF) due to its lower charge density. Atomic force microscopy (AFM) was used to investigate SMIL properties directly on the inner capillary surface and to relate them to EOF measurements and results of associated CZE separations of a mixture of model proteins and peptides that were performed in the same capillary. For the first time, AFM-based biosensing topography and recognition imaging mode (TREC) under liquid conditions was applied for a sequential characterization of the inner surface of a SMIL coated capillary after selected treatments including pristine SMIL, SMIL after contact with the model mixture, after alkaline rinsing, and the replenishment of the terminal polyelectrolyte layer. A cantilever with tip tethered avidin was used to determine the charge homogeneity of the SMIL surface in the TREC mode. SMIL coated rectangular capillaries with 100 MUm internal diameter assured accessibility of the inner surface for this cantilever type. Observed changes in CZE performance and EOF mobility during capillary treatment were also reflected by alterations in surface roughness and charge distribution of the SMIL coating. A renewal of the terminal SMIL layer restored the original surface properties of SMIL and the separation performance. The alliance of the novel TREC approach and CZE results allows for an improved understanding and a comprehensive insight in effects occurring on capillary coatings. PMID- 27998479 TI - High adhesion strength and hybrid irreversible/reversible full-PDMS microfluidic chips. AB - To the best of our knowledge, this paper outlines for the first time high adhesion and hybrid irreversible/reversible microfluidic devices fully composed of polydimethylsiloxane (PDMS). These chips were fabricated by the sandwich bonding (SWB), a method that was recently deployed by our group. SWB offers simple, fast, and low cost operation requiring only a laboratory oven. The devices showed burst pressures of up to 4.5 MPa. This value is more than tenfold the pressures withstood by the full-PDMS chips described in literature. In terms of the reversible behavior, the ability for disassembling the chip slides is crucial in research and development stages, especially when the device integrates high-cost components or harsh cleaning steps are needed. Following successive steps of detachment and bonding, the channels still withstood high pressures of approximately 1.8 MPa. Finally, the emulsification of corn oil 4.0% w/w to polyglycerol polyricinoleate with 10.0 MUmol L-1 rhodamine B aqueous solution was realized to show the relevance in enhancing the flow rate in microfluidics. Such experiment was conducted at total flow rates of 0.8-160.0 MUL min-1. The decrease in size and polydispersity of the droplets was observed at increasing flow rates. Monodisperse emulsions were achieved only at 160.0 MUL min-1. PMID- 27998480 TI - The peroxidase and oxidase-like activity of NiCo2O4 mesoporous spheres: Mechanistic understanding and colorimetric biosensing. AB - The synthesized NiCo2O4 mesoporous spheres (MS) displayed intrinsic peroxidase and oxidase-like activity were firstly reported. The catalytic mechanism of the oxidase-like activity of NiCo2O4 MS was analyzed in detail using the electron spin resonance (ESR) method. It is found that NiCo2O4 MS could directly oxidize 3,3',5,5'-tetramethylbenzidine (TMB) but did not produce 1O2 and .OH. And the mechanism of the peroxidase-like activity of NiCo2O4 MS was also verified that the oxidation of TMB stemmed from not only .OH but also 1O2. Based on the NiCo2O4 MS showed excellent peroxidase-like activity over a broad temperature range, especially at normal body temperature, a detection tool was designed for glucose determination in diabetics' serum samples. And this detection method based on NiCo2O4 MS gave a lower limit of detection than the method using Co3O4 NPs and NiO NPs, as the single-component oxides of NiCo2O4. Our study may open up the possibility to make a great influence on the next generation of enzyme mimetics system. PMID- 27998481 TI - Preparation and characterization of polymer inclusion membrane based optode for determination of Al3+ ion. AB - The use of a polymer inclusion membrane (PIM) as a sensing material is a new approach to overcome the selectivity and stability drawbacks of the optical chemical sensor (optode). In this study, non-plasticized PIM containing poly(vinyl chloride) as a support base, sodium morin-5-sulfonate (NaMSA) as a reagent and Aliquat 336 as a fixed carrier (ionophore) was prepared and its performance was tested for application in an optode to determine Al3+ ions. The results showed that PIM properties are greatly influenced by the membrane composition. The studies revealed that the optode response was dependent on film thickness, the presence of plasticizer, stirring effect, concentration of NaMSA, concentration of Aliquat 336 and pH of the aqueous solution used. The dynamic range of Al3+ ions concentration determined using this optode was linear from 5.19 * 10-7 to 6.00 * 10-5 mol L-1 and the calculated limit of detection (L.O.D.) was found to be 4.07 * 10-7 mol L-1. The maximum emission wavelength (lambdaem) for the PIM based optode was 512 nm. Scanning electron microscopy analysis of the PIM revealed that a dense texture was formed. Fourier transform infra-red and thermal gravimetry analysis characterizations proved that all of the constituents of the PIM remain within the membrane. The PIM developed in this work was found to be stable, has good mechanical strength, and is sensitive and reusable. Lastly, the PIM was successfully applied as an optical sensor for determination of Al3+ ions in an aqueous solution. PMID- 27998482 TI - Hyaluronidase reaction kinetics evaluated by capillary electrophoresis with UV and high-resolution mass spectrometry (HRMS) detection. AB - The biology of hyaluronidase activity on age related turnover of the hyaluronic acid (HA) in skin dermis and epidermis has not been established. Elucidation of this phenomenon enables discovery of novel compounds for skin health. As a simple and green technique, capillary electrophoresis (CE) was used for the first time for the determination of the kinetic constants (Km, Vmax and IC50) of the enzymatic degradation of HA. Reaction products were identified using CE/high resolution mass spectrometry (HRMS) after appropriate optimization. Best results in terms of signal sensitivity were obtained using 10 mM ammonium acetate (pH 9.0) BGE, a sheath liquid composed of methanol-water (80:20, v/v) with 0.02% (v/v) formic acid at 10 MUL min-1 and an ESI voltage at -4 kV. Km and Vmax were determined (n = 3) using CE/UV at 200 nm as 0.24 +/- 0.02 mg mL-1 and 150.4 +/- 0.1 nM s-1, respectively. They were also successfully obtained by CE/HRMS (n = 3) with Km of 0.49 +/- 0.02 mg mL-1 and Vmax of 155.7 +/- 0.2 nM s-1. IC50 of a standard natural inhibitor, epigallocatechin gallate, was also determined by CE UV/HRMS. Kinetic constant values obtained by CE compared well with literature which validated the developed CE-based assay. In addition, the activity of homemade tetrasaccharides of biotinylated chondroitin sulfate CS-A or CS-C (4- or 6- sulfated in a homogeneous or heterogeneous way) on the hydrolysis reaction of hyaluronidase was evaluated. Hyaluronidase was mostly dose-dependently inhibited by CS-A tetrasaccharides sulfated in a homogeneous way. Two trisaccharides from truncated linkage region of proteoglycans were also tested as inhibitors or activators. CE-based assay showed that even a small modification of one hydroxyl group changes the influence on hyaluronidase activity. CE-based assay can be used for the screening of natural and synthetic inhibitors of hyaluronidase activity for cosmetic and therapeutic applications. PMID- 27998483 TI - Dielectric barrier discharges applied for soft ionization and their mechanism. AB - Dielectric barrier discharges are used for analytical applications as dissociative source for optical emission spectrometry and for ambient-ionization techniques. In the range of ambient-ionization techniques it has attracted much attention in fields like food safety, biological analysis, mass spectrometry for reaction monitoring and imaging forensic identification. In this review some examples are given for the application as desorption/ionization source as well as for the sole application as ionization source with different sample introductions. It will be shown that the detection might depend on the certain distance of the plasma in reference to the sample or the kind of discharge which might be produced by different shapes of the applied high voltage. Some attempts of characterization are presented. A more detailed characterization of the dielectric barrier discharge realized with two ring electrodes, each separately covered with a dielectric layer, is described. PMID- 27998484 TI - Nonlinear calibration transfer based on hierarchical Bayesian models and Lagrange Multipliers: Error bounds of estimates via Monte Carlo - Markov Chain sampling. AB - The calibration of analytical systems is time-consuming and the effort for daily calibration routines should therefore be minimized, while maintaining the analytical accuracy and precision. The 'calibration transfer' approach proposes to combine calibration data already recorded with actual calibrations measurements. However, this strategy was developed for the multivariate, linear analysis of spectroscopic data, and thus, cannot be applied to sensors with a single response channel and/or a non-linear relationship between signal and desired analytical concentration. To fill this gap for a non-linear calibration equation, we assume that the coefficients for the equation, collected over several calibration runs, are normally distributed. Considering that coefficients of an actual calibration are a sample of this distribution, only a few standards are needed for a complete calibration data set. The resulting calibration transfer approach is demonstrated for a fluorescence oxygen sensor and implemented as a hierarchical Bayesian model, combined with a Lagrange Multipliers technique and Monte-Carlo Markov-Chain sampling. The latter provides realistic estimates for coefficients and prediction together with accurate error bounds by simulating known measurement errors and system fluctuations. Performance criteria for validation and optimal selection of a reduced set of calibration samples were developed and lead to a setup which maintains the analytical performance of a full calibration. Strategies for a rapid determination of problems occurring in a daily calibration routine, are proposed, thereby opening the possibility of correcting the problem just in time. PMID- 27998485 TI - Diagonal designs for a multi-component calibration experiment. AB - Modern spectroscopic and sensor technologies combined with multivariate modelling are increasingly used for the quantitative analysis of complex mixtures. Their performance depends directly on the data design chosen for model training and validation. A well-balanced calibration experiment with the fewest samples possible presents additional challenges when several mixture components (factors) need to be calibrated on the same dataset and subsequently quantified from the same multivariate measurement. This practically important problem stays poorly addressed by the theory of experimental design. This theoretical work systematically formulates the requirements to an optimal calibration/validation dataset and introduces a new family of calibration designs, where the samples are placed along the diagonals of an experimental space that is a hypercube. Such placement is appropriate due to reasonable assumptions about the linear nature of analytical response. Suggested filling schemes allow economical diagonal designs with intrinsic validation to be built for multiple factors presented in as many levels as the number of samples. The most important practical cases of two and three factors are considered in detail, and generalization to higher dimensions is outlined. Diagonal designs of any complexity can be generated using a simple geometrical scheme or with a supplied script. PMID- 27998486 TI - Graphene oxide directed in-situ deposition of electroactive silver nanoparticles and its electrochemical sensing application for DNA analysis. AB - The development of high-performance biosensing platform is heavily dependent on the recognition property of the sensing layer and the output intensity of the signal probe. Herein, we present a simple and highly sensitive biosensing interface for DNA detection on the basis of graphene oxide nanosheets (GONs) directed in-situ deposition of silver nanoparticles (AgNPs). The fabrication process and electrochemical properties of the biosensing interface were probed by electrochemical techniques and scanning electron microscopy. The results indicate that GONs can specifically adsorb at the single-stranded DNA probe surface, and induces the deposition of highly electroactive AgNPs. Upon hybridization with complementary oligonucleotides to generate the duplex DNA on the electrode surface, the GONs with the deposited AgNPs will be liberated from the sensing interface due to the inferior affinity of GONs and duplex DNA, resulting in the reduction of the electrochemical signal. Such a strategy combines the superior recognition of GONs toward single-stranded DNA and double-stranded DNA, and the strong electrochemical response of in-situ deposited AgNPs. Under optimal conditions, the biosensor can detect target DNA over a wide range from 10 fM to 10 nM with a detection limit of 7.6 fM. Also, the developed biosensor shows outstanding discriminating ability toward oligonucleotides with different mismatching degrees. PMID- 27998487 TI - Molecularly imprinted phloroglucinol-formaldehyde-melamine resin prepared in a deep eutectic solvent for selective recognition of clorprenaline and bambuterol in urine. AB - A new molecularly imprinted phloroglucinol-formaldehyde-melamine resin (MIPFMR) was synthesized in a deep eutectic solvent (DES) using phenylephrine as a dummy template. The MIPFMR was used as a solid phase extraction (SPE) sorbent for the selective isolation and recognition of clorprenaline (CLP) and bambuterol (BAM) in urine. Phloroglucinol and melamine were used as double functional monomers that introduced abundant hydrophilic groups (such as hydroxyl groups, imino groups, and ether linkages) into the MIPFMR, making it compatible with aqueous solvents. In addition, the formation of DES by combining the quaternary ammonium salt of choline chloride with ethylene glycol as a hydrogen bond donor was an environmentally safe alternative to toxic organic solvents such as chloroform and dimethylsulfoxide that are typically used in the preparation of most molecularly imprinted polymers (MIPs). Moreover, MIPFMR-based SPE of CLP and BAM in urine resulted in higher recoveries and purer extracts than those obtained by using other SPE materials (e.g., SCX, C18, HLB, and non-imprinted phloroglucinol formaldehyde-melamine resin (NIPFMR)). The optimized MIPFMR-SPE-HPLC-UV method had good linearity (r2 >= 0.9996) ranging from 15.0 to 3000.0 ng mL-1 for CLP and BAM, and the recoveries at three spiked levels ranged from 91.7% to 100.1% with RSDs <=7.6%. The novel MIPFMR-SPE-HPLC-UV method is simple, selective, and accurate, and can be used for the determination of CLP and BAM in urine samples. PMID- 27998488 TI - Stirring-controlled solidified floating solid-liquid drop microextraction as a new solid phase-enhanced liquid-phase microextraction method by exploiting magnetic carbon nanotube-nickel hybrid. AB - A specific technique is introduced to overcome limitations of classical solidification of floating organic drop microextraction, such as tedious and time consuming centrifuge step and using disperser solvent, by facile and efficient participation of solid and liquid phases. In this proposed method of stirring controlled solidified floating solid-liquid drop microextraction (SC-SF-SLDME), magnetic carbon nanotube-nickel hybrid (MNi-CNT) as a solid part of the extractors are dispersed ultrasonically in sample solution, and the procedure followed by dispersion of liquid phase (1-undecanol) through high-rate stirring and easily recollection of MNi-CNT in organic solvent droplets through hydrophobic force. With the reduction in speed of stirring, one solid-liquid drop is formed on top of the solution. MNi-CNT acts as both extractor and the coalescence helper between organic droplets for a facile recollection. MNi-CNT was prepared by spray pyrolysis of nickel oleate/toluene mixture at 1000 degrees C. Four tyrosine kinase inhibitors were selected as model analytes and the effecting parameters were investigated. The results confirmed that magnetic nanoadsorbent has an important role in the procedure and complete collection of dispersed solvent is not achieved in the absence of the solid phase. Also, short extraction time exhibited success of the proposed method and effect of dispersed solid/liquid phases. The limits of quantification (LOQs) for imatinib, sunitinib, erlotinib, and nilotinib were determined to be as low as 0.7, 1.7, 0.6, and 1.0 MUg L-1, respectively. The intra-day precisions (RSDs) were lower than 4.5%. Method performance was investigated by determination of mentioned tyrosine kinase inhibitors (TKIs) in human serum and cerebrospinal fluid samples with good recoveries in the range of 93-98%. PMID- 27998489 TI - A comprehensive profiling of sulfatides in myelin from mouse brain using liquid chromatography coupled to high-resolution accurate tandem mass spectrometry. AB - Sulfatides are sulfoglycolipids found in the myelin sheath. The composition ratio of sulfatide molecular species changes with age, and it has also been associated with the pathogenesis of various human central nervous system diseases. However, profiling sulfatides in biological samples is difficult, due to the great variety of molecular species. In this work, a new, easy and reliable liquid chromatography-electrospray tandem mass spectrometry (LC-ESI(+)-MS/MS) method has been developed to profile sulfatide content in biological samples of myelin. The 'wrong-way-round' ionization effect has been described for this type of molecules for the first time, making it possible to correctly identify as many as 37 different sulfatides in mouse brain myelin samples, including molecules with different fatty acid chain lengths and varying degrees of unsaturation and hydroxylation. A chemometric analysis of their relative abundances showed that the main difference among individuals of different ages was the content of sulfatides with odd-numbered fatty acid chains, in addition to hydroxylated species. PMID- 27998490 TI - Impact of storage conditions on the urinary metabolomics fingerprint. AB - Urine stability during storage is essential in metabolomics to avoid misleading conclusions or erroneous interpretations. Facing the lack of comprehensive studies on urine metabolome stability, the present work performed a follow-up of potential modifications in urinary chemical profile using LC-HRMS on the basis of two parameters: the storage temperature (+4 degrees C, -20 degrees C, -80 degrees C and freeze-dried stored at -80 degrees C) and the storage duration (5 144 days). Both HILIC and RP chromatographies have been implemented in order to globally monitor the urinary metabolome. Using an original data processing associated to univariate and multivariate data analysis, our study confirms that chemical profiles of urine samples stored at +4 degrees C are very rapidly modified, as observed for instance for compounds such as:N-acetyl Glycine, Adenosine, 4-Amino benzoic acid, N-Amino diglycine, creatine, glucuronic acid, 3 hydroxy-benzoic acid, pyridoxal, l-pyroglutamic acid, shikimic acid, succinic acid, thymidine, trigonelline and valeryl-carnitine, while it also demonstrates that urine samples stored at -20 degrees C exhibit a global stability over a long period with no major modifications compared to -80 degrees C condition. This study is the first to investigate long term stability of urine samples and report potential modifications in the urinary metabolome, using both targeted approach monitoring individually a large number (n > 200) of urinary metabolites and an untargeted strategy enabling assessing for global impact of storage conditions. PMID- 27998491 TI - TB care in Private Sector: Much more needed. PMID- 27998492 TI - Abdominal tuberculosis: A retrospective analysis of 45 cases. AB - Abdominal tuberculosis is defined as infection of the peritoneum, hollow or solid abdominal organs with Mycobacterium tuberculosis. The peritoneum and the ileocaecal region are the most likely sites of infection and are involved in the majority of the cases by haematogenous spread or through swallowing of infected sputum from primary pulmonary tuberculosis. Pulmonary tuberculosis is apparent in less than half of the patients. Patients usually present with abdominal pain, and the cause is usually identified through a combination of radiologic, endoscopic, microbiologic, histologic and molecular techniques. Anti-microbial treatment is the same as for pulmonary tuberculosis. Surgery is occasionally required. PMID- 27998493 TI - Periodontal status of tuberculosis patients - Is there a two-way link? AB - BACKGROUND: The influence of systemic disorders on periodontal tissues is well established. Amongst various chronic debilitating diseases, tuberculosis (TB) is one of the major health problems in most developing countries. Although it has a definite affinity for the lungs, it can affect any part of the body including the oral cavity. TB and periodontitis are the two distinct disease processes. But environmental and biological factors play a key role in etiopathogenesis of both the diseases. These factors alter tissue microenvironment leading to cascade of untoward events. AIM: To assess and compare the periodontal status of TB patients with that of non-TB subjects. MATERIALS AND METHODS: 50 subjects were recruited and divided into 2 groups. Group A consisted of subjects suffering from TB serving as Test group while group B included non-TB subjects serving as Control group. STATISTICAL ANALYSIS: Unpaired t-test was used. RESULTS AND CONCLUSION: Statistically significant difference in probing pocket depth and bleeding on probing was found between groups A and B, with the difference being higher in group A subjects, thus concluding that periodontal status might be linked with TB. PMID- 27998494 TI - Pattern of socio-economic and health aspects among TB patients and controls. AB - BACKGROUND: Socio-economic and health-related factors have a significant impact on tuberculosis (TB) incidence among population residing in resource-scare settings. OBJECTIVE: To evaluate the pattern of socio-economic and health-related factors among TB patients and control in Delhi, India. METHODS: The present cross sectional study was performed among 893 TB patients (or cases) and 333 healthy disease-free controls. The data for the present study was obtained from several district TB centres in north, west and south Delhi. The collected data was edited, coded and statistical analysed with the help of SPSS 20.0 version. RESULTS: Illiteracy and primary education were significant risk factors being associated with a TB. Rented housing condition had an odds ratio (OR) of 1.4 (95% confidence interval [CI]: 1.09-1.89) compared to owned housing condition. 3-5 individuals per room were 3 times more likely to be associated with a case of TB (95% CI: 2.49-4.41). Migrant individuals were 13 times more likely to be associated with a case of TB (95% CI: 8.77-19.78) in comparison to settled population. Daily consumption of non-vegetarian food also significantly contributed to case of TB with an OR of 3.4 (95% CI: 2.51-4.72). Loss of appetite and family TB served as significant health-related factors associated with TB risk. CONCLUSION: Lower educational status, rented household, individuals per room (as a measure of overcrowding) and migratory status served as prominent risk factors for TB disease. Preference and frequency of non-vegetarian food being consumed, night sweating, weight loss, loss of appetite, earlier TB and family TB were principle health-related risk factors associated with TB disease. PMID- 27998495 TI - Prevalence & pattern of respiratory diseases including Tuberculosis in elderly in Ghaziabad - Delhi - NCR. AB - Elderly population is continuously increasing all over the world including India. Old age is associated with significant prevalence of chronic illnesses. Population based study to find prevalence & pattern of respiratory diseases in elderly in India is difficult to find. Present study was done in an urban locality of Ghaziabad inhabited mainly by low socio - economic status population. Two part questionnaire was used as main tool. Through part one 1522 elderly were screened for respiratory disease. Respiratory disease was confirmed & diagnosed by part two of questionnaire, physical examination & necessary investigations. Prevalence of respiratory diseases was 18.8% in this study. Prevalence of respiratory diseases was almost double in elderly males as compared to females. COPD was most prevalent respiratory disease followed by Bronchial asthma. PMID- 27998496 TI - Association of ABO blood group polymorphism and tuberculosis: A study on Bengalee Hindu caste population, West Bengal, India. AB - Tuberculosis (TB) is an infectious disease commonly caused by the bacillus mycobacterium and worldwide estimation demonstrated that more than 8.6 million people are infected by TB. Many of the previous studies reported the association between TB and ABO blood group polymorphism. In this context, the objective of the present study is to understand the association of ABO blood group polymorphism and TB in Bengalee Hindu caste population. The present study consists of 100 clinically diagnosed TB patients and 100 apparently healthy individuals with no previous history of TB from the same population of the same area. The distribution of ABO phenotypes demonstrated significant (p<0.05) excess of AB blood group in TB patients and significant (p<0.05) decrease of O blood group in controls. Logistic regression analysis revealed that individuals with non O blood group have 1.97 times (95% CI 1.04-3.75) greater chance of developing TB than individuals with O blood group. PMID- 27998497 TI - A retrospective cohort study of 756 cases of abdominal tuberculosis: Two decades single centre experience. AB - AIM/OBJECTIVE: India accounts for the highest tuberculosis burden in the world, and abdominal tuberculosis has been an endemic surgical and gastroenterological problem. Aim of this study is to present our two decades experience on abdominal (gastrointestinal) tuberculosis. METHOD: 756 patients, who received standard antituberculous treatment with or without surgical treatment with the diagnosis of abdominal tuberculosis from January 1996 and May 2014, were reviewed retrospectively. On the basis of clinical presentation, four groups of clinical presentation were identified and various diagnostic measures used in different groups were studied. Numeric values were determined as percent or mean+/-standard deviation. Kruskal-Wallis test was used for quantitative results and chi-square test was used for qualitative results between groups. p value of less than 0.05 was considered to indicate the statistical significance. RESULTS: The duration of symptoms was variable in this study. Out of 756 patients, 64 patients gave definite past history of tuberculosis. Most of the patients in the acute pain abdomen group required surgery while most patients in chronic pain group responded well to medical management. There was significant difference in mortality among the four groups (p=0.025). CONCLUSION: Prognosis seems significantly related to the severity of disease, with graver prognosis and less symptomatic improvement in more seriously ill presentations. PMID- 27998498 TI - TB management by private practitioners - Is it bad everywhere? AB - INTRODUCTION: Poor prescribing practice is alleged to be one of the major factors fuelling the drug-resistant tuberculosis (DR TB) emergence. A study in Mumbai revealed the extent of inappropriate tuberculosis (TB) management practices of private practitioners and discussed that with the context of high DR TB. Kerala is rated among the well performing States in India as far as TB control is concerned with evidences for a lower level of TB transmission and DR TB. The current study was done in Kerala State to assess the prescribing practices of private sector doctors in the treatment of TB. METHODS: Survey questionnaire to write a standard prescription for treating TB was administered to private practitioners dealing with TB, who attended continuing medical education programme on TB at two major cities in Kerala. RESULTS: Responses from a total of 124 questionnaires were studied. None of them prescribed anti-TB regimen for less than 6 months. Only 7 (5.6%) prescribed a regimen without complete four drugs (H, R, Z, E) in the intensive phase. Out of the 81 doctors who prescribed private anti-TB regimen, 67 (82.7%) had of the opinion that not less than 80% of their patients complete the treatment for the prescribed duration. CONCLUSION: The current study reports a reasonable TB management practice among the private sector doctors from a State with a low prevalence of DR TB and compliments the argument that effective treatment of TB following the principles of standards for TB care can prevent the emergence of DR TB. PMID- 27998499 TI - Study of factors influencing response and outcome of Cat-IV regimen in MDRTB patients. AB - BACKGROUND: CAT IV regimen or the standardized drug regimen (SDR) under the Revised National Control Program (RNTCP) uses six second-line anti-tubercular drugs in the initial intensive phase (IP). These drugs have many side effects and toxicity; they are less efficacious and have poor acceptability. The present study was conducted to evaluate the efficacy and outcome of Cat-IV regimen and the factors which influence the treatment outcome in MDR TB patients. METHODS: It was a prospective observational study, which was done in the CAT II treatment failure, LPA proven MDR TB patients, above the age of 18 years, who were referred to DOTS Plus center for treatment. The study was approved by the hospital ethics committee and patient consent was obtained before inclusion. RESULTS: We observed culture conversion in 63.04% and ADR in 96.5%, default in 15.65%, and death in11.3% cases. The factors which influenced outcome included low body weight, long duration of illness cavitatory disease and indulgence in both tobacco & alcohol. The radiological favorable response strongly and significantly correlated with the bacteriological and clinical response during the IP. CONCLUSION: We suggest that the efficacy can be further augmented by reducing default and controlling deaths which accounts for substantial numbers and occur mostly during IP. PMID- 27998500 TI - Tubercular sialadenitis of parotid gland - An extremely rare case series. AB - Tuberculosis is a potentially fatal infectious disease caused by Mycobacterium Tuberculosis. It most commonly involves the lungs (Pulmonary Tuberculosis), although it can involve any organ system in the body. However even in a country like India which has high burden of this disease, the tubercular invasion of parotid gland is extremely rare. Here we describe two such cases. Both patients were immune competent and presented with fever and swelling in the parotid region. They were diagnosed as tuberculosis of parotid gland by ultrasound guided fine needle aspiration and confirmed bacteriologically. PMID- 27998501 TI - Chest wall tuberculous ulcer: A rare complication of pulmonary tuberculosis. AB - Tuberculous ulcer of the anterior chest wall as a result of direct extension from underlying pleural and pulmonary tuberculosis is a very rare entity. Its clinical presentation may resemble a tumor or abscess. Isolated chest wall tuberculous ulcer without bone involvement is even rarer. An illustrated case report is presented. PMID- 27998502 TI - Sinonasal tuberculosis: Report of three atypical cases. AB - Primary sinonasal/nasal tuberculosis is rare amongst the commonly seen cases of extrapulmonary tuberculosis. We report three cases, two of primary sinonasal tuberculosis and one case of nasal tuberculosis in otherwise healthy patients. The diagnosis was based on radiological and histopathological findings. Treatment with antitubercular drug therapy was successful in all three of them. Sinonasal region tuberculosis, despite its rarity, should be added to differential diagnosis of nasal and paranasal sinus disorders particularly with intractable symptoms. Radiological imaging and nasal endoscopy with biopsy should be supplemented for confirmation. PMID- 27998503 TI - Mycobacterium abscessus complex bacteremia due to prostatitis after prostate biopsy. AB - We present the case of a 49-year-old man, who developed Mycobacterium abscessus complex (M. abscessus complex) bacteremia and prostatitis after prostate biopsy. The patient was successfully treated with amikacin with imipenem-cilastatin with clarithromycin. Infections caused by M. abscessus complex have been increasingly described as a complication associated with many invasive procedures. Invasive procedures might have contributed to the occurrence of the M. abscessus complex. Although M. abscessus complex infection is difficult to diagnose and treat, we should pay more attention to this kind of infection, and the correct treatment strategy will be achieved by physicians. PMID- 27998504 TI - Spontaneous resolution of chronic maxillary atelectasis in a paediatric patient: An exceptional case. PMID- 27998505 TI - Testosterone Replacement Should be Given to Men with Erectile Dysfunction: Pro. PMID- 27998506 TI - Testosterone Replacement Should be Given to Men with Erectile Dysfunction: Con. PMID- 27998507 TI - Fatigue and psychosocial variables in autoimmune rheumatic disease and chronic fatigue syndrome: A cross-sectional comparison. AB - OBJECTIVE: Fatigue is common in autoimmune rheumatic diseases (ARD). This study compared symptom-related cognitions, beliefs, behaviours, quality of sleep, lack of acceptance and distress in participants with ARD such as rheumatoid arthritis (RA), seronegative spondyloarthropathy (SpA), and connective tissue disease (CTD), and participants with chronic fatigue syndrome (CFS). METHODS: 303 participants with RA, SpA, CTD and CFS completed questionnaire measures of fatigue, social adjustment, cognitive-behavioural responses, lack of acceptance, distress and quality of sleep. The RA, SpA and CTD groups were first compared with each other. They were then combined into one group and compared with the CFS group. RESULTS: There were no statistically significant differences between the RA, SpA or CTD groups for any of the measures. The CFS group was more fatigued, reported more distress and sleep disturbance and had worse social adjustment than the ARD group after adjustment for age and illness duration. After adjustment for fatigue, age, and illness duration, the CFS group scored more highly on lack of acceptance and avoidance/resting behaviour while the ARD group showed significantly higher levels of catastrophizing, damage beliefs, and symptom focusing than the CFS group. CONCLUSION: Fatigue in rheumatic diseases may be perpetuated by similar underlying transdiagnostic processes. The ARD and CFS groups showed similarities but also key differences in their responses to symptoms. Specific aspects of treatment may need to be tailored towards each group. For example, lack of acceptance and avoidance behaviour may be particularly important in perpetuating fatigue in CFS. PMID- 27998508 TI - Effectiveness of traditional meditation retreats: A systematic review and meta analysis. AB - BACKGROUND: An increasing number of studies are investigating traditional meditation retreats. Very little, however, is known about their effectiveness. OBJECTIVE: To evaluate the effectiveness of meditation retreats on improving psychological outcomes in general population. DATA SOURCES: A systematic review of studies published in journals or as dissertations in PSYCINFO, PUBMED, CINAHL or Web of Science from the first available date until October 22, 2016. REVIEW METHODS: A total of 20 papers (21 studies, N=2912) were included. RESULTS: Effect size estimates of outcomes combined suggested that traditional meditation retreats are moderately effective in pre-post analyses (n=19; Hedge's g=0.45; 95% CI [0.35, 0.54], p<0.00001) and in analyses comparing retreats to controls (n=14; Hedge's g=0.49; 95% CI [0.36, 0.61], p<0.00001). Results were maintained at follow-up. No differences were observed between meditation styles. Results suggested large effects on measures of anxiety, depression and stress, and moderate effects on measures of emotional regulation and quality of life. As to potential mechanisms of actions, results showed large effects on measures of mindfulness and compassion, and moderate effects on measures of acceptance. In addition, changes in mindfulness levels strongly moderated clinical effect sizes. However, heterogeneity was significant among trials, probably due to differences in study designs, types and duration of the retreats and assessed outcomes, limiting therefore the implications of the results. CONCLUSION: Meditation retreats are moderately to largely effective in reducing depression, anxiety, stress and in ameliorating the quality of life of participants. PMID- 27998509 TI - Visual selective attention in body dysmorphic disorder, bulimia nervosa and healthy controls. AB - OBJECTIVE: Cognitive behavioral models postulate that selective attention plays an important role in the maintenance of body dysmorphic disorder (BDD). It is suggested that individuals with BDD overfocus on perceived defects in their appearance, which may contribute to the excessive preoccupation with their appearance. METHODS: The present study used eye tracking to examine visual selective attention in individuals with BDD (n=19), as compared to individuals with bulimia nervosa (BN) (n=21) and healthy controls (HCs) (n=21). Participants completed interviews, questionnaires, rating scales and an eye tracking task: Eye movements were recorded while participants viewed photographs of their own face and attractive as well as unattractive other faces. RESULTS: Eye tracking data showed that BDD and BN participants focused less on their self-rated most attractive facial part than HCs. Scanning patterns in own and other faces showed that BDD and BN participants paid as much attention to attractive as to unattractive features in their own face, whereas they focused more on attractive features in attractive other faces. HCs paid more attention to attractive features in their own face and did the same in attractive other faces. CONCLUSION: Results indicate an attentional bias in BDD and BN participants manifesting itself in a neglect of positive features compared to HCs. Perceptual retraining may be an important aspect to focus on in therapy in order to overcome the neglect of positive facial aspects. Future research should aim to disentangle attentional processes in BDD by examining the time course of attentional processing. PMID- 27998510 TI - Stress, burnout and depression: A systematic review on DNA methylation mechanisms. AB - Despite that burnout presents a serious burden for modern society, there are no diagnostic criteria. Additional difficulty is the differential diagnosis with depression. Consequently, there is a need to dispose of a burnout biomarker. Epigenetic studies suggest that DNA methylation is a possible mediator linking individual response to stress and psychopathology and could be considered as a potential biomarker of stress-related mental disorders. Thus, the aim of this review is to provide an overview of DNA methylation mechanisms in stress, burnout and depression. In addition to state-of-the-art overview, the goal of this review is to provide a scientific base for burnout biomarker research. We performed a systematic literature search and identified 25 pertinent articles. Among these, 15 focused on depression, 7 on chronic stress and only 3 on work stress/burnout. Three epigenome-wide studies were identified and the majority of studies used the candidate-gene approach, assessing 12 different genes. The glucocorticoid receptor gene (NR3C1) displayed different methylation patterns in chronic stress and depression. The serotonin transporter gene (SLC6A4) methylation was similarly affected in stress, depression and burnout. Work-related stress and depressive symptoms were associated with different methylation patterns of the brain derived neurotrophic factor gene (BDNF) in the same human sample. The tyrosine hydroxylase (TH) methylation was correlated with work stress in a single study. Additional, thoroughly designed longitudinal studies are necessary for revealing the cause-effect relationship of work stress, epigenetics and burnout, including its overlap with depression. PMID- 27998511 TI - A comparison of the Work and Social Adjustment Scale (WSAS) across different patient populations using Rasch analysis and exploratory factor analysis. AB - INTRODUCTION: The Work and Social Adjustment Scale (WSAS) is designed to measure patients' perceived functional impairment associated with a health problem. There is a paucity of studies that explore the stability of the item hierarchy in the WSAS across different disease populations. This study investigated the unidimensional structure of the WSAS across different disease populations. METHODS: Secondary data analysis was conducted on pooled patient data (HIV, breast cancer, and inflammatory conditions) to create a new dataset (n=554). The data were analysed using Rasch analysis and exploratory factor analysis. RESULTS: Exploratory factor analysis and principle component analysis of the WSAS showed a good fit as a unidimensional scale, person and item separation indices were >2 suggesting that the WSAS is sensitive enough to distinguish between participants of varying levels of ability. Some differential item functioning was seen by diagnosis and by sex for items 1 and 5 of the WSAS. CONCLUSIONS: Overall, a one dimensional structure was identified for the WSAS. However, a small number of differential item functioning (DIF) was identified, suggesting that scores from the WSAS cannot be compared across groups. PMID- 27998512 TI - Depression and inflammatory arthritis are associated in both Western and Non Western countries: Findings from the World Health Survey 2002. AB - OBJECTIVES: Epidemiological studies have linked arthritis to depression. However, it remains unclear to what degree the association between arthritis and depression extends to low income countries and whether it can be replicated for inflammatory arthritis (IA). We aimed to address these knowledge gaps based on a large multi-national sample. METHODS: Cross-sectional data was drawn from the 2002 World Health Survey. IA was defined as reports of either a diagnosis or treatment of arthritis and morning stiffness for >30min. Self-reported depression was defined as positive if participants reported its prior diagnosis or treatment or if they were classified as suffering from a major depressive episode by a seven-item screening instrument. Multivariable logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the entire sample and stratified by sex and continent. RESULTS: The odds of IA was 2.6-fold increased in those with depression compared to those without (OR=2.64, 95% CI 2.18-3.21) in the entire sample. This association was observed in both men (OR=3.06, 95% CI 2.19-4.27) and women (OR=2.50, 95% CI 1.95-3.21). Similar associations were found on the continent level, but were generally stronger for the Americas and Asia compared to Africa and Europe. CONCLUSIONS: Although our definition of IA was limited by the use of self-reported morning stiffness, this study suggests that there is a positive association between inflammatory arthritis and depression in Western and Non-Western countries, suggesting that this relationship represents a universal phenomenon. PMID- 27998513 TI - Sexual orientation and medical history among Iranian people with Complete Androgen Insensitivity Syndrome and Congenital Adrenal Hyperplasia. AB - OBJECTIVE: To report sexual orientation, relationship status and medical history of Iranian people with Differences of Sex Development (DSD) who were raised female. METHODS: Our participants consisted of nineteen 46,XY individuals with Complete Androgen Insensitivity Syndrome (CAIS) and eighteen 46,XX individuals with Congenital Adrenal Hyperplasia (CAH) who were raised as females and older than 13years. As well as their relationship status and detailed medical history, an expert psychiatrist assessed their sexual orientation by a semi-structured psychiatric interview with them and, where applicable, their parents. RESULTS: Five percent of CAH participants and 42% of CAIS participants were in a relationship, which was significantly different. All CAH individuals had been diagnosed at birth; 89% of CAIS had been diagnosed after puberty and due to primary amenorrhea and 11% were diagnosed in childhood due to inguinal hernia. Genital reconstructive surgery had been performed in 100% of CAH participants and 37% of CAIS. Regarding sexual contact experiences and sexual fantasies (androphilic, gynephilic or both), no significant differences were found. However, CAH females had significantly more gynephilic dreams (P=0.045). CONCLUSION: This study, notable as one of the rare from a non-western culture, described sexual, medical and socioeconomic status of 46,XX CAH and 46,XY CAIS individuals living in Iran. Although broadly in line with previous findings from Western cultures, Iranian CAH individuals had fewer romantic relationships, but in contrast to previous studies their sexual orientation was only different from CAIS in the contents of sexual dreams. PMID- 27998514 TI - Combined exposure to adverse psychosocial work factors and medically certified absence for mental health problems: A 5-year prospective study. PMID- 27998515 TI - 2017: The unifying power of health. PMID- 27998516 TI - Predicting pandemics. PMID- 27998517 TI - Winnable battles: what is next? PMID- 27998518 TI - The Lancet-American University of Beirut Commission on Syria: a new role for global health in conflict and a call for papers. PMID- 27998519 TI - China-a call for papers. PMID- 27998521 TI - Offline: 2016-some lessons to consider. PMID- 27998520 TI - 2016 Wakley Prize: connections and memories. PMID- 27998522 TI - 2016: year in review. PMID- 27998523 TI - Profile: Inserm, Paris, France. PMID- 27998524 TI - Frontline: Working to include London's excluded populations. PMID- 27998525 TI - Medical romance: love never dies. PMID- 27998526 TI - A peek into the Galapagos of the medical research field. PMID- 27998527 TI - Village Drama Against Malaria. PMID- 27998528 TI - E-learning resources in Myanmar. PMID- 27998529 TI - Health-care services in southeast Anatolia, Turkey. PMID- 27998530 TI - Patient-physician trust in China: health education for the public. PMID- 27998531 TI - Expanding the benefits of HPV vaccination to boys and men. PMID- 27998532 TI - Human resources for health. PMID- 27998533 TI - Human resources for health. PMID- 27998534 TI - Human resources for health - Authors' reply. PMID- 27998535 TI - The HubBle trial: a word of caution. PMID- 27998536 TI - The HubBle trial: a word of caution. PMID- 27998537 TI - The HubBle trial: a word of caution - Authors' reply. PMID- 27998538 TI - Stay with me. PMID- 27998539 TI - Distinct Roles for Conformational Dynamics in Protein-Ligand Interactions. AB - Conformational dynamics has an established role in enzyme catalysis, but its contribution to ligand binding and specificity is largely unexplored. Here we used the Tiam1 PDZ domain and an engineered variant (QM PDZ) with broadened specificity to investigate the role of structure and conformational dynamics in molecular recognition. Crystal structures of the QM PDZ domain both free and bound to ligands showed structural features central to binding (enthalpy), while nuclear-magnetic-resonance-based methyl relaxation experiments and isothermal titration calorimetry revealed that conformational entropy contributes to affinity. In addition to motions relevant to thermodynamics, slower microsecond to millisecond switching was prevalent in the QM PDZ ligand-binding site consistent with a role in ligand specificity. Our data indicate that conformational dynamics plays distinct and fundamental roles in tuning the affinity (conformational entropy) and specificity (excited-state conformations) of molecular interactions. More broadly, our results have important implications for the evolution, regulation, and design of protein-ligand interactions. PMID- 27998540 TI - Expanding the PP2A Interactome by Defining a B56-Specific SLiM. AB - Specific interactions between proteins govern essential physiological processes including signaling. Many enzymes, especially the family of serine/threonine phosphatases (PSPs: PP1, PP2A, and PP2B/calcineurin/CN), recruit substrates and regulatory proteins by binding short linear motifs (SLiMs), short sequences found within intrinsically disordered regions that mediate specific protein-protein interactions. While tremendous progress had been made in identifying where and how SLiMs bind PSPs, especially PP1 and CN, essentially nothing is known about how SLiMs bind PP2A, a validated cancer drug target. Here we describe three structures of a PP2A-SLiM interaction (B56:pS-RepoMan, B56:pS-BubR1, and B56:pSpS BubR1), show that this PP2A-specific SLiM is defined as LSPIxE, and then use these data to discover scores of likely PP2A regulators and substrates. Together, these data provide a powerful approach not only for dissecting PP2A interaction networks in cells but also for targeting PP2A diseases, such as cancer. PMID- 27998541 TI - [Incidence of hip and knee prosthetic infections in a specialized center of Mexico City]. AB - BACKGROUND: Hip and knee prosthetic replacements have proven to be the most appropriate treatment in the joints that do not benefit from medical or arthroscopic interventions; however, infections are the most feared complication. It is recommended that the incidence of infection should not exceed 2%. MATERIAL AND METHODS: This was an observational, prospective, longitudinal and observational study conducted in patients fitted with a prosthetic joint from August 2011 to July 2012. Patients were followed up pre and post-surgery for one year to identify a prosthetic infection, diagnosed using international parameters. We calculated the incidence of prosthetic infection, as well as the incidence density. RESULTS: A total of 339 patients (179 hip and 160 knee) were included. Variations in the time of pre-operative antibiotics' administration were observed. Six prosthetic infections were identified with an incidence rate of 1.79/339 arthroplasties, 2.2/179 hip procedures, and 1.25/160 knee arthroplasties. An incidence density of 0.02/year for hip arthroplasties and 0.11/year for knee procedures was identified. There were 4 infections of hip and 2 of knee. Five infections were acute and one chronic. The isolated microorganisms were E. faecalis, S. epidermidis (2), S. mitis, S. aureus and P. stomatis. CONCLUSIONS: The incidence of prosthetic joint infection in the first year of follow-up at our centre is within the recommended parameters. Surgical techniques and organizational practices influence the results. PMID- 27998542 TI - [Metabolic control in the critically ill patient an update: hyperglycemia, glucose variability hypoglycemia and relative hypoglycemia]. AB - BACKGROUND: Metabolic changes of glucose in critically ill patients increase morbidity and mortality. The appropriate level of blood glucose has not been established so far and should be adjusted for different populations. However concepts such as glucose variability and relative hypoglycemia of critically ill patients are concepts that are changing management methods and achieving closer monitoring. OBJECTIVES: The purpose of this review is to present new data about the management and metabolic control of patients in critical areas. CONCLUSIONS: Currently glucose can no longer be regarded as an innocent element in critical patients; both hyperglycemia and hypoglycemia increase morbidity and mortality of patients. Protocols and better instruments for continuous measurement are necessary to achieve the metabolic control of our patients. PMID- 27998544 TI - Can low-BMI Chinese patients with type 2 diabetes benefit from laparoscopic Roux en-Y gastric bypass surgery? PMID- 27998543 TI - Gastrojejunal anastomotic reduction for weight regain in roux-en-y gastric bypass patients: physiological, behavioral, and anatomical effects of endoscopic suturing and sclerotherapy. AB - BACKGROUND: Weight regain is common after Roux-en-Y gastric bypass. OBJECTIVES: To assess the mechanisms of weight loss after 2 gastrojejunal anastomotic reduction (GJAR) procedures to treat weight regain. SETTING: University hospital, United States. METHODS: Forty-three Roux-en-Y gastric bypass patients with weight regain were prospectively enrolled. Weight, ghrelin levels, responses to the 21 item three-factor eating questionnaire, and gastrojejunal anastomotic diameter were assessed. Nine patients underwent endoscopic suturing and 34 patients underwent sclerotherapy. At 3 months, weight, ghrelin levels, eating behavior, and outlet diameter were reassessed. RESULTS: Patients were aged 47+/-10 years and regained 43%+/-26% of maximal lost weight. Ghrelin levels were 123+/-106 ng/mL and outlet diameter was 21+/-6.3 mm. At 3 months, the entire cohort lost 4.1%+/-5.9% of total weight (TBW) and showed improvement in cognitive eating habits (P<.01). Endoscopic suturing and sclerotherapy patients lost 10.4%+/-2.2% TBW and 2.7%+/-5.5% TBW (P<.01), respectively. Suturing and sclerotherapy reduced the outlet diameter by 15.0+/-6.7 mm and 2.6+/-5.7 mm (P<.01). Ghrelin levels increased after suturing by 46+/-55 ng/mL and decreased by 37+/-110 ng/mL after sclerotherapy (P = .02). Suturing resulted in greater improvement in cognitive eating behavior than sclerotherapy (P = .03). Reduction in outlet size and changes in cognitive and emotional eating behaviors were predictors of weight loss after GJAR on a univariate analysis. On a multivariate analysis, the only predictor of weight loss was a reduction in outlet size (P< .01). CONCLUSIONS: Endoscopic suturing resulted in greater reduction in outlet size, improvement in eating behavior, and weight loss than sclerotherapy. Reduction of anastomosis size was a significant predictor of weight loss after GJAR. PMID- 27998545 TI - Measuring changes in renal function after bariatric surgery: Why estimated glomerular filtration rate is not good enough. PMID- 27998546 TI - Wernicke's encephalopathy after conversion from sleeve gastrectomy to gastric bypass. PMID- 27998547 TI - Spatial and seasonal variation of pollution sources in proximity of the Jaranman Saryangdo area in Korea. AB - We aimed to compare the spatial and seasonal distributions of fecal coliforms (FCs) and other physiochemical factors in the drainage basin of the Jaranman Saryangdo area. Among the pollution sources, the mean daily loads and half-circle radii of FCs were the highest in June. However, the pollutants did not reach the boundary line of the designated area due to an existing buffer zone. The value of the FC geometric mean at station 1 was highest in August during periods of heavy rainfall; however, this value was lower than the regulation limit. The highest daily loads of chemical oxygen demand (COD) and chlorophyll-a (Chl-a) in seawater were in the surface layer in August; however, dissolved oxygen (DO) in the bottom water layer was at its lowest in August. This study demonstrated that season and rainfall have significant effects on the FC, COD, DO, and Chl-a concentrations in seawater. PMID- 27998548 TI - Do errors and critical events relate to hernia repair outcomes? AB - BACKGROUND: The study aimed to validate an error checklist for simulated laparoscopic ventral hernia (LVH) repair procedures. We hypothesize that residents' errors can be assessed with a structured checklist and the results will correlate significantly with procedural outcomes. METHODS: Senior residents' (N = 7) performance on a LVH simulator were video-recorded and analyzed using a human error checklist. Junior residents (N = 38) performed two steps of the same simulated LVH procedure. Performance was evaluated using the error checklist and repair quality scores. RESULTS: There were no significant differences between senior and junior residents' checklist errors (p > 0.1). Junior residents' errors correlated with hernia repair quality (p = 0.05). CONCLUSIONS: The newly developed assessment tool showed significant correlations between performance errors, critical events, and hernia repair quality. These results provide validity evidence for the use of errors in performance assessments. SUMMARY: This study validated an error checklist for simulated laparoscopic ventral hernia (LVH) repair procedures. The checklist was designed based on errors committed by chief surgery residents during LVH repairs. In a separate data collection, junior residents were evaluated using the checklist. Hernia repair quality was also assessed. Errors significantly correlated with hernia repair quality (p = 0.05). PMID- 27998549 TI - Patient Hand-Off iNitiation and Evaluation (PHONE) study: A randomized trial of patient handoff methods. AB - BACKGROUND: As residency work hour restrictions have tightened, transitions of care have become more frequent. Many institutions dedicate significant time and resources to patient handoffs despite the fact that the ideal method is relatively unknown. We sought to compare the effect of a rigorous formal handoff approach to a minimized but focused handoff process on patient outcomes. METHODS: A randomized prospective trial was conducted at a large teaching hospital over ten months. Patients were assigned to services employing either formal or focused handoffs. Residents were trained on handoff techniques and then observed by trained researchers. Outcome data including mortality, negative events, adverse events, and length of stay were collected and compared between formal and focused handoff groups using t-tests and a multivariate regression analysis. RESULTS: A total of 5157 unique patient-admissions were stratified into the two study groups. Focused handoffs were significantly shorter and included fewer patients (mean 6.3 patients discussed over 6.7 min vs. 35.2 patients over 20.6 min, both p < 0.001). Adverse events occurred during 16.7% of patient admissions. While overall length of stay was slightly shorter in the formal handoff group (5.50 days vs 5.88 days, p = 0.024) in univariate analysis only, there were no significant differences in patient outcomes between the two handoff methods (all p > 0.05). CONCLUSIONS: This large randomized trial comparing two contrasting handoff techniques demonstrated no clinically significant differences in patient outcomes. A minimalistic handoff process may save time and resources without negatively affecting patient outcomes. PMID- 27998550 TI - The clinical implication of the number of lymph nodes harvested during sentinel lymph node biopsy and its effects on survival outcome in patients with node negative breast cancer. AB - BACKGROUND: The optimal number of sentinel lymph nodes (SLN) that need to be harvested to achieve favorable survival outcome during a SLN biopsy (SLNB) has not yet been established. METHODS: Six hundred and thirteen patients with clinically node-negative breast cancer who underwent SLNB were reviewed. Survival outcomes according to the number of total harvested lymph nodes (THLNs), defined as the sum of enumerated SLNs and non-SLNs were analyzed. RESULTS: Patients with only 1 THLN showed lower recurrence-free survival (RFS) as compared to those with >=2 THLNs (p = 0.049). In multivariate analysis, only 1 THLN was associated with poor RFS (HR = 2.711; p = 0.029). CONCLUSIONS: Removing at least 2 lymph nodes during SLNB may be acceptable. Harvesting only 1 lymph node should be undertaken cautiously because of false negative results and increasing the subsequent recurrence rate. PMID- 27998551 TI - Securing gains against malaria in uncertain times. PMID- 27998552 TI - Reducing uncertainty about flavivirus infections. PMID- 27998553 TI - First published report of Zika virus infection in people: Simpson, not MacNamara. PMID- 27998554 TI - Corrections. PMID- 27998556 TI - Corrections. PMID- 27998555 TI - Corrections. PMID- 27998557 TI - The cover artist for this year. PMID- 27998558 TI - Corrections. PMID- 27998559 TI - Nivolumab plus interferon-gamma in the treatment of intractable mucormycosis. PMID- 27998560 TI - HPV vaccinations: a Middle Eastern and north African dilemma. PMID- 27998561 TI - The safety of Cervarix? PMID- 27998562 TI - The safety of Cervarix? - Authors' reply. PMID- 27998563 TI - Interagency cooperation is the key to an effective pandemic response. PMID- 27998564 TI - The promise of multipurpose pregnancy, STI, and HIV prevention. PMID- 27998565 TI - Questioning effectiveness of vaccines against malaria - Authors' reply. PMID- 27998566 TI - Questioning effectiveness of vaccines against malaria. PMID- 27998567 TI - India needs to refine a strategy to tackle the tuberculosis epidemic. PMID- 27998568 TI - Resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones. PMID- 27998569 TI - Resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones - Authors' reply. PMID- 27998570 TI - Community-associated meticillin-resistant Staphylococcus aureus pneumonia in China. PMID- 27998573 TI - Obituary-John (Jack) Payne Woodall. PMID- 27998571 TI - Plasmid-mediated or chromosomally mediated colistin resistance in Klebsiella pneumoniae? PMID- 27998572 TI - Ending malaria. PMID- 27998574 TI - Highlights from IDWeek 2016. PMID- 27998575 TI - HIV pre-exposure prophylaxis: a tale of two countries. PMID- 27998578 TI - Jared Baeten-aiming to see off HIV. PMID- 27998579 TI - Infectious disease emergencies: taking the long-term view. PMID- 27998580 TI - Zika virus has arrived in Singapore. PMID- 27998581 TI - Rift valley fever epidemic in Niger near border with Mali. PMID- 27998582 TI - Sex-specific maps of HIV epidemics in sub-Saharan Africa. PMID- 27998583 TI - Human papillomavirus vaccine approval in China: a major step forward but challenges ahead. PMID- 27998584 TI - Corrections. PMID- 27998585 TI - Direct-acting antiviral treatment for HCV. PMID- 27998586 TI - Introduction of a hepatitis B vaccine into the national routine immunisation programme of Japan. PMID- 27998587 TI - Emerging resistant clone of Mycobacterium tuberculosis in west Asia. PMID- 27998588 TI - A precise and objective tool for tuberculosis detection. PMID- 27998589 TI - Tuberculosis burden in India's private sector. PMID- 27998590 TI - A precise and objective tool for tuberculosis detection - Author's reply. PMID- 27998591 TI - Tuberculosis burden in India's private sector - Authors' reply. PMID- 27998592 TI - Motavizumab, RSV, and subsequent wheezing - Authors' reply. PMID- 27998593 TI - Vaccination against respiratory syncytial virus in pregnancy. PMID- 27998594 TI - Zika virus and microcephaly. PMID- 27998595 TI - Zika virus and microcephaly - Authors' reply. PMID- 27998596 TI - Crimean-Congo haemorrhagic fever virus and Eid-Ul-Adha festival in Pakistan. PMID- 27998597 TI - Crimean-Congo haemorrhagic fever in Pakistan. PMID- 27998598 TI - Herd protection from the female HPV vaccination programme. PMID- 27998600 TI - Obituary-Stephen David Lawn. PMID- 27998599 TI - Herd protection from the female HPV vaccination programme - Authors' reply. PMID- 27998601 TI - Multidrug resistant tuberculosis: a continuing crisis. PMID- 27998602 TI - Homophobic sentiment hinders Indonesia's anti-HIV drive. PMID- 27998605 TI - Invasive pulmonary aspergillosis after near-drowning. PMID- 27998606 TI - New coronary transfer technique for transposition of the great arteries with a single coronary artery. PMID- 27998607 TI - Cardiac magnetic resonance imaging for ischemic mitral regurgitation: A guide through complex surgical terrain. PMID- 27998609 TI - What is the status of liver health in adults living with the Fontan circulation? Now that is a good question. PMID- 27998608 TI - A score to estimate 30-day mortality after intensive care admission after cardiac surgery. AB - OBJECTIVE: Several risk-scoring systems have been developed to predict surgical mortality and complications in cardiac surgical patients, but none of the current systems include factors related to the intraoperative period. The purpose of this study was to develop a score that incorporates both preoperative and intraoperative factors so that it could be used for patients admitted to a cardiac surgical intensive care unit (ICU) immediately after surgery. METHOD: Preoperative and intraoperative data from 30,350 patients in four hospitals were used to build a multiple logistic regression model estimating 30-day mortality after cardiac surgery. Sixty percent of the patients were used as a derivation group and forty percent as a validation group. RESULTS: Mortality occurred in 2.6% of patients (n = 790). Preoperative factors identified in the model were age, female sex, emergency status, pulmonary hypertension, peripheral vascular disease, renal dysfunction, diabetes, peptic ulcer disease, history of alcohol abuse, and refusal of blood products. Intraoperative risk factors included the need for an intra-aortic balloon pump, ventricular assist device or extracorporeal membrane oxygenation leaving the operating room, presence of any intraoperative complication reported by the surgeon, the use of inotropes, high dose vasopressors, red blood cell transfusion, and cardiopulmonary bypass time. When used after surgery at ICU admission, the model had C-statistics of 0.86 in both derivation and validation sets to estimate the 30-day mortality. CONCLUSIONS: Preoperative and intraoperative variables can be used on admission to a cardiac surgical ICU to estimate 30-day mortality. The score could be used for risk stratification after cardiac surgery and evaluation of performance of cardiac surgical ICUs. PMID- 27998610 TI - Preoperative and intraoperative variables to predict mortality: Which comes first, the chicken or the egg? PMID- 27998611 TI - Bilateral sympathectomy improves postinfarction left ventricular remodeling and function. AB - OBJECTIVES: To evaluate the influence of bilateral or left sympathectomy on left ventricular remodeling and function after myocardial infarction in rats. METHODS: Myocardial infarction was induced in rats by ligation of the left anterior descending coronary. Seven days later, rats were divided into 4 groups: the myocardial infarction, myocardial infarction with left sympathectomy, myocardial infarction with bilateral sympathectomy, and sham groups. After 8 weeks, left ventricular function was evaluated with the use of a pressure-volume conductance catheter under steady-state conditions and pharmacological stress. Infarct size and extracellular matrix fibrosis were evaluated, and cardiac matrix metalloproteinases and myocardial inflammatory markers were analyzed. RESULTS: The myocardial infarction and left sympathectomy group had an increased end diastolic volume, whereas the bilateral sympathectomy group had a mean end diastolic volume similar to that of the sham group (P < .002). Significant reduction in ejection fraction was observed in the myocardial infarction and left sympathectomy group, whereas it was preserved after bilateral sympathectomy (P < .001). In response to dobutamine, left ventricular contractility increased in sham rats, rising stroke work, cardiac output, systolic volume, end-diastolic volume, ejection fraction, and dP/dt max. Only bilateral sympathectomy rats had significant increases in ejection fraction (P < .001) with dobutamine. Fibrotic tissue and matrix metalloproteinase expression decreased in the bilateral sympathectomy group compared to that in the myocardial infarction group (P < .001) and was associated with left ventricular wall thickness maintenance and better apoptotic markers in noninfarcted myocardium. CONCLUSIONS: Bilateral sympathectomy effectively attenuated left ventricular remodeling and preserved systolic function after myocardial infarction induction in rats. PMID- 27998612 TI - Corrigendum to "Evaluation of the environmental plasticity in the xerohalophyte Zygophyllum fabago L. for the phytomanagement of mine tailings in semiarid areas" [Chemosphere 161 (2016) 259-265]. PMID- 27998613 TI - ABA and GA3 regulate the synthesis of primary and secondary metabolites related to alleviation from biotic and abiotic stresses in grapevine. AB - Plants are able to synthesize a large number of organic compounds. Among them, primary metabolites are known to participate in plant growth and development, whereas secondary metabolites are mostly involved in defense and other facultative processes. In grapevine, one of the major fruit crops in the world, secondary metabolites, mainly polyphenols, are of great interest for the wine industry. Even though there is an extensive literature on the content and profile of those compounds in berries, scarce or no information is available regarding polyphenols in other organs. In addition, little is known about the effect of plant growth regulators (PGRs), ABA and GA3 (extensively used in table grapes) on the synthesis of primary and secondary metabolites in wine grapes. In table grapes, cultural practices include the use of GA3 sprays shortly before veraison, to increase berry and bunch size, and sugar content in fruits. Meanwhile, ABA applications to the berries on pre-veraison improve the skin coloring and sugar accumulation, anticipating the onset of veraison. Accordingly, the aim of this study was to assess and characterize primary and secondary metabolites in leaves, berries and roots of grapevine plants cv. Malbec at veraison, and changes in compositions after ABA and GA3 aerial sprayings. Metabolic profiling was conducted using GC-MS, GC-FID and HPLC-MWD. A large set of metabolites was identified: sugars, alditols, organic acids, amino acids, polyphenols (flavonoids and non-flavonoids) and terpenes (mono-, sesqui-, di- and triterpenes). The obtained results showed that ABA applications elicited synthesis of mono- and sesquiterpenes in all assessed tissues, as well as L-proline, acidic amino acids and anthocyanins in leaves. Additionally, applications with GA3 elicited synthesis of L-proline in berries, and mono- and sesquiterpenes in all the tissues. However, treatment with GA3 seemed to block polyphenol synthesis, mainly in berries. In conclusion, ABA and GA3 applications to grapevine plants cv. Malbec influenced the synthesis of primary and secondary metabolites known to be essential for coping with biotic and abiotic stresses. PMID- 27998614 TI - The de Winter electrocardiographic pattern of proximal left anterior descending occlusion. AB - Prompt recognition of electrocardiographic signs of acute left anterior descending (LAD) occlusion is essential for timely restoration of flow. However, some patients may present with atypical electrocardiographic signs, and early diagnosis of these patients may constitute a clinical challenge. Here, we report two cases presenting with an atypical electrocardiographic manifestation despite angiographically confirmed acute thrombotic occlusion of proximal LAD. These cases highlight the importance of recognizing the de Winter electrocardiogram pattern in cases of suspected acute myocardial infarction (AMI). An emergency percutaneous coronary intervention (PCI) should be performed in suspected AMI patients as early as possible. PMID- 27998615 TI - Analysis of intraosseous blood samples using an EPOC point of care analyzer during resuscitation. AB - BACKGROUND: In the early phases of resuscitation in a critically ill patient, especially those in cardiac arrest, intravenous (IV) access can be difficult to obtain. Intraosseous (IO) access is often used in these critical situations to allow medication administration. When no IV access is available, it is difficult to obtain blood for point of care analysis, yet this information can be crucial in directing the resuscitation. We hypothesized that IO samples may be used with a point of care device to obtain useful information when seconds really do matter. METHODS: Patients presenting to the emergency department requiring resuscitation and IO placement were prospectively enrolled in a convenience sample. 17 patients were enrolled. IO and IV samples obtained within five minutes of one another were analyzed using separate EPOC(r) point of care analyzers. Analytes were compared using Bland Altman Plots and intraclass correlation coefficients. RESULTS: In this analysis of convenience sampled critically ill patients, the EPOC(r) point of care analyzer provided results from IO samples. IO and IV samples were most comparable for pH, bicarbonate, sodium and base excess, and potentially for lactic acid; single outliers for bicarbonate, sodium and base excess were observed. Intraclass correlation coefficients were excellent for sodium and reasonable for pH, pO2, bicarbonate, and glucose. Correlations for other variables measured by the EPOC(r) analyzer were not as robust. CONCLUSION: IO samples can be used with a bedside point of care analyzer to rapidly obtain certain laboratory information during resuscitations when IV access is difficult. PMID- 27998616 TI - Spontaneous coronary artery dissection in a young woman with polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) affects 4% to 12% of women in reproductive age, representing a clinical condition that could predispose to cardiovascular diseases. We report a case of a 34-year-old woman with PCOS, presenting with chest pain, onset two days before, and ST segment-elevation myocardial infarction. She was not pregnant or in a postpartum state. Subsequent cardiac angiography revealed spontaneous left anterior descending coronary artery dissections, managed by conservative approach. The patient was discharged in medical therapy after 5days. This is the first observation of spontaneous coronary artery dissection occurring in a PCOS patient. PMID- 27998617 TI - Biophysical, Molecular, and Pharmacological Characterization of Voltage-Dependent Sodium Channels From Induced Pluripotent Stem Cell-Derived Cardiomyocytes. AB - BACKGROUND: The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current voltage curves used hiPSC-CM to model voltage-gated Na+ channel (Nav) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Nav channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Nav channels from hiPSC-CM and assess the appropriateness of this novel cell model. METHODS: We generated hiPSC CM using the recently described monolayer-based differentiation protocol. RESULTS: hiPSC-CM expressed cardiac-specific markers, exhibited spontaneous electrical and contractile activities, and expressed distinct Nav channels subtypes. Electrophysiological, pharmacological, and molecular characterizations revealed that, in addition to the main Nav1.5 channel, the neuronal tetrodotoxin (TTX)-sensitive Nav1.7 channel was also significantly expressed in hiPSC-CM. Most of the Na+ currents were resistant to TTX block. Therapeutic concentrations of lidocaine, a class I antiarrhythmic drug, also inhibited Na+ currents in a use dependent manner. Nav1.5 and Nav1.7 expression and maturation patterns of hiPSC CM and native human cardiac tissues appeared to be similar. The 4 Navbeta regulatory subunits were expressed in hiPSC-CM, with beta3 being the preponderant subtype. CONCLUSIONS: The findings indicated that hiPSC-CM robustly express Nav1.5 channels, which exhibited molecular and pharmacological properties similar to those in native cardiac tissues. Interestingly, neuronal Nav1.7 channels were also expressed in hiPSC-CM and are likely to be responsible for the TTX-sensitive Nav current. PMID- 27998618 TI - Which Patients With Atrial Fibrillation and Chronic Kidney Disease Should Receive Anticoagulation-And With Which Anticoagulant? PMID- 27998619 TI - How do you decide on hormone replacement therapy in women with risk of venous thromboembolism? AB - Women are increasingly encouraged to participate in making decisions about hormone replacement therapy (HRT). In postmenopausal women with severe vasomotor symptoms, HRT can significantly improve the quality of life. However, the use of HRT may also increase the risk of venous thromboembolism (VTE), the risk which depends of both treatment-related and patient-related factors. This review summarizes some important points about the selection of the safest hormonal replacement modality in women with a history of VTE and management of VTE risks in postmenopausal women wishing to take HRT. PMID- 27998620 TI - Newly diagnosed vs. relapsing giant cell arteritis: Baseline data from the GiACTA trial. AB - OBJECTIVE: To report entry criteria and clinical features of patients with newly diagnosed and relapsing giant cell arteritis (GCA) enrolled in a randomized trial of tocilizumab, an interleukin-6 receptor-alpha inhibitor. METHODS: Newly diagnosed GCA was defined as diagnosis <=6 weeks before baseline. Relapsing GCA was defined as diagnosis >6 weeks before baseline with >=2 consecutive weeks of prednisone >=40mg/day. All patients had active GCA within 6 weeks of baseline. All statistical results are exploratory. RESULTS: Of 251 patients, 119 (47%) had newly diagnosed and 132 (53%) had relapsing GCA. Mean age was 69 years in both subsets; 75% were women. Relapsing patients were heavier [difference in means (95% CI): women, 4.18kg (0.49-7.87, P = 0.027); men, 8.25kg (1.42-15.09, P = 0.019)] and had higher mean body mass index [difference in means (95% CI): women, 1.72kg/m2 (0.44-2.99, P = 0.009); men, 2.85kg/m2 (0.32-5.37, P = 0.028)]. Relapsers had higher baseline prevalence of depression (16% vs. 4%) and osteopenia/osteoporosis (33% vs. 23%, P = 0.002 and P = 0.062, respectively). At diagnosis, 67% had new-onset headaches; 34% had mouth pain/jaw claudication. One fifth had polymyalgia rheumatica symptoms but no cranial manifestations; 62% had positive temporal artery biopsy findings; 37% were enrolled on the basis of cross sectional imaging study findings. CONCLUSIONS: Demographics of the GiACTA population reflect the epidemiologic profile of GCA. Baseline comorbidities associated with glucocorticoids were more prevalent among relapsing patients than among those with newly diagnosed disease, highlighting the need for new GCA treatment options. More than one-third of patients were enrolled based on large vessel imaging. PMID- 27998621 TI - Brain tau deposition linked to systemic causes of death in normal elderly. AB - The relationship between causes of death and 4 major neurodegenerative brain proteins (beta-amyloid, tau, alpha-synuclein, and the TAR DNA-binding protein of 43 kDa (TDP-43) were assessed in 94 cognitively normal elderly participants that died without a neurodegenerative disease. There was an association between tau and causes of death (p = 0.01). Tau in the brain was associated with a reduced likelihood of dying from systemic cancers (p = 0.046), and with an increased likelihood of dying from pulmonary (p = 0.03) and gastrointestinal (p = 0.049) diseases. There were no associations between beta-amyloid, alpha-synuclein, or TDP-43 and causes of death. Tau deposition in the brain may have a relationship with systemic causes of death, including cancer, in the cognitively normal elderly. PMID- 27998622 TI - Myocardial calcification: A rare complication of pneumonia and sepsis. PMID- 27998623 TI - Growth in retail-based clinics after nurse practitioner scope of practice reform. AB - BACKGROUND: Retail clinics are largely staffed by nurse practitioners (NPs) and are a popular destination for nonemergent care. PURPOSE: We examined if there was a relationship between NP practice regulations and retail clinic growth after the passage of a scope of practice (SOP) reform bill in Pennsylvania. METHODS: General linear regression models were used to compare retail clinic openings in Pennsylvania, New Jersey, and Maryland between 2006 and 2013. DISCUSSION: From 2006 to 2008, Pennsylvania experienced a significant growth rate in net retail clinic openings per capita (p = .046), whereas New Jersey and Maryland experienced no significant increase (p = .109 and .053, respectively). From 2009 to 2013, Pennsylvania opened 0.20 clinics (p = .129), New Jersey opened 0.23 clinics (p = .086), and Maryland opened 0.34 clinics per capita per year (p = .017). CONCLUSIONS: Our study of three states with varying levels of SOP restraint reveals an association between relaxation of practice regulations and retail clinic growth. PMID- 27998624 TI - Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation. AB - BACKGROUND: The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain. STUDY DESIGN: Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada. SETTING & PARTICIPANTS: 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded. PREDICTOR: Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis. OUTCOMES: Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding. MEASUREMENTS: Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories: >=90, 60 to 89, 45 to 59, 30 to 44, and <30mL/min/1.73m2. Information for baseline characteristics (sociodemographics, comorbid conditions, and prescription drug use) was obtained. RESULTS: Across eGFR categories, warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories >= 90, 60-89, 45-59, 30-44, and <30mL/min/1.73m2: 0.59 [0.35 1.01], 0.61 [0.54-0.70], 0.55 [0.47-0.65], 0.54 [0.44-0.67], and 0.64 [0.47-0.87] mL/min/1.73m2, respectively). Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89mL/min/1.73m2 (HR, 1.36; 95% CI, 1.13-1.64). LIMITATIONS: Selection bias. CONCLUSIONS: Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk for the composite outcome across all strata of kidney function. The risk for major bleeding associated with warfarin use was increased only among those with eGFRs of 60 to 89mL/min/1.73m2. PMID- 27998626 TI - Cardiac biomarkers and haemodynamically significant patent ductus arteriosus in preterm infants. AB - Accurately defining haemodynamically significant patent ductus arteriosus (PDA) in preterm infants who are at risk of PDA related morbidities are active areas of neonatal research. Natriuretic peptides are cardiac hormones that respond to volume and pressure loading, with elevated plasma levels found in infants with PDA. In the preterm neonatal setting, studies to date have predominantly investigated the ability of these biomarkers to discriminate between infants with and without a PDA at various postnatal ages. Their clinical utility has therefore been exclusively evaluated as a method of triaging cases of suspected hsPDA to decrease the need for echocardiograms, and to monitor treatment response. Biomarkers are yet to be robustly investigated for their ability to predict important PDA associated morbidities. In this review, we examine the most recent literature to date on the use of biomarkers in the management of PDA. PMID- 27998627 TI - Distribution of radon concentrations in child-care facilities in South Korea. AB - This study was conducted to provide fundamental data on the distribution of radon concentrations in child day-care facilities in South Korea and to help establish radon mitigation strategies. For this study, 230 child-care centers were randomly chosen from all child-care centers nationwide, and alpha track detectors were used to examine cumulative radon exposure concentrations from January to May 2015. The mean radon concentration measured in Korean child-care centers is approximately 52 Bq m-3, about one-third of the upper limit of 148 Bq m-3, which is recommended by South Korea's Indoor Air Quality Control in Public Use Facilities, etc. Act and the U.S. Environmental Protection Agency (EPA). Furthermore, this concentration is about 50% lower than 102 Bq m-3, which is the measured concentration of radon in houses nationwide from December 2013 to February 2014. Our results indicate that the amount of ventilation, as a major determining factor for indoor radon concentrations, is strongly correlated with the fluctuation of indoor radon concentrations in Korean child-care centers. PMID- 27998628 TI - Radiological impact of NORM generated by oil and gas industries in the kingdom of Bahrain. AB - A study of the external background radiation in areas affected by NORM generated by oil and gas industrial activities has been performed in the Kingdom of Bahrain. In this framework, two experimental residential areas, Awali and Riffa Views, were selected due to the presence of extensive oil and gas exploration and transportation. Additionally, two control residential areas, Isa Town and Al Budaiya Village, were selected as they lack any industrial activities that would disrupt the radiation profile. The radiation dose rates were measured using Colibri Very Low Dose radiation survey meter with a built-in GPS. A total of 317 dose rates with their GPS coordinates were acquired. The lowest dose rate was 0.02 MUSv/h acquired in Isa Town while the highest dose rate was 0.37 MUSv/h acquired in Awali. Since there were no studies performed in the Kingdom to measure the average background radiation, the average external background radiation calculated from the control areas was used in this study which is 0.75 +/- 0.31 mSv/y. The measured mean annual equivalent doses above the background radiation levels in Isa Town, Al-Budaiya, Riffa Views and Awali were -0.05 +/- 0.05 mSv/y, 0.04 +/- 0.04 mSv/y, 0.62 +/- 0.13 mSv/y and 1.32 +/- 0.35 mSv/y respectively. In other words, the radiation measurements were notably higher in the experimental areas. This was particularly true in south and southwestern Awali where the annual equivalent dose in some areas reached 2.49 mSv/y above average background levels. The geological constituent of the earth crust could be one source that contribute to overall background radiation. However, presence of NORM generated by extensive oil and gas operations and transportation is stronger justification for the higher radiation readings in the experimental areas than geological characteristic factor. Such high radiation values were found only near oil and gas installations and not in other locations of the same areas. PMID- 27998625 TI - A Consensus-Driven Agenda for Emergency Medicine Firearm Injury Prevention Research. AB - STUDY OBJECTIVE: To identify critical emergency medicine-focused firearm injury research questions and develop an evidence-based research agenda. METHODS: National content experts were recruited to a technical advisory group for the American College of Emergency Physicians Research Committee. Nominal group technique was used to identify research questions by consensus. The technical advisory group decided to focus on 5 widely accepted categorizations of firearm injury. Subgroups conducted literature reviews on each topic and developed preliminary lists of emergency medicine-relevant research questions. In-person meetings and conference calls were held to iteratively refine the extensive list of research questions, following nominal group technique guidelines. Feedback from external stakeholders was reviewed and integrated. RESULTS: Fifty-nine final emergency medicine-relevant research questions were identified, including questions that cut across all firearm injury topics and questions specific to self-directed violence (suicide and attempted suicide), intimate partner violence, peer (nonpartner) violence, mass violence, and unintentional ("accidental") injury. Some questions could be addressed through research conducted in emergency departments; others would require work in other settings. CONCLUSION: The technical advisory group identified key emergency medicine relevant firearm injury research questions. Emergency medicine-specific data are limited for most of these questions. Funders and researchers should consider increasing their attention to firearm injury prevention and control, particularly to the questions identified here and in other recently developed research agendas. PMID- 27998629 TI - Usefulness of Hemospray in a patient with refractory lower gastrointestinal bleeding secondary to a caecal ulcer caused by cytomegalovirus. PMID- 27998630 TI - Nonsteroidal anti-inflammatory drugs-induced small bowel enteropathy and obscure gastrointestinal bleeding. PMID- 27998631 TI - Emergency Department Cardiopulmonary Evaluation of Low-Risk Chest Pain Patients with Self-Reported Stress and Anxiety. AB - BACKGROUND: Chest pain is a high-risk emergency department (ED) chief complaint; the majority of clinical resources are directed toward detecting and treating cardiopulmonary emergencies. However, at follow-up, 80%-95% of these patients have only a symptom-based diagnosis; a large number have undiagnosed anxiety disorders. OBJECTIVE: Our aim was to measure the frequency of self-identified stress or anxiety among chest pain patients, and compare their pretest probabilities, care processes, and outcomes. METHODS: Patients were divided into two groups: explicitly self-reported anxiety and stress or not at 90-day follow up, then compared on several variables: ultralow (<2.5%) pretest probability, outcome rates for acute coronary syndrome (ACS) and pulmonary embolism (PE), radiation exposure, total costs at 30 days, and 90-day recidivism. RESULTS: Eight hundred and forty-five patients were studied. Sixty-seven (8%) explicitly attributed their chest pain to "stress" or "anxiety"; their mean ACS pretest probability was 4% (95% confidence interval 2.9%-5.7%) and 49% (33/67) had ultralow pretest probability (0/33 with ACS or PE). None (0/67) were diagnosed with anxiety. Seven hundred and seventy-eight did not report stress or anxiety and, of these, 52% (403/778) had ultralow ACS pretest probability. Only one patient (0.2%; 1/403) was diagnosed with ACS and one patient (0.4%; 1/268) was diagnosed with PE. Patients with self-reported anxiety had similar radiation exposure, associated costs, and nearly identical (25.4% vs. 25.7%) ED recidivism to patients without reported anxiety. CONCLUSIONS: Without prompting, 8% of patients self-identified "stress" or "anxiety" as the etiology for their chest pain. Most had low pretest probability, were over-investigated for ACS and PE, and not investigated for anxiety syndromes. PMID- 27998632 TI - Reply to Jansen et al. PMID- 27998633 TI - Limitations in Prehospital Communication Between Trauma Helicopter, Ambulance Services, and Dispatch Centers. AB - BACKGROUND: Prehospital communication with Emergency Medical Services (EMS) is carried out in hectic situations. Proper communication among all medical personal is required to enhance collaboration, to provide the best care and enable shared situational awareness. OBJECTIVE: The objective of this article was to give insight into current Dutch prehospital emergency care communication among all EMS and evaluate the usage of a new physician staffed helicopter EMS (P-HEMS) cancellation model. METHODS: Trauma-related P-HEMS dispatches between November 1, 2014 and May 31, 2015 for the Lifeliner 1 were included; a random sample of 100 dispatches was generated. Tape recordings on all verbal prehospital communication between the dispatch center, EMS, and P-HEMS were transcribed and analyzed. Qualitative content analysis was performed, using open coding to code key messages. RESULTS: Ninety-two tape recordings were analyzed. The most frequent reason for P-HEMS dispatch was suspicion of brain injury (24%). The cancellation model was followed in 66%, overruled in 9%, and not applicable in 25%. The main reason for not adhering to the model was hemodynamic stability. In 5% of P-HEMS dispatches, a complete ABCD (airway, breathing, circulation, disability) methodology was used for handover, in 9% a complete Situation-Background Assessment-Recommendation technique, in 2% a complete Mechanism-Injuries-Signs Treatment method was used. The other handovers were incomplete. CONCLUSIONS: Prehospital handover between EMS on-scene and P-HEMS often entails insufficient information. The cancellation model for P-HEMS is frequently used and promotes adequate information transfer. To increase joined decision-making, more patient and situational information needs to be handed over. Standardization of prehospital trauma handovers will facilitate this and improve trauma patient's outcome. PMID- 27998634 TI - Transient Coagulopathy Due to Wasp Sting: A Case Report. AB - BACKGROUND: Insect venom anaphylaxis is a potentially life-threatening disorder. Transient coagulopathy in insect venom anaphylaxis is a rare phenomenon. CASE REPORT: A 41-year-old man presented to the Emergency Department (ED) with hypotension after a run in a park. History and examination revealed signs of anaphylactic shock. A deranged coagulation profile with a normal platelet count led to the diagnosis of wasp sting anaphylaxis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Transient deranged coagulation profile with a normal platelet count may arise from insect venom anaphylaxis. This specific finding may aid the emergency physician in making a diagnosis of anaphylactic shock in an otherwise healthy patient presenting with shock with no apparent cause. PMID- 27998635 TI - Predictors of Intrathoracic Injury after Blunt Torso Trauma in Children Presenting to an Emergency Department as Trauma Activations. AB - BACKGROUND: Thoracic injuries are a major cause of death associated with blunt trauma in children. Screening for injury with chest x-ray study, compared with chest computed tomography (CT) scan, has been controversial, weighing the benefits of specificity with the detriment of radiation exposure. OBJECTIVE: To identify predictors of thoracic injury in children presenting as trauma activations to a Level I trauma center after blunt torso trauma, and to compare these predictors with those previously reported in the literature. METHODS: We performed a retrospective chart review of pediatric patients (<18 years of age) who presented to the Emergency Department of a Level I trauma center between June 2010 and June 2013 as a trauma activation after sustaining a blunt torso trauma and who received diagnostic imaging of the chest as part of their initial evaluation. RESULTS: Data analysis was performed on 166 patients. There were 33 patients (20%) with 45 abnormalities detected on diagnostic imaging of the chest, with the most common abnormalities being lung contusion (36%), pneumothorax (22%), and rib fracture (13%). Statistically significant predictors of abnormal diagnostic imaging of the chest included Glasgow Coma Scale score (GCS) < 15 (27% with abnormality vs. 13% without abnormality), hypoxia (22% vs. 5%), syncope/loss of consciousness (55% vs. 35%), cervical spine tenderness (12% vs. 3%), thoraco lumbar-sacral spine tenderness (41% vs. 17%), and abdominal/pelvic tenderness (12% vs. 3%). CONCLUSIONS: Based on our data, predictors of thoracic injury in children after blunt torso trauma include GCS < 15, hypoxia, syncope/dizziness, cervical spine tenderness, thoraco-lumbar-sacral spine tenderness, and abdominal/pelvic tenderness. PMID- 27998636 TI - Use of Point-of-Care Ultrasound for the Diagnosis of Ovarian Hyperstimulation Syndrome. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) occurs when ovaries are overstimulated and enlarged due to fertility treatments resulting in a shift of serum from the intravascular space to the third space, mainly the abdominal cavity. It is the most serious complication of ovarian hyperstimulation for assisted reproduction. CASE REPORT: We present the case of a 40-year-old woman who presented with abdominal bloating and nausea 2 weeks after undergoing in vitro fertilization (IVF); she was diagnosed by an outside radiology ultrasound as having a ruptured ovarian cyst. A point-of-care emergency ultrasound performed by the emergency physician made the diagnosis of ovarian hyperstimulation syndrome. This led to more expedient management and obstetrical consultation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Abdominal bloating and nausea are common presenting complaints in pregnant women. OHSS is a rare but potentially fatal complication of IVF. Recognition and early diagnosis by the emergency physician can lead to appropriate intervention and consultation. PMID- 27998637 TI - Reply to letter to editor: "Genetic basis of dilated cardiomyopathy". PMID- 27998638 TI - Response to the letter to editor: Prediction of thromboembolic events for patients with non-valvular atrial fibrillation CHA2DS2-VASc-UA2-VitD. PMID- 27998639 TI - Characterization of O-antigen delivered by Generalized Modules for Membrane Antigens (GMMA) vaccine candidates against nontyphoidal Salmonella. AB - Invasive nontyphoidal Salmonella disease (iNTS) is a leading cause of death and morbidity in Africa. The most common pathogens are Salmonella enterica serovars Typhimurium and Enteritidis. The O-antigen portion of their lipopolysaccharide is a target of protective immunity and vaccines targeting O-antigen are currently in development. Here we investigate the use of Generalized Modules for Membrane Antigens (GMMA) as delivery system for S. Typhimurium and S. Enteritidis O antigen. Gram-negative bacteria naturally shed outer membrane in a blebbing process. By deletion of the tolR gene, the level of shedding was greatly enhanced. Further genetic modifications were introduced into the GMMA-producing strains in order to reduce reactogenicity, by detoxifying the lipid A moiety of lipopolysaccharide. We found that genetic mutations can impact on expression of O antigen chains. All S. Enteritidis GMMA characterized had an O-antigen to protein w/w ratio higher than 0.6, while the ratio was 0.7 for S. Typhimurium DeltatolR GMMA, but decreased to less than 0.1 when further mutations for lipid A detoxification were introduced. Changes were also observed in O-antigen chain length and level and/or position of O-acetylation. When tested in mice, the GMMA induced high levels of anti-O-antigen-specific IgG functional antibodies, despite variation in density and O-antigen structural modifications. In conclusion, simplicity of manufacturing process and low costs of production, coupled with encouraging immunogenicity data, make GMMA an attractive strategy to further investigate for the development of a vaccine against iNTS. PMID- 27998641 TI - Biocomposite Implants Composed of Poly(Lactide-co-Glycolide)/beta-Tricalcium Phosphate: Systematic Review of Imaging, Complication, and Performance Outcomes. AB - PURPOSE: To determine the degradation and performance outcomes of poly(lactide-co glycolide)/beta-tricalcium phosphate (PLGA/beta-TCP) implants. METHODS: A MEDLINE and Embase search for randomized or nonrandomized controlled studies and prospective or retrospective case series that used biocomposite interference screws or suture anchors composed of PLGA/beta-TCP was performed. Main outcomes included volume of implant resorption and incidence of osteoconductivity at implant sites, imaging findings, adverse events, and the frequency of reoperations. RESULTS: A total of 13 studies representing 668 patients with either knee or shoulder implants were included. Median follow-up was 28 months (range: 12-37 months). Biocomposite implants lost 88% of their original volume during follow-up. Osteoconductivity at the implant site was identified in 63% of cases. Adverse events included tunnel widening (3%), effusion (5%), and cyst formation (4%). Synovitis was not reported. CONCLUSIONS: Biocomposite interference screws or suture anchors composed of PLGA/beta-TCP almost fully absorb over 3 years while promoting osteoconductivity with few reported adverse events. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies. PMID- 27998640 TI - Vaccine coverage and adherence to EPI schedules in eight resource poor settings in the MAL-ED cohort study. AB - BACKGROUND: Launched in 1974, the Expanded Program on Immunization (EPI) is estimated to prevent two-three million deaths annually from polio, diphtheria, tuberculosis, pertussis, measles, and tetanus. Additional lives could be saved through better understanding what influences adherence to the EPI schedule in specific settings. METHODS: The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study followed cohorts in eight sites in South Asia, Africa, and South America and monitored vaccine receipt over the first two years of life for the children enrolled in the study. Vaccination histories were obtained monthly from vaccination cards, local clinic records and/or caregiver reports. Vaccination histories were compared against the prescribed EPI schedules for each country, and coverage rates were examined in relation to the timing of vaccination. The influence of socioeconomic factors on vaccine timing and coverage was also considered. RESULTS: Coverage rates for EPI vaccines varied between sites and by type of vaccine; overall, coverage was highest in the Nepal and Bangladesh sites and lowest in the Tanzania and Brazil sites. Bacillus Calmette-Guerin coverage was high across all sites, 87-100%, whereas measles vaccination rates ranged widely, 73-100%. Significant delays between the scheduled administration age and actual vaccination date were present in all sites, especially for measles vaccine where less than 40% were administered on schedule. A range of socioeconomic factors were significantly associated with vaccination status in study children but these results were largely site specific. CONCLUSIONS: Our findings highlight the need to improve measles vaccination rates and reduce delayed vaccination to achieve EPI targets related to the establishment of herd immunity and reduction in disease transmission. PMID- 27998642 TI - Bone histomorphometry in de novo renal transplant recipients indicates a further decline in bone resorption 1 year posttransplantation. AB - Renal transplantation is believed to have a major impact on bone health. The present prospective observational bone biopsy study aimed to define the natural history of bone histomorphometry parameters in contemporaneous de novo renal transplant recipients. Paired bone biopsies were performed at the time of transplantation and at one-year posttransplantation in an unselected cohort of 36 patients referred for deceased kidney replacement. Parameters of mineral metabolism and circulating bone turnover markers were monitored as well. Static parameters of bone formation and especially bone resorption being already low normal in the majority of patients at the time of renal transplantation, further declined during the first posttransplant year. However, interindividual variation was substantial, and significance was reached only for bone resorption parameters. Bone mineralization and trabecular bone volume were within the normal range at the time of transplantation (83.3% and 91.7% of graft recipients, respectively) and showed little change one-year posttransplantation. Changes in osteoclast number were paralleled by changes in circulating tartrate-resistant acid phosphatase 5b levels. Finally, cumulative glucocorticoid dose, but not the posttransplantation parathyroid hormone level, associated with trabecular bone loss. Thus, the impact of renal transplantation on bone histomorphometry is limited with only bone resorption, being already low at the time of transplantation, showing a further decline. PMID- 27998643 TI - Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion. AB - The glycoprotein CD44 is barely detected in normal mouse and human glomeruli, but is increased in glomerular parietal epithelial cells following podocyte injury in focal segmental glomerulosclerosis (FSGS). To determine the biological role and regulation of CD44 in these cells, we employed an in vivo and in vitro approach. Experimental FSGS was induced in CD44 knockout and wild-type mice with a cytotoxic podocyte antibody. Albuminuria, focal and global glomerulosclerosis (periodic acid-Schiff stain), and collagen IV staining were lower in CD44 knockout compared with wild-type mice with FSGS. Parietal epithelial cells had lower migration from Bowman's capsule to the glomerular tuft in CD44 knockout mice with disease compared with wild type mice. In cultured murine parietal epithelial cells, overexpressing CD44 with a retroviral vector encoding CD44 was accompanied by significantly increased collagen IV expression and parietal epithelial cell migration. Because our results showed de novo co-staining for activated ERK1/2 (pERK) in parietal epithelial cells in experimental FSGS, and also in biopsies from patients with FSGS, two in vitro strategies were employed to prove that pERK regulated CD44 levels. First, mouse parietal epithelial cells were infected with a retroviral vector for the upstream kinase MEK-DD to increase pERK, which was accompanied by increased CD44 levels. Second, in CD44 overexpressing parietal epithelial cells, decreasing pERK with U0126 was accompanied by reduced CD44. Finally, parietal epithelial cell migration was higher in cells with increased and reduced in cells with decreased pERK. Thus, pERK is a regulator of CD44 expression, and increased CD44 expression leads to a pro-sclerotic and migratory parietal epithelial cell phenotype. PMID- 27998644 TI - Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. AB - Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized. PMID- 27998646 TI - Antibiotic prophylaxis against ventilator-associated pneumonia in patients with coma: Where are we now? PMID- 27998647 TI - Glucose metabolism during the acute prostate cancer treatment trajectory: The influence of age and obesity. AB - BACKGROUND & AIMS: Obesity and age, key risk factors for aggressive prostate cancer, are associated with insulin resistance. Glucose-related parameters in patients with aggressive prostate cancer were compared with 2 reference groups: men of similar age and body mass index (BMI) without cancer, and healthy young men. Acute changes in these parameters following radiation treatment were also evaluated. METHODS: Nine patients with aggressive prostate cancer underwent metabolic assessments prior to treatment (baseline), 7 and 33 weeks post-baseline (post-treatment initiation). Baseline measures were compared with the 2 reference groups. Evaluations included: 1) fasting and oral glucose tolerance test (OGTT) blood samples for glucose, C-peptide, and insulin, 2) fasting blood samples for triglycerides, cholesterols, leptin, adiponectin, IL-6, and TNF-alpha, 3) body composition, 4) nutrition, and 5) physical activity. RESULTS: At baseline, patients had normal fasting glucose concentrations (<5.6 mM; 4.9 +/- 1.2 mM) but impaired 2-h OGTT glucose concentrations (>7.8 mM; 8.7 +/- 2.9 mM). Both reference groups had normal fasting (matched males: 4.2 +/- 0.5 mM; young males: 3.7 +/- 0.4 mM) and 2-h OGTT glucose concentrations (matched males: 5.6 +/- 1.8 mM; young males: 3.1 +/- 0.1 mM) that were significantly lower than patient values. During the OGTT, patients had higher insulin (120 min) and C-peptide (45, 60, 90, 120 min) concentrations compared to the matched males. At 7 weeks, 2-h OGTT glucose concentrations in patients improved to healthy ranges without changes in insulin, C-peptide, IGF-1, IGFBP-3 or other metabolic parameters. CONCLUSIONS: At baseline patients with aggressive prostate cancer demonstrated impaired glucose tolerance compared with men of similar age and body size. Following treatment, glucose tolerance improved in the absence of changes in expected modifiers of glucose metabolism. These improvements may be related to treatment. PMID- 27998645 TI - Thrombotic microangiopathy associated with monoclonal gammopathy. AB - Thrombotic microangiopathy (TMA) is a rare disease comprising of a diverse set of disorders linked by a common histologic finding of endothelial injury. Monoclonal immunoglobulins may act as a potential trigger in the pathogenesis of TMA. To determine the prevalence of monoclonal gammopathy and clinicopathological features of TMA associated with monoclonal immunoglobulin, we performed a retrospective study in adults (18 and older) with a clinical diagnosis of TMA. Of 146 patients with TMA, we detected monoclonal immunoglobulin in 20 patients (13.7%). Among patients 50 and older, the prevalence of monoclonal gammopathy was 21%, which is approximately five-fold higher than the 4.2% expected rate in this population. Fifteen patients had monoclonal gammopathy of undetermined significance, one had multiple myeloma, one with smoldering myeloma, two had POEMS syndrome, and one had T-cell lymphocytic leukemia. Renal biopsy was performed in 15 cases, of which six showed thrombi, 11 showed mesangiolysis, and all showed double contours along glomerular capillary walls. Acute tubular injury was present in 12 cases. Treatment options were varied and included therapeutic plasma exchange in 11 patients. Ten patients progressed to end-stage renal disease, of which two received kidney transplant. Thus, our study shows an unexpectedly high prevalence of monoclonal gammopathy in patients with TMA, suggesting a potential pathogenetic mechanism. This study underscores the importance of evaluating for a monoclonal gammopathy in patients with TMA as well as the potential for targeting the underlying hematologic disorder as an approach to treating TMA. PMID- 27998648 TI - Russell-Silver syndrome presenting with ambiguous genitalia. PMID- 27998649 TI - Differential relations of locus of control to perceived social stress among help seeking adolescents at low vs. high clinical risk of psychosis. AB - Research suggests that perceived social stress influences illness presentation and course among youth in the clinical high-risk (CHR) phase of psychosis. Little is known, however, about the social cognitive factors associated with social stress perception in this population, particularly relative to youth with non-CHR psychopathology. Individuals with psychosis tend to endorse an external locus of control (LOC), which is associated with the stress response in healthy individuals. LOC may therefore be related to perceived social stress in youth at CHR. We examined the differential relations of self-reported LOC and perceived social stress, as measured by the Behavior Assessment System for Children, Second Edition, across 45 CHR and 65 help-seeking control (HSC) participants. Youth at CHR reported more social stress (F[1, 107]=6.28, p=0.01) and a more external LOC (F[1, 107]=4.98, p=0.03) than HSCs. Further, external LOC was more strongly associated with feelings of social stress in the CHR group relative to the HSC group (interaction: b=0.35, t[105]=2.32, p<0.05, f2=0.05). Group differences in social stress, however, were nonsignificant at internal levels of LOC (b=-2.0, t[105]=-0.72, p=0.48; f2=0.00). Results suggest that perceptions of uncontrollability over one's social environment may more often induce or exacerbate feelings of stress and tension in CHR youth relative to HSCs. A better understanding of the social cognition-stress relation may improve understanding of CHR phenomenology, etiology, and treatment. PMID- 27998650 TI - Identification of hemodynamically compromised regions by means of cerebral blood volume mapping utilizing computed tomography perfusion imaging. AB - The aim of the study was to evaluate the potential role of computed tomography perfusion (CTP) imaging in identifying hemodynamically compromised regions in patients with occlusive cerebrovascular disease. Twelve patients diagnosed with either occlusion or severe stenosis of the internal carotid artery or the M1 portion of the middle cerebral artery underwent CTP imaging. The data was analyzed by an automated ROI-determining software. Patients were classified into two subgroups: an asymptomatic group consisting of three patients in whom perfusion pressure distal to the site of occlusion/stenosis (PPdis) could be maintained in spite of the arterial occlusion/stenosis, and a symptomatic group consisting of nine patients in whom PPdis could not be maintained enough to avoid watershed infarction. Four CTP-related parameters were independently compared between the two groups. Significant differences were determined using a two sample t-test. When statistically significant differences were identified, cut off points were calculated using ROC curves. Analysis revealed statistically significant differences between the asymptomatic and symptomatic subgroups only in the measure of relCBV (p=0.028). Higher relCBV values were observed in the symptomatic subgroup. ROC curve analysis revealed 1.059 to be the optimal relCBV cut-off value for distinguishing between the asymptomatic and symptomatic subgroups. The data revealed that, in patients whose PPdis is maintained, relCBV remains around 1.00. Conversely, in patients whose PPdis decreased, relCBV increased. From these findings, we conclude that elevation of relCBV as observed using CTP imaging accurately reflects the extent of compensatory vasodilatation involvement and can identify hemodynamically compromised regions. PMID- 27998651 TI - Clinical recovery from stroke lesions and related outcomes. AB - Stroke lesions affect neurological status and are a critical determinant of treatment. This study investigated stroke lesions in terms of clinical recovery and related outcomes. Twenty-seven stroke patients were assessed via longitudinal observational study. Brain lesions were evaluated using MRI. The Fugl-Meyer Assessment and clinical evaluations were performed monthly between 1 and 6months after onset. The anterior limb (ICAL) and genu (ICG) of the internal capsule were associated with recovery of the upper limbs in chronic stroke patients. Involvement of the anterior half of the middle third of the corona radiata, the ICAL, the ICG, and the caudate nucleus were related to recovery of the lower limbs. Involvement of the middle third of the corona radiata, the ICAL, the ICG, and the lentiform nucleus were associated with sensory recovery. Clinical recovery from stroke, in terms of motor and sensory function, was related to injury in several white matter areas, such as the corona radiata and internal capsule, and was also associated with the basal ganglia as a gait pattern generator. Clinicians should be aware of stroke lesions, and should design therapeutic strategies accordingly, also with respect to treatment duration. PMID- 27998652 TI - The need for non-oral therapy in Parkinson's disease; a potential role for apomorphine. AB - In the course of Parkinson's disease (PD), oral medication may lose its effectiveness due to several reasons, like dysphagia, impaired absorption from the gastro-intestinal tract and delayed emptying of the stomach. If these problems occur, a non-oral therapy should be considered. Examples of non-oral therapies are transdermal patches, (e.g. rotigotine) which may overcome motor and nonmotor nighttime problems, and may serve as well to treat daytime response fluctuations, if oral therapies fail to do so. Other options are injections with apomorphine to treat early morning dystonia and random off-periods during daytime, as well as continuously infused subcutaneous apomorphine for random fluctuations in PD patients. Low-dose apomorphine infusions also may be useful in the peri-operative phase, when PD patients may not be able to swallow oral medication. Finally, levodopa-carbidopa intestinal gel (LCIG) infusions or DBS have shown to be effective non-oral options to treat PD patients adequately, if they are not properly controlled by oral options. PMID- 27998653 TI - European environmental scenarios of chemical bioavailability in freshwater systems. AB - In exposure prediction for environmental risk assessment, the transition to more dynamic and realistic modelling approaches and scenarios has been recently identified as a major challenge, since it would allow a more accurate prediction of bioavailable concentrations and their variations in space and time. In this work, an improved version of the multimedia model ChimERA fate, including a phytoplankton compartment and equations to calculate phytoplankton, detritus and dissolved organic matter variations in time, was developed. The model was parameterized to simulate five dynamic scenarios for shallow meso-eutrophic water bodies based on a latitudinal gradient (in Europe); such scenarios include seasonal profiles of water temperature, phytoplankton biomass, detritus, and dissolved organic matter. Model runs were performed for each scenario for 8 hydrophobic chemicals (PCB congeners), with the aim of investigating the influence of scenario characteristics and compound properties on bioavailable concentrations. The key processes were adsorption/uptake by phytoplankton and deposition to sediment of detritus-bound chemicals. The northern scenarios ("Scandinavia" and "UK") showed the highest bioavailable concentrations, with annual maximum/minimum concentration up to 25; in contrast, for example, maximum concentrations in the "Mediterranean" scenario were lower by a factor of 2 to 9 with respect to the northern ones (depending on chemical hydrophobicity), due to the generally higher biomass and carbon levels, and showed only limited seasonal variability (up to a factor of 4). These results highlight the importance of including biomass and organic carbon dynamics in both modelling approaches and scenarios for the evaluation of exposure concentrations in aquatic environments. PMID- 27998654 TI - Tree ring-based chronology of hydro-geomorphic processes as a fundament for identification of hydro-meteorological triggers in the Hruby Jesenik Mountains (Central Europe). AB - Hydro-geomorphic processes have significantly influenced the recent development of valley floors, river banks and depositional forms in mountain environments, have caused considerable damage to manmade developments and have disrupted forest management. Trees growing along streams are affected by the transported debris mass and provide valuable records of debris flow/flood histories in their tree ring series. Dendrogeomorphic approaches are currently the most accurate methods for creating a chronology of the debris flow/flood events in forested catchments without any field-monitoring or a stream-gauging station. Comprehensive studies focusing on the detailed chronology of hydro-geomorphic events and analysis of meteorological triggers and weather circulation patterns are still lacking for the studied area. We provide a spatio-temporal reconstruction of hydro-geomorphic events in four catchments of the Hruby Jesenik Mountains, Czech Republic, with an analysis of their triggering factors using meteorological data from four nearby rain gauges. Increment cores from 794 coniferous trees (Picea abies [L.] Karst.) allowed the identification of 40 hydro-geomorphic events during the period of 1889-2013. Most of the events can be explained by extreme daily rainfalls (>=50mm) occurring in at least one rain gauge. However, in several cases, there was no record of extreme precipitation at rain gauges during the debris flow/flood event year, suggesting extremely localised rainstorms at the mountain summits. We concluded that the localisation, intensity and duration of rainstorms; antecedent moisture conditions; and amount of available sediments all influenced the initiation, spatial distribution and characteristics of hydro geomorphic events. The most frequent synoptic situations responsible for the extreme rainfalls (1946-2015) were related to the meridional atmospheric circulation pattern. Our results enhance current knowledge of the occurrences and triggers of debris flows/floods in the Central European mountains in transition between temperate oceanic and continental climatic conditions and may prompt further research of these phenomena in the Eastern Sudetes in general. PMID- 27998655 TI - Persistence and risk of antibiotic residues and antibiotic resistance genes in major mariculture sites in Southeast China. AB - Antibiotics are widely used in mariculture industry, and this study attempts to determine the extent of water and sediment pollution by antibiotic residues in 13 major mariculture sites in China. Through chemical and molecular biology analysis, the results showed that the total concentrations of sulfonamides and tetracyclines were in the range 62.0-373.8ngL-1 and 0.2-259.1ngL-1 respectively in water samples, and in the range 0.19-1.59ngg-1 dry weight and 3.45-74.84ngg-1 dry weight respectively, in sediments samples. The occurrence of antibiotic resistance genes (ARGs) was detected in all sites. Compared with the tetracyclines resistance genes, the absolute copy number and relative abundance of the sulfonamides resistance genes were 4.3 times and 2.3 times higher in water and sediment from the mariculture sites, with the dominant resistance genes being sul2. The abundance of sul3 in the water phase was significantly correlated with the concentrations of sulfamerazine, while the abundance of sul2 in the sediment phase was significantly with sulfadiazine concentrations. The abundance of tetM in the sediment phase was significantly correlated with the concentrations of oxytetracycline. The findings demonstrate the persistence of antibiotic residues and ARGs in major mariculture sites in Southeast China. PMID- 27998656 TI - Impact of Primary Tumor Surgery in Stage IV Male Breast Cancer. AB - BACKGROUND: Primary tumor surgery (PTS) is not a standard treatment modality in stage IV breast cancer. Retrospective studies in female breast cancer show improved survival in women undergoing PTS; however, data regarding the impact of surgery in male breast cancer are lacking. The objective of this study was to analyze the impact of PTS on survival among men with metastatic breast cancer. METHODS: A retrospective study was conducted of men diagnosed with metastatic breast cancer at diagnosis were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2011. Cox proportional hazards regression models were used to compare the differences in survival in men who did and did not undergo PTS. RESULTS: A total of 439 men with stage IV breast cancer at diagnosis were identified, of which 222 (51%) underwent PTS, 171 (77%) mastectomy, and 51 (23%) partial mastectomy. The median age was 65 years; 74% of participants were white, 51% had tumors <= T2, 65% had estrogen receptor (ER) positive tumor, and 24% had unknown ER status. Univariate analysis between the surgery and no-surgery arms showed that white race (P = .04), lower T stage and grade (P = .0003, P = .004), ER positivity (P = .0002), and later year of diagnosis (P < .0001) were associated with better survival. PTS was associated with improvement in median overall survival (29 vs. 11 months, P < .0001). On Cox regression analysis, ER negativity (hazard ratio = 2.08; 95% confidence interval, 1.41-3.01; P < .0003) and not undergoing PTS were associated with diminished survival (hazard ratio = 1.81; 95% confidence interval, 1.42-2.31; P < .0001). CONCLUSION: PTS among men with metastatic breast cancer was associated with improved survival in this retrospective analysis. PMID- 27998657 TI - The Relationship Between Polyethylene Wear and Periprosthetic Osteolysis in Total Hip Arthroplasty at 12 Years in a Randomized Controlled Trial Cohort. AB - BACKGROUND: Polyethylene acetabular components are common in hip arthroplasty. Highly cross-linked polyethylene (HXLPE) has lower wear than ultra-high molecular weight polyethylene (UHMWPE). Evidence suggests that wear particles induce inflammation causing periprosthetic osteolysis contributing to implant loosening with wear rates of 0.05 mm/y were considered safe. We aimed to compare incidence and volume of periacetabular osteolysis between HXLPE and UHMWPE using computed tomography. METHODS: Initially, 54 hips in 53 patients were randomized to HXLPE or UHMWPE acetabular liner. At 10 years, 39 hips in 38 patients remained for the radiostereometric analysis' demonstrating significantly lower wear in the HXLPE group. At 12 years, 14 hips in 13 patients were lost to follow-up leaving 25 hips for computed tomography assessment. Images were reconstructed to detect osteolysis and where identified, areas were segmented and volumized. RESULTS: Osteolysis was observed in 8 patients, 7 from the UHMWPE group and only 1 from the HXLPE group (Fisher exact, P = .042). There was no correlation between the amount of polyethylene wear and osteolysis volume; however, the radiostereometric analysis-measured wear rate in patients with osteolysis from both groups was significantly higher than overall average wear rate. CONCLUSION: This data demonstrates lower incidence of periacetabular osteolysis in the HXLPE group of a small cohort. Although numbers are too low to estimate causation, in the context of lower wear in the HXLPE group, this finding supports the hypothesis that HXLPE may not elevate osteolysis risk, and hence does not suggest that HXLPE wear particles are more biologically active than those generated by earlier generations of polyethylene. PMID- 27998658 TI - Authorship Trends in 30 Years of the Journal of Arthroplasty. AB - BACKGROUND: While various studies have investigated trends in characteristics of authors in other medical literature, no study has examined these characteristics in the field of arthroplasty. METHODS: A database was created of all articles published in The Journal of Arthroplasty in 1986, 1990, 1995, 2000, 2005, 2010, and 2015. Degree(s) of authors, number of authors, number of references, and region of institution were recorded. RESULTS: A total of 1343 original articles were assessed over the study period. There was a significant increase in the number of authors per publication from 3.45 in 1986 to 4.98 in 2015 (P < .001) and number of references per article from 17.36 to 29.76 (P < .001). There was a significant increase in proportion of first authors with a bachelor's degree (P = .001), MD/PhD (P < .001), and MD/MBA (P = .016), with a significant decrease in first authors with an MD degree only (P < .001). There was a significant increase in number of last authors with an MD/PhD (P = .001) and MD/MBA (P = .003). There has been a significant growth in papers from outside North America (P = .007), with a decrease in articles from the UK/Ireland (P = .003) and an increase in contributions from the Far East (P < .001). CONCLUSION: Trends of authorship characteristics in the arthroplasty literature largely mirror those seen in other medical literature including increased number of authors per article over time, changes in author qualifications, and increased contributions from international author groups. PMID- 27998660 TI - Prosthetic Dislocation and Revision After Primary Total Hip Arthroplasty in Lumbar Fusion Patients: A Propensity Score Matched-Pair Analysis. AB - BACKGROUND: Lumbar-pelvic fusion reduces the variation in pelvic tilt in functional situations by reducing lumbar spine flexibility, which is thought to be important in maintaining stability of a total hip arthroplasty (THA). We compared dislocation and revision rates for patients with lumbar fusion and subsequent THA to a matched comparison cohort with hip and spine degenerative changes undergoing only THA. METHODS: We identified patients in New York State who underwent primary elective lumbar fusion for degenerative disc disease pathology and subsequent THA between January 2005 and December 2012. A propensity score match was performed to compare 934 patients with prior lumbar fusion to 934 patients with only THA according to age, gender, race, Deyo comorbidity score, year of surgery, and surgeon volume. Revision and dislocation rates were assessed at 3, 6, and 12 months post-THA. RESULTS: At 12 months, patients with prior lumbar fusion had significantly increased rates of THA dislocation (control: 0.4%; fusion: 3.0%; P < .001) and revision (control: 0.9%; fusion: 3.9%; P < .001). At 12 months, fusion patients were 7.19 times more likely to dislocate their THA (P < .001) and 4.64 times more likely to undergo revision (P < .001). CONCLUSION: Patients undergoing lumbar fusion and subsequent THA have significantly higher risks of dislocation and revision of their hip arthroplasty than a matched cohort of patients with similar hip and spine pathology but only undergoing THA. During preoperative consultation for patients with prior lumbar fusion, orthopedic surgeons must educate the patient and family about the increased risk of dislocation and revision. PMID- 27998659 TI - Radiographic Imaging in the Postanesthesia Care Unit is Unnecessary After Partial Knee Arthroplasty. AB - BACKGROUND: Obtaining routine radiographs in the postanesthesia care unit (PACU) after primary uncomplicated partial knee arthroplasty (PKA) is a common practice with unclear utility. The objective of this study is to determine the rate at which immediate postoperative radiographs identify an actionable problem after primary uncomplicated PKA and to determine the potential cost savings associated with foregoing the routine acquisition of these radiographs. METHODS: This was a retrospective review that assessed a consecutive series of 1366 primary uncomplicated PKAs (including 873 unicondylar knee arthroplasties, 313 patellofemoral arthroplasties, and 180 bicompartmental knee arthroplasties) performed between January 2008 and March 2016. Patients were separated into 2 cohorts: (1) those who had PACU radiographs (n = 1184), and (2) those who did not (n = 182). Operative reports and clinical follow-up records at the initial postoperative visit were reviewed to determine whether patients underwent early reoperation based on radiographic findings. The direct cost of PACU radiographs was estimated to be $33.63 based on average global Medicare payments from our institution. RESULTS: The rate of reoperation because of radiographic findings in the PACU or at the first follow-up was 0% (95% confidence interval: 0.0%-0.027%). The estimated direct radiographic expenditure for our 1366 patient cohort was nearly $46,000. CONCLUSION: Routine immediate postoperative PACU radiographs after primary uncomplicated PKA have limited clinical utility. Therefore, delaying postoperative radiographs until the initial follow-up office visit would result in substantial cost-savings without compromising the quality of patient care. PMID- 27998661 TI - Exposure of the examiner to radiation during myelography versus radiculography and root block: A comparative study. AB - BACKGROUND: Exposure to radiation over many years prompts concerns regarding potential health-related effects, particularly the incidence of cataracts and the development of cancer. The purpose of this study was to examine and compare the exposure of the examiner to radiation during myelography versus radiculography and root block. METHODS: A total of 114 examinations were performed in our institute in the 6 months. Sixty-two examinations were performed during myelography in the first 3 months (MG group), while 52 were performed during radiculography and root block in the last 3 months (RB group). The examiner wore a torso protector, a neck protector, radiation protection gloves, and radiation protection glasses. Optically stimulated luminescence (OSL) dosimeter badges were placed on both the inside and the outside of each protector. The dosimeters were exchanged every month. Radiation doses (mSv) were measured as the integrated radiation quantity every month from the OSL dosimeters. The effective dose and the equivalent doses of hand, skin, and eyes were investigated. RESULTS: The mean equivalent doses were significantly lower outside the neck, torso, eye protectors, and inside the torso protector in the RB group than in the MG group. Conversely, the mean equivalent dose was significantly lower outside the hand protector in the MG group than in the RB group. The use of a neck protector significantly decreased the effective dose compared to the non-use of a neck protector in the RB group. CONCLUSIONS: The present study showed the standard radiation exposure to the examiner during myelography, radiculography, and root block. Receiving full protection including a neck protector and protection gloves is an easy and reliable means to reduce radiation exposure. PMID- 27998662 TI - A rare case of a flail tricuspid valve in a patient with pulmonary artery hypertension. PMID- 27998663 TI - Reconstruction with soft tissue free flaps for large defects after the resection of giant facial neurofibroma. AB - Giant facial neurofibroma leads to disfigurement and functional and neurological deficits. Surgical resection is the mainstay of treatment and poses a great challenge to the surgeon with regard to the restoration of the defects arising from tumour resection. The cases of three male and three female patients diagnosed with giant facial neurofibroma, who underwent radical resection and reconstruction with soft tissue free flaps between 2008 and 2015, were analyzed retrospectively. Clinical data including patient sex, age, preoperative embolization of the nutrient artery, volume of blood loss, type and size of flaps used for reconstruction, and complications were recorded. Three of the six patients underwent preoperative embolization of the nutrient artery. The average volume of blood loss was 2850ml. Reconstruction was performed with anterolateral thigh flaps in four patients and latissimus dorsi myocutaneous flaps in two patients. All free flap reconstructions were successful. Partial necrosis of the scalp and wound dehiscence occurred in one patient each. All complications were managed successfully. In conclusion, the soft tissue free flap is a good choice for the coverage of defects after giant facial neurofibroma resection. Multi disciplinary treatment should be strengthened to minimize the risks of complications, as well as improving quality of life. PMID- 27998664 TI - Short-term complications after surgically assisted rapid palatal expansion: a retrospective cohort study. AB - Surgically assisted rapid palatal expansion (SARPE) has been considered a safe procedure with minimal patient morbidity. The aim of this study was to identify short-term complications encountered after tooth-borne expansion with a standardized approach to inform surgeons and orthodontists of the patient risk. In this retrospective cohort study, 55 patients (35 female, 20 male) undergoing SARPE between January 2013 and December 2014 were evaluated. Twenty-eight patients developed one or more complications. Postoperative haemorrhage was seen in six patients. Sixteen patients presented with injury to the infraorbital nerve, five had dental complications, and four had severe postoperative pain. A prolonged hospital stay was necessary for six patients and additional surgery was required in two cases. It is concluded that the short-term complications after tooth-borne SARPE are generally mild; however, the number of complications encountered indicates that SARPE is not free of risk and should be preceded by careful patient selection and planning. PMID- 27998665 TI - A study to evaluate the reliability of using two-dimensional photographs, three dimensional images, and stereoscopic projected three-dimensional images for patient assessment. AB - Clinicians are accustomed to viewing conventional two-dimensional (2D) photographs and assume that viewing three-dimensional (3D) images is similar. Facial images captured in 3D are not viewed in true 3D; this may alter clinical judgement. The aim of this study was to evaluate the reliability of using conventional photographs, 3D images, and stereoscopic projected 3D images to rate the severity of the deformity in pre-surgical class III patients. Forty adult patients were recruited. Eight raters assessed facial height, symmetry, and profile using the three different viewing media and a 100-mm visual analogue scale (VAS), and appraised the most informative viewing medium. Inter-rater consistency was above good for all three media. Intra-rater reliability was not significantly different for rating facial height using 2D (P=0.704), symmetry using 3D (P=0.056), and profile using projected 3D (P=0.749). Using projected 3D for rating profile and symmetry resulted in significantly lower median VAS scores than either 3D or 2D images (all P<0.05). For 75% of the raters, stereoscopic 3D projection was the preferred method for rating. The reliability of assessing specific characteristics was dependent on the viewing medium. Clinicians should be aware that the visual information provided when viewing 3D images is not the same as when viewing 2D photographs, especially for facial depth, and this may change the clinical impression. PMID- 27998666 TI - Feasibility of CBCT-based proton dose calculation using a histogram-matching algorithm in proton beam therapy. AB - The aim of this study was to confirm On-Board Imager cone-beam computed tomography (CBCT) using the histogram-matching algorithm as a useful method for proton dose calculation. We studied one head and neck phantom, one pelvic phantom, and ten patients with head and neck cancer treated using intensity modulated radiation therapy (IMRT) and proton beam therapy. We modified Hounsfield unit (HU) values of CBCT and generated two modified CBCTs (mCBCT-RR, mCBCT-DIR) using the histogram-matching algorithm: modified CBCT with rigid registration (mCBCT-RR) and that with deformable image registration (mCBCT-DIR). Rigid and deformable image registration were applied to match the CBCT to planning CT. To evaluate the accuracy of the proton dose calculation, we compared dose differences in the dosimetric parameters (D2% and D98%) for clinical target volume (CTV) and planning target volume (PTV). We also evaluated the accuracy of the dosimetric parameters (Dmean and D2%) for some organs at risk, and compared the proton ranges (PR) between planning CT (reference) and CBCT or mCBCTs, and the gamma passing rates of CBCT and mCBCTs. For patients, the average dose and PR differences of mCBCTs were smaller than those of CBCT. Additionally, the average gamma passing rates of mCBCTs were larger than those of CBCT (e.g., 94.1+/-3.5% in mCBCT-DIR vs. 87.8+/-7.4% in CBCT). We evaluated the accuracy of the proton dose calculation in CBCT and mCBCTs for two phantoms and ten patients. Our results showed that HU modification using the histogram-matching algorithm could improve the accuracy of the proton dose calculation. PMID- 27998667 TI - Validity and reliability of a novel instrumented one-legged hop test in patients with knee injuries. AB - BACKGROUND: Conventional one-legged hop tests simply evaluate the total hop distance, thus neglecting important temporal and spatial parameters related to the strategy of execution, such as foot contact time. AIM: To examine the validity and reliability of an instrumented one-legged hop test, the "four hops, three contacts" (4H3C) test, in patients with knee injuries. METHODS: The 4H3C test consists of four consecutive one-legged hops, of which individual hop distance and foot contact time are recorded by a validated floor-based photocell system. We examined the test-retest reliability, discriminant validity (involved vs. uninvolved side) and convergent validity (relation with maximal voluntary strength) of consecutive hop distance and foot contact time parameters in 50 patients with unilateral knee injuries. RESULTS: Test-retest reliability was very high for hop distance (intraclass correlation coefficients: 0.91 to 0.97) and high for contact time variables (intraclass correlation coefficients: 0.75 to 0.88). The difference between the involved and the uninvolved side was significant for all hop distance and contact time parameters (p<0.05). Maximal voluntary strength was correlated to both hop distance (r=0.67; p<0.001) and contact time (r=-0.42; p<0.01) variables. CONCLUSION: The 4H3C is a valid and reliable test for the evaluation of single hops in patients with knee injuries and may be useful in sport and clinical settings. The interpretation of foot contact time data requires however some caution. PMID- 27998668 TI - [Peculiarities of the transesophageal echocardiography in octogenarian patients]. AB - The growing trend in the absolute and relative number of elderly in the population scheme, the increasing prevalence of heart disease as people get older and the impressive technological development of ultrasound devices have all together recently contributed to promote an increasing number of transesophageal echocardiograms in older patients, however, the already published information about the distinguishing features of this diagnostic methodology in elderly patients is still scarce and seems to be insufficient. This review focuses on the already published methodological and diagnostic features related to the transesophageal echocardiography in the octogenarian -or even older patient- in order to show them in an orderly and systematic manner to provide elements that induce useful clinical criteria for the physician who attends patients in this age group in whom this diagnostic modality is now increasingly requested. PMID- 27998669 TI - Global vision system in laparoscopy. AB - OBJECTIVE: The main difficulty in laparoscopic or robot-assisted surgery is the narrow visual field, restricted by the endoscope's access port. This restriction is coupled with the difficulty of handling the instruments, which is due not only to the access port but also to the loss of depth of field and perspective due to the lack of natural lighting. In this article, we describe a global vision system and report on our initial experience in a porcine model. MATERIAL AND METHODS: The global vision system consists of a series of intraabdominal devices, which increase the visual field and help recover perspective through the simulation of natural shadows. These devices are a series of high-definition cameras and LED lights, which are inserted and fixed to the wall using magnets. The system's efficacy was assessed in a varicocelectomy and nephrectomy. RESULTS: The various intraabdominal cameras offer a greater number of intuitive points of view of the surgical field compared with the conventional telescope and appear to provide a similar view as that in open surgery. Areas previously inaccessible to the standard telescope can now be reached. The additional light sources create shadows that increase the perspective of the surgical field. CONCLUSION: This system appears to increase the possibilities for laparoscopic or robot-assisted surgery because it offers an instant view of almost the entire abdomen, enabling more complex procedures, which currently require an open pathway. PMID- 27998670 TI - Improvement of 1,3-propanediol production using an engineered cyanobacterium, Synechococcus elongatus by optimization of the gene expression level of a synthetic metabolic pathway and production conditions. AB - The introduction of a synthetic metabolic pathway consisting of multiple genes derived from various organisms enables cyanobacteria to directly produce valuable chemicals from carbon dioxide. We previously constructed a synthetic metabolic pathway composed of genes from Escherichia coli, Saccharomyces cerevisiae, and Klebsiella pneumoniae. This pathway enabled 1,3-propanediol (1,3-PDO) production from cellular DHAP via glycerol in the cyanobacterium, Synechococcus elongatus PCC 7942. The production of 1,3-PDO (3.79mM, 0.29g/l) directly from carbon dioxide by engineered S. elongatus PCC 7942 was successfully accomplished. However, the constructed strain accumulated a remarkable amount of glycerol (12.6mM, 1.16g/l), an intermediate metabolite in 1,3-PDO production. Notably, enhancement of latter reactions of synthetic metabolic pathway for conversion of glycerol to 1,3-PDO increases 1,3-PDO production. In this study, we aimed to increase the observed 1,3-PDO production titer. First, the weaker S. elongatus PCC 7942 promoter, PLlacO1, was replaced with a stronger promoter (Ptrc) to regulate genes involved in the conversion of glycerol to 1,3-PDO. Second, the induction timing for gene expression and medium composition were optimized. Promoter replacement resulted in higher 1,3-PDO production than glycerol accumulation, and the amount of products (1,3-PDO and glycerol) generated via the synthetic metabolic pathway increased with optimization of medium composition. Accordingly, we achieved the highest titer of 1,3-PDO (16.1mM, 1.22g/l) and this was higher than glycerol accumulation (9.46mM, 0.87g/l). The improved titer was over 4-fold higher than that of our previous study. PMID- 27998671 TI - Synthesis, physicochemical and biological studies of technetium-99m labeled tacrine derivative as a diagnostic tool for evaluation of cholinesterase level. AB - In the present work the synthesis and physicochemical investigations of new tacrine analogues labeled with technetium-99m are reported. All obtained novel radioconjugates showed high stability in the presence of an excess of standard amino acids cysteine or histidine, as well as in human serum. Lipophilicity (LogD values) of these compounds is within the range from 0.92 to 1.56. For the selected radioconjugate 99mTc(NS3)(CN-NH(CH2)7Tac) (LogD=1.56) the biological activity studies in the course of inhibition of acetylcholinesterase action have been performed (IC50=45.0nM, estimated by means of Ellman's method). Biodistribution studies of this compound showed its uptake in brain on the level of 0.07%ID/g and its clearance through the hepatic and renal route in comparable degree. The ascertained presence of the radioconjugate in brain indicates its possibility to cross the blood-brain barrier. Molecular modeling of 99mTc(NS3)(CN NH(CH2)7Tac) radioconjugate showed that the main structural fragment is tacrine moiety which is responsible for most interactions within catalytic and peripheral active sites and provides the anti-acetylcholinesterase activity. The 99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate may be considered to be a diagnostic tool for patients suffering from Alzheimer's disease as well as a marker to determine the physiological condition of liver and intestines. PMID- 27998672 TI - Quantitation of bleeding symptoms in a national registry of patients with inherited platelet disorders. AB - BACKGROUND: Inherited platelet deficiency and/or dysfunction may be more common in the general population than has previously been appreciated. In 2013 the Israeli Inherited Platelet Disorder (IPD) Registry was established. METHODS: Clinical and laboratory data were collected to pre-specified registration forms. The study protocol was approved by the local hospital ethics committees. RESULTS: To date we have included in the registry 89 patients (male 52%) from 79 families. Most patients (74%) have a not-yet specified inherited thrombocytopenia (n=39) or non-specific platelet function disorder (n=27). Full clinical data were available for 81 (91%) patients. The median (range) age at presentation and time of follow up were 1.8years (1day-17.8years) and 4.7 (0-26) years, respectively. The Pediatric Bleeding Questionnaire was available for 78patients; abnormal bleeding score (>=2) was recorded in 47 (52.8%, 95% CI 42%-63.5%) patients and was less frequent in patients followed for isolated thrombocytopenia. Abnormal score was associated with a longer time of follow-up, OR 1.19 (95% CI 1.04-1.36). CONCLUSION: Long term follow-up of patients with IPDs is important as bleeding risks may increase with time. We expect that clinical and laboratory information of patients/families with IPDs gathered in a systemic format will allow for better diagnosis and treatment of these patients. PMID- 27998673 TI - Production of recombinant human epidermal growth factor in Pichia pastoris. AB - This study was carried out to express human epidermal growth factor (hEGF) in Pichia pastoris GS115. For this aim, the hEGF gene was cloned into the pPIC9K expression vector, and then integrated into P. pastoris by electroporation. ELISA based assay showed that the amount of hEGF secreted into the medium can be affected by the fermentation conditions especially by culture medium, pH and temperature. The best medium for the optimal hEGF production was BMMY buffered at a pH range of 6.0 and 7.0. The highest amount of hEGF with an average yield of 2.27MUg/mL was obtained through an induction of the culture with 0.5% (v/v) methanol for 60h. The artificial neural network (ANN) analysis revealed that changes in both pH and temperature significantly affected the hEGF production with the pH change had slightly higher impact on hEGF production than variations in the temperature. PMID- 27998674 TI - Modified Carba NP test for the detection of carbapenemase production in gram negative rods: optimized handling of multiple samples. AB - The modified Carba NP test presented here may be a valuable tool for laboratories interested in investigating a large number of carbapenemase-producing bacteria in a less-costly way. The test was evaluated against 48 carbapenemase-producing and carbapenemase-non-producing gram-negative bacteria. No false-positive results were obtained, but false-negative results were observed with OXA-23- and GES carbapenemase-producing isolates. Aeromonas sp. are not testable by Modified Carba NP. PMID- 27998675 TI - Occurrence of brominated diphenyl ethers, dibenzo-p-dioxins and dibenzofurans in foam materials in scrapped car seats from 1985 to 2012. AB - The purpose of this study was to evaluate the occurrence of polybrominated diphenyl ethers (PBDEs), dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs) in polyurethane foam (PUF) from car seats of end-of-life vehicles (ELVs) and compare the concentrations of PBDEs with the stipulated regulations in the POP Directive. The method comprised screening by X-ray fluorescence (XRF) and GG-MS analysis. Of 59 tested samples from ELVs, 17 samples showed lines above limit of detection (LOD) levels when screening by XRF. Those samples were selected as replicates and for further analysis by GC-MS. The majority of the studied samples showed low or non-detectable concentrations of PBDEs and PBDD/Fs, but two samples showed concentrations of Sigma Te-HpBDEs close to the regulated level for Te-HpBDEs in waste (1000mgkg-1); one was slightly higher (1390mgkg-1) and the other slightly lower (570mgkg-1). It was concluded that brominated pollutants such as Te-HpBDEs occur in low levels in automotive applications in scrapped cars produced in years when brominated flame retardants were used. However, two of the 59 samples tested showed levels close to those stipulated by regulations concerning POPs in waste. PMID- 27998676 TI - Field study and theoretical evidence for the profiles and underlying mechanisms of PCDD/F formation in cement kilns co-incinerating municipal solid waste and sewage sludge. AB - A field study and theoretical calculations on the profile and formation mechanism of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) from two cement kilns co-incinerating municipal solid waste and sewage sludge were performed, and the PCDFs were mainly focused. The back-end areas of the cement kilns were identified to be the major sites of PCDD/F formation according to their distributions in particulate samples from different process stages. The proportions of tetra- to hexa-chlorinated dibenzofurans (?Cl4-6CDFs) at the kiln back-end areas were in the range of 50-80% of the total PCDD/Fs in mass concentrations and 62-87% in toxic equivalent concentrations. These results indicated that ?Cl4-6CDFs are the dominant homologs that should be the focus for reducing PCDD/F emissions in cement kilns that co-incinerate municipal solid waste and sewage sludge. It is speculated that the low contents of oxygen and copper compounds, as well as the alkaline conditions, may contribute to the dominance of ?Cl4-6CDFs in the PCDD/Fs formed. Chlorination was assumed to be the mechanism of formation of PCDFs. The results from model predictions and thermodynamic calculations used to test this assumption were consistent with the PCDF profiles observed from the field study. PMID- 27998677 TI - Clinically localized prostate cancer in 2017: A review of comparative effectiveness. AB - Introducing the topic of comparative effectiveness for prostate cancer treatments with a reminder of the disease's heterogeneity risks tautology. However, the profound variation both in this cancer's biology and its clinical course is increasingly widely recognized, while management alternatives for clinically localized prostate cancer have exploded. Available options now include active surveillance, multiple surgical approaches to prostatectomy, various forms of external-beam and interstitial radiation, and a growing list of energy ablative technologies. Each treatment option has its own efficacy rate as well as its own set of complications, side effects and financial costs. Difficulties comparing these options, together with the high prevalence of the disease, led the Institute of Medicine to include localized prostate cancer among the top 25 priority conditions for future comparative effectiveness research. The sheer volume of possible treatment options, with their individual risks and benefits, can be confusing for patients and clinicians to research, understand and explain. To help clinicians navigate these treatment options, we have assembled this Urologic Oncology Seminar on the comparative effectiveness of treatments for clinically localized prostate cancer. The articles focus on high quality evidence based medicine and most have included useful tables summarizing seminal trials and available resources. PMID- 27998678 TI - Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates. AB - The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1MUM) led to the most potent compound 27 (IC50: 0.038MUM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180 degrees flip for the triazolo[1,5-a]pyrimdine bicyclic template. PMID- 27998679 TI - Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIalpha. AB - A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4 dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIalpha. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ~5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIalpha in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIalpha, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons. PMID- 27998680 TI - Free flap surgery in the elderly: Experience with 110 cases aged >=70 years. AB - We report our experience with free tissue transfer in the elderly based on a retrospective review of patients aged >=70 years who underwent surgery during a 7 year period. A total of 110 free tissue transfers in 104 patients, with a mean age of 78 years (range: 70-92 years), were identified for inclusion. The demographic and operative variables and postoperative medical and surgical complications were analyzed. Sixty-four of the 110 procedures encountered at least one complication. Medical complications were observed in 25 cases and were predominantly pulmonary, whereas surgical complications occurred in 54 cases in addition to one perioperative death. Successful free tissue transfer was achieved in 105 of the 110 flaps. There was no statistically significant difference in the rate of postoperative complications between patients aged 70-79 years and those aged >=80 years. Anesthetic time was a statistically significant predictor of postoperative medical complications (odds ratio 1.345, 95% confidence interval 1.117-1.663, P = 0.001). Preoperative comorbidity status, graded according to the ACE-27 index, was a statistically significant predictor of flap recipient site complications. Free tissue transfer may be performed in aging patients with a high degree of technical success and low operative mortality. Chronological age alone should not be used as a criterion when evaluating a patient for free tissue transfer. The patient's premorbid status should be carefully assessed. To minimize postoperative medical complications, duration of general anesthesia should be kept to a minimum. PMID- 27998681 TI - Prognostic Importance of Low Admission Serum Creatinine Concentration for Mortality in Hospitalized Patients. AB - OBJECTIVE: The study objective was to assess the association between low serum creatinine value at admission and in-hospital mortality in hospitalized patients. METHODS: This was a retrospective single-center cohort study conducted at a tertiary referral hospital. All hospitalized adult patients between 2011 and 2013 who had an admission creatinine value available were identified for inclusion in this study. Admission creatinine value was categorized into 7 groups: <=0.4, 0.5 to 0.6, 0.7 to 0.8, 0.9 to 1.0, 1.1 to 1.2, 1.3 to 1.4, and >=1.5 mg/dL. The primary outcome was in-hospital mortality. Logistic regression analysis was performed to obtain the odds ratio of in-hospital mortality for the various admission creatinine levels, using a creatinine value of 0.7 to 0.8 mg/dL as the reference group in the analysis of all patients and female patients and of 0.9 to 1.0 mg/dL in the analysis of male patients because it was associated with the lowest in-hospital mortality. RESULTS: Of 73,994 included patients, 973 (1.3%) died in the hospital. The association between different categories of admission creatinine value and in-hospital mortality assumed a U-shaped distribution, with both low and high creatinine values associated with higher in-hospital mortality. After adjustment for age, sex, ethnicity, principal diagnosis, and comorbid conditions, very low creatinine value (<=0.4 mg/dL) was significantly associated with increased mortality (odds ratio, 3.29; 95% confidence interval, 2.08-5.00), exceeding the risk related to a markedly increased creatinine value of >=1.5 mg/dL (odds ratio, 2.56; 95% confidence interval, 2.07-3.17). The association remained significant in the subgroup analysis of male and female patients. CONCLUSIONS: Low creatinine value at admission is independently associated with increased in-hospital mortality in hospitalized patients. PMID- 27998682 TI - Telemedicine Specialty Support Promotes Hepatitis C Treatment by Primary Care Providers in the Department of Veterans Affairs. AB - BACKGROUND: The Department of Veterans Affairs is the largest US provider of hepatitis C treatment. Although antiviral regimens are becoming simpler, hepatitis C antivirals are not typically prescribed by primary care providers. The Veterans Affairs Extension for Community Health Outcomes (VA-ECHO) program was launched to promote primary care-based hepatitis C treatment using videoconferencing-based specialist support. We aimed to assess whether primary care provider participation in VA-ECHO was associated with hepatitis C treatment and sustained virologic response. METHODS: We identified 4173 primary care providers (n = 152 sites) responsible for 38,753 patients with chronic hepatitis C infection. A total of 6431 patients had a primary care provider participating in VA-ECHO; 32,322 patients had an unexposed primary care provider. Exposure was modeled as a patient-level time-varying covariate. Patients became exposed after primary care provider participation in >=1 VA-ECHO session. Multivariable Cox proportional hazards frailty modeling assessed the association between VA-ECHO exposure and hepatitis C treatment. Among treated patients, modified Poisson regression assessed the relationship between exposure and sustained virologic response. RESULTS: After adjustment, exposed patients received significantly higher rates of antiviral treatment compared with unexposed patients (adjusted hazard ratio, 1.20; 95% confidence interval, 1.10-1.32; P <.01). The rate of primary care provider-initiated antiviral medication was 21.4% among treated patients reviewed on VA-ECHO teleconferences compared with 2.5% among unexposed patients (P <.01). No difference in adjusted rates of sustained virologic response was observed for patients with exposed primary care providers (P = .32), with similar crude rates for primary care providers versus specialists. CONCLUSIONS: National implementation of VA-ECHO was positively associated with hepatitis C treatment initiation by primary care providers, without differences in sustained virologic response. PMID- 27998683 TI - Effect of positional isomerism and vanadium substitution on 51V magic angle spinning NMR Spectra Of Wells-Dawson polyoxotungstates. AB - We examined the positional isomerism and vanadium substitution on the 51V magic angle spinning NMR spectra of potassium salts of vanadium-substituted polyoxotungstates of the Wells-Dawson series. NMR parameters of this class of catalytically active polyoxotungstates effect of are reported. Multiple species, indicative of differences in the local environment at the substitution sites, are observed in solid-state NMR spectra of the di- and tri- substituted complexes in contrast to solution NMR spectra, where single average chemical shift was observed. The quadrupolar and chemical shift anisotropy parameters depend strongly on the position and the degree of the vanadium substitution into the oxoanion core establishing 51V SATRAS NMR spectroscopy as a sensitive probe of the local electronic environment in these catalytically active solids. PMID- 27998684 TI - The First Trial-When Will We Examine the Effect of Duty Hours on Resident Burnout? PMID- 27998685 TI - Comprehensive Clinical Implementation of DICOM Structured Reporting Across a Radiology Ultrasound Practice: Lessons Learned. PMID- 27998686 TI - Social Determinants and Health Disparities Associated With Outcomes of Women of Childbearing Age Who Receive Public Health Nurse Home Visiting Services. AB - OBJECTIVE: To examine the associations between social and behavioral determinants of health (SBDH), health disparities, and the outcomes of women who received public health nurse home visits for pregnancy and parenting support. DESIGN: Observational exploratory data analysis and comparative outcome evaluation. SETTING: An extant dataset from women served in a Midwestern U.S. state, including demographics and Omaha System problems, signs/symptoms, interventions, and outcome assessments. PARTICIPANTS: Women (N = 4,263) with an average age of 23.6 years (SD = 6.1); 21.4% were married, and 39.1% were White. METHODS: An evaluation dataset was constructed that included all women of childbearing age, their demographics, and outcome assessments. A summative SBDH Index based on Institute of Medicine-recommended instruments was computed based on sign/symptom data. Visualizations were developed using Microsoft Excel, and outcome significance statistics were computed using SPSS version 22 and SAS version 9.4. RESULTS: Outcome evaluation showed positive, significant changes from baseline after public health nurse intervention. Visualization showed variable concentrations of problem-specific signs/symptoms by SBDH Index subgroups. There were between-group differences in overall outcome attainment across SBDH Index subgroups. Compared with White women, minority women had greater improvement; however, despite these gains overall minority final ratings were lower. CONCLUSION: An informatics approach showed that SBDH are important factors for understanding a comprehensive and holistic view of health and health care outcomes. There is potential to use large datasets to further explore intervention effectiveness and progress toward health equity related to SBDH. PMID- 27998687 TI - Effects of applied stress ratio on the fatigue behavior of additively manufactured porous biomaterials under compressive loading. AB - Additively manufactured (AM) porous metallic biomaterials are considered promising candidates for bone substitution. In particular, AM porous titanium can be designed to exhibit mechanical properties similar to bone. There is some experimental data available in the literature regarding the fatigue behavior of AM porous titanium, but the effect of stress ratio on the fatigue behavior of those materials has not been studied before. In this paper, we study the effect of applied stress ratio on the compression-compression fatigue behavior of selective laser melted porous titanium (Ti-6Al-4V) based on the diamond unit cell. The porous titanium biomaterial is treated as a meta-material in the context of this work, meaning that R-ratios are calculated based on the applied stresses acting on a homogenized volume. After morphological characterization using micro computed tomography and quasi-static mechanical testing, the porous structures were tested under cyclic loading using five different stress ratios, i.e. R = 0.1, 0.3, 0.5, 0.7 and 0.8, to determine their S-N curves. Feature tracking algorithms were used for full-field deformation measurements during the fatigue tests. It was observed that the S-N curves of the porous structures shift upwards as the stress ratio increases. The stress amplitude was the most important factor determining the fatigue life. Constant fatigue life diagrams were constructed and compared with similar diagrams for bulk Ti-6Al-4V. Contrary to the bulk material, there was limited dependency of the constant life diagrams to mean stress. The notches present in the AM biomaterials were the sites of crack initiation. This observation and other evidence suggest that the notches created by the AM process cause the insensitivity of the fatigue life diagrams to mean stress. Feature tracking algorithms visualized the deformation during fatigue tests and demonstrated the root cause of inclined (45 degrees ) planes of specimen failure. In conclusion, the R-ratio behavior of AM porous biomaterials is both quantitatively and qualitatively different from that of bulk materials. PMID- 27998688 TI - Follow-up Electrocardiograms in a Patient With Incarcerated Bowel-Triggered Takotsubo Syndrome Complicated by Cardiogenic Shock. PMID- 27998690 TI - Preeclampsia and Preterm Birth Associated With Visceral Adiposity in Early Pregnancy. AB - OBJECTIVE: To determine if an increasing amount of visceral adipose tissue, measured by ultrasound in early pregnancy, is associated with a higher risk of preeclampsia and preterm birth (PTB). METHODS: We completed a prospective cohort study of 463 pregnant women. Maternal visceral adiposity tissue (VAT) depth was measured by ultrasound at 11 to 14 weeks' gestation. Relative risks (RR) were adjusted for age, parity, chronic hypertension, pre-pregnancy BMI, and use of acetylsalicylic acid. RESULTS: The rate of preeclampsia was much higher at quintile (Q) 5 of VAT depth (9.8%) than at Q1 to Q4 (1.6%) but not significantly so in the adjusted model (RR 3.39, 95% CI 0.86 to 13.39). The adjusted RR of PTB was significantly elevated at Q5 VAT depth (6.53, 95% CI 1.47 to 6.53), as was preeclampsia with PTB (16.91, 95% CI 1.24 to 231.07). CONCLUSION: Higher amounts of VAT in pregnancy may play a direct role in the pathogenesis of preeclampsia, including early onset preeclampsia necessitating preterm delivery. PMID- 27998689 TI - Plasma membrane organization and dynamics is probe and cell line dependent. AB - The action and interaction of membrane receptor proteins take place within the plasma membrane. The plasma membrane, however, is not a passive matrix. It rather takes an active role and regulates receptor distribution and function by its composition and the interaction of its lipid components with embedded and surrounding proteins. Furthermore, it is not a homogenous fluid but contains lipid and protein domains of various sizes and characteristic lifetimes which are important in regulating receptor function and signaling. The precise lateral organization of the plasma membrane, the differences between the inner and outer leaflet, and the influence of the cytoskeleton are still debated. Furthermore, there is a lack of comparisons of the organization and dynamics of the plasma membrane of different cell types. Therefore, we used four different specific membrane markers to test the lateral organization, the differences between the inner and outer membrane leaflet, and the influence of the cytoskeleton of up to five different cell lines, including Chinese hamster ovary (CHO-K1), Human cervical carcinoma (HeLa), neuroblastoma (SH-SY5Y), fibroblast (WI-38) and rat basophilic leukemia (RBL-2H3) cells by Imaging Total Internal Reflection (ITIR) Fluorescence Correlation Spectroscopy (FCS). We measure diffusion in the temperature range of 298-310K to measure the Arrhenius activation energy (EArr) of diffusion and apply the FCS diffusion law to obtain information on the spatial organization of the probe molecules on the various cell membranes. Our results show clear differences of the FCS diffusion law and EArr for the different probes in dependence of their localization. These differences are similar in the outer and inner leaflet of the membrane. However, these values can differ significantly between different cell lines raising the question how molecular plasma membrane events measured in different cell lines can be compared. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova. PMID- 27998691 TI - Influence of the skin barrier on the penetration of topically-applied dexamethasone probed by soft X-ray spectromicroscopy. AB - The penetration of dexamethasone into human skin ex vivo is reported. X-ray microscopy is used for label-free probing of the drug and quantification of the local drug concentration with a spatial resolution reaching 70+/-5nm. This is accomplished by selective probing the dexamethasone by X-ray absorption. Varying the penetration time between 10min and 1000min provides detailed information on the penetration process. In addition, the stratum corneum has been damaged by tape-stripping in order to determine the importance of this barrier regarding temporally resolved drug penetration profiles. Dexamethasone concentrations distinctly vary, especially close to the border of the stratum corneum and the viable epidermis, where a local minimum in drug concentration is observed. Furthermore, near the basal membrane the drug concentration strongly drops. High spatial resolution studies along with a de-convolution procedure reveal the spatial distribution of dexamethasone in the interspaces between the corneocytes consisting of stratum corneum lipids. These results on local drug concentrations are interpreted in terms of barriers affecting the drug penetration in human skin. PMID- 27998692 TI - Squill Oxymel, a traditional formulation from Drimia Maritima (L.) Stearn, as an add-on treatment in patients with moderate to severe persistent asthma: A pilot, triple-blind, randomized clinical trial. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Iranian Medicine (TIM), Squill (Drimia maritima (L.) Stearn) Oxymel was utilized in the treatment of asthma. Squill has been reported to exert anti-inflammatory, anti-oxidant, anti cholinergic, and mucus secretion modulating effects. OBJECTIVE: This study aimed to make a preliminary evaluation of the efficacy and safety of an add-on Squill Oxymel treatment in patients with moderate to severe persistent asthma. METHODS: In a 6-week, triple-blind, randomized, placebo-controlled trial, 60 patients with stable moderate to severe persistent asthma were randomly allocated to receive either 10ml syrup of Squill Oxymel, simple oxymel, or a placebo 2 times a day, as an add-on to their routine treatment (inhaled corticosteroids and beta2 agonists). Spirometry and plethysmography were performed on patients to evaluate the effect of the treatment at baseline and end of intervention. Forced Expiratory Volume in first second (FEV1) was considered the primary outcome. St. George's respiratory questionnaire (SGRQ) was also used for the subjective evaluation of patients' responses. RESULTS: Fifty-four patients completed the study. The results showed significant improvement in spirometry parameters, especially FEV1 (1.54+/-.38 vs. 2.11+/-.49l), in the Squill Oxymel group compared with the other groups. The increases in FEV1 liter, FEV1%, FEV1/FVC%, and MEF 25 75% during the intervention were significantly higher in the Squill Oxymel group than in the other groups (p<.001). However, the improvement of plethysmographic parameters showed no significant difference between the study groups (p>.05). The SGRQ scores (symptoms, activity, and total score) were significantly improved after intervention in both the Squill Oxymel and the simple honey oxymel groups (p<.001), but not in the placebo group. Nausea and vomiting was reported in 5 patients in Squill oxymel and simple oxymel groups. No other serious adverse event was observed. CONCLUSIONS: The results of the current study show preliminary evidence for the efficacy and safety of the add-on treatment of Squill Oxymel in patients with moderate to severe persistent asthma. PMID- 27998693 TI - Perceptions of the Healthfulness of Foods of New Zealand Adults Living With Prediabetes and Type 2 Diabetes: A Pilot Study. AB - OBJECTIVE: To investigate dietary perceptions of adults with prediabetes and type 2 diabetes. METHODS: Three discussion groups (n = 12) were conducted to investigate how participants source dietary information and evaluate the healthfulness of foods. Participants were men and women with prediabetes or type 2 diabetes. White board notes were photographed and audio recordings transcribed. Codes were applied and themes generated using an inductive approach. RESULTS: Four themes emerged: (1) perception of food components, (2) factors perceived to influence the healthfulness of foods, (3) perceptions of dietary information, and (4) challenges to forming accurate perceptions. Participants perceived the healthfulness of food to be influenced largely by carbohydrates, fat, and sugar. CONCLUSIONS AND IMPLICATIONS: Perception of the healthfulness of food varied among participants and at times was contrary to dietary guidelines. Participants were wary of dietary advice and sought consistent, reliable, and up-to-date sources of information to guide food choices. PMID- 27998694 TI - Securing a Stop to the Summer Setback: Policy Considerations in the Future Expansion of the Summer Electronic Benefit Transfer for Children. AB - The Summer Electronic Benefits Transfer for Children (SEBTC) has been proposed as a solution to address the problem of child food security during the summer. Initial SEBTC findings from a demonstration project show promise and the federal government has approved substantial funding for its continuation. This report reviews empirical assessments of SEBTC and Electronic Benefits Transfer research, and presents policy considerations in the program's future expansion. PMID- 27998695 TI - Influence of Label Design on Children's Perception of 2 Snack Foods. AB - OBJECTIVE: To evaluate the influence of label design on children's perception of 2 popular snack foods across 3 income levels. DESIGN: Labels of 2 snack products (yogurt and sponge cake) were designed using a fractional factorial design with 3 2-level variables: cartoon character, nutrition claims, and front-of-package nutritional information. PARTICIPANTS: A total of 221 children (aged 9-13 years) from Montevideo, Uruguay, with different income levels, participated in the study. MAIN OUTCOME MEASURES: Children's attitude toward and liking of 2 food products. RESULTS: Low-income children showed a more positive attitude toward the products than did middle- and high-income children. The inclusion of a cartoon character in sponge cake labels significantly affected hedonic expectations regardless of income. Middle- and high-income children tended to use the term funny more frequently and the term boring less frequently to describe labels that included the cartoon character, compared with those that did not. CONCLUSIONS AND IMPLICATIONS: Results showed that the inclusion of cartoon characters on food labels is associated with fun. Low-income children seem more susceptible to the marketing strategies of food companies than do middle- and high-income children. PMID- 27998696 TI - Food Insecurity Experience: Building Empathy in Future Food and Nutrition Professionals. AB - OBJECTIVE: To assess changes in empathy in students completing a food insecurity experience. DESIGN: Mixed methods; quantitative data from survey in years 1 and 2; qualitative data extracted from students' workbooks in years 2-5. This study was conducted over 10 weeks annually for 5 years. SETTING: Northwest US land grant university. PARTICIPANTS: Students enrolled in a community nutrition course who chose to complete the food insecurity exercise. Total included 58 students in quantitative analysis in years 1 and 2 and 119 in qualitative analysis, years 2 5. INTERVENTION(S): The intervention was a food insecurity experience in which participants spent no more than $3/d on food for 5 days ($15 total) while striving for a nutritious diet and reflecting on their experience. MAIN OUTCOME MEASURES: Empathy scores measured by Likert scales; participant responses and reflections recorded in workbook journals. ANALYSIS: Comparison of means across time using paired t tests (P < .05); coding and sorting themes from workbook journals. RESULTS: Quantitative findings indicated that both classroom content and experiential exercises were important for enhancing empathy about food insecurity. Empathy scores increased from time I to time II and from time I to time III. Qualitative reflections among participants included terms such as guilt, empathy, compassion, and raised consciousness about food insecurity. CONCLUSIONS AND IMPLICATIONS: Experiential and transformational learning to develop empathy can take place in a 5-day food insecurity experience during a typical university-level community nutrition course. This intervention can be tested for applications in other contexts. PMID- 27998697 TI - The choroid plexus as a sex hormone target: Functional implications. AB - The choroid plexuses (CPs) are highly vascularized branched structures that protrude into the ventricles of the brain, and form a unique interface between the blood and the cerebrospinal fluid (CSF). In recent years, novel functions have been attributed to this tissue such as in immune and chemical surveillance of the central nervous system, brain development, adult neurogenesis and circadian rhythm regulation. Sex hormones (SH) are widely recognized as modulators in several neurodegenerative diseases, and there is evidence that estrogens and androgens regulate several fundamental biological functions in the CPs. Therefore, SH are likely to affect the composition of the CSF impacting on brain homeostasis. This review will look at implications of the CPs' sex-related specificities. PMID- 27998699 TI - Effect of a Prior History of Overweight on Return of Menses in Adolescents With Eating Disorders. AB - PURPOSE: The purpose of this study was to determine whether a history of overweight, weight suppression, and weight gain during treatment have an effect on return of menses (ROM) in adolescents with eating disorders (EDs). METHODS: Retrospective chart review of female adolescents presenting to an ED program from January 2007 to June 2009. RESULTS: One hundred sixty-three participants (mean age, 16.6 +/- 2.1 years) met eligibility criteria. The mean median body mass index percent at ROM for those previously overweight was 106.1 +/- 11.7 versus 94.2 +/- 8.9 for those not previously overweight (p < .001). Both groups needed to gain weight for ROM. Greater weight suppression (odds ratio, 0.90; 95% confidence interval, 0.84-0.98; p = .013) was associated with lower likelihood of ROM, and greater weight gain during treatment (odds ratio, 1.20; 95% confidence interval, 1.07-1.36; p = .002) was associated with higher likelihood of ROM in those not previously overweight. CONCLUSIONS: Previously overweight amenorrheic patients with EDs needed to be at a higher median body mass index percent for ROM compared to those who were not previously overweight. PMID- 27998698 TI - Ocular Complications in Survivors of the Ebola Outbreak in Guinea. AB - PURPOSE: The Ebola outbreak of 2013-2016 severely affected West Africa and resulted in 2544 deaths and 1270 survivors in Guinea, the country where it began. This Ebola virus was the Zaire strain of the virus family Filoviridae. In this outbreak the case fatality rate was about 67%. The survivors, declared cured after 2 negative blood polymerase chain reaction (PCR) results, face psychosocial disorders and rheumatic, ear-nose-throat, neurocognitive, and ophthalmologic complications. The goal of this study was to detect and describe ocular complications afflicting these survivors and to observe their occurrence and recurrences. DESIGN: Prospective observational cohort study. METHODS: This prospective observational multicenter cohort study was initiated in March 2015. The cohort study included 341 survivors followed up in the infectious disease ward of Conakry, Forecariah, and Nzerekore as of May 2016. The patients received multidisciplinary medical follow-up expected to last at least 1 year that included an eye examination as part of complete, free treatment. RESULTS: Systematic examination of 341 patients revealed 46 cases of uveitis (13.5%), 6 cases of episcleritis (1.8%), and 3 cases of interstitial keratitis (0.9%). Uveitis was most frequently unilateral (78.3%) and anterior (47.8%) and occurred within the 2 months after discharge from the Ebola treatment center. Moreover, uveitis relapses were found up to 13 months after the negative PCR result for Ebola in the blood. CONCLUSION: Nearly 1 out of 6 survivors presented ocular disorders after discharge from the Ebola treatment center. An ophthalmologic follow-up for Ebola-infected patients should start, if possible, during the acute phase of the disease and last more than 1 year. Treatment guidelines need to be urgently developed and implemented. PMID- 27998700 TI - Adolescence Is a Sensitive Period for Housing Mobility to Influence Risky Behaviors: An Experimental Design. AB - PURPOSE: Test whether neighborhood mobility effects on adolescent risky behaviors varies at different developmental ages and gender. METHODS: The Moving to Opportunity (MTO) study randomly assigned volunteer families (1994-1997) to receive a Section 8 voucher to move to lower poverty neighborhoods versus a public housing control group. We tested three-way treatment, gender, and age-at randomization interactions using intent-to-treat linear regression predicting a risky behavior index (RBI; measured in 2002, N = 2,829), defined as the fraction of 10 behaviors the youth reported (six measuring risky substance use [RSU], four measuring risky sexual behavior), and the RSU and risky sexual behavior subscales. RESULTS: The treatment main effect on RBI was nonsignificant for girls (B = -.01, 95% confidence interval -.024 to .014) and harmful for boys (B = .03, 95% confidence interval .009 to .059; treatment-gender interaction p = .01). The treatment, gender, and age interaction was significant for RBI (p = .02) and RSU (p <= .001). Treatment boys 10 years or older at randomization were more likely (p < .05) than controls to exhibit RBI and RSU, whereas there was no effect of treatment for boys <10 years. There were no treatment control differences by age for girls' RBI, but girls 9+ years were less likely than girls <=8 years to exhibit RSU (p < .05). CONCLUSIONS: Moving families of boys aged 10 years or older with rental vouchers may have adverse consequences on risky behaviors but may be beneficial for girls' substance use. Developmental windows are different by gender for the effects of improving neighborhood contexts on adolescent risky behavior. PMID- 27998701 TI - Anti-Mullerian Hormone in Obese Adolescent Girls With Polycystic Ovary Syndrome. AB - PURPOSE: Anti-Mullerian hormone (AMH) is proposed as a biomarker of polycystic ovary syndrome (PCOS). This study investigated: (1) AMH concentrations in obese adolescents with PCOS versus without PCOS; (2) the relationship of AMH to sex steroid hormones, adiposity, and insulin resistance; and (3) the optimal AMH value and the multivariable prediction model to determine PCOS in obese adolescents. METHODS: AMH levels were measured in 46 obese PCOS girls and 43 obese non-PCOS girls. Sex steroid hormones, clamp-measured insulin sensitivity and secretion, body composition, and abdominal adiposity were evaluated. Logistic regression and receiver-operating characteristic curve analyses were used, and multivariate prediction models were developed to test the utility of AMH for the diagnosis of PCOS. RESULTS: AMH levels were higher in obese PCOS versus non-PCOS girls (8.3 +/- .6 vs. 4.3 +/- .4 ng/mL, p < .0001), of comparable age and puberty. AMH concentrations correlated positively with age in both groups, total and free testosterone in PCOS girls only, abdominal adipose tissue in non-PCOS girls, with no correlation to in vivo insulin sensitivity and secretion in either groups. A multivariate model including AMH (cutoff 6.26 ng/mL, area under the curve .788) together with sex hormone-binding globulin and total testosterone exhibited 93.4% predictive power for diagnosing PCOS. CONCLUSIONS: AMH may be a useful biomarker for the diagnosis of PCOS in obese adolescent girls. PMID- 27998702 TI - Provider Influences on Sperm Banking Outcomes Among Adolescent Males Newly Diagnosed With Cancer. AB - PURPOSE: The purpose of this study was to examine provider communication and sociodemographic factors which associate with sperm banking outcomes in at-risk adolescents newly diagnosed with cancer. METHODS: A prospective single-group quasi-experimental study design was used to test the contributions of provider factors on sperm banking outcomes. Medical providers (N = 52, 86.5% oncologists) and 99 of their at-risk adolescent patients from eight leading pediatric oncology centers in North America completed questionnaires querying provider factors and patient sperm banking outcomes. Logistic regression with single covariates was used to test each provider factor as a potential correlate of the two binary sperm banking study outcomes (collection attempt/no attempt and successful sperm bank/no bank). Multicovariate logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for specified banking outcomes. RESULTS: Fertility referral (OR, 9.01; 95% CI, 2.54-31.90; p < .001) and provider comfort/skills in negotiating barriers to sperm banking with families (OR, 1.94; 95% CI, 1.03-3.63; p < .04) were associated with collection attempts. Adolescents who were referred for a specialized fertility consultation were also almost five times more likely to successfully bank (OR, 4.96; 95% CI, 1.54-16.00; p < .01) compared to those who were not. CONCLUSIONS: Provider training in communicating/managing adolescents and their families about sperm banking, and increasing utilization of fertility preservation referrals, should increase the proportion of at-risk males preserving fertility before treatment initiation. PMID- 27998703 TI - Rural-Urban Differences in Awareness and Use of Family Planning Services Among Adolescent Women in California. AB - PURPOSE: The purpose of this study was to compare awareness and use of family planning services by rural and urban program site among a sample of adolescent women before participation in the federal Personal Responsibility Education Program in California. METHODS: We conducted a secondary analysis of survey data collected from youth before participation in California's Personal Responsibility Education Program. Bivariate and multivariate analyses were conducted for a sample of 4,614 females ages 14-18 years to compare awareness and use of family planning services between participants at rural and urban program sites, controlling for the program setting and participant demographic, sexual, and reproductive characteristics. RESULTS: Overall, 61% of participants had heard of a family planning provider in their community, and 24% had visited a family planning provider. Awareness and use of family planning services were lower among rural participants than urban participants. After adjusting for the program setting and participant characteristics, rural participants were less likely to know about a family planning provider in their community (odds ratio, .64; 95% confidence interval, .50-.81) or receive family planning services (odds ratio, .76; 95% confidence interval, .58-.99) than urban participants. CONCLUSIONS: Findings suggest that adolescents in rural areas face greater barriers to accessing family planning services than adolescents in urban areas. Targeted efforts to increase awareness and use of family planning services among adolescents in rural areas and among other underserved populations are needed. PMID- 27998704 TI - Nonmedical Prescription Stimulant Use Among Girls 10-18 Years of Age: Associations With Other Risky Behavior. AB - PURPOSE: Little is known about the risk factors for nonmedical use (NMU) of prescription stimulants among adolescent girls. We aimed to measure the association of nonmedical prescription stimulant use with empirically linked risk factors, including weight control behavior (WCB), gambling, and depressed mood, in pre-teen and teenaged girls. METHODS: We assessed the relationship between age and race, gambling, WCB, depressive mood, and nonmedical prescription stimulant use using multivariable logistic regression. The study sample included 5,585 females, aged 10-18 years, recruited via an entertainment venue intercept method in 10 U.S. metropolitan areas as part of the National Monitoring of Adolescent Prescription Stimulants Study (2008-2011). RESULTS: NMU of prescription stimulants was reported by 6.6% (n = 370) of the sample. In multivariable logistic regression, 1-year increase in age was associated with a 21% (95% confidence interval [CI]: .15, .28) increase in risk for NMU. Whites and other race/ethnicity girls had 2.67 (CI: 1.85, 3.87) and 1.71 (1.11, 2.65) times higher odds for NMU, compared to African-Americans. Depressive mood (adjusted odds ratio: 2.69, CI: 2.04, 5.57) and gambling (adjusted odds ratio: 1.90, 1.23, 2.92) were associated with increased odds for NMU. A dose-response was identified between WCB and NMU, where girls with unhealthy and extreme WCB were over five times more likely to endorse NMU. CONCLUSIONS: We contribute to the literature linking WCB, depression, gambling, and the NMU of prescription stimulants in any population and uniquely do so among girls. PMID- 27998705 TI - In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey. AB - Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A set of ester prodrugs were evaluated using in vitro permeability (parallel artificial membrane permeability assay and Madin-Darby canine kidney cell line-low efflux) and intestinal stability (intestine S9) assays, as well as in vivo portal vein-cannulated cynomolgus monkey. In vitro-in vivo extrapolation (IVIVE) of FaFg was developed with a number of modeling approaches, including a full physiologically based pharmacokinetic (PBPK) model as well as a simplified competitive-rate analytical solution. Both methods converged as in the PBPK simulations enterocyte blood flow behaved as a sink, a key assumption in the competitive-rate analysis. For this specific compound set, the straightforward analytical solution therefore can be used to generate in vivo predictions. Strong IVIVE of FaFg was observed for cynomolgus monkey with R2 of 0.71-0.93. The results suggested in vitro assays can be used to predict in vivo FaFg for CES substrates with high confidence. PMID- 27998706 TI - Acute Leukemia of Ambiguous Lineage in Elderly Patients - Analysis of Survival Using Surveillance Epidemiology and End Results-Medicare Database. AB - BACKGROUND: Acute leukemia of ambiguous lineage (ALAL) is a rare leukemia with sparse data availability about the survival and management strategies in elderly patients. METHODS: We used the Surveillance Epidemiology and End Results (SEER) Medicare database to describe the overall survival (OS) and treatment pattern of elderly patients (age > 65 years) with ALAL. OS analysis was done using the Kaplan-Meier method, and its determinants were analyzed using the Cox proportional hazard regression method with a significant P < .05. RESULTS: We included 705 patients with ALAL and a median age of 80 years. The 2-year OS was 16.4% for patients aged 66 to 70 years, 8.1% for patients aged 71 to 75 years, 5.5% for patients aged 76 to 80 years, and 3.7% for patients aged > 80 years (P < .01). Two-year OS did not significantly vary by race or gender. Among the study cohort, 151 patients received chemotherapy. Two-year OS was 17% in the chemotherapy group and 3% in the no-chemotherapy group (P < .001). On multivariate analysis, age less than 80 years (Age 66-70 years: hazard ratio [HR]; 0.66, 95% confidence interval [CI], 0.52-0.85; age 71-75 years: HR, 0.80; 95% CI, 0.65-0.99; age 76-80 years: HR, 0.80; 95% CI, 0.66-0.98; P = .004) and chemotherapy (HR, 0.51; 95% CI, 0.42-0.62; P = .001) significantly reduced the hazard for mortality. CONCLUSION: Our study suggests that the OS of elderly patients with ALAL remains poor. Although treatment improved the OS, only 21.5% of patients received therapy. The optimal choice of therapy needs to be determined by prospective studies. PMID- 27998707 TI - Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era. AB - BACKGROUND: The standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (<= 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy. MATERIALS AND METHODS: A retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (<= 1 year and > 1 year after ASCT). RESULTS: The median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at <= 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years. CONCLUSION: Patients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression. PMID- 27998708 TI - Conformations of JNK3alpha splice variants analyzed by hydrogen/deuterium exchange mass spectrometry. AB - c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family that regulate apoptosis, inflammation, cytokine production, and metabolism. MAPKs undergo various splicing within their kinase domains. Unlike other MAPKs, JNKs have alternative splicing at the C-terminus, resulting in long and short variants. Functional or conformational effects due to the elongated C-terminal tail in the long splice variants have not been investigated nor has the conformation of the C-terminal tail been analyzed. Here, we analyzed the conformation of the elongated C-terminal tail and investigated conformational differences between long and short splice variants of JNKs using JNK3alpha2 and JNK3alpha1 as models. We adopted hydrogen/deuterium exchange mass spectrometry (HDX-MS) to analyze the conformation. HDX-MS revealed that the C-terminal tail is mostly intrinsically disordered, and that the conformation of the kinase domain of JNK3alpha2 is more dynamic than that of JNK3alpha1. The different conformation dynamics between long and short splice variants of JNK3alpha might affect the cellular functions of JNK3. PMID- 27998709 TI - Author response: Optical coherence tomography angiography and retinal microvascular ramification in AMN and PAMM. PMID- 27998710 TI - Optical coherence tomography angiography and retinal microvascular ramification in acute macular neuroretinopathy and paracentral acute middle maculopathy. PMID- 27998711 TI - Progress and promise of antisense oligonucleotide therapeutics for central nervous system diseases. AB - Antisense oligonucleotide (ASO) drugs are an emerging class of therapeutics that have recently demonstrated progress and promise to treat diseases of the central nervous system (CNS). ASOs for a variety of targets and mechanisms are currently being investigated in clinical trials and pre-clinically for a number of CNS diseases. This review examines the available data regarding central ASO delivery, distribution, pharmacokinetics, pharmacodynamics and therapeutic opportunities. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders". PMID- 27998712 TI - Impacts of femoral artery and vein excision versus femoral artery excision on the hindlimb ischemic model in CD-1 mice. AB - BACKGROUND AND AIM: Although femoral artery ligation-induced ischemia is commonly used in C57BL/6 or Balb/c mice, direct comparisons between femoral artery/vein (FAV) versus femoral artery (FA) excisions have not been reported. The goal of the present study is to investigate the effects of FAV versus FA excisions on hindlimb models using adult CD-1 mice. METHODS: Two groups (n=10/group) of adult, mixed gender CD-1 mice were used to generate hindlimb ischemic models by excising either the FAV or FA. Laser Doppler Imaging was used to evaluate blood flow before surgery, immediately after surgery (Day 0), and then on Days 14 and 28. Toe necrosis was checked every 14days while skeletal muscle cellular remodeling and vascular networks were analyzed at the end of the experiment using pathohistological, Dil-vessel painting, and immunohistochemical approaches. RESULTS: During the 4-week period, no statistical differences were found between FAV and FA excision-induced ischemia in terms of reduction of limb blood flow, paw size, number of necrotic toes, or skeletal muscle cell sizes. However, significant increases in centrally-located nuclei cells, adipose cells, diameters of Dil-stained arterioles, and CD31+ capillary densities, but decreases in arteriole densities/lengths were observed in ischemic limbs of both FAV and FA groups compared to control limbs. CONCLUSION: We conclude that FAV and FA excision in CD-1 mice generate a comparable degree of hindlimb ischemia, suggesting that, as expected, FAV is no more severe than FA. These findings may provide important information for researchers when selecting ligation methods for their hindlimb models. PMID- 27998713 TI - Dendritic spine classification using shape and appearance features based on two photon microscopy. AB - BACKGROUND: Neuronal morphology and function are highly coupled. In particular, dendritic spine morphology is strongly governed by the incoming neuronal activity. The first step towards understanding the structure-function relationships is to classify spine shapes into the main spine types suggested in the literature. Due to the lack of reliable automated analysis tools, classification is mostly performed manually, which is a time-intensive task and prone to subjectivity. NEW METHOD: We propose an automated method to classify dendritic spines using shape and appearance features based on challenging two photon laser scanning microscopy (2PLSM) data. Disjunctive Normal Shape Models (DNSM) is a recently proposed parametric shape representation. We perform segmentation of spine images by applying DNSM and use the resulting representation as shape features. Furthermore, we use Histogram of oriented gradients (HOG) to extract appearance features. In this context, we propose a kernel density estimation (KDE) based framework for dendritic spine classification, which uses these shape and appearance features. RESULTS: Our shape and appearance features based approach combined with Neural Network (NN) correctly classifies 87.06% of spines on a dataset of 456 spines. COMPARISON WITH EXISTING METHODS: Our proposed method outperforms standard morphological feature based approaches. Our KDE based framework also enables neuroscientists to analyze the separability of spine shape classes in the likelihood ratio space, which leads to further insights about nature of the spine shape analysis problem. CONCLUSIONS: Results validate that performance of our proposed approach is comparable to a human expert. It also enable neuroscientists to study shape statistics in the likelihood ratio space. PMID- 27998714 TI - A nutraceutical approach (Armolipid Plus) to reduce total and LDL cholesterol in individuals with mild to moderate dyslipidemia: Review of the clinical evidence. AB - Compelling evidence supports the effectiveness of the reduction of total and LDL cholesterol (TC and LDL-C) in primarily preventing cardiovascular events, within the framework of life-long prevention programs mainly consisting in lifestyle changes. Pharmacological treatment should be introduced when lifestyle changes, including use of nutraceuticals, have failed. ESC/EAS guidelines list a number of nutraceutical compounds and functional foods which have been individually studied in randomized, controlled clinical trials (RCTs). To date only a proprietary formulation of three naturally occurring substances with putative complementary lipid-lowering properties - red yeast rice, policosanol and berberine - combined with folic acid, astaxanthin, and coenzyme Q10 (Armolipid Plus(r)) has been extensively investigated in several RCTs, 7 of which were placebo-controlled, 2 were ezetimibe comparators and 4 were "real life" studies comparing diet and Armolipid Plus to diet alone. The trials included mostly patients with mild to moderate dyslipidemia, treated for 6-48 weeks. The trials also included special populations and patients in whom statins were contraindicated or who could not tolerate them. Armolipid Plus has proved to be able to achieve significant reductions in TC (11-21%) and in LDL-C (15-31%) levels, which is equivalent to expectations from low dose statins. In patients intolerant to statins, who do not achieve their therapeutic target with ezetimibe, Armolipid Plus can achieve a further 10% improvement in TC and LDL-C. The safety and tolerability of Armolipid Plus were excellent, thought likely due to the intentional combination of low doses of its active ingredients: low enough not to be associated with untoward effects, but high enough to exert therapeutic effects in combination with other complementary substances. Consequently, in the event of intolerance to statins, Armolipid Plus offers an effective alternative, which is devoid of the safety risks associated with synthetic pharmacological therapy. In conclusion Armolipid Plus, in addition to dietary measures, could be a rational choice for individuals with mild to moderate hyperlipidemia and for all dyslipidemic patients in whom statins are not indicated or who cannot tolerate them. PMID- 27998715 TI - Diagnostic algorithm for familial chylomicronemia syndrome. AB - BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare genetic disease that leads to severe hypertriglyceridemia often associated with recurrent episodes of pancreatitis. The recognition and correct diagnosis of the disease is challenging due to its rarity, and to the lack of specificity of signs and symptoms. Lipid experts, endocrinologists, gastroenterologists, pancreatologists, and general practitioners may encounter patients who potentially have FCS. Therefore, cooperation between experts and improved knowledge of FCS is essential in improving the diagnosis. Currently, a consensus on best practice for the diagnosis of FCS is lacking. METHODS: Aiming to define a diagnostic algorithm for FCS, a board of European experts was instituted. Such an algorithm for FCS is important to guide practitioners in the diagnosis of suspected FCS and to optimize therapeutic strategies. RESULTS: The multidisciplinary views were merged, leading to a diagnostic algorithm, proposed here. CONCLUSION: This diagnostic algorithm represents a potentially useful tool to support primary and secondary care practitioners in the recognition of signs and clinical manifestations in individuals potentially affected by FCS. PMID- 27998716 TI - DXA: 30years and counting: Introduction to the 30th anniversary issue. AB - Dual-energy X-ray absorptiometry (DXA) has a colorful history of development and evolution over the past 30years, from early predecessors that were cumbersome and limited in their clinical applications to current elegant instruments with a wide range of uses. DXA is used to diagnose osteoporosis, assess fracture risk, and monitor changes in bone mineral density (BMD). Non-BMD applications include vertebral fracture assessment, measurement of hip geometry, measurement of whole body tissue mass (i.e., bone, fat, and lean mass), abdominal aortic calcification detection and trabecular bone score measurement. This is an introduction to a special issue of this journal devoted to the celebration of the innovators in this field, the progress that has been made, and the challenges that remain. PMID- 27998717 TI - Foreword. PMID- 27998719 TI - The changing face of nanomaterials: Risk assessment challenges along the value chain. AB - Risk assessment (RA) of manufactured nanomaterials (MNM) is essential for regulatory purposes and risk management activities. Similar to RA of "classical" chemicals, MNM RA requires knowledge about exposure as well as of hazard potential and dose response relationships. What makes MNM RA especially challenging is the multitude of materials (which is expected to increase substantially in the future), the complexity of MNM value chains and life cycles, the accompanying possible changes in material properties over time and in contact with various environmental and organismal milieus, and the difficulties to obtain proper exposure data and to consider the proper dose metric. This article discusses these challenges and also critically overviews the current state of the art regarding MNM RA approaches. PMID- 27998718 TI - CaMKII-mediated phosphorylation of GluN2B regulates recombinant NMDA receptor currents in a chloride-dependent manner. AB - Some forms of long-term synaptic plasticity require docking of Ca2+/calmodulin dependent protein kinase II alpha (CaMKIIalpha) to residues 1290-1309 within the intracellular C-terminal tail of the N-methyl-d-aspartate (NMDA) receptor GluN2B subunit. The phosphorylation of Ser1303 within this region destabilizes CaMKII binding. Interestingly, Ser1303 is a substrate for CaMKII itself, as well as PKC and DAPK1, but these kinases have been reported to have contradictory effects on the activity of GluN2B-containing NMDA receptors. Here, we re-assessed the effect of CaMKII on NMDA receptor desensitization in heterologous cells, as measured by the ratio of steady-state to peak currents induced during 3s agonist applications. CaMKIIalpha co-expression or infusion of constitutively active CaMKII limits the extent of desensitization and preserves current amplitude with repeated stimulation of recombinant GluN1A/GluN2B when examined using low intracellular chloride (Cl-) levels, characteristic of neurons beyond the first postnatal week. In contrast, CaMKIIalpha enhances the acute rate and extent of desensitization when intracellular Cl- concentrations are high. The apparent dependence of CaMKIIalpha effects on NMDA receptor desensitization on Cl- concentrations is consistent with the presence of a Ca2+-activated Cl- conductance endogenous to HEK 293 cells, which was confirmed by photolysis of caged-Ca2+. However, Ca2+-activated Cl- conductances are unaffected by CaMKIIalpha expression, indicating that CaMKII affects agonist-induced whole cell currents via modulation of the NMDA receptor. In support of this idea, CaMKIIalpha modulation of GluN2B-NMDA receptors is abrogated by the phospho-null mutation of Ser1303 in GluN2B to alanine and occluded by phospho-mimetic mutation of Ser1303 to aspartate regardless of intracellular Cl- concentration. Thus, CaMKII-mediated phosphorylation of GluN2B-containing NMDA receptors reduces desensitization at physiological (low) intracellular Cl-, perhaps serving as a feed-forward mechanism to sustain NMDA-mediated Ca2+ entry and continued CaMKII activation during learning and memory. PMID- 27998720 TI - Genetics Variants and Serum Levels of MHC Class I Chain-related A in Predicting Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients Post Antiviral Treatment. AB - BACKGROUND/AIMS: The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCV) related hepatocellular carcinoma (HCC). The impact of the genetic variants and its serum levels on post-treatment cohort is elusive [corrected]. METHODS: MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. RESULTS: Fifty-eight (8.2%) patients developed HCC, with a median follow-up period of 48.2 months (range: 6-129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5.93/1.86-26.38, P = 0.002) [corrected] and the MICA rs2596542 A allele (HR/CI: 4.37/1.52-12.07, P = 0.002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA > 175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. CONCLUSIONS: Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy. PMID- 27998723 TI - Corrigendum to "Proposal and Validation of a Basic Progression Scoring System for Patients with Skull Base Chordoma" [World Neurosurg. 91 (2016) 409-418]. PMID- 27998721 TI - Exploring the nexus of Alzheimer's disease and related dementias with cancer and cancer therapies: A convening of the Alzheimer's Association & Alzheimer's Drug Discovery Foundation. AB - Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one-day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action. PMID- 27998722 TI - Intermittent access to a nutritionally complete high-fat diet attenuates alcohol drinking in rats. AB - Binge eating disorder and alcohol use disorder (AUD) frequently co-occur in the presence of other psychiatric conditions. Data suggest that binge eating engages similar behavioral and neurochemical processes common to AUD, which might contribute to the etiology or maintenance of alcoholism. However, it is unclear how binge feeding behavior and alcohol intake interact to promote initiation or maintenance of AUD. We investigated the impact of binge-like feeding on alcohol intake and anxiety-like behavior in male Long Evans rats. Rats received chow (controls) or extended intermittent access (24h twice a week; Int-HFD) to a nutritionally complete high-fat diet for six weeks. Standard rodent chow was available ad-libitum to all groups and food intake was measured. Following HFD exposure, 20.0% ethanol, 2.0% sucrose intake and endocrine peptide levels were evaluated. Anxiety-like behavior was measured using a light-dark (LD) box apparatus. Rats in the Int-HFD group displayed a binge-like pattern of feeding (alternations between caloric overconsumption and voluntary caloric restriction). Surprisingly, alcohol intake was significantly attenuated in the Int-HFD group whereas sugar consumption was unaffected. Plasma acyl-ghrelin levels were significantly elevated in the Int-HFD group, whereas glucagon-like peptide-1 levels did not change. Moreover, rats in the Int-HFD group spent more time in the light side of the LD box compared to controls, indicating that binge-like feeding induced anxiolytic effects. Collectively, these data suggest that intermittent access to HFD attenuates alcohol intake through reducing anxiety-like behavior, a process potentially controlled by elevated plasma ghrelin levels. PMID- 27998724 TI - Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis. AB - We established a mouse model of developmental nonalcoholic steatohepatitis (NASH) by feeding a high polyunsaturated fat liquid diet to female glutathione-S transferase 4-4 (Gsta4-/-)/peroxisome proliferator activated receptor alpha (Ppara-/-) double knockout 129/SvJ mice for 12 weeks from weaning. We used it to probe the importance of lipid peroxidation in progression of NASH beyond simple steatosis. Feeding Gsta4-/-/Ppara-/- double-knockout (dKO) mice liquid diets containing corn oil resulted in a percentage fat-dependent increase in steatosis and necroinflammatory injury (P < 0.05). Increasing fat to 70% from 35% resulted in increases in formation of 4-hydroxynonenal protein adducts accompanied by evidence of stellate cell activation, matrix remodeling, and fibrosis (P < 0.05). Comparison of dKO mice with wild-type (Wt) and single knockout mice revealed additive effects of Gsta4-/- and Ppara-/- silencing on steatosis, 4 hydroxynonenal adduct formation, oxidative stress, serum alanine amino transferase, expression of tumor necrosis factor alpha, Il6, interferon mRNA, and liver pathology (P < 0.05). Induction of Cyp2e1 protein by high-fat diet was suppressed in Gsta4-/- and dKO groups (P < 0.05). The dKO mice had similar levels of markers of stellate cell activation and matrix remodeling as Ppara-/- single KO mice. These data suggest that lipid peroxidation products play a role in progression of liver injury to steatohepatitis in NASH produced by high-fat feeding during development but appear less important in development of fibrosis. PMID- 27998726 TI - Characterization and Purification of Neoplastic Cells of Nodular Lymphocyte Predominant Hodgkin Lymphoma from Lymph Nodes by Flow Cytometry and Flow Cytometric Cell Sorting. AB - We report the flow cytometric (FC) identification and characterization of lymphocyte predominant (LP) cells from tissues involved by nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). First, we immunophenotyped the NLPHL cell line (DEV) confirming a germinal center immunophenotype, lack of expression of CD32 and CD58, and expression of CD54. Nineteen of 26 lymph nodes involved by NLPHL demonstrated a population with an LP immunophenotype (73%), which included expression of germinal center markers (CD75/Bcl-6-positive, CD32-weak/negative without CD10), a B-cell immunophenotype (CD19/CD20/CD40+), IgD and/or IgM expression (67%), and lack of programmed death-ligand 1/ligand 2. The LP cells demonstrated an adhesion macromolecule expression pattern distinct from Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (CHL) (uniform CD50 and variable CD58 for NLPHL; minimal CD50, bright CD58 expression for CHL). A two tube consensus assay identified LP cells in all seven NLPHL cases examined and only one non-NLPHL case (94 cases evaluated). Finally, FC cell sorting studies confirm that FC-defined populations have an LP cytomorphology. Taken together, these findings demonstrate a two-tube consensus assay can be used to immunophenotype NLHPL with high specificity and sensitivity and rapidly purify LP cells for genetic studies. This study also confirms aneuploidy in LP cells, provides antigens that may be helpful in distinguishing NLPHL from CHL, and suggests that T cells interact less avidly with LP cells than with Hodgkin and Reed-Sternberg cells. PMID- 27998727 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 27998725 TI - cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium. AB - Signaling through cGMP has therapeutic potential in the colon, where it has been implicated in the suppression of colitis and colon cancer. In this study, we tested the ability of cGMP and type 2 cGMP-dependent protein kinase (PKG2) to activate forkhead box O (FoxO) in colon cancer cells and in the colon epithelium of mice. We show that activation of PKG2 in colon cancer cells inhibited cell proliferation, inhibited AKT, and activated FoxO. Treatment of colon explants with 8Br-cGMP also activated FoxO target gene expression at both RNA and protein levels, and reduced epithelial reduction-oxidation (redox) stress. FoxO3a was the most prominent isoform in the distal colon epithelium, with prominent luminal staining. FoxO3a levels were reduced in Prkg2-/- animals, and FoxO target genes were unaffected by 8Br-cGMP challenge in vitro. Treatment of mice with the phosphodiesterase-5 inhibitor vardenafil (Levitra) mobilized FoxO3a to the nucleus of luminal epithelial cells, which corresponded to increased FoxO target gene expression, reduced redox stress, and increased epithelial barrier integrity. Treatment of human colonic biopsy specimens with 8Br-cGMP also activated catalase and manganese superoxide dismutase expression, indicating that this pathway is conserved in humans. Taken together, these results identify a novel signaling pathway in the colon epithelium, where FoxO tumor suppressors could provide protection from redox stress. Moreover, this pathway is regulated by endogenous cGMP/PKG2 signaling, and can be targeted using phosphodiesterase-5 inhibitors. PMID- 27998729 TI - In Vivo Imaging of Inflamed Glomeruli Reveals Dynamics of Neutrophil Extracellular Trap Formation in Glomerular Capillaries. AB - Neutrophil extracellular traps (NETs) have been documented in glomeruli of patients with glomerulonephritis. However, the dynamics of NET formation in the glomerulus and their functional contribution to acute glomerular injury are poorly understood. Herein, we used in vivo multiphoton microscopy to investigate NET formation in the acutely inflamed glomerulus. Glomerular inflammation was induced using an antibody against the glomerular basement membrane. After induction of inflammation, multiphoton microscopy revealed that approximately 20% of glomeruli contained structures composed of extracellular DNA within the capillaries. These structures were not seen in mice depleted of neutrophils, consistent with them being NETs. Most contained myeloperoxidase, as seen in NETs in other tissues, whereas intraglomerular NETs did not contain significant levels of the histone H2Ax or neutrophil elastase. In vivo imaging revealed that intraglomerular NETs were present only transiently, suggesting that NETs were susceptible to disruption under the high shear conditions in glomerular capillaries. Investigation of NETs under flow conditions in vitro supported this concept. Dissolution of NETs via DNase I did not alter anti-glomerular basement membrane antibody-induced glomerular injury, as assessed via albuminuria, although the degree of microscopic hematuria was reduced by this intervention. These data indicate that in this model of acute, neutrophil-dependent glomerulonephritis, NETs are generated in the glomerular capillaries, where they are short lived and make a modest contribution to glomerular injury. PMID- 27998728 TI - IL-1beta and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1alpha or Caspase-8 in a Mouse Model of Familial Mediterranean Fever. AB - Mutations in the gene encoding pyrin are associated with autoinflammatory disorder Familial Mediterranean Fever (FMF). A FMF-knock-in mouse strain that expresses chimeric pyrin protein with a V726A mutation (MefvV726A/V726A) was generated to model human FMF. This mouse strain shows an autoinflammatory disorder that is prevented by genetic deletion of IL-1 (IL-1) receptor or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC-mediated cell death leads to the release of IL 1alpha and IL-1beta, both of which signal through IL-1 receptor. Furthermore, caspase-1 and caspase-8 can interact with ASC to mediate secretion of IL-1 cytokines. The specific IL-1 cytokine instigating development of FMF and the enzymatic caspase involved in its secretion currently are unknown. In this study, we show that the autoinflammation observed in MefvV726A/V726A mice is mediated specifically by IL-1beta and not IL-1alpha. Furthermore, the disorder is dependent on the caspase-1-ASC axis, whereas caspase-8 is dispensable. Concurrently, aberrant IL-1beta release by MefvV726A/V726A monocytes in response to stimulation with lipopolysaccharide also is dependent on the caspase-1-ASC axis. In conclusion, our studies have uncovered a specific role for caspase-1 mediated IL-1beta release in the manifestation of FMF. PMID- 27998730 TI - Tuberculosis cases caused by heterogeneous infection in Eastern Europe and their influence on outcomes. AB - INTRODUCTION: Mycobacterium tuberculosis superinfection is known to occur in areas with high rates of tuberculosis (TB) and has a significant impact on overall clinical TB management. AIM: We aimed to estimate the superinfection rate in cohorts of drug sensitive and multi-drug resistant tuberculosis (MDR TB) patients from Eastern Europe and the potential role of a second MDR TB strain infecting a patient with active non-MDR TB in treatment outcome. METHODS: The study population included 512 serial M. tuberculosis isolates obtained from 84 MDR- and 136 non-MDR TB patients recruited sequentially at sites in Lithuania, Latvia and Russia in 2011-2013. Strains were genotyped using standardized 24-loci Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU VNTR) typing. RESULTS: Changes in two or more MIRU-VNTR loci suggesting superinfection were detected in 13 patients (5.9%). We found 4 initially non-MDR TB patients superinfected with an MDR TB strain during treatment and 3 of them had an unsuccessful outcome. CONCLUSIONS: An unsuccessful treatment outcome in patients initially diagnosed with drug sensitive TB might be explained by superinfection with an MDR TB strain. Bacteriological reversion could be indicative of superinfection with another strain. Archiving of all serial isolates and their genotyping in case of culture reversion could support therapeutic strategies in high MDR TB burden settings if resources are available. PMID- 27998731 TI - Bactericidal effect of hydroxyl radicals generated by the sonolysis and photolysis of hydrogen peroxide for endodontic applications. AB - The aim of endodontic root canal treatment is the elimination of bacteria and their products from an infected tooth root canal. To effectively disinfect a root canal, an ultrasonic irrigation system, in which hydroxyl radicals (HO.) generated artificially by sonolysis of H2O2, was developed previously for endodontic applications and was demonstrated to have bactericidal efficacy against Enterococcus faecalis. To improve this system, we examined the in vitro bactericidal effects of HO. generated from H2O2, activated by simultaneous irradiation with ultrasound for sonolysis and dental LED light for photolysis with a peak wavelength of 405 nm. Regarding the LED irradiation, two methods were used: (i) 'ideal' experimental conditions (irradiation close to the glass tube), and (ii) simulated endodontic conditions (more distant irradiation of a masked glass tube). In these conditions, HO. generation from H2O2 was detected by electron spin resonance (ESR) spectroscopy, and bactericidal efficacy against E. faecalis was assessed by measuring the colony forming units (CFU)/mL. The results indicated that HO. generation by ESR measurements and the bactericidal effect on E. faecalis by viable count using CFU/mL were enhanced significantly in a time dependent manner in both conditions. In a comparison of these conditions, bactericidal activity under 'ideal' experimental conditions was similar to that under simulated endodontic conditions. Moreover, the irradiation time for effective killing of E. faecalis through the sonolysis and photolysis of H2O2 under simulated endodontic conditions was shorter than that with sonolysis alone. These results demonstrate that H2O2 activated by ultrasound and LED light may be a safe and effective disinfection technique for endodontic root canal treatment. PMID- 27998732 TI - Pathogenesis of microbial keratitis. AB - Microbial keratitis is a sight-threatening ocular infection caused by bacteria, fungi, and protist pathogens. Epithelial defects and injuries are key predisposing factors making the eye susceptible to corneal pathogens. Among bacterial pathogens, the most common agents responsible for keratitis include Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia and Serratia species. Fungal agents of corneal infections include both filamentous as well as yeast, including Fusarium, Aspergillus, Phaeohyphomycetes, Curvularia, Paecilomyces, Scedosporium and Candida species, while in protists, Acanthamoeba spp. are responsible for causing ocular disease. Clinical features include redness, pain, tearing, blur vision and inflammation but symptoms vary depending on the causative agent. The underlying molecular mechanisms associated with microbial pathogenesis include virulence factors as well as the host factors that aid in the progression of keratitis, resulting in damage to the ocular tissue. The treatment therefore should focus not only on the elimination of the culprit but also on the neutralization of virulence factors to minimize the damage, in addition to repairing the damaged tissue. A complete understanding of the pathogenesis of microbial keratitis will lead to the rational development of therapeutic interventions. This is a timely review of our current understanding of the advances made in this field in a comprehensible manner. Coupled with the recently available genome sequence information and high throughput genomics technology, and the availability of innovative approaches, this will stimulate interest in this field. PMID- 27998733 TI - In vitro mutagenicity, NMR metabolite characterization of azo and triphenylmethanes dyes by adherents bacteria and the role of the "cna" adhesion gene in activated sludge. AB - Staphylococcus aureus, showing the greatest decolorization ability, was further investigated for Methyl Red (MR) Congo Red (CR), Crystal Violet (CV) and Malachite Green (MG) decolorization using response surface methodology (RSM). The chemometric methods use, based on statistical design of experiments (DOEs) such as RSM is becoming increasingly widespread in several sciences such as analytical chemistry, engineering and environmental chemistry. Stapphylococcus aureus ATCC 25923, Stapphylococcus aureus (S1) and Stapphylococcus aureus (S2), were isolated from textile wastewater plant located in KsarHellal, Tunisia and were tested for their decolorization capacity. PCR technique was utilized to identify the 3 bacterial strains and to detect the adhesin gene "cna". Biodegradation of MR, CR, CV and MG (750 ppm), were investigated under shaking condition in Mineral Salt Medium (MSM) solution at pH 7.5 and temperature 30 degrees C, using a 3.7 * 105 CFU/ml as inoculum size. Our results showed that Staphylococcus aureus had a high decolorization capacity. Nuclear magnetic resonance (NMR) spectroscopy analysis confirmed the biodegradation of dyes. The four dyes mutagenicity with the S9 metabolizing system decreased significantly after biodegradation and totally disappeared. Nuclear magnetic resonance (NMR) spectroscopy analysis confirmed the biodegradation of dyes. PMID- 27998734 TI - Correspondence to: International medical graduates among top US transplant surgeons. PMID- 27998735 TI - Real-time nucleic acid sequence-based amplification (NASBA) assay targeting MIC1 for detection of Cryptosporidium parvum and Cryptosporidium hominis oocysts. AB - Both Cryptosporidium parvum and Cryptosporidium hominis are often associated with cryptosporidiosis in humans, but whereas humans are the main host for C. hominis, C. parvum is zoonotic and able to infect a variety of species. The oocyst transmission stages of both species of parasites are morphologically identical and molecular techniques, usually polymerase chain reaction (PCR), are required to distinguish between oocysts detected by standard methods in environmental samples, such as water. In this study, we developed two primer sets for real-time nucleic acid sequence-based amplification (NASBA), targeting the MIC1 transcript in C. parvum (CpMIC1) and C. hominis (ChMIC1). Using these primer sets, we were not only able to detect low numbers of C. parvum and C. hominis oocysts (down to 5 oocysts in 10 MUl, and down to 1 oocyst using diluted RNA samples), but also distinguish between them. One of the primer sets targeted an exon only occurring in CpMIC1, thereby providing a tool for distinguishing C. parvum from other Cryptosporidium species. Although mRNA has been suggested as a tool for assessing viability of Cryptosporidium oocysts, as it is short-lived and may have high transcription, this NASBA assay detected MIC1 mRNA in inactivated oocysts. RNA within the oocysts seems to be protected from degradation, even when the oocysts have been killed by heating or freeze-thawing. Thus, our approach detects both viable and non-viable oocysts, and RNA does not seem to be a suitable marker for assessing oocyst viability. PMID- 27998736 TI - Clinical and 3-Dimensional Radiographic Evaluation of Autogenous Iliac Block Bone Grafting and Guided Bone Regeneration in Patients With Atrophic Maxilla. AB - PURPOSE: To evaluate the rate of graft resorption in autogenous iliac bone grafting (IBG) and guided bone regeneration (GBR) in patients with atrophic maxillae. MATERIALS AND METHODS: We performed a retrospective study involving patients requiring implant placement who underwent IBG or GBR. Volumetric changes of the graft sites were evaluated by imaging studies. The primary predictor and outcome variables were augmentation technique and rate of volumetric resorption, respectively. Secondary outcome variables included bone gain, success of grafting, insertion torque of implants, and requirement for vestibuloplasty. RESULTS: The sample comprised 39 patients (21 with GBR and 18 with IBG). One patient in the IBG group had temporary sensory disturbance at the donor site, and one patient in the GBR group had late exposure of the nonresorbable membrane. The average values of percent volume reduction in the GBR and IBG groups were 12.26% +/- 2.35% and 35.94% +/- 7.94%, respectively, after healing and 15.87% +/- 1.99% and 41.62% +/- 6.97%, respectively, at last follow-up. The IBG group exhibited a significantly higher reduction in bone volume than the GBR group at both time points (P = .001). The mean values of horizontal and vertical bone gain after healing in the IBG group were significantly higher than those in the GBR group (P = .006 and P = .001, respectively). The mean implant torque during implant placement in the GBR group was significantly higher than that in the IBG group (P = .024). There was no significant difference in the requirement for vestibuloplasty between the two groups (P > .05). CONCLUSIONS: Although both hard tissue augmentation approaches provide an adequate volume of bone graft for implant insertion, IBG results in greater graft resorption at maxillary augmented sites than GBR. Clinicians should consider the differences in the extent of graft resorption between the two methods while choosing the treatment approach. PMID- 27998737 TI - Anatomical Study and Clinical Application of Facial Artery Perforator Flaps in Intraoral Reconstruction: Focusing on Venous System. AB - PURPOSE: Facial artery perforator flaps (FAPFs) are preferred for the repair of intraoral and peri-nasal defects because it is a convenient procedure with minimal donor-site morbidity. The purpose of this study was to investigate the anatomic features of FAPFs and present their clinical application in intraoral reconstruction. MATERIALS AND METHODS: Five cadaver specimens (10 sides) of the head and neck region and 90 clinical cases (90 sides) of neck dissection were analyzed to explore the facial venous drainage system of FAPFs. In addition, anatomic features of the facial artery and vein and the marginal mandibular branch of the facial nerve were investigated in cadaver specimens. Furthermore, the authors reviewed a series of 33 intraoral reconstruction cases using their designed FAPFs focusing on flap survival and facial venous drainage system types. RESULTS: Based on cadaveric and clinical observations, the facial vein drainage system was divided into 3 types: type A drained into the internal jugular vein (47%); type B drained into the external jugular vein (37%); and type C drained into the anterior jugular vein (16%). The mean distances from the facial artery to the vein at the region of the FAPF pedicle and tip were 2.79 +/- 0.51 and 10.24 +/- 0.70 mm, respectively. Most cases using the authors' designed FAPFs yielded satisfactory esthetic and functional outcomes, whereas 3 cases presented with venous congestion from type C facial vein drainage. CONCLUSION: This study improved the understanding of the anatomic features and clinical application of FAPFs in intraoral reconstruction. This FAPF design could be used to achieve superior intraoral defect reconstruction, and type C facial vein drainage might be a risk factor for flap survival. PMID- 27998738 TI - What Is Important for Confirming Negative Margins When Resecting Mandibular Ameloblastomas? AB - PURPOSE: The purpose of this study was to assess the utility of intraoperative radiographs and frozen sections in achieving negative margins and preventing recurrence of mandibular ameloblastomas. MATERIALS AND METHODS: This was a retrospective cohort study of patients who underwent resection (>=1 cm) of mandibular ameloblastomas from 2005 through 2015. Patients were included if they had at least 1-year follow-up and complete records. Demographic variables included age, gender, and type of resection (segmental vs marginal). Predictor variables were type of margin assessment: 1) frozen section, 2) intraoperative ex vivo specimen radiograph, 3) both, or 4) none. The outcome variables were final margin status and recurrence rate. Accuracy of intraoperative radiographic margins was determined by comparison with histologic margin distance. Descriptive statistics were conducted with the Fisher exact test. RESULTS: The study sample consisted of 35 patients (47.5 +/- 20.4 yr old; 16 men) who underwent 25 segmental and 10 marginal resections. Ten had frozen sections only, 3 had ex vivo specimen radiographs only, 10 had no intraoperative measurements, and 12 had both. There were no positive frozen sections. One patient had a positive posterior bony margin at final pathology despite negative frozen section histology. There was no difference in recurrence rate at latest follow-up among cohorts. The anterior radiographic margin was 11.8 +/- 5.9 mm compared with 11.5 +/- 7.5 mm by histology (P = .124). The posterior radiographic margin was 12.3 +/ 5.3 mm compared with 9.8 +/- 6.5 mm histologically (P = .546). Margin distances that were at least 5 mm when measured with specimen radiographs had histologic margin distances of at least 5 mm in 25 of 30 resection margins (83.3%). CONCLUSION: Resection of ameloblastoma with planned margins of at least 1 cm is sufficient to prevent recurrence of ameloblastoma. Achieving a radiographic margin of at least 5 mm provided a histologic margin of at least 5 mm 83.3% of the time. PMID- 27998739 TI - Can Differences in Vascularity Serve as a Diagnostic Aid in Fibro-Osseous Lesions of the Jaws? AB - PURPOSE: Different lesions in the fibro-osseous group share microscopic features; thus, establishing a definitive diagnosis based on microscopic features alone can be a challenge. There is a need for additional microscopic tools to aid in differentiating these lesions. This study compared parameters related to vascularity among 3 lesions in the fibro-osseous group: fibrous dysplasia (FD), central ossifying fibroma (COF), and cemento-osseous dysplasia (COD). MATERIALS AND METHODS: This study was a cross-sectional analysis of biopsied lesions retrieved from 3 medical centers over a 14-year period. The primary predictor variables were the vascularity parameters (number, perimeter, and area). The outcome variables were diagnoses of FD, COF, and COD. Diagnosis was based on clinical, microscopic, and radiologic correlations. From each histopathologic slide, 5 representative fields were captured with a computerized digital camera. The number of blood vessels was counted, and the surface area and vascular perimeter were measured by tracing the perimeter of each vessel. Data were statistically analyzed using analysis of variance with logarithmic transformation and a Tukey adjustment. RESULTS: Sixty-six cases were included in the study (26 in FD group, 26 in COF group, and 14 in COD group). The mean number of vessels showed only a tendency to be larger in the FD group compared with the COF and COD groups (5.4 +/- 2.6, 3.7 +/- 2.3, and 3.6 +/- 1.7, respectively), but the results did not reach the threshold for significance. The mean vascular perimeter was 1,385.8 +/- 859.2 pixels in the FD group and 742.6 +/- 661.8 in COF group after logarithmic transformation (P = .012). The perimeter in the COD group was smaller (941.1 +/- 502) compared with that in the FD group, but the difference did not reach the threshold for significance. The mean area was 25,061 +/- 24,875.6 in the FD group and 11,773.8 +/- 21,734.4 in the COF group after logarithmic transformation (P = .004). The perimeter in the COD group was smaller (13,011.1 +/- 8,338.3) compared with the FD group, but the difference did not reach the threshold for significance. CONCLUSION: The vascular content of the FD group was markedly higher than of the COF group. These vascular changes can aid in differentiating these lesions microscopically. PMID- 27998740 TI - Identification and functional characterization of the house finch interleukin 1beta. AB - Interleukin-1beta (IL-1beta), an inflammatory cytokine of the IL-1 family, is primarily produced as a precursor protein by monocytes and macrophages, then matures and becomes activated through proteolytic catalysis. Although the biological characteristics of avian IL-1beta are well known, little information is available about its biological role in songbird species such as house finches that are vulnerable to naturally-occurring inflammatory diseases. In this study, house finch IL-1beta (HfIL-1beta) was cloned, expressed, and its biological function examined. Both precursor and mature forms of HfIL-1beta consisting of 269 and 162 amino acids, respectively, were amplified from total RNA of spleen and cloned into expression vectors. HfIL-1beta showed high sequential and tertiary structural similarity to chicken homologue that allowed detection of the expressed mature recombinant HfIL-1beta (rHfIL-1beta) with anti-ChIL-1beta antibody by immunoblot analysis. For further characterization, we used primary splenocytes and hepatocytes that are predominant sources of IL-1beta upon stimulation, as well as suitable targets to stimulation by IL-1beta. Isolated house finch splenocytes were stimulated with rHfIL-1beta in the presence and absence of concanavalin A (Con A), RNA was extracted and transcript levels of Th1/Th2 cytokines and a chemokine were measured by qRT-PCR. The addition of rHfIL 1beta induced significant enhancement of IL-2 transcript, a Th1 cytokine, while transcription of IL-1beta and the Th2 cytokine IL-10 was slightly enhanced by rHfIL-1beta treatment. rHfIL-1beta also led to elevated levels of the chemokine CXCL1 and nitric oxide production regardless of co-stimulation with Con A. In addition, the production of the acute phase protein serum amyloid A and the antimicrobial peptide LEAP2 was observed in HfIL-1beta-stimulated hepatocytes. Taken together, these observations revealed the basic functions of HfIL-1beta including the stimulatory effect on cell proliferation, production of Th1/Th2 cytokines and acute phase proteins by immune cells, thus providing valuable insight into how HfIL-1beta is involved in regulating inflammatory response. PMID- 27998741 TI - The scolopidial accessory organ in the Jerusalem cricket (Orthoptera: Stenopelmatidae). AB - Multiple mechanosensory organs form the subgenual organ complex in orthopteroid insects, located in the proximal tibia. In several Ensifera (Orthoptera), a small chordotonal organ, the so-called accessory organ, is the most posterior part of this sensory complex. In order to document the presence of this accessory organ among the Ensifera, the chordotonal sensilla and their innervation in the posterior tibia of two species of Jerusalem crickets (Stenopelmatidae: Stenopelmatus) is described. The sensory structures were stained by axonal tracing. Scolopidial sensilla occur in the posterior subgenual organ and the accessory organ in all leg pairs. The accessory organ contains 10-17 scolopidial sensilla. Both groups of sensilla are commonly spatially separated. However, in few cases neuronal fibres occurred between both organs. The two sensillum groups are considered as separate organs by the general spatial separation and innervation by different nerve branches. A functional role for mechanoreception is considered: since the accessory organ is located closely under the cuticle, sensilla may be suited to detect vibrations transferred over the leg's surface. This study extends the known taxa with an accessory organ, which occurs in several taxa of Ensifera. Comparative neuroanatomy thus suggests that the accessory organ may be conserved at least in Tettigoniidea. PMID- 27998742 TI - Structure and postembryonic development of the intersegmental nodules in the non muscular joints of the antennae in Rhodnius prolixus. AB - The antennae of Insecta consist of two basal segments and the distal annulated flagellum lacking intrinsic muscles. Non-muscular joints are important to preserve the flexibility and structure of the long heteropteran antennae which bear an intersegmental nodule on each non-muscular joint. Little is known about their properties or function. Here we characterize the structure and postembryonic development of the non-muscular joints of Rhodnius prolixus antennae. Using Scanning Electron Microscopy, we tracked the changes in shape and size of both intersegmental nodules during the course of the hemimetabolous insect life cycle. Using Atomic Force Microscopy, we established a qualitative correlation between the topography of the surface and the rigidity of the joint between pedicel and flagellum. Our results confirmed the presence of two sub articulations on each non-muscular joint. Also, the two intersegmental nodules have different origins: the one between the two flagellar segments (intraflagelloid) is a sclerite already present from the early nymph, while the nodule between pedicel and flagellum (prebasiflagellite) originates by gradual separation of the proximal end of the basiflagellum during postembryonic development. Various changes occur in the non-muscular joints and segments of the antenna during the life cycle of R. prolixus. PMID- 27998744 TI - Montreal Accord on Patient-Reported Outcomes (PROs) use series-Paper 7: modern perspectives of measurement validation emphasize justification of inferences based on patient reported outcome scores. AB - BACKGROUND: Obtaining the patient's view about the outcome of care is an essential component of patient-centered care. Many patient-reported outcome (PRO) instruments for different purposes have been developed since the 1960s. Measurement validation is fundamental in the development, evaluation, and use of PRO instruments. OBJECTIVES: This paper provides a review of modern perspectives of measurement validation in relation to the followings three questions as applied to PROs: (1) What evidence is needed to warrant comparisons between groups and individuals? (2) What evidence is needed to warrant comparisons over time? and (3) What are the value implications, including personal and societal consequences, of using PRO scores? DISCUSSION: Measurement validation is an ongoing process that involves the accumulation of evidence regarding the justification of inferences, actions, and decisions based on measurement scores. These include inferences pertaining to comparisons between groups and comparisons over time as well as consideration of value implications of using PRO scores. Personal and societal consequences must be examined as part of a comprehensive approach to measurement validation. The answers to these three questions are fundamental to the the validity of different types of inferences, actions, and decisions made on PRO scores in health research, health care administration, and clinical practice. PMID- 27998743 TI - Ampelopsin attenuates lipopolysaccharide-induced inflammatory response through the inhibition of the NF-kappaB and JAK2/STAT3 signaling pathways in microglia. AB - Increasing evidence suggests that microglia are a major cellular contributor to neuroinflammation. The present study investigated whether Ampelopsin (Amp), a type of flavanonol derivative from Ampelopsis grossedentata, may exert an anti inflammatory effect on lipopolysaccharide (LPS)-induced BV2 and primary microglia cells. We found that pre-treatment of microglia cells with Amp before LPS with a non-cytotoxic concentration range decreased the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Amp also suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels. In addition, LPS-induced production of pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) was obviously reduced by Amp. Our mechanistic study indicated that Amp suppressed LPS induced activation of the IkappaB/NF-kappaB inflammation pathway without affecting changes in the phosphorylation levels of mitogen-activated protein kinases (MAPKs) in BV2 cells. Further studies revealed that Amp markedly reduced the phosphorylation levels of JAK2-STAT3 and STAT3 nuclear translocation. Overall, our data suggest that Amp can suppress the LPS-induced inflammatory response of microglial cells, indicating that Amp has potential for the treatment of inflammation-mediated neurodegenerative diseases. PMID- 27998745 TI - Clinical feasibility of 3D-QALAS - Single breath-hold 3D myocardial T1- and T2 mapping. AB - PURPOSE: To investigate the in-vivo precision and clinical feasibility of 3D QALAS - a novel method for simultaneous three-dimensional myocardial T1- and T2 mapping. METHODS: Ten healthy subjects and 23 patients with different cardiac pathologies underwent cardiovascular 3T MRI examinations including 3D-QALAS, MOLLI and T2-GraSE acquisitions. Precision was investigated in the healthy subjects between independent scans, between dependent scans and as standard deviation of consecutive scans. Clinical feasibility of 3D-QALAS was investigated for native and contrast enhanced myocardium in patients. Data were analyzed using mean value and 95% confidence interval, Pearson correlation, Paired t-tests, intraclass correlation and Bland-Altman analysis. RESULTS: Average myocardial relaxation time values and SD from eight repeated acquisitions within the group of healthy subjects were 1178+/-18.5ms (1.6%) for T1 with 3D-QALAS, 52.7+/-1.2ms (2.3%) for T2 with 3D-QALAS, 1145+/-10.0ms (0.9%) for T1 with MOLLI and 49.2+/ 0.8ms (1.6%) for T2 with GraSE. Myocardial T1 and T2 relaxation times obtained with 3D-QALAS correlated very well with reference methods; MOLLI for T1 (r=0.994) and T2-GraSE for T2 (r=0.818) in the 23 patients. Average native/post-contrast myocardial T1 values from the patients were 1166.2ms/411.8ms for 3D-QALAS and 1174.4ms/438.9ms for MOLLI. Average native myocardial T2 values from the patients were 53.2ms for 3D-QALAS and 54.4ms for T2-GraSE. CONCLUSIONS: Repeated independent and dependent scans together with the intra-scan repeatability, demonstrated all a very good precision for the 3D-QALAS method in healthy volunteers. This study shows that 3D T1 and T2 mapping in the left ventricle is feasible in one breath hold for patients with different cardiac pathologies using 3D-QALAS. PMID- 27998746 TI - MRI and MRS on preserved samples as a tool in fish ecology. AB - Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) gain increasing attention and importance as a tool in marine ecology. So far, studies were largely limited to morphological studies, e.g. for the creation of digital libraries. Here, the utility of MRI and MRS for ecologists is tested and exemplified using formalin preserved samples of the Antarctic silverfish, Pleuragramma antarctica. As this species lacks a swim bladder, buoyancy is attained by the deposition of large amounts of lipids that are mainly stored in subcutaneous and intermuscular lipid sacs. In this study MRI and MRS are not only used to study internal morphology, but additionally to investigate functional morphology and to measure parameters of high ecological interest. The data are compared with literature data obtained by means of traditional ecological methods. The results from this study show that MR scans are not only an alternative to histological sections (as shown before), but even allow the visualization of particular features in delicate soft tissues, such as Pleuragramma's lipid sacs. 3D rendering techniques proved to be a useful tool to study organ volumes and lipid content, which usually requires laborious chemical lipid extraction and analysis. Moreover, the application of MRS even allows for an analysis of lipids and fatty acids within lipid sacs, which wouldn't be possible using destructive methods. MRI and MRS, in particular when used in combination, have the capacity to provide useful data on parameters of high ecological relevance and thus have proven to be a highly valuable addition, if not alternative, to the classical methods. PMID- 27998747 TI - DC artifact correction for arbitrary phase-cycling sequence. AB - In magnetic resonance imaging (MRI), a non-zero offset in the receiver baseline signal during acquisition results in a bright spot or a line artifact in the center of the image known as a direct current (DC) artifact. Several methods have been suggested in the past for the removal or correction of DC artifacts in MR images, however, these methods cannot be applied directly when a specific phase cycling technique is used in the imaging sequence. In this work, we proposed a new, simple technique that enables correction of DC artifacts for any arbitrary phase-cycling imaging sequences. The technique is composed of phase unification, DC offset estimation and correction, and phase restoration. The feasibility of the proposed method was demonstrated via phantom and in vivo experiments with a multiple phase-cycling balanced steady-state free precession (bSSFP) imaging sequence. Results showed successful removal of the DC artifacts in images acquired using bSSFP with phase-cycling angles of 0 degrees , 90 degrees , 180 degrees , and 270 degrees , indicating potential feasibility of the proposed method to any imaging sequence with arbitrary phase-cycling angles. PMID- 27998748 TI - HEV infection in French HIV-infected patients. AB - OBJECTIVES: The reported prevalence of anti-hepatitis E virus antibodies in HIV positive patients from industrialized countries varies greatly. It is also difficult to compare these data with the anti-IgG prevalence in the general population because age and sex are not matched in most studies. Moreover, MSM are at increased risk of viral hepatitis. METHODS: HEV is endemic in southwestern France. We investigated therefore 300 HIV-infected patients consecutively attending the out-patient clinic of Toulouse University Hospital. Each HIV infected patient was matched for sex and age with 2 healthy blood donors from the same area. They were tested for anti-HEV IgM and IgG. RESULTS: Anti-HEV IgG was found in 116 HIV-infected patients (38.7%) and in 284 matched controls (47.3%, p = 0.027). However, anti-HEV IgG concentration tended to be lower in HIV-patients than in controls. Anti-HEV IgM prevalence was similar HIV-infected patients (3.6%) and in matched controls (3.8%, p = 0.85). CONCLUSION: The prevalence and concentrations of anti-HEV IgG in HIV-infected patients from Southern-France were lower than in controls, suggesting a weaker humoral response. But their prevalences of anti-HEV IgM were similar, indicating a high incidence of HEV infection. These data do not indicate that HEV is transmitted sexually. PMID- 27998749 TI - The history of plasma viral load and CD4 count impacts the size of HIV-1 reservoir. PMID- 27998750 TI - Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities. AB - The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy. PMID- 27998751 TI - Laboratory features of 160 CCHF confirmed cases in Zabol of Iran: A 10-year study. PMID- 27998752 TI - Drug resistant TB: UK multicentre study (DRUMS): Treatment, management and outcomes in London and West Midlands 2008-2014. AB - OBJECTIVES: Detailed information regarding treatment practices and outcomes of MDR-TB treatment in the UK is required as a baseline for care improvements. METHODS: 100 consecutive cases between 2008 and 2014 were reviewed retrospectively at 4 MDR-TB treatment centres in England to obtain information on drug treatment choices, hospital admission duration and outcomes for MDR-TB. RESULTS: Initial hospital admission was long, median 62.5 (IQR 20-106, n = 92) days, and 13% (12/92) of patients lost their home during this period. Prolonged admission was associated with pulmonary cases, cavities on chest radiograph, a public health policy of waiting for sputum culture conversion (CC) and loss of the patient's home. Sputum CC occurred at a median of 33.5 (IQR 16-55, n = 46) days. Treatment success was high (74%, 74/100) and mortality low (1%, 1/100). A significant proportion of the cohort had "neutral" results due to deportation and transfer overseas (12%, (12/100)). 14% (14/100) had negative outcomes for which poor adherence was the main reason (62%, 9/14). CONCLUSIONS: Successful outcome is common in recognised centres and limited by adherence rather than microbiological failure. Duration of hospital admission is influenced by lack of suitable housing and some variation in public health practice. Wider access to long-term assisted living facilities could improve completion rates. PMID- 27998753 TI - Effects of intra-hippocampal microinjection of vitamin B12 on the orofacial pain and memory impairments induced by scopolamine and orofacial pain in rats. AB - In the present study, we investigated the effects of microinjection of vitamin B12 into the hippocampus on the orofacial pain and memory impairments induced by scopolamine and orofacial pain. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Orofacial pain was induced by subcutaneous injection of formalin (1.5%, 50MUl) into the right vibrissa pad, and the durations of face rubbing were recorded at 3-min blocks for 45min. Morris water maze (MWM) was used for evaluation of learning and memory. Finally, locomotor activity was assessed using an open-field test. Vitamin B12 attenuated both phases of formalin-induced orofacial pain. Prior administration of naloxone and naloxonazine, but not naltrindole and nor-binaltorphimine, prevented this effect. Vitamin B12 and physostigmine decreased latency time as well as traveled distance in Morris water maze. In addition, these chemicals improved scopolamine-induced memory impairment. The memory impairment induced by orofacial pain was improved by vitamin B12 and physostigmine used alone. Naloxone prevented, whereas physostigmine enhanced the memory improving effect of vitamin B12 in the pain induced memory impairment. All the above-mentioned chemicals did not alter locomotor activity. The results of the present study showed that at the level of the dorsal hippocampus, vitamin B12 modulated orofacial pain through a mu-opioid receptor mechanism. In addition, vitamin B12 contributed to hippocampal cholinergic system in processing of memory. Moreover, cholinergic and opioid systems may be involved in improving effect of vitamin B12 on pain-induced memory impairment. PMID- 27998754 TI - Comparison of cocaine reinforcement in lean and obese Zucker rats: Relative potency and reinstatement of extinguished operant responding. AB - AIMS: Evidence indicates that obese individuals exhibit alterations in brain reward function that are anatomically and functionally similar to what has been observed in drug addicts, which could theoretically make obese individuals vulnerable to drug abuse and drug abusers vulnerable to overeating. However, few studies have investigated the cross-generality of these phenotypes. We recently reported that the reinforcing effectiveness (i.e., value) of a fat was greater in obese Zucker rats than in their lean counterparts, but found no differences in the reinforcing effectiveness of cocaine between groups, suggesting psychostimulant reinforcement is similar in lean and obese Zucker rats. However, it is unknown if other aspects of reinforcement such as cocaine's potency as a reinforcer or its reinstating effects differ in lean and obese Zucker rats. METHODS: The current study compared cocaine's potency as a reinforcer in lean and obese Zucker rats self-administering intravenous cocaine (0.06-1.0mg/kg/inj), and subsequently tested these subjects in cue- (light) and drug-primed (intraperitoneal cocaine; 10mg/kg) reinstatement of extinguished operant responding. RESULTS: All rats acquired cocaine self-administration and generated "inverted-U" dose-response functions. Following extinction of responding, the cue and drug-primes increased lever-pressing in both groups (i.e., reinstatement). No significant differences in the reinforcing potency or reinstating effects of cocaine were observed as a function of obesity. CONCLUSIONS: These results, combined with our previous observations, demonstrate that cocaine's reinforcing effects are comparable in lean and obese Zucker rats and do not support the hypothesis that obesity is associated with an altered reinforcing effect of psychostimulants. PMID- 27998755 TI - Circadian rhythms accelerate wound healing in female Siberian hamsters. AB - Circadian rhythms (CRs) provide temporal regulation and coordination of numerous physiological traits, including immune function. CRs in multiple aspects of immune function are impaired in rodents that have been rendered circadian arrhythmic through various methods. In Siberian hamsters, circadian arrhythmia can be induced by disruptive light treatments (DPS). Here we examined CRs in wound healing, and the effects of circadian disruption on wound healing in DPS arrhythmic hamsters. Circadian entrained/rhythmic (RHYTH) and behaviorally arrhythmic (ARR) female hamsters were administered a cutaneous wound either 3h after light onset (ZT03) or 2h after dark onset (ZT18); wound size was quantified daily using image analyses. Among RHYTH hamsters, ZT03 wounds healed faster than ZT18 wounds, whereas in ARR hamsters, circadian phase did not affect wound healing. In addition, wounds healed slower in ARR hamsters. The results document a clear CR in wound healing, and indicate that the mere presence of organismal circadian organization enhances this aspect of immune function. Faster wound healing in CR-competent hamsters may be mediated by CR-driven coordination of the temporal order of mechanisms (inflammation, leukocyte trafficking, tissue remodeling) underlying cutaneous wound healing. PMID- 27998756 TI - Effects of 24-epibrassinolide and green light on plastid gene transcription and cytokinin content of barley leaves. AB - In order to evaluate whether brassinosteroids (BS) and green light regulate the transcription of plastid genes in a cross-talk with cytokinins (CKs), transcription rates of 12 plastid genes (ndhF, rrn23, rpoB, psaA, psaB, rrn16, psbA, psbD, psbK, rbcL, atpB, and trnE/trnY) as well as the accumulation of transcripts of some photoreceptors (PHYA, CRY2, CRY1A, and CRY1B) and signaling (SERK and CAS) genes were followed in detached etiolated barley leaves exposed to darkness, green or white light +/-1MUm 24-epibrassinolide (EBL). EBL in the dark was shown to up-regulate the transcription of 12 plastid genes, while green light activated 10 genes and the EBL combined with the green light affected the transcription of only two genes (psaB and rpoB). Green light inhibited the expression of photoreceptor genes, except for CRY1A. Under the green light, EBL practically did not affect the expression of CRY1A, CAS and SERK genes, but it reduced the influence of white light on the accumulation of CAS, CRY1A, CRY1B, and SERK gene transcripts. The total content of BS in the dark and under white light remained largely unchanged, while under green light the total content of BRs (brassinolide, castasterone, and 6-deoxocastasterone) and HBRs (28 homobrassinolide, 28-homocastasterone, and 6-deoxo-28-homocastasterone) increased. The EBL-dependent up-regulation of plastome transcription in the dark was accompanied by a significant decrease in CK deactivation by O-glucosylation. However, no significant effect on the content of active CKs was detected. EBL combined with green light moderately increased the contents of trans-zeatin and isopentenyladenine, but had a negative effect on cis-zeatin. The most significant promotive effect of EBL on active CK bases was observed in white light. The data obtained suggest the involvement of CKs in the BS- and light-dependent transcription regulation of plastid genes. PMID- 27998757 TI - Intraindividual stability of cortisol and cortisone and the ratio of cortisol to cortisone in saliva, urine and hair. AB - BACKGROUND: Cortisol, cortisone and the ratio of cortisol to cortisone in saliva, urine and hair are acute, short-term and long-term biomarkers to reliably assess the activity of hypothalamic-pituitary-adrenal (HPA) axis and 11beta hydroxysteroid dehydrogenase (11beta-HSD). One key issue is whether these biomarkers have intraindividual relative stability. Salivary, urinary and hair cortisol was proven to show considerable long-term intraindividual relative stability. However, currently unknown is whether cortisone and the ratio in saliva, urine and hair show intraindividual relative stability. METHODS: The present study utilized a longitudinal design to validate long-term stability within two weeks of three biomarkers in saliva and urine, and long-term stability within twelve months of three hair biomarkers. Salivary, urinary and hair steroids were measured with high performance liquid chromatography tandem mass spectrometry. RESULTS: Three biomarkers in urine and hair showed moderate test retest correlations with coefficient (r) ranging between 0.22 and 0.56 and good multiple-test consistencies with coefficient of intraclass correlation (ICC) ranging between 0.42 and 0.67. Three single-point salivary biomarkers showed weak to moderate test-retest correlations (r's between 0.01 and 0.38) and poor to fair multiple-test consistencies (ICC's between 0.29 and 0.53) within two weeks. Three single-day salivary biomarkers showed moderate test-retest correlations (r's between 0.23 and 0.53) and good multiple-test consistencies (ICC's between 0.56 and 0.66) within two weeks. CONCLUSIONS: Three biomarkers in urine and hair showed moderate long-term intraindividual relative stability. Three single-point salivary biomarkers showed weak to moderate short-term and long-term intraindividual relative stability, but three single-day salivary biomarkers showed moderate short-term and long-term intraindividual relative stability. PMID- 27998758 TI - The synthesis and antifungal activity of (20S)-3beta-acetoxy-5alpha-pregnane 20,16beta-carbolactone against fluconazole - Resistant Candida cells. AB - An efficient procedure for the synthesis of (20S)-3beta-acetoxy-5alpha-pregnane 20,16beta-carbolactone is described. Bactericidal and fungicidal activity of the lactone against different bacteria such as MSSA, MRSA, E. coli ESBL, P. aeruginosa and clinical isolates of Candida spp., in planktonic and biofilm growth stage were assessed. Additionally, the affinity of this new compound to microbial plasma membrane and hemoglobin release from human red blood cells were determined using fluorometric and colorimetric assay, respectively. Our studies revealed that the lactone exhibits strong antifungal activity, and the ability to prevent pathogens' biofilm formation. Additionally, upon lactone treatment a significant affinity to fungal, but not to human cell membranes, indicating suitable biocompatibility was observed. PMID- 27998759 TI - The CRISPR/Cas9 system targeting EGFR exon 17 abrogates NF-kappaB activation via epigenetic modulation of UBXN1 in EGFRwt/vIII glioma cells. AB - Worldwide, glioblastoma (GBM) is the most lethal and frequent intracranial tumor. Despite decades of study, the overall survival of GBM patients remains unchanged. epidermal growth factor receptor (EGFR) amplification and gene mutation are thought to be negatively correlated with prognosis. In this study, we used proteomics to determine that UBXN1 is a negative downstream regulator of the EGFR mutation vIII (EGFRvIII). Via bioinformatics analysis, we found that UBXN1 is a factor that can improve glioma patients' overall survival time. We also determined that the down-regulation of UBXN1 is mediated by the upregulation of H3K27me3 in the presence of EGFRvIII. Because NF-kappaB can be negatively regulated by UBXN1, we believe that EGFRwt/vIII activates NF-kappaB by suppressing UBXN1 expression. Importantly, we used the latest genomic editing tool, CRISPR/Cas9, to knockout EGFRwt/vIII on exon 17 and further proved that UBXN1 is negatively regulated by EGFRwt/vIII. Furthermore, knockout of EGFR/EGFRvIII could benefit GBM in vitro and in vivo, indicating that CRISPR/Cas9 is a promising therapeutic strategy for both EGFR amplification and EGFR mutation bearing patients. PMID- 27998760 TI - Nucleostemin/GNL3 promotes nucleolar polyubiquitylation of p27kip1 to drive hepatocellular carcinoma progression. AB - p27kip, as a cyclin dependent kinase inhibitor (CDKI), plays a pivotal role in the regulation of cell cycle progression and hepatocarcinogenesis. Herein, we revealed that p27 exhibited apparent nucleolar distribution and interacted with nucleolar protein nucleostemin (NS) in Hepatocellular carcinoma (HCC) cells. Furthermore, subcellular fractionation experiments demonstrated that nucleolar p27 had significantly higher level of polyubiquitylation, compared with nucleoplasmic fraction. Depletion of NS inhibited nucleolar polyubiquitylation of p27, indicating an involvement of NS in triggering p27 ubiquitylation and inactivation during HCC development. Moreover, we found that knockdown of NS promoted p27 to bind to CDK2-Cyclin E complex and inhibited the activity of CDK2, resulting in consequent cell cycle arrest in HCC cells. Furthermore, silencing NS expression reduced in vitro colony formation and in vivo tumor growth of HCC cells. Finally, we found that NS was upregulated in HCC tissues, compared with adjacent non-tumorous tissues. Kaplan-Meier analysis indicated patients with high expression of NS and low expression of p27 had significantly worsened prognosis. Our results suggested NS mediated p27-dependent cell cycle control via inducing nucleolar sequestration and polyubiquitylation of p27 in HCC. These findings help gain an insightful view into the mechanism underlying aberrant cell cycle progression during hepatocarcinogenesis, and thus benefit the development of molecular-targeted therapies in HCC. PMID- 27998761 TI - LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through up-regulating EZH2. AB - Emerging evidences have indicated that long non-coding RNAs (LncRNAs) play vital roles in cancer development and progression. Previous studies have suggested that overexpression of SPRY4-IT1 predicates poor prognosis and promotes tumor progress in several cancers. However, the underlying mechanism of SPRY4-IT1 in bladder cancer remains unknown. In this study, we found that SPRY4-IT1 knockdown induced inhibition of cell proliferation, cell migration and invasion ability, and caused promotion of apoptosis in bladder cancer both in vitro and in vivo. Mechanistically, knockdown of SPRY4-IT1 increased the expression of miR-101-3p and subsequently inhibited the expression of EZH2 at posttranscriptional level. Importantly, SPRY4-IT1 could directly interact with miR-101-3p and down regulation of miR-101-3p efficiently reversed the suppression of EZH2 induced by SPRY4-IT1 shRNA. Thus, SPRY4-IT1 positively regulated the expression of EZH2 through sponging miR-101-3p, and played an oncogenic role in bladder cancer progression. Together, our study elucidates the role of LncRNA SPRY4-IT1 as a miRNA sponge in bladder cancer, and sheds new light on LncRNA-directed diagnostics and therapeutics in bladder cancer. PMID- 27998762 TI - Rocaglamide breaks TRAIL-resistance in human multiple myeloma and acute T-cell leukemia in vivo in a mouse xenogtraft model. AB - Multiple myeloma (MM) is an incurable malignancy by the presently known therapies. TRAIL is a promising anticancer agent that virtually not shows any toxicity to normal cells. We have recently carried out clinical trials with a human circularly permuted TRAIL, CPT, against MM saw a partial response in approximate 20-30% of patients. In the current study, we investigated the cause of CPT resistance and revealed that the majority of the MM patients express elevated levels of c-FLIP. Knockdown of c-FLIP expression by siRNA alone was sufficient to increase CPT-mediated apoptosis in a CPT-resistant human MM cell line U266. To overcome CPT resistance, we investigated the combination of CPT with Rocaglamides(s) in MM which has been shown to inhibit c-FLIP expression in vitro. We show that Rocaglamide(s) overcomes CPT resistance in U266 in vitro and significant increases in anti-tumor efficacies of CPT in mice xenografted with U266. Similar results were also obtained in mice xenografted with the CPT resistant human acute T-cell leukemia cell line Molt-4. Our study suggests that the combination of Rocaglamide(s) with CPT may provide a more efficient treatment against myeloma and leukemia. PMID- 27998763 TI - Doxorubicin and edelfosine lipid nanoparticles are effective acting synergistically against drug-resistant osteosarcoma cancer cells. AB - Despite the great advances that have been made in osteosarcoma therapy during recent decades, recurrence and metastases are still the most common outcome of the primary disease. Current treatments include drugs such as doxorubicin (DOX) that produce an effective response during the initial exposure of tumor cells but sometimes induce drug resistance within a few cycles of chemotherapy. New therapeutic strategies are therefore needed to overcome this resistance. To this end, DOX was loaded into lipid nanoparticles (LN) and its efficacy was evaluated in commercial and patient-derived metastatic osteosarcoma cell lines. DOX efficacy was heavily influenced by passage number in metastatic cells, in which an overexpression of P-gp was observed. Notably, DOX-LN overcame the resistance associated with cell passage and improved DOX efficacy fivefold. Moreover, when DOX was co-administered with either free or encapsulated edelfosine (ET), a synergistic effect was observed. This higher efficacy of the combined treatment was found to be at least partially due to an increase in caspase-dependent cell death. The combination of DOX and ET is thus likely to be effective against osteosarcoma. PMID- 27998764 TI - Mitochondrial proteins NIP-SNAP-1 and -2 are a target for the immunomodulatory activity of clarithromycin, which involves NF-kappaB-mediated cytokine production. AB - Macrolide antibiotics have immunomodulatory activities, including suppression of cytokine production, cell adhesion molecule expression, and mucin production. These immunomodulatory activities improve the symptoms of respiratory diseases associated with chronic inflammation. However, the underlying molecular mechanism(s) is not well understood yet. To address this, we prepared clarithromycin (CAM)-conjugated Sepharose and examined bound cellular proteins by proteome analysis. We identified mitochondrial proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25-like protein homolog (NIP-SNAP)-1 and -2 and very long-chain acyl-CoA dehydrogenase (VLCAD) as CAM binding proteins. Production of proinflammatory cytokines (IL-8 and IL-6) induced by lipopolysaccharides (LPSs) and Pam3-CSK4 in human epithelial cell lines BEAS 2B and T24 were suppressed by knockdown of NIP-SNAP-1 or -2, and partly by knockdown of VLCAD. Also, knockdown of NIP-SNAP-1 or -2 in various cell lines suppressed LPS-induced expression of IL-8 and IL-6 mRNA and NF-kappaB activity. Thus, CAM suppresses NF-kappaB-mediated proinflammatory cytokine production by interacting with mitochondrial proteins, NIP-SNAP-1 and -2. PMID- 27998766 TI - Evaluation of deoxynivalenol-induced toxic effects on mouse endometrial stromal cells: Cell apoptosis and cell cycle. AB - Deoxynivalenol (DON) is a type B trichothecene mycotoxin which has toxic effects on humans and animals. Although DON has been studied in various cell types for its cytotoxicity, there is litter information about the effects of DON on mouse endometrial stromal cells (ESCs). Thus, in this study, we investigated the toxic effects of DON on mouse ESCs and its possible mechanisms. DON inhibited the cell viability in a dose- and time-dependent manner. TUNEL assay results showed that DON caused apoptosis and TUNEL-positive cells increased with increasing DON concentrations in mouse ESCs. Western blot showed that DON significantly increased the expression levels of apoptosis-related protein including Caspase-9, Caspase-3, poly (ADP-ribose) polymerase (PARP) and the ratio of Bax/Bcl-2. After DON treatment, the expression levels of cell cycle-related protein including p38/p-p38, Cdc25C/p-Cdc25C, Cdc2/p-Cdc2 and cyclinB1 were significantly decreased and immunoprecipitation analysis showed that cyclinB1-Cdc2 complex was significantly decreased. However, the combination of SB203580 (p38 specific inhibitor) and DON treatment significantly reversed the depression of Cdc25C/p Cdc25C, Cdc2/p-Cdc2, cyclinB1 and cyclinB1-Cdc2 complex. Collectively, these data suggest that DON causes apoptosis via mitochondria apoptosis pathway and induces G2 arrest via p38 MAPK signaling pathway in mouse ESCs. PMID- 27998765 TI - MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation. AB - Hepatocellular carcinoma (HCC) is a common digestive malignancy. MiR-223, a well identified miRNA, exhibits diverse properties in different cancers. In this study, we demonstrated that miR-223 could suppress cell growth and promote apoptosis in HepG2 and Bel-7402 HCC cell lines. We screened and identified a novel miR-223 target, Ras-related protein Rab-1(Rab1). Upregulation of miR-223 would specifically and markedly down-regulate Rab1 expression. In addition, miR 223-overexpressing subclones showed significant cell growth inhibition by increasing cell apoptosis in HepG2 and Bel-7402 cells. To identify the mechanisms, we firstly investigated the mTOR pathway and found that pmTOR, p70S6K and Bcl-2 were dramatically down-regulated after miR-223 transfection, while no changes in the level of Bax was visualized. Furthermore, our data showed that the anti-tumor effects arising from miR-223 transfection in HCC cells may be due to the deactivation of mTOR pathway caused by the suppression of Rab1 expression when miR-223 is overexpressed. In summary, our results indicate that miR-223 functions as a tumor suppressor and plays a critical role in inhibiting the tumorigenesis and promoting the apoptosis of HCC through the mTOR signaling pathway in vitro. By targeting Rab1, miR-223 efficiently mediates the mTOR pathway. Given these, miR-223 may be a potential therapeutic target for treating HCC. PMID- 27998767 TI - Maternal exosomes in diabetes contribute to the cardiac development deficiency. AB - Maternal diabetes mellitus induces an increased risk of congenital heart defects (CHD), however, the exact mechanisms are still not fully illustrated. In this study, diabetic pregnant C57BL/6 mice were induced by injection of streptozotocin before mating. Compared with the control normal mice, diabetic pregnant mice displayed significant changes of the exosomal miRNA contents in the blood, as revealed by RNA-seq analysis. Multiple of these miRNAs were found involved in cardiac development regulation. Moreover, fluorescence labeled exosomes and gold nanoparticles could cross the placenta barrier and infiltrated into the embryonic organs/tissues, including the heart, during embryonic development. Injection of diabetic maternal exosomes strikingly increased the risk of CHD in the normal recipient pregnant mice. Taken together, we could draw the conclusion that maternal exosomes in diabetes could cross the maternal-fetal barrier and contribute to the cardiac development deficiency possibly via miRNAs, providing new insights in CHD prevention and treatment. PMID- 27998768 TI - Low grade inflammation inhibits VEGF induced HUVECs migration in p53 dependent manner. AB - In the course of studying crosstalk between inflammation and angiogenesis, high doses of pro-inflammatory factors have been reported to induce apoptosis in cells. Under normal circumstances also the pro-inflammatory cytokines are being released in low doses and are actively involved in cell signaling pathways. We studied the effects of low grade inflammation in growth factor induced angiogenesis using tumor necrosis factor alfa (TNFalpha) and vascular endothelial growth factor A (VEGF) respectively. We found that low dose of TNFalpha can inhibit VEGF induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Low dose of TNFalpha induces mild upregulation and moreover nuclear localization of tumor suppressor protein 53 (P53) which causes decrease in inhibitor of DNA binding-1 (Id1) expression and shuttling to the cytoplasm. In absence of Id1, HUVECs fail to upregulate beta3-integrin and cell migration is decreased. Connecting low dose of TNFalpha induced p53 to beta3-integrin through Id1, we present additional link in cross talk between inflammation and angiogenesis. PMID- 27998769 TI - Passive immunization targeting the N-terminal region of phosphorylated tau (residues 68-71) improves spatial memory in okadaic acid induced tauopathy model rats. AB - Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive loss of memory and other cognitive functions. The cognitive impairment in patients with AD is closely associated with loss of synapses and the formation of neurofibrillary tangles (NFT) containing hyperphosphorylated tau in the hippocampus. Effective treatment for AD is still not available. In this study, the sequence comprising of residues 50-71 in the N-terminal region of tau, containing theoretically predicted B- and T-cell epitopes in close proximity to pathologically relevant phospho-serine (residue 68) and phospho-threonine (residues 69, 71) was selected as a potential immunotherapeutic peptide. This 22 residue long phospho-peptide (50TPTEDGSEEPGSETSDAKpSpTPpT71) was custom synthesized and its therapeutic potential was tested in experimental rats. For this purpose, adult Sprague-Dawley rats were intranasally treated with okadaic acid (OA), a selective inhibitor of protein phosphatase PP2A. Within a day of OA administration, these rats showed marked impairment in cognitive functions with a significant increase in p-tau/t-tau ratio in the hippocampal homogenates. Passive immunization studies conducted in these OA treated rats with polyclonal anti phospho-peptide antibodies resulted in a significant improvement in learning and memory functions in Barne's maze task. Further, p-tau levels in the hippocampal homogenates were reduced. In addition, these antibodies effectively prevented the aggregation of recombinant tau in vitro. These results demonstrate that targeting N-terminal region of tau harbouring the phospho-residue cluster 68-71 would be beneficial and may present an effective therapeutic opportunity for AD and other tauopathies. PMID- 27998770 TI - MicroRNA-340 inhibits the proliferation and invasion of hepatocellular carcinoma cells by targeting JAK1. AB - Increasing evidence indicates that dysregulation of microRNAs (miRNAs) contributes to tumorigenesis. MicroRNA-340 (miR-340) is downregulated in several types of cancer. However, the functional mechanism of miR-340 in hepatocellular carcinoma (HCC) remains unclear. Here, we showed that miR-340 was significantly downregulated in HCC tissues and cell lines. Gain-of-function experiments demonstrated that miR-340 overexpression inhibited HCC cell proliferation, migration, and invasion in vitro, and suppressed tumor growth in vivo. Janus kinase 1 (JAK1) was identified as a direct target of miR-340 in HCC cells. Ectopic expression of JAK1 reversed the inhibitory effects of miR-340. Further investigations showed that miR-340 dramatically inhibited the expression of signal transducer and activator of transcription (STAT)3 downstream molecules including Bcl-2, cyclin D1, and matrix metalloprotease (MMP)-2. The present findings indicated that miR-340 suppressed HCC cell proliferation and invasion by regulating the JAK1/STAT3 pathway, suggesting its potential as a novel therapeutic target for HCC. PMID- 27998771 TI - Deficiency in ubiquitin-like protein Ubl4A impairs migration of fibroblasts and macrophages. AB - Ubiquitin-like protein Ubl4A is a small, multi-functional protein with no ubiquitination activity. We have previously demonstrated that Ubl4A directly interacts with actin-related protein 2/3 complex (Arp2/3) and promotes Arp2/3 dependent actin branching, thereby accelerating plasma membrane translocation of protein kinase Akt upon insulin stimulation. Here, we show that Ubl4A is critical for plasma membrane protrusion and cell migration. Ubl4A, F-actin and Arp2/3 are co-localized at the cell leading edges during wound closure. Knockout of Ubl4A significantly reduces actin-mediated membrane protrusion and delays wound healing by primary mouse embryonic fibroblasts. Consistently, the ability of fibroblasts to migrate out of corneal tissue ex vivo is also impaired in Ubl4A-deficient mice. Furthermore, cell motility, but not phagocytosis, is significantly decreased in Ubl4A-deficient macrophages compared with wild-type controls. These results imply an important role for Ubl4A in cell migration-associated pathophysiological processes. PMID- 27998772 TI - Zinc induces apoptosis on cervical carcinoma cells by p53-dependent and independent pathway. AB - OBJECTIVE: There is evidence that the mineral zinc is involved in the apoptotic cell death of various carcinoma cells. In this study, we aim to determine whether zinc in the form of CIZAR induces apoptosis in cervical carcinoma cells by increasing intracellular zinc concentration. STUDY DESIGN: CaSki and HeLa cervical carcinoma cells and HPV-16 DNA-transformed keratinocyte (CRL2404) were treated with different concentrations of CIZAR. The cell viability test was carried out, the intracellular level of zinc was determined, and apoptosis was confirmed by flow cytometry after propidium iodide (PI) staining and fluorescence microscopy under DAPI staining. The expression of cell-cycle regulators was analyzed by Western blot, including the knock down of p53 and expression of HPV E6 and E7 genes by RT-PCR. RESULTS: Intracellular zinc accumulation induced the down-regulation of E6/E7 proteins through targeting of the specific transcriptional factors in the upstream regulatory region. p53 was induced after CIZAR treatment and p53-dependent apoptosis did not occur after knock down by p53 siRNA. In cervical carcinoma cells, regardless of HPV-infection, CIZAR induces apoptosis by the activation of the p53-independent pathways through the up regulation of p21waf1, the down-regulation of c-Myc, and by decreasing the Bcl 2/Bax ratio. CONCLUSIONS: CIZAR induces apoptosis not only through the restoration of p53/Rb-dependent pathways in HPV-positive cells, but also through the activation of p53/Rb-independent pathways and the mitochondrial death-signal pathway in cervical carcinoma cells regardless of HPV-infection. PMID- 27998773 TI - Scutellarin suppresses migration and invasion of human hepatocellular carcinoma by inhibiting the STAT3/Girdin/Akt activity. AB - Scutellarin is an active flavone from Erigeron breviscapine (vant) Hand Mass. This study aimed to investigate the potential role of scutellarin in migration and invasion of human hepatocellular carcinoma (HCC) cells and its possible mechanism. In comparison with the vehicle-treated controls, treatment with scutellarin (50 mg/kg/day) for 35 days significantly mitigated the lung and intrahepatic metastasis of HCC tumors in vivo. Scutellarin treatment significantly reduced HepG2 cell viability in a dose-dependent manner, and inhibited migration and invasion of HCC cells in vitro. Scutellarin treatment significantly reduced STAT3 and Girders of actin filaments (Girdin) expression, STAT3 and Akt phosphorylation in HCC cells. Introduction of STAT3 overexpression restored the scutellarin-downregulated Girdin expression, Akt activation, migration and invasion of HCC cells. Furthermore, induction of Girdin overexpression completely abrogated the inhibition of scutellarin on the Akt phosphorylation, migration and invasion of HCC cells. Scutellarin can inhibit HCC cell metastasis in vivo, and migration and invasion in vitro by down-regulating the STAT3/Girdin/Akt signaling. PMID- 27998774 TI - Downregulation of bone morphogenetic protein receptor 2 promotes the development of neuroblastoma. AB - Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In this study, we examined the expression of bone morphogenetic protein receptor 2 (BMPR2) in primary NB and adjacent non-tumor samples (adrenal gland). BMPR2 expression was significantly downregulated in NB tissues, particularly in high grade NB, and was inversely related to the expression of the NB differentiation markers ferritin and enolase. The significance of the downregulation was further explored in cultured NB cells. While enforced expression of BMPR2 decreased cell proliferation and colony-forming activity, shRNA-mediated knockdown of BMPR2 led to increased cell growth and clonogenicity. In mice, NB cells harboring BMPR2 shRNA showed significantly increased tumorigenicity compared with control cells. We also performed a retrospective analysis of NB patients and identified a significant positive correlation between tumor BMPR2 expression and overall survival. These findings suggest that BMPR2 may play an important role in the development of NB. PMID- 27998775 TI - In vitro effects of the anti-Alzheimer drug memantine on the human erythrocyte membrane and molecular models. AB - Memantine is a NMDA antagonist receptor clinically used for treating Alzheimer's disease. NMDA receptors are present in the human neurons and erythrocyte membranes. The aim of the present study was to investigate the effects of memantine on human erythrocytes. With this purpose, the drug was developed to in vitro interact with human red cells and bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). The latter represent lipids respectively present in both outer and inner monolayers of the red cell membrane. Results obtained by scanning electron microscopy (SEM) showed that memantine changed the normal biconcave shape of red cells to cup-shaped stomatocytes. According to the bilayer-couple hypothesis the drug intercalated into the inner monolayer of the erythrocyte membrane. Experimental results obtained by X-ray diffraction on multibilayers of DMPC and DMPE, and by differential scanning calorimetry on multilamellar vesicles indicated that memantine preferentially interacted with DMPC in a concentration dependent manner. Thus, it can be concluded that in the low therapeutic plasma concentration of circa 1 MUM memantine is located in NMDA receptor channel without affecting the erythrocyte shape. However, at higher concentrations, once the receptors became saturated excess of memantine molecules (20 MUM) would interact with phosphoinositide lipids present in the inner monolayer of the erythrocyte membrane inducing the formation of stomatocytes. However, 40-50 MUM memantine was required to interact with isolated phosphatidylcholine bilayers. PMID- 27998776 TI - Follicular thyroglobulin induces cathepsin H expression and activity in thyrocytes. AB - Thyroglobulin (Tg) stored in thyroid follicles exerts a potent negative-feedback effect on each step of pre-hormone biosynthesis, including Tg gene transcription and iodine uptake and organification, by suppressing the expression of specific transcription factors that regulate these steps. Pre-hormones are stored in the follicular colloid before being reabsorbed. Following lysosomal proteolysis of its precursor, thyroid hormone (TH) is released from thyroid follicles. Although the suppressive effects of follicular Tg on each step of pre-hormone biosynthesis have been extensively characterized, whether follicular Tg accumulation also affects hormone reabsorption, proteolysis, and secretion is unclear. In this study we explored whether follicular Tg can regulate the expression and function of the lysosomal endopeptidases cathepsins. We found that in the rat thyroid cell line FRTL-5 follicular Tg induced cathepsin H mRNA and protein expression, as well as cathepsin H enzyme activity. Double immunofluorescence staining showed that Tg endocytosis promoted cathepsin H translocalization into lysosomes where it co-localized with internalized Tg. These results suggest that cathepsin H is an active participant in lysosome-mediated pre-hormone degradation, and that follicular Tg stimulates mobilization of pre-hormones by activating cathepsin H associated proteolysis pathways. PMID- 27998777 TI - Menopause-related brain activation patterns during visual sexual arousal in menopausal women: An fMRI pilot study using time-course analysis. AB - The aging process and menopausal transition are important factors in sexual dysfunction of menopausal women. No neuroimaging study has assessed the age- and menopause-related changes on brain activation areas associated with sexual arousal in menopausal women. The purpose of this study was to evaluate the time course of regional brain activity associated with sexual arousal evoked by visual stimulation in premenopausal and menopausal women, and further to assess the effect of menopause on the brain areas associated with sexual arousal in menopausal women using functional magnetic resonance imaging (fMRI). Thirty volunteers consisting of 15 premenopausal and 15 menopausal women underwent the fMRI. For the activation condition, volunteers viewed sexually arousing visual stimulation. The brain areas with significantly higher activation in premenopausal women compared with menopausal women included the thalamus, amygdala, and anterior cingulate cortex (ACC) using analysis of covariance adjusting for age (p<0.005). Blood-oxygen-level-dependent signal changes in the amygdala while viewing erotic video were positively correlated with estrogen levels in the two groups. Our findings suggest that reduced brain activity of the thalamus, amygdala, and ACC in menopausal women may be associated with menopause related decrease in sexual arousal. These findings might help elucidate the neural mechanisms associated with sexual dysfunction in menopausal women. PMID- 27998779 TI - Systemic blood pressure alters cortical blood flow and neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat. AB - Inference on nociceptive and pain-related processes from functional magnetic resonance imaging is made with the assumption that the coupling of neuronal activity and cerebral hemodynamic changes is stable. However, since nociceptive stimulation is associated with increases in systemic arterial pressure, it is essential to determine whether this coupling remains the same during different levels of nociception and pain. The main objective of the present study was to compare the amplitude of local field potentials (LFP) and cerebral blood flow (CBF) changes in the primary somatosensory cortex during nociceptive electrical stimulation of the contralateral or ipsilateral forepaw in isoflurane anesthetized rats, while manipulating mean arterial pressure (MAP). MAP changes induced by nociceptive stimulation were manipulated by transecting the spinal cord at the upper thoracic segments (T1-T2), which interrupts sympathetic pathways and prevents nociception-related MAP increases, while sensory pathways between the forepaws and the brain remain intact. Intensity-dependent increases in MAP and CBF were observed and these effects were abolished or significantly decreased after spinal transection (p<0.001 and p<0.05, respectively). In contrast, the intensity-dependent changes in LFP amplitude were decreased for the contralateral stimulation but increased for the ipsilateral stimulation after spinal transection (p<0.05). Thus, neurovascular coupling was altered differently by stimulus-induced MAP changes, depending on stimulus intensity and location. This demonstrates that CBF changes evoked by nociceptive processing do not always match neuronal activity, which may lead to inaccurate estimation of neuronal activity from hemodynamic changes. These results have important implications for neuroimaging of nociceptive and pain-related processes. PMID- 27998778 TI - Polyunsaturated fatty acid biostatus, phospholipase A2 activity and brain white matter microstructure across adolescence. AB - Adolescence is a period of major brain white matter (WM) changes, and membrane lipid metabolism likely plays a critical role in brain WM myelination. Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential components of cell membranes including oligodendrocytes, and LC-PUFA release and turnover in membranes is regulated by phospholipase A2 enzymes. To investigate the role of membrane lipid metabolism in healthy WM myelination across adolescence, the present study examined the relationship between membrane LC-PUFA biostatus, phospholipase A2 activity, and brain WM microstructure in healthy subjects aged 9-20years (n=30). Diffusion tensor imaging (DTI) was performed to measure average fractional anisotropy (FA) and diffusivity (indices sensitive to WM myelination) of nine major cerebral WM tracts. Blood samples were collected to measure erythrocyte membrane fatty acid concentrations and plasma intracellular phospholipase A2 activity (inPLA2). Plasma inPLA2 activity showed a significant U-curved association with WM radial diffusivity, and an inverted U-curved association with WM FA, independent of age. A significant positive linear correlation was observed between docosahexaenoic acid concentration and axial diffusivity in the corpus callosum. These findings suggest that there may be optimal physiological inPLA2 activity levels associated with healthy WM myelination in late childhood and adolescence. Myelination may be mediated by cleavage of docosahexaenoic acid from membrane phospholipids by inPLA2. These findings have implications for our understanding of the role of LC-PUFA homeostasis in myelin-related neurodevelopmental disorders. PMID- 27998782 TI - Improvement of wastewater sludge dewatering performance using titanium salt coagulants (TSCs) in combination with magnetic nano-particles: Significance of titanium speciation. AB - In this study, the effects of chemical conditioning using titanium salt coagulants (TSCs) of different hydrolysis speciation in combination with magnetic nano-particles on dewatering performance of waste activated sludge were evaluated by means of specific resistance to filtration (SRF) and capillary suction time (CST). The morphological and extracellular polymeric substances (EPS) properties under chemical conditioning were investigated in detail to understand the reaction mechanisms involved. The results showed that the TSC with basicity of 0.5 performed better in improving sludge dewatering performance than other TSCs. Sludge floc formed by TSC0.5 treatment was characterized by larger floc size and higher floc strength than that conditioned by other TSCs. EPS compression and densification were the major mechanisms of sludge conditioning, and TSC0.5 had better performance in compressing EPS structure. In addition, reduction of soluble EPS concentration, especially protein-like substances contributed to improvement of sludge filterability under conditioning. Furthermore, addition of Fe2O3 nanoparticles could further improve dewatering performance and decrease compressibility of sludge system by acting as skeleton builders and enhancing floc strength. The sludge particles aggregation efficiency was effectively improved with addition of nano-Fe2O3. They also were able to bind with protein like substance in EPS component, which might contribute to promotion of sludge filterability. PMID- 27998781 TI - TFP5 is comparable to mild hypothermia in improving neurological outcomes in early-stage ischemic stroke of adult rats. AB - AIM: We compared the efficacy of a modified truncated 24-aa peptide (TFP5), derived from the cyclin-dependent kinase 5 (CDK5)-activating cofactor p35, with mild hypothermia (MH), and determined whether the efficacy of TFP5 is affected by MH. METHODS: Ischemic stroke was induced in adult male Sprague-Dawley rats for 2h. Immediately after initiating reperfusion, TFP5, MH, or the combination of the two were administrated. 48h after reperfusion, neurological outcomes were evaluated. RESULTS: Rats that received either MH, TFP5, or the combined treatment showed smaller brain infarct size than normothermia control (NT), and there was no apparent difference among these three treatment groups. The neurological deficit was significantly improved only by the combined treatment. MH or TFP5 ameliorated the blood-brain barrier (BBB) disruption in ischemic regions with similar efficacy, whereas the combination of them had a trend toward better effect. Besides, the cleavage of p35 into p25 and apoptosis in ischemic regions was inhibited by TFP5 or the combination, but not by MH alone. CONCLUSIONS: TFP5 is comparable to MH in improving neurological outcomes in early-stage adult ischemic stroke. When TFP5 is given along with MH, less neurological deficit tends to be achieved. PMID- 27998780 TI - Paternal deprivation affects social behaviors and neurochemical systems in the offspring of socially monogamous prairie voles. AB - Early life experiences, particularly the experience with parents, are crucial to phenotypic outcomes in both humans and animals. Although the effects of maternal deprivation on offspring well-being have been studied, paternal deprivation (PD) has received little attention despite documented associations between father absence and children health problems in humans. In the present study, we utilized the socially monogamous prairie vole (Microtus ochrogaster), which displays male female pair bonding and bi-parental care, to examine the effects of PD on adult behaviors and neurochemical expression in the hippocampus. Male and female subjects were randomly assigned into one of two experimental groups that grew up with both the mother and father (MF) or with the mother-only (MO, to generate PD experience). Our data show that MO subjects received less parental licking/grooming and carrying and were left alone in the nest more frequently than MF subjects. At adulthood (~75days of age), MO subjects displayed increased social affiliation (SOA) toward a conspecific compared to MF subjects, but the two groups did not differ in social recognition (SOR) and anxiety-like behavior. Interestingly, MO subjects showed consistent increases in both gene and protein expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) as well as the levels of total histone 3 and histone 3 acetylation in the hippocampus compared to MF subjects. Further, PD experience increased glucocorticoid receptor beta (GRbeta) protein expression in the hippocampus of females as well as increased corticotrophin receptor 2 (CRHR2) protein expression in the hippocampus of males, but decreased CRHR2 mRNA in both sexes. Together, our data suggest that PD has a long-lasting, behavior-specific effect on SOA and alters hippocampal neurochemical systems in the vole brain. The functional role of such altered neurochemical systems in social behaviors and the potential involvement of epigenetic events should be further studied. PMID- 27998783 TI - Decoupling of DAMO archaea from DAMO bacteria in a methane-driven microbial fuel cell. AB - Anaerobic oxidation of methane (AOM) contributes significantly to the global methane sink. Previously, studies of anaerobic methanotrophic (ANME) archaea have been limited as they have not been separable from their bacterial partners during the AOM process because of their dependence on the bacteria. A microbial fuel cell (MFC) is a device capable of directly transforming chemical energy to electrical energy via electrochemical reactions involving biochemical pathways. In this study, decoupling of denitrifying anaerobic methane oxidation (DAMO) archaea and DAMO bacteria was investigated in an microbial fuel cell (MFC) using methane as the fuel. The DAMO fuel cell worked successfully but demonstrated weak electrogenic capability with around 25 mV production. After 45 days' enrichment, the sequencing and fluorescence in situ hybridization results showed the DAMO archaea percentage had increased from 26.96% (inoculum) to 65.77% (electrode biofilm), while the DAMO bacteria percentage decreased from 24.39% to 2.07%. Moreover, the amount of ANME-2d had doubled in the electrode biofilm compared with the inoculum. The sequencing results also showed substantial enrichment of the Ignavibacterium and Geobacter genera. The roles of Ignavibacterium and Geobacter in the MFC system need to be further investigated. Nevertheless, these results illustrate that an MFC device may provide a possible approach to separate DAMO archaea from DAMO bacteria. PMID- 27998784 TI - The roles of bacteriophages in membrane-based water and wastewater treatment processes: A review. AB - Membrane filtration processes have been widely applied in water and wastewater treatment for many decades. Concerns related to membrane treatment effectiveness, membrane lifespan, and membrane fouling control have been paid great attention. To achieve sustainable membrane operation with regards to low energy and maintenance cost, monitoring membrane performance and applying suitable membrane control strategies are required. As the most abundant species in water and wastewater, bacteriophages have shown great potential to be employed in membrane processes as (1) indicators to assess membrane performance considering their similar properties to human pathogenic waterborne viruses; (2) surrogate particles to monitor membrane integrity due to their nano-sized nature; and (3) biological agents to alleviate membrane fouling because of their antimicrobial properties. This study aims to provide a comprehensive review on the roles of bacteriophages in membrane-based water and wastewater treatment processes, with focuses on their uses for membrane performance examination, membrane integrity monitoring, and membrane biofouling control. The advantages, limitations, and influencing factors for bacteriophage-based applications are reported. Finally, the challenges and prospects of bacteriophage-based applications in membrane processes for water treatment are highlighted. PMID- 27998785 TI - Integrating microbial fuel cells with anaerobic acidification and forward osmosis membrane for enhancing bio-electricity and water recovery from low-strength wastewater. AB - Microbial fuel cells (MFCs) and forward osmosis (FO) are two emerging technologies with great potential for energy-efficient wastewater treatment. In this study, anaerobic acidification and FO membrane were simultaneously integrated into an air-cathode MFC (AAFO-MFC) for enhancing bio-electricity and water recovery from low-strength wastewater. During a long-term operation of approximately 40 days, the AAFO-MFC system achieved a continuous and relatively stable power generation, and the maximum power density reached 4.38 W/m3. The higher bio-electricity production in the AAFO-MFC system was mainly due to the accumulation of ethanol resulted from anaerobic acidification process and the rejection of FO membrane. In addition, a proper salinity environment in the system controlled by the addition of MF membrane enhanced the electricity production. Furthermore, the AAFO-MFC system produced a high quality effluent, with the removal rates of organic matters and total phosphorus of more than 97%. However, the nitrogen removal was limited for the lower rejection of FO membrane. The combined biofouling and inorganic fouling were responsible for the lower water flux of FO membrane, and the Desulfuromonas sp. utilized the ethanol for bio-electricity production was observed in the anode. These results substantially improve the prospects for simultaneous wastewater treatment and energy recovery, and further studies are needed to optimize the system integration and operating parameters. PMID- 27998786 TI - Combination of cupric ion with hydroxylamine and hydrogen peroxide for the control of bacterial biofilms on RO membranes. AB - Combinations of Cu(II) with hydroxylamine (HA) and hydrogen peroxide (H2O2) (i.e., Cu(II)/HA, Cu(II)/H2O2, and Cu(II)/HA/H2O2 systems) were investigated for the control of P. aeruginosa biofilms on reverse osmosis (RO) membranes. These Cu(II)-based disinfection systems effectively inactivated P. aeruginosa cells, exhibiting different behaviors depending on the state of bacterial cells (planktonic or biofilm) and the condition of biofilm growth and treatment (normal or pressurized condition). The Cu(II)/HA and Cu(II)/HA/H2O2 systems were the most effective reagents for the inactivation of planktonic cells. However, these systems were not effective in inactivating cells in biofilms on the RO membranes possibly due to the interactions of Cu(I) with extracellular polymeric substances (EPS), where biofilms were grown and treated in center for disease control (CDC) reactors. Different from the results using CDC reactors, in a pressurized cross flow RO filtration unit, the Cu(II)/HA/H2O2 treatment significantly inactivated biofilm cells formed on the RO membranes, successfully recovering the permeate flux reduced by the biofouling. The pretreatment of feed solutions by Cu(II)/HA and Cu(II)/HA/H2O2 systems (applied before the biofilm formation) effectively mitigated the permeate flux decline by preventing the biofilm growth on the RO membranes. PMID- 27998787 TI - Formation and reactivity of inorganic and organic chloramines and bromamines during oxidative water treatment. AB - The formation and further reactions of halamines during oxidative water treatment can be relevant for water quality. In this study, we investigated the formation and reactivity of several inorganic and organic halamines (monochloramine, N chloromethylamine, N-chlorodimethylamine, monobromamine, dibromamine, N bromomethylamine, N,N-dibromomethylamine, and N-bromodimethylamine) by kinetic experiments, transformation product analysis, and quantum chemical computations. Kinetic model simulations were conducted to evaluate the relevance of halamines for various water treatment scenarios. Halamines were quickly formed from the reaction of chlorine and bromine with ammonia or organic amines. Species-specific second-order rate constants for the reaction of chlorine and bromine with ammonia, methyl- and dimethylamine were in the order of 106-108 M-1s-1. The formed halamines were found to be reactive towards phenolic compounds, forming halogenated phenols via electrophilic aromatic substitution (phenol and resorcinol) or quinones via electron transfer (catechol and hydroquinone). At near neutral pH, apparent second-order rate constants for these reactions were in the order of 10-4-10-1 M-1s-1 for chloramines and 101-102 M-1s-1 for bromamines. Quantum chemical computations were used to determine previously unknown aqueous pKa values, gas phase bond dissociation energies (BDE) and partial atomic charges of the halamines, allowing a better understanding of their reactivities. Kinetic model simulations, based on the results of this study, showed that during chlorination inorganic and organic chloramines are the main halamines formed. However, their further reactions with organic matter are outcompeted kinetically by chlorine. During ozonation, mainly inorganic bromamines are formed, since ozone quickly oxidizes organic amines. The further reactions of bromamine are typically outcompeted by ozone and thus generally of minor importance. The use of peracetic acid for saline ballast water treatment can result in the formation of substantial amounts of bromamines, which can react with dissolved organic matter and contribute to the formation of brominated products. PMID- 27998788 TI - Health benefits of fermented foods: microbiota and beyond. AB - Fermented foods and beverages were among the first processed food products consumed by humans. The production of foods such as yogurt and cultured milk, wine and beer, sauerkraut and kimchi, and fermented sausage were initially valued because of their improved shelf life, safety, and organoleptic properties. It is increasingly understood that fermented foods can also have enhanced nutritional and functional properties due to transformation of substrates and formation of bioactive or bioavailable end-products. Many fermented foods also contain living microorganisms of which some are genetically similar to strains used as probiotics. Although only a limited number of clinical studies on fermented foods have been performed, there is evidence that these foods provide health benefits well-beyond the starting food materials. PMID- 27998789 TI - DNA methylation contributes to deregulation of 12 cancer-associated microRNAs and breast cancer progression. AB - The methylation of promoter CpG islands and the interaction between microRNAs (miRNAs) and messenger RNAs (mRNAs) of target genes are considered two crucial mechanisms for gene and pathway deregulation in malignant tumors. The aim of this study was to analyze the role of promoter methylation in altering the expression of 13 miRNAs that are associated with breast cancer (BC): miR-124, -125b, -127, 132, -137, -148a, -191, -193a, -203, -212, -34b, -375, -9. The role of methylation in the deregulation of these miRNAs has not been previously assessed in the representative set of BC samples. We used a set of 58 paired (tumor/normal) breast tissue samples and methylation-specific PCR to demonstrate significant aberrations in the methylation patterns of 9 miRNA genes. In particular, we observed hypermethylation of MIR-127, -132, and -193a, and hypomethylation of MIR-191 for the first time. Using quantitative PCR, we established a strong correlation between promoter methylation and expression levels for 12 miRNA genes (all except MIR-212); this finding demonstrates the functional importance of altered methylation patterns. We also performed a correlation analysis between expression levels of the 13 miRNAs and 5 cancer associated genes, namely RASSF1(A), CHL1, APAF1, DAPK1, and BCL2, which were predicted as targets for these miRNAs, to investigate the impact of these miRNAs on these genes with key cellular functions in BC. Significant negative correlation was revealed for the following miRNA-mRNA pairs: miR-127-5p and DAPK1, miR-375 and RASSF1(A), and miR-124-3p and BCL2. Additionally, we also found a strong association between hypermethylation of MIR-127 and MIR-125b-1 and BC progression, particularly metastasis. Thus, our findings provide evidence for the significant role of methylation in the deregulation of 12 miRNA genes in BC, identify putative novel functional miRNA-mRNA pairs, and suggest MIR-127 and MIR 125b-1 hypermethylation to be potential biomarkers of BC metastasis. PMID- 27998790 TI - A 15-gene signature for prediction of colon cancer recurrence and prognosis based on SVM. AB - OBJECTIVE: To screen the gene signature for distinguishing patients with high risks from those with low-risks for colon cancer recurrence and predicting their prognosis. METHODS: Five microarray datasets of colon cancer samples were collected from Gene Expression Omnibus database and one was obtained from The Cancer Genome Atlas (TCGA). After preprocessing, data in GSE17537 were analyzed using the Linear Models for Microarray data (LIMMA) method to identify the differentially expressed genes (DEGs). The DEGs further underwent PPI network based neighborhood scoring and support vector machine (SVM) analyses to screen the feature genes associated with recurrence and prognosis, which were then validated by four datasets GSE38832, GSE17538, GSE28814 and TCGA using SVM and Cox regression analyses. RESULTS: A total of 1207 genes were identified as DEGs between recurrence and no-recurrence samples, including 726 downregulated and 481 upregulated genes. Using SVM analysis and five gene expression profile data confirmation, a 15-gene signature (HES5, ZNF417, GLRA2, OR8D2, HOXA7, FABP6, MUSK, HTR6, GRIP2, KLRK1, VEGFA, AKAP12, RHEB, NCRNA00152 and PMEPA1) were identified as a predictor of recurrence risk and prognosis for colon cancer patients. CONCLUSION: Our identified 15-gene signature may be useful to classify colon cancer patients with different prognosis and some genes in this signature may represent new therapeutic targets. PMID- 27998791 TI - Molecular modelling, dynamics simulation and characterization of antifungal chitinase from Sechium edule. AB - Chitinases are varied sized proteins which have the ability to degrade chitin and are present in a huge range of organisms like fungi, yeasts, arthropods, humans etc. and have been getting increased attention due to their biocontrol properties. In silico analysis sheds light on the extensive properties of this plant protein. In this paper, a particular antifungal protein Chitinase sourced from Sechium edule from East Khasi Hills, Meghalaya was characterized using an array of bioinformatics tools. The modelled protein showed conserved domains characteristic to glycosyl hydrolase, family 18 superfamily. Likewise, a part of the conserved domain area fits in with xylanase inhibitor Xip-1 and the class IotaIotaIota plant chitinases, for example, concanavalin B, hevamine, which have a GH18 area. The modelled wild type protein exhibited secondary characteristics comprising of 48.8% helix, 62.2% sheets and 13.8% turns, displaying an aliphatic index of 80.53 and instability index of 48.88 inferring upon the fact that the protein is relatively unstable without its appropriate environment. The paper functions as the first attempt to portray molecular dynamics simulation of Chitinase from Sechium edule reinforced by modelling and thorough characteristic analysis of the protein by employing parameters like Ramachandran Plot, Chou and Fasman Secondary Structure prediction, ProtParam etc. Further approaches like protein engineering and activity analysis suggested. PMID- 27998792 TI - Factors influencing local ecological knowledge of forage resources: Ethnobotanical evidence from West Africa's savannas. AB - Recording local ecological knowledge (LEK) is a useful approach to understanding interactions of the complex social-ecological systems. In spite of the recent growing interest in LEK studies on the effects of climate and land use changes, livestock mobility decisions and other aspects of agro-pastoral systems, LEK on forage plants has still been vastly under-documented in the West African savannas. Using a study area ranging from northern Ghana to central Burkina Faso, we thus aimed at exploring how aridity and socio-demographic factors drive the distributional patterns of forage-related LEK among its holders. With stratified random sampling, we elicited LEK among 450 informants in 15 villages (seven in Ghana and eight in Burkina Faso) via free list tasks coupled with ethnobotanical walks and direct field observations. We performed generalized linear mixed effects models (aridity- and ethnicity-based models) and robust model selection procedures. Our findings revealed that LEK for woody and herbaceous forage plants was strongly influenced by the ethnicity-based model, while aridity-based model performed better for LEK on overall forage resources and crop-related forage plants. We also found that climatic aridity had negative effect on the forage related LEK across gender and age groups, while agro- and floristic diversity had positive effect on the body of LEK. About 135 species belonging to 95 genera and 52 families were cited. Our findings shed more light on how ethnicity and environmental harshness can markedly shape the body of LEK in the face of global climate change. Better understanding of such a place-based knowledge system is relevant for sustainable forage plants utilization and livestock production. PMID- 27998793 TI - The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases. AB - INTRODUCTION: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise kappa scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC. METHODS: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3). RESULTS: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, kappa scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64. CONCLUSIONS: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided. PMID- 27998794 TI - Effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits in the hippocampus of streptozotocin-induced type 1 diabetes mellitus rats. AB - Increasing evidence demonstrates an association between diabetes and hippocampal neuron damage. This study aimed to determine the effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits (GCLM and GCLC) in the hippocampus of streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. At 12weeks after streptozotocin injection, T1DM rats were randomly divided into 4 groups (n=15 each group) to receive no treatment (T1DM), saline (T1DM+saline), alpha-lipoic acid (T1DM+alpha-lipoic acid), and troxerutin (T1DM+troxerutin), respectively, for 6weeks. Meanwhile, 10 control animals (NC group) were assessed in parallel. Learning performance was evaluated by the Morris water maze. After treatment, hippocampi were collected for pathological examination by hematoxylin and eosin (H&E) staining. Next, hippocampal superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were assessed. Finally, glutamate cysteine ligase catalytic (GCLC) and glutamate cysteine ligase modifier (GCLM) subunit mRNA and protein levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Compared with T1DM and T1DM+saline groups, escape latency was overtly reduced in T1DM+alpha lipoic acid and T1DM+troxerutin groups. Significantly increased GCLM and GCLC mRNA levels, GCLC protein amounts, SOD activity, and GSH levels, and reduced MDA amounts were observed in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. In T1DM and T1DM+saline groups, H&E staining showed less pyramidal cells in the hippocampus, with disorganized layers, karyopyknosis, decreased endochylema, and cavitation, effects relieved in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Troxerutin alleviates oxidative stress and promotes learning in streptozotocin-induced T1DM rats, a process involving GCLC expression. PMID- 27998796 TI - Propofol postconditioning attenuates hippocampus ischemia-reperfusion injury via modulating JAK2/STAT3 pathway in rats after autogenous orthotropic liver transplantation. AB - Liver transplantation has been a routine treatment for the end stage liver diseases. Severe changes in circulation system and internal environment may occur during transplant surgery and cause injury to many organs including brain. Specific mechanisms of brain injury associated with liver transplantation are not yet elucidated. Previous studies have shown that the JAK/STAT signal transduction pathways are involved in the development of the central nervous system, such as nerve cell proliferation, survival, differentiation, and it also have a role in the disease processes, including brain tumor, brain ischemia and other diseases of the central nervous system. In this study we investigate whether propofol plays an important role in protecting the hippocampus through JAK2/STAT3 pathway. Thirty-two healthy male Sprague-Dawley rats, were randomly divided into four groups (n=8). Sham operation group (group S), autogenous orthotropic liver transplantation group (group I), autogenous orthotropic liver transplantation+propofol treatment group (group P) and autogenous orthotropic liver transplantation+propofol+AG490 treatment group (group A). We evaluated histological damage, inflammation, oxidative stress and apoptosis in hippocampus using HE staining, light microscope, real-time PCR and western blot. The results showed that there was a significant damage of hippocampus in group I compared to the sham group as demonstrated by increased serum levels of S100beta, NSE and the histological changes. However, an induction of propofol reduced the levels of MDA, TNFalpha, S100beta, NSE and increased activity of SOD, IL-10, and attenuated the expression of JAK2 and STAT3, meanwhile. Consistently, pretreatment with JAK2/STAT3 pathway inhibitor AG490, decreased the levels of MDA, TNFalpha, S100beta, NSE and increased activity of SOD, IL-10, and attenuated the expression of JAK2 and STAT3. These results reveal that autogenous orthotropic liver transplantation induces the activation of JAK2/STAT3 signaling pathway in hippocampus. Pretreatment with propofol attenuates autogenous orthotropic liver transplantation induces hippocampal injury via JAK2/STAT3 pathway. PMID- 27998797 TI - How optimally foraging predators promote prey coexistence in a variable environment. AB - Optimal foraging is one of the major predictive theories of predator foraging behavior. However, how an optimally foraging predator affects the coexistence of competing prey is not well understood either in a constant or variable environment, especially for multiple prey species. We study the impact of optimal foraging on prey coexistence using an annual plant model, with and without annual variation in seed germination. Seed predators are modeled using Charnov's model of adaptive diet choice. Our results reveal that multiple prey species can coexist because of this type of predator, and that their effect is not greatly modified by environmental variation. However, in diverse communities, the requirements for coexistence by optimal foraging alone are very restrictive. Optimally foraging predators can have a strong equalizing effect on their prey by creating a competition-predation trade-off. Thus, their main role in promoting diversity may be to reduce species-average fitness differences, making it easier for other mechanisms, such as the storage effect, to allow multiple species to coexist. Like previous models, our model showed that when germination rates vary, the storage effect from competition promotes coexistence. Our results also show that optimally foraging predators can generate a negative storage effect from predation, undermining coexistence, but that this effect will be minor whenever predators commonly differentiate their prey. PMID- 27998795 TI - Mechanisms of modulation of brain microvascular endothelial cells function by thrombin. AB - Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of the blood-brain barrier, via incompletely characterized mechanisms. We examined the underlying mechanisms evoked by thrombin in rat brain microvascular endothelial cells (RBMVEC). Our results indicate that thrombin, acting on protease-activated receptor 1 (PAR1) increases cytosolic Ca2+ concentration in RBMVEC via Ca2+ release from endoplasmic reticulum through inositol 1,4,5-trisphosphate receptors and Ca2+ influx from extracellular space. Thrombin increases nitric oxide production; the effect is abolished by inhibition of the nitric oxide synthase or by antagonism of PAR1 receptors. In addition, thrombin increases mitochondrial and cytosolic reactive oxygen species production via PAR1-dependent mechanisms. Immunocytochemistry studies indicate that thrombin increases F-actin stress fibers, and disrupts the tight junctions. Thrombin increased the RBMVEC permeability assessed by a fluorescent flux assay. Taken together, our results indicate multiple mechanisms by which thrombin modulates the function of RBMVEC and may contribute to the blood-brain barrier dysfunction. PMID- 27998798 TI - Recursions for the exchangeable partition function of the seedbank coalescent. AB - For the seedbank coalescent with mutation under the infinite alleles assumption, which describes the gene genealogy of a population with a strong seedbank effect subject to mutations, we study the distribution of the final partition with mutation. This generalizes the coalescent with freeze by Dong et al. (2007) to coalescents where ancestral lineages are blocked from coalescing. We derive an implicit recursion which we show to have a unique solution and give an interpretation in terms of absorption problems of a random walk. Moreover, we derive recursions for the distribution of the number of blocks in the final partition. PMID- 27998799 TI - Phospholipid complex enriched micelles: A novel drug delivery approach for promoting the antidiabetic effect of repaglinide. AB - To enhance the oral antidiabetic effect of repaglinide (RG), a newly emerging approach, based on the combination of phospholipid complexation and micelle techniques, was employed. Repaglinide-phospholipid complex (RG-PLC) was prepared by the solvent-evaporation method then characterized using Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and X-ray powder diffraction (XPRD). The results revealed obvious disappearance of the characteristic peaks of the prepared RG-PLCs confirming the formation of drug phospholipid complex. RG-PLC enriched micelles (RG-PLC-Ms) were prepared by the solvent-evaporation technique employing poloxamer 188 as surfactant. The prepared RG-PLC-Ms showed high drug encapsulation efficiencies (93.81-99.38%), with nanometric particle diameters (500.61-665.32nm) of monodisperse distribution and high stability (Zeta potential < -29.8mV). The in vitro release of RG from RG-PLC Ms was pH-dependant according to the release media. A higher release pattern was reported in pH=1.2 compared to a more retarded release in pH=6.8 owing to two different kinetics of drug release. Oral antidiabetic effect of two optimized RG PLC-M formulations was evaluated in an alloxan-induced diabetic rat model for 7 day treatment protocol. The two investigated formulations depicted normal blood glucose, serum malondialdehyde and insulin levels as well as an improved lipid profile, at the end of daily oral treatment, in contrast to RG marketed tablets implying enhanced antidiabetic effect of the drug. Hence, phospholipid-complex enriched micelles approach holds a promising potential for promoting the antidiabetic effect of RG. PMID- 27998800 TI - Patients' in-session experiences and symptom change: Session-to-session effects on a within- and between-patient level. AB - OBJECTIVE: Knowledge of patients' in-session experiences that lead to symptom change in psychotherapy is limited. This study aims to investigate the within- and between-patient relationships between three in-session processes in psychotherapy (coping skills, therapeutic relationship quality, and emotional involvement) and symptom change on a session-by-session level. METHOD: Participants (n = 1550) with various disorders, including primarily depression and anxiety, were treated with CBT in a German outpatient clinic. Symptom distress was assessed before each session and patients' in-session experiences were assessed at the end of each session using session reports. Person-mean centering was applied to disaggregate within- and between-patients. Within- and between-patient process scores were tested in multilevel models as predictors of next session symptom change. RESULTS: On a within-patient level, better session specific coping skills, better therapeutic alliance, and deeper emotional involvement were followed by next session symptom improvements. In a combined model, only coping skills specifically predicted next session symptom change. Additionally, these coping skills were especially helpful when combined with a better therapeutic relationship quality. On a between-patient level, better therapeutic alliance and more coping skills were associated with lower symptom scores during treatment, while deeper emotional involvement was associated with higher symptom scores. Testing these between-patient effects in a combined model left only coping skills (the more, the greater symptom improvement) and emotional involvement (the deeper, the less symptom improvement) as significant predictors. These two also exhibited a combined effect on symptom change on the between patient level. DISCUSSION: The results highlight the importance of a thorough disaggregation of within- and between-patient variability in psychotherapy process-outcome research as well as the consideration of several potentially important time-varying covariates. While coping skills showed to be the most central for subsequent symptom change, therapeutic relationship quality only seemed to be a facilitative factor in enhancing these effects, but was not sufficiently helpful on its own. PMID- 27998801 TI - The impact of KIR2DS4 gene on clinical outcome after hematopoietic stem cell transplantation. AB - Killer cell immunoglobulin-like receptors (KIR) are a family of inhibitory/activating receptors expressed on NK cells. Interactions of KIR receptors with KIR ligands have been shown to modify hematopoietic stem cell transplantation (HSCT) outcome. The aim of this research was to determine the KIR2DS4 allele variants distribution among 111 patients with different hematological malignancy who underwent HSCT and their donors, and to evaluate KIR2DS4 alleles' impact on HSCT outcome. The KIR gene frequency analysis showed a significantly higher incidence of full-length KIR2DS4 alleles among patients. The impact of KIR2DS4 alleles on transplantation outcomes revealed that donors' full length KIR2DS4 alleles is associated with lower overall survival rates, higher risk of GVHD and higher relapse incidence. The expression of full-length KIR2DS4 allele variants may contribute to a worse clinical outcome after HSCT. KIR typing for KIR2DS4 could be used as an additional criterion for selecting suitable donors in cases when more than one HLA identical donor is identified for a specific patient. PMID- 27998803 TI - A pilot study on Hla-G locus control region haplotypes and cervical intraepithelial neoplasias. AB - Human papillomavirus (HPV) can induce cervical intraepithelial neoplasias (CIN) grades 1, 2 and 3. Untreated, these lesions may progress to cervical cancer (CC) which is the third most common cancer in women worldwide. HLA-G plays an immunotolerant role in the immune response. The aim of this study was to characterize the configuration of SNPs located at the distal promoter of HLA-G in patients with CIN2 and CIN3 and control women. The study sample was composed of 207 women as follows: 73 diagnosed with CIN2 lesions, 56 with CIN3 and 78 healthy control women. Genotyping was performed by sequence base typing. Eleven haplotype configurations subdivided in two main haplogroups (H1dist and H2dist), were characterized and compared between patients and controls. The haplotypes H1.1Dist (GAGAACGC) and H2.1Dist (AGGTACAC) were more frequent in Euro-Descendants as well as in Brazilian Mixed. Nevertheless, the haplotype H2.1Dist standed out as a susceptibility haplotype in Brazilian Mixed patients while the H1.1Dist presented a protector effect in this same ethnic group. Whether such LCR haplotype configurations can impact on HLA-G gene expression levels in women who developed cervical intraepithelial neoplasia is still unknown and it is of utmost importance that more investigation on this field be pursued. PMID- 27998802 TI - Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges? AB - Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (gammac). The gammac is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family. Clinical outcomes have validated tofacitinib's pan-JAK activity in kidney transplantation after demonstrating an increased risk of infection and malignancy as compared to CNI-based regimens. After these trials, tofacitinib investigation for use in transplantation has effectively ceased. However, a post-hoc analysis has shed new light on the monitoring of tofacitinib exposure in order to predict infection and oncologic events. With new methods to monitor tofacitinib exposure, clinicians may be able to effectively reduce toxicities while providing a high level of immunosuppression. The purpose of this review to identify when, and for whom, JAK inhibitors may provide benefit in solid organ transplantation. PMID- 27998804 TI - Isospora lunaris n. sp. (Apicomplexa: Eimeriidae) from the domestic Java sparrow in Japan. AB - Five individuals of the domestic Java sparrows, Lonchura oryzivora (Aves: Estrildidae), were examined for coccidian parasites. Sporulated oocysts had two sporocysts containing four sporozoites each. Sporulated oocysts (n=30) were spherical, with a two splinter-like polar granules. Oocyst size was 22.1*20.7 (20.0-25.0*20.0-22.5)MUm. They had a thick wall that consisted of a pale yellow outer layer and a dark yellow inner layer, and lacked micropyle and residuum. Sporocysts (n=60) were elongated ovoid 14.1*9.8 (12.5-15.0*7.5-10.0)MUm, smooth walled, and colorless, with crescent-shaped Stieda and indistinct substieda bodies. Sporocyst residuum was interspersed between sporozoites. Sporozoites were oriented transverse to the sporocyst longitudinal axis. On the basis of morphological data, the species isolated in the present study is a new species of Isospora and propose the name Isospora lunaris n. sp. PMID- 27998805 TI - Acromegaly, genetic variants of the aryl hydrocarbon receptor pathway and environmental burden. AB - Increasing evidence suggests that environmental contaminants can exert endocrine disruptors activities and that pollution exposition can have a role in tumorigenic processes. Several environmental pollutants have been shown to affect pituitary cells biology and function. The aryl hydrocarbon receptor (AHR) pathway is involved in xenobiotics' metabolism and in tumorigenesis. A deregulation of the AHR pathway could have a role in pituitary tumours' pathophysiology, especially in the GH secreting ones. AHR-interacting protein (AIP) is one of the key partners of AHR and is implicated in pituitary tumours' pathogenesis. Moreover, an increased prevalence of acromegaly has been reported in a highly polluted area of the province of Messina (Sicily, Italy). Nevertheless, at present, few data are available about the potential role of environmental factors in the pathogenesis and clinical expression of GH secreting pituitary tumours. This review is aimed at discussing the evidences on the potential links among environmental pollutants, the AHR pathway and the pathophysiology of GH-secreting pituitary adenomas. PMID- 27998806 TI - Expert patient illness narratives as a teaching methodology: A mixed method study of student nurses satisfaction. AB - OBJECTIVE: To evaluate nursing students' satisfaction with Expert Patient Illness Narratives as a teaching and learning methodology based on patient involvement. METHODS AND DESIGN: Mixed methods were used in this study: online survey with quantitative and qualitative items designed by researchers. SETTINGS AND PARTICIPANTS: Sixty-four nursing students of the Universitat Autonoma de Barcelona, attending a Medical Anthropology elective course. RESULTS: Women more frequently considered that the new learning methodology was useful in developing the competency "to reason to reason the presence of the triad Health-Illness-Care in all the groups, societies and historical moments" (p-value=0.02) and in that it was consolidated as a learning outcome (p-value=0.022). On the other hand, men considered that this methodology facilitated the development of critical thinking (p=0.01) and the ability to identify normalized or deviant care situations (p=0.007). Students recognized the value of Expert Patient Illness Narratives in their nursing training as a way to acquire new nursing skills and broaden previously acquired knowledge. This educational innovation improved nursing skills and provided a different and richer perspective of humanization of care. CONCLUSIONS: The results of the present study demonstrate that nursing students found Expert Patient Illness Narratives satisfactory as a learning and teaching methodology, and reported improvement in different areas of their training and also the integration of new knowledge, meaning, theory applicability, as well las critical and reflective thinking. Involvement of patients as storytellers also provides a new humanizing perspective of care. Nonetheless, further studies of Expert Patient Illness Narratives are needed in order to improve its benefits as a teaching and learning methodology. PMID- 27998807 TI - Differential effects of Helenalin, an anti-inflammatory sesquiterpene lactone, on the proteome, metabolome and the oxidative stress response in several immune cell types. AB - Extracts of Arnica spp. are traditionally used due to their anti-inflammatory effects for the topical treatment of e.g. haematoma or muscle distortions. One of the main active compounds is Helenalin, a sesquiterpene lactone that can be found in various Asteraceae. However, immunotoxic effects of the compound are only poorly analysed. In this study, a 2D gel electrophoresis based proteomic approach together with a membrane based proteomic assay, metabolomics and the detection of intracellular reactive oxygen species (iROS) were used to investigate potential immunotoxic properties of Helenalin on the human immune cell lines Jurkat and THP 1 and on human peripheral blood mononuclear cells (PBMC). The study revealed a dose-dependent cytotoxicity towards both tested cell lines and the PBMC. However, the cell lines were less sensitive to the Helenalin treatment than the PBMC. The proteomic assays showed strong effects on the carbohydrate metabolism and the protein folding in THP-1 cells but only weak impact on Jurkat cells. Metabolomic studies as well as iROS detection in THP-1 cells verified the results of the proteomic analysis. In summary, the approaches used in this study were able to identify target pathways of Helenalin especially in THP-1 monocytes and thus enable a risk assessment of the substance. PMID- 27998809 TI - Explaining and reducing the variation in inter-laboratory reported values for International Normalised Ratio. AB - INTRODUCTION: Monitoring of vitamin K antagonist (VKA) therapy is usually achieved using the International Normalised Ratio (INR). However, despite international standardisation, there remains considerable concern regarding ongoing high levels of inter-laboratory variation, as generated by different laboratories using the same homogeneous plasma sample. Notably, significant discrepancies continue to be evidenced in external quality assessment (EQA) environments, prompting additional investigations to determine causes and to identify potential inconsistencies of practice. MATERIALS AND METHODS: Several investigations involving all 580 participants in the Haemostasis program of the RCPAQAP Haematology were undertaken from 2009 to 2016, gathering details of methodology, and comparative assessments of INR values differentially obtained directly from participants versus values calculated using raw data for PT, ISI and MNPT provided by the same participants. RESULTS: Up to 6% of laboratories reported substantially different INR results compared to results calculated using differentially provided ISI, MNPT and PT data in 6 out of 8 surveys in 2009, highlighting discrepancies in ISI and MNPT values reported vs used by laboratories. Subsequent highlighting of issues to laboratories led to significant improvements in later surveys, with <1% of laboratories yielding different values in 2012, 2013 and 2016. CONCLUSIONS: Our study identified that pre- or post- analytical errors explained a large proportion of inter-laboratory variation in INR. These errors can lead to serious clinical consequences if such data discrepancies are applied to patients, with incorrectly reported INRs potentially leading to altered warfarin therapy. Further education in the importance of the INR process appears warranted. PMID- 27998808 TI - Merkel cells are long-lived cells whose production is stimulated by skin injury. AB - Mechanosensitive Merkel cells are thought to have finite lifespans, but controversy surrounds the frequency of their replacement and which precursor cells maintain the population. We found by embryonic EdU administration that Merkel cells undergo terminal cell division in late embryogenesis and survive long into adulthood. We also found that new Merkel cells are produced infrequently during normal skin homeostasis and that their numbers do not change during natural or induced hair cycles. In contrast, live imaging and EdU experiments showed that mild mechanical injury produced by skin shaving dramatically increases Merkel cell production. We confirmed with genetic cell ablation and fate-mapping experiments that new touch dome Merkel cells in adult mice arise from touch dome keratinocytes. Together, these independent lines of evidence show that Merkel cells in adult mice are long-lived, are replaced rarely during normal adult skin homeostasis, and that their production can be induced by repeated shaving. These results have profound implications for understanding sensory neurobiology and human diseases such as Merkel cell carcinoma. PMID- 27998810 TI - Advances and limitations of visual conditioning protocols in harnessed bees. AB - Bees are excellent invertebrate models for studying visual learning and memory mechanisms, because of their sophisticated visual system and impressive cognitive capacities associated with a relatively simple brain. Visual learning in free flying bees has been traditionally studied using an operant conditioning paradigm. This well-established protocol, however, can hardly be combined with invasive procedures for studying the neurobiological basis of visual learning. Different efforts have been made to develop protocols in which harnessed honey bees could associate visual cues with reinforcement, though learning performances remain poorer than those obtained with free-flying animals. Especially in the last decade, the intention of improving visual learning performances of harnessed bees led many authors to adopt distinct visual conditioning protocols, altering parameters like harnessing method, nature and duration of visual stimulation, number of trials, inter-trial intervals, among others. As a result, the literature provides data hardly comparable and sometimes contradictory. In the present review, we provide an extensive analysis of the literature available on visual conditioning of harnessed bees, with special emphasis on the comparison of diverse conditioning parameters adopted by different authors. Together with this comparative overview, we discuss how these diverse conditioning parameters could modulate visual learning performances of harnessed bees. PMID- 27998811 TI - Plant Proteins Are Smaller Because They Are Encoded by Fewer Exons than Animal Proteins. AB - Protein size is an important biochemical feature since longer proteins can harbor more domains and therefore can display more biological functionalities than shorter proteins. We found remarkable differences in protein length, exon structure, and domain count among different phylogenetic lineages. While eukaryotic proteins have an average size of 472 amino acid residues (aa), average protein sizes in plant genomes are smaller than those of animals and fungi. Proteins unique to plants are ~81aa shorter than plant proteins conserved among other eukaryotic lineages. The smaller average size of plant proteins could neither be explained by endosymbiosis nor subcellular compartmentation nor exon size, but rather due to exon number. Metazoan proteins are encoded on average by ~10 exons of small size [~176 nucleotides (nt)]. Streptophyta have on average only ~5.7 exons of medium size (~230nt). Multicellular species code for large proteins by increasing the exon number, while most unicellular organisms employ rather larger exons (>400nt). Among subcellular compartments, membrane proteins are the largest (~520aa), whereas the smallest proteins correspond to the gene ontology group of ribosome (~240aa). Plant genes are encoded by half the number of exons and also contain fewer domains than animal proteins on average. Interestingly, endosymbiotic proteins that migrated to the plant nucleus became larger than their cyanobacterial orthologs. We thus conclude that plants have proteins larger than bacteria but smaller than animals or fungi. Compared to the average of eukaryotic species, plants have ~34% more but ~20% smaller proteins. This suggests that photosynthetic organisms are unique and deserve therefore special attention with regard to the evolutionary forces acting on their genomes and proteomes. PMID- 27998812 TI - Aqueous synthesis of Ag and Mn co-doped In2S3/ZnS quantum dots with tunable emission for dual-modal targeted imaging. AB - : Here, we present the microwave-assisted synthesis of In2S3/ZnS core/shell quantum dots (QDs) co-doped with Ag+ and Mn2+ (referred to as AgMn:In2S3/ZnS). Ag+ altered the optical properties of the host QDs, whereas the spin magnetic moment (S=5/2) of Mn2+ efficiently induced the longitudinal relaxation of water protons. To the best of our knowledge, this is the first report of the aqueous synthesis of color-tunable AgMn:In2S3/ZnS core/shell QDs with magnetic properties. The synthetic procedure is rapid, facile, reproducible, and scalable. The obtained QDs offered a satisfactory quantum yield (45%), high longitudinal relaxivity (6.84s-1mM-1), and robust photostability. In addition, they exhibited excellent stability over a wide pH range (5-12) and high ionic strength (0.15 2.0M NaCl). As seen by confocal microscopy and magnetic resonance imaging, AgMn:In2S3/ZnS conjugated to hyaluronic acid (referred to as AgMn:In2S3/ZnS@HA) efficiently and specifically targeted cluster determinant 44, a receptor overexpressed on cancer cells. Moreover, AgMn:In2S3/ZnS@HA showed negligible cytotoxicity in vitro and in vivo, rendering it a promising diagnostic probe for dual-modal imaging in clinical applications. STATEMENT OF SIGNIFICANCE: In this manuscript, we reported a facial and rapid method to prepare In2S3/ZnS core/shell quantum dots (QDs) co-doped with Ag+ and Mn2+ (referred to as AgMn:In2S3/ZnS). Ag+ dopants were used to alter the optical properties of the In2S3 host, whereas Mn2+ co-dopants with their unpaired electrons provided paramagnetic properties. The emission wavelength of the core/shell QDs could be tuned from 550 to 743nm with a maximum PL quantum yield of 45%. The resulting core/shell QDs also maintained a stable emission in aqueous solution at broad ranges of pH (5-12) and ionic strength (0.15-2.0M NaCl), as well as a high photostability under continuous irradiation. In vivo cytotoxicity experiments showed that up to 500MUg/mL AgMn:In2S3/ZnS@HA did not cause obvious toxicity to zebrafish embryos. In vitro targeted cell luminescence and magnetic resonance imaging showed that AgMn:In2S3/ZnS conjugated to hyaluronic acid was selectively and efficiently internalized in CD44-expressing tumor cells, confirming that the resultant QDs could function as dual-modal imaging probes for accurate diagnosis. PMID- 27998813 TI - Controlling the selective and directional migration of hepatocytes by a complementary density gradient of glycosylated hyperbranched polymers and poly(ethylene glycol) molecules. AB - Repair and regeneration of defected tissues and organs depends strongly on the directional migration of targeted cells, for example, the enhancement of directional migration of hepatocytes could be helpful in liver regeneration and transplantation. Herein a complementary gradient of galactose-modified hyperbranched polymers (LA-HPMA) and poly(ethylene glycol) (PEG) molecules was designed and prepared on a same substrate. Characterizations of X-ray photoelectron spectrometry and quartz crystal microbalance with dissipation (QCM d) demonstrated the unidirectional change in grafting density of LA-HPMA and PEG molecules, respectively. On the LA-HPMA/PEG complementary gradient surface, the human hepatoma (HepG2) cells showed preferential orientation and enhanced directional migration toward the region of lower PEG density and higher LA-HPMA density. By contrast, the mouse embryonic fibroblasts (NIH3T3) showed random migration irrelevant to the gradient. The success of the complementary gradient relies on the specific interaction between galactose and asialoglycoprotein receptor (ASGPR) expressed on HepG2 cells. STATEMENT OF SIGNIFICANCE. PMID- 27998814 TI - The learners' stress during high fidelity simulation. An equation with multiple unknowns. PMID- 27998815 TI - Total evidence phylogeny and the evolution of adult bioluminescence in fireflies (Coleoptera: Lampyridae). AB - Fireflies are some of the most captivating organisms on the planet. They have a rich history as subjects of scientific study, especially in relation to their bioluminescent behavior. Yet, the phylogenetic relationships of fireflies are still poorly understood. Here, we present the first total evidence approach to reconstruct lampyrid phylogeny using both a molecular matrix from six loci and an extensive morphological matrix. Using this phylogeny we test the hypothesis that adult bioluminescence evolved after the origin of the firefly clade. The ancestral state of adult bioluminescence is recovered as non-bioluminescent with one to six gains and five to ten subsequent losses. The monophyly of the family, as well as the subfamilies is also tested. Ototretinae, Cyphonocerinae, Luciolinae (incl. Pristolycus), Amydetinae, "cheguevarinae" sensu Jeng 2008, and Photurinae are highly supported as monophyletic. With the exception of four taxa, Lampyrinae is also recovered as monophyletic with high support. Based on phylogenetic and morphological data Lamprohiza, Phausis, and Lamprigera are transferred to Lampyridae incertae sedis. PMID- 27998816 TI - Out of southern Africa: Origin, biogeography and age of the Aizooideae (Aizoaceae). AB - The Aizooideae is an early-diverging lineage within the Aizoaceae. It is most diverse in southern Africa, but also has endemic species in Australasia, Eurasia and South America. We derived a phylogenetic hypothesis from Bayesian and Maximum Likelihood analyses of plastid DNA-sequences. We find that one of the seven genera, the fynbos-endemic Acrosanthes, does not belong to the Aizooideae, but is an ancient sister-lineage to the subfamilies Mesembryanthemoideae & Ruschioideae. Galenia and Plinthus are embedded inside Aizoon and Aizoanthemum is polyphyletic. The Namibian endemic Tetragonia schenckii is sister to Tribulocarpus of the Sesuvioideae. For the Aizooideae, we explored their possible age by means of relaxed Bayesian dating and used Bayesian Binary MCMC reconstruction of ancestral areas to investigate their area of origin. Early diversification occurred in southern Africa in the Eocene-Oligocene, with a split into a mainly African lineage and an Eurasian-Australasian-African-South American lineage. These subsequently radiated in the early Miocene. For Tetragonia, colonisation of Australasia via long-distance dispersal from Eurasia gave rise to the Australasian lineage from which there were subsequent dispersals to South America and Southern Africa. Despite the relatively old age of the Aizooideae, more than half the species have radiated since the Pleiocene, coinciding with the large and rapid diversification of the Ruschioideae. The lineage made up of Tetragonia schenckii &Tribulocarpus split from the remainder of the Sesuvioideae already in the mid Oligocene and its disjunct distribution between Namibia and north-east Africa may be the result of a previously wider distribution within an early Arid African flora. Our reconstruction of ancestral character-states indicates that the expanding keels giving rise to hygrochastic fruits originated only once, i.e. after the split of the Sesuvioideae from the remainder of the Aizoaceae and that they were subsequently lost many times. Variously winged and spiky fruits, adapted to dispersal by wind and animals, have evolved independently in the Aizooideae and the Sesuvioideae. There is then a greater diversity of dispersal systems in the earlier lineages than in the Mesembryanthemoideae and Ruschioideae, where dispersal is mainly achieved by rain. PMID- 27998817 TI - The phylogeny of Heliconia (Heliconiaceae) and the evolution of floral presentation. AB - Heliconia (Heliconiaceae, order Zingiberales) is among the showiest plants of the Neotropical rainforest and represent a spectacular co-evolutionary radiation with hummingbirds. Despite the attractiveness and ecological importance of many Heliconia, the genus has been the subject of limited molecular phylogenetic studies. We sample seven markers from the plastid and nuclear genomes for 202 samples of Heliconia. This represents ca. 75% of accepted species and includes coverage of all taxonomic subgenera and sections. We date this phylogeny using fossils associated with other families in the Zingiberales; in particular we review and evaluate the Eocene fossil Ensete oregonense. We use this dated phylogenetic framework to evaluate the evolution of two components of flower orientation that are hypothesized to be important for modulating pollinator discrimination and pollen placement: resupination and erect versus pendant inflorescence habit. Our phylogenetic results suggest that the monophyletic Melanesian subgenus Heliconiopsis and a small clade of Ecuadorian species are together the sister group to the rest of Heliconia. Extant diversity of Heliconia originated in the Late Eocene (39Ma) with rapid diversification through the Early Miocene, making it the oldest known clade of hummingbird-pollinated plants. Most described subgenera and sections are not monophyletic, though closely related groups of species, often defined by shared geography, mirror earlier morphological cladistic analyses. Evaluation of changes in resupination and inflorescence habit suggests that these characters are more homoplasious than expected, and this largely explains the non-monophyly of previously circumscribed subgenera, which were based on these characters. We also find strong evidence for the correlated evolution of resupination and inflorescence habit. The correlated model suggests that the most recent common ancestor of all extant Heliconia had resupinate flowers and erect inflorescences. Finally, we note our nearly complete species sampling and dated phylogeny allow for an assessment of taxonomic history in terms of phylogenetic diversity. We find approximately half of the currently recognized species, corresponding to half of the phylogenetic diversity, have been described since 1975, highlighting the continued importance of basic taxonomic research and conservation initiatives to preserve both described and undiscovered species of Heliconia. PMID- 27998818 TI - Does specific parameterization of WHAM improve the prediction of copper competitive binding and toxicity on plant roots? AB - We aimed at assessing whether the binding and rhizotoxicity of metal cations such as copper that exhibit high affinity for plant roots could be adequately predicted using the Windermere Humic Aqueous Model (WHAM) default parameterization. Accordingly, we first compared the ability of the default parameterization of WHAM and a specific parameterization for terrestrial higher plants (WHAM-THP) to model the competitive binding of copper on wheat (Triticum aestivum L.) and tomato (Solanum lycopersicum L.) roots. Secondly, in an external dataset, we evaluated the ability of WHAM-THP to predict the copper concentration and toxicity to pea (Pisum sativum L.) roots relative to WHAM. WHAM-THP estimates generated a slightly better fit for the competitive binding of copper on wheat and tomato roots (log10 of the root-mean-square error, RMSE = 0.15) than WHAM estimates (RMSE = 0.24). WHAM-THP estimates slightly better fitted the copper concentration in pea roots (RMSE <= 0.49) than WHAM estimates (RMSE <= 0.67) at low copper exposure and pH <= 5. However, WHAM-THP did not at all improve the prediction of copper toxicity to pea roots (RMSE = 13% as also for WHAM). We thus conclude that, although the default parameterization of WHAM does not neatly predict the binding of metal cations on roots, it could however be used with confidence in predictive ecotoxicology for terrestrial higher plants without any specific parameterization. PMID- 27998819 TI - Quantamatrix Multiplexed Assay Platform system for direct detection of bacteria and antibiotic resistance determinants in positive blood culture bottles. AB - OBJECTIVES: Rapid and accurate identification of the causative pathogens of bloodstream infections (BSIs) is crucial for initiating appropriate antimicrobial therapy, which decreases the related morbidity and mortality rates. The aim of this study was to evaluate the usefulness of a newly developed multiplexed, bead based bioassay system, the Quantamatrix Multiplexed Assay Platform (QMAP) system, obtained directly from blood culture bottles, to simultaneously detect the presence of bacteria and identify the genes for antibiotic resistance. METHODS: The QMAP system was used to evaluate 619 blood culture bottles from patients with BSIs and to compare the results of conventional culture methods. RESULTS: Using conventional bacterial cultures as the reference standard, the sensitivity, specificity, positive predictive value, and negative predictive value of the QMAP system for detection of bacterial pathogens in positive blood culture (PBC) samples were 99.8% (n=592, 95% CI 0.9852-1.000, p <0.001), 100% (95% CI 0.983 1.000, p <0.001), 100% (95% CI 0.9922-1.000, p <0.001), and 99.5% (95% CI 0.9695 1.000, p <0.001), respectively. In addition, sensitivity and specificity of the QMAP system for identification of the genes for antibiotic resistance were 99.4% (n=158, 95% CI 0.9617-0.9999, p <0.009) and 99.6% (95% CI 0.9763-0.9999, p <0.0001), respectively. CONCLUSIONS: Obtaining results using the QMAP system takes about 3 hr, while culture methods can take 48-72 hr. Therefore, analysis using the QMAP system is rapid and reliable for characterizing causative pathogens in BSIs. PMID- 27998821 TI - Re. 'Managing atypical and typical herpetic central nervous system infections: results of a multinational study'. PMID- 27998820 TI - Core I97L mutation in conjunction with P79Q is associated with persistent low HBV DNA and HBs antigen clearance in patients with chronic hepatitis B. AB - OBJECTIVES: When considering treatment for chronic hepatitis B (CHB), it is important to discriminate between patients with persistent low HBV DNA and patients with active hepatitis, who may proceed to cirrhosis. In this study, we sought to identify mutations in patients expected to have persistent low HBV DNA and ultimately exhibit clearance of hepatitis B surface antigen (HBsAg). METHODS: Serum samples were obtained from 33 CHB genotype C patients, divided based on HBV DNA and alanine aminotransferase (ALT) levels following observation for >2 years: Group A (n=10), transient HBV DNA >=5.0 log copies/mL and ALT >=120 IU/L; Group B (n=11), persistent HBV DNA <5.0 and ALT <60; and Group C (n=12), persistent HBV DNA <4.0 and ALT <30. Full-length HBV sequences were compared among groups. Subsequently, 82 patients with CHB were evaluated for the I97L mutation and the additional mutation P79Q. We compared cumulative incidences of persistent low HBV DNA and HBsAg clearance in patients with or without I97L and P79Q by the Kaplan Meier method. RESULTS: Incidence of Core mutation I97L differed significantly among groups: A, 30% (3/10); B, 36.4% (4/11); C, 83.3% (10/12) (p = 0.021). Cumulative incidences of persistent low HBV DNA and HBsAg clearance were significantly higher in patients with I97L than in those with wild-type I97 (p = 0.003 and p = 0.016, respectively), and even higher in those with P79Q. CONCLUSIONS: In patients with CHB, measurement of I97L and additional mutation P79Q would be useful for predicting persistent low HBV DNA, normal ALT, and HBsAg clearance. PMID- 27998822 TI - Novel rapid PCR for the detection of Ile491Phe rpoB mutation of Mycobacterium tuberculosis, a rifampicin-resistance-conferring mutation undetected by commercial assays. AB - OBJECTIVES: Neither the liquid medium-based Bactec MGIT, nor commercial molecular assays such as the Xpert MTB/RIF and the MTBDRplus V2.0 assays are capable of detecting up to 30% of rifampicin-resistant Mycobacterium tuberculosis strains in Swaziland because of the large proportion of the rpoB Ile491Phe mutations. In other countries, the frequency of this mutation is thought to be low. METHODS: We designed a real-time multiplex allele-specific PCR assay to identify the rpoB Ile491Phe mutation responsible for these undetected resistant M. tuberculosis strains. RESULTS: The technique showed 100% similarity with rpoB sequencing on a panel of 78 strains from Swaziland. CONCLUSIONS: We propose that the detection of the rpoB Ile491Phe rpoB mutation should complement commercial assays for the diagnosis of rifampicin-resistant M. tuberculosis in routine conditions, particularly in countries where this specific mutation is frequent. The technique proposed in this paper is adapted for most reference laboratories. PMID- 27998824 TI - Plaque surface irregularity and calcification length within carotid plaque predict secondary events in patients with coronary artery disease. AB - BACKGROUND AND AIMS: Although comprehensive risk factor modification is recommended, a uniform management strategy does not necessarily prevent secondary events in patients with coronary artery disease (CAD). Therefore, identification of high-risk patients who may benefit from more intensive interventions may improve prognosis. Carotid ultrasound can reliably identify systemic atherosclerosis, and carotid plaque and intima-media thickness (IMT) are known independent risk factors for CAD. However, it is unclear whether findings on carotid ultrasound can improve prediction of secondary CAD events. METHODS: The study population comprised 146 consecutive patients with CAD (mean age, 66 +/- 9 years; 126 with angina pectoris, 20 with acute myocardial infarction). IMT, plaque score, plaque area, plaque surface irregularity, and calcification length (calculated by summing the calcified lesions within each plaque accompanied by acoustic shadow) were measured at baseline. Patients were followed for 10 years to ascertain secondary CAD events defined as hard major adverse cardiovascular events (MACE; cardiac death and acute myocardial infarction) and as total MACE (hard MACE and angina pectoris with coronary revascularization). RESULTS: Multiple regression analysis demonstrated that calcification length (p < 0.05) and plaque surface irregularity (p < 0.01) remained independently associated with total MACE after adjustment for age, sex, diabetes mellitus, dyslipidemia, hypertension, chronic kidney disease, smoking, and multivessel CAD. CONCLUSIONS: These findings suggest that the combination of calcification length and plaque surface irregularity has additional value beyond traditional risk classification. Intensive intervention for these high-risk patients may avoid or delay progression of atherosclerosis towards secondary CAD events. PMID- 27998823 TI - Benzalkonium tolerance genes and outcome in Listeria monocytogenes meningitis. AB - OBJECTIVES: Listeria monocytogenes is a food-borne pathogen that can cause meningitis. The listerial genotype ST6 has been linked to increasing rates of unfavourable outcome over time. We investigated listerial genetic variation and the relation with clinical outcome in meningitis. METHODS: We sequenced 96 isolates from adults with listerial meningitis included in two prospective nationwide cohort studies by whole genome sequencing, and evaluated associations between bacterial genetic variation and clinical outcome. We validated these results by screening listerial genotypes of 445 cerebrospinal fluid and blood isolates from patients over a 30-year period from the Dutch national surveillance cohort. RESULTS: We identified a bacteriophage, phiLMST6 co-occurring with a novel plasmid, pLMST6, in ST6 isolates to be associated with unfavourable outcome in patients (p 2.83e-05). The plasmid carries a benzalkonium chloride tolerance gene, emrC, conferring decreased susceptibility to disinfectants used in the food processing industry. Isolates harbouring emrC were growth inhibited at higher levels of benzalkonium chloride (median 60 mg/L versus 15 mg/L; p <0.001), and had higher MICs for amoxicillin and gentamicin compared with isolates without emrC (both p <0.001). Transformation of pLMST6 into naive strains led to benzalkonium chloride tolerance and higher MICs for gentamicin. CONCLUSIONS: These results show that a novel plasmid, carrying the efflux transporter emrC, is associated with increased incidence of ST6 listerial meningitis in the Netherlands. Suggesting increased disease severity, our findings warrant consideration of disinfectants used in the food-processing industry that select for resistance mechanisms and may, inadvertently, lead to increased risk of poor disease outcome. PMID- 27998825 TI - Hematopoietic arginase 1 deficiency results in decreased leukocytosis and increased foam cell formation but does not affect atherosclerosis. AB - BACKGROUND AND AIMS: Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l arginine availability, Arg1 limits the production of nitric oxide (NO), a pro atherogenic factor in macrophages. In endothelial cells, conversely, NO is strongly anti-atherogenic. However, until now, the role of Arg1 in atherosclerosis is largely unknown. The aim of this study is to specifically investigate the effect of Arg1 deletion in hematopoietic cells on atherosclerosis susceptibility. METHODS: Ldlr KO mice were transplanted with Arg1flox/flox;Tie2 Cre (Arg1 KO) bone marrow (BM) or wildtype (WT) BM. After 8 weeks of recovery on chow diet, recipients mice were fed a Western-Type Diet (WTD) for 10 weeks to induce atherosclerosis. RESULTS: After 10-week WTD challenge, blood leukocyte counts were decreased by 25% (p < 0.001), and spleen leukocytes were decreased by 35% (p = 0.05) in Ldlr KO mice transplanted with Arg1 KO BM compared to mice transplanted with WT BM. The decrease in leukocytes was due to lower B lymphocyte counts. However, oxLDL-specific antibodies were increased in plasma of Ldlr KO mice transplanted with Arg1 KO BM compared to WT BM transplanted controls, whereas oxLDL-specific IgM was not affected. On the other hand, peritoneal foam cells in Arg1 KO BM recipients were increased 3-fold (p < 0.001) compared to WT BM recipients. No change in blood cholesterol was found. Despite changes in leukocyte counts and macrophage foam cell formation, we did not observe differences in atherosclerotic plaque size or plaque macrophage content in the aortic root. Surprisingly, there was also no difference in plaque collagen content, indicating that absence of macrophage Arg1 function does not reduce plaque stability. CONCLUSIONS: Deletion of Arg1 in hematopoietic cells adversely affects blood leukocyte counts and increases foam cell formation. However, no effects on atherosclerosis could be demonstrated, indicating that hematopoietic Arg1 function is not a decisive factor in atherosclerotic plaque formation. PMID- 27998827 TI - "Ebola kills generations": Qualitative discussions with Liberian healthcare providers. AB - OBJECTIVE: the purpose of this study was to explore healthcare providers' perceptions and reactions to the Ebola Virus Disease (EVD) epidemic. DESIGN: a descriptive, qualitative study design was employed. Focus groups were conducted with Liberian healthcare providers who participated in care of patients with EVD. SETTING: the study was conducted in Bong County, Liberia (population: 333,000), which was severely affected, with over 650 reported cases and close to 200 deaths by the end of 2015. PARTICIPANTS: the total sample of 58 participants, included 11 nurses, ten traditional birth attendants (TBAs), four midwives, 28 general community health volunteers, three physician assistants, one community member and one pharmacy dispenser. MEASUREMENTS AND FINDINGS: five core themes related to changes in healthcare practices and interactions since the EVD outbreak were identified based on the results of the focus groups; fear, stigma, resource constraints, lack of knowledge and training, and shifting cultural practices. KEY CONCLUSIONS: this work represents a preliminary understanding of Liberian healthcare workers reactions to the EVD epidemic, and highlights the significant issues they faced as they attempted to care for patients and protect themselves. IMPLICATIONS FOR PRACTICE: while the EVD epidemic has been declared over, preparedness activities for future disease outbreaks must continue. This study can inform future healthcare policy initiatives as well as preparedness activities targeted towards healthcare workers in low resource settings. PMID- 27998826 TI - Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: The EPIC-Norfolk prospective population study. AB - BACKGROUND AND AIMS: Lipoprotein(a) (Lp[a]) is a strong genetic risk factor for cardiovascular disease (CVD). The American Heart Association has prioritised seven cardiovascular health metrics to reduce the burden of CVD: body mass index, healthy diet, physical activity, smoking status, blood pressure, diabetes and cholesterol levels (together also known as ideal cardiovascular health). Our objective was to determine if individuals with high Lp(a) levels could derive cardiovascular benefits if characterized by ideal cardiovascular health. METHODS: A total of 14,051 participants of the EPIC-Norfolk study were stratified according to the cardiovascular health score (based on the number of health metrics with an ideal, intermediate or poor status). Of them, 1732 had a CVD event during a mean follow-up of 11.5 years. Cox proportional hazards models were used to describe the association between the cardiovascular health score and Lp(a) level or genotype (as estimated by the rs10455872 variant) with the risk of CVD. RESULTS: We observed little or no differences in serum Lp(a) levels across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels >=50 mg/dl), those in the highest (i.e. healthiest) cardiovascular health score category (10-14) had an adjusted hazard ratio for cardiovascular disease of 0.33 (95% CI = 0.17-0.63, p = 0.001) compared to participants in the lowest (i.e. unhealthiest) cardiovascular health score category(0-4). Similar results were obtained when we replaced Lp(a) with rs10455872. CONCLUSIONS: Although Lp(a) levels are only slightly influenced by cardiovascular health metrics, an ideal cardiovascular health could substantially reduce CVD risk associated with high Lp(a) levels or genotype. PMID- 27998828 TI - Nutritionally relevant concentrations of resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocytes and monocytes and the production of pro inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. AB - The health benefits of bio-active phenolic compounds have been largely investigated in vitro at concentrations which exceed those reachable in vivo. We investigated and compared the anti-inflammatory effects of resveratrol, hydroxytyrosol and oleuropein at physiologically relevant concentrations by using in vitro models of inflammation. Human granulocytes and monocytes were stimulated with phorbol myristate acetate (PMA) and the ability of resveratrol, hydroxytyrosol and oleuropein to inhibit the oxidative burst and CD11b expression was measured. Nitric oxide (NO), prostaglandin E2 (PGE2) levels, COX-2, iNOS, TNFalpha, IL-1beta and miR-146a expression and activation of the transcription factor Nrf2 were evaluated in macrophages RAW 264.7 stimulated with LPS (1MUg/ml) for 18h, exposed to resveratrol, hydroxytyrosol and oleuropein (5 and 10MUM). Synergistic effects were explored as well, together with the levels of PGE2, COX 2 and IL-1beta expression in macrophages after 6h of LPS stimulation. PGE2 and COX-2 expression were also assessed on human monocytes. All the tested compounds inhibited granulocytes oxidative burst in a concentration dependent manner and CD11b expression was also significantly counteracted by resveratrol and hydroxytyrosol. The measurement of oxidative burst in human monocytes produced similar effects being resveratrol more active. Hydroxytyrosol and resveratrol inhibited the production of NO and PGE2 but did not reduce iNOS, TNFalpha or IL 1beta gene expression in LPS-stimulated RAW 264.7 for 18h. Resveratrol slightly decreased COX-2 expression after 18h but not after 6h, but reduced PGE2 levels after 6h. Resveratrol and hydroxytyrosol 10MUM induced NRf2 nuclear translocation and reduced miR-146a expression in LPS treated RAW 264.7. Overall, we reported an anti-inflammatory effect of resveratrol and hydroxytyrosol at low, nutritionally relevant concentrations, involving the inhibition of granulocytes and monocytes activation, the modulation of miR-146a expression and the activation of Nrf2. A regular dietary intake of resveratrol and hydroxytyrosol may be a useful complementary strategy to control inflammatory diseases. PMID- 27998829 TI - CD14++ CD16- monocytes are the main source of 11beta-HSD type 1 after IL-4 stimulation. AB - The anti-inflammatory actions of IL-4 are well established through earlier findings. However, the exact mechanism it uses to downregulate the pro inflammatory cytokine production through monocytes and macrophages is poorly understood. In this study, we examined the effect of IL-4 in the induction of 11beta-HSD1 in the two main classes of monocytes, CD14++ CD16- (CD14) and CD14+ CD16+ (CD16). Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 17 healthy donors and were sorted into CD14 and CD16 subpopulations using cell sorting. Effect of IL-4 on 11beta-HSD1-enzyme activity was measured in sorted and unsorted monocytes using Homogeneous Time-Resolved Fluorescence (HTRF) and M1/M2 polarization analysis was performed by flow cytometry. Our results indicate that CD14 cells are the major source of 11beta-HSD1 enzyme after IL-4 stimulation and that M2 phenotype is not a pre-requisite for its synthesis. PMID- 27998831 TI - Selective use of contemporary drug-eluting stents in primary angioplasty for ST elevation myocardial infarction: pooled analysis of COMFORTABLE AMI and EXAMINATION. AB - AIMS: Selective use of DES only in patients at higher risk of MACE is common practice, particularly in healthcare systems with a large premium payable for DES. We aimed to identify subgroups of patients in which the use of BMS in primary percutaneous coronary intervention (PPCI) for STEMI can still be justified. METHODS AND RESULTS: We performed a patient-level pooled analysis of COMFORTABLE AMI and EXAMINATION comparing contemporary DES with BMS in PPCI. A risk score was applied using three parameters: lesion length >15 mm, vessel size <3 mm, and diabetes mellitus. Individual data were available for 2,655 patients. The incidence of MACE at one year was incrementally higher in patients with risk scores of 1 or 2/3. MACE rates were lower in patients with a risk score 0 or 1 who were treated with DES (p=0.0073 and p=0.008). No difference in death or reinfarction was seen between DES and BMS in any group. There was a significant reduction in TLR with DES in all three groups. CONCLUSIONS: A score comprising vessel size, lesion length, and diabetes did not identify patients at low risk with equivalent or better results from BMS use. The results suggest that the practice of only selective use of DES in primary PCI should be discouraged. PMID- 27998830 TI - Development of an academic identity through PhD supervision-an issue for debate. AB - This paper provides reflection on the journey of completing a PhD by using emergent themes that occurred in supervision sessions as recorded in a reflective journal. The paper highlights the need to reflect and accept decisions that can be challenging. The paper also indicates examples where past understandings are questioned and newer insights have to be explored. A conclusion related to accepting responsibility for what happens as a consequence of supervision sessions is debated. Finally a new insight into identity is arrived at. PMID- 27998832 TI - Patient selection for transcatheter or surgical intervention: the Heart Team TRUMPS the STS. PMID- 27998833 TI - Rotational atherectomy: you will never regret using it but you often regret not having used it! PMID- 27998834 TI - Drug-eluting stents in the superficial femoral artery: seeing is believing. PMID- 27998835 TI - Building the future together. PMID- 27998836 TI - In-hospital and midterm clinical outcomes of rotational atherectomy followed by stent implantation: the ROTATE multicentre registry. AB - AIMS: The aim of this multicentre study was to investigate the in-hospital and midterm outcomes of rotational atherectomy (RA) followed by metallic stent implantation. METHODS AND RESULTS: Between 2002 and 2013, 1,176 de novo lesions with calcified coronary lesions treated by RA and metallic stent implantation at nine institutions were assessed. Patients with ST-segment elevation myocardial infarction (STEMI) within 30 days, cardiogenic shock before the procedure, lesions with thrombus, and in-stent restenosis were excluded from the current analysis. In-hospital major adverse cardiac events (MACE) occurred in 8.3% of cases, mainly driven by periprocedural myocardial infarction. The incidence of MACE was 16.0% at one-year and 24.9% at two-year follow-up, both driven by target vessel revascularisation (13.5% at one year and 19.8% at two years). Multivariable analysis revealed that dialysis was an independent predictor for both in-hospital MACE (OR 2.33, 95% CI: 1.11-4.87, p=0.03) and follow-up MACE (HR 4.14, 95% CI: 2.87-5.96, p<0.001), whilst drug-eluting stent (DES) use was associated with a reduction in follow-up MACE (HR 0.42, 95% CI: 0.26-0.67, p<0.001). CONCLUSIONS: RA appears to be safe and effective with acceptable in hospital and follow-up MACE considering the severity of patient and lesion characteristics. DES implantation following RA was associated with a reduction in MACE during the follow-up period. PMID- 27998837 TI - ROTational AThErectomy in acute coronary syndrome: early and midterm outcomes from a multicentre registry. AB - AIMS: The safety and efficacy of rotational atherectomy (RA) in patients presenting with non-ST-elevation myocardial infarction (NSTE-ACS) remain to be defined. The aim of our study was to assess the safety and efficacy of RA in NSTE ACS patients with reference to both short- and long-term follow-up. METHODS AND RESULTS: This was an observational retrospective registry which enrolled all consecutive patients undergoing RA, comparing patients with stable angina (SA) and NSTE-ACS. In addition, ACS patients were matched with those not undergoing RA. The primary endpoint was angiographic success. Procedural complications and in-hospital MACE were secondary endpoints along with MACE during follow-up. One thousand three hundred and eight patients were included: 37% (484) with an NSTE ACS diagnosis and 63% (824) in the SA group. Angiographic success did not differ between the groups (98.8% vs. 99.2%, p=0.57). By univariate analysis procedural complications were more frequent in the NSTE-ACS group (11.3% vs. 8.0%, p=0.04). In-hospital MACE rates were comparable (5.7% vs. 5.8%, p=0.93); by multivariate analysis NSTE-ACS patients showed a non-significant trend towards a higher risk of adverse events (HR 2.39, CI: 0.96-5.96, p=0.061). MACE after a median of 27.9 months was significantly higher in the NSTE-ACS group compared with the SA group (32.4% vs. 24.2%, log-rank p<0.001), results confirmed by multivariate analysis. After propensity score matching, NSTE-ACS patients undergoing RA had similar outcomes to ACS patients who did not undergo RA (16% vs. 13%, log-rank p=0.14). CONCLUSIONS: Rotational atherectomy has similar safety and angiographic outcome in patients with NSTE-ACS or SA. The higher rate of adverse cardiac events at follow-up in NSTE-ACS patients undergoing RA is comparable with a matched population of NSTE-ACS patients not undergoing RA. PMID- 27998838 TI - Emergency percutaneous implantation of veno-arterial extracorporeal membrane oxygenation in the catheterisation laboratory. AB - AIMS: Our aim was to describe our protocol for emergency percutaneous implantation of femoral veno-arterial extracorporeal membrane oxygenation (VA ECMO) in the catheterisation laboratory and to compare its effectiveness and safety with implantation in the intensive care unit and the operating room. METHODS AND RESULTS: Our retrospective observational study enrolled 56 consecutive patients undergoing VA ECMO implantation in the catheterisation laboratory (n=23), the intensive care unit (n=8) and the operating room (n=25). Among patients undergoing catheterisation laboratory implantation, 11 patients had profound cardiogenic shock but preserved arterial pulsations, and 12 patients had refractory cardiac arrest undergoing automated mechanical chest compression. Using our fluoroscopy-guided protocol, arterial and venous cannulas were successfully implanted and the desired ECMO flow obtained in each patient. There was no vessel perforation/dissection. Moderate/severe GUSTO or BARC 3 and 5 bleeding occurred in 13%. Ipsilateral limb ischaemia occurred in one of eight patients (13%) with upfront perfusion sheath implantation, and in two of three patients (75%) in whom this strategy was not used (p=0.15). There was no infection at the site of cannula implantation. Complications related to implantation in the catheterisation laboratory were comparable to surgical implantation in the operating room and percutaneous implantation in the intensive care unit using ultrasound guidance. CONCLUSIONS: Fluoroscopy-guided emergency implantation of femoral VA ECMO by an interventional cardiologist in the catheterisation laboratory is effective and safe for both patients in cardiogenic shock and those in refractory cardiac arrest. PMID- 27998839 TI - FFR result post PCI is suboptimal in long diffuse coronary artery disease. AB - AIMS: The aim of this study was to evaluate the functional result immediately post PCI and at nine-month follow-up, and to ascertain how often a functionally optimal result of >0.95 can be achieved in long coronary lesions treated with long second- or newer-generation DES. METHODS AND RESULTS: Patients receiving DES measuring >=30 mm with FFR value <=0.8 were included in the study. Stent length was defined as long (30 to 49 mm; L-DES) and ultra-long (>=50 mm; UL-DES). Angiographic and FFR evaluation was performed before and after PCI and at nine month follow-up. A total of 74 patients each received a mean stent length of 50.72+/-14.6 mm. Mean FFR post PCI was 0.88+/-0.06. An optimal post PCI FFR value of >0.95 was achieved in only 9/74 patients (12.2%), and was not achieved in any UL-DES patients. Only 12/74 (16.2%) had FFR post PCI of 0.91 to 0.95; 8/74 (10.8%) patients remained ischaemic (<=0.8). FFR gradient across the stent was higher in UL-DES patients compared to L-DES patients (0.07+/-0.03 vs. 0.04+/ 0.03; p=0.001). At follow-up, the angiographic restenosis rate was 4.7%, and the functional restenosis rate was 15.1%. CONCLUSIONS: The FFR result post PCI was suboptimal in the majority of patients treated with long DES and was particularly poor when the total stent length exceeded 50 mm. PMID- 27998840 TI - Quantification and characterisation of released plaque material during bioresorbable vascular scaffold implantation into right coronary artery lesions by multimodality intracoronary imaging. AB - AIMS: We aimed to compare intravascular ultrasound with virtual histology (VH IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS) for their ability to quantify the true amount and characterise the nature of released plaque material during bioresorbable vascular scaffold (BVS) implantation into right coronary artery (RCA) lesions using a distal occlusion and aspiration device. METHODS AND RESULTS: Seventeen patients underwent BVS implantation into the right coronary artery under distal protection with intracoronary imaging using VH-IVUS, OCT and NIRS. The amount of released plaque material and its lipid content (LC) were determined. Necrotic core volume and minimal fibrous cap thickness correlated with the amount of released plaque material (r=0.80 and r=-0.65, respectively) and its LC (r=0.75 and r=-0.78, respectively), but not maximal lipid core burden index (LCBI). OCT-identified thin-cap fibroatheromata (TCFA) were associated with the greatest amount of released plaque material compared to non-TCFA (46.8 [29.0;49.2] mg vs. 14.2 [11.3;19.4] mg; p=0.003) and LC (4.4 [4.0;4.8] mg vs. 2.0 [1.8;2.5] mg; p=0.000). CONCLUSIONS: VH-IVUS and OCT but not NIRS parameters quantify and characterise the amount of released plaque material. TCFA is associated with the highest amount of released plaque material and may therefore benefit from the use of protection devices. PMID- 27998841 TI - Automated characterisation of lipid core plaques in vivo by quantitative optical coherence tomography tissue type imaging. AB - AIMS: Qualitative criteria for plaque tissue characterisation by OCT are well established, but quantitative methods lack systematic validation in vivo. High optical attenuation coefficient ut has been associated with unstable plaque features, such as lipid core. The purpose of this study was to validate optical coherence tomography (OCT) attenuation imaging for tissue characterisation in vivo, specifically to detect lipid core in coronary atherosclerotic plaques, and to evaluate quantitatively the ability of OCT attenuation imaging to differentiate thin-cap (TCFA) and thick-cap fibroatheroma (FA). METHODS AND RESULTS: We prospectively enrolled 85 patients undergoing imaging of a native coronary segment by both OCT and near-infrared spectroscopy and intravascular ultrasound (NIRS-IVUS). Ninety-eight NIRS-positive 4 mm plaque segments were selected and matched to the OCT data. Two experienced OCT readers classified the plaque type using OCT criteria. A cap thickness of 65 MUm was used to differentiate TCFA and FA. We computed an index of plaque attenuation (IPA) in the 4 mm blocks, and assessed the association of this index with plaque type. IPA differentiated between TCFA and FA (AUC=0.82 in ROC analysis; p<0.0001). LCBI was numerically, but not significantly, higher in TCFA compared to FA (p=0.097). CONCLUSIONS: IPA is an unbiased reproducible measure of tissue optical properties. The fraction of pixels with attenuation coefficient >=11 mm-1 can identify TCFA. PMID- 27998842 TI - Four-year polymer biocompatibility and vascular healing profile of a novel ultrahigh molecular weight amorphous PLLA bioresorbable vascular scaffold: an OCT study in healthy porcine coronary arteries. AB - AIMS: The vascular healing profile of polymers used in bioresorbable vascular scaffolds (BRS) has not been fully characterised in the absence of antiproliferative drugs. In this study, we aimed to compare the polymer biocompatibility profile and vascular healing response of a novel ultrahigh molecular weight amorphous PLLA BRS (FORTITUDE(r); Amaranth Medical, Mountain View, CA, USA) against bare metal stent (BMS) controls in porcine coronary arteries. METHODS AND RESULTS: Following device implantation, optical coherence tomography (OCT) evaluation was performed at 0 and 28 days, and at one, two, three and four years. A second group of animals underwent histomorphometric evaluation at 28 and 90 days. At four years, both lumen (BRS 13.19+/-1.50 mm2 vs. BMS 7.69+/-2.41 mm2) and scaffold areas (BRS 15.62+/-1.95 mm2 vs. BMS 8.65+/-2.37 mm2) were significantly greater for BRS than BMS controls. The degree of neointimal proliferation was comparable between groups. Histology up to 90 days showed comparable healing and inflammation profiles for both devices. CONCLUSIONS: At four years, the novel PLLA BRS elicited a vascular healing response comparable to BMS in healthy pigs. Expansive vascular remodelling was evident only in the BRS group, a biological phenomenon that appears to be independent of the presence of antiproliferative drugs. PMID- 27998843 TI - Coronary magnetic resonance angiographic images of a lesion treated with a metal stent and fully bioresorbable polymeric everolimus-eluting scaffold. PMID- 27998844 TI - Transcatheter implantation of aortic valve prostheses into degenerated mitral valve bioprostheses and failed annuloplasty rings: outcomes according to access route and Mitral Valve Academic Research Consortium (MVARC) criteria. AB - AIMS: The study sought to assess outcomes of transcatheter mitral valve-in-valve implantation (TMVIV) for degenerated bioprostheses and transcatheter mitral valve in-ring implantation (TMVIR) for failed annuloplasty rings according to access route and the Mitral Valve Academic Research Consortium (MVARC) criteria. METHODS AND RESULTS: Twenty-four patients (72+/-13 years; eight men [33%]) underwent TMVIV (n=14) or TMVIR (n=10) for mitral regurgitation (MR; n=17) or stenosis (n=7) using balloon-expandable bioprostheses. Transapical (TA) access was chosen in 13, and transseptal (TS) access in 11 patients. MVARC technical success, device success and procedural success were 95.8%, 41.7% and 33.3%, respectively, with no differences between access routes. Cardiac output (CO) increased significantly by 1.1+/-0.8 l/min in TS patients, but not in TA patients (DeltaCO=0.0+/-0.5 l/min; p=0.0051). Overall three-year survival was estimated at 57.6% (95% confidence interval: 33.9-81.3; TA 35.5% [5.2-65.9]; TS 90.9% [73.9 100]). Survival up to four years according to vascular access showed a clear benefit in patients treated transseptally (p=0.045). CONCLUSIONS: Regardless of the access route, TMVIV/TMVIR was associated with high technical success yet impaired device success. In the long term, TA access had a significant adverse impact on survival. PMID- 27998846 TI - Suction catheter for enhanced control and accuracy of transseptal access. AB - AIMS: Percutaneous structural heart therapies, such as mitral value repair, require site-specific transseptal access (TSA). This can be challenging for interventional cardiologists. We describe a TSA catheter (TSAC) that utilises suction for enhanced control and puncture accuracy. Here, we aim to evaluate the safety and efficacy of the device. METHODS AND RESULTS: Ex vivo interatrial septum preparations were dissected from swine (n=8) and diseased human hearts (n=6) to quantify TSAC suction and needle puncture force. TSAC suction was 6.5 fold greater than the opposing needle puncture force, and thus provides sufficient stabilisation for punctures. The safety and efficacy of TSAC was evaluated in a chronic mitral regurgitation swine model (n=10) and compared to a conventional TSA device. MR was induced by disrupting one to three mitral chordae tendineae, and the progression of heart disease was followed for three weeks. During device testing, procedure time and fluoroscopy exposure were not statistically different between devices. TSAC reduced septal displacement from 8.7+/-0.30 mm to 3.60+/-0.19 mm (p<0.05) and improved puncture accuracy 1.75 fold. CONCLUSIONS: TSAC provides controlled TSA and improves puncture accuracy, while maintaining procedure time and workflow. These findings provide a strong rationale for a first-in-man study to demonstrate the clinical utility of the device. PMID- 27998845 TI - Initial experience with live three-dimensional image overlay for ductal stenting in hypoplastic left heart syndrome. AB - AIMS: Precise visualisation of ductal morphology and adjacent vessels is crucial for accurate stent choice and placement during hybrid palliation of hypoplastic left heart syndrome (HLHS). We aimed to describe our initial experience with live three-dimensional reconstruction overlay derived from rotational angiography (RA) for ductal stenting in HLHS. METHODS AND RESULTS: We carried out a retrospective review of ductal stenting in 18 newborns with HLHS, including six patients with 3D reconstruction overlay used to guide the intervention. The median age at the intervention was 20 days (range 13-31 days) and the median weight was 3.25 kg (range 3-4 kg). Eleven RA runs were performed, pre and post stent implantation in five patients and before the intervention in one patient. 3D reconstructions from all RA runs had sufficient image quality to allow stent placement without additional contrast injections. Comparison with 2D angiography-guided ductal stenting showed similar contrast usage, with the 2D angiography patients receiving a higher radiation dose. CONCLUSIONS: Three-dimensional rotational angiography provides accurate visualisation of the ductal morphology and nearby structures. Three-dimensional reconstruction overlay with clear landing points enabled precise stent implantation with no additional contrast injections and lower radiation doses than conventional angiography in our patients. PMID- 27998847 TI - The failing right heart: implications and evolution in high-risk patients undergoing transcatheter aortic valve implantation. AB - AIMS: Right ventricular dysfunction (RVdy) is negatively associated with survival after left heart valve surgery. It is unclear whether RVdy has the same impact in patients undergoing transcatheter aortic valve implantation (TAVI). We sought to evaluate the prognostic impact of different grades of RVdy on TAVI, with and without concomitant left ventricular dysfunction (LVdy), and the possible impact of TAVI on RVdy. METHODS AND RESULTS: Among 870 consecutive patients with severe symptomatic aortic stenosis undergoing TAVI, 226 patients (26%) presented with a concomitant diagnosis of RVdy. Patients were divided into three groups, Group 1: normal RV systolic function, i.e., tricuspid annular plane systolic excursion (TAPSE) >16 mm (n=644, 74%); Group 2: mild-to-moderate RVdy, i.e., TAPSE 10-16 mm (n=180, 20.6%); Group 3: severe RVdy, i.e., TAPSE <10 mm (n=46, 5.2%). Patients in Groups 1 and 2 showed a similar overall mortality rate at one month (5% vs. 8%, OR 1.1 [0.7-1.55], p=0.2) and at one-year follow-up (15% vs. 19%, HR 1.5 [0.84-2.2], p=0.09), respectively. Compared to Groups 1 and 2, patients in Group 3 showed a significantly higher overall mortality at one month (22%, OR 3.3 [1.8 4.1], p<0.001, and OR 2.1 [1.7-3.1], p=0.02, respectively) as well as at one-year follow-up (45%, HR 2.6 [2.1-3.45], p<0.001, and HR 1.9 [1.5-2.7], p=0.02), respectively. Pulmonary hypertension >60 mmHg (HR 1.5 [1.1-2.2], p=0.03), AF (HR 1.6 [1.1-2.4], p=0.01), creatinine clearance <30 mL/min (HR 1.92 [1.3-2.5], p=0.003), LVEF <30% (HR 1.5 [1.1-2.9], p=0.03), severe RVdy (HR 2.9 [2.7-3.3], p=0.002), severe RV dilation (HR 1.7 [1.2-2.2], p=0.005) and severe biventricular dysfunction (HR 3.9 [2.7-4.1], p=0.002) were independent predictors of one-year mortality. Among survivors, the majority of patients in Groups 2 and 3 experienced a significant improvement in NYHA class. CONCLUSIONS: Severe RVdy limits the expected benefit of TAVI. In current risk scores right heart failure is not considered. The present study advocates the evaluation of this strong predictor in a more complete pre-procedural work-up. PMID- 27998848 TI - Percutaneous repair of severe coarctation of the aorta. PMID- 27998849 TI - Comparing the vascular response in implantation of self-expanding, bare metal nitinol stents or paclitaxel-eluting nitinol stents in superficial femoral artery lesions: a serial optical frequency domain imaging study. AB - AIMS: This study sought to investigate differences in vascular response between self-expanding bare metal nitinol stents (BMS) and paclitaxel-eluting nitinol stents (PES), in superficial femoral artery (SFA) disease, using optical frequency domain imaging (OFDI). METHODS AND RESULTS: Six months after stent implantation, follow-up quantitative vascular angiography (QVA) and OFDI assessment were scheduled to evaluate vascular response. Volume index (VI) was defined as volume divided by stent length. The primary endpoint was OFDI-derived late lumen area loss, defined as lumen VI post stent implantation minus lumen VI at follow-up. A total of 28 SFA lesions were analysed, with cases randomised to receive either BMS or PES implantation. QVA-derived diameter stenosis at six month follow-up was lower in the PES group than in the BMS group (28.5% vs. 39.7%, p=0.04). After six months, BMS VI increased by 33.8% (20.7+/-3.7 to 27.7+/ 3.5 mm3/mm), whilst PES exhibited an increase of 32.1% (19.0+/-2.3 to 25.1+/-4.7 mm3/mm). Neointimal VI was smaller (7.4+/-2.6 mm3/mm vs. 10.5+/-3.2 mm3/mm, p<0.01) and late lumen area loss was lower (2.9+/-1.3 mm3/mm vs. 5.6+/-2.8 mm3/mm, p<0.01) in the PES group. CONCLUSIONS: Serial volumetric OFDI analyses confirmed significantly smaller amounts of neointimal tissue and lower late lumen area loss following PES implantation for SFA lesions at short-term follow-up. PMID- 27998850 TI - [Subtractive SELEX using agar beads for screening DNA aptamers with specific affinity to HIV gp41 antigen]. AB - OBJECTIVE: To obtain DNA aptamers with a highly specific affinity to HIV gp41 antigen using SELEX screening for detection of HIV. METHODS: The specific DNA aptamers of HIV gp41 antigen were screened from the double-stranded DNA derived from the single-stranded DNA (ssDNA) library with agarose beads as the supportive medium and HIV gp41 antigen as the target molecule using SELEX technique and real time quantitative PCR. RESULTS: The secondary ssDNA library obtained after 6 rounds of screening was amplified by PCR to obtain dsDNA. The dsDNA was linked with pMDTM 18-T vector, cloned and sequenced to obtain 4 aptamers of HIV gp41 antigen. The affinities of the 4 aptamers (Kd) all reached the nanomolar level. Among the 4 aptamers, the No.15 aptamer showed the strongest affinity. Specificity analysis of the aptamers revealed that all these 4 aptamers had specific affinity to HIV gp41 antigen with no affinity to other non-specific proteins. CONCLUSION: We successfully obtained DNA aptamers with highly specific affinity to the HIV gp41 antigen from random single-stranded oligonucleotide library, and the obtained aptamers have the ability to antagonize HIV gp41 antigen. PMID- 27998852 TI - [Isolation, identification and lead adsorption study of lead-resistant Lactobacillus casei strains from feces of healthy newborns]. AB - OBJECTIVE: To isolate and identify lead-resistant Lactobacillus casei strains with lead adsorption ability from the stool of healthy newborns as a new source of bacteria for developing lead-eliminating food products. METHODS: MRS was used to isolate lead-resistant bacteria from the feces of 30 healthy and full-term neonates. A phylogenetic tree was constructed based on the morphological characteristics and 16S rRNA sequences of the isolated bacteria. Physiological and biochemical characterizations of the bacteria were performed according to the Berger's Systematic Bacteriology Handbook, followed by antimicrobial susceptibility test and acid-tolerant bile salt test. The adsorption capacity of Pb2+ of the bacteria was determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). RESULTS: Three strains of Lactobacillus casei were isolated, which were resistant to penicillin and ceftriaxone and could tolerate the exposure to 500 mg/L Pb2+. Acid-tolerant bile salt test showed that the bacteria were resistant to culture in the presence of artificial gastric juice (pH 2.0) for 3 h, and their survival rate reached 62.5% following exposure to 0.3% bile salt for 8 h. The bacteria showed a Pb2+ adsorption rate of 90.4% at a low Pb2+ concentration (1 mg/L) and of 86.27% at a high Pb2+ concentration (50 mg/L). CONCLUSION: Three Lactobacillus casei strains lead adsorption ability were isolated from the feces of newborns. These bacterial strains provide a new solution to alleviate lead poisoning by probiotic dietary. PMID- 27998851 TI - [Blue rubber bleb nevus syndrome complicated by a ventricular septal defect: a case report]. AB - OBJECTIVE: The co-occurrence of blue rubber bleb nevus syndrome (BRBNS) and ventricular septal defects is rare. Here we present a case of BRBNS in a 15-year old boy who was born with multiple cavernous hemangiomas and a ventricular septal defect. Examinations revealed the presence of hemangioma lesions in the subcutaneous and mucosal tissues as well as in the cerebrum, nasopharynx, tongue, esophagus, gastric body, sigmoid colon and adrenal gland. Combined imaging modalities played an important role in the diagnosis of hemangioma lesions. PMID- 27998853 TI - [Immunological balance of CD8+CD28+/CD8+CD28- T lymphocytes can predict gastrointestinal hemorrhage in patients with inflammatory bowel disease]. AB - OBJECTIVE: To evaluate the sensitivity and specificity of CD8+CD28+/CD8+CD28- T lymphocyte balance in predicting the gastrointestinal hemorrhage (GH) in patients with inflammatory bowel disease (IBD). METHODS: Forty-nine IBD patients, including 30 with ulcerous colitis (UC) and 19 with Crohn's disease (CD), were enrolled to test peripheral blood CD8+CD28+ and CD8+CD28- T cells using flow cytometry. All the patients were followed up for one year. The receiver-operating characteristic (ROC) curves were used to test the efficiency of CD8+CD28+/CD8+CD28- T lymphocyte balance to predict GH. The differences in lasting time of remission (LTR) under different factors were compared using Kaplan-Meier survival analysis, and the correlation between CD8+ T lymphocytes and the factors were analyzed. RESULTS: The utilization rates of immunosuppressant, steroids, and biological agent (BA) were significantly higher in CD patients than in UC patients (P=0.003, 0.043 and 0.002, respectively). The frequencies of CD8+CD28+T cells were obviously higher in UC patients than those in CD patients (t=3.022, P=0.004). CD8+CD28+T cells, CD8+CD28- T cells, and especially CD8+CD28+/CD8+CD28- ratio (area under curve of 0.977, P=0.000; cut-off value of 1.14 [13.95%/12.24%] with a sensitivity of 93.3% and a specificity of 91.2%) showed good efficiencies in predicting GH (P<0.01). The mean and median of LTR of IBD patients who did not receive BA or surgical treatment were significantly longer (Chi2=9.730, P=0.002; Chi2=15.981, P=0.000). CD8+CD28+/CD8+CD28- ratio was significantly related to both BA (P=0.009) and surgery (P=0.038). CONCLUSION: Both decreased CD8+CD28+T cells and elevated CD8+CD28-T cells are closely correlated with GH, and their ratio can predict the occurrence of GH with a high sensitivity and specificity and is correlated with BA and surgery at the cut-off value of 1.14. PMID- 27998854 TI - [Effect of different blood pressure control targets within 48 h after hypertensive cerebral hemorrhage on hematoma enlargement and prognosis]. AB - OBJECTIVE: To study the effect of different blood pressure control targets on hematoma enlargement and prognosis in patients within 48 h after hypertensive cerebral hemorrhage (HCH). METHODS: Between January, 2013 and July, 2016, 102 patients with HCH were randomized into group A (51 cases) and group B (51 cases) with different systolic blood pressure (SBP) control targets within 48 h. The patients in group A were given early active antihypertensive treatment with SBP control target of 130-140 mm Hg; those in group B received standard antihypertensive treatment with SBP control target of 170-180 mm Hg. The changes in the volume of hematomas and the patients' prognosis were compared between the two groups. RESULTS: After 48 h of treatment, SBP, hematoma volume and the National Institutes of Health Stroke Scale (NIHSS) score were significantly lower and Glasgou Coma Scale (GCS) score was significantly higher in group A than in group B (P<0.01 or 0.05). After 30 days of treatment, the patients in group A showed significantly better indicators of treatment efficacy than those in group B (Z=2.331, P=0.020). The mortality rate was lower in group A than in group B, but the difference was not statistically significant (Chi2=2.772, P=0.096). CONCLUSION: Early active antihypertensive treatment is safe and feasible in patients with HCH and can reduce the enlargement of the hematomas, alleviate deterioration of neurological function, and improve the prognosis of the patients. PMID- 27998855 TI - [Oestrogen inhibits invasion and metastasis of hepatocellular carcinoma MHCC97H cells by regulating the activity of AKT signaling pathway]. AB - OBJECTIVE: To explore the inhibitory effect of estrogen against metastasis of human hepatocellular carcinoma MHCC97H cells and explore the molecular mechanism. METHODS: The inhibitory effect of estrogen on the migration and invasion of MHCC97H cells was evaluated with wound healing assay and Transwell assay. Western blotting was used for investigating the expression of MMP-2, MMP-9, AKT and p-AKT in the cells treated with estrogen. RESULTS: Estrogen treatment significantly inhibited the migration and invasion of MHCC97H cells in a dose-dependent manner. Estrogen significantly down-regulated the protein expressions of MMP-2 and MMP-9 and lowered the phosphorylation level of AKT. CONCLUSION: The anti-metastatic effect of estrogen involves inhibition of MMP-2 and MMP-9 in MHCC97H cells probably by regulating AKT signal pathway. PMID- 27998856 TI - [Expression of ATPase inhibitory factor 1 in normal and pathological tissues of female reproductive system]. AB - OBJECTIVE: To determine ATPase inhibitory factor 1 (IF1) expression in normal and pathological tissue of female reproductive system to better understand the physiological role of IF1 in malignancies of the female reproductive system. METHODS: Surgical specimens of normal tissues and primary malignant tumors were obtained during the past 2 years, including 38 normal endometrium tissues, 33 endometriosis tissues, 30 endometrial adenocarcinoma tissues, 24 uterine myoideum tissues, 30 uterine fibroid tissues, 18 normal cervical tissues, 30 cervical squamous carcinoma tissues, 11 fallopian tube tissues, 19 fallopian tube adenocarcinoma tissues, 15 ovarian tissues, 21 ovarian endometrial adenocarinoma tissues, 30 decidua tissues, and 30 villus tissues. The expressions of IF1 protein and mRNA were assessed by immunohistochemistry, Western blotting and RT PCR. RESULTS: The expressions of IF1 were significantly increased in endometrial adenocarcinoma (P<0.01), cervical squamous carcinoma (P<0.01), fallopian tube adenocarcinoma (P<0.01) and ovarian endometrial adenocarinoma (P<0.01) as compared with those in normal tissues. In normal endometrium, IF1 expression was significantly reduced in the secretory phase as compared with the proliferation phase (P<0.01). In patients with endometriosis, IF1 protein expression increased obviously in endometriotic tissues as compared with eutopic and normal endometrial, but the expression IF1 mRNA was similar among the 3 tissues. CONCLUSION: IF1 expression, increases abnormally in malignant tumors of the female reproductive system and may serve as a marker for malignancies of the female reproductive system as well as a promising pharmacological target for cancer treatment. PMID- 27998857 TI - [Clinical outcome of in vitro fertilization or intracytoplasmic sperm injection embryo transfer in women aged 40 years and above]. AB - OBJECTIVE: To investigate the clinical outcomes in vitro fertilization or intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in women aged over 40 years. METHODS: We retrospectively analyzed 1050 non-donor IVF/ICSI-ET cycles performed from January, 2007 to December, 2015 in women at the age 40 years or above, including 393 women at 40 years of age, 266 at 41 years, 158 at 42 years, 107 at 43 years, 64 at 44 years, and 65 at 45-51 years. The clinical characteristics and outcomes of the women in different age groups were compared and analyzed. The pregnancy outcome of different ovarian stimulation protocols and different numbers of embryo transferred were also compared. RESULTS: Oocyte retrieval was achieved in 1032 treatment cycles. Of the 750 embryo transfer cycles, the clinical pregnancy rate was 17.7% (113/750), and the live birth rate was 8.5% (64/750). The clinical pregnancy rate in the 5 age groups was 23.4%, 21.0%, 13.1%, 9.2%, 5.6% and 0%, and the implantation rate was 11.2%, 10.2%, 6.3%, 5.1%, 2.3% and 0%, respectively; the early spontaneous abortion rate was 31.0%, 35.9%, 42.9%, 42.9% and 100%, and the live birth rate was 11.9%, 11.8%, 2.8% and 3.9%. The clinical pregnancy rates of long protocol, short prorocol, GnRHa antagonist protocol, and ovulation induction protocol were 23.6%, 10.2%, 13.3%, and 2.3%, respectively. In the 750 transfer cycles, the clinical pregnancy rate was 3.8% with single embryo transfer, 12.6% with double embryos transfer, and 23.0% with 3 embryos transfer. CONCLUSION: In women aged 40 years or above, the clinical pregnancy rate decreased significantly with age, and the live birth rate was extremely low in women aged beyond 44 years. Assisted reproductive technique is recommended for women aged 40 years and above even when no identifiable causes of sterility are present. For women aged above 44 years of age, oocyte donation may be a better option. PMID- 27998858 TI - [Interaction of polymorphisms of PPAR-gamma2 gene -C34G and NADPH oxidase subunit p22phox gene -C242T with Helicobacter pylori infection in esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the interaction of polymorphisms of PPAR-gamma2 gene C34G and NADPH oxidase subunit p22phox gene -C242T with helicobacter pylori (H. pylori) infection in esophageal squamous cell carcinoma (ESCC) . METHODS: A total of 200 cases of LSCC of Broder grade I, 200 of Broder grade II and of grade III were enrolled in this study with 200 healthy individuals as the control group. The genetic polymorphisms of PPAR-gamma2 gene -C34G and NADPH oxidase subunit p22phox gene -C242T were analyzed using PCR-RFLP in peripheral blood leukocytes. 14C-urea breath test (14C-UBT) was used to test 14C disntegration per minute (DPM) for evaluating the infection status of H. pylori. An unconditional logistic regression model was used to analyze the interaction of nucleotide polymorphisms and H. pylori infection. RESULTS: The risk of ESCC significantly increased in subjects with -C34G (CG), -C34G(GG), -C242T (CT), and -C242T (TT) genotypes. Combined analysis of the polymorphisms showed that the subjects carrying -C34G (GG)/ -C242T (TT) had a high risk of ESCC, and a positive interaction was found between -C34G (GG) and -C242T (TT) in increasing the risk of ESCC. Positive interactions in the pathogenesis of ESCC were also found between -C34G (CG) and C242T (TT), between -C34G (CG) and -C242T (CT), and between -C34G (GG) and -C242T (CT) (gamma>1). The risk of ESCC significantly increased in subjects with H. pylori infection, which showed positive interactions with -C34G (CG), -C34G (GG), -C242T (CT) and -C242T (TT) in increasing the risk of ESCC (gamma>1). CONCLUSION: Individuals carrying -C34G(CG), -C34G(GG), -C242T (CT) and -C242T (TT) genotypes have a high risk of developing ESCC, and these genotypes interact with H. pylori infection in the pathogenesis of LSCC, suggesting the importance of eradicating H. pylori for prevention of ESCC. PMID- 27998859 TI - [Effect of magnesium sulphate infusion on emergence agitation in patients undergoing esophageal carcinoma with general anesthesia: a randomized, double blind, controlled trial]. AB - OBJECTIVE: To evaluate the safety and effectiveness of magnesium sulphate for reducing the incidence of the emergence agitation in patients undergoing surgery for esophageal carcinoma with general anesthesia. METHODS: This randomized, double-blind, controlled clinical trial was conducted in patients undergoing elective radical resection of esophageal carcinoma in Sichuan Provincial People's Hospital between October, 2015 and March, 2016. The patients underwent surgeries under general intravenous anesthesia, and after anesthesia induction, the patients were infused with magnesium sulphate at the rate of 0.1 mL.kg-1.h-1 (2.5 g magnesium sulphate in 50 ml saline pumped at 5 mg.kg-1.h-1) or saline (control group) at the same speed until the end of the surgery. The Riker's sedation agitation scale, pain score, muscle tension score, extubation time, residence time in the postanesthesia care unit (PACU), and adverse reactions were recorded. RESULTS: A total of 108 patients were enrolled including 57 in magnesium sulphate group and 51 in the control group. Riker's sedation agitation scale in the PACU, pain score, and muscle tension score were all significantly lower but the extubation time was longer in magnesium sulphate group than in the control group (P<0.05). In all the patients, blood Ca2+ level was reduced significantly after the operation; blood Mg2+ level was significantly lowered postoperatively in the control group, and the postoperative Mg2+ level was significantly higher in magnesium sulphate group than in the control group (P<0.05). Mg2+ level underwent no significant variations in magnesium sulphate group after the operation (P>0.05). The residence time in the PACU, postoperative Riker's sedation agitation scale score, and blood K+ level were all similar between the two groups(P>0.05). CONCLUSION: Infusion of magnesium sulphate at 5 mg.kg-1.h-1 can significantly reduce the incidence of emergence agitation in patients undergoing esophageal carcinoma under general anesthesia without causing such complications such as muscle recovery delay or electrolyte disorder. PMID- 27998861 TI - [Risk factors for acute respiratory distress syndrome following surgeries for pediatric critical and complex congenital heart disease]. AB - OBJECTIVE: To explore the risk factors for acute respiratory distress syndrome (ARDS) in children receiving surgeries for critical and complex congenital heart disease (CCHD). METHODS: According to the 2011's Berlin definition of ARDS, the clinical data were collected from 75 children without ARDS (group I) and 80 children with ARDS (group II) following surgeries for CCHD performed in the Department of Cardiac Surgery of our hospital from January, 2009 to May, 2014. Univariate analyses and logistic regression were used to analyze the risk factors contributing to the occurrence of ARDS following the surgeries. RESULTS: In the 80 patients who developed ARDS postoperatively in group II, 27 had mild ARDS, 25 had moderate ARDS, and 28 had severe ARDS; death occurred in 17 (21%) cases. Univariate analyses showed that 23 parameters were significantly different between groups I and II (P<0.05), including weight; preoperative PCO2, left ventricular ejection fraction, pulmonary artery pressure, pulmonary infection, and coagulation abnormalities; early postoperative serum globulin; intraoperative aortic cross clamp (ACC) time; cardiopulmonary bypass (CPB) time; operation time; blood loss and blood transfusion amount intraoperatively and during the first 8 h after operation; lactic acid level immediately after the operation and its maximum increasing rate within 24 h postoperatively; postoperative serum levels of albumin and creatinine; serum levels of B-type natriuretic peptide, procalcitonin, C-reactive protein, and prealbumin 24 h after operation; and age. Logistic regression analyses showed that intraoperative ACC time, CPB time, the maximum increasing rate of lactic acid within 24 h after operation, serum procalcitonin 24 h after operation and intraoperative blood loss were independent risk factors for postoperative ARDS. CONCLUSION: The risk factors of ARDS identified in these children can predict the occurrence of ARDS following the surgeries and timely interventions can improve the success rate in treatment of postoperative ARDS in children with CCHD. PMID- 27998860 TI - [Anesthetic effect and safety of ultrasound-guided thoracic paravertebral blockade in sympathectomy for palmar hyperhidrosis: a randomized controlled trial]. AB - OBJECTIVE: To explore the anesthetic effect and safety of ultrasound-guided thoracic paravertebral blockade in video-assisted thoracoscopic sympathectomy for treatment of palmar hyperhidrosis. METHODS: A total of 120 patients undergoing video-assisted thoracoscopic sympathectomy for moderate or severe hyperhidrosis were randomized to receive ultrasound-guided thoracic paravertebral blockade (group A, n=60) or general anesthesia with tracheal intubation (group B, n=60). In both groups routine monitoring and radial artery catheterization were used. The patients in group A were given oxygen inhalation via a nasal tube after thoracic paravertebral blockade, and those in group B had intratracheal intubation. Blood gas analyses were conducted 5 min before and 5 min after the operation and the clinical outcomes and complications were recorded in each group. RESULTS: All the patients completed the operations safely and none of the patients with thoracic paravertebral blockade required conversion to general anesthesia. Significant differences were recorded between groups A and B in anesthetic preparation time (6.26?2.09 vs 46.32?15.76 min), awakening time (6.26?2.09 vs 46.32?15.76 min), and mean hospitalization expense (6355.54?426.00 vs 8932.25?725.98 RMB Yuan). Compared with those in group B, the patients in group A showed a significantly lower rate of postoperative throat discomfort (0% vs 100%), a shorter monitoring time (2 h vs 12 h), and faster recovery time for food intake (2 h vs 6 h). The parameters of artery blood gas analysis both before and after the operation were similar between the two groups, but the postoperative variations differed significantly between the two groups in pH value and PaCO2 but not in PaO2. CONCLUSION: Ultrasound-guided thoracic paravertebral blockade is safe and effective in video-assisted thoracoscopic sympathectomy for palmar hyperhidrosis and is associated with less complications and better postoperative recovery. PMID- 27998862 TI - [Expression of mir-106b in esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression of mir-106b in esophageal squamous cell carcinoma (ESCC) tissue and analyze its correlation with the clinicopathologic features of ESCC. METHODS: A total of 200 fresh surgical specimens of ESCC and adjacent tissues collected between 2001 and 2007 were examined for expressions of mir-106b using real-time PCR (RT-PCR). Northern blot analysis for mir-106b was performed in 4 pairs of samples to confirm the RT-PCR results. The relationship between mir-106b expression and clinicopathological features and prognosis of the patients were analyzed. RESULTS: Mir-106b was expressed at significantly higher levels in ESCC tissues than in the paired adjacent tissues. Overexpression of mir 106b was associated with lymph node metastasis, stage of TNM classification and smoking (P<0.05). The survival rate of patients with low mir-106b expression was higher than that of patients with high mir-106b expression (60 vs 37 months, P=0.024). Cox regression analysis indicated that the expression of mir-106b, lymph node metastasis and smoking were independent prognostic factors for ESCC (P<0.05). CONCLUSION: Mir-106b is overexpressed in ESCC tumors, and its overexpression is strongly associated with lymph node metastasis and a poor prognosis. Mir-106b expression is an independent prognostic factor for ESCC and can serve as a biomarker for diagnosis and prognostic evaluation of ESCC. PMID- 27998863 TI - [Staged retrograde flexible ureteroscopic lithotripsy versus miniaturized percutaneous nephrolithotomy for renal stones of 2-4 cm in diameter: a randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy and safety of staged retrograde flexible ureteroscopic lithotripsy (FURS) and miniaturized percutaneous nephrolithotomy (m PCNL) for treatment of renal stones of 2-4 cm in diameter. METHODS: This randomized controlled trial was conducted in 70 patients with renal stones of 2-4 cm in diameter admitted in our hospital between January 2013 and December 2015. The patients were randomized to receive staged FURS (35 cases) or m-PCNL (35 cases), and the total treatment time, total hospital stay after procedure, total medical cost, treatment success, decrease in hemoglobin level and complications were compared between the two groups. RESULTS: The treatment success rate was 100% in both groups, but the complete stone-free rate was significantly lowered in FURS group than m-PCNL group (65.71% vs 94.29%, P<0.01). The average decrease in hemoglobin level was 3.37?1.56 g/L in FURS group and 11.93?2.24 g/L in m-PCNL group (P<0.01). The overall complication rates in the two groups were 6.25% and 9.37%, respectively (P>0.05). Minor complications (grade I by Clavien-Dindo classification) occurred in one case in FURS group (fever) and two cases in m PCNL group (self-limiting hematuria); major complications (grade II) occurred in one case in FURS group (steinstrase) and one case in m-PCNL group (blood transfusion). In staged FURS and m-PCNL groups, the mean total treatment time was 4.06?1.11 vs 1.26?0.47 weeks (P<0.01), the mean hospital stay after procedure was 3.66?1.29 vs 5.13?0.43 days (P<0.01), and the mean total medical cost was 54 291.00 RMB ?6149.00 vs 23 482.00 RMB ?2317.00 (P<0.01), respectively. CONCLUSION: FURS is safe and effective for treatment of renal stones of 2-4 cm in diameter, and a staged procedure is necessary to achieve a stone-free status for large calculi. Both sophisticated equipment and rich surgical experience are essential to ensure treatment success. PMID- 27998864 TI - [Role of stromal cell-derived factor-1 and CXC chemokine receptor 4 in corneal graft rejection in rats]. AB - OBJECTIVE: To examine expression of stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) in rat cornea tissue and their role in corneal allograft rejection. METHODS: With 15 Wistar rats as the normal control group, 22 Wistar rats received autologous corneal graft transplantation, and 44 Wistar rats received transplantation of corneal graft from SD rats with penetrating keratoplasty. From the rats with allograft transplantation, 22 were selected randomly for treatment with TobraDex eye drops for 30 days after the operation (twice a day), and the remaining 22 rats were treated with normal saline only. Clinical assessment of the corneal grafts was carried out using Larkin's method; histopathological observation, immunohistochemistry, and real-time quantitative PCR of the corneal grafts were performed on days 5 and 9 after the transplantation. RESULTS: Graft rejection occurred in none of the rats in autograft group. In rats treated with TobraDex, the graft survival time was significantly longer than that in rats with saline treatment (24?0.32 vs 10?0.36 days, P<0.001), and histopathological examination revealed numerous inflammatory cells and neovascularization in the allografts in the latter group. SDF-1 and CXCR4 mRNA expression in the corneal tissue increased significantly in rats receiving allograft transplantation and saline treatment (P<0.001 on day 5 and P<0.01 on day 5), and their expression was obviously lowered in rats with TobraDex treatment. Immunohistochemical examination revealed that the expression of SDF-1 and CXCR4, found mainly in the corneal epithelium and stroma, was significantly increased in the allografts in rats with saline treatment. CONCLUSION: SDF-1/CXCR4 may participate in corneal graft rejection in rats early after transplantation possibly through the mechanism that SDF-1 specifically induces CXCR4+ cell maturation and chemotaxis toward the allograft to promote corneal neovascularization. PMID- 27998865 TI - [Interaction of DNAJB13 with HK1 in mouse]. AB - OBJECTIVE: To investigate the presence of interactions between DNAJB13 and HK1. METHODS: The open reading frame of Dnajb13 gene was amplified from mouse testis cDNA by PCR. The PCR products were then inserted into pGEX-4T-1 vector after double digestion and identified by sequencing. The recombinant plasmids were transformated into competent DH5a cells, and the fusion protein was expressed with IPTG induction. SDS-PAGE Coomassie brilliant blue staining and Western blot analysis were used to detect the fusion protein expression. The protein precipitated by GST-DNAJB13 in GST pull down assay was detected by Western blotting. RESULTS: The recombinant plasmid pGEX-4T-1-Dnajb13 was successfully constructed and verified. E.coli transformed with the recombinant plasmid expressed abundant fusion protein. GST pull down assay showed interactions between DNAJB13 and HK1. CONCLUSION: DNAJB13 interacts with HK1 in mouse testis and probably participates in spermatogenesis and the regulation of sperm motility. PMID- 27998866 TI - [Nosocomial septicemia in the early stage after stem cell transplantation in children with major beta-thalassemia]. AB - OBJECTIVE: To explore the clinical characteristics of nosocomial septicemia in the early stage after hematopoietic stem cell transplantation (HSCT) in children with major beta-thalassemia. METHODS: The clinical data were retrospectively analyzed of 55 consecutive children with major beta-thalassemia who developed septicemia early after HSCT between January, 2011 and June, 2016. RESULTS: Among the total of 416 consecutive children with major beta-thalassemia undergoing allogeneic HSCT, the incidence of nosocomial infection early after transplantation was 77.16% (321/416), and 55 (17.13%) children showed positive findings in blood culture test. The infections occurred most commonly in the oral cavity (65.5%), followed by the respiratory tract, intestinal tract and skin. Gram-negative bacteria, including Escherichia coli (27.3%), Klebsiella pneumoniae (21.8%) and Pseudomonas aeruginosa (9.1%), were the most common causes of infections. Fungal (Candida tropicalis) infection caused septicemia in 1 case. Of all the pathogens, extended-spectrum beta-lactamase (ESBL)-producing bacteria were found in 6 cases, methicillin-resistant Staphylococcus aureus (MRSA) in 2 cases, and multidrug-resistant (MDR) bacteria in 2 cases. CONCLUSION: Gram negative bacteria are the major pathogens causing septicemia in children early after HSCT for major beta-thalassemia, and the bacteria show a high level of drug resistance. Adequate preventive use of antibiotics and care of the oral cavity, the respiratory tract, and the perianal region following the transplantation are important measures to control nosoconial infection in these children. PMID- 27998867 TI - [Efficacy of ultrasound-guided lauromacrogol sclerotherapy for benign thyroid cysts and factors affecting the therapeutic effect]. AB - OBJECTIVE: To evaluate the clinical efficacy of ultrasound-guided lauromacrogol sclerotherapy for benign thyroid cysts and analyze the factors affecting the efficacy. METHODS: Ultrasound-guided lauromacrogol sclerotherapy was performed in 97 patients with a total of 99 benign thyroid cysts. The changes in cystic volume and other thyroid parameters were evaluated at 1, 3, 6, and 12 months after sclerotherapy. According to changes in the cystic volume, the efficacy of sclerotherapy was defined as therapeutic failure (with a volume reduction <50%), treatment success (volume reduction >=50%) and cure (volume reduction >=90%). The factors of affecting the efficacy of sclerotherapy was analyzed using COX regression. RESULTS: The mean cystic volume at 1, 3, 6 and 12 months after sclerotherapy were reduced from the baseline volume of 12.08?11.56 cm3 to 5.63?8.51 cm3, 5.96?8.42 cm3, 3.80?5.50 cm3 and 2.85?3.98 cm3, respectively, with an average cystic volume reduction rate of (70.02?33.72)%. Therapeutic success was achieved 82 of the 99 cysts (82.83%) and cure was achieved 63cysts (63.64%) at 12 months after the procedure. A second sclerotherapy was performed for 13 cysts which did not show a volume reduction at 1-3 months after the initial procedure. A disease course of over 12 months was an independent risk factor for a second sclerotherapy (23.7% [9/38] vs 6.6% [4/61], OR=4.473 [1.238-16.169], P=0.022). The efficacy of sclerotherapy was related to cystic cavity separation, cystic fluid viscosity, cystic/solid ratio and cystic wall thickness. COX regression analysis revealed that cystic cavity separation (HR=2.25, 95%CI: 1.19 4.25) and cystic fluid viscosity (HR=2.02, 95%CI: 1.19-3.43) were the major factors affecting the treatment efficacy. CONCLUSION: Ultrasound-guided lauromacrogol sclerotherapy is effective and safe for treatment of benign thyroid cysts, and the maximal treatment effect can be achieved at 6 months after sclerotherapy and in cases of uncomplicated cysts with non-viscous cystic fluid, no solid cystic cavity separation and a disease course of less than 12 months. PMID- 27998868 TI - [The MicroRNA miR-205 inhibits epithelial-messenchymal transition in HK-2 cells by down-regulating ZEB1 and ZEB2 expressions]. AB - OBJECTIVE: To explore the role of miR-205 in regulating epithelial-messenchymal transition (EMT) in proximal tubular cell line HK-2 cells and the underlying mechanism. METHODS: HK-2 cells transfected with miR-205 mimics or a scrambled control sequence were examined for miR-205 expressions and mRNA levels of ZEB1, E cadherin, and alpha-SMA using real-time qPCR; the protein levels of ZEB1, ZEB2, E cadherin, and alpha-SMA were detected with Western blotting. Immunohistochemistry was performed to examine the ectopic expression of beta-catenin and E-cadherin expression in the cells. RESULTS: The expression levels of ZEB1 and ZEB2 decreased significantly (P<0.01) while E-cadherin expression was up-regulated (P<0.01) in cells transfected with miR-205 mimics. Transfection with miR-205 mimics also markedly down-regulated the expression of alpha-SMA (P<0.01), a marker of mesenchymal cells that play an important role in EMT of HK-2 cells. The ectopic expression of beta-catenin was inhibited by miR-205 mimics in HK-2 cells. CONCLUSION: miR-205 inhibits EMT in HK-2 cells by down-regulating the expression levels of ZEB1 and ZEB2. PMID- 27998869 TI - [Role of autophagy in fasudil-induced Rho kinase inhibition for protection against myocardial ischemia-reperfusion injury in rats]. AB - OBJECTIVE: To investigate the changes of autophagy in ischemic myocardium of rats treated with fasudil for inhibiting Rho kinase. METHODS: The hearts isolated from male Sprague-Dawley rats were subjected to 30 min of occlusion of the left anterior descending artery followed by 120 min of reperfusion with or without treatment with fasudil or fasudil+Wort. The left ventricular hemodynamics were continuously recorded, and the coronary effluent was collected during the reperfusion to determine lactate dehydrogenase (LDH) levels. The mRNA expressions of autophagy-related genes Atg5 and Beclin1 and apoptosis-related genes bax and bcl-2 were detected by RT-PCR, and the protein expression of caspase-3 was detected by Western blotting. RESULTS: Compared with I/R group, fasudil significantly improved the left ventricular developed pressure, maximal rise/fall rate of left ventricular pressure and rate pressure product, reduced LDH release during reperfusion, increased Atg5 and Beclin1 mRNA expression and the ratio of Bcl-2/Bax, and lowered caspase 3 protein expression. The autophagy inhibitor Wort significantly attenuated the effect of fasudil in the rat hearts. CONCLUSION: Fasudil treatment for inhibiting Rho kinase promoted autophagy in ex vivo rat heart to protect against myocardial ischima-reperfusion injury possibly by reducing apoptosis of the cardiac myocytes. PMID- 27998870 TI - [Expressions of inflammatory cytokines in intestinal mucosa and their prognostic value in patients with ulcerative colitis]. AB - OBJECTIVE: To detect the expressions of IL-17, IL-23, IL-22 and IL-11 in the intestinal mucosa of patients with ulcerative colitis (UC) and analyze their prognostic values. METHODS: Forty patients with active UC, 15 with UC in remission and 15 healthy subjects were examined for the expressions and distribution of IL-17, IL-23, IL-22, and IL-11 in the colorectal mucosausing immunohistochemistry. We further collected the data from 40 patients with routine therapy and regular follow-up and compared the expressions of those cytokines according to the condition of mucosal healing. RESULTS: The expressions of cytokines in patients with active UC were significantly higher than those in patients with remittent UC and healthy control subjects (IL-17: 0.0727?0.0037 vs 0.0354?0.0243 vs 0.0330?0.0045; IL-23: 0.1407?0.0068 vs 0.0865?0.0051 vs 0.0442?0.0137; IL-22: 0.0522?0.0045 vs 0.0259?0.0063 vs 0.0115?0.0061; IL-11: 0.0479?0.0022 vs 0.0365?0.0024 vs 0.0232?0.0009, P<0.05). The expression levels of IL-17, IL-23, and IL-22 increased significantly with the increase of the disease activity (IL-17: 0.0545?0.0072 vs 0.0786? 0.0051 vs 0.0847?0.0197; IL-23: 0.1112?0.0046 vs 0.1480?0.0089 vs 0.1644?0.0190; IL-22: 0.0307?0.0063 vs 0.0548? 0.0071 vs 0.0719?0.0056, P<0.05). In patients with active UC, the expression levels of the 4 cytokines in the intestinal mucosa were positively correlated with the endoscopic activity grade (P<0.05), and IL-17 and IL-22 expression levels were also positively correlated with the histological grade (P<0.05). All the 4 cytokines were positively intercorrelated. The patients with low IL-17 expression (25.00%) showed a significantly lower rate of poor mucosal healing than those with high IL-17 expressions (25% vs 67%, P<0.05). CONCLUSION: The cytokines IL-17, IL-23, IL-22, and IL-11 all participate in the pathogenesis of UC and may serve as indicators for evaluating the inflammatory activity. The expression level of IL-17 can be a valuable indicator for predicting mucosal healing in UC patients after a short-term treatment. PMID- 27998871 TI - [Expressions of cyclooxygenase-2 and basic fibroblast growth factor in nasopharyngeal carcinoma and their association with radiotherapy sensitivity]. AB - OBJECTIVE: To detect the expressions of cyclooxygenase-2 (COX-2) and basic fibroblast growth factor (bFGF) and evaluate their value in predicting the radiotherapy sensitivity in nasopharyngeal carcinoma (NPC). METHODS: The expressions of COX-2 and bFGF were detected immunohistochemically in biopsy samples of NPC, and their relationship with the radiotherapy sensitivity of the tumors were analyzed. RESULTS: In 97 NPC cases, the positivity rates of COX-2 and bFGF were 71.1% (69/97) and 64.9% (63/97), respectively. Correlation analysis demonstrated that a positive COX-2 expression was positively correlated with an advanced T status and N status, and bFGF expression was positively associated with an advanced N status in NPCs. In radiotherapy-sensitive and radiotherapy insensitive cases, the positive rate of COX-2 was 62.8% and 92.6%, and that of bFGF was 57.1% and 85.2%, respectively. The expression of COX-2 was positively correlated with that of bFGF (r=0.486, P<0.05). The radiotherapy sensitivity differed significantly among patients with different statuses of COX-2 and bFGF positivity. CONCLUSION: COX-2 and bFGF can be effective and sensitive biomarkers for predicting radiotherapy sensitivity in NPC. PMID- 27998872 TI - [Association between gender and lung function in obese asthmatic children after inhaling corticosteroids]. AB - OBJECTIVE: To study the association between gender and lung function in obese asthmatic children before and after inhaling corticosteroids (ICS). METHODS: A total of 102 asthmatic boys (including 57 normal-weight and 45 obese boys) and 88 asthmatic girls (including 46 normal-weight and 42 obese girls) received ICS treatment for one year. Pulmonary functions were evaluated before and after the treatment for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), maximal expiratory flow 25 (MEF25) and maximal expiratory flow 50 (MEF50). RESULTS: The asthmatic children in the 4 subgroups showed similar pulmonary functions before the treatment. After inhalation of methacholine, FVC% and FEV1% were improved in both normal-weight boys and normal-weight girls; FVC% and FEV1% in obese boys were improved after the treatment, but the obese girls showed improvement only in FVC%. CONCLUSION: Inhalation of methacholine can improve large airway function in asthmatic children, and gender affects the improvement to a lesser extent in normal-weight children. In obese asthmatic children, methacholine inhalation better improves lung functions in boys than in girls. PMID- 27998873 TI - [LY294002 blocks the effect of dexamethasone in reducing urine protein in rats by inhibiting PI3K/Akt signaling pathway]. AB - OBJECTIVE: To investigate the involvement of PI3K/Akt signaling pathway in the changes of urine protein in adriamycin-induced nephropathic rats treated with dexamethasone and LY294002 (a PI3K inhibitor). METHODS: SD rats were randomized into normal control group, ariamycin-induced nephropathy group (ADR group), ariamycin+dexamethasone group (DEX group), and ADR+DEX+LY294002 group (LY294002 group). On days 7, 14 and 28 after the treatments, 24-h urine was collected from the rats to analyze the total urine proteins. The renal tissues were obtained on day 28 to examine the expressions of p-AKT, AKT and Bad proteins in the cortical tissues using Western blotting; the expression of Bad mRNA in the cortical tissues was measured by QPCR. RESULTS: Urine protein increased progressively in ADR group accompanied by significantly reduced p-AKT/AKT ratio and increased Bad mRNA expression in comparison with those in the normal control group (P<0.05). Urine protein was obviously reduced in DEX group with comparable p-AKT/AKT ratio and Bad mRNA expression level with those in the control group (P>0.05). Urine protein showed no significant reduction in LY294002 group, but the p-AKT/AKT ratio was significantly reduced and Bad mRNA expression was increased compared with those in DEX group (P<0.05). CONCLUSION: Dexamethasone increases the expression of Bad mRNA and reduces urine protein in adriamycin-induced nephropathic rats by activating PI3K/Akt signaling pathway. LY294002 can inhibit PI3K/Akt signaling pathway to block the effect of dexamethasone, suggesting that PI3K/Akt signaling pathway is one of the signaling pathways that mediate the effect of dexamethasone on proteinuria. PMID- 27998874 TI - [Analysis of pregnancy outcomes in 66 patients with systemic lupus erythematosus]. AB - OBJECTIVE: To analyze the outcomes of pregnancies in women with systemic lupus erythematosus (SLE) and the risk factors affecting the outcomes. METHODS: The data of SLE patients with pregnancy admitted from October, 2006 and September, 2015 were analyzed for assessing the maternal and fetal outcomes and complications. Their risk factors affecting the outcomes of the pregnancies were analyzed. RESULTS: The 66 SLE patients (69 pregnancies) had a mean age at SLE diagnosis of 22.9 ? 5.1 years with a mean duration of SLE of 4.1?3.6 years before pregnancy. Forty-five (65.2%) of the patients received oral medication for SLE treatment during pregnancy, and 44 (63.8%) were treated with prednisone and 19 (27.5%) were treated with hydroxychloroquine. The highest SLEDAI score was 6.8?7.4 during pregnancy. The patients with moderate-to-severe disease activity had a higher rate of fetal loss (12 [54.5%] vs 12 [25.5%]) with a significantly lower birth weight of the newborns than those with remittent or mild disease (2073.0? 778.7 vs 2817.8?533.7 g, P<0.05). The patients with moderate-to-severe disease activity also had higher rates of new-onset SLE (9 [40.9%] vs 6 [12.8%]), hypertension (12 [54.5%] vs 3 [6.4%]), active lupus nephritis (22 [100%] vs 4 [8.5%]), pneumonia (5 [22.7%] vs 2 [4.3%]), and renal insufficiency (8 [36.4%] vs 2 [4.3%]) compared with patients with remittent and mild disease (P<0.05). Active lupus nephritis (OR=6.10,95%CI: 1.43-25.96) was a significant predictor of adverse outcomes of the pregnancies. CONCLUSION: Fetal loss and maternal complications are common in patients with SLE in relation with the disease activity. Active lupus nephritis is a predictor for poor outcomes of pregnancies in SLE patients. PMID- 27998875 TI - [Progression of Behcet's disease with brain involvement: a case report]. AB - OBJECTIVE: Behcet's disease is a condition characterized by systemic vasculitis liable to thrombosis, and may involve the parenchyma and blood vessels in the brain. We report a case of Behcet's disease that progressed into central neural system involvement rapidly due to failure of tertiary prevention. This case demonstrates the importance of management of the high risk factors of thrombosis and timely prevention of disease progression. PMID- 27998876 TI - The Use and Effectiveness of Mobile Apps for Depression: Results From a Fully Remote Clinical Trial. AB - BACKGROUND: Mobile apps for mental health have the potential to overcome access barriers to mental health care, but there is little information on whether patients use the interventions as intended and the impact they have on mental health outcomes. OBJECTIVE: The objective of our study was to document and compare use patterns and clinical outcomes across the United States between 3 different self-guided mobile apps for depression. METHODS: Participants were recruited through Web-based advertisements and social media and were randomly assigned to 1 of 3 mood apps. Treatment and assessment were conducted remotely on each participant's smartphone or tablet with minimal contact with study staff. We enrolled 626 English-speaking adults (>=18 years old) with mild to moderate depression as determined by a 9-item Patient Health Questionnaire (PHQ-9) score >=5, or if their score on item 10 was >=2. The apps were (1) Project: EVO, a cognitive training app theorized to mitigate depressive symptoms by improving cognitive control, (2) iPST, an app based on an evidence-based psychotherapy for depression, and (3) Health Tips, a treatment control. Outcomes were scores on the PHQ-9 and the Sheehan Disability Scale. Adherence to treatment was measured as number of times participants opened and used the apps as instructed. RESULTS: We randomly assigned 211 participants to iPST, 209 to Project: EVO, and 206 to Health Tips. Among the participants, 77.0% (482/626) had a PHQ-9 score >10 (moderately depressed). Among the participants using the 2 active apps, 57.9% (243/420) did not download their assigned intervention app but did not differ demographically from those who did. Differential treatment effects were present in participants with baseline PHQ-9 score >10, with the cognitive training and problem-solving apps resulting in greater effects on mood than the information control app (chi22=6.46, P=.04). CONCLUSIONS: Mobile apps for depression appear to have their greatest impact on people with more moderate levels of depression. In particular, an app that is designed to engage cognitive correlates of depression had the strongest effect on depressed mood in this sample. This study suggests that mobile apps reach many people and are useful for more moderate levels of depression. CLINICALTRIAL: Clinicaltrials.gov NCT00540865; https://www.clinicaltrials.gov/ct2/show/NCT00540865 (Archived by WebCite at http://www.webcitation.org/6mj8IPqQr). PMID- 27998877 TI - Bridging the Health Data Divide. AB - Fundamental quality, safety, and cost problems have not been resolved by the increasing digitization of health care. This digitization has progressed alongside the presence of a persistent divide between clinicians, the domain experts, and the technical experts, such as data scientists. The disconnect between clinicians and data scientists translates into a waste of research and health care resources, slow uptake of innovations, and poorer outcomes than are desirable and achievable. The divide can be narrowed by creating a culture of collaboration between these two disciplines, exemplified by events such as datathons. However, in order to more fully and meaningfully bridge the divide, the infrastructure of medical education, publication, and funding processes must evolve to support and enhance a learning health care system. PMID- 27998878 TI - Developing an Unguided Internet-Delivered Intervention for Emotional Distress in Primary Care Patients: Applying Common Factor and Person-Based Approaches. AB - BACKGROUND: Developing effective, unguided Internet interventions for mental health represents a challenge. Without structured human guidance, engagement with these interventions is often limited and the effectiveness reduced. If their effectiveness can be increased, they have great potential for broad, low-cost dissemination. Improving unguided Internet interventions for mental health requires a renewed focus on the proposed underlying mechanisms of symptom improvement and the involvement of target users from the outset. OBJECTIVE: The aim of our study was to develop an unguided e-mental health intervention for distress in primary care patients, drawing on meta-theory of psychotherapeutic change and utilizing the person-based approach (PBA) to guide iterative qualitative piloting with patients. METHODS: Common factors meta-theory informed the selection and structure of therapeutic content, enabling flexibility whilst retaining the proposed necessary ingredients for effectiveness. A logic model was designed outlining intervention components and proposed mechanisms underlying improvement. The PBA provided a framework for systematically incorporating target user perspective into the intervention development. Primary care patients (N=20) who had consulted with emotional distress in the last 12 months took part in exploratory qualitative interviews, and a subsample (n=13) undertook think-aloud interviews with a prototype of the intervention. RESULTS: A flexible intervention was developed, to be used as and when patients need, diverting from a more traditional, linear approach. Based on the in-depth qualitative findings, disorder terms such as "depression" were avoided, and discussions of psychological symptoms were placed in the context of stressful life events. Think aloud interviews showed that patients were positive about the design and structure of the intervention. On the basis of patient feedback, modifications were made to increase immediate access to all therapeutic techniques. CONCLUSIONS: Detailing theoretical assumptions underlying Internet interventions for mental health, and integrating this approach with systematic in-depth qualitative research with target patients is important. These strategies may provide novel ways for addressing the challenges of unguided delivery. The resulting intervention, Healthy Paths, will be evaluated in primary care-based randomized controlled trials, and deployed as a massive open online intervention (MOOI). PMID- 27998879 TI - Using Patient Flow Information to Determine Risk of Hospital Presentation: Protocol for a Proof-of-Concept Study. AB - BACKGROUND: Every day, patients are admitted to the hospital with conditions that could have been effectively managed in the primary care sector. These admissions are expensive and in many cases are possible to avoid if early intervention occurs. General practitioners are in the best position to identify those at risk of imminent hospital presentation and admission; however, it is not always possible for all the factors to be considered. A lack of shared information contributes significantly to the challenge of understanding a patient's full medical history. Some health care systems around the world use algorithms to analyze patient data in order to predict events such as emergency presentation; however, those responsible for the design and use of such systems readily admit that the algorithms can only be used to assess the populations used to design the algorithm in the first place. The United Kingdom health care system has contributed data toward algorithm development, which is possible through the unified health care system in place there. The lack of unified patient records in Australia has made building an algorithm for local use a significant challenge. OBJECTIVE: Our objective is to use linked patient records to track patient flow through primary and secondary health care in order to develop a tool that can be applied in real time at the general practice level. This algorithm will allow the generation of reports for general practitioners that indicate the relative risk of patients presenting to an emergency department. METHODS: A previously designed tool was used to deidentify the general practice and hospital records of approximately 100,000 patients. Records were pooled for patients who had attended emergency departments within the Eastern Health Network of hospitals and general practices within the Eastern Health Network catchment. The next phase will involve development of a model using a predictive analytic machine learning algorithm. The model will be developed iteratively, testing the combination of variables that will provide the best predictive model. RESULTS: Records of approximately 97,000 patients who have attended both a general practice and an emergency department have been identified within the database. These records are currently being used to develop the predictive model. CONCLUSIONS: Records from general practice and emergency department visits have been identified and pooled for development of the algorithm. The next phase in the project will see validation and live testing of the algorithm in a practice setting. The algorithm will underpin a clinical decision support tool for general practitioners which will be tested for face validity in this initial study into its efficacy. PMID- 27998881 TI - Cholesterol paradox: a correlate does not a surrogate make. AB - The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information. PMID- 27998880 TI - Social Media Use Among Living Kidney Donors and Recipients: Survey on Current Practice and Potential. AB - BACKGROUND: In the United States, there is a national shortage of organs donated for transplant. Among the solid organs, most often kidneys are donated by living donors, but the lack of information and complicated processes limit the number of individuals who serve as living kidney donors. Social media can be a tool for advocacy, educating the public about the need, process, and outcomes of live kidney donors, yet little is known about social media use by kidney transplant patients. OBJECTIVE: The purpose of this study was to examine the social media use of potential kidney transplant patients and their willingness to use social media and their networks to advocate and educate about living kidney donation. METHODS: Using a validated survey, we modified the instrument to apply to the patient population of interest attending the Medical University of South Carolina, Charleston, SC, USA. The questions on the survey inquired about current social media use, sites visited, frequency and duration of social media use, and willingness to use social media to share the need for living kidney donors. We asked patients who had received a transplant and those awaiting a transplant to complete the survey during an office visit. Participation was voluntary. RESULTS: A total of 199 patients completed the survey. Approximately half of all kidney transplant patients surveyed used social media (104/199, 52.3%), and approximately one-third (66/199, 33.2%) had more than 100 friends in their social media network. Facebook was the most popular site, and 51% (102/199) reported that they would be willing to post information about living kidney donation on their social networks. More than a quarter of the sample (75/199, 37.7%) had posted about their health status in the past. CONCLUSIONS: Social media holds great promise for health-related education and awareness. Our study shows the current social media use of kidney transplant patients. In turn, such information can be used to design interventions to ensure appropriate decision making about live kidney donation. Transplant programs can help increase the number of living donors by providing guidance to kidney transplant patients in how to use social media, to be advocates, and to provide information about living kidney donation to their social network. PMID- 27998882 TI - Predicting Success: Left Ventricular Assist Device Explantation Evaluation Protocol Using Comprehensive Cardiopulmonary Exercise Testing. PMID- 27998885 TI - QUESTION 1: What is the risk of a repeat reaction to amoxicillin or a cephalosporin in children with a history of a non-immediate reaction to amoxicillin? PMID- 27998883 TI - Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1. AB - The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1-mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial-mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, beta-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers. Cancer Prev Res; 10(2); 142-52. (c)2016 AACR. PMID- 27998884 TI - Adult height of preterm infants: a longitudinal cohort study. AB - BACKGROUND: Many infants born prematurely experience growth failure following delivery, with subsequent catch-up growth. Traditionally catch-up was thought to be complete in the first few years of life. Most studies have focused on groups of infants defined by birth weight, for example <1500 g, resulting in disproportionate numbers of small for gestational age infants. This study aimed to determine whether appropriate weight for gestation (AGA) preterm born children reach their expected adult height when compared with term controls. METHODOLOGY: This UK based prospective longitudinal cohort study recruited 204 preterm children born at a tertiary neonatal unit during 1994 and 50 matched controls. Growth parameters have been assessed annually until the completion of growth. RESULTS: There was no significant difference in the final height SD score (SDS) of children born at term (n=30) and those born prematurely and AGA (n=70) (0.45 term vs 0.22 preterm). Catch-up growth however, continued throughout the whole of childhood. When the difference between final height SDS and mid-parental height SDS were compared, there were again no significant differences (0.13 term vs 0.03 preterm). CONCLUSIONS: Those born prematurely with an AGA achieve a comparable adult height to children born at term, however, catch-up growth continues for much longer than traditionally thought. PMID- 27998886 TI - The choking hazard of grapes: a plea for awareness. AB - Deaths from choking are a major cause of childhood mortality, especially in the very young. Whole grapes are ideally suited to cause paediatric airway obstruction and, though regularly implicated, knowledge that this popular fruit, and other similarly shaped foods, is a choking hazard is not widespread. We present the cases of three children who presented to our institution after grape aspiration. Increased dissemination of the learning points among health professionals working with children may aid in the prevention of further episodes. PMID- 27998888 TI - Give heavy drinkers scans to detect liver disease early, says NICE. PMID- 27998887 TI - First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation Therapy in Patients with Locally Advanced Soft Tissue Sarcomas. AB - Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS).Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion.Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10% 90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible.Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908-17. (c)2016 AACR. PMID- 27998889 TI - KIT blockade is sufficient for donor hematopoietic stem cell engraftment in Fanconi anemia mice. PMID- 27998890 TI - Extended thromboprophylaxis with direct oral anticoagulants for medical patients: a systematic review and meta-analysis. PMID- 27998891 TI - Inflammatory Cytokines and Lung Cancer Risk in 3 Prospective Studies. AB - To further investigate the role of inflammation in lung carcinogenesis, we evaluated associations between proinflammatory cytokines and lung cancer risk. We conducted a case-control study nested within 3 prospective cohort studies-the Melbourne Collaborative Cohort Study (1990-1994), the Malmo Diet and Cancer Study (1991-1996), and the Northern Sweden Health and Disease Study (initiated in 1985) involving 807 incident lung cancer cases and 807 smoking-matched controls. Conditional logistic regression models adjusting for serum cotinine concentrations were used to estimate odds ratios for lung cancer risk associated with concentrations of interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL-10, IL-12, interferon gamma, tumor necrosis factor alpha, and granulocyte-macrophage colony stimulating factor. We observed a higher lung cancer risk for participants with elevated concentrations of IL-6 and IL-8. These associations seemed to be stronger among former smokers (for fourth quartile vs. first quartile, odds ratio (OR) = 2.70, 95% confidence interval (CI): 1.55, 4.70) and current smokers (OR = 1.99, 95% CI: 1.15, 3.44) for IL-6 and among former smokers (OR = 2.83, 95% CI: 1.18, 6.75) and current smokers (OR = 1.30, 95% CI: 0.69, 2.44) for IL-8. No notable associations were observed among never smokers. Risk associations with IL 6 and IL-8 were observed for blood samples taken close to diagnosis (<5 years) as well as more than 15 years postdiagnosis. PMID- 27998893 TI - Management of children and young people with headache. AB - Headache is very common in children and young people. The correct advice and treatment requires consideration of a wide differential diagnosis between primary and secondary headaches, and also of the different types of primary headache. The International Classification of Headache Disorders gives useful descriptions and diagnostic criteria that are especially useful for primary headaches. The National Institute for Health and Care Excellence (NICE) Clinical Guideline 150 provides evidence-based recommendations on treatments for adults and young people from age 12 years. However, the same principles can be applied to younger children when a specific diagnosis can be made. Key recommendations from the NICE Quality Standards include, establishing a precise diagnosis if possible, avoiding, diagnosing and treating medication overuse headache, and combining a triptan with a non-steroidal anti-inflammatory drug or paracetamol as the first line acute/rescue treatment for migraine with or without aura. Although rare in children and young people, it is important to diagnose new daily persistent headache, as it responds poorly or not at all to medication; and paroxysmal hemicrania as it responds very well to indomethacin but not to other commonly used analgesics. When faced with difficulties in reaching a precise diagnosis or in finding effective therapies, further advice should be sought from a children's headache clinic or specialist. PMID- 27998894 TI - Modeling Successful Aging Over Time in the Context of a Disaster. AB - Objective: Positing that successful aging (SA) has independent, yet related components that are both objective and subjective, we examine how the indicators of SA change over time and how exposure to a disaster affects the developmental course of SA. Method: Data were gathered from 5,688 people aged 50-74 years living in New Jersey who participated in baseline telephone interviews between 2006 and 2008 and then were reassessed up to four times over the following 9 years. Multilevel mixed effects models were used to examine change in objective and subjective SA over time and to evaluate the impact of Hurricane Sandy on SA. Results: Over the 9-year period, controlling for age, gender, education, and income, average levels of both subjective SA and objective SA declined. People exposed to Hurricane Sandy experienced sharper declines in subjective SA and indicators of objective SA (pain and functional ability) than people not exposed. Discussion: Findings have important implications for expanding our conceptualization of SA, clarifying the measures used to understand SA, and the importance of accounting for the effects of disasters on SA. PMID- 27998895 TI - Elder Mistreatment Among Chinese American Families: Do Acculturation and Traditionalism Matter? AB - OBJECTIVES: This study examined the effect of acculturation and Chinese traditionalism on elder mistreatment (EM) among Chinese American older adults. METHOD: We used a mixed method design in this 2-phase cross-sectional exploratory study conducted in the Phoenix metropolitan area. In Phase I, we conducted four focus groups to develop a culturally relevant EM assessment tool. In Phase II, we administered a survey incorporating this tool to 266 community-dwelling Chinese American older adults aged 60 and older. Acculturation was measured using the Marin acculturation scale. Traditionalism was measured with questions drawn from the Traditionality-Modernity subscale of the Chinese Personality Assessment Inventory (CPAI-2). RESULTS: The prevalence rates of elder abuse and elder neglect are 8.3% and 5.3%, respectively. Higher levels of acculturation and depression are positively associated with the occurrence of elder abuse (odds ratio [OR] = 1.06). Traditionalism is not significantly related to elder abuse or elder neglect. DISCUSSION: The results suggest that promoting traditional Chinese beliefs may not necessarily prevent EM among members of this population. Rather, EM prevention efforts might focus on building "bi-cultural" identities among both older adults and their adult children. Future research could explore the effect of intergenerational acculturation discrepancies on EM among members of this population. PMID- 27998896 TI - Introduction of standard measles vaccination in an urban African community in 1979 and overall child survival: a reanalysis of data from a cohort study. AB - OBJECTIVE: To examine the effect of the first introduction of measles vaccine (MV) in Guinea-Bissau in 1979. SETTING: Urban community study of the anthropometric status of all children under 6 years of age. PARTICIPANTS: The study cohort included 1451 children in December 1978; 82% took part in the anthropometric survey. The cohort was followed for 2 years. INTERVENTION: In December 1979, the children were re-examined anthropometrically. The participating children, aged 6 months to 6 years, were offered MV if they did not have a history of measles infection. There were no routine vaccinations in 1979 1980. PRIMARY AND SECONDARY OUTCOME MEASURES: Age-adjusted mortality rate ratios (MRRs) for measles vaccinated and not vaccinated children; changes in nutritional status. RESULTS: The nutritional status deteriorated significantly from 1978 to 1979. Nonetheless, children who received MV at the December 1979 examination had significantly lower mortality in the following year (1980) compared with the children who had been present in the December 1978 examination but were not measles vaccinated. Among children still living in the community in December 1979, measles-vaccinated children aged 6-71 months had a mortality rate of 18/1000 person-years during the following year compared with 51/1000 person-years for absent children who were not measles vaccinated (MRR=0.30 (0.12-0.73)). The effect of MV was not explained by prevention of measles infection as the unvaccinated children did not die of measles infection. CONCLUSIONS: MV may have beneficial non-specific effects on child survival not related to the prevention of measles infection. PMID- 27998897 TI - Antithrombotic stewardship: a multidisciplinary team approach towards improving antithrombotic therapy outcomes during and after hospitalisation: a study protocol. AB - INTRODUCTION: Antithrombotic therapy carries high risks for patient safety. Antithrombotics belong to the top 5 medications involved in potentially preventable hospital admissions related to medication. To provide a standard for antithrombotic therapy and stress the importance of providing optimal care to patients on antithrombotic therapy, the Landelijke Standaard Ketenzorg Antistolling (LSKA; Dutch guideline on integrated antithrombotic care) was drafted. However, the mere publication of this guideline does not guarantee its implementation. This may require a multidisciplinary team effort. Therefore, we designed a study aiming to determine the influence of hospital-based antithrombotic stewardship on the effect and safety of antithrombotic therapy outcomes during and after hospitalisation. METHODS AND ANALYSIS: In this study, the effect of the implementation of a multidisciplinary antithrombotic team is compared with usual care using a pre-post study design. The study is performed at the Erasmus University Medical Center Rotterdam and the Reinier de Graaf Hospital Delft. Patients who are or will be treated with antithrombotics are included in the study. We aim to include 1900 patients, 950 in each hospital. Primary outcome is the proportion of patients with a composite end point consisting of >=1 bleeding or >=1 thrombotic event from the beginning of antithrombotic therapy (or hospitalisation) until 3 months after hospitalisation. Bleeding is defined according to the International Society of Thrombosis and Haemostasis (ISTH) classification. A thrombotic event is defined as any objectively confirmed arterial or venous thrombosis, including acute myocardial infarction or stroke for arterial thrombosis and deep venous thrombosis or pulmonary embolism or venous thrombosis. An economic evaluation is performed to determine whether the implementation of the multidisciplinary antithrombotic team will be cost effective. ETHICS AND DISSEMINATION: This protocol was approved by the Medical Ethical Committee of the Erasmus University Medical Center. The findings of the study will be disseminated through peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: NTR4887; pre-results. PMID- 27998898 TI - Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register based study. AB - OBJECTIVES: To determine the total cancer incidence in relation to a 5-year exposure to caesium-137 (137Cs) from the 1986 Chernobyl nuclear power plant accident. METHODS: A closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of 137Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the National Board of Health and Welfare. Individuals were assigned an annual 137Cs exposure based on their place of residence (1986-1990), from which 5-year cumulative 137Cs exposures were calculated, accounting for the physical decay of 137Cs and changing residencies. HRs were adjusted for age, sex, rural/non-rural residence and pre-Chernobyl total cancer incidence. RESULTS: The 734 537 people identified were categorised by exposure: the first quartile was low exposure (0.0-45.4 kBq/m2), the second and third quartiles were intermediate exposure (45.41-118.8 kBq/m2), and the fourth quartile was the highest exposure (118.81-564.71 kBq/m2). Between 1991 and 2010, 82 495 cancer cases were registered in the 3 counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure and 1.05 (1.03 to 1.07) for the highest exposure compared to the reference exposure. CONCLUSIONS: We found a small overall exposure-response pattern of the total cancer incidence related to 137Cs after adjustment for age, sex, rural residence and pre-Chernobyl cancer incidence. PMID- 27998899 TI - Effect of the type of maternal pushing during the second stage of labour on obstetric and neonatal outcome: a multicentre randomised trial-the EOLE study protocol. AB - INTRODUCTION: The scientific data currently available do not allow any definitive conclusion to be reached about what type of pushing should be recommended to women during the second stage of labour. The objective of this trial is to assess and compare the effectiveness of directed open-glottis pushing versus directed closed-glottis pushing. Secondary objectives are to assess, according to the type of pushing: immediate maternal and neonatal morbidity, intermediate-term maternal pelvic floor morbidity, uncomplicated birth, and women's satisfaction at 4 weeks post partum. METHODS AND ANALYSIS: This multicentre randomised clinical trial compares directed closed-glottis pushing (Valsalva) versus directed open-glottis pushing during the second stage of labour in 4 hospitals of France. The study population includes pregnant women who received instruction in both types of pushing, have no previous caesarean delivery, are at term and have a vaginal delivery planned. Randomisation takes place during labour once cervical dilation >=7 cm. The principal end point is assessed by a composite criterion: spontaneous delivery without perineal lesion (no episiotomy or spontaneous second-degree, third-degree or fourth-degree lacerations). We will need to recruit 125 women per group. The primary analysis will be by intention-to-treat analysis, with the principal results reported as crude relative risks (RRs) with their 95% CIs. A multivariate analysis will be performed to take prognostic and confounding factors into account to obtain adjusted RRs. ETHICS AND DISSEMINATION: This study was approved by a French Institutional Review Board (Comite de Protection des Personnes Sud Est 6:N degrees AU1168). Results will be reported in peer-reviewed journals and at scientific meetings. This study will make it possible to assess the effectiveness of 2 types of directed pushing used in French practice and to assess their potential maternal, fetal and neonatal effects. Findings from the study will be useful for counselling pregnant women before and during labour. TRIAL REGISTRATION NUMBER: Agence national de securite du medicament et des produits de sante (ANSM): 150099B-22 and IDRCB: 2014-A01920-47. ClinicalTrials.gov: NCT02474745. Pre-result stage. PMID- 27998900 TI - Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study. AB - INTRODUCTION: The mainstay treatment for reducing the symptoms of angina and long term risk of heart attacks in patients with heart disease is stent implantation in the diseased coronary artery. While this procedure has revolutionised treatment, the incidence of secondary events remains a concern. These repeat events are thought to be due, in part, to continued enhanced platelet reactivity, endothelial dysfunction and ultimately restenosis of the stented artery. In this study, we will investigate whether a once a day inorganic nitrate administration might favourably modulate platelet reactivity and endothelial function leading to a decrease in restenosis. METHODS AND DESIGN: NITRATE-OCT is a double-blind, randomised, single-centre, placebo-controlled phase II trial that will enrol 246 patients with stable angina due to have elective percutaneous coronary intervention procedure with stent implantation. Patients will be randomised to receive 6 months of a once a day dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo) starting up to 1 week before their procedure. The primary outcome is reduction of in-stent late loss assessed by quantitative coronary angiography and optical coherence tomography at 6 months. The study is powered to detect a 0.22+/-0.55 mm reduction in late loss in the treatment group compared with the placebo group. Secondary end points include change from baseline assessment of endothelial function measured using flow mediated dilation at 6 months, target vessel revascularisation (TVR), restenosis rate (diameter>50%) and in-segment late loss at 6 months, markers of inflammation and platelet reactivity and major adverse cardiac events (ie, myocardial infarction, death, cerebrovascular accident, TVR) at 12 and 24 months. ETHICS AND DISSEMINATION: The study was approved by the Local Ethics Committee (15/LO/0555). Trial results will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02529189 and ISRCTN17373946, Pre-results. PMID- 27998901 TI - Cancer risk awareness and screening uptake in individuals at higher risk for colon cancer: a cross-sectional study. AB - OBJECTIVE: We aimed to measure cancer knowledge and feasibility of a screening colonoscopy among a cohort of individuals at higher risk of colon cancer. METHODS: This study was conducted as part of an ongoing screening cohort, in which first degree relatives (FDRs) of patients with colon cancer are invited to participate in a free of charge screening colonoscopy. We enrolled 1017 FDRs in the study between 2013 and 2014 measuring their data on demographics, cancer knowledge and colonoscopy uptake. A p value of <0.05 was considered statistically significant. RESULTS: The relative's mean age was 48.7 years. Only about 28% of FDRs were aware of their increased risk for cancer, near 35.0% had ever heard about colonoscopy with 22% aware of the correct age to start screening. Comparing cancer knowledge of FDRs at high risk versus those at moderate risk, we recorded non-significant differences (p>0.05). Almost two-thirds of FDRs expressed willingness to undergo a colonoscopy and 49.2% completed the procedure, of which 12.8% had advanced neoplasm. CONCLUSIONS: Our data indicated that remarkable numbers of FDRs were not still informed of their cancer risk or never received a physician recommendation for screening. The desirable uptake at first invitation, which would be higher over successive invitations, supports the feasibility of a family-based recruitment approach for early screening. This has promising implications to introduce targeted screening colonoscopy into the healthcare system in Iran and other developing nations. PMID- 27998902 TI - Dural ossification associated with ossification of ligamentum flavum in the thoracic spine: a retrospective analysis. AB - OBJECTIVES: To investigate the incidence, distribution and radiological characteristics of dural ossification (DO) associated with ossification of ligamentum flavum (OLF) in the thoracic spine. DESIGN: A retrospective radiographical analysis. SETTING: This study was conducted at a single institution in China. PARTICIPANTS: 53 patients with OLF who underwent posterior decompression surgery between January 2011 and July 2015 in a single institution were enrolled in this study. The decompression segments were grouped according to imaging evaluation and intraoperative evidences. OUTCOME MEASURES: The demographic distribution, radiological data and detailed surgical records were collected. First, preoperative CT images of decompressed segments were evaluated to identify imaging signs of DO. The 'tram tack sign' (TTS), 'comma sign' and 'bridge sign' were considered as characteristic imaging findings of DO in OLF. 4 kinds of confusing signs (false TTS) were identified and excluded. Then detailed surgical records were reviewed to finally identify segments with DO. RESULTS: The incidence of DO in patients with OLF was 43.4%. The incidence of DO in OLF segments was 21.5%. OLF was more common in the lower thoracic spine, and more than half (53.8%) of the DO was located in T9-T12. TTS was the most common sign, but it might be misdiagnosed. After excluding 4 kinds of false TTS, the sensitivity and specificity of imaging diagnosis were 94.23% and 94.21%, respectively. CONCLUSIONS: DO was relatively common in thoracic OLF, especially in T9-T12. TTS might be misdiagnosed. After excluding 4 kinds of false TTS, the accuracy of imaging diagnosis was relatively high. PMID- 27998904 TI - Word Memory Test Performance Across Cognitive Domains, Psychiatric Presentations, and Mild Traumatic Brain Injury. AB - Objective: The current study addressed two aims: (i) determine how Word Memory Test (WMT) performance relates to test performance across numerous cognitive domains and (ii) evaluate how current psychiatric disorders or mild traumatic brain injury (mTBI) history affects performance on the WMT after excluding participants with poor symptom validity. Method: Participants were 235 Iraq and Afghanistan-era veterans (Mage = 35.5) who completed a comprehensive neuropsychological battery. Participants were divided into two groups based on WMT performance (Pass = 193, Fail = 42). Tests were grouped into cognitive domains and an average z-score was calculated for each domain. Results: Significant differences were found between those who passed and those who failed the WMT on the memory, attention, executive function, and motor output domain z scores. WMT failure was associated with a larger performance decrement in the memory domain than the sensation or visuospatial-construction domains. Participants with a current psychiatric diagnosis or mTBI history were significantly more likely to fail the WMT, even after removing participants with poor symptom validity. Conclusions: Results suggest that the WMT is most appropriate for assessing validity in the domains of attention, executive function, motor output and memory, with little relationship to performance in domains of sensation or visuospatial-construction. Comprehensive cognitive batteries would benefit from inclusion of additional performance validity tests in these domains. Additionally, symptom validity did not explain higher rates of WMT failure in individuals with a current psychiatric diagnosis or mTBI history. Further research is needed to better understand how these conditions may affect WMT performance. PMID- 27998906 TI - Biomedical Journals and Preprint Services: Friends or Foes? PMID- 27998903 TI - Prospective single-arm interventional pilot study to assess a smartphone-based system for measuring and supporting adherence to medication. AB - OBJECTIVES: Suboptimal medication adherence for infectious diseases such as tuberculosis (TB) results in poor clinical outcomes and ongoing infectivity. Directly observed therapy (DOT) is now standard of care for TB treatment monitoring but has a number of limitations. We aimed to develop and evaluate a smartphone-based system to facilitate remotely observed therapy via transmission of videos rather than in-person observation. DESIGN: We developed an integrated smartphone and web-based system (Mobile Interactive Supervised Therapy, MIST) to provide regular medication reminders and facilitate video recording of pill ingestion at predetermined timings each day, for upload and later review by a healthcare worker. We evaluated the system in a single arm, prospective study of adherence to a dietary supplement. Healthy volunteers were recruited through an online portal. Entry criteria included age >=21 and owning an iOS or Android based device. Participants took a dietary supplement pill once, twice or three times a day for 2 months. We instructed them to video each pill taking episode using the system. OUTCOME: Adherence as measured by the smartphone system and by pill count. RESULTS: 42 eligible participants were recruited (median age 24; 86% students). Videos were classified as received-confirmed pill intake (3475, 82.7% of the 4200 videos expected), received-uncertain pill intake (16, <1%), received fake pill intake (31, <1%), not received-technical issues (223, 5.3%) or not received-assumed non-adherence (455, 10.8%). Overall median estimated participant adherence by MIST was 90.0%, similar to that obtained by pill count (93.8%). There was a good relationship between participant adherence as measured by MIST and by pill count (Spearmans rs 0.66, p<0.001). CONCLUSIONS: We have demonstrated the feasibility, acceptability and accuracy of a smartphone-based adherence support and monitoring system. The system has the potential to supplement and support the provision of DOT for TB and also to improve adherence in other conditions such as HIV and hepatitis C. PMID- 27998905 TI - Care Variations and Outcomes for Children Hospitalized With Bacterial Tracheostomy-Associated Respiratory Infections. AB - OBJECTIVES: Identify hospital-level care variations and association with length of stay (LOS) and hospital revisit in children with tracheostomies hospitalized for bacterial respiratory tract infections (bRTIs). METHODS: A multicenter, retrospective cohort study that used the Pediatric Health Information System database between 2007 and 2014 of patients with tracheostomies aged <=18 years with a primary diagnosis of bRTI (eg, tracheitis) or a primary diagnosis of a bRTI symptom (eg, cough) and a secondary diagnosis of bRTI. Primary outcomes were LOS and 30-day all-cause revisit rates. Secondary outcomes included hospital level diagnostic testing and anti-Pseudomonas antibiotic use. We used mixed effects negative binomial (for LOS) and logistic (for revisit) regression to explore the relationship between hospital-level diagnostic test utilization and the outcomes. RESULTS: Data representing 4137 unique patients with a median age of 3 years (interquartile range: 1-9 years) were included. Median LOS was 4 days (interquartile range: 3-8 days), and the 30-day revisit rate was 24.9%. Use of diagnostic testing and empirical anti-Pseudomonas antibiotics varied significantly among hospitals (all P values <.001). After adjusting for patient and hospital characteristics, compared with low test utilization hospitals, there were no differences in 30-day all-cause revisit rates in moderate (adjusted odds ratio: 1.19; 95% confidence interval [CI]: 0.93-1.52) or high (adjusted odds ratio: 1.07; 95% CI: 0.82-1.39) utilization hospitals. LOS in hospitals with moderate (% difference: -0.8%; 95% CI: -14.4-14.9%) or high (% difference: 13.9%; 95% CI: -0.7-30.6%) test utilization was not significantly longer. CONCLUSIONS: Given that care variations were not associated with outcomes, future research should focus on standardizing diagnosis and treatment of bRTIs and readmission prevention in this population. PMID- 27998907 TI - CC-chemokine class inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis. AB - Increasing evidence shows that CC-chemokines promote inflammatory-driven angiogenesis, with little to no effect on hypoxia-mediated angiogenesis. Inhibition of the CC-chemokine class may therefore affect angiogenesis differently depending on the pathophysiological context. We compared the effect of CC-chemokine inhibition in inflammatory and physiological conditions. In vitro, the broad-spectrum CC-chemokine inhibitor "35K" inhibited inflammatory induced endothelial cell proliferation, migration, and tubulogenesis, with more modest effects in hypoxia. In vivo, adenoviruses were used to overexpress 35K (Ad35K) and GFP (AdGFP, control virus). Plasma chemokine activity was suppressed by Ad35K in both models. In the periarterial femoral cuff model of inflammatory driven angiogenesis, overexpression of 35K inhibited adventitial neovessel formation compared with control AdGFP-infused mice. In contrast, 35K preserved neovascularization in the hindlimb ischemia model and had no effect on physiological neovascularization in the chick chorioallantoic membrane assay. Mechanistically, 2 key angiogenic proteins (VEGF and hypoxia-inducible factor 1alpha) were conditionally regulated by 35K, such that expression was inhibited in inflammation but was unchanged in hypoxia. In conclusion, CC-chemokine inhibition by 35K suppresses inflammatory-driven angiogenesis while preserving physiological ischemia-mediated angiogenesis via conditional regulation of VEGF and hypoxia-inducible factor-1alpha. CC-chemokine inhibition may be an alternative therapeutic strategy for suppressing diseases associated with inflammatory angiogenesis without inducing the side effects caused by global inhibition.- Ridiandries, A., Tan, J. T. M., Ravindran, D., Williams, H., Medbury, H. J., Lindsay, L., Hawkins, C., Prosser, H. C. G., Bursill, C. A. CC chemokine class inhibition attenuates pathological angiogenesis while preserving physiological angiogenesis. PMID- 27998908 TI - Loss of laminin-alpha4 results in pre- and postsynaptic modifications at the neuromuscular junction. AB - Synaptic basal lamina such as laminin-421 (alpha4beta2gamma1) mediate differentiation of the neuromuscular junction (NMJ). Laminins interact with their pre- or postsynaptic receptors to provide stability and alignment of the pre- to postsynaptic specializations. Knockout of the laminin-alpha4 gene (lama4) does not alter gross NMJ morphogenesis. However, mice deficient in laminin-alpha4 (lama4-/- mice) display disruptions in the alignment of the active zones and postsynaptic folds at the NMJ, although the physiological consequences of this loss have not been examined. The present study investigated the differences in neurotransmission during the early development and maturation of the NMJ in lama4 /- and wild-type mice. Lama4-/- NMJs demonstrated a decrease in miniature end plate potential (EPP) frequency and increased amplitude of miniature EPPs and evoked EPPs. Binomial parameters analysis of neurotransmitter release revealed a decrease in quantal release, the result of a decrease in the number of active release sites, but not in the probability of transmitter release. Lama4-/- NMJs displayed higher levels of synaptic depression under high-frequency stimulation and altered facilitation, suggesting compromised delivery of synaptic vesicles. This idea is supported by our molecular investigations of lama4-/- NMJs, where we see altered distribution of Bassoon, a molecular component of active zones, presumably resulting from perturbed neurotransmission.-Chand, K. K., Lee, K. M., Lavidis, N. A., Noakes, P. G. Loss of laminin-alpha4 results in pre- and postsynaptic modifications at the neuromuscular junction. PMID- 27998909 TI - Association of Circulating Biomarkers (Adrenomedullin, TNFR1, and NT-proBNP) With Renal Function Decline in Patients With Type 2 Diabetes: A French Prospective Cohort. AB - OBJECTIVE: We explored the prognostic value of three circulating candidate biomarkers-midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)-for change in renal function in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Outcomes were defined as renal function loss (RFL), >=40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <-5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA1c, blood pressure, baseline eGFR, and urinary albumin-to-creatinine ratio [uACR]). C-statistics were used to assess the incremental predictive value of the biomarkers to these risk factors. RESULTS: Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope -1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34-1.89], P < 0.0001; 1.33 [1.14-1.55], P = 0.0003; and 1.22 [1.07-1.40], P = 0.004, respectively) and RRFD (adjusted odds ratio 1.56 [95% CI 1.7-2.09], P = 0.003; 1.72 [1.33-2.22], P < 0.0001; and 1.28 [1.03-1.59], P = 0.02, respectively). The combination of the three biomarkers yielded the highest discrimination (difference in C-statistic = 0.054, P < 0.0001; 0.067, P < 0.0001 for RFL; and 0.027, P < 0.0001 for RRFD). CONCLUSIONS: In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes. PMID- 27998910 TI - Pancreatic Effects of Liraglutide or Sitagliptin in Overweight Patients With Type 2 Diabetes: A 12-Week Randomized, Placebo-Controlled Trial. AB - OBJECTIVE: To assess the mechanistic effects of the glucagon-like peptide 1 (GLP 1) receptor agonist liraglutide and the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin on (exocrine) pancreatic physiology and morphology. RESEARCH DESIGN AND METHODS: For this randomized, double-blind, parallel-group trial, 55 patients with type 2 diabetes treated with metformin and/or sulfonylurea agents were included. Participants received liraglutide 1.8 mg (n = 19), sitagliptin 100 mg (n = 19), or matching placebos (n = 17) once daily for 12 weeks. The primary end point was change in exocrine function (intraduodenal pancreatic fluid secretion, lipase activity, fecal elastase-1, and chymotrypsin). Secondary end points included changes in plasma enzyme concentrations and pancreatic morphology (per MRI). RESULTS: No patient developed pancreatitis. Sitagliptin increased intraduodenal pancreatic fluid secretion by 16.3 mL (95% CI -0.3 to 32.9; P = 0.05), whereas liraglutide did not change exocrine pancreatic function. Neither therapy increased lipase/amylase levels after 12 weeks. However, liraglutide increased lipase levels after 6 weeks (23.5 U/L [95% CI 2.1-44.8]; P = 0.03) and sitagliptin increased amylase levels after 2 and 6 weeks (13.7 U/L [95% CI 3.4 23.9]; P = 0.03). Both drugs increased plasma trypsinogen after 12 weeks (liraglutide: 34.6 ug/mL [95% CI 15.1-54.2], P = 0.001; sitagliptin: 23.9 ug/mL [95% CI 4.9-42.9], P = 0.01). Neither changed pancreatic morphology, although liraglutide tended to increase pancreatic volume (7.7 cm3 [95% CI -1.2 to 16.6]; P = 0.09). Treatment-induced volume expansion was associated with increased amylase levels. CONCLUSIONS: A 12-week treatment with liraglutide or sitagliptin only resulted in a brief and modest increase of plasma pancreatic enzyme concentrations in patients with type 2 diabetes. Apart from a minimal sitagliptin induced increase in intraduodenal fluid secretion, pancreatic exocrine function was unaffected. The long-term clinical consequences of these discrete changes require further study. PMID- 27998911 TI - Life Expectancy and Cause-Specific Mortality in Type 2 Diabetes: A Population Based Cohort Study Quantifying Relationships in Ethnic Subgroups. AB - OBJECTIVES: This study 1) investigated life expectancy and cause-specific mortality rates associated with type 2 diabetes and 2) quantified these relationships in ethnic subgroups. RESEARCH DESIGN AND METHODS: This was a cohort study using Clinical Practice Research Datalink data from 383 general practices in England with linked hospitalization and mortality records. A total of 187,968 patients with incident type 2 diabetes from 1998 to 2015 were matched to 908,016 control subjects. Abridged life tables estimated years of life lost, and a competing risk survival model quantified cause-specific hazard ratios (HRs). RESULTS: A total of 40,286 deaths occurred in patients with type 2 diabetes. At age 40, white men with diabetes lost 5 years of life and white women lost 6 years compared with those without diabetes. A loss of between 1 and 2 years was observed for South Asians and blacks with diabetes. At age older than 65 years, South Asians with diabetes had up to 1.1 years' longer life expectancy than South Asians without diabetes. Compared with whites with diabetes, South Asians with diabetes had lower adjusted risks for mortality from cardiovascular (HR 0.82; 95% CI 0.75, 0.89), cancer (HR 0.43; 95% CI 0.36, 0.51), and respiratory diseases (HR 0.60; 95% CI 0.48, 0.76). A similar pattern was observed in blacks with diabetes compared with whites with diabetes. CONCLUSIONS: Type 2 diabetes was associated with more years of life lost among whites than among South Asians or blacks, with older South Asians experiencing longer life expectancy compared with South Asians without diabetes. The findings support optimized cardiovascular disease risk factor management, especially in whites with type 2 diabetes. PMID- 27998912 TI - Risk of Myopathy Associated With DPP-4 Inhibitors in Combination With Statins: A Disproportionality Analysis Using Data From the WHO and French Spontaneous Reporting Databases. PMID- 27998913 TI - Lifestyle Cardiovascular Risk Score, Genetic Risk Score, and Myocardial Infarction in Hispanic/Latino Adults Living in Costa Rica. AB - BACKGROUND: A lifestyle cardiovascular risk score (LCRS) and a genetic risk score (GRS) have been independently associated with myocardial infarction (MI) in Hispanics/Latinos. Interaction or joint association between these scores has not been examined. Thus, our aim was to assess interactive and joint associations between LCRS and GRS, and each individual lifestyle risk factor, on likelihood of MI. METHODS AND RESULTS: Data included 1534 Costa Rican adults with nonfatal acute MI and 1534 matched controls. The LCRS used estimated coefficients as weights for each factor: unhealthy diet, physical inactivity, smoking, elevated waist:hip ratio, low/high alcohol intake, low socioeconomic status. The GRS included 14 MI-associated risk alleles. Conditional logistic regressions were used to calculate adjusted odds ratios. The odds ratios for MI were 2.72 (2.33, 3.17) per LCRS unit and 1.13 (95% CI 1.06, 1.21) per GRS unit. A significant joint association for highest GRS tertile and highest LCRS tertile and odds of MI was detected (odds ratio=5.43 [3.71, 7.94]; P<1.00*10-7), compared to both lowest tertiles. The odds ratios were 1.74 (1.22, 2.49) under optimal lifestyle and unfavorable genetic profile, and 5.02 (3.46, 7.29) under unhealthy lifestyle but advantageous genetic profile. Significant joint associations were observed for the highest GRS tertile and the highest of each lifestyle component risk category. The interaction term was nonsignificant (P=0.33). CONCLUSIONS: Lifestyle risk factors and genetics are jointly associated with higher odds of MI among Hispanics/Latinos. Individual and combined lifestyle risk factors showed stronger associations. Efforts to improve lifestyle behaviors could help prevent MI regardless of genetic susceptibility. PMID- 27998914 TI - Human IgM Antibodies to Malondialdehyde Conjugated With Albumin Are Negatively Associated With Cardiovascular Disease Among 60-Year-Olds. AB - BACKGROUND: Malondialdehyde (MDA) is generated during lipid peroxidation as in oxidized low-density lipoprotein, but antibodies against oxidized low-density lipoprotein show variable results in clinical studies. We therefore studied the risk of cardiovascular disease (CVD) associated with IgM antibodies against MDA conjugated with human albumin (anti-MDA). METHODS AND RESULTS: In a 5- to 7-year follow-up of 60-year-old men and women from Stockholm County previously screened for cardiovascular risk factors (2039 men, 2193 women), 209 incident CVD cases (defined as new events of coronary heart disease, fatal and nonfatal myocardial infarction, ischemic stroke, and hospitalization for angina pectoris) and 620 age and sex-matched controls were tested for IgM anti-MDA by ELISA. Antibody peptide/protein characterization was done using a proteomics de novo sequencing approach. After adjustment for smoking, body-mass index, type 2 diabetes mellitus, hyperlipidemia, and hypertension, an increased CVD risk was observed in the low IgM anti-MDA percentiles (below 10th and 25th) (odds ratio and 95% CI: 2.0; 1.19-3.36 and 1.67; 1.16-2.41, respectively). Anti-MDA above the 66th percentile was associated with a decreased CVD risk (odds ratio 0.68; CI: 0.48 0.98). After stratification by sex, associations were only present among men. IgM anti-MDA levels were lower among cases (median [interquartile range]: 141.0 [112.7-164.3] versus 147.4 [123.5-169.6]; P=0.0177), even more so among men (130.6 [107.7-155.3] versus 143.0 [120.1-165.2]; P=0.001). The IgM anti-MDA variable region profiles are distinctly different and also more homologous in their content (correlates strongly with fewer peptides) than control antibodies (not binding MDA). CONCLUSIONS: IgM anti-MDA is a protection marker for CVD. This finding could have diagnostic and therapeutic implications. PMID- 27998915 TI - Adolescent Diet Quality and Cardiovascular Disease Risk Factors and Incident Cardiovascular Disease in Middle-Aged Women. AB - BACKGROUND: Primary prevention of cardiovascular disease (CVD) focuses on treatment of risk factors, including hypercholesterolemia, hypertension, and type 2 diabetes mellitus. We investigated whether a healthy diet in adolescence prevents development of clinical risk factors or incidence of CVD in adulthood. METHODS AND RESULTS: We examined the time to the first development of >=1 clinical risk factor (hypercholesterolemia, hypertension, or type 2 diabetes mellitus) or CVD in relation to a high school Alternative Healthy Eating Index (HS-AHEI) within the Nurses' Health Study II. Among those who completed a food frequency questionnaire about their high school diet and adult diet (mean age 42 years), 27 406 women free of clinical risk factors and 42 112 women free of CVD in 1998 were followed to June 2011. Hazard ratios (HRs) and 95% CIs were adjusted for potential confounders in high school and adulthood. We documented 11 542 first diagnoses of clinical risk factors and 423 CVD events. The HS-AHEI was associated with a lower rate of risk factors (HR highest versus lowest quintiles 0.82; 95% CI, 0.77-0.87 [P trend <0.001]), was inversely associated with risk of developing >=1 clinical risk factor in women with a low, medium, and high AHEI score during adulthood (HR high HS-AHEI/high adult AHEI versus low/low 0.79 [95% CI, 0.74-0.85]), but was not statistically significantly associated with incident CVD. CONCLUSIONS: A healthy diet during adolescence is associated with lower risk of developing CVD risk factors. As diet tracks throughout life, and adult diet prevents CVD, healthy dietary habits that begin early are important for primordial prevention of CVD. PMID- 27998916 TI - Growth of Carotid Intima-Media Thickness in Black and White Young Adults. AB - BACKGROUND: There are few longitudinal studies that have comprehensively examined the intima-media thickness (IMT) growth pattern and its determinants among racial population groups. METHODS AND RESULTS: Mean and maximum IMT were measured by B mode ultrasonography up to 3 times in 253 white and 268 black participants, aged 13 to 36 years (mean age+/-standard deviation 24+/-3.2 years old). The development of IMT was assessed using individual growth curve modeling. A total of 521 participants with 1015 IMT measurements were eligible for this study. We found higher IMT in both left and right sides in blacks compared to whites (P<0.001) in young adulthood. Both whites and blacks showed a strong linear increase in mean IMT with age. Body mass index and father's education level were associated with mean IMT, and only body mass index was associated with maximum IMT (P<0.05). We did not observe an interaction between age and race/ethnicity on the growth of IMT, suggesting that blacks and whites developed IMT in similar patterns. Interestingly, we found a faster increase in mean left-side IMT than mean right-side IMT (chi2=11.5, P<0.001) in both black and white subjects as well as in males and females. CONCLUSIONS: Our findings provide compelling prospective evidence that blacks may have thicker IMT compared to whites as young adults. These racial differences could not be explained by traditional risk factors. This implies that differences in this precursor of atherosclerosis may explain racial disparity in cerebrovascular disease. PMID- 27998917 TI - National Trends and Impact of Acute Kidney Injury Requiring Hemodialysis in Hospitalizations With Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is a common cause for hospitalization, but there are limited data regarding acute kidney injury requiring dialysis (AKI-D) in AF hospitalizations. We aimed to assess temporal trends and outcomes in AF hospitalizations complicated by AKI-D utilizing a nationally representative database. METHODS AND RESULTS: Utilizing the Nationwide Inpatient Sample, AF hospitalizations and AKI-D were identified using diagnostic and procedure codes. Trends were analyzed overall and within subgroups and utilized multivariable logistic regression to generate adjusted odds ratios (aOR) for predictors and outcomes including mortality and adverse discharge. Between 2003 and 2012, 3751 (0.11%) of 3 497 677 AF hospitalizations were complicated by AKI-D. The trend increased from 0.3/1000 hospitalizations in 2003 to 1.5/1000 hospitalizations in 2012, with higher increases in males and black patients. Temporal changes in demographics and comorbidities explained a substantial proportion but not the entire trend. Significant comorbidities associated with AKI-D included mechanical ventilation (aOR 13.12; 95% CI 9.88-17.43); sepsis (aOR 8.20; 95% CI 6.00-11.20); and liver failure (aOR 3.72; 95% CI 2.92-4.75). AKI-D was associated with higher risk of in-hospital mortality (aOR 3.54; 95% CI 2.81-4.47) and adverse discharge (aOR 4.01; 95% CI 3.12-5.17). Although percentage mortality within AKI-D decreased over the decade, attributable risk percentage mortality remained stable. CONCLUSIONS: AF hospitalizations complicated by AKI-D have quintupled over the last decade with differential increase by demographic groups. AKI-D is associated with significant morbidity and mortality. Without effective AKI-D therapies, focus should be on early risk stratification and prevention to avoid this devastating complication. PMID- 27998919 TI - Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. AB - INTRODUCTION: In sporadic acromegaly, downregulation of AIP protein of the adenomas associates with invasive tumor features and reduced responsiveness to somatostatin analogues. AIP is a regulator of Gai signaling, but it is not known how the biological function of the Gai pathway is controlled. AIM: To study GNAS and AIP mutation status, AIP and Gai-2 protein expressions, Ki-67 proliferation indices and clinical parameters in patients having primary surgery because of acromegaly at a single center between years 2000 and 2010. RESULTS: Sixty patients (F/M, 31/29), mean age 49 (median 50), mean follow-up 7.7 years (range 0.6-14.0) underwent primary surgery. Four adenoma specimens (6.8%) harbored an AIP and 21 (35.6%) an activating GNAS (Gsp+) mutation. Altogether 13/56 (23%) adenomas had low AIP protein levels, and 14/56 (25%) low Gai-2 staining. In regression modeling, AIP expression associated with Gai-2 (P = 2.33 * 10-9) and lower Ki-67 (P = 0.04). In pairwise comparison, low AIP protein predicted high GH at last follow-up (mean 7.7 years after surgery, q = 0.045). Extent of treatments given for acromegaly associated with higher preoperative GH (P = 7.94 * 10-4), KNOSP (P = 0.003) and preoperative hypopituitarism (P = 0.03) and remission at last follow-up with change in 3-month postoperative IGF1 (P = 2.07 * 10-7). CONCLUSIONS: We demonstrate, for the first time, that AIP protein expression associates with Gai-2 protein intensities in sporadic somatotropinomas, suggesting a joint regulation on somatostatin signaling. Low AIP level associates with higher proliferative activity and predicts high GH concentrations after long term follow-up. The AIP mutation rate of 6.8% is fairly high, reflecting the genetic composition of the Finnish population. PMID- 27998918 TI - Role of T-Cell Dysfunction, Inflammation, and Coagulation in Microvascular Disease in HIV. AB - BACKGROUND: Compared to uninfected adults, HIV-infected adults on antiretroviral therapy are at increased risk of cardiovascular disease. Given the increase in T cell dysfunction, inflammation, and coagulation in HIV infection, microvascular dysfunction is thought to contribute to this excess cardiovascular risk. However, the relationships between these variables remain undefined. METHODS AND RESULTS: This was a cross-sectional study of 358 HIV-infected adults from the SCOPE cohort. Macrovascular endothelial function was assessed using flow-mediated dilation of the brachial artery and microvascular function by reactive hyperemia. T-cell phenotype was determined by flow cytometry. Plasma markers of inflammation (tumor necrosis factor-alpha, interleukin-6, high-sensitivity C-reactive protein, sCD14) and coagulation (fibrinogen, D-dimer) were also measured. In all HIV+ subjects, markers of inflammation (tumor necrosis factor-alpha, high-sensitivity C-reactive protein), coagulation (D-dimer) and T-cell activation (CD8+PD1+, CD4+interferon+cytomegalovirus-specific) were associated with worse reactive hyperemia after adjusting for traditional cardiovascular risk factors and co infections. In treated and suppressed subjects, tumor necrosis factor-alpha and CD8+PD1+ cells remained associated with worse reactive hyperemia after adjustment. Compared to the untreated subjects, CD8+PD1+ cells were increased in the virally suppressed group. Reactive hyperemia was predictive of flow-mediated dilation. CONCLUSIONS: CD8+PD1+ cells and tumor necrosis factor-alpha were associated with microvascular dysfunction in all HIV+ subjects and the treated and suppressed group. Additionally, D-dimer, high-sensitivity C-reactive protein, sCD-14, and interleukin-6 were associated with microvascular dysfunction in all HIV+ subjects. Although T-cell dysfunction, inflammation, and microvascular dysfunction are thought to play a role in cardiovascular disease in HIV, this study is the first to look at which T-cell and inflammatory markers are associated with microvascular dysfunction in HIV-infected individuals. PMID- 27998920 TI - Relationship of Abnormal Chromatographic Pattern for Carbohydrate-Deficient Transferrin with Severe Liver Disease. AB - AIMS: Serum carbohydrate-deficient transferrin (CDT) is a validated test for chronic heavy alcohol drinking, but CDT abnormalities have been associated with liver disease, limiting its use in these patients. We report here on the association between poor chromatographic resolution of disialotransferrin from trisialotransferrin (the so-called 'di-tri bridging') and liver disease severity and etiology. METHODS: Subjects were patients in whom detailed clinical data, including histology results, were available on their existing liver diseases (n=139). Percent disialo-CDT (%dCDT) was measured by high-performance liquid chromatography, and the risks for di-tri bridging associated with cirrhosis, with and without adjustment for alcohol use and alcohol-related liver disease, were estimated. RESULTS: Di-tri bridging was present in 22/73 (30%) cirrhotic subjects and 7/66 (11%) non-cirrhotic subjects. The unadjusted risk for di-tri bridging in cirrhotics relative to non-cirrhotics was 3.6 (95% confidence interval 1.4-9.2). Adjustment for alcohol-related liver disease and current drinking had little effect on this estimate (adjusted odds ratio 3.4), and neither alcohol-related liver disease nor current drinking were independently associated with di-tri bridging after accounting for the effect of cirrhosis. CONCLUSIONS: The presence of di-tri bridging was associated with cirrhosis in individuals with both alcohol related and non-alcoholic liver disease, although most cirrhotic subjects did not exhibit di-tri bridging. When di-tri bridging is seen in individuals being tested for chronic heavy drinking, investigation for cirrhosis should be considered. SHORT SUMMARY: There are known liver-disease-associated abnormalities in CDT. In this study, we found that such abnormalities were strongly associated with cirrhosis rather than less-advanced disease, but were only clinically evident in 30% of cirrhotics. Abnormalities also occurred in severe hepatitis without cirrhosis and were not specific for liver disease etiology. PMID- 27998921 TI - The Performance of Alcohol Markers Including Ethyl Glucuronide and Ethyl Sulphate to Detect Alcohol Use in Clients in a Community Alcohol Treatment Programme. AB - AIMS: The ethanol metabolites ethyl glucuronide (EtG) and ethyl sulphate (EtS) are detectable for longer in urine than breath ethanol or urine ethanol after alcohol intake. This study compared the performance of breath ethanol, urine ethanol, urine EtG and EtS to detect alcohol consumption in clients in community alcohol treatment. METHODS: Clients attending the community alcohol treatment programme were asked to provide an alcohol diary, breathalyser test and urine for ethanol, EtG and EtS measurement (n = 42). Positive results were defined using the detection limits (breath ethanol and urine ethanol) or clinical cut-offs (EtG: 0.26 mg/L and EtS: 0.22 mg/L). The sensitivities and specificities of each marker to detect alcohol intake <24 and 48-72 h prior were calculated. RESULTS: The sensitivities of each alcohol marker to detect alcohol intake <24 h prior were 57, 71, 100 and 100% for breath ethanol, urine ethanol, urine EtG and urine EtS, respectively. The specificity was 100% for urine ethanol and urine EtS. The EtG specificity could be increased to 100% by using a higher cut-off (0.50 mg/L). The sensitivity of all markers (including EtG and EtS) to detect alcohol intake of <=10 units 48-72 h earlier decreased to 0%. CONCLUSIONS: In community alcohol treatment clients, urine EtG and EtS showed the optimum diagnostic performance to detect alcohol intake in the previous 24 h. We propose a flowchart to routinely use EtG and EtS for clients in community alcohol treatment. SHORT SUMMARY: The ability of breath ethanol, urine ethanol, urine EtG and urine EtS to detect continued alcohol consumption in clients in community alcohol treatment were compared. Urine EtG and EtS showed the optimum diagnostic performance and we propose a flowchart to routinely use EtG and EtS in community alcohol treatment. PMID- 27998922 TI - Measuring Time Spent Caring For Drinkers and Their Dependents. AB - AIMS: To quantify the extent of time spent by family and friends caring for drinkers and their dependents, to estimate the cost of this time and to measure which factors predict time spent caring. METHODS: Data are from a nationwide Alcohol's Harm to Others Survey of 2649 Australians, in which 778 respondents reported they were harmed by a known drinker. Time spent on four caring activities was self-reported by these respondents and tallied to estimate how many hours they spent caring for the drinker, the drinker's children or other dependents. Bivariate and multivariate linear regression models were employed to examine factors predicting time spent caring. RESULTS: Respondents who reported they were harmed by a drinker they knew had spent on average 32 h caring for this drinker and their dependents in the past 12 months. Applying these figures to the Australian population, but discounting by 90% because this time may be seen be a voluntary demonstration of connection, an annual cost of caring in 2008 would amount to AU$250 million. A significant positive association was found between time spent caring and the drinking level and drinking frequency of the heavy drinking other person. CONCLUSION: Caring for drinking family members, friends, co-workers and a drinker's dependents can be a substantial burden. Policy approaches that reduce population drinking and individual risky drinking levels are potential means to reduce the burden of caring due to others' drinking. PMID- 27998923 TI - Alcohol-Related Visits to US Emergency Departments, 2001-2011. AB - AIMS: Alcohol intoxication is a source of significant illness and injury commonly resulting in emergency department (ED) visits. We characterize recent trends in alcohol-related visits to US EDs using nationally representative data. METHODS: We conducted a retrospective review of data on national ED visits among patients aged 18 years or older with alcohol intoxication between 2001 and 2011 using the National Hospital Ambulatory Medical Care Survey (NHAMCS). Demographic and resource utilization trends in alcohol-related visits were examined. We also assessed ED length of stay (LOS) across the study period, as well as the total hours spent on ED care for alcohol-related complaints. RESULTS: Between 2001-2002 and 2010-2011, alcohol-related visits increased from 2,459,748 to 3,856,346 (P = 0.049). Utilization of resources such as laboratory tests, medications and radiography increased, with the use of advanced imaging (i.e. computed tomography and magnetic resonance imaging) increasing 232.2% (P < 0.001) from 2001-2002 to 2010-2011. Overall LOS increased 16.1% (P = 0.028), while LOS among patients admitted to the hospital increased 24.9% (P = 0.076). Total alcohol-related hours spent in EDs nationwide increased from 5.6 million in 2001 to 11.6 million in 2011, an increase of 108.5% (P < 0.001) compared with an increase in overall ED hours of 54.0% (P < 0.001). CONCLUSION: Alcohol-related ED visits are increasing at a greater rate than overall ED visits and represent a growing burden on hospital resources. PMID- 27998926 TI - Rethinking Excessive Habits and Addictive Behaviors. PMID- 27998924 TI - Reply to ''Alcohol and Liver Transplantation''. PMID- 27998927 TI - Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells. AB - Here, we show that the Wnt5a-haploinsufficient niche regenerates dysfunctional HSCs, which do not successfully engraft in secondary recipients. RNA sequencing of the regenerated donor Lin- SCA-1+ KIT+ (LSK) cells shows dysregulated expression of ZEB1-associated genes involved in the small GTPase-dependent actin polymerization pathway. Misexpression of DOCK2, WAVE2, and activation of CDC42 results in apolar F-actin localization, leading to defects in adhesion, migration and homing of HSCs regenerated in a Wnt5a-haploinsufficient microenvironment. Moreover, these cells show increased differentiation in vitro, with rapid loss of HSC-enriched LSK cells. Our study further shows that the Wnt5a-haploinsufficient environment similarly affects BCR-ABLp185 leukemia-initiating cells, which fail to generate leukemia in 42% of the studied recipients, or to transfer leukemia to secondary hosts. Thus, we show that WNT5A in the bone marrow niche is required to regenerate HSCs and leukemic cells with functional ability to rearrange the actin cytoskeleton and engraft successfully. PMID- 27998929 TI - SLICE: determining cell differentiation and lineage based on single cell entropy. AB - A complex organ contains a variety of cell types, each with its own distinct lineage and function. Understanding the lineage and differentiation state of each cell is fundamentally important for the ultimate delineation of organ formation and function. We developed SLICE, a novel algorithm that utilizes single-cell RNA seq (scRNA-seq) to quantitatively measure cellular differentiation states based on single cell entropy and predict cell differentiation lineages via the construction of entropy directed cell trajectories. We validated our approach using three independent data sets with known lineage and developmental time information from both Homo sapiens and Mus musculus. SLICE successfully measured the differentiation states of single cells and reconstructed cell differentiation trajectories that have been previously experimentally validated. We then applied SLICE to scRNA-seq of embryonic mouse lung at E16.5 to identify lung mesenchymal cell lineage relationships that currently remain poorly defined. A two-branched differentiation pathway of five fibroblastic subtypes was predicted using SLICE. The present study demonstrated the general applicability and high predictive accuracy of SLICE in determining cellular differentiation states and reconstructing cell differentiation lineages in scRNA-seq analysis. PMID- 27998928 TI - The cell cycle restricts activation-induced cytidine deaminase activity to early G1. AB - Activation-induced cytidine deaminase (AID) converts cytosine into uracil to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of antibody genes. In addition, this enzyme produces DNA lesions at off-target sites that lead to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic. Here, we show that AID is transiently in spatial contact with genomic DNA from the time the nuclear membrane breaks down in prometaphase until early G1, when it is actively exported into the cytoplasm. Consistent with this observation, the immunoglobulin (Igh) gene deamination as measured by uracil accumulation occurs primarily in early G1 after chromosomes decondense. Altering the timing of cell cycle-regulated AID nuclear residence increases DNA damage at off-target sites. Thus, the cell cycle-controlled breakdown and reassembly of the nuclear membrane and the restoration of transcription after mitosis constitute an essential time window for AID-induced deamination, and provide a novel DNA damage mechanism restricted to early G1. PMID- 27998930 TI - Flexibility and stabilization of HgII-mediated C:T and T:T base pairs in DNA duplex. AB - Owing to their great potentials in genetic code extension and the development of nucleic acid-based functional nanodevices, DNA duplexes containing HgII-mediated base pairs have been extensively studied during the past 60 years. However, structural basis underlying these base pairs remains poorly understood. Herein, we present five high-resolution crystal structures including one first-time reported C-HgII-T containing duplex, three T-HgII-T containing duplexes and one native duplex containing T-T pair without HgII. Our structures suggest that both C-T and T-T pairs are flexible in interacting with the HgII ion with various binding modes including N3-HgII-N3, N4-HgII-N3, O2-HgII-N3 and N3-HgII-O4. Our studies also reveal that the overall conformations of the C-HgII-T and T-HgII-T pairs are affected by their neighboring residues via the interactions with the solvent molecules or other metal ions, such as SrII. These results provide detailed insights into the interactions between HgII and nucleobases and the structural basis for the rational design of C-HgII-T or T-HgII-T containing DNA nanodevices in the future. PMID- 27998931 TI - Human population-specific gene expression and transcriptional network modification with polymorphic transposable elements. AB - Transposable element (TE) derived sequences are known to contribute to the regulation of the human genome. The majority of known TE-derived regulatory sequences correspond to relatively ancient insertions, which are fixed across human populations. The extent to which human genetic variation caused by recent TE activity leads to regulatory polymorphisms among populations has yet to be thoroughly explored. In this study, we searched for associations between polymorphic TE (polyTE) loci and human gene expression levels using an expression quantitative trait loci (eQTL) approach. We compared locus-specific polyTE insertion genotypes to B cell gene expression levels among 445 individuals from 5 human populations. Numerous human polyTE loci correspond to both cis and trans eQTL, and their regulatory effects are directly related to cell type-specific function in the immune system. PolyTE loci are associated with differences in expression between European and African population groups, and a single polyTE loci is indirectly associated with the expression of numerous genes via the regulation of the B cell-specific transcription factor PAX5. The polyTE-gene expression associations we found indicate that human TE genetic variation can have important phenotypic consequences. Our results reveal that TE-eQTL are involved in population-specific gene regulation as well as transcriptional network modification. PMID- 27998932 TI - Toxin inhibition in C. crescentus VapBC1 is mediated by a flexible pseudo palindromic protein motif and modulated by DNA binding. AB - Expression of bacterial type II toxin-antitoxin (TA) systems is regulated at the transcriptional level through direct binding of the antitoxin to pseudo palindromic sequences on operator DNA. In this context, the toxin functions as a co-repressor by stimulating DNA binding through direct interaction with the antitoxin. Here, we determine crystal structures of the complete 90 kDa heterooctameric VapBC1 complex from Caulobacter crescentus CB15 both in isolation and bound to its cognate DNA operator sequence at 1.6 and 2.7 A resolution, respectively. DNA binding is associated with a dramatic architectural rearrangement of conserved TA interactions in which C-terminal extended structures of the antitoxin VapB1 swap positions to interlock the complex in the DNA-bound state. We further show that a pseudo-palindromic protein sequence in the antitoxin is responsible for this interaction and required for binding and inactivation of the VapC1 toxin dimer. Sequence analysis of 4127 orthologous VapB sequences reveals that such palindromic protein sequences are widespread and unique to bacterial and archaeal VapB antitoxins suggesting a general principle governing regulation of VapBC TA systems. Finally, a structure of C-terminally truncated VapB1 bound to VapC1 reveals discrete states of the TA interaction that suggest a structural basis for toxin activation in vivo. PMID- 27998934 TI - Xenolog classification. AB - Motivation: Orthology analysis is a fundamental tool in comparative genomics. Sophisticated methods have been developed to distinguish between orthologs and paralogs and to classify paralogs into subtypes depending on the duplication mechanism and timing, relative to speciation. However, no comparable framework exists for xenologs: gene pairs whose history, since their divergence, includes a horizontal transfer. Further, the diversity of gene pairs that meet this broad definition calls for classification of xenologs with similar properties into subtypes. Results: We present a xenolog classification that uses phylogenetic reconciliation to assign each pair of genes to a class based on the event responsible for their divergence and the historical association between genes and species. Our classes distinguish between genes related through transfer alone and genes related through duplication and transfer. Further, they separate closely related genes in distantly-related species from distantly-related genes in closely-related species. We present formal rules that assign gene pairs to specific xenolog classes, given a reconciled gene tree with an arbitrary number of duplications and transfers. These xenology classification rules have been implemented in software and tested on a collection of ~13 000 prokaryotic gene families. In addition, we present a case study demonstrating the connection between xenolog classification and gene function prediction. Availability and Implementation: The xenolog classification rules have been implemented in N otung 2.9, a freely available phylogenetic reconciliation software package. http://www.cs.cmu.edu/~durand/Notung . Gene trees are available at http://dx.doi.org/10.7488/ds/1503 . Contact: durand@cmu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27998933 TI - MicroRNA-202 maintains spermatogonial stem cells by inhibiting cell cycle regulators and RNA binding proteins. AB - miRNAs play important roles during mammalian spermatogenesis. However, the function of most miRNAs in spermatogenesis and the underlying mechanisms remain unknown. Here, we report that miR-202 is highly expressed in mouse spermatogonial stem cells (SSCs), and is oppositely regulated by Glial cell-Derived Neurotrophic Factor (GDNF) and retinoic acid (RA), two key factors for SSC self-renewal and differentiation. We used inducible CRISPR-Cas9 to knockout miR-202 in cultured SSCs, and found that the knockout SSCs initiated premature differentiation accompanied by reduced stem cell activity and increased mitosis and apoptosis. Target genes were identified with iTRAQ-based proteomic analysis and RNA sequencing, and are enriched with cell cycle regulators and RNA-binding proteins. Rbfox2 and Cpeb1 were found to be direct targets of miR-202 and Rbfox2 but not Cpeb1, is essential for the differentiation of SSCs into meiotic cells. Accordingly, an SSC fate-regulatory network composed of signaling molecules of GDNF and RA, miR-202 and diverse downstream effectors has been identified. PMID- 27998935 TI - CymeR: cytometry analysis using KNIME, docker and R. AB - Summary: Here we present open-source software for the analysis of high dimensional cytometry data using state of the art algorithms. Importantly, use of the software requires no programming ability, and output files can either be interrogated directly in CymeR or they can be used downstream with any other cytometric data analysis platform. Also, because we use Docker to integrate the multitude of components that form the basis of CymeR, we have additionally developed a proof-of-concept of how future open-source bioinformatic programs with graphical user interfaces could be developed. Availability and Implementation: CymeR is open-source software that ties several components into a single program that is perhaps best thought of as a self-contained data analysis operating system. Please see https://github.com/bmuchmore/CymeR/wiki for detailed installation instructions. Contact: brian.muchmore@genyo.es or marta.alarcon@genyo.es. PMID- 27998936 TI - CellSort: a support vector machine tool for optimizing fluorescence-activated cell sorting and reducing experimental effort. AB - Motivation: High throughput screening by fluorescence activated cell sorting (FACS) is a common task in protein engineering and directed evolution. It can also be a rate-limiting step if high false positive or negative rates necessitate multiple rounds of enrichment. Current FACS software requires the user to define sorting gates by intuition and is practically limited to two dimensions. In cases when multiple rounds of enrichment are required, the software cannot forecast the enrichment effort required. Results: We have developed CellSort, a support vector machine (SVM) algorithm that identifies optimal sorting gates based on machine learning using positive and negative control populations. CellSort can take advantage of more than two dimensions to enhance the ability to distinguish between populations. We also present a Bayesian approach to predict the number of sorting rounds required to enrich a population from a given library size. This Bayesian approach allowed us to determine strategies for biasing the sorting gates in order to reduce the required number of enrichment rounds. This algorithm should be generally useful for improve sorting outcomes and reducing effort when using FACS. Availability and Implementation: Source code available at http://tyolab.northwestern.edu/tools/ . k-tyo@northwestern.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27998937 TI - Improving flux predictions by integrating data from multiple strains. AB - Motivation: Incorporating experimental data into constraint-based models can improve the quality and accuracy of their metabolic flux predictions. Unfortunately, routinely and easily measured experimental data such as growth rates, extracellular fluxes, transcriptomics and even proteomics are not always sufficient to significantly improve metabolic flux predictions. Results: We developed a new method (called REPPS) for incorporating experimental measurements of growth rates and extracellular fluxes from a set of perturbed reference strains (RSs) and a parental strain (PS) to substantially improve the predicted flux distribution of the parental strain. Using data from five single gene knockouts and the wild type strain, we decrease the mean squared error of predicted central metabolic fluxes by ~47% compared to parsimonious flux balance analysis (pFBA). This decrease in error further improves flux predictions for new knockout strains. Furthermore, REPPS is less sensitive to the completeness of the metabolic network than pFBA. Availability and Implementation: Code is available in the Supplementary data available at Bioinformatics online. Contact: reed@engr.wisc.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27998938 TI - Agent-based re-engineering of ErbB signaling: a modeling pipeline for integrative systems biology. AB - Motivation: Experiments in systems biology are generally supported by a computational model which quantitatively estimates the parameters of the system by finding the best fit to the experiment. Mathematical models have proved to be successful in reverse engineering the system. The data generated is interpreted to understand the dynamics of the underlying phenomena. The question we have sought to answer is that - is it possible to use an agent-based approach to re engineer a biological process, making use of the available knowledge from experimental and modelling efforts? Can the bottom-up approach benefit from the top-down exercise so as to create an integrated modelling formalism for systems biology? We propose a modelling pipeline that learns from the data given by reverse engineering, and uses it for re-engineering the system, to carry out in silico experiments. Results: A mathematical model that quantitatively predicts co expression of EGFR-HER2 receptors in activation and trafficking has been taken for this study. The pipeline architecture takes cues from the population model that gives the rates of biochemical reactions, to formulate knowledge-based rules for the particle model. Agent-based simulations using these rules, support the existing facts on EGFR-HER2 dynamics. We conclude that, re-engineering models, built using the results of reverse engineering, opens up the possibility of harnessing the power pack of data which now lies scattered in literature. Virtual experiments could then become more realistic when empowered with the findings of empirical cell biology and modelling studies. Availability and Implementation: Implemented on the Agent Modelling Framework developed in-house. C ++ code templates available in Supplementary material . Contact: liz.csir@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27998939 TI - A pipeline for local assembly of minisatellite alleles from single-molecule sequencing data. AB - Motivation: The advent of Next Generation Sequencing (NGS) has led to the generation of enormous volumes of short read sequence data, cheaply and in reasonable time scales. Nevertheless, the quality of genome assemblies generated using NGS technologies has been greatly affected, compared to those generated using Sanger DNA sequencing. This is largely due to the inability of short read sequence data to scaffold repetitive structures, creating gaps, inversions and rearrangements and resulting in assemblies that are, at best, draft forms. Third generation single-molecule sequencing (SMS) technologies (e.g. Pacific Biosciences Single Molecule Real Time (SMRT) system) address this challenge by generating sequences with increased read lengths, offering the prospect to better recover these complex repetitive structures, concomitantly improving assembly quality. Results: Here, we evaluate the ability of SMS data (specifically human genome Pacific Biosciences SMRT data) to recover poorly represented repetitive sequences (specifically, GC-rich human minisatellites). To do this we designed a pipeline for the collection, processing and local assembly of single-molecule sequence data to form accurate contiguous local reconstructions. Our results show the recovery of an allele of the non-coding minisatellite MS1 (located on chromosome 1 at 1p33-35) at greater than 97% identity to reference (GRCh38) from the unprocessed sequence data of a haploid complete hydatidiform mole (CHM1) cell line. Furthermore, our assembly revealed an allele of over 500 repeat units; much larger than the reference (GRCh38), but consistent in structure with naturally occurring alleles that are segregating in human populations. This local assembly's reconstruction was validated with the release of the whole genome assemblies GCA_001297185.1 and GCA_000772585.3, where this allele occurs. Additionally, application of this pipeline to coding minisatellites in the PRDM9 and ZNF93 genes enabled recovery of high identity allele structures for these sequence regions whose length was confirmed by PCR from cell line genomic DNA. The internal repeat structure of the PRDM9 allele recovered was consistent with common human-specific alleles. Availability and Implementation: Code available at https://github.com/ndliberial/smrt_pipeline. Contact: dno2@le.ac.uk. PMID- 27998940 TI - Recommendations for the Implementation of Telehealth in Cardiovascular and Stroke Care: A Policy Statement From the American Heart Association. AB - The aim of this policy statement is to provide a comprehensive review of the scientific evidence evaluating the use of telemedicine in cardiovascular and stroke care and to provide consensus policy suggestions. We evaluate the effectiveness of telehealth in advancing healthcare quality, identify legal and regulatory barriers that impede telehealth adoption or delivery, propose steps to overcome these barriers, and identify areas for future research to ensure that telehealth continues to enhance the quality of cardiovascular and stroke care. The result of these efforts is designed to promote telehealth models that ensure better patient access to high-quality cardiovascular and stroke care while striving for optimal protection of patient safety and privacy. PMID- 27998941 TI - miR-361-3p regulates FSH by targeting FSHB in a porcine anterior pituitary cell model. AB - FSH plays an essential role in processes involved in human reproduction, including spermatogenesis and the ovarian cycle. While the transcriptional regulatory mechanisms underlying its synthesis and secretion have been extensively studied, little is known about its posttranscriptional regulation. A bioinformatics analysis from our group indicated that a microRNA (miRNA; miR-361 3p) could regulate FSH secretion by potentially targeting the FSHB subunit. Herein, we sought to confirm these findings by investigating the miR-361-3p mediated regulation of FSH production in primary pig anterior pituitary cells. Gonadotropin-releasing hormone (GnRH) treatment resulted in an increase in FSHB synthesis at both the mRNA, protein/hormone level, along with a significant decrease in miR-361-3p and its precursor (pre-miR-361) levels in time- and dose dependent manner. Using the Dual-Luciferase Assay, we confirmed that miR-361-3p directly targets FSHB. Additionally, overexpression of miR-361-3p using mimics significantly decreased the FSHB production at both the mRNA and protein levels, with a reduction in both protein synthesis and secretion. Conversely, both synthesis and secretion were significantly increased following miR-361-3p blockade. To confirm that miR-361-3p targets FSHB, we designed FSH-targeted siRNAs, and co-transfected anterior pituitary cells with both the siRNA and miR 361-3p inhibitors. Our results indicated that the siRNA blocked the miR-361-3p inhibitor-mediated upregulation of FSH, while no significant effect on non-target expression. Taken together, our results demonstrate that miR-361-3p negatively regulates FSH synthesis and secretion by targeting FSHB, which provides more functional evidence that a miRNA is involved in the direct regulation of FSH. PMID- 27998942 TI - Integrins functioning in uterine endometrial stromal and epithelial cells in estrus. AB - Here, as a basic study in the construction of a non-cellular niche that supports artificial organization of three-dimensional endometrial tissue, we defined the types of integrin heterodimers that are expressed transcriptionally, translationally and functionally in endometrial stromal (ES) and endometrial epithelial (EE) cells isolated from the mouse uterus in estrus. Gene and protein expression of integrin subunits were analyzed at the transcriptional and translational level by real-time PCR and fluorescent immunoassay, respectively. Moreover, the functionality of integrin heterodimers was confirmed by attachment and antibody inhibition assays. Itga2, Itga5, Itga6, Itga9, Itgav, Itgb1, Itgb3 and Itgb5 in ES cells, and Itga2, Itga5, Itga6, Itga7, Itga9, Itgav, Itgb1, Itgb3, Itgb4, Itgb5 and Itga6 and in EE cells showed significantly higher transcriptional levels than the other integrin subunits. Furthermore, translational expression of the total integrin alpha and beta subunit genes that showed increased transcription was determined in ES and EE cells. ES cells showed significantly increased adhesion to collagen I, fibronectin and vitronectin, and functional blocking of integrin alpha2, alpha5 or alphaV significantly inhibited adhesion to these molecules. Moreover, EE cells showed significantly increased adhesion to collagen I, fibronectin, laminin and vitronectin, and functional blocking of integrin alpha2, alpha5, alpha6 or alphaV significantly inhibited adhesion to these molecules. Accordingly, we confirmed that integrin alpha2beta1, alpha5beta1, alphaVbeta1, alphaVbeta3 and/or alphaVbeta5, and integrin alpha2beta1, alpha5beta1, alpha6beta1 and/or alpha6beta4, alphaVbeta1, alphaVbeta3 and/or alphaVbeta5, actively function on the surface of ES and EE cells from mouse uterus in estrus phase, respectively. PMID- 27998943 TI - Genetic Risk and Altering Lipids With Lifestyle Changes and Metformin: Is Fate Modifiable? PMID- 27998944 TI - Predicting Incident Coronary Heart Disease Many Markers at a Time. PMID- 27998945 TI - New Insights Into the Genetic Basis of Inherited Arrhythmia Syndromes. PMID- 27998946 TI - Letter by Brown Regarding Article, "Genetic Risk Scores Predict Recurrence of Acute Coronary Syndrome". PMID- 27998947 TI - Letter by Finsterer and Zarrouk-Mahjoub Regarding Article, "Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction". PMID- 27998948 TI - Letter by Amin et al Regarding Article, "Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?" PMID- 27998949 TI - Response by Crotti et al to Letter Regarding Article, "Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?" PMID- 27998950 TI - Antiseptic mouthwash against pharyngeal Neisseria gonorrhoeae: a randomised controlled trial and an in vitro study. AB - BACKGROUND: Gonorrhoea is increasing among men who have sex with men (MSM). We aimed to determine whether Listerine, a commercial mouthwash product, has an inhibitory effect against Neisseria gonorrhoeae in a randomised controlled trial (RCT) and an in vitro study, and therefore may be a potentially useful agent for gonorrhoea control. METHODS: In vitro: a suspension of ~108 colony forming units per mL (CFU/mL) of N. gonorrhoeae was added to a serial of dilutions (up to 1:32) of alcohol-containing Listerine mouthwashes (Cool Mint and Total Care) for 1 min. A 10 uL aliquot was spread over the surface of a gonococcal agar plate and the number of N. gonorrhoeae colonies present at each dilution was calculated. The phosphate buffered saline (PBS) was used as a control. RCT: we recruited MSM with pharyngeal gonorrhoea who returned for treatment at the Melbourne Sexual Health Centre between May 2015 and February 2016. Untreated men were randomised to rinse and gargle either Listerine Cool Mint or saline for 1 min. Pharyngeal swabs were taken before and after rinsing and gargling for culture of N. gonorrhoeae. The analysis included only men who were culture positive for N. gonorrhoeae before using the allocated solution on the day of recruitment. RESULTS: In vitro: Listerine mouthwashes at dilutions of up to 1:4 for 1 min resulted in significant reduction of total N. gonorrhoeae counts but PBS has no inhibitory effect against N. gonorrhoeae. RCT: a total of 196 MSM were recruited, 58 (30%) were culture positive before using the solution. After gargling the allocated solution, men in the Listerine group were significantly less likely to be culture positive on the pharyngeal surface (52%) compared with men in the saline group (84%) (p=0.013). CONCLUSIONS: This data suggest Listerine, significantly reduces the amount of N. gonorrhoeae on the pharyngeal surface. With daily use it may increase gonococcal clearance and have important implications for prevention strategies. TRIAL REGISTRATION NUMBER: ACTRN12615000716561. PMID- 27998951 TI - A Proteomic Survey Indicates Sortilin as a Secondary Substrate of the ER Translocation Inhibitor Cyclotriazadisulfonamide (CADA). AB - The small molecule CADA was shown to down-modulate the expression of human CD4 in a signal peptide-dependent way through inhibition of its cotranslational translocation across the ER membrane. Previous studies characterizing general glycoprotein levels and the expression of 14 different cell surface receptors showed selectivity of CADA for human CD4. Here, a PowerBlot Western Array was used as a screen to analyze the proteome of CADA-treated SUP-T1 human CD4+ T lymphocytes. This high-throughput monoclonal antibody panel-based immunoblotting assay of cellular signaling proteins revealed that only a small subset of the 444 detected proteins was differentially expressed after treatment with CADA. Validation of these proteomic data with optimized immunoblot analysis confirmed the CADA-induced change in expression of the cell cycle progression regulator pRb2 and the transcription factor c-Jun. However, the up-regulation of pRb2 or down-modulation of c-Jun by CADA had no impact on cell cycle transition. Also, the reduced protein level of human CD4 did not inhibit T cell receptor signaling. Interestingly, the signal peptide-containing membrane protein sortilin was identified as a new substrate for CADA. Both cellular expression and in vitro cotranslational translocation of sortilin were significantly reduced by CADA, although to a lesser extent as compared with human CD4. Our data demonstrate that a small signal peptide-binding drug is able to down-modulate the expression of human CD4 and sortilin, apparently with low impact on the cellular proteome. PMID- 27998953 TI - Leptin pharmacokinetics in male mice. AB - Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in a female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected into adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, and 0.15% of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist in the distribution of leptin between the male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females. PMID- 27998954 TI - Glucagon-producing cells are increased in Mas-deficient mice. AB - It has been shown that angiotensin(1-7) (Ang(1-7)) produces several effects related to glucose homeostasis. In this study, we aimed to investigate the effects of genetic deletion of Ang(1-7), the GPCR Mas, on the glucagon-producing cells. C57BL6/N Mas-/- mice presented a significant and marked increase in pancreatic alpha-cells (number of cells: 146 +/- 21 vs 67 +/- 8 in WT; P < 0.001) and the percentage per islet (17.9 +/- 0.91 vs 12.3 +/- 0.9% in WT; P < 0.0001) with subsequent reduction of beta-cells percentage (82.1 +/- 0.91 vs 87.7 +/- 0.9% in WT; P < 0.0001). Accordingly, glucagon plasma levels were increased (516.7 +/- 36.35 vs 390.8 +/- 56.45 pg/mL in WT; P < 0.05) and insulin plasma levels were decreased in C57BL6/N Mas-/- mice (0.25 +/- 0.01 vs 0.31 +/- 56.45 pg/mL in WT; P = 0.02). In order to eliminate the possibility of a background related phenotype, we determined the number of glucagon-producing cells in FVB/N Mas-/- mice. In keeping with the observations in C57BL6/N Mas-/- mice, the number and percentage of pancreatic alpha-cells were also significantly increased in these mice (number of alpha-cells: 260 +/- 22 vs 156 +/- 12 in WT, P < 0.001; percentage per islet: 16 +/- 0.8 vs 10 +/- 0.5% in WT, P < 0.0001). These results suggest that Mas has a previously unexpected role on the pancreatic glucagon production. PMID- 27998952 TI - Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. AB - OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services. PMID- 27998955 TI - Latest generation of flat detector CT as a peri-interventional diagnostic tool: a comparative study with multidetector CT. AB - BACKGROUND AND PURPOSE: Flat detector CT (FDCT) has been used as a peri interventional diagnostic tool in numerous studies with mixed results regarding image quality and detection of intracranial lesions. We compared the diagnostic aspects of the latest generation FDCT with standard multidetector CT (MDCT). MATERIALS AND METHODS: 102 patients were included in our retrospective study. All patients had undergone interventional procedures. FDCT was acquired peri interventionally and compared with postinterventional MDCT regarding depiction of ventricular/subarachnoidal spaces, detection of intracranial hemorrhage, and delineation of ischemic lesions using an ordinal scale. Ischemic lesions were quantified with the Alberta Stroke Program Early CT Scale (ASPECTS) on both examinations. Two neuroradiologists with varying grades of experience and a medical student scored the anonymized images separately, blinded to the clinical history. RESULTS: The two methods were of equal diagnostic value regarding evaluation of the ventricular system and the subarachnoidal spaces. Subarachnoidal, intraventricular, and parenchymal hemorrhages were detected with a sensitivity of 95%, 97%, and 100% and specificity of 97%, 100%, and 99%, respectively, using FDCT. Gray-white differentiation was feasible in the majority of FDCT scans, and ischemic lesions were detected with a sensitivity of 71% on FDCT, compared with MDCT scans. The mean difference in ASPECTS values on FDCT and MDCT was 0.5 points (95% CI 0.12 to 0.88). CONCLUSIONS: The latest generation of FDCT is a reliable and accurate tool for the detection of intracranial hemorrhage. Gray-white differentiation is feasible in the supratentorial region. PMID- 27998956 TI - Mechanical thrombectomy for basilar artery thrombosis: a comparison of outcomes with anterior circulation occlusions. AB - BACKGROUND AND PURPOSE: The benefits of mechanical thrombectomy (MT) in basilar artery occlusions (BAO) have not been explored in recent clinical trials. We compared outcomes and procedural complications of MT in BAO with anterior circulation occlusions. METHODS: Data from the Madrid Stroke Network multicenter prospective registry were analyzed, including baseline characteristics, procedure times, procedural complications, symptomatic intracranial hemorrhage (SICH), modified Rankin Scale (mRS), and mortality at 3 months. RESULTS: Of 479 patients treated with MT, 52 (11%) had BAO. The onset to reperfusion time lapse was longer in patients with BAO (median (IQR) 385 min (320-540) vs 315 min (240-415), p<0.001), as was the duration of the procedures (100 min (40-130) vs 60 min (39 90), p=0.006). Moreover, the recanalization rate was lower (75% vs 84%, p=0.01). A trend toward more procedural complications was observed in patients with BAO (32% vs 21%, p=0.075). The frequency of SICH was 2% vs 5% (p=0.25). At 3 months, patients with BAO had a lower rate of independence (mRS 0-2) (40% vs 58%, p=0.016) and higher mortality (33% vs 12%, p<0.001). The rate of futile recanalization was 50% in BAO versus 35% in anterior circulation occlusions (p=0.05). Age and duration of the procedure were significant predictors of futile recanalization in BAO. CONCLUSIONS: MT is more laborious and shows more procedural complications in BAO than in anterior circulation strokes. The likelihood of futile recanalization is higher in BAO and is associated with greater age and longer procedure duration. A refinement of endovascular procedures for BAO might help optimize the results. PMID- 27998957 TI - Multicenter experience with the new SOFIA Plus catheter as a primary local aspiration catheter for acute stroke thrombectomy. AB - INTRODUCTION: The direct aspiration first pass technique (ADAPT) has been introduced as a rapid and safe endovascular treatment strategy in patients with ischemic stroke. OBJECTIVE: To determine the technical feasibility, safety, and functional outcome with ADAPT using the new large-bore 6F SOFIA Plus catheter. METHODS: A retrospective analysis of prospectively collected data from six university hospitals was performed. The following parameters of all acute stroke procedures (June 2015- January 2016) using the SOFIA Plus catheter were analyzed: accessibility of the thrombus with the catheter, recanalization success (Thrombolysis in Cerebral Infarction >=2b), time to recanalization, procedure related complications. Furthermore, National Institutes of Health Stroke Scale (NIHSS) scores at presentation and discharge and the modified Rankin scale (mRS) score at 90 days were recorded. RESULTS: 85 patients were treated using the SOFIA Plus catheter. The occlusion site was the anterior circulation in 94.1%. Median baseline NIHSS score was 18. In 64.7%, ADAPT alone was successful after a median procedure time of 21 min. With additional use of stent retrievers in the remaining cases, the recanalization rate was 96.5%. No catheter-related complications such as dissections were observed. Thrombus migration to a new vascular territory occurred in 4.7% and symptomatic hemorrhage in 4.7%. After 3 months, mRS 0-2 was achieved in 49.4%. Mortality rate was 20%. CONCLUSIONS: In the majority of cases, thrombus aspiration using the SOFIA Plus catheter results in successful recanalization after a short procedure time. With additional use of stent retrievers, a high recanalization rate can be achieved (96.5%). The complication rate was in line with those of previous publications. PMID- 27998958 TI - Bisphenol A and its analogues disrupt centrosome cycle and microtubule dynamics in prostate cancer. AB - Humans are increasingly exposed to structural analogues of bisphenol A (BPA), as BPA is being replaced by these compounds in BPA-free consumer products. We have previously shown that chronic and developmental exposure to BPA is associated with increased prostate cancer (PCa) risk in human and animal models. Here, we examine whether exposure of PCa cells (LNCaP, C4-2) to low-dose BPA and its structural analogues (BPS, BPF, BPAF, TBBPA, DMBPA and TMBPA) affects centrosome amplification (CA), a hallmark of cancer initiation and progression. We found that exposure to BPA, BPS, DMBPA and TBBPA, in descending order, increased the number of cells with CA, in a non-monotonic dose-response manner. Furthermore, cells treated with BPA and their analogues initiated centrosome duplication at 8 h after release from serum starvation, significantly earlier in G-1 phase than control cells. This response was attended by earlier release of nucleophosmin from unduplicated centrosomes. BPA-exposed cells exhibited increased expression of cyclin-dependent kinase CDK6 and decreased expression of CDK inhibitors (p21Waf1/CIP1 and p27KIP1). Using specific antagonists for estrogen/androgen receptors, CA in the presence of BPA or its analogues was likely to be mediated via ESR1 signaling. Change in microtubule dynamics was observed on exposure to these analogues, which, for BPA, was accompanied by increased expression of centrosome-associated protein CEP350 Similar to BPA, chronic treatment of cells with DMBPA, but not other analogues, resulted in the enhancement of anchorage independent growth. We thus conclude that selected BPA analogues, similar to BPA, disrupt centrosome function and microtubule organization, with DMBPA displaying the broadest spectrum of cancer-promoting effects. PMID- 27998959 TI - Exogenous H2S regulates endoplasmic reticulum-mitochondria cross-talk to inhibit apoptotic pathways in STZ-induced type I diabetes. AB - The upregulation of reactive oxygen species (ROS) is a primary cause of cardiomyocyte apoptosis in diabetes cardiomyopathy (DCM). Mitofusin-2 (Mfn-2) is a key protein that bridges the mitochondria and endoplasmic reticulum (ER). Hydrogen sulfide (H2S)-mediated cardioprotection is related to antioxidant effects. The present study demonstrated that H2S inhibited the interaction between the ER and mitochondrial apoptotic pathway. This study investigated cardiac function, ultrastructural changes in the ER and mitochondria, apoptotic rate using TUNEL, and the expression of ER stress-associated proteins and mitochondrial apoptotic proteins in cardiac tissues in STZ-induced type I diabetic rats treated with or without NaHS (donor of H2S). Mitochondria of cardiac tissues were isolated, and MPTP opening and cytochrome c (cyt C) and Mfn 2 expression were also detected. Our data showed that hyperglycemia decreased the cardiac function by ultrasound cardiogram, and the administration of exogenous H2S ameliorated these changes. We demonstrated that the expression of ER stress sensors and apoptotic rates were elevated in cardiac tissue of DCM and cultured H9C2 cells, but the expression of these proteins was reduced following exogenous H2S treatment. The expression of mitochondrial apoptotic proteins, cyt C, and mPTP opening was decreased following treatment with exogenous H2S. In our experiment, the expression and immunofluorescence of Mfn-2 were both decreased after transfection with Mfn-2-siRNA. Hyperglycemia stimulated ER interactions and mitochondrial apoptotic pathways, which were inhibited by exogenous H2S treatment through the regulation of Mfn-2 expression. PMID- 27998960 TI - Acute and chronic hyperglycemic effects of vasopressin in normal rats: involvement of V1A receptors. AB - Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V1A and V1B receptors (R) are expressed in the liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glucose homeostasis in normal Sprague Dawley rats, as well as the respective roles of V1AR and V1BR. We showed that acute injection of AVP induces a dose-dependent increase in glycemia. Pretreatment with a selective V1AR antagonist, but not a V1BR antagonist, dose dependently prevented the rise in glycemia. V1BR antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective V1AR or V1BR agonists confirmed the involvement of V1AR in the hyperglycemic effect of AVP. In chronic experiments, AVP levels were altered in both directions. Sustained AVP infusion through implantable minipumps induced a time-dependent increase in fasting glycemia, whereas lowering endogenous AVP by increasing water intake had no effect. After 4 wk of AVP infusion, the rise in glycemia amounted to 1.1 mmol/l (P < 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a V1AR antagonist. Similar results were observed in lean Zucker rats. These findings demonstrate for the first time a causal link between chronic high AVP and hyperglycemia through V1AR activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes. PMID- 27998961 TI - Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99. AB - Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated. Patients and methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after >=6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity. Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related. Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients. PMID- 27998964 TI - Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer. AB - Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment. PMID- 27998963 TI - Circulating tumor markers: harmonizing the yin and yang of CTCs and ctDNA for precision medicine. AB - Current trajectory of clinical care is heading in the direction of personalized medicine. In an ideal scenario, clinicians can obtain extensive diagnostic and prognostic information via minimally-invasive assays. Information available in the peripheral blood has the potential to bring us closer to this goal. In this review we highlight the contributions of circulating tumor cells and circulating tumor DNA and RNA (ctDNA/ctRNA) towards cancer therapeutic field. We discuss clinical relevance, summarize available and upcoming technologies, and hypothesize how future care could be impacted by a combined study. PMID- 27998965 TI - Does severe toxicity affect global quality of life in patients with metastatic colorectal cancer during palliative systemic treatment? A systematic review. AB - Background: New palliative systemic treatment regimens in patients with metastatic colorectal cancer (mCRC) have significantly improved overall survival and prognosis. These treatment regimens are often accompanied by increased toxicity, which may impair patients' quality of life (QOL). We systematically reviewed whether severe toxicity affects global QOL in patients with mCRC receiving palliative systemic treatment in recent published randomized controlled trials (RCTs). Materials and methods: Phase III RCTs evaluating palliative systemic treatments in patients with mCRC and published between 2004 and 2016 were considered. Studies were evaluated on the basis of global QOL scores, toxicity during treatment (assessed by scoring relevant adverse events) and primary outcomes (POs). Results: A total of 30 studies were identified in which 19863 patients were included. In 25 out of these 30 trials (83%), no difference in global QOL between treatment arms was observed. In contrast, 22 out of 30 trials (73%) showed increased toxicity during treatment in the experimental arm as compared with the control arm. In 19 out of 22 trials with higher toxicity (86%) global QOL outcomes remained unaffected or improved. In ten out of eleven studies with a better PO, no improvement in global QOL was seen. Conclusion: Global QOL of patients with mCRC included in phase III RCTs evaluating palliative systemic treatment did not differ across treatment arms despite consistently higher toxicity during treatment of the experimental compared with the standard treatment arms. Based on these findings we conclude that the use of global QOL for comparing treatment arms in RCTs for patients with mCRC does not provide information of clinical relevance. Further consideration of how to better assess the net effect of new agents on patients' QOL is urgently needed. PMID- 27998966 TI - Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials. AB - Background: Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting. Patients and methods: We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design. Results: A total of 19 RCTs were included in the meta-analysis (n = 62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07-1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended adjuvant setting (RR: 1.01, 95% CI: 0.85-1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45-0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77-1.07). Conclusions: The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer. PMID- 27998967 TI - Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. AB - Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under recognized impact of PD-1 biology in modulating humoral immunity. PMID- 27998969 TI - Management of CLL in the elderly. PMID- 27998968 TI - Drug-sensitive FGFR3 mutations in lung adenocarcinoma. AB - Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 * (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma. PMID- 27998970 TI - A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852). AB - Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting >=3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. Clinical trial information: NCT01281852. PMID- 27998972 TI - Looking beyond drivers and passengers in cancer genome sequencing data. AB - Cancer arises as a result of acquired changes in the DNA sequence of the genome of somatic cells. A subset of the genetic changes, dubbed driver mutations, propels tumor growth, and the remaining changes are passengers, apparently inconsequential for neoplastic transformation. Massive genome sequencing of thousands of tumors from all major cancer types has enabled cataloging of the so called driver and passenger mutations, and facilitated molecular classification of cancer, guiding precision medicine approach for the patients. Nonetheless, innovative analyses of cancer genomics data has led to novel, sometimes serendipitous findings that have aided to our understanding of other aspects of the biology of the disease and opened up new frontiers. For instance, emerging findings show that mutational patterns in cancer genomes can help detect signatures of known and novel DNA damage and repair processes, provide a likely chronological account of genomic changes in cancer genomes, and allow revisiting the models of cancer evolution. These findings have stimulated original approaches to identify disease etiology, stratify patients, target the disease, and monitor patient responses, complementing driver-mutation centric approaches. In this review, we discuss these emerging approaches and unexpected breakthroughs, and their implications for basic cancer research and clinical practices. PMID- 27998971 TI - A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder. AB - Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02 restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02 positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S 288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S 288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980. PMID- 27998973 TI - Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer. AB - Background: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular subtypes, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognostic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo. Materials and methods: We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs. Results: High nectin 4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal subtypes. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level. Conclusion: Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC. PMID- 27998974 TI - Xylem diameter changes during osmotic stress, desiccation and freezing in Pinus sylvestris and Populus tremula. AB - Trees experience low apoplastic water potential frequently in most environments. Low apoplastic water potential increases the risk of embolism formation in xylem conduits and creates dehydration stress for the living cells. We studied the magnitude and rate of xylem diameter change in response to decreasing apoplastic water potential and the role of living parenchyma cells in it to better understand xylem diameter changes in different environmental conditions. We compared responses of control and heat-injured xylem of Pinus sylvestris (L.) and Populus tremula (L.) branches to decreasing apoplastic water potential created by osmotic stress, desiccation and freezing. It was shown that xylem in control branches shrank more in response to decreasing apoplastic water potential in comparison with the samples that were preheated to damage living xylem parenchyma. By manipulating the osmotic pressure of the xylem sap, we observed xylem shrinkage due to decreasing apoplastic water potential even in the absence of water tension within the conduits. These results indicate that decreasing apoplastic water potential led to withdrawal of intracellular water from the xylem parenchyma, causing tissue shrinkage. The amount of xylem shrinkage per decrease in apoplastic water potential was higher during osmotic stress or desiccation compared with freezing. During desiccation, xylem diameter shrinkage involved both dehydration-related shrinkage of xylem parenchyma and water tension induced shrinkage of conduits, whereas dehydration-related shrinkage of xylem parenchyma was accompanied by swelling of apoplastic ice during freezing. It was also shown that the exchange of water between symplast and apoplast within xylem is clearly faster than previously reported between the phloem and the xylem. Time constant of xylem shrinkage was 40 and 2 times higher during osmotic stress than during freezing stress in P. sylvestris and P. tremula, respectively. Finally, it was concluded that the amount of water stored in the xylem parenchyma is an important reservoir for trees to buffer daily fluctuations in water relations. PMID- 27998975 TI - The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex. AB - Prozymes are catalytically inactive enzyme paralogs that dramatically stimulate the function of weakly active enzymes through complex formation. The two prozymes described to date reside in the polyamine biosynthesis pathway of the human parasite Trypanosoma brucei, an early branching eukaryote that lacks transcriptional regulation and regulates its proteome through posttranscriptional and posttranslational means. Arginine methylation is a common posttranslational modification in eukaryotes catalyzed by protein arginine methyltransferases (PRMTs) that are typically thought to function as homodimers. We demonstrate that a major T. brucei PRMT, TbPRMT1, functions as a heterotetrameric enzyme-prozyme pair. The inactive PRMT paralog, TbPRMT1PRO, is essential for catalytic activity of the TbPRMT1ENZ subunit. Mutational analysis definitively demonstrates that TbPRMT1ENZ is the cofactor-binding subunit and carries all catalytic activity of the complex. Our results are the first demonstration of an obligate heteromeric PRMT, and they suggest that enzyme-prozyme organization is expanded in trypanosomes as a posttranslational means of enzyme regulation. PMID- 27998976 TI - Sialylation Controls Prion Fate in Vivo. AB - Prions or PrPSc are proteinaceous infectious agents that consist of misfolded, self-replicating states of a sialoglycoprotein called the prion protein or PrPC The current work tests a new hypothesis that sialylation determines the fate of prions in an organism. To begin, we produced control PrPSc from PrPC using protein misfolding cyclic amplification with beads (PMCAb), and also generated PrPSc with reduced sialylation levels using the same method but with partially desialylated PrPC as a substrate (dsPMCAb). Syrian hamsters were inoculated intraperitoneally with brain-derived PrPSc or PrPSc produced in PMCAb or dsPMCAb and then monitored for disease. Animals inoculated with brain- or PMCAb-derived PrPSc developed prion disease, whereas administration of dsPMCAb-derived PrPSc with reduced sialylation did not cause prion disease. Animals inoculated with dsPMCAb-derived material were not subclinical carriers of scrapie, as no PrPSc was detected in brains or spleen of these animals by either Western blotting or after amplification by serial PMCAb. In subsequent experiments, trafficking of brain-, PMCAb-, and dsPMCAb-derived PrPSc to secondary lymphoid organs was monitored in wild type mice. PrPSc sialylation was found to be critical for effective trafficking of PrPSc to secondary lymphoid organs. By 6 hours after inoculation, brain- and PMCAb-derived PrPSc were found in spleen and lymph nodes, whereas dsPMCAb-derived PrPSc was found predominantly in liver. This study demonstrates that the outcome of prion transmission to a wild type host is determined by the sialylation status of the inoculated PrPSc Furthermore, this work suggests that the sialylation status of PrPSc plays an important role in prion lymphotropism. PMID- 27998977 TI - The Proprotein Convertase Subtilisin/Kexin Type 9-resistant R410S Low Density Lipoprotein Receptor Mutation: A NOVEL MECHANISM CAUSING FAMILIAL HYPERCHOLESTEROLEMIA. AB - Familial hypercholesterolemia (FH) is characterized by severely elevated low density lipoprotein (LDL) cholesterol. Herein, we identified an FH patient presenting novel compound heterozygote mutations R410S and G592E of the LDL receptor (LDLR). The patient responded modestly to maximum rosuvastatin plus ezetimibe therapy, even in combination with a PCSK9 monoclonal antibody injection. Using cell biology and molecular dynamics simulations, we aimed to define the underlying mechanism(s) by which these LDLR mutations affect LDL metabolism and lead to hypercholesterolemia. Our data showed that the LDLR-G592E is a class 2b mutant, because it mostly failed to exit the endoplasmic reticulum and was degraded. Even though LDLR-R410S and LDLR-WT were similar in levels of cell surface and total receptor and bound equally well to LDL or extracellular PCSK9, the LDLR-R410S was resistant to exogenous PCSK9-mediated degradation in endosomes/lysosomes and showed reduced LDL internalization and degradation relative to LDLR-WT. Evidence is provided for a tighter association of LDL with LDLR-R410S at acidic pH, a reduced LDL delivery to late endosomes/lysosomes, and an increased release in the medium of the bound/internalized LDL, as compared with LDLR-WT. These data suggested that LDLR-R410S recycles loaded with its LDL cargo. Our findings demonstrate that LDLR-R410S represents an LDLR loss-of function through a novel class 8 FH-causing mechanism, thereby rationalizing the observed phenotype. PMID- 27998978 TI - Three Tyrosine Residues in the Erythropoietin Receptor Are Essential for Janus Kinase 2 V617F Mutant-induced Tumorigenesis. AB - The erythropoietin receptor (EpoR) regulates development of blood cells, and its full activation normally requires the cytokine erythropoietin (Epo). In the case of myeloproliferative neoplasms (MPN), Epo-independent signaling through EpoR can be caused by a point mutation, V617F, in the EpoR-interacting tyrosine kinase Janus kinase 2 (JAK2). In cells expressing the JAK2 V617F mutant, eight tyrosine residues in the intracellular domain of EpoR are phosphorylated, but the functional role of these phosphorylations in oncogenic signaling is incompletely understood. Here, to evaluate the functional consequences of the phosphorylation of these tyrosine residues, we constructed an EpoR-8YF mutant in which we substituted all eight tyrosine residues with phenylalanine. Co-expression of EpoR 8YF with the JAK2 V617F mutant failed to induce cytokine-independent cell proliferation and tumorigenesis, indicating that JAK2-mediated EpoR phosphorylation is the reason for JAK2 V617F mutant-induced oncogenic signaling. An exhaustive mutational analysis of the eight EpoR tyrosine residues indicated that three of these residues, Tyr-343, Tyr-460, and Tyr-464, are required for the JAK2 V617F mutant to exhibit its oncogenic activity. We also showed that phosphorylation at these three residues was necessary for full activation of the transcription factor STAT5, which is a critical downstream factor of JAK2 V617F induced oncogenic signaling. In contrast, Epo stimulation could moderately stimulate the proliferation of cells expressing wild type JAK2 and EpoR-8YF, suggesting that the requirement of the phosphorylation of these three tyrosine residues seems to be specific for the oncogenic proliferation provoked by V617F mutation. Collectively, these results have revealed that phosphorylation of Tyr 343, Tyr-460, and Tyr-464 in EpoR underlies JAK2 V617F mutant-induced tumorigenesis. We propose that the targeted disruption of this pathway has therapeutic utility for managing MPN. PMID- 27998979 TI - alpha Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes. AB - Glucocorticoids are a general class of steroids that possess renoprotective activity in glomeruli through their interaction with the glucocorticoid receptor. However, the mechanisms by which glucocorticoids ameliorate proteinuria and glomerular disease are not well understood. In this study, we demonstrated that alpha actinin 4 (ACTN4), an actin-cross-linking protein known to coordinate cytoskeletal organization, interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes (HPCs), a key cell type in the glomerulus critical for kidney filtration function. The GR-ACTN4 complex enhances glucocorticoid response element (GRE)-driven reporter activity. Stable knockdown of ACTN4 by shRNA in HPCs significantly reduces dexamethasone-mediated induction of GR target genes and GRE-driven reporter activity without disrupting dexamethasone-induced nuclear translocation of GR. Synonymous mutations or protein expression losses in ACTN4 are associated with kidney diseases, including focal segmental glomerulosclerosis, characterized by proteinuria and podocyte injury. We found that focal segmental glomerulosclerosis-linked ACTN4 mutants lose their ability to bind liganded GR and support GRE-mediated transcriptional activity. Mechanistically, GR and ACTN4 interact in the nucleus of HPCs. Furthermore, disruption of the LXXLL nuclear receptor-interacting motif present in ACTN4 results in reduced GR interaction and dexamethasone-mediated transactivation of a GRE reporter while still maintaining its actin-binding activity. In contrast, an ACTN4 isoform, ACTN4 (Iso), that loses its actin-binding domain is still capable of potentiating a GRE reporter. Dexamethasone induces the recruitment of ACTN4 and GR to putative GREs in dexamethasone-transactivated promoters, SERPINE1, ANGPLT4, CCL20, and SAA1 as well as the NF-kappaB (p65) binding sites on GR transrepressed promoters such as IL-1beta, IL-6, and IL-8 Taken together, our data establish ACTN4 as a transcriptional co-regulator that modulates both dexamethasone-transactivated and -transrepressed genes in podocytes. PMID- 27998980 TI - Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution. AB - The interaction of glutamate and dopamine in the striatum is heavily dependent on signaling pathways that converge on the regulatory protein DARPP-32. The efficacy of dopamine/D1 receptor/PKA signaling is regulated by DARPP-32 phosphorylated at Thr-34 (the PKA site), a process that inhibits protein phosphatase 1 (PP1) and potentiates PKA action. Activation of dopamine/D1 receptor/PKA signaling also leads to dephosphorylation of DARPP-32 at Ser-97 (the CK2 site), leading to localization of phospho-Thr-34 DARPP-32 in the nucleus where it also inhibits PP1. In this study the role of glutamate in the regulation of DARPP-32 phosphorylation at four major sites was further investigated. Experiments using striatal slices revealed that glutamate decreased the phosphorylation states of DARPP-32 at Ser-97 as well as Thr-34, Thr-75, and Ser-130 by activating NMDA or AMPA receptors in both direct and indirect pathway striatal neurons. The effect of glutamate in decreasing Ser-97 phosphorylation was mediated by activation of PP2A. In vitro phosphatase assays indicated that the PP2A/PR72 heterotrimer complex was likely responsible for glutamate/Ca2+-regulated dephosphorylation of DARPP-32 at Ser-97. As a consequence of Ser-97 dephosphorylation, glutamate induced the nuclear localization in cultured striatal neurons of dephospho-Thr 34/dephospho-Ser-97 DARPP-32. It also reduced PKA-dependent DARPP-32 signaling in slices and in vivo Taken together, the results suggest that by inducing dephosphorylation of DARPP-32 at Ser-97 and altering its cytonuclear distribution, glutamate may counteract dopamine/D1 receptor/PKA signaling at multiple cellular levels. PMID- 27998981 TI - Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530. AB - Src-family tyrosine kinases are widely expressed in many cell types and participate in a variety of signal transduction pathways. Despite the significance of Src in suppression of apoptosis, its mechanism remains poorly understood. Here we show that Src acts as an effector for Ku70-dependent suppression of apoptosis. Inhibition of endogenous Src activity promotes UV induced apoptosis, which is impaired by Ku70 knockdown. Src phosphorylates Ku70 at Tyr-530, being close to the possible acetylation sites involved in promotion of apoptosis. Src-mediated phosphorylation of Ku70 at Tyr-530 decreases acetylation of Ku70, whereas Src inhibition augments acetylation of Ku70. Importantly, knockdown-rescue experiments with stable Ku70 knockdown cells show that the nonphosphorylatable Y530F mutant of Ku70 reduces the ability of Ku70 to suppress apoptosis accompanied by augmentation of Ku70 acetylation. Our results reveal that Src plays a protective role against hyperactive apoptotic cell death by reducing apoptotic susceptibility through phosphorylation of Ku70 at Tyr-530. PMID- 27998982 TI - The Human RecQ4 Helicase Contains a Functional RecQ C-terminal Region (RQC) That Is Essential for Activity. AB - RecQ helicases are essential in the maintenance of genome stability. Five paralogues (RecQ1, Bloom, Werner, RecQ4, and RecQ5) are found in human cells, with distinct but overlapping roles. Mutations in human RecQ4 give rise to three distinct genetic disorders (Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes), characterized by genetic instability, growth deficiency, and predisposition to cancer. Previous studies suggested that RecQ4 was unique because it did not seem to contain a RecQ C-terminal region (RQC) found in the other RecQ paralogues; such a region consists of a zinc domain and a winged helix domain and plays an important role in enzyme activity. However, our recent bioinformatic analysis identified in RecQ4 a putative RQC. To experimentally confirm this hypothesis, we report the purification and characterization of the catalytic core of human RecQ4. Inductively coupled plasma-atomic emission spectrometry detected the unusual presence of two zinc clusters within the zinc domain, consistent with the bioinformatic prediction. Analysis of site-directed mutants, targeting key RQC residues (putative zinc ligands and the aromatic residue predicted to be at the tip of the winged helix beta-hairpin), showed a decrease in DNA binding, unwinding, and annealing, as expected for a functional RQC domain. Low resolution structural information obtained by small angle X-ray scattering data suggests that RecQ4 interacts with DNA in a manner similar to RecQ1, whereas the winged helix domain may assume alternative conformations, as seen in the bacterial enzymes. These combined results experimentally confirm the presence of a functional RQC domain in human RecQ4. PMID- 27998984 TI - The Assembly Factor Pet117 Couples Heme a Synthase Activity to Cytochrome Oxidase Assembly. AB - Heme a is an essential metalloporphyrin cofactor of the mitochondrial respiratory enzyme cytochrome c oxidase (CcO). Its synthesis from heme b requires several enzymes, including the evolutionarily conserved heme a synthase (Cox15). Oligomerization of Cox15 appears to be important for the process of heme a biosynthesis and transfer to maturing CcO. However, the details of this process remain elusive, and the roles of any additional CcO assembly factors that may be involved remain unclear. Here we report the systematic analysis of one such uncharacterized assembly factor, Pet117, and demonstrate in Saccharomyces cerevisiae that this evolutionarily conserved protein is necessary for Cox15 oligomerization and function. Pet117 is shown to reside in the mitochondrial matrix, where it is associated with the inner membrane. Pet117 functions at the later maturation stages of the core CcO subunit Cox1 that precede Cox1 hemylation. Pet117 also physically interacts with Cox15 and specifically mediates the stability of Cox15 oligomeric complexes. This Cox15-Pet117 interaction observed by co-immunoprecipitation persists in the absence of heme a synthase activity, is dependent upon Cox1 synthesis and early maturation steps, and is further dependent upon the presence of the matrix-exposed, unstructured linker region of Cox15 needed for Cox15 oligomerization, suggesting that this region mediates the interaction or that the interaction is lost when Cox15 is unable to oligomerize. Based on these findings, it was concluded that Pet117 mediates coupling of heme a synthesis to the CcO assembly process in eukaryotes. PMID- 27998983 TI - Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels. AB - Cardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG. PMID- 27998986 TI - More than meets the eye. PMID- 27998985 TI - A rare cause of GI bleeding in a 56-year-old man. PMID- 27998987 TI - Health camps and surveys: marketing an unproved, unapproved drug in India. PMID- 27998990 TI - Activating the nuclear piston mechanism of 3D migration in tumor cells. AB - Primary human fibroblasts have the remarkable ability to use their nucleus like a piston, switching from low- to high-pressure protrusions in response to the surrounding three-dimensional (3D) matrix. Although migrating tumor cells can also change how they migrate in response to the 3D matrix, it is not clear if they can switch between high- and low-pressure protrusions like primary fibroblasts. We report that unlike primary fibroblasts, the nuclear piston is not active in fibrosarcoma cells. Protease inhibition rescued the nuclear piston mechanism in polarized HT1080 and SW684 cells and generated compartmentalized pressure. Achieving compartmentalized pressure required the nucleoskeleton cytoskeleton linker protein nesprin 3, actomyosin contractility, and integrin mediated adhesion, consistent with lobopodia-based fibroblast migration. In addition, this activation of the nuclear piston mechanism slowed the 3D movement of HT1080 cells. Together, these data indicate that inhibiting protease activity during polarized tumor cell 3D migration is sufficient to restore the nuclear piston migration mechanism with compartmentalized pressure characteristic of nonmalignant cells. PMID- 27998992 TI - To use or not to use the force: How B lymphocytes extract surface-tethered antigens. AB - Using an exquisite cell imaging approach based on DNA nanosensors, Spillane and Tolar (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201607064) explore how the physical properties of antigen-presenting cell surfaces affect how B cells internalize surface-tethered antigens. Soft and flexible surfaces promote mechanical force-mediated antigen extraction, whereas stiff surfaces lead to enzyme-mediated antigen release before subsequent internalization. PMID- 27998989 TI - INPP5E regulates phosphoinositide-dependent cilia transition zone function. AB - Human ciliopathies, including Joubert syndrome (JBTS), arise from cilia dysfunction. The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e-/- embryos exhibit aberrant Hedgehog-dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e-/- ciliopathy phenotypes and "normalizes" Hedgehog signaling. INPP5E's phosphoinositide substrates PI(4,5)P2 and PI(3,4,5)P3 accumulated at the transition zone (TZ) in Hedgehog-stimulated Inpp5e-/- cells, which was associated with reduced recruitment of TZ scaffolding proteins and reduced Smoothened levels at cilia. Expression of wild-type, but not 5-phosphatase-dead, INPP5E restored TZ molecular organization and Smoothened accumulation at cilia. Therefore, we identify INPP5E as an essential point of convergence between Hedgehog and phosphoinositide signaling at cilia that maintains TZ function and Hedgehog dependent embryonic development. PMID- 27998991 TI - Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release. AB - The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca2+ channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca2+ channel clusters for reliable and modifiable neurotransmitter release. PMID- 27998993 TI - Interpersonal violence in posttraumatic women: brain networks triggered by trauma related pictures. AB - Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. Trauma-related triggers have been proposed to evoke automatic emotional responses in PTSD. The present functional magnetic resonance study investigated the neural basis of trauma-related picture processing in women with IPV-PTSD (n = 18) relative to healthy controls (n = 18) using a newly standardized trauma-related picture set and a non-emotional vigilance task. We aimed to identify brain activation and connectivity evoked by trauma-related pictures, and associations with PTSD symptom severity. We found hyperactivation during trauma-related vs neutral picture processing in both subcortical [basolateral amygdala (BLA), thalamus, brainstem] and cortical [anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), insula, occipital cortex] regions in IPV-PTSD. In patients, brain activation in amygdala, ACC, insula, occipital cortex and brainstem correlated positively with symptom severity. Furthermore, connectivity analyses revealed hyperconnectivity between BLA and dorsal ACC/mPFC. Results show symptom severity dependent brain activation and hyperconnectivity in response to trauma-related pictures in brain regions related to fear and visual processing in women suffering from IPV-PTSD. These brain mechanisms appear to be associated with immediate responses to trauma-related triggers presented in a non-emotional context in this PTSD subgroup. PMID- 27998994 TI - Mechanisms of masked evaluative priming: task sets modulate behavioral and electrophysiological priming for picture and words differentially. AB - Research with the evaluative priming paradigm has shown that affective evaluation processes reliably influence cognition and behavior, even when triggered outside awareness. However, the precise mechanisms underlying such subliminal evaluative priming effects, response activation vs semantic processing, are matter of a debate. In this study, we determined the relative contribution of semantic processing and response activation to masked evaluative priming with pictures and words. To this end, we investigated the modulation of masked pictorial vs verbal priming by previously activated perceptual vs semantic task sets and assessed the electrophysiological correlates of priming using event-related potential (ERP) recordings. Behavioral and electrophysiological effects showed a differential modulation of pictorial and verbal subliminal priming by previously activated task sets: Pictorial priming was only observed during the perceptual but not during the semantic task set. Verbal priming, in contrast, was found when either task set was activated. Furthermore, only verbal priming was associated with a modulation of the N400 ERP component, an index of semantic processing, whereas a priming-related modulation of earlier ERPs, indexing visuo-motor S-R activation, was found for both picture and words. The results thus demonstrate that different neuro-cognitive processes contribute to unconscious evaluative priming depending on the stimulus format. PMID- 27998995 TI - The special status of sad infant faces: age and valence differences in adults' cortical face processing. AB - Understanding the relative and joint prioritization of age- and valence-related face characteristics in adults' cortical face processing remains elusive because these two characteristics have not been manipulated in a single study of neural face processing. We used electroencephalography to investigate adults' P1, N170, P2 and LPP responses to infant and adult faces with happy and sad facial expressions. Viewing infant vs adult faces was associated with significantly larger P1, N170, P2 and LPP responses, with hemisphere and/or participant gender moderating this effect in select cases. Sad faces were associated with significantly larger N170 responses than happy faces. Sad infant faces were associated with significantly larger N170 responses in the right hemisphere than all other combinations of face age and face valence characteristics. We discuss the relative and joint neural prioritization of infant face characteristics and negative facial affect, and their biological value as distinct caregiving and social cues. PMID- 27998996 TI - Effective amygdala-prefrontal connectivity predicts individual differences in successful emotion regulation. AB - The ability to voluntarily regulate our emotional response to threatening and highly arousing stimuli by using cognitive reappraisal strategies is essential for our mental and physical well-being. This might be achieved by prefrontal brain regions (e.g. inferior frontal gyrus, IFG) down-regulating activity in the amygdala. It is unknown, to which degree effective connectivity within the emotion-regulation network is linked to individual differences in reappraisal skills. Using psychophysiological interaction analyses of functional magnetic resonance imaging data, we examined changes in inter-regional connectivity between the amygdala and IFG with other brain regions during reappraisal of emotional responses and used emotion regulation success as an explicit regressor. During down-regulation of emotion, reappraisal success correlated with effective connectivity between IFG with dorsolateral, dorsomedial and ventromedial prefrontal cortex (PFC). During up-regulation of emotion, effective coupling between IFG with anterior cingulate cortex, dorsomedial and ventromedial PFC as well as the amygdala correlated with reappraisal success. Activity in the amygdala covaried with activity in lateral and medial prefrontal regions during the up-regulation of emotion and correlated with reappraisal success. These results suggest that successful reappraisal is linked to changes in effective connectivity between two systems, prefrontal cognitive control regions and regions crucially involved in emotional evaluation. PMID- 27998998 TI - Self-distancing improves interpersonal perceptions and behavior by decreasing medial prefrontal cortex activity during the provision of criticism. AB - Previous research suggests that people show increased self-referential processing when they provide criticism to others, and that this self-referential processing can have negative effects on interpersonal perceptions and behavior. The current research hypothesized that adopting a self-distanced perspective (i.e. thinking about a situation from a non-first person point of view), as compared with a typical self-immersed perspective (i.e. thinking about a situation from a first person point of view), would reduce self-referential processing during the provision of criticism, and in turn improve interpersonal perceptions and behavior. We tested this hypothesis in an interracial context since research suggests that self-referential processing plays a role in damaging interracial relations. White participants prepared for mentorship from a self-immersed or self-distanced perspective. They then conveyed negative and positive evaluations to a Black mentee while electroencephalogram (EEG) was recorded. Source analysis revealed that priming a self-distanced (vs self-immersed) perspective predicted decreased activity in regions linked to self-referential processing (medial prefrontal cortex; MPFC) when providing negative evaluations. This decreased MPFC activity during negative evaluations, in turn, predicted verbal feedback that was perceived to be more positive, warm and helpful. Results suggest that self distancing can improve interpersonal perceptions and behavior by decreasing self referential processing during the provision of criticism. PMID- 27998997 TI - Differential functional connectivity of rostral anterior cingulate cortex during emotional interference. AB - The rostral-ventral subdivision of the anterior cingulate cortex (rACC) plays a key role in the regulation of emotional processing. Although rACC has strong anatomical connections with anterior insular cortex (AIC), amygdala, prefrontal cortex and striatal brain regions, it is unclear whether the functional connectivity of rACC with these regions changes when regulating emotional processing. Furthermore, it is not known whether this connectivity changes with deficits in emotion regulation seen in different kinds of anxiety and depression. To address these questions regarding rACC functional connectivity, non-patients high in self-reported anxious apprehension (AP), anxious arousal (AR), anhedonic depression (AD) or none (CON) indicated the ink color of pleasant, neutral and unpleasant words during functional magnetic resonance imaging. While ignoring task-irrelevant unpleasant words, AD and CON showed an increase in the functional connectivity of rACC with AIC, putamen, caudate and ventral pallidum. There was a decrease in this connectivity in AP and AR, with AP showing greater reduction than AR. These findings provide support for the role of rACC in integrating interoceptive, emotional and cognitive functions via interactions with insula and striatal regions during effective emotion regulation in healthy individuals and a failure of this integration that may be specific to anxiety, particularly AP. PMID- 27999000 TI - Diabetes Care: "Taking It to the Limit One More Time". PMID- 27999002 TI - Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. AB - OBJECTIVE: Recent studies suggest the beneficial effects of metformin on glucose metabolism may be microbially mediated. We examined the association of type 2 diabetes, metformin, and gut microbiota in community-dwelling Colombian adults. On the basis of previous research, we hypothesized that metformin is associated with higher levels of short-chain fatty acid (SCFA)-producing and mucin-degrading microbiota. RESEARCH DESIGN AND METHODS: Participants were selected from a larger cohort of 459 participants. The present analyses focus on the 28 participants diagnosed with diabetes-14 taking metformin- and the 84 participants without diabetes who were matched (3-to-1) to participants with diabetes by sex, age, and BMI. We measured demographic information, anthropometry, and blood biochemical parameters and collected fecal samples from which we performed 16S rRNA gene sequencing to analyze the composition and structure of the gut microbiota. RESULTS: We found an association between diabetes and gut microbiota that was modified by metformin use. Compared with participants without diabetes, participants with diabetes taking metformin had higher relative abundance of Akkermansia muciniphila, a microbiota known for mucin degradation, and several gut microbiota known for production of SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella. In contrast, compared with participants without diabetes, participants with diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06 and a distinct operational taxonomic unit of Prevotella and a lower abundance of Enterococcus casseliflavus. CONCLUSIONS: Our results support the hypothesis that metformin shifts gut microbiota composition through the enrichment of mucin-degrading A. muciniphila as well as several SCFA-producing microbiota. Future studies are needed to determine if these shifts mediate metformin's glycemic and anti-inflammatory properties. PMID- 27999003 TI - Diabetic Neuropathy: A Position Statement by the American Diabetes Association. PMID- 27999005 TI - Home Monitoring of Fasting and Postprandial Triglycerides in Late Pregnancy: A Pilot Study. PMID- 27999001 TI - Glucose Metabolism After Gastric Banding and Gastric Bypass in Individuals With Type 2 Diabetes: Weight Loss Effect. AB - OBJECTIVE: The superior effect of Roux-en-Y gastric bypass (RYGB) on glucose control compared with laparoscopic adjustable gastric banding (LAGB) is confounded by the greater weight loss after RYGB. We therefore examined the effect of these two surgeries on metabolic parameters matched on small and large amounts of weight loss. RESEARCH DESIGN AND METHODS: Severely obese individuals with type 2 diabetes were tested for glucose metabolism, beta-cell function, and insulin sensitivity after oral and intravenous glucose stimuli, before and 1 year after RYGB and LAGB, and at 10% and 20% weight loss after each surgery. RESULTS: RYGB resulted in greater glucagon-like peptide 1 release and incretin effect, compared with LAGB, at any level of weight loss. RYGB decreased glucose levels (120 min and area under the curve for glucose) more than LAGB at 10% weight loss. However, the improvement in glucose metabolism, the rate of diabetes remission and use of diabetes medications, insulin sensitivity, and beta-cell function were similar after the two types of surgery after 20% equivalent weight loss. CONCLUSIONS: Although RYGB retained its unique effect on incretins, the superiority of the effect of RYGB over that of LAGB on glucose metabolism, which is apparent after 10% weight loss, was attenuated after larger weight loss. PMID- 27999006 TI - Comment on Pinsker et al. Randomized Crossover Comparison of Personalized MPC and PID Control Algorithms for the Artificial Pancreas. Diabetes Care 2016;39:1135 1142. PMID- 27999008 TI - Comment on: Benchmarking of methods for identification of antimicrobial resistance genes in bacterial whole genome data. PMID- 27999007 TI - Response to Comment on Pinsker et al. Randomized Crossover Comparison of Personalized MPC and PID Control Algorithms for the Artificial Pancreas. Diabetes Care 2016;39:1135-1142. PMID- 27999009 TI - Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs. AB - Background: Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model. Methods: In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated. Results: Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses. Conclusions: PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients. PMID- 27999010 TI - Pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus-coinfected patients with liver cirrhosis. AB - Objectives: To evaluate the plasma trough concentrations ( C trough ) of dolutegravir and rilpivirine used in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus (HCV)-coinfected patients with liver cirrhosis. Virological efficacy and safety of both ART and anti-HCV therapy were assessed. Patients and methods: A prospective observational study in HIV/HCV-coinfected patients with liver cirrhosis on ART with dolutegravir plus rilpivirine and treated with simeprevir plus sofosbuvir (+/-ribavirin) was conducted. Dolutegravir, rilpivirine, GS-331007 (sofosbuvir metabolite) and simeprevir C trough were evaluated with a validated HPLC method at anti-HCV treatment baseline and weeks 2 and 4. Geometric means were calculated to summarize C trough values. Results: Twelve patients were evaluated: 75% were males and the median (IQR) age was 53 (53-55) years. All patients were Child-Pugh stage A, except one who was stage B. The geometric mean (95% CI) of C trough of rilpivirine and dolutegravir did not change between baseline and week 4 ( P = 0.654 and P = 0.268, respectively), with corresponding overall values of 135 (102-177) and 1357 (970 1897) ng/mL. The overall geometric mean (95% CI) of GS-331007 and simeprevir C trough was 370 (268-512) and 2537 (1569-4101) ng/mL, respectively, without significant variation between weeks 2 and 4 ( P = 0.643 and P = 0.179, respectively). All patients completed anti-HCV treatment, achieving sustained virological response. All but two patients maintained undetectable HIV-RNA up to post-treatment week 24. Conclusions: Dolutegravir and rilpivirine C trough appeared not to be affected by concomitant treatment with simeprevir plus sofosbuvir in these HIV/HCV-coinfected patients with liver cirrhosis, supporting the use of this antiretroviral regimen in this setting. PMID- 27999011 TI - Intrinsic rifamycin resistance of Mycobacterium abscessus is mediated by ADP ribosyltransferase MAB_0591. AB - OBJECTIVES: Rifampicin, a potent first-line TB drug of the rifamycin group, shows only little activity against the emerging pathogen Mycobacterium abscessus. Reportedly, bacterial resistance to rifampicin is associated with polymorphisms in the target gene rpoB or the presence of enzymes that modify and thereby inactivate rifampicin. The aim of this study was to investigate the role of the MAB_0591 (arrMab)-encoded rifampicin ADP-ribosyltransferase (Arr_Mab) in innate high-level rifampicin resistance in M. abscessus. METHODS: Recombinant Escherichia coli and Mycobacterium tuberculosis strains expressing MAB_0591 were generated, as was an M. abscessus deletion mutant deficient for MAB_0591. MIC assays were used to study susceptibility to rifampicin and C25 carbamate-modified rifamycin derivatives. RESULTS: Heterologous expression of MAB_0591 conferred rifampicin resistance to E. coli and M. tuberculosis Rifamycin MIC values were consistently lower for the M. abscessus DeltaarrMab mutant as compared with the M. abscessus ATCC 19977 parental type strain. The rifamycin WT phenotype was restored after complementation of the M. abscessus DeltaarrMab mutant with arrMab Further MIC data demonstrated that a C25 modification increases rifamycin activity in WT M. abscessus However, MIC studies in the M. abscessus DeltaarrMab mutant suggest that C25 modified rifamycins are still subject to modification by Arr_Mab CONCLUSIONS: Our findings identify Arr_Mab as the major innate rifamycin resistance determinant of M. abscessus. Our data also indicate that Arr_Mab mediated rifamycin resistance in M. abscessus can only in part be overcome by C25 carbamate modification. PMID- 27999012 TI - High rate of slowly-killed-by-ampicillin phenotype among group B streptococci with reduced penicillin susceptibility. PMID- 27999013 TI - Pharmacological inhibition of p110delta subunit of PI3K confers protection against experimental leishmaniasis. AB - OBJECTIVES: This study aimed to evaluate the immuno-prophylactic and -therapeutic effect of p110delta-specific pharmacological inhibitors (CAL-101 and IC87114), either alone or in combination with amphotericin B, against experimental cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). METHODS: Female BALB/c mice were infected intravenously with Leishmania donovani or subcutaneously with Leishmania major Prophylactic treatment was initiated 24 h prior to infection, whereas therapeutic treatments with or without amphotericin B were initiated either 1 week or 2 weeks post-infection. At different times post infection, mice were sacrificed and parasite burden, regulatory T cell (Treg) numbers and cytokine production were assessed in the liver, spleen, draining lymph nodes and footpads. In addition, direct cytolytic effects of the inhibitors on parasite growth in axenic cultures and inside infected and uninfected macrophages were also assessed. RESULTS: Prophylactic and therapeutic administration of p110delta pharmacological inhibitors significantly reduced cutaneous lesion (in CL) and parasite burdens (in VL and CL) in the spleens, livers and footpads of infected mice. The reduction in parasite burden was associated with a concomitant reduction in Treg numbers and cytokine production by liver, spleen and lymph node cells. Combined low-dose CAL-101 and amphotericin B therapy caused complete clearance of parasites in mice infected with L. donovani CONCLUSIONS: Our studies clearly show a novel therapeutic option for leishmaniasis based on CAL-101 monotherapy or CAL-101 and amphotericin B combination therapy. These observations have important and direct implications for antimicrobial immunotherapy and drug/vaccine development against leishmaniasis. PMID- 27999014 TI - A validated bioluminescence-based assay for the rapid determination of the initial rate of kill for discovery antimalarials. AB - Objectives: A future treatment for uncomplicated malaria will contain at least one component that exerts a rapid rate of kill. We describe here the validation and application of a simple, robust and rapid bioluminescence-based assay for the determination of the initial rate of kill in intra-erythrocytic asexual stages of Plasmodium falciparum . Methods: A modification to the concentration-response bioluminescence [here termed bioluminescence relative rate of kill (BRRoK)] assay, utilizing exposure to fold-IC 50 concentrations (0.33* to 9*), was used to monitor the immediate cytocidal effect of 372 open-source compounds for antimalarial drug discovery available through the Medicines for Malaria Venture Malaria Box. Results: Antimalarial drugs that exert a rapid cytocidal effect produce a concentration-dependent loss of bioluminescence signal that correlates with available in vitro and in vivo estimates of parasite clearance time and parasite reduction ratio. Following the measurement of IC 50 for the Malaria Box compounds in Dd2 luc , the BRRoK assay was used to identify and rank 372 compounds for their initial cytocidal activity. Fifty-three compounds in the Malaria Box show an initial relative rate of kill greater than that of chloroquine, with 17 of these having an initial relative rate of kill greater than that of dihydroartemisinin. Conclusions: The BRRoK assay provides a rapid assay format for the estimation of a key pharmacodynamic property of antimalarial drug action. The simplicity and robustness of the assay suggests it would be readily scalable for high-throughput screening and a critical decision-making tool for antimalarial drug development. PMID- 27999015 TI - A single dose of epidermicin NI01 is sufficient to eradicate MRSA from the nares of cotton rats. AB - Objectives: To investigate the efficacy of a potent novel antimicrobial protein of mass 6 kDa, epidermicin NI01, for eradicating the nasal burden of MRSA in a cotton rat ( Sigmodon hispidus ) model. Methods: MRSA strain ATCC 43300 was used to establish a robust colonization of cotton rat nares. This model was used to evaluate the efficacy of topical 0.04% and 0.2% epidermicin NI01, administered twice daily for 3 days consecutively, and topical 0.8% epidermicin NI01 administered once, for reducing nasal MRSA burden. Control groups remained untreated or were administered vehicle only (0.5% hydroxypropylmethylcellulose) or 2% mupirocin twice daily for 3 days. The experiment was terminated at day 5 and MRSA quantitative counts were determined. Tissues recovered from animals treated with 0.2% epidermicin twice daily for 3 days were examined for histological changes. Results: Mupirocin treatment resulted in a reduction in burden of log 10 (log R) of 2.59 cfu/nares compared with vehicle ( P < 0.0001). Epidermicin NI01 administered once at 0.8% showed excellent efficacy, resulting in a log R of 2.10 cfu/nares ( P = 0.0004), which was equivalent to mupirocin. Epidermicin NI01 administered at 0.2% or 0.04% twice daily for 3 days did not have a significant impact on the tissue burden recovered from the nares. Mild to marked histological abnormalities were noted, but these were determined to be reversible. Conclusion: A single dose of topical epidermicin NI01 was as effective as mupirocin administered twice daily for 3 days in eradication of MRSA from the nares of cotton rats. This justifies further development of epidermicin for this indication. PMID- 27999016 TI - Evidence of transmission of an NDM-5-producing Klebsiella pneumoniae in a healthcare facility in New Zealand. PMID- 27999017 TI - Efficacy and tolerance of dolutegravir-based combined ART in perinatally HIV-1 infected adolescents: a French multicentre retrospective study. AB - Objectives: To assess the safety and efficacy of a dolutegravir-based regimen in perinatally HIV-1-infected adolescents. Patients and methods: We conducted a retrospective multicentre study of 50 adolescents beginning dolutegravir-based treatment regimens between January 2014 and December 2015. Clinical and biological data collected before and after dolutegravir initiation were analysed. The primary endpoint was the proportion of patients achieving a plasma viral load (PVL) <50 copies/mL within 3 months of dolutegravir initiation (for patients with detectable viraemia at baseline) and maintaining virological suppression (PVL <50 copies/mL) until the last follow-up visit (for all patients). Results: Virological suppression was noted for 17/50 adolescents at baseline. Dolutegravir based regimens maintained virological success in 14/17 patients (82%). The other three patients experienced a transient viral rebound, before PVL fell to < 50 copies/mL again, with no need to change the antiretroviral regimen. Thirty-three viraemic adolescents were enrolled. All but one had already received antiretroviral drugs. Virological success was achieved and maintained in 19/33 subjects (58%). Another three adolescents with initial virological failure had an undetectable PVL at the end of follow-up, with reinforced measures to improve compliance. Overall, sustained virological success was observed in 66% of patients and 78% of patients had an undetectable PVL at the last visit. Dolutegravir was well tolerated. Only one patient stopped treatment for severe drug-related adverse effects (dizziness and sleep disturbance). No emergence of resistance mutations was observed in patients with virological failure. Conclusions: Dolutegravir was safe and virologically effective in these patients, for whom multiple interventions were required to improve compliance. PMID- 27999018 TI - Cyclosporine A in addition to standard ART during primary HIV-1 infection: pilot randomized clinical trial. AB - Background: Initiating ART during acute/recent HIV-1 infection reduces viral reservoir formation. It has been proposed that, during this phase, the size of the viral reservoir could be further reduced by the association of immunomodulatory therapy with ART. Contradictory results have emerged, however, from two trials evaluating the impact on immune recovery and the viral reservoir of adding cyclosporine A to ART during primary HIV-1 infection. Patients and methods: Twenty patients with acute/recent HIV-1 infection were randomized to receive ART alone (tenofovir, emtricitabine and lopinavir/ritonavir) or associated with 8 weeks of cyclosporine A (0.3-0.6 mg/kg twice daily). The impact on viral load, immune response and integrated and non-integrated DNA viral reservoir at 0, 8 and 36 weeks of treatment was evaluated. Results: The estimated median time from HIV-1 infection to ART onset was 63 days (IQR 53; 79.5) with 90% of patients at Fiebig V stage. No significant differences were observed in viral load decay, CD4 T cell recovery, immune response markers or the evolution of integrated DNA at week 8 (end of cyclosporine A) and week 36 between groups. However, non-integrated DNA significantly increased in the cyclosporine A arm between weeks 0 and 36. Cyclosporine A was well tolerated. Conclusions: Adding cyclosporine A to ART during acute/recent infection did not improve immune recovery. However, unintegrated DNA increased in the cyclosporine A group, suggesting an anti-integration effect, a point warranting further research (ClinicalTrials.gov Identifier: NCT00979706). PMID- 27999019 TI - Prolonged use of tedizolid in a pulmonary non-tuberculous mycobacterial infection after linezolid-induced toxicity. PMID- 27999021 TI - Development of operationalized intravenous to oral antibiotic switch criteria. AB - OBJECTIVES: Despite huge overlap in suggested criteria for a safe intravenous (iv)-to-oral antibiotic switch, there is considerable variation in their operationalization. The objective of this study was to develop a set of measurable conditions that should be met in adult hospitalized patients for a safe iv-to-oral switch. METHODS: A RAND-modified Delphi procedure was performed to develop a set of operationalized iv-to-oral switch criteria. Switch criteria and their accompanying suggested measurable conditions were extracted from the literature and appraised by a multidisciplinary expert panel during two questionnaire rounds with a face-to-face meeting between these two rounds. In a final step, the experts could approve the set of developed operationalized switch criteria. RESULTS: Seven switch criteria and 41 accompanying measurable conditions extracted from the literature were appraised. Sixteen measurable conditions that operationalize six switch criteria were selected: (i) stable systolic blood pressure; and the absence of (ii) fever, (iii) temperature <36 degrees C, (iv) malabsorption syndrome, (v) short bowel syndrome, (vi) severe gastroparesis, (vii) ileus, (viii) continuous nasogastric suction, (ix) vomiting, (x) (severe) sepsis, (xi) fasciitis necroticans, (xii) CNS infection, (xiii) Staphylococcus aureus bacteraemia, and (xiv) endovascular infection. In addition, (xv) the patient should be cooperative and (xvi) adequate antimicrobial concentration should be achievable at the site of infection by oral administration. CONCLUSIONS: These operationalized criteria can be used in daily clinical practice. Future use of these criteria in audits and as rules in clinical decision support systems will facilitate the performance and evaluation of iv-oral switch programmes. PMID- 27999020 TI - Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models. AB - Objectives: New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents. Methods: The efficacy of 1599 or 1810 was tested in combination in three increasingly advanced TB mouse models. Mice were infected by aerosol and allowed to establish acute or chronic infection, followed by treatment (<=4 weeks) with the spectinamides alone or in two- and three-drug combination regimens with existing and novel therapeutic agents. Bacteria were enumerated from lungs by plating for cfu. Results: Herein we show the following: (i) 1599 exhibits additive or synergistic activity with most of the first-line agents; (ii) 1599 in combination with rifampicin and pyrazinamide or with bedaquiline and pyrazinamide promotes significantly improved efficacy in the high-dose aerosol model; (iii) 1599 enhances efficacy of rifampicin or pyrazinamide in chronically infected BALB/c mice; and (iv) 1599 is synergistic when administered in combination with rifampicin and pyrazinamide in the C3HeB/FeJ mouse model showing caseous necrotic pulmonary lesions. Conclusions: Spectinamides were effective partner agents for multiple anti-TB agents including bedaquiline, rifampicin and pyrazinamide. None of these in vivo synergistic interactions was predicted from in vitro MIC chequerboard assays. These data support further development of the spectinamides as combination partners with existing and experimental anti-TB agents. PMID- 27999022 TI - Synergistic activity of fosfomycin, beta-lactams and peptidoglycan recycling inhibition against Pseudomonas aeruginosa. AB - OBJECTIVES: To evaluate the interconnection between peptidoglycan (PG) recycling, fosfomycin susceptibility and synergy between fosfomycin and beta-lactams in Pseudomonas aeruginosa METHODS: Fosfomycin MICs were determined by broth microdilution and Etest for a panel of 47 PAO1 mutants defective in several components of PG recycling and/or AmpC induction pathways. PAO1 fosfomycin MICs were also determined in the presence of a 5 mM concentration of the NagZ inhibitor PUGNAc. Population analysis of fosfomycin susceptibility and characterization of the resistant mutants that emerged was also performed for selected strains. Finally, fosfomycin, imipenem and fosfomycin + imipenem killing curves were assessed. RESULTS: Mutants defective in AmpG, NagZ or all three AmpD amidases showed a marked increase in fosfomycin susceptibility (at least two 2 fold dilutions with respect to WT PAO1). Moreover, PAO1 fosfomycin MICs were consistently reduced from 48 to 24 mg/L in the presence of a 5 mM concentration of PUGNAc. Fosfomycin hypersusceptibility of the ampG, nagZ and triple ampD mutants was also clearly confirmed in the performed population analysis, although the emergence of resistant mutants, through GlpT mutations, was not avoided. Synergy between fosfomycin and imipenem was evidenced for the WT strain, the AmpC hyperproducing strain (triple AmpD mutant) and the NagZ and AmpG mutants in killing curves. Moreover, regrowth of resistant mutants was not evidenced for the combination. CONCLUSIONS: PG recycling inhibitors are envisaged as useful adjuvants in the treatment of P. aeruginosa infections with beta-lactams and fosfomycin and therefore further development of these molecules is encouraged. PMID- 27999023 TI - Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: systematic review and meta analysis. AB - Background: Carbapenem-resistant Gram-negative bacteria are recognized as a cause of difficult-to-treat infections associated with high mortality. Objectives: To perform a systematic review of currently available data on distribution, characteristics and outcome associated with carbapenem-resistant bloodstream infections in adult neutropenic patients. Methods: Included studies were identified through Medline, Embase and Cochrane databases between January 1995 and April 2016. Random effect meta-analysis was used to quantify the association between carbapenem resistance and mortality and between carbapenem exposure and resistance. Results: A total of 30 studies from 21 countries were included. Overall carbapenem resistance varied from 2% to 53% (median 9%) among studies. Infections due to carbapenem-resistant Pseudomonas spp . were reported in 18 (60%) studies showing high median resistance rates (44% of all carbapenem resistant Gram-negatives and 19% of Pseudomonas isolates). Resistance of Enterobacteriaceae was less commonly reported and bloodstream infections due to carbapenem-resistant Klebsiella spp. were mainly documented from endemic areas (Greece, Italy, Israel). Carbapenem resistance in Acinetobacter spp. was reported in 9 (30%) studies (median resistance 58% of Acinetobacter isolates). Mortality rates ranged from 33% to 71% (median 50%) in patients with carbapenem-resistant infections. Carbapenem resistance appeared to correlate with mortality (OR 4.89, 95% CI 3.30-7.26) and previous exposure to carbapenems (OR 4.63, 95% CI 3.08 6.96). Conclusions: Carbapenem resistance represents a threat to neutropenic patients. In this group, resistance is likely promoted by previous carbapenem use and leads to high mortality rates. The knowledge of resistance patterns is crucial and can direct clinicians in the use of alternatives to carbapenem-based regimens. PMID- 27999024 TI - Does moderate renal impairment affect clinical outcomes in complicated intra abdominal and complicated urinary tract infections? Analysis of two randomized controlled trials with ceftolozane/tazobactam. AB - Objectives: For reasons not well understood, antibacterials can yield lower cure rates in renally impaired patients. We explored this subject for the novel antibacterial ceftolozane/tazobactam. Methods: ASPECT-complicated intra-abdominal infections (cIAIs) and ASPECT-complicated urinary tract infections (cUTIs) were randomized, double-blinded clinical trials. Analyses in moderate [creatinine clearance (CL CR ) 30-50 mL/min] and mild/no (CL CR > 50 mL/min) renal impairment (RI) patients were pre-specified as exploratory endpoints in the statistical analysis plans. We also explored variables potentially impacting outcomes in these subgroups. Clinicaltrials.gov NCT01445665/NCT01445678 and NCT01345929/NCT01345955. Results: At baseline, 4.5% (36/806) of cIAI patients and 7.3% (58/795) of cUTI patients had moderate RI. Moderate RI patients were older, had more comorbid conditions and had higher APACHE-II scores. In the cIAI microbiological intent-to-treat population, response rates were 48% and 69% in moderate RI patients receiving ceftolozane/tazobactam and meropenem, respectively; among moderate RI cIAI patients considered treatment failures, indeterminate responses were more frequent with ceftolozane/tazobactam (39%; 9/23) than meropenem (8%; 1/13). In the cUTI microbiological modified intent-to treat population, response rates were 81% and 78% in moderate RI patients receiving ceftolozane/tazobactam and levofloxacin, respectively. In both studies, response rates in moderate RI patients were similar between treatment arms in microbiologically evaluable populations, which excluded indeterminate responses due to missing data/protocol deviations (cIAI: 72.7% ceftolozane/tazobactam versus 71.4% meropenem; cUTI: 87% ceftolozane/tazobactam versus 80% levofloxacin). Conclusions: Regardless of treatment, clinical cure rates in cIAI and cUTI were lower in moderate versus mild/no RI patients. In moderate RI cIAI patients, numerical differences in response rates between treatments were attributable to imbalances in the numerical patients deemed indeterminate. PMID- 27999025 TI - Retrospective analysis of genome sequences revealed the wide dissemination of optrA in Gram-positive bacteria. PMID- 27999026 TI - Genomic islands 1 and 2 carry multiple antibiotic resistance genes in Pseudomonas aeruginosa ST235, ST253, ST111 and ST175 and are globally dispersed. PMID- 27999027 TI - Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection. AB - BACKGROUND: Recipients of faecal microbiota transplantation (FMT) in treatment of recurrent Clostridium difficile infection (RCDI) remain at markedly increased risk of re-infection with C. difficile with new antibiotic provocations. Urinary tract infections (UTIs) are common indications for antibiotics in these patients, often resulting in C. difficile re-infection. METHODS: We present a case series of 19 patients treated with parenteral aminoglycosides for UTI following FMT for RCDI. A 3 day outpatient regimen of once-daily intramuscular administration of gentamicin was used to treat 18 consecutive FMT recipients with uncomplicated UTI. One other patient was treated for a complicated UTI with intravenous amikacin. Profiling of 16S rRNA genes was used to track changes in faecal microbial community structure during this regimen in three patients. RESULTS: The protocol was highly effective in treating UTI symptoms. None of the patients suffered a re-infection with C. difficile The faecal microbial communities remained undisturbed by treatment with intramuscular administration of gentamicin. CONCLUSIONS: Despite falling out of favour in recent years, aminoglycoside antibiotics given parenterally have the advantage of minimal penetration into the gut lumen. A brief (3 day) course of parenteral gentamicin was safe and effective in curing UTI in patients at high risk of C. difficile infection without perturbing their gut microbiota. PMID- 27999028 TI - Relationship between vancomycin tolerance and clinical outcomes in Staphylococcus aureus bacteraemia. AB - BACKGROUND: Previous data have demonstrated the clinical importance of vancomycin MIC values in Staphylococcus aureus bacteraemia (SAB); however, the impact of vancomycin tolerance (VT) is unknown. OBJECTIVES: To compare the frequency of clinical failure between patients with VT and non-VT isolates in SAB. METHODS: This was a retrospective cohort study of patients with SAB, excluding treatment <48 h or polymicrobial bacteraemia. The primary outcome was clinical failure (composite of 30 day mortality, non-resolving signs and symptoms, and 60 day recurrence). Vancomycin MIC and MBC were determined by broth microdilution. The association between VT (MBC/MIC >=32) and clinical failure was evaluated by multivariable Poisson regression. RESULTS: Of the 225 patients, 26.7% had VT isolates. VT was associated with clinical failure (48.0% overall) in unadjusted analysis [68.3% (n = 41/60) versus 40.6% (n = 67/165); P < 0.001] and this relationship persisted in multivariable analysis (adjusted risk ratio, 1.74; 95% CI, 1.36-2.24; P < 0.001). The association between VT and clinical failure was also consistent within strata of methicillin susceptibility [methicillin susceptible (n = 125, risk ratio, 1.67; 95% CI, 1.20-2.32; P = 0.002); methicillin resistant (n = 100, risk ratio, 1.69; 95% CI, 1.14-2.51; P = 0.010)]. Among methicillin-susceptible SAB cases treated with beta-lactam therapy, VT remained associated with clinical failure (risk ratio, 1.77; 95% CI, 1.19-2.61; P = 0.004). CONCLUSIONS: VT was associated with clinical failure in SAB, irrespective of methicillin susceptibility or definitive treatment. VT may decrease the effectiveness of cell-wall-active therapy or be a surrogate marker of some other pathogen-specific factor associated with poor outcomes. Future research should evaluate if bactericidal non-cell-wall-active agents improve outcomes in VT SAB. PMID- 27999029 TI - Epidemiology and susceptibility to antimicrobial agents of the main Nocardia species in Spain. AB - Objectives: The aims of this study were to explore the clinical distribution, by species, of the genus Nocardia and to assess the antimicrobial susceptibilities of the 10 most prevalent species identified in Spain. Methods: Over a 10 year period (2005-14), 1119 Nocardia strains were molecularly identified and subjected to the Etest. The distribution and resistance trends over the sub-periods 2005-09 and 2010-14 were also examined. Results: Of the strains examined, 82.9% belonged to the following species: Nocardia cyriacigeorgica (25.3%), Nocardia nova (15.0%), Nocardia abscessus (12.7%), Nocardia farcinica (11.4%), Nocardia carnea (4.3%), Nocardia brasiliensis (3.5%), Nocardia otitidiscaviarum (3.1%), Nocardia flavorosea (2.6%), Nocardia rhamnosiphila (2.6%) and Nocardia transvalensis (2.4%). Their prevalence values were similar during 2005-09 and 2010-14, except for those of N. abscessus , N. farcinica and N. transvalensis , which fell significantly in the second sub-period ( P <= 0.05). The major location of isolation was the respiratory tract (~86%). Half (13/27) of all strains from the CNS were N. farcinica . Significant differences in MIC results were recorded for some species between the two sub-periods. According to the CLSI's breakpoints, low resistance rates (<=15%) were recorded for seven species with respect to cefotaxime, imipenem and tobramycin; five species showed similar rates with respect to trimethoprim/sulfamethoxazole. Linezolid and amikacin were the most frequently active agents. Conclusion: The accurate identification of the infecting species and the determination of its susceptibility to antimicrobial agents, given the large number of strains with atypical patterns, are crucial if patients with nocardiosis are to be successfully treated. PMID- 27999030 TI - Prevalence and correlates of MRSA and MSSA nasal carriage at a Ugandan regional referral hospital. AB - Background: Despite increasing antimicrobial resistance globally, data are lacking on prevalence and factors associated with Staphylococcus aureus (SA) and MRSA carriage in resource-limited settings. Objectives: To determine the prevalence of SA and MRSA nasal carriage and factors associated with carriage among Ugandan regional referral hospital patients. Methods: We enrolled a cross section of 500 adults, sampling anterior nares for SA and MRSA carriage using Cepheid Xpert SA Nasal Complete. Results: Mean age was 37 years; 321 (64%) were female and 166 (33%) were HIV infected. Overall, 316 (63%) reported risk factors for invasive SA infection; 368 (74%) reported current antibiotic use. SA was detected in 29% and MRSA in 2.8%. MRSA and MSSA carriers were less likely than SA non-carriers to be female (50% and 56% versus 68%, P = 0.03) or to have recently used beta-lactam antibiotics (43% and 65% versus 73%, P = 0.01). MRSA carriers were more likely to have open wounds than MSSA carriers and SA non-carriers (71% versus 27% and 40%, P = 0.001) and contact with pigs (21% versus 2% and 6%, P = 0.008). MRSA carriage ranged from 0% of HIV clinic participants to 8% of inpatient surgical ward participants ( P = 0.01). In multivariable logistic regression analysis, male sex was independently associated with SA carriage (OR 1.68, 95% CI 1.12-2.53, P = 0.01) and recent beta-lactam antibiotic use was associated with reduced odds of SA carriage (OR 0.61, 95% CI 0.38-0.97, P = 0.04). Conclusions: MRSA nasal carriage prevalence was low and associated with pig contact, open wounds and surgical ward admission, but not with HIV infection. PMID- 27999031 TI - MRSA in persons not living or working on a farm in a livestock-dense area: prevalence and risk factors. AB - Objectives: MRSA emerged in livestock and persons in contact with livestock is referred to as livestock-associated MRSA (LA-MRSA). We assessed the prevalence and risk factors for MRSA carriage in persons not living or working on a farm. Methods: A cross-sectional study was performed among 2492 adults living in close proximity of livestock farms. Persons working and/or living on farms were excluded. Nasal swabs were cultured using selective media. Participants completed questionnaires and the distance from the residential address to the nearest farm was calculated. The Mann-Whitney U -test was used to compare median distances. Risk factors were explored with logistic regression. Results: Fourteen persons carried MRSA (0.56%; 95% CI 0.32%-0.92%), 10 of which carried LA-MRSA of multiple locus variable-number tandem repeat analysis complex (MC) 398 (0.40%; 95% CI 0.20%-0.71%). MRSA MC 398 carriers lived significantly closer to the nearest farm than non-carriers (median: 184 versus 402 m; P < 0.01). In bivariate analyses correcting for contact with livestock, this difference remained significant. Conclusions: Although the prevalence was low, living near farms increased the risk of MRSA MC 398 carriage for persons not living or working on a farm. Further research is necessary to identify the transmission routes. PMID- 27999033 TI - Appropriate antibiotic use reduces length of hospital stay. AB - Objectives: To define appropriate antibiotic use in hospitalized adults treated for a bacterial infection, we previously developed and validated a set of six generic quality indicators (QIs) covering all steps in the process of antibiotic use. We assessed the association between appropriate antibiotic use, defined by these QIs, and length of hospital stay (LOS). Methods: An observational multicentre study in 22 hospitals in the Netherlands included 1890 adult, non-ICU patients using antibiotics for a suspected bacterial infection. Performance scores were calculated for all QIs separately (appropriate or not), and a sum score described performance on the total set of QIs. We divided the sum scores into two groups: low (0%-49%) versus high (50%-100%). Multilevel analyses, correcting for confounders, were used to correlate QI performance (single and combined) with (log-transformed) LOS and in-hospital mortality. Results: The only single QI associated with shorter LOS was appropriate intravenous-oral switch (geometric means 6.5 versus 11.2 days; P < 0.001). A high sum score was associated with a shorter LOS in the total group (10.1 versus 11.2 days; P = 0.002) and in the subgroup of community-acquired infections (9.7 versus 10.9 days; P = 0.007), but not in the subgroup of hospital-acquired infections. We found no association between performance on QIs and in-hospital mortality or readmission rate. Conclusions: Appropriate antibiotic use, defined by validated process QIs, in hospitalized adult patients with a suspected bacterial infection appears to be associated with a shorter LOS and therefore positively contributes to patient outcome and healthcare costs. PMID- 27999032 TI - Occurrence and characterization of mcr-1-harbouring Escherichia coli isolated from pigs in Great Britain from 2013 to 2015. AB - Objectives: To determine the occurrence of mcr-1 -harbouring Escherichia coli in archived pig material originating in Great Britain (GB) from 2013 to 2015 and characterize mcr-1 plasmids. Methods: Enrichment and selective culture of 387 archived porcine caecal contents and recovery from archive of 1109 E. coli isolates to identify colistin-resistant bacteria by testing for the presence of mcr-1 by PCR and RT-PCR. mcr-1 -harbouring E. coli were characterized by WGS and compared with other available mcr-1 WGS. Results: Using selective isolation following enrichment, the occurrence of mcr-1 E. coli in caeca from healthy pigs at slaughter from unique farms in GB was 0.6% (95% CI 0%-1.5%) in 2015. mcr-1 E. coli were also detected in isolates from two porcine veterinary diagnostic submissions in 2015. All isolates prior to 2015 were negative. WGS analysis of the four mcr-1 -positive E. coli indicated no other antimicrobial resistance (AMR) genes were linked to mcr-1 -plasmid-bearing contigs, despite all harbouring multiple AMR genes. The sequence similarity between mcr-1 -plasmid-bearing contigs identified and those found in GB, Chinese and South African human isolates and Danish, French and Estonian livestock-associated isolates was 90% 99%. Conclusions: mcr-1- harbouring plasmids were diverse, implying transposable elements are involved in mcr-1 transmission in GB. The low number of mcr-1 positive E. coli isolates identified suggested mcr-1 is currently uncommon in E. coli from pigs within GB. The high sequence similarity between mcr-1 plasmid draft genomes identified in pig E. coli and plasmids found in human and livestock associated isolates globally requires further investigation to understand the full implications. PMID- 27999034 TI - Sustained impact of a computer-assisted antimicrobial stewardship intervention on antimicrobial use and length of stay. AB - Objectives: : Prospective audit and feedback interventions are the core components of an antimicrobial stewardship programme. Herein, we describe the sustained impact of an antimicrobial stewardship programme, based on a novel clinical decision-support system (Antimicrobial Prescription Surveillance System; APSS), on antimicrobial use and costs, hospital length of stay (LOS) in days and the proportion of inappropriate antimicrobial prescriptions. Methods: A quasi experimental, retrospective study was conducted using interrupted time series between 2008 and 2013. Data on all hospitalized adults receiving antimicrobials were extracted from the data warehouse of a 677 bed academic centre. The intervention started in August 2010. Prospective audit and feedback interventions, led by a pharmacist, were triggered by APSS based on deviations from published and local guidelines. Changes in outcomes before and after the intervention were compared using segmented regression analysis. Results: APSS reviewed 40 605 hospitalizations for 35 778 patients who received antimicrobials. The intervention was associated with a decrease in the average LOS (level change 0.92, P < 0.01; trend -0.08, P < 0.01; intercept 11.4 days), antimicrobial consumption in DDDs/1000 inpatient days (level change -32.4, P < 0.01; trend 1.12, P < 0.02; intercept 243 DDDs per 1000 days of hospitalization), antimicrobial spending in Canadian dollars (level change -19 649, P = 0.01; trend -1881, P < 0.01; intercept $74 683) and proportion of non-concordance with local guidelines for prescribing antimicrobials (level change -2.3, P = 0.04; intercept 41%). Conclusions: The implementation of the APSS-initiated strategy was associated with a positive impact on antimicrobial use and spending, LOS and inappropriate prescriptions. The high rate of accepted interventions may have contributed to these results. PMID- 27999035 TI - Impact of vancomycin protein binding on target attainment in critically ill children: back to the drawing board? AB - Objectives: The objectives of this observational study were to investigate plasma protein binding and to evaluate target attainment rates of vancomycin therapy in critically ill children. Patients and methods: Paediatric ICU patients, in whom intravenous intermittent dosing (ID) or continuous dosing (CD) with vancomycin was indicated, were included. Covariates on unbound vancomycin fraction and concentration were tested using a linear mixed model analysis and attainment of currently used pharmacokinetic/pharmacodynamic (PK/PD) targets was evaluated. Clinicaltrials.gov: NCT02456974. Results: One hundred and eighty-eight plasma samples were collected from 32 patients. The unbound vancomycin fraction (median = 71.1%; IQR = 65.4%-79.7%) was highly variable within and between patients and significantly correlated with total protein and albumin concentration, which were both decreased in our population. Total trough concentration (ID) and total concentration (CD) were within the aimed target concentrations in 8% of patients. The targets of AUC/MIC >=400 and f AUC/MIC >=200 were achieved in 54% and 83% of patients, respectively. Unbound vancomycin concentrations were adequately predicted using the following equation: unbound vancomycin concentration (mg/L) = 5.38 + [0.71 * total vancomycin concentration (mg/L)] - [0.085 * total protein concentration (g/L)]. This final model was externally validated using 51 samples from another six patients. Conclusions: The protein binding of vancomycin in our paediatric population was lower than reported in non-critically ill adults and exhibited large variability. Higher target attainment rates were achieved when using PK/PD indices based on unbound concentrations, when compared with total concentrations. These results highlight the need for protein binding assessment in future vancomycin PK/PD research. PMID- 27999036 TI - Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors? AB - Background: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance. Objectives: Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC-p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions. Methods: Resistance information on plasma samples from 2004-12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models. Results: More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure. Conclusions: Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated. PMID- 27999037 TI - Emergence and molecular characterization of Haemophilus influenzae harbouring mef(A). PMID- 27999038 TI - Pharmacokinetics and tolerability of ABX464, a novel first-in-class compound to treat HIV infection, in healthy HIV-uninfected subjects. AB - Background: An anti-HIV compound (ABX464) has been developed with a novel mechanism of activity in that it blocks viral gene expression in cells that are already infected. Objectives: A first-in-man study was conducted to determine the pharmacokinetic and safety profiles of ABX464. This was carried out as an open label, parallel group, single ascending dose, exploratory study. Methods: Twenty four male subjects in good health without HIV infection, aged from 18 to 55 years old, with BMIs of 18-27 kg/m 2 were included. A single oral dose of ABX464 (50, 100, 150 or 200 mg) was administered on the morning of day 0 after overnight fasting, with follow-up for 45 days. Safety assessments consisted of vital signs, electrocardiogram, physical examination, laboratory tests and urinalysis. Pharmacokinetic parameters were calculated for ABX464 and its main metabolite ABX 464- N -glucuronide (ABX464-NGlc). The study was registered at https://www.clinicaltrials (trial number NCT02792686). Results: ABX464 was well tolerated; the most frequent related treatment-emergent adverse events were headaches, nausea and vomiting; they were not considered as treatment-limiting effects. ABX464's C max was observed approximately 2 h after administration in all groups. ABX464 was rapidly and substantially metabolized into ABX464-NGlc. The C max of ABX464-NGlc was observed approximately 4 h post-dose and was about 160-fold higher than that of the parent with a much longer t 1/2 (90-110 h). The ratio of metabolite to parent drug was consistent across the complete dose range. Conclusions: These studies confirmed that ABX464 is well tolerated and rapidly and substantially metabolized into ABX464-NGlc in human subjects. PMID- 27999039 TI - Detection of linezolid resistance due to the optrA gene in Enterococcus faecalis from poultry meat from the American continent (Colombia). AB - Background: Three Enterococcus isolates obtained from retail chicken collected in 2010-11 as part of the Colombian Integrated Program for Antimicrobial Resistance Surveillance (COIPARS) showed reduced susceptibility towards linezolid (MIC 8 mg/L). Objectives: This study aimed at characterizing the isolates resistant to linezolid and detecting the resistance mechanism. Methods: Strains were analysed in 2011-12 without successful detection of the resistance mechanism. All isolates were found negative for the cfr gene and no 23S rRNA mutations were detected. In 2016, with the novel resistance gene optrA being described, the WGS data were re analysed using in silico genomic tools for confirmation of species, detection of virulence and resistance genes, MLST and SNP analyses and comparison of the genetic environment with the previously published plasmid pE349. Results: : Three Enterococcus faecalis isolates were found positive for the optrA gene encoding resistance to linezolid and phenicols. Additional screening of 37 enterococci strains from the same study did not detect any further positives. Typing showed that two of the isolates belong to ST59, while the last belongs to ST489. All isolates carry genes encoding resistance to macrolide-lincosamide-streptogramin B, tetracycline and phenicols. In addition, the ST489 isolate also carries genes conferring aminoglycoside resistance and is resistant to quinolones, but no plasmid-mediated gene was detected. The optrA gene regions of the three plasmids showed high similarity to the originally reported optrA -carrying plasmid pE349. Conclusions: To the best of our knowledge, this is the first description of the optrA gene in E. faecalis isolated from poultry meat in the Americas. PMID- 27999040 TI - Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery. AB - Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis. PMID- 27999042 TI - Successful treatment of MDR Pseudomonas aeruginosa skin and soft-tissue infection with ceftolozane/tazobactam. PMID- 27999041 TI - Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo. AB - Objectives: The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-beta- lactamase (NDM-1). Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene. Methods: We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo . Results: In vitro , the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. In a murine model of lethal E. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem. Conclusions: These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem resistant infections in multiple genera of Gram-negative pathogens. PMID- 27999043 TI - Changes in the rates of Neisseria gonorrhoeae antimicrobial resistance are primarily driven by dynamic fluctuations in common gonococcal genotypes. AB - Objectives: To examine how gonococcal genotypes and associated changes over time influence rates of Neisseria gonorrhoeae antimicrobial resistance. Methods: All available N. gonorrhoeae isolates collected in New South Wales, Australia in the first half of both 2012 and 2014 were genotyped using the Agena MassARRAY iPLEX platform. Genotypic data were compared with phenotypic antimicrobial resistance profiles over time. We focused on penicillin and ciprofloxacin as significant increases in resistance to both antibiotics were observed over this time period. Results: Genotyping data were obtained for 760 and 782 isolates in 2012 and 2014, respectively. A total of 162 distinct genotypes were identified in the study, including 36 (22.2%) genotypes present in both years ( persisting genotypes), 54 (33.3%) observed in 2012 only and 72 (44.4%) observed in 2014 only (s ingle-year genotypes). Overall, persisting genotypes comprised 15 of the 20 most common genotypes, 8 of which showed a significant change in proportion from 2012 to 2014. Persisting genotypes also comprised the majority (>70%) of ciprofloxacin- and penicillin-resistant isolates in both years. Significant fluctuations in the most common persisting genotypes accounted for the majority of observed increases in both ciprofloxacin and penicillin resistance. Single-year genotypes contributed to ~20% of ciprofloxacin and penicillin resistance in each year. Conclusions: The results show that the gonococcal genotypes persisting in the study population fluctuated significantly within a 3 year period, with numerous other genotypes appearing or disappearing. It is the net effect of these changes that determines N. gonorrhoeae antimicrobial resistance levels within the population. PMID- 27999044 TI - Influence of antimicrobial susceptibility reporting on junior doctors' decision to prescribe antimicrobials inappropriately. AB - Objectives: Inappropriate antimicrobial use drives antimicrobial resistance and is a global public health problem. This study examined whether withholding antimicrobial susceptibilities in combination with interpretive comments on microbiological reports influenced the decision to inappropriately prescribe antibiotics in a controlled survey. Methods: Seventy junior doctors attending educational sessions were given one of two surveys describing four clinical case vignettes (scenarios) in which antimicrobial treatment was not indicated. They were asked to select their preferred treatment from multiple choices. In the scenarios labelled 'A', the laboratory report did not report antibiotic susceptibilities, but included comments from the microbiologist. In the scenarios labelled 'B', the laboratory report included full organism identification and susceptibility results without additional comments. Results: For scenarios 1, 2 and 3 there was a significantly higher probability ( P < 0.01) that the doctor selected an answer involving antibiotic treatment if he/she received the 'B' version of the scenario where reports included antimicrobial susceptibilities, but no interpretive comments. This was significant in both interns and more senior doctors. In scenario 4, of which there were two versions, there was no difference seen in the answers between the groups given scenario A or B. Conclusions: The results of this survey suggest that withholding antimicrobial susceptibility results in combination with interpretive comments on microbiology reports significantly influences the decision of junior doctors to prescribe antibiotics in low-acuity outpatient setting scenarios (represented in scenarios 1-3), but not in inpatient scenarios (represented in scenario 4). PMID- 27999045 TI - Emergence and dissemination of a linezolid-resistant Staphylococcus capitis clone in Europe. AB - Objectives: We investigated the epidemiological, clinical, microbiological and genetic characteristics of linezolid-resistant (LZR) Staphylococcus capitis isolates from French ICUs, and compared them with LZR S. capitis isolates from other European countries. Methods: All LZR isolates were subjected to antimicrobial susceptibility testing (AST) and the presence of cfr and optrA genes as well as mutations in the 23S rRNA and ribosomal proteins were investigated using specific PCR with sequencing. The genetic relationship between isolates was investigated using PFGE and WGS. Epidemiological data concerning LZR S. capitis were collected retrospectively in French microbiology laboratories. Results: Twenty-one LZR isolates were studied: 9 from France, 11 from Greece and 1 from Finland. All were resistant to methicillin and aminoglycosides. In addition, this unusual AST profile was identified in S. capitis isolates from seven French hospitals, and represented up to 12% of the S. capitis isolates in one centre. A G2576T mutation in 23S rRNA was identified in all isolates; cfr and optrA genes were absent. All isolates belonged to the same clone on the basis of their PFGE profiles, whatever their geographical origin. WGS found at most 212 SNPs between core genomes of the LZR isolates. Conclusions: We identified and characterized an LZR S. capitis clone disseminated in three European countries, harbouring the same multiple resistance and a G2576T mutation in the 23S rRNA. The possible unrecognized wider distribution of this clone, belonging to a species classically regarded as a low-virulence skin colonizer, is of major concern not least because of the increasing use of oxazolidinones. PMID- 27999046 TI - Rapid EUCAST disc diffusion testing of MDR Escherichia coli and Klebsiella pneumoniae: inhibition zones for extended-spectrum cephalosporins can be reliably read after 6 h of incubation. AB - Objectives: The need for rapid antibiotic susceptibility testing increases with escalating levels of antimicrobial resistance in Enterobacteriaceae. Our objective was to evaluate the accuracy of reading EUCAST disc diffusion, ROSCO ESBL and carbapenemase detection kits and the Mast Carbapenemase Activity Test (CAT-ID) disc, after 6 h of incubation. Methods: We used a collection of 128 isolates of Escherichia coli and Klebsiella pneumoniae with a wide variety of resistance mechanisms. Inhibition zones read from digital photo images with the BD KiestraTM Total Lab Automation System after 6 h of incubation were compared with standard reading, after 18 h, of the same Mueller-Hinton agar plates. Results: For WT isolates, zones were generally smaller at 6 h than at 18 h. Cefotaxime had excellent categorical agreement of 99%, despite the high number of challenge isolates. However, for some other antimicrobials, hetero-resistant subpopulations were commonly invisible at 6 h, which resulted in an unacceptable number of errors when using standard EUCAST breakpoints. Accurate ESBL detection was possible at 6 h for isolates lacking other beta-lactamases. Carbapenemase detection was not reliable after 6 h. Conclusions: Inhibition zone reading at 6 h is an accurate method for susceptibility testing of extended-spectrum cephalosporins for Enterobacteriaceae. For other antimicrobials, 6 h reading can be used for preliminary reports of clearly resistant or susceptible isolates, preferably with application of adjusted breakpoints including an area of uncertainty between susceptible and resistant values. PMID- 27999047 TI - Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator associated pneumonia caused by Pseudomonas aeruginosa. AB - Background: Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system. Methods: The mice were treated for 5 min, once daily, with placebo, 3, 10 or 30 mg/mL ME1100 or 30 mg/mL amikacin. Results: In the survival study, the survival rate was significantly improved in the 10 and 30 mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30 mg/mL ME1100 treatment group at 6 h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30 mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2 mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin. Conclusions: The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin. PMID- 27999048 TI - Pre-existent NRTI and NNRTI resistance impacts on maintenance of virological suppression in HIV-1-infected patients who switch to a tenofovir/emtricitabine/rilpivirine single-tablet regimen. AB - Objectives: To evaluate the maintenance of virological suppression (VS) in antiretroviral-treated HIV-1-suppressed patients switching to a tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV) single-tablet regimen, by considering pre-existent resistance (pRes). Methods: pRes was evaluated according to resistance on all previous plasma genotypic resistance tests. Probability and predictors of virological rebound (VR) were evaluated. Results: Three hundred and nine patients were analysed; 5.8% of them showed resistance to both NRTIs and NNRTIs, while 12.6% showed resistance to only one of these drug classes. By 72 weeks, the probability of VR was 11.3%. A higher probability of VR was found in the following groups: (i) patients with NRTI + NNRTI pRes compared with those harbouring NRTI or NNRTI pRes and with those without reverse transcriptase inhibitor pRes (39.2% versus 11.5% versus 9.4%, P < 0.0001); (ii) patients with a virus with full/intermediate resistance to both tenofovir/emtricitabine and rilpivirine compared with those having a virus with full/intermediate resistance to tenofovir/emtricitabine or rilpivirine and those having a virus fully susceptible to TDF/FTC/RPV (36.4% versus 17.8% versus 9.7%, P < 0.001); and (iii) patients with pre-therapy viraemia >500 000 copies/mL compared with those with lower viraemia levels (>500 000: 16.0%; 100 000-500 000: 9.3%; <100 000 copies/mL: 4.8%, P = 0.009). pRes and pre-therapy viraemia >500 000 copies/mL were independent predictors of VR by multivariable Cox regression. Conclusions: TDF/FTC/RPV as a treatment simplification strategy shows a very high rate of VS maintenance. The presence of pRes to both NRTIs and NNRTIs and a pre therapy viraemia >500 000 copies/mL are associated with an increased risk of VR, highlighting the need for an accurate selection of patients before simplification. PMID- 27999049 TI - Improving feedback of surveillance data on antimicrobial consumption, resistance and stewardship in England: putting the data at your Fingertips. AB - The provision of better access to and use of surveillance data is a key component of the UK 5 Year Antimicrobial Resistance (AMR) Strategy. Since April 2016, PHE has made data on practice (infection prevention and control; antimicrobial stewardship) and outcome (prevalence of AMR, antibiotic use and healthcare associated infections) available through Fingertips, a publicly accessible web tool (https://fingertips.phe.org.uk/profile/amr-local-indicators). Fingertips provides access to a wide range of public health data presented as thematic profiles, with the above data being available through the 'AMR local indicators' profile. Local data on a range of indicators can be viewed at the level of National Health Service acute trusts, Clinical Commissioning Groups or general practitioner practices, all of which can be compared with the corresponding aggregate values for England to allow benchmarking. The data can be viewed in a range of formats including an overview showing counts and rates, interactive maps, spine charts and graphs that show temporal trends over a range of time scales or allow correlations between pairs of indicators. The aim of the AMR local indicators profile on Fingertips is to support the development of local action plans to optimize antibiotic prescribing and reduce AMR and healthcare associated infections. Provision of access to relevant information in an easy to use format will help local stakeholders, including healthcare staff, commissioners, Directors of Public Health, academics and the public, to benchmark relevant local AMR data and to monitor the impact of local initiatives to tackle AMR over time. PMID- 27999050 TI - Complete genetic analysis of plasmids carrying mcr-1 and other resistance genes in an Escherichia coli isolate of animal origin. AB - Objectives: To investigate the genetic features of three plasmids recovered from an MCR-1 and ESBL-producing Escherichia coli strain, HYEC7, and characterize the transmission mechanism of mcr-1 . Methods: The genetic profiles of three plasmids were determined by PCR, S1-PFGE, Southern hybridization and WGS analysis. The ability of the mcr-1 -bearing plasmid to undergo conjugation was also assessed. The mcr-1 -bearing transposon Tn 6330 was characterized by PCR and DNA sequencing. Results: Complete sequences of three plasmids were obtained. A non conjugative phage P7-like plasmid, pHYEC7- mcr1 , was found to harbour the mcr-1 bearing transposon Tn 6330 , which could be excised from the plasmid by generating a circular intermediate harbouring mcr-1 and the IS Apl1 element. The insertion of the circular intermediate into another plasmid, pHYEC7-IncHI2, could form pHNSHP45-2, the original IncHI2-type mcr-1 -carrying plasmid that was reported. The third plasmid, pHYEC7-110, harboured two replicons, IncX1 and IncFIB, and comprised multiple antimicrobial resistance mobile elements, some of which were shared by pHYEC7-IncHI2. Conclusions: The Tn 6330 element located in the phage-like plasmid pHYEC7- mcr1 could be excised from the plasmid and formed a circular intermediate that could be integrated into plasmids containing the IS Apl1 element. This phenomenon indicated that Tn 6330 is a key element responsible for widespread dissemination of mcr-1 among various types of plasmids and bacterial chromosomes. The dissemination rate of such an element may be further enhanced upon translocation into phage-like vectors, which may also be transmitted via transduction events. PMID- 27999051 TI - Pharmacokinetic interactions between cobicistat-boosted elvitegravir and darunavir in HIV-infected patients. AB - Objectives: To evaluate if there are significant drug-drug interactions between cobicistat-boosted elvitegravir and 800 mg darunavir once daily taken simultaneously, as has been suggested previously. Methods: The study population consisted of three groups of unselected volunteers taking a regimen of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (150, 150, 200 and 300 mg, respectively) co-formulated in a single tablet plus 800 mg darunavir (group A); only co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (group B); and cobicistat-boosted darunavir (800 mg darunavir + 150 mg cobicistat) plus two nucleos(t)ide analogues (group C). Elvitegravir, cobicistat and darunavir concentrations at the end of the dosing interval ( C 24 ) were quantified using a validated LC with tandem MS method. Results: A total of 170 samples were obtained from 24, 32 and 32 patients in groups A, B and C, respectively. In group A, the elvitegravir C 24 were similar to those in group B (233.67 versus 250.39 ng/mL) ( P = 0.406) and the darunavir C 24 were similar to those in group C (1293.54 versus 1319.34 ng/mL) ( P = 0.908). The cobicistat C 24 were comparable in groups A and B (20.2 versus 20.9 ng/mL) and slightly higher in group C (27.7 ng/mL) ( P = 0.059). Conclusions: The results provide evidence of similar elvitegravir and darunavir C 24 concentrations when these drugs are co-administered as co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate plus 800 mg darunavir or dosed separately. PMID- 27999052 TI - Trimethoprim/sulfamethoxazole versus vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia: a case-control study. AB - Objectives: Therapeutic options available to treat MRSA pneumonia are limited. Trimethoprim/sulfamethoxazole is an attractive treatment because of its bactericidal anti-MRSA activity, oral and parenteral formulations and good penetration to the lung tissue. We aimed to compare the efficacy and safety of trimethoprim/sulfamethoxazole with vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia. Methods: We carried out a retrospective case-control study of all consecutive hospitalized adult patients diagnosed with MRSA pneumonia at Beilinson Hospital during 2010-15 and treated with either vancomycin or trimethoprim/sulfamethoxazole. The primary outcomes were all-cause mortality at 30 days and clinical failure at the end of treatment. In order to reduce bias affecting the decision to use a specific antibiotic and as a sensitivity analysis, a propensity-score model for choosing between vancomycin and trimethoprim/sulfamethoxazole was used. Results: We identified 42 patients with MRSA pneumonia treated with trimethoprim/sulfamethoxazole and 39 treated with vancomycin. There were no significant differences in the baseline characteristics between the groups. Vancomycin-treated patients showed significantly higher 30 day mortality on both multivariate analysis (HR = 5.28; 95% CI = 1.50-18.60; P < 0.05) and sensitivity analysis with propensity score [vancomycin 13/24 (54.1%) versus trimethoprim/sulfamethoxazole 4/24 (16.7%); P < 0.05], and higher clinical failure rates [vancomycin 23/39 (59%) versus trimethoprim/sulfamethoxazole 15/42 (35.7%); P < 0.05], also in the sensitivity analysis with propensity score [vancomycin 14/24 (58.3%) versus trimethoprim/sulfamethoxazole 6/24 (25%); P < 0.05]. The rates of side effects in both arms were comparable. Conclusions: Trimethoprim/sulfamethoxazole appears to be superior to vancomycin in the treatment of MRSA pneumonia. A large-scale randomized controlled trial is needed to evaluate these findings. PMID- 27999053 TI - Issues in antifungal stewardship: an opportunity that should not be lost. AB - Many countries have observed an increase in the incidence of invasive fungal infections (IFIs) over the past two decades with emergence of new risk factors and isolation of new fungal pathogens. Early diagnosis and appropriate antifungal treatment remain the cornerstones of successful outcomes. However, due to non specific clinical presentations and limited availability of rapid diagnostic tests, in more than half of cases antifungal treatment is inappropriate. As a result, the emergence of antifungal resistance both in yeasts and mycelial fungi is becoming increasingly common. The Delhi Chapter of the Indian Association of Medical Microbiologists (IAMM-DC) organized a 1 day workshop in collaboration with BSAC on 10 December 2015 in New Delhi to design a road map towards the development of a robust antifungal stewardship programme in the context of conditions in India. The workshop aimed at developing a road map for optimizing better outcomes in patients with IFIs while minimizing unintended consequences of antifungal use, ultimately leading to reduced healthcare costs and prevention development of resistance to antifungals. The workshop was a conclave of all stakeholders, eminent experts from India and the UK, including clinical microbiologists, critical care specialists and infectious disease physicians. Various issues in managing IFIs were discussed, including epidemiology, diagnostic and therapeutic algorithms in different healthcare settings. At the end of the deliberations, a consensus opinion and key messages were formulated, outlining a step-by-step approach to tackling the growing incidence of IFIs and antifungal resistance, particularly in the Indian scenario. PMID- 27999054 TI - Effects of isoniazid resistance on TB treatment outcomes under programmatic conditions in a high-TB and -HIV setting: a prospective multicentre study. AB - Objectives: The scale and impact of background isoniazid resistance in TB- and HIV-endemic countries requires definition to improve treatment success and guide the scale-up of isoniazid preventive therapy (IPT). We describe the effects of isoniazid resistance on TB treatment outcomes among patients with or without HIV infection in Dar es Salaam, Tanzania. Methods: A multicentre, prospective observational study was conducted among TB patients commencing WHO-recommended first-line TB treatment. In multivariate analysis we ascertained the relationship between isoniazid resistance at presentation with a composite of poor treatment outcomes (death, failure or default from TB therapy). Results: Of 861 patients, 250 (29.0%) were HIV infected and 23 (2.7%) had isoniazid resistance. Seven hundred and ninety-seven (92.6%) of the patients were successfully treated and 25 (2.9%) died. Isoniazid resistance [relative risk (RR) = 6.0; 95% CI = 1.9-18.7; P < 0.01] and HIV infection with (RR = 2.3; 95% CI = 1.0-5.2; P = 0.05) or without (RR = 3.1; 95% CI = 1.5-6.2; P < 0.01) ART were independent predictors of poor treatment outcomes. Conclusions: Background isoniazid resistance and HIV infection adversely affected TB treatment outcomes. Early laboratory detection of isoniazid resistance is important for successful TB therapy. Studies on the impact of background isoniazid resistance on the efficacy of isoniazid prophylaxis are recommended. PMID- 27999055 TI - Unravelling the dynamics of selection of multiresistant variants to integrase inhibitors in an HIV-1-infected child using ultra-deep sequencing. AB - Background: Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs). Objectives: We analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen. Methods: Longitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample. Sanger sequencing and UDS were performed on the integrase gene using Roche 454 GS-Junior. A bioinformatic workflow was developed to identify the major DRMs, accessory mutations and the linkage between mutations. Results: In Sanger sequencing and UDS, no MRV in the integrase gene was detected at baseline in either the mother or the child. The major DRM N155H conferring resistance to raltegravir and elvitegravir was detected in 4% of the sequences by week 4 using UDS, whereas it was not detected by Sanger sequencing. The double mutant E92Q + N155H, conferring resistance to the entire integrase inhibitor class, including dolutegravir, emerged at week 8 (16%) and became rapidly dominant (57% by week 13). At the last timepoint under raltegravir (week 17), Y143R emerged, leading to different resistance mutation patterns: single mutants N155H (47%) and Y143R (24%) and double mutants E92Q + N155H (13%), Y143R + N155H (2%) and E92Q + Y143R (2%). The polymorphic substitution M50I was preferentially selected on resistant variants, especially on E92Q + N155H variants. Conclusions: This case study illustrates the usefulness of UDS in detecting early MRVs and determining the dynamics of selected HIV-1 variants in longitudinal analysis. PMID- 27999056 TI - Switching from a ritonavir-boosted PI to dolutegravir as an alternative strategy in virologically suppressed HIV-infected individuals. AB - Background: Switching from PIs to dolutegravir in virologically suppressed HIV infected individuals has not been assessed. Objectives: The principal aim was to assess the evolution of bone mineral density (BMD) when switching from a ritonavir-boosted PI to dolutegravir in HIV-infected patients with osteopenia or osteoporosis. The secondary objective was to assess the antiviral efficacy and safety of the switch therapy. Methods: This randomized, multicentre study assessed changes in BMD, bone turnover markers, and antiviral efficacy and safety in 73 virologically suppressed patients with osteopenia/osteoporosis taking a ritonavir-boosted PI plus abacavir/lamivudine who were randomized to switch from PI to dolutegravir (DOLU group, n = 37) or continue with a PI (PI group, n = 36). Clinical Trials: NCT02577042. Results: One and three patients from the DOLU and PI groups, respectively, withdrew prematurely (unrelated to treatment). At 48 weeks, 97.3% versus 91.7%, respectively, maintained viral suppression (snapshot analysis, ITT, M = F). No significant differences were seen between the groups in percentage change from baseline to week 48 in femoral ( P = 0.56) and lumbar spine ( P = 0.29) BMD, although lumbar spine BMD improved by 1.43% (-1.36; 2.92) in the DOLU group [0.12% (-2.83; 2.89) in the PI group]. Bone marker values did not vary significantly. At week 48, triglycerides were lower ( P < 0.001) and HDL cholesterol higher ( P = 0.027) in the DOLU group. Conclusions: Dolutegravir + Kivexa (r) was safe and well-tolerated in virologically suppressed patients receiving a PI-based regimen. The lipid profile was better, albeit without significant changes in BMD, probably because of the short follow-up. PMID- 27999058 TI - Systematic review of public-targeted communication interventions to improve antibiotic use. AB - Background: Excessive use of antibiotics accelerates the acquisition/spread of antimicrobial resistance. A systematic review was conducted to identify the components of successful communication interventions targeted at the general public to improve antibiotic use. Methods: The databases MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library were searched. Search terms were related to the population (public, community), intervention (campaign, mass media) and outcomes (antibiotic, antimicrobial resistance). References were screened for inclusion by one author with a random subset of 10% screened by a second author. No date restrictions were applied and only articles in the English language were considered. Studies had to have a control group or be an interrupted time-series. Outcomes had to measure change in antibiotic-related prescribing/consumption and/or the public's knowledge, attitudes or behaviour. Two reviewers assessed the quality of studies. Narrative synthesis was performed. Results: Fourteen studies were included with an estimated 74-75 million participants. Most studies were conducted in the United States or Europe and targeted both the general public and clinicians. Twelve of the studies measured changes in antibiotic prescribing. There was quite strong ( P < 0.05 to >= 0.01) to very strong ( P < 0.001) evidence that interventions that targeted prescribing for RTIs were associated with decreases in antibiotic prescribing; the majority of these studies reported reductions of greater than -14% with the largest effect size reaching -30%. Conclusion: Multi-faceted communication interventions that target both the general public and clinicians can reduce antibiotic prescribing in high-income countries but the sustainability of reductions in antibiotic prescribing is unclear. PMID- 27999057 TI - Structural and mechanistic insights into the inhibition of class C beta lactamases through the adenylylation of the nucleophilic serine. AB - Objectives: : Investigation into the adenylylation of the nucleophilic serine in AmpC BER and CMY-10 extended-spectrum class C beta-lactamases. Methods: : The formation and the stability of the adenylate adduct were examined by X-ray crystallography and MS. Inhibition assays for kinetic parameters were performed by monitoring the hydrolytic activity of AmpC BER and CMY-10 using nitrocefin as a reporter substrate. The effect of adenosine 5'-(P-acetyl)monophosphate (acAMP) on the MIC of ceftazidime was tested with four Gram-negative clinical isolates. Results: : The crystal structures and MS analyses confirmed the acAMP-mediated adenylylation of the nucleophilic serine in AmpC BER and CMY-10. acAMP inhibited AmpC BER and CMY-10 through the adenylylation of the nucleophilic serine, which could be modelled as a two-step mechanism. The initial non-covalent binding of acAMP to the active site is followed by the covalent attachment of its AMP moiety to the nucleophilic serine. The inhibition efficiencies ( k inact / K I ) of acAMP against AmpC BER and CMY-10 were determined to be 320 and 140 M -1 s -1 , respectively. The combination of ceftazidime and acAMP reduced the MIC of ceftazidime against the tested bacteria. Conclusions: : Our structural and kinetic studies revealed the detailed mechanism of adenylylation of the nucleophilic serine and may serve as a starting point for the design of novel class C beta-lactamase inhibitors on the basis of the nucleotide scaffold. PMID- 27999060 TI - Fortuitous diagnosis of NDM-1-producing Acinetobacter pittii carriage in a patient from France with no recent history of travel. PMID- 27999059 TI - WalK(S221P), a naturally occurring mutation, confers vancomycin resistance in VISA strain XN108. AB - Objectives: Vancomycin-intermediate Staphylococcus aureus (VISA) strains have spread globally. We previously isolated an ST239 VISA (XN108) with a vancomycin MIC of 12 mg/L. The mechanism for XN108 resistance to vancomycin was investigated in this study. Methods: Genome comparison was performed to characterize mutations that might contribute to the XN108 resistance phenotype. The novel mutation WalK(S221P) was identified and investigated using allelic replacement experiments. Vancomycin susceptibilities, autolytic activities and morphologies of the strains were examined. Autophosphorylation activities of WalK and the WalK(S221P) mutant were determined in vitro with [lambda- 32 P]ATP, and binding activity of WalK(S221P)-activated WalR to the promoter region of its target gene lytM was determined by electrophoretic mobility shift assay. Results: Genome comparison revealed three mutations, GraS(T136I), RpoB(H481N) and WalK(S221P), which might be responsible for vancomycin resistance in XN108. The introduction of WalK(S221P) to the vancomycin-susceptible strain N315 increased its vancomycin MIC from 1.5 to 8 mg/L, whereas the allelic replacement of WalK(S221P) with the native N315 WalK allele in XN108 decreased its vancomycin MIC from 12 to 4 mg/L. The VISA strains have thickened cell walls and decreased autolysis, consistent with observed changes in the expression of genes involved in cell wall metabolism and virulence regulation. WalK(S221P) exhibited reduced autophosphorylation, which may lead to reduced phosphorylation of WalR. WalK(S221P)-phosphorylated WalR also exhibited a reduced capacity to bind to the lytM promoter. Conclusions: The naturally occurring WalK(S221P) mutation plays a key role in vancomycin resistance in XN108. PMID- 27999061 TI - From guidelines to practice: a pharmacist-driven prospective audit and feedback improvement model for peri-operative antibiotic prophylaxis in 34 South African hospitals. AB - Background: Few data exist on the implementation of process measures to facilitate adherence to peri-operative antibiotic prophylaxis (PAP) guidelines in Africa. Objectives: To implement an improvement model for PAP utilizing existing resources, in order to achieve a reduction in surgical site infections (SSIs) across a heterogeneous group of 34 urban and rural South African hospitals. Methods: A pharmacist-driven, prospective audit and feedback strategy involving change management and improvement principles was utilized. This 2.5 year intervention involved a pre-implementation phase to test a PAP guideline and a 'toolkit' at pilot sites. Following antimicrobial stewardship committee and clinician endorsement, the model was introduced in all institutions and a survey of baseline SSI and compliance rates with four process measures (antibiotic choice, dose, administration time and duration) was performed. The post implementation phase involved audit, intervention and monthly feedback to facilitate improvements in compliance. Results: For 70 weeks of standardized measurements and feedback, 24 206 surgical cases were reviewed. There was a significant improvement in compliance with all process measures (composite compliance) from 66.8% (95% CI 64.8-68.7) to 83.3% (95% CI 80.8-85.8), representing a 24.7% increase ( P < 0.0001). The SSI rate decreased by 19.7% from a mean group rate of 2.46 (95% CI 2.18-2.73) pre-intervention to 1.97 post intervention (95% CI 1.79-2.15) ( P = 0.0029). Conclusions: The implementation of process improvement initiatives and principles targeted to institutional needs utilizing pharmacists can effectively improve PAP guideline compliance and sustainable patient outcomes. PMID- 27999062 TI - 5-Hydroxyethyl-3-tetradecanoyltetramic acid represents a novel treatment for intravascular catheter infections due to Staphylococcus aureus. AB - Objectives: Biofilm infections of intravascular catheters caused by Staphylococcus aureus may be treated with catheter lock solutions (CLSs). Here we investigated the antibacterial activity, cytotoxicity and CLS potential of 5 hydroxyethyl-3-tetradecanoyltetramic acid (5HE-C14-TMA) compared with the related compounds 3-tetradecanoyltetronic (C14-TOA) and 3-tetradecanoylthiotetronic (C14 TTA), which are variants of quorum sensing signalling molecules produced by Pseudomonas aeruginosa . Methods: Antibacterial activity and mechanism of action of 5HE-C14-TMA, C14-TOA and C14-TTA were determined via MIC, bacterial killing, membrane potential and permeability assays. Susceptibility of S. aureus biofilms formed in the presence of plasma in vitro was investigated, MTT cytotoxicity testing was undertaken and cytokine release in human blood upon exposure to 5HE C14-TMA and/or S. aureus biofilms was quantified. The effectiveness of 5HE-C14 TMA as CLS therapy in vivo was assessed using a rat intravascular catheter biofilm infection model. Results: MICs of 5HE-C14-TMA, C14-TOA and C14-TTA ranged from 2 to 4 mg/L. 5HE-C14-TMA and C14-TTA were bactericidal; all three compounds perturbed the staphylococcal membrane by increasing membrane permeability, depolarized the transmembrane potential and caused ATP leakage. Cytotoxicity and haemolytic activity were compound and target cell type-dependent. 5HE-C14-TMA reduced S. aureus biofilm viability in a dose-dependent manner in vitro and in vivo and did not trigger release of cytokines in human blood, but inhibited the high levels of IL-8 and TNF-alpha induced by S. aureus biofilms. Conclusions: 5HE C14-TMA, C14-TOA and C14-TTA are membrane-active agents. 5HE-C14-TMA was the most potent, eradicating S. aureus biofilms at 512-1024 mg/L both in vitro and in vivo as a CLS. PMID- 27999064 TI - Cumulative and temporal associations between antimicrobial prescribing and community-associated Clostridium difficile infection: population-based case control study using administrative data. AB - Background: Community-associated Clostridium difficile infection (CA-CDI; defined as cases without prior hospitalization in the previous 12 weeks who were either tested outside of hospital or tested within 2 days of admission to hospital) is a major public health problem. This study estimates the magnitude of the association between temporal and cumulative prescribing of antimicrobials in primary care and CA-CDI. Methods: Three national patient-level datasets, covering CDI cases, community prescriptions and hospitalizations, were linked by the NHS Scotland unique patient identifier, the Community Health Index (CHI). All validated cases of CDI from August 2010 to July 2013 were extracted and up to six population-based controls were matched to each case from the CHI register for Scotland. Statistical analysis used conditional logistic regression. Results: The 1446 unique cases of CA-CDI were linked with 7964 age-, sex- and location-matched controls. Cumulative exposure to any antimicrobial in the previous 6 months has a monotonic dose-response association with CA-CDI. Individuals with more than 28 DDDs to any antimicrobial (19.9% of cases) had an OR of 4.4 (95% CI 3.4-5.6) compared with those unexposed. Individuals exposed to 29+ DDDs of high-risk antimicrobials (cephalosporins, clindamycin, co-amoxiclav or fluoroquinolones) had an OR of 17.9 (95% CI 7.6-42.2). Elevated CA-CDI risk following high-risk antimicrobial exposure was greatest in the first month (OR = 12.5, 95% CI 8.9 17.4), but was still present 4-6 months later (OR = 2.6, 95% CI 1.7-3.9). Cases exposed to 29+ DDDs had prescription patterns more consistent with repeated therapeutic courses, using different antimicrobials, than long-term prophylactic use. Conclusions: This analysis demonstrated temporal and dose-response associations between CA-CDI risk and antimicrobials, with an impact of exposure to high-risk antimicrobials remaining 4-6 months later. PMID- 27999063 TI - Antibiotic prescribing in patients with self-reported sore throat. AB - Objectives: To investigate the predictors of general practitioner (GP) consultation and antibiotic use in those developing sore throat. Methods: We conducted a prospective population-based cohort study on 4461 participants in two rounds (2010-11) from 1897 households. Results: Participants reported 2193 sore throat illnesses, giving a community sore throat incidence of 1.57/ person-year. 13% of sore throat illnesses led to a GP consultation and 56% of these consultations led to antibiotic use. Participants most likely to have sore throats included women and children (e.g. school compared with retirement age); adjusted incidence rate ratio (aIRR) of 1.33 and 1.52, respectively. Participants with sore throat were more likely to consult their GP if they were preschool compared with retirement age [adjusted OR (aOR) 3.22], had more days of sore throat (aOR 1.11), reported more severe pain (aOR 4.24) or reported fever (aOR 3.82). Antibiotics were more often used by chronically ill individuals (aOR 1.78), those reporting severe pain (aOR 4.14), those reporting fever (aOR 2.58) or children with earache (aOR 1.85). Among those who consulted, males and adults who reported feeling anxious were more likely to use antibiotics; aOR 1.87 and 5.36, respectively. Conclusions: Only 1 in 10 people who have a sore throat see a doctor and more than half of those attending get antibiotics. Further efforts to curb antibiotic use should focus on reducing initial GP consultations through public information promoting safe self-management, targeted at groups identified above as most likely to attend with sore throats. PMID- 27999065 TI - Electronic prescribing system design priorities for antimicrobial stewardship: a cross-sectional survey of 142 UK infection specialists. AB - Background: The implementation of electronic prescribing and medication administration (EPMA) systems is a priority for hospitals and a potential component of antimicrobial stewardship (AMS). Objectives: To identify software features within EPMA systems that could potentially facilitate AMS and to survey practising UK infection specialist healthcare professionals in order to assign priority to these software features. Methods: A questionnaire was developed using nominal group technique and transmitted via email links through professional networks. The questionnaire collected demographic data, information on priority areas and anticipated impact of EPMA. Responses from different respondent groups were compared using the Mann-Whitney U -test. Results: Responses were received from 164 individuals (142 analysable). Respondents were predominantly specialist infection pharmacists (48%) or medical microbiologists (37%). Of the pharmacists, 59% had experience of EPMA in their hospitals compared with 35% of microbiologists. Pharmacists assigned higher priority to indication prompt ( P < 0.001), allergy checker ( P = 0.003), treatment protocols ( P = 0.003), drug-indication mismatch alerts ( P = 0.031) and prolonged course alerts ( P = 0.041) and lower priority to a dose checker for adults ( P = 0.02) and an interaction checker ( P < 0.05) than microbiologists. A 'soft stop' functionality was rated essential or high priority by 89% of respondents. Potential EPMA software features were expected to have the greatest impact on stewardship, treatment efficacy and patient safety outcomes with lowest impact on Clostridium difficile infection, antimicrobial resistance and drug expenditure. Conclusions: The survey demonstrates key differences in health professionals' opinions of potential healthcare benefits of EPMA, but a consensus of anticipated positive impact on patient safety and AMS. PMID- 27999066 TI - Public health risk of antimicrobial resistance transfer from companion animals. AB - Antimicrobials are important tools for the therapy of infectious bacterial diseases in companion animals. Loss of efficacy of antimicrobial substances can seriously compromise animal health and welfare. A need for the development of new antimicrobials for the therapy of multiresistant infections, particularly those caused by Gram-negative bacteria, has been acknowledged in human medicine and a future corresponding need in veterinary medicine is expected. A unique aspect related to antimicrobial resistance and risk of resistance transfer in companion animals is their close contact with humans. This creates opportunities for interspecies transmission of resistant bacteria. Yet, the current knowledge of this field is limited and no risk assessment is performed when approving new veterinary antimicrobials. The objective of this review is to summarize the current knowledge on the use and indications for antimicrobials in companion animals, drug-resistant bacteria of concern among companion animals, risk factors for colonization of companion animals with resistant bacteria and transmission of antimicrobial resistance (bacteria and/or resistance determinants) between animals and humans. The major antimicrobial resistance microbiological hazards originating from companion animals that directly or indirectly may cause adverse health effects in humans are MRSA, methicillin-resistant Staphylococcus pseudintermedius, VRE, ESBL- or carbapenemase-producing Enterobacteriaceae and Gram-negative bacteria. In the face of the previously recognized microbiological hazards, a risk assessment tool could be applied in applications for marketing authorization for medicinal products for companion animals. This would allow the approval of new veterinary medicinal antimicrobials for which risk levels are estimated as acceptable for public health. PMID- 27999067 TI - HIV-1 diagnosis with unquantifiable viraemia: don't be naive, look for antiretroviral drugs. PMID- 27999068 TI - Linezolid: a promising option in the treatment of Gram-positives. AB - Linezolid, an oxazolidinone antimicrobial agent that acts by inhibiting protein synthesis in a unique fashion, is used in the treatment of community-acquired pneumonia, skin and soft-tissue infections and other infections caused by Gram positive bacteria including VRE and methicillin-resistant staphylococci. Currently, linezolid resistance among these pathogens remains low, commonly <1.0%, although the prevalence of antibiotic resistance is increasing in many countries. Therefore, the development of resistance by clinical isolates should prompt increased attention of clinical laboratories to routinely perform linezolid susceptibility testing for this important agent and should be taken into account when considering its therapeutic use. Considering the importance of linezolid in the treatment of infections caused by Gram-positive bacteria, this review was undertaken to optimize the clinical use of this antibiotic. PMID- 27999069 TI - Genotypic susceptibility score (GSS) and CD4+ T cell recovery in HIV-1 patients with suppressed viral load. AB - OBJECTIVES: HIV drug resistance, measured by the genotypic susceptibility score (GSS), has a deleterious effect on the virological outcome of HIV-1-infected patients. However, it is not known if GSS retains any predictive value for CD4 recovery in patients with suppressed viral load. METHODS: Four hundred and six patients on virological failure (>500 copies/mL) with GSS : <6 months prior to switch therapy who achieved undetectable plasma viral load (<50 copies/mL) within 1 year, remained undetectable >1 year on an unchanged regimen and had CD4 data available during entire follow-up were included. Adjusted and unadjusted analyses of all characteristics at switch related to CD4 recovery were made for three time frames: (i) 'switch-suppression'; (ii) 'suppression-1 year'; and (iii) 'switch-1 year'. RESULTS: Higher GSS was associated with a greater CD4 recovery between 'switch' and '1 year' in the unadjusted analysis (P = 0.010); however, the effect of GSS was no longer statistically significant after adjusting for pre-switch clinical (CD4 count and plasma viral load) and demographic variables. Furthermore, only a lower pre-switch CD4 count was associated with increased CD4 recovery in the 'suppression-1 year' period in both unadjusted and adjusted models. The main CD4 recovery occurred in 'switch-suppression' and the variables associated, both unadjusted and adjusted, were CD4 and plasma viral load at switch, maintaining a trend for GSS (P = 0.06). CONCLUSIONS: In individuals who re-suppressed HIV viraemia after switching therapy, regimens having a higher GSS were associated with improved CD4 recovery only during the period from switch to virological suppression, but, once viral load is re-suppressed, the GSS of the new regimen has no further effect on subsequent CD4 recovery. PMID- 27999070 TI - Alarming increase in pretreatment HIV drug resistance in children living in sub Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: Children have an augmented risk of pretreatment HIV drug resistance (PDR) due to exposure to antiretroviral drugs for the prevention of mother-to child transmission (PMTCT). Paediatric data are essential to evaluate the effectiveness of the restricted number of paediatric regimens currently available, but these data are scarce. METHODS: We conducted a systematic review of the literature on PDR in children (median age <=12 years) in sub-Saharan Africa. We separately extracted the proportion of children with PDR for children with and without prior PMTCT exposure, used random-effects meta-analysis to pool proportions and used meta-regression to assess subgroup differences. RESULTS: We included 19 studies representing 2617 children from 13 countries. The pooled PDR prevalence was 42.7% (95% CI 26.2%-59.1%) among PMTCT-exposed children and 12.7% (95% CI 6.7%-18.7%) among PMTCT-unexposed children (P = 0.004). The PDR prevalence in PMTCT-unexposed children increased from 0% in 2004 to 26.8% in 2013 (P = 0.009). NNRTI mutations were detected in 32.4% (95% CI 18.7%-46.1%) of PMTCT exposed children and in 9.7% (95% CI 4.6%-14.8%) of PMTCT-unexposed children; PI mutations were uncommon (<2.5%). PDR was more common in children aged <3 years compared with children aged >=3 years [40.9% (95% CI 27.6%-54.3%) versus 17.6% (95% CI 8.9%-26.3%), respectively (P = 0.025)]. CONCLUSIONS: The PDR prevalence in African children is high and rapidly increasing. Even in PMTCT-unexposed children, the most recent reports indicate that PDR is present in up to a third of children starting first-line therapy. Our data underscore the importance of initiating PI-based first-line ART in young children (<3 years of age) and suggest that older children may also benefit from this approach. PMID- 27999071 TI - In vitro activity of gentamicin as an adjunct to penicillin against biofilm group B Streptococcus. AB - OBJECTIVES: Group B Streptococcus (GBS) increasingly causes invasive disease in non-pregnant adults, particularly in elderly persons and those with underlying diseases. Combination therapy with penicillin plus gentamicin has been suggested for periprosthetic joint infection. The postulated synergism of this combination is based on experiments with planktonic bacteria. We aimed to assess the efficacy of this combination against sessile bacteria. METHODS: Four different GBS strains were used. We compared results of MICs with those of minimal biofilm eradication concentrations (MBECs), applied chequerboard assays to the MBEC device and calculated the fractional inhibitory concentration index. Synergism was evaluated with time-kill assays against bacteria adherent to cement beads, using penicillin (0.048, 0.2 and 3 mg/L), gentamicin (4 and 12.5 mg/L) and a combination thereof. Results were evaluated via colony counting after sonication of beads and scanning electron microscopy. RESULTS: MBEC/MIC ratios were 2000-4000 for penicillin and 1 4 for gentamicin. In chequerboard assays, synergism was observed in all four isolates. In time-kill assays, penicillin and 12.5 mg/L gentamicin showed synergism in two isolates. In the other two isolates 12.5 mg/L gentamicin alone was as efficient as the combination therapy. CONCLUSIONS: These in vitro investigations show activity of 12.5 mg/L gentamicin, alone or as an adjunct to penicillin, against four strains of biofilm GBS. This concentration cannot be achieved in bone with systemic administration, but can be reached if administered locally. The combination of systemic penicillin plus local gentamicin indicates a potential application in orthopaedic-device-associated GBS infections. Studies with a larger number of strains are required to confirm our results. PMID- 27999072 TI - The extracellular isoform of superoxide dismutase has a significant impact on cardiovascular ischaemia and reperfusion injury during cardiopulmonary bypass. AB - OBJECTIVES: Cardiac surgery with cardiopulmonary bypass (CPB) provokes ischaemia and reperfusion injury (IRI). Superoxide is a main mediator of IRI and is detoxified by superoxide dismutases (SODs). Extracellular SOD (SOD3) is the prevailing isoform in the cardiovascular system. Its mutation is associated with elevated risk for ischaemic heart disease as epidemiological and experimental studies suggest. We investigated the influence of SOD3 on IRI in the context of CPB and hypothesized a protective role for this enzyme. METHODS: Mutant rats with loss of SOD3 function induced by amino acid shift, SOD3-E124D, (SOD3 mutant; n = 9) were examined in a model of CPB with deep hypothermic circulatory arrest provoking global IRI and compared with SOD3 competent controls (n = 8) as well as sham animals (n = 7). SOD3 plasma activity was photometrically measured with a diazo dye-forming reagent. Activation of cardioprotective rescue pathways (p44-42 MAPK and STAT3), cleavage of PARP-1, expression of SOD isoforms (SOD1, 2 and 3) and nitric oxide metabolism were analysed on the protein level by western blot. To evaluate whether SOD3 inactivity directly affects the myocardium, we isolated adult cardiac myocytes, which underwent hypoxia prior to protein analyses. RESULTS: Relative SOD3 plasma activity in SOD3 mutant rats was significantly decreased by at least 50% compared with that in SOD3 competent controls (prior to euthanasia P = 0.008). Effectively, physiological parameters [heart rate and mean arterial pressure (MAP)] indicated a trend toward impaired handling of ischaemia and reperfusion in SOD3 mutants: after reperfusion, mean heart rate was 46 bpm lower (P = 0.083) and MAP 8 mmHg lower (P = 0.288) than that in SOD competent controls. Decreased SOD3 activity led to reduced activation of cardioprotective rescue pathways in vivo and in vitro: relative activation of p44-42 MAPK (P = 0.074) and STAT3 (P = 0.027) was more than 30% decreased in heart and aortic tissue of SOD3 mutants (activity normalized to sham control as 1). After CPB, cleavage of PARP-1 was doubled in the control group (P = 0.017), but increased 3 fold in SOD3 mutants (P = 0.002). Furthermore, 3-nitrotyrosine as a measure of decreased nitric oxide bioavailability and other SOD isoforms (SOD1 and 2) were increased. CONCLUSIONS: Collectively, SOD3 has a significant cardioprotective role in cases of IRI and directly affects the myocardium as hypothesized. Exploration of intervention strategies targeting SOD3 may provide therapeutic options against IRI and associated systemic inflammation. PMID- 27999075 TI - Spotlight on recently published ICVTS articles. PMID- 27999073 TI - Prognostic impact of tumour size in completely resected thymic epithelial tumours. AB - OBJECTIVES: The T descriptor of thymic epithelial tumours proposed by the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group as well as the Masaoka-Koga system is defined by the anatomical extent of primary tumours, regardless of their size. However, the prognostic significance of tumour size in thymic epithelial tumours has not been fully elucidated. METHODS: We evaluated the prognostic significance of tumour size in 154 consecutive patients with thymic epithelial tumours including 124 thymomas, 21 thymic carcinomas and 9 neuroendocrine tumours, who underwent complete resection between 2001 and 2014. RESULTS: Among all tumours, the median tumour size was 4.9 cm. The median thymoma, thymic carcinoma and neuroendocrine tumour sizes were 4.8, 5.7 and 5.8, respectively, although the differences were not significant. In survival analysis, the 5- and 10-year overall survival (OS) and recurrence-free survival (RFS) rates for all patients were 91 and 81%, and 80 and 69%, respectively. Under the stratification of tumour size, no trend was observed for OS, whereas RFS showed stepwise deterioration as tumour size increased. For 119 patients with Stage I disease, RFS showed deterioration as tumour size increased. Multivariate analysis revealed that tumour size >4.0 cm was an independent prognostic factor for worsening RFS (P = 0.03). CONCLUSIONS: Patients with tumours >4.0 cm showed significantly worse outcomes in RFS compared with those with smaller tumours. This relationship was also noted in patients with Stage I disease. PMID- 27999074 TI - Thymic malignancies: does size matter? PMID- 27999076 TI - HPLC Identification of Copper (II)-Trans-Resveratrol Complexes in Ethanolic Aqueous Solution. AB - Reversed-phase high-performance liquid chromatography assay with the diode array detector was applied for detection of trans-resveratrol complexes with copper (II). Two complexes with copper to resveratrol ratio 3:2 and 1:1 were identified in ethanolic-aqueous solutions in neutral and acidic conditions. The matrix assisted laser desorption ionization-time of flight mass spectrometry was used for evaluation of complexes in eluate liquid fraction. The structures of complexes were modeled by Titan, Spartan and HyperChem software. The findings obtained satisfactorily explain the chromatographic data and could provide useful an additional data about these forms in which is present trans-resveratrol in wine (free and/or forming complex with copper). PMID- 27999077 TI - Analysis of Dithiocarbamate Fungicides in Vegetable Matrices Using HPLC-UV Followed by Atomic Absorption Spectrometry. AB - A simple method combining ion-pair methylation, high-performance liquid chromatography (HPLC) analysis with detection at 272 nm and atomic absorption spectrometry was developed in order to determine 10 dithiocarbamate fungicides (Dazomet, Metam-sodium, Ferbam, Ziram, Zineb, Maneb, Mancozeb, Metiram, Nabam and Propineb) and distinguish ethylenbisdithiocarbamates (EBDTCs) Zineb, Maneb and Mancozeb in diverse matrices. This method associates reverse phase analysis by HPLC analysis with detection at 272 nm, with atomic absorption spectrometry in order to distinguish, with the same extraction protocol, Maneb, Mancozeb and Zineb. The limits of detection (0.4, 0.8, 0.5, 1.25 and 1.97) and quantification (1.18, 2.5, 1.52, 4.2 and 6.52) calculated in injected nanogram, respectively, for Dazomet, Metam-Na, dimethyldithiocarbamates (DMDTCs), EBDTCs and propylenebisdithiocarbamates (PBDTCs) justify the sensitivity of the method used. The coefficients of determination R2 were 0.9985, 0.9978, 0.9949, 0.988 and 0.9794, respectively, for Dazomet, Metam-Na, DMDTCs, EBDTCs and PBDTCs, and the recovery from fortified apple and leek samples was above 90%. Results obtained with the atomic absorption method in comparison with spectrophotometric analysis focus on the importance of the atomic absorption as a complementary specific method for the distinction between different EBDTCs fungicides. PMID- 27999078 TI - Life-history correlations with seasonal cold hardiness in maritime pine. AB - PREMISE OF THE STUDY: Plants have developed mechanisms to withstand stressful environmental conditions, but the high energetic cost of these mechanisms may involve exchanges with other key functions. While trade-offs between cold hardiness and growth rates are a general assumption, we lack information regarding genetically based trade-offs between cold hardiness and other life history traits. Such information has strong implications for tree conservation and breeding, especially in the context of ongoing climate change. METHODS: We used a common garden progeny test to examine the relationships between seasonal cold hardiness and life-history traits of growth, reproduction, juvenile ontogeny, and phenology in 75 families of six maritime pine (Pinus pinaster Ait.) populations, three of continental and three of coastal origins. KEY RESULTS: We found a clear differentiation among populations with regard to cold hardiness and life-history traits. Two continental Iberian populations showed high cold tolerance and slower growth, but faster ontogenetic development in relation to both vegetative heteroblastic change in juveniles and the onset of female reproduction. The coastal populations displayed the opposite behavior, while the continental Moroccan population presented a unique combination of traits. We confirmed trade-offs between cold-hardiness and growth at the population level, but not within populations. There were no trade-offs with other life-history traits at either level. CONCLUSIONS: Relevant local adaptation syndromes were identified in the relationship between cold hardiness and life-history traits. These should be considered in developing tree management guidelines aimed at increasing productivity or adaptability under the expected conditions of climate change. PMID- 27999080 TI - A subgeneric classification of Selaginella (Selaginellaceae). AB - PREMISE OF THE STUDY: The lycophyte family Selaginellaceae includes approximately 750 herbaceous species worldwide, with the main species richness in the tropics and subtropics. We recently presented a phylogenetic analysis of Selaginellaceae based on DNA sequence data and, with the phylogeny as a framework, the study discussed the character evolution of the group focusing on gross morphology. Here we translate these findings into a new classification. METHODS: To present a robust and useful classification, we identified well-supported monophyletic groups from our previous phylogenetic analysis of 223 species, which together represent the diversity of the family with respect to morphology, taxonomy, and geographical distribution. Care was taken to choose groups with supporting morphology. KEY RESULTS: In this classification, we recognize a single genus Selaginella and seven subgenera: Selaginella, Rupestrae, Lepidophyllae, Gymnogynum, Exaltatae, Ericetorum, and Stachygynandrum. The subgenera are all well supported based on analysis of DNA sequence data and morphology. A key to the subgenera is presented. CONCLUSIONS: Our new classification is based on a well-founded hypothesis of the evolutionary relationships of Selaginella, and each subgenus can be identified by a suite of morphological features, most of them possible to study in the field. Our intention is that the classification will be useful not only to experts in the field, but also to a broader audience. PMID- 27999079 TI - Evolutionary history and gene flow of an endemic island oak: Quercus pacifica. AB - PREMISE OF THE STUDY: Understanding historical patterns of colonization and subsequent gene flow clarifies the evolutionary origins and history of endemic island species. METHODS: Here we use DNA microsatellite markers to characterize the genetic structure of the island endemic species Quercus pacifica K. Nixon & C.H. Mull., found on three of the California Channel Islands, and to examine its relationship to two mainland oaks, Q. berberidifolia and Q. dumosa. KEY RESULTS: We found that Q. pacifica is a genetically cohesive and differentiated evolutionary lineage, diverging from mainland scrub oaks in the Pleistocene with little subsequent introgression. Genetic differentiation of Q. pacifica among islands is small but significant. Both recent and historical gene flow were surprisingly high considering the disjunct distribution of Q. pacifica on islands separated by as much as 125 km of open ocean. Gene flow estimates were highest between the two northern islands and from the northern islands to Santa Catalina. While there is no evidence of recent bottlenecks, historical bottlenecks are indicated on each of the islands. CONCLUSIONS: The genetic cohesiveness of the Q. pacifica species suggests allopatric speciation on the islands with subsequent gene flow that has maintained genetic continuity over great distances. PMID- 27999082 TI - Phylogeny of Selaginellaceae: There is value in morphology after all! AB - PREMISE OF THE STUDY: The cosmopolitan lycophyte family Selaginellaceae, dating back to the Late Devonian-Early Carboniferous, is notorious for its many species with a seemingly undifferentiated gross morphology. This morphological stasis has for a long time hampered our understanding of the evolutionary history of the single genus Selaginella. Here we present a large-scale phylogenetic analysis of Selaginella, and based on the resulting phylogeny, we discuss morphological evolution in the group. METHODS: We sampled about one-third of the approximately 750 recognized Selaginella species. Evolutionary relationships were inferred from both chloroplast (rbcL) and single-copy nuclear gene data (pgiC and SQD1) using a Bayesian inference approach. The morphology of the group was studied and important features mapped onto the phylogeny. KEY RESULTS: We present an overall well-supported phylogeny of Selaginella, and the phylogenetic positions of some previously problematic taxa (i.e., S. sinensis and allies) are now resolved with strong support. We show that even though the evolution of most morphological characters involves reversals and/or parallelisms, several characters are phylogenetically informative. Seven major clades are identified, which each can be uniquely diagnosed by a suite of morphological features. There is value in morphology after all! CONCLUSIONS: Our hypothesis of the evolutionary relationships of Selaginella is well founded based on DNA sequence data, as well as morphology, and is in line with previous findings. It will serve as a firm basis for further studies on Selaginella with respect to, e.g., the poorly known alpha taxonomy, as well as evolutionary questions such as historical biogeographic reconstructions. PMID- 27999083 TI - Stability of Single-Parent Gene Expression Complementation in Maize Hybrids upon Water Deficit Stress. AB - Heterosis is the superior performance of F1 hybrids compared with their homozygous, genetically distinct parents. In this study, we monitored the transcriptomic divergence of the maize (Zea mays) inbred lines B73 and Mo17 and their reciprocal F1 hybrid progeny in primary roots under control and water deficit conditions simulated by polyethylene glycol treatment. Single-parent expression (SPE) of genes is an extreme instance of gene expression complementation, in which genes are active in only one of two parents but are expressed in both reciprocal hybrids. In this study, 1,997 genes only expressed in B73 and 2,024 genes only expressed in Mo17 displayed SPE complementation under control and water deficit conditions. As a consequence, the number of active genes in hybrids exceeded the number of active genes in the parental inbred lines significantly independent of treatment. SPE patterns were substantially more stable to expression changes by water deficit treatment than other genotype specific expression profiles. While, on average, 75% of all SPE patterns were not altered in response to polyethylene glycol treatment, only 17% of the remaining genotype-specific expression patterns were not changed by water deficit. Nonsyntenic genes that lack syntenic orthologs in other grass species, and thus evolved late in the grass lineage, were significantly overrepresented among SPE genes. Hence, the significant overrepresentation of nonsyntenic genes among SPE patterns and their stability under water limitation might suggest a function of these genes during the early developmental manifestation of heterosis under fluctuating environmental conditions in hybrid progeny of the inbred lines B73 and Mo17. PMID- 27999084 TI - CNGC2 Is a Ca2+ Influx Channel That Prevents Accumulation of Apoplastic Ca2+ in the Leaf. AB - Ca2+ is absorbed by roots and transported upward through the xylem to the apoplastic space of the leaf, after which it is deposited into the leaf cell. In Arabidopsis (Arabidopsis thaliana), the tonoplast-localized Ca2+/H+ transporters CATION EXCHANGER1 (CAX1) and CAX3 sequester Ca2+ from the cytosol into the vacuole, but it is not known what transporter mediates the initial Ca2+ influx from the apoplast to the cytosol. Here, we report that Arabidopsis CYCLIC NUCLEOTIDE-GATED CHANNEL2 (CNGC2) encodes a protein with Ca2+ influx channel activity and is expressed in the leaf areas surrounding the free endings of minor veins, which is the primary site for Ca2+ unloading from the vasculature and influx into leaf cells. Under hydroponic growth conditions, with 0.1 mm Ca2+, both Arabidopsis cngc2 and cax1cax3 loss-of-function mutants grew normally. Increasing the Ca2+ concentration to 10 mm induced H2O2 accumulation, cell death, and leaf senescence and partially suppressed the hypersensitive response to avirulent pathogens in the mutants but not in the wild type. In vivo apoplastic Ca2+ overaccumulation was found in the leaves of cngc2 and cax1cax3 but not the wild type under the 10 mm Ca2+ condition, as monitored by Oregon Green BAPTA 488 5N, a low-affinity and membrane-impermeable Ca2+ probe. Our results indicate that CNGC2 likely has no direct roles in leaf development or the hypersensitive response but, instead, that CNGC2 could mediate Ca2+ influx into leaf cells. Finally, the in vivo extracellular Ca2+ imaging method developed in this study provides a new tool for investigating Ca2+ dynamics in plant cells. PMID- 27999085 TI - The Binding Specificity of the PHD-Finger Domain of VIN3 Moderates Vernalization Response. AB - Vernalization is a response to winter cold to initiate flowering in spring. VERNALIZATION INSENSITIVE3 (VIN3) is induced by winter cold and is essential to vernalization response in Arabidopsis (Arabidopsis thaliana). VIN3 encodes a PHD finger domain that binds to modified histones in vitro. An alteration in the binding specificity of the PHD-finger domain of VIN3 results in a hypervernalization response. The hypervernalization response is achieved by increased enrichments of VIN3 and trimethylation of Histone H3 Lys 27 at the FLC locus without invoking the increased enrichment of Polycomb Repressive Complex 2. Our result shows that the binding specificity of the PHD-finger domain of VIN3 plays a role in mediating a proper vernalization response in Arabidopsis. PMID- 27999087 TI - Selye's general adaptation syndrome: stress-induced gastro-duodenal ulceration and inflammatory bowel disease. AB - Hans Selye in a note to Nature in 1936 initiated the field of stress research by showing that rats exposed to nocuous stimuli responded by way of a 'general adaptation syndrome' (GAS). One of the main features of the GAS was the 'formation of acute erosions in the digestive tract, particularly in the stomach, small intestine and appendix'. This provided experimental evidence for the view based on clinical data that gastro-duodenal (peptic) ulcers could be caused by stress. This hypothesis was challenged by Marshall and Warren's Nobel Prize (2005)-winning discovery of a causal association between Helicobacter pylori and peptic ulcers. However, clinical and experimental studies suggest that stress can cause peptic ulceration in the absence of H. pylori Predictably, the etiological pendulum of gastric and duodenal ulceration has swung from 'all stress' to 'all bacteria' followed by a sober realization that both factors play a role, separately as well as together. This raises the question as to whether stress and H. pylori interact, and if so, how? Stress has also been implicated in inflammatory bowel disease (IBD) and related disorders; however, there is no proof yet that stress is the primary etiological trigger for IBD. Central dopamine mechanisms seem to be involved in the stress induction of peptic ulceration, whereas activation of the sympathetic nervous system and central and peripheral corticotrophin-releasing factor appears to mediate stress-induced IBD. PMID- 27999086 TI - Constitutive Expression of Arabidopsis SMALL AUXIN UP RNA19 (SAUR19) in Tomato Confers Auxin-Independent Hypocotyl Elongation. AB - The plant hormone indole-3-acetic acid (IAA or auxin) mediates the elongation growth of shoot tissues by promoting cell expansion. According to the acid growth theory proposed in the 1970s, auxin activates plasma membrane H+-ATPases (PM H+ ATPases) to facilitate cell expansion by both loosening the cell wall through acidification and promoting solute uptake. Mechanistically, however, this process is poorly understood. Recent findings in Arabidopsis (Arabidopsis thaliana) have demonstrated that auxin-induced SMALL AUXIN UP RNA (SAUR) genes promote elongation growth and play a key role in PM H+-ATPase activation by inhibiting PP2C.D family protein phosphatases. Here, we extend these findings by demonstrating that SAUR proteins also inhibit tomato PP2C.D family phosphatases and that AtSAUR19 overexpression in tomato (Solanum lycopersicum) confers the same suite of phenotypes as previously reported for Arabidopsis. Furthermore, we employ a custom image-based method for measuring hypocotyl segment elongation with high resolution and a method for measuring cell wall mechanical properties, to add mechanistic details to the emerging description of auxin-mediated cell expansion. We find that constitutive expression of GFP-AtSAUR19 bypasses the normal requirement of auxin for elongation growth by increasing the mechanical extensibility of excised hypocotyl segments. In contrast, hypocotyl segments overexpressing a PP2C.D phosphatase are specifically impaired in auxin-mediated elongation. The time courses of auxin-induced SAUR expression and auxin-dependent elongation growth were closely correlated. These findings indicate that induction of SAUR expression is sufficient to elicit auxin-mediated expansion growth by activating PM H+-ATPases to facilitate apoplast acidification and mechanical wall loosening. PMID- 27999088 TI - Interplay between the endocrine and circadian systems in fishes. AB - The circadian system is responsible for the temporal organisation of physiological functions which, in part, involves daily cycles of hormonal activity. In this review, we analyse the interplay between the circadian and endocrine systems in fishes. We first describe the current model of fish circadian system organisation and the basis of the molecular clockwork that enables different tissues to act as internal pacemakers. This system consists of a net of central and peripherally located oscillators and can be synchronised by the light-darkness and feeding-fasting cycles. We then focus on two central neuroendocrine transducers (melatonin and orexin) and three peripheral hormones (leptin, ghrelin and cortisol), which are involved in the synchronisation of the circadian system in mammals and/or energy status signalling. We review the role of each of these as overt rhythms (i.e. outputs of the circadian system) and, for the first time, as key internal temporal messengers that act as inputs for other endogenous oscillators. Based on acute changes in clock gene expression, we describe the currently accepted model of endogenous oscillator entrainment by the light-darkness cycle and propose a new model for non-photic (endocrine) entrainment, highlighting the importance of the bidirectional cross-talking between the endocrine and circadian systems in fishes. The flexibility of the fish circadian system combined with the absence of a master clock makes these vertebrates a very attractive model for studying communication among oscillators to drive functionally coordinated outputs. PMID- 27999089 TI - Acute effect of exercise intensity and duration on acylated ghrelin and hunger in men. AB - Acute exercise transiently suppresses the orexigenic gut hormone acylated ghrelin, but the extent to which exercise intensity and duration determine this response is not fully understood. The effects of manipulating exercise intensity and duration on acylated ghrelin concentrations and hunger were examined in two experiments. In experiment one, nine healthy males completed three, 4-h conditions (control, moderate-intensity running (MOD) and vigorous-intensity running (VIG)), with an energy expenditure of ~2.5 MJ induced in both MOD (55-min running at 52% peak oxygen uptake (V.O2peak)) and VIG (36-min running at 75% V.O2peak). In experiment two, nine healthy males completed three, 9-h conditions (control, 45-min running (EX45) and 90-min running (EX90)). Exercise was performed at 70% V.O2peak In both experiments, participants consumed standardised meals, and acylated ghrelin concentrations and hunger were quantified at predetermined intervals. In experiment one, delta acylated ghrelin concentrations were lower than control in MOD (ES = 0.44, P = 0.01) and VIG (ES = 0.98, P < 0.001); VIG was lower than MOD (ES = 0.54, P = 0.003). Hunger ratings were similar across the conditions (P = 0.35). In experiment two, delta acylated ghrelin concentrations were lower than control in EX45 (ES = 0.77, P < 0.001) and EX90 (ES = 0.68, P < 0.001); EX45 and EX90 were similar (ES = 0.09, P = 0.55). Hunger ratings were lower than control in EX45 (ES = 0.20, P = 0.01) and EX90 (ES = 0.27, P = 0.001); EX45 and EX90 were similar (ES = 0.07, P = 0.34). Hunger and delta acylated ghrelin concentrations remained suppressed at 1.5 h in EX90 but not EX45. In conclusion, exercise intensity, and to a lesser extent duration, are determinants of the acylated ghrelin response to acute exercise. PMID- 27999090 TI - Biologically active recombinant carp LH as a spawning-inducing agent for carp. AB - Currently, spawning is induced in carp species by carp pituitary extract (CPE) and a combination of synthetic agonist of GnRH combined with a dopamine antagonist. The main goal of this study was the production of recombinant gonadotropins (GtHs) on a large scale to serve as an alternative to currently used agents. We produced carp (c) recombinant (r) Lh as a single chain in the methylotrophic yeast Pichia pastoris Lha subunit was joined with Lhb subunit with a flexible linker of three glycine-serine repeats and six Histidines to form a mature protein, the beta-subunit formed the N-terminal part and the alpha-subunit formed the C-terminal part. The ability of the rcLh to elicit biological response was tested by in vivo stimulation of estradiol (E2) and 17alpha,20beta-dihydroxy 4-pregnen-3-one (DHP) and by its in vivo potency to induce ovulation and spawning induction. rcLh tested in this work significantly enhanced both E2 and DHP secretion in a dose-dependent manner similar to the results obtained with CPE. E2 levels showed a moderate rise following the priming injection and a subsequent decrease during the rest of the trial. DHP levels were only increased after the resolving injection, approximately 5 h before spawning. At the highest dose of rcLh (350 ug/kg BW), the recombinant protein was more efficient than CPE in terms of both spawning success and fertilization rate. It is shown here that rcLh can elicit the secretion of DHP in vivo and actually trigger spawning. These novel findings introduce the potential of utilizing recombinant gonadotropins in aquaculture. PMID- 27999091 TI - Regulation of bone growth via ligand-specific activation of estrogen receptor alpha. AB - Estrogens are well known for their capacity to promote bone maturation and at high doses to induce growth plate closure and thereby stop further growth. High dose estrogen treatment has therefore been used to limit growth in extremely tall girls. However, recent data suggest that this treatment may have severe side effects, including increased risk of cancer and reduced fertility. We hypothesized that estrogenic effects in bone are mediated via ERalpha signaling. Twelve-week-old ovariectomized female C57BL/6 mice were subcutaneously injected for 4 weeks with E2 or selective ERalpha (PPT) or ERbeta (DPN) agonists. After killing, tibia and femur lengths were measured, and growth plate morphology was analyzed. E2- and PPT-treated mice had shorter tibiae and femur bones when compared to vehicle-treated controls, whereas animals treated with DPN had similar bone lengths compared to controls. Growth plate height and hypertrophic zone height were reduced in animals treated with E2 or PPT but not in those treated with DPN, supporting that the effect was mediated via ERalpha. Moreover, PCNA staining revealed suppressed proliferation of chondrocytes in the tibia growth plate in PPT- or E2-treated mice compared to controls. Our data show that estrogenic effects on bone growth and growth plate maturation are mainly mediated via ERalpha. Our findings may have direct implications for the development of new and more selective treatment modalities of extreme tall stature using selective estrogen receptor modulators that may have low side effects than high-dose E2 treatment. PMID- 27999092 TI - A theoretical study on the reactivity of the Mo/Cu-containing carbon monoxide dehydrogenase with dihydrogen. AB - The Mo/Cu-dependent CO dehydrogenase from Oligotropha carboxidovorans is an enzyme that is able to catalyze CO oxidation to CO2; moreover, it can also oxidize H2, thus eliciting a characteristic EPR signal. Interestingly, the Ag substituted enzyme form proved unable to catalyze H2 oxidation. In the present contribution, we characterized the reactivity of the enzyme with H2 by quantum chemical calculations. It was found that dihydrogen binding to the wild-type enzyme requires significant structural rearrangements of the active site Theoretical EPR spectra for plausible H2-bound models of the partially reduced, paramagnetic active site are also presented and compared with the experimental counterpart. Finally, density functional theory modeling shows that Ag substitution impairs H2 binding at the active site. PMID- 27999093 TI - A robust cosolvent-compatible halohydrin dehalogenase by computational library design. AB - To improve the applicability of halohydrin dehalogenase as a catalyst for reactions in the presence of organic cosolvents, we explored a computational library design strategy (Framework for Rapid Enzyme Stabilization by Computational libraries) that involves discovery and in silico evaluation of stabilizing mutations. Energy calculations, disulfide bond predictions and molecular dynamics simulations identified 218 point mutations and 35 disulfide bonds with predicted stabilizing effects. Experiments confirmed 29 stabilizing point mutations, most of which were located in two distinct regions, whereas introduction of disulfide bonds was not effective. Combining the best mutations resulted in a 12-fold mutant (HheC-H12) with a 28 degrees C higher apparent melting temperature and a remarkable increase in resistance to cosolvents. This variant also showed a higher optimum temperature for catalysis while activity at low temperature was preserved. Mutant H12 was used as a template for the introduction of mutations that enhance enantioselectivity or activity. Crystal structures showed that the structural changes in the H12 mutant mostly agreed with the computational predictions and that the enhanced stability was mainly due to mutations that redistributed surface charges and improved interactions between subunits, the latter including better interactions of water molecules at the subunit interfaces. PMID- 27999095 TI - A Case Report of Fatal Desmethyl Carbodenafil Toxicity. AB - We present the case report of a 34-year-old Hispanic male who was found unresponsive in the carport of his residence. Surveillance video footage from a security camera showed that he collapsed as he was walking to his vehicle. The decedent had no medical history and no history of illicit drug use. Initial toxicology testing revealed no alcohol or illicit drugs. Autopsy findings indicated a need for additional toxicological analysis due to a lack of trauma and the paucity of pathophysiologically significant natural disease. Liquid chromatography time-of-flight mass spectrometry of postmortem blood revealed the presence of two large peaks corresponding to desmethyl carbodenafil, an unapproved sildenafil analogue and its hydroxy metabolite. Species that are probable desmethyl and hydroxydesmethyl metabolites of desmethyl carbodenafil were also found. The mass and retention time of the parent compound in the decedent's sample were matched to those of a commercial standard. Based on this preliminary match, a method was developed and validated to quantify desmethyl carbodenafil in human blood. This is the first known case of fatal intoxication by desmethyl carbodenafil, a phosphodiesterase-5 inhibitor that is not approved for use in the United States. Over the past several years, retailers have issued voluntary recalls for dietary supplements marketed as sexual performance enhancers on the basis that these supplements may contain undeclared desmethyl carbodenafil. PMID- 27999096 TI - When the tax stamp covers the health warning label: conflicting 'best practices' for tobacco control policy. PMID- 27999098 TI - A Few Words of Introduction From Your New Diabetes Editorial Board. PMID- 27999094 TI - The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells. AB - Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome. PMID- 27999099 TI - Reflections on Diabetes Editorship (2012-2016). PMID- 27999100 TI - Platelet Hyperreactivity in Diabetes: Focus on GPVI Signaling-Are Useful Drugs Already Available? AB - Adults with diabetes are 2-4 times more likely to suffer from heart disease or ischemic stroke than adults without diabetes, yet standard antiplatelet therapy, which is the cornerstone for primary and secondary prevention of cardiovascular disease, fails in many patients with diabetes. Three independent but often interrelated variables that contribute to platelet hyperreactivity-high blood glucose, oxidative stress, and elevated vascular shear forces-coexist in patients with diabetes, creating a perilous concurrence of risk factors for cardiovascular events. Recent research has focused attention on the platelet-specific collagen receptor glycoprotein VI (GPVI) as a potential antithrombotic target. Signaling events downstream of GPVI are influenced by hyperglycemia, oxidative stress, and shear stress. Importantly, drugs targeting these GPVI signaling pathways are already in existence. The potential to repurpose existing drugs is a high-gain strategy for yielding new antiplatelet agents and could have particular benefit in individuals with diabetes. PMID- 27999101 TI - Back to the Future: Glomerular Hyperfiltration and the Diabetic Kidney. PMID- 27999102 TI - Getting a "GRiP" on Hypothalamic Endoplasmic Reticulum Stress to Combat Obesity. PMID- 27999103 TI - Exocrine and Endocrine Interactions in Cystic Fibrosis: A Potential Key to Understanding Insulin Secretion in Health and Disease? PMID- 27999104 TI - The Unraveling Truth About IRE1 and MicroRNAs in Diabetes. PMID- 27999105 TI - Hepatic DPP4 DNA Methylation Associates With Fatty Liver. AB - Hepatic DPP4 expression is elevated in subjects with ectopic fat accumulation in the liver. However, whether increased dipeptidyl peptidase 4 (DPP4) is involved in the pathogenesis or is rather a consequence of metabolic disease is not known. We therefore studied the transcriptional regulation of hepatic Dpp4 in young mice prone to diet-induced obesity. Already at 6 weeks of age, expression of hepatic Dpp4 was increased in mice with high weight gain, independent of liver fat content. In the same animals, methylation of four intronic CpG sites was decreased, amplifying glucose-induced transcription of hepatic Dpp4 In older mice, hepatic triglyceride content was increased only in animals with elevated Dpp4 expression. Expression and release of DPP4 were markedly higher in the liver compared with adipose depots. Analysis of human liver biopsy specimens revealed a correlation of DPP4 expression and DNA methylation to stages of hepatosteatosis and nonalcoholic steatohepatitis. In summary, our results indicate a crucial role of the liver in participation to systemic DPP4 levels. Furthermore, the data show that glucose-induced expression of Dpp4 in the liver is facilitated by demethylation of the Dpp4 gene early in life. This might contribute to early deteriorations in hepatic function, which in turn result in metabolic disease such as hepatosteatosis later in life. PMID- 27999106 TI - Effects of 13-Hour Hyperglucagonemia on Energy Expenditure and Hepatic Glucose Production in Humans. AB - Glucagon (GCG) acutely stimulates energy expenditure (EE) and hepatic glucose production (HGP) in humans, but whether these effects persist during hyperglucagonemia of longer duration is unclear. Using a prospective, randomized, single-blind, crossover study design, we therefore measured EE and rates of glucose appearance (glucose RA) during three separate infusion protocols in healthy lean males: A) 10-h overnight GCG infusion (6 ng/[kg * min]) followed by 3-h infusion of GCG, octreotide (OCT), and insulin (INS) for basal replacement; B) overnight saline (SAL) infusion followed by GCG/OCT/INS infusion; and C) overnight SAL infusion followed by SAL/OCT/INS infusion. Sleep EE, measured at 6 to 7 h of the overnight infusion, was increased 65-70 kcal/24 h in A compared with B and C. During the 3-h infusion, mean resting EE remained significantly increased in A versus C by ~50 kcal/24 h; in B, resting EE increased with a statistical trend but was not significantly greater than in C. Glucose RA increased to comparable levels in A and B. We conclude that in healthy lean males, stimulation of EE and HGP is sustained during hyperglucagonemia of longer duration when insulin secretion is inhibited. The increase in EE at the present GCG dose was of marginal clinical significance. PMID- 27999107 TI - Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes. AB - Heparanase, a protein with enzymatic and nonenzymatic properties, contributes toward disease progression and prevention. In the current study, a fortuitous observation in transgenic mice globally overexpressing heparanase (hep-tg) was the discovery of improved glucose homeostasis. We examined the mechanisms that contribute toward this improved glucose metabolism. Heparanase overexpression was associated with enhanced glucose-stimulated insulin secretion and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in hep-tg mice, with >2,000 genes differentially expressed versus control. The upregulated genes were enriched for diverse functions including cell death regulation, extracellular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple low-dose streptozotocin (STZ), hep-tg animals developed less severe hyperglycemia compared with wild-type, an effect likely related to their beta-cells being more functionally efficient. In animals given a single high dose of STZ causing severe and rapid development of hyperglycemia related to the catastrophic loss of insulin, hep-tg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of fibroblast growth factor 21 and glucagon-like peptide 1. This study uncovers the opportunity to use properties of heparanase in management of diabetes. PMID- 27999108 TI - Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I. AB - Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes. PMID- 27999109 TI - A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats. AB - The pathogenesis of human type 1 diabetes, characterized by immune-mediated damage of insulin-producing beta-cells of pancreatic islets, may involve viral infection. Essential components of the innate immune antiviral response, including type I interferon (IFN) and IFN receptor-mediated signaling pathways, are candidates for determining susceptibility to human type 1 diabetes. Numerous aspects of human type 1 diabetes pathogenesis are recapitulated in the LEW.1WR1 rat model. Diabetes can be induced in LEW.1WR1 weanling rats challenged with virus or with the viral mimetic polyinosinic:polycytidylic acid (poly I:C). We hypothesized that disrupting the cognate type I IFN receptor (type I IFN alpha/beta receptor [IFNAR]) to interrupt IFN signaling would prevent or delay the development of virus-induced diabetes. We generated IFNAR1 subunit-deficient LEW.1WR1 rats using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) genome editing and confirmed functional disruption of the Ifnar1 gene. IFNAR1 deficiency significantly delayed the onset and frequency of diabetes and greatly reduced the intensity of insulitis after poly I:C treatment. The occurrence of Kilham rat virus-induced diabetes was also diminished in IFNAR1-deficient animals. These findings firmly establish that alterations in innate immunity influence the course of autoimmune diabetes and support the use of targeted strategies to limit or prevent the development of type 1 diabetes. PMID- 27999110 TI - Subclinical Disease Burden as Assessed by Whole-Body MRI in Subjects With Prediabetes, Subjects With Diabetes, and Normal Control Subjects From the General Population: The KORA-MRI Study. AB - Detailed pathophysiological manifestations of early disease in the context of prediabetes are poorly understood. This study aimed to evaluate the extent of early signs of metabolic and cardio-cerebrovascular complications affecting multiple organs in individuals with prediabetes. Subjects without a history of stroke, coronary artery disease, or peripheral artery disease were enrolled in a case-control study nested within the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and underwent comprehensive MRI assessment to characterize cerebral parameters (white matter lesions, microbleeds), cardiovascular parameters (carotid plaque, left ventricular function, and myocardial late gadolinium enhancement [LGE]), and metabolic parameters (hepatic proton-density fat fraction [PDFF] and subcutaneous and visceral abdominal fat). Among 400 subjects who underwent MRI, 103 subjects had prediabetes and 54 had established diabetes. Subjects with prediabetes had an increased risk for carotid plaque and adverse functional cardiac parameters, including reduced early diastolic filling rates as well as a higher prevalence of LGE compared with healthy control subjects. In addition, people with prediabetes had significantly elevated levels of PDFF and total and visceral fat. Thus, subjects with prediabetes show early signs of subclinical disease that include vascular, cardiac, and metabolic changes, as measured by whole-body MRI after adjusting for cardiometabolic risk factors. PMID- 27999112 TI - Accelerated Evolution of Developmentally Biased Genes in the Tetraphenic Ant Cardiocondyla obscurior. AB - Plastic gene expression underlies phenotypic plasticity and plastically expressed genes evolve under different selection regimes compared with ubiquitously expressed genes. Social insects are well-suited models to elucidate the evolutionary dynamics of plastic genes for their genetically and environmentally induced discrete polymorphisms. Here, we study the evolution of plastically expressed genes in the ant Cardiocondyla obscurior-a species that produces two discrete male morphs in addition to the typical female polymorphism of workers and queens. Based on individual-level gene expression data from 28 early third instar larvae, we test whether the same evolutionary dynamics that pertain to plastically expressed genes in adults also pertain to genes with plastic expression during development. In order to quantify plasticity of gene expression over multiple contrasts, we develop a novel geometric measure. For genes expressed during development, we show that plasticity of expression is positively correlated with evolutionary rates. We furthermore find a strong correlation between expression plasticity and expression variation within morphs, suggesting a close link between active and passive plasticity of gene expression. Our results support the notion of relaxed selection and neutral processes as important drivers in the evolution of adaptive plasticity. PMID- 27999114 TI - Improved Management of Harlequin Ichthyosis With Advances in Neonatal Intensive Care. AB - Harlequin ichthyosis (HI) is the most severe phenotype of the autosomal recessive congenital ichthyoses. HI is caused by mutations in the lipid transporter adenosine triphosphate binding cassette A 12 (ABCA12). Neonates are born with a distinct clinical appearance, encased in a dense, platelike keratotic scale separated by deep erythematous fissures. Facial features are distorted by severe ectropion, eclabium, flattened nose, and rudimentary ears. Skin barrier function is markedly impaired, which can lead to hypernatremic dehydration, impaired thermoregulation, increased metabolic demands, and increased risk of respiratory dysfunction and infection. Historically, infants with HI did not survive beyond the neonatal period; however, recent advances in neonatal intensive care and coordinated multidisciplinary management have greatly improved survival. In this review, the authors combine the growing HI literature with their collective experiences to provide a comprehensive review of the management of neonates with HI. PMID- 27999113 TI - The Composite Regulatory Basis of the Large X-Effect in Mouse Speciation. AB - The disruption of meiotic sex chromosome inactivation (MSCI) has been proposed to be a major developmental mechanism underlying the rapid evolution of hybrid male sterility. We tested this idea by analyzing cell-specific gene expression across spermatogenesis in two lineages of house mice and their sterile and fertile reciprocal hybrids. We found pervasive disruption of sex chromosome gene expression in sterile hybrids at every stage of spermatogenesis. Failure of MSCI was developmentally preceded by increased silencing of autosomal genes, supporting the hypothesis that divergence at the hybrid incompatibility gene, Prdm9, results in increased rates of autosomal asynapsis which in turn triggers widespread silencing of unsynapsed chromatin. We also detected opposite patterns of postmeiotic overexpression or hyper-repression of the sex chromosomes in reciprocal hybrids, supporting the hypothesis that genomic conflict has driven functional divergence that leads to deleterious X-Y dosage imbalances in hybrids. Our developmental timeline also exposed more subtle patterns of mitotic misregulation on the X chromosome, a previously undocumented stage of spermatogenic disruption in this cross. These results indicate that multiple hybrid incompatibilities have converged on a common regulatory phenotype, the disrupted expression of the sex chromosomes during spermatogenesis. Collectively, these data reveal a composite regulatory basis to hybrid male sterility in mice that helps resolve the mechanistic underpinnings of the well-documented large X effect in mice speciation. We propose that the inherent sensitivity of spermatogenesis to X-linked regulatory disruption has the potential to be a major driver of reproductive isolation in species with chromosomal sex determination. PMID- 27999115 TI - The performance of deleteriousness prediction scores for rare non-protein changing single nucleotide variants in human genes. PMID- 27999116 TI - Revisiting GNRA and UNCG folds: U-turns versus Z-turns in RNA hairpin loops. AB - When thinking about RNA three-dimensional structures, coming across GNRA and UNCG tetraloops is perceived as a boon since their folds have been extensively described. Nevertheless, analyzing loop conformations within RNA and RNP structures led us to uncover several instances of GNRA and UNCG loops that do not fold as expected. We noticed that when a GNRA does not assume its "natural" fold, it adopts the one we typically associate with a UNCG sequence. The same folding interconversion may occur for loops with UNCG sequences, for instance within tRNA anticodon loops. Hence, we show that some structured tetranucleotide sequences starting with G or U can adopt either of these folds. The underlying structural basis that defines these two fold types is the mutually exclusive stacking of a backbone oxygen on either the first (in GNRA) or the last nucleobase (in UNCG), generating an oxygen-pi contact. We thereby propose to refrain from using sequences to distinguish between loop conformations. Instead, we suggest using descriptors such as U-turn (for "GNRA-type" folds) and a newly described Z-turn (for "UNCG-type" folds). Because tetraloops adopt for the largest part only two (inter)convertible turns, we are better able to interpret from a structural perspective loop interchangeability occurring in ribosomes and viral RNA. In this respect, we propose a general view on the inclination for a given sequence to adopt (or not) a specific fold. We also suggest how long-noncoding RNAs may adopt discrete but transient structures, which are therefore hard to predict. PMID- 27999117 TI - Performance of mass spectrometry steroid profiling for diagnosis of polycystic ovary syndrome. AB - STUDY QUESTION: How well does multi-analyte steroid mass spectrometry (MS) profiling classify women with and without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Our liquid chromatography MS (LC-MS) steroid profiling only minimally improves discrimination of women with and without PCOS compared with a direct testosterone immunoassay (T_IA) and the free androgen index (FAI). WHAT IS KNOWN ALREADY: Blood testosterone measured by direct (non-extraction) immunoassay overlaps between women with and without PCOS. Multi-analyte MS provides greater specificity and accuracy for steroid measurement so might improve the classification. STUDY DESIGN, SIZE, DURATION: An observational, cross-sectional study of women with PCOS (n = 152) defined by Rotterdam criteria and matched non PCOS (n = 45) control women was conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum steroid profiles of testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), androstenedione (A4), estradiol (E2), estrone (E1), 17 hydroxy progesterone (17OHP4), progesterone (P4) and cortisol were measured by LC-MS; T_IA and sex hormone binding globulin were measured by immunoassay; and FAI, calculated free testosterone (cFT) and total androgen index (TAI) were calculated. Classification was based on logistic regression with corresponding univariate and multivariate C-statistics. MAIN RESULTS AND THE ROLE OF CHANCE: Serum testosterone by immunoassay demonstrated levels more than 100% higher than that measured by LC-MS. Compared with the controls, women with PCOS had higher serum T, DHEA, A4, TAI, T_IA, cFT, FAI and E2 but not serum DHT, E1, P4, 17OHP4 or cortisol. Univariate C-statistics were highest for FAI (0.89) and T_IA (0.82) compared with other androgens (T [0.72], DHT [0.40]), pro-androgens (A4 [0.74], DHEA[0.71]) or derivatives (cFT [0.75], TAI [0.60]). For all multivariate models, the overall correct predictions (81-86%) featured high sensitivity (92-96%) but low specificity (28-43%). and substituting LC-MS steroid measurements for T_IA and FAI produced only minimal improvements in classification. LIMITATIONS REASONS FOR CAUTION: The study cohort is limited in size and only unconjugated steroids were measured. WIDER IMPLICATIONS OF THE FINDINGS: Multi-analyte steroid profiling of unconjugated circulating steroids provides only limited improvement on direct T_IA in classifying women with and without PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. PMID- 27999119 TI - Transgender men's experiences of fertility preservation: a qualitative study. AB - STUDY QUESTION: How do transgender men experience fertility preservation (FP) by cryopreservation of oocytes? SUMMARY ANSWER: The procedures required prior to oocyte cryopreservation, such as hormonal ovarian stimulation and transvaginal ultrasound (TVS), have a negative impact on gender dysphoria as they are closely linked to the men's female assigned sex at birth, which is incompatible with their current status. WHAT IS KNOWN ALREADY: Transgender persons often have high dissatisfaction with assigned sex-specific body features, such as the genital organs and androgen/oestrogen-responsive features. Thus, undergoing FP that requires genital-specific examinations, aimed at obtaining oocytes to cryopreserve, could be distressing. As no previous studies have investigated transgender men's experiences of FP involving cryopreservation of oocytes, little is known about their experience of the procedures. STUDY DESIGN, SIZE, DURATION: This is a prospective study among adult transgender men referred for FP between March 2014 and December 2015. Individual in-depth qualitative interviews were conducted shortly after FP treatment. The interviews lasted between 62 and 111 min (mean 81 min) and were digitally recorded and transcribed verbatim. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recruited on their first visit to the assisted reproduction clinic for reproductive counseling. There were 15 men, scheduled for FP, who chose to participate in the study (age 19-35); none had given birth and eight had a partner. Data were analyzed by thematic content analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The analysis resulted in three main categories: the journey to FP, reactions to the FP proceedings and strategies for coping. The referral for FP was an important part of the assessment and diagnosis and sometimes lined with frustrating waits and doubts. The reaction to the FP proceedings revealed that the genital examinations and the physical changes associated with discontinuation of testosterone or hormonal stimulation treatment triggered gender incongruence and dysphoria. However, for some, the negative expectations were not met. The participants used several coping strategies in order to manage the procedure, such as focusing on their reasons for undergoing FP, reaching out to friends and family for support and the cognitive approaches of not hating their body or using non-gendered names for their body parts. The results demonstrate the importance of contextual sensitivity during FP procedures. LIMITATIONS, REASONS FOR CAUTION: The authors have strived to be reflective about their pre-understanding of the phenomenon. The majority of the participants resided in large urban areas; it is possible that transgender men living in rural areas have different experiences. WIDER IMPLICATIONS OF THE FINDINGS: As the results are based on qualitative data from 15 transgender men, the results cannot readily be generalized to larger populations. However, the results are suggested to be applicable to other transgender men who want to undergo FP by cryopreservation of oocytes. The results show that transgender men's experience of FP places may elicit gender incongruence and gender dysphoria. However, health care personnel can alleviate distress by using a gender-neutral language and the preferred pronoun. Also, reassuringly, the men also have coping strategies of how to handle the situation. This knowledge is important to ensure adequate professional support for patients with gender dysphoria during FP. STUDY FUNDING/COMPETING INTERESTS: Swedish Society of Medicine, Stockholm County Council and Karolinska Institutet (to K.A.R.-W.). TRIAL REGISTRATION NUMBER: N/A. PMID- 27999120 TI - The Effect of mandible advancement splints in mild, moderate, and severe obstructive sleep apnea-the need for sleep registrations during follow up. AB - Objective and design: Our aim was to evaluate the effect of mandible advancement splint (MAS) in mild, moderate, and severe obstructive sleep apnea (OSA). We also determined, if and in which OSA-groups the adequate forward movement in MAS could be quantified without sleep registration for different OSA levels. A retrospective study. Settings: The effect of MAS was measured with clinical methods and by sleep registration. Participants: The series consisted of 103 patients, 75 males and 28 females (mean age 52 years) suffering from mild (32 per cent), moderate (32 per cent), or severe (36 per cent) OSA, who were treated with MAS at Helsinki University Hospital, Finland during the years 2011-2012. Seventy per cent of the patients had tried continuous positive airway pressure (CPAP) before MAS. Results: The lower the body mass index (BMI) was the bigger the probability was to get apnea/hypopnea index (AHI) values <5 per hour with MAS (P < 0.01). The total AHI decreased significantly from the baseline with MAS: 23 per hour (range 5-89) to 6 per hour (range 0.3-54), (P < 0.001). The mean oxygen desaturation index (ODI4%) improved significantly from 16 per hour (range 1-76) to 5.3 per hour (range 0.2-49), (P < 0.01), and the minimum oxygen saturation improved significantly from 84 per cent (67-91) to 87 per cent (68-93), (P < 0.01). The reduction of AHI with MAS was significantly bigger in patients with a previous CPAP experience (73 per cent) than those who did not tried CPAP therapy. The positive correlation was found between the decrease in AHI and the increase of the protrusion in MAS. Conclusion: Both sleep recordings and subjective indicators demonstrated that MAS therapy was successful in OSA based on ESS, total AHI, ODI4%, and minimum oxygen saturation values. It seems useful to increase the protrusion at its maximal clinical tolerance. An experienced dentist could make therapeutically decision concerning the follow up of MAS efficacy regardless of the result of sleep study. We suggest that MAS is a valuable treatment alternative for CPAP. However, the previous use of CPAP with MAS as well as lower baseline BMI seem to have a positive correlation with the success of MAS therapy. PMID- 27999118 TI - Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome. AB - STUDY QUESTION: Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: OCs used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs. WHAT IS KNOWN ALREADY: Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth. STUDY DESIGN, SIZE, DURATION: This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups. MAIN RESULTS AND THE ROLE OF CHANCE: With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66-0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61-0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28-3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth. LIMITATIONS, REASONS FOR CAUTION: The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTERESTS: This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures. TRIAL REGISTRATION NUMBER: Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528. PMID- 27999121 TI - Reliability of upper pharyngeal airway assessment using dental CBCT: a systematic review. AB - Background: Upper airway analysis is an often-cited use of cone beam computed tomography (CBCT) imaging in orthodontics. However, the reliability of this process in a clinical setting is largely unknown. Objective: Our objective was to systematically review the literature to evaluate the reliability of upper pharyngeal airway assessment using dental CBCT. Search methods: MEDLINE, EMBASE, Web of Science, and Google Scholar were searched through June 2015. Selection criteria: Human studies that measured reliability of upper airway assessment in patients using CBCT as part of the study protocol were considered. Data collection and analysis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was followed. Data were collected on overall study characteristics and measurements, CBCT unit and machine settings used, and examination characteristics of the included studies. Methodological quality of the included studies was evaluated. Results: Forty-two studies were evaluated, representing the CBCT scans of 956 patients. Studies included a wide variety of patients and CBCT machines with various scan settings. Only five studies were deemed high quality. The available evidence indicates that under specific restricted conditions there is moderate to excellent intra- and inter-examiner reliability. Airway volume demonstrated greater intra- and inter-examiner reliability than did minimum cross-sectional area. However, significant methodological limitations of the current literature, most importantly a lack of manual orientation of the images and selection of threshold sensitivity in study protocols, suggest that reliability has not been adequately established. Conclusions: The current literature reports moderate to excellent reliability, with airway volume having higher reliability than minimum cross-sectional area. However, only limited aspects of the process of airway analysis have been evaluated, indicating that further research is required to adequately establish the reliability of upper pharyngeal airway assessment of patients using dental CBCT. Registration: None. PMID- 27999122 TI - Spatiotemporal Dynamics of Attention Networks Revealed by Representational Similarity Analysis of EEG and fMRI. AB - The fronto-parietal attention networks have been extensively studied with functional magnetic resonance imaging (fMRI), but spatiotemporal dynamics of these networks are not well understood. We measured event-related potentials (ERPs) with electroencephalography (EEG) and collected fMRI data from identical experiments where participants performed visual and auditory discrimination tasks separately or simultaneously and with or without distractors. To overcome the low temporal resolution of fMRI, we used a novel ERP-based application of multivariate representational similarity analysis (RSA) to parse time-averaged fMRI pattern activity into distinct spatial maps that each corresponded, in representational structure, to a short temporal ERP segment. Discriminant analysis of ERP-fMRI correlations revealed 8 cortical networks-2 sensory, 3 attention, and 3 other-segregated by 4 orthogonal, temporally multifaceted and spatially distributed functions. We interpret these functions as 4 spatiotemporal components of attention: modality-dependent and stimulus-driven orienting, top down control, mode transition, and response preparation, selection and execution. PMID- 27999123 TI - Early Alterations of Hippocampal Neuronal Firing Induced by Abeta42. AB - We studied the effect of Amyloid beta 1-42 oligomers (Abeta42) on Ca2+ dependent excitability profile of hippocampal neurons. Abeta42 is one of the Amyloid beta peptides produced by the proteolytic processing of the amyloid precursor protein and participates in the initiating event triggering the progressive dismantling of synapses and neuronal circuits. Our experiments on cultured hippocampal network reveal that Abeta42 increases intracellular Ca2+ concentration by 46% and inhibits firing discharge by 19%. More precisely, Abeta42 differently regulates ryanodine (RyRs), NMDA receptors (NMDARs), and voltage gated calcium channels (VGCCs) by increasing Ca2+ release through RyRs and inhibiting Ca2+ influx through NMDARs and VGCCs. The overall increased intracellular Ca2+ concentration causes stimulation of K+ current carried by big conductance Ca2+ activated potassium (BK) channels and hippocampal network firing inhibition. We conclude that Abeta42 alters neuronal function by means of at least 4 main targets: RyRs, NMDARs, VGCCs, and BK channels. The development of selective modulators of these channels may in turn be useful for developing effective therapies that could enhance the quality of life of AD patients during the early onset of the pathology. PMID- 27999124 TI - Activity-Independent Effects of CREB on Neuronal Survival and Differentiation during Mouse Cerebral Cortex Development. AB - Neuronal survival and morphological maturation depends on the action of the transcription factor calcium responsive element binding protein (CREB), which regulates expression of several target genes in an activity-dependent manner. However, it remains largely unknown whether CREB-mediated transcription could play a role at early stages of neuronal differentiation, prior to the establishment of functional synaptic contacts. Here, we show that CREB is phosphorylated at very early stages of neuronal differentiation in vivo and in vitro, even in the absence of depolarizing agents. Using genetic tools, we also show that inhibition of CREB-signaling affects neuronal growth and survival in vitro without affecting cell proliferation and neurogenesis. Expression of A-CREB or M-CREB, 2 dominant-negative inhibitors of CREB, decreases cell survival and the complexity of neuronal arborization. Similar changes are observed in neurons treated with protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors, which also show decreased levels of pCREBSer133. Notably, expression of CREB-FY, a Tyr134Phe CREB mutant with a lower Km for phosphorylation, partly rescues the effects of PKA and CaMKII inhibition. Our data indicate that CREB-mediated signaling play important roles at early stages of cortical neuron differentiation, prior to the establishment of fully functional synaptic contacts. PMID- 27999125 TI - Delta-Band Oscillations in Motor Regions Predict Hand Selection for Reaching. AB - Current models hold that action selection is achieved by competitive interactions between co-existing motor representations associated with each potential action. Critically, selection via competition requires biasing signals to enable one of these alternatives to be selected. This study tested the hypothesis that selection is related to the prestimulus excitability of neuronal ensembles in which movements are encoded, as assessed through the phase of delta-band oscillations (2-4 Hz). Electroencephalography was recorded while participants performed speeded reaches toward appearing visual targets using the hand of their choice. The target locations were controlled such that only targets for which the left and right hands were selected equally often were used for analysis. Results revealed that hand selection as well as reach reaction times strongly depended upon the instantaneous phase of delta at the moment of target onset. This effect was maximal over contralateral motor regions, and occurred in the absence of prestimulus alpha- (8-12 Hz) and beta-band (15-30 Hz) amplitude modulations. These findings demonstrate that the excitability of motor regions acts as a modulatory factor for hand choice during reaching. They extend current models by showing that action selection is related to the underlying brain state independently of previously known decision variables. PMID- 27999126 TI - Moving target: transient rotational stenosis precipitating jugular bow hunter's syndrome. AB - A 60-year-old man presented with a 10-month history of of stereotypical spells characterized by vertigo, tinnitus, blurred vision, left hemibody numbness, and occasional syncope, precipitated by turning his head leftwards. Cerebral angiography and CT angiography of the head and neck with provocative maneuvers did not demonstrate vertebral artery narrowing. However, there was narrowing of the left internal jugular vein due to extrinsic compression from the sternocleidomastoid with leftward head rotation in the setting of hypoplasia of the right internal jugular vein. The patient underwent a cervical venogram which confirmed the finding. Manometric evaluation demonstrated a gradient of 29 mm Hg across the stenosis with the head turned leftwards compared with 1 mm Hg in the neutral position. The patient was treated with myectomies of the left sternocleidomastoid, posterior belly of the digastric, stylohyoid and omohyoid and styloid process removal. Following surgery, the patient reported complete resolution of symptoms. Repeat venography demonstrated resolution of the stenosis and pressure gradient. PMID- 27999127 TI - Bilateral choroidal detachment with exudative retinal detachment in a patient with septicaemia. AB - We present a case of bilateral choroidal and exudative retinal detachment with hypotony in a patient with septicaemia. Our patient after initial hospitalisation was treated by the local ophthalmologist as a case of sterile pan uveitis with systemic and topical steroids that did not have any effect. Our patient responded well to timely surgical intervention of choroidal drainage and vitrectomy with silicone oil tamponade followed by steroids and antibiotics. Cataract progression in both eyes occurred due to hypotony, inflammation, use of steroids and the vitreous surgery. It was successfully managed with timely surgical removal of cataract and intraocular lens implantation in both eyes facilitating early visual rehabilitation. Topical medications included frequent topical steroids and antibiotics as per our published protocols. PMID- 27999128 TI - Blue rubber bleb naevus syndrome: a rare cause of chronic occult blood loss and iron deficiency anaemia. AB - Blue rubber bleb naevus syndrome (BRBNS) is a rare vascular disorder with malformed veins, or blebs, appearing in the skin or internal organs. Gastrointestinal tract involvement is the most common feature and often subject to bleeding, potentially resulting in chronic occult blood loss and iron deficiency anaemia. We present the case of a 10-year-old boy with venous malformations on the feet and severe anaemia. Although massive sudden haemorrhage rarely occurs, awareness of the illness is necessary to prevent complications. PMID- 27999129 TI - Ascending aortic dissection presented as inferior myocardial infarction: a clinical and diagnostic mimicry. AB - Acute ST segment elevation myocardial infarction (STEMI) is typically associated with acute coronary thrombosis or plaque rupture. Rarely, STEMI can be associated with ascending aortic dissection, which represents the majority of acute aortic syndrome aetiologies and carries dreadful outcomes. Routine cardiac intervention with emergent cardiac catheterisation may lead to a higher mortality rate in this group of patients. We present a case of painless inferior STEMI in the setting of ascending aortic dissection. The patient had an inferior STEMI due to the involvement of the right coronary artery as an extension of the ascending aortic dissection. In this era of protocol-driven practice and the pressure to fulfil quality measures, we aim to alert emergency physicians, cardiologists and interventionalists of the possible presentation of painless ascending aortic dissection as an STEMI. The two pathologies characterise by crucial differences in their initial and ultimate management. PMID- 27999130 TI - Tibialis anterior muscle hernia: rare but not uncommon. AB - Muscular hernias in the lower limb are a rare entity that have seldom been described in the literature, to the extent that the seminal paper on the subject remains a case series from 1929. Here, we present a case of tibialis anterior muscle hernia and discuss the aetiology behind the same. Furthermore, we attempt to amalgamate existing knowledge to provide some guidance for investigation and management of this important diagnostic consideration. PMID- 27999131 TI - Melanoderma: uncommon presentation of a common condition. AB - A 64-year-old man presented with blackish pigmentation of skin and tongue for more than 2 years that did not improve with local remedies. He had no history of comorbid medical or surgical illnesses. General examination showed severe hyperpigmentation of skin and mucosa and also showed anaemia. Systemic examination was unremarkable except for Romberg sign and mild hyperreflexia. Adrenal insufficiency was ruled out by normal cortisol levels and haemogram showed macrocytosis with hypersegmented neutrophils suggestive of severe vitamin B12 deficiency which confirmed by low serum B12 levels. After 3 months of parenteral vitamin B12 treatment, the pigmentation and anaemia improved significantly. The mechanism of hyperpigmentation due to B12 deficiency is postulated to be increased melanin deposition in the basal layer of the epidermis. Since vitamin B12 deficiency is not uncommonly encountered in general practice, atypical presentation of this easily diagnosable and treatable condition is emphasised. PMID- 27999132 TI - Patch of hair in the hyoid region. PMID- 27999133 TI - Uterine leiomyomatosis with intracardiac extension. PMID- 27999134 TI - Letter by El-Battrawy et al Regarding Article, "Takotsubo-Like Myocardial Dysfunction in Ischemic Stroke: A Hospital-Based Registry and Systematic Literature Review". PMID- 27999135 TI - Optimal Timing of Anticoagulant Treatment After Intracerebral Hemorrhage in Patients With Atrial Fibrillation. AB - BACKGROUND AND PURPOSE: This study aims to provide observational data on the relationship between the timing of antithrombotic treatment and the competing risks of severe thrombotic and hemorrhagic events in a cohort of Swedish patients with atrial fibrillation and intracerebral hemorrhage (ICH). METHODS: Patients with atrial fibrillation and a first-ever ICH were identified in the Swedish Stroke Register, Riksstroke, 2005 to 2012. Riksstroke was linked with other national registers to find information on treatment, comorbidity, and outcome. The optimal timing of treatment in patients with low and high thromboembolic risk was described through cumulative incidence functions separately for thrombotic and hemorrhagic events and for the combined end point vascular death or nonfatal stroke. RESULTS: The study included 2619 ICH survivors with atrial fibrillation with 5759 person-years of follow-up. Anticoagulant treatment was associated with a reduced risk of vascular death and nonfatal stroke in high-risk patients with no significantly increased risk of severe hemorrhage. The benefit seemed to be greatest when treatment was started 7 to 8 weeks after ICH. For high-risk women, the total risk of vascular death or stroke recurrence within 3 years was 17.0% when anticoagulant treatment was initiated 8 weeks after ICH and 28.6% without any antithrombotic treatment (95% confidence interval for difference, 1.4% 21.8%). For high-risk men, the corresponding risks were 14.3% versus 23.6% (95% confidence interval for difference, 0.4%-18.2%). CONCLUSIONS: This nationwide observational study suggests that anticoagulant treatment may be initiated 7 to 8 weeks after ICH in patients with atrial fibrillation to optimize the benefit from treatment and minimize risk. PMID- 27999136 TI - Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model. AB - BACKGROUND AND PURPOSE: Multilineage-differentiating stress-enduring (muse) cells are endogenous nontumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3+ cells from the bone marrow from cultured bone marrow mesenchymal stem cells. After transplantation into neurological disease models, muse cells exert repair effects, but the exact mechanism remains inconclusive. METHODS: We conducted mechanism-based experiments by transplanting serum/xeno free cultured-human bone marrow-muse cells into the perilesion brain at 2 weeks after lacunar infarction in immunodeficient mice. RESULTS: Approximately 28% of initially transplanted muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (~62%), MAP2 (~30%), and GST-pi (~12%). Dextran tracing revealed connections between host neurons and muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side, and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post transplantation, human-specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation. CONCLUSIONS: Transplantation at the delayed subacute phase showed muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke. PMID- 27999137 TI - Cystatin C Is a Crucial Endogenous Protective Determinant Against Stroke. AB - BACKGROUND AND PURPOSE: Endogenous neuroprotection can be induced by ischemic and nonischemic preconditioning. However, not all subjects that undergo preconditioning exhibit similar favorable outcome. This study is to explore the molecules responsible for this phenomenon and find new therapeutic targets for stroke. METHODS: Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion. High-throughput proteomic technique, isobaric tag for relative and absolute quantification, was used to screen differentially expressed proteins in the rats that developed ischemic tolerance from hyperbaric oxygen (HBO) preconditioning. The proteomic results were verified by Western blot and ELISA. Then, short interfering RNA and gene knockout rats were used to further determine the pivotal role of candidate proteins in HBO preconditioning induced endogenous neuroprotection. Finally, lysosomal permeability was tested to elaborate the mechanism underlying this intrinsic neuroprotective effect. RESULTS: Nine proteins differentially expressed in the serum of rats, which acquired benefits from HBO preconditioning, were screened and identified. Western blot and ELISA revealed that cystatin C (CysC) and mannose-binding lectin protein C were uniquely changed in rats with smaller infarction after HBO preconditioning and cerebral ischemia. Knockdown and knockout of CysC abolished HBO-induced neuroprotection. Moreover, HBO-induced endogenous CysC elevation preserved lysosomal membrane integrity after stroke in wild-type rats but not in CysC siRNA infusion or CysC-/- rats. Most importantly, exogenous CysC also induced neuroprotection against ischemic/reperfusion injury. CONCLUSIONS: CysC is a crucial determinant contributing to endogenous neuroprotection. It is also a novel candidate for stroke treatment through maintaining lysosomal membrane integrity. PMID- 27999138 TI - Response by Jung et al to Letter Regarding Article, "Takotsubo-Like Myocardial Dysfunction in Ischemic Stroke: A Hospital-Based Registry and Systematic Literature Review". PMID- 27999141 TI - Inner Workings: Orbiting experiment may help decode the mysteries of rubbly asteroids. PMID- 27999139 TI - Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta Analysis. AB - BACKGROUND AND PURPOSE: Pioglitazone reduced major vascular events after ischemic stroke in a recent randomized controlled trial. The purpose of this study was to conduct a meta-analysis of randomized controlled trials to evaluate the effect of pioglitazone therapy in reducing the risk of recurrent stroke in stroke patients. METHODS: Pubmed, EMBASE, Medline, and Cochrane Central Register of Controlled Trials from 1966 to March 2016 were searched to identify relevant studies. We included randomized controlled trials that included comparison of pioglitazone versus control and trials in which quantitative estimates of the hazard ratio and 95% confidence interval for recurrent stroke associated with pioglitazone therapy among stroke patients were reported. Hazard ratios with 95% confidence intervals were used as a measure of the association between use of pioglitazone and risks of recurrent stroke (ischemic and hemorrhagic) and major vascular events (nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death) after pooling data across trials. Between-study heterogeneity was assessed using the I2 statistic. RESULTS: Three randomized controlled trials with 4980 participants were identified. Use of pioglitazone in stroke patients with insulin resistance, prediabetes, and diabetes mellitus was associated with lower risk of recurrent stroke (hazard ratio 0.68; 95% confidence interval, 0.50-0.92; P=0.01) and future major vascular events (hazard ratio 0.75; 95% confidence interval, 0.64-0.87; P=0.0001). There was no heterogeneity across trials. There was no evidence of an effect on all-cause mortality and heart failure. CONCLUSIONS: Pioglitazone reduces recurrent stroke and major vascular events in ischemic stroke patients with insulin resistance, prediabetes, and diabetes mellitus. PMID- 27999143 TI - Aspirin Use and Reduced Risk of Pancreatic Cancer. AB - BACKGROUND: Few options besides the avoidance of smoking and obesity are available to prevent pancreatic cancer. The association between aspirin use and risk of pancreatic cancer has been inconsistent across studies. METHODS: We performed a population-based study of 761 case and 794 control subjects frequency matched on sex and age during 2006 to 2011 in Shanghai, China. Participants were asked about episodes of regular use of aspirin, tablets per day or week, and ages that the use started and stopped. Data were analyzed by unconditional logistic regression, with adjustments for age, sex, education, body mass index, years of cigarette smoking, cigarettes smoked per day, Helicobacter pylori CagA seropositivity, ABO blood group, and history of diabetes mellitus. Meta regression was carried out to summarize the literature. RESULTS: Ever-regular use of aspirin was associated with lowered risk of pancreatic cancer: OR = 0.54; 95% confidence interval (CI), 0.40-0.73; P = 10-4.2 Risk decreased 8% per each cumulative year of use: ORtrend = 0.92; 95% CI, 0.87-0.97; P = 0.0034. Across this and 18 published studies of this association, the OR for ever-regular use decreased with increasingly more recent mid-study year, for any aspirin type (Ptrend = 10-5.1), and for low-dose aspirin (Ptrend = 0.0014). CONCLUSIONS: Regular use of aspirin thus appears to reduce risk of pancreatic cancer by almost half. IMPACT: People who take aspirin for prevention of other diseases likely also reduce their risk of pancreatic cancer. Aside from benefits for both cardiovascular disease and certain cancers, long-term aspirin use entails some risks of bleeding complications, which necessitates risk-benefit analysis for individual decisions about use. Cancer Epidemiol Biomarkers Prev; 26(1); 68-74. (c)2016 AACR. PMID- 27999144 TI - Long-term Follow-up of Patients Having False-Positive Multitarget Stool DNA Tests after Negative Screening Colonoscopy: The LONG-HAUL Cohort Study. AB - Background: Studies of colorectal cancer screening by multitarget stool DNA (MT sDNA) show false-positive (FP) rates of 7% to 13%. It is unclear whether FP patients are at increased long-term risk of adverse outcomes.Methods: We compared subsequent clinical events among patients with apparent FP MT-sDNA with those in patients reported as true negative (TN). This was a retrospective cohort study of participants in pre-FDA approval MT-sDNA studies having nonadvanced or negative baseline colonoscopy findings from a single referral center. Per-protocol and calibrated cutoffs defined FP and TN groups. From the time of stool collection, we measured differences between FP and TN groups in time to death, subsequent cancer diagnosis, and onset of alarm symptoms.Results: Of 1,050 eligible patients, only 6 were lost to follow-up. Median age was 65.6 years [interquartile range (IQR), 56.8-72.3]; 54% were female. Median follow-up time was 4 years (IQR, 3.5-5.3). Eight aerodigestive (lung and gastrointestinal tract) cancers occurred. FP status by calibrated, but not per-protocol, cutoffs was associated with subsequent aerodigestive cancer; however, cumulative incidence did not exceed SEER expectations from the general population. By any cutoff method, FP status was not associated with mortality or alarm symptoms.Conclusions: Although FP status was associated with long-term aerodigestive cancers, new cases were not temporally related and did not exceed incidence estimates from general population.Impact: These observations do not justify aggressive follow-up evaluation for patients with FP MT-sDNA at this time. Larger studies are needed to confirm these early findings. Cancer Epidemiol Biomarkers Prev; 26(4); 614-21. (c)2016 AACR. PMID- 27999146 TI - Why care about kids? PMID- 27999145 TI - Progress in ciliary ion channel physiology. AB - Mammalian cilia are ubiquitous appendages found on the apical surface of cells. Primary and motile cilia are distinct in both morphology and function. Most cells have a solitary primary cilium (9+0), which lacks the central microtubule doublet characteristic of motile cilia (9+2). The immotile primary cilia house unique signaling components and sequester several important transcription factors. In contrast, motile cilia commonly extend into the lumen of respiratory airways, fallopian tubes, and brain ventricles to move their contents and/or produce gradients. In this review, we focus on the composition of putative ion channels found in both types of cilia and in the periciliary membrane and discuss their proposed functions. Our discussion does not cover specialized cilia in photoreceptor or olfactory cells, which express many more ion channels. PMID- 27999148 TI - Inflammasome biology taught by Legionella pneumophila. AB - Inflammasomes are multimeric protein complexes that assemble in the cytosol of many types of cells, including innate immune cells. The inflammasomes can be activated in response to infection or in response to stress signals that induce damage in the host cell membranes. These platforms trigger inflammatory processes, cell death, and the control of microbial replication. Many inflammasomes have been described so far, including NLRP3, NAIP/NLRC4, caspase 11, and AIM2. The ligand for NLRP3 is still unidentified, but the efflux of K+ is essential for NLRP3 activation. By contrast, inflammasomes, such as those composed of NAIP/NLRC4, caspase-11, and AIM2, can be activated by bacterial flagellin, LPS, and dsDNA. The knowledge of inflammasome biology has advanced tremendously in the last decade, fostered by the use of model organisms, such as Legionella pneumophila This bacterium evolved, infecting unicellular protozoa in freshwater environments, and the human infection is accidental. Thus, L. pneumophila did not evolve sophisticated mechanisms to inhibit mammalian innate immunity. For this reason, it has emerged as a very appropriate model of a pathogenic microbe for the investigation of inflammasome biology. In this review, we highlight the current information regarding the biology of inflammasomes and emphasize the advances achieved using L. pneumophila We also describe the inflammasomes activated in response to L. pneumophila infection and discuss the effector mechanisms that operate to clear the infection. PMID- 27999147 TI - Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS. AB - Endocannabinoids, a class of lipid messengers, have emerged as crucial regulators of synaptic communication in the CNS. Dysregulation of these compounds has been implicated in many brain disorders. Although some studies have identified and quantified a limited number of target compounds, a method that provides comprehensive quantitative information on endocannabinoids and related N acylethanolamines (NAEs) in cerebrospinal fluid (CSF) is currently lacking, as measurements are challenging due to low concentrations under normal physiological conditions. Here we developed and validated a high-throughput nano LC-ESI-MS/MS platform for the simultaneous quantification of endocannabinoids (anandamide and 2-arachidonoylglycerol), ten related NAEs, and eight additional putatively annotated NAEs in human CSF. Requiring only 200 MUl of CSF, our method has limits of detection from 0.28 to 61.2 pM with precisions of relative SD <15% for most compounds. We applied our method to CSF from 45 healthy humans and demonstrated potential age and gender effects on concentrations of endocannabinoids and NAEs. Notably, our results show that docosahexaenoylethanolamide concentrations increase with age in males. Our method may offer new opportunities to gain insight into regulatory functions of endocannabinoids in the context of (ab)normal brain function. PMID- 27999149 TI - Time Required to Rectify Inhaler Errors Among Experienced Subjects With Faulty Technique. AB - BACKGROUND: Regardless of the device used, many patients have difficulty maintaining proper inhaler technique over time. Repeated education from caregivers is required to ensure persistence of correct inhaler technique, but no information is available to evaluate the time required to rectify inhaler errors in experienced users with a baseline faulty technique and whether this time of re education to restore inhaler mastery can differ between devices. METHODS: This was a multi-center, single-visit, open-label, cross-sectional study in a large group of 981 adult subjects (mean +/- SD age 64 +/- 15 y) experienced with inhaler use, mainly suffering from COPD and asthma, who showed faulty inhaler technique at a follow-up visit in chest clinics. These subjects received face-to face practical education from trained caregivers until proper inhaler use could be demonstrated, and the time of instruction was recorded. RESULTS: The mean times (95% CIs) in minutes of instruction required for rectifying misuse and demonstrating inhaler mastery were 5.0 (3.6-6.4) min for the Diskus (n = 199), 5.3 (3.7-6.8) min for the HandiHaler (n = 219), 8.1 (5.6-10.5) min for the metered-dose inhaler (MDI) (n = 532), and 6.0 (5.0-7.0) min for the Turbuhaler (n = 169). The time to demonstrate good inhaler use for MDIs was higher (P < .05) than for all dry powder inhalers (DPIs). Between the DPIs, only the HandiHaler required more time for achieving mastery than the Diskus (P = .005). The variables associated with increasing time for correcting inhaler errors were an older age (0.05 min/y, 95% CI 0.03-0.07), a lower level of education (0.4 min/schooling level, 95% CI 0.7-0.1), and no reported previous instruction in inhaler use (1.96 min, 95% CI 1.35-2.58). CONCLUSIONS: In experienced subjects with baseline faulty inhaler use, the mean time of education required to achieve and demonstrate mastery with DPIs was lower than with MDIs. PMID- 27999150 TI - The Concave Shape of the Forced Expiratory Flow-Volume Curve in 3 Seconds Is a Practical Surrogate of FEV1/FVC for the Diagnosis of Airway Limitation in Inadequate Spirometry. AB - BACKGROUND: Spirometry is important for the differential diagnosis of dyspnea. However, some patients cannot exhale for >=6 s to achieve the American Thoracic Society/European Respiratory Society criteria. The aim of this study was to demonstrate the reliability of a new parameter that quantifies the degree of concavity in the first 3 s to define airway limitation as a surrogate for the FEV1/FVC. METHODS: Four hundred spirometry test results were selected through complete random sampling. The new parameter, termed the AUC3/AT3, was calculated as the area under the descending limb of the expiratory flow-volume curve before the end of the first 3 s (AUC3) divided by the area of the triangle before the end of the first 3 s (AT3). The AUC3/AT3 was compared with the FEV1/FVC using Pearson's correlation analysis. The level of agreement between the AUC3/AT3 and the FEV1/FVC in the detection of airway obstruction was analyzed using the kappa statistic. We also compared the diagnostic accuracy of the new index with that of the FEV1/forced expiratory volume in the first 3 s (FEV3). RESULTS: There was a strong correlation (r = 0.88, P < .001) between the AUC3/AT3 and the FEV1/FVC. There was also strong agreement between the AUC3/AT3 and the FEV1/FVC in the detection of obstruction with kappa indices of 0.72 (Global Initiative for Chronic Obstructive Lung Disease [GOLD] criterion) and 0.67 (lower limit of normal criterion), and these values were greater than those obtained for the FEV1/FEV3. The AUC3/AT3 also exhibited acceptable sensitivity, specificity, positive predictive value, and negative predictive value. The diagnostic accuracies of the AUC3/AT3 were 86.3% (GOLD criterion) and 83.8% (lower limit of normal criterion), which were greater than the 76.0 and 74.0% obtained for the FEV1/FEV3, respectively. CONCLUSIONS: The AUC3/AT3 can be utilized as a surrogate parameter for the FEV1/FVC when patients cannot complete a 6-s expiratory effort. Additionally, the performance of this index is better than that of the FEV1/FEV3 in the identification of airway limitations. PMID- 27999151 TI - Endotracheal Intubation Training and Skill Maintenance for Respiratory Therapists. AB - BACKGROUND: Endotracheal intubation is commonly performed outside the operating room (OR). Although respiratory therapists (RTs) performing endotracheal intubation is a well-established practice, the optimum way for RTs to be trained and maintain their skills is unspecified. The purpose of this study was to describe training methods and skills maintenance methods and to identify barriers that prevent RTs from intubating in some institutions. METHODS: A survey instrument was developed by the author. The survey was posted on the AARConnect online social media platform management section in March of 2015 after approval from our institutional review board and approval from the American Association for Respiratory Care board of directors. Respondents from institutions where RTs intubate received questions about RT training and skill maintenance, whereas the other respondents received questions about barriers to RTs performing endotracheal intubation. Both groups answered questions about attitudes about endotracheal intubation practice. RESULTS: There were 74 respondents who completed the survey. Half (50%) of the respondents were from institutions where RTs performed endotracheal intubation. These institutions were larger in bed capacity and had more adult ICU beds. Other demographic data were similar. The most common training methods identified were simulation training (86%), supervised intubations (84%), and classroom training (65%). Classroom training lasted a mean of 4.3 h with a range of 1-16 h. The majority (91%) were required to complete 10 or fewer supervised endotracheal intubations before competency validation. Skill recertification was automatic if a minimum number of endotracheal intubations were performed annually in 78% of centers, and 11% required a written test or classroom training annually. The primary barrier cited for RTs not intubating was lack of need. CONCLUSIONS: Endotracheal intubation training for RTs varied among those surveyed. Simulation training and supervised endotracheal intubations were the most common training methods. Endotracheal intubation recertification methods were also wide-ranging, with most RTs being recertified if completing a minimum number of endotracheal intubations. PMID- 27999152 TI - Optimizing PEEP by Electrical Impedance Tomography in a Porcine Animal Model of ARDS. AB - BACKGROUND: Mechanical ventilation is necessary in diverse clinical circumstances. Especially in the context of ARDS, so-called protective ventilation strategies must be followed. It is already known that PEEP might enhance oxygenation in ARDS. However, determining the optimal PEEP settings in clinical routines is challenging. Electrical impedance tomography (EIT) is a promising technique with which to adjust ventilator settings. We investigated whether the combination of different EIT parameters, namely the global inhomogeneity and hyperdistension indices, may lead to a feasible and safe PEEP setting. METHODS: ARDS was induced by a double-hit approach in 18 pigs weighing, on average, 34.8 +/- 3.97 kg. First, a surfactant washout was conducted; second, the tidal volume was increased to 20 mL/kg body weight, triggering a ventilator induced lung injury. Subsequently, pigs were randomized to either the EIT or control groups, followed by an observation time of 24 h. In the control group, PEEP was set according to the ARDS network table. In the EIT group, a PEEP trial was conducted to determine an appropriate PEEP. At defined time points, hemodynamic measures, ventilation parameters, and EIT recordings, as well as blood samples, were taken. After euthanization, lungs were removed for subsequent histopathological and cytological examination. RESULTS: The combination of PEEP and FIO2 differed between groups, although respiratory compliance, gas exchange, and histopathological examinations, as well as hemodynamics, did not show any statistical differences between the EIT and control groups. However, in the control group, the PEEP/FIO2 settings followed the given coupling; in the EIT group, divergent individual combinations of PEEP and FIO2 ranges occurred. CONCLUSIONS: PEEP setting by EIT facilitates a more individual ventilation therapy. However, in our relatively short ARDS observation period of 24 h, no significant differences appeared in common clinical parameters compared with a control group. PMID- 27999153 TI - Rhipicephalus sanguineus importation into the UK: surveillance, risk, public health awareness and One Health response. AB - As part of Public Health England's assessment of vectorborne disease risk to public health in the UK, tick specimens are regularly submitted by veterinarians for identification via the Tick Surveillance Scheme. Recently, a number of these specimens have been identified as the brown dog tick, Rhipicephalus sanguineus This species is non-endemic to the UK and presents a risk to both human and animal health due to its role in the transmission of various tickborne pathogens. Although current climatic conditions in the UK are unlikely to permit the survival of this species outdoors, indoor infestations can occur and this can present a risk of disease transmission within an infested property. This paper documents 40 importation events involving R sanguineus on recently travelled or imported dogs into the UK since 2012. It also provides details of the response following these detections in line with the One Health concept. With the increasing number of dogs travelling or being imported, it is likely that importation and infestation events in the UK will continue and may result in pathogen transmission. It is therefore important to raise awareness of this risk and share lessons learned to improve our prevention and response strategies to this emerging issue. PMID- 27999154 TI - Pectinate ligament dysplasia in the Border Collie, Hungarian Vizsla and Golden Retriever. AB - Pectinate ligament dysplasia (PLD) is significantly associated with primary closed angle glaucoma (PCAG) in several dog breeds. Gonioscopy screening for PLD is advised in breeds in which PLD and PCAG are particularly prevalent in order that affected dogs may be eliminated from the breeding population. The Border Collie (BC), Hungarian Vizsla (HV) and Golden Retriever (GR) breeds are currently under investigation for PLD by the British Veterinary Association/Kennel Club/International Sheep Dog Society (BVA/KC/ISDS) Eye Scheme. The authors aimed to determine the prevalence of PLD in UK populations of BC, HV and GR and to investigate possible associations between the degree of PLD and age and sex. Gonioscopy was performed in 102 BCs, 112 HVs and 230 GRs and the percentage of iridocorneal angle affected by PLD was estimated and classified as unaffected (0 per cent), mildly affected (<20 per cent), moderately affected (20-90 per cent) or severely affected (>90 per cent). Eleven of 102 (13.8 per cent) BCs, 16/112 (14.3 per cent) HVs and 60/230 (26.1 per cent) GRs were moderately or severely affected by PLD. The prevalence of PLD was significantly higher in GR than both BC and HV. There was a significant positive correlation between PLD and age in the HV and GR but not in the BC. There was no association between PLD and sex in any breed. PMID- 27999155 TI - Ethnic differences in longitudinal latent verbal profiles in the millennium cohort study. AB - BACKGROUND: Development of verbal skills during early childhood and school age years is consequential for children's educational achievement and adult outcomes. We examine ethnic differences in longitudinal latent verbal profiles and assess the contribution of family process and family resource factors to observed differences. METHODS: Using data from the UK Millennium Cohort Study and the latent profile analysis, we estimate longitudinal latent verbal profiles using verbal skills measured 4 times from age 3-11 years. We investigate the odds of verbal profiles by ethnicity (reported in infancy), and the extent observed differences are mediated by the home learning environment, family routines, and psychosocial environment (measured at age 3). RESULTS: Indian children were twice as likely (OR = 2.14, CI: 1.37-3.33) to be in the high achieving profile, compared to White children. Socioeconomic markers attenuated this advantage to nonsignificance. Pakistani and Bangladeshi children were significantly more likely to be in the low performing group (OR = 2.23, CI: 1.61-3.11; OR = 3.37, CI: 2.20-5.17, respectively). Socioeconomic and psychosocial factors had the strongest mediating influence on the association between lower achieving profiles and Pakistani children, whereas for Bangladeshi children, there was mediation by the home learning environment, family routines, and psychosocial factors. CONCLUSION: Family process and resource factors explain ethnic differences in longitudinal latent verbal profiles. Family resources explain verbal advantages for Indian children, whereas a range of home environment and socioeconomic factors explain disparities for Pakistani and Bangladeshi children. Future policy initiatives focused on reducing ethnic disparities in children's development should consider supporting and enhancing family resources and processes. PMID- 27999158 TI - Disturbance Regimes Predictably Alter Diversity in an Ecologically Complex Bacterial System. AB - : Diversity is often associated with the functional stability of ecological communities from microbes to macroorganisms. Understanding how diversity responds to environmental perturbations and the consequences of this relationship for ecosystem function are thus central challenges in microbial ecology. Unimodal diversity-disturbance relationships, in which maximum diversity occurs at intermediate levels of disturbance, have been predicted for ecosystems where life history tradeoffs separate organisms along a disturbance gradient. However, empirical support for such peaked relationships in macrosystems is mixed, and few studies have explored these relationships in microbial systems. Here we use complex microbial microcosm communities to systematically determine diversity disturbance relationships over a range of disturbance regimes. We observed a reproducible switch between community states, which gave rise to transient diversity maxima when community states were forced to mix. Communities showed reduced compositional stability when diversity was highest. To further explore these dynamics, we formulated a simple model that reveals specific regimes under which diversity maxima are stable. Together, our results show how both unimodal and non-unimodal diversity-disturbance relationships can be observed as a system switches between two distinct microbial community states; this process likely occurs across a wide range of spatially and temporally heterogeneous microbial ecosystems. IMPORTANCE: The diversity of microbial communities is linked to the functioning and stability of ecosystems. As humanity continues to impact ecosystems worldwide, and as diet and disease perturb our own commensal microbial communities, the ability to predict how microbial diversity will respond to disturbance is of critical importance. Using microbial microcosm experiments, we find that community diversity responds to different disturbance regimes in a reproducible and predictable way. Maximum diversity occurs when two communities, each suited to different environmental conditions, are mixed due to disturbance. This maximum diversity is transient except under specific regimes. Using a simple mathematical model, we show that transient unimodality is likely a common feature of microbial diversity-disturbance relationships in fluctuating environments. PMID- 27999160 TI - 25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation. AB - : Lassa virus (LASV) infection is a major public health concern due to high fatality rates and limited effective treatment. The interferon-stimulated gene cholesterol 25-hydroxylase (CH25H) encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. Here, we show a previously unrecognized role of CH25H in inhibiting LASV glycoprotein glycosylation and the production of infectious virus. Overexpression of CH25H or treatment with 25HC decreased LASV G1 glycoprotein N-glycan maturation and reduced the production of infectious LASV. Depletion of endogenous CH25H using small interfering RNA (siRNA) enhanced the levels of fully glycosylated G1 and increased infectious LASV production. Finally, LASV particles produced from 25HC-treated cells were found to be less infectious, to incorporate aberrantly glycosylated GP1 species, and to be defective in binding alpha-dystroglycan, an attachment and entry receptor. Our findings identify a novel role for CH25H in controlling LASV propagation and indicate that manipulation of the expression of CH25H or the administration of 25HC may be a useful anti-LASV therapy. IMPORTANCE: Lassa fever is an acute viral hemorrhagic fever in humans caused by Lassa virus (LASV). No vaccine for LASV is currently available. Treatment is limited to the administration of ribavirin, which is only effective when given early in the course of illness. Cholesterol 25 hydroxylase (CH25H) is a recently identified interferon-stimulated gene (ISG); it encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC), which inhibits several viruses. Here, we identify a novel antiviral mechanism of 25HC that is dependent on inhibiting the glycosylation of Lassa virus (LASV) glycoprotein and reducing the infectivity of LASV as a means of suppressing viral replication. Since N-linked glycosylation is a critical feature of other enveloped-virus glycoproteins, 25HC may be a broad inhibitor of virus infectivity. PMID- 27999159 TI - Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory. AB - Antibiotic intervention is an effective treatment strategy for many bacterial infections and liberates bacterial antigens and stimulatory products that can induce an inflammatory response. Despite the opportunity for bacterial killing to enhance the development of adaptive immunity, patients treated successfully with antibiotics can suffer from reinfection. Studies in mouse models of Salmonella and Chlamydia infection also demonstrate that early antibiotic intervention reduces host protective immunity to subsequent infection. This heightened susceptibility to reinfection correlates with poor development of Th1 and antibody responses in antibiotic-treated mice but can be overcome by delayed antibiotic intervention, thus suggesting a requirement for sustained T cell stimulation for protection. Although the contribution of memory T cell subsets is imperfectly understood in both of these infection models, a protective role for noncirculating memory cells is suggested by recent studies. Together, these data propose a model where antibiotic treatment specifically interrupts tissue resident memory T cell formation. Greater understanding of the mechanistic basis of this phenomenon might suggest therapeutic interventions to restore a protective memory response in antibiotic-treated patients, thus reducing the incidence of reinfection. PMID- 27999161 TI - Networked Chemoreceptors Benefit Bacterial Chemotaxis Performance. AB - : Motile bacteria use large receptor arrays to detect and follow chemical gradients in their environment. Extended receptor arrays, composed of networked signaling complexes, promote cooperative stimulus control of their associated signaling kinases. Here, we used structural lesions at the communication interface between core complexes to create an Escherichia coli strain with functional but dispersed signaling complexes. This strain allowed us to directly study how networking of signaling complexes affects chemotactic signaling and gradient-tracking performance. We demonstrate that networking of receptor complexes provides bacterial cells with about 10-fold-heightened detection sensitivity to attractants while maintaining a wide dynamic range over which receptor adaptational modifications can tune response sensitivity. These advantages proved especially critical for chemotaxis toward an attractant source under conditions in which bacteria are unable to alter the attractant gradient. IMPORTANCE: Chemoreceptor arrays are found in many motile bacteria. However, although our understanding of bacterial chemotaxis is quite detailed, the signaling and behavioral advantages of networked receptor arrays had not been directly studied in cells. We have recently shown that lesions in a key interface of the E. coli receptor array diminish physical connections and functional coupling between core signaling complexes while maintaining their basic signaling capacity. In this study, we exploited an interface 2 mutant to show, for the first time, that coupling between core complexes substantially enhances stimulus detection and chemotaxis performance. PMID- 27999162 TI - Complete Microbiota Engraftment Is Not Essential for Recovery from Recurrent Clostridium difficile Infection following Fecal Microbiota Transplantation. AB - : Bacterial communities from subjects treated for recurrent Clostridium difficile infection (rCDI) by fecal microbiota transplantation (FMT), using either heterologous donor stool samples or autologous stool samples, were characterized by Illumina next-generation sequencing. As previously reported, the success of heterologous FMT (90%) was superior to that of autologous FMT (43%) (P = 0.019), and post-FMT intestinal bacterial communities differed significantly between treatment arms (P < 0.001). Subjects cured by autologous FMT typically had greater abundances of the Clostridium XIVa clade and Holdemania bacteria prior to treatment, and the relative abundances of these groups increased significantly after FMT compared to heterologous FMT and pre-FMT samples. The typical shift to post-FMT, donor-like assemblages, featuring high relative abundances of genera within the Bacteroidetes and Firmicutes phyla, was not observed in the autologous FMT subjects. Autologous FMT patient bacterial communities were significantly different in composition than those for heterologous FMT patients and donors (P < 0.001). The SourceTracker program, which employs a Bayesian algorithm to determine source contributions to sink communities, showed that patients initially treated by heterologous FMT had significantly higher percentages of engraftment (i.e., similarity to donor communities, mean value of 74%) compared to those who suffered recurrence following autologous FMT (1%) (P <= 0.013). The findings of this study suggest that complete donor engraftment may be not necessary if functionally critical taxa are present in subjects following antibiotic therapy. IMPORTANCE: This study provides a detailed characterization of fecal bacterial communities in subjects who participated in a previously published randomized clinical trial to treat recurrent C. difficile infection (rCDI). Bacterial communities were characterized to determine differences between subjects who received fecal bacteria either from healthy donor stool samples or their own stool samples as "placebo" in order to determine which groups of bacteria were most important in achieving a cure. The results of this study suggested that bacteria associated with secondary bile acid metabolism could potentially provide resistance to infection and that complete transfer of healthy donor microorganisms was not necessary to resolve CDI following unsuccessful antibiotic treatment. PMID- 27999163 TI - Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells. AB - : We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli heat-labile toxin. LPS-specific MAbs uniformly targeted the O specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera. IMPORTANCE: Cholera is a diarrheal disease that results in significant mortality. While oral cholera vaccines are beneficial, they do not achieve equivalent protection compared to infection with Vibrio cholerae Although antibodies likely mediate protection, the mechanisms of immunity following cholera are poorly understood, and a detailed understanding of antibody responses to cholera is of significance for human health. In this study, we characterized the human response to cholera at the single-plasmablast, monoclonal antibody level. Although this approach has not been widely applied to the study of human bacterial infection, we were able to uncover the basis of cross-reactivity between different V. cholerae serotypes and the likely impact of prior enterotoxigenic Escherichia coli exposure on the response to cholera, as well as identify novel antigenic targets. In addition to improving our understanding of the repertoire and function of the antibody response to cholera in humans, this study has implications for future cholera vaccination efforts. PMID- 27999165 TI - Strain Prioritization and Genome Mining for Enediyne Natural Products. AB - : The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE: Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family. PMID- 27999167 TI - Erratum for Chu et al., Function of the Borrelia burgdorferi FtsH Homolog Is Essential for Viability both In Vitro and In Vivo and Independent of HflK/C. PMID- 27999164 TI - Cytochrome bd-Dependent Bioenergetics and Antinitrosative Defenses in Salmonella Pathogenesis. AB - : In the course of an infection, Salmonella enterica occupies diverse anatomical sites with various concentrations of oxygen (O2) and nitric oxide (NO). These diatomic gases compete for binding to catalytic metal groups of quinol oxidases. Enterobacteriaceae express two evolutionarily distinct classes of quinol oxidases that differ in affinity for O2 and NO as well as stoichiometry of H+ translocated across the cytoplasmic membrane. The investigations presented here show that the dual function of bacterial cytochrome bd in bioenergetics and antinitrosative defense enhances Salmonella virulence. The high affinity of cytochrome bd for O2 optimizes respiratory rates in hypoxic cultures, and thus, this quinol oxidase maximizes bacterial growth under O2-limiting conditions. Our investigations also indicate that cytochrome bd, rather than cytochrome bo, is an intrinsic component of the adaptive antinitrosative toolbox of Salmonella Accordingly, induction of cytochrome bd helps Salmonella grow and respire in the presence of inhibitory NO. The combined antinitrosative defenses of cytochrome bd and the flavohemoglobin Hmp account for a great part of the adaptations that help Salmonella recover from the antimicrobial activity of NO. Moreover, the antinitrosative defenses of cytochrome bd and flavohemoglobin Hmp synergize to promote Salmonella growth in systemic tissues. Collectively, our investigations indicate that cytochrome bd is a critical means by which Salmonella resists the nitrosative stress that is engendered in the innate response of mammalian hosts while it concomitantly allows for proper O2 utilization in tissue hypoxia. IMPORTANCE: It is becoming quite apparent that metabolism is critically important to the virulence potential of pathogenic microorganisms. Bacterial cells use a variety of terminal electron acceptors to power electron transport chains and metabolic processes. Of all the electron acceptors available to bacteria, utilization of O2 yields the most energy while diversifying the type of substrates that a pathogen can use. Recent investigations have demonstrated important roles for bd-type quinol oxidases with high affinity for O2 in bacterial pathogenesis. The investigations presented here have revealed that cytochrome bd potentiates virulence of a clinically relevant bacterial pathogen by fueling bioenergetics of prokaryotic cells while protecting the respiratory chain against NO toxicity. The adaptive antinitrosative defenses afforded by cytochrome bd synergize with other NO-detoxifying systems to preserve cellular bioenergetics, thereby promoting bacterial virulence in tissue hypoxia. PMID- 27999166 TI - The Cytolethal Distending Toxin Produced by Nontyphoidal Salmonella Serotypes Javiana, Montevideo, Oranienburg, and Mississippi Induces DNA Damage in a Manner Similar to That of Serotype Typhi. AB - : Select nontyphoidal Salmonella enterica (NTS) serotypes were recently found to encode the Salmonella cytolethal distending toxin (S-CDT), an important virulence factor for serotype Typhi, the causative agent of typhoid fever. Using a PCR based assay, we determined that among 21 NTS serotypes causing the majority of food-borne salmonellosis cases in the United States, genes encoding S-CDT are conserved in isolates representing serotypes Javiana, Montevideo, and Oranienburg but that among serotype Mississippi isolates, the presence of S-CDT-encoding genes is clade associated. HeLa cells infected with representative strains of these S-CDT-positive serotypes had a significantly higher proportion of cells arrested in the G2/M phase than HeLa cells infected with representative strains of S-CDT-negative serotypes Typhimurium, Newport, and Enteritidis. The G2/M cell cycle arrest was dependent on CdtB, the active subunit of S-CDT, as infection with isogenic DeltacdtB mutants abolished their ability to induce a G2/M cell cycle arrest. Infection with S-CDT-encoding serotypes was significantly associated with activation of the host cell's DNA damage response (DDR), a signaling cascade that is important for detecting and repairing damaged DNA. HeLa cell populations infected with S-CDT-positive serotypes had a significantly higher proportion of cells with DDR protein 53BP1 and gammaH2AX foci than cells infected with either S-CDT-negative serotypes or isogenic DeltacdtB strains. Intoxication with S-CDT occurred via autocrine and paracrine pathways, as uninfected HeLa cells among populations of infected cells also had an activated DDR. Overall, we show that S-CDT plays a significant role in the cellular outcome of infection with NTS serotypes. IMPORTANCE: The recent discovery that multiple serotypes encode S-CDT, which was previously established as an important virulence factor for serotype Typhi, suggested that this toxin may also contribute to the outcome of infection with nontyphoidal serotypes. In this study, we demonstrate that at a cellular level, S-CDT significantly alters the outcome of infection by inducing DNA damage which is associated with a cell cycle arrest and activation of the host cell's DDR. Importantly, these results contribute valuable information for assessing the public health implications of S CDT in infections with NTS serotypes. Our data suggest that infection with Salmonella strains that encode S-CDT has the potential to result in DNA damage, which may contribute to long-term sequelae. PMID- 27999168 TI - Author Correction for Cote et al., The Genome-Wide Interaction Network of Nutrient Stress Genes in Escherichia coli. PMID- 27999169 TI - A case for the therapeutic use of perfluorocarbon in pulmonary atelectasis. PMID- 27999170 TI - Endobronchial valves for patients with heterogeneous emphysema and without interlobar collateral ventilation: open label treatment following the BeLieVeR HIFi study. AB - : Outcomes in early trials of bronchoscopic lung volume reduction using endobronchial valves for the treatment of patients with advanced emphysema were inconsistent. However improvements in patient selection with focus on excluding those with interlobar collateral ventilation and homogeneous emphysema resulted in significant benefits in the BeLieVeR-HIFi study compared with sham treated controls. In this manuscript we present data from the control patients in the BeLieVeR-HIFi study who went on to have open label endobronchial valve treatment after completion of the clinical trial (n=12), combined with data from those in the treatment arm who did not have collateral ventilation (n=19). Three months after treatment FEV1 increased by 27.3 (36.4)%, residual volume reduced by 0.49 (0.76) L, the 6 min walk distance increased by 32.6 (68.7) m and the St George Respiratory Questionnaire for COPD score improved by 8.2 (20.2) points. These data extend the evidence for endobronchial valve placement in appropriately selected patients with COPD. TRIAL REGISTRATION NUMBER: ISRCTN04761234; Results. PMID- 27999171 TI - Cured meat intake is associated with worsening asthma symptoms. AB - BACKGROUND: Cured meat intake-a recent carcinogenic factor-may increase the risk of COPD, but its association with asthma remains unknown. Though body mass index (BMI) is a likely risk factor for asthma, its role in the diet-asthma association as a mediator has never been studied. We investigated the association between cured meat intake and worsening asthma symptoms in adults, and the role of BMI as a potential mediator. METHODS: Using data from the French prospective EGEA study (baseline: 2003-2007; follow-up: 2011-2013), we applied a mediation analysis in the counterfactual framework, a marginal structural model (MSM), to estimate the direct effect of baseline cured meat intake (<1, 1-3.9, >=4 servings/week) on change in asthma symptom score (worsening or not), and the indirect effect mediated by BMI. RESULTS: Among the 971 participants (mean age 43 years; 49% men; 42% with asthma), 20% reported worsening asthma symptoms during the mean follow up time of 7 years. Using the MSM, we reported a positive direct effect of cured meat intake on worsening asthma symptoms (multivariable OR=1.76, 95% CI 1.01 to 3.06 for >=4 vs <1 serving/week). We also reported an indirect effect mediated by BMI (OR=1.07; 95% CI 1.01 to 1.14), accounting for 14% of the total effect. CONCLUSIONS: Higher cured meat intake was associated with worsening asthma symptoms over time, through a direct effect and to a lesser extent an effect mediated by BMI. This research extends the effect of diet on asthma in adults. PMID- 27999172 TI - Science Signaling Podcast for 20 December 2016: Trans-inhibition by Fc receptors. AB - This Podcast features an interview with Marc Daeron, author of a Research Article that appears in the 20 December 2016 issue of Science Signaling, about a mechanism by which an Fc receptor can inhibit signaling by other receptors without aggregating with those other receptors. Engagement of Fc receptors on basophils and mast cells can either activate these cells, which promotes autoimmune and allergic inflammation, or prevent these cells from being activated. Whether these cells are activated depends upon which Fc receptors are present in clusters, because some Fc receptors can inhibit signaling by other Fc receptors that are present in the same signalosome, a phenomenon known as cis inhibition. Malbec et al. identified a mechanism whereby inhibitory Fc receptors limit signaling by activating Fc receptors without being present in the same signalosome. This mechanism of trans-inhibition also allowed inhibitory Fc receptors to limit signaling by growth factor receptors in mast cells and oncogene-induced proliferation in mastocytoma cells.Listen to Podcast. PMID- 27999173 TI - Rac signal adaptation controls neutrophil mobilization from the bone marrow. AB - Mobilization of neutrophils from the bone marrow determines neutrophil blood counts and thus is medically important. Balanced neutrophil mobilization from the bone marrow depends on the retention-promoting chemokine CXCL12 and its receptor CXCR4 and the egression-promoting chemokine CXCL2 and its receptor CXCR2. Both pathways activate the small guanosine triphosphatase Rac, leaving the role of this signaling event in neutrophil retention and egression ambiguous. On the assumption that active Rac determines persistent directional cell migration, we generated a mathematical model to link chemokine-mediated Rac modulation to neutrophil egression time. Our computer simulation indicated that, in the bone marrow, where the retention signal predominated, egression time strictly depended on the time it took Rac to return to its basal activity (namely, adaptation). This prediction was validated in mice lacking the Rac inhibitor ArhGAP15. Neutrophils in these mice showed prolonged Rac adaptation and cell-autonomous retention in the bone marrow. Our model thus demonstrates that mobilization in the presence of two spatially defined opposing chemotactic cues strictly depends on inhibitors shaping the time course of signal adaptation. Furthermore, our findings might help to find new modes of intervention to treat conditions characterized by excessively low or high circulating neutrophils. PMID- 27999174 TI - The histone deubiquitinase OTLD1 targets euchromatin to regulate plant growth. AB - Histone monoubiquitination is associated with active chromatin and plays an important role in epigenetic regulation of gene expression in plants. Deubiquitinating enzymes remove the ubiquitin group from histones and thereby contribute to gene repression. The Arabidopsis thaliana genome encodes 50 deubiquitinases, yet only 2 of them-UBP26 and OTLD1, members of the USP/UBP (ubiquitin-specific protease and ubiquitin-binding protein) and OTU (ovarian tumor protease) deubiquitinase families-are known to target histones. Furthermore, UBP26 is the only plant histone deubiquitinase for which the functional role has been characterized in detail. We used gain- and loss-of function alleles of OTLD1 to examine its role in the plant life cycle and showed that OTLD1 stimulates plant growth, increases cell size, and induces transcriptional repression of five major regulators of plant organ growth and development: GA20OX, WUS, OSR2, ARL, and ABI5 OTLD1 associated with chromatin at each of these target genes and promoted the removal of euchromatic histone acetylation, ubiquitination, and methylation marks. Thus, these data indicate that OTLD1 promotes the concerted epigenetic regulation of a set of genes that collectively limit plant growth. PMID- 27999175 TI - Trans-inhibition of activation and proliferation signals by Fc receptors in mast cells and basophils. AB - Allergic and autoimmune inflammation are associated with the activation of mast cells and basophils by antibodies against allergens or auto-antigens, respectively. Both cell types express several receptors for the Fc portion of antibodies, the engagement of which by antigen-antibody complexes controls their responses. When aggregated on the plasma membrane, high-affinity immunoglobulin E (IgE) receptors (FcepsilonRI) and low-affinity IgG receptors (FcgammaRIIIA in mice, FcgammaRIIA in humans) induce these cells to release and secrete proinflammatory mediators, chemokines, and cytokines that account for clinical symptoms. When coaggregated with activating receptors on the same cells, other low-affinity IgG receptors (FcgammaRIIB in both species) inhibit mast cell and basophil activation. We found that FcgammaRIIB inhibited not only signals triggered by activating receptors with which they were coengaged (cis inhibition), but also signals triggered by receptors engaged independently (trans inhibition). Trans-inhibition acted upon the FcepsilonRI-dependent activation of mouse mast cells, mouse basophils, and human basophils, and upon growth factor receptor (Kit)-dependent normal mouse mast cell proliferation, as well as the constitutive in vitro proliferation and the in vivo growth of oncogene (v-Abl) transformed mastocytoma cells. Trans-inhibition was induced by receptors, whether inhibitory (FcgammaRIIB) or activating (FcepsilonRI), which recruited the lipid phosphatase SHIP1. By hydrolyzing PI(3,4,5)P3, SHIP1 induced a global unresponsiveness that affected biological responses triggered by receptors that use phosphoinositide 3-kinase to signal. These data suggest that trans-inhibition controls numerous physiological and pathological processes, and that it may be used as a therapeutic tool in inflammation, especially but not exclusively, in allergy and autoimmunity. PMID- 27999176 TI - Diacylglycerol kinase zeta limits the polarized recruitment of diacylglycerol enriched organelles to the immune synapse in T cells. AB - The antigen-induced formation of an immune synapse (IS) between T cells and antigen-presenting cells results in the rapid generation of the lipid second messenger diacylglycerol (DAG) in T cells. Diacylglycerol kinase zeta (DGKzeta) converts DAG into phosphatidic acid (PA). Cytotoxic T lymphocytes (CTLs) from mice deficient in DGKzeta have enhanced antiviral and antitumor activities, indicating that the amount of DAG controls the effectiveness of the T cell response. We characterized the second C1 domain of protein kinase Ctheta (PKCtheta), a DAG-binding protein that is specifically recruited to the IS, as a biological sensor to observe the generation of a DAG gradient during IS formation. In experiments with transgenic mouse CTLs expressing the OT-I T cell receptor (TCR), we showed that both strong and weak interactions between antigen and the TCR led to the rapid generation of DAG, whereas only strong interactions induced the movement of DAG-enriched organelles toward the IS. In DGKzeta deficient CTLs, antigen stimulation led to the enhanced accumulation of DAG containing organelles at the IS; however, impaired activation of the PA effector PKCzeta resulted in lack of reorientation of the microtubule-organizing center toward the IS, a process needed for effective T cell activation. Together, these data suggest that the activation of DGKzeta downstream of antigen recognition provides a mechanism that ensures the activation of PA-dependent signaling as a direct result of the strength of TCR-dependent DAG mobilization. PMID- 27999178 TI - Celebrating our 20th digital anniversary. PMID- 27999177 TI - Modifications to a LATE MERISTEM IDENTITY1 gene are responsible for the major leaf shapes of Upland cotton (Gossypium hirsutum L.). AB - Leaf shape varies spectacularly among plants. Leaves are the primary source of photoassimilate in crop plants, and understanding the genetic basis of variation in leaf morphology is critical to improving agricultural productivity. Leaf shape played a unique role in cotton improvement, as breeders have selected for entire and lobed leaf morphs resulting from a single locus, okra (l-D1), which is responsible for the major leaf shapes in cotton. The l-D1 locus is not only of agricultural importance in cotton, but through pioneering chimeric and morphometric studies, it has contributed to fundamental knowledge about leaf development. Here we show that an HD-Zip transcription factor homologous to the LATE MERISTEM IDENTITY1 (LMI1) gene of Arabidopsis is the causal gene underlying the l-D1 locus. The classical okra leaf shape allele has a 133-bp tandem duplication in the promoter, correlated with elevated expression, whereas an 8-bp deletion in the third exon of the presumed wild-type normal allele causes a frame shifted and truncated coding sequence. Our results indicate that subokra is the ancestral leaf shape of tetraploid cotton that gave rise to the okra allele and that normal is a derived mutant allele that came to predominate and define the leaf shape of cultivated cotton. Virus-induced gene silencing (VIGS) of the LMI1 like gene in an okra variety was sufficient to induce normal leaf formation. The developmental changes in leaves conferred by this gene are associated with a photosynthetic transcriptomic signature, substantiating its use by breeders to produce a superior cotton ideotype. PMID- 27999179 TI - Sensing danger. PMID- 27999180 TI - A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. AB - Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/betaGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/betaGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/betaGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders. PMID- 27999181 TI - Arabidopsis B-BOX32 interacts with CONSTANS-LIKE3 to regulate flowering. AB - Plants have the ability to respond to seasonal environmental variations by monitoring day length to initiate flowering. The transition from vegetative to the reproductive stage is the critical developmental switch in flowering plants to ensure optimal fitness and/or yield. It has been previously reported that B BOX32 (BBX32) has the potential to increase grain yield when ectopically expressed in soybean. In the present study, we performed a detailed molecular characterization of the Arabidopsis B-box domain gene BBX32 We showed that the circadian clock in Arabidopsis regulates BBX32 and expressed in the early morning. To understand the molecular mechanism of BBX32 regulation, we performed a large-scale yeast two-hybrid screen and identified CONSTANS-LIKE 3 (COL3)/BBX4 as one of its interacting protein partners. Using different genetic and biochemical assays, we have validated this interaction and shown that COL3 targets FT in the presence of BBX32 to regulate the flowering pathway. Based on these findings, we hypothesized that this BBX32-COL3 module could be an additional regulatory mechanism affecting the reproductive development in Arabidopsis that could be translated to crops for increased agricultural productivity. PMID- 27999182 TI - Multimode optomechanical system in the quantum regime. AB - We realize a simple and robust optomechanical system with a multitude of long lived (Q > 107) mechanical modes in a phononic-bandgap shielded membrane resonator. An optical mode of a compact Fabry-Perot resonator detects these modes' motion with a measurement rate (96 kHz) that exceeds the mechanical decoherence rates already at moderate cryogenic temperatures (10 K). Reaching this quantum regime entails, inter alia, quantum measurement backaction exceeding thermal forces and thus strong optomechanical quantum correlations. In particular, we observe ponderomotive squeezing of the output light mediated by a multitude of mechanical resonator modes, with quantum noise suppression up to 2.4 dB (-3.6 dB if corrected for detection losses) and bandwidths ?90 kHz. The multimode nature of the membrane and Fabry-Perot resonators will allow multimode entanglement involving electromagnetic, mechanical, and spin degrees of freedom. PMID- 27999183 TI - Block models and personalized PageRank. AB - Methods for ranking the importance of nodes in a network have a rich history in machine learning and across domains that analyze structured data. Recent work has evaluated these methods through the "seed set expansion problem": given a subset [Formula: see text] of nodes from a community of interest in an underlying graph, can we reliably identify the rest of the community? We start from the observation that the most widely used techniques for this problem, personalized PageRank and heat kernel methods, operate in the space of "landing probabilities" of a random walk rooted at the seed set, ranking nodes according to weighted sums of landing probabilities of different length walks. Both schemes, however, lack an a priori relationship to the seed set objective. In this work, we develop a principled framework for evaluating ranking methods by studying seed set expansion applied to the stochastic block model. We derive the optimal gradient for separating the landing probabilities of two classes in a stochastic block model and find, surprisingly, that under reasonable assumptions the gradient is asymptotically equivalent to personalized PageRank for a specific choice of the PageRank parameter [Formula: see text] that depends on the block model parameters. This connection provides a formal motivation for the success of personalized PageRank in seed set expansion and node ranking generally. We use this connection to propose more advanced techniques incorporating higher moments of landing probabilities; our advanced methods exhibit greatly improved performance, despite being simple linear classification rules, and are even competitive with belief propagation. PMID- 27999184 TI - Chiral twist drives raft formation and organization in membranes composed of rod like particles. AB - Lipid rafts are hypothesized to facilitate protein interaction, tension regulation, and trafficking in biological membranes, but the mechanisms responsible for their formation and maintenance are not clear. Insights into many other condensed matter phenomena have come from colloidal systems, whose micron scale particles mimic basic properties of atoms and molecules but permit dynamic visualization with single-particle resolution. Recently, experiments showed that bidisperse mixtures of filamentous viruses can self-assemble into colloidal monolayers with thermodynamically stable rafts exhibiting chiral structure and repulsive interactions. We quantitatively explain these observations by modeling the membrane particles as chiral liquid crystals. Chiral twist promotes the formation of finite-sized rafts and mediates a repulsion that distributes them evenly throughout the membrane. Although this system is composed of filamentous viruses whose aggregation is entropically driven by dextran depletants instead of phospholipids and cholesterol with prominent electrostatic interactions, colloidal and biological membranes share many of the same physical symmetries. Chiral twist can contribute to the behavior of both systems and may account for certain stereospecific effects observed in molecular membranes. PMID- 27999185 TI - Early and progressive deficit of neuronal activity patterns in a model of local amyloid pathology in mouse prefrontal cortex. AB - Alzheimer's Disease (AD) is the most common form of dementia. The condition predominantly affects the cerebral cortex and hippocampus and is characterized by the spread of amyloid plaques and neurofibrillary tangles (NFTs). But soluble amyloid-beta (Abeta) oligomers have also been identified to accumulate in the brains of AD patients and correlate with cognitive dysfunction more than the extent of plaque deposition. Here, we developed an adeno-associated viral vector expressing the human mutated amyloid precursor protein (AAV-hAPP). Intracranial injection of the AAV into the prefrontal cortex (PFC) allowed the induction of AD like deficits in adult mice, thereby modelling human pathology. AAV-hAPP expression caused accumulation of Abeta oligomers, microglial activation, astrocytosis and the gradual formation of amyloid plaques and NFTs. In vivo two photon imaging revealed an increase in neuronal activity, a dysfunction characteristic of the pathology, already during the accumulation of soluble oligomers. Importantly, we found that Abeta disrupts the synchronous spontaneous activity of neurons in PFC that, as in humans, is characterized by ultraslow fluctuation patterns. Our work allowed us to track brain activity changes during disease progression and provides new insight into the early deficits of synchronous ongoing brain activity, the "default network", in the presence of Abeta peptide. PMID- 27999186 TI - LHBs can elevate the expression of MDR1 through HIF-1alpha in patients with CHB infection: a comparative proteomic study. AB - BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). To gain a better understanding of the pathogenesis of HBV infection, this study aimed to investigate the differentially expressed proteins (DEPs) in liver tissues from patients with chronic hepatitis B (CHB) infection. RESULTS: Seventy-one DEPs were identified. Overexpression of multi-drug resistance protein 1 (MDR1) was validated by RT-qPCR and western blot analyses. Moreover, its expression was increased at both the mRNA and protein levels in response to overexpression of HBV large surface protein (LHBs). Furthermore, screening of transcription factors suggested the possible involvement of hypoxia-inducible factor 1alpha (HIF 1alpha) in the interaction between LHBs and MDR1. The function of HIF-1alpha in the MDR1 activation was confirmed by EMSA and reporter gene analyses. MATERIALS AND METHODS: Liver samples from CHB patients and controls without HBV infection were collected and subjected to isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometric analysis. CONCLUSIONS: These results imply that LHBs, in association with HIF-1alpha, induces MDR1 overexpression, which may contribute to the pathogenic changes in CHB infection. PMID- 27999187 TI - Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti cancer strategies. AB - Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2'O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies. PMID- 27999188 TI - The prognostic value of node status in different breast cancer subtypes. AB - Nodal metastases and breast cancer subtypes (BCS) are both well-recognized prognostic indicators. However, the association between nodal metastases and BCS, and the prognostic value of nodal metastases in different BCS are still remains unclear. Our aim was to investigate the association between nodal metastases and BCS, and the prognostic value of nodal metastases in the different BCS.We found that the breast cancer subtype was closely associated with the pN stage. pN stage and breast cancer subtype were significantly associated with disease-free survival. The subgroup analysis showed that the patients in higher pN stage had a poor outcome than patients in lower pN stage in each breast cancer subtype. Furthermore, when the analysis was stratified by breast cancer subtype, we found that even in the same pN stage (pN0-pN2), there was significant survival difference among patients in different BCS, and Luminal A breast cancer patients had the best survival outcome. However, there were no significant survival difference between Luminal A patients and other breast cancer subtype when patients in pN3 stage. Thus, our study suggested that both lymph node status and molecular subtype played important roles in the outcome of breast cancer patients and they cannot replace each other. PMID- 27999189 TI - Mesenchymal marker expression is elevated in Muller cells exposed to high glucose and in animal models of diabetic retinopathy. AB - Muller cells are retinal glial cells and exhibit a fibroblast-like phenotype and ability to migrate in diabetic retinopathy (DR). However, expression of mesenchymal markers, which promote fibrosis in various organs, has not been characterized in the diabetic retina. We examined changes in the expression of these markers in Muller cells exposed to high glucose and in animal models of diabetic retinopathy. High glucose conditions increased mesenchymal maker expression and migration in Muller cells. Snail, N-cadherin, Vimentin, beta catenin, and alpha-smooth muscle actin (alpha-SMA) levels were all dramatically increased in retinas from humans with diabetic retinopathy (DR) and from DR mouse models. In addition, Snail overexpression increased the expression of connective tissue growth factor (CTGF) and fibronectin, while Snail knockdown attenuated high glucose-induced increases in fibronectin and CTGF expression. These results demonstrate for the first time that mesenchymal markers are upregulated in retinas from a diabetic mouse model, and that Snail and N-cadherin levels are also increased in Muller cells exposed to high glucose. This suggests mesenchymal proteins may play a crucial role in the development of DR. PMID- 27999190 TI - Leptin-Notch signaling axis is involved in pancreatic cancer progression. AB - Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa 2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients. PMID- 27999191 TI - NHERF1 regulates the progression of colorectal cancer through the interplay with VEGFR2 pathway. AB - The oncogenic role of ectopic expression of Na+/H+ exchanger regulatory factor 1 (NHERF1) was recently suggested in colorectal cancer, where it was implicated in playing a role in the tumor hypoxia microenvironment. Here we showed that a high level expression of NHERF1 was found in colorectal cancer tissues and that the expression of NHERF1 was positively correlated with VEGFR2 expression. The prognostic value of VEGFR2 expression in colorectal cancer relied on the expression of NHERF1. The up-regulation of NHERF1 induced by the exposure to hypoxia in colon cancer cells depended on the activation of VEGFR2 signaling. NHERF1 in turn inhibited the activation of VEGFR2 signaling which could be regulated by the interaction between NHERF1 and VEGFR2, resulting in the reduction of migration and invasion of colon cancer cells. These results suggest a dynamic interplay between NHERF1 and VEGFR2 signaling in colorectal cancer, which could explain the contribution of NHERF1 to the regulation of tumor cell responses to the hypoxia microenvironment. PMID- 27999192 TI - Superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic adenocarcinoma. AB - The aim of this study is trying to describe more details of superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, to evaluate biological and prognostic implications of tumor budding in this margin, and to provide more evidence for evaluation of R0 surgery in pancreaticoduodenectomy. 46 patients in 5-years period are included in this study. Immunochemistry and immunofluorescence are used to analyze tumor budding and epithelial-mesenchymal transition. Superior mesenteric artery margin might be described from four aspects including location, gross appearance, microscopic appearance and tumor budding. We find that 1mm rule for R1 surgery is more appropriate to predict prognosis (P = 0.009) than 0mm rule (P = 0.141). Expression of cytokeratin in tumor budding is significantly lower than primary tumor (P = 0.001), and it suggests that tumor budding may participate the procedure of epithelial-mesenchymal transition. High-grade tumor budding and decreasing cytokeratin of tumor budding correlate with distant metastasis and has negative influence on prognosis. So superior mesenteric artery margin might be not only an area that tumor cells may invade, but also a pathway for distant metastasis. It is necessary to evaluate superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic cancer. PMID- 27999194 TI - Radiation-induced SOD2 overexpression sensitizes colorectal cancer to radiation while protecting normal tissue. AB - This study investigated whether radiation-induced overexpression of superoxide dismutase 2 (SOD2) exerts radio-sensitizing effects on tumor cells while having radio-protective effects on normal cells during radio-activated gene therapy for human colorectal cancer. A chimeric promoter, C9BC, was generated by directly linking nine tandem CArG boxes to a CMV basic promoter, after which lentiviral vectors containing GFP and SOD2 gene driven by the C9BC promoter were constructed. Stably transfected HT-29 colorectal cancer cells and CCD 841 CoN normal colorectal cells were irradiated to a dose of 6-Gy, and cell proliferation and apoptosis were observed. Tumor xenografts and peritumoral skin tissue in BALB/c mice were infected with the therapeutic lentivirus and subsequently irradiated with a total dose of 6 Gy. In vitro experiments revealed that radiation-induced SOD2 overexpression inhibited tumor cell proliferation (61.89% vs. 40.17%, P < 0.01) and decreased apoptosis among normal cells (14.8% vs. 9.6%, P = 0.02) as compared to untransfected cells. Similar effects were observed in vivo. Thus radiation-induced SOD2 overexpression via the chimeric C9BC promoter increased the radiosensitivity of HT-29 human colorectal cancer cells and concurrently protected normal CCD 841 CoN colorectal cells from radiation damage. PMID- 27999193 TI - The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins. AB - Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53 dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant. The response to JNJ-26854165 is associated with the downregulation of BCR/ABL dependently of proteosome activation. Moreover, in all tested CML cells, with the exception of T315I mutation cells, combining JNJ-26854165 and tyrosine kinase inhibitor (TKI) Imatinib or PD180970 leads to a synergistic effect. In conclusion, our results suggest that JNJ-26854165, used either alone or in combination with TKIs, represents a promising novel targeted approach to overcome TKI resistance and improve patient outcome in CML. PMID- 27999195 TI - Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3 triazole compound. AB - Hypoxia occurs in a variety of pathological events, including the formation of solid tumors. Hypoxia-inducible factor (HIF)-1alpha is stabilized under hypoxic conditions and is a key molecule in tumor growth and angiogenesis. Seeking to develop novel cancer therapeutics, we investigated small molecules from our in house chemical libraries to target HIF-1alpha. We employed a dual-luciferase assay that uses a luciferase (Luc) reporter vector harboring five copies of hypoxia-responsive element (HRE) in the promoter. Under hypoxic conditions that increased Luc reporter activity by four-fold, we screened 144 different compounds, nine of which showed 30-50% inhibition of hypoxia-induced Luc reporter activity. Among these, "Compound 12, a benzopyranyl 1,2,3-triazole" was the most efficient at inhibiting the expression of HIF-1alpha under hypoxic conditions, reducing its expression by 80%. Under hypoxic conditions, the half maximal IC50 of the compound was 24 nM in HEK-293 human embryonic kidney cells, and 2 nM in A549 human lung carcinoma cells. Under hypoxic conditions, Compound 12 increased hydroxylated HIF-1alpha levels and HIF-1alpha ubiquitination, and also dose dependently decreased HIF-1alpha target gene expression as well as vascular endothelial growth factor (VEGF) secretion. Furthermore, this compound inhibited VEGF-induced in vitro angiogenesis in human umbilical vein endothelial cells (HUVECs), and in vivo, it inhibited chick chorioallantoic membrane angiogenesis. In allogaft assays, cotreatment with Compound 12 and gefitinib significantly inhibited tumor growth and angiogenesis. Compound 12 can be a novel inhibitor of HIF-1alpha by accelerating its degradation, and shows much potential as an anti cancer agent through its ability to suppress tumor growth and angiogenesis. PMID- 27999196 TI - CHIR99021 combined with retinoic acid promotes the differentiation of primordial germ cells from human embryonic stem cells. AB - Primordial germ cells (PGCs) derived from human embryonic stem cells (hESCs) represent as a desirable experimental model as well as a potential strategy for treating male infertility. Here, we developed a simple and feasible method for differentiation of PGCs from hESCs by using CHIR99021 (an inhibitor of glycogen synthase kinase 3) and retinoic acid (RA). We firstly found that the deleted in azoospermia-like (DAZL) protein can be detected in 3 d CHIR99021 plus 9 d retinoic acid treated cultures and 12 d CHIR99021 plus retinoic acid co-treated cultures, but not expressed in single CHIR99021 treated cultures, single retinoic acid treated cultures, as well as 3 d retinoic acid plus 9 d CHIR99021 treated cultures. Next, we showed that several PGCs' markers were expressed in the 12 d CHIR99021 and retinoic acid co-treated cultures or 3 d CHIR99021 plus 9 d retinoic acid treated cultures. Moreover, meiosis was initiated in CHIR99021 and retinoic acid co-treated cultures as evidenced by a significant expression of the punctate synaptonemal complex protein 3 (SCP3). Fluorescent in situ hybridization (FISH) analysis indicated that a small percentage of putative 1N populations were formed. Mechanically, we found that beta-catenin relocated into nucleus after the treatment of 3 d CHIR99021 suggesting that Wnt signaling pathway was activated. Furthermore, blockade of Wnt signaling pathway by IWR-1 can reverse CHIR99021 and retinoic acid mediated-effects. Taken together, our results indicate that CHIR99021 combined with retinoic acid can effectively differentiate hESCs into PGCs via activating Wnt signaling pathway. PMID- 27999197 TI - Effects of lipopolysaccharide on maturation of bovine oocyte in vitro and its possible mechanisms. AB - Lipopolysaccharide disturbs the secretion of gonadotropin, endometrial function and implantation efficiency. However, there is little information regarding the effects of lipopolysaccharide on cyclic ovary activity, especially oocyte maturation. Therefore, we aimed to investigate the effects of lipopolysaccharide on the maturation potential of bovine oocytes. We found that lipopolysaccharide exposure significantly decreased the first polar body extrusion rate and delayed the cell cycle progression. The abnormal spindle rate was significantly increased in lipopolysaccharide treatment group, accompanied by disrupted localization and level of phosphorylated mitogen-activated protein kinase (p-MAPK). Moreover, lipopolysaccharide treatment significantly increased intracellular reactive oxygen species (ROS) levels and the early apoptotic rate in oocytes. The pro apoptotic caspase-3 and Bax mRNA levels and caspase-3 protein level were significantly increased, whereas the anti-apoptotic Bcl-2 and XIAP transcript abundance were significantly decreased in lipopolysaccharide exposure group. Furthermore, the dimethyl-histone H3 lysine 4 (H3K4me2) level was significantly increased, while the DNA methylation (5-mC) and dimethyl-histone H3 lysine 9 (H3K9me2) levels were markedly decreased in oocytes treated with lipopolysaccharide. In conclusion, lipopolysaccharide exposure inhibits the maturation potential of bovine oocytes by affecting cell cycle, cytoskeletal dynamics, oxidative stress, and epigenetic modifications. PMID- 27999199 TI - Rottlerin exhibits antitumor activity via down-regulation of TAZ in non-small cell lung cancer. AB - Rottlerin, a polyphenolic compound derived from Mallotus philipinensis, has been reported to exhibit anti-tumor activities in a variety of human malignancies including NSCLC (non-small cell lung cancer). TAZ (transcriptional co-activator with PDZ-binding motif), one of the key activators in Hippo pathway, has been characterized as an oncoprotein. Therefore, inhibition of TAZ could be useful for the treatment of human cancers. In the current study, we aimed to explore whether rottlerin inhibits the expression of TAZ in NSCLC, leading to its anti-cancer activity. Multiple approaches were applied for determining the mechanism of rottlerin-mediated anti-tumor function, including cell growth assay, Flow cytometry, wound healing assay, invasion assay, Western blotting, and transfection. We found that rottlerin inhibited cell growth, triggered apoptosis, arrested cell cycle, and retarded cell invasion in NSCLC cells. Moreover, our results showed that overexpression of TAZ enhanced cell growth, stimulated apoptosis, and promoted cell migration and invasion. Consistently, inhibition of TAZ exhibited anti-tumor activity in NSCLC cells. Notably, we validated that rottlerin exerted its tumor suppressive function via inactivation of TAZ in NSCLC cells. Taken together, our study indicates that inhibition of TAZ by rottlerin could be a promising strategy for the prevention and therapy of NSCLC. PMID- 27999198 TI - Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression. AB - Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (~150-1000 nm) and exosomes (~40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a 'fingerprint' of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression. PMID- 27999201 TI - The different outcomes between breast-conserving surgery and mastectomy in triple negative breast cancer: a population-based study from the SEER 18 database. AB - Breast-conserving surgery (BCS) including radiotherapy (RT) has been demonstrated to provide at least equivalent prognosis to mastectomy in early-stage breast cancer. However, studies on triple-negative breast cancer (TNBC) patients are relatively scarce. The current population-based study aimed to investigate the distinct outcomes between BCS+RT and mastectomy in patients with TNBC. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we enrolled 11,514 female TNBC cases diagnosed during the years 2010-2013. Those patients were subdivided into BCS+RT (5,469) and mastectomy groups (6,045), and we conducted a survival comparison between the two groups. The endpoints were breast cancer-specific survival (BCSS) and overall survival (OS). In the overall cohort, patients with BCS+RT exhibited distinctly better breast cancer-specific survival (BCSS) (log-rank, p < 0.001) and overall survival (OS) (log-rank, p < 0.001) than did mastectomy patients. When stratifying the TNBC patients according to age, histology grade, TNM stage, tumor size, and lymph node (LN) status, most patients in the BCS+RT group presented with better survival than did the patients in the mastectomy group, except for the grade I (log-rank, p = 0.830, both BCSS and OS) and stage I (log-rank, BCSS, p = 0.127; OS, p = 0.093) patients. In addition, after adjusting for confounding variables by multivariable Cox proportional hazard analysis, BCS+RT still tended to present with higher BCSS and OS. In conclusion, from our study on SEER data, BCS+RT displayed elevated BCSS and OS in TNBC patients compared to mastectomy, at least equally. Our study provided further evidence for surgeons that BCS with RT is available for TNBC patients. PMID- 27999200 TI - Metalloproteinase meprin alpha regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin. AB - Hepatocellular carcinoma is associated with a high rate of intra-hepatic invasion that carries a poor prognosis. Meprin alpha (Mep1A) is a secreted metalloproteinase with many substrates relevant to cancer invasion. We found that Mep1A was a target of Reptin, a protein that is oncogenic in HCC. We studied Mep1A regulation by Reptin, its role in HCC, and whether it mediates Reptin oncogenic effects.MepA and Reptin expression was measured in human HCC by qRT-PCR and in cultured cells by PCR, western blot and enzymatic activity measurements. Cell growth was assessed by counting and MTS assay. Cell migration was measured in Boyden chambers and wound healing assays, and cell invasion in Boyden chambers.Silencing Reptin decreased Mep1A expression and activity, without affecting meprin beta. Mep1A, but not meprin beta, was overexpressed in a series of 242 human HCC (2.04 fold, p < 0.0001), and a high expression correlated with a poor prognosis. Mep1A and Reptin expressions were positively correlated (r = 0.39, p < 0.0001). Silencing Mep1A had little effect on cell proliferation, but decreased cell migration and invasion of HuH7 and Hep3B cells. Conversely, overexpression of Mep1A or addition of recombinant Mep1A increased migration and invasion. Finally, overexpression of Mep1A restored a normal cell migration in cells where Reptin was depleted.Mep1A is overexpressed in most HCC and induces HCC cell migration and invasion. Mep1A expression is regulated by Reptin, and Mep1A mediates Reptin-induced migration. Overall, we suggest that Mep1A may be a useful target in HCC. PMID- 27999202 TI - LncRNA16 is a potential biomarker for diagnosis of early-stage lung cancer that promotes cell proliferation by regulating the cell cycle. AB - Early diagnosis of lung cancer greatly reduces mortality; however, the lack of suitable plasma biomarkers presents a major obstacle. Recent studies showed that long noncoding RNAs (lncRNAs) played important roles in cancer initiation and development. Here, we identified differentially expressed lncRNAs in 20 lung cancer samples by using custom designed microarray and evaluated their expression in 118 lung cancer samples by real-time PCR (qRT-PCR). lncRNA16 (ENST00000539303) expression was significantly higher in lung cancer tissues (80/118) than in adjacent matched normal tissues. Importantly, this increase was similar to that in plasma (53/84) of lung cancer patients, including early stage. The role of lncRNA16 in lung cancer was studied in vitro and in vivo by using the lung cancer cell lines and xenograft mouse models. The results reveal that knockdown of lncRNA16 inhibited proliferation of PC9 cells in vitro and also inhibited tumor growth in xenograft mouse models. Overexpression of lncRNA16 promoted proliferation of A549 cells in vitro and also promoted tumor growth in xenograft mouse models. Specifically, we showed that lncRNA16 promoted G2/M transition by regulating cyclin B1 transcription. Together, our findings suggest that lncRNA16 is a promising biomarker suitable for early diagnosis of lung cancer, and a potential target for lung cancer treatment. PMID- 27999203 TI - Serine protease inhibitor kazal-type 6 inhibits tumorigenesis of human hepatocellular carcinoma cells via its extracellular action. AB - Hepatocellular carcinoma (HCC) causes significant medical burdens worldwide. Diagnosis, especially in the early stages, is still challenging. Therapeutic options are limited and often ineffective. Although several risk factors have been known important for development of HCC, the molecular basis of the process is rather complex and has not been fully understood. We have found that a subpopulation of HCC cells which are resistant to oncolytic parvovirus H1 superinfection highly express serine protease inhibitor Kazal-type 6 (SPINK6). This protein is specifically reduced in all HCC cell lines and tissues we analyzed. When upregulated, SPINK6 could suppress the malignant phenotypes of the HCC cells in several in vitro models. The putative tumor suppression role of SPINK6 is, however, independent of its protease inhibitory activity. To suppress the malignancy of HCC cells, SPINK6 has to be secreted to trigger signals which regulate an intracellular signaling molecule, ERK1/2, as well as a series of downstream factors involved in cell cycle progression, apoptosis and migration. Our study supports that SPINK6 is an important tumor suppressor in liver, and further investigations may help develop more effective diagnostic and therapeutic approaches. PMID- 27999204 TI - Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes. AB - Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. The RG7787 RIT targets the cancer antigen mesothelin to deliver a recombinantly-engineered, reduced immunogenicity variant of Pseudomonas exotoxin A (PE) to the cytosol where it inhibits protein synthesis. Here we demonstrate that maximal doses of RG7787 temporarily halt growth of pancreatic cancer tumor xenografts, similar to the approved drugs gemcitabine and nab-paclitaxel, however, combination of the RIT with nab-paclitaxel produces durable complete regressions in most mice. Synergy between taxane and anti-MSLN RITs has been previously demonstrated in mouse models, but direct interaction of the combination in cell culture was not observed. Here, we show that this favorable interaction occurs in cell culture, is dependent on the dose and duration of RG7787 exposure, requires the catalytically active PE, and still occurs with RIT targeting a non-MSLN surface antigen. Unexpectedly, the combination does not increase RG7787-mediated protein synthesis inhibition nor perturb downstream apoptotic markers of RIT-mediated killing, but does augment levels of acetylated tubulin, a marker of taxane activity. Taken together, these data suggest that PE increases cell sensitivity to taxane-mediated killing by increasing taxane mediated microtubule stability and priming cells for apoptosis by decreasing levels of the pro-survival factor Mcl-1. PMID- 27999205 TI - MutY-Homolog (MYH) inhibition reduces pancreatic cancer cell growth and increases chemosensitivity. AB - Patients with pancreatic ductal adenocarcinoma (PC) have a poor prognosis due to metastases and chemoresistance. PC is characterized by extensive fibrosis, which creates a hypoxic microenvironment, and leads to increased chemoresistance and intracellular oxidative stress. Thus, proteins that protect against oxidative stress are potential therapeutic targets for PC. A key protein that maintains genomic integrity against oxidative damage is MutY-Homolog (MYH). No prior studies have investigated the function of MYH in PC cells. Using siRNA, we showed that knockdown of MYH in PC cells 1) reduced PC cell proliferation and increased apoptosis; 2) further decreased PC cell growth in the presence of oxidative stress and chemotherapy agents (gemcitabine, paclitaxel and vincristine); 3) reduced PC cell metastatic potential; and 4) decreased PC tumor growth in a subcutaneous mouse model in vivo. The results from this study suggest MYH may be a novel therapeutic target for PC that could potentially improve patient outcome by reducing PC cell survival, increasing the efficacy of existing drugs and reducing metastatic spread. PMID- 27999206 TI - Clinicopathological and prognostic significance of COX-2 immunohistochemical expression in breast cancer: a meta-analysis. AB - The prognostic significance of COX-2 in patients with breast cancer remains controversial. The aims of our meta-analysis are to evaluate its association with clinicopathological characteristics and prognostic value in patients with breast cancer. PubMed, EMBASE, Web of Science, the Ovid Database and Grey literature were systematically searched up to May 2016. Twenty-one studies including 6739 patients with breast cancer were analyzed. The meta-analysis indicated that the incidence difference of COX-2 expression was significant when comparing the lymph node positive group to negative group (OR = 1.76, 95% CI [1.30, 2.39]) and the tumor size >= 2cm group to the tumor size < 2cm group (OR = 1.71, 95% CI [1.22, 2.39]). None of other clinicopathological parameters such as the ER status, PR status, HER2 status and the vascular invasion status were associated with COX-2 overexpression. The detection of COX-2 was significantly correlated with the disease-free survival (DFS) of patients (HR = 1.58, 95% CI [1.23, 2.03]) and the overall survival (OS) of patients (HR = 1.51, 95% CI [1.31, 1.72]). Our meta analysis demonstrates that the presence of high levels of COX-2 is associated with poor prognosis for breast cancer patients and predicts bigger tumor size and lymph node metastasis. PMID- 27999208 TI - Detection of 14-3-3 sigma (sigma) promoter methylation as a noninvasive biomarker using blood samples for breast cancer diagnosis. AB - As a tumor suppressor gene, 14-3-3 sigma has been reported to be frequently methylated in breast cancer. However, the clinical effect of 14-3-3 sigma promoter methylation remains to be verified. This study was performed to assess the clinicopathological significance and diagnostic value of 14-3-3 sigma promoter methylation in breast cancer. 14-3-3 sigma promoter methylation was found to be notably higher in breast cancer than in benign lesions and normal breast tissue samples. We did not observe that 14-3-3 sigma promoter methylation was linked to the age status, tumor grade, clinic stage, lymph node status, histological subtype, ER status, PR status, HER2 status, or overall survival of patients with breast cancer. The combined sensitivity, specificity, AUC (area under the curve), positive likelihood ratios (PLR), negative likelihood ratios (NLR), diagnostic odds ratio (DOR), and post-test probability values (if the pretest probability was 30%) of 14-3-3 sigma promoter methylation in blood samples of breast cancer patients vs. healthy subjects were 0.69, 0.99, 0.86, 95, 0.31, 302, and 98%, respectively. Our findings suggest that 14-3-3 sigma promoter methylation may be associated with the carcinogenesis of breast cancer and that the use of 14-3-3 sigma promoter methylation might represent a useful blood-based biomarker for the clinical diagnosis of breast cancer. PMID- 27999207 TI - Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells. AB - Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed. PMID- 27999209 TI - S4S8-RPA phosphorylation as an indicator of cancer progression in oral squamous cell carcinomas. AB - Oral cancers are easily accessible compared to many other cancers. Nevertheless, oral cancer is often diagnosed late, resulting in a poor prognosis. Most oral cancers are squamous cell carcinomas that predominantly develop from cell hyperplasias and dysplasias. DNA damage is induced in these tissues directly or indirectly in response to oncogene-induced deregulation of cellular proliferation. Consequently, a DNA Damage response (DDR) and a cell cycle checkpoint is activated. As dysplasia transitions to cancer, proteins involved in DNA damage and checkpoint signaling are mutated or silenced decreasing cell death while increasing genomic instability and allowing continued tumor progression. Hyperphosphorylation of Replication Protein A (RPA), including phosphorylation of Ser4 and Ser8 of RPA2, is a well-known indicator of DNA damage and checkpoint activation. In this study, we utilize S4S8-RPA phosphorylation as a marker for cancer development and progression in oral squamous cell carcinomas (OSCC). S4S8 RPA phosphorylation was observed to be low in normal cells, high in dysplasias, moderate in early grade tumors, and low in late stage tumors, essentially supporting the model of the DDR as an early barrier to tumorigenesis in certain types of cancers. In contrast, overall RPA expression was not correlative to DDR activation or tumor progression. Utilizing S4S8-RPA phosphorylation to indicate competent DDR activation in the future may have clinical significance in OSCC treatment decisions, by predicting the susceptibility of cancer cells to first line platinum-based therapies for locally advanced, metastatic and recurrent OSCC. PMID- 27999210 TI - LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. AB - Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms. Here, we further examined the effects of LY3009120, a panRAF and RAF dimer inhibitor, in human models of CRC with various mutational backgrounds. We demonstrate that LY3009120 induced anti proliferative effects in BRAFmut and KRASmut CRC cell lines through G1-cell cycle arrest. The anti-proliferative effects of LY3009120 in KRASmut CRC cell lines phenocopied molecular inhibition of RAF isoforms by simultaneous siRNA-mediated knockdown of ARAF, BRAF and CRAF. Additionally, LY3009120 displayed significant activity in in vivo BRAFmut and KRASmut CRC xenograft models. Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRASmut CRC cell line HCT 116. These findings describe the preclinical activity of a panRAF inhibitor in a BRAFmut and KRASmut CRC setting. PMID- 27999211 TI - The role of T790M mutation in EGFR-TKI re-challenge for patients with EGFR-mutant advanced lung adenocarcinoma. AB - Epidermal growth factor receptor (EGFR) T790M mutation has shown to be associated with the clinical outcomes of patients after initial EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy in EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, its predictive role in EGFR-TKI re-challenge remains unknown. The present study was aimed to explore the correlation between T790M mutation and any benefits from EGFR-TKI re-challenge. We retrospectively reviewed 922 consecutive patients with EGFR-mutant non-small cell lung cancer (NSCLC) patients administered with gefitinib/erlotinib at Guangdong General Hospital. Progression free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were analyzed respectively. In total, 66 EGFR-mutant patients with stage IV adenocarcinoma were eligible, of whom 51 underwent re biopsy upon initial progression. Among them, 18 (35.3%) harbored T790M mutation. No statistical significant differences were seen between T790M-positive and T790M negative patients in PFS, OS, ORR or DCR. The median PFS, median OS, ORR, and DCR of the overall 66 patients were 2.0 months, 6.8 months, 6.1% and 39.4%, respectively. Good performance status (PS) was found to be independent favorable prognostic factor and long TKI-free interval to be associated with superior PFS. In conclusion, T790M mutation might not predict the clinical outcomes in first generation EGFR-TKI re-challenge. Based on the poor efficacy from our data, re challenge of first-generation EGFR-TKIs could not be recommended routinely, but for those with good PS and long TKI-free interval, it might be an alternative option. PMID- 27999213 TI - Poliomyelitis: residual hurdles to global eradication. Commentary. AB - The global eradication of polio is close to achieving success. However, transmission of wild poliovirus persists in countries where the disease is endemic, and outbreaks may also occur in previously polio-free countries where population immunity is not maintained. To achieve polio eradication, several key actions are required: (1) to detect any poliovirus transmission, (2) to strengthen immunization systems and withdraw all oral polio vaccines from use, (3) to contain polioviruses and certify interruption of transmission, and (4) to sustain ongoing public health programs. In this context, residual hurdles to global polio eradication have been identified, from unstable political situation in affected countries to population movements from and to endemic areas, and opposition to immunization strategies. Global efforts are needed in order to promote routine immunization campaigns and large-scale vaccination rounds, which may provide direct protection of individuals and minimize virus circulation. PMID- 27999214 TI - Contamined sites: a global issue. Preface. PMID- 27999215 TI - Exploring available options in characterising the health impact of industrially contaminated sites. AB - Industrially contaminated sites (ICS) are of high concern from an environmental public health perspective, since industrial plants may produce a widespread contamination that can result in several health impacts on the populations living in their neighbourhood. The objective of this contribution is to briefly explore available options in studying the health impact of ICS, mainly referring to information provided by documents and activities developed by the WHO and the WHO Collaborating Center for Environmental Health in Contaminated Sites. In current practice the health impact of ICS is evaluated using studies and assessments falling in two broad types of strategies: one based on epidemiology and the other on risk assessment methods. In recent years, traditional approaches to assess relationships between environmental risks and health has been evolved considering the intricate nature between them and other factors. New developments should be explored in the context of ICS to find common strategies and tools to assess their impacts and to guide public health interventions. PMID- 27999216 TI - Ethical aspects of epidemiological research in contaminated sites. AB - This paper brings understanding to the ethical dimensions of human health research conducted in the context of contaminated sites. Principle-based ethical analysis, complemented with virtuous traits of character, aid in bringing clarity to recommendations for actions following research. Epidemiology is the discipline for conducting health research not only because of its methodological foundations, but also because of its social justice focus. Because contaminated sites include communities that have been exposed to excessive concentrations of hazardous substances, extra care is needed when using epidemiology. For instance, vigilance over potential influence and engagement with affected communities are needed. Community engagement not only aids in understanding the contextual framework, but also demonstrates respect for both community and individual autonomy. Ethical analysis makes transparent the rationale for decisions against which researchers can be held accountable and provides a basis for evaluating observed outcomes as a function of the rationale provided for past actions. PMID- 27999212 TI - MicroRNAs as regulators and mediators of forkhead box transcription factors function in human cancers. AB - Evidence has shown that microRNAs are widely implicated as indispensable components of tumor suppressive and oncogenic pathways in human cancers. Thus, identification of microRNA targets and their relevant pathways will contribute to the development of microRNA-based therapeutics. The forkhead box transcription factors regulate numerous processes including cell cycle progression, metabolism, metastasis and angiogenesis, thereby facilitating tumor initiation and progression. A complex network of protein and non-coding RNAs mediates the expression and activity of forkhead box transcription factors. In this review, we summarize the current knowledge and concepts concerning the involvement of microRNAs and forkhead box transcription factors and describe the roles of microRNAs-forkhead box axis in various disease states including tumor initiation and progression. Additionally, we describe some of the technical challenges in the use of the microRNA-forkhead box signaling pathway in cancer treatment. PMID- 27999217 TI - A survey on lifestyle and level of biomarkers of environmental exposure in residents in Civitavecchia (Italy). AB - BACKGROUND: The assessment of individual exposure to toxicants in industrially contaminated areas is difficult when multiple productions are active close to residential areas. Two thermoelectric power plants and a large harbor have been operating since the '60s in the area of Civitavecchia (North of Rome). METHODS: The ABC (Ambiente e Biomonitoraggio nell'area di Civitavecchia, Environment and Biomonitoring in Civitavecchia) program involved, in the period 2013-2014, residents in Civitavecchia and in the nearby municipalities (Santa Marinella, Allumiere, Tolfa and Tarquinia). They were randomly selected from the Municipal Register's data and their residence addresses were geocoded using GIS techniques. Biomonitoring of the following urinary metals, Sb, Be, Mo, Cd, Sn, W, Ir, Pt, Hg, Tl, V, Cr, Mn, Co, Ni, Cu, Zn, Rh, Pd, As were performed. Glucose and lipid metabolism, liver, renal, and endocrine function were evaluated through blood laboratory tests. Tests of lung functionwere also carried out as well as saturometry (oxygen rate in the blood with an illuminated sensor placed on the fingertip), anthropometric and blood pressure measurements. Information on individual characteristics, histories of exposure, such as the consumption of local food, occupational history, lifestyle and medical history were collected through a validated questionnaire. Samples of nails and hair were also collected. The biological material (blood, urine, nails and hair) was stored in a biobank for future analysis related to the possible mechanisms of biological damage. The study protocol received the approval of the local ethics committee. RESULTS: A total of 1177 residents were enrolled (58% female, 60% with a secondary or graduate school degree). No particular differences in metal concentrations based on the municipality of residence were observed. For arsenic, mercury, lead, and tungsten some differences between the two geographical areas were observed, probably due to different diet, lifestyle (e.g., alcohol consumption, smoking, use of jewelry and piercings, tattoos, physical activity, hormonal and mineral supplements, and drugs), and occupational exposure. CONCLUSIONS: The undergoing study on the association between biomarkers concentration and pollutants concentrations - estimated using a dispersion modeling approach, and adjusting for personal characteristics and concomitant other environmental exposure - could clarify the individual exposure of the residents in this industrial area. PMID- 27999218 TI - Environmental nickel exposure from oil refinery emissions: a case study in Ecuador. AB - INTRODUCTION: Nickel is a strong skin and respiratory sensitizer and a recognized carcinogen. Oil refineries are important sources of atmospheric emissions of toxic pollutants, including nickel. Populations residing close to oil refineries are at potential risk. The aim of this study was to evaluate the exposure to nickel in a population living close to the largest oil refinery in Ecuador, located in the city of Esmeraldas. METHODOLOGY: We recruited 47 workers from the oil refinery as well as 195 students from 4 different schools close to the plant and 94 students from another school 25 km far from the industry. Urinary nickel concentrations were used to assess the exposure to nickel. RESULTS: Students from the school next to the oil refinery showed the highest urinary nickel concentrations while workers from the refinery showed the lowest concentrations. Median nickel concentrations were > 2ug/L in all study groups. CONCLUSIONS: The populations living close to the oil refineries are potentially exposed to nickel from atmospheric emissions. Further studies investigating nickel-related health effects in the population residing close to the refinery of Esmeralda are needed. PMID- 27999219 TI - Agricultural areas in potentially contaminated sites: characterization, risk, management. AB - INTRODUCTION: In Italy, the current legislation for contaminants in soils provides two land uses: residential/public or private gardens and commercial/industrial; there are not specific reference values for agricultural soils, even if a special decree has been developed and is currently going through the legislative approval process. The topic of agricultural areas is relevant, also in consideration of their presence near potentially contaminated sites. Aim and results. In this paper, contamination sources and transport modes of contaminants from sources to the target in agricultural areas are examined and a suitable "conceptual model" to define appropriate characterization methods and risk assessment procedures is proposed. These procedures have already been used by the National Institute of Health in various Italian areas characterized by different agricultural settings. CONCLUSION: Finally, specific remediation techniques are suggested to preserve soil resources and, if possible, its particular land use. PMID- 27999220 TI - The relevance of the food production chain with regard to the population exposure to chemical substances and its role in contaminated sites. AB - Food may be contaminated with many chemical substances at any level along the production chain. Chemicals that may be found in food items can simultaneously be present in other matrices, as air, water, soil and dust; therefore, human exposure to chemicals via food has to be summed to the exposure through all the other possible routes. The role played by the food production chain with regard to the population exposure to chemicals assumes amplified proportions when considering contaminated sites. Indeed the link between environment and food production is undeniable and consequently, when population chemical exposure is considered, an integrated approach assessing the contribution of the different routes of exposure, including dietary exposure, is needed. Such integrated approach allows a realistic and comprehensive risk assessment of chemical substances in order to identify and deploy effective prevention and intervention measures to protect human health. PMID- 27999221 TI - Fostering public health awareness on risks in contaminated sites. Capacity building and dissemination of scientific evidence. AB - The article focuses on the multidisciplinary nature of public health and the need to develop target oriented capacity building and dissemination plans taking into account both scientific evidence and the information needs of the different stakeholders. In particular, issues regarding stakeholders' involvement in epidemiological studies in contaminated sites, considering their different levels of awareness on risk characterization and management, are discussed. In a public health perspective, the main stakeholders in contaminated sites are researchers and public health officers, risk managers and policy makers, population residing in the contaminated areas, environmental associations, patient's organizations. The different components of a dissemination strategy addressed to different stakeholders are analyzed with the objective to create awareness and preparedness to facilitate management in contaminated sites, foster scientific knowledge and informed decisions to consolidate risk perception through science-driven information. PMID- 27999222 TI - A cross-disciplinary approach to global environmental health: the case of contaminated sites. AB - Cross-disciplinary approaches to Global Environmental Health are essential to address environmental health threats within and beyond national boundaries, taking into account the links among health, environment and socio-economic development. The aim of this study is to present a cross-disciplinary approach where knowledge and findings from environmental epidemiology and social research are integrated in studying environmental health issues, focusing on environmental health inequities, public and environmental health literacy, and international scientific cooperation. In the case of contaminated sites, environmental epidemiology can contribute investigating the multidimensionality of equity for sustainable development practices. These practices entail a better understanding of environmental contamination, health effects pathways and improved capacities of different stakeholders to identify policy options for environmental risk prevention, remediation and management that will foster informed participation in decisions influencing communities. International scientific cooperation frameworks adopting equity principles shared by scientific community, populations and decision-makers may be of valuable support to this task. PMID- 27999223 TI - Health software: a new CEI Guide for software management in medical environment. AB - INTRODUCTION: The increasing spread of software components in the healthcare context renders explanatory guides relevant and mandatory to interpret laws and standards, and to support safe management of software products in healthcare. METHODOLOGY: In 2012 a working group has been settled for the above purposes at Italian Electrotechnical Committee (CEI), made of experts from Italian National Institute of Health (ISS), representatives of industry, and representatives of the healthcare organizations. RESULTS: As a first outcome of the group activity, Guide CEI 62-237 was published in February 2015. The Guide incorporates an innovative approach based on the proper contextualization of software products, either medical devices or not, to the specific healthcare scenario, and addresses the risk management of IT systems. CONCLUSIONS: The Guide provides operators and manufacturers with an interpretative support with many detailed examples to facilitate the proper contextualization and management of health software, in compliance with related European and international regulations and standards. PMID- 27999224 TI - Knowledge of HIV infection and transmission: a knowledge, attitudes, beliefs and practices (KABP) survey among a sample of students at the "Magna Graecia", University of Catanzaro. AB - BACKGROUND: Continuous spreading of HIV infection may be due to lack of knowledge, especially among young people. It is important to monitor level of knowledge and risk behaviours especially in young people to set up appropriate preventative and informative campaigns. METHODS: We assessed knowledge of HIV infection and risk factors in a sample of students at the "Magna Graecia" University of Catanzaro, using an anonymous multiple-choice questionnaire. RESULTS: Two-hundred and sixteen medical students attending the first year at "Magna Graecia" University (age: 18-20 years) were prescribed an anonymous multiple-choice questionnaire. Knowledge of HIV infection was scarce in a significant percentage of students. They were often practicing risk behaviours at risk for acquisition of HIV infection and other sexually transmitted infections. CONCLUSION: This study shows that preventative and informative campaigns are urgently needed in earlier stage of adolescence to avoid acquisition of HIV infection and other sexually transmitted diseases. PMID- 27999225 TI - PASSI d'Argento (Silver Steps): the main features of the new nationwide surveillance system for the ageing Italian population, Italy 2013-2014. AB - BACKGROUND: Italy is particularly concerned by population ageing. The costs for society are substantial. In this context a national, representative surveillance system, Passi D'Argento (PDA), was implemented in 2009 to monitor "active aging" and health status in people aged over 64 and to develop preventive health programs to reduce frailty. METHODS/DESIGN: PDA recruited a representative sample of 24 129 individuals (March 2012-January 2013) aged over 64 who were interviewed by trained staff using a standardized questionnaire. The PDA collects information about participation in society and employment, independent living, health conditions, safety and living environment. Indicator values are used to obtain population health profiles and to compare different LHUs' profiles within the same region or between different regions. DISCUSSION: The PDA surveillance system proved to be feasible and to be a powerful and innovative local and national tool for monitoring health status, frailty in Italy's elderly population and the essential levels of care currently provided to the elderly. PMID- 27999226 TI - Gestational age and hospital utilization: three-years follow-up of an area-based birth cohort. AB - OBJECTIVE: To investigate differences by gestational age in emergency department visits and re-hospitalizations during the three years following childbirth discharge. METHODS: We performed a historical cohort study in Lazio Region, Italy, for infants born in 2007-2008 to resident mothers. Health administrative data were used. Analysis was performed by multinomial logistic regression. RESULTS: Of 90 545 infants, more than 50% had at least one emergency department visit, and 18.8% at least one re-hospitalization. After the exclusion of infants with congenital anomalies, relative risk ratios of re-hospitalization and, to a lesser extent, of emergency department visits increased by decreasing gestational age; the two events were also higher for mothers <=35 years of age, with low education and of Italian nationality. Residency outside the metropolitan area was associated with an increased risk of re-hospitalization and a decreased risk of emergency department visits. CONCLUSION: During the three years following childbirth discharge, re-hospitalizations and, to a lesser extent, emergency department use are inversely related to gestational age at birth; socio demographic factors have an effect on the risk of infant use of hospital resources independent of gestational age. PMID- 27999227 TI - The changing phenotype of iodine deficiency disorders: a review of thirty-five years of research in north-eastern Sicily. AB - Iodine deficiency disorders (IDD) still represent a major public health problem, with almost 30% of the world population being exposed to the consequences of nutritional iodine deficiency (ID). In Italy, despite a sustained policy of iodine prophylaxis, more than 10% of people is still affected with goiter, and a presumably higher rate of subjects may suffer from minor cognitive deficits due to inadequate iodine supply during antenatal life. This review of systematic observational studies carried out over thirty-five years (1980-2015) in a sentinel ID area in North-eastern Sicily highlights the changing phenotypes of IDD in this region. Over the years profound improvements in nutritional iodine status in North-eastern Sicily has occurred, due to both silent and active iodine prophylaxis. Endemic cretinism, resulting from severe iodine deficiency, has been progressively replaced by less serious deficits of intellectual and cognitive abilities, which nevertheless deserve proper attention. PMID- 27999228 TI - Barriers to the development of pediatric palliative care in Italy. AB - INTRODUCTION: In recent years the emergence of new types of patient, clinical situations, technological frontiers and "health" objectives have changed considerably the needs of ill children, this also concerns pediatric palliative care (PPC). In Italy, despite the introduction of legislation (Law 38/2010) stipulating the right of children and families to access appropriate services for pain control and pediatric palliative care, the availability of these services is still limited. AIM: The aim of this study is to highlight, through a review of the existing data and published literature, the critical issues that obstacle the planning and development of PPC services in Italy. RESULTS: Four main areas identified were: socio-cultural setting; types of patients and nature of diseases requiring PPC; training for PPC providers; regulatory and political issues. CONCLUSIONS: This type of analysis can provide the rational for advancing proposals and developing supportive, corrective and implementation strategies. PMID- 27999229 TI - Continuous professional development and health sector governance in Egypt. AB - The Authors present the main activities and results of a Project financed by the Italian-Egyptian Debt Swap Agreement (IEDDS/DS) of the Italian Development Cooperation to repay public debt. The Health Governance Project operated within the Egyptian health reform paradigm and aimed at producing evidence for policy makers to direct and reorient the health sector and service management. It developed along three phases: i) preparatory training of trainers, ii) training in health governance according to modern andragogic methods, such as problem based learning, iii) following implementation. Project strategy focused on a training of trainers method that allowed establishing a Health Governance Unit, that is successfully replicating the Health Governance Course. It established a collaborative ground in Alexandria Governorate, jointly with public and private sector stakeholders. PMID- 27999230 TI - Melanoma prevention in children: knowledge, attitudes and behaviors of pediatricians in Italy. AB - INTRODUCTION: The aims of this study were to assess the levels of knowledge, attitudes and behaviors of pediatricians about melanoma and to estimate any variables associated with this outcome of interest. MATERIALS AND METHODS: A cross-sectional survey was conducted on a sample of pediatricians using a questionnaire sent by postal mail. RESULTS: 40.8% and 41.6% of pediatricians respectively stated that they "often" and "always" carried out a full skin examination during routine checkups of children. Only 14.1% and 21.1% "always" informed parents about risk factors for melanoma and about preventive interventions respectively. The results of the multivariate logistic regression analysis have revealed that older pediatricians, those who believed the role of pediatricians in the prevention of melanoma is very important, those who considered a skin examination during routine visits to be very important and those who acquired information about melanoma were more likely to "always" perform a full skin examination of children and inform parents about preventive interventions for melanoma. CONCLUSIONS: The findings indicate that pediatricians need to be more careful regarding malignant melanoma prevention in order to play a crucial role in the educational instruction of parents and the dissemination of the most effective intervention screenings. PMID- 27999232 TI - The relationship between medical ethics and the legal system in Italy: food for thought. AB - Relations between ethics in general - and medical ethics in particular - and legal systems are complex and have been extensively examined in the literature. The topic is important not only for ethicists and jurists, but also for members of the public, who benefit from the services offered by the professions. While the Italian Institute of Health does not claim to propose new avenues for exploration of the relations between ethics and legal systems, it offers some food for thought in the ongoing debate. PMID- 27999231 TI - Adverse reproductive outcomes associated with exposure to a municipal solid waste incinerator. AB - INTRODUCTION: The association between reproductive health outcomes and exposure to municipal solid waste incinerators (MSWIs) is inconclusive. This study investigates the association between exposure to a MSWI and various reproductive outcomes (preterm birth, low birth weight, small for gestational age, and sex ratio), taking into account other sources of pollution (industrial plants, highway, major roads with high traffic flows) and maternal factors, including the socioeconomic status. METHODS: PM10 concentration maps were used for the exposure assessment to the MSWI and to other sources of pollution in the study area. Information on resident births and maternal covariates were selected from the delivery certificates referred to the period 2001-2010. Mothers' addresses were geocoded in order to attribute the individual level of exposure. Odds ratios (ORs) with a 95% confidence interval (CI) adjusted for maternal covariates and exposure to other pollution sources were calculated. RESULTS: A total of 3153 newborns to 2401 mothers residing in area during the study period were analyzed. A risk of preterm birth associated with increased exposure was detected (OR = 1.61; 95% CI: 0.88-2.94; p test for trend 0.098). When newborns to primiparous women were considered an OR of 2.18 (95% CI: 1.05-4.53) and a significant trend were observed (p = 0.033). No significant results for the other investigated outcomes were observed. CONCLUSIONS: The study detected a slight association between exposure at MSWI and preterm births. The results are in agreement with those of a previous multi-site study with similar design, and they strengthen the recommendation to consider gestational age in studies and surveillance in areas with MSWIs and similar sources of pollution. PMID- 27999233 TI - Smallpox as an actual biothreat: lessons learned from its outbreak in ex Yugoslavia in 1972. AB - Variola (smallpox) virus is classified as class A of potential biological weapons, due to its microbiological, genetic, antigenic and epidemiological characteristics. The potential danger is more real because vaccination against smallpox has stopped since disease eradication in 1979. That is why we want to share our unique, rich experience and acquired knowledge in the fight against this highly contagious and deadly disease during the smallpox outbreak in ex Yugoslavia in 1972. It was the largest postwar outbreak in Europe when there were officially registered 175 ill patients, 35 of them with lethal outcome. This outbreak was specific by the time of its occurrence, the affected territory, dimensions and some epidemiological characteristics, but also by the well organized, synchronized and efficient reaction of the competent state services in the fight against it. PMID- 27999234 TI - Teleretinography into diabetes integrated care: an Italian experience. AB - INTRODUCTION: Integrated care, by allowing information exchange among health professionals, improves outcomes and favours a reduction in hospital admission in diabetes. Retinal complications can be sight-threatening, and diabetic patients often miss the suggested yearly clinical examination. METHODS: Teleretinography can be easily performed in patients attending Diabetes Clinics: images are sent to a remote ophthalmologist, grading and instructions are received and forwarded to General Practitioners by a dedicated software. RESULTS: We here report the results of teleretinography performed in our Diabetes Clinic in 362 patients missing the yearly fundus examination: 253 patients showed no diabetic retinopathy, 86 a mild form, and 23 needed referral to hospital settings. CONCLUSIONS: Teleretinography is a user-friendly, time-saving and cost-effective technique, easily integrable into integrated care, allowing a better adherence to guidelines. PMID- 27999235 TI - Drug-resistant tuberculosis in Naples, 2008-2013. AB - BACKGROUND: Drug-resistant tuberculosis (TB) is a serious threat in industrialized countries, but information from Southern Italy is lacking. Here, we present the results of a retrospective study of TB cases diagnosed in 2008 2013 in Naples, the largest city in Southern Italy. METHODS: Six hundred ninety Mycobacterium tuberculosis strains were isolated at the Ospedali dei Colli of Naples, and resistance to first-line and second-line drugs was determined. RESULTS: Multidrug-resistant (MDR) TB increased from 2008 to 2013, with 77.4% of strains isolated from migrants from 41 countries. Overall, 4.5% of strains were MDR: Italian-born persons, 2.2%; Romania, 7.5%; Former Soviet Union countries (Ukraine, Russia, Armenia, Georgia), 22.4%; all other foreign countries, 2.0%. Resistance of MDR strains to second-line drugs was high against kanamycin, ofloxacin, capreomycin. CONCLUSIONS: MDR-TB in Naples increased in 2008-13 and was observed predominantly in migrants, indicating the need to intensify diagnosis and treatment of these populations in this town. PMID- 27999236 TI - CD8+ T Lymphocyte Subsets in Bladder Tumor Draining Lymph Nodes. AB - BACKGROUND: Cytotoxic CD8+ T cells, as essential parts of the adaptive immune system, play pivotal roles in anti-tumor immune responses. It is well documented that cytokine expression profiles and activation status of these cells during anti-tumor immune responses affect the outcome of host-tumor interaction. OBJECTIVE: To investigate the percentages of CD8+ lymphocytes and their subsets in tumor draining lymph nodes of patients with bladder cancer. METHODS: Forty five patients with bladder cancer, candidate for radical cystectomy, were recruited. Mononuclear cells were isolated from draining lymph nodes using Ficoll Hypaque gradient centrifugation, and were activated by PMA/Ionomycin in the presence of Golgi inhibitors. The cells were then permeabilized and stained with appropriate flourochrome conjugated antibodies against CD3, CD8, IFN-gamma, IL-17 and IL-4 molecules. Data were collected on a four-color flow cytometer and analyzed by CellQuestPro software. RESULTS: Despite no difference in the frequency of IL-17 producing CD8+ (Tc17) lymphocytes, the mean expression of IL 17 in this subset was significantly elevated in high-grade patients (p=0.011). The percentage of double positive IFN-gamma/IL-17 CD8+ lymphocytes was also significantly increased in node positive patients compared to node negative ones (p=0.046). Our results also demonstrated that the percentage of IFN-gamma producing CD8+ (Tc1) lymphocytes was significantly increased in the patients with higher histological grade compared to those with lower ones (p=0.038). CONCLUSION: IFN-gamma and IL-17 producing CD8+ T cells may increase in advanced stages of bladder cancer, but their correlation with tumor prognosis remains to be investigated. PMID- 27999237 TI - Resting and Activated Natural Tregs Decrease in the Peripheral Blood of Patients with Atherosclerosis. AB - BACKGROUND: Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries. CD4+ T cells are known to play a role in the progression of the disease. CD4+CD25+Foxp3+ natural Treg (nTreg) cells seem to have a protective role in the disease and their reduction in acute coronary syndrome is recently shown. OBJECTIVE: To investigate the frequency of nTreg subsets in the peripheral blood of patients with atherosclerosis. METHODS: Confirmation of atherosclerosis was done by angiography and 15 ml heparinized blood was obtained from each of the 13 non-diabetic patients and 13 non-diabetic, non-smoker individuals with normal/insignificant coronary artery disease confirmed by angiography. Lipid profiles of the patients and controls were measured at the time of sampling. Mononuclear cells were used for both RNA extraction and immunophenotyping by real time PCR and flowcytometry techniques, respectively. RESULTS: In natural Treg subsets, the frequency of CD4+CD45RO-CD25+Foxp3lo T-cells (resting nTregs) was greater in controls than patients (p=0.02). The frequency of CD4+CD45RO+CD25hiFoxp3hi T-cells (activated nTregs) was significantly higher in controls compared with patients (p=0.02). However, the frequency of CD4+CD25+CD45RO+Foxp3- T-cells (effector/memory T-cell) increased in patients compared with controls (p=0.01). Both the MFI and gene expression of Foxp3 were higher in control group than in patients (p=0.015 and p=0.017, respectively). Moreover, the TGF-beta gene expression showed a decrease in the peripheral blood mononuclear cells of patients compared with controls (p=0.03). CONCLUSION: Decrease in both subsets of resting and activated nTregs along with a decrease in the expression of Foxp3 and TGF-beta genes in patients with atherosclerosis suggests phenotypic changes in these subsets, which may as well be correlated with a more inflammatory profile in their lymphocytes. PMID- 27999238 TI - The Effect of Safranal on Th1/Th2 Cytokine Balance. AB - BACKGROUND: Several biological and medical benefits of Saffron, Crocus sativus (Iridaceae), have been demonstrated. However, mechanisms of actions for purified constituents are greatly unknown. OBJECTIVE: To examine the effects of Safranal, a main constituent of Saffron stigma, on cell viability and cytokine profile of peripheral blood mononuclear cells (PBMC) were examined. METHODS: Effects of Safranal at 0.1, 0.5 and 1 mM concentrations were evaluated on cell viability and production of interleukin 4 (IL-4), IL-10 and interferon-gamma (IFN-gamma) from non-stimulated and phytohemagglutinin (PHA) stimulated PBMCs, compared to 0.1 mM dexamethasone and saline. RESULTS: In stimulated cells, different concentrations of Safranal caused significant decrease of lymphocytes viability (p<0.001 for all concentrations). All concentrations of Safranal inhibited IFN-gamma and IL-10 secretion in stimulated cells (p<0.01). In addition, higher concentrations of Safranal significantly decreased cell viability of non-stimulated PBMCs (p<0.001). The effect of 1 mM Safranal on IL-4 secretion was less than dexamethasone (p<0.05). Safranal showed a stimulatory effect on IFN-gamma secretion in non-stimulated cells. The IFN-gamma/IL-4 ratio at the presence of two higher Safranal concentrations both in non-stimulated and stimulated cells were significantly higher than those of control and PHA stimulated groups, respectively (p<0.05). CONCLUSION: The IFN-gamma/IL-4 ratio increases in the presence of Safranal which indicates an effect on Th1/Th2 balance. Therefore, Safranal may have therapeutic effects in inflammatory diseases associated with Th1/Th2 imbalance. PMID- 27999239 TI - Effect of Mesenchymal Stem Cells on ILT3 Expression in the Splenocytes of Skin Graft Recipient Mice. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are considered as effective therapeutic cells in transplantation due to their immunomodulatory activities. However, precise mechanism of MSCs immunomodulatory activity is not completely understood. OBJECTIVES: To study the role of Immunoglobulin-like transcripts-3 (ILT3) immunomodulatory receptor in immune tolerance induced by MSCs in skin transplantation model and induction of tolerogenic dendritic cells (Tol-DCs) by MSCs through up-regulation of ILT3. METHODS: C57BL/6 skin grafts were transplanted to the back of BALB/c mice. Recipient mice received MSCs on days 0, 1 and 2 post transplantation. On days 2, 5 and 10 post skin transplantation, ILT3 and forkhead box P3 (FOXP3) expression in the spleens of MSCs treated mice were evaluated. Furthermore, MSCs and DCs were co-cultured in cell culture plates and transwell systems. Then, the expressions of ILT3 mRNA and protein in MSC-treated DCs were evaluated. Additionally, MSC-treated DCs were co-cultured with allogeneic T-cells and FOXP3 expression in T-cells was evaluated. RESULTS: The expression of ILT3 and FOXP3 were higher in the splenocytes of MSCs-treated mice early post-transplantation. Furthermore, we observed that MSC-treated DCs can increase FOXP3 expression in T-cells. But, we could not find any differences in ILT3 expression between MSC-treated DCs and untreated ones. CONCLUSION: One of the mechanisms underlying MSCs immunomodulatory function could be up-regulating ILT3 expression in splenocytes. But our results did not support the hypothesis that MSCs induce Tolergenic DCs by up-regulation of ILT3. PMID- 27999240 TI - Immunogenicity of a DNA Vaccine Encoding Ag85a-Tb10.4 Antigens from Mycobacterium Tuberculosis. AB - BACKGROUND: Tuberculosis is a life threatening disease that is partially prevented by BCG vaccine. Development of more effective vaccines is an urgent priority in TB control. Ag85a and Tb10.4 are the members of culture filter protein (CFP) of M. tuberculosis that have high immunogenicity. OBJECTIVE: To analyze the immunogenicity of Ag85a-Tb10.4 DNA vaccine by enzyme-linked immunosorbent assay (ELISA). METHODS: In this study a previously described plasmid DNA vaccine encoding Ag85a-Tb10.4 was used to examine its capability in the stimulation of immune responses in an animal model. Female BALB/c mice were vaccinated with 100 MUg of purified recombinant vector intramuscularly 3 times at two-week intervals and the levels of five cytokines including IFN-gamma, IL-12, IL-4, IL-10 and TGF-beta were measured. RESULTS: The levels of IFN-gamma and IL 12 for the mice following immunization with Ag85A-Tb10.4 was significantly greater than that of the BCG and control group (p<0.05). However, there was no significant difference in the levels of IL-4, IL-10 and TGF-beta between groups. CONCLUSION: IFN-gamma and IL-12 Th1 cytokines increased significantly in mice vaccinated with Ag85a-TB10.4 DNA vaccine in comparison to the control and BCG groups. Our results may serve as a groundwork for further research into the prevention and treatment of tuberculosis. PMID- 27999241 TI - The Expression of T-Helper Associated Transcription Factors and Cytokine Genes in Pre-Eclampsia. AB - BACKGROUND: Pre-eclampsia (PE) is known as a main factor contributing to fetomaternal mortality, which might affect 2-8% of all pregnancies after the twentieth week of gestation. The balance of T helper subsets is essential to sustain a normal pregnancy and preventing fetomaternal complications. OBJECTIVE: To investigate differences in the levels of transcription factors and cytokine gene expression of Th1/Th2/Th17/Treg subsets within decidual and chorionic layers of placentas from 15 PE-afflicted and 15 healthy Iranian women in their third trimester of pregnancy. METHODS: Using Quantitative real-time PCR (Q-PCR), the expression of T-BET, GATA-3, ROR-gammat, FOXP3, and cytokines, including IL-1, IL 6, TNF-alpha, IFN-gamma, IL-4, IL-31, IL-17, IL-23, TGF-beta1, TGF-beta2, TGF beta3, and IL-35 in the placenta were compared at mRNA levels between groups. RESULTS: FOXP3 and GATA-3 were significantly down-regulated, while T-BET was up regulated in PE deciduae compared to the control group (p<0.0001, p<0.02, and p<0.01, respectively). Concerning the chorionic samples, FOXP3 significantly decreased, while ROR-gammat increased in the PE placentas compared to the healthy ones (p<0.0006 and p<0.02, respectively). Besides, most inflammatory cytokines were up-regulated, while anti-inflammatory cytokines were down-regulated in the PE placentas. Additionally, TNF-alpha/IL-35, IFN-gamma/IL-35, IL-6/IL-35, and IL 23/IL-35 ratios were significantly higher (p<0.01) and IL-35/IL-17 ratio was significantly lower (p<0.05) in the pre-eclamptic patients compared to the healthy controls. CONCLUSION: Our results shed more light on the contribution of Th1/Th2/Th17/Treg balance within placenta in the fate of a normal pregnancy. Moreover, regulatory T cells and IL-35 seem to play a notable role in pre eclampsia. PMID- 27999242 TI - Tumor Necrosis Factor-alpha and Interleukin-1-beta Polymorphisms in Pre Eclampsia. AB - BACKGROUND: Pre-eclampsia is the most common critical condition during pregnancy. Plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1beta) increase in pregnant women with pre-eclampsia, compared to normal pregnant women. OBJECTIVE: To investigate the polymorphisms of IL-1beta (C+3954T), TNF-alpha (G-308A), and (G-238A) in pre-eclemptic women in northeastern Iran. METHODS: This study was conducted on 153 pre-eclamptic women (case group) and 150 healthy pregnant women (control group), admitted to Ghaem and Imam Reza hospitals of Mashhad, Iran. IL-1beta (C+3954T), TNF- alpha (G-238A) and TNF-alpha (G-308A) gene polymorphisms in the promoter region were screened by polymerase chain reaction. Data were analyzed, using SPSS version 16.0. RESULTS: The mean age of the participants in the case and control groups was 28.2 +/- 6.1 and 27.1 +/- 6.3 years, respectively (P=0.68). The frequency of G-308A polymorphism was significantly higher in the case group, compared to the control group (p<0.001). However, no significant relationship was found between IL-1beta genotype and pre-eclampsia (p=0.39). The frequency of TNF- alpha (G-238A) AA genotype was significantly higher in the case group, while GG genotype was less frequently detected in the case group, compared to the control group (p<0.001 for both genotypes). Moreover, the frequencies of AA genotypes of -238 TNF-alpha and G-308A polymorphisms were significantly higher in the case group, compared to the control group (p<0.001). CONCLUSION: The significant correlation between inflammation promoting genotypes of TNF-alpha and pre-eclampsia is noteworthy and provides evidence on the contribution of immune related genes in this disease. PMID- 27999243 TI - Serum Levels of IL-10 and IL-22 Cytokines in Patients with Psoriasis. AB - BACKGROUND: As a chronic inflammatory condition, psoriasis results from an interaction between genetic and immunologic factors in a predisposing environment. In spite of compelling evidence for the role of T cells and cytokines in psoriasis, interleukin (IL)-10 and IL-22 have not been sufficiently investigated. OBJECTIVE: To assess the serum levels of IL-10 and IL-22 in patients with psoriasis compared to healthy controls. METHODS: A total of 28 patients with psoriasis were compared with 28 age and sex-matched healthy subjects. Psoriasis Area and Severity Index (PASI) criteria were used to measure the severity of the disease. Serum levels of IL-10 and IL-22 were measured in both groups and compared. RESULTS: The mean serum level of IL-10 was 89.5+/-18.7 in patients compared to 117.2+/-23.4 pg/ml in the controls (p=0.36). Also, serum level of IL-22 was 284.1+/-49.7 in patients versus 425.4+/-82.8 pg/ml in control group (p=0.17). There was a significant direct correlation between levels of IL 10 and IL-22 in patients group (p=0.0005). The clinical severity of psoriasis was significantly correlated with high levels of IL-22 (p<0.0001). CONCLUSION: The direct correlation between higher levels of IL-22 and disease severity supports the clinical implication of this cytokine in psoriasis. PMID- 27999245 TI - Tapered Polymer Fiber Sensors for Reinforced Concrete Beam Vibration Detection. AB - In this study, tapered polymer fiber sensors (TPFSs) have been employed to detect the vibration of a reinforced concrete beam (RC beam). The sensing principle was based on transmission modes theory. The natural frequency of an RC beam was theoretically analyzed. Experiments were carried out with sensors mounted on the surface or embedded in the RC beam. Vibration detection results agreed well with Kistler accelerometers. The experimental results found that both the accelerometer and TPFS detected the natural frequency function of a vibrated RC beam well. The mode shapes of the RC beam were also found by using the TPFSs. The proposed vibration detection method provides a cost-comparable solution for a structural health monitoring (SHM) system in civil engineering. PMID- 27999244 TI - The Effect of West Nile Virus Infection on the Midgut Gene Expression of Culex pipiens quinquefasciatus Say (Diptera: Culicidae). AB - The interaction of the mosquito and the invading virus is complex and can result in physiological and gene expression alterations in the insect. The association of West Nile virus (WNV) and Culex pipiens quinquefasciatus mosquitoes results in measurable changes in gene expression; 22 gene products were shown previously to have altered expression. Sequence analysis of one product, CQ G1A1, revealed 100% amino acid identity to gram negative bacteria binding proteins (CPQGBP) in Cx. p. quinquefasciatus, Aedes aegypti (70%) and Anopheles gambiae (63%) that function in pathogen recognition. CQ G1A1 also was differentially expressed following WNV infection in two populations of Cx. p. quinquefasciatus colonized from Florida with known differences in vector competence for WNV and showed spatial and temporal gene expression differences in midgut, thorax, and carcass tissues. These data suggest gene expression of CQ G1A1 is influenced by WNV infection and the WNV infection-controlled expression differs between populations and tissues. PMID- 27999246 TI - Design and Sensitivity Analysis Simulation of a Novel 3D Force Sensor Based on a Parallel Mechanism. AB - Automated force measurement is one of the most important technologies in realizing intelligent automation systems. However, while many methods are available for micro-force sensing, measuring large three-dimensional (3D) forces and loads remains a significant challenge. Accordingly, the present study proposes a novel 3D force sensor based on a parallel mechanism. The transformation function and sensitivity index of the proposed sensor are analytically derived. The simulation results show that the sensor has a larger effective measuring capability than traditional force sensors. Moreover, the sensor has a greater measurement sensitivity for horizontal forces than for vertical forces over most of the measurable force region. In other words, compared to traditional force sensors, the proposed sensor is more sensitive to shear forces than normal forces. PMID- 27999247 TI - Representing Geospatial Environment Observation Capability Information: A Case Study of Managing Flood Monitoring Sensors in the Jinsha River Basin. AB - Sensor inquirers cannot understand comprehensive or accurate observation capability information because current observation capability modeling does not consider the union of multiple sensors nor the effect of geospatial environmental features on the observation capability of sensors. These limitations result in a failure to discover credible sensors or plan for their collaboration for environmental monitoring. The Geospatial Environmental Observation Capability (GEOC) is proposed in this study and can be used as an information basis for the reliable discovery and collaborative planning of multiple environmental sensors. A field-based GEOC (GEOCF) information representation model is built. Quintuple GEOCF feature components and two GEOCF operations are formulated based on the geospatial field conceptual framework. The proposed GEOCF markup language is used to formalize the proposed GEOCF. A prototype system called GEOCapabilityManager is developed, and a case study is conducted for flood observation in the lower reaches of the Jinsha River Basin. The applicability of the GEOCF is verified through the reliable discovery of flood monitoring sensors and planning for the collaboration of these sensors. PMID- 27999248 TI - A Sensitive and Label-Free Pb(II) Fluorescence Sensor Based on a DNAzyme Controlled G-Quadruplex/Thioflavin T Conformation. AB - Pb(II) can cause serious damaging effects to human health, and thus, the study of Pb2+ detection methods to sensitively and selectively monitor Pb(II) pollution has significant importance. In this work, we have developed a label-free fluorescence sensing strategy based on a Pb(II) DNAzyme cleavage and the ThT/G quadruplex complex. In the presence of Pb(II), a G-rich tail was cut and released from the substrate strand, which then would form a G-quadruplex structure by combination with ThT dye. The fluorescence signal increase was then measured for sensitive Pb(II) quantification with a limit of detection of 0.06 nM. Our sensor also demonstrated high selectivity against six different metal ions, which is very important for the analysis of complex samples. PMID- 27999249 TI - Genetic Structure and Molecular Variability Analysis of Citrus sudden death associated virus Isolates from Infected Plants Grown in Brazil. AB - Citrus sudden death-associated virus (CSDaV) is a monopartite positive-sense single-stranded RNA virus that was suggested to be associated with citrus sudden death (CSD) disease in Brazil. Here, we report the first study of the genetic structure and molecular variability among 31 CSDaV isolates collected from both symptomatic and asymptomatic trees in CSD-affected areas. Analyses of partial nucleotide sequences of five domains of the CSDaV genomic RNA, including those encoding for the methyltransferase, the multi-domain region (MDR), the helicase, the RNA-dependent RNA polymerase and the coat protein, showed that the MDR coding region was the most diverse region assessed here, and a possible association between this region and virus adaption to different host or plant tissues is considered. Overall, the nucleotide diversity (pi) was low for CSDaV isolates, but the phylogenetic analyses revealed the predominance of two main groups, one of which showed a higher association with CSD-symptomatic plants. Isolates obtained from CSD-symptomatic plants, compared to those obtained from asymptomatic plants, showed higher nucleotide diversity, nonsynonymous and synonymous substitution rates and number of amino acid changes on the coding regions located closer to the 5' end region of the genomic RNA. This work provides new insights into the genetic diversity of the CSDaV, giving support for further epidemiological studies. PMID- 27999250 TI - Bi-Directional Brillouin Optical Time Domain Analyzer System for Long Range Distributed Sensing. AB - We propose and experimentally demonstrate a novel scheme of bi-directional Brillouin time domain analyzer (BD-BOTDA) to extend the sensing range. By deploying two pump-probe pairs at two different wavelengths, the Brillouin frequency shift (BFS) distribution over each half of the whole fiber can be obtained with the simultaneous detection of Brillouin signals in both channels. Compared to the conventional unidirectional BOTDA system of the same sensing range, the proposed BD-BOTDA scheme enables distributed sensing with a performance level comparable to the conventional one with half of the sensing range and a spatial resolution of 2 m, while maintaining the Brillouin signal-to noise ratio (SNR) and the BFS uncertainty. Based on this technique, we have achieved distributed temperature sensing with a measurement range of 81.9 km fiber at a spatial resolution of 2 m and BFS uncertainty of ~0.44 MHz without introducing any complicated components or schemes. PMID- 27999251 TI - A Flexible and Highly Sensitive Pressure Sensor Based on a PDMS Foam Coated with Graphene Nanoplatelets. AB - The demand for high performance multifunctional wearable devices is more and more pushing towards the development of novel low-cost, soft and flexible sensors with high sensitivity. In the present work, we describe the fabrication process and the properties of new polydimethylsiloxane (PDMS) foams loaded with multilayer graphene nanoplatelets (MLGs) for application as high sensitive piezoresistive pressure sensors. The effective DC conductivity of the produced foams is measured as a function of MLG loading. The piezoresistive response of the MLG-PDMS foam based sensor at different strain rates is assessed through quasi-static pressure tests. The results of the experimental investigations demonstrated that sensor loaded with 0.96 wt.% of MLGs is characterized by a highly repeatable pressure dependent conductance after a few stabilization cycles and it is suitable for detecting compressive stresses as low as 10 kPa, with a sensitivity of 0.23 kPa 1, corresponding to an applied pressure of 70 kPa. Moreover, it is estimated that the sensor is able to detect pressure variations of ~1 Pa. Therefore, the new graphene-PDMS composite foam is a lightweight cost-effective material, suitable for sensing applications in the subtle or low and medium pressure ranges. PMID- 27999252 TI - A Visualization Method for Corrosion Damage on Aluminum Plates Using an Nd:YAG Pulsed Laser Scanning System. AB - This paper proposes a non-contact nondestructive evaluation (NDE) technique that uses laser-induced ultrasonic waves to visualize corrosion damage in aluminum alloy plate structures. The non-contact, pulsed-laser ultrasonic measurement system generates ultrasonic waves using a galvanometer-based Q-switched Nd:YAG laser and measures the ultrasonic waves using a piezoelectric (PZT) sensor. During scanning, a wavefield can be acquired by changing the excitation location of the laser point and measuring waves using the PZT sensor. The corrosion damage can be detected in the wavefield snapshots using the scattering characteristics of the waves that encounter corrosion. The structural damage is visualized by calculating the logarithmic values of the root mean square (RMS), with a weighting parameter to compensate for the attenuation caused by geometrical spreading and dispersion of the waves. An intact specimen is used to conduct a comparison with corrosion at different depths and sizes in other specimens. Both sides of the plate are scanned with the same scanning area to observe the effect of the location where corrosion has formed. The results show that the damage can be successfully visualized for almost all cases using the RMS-based functions, whether it formed on the front or back side. Also, the system is confirmed to have distinguished corroded areas at different depths. PMID- 27999254 TI - A Photonic Crystal Magnetic Field Sensor Using a Shoulder-Coupled Resonant Cavity Infiltrated with Magnetic Fluid. AB - A kind of photonic crystal magnetic field sensor is proposed and investigated numerically. The shoulder-coupled resonant cavity is introduced in the photonic crystal, which is infiltrated with magnetic fluid. Through monitoring the shift of resonant wavelength, the magnetic field sensing is realized. According to the designed infiltration schemes, both the magnetic field sensitivity and full width at half maximum increase with the number of infiltrated air holes. The figure of merit of the structure is defined to evaluate the sensing performance comprehensively. The best structure corresponding to the optimal infiltration scheme with eight air holes infiltrated with magnetic fluid is obtained. PMID- 27999253 TI - Treatment of Post-Traumatic Stress Disorder Nightmares at a Veterans Affairs Medical Center. AB - The effectiveness of medications for PTSD in general has been well studied, but the effectiveness of medicatio.ns prescribed specifically for post-traumatic stress disorder (PTSD) nightmares is less well known. This retrospective chart review examined the efficacy of various medications used in actual treatment of PTSD nightmares at one Veteran Affairs Hospital. Records at the Salem, VA Veterans Affairs Medical Center (VAMC) were examined from 2009 to 2013 to check for the efficacy of actual treatments used in comparis.on with treatments suggested in three main review articles. The final sample consisted of 327 patients and 478 separate medication trials involving 21 individual medications plus 13 different medication combinations. The three most frequently utilized medications were prazosin (107 trials), risperidone (81 trials), and quetiapine (72 trials). Five medications had 20 or more trials with successful results (partial to full nightmare cessation) in >50% of trials: risperidone (77%, 1.0 6.0 mg), clonidine (63%, 0.1-2.0 mg), quetiapine (50%, 12.5-800.0 mg), mirtazapine (50%; 7.5-30.0 mg), and terazosin (64%, 50.0-300.0 mg). Notably, olanzapine (2.5-10.0) was successful (full remission) in all five prescription trials in five separate patients. Based on the clinical results, the use of risperidone, clonidine, terazosin, and olanzapine warrants additional investigation in clinically controlled trials as medications prescribed specifically for PTSD nightmares. PMID- 27999255 TI - Accelerometry-Based Activity Recognition and Assessment in Rheumatic and Musculoskeletal Diseases. AB - One of the important aspects to be considered in rheumatic and musculoskeletal diseases is the patient's activity capacity (or performance), defined as the ability to perform a task. Currently, it is assessed by physicians or health professionals mainly by means of a patient-reported questionnaire, sometimes combined with the therapist's judgment on performance-based tasks. This work introduces an approach to assess the activity capacity at home in a more objective, yet interpretable way. It offers a pilot study on 28 patients suffering from axial spondyloarthritis (axSpA) to demonstrate its efficacy. Firstly, a protocol is introduced to recognize a limited set of six transition activities in the home environment using a single accelerometer. To this end, a hierarchical classifier with the rejection of non-informative activity segments has been developed drawing on both direct pattern recognition and statistical signal features. Secondly, the recognized activities should be assessed, similarly to the scoring performed by patients themselves. This is achieved through the interval coded scoring (ICS) system, a novel method to extract an interpretable scoring system from data. The activity recognition reaches an average accuracy of 93.5%; assessment is currently 64.3% accurate. These results indicate the potential of the approach; a next step should be its validation in a larger patient study. PMID- 27999256 TI - Recent Progress in Machine Learning-Based Methods for Protein Fold Recognition. AB - Knowledge on protein folding has a profound impact on understanding the heterogeneity and molecular function of proteins, further facilitating drug design. Predicting the 3D structure (fold) of a protein is a key problem in molecular biology. Determination of the fold of a protein mainly relies on molecular experimental methods. With the development of next-generation sequencing techniques, the discovery of new protein sequences has been rapidly increasing. With such a great number of proteins, the use of experimental techniques to determine protein folding is extremely difficult because these techniques are time consuming and expensive. Thus, developing computational prediction methods that can automatically, rapidly, and accurately classify unknown protein sequences into specific fold categories is urgently needed. Computational recognition of protein folds has been a recent research hotspot in bioinformatics and computational biology. Many computational efforts have been made, generating a variety of computational prediction methods. In this review, we conduct a comprehensive survey of recent computational methods, especially machine learning-based methods, for protein fold recognition. This review is anticipated to assist researchers in their pursuit to systematically understand the computational recognition of protein folds. PMID- 27999258 TI - MB-OFDM-UWB Based Wireless Multimedia Sensor Networks for Underground Coalmine: A Survey. AB - Safety production of coalmines is a task of top priority which plays an important role in guaranteeing, supporting and promoting the continuous development of the coal industry. Since traditional wireless sensor networks (WSNs) cannot fully meet the requirements of comprehensive environment monitoring of underground coalmines, wireless multimedia sensor networks (WMSNs), enabling the retrieval of multimedia information, are introduced to realize fine-grained and precise environment surveillance. In this paper, a framework for designing underground coalmine WMSNs based on Multi-Band Orthogonal Frequency-Division Multiplexing Ultra-wide Band (MB-OFDM-UWB) is presented. The selection of MB-OFDM-UWB wireless transmission solution is based on the characteristics of underground coalmines. Network structure and design challenges are analyzed first, which is the foundation for further discussion. Then, key supporting technologies and open research areas in different layers are surveyed, and we provide a detailed literature review of the state of the art strategies, algorithms and general solutions in these issues. Finally, other research issues like localization, information processing, and network management are discussed. PMID- 27999259 TI - Data Field Modeling and Spectral-Spatial Feature Fusion for Hyperspectral Data Classification. AB - Classification is a significant subject in hyperspectral remote sensing image processing. This study proposes a spectral-spatial feature fusion algorithm for the classification of hyperspectral images (HSI). Unlike existing spectral spatial classification methods, the influences and interactions of the surroundings on each measured pixel were taken into consideration in this paper. Data field theory was employed as the mathematical realization of the field theory concept in physics, and both the spectral and spatial domains of HSI were considered as data fields. Therefore, the inherent dependency of interacting pixels was modeled. Using data field modeling, spatial and spectral features were transformed into a unified radiation form and further fused into a new feature by using a linear model. In contrast to the current spectral-spatial classification methods, which usually simply stack spectral and spatial features together, the proposed method builds the inner connection between the spectral and spatial features, and explores the hidden information that contributed to classification. Therefore, new information is included for classification. The final classification result was obtained using a random forest (RF) classifier. The proposed method was tested with the University of Pavia and Indian Pines, two well-known standard hyperspectral datasets. The experimental results demonstrate that the proposed method has higher classification accuracies than those obtained by the traditional approaches. PMID- 27999260 TI - Repair of DNA Double-Strand Breaks in Heterochromatin. AB - DNA double-strand breaks (DSBs) are among the most damaging lesions in DNA, since, if not identified and repaired, they can lead to insertions, deletions or chromosomal rearrangements. DSBs can be in the form of simple or complex breaks, and may be repaired by one of a number of processes, the nature of which depends on the complexity of the break or the position of the break within the chromatin. In eukaryotic cells, nuclear DNA is maintained as either euchromatin (EC) which is loosely packed, or in a denser form, much of which is heterochromatin (HC). Due to the less accessible nature of the DNA in HC as compared to that in EC, repair of damage in HC is not as straightforward as repair in EC. Here we review the literature on how cells deal with DSBs in HC. PMID- 27999261 TI - Classification of Clouds in Satellite Imagery Using Adaptive Fuzzy Sparse Representation. AB - Automatic cloud detection and classification using satellite cloud imagery have various meteorological applications such as weather forecasting and climate monitoring. Cloud pattern analysis is one of the research hotspots recently. Since satellites sense the clouds remotely from space, and different cloud types often overlap and convert into each other, there must be some fuzziness and uncertainty in satellite cloud imagery. Satellite observation is susceptible to noises, while traditional cloud classification methods are sensitive to noises and outliers; it is hard for traditional cloud classification methods to achieve reliable results. To deal with these problems, a satellite cloud classification method using adaptive fuzzy sparse representation-based classification (AFSRC) is proposed. Firstly, by defining adaptive parameters related to attenuation rate and critical membership, an improved fuzzy membership is introduced to accommodate the fuzziness and uncertainty of satellite cloud imagery; secondly, by effective combination of the improved fuzzy membership function and sparse representation-based classification (SRC), atoms in training dictionary are optimized; finally, an adaptive fuzzy sparse representation classifier for cloud classification is proposed. Experiment results on FY-2G satellite cloud image show that, the proposed method not only improves the accuracy of cloud classification, but also has strong stability and adaptability with high computational efficiency. PMID- 27999262 TI - Crapemyrtle Bark Scale: A New Threat for Crapemyrtles, a Popular Landscape Plant in the U.S. AB - Crapemyrtle bark scale, Acanthococcus (=Eriococcus) lagerstroemiae (Kuwana) (Hemiptera: Eriococcidae), is a newly introduced insect pest on crapemyrtles, Lagerstroemia spp. (Myrtales: Lythraceae), one of the most popular flowering shrubs in the U.S. Since first detected in Texas in 2004, this pest has spread to twelve states causing losses to stakeholders. To develop a management plan, we reviewed current knowledge about the pest's biology and ecology, and suggested research approaches including studying its thermal tolerance, host range, plant resistance and biological control. Parasitoids and predators have been reared from A. lagerstroemiae in the U.S. and China. However, new surveys of natural enemies should be conducted in China, and studies on the host range and impacts of natural enemies on A. lagerstroemiae may help determine the potential for classical biological control. The life history, preying efficiency and rearing methods are important for coccinellid predators found in the U.S. including Chilocorus cacti L. and Hyperaspis spp. To enhance natural enemy performance, it is important to evaluate a sustainable insecticide program that considers efficacy, timing, rate and impact on pollinator health. Finally, an integrated management program of A. lagerstroemiae is discussed including planting resistant cultivars, using host specific natural enemies, and prudent use of insecticides. PMID- 27999263 TI - Chemical Studies of Yellow Tamarillo (Solanum betaceum Cav.) Fruit Flavor by Using a Molecular Sensory Approach. AB - The odor-active volatile compounds of yellow tamarillo fruit (S. betaceum Cav.) were identified and quantified by using a sensomics approach, combining a gentle volatile extraction (solvent-assisted flavor evaporation (SAFE)), gas chromatography-mass spectrometry (GC-MS), and sensory analyses (gas chromatography-olfactometry (GC-O) and aroma extract dilution analysis (AEDA)). The medium-term purpose of this work is to evaluate the change of odor-active volatiles during processing. Thus, (Z)-3-hexenal, hexanal, and ethyl butanoate were identified as key aroma compounds of yellow tamarillo. The C6-aliphatic compounds, aliphatic esters, and terpenols were characterized as the volatiles responsible for the herbal-green, fruity, and fresh-mint odor notes of this variety, respectively. Additionally, one non-volatile compound contributing to the residual bitter taste of this fruit was isolated by a bioguided (taste sensory analyses) fractionation. The freeze-dried fruit was sequentially liquid liquid partitioned with solvents of different polarity, and then the ethyl acetate fraction was submitted to size exclusion chromatography. Then, its structure was elucidated as rosmarinic acid, by using common spectroscopic methods (mass spectrometry (MS) and nuclear magnetic resonance (NMR)). The amount of rosmarinic acid was quantified as 46.17 +/- 1.20 mg/100 g of dried fruit, by the external standard method. Its bitter taste threshold value was determined by using the 3AFC (alternative forced choice) method to be 37.00 +/- 1.25 mg/L. PMID- 27999257 TI - Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins. AB - Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity. PMID- 27999264 TI - Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach. AB - Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)-a famous traditional Chinese medicine formula-has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS. PMID- 27999265 TI - Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis. AB - Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood. PMID- 27999266 TI - Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis. AB - Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor kappaB (NF kappaB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk. PMID- 27999267 TI - Zebrafish as a Vertebrate Model System to Evaluate Effects of Environmental Toxicants on Cardiac Development and Function. AB - Environmental pollution is a serious problem of the modern world that possesses a major threat to public health. Exposure to environmental pollutants during embryonic development is particularly risky. Although many pollutants have been verified as potential toxicants, there are new chemicals in the environment that need assessment. Heart development is an extremely sensitive process, which can be affected by environmentally toxic molecule exposure during embryonic development. Congenital heart defects are the most common life-threatening global health problems, and the etiology is mostly unknown. The zebrafish has emerged as an invaluable model to examine substance toxicity on vertebrate development, particularly on cardiac development. The zebrafish offers numerous advantages for toxicology research not found in other model systems. Many laboratories have used the zebrafish to study the effects of widespread chemicals in the environment on heart development, including pesticides, nanoparticles, and various organic pollutants. Here, we review the uses of the zebrafish in examining effects of exposure to external molecules during embryonic development in causing cardiac defects, including chemicals ubiquitous in the environment and illicit drugs. Known or potential mechanisms of toxicity and how zebrafish research can be used to provide mechanistic understanding of cardiac defects are discussed. PMID- 27999268 TI - Knockdown of ELMO3 Suppresses Growth, Invasion and Metastasis of Colorectal Cancer. AB - The engulfment and cell motility (ELMOs) family of proteins plays a crucial role in tumor cell migration and invasion. However, the function of ELMO3 is poorly defined. To elucidate its role in the development and progression of colorectal cancer (CRC), we examined the expression of ELMO3 in 45 cases of paired CRC tumor tissues and adjacent normal tissues. Furthermore, we assessed the effect of the knockdown of ELMO3 on cell proliferation, cell cycle, migration, invasion and F actin polymerization in HCT116 cells. The result shows that the expression of ELMO3 in CRC tissues was significantly increased in comparison to the adjacent normal colorectal tissues. Moreover, this overexpression was associated with tumor size (p = 0.007), tumor differentiation (p = 0.001), depth of invasion (p = 0.009), lymph node metastasis (p = 0.003), distant metastasis (p = 0.013) and tumor, node, metastasis (TNM)-based classification (p = 0.000). In in vitro experiments, the silencing of ELMO3 inhibited cell proliferation, invasion, metastasis, and F-actin polymerization, and induced Gap 1 (G1) phase cell cycle arrest. Our study demonstrates that ELMO3 is involved in the processes of growth, invasion and metastasis of CRC, and could be used a potential molecular diagnostic tool or therapy target of CRC. PMID- 27999269 TI - Biological Potential of Chitinolytic Marine Bacteria. AB - Chitinolytic microorganisms secrete a range of chitin modifying enzymes, which can be exploited for production of chitin derived products or as fungal or pest control agents. Here, we explored the potential of 11 marine bacteria (Pseudoalteromonadaceae, Vibrionaceae) for chitin degradation using in silico and phenotypic assays. Of 10 chitinolytic strains, three strains, Photobacterium galatheae S2753, Pseudoalteromonas piscicida S2040 and S2724, produced large clearing zones on chitin plates. All strains were antifungal, but against different fungal targets. One strain, Pseudoalteromonas piscicida S2040, had a pronounced antifungal activity against all seven fungal strains. There was no correlation between the number of chitin modifying enzymes as found by genome mining and the chitin degrading activity as measured by size of clearing zones on chitin agar. Based on in silico and in vitro analyses, we cloned and expressed two ChiA-like chitinases from the two most potent candidates to exemplify the industrial potential. PMID- 27999270 TI - Clinical Application of Targeted Next Generation Sequencing for Colorectal Cancers. AB - Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the theranostic and prognostic role of molecular biomarkers, which is a strong incentive for a validated, sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials. Next generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. Targeted NGS is a method that allows parallel sequencing of thousands of short DNA sequences in a single test offering a cost effective approach for detecting multiple genetic alterations with a minimum amount of DNA. In the present review, we collected data concerning the clinical application of NGS technology in the setting of colorectal cancer. PMID- 27999272 TI - Sustainable Lifestyle Change-Participatory Design of Support Together with Persons with Obesity in the Third Age. AB - Sustainable lifestyle changes due to obesity are difficult to achieve regardless methods used. We need to know more about the lived experience of obesity and older persons' needs for support to make a sustainable change. This paper focuses on the need-finding process in designing support for a sustainable lifestyle change. Multistage focus group interviews were conducted with persons aged 61-72 living in Northern Sweden. A participatory and appreciative reflection and action (PAAR) approach was used in the group-sessions. Probes were used to increase reflections and achieve a deeper knowledge about the participants' needs of support. Data were analysed using qualitative thematic content analysis. Our findings revealed that to be able to succeed with a lifestyle change a focus has to be on a converted way of thinking, managing vulnerability, and achieving an emotional balance. To achieve a sustainable lifestyle change due to obesity in the third age the focus has to be on a health identity instead of a weight identity. Personalised support with enjoyable physical activities should be designed and developed. Strategies for emotional balance based on autonomy and self-empowerment must be included. This knowledge is important when designing support for sustainable change. PMID- 27999273 TI - Comments to Article by Thoene M et al., Nutrients 2016, 8, 451. AB - To the Editor:[...]. PMID- 27999271 TI - Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses. AB - Appropriate diagnosis is the key factor for treatment of viral diseases. Time is the most important factor in rapidly developing and epidemiologically dangerous diseases, such as influenza, Ebola and SARS. Chronic viral diseases such as HIV-1 or HCV are asymptomatic or oligosymptomatic and the therapeutic success mainly depends on early detection of the infective agent. Over the last years, aptamer technology has been used in a wide range of diagnostic and therapeutic applications and, concretely, several strategies are currently being explored using aptamers against virus proteins. From a diagnostics point of view, aptamers are being designed as a bio-recognition element in diagnostic systems to detect viral proteins either in the blood (serum or plasma) or into infected cells. Another potential use of aptamers is for therapeutics of viral infections, interfering in the interaction between the virus and the host using aptamers targeting host-cell matrix receptors, or attacking the virus intracellularly, targeting proteins implicated in the viral replication cycle. In this paper, we review how aptamers working against viral proteins are discovered, with a focus on recent advances that improve the aptamers' properties as a real tool for viral infection detection and treatment. PMID- 27999276 TI - Response to Dr. Moya's Comments to Article by Thoene M et al., Nutrients 2016, 8, 451. AB - This reply is a supplementary addition to our previous article entitled "Comparison of a Powdered, Acidified Liquid, and Non-Acidified Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants" as published in Nutrients in July 2016. It provides a response to a comment made by Dr. Fernando Moya to this original article, so the purpose of this is to compare and contrast various perspectives between researchers conducting nutrition research in the preterm infant population. It specifically focuses on human milk fortification and subsequent outcomes. PMID- 27999275 TI - HIV, Other Blood-Borne Viruses and Sexually Transmitted Infections amongst Expatriates and Travellers to Low- and Middle-Income Countries: A Systematic Review. AB - In some high-income countries, a proportion of human immunodeficiency virus (HIV), other blood-borne virus (BBV) or sexually transmitted infection (STI) diagnoses have been reported as acquired overseas in low- and middle-income countries. A review was conducted to explore HIV, other BBV or STI related knowledge, risk behavior and acquisition amongst expatriates and travelers, particularly males, travelling from high to low- and middle-income countries. Seven academic databases were searched for 26 peer reviewed articles that met inclusion criteria. Significant variability in the studies was noted, in age, travel duration and frequency and outcomes/risk factors measured and reported on. Risk factors described included longer duration of stay; being single; travel for romance or sex; alcohol and other drug use; lack of travel advice; being male; higher number of sexual partners; and inconsistent condom use. Vaccination, pre travel health advice, and having fewer sexual partners were described as protective. Studies are needed focusing on the social context in which risk taking occurs. Better collaboration is essential to deliver comprehensive health promotion interventions alongside more consistent pre- and post- travel testing and advice. Policy measures are crucial, including consistent evaluation indicators to assess impacts of HIV, other BBVs or STIs in the context of mobility. Risks and responses for these epidemics are shared globally. PMID- 27999274 TI - Microbial Etiology of Pneumonia: Epidemiology, Diagnosis and Resistance Patterns. AB - Globally, pneumonia is a serious public health concern and a major cause of mortality and morbidity. Despite advances in antimicrobial therapies, microbiological diagnostic tests and prevention measures, pneumonia remains the main cause of death from infectious disease in the world. An important reason for the increased global mortality is the impact of pneumonia on chronic diseases, along with the increasing age of the population and the virulence factors of the causative microorganism. The increasing number of multidrug-resistant bacteria, difficult-to-treat microorganisms, and the emergence of new pathogens are a major problem for clinicians when deciding antimicrobial therapy. A key factor for managing and effectively guiding appropriate antimicrobial therapy is an understanding of the role of the different causative microorganisms in the etiology of pneumonia, since it has been shown that the adequacy of initial antimicrobial therapy is a key factor for prognosis in pneumonia. Furthermore, broad-spectrum antibiotic therapies are sometimes given until microbiological results are available and de-escalation cannot be performed quickly. This review provides an overview of microbial etiology, resistance patterns, epidemiology and microbial diagnosis of pneumonia. PMID- 27999278 TI - Exploration of Pedestrian Head Injuries-Collision Parameter Relationships through a Combination of Retrospective Analysis and Finite Element Method. AB - There are a very limited number of reports concerning the relationship between pedestrian head injuries and collision parameters through a combination of statistical analysis methods and finite element method (FEM). This study aims to explore the characteristics of pedestrian head injuries in car-pedestrian collisions at different parameters by using the two means above. A retrospective analysis of pedestrian head injuries was performed based on detailed investigation data of 61 car-pedestrian collision cases. The head damage assessment parameters (head injury criterion (HIC), peak stress on the skull, maximal principal strain for the brain) in car-pedestrian simulation experiments with four contact angles and three impact velocities were obtained by FEM. The characteristics of the pedestrian head injuries were discussed by comparing and analyzing the statistical analysis results and finite element analysis results. The statistical analysis results demonstrated a significant difference in skull fractures, contusion and laceration of brain and head injuries on the abbreviated injury scale (AIS)3+ was found at different velocities (p < 0.05) and angles (p < 0.05). The simulation results showed that, in pedestrian head-to-hood impacts, the values of head damage assessment parameters increased with impact velocities. At the same velocity, these values from the impact on the pedestrian's back were successively greater than on the front or the side. Furthermore, head injury reconstruction and prediction results of two selected cases were consistent with the real injuries. Overall, it was further spelled out that, for shorter stature pedestrians, increased head impact velocity results in greater head injury severity in car-pedestrian collision, especially in pedestrian head-to-hood impacts. Under a back impact, the head has also been found to be at greater damage risk for shorter stature pedestrians, which may have implications on automotive design and pedestrian protection research if prevention and treatment of these injuries is to be prioritized over head injuries under a front or side impact. PMID- 27999277 TI - Household Food Insecurity Is Associated with Adverse Mental Health Indicators and Lower Quality of Life among Koreans: Results from the Korea National Health and Nutrition Examination Survey 2012-2013. AB - Food insecurity is an ongoing public health issue and contributes to mental health status. We investigated whether food insecurity is associated with inadequate nutrient intake and whether it affects mental health indicators (perceived stress/experience of depressive symptom/suicidal ideation) and quality of life (QOL) among Koreans (n = 5862, 20-64 years) using data from the Korea National Health and Nutritional Examination Survey (2012-2013). Household food security status was categorized as "food-secure household", "food-insecure household without hunger", and "food-insecure household with hunger". Data on food insecurity, sociodemographic factors, nutrient intake, mental health indicators, and QOL were used. A logistic regression model was conducted to determine odds ratios (ORs) for psychological health. A greater proportion of food-insecure participants were nutritionally deficient compared with expectations of the 2015 Korean Dietary Reference Intakes. These deficiencies were generally higher in both "food-insecure household" groups. Both "food insecure household" groups, particularly the "food-insecure household with hunger" group showed significantly adverse mental health status (ORs: 1.52-3.83) and lower QOL (ORs: 1.49-3.92) than did the "food-secure household" group before and after adjusting for sex, age, education, household income, smoking/alcohol consumption, physical activity, marital status, and receiving food assistance. In conclusion, food insecurity may be significantly associated with adverse mental health indicators and decreased QOL in young/middle-aged Koreans. PMID- 27999279 TI - Spatiotemporal Variations in Lung Cancer Mortality in China between 2006 and 2012: A Multilevel Analysis. AB - We investigated temporal trends and geographical variations in lung cancer mortality in China from 2006 to 2012. Lung cancer mortality counts for people aged over 40 years were extracted from the China Mortality Surveillance System for 161 disease surveillance points. Negative binomial regression was used to investigate potential spatiotemporal variation and correlations with age, gender, urbanization, and region. Lung cancer mortality increased in China over the study period from 78.77 to 85.63 (1/100,000), with higher mortality rates evident in men compared to women. Median rate ratios (MRRs) indicated important geographical variation in lung cancer mortality between provinces (MRR = 1.622) and counties/districts (MRR = 1.447). On average, lung cancer mortality increased over time and was positively associated with county-level urbanization (relative risk (RR) = 1.15). Lung cancer mortality seemed to decrease in urban and increase in rural areas. Compared to the northwest, mortality was higher in the north (RR = 1.98), east (RR = 1.87), central (RR = 1.87), and northeast (RR = 2.44). Regional differences and county-level urbanization accounted for 49.4% and 8.7% of provincial and county variation, respectively. Reductions in lung cancer mortality in urban areas may reflect improvements in access to preventive healthcare and treatment services. Rising mortality in rural areas may reflect a clustering of risk factors associated with rapid urbanization. PMID- 27999280 TI - Recruiting Diverse Smokers: Enrollment Yields and Cost. AB - To help tobacco control research better include vulnerable populations, we sought to identify effective ways to recruit diverse smokers. In 2014-2015, we recruited 2149 adult cigarette smokers in California and North Carolina, United States, to participate in a randomized trial of pictorial cigarette pack warnings. The most effective means of recruiting smokers were the classified advertising website Craigslist (28% of participants), word of mouth (23%), Facebook (16%), and flyers or postcards (14%). Low-income and African American smokers were more likely to respond to interpersonal contact (including staff in-person recruitment and word of mouth) than were high-income and non-African American smokers (all p < 0.05). Hispanic and gay, lesbian, and bisexual smokers were more likely to be recruited by Craigslist than non-Hispanic and straight smokers (both p < 0.05). Of the recruitment methods requiring cost, the cheapest was Craigslist ($3-7 per smoker). The most expensive methods were newspaper ads in California ($375 per smoker) and staff in-person recruiting in North Carolina ($180 per smoker). Successfully recruiting diverse smokers requires using multiple methods including interpersonal, online, and other media. Craigslist and word of mouth are especially useful and low-cost ways to recruit diverse smokers. PMID- 27999282 TI - Secure Distributed Detection under Energy Constraint in IoT-Oriented Sensor Networks. AB - We study the secure distributed detection problems under energy constraint for IoT-oriented sensor networks. The conventional channel-aware encryption (CAE) is an efficient physical-layer secure distributed detection scheme in light of its energy efficiency, good scalability and robustness over diverse eavesdropping scenarios. However, in the CAE scheme, it remains an open problem of how to optimize the key thresholds for the estimated channel gain, which are used to determine the sensor's reporting action. Moreover, the CAE scheme does not jointly consider the accuracy of local detection results in determining whether to stay dormant for a sensor. To solve these problems, we first analyze the error probability and derive the optimal thresholds in the CAE scheme under a specified energy constraint. These results build a convenient mathematic framework for our further innovative design. Under this framework, we propose a hybrid secure distributed detection scheme. Our proposal can satisfy the energy constraint by keeping some sensors inactive according to the local detection confidence level, which is characterized by likelihood ratio. In the meanwhile, the security is guaranteed through randomly flipping the local decisions forwarded to the fusion center based on the channel amplitude. We further optimize the key parameters of our hybrid scheme, including two local decision thresholds and one channel comparison threshold. Performance evaluation results demonstrate that our hybrid scheme outperforms the CAE under stringent energy constraints, especially in the high signal-to-noise ratio scenario, while the security is still assured. PMID- 27999281 TI - Probiotic Microorganisms Inhibit Epithelial Cell Internalization of Botulinum Neurotoxin Serotype A. AB - Botulinum neurotoxins (BoNTs) are some of the most poisonous natural toxins known to man and are threats to public health and safety. Previous work from our laboratory showed that both BoNT serotype A complex and holotoxin can bind and transit through the intestinal epithelia to disseminate in the blood. The timing of BoNT/A toxin internalization was shown to be comparable in both the Caco-2 in vitro cell culture and in the oral mouse intoxication models. Probiotic microorganisms have been extensively studied for their beneficial effects in not only maintaining the normal gut mucosa but also protection from allergens, pathogens, and toxins. In this study, we evaluate whether probiotic microorganisms will block BoNT/A uptake in the in vitro cell culture system using Caco-2 cells. Several probiotics tested (Saccharomyces boulardii, Lactobacillus acidophilus, Lactobacillus rhamnosus LGG, and Lactobacillus reuteri) blocked BoNT/A uptake in a dose-dependent manner whereas a non-probiotic strain of Escherichia coli did not. We also showed that inhibition of BoNT/A uptake was not due to the degradation of BoNT/A nor by sequestration of toxin via binding to probiotics. These results show for the first time that probiotic treatment can inhibit BoNT/A binding and internalization in vitro and may lead to the development of new therapies. PMID- 27999283 TI - Synthesis and Structural Investigation of New Bio-Relevant Complexes of Lanthanides with 5-Hydroxyflavone: DNA Binding and Protein Interaction Studies. AB - In the present work, we attempted to develop new metal coordination complexes of the natural flavonoid 5-hydroxyflavone with Sm(III), Eu(III), Gd(III), Tb(III). The resultant hydroxo complexes have been characterized by a variety of spectroscopic techniques, including fluorescence, FT-IR, UV-Vis, EPR and mass spectral studies. The general chemical formula of the complexes is [Ln(C15H9O3)3(OH)2(H2O)x].nH2O, where Ln is the lanthanide cation and x = 0 for Sm(III), x = 1 for Eu(III), Gd(III), Tb(III) and n = 0 for Sm(III), Gd(III), Tb(III), n = 1 for Eu(III), respectively. The proposed structures of the complexes were optimized by DFT calculations. Theoretical calculations and experimental determinations sustain the proposed structures of the hydroxo complexes, with two molecules of 5-hydroxyflavone acting as monoanionic bidentate chelate ligands. The interaction of the complexes with calf thymus DNA has been explored by fluorescence titration and UV-Vis absorption binding studies, and revealed that the synthesized complexes interact with DNA with binding constants (Kb) ~ 104. Human serum albumin (HSA) and transferrin (Tf) binding studies have also been performed by fluorescence titration techniques (fluorescence quenching studies, synchronous fluorescence spectra). The apparent association constants (Ka) and thermodynamic parameters have been calculated from the fluorescence quenching experiment at 299 K, 308 K, and 318 K. The quenching curves indicate that the complexes bind to HSA with smaller affinity than the ligand, but to Tf with higher binding affinities than the ligand. PMID- 27999284 TI - Aspirin down Regulates Hepcidin by Inhibiting NF-kappaB and IL6/JAK2/STAT3 Pathways in BV-2 Microglial Cells Treated with Lipopolysaccharide. AB - Aspirin down regulates transferrin receptor 1 (TfR1) and up regulates ferroportin 1 (Fpn1) and ferritin expression in BV-2 microglial cells treated without lipopolysaccharides (LPS), as well as down regulates hepcidin and interleukin 6 (IL-6) in cells treated with LPS. However, the relevant mechanisms are unknown. Here, we investigate the effects of aspirin on expression of hepcidin and iron regulatory protein 1 (IRP1), phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and P65 (nuclear factor kappaB), and the production of nitric oxide (NO) in BV-2 microglial cells treated with and without LPS. We demonstrated that aspirin inhibited hepcidin mRNA as well as NO production in cells treated with LPS, but not in cells without LPS, suppresses IL-6, JAK2, STAT3, and P65 (nuclear factor-kappaB) phosphorylation and has no effect on IRP1 in cells treated with or without LPS. These findings provide evidence that aspirin down regulates hepcidin by inhibiting IL6/JAK2/STAT3 and P65 (nuclear factor-kappaB) pathways in the cells under inflammatory conditions, and imply that an aspirin-induced reduction in TfR1 and an increase in ferritin are not associated with IRP1 and NO. PMID- 27999285 TI - Simultaneous Determination of Multiple Components in Guanjiekang in Rat Plasma via the UPLC-MS/MS Method and Its Application in Pharmacokinetic Study. AB - Guanjiekang (GJK) that is formed by five medicinal herbs including Astragali Radix, Aconiti Lateralis Radix Praeparaia, Glycyrrhizae Radix et Rhizoma, Corydalis Rhizoma and Paeoniae Radix Alba was used for the treatment of rheumatoid arthritis (RA). However, the pharmacokinetic (PK) profile of active components in GJK remains unclear. This study aims to evaluate the pharmacokinetic behavior of seven representative active constituents in GJK (i.e., benzoylhypaconine, benzoylmesaconine, paeoniflorin, tetrahydropalmatine, calycosin-7-glucoside, formononetin and isoliquiritigenin) after oral administration of GJK in rats. A rapid, sensitive and reliable ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) method has been successfully developed for the simultaneous determination of these seven constituents in rat plasma. Chromatographic separation was achieved on a C18 column with a gradient elution program that consists of acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.35 mL/min. Detection was performed under the multiple reaction monitoring (MRM) in the positive electrospray ionization (ESI) mode. The calibration curves exhibited good linearity (R2 > 0.99) over a wide concentration range for all constituents. The accuracies ranged from 92.9% to 107.8%, and the intra-day and inter-day precisions at three different levels were below 15%. Our PK results showed that these seven compounds were quickly absorbed after the administration of the GJK product, and Tmax ranged from 30 min to 189 min. The in vivo concentrations of paeoniflorin and isoliquiritigenin were significantly higher than the reported in vitro effective doses, indicating that they could partly contribute to the therapeutic effect of GJK. Therefore, we conclude that pharmacokinetic studies of representative bioactive chemicals after administration of complex herbal products are not only necessary but also feasible. Moreover, these seven compounds that were absorbed in vivo can be used as indicator standards for quality control and for determining pharmacokinetic behavior of herbal medicines in clinical studies. PMID- 27999286 TI - Testosterone Deficiency Induces Changes of the Transcriptomes of Visceral Adipose Tissue in Miniature Pigs Fed a High-Fat and High-Cholesterol Diet. AB - Testosterone deficiency causes fat deposition, particularly in visceral fat, and its replacement might reverse fat accumulation, however, the underlying mechanisms of such processes under diet-induced adiposity are largely unknown. To gain insights into the genome-wide role of androgen on visceral adipose tissue (VAT), RNA-Seq was used to investigate testosterone deficiency induced changes of VAT in miniature pigs fed a high-fat and high-cholesterol (HFC) diet among intact male pigs (IM), castrated male pigs (CM), and castrated male pigs with testosterone replacement (CMT) treatments. The results showed that testosterone deficiency significantly increased VAT deposition and serum leptin concentrations. Moreover, a total of 1732 differentially expressed genes (DEGs) were identified between any two groups. Compared with gene expression profiles in IM and CMT pigs, upregulated genes in CM pigs, i.e., LOC100520753 (CD68), LCN2, EMR1, S100A9, NCF1 (p47phox), and LEP, were mainly involved in inflammatory response, oxidation-reduction process, and lipid metabolic process, while downregulated genes in CM pigs, i.e., ABHD5, SPP1, and GAS6, were focused on cell differentiation and cell adhesion. Taken together, our study demonstrates that testosterone deficiency alters the expression of numerous genes involved in key biological processes of VAT accumulation under HFC diet and provides a novel genome-wide view on the role of androgen on VAT deposition under HFC diet, thus improving our understanding of the molecular mechanisms involved in VAT changes induced by testosterone deficiency. PMID- 27999287 TI - Simultaneous Qualitation and Quantitation of Chlorogenic Acids in Kuding Tea Using Ultra-High-Performance Liquid Chromatography-Diode Array Detection Coupled with Linear Ion Trap-Orbitrap Mass Spectrometer. AB - Kuding tea, the leaves of Ilex Kudingcha C.J. Tseng, has been applied for treating obesity, hypertension, cardiovascular disease, hyperlipidemia, and so on. The chlorogenic acids (CGAs) in Kuding tea have shown excellent antioxidative, antiobesity, anti-atherosclerotic and anticancer activities. Nevertheless, the chemical profiles of CGAs in Kuding tea have not been comprehensively studied yet, which hinders further quality control. In the present study, a sensitive ultra-high-performance liquid chromatography-diode array detection coupled with a linear ion trap-Orbitrap (UHPLC-DAD-LTQ-Orbitrap) method was established to screen and identify CGAs in Kuding tea. Six CGA standards were first analyzed in negative ion mode with a CID-MS/MS experiment and then the diagnostic product ions (DPIs) were summarized. According to the retention behavior in the RP-ODS column, accurate mass measurement, DPIs and relevant bibliography data, a total of 68 CGA candidates attributed to 12 categories were unambiguously or preliminarily screened and characterized within 18 min of chromatographic time. This was the first systematic report on the distribution of CGAs in Kuding tea. Meanwhile, the contents of 6 major CGAs in Kuding tea were also determined by the UHPLC-DAD method. All the results indicated that the established analytical method could be employed as an effective technique for the comprehensive and systematic characterization of CGAs and quality control of the botanic extracts or Chinese medicinal formulas that contain various CGAs. PMID- 27999289 TI - Characterization of the Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma. AB - Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes (RLN) were analyzed by flow cytometry for the main immune cells and multiple specific subpopulations. To discriminate between cells in or outside the tumor cell area, we used CD26. We observed significantly lower levels of CD20+ B-cells and CD56+ NK cells and higher levels of CD4+ T-cells in NLPHL in comparison to RLN. In the subpopulations, we observed increased numbers of PD-1+CD4+ T follicular helper cells (TFH), CD69+CD4+ and CD69+CD8+ T-cells and CCR7-CD45RA-CD4+ effector memory T-cells, while FoxP3+CD4+ T regulatory cells (Tregs) and CCR7-CD45RA+ terminally differentiated CD4+ T-cells were decreased in NLPHL compared to RLN. CD69+ cells were increased in the tumor cell area in CD4+ and CD8+ T-cells, while FoxP3+CD25+CD4+ Tregs and CD25+CD8+ T-cells were significantly increased outside the tumor area. Thus, we show a markedly altered microenvironment in NLPHL, with lower numbers of NK cells and Tregs. PD-1+CD4+ and CD69+ T-cells were located inside, and Tregs and CD25+CD8+ cells outside the tumor cell area. PMID- 27999290 TI - Validation and Application of an Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry Method for Yuanhuacine Determination in Rat Plasma after Pulmonary Administration: Pharmacokinetic Evaluation of a New Drug Delivery System. AB - Yuanhuacine was found to have significant inhibitory activity against A-549 human lung cancer cells. However, there would be serious adverse toxicity effects after systemic administration of yuanhuacine, such as by oral and intravenous ways. In order to achieve better curative effect and to alleviate the adverse toxicity effects, we tried to deliver yuanhuacine directly into the lungs. Ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was used to detect the analyte and IS. After extraction (ether:dichloromethane = 8:1), the analyte and IS were separated on a Waters BEH-C18 column (100 mm * 2.1 mm, 1.7 MUm) under a 5 min gradient elution using a mixture of acetonitrile and 0.1% formic acid aqueous solution as mobile phase at a flow rate of 0.3 mL/min. ESI positive mode was chosen for detection. The method was fully validated for its selectivity, accuracy, precision, stability, matrix effect, and extraction recovery. This new method for yuanhuacine concentration determination in rat plasma was reliable and could be applied for its preclinical and clinical monitoring purpose. PMID- 27999291 TI - Development of Lateral Flow Assay Based on Size-Controlled Gold Nanoparticles for Detection of Hepatitis B Surface Antigen. AB - In this study, we developed lateral flow assay (LFA) biosensors for the detection of hepatitis B surface antigens using well-controlled gold nanoparticles (AuNPs). To enhance colorimetric signals, a seeded growth method was used for the preparation of size-controlled AuNPs with a narrow size distribution. Different sizes of AuNPs in the range of 342-137.8 nm were conjugated with antibodies and then optimized for the efficient detection of LFA biosensors. The conjugation stability was investigated by UV-vis spectroscopy of AuNP dispersion at various pH values and concentrations of antibody. Based on optimized conjugation conditions, the use of 42.7 +/- 0.8 nm AuNPs exhibited superior performance for the detection of LFAs relative to other sizes of AuNPs. PMID- 27999288 TI - Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics. AB - Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. PMID- 27999292 TI - Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B. AB - By imitating the scaffold of lithocholic acid (LCA), a natural steroidal compound displaying Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, a series of stilbene derivatives containing phenyl-substituted isoxazoles were designed and synthesized. The structures of the title compounds were confirmed by 1H-NMR, 13C-NMR and HRMS. Activities of the title compounds were evaluated on PTP1B and the homologous enzyme TCPTP by using a colorimetric assay. Most of the target compounds had good activities against PTP1B. Among them, compound 29 (IC50 = 0.91 +/- 0.33 MUM), characterized by a 5-(2,3-dichlorophenyl) isoxazole moiety, exhibited an activity about 14-fold higher than the lead compound LCA and a 4.2 fold selectivity over TCPTP. Compound 29 was identified as a competitive inhibitor of PTP1B with a Ki value of 0.78 MUM in enzyme kinetic studies. PMID- 27999293 TI - Antimutagenic Effects of Selenium-Enriched Polysaccharides from Pyracantha fortuneana through Suppression of Cytochrome P450 1A Subfamily in the Mouse Liver. AB - Both selenium (Se) and polysaccharides from Pyracantha fortuneana (Maxim.) Li (PFPs) (P. fortuneana) have been reported to possess antioxidative and immuno protective activities. Whether or not Se-containing polysaccharides (Se-PFPs) have synergistic effect of Se and polysaccharides on enhancing the antioxidant and immune activities remains to be determined. We previously reported that polysaccharides isolated from Se-enriched P. fortuneana (Se-PFPs) possessed hepatoprotective effects. However, it is not clear whether or not they have anti mutagenic effects. In the present study, we compared and evaluated anti-mutagenic effects of Se-PFPs at three concentrations (1.35, 2.7 and 5.4 g/kg body weight) with those of PFPs, Se alone or Se + PFPs in mice using micronucleus assay in bone marrow and peripheral blood as well as mitomycin C-induced chromosomal aberrations in mouse testicular cells. We also elucidated the underlying mechanism. Our results demonstrated that Se-PFPs inhibited cyclophosphamide (CP) induced micronucleus formation in both bone marrow and peripheral blood, enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in mouse liver, and reduced the activity and expression of cytochrome P450 1A (CYP4501A) in mouse liver in a dose-dependent manner. In addition, we found that the anti-mutagenic potential of Se-PFPs was higher than those of PFPs, Se alone or Se + PFPs at the same level. These results suggest that the anti-mutagenic potential of Se-PFPs may be mediated through the inhibition of the activity and expression of CYP4501A. This study indicates that application of Se-PFPs may provide an alternative strategy for cancer therapy by targeting CYP1A family. PMID- 27999294 TI - Phase and Index of Refraction Imaging by Hyperspectral Reflectance Confocal Microscopy. AB - A hyperspectral reflectance confocal microscope (HSCM) was realized by CNR-ISC (Consiglio Nazionale delle Ricerche-Istituto dei Sistemi Complessi) a few years ago. The instrument and data have been already presented and discussed. The main activity of this HSCM has been within biology, and reflectance data have shown good matching between spectral signatures and the nature or evolution on many types of cells. Such a relationship has been demonstrated mainly with statistical tools like Principal Component Analysis (PCA), or similar concepts, which represent a very common approach for hyperspectral imaging. However, the point is that reflectance data contains much more useful information and, moreover, there is an obvious interest to go from reflectance, bound to the single experiment, to reflectivity, or other physical quantities, related to the sample alone. To accomplish this aim, we can follow well-established analyses and methods used in reflectance spectroscopy. Therefore, we show methods of calculations for index of refraction n, extinction coefficient k and local thicknesses of frequency starting from phase images by fast Kramers-Kronig (KK) algorithms and the Abeles matrix formalism. Details, limitations and problems of the presented calculations as well as alternative procedures are given for an example of HSCM images of red blood cells (RBC). PMID- 27999295 TI - Special Issue: "Molecules against Alzheimer". AB - This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, beta-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/beta catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue. PMID- 27999297 TI - Safe Synthesis of Alkylhydroxy and Alkylamino Nitramines. AB - Three different protocols for the syntheses of hydroxyalkylnitramines are presented and compared. Safety issues regarding the synthesis of nitramines are also discussed. PMID- 27999296 TI - The Health Benefiting Mechanisms of Virgin Olive Oil Phenolic Compounds. AB - Virgin olive oil (VOO) is credited as being one of the many healthful components associated with the Mediterranean diet. Mediterranean populations experience reduced incidence of chronic inflammatory disease states and VOO is readily consumed as part of an everyday Mediterranean dietary pattern. VOO is rich in phenolic compounds and the health promoting benefits of these phenolics are now established. Recent studies have highlighted the biological properties of VOO phenolic compounds elucidating their anti-inflammatory activities. This paper will review current knowledge on the anti-inflammatory and nutrigenomic, chemoprotective and anti-atherosclerotic activities of VOO phenolics. In addition the concentration, metabolism and bioavailability of specific phenolic compounds will be discussed. The evidence presented in the review concludes that oleurepein, hydroxytyrosol and oleocanthal have potent pharmacological activities in vitro and in vivo; however, intervention studies with biologically relevant concentrations of these phenolic compounds are required. PMID- 27999298 TI - Visualization of Fluoride Ions In Vivo Using a Gadolinium(III)-Coumarin Complex Based Fluorescence/MRI Dual-Modal Probe. AB - A new Gadolinium(III)-coumarin complex, DO3A-Gd-CA, was designed and prepared as a dual-modal probe for simultaneous fluorescence and relaxivity responses to fluoride ions (F-) in aqueous media and mice. DO3A-Gd-CA was designed by using Gd(III) center as an MRI signal output unit and fluoride binding site, and the 4 (diethylamino)-coumarin-3-carboxylic acid (CA) as a fluorescence reporter. Upon the addition of fluoride ions to the solution of DO3A-Gd-CA, the liberation of the coordinated CA ligand led to a 5.7-fold fluorescence enhancement and a 75% increase in the longitudinal relaxivity (r1). The fluorescent detection limit for fluoride ions was determined to be 8 MUM based on a 3sigma/slope. The desirable features of the proposed DO3A-Gd-CA, such as high sensitivity and specificity, reliability at physiological pH and low cytotoxicity enable its application in visualization of fluoride ion in mice. The successful in vivo imaging indicates that DO3A-Gd-CA could be potentially used in biomedical diagnosis fields. PMID- 27999299 TI - Review of the Usefulness of Various Rotational Seismometers with Laboratory Results of Fibre-Optic Ones Tested for Engineering Applications. AB - Starting with descriptions of rotational seismology, areas of interest and historical field measurements, the fundamental requirements for rotational seismometers for seismological and engineering application are formulated. On the above basis, a review of all existing rotational seismometers is presented with a description of the principles of their operation as well as possibilities to fulfill formulated requirements. This review includes mechanical, acoustical, electrochemical and optical devices and shows that the last of these types are the most promising. It is shown that optical rotational seismometer based on the ring-laser gyroscope concept is the best for seismological applications, whereas systems based on fiber-optic gyroscopes demonstrate parameters which are also required for engineering applications. Laboratory results of the Fibre-Optic System for Rotational Events & Phenomena Monitoring using a small 1-D shaking table modified to generate rotational excitations are presented. The harmonic and time-history tests demonstrate its usefulness for recording rotational motions with rates up to 0.25 rad/s. PMID- 27999300 TI - A Novel MOS Nanowire Gas Sensor Device (S3) and GC-MS-Based Approach for the Characterization of Grated Parmigiano Reggiano Cheese. AB - To determine the originality of a typical Italian Parmigiano Reggiano cheese, it is crucial to define and characterize its quality, ripening period, and geographical origin. Different analytical techniques have been applied aimed at studying the organoleptic and characteristic volatile organic compounds (VOCs) profile of this cheese. However, most of the classical methods are time consuming and costly. The aim of this work was to illustrate a new simple, portable, fast, reliable, non-destructive, and economic sensor device S3 based on an array of six metal oxide semiconductor nanowire gas sensors to assess and discriminate the quality ranking of grated Parmigiano Reggiano cheese samples and to identify the VOC biomarkers using a headspace SPME-GC-MS. The device could clearly differentiate cheese samples varying in quality and ripening time when the results were analyzed by multivariate statistical analysis involving principal component analysis (PCA). Similarly, the volatile constituents of Parmigiano Reggiano identified were consistent with the compounds intimated in the literature. The obtained results show the applicability of an S3 device combined with SPME-GC-MS and sensory evaluation for a fast and high-sensitivity analysis of VOCs in Parmigiano Reggiano cheese and for the quality control of this class of cheese. PMID- 27999301 TI - Recognition of Damaged Arrow-Road Markings by Visible Light Camera Sensor Based on Convolutional Neural Network. AB - Automobile driver information as displayed on marked road signs indicates the state of the road, traffic conditions, proximity to schools, etc. These signs are important to insure the safety of the driver and pedestrians. They are also important input to the automated advanced driver assistance system (ADAS), installed in many automobiles. Over time, the arrow-road markings may be eroded or otherwise damaged by automobile contact, making it difficult for the driver to correctly identify the marking. Failure to properly identify an arrow-road marker creates a dangerous situation that may result in traffic accidents or pedestrian injury. Very little research exists that studies the problem of automated identification of damaged arrow-road marking painted on the road. In this study, we propose a method that uses a convolutional neural network (CNN) to recognize six types of arrow-road markings, possibly damaged, by visible light camera sensor. Experimental results with six databases of Road marking dataset, KITTI dataset, Malaga dataset 2009, Malaga urban dataset, Naver street view dataset, and Road/Lane detection evaluation 2013 dataset, show that our method outperforms conventional methods. PMID- 27999303 TI - Catch-Up Growth in Former Preterm Neonates: No Time to Waste. AB - n/a. PMID- 27999302 TI - The Effect of Using Mobile Technology-Based Methods That Record Food or Nutrient Intake on Diabetes Control and Nutrition Outcomes: A Systematic Review. AB - (1) Background: Mobile technologies may be utilised for dietary intake assessment for people with diabetes. The published literature was systematically reviewed to determine the effect of using mobile electronic devices to record food or nutrient intake on diabetes control and nutrition outcomes; (2) Methods: The review protocol was registered with PROSPERO: registration number CRD42016050079, and followed PRISMA guidelines. Original research of mobile electronic devices where food or nutrient intake was recorded in people with diabetes with any treatment regimen, and where this intervention was compared with usual care or alternative treatment models, was considered. Quality was assessed using the Quality Criteria Checklist for Primary Research; (3) Results: Nine papers formed the final library with a range of interventions and control practices investigated. The food/nutrient intake recording component of the intervention and patient engagement with the technology was not well described. When assessed for quality, three studies rated positive, five were neutral and one negative. There was significantly greater improvement in HbA1c in the intervention group compared to the control group in four of the nine studies; (4) Conclusion: Based on the available evidence there are no clear recommendations for using technology to record dietary data in this population. PMID- 27999306 TI - A Mathematical Model of a Novel 3D Fractal-Inspired Piezoelectric Ultrasonic Transducer. AB - Piezoelectric ultrasonic transducers have the potential to operate as both a sensor and as an actuator of ultrasonic waves. Currently, manufactured transducers operate effectively over narrow bandwidths as a result of their regular structures which incorporate a single length scale. To increase the operational bandwidth of these devices, consideration has been given in the literature to the implementation of designs which contain a range of length scales. In this paper, a mathematical model of a novel Sierpinski tetrix fractal inspired transducer for sensor applications is presented. To accompany the growing body of research based on fractal-inspired transducers, this paper offers the first sensor design based on a three-dimensional fractal. The three dimensional model reduces to an effective one-dimensional model by allowing for a number of assumptions of the propagating wave in the fractal lattice. The reception sensitivity of the sensor is investigated. Comparisons of reception force response (RFR) are performed between this novel design along with a previously investigated Sierpinski gasket-inspired device and standard Euclidean design. The results indicate that the proposed device surpasses traditional design sensors. PMID- 27999305 TI - Mosquito (Diptera: Culicidae) Habitat Surveillance by Android Mobile Devices in Guangzhou, China. AB - In 2014, Guangzhou City, South China, suffered from its worst outbreak of dengue fever in decades. Larval mosquito habitat surveillance was carried out by using android mobile devices in four study sites in May 2015. The habitats with larval mosquitoes were recorded as photo waypoints in OruxMaps or in videos. The total number of potential mosquito habitats was 342, of which 166 (49%) were found to have mosquito larvae or pupae. Small containers were the most abundant potential habitats, accounting for 26% of the total number. More mosquito larvae and pupae, were found in small containers than in other objects holding water, for example, potted or hydroponic plants (p < 0.05). Mosquito larvae were collected from all plastic road barriers, used tires, and underground water. Aedes albopictus larvae were found from small and large containers, stumps, among others. The overall route index (RI) was 11.3, which was 14.2 times higher than the grade C criteria of the National Patriotic Health Campaign Committee (NPHCC), China. The higher RIs were found from the bird and flower markets, schools, and underground parking lots. The results indicated that Android mobile devices are a convenient and useful tool for surveillance of mosquito habitats, and the enhancement of source reduction may benefit the prevention and control of dengue vector mosquitoes. PMID- 27999304 TI - Identification of Heat Shock Transcription Factor Genes Involved in Thermotolerance of Octoploid Cultivated Strawberry. AB - Heat shock transcription factors (HSFs) are mainly involved in the activation of genes in response to heat stress as well as other abiotic and biotic stresses. The growth, development, reproduction, and yield of strawberry are strongly limited by extreme temperatures and droughts. In this study, we used Illumina sequencing and obtained transcriptome data set from Fragaria * ananassa Duchessne cv. Toyonoka. Six contigs and three unigenes were confirmed to encode HSF proteins (FaTHSFs). Subsequently, we characterized the biological functions of two particularly selected unigenes, FaTHSFA2a and FaTHSFB1a, which were classified into class A2 and B HSFs, respectively. Expression assays revealed that FaTHSFA2a and FaTHSFB1a expression was induced by heat shock and correlated well with elevated ambient temperatures. Overexpression of FaTHSFA2a and FaTHSFB1a resulted in the activation of their downstream stress-associated genes, and notably enhanced the thermotolerance of transgenic Arabidopsis plants. Besides, both FaTHSFA2a and FaTHSFB1a fusion proteins localized in the nucleus, indicating their similar subcellular distributions as transcription factors. Our yeast one-hybrid assay suggested that FaTHSFA2a has trans-activation activity, whereas FaTHSFB1a expresses trans-repression function. Altogether, our annotated transcriptome sequences provide a beneficial resource for identifying most genes expressed in octoploid strawberry. Furthermore, HSF studies revealed the possible insights into the molecular mechanisms of thermotolerance, thus rendering valuable molecular breeding to improve the tolerance of strawberry in response to high-temperature stress. PMID- 27999307 TI - Autonomous Aeromagnetic Surveys Using a Fluxgate Magnetometer. AB - Recent advances in the research of autonomous vehicles have showed a vast range of applications, such as exploration, surveillance and environmental monitoring. Considering the mining industry, it is possible to use such vehicles in the prospection of minerals of commercial interest beneath the ground. However, tasks such as geophysical surveys are highly dependent on specific sensors, which mostly are not designed to be used in these new range of autonomous vehicles. In this work, we propose a novel magnetic survey pipeline that aims to increase versatility, speed and robustness by using autonomous rotary-wing Unmanned Aerial Vehicles (UAVs). We also discuss the development of a state-of-the-art three-axis fluxgate, where our goal in this work was to refine and adjust the sensor topology and coupled electronics specifically for this type of vehicle and application. The sensor was built with two ring-cores using a specially developed stress-annealed CoFeSiB amorphous ribbon, in order to get sufficient resolution to detect concentrations of small ferrous minerals. Finally, we report on the results of experiments performed with a real UAV in an outdoor environment, showing the efficacy of the methodology in detecting an artificial ferrous anomaly. PMID- 27999309 TI - Underwater Electromagnetic Sensor Networks, Part II: Localization and Network Simulations. AB - In the first part of the paper, we modeled and characterized the underwater radio channel in shallowwaters. In the second part,we analyze the application requirements for an underwaterwireless sensor network (U-WSN) operating in the same environment and perform detailed simulations. We consider two localization applications, namely self-localization and navigation aid, and propose algorithms that work well under the specific constraints associated with U-WSN, namely low connectivity, low data rates and high packet loss probability. We propose an algorithm where the sensor nodes collaboratively estimate their unknown positions in the network using a low number of anchor nodes and distance measurements from the underwater channel. Once the network has been self-located, we consider a node estimating its position for underwater navigation communicating with neighboring nodes. We also propose a communication system and simulate the whole electromagnetic U-WSN in the Castalia simulator to evaluate the network performance, including propagation impairments (e.g., noise, interference), radio parameters (e.g., modulation scheme, bandwidth, transmit power), hardware limitations (e.g., clock drift, transmission buffer) and complete MAC and routing protocols. We also explain the changes that have to be done to Castalia in order to perform the simulations. In addition, we propose a parametric model of the communication channel that matches well with the results from the first part of this paper. Finally, we provide simulation results for some illustrative scenarios. PMID- 27999308 TI - Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid. AB - BACKGROUND: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. RESULTS: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. CONCLUSION: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS. PMID- 27999311 TI - Metabolomic Approaches to Explore Chemical Diversity of Human Breast-Milk, Formula Milk and Bovine Milk. AB - Although many studies have been conducted on the components present in human breast milk (HM), research on the differences of chemical metabolites between HM, bovine milk (BM) and formula milk (FM) is limited. This study was to explore the chemical diversity of HM, BM and FM by metabolomic approaches. GC-TOFMS and UPLC QTOFMS were applied to investigate the metabolic compositions in 30 HM samples, 20 FM samples and 20 BM samples. Metabolite profiling identified that most of the non-esterified fatty acids, which reflected the hydrolysis of triglycerides, were much more abundant in HM than those in FM and BM, except for palmitic acid and stearic acid. The levels of tricarboxylic acid (TCA) intermediates were much higher in FM and BM than those in HM. Each type of milk also showed its unique composition of free amino acids and free carbohydrates. In conclusion, higher levels of non-esterified saturated fatty acids with aliphatic tails <16 carbons, monounsaturated fatty acids and polyunsaturated fatty acids and lower levels of TCA intermediates are characteristic of HM, as compared with FM and BM. The content of non-esterified fatty acids may reflect the hydrolysis of triglycerides in different milk types. PMID- 27999314 TI - Molecular Mechanisms and Metabolomics of Natural Polyphenols Interfering with Breast Cancer Metastasis. AB - Metastatic cancers are the main cause of cancer-related death. In breast primary cancer, the five-year survival rate is close to 100%; however, for metastatic breast cancer, that rate drops to a mere 25%, due in part to the paucity of effective therapeutic options for treating metastases. Several in vitro and in vivo studies have indicated that consumption of natural polyphenols significantly reduces the risk of cancer metastasis. Therefore, this review summarizes the research findings involving the molecular mechanisms and metabolomics of natural polyphenols and how they may be blocking breast cancer metastasis. Most natural polyphenols are thought to impair breast cancer metastasis through downregulation of MMPs expression, interference with the VEGF signaling pathway, modulation of EMT regulator, inhibition of NF-kappaB and mTOR expression, and other related mechanisms. Intake of natural polyphenols has been shown to impact endogenous metabolites and complex biological metabolic pathways in vivo. Breast cancer metastasis is a complicated process in which each step is modulated by a complex network of signaling pathways. We hope that by detailing the reported interactions between breast cancer metastasis and natural polyphenols, more attention will be directed to these promising candidates as effective adjunct therapies against metastatic breast cancer in the clinic. PMID- 27999313 TI - Implementation of a Nutrition Program Reduced Post-Discharge Growth Restriction in Thai Very Low Birth Weight Preterm Infants. AB - Very low birth weight (VLBW) preterm infants are vulnerable to growth restriction after discharge due to cumulative protein and energy deficits during their hospital stay and early post-discharge period. The current study evaluated the effectiveness of the preterm infant, post-discharge nutrition (PIN) program to reduce post-discharge growth restriction in Thai VLBW preterm infants. A prospective, non-randomized interventional cohort study was undertaken to assess the growth of 22 VLBW preterm infants who received the PIN program and compared them with 22 VLBW preterm infants who received conventional nutrition services. Infant's growth was recorded monthly until the infants reached six months' corrected age (6-moCA). Intervention infants had significantly greater body weights (p = 0.013) and head circumferences (p = 0.009). Also, a greater proportion of the intervention group recovered their weight to the standard weight at 4-moCA (p = 0.027) and at 6-moCA (p = 0.007) and their head circumference to the standard head circumference at 6-moCA (p = 0.004) compared to their historical comparison counterparts. Enlistment in the PIN program thus resulted in significantly reduced post-discharge growth restriction in VLBW preterm infants. Further research on longer term effects of the program on infant's growth and development is warranted. PMID- 27999312 TI - A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one's susceptibility to AS remain to be unraveled. With 100 trillion bacteria residing in the mammalian gut having established a symbiotic relation with their host influencing many aspects of host metabolism, physiology, and immunity, a growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. In this review, the existing evidence for the involvement of the microbiome in AS pathogenesis was discussed and the potential of intestinal microbiome-targeting strategies in the prevention and treatment of AS was evaluated. PMID- 27999315 TI - Synthesis, Characterization, and Sensor Applications of Spinel ZnCo2O4 Nanoparticles. AB - Spinel ZnCo2O4 nanoparticles were synthesized by means of the microwave-assisted colloidal method. A solution containing ethanol, Co-nitrate, Zn-nitrate, and dodecylamine was stirred for 24 h and evaporated by a microwave oven. The resulting solid material was dried at 200 degrees C and subsequently calcined at 500 degrees C for 5 h. The samples were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectroscopy, confirming the formation of spinel ZnCo2O4 nanoparticles with average sizes between 49 and 75 nm. It was found that the average particle size decreased when the dodecylamine concentration increased. Pellets containing ZnCo2O4 nanoparticles were fabricated and tested as sensors in carbon monoxide (CO) and propane (C3H8) gases at different concentrations and temperatures. Sensor performance tests revealed an extremely high response to 300 ppm of CO at an operating temperature of 200 degrees C. PMID- 27999317 TI - High Accuracy Acquisition of 3-D Flight Trajectory of Individual Insect Based on Phase Measurement. AB - Accurate acquisition of 3-D flight trajectory of individual insect could be of benefit to the research of insect migration behaviors and the development of migratory entomology. This paper proposes a novel method to acquire 3-D flight trajectory of individual insect. First, based on the high range resolution synthesizing and the Doppler coherent processing, insects can be detected effectively, and the range resolution and velocity resolution are combined together to discriminate insects. Then, high accuracy range measurement with the carrier phase is proposed. The range measurement accuracy can reach millimeter level and benefits the acquisition of 3-D trajectory information significantly. Finally, based on the multi-baselines interferometry theory, the azimuth and elevation angles can be obtained with high accuracy. Simulation results prove that the retrieval accuracy of a simulated target's 3-D coordinates can reach centimeter level. Experiments utilizing S-band radar in an anechoic chamber were taken and results showed that the insects' flight behaviors and 3-D coordinates' variation matched the practical cases well. In conclusion, both the simulated and experimental datasets validate the feasibility of the proposed method, which could be a novel measurement way of monitoring flight trajectory of aerial free fly insects. PMID- 27999318 TI - Differential GNSS and Vision-Based Tracking to Improve Navigation Performance in Cooperative Multi-UAV Systems. AB - Autonomous navigation of micro-UAVs is typically based on the integration of low cost Global Navigation Satellite System (GNSS) receivers and Micro-Electro Mechanical Systems (MEMS)-based inertial and magnetic sensors to stabilize and control the flight. The resulting navigation performance in terms of position and attitude accuracy may not suffice for other mission needs, such as the ones relevant to fine sensor pointing. In this framework, this paper presents a cooperative UAV navigation algorithm that allows a chief vehicle, equipped with inertial and magnetic sensors, a Global Positioning System (GPS) receiver, and a vision system, to improve its navigation performance (in real time or in the post processing phase) exploiting formation flying deputy vehicles equipped with GPS receivers. The focus is set on outdoor environments and the key concept is to exploit differential GPS among vehicles and vision-based tracking (DGPS/Vision) to build a virtual additional navigation sensor whose information is then integrated in a sensor fusion algorithm based on an Extended Kalman Filter. The developed concept and processing architecture are described, with a focus on DGPS/Vision attitude determination algorithm. Performance assessment is carried out on the basis of both numerical simulations and flight tests. In the latter ones, navigation estimates derived from the DGPS/Vision approach are compared with those provided by the onboard autopilot system of a customized quadrotor. The analysis shows the potential of the developed approach, mainly deriving from the possibility to exploit magnetic- and inertial-independent accurate attitude information. PMID- 27999310 TI - Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease. AB - The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17beta-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease. PMID- 27999316 TI - A Smartphone Application for Personal Assessments of Body Composition and Phenotyping. AB - Personal assessments of body phenotype can enhance success in weight management but are limited by the lack of availability of practical methods. We describe a novel smart phone application of digital photography (DP) and determine its validity to estimate fat mass (FM). This approach utilizes the percent (%) occupancy of an individual lateral whole-body digital image and regions indicative of adipose accumulation associated with increased risk of cardio metabolic disease. We measured 117 healthy adults (63 females and 54 males aged 19 to 65 years) with DP and dual X-ray absorptiometry (DXA) and report here the development and validation of this application. Inter-observer variability of the determination of % occupancy was 0.02%. Predicted and reference FM values were significantly related in females (R2 = 0.949, SEE = 2.83) and males (R2 = 0.907, SEE = 2.71). Differences between predicted and measured FM values were small (0.02 kg, p = 0.96 and 0.07 kg, p = 0.96) for females and males, respectively. No significant bias was found; limits of agreement ranged from 5.6 to -5.4 kg for females and from 5.6 to -5.7 kg for males. These promising results indicate that DP is a practical and valid method for personal body composition assessments. PMID- 27999320 TI - Volatile and Nonvolatile Constituents and Antioxidant Capacity of Oleoresins in Three Taiwan Citrus Varieties as Determined by Supercritical Fluid Extraction. AB - As local varieties of citrus fruit in Taiwan, Ponkan (Citrus reticulata Blanco), Tankan (C. tankan Hayata), and Murcott (C. reticulate * C. sinensis) face substantial competition on the market. In this study, we used carbon dioxide supercritical technology to extract oleoresin from the peels of the three citrus varieties, adding alcohol as a solvent assistant to enhance the extraction rate. The supercritical fluid extraction was fractionated with lower terpene compounds in order to improve the oxygenated amounts of the volatile resins. The contents of oleoresin from the three varieties of citrus peels were then analyzed with GC/MS in order to identify 33 volatile compounds. In addition, the analysis results indicated that the non-volatile oleoresin extracted from the samples contains polymethoxyflavones (86.2~259.5 mg/g), limonoids (111.7~406.2 mg/g), and phytosterols (686.1~1316.4 MUg/g). The DPPH (1,1-Diphenyl-2-picrylhydrazyl), ABTS [2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)] scavenging and inhibition of lipid oxidation, which test the oleoresin from the three kinds of citrus, exhibited significant antioxidant capacity. The component polymethoxyflavones contributed the greatest share of the overall antioxidant capacity, while the limonoid and phytosterol components effectively coordinated with its effects. PMID- 27999321 TI - Estimation of Temporal Gait Parameters Using a Wearable Microphone-Sensor-Based System. AB - Most existing wearable gait analysis methods focus on the analysis of data obtained from inertial sensors. This paper proposes a novel, low-cost, wireless and wearable gait analysis system which uses microphone sensors to collect footstep sound signals during walking. This is the first time a microphone sensor is used as a wearable gait analysis device as far as we know. Based on this system, a gait analysis algorithm for estimating the temporal parameters of gait is presented. The algorithm fully uses the fusion of two feet footstep sound signals and includes three stages: footstep detection, heel-strike event and toe on event detection, and calculation of gait temporal parameters. Experimental results show that with a total of 240 data sequences and 1732 steps collected using three different gait data collection strategies from 15 healthy subjects, the proposed system achieves an average 0.955 F1-measure for footstep detection, an average 94.52% accuracy rate for heel-strike detection and 94.25% accuracy rate for toe-on detection. Using these detection results, nine temporal related gait parameters are calculated and these parameters are consistent with their corresponding normal gait temporal parameters and labeled data calculation results. The results verify the effectiveness of our proposed system and algorithm for temporal gait parameter estimation. PMID- 27999322 TI - A Modified Magnetic Gradient Contraction Based Method for Ferromagnetic Target Localization. AB - The Scalar Triangulation and Ranging (STAR) method, which is based upon the unique properties of magnetic gradient contraction, is a high real-time ferromagnetic target localization method. Only one measurement point is required in the STAR method and it is not sensitive to changes in sensing platform orientation. However, the localization accuracy of the method is limited by the asphericity errors and the inaccurate value of position leads to larger errors in the estimation of magnetic moment. To improve the localization accuracy, a modified STAR method is proposed. In the proposed method, the asphericity errors of the traditional STAR method are compensated with an iterative algorithm. The proposed method has a fast convergence rate which meets the requirement of high real-time localization. Simulations and field experiments have been done to evaluate the performance of the proposed method. The results indicate that target parameters estimated by the modified STAR method are more accurate than the traditional STAR method. PMID- 27999319 TI - Exercise and Beta-Glucan Consumption (Saccharomyces cerevisiae) Improve the Metabolic Profile and Reduce the Atherogenic Index in Type 2 Diabetic Rats (HFD/STZ). AB - Physical activity and the ingestion of dietary fiber are non-drug alternatives commonly used as adjuvants to glycemic control in diabetic individuals. Among these fibers, we can highlight beta-glucans. However, few studies have compared isolated and synergic effects of physical exercise and beta-glucan ingestion, especially in type 2 diabetic rats. Therefore, we evaluated the effects beta glucan (Saccharomyces cerevisiae) consumption, associated or not to exercise, on metabolic parameters of diabetic Wistar rats. The diabetes mellitus (DM) was induced by high-fat diet (HFD) associated with a low dose of streptozotocin (STZ 35 mg/kg). Trained groups were submitted to eight weeks of exercise in aquatic environment. In the last 28 days of experiment, animals received 30 mg/kg/day of beta-glucan by gavage. Isolated use of beta-glucan decreased glucose levels in fasting, Glycated hemoglobin (HbA1c), triglycerides (TAG), total cholesterol (TC), low-density lipoprotein (LDL-C), the atherogenic index of plasma. Exercise alone also decreased blood glucose levels, HbA1c, and renal lesions. An additive effect for reducing the atherogenic index of plasma and renal lesions was observed when both treatments were combined. It was concluded that both beta glucan and exercise improved metabolic parameters in type 2 (HFD/STZ) diabetic rats. PMID- 27999323 TI - Circulating Cell-Free DNA Levels Could Predict Oncological Outcomes of Patients Undergoing Esophagectomy for Esophageal Squamous Cell Carcinoma. AB - Circulating cell-free DNA (cfDNA) is a potential biomarker for cancer progression but its role is unclear in patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. We investigated relationships between plasma cfDNA levels and clinicopathological parameters in ESCC patients. Eighty-one ESCC patients who received esophagectomy were enrolled. Plasma samples from these patients and 95 normal controls were collected. DNA copy numbers were measured by real-time quantitative PCR. Subjects were divided into two groups by cfDNA level. Clinicopathological data were collected retrospectively and relationships between cfDNA levels and clinical parameters were evaluated. The cfDNA level in normal controls ranged from 0-4157 copies/mL. The cfDNA level of 96.3% ESCC patients was higher than the cutoff value (2447.26 copies/mL) with a specificity of 94.1%. The mean cfDNA concentration was 5918 copies/mL in lower and 53,311 copies/mL in higher cfDNA groups. No correlations were found between clinicopathological factors and cfDNA levels except for lymphovascular invasion. Higher cfDNA levels were associated with tumor relapse (p = 0.018). Five-year disease-free survival (DFS) and overall survival (OS) rates were 34.7% and 33.8%, respectively. Patients with higher cfDNA levels had poorer DFS (p = 0.013). Patients with higher cfDNA levels had poorer OS, but not significantly (p = 0.164). Circulating cfDNA could be a biomarker for tumor relapse of ESCC with high sensitivity and specificity. Higher cfDNA levels were associated with tumor relapse and shorter DFS after esophagectomy in ESCC patients. PMID- 27999324 TI - Development of a Wearable Instrumented Vest for Posture Monitoring and System Usability Verification Based on the Technology Acceptance Model. AB - Body posture and activity are important indices for assessing health and quality of life, especially for elderly people. Therefore, an easily wearable device or instrumented garment would be valuable for monitoring elderly people's postures and activities to facilitate healthy aging. In particular, such devices should be accepted by elderly people so that they are willing to wear it all the time. This paper presents the design and development of a novel, textile-based, intelligent wearable vest for real-time posture monitoring and emergency warnings. The vest provides a highly portable and low-cost solution that can be used both indoors and outdoors in order to provide long-term care at home, including health promotion, healthy aging assessments, and health abnormality alerts. The usability of the system was verified using a technology acceptance model-based study of 50 elderly people. The results indicated that although elderly people are anxious about some newly developed wearable technologies, they look forward to wearing this instrumented posture-monitoring vest in the future. PMID- 27999325 TI - Pharmacokinetics of the Antiviral Lectin Griffithsin Administered by Different Routes Indicates Multiple Potential Uses. AB - Griffithsin (GRFT) is a red alga-derived lectin with demonstrated broad spectrum antiviral activity against enveloped viruses, including severe acute respiratory syndrome-Coronavirus (SARS-CoV), Japanese encephalitis virus (JEV), hepatitis C virus (HCV), and herpes simplex virus-2 (HSV-2). However, its pharmacokinetic profile remains largely undefined. Here, Sprague Dawley rats were administered a single dose of GRFT at 10 or 20 mg/kg by intravenous, oral, and subcutaneous routes, respectively, and serum GRFT levels were measured at select time points. In addition, the potential for systemic accumulation after oral dosing was assessed in rats after 10 daily treatments with GRFT (20 or 40 mg/kg). We found that parenterally-administered GRFT in rats displayed a complex elimination profile, which varied according to administration routes. However, GRFT was not orally bioavailable, even after chronic treatment. Nonetheless, active GRFT capable of neutralizing HIV-Env pseudoviruses was detected in rat fecal extracts after chronic oral dosing. These findings support further evaluation of GRFT for pre-exposure prophylaxis against emerging epidemics for which specific therapeutics are not available, including systemic and enteric infections caused by susceptible enveloped viruses. In addition, GRFT should be considered for antiviral therapy and the prevention of rectal transmission of HIV-1 and other susceptible viruses. PMID- 27999327 TI - Antimicrobial Activity and Urease Inhibition of Schiff Bases Derived from Isoniazid and Fluorinated Benzaldehydes and of Their Copper(II) Complexes. AB - In order to evaluate the influence of substitution on biological properties of Schiff bases and their metal complexes, a series of differently substituted fluorine-containing Schiff bases starting from the drug isoniazid (isonicotinylhydrazide) were prepared and their structures were established by single-crystal X-ray diffraction. Also, four copper(II) complexes of these Schiff bases were synthesized. The prepared compounds were evaluated for their antimicrobial activity and urease inhibition. Two of the Schiff bases exerted activity against C. albicans. All copper(II) complexes showed excellent inhibitory properties against jack bean urease, considerably better than that of the standard inhibitor acetohydroxamic acid. PMID- 27999326 TI - Oral Biofluid Biomarker Research: Current Status and Emerging Frontiers. AB - Salivary diagnostics is a rapidly advancing field that offers clinicians and patients the potential of rapid, noninvasive diagnostics with excellent accuracy. In order for the complete realization of the potential of saliva, however, extensive profiling of constituents must be conducted and diagnostic biomarkers must be thoroughly validated. This article briefly overviews the process of conducting a study of salivary biomarkers in a patient cohort and highlights the studies that have been conducted on different classes of molecules in the saliva. Emerging frontiers in salivary diagnostics research that may significantly advance the field will also be highlighted. PMID- 27999329 TI - Photochemically Immobilized 4-Methylbenzoyl Cellulose as a Powerful Chiral Stationary Phase for Enantioselective Chromatography. AB - A process to immobilize para-methylbenzoyl cellulose (PMBC) on silica gel has been developed and applied to prepare chiral stationary phases (CSPs) for enantioselective chromatography. The immobilization was achieved by simple irradiation of the polysaccharide derivative with ultraviolet light after coating on a silica gel support. The influence of parameters such as irradiation time and solvent on immobilization effectiveness were investigated. The performance of the prepared immobilized phases were evaluated by injection of a series of racemic compounds onto the packed columns and determination of their chiral recognition ability. By contrast to the classical coated phase, the immobilized CSP can be used under various chromatographic conditions without limitation of organic solvent types as the mobile phase. This extended applicability permits to improve selectivity and to resolve chiral compounds which are not or only poorly soluble in the mobile phases which are compatible with the non-immobilized PMBC stationary phase. PMID- 27999328 TI - The Dual Role of Neutrophils in Inflammatory Bowel Diseases. AB - Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are characterised by aberrant immunological responses leading to chronic inflammation without tissue regeneration. These two diseases are considered distinct entities, and there is some evidence that neutrophil behaviour, above all other aspects of immunity, clearly separate them. Neutrophils are the first immune cells recruited to the site of inflammation, and their action is crucial to limit invasion by microorganisms. Furthermore, they play an essential role in proper resolution of inflammation. When these processes are not tightly regulated, they can trigger positive feedback amplification loops that promote neutrophil activation, leading to significant tissue damage and evolution toward chronic disease. Defective chemotaxis, as observed in Crohn's disease, can also contribute to the disease through impaired microbe elimination. In addition, through NET production, neutrophils may be involved in thrombo-embolic events frequently observed in IBD patients. While the role of neutrophils has been studied in different animal models of IBD for many years, their contribution to the pathogenesis of IBD remains poorly understood, and no molecules targeting neutrophils are used and validated for the treatment of these pathologies. Therefore, it is crucial to improve our understanding of their mode of action in these particular conditions in order to provide new therapeutic avenues for IBD. PMID- 27999330 TI - Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma. AB - A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma. NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities. This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively. In addition, the emerging field of research focusing on miRNA single nucleotide polymorphisms (miRSNPs) in genes of the miRNA biogenesis pathway, in miRNA genes themselves, and in their target sites may provide new insights on gene expression changes in these genes. These miRSNPs may impact miRNA networks and have been shown to play a role in a host of different cancer types including haematological malignancies. With respect to NHL, a number of SNPs in miRNA-binding sites in target genes have been shown to be associated with overall survival. PMID- 27999331 TI - Control of Pollutants in the Trans-Boundary Area of Taihu Basin, Yangtze Delta. AB - This work focuses on pollution control in the trans-boundary area of Taihu Basin. Considering the unique characteristics of the river network in the study area, a new methodology of pollution control is proposed aiming at improving the water quality in the trans-boundary area and reducing conflicts between up and downstream regions. Based on monitoring data and statistical analysis, important trans-boundary cross sections identified by the regional government were selected as important areas for consideration in developing management objectives; using a 1-D mathematicmodel and an effective weight evaluation model, the trans-boundary effective control scope (TECS) of the study area was identified as the scope for pollutant control; the acceptable pollution load was then estimated using an established model targeting bi-directional flow. The results suggest that the water environmental capacity for chemical oxygen demand (COD), in order to guarantee reaching the target water quality standard in the TECS, is 160,806 t/year, and amounts to 16,098 t/year, 3493 t/year, and 39,768 t/year for ammonia nitrogen, total nitrogen, and total phosphorus, respectively. Our study method and results have been incorporated into the local government management project, and have been proven to be useful in designing a pollution control strategy and management policy. PMID- 27999333 TI - A Cooperative Traffic Control of Vehicle-Intersection (CTCVI) for the Reduction of Traffic Delays and Fuel Consumption. AB - The problem of reducing traffic delays and decreasing fuel consumption simultaneously in a network of intersections without traffic lights is solved by a cooperative traffic control algorithm, where the cooperation is executed based on the connection of Vehicle-to-Infrastructure (V2I). This resolution of the problem contains two main steps. The first step concerns the itinerary of which intersections are chosen by vehicles to arrive at their destination from their starting point. Based on the principle of minimal travel distance, each vehicle chooses its itinerary dynamically based on the traffic loads in the adjacent intersections. The second step is related to the following proposed cooperative procedures to allow vehicles to pass through each intersection rapidly and economically: on one hand, according to the real-time information sent by vehicles via V2I in the edge of the communication zone, each intersection applies Dynamic Programming (DP) to cooperatively optimize the vehicle passing sequence with minimal traffic delays so that the vehicles may rapidly pass the intersection under the relevant safety constraints; on the other hand, after receiving this sequence, each vehicle finds the optimal speed profiles with the minimal fuel consumption by an exhaustive search. The simulation results reveal that the proposed algorithm can significantly reduce both travel delays and fuel consumption compared with other papers under different traffic volumes. PMID- 27999332 TI - Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases. AB - Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double stranded RNA (dsRNA). Among the three types of mammalian ADARs, ADAR1 has long been recognized as an essential enzyme for normal development. The interferon inducible ADAR1p150 is involved in immune responses to both exogenous and endogenous triggers, whereas the functions of the constitutively expressed ADAR1p110 are variable. Recent findings that ADAR1 is involved in the recognition of self versus non-self dsRNA provide potential explanations for its links to hematopoiesis, type I interferonopathies, and viral infections. Editing in both coding and noncoding sequences results in diseases ranging from cancers to neurological abnormalities. Furthermore, editing of noncoding sequences, like microRNAs, can regulate protein expression, while editing of Alu sequences can affect translational efficiency and editing of proximal sequences. Novel identifications of long noncoding RNA and retrotransposons as editing targets further expand the effects of A-to-I editing. Besides editing, ADAR1 also interacts with other dsRNA-binding proteins in editing-independent manners. Elucidating the disease-specific patterns of editing and/or ADAR1 expression may be useful in making diagnoses and prognoses. In this review, we relate the mechanisms of ADAR1's actions to its pathological implications, and suggest possible mechanisms for the unexplained associations between ADAR1 and human diseases. PMID- 27999334 TI - Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene. AB - Neurofibromatosis 1 (NF1) is one of the most common genetic disorders and is caused by mutations in the NF1 gene. NF1 gene mutational analysis presents a considerable challenge because of its large size, existence of highly homologous pseudogenes located throughout the human genome, absence of mutational hotspots, and diversity of mutations types, including deep intronic splicing mutations. We aimed to evaluate the use of hybridization capture-based next-generation sequencing to screen coding and noncoding NF1 regions. Hybridization capture based next-generation sequencing, with genomic DNA as starting material, was used to sequence the whole NF1 gene (exons and introns) from 11 unrelated individuals and 1 relative, who all had NF1. All of them met the NF1 clinical diagnostic criteria. We showed a mutation detection rate of 91% (10 out of 11). We identified eight recurrent and two novel mutations, which were all confirmed by Sanger methodology. In the Sanger sequencing confirmation, we also included another three relatives with NF1. Splicing alterations accounted for 50% of the mutations. One of them was caused by a deep intronic mutation (c.1260 + 1604A > G). Frameshift truncation and missense mutations corresponded to 30% and 20% of the pathogenic variants, respectively. In conclusion, we show the use of a simple and fast approach to screen, at once, the entire NF1 gene (exons and introns) for different types of pathogenic variations, including the deep intronic splicing mutations. PMID- 27999335 TI - Mutant CAG Repeats Effectively Targeted by RNA Interference in SCA7 Cells. AB - Spinocerebellar ataxia type 7 (SCA7) is a human neurodegenerative polyglutamine (polyQ) disease caused by a CAG repeat expansion in the open reading frame of the ATXN7 gene. The allele-selective silencing of mutant transcripts using a repeat targeting strategy has previously been used for several polyQ diseases. Herein, we demonstrate that the selective targeting of a repeat tract in a mutant ATXN7 transcript by RNA interference is a feasible approach and results in an efficient decrease of mutant ataxin-7 protein in patient-derived cells. Oligonucleotides (ONs) containing specific base substitutions cause the downregulation of the ATXN7 mutant allele together with the upregulation of its normal allele. The A2 ON shows high allele selectivity at a broad range of concentrations and also restores UCHL1 expression, which is downregulated in SCA7. PMID- 27999336 TI - DeBouganin Diabody Fusion Protein Overcomes Drug Resistance to ADCs Comprised of Anti-Microtubule Agents. AB - Antibody drug conjugates (ADC), comprised of highly potent small molecule payloads chemically conjugated to a full-length antibody, represent a growing class of therapeutic agents. The targeting of cytotoxic payloads via the specificity and selectivity of the antibody has led to substantial clinical benefits. However, ADC potency can be altered by mechanisms of resistance such as overexpression of efflux pumps or anti-apoptotic proteins. DeBouganin is a de immunized variant of bouganin, a ribosome-inactivating protein (RIP) that blocks protein synthesis, thereby leading to apoptosis. When conjugated to trastuzumab (T-deB), deBouganin was more potent than ado-trastuzumab-emtansine (T-DM1) and unaffected by resistance mechanisms to which DM1 is susceptible. To further highlight the differentiating mechanism of action of deBouganin, HCC1419 and BT 474 tumor cells that survived T-DM1 or trastuzumab-MMAE (T-MMAE) treatment were treated with an anti-HER2 C6.5 diabody-deBouganin fusion protein or T-deB. C6.5 diabody-deBouganin and T-deB were potent against HCC1419 and BT-474 cells that were resistant to T-DM1 or T-MMAE killing. The resistant phenotype involved MDR pumps, Bcl-2 family members, and the presence of additional unknown pathways. Overall, the data suggest that deBouganin is effective against tumor cell resistance mechanisms selected in response to ADCs composed of anti-microtubule payloads. PMID- 27999337 TI - Adaptive Local Spatiotemporal Features from RGB-D Data for One-Shot Learning Gesture Recognition. AB - Noise and constant empirical motion constraints affect the extraction of distinctive spatiotemporal features from one or a few samples per gesture class. To tackle these problems, an adaptive local spatiotemporal feature (ALSTF) using fused RGB-D data is proposed. First, motion regions of interest (MRoIs) are adaptively extracted using grayscale and depth velocity variance information to greatly reduce the impact of noise. Then, corners are used as keypoints if their depth, and velocities of grayscale and of depth meet several adaptive local constraints in each MRoI. With further filtering of noise, an accurate and sufficient number of keypoints is obtained within the desired moving body parts (MBPs). Finally, four kinds of multiple descriptors are calculated and combined in extended gradient and motion spaces to represent the appearance and motion features of gestures. The experimental results on the ChaLearn gesture, CAD-60 and MSRDailyActivity3D datasets demonstrate that the proposed feature achieves higher performance compared with published state-of-the-art approaches under the one-shot learning setting and comparable accuracy under the leave-one-out cross validation. PMID- 27999338 TI - Robust and Accurate Vision-Based Pose Estimation Algorithm Based on Four Coplanar Feature Points. AB - Vision-based pose estimation is an important application of machine vision. Currently, analytical and iterative methods are used to solve the object pose. The analytical solutions generally take less computation time. However, the analytical solutions are extremely susceptible to noise. The iterative solutions minimize the distance error between feature points based on 2D image pixel coordinates. However, the non-linear optimization needs a good initial estimate of the true solution, otherwise they are more time consuming than analytical solutions. Moreover, the image processing error grows rapidly with measurement range increase. This leads to pose estimation errors. All the reasons mentioned above will cause accuracy to decrease. To solve this problem, a novel pose estimation method based on four coplanar points is proposed. Firstly, the coordinates of feature points are determined according to the linear constraints formed by the four points. The initial coordinates of feature points acquired through the linear method are then optimized through an iterative method. Finally, the coordinate system of object motion is established and a method is introduced to solve the object pose. The growing image processing error causes pose estimation errors the measurement range increases. Through the coordinate system, the pose estimation errors could be decreased. The proposed method is compared with two other existing methods through experiments. Experimental results demonstrate that the proposed method works efficiently and stably. PMID- 27999339 TI - Association between Plain Water and Sugar-Sweetened Beverages and Total Energy Intake among Mexican School-Age Children. AB - Water consumption promotes a decrease in total diet energy intake, and one explanation for this fact is the replacement of sugar-sweetened beverages (SSBs) by plain water (PW). The objective of this study was to analyze the association between SSB and PW consumption as a part of the total energy intake. Dietary information was obtained by one 24 h recall of 2536 school-age children who participated in the National Nutrition Survey in Mexico. PW and SSB consumption was measured in mL and servings (240 mL), and consumption was stratified into two levels (<2 and >=2 servings/day). Linear regression models were used to evaluate the association between PW and SSB consumption in relation to total energy intake. Models were adjusted for age, sex, the proportion of energy obtained from non-beverage food, area of residence, and socioeconomic status (based on information regarding housing conditions and ownership of home appliances). PW consumption at the national level was two servings/day, and was not associated with total energy intake. However, the combination of the high consumption of PW and the low consumption of SSB was associated with less total energy intake (p < 0.05). Promoting higher PW and lower SSB consumption provides a useful public health strategy for reducing total energy intake and preventing overconsumption among Mexican school-age children. PMID- 27999341 TI - Exploring the Role of Vitamin D. Comments on Fleury et al. Sun Exposure and Its Effects on Human Health: Mechanisms through Which Sun Exposure Could Reduce the Risk of Developing Obesity and Cardiometabolic Dysfunction. Int. J. Environ. Res. Public Health 2016, 13, 999. AB - n/a. PMID- 27999340 TI - Equine Immunoglobulin and Equine Neutralizing F(ab')2 Protect Mice from West Nile Virus Infection. AB - West Nile virus (WNV) is prevalent in Africa, Europe, the Middle East, West Asia, and North America, and causes epidemic encephalitis. To date, no effective therapy for WNV infection has been developed; therefore, there is urgent need to find an efficient method to prevent WNV disease. In this study, we prepared and evaluated the protective efficacy of immune serum IgG and pepsin-digested F(ab')2 fragments from horses immunized with the WNV virus-like particles (VLP) expressing the WNV M and E proteins. Immune equine F(ab')2 fragments and immune horse sera efficiently neutralized WNV infection in tissue culture. The passive transfer of equine immune antibodies significantly accelerated the virus clearance in the spleens and brains of WNV infected mice, and reduced mortality. Thus, equine immunoglobulin or equine neutralizing F(ab')2 passive immunotherapy is a potential strategy for the prophylactic or therapeutic treatment of patients infected with WNV. PMID- 27999342 TI - Perception of Environmental Risks and Health Promotion Attitudes of French Perinatal Health Professionals. AB - The exposure of pregnant women to environmental contaminants is a subject of international concern. However, the risk perception of these contaminants by health professionals (HP) has not been extensively investigated. The main objective of the PERI-HELPE study (Perception of Risk-HEaLth Professionals & Environment Study) was to assess the risk perception of environmental exposure of pregnant women by perinatal HPs. The secondary objectives were to describe the preventive attitudes of perinatal HPs concerning chemicals exposure of pregnant women and to identify the barriers to preventive attitude. A cross-sectional study was performed in 2015 in France. One hundred eighty-nine HPs (obstetricians, midwives, and general practitioners) replied to an online self administered questionnaire (participation rate: 11%). Carbon monoxide, pesticides and lead were the contaminants most frequently perceived as a high risk for pregnant women. A minority of HPs asked women about their chemical exposure and advised them to reduce exposure. The lack of information, training and scientific evidence in environmental health were the main difficulties declared by the HPs to advise pregnant women. Despite the low response rate, our findings provide important information to encourage French health authorities to take into account the difficulties encountered by HPs and set up appropriate training programs in Environmental health. PMID- 27999343 TI - On-Line Monitoring the Growth of E. coli or HeLa Cells Using an Annular Microelectrode Piezoelectric Biosensor. AB - Biological information is obtained from the interaction between the series detection electrode and the organism or the physical field of biological cultures in the non-mass responsive piezoelectric biosensor. Therefore, electric parameter of the electrode will affect the biosensor signal. The electric field distribution of the microelectrode used in this study was simulated using the COMSOL Multiphysics analytical tool. This process showed that the electric field spatial distribution is affected by the width of the electrode finger or the space between the electrodes. In addition, the characteristic response of the piezoelectric sensor constructed serially with an annular microelectrode was tested and applied for the continuous detection of Escherichia coli culture or HeLa cell culture. Results indicated that the piezoelectric biosensor with an annular microelectrode meets the requirements for the real-time detection of E. coli or HeLa cells in culture. Moreover, this kind of piezoelectric biosensor is more sensitive than the sensor with an interdigital microelectrode. Thus, the piezoelectric biosensor acts as an effective analysis tool for acquiring online cell or microbial culture information. PMID- 27999345 TI - Combined Use of S. pombe and L. thermotolerans in Winemaking. Beneficial Effects Determined Through the Study of Wines' Analytical Characteristics. AB - The most common way to produce red wine is through the use of Saccharomyces cerevisiae strains for alcoholic fermentation and lactic acid bacteria for malolactic fermentation. This traditional winemaking methodology produces microbiologically stable red wines. However, under specific conditions off flavours can occur, wine quality can suffer and human health problems are possible, especially after the second fermentation by the lactic acid bacteria. In warm countries, problems during the malolactic fermentation arise because of the high pH of the must, which makes it very difficult to properly control the process. Under such conditions, wines with high acetic acid and histamine concentrations are commonly produced. This study investigates a recent red wine making technology that uses a combination of Lachancea thermotolerans and Schizosaccharomyces pombe as an alternative to the conventional malolactic fermentation. This work studies new parameters such as aroma compounds, amino acids, ethanol index and sensory evaluation. Schizosaccharomyces pombe totally consumes malic acid while Lachancea thermotolerans produces lactic acid, avoiding excessive deacidification of musts with low acidity in warm viticulture areas. This methodology also reduces the malolactic fermentation hazards in wines with low acidity. The main products are wines that contain less acetic acid, less biogenic amines and precursors and less ethyl carbamate precursors than the traditional wines produced via conventional fermentation techniques. PMID- 27999344 TI - EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer. AB - BACKGROUND: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. METHODS: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients' outcome were assessed. RESULTS: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743-43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078-0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240-41.012], p = 0.028), but not MVA. CONCLUSIONS: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM. PMID- 27999346 TI - Annealing Effects of Parylene-Caulked Polydimethylsiloxane as a Substrate of Electrodes. AB - This paper investigates the effects of annealing of the electrodes based on parylene-caulked polydimethylsiloxane (pc-PDMS) in terms of mechanical strength and long-term electrical property. Previously, the electrodes based on pc-PDMS showed a better ability to withstand in vivo environments because of the low water absorption and beneficial mechanical properties of the substrate, compared to native PDMS. Moreover, annealing is expected to even strengthen the mechanical strength and lower the water absorption of the pc-PDMS substrate. To characterize the mechanical strength and water absorption of the annealed pc-PDMS, tensile tests were carried out and infrared (IR) spectra were measured using Fourier transform infrared spectroscopy over a month. The results showed that annealed pc PDMS had higher mechanical strength and lower water absorption than non-annealed pc-PDMS. Then, electrochemical impedance spectroscopy was measured to evaluate the electrical stability of the electrodes based on annealed pc-PDMS in phosphate buffered saline solution at 36.5 degrees C. The impedance magnitude of the electrodes on annealed pc-PDMS was twice higher than that of the electrodes on non-annealed pc-PDMS in the initial days, but the impedance magnitude of the electrodes based on two different substrates converged to a similar value after eight months, indicating that the annealing effects disappear after a certain period of time in a physiological environment. PMID- 27999347 TI - A Novel Probabilistic Data Association for Target Tracking in a Cluttered Environment. AB - The problem of data association for target tracking in a cluttered environment is discussed. In order to improve the real-time processing and accuracy of target tracking, based on a probabilistic data association algorithm, a novel data association algorithm using distance weighting was proposed, which can enhance the association probability of measurement originated from target, and then using a Kalman filter to estimate the target state more accurately. Thus, the tracking performance of the proposed algorithm when tracking non-maneuvering targets in a densely cluttered environment has improved, and also does better when two targets are parallel to each other, or at a small-angle crossing in a densely cluttered environment. As for maneuvering target issues, usually with an interactive multi model framework, combined with the improved probabilistic data association method, we propose an improved algorithm using a combined interactive multiple model probabilistic data association algorithm to track a maneuvering target in a densely cluttered environment. Through Monte Carlo simulation, the results show that the proposed algorithm can be more effective and reliable for different scenarios of target tracking in a densely cluttered environment. PMID- 27999348 TI - Chemical Basis of the Fungicidal Activity of Tobacco Extracts against Valsa mali. AB - Under pressure from social criticism and an unclear future, tobacco researchers have begun to seek alternative uses for the product. Here, we present our study on isolating tobacco compounds with fungicidal activity, which could be used as plant-derived pesticides. Using Valsa mali as the target fungus, agar plate tests were conducted to evaluate the fungicidal activity of various tobacco extracts, including tobacco leaves extracts prepared with different solvents, extracts of different tobacco cultivars, and samples from different tobacco organs. Fungal growth morphology was used as the criterion to evaluate the fungicidal activity of tobacco extracts. Correlation analyses between the fungicidal activities and the chemical components of tobacco extracts indicated the major chemical constituents with fungicidal activity. Then, the active compounds were isolated and their effects on the ultra-microstructures of V. mali was analyzed using scanning- and transmission-electron microscopy. The results suggested that tobacco extracts prepared with solvents of weaker polarity had higher fungicidal activity, and the inhibitory activity of tobacco extracts against V. mali was also cultivar dependent. Furthermore, the fungicidal effects of tobacco flower extracts were higher than those of the leaf extracts. Chemical analysis indicated that cembranoids were the main fungicidal substances, which act by destroying the endometrial structure of the fungus. Tobacco cembranoids at 80 MUg/mL could completely inhibit the growth of V.mali, with an EC50 value of 13.18 MUg/mL. Our study therefore suggests that tobacco leaves and inflorescences are excellent plant resources for the biological control of V. mali. PMID- 27999350 TI - Response to the Boucher et al. Comments on Fleury et al. Sun Exposure and Its Effects on Human Health: Mechanisms through Which Sun Exposure Could Reduce the Risk of Developing Obesity and Cardiometabolic Dysfunction. Int. J. Environ. Res. Public Health 2016, 13, 999. AB - We thank Boucher et al. [1] for their interest in our recently published review [2]. [...]. PMID- 27999349 TI - Vision Marker-Based In Situ Examination of Bacterial Growth in Liquid Culture Media. AB - The detection of bacterial growth in liquid media is an essential process in determining antibiotic susceptibility or the level of bacterial presence for clinical or research purposes. We have developed a system, which enables simplified and automated detection using a camera and a striped pattern marker. The quantification of bacterial growth is possible as the bacterial growth in the culturing vessel blurs the marker image, which is placed on the back of the vessel, and the blurring results in a decrease in the high-frequency spectrum region of the marker image. The experiment results show that the FFT (fast Fourier transform)-based growth detection method is robust to the variations in the type of bacterial carrier and vessels ranging from the culture tubes to the microfluidic devices. Moreover, the automated incubator and image acquisition system are developed to be used as a comprehensive in situ detection system. We expect that this result can be applied in the automation of biological experiments, such as the Antibiotics Susceptibility Test or toxicity measurement. Furthermore, the simple framework of the proposed growth measurement method may be further utilized as an effective and convenient method for building point-of care devices for developing countries. PMID- 27999351 TI - Gravity Compensation Using EGM2008 for High-Precision Long-Term Inertial Navigation Systems. AB - The gravity disturbance vector is one of the major error sources in high precision and long-term inertial navigation applications. Specific to the inertial navigation systems (INSs) with high-order horizontal damping networks, analyses of the error propagation show that the gravity-induced errors exist almost exclusively in the horizontal channels and are mostly caused by deflections of the vertical (DOV). Low-frequency components of the DOV propagate into the latitude and longitude errors at a ratio of 1:1 and time-varying fluctuations in the DOV excite Schuler oscillation. This paper presents two gravity compensation methods using the Earth Gravitational Model 2008 (EGM2008), namely, interpolation from the off-line database and computing gravity vectors directly using the spherical harmonic model. Particular attention is given to the error contribution of the gravity update interval and computing time delay. It is recommended for the marine navigation that a gravity vector should be calculated within 1 s and updated every 100 s at most. To meet this demand, the time duration of calculating the current gravity vector using EGM2008 has been reduced to less than 1 s by optimizing the calculation procedure. A few off-line experiments were conducted using the data of a shipborne INS collected during an actual sea test. With the aid of EGM2008, most of the low-frequency components of the position errors caused by the gravity disturbance vector have been removed and the Schuler oscillation has been attenuated effectively. In the rugged terrain, the horizontal position error could be reduced at best 48.85% of its regional maximum. The experimental results match with the theoretical analysis and indicate that EGM2008 is suitable for gravity compensation of the high precision and long-term INSs. PMID- 27999352 TI - Development and Application of a Synthetically-Derived Lead Biosensor Construct for Use in Gram-Negative Bacteria. AB - The use of lead in manufacturing has decreased significantly over the last few decades. However, previous widespread use of lead-containing products and their incorrect disposal has resulted in environmental contamination. Accumulation of harmful quantities of lead pose a threat to all living organisms, through inhalation, ingestion, or direct contact, resulting in lead poisoning. This study utilized synthetic biology principles to develop plasmid-based whole-cell bacterial biosensors for detection of lead. The genetic element of the lead biosensor construct consists of pbrR, which encodes the regulatory protein, together with its divergent promoter region and a promoterless gfp. GFP expression is controlled by PbrR in response to the presence of lead. The lead biosensor genetic element was cloned onto a low-copy number broad host range plasmid, which can stably exist in a range of laboratory and environmental isolates, including Pseudomonas, Shewanella, and Enterobacter. The biosensors constructed were found to be sensitive, rapid, and specific and could, as such, serve as monitoring tools for lead-contaminated water. PMID- 27999354 TI - Local Coverage Optimization Strategy Based on Voronoi for Directional Sensor Networks. AB - In this paper, we study the area coverage of directional sensor networks (DSNs) with random node distribution. The coverage of DSNs depends on the sensor's locations, the sensing radiuses, and the working directions, as well as the angle of view (AoV), which is challenging to analyze. We transform the network area coverage problem into cell coverage problems by exploiting the Voronoi diagram, which only needs to optimize local coverage for each cell in a decentralized way. To address the cell coverage problem, we propose three local coverage optimization algorithms to improve the cell coverage, namely Move Inside Cell Algorithm (MIC), Rotate Working Direction Algorithm (RWD) and Rotation based on boundary (RB), respectively. Extensive simulations are performed to prove the effectiveness of our proposed algorithms in terms of the coverage ratio. PMID- 27999353 TI - Label-Free Aptasensors for the Detection of Mycotoxins. AB - Various methodologies have been reported in the literature for the qualitative and quantitative monitoring of mycotoxins in food and feed samples. Based on their enhanced specificity, selectivity and versatility, bio-affinity assays have inspired many researchers to develop sensors by exploring bio-recognition phenomena. However, a significant problem in the fabrication of these devices is that most of the biomolecules do not generate an easily measurable signal upon binding to the target analytes, and signal-generating labels are required to perform the measurements. In this context, aptamers have been emerged as a potential and attractive bio-recognition element to design label-free aptasensors for various target analytes. Contrary to other bioreceptor-based approaches, the aptamer-based assays rely on antigen binding-induced conformational changes or oligomerization states rather than binding-assisted changes in adsorbed mass or charge. This review will focus on current designs in label-free conformational switchable design strategies, with a particular focus on applications in the detection of mycotoxins. PMID- 27999355 TI - The Longitudinal Force Measurement of CWR Tracks with Hetero-Cladding FBG Sensors: A Proof of Concept. AB - A new method has been proposed to accurately determine longitudinal additional force in continuous welded rail (CWR) on bridges via hetero-cladding fiber Bragg grating (HC-FBG) sensors. The HC-FBG sensor consists of two FBGs written in the same type of fiber but with different cladding diameters. The HC-FBGs have the same temperature sensitivity but different strain sensitivity because of the different areas of the cross section. The differential strain coefficient is defined as the relative wavelength differences of two FBGs with the change of applied longitudinal force. In the verification experiment in the lab, the HC FBGs were attached on a section of rail model of which the material property is the same as that of rail on line. The temperature and differential strain sensitivity were calibrated using a universal testing machine. As shown by the test results, the linearity between the relative wavelength difference and the longitudinal additional force is greater than 0.9999. The differential strain sensitivity is 4.85 * 10-6/N. Moreover, the relative wavelength difference is not affected by the temperature change. Compared to the theoretical results, the accumulated error is controlled within 5.0%. PMID- 27999357 TI - Recent Methods for Purification and Structure Determination of Oligonucleotides. AB - Aptamers are single-stranded DNA or RNA oligonucleotides that can interact with target molecules through specific three-dimensional structures. The excellent features, such as high specificity and affinity for target proteins, small size, chemical stability, low immunogenicity, facile chemical synthesis, versatility in structural design and engineering, and accessible for site-specific modifications with functional moieties, make aptamers attractive molecules in the fields of clinical diagnostics and biopharmaceutical therapeutics. However, difficulties in purification and structural identification of aptamers remain a major impediment to their broad clinical application. In this mini-review, we present the recently attractive developments regarding the purification and identification of aptamers. We also discuss the advantages, limitations, and prospects for the major methods applied in purifying and identifying aptamers, which could facilitate the application of aptamers. PMID- 27999356 TI - Modulation of GLO1 Expression Affects Malignant Properties of Cells. AB - The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed. PMID- 27999358 TI - Review of Toxic Epidermal Necrolysis. AB - Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of TEN is incompletely understood. Historically, it has been regarded as a drug-induced immune reaction initiated by cytotoxic lymphocytes via a human leukocyte antigen (HLA)-restricted pathway. Several mediators have been identified as contributors to the cell death seen in TEN, including; granulysin, soluble Fas ligand, perforin/granzyme, tumour necrosis factor-alpha (TNF-alpha), and TNF-related apoptosis-inducing ligand. Currently, granulysin is accepted as the most important mediator of T cell proliferation. There is uncertainty around the accepted management of TEN. The lack of definitive management guidelines for TEN is explained in part by the rarity of the disease and its high mortality rate, which makes it difficult to conduct randomised control trials on emerging therapies. Developments have been made in pharmacogenomics, with numerous HLA alleles identified; however, these have largely been ethnically specific. These associations have translated into screening recommendations for Han Chinese. PMID- 27999359 TI - Diabetic Cardiomyopathy: Does the Type of Diabetes Matter? AB - In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic that parallels the increased prevalence of obesity and which markedly increases the risk of cardiovascular disease across the globe. While ischemic heart disease represents the major cause of death in diabetic subjects, diabetic cardiomyopathy (DC) summarizes adverse effects of diabetes mellitus on the heart that are independent of coronary artery disease (CAD) and hypertension. DC increases the risk of heart failure (HF) and may lead to both heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie DC that partially overlap with mechanisms believed to contribute to heart failure. Nevertheless, the existence of DC remains a topic of controversy, although the clinical relevance of DC is increasingly recognized by scientists and clinicians. In addition, relatively little attention has been attributed to the fact that both underlying mechanisms and clinical features of DC may be partially distinct in type 1 versus type 2 diabetes. In the following review, we will discuss clinical and preclinical literature on the existence of human DC in the context of the two different types of diabetes mellitus. PMID- 27999360 TI - Self-Reported Dietary Restrictions and Dietary Patterns in Polish Girls: A Short Research Report (GEBaHealth Study). AB - Dietary restraint is a commonly reported practice observed among young females. The practice remains controversial and can be interpreted as a beneficial self regulating behavior or the opposite, an eating disorder that may have a detrimental effect on health. The aim of this short report was to investigate if dietary restrictions are associated with dietary patterns in a representative sample of Polish girls. Analyses were carried out on data from the Girls' Eating Behavior and Health (GEBaHealth) study. The sample included 1107 girls, ranging in age from 13 to 21 years old. Restrictions regarding food quantities and selected food groups were assessed using a standardized interview. Dietary patterns were identified with Principal Component Analysis (PCA), based on dietary data collected with Food Frequency Questionnaires (FFQs). Logistic regression analysis was used to study the associations between self-reported restrictions and each dietary pattern. In the total sample, 30.5% of girls reported following some food restrictions. The most common restrictions regarded consumption of sugar and/or sweets (23.7%), high-fat foods (22.4%), and fats (21.3%). Girls who declared following any restrictions, restrictions in food quantity and restrictions in the consumption of sugar and/or sweets, high-fat foods, fats, cereals and/or bread and/or potatoes were more likely to adhere to the "fruit and vegetables" (considered pro-healthy) dietary pattern (adjusted odds ratios (ORs): 1.55, 95% CI: 1.14-2.12; 1.61, 95% CI: 1.17-2.21; 1.81, 95% CI: 1.30-2.52; 1.46, 95% CI: 1.04-2.06; 1.96, 95% CI: 1.38-2.80 and 3.25, 95% CI: 1.97-5.37, respectively), and less likely to adhere to the "fast foods and sweets" (unhealthy) and "traditional Polish" (rather unhealthy) patterns, compared to girls who declared no restrictions. Declared restrictions in the consumption of foods high in sugar, fat, and starch were observed in girls in the "fruit and vegetables" pattern and were uncommon in girls with unhealthy dietary patterns. Although cautious interpretation is needed when considering restrictions in the overall quantity of food consumed, the results indicate that dietary restrictions of sugar, high-fat foods, fats, and starch may be considered predictors of both pro-healthy and unhealthy dietary patterns in the population of Polish girls. PMID- 27999361 TI - A New Adaptive H-Infinity Filtering Algorithm for the GPS/INS Integrated Navigation. AB - The Kalman filter is an optimal estimator with numerous applications in technology, especially in systems with Gaussian distributed noise. Moreover, the adaptive Kalman filtering algorithms, based on the Kalman filter, can control the influence of dynamic model errors. In contrast to the adaptive Kalman filtering algorithms, the H-infinity filter is able to address the interference of the stochastic model by minimization of the worst-case estimation error. In this paper, a novel adaptive H-infinity filtering algorithm, which integrates the adaptive Kalman filter and the H-infinity filter in order to perform a comprehensive filtering algorithm, is presented. In the proposed algorithm, a robust estimation method is employed to control the influence of outliers. In order to verify the proposed algorithm, experiments with real data of the Global Positioning System (GPS) and Inertial Navigation System (INS) integrated navigation, were conducted. The experimental results have shown that the proposed algorithm has multiple advantages compared to the other filtering algorithms. PMID- 27999362 TI - Body-Machine Interfaces after Spinal Cord Injury: Rehabilitation and Brain Plasticity. AB - The purpose of this study was to identify rehabilitative effects and changes in white matter microstructure in people with high-level spinal cord injury following bilateral upper-extremity motor skill training. Five subjects with high level (C5-C6) spinal cord injury (SCI) performed five visuo-spatial motor training tasks over 12 sessions (2-3 sessions per week). Subjects controlled a two-dimensional cursor with bilateral simultaneous movements of the shoulders using a non-invasive inertial measurement unit-based body-machine interface. Subjects' upper-body ability was evaluated before the start, in the middle and a day after the completion of training. MR imaging data were acquired before the start and within two days of the completion of training. Subjects learned to use upper-body movements that survived the injury to control the body-machine interface and improved their performance with practice. Motor training increased Manual Muscle Test scores and the isometric force of subjects' shoulders and upper arms. Moreover, motor training increased fractional anisotropy (FA) values in the cingulum of the left hemisphere by 6.02% on average, indicating localized white matter microstructure changes induced by activity-dependent modulation of axon diameter, myelin thickness or axon number. This body-machine interface may serve as a platform to develop a new generation of assistive-rehabilitative devices that promote the use of, and that re-strengthen, the motor and sensory functions that survived the injury. PMID- 27999364 TI - Incorporation of Graphene-Related Carbon Nanosheets in Membrane Fabrication for Water Treatment: A Review. AB - The minimization of the trade-off between the flux and the selectivity of membranes is a key area that researchers are continually working to optimise, particularly in the area of fabrication of novel membranes. Flux versus selectivity issues apply in many industrial applications of membranes, for example the unwanted diffusion of methanol in fuel cells, retention of valuable proteins in downstream processing of biopharmaceuticals, rejection of organic matter and micro-organisms in water treatment, or salt permeation in desalination. The incorporation of nanosheets within membrane structures can potentially lead to enhancements in such properties as the antifouling ability, hydrophilicy and permeability of membranes, with concomitant improvements in the flux/selectivity balance. Graphene nanosheets and derivatives such as graphene oxide and reduced graphene oxide have been investigated for this purpose, for example inclusion of nanosheets within the active layer of Reverse Osmosis or Nanofiltration membranes or the blending of nanosheets as fillers within Ultrafiltration membranes. This review summarizes the incorporation of graphene derivatives into polymeric membranes for water treatment with a focus on a number of industrial applications, including desalination and pharmaceutical removal, where enhancement of productivity and reduction in fouling characteristics have been afforded by appropriate incorporation of graphene derived nanosheets during membrane fabrication. PMID- 27999363 TI - Neurotoxicity of a Biopesticide Analog on Zebrafish Larvae at Nanomolar Concentrations. AB - Despite the ever-increasing role of pesticides in modern agriculture, their deleterious effects are still underexplored. Here we examine the effect of A6, a pesticide derived from the naturally-occurring alpha-terthienyl, and structurally related to the endocrine disrupting pesticides anilinopyrimidines, on living zebrafish larvae. We show that both A6 and an anilinopyrimidine, cyprodinyl, decrease larval survival and affect central neurons at micromolar concentrations. Focusing on a superficial and easily observable sensory system, the lateral line system, we found that defects in axonal and sensory cell regeneration can be observed at much lower doses, in the nanomolar range. We also show that A6 accumulates preferentially in lateral line neurons and hair cells. We examined whether A6 affects the expression of putative target genes, and found that genes involved in apoptosis/cell proliferation are down-regulated, as well as genes reflecting estrogen receptor activation, consistent with previous reports that anilinopyrimidines act as endocrine disruptors. On the other hand, canonical targets of endocrine signaling are not affected, suggesting that the neurotoxic effect of A6 may be due to the binding of this compound to a recently identified, neuron-specific estrogen receptor. PMID- 27999366 TI - Preconditioning of Spatial and Auditory Cues: Roles of the Hippocampus, Frontal Cortex, and Cue-Directed Attention. AB - Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue was experienced. Here, we examined the roles of the rodent hippocampus and frontal cortex in cue-directed attention during encoding of memory for the location of a single incidentally experienced cue. During a spatial sensory preconditioning task, rats explored an elevated platform while an auditory cue was incidentally presented at one corner. The opposite corner acted as an unpaired control location. The rats demonstrated recollection of location by avoiding the paired corner after the auditory cue was in turn paired with shock. Damage to either the dorsal hippocampus or the frontal cortex impaired this memory ability. However, we also found that hippocampal lesions enhanced attention directed towards the cue during the encoding phase, while frontal cortical lesions reduced cue-directed attention. These results suggest that the deficit in spatial sensory preconditioning caused by frontal cortical damage may be mediated by inattention to the location of cues during the latent encoding phase, while deficits following hippocampal damage must be related to other mechanisms such as generation of neural plasticity. PMID- 27999365 TI - Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications. AB - Pancreatic cancer is one of the most aggressive human cancer types with a five year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most important mechanisms of epigenetic regulations include DNA methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (RNAs). These modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. However, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. This mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer. PMID- 27999367 TI - Phenotypic Stability of Energy Balance Responses to Experimental Total Sleep Deprivation and Sleep Restriction in Healthy Adults. AB - Experimental studies have shown that sleep restriction (SR) and total sleep deprivation (TSD) produce increased caloric intake, greater fat consumption, and increased late-night eating. However, whether individuals show similar energy intake responses to both SR and TSD remains unknown. A total of N = 66 healthy adults (aged 21-50 years, 48.5% women, 72.7% African American) participated in a within-subjects laboratory protocol to compare daily and late-night intake between one night of SR (4 h time in bed, 04:00-08:00) and one night of TSD (0 h time in bed) conditions. We also examined intake responses during subsequent recovery from SR or TSD and investigated gender differences. Caloric and macronutrient intake during the day following SR and TSD were moderately to substantially consistent within individuals (Intraclass Correlation Coefficients: 0.34-0.75). During the late-night period of SR (22:00-04:00) and TSD (22:00 06:00), such consistency was slight to moderate, and participants consumed a greater percentage of calories from protein (p = 0.01) and saturated fat (p = 0.02) during SR, despite comparable caloric intake (p = 0.12). Similarly, participants consumed a greater percentage of calories from saturated fat during the day following SR than TSD (p = 0.03). Participants also consumed a greater percentage of calories from protein during recovery after TSD (p < 0.001). Caloric intake was greater in men during late-night hours and the day following sleep loss. This is the first evidence of phenotypic trait-like stability and differential vulnerability of energy balance responses to two commonly experienced types of sleep loss: our findings open the door for biomarker discovery and countermeasure development to predict and mitigate this critical health-related vulnerability. PMID- 27999368 TI - Structure and Nanomechanics of Model Membranes by Atomic Force Microscopy and Spectroscopy: Insights into the Role of Cholesterol and Sphingolipids. AB - Biological membranes mediate several biological processes that are directly associated with their physical properties but sometimes difficult to evaluate. Supported lipid bilayers (SLBs) are model systems widely used to characterize the structure of biological membranes. Cholesterol (Chol) plays an essential role in the modulation of membrane physical properties. It directly influences the order and mechanical stability of the lipid bilayers, and it is known to laterally segregate in rafts in the outer leaflet of the membrane together with sphingolipids (SLs). Atomic force microscope (AFM) is a powerful tool as it is capable to sense and apply forces with high accuracy, with distance and force resolution at the nanoscale, and in a controlled environment. AFM-based force spectroscopy (AFM-FS) has become a crucial technique to study the nanomechanical stability of SLBs by controlling the liquid media and the temperature variations. In this contribution, we review recent AFM and AFM-FS studies on the effect of Chol on the morphology and mechanical properties of model SLBs, including complex bilayers containing SLs. We also introduce a promising combination of AFM and X ray (XR) techniques that allows for in situ characterization of dynamic processes, providing structural, morphological, and nanomechanical information. PMID- 27999369 TI - Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol Induced Liver Injury in Rats. AB - Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM) on the development of liver fibrosis in an in vivo ethanol carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4)-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4 treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1)-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme's activity and reduced intracellular thiobarbituric acid reactive substances (TBARS) levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury. PMID- 27999371 TI - Israeli Acute Paralysis Virus Infection Leads to an Enhanced RNA Interference Response and Not Its Suppression in the Bumblebee Bombus terrestris. AB - RNA interference (RNAi) is the primary antiviral defense system in insects and its importance for pollinator health is indisputable. In this work, we examined the effect of Israeli acute paralysis virus (IAPV) infection on the RNAi process in the bumblebee, Bombus terrestris, and whether the presence of possible functional viral suppressors could alter the potency of the host's immune response. For this, a two-fold approach was used. Through a functional RNAi assay, we observed an enhancement of the RNAi system after IAPV infection instead of its suppression, despite only minimal upregulation of the genes involved in RNAi. Besides, the presence of the proposed suppressor 1A and the predicted OrfX protein in IAPV could not be confirmed using high definition mass spectrometry. In parallel, when bumblebees were infected with cricket paralysis virus (CrPV), known to encode a suppressor of RNAi, no increase in RNAi efficiency was seen. For both viruses, pre-infection with the one virus lead to a decreased replication of the other virus, indicating a major effect of competition. These results are compelling in the context of Dicistroviridae in multi-virus/multi host networks as the effect of a viral infection on the RNAi machinery may influence subsequent virus infections. PMID- 27999370 TI - Effect of Lead (Pb) on Inflammatory Processes in the Brain. AB - That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, we present recent literature reports on the effect of Pb on the inflammatory processes in the brain, particularly the expression of selected cytokines in the brain (interleukin 6, TGF-beta1, interleukin 16, interleukin 18, and interleukin 10); expression and activity of enzymes participating in the inflammatory processes, such as cyclooxygenase 2, caspase 1, nitrogen oxide synthase (NOS 2) and proteases (carboxypeptidases, metalloproteinases and chymotrypsin); and the expression of purine receptors P2X4 and P2X7. A significant role in the development of inflammatory processes in the brain is also played by microglia (residual macrophages in the brain and the spinal cord), which act as the first line of defense in the central nervous system, and astrocytes-Whose most important function is to maintain homeostasis for the proper functioning of neurons. In this paper, we also present evidence that exposure to Pb may result in micro and astrogliosis by triggering TLR4-MyD88-NF-kappaB signaling cascade and the production of pro-inflammatory cytokines. PMID- 27999372 TI - Triptolide Combined with Radiotherapy for the Treatment of Nasopharyngeal Carcinoma via NF-kappaB-Related Mechanism. AB - Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis because of the lack of an effective treatment. Here we explored the efficiency and the molecular mechanisms of combined treatment with triptolide and ionizing radiation for treating NPC. Human nasopharyngeal carcinoma (CNE) cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation in vitro. Tumor potency was examined in an in vivo CNE cell xenograft mouse model, which was treated as above. Our results demonstrated that triptolide caused a significant reduction in cell growth and colony number, and induced a marked apoptosis that was further enhanced with increasing doses of ionizing radiation. Combination treatment synergistically reduced tumor weight and volume without obvious toxicity. Western blot analysis in vitro and in vivo showed that triptolide induced apoptotic protein Bax expression and inhibited phosph-NF kappaB p65, Bcl-2 and VEGF proteins without affecting other NF-kappaB related protein expression. In conclusion, our findings revealed that triptolide plus ionizing radiation had synergistic anti-tumor and anti-angiogenesis effects in NPC via down-regulating NF-kappaB p65 phosphorylation. The combination therapy may provide novel mechanism insights into inhibit NPC. PMID- 27999373 TI - Characterization of Fractional Polysaccharides from Gleditsia sinensis and Gleditsia microphylla Gums. AB - The seeds of Gleditsia sinensis and Gleditsia microphylla, widespread in China, are an important source of galactomannans. G. sinensis gum (GSG) and G. microphylla gum (GMG) were purified and precipitated using different concentrations of ethanol and isopropanol. The GSG and GMG, precipitated in different stages, presented different characteristics, including polymer recovery, mannose/galactose ratio, chemical composition, molecular weight, and morphological appearance. The galactomannan recovery of GSG and GMG in 33.3% ethanol was 81.7% and 82.5%, respectively, while that in 28.8% isopropanol was 81.3% and 82.9%, respectively. To achieve similar precipitation efficiency, the amount of isopropanol should be lower than that of ethanol because of the lower dielectric constant of isopropanol (20 vs. 25 for ethanol). The precipitation behavior of galactomannans in polar organic solvents was dependent on the molecular structures and properties of the solvent. A higher mannose/galactose ratio and a higher molecular weight was obtained in a lower concentration of alcohols. PMID- 27999374 TI - Targeting Cancer Stem Cells with Novel 4-(4-Substituted phenyl)-5-(3,4,5 trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thiones. AB - Novel 4-(4-substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4 dihydropyrimidine-2(1H)-one/thione derivatives (DHP1-9) were designed, synthesized, characterized and evaluated for antitumor activity against cancer stem cells. The compounds were synthesized in one pot. Enaminones E1 and E2 were reacted with substituted benzaldehydes and urea/thiourea in the presence of glacial acetic acid. The synthesized compounds were characterized by spectral analysis. The compounds were screened in vitro against colon cancer cell line (LOVO) colon cancer stem cells. Most of the compounds were found to be active against side population cancer stem cells with an inhibition of >50% at a 10 MUM concentration. Compounds DHP-1, DHP-7 and DHP-9 were found to be inactive. Compound DHP-5 exhibited an in vitro anti-proliferative effect and arrested cancer cells at the Gap 2 phase (G2) checkpoint and demonstrated an inhibitory effect on tumor growth for a LOVO xenograft in a nude mouse experiment. PMID- 27999375 TI - A Method of Detections' Fusion for GNSS Anti-Spoofing. AB - The spoofing attack is one of the security threats of systems depending on the Global Navigation Satellite System (GNSS). There have been many GNSS spoofing detection methods, and each of them focuses on a characteristic of the GNSS signal or a measurement that the receiver has obtained. The method based on a single detector is insufficient against spoofing attacks in some scenarios. How to fuse multiple detections together is a problem that concerns the performance of GNSS anti-spoofing. Scholars have put forward a model to fuse different detection results based on the Dempster-Shafer theory (DST) of evidence combination. However, there are some problems in the application. The main challenge is the valuation of the belief function, which is a key issue in DST. This paper proposes a practical method of detections' fusion based on an approach to assign the belief function for spoofing detections. The frame of discernment is simplified, and the hard decision of hypothesis testing is replaced by the soft decision; then, the belief functions for some detections can be evaluated. The method is discussed in detail, and a performance evaluation is provided, as well. Detections' fusion reduces false alarms of detection and makes the result more reliable. Experimental results based on public test datasets demonstrate the performance of the proposed method. PMID- 27999376 TI - A Novel Fisheye-Lens-Based Photoacoustic System. AB - This paper presents a novel fisheye-lens-based photoacoustic (PA) system. In conventional PA systems, mechanical motors are utilized to obtain the target information due to the small fields of view of such systems. The use of such motors introduces mechanical noise, which is difficult to remove when processing the echo signals. A fisheye lens system offering a wide field of view would effectively reduce the motor effects (i.e., the noise) and enable the system to have a wide field of view. Therefore, in this work, we propose a novel fisheye lens scheme and describe a PA system based on the developed lens scheme. In addition, to confirm the feasibility of the fisheye-lens-based PA system, we present the typical pulse-echo responses obtained using a 20 MHz single element immersion transducer and the echo signals measured from bull's eye tissue samples separated by approximately 4, 6, 8, and 10 cm diagonally and 2 cm vertically from the fisheye lens. The experimental results demonstrate that the echo signal amplitudes, their center frequencies, and the -6 dB bandwidths obtained using red, green, and blue lights and a fisheye lens are acceptable when the fisheye lens is separated from a sample both diagonally and vertically. Therefore, fisheye-lens-based PA systems could be a potential method of achieving wide fields of view while reducing the mechanical motor effects. PMID- 27999377 TI - A Novel Modification of PSO Algorithm for SML Estimation of DOA. AB - This paper addresses the issue of reducing the computational complexity of Stochastic Maximum Likelihood (SML) estimation of Direction-of-Arrival (DOA). The SML algorithm is well-known for its high accuracy of DOA estimation in sensor array signal processing. However, its computational complexity is very high because the estimation of SML criteria is a multi-dimensional non-linear optimization problem. As a result, it is hard to apply the SML algorithm to real systems. The Particle Swarm Optimization (PSO) algorithm is considered as a rather efficient method for multi-dimensional non-linear optimization problems in DOA estimation. However, the conventional PSO algorithm suffers two defects, namely, too many particles and too many iteration times. Therefore, the computational complexity of SML estimation using conventional PSO algorithm is still a little high. To overcome these two defects and to reduce computational complexity further, this paper proposes a novel modification of the conventional PSO algorithm for SML estimation and we call it Joint-PSO algorithm. The core idea of the modification lies in that it uses the solution of Estimation of Signal Parameters via Rotational Invariance Techniques (ESPRIT) and stochastic Cramer-Rao bound (CRB) to determine a novel initialization space. Since this initialization space is already close to the solution of SML, fewer particles and fewer iteration times are needed. As a result, the computational complexity can be greatly reduced. In simulation, we compare the proposed algorithm with the conventional PSO algorithm, the classic Altering Minimization (AM) algorithm and Genetic algorithm (GA). Simulation results show that our proposed algorithm is one of the most efficient solving algorithms and it shows great potential for the application of SML in real systems. PMID- 27999378 TI - Effect of 5-HT2A Receptor Polymorphisms, Work Stressors, and Social Support on Job Strain among Petroleum Workers in Xinjiang, China. AB - Previous studies have shown that work stressors and social support influence job strain. However, few studies have examined the impact of individual differences on job strain. In Xinjiang, there are a large number of petroleum workers in arid deserts. The present study investigated the effects of work stressors, social support, and 5-hydroxytryptamine receptor (5-HTR2A) genotype on the etiology of job strain among petroleum workers in Xinjiang. A cross-sectional study was carried out between January and August 2013. A total of 700 workers were selected by a three-stage stratified sampling method. 5-HTR2A genotypes were determined with the SNaPshot single nucleotide polymorphism assay. Work stressors and job strain were evaluated with the Occupational Stress Inventory-Revised questionnaire. Social support was assessed with the Chinese Social Support Rating Scale. Work overload and responsibility were significantly associated with job strain. Low social support was associated with severe vocational and interpersonal strain. High social support was a protective factor against job strain (odds ratio (OR) = 0.32, 95% confidence interval (CI): 0.14-0.76). The CC genotype of rs6313 and the AA genotype of rs2070040 were linked to severe vocational strain. Ordinal logistic regression analysis revealed that the CC genotype of rs6313 was linked to higher risk of job strain than the TT genotype (OR = 1.88, 95% CI: 1.10-3.23). These data provide evidence that work stressors, low social support, and 5-HTR2A gene polymorphism contributes to the risk of job strain. PMID- 27999379 TI - Alginate Oligosaccharide Prevents Acute Doxorubicin Cardiotoxicity by Suppressing Oxidative Stress and Endoplasmic Reticulum-Mediated Apoptosis. AB - Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4 hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis. PMID- 27999381 TI - Evaluation of Teaching Signals for Motor Control in the Cerebellum during Real World Robot Application. AB - Motor learning in the cerebellum is believed to entail plastic changes at synapses between parallel fibers and Purkinje cells, induced by the teaching signal conveyed in the climbing fiber (CF) input. Despite the abundant research on the cerebellum, the nature of this signal is still a matter of debate. Two types of movement error information have been proposed to be plausible teaching signals: sensory error (SE) and motor command error (ME); however, their plausibility has not been tested in the real world. Here, we conducted a comparison of different types of CF teaching signals in real-world engineering applications by using a realistic neuronal network model of the cerebellum. We employed a direct current motor (simple task) and a two-wheeled balancing robot (difficult task). We demonstrate that SE, ME or a linear combination of the two is sufficient to yield comparable performance in a simple task. When the task is more difficult, although SE slightly outperformed ME, these types of error information are all able to adequately control the robot. We categorize granular cells according to their inputs and the error signal revealing that different granule cells are preferably engaged for SE, ME or their combination. Thus, unlike previous theoretical and simulation studies that support either SE or ME, it is demonstrated for the first time in a real-world engineering application that both SE and ME are adequate as the CF teaching signal in a realistic computational cerebellar model, even when the control task is as difficult as stabilizing a two-wheeled balancing robot. PMID- 27999380 TI - Meta-Analysis of Milk Consumption and the Risk of Cognitive Disorders. AB - The association between milk intake and cognitive disorders has been investigated in several epidemiological studies, but the findings are still conflicting. No quantitative assessment has been performed to evaluate the potential relationship of milk intake and cognitive disorders. From the inception to October 2016, the PubMed and the Embase databases were searched for observational studies reporting the association of milk consumption and cognitive disorders (Alzheimer's disease, dementia, and cognitive decline/impairment). A generic inverse-variance random effects method was used to pool the Odds Ratios (ORs) and corresponding 95% confidence intervals (CIs) for the highest compared with the lowest level of milk intake. Subgroup and meta-regression analyses were used to assess the heterogeneity between subgroups. We identified seven articles involving a total of 10,941 participants. The highest level of milk consumption was significantly associated with a decreased risk of cognitive disorders, and the pooled OR (95% CI) was 0.72 (0.56, 0.93), with evidence of significant heterogeneity (I2 = 64%, p = 0.001). Subgroup analysis indicated that the association was more pronounced in ischemic stroke patients based on a single study. Furthermore, the inverse association between milk intake and cognitive disorders was limited to Asian subjects, and the African populations showed an intermediate non-significant trend. Although we have obtained a significant association, an established relationship cannot be drawn due to the study limitation. Large prospective studies are needed to quantify the potential dose-response patterns of milk intake and to explore the association in populations with different characteristics. PMID- 27999382 TI - Rapid Detection of Bacillus anthracis Spores Using Immunomagnetic Separation and Amperometry. AB - Portable detection and quantitation methods for Bacillus anthracis (anthrax) spores in pure culture or in environmental samples are lacking. Here, an amperometric immunoassay has been developed utilizing immunomagnetic separation to capture the spores and remove potential interferents from test samples followed by amperometric measurement on a field-portable instrument. Antibody conjugated magnetic beads and antibody-conjugated glucose oxidase were used in a sandwich format for the capture and detection of target spores. Glucose oxidase activity of spore pellets was measured indirectly via amperometry by applying a bias voltage after incubation with glucose, horseradish peroxidase, and the electron mediator 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid). Target capture was mediated by polyclonal antisera, whereas monoclonal antibodies were used for signal generation. This strategy maximized sensitivity (500 target spores, 5000 cfu/mL), while also providing a good specificity for Bacillus anthracis spores. Minimal signal deviation occurs in the presence of environmental interferents including soil and modified pH conditions, demonstrating the strengths of immunomagnetic separation. The simultaneous incubation of capture and detection antibodies and rapid substrate development (5 min) result in short sample-to-signal times (less than an hour). With attributes comparable or exceeding that of ELISA and LFDs, amperometry is a low-cost, low weight, and practical method for detecting anthrax spores in the field. PMID- 27999384 TI - BDS Precise Point Positioning for Seismic Displacements Monitoring: Benefit from the High-Rate Satellite Clock Corrections. AB - In order to satisfy the requirement of high-rate high-precision applications, 1 Hz BeiDou Navigation Satellite System (BDS) satellite clock corrections are generated based on precise orbit products, and the quality of the generated clock products is assessed by comparing with those from the other analysis centers. The comparisons show that the root mean square (RMS) of clock errors of geostationary Earth orbits (GEO) is about 0.63 ns, whereas those of inclined geosynchronous orbits (IGSO) and medium Earth orbits (MEO) are about 0.2-0.3 ns and 0.1 ns, respectively. Then, the 1 Hz clock products are used for BDS precise point positioning (PPP) to retrieve seismic displacements of the 2015 Mw 7.8 Gorkha, Nepal, earthquake. The derived seismic displacements from BDS PPP are consistent with those from the Global Positioning System (GPS) PPP, with RMS of 0.29, 0.38, and 1.08 cm in east, north, and vertical components, respectively. In addition, the BDS PPP solutions with different clock intervals of 1 s, 5 s, 30 s, and 300 s are processed and compared with each other. The results demonstrate that PPP with 300 s clock intervals is the worst and that with 1 s clock interval is the best. For the scenario of 5 s clock intervals, the precision of PPP solutions is almost the same to 1 s results. Considering the time consumption of clock estimates, we suggest that 5 s clock interval is competent for high-rate BDS solutions. PMID- 27999383 TI - The Use of Enteral Nutrition in the Management of Stroke. AB - This article discusses the use of enteral nutrition in the management of stroke. Stroke is a major source of disability, including dysphagia. The clinical manifestation of swallowing difficulties in stroke patients may lead to malnutrition which has implications for health status and clinical outcomes including morbidity, mortality and cost to the health service. The prevalence of malnutrition following an acute stroke could range from 8% to 34%. Therefore, the need to develop and implement the use of enteral nutrition support in stroke patients becomes pertinent. A range of enteral feeding tubes and feeding methods may be used to support stroke patients who are unable to meet their nutritional requirements through oral intake alone, although each of these approaches has its merits and limitations. Based on this review, there is evidence that enteral nutrition support is a useful method of providing nutrition for patients with dysphagia following a stroke in order to enhance their nutritional status and promote their health. However, there are challenges in the use of enteral tube feeding in these patients. PMID- 27999385 TI - An Interference-Aware Traffic-Priority-Based Link Scheduling Algorithm for Interference Mitigation in Multiple Wireless Body Area Networks. AB - Currently, wireless body area networks (WBANs) are effectively used for health monitoring services. However, in cases where WBANs are densely deployed, interference among WBANs can cause serious degradation of network performance and reliability. Inter-WBAN interference can be reduced by scheduling the communication links of interfering WBANs. In this paper, we propose an interference-aware traffic-priority-based link scheduling (ITLS) algorithm to overcome inter-WBAN interference in densely deployed WBANs. First, we model a network with multiple WBANs as an interference graph where node-level interference and traffic priority are taken into account. Second, we formulate link scheduling for multiple WBANs as an optimization model where the objective is to maximize the throughput of the entire network while ensuring the traffic priority of sensor nodes. Finally, we propose the ITLS algorithm for multiple WBANs on the basis of the optimization model. High spatial reuse is also achieved in the proposed ITLS algorithm. The proposed ITLS achieves high spatial reuse while considering traffic priority, packet length, and the number of interfered sensor nodes. Our simulation results show that the proposed ITLS significantly increases spatial reuse and network throughput with lower delay by mitigating inter-WBAN interference. PMID- 27999386 TI - Reduced Diversity in the Bacteriome of the Phytophagous Mite Brevipalpus yothersi (Acari: Tenuipalpidae). AB - Tenuipalpidae comprises mites that transmit viruses to agriculturally important plants. Several tenuipalpid species present parthenogenesis, and in Brevipalpus yothersi, the endosymbiont Cardinium has been associated with female-only colonies. It is unclear what the bacterial composition of B. yothersi is, and how common Cardinium is in those microbiomes. We performed a comparative analysis of the bacteriomes in three populations of B. yothersi and three additional Tetranychoidea species using sequences from V4-fragment of 16S DNA. The bacteriomes were dominated by Bacteroidetes (especially Cardinium) and Proteobacteria, showing a remarkably low alpha diversity. Cardinium was present in about 22% of all sequences; however, it was not present in R. indica and T. evansi. In B. yothersi, the proportion of Cardinium was higher in adults than eggs, suggesting that proliferation of the bacteria could be the result of selective pressures from the host. This hypothesis was further supported because colonies of B. yothersi from different populations showed different bacterial assemblages, and bacteriomes from different mite species showed similar abundances of Cardinium. A phylogenetic analysis of Cardinium revealed that not only specialization but horizontal transmission has been important for this symbiosis. Together, these results represent a glimpse into the evolution of the Tetranychoidea and Cardinium. PMID- 27999387 TI - Genetic Pathways to Insomnia. AB - This review summarizes current research on the genetics of insomnia, as genetic contributions are thought to be important for insomnia etiology. We begin by providing an overview of genetic methods (both quantitative and measured gene), followed by a discussion of the insomnia genetics literature with regard to each of the following common methodologies: twin and family studies, candidate gene studies, and genome-wide association studies (GWAS). Next, we summarize the most recent gene identification efforts (primarily GWAS results) and propose several potential mechanisms through which identified genes may contribute to the disorder. Finally, we discuss new genetic approaches and how these may prove useful for insomnia, proposing an agenda for future insomnia genetics research. PMID- 27999388 TI - Cytoglobosins H and I, New Antiproliferative Cytochalasans from Deep-Sea-Derived Fungus Chaetomium globosum. AB - Cytoglobosins H (1) and I (2), together with seven known cytochalasan alkaloids (3-9), were isolated from the deep-sea-derived fungus Chaetomium globosum. The structures of new compounds 1 and 2 were elucidated by extensive 1D and 2D NMR and mass spectroscopic data. All the compounds were evaluated for their antiproliferative activities against MDA-MB-231 human breast cancer cells, LNCaP human prostate cancer cells, and B16F10 mouse melanoma cells. Compound 6 showed significant antiproliferative activity against LNCaP and B16F10 cell lines with IC50 values of 0.62 and 2.78 MUM, respectively. Further testing confirmed that compound 6 inhibited the growth of LNCaP cells by inducing apoptosis. PMID- 27999389 TI - Transcriptome Analysis to Understand the Toxicity of Latrodectus tredecimguttatus Eggs. AB - Latrodectus tredecimguttatus is a kind of highly venomous black widow spider, with toxicity coming from not only venomous glands but also other parts of its body as well as newborn spiderlings and eggs. Up to date, although L. tredecimguttatus eggs have been demonstrated to be rich in proteinaceous toxins, there is no systematic investigation on such active components at transcriptome level. In this study, we performed a high-throughput transcriptome sequencing of L. tredecimguttatus eggs with Illumina sequencing technology. As a result, 53,284 protein-coding unigenes were identified, of which 14,185 unigenes produced significant hits in the available databases, including 280 unigenes encoding proteins or peptides homologous to known proteinaceous toxins. GO term and KEGG pathway enrichment analyses of the 280 unigenes showed that 375 GO terms and 18 KEGG pathways were significantly enriched. Functional analysis indicated that these unigene-coded toxins have the bioactivities to degrade tissue proteins, inhibit ion channels, block neuromuscular transmission, provoke anaphylaxis, induce apoptosis and hyperalgesia, etc. No known typical proteinaceous toxins in L. tredecimguttatus venomous glands, such as latrotoxins, were identified, suggesting that the eggs have a different toxicity mechanism from that of the venom. Our present transcriptome analysis not only helps to reveal the gene expression profile and toxicity mechanism of the L. tredecimguttatus eggs, but also provides references for the further related researches. PMID- 27999390 TI - Comparative Study on Trace Element Excretions between Nonanuric and Anuric Patients Undergoing Continuous Ambulatory Peritoneal Dialysis. AB - Few studies have been reported on alterations of trace elements (TE) in peritoneal dialysis patients. Our objective was to investigate and assess the characteristics of daily TE excretions in continuous ambulatory peritoneal dialysis (CAPD) patients. This cross-sectional study included 61 CAPD patients (nonanuric/anuric: 45/16) and 11 healthy subjects in Wuhan, China between 2013 and 2014. The dialysate and urine of patients and urine of healthy subjects were collected. The concentrations of copper (Cu), zinc (Zn), selenium (Se), molybdenum (Mo), and arsenic (As) in dialysate and urine were determined using inductively coupled plasma mass spectrometer (ICP-MS). Various clinical variables were obtained from automatic biochemical analyzer. Daily Cu, Zn, Se, and Mo excretions in nonanuric patients were higher than healthy subjects, while arsenic excretion in anuric patients was lower. A strong and positive correlation was observed between Se and Mo excretion in both dialysate (beta = 0.869, p < 0.010) and urine (beta = 0.968, p < 0.010). Furthermore, the clinical variables associated with Se excretion were found to be correlated with Mo excretion. Our findings indicated that nonanuric CAPD patients may suffer from deficiency of some essential TEs, while anuric patients are at risk of arsenic accumulation. A close association between Se and Mo excretion was also found. PMID- 27999391 TI - Adenovirus with DNA Packaging Gene Mutations Increased Virus Release. AB - Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously (Wechman, S. L. et al. Development of an Oncolytic Adenovirus with Enhanced Spread Ability through Repeated UV Irradiation and Cancer Selection. Viruses2016, 8, 6). In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis. PMID- 27999392 TI - Smart Pipe System for a Shipyard 4.0. AB - As a result of the progressive implantation of the Industry 4.0 paradigm, many industries are experimenting a revolution that shipyards cannot ignore. Therefore, the application of the principles of Industry 4.0 to shipyards are leading to the creation of Shipyards 4.0. Due to this, Navantia, one of the 10 largest shipbuilders in the world, is updating its whole inner workings to keep up with the near-future challenges that a Shipyard 4.0 will have to face. Such challenges can be divided into three groups: the vertical integration of production systems, the horizontal integration of a new generation of value creation networks, and the re-engineering of the entire production chain, making changes that affect the entire life cycle of each piece of a ship. Pipes, which exist in a huge number and varied typology on a ship, are one of the key pieces, and its monitoring constitutes a prospective cyber-physical system. Their improved identification, traceability, and indoor location, from production and through their life, can enhance shipyard productivity and safety. In order to perform such tasks, this article first conducts a thorough analysis of the shipyard environment. From this analysis, the essential hardware and software technical requirements are determined. Next, the concept of smart pipe is presented and defined as an object able to transmit signals periodically that allows for providing enhanced services in a shipyard. In order to build a smart pipe system, different technologies are selected and evaluated, concluding that passive and active RFID (Radio Frequency Identification) are currently the most appropriate technologies to create it. Furthermore, some promising indoor positioning results obtained in a pipe workshop are presented, showing that multi antenna algorithms and Kalman filtering can help to stabilize Received Signal Strength (RSS) and improve the overall accuracy of the system. PMID- 27999394 TI - Nanofiber Ion-Exchange Membranes for the Rapid Uptake and Recovery of Heavy Metals from Water. AB - An evaluation of the performance of polyelectrolyte-modified nanofiber membranes was undertaken to determine their efficacy in the rapid uptake and recovery of heavy metals from impaired waters. The membranes were prepared by grafting poly(acrylic acid) (PAA) and poly(itaconic acid) (PIA) to cellulose nanofiber mats. Performance measurements quantified the dynamic ion-exchange capacity for cadmium (Cd), productivity, and recovery of Cd(II) from the membranes by regeneration. The dynamic binding capacities of Cd(II) on both types of nanofiber membrane were independent of the linear flow velocity, with a residence time of as low as 2 s. Analysis of breakthrough curves indicated that the mass flow rate increased rapidly at constant applied pressure after membranes approached equilibrium load capacity for Cd(II), apparently due to a collapse of the polymer chains on the membrane surface, leading to an increased porosity. This mechanism is supported by hydrodynamic radius (Rh) measurements for PAA and PIA obtained from dynamic light scattering, which show that Rh values decrease upon Cd(II) binding. Volumetric productivity was high for the nanofiber membranes, and reached 0.55 mg Cd/g/min. The use of ethylenediaminetetraacetic acid as regeneration reagent was effective in fully recovering Cd(II) from the membranes. Ion-exchange capacities were constant over five cycles of binding-regeneration. PMID- 27999396 TI - Omni-Directional Scanning Localization Method of a Mobile Robot Based on Ultrasonic Sensors. AB - Improved ranging accuracy is obtained by the development of a novel ultrasonic sensor ranging algorithm, unlike the conventional ranging algorithm, which considers the divergence angle and the incidence angle of the ultrasonic sensor synchronously. An ultrasonic sensor scanning method is developed based on this algorithm for the recognition of an inclined plate and to obtain the localization of the ultrasonic sensor relative to the inclined plate reference frame. The ultrasonic sensor scanning method is then leveraged for the omni-directional localization of a mobile robot, where the ultrasonic sensors are installed on a mobile robot and follow the spin of the robot, the inclined plate is recognized and the position and posture of the robot are acquired with respect to the coordinate system of the inclined plate, realizing the localization of the robot. Finally, the localization method is implemented into an omni-directional scanning localization experiment with the independently researched and developed mobile robot. Localization accuracies of up to +/-3.33 mm for the front, up to +/-6.21 for the lateral and up to +/-0.20 degrees for the posture are obtained, verifying the correctness and effectiveness of the proposed localization method. PMID- 27999393 TI - Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways. AB - To successfully replicate, viruses protect their genomic material from degradation by the host cell. RNA viruses must contend with numerous destabilizing host cell processes including mRNA decay pathways and viral RNA (vRNA) degradation resulting from the antiviral response. Members of the Picornaviridae family of small RNA viruses have evolved numerous diverse strategies to evade RNA decay, including incorporation of stabilizing elements into vRNA and re-purposing host stability factors. Viral proteins are deployed to disrupt and inhibit components of the decay machinery and to redirect decay machinery to the advantage of the virus. This review summarizes documented interactions of picornaviruses with cellular RNA decay pathways and processes. PMID- 27999395 TI - Stem-Loop RT-qPCR as an Efficient Tool for the Detection and Quantification of Small RNAs in Giardia lamblia. AB - Stem-loop quantitative reverse transcription PCR (RT-qPCR) is a molecular technique used for identification and quantification of individual small RNAs in cells. In this work, we used a Universal ProbeLibrary (UPL)-based design to detect-in a rapid, sensitive, specific, and reproducible way-the small nucleolar RNA (snoRNA) GlsR17 and its derived miRNA (miR2) of Giardia lamblia using a stem loop RT-qPCR approach. Both small RNAs could be isolated from both total RNA and small RNA samples. Identification of the two small RNAs was carried out by sequencing the PCR-amplified small RNA products upon ligation into the pJET1.2/blunt vector. GlsR17 is constitutively expressed during the 72 h cultures of trophozoites, while the mature miR2 is present in 2-fold higher abundance during the first 48 h than at 72 h. Because it has been suggested that miRNAs in G. lamblia have an important role in the regulation of gene expression, the use of the stem-loop RT-qPCR method could be valuable for the study of miRNAs of G. lamblia. This methodology will be a powerful tool for studying gene regulation in G. lamblia, and will help to better understand the features and functions of these regulatory molecules and how they work within the RNA interference (RNAi) pathway in G. lamblia. PMID- 27999397 TI - A Sum-of-Squares and Semidefinite Programming Approach for Maximum Likelihood DOA Estimation. AB - Direction of arrival (DOA) estimation using a uniform linear array (ULA) is a classical problem in array signal processing. In this paper, we focus on DOA estimation based on the maximum likelihood (ML) criterion, transform the estimation problem into a novel formulation, named as sum-of-squares (SOS), and then solve it using semidefinite programming (SDP). We first derive the SOS and SDP method for DOA estimation in the scenario of a single source and then extend it under the framework of alternating projection for multiple DOA estimation. The simulations demonstrate that the SOS- and SDP-based algorithms can provide stable and accurate DOA estimation when the number of snapshots is small and the signal to-noise ratio (SNR) is low. Moveover, it has a higher spatial resolution compared to existing methods based on the ML criterion. PMID- 27999398 TI - Sci-Fin: Visual Mining Spatial and Temporal Behavior Features from Social Media. AB - Check-in records are usually available in social services, which offer us the opportunity to capture and analyze users' spatial and temporal behaviors. Mining such behavior features is essential to social analysis and business intelligence. However, the complexity and incompleteness of check-in records bring challenges to achieve such a task. Different from the previous work on social behavior analysis, in this paper, we present a visual analytics system, Social Check-in Fingerprinting (Sci-Fin), to facilitate the analysis and visualization of social check-in data. We focus on three major components of user check-in data: location, activity, and profile. Visual fingerprints for location, activity, and profile are designed to intuitively represent the high-dimensional attributes. To visually mine and demonstrate the behavior features, we integrate WorldMapper and Voronoi Treemap into our glyph-like designs. Such visual fingerprint designs offer us the opportunity to summarize the interesting features and patterns from different check-in locations, activities and users (groups). We demonstrate the effectiveness and usability of our system by conducting extensive case studies on real check-in data collected from a popular microblogging service. Interesting findings are reported and discussed at last. PMID- 27999399 TI - Configurations of Splitter/Combiner Microstrip Sections Loaded with Stepped Impedance Resonators (SIRs) for Sensing Applications. AB - In this paper, several configurations of splitter/combiner microstrip sections loaded with stepped impedance resonators (SIRs) are analyzed. Such structures are useful as sensors and comparators, and the main aim of the paper is to show that the proposed configurations are useful for the optimization of sensitivity and discrimination. Specifically, for comparison purposes, i.e., to determine anomalies, abnormalities or defects of a sample under test (SUT) in comparison to a reference sample, it is shown that up to three samples can be simultaneously tested. Simple models of the proposed structures are presented, and these models are validated through electromagnetic simulation and experiment. Finally, the principle of operation is validated through a proof-of-concept demonstrator. PMID- 27999400 TI - Comparative Study on the Characteristics of Weissella cibaria CMU and Probiotic Strains for Oral Care. AB - Probiotics have been demonstrated as a new paradigm to substitute antibiotic treatment for dental caries, gingivitis, and chronic periodontitis. The present work was conducted to compare the characteristics of oral care probiotics: Weissella cibaria CMU (Chonnam Medical University) and four commercial probiotic strains. Survival rates under poor oral conditions, acid production, hydrogen peroxide production, as well as inhibition of biofilm formation, coaggregation, antibacterial activity, and inhibition of volatile sulfur compounds were evaluated. The viability of W. cibaria CMU was not affected by treatment of 100 mg/L lysozyme for 90 min and 1 mM hydrogen peroxide for 6 h. Interestingly, W. cibaria produced less acid and more hydrogen peroxide than the other four probiotics. W. cibaria inhibited biofilm formation by Streptococcus mutans at lower concentrations (S. mutans/CMU = 8) and efficiently coaggregated with Fusobacterium nucleatum. W. cibaria CMU and two commercial probiotics, including Lactobacillus salivarius and Lactobacillus reuteri, showed high antibacterial activities (>97%) against cariogens (S. mutans and Streptococcus sobrinus), and against periodontopathogens (F. nucleatum and Porphyromonas gingivalis). All of the lactic acid bacterial strains in this study significantly reduced levels of hydrogen sulfide and methyl mercaptan produced by F. nucleatum and P. gingivalis (p < 0.05). These results suggest that W. cibaria CMU is applicable as an oral care probiotic. PMID- 27999402 TI - A Review of the Botany, Phytochemistry, Pharmacology and Toxicology of Rubiae Radix et Rhizoma. AB - Rubia cordifolia Linn (Rubiaceae) is a climbing perennial herbal plant, which is widely distributed in China and India. Its root and rhizome, Rubiae Radix et Rhizoma (called Qiancao in China and Indian madder in India), is a well known phytomedicine used for hematemesis, epistaxis, flooding, spotting, traumatic bleeding, amenorrhea caused by obstruction, joint impediment pain, swelling and pain caused by injuries from falls. In addition, it is a kind of pigment utilized as a food additive and a dye for wool or fiber. This review mainly concentrates on studies of the botany, phytochemistry, pharmacology and toxicology of this Traditional Chinese Medicine. The phytochemical evidences indicated that over a hundred chemical components have been found and isolated from the medicine, such as anthraquinones, naphthoquinones, triterpenoids, cyclic hexapeptides and others. These components are considered responsible for the various bioactivities of the herbal drug, including anti-oxidation, anti-inflammation, immunomodulation, antitumor, effects on coagulation-fibrinolysis system, neuroprotection and other effects. Additionally, based on these existing results, we also propose some interesting future research directions. Consequently, this review should help us to more comprehensively understand and to more fully utilize the herbal medicine Rubiae Radix et Rhizoma. PMID- 27999401 TI - Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis. AB - Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39-0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk. PMID- 27999403 TI - Monitoring Building Deformation with InSAR: Experiments and Validation. AB - Synthetic Aperture Radar Interferometry (InSAR) techniques are increasingly applied for monitoring land subsidence. The advantages of InSAR include high accuracy and the ability to cover large areas; nevertheless, research validating the use of InSAR on building deformation is limited. In this paper, we test the monitoring capability of the InSAR in experiments using two landmark buildings; the Bohai Building and the China Theater, located in Tianjin, China. They were selected as real examples to compare InSAR and leveling approaches for building deformation. Ten TerraSAR-X images spanning half a year were used in Permanent Scatterer InSAR processing. These extracted InSAR results were processed considering the diversity in both direction and spatial distribution, and were compared with true leveling values in both Ordinary Least Squares (OLS) regression and measurement of error analyses. The detailed experimental results for the Bohai Building and the China Theater showed a high correlation between InSAR results and the leveling values. At the same time, the two Root Mean Square Error (RMSE) indexes had values of approximately 1 mm. These analyses show that a millimeter level of accuracy can be achieved by means of InSAR technique when measuring building deformation. We discuss the differences in accuracy between OLS regression and measurement of error analyses, and compare the accuracy index of leveling in order to propose InSAR accuracy levels appropriate for monitoring buildings deformation. After assessing the advantages and limitations of InSAR techniques in monitoring buildings, further applications are evaluated. PMID- 27999404 TI - Nondestructive In Situ Measurement Method for Kernel Moisture Content in Corn Ear. AB - Moisture content is an important factor in corn breeding and cultivation. A corn breed with low moisture at harvest is beneficial for mechanical operations, reduces drying and storage costs after harvesting and, thus, reduces energy consumption. Nondestructive measurement of kernel moisture in an intact corn ear allows us to select corn varieties with seeds that have high dehydration speeds in the mature period. We designed a sensor using a ring electrode pair for nondestructive measurement of the kernel moisture in a corn ear based on a high frequency detection circuit. Through experiments using the effective scope of the electrodes' electric field, we confirmed that the moisture in the corn cob has little effect on corn kernel moisture measurement. Before the sensor was applied in practice, we investigated temperature and conductivity effects on the output impedance. Results showed that the temperature was linearly related to the output impedance (both real and imaginary parts) of the measurement electrodes and the detection circuit's output voltage. However, the conductivity has a non-monotonic dependence on the output impedance (both real and imaginary parts) of the measurement electrodes and the output voltage of the high-frequency detection circuit. Therefore, we reduced the effect of conductivity on the measurement results through measurement frequency selection. Corn moisture measurement results showed a quadric regression between corn ear moisture and the imaginary part of the output impedance, and there is also a quadric regression between corn kernel moisture and the high-frequency detection circuit output voltage at 100 MHz. In this study, two corn breeds were measured using our sensor and gave R2 values for the quadric regression equation of 0.7853 and 0.8496. PMID- 27999406 TI - Natural Products in Anti-Obesity Therapy. AB - Obesity is regulated by genetic, endocrine, metabolic, neurological, pharmacological, environmental, and nutritional factors. [...]. PMID- 27999405 TI - Moringa oleifera Seeds and Oil: Characteristics and Uses for Human Health. AB - Moringa oleifera seeds are a promising resource for food and non-food applications, due to their content of monounsaturated fatty acids with a high monounsaturated/saturated fatty acids (MUFA/SFA) ratio, sterols and tocopherols, as well as proteins rich in sulfated amino acids. The rapid growth of Moringa trees in subtropical and tropical areas, even under conditions of prolonged drought, makes this plant a reliable resource to enhance the nutritional status of local populations and, if rationalized cultivation practices are exploited, their economy, given that a biodiesel fuel could be produced from a source not in competition with human food crops. Despite the relatively diffuse use of Moringa seeds and their oil in traditional medicine, no pharmacological activity study has been conducted on humans. Some encouraging evidence, however, justifies new efforts to obtain clear and definitive information on the benefits to human health arising from seed consumption. A critical review of literature data concerning the composition of Moringa oil has set in motion a plan for future investigations. Such investigations, using the seeds and oil, will focus on cultivation conditions to improve plant production, and will study the health effects on human consumers of Moringa seeds and their oil. PMID- 27999408 TI - Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol Associated Vascular and Neurodegenerative Diseases. AB - Cardiovascular diseases, like atherosclerosis, and neurodegenerative diseases affecting the central nervous system (CNS) are closely linked to alterations of cholesterol metabolism. Therefore, innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potential. However, these approaches need to take into account the existence of biological barriers such as intestinal and blood-brain barriers which participate in the organ homeostasis and are major defense systems against xenobiotics. Interest in cyclodextrins (CDs) as medicinal agents has increased continuously based on their ability to actively extract lipids from cell membranes and to provide suitable carrier system for drug delivery. Many novel CD derivatives are constantly generated with the objective to improve CD bioavailability, biocompatibility and therapeutic outcomes. Newly designed drug formulation complexes incorporating CDs as drug carriers have demonstrated better efficiency in treating cardiovascular and neurodegenerative diseases. CD-based therapies as cholesterol-sequestrating agent have recently demonstrated promising advances with KLEPTOSE(r) CRYSMEB in atherosclerosis as well as with the 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) in clinical trials for Niemann-Pick type C disease. Based on this success, many investigations evaluating the therapeutical beneficial of CDs in Alzheimer's, Parkinson's and Huntington's diseases are currently on-going. PMID- 27999407 TI - Tumour Heterogeneity: The Key Advantages of Single-Cell Analysis. AB - Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level. PMID- 27999409 TI - Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein. AB - We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA+-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA+ M2BP (>=2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB 4) index (>=3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA+-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA+-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA+-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA+-M2BP level is a useful predictor for HCC development after achieving SVR. PMID- 27999410 TI - Effects of Quercetin in a Rat Model of Hemorrhagic Traumatic Shock and Reperfusion. AB - BACKGROUND: We hypothesized that treatment with quercetin could result in improved hemodynamics, lung inflammatory parameters and mortality in a rat model of hemorrhagic shock. METHODS: Rats were anesthetized (80 mg/kg ketamine plus 8 mg/kg xylazine i.p.). The protocol included laparotomy for 15 min (trauma), hemorrhagic shock (blood withdrawal to reduce the mean arterial pressure to 35 mmHg) for 75 min and resuscitation by re-infusion of all the shed blood plus lactate Ringer for 90 min. Intravenous quercetin (50 mg/kg) or vehicle were administered during resuscitation. RESULTS: There was a trend for increased survival 84.6% (11/13) in the treated group vs. the shock group 68.4% (13/19, p > 0.05 Kaplan-Meier). Quercetin fully prevented the development of lung edema. The activity of aSMase was increased in the shock group compared to the sham group and the quercetin prevented this effect. However, other inflammatory markers such as myeloperoxidase activity, interleukin-6 in plasma or bronchoalveolar fluid were similar in the sham and shock groups. We found no bacterial DNA in plasma in these animals. CONCLUSIONS: Quercetin partially prevented the changes in blood pressure and lung injury in shock associated to hemorrhage and reperfusion. PMID- 27999411 TI - Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors. AB - Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors of surrounding cells, including engulfment, proliferation, and production of mechanical forces. Such interactions can be bidirectional, and apoptosis is non-autonomously induced in a cellular community. Of note, it is becoming evident that active communication between apoptotic cells and living cells contributes to physiological processes during tissue remodeling, regeneration, and morphogenesis. In this review, we focus on the mutual interactions between apoptotic cells and their neighbors in cellular society and discuss issues relevant to future studies of apoptosis. PMID- 27999414 TI - Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment. AB - Benefiting from the development of nanotechnology, drug delivery systems (DDSs) with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs), quantum dots (QDs) and carbon nanotubes (CNTs). The second section presents the main types of stimuli responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules) and extrinsic (temperature, light irradiation, magnetic field and ultrasound) ones. Clinical applications of DDS, future challenges and perspectives are also mentioned. PMID- 27999413 TI - Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women. AB - Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general and brain aging in particular. Functional hypothalamic amenorrhea, a phenotypically recognizable form of stress, is due to stress-induced suppression of endogenous gonadotropin-releasing hormone secretion. Reversal of functional hypothalamic amenorrhea includes restoration of ovulatory ovarian function and fertility and amelioration of hypercortisolism and hypothyroidism. Taken together, recovery from functional hypothalamic amenorrhea putatively offers neuroprotection and ameliorates stress-induced premature brain aging and possibly syndromic Alzheimer's disease. Amenorrhea may be viewed as a sentinel indicator of stress. Hypothalamic hypogonadism is less clinically evident in men and the diagnosis is difficult to establish. Whether there are other sex differences in the impact of stress on brain aging remains to be better investigated, but it is likely that both low estradiol from stress-induced anovulation and low testosterone from stress-induced hypogonadism compromise brain health. PMID- 27999412 TI - Antioxidants and Dementia Risk: Consideration through a Cerebrovascular Perspective. AB - A number of natural and chemical compounds that exert anti-oxidative properties are demonstrated to be beneficial for brain and cognitive function, and some are reported to reduce the risk of dementia. However, the detailed mechanisms by which those anti-oxidative compounds show positive effects on cognition and dementia are still unclear. An emerging body of evidence suggests that the integrity of the cerebrovascular blood-brain barrier (BBB) is centrally involved in the onset and progression of cognitive impairment and dementia. While recent studies revealed that some anti-oxidative agents appear to be protective against the disruption of BBB integrity and structure, few studies considered the neuroprotective effects of antioxidants in the context of cerebrovascular integrity. Therefore, in this review, we examine the mechanistic insights of antioxidants as a pleiotropic agent for cognitive impairment and dementia through a cerebrovascular axis by primarily focusing on the current available data from physiological studies. Conclusively, there is a compelling body of evidence that suggest antioxidants may prevent cognitive decline and dementia by protecting the integrity and function of BBB and, indeed, further studies are needed to directly examine these effects in addition to underlying molecular mechanisms. PMID- 27999415 TI - Feasibility of a Gelatin Temperature Sensor Based on Electrical Capacitance. AB - The innovative use of gelatin as a temperature sensor based on capacitance was studied at a temperature range normally used for meat cooking (20-80 degrees C). Interdigital electrodes coated by gelatin solution and two sensors of different thicknesses (38 and 125 um) were studied between 300 MHz and 900 MHz. At 38 um, the capacitance was adequately measured, but for 125 um the slope capacitance versus temperature curve decreased before 900 MHz due to the electrothermal breakdown between 60 degrees C and 80 degrees C. Thus, for 125 um, the capacitance was studied applying 600 MHz. Sensitivity at 38 um at 868 MHz (0.045 pF/ degrees C) was lower than 125 um at 600 MHz (0.14 pF/ degrees C), influencing the results in the simulation (temperature range versus time) of meat cooking; at 125 um, the sensitivity was greater, mainly during chilling steps. The potential of gelatin as a temperature sensor was demonstrated, and a balance between thickness and frequency should be considered to increase the sensitivity. PMID- 27999416 TI - Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice. AB - Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreERT2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in PtenLoxP/LoxP;BrafCA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4 hydroxytamoxifen-induced tumors in Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies. PMID- 27999418 TI - Impact of Time-Varying Treatment Exposures on the Risk of Venous Thromboembolism in Multiple Myeloma. AB - Multiple myeloma (MM) has one of the highest risks of venous thromboembolism (VTE) of all cancers due to pathologic changes and treatment-related exposures. This study assessed the one-year incidence of VTE in newly diagnosed MM and to determine the baseline and time-varying treatment-related factors associated with VTE risk in a U.S.-based cohort. MM patients were identified and age, gender, and baseline comorbidities were determined. Treatment-related exposures included thalidomide derivatives (IMIDs), proteasome inhibitors, cytotoxic chemotherapy, steroids, erythropoietin-stimulating agents (ESAs), stem cell transplants (SCT), hospitalizations, infection, and central venous catheters (CVC). Multiple statistical models were used including a baseline competing risks model, a time varying exposure Cox proportional hazard (CPH) model, and a case-time-control analysis. The overall incidence of VTE was 107.2 per 1000 person-years with one half of the VTEs occurring in the first 90 days. The baseline model showed that increasing age, heart failure, and hypertension were associated with one-year incidence of VTE. MM-specific IMID treatment had lower than expected associations with VTE based on prior literature. Instead, exposure to ESAs, SCT, CVC, and infection had higher associations. Based on these results, VTE risk in MM may be less straightforward than considering only chemotherapy exposures, and other treatment-related exposures should be considered to determine patient risk. PMID- 27999419 TI - Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV). AB - Transspecies transmission of retroviruses is a frequent event, and the human immunodeficiency virus-1 (HIV-1) is a well-known example. The gibbon ape leukaemia virus (GaLV) and koala retrovirus (KoRV), two gammaretroviruses, are also the result of a transspecies transmission, however from a still unknown host. Related retroviruses have been found in Southeast Asian mice although the sequence similarity was limited. Viruses with a higher sequence homology were isolated from Melomys burtoni, the Australian and Indonesian grassland melomys. However, only the habitats of the koalas and the grassland melomys in Australia are overlapping, indicating that the melomys virus may not be the precursor of the GaLV. Viruses closely related to GaLV/KoRV were also detected in bats. Therefore, given the fact that the habitats of the gibbons in Thailand and the koalas in Australia are far away, and that bats are able to fly over long distances, the hypothesis that retroviruses of bats are the origin of GaLV and KoRV deserves consideration. Analysis of previous transspecies transmissions of retroviruses may help to evaluate the potential of transmission of related retroviruses in the future, e.g., that of porcine endogenous retroviruses (PERVs) during xenotransplantation using pig cells, tissues or organs. PMID- 27999420 TI - Spatiotemporal Frameworks for Infectious Disease Diffusion and Epidemiology. AB - Emerging infectious diseases, and the resurgence of previously controlled infectious disease (e.g., malaria, tuberculosis), are a major focus for public health concern, as well as providing challenges for establishing aetiology and transmission. [...]. PMID- 27999422 TI - Plasma Intermedin Level Indicates Severity and Treatment Efficacy of Septic Shock in Sprague-Dawley (SD) Rats. AB - BACKGROUND The aim of this study was to investigate the value of plasma intermedin (IMD) in assessing severity and treatment efficacy of septic shock. MATERIAL AND METHODS Healthy male Sprague-Dawley (SD) rats were chosen and divided into a normal control group (n=15) and a shock model group (n=27) that received intravenous injection of lipopolysaccharide (LPS). Then, 3 specimens were taken from each group. The shock model group rats were divided into an LPS group and a treatment group with 12 rats each. The treatment group received intravenous injection of compound sodium lactate solution. Plasma IMD and IMD1-47 mRNA expressions were compared and analyzed. RESULTS Mean arterial pressure (MAP) was lower while white blood cell count and TNF-alpha were higher in the shock model group than in the normal control group (P<0.05). After 10 h and 20 h, the treatment group had lower plasma IMD and IMD1-47 mRNA expressions compared with the LPS group (P<0.05). Plasma IMD and IMD1-47 mRNA expressions in the LPS group after 20 h were significantly higher than after 10 h (P<0.05). IMD was positively correlated with interleukins (IL-3, IL-6, and IL-8), white blood cell count, and body temperature (all P<0.05), but were negatively correlated with systolic pressure (r=-0.8474, P=0.0040). CONCLUSIONS Plasma IMD level can effectively reflect the severity of septic shock and can be used as an important indicator of septic shock treatment effectiveness. PMID- 27999421 TI - The Detoxification and Degradation of Benzothiazole from the Wastewater in Microbial Electrolysis Cells. AB - In this study, the high-production-volume chemical benzothiazole (BTH) from synthetic water was fully degraded into less toxic intermediates of simple organic acids using an up-flow internal circulation microbial electrolysis reactor (UICMER) under the hydraulic retention time (HRT) of 24 h. The bioelectrochemical system was operated at 25 +/- 2 degrees C and continuous-flow mode. The BTH loading rate varied during experiments from 20 g.m-3.day-1 to 110 g.m-3.day-1. BTH and soluble COD (Chemical Oxygen Demand) removal efficiency reached 80% to 90% under all BTH loading rates. Bioluminescence based Shewanella oneidensis strain MR-1 ecotoxicity testing demonstrated that toxicity was largely decreased compared to the BTH wastewater influent and effluent of two control experiments. The results indicated that MEC (Microbial Electrolysis Cell) was useful and reliable for improving BTH wastewater treatment efficiency, enabling the microbiological reactor to more easily respond to the requirements of higher loading rate, which is meaningful for economic and efficient operation in future scale-up. PMID- 27999417 TI - Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis. AB - Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1beta (IL-1beta), Tumor Necrosis factor-alpha (TNF-alpha), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF 1alpha/HIF-2alpha imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression. PMID- 27999423 TI - Characterization of community-associated Staphylococcus aureus from skin and soft tissue infections: a multicenter study in China. AB - We evaluated the epidemiological and molecular features of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and methicillin-sensitive S. aureus (MSSA) from children and adult patients with skin and soft-tissue infections (SSTIs) in China. Prospective community-acquired S. aureus SSTI surveillance was conducted in 23 hospitals over a 24-month period. Susceptibility to 16 antimicrobials was evaluated using the agar dilution method. StatApriori was used to determine statistically significant association trends. The genotypic characteristics of CA-MRSA isolates were tested by staphylococcal cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) typing, and multilocus sequence typing. The presence of Panton-Valentine leukocidin (pvl) genes was determined. Overall, 71.6% (1946/2716) of cases were community associated S. aureus. CA-MRSA accounted for 2.6% (51). Out of 1895 methicillin sensitive S. aureus strains, 97.3% were resistant to erythromycin, 96.6% to penicillin and 89.1% to clindamycin. No S. aureus strains were resistant to vancomycin. Thirteen sequence types (STs) and 17 spa types were detected among the CA-MRSA strains. The most prevalent sequence type was ST121 (19/51, 37.3%), followed by ST59 (13/51, 25.5%). In addition, t437 was predominant, accounting for 43.1% (22/51). Only five (9.8%) of the CA-MRSA strains harbored pvl genes. There were no significant differences in antibiotic sensitivity profiles between ST121 and non-ST121 MRSA isolates. However, ST121 strains tended to be more resistant to cefazolin, whereas non-ST121 strains were more resistant to chloramphenicol. In conclusion, CA-MRSA infections are rare among Chinese SSTI patients. MRSA strains in China have diverse genetic backgrounds, with ST121 being the predominant clone. Fusidic acid and mupirocin remain effective for topical treatment. PMID- 27999424 TI - Polyphyletic origin of MERS coronaviruses and isolation of a novel clade A strain from dromedary camels in the United Arab Emirates. AB - Little is known regarding the molecular epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) circulating in dromedaries outside Saudi Arabia. To address this knowledge gap, we sequenced 10 complete genomes of MERS-CoVs isolated from 2 live and 8 dead dromedaries from different regions in the United Arab Emirates (UAE). Phylogenetic analysis revealed one novel clade A strain, the first detected in the UAE, and nine clade B strains. Strain D998/15 had a distinct phylogenetic position within clade A, being more closely related to the dromedary isolate NRCE-HKU205 from Egypt than to the human isolates EMC/2012 and Jordan-N3/2012. A comparison of predicted protein sequences also demonstrated the existence of two clade A lineages with unique amino acid substitutions, A1 (EMC/2012 and Jordan-N3/2012) and A2 (D998/15 and NRCE-HKU205), circulating in humans and camels, respectively. The nine clade B isolates belong to three distinct lineages: B1, B3 and B5. Two B3 strains, D1271/15 and D1189.1/15, showed evidence of recombination between lineages B4 and B5 in ORF1ab. Molecular clock analysis dated the time of the most recent common ancestor (tMRCA) of clade A to March 2011 and that of clade B to November 2011. Our data support a polyphyletic origin of MERS-CoV in dromedaries and the co-circulation of diverse MERS-CoVs including recombinant strains in the UAE. PMID- 27999427 TI - Cancer genetics: X-inactivation and cancer incidence. PMID- 27999426 TI - A camel-derived MERS-CoV with a variant spike protein cleavage site and distinct fusion activation properties. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) continues to circulate in both humans and camels, and the origin and evolution of the virus remain unclear. Here we characterize the spike protein of a camel-derived MERS-CoV (NRCE-HKU205) identified in 2013, early in the MERS outbreak. NRCE-HKU205 spike protein has a variant cleavage motif with regard to the S2' fusion activation site-notably, a novel substitution of isoleucine for the otherwise invariant serine at the critical P1' cleavage site position. The substitutions resulted in a loss of furin-mediated cleavage, as shown by fluorogenic peptide cleavage and western blot assays. Cell-cell fusion and pseudotyped virus infectivity assays demonstrated that the S2' substitutions decreased spike-mediated fusion and viral entry. However, cathepsin and trypsin-like protease activation were retained, albeit with much reduced efficiency compared with the prototypical EMC/2012 human strain. We show that NRCE-HKU205 has more limited fusion activation properties possibly resulting in more restricted viral tropism and may represent an intermediate in the complex pattern of MERS-CoV ecology and evolution. PMID- 27999425 TI - First documented case of avian influenza (H5N1) virus infection in a lion. PMID- 27999428 TI - Tumour-Initiating cells: The cell that rocks the tumour. PMID- 27999429 TI - Chemotherapy: Less is more. PMID- 27999430 TI - Leukaemia: Don't let sleeping cells lie. PMID- 27999431 TI - Retraction: Capturing carbon dioxide as a polymer from natural gas. PMID- 27999432 TI - Targeting cancer-related inflammation in the era of immunotherapy. AB - Recent advances in cancer immunotherapy, particularly immune checkpoint blockade therapy have dramatically changed the therapeutic strategy against advanced malignancies. Still, only a subset of patients shows a good response to any single therapy. Moreover, it remains largely unsolved how we can maintain durable clinical responses, or how we can successfully treat a broader range of cancers by immunotherapy. Growing evidence suggests that the major barrier to more successful cancer immunotherapy is the tumour microenvironment (TME), where chronic inflammation has a predominant role in tumour survival and proliferation, angiogenesis and immunosuppression. Over the past decades, our understanding of cancer-related inflammation has significantly evolved, and now we have various therapeutic options tailored to the TME. These therapeutic strategies include inhibiting inflammatory mediators or their downstream signalling molecules, blocking the recruitment of myeloid cells, modulating immunosuppressive functions in myeloid cells and re-educating the TME. In this review, we discuss the role of cancer-related inflammation as a potential target in the era of immunotherapy. PMID- 27999433 TI - Insane in the membrane: a structural perspective of MLKL function in necroptosis. AB - Necroptosis (or 'programmed necrosis') is a caspase-independent cell death pathway that operates downstream of death receptors, including Tumour Necrosis Factor Receptor-1 (TNFR1), and the Toll-like receptors, TLR3 and TLR4. Owing to its immunogenicity, necroptosis has been attributed roles in the pathogenesis of several diseases, including inflammatory bowel disease and the tissue damage arising from ischaemic-reperfusion injuries. Only over the past 7 years has the core machinery of this pathway, the receptor-interacting protein kinase-3 (RIPK3) and the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), been defined. Our current understanding of the pathway is that RIPK3-mediated phosphorylation activates cytoplasmic MLKL, which is the most terminal known effector in the pathway, leading to MLKL's oligomerisation, translocation to, and permeabilisation of, the plasma membrane. Here, we discuss the insights gleaned from structural and biophysical studies of MLKL and highlight the known unknowns surrounding MLKL's mechanism of action and activation. PMID- 27999435 TI - Gut microbiota: Intestinal microbiota oscillations regulate host circadian physiology. PMID- 27999434 TI - Adoptive cellular immunotherapy for virus-associated cancers: a new paradigm in personalized medicine. AB - Persistent viral infections are associated with the majority of human cancers where infectious agents have been recognized as the primary etiological agent. These viruses contribute to the malignant transformation of human cells either through the expression of oncogenic proteins or chronic inflammation. In spite of the high prevalence of these viral infections in humans, only a small proportion of these individuals who may have an underlying immune defect develop malignant disease. Furthermore, many of these viruses have evolved unique mechanisms to avoid the host immune system to successfully establish latent infection with limited gene expression. Technological advances in delineating the role of cellular immune responses in the control of viral infections and ability to rapidly expand these effector cells in vitro have provided an important platform for the development of novel immunotherapeutic strategies to treat virus associated cancers. While autologous T cell therapies have provided promising results, development of 'off-the-shelf' third-party allogeneic virus-specific T cell therapies have emerged as powerful tools to treat many of the virus associated diseases. It is anticipated that adoptive T cell therapy in combination with newly emerging immune checkpoint inhibitors and therapeutic vaccines will provide opportunities to successfully treat advanced metastatic virus-associated cancers which are currently not amenable to standard therapeutic strategies. PMID- 27999436 TI - Food allergy and the gut. AB - Food allergy develops as a consequence of a failure in oral tolerance, which is a default immune response by the gut-associated lymphoid tissues to ingested antigens that is modified by the gut microbiota. Food allergy is classified on the basis of the involvement of IgE antibodies in allergic pathophysiology, either as classic IgE, mixed pathophysiology or non-IgE-mediated food allergy. Gastrointestinal manifestations of food allergy include emesis, nausea, diarrhoea, abdominal pain, dysphagia, food impaction, protein-losing enteropathy and failure to thrive. Childhood food allergy has a generally favourable prognosis, whereas natural history in adults is not as well known. Elimination of the offending foods from the diet is the current standard of care; however, future therapies focus on gradual reintroduction of foods via oral, sublingual or epicutaneous food immunotherapy. Vaccines, modified hypoallergenic foods and modification of the gut microbiota represent additional approaches to treatment of food allergy. PMID- 27999437 TI - The nuclear pore complex: understanding its function through structural insight. AB - Nuclear pore complexes (NPCs) fuse the inner and outer nuclear membranes to form channels across the nuclear envelope. They are large macromolecular assemblies with a complex composition and diverse functions. Apart from facilitating nucleocytoplasmic transport, NPCs are involved in chromatin organization, the regulation of gene expression and DNA repair. Understanding the molecular mechanisms underlying these functions has been hampered by a lack of structural knowledge about the NPC. The recent convergence of crystallographic and biochemical in vitro analysis of nucleoporins (NUPs), the components of the NPC, with cryo-electron microscopic imaging of the entire NPC in situ has provided first pseudo-atomic view of its central core and revealed that an unexpected network of short linear motifs is an important spatial organization principle. These breakthroughs have transformed the way we understand NPC structure, and they provide an important base for functional investigations, including the elucidation of the molecular mechanisms underlying clinically manifested mutations of the nucleocytoplasmic transport system. PMID- 27999438 TI - Necroptosis in development, inflammation and disease. AB - In the early 2000s, receptor-interacting serine/threonine protein kinase 1 (RIPK1), a molecule already recognized as an important regulator of cell survival, inflammation and disease, was attributed an additional function: the regulation of a novel cell death pathway that came to be known as necroptosis. Subsequently, the related kinase RIPK3 and its substrate mixed-lineage kinase domain-like protein (MLKL) were also implicated in the necroptotic pathway, and links between this pathway and apoptosis were established. In this Timeline article, we outline the discoveries that have helped to identify the roles of RIPK1, RIPK3, MLKL and other regulators of necroptosis, and how they interact to determine cell fate. PMID- 27999440 TI - Antibacterial effect of antibiotic-loaded SBA-15 on biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis. AB - Staphylococcus aureus and Staphylococcus epidermidis are human pathogens involved in implant-related infections. During those diseases, they are able to form biofilms showing resistance to the effect of many different antibiotics. Drug delivery systems allow a local and effective delivery of antibiotics at high concentrations in the infected tissue without causing the cytotoxic effects commonly linked to systemic administration. We report the use of a porous ceramic biomaterial, such as SBA-15 loaded with antibiotics, to deliver them directly to the infected tissue. SBA-15 discs were loaded with Vancomycin, Rifampin and a combination of both, introduced in a suspension of S. aureus 15981 and S. epidermidis ATCC 35984 and incubated during 6 and 24 h. A statistically significant decrease in the biofilm density and the number of viable bacteria was detected for all antibiotics at 6 h in both bacteria. Rifampin showed an increase in the biofilm density and the number of viable bacteria at 24 h. No differences were detected between Vancomycin and the combination of antibiotics. S. epidermidis was more sensitive to the effect of the antibiotics than S. aureus. Here we have demonstrated that SBA-15 is able to act as an effective drug delivery system not only from a pharmaceutical point of view, but also from a biological one. PMID- 27999442 TI - Precursor-directed in situ synthesis of Saccharothriolides G and H by the Actinomycete Saccharothrix sp. A1506. PMID- 27999439 TI - Angucycline antibiotic waldiomycin recognizes common structural motif conserved in bacterial histidine kinases. AB - Two-component signal transduction systems (TCSs), composed of a histidine kinase sensor (HK) and its cognate response regulator, sense and respond to environmental changes and are related to the virulence of pathogens. TCSs are potential targets for alternative antibiotics and anti-virulence agents. Here we found that waldiomycin, an angucycline antibiotic that inhibits a growth essential HK, WalK, in Gram-positive bacteria, also inhibits several class I HKs from the Gram-negative Escherichia coli. NMR analyses and site-directed mutagenesis studies using the osmo-sensing EnvZ, a prototypical HK of E. coli, showed that waldiomycin directly binds to both H-box and X-region, which are the two conserved regions in the dimerization-inducing and histidine-containing phosphotransfer (DHp) domain of HKs. Waldiomycin inhibits phosphorylation of the conserved histidine in the H-box. Analysis of waldiomycin derivatives suggests that the angucyclic ring, situated near the H-box in the waldiomycin-EnvZ DHp domain complex model, is responsible for the inhibitory activity. We demonstrate that waldiomycin is an HK inhibitor binding to the H-box region and has the potential of inhibiting a broad spectrum of HKs. PMID- 27999441 TI - In vitro and in vivo activities of the diazabicyclooctane OP0595 against AmpC derepressed Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a common cause for healthcare-associated infections, which have been historically treated by antipseudomonal beta-lactam agents in the clinical setting. However, P. aeruginosa has evolved to overcome these beta lactam agents via multiple endogenous resistance mechanisms, including derepression of the chromosomal cephalosporinase (AmpC). In this article, we investigated the effective concentration of OP0595 for combination with piperacillin, cefepime or meropenem in in vitro susceptibility tests, and the antibacterial activity of cefepime in combination with OP0595 in both in vitro time-kill studies and in vivo murine thigh infection model study with AmpC derepressed P. aeruginosa. The sufficient combinational concentration of OP0595 was a 4 MUg ml-1 with all these three beta-lactam agents. OP0595 increased the antibacterial activity of cefepime in both in vitro and in vivo studies against all strains tested. Taken together, OP0595 is the diazabicyclooctane serine beta lactamase inhibitor with activity against AmpC-derepressed P. aeruginosa and its combinational use with a beta-lactam agent will provide a new approach for the treatment of P. aeruginosa infections. PMID- 27999443 TI - Isomethoxyneihumicin, a new cytotoxic agent produced by marine Nocardiopsis alba KM6-1. AB - A new cytotoxic agent designated isomethoxyneihumicin (1 and 2), a mixture of lactam-lactim tautomers, was isolated along with methoxyneihumicin (3) from the culture broth of the marine Nocardiopsis alba KM6-1. The structures of 1 and 2 were elucidated in spectroscopic analyses (1D and 2D NMR data, and ROESY correlations). Isomethoxyneihumicin (15.0 MUM) and 3 (15.0 MUM) arrested the cell cycle of Jurkat cells at the G2/M phase (66 and 67%) in 12 h. Isomethoxyneihumicin and 3 exhibited cytotoxicity against Jurkat cells with IC50 values of 6.98 and 30.5 MUM in 20 h, respectively. These results strongly suggest that isomethoxyneihumicin and 3 exhibit cytotoxicity against Jurkat cells by inhibiting the cell cycle at the G2/M phase. PMID- 27999444 TI - Studies at the ionizable position of cephalosporins and penicillins: hydroxamates as substitutes for the traditional carboxylate group. AB - Classically, beta-lactams need an ionizable group to potentiate antibacterial activity. Sets of cephalosporins and penicillins featuring different substituted hydroxamates in place of the traditional carboxylate group have been synthesized and tested for antibiotic activity. Many of the compounds exhibited anti bacterial activities with notable MIC values in the range of 6-0.2 MUM. PMID- 27999445 TI - Identification of new geldanamycin derivatives from unexplored microbial culture extracts using a MS/MS library. PMID- 27999446 TI - Antimicrobial activity and interactions of cationic peptides derived from Galleria mellonella cecropin D-like peptide with model membranes. AB - Antimicrobial peptides are effector molecules of the innate immune system against invading pathogens. The cationic charge in their structures has a strong correlation with antimicrobial activity, being responsible for the initial electrostatic interaction between peptides and the anionic microbial surface. This paper contains evidence that charge modification in the neutral peptide Gm cecropin D-like (WT) improved the antimicrobial activity of the modified peptides. Two cationic peptides derived from WT sequence named as DeltaM1 and DeltaM2, with net charge of +5 and +9, respectively, showed at least an eightfold increase in their antimicrobial activity in comparison to WT. The mechanism of action of these peptides was investigated using small unilamellar vesicles (SUVs) as model membranes. To study permeabilization effects of the peptides on cell membranes, entrapped calcein liposomes were used and the results showed that all peptides induced calcein release from 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoglycerol (POPG) SUVs, whereas in 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC), POPC/POPG and 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoethanolamine (POPE)/POPG SUVs, only DeltaM1 and DeltaM2 induced a notable permeabilization. In addition, interactions of these peptides with phospholipids at the level of the glycerol backbone and hydrophobic domain were studied through observed changes in generalized polarization and fluorescence anisotropy using probes such as Laurdan and DPH, respectively. The results suggest that peptides slightly ordered the bilayer structure at the level of glycerol backbone and on the hydrophobic core in 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) SUVs, whereas in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/DMPG SUVs, only DeltaM1 and DeltaM2 peptides increased the order of bilayers. Thus, peptides would be inducing clustering of phospholipids creating phospholipid domains with a higher phase transition temperature. PMID- 27999448 TI - Thrombosis Related ABO, F5, MTHFR, and FGG Gene Polymorphisms in Morbidly Obese Patients. AB - Objective. Obesity is a well-known risk factor for thrombotic complications. The aim of the present study was to determine the frequency of thrombosis related ABO, F5, MTHFR, and FGG gene polymorphisms in morbidly obese patients and compare them with the group of nonobese individuals. Methods. Gene polymorphisms were analyzed in 320 morbidly obese patients (BMI > 40 kg/m2) and 303 control individuals (BMI < 30 kg/m2) of European descent. ABO C>T (rs505922), F5 C>G (rs6427196), MTHFR C>T (rs1801133), and FGG C>T (rs6536024) SNPs were genotyped by RT-PCR. Results. We observed a tendency for MTHFR rs1801133 TT genotype to be linked with morbid obesity when compared to CC genotype; however, the difference did not reach the significant P value (OR 1.84, 95% CI 0.83-4.05, P = 0.129). Overall, the genotypes and alleles of rs505922, rs6427196, rs1801133, and rs6536024 SNPs had similar distribution between morbidly obese and nonobese control individuals. Distribution of height and weight means among individuals carrying different rs505922, rs6427196, rs1801133, and rs6536024 genotypes did not differ significantly. Conclusions. Gene polymorphisms ABO C>T (rs505922), F5 C>G (rs6427196), MTHFR C>T (rs1801133), and FGG C>T (rs6536024) were not associated with height, weight, or morbid obesity among European subjects. PMID- 27999449 TI - The Ratio of Hmox1/Nrf2 mRNA Level in the Tumor Tissue Is a Predictor of Distant Metastasis in Colorectal Cancer. AB - Heme oxygenase 1 (Hmox1) plays an important role in the growth and spread of tumor, and its expression is regulated positively by Nrf2 [nuclear factor (erythroid-derived 2)-like 2; NFE2L2] and negatively by kelch-like ECH-associated protein 1 (Keap1) and by BTB and CNC homology 1 (Bach1). Both Hmox1 and Nrf2 contribute to distant metastasis of cancer. The mRNA levels of Hmox1, Nrf2, Keap1, and Bach1 in the tumor and normal tissues of 84 subjects with colorectal cancer (CRC) were determined by real-time polymerase chain reaction. The tumor had lower Hmox1 but higher Bach1 mRNA levels than the normal tissue. The correlations of Hmox1 with components of the Nrf2 pathway were not significant in the tumor tissue of CRC subjects with distant metastasis. The ratio of Hmox1/Nrf2 mRNA level (by percentage) in the tumor tissue was lower in the subjects with distant metastasis (97.4% (84.4-111.1%)) than in those without (101.0% (92.7 136.5%)) and was a predictor for distant metastasis in CRC (odds ratio: 0.83; 95% confidence interval: 0.68-0.97) along with serum carcinoembryonic antigen (1.0027, 1.006-1.064). The mRNA level of Hmox1 in the tumor tissue of CRC is not correlated with that of the Nrf2 pathway molecules, and its ratio to the Nrf2 level may be useful for suggesting distant metastasis in CRC. PMID- 27999450 TI - Association between Vascular Endothelial Growth Factor Polymorphisms and Age Related Macular Degeneration: An Updated Meta-Analysis. AB - Age-related macular degeneration (AMD) is the most common cause of blindness in elderly people worldwide and the major degenerative disease of the retina that leads to progressive impairment of central vision. Several polymorphisms in different genes have been proposed as factors that increase the disease susceptibility. The aim of the present study is to carry out a systematic review and an updated meta-analysis in order to summarize the current published studies and to evaluate the associations between four common vascular endothelial growth factor (VEGF) polymorphisms (rs833061, rs1413711, rs3025039, and rs2010963) and AMD risk, also stratifying for AMD subtypes and ethnicity. A systematic literature search in the Medline database, using PubMed, was carried out for epidemiological studies, published before June 2016. Associations of VEGF polymorphisms with AMD were estimated by calculating pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) based on different models. Twelve articles were included in the analysis. The present meta-analysis constitutes a useful guide for readers to study AMD and adds new evidence to the growing literature on the role of VEGF polymorphisms in the risk of AMD. Significant associations with AMD risk were showed for rs833061, rs1413711, and rs3025039 polymorphisms but not for rs2010963. PMID- 27999451 TI - FFAR4 (GPR120) Signaling Is Not Required for Anti-Inflammatory and Insulin Sensitizing Effects of Omega-3 Fatty Acids. AB - Free fatty acid receptor-4 (FFAR4), also known as GPR120, has been reported to mediate the beneficial effects of omega-3 polyunsaturated fatty acids (omega3 PUFAs) by inducing an anti-inflammatory immune response. Thus, activation of FFAR4 has been reported to ameliorate chronic low-grade inflammation and insulin resistance accompanying obesity. However, conflicting reports on the role of FFAR4 in mediating the effects of omega3-PUFAs are emerging, suggesting that FFAR4 may not be the sole effector. Hence analyses of the importance of this receptor in relation to other signaling pathways and prominent effects of omega3 PUFAs remain to be elucidated. In the present study, we used Ffar4 knockouts (KO) and heterozygous (HET) mice fed either low fat, low sucrose reference diet; high fat, high sucrose omega3-PUFA; or high fat, high sucrose omega6-PUFA diet for 36 weeks. We demonstrate that both KO and HET mice fed omega3-PUFAs were protected against obesity, hepatic triacylglycerol accumulation, and whole-body insulin resistance. Moreover, omega3-PUFA fed mice had increased circulating protein levels of the anti-inflammatory adipokine, adiponectin, decreased fasting insulin levels, and decreased mRNA expression of several proinflammatory molecules within visceral adipose tissue. In conclusion, we find that FFAR4 signaling is not required for the reported anti-inflammatory and insulin-sensitizing effects mediated by omega3-PUFAs. PMID- 27999452 TI - MicroRNA Regulation of Endothelial Junction Proteins and Clinical Consequence. AB - Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM 1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden 1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE cadherin, beta-catenin, plakoglobin, P120, and vinculin. VE-cadherin and beta catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin-beta-catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin beta4, paxillin, and focal adhesion kinase (FAK). Integrin beta4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases. PMID- 27999453 TI - Frequency of TNFA, INFG, and IL10 Gene Polymorphisms and Their Association with Malaria Vivax and Genomic Ancestry. AB - Polymorphisms in cytokine genes can alter the production of these proteins and consequently affect the immune response. The trihybrid heterogeneity of the Brazilian population is characterized as a condition for the use of ancestry informative markers. The objective of this study was to evaluate the frequency of -1031T>C, -308G>A and -238G>A TNFA, +874 A>T IFNG and -819C>T, and -592C>A IL10 gene polymorphisms and their association with malaria vivax and genomic ancestry. Samples from 90 vivax malaria-infected individuals and 51 noninfected individuals from northern Brazil were evaluated. Genotyping was carried out by using ASO-PCR or PCR/RFLP. The genomic ancestry of the individuals was classified using 48 insertion/deletion polymorphism biallelic markers. There were no differences in the proportions of African, European, and Native American ancestry between men and women. No significant association was observed for the allele and genotype frequencies of the 6 SNPs between malaria-infected and noninfected individuals. However, there was a trend toward decreasing the frequency of individuals carrying the TNF-308A allele with the increasing proportion of European ancestry. No ethnic-specific SNPs were identified, and there was no allelic or genotype association with susceptibility or resistance to vivax malaria. Understanding the genomic mechanisms by which ancestry influences this association is critical and requires further study. PMID- 27999455 TI - Intramedullary Fixation of Metacarpal Fractures Using Headless Compression Screws. AB - Introduction The purpose of this study is to examine the clinical results of retrograde intramedullary headless screw (IMHS) fixation for metacarpal fractures. Methods A retrospective review was performed on 16 patients with 18 metacarpal fractures who underwent IMHS fixation at a single institution. The average age was 32 years. The indications for surgery included rotational malalignment (five patients), multiple metacarpal fractures (five patients), angular deformity (four patients), and shortening greater than 5 mm (two patients). The average length of follow-up was 19.4 weeks (median 10.2 weeks). Results Functional outcome was considered excellent in all patients with total active motion in excess of 240 degrees. Active motion was initiated within 1 week of surgery. No secondary surgeries were performed related to a complication of IMHS fixation. Conclusion IMHS fixation of metacarpal fractures is an efficacious treatment modality for patients with comminution, multiple fractures, malrotation, and those who require rapid mobilization. It obviates the need for immobilization or more extensive plate and screw fixation techniques with excellent clinical results. PMID- 27999456 TI - Investigating the Effect of Intra-articular Platelet-Rich Plasma Injection on Union: Pain and Function Improvement in Patients with Scaphoid Fracture. AB - Introduction Fracture of the scaphoid bone is the most common fracture of the carpus. However, the fracture union occurs late or may not heal. Sometimes, fracture healing requires prolong immobilization. Because of potential for joint stiffness, muscle atrophy, or the inability to use the hand during and after prolonged immobilization, there is great incentive to develop therapies that will accelerate bone healing and allow a quick return to work. To date, the effect of platelet-rich plasma (PRP) on scaphoid fracture has not been studied. We aimed to assess the effect of intra-articular PRP injection on union: pain, range of motion, and function in patients with scaphoid fracture. Hypothesis Union: pain reduction and functional improvement can be noticed after PRP use in scaphoid fracture. Materials and Methods A randomized controlled trial was designed with 14 patients with scaphoid fractures (Herbert type B2). Casting was done for them. Seven patients received intra-articular autologous PRP. Patients were followed up 2 weeks after casting using radiography and then at 2 months using radiography and computed tomography (CT) scan to check bone healing. Then patients were followed up for 3 and 6 months and after evaluation of healing by CT scan, the patient-rated wrist evaluation questionnaire was completed and the range of motion of the wrist was measured. Results Analysis revealed significant improvement in pain at rest, as well as during specific and usual activities following PRP injection in the case group. However, no statistically significant difference in wrist motion including radial and ulnar deviation, flexion, and extension was found in 6 months follow-up except some improvement in ulnar deviation after 3 months. However, this study showed that scaphoid union occurred earlier in the case group, but it was not statistically significant. Conclusion PRP may have a significant effect on pain reduction at rest and amount of difficulty in functions including specific and usual activities in patients with scaphoid fractures. Level of Evidence This is a level III, therapeutic trial. PMID- 27999457 TI - Demographic Characteristics, Anatomical Distribution, and Clinical Presentations of Lipomatosis Tumors Arising from Hand and Wrist. AB - The aim of this study is to analyze demographic characteristics, anatomical distribution, and clinic presentations of the lipomatosis masses in hand and wrist. The hand and wrist magnetic resonance (MR) images of 2,453 patients were evaluated retrospectively. Nineteen cases were included in the study that is seen fat component in mass in MR images. Patients' age, sex, and clinical symptoms were noted. The size and the localization area of the mass were evaluated. Ordinary lipomas were detected in 18 (95%) patients, and fibrolipomatous hamartoma of the median nerve was detected in 1 patient (5%). Benign ordinary lipomas were most frequently observed in palmar and ventral sides. Lipomas located in palmar area tend to be bigger size comparing with other locations. Deep-seated lipoma is localized in central area frequently. In ordinary lipoma cases, patients are generally (78%) asymptomatic. The most frequent clinical symptom is limitation in movement depending on mass dimension. PMID- 27999454 TI - Clinical Advancements in the Targeted Therapies against Liver Fibrosis. AB - Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis. PMID- 27999458 TI - Titanium versus Stainless-Steel Plating in the Surgical Treatment of Distal Radius Fractures: A Randomized Trial. AB - Our purpose was to compare postoperative complications and rate of plate removal in titanium and stainless-steel plating of distal radius fractures (DRF). Patients following DRF were randomly fixed with titanium or stainless-steel plates using the same plating system. Complications, second surgeries, and plate prominence were documented. A total of 41 patients were treated with stainless steel and 22 with titanium plates. Average follow-up was 60 +/- 5.6 months. There was no difference in demographics, fracture characteristics, or follow-up between the groups. Plate prominence was found in 50% of radiographs (mean distance: 1.4 mm). Four titanium plates and three stainless-steel plates were removed (11%). Mean time to plate removal was 18.4 +/- 4.6 months. There was no difference in removal rates between the groups. Plate material and prominence, age, fracture comminution and smoking status were not associated with plate removal. Our results support using volar and dorsal plates regardless of the plate material. PMID- 27999459 TI - The Use of Minilocked Plate for Management of Unstable Metacarpal Fractures. AB - Objective This study aims to evaluate the use of minilocked plates in the treatment of the metacarpal fractures. Method A total of 30 patients of metacarpal fractures were treated by minilocked plates. Results Union was achieved in all patients. There were 27 (90%) patients having satisfactory results (excellent and good results) and 3 patients (10%) had poor results. Conclusion The use of minilocked plate is recommended for fixation of periarticular, comminuted, and osteoporotic metacarpal fractures that offer rigid fixation early mobilization, decreases the incidence of joints stiffness, and tendon adherence which maximized the hand function. PMID- 27999461 TI - Radial Artery Pseudoaneurysm with Aberrant Radial Artery Anatomy: An Unusual Presentation of Flexor Tenosynovitis. AB - Purpose Radial artery pseudoaneurysm is uncommon and mainly associated with radial artery cannulization for cardiac intervention or invasive hemodynamic monitoring. It is rarely seen as a result of intra-arterial recreational drug injection. Methods We present the case of a 35-year-old man with a 12-year history of intravenous drug use and 1-year history of intra-arterial drug use who developed radial artery pseudoaneurysm with a right long finger suppurative flexor tenosynovitis and subsequent acute radial-sided hand ischemia. Computed tomography (CT) angiography with three-dimensional reconstructions was used in diagnosis. We treated him with parenteral antibiotics followed by surgical debridement of his infection and removal of the infected pseudoaneurysm. Results Examination of the three-dimensional CT angiogram showed an unusual anatomical variant that likely predisposed him to isolated long finger flexor tenosynovitis. Conclusion Prompt diagnosis and treatment of pseudoaneurysm in this context is crucial to avoiding sepsis, hemorrhage, and irreversible ischemia. In rare cases, imaging can demonstrate an underlying anatomical variant that may be a predisposing factor. PMID- 27999460 TI - Minimally Displaced Distal Radius Fracture Treated with Closed Reduction and Percutaneous Fixation Resulting in an Iatrogenic Galeazzi Lesion. AB - Galeazzi fracture in skeletally immature patients is a relatively uncommon injury. No previously published case has been associated with an iatrogenic mechanism. Here, we report a case of a 10-year-old boy with a minimally displaced distal radius fracture evolving into a Galeazzi lesion after unnecessary surgical treatment. Unnecessary surgical procedure associated with poor knowledge of bone growth and physiology contributed significantly to the reported condition. PMID- 27999462 TI - Radial Artery Forearm Flap Anomaly: A Rare Anomaly and the Importance of the Proximal Exploratory Incision. AB - During a free radial forearm flap harvest, we encountered a variant anatomy of the arterial system. The brachial artery was found to travel with the median nerve and bifurcate 10 cm below the antecubital fossa, under cover of the pronator teres. The radial artery then emerged from the pronator and continued on its usual path. This anomaly has been reported only once thus far. We report this case to highlight our practice of always starting with a proximal exploratory incision to identify the anatomy before raising the flap, which is what enabled us to adapt to this variation with a satisfactory outcome. PMID- 27999463 TI - The Amputated Hand of the Brabo Fountain, Antwerp, Belgium. PMID- 27999464 TI - Simultaneous Arthrodesis of Proximal and Distal Interphalangeal Joints in Hand Trauma. PMID- 27999465 TI - Finger Imaging by RadioVisioGraphy Digital Dental Radiography Imaging System. PMID- 27999466 TI - Open Reduction of the Dislocated Pisiform Bone. PMID- 27999467 TI - The "Bowstring Arch Bridge" Analogy to Guide Sequential Portal Placement during Needle Aponeurotomy in the Treatment of Dupuytren Contracture. PMID- 27999468 TI - Evaluation of anxiolytic effects of aripiprazole and hydroxyzine as a combination in mice. AB - CONTEXT: Anxiety disorders are chronic, common, and often comorbid. There is an unmet need in its treatment. Aripiprazole and hydroxyzine are well-known therapeutic options used as monotherapy in clinics. They have different mechanisms and site of actions. AIM: The objective of the present study was to evaluate the anxiolytic effect of aripiprazole and hydroxyzine in combination. MATERIALS AND METHODS: Swiss albino mice (male) received treatment of 5% of Tween 80 in 0.9% saline (10 ml/kg; control group), "aripiprazole alone" (1 mg/kg), "hydroxyzine alone" (3 mg/kg), and aripiprazole (0.5 mg/kg) + hydroxyzine (1.5 mg/kg) through the intraperitoneal route. RESULTS: The in vivo outcomes (elevated plus maze, light/dark transition, and marble burying tests) of hydroxyzine monotherapy-treated group showed a significant anxiolytic activity. The combination-treated group was found to be better than control and aripiprazole treated groups. The combination-treated group showed a significant increase in the level of serotonin in different brain regions as compared to aripiprazole treated group but not better than the hydroxyzine group. The in vitro results were in compliance with the in vivo results. The combinational approach was found to be beneficial in anxiolytic treatment as compared to aripiprazole monotherapy. However, hydroxyzine showed better anxiolytic activity when compared to control, aripiprazole monotherapy, and combination groups. CONCLUSIONS: The anxiolytic effect of combination-treated group was found to be better than aripiprazole monotherapy and lesser than hydroxyzine monotherapy. PMID- 27999469 TI - Evaluation of self-reported medication adherence and its associated factors among epilepsy patients in Hospital Kuala Lumpur. AB - INTRODUCTION: Reports on medication adherence and its associated factors in patients with epilepsy in South East Asian countries are lacking. The primary purpose of this study was to assess the degree of medication adherence and its relationship with patient's satisfaction, psychosocial factors, quality of life and mental health in a sample of Malaysian epilepsy patients. METHODOLOGY: It is a cross-sectional study and was carried out in the outpatient Neurology Department of Hospital Kuala Lumpur, Malaysia (n=272). Data was collected by administering the structured questionnaire. RESULTS AND DISCUSSION: Results showed that 49.3% of the epilepsy patients were non-adherent to their prescribed regimen. Univariate analysis showed significant associations between medication adherence and the following factors: race, seizure frequency, overall patient satisfaction, medication taste and smell, medication cost and physical appearance, medication effectiveness, complexity of medication regimen, patient barrier, patient understanding, patient role functioning, patient positivity, vitality and general interest. Multiple regression analysis indicated that factors that are influencing medication adherence are seizure frequency (P = 0.048), overall patient satisfaction (P = 0.043) and patient understanding about their illness (P = 0.001). The model chosen for testing the relationship between medication adherence and its associated factors give an R2 value of 25.2% with an adjusted R2 of 21.4%. The F value was also significant (P = 0.000). Based on the research findings, the researchers recommends that clinicians need to play a vital role in educating the patients on their disease conditions. By educating the patients on nature of epilepsy, different modalities of treatment and benefits of adherence to treatment will help in the better adherence and management. PMID- 27999470 TI - Prevalence of potentially inappropriate medications and prescription cost analysis among older cardiac patients in an outpatient department of a tertiary care hospital in India. AB - AIMS: The aim of this study is to evaluate potentially inappropriate medications (PIMs) in the elderly at cardiology outpatient department (OPD) of a tertiary care teaching hospital using Beers criteria and to find the direct cost burden of PIMs. MATERIALS AND METHODS: The present study was an observational cross sectional study. Prescriptions of the patients' aged >=65 years were collected from the cardiology OPD and were analyzed. PIMs were identified with the help of Beers 2012 criteria. Direct costs of prescribed drugs were calculated. Predictors (comorbid conditions, number of drugs prescribed) associated with PIM use were identified using bivariate analysis. Multivariate logistic regression was then applied to study the influence of these variables on PIM use. A P < 0.05 was considered statistically significant. RESULTS: A total of 236 patients received 1443 drugs. According to Beers 2012 criteria, 29.3% patients received at least one PIM followed by two and three PIMs in 10 and 23 patients, respectively. The most commonly prescribed PIM was spironolactone in 15.7% patients followed by benzodiazepines in 15 patients. The total cost of therapy for 1 day was Indian Rupee (INR) 10,029.2 while total cost of all prescribed medications in per day was INR 42.5. CONCLUSIONS: This study showed higher use of PIMs among the elderly in cardiac OPD. It is important to improve the situation of older cardiac patients who have higher use of PIMs. In older patients, high prevalence of PIMs was associated with increased cost. The use of regular continuing medical education program by the hospital and educating and training doctors on rational prescribing will help alleviate this issue. PMID- 27999471 TI - Use of simulated patient approach to assess the community pharmacists' knowledge of appropriate use of metered dose inhaler. AB - RATIONALE: The pharmacist charged with the responsibility of drug administration and counseling should have the basic knowledge and skills necessary to demonstrate the use of metered dose inhalers (MDIs) to asthma patients for the maximization of treatment outcomes. OBJECTIVE: This study was designed to evaluate the community pharmacists' knowledge of the appropriate use of MDIs in Anambra State, Nigeria. METHODS: The study was carried out in two major cities in Anambra State, Nigeria, using 41 registered community pharmacists. A simulated patient approach utilizing two adequately trained pharmacy students were used. Obtained data were analyzed using independent t-test and one-way ANOVA through SPSS version 18. RESULTS: The pharmacists had a mean demonstration score of 45.45%. Step number seven of the correct use of MDI, which involves breathing in and depressing the canister was the most demonstrated step (90.2%) while step 4 which involves tilting the head back slightly was the least demonstrated (14.6%) by the pharmacists. Among five identified critical steps in asthma guideline used, two were well demonstrated (75.6% and 90.2%): one averagely demonstrated (51.2%) and two poorly demonstrated (39% and 31.7%). Sociodemographic characteristics did not influence the demonstration ability of the pharmacists in this study. CONCLUSION: The study indicated that community pharmacists lacked the adequate knowledge of appropriate use of MDI. Training programs for pharmacists focusing on the use of such devices will enable them to educate patients on the effective use of MDIs in patients with asthma. PMID- 27999472 TI - Carbamazepine-induced angioedema. AB - Angioedema is a rare adverse reaction of carbamazepine, which causes localized tissue edema in submucosal and subcutaneous tissue mediated by histamine, serotonin, and kinins (bradykinin). We report a case of 34-year-old female who developed angioedema, 24 h after administration of carbamazepine for treating bipolar disorder. Patient's symptoms responded rapidly with antihistamine therapy and with the withdrawal of carbamazepine, the offending drug. Carbamazepine induced angioedema is a life-threatening reaction which requires immediate treatment and monitoring in order to avoid morbidity and mortality. PMID- 27999473 TI - The Relation between the Fear-Avoidance Model and Constructs from the Social Cognitive Theory in Acute WAD. AB - In the fear-avoidance (FA) model social cognitive constructs could add to explaining the disabling process in whiplash associated disorder (WAD). The aim was to exemplify the possible input from Social Cognitive Theory on the FA model. Specifically the role of functional self-efficacy and perceived responses from a spouse/intimate partner was studied. A cross-sectional and correlational design was used. Data from 64 patients with acute WAD were used. Measures were pain intensity measured with a numerical rating scale, the Pain Disability Index, support, punishing responses, solicitous responses, and distracting responses subscales from the Multidimensional Pain Inventory, the Catastrophizing subscale from the Coping Strategies Questionnaire, the Tampa Scale of Kinesiophobia, and the Self-Efficacy Scale. Bivariate correlational, simple linear regression, and multiple regression analyses were used. In the statistical prediction models high pain intensity indicated high punishing responses, which indicated high catastrophizing. High catastrophizing indicated high fear of movement, which indicated low self-efficacy. Low self-efficacy indicated high disability, which indicated high pain intensity. All independent variables together explained 66.4% of the variance in pain disability, p < 0.001. Results suggest a possible link between one aspect of the social environment, perceived punishing responses from a spouse/intimate partner, pain intensity, and catastrophizing. Further, results support a mediating role of self-efficacy between fear of movement and disability in WAD. PMID- 27999474 TI - Giant Cell Tumor: A Rare Condition in the Immature Skeleton-A Retrospective Study of Symptoms, Treatment, and Outcome in 16 Children. AB - Background. Pediatric giant cell tumor (GCT) of bone is rare and the course of the disease in the immature skeleton is sparsely described. We performed a retrospective study addressing symptoms, treatment, and outcome in children with GCT. Methods. Review of medical records and images of patients with GCT. Patients were detected from our hospital prospective database and those with open epiphyseal cartilages were included. Results. 16 children (75% girls) from 6 to 15 years old were identified. Eight lesions (50%) were in long bones and 4 (25%) in flat bones. One lesion appeared to be purely epiphyseal. All patients had pain as the initial symptom. Local recurrence developed in 2 patients. 14 of 16 patients returned to normal activity with no sequelae. One patient developed anisomelia after surgery. Conclusions. The biological tumor behavior in children does not seem to differ from what is reported in adults. Lesions in flat bones are very unusual, but our data alone do not provide enough evidence to conclude that this is more common in the immature skeleton. Literature review showed only one previous case report describing a purely epiphyseal GCT. Intralesional curettage is appropriate treatment and gives good functional results with acceptable recurrence rates. PMID- 27999476 TI - Advancing aged care: a systematic review of economic evaluations of workforce structures and care processes in a residential care setting. AB - Long-term care for older people is provided in both residential and non residential settings, with residential settings tending to cater for individuals with higher care needs. Evidence relating to the costs and effectiveness of different workforce structures and care processes is important to facilitate the future planning of residential aged care services to promote high quality care and to enhance the quality of life of individuals living in residential care. A systematic review conducted up to December 2015 identified 19 studies containing an economic component; seven included a complete economic evaluation and 12 contained a cost analysis only. Key findings include the potential to create cost savings from a societal perspective through enhanced staffing levels and quality improvement interventions within residential aged care facilities, while integrated care models, including the integration of health disciplines and the integration between residents and care staff, were shown to have limited cost saving potential. Six of the 19 identified studies examined dementia-specific structures and processes, in which person-centred interventions demonstrated the potential to reduce agitation and improve residents' quality of life. Importantly, this review highlights methodological limitations in the existing evidence and an urgent need for future research to identify appropriate and meaningful outcome measures that can be used at a service planning level. PMID- 27999475 TI - Pre-analytical issues in the haemostasis laboratory: guidance for the clinical laboratories. AB - Ensuring quality has become a daily requirement in laboratories. In haemostasis, even more than in other disciplines of biology, quality is determined by a pre analytical step that encompasses all procedures, starting with the formulation of the medical question, and includes patient preparation, sample collection, handling, transportation, processing, and storage until time of analysis. This step, based on a variety of manual activities, is the most vulnerable part of the total testing process and is a major component of the reliability and validity of results in haemostasis and constitutes the most important source of erroneous or un-interpretable results. Pre-analytical errors may occur throughout the testing process and arise from unsuitable, inappropriate or wrongly handled procedures. Problems may arise during the collection of blood specimens such as misidentification of the sample, use of inadequate devices or needles, incorrect order of draw, prolonged tourniquet placing, unsuccessful attempts to locate the vein, incorrect use of additive tubes, collection of unsuitable samples for quality or quantity, inappropriate mixing of a sample, etc. Some factors can alter the result of a sample constituent after collection during transportation, preparation and storage. Laboratory errors can often have serious adverse consequences. Lack of standardized procedures for sample collection accounts for most of the errors encountered within the total testing process. They can also have clinical consequences as well as a significant impact on patient care, especially those related to specialized tests as these are often considered as "diagnostic". Controlling pre-analytical variables is critical since this has a direct influence on the quality of results and on their clinical reliability. The accurate standardization of the pre-analytical phase is of pivotal importance for achieving reliable results of coagulation tests and should reduce the side effects of the influence factors. This review is a summary of the most important recommendations regarding the importance of pre-analytical factors for coagulation testing and should be a tool to increase awareness about the importance of pre-analytical factors for coagulation testing. PMID- 27999477 TI - DETECTION, RIBOTYPING AND ANTIMICROBIAL RESISTANCE PROPERTIES OF CLOSTRIDIUM DIFFICILE STRAINS ISOLATED FROM THE CASES OF DIARRHEA. AB - BACKGROUND: Clostridium difficile is the most prevalent cause of antibiotic associated infectious diarrhea al-around the world. Prevalence of virulent and resistant strains of Clostridium difficile is increasing now a day. The present investigation was carried out to study the prevalence, ribotyping and antibiotic resistance pattern of C. difficile isolated from diarrheic and non-diarrheic pediatrics. MATERIALS AND METHODS: Four-hundred stool specimens were collected from the diarrheic and non-diarrheic pediatrics hospitalized due to the diseases other than diarrhea. Samples were cultured and their positive results were subjected to disk diffusion and PCR-based ribotyping. RESULTS: Thirty-five out of 400 (8.75%) samples were positive for C. difficile. Prevalence of C. difficile in diarrheic and non-diarrheic pediatrics were 11.25% and 4.16%, respectively. Male had the higher prevalence of bacteria than female (P < 0.05). eight to twelve months old pediatrics were the most commonly infected group. R27 (14.28%), R1 (10.71%), R12 (7.14%), R13 (7.14%) and R18 (7.14%) were most commonly detected ribotypes. There were no positive results for studied ribotypes in non-diarrheic pediatrics. C. difficile strains had the highest levels of resistance against tetracycline (71.42%), erythromycin (57.14%), moxifloxacin (48.57%), metronidazole (28.57%) and clindamycin (22.85%) antibiotics. CONCLUSION: Prescription of antibiotics in diarrheic pediatrics, males and also 8-12 months old pediatrics should be done in a regular and cautious manner. PMID- 27999478 TI - PREVALENCE OF GESTATIONAL DIABETES IN THE SOUTHERN PART OF BOSNIA AND HERZEGOVINA. AB - BACKGROUND: The prevalence of gestational diabetes mellitus (GDM), as a complex problem in pregnancy, is increasing all over the world, but most noticeable in developing countries. AIMS: To estimate GDM prevalence and associated pregnancy features in the southern part of Bosnia and Herzegovina. METHODS: A cross sectional observational study was conducted from October 2010 through March 2011. A total of 285 pregnant women with singleton pregnancies participated and were asigned to the study in the order they came for their usual ante-natal clinic examination. They underwent an oral glucose tolerance test (OGTT) with 75 g of glucose. Information on OGTT results, maternal characteristics and pregnancy outcomes were collected from database and medical records. RESULTS: Prevalence of GDM was 10.9% according to 1999 World Health Organisation (WHO) diagnostic criteria. Prenatal cigarette smoking, previous GDM, cesarean delivery rate and neonatal hypoglycemia were significantly more frequent in the GDM group compared to the group of pregnancies with normal glucose tolerance (p = 0.015, p < 0.001, p = 0.015, p = 0.002). CONCLUSION: This study presents a relatively high prevalence of GDM in Bosnia and Herzegovina. There is a need for large well designed study on GDM prevalence and its other features. PMID- 27999479 TI - SIDE TO SIDE DIFFERENCES BETWEEN DOMINANT AND NON-DOMINANT ARM'S BONE DENSITY AND ISOMETRIC HANDGRIP STRENGTH IN MALES AND FEMALES AGED 40-65 YEARS OLD. AB - OBJECTIVE: This observational, cross-sectional study, investigates and compares the differences of BMD, T-score, Z-score and isometric strength between dominant (D) versus non-dominant (ND) arms of 162 subjects aged 40-65 in a developing, low income country (Kosova). MATERIAL AND METHODS: Bone Mineral Density (BMD), T score and Z-score at distal forearm regions of both arms (measured by DXA scan), together with the Handgrip Isometric Strength (HIS) (by handgrip) were evaluated in a total subjects (53 Males and 109 Females). Additionally, General Healthcare Status Questionnaire together with self-administrated International Physical Activity Questionnaire (IPAQ) were filled. RESULTS: Significant differences (p<0.05) between arms were found in BMD, T-score, and Z-score in total subjects and in females, whereas not significant differences (p>0.05) were observed in Males BMD comparing to significantly higher results (p<0.05) in T-score and Z score. Significant differences (p<0.05) were also found in total subjects and in females handgrip, but not (p>0.05) in males. When comparing the total subject's BMD, T-score, Z-score and Handgrip based on the PA levels (1 to 3 according to IPAQ scoring) no significant differences (p>0.05) were found between PA1, as well as PA3 whereas significantly differences (p<0.05) were found in D arms of PA2 level. CONCLUSION: The study analyses side-to-side differences in bone density and muscular force between D and ND arms amongst a population which is frequently exposed to diagnostic screenings for age related osteomuscular conditions (aged 40-60), and demonstrates that these differences should be in consideration amongst clinicians, but not in the way it is done right now. PMID- 27999480 TI - THE EFFECT OF PERCEIVED SOCIAL SUPPORT ON HEMODIALYSIS PATIENTS' QUALITY OF LIFE. AB - BACKGROUND: Association between perceived social support and quality of life in hemodialysis patients represents a new area of interest. AIM: The aim of this study was to explore the effect of social support on the quality of life of hemodialysis patients. MATERIAL AND METHODS: In this study 258 hemodialysis patients were enrolled. Data was collected using a questionnaire which consisted of three parts: a) the Multidimensional Scale of Perceived Social Support (MSPSS) to assess perceived social support, b) the Missoula-VITAS Quality of Life Index (MVQOLI-15) to assess quality of patients' life and c) the socio-demographic, clinical and other variables of patients. To test the existence of association between quality of life and social support the correlation coefficient of Spearman was used. Multiple linear regression was performed to estimate the effect of social support on quality of life (dependent variable), adjusted for potential confounders. The analysis was performed on SPSS v20. RESULTS: Patients felt high support from significant others and family and less from friends (median 6, 6 and 4.5 respectively). Patients evaluated their quality of life in its entirety as moderate in the total and "overall quality of life" score (median 17.2 and 3 respectively). Regarding the association between social support and quality of life, results showed that the more support patients had from their significant others, family and friends, the better quality of life they had. (rho =0,395, rho =0,399 and rho=0,359, respectively). CONCLUSIONS: Understanding the relation between social support and quality of life should prompt health professionals to provide beneficial care to hemodialysis patients. PMID- 27999482 TI - A COMPARATIVE STUDY BETWEEN POVIDONE-IODINE AND MANUGEL 85 ON SURGICAL SCRUB. AB - BACKGROUND: Direct transmission through skin contact is one of ways for disease transmission. Medical staffs have contact with many patients, so their hand can be a factor for the transmission of disease. Surgical scrub is a process that leads to destruction immigrant and stable microbus of hands and arms through friction washing by use of antiseptic solution prior to surgery. The aim of this study was to compare the effectiveness of disinfection of Povidone-Iodine and Manugel 85 in surgical scrub. METHODS: This study was a clinical trial that done before and after Surgical scrub. 33 person of surgical team in hospital were surveyed during. Four samples were done for every person: first before surgical scrub with Povidone-Iodine solution, second immediately after surgical scrub, then after one week third test done before surgical scrub with Manugel 85, and forth one immediately after surgical scrub. Paired t-test was used for statistical analysis and SPSS analysis. RESULTS: Data analysis showed that the effect of Povidone-Iodine and Manugel 85, separately, before and after surgical scrub on number of colonies is significant. But the effect of these two solutions on behalf of number of colonies was not significant. The 100% grown cultures before surgical scrub with Povidone-Iodine solution and 90.91% before surgical scrub with Manugel 85 were staphylococcus. CONCLUSION: The disinfection effect of Povidone-Iodine and Manuge l85 on surgical scrub is the same. PMID- 27999481 TI - COMPARISON OF PATIENTS' ADMISSION, MEAN AND HIGHEST SOFA SCORES IN PREDICTION OF ICU MORTALITY: A PROSPECTIVE OBSERVATIONAL STUDY. AB - BACKGROUND: Use of valid criteria for evaluation of patients admitted to intensive care unit (ICU) is essential to assess the quality of services provided. This study was conducted to evaluate admission, mean and the highest Sequential Organ Failure Assessment (SOFA) scores in predicting mortality and outcome of patients admitted to the ICU. METHODS: This prospective observational study was conducted on 300 patients admitted to the ICU of Imam Khomeini Hospital, Sari, Iran, in 2015. The SOFA tool was applied at the beginning of the admission of patients in the ICU and then every 24 hours. Functions of six vital organs were recorded on a daily basis for scoring with SOFA. Demographic profile, the main diagnosis leading to hospitalization in the ICU, previous interventions, complications and hospital outcomes were recorded for each patient. The patients' admission, mean and highest SOFA scores were also evaluated and recorded during the study period. These scores were compared between deceased and survived patients. ROC curve determined the best cut-off point of score calculated. RESULTS: Among all 300 patients who were enrolled in the study, 189 (63%) cases were males. Trauma was the most common cause of hospitalization and mortality. Thirty point seven percent of 92 deceased patients needed to intubation. Mean length of ICU and hospital stay were significantly longer for deceased patients than the survivors (P <0.001). The admission, mean and highest SOFA scores were 11.72, 16.38 and 16.45 in deceased patients, as well as 6.52, 5.82 and 6.5 in survived patients, respectively. The area under the curve (AUC) for the admission, mean and highest SOFA scores were 0.875, 0.988 and 0982, respectively. All three models were able to predict the outcome of patients significantly (P <0.0001). The cut-off point of 10.6 for the mean SOFA had the highest sensitivity and specificity in predicting mortality. CONCLUSION: The results of this study showed that the mean SOFA score had the highest sensitivity and specificity in prediction of ICU mortality. Therefore, this criterion is a valuable indicator to better predictions of mortality and morbidity rate in the ICU patients, which can lead to appropriate health care and therapeutic interventions in these patients. PMID- 27999483 TI - LEVEL OF COMPETENCIES OF FAMILY PHYSICIANS IN KOSOVO FROM DIFFERENT PERSPECTIVES. AB - AIM: The aim of this analysis was to compare the level of self-perceived competencies of primary health care physicians in Kosovo with patients' viewpoint, as well as the necessary (required) level of such competencies from decision-makers' standpoint. METHODS: Three cross-sectional studies were carried out in Kosovo in 2013 including: i) a representative sample of 1340 primary health care users aged >=18 years (49% men; overall mean age: 50.5+/-17.9 years; response rate: 89%); ii) a representative sample of 597 primary health care physicians (49% men; overall mean age: 46.0+/-9.4 years; response rate: 90%), and; iii) a nationwide representative sample of 100 decision-makers operating at different primary health care institutions or public health agencies in Kosovo (63% men; mean age: 47.7+/-5.7 years). A structured self-administered questionnaire (consisting of 37 items) was used in the three surveys in order to assess physicians' competencies regarding different domains of the quality of health care. RESULTS: There was a significant gap in the level of self-perceived physicians' competencies and patients' perspective in transitional Kosovo. Furthermore, there was a gap in the level of self-perceived physicians' competencies and the necessary (required) level of physicians' competencies from decision-makers perspective which was less evident in Prishtina, but considerable in the other regions of Kosovo. CONCLUSION: Our analysis provides valuable evidence about the level of competencies of primary health care physicians in Kosovo from different stakeholders' perspectives. There is an urgent need for continuous professional development of family physicians in post-war Kosovo. PMID- 27999484 TI - EFFECTS OF HOME-CARE TRAINING ON THE SELF-EFFICACY OF PATIENTS WITH BETA THALASSEMIA MAJOR. AB - BACKGROUND: The self-efficacy of thalassemia patients is an important factor in creating behavioral changes in such patients. Home-care training reduces hospitalization duration as well as relevant costs and improves disease outcomes. This study was designed to assess the effect of home-care training on the self efficacy of patients with beta thalassemia major. METHODOLOGY: This was a quasi experimental, case-control, before and after intervention study conducted on 136 thalassemia cases from January 2014 to October 2015. Data was collected through Shere general self-efficacy questionnaire (SGSES). Home-care trainings were provided in the form of training courses with respect to the training needs of thalassemia major cases. Two (2) months after the end of training courses, SGSES questionnaire was filled again and the obtained data was analyzed by SPSS 21 as well as descriptive-inferential statistics (significance level=P<=0.05). RESULTS: The results of this study revealed that the mean self-efficacy score of control group was 48.69+/-6.82 before intervention which increased to 46.69+/-6.81 after intervention. The mean self-efficacy score of case group was 44.58+/-5.23 before intervention which increased to 49.5+/-6.66 after intervention. The rise of self efficacy score, after intervention, was significantly higher in the case group compared with the control group (P<=.001). CONCLUSION: According to results, home care training can develop self-efficacy in thalassemia patients. In home-care training procedure patients play an active role. By providing home-care trainings, therefore, an effective step should be taken to promote the self efficacy of the patients and to decrease associated problems. PMID- 27999485 TI - EFFECT OF PERCEIVED SOCIAL SUPPORT ON THE LEVELS OF ANXIETY AND DEPRESSION OF HEMODIALYSIS PATIENTS. AB - PURPOSE: of this study was to explore the effect of social support on the levels of anxiety and depression of hemodialysis patients. MATERIAL AND METHODS: 258 patients undergoing hemodialysis were enrolled. A questionnaire developed for the purpose of the study was used to collect data through the interview process. Apart from socio-demographic, clinical and other characteristics, the questionnaire also included the Multidimensional Scale of Perceived Social Support (MSPSS) to assess social support from significant others, family and friends, and the questionnaire Hospital Anxiety and Depression Scale (HADs) to assess the levels of anxiety and depression of patients. RESULTS: 53,9% of the participants were male while 34,1% of the participants were >70 years old. 32,9% and 30,2% of the participants felt high levels of anxiety and depression, respectively. Analysis of data showed a statistically significant association between anxiety/depression and social support from significant others, family and friends (p=<0,001 for all associations). In particular, patients with high levels of anxiety and depression felt less support from their significant others, family and friends. The multinomial logistic regression, showed a statistically significant effect of social support from friends in anxiety levels (p=0,004). An one point increase of the support from friends seems to reduce by 57% the probability of having high levels of anxiety. In addition, statistically significant effect of social support from significant others, family and friends was observed on the levels of depression (p=<0,001, p=0,001 & p=0,003, respectively). Specifically, an one point increase of the support from significant others, family and friends it was found to reduce by 77%, 71% and 56% respectively the probability of experiencing high levels of depression. CONCLUSIONS: Phyco-social evaluation is essential when providing holistic care to hemodialysis patients. PMID- 27999486 TI - IDENTIFYING ELEVEN FACTORS OF SERVICE MARKETING MIX (4PS) EFFECTIVE ON TENDENCY OF PATIENTS TOWARD PRIVATE HOSPITAL. AB - INTRODUCTION: One of the important factors of correct management is to identify the reasons for patient tendency toward private hospitals. This study measures these factors based on service marketing mixes. PATIENTS AND METHODS: This study used a cross sectional descriptive methodology. The study was conducted during 6 months in 2015. The studied population included patients of private hospitals in Tehran. Random sampling was used (n = 200). Data was collected by an author-made questionnaire for service marketing factors. Reliability and validity of the questionnaire were confirmed. Data analysis was done using factor analysis test in SPSS 20. RESULTS: The results showed that constant attendance of physicians and nurses has the highest effect (0.707%) on patient tendency toward private hospitals. PMID- 27999487 TI - ORAL HEALTH OF DOWN SYNDROME CHILDREN IN BOSNIA AND HERZEGOVINA. AB - INTRODUCTION: The objective of this study was to determine the oral health condition Down syndrome (DS) children in Bosnia and Herzegovina, by analizing oral health of Down syndrome individuals in two largest regions, Sarajevo and Tuzla Canton. PATIENTS AND METHODS: Caries and oral health status of Down syndrome children aged 6-18 years were examined and assessed according WHO 1997 criteria. DS individuals were divided in to four age groups: I (0-6 yrs); II (7 12 yrs); III (13-18 yrs). RESULTS: The mean dmft/DMFT index for age group I is (6,40+/-6,05); II (2,05+/-2,04) and III (10,30+/-6,80). The analysis of oral hygiene of Down syndrome children by using the debris index, it was found that 43,9% have very good oral hygiene, 33,3% respondents have good oral hygiene, 15,8% were with poor oral hygiene, while the very poor hygiene had 7% subjects. By using Pearson's correlation to the value of DMFT, debris index and age of examinees with Down syndrome, it is established a statistically significant positive correlation between analyzed variables. Values of CPI index according to age groups were as follows: I (0,1); II (0,17) and III group (0,4). PMID- 27999488 TI - THE INFLUENCE OF INFORMATION AND RELIGION ON ORGAN DONATION, AS SEEN BY SCHOOL TEACHERS IN BOSNIA AND HERZEGOVINA. AB - INTRODUCTION: Transplantation of organs is the treatment of choice for severe organ failure worldwide. AIM: The aims of the present study were to determine the influence of religion on attitudes towards organ donation among staff at schools in Tuzla. MATERIAL AND METHODS: In the Tuzla region there are 42 schools and 1580 school staff. A total of 21 schools were selected randomly, which were stratified by geographical location. 499 employees were invited to participate in the study, and 475 agreed to participate. According to the definition of their attitude towards religion the subjects were divided into three groups: non-religious, only religious and practical believers. RESULTS: None of the subjects possesses a donor card. To the question whether the subjects support the idea of organ transplantation, most replied that they support the idea of donating organs both during life and after death. Regarding this question there is a significant difference between the groups (p = 0.0063). To the question whether they are prepared to donate an organ of a deceased family member, most replied that they would consent to donating an organ, whilst a significant number also replied that they were not sure. The results show that there is no significant difference between the replies given by the groups (p = 0.7694). To the question regarding to whom they were prepared to donate an organ, most said they were prepared to donate one to a member of their family, then to a close relative, whilst the least would donate to a stranger. The results show that there is a significant difference between the groups (p = 0.0002). CONCLUSION: In order to reduce the wide disparity between the need and organ donation amongst other things a more active relationship is necessary between health workers, religious officials and school staff. PMID- 27999489 TI - NEUTROPHIL/LYMPHOCYTE RATIO AND PLATELET/LYMPHOCYTE RATIO IN PATIENTS WITH NSCLC. AB - OBJECTIVE: to compare neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in patients with NSCLC (Non- Small- Cell Lung Cancer): with and without metastases at the time of diagnosis to find out if there is the importance of these cell ratios in the assessment of severity NSCLC. MATERIAL AND METHODS: this is the retrospective analysis of NRL and PRL in patients with NSCLC at the time of the diagnosis of disease before any anti tumor treatment (chemotherapy, radiotherapy, surgery). 57 of patients with NSCLC treated in the first three months of 2016. year were chosen at random regardless of sex and age. We examined full blood count cells (FBC), calculated NLR and PLR in every patient and compared obtained values in patients with and patients without metastases. RESULTS: In 57 patients with NSCLC there were 15 males with metastases, 28 without metastases, and 8 females with metastases, 6 without metastases. Since there was no regularity in the distribution of obtained values of NLR and PLR we made the Mann-Whitney U test. Mean values are presented with a median and interquartile percentiles. There was no significant difference in NLR between patients without and with metastases (p = 0.614; p = NS) as well as in PLR (p=0,068; p=NS). CONCLUSION: There must be a link between the immune status of the organism and lung cancer development. Immune cells have become of interest in recent years and much work has been done to study their role in the genesis of cancer but it did not give satisfactory results. Further clinical studies on large number of patients and further laboratory examination of the role of immune cells in cancer development and suppression are required. PMID- 27999490 TI - PREDICTORS FOR POST- STROKE DELIRIUM OUTCOME. AB - BACKGROUND: There have been only a small number of studies that have evaluated the outcome of post-stroke delirium. OBJECTIVES: To evaluate the effects of gender, age, stroke localization, delirium severity, previous illnesses, associated medical complications on delirium outcome as well as, to determine effects of delirium on cognitive functioning one year after stroke. PATIENTS AND METHODS: Comprehensive neuropsychological assessments were performed within the first week of stroke onset, at hospital discharge, and followed-up for 3, 6 and 12 months after stroke. We used diagnostic tools such as Glazgow Coma Scale, Delirium Rating Scale, National Institutes of Health Stroke Scale and Mini-Mental State. RESULTS: Patients who developed post-stroke delirium had significantly more complications (p = 0.0005). Direct logistic regression was performed to assess the impact of several factors on the likelihood that patients will die. The strongest predictor of outcome was age, mean age >= 65 years with a odds ratio (OR) 4.9. Cox's regression survival was conducted to assess the impact of multiple factors on survival. The accompanying medical complications were the strongest predictor of respondents poore outcome with Hazard-risk 3.3. Cognitive assessments including Mini Mental State score have showen that post-stroke delirium patients had significant cognitive impairment, three (p = 0.0005), six months (p = 0.0005) and one year (p = 0.0005) after stroke, compared to patients without delirium. CONCLUSION: Patient gender, age, localization of stroke, severity of delirium, chronic diseases and emerging complications significantly affect the outcome of post- stroke delirium. Delirium significantly reduced cognitive functioning of after stroke patients. PMID- 27999491 TI - RELIABILITY, VALIDITY, AND PSYCHOMETRIC PROPERTIES OF THE GREEK TRANSLATION OF THE CAMBRIDGE DEPERSONALIZATION SCALE (CDS). AB - INTRODUCTION: The Cambridge Depersonalisation Scale is meant to capture the frequency and duration of depersonalisation symptoms over the 'last 6 months'. METHODS: In order to develop a Greek version of CDS scale, the CDS scale was translated in Greek by 2 psychiatrists. Then, the Greek version of CDS scale was back-translated by a person who did not knew the original English version. The back-translated version was reviewed in order to establish whether is consistent with the original English version. After this procedure we administered the Greek version of CDS scale to a sample of 294 Greeks in order to assess the reliability and the validity of the Greek version of scale. RESULTS: The five components solution accounted for 58.204% of the total variation. Initial eigenvalues of the five components were: factor 1=11.555, factor 2=1.564, factor 3=1.356, factor 4=1.247 and factor 5=1.157. Six items did not load on any factor. Correlations between factors were low ranged from 0.134 to 0.314 and no complex variables were found. Cronbach's alpha and Guttman split-half coefficient were used to evaluate interval consistency of CDS scale in 294 individuals. The alpha coefficients and Guttman split-half coefficient of the CDS scale were 0.938 and 0.921, respectively. The test-retest reliability proved to be satisfactory. The intraclass correlation coefficients for the total CDS score was very good and equal to 0,883. The CDS scale correlated highly with the SCL-90 and all subscales (p-value<0.0001). CONCLUSION: The psychometric strength of CDS - Greek its reliable for its future use, particularly for screening for subjects with possible diagnosis of CDS. PMID- 27999492 TI - EVALUATION OF DENTURE-RELATED FACTORS PREDISPOSING TO DENTURE STOMATITIS IN A LEBANESE POPULATION. AB - BACKGROUND: Denture stomatitis is a common fungal oral infection of multifactorial etiology. Denture-related factors such as denture's age, hygiene, night wearing and colonization by Candida albicans are known to predispose to denture stomatitis. The aim of this study was to evaluate these factors and their relationship with the occurrence of denture stomatitis in a Lebanese population. MATERIAL AND METHODS: Sixty patients (40 women, 20 men; age range 40-80 years) showing clinical evidence of denture-related stomatitis were selected for this study. Swab samples from the palate and the palatal surfaces of the upper dentures of these patients were collected and examined mycologically. Denture's age, hygiene, night wearing and colonization by Candida albicans were evaluated and analyzed statistically. RESULTS: The statistical analysis showed a significant role for denture's hygiene, night wearing, and colonization by Candida albicans in the installation of the denture stomatitis. Patient's gender and age, as well as the denture's age, were not significant predictors of the disease. CONCLUSION: In a sample of Lebanese population, poor denture hygiene, continuous denture use, and Candida denture colonization are important etiological factors that contribute to denture stomatitis. PMID- 27999494 TI - From the Editor's Desk: A Focus on Orthopedics and Sports Medicine. PMID- 27999493 TI - ECONOMIC IMPORTANCE OF THE PREVENTIVE MEASURES IN DENTISTRY. AB - INTRODUCTION: Previous studies have shown that the state of oral health in the area of Podrinje Canton is really poor. Taking into account that in the last five years are implemented two projects in the municipality it is necessary to examine the impact of preventive measures in dentistry on the oral health. THE RESEARCH GOALS ARE: a) To evaluate the impact of continuing education and local fluoridation on the state of oral health; b) To analyze the economic importance of preventive measures. THE EXAMINEES AND METHODS: For the purpose of the research on activities of continuing education on the importance of oral health and local fluoridation of teeth and to determine the economic aspects of the application of preventive measures is tested and reviewed 900 students from fourth to ninth grade. The children were divided into three groups of 300 students in each group: a) In the first group of children is carried out continuous education about proper tooth brushing and the importance of oral hygiene and local fluoridation twice a year during the last three years, b) In the second group children carried out local fluoridation twice a year during the last three years while in the third group, there were no continuous prevention measures; c) Used is a single questionnaire for all respondents. Data obtained in this study were analyzed by descriptive and inferential statistical methods. THE RESULTS AND CONCLUSIONS: The importance of continuing education and local fluoridation is clearly reflected in the different values DMF-index, which was the subject of research. In the first group, in which is carried out continuous education and local fluoridation value of DMF index was 2.7, in the second group with local fluorination this value was 3.56, while in the third group, in which is not implemented preventive measures, the value DMF- index was 5.93. From an economic point the preventive measures are the cheapest, most effective and the best solution in order to maintain oral health. PMID- 27999495 TI - Letters to the Editor. PMID- 27999496 TI - Bioethics in Practice: Therapeutic Misconception. PMID- 27999497 TI - Clinical Images: Imaging Manifestations of Orbital Neurofibromatosis Type 1. PMID- 27999498 TI - Erratum. AB - [This corrects the article on p. 473 in vol. 15, PMID: 26730237.]. PMID- 27999499 TI - Perineural Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Upper Extremity Orthopedic Surgery: A Prospective and Randomized Pilot Study. AB - BACKGROUND: Upper extremity surgery is commonly performed in the ambulatory setting and is associated with moderate to severe postoperative pain. METHODS: Patients scheduled for upper extremity orthopedic surgery with a peripheral nerve block were randomized to receive either an ultrasound-guided single-injection supraclavicular block or ultrasound-guided median, ulnar, and radial nerve blocks (forearm blocks) performed at the level of the mid to proximal forearm with liposomal bupivacaine (Exparel) combined with a short-acting supraclavicular block. A sham block was performed in an attempt to blind enrollees in the control group. We administered the EuroQol 5D-5L questionnaire preoperatively and on postoperative days 1-3 and considered the results the primary outcome of our investigation. Block procedure times, postanesthesia care unit (PACU) length of stay, instances of nausea/vomiting, need for narcotic administration, and patient satisfaction were also assessed. RESULTS: We observed no significant differences in postoperative EuroQol scores between the 2 groups and no significant differences in patient demographics, PACU length of stay, or side effects in the PACU. In some instances, the short-acting supraclavicular block resolved in the PACU, and these patients reported higher pain scores and required titration of analgesics prior to discharge. CONCLUSION: Larger prospective studies are needed to determine the safety and efficacy of liposomal bupivacaine in patients undergoing upper extremity surgery. Liposomal bupivacaine is currently only approved for local anesthetic infiltration use. PMID- 27999501 TI - Axillary Block-Induced Chemical Sympathectomy in the Setting of Digital Ischemia. AB - BACKGROUND: Digital ischemia is associated with several rheumatologic disorders and is often difficult to treat. Symptoms and sequelae can include pain, disability, need for amputation, and poor quality of life. METHODS: Patients diagnosed with digital ischemia were referred for an ultrasound-guided axillary nerve block using liposomal bupivacaine (Exparel, Pacira Pharmaceuticals). The primary outcome measure was radial and ulnar artery diameter preprocedure and postprocedure. Doppler waveform analyses were performed to measure arterial diameter and blood flow velocity. The QuickDASH questionnaire was administered to evaluate upper extremity function and perceived disability. RESULTS: Mean radial and ulnar artery diameters increased from 0.19 cm and 0.16 cm to 0.23 cm and 0.20 cm, respectively, 1 hour postprocedure. Concomitant increases in blood flow velocities and hand temperature and lower pain scores were also noted. Although pain generally returned to baseline after 1 week, QuickDASH symptom/disability scores improved at 30 days, and 2 patients' ischemic symptoms resolved spontaneously during the study period in the absence of other interventions. CONCLUSION: Data regarding chemical sympathectomy using regional anesthesia are limited at this time. Our experience suggests a potential role in the treatment and evaluation of digital ischemia. Patients with digital ischemia from rheumatologic conditions appeared to have a greater benefit from a chemical sympathectomy than patients whose conditions had an atherosclerotic or anatomic etiology. Even when the vasodilatory effects are transient, such an intervention may be useful when a more permanent option such as surgical sympathectomy is being considered. Liposomal bupivacaine is only approved for surgical infiltration at this time. PMID- 27999500 TI - Benefits of Limited Use of a Tourniquet Combined With Intravenous Tranexamic Acid During Total Knee Arthroplasty. AB - BACKGROUND: Blood loss during total knee arthroplasty (TKA) may require blood transfusions that are associated with increased risk, morbidity, and cost. Multiple techniques exist to reduce blood loss in TKA, including the use of a tourniquet and tranexamic acid (TXA). While multiple studies suggest that TXA is effective in reducing blood loss, the use of a tourniquet is more controversial. We studied the combined effect of TXA with a limited-use tourniquet on blood loss and complications in the setting of primary TKA. METHODS: A retrospective review of a prospectively gathered arthroplasty database from a single institution was performed. We compared our limited-use cohort data with the published results of randomized controlled trials evaluating the effectiveness of tourniquets used during the entire TKA procedure. RESULTS: Fifty-one procedures from our institution's database met the inclusion criteria. TXA (administered in a single 15-mg/kg dose) with limited tourniquet use (a mean duration of 26.3 minutes) resulted in an average intraoperative estimated blood loss of 94.7 mL. The mean decrease in hemoglobin from the preprocedure baseline to postoperative day 1 was 2.6 +/- 0.9 g/dL (P<0.001), and only 2 of the 51 procedures required a blood transfusion. When compared to recent randomized controlled trials, the 51 procedures demonstrated lower levels of blood loss, similar operative time, and no increase in morbidity or mortality. CONCLUSION: Our study results suggest that using TXA in combination with a tourniquet during the cementation portion only of a TKA provides a reasonable operative time and low intraoperative blood loss without increasing perioperative morbidity or complications. PMID- 27999503 TI - Factors Affecting the Union of Opening Wedge High Tibial Osteotomy Using a Titanium Wedge Plate. AB - BACKGROUND: Factors that can affect the success rate of high tibial osteotomy (HTO) include patient selection, surgical technique, type of fixation hardware, supplemental fixation, choice of bone graft, and rehabilitation protocol. The purpose of this study was to define the role of cortical hinge fractures in the risk of nonunion and collapse of opening wedge high tibial osteotomy. METHODS: A total of 60 patients (mean age, 40 years) who underwent 64 primary HTO procedures were identified from our operational database and observed at a mean follow-up of 2 years. Surgical correction was followed by immediate range of motion and a progressive weight-bearing protocol. Clinical and radiographic data were reviewed for patient demographics, bony union, cortical hinge fractures, loss of correction, and other complications. RESULTS: The average time to radiographic union was 14.8 weeks (range, 8-24). Loss of correction and/or collapse occurred in 6 cases (9.4%). Nine unrecognized cortical hinge fractures were retrospectively identified, of which 4 resulted in nonunion and collapse. We found a significantly higher incidence of unrecognized cortical hinge fractures in cases that collapsed (4/6, 66.7%) compared to cases that healed uneventfully (5/58, 8.6%) (P=0.003). CONCLUSION: A high index of suspicion must be maintained intraoperatively and postoperatively to identify and treat unstable constructs that increase the risk of nonunion and collapse after opening wedge HTO. This study's patient series explores the relationship between cortical hinge fracture and patient outcomes in the clinical setting by demonstrating a significantly higher rate of collapse and nonunion with unstable constructs. PMID- 27999502 TI - Pain, Functional Scores, and Radiographic Severity of Illness Influence the Perception of Time Spent With the Physician by Patients Presenting for Initial Evaluation of Knee Osteoarthritis. AB - BACKGROUND: Patient satisfaction has become a significant factor in reimbursement schedules for physicians. A matter of debate is whether the patient's perception of time spent with the physician improves patient satisfaction. We sought to determine whether patient-physican time correlates with patient satisfaction and which factors are associated with patient perception of time. METHODS: A total of 73 patients who presented for an initial evaluation of knee osteoarthritis were evaluated by the same orthopedic surgeon at an outpatient clinic in New Orleans, LA. Each encounter was timed with a stopwatch. After the physician encounter, patients were asked to fill out a questionnaire assessing their perception of time spent with the physician, subjective pain, satisfaction with the visit, and understanding of the diagnosis and treatment plan. Patients were also asked to complete 4 functionality surveys. Radiographs of the patients' knees were taken and quantified using Kellgren-Lawrence and Ahlback grading scales. RESULTS: We noted no relationship between patient satisfaction and patients' perception of time spent with the physician. Patients perceived their time with the physician to be an average of 6.5 minutes more than the actual time. However, patients who reported higher subjective pain scores (>7 on a 10-point scale) misestimated their time with the physician by nearly 96%, while patients with lower subjective pain scores (<7 on a 10-point scale) misestimated their time with the physician by only 54% (P<0.007). We discovered similar findings in patients with worse Kellgren-Lawrence radiographic scores as well as worse Oxford Knee Scores and Knee injury and Osteoarthritis Outcome Scores. The actual time spent was not different among patients. CONCLUSION: Patients with greater subjective pain and worse functional status and patients with worse radiographic severity of knee osteoarthritis perceived greater time spent with the physician. However, no relationship between these variables and patient satisfaction scores was seen. PMID- 27999504 TI - Neurectomy Outcomes in Patients With Morton Neuroma: Comparison of Plantar vs Dorsal Approaches. AB - BACKGROUND: Morton neuroma is a compressive neuropathy of the plantar digital nerve. Several surgical approaches have been used to treat painful Morton neuroma, with each approach having distinct advantages and disadvantages. For this study, we used validated outcome assessment tools to retrospectively compare patient satisfaction with 2 approaches. METHODS: The medical records and survey responses of 37 patients with 42 neuromas were evaluated with respect to outcomes and patient satisfaction after neurectomies performed through either a plantar or dorsal surgical approach by one Ochsner Clinic Foundation attending physician. Outcomes were evaluated using the 36-Item Short Form Health Survey (SF-36) and the Foot Function Index (FFI) self-assessments. RESULTS: Twenty patients underwent neurectomy through a dorsal approach, and 17 patients underwent neurectomy through a plantar approach. We found no statistically significant differences between the dorsal and plantar approach groups with respect to outcomes and patient satisfaction as measured by the SF-36 or the FFI. CONCLUSION: This study supports the use of either the plantar or dorsal approach for the resection of Morton neuroma and suggests that a plantar approach for neurectomy can produce satisfactory results. PMID- 27999505 TI - Osteochondral Allograft Transplantation for Femoral Trochlear Dysplasia. AB - BACKGROUND: The risk factors for patellofemoral joint instability include laxity of medial patellar restraints, abnormal limb geometry, femoral and tibial malrotation, patella alta, and trochlear dysplasia. Femoral trochlear dysplasia is characterized by a hypoplastic or shallow trochlear groove. CASE REPORT: We report the case of a 31-year-old female with trochlear dysplasia and recurrent patella dislocations, laxity of the medial patellofemoral ligament (MPFL), and high-grade chondromalacia of the trochlea and the patella. Surgical treatment goals were to re-create a trochlear groove, restore bony restraint, and realign and offload the patella. First, a triplane tibial tubercle osteotomy (TTO) was performed, and the patella was everted 360 degrees with a subvastus approach. The MPFL was reconstructed using a gracilis allograft. A fresh osteochondral allograft transplant trochlea was sized, and a 35-mm diameter graft was transplanted to re-create the groove. The TTO was secured in a new anterior, medial, and distal position. The patient was braced for 6 weeks and completed a rehabilitation protocol. At 9-month follow-up, she had made significant gains in range of motion (0 degrees -140 degrees ) and activity compared to her preoperative status. She reported no pain or recurrent dislocations. CONCLUSION: This case demonstrates a viable surgical option for treatment of instability resulting from trochlear dysplasia with patellofemoral chondromalacia. The osteochondral allograft transplantation surgery technique allows patients to have a stable, pain-free knee joint and participate in activities compared to nonoperative management. However, the long-term outcomes of this procedure are unknown. PMID- 27999506 TI - Preoperative Acute Inflammatory Markers as Predictors for Postoperative Complications in Primary Total Knee Arthroplasty. AB - BACKGROUND: C-reactive protein (CRP) has been suggested as an independent risk factor for cardiovascular pathology in the nonsurgical setting. While postoperative CRP and erythrocyte sedimentation rate (ESR) have an established role in aiding the diagnosis of periprosthetic joint infections, some authors suggest a link between preoperative CRP and postoperative complications in patients undergoing total joint arthroplasty. METHODS: We conducted a retrospective cohort study of 351 patients who underwent unilateral primary total knee arthroplasty by a single surgeon during a 28-month period (January 2013 through April 2015). Patient medical records were reviewed for the following complications occurring within 90 days postoperatively: myocardial infarction, arrhythmia, pulmonary embolism, wound infection, acute renal failure, and reoperation. RESULTS: We found no statistically significant link between postoperative complications and preoperative CRP levels (P=0.5005) or ESR levels (P=0.1610). CONCLUSION: The results of this study do not support the routine inclusion of CRP and ESR analysis as part of the preoperative evaluation for elective total knee arthroplasty. PMID- 27999507 TI - The Penumbra 5MAX ACE Catheter Is Safe, Efficient, and Cost Saving as a Primary Mechanical Thrombectomy Device for Large Vessel Occlusions in Acute Ischemic Stroke. AB - BACKGROUND: Reperfusion of large vessel occlusions in acute stroke can improve patient outcomes. The purposes of this study were to assess the safety and efficacy of the Penumbra 5MAX ACE catheter for revascularization of large vessels and to compare its cost to the cost of stent retrievers. METHODS: In this retrospective, single-center case review study, data were captured on consecutive patients treated with the Penumbra 5MAX ACE as first-line therapy during an 11 month period. Good functional outcome was defined as a modified Rankin Scale score of <=2 at discharge. Results were directly compared with previously published data for stent retrievers, and length of stay was analyzed in relation to revascularization. RESULTS: The 31 patients studied had a mean age of 66.3 +/- 17.8 years and a mean National Institutes of Health Stroke Scale score of 19.4 +/ 5.7. Intravenous tissue recombinant plasminogen activator therapy was initiated in 35.5% (11/31) of patients. A Thrombolysis in Cerebral Infarction (TICI) grade of 2b-3 reperfusion after endovascular therapy was achieved in 26/31 (83.9%) of cases; TICI grade 3 was achieved in 19/31 (61.3%) patients. The average time from groin puncture to TICI grade 2b-3 reperfusion was 40 minutes. The average estimated cost for aspiration with the 5MAX ACE alone was $4,916 per case compared with an estimated cost of $9,620 if a stent retriever was used as the primary device. Our actual average cost per case, including all adjunctive devices used in the neurointerventional procedure, was $6,997. Good functional outcome was achieved in 19/31 (61.3%) patients. Two patients experienced symptomatic intracerebral hemorrhage (6.5%), and 1 (3.2%) patient died. The length of stay was significantly shorter among patients with TICI grade 2b-3 reperfusion compared to patients with TICI grade <2 (6.8 +/- 5.34 days vs 15.8 +/ 11.32 days, respectively; P<0.05). CONCLUSION: These findings suggest that direct aspiration with the large-bore 5MAX ACE catheter can be considered a first line approach to mechanical thrombectomy for large vessel occlusions. Our results demonstrated high rates of successful reperfusion in a timely manner with excellent clinical outcomes, although our sample size was small. In addition, this direct-aspiration technique has important cost-savings potential compared to stent retrievers. PMID- 27999508 TI - Validation of the Patient Global Impression of Improvement for Penile Prosthesis. AB - BACKGROUND: No consensus on the preferred means of evaluating patients after surgical placement of an inflatable penile prosthesis (IPP) currently exists. Many self-assessment questionnaires are available, but none specifically targets patients with IPPs. The purpose of this study was to assess the construct validity of the Patient Global Impression of Improvement (PGI-I) for evaluating patient satisfaction after placement of an IPP. METHODS: We conducted a multicenter prospective trial and enrolled patients who elected to have a 3-piece IPP surgically implanted. Postoperatively, patients completed the Sexual Health Inventory for Men (SHIM), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), and PGI-I at 3, 6, and 12 months. The Pearson correlation coefficient (PCC) was used to compare scores over time. RESULTS: Fifty-six patients were enrolled, and complete data were available for 39 patients. At 3 months, the PGI-I correlated with the EDITS (PCC=0.83, P<0.01) and with the SHIM (PCC=0.73, P<0.01). At 6 months, the PGI-I correlated with the EDITS (PCC=0.74, P<0.01). At 6 months, the PCC between the PGI-I and the SHIM was 0.41 (P<0.05). At 12 months, the PCC between the PGI-I and the EDITS was 0.83 (P<0.01), and the PCC between the PGI-I and the SHIM was 0.61 (P<0.01). CONCLUSIONS: Overall, the PGI-I appears to correlate with both the SHIM and EDITS and is a valid evaluation tool for use with patients after IPP placement. PMID- 27999509 TI - The Close Exposure to Radiology Program: Educational Benefits to Medical Students. AB - BACKGROUND: Radiology clerkships during medical school provide a suboptimal training experience in the Chinese medical doctor training program. Staff radiologists are heavily occupied with clinic tasks which decreases teaching quality. The close exposure to radiology program (CERP) is a novel pathway designed to improve teaching quality, yet students' expectations of the potential benefits of such a program and their willingness to join CERP still have not been investigated among Chinese medical students. METHODS: A survey was conducted among medical students of both sexes with various majors and at different levels of training. The students were asked to identify the potential benefits of CERP as well as to indicate if they were willing to join CERP. RESULTS: Of the 1,600 surveys distributed to medical students, 1,394 were returned and analyzed. Most of the returned surveys were from males (1,268, 91%), and most respondents had not had a radiology clerkship experience (1,376, 99%). Most responding students were in a 5-year training program (94%) and in their third grade of training (41%). More than 60% of the surveyed students acknowledged each of the 5 benefits listed on the survey, although no statistically significant differences were seen between sexes, training grades, those with and without prior radiology experience, program length, or majors in how the questions were answered. Students most willing to participate in CERP were those enrolled in a 5-year training program (71%) and those who had previous radiology clerkship experience (89%). Students least willing to join CERP were majoring in somatology medicine (54%) and medical psychology (55%), and only 45% of students in 8-year programs indicated a willingness to join CERP. Chi-square tests indicated that the willingness to join CERP was not associated with sex (chi2(df = 1393) = 128.6, P=1.00), training program (chi2(df = 1393) = 111.3, P=1.00), training grade (chi2(df = 1393) = 266.1, P=1.00), major (chi2(df = 1393) = 456.1, P=1.00), or previous experience with radiology (chi2(df = 1393) = 142.2, P=1.00). CONCLUSION: Medical students enrolled at Fourth Military Medical University developed an awareness of the potential benefits of CERP; however, this awareness did not correlate with their willingness to join CERP. PMID- 27999510 TI - Age-Related Macular Degeneration and Intracrine Biology: An Hypothesis. AB - This laboratory has studied the intracellular actions of angiotensin II and other signaling proteins that can act in the intracellular space-peptides/proteins we have called intracrines. Moreover, we have suggested that general principles of intracrine action exist and can help explain the progression of some chronic degenerative diseases such as diabetic nephropathy and congestive heart failure. Here, a similar analysis is carried out in the case of age-related macular degeneration. We propose that intracrine mechanisms are operative in this disorder. In particular, we hypothesize that intracrine loops involving renin, angiotensin II, transforming growth factor-beta, vascular endothelial growth factor, bone morphogenetic protein-4, and p53, among other factors, are involved. If this analysis is correct, it suggests a commonality of mechanism linking chronic progressive renal diseases, congestive heart failure, and macular degeneration. PMID- 27999512 TI - Review of the Diagnostic Evaluation of Renal Tubular Acidosis. AB - BACKGROUND: The term renal tubular acidosis (RTA) describes a group of uncommon kidney disorders characterized by defective acid-base regulation. Reaching the diagnosis of RTA is complex and often delayed, resulting in suboptimal treatment. METHODS: This article provides an overview of the clinical features of RTA and diagnostic approaches in a format accessible to physicians for everyday use. RESULTS: The 3 major forms of disease are classified by their respective tubular transport defects, each of which produces persistent hyperchloremic metabolic acidosis. Distal RTA is characterized by limited urinary acid secretion, proximal RTA by restricted urinary bicarbonate reabsorption, and hyperkalemic RTA by absolute or relative hypoaldosteronism. RTA is often detected incidentally as a biochemical diagnosis in asymptomatic individuals. When present, clinical features may range from mild nonspecific complaints to life-threatening physiologic disturbances. CONCLUSION: RTA is a complex condition that requires thoughtful investigation. Physicians should be aware of the presentation of RTA and the investigative options available to confirm the diagnosis. PMID- 27999511 TI - A Review of Herbal and Pharmaceutical Galactagogues for Breast-Feeding. AB - BACKGROUND: Therapeutic approaches to addressing insufficient lactation are available but remain poorly understood. Current trends in maternal health, such as increasing rates of obesity, delayed age at childbearing, and high rates of cesarean section, may be associated with physiological challenges for lactation that cannot be managed by counseling alone. Women who have not had success with counseling alone, including adoptive mothers seeking to induce lactation, may use galactagogues (pharmaceutical and herbal compounds used to increase lactation). We present a review of selected studies of galactagogues and data indicating popular demand for such products. METHODS: A systematic search was conducted for published studies on the use of galactagogues for breast-feeding. The following databases were searched: MEDLINE (PubMed), EBSCO (Academic Search Complete), and EMBASE. The search was conducted between July 15, 2015, and August 18, 2015; only English language articles were included, and we imposed no restrictions on publication date. Two authors independently reviewed the studies and extracted data. RESULTS: Blinded, placebo-controlled clinical trials of 2 pharmaceutical galactagogues (domperidone and metoclopramide) and 5 popular herbal galactagogues (shatavari, fenugreek, silymarin, garlic, and malunggay) were identified. All of the studies identified for domperidone showed a significant difference in milk production between the treatment and placebo groups. Of the 6 trials of metoclopramide, only 1 study showed a significant difference in milk production compared to placebo. Results of the clinical trials on herbal galactagogues were mixed. Our review of the evidence for the efficacy of popular pharmaceutical and herbal galactagogues revealed a dearth of high-quality clinical trials and mixed results. CONCLUSION: Health providers face the challenge of prescribing or recommending galactagogues without the benefit of robust evidence. Given the suboptimal rates of exclusive breast-feeding worldwide and the availability and demand for medical and herbal lactation therapies, controlled trials and analyses investigating these medicines are urgently warranted. PMID- 27999513 TI - Choosing Non-Vitamin K Antagonist Oral Anticoagulants: Practical Considerations We Need to Know. AB - BACKGROUND: Warfarin is a well-established agent for use in the prevention of stroke or systemic embolic event (SEE) in patients with nonvalvular atrial fibrillation (NVAF) and for the treatment of venous thromboembolism (VTE). However, management of patients requiring oral anticoagulation with warfarin can be complicated by the need for frequent monitoring, drug-drug and drug-food interactions, and a variable response based on genetic polymorphisms. The non vitamin K antagonist oral anticoagulants (NOACs) were developed as alternatives to warfarin; they do not require routine monitoring and have predictable pharmacokinetics, fewer drug-drug interactions, and limited drug-food interactions. Four NOACs-dabigatran, rivaroxaban, apixaban, and edoxaban-have received approval from the US Food and Drug Administration for the prevention of stroke or SEE in NVAF and for the treatment of VTE. Selecting the most appropriate agent for each patient should be done in consideration of patient preferences and characteristics, including renal function, bleeding risk, and the need for other medications. METHODS: A search was performed on the terms atrial fibrillation and venous thromboembolism with individual terms dabigatran, apixaban, edoxaban, or rivaroxaban to identify relevant manuscripts; large randomized clinical trials, metaanalyses, and treatment guideline recommendations were given preference. Searches to identify registries, treatment guidelines, and metaanalyses relevant to specific subgroups were also used. RESULTS: NOACs are effective in reducing the risk of stroke or SEE in patients with NVAF and are associated with fewer incidents of intracranial bleeding vs warfarin. CONCLUSION: NOACs provide a convenient and safe alternative to warfarin and may result in improved therapeutic outcomes for patients with NVAF or VTE. The use of NOACs in other indications and patient populations is under investigation, and clinical trials investigating their use in acute coronary syndrome, medically ill patients, percutaneous coronary intervention, cardioversion, catheter ablation, coronary arterial disease, and heart failure have been announced. PMID- 27999515 TI - Spontaneous Unscarred Uterine Rupture at 15 Weeks of Pregnancy: A Case Report. AB - BACKGROUND: Uterine rupture during pregnancy is a serious obstetric complication. The presence of a previous uterine scar is the most important risk factor, whereas rupture in an unscarred uterus is a rare event. CASE REPORT: A 34-year old woman, gravida 3 para 1, presented with sudden acute hypogastric pain at 15 weeks of gestation. The patient had no history of cesarean delivery. Ultrasound scans showed an empty endometrial cavity continuing directly into the amniotic sac that developed mainly outside the uterus. Because of the ultrasound findings and the patient's progressive anemia, a laparoscopy was performed that revealed a massive hemoperitoneum caused by the rupture of the uterine fundus with exteriorization of most of the amniotic sac. Laparoscopy was converted to laparotomy, the pregnancy was removed, and the uterine disruption was repaired. CONCLUSION: Early diagnosis and prompt treatment of uterine rupture may significantly improve prognosis. This severe obstetric complication should be considered even in early gestational age pregnancies and in the absence of known risk factors. PMID- 27999514 TI - Hemorrhagic Stroke Resulting From Venous Malformation at 20 Weeks of Pregnancy. AB - BACKGROUND: Stroke in the pregnant patient is not a common occurrence. Despite its relative rarity, stroke during pregnancy is associated with high morbidity and mortality for both mother and infant. We report the case of a patient who experienced a hemorrhagic stroke during pregnancy because of venous cavernoma. CASE REPORT: A 34-year-old patient, gravida 5 para 1-0-3-1, presented to labor and delivery triage at 21 weeks, 0 days' gestation with the concern of sudden onset right-sided facial, arm, and leg numbness and weakness. Intracranial imaging via magnetic resonance imaging demonstrated a small left midbrain venous cavernoma in the periaqueductal region of the posterior lateral cerebral peduncle area with evidence of edema and focal hemorrhage. During a 3-day hospital admission, the patient's deficits slowly improved, and she was discharged home. She subsequently delivered vaginally without incident. Six days postpartum, the patient presented with symptoms that were similar to her initial presentation. She was correctly diagnosed with migraine with aura after the appropriate neuroimaging studies did not show an acute stroke. CONCLUSION: This case demonstrates the similarities between the perilous diagnosis of stroke and the more routine diagnosis of migraine. The case also highlights the need for caution and for a multidisciplinary treatment approach when the diagnosis of stroke is considered, particularly in the pregnant patient. PMID- 27999516 TI - Atypical Presentation of Cervical Carcinoma With Cerebral Metastasis. AB - BACKGROUND: Cervical cancer is a leading cause of morbidity and mortality in women, but cerebral metastasis from cervical carcinoma is a rare event with a reported incidence of 0.57%. CASE REPORT: We describe a case of brain metastasis from primary cervical adenocarcinoma with several distinct features. This case illustrates uncommon presenting neurologic symptoms, a rare combination of histopathologic features, and atypical findings on radiographic evaluation. CONCLUSION: Clinicians must maintain a high index of suspicion for cerebral metastasis to make an accurate diagnosis and initiate appropriate management of advanced cervical cancer. PMID- 27999518 TI - Serotonin Syndrome With Fluoxetine: Two Case Reports. AB - BACKGROUND: Serotonin syndrome is a rare but serious complication of treatment with serotonergic agents. In its severe manifestations, death can ensue. Early recognition and aggressive management are crucial to mitigating the syndrome. Often the presentation can be subtle and easy to miss. CASE REPORTS: We present 2 cases of serotonin syndrome seen in the psychiatric consultation service of a busy academic hospital. Both patients had favorable outcomes because of early recognition and aggressive management. CONCLUSION: Physicians should carefully consider and rule out the clinical diagnosis of serotonin syndrome when presented with an agitated or confused patient who is taking serotonergic agents. PMID- 27999517 TI - Sarcoid Uveitis: A Look Beyond The Eyes. AB - BACKGROUND: Bilateral acute uveitis can cause significant morbidity, and a complete workup is often warranted. This report illustrates a case of sarcoid uveitis definitively diagnosed by skin biopsy in a patient with red tattoo ink. CASE REPORT: A 40-year-old African American male presented with bilateral photophobia and intraocular pressures of 26 mmHg in both eyes, 1+ grade cell and flare in both eyes, and granulomatous (mutton fat) keratic precipitates in both eyes. Serum angiotensin-converting enzyme level was elevated at 146 U/mL (normal value <40 U/mL), and computed tomography imaging revealed mediastinal and hilar lymphadenopathy. Multifocal induration and elevation in the areas of red pigment of a tattoo were also present and on punch biopsy revealed noncaseating granulomas, confirming the diagnosis of sarcoid uveitis. CONCLUSION: Our case suggests that a complete physical examination and inquiry about the presence of any tattoos should be conducted as part of the workup of uveitis. PMID- 27999519 TI - Esophageal Granular Cell Tumor: A Benign Tumor or an Insidious Cause for Concern? AB - BACKGROUND: Esophageal granular cell tumors (GCTs) are rare, often benign tumors of neurogenic origin. GCTs most frequently occur in the skin and subcutaneous tissues but are found in the gastrointestinal (GI) tract in 6%-10% of cases, with the distal two-thirds of the esophagus being the most common site. Owing to the insidious nature of GCTs, presentation is typically asymptomatic. In fact, GCTs are often discovered incidentally during investigation of other GI disturbances. CASE REPORT: We report the case of a 36-year-old white male who had a 2.3 * 2.0 cm submucosal mass of the midesophagus found during esophagogastroduodenoscopy (EGD) at an outside hospital for workup of chronic diarrhea. He was referred to us for further evaluation that led to a diagnosis of a large esophageal GCT. CONCLUSION: Because of the rarity of GCTs in clinical practice and their poorly defined malignant classification, proper workup and management are essential to avoid the potential morbidity and mortality associated with large and/or malignant tumors. Although malignancy is uncommon, approximately 1%-2% of esophageal GCTs are malignant. Conservative management is tolerated for benign, asymptomatic lesions <10 mm in diameter, but endoscopic removal is recommended for large, symptomatic tumors or those with features suggestive of malignancy. Routine surveillance often includes EGD and/or esophageal ultrasonography to evaluate tumor size, location, and depth and to exclude malignancy or lymph node involvement. PMID- 27999520 TI - Comorbidity in Multiple Sclerosis: Some Answers, More Questions. PMID- 27999521 TI - Screening Tools for Anxiety in People with Multiple Sclerosis: A Systematic Review. AB - Background: Anxiety is prevalent in people with multiple sclerosis (MS). Screening measures are used to identify symptoms of anxiety, but the optimal measure to screen for anxiety disorders in MS has not been established. Methods: We searched the MEDLINE, Embase, PsycINFO, PsycARTICLES Full Text, Cumulative Index to Nursing and Allied Health Literature, Web of Science, and Scopus databases from database inception until August 7, 2015. Two independent reviewers screened abstracts and full-text reports for study inclusion, extracted data, and assessed risk of bias. We included studies that evaluated the criterion validity of anxiety screening tools when measuring anxiety in individuals with well documented MS, as measured by sensitivity, specificity, and positive and negative predictive values. Results: Of the 3181 abstracts screened, 18 articles were reviewed in full text, of which 4 met the inclusion criteria. The criterion validity of three screening tools was assessed: the Hospital Anxiety and Depression Scale-Anxiety (HADS-A), Beck Anxiety Inventory (BAI), and 7-item Generalized Anxiety Disorder Scale (GAD-7). The HADS-A was validated against the Structured Clinical Interview for DSM-IV, the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview, and the BAI. The BAI was validated against the SCAN, and the GAD-7 was validated against the HADS-A. The HADS-A had higher measures of sensitivity and specificity than did the BAI and the GAD-7. Conclusions: Based on this small sample, the HADS-A shows promise as an applicable measure for people with MS. Screening scales used to identify anxiety in MS must be validated against appropriate reference standards. PMID- 27999524 TI - Individual and Co-occurring SNAP Risk Factors: Smoking, Nutrition, Alcohol Consumption, and Physical Activity in People with Multiple Sclerosis. AB - Background: Smoking, poor nutrition, excess alcohol consumption, and insufficient physical activity underlie most preventable causes of morbidity in the general population and may be associated with comorbidities and health outcomes in multiple sclerosis (MS). However, the frequency of co-occurrence of these risk factors in people with MS remains unclear. Methods: Sixty-nine individuals with MS completed self-report measures of smoking status, nutrition, alcohol use, physical activity levels, and sociodemographic and clinical characteristics. The data were analyzed using t tests and chi2 analyses. Results: Poor diet was the most common risk factor, with 85.5% of the sample not meeting dietary guidelines. Of participants with two risk factors, 90.3% were not meeting dietary and physical activity guidelines. Seventy-three percent of women were not meeting physical activity guidelines, compared with 38% of men (chi2 = 7.5, P < .01). There were also differential rates by sex of the most commonly co-occurring risk factors: 65% of women reported the co-occurrence of insufficient physical activity and poor diet, compared with 38% of men (chi2 = 4.2, P = .05). Conclusions: These results indicate that 85.5% of the sample was not meeting nutrition guidelines, 90.3% of participants with two risk factors reported the co occurrence of poor diet and insufficient levels of physical activity, and physical activity levels and the total number of risk factors varied across sex. PMID- 27999523 TI - Assessment and Treatment of Psychiatric Distress, Sexual Dysfunction, Sleep Disturbances, and Pain in Multiple Sclerosis: A Survey of Members of the Consortium of Multiple Sclerosis Centers. AB - Background: Psychiatric distress (depression and anxiety), sexual dysfunction, sleep disturbances, and pain are frequent comorbidities in multiple sclerosis (MS) that have the potential to interfere with functioning and quality of life. Often, patients benefit from a combination of medical and psychotherapeutic interventions. However, the literature suggests that many of these issues have been underdiagnosed or undertreated. To better understand current practices, this study aimed to gain a multidisciplinary perspective on how MS providers assess and treat these five problems. Methods: An online questionnaire was completed by 42 members of the Consortium of Multiple Sclerosis Centers on their assessment procedures, treatment recommendations, and prevalence rates of these issues in their practices. Results: More than 80% of participants reported routinely assessing for depression, anxiety, sleep, and pain, but only slightly more than half ask about sexual dysfunction. Most of these health-care providers endorsed using a general question in their assessments and recommending a pharmaceutical intervention. Conclusions: Health-care providers are aware of the prevalence of these issues in their patients with MS. Promoting the use of validated screening measures and increased research on psychotherapeutic interventions for sleep and pain are two potential avenues for improving patient care. PMID- 27999522 TI - Effect of Comorbidities on Outcomes of Neurorehabilitation Interventions in Multiple Sclerosis: A Scoping Review. AB - Background: Interest in comorbidities has increased in the past few years, but the effect of comorbidities on outcomes of multiple sclerosis (MS) neurorehabilitation interventions is unclear. The aim of this review was to identify and summarize the existing evidence regarding the effect of comorbidities on outcomes of neurorehabilitation interventions targeting people with MS. Methods: Five databases (Embase, MEDLINE through Ovid, PubMed Central, Cumulative Index to Nursing and Allied Health Literature, and Web of Science) were searched using index terms and keywords relating to MS and a wide range of rehabilitation interventions. Studies screened were limited to English-language randomized controlled trials. Information related to included and excluded comorbidities and how they were reported and described was extracted from the included studies. Results: Fifty-four neurorehabilitation randomized controlled trials were included and were grouped into categories: robotics/technology enhanced (n = 7), task-oriented training/neurorehabilitation principles (n = 7), electrical stimulation (n = 12), temperature regulation (n = 6), magnetic field therapy (n = 5), vibration (n = 9), and miscellaneous (n = 8). Although the issue of comorbidity was considered in 40 studies, it was limited to excluding individuals from participating in the trials. Only two studies reported on comorbidity, but neither examined the possible mediating or moderating effect of comorbidities on intervention outcomes. Conclusions: This review documents important knowledge gaps about the effect of comorbidity on neurorehabilitation outcomes and identifies a critical need for future studies to address this issue. Without this information, we limit our understanding of the mechanisms of comorbidity and its effects on relevant clinical and research outcomes specific to neurorehabilitation. PMID- 27999525 TI - Antidepressant Drug Treatment in Association with Multiple Sclerosis Disease Modifying Therapy: Using Explorys in the MS Population. AB - Background: The Explorys Enterprise Performance Management (EPM) database contains de-identified clinical data for 50 million patients. Multiple sclerosis (MS) disease-modifying therapies (DMTs), specifically interferon beta (IFNbeta) treatments, may potentiate depression. Conflicting data have emerged, and a large scale claims-based study by Patten et al. did not support such an association. This study compares the results of Patten et al. with those using the EPM database. Methods: "Power searches" were built to test the relationship between antidepressant drug use and DMT in the MS population. Searches were built to produce a cohort of individuals diagnosed as having MS in the past 3 years taking a specific DMT who were then given any antidepressant drug. The antidepressant drug therapy prevalence was tested in the MS population on the following DMTs: IFNbeta-1a, IFNbeta-1b, combined IFNbeta, glatiramer acetate, natalizumab, fingolimod, and dimethyl fumarate. Results: In patients with MS, the rate of antidepressant drug use in those receiving DMTs was 40.60% to 44.57%. The rate of antidepressant drug use for combined IFNbeta DMTs was 41.61% (males: 31.25% 39.62%; females: 43.10%-47.33%). Antidepressant drug use peaked in the group aged 45 to 54 years for five of six DMTs. Conclusions: We found no association between IFNbeta treatment and antidepressant drug use in the MS population compared with other DMTs. The EPM database has been validated against the Patten et al. data for future use in the MS population. PMID- 27999526 TI - CME/CNE Article: A Framework of Care in Multiple Sclerosis, Part 1: Updated Disease Classification and Disease-Modifying Therapy Use in Specific Circumstances. AB - : Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org. TARGET AUDIENCE: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). LEARNING OBJECTIVES: Apply new information about MS to a comprehensive individualized treatment plan for patients with MSIntegrate the team approach into long-term planning in order to optimize rehabilitation care of patients with MSAccreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NPA designates this enduring material for 1.0 Continuing Nursing Education credit. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has received royalties from Springer Publishing and has received intellectual property rights from Biogen. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Scott D. Newsome, DO, MSCS (author), has served on scientific advisory boards for Biogen, Genentech, Novartis, and Genzyme, and has performed contracted research (institution received funds) for Biogen, Genentech, and Novartis. Philip J. Aliotta, MD, MSHA, CHCQM, FACS (author), has served on speakers' bureaus for Astellas Pharma, Actavis, Augmenix, and Allergan and has performed contracted research for Allergan. Jacquelyn Bainbridge, PharmD (author), has disclosed no relevant financial relationships. Susan E. Bennett, PT, DPT, EdD, NCS, MSCS (author), has served on speakers' bureaus for Acorda Therapeutics, Biogen, and Medtronic; has received consulting fees from and performed contracted research for Acorda Therapeutics; and is chair of the Clinical Events Committee at Innovative Technologies. Gary Cutter, PhD (author), has participated on Data and Safety Monitoring Committees for AMO Pharma, Apotek, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck, Merck/Pfizer, Opko Biologics, Neuren, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), and NICHD (OPRU Oversight Committee); has received consulting fees from and/or served on speakers' bureaus and scientific advisory boards for Cerespir, Genzyme, Genentech, Innate Therapeutics, Janssen Pharmaceuticals, Klein-Buendel Incorporated, MedImmune, Medday, Nivalis, Novartis, Opexa Therapeutics, Roche, Savara, Somahlution, Teva Pharmaceuticals, Transparency Life Sciences, and TG Therapeutics; and is President of Pythagoras, Inc., a private consulting company located in Birmingham, AL. Kaylan Fenton, CRNP, APNP, MSCN (author), has disclosed no relevant financial relationships. Fred Lublin, MD (author), has received consulting fees/fees for non-CME/CE activities from Bayer HealthCare Pharmaceuticals, Biogen, EMD Serono, Novartis, Teva Neuroscience, Actelion, Sanofi/Genzyme, Acorda, Questcor/Mallinckrodt, Roche/Genentech, MedImmune, Osmotica, Xenoport, Receptos/Celgene, Forward Pharma, Akros, TG Therapeutics, AbbVie, Toyama, Amgen, Medday, Atara Biotherapeutics, Polypharma, Pfizer, Johnson & Johnson, Revalesio, Coronado Bioscience, and Bristol-Myers Squibb; has served on speakers' bureaus for Genentech/Roche and Genzyme/Sanofi; has performed contracted research for Acorda, Biogen, Novartis, Teva Neuroscience, Genzyme, Xenoport, and Receptos; is the co-chief editor of Multiple Sclerosis and Related Disorders; and has an ownership interest in Cognition Pharmaceuticals. Dorothy Northrop, MSW, ACSW (author), has disclosed no relevant financial relationships. David Rintell, EdD (author), has received consulting fees from Novartis and has served as a patient education speaker for Teva Neuroscience. He started as a salaried employee of Sanofi Genzyme in November 2015. Dr. Rintell's work on this project was completed before he became a salaried employee of Sanofi Genzyme.Bryan D. Walker, MHS, PA-C (author), has served on scientific advisory boards for EMD Serono and Sanofi Genzyme and owns stock in Biogen. Megan Weigel, DNP, ARNP-C, MSCN (author), has received consulting fees from Mallinckrodt, Genzyme, and Genentech, and has served on speakers' bureaus for Bayer Corp, Acorda Therapeutics, Teva Neuroscience, Biogen, Mallinckrodt, Genzyme, Novartis, and Pfizer. Kathleen Zackowski, PhD, OTR, MSCS (author), has performed contracted research for Acorda Therapeutics. David E. Jones, MD (author), has received consulting fees from Biogen and Novartis, and has performed contracted research for Biogen. One anonymous peer reviewer for the IJMSC has performed contracted research (institution received funds) for Novartis, Chugai, and Biogen. Another reviewer has received consulting fees and served on speakers' bureaus for Biogen, Sanofi Genzyme, Genentech, EMD Serono, and Novartis. The third reviewer has disclosed no relevant financial relationships. Lori Saslow, MS (medical writer), has disclosed no relevant financial relationships. The staff at the IJMSC, CMSC, NPA, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Note: Disclosures listed for authors are those applicable at the time of their work on this project and within 12 months previously. Financial relationships for some authors may have changed in the interval between the time of their work on this project and publication of the article. Funding/Support: Funding for the Framework of Care consensus conference was provided by the Consortium of Multiple Sclerosis Centers, Mallinckrodt Pharmaceuticals, and Mylan Pharmaceuticals. Method of Participation: Release Date: December 1, 2016 Valid for Credit Through: December 1, 2017 In order to receive CME/CNE credit, participants must: Review the CME/CNE information, including learning objectives and author disclosures.Study the educational content.Complete the post-test and evaluation, which are available at http://www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities. PMID- 27999527 TI - ACTH Action on StAR Biology. AB - Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies. PMID- 27999528 TI - Quality Control of Structural MRI Images Applied Using FreeSurfer-A Hands-On Workflow to Rate Motion Artifacts. AB - In structural magnetic resonance imaging motion artifacts are common, especially when not scanning healthy young adults. It has been shown that motion affects the analysis with automated image-processing techniques (e.g., FreeSurfer). This can bias results. Several developmental and adult studies have found reduced volume and thickness of gray matter due to motion artifacts. Thus, quality control is necessary in order to ensure an acceptable level of quality and to define exclusion criteria of images (i.e., determine participants with most severe artifacts). However, information about the quality control workflow and image exclusion procedure is largely lacking in the current literature and the existing rating systems differ. Here, we propose a stringent workflow of quality control steps during and after acquisition of T1-weighted images, which enables researchers dealing with populations that are typically affected by motion artifacts to enhance data quality and maximize sample sizes. As an underlying aim we established a thorough quality control rating system for T1-weighted images and applied it to the analysis of developmental clinical data using the automated processing pipeline FreeSurfer. This hands-on workflow and quality control rating system will aid researchers in minimizing motion artifacts in the final data set, and therefore enhance the quality of structural magnetic resonance imaging studies. PMID- 27999529 TI - Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats. AB - Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ~10 g/kg/day, LKE), high dose ketone ester (HKE; ~25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (betaHB-S; ~25 g/kg/day, KS) and betaHB-S + medium chain triglyceride (MCT; ~25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood betaHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood betaHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis. PMID- 27999530 TI - Disturbed Interhemispheric Functional Connectivity Rather than Structural Connectivity in Irritable Bowel Syndrome. AB - Neuroimaging studies have demonstrated that irritable bowel syndrome (IBS)-a relapsing functional bowel disorder-presents with disrupted brain connections. However, little is known about the alterations of interhemispheric functional connectivity and underlying structural connectivity in IBS. This study combined resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) to investigate changes in interhemispheric coordination in IBS patients. Resting-state functional and structural magnetic resonance images were acquired from 65 IBS patients and 67 healthy controls (HCs; matched for age, sex and educational level). Interhemispheric voxel-mirrored homotopic connectivity (VMHC) was calculated and compared between groups. Homotopic regions showing abnormal VMHC in patients were targeted as regions of interest (ROIs) for analysis of DTI tractography. The fractional anisotropy (FA), fiber number and fiber length were compared between groups. Statistical analysis was also performed by including anxiety and depression as covariates to evaluate their effect. A Pearson correlation analysis between abnormal interhemispheric connectivity and clinical indices of IBS patients was performed. Compared to HCs, IBS patients had higher interhemispheric functional connectivity between bilateral thalami, cuneus, posterior cingulate cortices (PCC), lingual gyri and inferior occipital/cerebellum lobes, as well as lower interhemispheric functional connectivity between bilateral ventral anterior cingulate cortices (vACC) and inferior parietal lobules (IPL). The inclusion of anxiety and depression as covariates abolished VMHC difference in vACC. Microstructural features of white matter tracts connecting functionally abnormal regions did not reveal any differences between the groups. VMHC values in vACC negatively correlated with the quality of life (QOL) scores of patients. In conclusion, this study provides preliminary evidence of the disrupted functional coordination rather than anatomic coordination between interhemispheric regions within the cortex-thalamus circuit in IBS patients, which could partly account for the enhanced visceral information processing and impaired endogenous pain or emotion inhibition associated with IBS. PMID- 27999531 TI - Ingenuity Pathway Analysis of Gene Expression Profiles in Distal Nerve Stump following Nerve Injury: Insights into Wallerian Degeneration. AB - Nerve injury is a common and difficult clinical problem worldwide with a high disability rate. Different from the central nervous system, the peripheral nervous system is able to regenerate after injury. Wallerian degeneration in the distal nerve stump contributes to the construction of a permissible microenvironment for peripheral nerve regeneration. To gain new molecular insights into Wallerian degeneration, this study aimed to identify differentially expressed genes and elucidate significantly involved pathways and cellular functions in the distal nerve stump following nerve injury. Microarray analysis showed that a few genes were differentially expressed at 0.5 and 1 h post nerve injury and later on a relatively larger number of genes were up-regulated or down regulated. Ingenuity pathway analysis indicated that inflammation and immune response, cytokine signaling, cellular growth and movement, as well as tissue development and function were significantly activated following sciatic nerve injury. Notably, a cellular function highly related to nerve regeneration, which is called Nervous System Development and Function, was continuously activated from 4 days until 4 weeks post injury. Our results may provide further understanding of Wallerian degeneration from a genetic perspective, thus aiding the development of potential therapies for peripheral nerve injury. PMID- 27999533 TI - Ultrastructure of GABA- and Tachykinin-Immunoreactive Neurons in the Lower Division of the Central Body of the Desert Locust. AB - The central complex, a group of neuropils spanning the midline of the insect brain, plays a key role in spatial orientation and navigation. In the desert locust and other species, many neurons of the central complex are sensitive to the oscillation plane of polarized light above the animal and are likely involved in the coding of compass directions derived from the polarization pattern of the sky. Polarized light signals enter the locust central complex primarily through two types of gamma-aminobutyric acid (GABA)-immunoreactive tangential neurons, termed TL2 and TL3 that innervate specific layers of the lower division of the central body (CBL). Candidate postsynaptic partners are columnar neurons (CL1) connecting the CBL to the protocerebral bridge (PB). Subsets of CL1 neurons are immunoreactive to antisera against locustatachykinin (LomTK). To better understand the synaptic connectivities of tangential and columnar neurons in the CBL, we studied its ultrastructural organization in the desert locust, both with conventional electron microscopy and in preparations immunolabeled for GABA or LomTK. Neuronal profiles in the CBL were rich in mitochondria and vesicles. Three types of vesicles were distinguished: small clear vesicles with diameters of 20 40 nm, dark dense-core vesicles (diameter 70-120 nm), and granular dense-core vesicles (diameter 70-80 nm). Neurons were connected via divergent dyads and, less frequently, through convergent dyads. GABA-immunoreactive neurons contained small clear vesicles and small numbers of dark dense core vesicles. They had both pre- and postsynaptic contacts but output synapses were observed more frequently than input synapses. LomTK immunostaining was concentrated on large granular vesicles; neurons had pre- and postsynaptic connections often with neurons assumed to be GABAergic. The data suggest that GABA-immunoreactive tangential neurons provide signals to postsynaptic neurons in the CBL, including LomTK immunolabeled CL1 neurons, but in addition also receive input from LomTK-labeled neurons. Both types of neuron are additionally involved in local circuits with other constituents of the CBL. PMID- 27999532 TI - Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input. AB - Mental functions involve coordinated activities of specific neuronal ensembles that are embedded in complex brain circuits. Aberrant neuronal ensemble dynamics is thought to form the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles and determine what molecular mechanisms constrain their emergence and consolidation during development and learning. Here, we provide a perspective based on recent studies that use activity-dependent gene Arc/Arg3.1 as a cellular marker to identify neuronal ensembles and a molecular probe to modulate circuit functions. These studies have demonstrated that the transcription of Arc is activated in selective groups of frontal cortical neurons in response to specific behavioral tasks. Arc expression regulates the persistent firing of individual neurons and predicts the consolidation of neuronal ensembles during repeated learning. Therefore, the Arc pathway represents a prototypical example of activity dependent genetic feedback regulation of neuronal ensembles. The activation of this pathway in the frontal cortex starts during early postnatal development and requires dopaminergic (DA) input. Conversely, genetic disruption of Arc leads to a hypoactive mesofrontal dopamine circuit and its related cognitive deficit. This mutual interaction suggests an auto-regulatory mechanism to amplify the impact of neuromodulators and activity-regulated genes during postnatal development. Such a mechanism may contribute to the association of mutations in dopamine and Arc pathways with neurodevelopmental psychiatric disorders. As the mesofrontal dopamine circuit shows extensive activity-dependent developmental plasticity, activity-guided modulation of DA projections or Arc ensembles during development may help to repair circuit deficits related to neuropsychiatric disorders. PMID- 27999534 TI - Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson's Disease. AB - Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson's disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (FP CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross hemispheric coupling, thus allowing fine-tuning of movement. PMID- 27999535 TI - Dynamic Determinants of the Uncontrolled Manifold during Human Quiet Stance. AB - Human postural sway during stance arises from coordinated multi-joint movements. Thus, a sway trajectory represented by a time-varying postural vector in the multiple-joint-angle-space tends to be constrained to a low-dimensional subspace. It has been proposed that the subspace corresponds to a manifold defined by a kinematic constraint, such that the position of the center of mass (CoM) of the whole body is constant in time, referred to as the kinematic uncontrolled manifold (kinematic-UCM). A control strategy related to this hypothesis (CoM control-strategy) claims that the central nervous system (CNS) aims to keep the posture close to the kinematic-UCM using a continuous feedback controller, leading to sway patterns that mostly occur within the kinematic-UCM, where no corrective control is exerted. An alternative strategy proposed by the authors (intermittent control-strategy) claims that the CNS stabilizes posture by intermittently suspending the active feedback controller, in such a way to allow the CNS to exploit a stable manifold of the saddle-type upright equilibrium in the state-space of the system, referred to as the dynamic-UCM, when the state point is on or near the manifold. Although the mathematical definitions of the kinematic- and dynamic-UCM are completely different, both UCMs play similar roles in the stabilization of multi-joint upright posture. The purpose of this study was to compare the dynamic performance of the two control strategies. In particular, we considered a double-inverted-pendulum-model of postural control, and analyzed the two UCMs defined above. We first showed that the geometric configurations of the two UCMs are almost identical. We then investigated whether the UCM-component of experimental sway could be considered as passive dynamics with no active control, and showed that such UCM-component mainly consists of high frequency oscillations above 1 Hz, corresponding to anti-phase coordination between the ankle and hip. We also showed that this result can be better characterized by an eigenfrequency associated with the dynamic-UCM. In summary, our analysis highlights the close relationship between the two control strategies, namely their ability to simultaneously establish small CoM variations and postural stability, but also make it clear that the intermittent control hypothesis better explains the spectral characteristics of sway. PMID- 27999536 TI - Cortical Asymmetries during Hand Laterality Task Vary with Hand Laterality: A fMRI Study in 295 Participants. AB - The aim of this study was to characterize, using fMRI, the functional asymmetries of hand laterality task (HLT) in a sample of 295 participants balanced for handedness. During HLT, participants have to decide whether the displayed picture of a hand represent a right or a left hand. Pictures of hands' back view were presented for 150 ms in the right or left hemifield. At the whole hemisphere level, we evidenced that the laterality of the hand and of the hemifield in which the picture was displayed combined their effects on the hemispheric asymmetry in an additive way. We then identified a set of 17 functional homotopic regions of interest (hROIs) including premotor, motor, somatosensory and parietal regions, whose activity and asymmetry varied with the laterality of the presented hands. When the laterality of a right hand had to be evaluated, these areas showed stronger leftward asymmetry, the hROI located in the primary motor area showing a significant larger effect than all other hROIs. In addition a subset of six parietal regions involved in visuo-motor integration together with two postcentral areas showed a variation in asymmetry with hemifield of presentation. Finally, while handedness had no effect at the hemispheric level, two regions located in the parietal operculum and intraparietal sulcus exhibited larger leftward asymmetry with right handedness independently of the hand of presentation. The present results extend those of previous works in showing a shift of asymmetries during HLT according to the hand presented in sensorimotor areas including primary motor cortex. This shift was not affected by manual preference. They also demonstrate that the coordination of visual information and handedness identification of hands relied on the coexistence of contralateral motor and visual representations in the superior parietal lobe and the postcentral gyrus. PMID- 27999537 TI - Nonlinear Coupling between Cortical Oscillations and Muscle Activity during Isotonic Wrist Flexion. AB - Coupling between cortical oscillations and muscle activity facilitates neuronal communication during motor control. The linear part of this coupling, known as corticomuscular coherence, has received substantial attention, even though neuronal communication underlying motor control has been demonstrated to be highly nonlinear. A full assessment of corticomuscular coupling, including the nonlinear part, is essential to understand the neuronal communication within the sensorimotor system. In this study, we applied the recently developed n:m coherence method to assess nonlinear corticomuscular coupling during isotonic wrist flexion. The n:m coherence is a generalized metric for quantifying nonlinear cross-frequency coupling as well as linear iso-frequency coupling. By using independent component analysis (ICA) and equivalent current dipole source localization, we identify four sensorimotor related brain areas based on the locations of the dipoles, i.e., the contralateral primary sensorimotor areas, supplementary motor area (SMA), prefrontal area (PFA) and posterior parietal cortex (PPC). For all these areas, linear coupling between electroencephalogram (EEG) and electromyogram (EMG) is present with peaks in the beta band (15-35 Hz), while nonlinear coupling is detected with both integer (1:2, 1:3, 1:4) and non integer (2:3) harmonics. Significant differences between brain areas is shown in linear coupling with stronger coherence for the primary sensorimotor areas and motor association cortices (SMA, PFA) compared to the sensory association area (PPC); but not for the nonlinear coupling. Moreover, the detected nonlinear coupling is similar to previously reported nonlinear coupling of cortical activity to somatosensory stimuli. We suggest that the descending motor pathways mainly contribute to linear corticomuscular coupling, while nonlinear coupling likely originates from sensory feedback. PMID- 27999538 TI - Robotic and Virtual Reality BCIs Using Spatial Tactile and Auditory Oddball Paradigms. AB - The paper reviews nine robotic and virtual reality (VR) brain-computer interface (BCI) projects developed by the author, in collaboration with his graduate students, within the BCI-lab research group during its association with University of Tsukuba, Japan. The nine novel approaches are discussed in applications to direct brain-robot and brain-virtual-reality-agent control interfaces using tactile and auditory BCI technologies. The BCI user intentions are decoded from the brainwaves in realtime using a non-invasive electroencephalography (EEG) and they are translated to a symbiotic robot or virtual reality agent thought-based only control. A communication protocol between the BCI output and the robot or the virtual environment is realized in a symbiotic communication scenario using an user datagram protocol (UDP), which constitutes an internet of things (IoT) control scenario. Results obtained from healthy users reproducing simple brain-robot and brain-virtual-agent control tasks in online experiments support the research goal of a possibility to interact with robotic devices and virtual reality agents using symbiotic thought based BCI technologies. An offline BCI classification accuracy boosting method, using a previously proposed information geometry derived approach, is also discussed in order to further support the reviewed robotic and virtual reality thought-based control paradigms. PMID- 27999539 TI - An Overview of Systematic Reviews of Ginkgo biloba Extracts for Mild Cognitive Impairment and Dementia. AB - Ginkgo biloba extracts (GBEs) have been recommended to improve cognitive function and to prevent cognitive decline, but earlier evidence was inconclusive. Here, we evaluated all systematic reviews of GBEs for prevention of cognitive decline, and intervention of mild cognitive impairment (MCI) and dementia. Six databases from their inception to September 2015 were searched. Ten systematic reviews were identified, including reviews about Alzheimer's disease (n = 3), about vascular dementia (n = 1), about both Alzheimer's disease and vascular dementia (n = 2), about Alzheimer's disease, vascular dementia and mixed dementia (n = 3), and a review about MCI (n = 1). Based on the overview quality assessment questionnaire, eight studies were scored with at least 5 points, while the other two scored 4 points and 3 points, respectively. Medication with GBEs showed improvement in cognition, neuropsychiatric symptoms, and daily activities, and the effect was dose-dependent. Efficacy was convincingly demonstrated only when high daily dose (240 mg) was applied. Compared with placebo, overall adverse events and serious adverse events were at the same level as placebo, with less adverse events in favor of GBE in the subgroup of Alzheimer's disease patients, and fewer incidences in vertigo, tinnitus, angina pectoris, and headache. In conclusion, there is clear evidence to support the efficacy of GBEs for MCI and dementia, whereas the question on efficacy to prevent cognitive decline is still open. In addition, GBEs seem to be generally safe. PMID- 27999540 TI - A Novel Missense Mutation of the DDHD1 Gene Associated with Juvenile Amyotrophic Lateral Sclerosis. AB - Background: Juvenile amyotrophic lateral sclerosis (jALS) is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients. Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS) technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis. Results: We identified a novel c.1483A>G (p.Met495Val) homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the database of dbSNP, ExAC and 1000G. Conclusion: The novel c.1483A>G (p.Met495Val) missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS. PMID- 27999542 TI - Formulation and In vitro Interaction of Rhodamine-B Loaded PLGA Nanoparticles with Cardiac Myocytes. AB - This study aims to characterize rhodamine B (Rh B) loaded poly(D,L-lactide-co glycolide; PLGA) nanoparticles (NPs) and their interactions with cardiac myocytes. PLGA NPs were formulated using single emulsion solvent evaporation technique. The influence of varying parameters such as the stabilizer concentration, the sonication time, and the organic to aqueous ratio were investigated. The diameter, the dispersity, the encapsulation efficiency and the zeta potential of the optimized NPs were about 184 nm, 0.19, 40% and -21.7 mV, respectively. In vitro release showed that 29% of the Rh B was released within the first 8 h. Scanning electron microscopy measurements performed on the optimized NPs showed smooth surface and spherical shapes. No significant cytotoxic or apoptotic effects were observed on cardiac myocytes after 24 and 48 h of exposure with concentrations up to 200 MUg/mL. The kinetic of the intracellular uptake was confirmed by confocal microscopy and cells took up PLGA NPs within the 1st hours. Interestingly, our data show an increase in the NPs' uptake with time of exposure. Taken together, we demonstrate for the first time that the designed NPs can be used as potential probes for drug delivery in cardiac myocytes. PMID- 27999541 TI - Parahippocampal Cortex Mediates the Relationship between Lutein and Crystallized Intelligence in Healthy, Older Adults. AB - Introduction: Although, diet has a substantial influence on the aging brain, the relationship between dietary nutrients and aspects of brain health remains unclear. This study examines the neural mechanisms that mediate the relationship between a carotenoid important for brain health across the lifespan, lutein, and crystallized intelligence in cognitively intact older adults. We hypothesized that higher serum levels of lutein are associated with better performance on a task of crystallized intelligence, and that this relationship is mediated by gray matter structure of regions within the temporal cortex. This investigation aims to contribute to a growing line of evidence, which suggests that particular nutrients may slow or prevent aspects of cognitive decline by targeting specific features of brain aging. Methods: We examined 76 cognitively intact adults between the ages of 65 and 75 to investigate the relationship between serum lutein, tests of crystallized intelligence (measured by the Wechsler Abbreviated Scale of Intelligence), and gray matter volume of regions within the temporal cortex. A three-step mediation analysis was implemented using multivariate linear regressions to control for age, sex, education, income, depression status, and body mass index. Results: The mediation analysis revealed that gray matter thickness of one region within the temporal cortex, the right parahippocampal cortex (Brodmann's Area 34), partially mediates the relationship between serum lutein and crystallized intelligence. Conclusion: These results suggest that the parahippocampal cortex acts as a mediator of the relationship between serum lutein and crystallized intelligence in cognitively intact older adults. Prior findings substantiate the individual relationships reported within the mediation, specifically the links between (i) serum lutein and temporal cortex structure, (ii) serum lutein and crystallized intelligence, and (iii) parahippocampal cortex structure and crystallized intelligence. This report demonstrates a novel structural mediation between lutein status and crystallized intelligence, and therefore provides further evidence that specific nutrients may slow or prevent features of cognitive decline by hindering particular aspects of brain aging. Future work should examine the potential mechanisms underlying this mediation, including the antioxidant, anti-inflammatory, and membrane modulating properties of lutein. PMID- 27999543 TI - Opportunities and Challenges for Drug Development: Public-Private Partnerships, Adaptive Designs and Big Data. AB - Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development. PMID- 27999544 TI - Mitragyna speciosa Leaf Extract Exhibits Antipsychotic-Like Effect with the Potential to Alleviate Positive and Negative Symptoms of Psychosis in Mice. AB - In this study, we investigated the antipsychotic-like effect of methanolic extract of Mitragyna speciosa leaf (MMS) using in vivo and ex vivo studies. In vivo studies comprised of apomorphine-induced climbing behavior, haloperidol induced catalepsy, and ketamine-induced social withdrawal tests in mice whereas the ex vivo study was conducted utilizing isolated rat vas deferens preparation. Acute oral administration of MMS (50-500 mg/kg) showed an inverted bell-shaped dose-response in apomorphine-induced cage climbing behavior in mice. The effective inhibitory doses of MMS (75 and 100 mg/kg, p.o.) obtained from the apomorphine study was further tested on haloperidol (subcataleptic dose; 0.1 mg/kg, i.p.)-induced catalepsy in the mouse bar test. MMS (75 and 100 mg/kg, p.o.) significantly potentiated the haloperidol-induced catalepsy in mice. Interestingly, MMS at the same effective doses (75 and 100 mg/kg, p.o.) significantly facilitated the social interaction in ketamine-induced social withdrawal mice. Furthermore, MMS inhibited the dopamine-induced contractile response dose-dependently in the isolated rat vas deferens preparations. In conclusion, this investigation provides first evidence that MMS exhibits antipsychotic-like activity with potential to alleviate positive as well as negative symptoms of psychosis in mice. This study also suggests the antidopaminergic activity of MMS that could be responsible for alleviating positive symptoms of psychosis. PMID- 27999545 TI - IL-1 Inhibition in Systemic Juvenile Idiopathic Arthritis. AB - Systemic juvenile idiopathic arthritis (sJIA) is the form of childhood arthritis whose treatment is most challenging. The demonstration of the prominent involvement of interleukin (IL)-1 in disease pathogenesis has provided the rationale for the treatment with biologic medications that antagonize this cytokine. The three IL-1 blockers that have been tested so far (anakinra, canakinumab, and rilonacept) have all been proven effective and safe, although only canakinumab is currently approved for use in sJIA. The studies on IL-1 inhibition in sJIA published in the past few years suggest that children with fewer affected joints, higher neutrophil count, younger age at disease onset, shorter disease duration, or, possibly, higher ferritin level may respond better to anti-IL-1 treatment. In addition, it has been postulated that use of IL-1 blockade as first-line therapy may take advantage of a "window of opportunity," in which disease pathophysiology can be altered to prevent the occurrence of chronic arthritis. In this review, we analyze the published literature on IL-1 inhibitors in sJIA and discuss the rationale underlying the use of these medications, the results of therapeutic studies, and the controversial issues. PMID- 27999546 TI - Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation. AB - Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment. PMID- 27999547 TI - Myocardial Contractile Dysfunction Is Present without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and Is Prevented after Claudin-5 Virotherapy. AB - Mutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the delta-sarcoglycan null mouse model (Sgcd-/-) of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy withclaudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd-/- mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care. PMID- 27999548 TI - Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner. AB - Lithium at serum concentrations up to 1 mmol/L has been used in patients suffering from bipolar disorder for decades and has recently been shown to reduce the risk for ischemic stroke in these patients. The risk for stroke and thromboembolism depend not only on cerebral but also on general endothelial function and health; the entire endothelium as an organ is therefore pathophysiologically relevant. Regardless, the knowledge about the direct impact of lithium on endothelial function remains poor. We conducted an experimental study using lithium as pharmacologic pretreatment for murine, porcine and human vascular endothelium. We predominantly investigated endothelial vasorelaxation capacities in addition to human basal and dynamic (thrombin-/PAR-1 receptor agonist-impaired) barrier functioning including myosin light chain (MLC) phosphorylation (MLC-P). Low-dose therapeutic lithium concentrations (0.4 mmol/L) significantly augment the cholinergic endothelium-dependent vasorelaxation capacities of cerebral and thoracic arteries, independently of central and autonomic nerve system influences. Similar concentrations of lithium (0.2-0.4 mmol/L) significantly stabilized the dynamic thrombin-induced and PAR-1 receptor agonist-induced permeability of human endothelium, while even the basal permeability appeared to be stabilized. The lithium-attenuated dynamic permeability was mediated by a reduced endothelial MLC-P known to be followed by a lessening of endothelial cell contraction and paracellular gap formation. The well-known lithium-associated inhibition of inositol monophosphatase/glycogen synthase kinase-3-beta signaling-pathways involving intracellular calcium concentrations in neurons seems to similarly occur in endothelial cells, too, but with different down-stream effects such as MLC-P reduction. This is the first study discovering low-dose lithium as a drug directly stabilizing human endothelium and ubiquitously augmenting cholinergic endothelium-mediated vasorelaxation. Our findings have translational and potentially clinical impact on cardiovascular and cerebrovascular disease associated with inflammation explaining why lithium can reduce, e.g., the risk for stroke. However, further clinical studies are warranted. PMID- 27999552 TI - I Can't Get No (Boolean) Satisfaction: A Reply to Barrett et al. (2015). PMID- 27999550 TI - The Use of Berlin Heart EXCOR VAD in Children Less than 10 kg: A Single Center Experience. AB - Objective: Despite the improvement in ventricular assist device (VAD) therapy in adults and in adolescents, in infant population only Berlin Heart EXCOR (BHE) is licensed as long term VAD to bridge children to Heart Transplantation (HTx). Particularly demanding in terms of morbidity and mortality are smallest patients namely the ones implanted in the first year of life or with a lower body surface area. This work aims at retrospective reviewing a single center experience in using BHE in children with a body weight under 10 kg. Methods: Data of all pediatric patients under 10 kg undergoing BHE implantation in our institution from March 2002 to March 2016 were retrospectively reviewed. Results: Of the 30 patients enrolled in the study, 53% were male, 87% were affected by a dilated cardiomyopathy with an average weight and age at the implantation of 6.75 +/- 2.16 Kg and 11.57 +/- 10.12 months, respectively. Three patients (10%) required a BIVAD implantation. After the implantation, 7 patients (23%) required re intervention for bleeding and 9 patients (30%) experienced BHE cannulas infection. A total of 56 BHE pump were changed for thrombus formation (1.86 BHE pump for patient). The average duration of VAD support was 132.8 +/- 94.4 days. Twenty patients (67%) were successfully transplanted and 10 patients (33%) died: 7 for major neurological complication and 3 for sepsis. Conclusion: Mechanical support in smaller children with end stage heart failure is an effective strategy for bridging patients to HTx. The need for BIVAD was relegated, in the last years, only to restrictive cardiomiopathy. Further efforts are required in small infants to improve anticoagulation strategy to reduce neurological events and BHE pump changes. PMID- 27999549 TI - The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches. AB - Gap junctions are intercellular proteins responsible for mediating both electrical and biochemical coupling through the exchange of ions, second messengers and small metabolites. They consist of two connexons, with (one) connexon supplied by each cell. A connexon is a hexamer of connexins and currently more than 20 connexin isoforms have been described in the literature thus far. Connexins have a short half-life, and therefore gap junction remodeling constantly occurs with a high turnover rate. Post-translational modification, such as phosphorylation, can modify their channel activities. In this article, the roles of connexins in wound healing and repair are reviewed. Novel strategies for modulating the function or expression of connexins, such as the use of antisense technology, synthetic mimetic peptides and bioactive materials for the treatment of skin wounds, diabetic and pressure ulcers as well as cornea wounds, are considered. PMID- 27999551 TI - How to Measure the Psychological "Flow"? A Neuroscience Perspective. PMID- 27999553 TI - Beta/Gamma Oscillations and Event-Related Potentials Indicate Aberrant Multisensory Processing in Schizophrenia. AB - Recent behavioral and neuroimaging studies have suggested multisensory processing deficits in patients with schizophrenia (SCZ). Thus far, the neural mechanisms underlying these deficits are not well understood. Previous studies with unisensory stimulation have shown altered neural oscillations in SCZ. As such, altered oscillations could contribute to aberrant multisensory processing in this patient group. To test this assumption, we conducted an electroencephalography (EEG) study in 15 SCZ and 15 control participants in whom we examined neural oscillations and event-related potentials (ERPs) in the sound-induced flash illusion (SIFI). In the SIFI multiple auditory stimuli that are presented alongside a single visual stimulus can induce the illusory percept of multiple visual stimuli. In SCZ and control participants we compared ERPs and neural oscillations between trials that induced an illusion and trials that did not induce an illusion. On the behavioral level, SCZ (55.7%) and control participants (55.4%) did not significantly differ in illusion rates. The analysis of ERPs revealed diminished amplitudes and altered multisensory processing in SCZ compared to controls around 135 ms after stimulus onset. Moreover, the analysis of neural oscillations revealed altered 25-35 Hz power after 100 to 150 ms over occipital scalp for SCZ compared to controls. Our findings extend previous observations of aberrant neural oscillations in unisensory perception paradigms. They suggest that altered ERPs and altered occipital beta/gamma band power reflect aberrant multisensory processing in SCZ. PMID- 27999554 TI - Validation of the Spanish Version of the Psychological Sense of School Membership (PSSM) Scale in Chilean Adolescents and Its Association with School-Related Outcomes and Substance Use. AB - School membership appears to be an important factor in explaining the relationship between students and schools, including school staff. School membership is associated with several school-related outcomes, such as academic performance and expectations. Most studies on school membership have been conducted in developed countries. The Psychological Sense of School Membership (PSSM) scale (18 items: 13 positively worded items, 5 negatively worded items) has been widely used to measure this construct, but no studies regarding its validity and reliability have been conducted in Spanish-speaking Latin American countries. This study investigates the psychometric properties, factor structure and reliability of this scale in a sample of 1250 early adolescents in Chile. Both exploratory and confirmatory factor analyses provide evidence of an excellent fit for a one-factor solution after removing the negatively worded items. The internal consistency of this new abbreviated version was 0.92. The association analyses demonstrated that high school membership was associated with better academic performance, stronger school bonding, a reduced likelihood of school misbehavior, and reduced likelihood of substance use. Analyses showed support for the reliability and validity of the PSSM among Chilean adolescents. PMID- 27999555 TI - Intergenerational Transmission of Reflective Functioning. AB - The present study investigated whether, and to what extent, reflective functioning (RF) during preadolescence is associated with maternal attachment security and RF, and with the child's attachment security. Thirty-nine mother preadolescent child dyads from a non-clinical population participated in the study. Maternal and child RF were assessed by applying the Reflective Functioning Scale to the Adult Attachment Interview (AAI) and to the Child Attachment Interview transcripts. Children of mothers who showed a secure attachment model regarding the relationship with their parents during childhood reported higher levels of RF than the children of mothers who were classified as insecure on the AAI. Child RF was positively associated with maternal "Coherence of the Mind" on the AAI and negatively associated with maternal derogation of attachment. A strong, significant association was also found between child attachment security and child RF. Children who were rated as being more emotionally open, more able to balance positive and negative descriptions of their parents, more prone to support their assertions through examples, and more able to positively resolve conflicts with their parents showed higher RF. On the contrary, children who resorted to a higher extent to idealization and dismissal toward their parents showed a lesser degree of RF. Notably, a very strong association was found between the score on the "Overall coherence" subscale and the child's ability to mentalize mixed-ambivalent mental states in the context of their family relationships. As expected, child and maternal RF resulted significantly positively correlated with each other. In particular, only maternal RF (and not maternal attachment security) predicted child RF, and only maternal ability to mentalize mixed-ambivalent mental states predicted the corresponding ability in the children. PMID- 27999556 TI - Affective Meaning, Concreteness, and Subjective Frequency Norms for Indonesian Words. AB - This study investigated the lexical-semantic space organized by the semantic and affective features of Indonesian words and their relationship with gender and cultural aspects. We recruited 1,402 participants who were native speakers of Indonesian to rate affective and lexico-semantic properties of 1,490 Indonesian words. Valence, Arousal, Dominance, Predictability, Subjective Frequency, and Concreteness ratings were collected for each word from at least 52 people. We explored cultural differences between American English ANEW (affective norms for English words), Spanish ANEW, and the new Indonesian inventory [called CEFI (concreteness, emotion, and subjective frequency norms for Indonesian words)]. We found functional relationships between the affective dimensions that were similar across languages, but also cultural differences dependent on gender. PMID- 27999557 TI - Playing 'Pong' Together: Emergent Coordination in a Doubles Interception Task. AB - In this contribution we set out to study how a team of two players coordinated their actions so as to intercept an approaching ball. Adopting a doubles-pong task, six teams of two participants each intercepted balls moving downward across a screen toward an interception axis by laterally displacing participant controlled on-screen paddles. With collisions between paddles resulting in unsuccessful interception, on each trial participants had to decide amongst them who would intercept the ball and who would not. In the absence of possibilities for overt communication, such team decisions were informed exclusively by the visual information provided on the screen. Results demonstrated that collisions were rare and that 91.3 +/- 3.4% of all balls were intercepted. While all teams demonstrated a global division of interception space, boundaries between interception domains were fuzzy and could moreover be shifted away from the center of the screen. Balls arriving between the participants' initial paddle positions often gave rise to both participants initiating an interception movement, requiring one of the participants to abandon the interception attempt at some point so as to allow the other participant to intercept the ball. A simulation of on-the-fly decision making of who intercepted the ball based on a measure capturing the triangular relations between the two paddles and the ball allowed the qualitative aspects of the pattern of observed results to be reproduced, including the timing of abandoning. Overall, the results thus suggest that decisions regarding who intercepts the ball emerge from between-participant interactions. PMID- 27999559 TI - Will I Regret It? Anticipated Negative Emotions Modulate Choices in Moral Dilemmas. AB - We tested if post-decisional emotions of regret, guilt, shame, anger, and disgust can account for individuals' choices in moral dilemmas depicting the choice of letting some people die (non-utilitarian option) or sacrificing one person to save them (utilitarian option). We collected participants' choices and post decisional emotional ratings for each option using Footbridge-type dilemmas, in which the sacrifice of one person is the means to save more people, and Trolley type dilemmas, in which the sacrifice is only a side effect. Moreover, we computed the EEG Readiness Potential to test if the neural activity related to the last phase of decision-making was related to the emotional conflict. Participants reported generally stronger emotions for the utilitarian as compared to the non-utilitarian options, with the exception of anger and regret, which in Trolley-type dilemmas were stronger for the non-utilitarian option. Moreover, participants tended to choose the option that minimized the intensity of negative emotions, irrespective of dilemma type. No significant relationship between emotions and the amplitude of the Readiness Potential emerged. It is possible that anticipated post-decisional emotions play a role in earlier stages of decision-making. PMID- 27999558 TI - An Embodied Approach to Understanding: Making Sense of the World Through Simulated Bodily Activity. AB - Even though understanding is a very widely used concept, both colloquially and in scholarly work, its definition is nebulous and it is not well-studied as a psychological construct, compared to other psychological constructs like learning and memory. Studying understanding based on third-person (e.g., behavioral, neuroimaging) data alone presents unique challenges. Understanding refers to a first-person experience of making sense of an event or a conceptual domain, and therefore requires incorporation of multiple levels of study, at the first-person (phenomenological), behavioral, and neural levels. Previously, psychological understanding was defined as a form of conscious knowing. Alternatively, biofunctional approach extends to unconscious, implicit, automatic, and intuitive aspects of cognition. Here, to bridge these two approaches an embodied and evolutionary perspective is provided to situate biofunctional understanding in theories of embodiment, and to discuss how simulation theories of cognition, which regard simulation of sensorimotor and affective states as a central tenet of cognition, can bridge the gap between biofunctional and psychological understanding. PMID- 27999561 TI - Editorial: Adaptive Hot Cognition: How Emotion Drives Information Processing and Cognition Steers Affective Processing. PMID- 27999560 TI - Weighty: NICE's Not-So-Nice Words. PMID- 27999562 TI - Treatment for Spontaneous Intracranial Dissecting Aneurysms in Childhood: A Retrospective Study of 26 Cases. AB - OBJECTIVE: This study aimed to assess the clinicoradiological features and treatment outcomes of intracranial dissecting aneurysms (IDAs) in childhood. METHODS: We conducted a retrospective study of pediatric patients who were treated for spontaneous IDAs in our institute between January 2010 and December 2015. The clinical presentation, aneurysm characteristics, treatment modality, and outcome were studied. RESULTS: We studied 26 pediatric patients (mean age, 13.4 years; range, 4-18 years) with 31 IDAs who comprised 6.9% of all IDA patients treated during the same period. Seventeen (65.4%) patients were males, and nine (34.6%) were females. The incidence of large (>=10 mm in size) or giant aneurysms (>=25 mm in size) was 65.5%. Twenty-one (80.8%) patients underwent endovascular or surgical treatment and five (19.2%) received conservative treatment. Perioperative complications occurred in three patients, in whom two eventually recovered completely with a Glasgow Outcome Scale (GOS) score of 5 and one partially recovered with a GOS score 4. Overall, 25 (96.2%) patients had a favorable outcome and one (3.8%) had an unfavorable outcome at a mean follow-up of 22.8 months (range, 6-60 months). CONCLUSION: Pediatric IDAs are rare. In this series, endovascular management was a relatively safe and effective method of treatment for pediatric IDAs. However, continued follow-up is required because of the possibility of aneurysm recurrence and de novo aneurysm formation after treatment. PMID- 27999563 TI - Role of lncRNAs in Cellular Aging. AB - Aging is a universal, intrinsic, and time-dependent biological decay that is linked to intricate cellular processes including cellular senescence, telomere shortening, stem cell exhaustion, mitochondrial dysfunction, and deregulated metabolism. Cellular senescence is accepted as one of the core processes of aging at the organism level. Understanding the molecular mechanism underlying senescence could facilitate the development of potential therapeutics for aging and age-related diseases. Recently, the discovery of long non-coding RNAs (lncRNA) provided insights into a novel regulatory layer that can intervene with cellular senescence. Increasing evidence indicates that targeting lncRNAs may impact on senescence pathways. In this review, we will focus on lncRNAs involved in mechanistic pathways governing cellular senescence. PMID- 27999564 TI - Distinct Hepatic Macrophage Populations in Lean and Obese Mice. AB - Obesity is a complex metabolic disorder associated with the development of non communicable diseases such as cirrhosis, non-alcoholic fatty liver disease, and type 2 diabetes. In humans and rodents, obesity promotes hepatic steatosis and inflammation, which leads to increased production of pro-inflammatory cytokines and acute-phase proteins. Liver macrophages (resident as well as recruited) play a significant role in hepatic inflammation and insulin resistance (IR). Interestingly, depletion of hepatic macrophages protects against the development of high-fat-induced steatosis, inflammation, and IR. Kupffer cells (KCs), liver resident macrophages, are the first-line defense against invading pathogens, clear toxic or immunogenic molecules, and help to maintain the liver in a tolerogenic immune environment. During high fat diet feeding and steatosis, there is an increased number of recruited hepatic macrophages (RHMs) in the liver and activation of KCs to a more inflammatory or M1 state. In this review, we will focus on the role of liver macrophages (KCs and RHMs) during obesity. PMID- 27999565 TI - Microbial Community of High Arsenic Groundwater in Agricultural Irrigation Area of Hetao Plain, Inner Mongolia. AB - Microbial communities can play important role in arsenic release in groundwater aquifers. To investigate the microbial communities in high arsenic groundwater aquifers in agricultural irrigation area, 17 groundwater samples with different arsenic concentrations were collected along the agricultural drainage channels of Hangjinhouqi County, Inner Mongolia and examined by illumina MiSeq sequencing approach targeting the V4 region of the 16S rRNA genes. Both principal component analysis and hierarchical clustering results indicated that these samples were divided into two groups (high and low arsenic groups) according to the variation of geochemical characteristics. Arsenic concentrations showed strongly positive correlations with [Formula: see text] and total organic carbon (TOC). Sequencing results revealed that a total of 329-2823 operational taxonomic units (OTUs) were observed at the 97% OTU level. Microbial richness and diversity of high arsenic groundwater samples along the drainage channels were lower than those of low arsenic groundwater samples but higher than those of high arsenic groundwaters from strongly reducing areas. The microbial community structure in groundwater along the drainage channels was different from those in strongly reducing arsenic rich aquifers of Hetao Plain and other high arsenic groundwater aquifers including Bangladesh, West Bengal, and Vietnam. Acinetobacter and Pseudomonas dominated with high percentages in both high and low arsenic groundwaters. Alishewanella, Psychrobacter, Methylotenera, and Crenothrix showed relatively high abundances in high arsenic groundwater, while Rheinheimera and the unidentified OP3 were predominant populations in low arsenic groundwater. Archaeal populations displayed a low occurrence and mainly dominated by methanogens such as Methanocorpusculum and Methanospirillum. Microbial community compositions were different between high and low arsenic groundwater samples based on the results of principal coordinate analysis and co-inertia analysis. Other geochemical variables including TOC, [Formula: see text], oxidation reduction potential, and Fe might also affect the microbial composition. PMID- 27999566 TI - Isolation, Screening, and Identification of Novel Isolates of Actinomycetes from India for Antimicrobial Applications. AB - The search for novel bioactive compounds from the natural environment has rapidly been gaining momentum with the increase in multi-drug resistant (MDR) pathogens. In the present study, the antimicrobial potential of novel actinomycetes has been evaluated by initial screening of six soil samples. Primary and secondary screening was performed against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Candida albicans, Candida tropicalis, Trichophyton rubrum, and other MDR bacterial and fungal test strains, thirteen active isolates were selected for further study. Microbial strains were identified on the basis of growth conditions and other biochemical characters. Five most active microbial strains were identified using 16S rRNA sequence homology and designated as Streptomyces xanthophaeus MTCC 11938, Streptomyces variabilis MTCC 12266, Streptomyces xanthochromogenes MTCC 11937, Streptomyces levis EU 124569, and Streptomyces sp. NCIM 5500. Four antibacterial and three antifungal compounds isolated from the above five isolates were purified and partially characterized using UV absorption and IR spectra. Two antibacterial metabolites, belong to chromone and peptide antibiotic, respectively. The antifungal compounds were found to be of non-polyene nature. In conclusion, we study the isolation of novel bacterial strains of actinomycetes for producing novel compounds having antibacterial and antifungal activities from the unexplored agro-ecological niches of India. Also, this study paves the way for further characterization of these isolates of Streptomyces sp. for their optimum utilization for antimicrobial purposes. PMID- 27999567 TI - Efflux in the Oral Metagenome: The Discovery of a Novel Tetracycline and Tigecycline ABC Transporter. AB - Antibiotic resistance in human bacterial pathogens and commensals is threatening our ability to treat infections and conduct common medical procedures. As novel antibiotics are discovered and marketed it is important that we understand how resistance to them may arise and know what environments may act as reservoirs for such resistance genes. In this study a tetracycline and tigecycline resistant clone was identified by screening a human saliva metagenomic library in Escherichia coli EPI300 on agar containing 5 MUg/ml tetracycline. Sequencing of the DNA insert present within the tetracycline resistant clone revealed it to contain a 7,765 bp fragment harboring novel ABC half transporter genes, tetAB(60). Mutagenesis studies performed on these genes confirmed that they were responsible for the tetracycline and tigecycline resistance phenotypes. Growth studies performed using E. coli EPI300 clones that harbored either the wild type, the mutated, or none of these genes indicated that there was a fitness cost associated with presence of these genes, with the isolate harboring both genes exhibiting a significantly slower growth than control strains. Given the emergence of E. coli strains that are sensitive only to tigecycline and doxycycline it is concerning that such a resistance mechanism has been identified in the human oral cavity. PMID- 27999569 TI - Local and Regional Diversity Reveals Dispersal Limitation and Drift as Drivers for Groundwater Bacterial Communities from a Fractured Granite Formation. AB - Microorganisms found in terrestrial subsurface environments make up a large proportion of the Earth's biomass. Biogeochemical cycles catalyzed by subsurface microbes have the potential to influence the speciation and transport of radionuclides managed in geological repositories. To gain insight on factors that constrain microbial processes within a formation with restricted groundwater flow we performed a meta-community analysis on groundwater collected from multiple discrete fractures underlying the Chalk River Laboratories site (located in Ontario, Canada). Bacterial taxa were numerically dominant in the groundwater. Although these were mainly uncultured, the closest cultivated representatives were from the phenotypically diverse Betaproteobacteria, Deltaproteobacteria, Bacteroidetes, Actinobacteria, Nitrospirae, and Firmicutes. Hundreds of taxa were identified but only a few were found in abundance (>1%) across all assemblages. The remainder of the taxa were low abundance. Within an ecological framework of selection, dispersal and drift, the local and regional diversity revealed fewer taxa within each assemblage relative to the meta-community, but the taxa that were present were more related than predicted by chance. The combination of dispersion at one phylogenetic depth and clustering at another phylogenetic depth suggest both niche (dispersion) and filtering (clustering) as drivers of local assembly. Distance decay of similarity reveals apparent biogeography of 1.5 km. Beta diversity revealed greater influence of selection at shallow sampling locations while the influences of dispersal limitation and randomness were greater at deeper sampling locations. Although selection has shaped each assemblage, the spatial scale of groundwater sampling favored detection of neutral processes over selective processes. Dispersal limitation between assemblages combined with local selection means the meta-community is subject to drift, and therefore, likely reflects the differential historical events that have influenced the current bacterial composition. Categorizing the study site into smaller regions of interest of more closely spaced fractures, or of potentially hydraulically connected fractures, might improve the resolution of an analysis to reveal environmental influences that have shaped these bacterial communities. PMID- 27999568 TI - Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade-A Review. AB - Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 MUg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation. PMID- 27999571 TI - Microbial Community Coalescence for Microbiome Engineering. PMID- 27999570 TI - Gene Turnover Contributes to the Evolutionary Adaptation of Acidithiobacillus caldus: Insights from Comparative Genomics. AB - Acidithiobacillus caldus is an extremely acidophilic sulfur-oxidizer with specialized characteristics, such as tolerance to low pH and heavy metal resistance. To gain novel insights into its genetic complexity, we chosen six A. caldus strains for comparative survey. All strains analyzed in this study differ in geographic origins as well as in ecological preferences. Based on phylogenomic analysis, we clustered the six A. caldus strains isolated from various ecological niches into two groups: group 1 strains with smaller genomes and group 2 strains with larger genomes. We found no obvious intraspecific divergence with respect to predicted genes that are related to central metabolism and stress management strategies between these two groups. Although numerous highly homogeneous genes were observed, high genetic diversity was also detected. Preliminary inspection provided a first glimpse of the potential correlation between intraspecific diversity at the genome level and environmental variation, especially geochemical conditions. Evolutionary genetic analyses further showed evidence that the difference in environmental conditions might be a crucial factor to drive the divergent evolution of A. caldus species. We identified a diverse pool of mobile genetic elements including insertion sequences and genomic islands, which suggests a high frequency of genetic exchange in these harsh habitats. Comprehensive analysis revealed that gene gains and losses were both dominant evolutionary forces that directed the genomic diversification of A. caldus species. For instance, horizontal gene transfer and gene duplication events in group 2 strains might contribute to an increase in microbial DNA content and novel functions. Moreover, genomes undergo extensive changes in group 1 strains such as removal of potential non-functional DNA, which results in the formation of compact and streamlined genomes. Taken together, the findings presented herein show highly frequent gene turnover of A. caldus species that inhabit extremely acidic environments, and shed new light on the contribution of gene turnover to the evolutionary adaptation of acidophiles. PMID- 27999572 TI - Histone Deacetylase Inhibitors Reduce the Number of Herpes Simplex Virus-1 Genomes Initiating Expression in Individual Cells. AB - Although many viral particles can enter a single cell, the number of viral genomes per cell that establish infection is limited. However, mechanisms underlying this restriction were not explored in depth. For herpesviruses, one of the possible mechanisms suggested is chromatinization and silencing of the incoming genomes. To test this hypothesis, we followed infection with three herpes simplex virus 1 (HSV-1) fluorescence expressing recombinants in the presence or absence of histone deacetylases inhibitors (HDACi's). Unexpectedly, a lower number of viral genomes initiated expression in the presence of these inhibitors. This phenomenon was observed using several HDACi: Trichostatin A (TSA), Suberohydroxamic Acid, Valporic Acid, and Suberoylanilide Hydroxamic Acid. We found that HDACi presence did not change the progeny outcome from the infected cells but did alter the kinetic of the gene expression from the viral genomes. Different cell types (HFF, Vero, and U2OS), which vary in their capability to activate intrinsic and innate immunity, show a cell specific basal average number of viral genomes establishing infection. Importantly, in all cell types, treatment with TSA reduced the number of viral genomes. ND10 nuclear bodies are known to interact with the incoming herpes genomes and repress viral replication. The viral immediate early protein, ICP0, is known to disassemble the ND10 bodies and to induce degradation of some of the host proteins in these domains. HDACi treated cells expressed higher levels of some of the host ND10 proteins (promyelocytic leukemia and ATRX), which may explain the lower number of viral genomes initiating expression per cell. Corroborating this hypothesis, infection with three HSV-1 recombinants carrying a deletion in the gene coding for ICP0, show a reduction in the number of genomes being expressed in U2OS cells. We suggest that alterations in the levels of host proteins involved in intrinsic antiviral defense may result in differences in the number of genomes that initiate expression. PMID- 27999573 TI - Reconstruction of Transcription Control Networks in Mollicutes by High-Throughput Identification of Promoters. AB - Bacteria of the class Mollicutes have significantly reduced genomes and gene expression control systems. They are also efficient pathogens that can colonize a broad range of hosts including plants and animals. Despite their simplicity, Mollicutes demonstrate complex transcriptional responses to various conditions, which contradicts their reduction in gene expression regulation mechanisms. We analyzed the conservation and distribution of transcription regulators across the 50 Mollicutes species. The majority of the transcription factors regulate transport and metabolism, and there are four transcription factors that demonstrate significant conservation across the analyzed bacteria. These factors include repressors of chaperone HrcA, cell cycle regulator MraZ and two regulators with unclear function from the WhiA and YebC/PmpR families. We then used three representative species of the major clades of Mollicutes (Acholeplasma laidlawii, Spiroplasma melliferum, and Mycoplasma gallisepticum) to perform promoter mapping and activity quantitation. We revealed that Mollicutes evolved towards a promoter architecture simplification that correlates with a diminishing role of transcription regulation and an increase in transcriptional noise. Using the identified operons structure and a comparative genomics approach, we reconstructed the transcription control networks for these three species. The organization of the networks reflects the adaptation of bacteria to specific conditions and hosts. PMID- 27999574 TI - A Previous Miscarriage and a Previous Successful Pregnancy Have a Different Impact on HLA Antibody Formation during a Subsequent Successful Pregnancy. AB - Inherited paternal HLA antigens from the semi-allogeneic fetus may trigger maternal immune responses during pregnancy, leading to the production of child specific HLA antibodies. The prevalence of these HLA antibodies increases with the number of successful pregnancies. In the present study, we investigated the effect of a single prior miscarriage on HLA antibody formation during a subsequent successful pregnancy. Women with a successful pregnancy with one or more prior miscarriages (n = 229) and women with a successful pregnancy without a prior miscarriage (n = 58), and their children were HLA typed. HLA antibody analyses were performed in these women to identify whether HLA antibodies were formed against mismatched HLA class-I antigens of the last child. The percentage of immunogenic antigens was significantly lower after a single successful pregnancy that was preceded by a single miscarriage (n = 18 women) compared to a successful pregnancy that was preceded by a first successful pregnancy (n = 62 women). Thus, our data suggest that a previous miscarriage has a different impact on child-specific HLA antibody formation during a subsequent successful pregnancy than a previous successful pregnancy. The lower immunogenicity in these women cannot be explained by reduced numbers of immunogenic B-cell and T-cell epitopes. In conclusion, our observations indicate that increasing gravidity is not related to an increased prevalence of HLA antibodies in a single successful pregnancy that was preceded by a single prior miscarriage. PMID- 27999576 TI - Optimizing Research Methods to Understand HIV-Exposed Uninfected Infant and Child Morbidity: Report of the Second HEU Infant and Child Workshop. PMID- 27999577 TI - Latin America: A Development Pole for Phenomics. AB - Latin America and the Caribbean (LAC) has long been associated with the production and export of a diverse range of agricultural commodities. Due to its strategic geographic location, which encompasses a wide range of climates, it is possible to produce almost any crop. The climate diversity in LAC is a major factor in its agricultural potential but this also means climate change represents a real threat to the region. Therefore, LAC farming must prepare and quickly adapt to an environment that is likely to feature long periods of drought, excessive rainfall and extreme temperatures. With the aim of moving toward a more resilient agriculture, LAC scientists have created the Latin American Plant Phenomics Network (LatPPN) which focuses on LAC's economically important crops. LatPPN's key strategies to achieve its main goal are: (1) training of LAC members on plant phenomics and phenotyping, (2) establish international and multidisciplinary collaborations, (3) develop standards for data exchange and research protocols, (4) share equipment and infrastructure, (5) disseminate data and research results, (6) identify funding opportunities and (7) develop strategies to guarantee LatPPN's relevance and sustainability across time. Despite the challenges ahead, LatPPN represents a big step forward toward the consolidation of a common mind-set in the field of plant phenotyping and phenomics in LAC. PMID- 27999575 TI - New Insights into Regulatory T Cells: Exosome- and Non-Coding RNA-Mediated Regulation of Homeostasis and Resident Treg Cells. AB - Regulatory T (Treg) cells are a group of cells that are heterogeneous in origin and in functional activity. Treg cells comprise a necessary balance to adaptive immune responses. As key regulators of self-tolerance, Treg cells have been involved in a series of pathologic processes and considered as therapeutic targets. Here, we summarize recent research regarding Treg cell origins and their functional classification, highlight the role of exosomes and non-coding RNA in modulating Treg cell homeostasis, and discuss the current understanding of resident Treg cells. PMID- 27999578 TI - Genome-Wide Survey of Flavonoid Biosynthesis Genes and Gene Expression Analysis between Black- and Yellow-Seeded Brassica napus. AB - Flavonoids, the compounds that impart color to fruits, flowers, and seeds, are the most widespread secondary metabolites in plants. However, a systematic analysis of these loci has not been performed in Brassicaceae. In this study, we isolated 649 nucleotide sequences related to flavonoid biosynthesis, i.e., the Transparent Testa (TT) genes, and their associated amino acid sequences in 17 Brassicaceae species, grouped into Arabidopsis or Brassicaceae subgroups. Moreover, 36 copies of 21 genes of the flavonoid biosynthesis pathway were identified in Arabidopsis thaliana, 53 were identified in Brassica rapa, 50 in Brassica oleracea, and 95 in B. napus, followed the genomic distribution, collinearity analysis and genes triplication of them among Brassicaceae species. The results showed that the extensive gene loss, whole genome triplication, and diploidization that occurred after divergence from the common ancestor. Using qRT PCR methods, we analyzed the expression of 18 flavonoid biosynthesis genes in 6 yellow- and black-seeded B. napus inbred lines with different genetic background, found that 12 of which were preferentially expressed during seed development, whereas the remaining genes were expressed in all B. napus tissues examined. Moreover, 14 of these genes showed significant differences in expression level during seed development, and all but four of these (i.e., BnTT5, BnTT7, BnTT10, and BnTTG1) had similar expression patterns among the yellow- and black-seeded B. napus. Results showed that the structural genes (BnTT3, BnTT18, and BnBAN), regulatory genes (BnTTG2 and BnTT16) and three encoding transfer proteins (BnTT12, BnTT19, and BnAHA10) might play an crucial roles in the formation of different seed coat colors in B. napus. These data will be helpful for illustrating the molecular mechanisms of flavonoid biosynthesis in Brassicaceae species. PMID- 27999579 TI - Genome-Wide Association Analysis of the Anthocyanin and Carotenoid Contents of Rose Petals. AB - Petal color is one of the key characteristics determining the attractiveness and therefore the commercial value of an ornamental crop. Here, we present the first genome-wide association study for the important ornamental crop rose, focusing on the anthocyanin and carotenoid contents in petals of 96 diverse tetraploid garden rose genotypes. Cultivated roses display a vast phenotypic and genetic diversity and are therefore ideal targets for association genetics. For marker analysis, we used a recently designed Axiom SNP chip comprising 68,000 SNPs with additionally 281 SSRs, 400 AFLPs and 246 markers from candidate genes. An analysis of the structure of the rose population revealed three subpopulations with most of the genetic variation between individual genotypes rather than between clusters and with a high average proportion of heterozygous loci. The mapping of markers significantly associated with anthocyanin and carotenoid content to the related Fragaria and Prunus genomes revealed clusters of associated markers indicating five genomic regions associated with the total anthocyanin content and two large clusters associated with the carotenoid content. Among the marker clusters associated with the phenotypes, we found several candidate genes with known functions in either the anthocyanin or the carotenoid biosynthesis pathways. Among others, we identified a glutathione-S-transferase, 4CL, an auxin response factor and F3'H as candidate genes affecting anthocyanin concentration, and CCD4 and Zeaxanthine epoxidase as candidates affecting the concentration of carotenoids. These markers are starting points for future validation experiments in independent populations as well as for functional genomic studies to identify the causal factors for the observed color phenotypes. Furthermore, validated markers may be interesting tools for marker-assisted selection in commercial breeding programmes in that they provide the tools to identify superior parental combinations that combine several associated markers in higher dosages. PMID- 27999580 TI - Methodology for High-Throughput Field Phenotyping of Canopy Temperature Using Airborne Thermography. AB - Lower canopy temperature (CT), resulting from increased stomatal conductance, has been associated with increased yield in wheat. Historically, CT has been measured with hand-held infrared thermometers. Using the hand-held CT method on large field trials is problematic, mostly because measurements are confounded by temporal weather changes during the time required to measure all plots. The hand held CT method is laborious and yet the resulting heritability low, thereby reducing confidence in selection in large scale breeding endeavors. We have developed a reliable and scalable crop phenotyping method for assessing CT in large field experiments. The method involves airborne thermography from a manned helicopter using a radiometrically-calibrated thermal camera. Thermal image data is acquired from large experiments in the order of seconds, thereby enabling simultaneous measurement of CT on potentially 1000s of plots. Effects of temporal weather variation when phenotyping large experiments using hand-held infrared thermometers are therefore reduced. The method is designed for cost-effective and large-scale use by the non-technical user and includes custom-developed software for data processing to obtain CT data on a single-plot basis for analysis. Broad sense heritability was routinely >0.50, and as high as 0.79, for airborne thermography CT measured near anthesis on a wheat experiment comprising 768 plots of size 2 * 6 m. Image analysis based on the frequency distribution of temperature pixels to remove the possible influence of background soil did not improve broad-sense heritability. Total image acquisition and processing time was ca. 25 min and required only one person (excluding the helicopter pilot). The results indicate the potential to phenotype CT on large populations in genetics studies or for selection within a plant breeding program. PMID- 27999581 TI - Melatonin Increases the Chilling Tolerance of Chloroplast in Cucumber Seedlings by Regulating Photosynthetic Electron Flux and the Ascorbate-Glutathione Cycle. AB - The aim of the study was to monitor the effects of exogenous melatonin on cucumber (Cucumis sativus L.) chloroplasts and explore the mechanisms through which it mitigates chilling stress. Under chilling stress, chloroplast structure was seriously damaged as a result of over-accumulation of reactive oxygen species (ROS), as evidenced by the high levels of superoxide anion (O2-) and hydrogen peroxide (H2O2). However, pretreatment with 200 MUM melatonin effectively mitigated this by suppressing the levels of ROS in chloroplasts. On the one hand, melatonin enhanced the scavenging ability of ROS by stimulating the ascorbate glutathione (AsA-GSH) cycle in chloroplasts. The application of melatonin led to high levels of AsA and GSH, and increased the activity of total superoxide dismutase (SOD, EC 1.15.1.1), ascorbate peroxidase (APX, EC 1.11.1.11), monodehydroascorbate reductase (MDHAR, EC 1.6.5.4) dehydroascorbate reductase (DHAR, EC 1.5.5.1), glutathione reductase (GR, EC1.6.4.2) in the AsA-GSH cycle. On the other hand, melatonin lessened the production of ROS in chloroplasts by balancing the distribution of photosynthetic electron flux. Melatonin helped maintain a high level of electron flux in the PCR cycle [ Je (PCR)] and in the PCO cycle [ Je (PCO)], and suppressed the O2-dependent alternative electron flux Ja (O2-dependent) which is one important ROS source. Results indicate that melatonin increased the chilling tolerance of chloroplast in cucumber seedlings by accelerating the AsA-GSH cycle to enhance ROS scavenging ability and by balancing the distribution of photosynthetic electron flux so as to suppress ROS production. PMID- 27999585 TI - Poaceae Pollen from Southern Brazil: Distinguishing Grasslands (Campos) from Forests by Analyzing a Diverse Range of Poaceae Species. AB - This aim of this study was to distinguish grasslands from forests in southern Brazil by analyzing Poaceae pollen grains. Through light microscopy analysis, we measured the size of the pollen grain, pore, and annulus from 68 species of Rio Grande do Sul. Measurements were recorded of 10 forest species and 58 grassland species, representing all tribes of the Poaceae in Rio Grande do Sul. We measured the polar, equatorial, pore, and annulus diameter. Results of statistical tests showed that arboreous forest species have larger pollen grain sizes than grassland and herbaceous forest species, and in particular there are strongly significant differences between arboreous and grassland species. Discriminant analysis identified three distinct groups representing each vegetation type. Through the pollen measurements we established three pollen types: larger grains (>46 MUm), from the Bambuseae pollen type, medium-sized grains (46-22 MUm), from herbaceous pollen type, and small grains (<22 MUm), from grassland pollen type. The results of our compiled Poaceae pollen dataset may be applied to the fossil pollen of Quaternary sediments. PMID- 27999584 TI - Species Delimitation and Interspecific Relationships of the Genus Orychophragmus (Brassicaceae) Inferred from Whole Chloroplast Genomes. AB - Genetic variations from few chloroplast DNA fragments show lower discriminatory power in the delimitation of closely related species and less resolution ability in discerning interspecific relationships than from nrITS. Here we use Orychophragmus (Brassicaceae) as a model system to test the hypothesis that the whole chloroplast genomes (plastomes), with accumulation of more variations despite the slow evolution, can overcome these weaknesses. We used Illumina sequencing technology via a reference-guided assembly to construct complete plastomes of 17 individuals from six putatively assumed species in the genus. All plastomes are highly conserved in genome structure, gene order, and orientation, and they are around 153 kb in length and contain 113 unique genes. However, nucleotide variations are quite substantial to support the delimitation of all sampled species and to resolve interspecific relationships with high statistical supports. As expected, the estimated divergences between major clades and species are lower than those estimated from nrITS probably due to the slow substitution rate of the plastomes. However, the plastome and nrITS phylogenies were contradictory in the placements of most species, thus suggesting that these species may have experienced complex non-bifurcating evolutions with incomplete lineage sorting and/or hybrid introgressions. Overall, our case study highlights the importance of using plastomes to examine species boundaries and establish an independent phylogeny to infer the speciation history of plants. PMID- 27999582 TI - The Propensity of Pentatricopeptide Repeat Genes to Evolve into Restorers of Cytoplasmic Male Sterility. AB - Cytoplasmic male sterility (CMS) is a widespread phenotype in plants, which present a defect in the production of functional pollen. The male sterilizing factors usually consist of unusual genes or open reading frames encoded by the mitochondrial genome. CMS can be suppressed by specific nuclear genes called restorers of fertility (Rfs). In the majority of cases, Rf genes produce proteins that act directly on the CMS conferring mitochondrial transcripts by binding them specifically and promoting processing events. In this review, we explore the wide array of mechanisms guiding fertility restoration. PPR proteins represent the most frequent protein class among identified Rfs and they exhibit ideal characteristics to evolve into restorer of fertility when the mechanism of restoration implies a post-transcriptional action. Here, we review the literature that highlights those characteristics and help explain why PPR proteins are ideal for the roles they play as restorers of fertility. PMID- 27999586 TI - Glyphosate-Resistant Parthenium hysterophorus in the Caribbean Islands: Non Target Site Resistance and Target Site Resistance in Relation to Resistance Levels. AB - Glyphosate has been the most intensely herbicide used worldwide for decades, and continues to be a single tool for controlling weeds in woody crops. However, the adoption of this herbicide in a wide range of culture systems has led to the emergence of resistant weeds. Glyphosate has been widely used primarily on citrus in the Caribbean area, but a study of resistance in the Caribbean islands of Cuba and the Dominican Republic has never been carried out. Unfortunately, Parthenium hysterophorus has developed glyphosate-resistance in both islands, independently. The resistance level and mechanisms of different P. hysterophorus accessions (three collected in Cuba (Cu-R) and four collected in the Dominican Republic (Do R) have been studied under greenhouse and laboratory conditions. In in vivo assays (glyphosate dose causing 50% reduction in above-ground vegetative biomass and survival), the resistance factor levels showed susceptible accessions (Cu-S >= Do-S), low-resistance accessions (Cu-R3 < Do-R4), medium-resistance accessions (Do-R3 < Cu-R2 < Do-R2) and high-resistance accessions (Do-R1 < Cu-R1). In addition, the resistance factor levels were similar to those found in the shikimic acid accumulation at 1000 MUM of glyphosate (Cu-R1 >= Do-R1 > Do-R2 > Cu R2 > Do-R3 > Do-R4 > Cu-R3 >> Cu-S >= Do-S). Glyphosate was degraded to aminomethylphosphonic acid, glyoxylate and sarcosine by >88% in resistant accessions except in Cu-R3 and Do-R4 resistant accessions (51.12 and 44.21, respectively), whereas a little glyphosate (<9.32%) was degraded in both susceptible accessions at 96 h after treatment. There were significant differences between P. hysterophorus accessions in the 5-enolpyruvylshikimate-3 phosphate synthase (EPSPS) activity enzyme with and without different glyphosate rates. The R accessions showed values of between 0.026 and 0.21 MUmol MUg-1 TSP protein min-1 basal EPSPS activity values with respect to the S (0.024 and 0.025) accessions. The same trend was found in the EPSPS enzyme activity treated with glyphosate, where a higher enzyme activity inhibition (glyphosate MUM) corresponded to greater resistance levels in P. hysterophorus accessions. One amino acid substitution was found at position 106 in EPSPS, consisting of a proline to serine change in Cu-R1, Do-R1 Do-R2. The above-mentioned results indicate that high resistance values are determined by the number of defense mechanisms (target-site and non-target-site resistance) possessed by the different P. hysterophorus accessions, concurrently. PMID- 27999583 TI - Structural Basis for Redox Regulation of Cytoplasmic and Chloroplastic Triosephosphate Isomerases from Arabidopsis thaliana. AB - In plants triosephosphate isomerase (TPI) interconverts glyceraldehyde 3 phosphate (G3P) and dihydroxyacetone phosphate (DHAP) during glycolysis, gluconeogenesis, and the Calvin-Benson cycle. The nuclear genome of land plants encodes two tpi genes, one gene product is located in the cytoplasm and the other is imported into the chloroplast. Herein we report the crystal structures of the TPIs from the vascular plant Arabidopsis thaliana (AtTPIs) and address their enzymatic modulation by redox agents. Cytoplasmic TPI (cTPI) and chloroplast TPI (pdTPI) share more than 60% amino acid identity and assemble as (beta-alpha)8 dimers with high structural homology. cTPI and pdTPI harbor two and one accessible thiol groups per monomer respectively. cTPI and pdTPI present a cysteine at an equivalent structural position (C13 and C15 respectively) and cTPI also contains a specific solvent accessible cysteine at residue 218 (cTPI-C218). Site directed mutagenesis of residues pdTPI-C15, cTPI-C13, and cTPI-C218 to serine substantially decreases enzymatic activity, indicating that the structural integrity of these cysteines is necessary for catalysis. AtTPIs exhibit differential responses to oxidative agents, cTPI is susceptible to oxidative agents such as diamide and H2O2, whereas pdTPI is resistant to inhibition. Incubation of AtTPIs with the sulfhydryl conjugating reagents methylmethane thiosulfonate (MMTS) and glutathione inhibits enzymatic activity. However, the concentration necessary to inhibit pdTPI is at least two orders of magnitude higher than the concentration needed to inhibit cTPI. Western-blot analysis indicates that residues cTPI-C13, cTPI-C218, and pdTPI-C15 conjugate with glutathione. In summary, our data indicate that AtTPIs could be redox regulated by the derivatization of specific AtTPI cysteines (cTPI-C13 and pdTPI-C15 and cTPI-C218). Since AtTPIs have evolved by gene duplication, the higher resistance of pdTPI to redox agents may be an adaptive consequence to the redox environment in the chloroplast. PMID- 27999587 TI - Phenotyping: Using Machine Learning for Improved Pairwise Genotype Classification Based on Root Traits. AB - Phenotyping local crop cultivars is becoming more and more important, as they are an important genetic source for breeding - especially in regard to inherent root system architectures. Machine learning algorithms are promising tools to assist in the analysis of complex data sets; novel approaches are need to apply them on root phenotyping data of mature plants. A greenhouse experiment was conducted in large, sand-filled columns to differentiate 16 European Pisum sativum cultivars based on 36 manually derived root traits. Through combining random forest and support vector machine models, machine learning algorithms were successfully used for unbiased identification of most distinguishing root traits and subsequent pairwise cultivar differentiation. Up to 86% of pea cultivar pairs could be distinguished based on top five important root traits (Timp5) - Timp5 differed widely between cultivar pairs. Selecting top important root traits (Timp) provided a significant improved classification compared to using all available traits or randomly selected trait sets. The most frequent Timp of mature pea cultivars was total surface area of lateral roots originating from tap root segments at 0-5 cm depth. The high classification rate implies that culturing did not lead to a major loss of variability in root system architecture in the studied pea cultivars. Our results illustrate the potential of machine learning approaches for unbiased (root) trait selection and cultivar classification based on rather small, complex phenotypic data sets derived from pot experiments. Powerful statistical approaches are essential to make use of the increasing amount of (root) phenotyping information, integrating the complex trait sets describing crop cultivars. PMID- 27999588 TI - Divergent Regulation of CBF Regulon on Cold Tolerance and Plant Phenotype in Cassava Overexpressing Arabidopsis CBF3 Gene. AB - Cassava is a tropical origin plant that is sensitive to chilling stress. In order to understand the CBF cold response pathway, a well-recognized regulatory mechanism in temperate plants, in cassava, overexpression of an Arabidopsis CBF3 gene is studied. This gene renders cassava increasingly tolerant to cold and drought stresses but is associated with retarded plant growth, leaf curling, reduced storage root yield, and reduced anthocyanin accumulation in a transcript abundance-dependent manner. Physiological analysis revealed that the transgenic cassava increased proline accumulation, reduced malondialdehyde production, and electrolyte leakage under cold stress. These transgenic lines also showed high relative water content when faced with drought. The expression of partial CBF targeted genes in response to cold displayed temporal and spatial variations in the wild-type and transgenic plants: highly inducible in leaves and less altered in apical buds. In addition, anthocyanin accumulation was inhibited by downregulating the expression of genes involved in its biosynthesis and by interplaying between the CBF3 and the endogenous transcription factors. Thus, the heterologous CBF3 modulates the expression of stress-related genes and carries out a series of physiological adjustments under stressful conditions, showing a varied regulation pattern of CBF regulon from that of cassava CBFs. PMID- 27999590 TI - Annealing Ant Colony Optimization with Mutation Operator for Solving TSP. AB - Ant Colony Optimization (ACO) has been successfully applied to solve a wide range of combinatorial optimization problems such as minimum spanning tree, traveling salesman problem, and quadratic assignment problem. Basic ACO has drawbacks of trapping into local minimum and low convergence rate. Simulated annealing (SA) and mutation operator have the jumping ability and global convergence; and local search has the ability to speed up the convergence. Therefore, this paper proposed a hybrid ACO algorithm integrating the advantages of ACO, SA, mutation operator, and local search procedure to solve the traveling salesman problem. The core of algorithm is based on the ACO. SA and mutation operator were used to increase the ants population diversity from time to time and the local search was used to exploit the current search area efficiently. The comparative experiments, using 24 TSP instances from TSPLIB, show that the proposed algorithm outperformed some well-known algorithms in the literature in terms of solution quality. PMID- 27999589 TI - Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms. AB - Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a three-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, three of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the three long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the three mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal, and osmotic stresses. Our findings empirically validate the hypothesis suggesting that hormetic selective forces can drive the evolution of longevity regulation mechanisms within an ecosystem. PMID- 27999592 TI - Corrigendum to "Radiological Features of Gastrointestinal Lymphoma". AB - [This corrects the article DOI: 10.1155/2016/2498143.]. PMID- 27999591 TI - Endoscopic Management of the Difficult Bile Duct Stones: A Single Tertiary Center Experience. AB - Background. Most common bile duct (CBD) stones can be removed with standard techniques using endoscopic retrograde cholangiopancreatography (ERCP), but in some cases additional methods are needed. In this study we aimed to investigate the management of patients with difficult stones and the factors that affect the outcome of patients that have undergone periodic endobiliary stenting. Materials and Methods. Data of 1529 patients with naive papilla who had undergone ERCP with an indication of CBD stones was evaluated retrospectively. Stones that could not be removed with standard techniques were defined as "difficult stones." Cholangiograms of patients who had difficult stones were revised prospectively. Results. Two hundred and eight patients (13.6%) had difficult stones; 150 of these patients were followed up with periodic endobiliary stenting and successful biliary clearance was achieved in 85.3% of them. Both CBD (p < 0.001) and largest stone size (p < 0.001) were observed to be significantly reduced between the first and the last procedure. This difference was even more significant in successfully treated patients. Conclusions. Periodic endobiliary stenting can be used as an effective treatment for patients with difficult stones. Sizes of the CBD and of the largest stone are independent risk factors that affect the success rate. PMID- 27999594 TI - CBCT Assessment of Mental Foramen Position Relative to Anatomical Landmarks. AB - Purpose. This study was carried out on an Iranian population aiming to investigate mental foramen position relative to inferior border of mandible and skeletal midline and its gender and age differences on CBCT projections. Materials and Methods. A number of 180 CBCT images of patients were analyzed in different planes (tangential, cross-sectional, and axial). The distances from the superior border of mental foramen to the inferior border of mandible and from the anterior border of mental foramen to the midline were calculated. Results. The mean distance from mental foramen to the inferior border of mandible in the right side was 13.26 mm (SD +/- 2.34) and in the left side was 13.37 mm (SD +/- 2.19). There was a statistically significant difference between genders in terms of the distance between mental foramen and inferior border of mandible (P value = 0.000). The mean distances from mental foramen to midline were 25.86 mm (SD +/- 0.27) and 25.53 mm (SD +/- 0.31) in the right and left sides, respectively. Conclusions. The vertical and horizontal positions of mental foramen can be determined from stable anatomical landmarks such as mandibular inferior border and skeletal midline in both dentulous and edentulous patients. The distance from the superior border of mental foramen to the inferior border of mandible exhibited sexual dimorphism. PMID- 27999593 TI - Long-Term Clinical Outcomes of Invasive Giant Prolactinomas after a Mean Ten-Year Followup. AB - Objective. The aim of this study is to observe clinical outcomes after more than ten years of followup in a group of patients with invasive giant prolactinomas (IGPs) treated with dopamine agonists (DAs). Methods. Twenty-five patients met the criteria of IGPs, among which 16 patients primarily received bromocriptine (BRC) and the other nine had undergone unsuccessful microsurgery prior to BRC treatment. Results. After a mean follow-up period of 135.5 +/- 4.7 months, the clinical symptoms in all patients improved by different degrees. Tumor volume was decreased by a mean of 98.6%, and the tumors of 19 patients had almost completely disappeared. The mean duration of treatment at maximal doses of BRC was 48.5 months. At the last follow-up visit, nineteen patients had normal PRL levels, and 14 of these patients had received the low-dose BRC treatment (at an average of 2.9 +/- 0.3 mg/d). Younger patients < 25 years had a significantly higher rate of persistent hyperprolactinemia after long-term BRC treatment (p = 0.043). Conclusion. DAs are a first-line therapy for IGPs because they can effectively achieve long-term control in both shrinking tumor volume and normalizing the PRL level, and majority of patients need low-dose DA maintenance. Younger patients are prone to persistent hyperprolactinemia despite long-term DA treatment. PMID- 27999595 TI - Seborrheic Keratoses as the First Sign of Bladder Carcinoma: Case Report of Leser Trelat Sign in a Rare Association with Urinary Tract Cancer. AB - Introduction. Skin disorders can be the first manifestation of occult diseases. The recognition of typical paraneoplastic dermatoses may anticipate the cancer diagnosis and improve its prognosis. Although rarely observed, the sudden appearance and/or rapid increase in number and size of seborrheic keratoses can be associated with malignant neoplasms, known as the sign of Leser-Trelat. The aim of this report is to unveil a case of a patient whose recently erupted seborrheic keratoses led to investigation and consequent diagnosis of bladder cancer. Case Presentation. A 67-year-old man was admitted to the intensive care unit due to an exacerbation of chronic obstructive pulmonary disease (COPD). On physical examination, multiple seborrheic keratoses on the back of the hands, elbows, and trunk were observed; the patient had a 4-month history of these lesions yet was asymptomatic. The possibility of Leser-Trelat syndrome justified the investigation for neoplasia, and a bladder carcinoma was detected by CT-scan. The patient denied previous hematuria or any other related symptoms. Many of the lesions regressed during oncologic treatment. Conclusion. Despite the critics on the validity of the sign of Leser-Trelat, our patient fulfills the description of the disease, though urinary malignancy is a rare association. That corroborates the need of further investigation when there is a possibility of paraneoplastic manifestation. PMID- 27999596 TI - Traumatic Pseudoaneurysm of the Internal Maxillary Artery: A Rare Life Threatening Hemorrhage as a Complication of Maxillofacial Fractures. AB - Pseudoaneurysm of the internal maxillary artery due to a traumatic event is a rare condition. Pseudoaneurysms are usually directly produced by arteries break with extravasation of blood. The compressed perivascular tissue forms the wall of aneurysmal sac. Then, this sac gradually expands and can be damaged. It is rare to see pseudoaneurysms of IMA. They are usually associated with fracture of the neck of the mandible. To the best of our knowledge the pseudoaneurysm of the internal maxillary artery related to maxillofacial trauma is an event extremely rare in the literature and if not quickly managed can lead to the patient's death. This case underlines how the close cooperation between surgeons and radiologists results in a quick diagnosis and management of such pathological events. PMID- 27999598 TI - Hematopoietic and Mesenchymal Stem Cells in Biomedical and Clinical Applications. PMID- 27999599 TI - In Vitro Characterization of Human Mesenchymal Stem Cells Isolated from Different Tissues with a Potential to Promote Complex Bone Regeneration. AB - Bone tissue regeneration is a major, worldwide medical need, and several strategies have been developed to support the regeneration of extensive bone defects, including stem cell based bone grafts. In addition to the application of stem cells with high osteogenic potential, it is important to maintain proper blood flow in a bone graft to avoid inner graft necrosis. Mesenchymal stem cells (MSCs) may form both osteocytes and endothelial cells; therefore we examined the combined in vitro osteogenic and endothelial differentiation capacities of MSCs derived from adipose tissue, Wharton's jelly, and periodontal ligament. Based on a detailed characterization presented here, MSCs isolated from adipose tissue and periodontal ligament may be most appropriate for generating vascularized bone grafts. PMID- 27999597 TI - Construction of a Dual-Fluorescence Reporter System to Monitor the Dynamic Progression of Pluripotent Cell Differentiation. AB - Oct4 is a crucial germ line-specific transcription factor expressed in different pluripotent cells and downregulated in the process of differentiation. There are two conserved enhancers, called the distal enhancer (DE) and proximal enhancer (PE), in the 5' upstream regulatory sequences (URSs) of the mouse Oct4 gene, which were demonstrated to control Oct4 expression independently in embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). We analyzed the URSs of the pig Oct4 and identified two similar enhancers that were highly consistent with the mouse DE and PE. A dual-fluorescence reporter was later constructed by combining a DE-free-Oct4-promoter-driven EGFP reporter cassette with a PE-free Oct4-promoter-driven mCherry reporter cassette. Then, it was tested in a mouse ESC-like cell line (F9) and a mouse EpiSC-like cell line (P19) before it is formally used for pig. As a result, a higher red fluorescence was observed in F9 cells, while green fluorescence was primarily detected in P19 cells. This fluorescence expression pattern in the two cell lines was consistent with that in the early naive pluripotent state and late primed pluripotent state during differentiation of mouse ESCs. Hence, this reporter system will be a convenient tool for screening out ESC-like naive pluripotent stem cells from other metastable state cells in a heterogenous population. PMID- 27999600 TI - Mesenchymal Stem Cells as Therapeutics Agents: Quality and Environmental Regulatory Aspects. AB - Mesenchymal stem cells (MSCs) are one of the main stem cells that have been used for advanced therapies and regenerative medicine. To carry out the translational clinical application of MSCs, their manufacturing and administration in human must be controlled; therefore they should be considered as medicine: stem cell based medicinal products (SCMPs). The development of MSCs as SCMPs represents complicated therapeutics due to their extreme complex nature and rigorous regulatory oversights. The manufacturing process of MSCs needs to be addressed in clean environments in compliance with requirements of Good Manufacturing Practice (GMP). Facilities should maintain these GMP conditions according to international and national medicinal regulatory frameworks that introduce a number of specifications in order to produce MSCs as safe SCMPs. One of these important and complex requirements is the environmental monitoring. Although a number of environmental requirements are clearly defined, some others are provided as recommendations. In this review we aim to outline the current issues with regard to international guidelines which impact environmental monitoring in cleanrooms and clean areas for the manufacturing of MSCs. PMID- 27999601 TI - Reservoir Cannulas for Pediatric Oxygen Therapy: A Proof-of-Concept Study. AB - Hypoxemia is a complication of pneumonia-the leading infectious cause of death in children worldwide. Treatment generally requires oxygen-enriched air, but access in low-resource settings is expensive and unreliable. We explored use of reservoir cannulas (RCs), which yield oxygen savings in adults but have not been examined in children. Toddler, small child, and adolescent breathing profiles were simulated with artificial lung and airway models. An oxygen concentrator provided flow rates of 0 to 5 L/min via a standard nasal cannula (NC) or RC, and delivered oxygen fraction (FdO2) was measured. The oxygen savings ratio (SR) and absolute flow savings (AFS) were calculated, comparing NC and RC. We demonstrated proof-of-concept that pendant RCs could conserve oxygen during pediatric therapy. SR mean and standard deviation were 1.1 +/- 0.2 to 1.4 +/- 0.4, 1.1 +/- 0.1 to 1.7 +/- 0.3, and 1.3 +/- 0.1 to 2.4 +/- 0.3 for toddler, small child, and adolescent models, respectively. Maximum AFS observed were 0.3 +/- 0.3, 0.2 +/- 0.1, and 1.4 +/- 0.3 L/min for the same models. RCs have the potential to reduce oxygen consumption during treatment of hypoxemia in children; however, further evaluation of products is needed, followed by clinical analysis in patients. PMID- 27999602 TI - Anaphylaxis to supplemental oral lactase enzyme. AB - BACKGROUND: Anaphylactic reactions involving IgE mediated hypersensitivity have been frequently reported for a number of uncommon foods. However, cases of anaphylaxis to over the counter vitamins and oral supplements have been rarely published. Lactose intolerance affects approximately 20% of Canadians and roughly 70% of the world's population of any age. Lactose intolerance develops primarily due to the absence of the enzyme lactase and treatment involves avoidance of lactose-containing foods or ingestion of commercially available lactase enzyme preparations prior to their consumption. This case report represents the first documented evidence of anaphylaxis after exposure to supplemental lactase enzyme preparation. CASE PRESENTATION: A 38 years old Caucasian female presented with a history of self-diagnosed adult-onset lactose intolerance and a suspected allergy to lactase containing tablets. She reported an episode of bilateral orbital swelling, shortness of breath, and throat constriction after oral ingestion of a supplemental lactase enzyme tablet. Her symptoms slowly resolved with the administration of inhaled salbutamol and oral diphenhydramine. She handled lactase tablets for years to her children who were lactose intolerant, but had never ingested the tablets herself prior to the reported episode. In clinic, physical examination was benign, and skin prick testing to a slurry of the lactase tablet revealed a strongly positive reaction wheal size of 10 mm and flare of 60 mm with normal controls. The patient reported throat tightness and constriction after skin prick testing and required cetirizine treatment and observation in clinic. Subsequent skin testing was performed with individual ingredients of the lactase tablet provided by the manufacturer and Aspergillus niger, a common bacteria used in lactase preparations. Only concentrated lactase enzyme elicited a positive response. The patient was diagnosed with lactase tablet induced anaphylaxis due to synthetic lactase enzyme IgE mediated allergy, and was advised to avoid all products containing lactase enzymes as an ingredient and to carry an epinephrine auto-injector. CONCLUSION: This is the first documented case report of an anaphylactic reaction to supplemental lactase enzyme. This case report reinforces the importance of thorough allergy assessment, education on avoidance of triggers, in particular with uncommon allergens. PMID- 27999603 TI - Polyethylene glycol as a cause of anaphylaxis. AB - BACKGROUND: Polyethylene glycols (PEGs) or macrogols are polyether compounds and are widely used as additives in pharmaceuticals, cosmetics, and food. CASE REPORT: We report on a Caucasian patient experiencing recurrent severe allergic reactions to several drugs. An extensive diagnostic workup including skin prick tests, intradermal tests (IDT) and a double-blind oral challenge was performed to identify the trigger of anaphylaxis. In the present case hypersensitivity to the additive polyethylene glycol was confirmed by an IDT suggesting an Immunoglobulin E-dependent mechanism as a cause of the reaction. CONCLUSION: Potential life threatening hypersensitivity reactions to hidden molecules like macrogol may be underdiagnosed. Cases of immediate-type PEG hypersensitivity were reported with increasing frequency. The awareness regarding the allergenic potential of PEG should be raised and a proper product labelling is crucial to prevent PEG mediated hypersensitivity. PMID- 27999604 TI - The Construction of Unsmooth Pulse Images in Traditional Chinese Medicine Based on Wave Intensity Technology. AB - Unsmooth pulse is one of the most important pulses in TCM diagnostics. We constructed the wave intensity (WI) images of unsmooth pulse based on the pressure wave (P), flow velocity wave (U), and WI [(dP/dt)(dU/dt)] by ALOKA Prosound alpha 10 Color Doppler. The characteristic of Cunkou normal pulse could be summarized as follows: compared to Renying pulse, its W1 amplitude is smaller and NA wave is more obvious, while the W2 wave is indistinct or even invisible, and the R-1st is longer than that of Renying pulse. The principal U wave of Renying pulse looks like "Lambda" shape, while it looks like an arched blunt "?" shape in Cunkou pulse, and the amplitude of U wave in Cunkou pulse is smaller. The direction of the principal U wave in Cunkou unsmooth pulse is up, which shows hoof boots "h" shape with high amplitude and a significant notch on declined branch; the amplitude of predicrotic wave in unsmooth pulse P wave is significantly higher, which could be even higher than that of h1, resulting in early appearance of h3 or integrating with h1, which forms a wide and blunt peak. Unsmooth pulse shows poorer vascular elasticity and greater vascular stiffness. PMID- 27999606 TI - Traditional Chinese Medicine QPYF as Preventive Treatment for Clostridium difficile Associated Diarrhea in a Mouse Model. AB - Traditional Chinese medicine QPYF has a good effect for treating antibiotic associated diarrhea in clinical practice. The aim of this study is to test its efficacy to prevent Clostridium difficile associated diarrhea (CDAD) in a mouse model. C57BL/6 mice were infected with Clostridium difficile VPI 10463 after exposure to antimicrobial mixture. QPYF was administered from 7 days prior to Clostridium difficile infection to 20 days after infection, and its effect was compared with no treatment and receiving placebo. The mice were monitored for 20 days and the percent survival, disease activity index, weight loss, colon histopathology, and the levels of toxins in the feces were measured. The expressions of TNF alpha, MCP-1, NF-kappaB p65, and phospho-NF-kappaB p65 in the colon were presented by immunohistochemistry. The survival rate of QPYF group (93.75%) was higher than that of model control group (65%). The mice treated with QPYF had a lower weight loss and disease activity index, compared to the mice with placebo. A significantly lower level of histopathology scores, toxins in the feces, and TNF alpha, MCP-1, NF-kappaB p65, and phospho-NF-kappaB p65 were detected for QPYF-treated mice. Traditional Chinese medicine QPYF showed a good preventive effect for CDAD in a mouse model. PMID- 27999605 TI - Fever: Views in Anthroposophic Medicine and Their Scientific Validity. AB - Objective. To conduct a scoping review to characterize how fever is viewed in anthroposophic medicine (AM) and discuss the scientific validity of these views. Methods. Systematic searches were run in Medline, Embase, CAMbase, and Google Scholar. Material from anthroposophic medical textbooks and articles was also used. Data was extracted and interpreted. Results. Most of the anthroposophic literature on this subject is in the German language. Anthroposophic physicians hold a beneficial view on fever, rarely suppress fever with antipyretics, and often use complementary means of alleviating discomfort. In AM, fever is considered to have the following potential benefits: promoting more complete recovery; preventing infection recurrences and atopic diseases; providing a unique opportunity for caregivers to provide loving care; facilitating individual development and resilience; protecting against cancer and boosting the anticancer effects of mistletoe products. These views are discussed with regard to the available scientific data. Conclusion. AM postulates that fever can be of short term and long-term benefit in several ways; many of these opinions have become evidence-based (though still often not practiced) while others still need empirical studies to be validated, refuted, or modified. PMID- 27999607 TI - Effect of Loquat Leaf Extract on Muscle Strength, Muscle Mass, and Muscle Function in Healthy Adults: A Randomized, Double-Blinded, and Placebo-Controlled Trial. AB - Ursolic acid (UA) is the major active component of the loquat leaf extract (LLE) and several previous studies have indicated that UA may have the ability to prevent skeletal muscle atrophy. Therefore, we conducted a randomized, double blind, and placebo-controlled study to investigate the effects of the LLE on muscle strength, muscle mass, muscle function, and metabolic markers in healthy adults; the safety of the compound was also evaluated. We examined the peak torque/body weight at 60 degrees /s knee extension, handgrip strength, skeletal muscle mass, physical performance, and metabolic parameters at baseline, as well as after 4 and 12 weeks of intervention. Either 500 mg of LLE (50.94 mg of UA) or a placebo was administered to fifty-four healthy adults each day for 12 weeks; no differences in muscle strength, muscle mass, and physical performance were observed between the two groups. However, the right-handgrip strength of female subjects in the LLE group was found to be significantly better than that of subjects in the control group (P = 0.047). Further studies are required to determine the optimal dose and duration of LLE supplementation to confirm the first-stage study results for clinical application. ClinicalTrials.gov Identifier is NCT02401113. PMID- 27999608 TI - Anticancer Activity, Antioxidant Activity, and Phenolic and Flavonoids Content of Wild Tragopogon porrifolius Plant Extracts. AB - Tragopogon porrifolius, commonly referred to as white salsify, is an edible herb used in folk medicine to treat cancer. Samples of Tragopogon porrifolius plant grown wild in Palestine were extracted with different solvents: water, 80% ethanol, and 100% ethanol. The extracts were analyzed for their total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity (AA). Four different antioxidant assays were used to evaluate AA of the extracts: two measures the reducing power of the extracts (ferric reducing antioxidant power (FRAP) and cupric reducing antioxidant power (CUPRAC)), while two other assays measure the scavenging ability of the extracts (2,2-azino-di-(3 ethylbenzothialozine-sulphonic acid (ABTS)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH)). Anticancer activity of the plant extracts were also tested on HOS and KHOS osteosarcoma cell lines. The results revealed that the polarity of the extraction solvent affects the TPC, TFC, and AA. It was found that both TPC and AA are highest for plant extracted with 80% ethanol, followed by water, and finally with 100% ethanol. TFC however was the highest in the following order: 80% ethanol > 100% ethanol > water. The plant extracts showed anticancer activities against KHOS cancer cell lines; they reduced total cell count and induced cell death in a drastic manner. PMID- 27999609 TI - It is worth 10 million working hours a year to have your toilet paper folded? AB - BACKGROUND: From our experience the toilet paper is folded in the bathrooms in rooms in branded hotels. We aimed to study the total time yearly spent in the world on folding hotel toilet paper. METHOD: Three investigators clocked 60 folding toilet paper events and calculated the mean time. The mean folding time was 5.73 s (interquartile range 4.50-6.56). Using the calculated extra time it takes to fold the toilet paper and the number of hotel nights spent we estimated the total time spent in the world each year to fold the toilet paper. For sensitivity analyses we used different assumptions on number of hotel beds, occupancy rate and folding time. RESULTS: Assuming an extra 10 s spent on folding toilet paper, approximately 10 million hours are globally spent on folding toilet paper every year. This corresponds to more than 5000 man-years of work. In a hotel with yearly full coverage of 200 beds skipping folding the toilet paper corresponds to around 200 h of time that could be spent elsewhere. CONCLUSION: To take away unnecessary duties from hotel room cleaners would increase their health and well-being and save time that could be better spent. Is it really defendable and appropriate that someone else has spent time on folding the toilet paper you are just about to use? PMID- 27999610 TI - Selected toxic and essential heavy metals in impacted teeth and the surrounding mandibular bones of people exposed to heavy metals in the environment. AB - BACKGROUND: The elemental composition of bones and teeth can allow exposure to heavy metals in the environment to be estimated. The aim of this study was to determine whether impacted mandibular teeth and the surrounding bones can be used as biomonitoring media to assess exposure to heavy metals. METHODS: The research materials were 67 impacted lower third molars and samples of the cortical bone removed when the wisdom teeth were surgically extracted. The samples were from people living in two areas with different environmental concentrations of heavy metals. The cadmium, chromium, copper, iron, lead, manganese, and zinc concentrations in the samples were determined by atomic absorption spectrometry with flame atomization. RESULTS: The cadmium and lead concentrations in the impacted third molars and the bones surrounding the teeth were significantly higher for people living in the relatively polluted Ruda Slaska region than for people living in Bielsko-Biala region. Significantly higher chromium, copper, manganese, and zinc concentrations were found in the bones surrounding the impacted teeth from people living in Ruda Slaska than in the bones surrounding the impacted teeth from people living in Bielsko-Biala. The cadmium concentrations in impacted teeth and the surrounding bones were significantly positively correlated. CONCLUSION: The results indicated that impacted mandibular teeth and the surrounding mandibular bones may reflect the exposure of people to cadmium and lead in the environment. This conclusion, however, must be verified in future research projects designed to exclude the possibility of additional dietary, occupational, and other types of exposure to heavy metals. PMID- 27999611 TI - Poisson Mixture Regression Models for Heart Disease Prediction. AB - Early heart disease control can be achieved by high disease prediction and diagnosis efficiency. This paper focuses on the use of model based clustering techniques to predict and diagnose heart disease via Poisson mixture regression models. Analysis and application of Poisson mixture regression models is here addressed under two different classes: standard and concomitant variable mixture regression models. Results show that a two-component concomitant variable Poisson mixture regression model predicts heart disease better than both the standard Poisson mixture regression model and the ordinary general linear Poisson regression model due to its low Bayesian Information Criteria value. Furthermore, a Zero Inflated Poisson Mixture Regression model turned out to be the best model for heart prediction over all models as it both clusters individuals into high or low risk category and predicts rate to heart disease componentwise given clusters available. It is deduced that heart disease prediction can be effectively done by identifying the major risks componentwise using Poisson mixture regression model. PMID- 27999612 TI - PureCN: copy number calling and SNV classification using targeted short read sequencing. AB - BACKGROUND: Matched sequencing of both tumor and normal tissue is routinely used to classify variants of uncertain significance (VUS) into somatic vs. germline. However, assays used in molecular diagnostics focus on known somatic alterations in cancer genes and often only sequence tumors. Therefore, an algorithm that reliably classifies variants would be helpful for retrospective exploratory analyses. Contamination of tumor samples with normal cells results in differences in expected allelic fractions of germline and somatic variants, which can be exploited to accurately infer genotypes after adjusting for local copy number. However, existing algorithms for determining tumor purity, ploidy and copy number are not designed for unmatched short read sequencing data. RESULTS: We describe a methodology and corresponding open source software for estimating tumor purity, copy number, loss of heterozygosity (LOH), and contamination, and for classification of single nucleotide variants (SNVs) by somatic status and clonality. This R package, PureCN, is optimized for targeted short read sequencing data, integrates well with standard somatic variant detection pipelines, and has support for matched and unmatched tumor samples. Accuracy is demonstrated on simulated data and on real whole exome sequencing data. CONCLUSIONS: Our algorithm provides accurate estimates of tumor purity and ploidy, even if matched normal samples are not available. This in turn allows accurate classification of SNVs. The software is provided as open source (Artistic License 2.0) R/Bioconductor package PureCN (http://bioconductor.org/packages/PureCN/). PMID- 27999613 TI - A bedr way of genomic interval processing. AB - BACKGROUND: Next-generation sequencing is making it critical to robustly and rapidly handle genomic ranges within standard pipelines. Standard use-cases include annotating sequence ranges with gene or other genomic annotation, merging multiple experiments together and subsequently quantifying and visualizing the overlap. The most widely-used tools for these tasks work at the command-line (e.g. BEDTools) and the small number of available R packages are either slow or have distinct semantics and features from command-line interfaces. RESULTS: To provide a robust R-based interface to standard command-line tools for genomic coordinate manipulation, we created bedr. This open-source R package can use either BEDTools or BEDOPS as a back-end and performs data-manipulation extremely quickly, creating R data structures that can be readily interfaced with existing computational pipelines. It includes data-visualization capabilities and a number of data-access functions that interface with standard databases like UCSC and COSMIC. CONCLUSIONS: bedr package provides an open source solution to enable genomic interval data manipulation and restructuring in R programming language which is commonly used in bioinformatics, and therefore would be useful to bioinformaticians and genomic researchers. PMID- 27999614 TI - History, concepts and aims of internationally active societies in psychosomatic and behavioural medicine. PMID- 27999615 TI - A preliminary study of movement intensity during a Go/No-Go task and its association with ADHD outcomes and symptom severity. AB - OBJECTIVE: At present, there are no well-validated biomarkers for attention deficit/hyperactivity disorder (ADHD). The present study used an infrared motion tracking system to monitor and record the movement intensity of children and to determine its diagnostic precision for ADHD and its possible associations with ratings of ADHD symptom severity. METHODS: A Microsoft motion sensing camera recorded the movement of children during a modified Go/No-Go Task. Movement intensity measures extracted from these data included a composite measure of total movement intensity (TMI measure) and a movement intensity distribution (MID measure) measure across 15 frequency bands (FB measures). In phase 1 of the study, 30 children diagnosed with ADHD or at subthreshold for ADHD and 30 matched healthy controls were compared to determine if measures of movement intensity successfully distinguished children with ADHD from healthy control children. In phase 2, associations between measures of movement intensity and clinician-rated ADHD symptom severity (Clinical Global Impression Scale [CGI] and the ADHD-Rating Scale IV [ADHD-RS]) were examined in a subset of children with ADHD (n = 14) from the phase I sample. RESULTS: Both measures of movement intensity were able to distinguish children with ADHD from healthy controls. However, only the measures linked to the 15 pre-determined 1 Hz frequency bands were significantly correlated with both the CGI scores and ADHD-RS total scores. CONCLUSIONS: Preliminary findings suggest that measures of movement intensity, particularly measures linked to the 10-11 and 12-13 Hz frequency bands, have the potential to become valid biomarkers for ADHD. PMID- 27999617 TI - Intraoperative radiation safety in orthopaedics: a review of the ALARA (As low as reasonably achievable) principle. AB - The use of fluoroscopy has become commonplace in many orthopaedic surgery procedures. The benefits of fluoroscopy are not without risk of radiation to patient, surgeon, and operating room staff. There is a paucity of knowledge by the average orthopaedic resident in terms proper usage and safety. Personal protective equipment, proper positioning, effective communication with the radiology technician are just of few of the ways outlined in this article to decrease the amount of radiation exposure in the operating room. This knowledge ensures that the amount of radiation exposure is as low as reasonably achievable. Currently, in the United States, guidelines for teaching radiation safety in orthopaedic surgery residency training is non-existent. In Europe, studies have also exhibited a lack of standardized teaching on the basics of radiation safety in the operating room. This review article will outline the basics of fluoroscopy and educate the reader on how to safe fluoroscopic image utilization. PMID- 27999616 TI - Bioelectronic nose and its application to smell visualization. AB - There have been many trials to visualize smell using various techniques in order to objectively express the smell because information obtained from the sense of smell in human is very subjective. So far, well-trained experts such as a perfumer, complex and large-scale equipment such as GC-MS, and an electronic nose have played major roles in objectively detecting and recognizing odors. Recently, an optoelectronic nose was developed to achieve this purpose, but some limitations regarding the sensitivity and the number of smells that can be visualized still persist. Since the elucidation of the olfactory mechanism, numerous researches have been accomplished for the development of a sensing device by mimicking human olfactory system. Engineered olfactory cells were constructed to mimic the human olfactory system, and the use of engineered olfactory cells for smell visualization has been attempted with the use of various methods such as calcium imaging, CRE reporter assay, BRET, and membrane potential assay; however, it is not easy to consistently control the condition of cells and it is impossible to detect low odorant concentration. Recently, the bioelectronic nose was developed, and much improved along with the improvement of nano-biotechnology. The bioelectronic nose consists of the following two parts: primary transducer and secondary transducer. Biological materials as a primary transducer improved the selectivity of the sensor, and nanomaterials as a secondary transducer increased the sensitivity. Especially, the bioelectronic noses using various nanomaterials combined with human olfactory receptors or nanovesicles derived from engineered olfactory cells have a potential which can detect almost all of the smells recognized by human because an engineered olfactory cell might be able to express any human olfactory receptor as well as can mimic human olfactory system. Therefore, bioelectronic nose will be a potent tool for smell visualization, but only if two technologies are completed. First, a multi-channel array-sensing system has to be applied for the integration of all of the olfactory receptors into a single chip for mimicking the performance of human nose. Second, the processing technique of the multi-channel system signals should be simultaneously established with the conversion of the signals to visual images. With the use of this latest sensing technology, the realization of a proper smell-visualization technology is expected in the near future. PMID- 27999618 TI - Complex systems analysis of bladder cancer susceptibility reveals a role for decarboxylase activity in two genome-wide association studies. AB - BACKGROUND: Bladder cancer is common disease with a complex etiology that is likely due to many different genetic and environmental factors. The goal of this study was to embrace this complexity using a bioinformatics analysis pipeline designed to use machine learning to measure synergistic interactions between single nucleotide polymorphisms (SNPs) in two genome-wide association studies (GWAS) and then to assess their enrichment within functional groups defined by Gene Ontology. The significance of the results was evaluated using permutation testing and those results that replicated between the two GWAS data sets were reported. RESULTS: In the first step of our bioinformatics pipeline, we estimated the pairwise synergistic effects of SNPs on bladder cancer risk in both GWAS data sets using Multifactor Dimensionality Reduction (MDR) machine learning method that is designed specifically for this purpose. Statistical significance was assessed using a 1000-fold permutation test. Each single SNP was assigned a p value based on its strongest pairwise association. Each SNP was then mapped to one or more genes using a window of 500 kb upstream and downstream from each gene boundary. This window was chosen to capture as many regulatory variants as possible. Using Exploratory Visual Analysis (EVA), we then carried out a gene set enrichment analysis at the gene level to identify those genes with an overabundance of significant SNPs relative to the size of their mapped regions. Each gene was assigned to a biological functional group defined by Gene Ontology (GO). We next used EVA to evaluate the overabundance of significant genes in biological functional groups. Our study yielded one GO category, carboxy-lysase activity (GO:0016831), that was significant in analyses from both GWAS data sets. Interestingly, only the gamma-glutamyl carboxylase (GGCX) gene from this GO group was significant in both the detection and replication data, highlighting the complexity of the pathway-level effects on risk. The GGCX gene is expressed in the bladder, but has not been previously associated with bladder cancer in univariate GWAS. However, there is some experimental evidence that carboxy-lysase activity might play a role in cancer and that genes in this pathway should be explored as drug targets. This study provides a genetic basis for that observation. CONCLUSIONS: Our machine learning analysis of genetic associations in two GWAS for bladder cancer identified numerous associations with pairs of SNPs. Gene set enrichment analysis found aggregation of risk-associated SNPs in genes and significant genes in GO functional groups. This study supports a role for decarboxylase protein complexes in bladder cancer susceptibility. Previous research has implicated decarboxylases in bladder cancer etiology; however, the genes that we found to be significant in the detection and replication data are not known to have direct influence on bladder cancer, suggesting some novel hypotheses. This study highlights the need for a complex systems approach to the genetic and genomic analysis of common diseases such as cancer. PMID- 27999619 TI - Comparative genomics analyses revealed two virulent Listeria monocytogenes strains isolated from ready-to-eat food. AB - BACKGROUND: Listeria monocytogenes is an important foodborne pathogen that causes considerable morbidity in humans with high mortality rates. In this study, we have sequenced the genomes and performed comparative genomics analyses on two strains, LM115 and LM41, isolated from ready-to-eat food in Malaysia. RESULTS: The genome size of LM115 and LM41 was 2,959,041 and 2,963,111 bp, respectively. These two strains shared approximately 90% homologous genes. Comparative genomics and phylogenomic analyses revealed that LM115 and LM41 were more closely related to the reference strains F2365 and EGD-e, respectively. Our virulence profiling indicated a total of 31 virulence genes shared by both analysed strains. These shared genes included those that encode for internalins and L. monocytogenes pathogenicity island 1 (LIPI-1). Both the Malaysian L. monocytogenes strains also harboured several genes associated with stress tolerance to counter the adverse conditions. Seven antibiotic and efflux pump related genes which may confer resistance against lincomycin, erythromycin, fosfomycin, quinolone, tetracycline, and penicillin, and macrolides were identified in the genomes of both strains. CONCLUSIONS: Whole genome sequencing and comparative genomics analyses revealed two virulent L. monocytogenes strains isolated from ready-to-eat foods in Malaysia. The identification of strains with pathogenic, persistent, and antibiotic resistant potentials from minimally processed food warrant close attention from both healthcare and food industry. PMID- 27999620 TI - Effects of Escherichia coli Nissle 1917 and Ciprofloxacin on small intestinal epithelial cell mRNA expression in the neonatal piglet model of human rotavirus infection. AB - We evaluated the effects of the probiotic Escherichia coli Nissle 1917 (EcN) and the antibiotic Ciprofloxacin (Cipro) on mRNA expression of intestinal epithelial cells (IEC) in gnotobiotic (Gn) piglets colonized with a defined commensal microflora (DMF) and inoculated with human rotavirus (HRV) that infects IECs. We analyzed mRNA levels of IEC genes for enteroendocrine cells [chromogranin A (CgA)], goblet cells [mucin 2 (MUC2)], transient amplifying progenitor cell [proliferating cell nuclear antigen (PCNA)], intestinal epithelial stem cell (SOX9) and enterocytes (villin). Cipro treatment enhanced HRV diarrhea and decreased the mRNA levels of MUC2 and villin but increased PCNA. These results suggest that Cipro alters the epithelial barrier, potentially decreasing the numbers of mature enterocytes (villin) and goblet cells secreting protective mucin (MUC2). These alterations may induce increased IEC proliferation (PCNA expression) to restore the integrity of the epithelial layer. Coincidental with decreased diarrhea severity in EcN treated groups, the expression of CgA and villin was increased, while SOX9 expression was decreased representing higher epithelial integrity indicative of inhibition of cellular proliferation. Thus, EcN protects the intestinal epithelium from damage by increasing the gene expression of enterocytes and enteroendocrine cells, maintaining the absorptive function and, consequently, decreasing the severity of diarrhea in HRV infection. PMID- 27999622 TI - Purification, Characterization and Comparison between Two New L-asparaginases from Bacillus PG03 and Bacillus PG04. AB - BACKGROUND: L-asparaginase has been used as a chemotherapeutic agent in treatment of lymphoblastic leukemia. In the present investigation, Bacillus sp. PG03 and Bacillus sp. PG04 were studied. METHODS: L- asparaginases were produced using different culture media and were purified using ion exchange chromatography. RESULTS: Maximum productivity was obtained when asparagine was used as the nitrogen source at pH 7 and 48 h after cultivation. New intracellular L asparaginases showed an apparent molecular weight of 25 kDa and 30 kDa by SDS PAGE respectively. These enzymes were active in a wide pH range (3-9) with maximum activity at pH 6 for Bacillus PG03 and pH 7 for Bacillus PG04 L asparaginase. Bacillus PG03 enzyme was optimally active at 37 C and Bacillus PG04 maximum activity was observed at 40C. Kinetic parameters km and Vmax of both enzymes were studied using L-asparagine as the substrate. Thermal inactivation studies of Bacillus PG03 and Bacillus PG04 L-asparaginase exhibited t1/2 of 69.3 min and 34.6 min in 37 C respectively. Also T50 and ?G of inactivation were measured for both enzymes. CONCLUSION: The results revealed that both enzymes had appropriate characteristics and thus could be a potential candidate for medical applications. PMID- 27999621 TI - Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract. AB - BACKGROUND: Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC. METHODS: Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival. RESULTS: SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873). CONCLUSIONS: SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens. PMID- 27999624 TI - Complete genome sequence of new bacteriophage phiE142, which causes simultaneously lysis of multidrug-resistant Escherichia coli O157:H7 and Salmonella enterica. AB - The emergence of antibiotic-resistant foodborne bacteria is a global health problem that requires immediate attention. Bacteriophages are a promising biotechnological alternative approach against bacterial pathogens. However, a detailed analysis of phage genomes is essential to assess the safety of the phages prior to their use as biocontrol agents. Therefore, here we report the complete genome sequence of bacteriophage phiE142, which is able to lyse Salmonella and multidrug-resistant Escherichia coli O157:H7 strains. Bacteriophage phiE142 belongs to the Myoviridae family due to the presence of long non-flexible tail and icosahedral head. The genome is composed of 121,442 bp and contains 194 ORFs, and 2 tRNAs. Furthermore, the phiE142 genome does not contain any genes coding for food-borne allergens, antibiotics resistance, virulence factors, or associated with lysogenic conversion. The bacteriophage phiE142 is characterized by broad host range and compelling genetic attributes making them potential candidates as a biocontrol agent. PMID- 27999623 TI - Personalized approach in brain protection by hypothermia: individual changes in non-pathological and ischemia-related glutamate transport in brain nerve terminals. AB - BACKGROUND: Both deep and profound hypothermia are effectively applied in cardiac surgery of the aortic arch, when the reduction of cerebral circulation facilitates operations, and for the prevention of ischemic stroke consequences. Neurochemical discrimination of the effects of deep and profound hypothermia (27 and 17 degrees C, respectively) on non-pathological and pathological ischemia related mechanisms of presynaptic glutamate transport with its potential contribution to predictive, preventive and personalized medicine (PPPM) was performed. METHODS: Experiments were conducted using nerve terminals isolated from rat cortex (synaptosomes). Glutamate transport in synaptosomes was analyzed using radiolabel l-[14C]glutamate. Diameter of synaptosomes was assessed by dynamic light scattering. RESULTS: Synaptosomal transporter-mediated uptake and tonic release of l-[14C]glutamate (oppositely directed processes, dynamic balance of which determines the physiological extracellular level of the neurotransmitter) decreased in a different range in deep/profound hypothermia. As a result, hypothermia-induced changes in extracellular l-[14C]glutamate are not evident (in one half of animals it increased, and in other it decreased). A progressive decrease from deep to profound hypothermia was shown for pathological mechanisms of presynaptic glutamate transport, that is, transporter-mediated l [14C]glutamate release (*) stimulated by depolarization of the plasma membrane and (**) during dissipation of the proton gradient of synaptic vesicles by the protonophore FCCP. CONCLUSIONS: Therefore, the direction of hypothermia-induced changes in extracellular glutamate is unpredictable in "healthy" nerve terminals and depends on hypothermia sensitivity of uptake vs. tonic release. In affected nerve terminals (e.g., in brain regions suffering from a reduction of blood circulation during cardiac surgery, and core and penumbra zones of the insult), pathological transporter-mediated glutamate release from nerve terminals decreases with progressive significance from deep to profound hypothermia, thereby underlying its potent neuroprotective action. So, alterations in extracellular glutamate during hypothermia can be unique for each patient. An extent of a decrease in pathological glutamate transporter reversal depends on the size of damaged brain zone in each incident. Therefore, test parameters and clinical criteria of neuromonitoring for the evaluation of individual hypothermia induced effects should be developed and delivered in practice in PPPM. PMID- 27999626 TI - Top Research Papers. PMID- 27999627 TI - Trickle-Down Behavior Analysis. PMID- 27999625 TI - Genome sequence and overview of Oligoflexus tunisiensis Shr3T in the eighth class Oligoflexia of the phylum Proteobacteria. AB - Oligoflexus tunisiensis Shr3T is the first strain described in the newest (eighth) class Oligoflexia of the phylum Proteobacteria. This strain was isolated from the 0.2-MUm filtrate of a suspension of sand gravels collected in the Sahara Desert in the Republic of Tunisia. The genome of O. tunisiensis Shr3T is 7,569,109 bp long and consists of one scaffold with a 54.3% G + C content. A total of 6,463 genes were predicted, comprising 6,406 protein-coding and 57 RNA genes. Genome sequence analysis suggested that strain Shr3T had multiple terminal oxidases for aerobic respiration and various transporters, including the resistance-nodulation-cell division-type efflux pumps. Additionally, gene sequences related to the incomplete denitrification pathway lacking the final step to reduce nitrous oxide (N2O) to nitrogen gas (N2) were found in the O. tunisiensis Shr3T genome. The results presented herein provide insight into the metabolic versatility and N2O-producing activity of Oligoflexus species. PMID- 27999628 TI - Teaching Practitioners to Conduct Behavioral Skills Training: A Pyramidal Approach for Training Multiple Human Service Staff. AB - A job responsibility of many behavior analysts that can involve significant amounts of time is training human service staff in behavior-change and related procedures. We evaluated a pyramidal approach using behavioral skills training (BST) for a trainer to train multiple staff. The BST skills of 10 practitioners in a human service setting were assessed as they trained a staff person in simulation before and after being trained (with BST) to conduct BST. Results indicated all participants improved their use of BST during the assessments following training and demonstrated proficient application of BST while training a staff person in the regular work setting. Acceptability measures suggested the training process was well received by the participants. Results are discussed regarding practical considerations with BST-based pyramidal training, including the conditions in which this training approach may be most advantageous. PMID- 27999629 TI - A Review of Board Standards Across Behavioral Health Professions: Where Does the BCBA Credential Stand? AB - The increasing demand for behavior analytic services and the number of individuals pursuing credentials to provide these services evoke questions regarding certification and how the requirements for becoming a Board Certified Behavior Analyst(r) (BCBA(r)) compare with those for other professions. In this paper, we compared licensure and board certification requirements across similar behavioral health professions (i.e., behavior analysis, clinical social work, educational psychology, marriage and family therapy, and clinical psychology) and found that the minimum requirements for certification of behavior analysts were commensurate. We discuss the implications of our comparisons for practitioners, consumers, and the field and offer some recommendations for future consideration. PMID- 27999630 TI - Unexpected Results From a Change in Token Type. AB - We have noted an unusual phenomenon in our association with an inpatient behavioral health facility located in the midwestern United States. Most consumers treated in this facility exhibit conduct disorders, oppositional defiant disorder or attention deficit disorders. The facility also treats individuals with various anxiety disorders, posttraumatic stress disorder, and autism. Within the facility, we collected data from a unit that monthly serves a population of 38 to 47 children ages 3 to 11 years old. PMID- 27999631 TI - Response to Ahrendt, Houlihan, and Buchanan. AB - While the authors ask a broad question regarding the utility of reinforcement based programs, I will use token economies as the exemplar in my response below, given that the piece leading to the questions related to changes in the seeming effectiveness of a token economy. The question has two parts, and each part will be addressed separately. PMID- 27999632 TI - Response to Ahrendt, Houlihan, and Buchanan. AB - This paper reports some puzzling results from a token economy in an inpatient behavioral treatment facility. A seemingly insignificant change from poker chip tokens to sticker tokens produced substantial increases in problem behavior-as measured by frequency of time-outs for problem behavior. The results are puzzling because it is generally assumed that qualitative aspects of the tokens-such as whether or not they are handled-should not matter. What should matter is simply the correlation between tokens and other reinforcers for which they are exchanged. Indeed, the successful use of check marks, stickers, and stars in scores of token systems over the years shows pretty clearly that stickers and other nonhandled tokens are up to the job. PMID- 27999633 TI - Response to Ahrendt, Houlihan, and Buchanan. AB - The implementation of seclusion time-out (STO) described by Ahrendt, Houlihan, and Buchanan (2013) reveals several contemporary practice standards within the domain of clinical behavior analysis. First, the "time-in" environment of the inpatient facility included a token-based incentive program by which staff reinforced "positive behavior" and consumers exchanged tokens for primary reinforcers. Thus, the intent was to increase motivation to avoid STO in favor of remaining in the reinforcing environment (Marlow, Tingstrom, Olmi, & Edwards, 1997). PMID- 27999634 TI - Were Increased Closed Seclusions the Result of a Reinforcer-Abolishing Effect? AB - In recent years, the motivating operation (MO) concept and the terms associated with it, including "reinforcer-abolishing effect" (Laraway, Snycerski, Michael, & Poling, 2003), have been widely used in the behavior-analytic literature (Laraway, Snycerski, Olson, Becker, & Poling, in press) and elsewhere (Lotfizadeh, Edwards, & Poling, 2013). MOs are changes in the environment that alter the reinforcing effectiveness of designated classes of stimuli, such as food or water. PMID- 27999635 TI - A Staff-Training Program to Increase Spontaneous Vocal Requests in Children With Autism. AB - This study evaluated a staff-training and feedback program to increase (a) staff use of naturalistic language training techniques, and (b) child production of spontaneous vocal requests in a school setting for young children with autism. Training was conducted in integrated preschool centers and in an art group. The results revealed that the training and feedback procedure was successful in increasing staff use of naturalistic language training techniques. Further, these increased strategies were associated with corresponding increases in spontaneous vocal requests for all children during embedded training and ongoing feedback conditions. In addition, probes collected by an unobtrusive observer revealed durability of child requesting when staff feedback was discontinued. Social validity measures from front-line staff regarding the intervention revealed positive ratings. The results are discussed in relation to the continued search for effective service-delivery systems to improve communication for children with autism in the public school setting. PMID- 27999636 TI - Functional Analysis With Typically Developing Children: Best Practice or Too Early to Tell?: In Response to. AB - Hanley (2012) provided a guide to practitioners and researchers in the conduct of functional assessment for problem behavior, citing a body of empirical work to support his view. Much of the work Hanley drew upon was conducted with individuals with developmental delay in hospitals or outpatient clinic settings. In this paper, we argue that the guidelines he put forth are not necessarily applicable to work in schools or with typically developing individuals. We examine the evidence supporting use of functional analysis with typically developing children, emphasizing school-based consultation, and conclude by recommending a tiered assessment approach from least to most intensive based on the needs of the individual child. PMID- 27999637 TI - Lovaas Institute for Early Intervention (LIFE). AB - For many years, O. Ivar Lovaas ran a small clinic for children with autism through the department of psychology at UCLA, with undergraduate students providing most of the direct instruction. Throughout the 1970s, the clinic enrolled just a few children in treatment at a time. By the early 1980s, the active caseload had increased to about 5-10 children, and this number rose slowly over the next few years. However, after the publication of Lovaas's landmark study of early intensive behavioral intervention (EIBI) in 1987, followed by an extraordinary firsthand account of one family's experience with the intervention (Maurice, 1993), Lovaas began receiving more requests for treatment in a single day than he had previously received over an entire year. PMID- 27999638 TI - Sex, Drugs, and...Behavior Analysis? AB - Close your eyes for a moment and imagine a stereotypic picture of behavior analysis in practice before reading onward. If you are even remotely familiar with applied behavior analysis, you likely pictured a child sitting knee to knee with a therapist who is holding reinforcers with some academic-related task nearby. Alternatively, you may have imagined a classroom of students under the instruction of a teacher or a team of staff undergoing behavioral skills training in a workplace. PMID- 27999639 TI - Living the Behavioral Dream. AB - Most of us have had a workday where we left a bit frustrated about one thing or another and thought "if I was in charge, I know I could do it better." We dream of a better tomorrow where we tell our employer goodbye and become our own boss. Is that not the American Dream? We are told from early childhood that anything is possible and we can be anything we want to be if we just work hard. Somewhere between those naive childhood years and today we probably have come to realize these grand promises are more myths than truths and we become content with an approximation of this dream. To some individuals, however, approximations are not close enough. PMID- 27999641 TI - Assessment of transient elastography (FibroScan) for diagnosis of fibrosis in non alcoholic fatty liver disease: A systematic review and meta-analysis. AB - BACKGROUND: Transient elastography (TE) is a new modality for the diagnosis of liver fibrosis caused by various etiologies. This study was conducted to determine the accuracy of TE in detecting the different stages of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) patients. METHODS: MEDLINE/PubMed, Embase, Ovid, Cochrane Library, American College of Physicians (ACP) Journal Club, Google Scholar, Database of Abstracts of Reviews of Effects, and Web of Science that evaluated the liver stiffness by means of TE and liver biopsy were enrolled in this systematic review and meta-analysis. Published articles were extracted from 2002 to March 2015. RESULTS: A total of 7 articles from 114 papers were included which consisted of 698 patients. The results indicated that when F >=3, the outcomes were 93.7% (95% confidence interval (CI): 92-95.5), 91.1% (95% CI: 89-93.2), 82.4% (95% CI: 79.9-84.9), and 95.9% (95% CI: 94.4-97.4) for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), respectively. With fibrosis stage >=4, it has reached the sensitivity of 96.2 % (95% CI: 94.5-97.8), a specificity of 92.2% (95% CI: 89.9 94.6), a PPV of 5.5% (95% CI: 51.2-59.8) and NPV of 98.5% (95% CI: 97.4-99.5). CONCLUSION: We concluded that as the pathological fibrosis increases, the sensitivity, specificity and NPV of TE in the diagnosis of fibrosis improves in NAFLD patients. TE can be considered as a unique alternative instead of liver biopsy in NAFLD patients and it has an important role in the exclusion of liver cirrhosis. More studies are required to confirm the results. PMID- 27999640 TI - Toxoplasmosis in Iran: A guide for general physicians working in the Iranian health network setting: A systematic review. AB - BACKGROUND: Human toxoplasmosis is an important zoonotic infection worldwide which is caused by the intracellular parasite Toxoplasma gondii (T.gondii). The aim of this study was to review briefly the general aspects of toxoplasma infection in in Iranian health system network. METHODS: We searched published toxoplasmosis related articles in English databases including Science Direct, Pub Med, Scopus, Google Scholar, Magiran, Iran Medex, Iran Doc and Scientific Information Database (SID) for toxoplasmosis. RESULTS: Out of 1267 articles from the English and Persian databases search, 40 articles were suitable with our research objectives and so were selected for the study. It is estimated that at least a third of the world human population is infected with T.gondii, suggesting it as one of the most common parasitic infections through the world. Maternal infection during pregnancy may affect dangerous outcome for the fetus, or even cause intrauterine death. Reactivation of a previous infection in immunocompromised patient such as drug induced, AIDS and organ transplantation can cause life-threating central nervous system infection. Ocular toxoplasmosis is one of the most important causes of blindness, especially in individuals with a deficient immune system. CONCLUSION: According to the increasing burden of toxoplasmosis on human health, the findings of this study highlight the appropriate preventive measures, diagnosis, and management of this disease. PMID- 27999642 TI - Benefits from the correction of vitamin D deficiency in patients with pulmonary hypertension. AB - BACKGROUND: Vitamin D (Vit D) is linked to various conditions including musculoskeletal, metabolic and cardiopulmonary diseases. However, it is not clear whether correction of vit D deficiency exerts any beneficial effect in patients with pulmonary hypertension. METHODS: This study was a prospective uncontrolled longitudinal study. Patients with pulmonary hypertension and vit D deficiency were enrolled into this study. All patients in addition to standard treatment for pulmonary hypertension received cholecalciferol at a dose of 50,000 IU weekly plus calcicare (at a dose of 200 mg magnesium + 8 mg zinc + 400 IU vit D) daily for 3 months. Serum level of 25-hydroxy vit D, serum level of pro-brain natriuretic peptide, six minute walk test (6MWT), peak and mean pulmonary artery pressure, right ventricular size and function, ejection fraction (EF) and New York Heart Association (NYHA) functional class were measured at baseline and after 3 months of treatment. RESULTS: Twenty-two patients with pulmonary hypertension and vit D deficiency were enrolled into the study. At endpoint, the serum vit D level increased significantly to 54.8 ng/ml, the mean of baseline distance of 6MWT increased significantly to 81.6 m and the RV size significantly improved. The mean pulmonary artery pressure also improved after the intervention, but their changes did not reach to statistically significant levels. CONCLUSION: Vit D replacement therapy in patients with pulmonary arterial hypertension and vit D deficiency results in significant improvement of right ventricular size and 6 MWT. Moreover, mean pulmonary artery pressure improves nonsignificantly. This issue requires further studies with long-term follow-up period. PMID- 27999643 TI - The HPLC assay of concentration of azithromycin from two different manufacturers in gingival crevicular fluid (GCF). AB - BACKGROUND: Azithromycin (AZM) is used in periodontal infections. The present study compared gingival crevicular fluid concentration of azithromycin of two pharmaceutical companies through the HPLC method. METHODS: Two groups (n=15) of healthy volunteers participated in this study. The first group received an imported azithromycin (ImAZM) tablet (250 mg, PO) and the second group received an azithromycin tablet (250 mg PO) manufactured by an Iranian pharmaceutical company (IrAZM). Intrasulcular paper points (#30) were used in inter-proximal areas of molars and canines to collect gingival crevicular fluid samples at 6, 12, 36, 84 and 156 hours after drug administration. RESULTS: The maximum concentration of AZM in gingival crevicular fluid was detected in each group 36 hour after administration. The concentration levels for the participants receiving ImAZM and IrAZM were 14.38+/-5.75 and 12.64+/-3.53 ng/mL, respectively. The pharmacokinetic (PK) modeling data showed half-life of AZM was 107.47 hr & 91.42 hr while the clearance was 113.02 hr &119.0 hr for the group receiving ImAZM and IrAZM, respectively. No significant differences were observed in other PK parameters, areas under the concentration time curves for the groups were almost identical. CONCLUSION: According to the results, there were no significant differences between the PK parameters of ImAZM and IrAZM products. It may be concluded that different doses of AZM have relatively similar PK parameters among the healthy participants. PMID- 27999644 TI - Comparison of levofloxacin versus clarithromycin efficacy in the eradication of Helicobacter pylori infection. AB - BACKGROUND: Helicobacter pylori (H.pylori) infection causes multiple upper gastrointestinal diseases but optimal therapeutic regimen which can eradicate infection in all the cases has not yet been defined. This study was designed to evaluate the efficacy of triple levofloxacin-based versus clarithromycin-based therapy. METHODS: In this open-label randomized clinical trial study 120 patients who had esophagogastroduodenoscopy (EGD) with positive rapid urease test (RUT) were enrolled and divided into 2 groups. Case group was treated with levofloxacin (500 mg daily) plus amoxicillin (1 gr twice a day) plus omeprazole (20 mg daily) for 2 weeks. Control group was treated with clarithromycin (500 mg twice a day) plus omeprazole (20 mg daily) for 2 weeks. After the main course of treatment, they received maintenance treatment with omeprazole for 4 weeks. Stool antigen test was performed on them after two weeks of not having any medicine. RESULTS: H.pylori eradication (intention to treat analysis) was successful in 75% of case group and 51.7% of control group showing a significant difference (P=0.008). H.p infection eradication (per-protocol analysis) was successful in 80.4% in case group and 57.4%% in control group showing significant difference (P=0.009). Drugs adverse effects causing discontinuation treatment were seen in 5% of case group and 3.3% of control group which have not shown a significant difference between the two groups (P=0.648). CONCLUSION: Triple therapy with levofloxacin-based regimen has better efficacy than clarithromycin-based regimen and as safe as it is. PMID- 27999645 TI - Serum alpha-actinin antibody status in systemic lupus erythematosus and its potential in the diagnosis of lupus nephritis. AB - BACKGROUND: In lupus nephritis (LN), deposition of pathogenic autoantibodies in the glomeruli is mediated via cross-reactivity with alpha-actinin. Association of serum alpha-actinin antibody (AalphaA) with LN has been shown in a few studies but the results are controversial. METHODS: Eighty patients into entered the study. The diagnosis of SLE was confirmed according to the American College of Rheumatology criteria and LN was diagnosed by proteinuria >= 500 mg/24 hour and kidney biopsy. Serum AalphaA was measured with ELISA method. Receiver operating characteristics curve (ROC) analysis was applied to determine an optimal cutoff value for AalphaA to discriminate patients with and without LN at the highest sensitivity and specificity. The association of AalphaA with LN was determined by logistic regression analysis with calculation of odds ratio (OR). RESULTS: Serum AalphaA was significantly lower in LN as compared with SLE patients without LN (P=0.001). Serum AalphaA at cutoff levels <= 59.5 pg/ml discriminated the two groups with sensitivity, specificity, positive predictive values of 60%. 90% and 85.7%, respectively. Serum AalphaA level <= 59.5 pg/ml was significantly associated with LN (OR=13.5, P=0.001) and the OR increased to 25.2 (P=0.003) after adjustment for age, sex, C3, C4, anti-ds-DNA, SLEDAI. CONCLUSION: This study indicates that serum AalphaA decreases in LN and serum level <= 59.5 pg/ml is SLE and is predictive of nephritis. PMID- 27999646 TI - Higher rate of microscopic hematuria in elderly patients who take regular doses of aspirin: Result from AHAP Study. AB - BACKGROUND: Aspirin is the most widely used drug in medicine for cardiovascular and as recently for its role in cancer prevention. Although the risk of bleeding events increased following regular use of aspirin, little is known about the association of aspirin and hematuria. The present study aimed to evaluate the association of regular aspirin use and microscopic hematuria in elderly. METHODS: In this study, we have extracted the data of elderly people who participated in Amirkola Health and Aging Project (AHAP) and taking regular doses of aspirin. The prevalence of microscopic hematuria was compared between the elderly who took aspirin regularly and those who did not take it. RESULTS: A total of 1243 individuals (54.22% males, 45.78% females) were entered in to the study. Two hundred and eighty-four (23%) elderly took regular doses of aspirin. Microscopic hematuria was seen in 305 (24.54%) elderly. The prevalence of microscopic hematuria was 27.27% in regular users of aspirin and 23.72% in non-users of aspirin (P=0.126). The prevalence of microscopic hematuria was significantly higher among the regular users of aspirin compared to non-users in multiple logistic regression analysis (P=0.035, OR=1.40, 95%CI: 1.02-1.92). CONCLUSION: Taking regular doses of aspirin was accompanied with higher rate of microscopic hematuria in the elderly. PMID- 27999648 TI - Comparison of long-pulsed alexandrite laser and topical tretinoin-ammonium lactate in axillary acanthosis nigricans: A case series of patients in a before after trial. AB - BACKGROUND: Acanthosis nigricans (AN) is a brown to black, velvety hyperpigmentation of the skin that usually involves cutaneous folds. Treatment of AN is important regarding cosmetic reasons and various therapeutic modalities have been used for these purposes. The goal of this study was to compare the effectiveness of long-pulsed alexandrite laser and topical tretinoin-ammonium lactate for treatment of axillary-AN. METHODS: Fifteen patients with bilateral axillary-AN were studied in Razi Hospital, Tehran, Iran. Diagnosis was confirmed by two independent dermatologists. Each side skin lesion was randomly allocated to either topical mixed cream of tretinoin 0.05%- ammonium lactate 12% or long pulsed alexandrite laser. Duration of treatment was 14 weeks. At endpoint, the mean percent reduction from baseline in pigmentation area was compared between the two groups. RESULTS: The study population consisted of 15 patients three males and 12, females. The mean age of patients was 28.5+/-4.9 years. The mean percent reduction was 18.3+/-10.6%, in tretinoin/ammonium lactate group and 25.7+/-11.8% in laser group (P=0.004). CONCLUSION: These findings indicate that the application of alexandrite laser is a relative effective method for treatment of axillary-AN. However, this issue requires further studies with prolonged follow-up period. PMID- 27999647 TI - Both immune hormone IL-10 and parathormone tend to increase in serum of old osteoporotic people independently of 1, 25 dihydroxy vitamin D3. AB - BACKGROUND: In this study, we determined the serum levels of IL-17A and IL-10 in context with 1, 2 dihydroxy vitamin D3, parathormone and Ca2+/Pi ions to investigate their pathological or protective roles respectively in bone metabolism. METHODS: The bone mineral density (BMD) was determined for 1203 participants using energy X-ray absorptiometry. Subjects with a history of diseases and using bone metabolism medications were excluded and finally serum IL 10 was measured in 82 osteoporotic and 74 healthy individuals (mean age +/-SD of 71.04+/-6.9 and 68.58+/-6.9 respectively). Also, the serum level of IL-17A was assessed in 42 osteoporotic and 39 non-osteoporotic subjects (mean age+/-SD of 69.40+/-6.7 and 70.77+/-7.1, respectively). Serum levels of 1, 25 dihydroxyvitamin D3, Ca2+/Pi ions and parathormone were extracted from AHAP cohort data bank. RESULTS: IL-17A was detectable in 7.42(16.67%) osteoporotic subjects and 3.39(7.69%) normal subjects. Surprisingly, patient subjects exhibited a higher level of serum IL-10 than normal subjects (P=0.023). We found that the serum parathormone levels tend to increase in patient group (P=0.003) in comparison to normal control with no correlation with Il-10 levels. There was no significant difference between the two groups in the serum levels of 1, 25 dihydroxyvitamin D3, Ca2+and Pi ions. CONCLUSION: In reaction to chronic inflammation old osteoporotic patients independent of 1, 25 dihydroxy vitamin D3 may produce a higher level of IL-10 to dampen production of inflammatory cytokines including IL-17A which in turn leads to speeding up parathormone production ultimately reaching a new homeostasis status in bone metabolism with normal serum Ca2+ /Pi ions. PMID- 27999649 TI - Implantable cardioverter-defibrillator in a patient with dextrocardia situs inversus. AB - BACKGROUND: Dextrocardia is a congenital anomaly, which may have coexistent coronary artery disease (CAD), arrhythmias and conventional indications for device therapy. However, the implantation of transvenous leads can be technically challenging and the approach needs to be tailored to the patient's individual anatomy. CASE PRESENTATION: A 54-year-old male with dextrocardia situs inversus and ischemic left ventricular dysfunction developed ventricular tachycardia and fibrillation. Therefore, left- sided approach, dual chamber implantable cardioverter-defibrillator (ICD) was applied using a conventional method and standard equipment after complete evaluation of cardiac anatomy and vascular assessment. CONCLUSION: Electrical device implantation in patients with dextrocardia is possible after obtaining complete information about anatomy and/or coexisting congenital abnormalities, which helps in obtaining appropriate implantation approach. PMID- 27999651 TI - Destructive effect of quinone-containing compounds on cytochrome P450: Arbutin as a double-edged sword. PMID- 27999650 TI - Subclavian artery-esophageal fistula after placement of a self-expanding metal stent in a patient with esophagogastric anastomosis stenosis. AB - BACKGROUND: There have been reports on stent-related vascular erosions about patients with benign or malignant stenosis of the esophagus who received endoscopic stent insertion for palliative intention for oral intake. CASE PRESENTATION: A 61-year-old woman with esophageal cancer located in the middle part of esophagus was treated with esophagectomy. Two years following the surgery, malignant stenosis recurred in the esophagogastric anastomosis. A non covered self-expanding metal stent (10 cm length with a diameter of 18 mm at expanded state) was inserted. Three months later, a massive hematemesis with subsequent hemorrhagic shock developed from the proximal end of the stent which resulted in the final diagnosis of arterioesophageal fistula on the left subclavian artery. An endovascular repair using a stent graft for the left subclavian artery via the right common iliac artery was performed and the patient remained well until discharge. CONCLUSION: Increase in the treatment of esophageal strictures by stent insertion increases the risk of stent-related vascular fistula. These complications should be considered in any patients with massive upper gastrointestinal bleeding. PMID- 27999652 TI - Prevalence of hepatitis A across various countries in the Middle East, African and Eastern European countries. PMID- 27999653 TI - Erythema nodosum: what should we consider about it? PMID- 27999655 TI - Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour. AB - BACKGROUND: Imatinib mesylate (IM) is the preferred treatment for the majority of patients with metastatic gastrointestinal stromal tumour (GIST). Low trough IM concentration (Cmin) values have been associated with poor clinical outcomes in GIST patients. However, there are few studies of repeated measurements of IM levels, and therapeutic drug monitoring is not yet a part of routine clinical practice. This study was conducted to reveal clinical scenarios where plasma concentration measurement of IM trough level (Cmin) is advantageous. METHODS: Patients with advanced GIST receiving IM were included from January 2011 to April 2015. Heparin plasma was collected at each follow-up visit. Ninety-six samples from 24 patients were selected for IM concentration measurement. Associations between IM plasma concentration and clinical variables were analyzed by Students' t test, univariate and multivariate linear regression analyses. RESULTS: The mean IM Cmin plasma concentrations for patients taking <400, 400 and >400 mg daily were 782, 1132 and 1665 ng/mL, respectively (p = 0.010). High IM Cmin levels were correlated with age, low body surface area, low haemoglobin concentration, low creatinine clearance, absence of liver metastasis and no prior gastric resection in univariate analysis. In multivariate analysis age, gastric resection and liver metastasis were included in the final model. Eight patients had disease progression during the study, and mean IM levels were significantly lower at time of progression compared to the previous measurement for the same patients (770 and 1223 ng/mL, respectively; p = 0.020). CONCLUSIONS: Our results do not support repeated monitoring of IM levels on a routine basis in all patients. However, we have revealed clinical scenarios where drug measurement could be beneficial, such as for patients who have undergone gastric resection, suspicion of non compliance, subjectively reported side effects, in elderly patients and at the time of disease progression. PMID- 27999654 TI - A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. AB - In animals with heteromorphic sex chromosomes, all sex differences originate from the sex chromosomes, which are the only factors that are consistently different in male and female zygotes. In mammals, the imbalance in Y gene expression, specifically the presence vs. absence of Sry, initiates the differentiation of testes in males, setting up lifelong sex differences in the level of gonadal hormones, which in turn cause many sex differences in the phenotype of non gonadal tissues. The inherent imbalance in the expression of X and Y genes, or in the epigenetic impact of X and Y chromosomes, also has the potential to contribute directly to the sexual differentiation of non-gonadal cells. Here, we review the research strategies to identify the X and Y genes or chromosomal regions that cause direct, sexually differentiating effects on non-gonadal cells. Some mouse models are useful for separating the effects of sex chromosomes from those of gonadal hormones. Once direct "sex chromosome effects" are detected in these models, further studies are required to narrow down the list of candidate X and/or Y genes and then to identify the sexually differentiating genes themselves. Logical approaches to the search for these genes are reviewed here. PMID- 27999656 TI - Small GTPase Arl6 controls RH30 rhabdomyosarcoma cell growth through ciliogenesis and Hedgehog signaling. AB - BACKGROUND: Rhabdomyosarcoma (RMS) originates from skeletal muscle precursors that fail to differentiate. Hedgehog (Hh) signaling and primary cilia contribute to the pathobiology of RMS. RESULTS: Here we showed ADP ribosylation factor like GTPase 6 (ARL6) localizes at the base of primary cilium, controls ciliogenesis and Hh signaling. The transcription of Arl6 is dynamic during the differentiation of myoblasts, companying with the growth and elimination of primary cilia. Arl6 expression is significantly up regulated in cilia-dependent RMS cells and tissues. Knockdown of Arl6 inhibits proliferation and promotes apoptosis of RMS RH30 cells through defected ciliogenesis and reduced Hh activity. CONCLUSIONS: Taken together, the functions of Arl6 in ciliogenesis and Hh signaling suggest it as a potential RMS drug target. PMID- 27999657 TI - Should Men who have sex with Men be allowed to donate blood in Israel? AB - BACKGROUND: The present permanent deferral policy in Israel for MSM was established in 1977 and was based on the previous (now outdated) USA Food and Drug Administration standards. This study analyses epidemiological data regarding blood donations among MSM, in order to estimate the risk for HIV transfusion transmitted infection (TTI) if the policy is changed to allow at-risk MSM to donate blood. METHODS: An Excel based spreadsheet model integrated demographic, epidemiological data from the HIV National Register, laboratory, blood donation and testing data in order to calculate TTI due to false-negatives in known HIV+ donors, windows period donations, asymptomatic carriers and laboratory misclassification errors. A sensitivity analysis of our estimated TTIs for deferral periods for MSM was performed based on a literature review regarding this overall policy issue worldwide. RESULTS: MSM in Israel have a considerably higher relative risk (RR) of both prevalence (115) and incidence (143) of being HIV+ than persons without a risk factor. Allowing MSM to donate blood, without any deferral period, will add an additional five HIV TTI cases over the next decade. Imposition of a 1 or 5 years deferral of abstinence will increase the number of HIV TTI cases only by 0.10 and 0.05 cases, respectively. CONCLUSION: A 1 year deferral period for blood donations from MSM in Israel is recommended. PMID- 27999658 TI - Exploratory analysis of CD63 and CD203c expression in basophils from hazelnut sensitized and allergic individuals. AB - BACKGROUND: Sensitization to hazelnut (HN) is frequent and requires clarification to determine whether this sensitization is clinically relevant. The aim of this study was to investigate basophil activation profiles in HN-sensitized and allergic subjects. METHODS: Basophil activation was determined by flow cytometric analyses of CD63 and CD203c expression using several HN allergen concentrations. Depending on their clinical reaction pattern, an oral allergy symptom group (OAS, n = 20), a systemic reaction group (n = 12) and a sensitized group without clinical symptoms (n = 20) were identified. Additionally, 10 non-allergic and non sensitized individuals served as controls. RESULTS: CD63 and CD203c expression differed between allergic (OAS and systemic group) and sensitized subjects. The HN concentration required to activate 30% of CD203c+ basophils [effective concentration (EC)30] was significantly higher in sensitized versus the allergic group (p = 0.0089). This was more pronounced when the basophil allergen threshold sensitivity (CD-sens) was calculated (CD63: p = 0.018; CD203c: p = 0.009). CONCLUSION: Our data indicate that the basophil activation test may provide information to better distinguish between sensitized and allergic subjects if several allergen concentrations are considered. CD203c expression displayed a better discrimination compared to CD63; therefore, its diagnostic value might be superior compared with CD63. PMID- 27999659 TI - The effect of obesity on treatment outcomes for low back pain. AB - BACKGROUND: The objective of this study was to estimate the effect of obesity, as measured by body mass index (BMI), on treatment outcomes for low back pain (LBP). METHODS: Data from the University of California, Los Angeles, and Friendly Hills Healthcare Network low back pain study (collected from 1995 to 2000) were used to perform a secondary data analysis of this randomized clinical trial on adults who sought care for LBP. BMI was the primary predictor variable. Binary logistic regression modeling was performed to estimate odds ratios adjusted for the effects of confounders. RESULTS: Using normal weight as the referent population, underweight and overweight populations did not display significant odds ratios for any of the outcome variables. The obese population demonstrated odds ratios of 0.615 (0.379, 0.998) for improvement of disability and 0.550 (0.341, 0.889) for improvement of most severe back pain. CONCLUSION: The results of this study support an association between obesity and less effective treatment outcomes whether measured by disability (Roland-Morris scale) or pain (most severe pain NRS). Overweight and underweight populations do not appear to have significantly different outcomes than normal weight populations. TRIAL REGISTRATION: This trial was designed and conducted prior to the advent of registries. PMID- 27999660 TI - 'PICO-D Management'; a decision-aid for evidence-based chiropractic education and clinical practice. AB - BACKGROUND: Various models and decision-making aids exist for chiropractic clinical practice. RESULTS: "PICO-D Man" (Patient-Intervention-Comparator-Outcome Duration Management) is a decision-aid developed in an educational setting which field practitioners may also find useful for applying defensible evidence-based practice. Clinical decision-making involves understanding and evaluating both the proposed clinicalintervention(s) and the relevant and available management options with respect to describing the patient and their problem, clinical and cost effectiveness, safety, feasibility and time-frame. CONCLUSIONS: For people consulting chiropractors this decision-aid usually requires the practitioner to consider a comparison of usual chiropractic care, (clinical management including a combination of active care and passive manual interventions), to usual medical care usually including medications, or other allied healthmanagement options while being mindful of the natural history of the persons' condition. PMID- 27990250 TI - Increased abundance of ADAM9 transcripts in the blood is associated with tissue damage. AB - Background: Members of the ADAM (a disintegrin and metalloprotease domain) family have emerged as critical regulators of cell-cell signaling during development and homeostasis. ADAM9 is consistently overexpressed in various human cancers, and has been shown to play an important role in tumorigenesis. However, little is known about the involvement of ADAM9 during immune-mediated processes. Results: Mining of an extensive compendium of transcriptomic datasets identified important gaps in knowledge regarding the possible role of ADAM9 in immunological homeostasis and inflammation: 1) The abundance of ADAM9 transcripts in the blood was increased in patients with acute infection but, 2) changed very little after in vitro exposure to a wide range of pathogen-associated molecular patterns (PAMPs). 3) Furthermore it was found to increase significantly in subjects as a result of tissue injury or tissue remodeling, in absence of infectious processes. Conclusions: Our findings indicate that ADAM9 may constitute a valuable biomarker for the assessment of tissue damage, especially in clinical situations where other inflammatory markers are confounded by infectious processes. PMID- 27239277 TI - Use of cidofovir in pediatric patients with adenovirus infection. AB - Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity. Methods: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction. Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted. PMID- 27999663 TI - Implementation of goal-directed fluid therapy during hip revision arthroplasty: a matched cohort study. AB - BACKGROUND: Several randomized controlled trials (RCTs) have demonstrated that intraoperative goal-directed fluid therapy (GDFT) can decrease postsurgical complications in patients undergoing major abdominal surgery. However, very few studies have demonstrated the value of goal-directed therapy (GDT) in patients undergoing orthopaedic surgery and confirmed it is as useful in real-life conditions. Therefore, we initiated a GDFT implementation programme in patients undergoing hip revision arthroplasty in order to assess its effects on postoperative complications (e.g. infection, cardiac, neurological, renal) (primary outcome) and hospital and intensive care unit (ICU) length of stay (secondary outcomes). METHODS: We developed a GDFT protocol for the haemodynamic management of patients undergoing hip revision arthroplasty. The GDFT protocol was based on continuous monitoring and optimization of stroke volume during the surgical procedure. From December 2012 and for a period of 17 months, 130 patients were treated according to the GDFT protocol (GDFT group). The pre-, intra-, and postoperative characteristics of patients from the GDFT group were compared to those of 130 historical matched patients (control group) who had the same surgery between January 2011 and August 2012. RESULTS: Patients from the GDFT and from the control group were comparable in terms of age, comorbidities, and P-POSSUM score. Duration of anaesthesia and surgery were also comparable. The GDFT group had a significantly lower morbidity rate (49.2 vs. 66.9%; p = 0.006) and a shorter median hospital length of stay (11 days (9-15) vs. 9 days (8-12); p = 0.003) than the control group. Patients from the control group post-anaesthesia care unit (PACU)/ICU stayed significantly longer at PACU/ICU than patients from the GDFT group (control group vs. GDFT group, 960 min (360-1210) vs. 400 min (207 825); p < 0.001) Patients from the GDFT group received less crystalloids but more colloids during surgery. They also received more often inotropic therapy. CONCLUSIONS: In patients undergoing hip revision arthroplasty, the implementation of GDT as a new standard operating procedure was successful and associated with reduced postsurgical complications, most importantly a reduction in postoperative bleeding as well as hospital and ICU stay. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01753050. PMID- 27999664 TI - Daptomycin-induced eosinophilic pneumonia - a systematic review. AB - PURPOSE: Eosinophilic pneumonia comprises a group of lung diseases in which eosinophils appear in increased numbers in the lungs and sometimes in the bloodstream. Several case reports link daptomycin use to this phenomenon. SUMMARY: We performed a systematic literature review to identify cases of eosinophilic pneumonia associated with daptomycin use. Relevant studies were identified by searching Pubmed/Medline, EMBASE, Google Scholar, Cochrane Database of Systematic Reviews, and Clin-Alert from inception to May 2016, and manual searches of reference lists. All case reports that include information regarding patient age, indication, clinical and objective findings, treatment and outcome were evaluated. Abstracts from conference proceedings as well as case reports not in English were excluded. Descriptive statistics were used to analyze the data. Thirty-five patient-cases were included in the final analysis. Patients most likely to be identified with daptomycin-induced eosinophilic pneumonia were male (83%) and elderly (mean age 65.4 +/- 15 years). The dose for daptomycin ranged from 4 to 10 mg/kg/day, but included a large number of patients with renal dysfunction. The average duration of daptomycin therapy upon onset of EP symptoms was 2.8 +/- 1.6 weeks. Majority of patients presented with dyspnea (94%), fever (57%) and were also found to have peripheral eosinophilia (77%) and infiltrates/opacities of CT/CXR (86%). Symptom improvement was seen after daptomycin discontinuation (24 h to 1 week). The majority of patients were also prescribed treatment with corticosteroids (66%). CONCLUSION: Clinicians should be aware of daptomycin-induced eosinophilic pneumonia and its symptoms along with its presentation and treatment. PMID- 27999665 TI - Estimating the morbidity and mortality associated with infections due to multidrug-resistant bacteria (MDRB), France, 2012. AB - BACKGROUND: A study based on 2007 data estimated that 386,000 infections due to multidrug-resistant bacteria (MDRB) occurred in Europe that year and 25,000 patients died from these infections. Our objective was to estimate the morbidity and mortality associated with these infections in France. METHODS: The MDRB considered were methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide resistant enterococci, third-generation cephalosporin-resistant (3GC-R) Escherichia coli and Klebsiella pneumoniae, carbapenem-resistant Klebsiella pneumoniae, Acinetobacter spp. and Pseudomonas aeruginosa (CR P. aeruginosa). The number of invasive infections (infections with bacteria isolated from blood or cerebrospinal fluid) due to MDRB, as reported by France to EARS-Net in 2012, was corrected for the coverage of our surveillance network and extrapolated to other body sites using ratios from the French healthcare-associated infections point prevalence survey and the literature. Mortality associated with MDRB infection was estimated using proportions from the literature. Methods and parameters were reviewed by a panel of experts. RESULTS: We estimate that 158,000 (127,000 to 245,000) infections due to MDRB occurred in 2012 in France (incidence: 1.48 to 2.85 per 1000 hospital days), including 16,000 invasive infections. MRSA, 3GC-R E. coli and K. pneumoniae were responsible for 120,000 (90,000 to 172,000) infections, i.e., 75% of the total. An estimated 12,500 (11,500 to 17,500) deaths were associated with these infections, including 2,700 associated with invasive infections. MRSA, 3GC-R E. coli and CR P. aeruginosa accounted for 88% of these deaths. CONCLUSION: These first estimates confirm that MRSA, 3GC-R Escherichia coli and Klebsiella pneumoniae account for the largest portion of the morbidity and mortality of infections due to MDRB in France. These results are not directly comparable with the European study because the methodology used differs in many respects. The differences identified between our study and previous studies underline the need to define a standardised protocol for international assessments of the morbidity and mortality of antibiotic resistance. Estimating morbidity and mortality will facilitate communication and awareness in order to reinforce adherence and support of healthcare professionals and policy-makers to MDRB prevention programs. PMID- 27999666 TI - Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice. AB - BACKGROUND: Diabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1 mediated autophagy might be involved in thepahological process. METHODS: High-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy. RESULTS: 1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05), and increasing tendency of depression (P < 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P < 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P < 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups. CONCLUSION: Compared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice. PMID- 27999668 TI - Development of a vivo rabbit ligated intestinal Loop Model for HCMV infection. AB - BACKGROUND: Human Cytomegalovirus (HCMV) infections can be found throughout the body, especially in epithelial tissue. Animal model was established by inoculation of HCMV (strain AD-169) or coinoculation with Hepatitis E virus (HEV) into the ligated sacculus rotundus and vermiform appendix in living rabbits. The specimens were collected from animals sacrificed 1 and a half hours after infection. RESULTS: The virus was found to be capable of reproducing in these specimens through RT-PCR and Western-blot. Severe inflammation damage was found in HCMV-infected tissue. The viral protein could be detected in high amounts in the mucosal epithelium and lamina propria by immunohistochemistry and immunofluorescense. Moreover, there are strong positive signals in lymphocytes, macrophages, and lymphoid follicles. Quantitative statistics indicate that lymphocytes among epithlium cells increased significantly in viral infection groups. CONCLUSIONS: The results showed that HCMV or HEV + HCMV can efficiently infect in rabbits by vivo ligated intestine loop inoculation. The present study successfully developed an infective model in vivo rabbit ligated intestinal Loop for HCMV pathogenesis study. This rabbit model can be helpful for understanding modulation of the gut immune system with HCMV infection. PMID- 27999669 TI - The diabesity health economic crisis-the size of the crisis in a European island state following a cross-sectional study. AB - BACKGROUND: Diabetes type 2 and obesity are well-established global epidemics and contributors to clinical, social and economic health burdens. The prevalence rates of these diseases are still on the rise among countries resulting in a corresponding public health burden. The Mediterranean island of Malta, known for it's high diabetes and obesity rates, provides a good fundamental basis to portray the economical health burden of these diseases. METHOD: A recent randomised stratified representative cross-sectional survey conducted in Malta tackling diabetes, obesity and other determinants, was used to work out the population prevalence of these diseases. The cost burden of diabetes and obesity, based on published data, was incorporated to the established population prevalence rates, in order to estimate the Maltese economical burden. Projections to the year 2050 by a bottom-up prevalence based design were performed. RESULTS: One eight of the Maltese adults (25 to 64 years) suffered from diabetes out of which approximately 10,000 adults were unaware of the disease. Alarmingly, more than a third of the Maltese population suffer from obesity. The approximate health care costs (direct and indirect) for the diabetic adult population was of ?29,159,217 (?21,994,676 - ?38,919,121) annually, amounting to 3.64% (2.75 4.875%) of the total health expenditure in Malta. The obesity cost burden was of ?23,732,781 (?21,514,972-?26,049,204) annually contributing for 2.97% (2.69 3.26%) of the total health expenditure. The projected prevalence and costs for 2050 exhibited an estimated cost burden increase of ?33,751,487 (?25,458,606 ?45,048,473) for the diabetes mellitus population and ?46,532,294 (?42,183,889 ?51,074,049) for the obese population. These projected cost burdens are expected to increase exponentially the total health care expenditure in Malta by 2050. CONCLUSION: Having an understanding of the prevalence and the economic cost burden of diabetes and obesity within a country, along with projections of the expected burden will enable policy and public health officials to clearly visualize this growing problem. It also helps in establishing effective preventive strategies and screening programs targeting these epidemics. PMID- 27999670 TI - A qualitative analysis of participants' reflections on body image during participation in a randomized controlled trial of acceptance and commitment therapy. AB - BACKGROUND: Negative body image is a risk factor for development and relapse in eating disorders (ED). Many patients continue to be dissatisfied with their body shape or weight after treatment. This study presents a qualitative analysis of written reflections on body image from patients with an ED and a negative body image before and after an Acceptance and Commitment Therapy group treatment at a specialized ED-unit. METHOD: Before and after the treatment participants (n = 47) answered a questionnaire with open ended questions on their thoughts on body image. Data were analyzed through conventional content analysis. RESULTS: Body image meant different things for different participants. For some it had to do with how you evaluate your body, whereas others focused on whether their body image was realistic or not. Some emphasized their relationship with their body, while some described body image as strongly related to global self-esteem. These different views on the concept of body image affected the participants' descriptions of their own body image, and how they wanted it to change. Body image was considered a state that fluctuated from day to day. After treatment the participants described changes in their body image, for instance perceiving oneself as less judgmental towards one's body, and a shift in focus to the important things in life. CONCLUSIONS: The participants had different views on body image and how they wished it to change. Thus treatment interventions targeting negative body image needs to address various aspects of this complex construct. TRIAL REGISTRATION: This study is part of an RCT registered 02/06/2014 in Clinical Trials, registration number: NCT02058121. PMID- 27999667 TI - Antimicrobial usage and resistance in beef production. AB - Antimicrobials are critical to contemporary high-intensity beef production. Many different antimicrobials are approved for beef cattle, and are used judiciously for animal welfare, and controversially, to promote growth and feed efficiency. Antimicrobial administration provides a powerful selective pressure that acts on the microbial community, selecting for resistance gene determinants and antimicrobial-resistant bacteria resident in the bovine flora. The bovine microbiota includes many harmless bacteria, but also opportunistic pathogens that may acquire and propagate resistance genes within the microbial community via horizontal gene transfer. Antimicrobial-resistant bovine pathogens can also complicate the prevention and treatment of infectious diseases in beef feedlots, threatening the efficiency of the beef production system. Likewise, the transmission of antimicrobial resistance genes to bovine-associated human pathogens is a potential public health concern. This review outlines current antimicrobial use practices pertaining to beef production, and explores the frequency of antimicrobial resistance in major bovine pathogens. The effect of antimicrobials on the composition of the bovine microbiota is examined, as are the effects on the beef production resistome. Antimicrobial resistance is further explored within the context of the wider beef production continuum, with emphasis on antimicrobial resistance genes in the food chain, and risk to the human population. PMID- 27999671 TI - Plasma microRNA biomarker detection for mild cognitive impairment using differential correlation analysis. AB - BACKGROUND: Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia including Alzheimer's disease. Early detection of dementia, and MCI, is a crucial issue in terms of secondary prevention. Blood biomarker detection is a possible way for early detection of MCI. Although disease biomarkers are detected by, in general, using single molecular analysis such as t-test, another possible approach is based on interaction between molecules. RESULTS: Differential correlation analysis, which detects difference on correlation of two variables in case/control study, was carried out to plasma microRNA (miRNA) expression profiles of 30 age- and race-matched controls and 23 Japanese MCI patients. The 20 pairs of miRNAs, which consist of 20 miRNAs, were selected as MCI markers. Two pairs of miRNAs (hsa-miR-191 and hsa-miR-101, and hsa-miR-103 and hsa-miR-222) out of 20 attained the highest area under the curve (AUC) value of 0.962 for MCI detection. Other two miRNA pairs that include hsa miR-191 and hsa-miR-125b also attained high AUC value of >= 0.95. Pathway analysis was performed to the MCI markers for further understanding of biological implications. As a result, collapsed correlation on hsa-miR-191 and emerged correlation on hsa-miR-125b might have key role in MCI and dementia progression. CONCLUSION: Differential correlation analysis, a bioinformatics tool to elucidate complicated and interdependent biological systems behind diseases, detects effective MCI markers that cannot be found by single molecule analysis such as t test. PMID- 27999672 TI - Dental implant bioactive surface modifications and their effects on osseointegration: a review. AB - BACKGROUND: The purpose of this article is to review and update the current developments of biologically active dental implant surfaces and their effect on osseointegration. METHODS: PubMed was searched for entries from January 2006 to January 2016. Only in-vivo studies that evaluated the effects of biomolecular coatings on titanium dental implants inserted into the bone of animals or humans were included. RESULTS: Thirty four non-review studies provided data and observations were included in this review. Within the criteria, four categories of biomolecular coatings were evaluated. The potential biomolecules include bone morphogenetic proteins in 8 articles, other growth factors in 8 articles, peptides in 5 articles, and extracellular matrix in 13 articles. Most articles had a healing period of 1 to 3 months and the longest time of study was 6 months. In addition, all studies comprised of implants inserted in animals except for one, which evaluated implants placed in both animals and humans. The results indicate that dental implant surface modification with biological molecules seem to improve performance as demonstrated by histomorphometric analysis (such as percentage of bone-to-implant contact and peri-implant bone density) and biomechanical testing (such as removal torque, push-out/pull-out tests, and resonance frequency analysis). CONCLUSIONS: Bioactive surface modifications on implant surfaces do not always offer a beneficial effect on osseointegration. Nevertheless, surface modifications of titanium dental implants with biomolecular coatings seem to promote peri-implant bone formation, resulting in enhanced osseointegration during the early stages of healing. However, long-term clinical studies are needed to validate this result. In addition, clinicians must keep in mind that results from animal experiments need not necessarily reflect the human clinical reality. PMID- 27999675 TI - Mechanical insufflation-exsufflation for an individual with Duchenne muscular dystrophy and a lower respiratory infection. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy associated with progressive muscle weakness and wasting, loss of ambulation, respiratory insufficiency, weak cough, repeated respiratory infections, and ultimately death from respiratory failure in early adulthood. Mechanical insufflation-exsufflation (MI-E) devices, such as the CoughAssist(r), are used in individuals with neuromuscular weakness to augment cough and help clear secretions; however, there is no consensus on the optimal treatment regimen. We present the challenging case of a patient with DMD admitted to a tertiary hospital with a severe lower respiratory infection, and discuss how MI-E was used by physiotherapists to assist secretion clearance and prevent further deterioration. PMID- 27999673 TI - Application of multi-target phytotherapeutic concept in malaria drug discovery: a systems biology approach in biomarker identification. AB - There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly-pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development. PMID- 27999674 TI - Development and validation of a novel bioassay to determine glucocorticoid sensitivity. AB - BACKGROUND: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. RESULTS: Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. CONCLUSIONS: The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort. PMID- 27999676 TI - Recurrent pneumothorax related to diffuse dendriform pulmonary ossification in genetically predisposed individual. AB - Diffuse pulmonary ossification (DPO) is a rare disease with unknown pathogenesis, clinical manifestations, and treatment options. This report describes the diagnosis of DPO in an otherwise healthy 26-year-old man with recurrent spontaneous pneumothorax. His father was diagnosed with a similar lung condition in his 30's with computed tomography (CT) images that were strikingly similar to those of the patient. This report suggests that DPO can induce spontaneous pneumothorax and its pathogenesis may have a possible genetic predisposition that needs further research. PMID- 27999677 TI - Affective instability and impulsivity predict nonsuicidal self-injury in the general population: a longitudinal analysis. AB - BACKGROUND: Impulsivity and affective instability are related traits known to be associated with nonsuicidal self-injury, although few longitudinal studies have examined this relationship. The purpose of this study was to determine if impulsivity and affective instability predict future nonsuicidal self-injury in the general population while accounting for the overlap between these traits. METHODS: Logistic regression analyses were conducted on data from 2344 participants who completed an 18-month follow-up of the 2000 British National Psychiatric Morbidity Survey. Affective instability and impulsivity were assessed at baseline with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders. Nonsuicidal self-injury was assessed at baseline and follow-up during semi-structured interviews. RESULTS: Affective instability and impulsivity predicted the onset of nonsuicidal self-injury during the follow-up period. Affective instability, but not impulsivity, predicted the continuation of nonsuicidal self-injury during the follow-up period. Affective instability accounted for part of the relationship between impulsivity and nonsuicidal self injury. CONCLUSIONS: Affective instability and impulsivity are important predictors of nonsuicidal self-injury in the general population. It may be more useful to target affective instability over impulsivity for the treatment of nonsuicidal self-injury. PMID- 27999678 TI - Associations between obesity and mental distress in late midlife: results from a large Danish community sample. AB - BACKGROUND: To examine associations of Body mass Index (BMI) and mental distress in late midlife in a large Danish community sample and to investigate the effect of socio-demographic factors. METHODS: The study sample comprised 3613 Danish men and 1673 women aged 49-63 years from the Copenhagen Ageing and Midlife Biobank (CAMB) with complete information on measured BMI, severity of mental symptoms assessed by the Symptom Check-List' (SCL-90), and socio-demographic factors including sex, age, occupational social class, and educational duration. Linear and logistic regression were used to evaluate associations between BMI category and SCL-90. RESULTS: Unadjusted SCL-90 subscale scores differed significantly across BMI categories (p < 0.001) among both men and women with more mental distress in the underweight, obese and severely obese BMI categories except for the anxiety scale which was not associated with BMI category in women. In the adjusted analyses, all symptom scales remained significantly associated with BMI among men after adjusting for socio-demographic factors while only associations with somatization and depression scales remained significant for women.. When SCL 90 case status was applied as an outcome, significant unadjusted associations with BMI category were observed for somatization (p < 0.001), depression (p = 0.026) and the General Severity Index (p = 0.002) among men and somatization (p = 0.002) among women. Furthermore, somatization case-status was significantly predicted by BMI category (p < 0.001) in men after adjusting for socio demographic factors. CONCLUSION: Results indicate more mental distress among underweight, obese and severely obese men and women after adjusting for socio demographic factors. Furthermore, obese men have higher risk of reporting clinically relevant symptoms of somatization independently of socio-demographic factors. PMID- 27999679 TI - Early rapid weight gain and subsequent overweight and obesity in middle childhood in Peru. AB - BACKGROUND: Rapid postnatal weight gain is associated with risk of overweight and obesity, but it's unclear whether this holds in populations exposed to concurrent obesogenic risk factors and for children who have been extensively breastfed. This study investigates whether an increase in weight for age from birth to 1 year (infancy) and from 1 to 5 years (early childhood) predicts overweight and obesity, and waist circumference at 8 years, using data from a longitudinal cohort study in Peru. METHODS: Generalized estimating equations (GEE) models were constructed for overweight and obesity, obesity alone and waist circumference at 8 years versus rapid weight gain in infancy, and early childhood including adjusted models to account for confounders. RESULTS: Rapid weight gain in both periods was associated with double the risk of overweight and obesity, obesity alone at 8 years and increased waist circumference even after controlling for maternal BMI and education level, sex of child, height-for-age at 8 years, consumption of "fast food" and number of days of active exercise. The association was significant, with some differences, for children in both rural and urban environments. CONCLUSIONS: Rapid weight gain in infancy and in early childhood in Peru is associated with overweight and obesity at age 8 years even when considering other determinants of childhood obesity. PMID- 27999681 TI - Timing and Outcomes of Vitreoretinal Surgery after Traumatic Retinal Detachment. AB - Traumatic retinal detachments are a significant cause of morbidity. There are currently no evidence-based guidelines on the appropriate time to perform vitreoretinal surgery to repair a traumatic retinal detachment. Early intervention, within seven days of the inciting trauma, may decrease proliferative vitreoretinopathy and postoperative endophthalmitis. Later intervention may yield a reduced risk of inflammation and hemorrhage, particularly in cases of concomitant open globe injuries. This article reviews the literature on the management of retinal detachments associated with ocular trauma from the years 2006 to 2016. Particular focus was placed on the timing of surgery, concomitant open globe injury, anatomical success rates, visual acuity, and complication rates. In this review, anatomical success was not significantly related to timing of intervention when compared between early and delayed intervention in eyes with and without concomitant open globe injuries. Visual acuities postoperatively varied widely despite timing of intervention due to the large variation in mechanism and extent of ocular injuries. Proliferative vitreoretinopathy was a common complication. Preliminary data indicate that endophthalmitis rates may be lower when early vitreoretinal surgery is performed. There is insufficient data to conclude whether early or delayed surgery leads to improved outcomes, highlighting the need for further research in this domain. PMID- 27999682 TI - When Women with Cystic Fibrosis Become Mothers: Psychosocial Impact and Adjustments. AB - Advances in the treatment and life expectancy of cystic fibrosis (CF) patients mean that motherhood is now a realistic option for many women with CF. This qualitative study explored the psychosocial impact and adjustments made when women with CF become mothers. Women with CF (n = 11) were recruited via an online forum and participated in semistructured telephone interviews about their experiences of becoming a mother. Transcriptions were analysed using Grounded Theory. Analysis revealed three core categories: (i) "Living with CF": how becoming a mother impacted on health and treatment adherence, requiring a change in support from the CF team, (ii) "Becoming a Mother": balancing issues common to new mothers with their CF, and (iii) "Pooling Personal Resources": coping strategies in managing the dual demands of child and CF care. Participants experienced a variety of complex psychosocial processes. Most participants acknowledged an initial negative impact on CF care; however over time they reported successful adaptation to managing dual commitments and that adherence and motivation to stay well had improved. This study highlights the need for preconceptual psychosocial counselling and postpartum adjustment to CF care. PMID- 27999683 TI - A Preliminary Investigation of a Specialized Music Therapy Model for Children with Disabilities Delivered in a Classroom Setting. AB - Music therapy is gaining popularity as an intervention strategy for children with developmental disabilities, including autism spectrum disorder (ASD). This study was a pilot investigation of a classroom-based music-based intervention, Voices Together(r), for improving communication skills in children with ASD and children with intellectual disabilities. Four local public elementary school special education classrooms, serving 5 children with a classification of autistic disorder and 32 children with intellectual disability without autism, were randomly selected to receive one of two levels of exposure to Voices Together music therapy: "long-term" (15 weeks beginning in January 2015 (Time 1), n = 14) or "short-term" (7 weeks beginning 7 weeks later in February (Time 2), n = 17). Using observational ratings, investigators reliably scored participants live in terms of their level of verbal responsiveness to prompts during three songs featured each week of the program. Both groups demonstrated increases in verbal responses over time; however, only the long-term group demonstrated significant within-group increases. Preliminary findings suggest that music therapy delivered in a classroom in 45-minute weekly sessions for 15 weeks can promote improvements in verbal responsiveness among individuals with autism and other developmental disabilities. Findings warrant further investigation into the efficacy of classroom-based music therapy programs. PMID- 27999680 TI - New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care. AB - Endometrial carcinoma (EC) is the fourth most common cancer in women in the developed world. Classification of ECs by histomorphologic criteria has limited reproducibility and better tools are needed to distinguish these tumors and enable a subtype-specific approach to research and clinical care. Based on the Cancer Genome Atlas, two research teams have developed pragmatic molecular classifiers that identify four prognostically distinct molecular subgroups. These methods can be applied to diagnostic specimens (e.g., endometrial biopsy) with the potential to completely change the current risk stratification systems and enable earlier informed decision making. The evolution of genomic classification in ECs is shared herein, as well as potential applications and discussion of the essential research still needed in order to optimally integrate molecular classification in to current standard of care. PMID- 27999684 TI - A Perspective of the Diagnosis and Management of Congenital Tuberculosis. AB - Tuberculosis continues to be a prevalent disease in the world and a global public health issue in many countries. The disease is more complicated in pregnant women because it imperils unborn offspring and results in congenital tuberculosis later if undiagnosed and untreated. Congenital tuberculosis is rare entity and an uncommon disease along with a high mortality rate. Congenital tuberculosis, a severe clinical type of tuberculosis caused by Mycobacterium tuberculosis, is a serious and fatal disease if left untreated. Our study emphasizes that it is necessary and mandatory to consider congenital tuberculosis in the differential diagnosis of neonatal or pulmonary infections in infants, essentially in countries where the incidence of tuberculosis is high burden. Mother to neonatal transmission of disease is well known via transplacental transmission through the umbilical vein to the fetus, through the ingestion of infected amniotic fluid. Early detection is challenging, because of the nonspecific nature of the signs and symptoms in tuberculosis during pregnancy and infancy. The degree of clinical suspicion is the essential component of diagnosis. Furthermore, it generally has a difficult treatment and it should not be delayed while waiting for diagnostic test results. Prompt identification and proper treatment regimens for congenital tuberculosis strongly relate with enhanced outcomes. PMID- 27999685 TI - Impact of Active Ankle Movement Frequency on Velocity of Lower Limb Venous Flow following Total Hip Arthroplasty. AB - Background. Although active ankle movement plays a predominant role in mechanical thromboprophylaxis following total hip arthroplasty (THA), the most effective frequency of movement remains unclear. Materials and Methods. In 29 consecutive patients undergoing THA, the velocity of blood flow in the profunda femoris was measured after various frequencies of ankle movement two days after THA using a pulse wave Doppler ultrasound system. To test the interobserver reliabilities for the velocity measured with Doppler ultrasound system, the intraclass correlation coefficient was calculated based on the measurement in 10 limbs of healthy volunteers. Results. At 0, 1, and 2 minutes after ankle movement, the velocity after movement at 60 contractions per minute was significantly faster than that after movement at 40 or 80 contractions per minute (p = 0.0007, repeated-measures analysis of variance). The intraclass correlation coefficient score in two investigators was 0.849 (95% confidence interval, 0.428 to 0.962). Conclusions. Active ankle movement at 60 contractions per minute is recommended in patients receiving THA to obtain optimal venous blood flow. PMID- 27999686 TI - The Importance of Bone Mineral Density in Hip Arthroplasty: Results of a Survey Asking Orthopaedic Surgeons about Their Opinions and Attitudes Concerning Osteoporosis and Hip Arthroplasty. AB - Objective. In patients scheduled to undergo total joint arthroplasty of the hip, the bone quality around the joint affects the safety of prosthetic implantation. Bone strength is clinically assessed by measuring bone mineral density (BMD); therefore we asked if BMD is important to orthopaedic surgeons performing hip arthroplasty. Methods. In a 14-question survey, we asked about treatment patterns with respect to BMD, osteoporosis work-up, and treatment for patients with low BMD scheduled to undergo hip arthroplasty. Results. 72% of all asked orthopaedics reported to use cementless implants as a standard in hip arthroplasty. Over 60% reported that low BMD is a reason to reconsider operation strategies, but only 4% performed BMD measurement preoperatively. 26% would change their treatment strategy in case of a BMD (T-Score) between -1.5 and -2 and 40% in case of a T score between -2 and -2.5, and 29% would change their intraoperative strategy if a T-score smaller than -2.5 was measured. Conclusion. The majority of orthopaedic surgeons who responded to the survey reported that they do not perform routine measurement of BMD before arthroplasty. However, most surgeons commented that low bone mineral density will influence their surgical plan and the implant design. PMID- 27999688 TI - Percutaneous Coronary Intervention for the Anomalous Left Coronary Artery Originating from the Noncoronary Cusp. AB - Percutaneous coronary intervention (PCI) for anomalous left coronary artery (LCA) originating from the noncoronary cusp (NCC) is challenging, as it poses difficulties with the engagement of the guiding catheter and the establishment of backup support. This report examines the case of a 69-year-old woman with unstable angina of anomalous LCA origin. The computed tomography showed a diffuse plaque in the middle of the left anterior descending (LAD) artery and an anomalous LCA originating from the NCC. After successful engagement of a straightened Judkins-Left diagnostic catheter, the angiography revealed a diffuse plaque in the middle of the LAD artery. We then engaged a Judkins-Right guiding catheter. Due to the weak backup support of the guiding catheter, we used another wire to stabilize it, and the stent was then implanted successfully. To our knowledge, this is the first case report of PCI for an anomalous LCA originating from the NCC. PMID- 27999687 TI - A Novel Nonsense Mutation of POU4F3 Gene Causes Autosomal Dominant Hearing Loss. AB - POU4F3 gene encodes a transcription factor which plays an essential role in the maturation and maintenance of hair cells in cochlea and vestibular system. Several mutations of POU4F3 have been reported to cause autosomal dominant nonsyndromic hearing loss in recent years. In this study, we describe a pathogenic nonsense mutation located in POU4F3 in a four-generation Chinese family. Target region capture sequencing was performed to search for the candidate mutations from 81 genes related to nonsyndromic hearing loss in this family. A novel nonsense mutation of POU4F3, c.337C>T (p. Gln113*), was identified in a Chinese family characterized by late-onset progressive nonsyndromic hearing loss. The novel mutation cosegregated with hearing loss in this family and was absent in 200 ethnicity-matched controls. The mutation led to a stop codon and thus a truncated protein with no functional domains remained. Transient transfection and immunofluorescence assay revealed that the subcellular localization of the truncated protein differed markedly from normal protein, which could be the underlying reason for complete loss of its normal function. Here, we report the first nonsense mutation of POU4F3 associated with progressive hearing loss and explored the possible underlying mechanism. Routine examination of POU4F3 is necessary for the genetic diagnosis of hereditary hearing loss in the future. PMID- 27999689 TI - Bradycardia Associated with Steroid Use for Laryngeal Edema in an Adult: A Case Report and Literature Review. AB - Steroids are used for specific indications in the perioperative period to reduce laryngeal or spinal cord edema, or for prophylaxis and treatment of postoperative nausea and vomiting. Given the other potential causes for hemodynamic alterations in the perioperative setting, it is important for physicians to be aware of cardiovascular side effects of short term steroids. Changes in blood pressure and heart rate, cardiac dysrhythmias, and even death have been described in patients receiving short term intravenous steroids. Bradycardia has been reported following short term methylprednisolone and dexamethasone therapy in both adult and pediatric patients. There are only two case reports in the literature of bradycardia following short term intravenous dexamethasone use in adult patients. This is the first case report that describes bradycardia following the use of dexamethasone in the postoperative setting for management of laryngeal edema in an adult. Telemetry and twelve lead electrocardiograms revealed sinus bradycardia and correlated directly with administration of dexamethasone in our patient. Bradycardia resolved following discontinuation of dexamethasone. We advocate for hemodynamic monitoring in patients receiving more than one dose of intravenous steroid therapy in the perioperative period, especially those with known cardiac and hepatic comorbidities and those taking medications with negative chronotropic effects. PMID- 27999690 TI - Peripheral Giant Cell Granuloma in a Child Associated with Ectopic Eruption and Traumatic Habit with Control of Four Years. AB - Peripheral giant cell granuloma (PGCG) is a nonneoplastic lesion that may affect any region of the gingiva or alveolar mucosa of edentulous and toothed areas, preferentially in the mandible and rarely occurring in children. This report describes the clinical and histopathological findings of a PGCG diagnosed in the maxilla of a 9-year-old boy associated with a tooth erupting improperly and a traumatic habit. The patient did not present anything noteworthy on extraoral physical examination or medical history, but the habit of picking his teeth and "poking" the gingiva. The oral lesion consisted of an asymptomatic, rounded, pink colored, smooth surface, soft tissue injury with fibrous consistency and approximated size of 1.5 cm located in the attached gingiva between the upper left permanent lateral incisor and the primary canine of the same side. Excisional biopsy was performed through curettage and removal of the periosteum, periodontal ligament, and curettage of the involved teeth with vestibular access. The histopathological analysis led to the diagnosis of PGCG. The prompt diagnosis and treatment of the PGCG resulted in a more conservative surgery and a reduced risk for tooth and bone loss and recurrence of the lesion. After four years of control, patient had no relapse of the lesion and good gingival and osseous health. PMID- 27999691 TI - Evolution of Skin during Rehabilitation for Elephantiasis Using Intensive Treatment. AB - The objective of this study is to describe the evolution of the skin during rehabilitation for elephantiasis using intensive treatment. We report on the case of a 55-year-old patient with a seven-year history of leg edema. The patient reported that it began with repeated outbreaks of erysipelas over several years. One leg evolved with significant edema leading to an inability to ambulate and for about one month the patient said that he could not get out of bed. Moreover the patient was obese weighing 130 kilos and with a BMI of 39. Intensive treatment was performed over three weeks resulting in a significant reduction in limb volume. The treatment consisted of Mechanical Lymphatic Therapy (RAGodoy), Cervical Lymphatic Stimulation (Godoy & Godoy technique), and a custom-made inelastic stocking of a grosgrain textile. What caught the attention during therapy were the open wounds resulting from fragmentation of the plaque as the edema reduced; the plaque was about 0.5 cm thick. As the treatment evolved the plaque disappeared and the wounds healed. The limb size decreased by more than 80% in three weeks after which the patient began to be treated in an outpatient setting with ambulation using a grosgrain stocking. PMID- 27999692 TI - Polypoid Dysplasia in Barrett's Esophagus: Diagnosis, Management, and Very Different Outcomes in Two Consecutive Cases. AB - Background. Barrett's esophagus is associated with an increased risk of adenocarcinoma. Dysplasia in Barrett's esophagus is a precursor to adenocarcinoma. Rarely, dysplastic polypoid lesions are superimposed on Barrett's esophagus. Most reported cases of polypoid dysplasia in Barrett's esophagus have been advanced on presentation and treated with esophagectomy. We describe two cases of polypoid changes in Barrett's esophagus and treatment with polypectomy followed by radiofrequency ablation. Cases. A 75 yo male presented with esophageal polyps, which on biopsy showed gastric cardia/foveolar mucosa with focal intestinal metaplasia without dysplasia. Biopsy of intervening flat mucosa was consistent with nondysplastic Barrett's esophagus. Extensive hot snare polypectomies were performed followed by RFA. One year later, repeat EGD revealed no evidence of Barrett's esophagus. A 61 yo male presented with esophageal polyps, which on biopsy showed gastric cardia/foveolar mucosa with intestinal metaplasia and foci of low-grade dysplasia. Extensive hot snare polypectomies were performed followed by RFA. At repeat EGD, four months later, an esophageal mass was found. Biopsy of the mass showed invasive adenocarcinoma. The patient was referred for esophagectomy. Conclusion. This case series shows two outcomes, one with successful eradication of dysplasia and the other with disease progression to invasive adenocarcinoma requiring esophagectomy. PMID- 27999693 TI - Severe Anemia with Hemoperitoneum as a First Presentation for Multinodular Hepatocellular Carcinoma: A Rare Event in Western Countries. AB - Hemoperitoneum due to spontaneous rupture of hepatocellular carcinoma is a life threatening and rare condition in western countries with an incidence of less than 3% because of early detection of cirrhosis and neoplasm. Here, we describe a case of a 66-year-old male patient with altered mental status with hemorrhagic shock. Computed tomography scan of abdomen revealed hemoperitoneum and mass in liver. Patient underwent resection of liver tumor and biopsy revealed multinodular hepatocellular carcinoma. A high degree of suspicion is required where severe anemia and hemoperitoneum can be a first presentation for hepatocellular carcinoma especially in patients with chronic hepatitis C infection. Early diagnosis is crucial since mortality rates remain high for untreated cases. PMID- 27999694 TI - A Case of Pulmonary-Renal Syndrome Leading to the Diagnosis of Legionnaires' Disease. AB - We report a case of a 51-year-old Caucasian man referred at our department due to acute renal failure (ARF) complicating respiratory failure during hospitalization in a regional hospital. The patient was previously started on steroids due to the suspicion of rapidly progressive glomerulonephritis (RPGN) in the context of Goodpasture syndrome. However, clinical and laboratory findings did not support this diagnosis; instead a careful evaluation limited differential diagnosis of the renal insult to acute tubular necrosis or acute interstitial nephritis (AIN) following respiratory infection. With lung function fully improved but renal function not recovering, a renal biopsy revealed AIN, a finding leading to further diagnostic testing and finally to the diagnosis of Legionnaires' disease as a cause of this patient's pulmonary-renal syndrome. The management consisted of progressive tapering of oral steroids associated with full recovery of the patient's renal function. This is a rare case of Legionnaires' disease causing immune-mediated AIN and highlights the possibility of Legionella infection as a cause of pulmonary-renal syndrome. PMID- 27999695 TI - A Case of Intestinal Obstruction in Pregnancy Diagnosed by MRI and Treated by Intravenous Hyperalimentation. AB - Intestinal obstruction in pregnancy is rare and is mainly caused by prior pelvic surgery. We herein report a case of intestinal obstruction in a pregnant female with a history of laparoscopic myomectomy, who presented with hypogastric pain, abdominal distension, and vomiting at 26 weeks of gestation. A simple intestinal obstruction was diagnosed by MRI. Conservative treatments, including intravenous hyperalimentation and the placement of an ileus tube, were provided and her abdominal symptoms improved for 14 days. After restarting oral intake, she had no abdominal symptoms. She gave birth to a 2,146 g female infant by caesarean section at 37 weeks and 1 day of gestation. Although an area of cicatrization, which was thought to have been the starting point of the occlusion that caused the intestinal obstruction, was found, the excision of the small intestine was not necessary. Her postoperative course was uneventful. Intestinal obstruction requires a prompt diagnosis and aggressive intervention may be necessary to minimize the morbidity and mortality associated with this rare complication of pregnancy. MRI can be safely used during pregnancy to diagnose intestinal obstruction and intravenous hyperalimentation may improve the maternal and fetal prognoses. PMID- 27999697 TI - Modified Surgical Techniques for Managing Intraoperative Floppy Iris Syndrome. AB - Purpose. To report a modified surgical strategy in the management of intraoperative floppy iris syndrome-associated iris prolapse. Methods. Prolapsed iris is left as is and a new corneal incision near the original wound but at a different site is created. Depending on the location of the original incision and the surgeon's preference, this additional incision can be used as a new port for phacoemulsification tip or can be the new site for the iris to securely prolapse, allowing for the surgery to proceed safely. Results. We present 2 cases of iris prolapse and inadequate pupil dilation in patients with IFIS. Along with our modified technique, additional iris retractors were placed to increase the workspace for the phacoemulsification tip. The cataract surgery was performed successfully without further complications in both cases. Conclusion. This surgical technique could be an adjunct to allow the surgeons to expand the armamentarium for the management of IFIS-associated iris prolapse. PMID- 27999698 TI - Necrotizing Retinitis Secondary to Congenital Cytomegalovirus Infection Associated with Severe Combined Immunodeficiency. AB - A 20-day-old male infant who was born at 39 weeks of gestation was admitted to neonatal intensive care unit due to severe respiratory insufficiency. In retinal examination, peripheric retinal white-black color areas that correspond to necrotizing retinitis, moderate vitritis, macular and optic nerve head involvement, vascular leakage, and sheathing indicating perivasculitis were revealed. Despite the fact that CMV specific IgM was undetectable, CMV DNA with high viral load was found in his blood sample by means of real-time polymerase chain reaction assay. Serologic examination (IgM) for rubella, toxoplasma, herpes simplex type 2, and human immunodeficiency virus (anti-HIV) was negative. During the further evaluation for systemic immune dysfunction, decreased immunoglobulin and lymphocyte levels that confirm the diagnosis of severe combined immunodeficiency have been reached. Although given systemic intravenous ganciclovir and antibiotics treatment, the patient died at the 4th month of life due to respiratory insufficiency. PMID- 27999696 TI - A Novel Case of Penile Gangrene in a Patient Treated with Ibrutinib for Chronic Lymphocytic Leukemia. AB - Introduction. Ibrutinib is commonly used for the treatment of patients with CLL in either first-line or relapsed/refractory settings. Case Presentation. We present the case of a 74-year-old Caucasian man with CLL who presented with penile gangrene upon initiation of ibrutinib treatment. Our case is the first showing the complication of penile gangrene associated with ibrutinib use. The gangrene was self-limited upon discontinuing ibrutinib. Conclusion. Our finding describes a very rare yet important adverse event associated with ibrutinib use. PMID- 27999699 TI - Location of a Dexamethasone Implant at the Macula after Intravitreal Injection in a Silicone Oil-Filled Eye. AB - Here, we report a case with cystoid macular edema (CME) due to central retinal vein occlusion (CRVO) presented with a dexamethasone implant (Ozurdex) trapped at the macula in her silicone oil- (SO-) filled eye after injection. No additional complications such as intraocular pressure (IOP) rise or retinal damage were observed. The CME was resolved during the follow-up period. At the last visit, 3 months following the injection, Ozurdex implant was found to be mostly dissolved without any additional ocular complications. PMID- 27999700 TI - Unusual Presentation of Popliteal Cyst on Magnetic Resonance Imaging. AB - Popliteal cyst commonly presents as an ellipsoid mass with uniform low signal intensity on T1-weighted magnetic resonance images and high signal intensity on T2-weighted images. Here, we describe a popliteal cyst with unusual appearance on magnetic resonance imaging, including heterogeneous intermediate signal intensity on T2-weighted images. Arthroscopic cyst decompression revealed that the cyst was filled with necrotic synovial villi, indicative of rheumatoid arthritis. Arthroscopic enlargement of unidirectional valvular slits with synovectomy was useful for the final diagnosis and treatment. PMID- 27999701 TI - An Unusual Laryngeal Foreign Body in Adult. AB - The accidental aspiration of a foreign body is a frequent domestic accident among children but a rare occurrence in adults. The laryngeal impaction of a coin is an unusual accident; only a few cases have been reported in the literature. Diagnosis is mostly achieved by clinicoradiological examinations. The authors report an uncommon case of laryngeal impaction of a coin in a 21-year-old patient, presenting with dysphonia without dyspnea or stridor. The extraction was performed by endoscopy. PMID- 27999702 TI - Serous Cystadenocarcinoma Arising in Presumed Vitelline Duct Remnant: A Case Report and Implications in the Management of Cancer of Unknown Primary. AB - Background. Malignant neoplasms arising in Meckel's diverticulum, a vitelline duct remnant, are rare yet well-documented. Case Presentation. A 53-year-old previously healthy female presented with an enlarging midline abdominal wall mass. A computed tomography scan revealed a mass involving the linea alba, bilateral rectus abdominis, and subcutaneous fat. Extensive clinical workup failed to demonstrate other lesions, except local and paratracheal/hilar lymphadenopathy. Histopathologic examination of the resected tumor demonstrated a spectrum of serous neoplasia including serous cystadenoma, papillary serous carcinoma with numerous Psammoma bodies, and a poorly differentiated component. Immunophenotypically, the tumor cells were strongly positive for CK7, CK19, CA19.9, and MUC1 but negative for other lineage markers, findings suggestive of pancreatobiliary type differentiation. The patient died of the disease one year after the initial presentation despite chemotherapy, radiation, and surgery. Conclusion. We present a case of adenocarcinoma arising from the anterior midline abdominal wall, from presumed vitelline duct remnant, with histologic and immunophenotypic features of serous cystadenocarcinoma of pancreatobiliary origin. Though the origin from vitelline duct remnant is difficult to prove in this single case, understanding tumorigenesis of embryonic remnant origin is potentially important to improve the management of cancer of unknown primary. PMID- 27999703 TI - A Rare Type of Primary Internal Hernia Causing Small Intestinal Obstruction. AB - Primary internal hernias are extremely rare in adults. They are an important cause of small intestinal obstruction and lead to high morbidity and mortality if left untreated. Clinical presentation of internal hernia is nonspecific. Imaging has been of limited utility in cases of acute intestinal obstruction; moreover, interpretation of imaging features is operator dependant. Thus, internal hernias are usually detected at laparotomy and preoperative diagnosis in an emergency setting is either difficult or most of the time not suspected. We report herein a case of a 45-year-old male who presented with acute intestinal obstruction which was attributed later to a very rare type of internal hernia on exploratory laparotomy. A loop of ileum was found to enter the retroperitoneum through a hernia gate which was located lateral to the sigmoid colon in the left paracolic gutter. The segment of intestine was reduced and the hernial defect was closed. Our finding represents an extremely rare variant of retroperitoneal hernias. PMID- 27999704 TI - Rectus Abdominis Endometrioma after Caesarean Section. AB - Isolated rectus abdominis muscle endometriosis is very uncommon with less than 20 case reports being published to date since its first description in 1984 by Amato and Levitt. We report another case of isolated rectus abdominis endometriosis in a 37-year-old patient with a previous caesarian section. We also discuss the diagnostic and treatment particularities in these patients. In our case, the treatment was only surgical and currently the patient is disease-free during the 24-month follow-up. PMID- 27999705 TI - Urethral Leiomyoma: A Rare Clinical Entity. AB - Extrauterine leiomyomas are encountered occasionally, which can pose a diagnostic dilemma and challenge to the gynaecologist. We report a rare case of urethral leiomyoma. A 31-year-old woman with history of primary subfertility presented with mass at her urethral meatus and lower urinary tract symptoms. She underwent examination under anaesthesia and excision of the urethral mass. Histopathological examination confirmed leiomyoma. Diagnosis and management of this common growth situated at a rare location were reviewed and discussed. PMID- 27999706 TI - Aerobic Exercise Preserves Olfaction Function in Individuals with Parkinson's Disease. AB - Introduction. Based on anecdotal reports of improved olfaction following aerobic exercise, the aim of this study was to evaluate the effects of an 8-week aerobic exercise program on olfaction function in individuals with Parkinson's disease (PD). Methods. Thirty-eight participants with idiopathic PD were randomized to either an aerobic exercise group (n = 23) or a nonexercise control group (n = 15). The aerobic exercise group completed a 60-minute cycling session three times per week for eight weeks while the nonexercise control group received no intervention. All participants completed the University of Pennsylvania Smell Identification Test (UPSIT) at baseline, end of treatment, and a four-week follow up. Results. Change in UPSIT scores between the exercise and nonexercise groups from baseline to EOT (p = 0.01) and from baseline to EOT+4 (p = 0.02) favored the aerobic exercise group. Individuals in the nonexercise group had worsening olfaction function over time, while the exercise group was spared from decline. Discussion. The difference in UPSIT scores suggested that aerobic exercise may be altering central nervous system pathways that regulate the physiologic or cognitive processes controlling olfaction in individuals with PD. While these results provide promising preliminary evidence that exercise may modify the disease process, further systematic evaluation is necessary. PMID- 27999707 TI - Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation. AB - The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA B*57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self peptides but also between the alpha1 and alpha2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B*58:01 restricted allopurinol hypersensitivity reactions. PMID- 27999708 TI - [Hemangioblastomas of the posterior fossa: Report of 16 cases and literature review]. AB - OBJECTIVE: The aim of this study is to describe the results of 16 patients with posterior fossa hemangioblastoma, treated with microsurgical techniques. METHOD: Between June 2005 and December 2015, 16 patients with posterior fossa hemangioblastoma were operated on, underwent microsurgical resection. The sex, age, imaging findings, symptoms, and postoperative results were analyzed. RESULTS: Eleven patients were men and 5 were women. The average age of the patients was 44 years. The most common form was cystic with nodule (57%); in 31% of the cases the lesion was purely solid. One case (6%) showed a lesion purely cystic, and one case was solid-cystic (6%). The major presenting symptoms were headache and cerebellar syndrome (43%); in 25% of the cases the patients suffered intracranial hypertension syndrome. The total resection was achieved in all the cases; in one patient an embolization was performed before surgery. Regarding postoperative complications: two patients developed ataxia (improved after three months), 1 patient presented a CSF leak (improve with an external spinal drainage). In addition, one patient died because postoperative complications. CONCLUSION: The major features in patients with posterior fossa hemangioblastoma are a cystic with nodule form, presenting symptoms of headache and cerebellar syndrome. The total resection is possible, with a low morbi-mortality rate. PMID- 27999709 TI - [Microsurgical approach to the ambient cistern]. AB - OBJECTIVE: To describe a step-by-step approach to the ambient cistern by the suboccipital retrosigmoid supracerebellar infratentorial (RSI) approach. DESCRIPTION: The RSI approach is performed in the same manner as the suboccipital retrosigmoid approach, usually used to access the pathology of the cerebellopontine angle, with the following modifications: (1) we always use the semi-sitting position, (2) the craniotomy-craniectomy must expose the transverse sinus and extend 5 cm medially to the inion, (3) when performing the dural opening it is necessary to mobilize the dura with the transverse sinus upwards, (4) under magnification with surgical microscope the cerebellomedullary cistern should be opened in order to drain cerebrospinal fluid for relaxing the cerebellum, and (5) arachnoidal adherences and bridging veins must be coagulated and cut if necessary. These maneuvers create a wide corridor to the ambient cistern. CONCLUSION: This approach allows a safe access to the ambient cistern, especially to the infratentorial portion. PMID- 27999710 TI - An unusual case of repeated intracranial hemorrhage in vestibular schwannoma. AB - BACKGROUND: Symptomatic intratumoral hemorrhage (ITH) in vestibular schwannoma (VS) is rare. A repeated hemorrhage is, therefore, even more exceptional. Repeated ITH has been reported in four cases thus far in English literature. Here, we describe a patient with a Koos grade D VS who presented to our Skull Base team with repeated ITH and an unexpected disease course. CASE DESCRIPTION: A 76-year-old woman presented with hearing loss due to polycystic VS on the left side. Five years later, the patient was presented with facial palsy caused by hemorrhage in the VS. The patient had an eventful medical history that necessitated the use of anti-coagulants. The patient suffered from three subsequent hemorrhages preoperatively and one hemorrhage 36 h postoperatively. CONCLUSION: We have experienced multiple repeated hemorrhages in a patient with a polycystic VS, and despite surgical intervention, the outcome was unfavorable. PMID- 27999711 TI - Rapidly progressing interhemispheric subdural empyema showing a three-fold increase in size within 12 hours: Case report. AB - BACKGROUND: Subdural empyema is a rare form of intracranial infection. It is described as accumulation of purulent infective material between the inner layer of dura mater and outer layer of arachnoid membrane. CASE DESCRIPTION: A 17-year old girl was admitted to the emergency department with acute left hemiplegia and was diagnosed with interhemispheric subdural empyema that showed a three-fold increase in size within 12 hours. Complete recovery was achieved with emergency surgical evacuation and additional 3 weeks of antibiotic treatment. CONCLUSION: Subdural empyema should be diagnosed and managed early in time since it may progress very rapidly and can cause high morbidity and mortality. Complete recovery can be achieved if it is diagnosed early and treated in time. PMID- 27999712 TI - Fibrin glue injection into the hematoma cavity for refractory chronic subdural hematoma: A case report. AB - BACKGROUND: Repeat burr hole irrigation and drainage has been effective in most cases of recurrent chronic subdural hematoma (CSDH), however, refractory cases require further procedures or other interventions. CASE DESCRIPTION: An 85-year old male presented with left CSDH, which recurred five times. The hematoma was irrigated and drained through a left frontal burr hole during the first to third surgery and through a left parietal burr hole during the fourth and fifth surgery. The hematoma had no septation and was well-evacuated during each surgery. Antiplatelet therapy for preventing ischemic heart disease was stopped after the second surgery, the hematoma cavity was irrigated with artificial cerebrospinal fluid at the third surgery, and the direction of the drainage tube was changed to reduce the postoperative subdural air collection at the fourth surgery. However, none of these interventions was effective. He was successfully treated by fibrin glue injection into the hematoma cavity after the fifth surgery. CONCLUSION: This procedure may be effective for refractory CSDH in elderly patients. PMID- 27999713 TI - Intracranial aneurysm formation after radiotherapy for medulloblastoma. AB - BACKGROUND: The development of an intracranial aneurysm after radiotherapy is rare but secondary effect of cranial irradiation in a primary disease treatment. CASE DESCRIPTION: The patient was a 17-year-old male adolescent who was diagnosed as having a posterior fossa medulloblastoma when he was 8 years old. He had undergone tumor resection with radiotherapy and chemotherapy. A distal posterior inferior cerebellar artery aneurysm was identified by magnetic resonance imaging 8 years after radiotherapy and grew rapidly throughout the next 1 year. The patient underwent microsurgical clipping and was discharged without deficit. CONCLUSION: This experience demonstrates that physicians caring for patients who have undergone intracranial radiotherapy should carefully consider the possibility of an aneurysmal formation when conducting follow-up imaging. PMID- 27999714 TI - Hypervascular glioblastoma multiforme or arteriovenous malformation associated Glioma? A diagnostic and therapeutic challenge: A case report. AB - BACKGROUND: Simultaneous presentation of arteriovenous malformation (AVM) and glioblastoma multiforme (GBM) is rarely reported in the literature and needs to be differentiated from "angioglioma", a highly vascular glioma and other differential diagnosis such as hypervascular glioblastoma. Incorporating critical features of both, malignant glioma and AVM, such lesions lack a standard algorithm for diagnosis and therapy due to their rare incidence as well as their complex radiological and highly individualized clinical presentation. CASE DESCRIPTION: We present a case of a 71-year-old female with newly developing motor deficits and radiographic findings of a heterogeneously contrast enhancing right-sided thalamic lesion with highly prominent vasculature. While computed tomography angiogram and cerebral digital subtraction angiography supported the diagnosis of AVM, contrast-enhancing magnetic resonance imaging (MRI) and MR spectroscopy was suggestive of malignant glioma. A stereotactic biopsy revealed the diagnosis of a GBM (WHO IV) and the patient was treated accordingly. CONCLUSION: The coincidental presentation of vascular lesions such as AVM and malignant glioma is rare and presents a major challenge when establishing a diagnosis. The respective treatment decision is complicated by the fact that available treatment modalities (e.g. radiosurgery and/or open resection) carry disease specific complications for each entity. Finding a suitable solution for such cases requires standardization of early diagnostic and therapeutic management. PMID- 27999715 TI - Secretory paraspinal paraganglioma of thoracolumar spine: Case report and review of literature. AB - BACKGROUND: Pheochromocytomas are catecholamine secreting tumors of the adrenal medulla chromaffin cells, however, when present extra-adrenally they are called paragangliomas. Paragangliomas rarely produce catecholamine in excess, which is evident by clinical symptoms, urine, and blood biochemistry. Total resection of these tumors can lead to complete clinical and biochemical resolution. This case report presents the clinical features, radiological findings, and neurological outcome in a middle-aged female with a secretory paraganglioma. CASE DESCRIPTION: We present the case of a 34-year-old female who presented with a 2-year history of dizziness, flushing, headache, palpitations, and hypertension. Her blood workup showed raised urinary catecholamine levels. Magnetic resonance imaging (MRI) and iodine-123-meta-iodobenzylguanidine (MIBG) scans demonstrated a retroperitoneal mass located anterolateral to T11-T12 vertebral bodies reaching up to T12-L1 intervertebral disc. The patient was otherwise neurologically intact. She underwent resection of the tumor after alpha-adrenergic and beta adrenergic blockade. En bloc resection was achieved without neurological complications. Postoperatively, the patient was initially hypotensive and subsequently became normotensive, and on follow-up, the patient had resolution of her symptoms and was stable. CONCLUSION: Secretory paraganglioma of the dorsal spine are rare and difficult to excise, needs preoperative preparation with pharmacological intervention, good operative technique, and postoperative care. PMID- 27999716 TI - Primary cerebral echinoccocosis in a child: Case report - Surgical technique, technical pitfalls, and video atlas. AB - BACKGROUND: Hydatid disease is a life-threatening parasitic infestation caused by Echinococcus granulosus. Infection with E. granulosus typically results in the formation of hydatid cysts in the liver, lungs, kidney, and spleen. Primary intracranial hydatid cyst disease is extremely rare. Here, we are reporting an unusual case of Echinococcus, where the only identifiable lesion was a hydatid cyst in the brain without liver or lung involvement. We are also providing a description for the surgical technique used to remove the cyst, highlighting the possible surgical pitfalls. CASE DESCRIPTION: The patient is a 13-year-old male with a history of progressive headache for 1 month. Intracranial hydatid cyst was suspected based on computed tomography and magnetic resonance imaging findings. The cyst was delivered without rupture using hydrostatic dissection (Dowling's technique), and pathological analysis confirmed the diagnosis. Postoperatively, the patient showed marked neurological improvement and all signs and symptoms resolved. CONCLUSION: Intracranial hydatid cyst is very rare. Nevertheless, it should always be considered as a differential diagnosis in cerebral cystic lesions, especially in children. The surgical technique used to remove the cyst appears to be safe. However, several precautions must be applied intraoperatively to avoid the catastrophe of cyst rupture. PMID- 27999717 TI - A SYSTEMATIC REVIEW AND META-ANALYSIS COMPARING CARDIOPULMONARY EXERCISE TEST VALUES OBTAINED FROM THE ARM CYCLE AND THE LEG CYCLE RESPECTIVELY IN HEALTHY ADULTS. AB - INTRODUCTION: The cardiopulmonary exercise test (CPET) assesses maximal oxygen uptake (VO2max) and is commonly performed on a leg cycle ergometer (LC). However, some individuals would rather perform the CPET on an arm cycle ergometer (AC). OBJECTIVE: The objectives of this study were to undertake a systematic review and meta-analysis of the difference in VO2max achieved by AC compared to LC in healthy adults and to explore factors that may be predictive of this difference. METHODS: MEDLINE, EMBASE, CINAHL, and PEDro were searched in April 2015. The differences in VO2max (ACLCdiff) were pooled across studies using random effects meta-analysis and three different methods were used to estimate the ratio between the values obtained from the tests (ACLCratio). RESULTS: This paper included 41 studies with a total of 581 participants. The mean ACLCdiff across studies was 12.5 ml/kg/min and 0.89 l/min with a mean ACLCratio of 0.70. The ACLCdiff was lower in studies with higher mean age and lower aerobic capacity. CONCLUSION: There is linear association between the AC and LC values in healthy adults. The AC values were on average 70% of the LC values. The magnitude of this difference appeared to be reduced in studies on older and less active populations. LEVEL OF EVIDENCE: 3a. PMID- 27999718 TI - THE EFFECTS OF INSTRUMENT ASSISTED SOFT TISSUE MOBILIZATION ON LOWER EXTREMITY MUSCLE PERFORMANCE: A RANDOMIZED CONTROLLED TRIAL. AB - BACKGROUND: Instrument-Assisted Soft Tissue Mobilization (IASTM) is a non invasive therapeutic technique used to theoretically aid in scar tissue breakdown and absorption, fascial mobilization, and improved tissue healing. Researchers have hypothesized that utilizing IASTM will improve muscular efficiency and performance; yet previous Investigations has been focused on treating injury. OBJECTIVE: The purpose of this investigation was to explore the effects of IASTM on muscle performance to assess if typical treatment application affected measures of muscular performance. DESIGN: A pretest-posttest randomized control design. PARTICIPANTS: A convenience sample of 48 physically active adults (mean age 24 +/- 4 years), randomly assigned to one of three groups: quadriceps treatment group, triceps surae treatment group, or control group. INTERVENTIONS: Participants performed a five-minute warm-up on a Monark bicycle ergometer before performing three countermovement vertical jumps (CMJ). Immediately after, the IASTM treatment was applied by one researcher for three minutes on each leg at the specified site (e.g., quadriceps) for those assigned to the treatment groups, while the control group rested for six minutes. Immediately following treatment, participants performed three additional CMJs. Pre- and post-testing included measures of vertical jump height (JH), peak power (PP) and peak velocity (PV). RESULTS: There were no statistically significant differences found between treatment groups in JH, PP, or PV or across pre- and post-test trials. CONCLUSIONS: These preliminary findings suggest that standard treatment times of IASTM do not produce an immediate effect in muscular performance in healthy participants. This may help clinicians determine the optimal sequencing of IASTM when it is part of a pre-performance warm-up program. Future research should be conducted to determine the muscle performance effects of IASTM in individuals with known myofascial restriction and to determine optimal treatment parameters, such as instrument type, amount of pressure, and treatment time necessary to affect muscular performance. LEVEL OF EVIDENCE: 1b. PMID- 27999719 TI - IMMEDIATE EFFECTS OF DEEP TRUNK MUSCLE TRAINING ON SWIMMING START PERFORMANCE. AB - BACKGROUND: In recent years, deep trunk muscle training has been adopted in various sports, including swimming. This is performed both in everyday training and as part of the warm-up routine before competitive races. It is suggested that trunk stabilization exercises are effective in preventing injury, and aid in improving performance. However, conclusive evidence of the same is yet to be obtained. The time of start phase of swimming is a factor that can significantly influence competition performance in a swimming race. HYPOTHESIS/PURPOSE: If trunk stabilization exercises can provide instantaneous trunk stability, it is expected that they will lead to performance improvements in the start phase of swimming. The purpose of this study was to investigate the immediate effect of trunk stabilization exercises on the start phase in swimming. STUDY DESIGN: Intervention study. METHODS: Nine elite male swimmers (mean age 20.2 +/- 1.0 years; height 174.4 +/- 3.5 cm; weight 68.9 +/- 4.1 kg) performed the swimming start movement. The measurement variables studied included flying distance, and the time and velocity of subjects at hands' entry and on reaching five meters. Measurements were taken in trials immediately before and after the trunk stabilization exercises. A comparison between pre- and post-exercise measurements was assessed. RESULTS: The time to reach five meters (T5m) decreased significantly after trunk stabilization exercises, by 0.019 s (p = 0.02). Velocity at entry (Ventry) did not demonstrate significant change, while velocity at five meters (V5m) increased significantly after the exercises (p = 0.023). In addition, the speed reduction rate calculated from Ventry and V5m significantly decreased by 5.17% after the intervention (p = 0.036). CONCLUSION: Trunk stabilization exercises may help reduce the time from start to five meters in the start phase in swimming. The results support the hypothesis that these exercises may improve swimming performance. LEVELS OF EVIDENCE: Level 3b. PMID- 27999720 TI - CHANGES IN DYNAMIC BALANCE AND HIP STRENGTH AFTER AN EIGHT-WEEK CONDITIONING PROGRAM IN NCAA DIVISION I FEMALE SOCCER (FOOTBALL) ATHLETES. AB - BACKGROUND: Lower extremity injury commonly affects female soccer athletes. Decreased dynamic balance and hip strength are identified risk factors for lower extremity injury. Little is known about how these factors adapt to a training stimulus in this population. PURPOSE: To retrospectively investigate changes in lower extremity dynamic balance and isometric hip strength in Division I collegiate female soccer athletes after participating in an eight-week strength and conditioning program. STUDY DESIGN: Retrospective, non-experimental cohort study. METHODS: As part of a standard testing battery, soccer athletes completed athletic performance pre- and post-testing separated by an eight-week off-season conditioning program consisting of overall strength and technical skill development. Testing included lower extremity dynamic balance assessment through the Star Excursion Balance Test (SEBT) and isometric hip abduction and external rotation (ER) strength testing, normalized to limb length and percent body mass, respectively. Athletes rested for one week prior to post-testing. RESULTS: Seventeen healthy Division I female soccer athletes (age: 18.8 +/- 0.9 years, height: 1.7 +/- 0.06 m, mass: 68.0 +/- 8.2 kg) completed the protocol. Significant improvements in SEBT composite reach distance were observed in the dominant (DOM) (3.6 +/- 4.8%, 95% CI: 1.1 to 6.0) and nondominant (NDOM) (4.8 +/- 6.1%, 95% CI: 1.7 to 7.9) limbs. Significant improvements in DOM hip ER strength (2.4 +/- 2.3%, 95% CI: 1.3 to 3.6) and DOM SEBT anterior reach (2.1 +/- 2.8%, 95% CI: 0.6 to 3.5) were observed. Large effect sizes were observed for DOM and NDOM hip ER strength gains (0.87 - 1.0), while small-moderate effect sizes were noted for the anterior reach direction (0.40 - 0.66). Further, DOM hip ER strength gains were significantly associated with DOM anterior reach performance improvements (r2 = 0.37, p<.01). CONCLUSION: DOM hip ER strength gains appear to be associated with improved lower extremity dynamic balance on the ipsilateral limb for the SEBT anterior reach direction in collegiate, Division I female soccer athletes after an eight-week conditioning program. Future investigations should prospectively investigate intervention strategies to modify lower extremity injury risk factors in this population. LEVEL OF EVIDENCE: 2b. PMID- 27999721 TI - IMPROVEMENTS IN KNEE EXTENSION STRENGTH ARE ASSOCIATED WITH IMPROVEMENTS IN SELF REPORTED HIP FUNCTION FOLLOWING ARTHROSCOPY FOR FEMOROACETABULAR IMPINGEMENT SYNDROME. AB - BACKGROUND: Recovery of strength is critical for return to sport, and is a known predictor of functional outcomes in post-surgical orthopedic populations. Muscle weakness is a known impairment in patients with femoroacetabular impingement syndrome (FAIS) but whether improvements in muscle strength after arthroscopy are associated with improved hip function is unknown. HYPOTHESIS/PURPOSE: To examine the relationships between changes in hip and thigh muscle strength and self reported function in athletes undergoing arthroscopy for FAIS. STUDY DESIGN: Single cohort descriptive and correlational study. METHODS: Twenty-eight athletes underwent strength testing and completed the Hip Outcome Score Activities of Daily Living (HOS-ADL) and Sports (HOS-S) subscales prior to and six months after surgery. Isokinetic knee extension and flexion strength were measured using a Biodex dynamometer at 60 degrees /s and 300 degrees /s. Isometric hip abduction strength was measured using a custom dynamometer. Changes in strength, limb symmetry, and HOS scores were assessed using paired t-tests. Spearman's rank correlations were used to examine relationships between change in involved limb strength and change in HOS scores. RESULTS: Subjects were tested an average of 32 days before and 178 days after surgery. HOS-ADL and HOS-S subscales improved by a mean of 19.0 +/- 21.1 and 23.8 +/- 31.9, respectively, over time (p < 0.001). Hip abduction strength did not increase over time in either limb (p >= 0.27). Involved limb knee flexion and extension strength did not increase significantly over time (p-values: 0.10-0.48) with the exception of knee extension at 300 degrees /s (p = 0.04). Uninvolved limb knee extension strength at both velocities and knee flexion strength at 60 degrees /s improved significantly over time (p < 0.012). Increases in knee extension strength (60 degrees /s) of the involved limb were significantly correlated with improvements on the HOS-ADL (r = 0.431; 0 = 0.025) and HOS-S (r = 0.439; p = 0.025). There were no significant relationships between changes in involved limb hip abduction or knee flexion strength and HOS subscales (p>=0.123). CONCLUSION: Improvements in knee extension strength were associated with improvements in self-reported hip function in athletes following arthroscopy for FAIS. Individuals with knee extension strength deficits prior to surgery may benefit from targeted knee extension strengthening during post-operative rehabilitation to improve functional outcomes. LEVEL OF EVIDENCE: Level III (non-randomized controlled cohort study). PMID- 27999723 TI - MEASURING SPORT-SPECIFIC PHYSICAL ABILITIES IN MALE GYMNASTS: THE MEN'S GYMNASTICS FUNCTIONAL MEASUREMENT TOOL. AB - PURPOSE/BACKGROUND: Despite the availability of various field-tests for many competitive sports, a reliable and valid test specifically developed for use in men's gymnastics has not yet been developed. The Men's Gymnastics Functional Measurement Tool (MGFMT) was designed to assess sport-specific physical abilities in male competitive gymnasts. The purpose of this study was to develop the MGFMT by establishing a scoring system for individual test items and to initiate the process of establishing test-retest reliability and construct validity. METHODS: A total of 83 competitive male gymnasts ages 7-18 underwent testing using the MGFMT. Thirty of these subjects underwent re-testing one week later in order to assess test-retest reliability. Construct validity was assessed using a simple regression analysis between total MGFMT scores and the gymnasts' USA-Gymnastics competitive level to calculate the coefficient of determination (r2). Test-retest reliability was analyzed using Model 1 Intraclass correlation coefficients (ICC). Statistical significance was set at the p<0.05 level. RESULTS: The relationship between total MGFMT scores and subjects' current USA-Gymnastics competitive level was found to be good (r2 = 0.63). Reliability testing of the MGFMT composite test score showed excellent test-retest reliability over a one-week period (ICC = 0.97). Test-retest reliability of the individual component tests ranged from good to excellent (ICC = 0.75-0.97). CONCLUSIONS: The results of this study provide initial support for the construct validity and test-retest reliability of the MGFMT. LEVEL OF EVIDENCE: Level 3. PMID- 27999722 TI - EFFECT OF DIFFERENT FOAM ROLLING VOLUMES ON KNEE EXTENSION FATIGUE. AB - BACKGROUND: Foam rolling (FR) is a common intervention utilized for the purpose of acutely increasing range-of-motion without subsequent decreases in performance. FR is characterized as an active technique which subject performs upon themselves. Thus, it is believed that the accumulated fatigue can influence whether the task can be continued. PURPOSE: To analyze the effect of different foam rolling volumes on fatigue of the knee extensors. METHODS: Twenty-five recreationally active females (age 27.7 +/- 3.56 y, height 168.4 +/- 7.1 cm, weight 69.1 +/- 10.2 kg) were recruited for the study. The experiment involved three sets of knee extensions with a pre-determined 10 repetition maximum load to concentric failure. Then, subjects performed the control (CONT) and foam rolling (FR) conditions. FR conditions consisted of different anterior thigh rolling volumes (60-, 90-, and 120-seconds) which were performed during the inter-set rest period. After that, the fatigue index was calculated and compared between each experimental condition. Fatigue index indicates how much (%) resistance the subjects experienced, calculated by the equation: (thidset/firstset) x 100. RESULTS: Fatigue index was statistically significantly greater (greater fatigue resistance) for CONT compared to FR90 (p = 0.001) and FR120 (p = 0.001). Similarly, higher fatigue resistance was observed for FR60 when compared to FR120 (p = 0.048). There were no significant differences between the other conditions (p > 0.005). CONCLUSION: The finding of foam rolling fatigue index decline (less fatigue resistance) as compared to control conditions may have implications for foam rolling prescription and implementation, in both rehabilitation and athletic populations. For the purposes of maximum repetition performance, foam rolling should not be applied to the agonist muscle group between sets of knee extensions. Moreover, it seems that volumes greater than 90-seconds are detrimental to the ability to continually produce force. LEVEL OF EVIDENCE: 2b. PMID- 27999724 TI - THE RELIABILITY OF FABER TEST HIP RANGE OF MOTION MEASUREMENTS. AB - BACKGROUND: The Flexion ABduction External Rotation (FABER) test is typically used as a provocation special test, but has also been used as a measurement of combined hip range of motion (ROM). It is thought that limited ROM with this measurement may be indicative of hip pathology. To date, normative data, reliability, and minimal detectable change (MDC) of such measurements have not been established. PURPOSE: To determine normative FABER height, assess inter- and intra-rater reliability and MDC for FABER, and compare traditional FABER measurements to methods which account for differences in thigh length. STUDY DESIGN: Descriptive laboratory reliability study. METHODS: Nineteen healthy participants without low back, hip, or knee pain in the preceding three months were recruited. Measurements were performed during two sessions (three to seven days between sessions) by three clinicians. FABER height and thigh length measurements were performed. Thigh length normalized FABER range of motion (ROM) and side-to-side FABER ROM symmetry were calculated. One tester also measured FABER with a digital inclinometer. Inter- and intra-rater reliability were calculated using interclass correlation coefficients (ICC) and mean MDC values were calculated. RESULTS: Mean values for FABER height and normalized FABER ROM were 12.4 +/- 2.8 cm and 0.30 +/- 0.07, respectively. Inter-rater reliability for FABER and normalized FABER were good (ICC 0.67-0.68) and between session intra rater reliability were good to excellent (ICC 0.76-0.86). Mean FABER and normalized FABER ROM MDC were 3.7 cm and 0.04, respectively. Mean FABER ROM symmetry was 2.0 +/- 0.9 cm with poor inter-rater reliability (ICC 0.20), poor to good intra-rater reliability (ICC 0.38-0.66), and mean MDC of 4.0 cm. FABER measured with a ruler, normalized FABER ROM, and inclinometry all resulted in excellent intra-rater reliability, with the highest ICC being demonstrated for inclinometry (ICC 0.86, 0.86, and 0.91). CONCLUSIONS: Overall, FABER measurements were reliable, whether normalized to thigh length or not. Furthermore, use of inclinometry may increase reliability. Reliability was poor to good when assessing symmetry between limbs. LEVEL OF EVIDENCE: Level 3. PMID- 27999725 TI - MODIFYING MARCHING TECHNIQUE IN MILITARY SERVICE MEMBERS WITH CHRONIC EXERTIONAL COMPARTMENT SYNDROME: A CASE SERIES. AB - BACKGROUND AND PURPOSE: The long-term effectiveness of both operative and non operative management approaches for Chronic Exertional Compartment Syndrome of the lower legs (CECS) is moderate at best. Positive outcomes have recently been reported on modifying running technique in individuals with CECS. The purpose of this case series was to evaluate a training program aimed at changing marching technique in individuals with CECS, based on principles that aim to eliminate heel strike and decrease impact during foot strike. STUDY DESIGN: Case series. METHODS: Six service members with CECS underwent a five-week training program aimed at modifying marching technique. The program was comprised of foot/lower leg strengthening exercises, perception drills, and treadmill/outdoor marching bouts. Self-assessed leg condition, march endurance performance, and kinematic/kinetic measurements were assessed at baseline (T0), post-treatment (T5), and nine months post-intervention (T40). RESULTS: Moderate to fair pre- to post improvements on the self-assessed leg condition outcomes were demonstrated for most participants (4% to 73% improvements). These scores continued to improve until the 9 months follow-up. Marching performance improved during the intervention period in all but one subject, ranging from 6% to 38% improvement in marching time. Kinematic and kinetic data showed pre- to post-intervention changes that were reflective of the marching technique modification in most subjects. Post-intervention pain profiles of participants during marching showed that, in most subjects, the onset of leg pain was delayed compared to baseline. CONCLUSIONS: A five-week intervention aimed at altering marching technique has demonstrated moderately promising results in a group of service members with CECS of the lower legs who had previously undergone other conservative management interventions without success. Due to the relatively small sample size and the variability in subject outcomes, further research is warranted. LEVEL OF EVIDENCE: 4. PMID- 27999726 TI - ACUTE TEARING OF THE OBLIQUE ABDOMINAL WALL INSERTION ONTO THE ILIAC CREST IN AN AUSTRALIAN FOOTBALL PLAYER: A CASE REPORT. AB - BACKGROUND: Tears of the abdominal obliques have previously been reported in the vicinity of the lower ribs but they have not been reported in the vicinity of the iliac crest. The purpose of this case report is to describe the mechanism of injury and diagnosis of a distal abdominal oblique tear and subsequent rehabilitation programming. CASE DESCRIPTION: A 21-year-old male Australian football player experienced acute right-sided abdominal pain during a game while performing a commonly executed rotation skill. He was assessed clinically before being further examined with ultrasound and magnetic resonance imaging which revealed a rupture of the abdominal oblique wall at its insertion onto the iliac crest. The player then underwent a structured and graduated rehabilitation program with clear key performance indicators to optimize return to play and prevent recurrence. OUTCOMES: The player was able to return to play at 35 days post injury and had no recurrence or complications at 12 month follow up post injury. DISCUSSION: This is the first time an abdominal oblique wall rupture at its insertion onto the iliac crest has been reported. In players with acute abdominal pain following twisting an insertional oblique tear should be considered as a differential diagnosis. A structured rehabilitation program may also help optimize an athlete's return to play after distal abdominal oblique rupture. PMID- 27999727 TI - AN INTERVENTION-BASED CLINICAL REASONING FRAMEWORK TO GUIDE THE MANAGEMENT OF THORACIC PAIN IN A DANCER: A CASE REPORT. AB - BACKGROUND AND PURPOSE: As a result of the anatomical proximity of the thoracic spine to the cervical, lumbar, and shoulder regions, dysfunction in the thoracic spine can influence pain, mobility, and stability across these areas. Currently, a paucity of evidence exists addressing treatment of individuals with primary thoracic pain, especially in young, athletic patients. Furthermore, current research discussing clinical reasoning frameworks focus on the differential diagnostic process. The purpose of this case report was to present a framework that describes the clinical reasoning process for the implementation and sequencing of procedural interventions for the management of a dancer with thoracic pain. CASE DESCRIPTION: A 21-year-old female dancer presented to physical therapy with a medical diagnosis of thoracic pain. The patient reported exacerbation of left thoracic pain with prolonged sitting, twisting/arching her back during dance, and lifting >15 lbs overhead. Examination revealed hypomobility with positive pain provocation during mobility testing of T1-T3 and the sternocostal junction of ribs 2-4, with associated muscle guarding palpated in the left iliocostalis thoracis and levator scapulae. OUTCOMES: Following 10 visits, the patient had no pain, no functional deficits, and a Global Rating of Change (GROC) of + 6. She returned to full competition, and a 3-month follow-up revealed continued success with dancing and a GROC of +7. DISCUSSION: This case report described the successful management of a dancer with primary thoracic pain using a clinical reasoning framework for the sequencing of procedural interventions, while incorporating Olson's impairment-based classification system. A combination of manual therapy techniques and neuromuscular control exercises were incorporated to address mobility, stability, mobility on stability, and skill level impairments, which allowed the patient to return to dance activities safely. Future studies should consider the development of further treatment-based clinical reasoning frameworks that illustrate the importance of the sequencing within a session and across the episode of care. LEVEL OF EVIDENCE: 4. PMID- 27999728 TI - FROM ACUTE ACHILLES TENDON RUPTURE TO RETURN TO PLAY - A CASE REPORT EVALUATING RECOVERY OF TENDON STRUCTURE, MECHANICAL PROPERTIES, CLINICAL AND FUNCTIONAL OUTCOMES. AB - INTRODUCTION: Achilles tendon rupture results in significant functional deficits regardless of treatment strategy (surgical versus non-surgical intervention). Recovery post-rupture is highly variable, making comprehensive patient assessment critical. Assessment tools may change along the course of recovery as the patient progresses - for instance, moving from a seated heel-rise to standing heel-rise to jump testing. However, tools that serve as biomarkers for early recovery may be particularly useful in informing clinical decision-making. The purpose of this case report was to describe the progress of a young, athletic individual following Achilles tendon rupture managed non-surgically, using patient reported and functional performance outcome measures and comprehensively evaluating Achilles tendon structure and function incorporating a novel imaging technique (cSWE). SUBJECT DESCRIPTION: The subject is a 26 year-old, female basketball coach who sustained an Achilles tendon rupture and was managed non-surgically. OUTCOME: The subject was able to steadily progress using a gradual tendon loading treatment approach well-supported by the literature. Multiple evaluative techniques including the addition of diagnostic ultrasound imaging and continuous shear wave elastography (cSWE) to standard clinical tests and measures were used to assess patient-reported symptoms, tendon structure, and tendon functional performance. Five assessments were performed over the course of 2-14 months post rupture. By the 14-month follow-up, the subject had achieved full self-reported function. Tendon structural and mechanical properties showed similar shear modulus by 14 months, however, viscosity continued to be lower and tendon length longer on the ruptured side. Functional performance, evidenced by the heel-rise test and jump tests, also showed a positive trajectory, however, deficits of 12 28% remained between ruptured and non-ruptured sides at 14 months. DISCUSSION: This case report outlines comprehensive outcomes assessment in an athletic individual following non-surgically managed Achilles tendon rupture using a wide variety of tools that capture different aspects of tendon health. Interestingly, the course of recovery of patient symptoms, functional performance, and tendon structure do not occur in the same time frame. Therefore, it is important to assess patient outcomes using multiple outcome measures encompassing different aspects of patient performance to ensure the patient is progressing steadily with rehabilitation. LEVEL OF EVIDENCE: Level 4. PMID- 27999730 TI - POST OPERATIVE REHABILITATION OF GRADE III MEDIAL COLLATERAL LIGAMENT INJURIES: EVIDENCE BASED REHABILITATION AND RETURN TO PLAY. AB - : The medial collateral ligament is the most commonly injured ligament of the knee, with injury generally sustained in the athletic population as a result of valgus contact with or without tibial external rotation. The capacity of the medial collateral ligament to heal has been demonstrated in both laboratory and clinical studies; however, complete ruptures heal less consistently and may result in persistent instability. When operative intervention is deemed necessary, anatomical medial knee reconstruction is recommended. Post-operative rehabilitation focuses on early motion and the return of normal neuromuscular firing patterns with progression based on attainment of specific phase criteria and goals. The purpose of this clinical commentary is to discuss the determinants of phase progression and the importance of objectively assessing readiness for advancement that is consistent with post-operative healing. Additional tests and validated measures to assess readiness for sport are also presented. LEVEL OF EVIDENCE: 5. PMID- 27999729 TI - A NON-OPERATIVE APPROACH TO THE MANAGEMENT OF CHRONIC EXERTIONAL COMPARTMENT SYNDROME IN A TRIATHLETE: A CASE REPORT. AB - BACKGROUND & PURPOSE: Chronic Exertional Compartment Syndrome (CECS) causes significant exercise related pain secondary to increased intra-compartmental pressure (ICP) in the lower extremities. CECS is most often treated with surgery with minimal information available on non-operative approaches to care. This case report presents a case of CECS successfully managed with physical therapy. STUDY DESIGN: Case report. CASE DESCRIPTION: A 34-year-old competitive triathlete experienced bilateral anterior and posterior lower leg pain measured with a numerical pain rating scale of 7/10 at two miles of running. Pain decreased to resting levels of 4/10 two hours post exercise. The patient was diagnosed with bilateral CECS with left lower extremity ICP at rest measured at 36 mmHg (deep posterior), 36-38 mmHg (superficial posterior), and 25 mmHg (anterior). Surgery was recommended. INTERVENTIONS: The patient chose non-operative care and was treated with physical therapy using the Functional Manual Therapy approach aimed at addressing myofascial restrictions, neuromuscular function and motor control deficits throughout the lower quadrant for 23 visits over 3.5 months. OUTCOMES: At discharge the patient had returned to running pain free and training for an Olympic distance triathlon. The Lower Extremity Functional Scale improved from 62 to 80. The patient reported minimal post exercise tightness in bilateral lower extremities. Left lower extremity compartment pressure measurements at rest were in normal ranges measuring at 11 mmHg (deep posterior), 8 mmHg (superficial posterior), 19 mmHg (anterior), and 10 mmHg (lateral). Three-years post intervention the patient remained pain free with a Global Rating of Change of 6. DISCUSSION: This case report describes the successful treatment of a triathlete with Functional Manual Therapy resulting in a return to competitive sports without pain. LEVEL OF EVIDENCE: Level 4. PMID- 27999732 TI - Long noncoding RNAs: pivotal regulators in acute myeloid leukemia. AB - Long noncoding RNAs (lncRNAs) have emerged as a class of pivotal regulators of gene expression. Recent studies have shown that lncRNAs contribute to the initiation, maintenance, and development of acute myeloid leukemia (AML). In this review, we summarize the current knowledge of the lncRNAs that play critical roles in AML. We first briefly describe the characteristics of lncRNAs, and then focus on their regulatory roles in AML, including the modulation of differentiation, proliferation, cell cycle, and apoptosis. We further emphasize the action of lncRNAs during leukemogenesis by describing how they interact with RNA, protein and chromatin DNA to exert their functions. We also highlight an urgent need to investigate the mechanisms by which lncRNAs contribute to the pathogenesis of AML. Finally, we discuss the prognostic value of lncRNAs in AML patients. PMID- 27999733 TI - Know your neighbors: Different tumor microenvironments have implications in immunotherapeutic targeting strategies across MB subgroups. AB - Medulloblastoma (MB) is the most common pediatric brain tumor with few reports of successful immunologic targeting. We have recently demonstrated the immune tumor microenvironment as well as response to immune checkpoint blockade differ across subtypes of murine MB. PMID- 27999731 TI - CLINICAL COMMENTARY ON MIDFOOT AND FOREFOOT INVOLVEMENT IN LATERAL ANKLE SPRAINS AND CHRONIC ANKLE INSTABILITY. PART 2: CLINICAL CONSIDERATIONS. AB - Lateral ankle sprains (LAS) and chronic ankle instability (CAI) are common musculoskeletal injuries that are a result of inversion injury during sport. The midfoot and forefoot is frequently injured during a LAS, is often overlooked during clinical examination, and maybe contributory to the development of CAI. The purpose of part two of this clinical commentary and current concept review is to increase clinician's awareness of the contribution of midfoot and forefoot impairment to functional limitation and disability of individuals who experience LAS and CAI and to facilitate future research in this area. The importance of multisegmented foot and ankle assessment from a clinical and research perspective is stressed. Select physical assessment and manual therapeutic techniques are presented to assist the clinician in examination and treatment of the ankle-foot complex in patients with LAS and CAI. PMID- 27999734 TI - Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. AB - Background: PD-L1 has been widely reported as immune check points in a range of malignancies as well as some immune-originated diseases. In glioma, the role of PD-L1 remains unclear. We aimed at investigating its role at transcriptome level and relationship with clinical practice. Method and patients: In total, 976 glioma samples with transcriptome data, including 301 microarray data from Chinese Glioma Genome Atlas (CGGA project) and 675 RNAseq data from TCGA project, were enrolled into our study. Clinical and IDH mutation data were also available. R language was used as the main tool for statistical analysis and graphical work. Results: PD-L1 expression was found to be positively correlated with WHO grade of glioma. PD-L1 seemed to express more in mesenchymal subtype according to TCGA transcriptional classification scheme and may contribute as a potential marker for mesenchymal subtype in glioblastoma. Pearson correlation test indicated that PD-L1 showed robust correlation with PD1, PD-L2, and CD80 in CGGA dataset. Subsequent gene ontology analysis based on significantly correlated genes of PD L1 revealed that PD-L1 seemed to be profoundly associated with T cell activation. To further investigate the relationship between PD-L1 expression and immune response, we selected a series of immune signatures, which were then transformed into metagenes, and found that PD-L1 expression was particularly paralleled with T-cells and macrophages-related immune response instead of B cell linage-related immune response. In line with the corresponding biological process, PD-L1 exhibited predictive value for glioma patients: Higher PD-L1 indicated significantly shorter survival, especially in glioblastoma. Conclusion: PD-L1 is upregulated in glioblastoma, and is synergistic with other check point members. Moreover, PD-L1 is significantly associated with T-cell activation and macrophage related immune response and predicts much worse survival for patients, warranting clinical trials of PD1/PD-L1 checkpoint inhibitors for potential glioma treatment. PMID- 27999735 TI - Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases. AB - Neuroendocrine tumors (NETs) of the gastrointestinal tract are a rare and heterogeneous group of neoplasms with unique tumor biology and clinical management issues. While surgery is the only curative treatment option in patients with early stage NETs, the optimal management strategy for patients with advanced metastatic NETs is unknown. Based on the tremendous success of immunotherapeutic approaches, we sought to investigate such approaches in a case of metastatic rectal NET. Here, we apply an integrative approach using various computational and experimental methods to explore several aspects of the tumor host immune interactions for immunotherapeutic options. Sequencing of six different liver metastases revealed a quite homogenous set of mutations, and further analysis of these mutations for immunogenicity revealed few neo-epitopes with pre-existing T cell reactivity, which can be used in therapeutic vaccines. Staining for immunomodulatory proteins and cytokine profiling showed that the immune setting is surprisingly different, when compared to liver metastases of colorectal cancer for instance. Taken together, our results highlight the broad range and complexity of tumor-host immune interaction and underline the value of an integrative approach. PMID- 27999736 TI - Characterization of cytokinome landscape for clinical responses in human cancers. AB - Dysfunctional intratumoral immune reactions are shaped by complex networks of cytokines (including chemokines), and how the cytokinome landscape coordinates with tumors has not been systematically investigated. Using high-dimensional datasets of cancer specimens, we explored the transcript abundance, biomarker potential, and prognostic impact of local cytokines across 19 tumor types. We found that most cytokines are highly locally dysregulated (p = 0.024), revealing spatiotemporal pattern of local cytokines in the development of cancers. In addition, we noted the significant downregulation of CCL14 and CXCL12 in 9 and 10 cancer types, respectively, implying their crucial roles in tumor pathogenesis. We also found that cytokines showed significantly higher specificity properties compared to other protein-coding genes (PCGs) in primary tumor specimens (p << 0.001), indicating that tissue context remains an issue when considering cancer cytokinomes. Finally, we linked concentrations of local cytokines to patient survival. Our results thus provide a panoramic view of pan-cancer cytokinomes, which highlights tumor type specificity of cancer-related cytokines and their impacts on disease prognosis. PMID- 27999737 TI - Immunotherapies targeting CD38 in Multiple Myeloma. AB - Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells. PMID- 27999738 TI - The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat. AB - Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301. We found that entinostat significantly decreased granulocytic and monocytic MDSCs at cycle 1 day 15. MDSC CD40 was significantly downregulated by entinostat. A significant increase in HLA-DR expression on CD14+ monocytes by entinostat was observed. Entinostat did not impact T-cell subsets or T-cell immune checkpoint receptor expression. Our findings suggest that a significant interplay between this epigenetic regimen and host immune homeostatic mechanisms may impact therapeutic outcome. PMID- 27999739 TI - TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC. The subpopulation of monocytic MDSC (m-MDSC) was the most affected by R848 treatment with an up to 5-fold decrease in the tumor. We found that TLR7 stimulation in tumor-bearing mice led to a maturation and differentiation of MDSC with upregulation of the surface molecules CD11c, F4/80, MHC-I, and MHC-II. MDSC treated with R848 lost their immunosuppressive function and acquired instead an antigen-presenting phenotype with the capability to induce specific T-cell proliferation. Importantly, we found that MDSC co-injected s.c. with CT26 tumor cells lost their ability to support tumor growth after pretreatment with R848. Our results demonstrate that treatment of tumor-bearing mice with a TLR7/8 agonist acts directly on MDSC to induce their maturation and leads them to acquire a non-suppressive status. Considering the obstacles posed by MDSC for cancer immunotherapy, targeting these cells by a TLR7/8 agonist may improve immune responses against cancer. PMID- 27999741 TI - Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer. AB - Immune checkpoint inhibitors have led to considerable therapy improvement in cancer patients. Autoimmune side effects including skin reactions are frequently observed. In melanoma, those include rash and vitiligo and were shown to be associated with a prolonged overall survival. Little is known about skin reactions in non-small cell lung cancer (NSCLC) patients during immunotherapy. Here, we retrospectively investigated immune-related adverse skin reactions (irAEs) in 40 patients with metastatic NSCLC treated with the anti-PD-1 antibody nivolumab. 7 out of 40 patients (17%) developed an irAEs. Skin irAEs correlated with tumor responses in 5 of 12 responders (42%) as compared to 2 of 27 non responders (7%). Histologically, scaly plaques showed dermatitis consisting mainly of lymphocytes. We observed a positive correlation between skin irAEs and tumor responses in patients with NSCLC treated with nivolumab. Patterns of lymphocytic skin infiltration differed depending on the histological tumor subtype (adenocarcinoma versus squamous cell carcinoma NSCLC). PMID- 27999740 TI - From cell biology to immunology: Controlling metastatic progression of cancer via microRNA regulatory networks. AB - Recently, the study of microRNAs has expanded our knowledge of the fundamental processes of cancer biology and the underlying mechanisms behind tumor metastasis. Extensive research in the fields of microRNA and its novel mechanisms of actions against various cancers has more recently led to the trial of a first cancer-targeted microRNA drug, MRX34. Yet, these microRNAs are mostly being studied and clinically trialed solely based on the understanding of their cell biologic effects, thus, neglecting the important immunologic effects that are sometimes opposite of the cell biologic effects. Here, we summarize both the cell biologic and immunologic effects of various microRNAs and discuss the importance of considering both effects before using them in clinical settings. We stress the importance of understanding the miRNA's effect on cancer metastasis from a "systems" perspective before developing a miRNA-targeted therapeutic in treating cancer metastasis. PMID- 27999742 TI - Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses. AB - Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly(I:C) that mimics virally induced immune activation. Timing of the stimulations was important, as sequential stimulation with poly(I:C) and the TLR7 agonist R848 interspaced by 24 h induced higher MAPK and NFkB signaling in DC than the simultaneous application of the same ligands. DC activated by sequential poly(I:C)/R848 stimulation efficiently induced Th1 differentiation and primed NK-cell and cytotoxic T-cell responses. We have developed a treatment regimen taking advantage of TLR7 reprogram-ming that cured over 80% of large immunogenic tumors in mice by the action of NK cells and cytotoxic T cells. These results have direct implications for the use of these clinically established ligands in the immunotherapy of cancer. PMID- 27999743 TI - Targeting B-cell malignancies through human B-cell receptor specific CD4+ T cells. AB - The B-cell receptor (BCR) expressed by a clonal B cell tumor is a tumor specific antigen (idiotype). However, the T-cell epitopes within human BCRs which stimulate protective immunity still lack detailed characterization. In this study, we identified 17 BCR peptide-specific CD4+ T-cell epitopes derived from BCR heavy and light chain variable region sequences. Detailed analysis revealed these CD4+ T-cell epitopes stimulated normal donors' and patients' Th1 CD4+ T cells to directly recognize the autologous tumors by secretion of IFNgamma, indicating the epitopes are processed and presented by tumor cells. One BCR peptide-specific CD4+ T cell line was also cytotoxic and lysed autologous tumor cells through the perforin pathway. Sequence analysis of the epitopes revealed that 10 were shared by multiple primary patients' tumors, and 16 had the capacity to bind to more than one HLA DRB1 allele. T cells stimulated by shared epitopes recognized primary tumors expressing the same sequences on multiple HLA DRB1 alleles. In conclusion, we identified 17 BCR-derived CD4+ T-cell epitopes with promiscuous HLA DRB1 binding affinity that are shared by up to 36% of patients, suggesting a strategy to overcome the requirement for individual preparation of therapeutic agents targeting idiotype. PMID- 27999745 TI - microRNA-155 deficiency impairs dendritic cell function in breast cancer. AB - In antitumor immunity, dendritic cells (DCs) capture, process, and present tumor antigens to T cells, initiating a tumoricidal response. However, DCs are often dysfunctional due to their exposure to the tumor microenvironment (TME), leading to tumor escape from immune surveillance. Here, a vital role of microRNA-155 (miR 155) in regulating the function of DCs in breast cancer is reported. Host miR-155 deficiency enhanced breast cancer growth in mice, accompanied by reduced DCs in the tumors and draining lymph nodes. miR-155 deficiency in DCs impaired their maturation, migration ability, cytokine production, and the ability to activate T cells. We demonstrate that miR-155 regulates DC migration through epigenetic modulation of CCR7 expression. Moreover, IL-6 and IL-10, two cytokines abundant in the TME, are found to impair DC maturation by suppressing miR-155 expression. Furthermore, animal studies show that a lack of miR-155 diminishes the effectiveness of DC-based immunotherapy for breast cancer. In conclusion, these findings suggest that miR-155 is a master regulator of DC function in breast cancer, including maturation, cytokine secretion, migration toward lymph nodes, and activation of T-cells. These results suggest that boosting the expression of a single microRNA, miR-155, may significantly improve the efficacy of DC-based immunotherapies for breast cancer. PMID- 27999744 TI - Tumor-associated neutrophils display a distinct N1 profile following TGFbeta modulation: A transcriptomics analysis of pro- vs. antitumor TANs. AB - It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown. TGFbeta plays a significant role in the determination of neutrophils' phenotype, by shifting the balance from an antitumor (N1) toward a more permissive (N2) phenotype. The full range of mechanisms responsible for the pro- vs. antitumor effects of TANs has not yet been elucidated. Therefore, the ability to identify the different neutrophil subpopulations in the tumor is critical in order to understand TANs evolution and contribution throughout tumor progression. Using a transcriptomic approach, we identified alternations in gene expression profile following TGFbeta inhibition. We show that N1 and N2 TANs represent distinct subpopulations with different transcriptional signatures and both differ from naive bone marrow neutrophils. The analysis highlights a clear difference in pathways involved in neutrophil function such as cytoskeletal organization and antigen presentation, as well as alterations in chemokine profile, eventually affecting their effect on tumor cells and tumor growth. These data highlights several potential new pathways and mechanisms by which neutrophils can influence both the tumor cells and the adaptive immune system. PMID- 27999746 TI - Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion. AB - Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial lymphatic flow in vivo. Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-beta-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE cadherin-mediated lymphatic intercellular junctions. PMID- 27999747 TI - Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells. AB - The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n = 22) received the vaccine without any adjuvant; the next cohort (n = 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumor-specific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p = 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators. PMID- 27999748 TI - Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. AB - Kupffer cells represent the first line of defense against tumor cells in the liver. Myeloid-derived suppressor cells (MDSC) have recently been observed in the liver parenchyma of tumor-bearing animals. The present study investigates the function of the MDSC subsets, and their impact on Kupffer cell phenotype and function. RIL-175 mouse hepatocellular carcinoma (HCC) cells were injected into the median liver lobe of C57BL/6 mice. Three weeks later, the median lobe hosting the tumor nodule was removed, and Kupffer cells and MDSCs were sorted from the remaining liver. Mouse livers devoid of HCC served as control. Kupffer cells expressed less co-stimulatory CD86 and MHCII and more co-inhibitory CD274 molecules in HCC-bearing livers than in control livers. Corresponding to this phenotype, Kupffer cells from HCC-bearing mice were less efficient in their function as antigen-presenting cells. Three CD11b+ cell populations were identified and sorted from HCC-bearing mice. These cells had various phenotypes with different levels of MDSC-specific surface markers (Ly6Ghigh cells, Gr1high cells, and Ly6Clow cells), and may be considered as bonafide MDSCs given their suppression of antigen-specific T cell proliferation. Primary isolated Kupffer cells in co-culture with the three MDSC subsets showed a decrease in CCL2 and IL 18 secretion, and an increase in IL-10 and IL-1beta secretion, and an increased expression of CD86, CD274, and MHCII. In conclusion, these data demonstrated the existence of three MDSC subsets in HCC-bearing animals. These cells altered Kupffer cell function and may decrease the migration and activation of anticancer effector cells in the liver. PMID- 27999749 TI - Growth and metastasis of lung adenocarcinoma is potentiated by BMP4-mediated immunosuppression. AB - Cancer cells modulate the recruitment and function of inflammatory cells to create an immunosuppressive microenvironment that favors tumor growth and metastasis. However, the tumor-derived regulatory programs that promote intratumoral immunosuppression remain poorly defined. Here, we show in a KrasLA1/+p53R172HDeltag/+-based mouse model that bone morphogenetic protein-4 (BMP4) augments the expression of the T cell co-inhibitory receptor ligand PD-L1 in the mesenchymal subset of lung cancer cells, leading to profound CD8+ T cell mediated immunosuppression, producing tumor growth and metastasis. We previously reported in this model that BMP4 functions as a pro-tumorigenic factor regulated by miR-200 via GATA4/6. Thus, BMP4-mediated immunosuppression is part of a larger miR-200-directed gene expression program in tumors that promotes tumor progression, which could have important implications for cancer treatment. PMID- 27999751 TI - Responses to immune checkpoint inhibitors in nonagenarians. AB - The incidence of melanoma continues to rise with the most rapid increase seen in the elderly population. Historically, elderly patients with advanced melanoma have had dismal clinical outcomes, in part, due to distinct tumor biology, and often ineligibility for effective therapies during their development. In addition, due to relatively few geriatric patients being accrued to clinical trials of novel immunotherapeutics, there is a paucity of data regarding their safety and efficacy. Herein, we present the clinical course of three consecutive nonagenarians (>=90 y old) with metastatic melanoma, who were treated with single agent or combination immune checkpoint inhibitors. Two patients experienced complete or partial responses with acceptable safety profiles, and one other tolerated therapy well although a significant response was not noted. These cases suggest that with close monitoring, even very elderly patients with advanced cancers and acceptable performance status may tolerate and benefit from immune checkpoint inhibitors. PMID- 27999750 TI - Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor. AB - Due to their constant exposure to inhaled antigens, lungs represent a particularly immunosuppressive environment that limits excessive immune responses; however, cancer cells can exploit this unique environment for their growth. We previously described the ability of aerosolized CpG-ODN combined with Poly(I:C) (TLR9 and TLR3 agonists, respectively) to promote antitumor immunity in a B16 melanoma lung metastasis model. Here, we explored the possibility of improving the therapeutic efficacy of TLR9/TLR3 agonist combinations by including in the inhalant either an antibody directed to both Ly6G and Ly6C markers to locally deplete myeloid-derived suppressive cells (MDSCs) or IFNalpha to directly activate the natural killer (NK) and macrophage innate immune cells in the lung. Addition of nebulized anti-MDSC antibody RB6-8C5 to aerosolized CpG-ODN/Poly(I:C) resulted in reduced mRNA levels of immunsuppressive molecules (IL10, Arg-1, and Nos2), increased activation of resident NK cells and improved treatment outcome, with a significant reduction in established B16 melanoma lung metastases compared to treatment with CpG-ODN/Poly(I:C) alone. Likewise, addition of aerosolized IFNalpha led to increased mRNA levels of proinflammatory cytokines (IL15 and IFNgamma) in the lung and recruitment of highly activated NK cells, with no evident signs of toxicity and with a significantly improved antitumor effect as compared with aerosolized CpG-ODN/Poly(I:C). Combining both IFNalpha and RB6-8C5 with CpG-ODN/Poly(I:C) did not produce an additive effect compared to IFNalpha + CpG-ODN/Poly(I:C) or RB6-8C5 + CpG-ODN/Poly(I:C). Our results indicate that the inhalation therapy is a feasible and non-invasive strategy to deliver immunodulatory molecules, including antibodies and cytokines that reprogram the lung tumor microenvironment to foster immune destruction of tumors. PMID- 27999752 TI - Functional impairment of infiltrating T cells in human colorectal cancer. AB - T cells play a crucial role in preventing the growth and spread of colorectal cancer (CRC). However, immunotherapies against CRC have only shown limited success, which may be due to lack of understanding about the effect of the local tumor microenvironment (TME) on T cell function. The goal of this study was to determine whether T cells in tumor tissue were functionally impaired compared to T cells in non-tumor bowel (NTB) tissue from the same patients. We showed that T cell populations are affected differently by the TME. In the tumor, T cells produced more IL-17 and less IL-2 per cell than their counterparts from NTB tissue. T cells from tumor tissue also had impaired proliferative ability compared to T cells in NTB tissue. This impairment was not related to the frequency of IL-2 producing T cells or regulatory T cells, but T cells from the TME had a higher co-expression of inhibitory receptors than T cells from NTB. Overall, our data indicate that T cells in tumor tissue are functionally altered by the CRC TME, which is likely due to cell intrinsic factors. The TME is therefore an important consideration in predicting the effect of immune modulatory therapies. PMID- 27999753 TI - PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor infiltrating immune cells and clinical outcome. AB - Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8+, CD45, CD4+, CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression. PMID- 27999754 TI - Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival. AB - Polymorphisms in Fc-gamma-receptor (FCGR) genes as well as killer cell immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) repertoires may influence antitumor effects of monoclonal antibodies (mAb). Here, we systematically analyzed high- and low-affinity FCGR2A and -3A genotypes as well as stimulating and inhibitory KIR/KIRL combinations in 53 neuroblastoma (NB) patients treated by long-term infusion (LTI) of anti-GD2 IgG1 Ab ch14.18/CHO using validated real-time PCR methods. Patients with high-affinity FCGR2A and -3A genotypes showed a higher level of Ab-dependent cell-mediated cytotoxicity (ADCC) on day 8 after the start of ch14.18/CHO and superior event-free survival (EFS) compared to patients with low FCGR genotypes. Similar observations were made for patients with stimulatory KIR/KIRL haplotype B (combination of KIR genes including activating receptor genes) compared to inhibitory haplotype A (a fixed set of genes encoding for inhibitory receptors, except 2DS4) and stronger effects were found in patients when haplotype B and high-affinity FCGRs were combined. Surprisingly, independent analysis of KIRs showed a major role of activating KIR 2DS2 for high ADCC levels and prolongation of EFS. The greatest effect was observed in 2DS2-positive patients that also had high-affinity FCGR2A and -3A genotypes. In summary, the presence of the activating KIR 2DS2 has a major effect on ADCC levels and survival in NB patients treated by LTI of ch14.18/CHO and may therefore be a useful biomarker in combination with FCGR polymorphisms for Ab based immunotherapies. PMID- 27999755 TI - Immunosuppressive gammadelta T cells foster pancreatic carcinogenesis. PMID- 27999756 TI - Advancing targeted co-stimulation with antibody-fusion proteins by introducing TNF superfamily members in a single-chain format. AB - Co-stimulation via receptors of the tumor necrosis factor superfamily (TNFSF) emerges as promising strategy to support antitumor immune responses. Targeted strategies with antibody-fusion proteins composed of a tumor-directed antibody part and the extracellular domain of a co-stimulatory ligand of the TNFSF constitute an attractive option to focus the co-stimulatory activity to the tumor site. Since TNFSF members intrinsically form functional units of non-covalently linked homotrimers, the protein engineering of suitable antibody-fusion proteins is challenging. Aiming for molecules of simple and stable configuration, we used TNFSF ligands in a single-chain format (scTNFSF), i.e., three units of the ectodomain connected by polypeptide linkers, folding into an intramolecular trimer. By fusing tumor-directed scFv antibody fragments directed against EpCAM or FAP to co-stimulatory scTNFSF molecules (sc4-1BBL, scOX40L, scGITRL or scLIGHT), a set of monomeric scFv-scTNFSF fusion proteins was generated. In comparison to the scFv-TNFSF format, defined by intermolecular homotrimerization via the TNFSF part, scFv-scTNFSF showed equal or enhanced co-stimulatory activity despite reduced avidity in antibody binding. In addition, enhanced serum stability and improved bioavailability in mice were observed. We show that the scFv-scTNFSF format can be applied to various members of the TNFSF, presenting targeting-dependent co-stimulatory activity. Hence, this format exhibits favorable properties that make it a promising choice for further therapeutic fusion protein development. PMID- 27999757 TI - CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment. AB - Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22 expressing cells by activating specific T cells. We analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2- (HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cells in vitro. T cells recognizing an epitope derived from the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22 specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using the Enzyme-Linked ImmunoSPOT assay, we examined peripheral blood mononuclear cells from HLA-A2+ cancer patients and healthy volunteers for reactivity against the CCL22-derived T-cell epitope. This revealed spontaneous T-cell responses against the CCL22-derived epitope in cancer patients and in healthy donors. Finally, we performed tetramer enrichment/depletion experiments to examine the impact of HLA-A2-restricted CCL22 specific T cells on CCL22 levels among PMBCs. The addition or activation of CCL22 specific T cells decreased the CCL22 level in the microenvironment. Activating CCL22-specific T cells (e.g., by vaccination) may directly target cancer cells and tumor-associated macrophages, thereby modulating Treg recruitment into the tumor environment and augmenting anticancer immunity. PMID- 27999758 TI - Efficacy of glypican-3-derived peptide vaccine therapy on the survival of patients with refractory ovarian clear cell carcinoma. AB - Compared with other epithelial ovarian carcinoma subtypes, ovarian clear cell carcinoma (OCCC) has been recognized to show chemoresistance. Therefore, new treatment modalities are required for patients with OCCC that is refractory to chemotherapy. The carcinoembryonic antigen glypican-3 (GPC3) is expressed by approximately half of OCCC and is a promising immunotherapeutic target. The purpose of this study was to evaluate the effect of GPC3 peptide vaccine against refractory OCCC patients. We conducted a phase II trial with a GPC3-derived peptide vaccine in OCCC patients. Immunological responses were analyzed by ex vivo IFNgamma ELISPOT assay. We also evaluated control subjects, who received best supportive care without vaccinations during the same period. Thirty-two patients with refractory OCCC were enrolled between July 2010 and September 2015, and underwent GPC3 peptide vaccination. Fifteen patients were vaccinated less than six times because their general condition progressively deteriorated, and 17 patients were vaccinated at least six times. Three patients showed a partial response as the best overall response. The GPC3 peptide vaccine induced a GPC3 specific CTL response in 15 out of 24 patients who had PBMCs collected three times or more. The prognosis of palliative care patients without GPC3 peptide vaccinations was significantly poorer than that of those with GPC3 peptide vaccinations (post cancer-treatment survival: p = 0.002). Although the disease control rate was not high, our results suggest that GPC3 peptide vaccinations may hold a significant impact to prolong survival of patients with refractory OCCC, allowing them to maintain quality of life with no serious toxicities. PMID- 27999759 TI - Dectin-1-activated dendritic cells: A potent Th9 cell inducer for tumor immunotherapy. AB - Dendritic cell (DC)-based immunotherapy has great promise for cancer treatment. We have recently demonstrated that dectin-1-activated DCs trigger potent antitumor Th9 cells in vivo. Dectin-1-activated DC-induced antitumor responses rely on the induced Th9/IL-9. These findings offer new strategies for the development of more effective DC vaccines in tumor immunotherapy. PMID- 27999762 TI - Erratum. AB - [This corrects the article DOI: 10.4161/2162402X.2014.977164.]. PMID- 27999761 TI - Novel immunotherapy for adult T-cell leukemia/lymphoma: Targeting aurora kinase A. AB - Adult T-cell leukemia/lymphoma is caused by infection with HTLV-1, following a long latent period. Immunotherapy targeting Aurora kinase A, a tumor-associated antigen over-expressed in adult T-cell leukemia/lymphoma, holds great therapeutic potential. We review the evidence in favor of a therapeutic strategy combining vaccination and TCR-gene transfer against this target. PMID- 27999760 TI - LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. AB - Immunotherapy with immune checkpoint molecule-specific monoclonal antibody have obtained encouraging results from preclinical studies and clinical trials, which promoted us to explore whether this kind of immunotherapy could be applicable to head and neck squamous cell carcinoma (HNSCC). Lymphocyte activation gene-3 (LAG 3) is an immune checkpoint control protein that negatively regulates T cells and immune response. Here, using the human tissue samples, we report these findings that LAG-3 is overexpressed on tumor-infiltrating lymphocytes (TILs; p < 0.001) and its overexpression correlates with the high pathological grades, lager tumor size and positive lymph node status in human primary HNSCC. Survival analysis identifies LAG-3 as a prognostic factor independent of tumor size and pathological grades for primary HNSCC patients with negative lymph node status (p = 0.014). Study in immunocompetent genetically defined HNSCC mouse model reports that LAG-3 is upregulated on CD4+ T cells, CD8+ T cells and CD4+Foxp3+ regulatory T cells (Tregs). In vivo study, administration of LAG-3-specific antibody retards tumor growth in a way associated with enhanced systemic antitumor response by potentiating the antitumor response of CD8+ T cells and decreasing the population of immunosuppressive cells. Taken together, our results offer a preclinical proof supporting the immunomodulatory effects of LAG-3 and suggest a potential therapeutic target of immunotherapy for HNSCC. PMID- 27999765 TI - Spotlights on our sister journals: ChemistryOpen 3/2016. PMID- 27999764 TI - New Synthesis of Gold- and Silver-Based Nano-Tetracycline Composites. AB - Invited for this month's cover are collaborators from the University NOVA of Lisbon/FCT, The University of Tras-os-Montes e Alto Douro (both in Portugal), and the University of La Rioja (Spain). The cover picture is devoted to the nano tetracycline composites based on gold and silver nanoparticles that are able to detect aluminium (III) in water and can be used as antibacterial delivery tools. For more details, read the full text of the article at 10.1002/open.201600016. PMID- 27999766 TI - Cerebral Hemorrhage Following Chiropractic Activator Treatment - Case Report and Review of Literature. AB - Background Despite widespread utilization of chiropractic treatment for various ailments, there is a paucity of documentation regarding intracerebral hemorrhage related to chiropractic trauma. Stroke has been reported from cervical manipulation, although with a suggested low incidence. Activator treatment, an instrument that produces a high-velocity, low-amplitude impact to the spine, is considered especially safe. There are no prior reports of intracerebral hemorrhage resulting from a chiropractic activator treatment. Case Description A 75-year-old woman was admitted to the hospital with a history of headaches, visual difficulties on the right, and speech disturbance of relatively acute onset. CT scan showed a brain hemorrhage in an unusual location. Extensive evaluation was undertaken because this was thought to be a spontaneous event. No cause was found on imaging. Subsequent history revealed a chiropractic activator treatment applied directly to the junction of the back of her head and the upper cervical spine immediately prior to the onset of symptoms. Her clinical course is described. Conclusions This appears to be the first report linking traumatic intracerebral hemorrhage with a chiropractic activator treatment. The use of this modality in an elderly population, with widespread utilization of anticoagulants and platelet inhibitors, is of potential concern. PMID- 27999767 TI - Antimicrobial efficacy of the combination of chlorhexidine digluconate and dexpanthenol. AB - Objective: The objective of this standardised experimental study was to investigate the antimicrobial efficacy of the combination of chlorhexidine digluconate (CHX) and the anti-inflammatory pro-vitamin dexpanthenol, which stimulates wound-healing, in the form of Bepanthen(r) Antiseptic Wound Cream, in order to rule out possible antagonistic combination effects of CHX and the alcohol analogue of pantothenic acid (vitamin B5) dexpanthenol. Method: Testing was carried out using the quantitative suspension test at conditions simulating wound bio-burden. Test strains included Enterococcus hirae (ATCC 10541) and Candida albicans (ATCC 10231) in accordance with the standard methods of the German Hygiene and Microbiology Society with the following three organic challenges: i) cell culture medium MEM with Earle's salts, L-glutamine and 10% foetal calf serum (CCM); ii) 10% sheep's blood; iii) or a mixture of 4.5% albumin, 4.5% sheep's blood and 1% mucin. For methodological reasons, the wound cream was tested as a 55% dilution, prepared with 1% Tween 80 (equivalent to a content of 0.275% CHX instead of 0.5% as in the original preparation). CHX 0.275% was tested as control in an aqueous solution and in 1% Tween 80. Additionally, 1% Tween 80 was tested in order to rule out an interfering effect of the dilution medium. A combination of 3% Tween 80, 3% saponin, 0.1% histidine, 0.3% lecithin, 0.5% Na-thiosulphate and 1% ether sulphate was identified as the most appropriate neutraliser during the experiments. Results: Exposed to CCM or 10% sheep's blood, the tested wound cream fulfilled the requirements for a wound antiseptic against both test species with >=3 log reduction at 10 minutes. Even at the the worst case challenge test with 4.5% albumin, 4.5% sheep's blood and 1% mucin, the requirement for a >=3 log reduction was met after 24 hours of exposure. Interestingly, the aqueous solution of 0.275% CHX tested as control did not achieve the antimicrobial efficacy of the combination of CHX and 5% dexpanthenol. 1% Tween 80 was ineffective against both test species. Conclusion: Bepanthen(r) Antiseptic Wound Cream achieves the in vitro bactericidal and fungicidal efficacy required for a wound antiseptic under three different challenges, despite dilution to 55% of the original preparation. So far, the addition of dexpanthenol was intended to support wound healing. However, our results indicate that the antiseptic efficacy of CHX is synergistically increased by adding 5% dexpanthenol. Acknowledging the antimicrobial and residual efficacy of CHX, and bearing in the mind the contraindications to CHX (allergy and anaphylaxis), the tested wound cream should be regarded as better suitable to be used as wound antiseptic than preparations on basis of CHX alone. PMID- 27999768 TI - IL17-Producing gammadelta T Cells May Enhance Humoral Immunity during Pulmonary Pseudomonas aeruginosa Infection in Mice. AB - The host acquired immune response, especially the humoral immunity, plays key roles in preventing bacterial pneumonia in the lung. Our previous research demonstrated that interleukin 17-producing gammadelta T cells (IL17-gammadelta T cells) have a protective effect on the early innate immune response during acute pulmonary Pseudomonas aeruginosa infection. However, whether IL17-gammadelta T cells also play a role in humoral immunity is unknown. In this study, an acute pulmonary P. aeruginosa infection model was established in wild-type and gammadelta TCR-/- C57BL/6 mice. The expression of IL-17 on gammadelta T cells isolated from infected lung tissues increased rapidly and peaked at day 7 after acute infection with P. aeruginosa. Compared with wild-type infected mice, the levels of total immunoglobulins including IgA, IgG, and IgM in the serum and BALF were significantly decreased in gammadelta TCR-/- mice, with the exception of IgM in the BALF. Moreover, CD69 expression in B cells from the lungs and spleen and the level of BAFF in the plasma were also decreased in gammadelta TCR-/- mice. IL17-gammadelta T cell transfusion significantly improved the production of immunoglobulins, B cell activation and BAFF levels in gammadelta TCR-/- mice compared with gammadelta TCR-/- mice without transfusion; this effect was blocked when cells were pretreated with an IL-17 antibody. Together, these data demonstrate that IL17-gammadelta T cells are involved in CD19+ B cell activation and the production of immunoglobulins during acute pulmonary P. aeruginosa infection. Thus, we conclude that IL17-gammadelta T cells may facilitate the elimination of bacteria and improve survival through not only innate immunity but also humoral immunity. PMID- 27999769 TI - ExsE Is a Negative Regulator for T3SS Gene Expression in Vibrio alginolyticus. AB - Type III secretion systems (T3SSs) contribute to microbial pathogenesis of Vibrio species, but the regulatory mechanisms are complex. We determined if the classic ExsACDE protein-protein regulatory model from Pseudomonas aeruginosa applies to Vibrio alginolyticus. Deletion mutants in V. alginolyticus demonstrated that, as expected, the T3SS is positively regulated by ExsA and ExsC and negatively regulated by ExsD and ExsE. Interestingly, deletion of exsE enhanced the ability of V. alginolyticus to induce host-cell death while cytotoxicity was inhibited by in trans complementation of this gene in a wild-type strain, a result that differs from a similar experiment with Vibrio parahaemolyticus ExsE. We further showed that ExsE is a secreted protein that does not contribute to adhesion to Fathead minnow epithelial cells. An in vitro co-immunoprecipitation assay confirmed that ExsE binds to ExsC to exert negative regulatory effect on T3SS genes. T3SS in V. alginolyticus can be activated in the absence of physical contact with host cells and a separate regulatory pathway appears to contribute to the regulation of ExsA. Consequently, like ExsE from P. aeruginosa, ExsE is a negative regulator for T3SS gene expression in V. alginolyticus. Unlike the V. parahaemolyticus orthologue, however, deletion of exsE from V. alginolyticus enhanced in vitro cytotoxicity. PMID- 27999770 TI - Digital Recording and Documentation of Endoscopic Procedures: Do Patients and Doctors Think Alike? AB - Aims and Methods. Conducting a survey study of a large number of patients and gastroenterologists aimed at identifying relevant predictors of interest in digital recording and documentation (DRD) of endoscopic procedures. Outpatients presenting to the endoscopy unit at our institution for an endoscopy examination were anonymously surveyed, regarding their views and opinions of a possible recording of the procedure. A parallel survey for gastroenterologists was conducted. Results. 417 patients and 62 gastroenterologists participated in two parallel surveys regarding DRD of endoscopic procedures. 66.4% of the patients expressed interest in digital documentation of their endoscopic procedure, with 90.5% of them requesting a copy. 43.6% of the physicians supported digital recording while 27.4% opposed it, with 48.4% opposing to making a copy of the recording available to the patient. No sociodemographic or background factors predicted patient's interest in DRD. 66% of the physicians reported having recording facilities in their institutions, but only 43.6% of them stated performing recording. Having institutional guidelines for DRD was found to be the only significant predictor for routine recording. Conclusions. Our study exposes patients' positive views of digital recording and documentation of endoscopic procedures. In contrast, physicians appear to be much more reluctant towards DRD and are centrally motivated by legal concerns when opposing DRD, as well as when supporting it. PMID- 27999771 TI - Validation of Evidence-Based Fall Prevention Programs for Adults with Intellectual and/or Developmental Disorders: A Modified Otago Exercise Program. AB - INTRODUCTION: Evidence-based fall prevention (EBFP) programs significantly decrease fall risk, falls, and fall-related injuries in community-dwelling older adults. To date, EBFP programs are only validated for use among people with normal cognition and, therefore, are not evidence-based for adults with intellectual and/or developmental disorders (IDD) such as Alzheimer's disease and related dementias, cerebral vascular accident, or traumatic brain injury. BACKGROUND: Adults with IDD experience not only a higher rate of falls than their community-dwelling, cognitively intact peers but also higher rates and earlier onset of chronic diseases, also known to increase fall risk. Adults with IDD experience many barriers to health care and health promotion programs. As the lifespan for people with IDD continues to increase, issues of aging (including falls with associated injury) are on the rise and require effective and efficient prevention. METHODS: A modified group-based version of the Otago Exercise Program (OEP) was developed and implemented at a worksite employing adults with IDD in Montana. Participants were tested pre- and post-intervention using the Center for Disease Control and Prevention's (CDC) Stopping Elderly Accidents Deaths and Injuries (STEADI) tool kit. Participants participated in progressive once weekly, 1-h group exercise classes and home programs over a 7-week period. Discharge planning with consumers and caregivers included home exercise, walking, and an optional home assessment. RESULTS: Despite the limited number of participants (n = 15) and short length of participation, improvements were observed in the 30-s Chair Stand Test, 4-Stage Balance Test, and 2-Minute Walk Test. Additionally, three individuals experienced an improvement in ambulation independence. Participants reported no falls during the study period. DISCUSSION: Promising results of this preliminary project underline the need for further study of this modified OEP among adults with IDD. Future multicenter study should include more participants in diverse geographic regions with longer lengths of participation and follow-up. PMID- 27999772 TI - Evaluating and Using Observational Evidence: The Contrasting Views of Policy Makers and Epidemiologists. AB - BACKGROUND: Currently, little is known about the types of evidence used by policy makers. This study aimed to investigate how policy makers in the health domain use and evaluate evidence and how this differs from academic epidemiologists. By having a better understanding of how policy makers select, evaluate, and use evidence, academics can tailor the way in which that evidence is produced, potentially leading to more effective knowledge translation. METHODS: An exploratory mixed-methods study design was used. Quantitative measures were collected via an anonymous online survey (n = 28), with sampling from three health-related government and non-government organizations. Semi-structured interviews with policy makers (n = 20) and epidemiologists (n = 6) were conducted to gather qualitative data. RESULTS: Policy makers indicated systematic reviews were the preferred research resource (19%), followed closely by qualitative research (16%). Neither policy makers nor epidemiologists used grading instruments to evaluate evidence. In the web survey, policy makers reported that consistency and strength of evidence (93%), the quality of data (93%), bias in the evidence (79%), and recency of evidence (79%) were the most important factors taken into consideration when evaluating the available evidence. The same results were found in the qualitative interviews. Epidemiologists focused on the methodology used in the study. The most cited barriers to using robust evidence, according to policy makers, were political considerations (60%), time limitations (55%), funding (50%), and research not being applicable to current policies (50%). CONCLUSION: The policy maker's investigation did not report a systematic approach to evaluating evidence. Although there was some overlap between what policy makers and epidemiologists identified as high-quality evidence, there was also some important differences. This suggests that the best scientific evidence may not routinely be used in the development of policy. In essence, the policy making process relied on other jurisdictions' policies and the opinions of internal staff members as primary evidence sources to inform policy decisions. Findings of this study suggest that efforts should be directed toward making scientific information more systematically available to policy makers. PMID- 27999773 TI - In Vitro Evaluation of Biocompatibility of Uncoated Thermally Reduced Graphene and Carbon Nanotube-Loaded PVDF Membranes with Adult Neural Stem Cell-Derived Neurons and Glia. AB - Graphene, graphene-based nanomaterials (GBNs), and carbon nanotubes (CNTs) are being investigated as potential substrates for the growth of neural cells. However, in most in vitro studies, the cells were seeded on these materials coated with various proteins implying that the observed effects on the cells could not solely be attributed to the GBN and CNT properties. Here, we studied the biocompatibility of uncoated thermally reduced graphene (TRG) and poly(vinylidene fluoride) (PVDF) membranes loaded with multi-walled CNTs (MWCNTs) using neural stem cells isolated from the adult mouse olfactory bulb (termed aOBSCs). When aOBSCs were induced to differentiate on coverslips treated with TRG or control materials (polyethyleneimine-PEI and polyornithine plus fibronectin PLO/F) in a serum-free medium, neurons, astrocytes, and oligodendrocytes were generated in all conditions, indicating that TRG permits the multi-lineage differentiation of aOBSCs. However, the total number of cells was reduced on both PEI and TRG. In a serum-containing medium, aOBSC-derived neurons and oligodendrocytes grown on TRG were more numerous than in controls; the neurons developed synaptic boutons and oligodendrocytes were more branched. In contrast, neurons growing on PVDF membranes had reduced neurite branching, and on MWCNTs loaded membranes oligodendrocytes were lower in numbers than in controls. Overall, these findings indicate that uncoated TRG may be biocompatible with the generation, differentiation, and maturation of aOBSC-derived neurons and glial cells, implying a potential use for TRG to study functional neuronal networks. PMID- 27999775 TI - Protective Ventilation Improves Gas Exchange, Reduces Incidence of Atelectases, and Affects Metabolic Response in Major Pancreatoduodenal Surgery. AB - BACKGROUND: Protective perioperative ventilation has been shown to improve outcomes and reduce the incidence of postoperative pulmonary complications. The goal of this study was to assess the effects of ventilation with low tidal volume (VT) either alone or in a combination with moderate permissive hypercapnia in major pancreatoduodenal interventions. MATERIALS AND METHODS: Sixty adult patients scheduled for elective pancreatoduodenal surgery with duration >2 h were enrolled into a prospective single-center study. All patients were randomized to three groups receiving high VT [10 mL/kg of predicted body weight (PBW), the HVT group, n = 20], low VT (6 mL/kg PBW, the LVT group, n = 20), and low VT combined with a moderate hypercapnia and hypercapnic acidosis (6 mL/kg PBW, PaCO2 45-60 mm Hg, the LVT + HC group, n = 20). Cardiopulmonary parameters and the incidence of complications were registered during surgery and postoperatively. RESULTS AND DISCUSSION: The values of VT were 610 (563-712), 370 (321-400), and 340 (312-430) mL/kg for the HVT, the LVT, and the LVT + HC groups, respectively (p < 0.001). Compared to the HVT group, PaO2/FiO2 ratio was increased in the LVT group by 15%: 333 (301-381) vs. 382 (349-423) mm Hg at 24 h postoperatively (p < 0.05). The HVT group had significantly higher incidence of atelectases (n = 6), despite lower incidence of smoking compared with the LVT (n = 1) group (p = 0.017) and demonstrated longer length of hospital stay. The patients of the LVT + HC group had lower arterial lactate and bicarbonate excess values by the end of surgery. CONCLUSION: In major pancreatoduodenal interventions, preventively protective VT improves postoperative oxygenation, reduces the incidence of atelectases, and shortens length of hospital stay. The combination of low VT and permissive hypercapnia results in hypercapnic acidosis decreasing the lactate concentration but adding no additional benefits and warrants further investigations. PMID- 27999774 TI - HYAL-2-WWOX-SMAD4 Signaling in Cell Death and Anticancer Response. AB - Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-beta) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2-WWOX-SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2-WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2-WWOX-SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3- CD19- Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL 2-WWOX-SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2-WWOX-SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response. PMID- 27999777 TI - During economic crisis can sleep questionnaires improve the value of oximetry for assessing sleep apnea? AB - BACKGROUND: The diagnosis of obstructive sleep apnea/hypopnea syndrome (OSAHS) is essential but polysomnography (PSG) is expensive and time consuming. Oximetry has been used as a less expensive indicator of OSAHS. The aim of the study was to evaluate the clinical utility of the combination of oximetry with four different questionnaires: Stop, Stop Bang (S-B), Berlin questionnaire (BQ), Epworth Sleepiness Scale (ESS) in order to identify patients at risk for OSAHS compared with in-laboratory PSG. METHODS: Patients visiting a sleep clinic were prospectively studied. They completed Stop, S-B, BQ and ESS. Home oximetry and in laboratory PSG were performed within 3-20 days. RESULTS: A total of 204 patients were included in the study (77.5% males, mean age 51.8+/-13.8 years, BMI 32.8+/ 6.2 kg/m2, SaO2% awake 95.7+/-2). S-B had the highest sensitivity (Se) (97.5%) and negative predictive value (NPV) (62.5%) but the lowest specificity (Sp) (9%), whereas ESS had the best Sp (75%) and positive predictive values (PPV) (81.4%). The predictive values of questionnaires improved as the severity of OSAHS worsened. The predictive values of oximetry were high for severe but low for mild and moderate OSAHS. For that oximetry was combined with different sleep questionnaires in different OSAHS severity groups, but with no improvement in the predictive values. CONCLUSIONS: Oximetry may be used as a tool for identifying severe OSAHS. For mild and moderate disease the combination of questionnaires did not improve the diagnostic accuracy and especially for symptomatic patients with negative results, the need of PSG is essential. PMID- 27999776 TI - "Freeze, Don't Move": How to Arrest a Suspect in Heart Failure - A Review on Available GRK2 Inhibitors. AB - Cardiovascular disease and heart failure (HF) still collect the largest toll of death in western societies and all over the world. A growing number of molecular mechanisms represent possible targets for new therapeutic strategies, which can counteract the metabolic and structural changes observed in the failing heart. G protein-coupled receptor kinase 2 (GRK2) is one of such targets for which experimental and clinical evidence are established. Indeed, several strategies have been carried out in place to interface with the known GRK2 mechanisms of action in the failing heart. This review deals with results from basic and preclinical studies. It shows different strategies to inhibit GRK2 in HF in vivo (betaARK-ct gene therapy, treatment with gallein, and treatment with paroxetine) and in vitro (RNA aptamer, RKIP, and peptide-based inhibitors). These strategies are based either on the inhibition of the catalytic activity of the kinase ("Freeze!") or the prevention of its shuttling within the cell ("Don't Move!"). Here, we review the peculiarity of each strategy with regard to the ability to interact with the multiple tasks of GRK2 and the perspective development of eventual clinical use. PMID- 27999778 TI - Burnout syndrome and job satisfaction in Greek residents: exploring differences between trainees inside and outside the country. AB - BACKGROUND: The purpose of this study is to investigate the levels of burnout among Greek residents, highlighting potential differences between those practicing at home and abroad, as well as to investigate correlations with demographic, individual and labor factors. METHODS: The research was conducted on a sample of 131 residents, using an anonymous questionnaire which included demographic, individual and labor characteristics, Maslach's Burnout Inventory, questions regarding job and life satisfaction levels, working conditions and the impacts of the economic recession. RESULTS: Fifty two point seven percent of the sample were training in the Greek National Health Service (N.H.S.), 27.5% in Germany and 19.8% in the United Kingdom. One out of three residents in the Greek system showed high levels of burnout in all three dimensions of the syndrome, while 51.1%, 72.2% and 30.8% of the Greek, British and German team, respectively, appeared burnt out simultaneously in two dimensions. Levels of job and life satisfactions ranged on average, while workload appeared heavy. CONCLUSIONS: The occurrence of burnout was associated with gender, specialty, employment characteristics (working hours, autonomy, support etc.), proneness to accidents, country, job satisfaction and quality of life, but was not associated with age or marital status. No correlation was found with susceptibility to medical errors. PMID- 27999779 TI - Obstruction of the right stem bronchus due to ovarian local metastasis: a 5-year follow-up. AB - Currently interventional bronchoscopy is used for debulking, desobstruction and airway patency stabilization. The interventional techniques are being used for both benign and malignant cases. There are two types of stents that are currently being used, silicon and self-expandable metallic. The method of application and stent remains for the treating physician to choose. In the current case we will present a case of metastatic disease from ovarian cancer in the airway lumen and a long term follow-up. PMID- 27999780 TI - Coincidence of thymoma and breast cancer and in a 56-year-old female patient. AB - We present a case of a 56-year-old female, with a familial history of breast, lung and brain cancer, which revealed a breast tumor, located in the upper outer quadrant of the left breast. During the routinely staging examinations, a 15 cm intrathoracic tumor was found in the upper left mediastinum, penetrating the pericardium and a smaller tumor, in the left side of parietal pleura. Core biopsies from both lesions, revealed a lobular carcinoma of the breast classic type, grade II (e-cadherin-, ER+, PR+, Her-2-, Ki-67 10%) and a B3 thymoma (CK19+, CD5+) penetrating the pericardium and the left lung. A synchronous removal of both tumors was scheduled, including median sternotomy and left intrapericardial pneumonectomy, followed by a modified radical left mastectomy and a sentinel lymph node biopsy. The postoperative course was uneventful. This case advocates that thymoma patients appear to have a predisposition towards developing additional neoplasms, as breast carcinoma. Clinicians should be aware of the increased incidence of extrathymic cancers, occurring in thymoma patients. PMID- 27999781 TI - Fine-needle aspiration of skin metastasis in ovarian cancer-report of two cases and review of the literature. AB - Ovarian cancer is known to be the first cause of death of gynecological malignancy in Europe and United States. Skin metastases consist of an unusual event during the course of ovarian carcinoma and occur in 2-3.5% of the patients. We report two interested cases of patient with skin metastases, due to ovarian carcinoma, diagnosed by fine-needle aspiration (FNA). The clinical information, cytologic findings and immunocytochemical profile are described and further discussed, according to the relevant bibliographic data. The combination of FNA and thin layer cytology contribute to the accurate clarification of metastatic tumors with a known or unknown origin. It known that skin metastasis tend occurs in most ovarian carcinomas at a late stage course of the disease and it is usually associated with poor prognosis, in some cases the survival can be prolonged with appropriate therapy. So, an accurate cyto-immunodiagnosis is crucial for the best management of these patients. PMID- 27999782 TI - Successful surgical treatment of a complicated esophageal perforation, by use of primary closure and lung parenchyma reinforcement. AB - Esophageal perforation (EP) is a medical condition which demands urgent confrontation with significant complications. The cause of the perforation may be common, spontaneous or iatrogenic, with conservative or surgical therapeutic strategy, which is needed in the majority of incidents, depending on the characteristics of the lesion. We report a case of a 68-year-old man, with the existence of an ulcerative lesion 31 cm approximately from the dental barrier, and a coexistent stenosis, diagnosed through esophagogastroduodenoscopy, which evolved to an extensive purulent necrotic mediastinitis, diagnosed through a thorax CT scan after the patient began to complain of asphyxiation during eating. A right posterolateral thoracotomy was performed along with intensive wide spectrum antibiotic therapy. Primary closure of the perforation as well as pulmonary tenting was used with satisfactory results. There was no evidence of leakage after a 12-month "follow-up" period. The early diagnosis of an EP combined with immediate surgical procedure and frequent "follow-up" of the patient, eliminate the risks for the patient's life and ensure a satisfactory outcome. PMID- 27999783 TI - Percutaneous tracheostomy-beware of the thyroidea-ima artery. AB - Percutaneous tracheostomy is a minimally invasive operation performed in patients, in order to provide an air passage through the windpipe. A rare cause of severe bleeding during such operation is the injury of the thyroidea-ima artery. This case report presents a patient with hemorrhage after thyroidea-ima injury during percutaneous dilatational tracheostomy. Surgeons should always be aware of such anatomic variation, in order to prevent urgent sternotomy. PMID- 27999784 TI - A patient with situs inversus totalis and lung cancer-a rare combination. AB - Situs inversus totalis (SIT) is a rare clinical entity which is characterized by a complete reverse anatomy of the thoracic cage and abdomen. There are a few reports of patients with SIT and lung cancer. The number of the cases that have been treated surgically is also very small. We report a case of an 80 years old patient who underwent left lower lobectomy after staging with uniportal video assisted thoracoscopic surgery (VATS) and mediastinoscopy. PMID- 27999785 TI - Benign tracheal stenosis a case report and up to date management. AB - Benign tracheal stenosis is situation that occurs usually after stress is applied to a certain area in the trachea during the intubation of a patient or inflammation caused during an infection. In the current case report we will present a 65-year-old man with a benign tracheal stenosis due to a 15-day intubation with a high pressure and low volume intubation tube. Current methodology was applied in his case with an excellent result with a 1-year follow up. Cryotherapy, electrocautery-knife, balloon dilation and semi-rigid bronchoscopic technique were applied. Currently there are several techniques that can be used by pulmonary physicians or ear, nose and throat experts. It remains for the treating physician to choose its method based on his training, equipment and tissue damage. PMID- 27999786 TI - Sleep disordered breathing and autonomic function in overweight and obese children and adolescents. AB - Obstructive sleep apnoea (OSA), common in children with obesity, is associated with cardiovascular morbidity. Autonomic dysfunction has been suggested to be a key player in the development of these complications. We investigated the relationship between obesity, OSA and sympathetic activity in children. 191 children with obesity were included and distributed into two groups: 131 controls and 60 with OSA. Beat-to-beat RR interval data were extracted from polysomnography for heart rate variability analysis. Urinary free cortisol levels were determined. Urinary free cortisol did not differ between groups and was not associated with OSA, independent of the level of obesity. Differences in heart rate variability measures were found: mean RR interval decreased with OSA, while low/high-frequency band ratio and mean heart rate increased with OSA. Heart rate variability measures correlated with OSA, independent of obesity parameters and age: oxygen desaturation index correlated with mean heart rate (r=0.19, p=0.009) and mean RR interval (r= -0.18, p=0.02), while high-frequency bands and low/high frequency band ratio correlated with arterial oxygen saturation measured by pulse oximetry (SpO2 ) (r= -0.20, p=0.008 and r= -0.16, p=0.04) and SpO2 nadir (r=0.23, p=0.003 and r= -0.19, p=0.02). These results suggest that sympathetic heart activity is increased in children with obesity and OSA. Measures of hypoxia were related to increased sympathetic tone, suggesting that intermittent hypoxia is involved in autonomic dysfunction. PMID- 27999787 TI - The Outcome of Repeated Mid Urethral Sling in SUI Treatment after Vaginal Excisions of Primary Failed Sling: Preliminary Study. AB - Mid urethral sling is the standard in SUI treatment. Nevertheless, the risk of reoperation reaches 9%. There is no consensus as to the best treatment option for complications. A question is raised: what is the optimal way to achieve the best result in patients after primary failure? The aim of the study was to evaluate the outcomes of repeat MUS surgery in patients after excision of the sling with recurrent SUI. We compared its effectiveness with uncomplicated cases treated with TVT. 27 patients who underwent the repeated MUS and 50 consecutive patients after primary TVT were enrolled in the study. After 6 months, we have found that 24 (88.46%) patients from repeat sling group and 48 (96%) patients after primary sling were dry (1-hour pad test, 2 g or less). The difference between groups was not significant. We showed statistically significant improvement of quality of life in both groups. In conclusion, we showed that repeated sling after MUS excision is almost as effective as primary MUS. We postulate that sling excision and repeated MUS may be the best option for persistent SUI and/or complications after MUS procedures. Further multicenter observations are ongoing as to provide results on bigger group of cases. PMID- 27999789 TI - Marginal Bone Level Evaluation after Functional Loading Around Two Different Dental Implant Designs. AB - Purpose. To investigate peri-implant alveolar bone changes using periapical radiographs before and after prosthetic delivery in submerged and nonsubmerged dental implants. Methods. Digital periapical films of 60 ITI Straumann nonsubmerged dental implants and 60 Xive Dentsply submerged dental implants were taken before, immediately after, and 12 and 24 weeks after the prosthetic restoration was delivered. Results. The 60-nonsubmerged dental implant group showed mean marginal bone resorption at baseline of 0.10 +/- 0.23 mm and 24 weeks later, marginal bone resorption was 0.16 +/- 0.25 mm. The submerged dental implant group showed a significantly higher distal marginal bone resorption over the mesial side. Mean marginal bone resorption at baseline was 0.16 +/- 0.32 on the mesial and 0.41 +/- 0.56 on the distal side. Twenty-four weeks later, it was 0.69 +/- 0.69 mm on the mesial and 0.99 +/- 0.90 mm on the distal side. Conclusion. First, it was possible to determine that submerged implants had a higher mean marginal bone resorption and less bone-to-implant contact than nonsubmerged implants. And second, the distal side of submerged dental implants presented higher marginal bone loss than the mesial side. PMID- 27999788 TI - Environmental Characteristics of Polybrominated Diphenyl Ethers in Marine System, with Emphasis on Marine Organisms and Sediments. AB - Polybrominated diphenyl ethers (PBDEs), due to their widespread usage as flame retardants and their lipophilicity and persistence, have become ubiquitous in the environment. It is urgent to understand the environmental characteristics of PBDEs in marine system, but they have attracted little attention. We summarize the available data and analyze the regional distributions, controlling factors, and congener patterns of PBDEs in marine and associated environmental matrixes worldwide. Based on meta-analysis, after separating the estuarial sites from the marine sites, ignoring the extraordinary sample sites such as those located just near the point source, the PBDE concentration levels are still in the same order of magnitude from global scale. Despite Principal Component Analysis, the congener patterns of sediments are predominant with the heavy brominated congeners (BDE-209 contributing over 75% to the total load) while the biota abound with the light ones (BDE-47, BDE-99, and BDE-100 taking about 80%). The ratio between BDE-99 and BDE-100 for the lower trophic-level species often turns to be greater than 1, while for those higher species the ratio may be below 1, and some species feed mainly on the crustaceans and zooplankton seems to have a higher ratio value. The data of the PBDEs in marine system are currently limited; thus, data gaps are identified as well. PMID- 27999790 TI - Tumor Take Rate Optimization for Colorectal Carcinoma Patient-Derived Xenograft Models. AB - Background. For development of individualized treatment on a routine basis, transfer of patients' tumor tissue in a xenograft model (i.e., generation of patient-derived xenografts (PDX)) is desirable for molecular, biochemical, or functional analyses. Drawbacks are dissatisfactory tumor take rates, the necessity of fast tumor tissue processing, and extensive logistics demanding teamwork of surgeons, pathologists, and laboratory researchers. Methods. The take rates of ten colorectal cancer (CRC) tissue samples in immunodeficient mice were compared after direct cryopreservation and after a 24 h cooling period at 4 degrees C prior to cryopreservation. Additionally, the effect of simultaneous Matrigel application on the take rates was investigated. Beside take rates, tumor growth characteristics and cell culture success were analyzed. Results. Tumor takes of CRC tissue samples were significantly improved after Matrigel application (8 versus 15 takes, p = 0.04). As expected, they diminished furthermore after 24 h cooling. Application of Matrigel could counteract this decrease significantly (2 versus 7 takes, p = 0.03). Cumulative take rate after cryopreservation was satisfactory (70%). Conclusion. Matrigel application after 24 h delay in tissue processing facilitates CRC PDX model development. These data help developing strategies for individualized tumor therapies in the context of multicenter clinical studies and for basic research on primary patient tumors. PMID- 27999791 TI - How Sublaminar Bands Affect Postoperative Sagittal Alignment in AIS Patients with Preoperative Hypokyphosis? Results of a Series of 34 Patients with 2-Year Follow Up. AB - Hypokyphosis is currently observed in thoracic idiopathic scoliosis. The use of sublaminar bands allows a good restoration of sagittal balance of the spine. The aim of the study was to provide a middle-term radiographic analysis of patients with adolescent idiopathic scoliosis with preoperative hypokyphosis treated by posterior arthrodesis with sublaminar bands. This retrospective study included 34 patients with Lenke 1 scoliosis associated with hypokyphosis (TK < 20 degrees ). A radiographic evaluation was performed with a 2-year follow-up. Cobb angle, cervical lordosis, thoracic kyphosis, lumbar lordosis, and pelvic parameters were measured preoperatively, postoperatively, and at 6-month and 2-year follow-up. The mean preoperative thoracic kyphosis was 10.5 degrees versus 24.1 degrees postoperatively (p < 0.001), representing a mean gain of 13 degrees . Cobb angle ranged from 59.3 degrees to 17.9 degrees postoperatively (mean correction 69%, p < 0.001). Cobb angle increased between the immediate postoperative measurement and the 6-month follow-up (17.9 versus 19.9, p = 0.03). Cervical curvature changed from a 5.6 degrees kyphosis to a 3.5 degrees lordosis (p = 0.001). Concerning lumbar lordosis, preoperative measurement was 39.7 degrees versus 41.3 degrees postoperatively (p = 0.27). At 6-month follow-up, lumbar lordosis significantly increased to 43.6 degrees (p = 0.03). All parameters were stable at final follow-up. Correction performed by sublaminar bands is efficient for both fontal and sagittal planes. Moreover, the restoration of normal thoracic kyphosis is followed by an adaptation of the adjacent curvatures with improved cervical lordosis and lumbar lordosis. PMID- 27999792 TI - Inflammation Related MicroRNAs Are Modulated in Total Plasma and in Extracellular Vesicles from Rats with Chronic Ingestion of Sucrose. AB - Circulating microRNAs (miRNAs) and the functional implications of miRNAs contained in extracellular vesicles (EVs) have gained attention in the last decade. Little is known about the regulation of the abundance of plasma miRNAs in response to chronic ingestion of carbohydrates. Therefore, we explored the circulating levels of miR-21, miR-146a, miR-155, and miR-223 in rats consuming sucrose in drinking water. Weanling Wistar rats were 25 weeks with 30% sucrose in drinking water, and miRNAs expression was determined in total plasma and in microvesicles, by RT-qPCR with TaqMan probe based assays for miR-21, miR-146a, miR-155, and miR-223, using cel-miR-39 (as spike in control and reference). Endotoxemia was also measured. Sucrose-fed animals showed higher body weight and retroperitoneal adipose tissue as well as higher glucose and triglyceride plasma levels than controls. Plasma endotoxin levels were low and not different among groups. Plasma miR-21 and miR-223 were higher in the sucrose group (p < 0.05), whereas miR-155 tended to be lower (p = 0.0661), and miR-146a did not show significant differences. In the plasma EVs the same trend was found except for miR-146a that showed significantly higher levels (p < 0.05). Overall, our results show that high carbohydrate ingestion modulates circulating miRNAs levels related to an inflammatory response. PMID- 27999793 TI - Portal Vein Stenting Combined with Iodine-125 Seeds Endovascular Implantation Followed by Transcatheter Arterial Chemoembolization for Treatment of Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombus. AB - Aim was to assess the therapeutic value of portal vein stenting (PVS) combined with iodine-125 seed (125I seed) strand endovascular implantation followed by transcatheter arterial chemoembolization (TACE) for treating patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). This was a retrospective study of 34 patients aged 29-81 years, diagnosed HCC with PVTT, and treated with PVS combined with 125I seed strand endovascular implantation followed by TACE between January 2012 and August 2014. Survival, stent patency, technical success rate, complications related to the procedure, and adverse events were recorded. The technical success rate was 100%. No serious procedure related adverse event was recorded. The median survival was 147 days. The cumulative survival rates and stent patency rates at 90, 180, and 360 days were 94.1%, 61.8%, and 32.4% and 97.1% (33/34), 76.9% (24/34), and 29.4% (10/34), respectively. PVS combined with 125I seed strand endovascular implantation followed by TACE is feasible for patients with HCC and PVTT. It resulted in appropriate survival and stent patency, with no procedure-related adverse effects. PMID- 27999794 TI - HBV Infection Status and the Risk of Cholangiocarcinoma in Asia: A Meta-Analysis. AB - Background. The inconsistent finding was between hepatitis B virus (HBV) infections and cholangiocarcinoma (CCA). This meta-analysis is to explore this relationship in Asia. Methods. A literature search was performed using PubMed, Web of Science, and Cochrane Library to October 30, 2015. Pooled incidence rate and OR with 95% CI were calculated using STATA 11.0. Results. Thirty-nine studies were included. The pooled incidence rate of CCA patients with HBV infection was 31% (95% CI 22%-39%). The pooled OR showed increased risk of CCA incidence with HBV infection (OR = 2.72, 95% CI 1.90-3.88), especially in ICC (OR = 3.184, 95% CI 2.356-4.302), while it showed no risk in ECC (OR = 1.407, 95% CI 0.925-2.141). Also, the pooled OR showed increased risk of ICC and ECC incidence (OR = 6.857, 95% CI 4.421-10.633 and OR = 1.740, 95% CI 1.260-2.404) in patients with HBsAg+/HBcAb+. The pooled OR showed increased risk of ICC incidence (OR = 1.410, 95% CI 1.095-1.816) in patients with HBsAg-/HBcAb+. Conclusion. It is suggested that HBV infection is associated with an increased risk of CCA in Asia. Two HBV infection models (HBsAg+/HBcAb+ and HBsAg-/HBcAb+) increase the risk of CCA, and patients with HBsAg-/HBcAb+ also had a risk of ICC. This trial is registered with PROSPERO CRD42015029264. PMID- 27999795 TI - In Vivo Remodeling of Fibroblast-Derived Vascular Scaffolds Implanted for 6 Months in Rats. AB - There is a clinical need for tissue-engineered small-diameter (<6 mm) vascular grafts since clinical applications are halted by the limited suitability of autologous or synthetic grafts. This study uses the self-assembly approach to produce a fibroblast-derived decellularized vascular scaffold (FDVS) that can be available off-the-shelf. Briefly, extracellular matrix scaffolds were produced using human dermal fibroblasts sheets rolled around a mandrel, maintained in culture to allow for the formation of cohesive and three-dimensional tubular constructs, and decellularized by immersion in deionized water. The FDVSs were implanted as an aortic interpositional graft in six Sprague-Dawley rats for 6 months. Five out of the six implants were still patent 6 months after the surgery. Histological analysis showed the infiltration of cells on both abluminal and luminal sides, and immunofluorescence analysis suggested the formation of neomedia comprised of smooth muscle cells and lined underneath with an endothelium. Furthermore, to verify the feasibility of producing tissue engineered blood vessels of clinically relevant length and diameter, scaffolds with a 4.6 mm inner diameter and 17 cm in length were fabricated with success and stored for an extended period of time, while maintaining suitable properties following the storage period. This novel demonstration of the potential of the FDVS could accelerate the clinical availability of tissue-engineered blood vessels and warrants further preclinical studies. PMID- 27999796 TI - A Sparsity-Constrained Preconditioned Kaczmarz Reconstruction Method for Fluorescence Molecular Tomography. AB - Fluorescence molecular tomography (FMT) is an imaging technique that can localize and quantify fluorescent markers to resolve biological processes at molecular and cellular levels. Owing to a limited number of measurements and a large number of unknowns as well as the diffusive transport of photons in biological tissues, the inverse problem in FMT is usually highly ill-posed. In this work, a sparsity constrained preconditioned Kaczmarz (SCP-Kaczmarz) method is proposed to reconstruct the fluorescent target for FMT. The SCP-Kaczmarz method uses the preconditioning strategy to minimize the correlation between the rows of the forward matrix and constrains the Kaczmarz iteration results to be sparse. Numerical simulation and phantom and in vivo experiments were performed to test the efficiency of the proposed method. The results demonstrate that both the convergence and accuracy of the proposed method are improved compared with the classical memory-efficient low-cost Kaczmarz method. PMID- 27999797 TI - Random Subspace Aggregation for Cancer Prediction with Gene Expression Profiles. AB - Background. Precisely predicting cancer is crucial for cancer treatment. Gene expression profiles make it possible to analyze patterns between genes and cancers on the genome-wide scale. Gene expression data analysis, however, is confronted with enormous challenges for its characteristics, such as high dimensionality, small sample size, and low Signal-to-Noise Ratio. Results. This paper proposes a method, termed RS_SVM, to predict gene expression profiles via aggregating SVM trained on random subspaces. After choosing gene features through statistical analysis, RS_SVM randomly selects feature subsets to yield random subspaces and training SVM classifiers accordingly and then aggregates SVM classifiers to capture the advantage of ensemble learning. Experiments on eight real gene expression datasets are performed to validate the RS_SVM method. Experimental results show that RS_SVM achieved better classification accuracy and generalization performance in contrast with single SVM, K-nearest neighbor, decision tree, Bagging, AdaBoost, and the state-of-the-art methods. Experiments also explored the effect of subspace size on prediction performance. Conclusions. The proposed RS_SVM method yielded superior performance in analyzing gene expression profiles, which demonstrates that RS_SVM provides a good channel for such biological data. PMID- 27999798 TI - Impact of Orthodontic Brackets on the Intraoral Scan Data Accuracy. AB - This study aims to compare the impact of buccal and lingual brackets on the accuracy of dental arch data acquired by 4 different digital intraoral scanners. Two pairs of dental casts, one with buccal brackets and the other with lingual brackets, were used. Digital measurements of the 3D images were compared to the actual measurements of the dental models, which were considered standard values. The horizontal measurements included intercanine widths and intermolar widths. The Mann-Whitney U test was performed for comparisons. iTero(r) and Trios(r) both showed high accuracy with relatively small maximum deviation of measurements. iTero showed a significantly higher accuracy in most of the arch width measurements on the buccal bracket model than on the lingual model (P < 0.05). Zfx IntraScan(r) and E4D Dentist(r) produced maximum deviations of more than 2 mm from both the buccal and the lingual bracket models. After comparing the degree of distortion of the arch on the digital scans with actual measurements of the same models, iTero and Trios proved to be excellent in terms of trueness and precision. Nevertheless, digital intraoral scanners should be used more cautiously in arches with lingual brackets than in those with buccal brackets. PMID- 27999799 TI - Alveolar Ridge Reconstruction with Titanium Meshes and Simultaneous Implant Placement: A Retrospective, Multicenter Clinical Study. AB - Objective. To evaluate horizontal bone gain and implant survival and complication rates in patients treated with titanium meshes placed simultaneously with dental implants and fixed over them. Methods. Twenty-five patients treated with 40 implants and simultaneous guided bone regeneration with titanium meshes (i Gen(r), MegaGen, Gyeongbuk, Republic of Korea) were selected for inclusion in the present retrospective multicenter study. Primary outcomes were horizontal bone gain and implant survival; secondary outcomes were biological and prosthetic complications. Results. After the removal of titanium meshes, the CBCT evaluation revealed a mean horizontal bone gain of 3.67 mm (+/-0.89). The most frequent complications were mild postoperative edema (12/25 patients: 48%) and discomfort after surgery (10/25 patients: 40%); these complications were resolved within one week. Titanium mesh exposure occurred in 6 patients (6/25 : 24%): one of these suffered partial loss of the graft and another experienced complete graft loss and implant failure. An implant survival rate of 97.5% (implant-based) and a peri implant marginal bone loss of 0.43 mm (+/-0.15) were recorded after 1 year. Conclusions. The horizontal ridge reconstruction with titanium meshes placed simultaneously with dental implants achieved predictable satisfactory results. Prospective randomized controlled trials on a larger sample of patients are required to validate these positive outcomes. PMID- 27999800 TI - Effects of Raloxifene on the Proliferation and Apoptosis of Human Aortic Valve Interstitial Cells. AB - We aimed to explore the effects of raloxifene (RAL) on the proliferation and apoptosis of human aortic valve interstitial cells (AVICs). Different concentrations of RAL were used to act on AVICs. MTS kit is used to test the effects of different concentrations of RAL on the proliferation of AVICs. Cell cycle and apoptosis test used flow cytometry after seven-day treatment. The relative expression levels of caspase-3 and caspase-8 are tested with RT-qPCR and Western blot. The results of MTS testing revealed that the absorbance value (OD value) of the cells in the concentration groups of 10 and 100 nmol/L RAL at a wavelength of 490 nm at five, seven, and nine days significantly decreased compared with that in the control group. Meanwhile, the results of flow cytometry of the cells collected after seven days showed that the ratio of the S stage and the cell apoptosis rate of AVICs can be significantly reduced by RAL in the concentration groups of 10 and 100 nmol/L. The mRNA and protein expressions of caspase-3 and caspase-8 were significantly decreased compared with those in the control group. This study laid the foundation for further treatment of aortic valve disease by using RAL. PMID- 27999801 TI - Experimental Verification of Modeled Thermal Distribution Produced by a Piston Source in Physiotherapy Ultrasound. AB - Objectives. To present a quantitative comparison of thermal patterns produced by the piston-in-a-baffle approach with those generated by a physiotherapy ultrasonic device and to show the dependency among thermal patterns and acoustic intensity distributions. Methods. The finite element (FE) method was used to model an ideal acoustic field and the produced thermal pattern to be compared with the experimental acoustic and temperature distributions produced by a real ultrasonic applicator. A thermal model using the measured acoustic profile as input is also presented for comparison. Temperature measurements were carried out with thermocouples inserted in muscle phantom. The insertion place of thermocouples was monitored with ultrasound imaging. Results. Modeled and measured thermal profiles were compared within the first 10 cm of depth. The ideal acoustic field did not adequately represent the measured field having different temperature profiles (errors 10% to 20%). Experimental field was concentrated near the transducer producing a region with higher temperatures, while the modeled ideal temperature was linearly distributed along the depth. The error was reduced to 7% when introducing the measured acoustic field as the input variable in the FE temperature modeling. Conclusions. Temperature distributions are strongly related to the acoustic field distributions. PMID- 27999802 TI - Lower Level of Bacteroides in the Gut Microbiota Is Associated with Inflammatory Bowel Disease: A Meta-Analysis. AB - Background and Aims. Multiple studies have reported associations between inflammatory bowel disease (IBD) and the flora disequilibrium of Bacteroides. We performed a meta-analysis of the available data to provide a more precise estimate of the association between Bacteroides level in the gut and IBD. Methods. We searched PubMed/MEDLINE, EMBASE, Cochrane Library, Wiley Library, BIOSIS previews, Web of Science, CNKI, and ScienceDirect databases for published literature on IBD and gut microbiota from 1990 to 2016. Quality of all eligible studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). We compared the level of Bacteroides in IBD patients with that in a control group without IBD, different types of IBD patients, and IBD patients with active phase and in remission. Results. We identified 63 articles, 9 of which contained sufficient data for evaluation. The mean level of Bacteroides was significantly lower in Crohn's disease (CD) and ulcerative colitis (UC) patients in active phase than in normal controls. The level of Bacteroides in remission CD and UC patients was much lower than patients in the control group. Bacteroides level was even lower in patients with CD and UC in active phase than in remission. Conclusions. This analysis suggests that lower levels of Bacteroides are associated with IBD, especially in active phase. PMID- 27999803 TI - Efficacy of External Beam Radiation-Based Treatment plus Locoregional Therapy for Hepatocellular Carcinoma Associated with Portal Vein Tumor Thrombosis. AB - Background. Portal vein tumor thrombosis (PVTT) is a common event in advanced hepatocellular carcinoma (HCC). The optimal treatment for these patients remains controversial. Methods. A retrospective review of 149 patients who had unresectable HCC associated with PVTT between January 2005 and December 2012 was performed. Outcomes related to external beam radiation-based treatment were measured, and clinicopathological features and parameters affecting prognosis were analyzed as well. Results. The radiotherapeutic response of PVTT was an important element that affected the overall treatment response of HCC. Serum alpha-fetoprotein < 400 ng/mL, the presence of a radiotherapeutic response on PVTT, and receiving additional locoregional therapy were significant prognostic factors affecting the survival of patients. Patients who had received additional locoregional therapy obtained a better outcome, and six of them were eventually able to undergo surgical management with curative intent. Conclusion. The outcome of HCC associated with PVTT remains pessimistic. In addition to the current recommended treatment using sorafenib, a combination of external beam radiotherapy targeting PVTT and locoregional therapy for intrahepatic HCC might be a promising strategy for patients who had unresectable HCC with PVTT. This approach could perhaps offer patients a favorable outcome as well as a possible cure with following surgical management. PMID- 27999804 TI - Perinatal and Neonatal Outcomes of Patients Who Were Diagnosed with Neural Tube Defect in Midtrimester Fetal Ultrasound Scan and Refused Request for Termination of Pregnancy. AB - Objectives. In this study, we aimed to demonstrate the perinatal and neonatal outcomes of patients who were diagnosed with neural tube defect (NTD) in the midtrimester fetal ultrasound scan and refused the request for termination of pregnancy. Material and Methods. The records of 69 patients, for whom NTD was detected in the midtrimester fetal ultrasound scan and who preferred the continuation of the pregnancy after comprehensive counselling about the possible prognosis and treatment options during the period between January 2011 and February 2016, were reviewed retrospectively. Results. Of these patients, 66.7% were 25-35 years old; 95.7% were multiparous; and 1.4% had a history of a fetus having NTD in previous pregnancies. There were 7 (10.1%) neonatal deaths in these patients. Meningomyelocele closure procedure was the most performed surgery in the postnatal period (92%). Of these patients, 30.7% had paraplegia; 51.6% had neurogenic bladder; and 6.4% had infections due to surgery. Conclusion. The results of this study demonstrated perinatal and neonatal outcomes of fetuses with NTD who were not terminated by the preference of the family in midtrimester. The experience of our centre would be beneficial as a tool for nondirective counselling of these patients when considering the antenatal/postnatal care options and postnatal prognosis. PMID- 27999805 TI - Efficiency of Human Epiphyseal Chondrocytes with Differential Replication Numbers for Cellular Therapy Products. AB - The cell-based therapy for cartilage or bone requires a large number of cells; serial passages of chondrocytes are, therefore, needed. However, fates of expanded chondrocytes from extra fingers remain unclarified. The chondrocytes from human epiphyses morphologically changed from small polygonal cells to bipolar elongated spindle cells and to large polygonal cells with degeneration at early passages. Gene of type II collagen was expressed in the cells only at a primary culture (Passage 0) and Passage 1 (P1) cells. The nodules by implantation of P0 to P8 cells were composed of cartilage and perichondrium. The cartilage consisted of chondrocytes with round nuclei and type II collagen-positive matrix, and the perichondrium consisted of spindle cells with type I collage-positive matrix. The cartilage and perichondrium developed to bone with marrow cavity through enchondral ossification. Chondrogenesis and osteogenesis by epiphyseal chondrocytes depended on replication number in culture. It is noteworthy to take population doubling level in correlation with pharmaceutical efficacy into consideration when we use chondrocytes for cell-based therapies. PMID- 27999806 TI - Changes in Serum Concentrations of Fibroblast Growth Factor 23 and Soluble Klotho in Hemodialysis Patients after Total Parathyroidectomy. AB - Background. We examined the changes in circulating fibroblast growth factor 23 (FGF23) and Klotho concentrations in hemodialysis patients after parathyroidectomy (PTX). Methods. We enrolled a cohort of hemodialysis patients who received PTX. Postoperatively, patients received calcium supplements and/or vitamin D analogue (calcitriol) to maintain serum calcium within 7.0-8.0 mg/dL. Information on clinical parameters including bone-mineral metabolic variables was collected pre-PTX and on days 5 and 90 after PTX. Concomitantly, serum full length FGF23 and alpha-Klotho levels were measured. The relationship between FGF23 and clinical parameters was analyzed by single linear regression. Results. Forty-six participants (33 women; 13 men) were enrolled in the study. Their mean age was 56.49 years. Serum FGF23 and alpha-Klotho concentrations were elevated on days 5 and 90 after PTX compared to baseline (p > 0.05). Serum FGF23 concentrations negatively correlated with serum calcium concentrations pre-PTX (Beta -0.31; R2 0.0949; p = 0.040), day 5 post-PTX (Beta -0.31; R2 0.0982; p = 0.036), and day 90 post-PTX (Beta -0.39; R2 0.1528; p = 0.008). Conclusions. There was no change in circulating FGF23 and Klotho concentrations after PTX in hemodialysis patients given postoperative calcium supplements and/or vitamin D analogue. Serum FGF23 concentrations pre-PTX and at days 5 and 90 after PTX were inversely related to serum calcium concentrations. PMID- 27999807 TI - Clinical and Microbiological Characteristics of Visceral Leishmaniasis Outbreak in a Northern Italian Nonendemic Area: A Retrospective Observational Study. AB - Background. Visceral leishmaniasis (VL) caused by Leishmania infantum is endemic in the Mediterranean area. In the last decades a northward spread of the parasite has been observed in Italy. This paper describes a VL outbreak in Modena province (Emilia-Romagna, Northern Italy) between 2012 and 2015. Methods. Retrospective, observational study to evaluate epidemiological, microbiological characteristics, and clinical management of VL in patients referring to Policlinico Modena Hospital. Results. Sixteen cases of VL occurred in the study period. An immunosuppressive condition was present in 81.3%. Clinical presentation included anemia, fever, leukopenia, thrombocytopenia, and hepatosplenomegaly. Serology was positive in 73.3% of cases, peripheral blood PCR in 92.3%, and bone marrow blood PCR in 100%. Culture was positive in 3/6 cases (50%) and all the isolates were identified as L. infantum by ITS1/ITS2 sequencing. The median time between symptom onset and diagnosis was 22 days (range 6-131 days). All patients were treated with liposomal amphotericin b. 18.8% had a VL recurrence and were treated with miltefosine. Attributable mortality was 6.3%. Conclusions. VL due to L. infantum could determine periodical outbreaks, as the one described; thus it is important to include VL in the differential diagnosis of fever of unknown origin, even in low-endemic areas. PMID- 27999808 TI - A Feasibility Study for Measuring Accurate Chest Compression Depth and Rate on Soft Surfaces Using Two Accelerometers and Spectral Analysis. AB - Background. Cardiopulmonary resuscitation (CPR) feedback devices are being increasingly used. However, current accelerometer-based devices overestimate chest displacement when CPR is performed on soft surfaces, which may lead to insufficient compression depth. Aim. To assess the performance of a new algorithm for measuring compression depth and rate based on two accelerometers in a simulated resuscitation scenario. Materials and Methods. Compressions were provided to a manikin on two mattresses, foam and sprung, with and without a backboard. One accelerometer was placed on the chest and the second at the manikin's back. Chest displacement and mattress displacement were calculated from the spectral analysis of the corresponding acceleration every 2 seconds and subtracted to compute the actual sternal-spinal displacement. Compression rate was obtained from the chest acceleration. Results. Median unsigned error in depth was 2.1 mm (4.4%). Error was 2.4 mm in the foam and 1.7 mm in the sprung mattress (p < 0.001). Error was 3.1/2.0 mm and 1.8/1.6 mm with/without backboard for foam and sprung, respectively (p < 0.001). Median error in rate was 0.9 cpm (1.0%), with no significant differences between test conditions. Conclusion. The system provided accurate feedback on chest compression depth and rate on soft surfaces. Our solution compensated mattress displacement, avoiding overestimation of compression depth when CPR is performed on soft surfaces. PMID- 27999809 TI - Reproductive Toxicities Caused by Swainsonine from Locoweed in Mice. AB - Swainsonine is the primary toxin in locoweeds. It causes intention tremors, reproductive dysfunction, emaciation, and death. The objective of the present study was to evaluate the potential reproductive and developmental toxicities caused by swainsonine in mice. The treatment groups consisting of three generations of mice were given a range of concentrations of swainsonine by intraperitoneal injection (2.50 mg/kg body weight (BW), 1.20 mg/kg BW, 0.60 mg/kg BW, and 0 mg/kg BW). The 0 mg/kg BW group exhibited significantly fewer estrous cycles and an increased number of estrous ones compared to the 2.50 mg/kg BW, 1.20 mg/kg BW, and 0.60 mg/kg BW groups (P < 0.05). All three generations of mice treated with swainsonine had significantly higher spleen, liver, and kidney indices and significantly lower body weights compared to the 0 mg/kg BW group (P < 0.05). For the first and second generations of treatment group, the copulation indices and the numbers of live pups on postnatal days (PND) 0, 4, and 15 were significantly decreased compared to those of the 0 mg/kg BW group (P < 0.05). The fertility and gestation indices of the treatment group of the first generation were significantly increased compared to the 2.50 mg/kg BW, 1.20 mg/kg BW, and 0.60 mg/kg BW groups of the second generation (P < 0.05). Cumulatively, these results indicate that swainsonine may cause reproductive and developmental toxicities in mice in both parents and offspring. PMID- 27999810 TI - Development of a New Hybrid Biodegradable Drug-Eluting Stent for the Treatment of Peripheral Artery Disease. AB - This study aimed to develop a new biodegradable stent for peripheral artery disease (PAD) that could provide sufficient radial force to maintain long-term patency and flexibility. All self-expandable hybrid biodegradable stents were designed by using a knitting structure composed of poly-L-lactic acid (PLLA) and nitinol. Four different types of stents were implanted in 20 iliac arteries in 10 mini pigs as follows: a bare-metal stent (BMS) (group 1, n = 5), a drug-free hybrid stent (group 2, n = 5), a 50% (50 : 100, w/w) paclitaxel (PTX)/poly lactide-co-glycolic acid (PLGA; fast PTX-releasing form) hybrid stent (group 3, n = 5), and a 30% (30 : 100, w/w) PTX/PLGA (slow PTX-releasing form) hybrid stent (group 4, n = 5). We performed follow-up angiography and intravascular ultrasonography (IVUS) at 4 and 8 weeks. In a comparison of groups 1, 2, 3, and 4, less diameter stenosis was observed in the angiographic analysis for group 4 at the 4-week follow-up (19.0% +/- 12.7% versus 39.3% +/- 18.1% versus 46.8% +/- 38.0% versus 4.8% +/- 4.2%, resp.; p = 0.032). IVUS findings further suggested that the neointima of the patients in group 4 tended to be lesser than those of the others. Our new biodegradable 30% PTX/PLGA (slow-releasing form) stent showed more favorable results for patency than the other stent types. PMID- 27999811 TI - Impact of WHO Hand Hygiene Improvement Program Implementation: A Quasi Experimental Trial. AB - Objectives. As affirmed by the World Health Organization (WHO), hand hygiene is the most powerful preventive measure against healthcare-associated infections (HCAIs) and, thus, it has become one of the five key elements of patient safety program. The aim is to assess the effect of implementation of the WHO's Multimodal Hand Hygiene Improvement Strategy among healthcare workers of a tertiary teaching hospital in a developing country. Methods. Hand hygiene compliance was assessed among healthcare workers, according to five defined moments for hand hygiene of the WHO, before and after implementation of the WHO's Multimodal Hand Hygiene Improvement Strategy in fourteen wards of a tertiary teaching hospital in Shiraz, Iran. We used direct observation method and documented the results in WHO hand hygiene observation forms. Results. There was a significant change in compliance before and after implementation of WHO's Multimodal HH Improvement Strategy (29.8% and 70.98%, resp.). Conclusions. Implementing WHO hand hygiene program can significantly improve hand hygiene compliance among nurses. PMID- 27999812 TI - Integrative Characterization of Toxic Response of Zebra Fish (Danio rerio) to Deltamethrin Based on AChE Activity and Behavior Strength. AB - In order to characterize the toxic response of zebra fish (Danio rerio) to Deltamethrin (DM), behavior strength (BS) and muscle AChE activity of zebra fish were investigated. The results showed that the average values of both BS and AChE activity showed a similarly decreased tendency as DM concentration increased, which confirmed the dose-effect relationship, and high and low levels of AChE and BS partly matched low and high levels of exposure concentrations in self organizing map. These indicated that AChE and BS had slight different aspects of toxicity although overall trend was similar. Behavior activity suggested a possibility of reviving circadian rhythm in test organisms after exposure to the chemical in lower concentration (0.1 TU). This type of rhythm disappeared in higher concentrations (1.0 TU and 2.0 TU). Time series trend analysis of BS and AChE showed an evident time delayed effect of AChE, and a 2 h AChE inhibition delay with higher correlation coefficients (r) in different treatments was observed. It was confirmed that muscle AChE inhibition of zebra fish is a factor for swimming behavior change, though there was a 2 h delay, and other factors should be investigated to illustrate the detailed behavior response mechanism. PMID- 27999813 TI - Physiological Study on Association between Nicotinamide N-Methyltransferase Gene Polymorphisms and Hyperlipidemia. AB - Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide. Our previous works indicate that NNMT is involved in the body mass index and energy metabolism, and recently the association between a SNP (rs694539) of NNMT and a variety of cardiovascular diseases was reported. At present, more than 200 NNMT single nucleotide polymorphisms (SNPs) have been identified in the databases of the human genome projects; however, the association between rs694539 variation and hyperlipidemia has not been reported yet, and whether there are any SNPs in NNMT significantly associated with hyperlipidemia is still unclear. In this paper, we selected 19 SNPs in NNMT as the tagSNPs using Haploview software (Haploview 4.2) first and then performed a case-control study to observe the association between these tagSNPs and hyperlipidemia and finally applied physiological approaches to explore the possible mechanisms through which the NNMT polymorphism induces hyperlipidemia. The results show that a SNP (rs1941404) in NNMT is significantly associated with hyperlipidemia, and the influence of rs1941404 variation on the resting energy expenditure may be the possible mechanism for rs1941404 variation to induce hyperlipidemia. PMID- 27999814 TI - Sperm DNA Fragmentation Index and Hyaluronan Binding Ability in Men from Infertile Couples and Men with Testicular Germ Cell Tumor. AB - Objective. To investigate sperm DNA fragmentation and sperm functional maturity in men from infertile couples (IC) and men with testicular germ cell tumor (TGCT). Materials and Methods. Semen samples were collected from 312 IC men and 23 men with TGCT before unilateral orchiectomy and oncological treatment. The sperm chromatin dispersion test was performed to determine DNA fragmentation index (DFI) and the ability of sperm to bind with hyaluronan (HA) was assessed. Results. In comparison with the IC men, the men with TGCT had a higher percentage of sperm with fragmented DNA (median 28% versus 21%; p < 0.01) and a lower percentage of HA-bound sperm (24% versus 66%; p < 0.001). Normal results of both analyses were observed in 24% of IC men and 4% of men with TGCT. Negative Spearman's correlations were found between DFI and the percentage of HA-bound sperm in the whole group and in IC subjects and those with TGCT analyzed separately. Conclusions. Approximately 76% of IC men and 96% with TGCT awaiting orchiectomy demonstrated DNA fragmentation and/or sperm immaturity. We therefore recommend sperm banking after unilateral orchiectomy, but before irradiation and chemotherapy; the use of such a deposit appears to be a better strategy to obtain functionally efficient sperms. PMID- 27999815 TI - Assessment of the Number and Phenotype of Macrophages in the Human BMB Samples of CML. AB - Macrophages have emerged as a key player in tumor biology. However, their number and phenotype in human bone marrow of biopsy (BMB) samples of chronic myeloid leukemia (CML) and their association with disease progression from an initial chronic phase (CP) to accelerated phase (AP) to advanced blast phase (BP) are still unclear. BMB samples from 127 CML patients and 30 patients with iron deficiency anemia (IDA) as control group were analyzed by immunohistochemistry. The expression levels of CD68, CD163, and CD206 in BMB samples of CML patients were significantly higher than those in the patients of control group (P < 0.01), and we observed that their positive expression was gradually elevated during the transformation of CML-CP to AP to BP (P < 0.01). However, the expressions of CD68, CD163, and CD206 in released group were downregulated and contrasted to these in control group; there exists statistical significance (P < 0.01). The percentage ratio of CD163 and CD206 to CD68 was pronounced to be increasing from CML-CP to AP to BP (P < 0.01). Hence, the higher proportion of CD68+, CD163+ and CD206+ macrophages in BMB samples can be considered a key factor for disease progression of CML patients. Targeting macrophages, especially the M2 phenotype may help in designing therapeutic strategies for CML. PMID- 27999816 TI - Evidence for Altered Canonical Wnt Signaling in the Trabecular Bone of Elderly Postmenopausal Women with Fragility Femoral Fracture. AB - Wnt signaling, a major regulator of bone formation and homeostasis, might be involved in the bone loss of osteoporotic patients and the consequent impaired response to fracture. Therefore we analyzed Wnt-related, osteogenic, and adipogenic genes in bone tissue of elderly postmenopausal women undergoing hip replacement for either femoral fracture or osteoarthritis. Bone specimens derived from the intertrochanteric region of the femurs of 25 women with fracture (F) and 29 with osteoarthritis without fracture (OA) were analyzed. Specific miRNAs were analyzed in bone and in matched blood samples. RUNX2, BGP, and OPG showed lower expression in F than in OA samples, while OSX, OPN, BSP, and RANKL were not different. Inhibitory genes of Wnt pathway were lower in F versus OA. beta Catenin protein levels were higher in F versus OA, whereas its cotranscriptional regulator (Lef1) was lower in F group. miR-204, which targets RUNX2, and miR 130a, which inhibits PPARgamma, were lower and higher, respectively, in F versus OA serum samples. The present study showed an inefficient Wnt signal transduction in F group despite higher beta-catenin protein levels, consistent with the expected overall postfracture systemic activation towards osteogenesis. This transcriptional inefficiency could contribute to the osteoporotic bone fragility. PMID- 27999817 TI - EF24 Suppresses Invasion and Migration of Hepatocellular Carcinoma Cells In Vitro via Inhibiting the Phosphorylation of Src. AB - Diphenyl difluoroketone (EF24), a curcumin analog, is a promising anticancer compound that exerts its effects by inhibiting cell proliferation and inducing apoptosis. However, the efficacy of EF24 against cancer metastasis, particularly in hepatocellular carcinoma (HCC), remains elusive. In this study, the effect of EF24 on HCCLM-3 and HepG2 cell migration and invasion was detected by wound healing and transwell assay, respectively. The results revealed that EF24 suppressed the migration and invasion of both HCCLM-3 and HepG2 cells. Furthermore, EF24 treatment decreased the formation of filopodia on the cell surface and inhibited the phosphorylation of Src in both cell lines, which may help contribute towards understanding the mechanism underlying the suppressive effect of EF24 on HCC migration and invasion. Additionally, the expression of total- and phosphorylated-Src in primary HCC tissues and their paired lymph node metastatic tissues was detected, and phosphorylated-Src was found to be associated with HCC lymph node metastasis. The results of this study suggest that Src is a novel and promising therapeutic target in HCC and provide evidence to support the hypothesis that EF24 may be a useful therapeutic agent for the treatment of HCC. PMID- 27999818 TI - Expression, Purification, and Characterization of a Sucrose Nonfermenting 1 Related Protein Kinases 2 of Arabidopsis thaliana in E. coli-Based Cell-Free System. AB - The plant-specific sucrose nonfermenting 1-related protein kinase 2 (SnRK2) family is considered an important regulator of plant responses to abiotic stresses such as drought, cold, salinity, and nutrition deficiency. However, little information is available on how SnRK2s regulate sulfur deprivation responses in Arabidopsis. Large-scale production of SnRK2 kinases in vitro can help to elucidate the biochemical properties and physiological functions of this protein family. However, heterogenous expression of SnRK2s usually leads to inactive proteins. In this study, we expressed a recombinant Arabidopsis SnRK2.1 in a modified E. coli cell-free system, which combined two kinds of extracts allowing for a convenient and affordable protein preparation. The recombinant SnRK2.1 was produced in large-scale and the autophosphorylation activity of purified SnRK2.1 was characterized, allowing for further biochemical and substrate binding analysis in sulfur signaling. The application of this improved E. coli cell-free system provides us a promising and convenient platform to enhance expression of the target proteins economically. PMID- 27999819 TI - Detection of the Single-Session Complete Ablation Rate by Contrast-Enhanced Ultrasound during Ultrasound-Guided Laser Ablation for Benign Thyroid Nodules: A Prospective Study. AB - This study aimed to investigate the single-session complete ablation rate of ultrasound-guided percutaneous laser ablation (LA) for benign thyroid nodules. LA was performed in 90 patients with 118 benign thyroid nodules. Contrast-enhanced ultrasound (CEUS) was used to evaluate complete nodule ablation one day after ablation. Thyroid nodule volumes, thyroid functions, clinical symptoms and complications were evaluated 1, 3, 6, 12, and 18 months after ablation. Results showed that all benign thyroid nodules successfully underwent LA. The single session complete ablation rates for nodules with maximum diameters <=2 cm, 2-3 cm and >=3 cm were 93.4%, 70.3% and 61.1%, respectively. All nodule volumes significantly decreased than that one day after ablation (P < 0.05); at the final evaluation, the volume decreased from 6.16 +/- 5.21 mL to 0.05 +/- 0.01 mL. Thyroid functions did not show significant differences at one month after ablation compared with that before (P > 0.05). Three patients had obvious pain during ablation; one (1.1%) had recurrent laryngeal nerve injury, but the voice returned to normal within 6 months after treatment. Thus, ultrasound-guided LA can effectively inactivate benign thyroid nodules. LA is a potentially viable minimally invasive treatment that offers good cosmetic effects. PMID- 27999820 TI - How Should Disaster Base Hospitals Prepare for Dialysis Therapy after Earthquakes? Introduction of Double Water Piping Circuits Provided by Well Water System. AB - After earthquakes, continuing dialysis for patients with ESRD and patients suffering from crush syndrome is the serious problem. In this paper, we analyzed the failure of the provision of dialysis services observed in recent disasters and discussed how to prepare for disasters to continue dialysis therapy. Japan has frequently experienced devastating earthquakes. A lot of dialysis centers could not continue dialysis treatment owing to damage caused by these earthquakes. The survey by Japanese Society for Dialysis Treatment (JSDT) after the Great East Japan Earthquake in 2011 showed that failure of lifelines such as electric power and water supply was the leading cause of the malfunction of dialysis treatment. Our hospital is located in Shizuoka Prefecture, where one of the biggest earthquakes is predicted to occur in the near future. In addition to reconstructing earthquake-resistant buildings and facilities, we therefore have adopted double electric and water lifelines by introducing emergency generators and well water supply systems. It is very important to inform politicians, bureaucrats, and local water departments that dialysis treatment, a life sustaining therapy for patients with end stage renal diseases, requires a large amount of water. We cannot prevent an earthquake but can curb the extent of a disaster by preparing for earthquakes. PMID- 27999821 TI - Effects of Electroacupuncture on the Daily Rhythmicity of Intestinal Movement and Circadian Rhythmicity of Colonic Per2 Expression in Rats with Spinal Cord Injury. AB - Background. Spinal cord injury (SCI) leads to bowel dysfunction. Electroacupuncture (EA) may improve bowel function. Objective. To assess EA on daily rhythmicity of intestinal movement and circadian rhythmicity of colonic Per2 expression in rats with SCI. Methods. Rats were randomized to the sham, SCI, and SCI+EA groups. EA was performed at bilateral Zusanli point (ST36) during daytime (11:00-11:30) for 14 days following SCI. Intestinal transit and daily rhythmicity of intestinal movement were assessed. Circadian rhythmicity of colonic Per2 expression was assessed by real-time RT-PCR. Results. EA shortened the stool efflux time and increased the dry fecal weight within 24 h in SCI rats. Daily rhythmicity of intestinal movements was unaffected by SCI. The expression of colonic Per2 peaked at 20:00 and the nadir was observed at 8:00 in the SCI and sham groups. In the SCI+EA group, colonic Per2 expression peaked at 12:00 and 20:00, and the nadir was observed at 8:00. Conclusion. SCI did not change the circadian rhythmicity of colonic Per2 expression in rats, and daily intestinal movement rhythmicity was retained. EA changed the daily rhythmicity of intestinal movement and the circadian rhythmicity of colonic Per2 expression in rats with SCI, increasing Per2 expression shortly after EA treatment. PMID- 27999822 TI - Glucose >200 mg/dL during Continuous Glucose Monitoring Identifies Adult Patients at Risk for Development of Cystic Fibrosis Related Diabetes. AB - Rationale. Cystic fibrosis related diabetes (CFRD) is the most common comorbidity in patients with CF. In spite of increased screening, diagnosis, and treatment of CFRD, the mortality rate in patients with CFRD still far exceeds the mortality rate in those without CFRD. Guidelines suggest that screening for CFRD be performed annually using the 2-hour 75-gram oral glucose tolerance test (OGTT). Adherence to recommended screening has been poor, with only approximately one quarter of adults with CF undergoing OGTT in 2014. Use of continuous glucose monitoring (CGM) for diagnosis may become an alternative. Objectives. Our objective was to determine whether abnormal CGM predicts subsequent development of CFRD, lung function, and body mass index (BMI) decline and increased rate of CF pulmonary exacerbations in adults with CF. Methods. In a prospective single center pilot trial from September 2009 to September 2010, 21 adult patients due for routine OGTT were recruited to complete simultaneous 3-day CGM and 2-hour 75 gram OGTT. Subsequently, clinical information was reviewed from 2008 to 2015. Conclusions. There was a moderate correlation between interpreted results of 2 hour OGTT and CGM (p = 0.03); CGM indicated a greater level of glucose impairment than OGTT. Glucose >200 mg/dL by CGM predicted development of CFRD (p = 0.0002). PMID- 27999824 TI - Perinatal Outcome in Assisted Reproductive Pregnancies: Comparative Analysis of Reduced versus Unreduced Gestation. AB - Objectives. This study aims to evaluate perinatal outcomes such as gestational age at delivery and live birth rate in singleton and twin gestation with or without fetal reduction. Method. A retrospective analysis was done on patients which were divided into reduced and unreduced groups on the basis of order of reduction of one or more fetuses between 6 and 13 weeks of gestation. Patients records were studied to note gestational age at delivery/abortion, birth weight, and neonatal outcome. Result. The cohort included a total of 292 patients: 102 singletons and 190 twins. 52 pregnancies were reduced in singleton cohort and 68 were reduced in twin cohort. No statistical difference was observed in live birth rate, gestational age at delivery, and birth weight and significant higher incidence of IUGR was observed in reduced and unreduced twin gestation. In singleton pregnancies however preterm delivery rate increased with fetal reduction. Conclusion. Although reduction does not reduce the live birth rate, it does reduce gestation age of delivery and birth weight of newborn. This effect is more apparent when multiple gestation is reduced to singleton. PMID- 27999825 TI - Is there a relationship between non-obstructive coronary artery disease or cardiac syndrome X and migraine? An integrated multi-disciplinary approach. AB - Non-obstructive coronary artery disease (CAD) which is mostly called cardiac syndrome X (CSX) is noted in about 30% of men and 40%-60% of women and seems to be incremental. In addition, frequent myocardial perfusion defects with various levels of severity are often seen in this disease. Recently, we noticed that the frequency of migraine in patients with CSX was noticeably higher than in healthy people and in CAD patients. This may support the evolving story that CSX is related to migraine and to chest pain and that CSX and migraine may have a similar pathophysiology. Hence, myocardial perfusion imaging could be used as a complement any diagnostic test to support the relation between CSX and migraine. PMID- 27999826 TI - The diagnosis of silent myocardial ischemia. Motion-Frozen (or morphing) myocardial perfusion imaging. AB - Silent myocardial ischemia is typically defined as objective evidence of myocardial ischemia in patients without subjective ischemia symptoms. Currently, coronary artery angiography is the gold standard for diagnosis of asymptomatic coronary artery disease (CAD). Computed tomography coronary angiography (CTCA) can visually demonstrate the morphology, trend and extent of coronary stenosis and is commonly used in clinical screening of CAD. Myocardial perfusion imaging can be used not only to identify whether anatomical stenosis causes myocardial dysfunction, but to also assess the risk stratification and prognosis of myocardial disease (MD). Myocardial perfusion imaging using morphing combined with CTCA can simultaneously show the relationship between CAD and myocardial ischemia from an anatomical and functional aspect. This allows earlier diagnosis of asymptomatic CAD myocardial ischemia, accurate identification of the culprit vessels, and could prevent unnecessary interventional therapy. The 1-day dobutamine stress/resting met-hod is also one of the methods used. The combination of CTCA and the morphing technique can provide anatomical and functional information on coronary arteries at the same time, significantly improving the diagnostic sensitivity, specificity, and accuracy of MD. PMID- 27999823 TI - The Pathophysiological Impact of HLA Class Ia and HLA-G Expression and Regulatory T Cells in Malignant Melanoma: A Review. AB - Malignant melanoma, a very common type of cancer, is a rapidly growing cancer of the skin with an increase in incidence among the Caucasian population. The disease is seen through all age groups and is very common in the younger age groups. Several studies have examined the risk factors and pathophysiological mechanisms of malignant melanoma, which have enlightened our understanding of the development of the disease, but we have still to fully understand the complex immunological interactions. The examination of the interaction between the human leucocyte antigen (HLA) system and prognostic outcome has shown interesting results, and a correlation between the down- or upregulation of these antigens and prognosis has been seen through many different types of cancer. In malignant melanoma, HLA class Ia has been seen to influence the effects of pharmaceutical drug treatment as well as the overall prognosis, and the HLA class Ib and regulatory T cells have been correlated with tumor progression. Although there is still no standardized immunological treatment worldwide, the interaction between the human leucocyte antigen (HLA) system and tumor progression seems to be a promising focus in the way of optimizing the treatment of malignant melanoma. PMID- 27999827 TI - Cauda equina syndrome. An emergency, some unexpected severe symptoms and conservative treatment. AB - An 83 years old physician, doing only office work and no exercise, presented with cauda equine, due to a large intervertebral disk hernia between L1-L2 vertebrae, after an unorthodox movement. He also had a facet syndrome, a muscular spasm in the gluteus, a small fracture in the periphery of the body of the L2 vertebra and pain in the L4-L5, due to a previous vertebral hernia five years ago. All L1-L5 left lateral area was painful. He felt an unbearable pain. He also had a degree of paralysis of the gastrointestinal (GI) and the genitourinary system. He could not take analgesics or anti-inflammatory drugs per os because of the paralysis of the GI system. His pain was relieved only by intramuscular injections of parecoximbe (a cyclooxigenase-2 inhibitor, COX-2). The disc hernia was treated without surgery. After 43 days in bed, he was able to start exercising in order to treat muscles' atrophy. PMID- 27999829 TI - Regional cerebral blood flow changes in patients with internet addiction. AB - Dear Editor, Internet addiction (IA) has become a severe challenge of our modern world today, though little is known about its pathology. In this context, the interesting study by Liu et al. in the May-August 2016 issue of HJNM using 99mTc labelled ethylene biyldicysteinate dimer single photon emission tomography (SPET) at rest and after pharmaceutical (adenosine) stress is more than welcomed. As this seems to be the first perfusion SPET study in this indication, the obtained data may be discussed carefully. There are mainly the following questions: a) Regional cerebral blood flow (rCBF): There is no description on how the rCBF was calculated: Was it scaled relatively to the whole brain mean value or to the cerebellar mean value? b) P value threshold and clusters: There is no indication of whether the authors are performing any kind of correction for multiple comparisons in the statistical parametric mapping (SPM) t-test. This, combined with the use of a really "liberal" voxel P value of only 0.01 could be subject to providing many false positive results. Generally a P value threshold of 0.001 should be used. In addition, there is no information related to the clusters. For the question of the validity of parametric statistical methods used for the analysis of functional neuroimaging data, we would like to mention the important recent paper by Eklund et al. 2016. c) Data analysis: The authors state (p. 97): "As some abnormal rCBF in adenosine-stressed state might relate with normal responses to adenosine compared to resting state, we excluded those regions that showed abnormal rCBF in stressed state in healthy controls (Table 4) from those in IA group (Table 5). The rest abnormal regions were compared between the IA group and the control group". For this, with SPM a flexible factorial design with all the data rather than only t-tests would have been interesting to find out whether the difference between the groups at stress is the same difference observed between the groups at rest. In "traditional" region-of-interest statistics, a repeated 2-way ANOVA to account for individual variance would have been done. The authors are, however, just "manually" removing the regions that pop-up in the previous analysis. In conclusion, it would be of great scientific interest if the authors of this first SPET study on an important indication, IA, could give us some more details on their data. PMID- 27999828 TI - A case of abdominal mesenteric Castleman's disease with left renal cell carcinoma and stomach leiomyoma. AB - : A rare case of abdominal mesenteric Castleman's disease with left renal cell carcinoma and stomach leiomyoma is reported. A 57 years old male patient was transferred to our hospital for investigation of a left kidney tumor. Physical examination and routine laboratory tests were normal. Multi mode imaging by 64 slices spiral computed tomography (CT) scan, the enhanced CT scan and the fluorine-18-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) scan were applied. Computed tomography showed a 5.4cm*5.2cm mass in the abdomen. The radioactive distribution of the mass was high SUVmax about 4.5. Furthemore, a soft tissue mass, about 3.9cm*3.0cm, was detected in the left kidney, with significantly inhomogeneous enhancement in the arterial phase of the CT scan, while contrast agent CT showed activity in the venous phase. The radioactive distribution of this mass was slightly concentrated and its SUVmax was about 3.2. With the stomach filled with water , an oval shaped and slightly lobulated soft tissue mass was also observed in the cardia, with a size about 4.6cm*3.0cm. Computed tomography showed mild enhancement of radioactively in the arterial phase and delayed enhancement in the venous phase. The radioactive distribution of the mass was diffused and SUVmax was about 4.7. CONCLUSION: The patient was operated and pathology showed: a) A mesenteric mass and abdominal lymph nodes with cells of the hyaline vascular type of Castleman's disease. b) Renal clear cells carcinoma of the left kidney and c) Spindle cells leiomyoma tumor in the gastric cardia. Three tumors in the same patient are extremely rare. PMID- 27999830 TI - Regional cerebral blood flow changes in patients with internet addiction: Authors' reply. AB - To the comments of Prof. Andreas Otte to our work we reply as follows: As was mentioned by Prof. Andreas Otte, our study was the first study of regional cerebral blood flow changes in patients with internet addiction. Therefore, there was not much previous, established experience to refer to. As an exploration study, it was inevitable that there were some insufficiencies. We feel great appreciation to Prof. Andreas Otte for his comments on our work, which will improve our studying quality in this field in the future. Prof. Andreas Otte inquired in his letter how the regional cerebral blood flow (rCBF) was calculated, and was scaled, relatively to the whole brain mean value or to the cerebellar mean value. All rCBF data were scaled relatively to the whole brain, in our study. As for the question in relation to the test level, the P-value of 0.05 was only used when comparing intergroup differences of baseline or clinical information of patients using SPSS, while the P-value of 0.01 was used for the statistical parametric mapping (SPM) t-test. We had tried using the test level of P<0.001 to indicate the significance when performing the SPM t-test, but there were not very meaningful findings identified at this test level. This might be explained by the relatively old generation and low sensitivity of the SPET scanner used in our study. For the purpose to identify more potential cerebral regions with abnormal rCBF, we lowered down the test level to 0.01, although this might had resulted in some false-positive results. However, in order to control false-positive errors, we performed intragroup comparisons from rest to adenosine stressed status firstly by paired t test to identify cerebral regions with obvious rCBF changes because of administration of adenosine. On the basis of these cerebral regions, we subsequently performed a two-sample t test to compare intergroup differences to identify cerebral regions with rCBF that could have attributed to internet addiction. We believed that this "twostep" statistical mode might reduce the probability of falsepositive results to some extent. As for the cluster question in relation to SPM analysis, it seems more problematic and more prone for clusterwise inference to produce false-positive results than voxelwise inference, as mentioned in the paper by Eklund et al (2016). We did not take the two-way ANOVA analysis, instead, we performed the more suitable "twostep" statistical mode mentioned above. However, when facing multiple comparisons, we did adjust the P values with the relatively conservative Bonferroni method. Thanks again for the interesting and the meaningful comments of Prof. Andreas Otte to our study. If there are any more queries, please do not hesitate to contact us. PMID- 27999831 TI - Effect of the lipid II sugar moiety on bacterial transglycosylase: the 4-hydroxy epimer of lipid II is a TGase inhibitor. AB - Lipid II analogues bearing major modifications on the second sugar (GlcNAc) were synthesized and evaluated for their substrate activity toward TGases. Unexpectedly, N-deacetyled lipid II decreased its activity dramatically, and the C4-axial OH lipid II became an inhibitor (IC50 = 8 MUM) with an approximately 14 fold increase in binding affinity toward TGase (25 vs. 27). PMID- 27999832 TI - High oxidation state bromocarbyne complexes. AB - Bromination of the carbyne complexes [W([triple bond, length as m dash]CR)Br(CO)2(dcpe)] (R = Ph, SiPh3; dcpe = 1,2 bis(dicyclohexylphosphino)ethane) provides high oxidation state derivatives [W([triple bond, length as m-dash]CPh)Br3(dcpe)] and [W([triple bond, length as m dash]CBr)Br3(dcpe)], the latter via an unprecedented bromodesilylation process. PMID- 27999833 TI - A ratiometric nanoarchitecture for the simultaneous detection of pH and halide ions using UV plasmon-enhanced fluorescence. AB - In this work, we designed a ratiometric core-shell nanoarchitecture composed of an indium UV plasmonic core, an internal reference (rhodamine B), a pH-sensitive probe (fluorescein), and a halide ion sensor (6-methoxyquinolinium). Immobilizing the fluorophores in distinct silica layers at precise distances from the core modulates the plasmon coupling and tunes the linear concentration range of halide ion detection. PMID- 27999834 TI - Polyaspartamide-based graft copolymers encapsulating iron oxide nanoparticles for imaging and fluorescence labelling of immune cells. AB - Iron oxide nanoparticles (NPs) were encapsulated with polyaspartamide-based graft copolymers to bind and track the immune cells as imaging probes. Mono-disperse iron oxide NPs with a mean diameter of 10.7 nm were synthesized by the thermal decomposition method, and their shape and distribution were measured by electrophoretic light scattering and transmission electron microscopy. To enhance their biocompatibility, interfacial and hydrodynamic stability, and fluorescence detection, biodegradable polysuccinimide (PSI) grafted with several functional groups of octadecylamine (C18), ethanolamine (EA), ethylenediamine (EDA), 4-(N maleimidomethyl) cyclohexane carboxylic acid N-hydroxysuccinimide ester (SMCC), and fluorescein isothiocyanate (FITC) was coated on the iron oxide NPs. The structure of the C18/EA/SMCC/FITC-g-PSI copolymer was confirmed using 1H-NMR and FTIR spectroscopy, and its cell binding ability was investigated by flow cytometry and confocal laser scanning microscopy. The synthesized C18/EA/SMCC/FITC-g-PSI copolymer showed an excellent binding affinity to CD4+ T cells, and was highly biocompatible as the cell viability at the highest polymer concentration of 0.4 mg mL-1 was greater than 85 and 75% after 24 and 48 h, respectively, from MTT assay. PMID- 27999835 TI - The facile construction of an anion exchange membrane with 3D interconnected ionic nano-channels. AB - The co-organization of polymerizable imidazolium-based ionic liquids and p-xylene led to the formation of a bicontinuous cubic phase with a primitive-type periodic minimal surface, and for the first time an anion exchange membrane preserving 3D interconnected ionic nano-channels was fabricated through in-phase photopolymerization of bicontinuous cubic liquid crystals. PMID- 27999836 TI - Degradable fluorescent single-chain nanoparticles based on metathesis polymers. AB - We introduce the facile synthesis of fluorescent single-chain nanoparticles (SCNPs) based on chain-shattering acyclic diene metathesis (ADMET) polymers featuring self-immolative azobenzene motifs. An electrophilic alkoxyetherification is utilized to introduce the photoreactive moieties required for the subsequent chain collapse via UV-induced nitrile imine-mediated tetrazole ene cycloaddition (NITEC). PMID- 27999838 TI - Photoswitching adsorption selectivity in a diarylethene-azobenzene MOF. AB - The first MOF (metal-organic framework) built on both diarylethene and azobenzene photochromic units is reported here and displays distinct photoresponses for different guest molecules, thus creating an easy-to-use pathway to modulate the adsorption selectivity of MOF materials. PMID- 27999837 TI - Beyond chemotherapeutics: cisplatin as a temporary buckle to fabricate drug loaded nanogels. AB - A cisplatin templated nanogel with targeting capability was synthesized, inspired by cisplatin as a chemotherapeutic drug. After crosslinking the natural polysaccharide hyaluronan, a ligand for CD44, cisplatin could be removed by simple dialysis in a salt solution while the withheld drug remains entrapped. PMID- 27999839 TI - NIR imaging-guided combined photodynamic therapy and chemotherapy by a pH responsive amphiphilic polypeptide prodrug. AB - pH-Sensitive doxorubicin conjugated polymeric micelles entrapped with near infrared (NIR) photosensitizer BODIPY (which works as an imaging agent at the same time) were designed and synthesized by ring opening polymerization of N carboxyanhydride with mPEG-NH2 as the initiator, following reaction with doxorubicin to form the hydrazone-bond linker for pH responsiveness. Then the NIR dye (BODIPY) was loaded in the micelles for both bioimaging and photodynamic therapy (PDT). A significant cytotoxicity of NIR imaging-guided combined PDT and chemotherapy could be found by MTT assays, which was also confirmed with a fluorescence microscope, indicating a new kind of polymeric nanoparticle for potential theranostic treatment of cancers. In addition, the energy density of the laser for the PDT is extremely low. PMID- 27999840 TI - Identification and Characterization of Inter-Organizational Information Flows in the Portuguese National Health Service. AB - OBJECTIVES: To understand and build a collective vision of all existing institutions in the Portuguese National Health Service as well as to perceive how and how far the interaction between those multiple institutions is supported by Information Systems (IS). METHODS: Upon identification of the institutions involved in the healthcare process, a set of interviews with experienced people from those institutions was conducted, which produced about five hours of tape. The research was focused exclusively on processes involving two different organizations and any internal processes were altogether excluded from it. RESULTS: The study allowed the identification of about 50 recurrent interaction processes, which were classified into four different varieties in accordance with the nature of the information flow: administrative, clinical, identificational and statistical. In addition, these processes were divided in accordance with the way how that integration is achieved, from completely automated to email or telephone-based. CONCLUSIONS: Funds/Money related processes are technologically more rigid and standardized, whereas auditing and inspection ones are less supported by automatic systems. There emerged an interesting level of sharing and integration in clinical processes, although the integration is mostly made at the interface level. The authors identified 5 particularly relevant and dominant actors (2 classes of individuals and 3 institutions) with which there is a need for coordination and cooperation. The authors consider that, in future works, an effort should be made to provide the various institutions with guidelines/interfaces and prompt such institutions to elaborate upon these. PMID- 27999841 TI - A Novel Survey to Examine the Relationship between Health IT Adoption and Nurse Physician Communication. AB - BACKGROUND: As EHR adoption in US hospitals becomes ubiquitous, a wide range of IT options are theoretically available to facilitate physician-nurse communication, but we know little about the adoption rate of specific technologies or the impact of their use. OBJECTIVES: To measure adoption of hardware, software, and telephony relevant to nurse-physician communication in US hospitals. To assess the relationship between non-IT communication practices and hardware, software, and telephony adoption. To identify hospital characteristics associated with greater adoption of hardware, software, telephony, and non-IT communication practices. METHODS: We conducted a survey of 105 hospitals in the National Nursing Practice Network. The survey captured adoption of hardware, software, and telephony to support nurse-physician communication, along with non IT communication practices. We calculated descriptive statistics and then created four indices, one for each category, by scoring degree of adoption of technologies or practices within each category. Next, we examined correlations between the three technology indices and the non-IT communication practices index. We used multivariate OLS regression to assess whether certain types of hospitals had higher index scores. RESULTS: The majority of hospitals surveyed have a range of hardware, software, and telephony tools available to support nurse-physician communication; we found substantial heterogeneity across hospitals in non-IT communication practices. More intensive non-IT communication was associated with greater adoption of software (r=0.31, p=0.01), but was not correlated with hardware or telephony. Medium-sized hospitals had lower adoption of software (r =-1.14,p=0.04) in comparison to small hospitals, while federally owned hospitals had lower software (r=-2.57, p=0.02) and hardware adoption (r= 1.63, p=0.01). CONCLUSIONS: The positive relationship between non-IT communication and level of software adoption suggests that there is a complementary, rather than substitutive, relationship. Our results suggest that some technologies with the potential to further enhance communication, such as CPOE and secure messaging, are not being utilized to their full potential in many hospitals. PMID- 27999842 TI - Reduced skin blistering in experimental epidermolysis bullosa acquisita after anti-TNF treatment. AB - Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti type VII collagen antibodies. Different reports have indicated an increased concentration of tumor necrosis factor alpha (TNF) in the serum and blister fluid of patients with subepidermal AIBDs. Furthermore, successful anti-TNF treatment has been reported for individual patients with AIBDs. Here, we show that in mice, induction of experimental EBA by repeated injections of rabbit-anti mouse type VII collagen antibodies led to increased expression of TNF in skin, as determined by real-time PCR and immunohistochemistry. To investigate if the increased TNF expression is of functional relevance in experimental EBA, we inhibited TNF function using the soluble TNF receptor fusion protein etanercept (Enbrel(r)) or a monoclonal antibody to murine TNF. Interestingly, mice receiving either of these two treatments showed significantly milder disease progression than controls. In addition, immunohistochemical staining demonstrated reduced numbers of macrophages in lesional skin in mice treated with TNF inhibitors compared to controls. Furthermore, etanercept treatment significantly reduced the disease progression in immunization-induced EBA. In conclusion, the increased expression of TNF in experimental EBA is of functional relevance, as both the prophylactic blockade of TNF and the therapeutic use of etanercept impaired the induction and progression of experimental EBA. Thus, TNF is likely to serve as a new therapeutic target for EBA and AIBDs with a similar pathogenesis. PMID- 27999843 TI - Preference of Food Saltiness and Willingness to Consume Low-Sodium Content Food in a Chinese Population. AB - OBJECTIVE: To compare the preference of food saltiness and the willingness to consume low-sodium food among hypertensive older people, non-hypertensive older people and non-hypertensive young people in a Chinese population. DESIGN: A cross sectional study based on a quota sample. Three saltiness options (low-sodium, medium-sodium and high-sodium) of soup and bread were offered to each participant who rated the taste of each food on a 5-point Likert scale. Then, the participants rated their willingness to consume the low-sodium content foods on a 5-point Likert scale, given they were informed of the benefit of the low-sodium option. Generalised linear mixed model and multiple linear regression were used to analyse the data. SETTING: Elderly centres and community centres in Hong Kong. PARTICIPANTS: Sixty hypertensive older people, 49 non-hypertensive older people and 60 non-hypertensive young people were recruited from June to August 2014. MEASUREMENTS: The tastiness score and the willingness score were the primary outcome measures. The Chinese Health Literacy Scale for Low Salt Consumption - Hong Kong population (CHLSalt-HK) was also assessed. RESULTS: The tastiness rating of the high-sodium option of soup was significantly lower than the medium sodium option (p<0.001), but there was no significant difference between the low sodium and the medium-sodium options (p=0.204). For bread, tastiness rating of the low-sodium option and the high-sodium option were significantly lower than the medium-sodium option (p<0.001 for both options). The tastiness score of soup did not have significant difference across the groups (p=0.181), but that of bread from the hypertensive older adults (p=0.012) and the non-hypertensive older adults (p=0.006) was significantly higher than the non-hypertensive young adults. Higher willingness rating to consume the low-sodium option was significantly (p<0.001) associated with higher tastiness rating of the low-sodium option of soup and bread, and weakly associated with higher health literacy of low salt intake (soup: p=0.041; bread: p=0.024). Hypertensive older adults tended to be more willing to consume the low-sodium option than non-hypertensive older adults for soup (p=0.009), there was insignificant difference between non-hypertensive older adults and non-hypertensive young adults (p=0.156). For bread, there was insignificant difference in willingness rating to consume low-sodium option (p=0.375). CONCLUSION: Older people are at a higher risk of hypertension, reduction of salt intake is important for them to reduce their risk of cardiovascular diseases. There is room for reducing the sodium content of soup, while the sodium in bread should be reduced progressively. Improving the taste of low-sodium food may help to promote reduction in dietary sodium intake. PMID- 27999844 TI - Dietary Variety and Decline in Lean Mass and Physical Performance in Community Dwelling Older Japanese: A 4-year Follow-Up Study. AB - OBJECTIVES: To examine associations of dietary variety with changes in lean mass and physical performance during a 4-year period in an elderly Japanese population. DESIGN: Four-year prospective study. SETTING: The Hatoyama Cohort Study and Kusatsu Longitudinal Study, Japan. PARTICIPANTS: 935 community-dwelling Japanese aged 65 years or older. MEASUREMENTS: Dietary variety was assessed using a 10-item food frequency questionnaire. Body composition was determined by multifrequency bioelectrical impedance analysis, and physical performance (grip strength and usual gait speed) was measured in surveys at baseline and 4 years later. Longitudinal analysis included only participants who were originally in the upper three quartiles of lean body mass, appendicular lean mass, grip strength, and usual gait speed. The outcome measures were decline in lean body mass, appendicular lean mass, grip strength, and usual gait speed, defined as a decrease to the lowest baseline quartile level at the 4-year follow-up survey. Associations of dietary variety with the outcome measures were examined by logistic regression analysis adjusted for potential confounders. RESULTS: In the fully adjusted model, the odds ratios for decline in grip strength and usual gait speed were 0.43 (95% confidence interval, 0.19-0.99) and 0.43 (confidence interval, 0.19-0.99), respectively, for participants in the highest category of dietary variety score as compared with those in the lowest category. Dietary variety was not significantly associated with changes in lean body mass or appendicular lean mass. CONCLUSION: Among older adults, greater dietary variety may help maintain physical performance, such as grip strength and usual gait speed, but not lean mass. PMID- 27999845 TI - Formal and Informal Care of Community-Living Older People: A Population-Based Study from the Swedish National Study on Aging and Care. AB - OBJECTIVES: Study formal and informal care of community-living older people in the Swedish National study of Aging and Care (SNAC). DESIGN: Cross-sectional, population based cohort. SETTING: Three areas in Sweden: Municipality of Nordanstig, Stockholm and Skane County. PARTICIPANTS: 3,338 persons >=72 years. MEASUREMENTS: Patterns and amounts of informal and formal care by cognition and area of residence. RESULTS: 73% received no care; 14% formal care; and 17% informal care (7% received both). In the whole study population, including those who used no care, individuals in small municipalities received 9.6 hours of informal care/month; in mid-size municipalities, 6.6; and in urban areas, 5.6. Users of informal care received 33.1 hours of informal care/month in small municipalities, 54.6 in mid-size municipalities and 36.1 in urban areas. Individuals with cognitive impairment received 14.1 hours of informal care/month, 2.7 times more than people with no/slight impairment. In the whole study population, individuals in small municipalities received an average of 3.2 hours of formal care/month; in mid-size municipalities 1.4; and in urban areas, 2.6. Corresponding figures for formal care users were 29.4 hours in small municipalities, 13.6 in mid-size municipalities and 16.7 in urban areas. Formal care users received 7.1 hours, and informal care users, 5.9 hours for each hour/month received by people in the study population as a whole. CONCLUSIONS: More informal than formal care was provided. Informal care is more frequent in small municipalities than urban areas and for those with than without cognitive impairment. The relationship between data on the whole population and the data on users or care indicates that population-based data are needed to avoid overestimates of care. PMID- 27999846 TI - Comparison of Nutritional Status in the Elderly According to Living Situations. AB - AIM: This study aimed to evaluate the nutritional status of elderly individuals living alone and with their families. PARTICIPANTS AND METHOD: The sample of the study included 872 elderly individuals who agreed to participate in the study, were aged 65 or over, and lived in Ankara. The data were gathered from a survey, using face-to-face interviews. The Mini Nutritional Assessment (MNA) was used in evaluating each individual's nutrition. RESULTS: The rate of malnutrition in the study population was 5% while the malnutrition risk was 67%. The rate of malnutrition in the individuals living alone was found to be higher than that of those living with their families. The rates of malnutrition in individuals living alone and with their families were, respectively, 7% and 4%, and the rates of malnutrition risk in individuals living alone and with their families were, respectively, 73% and 66% (p<0.05). In both groups, there were significant relationships between individuals' ages, BMI values, mid-upper arm circumference (MUAC), and calf circumference measurements and their MNA scores. While there was a negative and significant relationship between age and MNA scores, the relationships between other parameters and MNA scores were positive and significant (p<0.01). CONCLUSION: In this study, it was revealed that the nutrition of elderly individuals living alone differs from the nutrition of elderly individuals living with their families. Malnutrition rates were higher in individuals living alone. Raising the awareness of elderly people and their families regarding the need to improve and maintain nutrition would be beneficial. PMID- 27999847 TI - Tube Feeding among Elder in Long-Term Care Facilities: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The use of tube feeding for elderly patients with poor nutritional intake is a ubiquitous method of feeding. This systematic review and meta analysis were carried out to compare nutritional benefits of enteral feeding versus oral feeding in long-term care facilities. SETTING: Databases including the Cochrane Library, ProQuest, PubMed, EMBASE, EBSCO, Web of Science and Google Scholar through April 2014 using keywords including enteral feeding, tube feeding or oral feeding combined with long term care facilities or nursing home. PARTICIPANTS: Eight articles, with 841 participants were included in meta analysis and 13 articles were included in systematic review. The elderly had to live in long-term care institutions and could not be on any mechanically assisted ventilation systems or be in any type of post-operative status. MEASUREMENTS: The three investigators extracted and appraised data using the same study design, baseline characteristics, and outcomes, independently. RESULTS: Following a systematic review, 13 articles out of 8218 original research articles were selected for this analysis. Meta-analysis of tube-fed patients found lower levels of hemoglobin (Weighted Mean Difference (WMD -0.21g/dl; 95% CI -0.42 to -0.01; p=0.04) and creatinine (WMD -0.08g/dl; 95% CI -0.17 to 0.00, p=0.05). Moreover, the results showed that there were no benefits regarding body mass index (BMI), albumin, dietary intake of proteins, total calories and fat. CONCLUSIONS: The results show that tube feeding does not increase patients' nutrients absorption to improve nutritional status. Instead, these results indicate that oral feeding is better regarding some nutritional biochemical parameters. PMID- 27999848 TI - Trajectories of Nutritional Status and Cognitive Impairment among Older Taiwanese with Hip Fracture. AB - OBJECTIVE: This paper describes the trajectories of nutritional status and cognitive impairment and their correlation among older Taiwanese over 1 year after hip-fracture surgery. DESIGN: Secondary analysis of data from a clinical trial evaluating the effects of three types of post-discharge care for 292 older hip-fracture patients (age >60 years). MEASUREMENTS: Nutritional status was assessed by the Mini Nutritional Assessment before and 1, 3, 6, 12 months after hospital discharge. Cognitive function was measured by the Mini-Mental State Examination before surgery, at hospital discharge, 6 and 12 months after discharge. Trajectories of nutritional status and cognitive impairment were depicted by latent class growth modeling, whereas linkages between nutritional status and cognitive-impairment trajectories were assessed by multinomial logistic regression. RESULTS: Nutritional status in general improved significantly, particularly during the first 3 months after discharge. We identified three trajectories of nutritional status: malnourished (15.4%), at risk for malnutrition (38.9%), and well-nourished (45.7%). In contrast, cognitive changes followed four largely linear but distinct trajectories: moderately impaired (12.2%), mildly impaired (27.8%), borderline impaired (21.8%), and cognitively intact (38.2%). Trajectories of nutritional status were significantly associated with cognitive-function trajectories. For instance, relative to malnourished patients, well-nourished patients were 95% less likely (OR=0.05, CI =0.01-0.24) to be moderately cognitively impaired. CONCLUSION: A good nutritional status trajectory after hip fracture was associated with better cognitive function. To treat and care for elderly hip-fractured patients, specific interventions need to target those who are malnourished or at risk of malnutrition to decrease their risk for cognitive impairment. PMID- 27999849 TI - Dietary Supplement Use in Older People Attending Memory Clinics in Australia. AB - BACKGROUND: Dietary supplement use is common in older adults. There has been limited research in people attending memory clinics. OBJECTIVES: To explore the use of dietary supplements in older people attending Australian memory clinics. DESIGN: Cross-sectional analysis of baseline data from the Prospective Research In MEmory clinics (PRIME) study. PARTICIPANTS: Community-dwelling older people who attended nine memory clinics and had a diagnosis of mild cognitive impairment (MCI) or dementia. MEASUREMENTS: Dietary supplement was defined as a product that contains one or more: vitamin, mineral, herb or other botanical, amino acid or other dietary substance. Non-prescribed supplement was defined as a supplement that is not usually prescribed by a medical practitioner. Polypharmacy was defined as use of five or more medications. RESULTS: 964 patients, mean age 77.6 years, were included. Dietary supplements were used by 550 (57.1%) patients; 353 (36.6%) used two or more. Non-prescribed supplements were used by 364 (36.8%) patients. Supplement use was associated with older age (OR: 1.12, 95% CI: 1.03 1.21), lower education level (OR: 1.53, 95% CI: 1.01-2.32) and a diagnosis of MCI rather than dementia (OR: 1.52, 95% CI: 1.05-2.21). Potential drug-supplement interactions were identified in 107 (11.1%) patients. Supplement users had increased prevalence of polypharmacy compared to non-users (80.5% vs. 48.1%, p<0.001). CONCLUSIONS: Dietary supplements, including non-prescribed supplements, were commonly used by people attending memory clinics. Supplement use increased the prevalence of polypharmacy and resulted in potential supplement-drug interactions. Further research is required to assess the clinical outcomes of supplement use. PMID- 27999850 TI - Omega-3 Fatty Acids and Vitamin D in Immobilisation: Part A- Modulation of Appendicular Mass Content, Composition and Structure. AB - OBJECTIVES: Muscle size decreases in response to short-term limb immobilisation. This study set out to determine whether two potential protein-sparing modulators (eicosapentaenoic acid and vitamin D) would attenuate immobilisation-induced changes in muscle characteristics. DESIGN: The study used a randomised, double blind, placebo-controlled design. SETTING: The study took part in a laboratory setting. PARTICIPANTS: Twenty-four male and female healthy participants, aged 23.0+/-5.8 years. INTERVENTION: The non-dominant arm was immobilised in a sling for a period of nine waking hours a day over two continuous weeks. Participants were randomly assigned to one of three groups: placebo (n=8, Lecithin, 2400 mg daily), omega-3 (omega-3) fatty acids (n=8, eicosapentaenoic acid (EPA); 1770 mg, and docosahexaenoic acid (DHA); 390 mg, daily) or vitamin D (n=8, 1,000 IU daily). MEASUREMENTS: Muscle and sub-cutaneous adipose thickness (B-mode ultrasonography), body composition (DXA) and arm girth (anthropometry) were measured before immobilisation, immediately on removal of the sling and two weeks after re-mobilisation. RESULTS: Muscle thickness (-5.4+/-4.3%), upper and lower arm girth (-1.3+/-0.4 and -0.8+/-0.8%, respectively), lean mass (-3.6+/-3.7%) and bone mineral content (BMC) (-2.3+/-1.5%) decreased significantly with limb immobilisation in the placebo group (P<0.05). Despite no significant effect of group, omega-3 and vitamin D supplementation showed trends (p>0.05) towards attenuating the decreases in muscle thickness, upper/lower arm girths and BMC observed in the placebo group. The omega-3 supplementation group demonstrated a non-significant attenuation of the decrease in DXA quantified lean mass observed in the placebo group. Sub-cutaneous adipose thickness increased in the placebo group (P<0.05). omega-3 and vitamin D both blunted this response, with omega-3 having a greater effect (P<0.05). All parameters had returned to baseline values at the re-mobilisation phase of the study. CONCLUSION: Overall, at the current doses, omega-3 and vitamin D supplementation only attenuated one of the changes associated with non-injurious limb immobilisation. These findings would necessitate further research into either a) supplementation linked to injury induced immobilisation, or b) larger doses of these supplements to confirm/refute the physiological reserve potential of the two supplements. PMID- 27999851 TI - Omega-3 Fatty Acids and Vitamin D in Immobilisation: Part B- Modulation of Muscle Functional, Vascular and Activation Profiles. AB - OBJECTIVES: This study set out to determine whether two potential protein-sparing modulators (eicosapentaenoic acid and vitamin D) would modulate the anticipated muscle functional and related blood vessels function deleterious effects of immobilisation. DESIGN: The study used a randomised, double-blind, placebo controlled design. SETTING: The study took part in a laboratory setting. PARTICIPANTS: Twenty-four male and female healthy participants, aged 23.0+/-5.8 years. INTERVENTION: The non-dominant arm was immobilised in a sling for a period of nine waking hours a day over two continuous weeks. Participants were randomly assigned to one of three groups: placebo (n=8, Lecithin, 2400 mg daily), omega-3 (omega-3) fatty acids (n=8, eicosapentaenoic acid (EPA); 1770 mg, and docosahexaenoic acid (DHA); 390 mg, daily) or vitamin D (n=8, 1,000 IU daily). MEASUREMENTS: Isometric and isokinetic torque, antagonist muscle co-contraction (activation profile), muscle fatigability indices, and arterial resting blood flow were measured before, at the end of the immobilisation period, and two weeks after re-mobilisation. RESULTS: Muscle elbow flexion and extension isometric and isokinetic torque decreased significantly with limb immobilisation in the placebo group (P<0.05). Despite no significant effect of supplementation, omega-3 and vitamin D supplementation showed trends (P>0.05) towards attenuating the decreases observed in the placebo group. There was no significant change in muscle fatigue parameters or co-contraction values with immobilisation and no effect of supplementation group (P>0.05). Similarly, this immobilisation model had no impact on the assessed blood flow characteristics. All parameters had returned to baseline values at the re-mobilisation phase of the study. CONCLUSION: Overall, at the current doses, neither omega-3 nor vitamin D supplementation significantly attenuated declines in torque associated with immobilisation. It would appear that muscle function (described here in Part B) might not be as useful a marker of the effectiveness of a supplement against the impact of immobilisation compared to tissue composition changes (described in Part A). PMID- 27999852 TI - Effect of a High-Protein Energy-Restricted Diet Combined with Resistance Training on Metabolic Profile in Older Individuals with Metabolic Impairments. AB - Adequate protein intake and resistance training are effective strategies to maintain muscle mass, but the effect of their combination on metabolic profile during weight loss remains to be determined in older adults. The main objective of this study was to determine the effect of a 16-week high-protein caloric restriction combined with resistance training on chronic disease risk factors in obese older individuals with metabolic impairments. A total of 26 overweight adults aged between 60 and 75 years (BMI 32.4 +/- 3.9 kg/m2) with at least 2 factors of the metabolic syndrome participated in this study and were randomized into two groups: 1) high-protein caloric restriction (HP; n= 12) and 2) high protein caloric restriction combined with dynamic-resistance training (HP+RT; n=14). Caloric intake was reduced by 500 kcal/d in all participants and protein intake equated 25-30% of total calories (~1.4 g/kg/d). Exercise training consisted of 3 session/week of resistance training on pulley machines. Outcome measures included total and trunk fat mass (FM), total and appendicular lean body mass (LBM), fasting glucose level, lipid profile and blood pressure. Our results showed that total and trunk FM (all p<0.0001) as well as fasting glucose (p<0.0001), triglycerides (p=0.002) and total cholesterol (p=0.03) levels decreased similarly in both groups. However, total (p=0.04) and appendicular (p=0.02) LBM decreased in the HP group only. Our data show that high-protein energy restriction improves health profile of obese elderly at high risk of chronic disease but needs to be combined with resistance training to maintain LBM. PMID- 27999853 TI - Nutritional Follow-Up after Discharge Prevents Readmission to Hospital - A Randomized Clinical Trial. AB - OBJECTIVE: To compare the effects of two individualized nutritional follow-up intervention strategies (home visit or telephone consultation) with no follow-up, with regard to acute readmissions to hospital at two points in time, 30 and 90 days after discharge from hospital. DESIGN: Randomized clinical trial with two intervention groups and one control group, and monitoring on readmission at 30 and 90 days after discharge. SETTING: Intervention in the participants' homes after discharge from hospital. PARTICIPANTS: Inclusion: Malnourished geriatric patients and patients at risk of malnutrition (MNA<24), aged 75 years and older, living at home and alone. Exclusion: Nursing home residents and patients with terminal illnesses or cognitive impairment. Randomization: Upon discharge, the patients were stratified according to nutritional status (MNA), and assigned to one of three groups: 'home visit', 'telephone', or 'control' group. INTERVENTION: Individualized nutritional counselling of the patient and the patient's daily home carer by a clinical dietician one, two, and four weeks after discharge from hospital. The counselling was either in-person at the patient's homes, or over the telephone. All patients received a diet plan on discharge. The control group received standard care, but no follow-up after discharge. MEASUREMENTS: Information on readmissions to hospital and mortality at 30 and 90 days after discharge was obtained from electronic patient records. Intention-to-treat (ITT) and per-protocol (PP) analyses were carried out. RESULTS: Two-hundred and eight participants were randomized, 73 to home visits, 68 to the telephone consultation group, and 67 to the control group. The mean age of the participants was 86.1 years. Home visit participants had a lower risk of readmission to hospital compared to control participants at 30 days after discharge (HR=0.4; 95% CI: 0.2 0.9, p=0.03) and 90 days after discharge (HR=0.4; 95% CI: 0.2-0.8, p<0.01). No significant difference was detected between the telephone consultation group and the control group, at either 30 days (HR=0.6, 95% CI: 0.3-1.3, p=0.18) or 90 days after discharge (HR=0.7, 95% CI: 0.4-1.3, p=0.23). The PP analysis revealed that the risk of readmission was significantly lower in the home visit group compared to the control group and the telephone consultation group compared to the control group, and this was evident at 30 days as well as at 90 days after discharge. CONCLUSION: An individualized nutritional follow-up performed as home visits seems to reduce readmission to hospital 30 and 90 days after discharge. Intervention by telephone consultations may also prevent readmission, but only among participants who receive the full intervention. PMID- 27999854 TI - Epidemiology and Postoperative Outcomes of Atypical Femoral Fractures in Older Adults: A Systematic Review. AB - OBJECTIVE: To review the literature on epidemiology and postoperative outcomes particularly surgical, functional and quality of life of atypical femoral fractures (AFFs) in the older population (aged >=65 years) using the first and second American Society of Bone Mineral Research (ASBMR) Task Force consensus definition. METHODS: Electronic search for articles on AFFs and bisphosphonates published in English was performed. Eligible studies were reviewed systematically in relation to (a) the epidemiology of AFFs in older people and (b) postoperative outcomes of AFFs. RESULTS: Twenty-three studies on AFFs were included: 14 on epidemiology and 11 on treatment outcomes (two articles reported on both aspects). The epidemiological studies showed that the incidence of AFFs is low (3.0-9.8 per 100,000 person-years) but relative risk increased with longer duration of bisphosphonates use, especially after more than three years. Most cases of AFFs occurred in older people aged 65 years and above. However, in six studies, the mean age of patients with bisphosphonate-related AFFs is younger than those with typical proximal femoral fractures (mean age range of 66-75 years versus 75-89 years respectively). Varying postoperative and functional outcomes have been reported but differences in study population, management approaches and endpoints may account for these variations. For incomplete AFFs, prophylactic surgical intervention is potentially beneficial. CONCLUSION: The benefits of bisphosphonates in reducing osteoporotic fractures still outweigh the risk of AFFs in view of its low absolute risk, when the ASBMR Task Force criteria for this type of fracture were applied. The risk of AFFs in different age groups is not well defined but tends to affect the younger patients more (aged <65 years) as compared to the older population (aged >=65 years). Evidence supporting different types of treatment in AFFs such as intramedullary or extramedullary surgical devices and the use of teriparatide, a parathyroid hormone analogue, is not yet well established. PMID- 27999856 TI - Predictors of Health-Related Quality of Life Decline after Transcatheter Aortic Valve Replacement in Older Patients with Severe Aortic Stenosis. AB - BACKGROUND: Transcatheter aortic-valve implantation (TAVI) has been shown to improve survival and quality of life in patients with severe aortic stenosis. However, one-third of patients have poor outcome as death, functional decline or quality of life (QoL) decline. The aim of this study was to determine cardiac and geriatric predictors of physical and mental QoL decline 6 months after a TAVI procedure in patients aged 75 and older. METHODS: Between January 2013 and June 2014, we did a prospective and multicenter study including patients >= 75 years old referred for TAVI. The primary outcome was the measure of QoL, assessed by the Short Form 36 survey (SF-36), before and 6 months after the intervention. Association between QoL decline and baseline characteristics including cardiac and geriatric factors was analysed by logistic regression models. RESULTS: Mean age of the 150 patients studied was 83.7 years old and 56% were men. The primary end point, mean SF-36 physical summary score, significantly improved between baseline and 6-month (33.6 vs. 36.4, p=0.003) whereas mental component score significantly decreased (48.2 vs. 36.4, p-value<0.001). However, patients with presence of depressive symptoms before the intervention had mental QoL improvement at six months (OR 0.04 [0.01-0.19], p-value<0.001) and no significant geriatric predictors were associated with physical QoL decline. CONCLUSION: The mental QoL significantly decreased and patients with preoperative depressive symptoms had mental QoL improvement at six months. Researches are needed to confirm that mental QoL of patients with depressive symptoms can be improved by TAVI. PMID- 27999857 TI - Association of Dynamics in Lean and Fat Mass Measures with Mortality in Frail Older Women. AB - OBJECTIVE: The relationship between body composition and mortality in frail older people is unclear. We used dual-x-ray absorptiometry (DXA) data to examine the association between dynamics in whole-body composition and appendicular (4 limbs) and central (trunk) compartments and all-cause mortality in frail older women. DESIGN: Prospective study with up to 19 years of follow up. SETTING: Community dwelling older (>=65) women. PARTICIPANTS: 876 frail older participants of the Women's Health Initiative Observational Study with a single measure of body composition and 581 participants with two measures. MEASUREMENTS: Frailty was determined using modified Fried's criteria. All-cause mortality hazard was modeled as a function of static (single-occasion) or dynamic changes (difference between two time points) in body composition using Cox regression. RESULTS: Analyses adjusted for age, ethnicity, income, smoking, cardiovascular disease, diabetes, stroke, number of frailty criteria and whole-body lean mass showed progressively decreased rates of mortality in women with higher appendicular fat mass (FM) (P for trend=0.01), higher trunk FM (P for trend=0.03) and higher whole body FM (P for trend=0.01). The hazard rate ratio for participants with more than a 5% decline in FM between two time points was 1.91; 1.67 and 1.71 for appendicular, trunk and whole-body compartment respectively as compared to women with relatively stable adiposity (p<0.05 for all). Dynamics of more than 5% in lean mass were not associated with mortality. CONCLUSION: Low body fat or a pronounced decline in adiposity is associated with increased risks of mortality in frail older women. These results indicate a need to re-evaluate healthy weight in persons with frailty. . PMID- 27999859 TI - Special Section Guest Editorial: Translational biophotonics. PMID- 27999858 TI - Frailty Syndrome: Visceral Adipose Tissue and Frailty in Patients with Symptomatic Severe Aortic Stenosis. AB - BACKGROUND/OBJECTIVES: In patients with severe aortic stenosis (AS), frailty is a clinically relevant measure of increased vulnerability that should be included in the preoperative risk assessment. Bioelectrical impedance analysis (BIA) derived phase angle (PA) reflects cell membrane integrity and function. Few studies are available on the relative contribution of adiposity distribution on frailty, and about the influences of frailty and visceral obesity in PA value. Therefore, we aimed to evaluate associations among frailty, visceral fat depots and PA in patients with symptomatic severe AS. METHODS: In a cohort of patients with symptomatic severe AS and preserved ejection fraction, we examined the associations between frailty, visceral fat depots and bioelectrical impedance analysis (BIA) derived phase angle (PA); and between visceral fat and PA. Frailty was defined according the Fried et al. scale criteria and the body fat distribution was determined by multidetector computed tomography and by BIA. RESULTS: Of the fifty-five included patients, 26 were frail (47%). Adjusting for age and gender, frailty was associated with indexed epicardial adipose tissue volume (EATVi) (the odds of frailty increased 4.1-fold per additional 100 cm3/m2 of EAT [95% confidence interval (CI) of 1.03 to 16.40, p=0.04] and with PA (OR of 0.50, 95% CI, 0.26 to 0.97, p=0.04), but not with body mass index (BMI), waist circumference (WC), indexed total, visceral and subcutaneous abdominal fat areas (TAFAi, VAFAi and SAFAi) nor with indexed mediastinal adipose tissue volume (MATVi). In an age and gender adjusted linear model, PA was inversely correlated with EATVi (beta=-0.008, 95% CI, -0.016 to -0.001, p=0.03), but not with BMI, WC, nor with MATVi, VAFAi, SAFAi and TAFAi. CONCLUSIONS: In patients with symptomatic severe AS, EATVi is associated with frailty, independently of age and gender, but not with MAFVi or VAFAi. Moreover, frailty and EATVi are associated with impaired cell membrane integrity and function assessed by PA. PMID- 27999860 TI - Fluorescence confocal endomicroscopy of the cervix: pilot study on the potential and limitations for clinical implementation. AB - Current diagnostic capabilities and limitations of fluorescence endomicroscopy in the cervix are assessed by qualitative and quantitative image analysis. Four cervical tissue types are investigated: normal columnar epithelium, normal and precancerous squamous epithelium, and stromal tissue. This study focuses on the perceived variability within and the subtle differences between the four tissue groups in the context of endomicroscopic in vivo pathology. Conclusions are drawn on the general ability to distinguish and diagnose tissue types, on the need for imaging depth control to enhance differentiation, and on the possible risks for diagnostic misinterpretations. PMID- 27999861 TI - Structural modifications induced in dentin by femtosecond laser. AB - The structural and chemical modifications induced in dentin by ultrafast laser ablation were studied. The laser experiments were performed with a Yb:KYW chirped pulse-regenerative amplification laser system (560-fs pulse duration, 1030-nm radiation wavelength), fluences in the range 2 to 14 ?? J / cm 2 , 1-kHz pulse repetition rate, and 5 - mm / s scanning speed. The ablation surfaces were characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. The ablation surfaces produced with 2 ?? J / cm 2 presented an irregular morphology with exposed dentinal tubules and no evidence of thermal effects. For 7 and 14 ?? J / cm 2 , the ablation surfaces were covered by a layer of redeposited ablation debris, consisting mainly of amorphous calcium phosphate. This layer is weakly adherent to the underlying tissue and can be easily removed by ultrasonication, revealing a surface with a morphology similar to the one obtained with 2 ?? J / cm 2 . The constitution of the dentin ablation surfaces is similar to the constitution of pristine dentin, showing that, within this fluence range, the laser treatment does not significantly modify the structure and constitution of dentin. The results achieved suggest an ablation mechanism where collagen is preferentially decomposed by the laser radiation, reducing the tissue cohesive strength and leading, ultimately, to its ablation. PMID- 27999862 TI - Self-guided reconstruction for time-domain fluorescence molecular lifetime tomography. AB - Fluorescence probes have distinct yields and lifetimes when located in different environments, which makes the reconstruction of fluorescence molecular lifetime tomography (FMLT) challenging. To enhance the reconstruction performance of time domain (TD) FMLT with heterogeneous targets, a self-guided L 1 regularization projected steepest descent (SGL1PSD) algorithm is proposed. Different from other algorithms performed in time domain, SGL1PSD introduces a time-resolved strategy into fluorescence yield reconstruction. The algorithm consists of four steps. Step 1 reconstructs the initial yield map with full time gate strategy; steps 2-4 reconstruct the inverse lifetime map, the yield map, and the inverse lifetime map again with time-resolved strategy, respectively. The reconstruction result of each step is used as a priori for the reconstruction of the next step. Projected iterated Tikhonov regularization algorithm is adopted for the yield map reconstructions in steps 1 and 3 to provide a solution with iterative refinement and nonnegative constraint. The inverse lifetime map reconstructions in steps 2 and 4 are based on L 1 regularization projected steepest descent algorithm, which employ the L 1 regularization to reduce the ill-posedness of the high-dimensional nonlinear problem. Phantom experiments with heterogeneous targets at different edge-to-edge distances demonstrate that SG PMID- 27999855 TI - Building Bridges for Innovation in Ageing: Synergies between Action Groups of the EIP on AHA. AB - The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases). PMID- 27999863 TI - Diffuse shear wave imaging: toward passive elastography using low-frame rate spectral-domain optical coherence tomography. AB - Optical coherence tomography (OCT) can map the stiffness of biological tissue by imaging mechanical perturbations (shear waves) propagating in the tissue. Most shear wave elastography (SWE) techniques rely on active shear sources to generate controlled displacements that are tracked at ultrafast imaging rates. Here, we propose a noise-correlation approach to retrieve stiffness information from the imaging of diffuse displacement fields using low-frame rate spectral-domain OCT. We demonstrated the method on tissue-mimicking phantoms and validated the results by comparison with classic ultrafast SWE. Then we investigated the in vivo feasibility on the eye of an anesthetized rat by applying noise correlation to naturally occurring displacements. The results suggest a great potential for passive elastography based on the detection of natural pulsatile motions using conventional spectral-domain OCT systems. This would facilitate the transfer of OCT-elastography to clinical practice, in particular, in ophthalmology or dermatology. PMID- 27999864 TI - Recovering fluorophore concentration profiles from confocal images near lateral refractive index step changes. AB - Optical aberrations due to refractive index mismatches occur in various types of microscopy due to refractive differences between the sample and the immersion fluid or within the sample. We study the effects of lateral refractive index differences by fluorescence confocal laser scanning microscopy due to glass or polydimethylsiloxane cuboids and glass cylinders immersed in aqueous fluorescent solution, thereby mimicking realistic imaging situations in the proximity of these materials. The reduction in fluorescence intensity near the embedded objects was found to depend on the geometry and the refractive index difference between the object and the surrounding solution. The observed fluorescence intensity gradients do not reflect the fluorophore concentration in the solution. It is suggested to apply a Gaussian fit or smoothing to the observed fluorescence intensity gradient and use this as a basis to recover the fluorophore concentration in the proximity of the refractive index step change. The method requires that the reference and sample objects have the same geometry and refractive index. The best results were obtained when the sample objects were also used for reference since small differences such as uneven surfaces will result in a different extent of aberration. PMID- 27999866 TI - Low-cost multimodal light sheet microscopy for optically cleared tissues and living specimens. AB - Light sheet microscopy techniques have expanded with designs to address many new applications. Due to rapid advancements in computing power, camera/detector technologies, and tissue clearing techniques, light sheet methods are becoming increasingly popular for biomedical imaging applications at the cellular and tissue levels. Light sheet imaging modalities couple rapid imaging rates, low levels of phototoxicity, and excellent signal to noise ratios, contributing to their popularity for experimental biology. However, the current major limitation of light sheet microscopy arises from optical aberrations, with the main drawback being the defocusing introduced by refractive index variations that accompany clearing techniques. Here, we propose an inexpensive and easy to build light sheet based instrumentation to overcome this limitation by optomechanically decoupling the sample scanning movement from the detection step. Our solution is relatively simple to implement and also provides increased modularity by using a swappable excitation arm. This expands the range of samples we can image on a single system, from high resolution for single cells at ? m spatial resolution, to tissues with mm spatial resolution. We demonstrate our approach, using the system to image iDISCO cleared embryos and sciatic nerves, and provide the full three-dimensional reconstruction of these objects in minutes. PMID- 27999867 TI - ? PMID- 27999865 TI - Vulnerable atherosclerotic plaque detection by resonance Raman spectroscopy. AB - A clear correlation has been observed between the resonance Raman (RR) spectra of plaques in the aortic tunica intimal wall of a human corpse and three states of plaque evolution: fibrolipid plaques, calcified and ossified plaques, and vulnerable atherosclerotic plaques (VPs). These three states of atherosclerotic plaque lesions demonstrated unique RR molecular fingerprints from key molecules, rendering their spectra unique with respect to one another. The vibrational modes of lipids, cholesterol, carotenoids, tryptophan and heme proteins, the amide I, II, III bands, and methyl/methylene groups from the intrinsic atherosclerotic VPs in tissues were studied. The salient outcome of the investigation was demonstrating the correlation between RR measurements of VPs and the thickness measurements of fibrous caps on VPs using standard histopathology methods, an important metric in evaluating the stability of a VP. The RR results show that VPs undergo a structural change when their caps thin to 66 ?? ? m , very close to the 65 - ? m empirical medical definition of a thin cap fibroatheroma plaque, the most unstable type of VP. PMID- 27999868 TI - [Phase II study with metastatic castration-resistant prostate cancer (mCRPC) patients]. PMID- 27999869 TI - [The ASA Classification - solid like a rock in anesthesiology]. PMID- 27999870 TI - [Progressive induration of the skin with rough papules]. PMID- 27999872 TI - [Whole-genome sequencing in German clinical practice : Economic impacts of its use in selected areas of application]. AB - BACKGROUND: The diagnostic use of whole-genome sequencing (WGS) is a growing issue in medical care. Due to limited resources in public health service, budget impact analyses are necessary prior to implementation. OBJECTIVE: A budget-impact analysis for WGS of all newborns and diagnostic investigation of tumor patients in different oncologic indications were evaluated. METHODS: A cost analysis of WGS based on a quality-assured process chart for WGS at the German Cancer Research Center (DKFZ), Heidelberg, constitutes the basis for this evaluation. Data from the National Association of Statutory Health Insurance Funds and the Robert-Koch-Institute, Berlin, were used for calculations of specific clinical applications. RESULTS AND DISCUSSION: WGS in newborn screening leads to costs of ? 2.85 bn and to an increase of total expenditure by 1.41%. Sequencing of all tumor patients would cost approximately ? 0.84 bn, which corresponds to 0.42% of total expenditures. In all scenarios, the sole consideration of procedure costs results in increasing costs. However, in cost discussions potential savings (reduction of disease-related follow-up-costs, improved cost-effectiveness of medical measures etc.) should be considered. Such considerations are the subject of economic indication-specific evaluations. WGS has the potential to generate a large number of deterministic findings for which treatment options are limited. Hence, it is necessary to limit indications, in which WGS has proven medical evidence. PMID- 27999871 TI - Loss of prohormone convertase 2 promotes beta cell dysfunction in a rodent transplant model expressing human pro-islet amyloid polypeptide. AB - AIMS/HYPOTHESIS: A contributor to beta cell failure in type 2 diabetes and islet transplants is amyloid formation by aggregation of the beta cell peptide, islet amyloid polypeptide (IAPP). Similar to the proinsulin processing pathway that generates insulin, IAPP is derived from a prohormone precursor, proIAPP, which requires cleavage by prohormone convertase (PC) 1/3 and PC2 in rodent pancreatic beta cells. We hypothesised that loss of PC2 would promote beta cell death and dysfunction in a rodent model of human beta cell proIAPP overexpression. METHODS: We generated an islet transplant model wherein immune-deficient mouse models of diabetes received islets expressing amyloidogenic human proIAPP and lacking PC2, leading to restoration of normoglycaemia accompanied by increased secretion of human proIAPP. Blood glucose levels were analysed for up to 16 weeks in transplant recipients and grafts were assessed for islet amyloid and beta cell number and death. RESULTS: Hyperglycaemia (blood glucose >16.9 mmol/l) returned in 94% of recipients of islets expressing human proIAPP and lacking PC2, whereas recipients of islets that express human proIAPP and normal PC2 levels remained normoglycaemic for at least 16 weeks. Islet graft failure was accompanied by a ~20% reduction in insulin-positive cells, yet the degree of amyloid deposition and beta cell apoptosis was similar to those of controls expressing human proIAPP with functional PC2 levels. CONCLUSIONS/INTERPRETATION: PC2 deficiency in transplanted mouse islets expressing human proIAPP promotes beta cell loss and graft failure. Our data suggest that impaired NH2-terminal processing and increased secretion of human proIAPP promote beta cell failure. PMID- 27999873 TI - Spinal osteoid osteoma progressed to osteoblastoma with paraspinal soft tissue mass: a unique presentation. AB - Osteoid osteoma and osteoblastoma are rare benign bone-forming tumors with very similar histological features. They are nowadays considered as two distinct entities. Progression of an osteoid osteoma to osteoblastoma is considered very rare with only a few cases reported in the literature. Herein we describe a case of an osteoid osteoma of the thoracic spine in a 29-year-old woman that was initially treated conservatively and progressed to osteoblastoma 5 years following the initial diagnosis. Imaging revealed an increase in the size of the spinal lesion that was surrounded by extensive paraspinal abnormal soft tissue that raised suspicion for sarcomatous transformation. The final diagnosis was established by CT-guided biopsy of both the bone lesion and the paraspinal soft tissue, which excluded malignancy and revealed an osteoblastoma surrounded by plasma cell-rich chronic inflammation. The patient then underwent wide surgical excision of the lesion and paraspinal soft tissue component that confirmed the diagnosis. Follow-up with MRI over the next 12 months was unremarkable, with no signs of recurrence or spinal instability. This unique presentation of an osteoblastoma has not been previously described. This case also demonstrates the importance of follow-up of osteoid osteomas that are treated conservatively. PMID- 27999875 TI - Outcomes of percutaneous nephrolithotomy in spinal cord injury patients as compared to a matched cohort. AB - Spinal cord injury patients are at increased risk of developing nephrolithiasis and may require percutaneous nephrolithotomy for treatment of large stone burdens. Our objective was to compare outcomes of PCNL in SCI patients as compared to a matched cohort of non-SCI patients. Data from the Healthcare Cost and Utilization Project State Inpatient Database for Florida and California were used to identify patients by ICD-9 codes who underwent PCNL between 2007 and 2011. SCI was identified by having a paralysis diagnosis on the chronic comorbidity indicator. One-to-one matching was performed based on age, race, gender, presence of preoperative UTI, and major comorbidities. Of the 39,868 unique patients identified, who underwent PCNL, 1918 (4.81%) were SCI patients. After matching, worse perioperative outcomes in SCI patients were demonstrated. SCI patients had significantly longer length of stay, higher rates of sepsis, and increased minor and moderate complications (p < 0.001). Multivariate analysis demonstrated an independently increased risk of mortality, minor and major complications, pneumonia, sepsis, and length of stay in SCI patients. PCNL in SCI patients is associated with a high complication rate and longer hospital stay even when controlling for presence of preoperative UTI and medical comorbidities. To our knowledge, this is the first study of outcomes of PCNL in a large population of SCI patients. These patients represent a high risk population and strategies to decrease complications need to be developed and implemented. PMID- 27999876 TI - Preface: physicochemical, biochemical and biological mechanisms of stone formation. PMID- 27999874 TI - Diversity and Assembling Processes of Bacterial Communities in Cryoconite Holes of a Karakoram Glacier. AB - Cryoconite holes are small ponds that form on the surface of glaciers that contain a dark debris, the cryoconite, at the bottom and host active ecological communities. Differences in the structure of bacterial communities have been documented among Arctic and mountain glaciers, and among glaciers in different areas of the world. In this study, we investigated the structure of bacterial communities of cryoconite holes of Baltoro Glacier, a large (62 km in length and 524 km2 of surface) glacier of the Karakoram, by high-throughput sequencing of the V5-V6 hypervariable regions of the 16S rRNA gene. We found that Betaproteobacteria dominated bacterial communities, with large abundance of genera Polaromonas, probably thanks to its highly versatile metabolism, and Limnohabitans, which may have been favoured by the presence of supraglacial lakes in the area where cryoconite holes were sampled. Variation in bacterial communities among different sampling areas of the glacier could be explained by divergent selective processes driven by variation in environmental conditions, particularly pH, which was the only environmental variable that significantly affected the structure of bacterial communities. This variability may be due to both temporal and spatial patterns of variation in environmental conditions. PMID- 27999877 TI - Influence of Road Proximity on the Concentrations of Heavy Metals in Korean Urban Agricultural Soils and Crops. AB - The urban agricultural (UA) environment near active roadways can be degraded by traffic-related particles (i.e., exhaust gases and road dust), which may contain heavy metals. The current study investigated changes in heavy-metal [cadmium (Cd), copper (Cu), chromium (Cr) nickel (Ni), lead (Pb) and zinc (Zn)] concentrations in soils located near highly trafficked roads in Korea and the subsequent uptake of these metals by Chinese cabbage. Heavy-metal plant concentrations were determined in both washed and unwashed plant leaves to determine whether foliar deposition played any role in plant metal uptake. Soil concentrations of Cd, Cu, Pb, and Zn were all lower than the Korean standard soil limits and showed no significant influence from road traffic. In contrast, both Ni and Cr concentrations in soils collected within 10 m of the road were 4 and 5 times greater, respectively, than those in soils collected 70 m from the road. Heavy-metal concentrations in unwashed Chinese cabbage leaf collected at 5 m from the road were consistently greater than those of washed leaf samples, thus indicating the deposition of traffic-related particles on the plant surface. With the exception of Cu, all heavy-metal concentration in washed plant samples collected at 5 m also showed greater accumulation compared with samples collected further away. This was mainly attributed to increased total soil heavy-metal concentrations and increased metal phytoavailability induced by decreases in soil pH near the road. However, overall heavy-metal soil concentrations were well lower than the allowable concentrations, and the levels observed in plants collected in this study were considered not to currently pose a significant risk to human health. However, some traffic-related heavy metals, in particular Cr and Ni, were being accumulated in the roadside UA environment, which may warrant some caution regarding the environment and/or health issues in the future. PMID- 27999878 TI - In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice. AB - We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale. PMID- 27999879 TI - [Perioperative patient management in orthogeriatrics]. AB - The management of major orthopedic surgery in the elderly prototypically reflects the perioperative risks of geriatric, often very frail patients reflecting an aging population. To improve outcome, the risks of anesthesia and surgery as well as of patient comorbidities must be thoroughly assessed and balanced using a multidisciplinary approach. Particular risks include cardiopulmonary morbidity, anemia, risk of hemorrhage and the management by anticoagulation, cerebral impairments as well as frailty and limited physiological reserves in general. Accordingly, an optimized therapy prior to, during, and after surgery will likely influence not only the immediate postoperative course but also hospital mortality and long-term outcome. Publications on the topic of perioperative management of geriatric patients are fortunately gaining in quality and quantity, not least against the background of the demographic developments. Accordingly, specific influencing factors relevant for perioperative management can be increasingly more identified. This short review summarizes the current state of knowledge to provide an overview and rationale for clinical decision making. PMID- 27999881 TI - Mercury Distribution Along the Food Chain of a Wetland Ecosystem at Sanjiang Plain, Northeast China. AB - Concentrations of total mercury (T-Hg) and methylmercury (MeHg) in a wetland food chain were determined at Majuan Island of the Sanjiang Plain in China. Four tissues (muscle, liver, kidney and brain) of three waterbird species (great cormorant, grey heron and great egret), muscle tissues of fish (grass carp, crucian carp and longnose gudgeon), insects (predacious diving beetle), aquatic plants (ditch reed) and soil were analyzed. The mean concentrations of T-Hg were 0.392 +/- 0.237 mg/kg for tissues of all juveniles, 1.999 +/- 2.053 mg/kg for great cormorant adults, and 0.029 +/- 0.019 mg/kg for fish muscle, respectively. While the relative contents of T-Hg of insects, plants and sediments were 0.012 +/- 0.002, 0.006 +/- 0.001 and 0.020 +/- 0.002 mg/kg, respectively. Bioaccumulation of Hg along the wetland food chain may be able to show the current situation of Hg contamination in remote regions of East Asia. PMID- 27999880 TI - [Pathomechanisms and clinical aspects of frontotemporal lobar degeneration]. AB - BACKGROUND: Frontotemporal lobar degeneration (FTLD) includes a spectrum of heterogeneous clinical and neuropathological diseases. In a strict sense this includes the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) and both variants can be associated with amyotrophic lateral sclerosis (FTD-ALS). In a broader sense FTLD also includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In recent years the strong genetic component of FTLD has become increasingly clear. OBJECTIVE: The association between clinical presentation, neuropathology, genetics and pathophysiological mechanisms of FTLD are presented. RESULTS: The diagnostic criteria and tools for the clinical differential diagnosis of FTLD are presented. At autopsy patients show neuronal and glial inclusions of Tau, TDP-43 or FUS. While Tau pathology is often associated with extrapyramidal symptoms, patients with TDP-43 and FUS inclusions often also show signs of ALS. Pathogenic mutations directly increase the aggregation propensity of these proteins or impair protein degradation through autophagy or the proteasome. Pathogenic mutations in most FTLD genes trigger cytoplasmic missorting and aggregation of the RNA-binding protein TDP-43 and thus lead to a nuclear loss of TDP-43 function. Microgliosis and mutations in GRN and TREM2 suggest an important role of neuroinflammation in FTLD. CONCLUSION: There is still no causal therapy for FTLD but preclinical studies focusing on pathogenic mutations in C9orf72, GRN and Tau may lead to clinical trials soon; therefore, establishing large well characterized patient cohorts is crucial for trial readiness. PMID- 27999882 TI - Effects of Organic Acids and Sylvite on Phytoextraction of 241Am Contaminated Soil. AB - Contamination of soil with Americium (241Am) at nuclear sites in China poses a serious problem. We screened six plants, from five families, for their 241Am enrichment potential. Europium (Eu), which is morphologically and chemically similar to the highly toxic 241Am, was used in its place. Moreover, the effects of sylvite, citric acid (CA), malic acid (MA), and humic acid (HA) on the absorption of 241Am by the plants, and its transport within them, were evaluated along with their effect on plant biomass and 241Am extraction volume. Barley and cabbage showed relatively stronger Eu accumulation capacities. Citric acid promoted the absorption of 241Am by barley roots and its transport within the plants. The effects of sylvite were not obvious and those of HA were the weakest in case of sunflower; HA, however, maximally increased the biomass of the plants. Our results could provide the basis for future radionuclide phytoremediation of contaminated soils. PMID- 27999884 TI - Frequency of high blood glucose prior to FDG PET. AB - PURPOSE: To assess the frequency of blood glucose level higher than 150 mg/dL in non-diabetic patients presenting for FDG PET. METHODS: We reviewed the electronic medical record (EMR) of all lymphoma patients who had at least one FDG PET/CT from July 1, 2014 through June 30, 2015. We extracted the blood glucose level at the time of the FDG PET during this 1-year time period and any previous PET scans these patients had. Patients' diabetic status was determined from EMR. RESULTS: One hundred seventeen patients with 574 scans were included: 91 non-diabetic with 429 scans and 26 diabetic patients with 145 scans. Blood glucose level ranged from 44 to 259 mg/dL: 44 to 144 mg/dL in non-diabetic patients and 73 to 259 mg/dL in diabetic patients. There was no non-diabetic patient with a glucose level higher than 150 mg/dL at any occasion. Only one scan was performed with 144 mg/dL of glucose. All other scans were performed with a glucose level less than 140 mg/dL. There were nine diabetic patients with glucose level less than 150 mg/dL prior to all of their scans and 17 diabetic patients with a glucose level higher than 150 mg/dL prior to PET at least on one occasion. CONCLUSIONS: In all non-diabetic patients, blood glucose level was below the lower limit of the recommended range prior to all their FDG PET scans while this was not the case in diabetic patients. We conclude that measuring blood glucose level prior to FDG PET may be limited to diabetic patients. PMID- 27999883 TI - The pharmacokinetics and pharmacodynamics of alogliptin in children, adolescents, and adults with type 2 diabetes mellitus. AB - PURPOSE: The aim of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 12.5- or 25-mg dose of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in pediatric (children and adolescents) and adult subjects with type 2 diabetes mellitus (T2DM). METHODS: A randomized, open-label, multicenter study was conducted in pediatric and adult subjects. Subjects in two pediatric groups (children and adolescents) were randomized 1:1 to receive a single oral dose of alogliptin 12.5 or 25 mg, respectively; all gender- and race matched adult subjects received alogliptin 25 mg. Blood and urine samples were collected at prespecified time points for PK/PD analyses. A PK/PD model was developed using data from the study for steady-state simulations. Safety was also assessed. RESULTS: In pediatric subjects receiving the 25-mg dose, the mean alogliptin peak plasma concentrations (Cmax) and AUC0-inf values were 26 and 23% lower, respectively, than in adults receiving the 25-mg dose, but maximum observed DPP-4 inhibition effect (Emax) and AUEC0-24 values were similar to those in adults. In pediatric subjects receiving the 12.5-mg dose, the mean alogliptin Cmax and AUC0-inf values were 58 and 54% lower, respectively, than those in adults, hence Emax and AUEC0-24 values were also lower by 11 and 17%, respectively. The PK/PD model simulated data were consistent with study results. No safety concern was found. CONCLUSIONS: A 25-mg dose of alogliptin in pediatric subjects achieved alogliptin exposures and DPP-4 inhibition similar to those in adult T2DM patients without safety concerns; therefore, this dose is recommended for a pediatric phase 3 trial. PMID- 27999885 TI - Multidetector CT enterography of focal small bowel lesions: a radiological pathological correlation. AB - Focal small bowel lesions present a diagnostic challenge for both the radiologist and gastroenterologist. Both the detection and characterization of small bowel masses have greatly improved with the advent of multidetector CT enterography (MD CTE). As such, MD-CTE is increasingly utilized in the workup of occult gastrointestinal bleeding. In this article, we review the spectrum of focal small bowel masses with pathologic correlation. Adenocarcinoma, the most common primary small bowel malignancy, presents as a focal irregular mass occasionally with circumferential extension leading to obstruction. Small bowel carcinoid tumors most commonly arise in the ileum and are characterized by avid enhancement and marked desmoplastic response of metastatic lesions. Aneurysmal dilatation of small bowel is pathognomonic for lymphoma and secondary findings of lymphadenopathy and splenomegaly should be sought. Benign small bowel masses such as leiomyoma and adenoma may be responsible for occult gastrointestinal bleeding. However, primary vascular lesions of the small bowel remain the most common cause for occult small bowel gastrointestinal bleeding. The arterial phase of contrast obtained with CTE aids in recognition of the vascular nature of these lesions. Systemic conditions such as Peutz-Jeghers syndrome and Crohn's disease may be suggested by the presence of multiple small bowel lesions. Lastly, potential pitfalls such as ingested material should be considered when faced with focal small bowel masses. PMID- 27999886 TI - Correlation between CT perfusion parameters and Fuhrman grade in pTlb renal cell carcinoma. AB - PURPOSE: To evaluate the correlation of CT perfusion parameters with the Fuhrman grade in pT1b (4-7 cm) renal cell carcinoma (RCC). METHODS: CT perfusion imaging and Fuhrman pathological grading of pT1b RCC were performed in 48 patients (10 grade 1, 27 grade 2, 9 grade 3, and 2 grade 4). Equivalent blood volume (BV Equiv), permeability surface area product (PS), and blood flow (BF) of tumors were measured. Grade 1 and 2 were defined as low-grade group (n = 37), meanwhile high-grade group (n = 11) included grade 3 and 4. Comparisons of CT perfusion parameters and tumor size of the two different groups were performed. Correlations between CT perfusion parameters, Fuhrman grade (grade 1, 2, 3, and 4), and tumor size were assessed. RESULTS: PS was significantly lower in high grade than in low-grade pT1b RCC (P = 0.004). However, no significant differences were found in BV Equiv and BF between the two groups (P > 0.05 for both). The optimal threshold value, sensitivity, specificity, and the area under the ROC curve for distinguishing the two groups using PS were 68.8 mL/100 g/min, 0.7, 0.8, and 0.8, respectively. Negative significant correlation was observed between PS and Fuhrman grade (r = -0.338, P = 0.019). CONCLUSIONS: The PS of pT1b RCC had negative significant correlation with Fuhrman grade. CT perfusion appeared to be a non-invasive means to predict high Fuhrman grade of pT1b RCC preoperatively and guide the optimal treatment for the patient. PMID- 27999887 TI - Imaging patterns and focal lesions in fatty liver: a pictorial review. AB - Non-alcoholic fatty liver disease is the most common cause of chronic liver disease and affects nearly one-third of US population. With the increasing trend of obesity in the population, associated fatty change in the liver will be a common feature observed in imaging studies. Fatty liver causes changes in liver parenchyma appearance on imaging modalities including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) and may affect the imaging characteristics of focal liver lesions (FLLs). The imaging characteristics of FLLs were classically described in a non-fatty liver. In addition, focal fatty change and focal fat sparing may also simulate FLLs. Knowledge of characteristic patterns of fatty change in the liver (diffuse, geographical, focal, subcapsular, and perivascular) and their impact on the detection and characterization of FLL is therefore important. In general, fatty change may improve detection of FLLs on MRI using fat suppression sequences, but may reduce sensitivity on a single-phase (portal venous) CT and conventional ultrasound. In patients with fatty liver, MRI is generally superior to ultrasound and CT for detection and characterization of FLL. In this pictorial essay, we describe the imaging patterns of fatty change in the liver and its effect on detection and characterization of FLLs on ultrasound, CT, MRI, and PET. PMID- 27999888 TI - Imaging of autoimmune hepatitis and overlap syndromes. AB - Autoimmune hepatitis (AIH) is an uncommon, chronic inflammatory, and relapsing liver disease of unknown origin that may lead to liver cirrhosis, hepatocellular carcinoma, liver transplantation, or death. AIH occurs in all age groups and races but can frequently manifest as acute fulminant hepatitis. Clinical presentation of AIH can have features similar to primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), and these diseases may coexist leading to overlap syndromes. Although histological diagnosis is necessary, imaging features often can demonstrate characteristics that may be helpful to distinguish these diseases. Imaging features of AIH are those of chronic liver disease, and imaging plays important role in detection of complications and ruling out other possible causes of chronic liver disease. Emerging techniques such as elastography provide non-invasive options for diagnosis of significant fibrosis and cirrhosis during clinical follow-up as well as assessment of response to treatment. In this study, we will describe imaging findings in AIH and overlap syndromes. PMID- 27999889 TI - Noise-optimized virtual monoenergetic dual-energy computed tomography: optimization of kiloelectron volt settings in patients with gastrointestinal stromal tumors. AB - PURPOSE: The aim of this study was to evaluate the impact of a noise-optimized virtual monoenergetic imaging (VMI+) reconstruction technique on quantitative and qualitative image analysis in patients with gastrointestinal stromal tumors (GISTs) at dual-energy computed tomography (DECT) of the abdomen. METHODS: Forty five DECT datasets of 21 patients (14 men; 63.7 +/- 9.2 years) with GISTs were reconstructed with the standard linearly blended (M_0.6) and VMI+ and traditional virtual monoenergetic (VMI) algorithm in 10-keV increments from 40 to 100 keV. Attenuation measurements were performed in GIST lesions and abdominal metastases to calculate objective signal-to-noise (SNR) and contrast-to-noise ratios (CNR). Five-point scales were used to evaluate overall image quality, lesion delineation, image sharpness, and image noise. RESULTS: Quantitative image parameters peaked at 40-keV VMI+ series (SNR 27.8 +/- 13.0; CNR 26.3 +/- 12.7), significantly superior to linearly blended (SNR 16.8 +/- 7.3; CNR 13.6 +/- 6.9) and all VMI series (all P < 0.001). Qualitative image parameters were highest for 60-keV VMI+ reconstructions regarding overall image quality and image sharpness (median 5, respectively; P <= 0.023). Qualitative assessment of lesion delineation peaked in 40 and 50-keV VMI+ series (median 5, respectively). Image noise was superior in 90 and 100-keV VMI and VMI+ reconstructions (all medians 5). CONCLUSIONS: Low-keV VMI+ reconstructions significantly increase SNR and CNR of GISTs and improve quantitative and qualitative image quality of abdominal DECT datasets compared to traditional VMI and standard linearly blended image series. PMID- 27999890 TI - [Prolonged reversible cortical blindness over 5 days after cardiac catheterization]. AB - We present a case of a 49-year-old man with angina pectoris. He developed transient cortical blindness (TCB) with focal neurological symptoms following coronary angiography. Two cranial magnet resonance studies within 3 days showed no morphological changes. Clinically the patient developed complex focal epilepsy, which was symptomatically treated. Under intensive monitoring, including hypertension control, the patient improved after 5 days of blindness with restoration of his vision on day 6. The exact mechanism of TCB is still speculative, but could be caused in this case by a toxic effect of contrast dye that was administered. There is no definitive evidence to suggest that a certain treatment regime improves the natural history of the disease. However, control of risk factors and prevention of selective cerebral angiography may increase preventive strategies for this highly devastating complication. PMID- 27999891 TI - [Mother and son between omnipotence and coma]. AB - An academic and his mother, both with Chinese roots, present to the emergency department due to acute confusion. After short latency nausea, complex-focal seizures and finally coma with preserved protective reflexes occur. The cardiorespiratory stable patients are observed in an intensive care unit. The extended emergency diagnostic work-up revealed no cause for the underlying symptoms. Following medical request, the apartment of the patient is inspected by the police, where a meal with self-picked mushrooms is found. Special laboratory exams lead to the diagnosis of pantherina syndrome. PMID- 27999892 TI - Electromyographic assessment of paratonia. AB - Many years after its initial description, paratonia remains a poorly understood concept. It is described as the inability to relax muscles during muscle tone assessment with the subject involuntary facilitating or opposing the examiner. Although related to cognitive impairment and frontal lobe function, the underlying mechanisms have not been clarified. Moreover, criteria to distinguish oppositional paratonia from parkinsonian rigidity or spasticity are not yet available. Paratonia is very frequently encountered in clinical practice and only semi-quantitative rating scales are available. The purpose of this study is to assess the feasibility of a quantitative measure of paratonia using surface electromyography. Paratonia was elicited by performing consecutive metronome synchronized continuous and discontinuous elbow movements in a group of paratonic patients with cognitive impairment. Goniometric and electromyographic recordings were performed on biceps and triceps brachii muscles. Facilitatory (mitgehen) and oppositional (gegenhalten) paratonia could be recorded on both muscles. After normalization with voluntary maximal contraction, biceps showed higher paratonia than triceps. Facilitatory paratonia was higher than oppositional on the biceps. Movement repetition induced increased paratonic burst amplitude only when flexion and extension movements were performed continuously. Both facilitatory and oppositional paratonia increased with movement repetition. Only oppositional paratonia increased following faster movements. This is the first study providing a quantitative and objective characterization of paratonia using electromyography. Unlike parkinsonian rigidity, oppositional paratonia increases with velocity and with consecutive movement repetition. Like spasticity, oppositional paratonia is velocity-dependent, but different from spasticity, it increases during movement repetition instead of decreasing. A quantitative measure of paratonia could help better understanding its pathophysiology and could be used for research purposes on cognitive impairment. PMID- 27999893 TI - Lifespan development of the bilateral deficit in a simple reaction time task. AB - Performing an action at a maximum speed or with a maximum strength simultaneously with two limbs leads to a lower performance than the sum of unimanual performances. This phenomenon is known as bilateral deficit. There is some evidence that the bilateral deficit changes over the lifespan, in a way that children and older adults show lower deficits than young adults. Inverse developmental changes of childrens' and older adults' brain structures connecting both hemispheres, i.e., the corpus callosum, might importantly contribute to this phenomenon. The seemingly similar developments have been observed with different experimental protocols in the different age groups, respectively. To test for similarities and differences in changes of the bilateral deficit at critical periods of the lifespan development of bimanual actions, children, young adults, and older adults performed a simple reaction time task uni- and bimanually. Reaction times and the resulting bilateral deficit, as well as reaction time variability were analyzed. As expected, reaction times were different for the young adults between the uni- and the bimanual task. Children and older adults performed both conditions with similar reaction times. However, a difference in the direction of the %bilateral deficit occurred between the two age groups. The findings demonstrated an absence of the bilateral deficit for children, but not for younger and older adults. PMID- 27999894 TI - Tomography-Based Quantification of Regional Differences in Cortical Bone Surface Remodeling and Mechano-Response. AB - Bone has an adaptive capacity to maintain structural integrity. However, there seems to be a heterogeneous cortical (re)modeling response to loading at different regions within the same bone, which may lead to inconsistent findings since most studies analyze only one region. It remains unclear if the local mechanical environment is responsible for this heterogeneous response and whether both formation and resorption are affected. Thus, we compared the formation and resorptive response to in vivo loading and the strain environment at two commonly analyzed regions in the mouse tibia, the mid-diaphysis and proximal metaphysis. We quantified cortical surface (re)modeling by tracking changes between geometrically aligned consecutive in vivo micro-tomography images (time lapse 15 days). We investigated the local mechanical strain environment using finite element analyses. The relationship between mechanical stimuli and surface (re)modeling was examined by sub-dividing the mid-diaphysis and proximal metaphysis into 32 sub-regions. In response to loading, metaphyseal cortical bone (re)modeled predominantly at the periosteal surface, whereas diaphyseal (re)modeling was more pronounced at the endocortical surface. Furthermore, different set points and slopes of the relationship between engendered strains and remodeling response were found for the endosteal and periosteal surfaces at the metaphyseal and diaphyseal regions. Resorption was correlated with strain at the endocortical, but not the periosteal surfaces, whereas, formation correlated with strain at all surfaces, except at the metaphyseal periosteal surface. Therefore, besides mechanical stimuli, other non-mechanical factors are likely driving regional differences in adaptation. Studies investigating adaptation to loading or other treatments should consider region-specific (re)modeling differences. PMID- 27999895 TI - Internal derangement in the temporomandibular joint of juveniles with clinical signs of TMD : MRI-assessed association with skeletal and dental classes. AB - AIM: The aim of this study was to investigate possible correlation of specific skeletal or dental class in children and adolescents with clinical signs of temporomandibular dysfunction (TMD) with the severity of internal derangement (ID) of the temporomandibular joint. MATERIALS AND METHODS: Based on MRI images, the ID of 232 juvenile temporomandibular joints in 116 patients were retrospectively recorded. The distribution of the ID stages within the skeletal and dental classes was compared by means of the chi 2 test. RESULTS: Excluding the comparison between skeletal Class I (S I) and skeletal Class II (S II; p < 0.05), no statistically significant differences in the distribution of the ID stages were found between the skeletal classes (p > 0.05). No statistically significant differences were found when comparing the distribution of the ID stages between the dental classes (p > 0.05). CONCLUSION: According to these findings, there is no skeletal or dental class that is related to higher degrees of internal derangement in the TMJs of children and adolescents presenting clinical signs of TMD. Therefore, it is not possible to draw conclusions about the severity of the ID in relation to the dental and skeletal class in symptomatic juvenile TMJs. PMID- 27999896 TI - Correlation of pretreatment 18F-FDG PET tumor textural features with gene expression in pharyngeal cancer and implications for radiotherapy-based treatment outcomes. AB - PURPOSE: This study investigated the correlation of the matrix heterogeneity of tumors on 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) with gene-expression profiling in patients with pharyngeal cancer and determined the prognostic factors for radiotherapy-based treatment outcomes. METHODS: We retrospectively reviewed the records of 57 patients with stage III-IV oropharyngeal or hypopharyngeal cancer who had completed definitive therapy. Four groups of the textural features as well as 31 indices were studied in addition to maximum standard uptake value, metastatic tumor volume, and total lesion glycolysis. Immunohistochemical data from pretreatment biopsy specimens (Glut1, CAIX, VEGF, HIF-1alpha, EGFR, Ki-67, Bcl-2, CLAUDIN-4, YAP-1, c-Met, and p16) were analyzed. The relationships between the indices and genomic expression were studied, and the robustness of various textural features relative to cause specific survival and primary relapse-free survival was analyzed. RESULTS: The overexpression of VEGF was positively associated with the increased values of the matrix heterogeneity obtained using gray-level nonuniformity for zone (GLNUz) and run-length nonuniformity (RLNU). Advanced T stage (p = 0.01, hazard ratio [HR] = 3.38), a VEGF immunoreactive score of >2 (p = 0.03, HR = 2.79), and a higher GLNUz value (p = 0.04, HR = 2.51) were prognostic factors for low cause-specific survival, whereas advanced T stage, a HIF-1alpha staining percentage of >=80%, and a higher GLNUz value were prognostic factors for low primary-relapse free survival. CONCLUSIONS: The overexpression of VEGF was associated with the increased matrix index of GLNUz and RLNU. For patients with pharyngeal cancer requiring radiotherapy, the treatment outcome can be stratified according to the textural features, T stage, and biomarkers. PMID- 27999900 TI - Effect of end-inspiratory plateau pressure duration on driving pressure. PMID- 27999897 TI - Protecting DNA from errors and damage: an overview of DNA repair mechanisms in plants compared to mammals. AB - The genome integrity of all organisms is constantly threatened by replication errors and DNA damage arising from endogenous and exogenous sources. Such base pair anomalies must be accurately repaired to prevent mutagenesis and/or lethality. Thus, it is not surprising that cells have evolved multiple and partially overlapping DNA repair pathways to correct specific types of DNA errors and lesions. Great progress in unraveling these repair mechanisms at the molecular level has been made by several talented researchers, among them Tomas Lindahl, Aziz Sancar, and Paul Modrich, all three Nobel laureates in Chemistry for 2015. Much of this knowledge comes from studies performed in bacteria, yeast, and mammals and has impacted research in plant systems. Two plant features should be mentioned. Plants differ from higher eukaryotes in that they lack a reserve germline and cannot avoid environmental stresses. Therefore, plants have evolved different strategies to sustain genome fidelity through generations and continuous exposure to genotoxic stresses. These strategies include the presence of unique or multiple paralogous genes with partially overlapping DNA repair activities. Yet, in spite (or because) of these differences, plants, especially Arabidopsis thaliana, can be used as a model organism for functional studies. Some advantages of this model system are worth mentioning: short life cycle, availability of both homozygous and heterozygous lines for many genes, plant transformation techniques, tissue culture methods and reporter systems for gene expression and function studies. Here, I provide a current understanding of DNA repair genes in plants, with a special focus on A. thaliana. It is expected that this review will be a valuable resource for future functional studies in the DNA repair field, both in plants and animals. PMID- 27999898 TI - Mechanisms of pluripotency maintenance in mouse embryonic stem cells. AB - Mouse embryonic stem cells (mESCs), characterized by their pluripotency and capacity for self-renewal, are driven by a complex gene expression program composed of several regulatory mechanisms. These mechanisms collaborate to maintain the delicate balance of pluripotency gene expression and their disruption leads to loss of pluripotency. In this review, we provide an extensive overview of the key pillars of mESC pluripotency by elaborating on the various essential transcription factor networks and signaling pathways that directly or indirectly support this state. Furthermore, we consider the latest developments in the role of epigenetic regulation, such as noncoding RNA signaling or histone modifications. PMID- 27999901 TI - Erratum to: Development of SCAR markers for rapid and specific detection of Pseudomonas syringae pv. morsprunorum races 1 and 2, using conventional and real time PCR. PMID- 27999899 TI - Control of signaling molecule range during developmental patterning. AB - Tissue patterning, through the concerted activity of a small number of signaling pathways, is critical to embryonic development. While patterning can involve signaling between neighbouring cells, in other contexts signals act over greater distances by traversing complex cellular landscapes to instruct the fate of distant cells. In this review, we explore different strategies adopted by cells to modulate signaling molecule range to allow correct patterning. We describe mechanisms for restricting signaling range and highlight how such short-range signaling can be exploited to not only control the fate of adjacent cells, but also to generate graded signaling within a field of cells. Other strategies include modulation of signaling molecule action by tissue architectural properties and the use of cellular membranous structures, such as signaling filopodia and exosomes, to actively deliver signaling ligands to target cells. Signaling filopodia can also be deployed to reach out and collect particular signals, thereby precisely controlling their site of action. PMID- 27999914 TI - A Retrograde Transvenous Embolization Technique with Balloon-Assisted Arterial Aspiration for a Peripheral Arteriovenous Malformation with a Venous Pouch. AB - Management of arteriovenous malformations (AVMs) is challenging, and there is no consensus regarding either the ideal approach or the treatment timing. Percutaneous embolization is the most frequent approach currently used and is considered the first-line technique for AVMs. There is an ongoing discussion about the best technical approach to embolize AVMs. AVMs associated with a dominant outflow vein (DOV) are rare. Embolization of both the DOV and the nidus is considered more effective. Herein, we report a novel technique of transvenous embolization of a DOV under negative pressure from an arterial balloon catheter in a case of a peripheral AVM. This technique allows the embolization of the DOV and the nidus retrogradely. PMID- 27999915 TI - The IR Point of View: Action Cameras for IR Action. PMID- 27999916 TI - Trerotola Device Fragmentation. PMID- 27999902 TI - Tunable recombinant protein expression in E. coli: promoter systems and genetic constraints. AB - Tuning of transcription is a promising strategy to overcome challenges associated with a non-suitable expression rate like outgrowth of segregants, inclusion body formation, metabolic burden and inefficient translocation. By adjusting the expression rate-even on line-to purposeful levels higher product titres and more cost-efficient production processes can be achieved by enabling culture long-term stability and constant product quality. Some tunable systems are registered for patents or already commercially available. Within this contribution, we discuss the induction mechanisms of various Escherichia coli inherent promoter systems with respect to their tunability and review studies using these systems for expression tuning. According to the current level of knowledge, some promoter systems were successfully used for expression tuning, and in some cases, analytical evidence on single-cell level is still pending. However, only a few studies using tunable strains apply a suitable process control strategy. So far, expression tuning has only gathered little attention, but we anticipate that expression tuning harbours great potential for enabling and optimizing the production of a broad spectrum of products in E. coli. PMID- 27999917 TI - Radiofrequency Ablation Combined with Hepatic Arterial Chemoembolization Using Degradable Starch Microsphere Mixed with Mitomycin C for the Treatment of Liver Metastasis from Colorectal Cancer: A Prospective Multicenter Study. AB - PURPOSE: This phase II prospective study investigates possible benefits of radiofrequency ablation (RFA) combined with hepatic arterial chemoembolization using degradable starch microsphere (DSM) mixed with mitomycin C (MMC) in non surgical candidates with colorectal liver metastases. MATERIALS AND METHODS: This study, approved by the respective institutional review board, included non surgical candidates with 3 or fewer liver tumors of 3 cm or smaller, or a single lesion 5 cm or smaller. Percutaneous RFA was performed immediately after chemoembolization using DSM-MMC. Primary and secondary endpoints were the local tumor control rate, safety, and 2-year recurrence-free and overall survival rates. RESULTS: This study examined 25 patients (22 males, 3 females) with 38 tumors of mean maximum diameter of 2.2 +/- 0.9 cm (standard deviation) (range 1.0 4.2 cm). Their mean age was 70.2 +/- 8.2 years (range 55-82 years). Local tumor progression developed in 3 tumors (7.9%, 3/38) of 3 patients (12%, 3/25) during the mean follow-up of 34.9 +/- 9.2 months (range 18.3-50.1 months). The 2-year local tumor control rates were 92.0% [95% confidence interval (CI), 81.4-100%] on a patient basis and 94.6% (95% CI, 87.3-100%) on a tumor basis. The respective 2 year overall and recurrence-free survival rates were 88.0% (95% CI, 75.3-98.5%) and 63.3% (95% CI, 44.2-82.5%), with median survival time of 48.4 months. Fever was the only adverse event requiring treatments in 2 patients (8%). CONCLUSIONS: This combination therapy is safe, exhibiting strong anticancer effects on colorectal liver metastasis, which might contribute to patient survival. PMID- 27999918 TI - Endovascular Management of Patients with Head and Neck Cancers Presenting with Acute Hemorrhage: A Single-Center Retrospective Study. AB - PURPOSE: Acute hemorrhage associated with cancers of the head and neck is a life threatening condition that requires immediate action. The aim of this study was to assess the safety and efficacy of endovascular embolization for acute hemorrhage in patients with head and neck cancers. MATERIALS AND METHODS: Data were retrospectively collected from patients with head and neck cancers who underwent endovascular embolization to treat acute hemorrhage. The primary endpoint was the rate of immediate control of hemorrhage during the first 24 h after embolization. The secondary endpoints were technical or clinical complications, rate of re-hemorrhage 24 h after the procedure, time from embolization to re-hemorrhage, hospitalization time, mortality rate, and time from embolization to death. RESULTS: Fifty-one patients underwent endovascular embolization. The primary endpoint was achieved in 94% of patients. The rate of technical complications was 5.8%, and no clinical complication was observed. Twelve patients (23.5%) had hemorrhage recurrence after an average time of 127.5 days. The average hospitalization time was 7.4 days, the mortality rate during the follow-up period was 66.6%, and the average time from embolization to death was 132.5 days. CONCLUSION: Endovascular embolization to treat acute hemorrhage in patients with head and neck cancers is a safe and effective method for the immediate control of hemorrhage and results in a high rate of hemorrhage control. Larger studies are necessary to determine which treatment strategy is best for improving patient outcomes. PMID- 27999919 TI - Interventional Radiology Management of a Ruptured Lumbar Artery Pseudoaneurysm after Cryoablation and Vertebroplasty of a Lumbar Metastasis. AB - We describe the management of a complication (a lumbar artery pseudoaneurysm and its rupture) after combined procedure (cryoablation and vertebroplasty) on a lumbar (L2) metastasis from renal cell carcinoma. Review of the literature is also presented with discussion about the measures to be taken to prevent these types of complications. PMID- 27999920 TI - Bilateral Arterial Embolization of the Prostate Through a Single Prostatic Artery: A Case Series. AB - Peri-prostatic shunts are frequent during PAE, carrying the risk of non-target embolization of penis/corpus cavernosum or rectum but also the potential advantage to irrigate the contralateral lobe. Sometimes, bilateral embolization is impossible, carrying the risk of limited clinical success. The possibility to reach contralateral prostatic territory from the ipsilateral prostatic artery (PA) and embolize it via peri/intra-prostatic anastomoses could be of interest in this situation. We describe a series of three consecutive patients (among 89 consecutive patients treated by PAE for symptomatic BPH) who underwent successful embolization of both prostatic lobes through catheterization of a PA on only one side. All patients had clinical success after a mean follow-up of 3.3 months. Dosimetry of these three procedures indicates that there may be radiation dose savings. PMID- 27999922 TI - Retraction note to: Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat. PMID- 27999921 TI - Examining the relationship between human resources and mortality: the effects of methodological choices. AB - OBJECTIVES: Relationship between human resources for health and mortality remains inconclusive despite numerous studies published on the topic in the last decades. This paper investigates how and why methodological trade-offs implicitly made by researchers when using macro-data can in part explains this puzzling lack of agreement. METHODS: Using data from the Global Health Observatory, we build a model of the relationship between human resources and mortality, which we progressively alter by changing its scope, variables and analysis period. Then, we compare results among themselves to isolate the impact of methodological choices from other changes in the data. RESULTS: Results demonstrate how methodological choices linked to (1) the analysis period, (2) the definition of health inputs, health outcomes and control variables and (3) the choice of specific variables as proxy for human resources and health outcomes affects the relationship between human resources and health outputs. CONCLUSIONS: Results presented highlights the need for complementing existing macro-analysis with other analytical strategies, for better documenting methodological choices in research studies, as well as for further supporting countries' efforts to produce reliable and consistent data. PMID- 27999923 TI - [Video contribution: Current surgical techniques : A new category in The Accident Surgeon]. PMID- 27999924 TI - Low friction arthroplasty and dual mobility cup: a new gold standard. AB - INTRODUCTION: Low friction arthroplasty (LFA) introduced by Sir John Charnley was the gold standard for many years. Dislocation and infection are the first causes for early revision. Late failures are polyethylene (PE) wear and loosening. Due to dislocation risk we slowly switched to the use of LFA with dual mobility cups (DMC). The purposes of this study are (1) to assess whether our changes have improved outcomes and (2) what is the new gold standard? MATERIAL AND METHODS: We selected from an observational registry of 1,091 cases of hybrid Charnley total hip arthroplasty (THA). The acetabular component was either DMC in 455 cases or fixed cup (FC) in 636 cases. RESULTS: Three dislocations (0.6%) occurred in the DMC group (none revised). In the FC group 54 dislocated (8.49%) and 20 were recurrent and underwent revision (revision rate 3.14%). In the DMC group, five acetabular and three femoral revisions were performed (revision rate for loosening 1.7%). In the FC group 19 cases underwent acetabular revision, and five cases had femoral component revised (revision rate for loosening 3.7%). DISCUSSION: Charnley's LFA has proven over 50 years of excellent survivorship. To decrease dislocation risk, one suggested increasing femoral head diameter. Gilles Bousquet proposed another way, namely, the DMC concept. Dislocation is no longer a critical issue with DMC as demonstrated in our series and main series. DMC in primary THA is still a subject of debate. Mid-term results do not demonstrate a higher rate of wear than LFA. What is the current gold standard? LFA was and is our current gold standard in association with a DMC. PMID- 27999925 TI - Total hip arthroplasty instability in Italy. AB - Hip dislocation is a major and common complication of total hip arthroplasty (THA), which appears with an incidence between 0.3% and 10% in primary total hip arthroplasties and up to 28% in revision THA. The hip dislocations can be classified into three groups: early, intermediate and late. Approximately two thirds of cases can be treated successfully with a non-operative approach. The rest require further surgical intervention. The prerequisite to developing an appropriate treatment strategy is a thorough evaluation to identify the causes of the dislocation. In addition, many factors that contribute to THA dislocation are related to the surgical technique, mainly including component orientation, femoral head diameter, restoration of femoral offset and leg length, cam impingement and condition of the soft tissues. The diagnosis of a dislocated hip is relatively easy because the clinical situation is very typical. Having identified a dislocated hip, the first step is to perform a closed reduction of the implant. After reduction you must perform a computed tomography scan to evaluate the surgical options for treatment of recurrent dislocation that include: revision arthroplasty, modular components exchange, dual-mobility cups, large femoral heads, constrained cups, elimination of impingement and soft tissue procedures. The objective is to avoid further dislocation, a devastating event which is increasing the number of operations on the hip. To obtain this goal is useful to follow an algorithm of treatment, but the best treatment remains prevention. PMID- 27999926 TI - Results of arthroscopic treatment in unresolved Osgood-Schlatter disease in athletes. AB - AIM OF THE STUDY: In this study we aimed to determine outcomes following arthroscopic ossicle excision in athletes with unresolved Osgood-Schlatter disease (OSD). METHOD: Arthroscopy was performed on 11 patients (11 knees) with OSD between September 2008 and November 2014. Surgical treatment inclusion criteria were determined as: failure of conservative treatment; isolated pain over the tibial tubercle and distal patellar tendon; pain limiting sporting performance at a competitive level. All patients had a documented history of OSD; the mean duration of persistent pain over the tibial tubercle was 15.5 months. The mean age was 23 years. The mean follow-up period was 66.1 months. RESULTS: The mean latency in returning to sports related training activities after the surgery was 6.7 weeks. The mean Kujala patello-femoral score improved from 82.9 points pre-operatively, to 98.5 points at the final follow-up (p < 0.01). The mean Lysholm knee scale score was 87.5 points in the pre-operative period, increasing to a score of 96.9 points at final follow-up (p < 0.01). The mean Tegner activity level score was 7.5 in the pre-operative period, increasing to 8.5 post-operatively (p < 0.01). DISCUSSION: We investigated the functional outcomes after arthroscopic treatment of unresolved OSD in athletes. All athletes with OSD showed satisfactory functional recovery following arthroscopic treatment. All patients were able to return to the same level of athletic activity. CONCLUSION: Arthroscopic surgery for unresolved OSD has the major advantage of faster recovery and avoiding damage to the patellar tendon. PMID- 27999928 TI - Erratum to: Focal salvage therapy for local prostate cancer recurrences after primary radiotherapy: a comprehensive review. PMID- 27999927 TI - Incidence and risk factors for the misplacement of pedicle screws in scoliosis surgery assisted by O-arm navigation-analysis of a large series of one thousand, one hundred and forty five screws. AB - PURPOSE: To assess the accuracy of O-arm-navigation-based pedicle screw placement in scoliosis surgery and identify the potential risk factors for the misplacement of pedicle screws. METHODS: One hundred forty four scoliosis patients treated with O-arm-navigation-based pedicle screw instrumentation were enrolled, and 1145 pedicle screws implanted in the apical region of the curves were retrospectively reviewed for accuracy according to post-operative CT images. The potential risk factors and independent predictive factor(s) for the misplaced screws were identified statistically. RESULTS: The overall malpositioning rate of pedicle screw was 9.8%; 54.5% of which were misplaced laterally. Univariate and multivariate logistic regression analysis of clinical and surgical treatment variables indicated that patients with congenital scoliosis (CS) [OR: 1.489 (95% CI: 1.002-2.213; P = 0.035)] and neurofibromatosis type I (NF-1) [OR: 1.785 (95% CI: 1267-2.045; P = 0.026)], middle-thoracic spine [OR: 1.661 (95% CI: 1.107 2.481; P = 0.021)], the concave pedicles [OR: 1.527 (95% CI: 1.020-2.285; P = 0.019)], and the segments three levels away from the tracker [OR: 3.522 (95% CI: 2.357-5.263; P = 0.001)] were independently associated with pedicle screw misplacement. CONCLUSION: O-arm-assisted navigation does improve the accuracy and safety of pedicle screw placement in scoliosis surgery. However, unavoidable screw malpositioning remained, which occurred significantly more often in patients with CS and NF-1, in middle-thoracic spine, in the concave pedicles, and in the segments three levels away from the tracker. PMID- 27999929 TI - Acute heart failure with mid-range left ventricular ejection fraction: clinical profile, in-hospital management, and short-term outcome. AB - BACKGROUND: Heart failure with mid-range left ventricular ejection fraction (HFmrEF) is a poorly characterized population as it has been studied either in the context of HF with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction (LVEF) depending on applied LVEF cutoffs. We sought to investigate the clinical profile, in-hospital management, and short-term outcome of HFmrEF patients in comparison with those with HFrEF or HFpEF in a large acute HF cohort. METHODS AND RESULTS: The Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF) included 4953 patients hospitalized for HF in nine countries in Europe, Latin America, and Australia. Baseline characteristics, clinical presentation, in-hospital therapies, and short-term mortality (all-cause in-hospital or 30-day mortality, whichever first) were compared among HFrEF (LVEF <40%), HFmrEF (LVEF 40-49%), and HFpEF (LVEF >=50%) patients. Among 3257 patients with documented LVEF, 52% had HFrEF, 25% HFmrEF, and 23% HFpEF. Patients with HFmrEF had a distinct demographic and clinical profile with many intermediate features between HFrEF and HFpEF. In addition, they had a higher prevalence of hypertension (p < 0.001), a lower prevalence of chronic renal disease (p = 0.003), more hospitalizations for acute coronary syndrome (p < 0.001), or infection (p = 0.003), and were more frequently treated with intravenous vasodilators compared to HFrEF or HFpEF. Adjusted short-term mortality in HFmrEF was lower than HFrEF [hazard ratio (HR) = 0.635 (0.419, 0.963), p = 0.033] but similar to HFpEF [HR = 1.026 (0.605, 1.741), p = 0.923]. CONCLUSION: Hospitalized HFmrEF patients represent a demographically and clinically diverse group with many intermediate features compared to HFrEF and HFpEF and carry a lower risk of short-term mortality than HFrEF but a similar risk with HFpEF. PMID- 27999930 TI - Impact of baseline tricuspid regurgitation on long-term clinical outcomes and survival after interventional edge-to-edge repair for mitral regurgitation. AB - AIMS: Tricuspid regurgitation (TR) in patients with mitral valve disease is associated with poor outcome and mortality. Only limited data on the impact of TR on functional outcome and survival in patients undergoing MitraClip procedures are available. METHODS AND RESULTS: 261 patients (mean age 76.6 +/- 10, EuroScore 15.9 +/- 15.1%) with symptomatic mitral regurgitation (MR) (75.2% functional MR) undergoing MitraClip procedure were included and followed for 721 +/- 19.4 days. At baseline 54.7% presented with TR grade 0/I, 29.5% with grade II, 13.4% with grade III and 2.3% with grade IV. When dividing groups according to baseline TR grades, follow-up (FU)-NYHA class was significantly improved only in patients with TR <= II (p = 0.05). FU-6-min walking distance increased significantly in the overall cohort (p = 0.05), in patients with TR <= II (p = 0.007), but not in patients with TR > II (p = 0.4). Moreover, FU-NT-pro-BNP levels were higher in patients with TR > II (p = 0.05), compared to patients with TR <= II. There was a higher mortality according to baseline TR > II and multivariate Cox regression revealed TR > II as the strongest independent predictor for mortality (hazard ratio 2.04). CONCLUSIONS: Concomitant TR at baseline negatively influences functional outcome and mortality in patients undergoing MitraClip procedures. Our results underline the need for dedicated interventional strategies for the treatment of TR in patients with symptomatic MR. PMID- 27999931 TI - [Epithelial ingrowth after evisceration]. AB - A 67-year old patient presented with persistent wound dehiscence after evisceration. The scleral shell and the implant were removed. The histopathological and immunohistochemical examination of the tumor revealed epithelial ingrowth and infection of the implant. Even if the intervention is known since the 16th century, technics and materials are still undergoing improvements and discussions. Incarceration or tension on the suture should be avoided in order to prevent secondary complications. PMID- 27999932 TI - Association of famine exposure during early life with the risk of type 2 diabetes in adulthood: a meta-analysis. AB - PURPOSE: The association between famine exposure (defined as lengthy and continuous deprivation of food) during early life and type 2 diabetes (T2DM) in adulthood remains controversial. A meta-analysis was performed to better clarify the relation of famine exposure to later T2DM risk. METHODS: A systematic literature search was performed in PubMed, Web of Science, Embase and China National Knowledge Infrastructure for relevant available articles. The articles were limited to those in English or Chinese from January 1990 to June 2016. Observational studies evaluating the association between famine exposure and T2DM were included. The pooled relative risk (RR) with 95% confidence interval (CI) was used to estimate the effect of famine exposure on T2DM. The I 2 was used to assess heterogeneity, and the random effects model (REM) was adopted as the pooling method. RESULTS: We included 11 published articles with 12391 T2DM cases for this meta-analysis. A significant association of early life famine exposure with increased risk of T2DM was observed (RR = 1.38, 95% CI 1.17-1.63; I 2 = 63.4%; P heterogeneity = 0.002). Compared with the unexposed, the RRs of T2DM were 1.36 (95% CI 1.12-1.65) for fetal-infant exposed and 1.40 (95% CI 0.98-1.99) for childhood exposed. After excluding one article that had a strong effect on heterogeneity, the pooled RR was 1.46 (95% CI 1.27-1.69). CONCLUSION: The meta analysis indicates that famine exposure during early life especially fetal-infant exposure may increase the risk of T2DM in adulthood. Measures should be taken to prevent malnutrition during important stages of growth and development to reduce the prevalence of T2DM. PMID- 27999933 TI - Vaginal vault suspension during hysterectomy for benign indications: a prospective register study of agreement on terminology and surgical procedure. AB - INTRODUCTION AND HYPOTHESIS: Several suspension methods are used to try to prevent pelvic organ prolapse (POP) after hysterectomy. We aimed to evaluate agreement on terminology and surgical procedure of these methods. METHODS: We randomly chose 532 medical records of women with a history of hysterectomy from the Danish Hysterectomy and Hysteroscopy Database (DHHD). Additionally, we video recorded 36 randomly chosen hysterectomies. The hysterectomies were registered in the DHHD. The material was categorized according to predefined suspension methods. Agreement compared suspension codes in DHHD (gynecologists' registrations) with medical records (gynecologists' descriptions) and with videos (reviewers' categorizations) respectively. Whether the vaginal vault was suspended (pooled suspension) or not (no suspension method + not described) was analyzed, in addition to each suspension method. RESULTS: Regarding medical records, agreement on terminology was good among patients undergoing pooled suspension in cases of hysterectomy via the abdominal and vaginal route (agreement 78.7, 92.3%). Regarding videos, agreement on surgical procedure was good among pooled suspension patients in cases of hysterectomy via the abdominal, laparoscopic, and vaginal routes (agreement 88.9, 97.8, 100%). Agreement on individual suspension methods differed regarding both medical records (agreement 0-90.1%) and videos (agreement 0-100%). CONCLUSIONS: Agreement on terminology and surgical procedure regarding suspension method was good in respect of pooled suspension. However, disagreement was observed when individual suspension methods and operative details were scrutinized. Better consensus of terminology and surgical procedure is warranted to enable further research aimed at preventing POP among women undergoing hysterectomy. PMID- 27999934 TI - Detrusor pressures in urodynamic studies during voiding in women. AB - INTRODUCTION AND HYPOTHESIS: To investigate detrusor pressure during voiding in women using urodynamic studies (UDS). METHODS: The study group comprised 57 women with non-neurogenic lower urinary tract symptoms. All patients underwent UDS between January 2010 and December 2014. UDS included filling cystometry, pressure flow study (PFS), uroflowmetry for the maximum flow rate (Qmax) and mean flow rate, and postvoid residuals. Existence of voluntary detrusor contraction was defined as a continuous and smooth increase in detrusor pressure (Pdet) after the instruction to micturate in the PFS. The bladder contractility index (BCI) was calculated as Pdet at Qmax + 5 * Qmax. Statistical analyses were performed using the Mann-Whitney U test and p < 0.05 was considered statistically significant. RESULTS: The PFS showed that 23 patients had detrusor contraction (Pdet+ group) and 34 patients had no detrusor contraction (Pdet- group) during voiding. There were no significant differences in urodynamic parameters between the Pdet+ and Pdet- groups except in Pdet at Qmax and BCI. In the Pdet- group, 21 patients showed an increase in abdominal pressure during voiding (Pabd+ group), while the other 13 patients did not (Pabd- group). There were no differences in any of the urodynamic parameters between the Pabd+ and Pabd- groups. CONCLUSIONS: Based on UDS, an increase in detrusor or abdominal pressure may not be necessary in micturition in women. The present study suggests that relaxation of pelvic floor muscles including normal urethral function are important for micturition in women. PMID- 27999935 TI - Laparoscopic sentinel node navigation surgery for early gastric cancer: a prospective multicenter trial. AB - BACKGROUND: Prospective multicenter trials have shown the feasibility of sentinel node (SN) navigation surgery using a dual tracer of dye and radioisotope for early gastric cancer. However, comparable trials using the indocyanine green (ICG) and the infrared ray laparoscopic system (IRLS) have not been reported. On the basis of our cohort studies, we assumed that the ICG imaging with the IRLS is as effective as the dual tracer in detecting SNs. Therefore, we conducted a prospective multicenter trial to assess the effectiveness and generalizability of the infrared ICG technique in patients with early gastric cancer. PATIENTS AND METHODS: Patients with previously untreated cT1 gastric adenocarcinomas less than 4 cm in gross diameter were eligible for inclusion in this study. SN mapping was performed by using ICG combined with IRLS technique. Following biopsy of the identified SNs, D2 or modified D2 laparoscopic gastrectomy was performed according to the current Japanese Gastric Cancer Association guidelines. RESULTS: Among the 47 patients who gave written informed consent, 44 were eligible from the surgical findings, for whom SN biopsy was performed. The detection rate of the lymphatic basin by the ICG with IRLS was 100% (44/44). The accuracy was also 100% (7/7) for detecting metastatic lymph node, which was verified on the permanent pathologic examination. Following the median follow-up of 114 months (range, 60 to 120 months), no recurrence (0/40) was observed. Although the number of patients was unequally distributed among the hospitals participating in the trial, the detection rates of SNs in low-volume hospitals were comparable to those in high-volume hospitals. Consequently, there was no learning curve in this trial. CONCLUSION: The infrared ICG imaging accurately detected the lymphatic basin and SNs with occult metastasis in SN-navigated gastrectomy for gastric cancer. This method was feasible even for low-volume surgeons and hospitals. PMID- 27999936 TI - Lack of evidence for tissue hypoxia as a contributing factor in anastomotic leak following colon anastomosis and segmental devascularization in rats. AB - PURPOSE: Current surgical dogma dictates that tissue ischemia and hypoxia are major contributing factors in anastomotic leak despite scant evidence. The aim of this study was to determine if tissue hypoxia is a feature of anastomotic leakage in rats following colon resection and segmental devascularization. METHODS: Rats were randomly assigned to undergo sham operation, segmental colon devascularization alone, colectomy alone, or segmental devascularization plus colectomy. Tissue hypoxia present at the colon anastomosis site across the various treatment groups was determined at sacrifice on postoperative day 6. Pimonidazole HCl was injected 30 min prior to sacrifice. Anastomotic tissues were examined and scored for healing versus leakage using an anastomotic healing score (AHS). Collagen content, hypoxia, enteric smooth muscle and periendothelial stromal patterning, and apoptosis were evaluated histologically. RESULTS: No differences in tissue hypoxia were noted in the 16% of anastomotic tissues with poor healing compared to the remaining 84% of rats whose anastomoses healed well. No significant changes were found in cell death in the submucosa of any group. Consistent with previous findings, poor healing was associated with lower collagen content. Submucosal thickness correlated with increased arteriole diameter (R 2 = 0.25, p < 0.005). CONCLUSIONS: These results demonstrate that tissue hypoxia is not a distinctive feature of anastomotic tissues that fail to heal and leak, even when their blood supply is interrupted. These findings suggest that compensatory factors may mitigate the effects of ischemia and hypoxia during healing of anastomotic tissues and that the process of leakage involves factors beyond their acute effects. PMID- 27999937 TI - [Update on nodular lymphocyte predominant Hodgkin's lymphoma and related lesions]. AB - The present article gives an overview of novel developments in the diagnosis of nodular lymphocyte predominant Hodgkin's lymphoma with reference to the revised WHO classification from 2016. Differential diagnoses that are discussed are progressively transformed germinal centers, T cell/histiocyte-rich large B cell lymphoma as well as transformation into a diffuse large B cell lymphoma. PMID- 27999938 TI - Characterization of Cinnamoyl Esterases from Different Lactobacilli and Bifidobacteria. AB - A high variety of plants that are used for food production contain esterified hydroxycinnamic acids. As their free forms display several benefits, like an enhanced absorption in human intestinal tract, anti-oxidative and anti carcinogenic effects, an improved protein solubility and reduced discoloration, the microbial ability to cleave the ester bond is highly desired. In order to examine potential fermentation strains for this purpose, six different lactic acid bacteria and one bifidobacterial strain were screened for their ability to degrade esterified hydroxycinnamic acids because these strains are commonly used for fermentation of plant-based foods. Moreover, their cinnamoyl esterase activity was examined by molecular biological analyses. The enzymes were heterologously expressed in Escherichia coli, purified and biochemically characterized. The purified esterases with a molecular mass around 27-29 kDa had their optimum predominantly between pH 7 and 8 at 20-30 degrees C. Bifidobacterium animalis subsp. lactis, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus plantarum and Lactobacillus fermentum displayed activities against a broad substrate range (methyl caffeate, methyl trans-p coumarate, chlorogenic acid as well as partially ethyl ferulate). Concerning substrate affinity, reaction velocity, thermal and pH stability, Lactobacillus gasseri showed the overall best performance. The herein studied lactic acid- and bifidobacteria are promising for the production of fermented plant-based foods with an increased quality and nutritional value. PMID- 27999939 TI - Heat Survival and Phenotype Microarray Profiling of Salmonella Typhimurium Mutants. AB - Contamination of food products by pathogenic microorganisms continues to be a major public health and food industry concern. Non-typhoidal Salmonella species have led to numerous outbreaks associated with various foods. A wide variety of methods have been applied and introduced for treatment of fresh foods to eliminate pathogenic as well as spoilage microorganisms. Salmonella can become exposed to elevated temperatures while associated with hosts such as poultry. In addition, heat treatment is also applied at various stages of processing to retain the shelf life of food products. Despite this, these microorganisms may overcome exposure to such treatments through the efficient expression of stress response mechanisms and result in illness following consumption. Thermal stress induces a range of destructive exposures to bacterial cells such as protein damage and DNA damage caused by reactive oxygen species. In this study, we chose three genes (?recD, ?STM14_5307, and ?aroD) associated with conditionally essential genes required for different aspects of optimal growth at 42 degrees C and evaluated the responses of wild type and mutant Salmonella Typhimurium strains to uncover potential mechanisms that may enable survival and resistance under thermal stress. The RecBCD complex that initiates repair of double-stranded DNA breaks through homologous recombination. STM14_5307 is a transcriptional regulator involved in stationary phase growth and inositol metabolism. The gene aroD is involved in metabolism and stationary phase growth. These strains were characterized via high throughput phenotypic profiling in response to two different growth temperatures (37 degrees C (human host temperature) and 42 degrees C (poultry host temperature)). The ?aroD strain exhibited the highest sensitivity to the various temperatures followed by the ?recD and ?STM14_5307 strains, respectively. Achieving more understanding of the molecular mechanisms of heat survival may lead to the development of more effective strategies to limit Salmonella in food products through thermal treatment by developing interventions that specifically target the pathways these genes are involved in. PMID- 27999941 TI - Extracellular phosphates enhance activities of voltage-gated proton channels and production of reactive oxygen species in murine osteoclast-like cells. AB - Osteoclasts are highly differentiated bone-resorbing cells and play a significant role in bone remodelling. In the resorption pit, inorganic phosphate (Pi) concentrations increase because of degradation of hydroxyapatite. We studied effects of extracellular Pi on voltage-gated H+ channels in osteoclast-like cells derived from a macrophage cell line (RAW264). Extracellular Pi (1.25-20 mM) increased the H+ channel currents dose dependently and reversibly. The Pi-induced increases were attenuated by removal of extracellular Na+ and by phosphonoformic acid, a blocker of Na+-dependent Pi transporters. Pi increased the maximal conductance, decreased activation time constant, increased deactivation time constant, and shifted the conductance-voltage relationship to more negative voltages. The most marked change was enhanced gating which was mainly caused by elevation of intracellular Pi levels. The Pi-induced enhanced gating was partially inhibited by protein kinase C (PKC) inhibitors, GF109203X and staurosporine, indicating that PKC-mediated phosphorylation was involved in part. The increase in the maximal conductance was mainly due to accompanying decrease in intracellular pH. These effects of Pi were not affected by intracellular Mg2+, bafilomycin A1 (V-ATPase inhibitor) and removal of intracellular ATP. Extracellular Pi also upregulated reactive oxygen species (ROS). Diphenyleneiodonium chloride, an inhibitor of NADPH oxidases, decreased ROS production and partially attenuated the enhanced gating. In the cells during later passages where osteoclastogenesis declined, H+ channel activities and ROS production were both modest. These results suggest that, in osteoclasts, ambient Pi is a common enhancer for H+ channels and ROS production and that potentiation of H+ channels may help ROS production. PMID- 27999942 TI - The prevalence and risk factors for serositis in patients with systemic lupus erythematosus: a cross-sectional study. AB - This study aims to estimate the prevalence of serositis and identify risk factors for serositis in a large cohort of systemic lupus erythematosus (SLE) patients. A cross-sectional study was conducted based on the medical records of patients hospitalized with SLE at the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital. Patients were diagnosed with serositis when they presented with symptoms and signs of pleuritis or/and pericarditis. We explored factors associated with the generation and quantity of serositis by using binary and ordinal logistic regression analysis. Among the 1668 lupus patients, 298 have serositis. Active lupus disease, fever (>=38 degrees C) and high D-dimer were all significantly associated with the generation and quantity of serositis. Male gender was independent significant risk factor for pleuritis but not for pericarditis, while low complement C4 and high erythrocyte sedimentation rate (ESR) were risk factors for pericarditis rather than for pleuritis. The possible prevalence of serositis in patients with SLE was 17.9%. The significant associations of active lupus disease, fever (>=38 degrees C) and high D-dimer with serositis suggest that higher disease activity and hypercoagulability may both contribute to the generation and development of serositis in SLE. The risk factors for pleuritis and pericarditis in SLE are similar but not identical. PMID- 27999940 TI - FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. AB - Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast, FHF2B positively regulated resurgent current and did not alter long term inactivation. Chimeric constructs of FHF2A and Navbeta4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents, suggesting that specific regions within FHF2A and Navbeta4 have important regulatory functions. Our data also indicate that FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies. PMID- 27999944 TI - The aberrant right subclavian artery: cadaveric study and literature review. AB - PURPOSE: Taking into consideration that the aberrant right subclavian artery (ARSA) is the commonest congenital aortic arch anomaly (prevalence 0.16-4.4%), our goal was to investigate its incidence in Greeks, with respect to location, course, and relationship to trachea and esophagus. Gender dimorphism, coexisting neural, and vascular variations were also examined. The clinical impact and embryological background of the variation are discussed. METHODS: Two hundred and sixty-seven (126 male and 141 female) formalin-embalmed Greek cadavers (mean age 59 +/- 13 years) were examined. RESULTS: The ARSA was detected in 6 cadavers (2.2%), 4 females (2.8%) and 2 males (1.6%). The artery followed a retroesophageal course in 83%, an interesophageotracheal course in 16.7%, while no pretracheal ARSA was detected. The ARSA coexisted with a bicarotid trunk, a Kommerell diverticulum, and a combination of them in one cadaver. Alpha combination of the ARSA with a thyroidea ima artery and a bilateral abnormal origin of the internal mammary artery was also detected in one case (17%), while no other associated anomaly was detected in a single case (17%). All ARSAs were accompanied with a right non-recurrent laryngeal nerve. CONCLUSION: The ARSA has a relative high incidence in Greeks and a female predominance. The aberrant vessel follows a retroesophageal course in most cases and only one case with a location between trachea and esophagus was detected. The retroesophageal ARSA justifies the wide variety of clinical manifestations and complications occurred. PMID- 27999943 TI - Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis. AB - This study aimed to determine whether the long-term use of biologic agents increases serious infections in elderly patients with rheumatoid arthritis (RA) and to determine the risk factors of serious infections in biologics-treated elderly RA patients. We retrospectively analyzed the incidence rate of serious infections that required hospitalization between biologics-treated and non biologic disease-modifying antirheumatic drug (DMARD)-treated elderly RA patients (aged over 65 years). We examined the risk factors for serious infections in biologics-treated elderly RA patients. We found that, during a 3-year observation period, the incidence rate of serious infections was not significantly different between biologics-treated and non-biologic DMARD-treated elderly RA patients [8.0 (95% CI 4.7-13.5) and 6.3 (95% CI 4.1-9.5) events per 100 person-years of follow up, respectively, P = 0.78]. The time to the first serious infection did not significantly differ between the two groups by the analysis of the Kaplan-Meier curves, either (P = 0.46). We then found that prednisolone doses alone were significantly associated with serious infections in biologics-treated elderly RA patients. Furthermore, we found that prednisolone at 1-4 mg/day was associated with serious infections in biologics-treated patients, but not non-biologic DMARD treated patients. On the other hand, prednisolone at greater than 5 mg/day was associated with serious infections in both biologics-treated and non-biologics treated patients. We show that there is not a significant difference between the incidence of serious infections between biologics group and non-biologics group in elderly RA patients (?65 years) and that even very low-dose glucocorticoid use (prednisolone 1-4 mg/day) is a risk factor for serious infections in biologics treated elderly RA patients. PMID- 27999945 TI - A rare branching pattern of hindgut: absence of inferior mesenteric artery. AB - The arterial system of the gastrointestinal tract has many variations. However, variation in the inferior mesenteric artery (IMA) is less common than for the other abdominal arteries. The case in the present cadaver subject showed a variation in the anatomy of the IMA that differed from those seen in previous studies, because it did not originate from the abdominal aorta and had no branches. A single artery arising from branches of the inferior pancreaticoduodenal and middle colic arteries supplied the hindgut. This variation generated blood vessels along the digestive tract during the later stages of development. The marginal artery of the colon in this case probably was more highly developed instead of the IMA. It is clinically important to know the range of variations, as these data are used in the diagnosis and treatment of abdominal diseases. This hitherto unknown variation might affect the health of patients, and we recommend radiographic examinations for diagnosis and treatment. PMID- 27999946 TI - Biokinetic measurements and modelling of urinary excretion of cerium citrate in humans. AB - Tracer kinetics in healthy human volunteers was studied applying stable isotopes of cerium citrate to obtain biokinetic human data for the urinary excretion of cerium. These data were then used to compare and validate the biokinetic model for lanthanides (cerium) proposed by Taylor and Leggett (Radiat Prot Dosim 105:193-198, 2003), which is substantially improved and more realistic than the biokinetic model currently recommended by the International Commission on Radiological Protection (ICRP Publication 67, 1993); both models are primarily based on animal data. In the present study, 16 adults were investigated and two cerium tracers were simultaneously administered, both intravenously and/or orally. The cerium concentrations in urine were determined by inductively coupled plasma mass spectrometry. Ingested cerium citrate was poorly absorbed, and its low excretion was similar to the prediction of the biokinetic model of Taylor and Leggett. In contrast, after injection of cerium citrate its urinary excretion was rapidly increased, and the model underestimated the experimental results. These results suggest that urinary excretion of cerium may be dependent on the administered chemical form of cerium (speciation). PMID- 27999947 TI - Comparison of in vivo immune responses following transplantation of vascularized and non-vascularized human dermo-epidermal skin substitutes. AB - PURPOSE: Autologous bio-engineered dermo-epidermal skin substitutes (DESS) represent an alternative therapeutic option for a definitive treatment of skin defects in human patients. Largely, the interaction of host immune cells with transplanted DESS is considered to be essential for the granulation tissue formation, graft take, and its functionality. The aim of this study was to compare the spatiotemporal distribution and density of host-derived monocytes/macrophages and granulocytes in vascularized (vascDESS) versus non vascularized DESS (non-vascDESS) in a rat model. METHODS: Keratinocytes and the stromal vascular fraction (SVF) were derived from human skin or human adipose tissue, respectively. Human SVF containing both endothelial and mesenchymal/stromal progenitors was used to develop a vascularized collagen type I-based dermal component in vitro. The donor-matched, monolayer-expanded adipose stromal cells lacking endothelial cells were used as a negative control. Subsequently, human keratinocytes were seeded on top of hydrogels to build dermo epidermal skin grafts. After transplantation onto full-thickness skin wounds on the back of immuno-incompetent rats, grafts were excised and analyzed after 1 and 3 weeks. The expression of distinct inflammatory cell markers specific for host derived monocytes/macrophages (CD11b, CD68) or granulocytes (HIS48) was analyzed by immunofluorescence microscopy. RESULTS: All skin grafts were infiltrated by host-derived monocytes/macrophages (CD11b+, CD68+) and granulocytes (HIS48+) between 1-3 week post-transplantation. When compared to non-vascDESS, the vascDESS showed an increased granulocyte infiltration at all time points analyzed with the majority of cells scattered throughout the whole dermal part. Whereas a moderate number of rat monocytes/macrophages (CD11b+, CD68+) were found in vascDESS at 1 week, only a few cells were detected in non-vascDESS. We observed a time-dependent decrease of monocytes/macrophages in all transplants at 3 weeks. CONCLUSIONS: These results demonstrate a distinct spatiotemporal distribution of monocytes/macrophages as well as granulocytes in our transplants that closely resemble the one observed during physiological wound healing. The differences identified between vascDESS and non-vascDESS may indicate that human endothelial cells lining blood capillaries of vascDESS accelerate infiltration of monocytes and leukocytes. PMID- 27999948 TI - Overestimation by echocardiography of the peak systolic pressure gradient between the right ventricle and right atrium due to tricuspid regurgitation and the usefulness of the early diastolic transpulmonary valve pressure gradient for estimating pulmonary artery pressure. AB - We investigated the influence of tricuspid regurgitation (TR) severity on the echocardiographic peak systolic transtricuspid pressure gradient (TRPG) and evaluated the usefulness of the peak early diastolic transpulmonary valve pressure gradient (PRPG) for estimating pulmonary artery (PA) pressure. In 55 consecutive right heart-catheterized patients, we measured the peak systolic right ventricular (RV)-right atrial (RA) pressure gradient (RV-RACATH), peak early diastolic PA-RV pressure gradient (PA-RVCATH), and mean PA pressure (MPAPCATH). Using echocardiography, we obtained the TRPG, PRPG, and an estimate of the mean PA pressure (EMPAP) as the sum of PRPG and the estimated RA pressure, and measured the vena contracta width of TR (VCTR). The difference between the TRPG and RV-RACATH was significantly greater in the very severe TR group (VCTR > 11 mm) than in the mild, moderate, and severe TR groups, and significantly greater in the severe TR group (7 < VCTR <= 11 mm) than in the mild TR group. The overestimation of the pressure gradient >10 mmHg by TRPG was not seen in the mild or moderate TR groups, but was observed in the severe and very severe TR groups (22 and 83%, respectively). In the ROC analysis, EMPAP could distinguish patients with MPAPCATH >= 25 mmHg with the area under the curve of 0.93, 100% sensitivity, and 87% specificity. In conclusion, TRPG frequently overestimated RV-RACATH when VCTR was >11 mm and sometimes did when VCTR was >7 mm, where EMPAP using PRPG was useful for estimating PA pressure. PMID- 27999949 TI - Anemia in nephrotic syndrome: approach to evaluation and treatment. AB - Nephrotic syndrome is one of the most common glomerular diseases that affect in children. Complications may occur in nephrotic syndrome as a result of the disease itself as well as its treatment. Most of these complications result from excessive urinary protein losses, and control of proteinuria is the most effective treatment strategy. Anemia is one of the many complications seen in patients with persistent nephrotic syndrome and may occur as a result of excessive urinary losses of iron, transferrin, erythropoietin, transcobalamin and/or metals. This leads to a deficiency of substrates necessary for effective erythropoiesis, requiring supplementation in order to correct the anemia. Supplementation of iron and erythropoietin alone often does not lead to correction of the anemia, suggesting other possible mechanisms which need further investigation. A clear understanding of the pathophysiologic mechanisms of anemia in nephrotic syndrome is necessary to guide appropriate therapy, but only limited evidence is currently available on the precise etiologic mechanisms of anemia in nephrotic syndrome. In this review we focus on the current state of knowledge on the pathogenesis of anemia in nephrotic syndrome. PMID- 27999950 TI - The single-center experience with the standardization of single-site laparoscopic colectomy for right-sided colon cancer. AB - PURPOSE: Complete mesocolic excision (CME) with central vascular ligation (CVL) has been widely accepted as a surgical treatment for right-sided colon cancer. Single-site laparoscopic colectomy (SLC) is associated with reduced pain and improved cosmesis, in comparison to the multi-site laparoscopic colectomy (MCL). Although the feasibility of CME + CVL under MCL has been reported, SLC for right sided colon cancer is generally challenging. The purpose of this study is to demonstrate our efforts to standardize the SLC for right-sided colon cancer. METHODS: This retrospective study enrolled 202 consecutive patients with right sided colon cancer who underwent laparoscopic colectomy for right-sided colon cancer, using an inferior approach and intraoperative navigation surgery, between 2008 and 2014. The patients were divided into 3 groups, based on the period of treatment, as follows: Period I (2008-2009, n = 56), Period II (2010-2011, n = 70), and Period III (2012-2014, n = 76). RESULTS: The patient's baseline characteristics did not differ among the three periods. The ratio of SLC significantly increased with the passage of the time. The short-term outcomes were similar among the three periods. As for oncological clearance, there was a significant increase in the number of resected lymph nodes with the passage of the time (P < 0.05). CONCLUSIONS: We successfully standardized SLC for right sided colon cancer. PMID- 27999952 TI - Franz Brentano and the beginning of experimental psychology: implications for the study of psychological phenomena today. AB - The manifestation of psychology as an academic discipline more than a 100 years ago was accompanied by a paradigm shift in our understanding of psychological phenomena-with both its light and shadow sides. On the one hand, this development allowed for a rigorous and experimentation-based approach to psychological phenomena; on the other, it led to an alienation from the experiential-or qualia facets as the topics under inquiry were researched increasingly through third person (e.g., behavioral or physiological) measures. At the turning point of this development stood an eminent but little known European scholar, Franz Brentano, who called for a synthesis of both third-person and first-person research methods in the study of psychological phenomena. On the occasion of his death, a hundred years ago on March 17, 1917 we wish to illustrate the historical background, introduce the reader to Brentano's approach and work and discuss its relevance for experimental psychology today. PMID- 27999951 TI - Physician role in physical activity for African-American males undergoing radical prostatectomy for prostate cancer. AB - PURPOSE: Physical activity is recognized as a complementary therapy to improve physical and physiological functions among prostate cancer survivors. Little is known about communication between health providers and African-American prostate cancer patients, a high risk population, regarding the health benefits of regular physical activity on their prognosis and recovery. This study explores African American prostate cancer survivors' experiences with physical activity prescription from their physicians. METHODS: Three focus group interviews were conducted with 12 African-American prostate cancer survivors in May 2014 in St. Louis, MO. Participants' ages ranged from 49 to 79 years, had completed radical prostatectomy, and their time out of surgery varied from 7 to 31 months. RESULTS: Emerged themes included physician role on prescribing physical activity, patients' perceived barriers to engaging in physical activity, perception of normalcy following surgery, and specific resources survivors' sought during treatment. Of the 12 men who participated, 8 men (67%) expressed that their physicians did not recommend physical activity for them. Although some participants revealed they were aware of the importance of sustained physical activity on their prognosis and recovery, some expressed concerns that urinary dysfunction, incontinence, and family commitments prevented them from engaging in active lifestyles. CONCLUSIONS: Transitioning from post radical prostatectomy treatment to normal life was an important concern to survivors. These findings highlight the importance of physical activity communication and prescription for prostate cancer patients. PMID- 27999953 TI - The role of magnetic resonance imaging in the evaluation of peripheral nerves following traumatic lesion: where do we stand? AB - BACKGROUND: Peripheral nerve injury is a common and important cause of morbidity and disability in patients who have suffered a traumatic injury, particularly younger people. Various different injuries can result in damage to specific nerves. In patients with multiple trauma, the prevalence of peripheral nerve injury is estimated at 2.8%, but can reach 5% with the inclusion of brachial plexus involvement. Physical examination, as well as the origin and location of the trauma, can indicate the nerve involved and the type of nerve damage. However, the depth and severity of damage, and the structures involved often cannot be determined initially, but depend on longer periods of observation to reach a definitive and accurate diagnosis for which treatment can be proposed. Current approaches to locate and assess the severity of traumatic nerve injury involve clinical and electrodiagnostic studies. From a clinical and neurophysiological point of view, nerve injuries are classified in an attempt to correlate the degree of injury with symptoms, type of pathology, and prognosis, as well as to determine the therapy to be adopted. OBJECTIVES: MRI in the diagnosis of traumatic peripheral nerve injury has increasingly been used by surgeons in clinical practice. In this article, we analyze the use of magnetic resonance (MR) for the evaluation of traumatic peripheral nerve diseases that are surgically treatable. We also consider basic concepts in the evaluation of technical and MR signs of peripheral nerve injuries. MATERIALS AND METHODS: Studies were identified following a computerized search of MEDLINE (1950 to present), EMBASE (1980 to present), and the Cochrane database. The MEDLINE search was conducted on PUBMED, the EMBASE search was conducted on OVID, and the Cochrane database was conducted using their online library. A set was created using the terms: 'traumatic', 'nerve', and 'resonance'. RESULTS: The included articles were identified using a computerized search and the resulting databases were then sorted according to the inclusion and exclusion criteria. This yielded 10,340 articles (MEDLINE, n = 758; EMBASE, n = 9564; and Cochrane, n = 18). A search strategy was then built by excluding articles that only concern plexus injury and adding the terms 'neuropathies', 'DTI' and 'neurotmesis'. In total, seven studies were included in the review effectively addressing the role of MRI in the evaluation of traumatic peripheral nerve injury. We extracted all relevant information on the imaging findings and the use of magnetic resonance in trauma. We did not include technical or specific radiological aspects of the imaging techniques. CONCLUSIONS: These seven articles were subsequently evaluated by analyzing their results, methodological approach, and conclusions presented. PMID- 27999954 TI - Hemorrhoids and the recurrent attempts to destroy them. PMID- 27999955 TI - Conservatism and "copy-if-better" in chimpanzees (Pan troglodytes). AB - Social learning is predicted to evolve in socially living animals provided the learning process is not random but biased by certain socio-ecological factors. One bias of particular interest for the emergence of (cumulative) culture is the tendency to forgo personal behaviour in favour of relatively better variants observed in others, also known as the "copy-if-better" strategy. We investigated whether chimpanzees employ copy-if-better in a simple token-exchange paradigm controlling for individual and random social learning. After being trained on one token-type, subjects were confronted with a conspecific demonstrator who either received the same food reward as the subject (control condition) or a higher value food reward than the subject (test condition) for exchanging another token type. In general, the chimpanzees persisted in exchanging the token-type they were trained on individually, indicating a form of conservatism consistent with previous studies. However, the chimpanzees were more inclined to copy the demonstrator in the test compared to the control condition, indicating a tendency to employ a copy-if-better strategy. We discuss the validity of our results by considering alternative explanations and relate our findings to the emergence of cumulative culture. PMID- 27999956 TI - Do domestic dogs (Canis lupus familiaris) perceive the Delboeuf illusion? AB - In the last decade, visual illusions have been repeatedly used as a tool to compare visual perception among species. Several studies have investigated whether non-human primates perceive visual illusions in a human-like fashion, but little attention has been paid to other mammals, and sensitivity to visual illusions has been never investigated in the dog. Here, we studied whether domestic dogs perceive the Delboeuf illusion. In human and non-human primates, this illusion creates a misperception of item size as a function of its surrounding context. To examine this effect in dogs, we adapted the spontaneous preference paradigm recently used with chimpanzees. Subjects were presented with two plates containing food. In control trials, two different amounts of food were presented in two identical plates. In this circumstance, dogs were expected to select the larger amount. In test trials, equal food portion sizes were presented in two plates differing in size: if dogs perceived the illusion as primates do, they were expected to select the amount of food presented in the smaller plate. Dogs significantly discriminated the two alternatives in control trials, whereas their performance did not differ from chance in test trials with the illusory pattern. The fact that dogs do not seem to be susceptible to the Delboeuf illusion suggests a potential discontinuity in the perceptual biases affecting size judgments between primates and dogs. PMID- 27999957 TI - Postoperative Ileus: Pathophysiology, Current Therapeutic Approaches. AB - Postoperative ileus, which develops after each abdominal surgical procedure, is an iatrogenic disorder characterized by a transient inhibition of gastrointestinal motility. Its pathophysiology is complex involving pharmacological (opioids, anesthetics), neural, and immune-mediated mechanisms. The early neural phase, triggered by activation of afferent nerves during the surgical procedure, is short lasting compared to the later inflammatory phase. The latter starts after 3-6 h and lasts several days, making it a more interesting target for treatment. Insight into the triggers and immune cells involved is of great importance for the development of new therapeutic strategies. In this chapter, the pathogenesis and the current therapeutic approaches to treat postoperative ileus are discussed. PMID- 27999959 TI - Validation of trauma scales: ISS, NISS, RTS and TRISS for predicting mortality in a Colombian population. AB - BACKGROUND: Our purpose was to validate the performance of the ISS, NISS, RTS and TRISS scales as predictors of mortality in a population of trauma patients in a Latin American setting. MATERIALS AND METHODS: Subjects older than 15 years with diagnosis of trauma, lesions in two or more body areas according to the AIS and whose initial attention was at the hospital in the first 24 h were included. The main outcome was inpatient mortality. Secondary outcomes were admission to the intensive care unit, requirement of mechanical ventilation and length of stay. A logistic regression model for hospital mortality was fitted with each of the scales as an independent variable, and its predictive accuracy was evaluated through discrimination and calibration statistics. RESULTS: Between January 2007 and July 2015, 4085 subjects were enrolled in the study. 84.2% (n = 3442) were male, the mean age was 36 years (SD = 16), and the most common trauma mechanism was blunt type (80.1%; n = 3273). The medians of ISS, NISS, TRISS and RTS were: 14 (IQR = 10-21), 17 (IQR = 11-27), 4.21 (IQR = 2.95-5.05) and 7.84 (IQR = 6.90 7.84), respectively. Mortality was 9.3%, and the discrimination for ISS, NISS, TRISS and RTS was: AUC 0.85, 0.89, 0.86 and 0.92, respectively. No one scale had appropriate calibration. CONCLUSION: Determining the severity of trauma is an essential tool to guide treatment and establish the necessary resources for attention. In a Colombian population from a capital city, trauma scales have adequate performance for the prediction of mortality in patients with trauma. PMID- 27999958 TI - Use of patient-specific cutting blocks reduces blood loss after total knee arthroplasty. AB - Total knee arthroplasty (TKA) is associated with substantial blood loss. Sources of bleeding are the femoral and tibial intramedullary canals, which are violated during implantation using standard instrumentation. Patient-specific instrumentation (PSI) and computer-assisted surgery (CAS) do not require violation of the intramedullary canals. Therefore, we sought to assess the impact of these methods on blood loss and transfusion requirement. A retrospective cohort study was conducted in a series of 107 consecutive primary TKAs. The first group (n = 32) was operated with standard instrumentation, the second group (n = 35) with CAS and the third group (n = 40) with PSI. A tourniquet was used in all cases. Mean (standard deviation) calculated total blood loss was 442 (160), 750 (271) and 700 (401) ml for the PSI, CAS and standard instrumentation groups, respectively (p < 0.001), with no significant differences between CAS and standard instrumentation (p = 0.799). Significant differences were found in terms of transfusion requirements, with 12.5, 42.9 and 21.8% of the patients requiring transfusion (p = 0.010). Post hoc analysis revealed that only the difference between PSI and CAS were statistically significant (p = 0.003). In conclusion, PSI reduces blood loss when compared to both CAS and standard instrumentation TKA performed with the use of a tourniquet. PMID- 27999960 TI - Quality of life of elderly patients on peritoneal dialysis versus hemodialysis: a single-center study. AB - BACKGROUND: The number of elderly dialysis patients in Japan is dramatically increasing. Receiving therapy with better satisfaction through home care is one of the important factors in their daily lives. Thus, the quality of life of elderly patients on hemodialysis (HD) or peritoneal dialysis (PD) was evaluated. METHODS: Clinical information of patients aged >=80 years who started dialysis at our hospital between January 2013 and December 2015 was retrospectively collected. The mortality rate, length of hospitalization, and place of death were identified to evaluate patient quality of life. RESULTS: In total, 56 patients (14 PD and 42 HD) were enrolled. The mean age of study subjects was 85.2 +/- 4.0 years. The proportion of PD patients who lived with their family or have professional caregivers who could assist them in their daily life was higher than that of HD patients (100 vs. 76.2%, respectively; p = 0.044). Mortality rate was higher in PD patients than in HD patients (p = 0.003), but long-term hospitalization of >180 days was observed only in HD patients (PD vs. HD: 0.0 vs. 16.7%; p = 0.102). In patients with Barthel index scores <100, the long-term hospitalization difference was significant (PD vs. HD: 0.0 vs. 30.4%; p = 0.040). Of note, 6 of 7 deceased PD patients and 1 of 10 deceased HD patients died at home (p = 0.002). CONCLUSION: PD is a desirable home care therapy for elderly patients, but the burden on caregivers should be considered. PMID- 27999962 TI - Human lung ex vivo infection models. AB - Pneumonia is counted among the leading causes of death worldwide. Viruses, bacteria and pathogen-related molecules interact with cells present in the human alveolus by numerous, yet poorly understood ways. Traditional cell culture models little reflect the cellular composition, matrix complexity and three-dimensional architecture of the human lung. Integrative animal models suffer from species differences, which are of particular importance for the investigation of zoonotic lung diseases. The use of cultured ex vivo infected human lung tissue may overcome some of these limitations and complement traditional models. The present review gives an overview of common bacterial lung infections, such as pneumococcal infection and of widely neglected pathogens modeled in ex vivo infected lung tissue. The role of ex vivo infected lung tissue for the investigation of emerging viral zoonosis including influenza A virus and Middle East respiratory syndrome coronavirus is discussed. Finally, further directions for the elaboration of such models are revealed. Overall, the introduced models represent meaningful and robust methods to investigate principles of pathogen host interaction in original human lung tissue. PMID- 27999961 TI - Long-term outcomes of initial therapy for idiopathic membranous nephropathy. AB - BACKGROUND: The objective of this study is to determine whether initial steroid therapy is actually effective for the treatment of iMN, and we examined a 40% reduction in estimated glomerular filtration rate (eGFR) and remission rates. METHODS: This was a retrospective study between 1993 and 2013. First, we divided patients with iMN having a urinary protein level of >=1 g/gCre into two groups: those who had received steroid therapy (Group S1; n = 52) within 6 months of diagnosis and those who had received supportive therapy (Group H1; n = 31). Second, we compared 20 cases using propensity score matching (Group S2, Group H2). Third, we compared patients with a urinary protein level of 1-3.5 g/gCre (Group S3, n = 18; Group H3, n = 19) and those with a urinary protein level >=3.5 g/gCre (Group S4, n = 34; Group H4, n = 12). The primary endpoint was a 40% reduction in eGFR, and the secondary endpoint was the achievement of complete remission (CR). RESULTS: In Group S1 and Group H1, a 40% reduction in the eGFR was observed at the end of 5 years in 18 and 17% of the patients, respectively (P = 0.93); at the end of 10 years, these rates had increased to 43% and 50%, respectively (P = 0.88). The CR rates at the end of 5 years were 58% and 32%, respectively (P = 0.02), while the rates at 10 years were 65 and 39%, respectively (P = 0.02). No difference in renal outcomes was observed between Group S1 and Group H1. No significant differences were observed between Group S2 and Group H2, between Group S3 and Group H3, or between Group S4 and Group H4. CONCLUSION: Initial steroid therapy is not superior to supportive care within the first 6 months after diagnosis in terms of a 40% reduction in eGFR. PMID- 27999963 TI - Identification of an endocannabinoid system in the rat pars tuberalis-a possible interface in the hypothalamic-pituitary-adrenal system? AB - Endocannabinoids (ECs) are ubiquitous endogenous lipid derivatives and play an important role in intercellular communication either in an autocrine/paracrine or in an endocrine fashion. Recently, an intrinsic EC system has been discovered in the hypophysial pars tuberalis (PT) of hamsters and humans. In hamsters, this EC system is under photoperiodic control and appears to influence the secretion of hormones such as prolactin from the adenohypophysis. We investigate the EC system in the PT of the rat, a frequently used species in endocrine research. By means of immunocytochemistry, enzymes involved in EC biosynthesis, e.g., N-arachidonoyl phosphatidylethanolamine-phospholipase D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLalpha) and enzymes involved in EC degradation, e.g., fatty acid amide hydrolase (FAAH) and cyclooxygenase-2 (COX-2), were demonstrated in PT cells of the rat. Immunoreactions (IR) for FAAH and for the cannabinoid receptor CB1 were observed in corticotrope cells of the rat adenohypophysis; these cells were identified by antibodies against proopiomelanocortin (POMC) or adrenocorticotrophic hormone (ACTH). In the outer zone of the median eminence, numerous nerve fibers and terminals displayed CB1 IR. The majority of these were also immunolabeled by an antibody against corticotropin-releasing factor (CRF). These results suggest that the EC system at the hypothalamo-hypophysial interface affects both the CRF-containing nerve fibers and the corticotrope cells in the adenohypophysis. Our data give rise to the hypothesis that, in addition to its well-known role in the reproductive axis, the PT might influence adrenal functions and, thus, the stress response and immune system. PMID- 27999964 TI - Arbuscular mycorrhizal fungi altered the hypericin, pseudohypericin, and hyperforin content in flowers of Hypericum perforatum grown under contrasting P availability in a highly organic substrate. AB - St. John's Wort (Hypericum perforatum) is a perennial herb able to produce water soluble active ingredients (a.i.), mostly in flowers, with a wide range of medicinal and biotechnological uses. However, information about the ability of arbuscular mycorrhizal fungi (AMF) to affect its biomass accumulation, flower production, and concentration of a.i. under contrasting nutrient availability is still scarce. In the present experiment, we evaluated the role of AMF on growth, flower production, and concentration of bioactive secondary metabolites (hypericin, pseudohypericin, and hyperforin) of H. perforatum under contrasting P availability. AMF stimulated the production of aboveground biomass under low P conditions and increased the production of root biomass. AMF almost halved the number of flowers per plant by means of a reduction of the number of flower bearing stems per plant under high P availability and through a lower number of flowers per stem in the low-P treatment. Flower hyperforin concentration was 17.5% lower in mycorrhizal than in non-mycorrhizal plants. On the contrary, pseudohypericin and hypericin concentrations increased by 166.8 and 279.2%, respectively, with AMF under low P availability, whereas no effect of AMF was found under high P availability. These results have implications for modulating the secondary metabolite production of H. perforatum. However, further studies are needed to evaluate the competition for photosynthates between AMF and flowers at different nutrient availabilities for both plant and AM fungus. PMID- 27999966 TI - Consolidated ethanol production from Jerusalem artichoke tubers at elevated temperature by Saccharomyces cerevisiae engineered with inulinase expression through cell surface display. AB - Ethanol fermentation from Jerusalem artichoke tubers was performed at elevated temperatures by the consolidated bioprocessing strategy using Saccharomyces cerevisiae MK01 expressing inulinase through cell surface display. No significant difference was observed in yeast growth when temperature was controlled at 38 and 40 degrees C, respectively, but inulinase activity with yeast cells was substantially enhanced at 40 degrees C. As a result, enzymatic hydrolysis of inulin was facilitated and ethanol production was improved with 89.3 g/L ethanol produced within 72 h from 198.2 g/L total inulin sugars consumed. Similar results were also observed in ethanol production from Jerusalem artichoke tubers with 85.2 g/L ethanol produced within 72 h from 185.7 g/L total sugars consumed. On the other hand, capital investment on cooling facilities and energy consumption for running the facilities would be saved, since regular cooling water instead of chill water could be used to cool down the fermentation system. PMID- 27999965 TI - Genotypic-dependent effects of N fertilizer, glutathione, silicon, zinc, and selenium on proteomic profiles, amino acid contents, and quality of rice genotypes with contrasting grain Cd accumulation. AB - Soil heavy metal (HM) contamination has posed a serious problem for safe food production. For restricting the translocation of HM into grain, many proteins were regulated to involve in the process. To identify these proteins, 2D-based proteomic analysis was carried out using different rice genotypes with distinct Cd accumulation in grains and as affected by an alleviating regulator (AR) in field experiments. AR application improved grain quality, with increased contents in Glu, Cys, His, Pro, and protein. Twenty-six low-grain HM accumulation associated protein species were identified and categorized as physiological functions via two-dimensional gel electrophoresis (2DE) and mass spectrometry. Among these proteins, 8, 9, and 9 proteins exhibited higher accumulation, lower accumulation, and unchanged accumulation, respectively, in Xiushui817 (low accumulator) vs R8097 (high accumulator) under control conditions but showed differential accumulation patterns after AR application. These proteins included sucrose synthase 3, alanine aminotransferase, glutelin, cupin family protein, and zinc finger CCCH domain-containing protein 32. The differential expression of these protein species might contribute to decreased HM accumulation in grain via decreasing the protein accumulation which had high affinity to HM or regulating energy metabolism and signal transduction. Our findings provide valuable insights into the mechanisms of low-grain HM accumulation in rice and possible utilization of candidate protein species in developing low-grain HM accumulation genotypes. PMID- 27999967 TI - High-yield production of aryl alcohol oxidase under limited growth conditions in small-scale systems using a mutant Aspergillus nidulans strain. AB - Aryl alcohol oxidase (MtGloA) is an enzyme that belongs to the ligninolytic consortium and can play an important role in the bioenergy industry. This study investigated production of an MtGloA client enzyme by a mutant strain of Aspergillus nidulans unable to synthesize its own pyridoxine. Pyridoxine limitation can be used to control cell growth, diverting substrate to protein production. In agitated culture, enzyme production was similar when using media with 1 mg/L and without pyridoxine (26.64 +/- 6.14 U/mg mycelia and 26.14 +/- 8.39 U/mg mycelia using media with and without pyridoxine, respectively). However, the treatment lacking pyridoxine had to be supplemented with pyridoxine after 156 h of fermentation to sustain continued enzyme production. Use of extremely diluted pyridoxine levels allowed reduced fungal growth while maintaining steady enzyme production. Concentrations of 9 and 13.5 ug/L pyridoxine allowed MtGloA production with a growth rate of only 5% of that observed when using the standard 1 mg/L pyridoxine media. PMID- 27999968 TI - RNA-seq for comparative transcript profiling of kenaf under salinity stress. AB - Kenaf (Hibiscus cannabinus L.) is an economically important global natural fiber crop. As a consequence of the increased demand for food crops and the reduction of available arable land, kenaf cultivation has increasingly shifted to saline and alkaline land. To investigate the molecular mechanism of salinity tolerance in kenaf, we performed Illumina high-throughput RNA sequencing on shoot tips of kenaf and identified 71,318 unigenes, which were annotated using four different protein databases. In total, 2,384 differentially expressed genes (DEGs) were identified between the salt-stressed and the control plants, 1,702 of these transcripts were up-regulated and 683 transcripts were down-regulated. Thirty seven transcripts belonging to 15 transcription-factor families that respond to salt stress were identified. Gene ontology function enrichment analysis revealed that the genes encoding antioxidant enzymes were up-regulated. The amino acid metabolism and carbohydrate metabolism pathways were highly enriched among these DEGs under salt stress conditions. In order to confirm the RNA-seq data, we randomly selected 20 unigenes for analysis using a quntitative real-time polymerase chain reaction. Our study not only provided the large-scale assessment of transcriptome resources of kenaf but also guidelines for understanding the mechanism underlying salt stress responses in kenaf. PMID- 27999969 TI - Functions of long intergenic non-coding (linc) RNAs in plants. AB - Whole transcriptome analyses in many organisms have revealed that most transcribed RNAs do not encode proteins. These non-coding RNAs likely contribute to the regulation of gene expression during the development of multicellular organisms. In eukaryotes, the roles of small RNAs, one class of non-coding RNAs, in transcriptional and post-transcriptional regulation have been well characterized. However, the functions of a second class of non-coding RNAs, long intergenic noncoding (linc) RNAs, are relatively unknown, especially in plants. Recent advances in RNA-seq and tiling microarray technologies have revealed the presence of many lincRNAs across plant species. This review focuses on the functions of lincRNAs that have been recently reported in plants. One of the most well characterized functions of lincRNAs is to epigenetically regulate gene expression by recruiting proteins for chromosome modification to specific loci. Second, lincRNAs are known to inhibit the physical interaction between microRNAs (miRNAs) and their target mRNAs thus controling protein levels of the target mRNAs. Lastly, lincRNAs control alternative splicing by binding and sequestering the proteins required for alternative splicing. PMID- 27999970 TI - Oral 30% glucose provides sufficient sedation in newborns during MRI. AB - PURPOSE: Newborns are often sedated during MRI but sedation itself creates adverse events and management is more challenging in this environment. Oral glucose/sucrose administration has been studied in newborns during painful procedures; however, its effectiveness in keeping newborns sleepy and motionlessness during painless procedures has not been demonstrated. The objective of this study was to describe effectiveness of oral 30% glucose administration by comparing with intravenous midazolam sedation for newborns during MRI. METHODS: One hundred twelve ASA II-III newborns who required care in the ICU and were scheduled for MRI with sedation were included. Group I received 30% glucose solution orally with 0.5-1 ml increments up to 2 ml/3 kg doses and group II received intravenous 0.1 mg/kg midazolam with 0.05 mg/kg repetition. The procedure was considered satisfactory when MRI images were not disturbed by patient movement after oral glucose or intravenous midazolam administration. The efficiency of the techniques, additional dose and rescue sedation requirements, blood glucose levels following oral 30% glucose suckling and presence of adverse events were recorded. RESULTS: Demographic data was similar between groups. The efficiency of the procedures were similar between groups (78.9%, in group I and 66.1%, in group II). The blood glucose levels were within normal range in group I whereas transient desaturation and apnea occurred in 8 neonates in group II (p = 0.006). CONCLUSION: Oral 30% glucose administration for newborns during MRI is as effective as standard sedation protocol with midazolam. Thereby, we recommend and support the integration of this safe and reliable technique into routine practice for newborns during MRI. PMID- 27999971 TI - The prevalence of multiple non-communicable diseases among middle-aged and elderly people: the Shanghai Changfeng Study. AB - OBJECTIVE: We set out to study the prevalence and combination of multiple non communicable diseases among middle-aged and elderly people in the Shanghai Changfeng community, China. METHODS: A cross-sectional survey through questionnaire, physical, and laboratory examinations, color ultrasound and DXA was performed on a typical sample of 6038 residents (ages greater than 45-years old) from the Shanghai Changfeng community between June 2009 and December 2012. RESULTS: The prevalence of chronic diseases (rating from high to low) was as follows: hypertension (55.3%), dyslipidemia (33.5%), diabetes (21.9%), obesity (12.4%), and osteoporosis (9.3%). There were sex-specific and age-specific differences in these diseases. Just less than half (40.5%) the study population suffered from two or more chronic diseases. Hypertension patients were more likely to suffer from obesity, diabetes, dyslipidemia, and risk factors for cardiovascular diseases, but not osteoporosis. The most common combination of multiple diseases was hypertension with dyslipidemia (9.95%) or diabetes (6.61%). CONCLUSION: In the Chinese middle-aged and elderly population, the most common multiple non-communicable diseases, including hypertension, dyslipidemia, diabetes, and obesity should be controlled to prevent cardiovascular disease. PMID- 27999972 TI - Decreased formation of branched-chain short fatty acids in Bacillus amyloliquefaciens by metabolic engineering. AB - OBJECTIVES: To reduce the unpleasant odor during 1-deoxynojirimycin (DNJ) production, the genes of leucine dehydrogenase (bcd) and phosphate butryltransferase (ptb) were deleted from Bacillus amyloliquefaciens HZ-12, and the concentrations of branched-chain short fatty acids (BCFAs) and DNJ were compared. RESULTS: By knockout of the ptb gene, 1.01 g BCFAs kg-1 was produced from fermented soybean by HZ-12Deltaptb. This was a 56% decrease compared with that of HZ-12 (2.27 g BCFAs kg-1). Moreover, no significant difference was found in the DNJ concentration (0.7 g kg-1). After further deletion of the bcd gene from HZ-12Deltaptb, no BCFAs was detected in fermented soybeans with HZ 12DeltaptbDeltabcd, while the DNJ yield decreased by 26% compared with HZ-12. CONCLUSIONS: HZ-12Deltaptb had decreased BCFAs formation but also maintained the stable DNJ yield, which contributed to producing DNJ-rich products with decreased unpleasant smell. PMID- 27999973 TI - Improvement of desulfurizing activity of haloalkaliphilic Thialkalivibrio versutus SOB306 with the expression of Vitreoscilla hemoglobin gene. AB - OBJECTIVE: To construct efficient transformation and expression system and further improve desulfurizing activity of cells through expression of Vitreoscilla hemoglobin (VHb) in haloalkaliphilic Thialkalivibrio versutus SOB306. RESULTS: We transferred plasmids pKT230 and pBBR-smr into T. versutus SOB306 via a conjugation method. We identified four promoters from among several predicted promoters by scoring for streptomycin resistance, and finally selected tac and p3 based on the efficiency of expression of red fluorescent protein (RFP). Expression of RFP when regulated by tac was more than three times that of p3 in SOB306. Further, we expressed VHb under the control of tac promoter in SOB306. Expression of VHb was verified using CO-difference spectra. The results showed that VHb expression can boost sulfur metabolism, as evidenced by an increase of about 11.7 +/- 1.8% in the average rate of thiosulfate removal in the presence of VHb. CONCLUSION: A conjugation transfer and an expression system for Thialkalivibrio, has been developed for the first time and used for expression of VHb to improve desulfurizing activity. PMID- 27999974 TI - Isolation and characterization of a novel L-glutamate oxidase with strict substrate specificity from Streptomyces diastatochromogenes. AB - OBJECTIVES: To find an L-glutamate oxidase (LGox), to be used for the quantitative analysis of L-glutamic acid, an lgox gene encoding LGox from Streptomyces diastatochromogenes was isolated, cloned and characterized. RESULTS: The gene had an ORF of 1974 bp encoding a protein of 657 amino acid residues. In comparison to the LGox precursor, the proteinase K-treated enzyme exhibited improved affinity to substrate and with a K m of 0.15 mM and V max of 62 MUmol min-1 mg-1. The 50% thermal inactivation temperature of the proteinase K treated enzyme was increased from 50 to 70 degrees C. The enzyme exhibited strict specificity for L-glutamate. CONCLUSIONS: LGox treated by proteinase K exhibited strict specificity for L-glutamate, good thermostability and high substrate affinity. PMID- 27999975 TI - Erratum to: Physiological differences and changes in global DNA methylation levels in Agave angustifolia Haw. albino variant somaclones during the micropropagation process. PMID- 27999976 TI - Changes in transcript expression patterns as a result of cryoprotectant treatment and liquid nitrogen exposure in Arabidopsis shoot tips. AB - KEY MESSAGE: Transcripts related to abiotic stress, oxidation, and wounding were differentially expressed in Arabidopsis shoot tips in response to cryoprotectant and liquid nitrogen treatment. Cryopreservation methods have been implemented in genebanks as a strategy to back-up plant genetic resource collections that are vegetatively propagated. Cryopreservation is frequently performed using vitrification methods, whereby shoot tips are treated with cryoprotectant solutions, such as Plant Vitrification Solution 2 (PVS2) or Plant Vitrification Solution 3 (PVS3); these solutions remove and/or replace freezable water within the meristem cells. We used the model system Arabidopsis thaliana to identify suites of transcripts that are up- or downregulated in response to PVS2 and PVS3 treatment and liquid nitrogen (LN) exposure. Our results suggest that there are many changes in transcript expression in shoot tips as a result of cryoprotection and that these changes exceed the number detected as a result of LN exposure. In total, 180 transcripts showed significant changes in expression level unique to treatment with either the cryoprotectant or cryopreservation followed by recovery. Of these 180 transcripts, 67 were related to stress, defense, wounding, lipid, carbohydrate, abscisic acid, oxidation, temperature (cold/heat), or osmoregulation. The responses of five transcripts were confirmed using qPCR methods. The transcripts responding to PVS2 + LN suggest an oxidative response to this treatment, whereas the PVS3 + LN treatment invoked a more general metabolic response. This work shows that the choice of cryoprotectant can have a major influence on the patterns of transcript expression, presumably due to the level and extent of stress experienced by the shoot tip. As a result, there may be divergent responses of study systems to PVS2 and PVS3 treatments. PMID- 27999977 TI - Auxin synthesis gene tms1 driven by tuber-specific promoter alters hormonal status of transgenic potato plants and their responses to exogenous phytohormones. AB - KEY MESSAGE: Ectopic auxin overproduction in transgenic potato leads to enhanced productivity accompanied with concerted and occasional changes in hormonal status, and causing altered response of transformants to exogenous auxin or cytokinin. Previously, we generated potato transformants expressing Agrobacterium derived auxin synthesis gene tms1 driven by tuber-specific patatin gene promoter (B33-promoter). Here, we studied the endogenous hormonal status and the response to exogenous phytohormones in tms1 transformants cultured in vitro. Adding indole 3-acetic acid (IAA) or kinetin to culture medium affected differently tuberization of tms1-transformed and control plants, depending also on sucrose content in the medium. Exogenous phytohormones ceased to stimulate the tuber initiation in transformants at high (5-8%) sucrose concentration, while in control plants the stimulation was observed in all experimental settings. Furthermore, exogenous auxin partly inhibited the tuber initiation, and exogenous cytokinin reduced the average tuber weight in most transformants at high sucrose content. The elevated auxin level in tubers of the transformants was accompanied with a decrease in content of cytokinin bases and their ribosides in tubers and most shoots. No concerted changes in contents of abscisic, jasmonic, salicylic acids and gibberellins in tubers were detected. The data on hormonal status indicated that the enhanced productivity of tms1 transformants was due to auxin and not mediated by other phytohormones. In addition, exogenous cytokinin was shown to upregulate the expression of genes encoding orthologs of auxin receptors. Overall, the results showed that tms1 expression and local increase in IAA level in transformants affect both the balance of endogenous cytokinins and the dynamics of tuberization in response to exogenous hormones (auxin, cytokinin), the latter reaction depending also on the carbohydrate supply. We introduce a basic model for the hormonal network controlling tuberization. PMID- 27999978 TI - The linin promoter is highly effective in enhancing punicic acid production in Arabidopsis. AB - KEY MESSAGE: Enhanced levels of punicic acid were produced in the seed oil of Arabidopsis over-expressing pomegranate FATTY ACID CONJUGASE driven by heterologous promoters, among which the linin promoter was the most efficient. Fatty acids with conjugated double bonds play a special role in determining both the nutritional and industrial uses of plant oils. Punicic acid (18:3Delta9cis,11trans,13cis ), a conjugated fatty acid naturally enriched in the pomegranate (Punica granatum) seeds, has gained increasing attention from the biotechnology community toward its production in metabolically engineered oilseed crops because of its significant health benefits. The present study focused on selecting the best heterologous promoter to drive the expression of the P. granatum FATTY ACID CONJUGASE (PgFADX) cDNA as a means of producing punicic acid in Arabidopsis seed oil. Among the four promoters of genes encoding seed storage proteins from different crop species, the linin promoter led to the highest accumulation of punicic acid (13.2% of total fatty acids in the best homozygous line). Analysis of the relative expression level of PgFADX in developing seeds further confirmed that the linin promoter was most efficient in Arabidopsis. In addition, a conserved profile of cis-regulatory elements were identified in four heterologous promoters by bioinformatic analysis, and their possible roles in regulating gene expression during plant development were also discussed based on the results of this study in combination with the literature. This study contributes to metabolic engineering strategies aimed at enhancing the production of bioactive fatty acids in oilseed crops. PMID- 27999980 TI - Commentary to "My Identical Twin Sequenced Our Genome": Cautionary Genomics. PMID- 27999979 TI - Salinity induced differential methylation patterns in contrasting cultivars of foxtail millet (Setaria italica L.). AB - KEY MESSAGE: Genome-wide methylation analysis of foxtail millet cultivars contrastingly differing in salinity tolerance revealed DNA demethylation events occurring in tolerant cultivar under salinity stress, eventually modulating the expression of stress-responsive genes. Reduced productivity and significant yield loss are the adverse effects of environmental conditions on physiological and biochemical pathways in crop plants. In this context, understanding the epigenetic machinery underlying the tolerance traits in a naturally stress tolerant crop is imperative. Foxtail millet (Setaria italica) is known for its better tolerance to abiotic stresses compared to other cereal crops. In the present study, methylation-sensitive amplified polymorphism (MSAP) technique was used to quantify the salt-induced methylation changes in two foxtail millet cultivars contrastingly differing in their tolerance levels to salt stress. The study highlighted that the DNA methylation level was significantly reduced in tolerant cultivar compared to sensitive cultivar. A total of 86 polymorphic MSAP fragments were identified, sequenced and functionally annotated. These fragments showed sequence similarity to several genes including ABC transporter, WRKY transcription factor, serine threonine-protein phosphatase, disease resistance, oxidoreductases, cell wall-related enzymes and retrotransposon and transposase like proteins, suggesting salt stress-induced methylation in these genes. Among these, four genes were chosen for expression profiling which showed differential expression pattern between both cultivars of foxtail millet. Altogether, the study infers that salinity stress induces genome-wide DNA demethylation, which in turn, modulates expression of corresponding genes. PMID- 27999981 TI - Phospholipids in mitochondrial dysfunction during hemorrhagic shock. AB - Energy deficiency plays a key role in the development of irreversible shock conditions. Therefore, identifying mitochondrial functional disturbances during hemorrhagic shock should be considered a prospective direction for studying its pathogenesis. Phospholipid (PL)-dependent mechanisms of mitochondrial dysfunction in the brain (i.e., in the frontal lobes of the cerebral hemispheres and medulla oblongata) and liver, which, when damaged, leads to an encephalopathy, are examined in this review. These mechanisms show strong regional specificity. Analyzing the data presented in this review suggests that the basis for mitochondrial functional disturbances is cholinergic hyperactivation, accompanied by a choline deficiency and membrane phosphatidylcholine (PC) depletion. Stabilization of the PL composition in mitochondrial membranes using "empty" PC liposomes could be one of the most important methods for eliminating energy deficiency during massive blood loss. PMID- 27999982 TI - The prognostic effect of DDX3 upregulation in distant breast cancer metastases. AB - Metastatic breast cancer remains one of the leading causes of death in women and identification of novel treatment targets is therefore warranted. Functional studies showed that the RNA helicase DDX3 promotes metastasis, but DDX3 expression was never studied in patient samples of metastatic cancer. In order to validate previous functional studies and to evaluate DDX3 as a potential therapeutic target, we investigated DDX3 expression in paired samples of primary and metastatic breast cancer. Samples from 79 breast cancer patients with distant metastases at various anatomical sites were immunohistochemically stained for DDX3. Both cytoplasmic and nuclear DDX3 expression were compared between primary and metastatic tumors. In addition, the correlation between DDX3 expression and overall survival was assessed. Upregulation of cytoplasmic (28%; OR 3.7; p = 0.002) was common in breast cancer metastases, especially in triple negative (TN) and high grade cases. High cytoplasmic DDX3 levels were most frequent in brain lesions (65%) and significantly correlated with high mitotic activity and triple negative subtype. In addition, worse overall survival was observed for patients with high DDX3 expression in the metastasis (HR 1.79, p = 0.039). Overall, we conclude that DDX3 expression is upregulated in distant breast cancer metastases, especially in the brain and in TN cases. In addition, high metastatic DDX3 expression correlates with worse survival, implying that DDX3 is a potential therapeutic target in metastatic breast cancer, in particular in the clinically important group of TN patients. PMID- 27999983 TI - Can lymphovascular invasion be predicted by preoperative multiphasic dynamic CT in patients with advanced gastric cancer? AB - OBJECTIVES: To determine whether multiphasic dynamic CT can preoperatively predict lymphovascular invasion (LVI) in advanced gastric cancer (AGC). METHODS: 278 patients with AGC who underwent preoperative multiphasic dynamic CT were retrospectively recruited. Tumour CT attenuation difference between non-contrast and arterial (DeltaAP), portal (DeltaPP) and delayed phase (DeltaDP), tumour spleen attenuation difference in the portal phase (DeltaT-S), tumour contrast enhancement ratios (CERs), tumour-to-spleen ratio (TSR) and tumour volumes were obtained. All CT-derived parameters and clinicopathological variables associated with LVI were analysed by univariate analysis, followed by multivariate and receiver operator characteristics (ROC) analysis. Associations between CT predictors for LVI and histopathological characteristics were evaluated by the chi-square test. RESULTS: DeltaPP (OR, 1.056; 95% CI: 1.032-1.080) and DeltaT-S (OR, 1.043; 95% CI: 1.020-1.066) are independent predictors for LVI in AGC. DeltaPP, DeltaT-S and their combination correctly predicted LVI in 74.8% (AUC, 0.775; sensitivity, 88.6%; specificity, 54.1%), 68.7% (AUC, 0.747; sensitivity, 68.3%; specificity, 69.4%) and 71.7% (AUC, 0.800; sensitivity, 67.6%; specificity, 77.8%), respectively. There were significant associations between CT predictors for LVI with tumour histological differentiation and Lauren classification. CONCLUSION: Multiphasic dynamic CT provides a non-invasive method to predict LVI in AGC through quantitative enhancement measurement. KEY POINTS: * Lymphovascular invasion rarely can be evaluated preoperatively in advanced gastric cancer (AGC). * Delta PP and Delta T-S were independent predictors for LVI in patients with AGC. * Delta PP and Delta T-S showed acceptable predictive performance for LVI. * Combination of Delta PP and Delta T-S improved predictive performance for LVI. * Multiphasic dynamic CT may be a useful adjunct for detecting LVI preoperatively. PMID- 27999984 TI - Is there an Added Value of T1-Weighted Contrast-Enhanced Fat-suppressed Spin-Echo MR Sequences Compared to STIR Sequences in MRI of the Foot and Ankle? AB - OBJECTIVES: To prospectively compare T1-weighted fat-suppressed spin-echo magnetic resonance (MR) sequences after gadolinium application (T1wGdFS) to STIR sequences in patients with acute and chronic foot pain. METHODS: In 51 patients referred for MRI of the foot and ankle, additional transverse and sagittal T1wGdFS sequences were obtained. Two sets of MR images (standard protocol with STIR or T1wGdFS) were analysed. Diagnosis, diagnostic confidence, and localization of the abnormality were noted. Standard of reference was established by an expert panel of two experienced MSK radiologists and one experienced foot surgeon based on MR images, clinical charts and surgical reports. Patients reported prospectively localization of pain. Descriptive statistics, McNemar test and Kappa test were used. RESULTS: Diagnostic accuracy with STIR protocol was 80% for reader 1, 67% for reader 2, with contrast-protocol 84%, both readers. Significance was found for reader 2. Diagnostic confidence for reader 1 was 1.7 with STIR, 1.3 with contrast-protocol; reader 2: 2.1/1.7. Significance was found for reader 1. Pain location correlated with STIR sequences in 64% and 52%, with gadolinium sequences in 70% and 71%. CONCLUSIONS: T1-weighted contrast material enhanced fat-suppressed spin-echo magnetic resonance sequences improve diagnostic accuracy, diagnostic confidence and correlation of MR abnormalities with pain location in MRI of the foot and ankle. However, the additional value is small. KEY POINTS: * Additional value of contrast-enhanced MR over standard MR with STIR sequences exists. * There is slightly more added value for soft tissue than for bony lesions. * This added value is limited. * Therefore, application of contrast material cannot be generally recommended. PMID- 27999985 TI - MRI of endolymphatic hydrops in patients with Meniere's disease: a case controlled study with a simplified classification based on saccular morphology. AB - OBJECTIVES: Endolymphatic hydrops (EH) can be studied in patients by MRI. With the semi-quantitative grading system, previous imaging studies showed discrepancies in the occurrence and grading of EH in patients with Meniere's disease (MD). Here, we compared the inversion of the saccule to utricle area ratio (SURI) with the semi-quantitative method of grading conventionally used to diagnose MD. METHODS: Imaging was carried out on a 3-T MRI scanner. We performed 3D-FLAIR sequences 4 h after a single intravenous dose of contrast agent. Two radiologists independently studied the morphology of the inner ear structures in the healthy subjects and MD patients. Each subject was then graded on the basis of the EH semi-quantitative analysis and on saccular morphology using axial and sagittal reference slices in the vestibule plane. RESULTS: Thirty healthy subjects and 30 MD patients had MRI scans. Using the semi-quantitative method, we found no significant difference in the number of subjects with EH between the two groups. SURI was found in 15 out of 30 MD patients and in none of the 30 healthy subjects. In three MD patients the saccule was not visible. CONCLUSION: SURI is currently the most specific criterion for imaging diagnosis of MD. KEY POINTS: * Half of MD patients presented with inversion of the saccule to utricle ratio. * Saccular analysis is crucial when assessing patients with Meniere's disease. * In some patients, the saccule is not visible, suggestive of intra-labyrinthine fistulae. PMID- 27999986 TI - Post-treatment changes of tumour perfusion parameters can help to predict survival in patients with high-grade astrocytoma. AB - OBJECTIVES: Vascular characteristics of tumour and peritumoral volumes of high grade gliomas change with treatment. This work evaluates the variations of T2* weighted perfusion parameters as overall survival (OS) predictors. METHODS: Forty five patients with histologically confirmed high-grade astrocytoma (8 grade III and 37 grade IV) were included. All patients underwent pre- and post-treatment T2*-weighted contrast-enhanced magnetic resonance (MR) imaging. Tumour, peritumoral and control volumes were segmented. Relative variations of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), Ktrans T2*, kep-T2*, ve-T2* and vp-T2* were calculated. Differences regarding tumour grade and surgical resection extension were evaluated with ANOVA tests. For each parameter, two groups were defined by non-supervised clusterisation. Survival analysis were performed on these groups. RESULTS: For the tumour region, the 90th percentile increase or stagnation of CBV was associated with shorter survival, while a decrease related to longer survival (393 +/- 189 vs 594 +/- 294 days; log rank p = 0.019; Cox hazard-ratio, 2.31; 95% confidence interval [CI], 1.12-4.74). Ktrans-T2* showed similar results (414 +/- 177 vs 553 +/- 312 days; log-rank p = 0.037; hazard-ratio, 2.19; 95% CI, 1.03-4.65). The peritumoral area values showed no relationship with OS. CONCLUSIONS: Post-treatment variations of the highest CBV and Ktrans-T2* values in the tumour volume are predictive factors of OS in patients with high-grade gliomas. KEY POINTS: * Vascular characteristics of high grade glioma tumour and peritumoral regions change with treatment. * Quantitative assessment of MRI perfusion provides valuable information regarding tumour aggressiveness. * Quantitative T2*-weighted perfusion parameters can help to predict overall survival. * Post-treatment variations of CBV and K trans-T2 values are predictive factors of OS. * Increased values may justify treatment intensification in these patients. PMID- 27999987 TI - Mapping and application of the twin-grain1 gene in rice. AB - MAIN CONCLUSION: The map-based cloning and application of a flower organ number gene twin - grain1 provide great potential for improving seed production in hybrid rice. A new germplasm for high-yield rice breeding, the twin-grain1 (tg1) mutant with more than one grain in a glume, was obtained from the Zhejing 22 rice variety via physical mutagenesis. The mapping results showed that TG1 is allelic to FLORAL ORGAN NUMBER2 (FON2)/FLORAL ORGAN NUMBER4 (FON4), a flower organ number gene located at 88.7 cM on chromosome 11. The novel tg1 gene allele was introgressed into the cytoplasmic male sterility (CMS) line Zhejing 22A, giving rise to a new CMS line Zhejing 22-tg1A. The Zhejing 22-tg1A line showed enhanced glume opening and stigma exsertion, which increased the outcrossing rate in hybrid rice. A small-scale hybrid rice seed production test demonstrated that the grain yield of the Zhejing 22-tg1A/Zhejinghui 5 line was significantly increased compared to that of the Zhejing 22A/Zhejinghui 5 line. The plot yield evaluation of the F1 hybrid lines showed a higher yield for the Zhejing 22-tg1A/Zhejinghui 5 line than that of the Zhejing 22A/Zhejinghui 5 line. The results implied great potentials for the tg1 gene in hybrid rice breeding. PMID- 27999989 TI - Pot binding as a variable confounding plant phenotype: theoretical derivation and experimental observations. AB - MAIN CONCLUSION: Theoretical derivation predicted growth retardation due to pot water limitations, i.e., pot binding. Experimental observations were consistent with these limitations. Combined, these results indicate a need for caution in high-throughput screening and phenotyping. Pot experiments are a mainstay in many plant studies, including the current emphasis on developing high-throughput, phenotyping systems. Pot studies can be vulnerable to decreased physiological activity of the plants particularly when pot volume is small, i.e., "pot binding". It is necessary to understand the conditions under which pot binding may exist to avoid the confounding influence of pot binding in interpreting experimental results. In this paper, a derivation is offered that gives well defined conditions for the occurrence of pot binding based on restricted water availability. These results showed that not only are pot volume and plant size important variables, but the potting media is critical. Artificial potting mixtures used in many studies, including many high-throughput phenotyping systems, are particularly susceptible to the confounding influences of pot binding. Experimental studies for several crop species are presented that clearly show the existence of thresholds of plant leaf area at which various pot sizes and potting media result in the induction of pot binding even though there may be no immediate, visual plant symptoms. The derivation and experimental results showed that pot binding can readily occur in plant experiments if care is not given to have sufficiently large pots, suitable potting media, and maintenance of pot water status. Clear guidelines are provided for avoiding the confounding effects of water-limited pot binding in studying plant phenotype. PMID- 27999988 TI - Arabidopsis phosphatidylinositol-phospholipase C2 (PLC2) is required for female gametogenesis and embryo development. AB - MAIN CONCLUSION: AtPLC2 is an essential gene in Arabidopsis, since it is required for female gametogenesis and embryo development. AtPLC2 might play a role in cell division during embryo-sac development and early embryogenesis. Phosphoinositide specific phospholipase C (PI-PLC) plays an important role in signal transduction during plant development and in the response to various biotic- and abiotic stresses. The Arabidopsis PI-PLC gene family is composed of nine members, named PLC1 to PLC9. Here, we report that PLC2 is involved in female gametophyte development and early embryogenesis. Using two Arabidopsis allelic T-DNA insertion lines with different phenotypic penetrations, we observed both female gametophytic defects and aberrant embryos. For the plc2-1 mutant (Ws background), no homozygous plants could be recovered in the offspring from self-pollinated plants. Nonetheless, plc2-1 hemizygous mutants are affected in female gametogenesis, showing embryo sacs arrested at early developmental stages. Allelic hemizygous plc2-2 mutant plants (Col-0 background) present reduced seed set and embryos arrested at the pre-globular stage with abnormal patterns of cell division. A low proportion (0.8%) of plc2-2 homozygous mutants was found to escape lethality and showed morphological defects and disrupted megagametogenesis. PLC2-promoter activity was observed during early megagametogenesis, and after fertilization in the embryo proper. Immunolocalization studies in early stage embryos revealed that PLC2 is restricted to the plasma membrane. Altogether, these results establish a role for PLC2 in both reproductive- and embryo development, presumably by controlling mitosis and/or the formation of cell-division planes. PMID- 27999990 TI - Carotenoid gene expression explains the difference of carotenoid accumulation in carrot root tissues. AB - Main conclusion Variations in gene expression can partially explain the difference of carotenoid accumulation in secondary phloem and xylem of fleshy carrot roots. The carrot root is well divided into two different tissues separated by vascular cambium: the secondary phloem and xylem. The equilibrium between these two tissues represents an important issue for carrot quality, but the knowledge about the respective carotenoid accumulation is sparse. The aim of this work was (i) to investigate if variation in carotenoid biosynthesis gene expression could explain differences in carotenoid content in phloem and xylem tissues and (ii) to investigate if this regulation is differentially modulated in the respective tissues by water-restricted growing conditions. In this work, five carrot genotypes contrasting by their root color were studied in control and water-restricted conditions. Carotenoid content and the relative expression of 13 genes along the carotenoid biosynthesis pathway were measured in the respective tissues. Results showed that in orange genotypes and the purple one, carotenoid content was higher in phloem compared to xylem. For the red one, no differences were observed. Moreover, in control condition, variations in gene expression explained the different carotenoid accumulations in both tissues, while in water restricted condition, no clear association between gene expression pattern and variations in carotenoid content could be detected except in orange-rooted genotypes. This work shows that the structural aspect of carrot root is more important for carotenoid accumulation in relation with gene expression levels than the consequences of expression changes upon water restriction. PMID- 27999991 TI - The Impact of Perceived Need and Relational Factors on Mental Health Service Use Among Generations of Asian Americans. AB - The present study examined generational differences in the patterns and predictors of formal and informal mental health service utilization among a nationally representative sample of 1850 Asian Americans from the National Latino and Asian American Study. We focused on the effects of perceived need and relational factors on service utilization among 1st-, 1.5-, and 2nd-generation Asian Americans. Results of hierarchical logistic regression showed significant intergenerational differences. Specifically, 1.5-generation Asian Americans exhibited distinctive pattern of service use, with perceived need being associated with a higher likelihood of using formal mental health services, but only for those with high level of social support. First- and second-generation Asian Americans, on the other hand, perceived need was independently associated with formal service use, and a significant predictor of informal service use for first generation. Greater family conflict was also associated with greater use of formal and informal services for both first- and second generations. However, family cohesion was associated with only informal service use among first generation Asian Americans. Implications for mental health service policy were discussed. PMID- 27999993 TI - The sugar code in neuronal physiology. AB - Carbohydrate-related interactions are necessary for the correct development and function of the nervous system. As we illustrate with several examples, those interactions are controlled by carbohydrate-modifying enzymes and by carbohydrate binding proteins that regulate a plethora of complex axonal processes. Among others, glycan-related proteins as sialidase Neu3 or galectins-1, -3, and -4 play central roles in the determination of axonal fate, axon growth, guidance and regeneration, as well as in polarized axonal glycoprotein transport. In addition, myelination is also highly dependent on glycans, and the stabilization of myelin architecture requires the interaction of the myelin-associated glycoprotein (siglec-4) with gangliosides in the axonal membrane. The roles of glycans in neuroscience are far from being completely understood, though the cases presented here underscore the importance and potential of carbohydrates to establish with precision key molecular mechanisms of the physiology of the nervous system. New specific applications in diagnosis as well as the definition of new molecular targets to treat neurological diseases related to lectins and/or glycans are envisioned in the future. PMID- 27999994 TI - Functional characterisation of the YIPF protein family in mammalian cells. AB - In this study, we carry out a systematic characterisation of the YIPF family of proteins with respect to their subcellular localisation profile, membrane topology and functional effects on the endomembrane system. YIPF proteins primarily localise to the Golgi complex and can be grouped into trans-Golgi localising YIPFs (YIPF1 and YIPF2) and cis-Golgi-localising YIPFs (YIPF3, YIPF4 and YIPF5), with YIPF6 and YIPF7 showing a broader profile being distributed throughout the Golgi stack. YIPF proteins have a long soluble N-terminal region, which is orientated towards the cytosol, followed by 5 closely stacked transmembrane domains, and a C terminus, orientated towards the lumen of the Golgi. The significance of YIPF proteins for the maintenance of the morphology of the Golgi was tested by RNA interference, revealing a number of specific morphological changes to this organelle on their depletion. We propose a role for this family of proteins in regulating membrane dynamics in the endomembrane system. PMID- 27999992 TI - C-type lectins: their network and roles in pathogen recognition and immunity. AB - C-type lectins (CTLs) represent the most complex family of animal/human lectins that comprises 17 different groups. During evolution, CTLs have developed by diversification to cover a broad range of glycan ligands. However, ligand binding by CTLs is not necessarily restricted to glycans as some CTLs also bind to proteins, lipids, inorganic molecules, or ice crystals. CTLs share a common fold that harbors a Ca2+ for contact to the sugar and about 18 invariant residues in a phylogenetically conserved pattern. In vertebrates, CTLs have numerous functions, including serum glycoprotein homeostasis, pathogen sensing, and the initiation of immune responses. Myeloid CTLs in innate immunity are mainly expressed by antigen presenting cells and play a prominent role in the recognition of a variety of pathogens such as fungi, bacteria, viruses, and parasites. However, myeloid CTLs such as the macrophage inducible CTL (Mincle) or Clec-9a may also bind to self antigens and thus contribute to immune homeostasis. While some CTLs induce pro inflammatory responses and thereby lead to activation of adaptive immune responses, other CTLs act as inhibitory receptors and dampen cellular functions. Since CTLs are key players in pathogen recognition and innate immunity, targeting CTLs may be a promising strategy for cell-specific delivery of drugs or vaccine antigens and to modulate immune responses. PMID- 27999996 TI - Fresh and in vitro osteodifferentiated human amniotic membrane, alone or associated with an additional scaffold, does not induce ectopic bone formation in Balb/c mice. AB - The human amniotic membrane (hAM) has been successfully used as a natural carrier containing amniotic mesenchymal stromal cells, epithelial cells and growth factors. It has a little or no immunogenicity, and possesses useful anti microbial, anti-inflammatory, anti-fibrotic and analgesic properties. It has been used for many years in several indications for soft tissue repair. We previously reported that hAM represents a natural and preformed sheet containing highly potent stem cells, and could thus be used for bone repair. Indeed, native hAM possesses pre-osteoblastic potential that can easily be stimulated, even as far as mineralization, by means of in vitro osteogenic culture. However, cell culture induces damage to the tissue, as well as to cell phenotype and function. The aim of this study was to evaluate new bone formation by fresh and in vitro osteodifferentiated hAM, alone or associated with an additional scaffold presenting osteoinductive properties. Moreover, we also aimed to determine the effect of in vitro hAM pre-osteodifferentiation on its in vivo biocompatibility/tissue degradation. Results showed that neither fresh nor osteodifferentiated hAM induced ectopic bone formation, whether or not it was associated with the osteoinductive scaffold. Secondly, fresh and osteodifferentiated hAM presented similar in vivo tissue degradation, suggesting that in vitro hAM pre-osteodifferentiation did not influence its in vivo biocompatibility. PMID- 27999997 TI - Level I lymph node involvement in patients with N1b papillary thyroid carcinoma: a prospective study. AB - Most of the studies on the incidence, pattern, and predictive factors of lymph node (LN) metastasis with papillary thyroid carcinoma (PTC) have been performed retrospectively and no common consensus has been reached regarding the predictors for the involvement of level I LNs. This study was conducted prospectively to determine the incidence and the possible predictors of level I involvement in N1b PTC patients. The study included 30 consecutive patients with N1b stage of PTC. All the patients underwent neck dissection (ND) including level I. The relation between involvement of level I LNs and various clinicopathological variables was studied. Unilateral neck dissection was performed in 24 patients and bilateral neck dissection in six patients leading to 36 NDs. Level I was excised in all patients, with five specimens (14%) positive for metastasis. Levels II, III, IV, V, VI, and VII were positive in 52.8, 58.3, 58.3, 33.3, 63, and 22.2%, respectively. Level I involvement was significantly related to the number of lymph node levels affected (p = 0.003) and macroscopic extranodal invasion (p = 0.04). It was not related to the involvement of other individual levels, gender, age, size of the largest thyroid nodule, size of the largest LN involved, or histo-pathological variant of the tumor. This study suggests that including level I in therapeutic neck dissection for N1b PTC patients might be recommended in selected cases of multiple level involvement and macroscopic extranodal invasion requiring sacrifice of internal jugular vein, spinal accessory nerve, or sternomastoid muscle. PMID- 27999995 TI - Lipid glycosylation: a primer for histochemists and cell biologists. AB - Glycolipids are glycoconjugates that are predominantly found on the extracellular surface of cells ranging from bacteria to men. In bacteria and plants, glycoglycerolipids represent the main glycolipid species. Ceramides as carrier for glycans, termed glycosphingolipids (GSLs), are characteristic for vertebrates and insects. The glycan part is involved in a variety of biological activities including cell adhesion and initiation of signaling. Most of these functions rest on two basic principles: (1) GSLs spontaneously contribute to organize lipid rafts in biological membranes, thereby forming functional complexes ('glycosynapses') with receptor proteins and ion channels and (2) their glycans are bound by receptors like galectins (protein-glycan recognition) or cognate glycans (glycan-glycan recognition). This interaction modulates cell adhesion, differentiation and growth processes. Besides their contribution to normal cell behavior, GSL expression patterns also influence disease processes by inducing cellular malfunctions when aberrant, as highlighted by inherited disorders of GSL metabolism like sphingolipidoses. Altered GSL patterns are also associated with common neurological diseases, autoimmune diseases and cancer. With respect to infections, various GSL-presented glycans are attachment sites for bacteria and viruses as well as primary targets for bacterial toxins. This review provides an introduction to GSL structures, their nomenclature and metabolism. Building on this, normal and pathological functions of GSL will be surveyed. PMID- 27999999 TI - Cartilage island on stapes: autologous PORP in the hypoventilated middle ear. AB - The most common technique in sound restoration of the middle ear is prosthetic surgery. Hypoventilation of the middle ear may cause adhesive otitis or atelectasis resulting in a higher risk of prosthetic extrusion rate and recurrence of the underlying cholesteatoma. We report long-term results using an island of tragal cartilage as an autologous PORP in selected patients with poor middle ear ventilation. Retrospective chart reviews were performed for procedures involving 52 patients between year 2000 and 2009. All patients that underwent surgery using tragal cartilage interposed between the suprastructure of the stapes and the tympanic membrane were included in this study. Audiological parameters using four frequencies, 0.5, 1, 2 and 3 kHz, according to AAO-HNS guidelines, were assessed pre-and postoperatively. The hearing results on different PTA frequencies were also investigated. We report long-term follow-up of patients with hypoventilated middle ear with a success rate of 71% (ABG <20%). With regards to the ABG, the low frequency component (5 and 1 kHz) showed a significantly (p < 0.05) larger improvement of mean values after surgery as compared to the high-frequency component (2 and 3 kHz). Cartilage island PORP on stapes is a stable and efficient method for selected patients with chronic middle ear disease. PMID- 27999998 TI - p16INK4 expression is of prognostic and predictive value in oropharyngeal cancers independent of human papillomavirus status: a Hungarian study. AB - Head and neck cancer treatment protocols still lack well-established biomarkers of prognostic and predictive value. It is well known that human papillomavirus (HPV)-related and non-HPV-related oropharyngeal cancers are distinct entities concerning tumor biology and clinical outcome. However, there is an ongoing debate whether tumor suppressor p16INK4 status alone or both p16INK4 and HPV detection should be used in clinical settings. The aim of this study was to investigate p16INK4-immunolabelled and HPV-induced rates and determine their clinical significance in 110 primary head and neck squamous cell carcinomas. The expression of p16INK4 protein was assessed with immunohistochemistry, while high risk HPV detection was performed using DNA PCR method. P16INK4 immunolabelling was detected in 17.3% of all tumor samples, and in 38.1% of oropharyngeal malignancies. Oropharyngeal, p16INK4-immunolabelled tumors showed an improved disease-specific survival compared to the non-p16INK4-immunolabelled group (median survival: 30.3 vs. 8.8 months, p < 0.001 with the log-rank test). Furthermore, 56% of p16INK4-immunolabelled cases were tested positive for HPV DNA. The HPV-induced group presented better disease-specific survival compared to the non-HPV-induced cases (median survival: 25.9 vs. 9.5 months, p = 0.024 with the log-rank test). Improved response rates to neoadjuvant chemotherapy were observed both in p16INK4-immunolabelled and p16INK4- immunolabelled/HPV DNA- containing groups (Fisher's exact test: p = 0.025 and p = 0.009). In conclusion, p16INK4 immunohistochemistry proved to be a reliable and affordable tool for prognostic and predictive testing of head and neck squamous cell cancers. The p16INK4 immunopositivity status alone was confirmed to be an equally precise indicator of clinical outcome as p16INK4/HPV DNA PCR double testing. PMID- 28000000 TI - Identifying Strategies to Cope with HIV-Related Stigma in a Group of Women Living with HIV/AIDS in the Dominican Republic: A Qualitative Study. AB - Internalized HIV-related stigma negatively impacts the mental and physical health of women living with HIV/AIDS (WLWHA). Yet, some women can successfully confront stigma. The present work uses qualitative methods to investigate the successful stigma coping strategies displayed by 19 WLWHA who reported the least internalized stigma possible on the Internalized AIDS-Related Stigma Scale out of a larger pool of 233 WLWHA in San Felipe de Puerto Plata, Dominican Republic. Such strategies included, HIV disclosure control; preemptive disclosure of HIV status; educating oneself/others about HIV; viewing HIV as a manageable condition; and looking to family, friends and partners for support. Our findings add to current knowledge about how WLWHA successfully manage internalized stigma, particularly in the context of the Dominican Republic. Clinicians should work closely with WLWHA to counsel them about the stigma coping strategies that best fit their life context. PMID- 28000001 TI - Role of integrins in mediating cardiac fibroblast-cardiomyocyte cross talk: a dynamic relationship in cardiac biology and pathophysiology. AB - Integrins are a family of heterodimeric proteins expressed by cardiac fibroblasts and cardiomyocytes that provide critical adhesive and signaling functions through their interactions with the extracellular matrix (ECM) and the actin cytoskeleton. These adhesive processes are important for paracrine signaling, ECM homeostasis and for the intercellular interactions that impact cardiac cell biology and pathophysiological adaptation in disease. Despite considerable progress, our understanding of the interplay between cardiac cells, the ECM and integrins remains largely elusive. In this review, we examine the role of integrins in adhesive and signaling functions, and how these functions enable communication between cardiac fibroblasts, cardiomyocytes and the ECM. These processes strongly influence cardiac development and, later, the progression into cardiac disease. An improved understanding of this multi-dimensional system in cardiac tissues is needed to decipher the biological, spatiotemporal and mechanical cues that regulate cardiac health and the manifestation of cardiac disease. Greater insight into integrin function in cardiac tissues may also suggest new treatments for the prevention of heart failure. PMID- 28000002 TI - Stress perfusion magnetic resonance imaging to detect coronary artery lesions in children. AB - BACKGROUND: Stress perfusion cardiovascular magnetic resonance (CMR) is used widely in adult ischemic heart disease, but data in children is limited. We sought to evaluate feasibility, accuracy and prognostic value of stress CMR in children with suspected coronary artery disease (CAD). METHODS: Stress CMR was reviewed from two pediatric centers over 5 years using a standard pharmacologic protocol. Wall motion abnormalities, perfusion deficits and late enhancement were correlated with coronary angiogram (CAG) when available, and clinical status at 1 year follow-up for major adverse cardiovascular events (MACE; coronary revascularization, non-fatal myocardial infarction and death due to CAD) was recorded. RESULTS: Sixty-four stress perfusion CMR studies in 48 children (10.9 +/- 4.8 years) using adenosine; 59 (92%) and dipyridamole; 5 (8%), were reviewed. Indications were Kawasaki disease (39%), post arterial switch operation (12.5%), post heart transplantation (12.5%), post anomalous coronary artery repair (11%), chest pain (11%), suspected myocarditis or CAD (3%), post coronary revascularization (3%), and others (8%). Twenty-six studies were performed under sedation. Of all studies performed, 66% showed no evidence of ischemia or infarction, 28% had perfusion deficits and 6% had late gadolinium enhancement (LGE) without perfusion deficit. Compared to CAG, the positive predictive value (PPV) of stress CMR was 80% with negative predictive value (NPV) of 88%. At 1 year clinical follow-up, the PPV and NPV of stress CMR to predict MACE were 78 and 98%. CONCLUSION: Stress-perfusion CMR, in combination with LGE and wall motion-analysis is a feasible and an accurate method of diagnosing CAD in children. In difficult cases, it also helps guide clinical intervention by complementing conventional CAG with functional information. PMID- 28000004 TI - An update on treatments in myasthenia gravis. PMID- 28000003 TI - Long-term risk of falls in an incident Parkinson's disease cohort: the Norwegian ParkWest study. AB - The objective of this study is to examine the frequency, development, concomitants, and risk factors of falls in a population-based incident Parkinson's disease (PD) cohort. One hundred eighty-one drug-naive patients with incident PD and 173 normal controls recruited from the Norwegian ParkWest study were prospectively monitored over 7 years. Information on falls was obtained biannually from patients, and at baseline and after 1, 3, 5, and 7 years of follow-up in control subjects. Generalized estimating equation models for correlated data were applied to investigate concomitant features of falls and risk factors for incident falls during 7 years of follow-up in PD. Overall, 64.1% of patients reported falling during the study period. The 7-year cumulative incidence of falls in non-falling patients at baseline (n = 153) was 57.5%, with a relative risk to controls of at least 3.1 (95% confidence interval 1.5-6.3; p < 0.002). Significant concomitants of falls in patients during the study period were higher age, Unified PD Rating Scale motor score, postural instability and gait difficulties (PIGD) phenotype, dementia, and follow-up time. Higher age at baseline, PIGD phenotype at 1-year visit, and follow-up time were independent risk factors for incident falls during follow-up. Nearly two-thirds of patients in the general PD population experience falls within 7 years of diagnosis, representing a more than threefold increased risk compared to age- and gender matched controls. Patients with higher age at baseline and early PIGD have the greatest risk of falling and may, therefore, be the prime target of specialized assessment and treatment interventions. PMID- 28000005 TI - Comparison of cerebrospinal fluid profiles in Alzheimer's disease with multiple cerebral microbleeds and cerebral amyloid angiopathy-related inflammation. AB - Brain magnetic resonance imaging (MRI) of patients with Alzheimer's disease (AD) sometimes reveals multiple cerebral microbleeds (CMBs) and confluent white matter hyperintensities (WMHs) similar to those observed in cerebral amyloid angiopathy related inflammation (CAA-I). To determine whether there might be common pathophysiological mechanisms underlying the MRI findings of multiple CMBs and confluent WMHs, we investigated the cerebrospinal fluid (CSF) profiles of 38 AD, five amnestic mild cognitive impairment (MCI), and six CAA-I patients. The AD and MCI patients were divided into groups of patients with (n = 10) or without (n = 33) multiple CMBs (n >= 2) on T2*-gradient echo sequences of brain MRI. We compared the CSF profiles of AD and MCI patients with or without multiple CMBs, and CAA-I patients. The brain MRIs of the patients with multiple CMBs revealed severe degrees of WMHs compared with the patients without multiple CMBs. The levels of CSF anti-amyloid beta autoantibody and interleukin 8, and CSF/serum albumin ratios and immunoglobulin G indexes, were significantly higher in CAA-I patients than the other groups. However, there were no significant differences in the CSF profiles of patients with or without multiple CMBs. Our study provides evidence for different pathophysiological mechanisms underlying these differential MRI findings in AD and CAA-I. PMID- 28000006 TI - MRI as outcome measure in facioscapulohumeral muscular dystrophy: 1-year follow up of 45 patients. AB - There is no effective treatment available for facioscapulohumeral muscular dystrophy type 1 (FSHD1), but emerging therapies are under way that call for a better understanding of natural history in this condition. In this prospective, longitudinal study, we used quantitative MRI to assess yearly disease progression in patients with FSHD1. Ambulatory patients with confirmed diagnosis of FSHD1 (25/20 men/women, age 20-75 years, FSHD score: 0-12) were tested with 359-560-day interval between tests. Using the MRI Dixon technique, muscle fat replacement was evaluated in paraspinal, thigh, and calf muscles. Changes were compared with those in FSHD score, muscle strength (hand-held dynamometry), 6-minute-walk distance, 14-step-stair-test, and 5-time-sit-to-stand-test. Composite absolute fat fraction of all assessed muscles increased by 0.036 (CI 0.026-0.046, P < 0.001), with increases in all measured muscle groups. The clinical severity FSHD score worsened (10%, P < 0.05), muscle strength decreased over the hip (8%), neck (8%), and back (17%) (P < 0.05), but other strength measures, 6-minute-walk distance, 5-times-sit-to-stand-test, and 14-step-stair-test were unchanged. Changes in muscle strength, FSHD score, and fat fraction did not correlate. This first study to systemically monitor quantitative fat replacement longitudinally in FSHD1 shows that MRI provides an objective measure of disease progression, often before changes can be appreciated in strength and functional tests. The study indicates that quantitative MRI can be a helpful end-point in follow-up and therapeutic trials of patients with FSHD1. PMID- 28000007 TI - Delayed symptomatic intracerebral hemorrhages in neuro-Behcet's disease. PMID- 28000008 TI - Primary intraventricular hemorrhage in adults: etiological causes and prognostic factors in Chinese population. AB - Primary intraventricular hemorrhage (PIVH) is a rare type of hemorrhagic stroke that is poorly understood. We aimed to explore the features of this disease in Chinese population via an institutional prospective study. Adult patients diagnosed with PIVH from January 2013 to January 2016 were enrolled in this study. Data, including clinical variables, radiological features, and yield of angiography, were collected to evaluate the clinical features, etiological causes, and prognostic factors of this disease. A total of 67 patients (73.6%) were diagnosed with PIVH which constituted 3.2% of contemporary patients with hemorrhagic stroke in our hospital. Thirty-four patients (52.3%) were diagnosed with vascular structural abnormality (VSA)-related PIVH, and the etiologies included Moyamoya disease (22.4%), arteriovenous malformations (17.9%), aneurysms (7.5%), bilateral internal carotid artery dissection (1.5%), and tumor (1.5%). Idiopathic PIVH was diagnosed in 31 patients (47.7%), including coagulopathy in 3 (4.5%). Patients with VSA-related PIVH were younger than idiopathic PIVH patients, with a mean age of 37.1 +/- 14.6 years, and idiopathic PIVH patients were more commonly hypertensive. The overall mortality rate was 11.9%, and 21 patients (31.3%) had a poor outcome at the 6-month follow-up. Patients with younger age, lower Graeb score, and a known etiology of arteriovenous malformation might be associated with a favorable outcome. We recommended routine thin-slice computed tomography (CT) scan, computed tomographic angiography (CTA), and digital subtraction angiography (DSA) for patients with PIVH. The etiological causes and prognostic factors of PIVH in Chinese patients were associated with distinctive features. PMID- 28000009 TI - Dyslipidemia in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) is associated with high risk for cardiovascular disease (CVD). This association is multifactorial, but CKD is often associated with dyslipidemia, which likely contributes. Patients with CKD have dyslipidemia even at early stages of renal dysfunction and dyslipidemia tends to progress with deterioration of kidney function. The dyslipidemia in CKD is largely due to increased triglyceride levels, decreased HDL-C and varying levels of LDL-C. Current management of CKD may also affect lipid levels. Robust clinical trials demonstrate that statins are safe and efficacious in both lipid lowering and prevention of CVD events in pre-end stage CKD and post-transplant. However, there is no evidence of improved CVD outcomes with statin use in dialysis patients. This review will focus on mechanisms underlying dyslipidemia in CKD and clinical trial evidence for lipid lowering therapy in patients with CKD. PMID- 28000010 TI - Two cases demonstrating thalidomide's efficacy in refractory lupus nephritis. AB - Renal involvement in systemic lupus erythematosus (SLE) is common and has been associated with an increased risk of mortality [1]. Early diagnosis is imperative to control proteinuria and prevent the progression to end-stage renal disease. Standard induction therapies include cyclophosphamide (CYC) and mycophenolate mofetil (MMF); however, it has been estimated that approximately 30% of patients are refractory to these standard treatments after 1 year [2]. We present two cases of patients diagnosed with lupus nephritis (LN) who demonstrated persistent proteinuria while on standard treatments that markedly improved after addition of thalidomide (THD). A literature review was performed indicating that THD use with prednisolone (PL) was more efficacious than MMF with PL in resolving lupus nephritis in a mouse model. Thalidomide, which was well tolerated, was associated with a reduction in the protein-to-creatinine ratio with sustained results in both of our patient cases. These cases suggest more clinical data is needed to explore the potential utility of thalidomide in the treatment of LN. PMID- 28000011 TI - Public health awareness of autoimmune diseases after the death of a celebrity. AB - Autoimmune disorders impose a high burden, in terms of morbidity and mortality worldwide. Vasculitis is an autoimmune disorder that causes inflammation and destruction of blood vessels. Harold Allen Ramis, a famous American actor, director, writer, and comedian, died on the February 24, 2014, of complications of an autoimmune inflammatory vasculitis. To investigate the relation between interests and awareness of an autoimmune disease after a relevant event such as the death of a celebrity, we systematically mined Google Trends, Wikitrends, Google News, YouTube, and Twitter, in any language, from their inception until October 31, 2016. Twenty-eight thousand eight hundred fifty-two tweets; 4,133,615 accesses to Wikipedia; 6780 news; and 11,400 YouTube videos were retrieved, processed, and analyzed. The Harold Ramis death of vasculitis resulted into an increase in vasculitis-related Google searches, Wikipedia page accesses, and tweet production, documenting a peak in February 2014. No trend could be detected concerning uploading YouTube videos. The usage of Big Data is promising in the fields of immunology and rheumatology. Clinical practitioners should be aware of this emerging phenomenon. PMID- 28000012 TI - Evaluation of the clinical relevance of anti-annexin-A5 antibodies in Chinese patients with antiphospholipid syndrome. AB - A hallmark feature of antiphospholipid syndrome (APS) is the presence of antiphospholipid antibodies (aPLs). Few studies have addressed the clinical relevance of anti-annexin A5 antibodies (aANXA5) in Chinese patients with APS. In this study, we evaluated the clinical performance of aANXA5 in the diagnosis of APS. Sera from 313 subjects were tested, including 170 samples from patients with APS, 104 samples from patients with non-APS diseases as disease controls (DC), and 39 healthy controls (HC). Serum IgG and IgM aANXA5 were determined by ELISA. Overall, the levels of both IgG and IgM aANXA5 were significantly increased in patients with primary APS (PAPS) and APS associated to other diseases (APSAOD) compared with DC and HC. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IgG and IgM aANXA5 in the diagnosis of APS were 33.5 and 15.3, 99.0 and 99.0, 98.3 and 96.3, and 47.7 and 41.7%, respectively. Significant associations between IgG aANXA5 and arterial thrombotic events (OR, 2.60; 95% CI, 1.44-4.71) and between IgG aANXA5 and venous thrombotic events (OR, 2.80; 95% CI, 1.55-5.06) were identified. No correlations were identified between IgG or IgM aANXA5 and obstetric complications. Our data suggest that aANXA5 could serve as a diagnosis biomarker for patients with APS. More importantly, our data highlighted a potential role of IgG aANXA5 in identifying APS patients with high risk of thrombosis. PMID- 28000013 TI - An Evaluation of Racial and Ethnic Health Differences in State Mental Health Inpatient Services: 2002-2005 Versus 2010-2011. AB - This study analyzed racial-ethnic differences previously documented in the Connecticut Department of Mental Health and Addiction Services mental health inpatient system across two time periods (2002-2005 and 2010-2011). Comparisons of logistic regression analyses from the two time periods showed that, at time 1, significant racial-ethnic differences were found for referral by other sources (e.g., outpatient), length of stay, discharge against medical advice, and some diagnostic differences (e.g., schizophrenia, other psychotic disorders, cluster B discharge diagnosis), but these differences were not significant at time 2. Other diagnostic differences remained significant at time 2 (e.g., mood disorders, substance use disorders, other axis I disorders, mental retardation) as well as racial-ethnic differences in self-referral. These results suggest that the multiple national and state cultural competence initiatives between time 1 and time 2 could have resulted in decreases in racial-ethnic differences. Targeted interventions to alleviate the remaining differences are needed. PMID- 28000014 TI - Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed. AB - PURPOSE: We hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation. METHODS: We identified women in British Columbia with MBC diagnosed between 01/2001 and 12/2009. OS from MBC was calculated for relapsed vs de novo cohorts in 3 subgroups, based on hormone receptors (HR) and HER2 status. Age at MBC, disease-free interval (DFI), de novo vs relapsed, year of MBC diagnosis, and systemic treatment were entered into univariable and multivariable analyses. RESULTS: We identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91 months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23 months (mos) (p < 0.0001), HR-/HER2- (TN) 11 versus 8 mos (p = 0.02), HER2+ 29 versus 15 mos (p < 0.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HR +/HER2- and the HER2 + groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2-1.5; p < 0.0001], and HzR 1.6 [95% CI 1.4 1.9; p < 0.0001], respectively) and age >50 (HzR 1.2 [95% CI 1.1-1.4; p = 0.001] and HzR 1.3 [95% CI 1.1-1.5; p = 0.01], respectively) were associated with increased risk of death on multivariable analysis. CONCLUSION: These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials. PMID- 28000015 TI - MicroRNA-567 dysregulation contributes to carcinogenesis of breast cancer, targeting tumor cell proliferation, and migration. AB - PURPOSE: We demonstrated that Hsa-miR-567 expression is significantly downregulated in poor prognosis breast cancer, compared to better prognosis breast cancer, having a role in the control of cell proliferation and migration by regulating KPNA4 gene. METHODS AND RESULTS: In this study, based on our previously published in silico results, we proved both in vitro (cell line studies) and ex vivo (clinical studies), that Hsa-miR-567 expression is significantly downregulated in breast cancer with poor prognosis when compared to breast cancer with better prognosis. More intriguingly, we demonstrated that the ectopic expression of Hsa-miR-567 in poor prognosis breast cancer cell line strongly inhibits in vitro cell proliferation and migration. Furthermore, we showed in vivo that breast cancer cells, stably expressing Hsa-miR-567, xenografted in mouse, reduce tumor growth ability. Consistently, we found that karyopherin 4 (KPNA4), predicted target gene of Hsa-miR-567 as identified by our in silico analysis, is upregulated in highly aggressive MDA-MB-231 breast cancer cell line and patient tissues with poor prognosis with respect to good prognosis. CONCLUSIONS: Our results suggest a potential role of Hsa-miR-567 as a novel prognostic biomarker for BC and as regulator of KPNA4. PMID- 28000017 TI - High-throughput development of genome-wide locus-specific informative SSR markers in wheat. PMID- 28000016 TI - Robotic-assisted partial nephrectomy provides better operative outcomes as compared to the laparoscopic and open approaches: results from a prospective cohort study. AB - The objective of this is to compare the surgical outcomes of partial nephrectomy (PN), performed via three different approaches: robot-assisted (RAPN), laparoscopic (LPN), and open (OPN), in a single non-academic regional center. The data of patients undergoing PN at our Department from 2005 to 2016 were prospectively collected. A logistic regression model adjusted for preoperative variables (age, tumor size, creatinine and hemoglobin, ASA and Padua scores) was performed to evaluate whether transfusion, conversion, and postoperative complication rate were influenced by the surgical approach. Overall 270 patients underwent PN: analysis included 253 cases (RAPN = 110, LPN = 70, OPN = 73). Preoperative variables did not differ significantly among the three groups. Shorter operative (130 vs 180 and 200') and ischaemia (12 vs 23 and 22') times and longer hospital stay (8 vs 7 and 6 days) were found in the OPN group as compared to LPN and RAPN, respectively. The RAPN group included a higher rate of pT1b (31.8 vs 14.2 and 15%) and malignant histotype (90 vs 82.9 and 68.5%) as compared to LPN and OPN, respectively. Clavien Grade III-IV complications were lower in the RAPN (7.2%) as compared to OPN (12.3%) and LPN (17.1%) groups. Multivariate analysis showed a lower risk for conversion, transfusion and overall complications in the RAPN group versus LPN and OPN. The surgical approach affects the perioperative outcomes in a regional setting. The advantages of RAPN over OPN (lower risk of conversion, transfusion, and overall complications) are extended over LPN as well, although OPN offered faster operative and ischemia times at the expense of greater blood loss and hospital stay. PMID- 28000018 TI - Branching out. PMID- 28000019 TI - Long-term biological hydrogen production by agar immobilized Rhodobacter capsulatus in a sequential batch photobioreactor. AB - In this study, agar immobilization technique was employed for biological hydrogen production using Rhodobacter capsulatus DSM 1710 (wild type) and YO3 (hup-mutant) strains in sequential batch process. Different agar and glutamate concentrations were tested with defined nutrient medium. Agar concentration 4% (w/v) and 4 mM glutamate were selected for bacterial immobilization in terms of rate and longevity of hydrogen production. Acetate concentration was increased from 40 to 60-100 and 60 mM gave best results with both bacterial strains immobilized in 4% (w/v) agar. Cell concentration was increased from 2.5 to 5 mg dcw mL-1 agar and it was found that increasing cell concentration of wild-type strain caused decrease in yield and productivity while these parameters improved by increasing cell concentration of mutant strain. Also, the hydrogen production time has extended from 17 days up to 60 days according to the process conditions and parameters. Hydrogen production by immobilized photosynthetic bacteria is a convenient technology for hydrogen production as it enables to produce hydrogen with high organic acid concentrations comparing to suspended cultures. Besides, immobilization increases the stability of the system and allowed sequential batch operation for long-term application. PMID- 28000020 TI - Structural brain imaging correlates of ASD and ADHD across the lifespan: a hypothesis-generating review on developmental ASD-ADHD subtypes. AB - We hypothesize that it is plausible that biologically distinct developmental ASD ADHD subtypes are present, each characterized by a distinct time of onset of symptoms, progression and combination of symptoms. The aim of the present narrative review was to explore if structural brain imaging studies may shed light on key brain areas that are linked to both ASD and ADHD symptoms and undergo significant changes during development. These findings may possibly pinpoint to brain mechanisms underlying differential developmental ASD-ADHD subtypes. To this end we brought together the literature on ASD and ADHD structural brain imaging symptoms and particularly highlight the adolescent years and beyond. Findings indicate that the vast majority of existing MRI studies has been cross-sectional and conducted in children, and sometimes did include adolescents as well, but without explicitly documenting on this age group. MRI studies documenting on age effects in adults with ASD and/or ADHD are rare, and if age is taken into account, only linear effects are examined. Data from various studies suggest that a crucial distinctive feature underlying different developmental ASD-ADHD subtypes may be the differential developmental thinning patterns of the anterior cingulate cortex and related connections towards other prefrontal regions. These regions are crucial for the development of cognitive/effortful control and socio-emotional functioning, with impairments in these features as key to both ASD and ADHD. PMID- 28000021 TI - Tree-to-tree variation in seed size and its consequences for seed dispersal versus predation by rodents. AB - Individual variation in seed size and seed production is high in many plant species. How does this variation affect seed-dispersing animals and, in turn, the fitness of individual plants? In this study, we first surveyed intraspecific variation in seed mass and production in a population of a Chinese white pine, Pinus armandii. For 134 target trees investigated in 2012, there was very high variation in seed size, with mean seed mass varying among trees almost tenfold, from 0.038 to 0.361 g. Furthermore, 30 of the 134 trees produced seeds 2 years later, and for these individuals there was a correlation in seed mass of 0.59 between years, implying consistent differences among individuals. For a subset of 67 trees, we monitored the foraging preferences of scatter-hoarding rodents on a total of 15,301 seeds: 8380 were ignored, 3184 were eaten in situ, 2651 were eaten after being cached, and 395 were successfully dispersed (cached and left intact). At the scale of individual seeds, seed mass affected almost every decision that rodents made to eat, remove, and cache individual seeds. At the level of individual trees, larger seeds had increased probabilities of both predation and successful dispersal: the effects of mean seed size on costs (predation) and benefits (caching) balanced out. Thus, despite seed size affecting rodent decisions, variation among trees in dispersal success associated with mean seed size was small once seeds were harvested. This might explain, at least in part, the maintenance of high variation in mean seed mass among tree individuals. PMID- 28000022 TI - Habitat fragmentation differentially affects trophic levels and alters behavior in a multi-trophic marine system. AB - Seagrass, an important subtidal marine ecosystem, is being lost at a rate of 110 km2 year-1, leading to fragmented seagrass seascapes. Habitat fragmentation is predicted to affect trophic levels differently, with higher trophic levels being more sensitive, stressing the importance of a multi-trophic perspective. Utilizing the trophic relationship between the blue crab (Callinectes sapidus) and hard clam (Mercenaria mercenaria), where adult blue crabs prey on juvenile blue crabs, and juvenile blue crabs prey on small hard clams, we examined whether predation rates, abundance, and behavior of predators and prey differed between continuous and fragmented seagrass in a multi-trophic context at two sites in Barnegat Bay, NJ. We tested the hypothesis that fragmented habitats would differentially affect trophic levels within a tri-trophic system, and our results supported this hypothesis. Densities of adult blue crabs were higher in fragmented than continuous habitats. Densities of juvenile blue crabs, the primary predator of hard clams, were lower in fragmented habitats than continuous, potentially due to increased predation by adult blue crabs. Clams experienced lower predation and burrowed to a shallower depth in fragmented habitats than in continuous habitat, likely due in part to the low densities of juvenile blue crabs, their primary predator. Our results suggest that while trophic levels are differentially affected, the impact of habitat fragmentation may be stronger on intermediate rather than top trophic levels in some marine systems. PMID- 28000023 TI - Extreme dehydration observed in Antarctic Turgidosculum complicatulum and in Prasiola crispa. AB - Gaseous phase hydration effect of extremely dehydrated thallus of the Antarctic lichenized fungus Turgidosculum complicatulum and of green alga Prasiola crispa was observed using hydration kinetics, sorption isotherm, 1H-NMR spectroscopy and relaxometry. Three bound water fractions were distinguished: (1) very tightly bound water, (2) tightly bound water and (3) a loosely bound water fraction detected at higher levels of hydration. Sorption isotherm was sigmoidal in form and well fitted using Dent model. The relative mass of water saturating primary water binding sites was DeltaM/m 0 = 0.055 for T. complicatulum and DeltaM/m 0 = 0.131 for P. crispa. 1H-NMR free induction decays (FIDs) for T. complicatulum and for P. crispa were superpositions of a solid signal component, and one averaged liquid signal component for P. crispa thallus ([Formula: see text] ~ 80 us) or two liquid signal components coming from a tightly bound ([Formula: see text]~ 71 us) and from a loosely bound water fraction ([Formula: see text]~ 278 us) for T. complicatulum. 1H-NMR spectra recorded for T. complicatulum and for P. crispa thalli revealed one averaged mobile proton signal component L. The total liquid signal component expressed in units of solid (L 1 + L 2)/S suggests the presence of water soluble fraction in T. complicatulum thallus. PMID- 28000024 TI - Current practice patterns for management of vulvodynia in the United States. AB - PURPOSE: To evaluate the current practice patterns for the management of vulvodynia in the United States (US) and to estimate healthcare costs related to this condition. METHODS: Truven MarketScan Commercial Claims and Encounters databases for years 2009-2013 were utilized for analysis. The study cohort included women, 18 years or older, with a diagnosis of vulvodynia (ICD-9 625.70), who had been continuously enrolled for 360 days from the date of diagnosis. Measures included the most common prescriptions, primary procedures, associated diagnoses, as well as net healthcare costs. Statistical Analysis Software 9.3 was used for statistical analysis. RESULTS: Among 24,122 subjects with vulvodynia, 12,584 met enrollment criteria. Mean age was 41.0 +/- 12.9 years. Vulvar biopsy (29.6%), urinalysis (27.8%), urine culture (27.5%) and wet mount for infectious agents (25.5%) were commonly performed primary procedures. The most common prescriptions were antidepressants (32.4%), followed by opiates (27.6%), antifungals (26.1%), and steroidal agents (22.7%). Vulvodynia was frequently associated with vulvovaginitis (32.0%), urinary tract infection (20.6%), and chronic fatigue (18.6%). The mean net cost per patient including pharmacy claims during the follow-up period was $9591.80 (SD $14,595.52; 95% CI $9333.45 $9850.13). CONCLUSIONS: Our findings confirm great variation in the current management of vulvodynia. The variety of treatment approaches is a reflection of the poor current understanding of the etiology and pathophysiology of vulvodynia. Further research is needed to determine which treatments are most effective in the management of each subtype of vulvodynia. PMID- 28000025 TI - Two novel classification systems for uterine fibroids and subsequent uterine reconstruction after myomectomy. AB - OBJECTIVE: Laparoscopic approaches are the gold standard surgical treatment for intramural and subserous fibroids, whereas submucosal myomas can be treated via hysteroscopy. Removal of intramural myomas often requires a subsequent reconstruction of the uterine wall that ranges from single- to multiple-layer sutures to complex reconstructions. Several classification systems are currently used to characterize uterine fibroids, all of which focus on the assessment of submucosal fibroids during hysteroscopic myomectomy. There are no classification systems for the comprehensive localization of fibroids or for uterine reconstruction after myomectomy. Therefore, the aim of this study was to validate a new scoring system developed by our group to classify uterine leiomyoma as well as a standardized assessment scoring system for uterine reconstruction after surgical myomectomy. METHODS/PATIENTS: To validate the uterine fibroid and uterine reconstruction classification systems, a retrospective review of 136 patients undergoing surgical myomectomy and uterine reconstruction at a single tertiary institution was performed. The age of the patient, duration of surgery, number, size, and location of excised fibroids, number of uterine incisions, level of uterine reconstruction, desire for future pregnancies, pre- and postoperative hemoglobin concentrations, duration of postoperative hospitalization, and operating surgeon were obtained by medical chart review. For each patient, a specific fibroid score and the level of uterine reconstruction were determined according to the classification systems. Correlations between the uterine fibroid and reconstruction scores, as well as between the classification scores and perioperative parameters, were analyzed. RESULTS: The newly developed classification system for uterine fibroids incorporates the number, location, and size of myomas, as well as the number of uterine incisions required for myomectomy. The uterine reconstruction scoring system comprises four levels of reconstruction, ranging from no reconstruction to advanced reconstruction. Outcomes from 136 patients showed a correlation between uterine fibroid and uterine reconstructive scores. High fibroid scores were correlated with higher levels of reconstruction. Both scoring systems showed associations with the duration of surgery, intraoperative blood loss, and days of hospitalization. CONCLUSIONS: This study presents the first scoring system for uterine fibroids that incorporates all possible fibroid locations and a standardized assessment of uterine reconstruction. Scoring systems were validated in a large cohort, and a correlation was identified between uterine fibroid and uterine reconstruction scores. In daily clinical practice, this scoring system allows a better planning of surgery, specifically of the estimated duration of surgery, blood loss, and time of hospitalization. PMID- 28000026 TI - Pregnancy outcomes in oocyte recipients with fibroids not impinging uterine cavity. AB - OBJECTIVE: To examine the effects of fibroid uterus on pregnancy outcomes and endometrial features in ovum donation recipients. METHODS: Retrospective analysis of 744 ovum donation cycles was conducted in two private IVF centers between 2005 and 2012. All the recipients underwent transvaginal ultrasound examination, including endometrial thickness and grade measurements. Clinical pregnancy, spontaneous miscarriage, and live birth rates were regarded as the primary outcomes. RESULTS: Leimyomas not distorting the uterine cavity were diagnosed in 264 (35.5%) of the cycles. This group exhibited lower endometrial thickness (8.33 +/- 1.8 vs. 8.73 +/- 2.03 mm, p = 0.009), lower rates of Grade A (16.1 vs. 30.1%, p < 0.0001), and higher rates of grade C endometrium (10.2 vs. 5.5%, p < 0.0001), compared to the group with sonographically normal uterine cavity. In addition, significantly higher spontaneous miscarriage rates were found in fibroid uteri group (25 vs. 14.5%, p = 0.036). CONCLUSION: Our study results suggest that uterine fibroids not distorting the uterine cavity could constitute a risk factor for spontaneous miscarriage in oocyte donation cycles, possibly via their adverse effect on endometrial receptivity. Further well-designed trials should widely explore this subject, particularly focusing on impact of myomectomy on fertility rates in these patients. PMID- 28000027 TI - Meta-analysis demonstrates no association between p16 ink4a promoter methylation and epithelial ovarian cancer. AB - BACKGROUND: p16 INK4A (p16) functions as a tumor suppressor gene in various malignancies. Aberrant p16 methylation has been proposed to be essential in ovarian carcinogenesis. However, it is unclear whether p16 can be used as a diagnostic marker owing to the small sample sizes in previous studies. METHODS: To determine whether p16 promoter methylation is associated with epithelial ovarian cancer and can thus be used as a diagnostic marker, we performed a meta analysis of published studies. The following databases were searched using a systematic search method: PubMed, Web of Science, EMBASE, and Chinese National Knowledge Infrastructure. We used a random-effects model to analyze the relative risk (RR); we also evaluated between-study heterogeneity, subgroup heterogeneity, and publication bias. RESULTS: Our meta-analysis included eight eligible studies, with 428 ovarian cancers and 278 normal tissue samples and benign neoplasms. p16 promoter methylation was identified in 5.4 to 43.2% (median 27.86%) of ovarian cancers and 0 to 37.5% (median 15.8%) of normal tissue and benign neoplasms indicating that no significant association exists between p16 promoter methylation and epithelial ovarian cancer. However, the pooled results also showed that the RR was 1.52 (95% CI 0.80-2.87) in the ovarian cancer cases versus the corresponding normal and benign cases under the random-effects model. Between study heterogeneity was determined through a sensitivity analysis; the I 2 value did not change when one study was excluded. CONCLUSIONS: Our study showed that p16 promoter methylation cannot be used to differentiate benign from malignant epithelial ovarian tumors. Therefore, p16 promoter methylation cannot be used as a marker for diagnosing the early stage of ovarian cancer. PMID- 28000028 TI - Demonstration of the herd effect in adults after the implementation of pneumococcal vaccination with PCV13 in children. AB - The purpose of this investigation was to describe the evolution of serotypes and antibiotic susceptibility of Streptococcus pneumoniae strains isolated from both adults and children from the same population area with invasive pneumococcal disease (IPD) or acute otitis media (AOM), 5 years after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). From 2009 to 2015, 839 strains of S. pneumoniae strains were collected (481 from adults and 358 from children). Serotyping by latex antisera and molecular methods was performed. Antimicrobial susceptibility was tested. Compared to 2009, the total number of strains isolated in 2015 decreased in children (263 vs. 53, respectively) and in adults (220 vs. 131, respectively). Serotype coverage of PCV13 for IPD decreased significantly in adults from 67.7% (149/220) to 25.2% (33/131) and in children from 75.1% (61/81) to 18.5% (5/27). Especially, serotypes 1, 7F and 19A decreased significantly in children, while serotypes 7F and 19A decreased significantly in adults. PCV13 serotypes involved in AOM decreased significantly over the 5-year period, from 85.7% (156/182) to 38.5% (10/26), and were more susceptible to penicillin, amoxicillin and cefotaxime, p < 0.05. Serotypes 8, 9N and 10A seemed to emerge in adults, whereas any serotype prevalence was observed in children. Between 2009 and 2015, the introduction of PCV13 has resulted in a significant decrease of the number of S. pneumoniae strains isolated from IPD in children as in adults. It highlights a strong herd effect of vaccination in adults. PMID- 28000029 TI - Prothionamide susceptibility testing of Mycobacterium tuberculosis using the resazurin microtitre assay and the BACTECMGIT 960 system. AB - Resazurin microtitre assay (RMA) has been successfully used to detect minimal inhibitory concentrations (MICs) of both first-line and several second-line drugs in drug susceptibility testing (DST) of Mycobacterium tuberculosis (MTB). In this study, we firstly compared prothionamide (PTH) susceptibility testing of Mycobacterium tuberculosis (MTB) using resazurin microtitre assay (RMA) and MGIT. Overall, the sensitivity and specificity of RMA for detecting PTH susceptibility was 96.5% [95% confidence interval (CI): 91.7-100.0] and 93.2% (95% CI: 89.6 96.8) respectively. In addition, the median time to positivity was significantly shorter for RMA than for the automated MGIT 960 (RMA, 8 days [range: 8-8 days] vs MGIT, 10.1 days, [range: 5.0-13.0]; P < 0.01). Concordance rate for MICs between RMA and MGIT for PTH-resistant group was 64.3% (95% CI: 46.5-82.0), which was significantly lower than that of PTH-susceptible group (85.9%, 95% CI: 78.8-93.0; P= 0.01). In conclusion, our data demonstrated that RMA can be used as an acceptable alternative for determination of PTH susceptibility with shorter turn around time. When compared with MGIT 960, RMA method was prone to produce higher MICs for PTH-resistant MTB strains. PMID- 28000030 TI - Colonization pressure as a risk factor of ICU-acquired multidrug resistant bacteria: a prospective observational study. AB - The primary objective of this study was to evaluate the impact of colonization pressure on intensive care unit (ICU)-acquired multidrug resistant bacteria (MDRB). All patients hospitalized for more than 48 h in the ICU were included in this prospective observational study. MDRB were defined as methicillin resistant Staphylococcus aureus, Pseudomonas aeruginosa resistant to ceftazidime or imipenem, Gram-negative bacilli producing extended-spectrum beta-lactamases (ESBL), and all strains of Acinetobacter baumannii and Stenotrophomonas maltophilia. Colonization pressure was daily calculated in the three participating ICUs. Univariate and multivariate analyses were used to determine risk factors for ICU-acquired MDRB. Two hundreds and four (34%) of the 593 included patients acquired an MDRB during their ICU stay. Multivariate analysis identified colonization pressure as an independent risk factor for ICU-acquired MDRB (OR (95% CI) 4.18 (1.03-17.01), p = 0.046). Other independent risk factors for ICU-acquired MDRB were mechanical ventilation (3.08 (1.28-7.38), p = 0.012), and arterial catheter use (OR, 3.04 (1.38-6.68), p = 0.006). ICU-acquired MDRB were associated with increased mortality, duration of mechanical ventilation, and ICU stay. However, ICU-acquired MDRB was not independently associated with ICU mortality. Colonization pressure is an independent risk factor for acquiring MDRB in the ICU. PMID- 28000032 TI - Gain of 12p encompassing CCND2 is associated with gemistocytic histology in IDH mutant astrocytomas. PMID- 28000031 TI - Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis. AB - Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking-but not forced alcohol exposure-reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression induced alcoholism. PMID- 28000033 TI - The protein phosphatase 2C clade A protein OsPP2C51 positively regulates seed germination by directly inactivating OsbZIP10. AB - Protein phosphatase 2C clade A members are major signaling components in the ABA dependent signaling cascade that regulates seed germination. To elucidate the role of PP2CA genes in germination of rice seed, we selected OsPP2C51, which shows highly specific expression in the embryo compared with other protein phosphatases based on microarray data. GUS histochemical assay confirmed that OsPP2C51 is expressed in the seed embryo and that this expression pattern is unique compared with those of other OsPP2CA genes. Data obtained from germination assays and alpha-amylase assays of OsPP2C51 knockout and overexpression lines suggest that OsPP2C51 positively regulates seed germination in rice. The expression of alpha-amylase synthesizing genes was high in OsPP2C51 overexpressing plants, suggesting that elevated levels of OsPP2C51 might enhance gene expression related to higher rates of seed germination. Analysis of protein interactions between ABA signaling components showed that OsPP2C51 interacts with OsPYL/RCAR5 in an ABA-dependent manner. Furthermore, interactions were observed between OsPP2C51 and SAPK2, and between OsPP2C51 and OsbZIP10 and we found out that OsPP2C51 can dephosphorylates OsbZIP10. These findings suggest the existence of a new branch in ABA signaling pathway consisting of OsPYL/RCAR-OsPP2C-bZIP apart from the previously reported OsPYL/RCAR-OsPP2C-SAPK-bZIP. Overall, our result suggests that OsPP2C51 is a positive regulator of seed germination by directly suppressing active phosphorylated OsbZIP10. PMID- 28000035 TI - Incontinence in persons with Angelman syndrome. AB - : Angelman syndrome (AS) is a congenital syndrome with a prevalence of 1:15,000. Individuals with AS often have severe intellectual disability, typical dysmorphic signs, and behavioral problems. The aim of the study was to investigate the rate of incontinence and associated psychological problems in children and adults with AS. Ninety children (4-18 years) and 54 adults (18-31 years) with AS were recruited through a parent support group (55.6% male, mean age 15.1 years). The Parental Questionnaire: Enuresis/Urinary Incontinence, the Incontinence Questionnaire-Pediatric Lower Urinary Tract Symptoms (ICIQ-CLUTS), as well as the Developmental Behaviour Checklist for parents (DBC-P) or for adults (DBC-A) were filled out by parents or caregivers. 85.6% of individuals with AS were affected by at least one subtype of incontinence (82.7% nocturnal enuresis (NE), 64.7% daytime urinary incontinence (DUI), and 57.1% fecal incontinence (FI)). 52.5% of the children and 32.6% of adults reached a clinically relevant DBC score. Incontinence was not associated with behavioral problems. NE and DUI were associated with genotype and epilepsy. CONCLUSION: Children with AS have high rates of incontinence. Many adults are still affected by NE, DUI, or even FI. Screening, assessment, and treatment of incontinence in individuals with AS are recommended. What is Known: * Incontinence in persons with Angelman syndrome (AS) is associated with younger age, lower level of adaptive functioning, and epilepsy. What is New: * Children and teens with AS are at special risk for incontinence, but older persons are also affected. * Comorbid epilepsy is significantly associated not only with nocturnal enuresis (NE) but also with daytime urinary incontinence (DUI). Underlying genotype is significantly associated with incontinence. PMID- 28000034 TI - Safety, pharmacokinetics, and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis. AB - Although once-yearly intravenous administration of zoledronic acid has been reported to inhibit bone resorption and increase bone mineral density, no studies have evaluated its effectiveness in treating osteoporosis in Japanese patients. Therefore, the purpose of this study was to investigate the pharmacokinetics and assess the safety of and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis. This was a single administration study with a single-blind parallel-group design. The study participants were 24 Japanese patients with primary osteoporosis. The patients were divided into two groups, with each group receiving a single injection of zoledronic acid (4 or 5 mg). Pharmacokinetics and urinary excretion were then compared, and drug-related adverse events and changes in the levels of bone turnover markers were assessed at 12 months. Mean plasma concentrations of zoledronic acid peaked in both groups immediately after administration, and decreased to 1% or less of peak levels after 24 h. Noncompartmental analysis revealed that C max and the area under the curve from time zero to infinity increased in proportion to the dose. The levels of bone resorption and formation markers decreased from day 15 and from 3 months after administration respectively, and suppression of these markers remained constant for the entire study period. No serious adverse events were reported. There was no large difference between the 4- and 5-mg groups in terms of pharmacokinetics, changes in the levels of bone turnover markers, and safety profiles. This study demonstrated acceptable pharmacokinetics and changes in bone metabolism associated with zoledronic acid treatment in female Japanese osteoporosis patients. Both the 4-mg dose and the 5-mg dose demonstrated acceptable safety and sustained antiresorptive effects for the duration of the study. PMID- 28000036 TI - Postural control of typical developing boys during the transition from double-leg stance to single-leg stance. AB - : Literature is lacking information about postural control performance of typically developing children during a transition task from double-leg stance to single-leg stance. The purpose of the present study was therefore to evaluate the clinical feasibility of a transition task in typical developing age groups as well as to study the correlation between associated balance measures and age.Thirty-three typically developing boys aged 6-20 years performed a standard transition task from DLS to SLS with eyes open (EO) and eyes closed (EC). Balance features derived from the center of pressure displacement captured by a single force platform were correlated with age on the one hand and considered for differences in the perspective of limb dominance on the other hand.All TDB (typically developing boys) were able to perform the transition task with EO. With respect to EC condition, all TDB from the age group 6-7 years and the youngest of the age group 8-12 years (N = 4) were unable to perform the task. No significant differences were observed between the balance measures of the dominant and non-dominant limbs.With respect to EO condition, correlation analyses indicated that time to new stability point (TNSP) as well as the sway measure after this TNSP were correlated with age (p < 0.0001). For the EC condition, only the anthropometrically scaled sway measure was found to be correlated (p = 0.03). CONCLUSION: The results provide additional insight into balance development in childhood and may serve as a useful basis for assessing balance impairments in higher functioning children with musculoskeletal problems. What is Known: * Reference data regarding postural balance of typically developing children during walking, running, sit-to-stand, and bipodal and unipodal stance has been well documented in the literature. * These reference data provided not only insight into the maturation process of the postural control system, but also served in diagnosing and managing functional repercussions of neurological and orthopedic pathologies. What is New: * Objective data regarding postural balance of typical developing children during a transition task from double-leg stance to single-leg stance. * Insight into the role of maturation on the postural control system. PMID- 28000037 TI - Use of AC impedance spectroscopy for monitoring sound teeth and incipient carious lesions. AB - OBJECTIVE: The objective of this study was to assess the ability of alternating current impedance spectroscopy technique (ACIST) to monitor sound tooth surfaces and incipient carious lesions. SUBJECTS AND METHODS: Two hundred ninety-two teeth were examined in 30 patients. Occlusal surfaces were classified according to International Caries Detection and Assessment System (ICDAS). Two consecutive ACIST measurements at the investigation sites already visually examined were taken (t1). Examinations were repeated after 6 (t2) and 12 months (t3). Reproducibility of ACIST findings was calculated with the intra-class correlation coefficient. Values of the ACIST measurements were categorized, and kappa values were calculated. Spearman correlation coefficients (r s) were calculated for correlations between ICDAS findings and ACIST measurements. To test whether ACIST detected changes similarly to ICDAS, Wilcoxon's test was used (alpha = 0.05). RESULTS: Intra-class correlation coefficient values of ACIST measurements ranged between 0.88 and 0.98. Kappa values for ACIST categories were 0.66-0.80. Rank correlation coefficient of ICDAS and ACIST readings was 0.38-0.65 at different time intervals (p < 0.01). Significant differences could be shown for ICDAS findings between t1/t2 (p = 0.001), t2/t3 (p = 0.021), and over the total duration of the study (t1/t3, p < 0.001). No significant differences between the various examination periods were found for the impedance measurements (p > 0.05). CONCLUSIONS: ACIST exhibited in vivo high reproducibility but moderate correlation to visual findings at each time of examination. CLINICAL RELEVANCE: ACIST can be used for monitoring sound teeth and early carious lesions although its suitability as a single detection method is limited since not all changes could be detected with respect to visual findings. PMID- 28000038 TI - Management of pulps exposed during carious tissue removal in adults: a multi national questionnaire-based survey. AB - OBJECTIVES: The aim of the present study was to investigate and compare the management of pulps exposed during carious tissue removal by French, German, and Norwegian general dental practitioners (GDPs). We further aimed to assess possible dentist- and patient-related factors associated with these management decisions. MATERIALS AND METHODS: A structured questionnaire was send via mail to a simple random sample of dentists. RESULTS: The analyzed sample consisted of 661 (33%) French GDPs, 622 (25%) German GDPs, and 199 (34%) Norwegian GDPs. No single management method gained uniform consensus in any of the three countries. However, the most preferred management option in all three countries was direct pulp capping (DPC) (68-93%) mainly performed with calcium hydroxide paste/slurry (CH). Alternatively, root canal treatment was performed (7-22%). The reasons that guided GDPs were the same in all three countries; "good results" and "ease of use, familiar with the technique." Having read scientific articles about cariology/operative dentistry in the last 5 years increased the odds for the preference of DPC instead of root canal treatment (OR = 2.1, 95% CI 1.3-3.2). CONCLUSIONS: Among GDPs in France, Germany, and Norway, there was no uniform management option for pulp exposures during carious tissue removal. DPC with CH was the most preferred management, even though the current evidence suggests DPC with mineral trioxide aggregate (MTA) to be more successful. The outcome expectations and the assumed ease of use were reasons for GDPs' choice. Moreover, knowledge on current evidence towards such management options influenced treatment decisions. CLINICAL RELEVANCE: GDPs are encouraged to adopt management options based on current scientific evidence. PMID- 28000039 TI - Clinical performance of a glass ionomer restorative system: a 6-year evaluation. AB - OBJECTIVES: The aim of this study is to evaluate the long-term clinical performance of a glass ionomer (GI) restorative system in the restoration of posterior teeth compared with a micro-filled hybrid posterior composite. MATERIALS AND METHODS: A total of 140 (80 Cl1 and 60 Cl2) lesions in 59 patients were restored with a GI system (Equia) or a micro hybrid composite (Gradia Direct). Restorations were evaluated at baseline and yearly during 6 years according to the modified-USPHS criteria. Negative replicas at each recall were observed under SEM to evaluate surface characteristics. Data were analyzed with Cohcran's Q and McNemar's tests (p < 0.05). RESULTS: One hundred fifteen (70 Cl1 and 45 Cl2) restorations were evaluated in 47 patients with a recall rate of 79.6% at 6 years. Significant differences were found in marginal adaptation and marginal discoloration for both restorative materials for Cl1 and Cl2 restorations (p < 0.05). However, none of the materials were superior to the other (p > 0.05). A significant decrease in color match was observed in Equia restorations (p < 0.05). Only one Cl2 Equia restoration was missing at 3 years and another one at 4 years. No failures were observed at 5 and 6 years. Both materials exhibited clinically successful performance after 6 years. SEM evaluations were in accordance with the clinical findings. CONCLUSIONS: Both materials showed a good clinical performance for the restoration of posterior teeth during the 6-year evaluation. CLINICAL RELEVANCE: The clinical effectiveness of Equia and Gradia Direct Posterior was acceptable in Cl1 and Cl2 cavities subsequent to 6-year evaluation. PMID- 28000040 TI - A monitor for Cellular Oxygen METabolism (COMET): monitoring tissue oxygenation at the mitochondrial level. AB - After introduction of the protoporphyrin IX-triplet state lifetime technique as a new method to measure mitochondrial oxygen tension in vivo, the development of a clinical monitor was started. This monitor is the "COMET", an acronym for Cellular Oxygen METabolism. The COMET is a non-invasive electrically powered optical device that allows measurements on the skin. The COMET is easy to transport, due to its lightweight and compact size. After 5-aminolevulinic acid application on the human skin, a biocompatible sensor enables detection of PpIX in the mitochondria. PpIX acts as a mitochondrially located oxygen-sensitive dye. Three measurement types are available in the touchscreen-integrated user interface, 'Single', 'Interval' and 'Dynamic measurement'. COMET is currently used in several clinical studies in our institution. In this first description of the COMET device we show an incidental finding during neurosurgery. To treat persisting intraoperative hypertension a patient was administered clonidine, but due to rapid administration an initial phase of peripheral vasoconstriction occurred. Microvascular flow and velocity parameters measured with laser-doppler (O2C, LEA Medizintechnik) decreased by 44 and 16% respectively, but not the venous-capillary oxygen saturation. However, mitochondrial oxygen tension in the skin detected by COMET decreased from a steady state of 48 to 16 mmHg along with the decrease in flow and velocity. We conclude that COMET is ready for clinical application and we see the future for this bedside monitor on the intensive care, operating theater, and testing of mitochondrial effect of pharmaceuticals. PMID- 28000041 TI - Continuous blood pressure monitoring via non-invasive radial artery applanation tonometry and invasive arterial catheter demonstrates good agreement in patients undergoing colon carcinoma surgery. AB - PURPOSE: Radial artery applanation tonometry (RAAT) has been developed and utilized for continuous arterial pressure monitoring. However, evidence is lacking to clinically verify the RAAT technology and identify appropriate patient groups before routine clinical use. This study aims to evaluate the RAAT technology by comparing systolic blood pressure (SBP), mean blood pressure (MBP) and diastolic blood pressure (DBP) values in patients undergoing colon carcinoma surgery. METHODS: Blood Pressure (BP) values obtained via RAAT (TL-300, Tensys Medical Inc., San Diego, CA, USA) and conventional arterial catheterization from 30 colon carcinoma surgical patients were collected and compared via Bland-Atman method, linear regression and 4-quadrant plot concordance analysis. RESULTS: For SBPs, MBPs and DBPs, means of the differences (+/-standard deviation; 95% limits of agreement) were -0.9 (+/-7.6; -15.7 to 13.9) mmHg, 3.1 (+/-6.5; -9.6 to 15.8) mmHg and 4.3 (+/-7.4; -10.3 to 18.8) mmHg, respectively. Linear regression coefficients of determination were 0.8706 for SBPs, 0.8353 for MBPs and 0.6858 for DBPs. Four-quadrant concordance correlation coefficients were 0.8740, 0.8522 and 0.7108 for SBPs, MBPs and DBPs, respectively. CONCLUSIONS: A highly selected patient collective undergoing colon carcinoma surgery was studied. BP measurements obtained via the TL-300 had clinically acceptable agreement with that acquired invasively using an arterial catheter. For use in clinical routine, it is necessary to take measures for improvement regarding movement artifacts and dilution of noise. A large sample size of patients under various conditions is also needed to further evaluate the RAAT technology before clinically routine use. PMID- 28000042 TI - hnRNPA1 autoregulates its own mRNA expression to remain non-cytotoxic. AB - Heterogeneous nuclear ribonucleoprotein (hnRNP)A1, a member of the hnRNP family, is involved in a variety of RNA metabolisms. The hnRNPA1 expression is altered in some human diseases and mutations of the hnRNPA1 gene cause amyotrophic lateral sclerosis and multisystem proteinopathy. It has been therefore assumed that the dysregulation of hnRNPA1 is linked to the pathogenesis of the diseases. However, the mechanism underlying the regulation of the hnRNPA1 expression remains unknown. In this study, using cell-based models, we have found that hnRNPA1 negatively regulates its own mRNA expression by inhibiting the intron10 splicing of hnRNPA1 pre-mRNA. This mechanism likely serves as an autoregulation of the hnRNPA1 expression. We have also found that a low-grade excess of hnRNPA1 expression causes cytotoxicity by activating the mitochondrial apoptosis pathway. Collectively, these data suggest that the level of hnRNPA1 is strictly controlled to be within a certain range by the mRNA autoregulation in the physiological condition so that the cytotoxicity-causative alteration of hnRNPA1 expression does not take place. PMID- 28000043 TI - Molecular defect of tissue-nonspecific alkaline phosphatase bearing a substitution at position 426 associated with hypophosphatasia. AB - Mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP) cause hypophosphatasia (HPP), a genetic disorder characterized by deficiency of serum ALP and hypomineralization of bone and teeth. Three missense mutations for glycine 426 (by standard nomenclature) of TNSALP have been reported: cysteine (p.G426C), serine (p.G426S), and aspartate (p.G426D). We expressed TNSALP mutants carrying each missense mutation in mammalian cells. All three TNSALP mutants appeared on the cell surface like the wild-type (WT) TNSALP, although the cells expressing each TNSALP mutant exhibited markedly reduced ALP activity. TNSALP (WT) was mainly present as a 140 kDa catalytically active dimeric form, whereas ~80 kDa monomers were the predominant molecular species in the cells expressing TNSALP (p.G426D) or TNSALP (p.G426S), suggesting that aspartate or serine at position 426 may hamper the subunit assembly essential for the enzymatic function of TNSALP. Alternatively, the subunits of TNSALP (p.G426C) were found to be aberrantly cross-linked by disulfide bonds, giving rise to a 200 kDa form lacking ALP activity. Taken together, our results reveal that the amino acid substitutions at position 426 of TNSALP differentially affect the structure and function of TNSALP, leading to understanding of the molecular and cellular basis of HPP. PMID- 28000045 TI - Nitrosative Stress Response in Vibrio cholerae: Role of S-Nitrosoglutathione Reductase. AB - Vibrio cholerae, the causative agent of cholera, poses serious threats to humans worldwide. V. cholerae faces host inflammatory response and encounters nitrosative stress before establishing successful colonization. It is not clear how V. cholerae combats nitric oxide and reactive nitrogen species. In the present study, we used three clinical strains of V. cholerae and tested their nitrosative stress response pattern towards sodium nitroprusside (SNP) and S Nitrosoglutathione (GSNO). Among them, V. cholerae, belonging to both O1 and O139 serotypes, showed moderate resistance to SNP and GSNO. However, a V. cholerae strain belonging to non O1 and non O139 showed sensitivity to SNP but resistance towards GSNO. Reduced glutathione and glutathione reductase play a significant role to combat nitrosative stress in V. cholerae. This is the first report where we show the presence of GSNO reductase activity in V. cholerae and that it plays an important role to detoxify S-Nitrosoglutathione. GSNO reductase activity of V. cholerae was regulated by posttranslational modification through S-nitrosylation under in vitro conditions which could be reversed by dithiothreitol (DTT). In addition, we show that biofilm formation remained unaffected under nitrosative stress in V. cholerae. PMID- 28000044 TI - Dysregulation between TRIM63/FBXO32 expression and soleus muscle wasting in diabetic rats: potential role of miR-1-3p, -29a/b-3p, and -133a/b-3p. AB - Diabetes mellitus (DM) induces a variable degree of muscle sarcopenia, which may be related to protein degradation and to the expression of both E3 ubiquitin ligases and some specific microRNAs (miRNAs). The present study investigated the effect of diabetes and acute muscle contraction upon the TRIM63 and FBXO32 expression as well as the potential involvement of some miRNAs. Diabetes was induced by streptozotocin and studied after 30 days. Soleus muscles were harvested, stimulated to contract in vitro for twitch tension analysis (0.5 Hz), 30 min later for tetanic analysis (100 Hz), and 30 min later were frozen. TRIM63 and FBXO32 proteins were quantified by western blotting; Trim63 mRNA, Fbxo32 mRNA, miR-1-3p, miR-29a-3p, miR-29b-3p, miR-133a-3p, and miR-133b-3p were quantified by qPCR. Diabetes induced sarcopenia by decreasing (P < 0.05) muscle weight/tibia length index, maximum tetanic contraction and relaxation rates, and absolute twitch and tetanic forces (P < 0.05). Diabetes decreased (P < 0.05) the Trim63 and Fbxo32 mRNAs (30%) and respective proteins (60%), and increased (P < 0.01) the miR-29b-3p (2.5-fold). In muscle from diabetic rats, acute contractile stimulus increased TRIM63 protein, miR-1-3p, miR-29a-3p, and miR-133a/b-3p, but decreased miR-29b-3p (P < 0.05). Independent of the metabolic condition, after muscle contraction, both TRIM63 and FBXO32 proteins correlated significantly with miR-1-3p, miR-29a/b-3p, and miR-133a/b-3p. All diabetes-induced regulations were reversed by insulin treatment. Concluding, the results depict that muscle wasting in long-term insulinopenic condition may not be accompanied by increased proteolysis, pointing out the protein synthesis as an important modulator of muscle sarcopenia in DM. PMID- 28000046 TI - Semi-Rational Engineering of Leucine Dehydrogenase for L-2-Aminobutyric Acid Production. AB - L-2-aminobutyric acid (L-ABA) as a precursor for the anticonvulsant and the antituberculotic is a key intermediate in the chemical and pharmaceutical industries. Recently, leucine dehydrogenase (LeuDH) with NAD+ regeneration was developed for L-ABA production on a large scale. Previously, the L-ABA yield was improved by optimizing conversion conditions, including cofactor regeneration and enzyme immobilization but not protein engineering on LeuDH due to lacking an applicable high-throughput screening (HTS) method. Recently, an HTS assay was developed by us, which enables researchers to engineer LeuDH in a relatively short period of time. Herein, a semirational engineering was performed on LeuDH to increase the catalytic efficiency of BcLeuDH. Firstly, the structure of wild type (WT) BcLeuDH was modeled and seven potentially beneficial positions were selected for mutation. Five beneficial variants were then identified from the seven site-saturation mutagenesis (SSM) libraries by HTS and confirmed by rescreening via amino acid analyzer. The "best" variant M5 (WT + Q358N) showed 44.5-fold higher catalytic efficiency (k cat/K M) than BcLeuDH WT, which suggested that BcLeuDH M5 is an attractive candidate for L-ABA production on a large scale. Furthermore, the structure-functional relationship was investigated based on the docking and kinetic results. PMID- 28000047 TI - Multipole analysis of the strain-mediated coupling between proteins adsorbed at tubular lipid membrane surface. AB - The tubular lipid membranes (TLMs) pulled out from vesicles are often used in in vitro studies of the interactions between curvature-inducing proteins and highly curved membranes. The protein molecules adsorbed at the membrane surface deform the TLM and couple with each other due to the induced strain. Here we propose an approach which models the single curvature-inducing protein action on the lipid bilayer by the multipole, the superposition of the point forces applied to the membrane in the region of the protein adsorption. We show that to be localized in the area of the protein size at the TLM surface, the force multipoles satisfying the mechanical equilibrium conditions should be composed of three or more point forces. The protein coupling energy mediated by the membrane strain is studied in detail. In the region of the tubular membrane stability the maximal distance between two neighboring interacting protein-induced force multipoles is estimated to be of the order of the TLM cross section perimeter. In the vicinity of the TLM instability in the region of the vanishing stretching force applied to the TLM, the interaction radius increases drastically. The high affinity of the single curvature-inducing protein molecule to the regions in the vicinity of the TLM ends is explained and related to the boundary conditions in the experimental set ups. The reasons for the aggregate formation on the membrane surface are also discussed. PMID- 28000048 TI - Influence of temperature and charge effects on thermophoresis of polystyrene beads?. AB - We study the thermodiffusion behavior of spherical polystyrene beads with a diameter of 25 nm by infrared thermal diffusion Forced Rayleigh Scattering (IR TDFRS). Similar beads were used to investigate the radial dependence of the Soret coefficient by different authors. While Duhr and Braun (Proc. Natl. Acad. Sci. U.S.A. 104, 9346 (2007)) observed a quadratic radial dependence Braibanti et al. (Phys. Rev. Lett. 100, 108303 (2008)) found a linear radial dependence of the Soret coefficient. We demonstrated that special care needs to be taken to obtain reliable thermophoretic data, because the measurements are very sensitive to surface properties. The colloidal particles were characterized by transmission electron microscopy and dynamic light scattering (DLS) experiments were performed. We carried out systematic thermophoretic measurements as a function of temperature, buffer and surfactant concentration. The temperature dependence was analyzed using an empirical formula. To describe the Debye length dependence we used a theoretical model by Dhont. The resulting surface charge density is in agreement with previous literature results. Finally, we analyze the dependence of the Soret coefficient on the concentration of the anionic surfactant sodium dodecyl sulfate (SDS), applying an empirical thermodynamic approach accounting for chemical contributions. PMID- 28000049 TI - Complete genome sequence of Menghai rhabdovirus, a novel mosquito-borne rhabdovirus from China. AB - Menghai rhabdovirus (MRV) was isolated from Aedes albopictus in Menghai county of Yunnan Province, China, in August 2010. Whole-genome sequencing of MRV was performed using an Ion PGMTM Sequencer. We found that MRV is a single-stranded, negative-sense RNA virus. The complete genome of MRV has 10,744 nt, with short inverted repeat termini, encoding five typical rhabdovirus proteins (N, P, M, G, and L) and an additional small hypothetical protein. Nucleotide BLAST analysis using the BLASTn method showed that the genome sequence most similar to that of MRV is that of Arboretum virus (NC_025393.1), with a Max score of 322, query coverage of 14%, and 66% identity. Genomic and phylogenetic analyses both demonstrated that MRV should be considered a member of a novel species of the family Rhabdoviridae. PMID- 28000050 TI - Merkel cell polyomavirus IgG antibody levels are associated with progression to AIDS among HIV-infected individuals. AB - The association of Merkel cell polyomavirus (MCPyV) with Merkel cell carcinoma (MCC) in immunocompromised individuals has been revealed in a number of surveys. The study of MCPyV specific antibody titers and viral loads in such patients has a great attraction for research groups interested in viral reactivation. In this cross-sectional study to evaluate MCPyV antibody titer, DNA prevalence and viral load in peripheral blood mononuclear cells (PBMCs), we examined 205 HIV-1 infected patients and 100 un-infected controls. The HIV-1 infected patients divided into two groups (HIV/AIDS and non-AIDS) according to their CD4 status. Total IgG antibody titer against MCPyV was analyzed by virus like particle (VLP) based enzyme linked immunosorbent assay (ELISA). Presence of MCPyV-DNA in subject's PBMCs was examined by quantitative real-time PCR assay. Levels of anti MCPyV IgG in HIV/AIDS patients were significantly higher than those in non-AIDS HIV-infected and control subjects (p value = <0.001). The prevalence rate of MCPyV-DNA in PBMCs of HIV/AIDS, non-AIDS HIV-infected and un-infected controls were 17%, 16%, and 14% respectively. The MCPyV viral load among the groups ranged between 0.15 to 2.9 copies/103cells (median, 1.9 copies/103cells), with no significant difference between the studied populations (p value = 0.3). PMID- 28000051 TI - Bridging culture and psychopathology in mental health care. PMID- 28000053 TI - Response to reliability of drug-induced sedation endoscopy: a methodological issue. PMID- 28000052 TI - iTRAQ-based quantitative proteomics reveals important host factors involved in the high pathogenicity of the H5N1 avian influenza virus in mice. AB - We previously reported a pair of H5N1 avian influenza viruses which are genetically similar but differ greatly in their virulence in mice. A/Chicken/Jiangsu/k0402/2010 (CK10) is highly lethal to mice, whereas A/Goose/Jiangsu/k0403/2010 (GS10) is avirulent. In this study, to investigate the host factors that account for their virulence discrepancy, we compared the pathology and host proteome of the CK10- or GS10-infected mouse lung. Moderate lung injury was observed from CK10-infected animals as early as the first day of infection, and the pathology steadily progressed at later time point. However, only mild lesions were observed in GS10-infected mouse lung at the late infection stage. Using the quantitative iTRAQ coupled LC-MS/MS method, we first found that more significantly differentially expressed (DE) proteins were stimulated by GS10 compared with CK10. However, bio-function analysis of the DE proteins suggested that CK10 induced much stronger inflammatory response-related functions than GS10. Canonical pathway analysis also demonstrated that CK10 highly activated the "Acute Phase Response Signaling," which results in a wide range of biological activities in response to viral infection, including many inflammatory processes. Further in-depth analysis showed that CK10 exacerbated acute lung injury associated responses, including inflammatory response, cell death, reactive oxygen species production and complement response. In addition, some of these identified proteins that associated with the lung injury were further confirmed to be regulated in vitro. Therefore, our findings suggest that the early increased lung injury-associated host response induced by CK10 may contribute to the lung pathology and the high virulence of this virus in mice. PMID- 28000054 TI - 5-Flurouracil disrupts nuclear export and nuclear pore permeability in a calcium dependent manner. AB - Regulation of nuclear transport is an essential component of apoptosis. As chemotherapy induced cell death progresses, nuclear transport and the nuclear pore complex (NPC) are slowly disrupted and dismantled. 5-Fluorouracil (5-FU) and the camptothecin derivatives irinotecan and topotecan, are linked to altered nuclear transport of specific proteins; however, their general effects on the NPC and transport during apoptosis have not been characterized. We demonstrate that 5 FU, but not topotecan, increases NPC permeability, and disrupts Ran-mediated nuclear transport before the disruption of the NPC. This increased permeability is dependent on increased cellular calcium, as the Ca2+ chelator BAPTA-AM, abolishes the effect. Furthermore, increased calcium alone was sufficient to disrupt the Ran gradient. Combination treatments of 5-FU with topotecan or irinotecan, similarly disrupted nuclear transport before disassembly of the NPC. In both single and combination treatments nuclear transport was disrupted before caspase 9 activation, indicating that 5-FU induces an early caspase-independent increase in NPC permeability and alteration of nuclear transport. Because Crm1 mediated nuclear export of tumor suppressors is linked to drug resistance we also examined the effect of 5-FU on the nuclear export of a specific target, topoisomerase. 5-FU treatment led to accumulation of topoisomerase in the nucleus and recovered the loss nuclear topoisomerase induced by irinotecan or topotecan, a known cause of drug resistance. Furthermore, 5-FU retains its ability to cause nuclear accumulation of p53 in the presence of irinotecan or topotecan. Our results reveal a new mechanism of action for these therapeutics during apoptosis, opening the door to other potential combination chemotherapies that employ 5-FU as a calcium mediated inhibitor of Crm1-induced nuclear export of tumor suppressors. PMID- 28000055 TI - Deinococcus knuensis sp. nov., a bacterium isolated from river water. AB - Strain 16F3HT, a Gram-negative, aerobic, non-motile, and oval-shaped bacterium, was isolated from river water collected from the Han River in South Korea. Growth of strain 16F3HT was observed at 10-42 degrees C (optimum at 25-30 degrees C), but no growth occurred at 4 degrees C. The strain is able to grow at pH 4-10 (optimum at pH 7-8) and tolerates up to 4% NaCl (w/v), with optimum growth at 0.5% NaCl. The isolate was found to be resistant to UV irradiation. Based on 16S rRNA gene sequence analysis, it is closely related to 'Deinococcus seoulensis' 16F1E (98.8%), Deinococcus aquaticus PB314T (98.1%) and Deinococcus caeni Ho-08T (98.0%). The level of DNA-DNA homology between the novel strain and the three related strains was 57.4, 41.2, and 35.8%, respectively. Chemotaxonomic data revealed that strain 16F3HT possesses MK-8 as the predominant respiratory quinone, an unidentified phosphoglycolipid as the major polar lipid, and C15:1 omega6c and C16:1 omega7c as the major fatty acids. The DNA G + C content was determined to be 65.7 mol%. Based on polyphasic evidence, strain 16F3HT (=KCTC 33794T = JCM 31406T) should be classified as the type strain of a novel Deinococcus species, for which the name Deinococcus knuensis sp. nov. is proposed. PMID- 28000056 TI - Identification and genomic analysis of antifungal property of a tomato root endophyte Pseudomonas sp. p21. AB - Pseudomonas sp., which occupy a variety of ecological niches, have been widely studied for their versatile metabolic capacity to promote plant growth, suppress microbial pathogens, and induce systemic resistance in plants. In this study, a Pseudomonas sp. strain p21, which was isolated from tomato root endophytes, was identified as having antagonism against Aspergillus niger. Further analysis showed that this strain had the ability to biosynthesise siderophores and was less effective in inhibiting the growth of A. niger with the supplementation of Fe3+ in the agar medium. Genomic sequencing and the secondary metabolite cluster analysis demonstrated that Pseudomonas sp. p21 harboured 2 pyoverdine biosynthetic gene clusters, which encode compounds with predicted core structures and two variable tetra-peptide or eleven-peptide chains. The results indicated that siderophore-mediated competition for iron might be an important mechanism in Pseudomonas suppression of the fungal pathogen A. niger and in microbe-pathogen plant interactions. PMID- 28000057 TI - Bovine in vitro embryo production: the effects of fibroblast growth factor 10 (FGF10). AB - PURPOSE: In an attempt to improve in vitro embryo production, we investigated the effect of fibroblast growth factor 10 (FGF10) during in vitro maturation on the developmental capacity of bovine oocytes. MATERIAL AND METHODS: Cumulus-oocyte complexes (COCs) were aspirated from follicles of 3-8 mm diameter. After selection, the COCs were matured in medium with or without 0.5 ng/mL of FGF10. The effect of FGF10 during in vitro maturation (IVM) on nuclear maturation kinetics and expansion of the cumulus cells was investigated. Oocyte competence was assessed by the production and development speed of embryos and the relative expression of genes associated with embryo quality. RESULTS: FGF10 delayed the resumption of meiosis from 8 h onwards, but did not affect the percentage of oocytes reaching metaphase II, nor did it increase cumulus expansion at 22 h of maturation. We found no difference between treatments regarding embryo production, developmental speed, and gene expression. CONCLUSION: In conclusion, the presence of FGF10 during IVM had no effect on embryo production, developmental speed, and gene expression. PMID- 28000058 TI - Maximum number of children per sperm donor based on false paternity rate. AB - PURPOSE: The aim of this study is to estimate the weight of each relevant factor in such unions of inadvertent consanguinity and to determine a "reasonable" limit for the number of children per donor, matching the probability of inadvertent consanguinity arising from the use of sperm donor in assisted reproduction with that of such a union arising from false paternity. METHODS: In this study, we applied to Spanish data a mathematical model of consanguineous unions, taking into account the following factors: maximum number of live births/donor, fertility rate, average number of births per donor in a pregnancy, donor success rate, matings per phenotype, number of newborns/year, and number of donors needed in the population/year and births by false paternity. RESULTS: In Spain, the number of inadvertent unions between descendants of the same donor in Spain has been estimated at 0.4/year (one every two and a half years), although this frequency decreases as the reference population increases. On the other hand, the frequency of unions between family members due to false paternity has been estimated at 6.1/year. Thus, only 6% of such unions are due to the use of donor sperm. CONCLUSION: A total of 25 children per sperm donor are needed to align the probability of inadvertant consanguinity arising from the use of assisted reproduction with that due to false paternity. Therefore, we consider this number to be the maximum "reasonable" number of children born per donor in Spain. PMID- 28000059 TI - Interleukin-33 Expression does not Correlate with Survival of Gastric Cancer Patients. AB - The aim of the study was to investigate IL-33 expression in gastric cancer (GC) and its association with the clinical characteristics and the prognosis. IL-33 protein in tumor and corresponding adjacent tissues were detected by immunohistochemistry in 179 GC patients and clinical features plus prognostic value were analyzed via Pearson's chi-square test and Kaplan-Meier test in Cox proportional hazards model, respectively. IL-33 protein levels were significantly lower in tumor tissues than adjacent tissues (29.05% vs. 78.77%, chi 2 = 89.05, P < 0.001). The positive rate of IL-33 in the ulcerative type group was the lowest among all groups (P < 0.05). IL-33 levels were correlated with age (P = 0.025) and invasion depth (P = 0.030) while not significantly associated with the overall survival of GC patients. IL-33 expression is associated with age and invasive depth of GC patients but not an independent risk factor of prognosis. PMID- 28000060 TI - A new strategy for full-length Ebola virus glycoprotein expression in E.coli. AB - Ebola virus (EBOV) causes severe hemorrhagic fever in humans and non-human primates with high rates of fatality. Glycoprotein (GP) is the only envelope protein of EBOV, which may play a critical role in virus attachment and entry as well as stimulating host protective immune responses. However, the lack of expression of full-length GP in Escherichia coli hinders the further study of its function in viral pathogenesis. In this study, the vp40 gene was fused to the full-length gp gene and cloned into a prokaryotic expression vector. We showed that the VP40-GP and GP-VP40 fusion proteins could be expressed in E.coli at 16 degrees C. In addition, it was shown that the position of vp40 in the fusion proteins affected the yields of the fusion proteins, with a higher level of production of the fusion protein when vp40 was upstream of gp compared to when it was downstream. The results provide a strategy for the expression of a large quantity of EBOV full-length GP, which is of importance for further analyzing the relationship between the structure and function of GP and developing an antibody for the treatment of EBOV infection. PMID- 28000061 TI - Depression during the menopause transition: impact on quality of life, social adjustment, and disability. AB - The impact of depression on quality of life (QOL) and social support has neither been well characterized in clinical samples of women with perimenopausal depression (PMD) nor have the relative contributions of depression and other menopausal symptoms (e.g., hot flushes) to declining QOL been clarified. In this study, we compared QOL measures, social support, and functional disability in PMD and non-depressed perimenopausal women. We evaluated women aged 40-60 years who presented with menstrual cycle irregularity, elevated plasma FSH levels, and met criteria for perimenopause. A structured clinical interview was administered to determine the presence or absence of major and minor depression. Outcome measures included the Quality of Life Enjoyment Scale Questionnaire, the Sheehan Disability Scale, the Global Assessment of Functioning, the Social Adjustment Scale, and the Duke Social Support Index. Kruskal-Wallis tests and ANOVAs were used to compare outcome measures. Ninety women with PMD and 51 control women participated in this study. Women with PMD reported significantly decreased QOL, social support, and adjustment and increased disability compared with non depressed perimenopausal women. Neither perimenopausal reproductive status alone nor the presence of hot flushes had a significant negative impact on QOL measures. PMD is accompanied by significant reductions in QOL, social support, and disability similar to depression in women at other stages of life. PMD may also contribute to decreased QOL in community- or clinic-based samples of perimenopausal women. It remains unclear whether the clinical characteristics we identified reflect pre-existing risk factors for depression during the perimenopause or the effects of a current depression. Future clinical and treatment studies in perimenopausal women should distinguish depressed women when outcome measures include QOL. PMID- 28000064 TI - The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents. AB - It has long been recognised that uncontrolled childhood epilepsy is detrimental to cognition and behaviour, impacting on a patient's ability to succeed academically. Patients who experience more frequent and serious seizures are at greater risk for cognitive decline, emphasising the need for more effective epilepsy treatments to bring seizures under control. That said, although more effective antiepileptic drugs (AEDs) have the potential to limit the impact of uncontrolled seizures on cognitive and behavioural function, recently it has been acknowledged that deficits in these functions may be caused by AEDs themselves. The cognitive and behavioural effects of older-generation AEDs have been determined largely from AE reporting rather than from specific assessment. Recently, clinical trials of newer-generation AEDs, such as topiramate, levetiracetam and perampanel, have included standardised neuropsychological tests as outcome measures to assess their impact on cognition and behaviour in children and adolescents. However, to understand how we may limit the cognitive and behavioural side effects of AEDs, it is necessary for us to gain a fuller, more accurate, characterisation of their true impact. Such insight will depend on sophisticated and standardised approaches to the design of AED clinical trials. This review provides a general overview of our current understanding of the impact of both epilepsy and AEDs on cognition and behaviour, before focusing on the AEDs for which more detailed assessment, using standardised cognitive and behavioural measures, has been undertaken. We will then go on to discuss the key elements in the design of future AED clinical trials to address current unmet needs. PMID- 28000062 TI - Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence. AB - PURPOSE: The Nijmegen breakage syndrome (NBS) is an inherited genetic disorder characterized by a typical facial appearance, microcephaly, growth retardation, immunodeficiency, and a strong predisposition to malignancies, especially of lymphoid origin. NBS patients have a mutation in the NBN gene which involves the repair of DNA double-strand breaks (DSBs). Here we studied the peripheral T cell compartment of NBS patients with a focus on immunological senescence. METHODS: The absolute numbers and frequencies of the different T cell subsets were determined in NBS patients from young age till adulthood and compared to age matched healthy individuals (HI). In addition, we determined the expression of senescent T cell markers and the signal joint T cell receptor excision circles (sjTRECs) content. RESULTS: Our results demonstrate that NBS patients have reduced T cell numbers. NBS patients showed lower numbers of alphabeta+ T cells, but normal gammadelta+ T cell numbers compared to HI. Concerning the alphabeta+ T cells, both CD4+ as well as CD8+ T cells were excessively reduced in numbers compared to aged-matched HI. In addition, NBS patients showed higher frequencies of the more differentiated T cells expressing the senescent cell marker CD57 and did not express co-stimulatory molecule CD28. These effects were already present in the youngest age group. Furthermore, NBS patients showed lower sjTREC content in their T cells possibly indicative of a lower thymic output. CONCLUSIONS: We conclude that circulating T cells from NBS patients show signs of a senescent phenotype which is already present from young age on and which might explain their T cell immune deficiency. PMID- 28000065 TI - Description of Males from Three Species of Eumeninae (Hymenoptera, Vespidae). AB - The external morphology and genitalia of the males of Stenonartonia mimica (Kohl 1907), Sphaeromenes discrepatus Giordani Soika, 1978 and Gamma bolivianum flavior Giordani Soika, 1990 are described for the first time. PMID- 28000066 TI - CORR Insights(r): Do Needleless Knots have Similar Strength as the Krackow Suture? An In Vitro Porcine Tendon Study. PMID- 28000067 TI - Gendered Innovations in Orthopaedic Science: Show Me the Money. PMID- 28000068 TI - Mercury-methylating genes dsrB and hgcA in soils/sediments of the Three Gorges Reservoir. AB - Previous research found that the water-level fluctuating zone (WLFZ) of the Three Gorges Reservoir (TGR) was an Hg-sensitive area. However, little research has been conducted on the distribution of Hg-methylating microorganisms in this area. The goal of this research was to provide an initial description of the distribution of the dsrB (for sulfate-reducing bacteria) and hgcA (one gene confirmed for Hg methylation) genes. Different types of soil were selected to analyze the abundance of the dsrB and hgcA in different periods, in inundated soil (SI, <=155 m, which becomes sediment during the wet period, SS) and in non inundated soil (>=175 m, SN) from Shibao, a typical WLFZ of the TGR. A significant positive correlation was observed between dsrB and hgcA abundance and MeHg concentrations, suggesting that microorganisms with these genes contribute to Hg methylation. Principal component analysis (PCA) indicated that dsrB diversity was highest in SI, followed by SS; SS had the highest diversity of hcgA. Six phylogenetic trees were constructed and showed that more strains were present in SI than in SS. HgcA sequences in SS were confined to three evolutionarily distant clades, delta-Proteobacteria, a methanogen group, and a Clostridia group, which was relatively rare among most clades. PMID- 28000069 TI - Does turbidity induced by Carassius carassius limit phytoplankton growth? A mesocosm study. AB - It is well established that benthivorous fish in shallow lakes can create turbid conditions that influence phytoplankton growth both positively, as a result of elevated nutrient concentration in the water column, and negatively, due to increased attenuation of light. The net effect depends upon the degree of turbidity induced by the benthivores. Stocked Carassius carassius dominate the benthivorous fish fauna in many nutrient-rich Chinese subtropical and tropical shallow lakes, but the role of the species as a potential limiting factor in phytoplankton growth is ambiguous. Clarification of this relationship will help determine the management strategy and cost of restoring eutrophic lakes in China and elsewhere. Our outdoor mesocosm experiment simulating the effect of high density of crucian carp on phytoplankton growth and community structure in eutrophic shallow lakes suggests that stocking with this species causes resuspension of sediment, thereby increasing light attenuation and elevating nutrient concentrations. However, the effect of light attenuation was insufficient to offset the impact of nutrient enhancement on phytoplankton growth, and significant increases in both phytoplankton biomass and chlorophyll a concentrations were recorded. Crucian carp stocking favored the dominance of diatoms and led to lower percentages (but not biomass) of buoyant cyanobacteria. The dominance of diatoms may be attributed to a competitive advantage of algal cells with high sedimentation velocity in an environment subjected to frequent crucian carp-induced resuspension and entrainment of benthic algae caused by the fish foraging activities. Our study demonstrates that turbidity induced by stocked crucian carp does not limit phytoplankton growth in eutrophic waters. Thus, removal of this species (and presumably other similar taxa) from subtropical or tropical shallow lakes, or suspension of aquaculture, is unlikely to boost phytoplankton growth, despite the resulting improvements in light availability. PMID- 28000070 TI - Accumulation of trace elements in edible crops and poplar grown on a titanium ore landfill. AB - Urban gardening has recently experienced rapid development; however, the risk of the transfer of toxic elements from neighboring industry needs to be evaluated. We performed a multi-elemental analysis with several common edible crops (cucumber, pepper, cabbage, and lettuce) and poplar grown directly on a titanium ore landfill as a maximized scenario of exposure. Despite elevated concentrations of soil Ca, Fe, Mn, and Ti resulting from the industrial process, we did not register higher accumulation of these elements in the edible parts of crops or in poplar leaves grown on red gypsum compared with the control soil. Only S concentrations were higher in plants grown on the red gypsum, especially for cabbage. The principal component analysis among elements for plants grown on red gypsum indicated that S and Mn were accumulated by different plant species than Cd, Cu, and Zn. The poplar clone had a significantly higher transfer of S and Cr than the control and is a suitable tree species for monitoring element transfer to vegetation in this industrial context. By comparing our data with tolerable daily intake (TDI) recommendations, we demonstrated the low risk of cultivating edible crops directly on an industrial substrate in a maximized scenario of exposure, except for Cr, for which the toxicity depends on the bioavailable form. However, we did not consider the cumulative effects of the various elements because there are no current guidelines, and further research is needed to address this question. PMID- 28000071 TI - Nitrogen removal in wood chip combined substrate baffled subsurface-flow constructed wetlands: impact of matrix arrangement and intermittent aeration. AB - In this study, two lab-scale baffled subsurface-flow constructed wetlands (BSFCWs), including gravel-wood chips-slag and gravel-slag-wood chips, were operated at different intermittent aeration to evaluate the effect of artificial aeration and slow-released carbon source on the treatment efficiency of high strength nitrogen wastewater. Results indicated that gravel-slag-wood chips extended aerobic/anaerobic alternating environment to gravel and slag zones and maintained anaerobic condition in the subsequent wood chip section. The order of gravel-slag-wood chip was more beneficial to pollutant removal. Sufficient carbon source supply resulted from wood-chip-framework substrate simultaneously obtained high removals of COD (97%), NH4+-N (95%), and TN (94%) in BSFCWs at 2 h aeration per day. The results suggest that intermittent aeration combined with wood chips could achieve high nitrogen removal in BSFCWs. PMID- 28000072 TI - Genotoxicity of citrate-coated silver nanoparticles to human keratinocytes assessed by the comet assay and cytokinesis blocked micronucleus assay. AB - Silver nanoparticles (AgNPs) are widely used in industrial, cosmetic, and biomedical products, and humans are frequently exposed to these products through the skin. It is widely recognized that the characteristics of AgNPs (e.g., size, coating) may influence their cytotoxic effects, but their correlation with DNA damage and mitotic disorders remains poorly explored. In this study, human keratinocytes (HaCaT cell line) were exposed to well-characterized 30 nm AgNPs coated with citrate, and their effects on viability, DNA fragmentation (assessed by the comet assay), and micronuclei (MNi) induction (assessed by the cytokinesis block micronucleus cytome assays, CBMN) were investigated. The results showed that 10 and 40 MUg/mL AgNPs decreased cell proliferation and viability, and induced a significant genetic damage. This was observed by an increase of DNA amount in comet tail, which linearly correlated with dose and time of exposure. Also, cytostaticity (increase of mononucleated cells) and MNi rates increased in treated cells. In contrast, no significant changes were observed in nucleoplasmatic bridges (NPBs) or nuclear buds (NBUDs), although NBUDs tended to increase in all conditions and periods. The cytostatic effects on HaCaT cells were also shown by the decrease of their nuclear division index. Thus, both comet and CBMN assays supported the observation that citrate-AgNPs induced genotoxic effects on HaCaT cells. Considering that AgNPs are present in a vast number of consumer products and also in multiple nanomedicine skin applications and formulations, more research is needed to determine the properties that confer less toxicity of AgNPs to different cell lines. PMID- 28000073 TI - Application of cellulose nanofibers to remove water-based flexographic inks from wastewaters. AB - Water-based or flexographic inks in paper and plastic industries are more environmentally favourable than organic solvent-based inks. However, their use also creates new challenges because they remain dissolved in water and alter the recycling process. Conventional deinking technologies such as flotation processes do not effectively remove them. Adsorption, coagulation/flocculation, biological and membrane processes are either expensive or have negative health impacts, making the development of alternative methods necessary. Cellulose nanofibers (CNF) are biodegradable, and their structural and mechanical properties are useful for wastewater treatment. TEMPO-oxidised CNF have been evaluated for the decolourisation of wastewaters that contained copper phthalocyanine blue, carbon black and diarlyide yellow pigments. CNF in combination with a cationic polyacrylamide (cPAM) has also been tested. Jar-test methodology was used to evaluate the efficiency of the different treatments and cationic/anionic demand, turbidity and ink concentration in waters were measured. Results show that dual component system for ink removal has a high potential as an alternative bio-based adsorbent for the removal of water-based inks. In addition, experiments varying CNF and cPAM concentrations were performed to optimise the ink-removal process. Ink concentration reductions of 100%, 87.5% and 83.3% were achieved for copper phthalocyanine blue, carbon black and diarlyide yellow pigments, respectively. Flocculation studies carried out show the decolourisation mechanism during the dual-component treatment of wastewaters containing water-based inks. PMID- 28000075 TI - Treatment Preferences for Routine Lymphadenectomy Versus No Lymphadenectomy in Early-Stage Endometrial Cancer. AB - BACKGROUND: Debate on the value of lymphadenectomy continues in endometrial cancer. The aim of this study was to investigate patient and clinician preferences for routine lymphadenectomy versus no lymphadenectomy in the surgical management of endometrial cancer. METHODS: A discrete choice experiment and trade off question were designed and distributed to 103 endometrial cancer patients and 90 gynecologic oncologists. Participant preferences were quantified with regression analysis using scenarios based on three attributes: 5-year progression free survival and the rates of acute and chronic complication. A trade-off technique varying the risk of recurrence for no lymphadenectomy was used to quantify any additional risk of recurrence that these participants would accept to receive no lymphadenectomy instead of routine lymphadenectomy. RESULTS: On the basis of discrete choice experiment, the recurrence rate and lymphedema risk had a statistically significant impact on respondents' preference. The trade-off question showed that the median additional accepted risk of having no lymphadenectomy was 2.8% for gynecologic oncologists (0.5-14%) and 3.0% for patients (0.5-10%), but this difference was not significant (p = 0.620). Patients who were younger or had a higher education level or no history of delivery or shorter duration since diagnosis were prepared to accept higher additional risks of having no lymphadenectomy. CONCLUSIONS: Our results show that the majority of endometrial cancer patients and clinicians will accept a small amount of recurrence risk to reduce the incidence of lymphedema. Regarding preference heterogeneity among patients, our results show that it is important for surgeons to take a patient-tailored approach when discussing surgical management. PMID- 28000074 TI - Enhancement of Cd phytoextraction by hyperaccumulator Sedum alfredii using electrical field and organic amendments. AB - The combined use of organic amendment-assisted phytoextraction and electrokinetic remediation to decontaminate Cd-polluted soil was demonstrated in a laboratory scale experiment. The plant species selected was the hyperaccumulator Sedum alfredii. Prior to the pot experiment, the loamy soil was treated with 15 g kg-1 of pig manure compost, 10 g kg-1 of humic acid, or 5 mmol kg-1 of EDTA, and untreated soil without application of any amendment was the control. Two conditions were applied to each treatment: no voltage (without an electrical field) and a direct current (DC) electrical field (1 V cm-1 with switching polarity every day). Results indicated that Cd concentrations in S. alfredii were significantly (p < 0.05) increased by application of the electrical field and soil amendments (pig manure compost, humic acid, and EDTA). By switching the polarity of the DC electrical field, significant pH variation from anode to cathode can be avoided, and no significant impact was observed on shoot biomass production. Electrical field application increased DTPA-extractable Cd in soils and the Cd accumulation in shoots by 6.06-15.64 and 24.53-52.31%, respectively. The addition of pig manure compost and humic acid enhanced shoot Cd accumulation by 1.54- to 1.92- and 1.38- to 1.64-fold because of their simultaneous enhancement of Cd concentration in shoots and biomass production. However, no enhancement of Cd accumulation was found in the EDTA treatment, which can be ascribed to the inhibition of plant growth caused by EDTA. In conclusion, pig manure compost or humic acid addition in combination with the application of a switched-polarity DC electrical field could significantly enhance Cd phytoextraction by hyperaccumulator S. alfredii. PMID- 28000076 TI - National Trends in the Use of Neoadjuvant Chemotherapy for Hormone Receptor Negative Breast Cancer: A National Cancer Data Base Study. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) downstages tumor size and nodal disease. This study evaluates national practice patterns of NAC use in hormone receptor-negative breast cancer. METHODS: We identified patients in the National Cancer Data Base (NCDB) with hormone receptor-negative invasive breast cancer (2004-2012). Univariate and multivariable logistic regression was used to assess associations and trends across time. RESULTS: Of 171,985 patients, 130,723 (76.0%) received chemotherapy and 41,262 (24.0%) did not. Chemotherapy use was higher in young patients and higher T- and N-stage disease (all p < 0.001). Of those patients treated with chemotherapy, 23,165 (17.7%) received NAC and 107,558 (82.3%) received adjuvant chemotherapy (AC). NAC use increased from 2004 to 2012 (13.0-23.5%; adjusted odds ratio [aOR] 1.42; p < 0.001). Higher clinical T stage (ORs 3.63, 11.81, and 22.34 for cT2, cT3, and cT4a-c, respectively, vs. cT1) and cN+ disease (OR 2.86) [each p < 0.001] were associated with NAC, as were younger patient age and better Charlson-Deyo comorbidity score. Furthermore, BCS rate was higher in the NAC group in cT2 and cT3 tumors (aOR 1.17 and 1.45, respectively; both p < 0.001). In patients with cN+ disease, NAC converted 43.7% to pN0. Less extensive axillary surgery (one to five nodes removed) was more likely in cN+ patients treated with NAC (aOR 1.66; p < 0.001). CONCLUSIONS: In hormone receptor negative breast cancer, chemotherapy was mostly administered adjuvantly, but neoadjuvant use increased over time and was more likely in younger patients and higher T- and N-stage disease. Node-positive patients treated with NAC were less likely to have pathologically positive nodes and more likely to have less extensive axillary surgery. PMID- 28000077 TI - Purulent pericarditis. PMID- 28000078 TI - Autistic Traits and Symptoms of Social Anxiety are Differentially Related to Attention to Others' Eyes in Social Anxiety Disorder. AB - Autism spectrum disorder (ASD) and social anxiety disorder (SAD) have partly overlapping symptoms. Gaze avoidance has been linked to both SAD and ASD, but little is known about differences in social attention between the two conditions. We studied eye movements in a group of treatment-seeking adolescents with SAD (N = 25), assessing SAD and ASD dimensionally. The results indicated a double dissociation between two measures of social attention and the two symptom dimensions. Controlling for social anxiety, elevated autistic traits were associated with delayed orienting to eyes presented among distractors. In contrast, elevated social anxiety levels were associated with faster orienting away from the eyes, when controlling for autistic traits. This distinction deepens our understanding of ASD and SAD. PMID- 28000079 TI - AKTs/PKBs: molecular characterization, tissue expression and transcriptional responses to insulin and/or wortmannin in yellow catfish Pelteobagrus fulvidraco. AB - In the present study, four AKT isoforms termed AKT1, AKT2, AKT3a and AKT3b were isolated and characterized from yellow catfish. Their molecular characterizations, tissue expressions and transcriptional responses to insulin and/or wortmannin were determined. The validated complementary DNA (cDNA) of yellow catfish AKT1, AKT2, AKT3a and AKT3b were 1422, 1431, 1389 and 1440 bp in length, encoding the peptide of 472, 475, 462 and 479 amino acid residues, respectively. The amino acid sequences of yellow catfish AKTs possessed all the characteristics of AKTs in other species. AKT1, AKT2 and AKT3b contained a conserved domain structure including a specific PH domain, a central catalytic domain and a C-terminal regulatory domain, while AKT3a lacked the C-terminal regulatory domain. All mRNAs of AKTs were expressed at the highest levels in the ovary. Among other tissues, the messenger RNA (mRNA) of AKT1 was widely distributed in all tested tissues, and AKT2 mRNA was more abundant in the muscle, liver and fat and lowest in other tested tissues, while AKT3a mRNA was predominant in the brain and showed no significant difference among other tested tissues, and AKT3b mRNA was highly expressed in the ovary, followed by the brain, muscle and fat and was relatively low in other tissues. Intraperitoneal insulin injection and incubation increased the mRNA expression of AKT1 and AKT2, but not that of AKT3a and AKT3b in the liver and hepatocytes of yellow catfish. Wortmannin reduced the mRNA level of all AKT isoforms and also alleviated the insulin-induced changes of AKT2 expression. The present study cloned full-length cDNA sequences of four AKTs in fish and determined their tissue expression profiles and studied their transcriptional responses to insulin and/or wortmannin, which serves to increase our understanding of their physiological function in lipid metabolism in fish. PMID- 28000080 TI - A bioinformatics pipeline to search functional motifs within whole-proteome data: a case study of poxviruses. AB - Proteins harbor domains or short linear motifs, which facilitate their functions and interactions. Finding functional motifs in protein sequences could predict the putative cellular roles or characteristics of hypothetical proteins. In this study, we present Shetti-Motif, which is an interactive tool to (i) map UniProt and PROSITE flat files, (ii) search for multiple pre-defined consensus patterns or experimentally validated functional motifs in large datasets protein sequences (proteome-wide), (iii) search for motifs containing repeated residues (low complexity regions, e.g., Leu-, SR-, PEST-rich motifs, etc.). As proof of principle, using this comparative proteomics pipeline, eleven proteomes encoded by member of Poxviridae family were searched against about 100 experimentally validated functional motifs. The closely related viruses and viruses infect the same host cells (e.g. vaccinia and variola viruses) show similar motif-containing proteins profile. The motifs encoded by these viruses are correlated, which explains why poxviruses are able to interact with wide range of host cells. In conclusion, this in silico analysis is useful to establish a dataset(s) or potential proteins for further investigation or compare between species. PMID- 28000081 TI - Rotavirus NSP486-175 interacts with H9c2(2-1) cells in vitro, elevates intracellular Ca2+ levels and can become cytotoxic: a possible mechanism for extra-intestinal pathogenesis. AB - Rotavirus (RV) is the predominant cause of infantile gastroenteritis with multiple pathogenic factors, among which enterotoxin NSP4 is the most significant factor. NSP4 has been shown to induce elevation of the intracellular calcium concentration, alteration of the cytoskeleton organization, and cytopathic effect among other processes. However, increasing evidence suggests that RVs can escape from the gastrointestinal tract and invade other organs and tissues to cause extra-intestinal diseases. In this study, we investigated whether NSP4 has a pathogenic effect on extra-intestinal cells and examined possible molecular mechanisms in vitro. Our results showed that NSP486-175 has important functions in increasing intracellular Ca2+ concentration, altering actin cytoskeleton organization and inducing cellular damage in H9c2(2-1) cells. Blockade of the integrin alpha2 receptor using a specific antibody attenuated the increase of intracellular Ca2+ concentration and alleviated the observed cytopathic effects, suggesting that integrin alpha2 may be a receptor for NSP486-175. Collectively, these results indicate that extracellular NSP486-175 can induce elevation of the intracellular Ca2+ concentration, cause cytotoxic changes, and disrupt the actin cytoskeleton in H9c2(2-1) cells, which may constitute a possible mechanism for RV extra-intestinal pathogenesis. PMID- 28000082 TI - The influence of action observation on action execution: Dissociating the contribution of action on perception, perception on action, and resolving conflict. AB - For more than 15 years, motor interference paradigms have been used to investigate the influence of action observation on action execution. Most research on so-called automatic imitation has focused on variables that play a modulating role or investigated potential confounding factors. Interestingly, furthermore, a number of functional magnetic resonance imaging (fMRI) studies have tried to shed light on the functional mechanisms and neural correlates involved in imitation inhibition. However, these fMRI studies, presumably due to poor temporal resolution, have primarily focused on high-level processes and have neglected the potential role of low-level motor and perceptual processes. In the current EEG study, we therefore aimed to disentangle the influence of low-level perceptual and motoric mechanisms from high-level cognitive mechanisms. We focused on potential congruency differences in the visual N190 - a component related to the processing of biological motion, the Readiness Potential - a component related to motor preparation, and the high-level P3 component. Interestingly, we detected congruency effects in each of these components, suggesting that the interference effect in an automatic imitation paradigm is not only related to high-level processes such as self-other distinction but also to more low-level influences of perception on action and action on perception. Moreover, we documented relationships of the neural effects with (autistic) behavior. PMID- 28000083 TI - Impulsivity in rodents with a genetic predisposition for excessive alcohol consumption is associated with a lack of a prospective strategy. AB - Increasing evidence supports the hypothesis that impulsive decision-making is a heritable risk factor for an alcohol use disorder (AUD). Clearly identifying a link between impulsivity and AUD risk, however, is complicated by the fact that both AUDs and impulsivity are heterogeneous constructs. Understanding the link between the two requires identifying the underlying cognitive factors that lead to impulsive choices. Rodent models have established that a family history of excessive drinking can lead to the expression of a transgenerational impulsive phenotype, suggesting heritable alterations in the decision-making process. In the present study, we explored the cognitive processes underlying impulsive choice in a validated, selectively bred rodent model of excessive drinking-the alcohol-preferring ("P") rat. Impulsivity was measured via delay discounting (DD), and P rats exhibited an impulsive phenotype as compared to their outbred foundation strain-Wistar rats. Steeper discounting in P rats was associated with a lack of a prospective behavioral strategy, which was observed in Wistar rats and was directly related to DD. To further explore the underlying cognitive factors mediating these observations, a drift diffusion model of DD was constructed. These simulations supported the hypothesis that prospective memory of the delayed reward guided choice decisions, slowed discounting, and optimized the fit of the model to the experimental data. Collectively, these data suggest that a deficit in forming or maintaining a prospective behavioral plan is a critical intermediary to delaying reward, and by extension, may underlie the inability to delay reward in those with increased AUD risk. PMID- 28000084 TI - Peripheral and central antinociceptive effects of the butanolic fraction of Byrsonima verbascifolia leaves on nociception-induced models in mice. AB - Byrsonima verbascifolia (Malpighiaceae), commonly known as 'murici', is used in folk medicine, for example, in the treatment of inflammation. The anti inflammatory activity of the butanolic fraction of B. verbascifolia leaves (BvBF) was previously reported by our group, and the present study was designed to evaluate their antinociceptive effects. BvBF (25, 50, and 100 mg/kg) administered intraperitoneally (i.p.) inhibited acetic acid induced abdominal writhing. In the formalin test, BvBF (10, 30 and 100 mg/kg, i.p.) caused a reduction in licking time in both the neurogenic and inflammatory phases. Moreover, we demonstrated that BvBF (30 and 100 mg/kg, i.p.) caused an increase in the latency to response in the hot-plate test. These results demonstrate that BvBF possesses marked peripheral and central antinociceptive activities. Pre-treatment with the non selective receptor antagonist naloxone (5 mg/kg, i.p.) abolished the antinociceptive effects of BvBF (100 mg/kg, i.p.) in the neurogenic phase of the formalin and hot-plate tests. The anti-inflammatory activity of BvBF (previously reported) as well as the participation of the opioidergic system seems to be responsible, at least in part, for these antinociceptive effects. Finally, BvBF at the doses investigated (25, 50 and 100 mg/Kg) did not cause any toxicity signals, showing that the antinociceptive activity is devoid of sedative and hypomotility effects. PMID- 28000085 TI - Lyophilization of an Adjuvanted Mycobacterium tuberculosis Vaccine in a Single Chamber Pharmaceutical Cartridge. AB - Although substantial effort has been made in the development of next-generation recombinant vaccine systems, maintenance of a cold chain is still typically required and remains a critical challenge in effective vaccine distribution. The ability to engineer alternative containment systems that improve distribution and administration represents potentially significant enhancements to vaccination strategies. In this work, we evaluate the ability to successfully lyophilize a previously demonstrated thermostable tuberculosis vaccine formulation (ID93 + GLA SE) in a cartridge format compared to a traditional vial container format. Due to differences in the shape of the container formats, a novel apparatus was developed to facilitate lyophilization in a cartridge. Following lyophilization, the lyophilizate was assessed visually, by determining residual moisture content, and by collecting melting profiles. Reconstituted formulations were assayed for particle size, protein presence, and GLA content. Based on assessment of the lyophilizate, the multicomponent vaccine was successfully lyophilized in both formats. Also, the physicochemical properties of the major components in the formulation, including antigen and adjuvant, were retained after lyophilization in either format. Ultimately, this study demonstrates that complex formulations can be lyophilized in alternative container formats to the standard pharmaceutical glass vial, potentially helping to increase the distribution of vaccines. PMID- 28000086 TI - Interaction of small heat shock proteins with light component of neurofilaments (NFL). AB - The interaction of human small heat shock protein HspB1, its point mutants associated with distal hereditary motor neuropathy, and three other small heat shock proteins (HspB5, HspB6, HspB8) with the light component of neurofilaments (NFL) was analyzed by differential centrifugation, analytical ultracentrifugation, and fluorescent spectroscopy. The wild-type HspB1 decreased the quantity of NFL in pellets obtained after low- and high-speed centrifugation and increased the quantity of NFL remaining in the supernatant after high-speed centrifugation. Part of HspB1 was detected in the pellet of NFL after high-speed centrifugation, and at saturation, 1 mol of HspB1 monomer was bound per 2 mol of NFL. Point mutants of HspB1 associated with distal hereditary motor neuropathy (G84R, L99M, R140G, K141Q, and P182S) were almost as effective as the wild-type HspB1 in modulation of NFL assembly. At low ionic strength, HspB1 weakly interacted with NFL tetramers, and this interaction was increased upon salt induced polymerization of NFL. HspB1 and HspB5 (alphaB-crystallin) decreased the rate of NFL polymerization measured by fluorescent spectroscopy. HspB6 (Hsp20) and HspB8 (Hsp22) were less effective than HspB1 (or HspB5) in modulation of NFL assembly. The data presented indicate that the small heat shock proteins affect NFL transition from tetramers to filaments, hydrodynamic properties of filaments, and their bundling and therefore probably modulate the formation of intermediate filament networks in neurons. PMID- 28000087 TI - The effect of diffusion gradient direction number on corticospinal tractography in the human brain: an along-tract analysis. AB - OBJECTIVES: We evaluated diffusion imaging measures of the corticospinal tract obtained with a probabilistic tractography algorithm applied to data of two acquisition protocols based on different numbers of diffusion gradient directions (NDGDs). MATERIALS AND METHODS: The corticospinal tracts (CST) of 18 healthy subjects were delineated using 22 and 66-NDGD data. An along-tract analysis of diffusion metrics was performed to detect possible local differences due to NDGD. RESULTS: FA values at 22-NDGD showed an increase along the central portion of the CST. The mean of partial volume fraction of the orientation of the second fiber (f2) was higher at 66-NDGD bilaterally, because for 66-NDGD data the algorithm more readily detects dominant fiber directions beyond the first, thus the increase in FA at 22-NDGD is due to a substantially reduced detection of crossing fiber volume. However, the good spatial correlation between the tracts drawn at 22 and 66 NDGD shows that the extent of the tract can be successfully defined even at lower NDGD. CONCLUSIONS: Given the spatial tract localization obtained even at 22-NDGD, local analysis of CST can be performed using a NDGD compatible with clinical protocols. The probabilistic approach was particularly powerful in evaluating crossing fibers when present. PMID- 28000088 TI - Dialysate temperature of 36 degrees C: association with clinical outcomes. AB - Dialysate cooling, either individualized based upon patient body temperature, or to a standardized temperature below 37 degrees C, has been proposed to minimize hemodynamic insults and improve outcomes among hemodialysis patients. However, low dialysate temperatures (35-35.5 degrees C) are associated with patient discomfort, and individualized dialysate cooling is difficult to operationalize. Here, we tested whether a standardized dialysate temperature of 36 degrees C (dT36) was associated with improved clinical outcomes compared to the default temperature of 37 degrees C (dT37). Because patients with known hemodynamic instability may be selectively prescribed dT36, we minimized selection bias by considering only incident adult in-center hemodialysis patients who, between Jan 2011 and Dec 2013 received their first-ever hemodialysis treatment at a large dialysis organization. Exposure status was based on the treatment order for this first-ever treatment. 313 dT36 patients were identified and propensity-score matched (1:5) to 1565 dT37 controls. Death, hospitalization, and missed hemodialysis treatments were considered from the date of first-ever hemodialysis treatment until the earliest of death, loss to follow-up, crossover (month in which prescribed dialysate temperature was consistent with patient's exposure group for <80% of treatments), or study end (June 2015). During follow-up, rates of death, hospitalization and missed hemodialysis treatments did not differ between the two groups. This study therefor showed no benefit of dT36 vs. dT37 with respect to these clinical outcomes. Our results do not favor conversion to a default dialysate temperature of 36 degrees C. Individualized dialysate cooling may provide a more reliable approach to achieve the hemodynamic benefits associated with reduced dialysate temperature. PMID- 28000089 TI - The Peri-operative Bariatric Surgery Care in the Middle East Region. AB - BACKGROUND: Bariatric surgery is common in the Middle East region. However, regional accreditation bodies and guidelines are lacking. We present the current peri-operative practice of bariatric surgery in the Middle East region. SETTING: Public and private practice in the Middle East region. METHODS: A questionnaire was designed to study trends of peri-operative care in bariatric surgery. It was sent to members of the Pan Arab Society for Metabolic and Bariatric Surgery (PASMBS). RESULTS: Ninety-three surgeons (88.6%) responded, 63.4% were in private practice, 68.5% have been in practice for more than 5 years, and 61.1% performed more than 125 cases per year. Laparoscopic sleeve gastrectomy (LSG) was the commonest procedure performed, then laparoscopic Roux-en-Y gastric bypass (LRYGB), one anastomosis gastric bypass/mini gastric bypass (OAGB/MGB), and laparoscopic adjustable gastric banding (LAGB). Pre-operatively as a routine, 65% referred patients for dietitian and (78.3%) for smoking cessation. In contrast as a routine, 22.6% referred patients to a psychologist, 30% screened for obstructive sleep apnea (OSA), and when they did, they did not use a questionnaire. For patients 50 years of age, 22% performed a screening colonoscopy and 33.7% referred patients to a cardiologist. Intra-operatively as a routine, 25.3% placed a drain and 42.2% placed urinary catheters. In contrast, 77.1% performed a leak test (82.7% as a methylene blue leak test). Post operatively, 79.5% used chemoprophylaxis for venous thromboembolism and 89% required patients to take vitamins. In contrast, 25% prescribed ursodeoxycholic acid. CONCLUSION: The wide variation in the peri-operative care of bariatric surgery in the Middle East region highlights the need for regional guidelines based on international guidelines. PMID- 28000090 TI - Letter to the Editor Regarding Equivalent Increases in Circulating GLP-1 Following Jejunal Delivery of Intact and Hydrolysed Casein: Relevance to Satiety Induction following Bariatric Surgery. PMID- 28000091 TI - Physicochemical Parameters and Antioxidant Activity of Bee Honey Enriched With Herbs. AB - Three groups of products enriched with herbs were studied: (1) commercial herb honeys (n = 5) produced by bees fed a syrup with an herbal extract, (2) natural herbal honey (n = 3) produced by bees from the nectar of herbs, and (3) creamed multifloral honey with added dried herbs (n = 5). As a control, multifloral honey (n = 5) was used. The physicochemical parameters (i.e., sugar extract, water content, specific rotation, conductivity, hydroxymethylfurfural content, pH and acidity), sugar profiles (HPLC analysis), antioxidant activity and total phenolic compounds content of the studied samples were compared. Although great diversity in the basic properties of the studied products was observed, they were comparable to multifloral honey and complied with honey regulations. Significant differences in sugar composition were observed, and adversely positive rotation (excluding nettle herb honey) was detected in group 1, likely resulting from the change in bee feeding. The best antioxidant activity for creamed honeys with dried herbs (group 2) was investigated, whereas herb honeys (group 1) exhibited similar antioxidant properties as multifloral honey. The use of controlled feeding of bees appears to be an effective method of enriching honey with desirable plant bioactive components to create innovative bee products. PMID- 28000092 TI - The Slippery Slope Argument in the Ethical Debate on Genetic Engineering of Humans. AB - This article applies tools from argumentation theory to slippery slope arguments used in current ethical debates on genetic engineering. Among the tools used are argumentation schemes, value-based argumentation, critical questions, and burden of proof. It is argued that so-called drivers such as social acceptance and rapid technological development are also important factors that need to be taken into account alongside the argumentation scheme. It is shown that the slippery slope argument is basically a reasonable (but defeasible) form of argument, but is often flawed when used in ethical debates because of failures to meet the requirements of its scheme. PMID- 28000093 TI - Engineering Students' Views of Corporate Social Responsibility: A Case Study from Petroleum Engineering. AB - The mining and energy industries present unique challenges to engineers, who must navigate sometimes competing responsibilities and codes of conduct, such as personal senses of right and wrong, professional ethics codes, and their employers' corporate social responsibility (CSR) policies. Corporate social responsibility (CSR) is the current dominant framework used by industry to conceptualize firms' responsibilities to their stakeholders, yet has it plays a relatively minor role in engineering ethics education. In this article, we report on an interdisciplinary pedagogical intervention in a petroleum engineering seminar that sought to better prepare engineering undergraduate students to critically appraise the strengths and limitations of CSR as an approach to reconciling the interests of industry and communities. We find that as a result of the curricular interventions, engineering students were able to expand their knowledge of the social, rather than simply environmental and economic dimensions of CSR. They remained hesitant, however, in identifying the links between those social aspects of CSR and their actual engineering work. The study suggests that CSR may be a fruitful arena from which to illustrate the profoundly sociotechnical dimensions of the engineering challenges relevant to students' future careers. PMID- 28000094 TI - Patient and caregiver goals for dementia care. AB - PURPOSE: Most health outcome measures for chronic diseases do not incorporate specific health goals of patients and caregivers. To elicit patient-centered goals for dementia care, we conducted a qualitative study using focus groups of people with early-stage dementia and dementia caregivers. METHODS: We conducted 5 focus groups with 43 participants (7 with early-stage dementia and 36 caregivers); 15 participants were Spanish-speaking. Verbatim transcriptions were independently analyzed line-by-line by two coders using both deductive and inductive approaches. Coded texts were grouped into domains and developed into a goal inventory for dementia care. RESULTS: Participants identified 41 goals for dementia care within five domains (medical care, physical quality of life, social and emotional quality of life, access to services and supports, and caregiver support). Caregiver goals included ensuring the safety of the person with dementia and managing caregiving stress. Participants with early-stage dementia identified engaging in meaningful activity (e.g., work, family functions) and not being a burden on family near the end of life as important goals. Participants articulated the need to readdress goals as the disease progressed and reported challenges in goal-setting when goals differed between the person with dementia and the caregiver (e.g., patient safety vs. living independently at home). While goals were similar among English- and Spanish-speaking participants, Spanish speaking participants emphasized the need to improve community education about dementia. CONCLUSIONS: Patient- and caregiver-identified goals for care are different than commonly measured health outcomes for dementia. Future work should incorporate patient-centered goals into clinical settings and assess their usefulness for dementia care. PMID- 28000095 TI - Exosomes from iPSCs Delivering siRNA Attenuate Intracellular Adhesion Molecule-1 Expression and Neutrophils Adhesion in Pulmonary Microvascular Endothelial Cells. AB - The pro-inflammatory activation of pulmonary microvascular endothelial cells resulting in continuous expression of cellular adhesion molecules, and subsequently recruiting primed neutrophils to form a firm neutrophils-endothelium (PMN-EC) adhesion, has been examined and found to play a vital role in acute lung injury (ALI). RNA interference (RNAi) is a cellular process through harnessing a natural pathway silencing target gene based on recognition and subsequent degradation of specific mRNA sequences. It opens a promising approach for precision medicine. However, this application was hampered by many obstacles, such as immunogenicity, instability, toxicity problems, and difficulty in across the biological membrane. In this study, we reprogrammed urine exfoliated renal epithelial cells into human induced pluripotent stem cells (huiPSCs) and purified the exosomes (Exo) from huiPSCs as RNAi delivery system. Through choosing the episomal system to deliver transcription factors, we obtained a non-integrating huiPSCs. Experiments in both vitro and vivo demonstrated that these huiPSCs possess the pluripotent properties. The exosomes of huiPSCs isolated by differential centrifugation were visualized by transmission electron microscopy (TEM) showing a typical exosomal appearance with an average diameter of 122 nm. Immunoblotting confirmed the presence of the typical exosomal markers, including CD63, TSG 101, and Alix. Co-cultured PKH26-labeled exosomes with human primary pulmonary microvascular endothelial cells (HMVECs) confirmed that they could be internalized by recipient cells at a time-dependent manner. Then, electroporation was used to introduce siRNA against intercellular adhesion molecule-1 (ICAM-1) into exosomes to form an Exo/siRNA compound. The Exo/siRNA compound efficiently delivered the target siRNA into HMVECs causing selective gene silencing, inhibiting the ICAM-1 protein expression, and PMN-EC adhesion induced by lipopolysaccharide (LPS). These data suggest that huiPSCs exosomes could be used as a natural gene delivery vector to transport therapeutic siRNAs for alleviating inflammatory responses in recipient cells. PMID- 28000096 TI - Relationship between Tissue Distributions of Modified Wuzi Yanzong Prescription () in Rats and Meridian Tropism Theory. AB - OBJECTIVE: To investigate the relationship between tissue distributions of modified Wuzi Yanzong prescription (, MWP) in rats and meridian tropism theory. METHODS: A high-performance liquid chromatography with Fourier transform-mass spectrometry (HPLC-FT) method was used to identify the metabolites of MWP in different tissues of rats after continued oral administration of MWP for 7 days. The relationship between MWP and meridian tropism theory was studied according to the tissue distributions of the metabolites of MWP in rats and the relevant literature. RESULTS: Nineteen metabolites, mainly flavanoid compounds, were detected in the different rat tissues and classified to each herb in MWP. Further, it was able to establish that the tissue distributions of the metabolites of MWP were consistent with the descriptions of meridian tropism of MWP available in literature, this result might be useful in clarifying the mechanism of MWP on meridian tropism. In the long run, these data might provide scientific evidence of the meridian tropism theory to further promote the reasonable, effective utilization, and modernization of Chinese medicine. CONCLUSION: The tissue distributions of MWP in vivo were consistent with the descriptions of meridian tropism of MWP. PMID- 28000097 TI - An overview of epigenetics in Chinese medicine researches. AB - Chinese medicine (CM) has contributed to human health care for several thousand years and is still popular in Asian countries. But the mechanisms underlying CM remain obscure, and need to be clarifified by modern biological subjects and methods. Recently, CM researches on epigenetics have gained obvious improvement following rapidly developed molecular technologies. In this review, we revealed mutual characteristics of epigenetics and CM, such as holism, yin-yang dynamic nature, reversibility and balance, and visceral manifestation. Moreover, epigenetic modifications, including DNA methylation, histone post-transcriptional modifications, micro RNA interference, etc. may help explore the molecular basis of CM syndrome classifification, and mechanisms of Chinese herbal medicine (CHM), CHM compounds and Chinese herbal formulae activities. Meanwhile, CM and epigenetics might promote each other and jointly develop following the continuous progress of epigenetics in CM researches. PMID- 28000098 TI - Insulin Formulation Characterization-the Thioflavin T Assays. AB - The insulin molecule was discovered in 1921. Shortly thereafter, its propensity towards amyloid fibril formation, fibrillation, was observed and described in the literature as a "precipitate." In the past decades, the increased incidence of type 2 diabetes has reached global epidemic proportions. This has emphasized the demands for both insulin production and the development of modern insulin products for unmet medical needs. Bringing such new insulin drug products to the market for the benefit of patients requires that many CMC-related processes are understood, described, and controlled. One potential undesired process is insulin fibril formation. The compound thioflavin T (ThT) is known as a fluorescent probe for amyloid fibrils. As such, ThT is utilized in a versatile research assay in microtiter plate format, the ThT assay. This review will describe an experimental set-up using not only a ThT microtiter plate assay but also two orthogonal methods. The use of the ThT assay in research and characterization of insulin analogues, as well as formulations of insulin, is described by cases drawn from the scientific literature and patents. The ThT assay is compared to other physical stability tests and in conclusion the advantages and limitations of the assay are compared. PMID- 28000099 TI - Phase 1 study of ixazomib alone or combined with lenalidomide-dexamethasone in Japanese patients with relapsed/refractory multiple myeloma. AB - We report the first clinical investigation conducted in Japan to confirm the safety, tolerability, and pharmacokinetics of ixazomib alone and combined with lenalidomide-dexamethasone (Rd) in Japanese patients with relapsed/refractory multiple myeloma. Adult patients with measurable disease and >=2 prior lines of therapy received oral ixazomib 4.0 mg on days 1, 8, 15 alone or combined with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, 22 in 28-day cycles. Fourteen patients who had received a median of seven prior therapies were enrolled (seven per cohort). One of six evaluable patients in each cohort experienced dose-limiting toxicities [diarrhea, nausea, hypokalemia, hypertension, thrombocytopenia, hyponatremia (ixazomib cohort); thrombocytopenia, and neutropenia (ixazomib + Rd cohort)]. The most common drug-related adverse events were neutropenia, thrombocytopenia, leukopenia, and lymphopenia. Drug related grade >=3 adverse events occurring in >=3 patients per cohort were (ixazomib/ixazomib + Rd cohort, n): neutropenia (4/2), thrombocytopenia (3/2), and lymphopenia (5/2). Ixazomib was rapidly absorbed with a median T max of approximately 1-2-h post-dose, and had a geometric mean terminal half-life of 5-6 days. Of 13 response-evaluable patients, one achieved a partial response (duration ~38 weeks; ixazomib cohort) and seven had stable disease. PMID- 28000100 TI - Marked response to imatinib mesylate in a patient with platelet-derived growth factor receptor beta-associated acute myeloid leukemia. AB - Abnormal platelet-derived growth factor receptor (PDGFR)-mediated signaling may cause hematologic neoplasm. The PDGFR beta (PDGFRB) gene, located at chromosome band 5q31-33, forms a fusion gene as a result of chromosome translocation. Although patients with PDGFRB rearrangement mostly present with myeloproliferative neoplasm and eosinophilia, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) have also been reported in this population. Treatment with imatinib mesylate alone has been shown to have excellent long-term efficacy against myeloproliferative neoplasms; however, its long-term effects on ALL and AML have not been elucidated. A 75-year-old man was diagnosed with acute myeloid leukemia having the PDGFRB and cGMP-dependent protein kinase 2 fusion gene with additional genetic abnormalities. Continuous therapy with single-agent imatinib mesylate resulted in cytogenetic remission and decreased molecular burden for 9 months; however, the leukemia subsequently recurred, and the patient died 1 year after initiation of treatment. This case report supports the importance of cytogenetic analysis during patient screening. PMID- 28000101 TI - Remarkable Pharmacokinetics of Monoclonal Antibodies: A Quest for an Explanation. AB - Monoclonal antibodies (MAbs) usually display slow and limited distribution with combined linear and non-linear elimination mechanisms. While studying individual pharmacokinetic profiles, it was noticed that MAb plasma concentration can vary abruptly over time, with one or more increases after the time to maximum plasma concentration when theoretically the concentration should only decline. This article summarizes the frequency of these additional peaks and assesses whether normal intra-subject and assay variability can explain the observations. For this analysis, we used a benchmark consisting of three registered (adalimumab, bevacizumab, and trastuzumab) and three unregistered immunoglobulin G1 MAbs. At a selected 'normal' intra-subject variability of 12%, at least 70% of the study participants (approximately 90% for certain MAbs) still had at least one additional peak, which decreased when the 'normal' variability was increased. There was no difference in occurrence between the high- and low-concentration ranges. Only a high sample density was associated with an increased likelihood of detecting additional peaks. Based on the analytical variability for the applied ligand-binding assays (5-10%, up to 15% at the lower limit of quantitation), the number of observed increases was extremely improbable (p < 0.01) for most MAbs, especially for the large excursions. Therefore, the fluctuations are likely genuine. We discuss the possible explanations and the relevance for clinical practice. PMID- 28000103 TI - Capsule Commentary on Behar et al., Acceptability of Naloxone Co-Prescription Among Primary Care Providers Treating Patients on Long-Term Opioid Therapy for Pain. PMID- 28000102 TI - Translational Modeling and Simulation in Supporting Early-Phase Clinical Development of New Drug: A Learn-Research-Confirm Process. AB - BACKGROUND AND OBJECTIVE: Pharmacokinetic/pharmacodynamic modeling and simulation can aid clinical drug development by dynamically integrating key system- and drug specific information into predictive profiles. In this study, we propose a methodology to predict pharmacokinetic/pharmacodynamic profiles of sinogliatin (HMS-5552, RO-5305552), a novel glucokinase activator to treat diabetes mellitus, for first-in-patient (FIP) studies. METHODS AND RESULTS: Initially, pharmacokinetic/pharmacodynamic profiles of sinogliatin and another glucokinase activator (US2) previously acquired from healthy subjects were fitted using Model A incorporating an indirect response mechanism. The pharmacokinetic/pharmacodynamic profiles of US2 in patients with type 2 diabetes mellitus (T2DM) were then fitted using Model B incorporating circadian rhythm and food effects after thoughtful research on the difference between healthy subjects and T2DM patients. The differences in results between the two US2 modeling populations were used to scale the values of the pharmacodynamic parameters and refine the pharmacodynamic model of sinogliatin, which was then utilized to project pharmacokinetic/pharmacodynamic profiles of sinogliatin in T2DM patients after an 8-day simulated treatment. Results showed that the projected pharmacokinetic/pharmacodynamic values of five parameters were within 70-130% of values fitted from observed clinical data while the other two remaining projected parameters were within a twofold error. Population pharmacokinetic/pharmacodynamic analysis conducted for sinogliatin also suggested that age and sex were significantly correlated to pharmacokinetic/pharmacodynamic characteristics. Additionally, Model B was combined with a glycosylated hemoglobin (HbA1c) compartment to form Model C, which was then used to project serum HbA1c levels in patients after a 1-month simulated treatment of sinogliatin. The predicted HbA1c changes were nearly identical to observed clinical values (0.82 vs. 0.78%). CONCLUSIONS: Model-based drug development methods utilizing a learn-research-confirm cycle may accurately project pharmacokinetic/pharmacodynamic profiles of new drugs in FIP studies. PMID- 28000104 TI - Immune Reconstitution Inflammatory Syndrome Presenting as Mycobacterium Avium Complex Lymphadenitis. PMID- 28000105 TI - Comparing pre-operative stereotactic radiosurgery (SRS) to post-operative whole brain radiation therapy (WBRT) for resectable brain metastases: a multi institutional analysis. AB - Pre-operative stereotactic radiosurgery (pre-SRS) has been shown as a viable treatment option for resectable brain metastases (BM). The aim of this study is to compare oncologic outcomes and toxicities for pre-SRS and post-operative WBRT (post-WBRT) for resectable BM. We reviewed records of consecutive patients who underwent resection of BM and either pre-SRS or post-WBRT between 2005 and 2013 at two institutions. Overall survival (OS) was calculated using the Kaplan-Meier method. Cumulative incidence was used for intracranial outcomes. Multivariate analysis (MVA) was performed using the Cox and Fine and Gray models, respectively. Overall, 102 patients underwent surgical resection of BM; 66 patients with 71 lesions received pre-SRS while 36 patients with 42 cavities received post-WBRT. Baseline characteristics were similar except for the pre-SRS cohort having more single lesions (65.2% vs. 38.9%, p = 0.001) and smaller median lesion volume (8.3 cc vs. 15.3 cc, p = 0.006). 1-year OS was similar between cohorts (58% vs. 56%, respectively) (p = 0.43). Intracranial outcomes were also similar (2-year outcomes, pre-SRS vs. post-WBRT): local recurrence: 24.5% vs. 25% (p = 0.81), distant brain failure (DBF): 53.2% vs. 45% (p = 0.66), and leptomeningeal disease (LMD) recurrence: 3.5% vs. 9.0% (p = 0.66). On MVA, radiation cohort was not independently associated with OS or any intracranial outcome. Crude rates of symptomatic radiation necrosis were 5.6 and 0%, respectively. OS and intracranial outcomes were similar for patients treated with pre-SRS or post-WBRT for resected BM. Pre-SRS is a viable alternative to post WBRT for resected BM. Further confirmatory studies with neuro-cognitive outcomes comparing these two treatment paradigms are needed. PMID- 28000106 TI - Knockdown of NUPR1 inhibits the proliferation of glioblastoma cells via ERK1/2, p38 MAPK and caspase-3. AB - Nuclear protein-1 (NUPR1), located on chromosome 16p11.2, is a stress response factor that plays an important role in the growth and migration of human malignant tumor cells. However, the role of NUPR1 in glioblastoma remains poorly understood. The expression level of NUPR1 was detected by quantitative real-time PCR and immunohistochemistry (IHC). Wound healing, MTT, cell counting and BrdU assays were used to analyze the migration and proliferation of glioblastoma cells after down-regulating NUPR1 expression using a lentiviral vector. FACS analysis and a signaling antibody array kit were used to detect the mechanism by which NUPR1 modulates cell cycle and apoptosis activities in glioblastoma cells. We confirmed that NUPR1 was up-regulated in glioblastoma tissues compared to NB tissues. Down-regulation of NUPR1 suppressed cell migration and proliferation, arrested the cell cycle in the G0/G1 phase and promoted apoptosis in U251 and U87 cells in vitro. Furthermore, the expression levels of phosphorylated ERK1/2, p38 MAPK and cleaved caspase-3 were decreased upon silencing NUPR1 expression in U251 and U87 cells. In summary, NUPR1 plays an important role in the growth and migration of human glioblastoma cells. Knockdown of NUPR1 suppressed glioblastoma cell growth by arresting the cell cycle and inducing cell apoptosis via decreases in the expression of ERK1/2, p38 MAPK and caspase-3. PMID- 28000107 TI - Analytical Validation of a Portable Mass Spectrometer Featuring Interchangeable, Ambient Ionization Sources for High Throughput Forensic Evidence Screening. AB - Forensic evidentiary backlogs are indicative of the growing need for cost effective, high-throughput instrumental methods. One such emerging technology that shows high promise in meeting this demand while also allowing on-site forensic investigation is portable mass spectrometric (MS) instrumentation, particularly that which enables the coupling to ambient ionization techniques. While the benefits of rapid, on-site screening of contraband can be anticipated, the inherent legal implications of field-collected data necessitates that the analytical performance of technology employed be commensurate with accepted techniques. To this end, comprehensive analytical validation studies are required before broad incorporation by forensic practitioners can be considered, and are the focus of this work. Pertinent performance characteristics such as throughput, selectivity, accuracy/precision, method robustness, and ruggedness have been investigated. Reliability in the form of false positive/negative response rates is also assessed, examining the effect of variables such as user training and experience level. To provide flexibility toward broad chemical evidence analysis, a suite of rapidly-interchangeable ion sources has been developed and characterized through the analysis of common illicit chemicals and emerging threats like substituted phenethylamines. Graphical Abstract ?. PMID- 28000109 TI - A Survey among Neonatologists on the Management of Patent Ductus Arteriosus. PMID- 28000108 TI - Pneumatosis Intestinalis in Meconium Inspissation Mimicking Necrotising Enterocolitis. PMID- 28000110 TI - Complexities in Genotype-Phenotype Correlation and Genetic Counseling in Collagen VI - Related Myopathy. PMID- 28000111 TI - Uncommon Disorders Masquerading as Acute Flaccid Paralysis in Children. AB - The syndrome of acute flaccid paralysis (AFP) is a common medical emergency in children. In the era of poliomyelitis eradication, the common causes of AFP include Guillain-Barre syndrome (GBS), transverse myelitis and traumatic neuritis. However, many common diseases can uncommonly present as AFP and some uncommon diseases may also masquerade like it. Uncommon causes of AFP seen at a tertiary care pediatric hospital are discussed along with relevant points in diagnosis and management. Also, common pitfalls in diagnosis of pediatric AFP and an approach to investigations are discussed. PMID- 28000112 TI - Aldehyde reduction in a novel pericardial tissue reduces calcification using rabbit intramuscular model. AB - Calcification is a major factor that limits the durability of bioprosthetic valve. A novel bovine pericardial tissue treated with aldehyde capping chemistry and glycerolization was evaluated for its resistance to calcification in comparison with porcine tissues treated with amino oleic acid and bovine pericardial tissue with ethanol rinsing in a rabbit intramuscular model. Tissue discs from the test and control tissues were implanted in rabbits for 60 days. The explanted discs were subject to X-ray imaging, calcium quantification and histology analysis. The test tissue showed 95 and 96 % reduction in calcification in comparison with amino oleic acid treatment and ethanol rinsing treatment, respectively. In addition, the test tissue showed the least inflammatory response as evidenced by a reduced amount of macrophages and giant cells in histology analysis. Furthermore, the aldehyde analysis of the pre-implanted samples showed associated reduction in free aldehyde levels with the test tissue. The reduction in calcification is consistent with previously reported results and is hypothesized to be attributed to the capping of free aldehydes in the test tissue. PMID- 28000113 TI - Adhesion and differentiation of Saos-2 osteoblast-like cells on chromium-doped diamond-like carbon coatings. AB - Diamond-like carbon (DLC) thin films are promising for use in coating orthopaedic, dental and cardiovascular implants. The problem of DLC layers lies in their weak layer adhesion to metal implants. Chromium is used as a dopant for improving the adhesion of DLC films. Cr-DLC layers were prepared by a hybrid technology, using a combination of pulsed laser deposition (PLD) from a graphite target and magnetron sputtering. Depending on the deposition conditions, the concentration of Cr in the DLC layers moved from zero to 10.0 at.%. The effect of DLC layers with 0.0, 0.9, 1.8, 7.3, 7.7 and 10.0 at.% Cr content on the adhesion and osteogenic differentiation of human osteoblast-like Saos-2 cells was assessed in vitro. The DLC samples that contained 7.7 and 10.0 at.% of Cr supported cell spreading on day 1 after seeding. On day three after seeding, the most apparent vinculin-containing focal adhesion plaques were also found on samples with higher concentrations of chromium. On the other hand, the expression of type I collagen and alkaline phosphatase at the mRNA and protein level was the highest on Cr-DLC samples with a lower concentration of Cr (0-1.8 at.%). We can conclude that higher concentrations of chromium supported cell adhesion; however DLC and DLC doped with a lower concentration of chromium supported osteogenic cell differentiation. PMID- 28000115 TI - Tied to expectations: Predicting features speeds processing even under adverse circumstances. AB - When participants predict the upcoming stimulus in a randomized choice reaction task, a match between prediction and stimulus increases processing speed at a level similar to that observed in cueing studies with highly valid cues. This might be taken to suggest that people cannot help but fully use their self generated, verbalized predictions for preparing task processing. Thus, we tested how flexibly participants can control formation and implementation of predictions. In Experiment 1, we varied validity and response-relevance of predictions. We observed that prediction effects on RT can be boosted by increasing validity, but prevail under adverse circumstances. This was not the case in a control group who read rather than predicted the feature words, suggesting that the effect was specific to predictions as such. Experiment 2 provided further evidence for limited control of participants over implementing and forming predictions. Participants were provided with practice on stimuli occurring with varying frequency, but neither learned to strategically choose predictions to maximize the number of match trials, nor did they reduce the amount of prediction-based preparation when predicting an infrequent stimulus. As sequential aftereffects of prediction match did not vary with validity, they were identified as an independent effect of verbalizing a response-relevant stimulus feature. The results are consistent with the view that the predicted stimulus feature is represented in the focus of attention in working memory and that the amount of implementation can be subject to weighting. PMID- 28000114 TI - Evaluation of a laminin-alginate biomaterial, adipocytes, and adipocyte-derived stem cells interaction in animal autologous fat grafting model using 7-Tesla magnetic resonance imaging. AB - Biomaterials are often added to autologous fat grafts both as supporting matrices for the grafted adipocytes and as cell carrier for adipose-derived stem cells (ADSCs). This in vivo study used an autologous fat graft model to test a lamininalginate biomaterial, adipocytes, and ADSCs in immune-competent rats. We transplanted different combinations of shredded autologous adipose tissue [designated "A" for adipose tissue]), laminin-alginate beads [designated "B" for bead], and ADSCs [designated "C" for cell]) into the backs of 15 Sprague-Dawley rats. Group A received only adipocytes, Group B received only laminin-alginate beads, Group AB received adipocytes mixed with laminin-alginate beads, Group BC received laminin-alginate beads encapsulating ADSCs, and Group ABC received adipocytes and laminin-alginate beads containing ADSCs. Seven-tesla magnetic resonance imaging was used to evaluate the rats at the 1st, 6th, and 12th weeks after transplantation. At the 12th week, the rats were sacrificed and the implanted materials were retrieved for gross examination and histological evaluation. The results based on MRI, gross evaluation, and histological data all showed that implants in Group ABC had better resorption of the biomaterial, improved survival of the grafted adipocytes, and adipogenic differentiation of ADSCs. Volume retention of grafts in Group ABC (89%) was also significantly greater than those in Group A (58%) (p < 0.01). Our findings support that the combination of shredded adipose tissue with ADSCs in laminin-alginate beads provided the best overall outcome. PMID- 28000116 TI - Communication Patterns in the Perioperative Environment During Epic Electronic Health Record System Implementation. AB - In April 2016, Massachusetts General Hospital (MGH) went live with the Epic electronic health records (EHR) system, replacing a variety of EHRs that previously existed in different departments throughout the hospital. At the time of implementation, the Vocera(r) Badge Communication System, a wireless hands free communication device distributed to perioperative team members, had increased perioperative communication flow and efficiency. As a quality improvement effort to better understand communication patterns during an EHR go live, we monitored our Vocera call volume and user volume before, during and after our go-live. We noticed that call volume and user volume significantly increased during our immediate go-live period and quickly returned to baseline levels. We also noticed that call volume increased during periods of unplanned EHR downtime long after our immediate go-live period. When planning the implementation of a new EHR, leadership must plan for and support this critical communication need at the time of the go-live and must also be aware of these needs during unplanned downtime. PMID- 28000117 TI - Monitoring Indoor Air Quality for Enhanced Occupational Health. AB - Indoor environments are characterized by several pollutant sources. Because people spend more than 90% of their time in indoor environments, several studies have pointed out the impact of indoor air quality on the etiopathogenesis of a wide number of non-specific symptoms which characterizes the "Sick Building Syndrome", involving the skin, the upper and lower respiratory tract, the eyes and the nervous system, as well as many building related diseases. Thus, indoor air quality (IAQ) is recognized as an important factor to be controlled for the occupants' health and comfort. The majority of the monitoring systems presently available is very expensive and only allow to collect random samples. This work describes the system (iAQ), a low-cost indoor air quality monitoring wireless sensor network system, developed using Arduino, XBee modules and micro sensors, for storage and availability of monitoring data on a web portal in real time. Five micro sensors of environmental parameters (air temperature, humidity, carbon monoxide, carbon dioxide and luminosity) were used. Other sensors can be added for monitoring specific pollutants. The results reveal that the system can provide an effective indoor air quality assessment to prevent exposure risk. In fact, the indoor air quality may be extremely different compared to what is expected for a quality living environment. Systems like this would have benefit as public health interventions to reduce the burden of symptoms and diseases related to "sick buildings". PMID- 28000118 TI - Smart Sensor-Based Motion Detection System for Hand Movement Training in Open Surgery. AB - We introduce a smart sensor-based motion detection technique for objective measurement and assessment of surgical dexterity among users at different experience levels. The goal is to allow trainees to evaluate their performance based on a reference model shared through communication technology, e.g., the Internet, without the physical presence of an evaluating surgeon. While in the current implementation we used a Leap Motion Controller to obtain motion data for analysis, our technique can be applied to motion data captured by other smart sensors, e.g., OptiTrack. To differentiate motions captured from different participants, measurement and assessment in our approach are achieved using two strategies: (1) low level descriptive statistical analysis, and (2) Hidden Markov Model (HMM) classification. Based on our surgical knot tying task experiment, we can conclude that finger motions generated from users with different surgical dexterity, e.g., expert and novice performers, display differences in path length, number of movements and task completion time. In order to validate the discriminatory ability of HMM for classifying different movement patterns, a non surgical task was included in our analysis. Experimental results demonstrate that our approach had 100 % accuracy in discriminating between expert and novice performances. Our proposed motion analysis technique applied to open surgical procedures is a promising step towards the development of objective computer assisted assessment and training systems. PMID- 28000119 TI - Overexpression of phytochelatin synthase (pcs) enhances abiotic stress tolerance by altering the proteome of transformed Anabaena sp. PCC 7120. AB - The present study provides data on the insertion of an extra copy of phytochelatin synthase (alr0975) in Anabaena sp. PCC 7120. The recombinant strain (AnFPN-pcs) compared to wild type showed approximately 22.3% increase in growth rate under UV-B, NaCl, heat, CuCl2, carbofuran, and CdCl2. It also registered 2.25-fold enhanced nitrogenase activity and 5-fold higher phytochelatin production. A comparison of the protein profile of wild type with the recombinant strain revealed that recombinant strain accumulated proteins belonging to the following categories: (i) detoxification (nutrient stress induced DNA binding protein, Mn-SOD, Alr0946 (CalA)), (ii) protein folding and modification (molecular chaperone DnaK, FKBP-type peptidyl-prolyl cis-trans isomerase), (iii) nucleotide and amino acid biosynthesis (dihydroorotase and Ketol-acid reductoisomerase), (iv) photosynthesis and respiration (coproporphyrinogen III oxidase, phycocyanin alpha chain, ferredoxin-NADP+ reductase), and (v) transport (sugar transport ATP-binding protein). Thus, it can be concluded that, above category proteins with their respective role in scavenging reactive oxygen species, proper folding of unfolded proteins, and protection of protein from degradation, sustained carbon fixation and energy pool and active transport of sugar together conceivably help the recombinant cyanobacterium (AnFPN-pcs) to cope with abiotic stress employed in the present study. Such recombinant strains have potential for future use as biofertilizer. PMID- 28000120 TI - Analysis of landscape changes as an indicator for environmental monitoring. AB - Mediterranean coastal landscapes are complex systems that are subject to rapid and extensive changes due to unprecedented human interference. Changes in these landscapes are strong indications of anthropogenic disturbances that should be monitored carefully in order to make effective management decisions. Landscape changes can be analyzed using many qualitative and quantitative techniques. In this respect, the importance of land cover information arises from the fact that any change in the composition and/or configuration of land cover can be used as a landscape-level environmental indicator. Therefore, proper understanding of spatial and temporal characteristics of this environmental attribute is of vital importance as it enables decision-makers to reveal causes of environmental issues and to cope with consequences of mismanagement. The aims of this paper are to analyze landscape-level changes using the largest patch index (LPI) as a simple pattern indicator and provide guidelines for studying change phenomena that take place in the Mediterranean coastal areas. In this respect, changes in the LPI values for agricultural and built-up areas in three different sites were analyzed using georeferenced Ikonos and Quickbird images. The concepts of pattern and process were highlighted as important indicators for studying landscapes and understanding their change. PMID- 28000122 TI - Potentially toxic trace element contamination, sources, and pollution assessment in farmlands, Bijie City, southwestern China. AB - Artisanal zinc smelting activities, which had been widely applied in Bijie City, Guizhou Province, southwestern of China, can pollute surrounding farmlands. In the present study, 177 farmland topsoil samples of Bijie City were collected and 11 potentially toxic trace elements (PTEs), namely Pb, Zn, Cu, Ni, Co, Mn, Cr, V, Hg, As, and Cd were tested to characterize the concentrations, sources, and ecological risks. Mean concentrations of these PTEs in soils were (mg/kg) as follows: Pb (127), Zn (379), Cu (93.1), Ni (54.6), Co (26.2), Mn (1095), Cr (133), V (206), Hg (0.15), As (16.2), and Cd (3.08). Pb, Zn, and Cd had coefficients of variation greater than 100% and showed a high uneven distribution and spatial variability in the study area. Correlation coefficient analysis and principal component analysis (PCA) were used to quantify potential pollution sources. Results showed that Cu, Ni, Co, Mn, and V came from natural sources, whereas Pb, Zn, Hg, As, and Cd came from anthropogenic pollution sources. Geoaccumulation index and potential ecological risk indices were employed to study the pollution degree of PTEs, which revealed that Pb and Cd shared the greatest contamination and would pose serious ecological risks to the surrounding environment. The results of this study could help the local government managers to establish pollution control strategies and to secure food safety. PMID- 28000121 TI - Detection of Bacillus and Stenotrophomonas species growing in an organic acid and endocrine-disrupting chemical-rich environment of distillery spent wash and its phytotoxicity. AB - Sugarcane molasses-based distillery spent wash (DSW) is well known for its toxicity and complex mixture of various recalcitrant organic pollutants with acidic pH, but the chemical nature of these pollutants is unknown. This study revealed the presence of toxic organic acids (butanedioic acid bis(TMS)ester; 2 hydroxysocaproic acid; benzenepropanoic acid, alpha-[(TMS)oxy], TMS ester; vanillylpropionic acid, bis(TMS)), and other recalcitrant organic pollutants (2 furancarboxylic acid, 5-[[(TMS)oxy] methyl], TMS ester; benzoic acid 3-methoxy-4 [(TMS)oxy], TMS ester; and tricarballylic acid 3TMS), which are listed as endocrine-disrupting chemicals. In addition, several major heavy metals were detected, including Fe (163.947), Mn (4.556), Zn (2.487), and Ni (1.175 mg l-1). Bacterial community analysis by restriction fragment length polymorphism revealed that Bacillus and Stenotrophomonas were dominant autochthonous bacterial communities belonging to the phylum Firmicutes and gamma-Proteobacteria, respectively. The presence of Bacillus and Stenotrophomonas species in highly acidic environments indicated its broad range adaptation. These findings indicated that these autochthonous bacterial communities were pioneer taxa for in situ remediation of this hazardous waste during ecological succession. Further, phytotoxicity assay of DSW with Phaseolus mungo L. and Triticum aestivum revealed that T. aestivum was more sensitive than P. mungo L. in the seed germination test. The results of this study may be useful for monitoring and toxicity assessment of sugarcane molasses-based distillery waste at disposal sites. PMID- 28000123 TI - Thermotolerant coliform loadings to coastal areas of Santa Catarina (Brazil) evidence the effect of growing urbanisation and insufficient provision of sewerage infrastructure. AB - Thermotolerant coliform (TC) loadings were quantified for 49 catchments draining into the North and South Bays of Santa Catarina (SC, southeastern Brazil), an area known for its tourism and aquaculture. TC loadings were calculated based on flow measurements taken in 26 rivers. TC concentrations ere quantified based on surface water samples collected at 49 catchment outlets in 2012 and 2013. Median TC loads ranged from 3.7 * 103 to 6.8 * 108 MPN s-1. TC loadings in the catchments increased in proportion to increases in resident human population, population density and percentage of urbanised area. Catchments with more than 60% of area covered by wastewater collection and treatment systems had higher TC loads per person than catchments with less than 25%. Based on the study catchments, these results indicate that current sewerage infrastructure is ineffective in reducing contamination of faecal origin to surface waters. These findings have important implications for the management of microbiological health hazards in bathing, recreational and shellfish aquaculture waters in the North and South Bays of Santa Catarina Island. PMID- 28000124 TI - Lead isotope ratios in lichen samples evaluated by ICP-ToF-MS to assess possible atmospheric pollution sources in Havana, Cuba. AB - Epiphytic lichens, collected from 119 sampling sites grown over "Roistonea Royal Palm" trees, were used to assess the spatial distribution pattern of lead (Pb) and identify possible pollution sources in Havana (Cuba). Lead concentrations in lichens and topsoils were determined by flame atomic absorption spectrophotometry and inductively coupled plasma (ICP) atomic emission spectrometry, respectively, while Pb in crude oils and gasoline samples were measured by ICP-time of flight mass spectrometry (ICP-ToF-MS). Lead isotopic ratios measurements for lichens, soils, and crude oils were obtained by ICP-ToF-MS. We found that enrichment factors (EF) reflected a moderate contamination for 71% of the samples (EF > 10). The 206Pb/207Pb ratio values for lichens ranged from 1.17 to 1.20 and were a mixture of natural radiogenic and industrial activities (e.g., crude oils and fire plants). The low concentration of Pb found in gasoline (<7.0 MUg L-1) confirms the official statement that leaded gasoline is no longer used in Cuba. PMID- 28000125 TI - Prevalence and Risk Factors for Early Seizure in Patients with Traumatic Brain Injury: Analysis from National Trauma Data Bank. AB - BACKGROUND: Traumatic brain injury (TBI) is a well-known risk factor for seizures. We aimed to identify the frequency and risk factors for seizure occurrence during hospitalization for TBI. METHODS: We used ICD-9-CM codes to identify patients 18 years of age or older from the National Trauma Data Bank who were admitted with TBI. We also used ICD-9-CM codes to identify the subset who had seizures during hospitalization. Patient demographics, comorbidities, Glasgow Coma Scale (GCS) score, Injury Severity Score Abbreviated Injury Scale (ISSAIS), in-hospital complications, and discharge disposition were compared in the seizure group (SG) and no-seizure group (NSG). RESULTS: A total of 1559 patients had in hospital seizures, comprising 0.4% of all patients admitted with TBI. The mean age of SG was 3 years older than NSG [51 vs. 48; p < 0.0001]. African-American ethnicity (20 vs. 12%, p < 0.0001) and moderate TBI (8 vs. 4%, p < 0.0001) were more common in SG. History of alcohol dependence was more common in the SG (25 vs. 11%, p < 0.0001). Fall was the most common mechanism of injury in SG (56 vs. 36% in NSG; p < 0.0001). Subdural hematoma was more common in SG (31 vs. 21%, p < 0.0001). SG had higher rates of pneumonia, ARDS, acute kidney injury, and increased ICP. The average length of hospital stay was significantly higher in SG (10 vs. 6 days, p < 0.0001), and these patients had higher rate of discharge to nursing facility (32 vs. 25%, p < 0.0001). CONCLUSION: In-hospital seizures occur in 0.4% of all TBI patients. Although infrequent, seizure occurrence is associated with higher rates of hospital complications such as pneumonia and ARDS and is an independent predictor of longer hospital stay and worse hospital outcome. PMID- 28000126 TI - Autophagy Biomarkers Beclin 1 and p62 are Increased in Cerebrospinal Fluid after Traumatic Brain Injury. AB - BACKGROUND: Autophagy is a process that recycles damaged proteins and organelles. Beclin 1 is involved in the nucleation phase, while p62 is consumed during the elongation phase. We hypothesized that these autophagy biomarkers are increased in cerebrospinal fluid (CSF) after traumatic brain injury (TBI) in children and associated with unfavorable outcome. METHODS: Thirty children with severe TBI had CSF collected on days 1, 3, and 7. Patients without TBI or meningoencephalitis served as controls. Beclin 1 and p62 were measured by ELISA. Outcome was assigned 6 months after injury (Glasgow Outcome Scale score; GOS). RESULTS: Mean and peak CSF beclin 1 and p62 levels were increased compared to controls (P < 0.05). Peak p62 levels were higher in patients with unfavorable versus favorable outcome (0.79 +/- 1.03 vs. 0.17 +/- 0.54 ng/ml, respectively; mean +/- SD, P = 0.002) and were independently associated with outcome when controlling for age and initial Glasgow Coma Scale score (P = 0.019; AUC 0.88, 95% CI 0.76, 1.00). CONCLUSIONS: Beclin 1 and p62 are increased in CSF after TBI, suggesting increased autophagy with impairment of, and/or exceeding the capacity for, autophagic flux. The association of increased p62 with unfavorable outcome suggests that autophagy in excess of the capacity to clear degradation products may be deleterious after TBI. PMID- 28000127 TI - Intensive Care Unit Admission for Patients in the INTERACT2 ICH Blood Pressure Treatment Trial: Characteristics, Predictors, and Outcomes. AB - BACKGROUND: Wide variation exists in criteria for accessing intensive care unit (ICU) facilities for managing patients with critical illnesses such as acute intracerebral hemorrhage (ICH). We aimed to determine the predictors of admission, length of stay, and outcome for ICU among participants of the main Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). METHODS: INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of 2839 ICH patients (<6 h) and elevated systolic blood pressure (SBP) allocated to receive intensive (target SBP <140 mmHg within 1 h) or guideline-recommended (target SBP <180 mmHg) BP-lowering treatment. The primary outcome was death or major disability, defined by modified Rankin scale scores 3-6 at 90 days. Logistic regression and propensity score analyses were used to determine independent associations. MAIN RESULTS: Predictors of ICU admission included younger age, recruitment in China, prior ischemic/undetermined stroke, high SBP, severe stroke [National Institute of Health stroke scale (NIHSS) score >=15], large ICH volume (>=15 mL), intraventricular hemorrhage (IVH) extension, early neurological deterioration, intubation and surgery. Determinants of prolonged ICU stay (>=5 days) were prior antihypertensive use, NIHSS >=15, large ICH volume, lobar ICH location, IVH, early neurological deterioration, intubation and surgery. ICU admission was associated with higher risk major disability at 90-day assessment compared to those without ICU admission. CONCLUSIONS: This study presents prognostic variables for ICU management and outcome of ICH patients included in a large international cohort. These data may assist in the selection and counseling of patients and families concerning ICU admission. PMID- 28000128 TI - Hemorrhagic Complications Associated with Ventriculostomy in Patients Undergoing Endovascular Treatment for Intracranial Aneurysms: A Single-Center Experience. AB - BACKGROUND: Currently, a complete understanding of post-ventriculostomy hemorrhagic complications in subarachnoid hemorrhage due to ruptured aneurysms remains unknown. The present study evaluates the impact of periprocedural risk factors on rates of external ventricular drain (EVD)-associated hemorrhage in the setting of endovascular treatment of intracranial aneurysms. METHODS: A retrospective chart review of 107 patients who underwent EVD placement within 24 h of endovascular coiling was performed. CT of head without contrast was obtained after drain placement and before endovascular treatment. Post-procedural CT was also obtained within 48 h of embolization and was reviewed for new/worsened track hemorrhages. Chi-squared test was used in evaluation. RESULTS: Ninety-three of the 107 patients reviewed met the inclusion criteria. Four (25%) of the 16 patients on antiplatelet medications at presentation experienced post-EVD hemorrhage compared to 11 (14.3%) of 77 that were not (p = 0.29). Of the 13 patients given intraprocedural antiplatelets, 3 (23.1%) demonstrated hemorrhage compared to 12 (15%) of 80 not administered these medications (p = 0.46). Further, of 36 patients with intraprocedural anticoagulation, 6 (16.7%) exhibited hemorrhage compared to 9 (15.8%) of 57 in those without (p = 0.91). In 17 patients who received DVT prophylaxis, 2 (11.8%) exhibited hemorrhage compared to 13 (17.1%) of 76 who did not (p = 0.59). No post-EVD hemorrhage had attributable neurologic morbidity. CONCLUSION: Our results, demonstrating no significant risk factor related to EVD-associated hemorrhage rates, support the safety of EVD placement in the peri-endovascular treatment period. PMID- 28000129 TI - Management of External Ventricular Drains After Subarachnoid Hemorrhage: A Multi Institutional Survey. AB - BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (SAH) often develop hydrocephalus requiring an external ventricular drain (EVD). The best available evidence suggests that a rapid EVD wean and intermittent CSF drainage is safe, reduces complications, and shortens ICU and hospital length of stay as compared to a gradual wean and continuous drainage. However, optimal EVD management remains controversial and the baseline practice among neurological ICUs is unclear. Therefore, we sought to determine current institutional practices of EVD management for patients with aneurysmal SAH. METHODS: An e-mail survey was sent to attending intensivists and neurosurgeons from 72 neurocritical care units that are registered with the Neurocritical Care Research Network or have been previously associated with the existing literature on the management of EVDs in critically ill patients. Only one response was counted per institution. RESULTS: There were 45 out of 72 institutional responses (63%). The majority of responding institutions (80%) had a single predominant EVD management approach. Of these, 78% favored a gradual EVD weaning strategy. For unsecured aneurysms, 81% kept the EVD continuously open and 19% used intermittent drainage. For secured aneurysms, 94% kept the EVD continuously open and 6% used intermittent drainage. Among continuously drained patients, the EVD was leveled at 18 (unsecured) and 11 cm H2O (secured) (p < 0.0001). When accounting for whether the EVD strategy was to enhance or minimize CSF drainage, there was a significant difference in the management of unsecured versus secured aneurysms with 42% using an enhance drainage approach in unsecured patients and 92% using an enhance drainage approach in secured patients (p < 0.0001). CONCLUSION: Most institutions utilize a single predominant EVD management approach, with a consensus toward a continuously open EVD to enhance CSF drainage in secured aneurysm patients coupled with a gradual weaning strategy. This finding is surprising given that the best available evidence suggests that the opposite approach is safe and can reduce ICU and hospital length of stay. We recommend a critical reassessment of the approach to the management of EVDs. Given the potential impact on patient outcomes and length of stay, more research needs to be done to reach a threshold for practice change, ideally via multicenter and randomized trials. PMID- 28000130 TI - Early Mobilization in the Neuro-ICU: How Far Can We Go? AB - Immobility that is frequently encountered in the intensive care unit (ICU) can lead to patient complications. Early mobilization of patients in the ICU has been shown to reduce the complications associated with critical illness; however, early mobilization in the neurological intensive care unit (NICU) presents a unique challenge for the multidisciplinary team. The early mobilization of patients with acute neurologic injuries such as acute ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, and neurotrauma varies because of differing disease processes and management. When developing an early mobility program in the NICU, the following should be considered: the effect of positional changes and exercise, the time from symptom onset to the initiation of early mobilization, and the type and intensity of the exercise prescribed. PMID- 28000131 TI - Transcranial Doppler Monitoring of Intracranial Pressure Plateau Waves. AB - BACKGROUND: Transcranial Doppler (TCD) has been used to estimate ICP noninvasively (nICP); however, its accuracy varies depending on different types of intracranial hypertension. Given the high specificity of TCD to detect cerebrovascular events, this study aimed to compare four TCD-based nICP methods during plateau waves of ICP. METHODS: A total of 36 plateau waves were identified in 27 patients (traumatic brain injury) with TCD, ICP, and ABP simultaneous recordings. The nICP methods were based on: (1) interaction between flow velocity (FV) and ABP using a "black-box" mathematical model (nICP_BB); (2) diastolic FV (nICP_FV d ); (3) critical closing pressure (nICP_CrCP), and (4) pulsatility index (nICP_PI). Analyses focused on relative changes in time domain between ICP and noninvasive estimators during plateau waves and the magnitude of changes (? between baseline and plateau) in real ICP and its estimators. A ROC analysis for an ICP threshold of 35 mmHg was performed. RESULTS: In time domain, nICP_PI, nICP_BB, and nICP_CrCP presented similar correlations: 0.80 +/- 0.24, 0.78 +/- 0.15, and 0.78 +/- 0.30, respectively. nICP_FV d presented a weaker correlation (R = 0.62 +/- 0.46). Correlations between ?ICP and ?nICP were better represented by nICP_CrCP and BB, R = 0.48, 0.44 (p < 0.05), respectively. nICP_FV d and PI presented nonsignificant ? correlations. ROC analysis showed moderate to good areas under the curve for all methods: nICP_BB, 0.82; nICP_FV d , 0.77; nICP_CrCP, 0.79; and nICP_PI, 0.81. CONCLUSIONS: Changes of ICP in time domain during plateau waves were replicated by nICP methods with strong correlations. In addition, the methods presented high performance for detection of intracranial hypertension. However, absolute accuracy for noninvasive ICP assessment using TCD is still low and requires further improvement. PMID- 28000132 TI - Biomarkers of Glycocalyx Injury are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Case Series Supporting a New Hypothesis. AB - BACKGROUND: Delayed cerebral ischemia (DCI) contributes to morbidity following aneurysmal subarachnoid hemorrhage; however, its etiology remains poorly understood. DCI is not only a consequence of angiographic vasospasm, but also involves microthrombosis and neuroinflammation, two events with unexplained phenomenology. The vascular endothelial glycocalyx mediates platelet aggregation and endothelial cell-leukocyte interactions and may play an important role in DCI pathogenesis. METHODS: We present a case series in which we conducted multiplex and singlet enzyme-linked immunosorbent assays of endothelial, glycocalyx, inflammatory, and neuroinjury proteins in both CSF and plasma in three patients during active DCI following SAH. Samples were obtained at baseline following surgical repair of SAH, and again at DCI onset. CSF was sampled at the same time points from in situ external ventricular drains. RESULTS: DCI was associated with significant elevations of soluble markers of endotheliopathy, including vascular adhesion protein-1, soluble fractions of endothelial cell adhesion molecules (CAMs), procoagulant tissue factor, and specific markers of glycocalyx injury, including syndecan-1, and CD44. These phenomena were also associated with an elevation of both circulating and CSF matrix metalloproteinases, which are known to cleave components of the glycocalyx. Elevation of vascular CAM-1 in the CSF with DCI indicated these events were possibly associated with the breakdown of brain microvasculature integrity. CONCLUSIONS: These preliminary data support the hypothesis that glycocalyx injury occurs in SAH, and might contribute to DCI by regulating cerebral microthrombosis and delayed neuroinflammation. PMID- 28000133 TI - Association of Early Hemodynamic Profile and the Development of Systolic Dysfunction Following Traumatic Brain Injury. AB - BACKGROUND: While systolic dysfunction has been observed following traumatic brain injury (TBI), the relationship between early hemodynamics and the development of systolic dysfunction has not been investigated. Our study aimed to determine the early hemodynamic profile that is associated with the development of systolic dysfunction after TBI. METHODS: We conducted a prospective cohort study among patients under 65 years old without cardiac comorbidities who sustained moderate-severe TBI. Transthoracic echocardiography was performed within the first day after TBI to assess for systolic dysfunction. Hourly systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate, and confounding clinical variables (sedatives, fluid balance, vasopressors, and osmotherapy) were collected during the first 24 h following admission. Multivariable linear mixed models assessed the early hemodynamic profile in patients who developed systolic dysfunction, compared to patients who did not develop systolic dysfunction. RESULTS: Thirty-two patients were included, and 7 (22 %) developed systolic dysfunction after TBI. Patients who developed systolic dysfunction experienced early elevation of SBP, MAP, and heart rate, compared to patients who did not develop systolic dysfunction (p < 0.01 for all comparisons). Patients who developed systolic dysfunction experienced a greater rate of decrease in SBP [-10.2 mmHg (95 % CI -16.1, -4.2)] and MAP [-9.1 mmHg (95 % CI 13.9, -4.3)] over the first day of hospitalization, compared to patients who did not develop systolic dysfunction (p < 0.01 for both comparisons). All sensitivity analyses revealed no substantial changes from the primary model. CONCLUSIONS: Patients who develop systolic dysfunction following TBI have a distinctive hemodynamic profile, with early hypertension and tachycardia, followed by a decrease in blood pressure over the first day after TBI. This profile suggests an early maladaptive catecholamine-excess state as a potential underlying mechanism of TBI-induced systolic dysfunction. PMID- 28000134 TI - Takotsubo Cardiomyopathy in Traumatic Brain Injury. AB - BACKGROUND: Takotsubo cardiomyopathy (TC) is a well-known complication after aneurysmal subarachnoid hemorrhage and has been rarely described in patients with traumatic brain injury (TBI). METHODS: Case report and review of literature. RESULTS: Here, we report a 73-year-old woman with mild traumatic brain injury (TBI) presenting in cardiogenic shock. Takotsubo cardiomyopathy (TC) was diagnosed by repeated echocardiography. Cardiovascular support by inotropic agents led to hemodynamic stabilization after initiation of levosimendan. Cardiac function fully recovered within 21 days. We performed an in-depth literature review and identified 16 reported patients with TBI and TC. Clinical course and characteristics are discussed in the context of our patient. CONCLUSION: Takotsubo cardiomyopathy is under-recognized after TBI and may negatively impact outcome if left untreated. PMID- 28000136 TI - ? PMID- 28000135 TI - Robotic Total Mesorectal Excision for Rectal Cancer: A Series of 392 Cases and Mid-Term Outcomes from A Single Center in China. AB - BACKGROUND: Robotic total mesorectal excision (RTME) for rectal cancer has recently been increasingly used; technical feasibility and short-term outcomes have been reported in detail. Few studies have presented clinical efficacy and mid-term outcomes for a large sample size. The aim of this study is to present oncologic efficacy and mid-term outcomes of robotic total mesorectal excision for rectal cancer and to provide our experiences regarding these surgically challenging issues. METHODS: Three hundred ninety-two patients received RTME between March 2010 and June 2015. Patient characteristics, perioperative clinical results, complications, pathologic details, recurrence, and mid-term outcomes were evaluated. RESULTS: Duration of surgery ranged from 80 to 388 min (median 224 min). There were no deaths during surgery and no anesthesiology complications in our series. The conversion rate was 1.1% (4/392). The postoperative complication rate was 10.2%; anastomosis leakage was the most common complication with an incidence of 4.1% (16/392). The median blood loss was 67.5+/-34.3 (20 600). The mean postoperative hospital stay was 12.1+/-6.1 (6-64). Circumferential resection margins were negative in 387 out of 392 cases (98.7%). The mean number of harvested lymph nodes was 14.6. Two deaths occurred during 30-day mortality. At a mean follow-up of 24 months (range 3-66 months), there were 35 deaths. CONCLUSION: Our results suggest that RTME is technically feasible for rectal cancer and can yield good short- and mid-term oncologic outcomes. PMID- 28000138 TI - Electron Beam Technology and Other Irradiation Technology Applications in the Food Industry. AB - Food irradiation is over 100 years old, with the original patent for X-ray treatment of foods being issued in early 1905, 20 years after there discovery by W. C. Roentgen in 1885. Since then, food irradiation technology has become one of the most extensively studied food processing technologies in the history of mankind. Unfortunately, it is the one of the most misunderstood technologies with the result that there are rampant misunderstandings of the core technology, the ideal applications, and how to use it effectively to derive the maximum benefits. There are a number of books, book chapters, and review articles that provide overviews of this technology [25, 32, 36, 39]. Over the last decade or so, the technology has come into greater focus because many of the other pathogen intervention technologies have been unable to provide sustainable solutions on how to address pathogen contamination in foods. The uniqueness of food irradiation is that this technology is a non-thermal food processing technology, which unto itself is a clear high-value differentiator from other competing technologies. PMID- 28000139 TI - Comparative metabolic state of microflora on the surface of the anode electrode in a microbial fuel cell operated at different pH conditions. AB - The metabolic state of microflora (mixed microbial cultures) in microbial fuel cells (MFCs) is currently unclear. Metabolomic analyses were conducted of microflora growing on the anodic electrodes of MFCs operated at pH 7.0, 5.5, or 4.0 and utilizing starch as the major carbon substrate. A much higher current was produced at pH 7.0 than at pH 5.5 and 4.0, correlating with an increased population ratio of Geobacter species to the total bacteria growing on the electrode. Most intracellular metabolites related to the tricarboxylic acid (TCA) cycle were present at a higher level at pH 7.0 than at pH 5.5 and 4.0, and the levels of metabolites correlated well with the obtained current densities. A high intracellular adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio at pH 7.0, compared to at pH 5.5 and 4.0, likewise supported current production. Overall, the metabolomic analyses demonstrated that activation of the TCA cycle and increased ATP generation are critical parameters for electricity generation by microflora. PMID- 28000140 TI - Flash Glucose-Sensing Technology as a Replacement for Blood Glucose Monitoring for the Management of Insulin-Treated Type 2 Diabetes: a Multicenter, Open-Label Randomized Controlled Trial. AB - INTRODUCTION: Glycemic control in participants with insulin-treated diabetes remains challenging. We assessed safety and efficacy of new flash glucose-sensing technology to replace self-monitoring of blood glucose (SMBG). METHODS: This open label randomized controlled study (ClinicalTrials.gov, NCT02082184) enrolled adults with type 2 diabetes on intensive insulin therapy from 26 European diabetes centers. Following 2 weeks of blinded sensor wear, 2:1 (intervention/control) randomization (centrally, using biased-coin minimization dependant on study center and insulin administration) was to control (SMBG) or intervention (glucose-sensing technology). Participants and investigators were not masked to group allocation. Primary outcome was difference in HbA1c at 6 months in the full analysis set. Prespecified secondary outcomes included time in hypoglycemia, effect of age, and patient satisfaction. RESULTS: Participants (n = 224) were randomized (149 intervention, 75 controls). At 6 months, there was no difference in the change in HbA1c between intervention and controls: -3.1 +/- 0.75 mmol/mol, [-0.29 +/- 0.07% (mean +/- SE)] and -3.4 +/- 1.04 mmol/mol (-0.31 +/- 0.09%) respectively; p = 0.8222. A difference was detected in participants aged <65 years [-5.7 +/- 0.96 mmol/mol (-0.53 +/- 0.09%) and -2.2 +/- 1.31 mmol/mol (-0.20 +/- 0.12%), respectively; p = 0.0301]. Time in hypoglycemia <3.9 mmol/L (70 mg/dL) reduced by 0.47 +/- 0.13 h/day [mean +/- SE (p = 0.0006)], and <3.1 mmol/L (55 mg/dL) reduced by 0.22 +/- 0.07 h/day (p = 0.0014) for intervention participants compared with controls; reductions of 43% and 53%, respectively. SMBG frequency, similar at baseline, decreased in intervention participants from 3.8 +/- 1.4 tests/day (mean +/- SD) to 0.3 +/- 0.7, remaining unchanged in controls. Treatment satisfaction was higher in intervention compared with controls (DTSQ 13.1 +/- 0.50 (mean +/- SE) and 9.0 +/- 0.72, respectively; p < 0.0001). No serious adverse events or severe hypoglycemic events were reported related to sensor data use. Forty-two serious events [16 (10.7%) intervention participants, 12 (16.0%) controls] were not device-related. Six intervention participants reported nine adverse events for sensor-wear reactions (two severe, six moderate, one mild). CONCLUSION: Flash glucose-sensing technology use in type 2 diabetes with intensive insulin therapy results in no difference in HbA1c change and reduced hypoglycemia, thus offering a safe, effective replacement for SMBG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02082184. FUNDING: Abbott Diabetes Care. PMID- 28000141 TI - Particulate Matter in the Air of the Underground Chamber Complex of the Wieliczka Salt Mine Health Resort. AB - This study evaluates the mass concentration and chemical composition of particulate matter (PM), collected in the chamber complex of the underground health resort located in the Wieliczka Salt Mine in southern Poland. Physical and chemical properties of PM were examined from the standpoint of their possible connection with therapeutic effects of the subterranean air in the mine. We found that in three underground spots we measured the average concentration of PM did not exceed 30 MUg/m3. Chemical composition of PM was dominated by sodium chloride, making up 88 % of its mass, on average. It was shown that the underground ambient concentration of PM and its chemical composition depended mostly on the nature of the rock material present in the ventilation tunnel of the health resort, filtering the incoming air. The presence and effect of external sources of PM, including patients' activity, also had an impact on the underground PM concentration. PMID- 28000142 TI - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with Teicoplanin: A Case Report. AB - Intramuscular teicoplanin (400 mg every 12 h for three doses, then 400 mg daily, intramuscularly) was prescribed for a 37-year-old woman with presumptive diagnosis of cellulitis. On the 14th day of treatment, she developed generalized maculopapular rash, accompanied by fever, wheezing, shortening of breath, and lymphadenopathy. Lab tests revealed abnormal liver enzymes, leukocytosis, and eosinophilia. The treatment was interrupted with suspicion of drug reaction. Fever subsided after 48 h. Skin eruption and respiratory symptoms began to resolve within 2 weeks. The follow-up lab tests performed 1 month later indicated resolution of liver dysfunction. With respect to delayed onset of symptoms including fever, generalized rash, lymphadenopathy, and organ involvement, drug reaction with eosinophilia and systemic symptoms (DRESS) was highly suspected. The causality was evaluated by conventional scoring systems. The reaction was rated as probable (score = 5) according to RegiSCAR and possible (score = 5) based on Kardaun et al.'s scoring system. However, DRESS was not confirmed by the Japanese group's criteria for diagnosis of DRESS/drug-induced hypersensitivity syndrome (DIHS). PMID- 28000143 TI - Update on Novel CCM Gene Mutations in Patients with Cerebral Cavernous Malformations. AB - Cerebral cavernous malformations (CCMs) are lesions affecting brain microvessels. The pathogenesis is not clearly understood. Conventional classification criterion is based on genetics, and thus, familial and sporadic forms can be distinguished; however, classification of sporadic cases with multiple lesions still remains uncertain. To date, three CCM causative genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. In our previous mutation screening, performed in a cohort of 95 Italian patients, with both sporadic and familial cases, we identified several mutations in CCM genes. This study represents further molecular screening in a cohort of 19 Italian patients enrolled by us in the few last years and classified into familial, sporadic and sporadic with multiple lesions cases. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect point mutations and large genomic rearrangements, respectively. Effects of detected mutations and single nucleotide polymorphisms (SNPs) were evaluated by an in silico approach and by western blot analysis. A novel nonsense mutation in CCM1 and a novel missense mutation in CCM2 were detected; moreover, several CCM2 gene polymorphisms in sporadic CCM patients were reported. We believe that these data enrich the mutation spectrum of CCM genes, which is useful for genetic counselling to identify both familial and sporadic CCM cases, as early as possible. PMID- 28000144 TI - Standing balance and strength measurements in older adults living in residential care communities. AB - Research on balance and mobility in older adults has been conducted primarily in lab-based settings in individuals who live in the community. Although they are at greater risk of falls, residents of long-term care facilities, specifically residential care communities (RCCs), have been investigated much less frequently. We sought to determine the feasibility of using portable technology-based measures of balance and muscle strength (i.e., an accelerometer and a load cell) that can be used in any RCC facility. Twenty-nine subjects (age 87 +/- 6 years) living in RCCs participated. An accelerometer placed on the back of the subjects measured body sway during different standing conditions. Sway in antero-posterior and mediolateral directions was calculated. Lower extremity strength was measured with a portable load cell and the within-visit reliability was determined. Assessments of grip strength, gait speed, frailty, and comorbidity were also examined. A significant increase in postural sway in both the AP and ML directions occurred as the balance conditions became more difficult due to alteration of sensory feedback (p < 0.001) or reducing the base of support (p < 0.001). There was an association between increased sway and increased frailty, more comorbidities and slower gait speed. All strength measurements were highly reliable (ICC = 0.93-0.99). An increase in lower extremity strength was associated with increased grip strength and gait speed. The portable instruments provide inexpensive ways for measuring balance and strength in the understudied RCC population, but additional studies are needed to examine their relationship with functional outcomes. PMID- 28000147 TI - Erratum to: Aflibercept, a New Way to Target Angiogenesis in the Second Line Treatment of Metastatic Colorectal Cancer (mCRC). PMID- 28000148 TI - Regadenoson-induced complete heart block and asystole: A real possibility nuclear laboratories should be aware of. PMID- 28000149 TI - Fibro/adipogenic progenitors safeguard themselves: a novel mechanism to reduce fibrosis is discovered. AB - PDGFRalpha regulates several cellular processes, and exacerbated PDGF signaling cause fibrosis in different tissues. Different research groups have shown that fibro/adipogenic progenitors (FAPs) are responsible for pathological fibrosis found in skeletal muscle disorders. Rando's Lab describes that an intronic polyadenylation of Pdgfra regulates FAPs activity, and therefore fibrosis. This discovery opens a new potential target for treating fibrosis. PMID- 28000146 TI - Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review. AB - Cannabinoid hyperemesis syndrome (CHS) is a syndrome of cyclic vomiting associated with cannabis use. Our objective is to summarize the available evidence on CHS diagnosis, pathophysiology, and treatment. We performed a systematic review using MEDLINE, Ovid MEDLINE, Embase, Web of Science, and the Cochrane Library from January 2000 through September 24, 2015. Articles eligible for inclusion were evaluated using the Grading and Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were abstracted from the articles and case reports and were combined in a cumulative synthesis. The frequency of identified diagnostic characteristics was calculated from the cumulative synthesis and evidence for pathophysiologic hypothesis as well as treatment options were evaluated using the GRADE criteria. The systematic search returned 2178 articles. After duplicates were removed, 1253 abstracts were reviewed and 183 were included. Fourteen diagnostic characteristics were identified, and the frequency of major characteristics was as follows: history of regular cannabis for any duration of time (100%), cyclic nausea and vomiting (100%), resolution of symptoms after stopping cannabis (96.8%), compulsive hot baths with symptom relief (92.3%), male predominance (72.9%), abdominal pain (85.1%), and at least weekly cannabis use (97.4%). The pathophysiology of CHS remains unclear with a dearth of research dedicated to investigating its underlying mechanism. Supportive care with intravenous fluids, dopamine antagonists, topical capsaicin cream, and avoidance of narcotic medications has shown some benefit in the acute setting. Cannabis cessation appears to be the best treatment. CHS is a cyclic vomiting syndrome, preceded by daily to weekly cannabis use, usually accompanied by symptom improvement with hot bathing, and resolution with cessation of cannabis. The pathophysiology underlying CHS is unclear. Cannabis cessation appears to be the best treatment. PMID- 28000150 TI - Atrial fibrillation following aortic valve replacement: impact of perioperative use of intravenous beta-blocker. AB - OBJECTIVES: Despite recent advances in perioperative management, postoperative atrial fibrillation/flutter (POAF) remains the most common complication after cardiac surgery. Therefore, it is important to determine related risk factors to establish effective management. However, most studies have focused on patients undergoing coronary artery bypass grafting and little is known about POAF in those who receive aortic valve replacement (AVR). We investigated the relationship of clinical predictors with POAF in patients undergoing AVR. METHODS: A total of 119 patients who underwent AVR were enrolled in this study, and the relationships between POAF incidence and perioperative (preoperative, operative, postoperative) factors were examined. RESULTS: POAF occurred in 47 patients (40%). In univariate analysis, older age was significantly associated with POAF occurrence, which was significantly related to prolonged intensive care unit (ICU) stay and postoperative stroke. It also showed patients with preoperative beta-blocker experienced POAF less frequently than those without beta-blocker. Multivariate analysis showed that preoperative beta-blocker usage was an independent predictor of POAF. In patients who received both preoperative oral and postoperative intravenous beta-blocker administrations, the incidence of POAF was reduced to 14% (3/22). CONCLUSIONS: POAF frequently occurred in patients undergoing AVR, and was significantly related to prolonged ICU stay and postoperative stroke. Our findings show that advanced age and absence of preoperative beta-blocker usage are risk factors for POAF. Furthermore, in patients undergoing AVR, perioperative intravenous beta-blocker administration may be useful for prevention. PMID- 28000151 TI - The Impact of Provider Networks on the Co-Prescriptions of Interacting Drugs: A Claims-Based Analysis. AB - INTRODUCTION: Multiple provider prescribing of interacting drugs is a preventable cause of morbidity and mortality, and fragmented care is a major contributing factor. We applied social network analysis to examine the impact of provider patient-sharing networks on the risk of multiple provider prescribing of interacting drugs. METHODS: We performed a retrospective analysis of commercial healthcare claims (years 2008-2011), including all non-elderly adult beneficiaries (n = 88,494) and their constellation of care providers. Patient sharing networks were derived based on shared patients, and care constellation cohesion was quantified using care density, defined as the ratio between the total number of patients shared by provider pairs and the total number of provider pairs within the care constellation around each patient. RESULTS: In our study, 2% (n = 1796) of patients were co-prescribed interacting drugs by multiple providers. Multiple provider prescribing of interacting drugs was associated with care density (odds ratio per unit increase in the natural logarithm of the value for care density 0.78; 95% confidence interval 0.74-0.83; p < 0.0001). The effect of care density was more pronounced with increasing constellation size: when constellation size exceeded ten providers, the risk of multiple provider prescribing of interacting drugs decreased by nearly 37% with each unit increase in the natural logarithm of care density (p < 0.0001). Other predictors included increasing age of patients, increasing number of providers, and greater morbidity. CONCLUSION: Improved care cohesion may mitigate unsafe prescribing practices, especially in larger care constellations. There is further potential to leverage network analytics to implement large-scale surveillance applications for monitoring prescribing safety. PMID- 28000153 TI - Non-essential blood tests in the intensive care unit: a prospective observational study. AB - PURPOSE: Non-essential blood testing in the acute care setting can be a prominent source of morbidity, patient discomfort, increased workload for the healthcare provider, and wasteful spending. The magnitude of such non-essential blood testing has not been well described. We aimed to measure the extent of unnecessary blood testing in a 33-bed intensive care unit (ICU) at a tertiary care teaching hospital in Ontario, Canada. METHODS: Over a period of four weeks, all ICU attending physicians were asked to select, from a comprehensive list, blood tests that they deemed essential to the appropriate care for each of their patients on the following day. The actual tests processed on the following day were recorded. Descriptive statistics were used to determine what proportion of all processed tests were deemed essential blood tests. The association between patient characteristics and the total cost of unnecessary tests was assessed using the Wilcoxon rank-sum test and the Spearman correlation coefficient, as appropriate. RESULTS: Nine attending physicians provided input for a total of 81 patient days. In 65 (80%) of these days, at least one test was considered non essential. Physicians deemed only 338 (48.7%) of 694 processed blood tests as essential, which amounted to $2,243.41 (46.0%) out of an overall cost of $4,882.11. Patients' age, sex, mechanical ventilation status, and treatment with vasoactive drugs on the study day were not associated with the number of non essential tests. CONCLUSIONS: Attending physicians deemed a substantial proportion of the blood tests processed in a tertiary care ICU setting as unnecessary. Furthermore, the non-essential tests incurred substantial additional cost. Further work is required to gain a better understanding of the underlying factors contributing to these wasteful practices. PMID- 28000152 TI - Inactivation of bone morphogenetic protein 1 (Bmp1) and tolloid-like 1 (Tll1) in cells expressing type I collagen leads to dental and periodontal defects in mice. AB - Bone morphogenetic protein 1 (BMP1) and tolloid-like 1 (TLL1) belong to the BMP1/tolloid-like proteinase family, which cleaves secretory proteins. The constitutive deletion of the Bmp1 or Tll1 genes causes perinatal or embryonic lethality in mice. In this study, we first studied the beta-galactosidase activity in mice in which an IRES-lacZ-Neo cassette was inserted in the intron of either the Bmp1 or the Tll1 gene; the beta-galactosidase activities were used to reflect the expression of endogenous Bmp1 and Tll1, respectively. Our X-gal staining results showed that the odontoblasts in the tooth and cells in the periodontal ligament express both Bmp1 and Tll1. We then created Bmp1 flox/flox and Tll1 flox/flox mice by removing the IRES-lacZ-Neo cassette. By breeding 2.3 kb Col1a1-Cre mice with the Bmp1 flox/flox and Tll1 flox/flox mice, we further generated Col1a1-Cre;Bmp1 flox/flox ;Tll1 flox/flox mice in which both Bmp1 and Tll1 were inactivated in the Type I collagen-expressing cells. We employed X-ray radiography, histology and immunohistochemistry approaches to characterize the Col1a1-Cre;Bmp1 flox/flox ;Tll1 flox/flox mice. Our results showed that the molars of the Col1a1-Cre;Bmp1 flox/flox ;Tll1 flox/flox mice had wider predentin, thinner dentin and larger pulp chambers than those of the normal controls. The dentinal tubules of the molars in the Col1a1-Cre;Bmp1 flox/flox ;Tll1 flox/flox mice appeared disorganized. The level of dentin sialophosphoprotein in the molars of the 6-week-old Col1a1-Cre;Bmp1 flox/flox ;Tll1 flox/flox mice was lower than in the normal controls. The periodontal ligaments of the Col1a1-Cre;Bmp1 flox/flox ;Tll1 flox/flox mice were disorganized and had less fibrillin-1. Our findings indicate that the proteinases encoded by Bmp1 and Tll1 genes play essential roles in the development and maintenance of mouse dentin and periodontal ligaments. PMID- 28000155 TI - Hepatocyte Nuclear Factor 4 Alpha Promotes Definitive Endoderm Differentiation from Human Induced Pluripotent Stem Cells. AB - Hepatocyte nuclear factor 4 alpha (HNF4alpha) is a key transcription factor for liver development. Although HNF4alpha is necessary for hepatoblast differentiation, the function of HNF4alpha before the hepatoblast differentiation, such as in definitive endoderm differentiation, is not well known. In addition, it is known that there are nine HNF4alpha isoforms, but the expression and function of each HNF4alpha isoform during the definitive endoderm differentiation is also not clear. In this study, we examined the expression pattern of HNF4alpha and its functions in the definitive endoderm differentiation from human induced pluripotent stem (iPS) cells. We found that the HNF4alpha-1D isoform expression levels were significantly increased during the definitive endoderm differentiation, while the HNF4alpha-1A isoform expression levels did not change. Therefore, we further examined the function of the HNF4alpha-1D isoform in definitive endoderm differentiation. HNF4alpha-1D overexpression or knockdown was found to promote or prevent the definitive endoderm differentiation, respectively. Interestingly, Lefty1 was directly regulated by HNF4alpha-1D, and Lefty1 knockdown also prevented the definitive endoderm differentiation. These results suggest that HNF4alpha-1D promotes definitive endoderm differentiation through the regulation of Lefty1. To our knowledge, this is the first report to clarify the expression pattern and function of HNF4alpha during the definitive endoderm differentiation. PMID- 28000156 TI - Predicting the Risk of Adverse Drug Reactions in Older Inpatients: External Validation of the GerontoNet ADR Risk Score Using the CRIME Cohort. AB - BACKGROUND: Adverse drug reactions (ADRs) in older people are often preventable, indicating that screening and prevention programs aimed at reducing their rate are needed in this population. OBJECTIVE: The aim of this study was to externally validate the GerontoNet ADR risk score and to assess its validity in specific subpopulations of older inpatients. METHODS: Data from the prospective CRIteria to assess appropriate Medication use among Elderly complex patients (CRIME) cohort were used. Dose-dependent and predictable ADRs were classified as type A, probable or definite ADRs were defined according to the Naranjo algorithm, and diagnostic accuracy was tested using receiver operating characteristic (ROC) analyses. Sensitivity and specificity were calculated for a cut-off point of 4. RESULTS: The mean age of the 1075 patients was 81.4 years (standard deviation 7.4) and the median number of drugs was 10 (range 7-13). At least one ADR was observed in 70 patients (6.5%); ADRs were classified as type A in 50 patients (4.7%) and defined as probable or definite in 41 patients (3.8%). Fair diagnostic accuracy to predict both type A and probable or definite ADRs was found in subpopulations aged <70 or >=80 years with heart failure, diabetes, or a previous ADR. Good accuracy to predict type A ADRs was found in patients with a low body mass index (BMI; >18.5 kg/m2) and a Mini-Mental State Examination (MMSE) score of >24/30 points, as well as in patients with osteoarthritis. The cut-off point of 4 points yielded very good sensitivity but poor specificity results in these subpopulations. CONCLUSION: This study suggests that the GerontoNet ADR risk score might represent a pragmatic approach to identifying specific subpopulations of older inpatients at increased risk of an ADR with a fair to good diagnostic accuracy. PMID- 28000157 TI - Out of sight, out of mind: Matching bias underlies confirmatory visual search. AB - Confirmation bias has recently been reported in visual search, where observers who were given a perceptual rule to test (e.g. "Is the p on a red circle?") search stimuli that could confirm the rule stimuli preferentially (Rajsic, Wilson, & Pratt, Journal of Experimental Psychology: Human Perception and Performance, 41(5), 1353-1364, 2015). In this study, we compared the ability of concrete and abstract visual templates to guide attention using the visual confirmation bias. Experiment 1 showed that confirmatory search tendencies do not result from simple low-level priming, as they occurred when color templates were verbally communicated. Experiment 2 showed that confirmation bias did not occur when targets needed to be reported as possessing or not possessing the absence of a feature (i.e., reporting whether a target was on a nonred circle). Experiment 3 showed that confirmatory search also did not occur when search prompts referred to a set of visually heterogenous features (i.e., reporting whether a target on a colorful circle, regardless of the color). Together, these results show that the confirmation bias likely results from a matching heuristic, such that visual codes involved in representing the search goal prioritize stimuli possessing these features. PMID- 28000158 TI - A Systematic Review and Critical Appraisal of Economic Evaluations of Pharmacological Interventions for People with Bipolar Disorder. AB - BACKGROUND: Bipolar disorder (BD) is a chronic mood disorder that causes substantial psychological and financial burden. Various pharmacological treatments are effective in the management and prevention of acute episodes of BD. In an era of tighter healthcare budgets and a need for more efficient use of resources, several economic evaluations have evaluated the cost effectiveness of treatments for BD. OBJECTIVE: The aim of this study was to systematically review and appraise published economic evaluations of pharmacological interventions for BD. METHODS: A systematic search combining search terms specific to BD with a health economics search filter was conducted on six bibliographic databases (EMBASE, MEDLINE, PsycINFO, HTA, NHS EED, CENTRAL) in order to identify trial- or model-based full economic evaluations of pharmacological treatments of any phase of the disorder that were published between 1 January 1990 and 18 December 2015. Studies that met the inclusion criteria were critically appraised using the Quality of Health Economic Studies (QHES) checklist, and synthesised in a narrative way. RESULTS: The review included 19 economic studies, which varied with regard to the type and number of interventions assessed, the study design, the phase of treatment (acute or maintenance), the source of efficacy data and the method for evidence synthesis, the outcome measures, the time horizon and the countries/settings in which the studies were conducted. The study quality was variable but the majority of studies were of high or fair quality. CONCLUSION: Pharmacological interventions are cost effective, compared with no treatment, in the management of BD, both in the acute and maintenance phases. However, it is difficult to draw safe conclusions on the relative cost effectiveness between drugs due to differences across studies and limitations characterising many of them. Future economic evaluations need to consider the whole range of treatment options available for the management of BD and adopt appropriate methods for evidence synthesis and economic modelling, to explore more robustly the relative cost effectiveness of pharmacological interventions for people with BD. PMID- 28000159 TI - HER3 as a Therapeutic Target in Cancer. AB - Targeting members of the human epidermal growth factor receptor family, especially EGFR and HER2, has been an established strategy for the treatment of tumors with abnormally activated receptors due to overexpression, mutation, ligand-dependent receptor dimerization and ligand-independent activation. Less attention has been paid to the oncogenic activity of HER3, although there is growing evidence that it mediates resistance to EGFR and HER2 pathway directed therapies. The main caveat for the development of effective HER3 targeted therapies is the absence of a strong enzymatic activity to target, as well as the limited potential for single-agent activity. In this review, we highlight the role of HER3 in cancer and, more specifically, in lung cancer. The basis for HER3 involvement in HER2 resistance and EGFR inhibition is discussed, as well as current pharmacologic strategies to combat HER3 inhibition. PMID- 28000160 TI - Radiotherapy and nipple-areolar complex necrosis after nipple-sparing mastectomy: a systematic review and meta-analysis. AB - OBJECTIVE: To perform a meta-analysis to determine the effect of radiotherapy (RT) on nipple-areolar complex (NAC) and skin flap necrosis, and local recurrence in women who undergo nipple-sparing mastectomy (NSM) and immediate breast reconstruction. METHODS: Medline, PubMed, Cochrane, and Google Scholar databases were searched until October 16, 2015. Randomized-controlled-trials, prospective, retrospective, and cohort studies were included. The primary outcome was the NAC necrosis rate, and the secondary outcomes were the skin flap necrosis and local recurrence rates. RESULTS: Of 186 studies identified, 2 prospective and 5 retrospective studies including a total of 3692 patients were included in the meta-analysis. Five, 3, and 2 studies reported data of NAC necrosis (3461 breasts), skin flap necrosis (2490 breasts), and local recurrence (988 breasts), respectively. Pooled results showed no difference in the odds of NAC necrosis [odds ratio (OR) = 1.250, 95% confidence interval (CI) 0.481-3.247, P = 0.647], or local recurrence (OR = 0.564, 95% CI 0.056-5.710, P = 0.627) between patients who received and did not receive RT. Patients treated with RT had a higher likelihood of skin flap necrosis (OR = 2.534, 95% CI 1.720-3.735, P < 0.001). Significant heterogeneity, however, was noted in the analysis of NAC and local recurrence. CONCLUSIONS: Because of the limitations of the small number of studies and heterogeneity in the analysis, this study does not allow drawing any definitive conclusions and highlights the need of well-controlled trials to determine the effect of RT in patients undergoing NSM. PMID- 28000161 TI - Upregulated TLR3 Promotes Neuropathic Pain by Regulating Autophagy in Rat With L5 Spinal Nerve Ligation Model. AB - Microglia, rapidly activated following peripheral nerve injury (PNI), accumulate within the spinal cord and adopt inflammation that contributes to development and maintenance of neuropathic pain. Microglia express functional Toll-like receptors (TLRs), which play pivotal roles in regulating inflammatory processes. However, little is known about the role of TLR3 in regulating neuropathic pain after PNI. Here TLR3 expression and autophagy activation was assayed in dorsal root ganglions and in microglia following PNI by using realtime PCR, western blot and immunohistochemistry. The role of TLR3/autophagy signaling in regulating tactile allodynia was evaluated by assaying paw mechanical withdrawal threshold and cold allodynia after intrathecal administration of Poly (I:C) and 3-methyladenine (3 MA). We found that L5 spinal nerve ligation (SNL) induces the expression of TLR3 in dorsal root ganglions and in primary rat microglia at the mRNA and protein level. Meanwhile, L5 SNL results in an increased activation of autophagy, which contributes to microglial activation and subsequent inflammatory response. Intrathecal administration of Poly (I:C), a TLR3 agonist, significantly increases the activation of microglial autophagy, whereas TLR3 knockdown markedly inhibits L5 SNL-induced microglial autophagy. Poly (I:C) treatment promotes the expression of proinflammatory mediators, whereas 3-MA (a specific inhibitor of autophagy) suppresses Poly (I:C)-induced secretion of proinflammatory cytokines. Autophagy inhibition further inhibits TLR3-mediated mechanical and cold hypersensitivity following SNL. These results suggest that inhibition of TLR3/autophagy signaling contributes to alleviate neurophathic pain triggered by SNL. PMID- 28000162 TI - Role of Cell Metabolism and Mitochondrial Function During Adult Neurogenesis. AB - Brain is the major consumer of glucose in the human body, whose pattern of consumption changes through lifetime, decreasing during adolescence up to adulthood. This evidence leads to the hypothesis that, in cerebral developmental stages, glycolysis might be the driving force for the high-energy requirement. Furthermore, several studies claim that neurogenesis process is accompanied by a shift into mitochondrial oxidative metabolism. Herein, we discuss recent work about cell metabolism during neuronal differentiation process, in particular the mitochondrial role in cellular bioenergy dynamics. PMID- 28000164 TI - Respiratory average CT for attenuation correction in myocardial perfusion SPECT/CT. AB - OBJECTIVE: Cine average CT (CACT) and interpolated average CT (IACT) have been proposed to improve attenuation correction (AC) for PET/CT in oncologic and cardiac studies. This study aims to evaluate their effectiveness on myocardial perfusion SPECT/CT using computer simulation and physical phantom experiments. METHODS: We first simulated normal male with 99mTc-sestamibi distribution using digital XCAT phantom with respiratory motion amplitudes of 2, 3, and 4 cm. Average activity and attenuation maps represented static SPECT and CACT, while the attenuation maps of end-inspiration and end-expiration represented two helical CTs (HCTs), respectively. Sixty noise-free and noisy projections were simulated over 180 degrees using an analytical parallel-hole projector. We then filled 673 MBq 99mTc into an anthropomorphic torso phantom with normal heart or heart with a defect which placed on a programmable respiratory platform to model various respiratory amplitudes. Sixty projections were acquired over 180 degrees using a clinical SPECT/CT scanner. The CACT, standard HCT, and 2 HCTs at extreme phases were acquired. Interpolated CT phases were generated between them using affine plus b-spline registration, and IACT was obtained by averaging the interpolated phases and the 2 original extreme phases for both simulation and phantom experiments. Projections were reconstructed with AC using CACT, IACT, and HCTs, respectively. Polar and 17-segment plots were analyzed by relative difference (RD) of the uptake. Two regions-of-interest (ROI) were drawn on the defect and background area to obtain the intensity ratio (IR). RESULTS: No substantial difference was observed on the polar plots generated from different AC methods, while the quantitative RD measurements showed that SPECTCACT were most similar to the original phantom, followed by SPECTIACT, with RDmax <8 and <10% in the simulation study. The RD of SPECTHCTs deviated from the original phantom and SPECTCACT in various segments, with RDmax of 19.76 and 16.68% in the simulation and phantom experiment, respectively. The IR of SPECTHCTs fluctuated more from the truth for higher motion amplitude. CONCLUSIONS: Both CACT-AC and IACT-AC reduced respiratory artifacts and improved quantitation in myocardial perfusion SPECT as compared to HCT-AC. The use of IACT further reduced the radiation dose. PMID- 28000163 TI - Pinocembrin Attenuates Mitochondrial Dysfunction in Human Neuroblastoma SH-SY5Y Cells Exposed to Methylglyoxal: Role for the Erk1/2-Nrf2 Signaling Pathway. AB - Pinocembrin (PB; 5,7-dihydroxyflavanone) is found in propolis and exhibits antioxidant activity in several experimental models. The antioxidant capacity of PB is associated with the activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. The Nrf2/ARE axis mediates the expression of antioxidant and detoxifying enzymes, such as glutathione peroxidase (GPx), glutathione reductase (GR), heme oxygenase-1 (HO 1), and the catalytic (GCLC) and regulatory (GCLM) subunits of the rate-limiting enzyme in the synthesis of glutathione (GSH), gamma-glutamate-cysteine ligase (gamma-GCL). Nonetheless, it is not clear how PB exerts mitochondrial protection in mammalian cells. Human neuroblastoma SH-SY5Y cells were pretreated (4 h) with PB (0-25 uM) and then exposed to methylglyoxal (MG; 500 uM) for further 24 h. Mitochondria were isolated by differential centrifugation. PB (25 uM) provided mitochondrial protection (decreased lipid peroxidation, protein carbonylation, and protein nitration in mitochondrial membranes; decreased mitochondrial free radical production; enhanced the content of GSH in mitochondria; rescued mitochondrial membrane potential-MMP) and blocked MG-triggered cell death by a mechanism dependent on the activation of the extracellular-related kinase (Erk1/2) and consequent upregulation of Nrf2. PB increased the levels of GPx, GR, HO-1, and mitochondrial GSH. The PB-induced effects were suppressed by silencing of Nrf2 with siRNA. Therefore, PB activated the Erk1/2-Nrf2 signaling pathway resulting in mitochondrial protection in SH-SY5Y cells exposed to MG. Our work shows that PB is a strong candidate to figure among mitochondria-focusing agents with pharmacological potential. PMID- 28000165 TI - Patient Satisfaction with Collection of Patient-Reported Outcome Measures in Routine Care. AB - INTRODUCTION: Systematic collection of patient-reported outcome measures (PROMs) during ambulatory clinic visits can enhance communication between patient and provider, and provide the ability to evaluate outcomes of care. Little is known about patient satisfaction of PROM data collection in routine clinical care. To evaluate patient reaction to the routine collection of PROMs in the ambulatory setting. METHODS: Before all ambulatory clinic visits at our neurological institute, patients electronically complete health status questionnaires. We administered an 8-question patient satisfaction survey to a sample of patients seen across the institute after their clinical visit. RESULTS: Of 343 patients approached, 323 agreed to participate. The majority responded that the questionnaire system was easy to use, was an appropriate length, and benefited their care overall (strongly agree or agree = 92.3%, 87.6%, and 77.3%, respectively). Provider review of the PROMs with the patient during the clinic visit was associated with significantly higher positive responses to all questions, even those regarding logistical aspects of the collection process. There were significant age and race differences in response to perceived benefit: those in the Black/other race category had a markedly lower probability of viewing the process favorably with increasing age. CONCLUSIONS: Systematic collection of PROMs via an electronic questionnaire appears to be well accepted by patients. A minority of patients did not feel the questionnaire content applied to their appointment or that the system was a beneficial feature of the clinical practice. The provider can significantly improve the patient's perception of PROM collection and the patient-physician encounter by reviewing the questionnaire results with the patient. PMID- 28000167 TI - Cost-Effectiveness of Different Strategies for the Prevention of Venous Thromboembolism After Total Hip Replacement in China. AB - INTRODUCTION: The aim of this study was to evaluate the cost-effectiveness of rivaroxaban and apixaban versus enoxaparin for the universal prophylaxis of venous thromboembolism (VTE) and associated long-term complications in Chinese patients after total hip replacement (THR). METHODS: A decision model, which included both acute VTE (represented as a decision tree) and the long-term complications of VTE (represented as a Markov model), was developed to assess the economic outcomes of the three prophylactic strategies for Chinese patients after THR. Transition probabilities for acute VTE were derived from two randomized controlled studies, RECORD1 and ADVANCE3, of patients after THR. The transition probabilities of long-term complications after acute VTE, utilities, and costs were derived from the published literature and local healthcare settings. One-way and probabilistic sensitivity analyses (PSA) were performed to test the uncertainty concerning the model parameters. The quality-adjusted life years (QALYs) and direct medical costs were reported over a 5-year horizon, and incremental cost-effectiveness ratios (ICERs) were also calculated. RESULTS: Thromboprophylaxis with apixaban was estimated to have a higher cost (US $178.70) and more health benefits (0.0025 QALY) than thromboprophylaxis with enoxaparin over a 5-year time horizon, which resulted in an ICER of US $71,244 per QALY gained and was more than three times the GDP per capita of China in 2014 (US $22,140). Owing to the higher cost and lower generated QALYs, rivaroxaban was inferior to enoxaparin among post-THR patients. The sensitivity analyses confirmed these results. CONCLUSIONS: The analysis found that apixaban was not cost-effective and that rivaroxaban was inferior to enoxaparin. This finding indicates that compared with enoxaparin, the use of apixaban for VTE prophylaxis after THR does not represent a good value for the cost at the acceptable threshold in China; in addition, the cost of rivaroxaban was higher with lower QALYs. PMID- 28000168 TI - Caregiver Preference and Treatment Compliance in Patients with Mild-to-Moderate Alzheimer's Disease in South Korea: RECAP Study Results. AB - INTRODUCTION: The aim of this study was to assess caregiver preference and treatment compliance with oral and transdermal medications in a "real-world" setting in patients with mild-to-moderate Alzheimer's disease (AD) in South Korea. METHODS: Real-world evaluation of compliance and preference in Alzheimer's disease treatment (RECAP) was a 24-week, multicenter, prospective, non interventional study in patients with AD treated with oral or transdermal therapy. Here, we report data from patients living in South Korea. Eligible patients were grouped into one of two treatment cohorts: oral (donepezil, galantamine, rivastigmine, or memantine) or transdermal (rivastigmine patch). Caregiver preference, patient compliance, and physician preference were assessed at week 24 (end of the study). Safety was assessed by reported adverse events (AEs). RESULTS: A total of 398 patients were enrolled (oral 51.8%; transdermal 48.2%) and 79.4% completed the study. Caregivers of patients that were exposed to either the oral or transdermal monotherapy showed a preference for the treatment to which the patients were exposed (both p < 0.0001). However, caregivers of patients that were exposed to both forms of treatments reported a higher preference for transdermal monotherapy (65.9%; p < 0.0041). Patients in both treatment cohorts showed good compliance, with an overall mean (SD) score of 8.84 (1.514) (a median of 9). Of the 15 participating physicians, eight indicated their preference for transdermal therapy and seven preferred oral therapy at week 24. A total of 133 (33.4%) patients reported at least one AE during the study period (oral: 60 patients; transdermal: 73 patients). CONCLUSION: The study showed higher caregiver preference for transdermal monotherapy over oral monotherapy when patients with AD were exposed to both forms of treatment and good patient compliance for both oral and transdermal treatments. PMID- 28000166 TI - Current Perspectives on the Use of Anti-VEGF Drugs as Adjuvant Therapy in Glaucoma. AB - The approval of one of the first anti-vascular endothelial growth factor (VEGF) agents for the treatment of neovascular age-related macular degeneration one decade ago marked the beginning of a new era in the management of several sight threatening retinal diseases. Since then, emerging evidence has demonstrated the utility of these therapies for the treatment of other ocular conditions characterized by elevated VEGF levels. In this article we review current perspectives on the use of anti-VEGF drugs as adjuvant therapy in the management of neovascular glaucoma (NVG). The use of anti-VEGFs for modifying wound healing in glaucoma filtration surgery (GFS) is also reviewed. Selected studies investigating the use of anti-VEGF agents or antimetabolites in GFS or the management of NVG have demonstrated that these agents can improve surgical outcomes. However, anti-VEGF agents have yet to demonstrate specific advantages over the more established agents commonly used today. Further studies are needed to evaluate the duration of action, dosing intervals, and toxicity profile of these treatments. PMID- 28000169 TI - Relative Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor, Dacarbazine, and Glycoprotein 100 in Metastatic Melanoma: An Indirect Treatment Comparison. AB - INTRODUCTION: Advances in the treatment of metastatic melanoma have been achieved in recent years: immunotherapies and targeted therapies have demonstrated survival benefits over older agents such as granulocyte-macrophage colony stimulating factor (GM-CSF), dacarbazine, and glycoprotein peptide vaccine (gp100) in pivotal phase 3 trials. It is important to compare therapies to guide the treatment decision-making process, and establishing the relationship between older agents can strengthen the networks of evidence for newer therapies. We report the outcome of an indirect comparison of GM-CSF, dacarbazine, and gp100 in metastatic melanoma through meta-analysis of absolute treatment effect. METHODS: A systematic literature review identified trials for inclusion in the meta analysis. A valid network meta-analysis was not feasible: treatment-specific meta analysis was conducted. A published algorithm was used to adjust overall survival estimates from trials of GM-CSF, dacarbazine, and gp100 for heterogeneity in baseline prognostic factors. Survival estimates were compared in three patient groups: stage IIIB-IV M1c, stage IIIB-IV M1a, and stage IV M1b/c. RESULTS: One trial of GM-CSF, four of dacarbazine, and one of gp100 were included in the analysis. After adjusting for differences in baseline prognostic factors, median overall survival (OS) in all patient groups was longer for those receiving GM-CSF than for those receiving dacarbazine or gp100. The observed survival over time for GM-CSF was similar to the adjusted survival for dacarbazine and greater than for gp100 in all patient groups. CONCLUSION: The relative treatment effect of GM CSF, dacarbazine, and gp100 has been reliably estimated by adjusting for differences in baseline prognostic factors. Results suggest that OS with GM-CSF is at least as good as with dacarbazine and greater than with gp100. Given the role of these agents as controls in phase 3 trials of new immunotherapies and targeted agents, these results can be used to contextualize the efficacy of newer therapies. FUNDING: Amgen Inc. PMID- 28000171 TI - Erratum to: Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage. PMID- 28000170 TI - Investigating the Co-Adsorption Behavior of Nucleic-Acid Base (Thymine and Cytosine) and Melamine at Liquid/Solid Interface. AB - The co-adsorption behavior of nucleic-acid base (thymine; cytosine) and melamine was investigated by scanning tunneling microscopy (STM) technique at liquid/solid (1-octanol/graphite) interface. STM characterization results indicate that phase separation happened after dropping the mixed solution of thymine-melamine onto highly oriented pyrolytic graphite (HOPG) surface, while the hetero-component cluster-like structure was observed when cytosine-melamine binary assembly system is used. From the viewpoints of non-covalent interactions calculated by using density functional theory (DFT) method, the formation mechanisms of these assembled structures were explored in detail. This work will supply a methodology to design the supramolecular assembled structures and the hetero-component materials composed by biological and chemical compound. PMID- 28000172 TI - Implementation of a Precision Pathology Program Focused on Oncology-Based Prognostic and Predictive Outcomes. AB - Personalized or precision medicine as a diagnostic and therapeutic paradigm was introduced some 10-15 years ago, with the advent of biomarker discovery as a mechanism for identifying prognostic and predictive attributes associated with treatment indication and outcome. While the concept is not new, the successful development and implementation of novel 'companion diagnostics', especially in oncology, continues to represent a significant challenge and is currently at the forefront of smart trial design and therapeutic choice. The ability to determine patient selection for a specific therapy has broad implications including better chances for a positive outcome, limited exposure to potentially toxic drugs and improved health economics. Importantly, a significant step in this paradigm is the role of predictive pathology or the accurate assessment of morphology at the microscopic level. In breast cancer, this has been most useful where histologic attributes such as the classification of tubular and cribriform carcinoma dictates surgery while neoadjuvant studies suggest that patients with lobular carcinoma are not likely to benefit from chemotherapy. The next level of 'personalized pathology' at the tissue-cellular level is the use of 'protein biomarker panels' to classify the disease process and ultimately drive tumor characterization and treatment. The following review article will focus on the evolution of predictive pathology from a subjective, 'opinion-based' approach to a quantitative science. In addition, we will discuss the individual components of the precise pathology platform including advanced image analysis, biomarker quantitation with mathematical modeling and the integration with fluid-based (i.e. blood, urine) analytics as drivers of next generation precise patient phenotyping. PMID- 28000173 TI - In Vitro Evaluation of Absorption Characteristics of Peramivir for Oral Delivery. AB - BACKGROUND AND OBJECTIVE: Peramivir is a novel antiviral agent approved for the treatment of severe influenza. However, the development of oral formulation of peramivir has been severely hurdled by poor bioavailability (human, <=3%). The present work aims to evaluate oral permeability characteristics of peramivir. METHODS: In vitro gastrointestinal stability, metabolic stability in human intestinal S9 fraction and Caco-2 permeability were performed. The liquid chromatography with tandem mass spectrometric (LC-MS/MS) was used to quantify peramivir in buffer and biological sample. Using GastroPlusTM software, intestinal effective permeability coefficient (P eff) of peramivir was estimated. RESULTS: Our results indicated that peramivir maintained stability in pH 5.5 and 7.4 buffers, fasted state simulated gastric fluid and fasted state simulated intestinal fluid, and human intestinal S9 fractions. The apparent permeability coefficient (P app) values of peramivir (10 MUM) were 3.29 +/- 0.73 * 10-7 cm/s in a Caco-2 cell model. In vivo intestinal effective permeability coefficient (P eff) was estimated to be 0.06 * 10-4 cm/s. Furthermore, co-incubating with cyclosporine, mitoxantrone, rifampicin, or paroxetine, the apical (AP) to basolateral (BL) flux of peramivir decreased (p < 0.05). The efflux and influx of peramivir was not significantly affected with co-incubation with verapamil, MK 571, or diclofenac (p > 0.05). CONCLUSIONS: These results revealed that carrier mediated transports, including OATP1B (organic anion transport 1B) and OCT1 (organic cation transport 1), might be involved in the absorption of peramivir. In conclusion, our results provide insight into the poor oral bioavailability of peramivir. Peramivir can be classified as a BCS-III (high solubility/low permeability) and BDDCS-III high solubility/poor metabolism) drug. The oral bioavailability of peramivir primarily depends on its permeability across cell membranes. Both of passive and active transports are involved in the permeability of peramivir. PMID- 28000174 TI - Gelatin Tannate for Acute Childhood Gastroenteritis: A Randomized, Single-Blind Controlled Trial. AB - BACKGROUND: Oral rehydration therapy is the recommended treatment for acute childhood gastroenteritis. The aim of this study was to assess the efficacy and safety of gelatin tannate plus oral rehydration compared with oral rehydration alone. METHODS: We conducted a multicenter, parallel, randomized, controlled, single-blind, prospective, open-label trial. A central randomization center used computer generated tables to allocate treatments. The study was performed in two medical centers in Italy. Sixty patients 3-72 months of age with acute gastroenteritis were recruited (median age 18 months; age range 3-66 months): 29 received an oral rehydration solution (ORS) and 31 an ORS plus gelatin tannate (ORS + G). The primary outcome was the number of bowel movements 48 and 72 h after initiating treatment. Secondary outcomes were: duration of diarrhea, stool characteristics and adverse events. RESULTS: No patient was lost at follow-up. No significant difference in the number of bowel movements after 48 h was reported (2.7 +/- 1.3 ORS + G; 3.2 +/- 0.8 ORS; p = 0.06), although the ORS + G group showed a significant improvement in stool consistency (3.7 +/- 1.0 vs. 4.3 +/- 0.8; p = 0.005). At 72 h, a significant reduction in bowel movements was reported in the ORS + G group compared with the ORS group (1.0 +/- 1.4 vs. 2.0 +/- 1.7; p = 0.01). Mean duration of diarrhea was significantly lower in the ORS + G group than in the ORS only group (76.8 +/- 19.2 vs. 108 +/- 24.0 h; p < 0.0001). No adverse events were reported. CONCLUSIONS: Gelatin tannate added to oral rehydration in children with acute diarrhea was associated with a significant decrease in bowel movements at 72 h, with an early improvement in the stool consistency and shorter disease duration. CLINICAL TRIAL REGISTRATION: NCT02644200-Gelatin Tannate as Treatment for Acute Childhood Gastroenteritis ( https://www.clinicaltrials.gov ). PMID- 28000176 TI - Pathology and molecular mechanisms of coarctation of the aorta and its association with the ductus arteriosus. AB - Coarctation of the aorta (CoA) is defined as a congenital stenosis of the thoracic aorta and is one of the most common congenital cardiovascular diseases. Despite successful surgical treatment for CoA, arterial abnormalities, including refractory hypertension, aortic aneurysm, and proatherogenic phenotypic changes, frequently affect patients' quality of life. Emerging evidence from morphological and molecular biological investigations suggest that the area of CoA is characterized by phenotypic modulation of smooth muscle cells, intimal thickening, and impaired elastic fiber formation. These changes extend to the pre and post-stenotic aorta and impair arterial elasticity. The aim of this review is to present current findings on the pathology and molecular mechanisms of vascular remodeling due to CoA. In particular, we will discuss the association between CoA and the ductus arteriosus since the most common site for the stenosis is in the proximity of the ductus arteriosus. PMID- 28000175 TI - Adaptation to microgravity, deconditioning, and countermeasures. AB - Humans are generally in standing or sitting positions on Earth during the day. The musculoskeletal system supports these positions and also allows motion. Gravity acting in the longitudinal direction of the body generates a hydrostatic pressure difference and induces footward fluid shift. The vestibular system senses the gravity of the body and reflexively controls the organs. During spaceflight or exposure to microgravity, the load on the musculoskeletal system and hydrostatic pressure difference is diminished. Thus, the skeletal muscle, particularly in the lower limbs, is atrophied, and bone minerals are lost via urinary excretion. In addition, the heart is atrophied, and the plasma volume is decreased, which may induce orthostatic intolerance. Vestibular-related control also declines; in particular, the otolith organs are more susceptible to exposure to microgravity than the semicircular canals. Using an advanced resistive exercise device with administration of bisphosphonate is an effective countermeasure against bone deconditioning. However, atrophy of skeletal muscle and the heart has not been completely prevented. Further ingenuity is needed in designing countermeasures for muscular, cardiovascular, and vestibular dysfunctions. PMID- 28000177 TI - Geniposide accelerates proteasome degradation of Txnip to inhibit insulin secretion in pancreatic beta-cells. AB - PURPOSE: To analyze the role of geniposide in the protein degradation of Txnip and to determine the impact of Txnip on geniposide-regulated GSIS in pancreatic INS-1 cells. METHODS: The content of Txnip protein was measured by western blot; insulin content and glucose uptake were determined by ELISA; and knockdown of Txnip was the method of RNA interference. RESULTS: Glucose induces a rapid increase in Txnip protein, and geniposide accelerates the degradation of Txnip via proteasome pathway in the presence of high glucose (25 mM) in INS-1 pancreatic beta-cells. And MG132, a proteasomal inhibitor, potentiates glucose uptake, metabolism (ATP production) and glucose-stimulated insulin secretion (GSIS) in high-glucose (25 mM)-treated INS-1 cells, but geniposide significantly prevents these effects. Furthermore, the combination of geniposide and Txnip knockdown shows substantial synergistic effects to reduce glucose uptake, metabolism and GSIS in high-glucose (25 mM)-treated INS-1 cells. CONCLUSIONS: Txnip protein played an essential role in glucose uptake, metabolism and GSIS, and geniposide could accelerate the degradation via proteasome pathway in high glucose-treated pancreatic INS-1 cells. PMID- 28000179 TI - Anesthesia mumps after thyroidectomy. PMID- 28000178 TI - Quercetin potentiates transdifferentiation of bone marrow mesenchymal stem cells into the beta cells in vitro. AB - PURPOSE: Type 1 diabetes is an autoimmune disease caused by the destruction of beta-cells in the pancreas. Bone marrow mesenchymal stem cells are multipotent and easy accessible adult stem cells that may provide options in the treatment of type 1 diabetes. Injured pancreatic extract can promote the differentiation of rat bone marrow mesenchymal stem cells into beta-cells. We aimed to observe the effect of quercetin in differentiation and insulin secretion in beta-cells. METHODS: Bone marrow mesenchymal stem cells were obtained from the tibiae of rats. Cell surface markers were analyzed by flow cytometry. The cells were treated with rat injured pancreatic extract and quercetin for 2 weeks. Insulin secretion was measured by ELISA. Insulin expression and some islet factors were evaluated by RT-PCR. PDX1, a marker for beta-cell function and differentiation, was evaluated by both immunocytochemistry and Western blot. beta-cell count was determined by stereology and cell count assay. RESULTS: ELISA showed significant differences in insulin secretion in the cells treated with RIPE + 20 MUM quercetin (0.55 +/- 0.01 ug/L) compared with the cells treated with RIPE alone (0.48 +/- 0.01 ug/L) (P = 0.026). RT-PCR results confirmed insulin expression in both groups. PDX1 protein was detected in both groups by Western blot and immunocytochemistry. Stereology results showed a significant increase in beta cell number in the RIPE + quercetin-treated cells (47 +/- 2.0) when compared with RIPE treatment alone (44 +/- 2.5) (P = 0.015). CONCLUSIONS: Quercetin has a strengthening effect on the differentiation of rat bone marrow mesenchymal stem cells into beta-cells and increases insulin secretion from the differentiated beta-cells in vitro. PMID- 28000181 TI - [Application of Roman IIII( criteria in the diagnosis of chronic constipation]. AB - In Rome IIII( diagnostic system, disorders associated with chronic constipation include functional constipation, opioid-induced constipation, irritable bowel syndrome with predominant constipation and functional defecation disorders, each disorder has the relative characteristics of clinical manifestations and underlying pathophysiology. Rome IIII( committee modified the diagnostic criteria based on current research achievements, and recommended to make the diagnosis of functional constipation disorders with minimal laboratory test and with indications for colonoscopy and pathophysiological tests. Understanding the clinical manifestations and pathophysiology of functional constipation disorders are helpful for clinicians to apply the Rome diagnostic criteria and improve the accuracy of diagnosis and treatment for the patients with chronic constipation. PMID- 28000182 TI - [Current situation in the diagnosis and treatment of rectovaginal fistula]. AB - The treatment of rectovaginal fistula is quite difficult. It is a formidable challenge for anorectal surgeons to successfully perform operations for rectovaginal fistulas, since both recurrence rate and incontinence rate are high. This commentary elucidates certain questions during the treatment course of rectovaginal fistula through reviewing relevant literature and our clinical practice, including the overall evaluation of the preoperative rectovaginal fistula, the choice of suitable operation timing, reasonable choice of operational procedure and standard perioperative management. Precise special examination is the base of diagnosis. Magnetic resonance and rectal Doppler ultrasound can be helpful to make a precise and standard diagnosis of rectovaginal fistula. Suitable operation timing and satisfactory intestinal preparation are the premise of successful operation. Despite the variety of the surgical treatment, there is still no standard surgical technique with respect to rectovaginal fistula. Individualization must be considered based on the anatomic features of rectovaginal fistula, its surrounding tissues, the integrity of anal sphincter, and operative repair before. Perioperative management is important both in the increase of successful operation rate and the decrease of recurrence rate. PMID- 28000180 TI - Reduction of calprotectin and phosphate during testosterone therapy in aging men: a randomized controlled trial. AB - OBJECTIVES: To investigate the effect of testosterone treatment on biomarkers calprotectin, fibroblast growth factor 23 (FGF23), soluble Klotho, phosphate, calcium, parathyroid hormone, creatinine and estimated glomerular filtration rate. DESIGN: Randomized, double-blinded, placebo-controlled study. SETTING: Odense Androgen Study-the effect of Testim and training in hypogonadal men. PARTICIPANTS: Men aged 60-78 years old with a low normal concentration of free of bioavailable testosterone <7.3 nmol/L and waist circumference >94 cm recruited from 2008 to 2009 (N = 48) by advertisement. INTERVENTION: Participants were randomized to receive 5-10 g gel/50-100 mg testosterone (Testim(r), Ipsen, France) or 5-10 g gel/placebo. RESULTS: The plasma levels of calprotectin and phosphate were significantly reduced in the group receiving testosterone therapy (gel) compared to the placebo group (p < 0.05). Testosterone treatment did not have any significant effect on plasma levels of FGF23 or soluble Klotho. The reduction in phosphate levels was inversely associated with bioavailable testosterone. CONCLUSION: Compared to the placebo group, 6 months of testosterone therapy (gel) reduced calprotectin and phosphate levels suggesting decreased inflammation and decreased cardiovascular risk. PMID- 28000183 TI - [Operation key points and efficacy evaluation of Jinling procedure for mixed refractory constipation]. AB - For chronic transit constipation (STC), surgery should be considered when all pharmacological interventions, biofeedback, and sacral nerve stimulation failed to relieve severe symptoms. Chronic functional constipation can be subdivided into three subtypes: colonic slow-transit constipation, outlet obstruction and mixed refractory constipation. The pathological changes of colonic slow transit and outlet obstruction constipation can influence each other. Mixed refractory constipation accounts for 90.2% of chronic constipation. Therefore the surgery procedure should solve two types of pathological changes at the same time. The Jinling procedure combines subtotal colectomy and side-to-side cecorectal anastomosis, aiming to solve the coexistence of obstructive defecation and slow transit constipation in one operation. A total of 1 768 patients with mixed refractory constipation received Jinling procedure from January 2001 to June 2016. Our clinical practice indicates that the Jinling procedure is safe and effective for refractory slow-transit constipation associated with obstructive defecation, with minimal major complications, significant improvement of quality of life, and a high satisfaction rate after long-term follow up. The safety and efficacy of Jinling procedure are improved continually with the progress of minimally invasive surgery, surgical instruments, recovery after surgery and perioperative management. Through long-term clinical and basic research, our institute has formed the comprehensive treatment strategy, such as Jinling procedure, intestinal microecological treatment, medication, biological feedback and sacral nerve stimulation in the treatment of functional constipation. PMID- 28000184 TI - [To improve the surgical outcome of chronic constipation: from bed to the bench]. AB - The prevalence of chronic constipation is about 16% in adults, and increases with age, especially after 60 years old. Usually, surgical intervention is recommended to patients with long standing intractable constipation, who have undergone various conservative therapies. Lots of surgical procedures have been reported for different kinds of constipation, including slow transit, outlet obstruction, etc. For slow transit constipation, total or subtotal colectomy is commonly used. Merely for the internal rectal prolapse, at least 10 procedures are commonly adopted in clinic. However, no single procedure has been reached a consensus, not to mention the operative indication, principle of procedure selection and outcome assessment. Objectively, the surgical result of chronic constipation is far from perfect. Especially for outlet obstructive constipation, the satisfactory rate is only about 70%. How to enhance the surgical therapeutic effects should be expected on clinical and translation research. Fortunately, sacral neuromodulation therapy and percutaneous tibial nerve stimulation in managing refractory constipation have brought expected outcomes in recent years. Relationship between microbiota of the colonic mucosa and symptoms, and the sensory nerve regulatory mechanism have attracted much attention. We believe that more translational medicine results can be helpful in the future to improve the comprehensive efficacy of constipation. PMID- 28000185 TI - [Standardization and implementation of operation for slow transit constipation]. AB - Slow transit constipation (STC) is one kind of chronic constipation. Medical treatment is adopted by most patients, but many patients do not respond to conservative treatment and require surgical intervention. There are several problems in clinical paratice, including non-rigorous patient selection, less standard preoperative assessment, less standard operation or insufficient post operative treatments and follow-up, which may lead to the overtreatment or serious complications. As the changes of living habits and diet, the incidence of STC increases gradually. Therefore it is important to make a standardized surgical treatment of STC. Because lots of factors may cause STC and the pathophysiology of STC is complicated, multidisciplinary treatment is recommended. This paper will discuss the standardized surgical treatment of STC base on the new literature and author's experience, concerning operative indications, preoperative assessment, choice of operation procedure, postoperative evaluation and follow-up. PMID- 28000186 TI - [Value of anorectal manometry in defecation disorders and its clinical interpretation]. AB - Bowel dysfunction affected by functional factors, mechanical factors or surgical damage may lead to constipation, fecal incontinence and other overlapped symptoms, which is only the tip of the iceberg. Anorectal manometry can provide combined dysfunction information of four subtypes, including sphincter dysfunction, dyssynergic defecation, sensory disability and insufficient rectal expel force, which are underlying pathophysiology of defecation dysfunction. Anorectal manometry can be helpful in optimizing protocol or predicting success in pelvic floor dyssynergic syndrome of defecation, fecal incontinence or anorectal pain, stoma closure and pediatric intractable constipation. Interpretation of manometry parameter or data must consider the age, sex, symptoms, digital rectal examination, pelvic floor radiology(ultrasound, MR and defecography), physiology (pelvic floor sEMG and evoked potential testing) and psychology, in order to perform comprehensive assessment. PMID- 28000187 TI - [Evaluation of test methods for defecation disorders]. AB - Defecation disorders is a common gastrointestinal disease characterized by slow colonic transit and/or paradoxical anal contraction. Gastrointestinal motility test plays an important role in the diagnosis, classification and treatment of defecation disorders. Anorectal manometry (ARM) provides comprehensive information about rectal and anal sphincter function, including resting anal sphincter pressure, squeeze anal sphincter pressure, the rectal and anal sphincter pressure changes during an attempted defecation, rectal sensory testing, rectoanal inhibitory reflex and rectal compliance. However, ARM can not diagnose the defecation disorders without the other tests. It should be combined with defecography and balloon expulsion test. Defecography demonstrates the anatomy and function of the anorectum and pelvic floor. Gastrointestinal transit test assesses regional and whole colon transit time. They are valuable methods in diagnosis of defecation disorders, but these tests have their respective advantages and disadvantages, and combined use should be carried out usually. PMID- 28000188 TI - [Role of transumbilical single port laparoscopic surgery in the treatment of chronic intractable constipation]. AB - With the development of laparoscopic technique, single port laparoscopic technique application is more and more common, further achieving the ideal effect without abdominal scar. Efficacy of colectomy by transumbilical single port laparoscopic surgery in treating patients with chronic intractable constipation was satisfactory in our hospital during the past two years. This paper mainly introduces the role and development of single port laparoscopic surgery in the treatment of chronic intractable constipation. In order to form the operation triangle as possible, and avoid the "apparatus fighting" between devices, incision protection device and rubber glove were used to make the multi-channel single incision puncture device. Advantages of this device can provide the surgeon with greater space to operate and more convenient operation, but owing to the poor fixation of rubber gloves and the absence of incumbent pivot in this devices, the proficiency of the camera holder is required in order to ensure a clear and stable vision. In the future, with the development of economy and equipment, single port laparoscopic surgery in the treatment of chronic intractable constipation will be used more widely. PMID- 28000189 TI - [Diagnosis and surgical treatment for rectovaginal fistula]. AB - Rectovaginal fistulas are distressing conditions to patients and present a therapeutic challenge to surgeons. Whether the etiology of the fistula is obstetric, Crohn's disease-related, or cryptoglandular, a thorough anatomy evaluation is required in order to select the correct repair. No single surgical technique is suitable for all rectovaginal fistulas as of now. Less invasive surgery should be selected in primary repair, and endorectal advancement flap repair was recommended as the first line therapy in most guidelines for the treatment of rectovaginal fistulas. Preoperative fecal diversion has not been shown consistently to lead to better outcomes, thus most surgeons suggested that diverting stoma is not imperative in majority of patients, unless the tissue interposition was undertaken. The tissue interposition or transabdominal repair should be considered for multiple failure or recurrent complex rectovaginal fistulas. Familiarity with the various surgical techniques described and the ability to apply the appropriate surgery to correct patients will increase the chance of a successful intervention. PMID- 28000190 TI - [Short-term efficacy on fecal microbiota transplantation combined with soluble dietary fiber and probiotics in the treatment of slow transit constipation]. AB - OBJECTIVE: To evaluate the efficacy and safety of fecal microbiota transplantation (FMT) combined with soluble dietary fiber and probiotics for slow transit constipation(STC). METHODS: Twenty-three patients with STC from Jinling Hospital, Medical School of Nanjing University were prospectively enrolled between April 2015 and January 2016. STC patients received FMT combined with soluble dietary fiber and probiotics. Fresh stool(100 g) was immediately mixed in a blender with 500 ml of 0.9% sterile saline for several seconds, which was then filtered through a gauze pad and a decreasing number of gauze screen (2.0 to 0.5 mm). The fecal bacteria suspension was stored frozen at -20centi-degree. The preparation time of FMT material was less than 1 hour. Total time of treatment was 9 days. An initial oral antibiotics(vancomycin 500 mg orally twice per day) was given for 3 consecutive days. Then the fecal microbiota(100 ml) was infused slowly(5 min) through nasojejunal tube for 6 consecutive days. After FMT, patients were recommended to receive soluble dietary fiber (pectin, 8 g/d) and probiotics (bifid triple viable capsules, twice per day) for 4 weeks. Rates of clinical improvement and remission, adverse events, constipation-related symptoms (PAC-SYM scores), bowel movements per week and gastrointestinal quality-of-life index (GIQLI) were recorded during the 12-week follow-up. This study was registered in the Clinical Trials.gov (NCT02016469). RESULTS: Among 23 patients, 7 were male, 16 were female, the mean age was (49.6+/-14.7) years, the body mass index was (21.2+/-2.2) kg/m2, the duration of constipation was (8.3+/-5.9) years, and the defecation frequency was 1.8+/-0.7 per week. Compared with pre-treatment, PAC-SYM scores decreased significantly from 2.3+/-0.5 to 1.3+/-0.4 at week 12 (P<0.01), defecation frequency increased from 1.8+/-0.7 per week to 4.8+/-2.0 per week at week 12 (P<0.01), and patients felt satisfied with improved GIQLI score (from 78.5+/-15.5 to 120.8+/-21.3, P<0.01). During the follow-up, the clinical improvement and remission of STC patients reached 69.6%(16/23) and 52.2%(12/23), respectively. No serious adverse events were observed. CONCLUSION: FMT combined with soluble dietary fiber and probiotics is safe and effective in treating slow transit constipation, which can improve the symptom and quality of life significantly. PMID- 28000191 TI - [Study of subtotal colectomy combined with psychological intervention in treating slow transit constipation]. AB - OBJECTIVE: To investigate the value of psychological intervention in treating slow transit constipation (STC), and to provide the reference to clinical treatment for STC patients with psychological disorder. METHODS: A total of 94 STC patients with psychological disorder admitted to the Anorectal Hospital of Chengdu from June 2010 to August 2012 were prospectively enrolled and divided into psychological intervention group(subtotal colectomy plus postoperative psychological intervention) and control group (subtotal colectomy without postoperative psychological intervention). Scores of Hamilton depression scale (HAMD), Hamilton anxiety scale(HAMA), Wexner constipation scale (WCS) and gastrointestinal quality-of-life index(GIQLI) were recorded 1, 3, 6, 12 and 24 months after operation. SPSS 17.0 statistical software was used to analyze the data. RESULTS: There were no differences in baseline data, operative time, blood loss, time to the first flatus and time to the first defecation between two groups(all P>0.05). The scores of HAMD and HAMA were significantly reduced in psychological intervention group compared with control group 3, 6, 12 and 24 months after operation (all P<0.05). Ratios of cure, obvious progress, progress and invalidation of depression symptoms in psychological intervention group were 2.6%(1/39), 66.7%(26/39), 25.6%(10/39) and 5.1% (2/39) respectively at postoperative 24-month, which were better than those [0, 34.2%(13/38), 44.7% (17/38) and 21.1%(8/38) respectively] in control group with significant difference(P=0.013). Ratios of cure, obvious progress, progress and invalidation of anxiety symptoms in psychological intervention group were 10.3%(4/39), 53.8%(21/39), 28.2%(11/39) and 7.7%(3/39) respectively at postoperative 24-month, which were better than those [0, 28.9%(11/38), 55.3%(21/38) and 15.8%(6/38) respectively] in control group with significant difference (P=0.011). The WCS scores in psychological intervention group were lower than those in control group 6, 12, 24 months after operation (all P<0.05). The GIQLI scores in psychological intervention group were higher than those in control group 3, 6, 12 and 24 months after operation(all P<0.05). CONCLUSION: Subtotal colectomy combined with psychological intervention not only can significantly improve psychological disorder, but also increase the efficacy of surgery in the treatment of slow transit constipation patients with psychological disorder. PMID- 28000192 TI - [Experimental study of Bisacodyl in the treatment of slow transit constipation model rats]. AB - OBJECTIVE: To explore the efficacy and the mechanism of Bisacodyl in treating slow transit constipation model rats. METHODS: A total of 30 healthy rats were enrolled. Twenty rats received intragastric diphenoxylate to develop slow transit constipation (STC) model, and 10 untreated rats were set as blank control. STC rats were subdivided into two groups: STC Bisacodyl group (fed with Bisacodyl) and STC control group (common feed). Body weight, number and dry weight of faeces, and intestinal transit time were compared among 3 groups. Interstitial cells of Cajal(ICC) and c-Kit protein expression were measured by immunohistochemical staining. Restults Compared to blank control rats, at 100-day of receiving intragastric diphenoxylate, above 20 rats presented the decrease of body weight and feces number, the increase of dry weight of faeces, and the delay of intestinal transit time, indicating the successful establishment of STC rat model. One month after feeding, compared to STC control group, STC Bisacodyl grap had an increased feces number[(36.6+/-6.8) pill/day vs. (26.8+/-6.0) pill/day], decreased dry weight of feces [(150.6+/-10.5) mg/pill vs. (171.6+/-16.3) mg/pill] and shortened intestinal transit time [(416.9+/-50.6) minutes vs. (495.3+/-66.8) minutes], and the differences were statistically significant(all P<0.05). Dissolution of ICC basement membrane, damage of connection between ICC and surrounding cells, and atrophy of ICC nucleus structure were found in STC control rats. ICC (8.20+/-1.92 per field] and c-Kit expression (12.68%+/-2.59% ) in STC control rats were significantly lower than those in blank control rats(36.00+/ 6.25 per field and 71.50 %+/-8.27%) (P=0.000). Compared to STC control group, the connection between ICC and surrounding cells enhanced obviously, ICC (18.80+/ 3.70 per field) and c-Kit expression (45.91%+/-6.80%) were significantly higher in STC Bisacodyl group (all P=0.000). CONCLUSION: Bisacodyl treatment can relieve STC symptoms, which may be associated with increased ICC number and c-Kit protein expression. PMID- 28000193 TI - [Clinical characteristics and risk factors for recurrence of anal fistula patients]. AB - OBJECTIVE: To investigate the epidemiology, internal opening location, and risk factors associated with recurrence of anal fistula. METHODS: Clinical data of 1783 hospitalized patients admitted for anal fistula treatment to Shanghai Shuguang Hospital from January 2013 to September 2015 were retrospectively analyzed. Fistula passing through anorectal ring or locating above was defined as high anal fistula (n=125). Internal opening location was defined as follows: posterior (5 to 7 o'clock), front(11 to 1 o'clock), left (2 to 4 o'clock) and right (8 to 10 o'clock). RESULTS: Among 1783 cases, 1526 were male with a median age of 36 years, 257 were female with a median age of 35 years, and the ratio of male to female was 5.9 vs 1.0. In high anal fistula cases, this ratio of male to female was 7.3 vs 1.0. Posterior internal opening accounted for 51.4%(884/1720), while this percentage was 66.4%(83/125) in high anal fistula cases, which was significantly higher than 50.2%(801/1595) in low anal fistula cases(P=0.002). Postoperative recurrence rate was 2.6%(45/1720) and the rates in high anal fistula and low anal fistula were 13.6%(17/125) and 1.8%(28/1595) respectively, with significant difference(P=0.000). Multivariate logistic regression analysis showed that fistula height(OR=5.475, 95%CI:2.230 to 13.445, P=0.000), treatment history(OR=2.671, 95% CI:1.315 to 5.424, P=0.007), seton placement history (OR=4.707, 95%CI:1.675 to 13.232, P=0.003) and concomitant colitis(OR=10.300, 95%CI:1.187 to 89.412, P=0.034) were independent risk factors for anal fistula recurrence. Seton placement history was an independent risk factor for high anal fistula recurrence (OR=6.476, 95%CI:1.116 to 37.589, P=0.037). CONCLUSIONS: Anal fistula occurs in young and middle-aged male patient. Internal opening locates in posterior more commonly, especially in high anal fistula patients. Postoperative recurrence rate of high anal fistula is quite high. Patient with both high anal fistula and seton placement history has significantly high rate of postoperative recurrence. PMID- 28000194 TI - [Efficacy analysis of acupuncture with biofeedback in the treatment of patients with functional anorectal pain]. AB - OBJECTIVE: To observe the short- and long-term efficacy of acupuncture combined with biofeedback in the treatment of functional anorectal pain (FARP). METHODS: Clinical data of 142 patients who met the functional gastrointestinal disorders and functional anorectal pain based on criteria of Rome III( undergoing acupuncture with biofeedback therapy from August 2010 to November 2015 in Pelvic Floor Center of The Third Affiliated Hospital of Nanjing University of Chinese Medicine were retrospectively analyzed. Telephone and outpatient clinic recheck were used as standard follow-up. The clinical effect of short-term and long-term data collected from the disease-based database was evaluated with visual analogue pain scale (VAS) (0-10 points), short form health survey questionnaire (SF-36) (0 148 points). The overall satisfaction and effectiveness (VAS was >30%) were evaluated at the end of treatment (short-term) and during follow-up (long-term). RESULTS: The effective follow-up data were obtained from 71.1%(101/142) of patients and the median follow-up time was 28(3-67) months. The VAS of 101 cases was 6.09+/-1.78, 1.99+/-1.89 and 3.55+/-2.60 before treatment, at the end of treatment and during follow-up respectively. Though the VAS during follow-up was higher than that at the end of treatment, but still significantly lower than that before treatment(P<0.05). The SF-36 score of 31 patients was 82.0+/-16.9, 94.0+/ 15.1 and 88.1+/-15.3 before treatment, at the end of treatment and during follow up respectively. Though the SF-36 score during follow-up was lower compared to at the end of treatment, but still significantly higher compared to before treatment (P<0.05). The effective rates were 85.9%(122/142) at the end of treatment and 75.2%(76/101) during follow-up, and the satisfactory rates were 92.3%(131/142) and 84.2%(85/101), respectively. CONCLUSION: Acupuncture with biofeedback has significant short-term and long-term efficacy in treating functional anorectal pain, and its degree of satisfaction is high. PMID- 28000195 TI - [Risk factors of early surgical intervention in Crohn's disease patients with spontaneous intra-abdominal abscess]. AB - OBJECTIVE: To investigate the risk factors of early surgical intervention in Crohn's disease (CD) patients with spontaneous intra-abdominal abscess. METHODS: Clinical data of 94 CD patients with spontaneous intra-abdominal abscess admitted to The Sixth Affiliated Hospital of Sun Yat-sen University between May 2008 and Dec 2015 were analyzed retrospectively. Univariate and multivariate analysis were applied to evaluate the early surgery risk of CD patients with spontaneous intra abdominal abscess using logistic regression model. RESULTS: A total of 94 eligible patients were identified from our registry, including 70 males and 24 females. The mean age at the diagnosis of CD and at development of abscess was 28.4 years and 30.4 years old, respectively. The median duration of CD between the diagnosis and development of an abscess was 3 years. According to the Montreal classification, L3 (ileocolonic) was the most common disease location (81.9%) in these patients. Most of the patients(76.6%) developed a single abscess, while multiple abscesses were detected in 22 patients(23.4%). Forty-four patients(46.8%) underwent surgery within 60 days after hospitalization due to spontaneous intra-abdominal abscess complicating CD. Multivariate logistic regression analysis revealed that history of abdominal surgery(OR=3.23, 95%CI:1.12 to 9.31, P=0.030), concomitant intestinal stenosis (OR=3.52, 95%CI:1.26 to 9.85, P=0.017) and concomitant intestinal fistula (OR=4.31, 95%CI:1.25 to 14.80, P=0.020) were the independent risk factors of early surgical intervention, while enteral nutrition (OR=0.18, 95%CI:0.05 to 0.62, P=0.007) was the independent protective factor. CONCLUSIONS: Nearly half of CD patients with spontaneous intra-abdominal abscess will undergo early surgical intervention. Patients with history of abdominal surgery, concomitant intestinal stenosis and concomitant intestinal fistula have higher risk of early surgical intervention, and appropriate application of enteral nutrition may reduce the risk. PMID- 28000196 TI - [Analysis of clinical characteristics of perianal Crohn's disease in a single center]. AB - OBJECTIVE: To discuss the clinical features of perianal Crohn disease (PCD). METHODS: Clinical data of 52 PCD patients who were treated at the Department of Colorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine from June 2011 to October 2014 were analyzed retrospectively. Montreal classification, clinical symptoms, the subtype of perianal lesions, history of perianal surgery and medical treatment, disease active indexes, serum inflammation markers and nutritional indexes were included. RESULTS: Among 52 patients, there were 40 males and 12 females with a mean age of (27.9+/-9.1) years. According to Montreal classification, 51.9%(27/52) of patients had ileocolic involvement and 75.0%(39/52) had inflammatory disease behavior. Thirteen (25.0%) and 15(28.8%) patients had abdominal pain and diarrhea respectively at admission. With respect to the subtype of perianal lesions, there were 32(61.5%) cases of anal fistula and 16(30.8%) cases of perianal abscess. Thirty-nine(75.0%) and 33(63.5%) patients had a history of perianal surgery and medical treatment before admission resepectively. Laboratory findings revealed high C-reaction protein level in 63.5%(33/52), high erythrocyte sedimentation rate in 61.5%(32/52), elevated platelet in 32.7%(17/52), low body weight in 44.2%(23/52), low albumin in 26.9%(14/52) and anemia in 42.3%(22/52) of patients. CONCLUSIONS: The clinical features of PCD patients include male predominant, early onset disease, high prevalence of ileocolic involvement and inflammation disease behavior. Features prompting underlying PCD diagnosis include characteristic gastrointestinal symptoms, requiring multiple perianal surgery, and abnormality of inflammation markers and nutritional indexes. PMID- 28000197 TI - [Efficacy evaluation of laparoscopic surgery for children with persistent cloaca]. AB - OBJECTIVE: To explore the feasibility and efficacy of laparoscopic surgery in the treatment of children with persistent cloaca. METHODS: Clinical data of 26 female children with high type persistent cloaca undergoing operation in the Capital Pediatric Institution between November 2005 and February 2015 were retrospectively analyzed. Mean age of these children was (1.4+/-1.6) years old. Distal end of rectum locating in the superior border of pubis was the standard of diagnosis. Laparoscopy-assisted anorectoplasty (LAARP), vaginoplasty and urethroplasty were performed in 17 cases (LAARP group), including 3-port laparoscopy in 12 cases and single-port laparoscopy in 5 cases. Abdominoperineal pull through (APPT), vaginoplasty and urethroplasty were performed in the other 9 cases (APPT group). Sacral ratio (SR), length of common channel, intraoperative blood loss, operation time, postoperative hospital stay, postoperative complications and bowel function were compared between two groups. Postoperative defecation was evaluated by the Krickenbeck standard. RESULTS: Operations were successfully performed in all patients and no case in LAARP group was transferred to open abdominal operation. There were no significant differences in SR value, length of common channel and age at operation between the two groups. As compared to APPT group, the mean operative time was shorter [(124.1+/-4.9) minutes vs. (131.8+/-3.2) minutes, P=0.000], the intraoperative blood loss was less [(10.5+/ 2.1) ml vs. (16.2+/-2.7) ml, P=0.000], and the postoperative hospital stay was shorter [(5.7+/-0.5) days vs. (9.2+/-0.4) days, P=0.000] in LAARP group. In LAARP group, there were no significant differences in operation time, intraoperative blood loss and postoperative hospital stay between 3-port and single-port laparoscopic surgery (all P>0.05). The mean follow-up period was (4.0+/-2.8) months in LAARP group and (6.0+/-2.3) months of APPT group. There is one case have wound infection in ARRT patients. The rates of voluntary bowel movement, soiling, constipation (grade 1, 2, 3) were similar in both groups, however, the overall bowel function after LAARP was better than that of ARRT according to the Krickenbeck classification (10.7+/-0.2 vs. 9.7+/-1.2, P=0.047). Postoperative rectal mucosa prolapse was found in 2 cases of LAARP group and 1 case in APPT group. One case of APPT group developed wound infection. No urethrovaginal fistula relapse, anal stenosis or urethral stricture was found in all the cases. CONCLUSIONS: The LAARP is safe and feasible in the treatment of persistent cloaca. PMID- 28000198 TI - [Study of the effect of LIG4 on the radiosensitivity enhancement of rectal cancer cells by curcumin]. AB - OBJECTIVE: To investigate the function of repair gene LIG4 in radiosensitivity enhancement of rectal cancer cells by curcumin. METHODS: Human rectal cancer cells HT-29 were cultured in normal. LIG4-overexpression HT-29 cells and blank control plasmid HT-29 cells were established by gene transfection. Both kind of HF-29 cells were further randomly divided into curcumin group, radiotherapy group, curcumin plus radiotherapy group (combined group) and control group. The growth inhibition and apoptosis of cells were detected by MTT and Annexin V/PI respectively. Change of tumor volume was observed in nude mouse xenograft model, and the apoptosis of tumor cells was analyzed by TUNEL. RESULTS: Regarding blank control plasmid HT-29 cells, the growth inhibition rate and apoptosis rate in combined group were significantly higher than those in radiotherapy group(all P<0.05); tumor volume of nude mouse in combined group was significantly smaller than that in radiotherapy group, and the apoptotic index in combined group was significantly higher than that in radiotherapy group (all P<0.05). However, regarding LIG4-overexpression HT-29 cells, the growth inhibition rate and apoptosis rate were not significantly different between combined group and radiotherapy group(all P>0.05); the tumor volume of nude mouse and the apoptotic index were also not significantly different between combined group and radiotherapy group (all P>0.05). CONCLUSION: Down-regulation of LIG4 is an important mechanism of radiosensitivity enhancement of rectal cancer cells by curcumin. PMID- 28000199 TI - [Meta analysis of incidence of postoperative complications for the modified posterior sagittal anorectoplasty treatment of intermediate or high anorectal malformations]. AB - OBJECTIVE: To evaluate the incidence of postoperative complications of children with intermediate or high anorectal malformations treated by one-stage modified posterior sagittal anorectoplasty(PSARP) by meta-analysis. METHODS: Cases with intermediate or high anorectal malformations treated by one-stage modified PSARP nearly a decade at home and abroad were collected by searching in Wanfang Data, CNKI, and PubMed database, then all the papers that recorded the number of cases of postoperative complications were screened out according to inclusion and exclusion criteria. Meta package in RevMan 3.2.5 software was used to perform the meta analysis for rate, and logit conversion method was applied to calculate the merger of the rates. Firstly, heterogeneity inspection was carried out. If the result was P>0.05, it was the homogeneity between the instructions included in the literatures, the fixed effect model was chosen. If the results was P<0.05, the random effect model was chosen. Then rank correlation test was used to estimate the number of research to evaluate publication bias. If P was 0.05 or less, the difference was statistically significant. RESULTS: Thirteen related articles were selected and added up to 566 cases with intermediate or high anorectal malformations treated by one-stage modified PSARP. The merged rate of the complications was 28%(95%CI: 19% to 40%). The three highest rate of complications were 8%(95%CI:4% ~ 14%) of corrupt dung, 7%(95%CI:5% ~11%)of fecal incontinence and 5%(95%CI:3% ~ 10%) of rectal mucosa prolapse. CONCLUSION: The most common postoperative complications of children with intermediate or high anorectal malformations treated by one-stage modified PSARP are rectal corrupt dung and fecal incontinence. PMID- 28000200 TI - [Efficacy and safety of surgery combined with hyperthermic intraperitoneal chemotherapy in the treatment of advanced gastric cancer: a meta-analysis]. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced gastric cancer (AGC). METHODS: Clinical control trials about the efficacy and safety of surgery combined with HIPEC in the treatment of advanced gastric cancer published before June 2014 were searched in Embase, PubMed, Cochrane Library, Wanfang database and CNKI database. Quality of enrolled articles was evaluated with the guidelines from Cochrane collaborative network. All the retrieved data were analyzed by RevMan 5.3 software for meta-analysis. Sensitivity analysis was performed by exclusion of non-randomly clinical control trials. Publication bias was evaluated by failure safe number (Nfs0.05). RESULTS: Of the 1489 AGC cases included from 16 literature, 698 underwent surgery with HIPEC (HIPEC group) while 791 underwent surgery alone (control group). According to whether or not the patient presented macroscopic peritoneal metastasis before the surgery, the HIPEC group was further divided into the curative HIPEC (n=102) and prophylactic HIPEC groups (n=421). The results of meta-analysis showed that, compared with control group, the 1-year (OR=2.26, 95%CI:1.71 ~ 3.00, P=0.000), 3 year (OR=2.27, 95%CI:1.80 - 2.87, P=0.000) and 5-year (OR=1.58, 95%CI:1.20 - 2.07, P=0.001) survival rates of HIPEC group were significantly improved with significantly decreased overall recurrence rate of liver, lung, bone or peritoneal metastasis (OR=0.43, 95%CI:0.26 - 0.71, P=0.001) and lower peritoneal metastasis recurrence rate (OR=0.30, 95%CI:0.17 - 0.52, P=0.000). However, there was higher incidence of procedure-related morbidity in the HIPEC group (OR=1.67, 95%CI:1.13 - 2.45, P=0.009), whereby the incidences of myelotoxicity (OR=4.90, 95%CI:1.05 - 22.83, P=0.040) and renal insufficiency were higher (OR=3.59, 95%CI:1.67 - 7.74, P=0.001). While the other complications, such as anastomotic leakage, intestinal obstruction and respiratory diseases were not significantly different between the two groups(all P>0.05). Subgroup analysis showed that compared with control group, the rates of peritoneal recurrence and metastasis in the prophylactic HIPEC group were significantly lower (OR=0.34, 95%CI:0.24 - 0.48, P=0.000), while such rates were not significantly different in curative HIPEC group (OR=0.07, 95%CI:0.00 - 1.88, P=0.110). CONCLUSIONS: Surgery combined with HIPEC can improve survival of AGC patients and reduce the recurrence rate after surgery. However its safety should be improved in the future. PMID- 28000201 TI - [Pathogenesis and treatment of slow transit constipation]. AB - Slow transit constipation (STC) is generally considered as a complex idiopathic disease affected by multiple factors synergistically. Primarily caused by the condition of gut dysmotility, the transit of intestinal contents turned so slow that the moisture absorption increases, defecation frequency decreases, bowel movement is weakened or even disappeared with or without abdominal distension, dry and hard stool. Its etiology and pathogenesis remains unclear.Recently some researches reported the pathogenesis may be associated with the changes of the enteric nervous system (ENS), such as the change or degeneration of intestinal nerve cells, gut glial cell damage and neurotransmitter changes. Besides, intestinal myopathy, ICC reduction, immune factors, endocrine factors, laxative, mental psychological factors, diet and exercise habits may also be associated with the occurrence and aggravation of STC. The current understanding of STC mechanism can not meet the needs of clinical diagnosis and treatment. Conservative treatment is the main treatment of STC nowadays. For those receiving normative medical treatment but with little effect, surgery is necessary. "Jingling procedure" and "antiperistaltic anastomosis" can both get good efficacy. Treatment aiming at causes of disease will be uncovered as the development of the researches on the pathogenesis and treatment of slow transit constipation. PMID- 28000202 TI - Micro-RNA signature of lymphovascular space involvement in type 1 endometrial cancer. AB - OBJECTIVE: Lymphovascular space involvement (LVSI) is a major prognostic factor in type 1 endometrial cancer (EC). However, its use has been criticized because of poor subjectivity. MicroRNA signatures have recently been linked to EC pathologic characteristics. The aim of this study was to evaluate whether microRNA profiles of type 1 EC can be related to LVSI status and used as a tool to adapt therapy. STUDY DESIGN: MicroRNA expression was assessed by chip analysis and qRT-PCR in 12 formalin-fixed paraffin-embedded grade 2 EC specimens with positive LVSI and in 12 specimens with negative LVSI. Various statistical analyses, including enrichment analysis and a minimum p-value approach, were performed. RESULTS: The expression levels of microRNAs 34c-5p, -23b-5p, and 23c were significantly lower in the EC with positive LVSI compared to those with negative LVSI. Women with a microRNA-34c-5p fold change <0.15 were more likely to have positive LVSI status (92.3%) compared with those with a microRNA-34c-5p fold change >0.15 (0.0%), p<0.001. Furthermore, women with a microRNA-23b-5p fold change <0.51 were more likely to have positive LVSI status (90.0%) compared with those with a microRNA-23b-5p fold change >0.51 (21.4%), p=0.003. CONCLUSION: This was the first study to investigate the relative expression of microRNA in type 1 EC according to LVSI status. This microRNA expression profile may provide a basis for further study of the microRNA function in EC, and be used as a diagnostic tool for LVSI status. PMID- 28000203 TI - Comparison of continuous epidural block and continuous paravertebral block in postoperative analgaesia after video-assisted thoracoscopic surgery lobectomy: a randomised, non-inferiority trial. AB - BACKGROUND: Video-assisted (VATS) lung lobectomy can be associated with stronger postoperative pain than is commonly believed. It is generally accepted to introduce multimodal analgaesic strategies based on regional blockade, opioids and non-steroidal anti-inflammatory drugs. However, there is still no consensus regarding the optimal regional technique. The aim of this study was to compare the analgaesic efficacy of continuous thoracic epidural block (TEA) and percutaneous continuous paravertebral block (PVB) in patients undergoing video assisted lung lobectomy. METHODS: Fifty-one patients undergoing VATS lobectomy were enrolled in the present prospective, randomised clinical trial. The same analgaesic regimen in both groups included continuous infusion of 0.25% bupivacaine with epinephrine, intravenous ketoprofen and paracetamol. The doses of local anaesthetics were determined to achieve the spread of at least 4 segments in both groups. Postoperative static and dynamic visual analogue pain scores, as well as patient-controlled morphine usage, were used to compare the efficacy of analgaesia. Side effects and failure rates of both blocks were analysed. RESULTS: Static and dynamic pain scores at 24 postoperative hours were significantly lower in the paravertebral group, as were the static pain score at 36 and 48 postoperative hours (P < 0.05). No difference between the treatment groups was identified regarding postoperative morphine usage. The failure rate was higher in the epidural group than in the paravertebral group. No complications were noted in either group, but side effects (urinary retention, hypotension) were more frequent in the epidural group (P < 0.05). CONCLUSIONS: Postoperative pain following VATS lung resection procedures is significant and requires the application of complex analgaesic techniques. Percutaneous paravertebral block is equally effective as thoracic epidural block in providing analgaesia in patients undergoing VATS lobectomy. Paravertebral block has a better safety profile than thoracic epidural block. PMID- 28000204 TI - Early severe acute respiratory distress syndrome: What's going on? Part I: pathophysiology. AB - Severe acute respiratory distress syndrome (ARDS, PaO2/FiO2 < 100 on PEEP >= 5 cm H2O) is treated using controlled mechanical ventilation (CMV), recently combined with muscle relaxation for 48 h and prone positioning. While the amplitude of tidal volume appears set < 6 mL kg-1, the level of positive end-expiratory pressure (PEEP) remains controversial. This overview summarizes several salient points, namely: a) ARDS is an oxygenation defect: consolidation/ difuse alveolar damage is reversed by PEEP and/or prone positioning, at least during the early phase of ARDS b) ARDS is a dynamic disease and partially iatrogenic. This implies that the management of the ventilator may be a life-saver by reducing the duration of mechanical ventilation, or detrimental by extending this duration, leading into critical care-acquired diseases. Indeed, a high PEEP (10-24 cm H2O) appears to be a life-saver in the context of early severe diffuse ARDS; c) tidal volume and plateau pressure cannot be identical for all patients; d) the only remaining rationale for CMV and muscle relaxation is to suppress patient ventilator asynchrony and to lower VO2, during the acute cardio-ventilatory distress. Therefore, in early severe diffuse ARDS, this review argues for a combination of a high PEEP (preferably titrated on transpulmonary pressure) with spontaneous ventilation + pressure support (or newer modes of ventilation). However, conditionalities are stringent: upfront circulatory optimization, upright positioning, lowered VO2, lowered acidotic and hypercapnic drives, sedation without ventilatory depression and without lowered muscular tone. As these propositions require evidence-based demonstration, the accepted practice remains, in 2016, controlled mechanical ventilation, muscle relaxation, and prone position. PMID- 28000205 TI - Early severe acute respiratory distress syndrome: What's going on? Part II: controlled vs. spontaneous ventilation? AB - The second part of this overview on early severe ARDS delineates the pros and cons of the following: a) controlled mechanical ventilation (CMV: lowered oxygen consumption and perfect patient-to-ventilator synchrony), to be used during acute cardio-ventilatory distress in order to "buy time" and correct circulatory insufficiency and metabolic defects (acidosis, etc.); b) spontaneous ventilation (SV: improved venous return, lowered intrathoracic pressure, absence of muscle atrophy). Given a stabilized early severe ARDS, as soon as the overall clinical situation improves, spontaneous ventilation will be used with the following stringent conditionalities: upfront circulatory optimization, upright positioning, lowered VO2, lowered acidotic and hypercapnic drives, sedation without ventilatory depression and without lowered muscular tone, as well as high PEEP (titrated on transpulmonary pressure, or as a second best: "trial"-PEEP) with spontaneous ventilation + pressure support (or newer modes of ventilation). As these propositions require evidence-based demonstration, the reader is reminded that the accepted practice remains, in 2016, controlled mechanical ventilation, muscle relaxation and prone position. PMID- 28000206 TI - Zika virus infection, issue on dermatological problem. PMID- 28000207 TI - Wavelet Analysis of Resultant Velocity Belonging to Genuine and Forged Signatures. AB - This study presents a wavelet analysis of resultant velocity features belonging to genuine and forged groups of signature sample. Signatures of individuals were initially classified based on visual human perceptions of their relative sizes, complexities, and legibilities of the genuine counterparts. Then, the resultant velocity was extracted and modeled through wavelet analysis from each sample. The wavelet signal was decomposed into several layers based on maximum overlap discrete wavelet transform (MODWT). Next, the zero crossing rate features were calculated from all the high wavelet sub-bands. A total of seven hypotheses were then tested using a two-way ANOVA testing methodology. Of these, four hypotheses were conducted to test for significance differences between distributions. In addition, three hypotheses were run to provide test for interaction between two factors of signature authentication versus perceived classification. The results demonstrated that both feature distributions belonging to genuine and forged groups of samples cannot be distinguished by themselves. Instead, they were significantly different under the influence of two other inherent factors, namely perceived size and legibility. Such new findings are useful information particularly in providing bases for forensic justifications in establishing the authenticity of handwritten signature specimens. PMID- 28000209 TI - Evaluation of Non-Natural Deaths among Veterans: New Mexico Medical Examiner Investigated Deaths, 2002-2011. AB - While it is recognized that veterans have increased rates of depression, post traumatic stress disorder (PTSD), suicide, and substance use disorders, rates of homicide and unintentional injury deaths in veterans have been minimally investigated. We evaluated all non-natural deaths in New Mexico veterans between 2002 and 2011 in comparison with non-natural deaths among non-veterans. We reviewed all decedents in New Mexico with a history of military service and investigated by the medical examiner, excluding natural deaths and deaths due to fall from standing height. The most common manner of death was unintentional injury (62%), most of these deaths due to motor vehicle accidents (29%) followed by unintentional overdose (26%). Suicide rates among veterans were consistently higher than the general population. The most common mechanism of suicide in men was gunshot wound (72%), and intentional overdose in women (49%). Services are needed for veterans that are tailored to all ages and both sexes. PMID- 28000208 TI - When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. AB - Primary antibody deficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) and immunoglobulin replacement forms the mainstay of therapy for many patients in this category. Secondary antibody deficiencies (SAD) represent a larger and expanding number of patients resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal or gastrointestinal immunoglobulin losses. While there are clear similarities between primary and secondary antibody deficiencies, there are also significant differences. This review describes a practical approach to the clinical, laboratory and radiological assessment of patients with antibody deficiency, focusing on the factors that determine whether or not immunoglobulin replacement should be used. The decision to treat is more straightforward when defined diagnostic criteria for some of the major PADs, such as common variable immunodeficiency disorders (CVID) or X-linked agammaglobulinaemia (XLA), are fulfilled or, indeed, when there is a very low level of immunoglobulin production in association with an increased frequency of severe or recurrent infections in SAD. However, the presentation of many patients is less clear-cut and represents a considerable challenge in terms of the decision whether or not to treat and the best way in which to assess the outcome of therapy. This decision is important, not least to improve individual quality of life and reduce the morbidity and mortality associated with recurrent infections but also to avoid inappropriate exposure to blood products and to ensure that immunoglobulin, a costly and limited resource, is used to maximal benefit. PMID- 28000210 TI - Behaviour of Arctic charr Salvelinus alpinus during an induced mating season in captivity: how male relative size influences male behavioural investment and female preference over time. AB - The behaviour of sexually mature Arctic charr Salvelinus alpinus specimens (fifth farm generation) was observed in captivity for four consecutive days. Only agonistic interactions between males of different size were facilitated on the first 2 days, while both agonistic and courtship interactions were possible from the third day up to the end of the experiment. The reliability of behavioural analysis was assessed in order to reduce the possibility of observer errors within the generated datasets. The behavioural investment of big males, small males and females was analysed using general linear models (two-way repeated measures ANOVAs with time and male size as factors). A peak in the agonistic interactions between males occurred during the first day of interactions, where the agonistic investment of big males was significantly higher than that of small males. This resulted in an increased investment in submissive behaviour by the small males, who consistently performed submissive behaviours from the second day of interactions up to the end of the trial. Big males were found to invest significantly more than small males in courtship behaviours for the duration of the trial. Even though females performed inter-sexual behaviours towards both big and small males for the entire observation period, female interaction rate towards big males was higher than towards small males. This study suggests that both male investment in mating behaviour and female preference might be related to male characteristics such as body length and that S. alpinus behavioural patterns and mate choice cues might be strongly context-related and characterized by high levels of behavioural plasticity (i.e. presence-absence of certain behavioural units or potential reversal of a mate choice cue) within the same species. Finally, in light of this, some conservation measures are discussed. In particular, effective management plans should take into account the high level of behavioural plasticity likely to be occurring in this species. PMID- 28000211 TI - Experimentally reducing species abundance indirectly affects food web structure and robustness. AB - Studies on the robustness of ecological communities suggest that the loss or reduction in abundance of individual species can lead to secondary and cascading extinctions. However, most such studies have been simulation-based analyses of the effect of primary extinction on food web structure. In a field experiment we tested the direct and indirect effects of reducing the abundance of a common species, focusing on the diverse and self-contained assemblage of arthropods associated with an abundant Brazilian shrub, Baccharis dracunculifolia D.C. (Asteraceae). Over a 5-month period we experimentally reduced the abundance of Baccharopelma dracunculifoliae (Sternorrhyncha: Psyllidae), the commonest galling species associated with B. dracunculifolia, in 15 replicate plots paired with 15 control plots. We investigated direct effects of the manipulation on parasitoids attacking B. dracunculifoliae, as well as indirect effects (mediated via a third species or through the environment) on 10 other galler species and 50 associated parasitoid species. The experimental manipulation significantly increased parasitism on B. dracunculifoliae in the treatment plots, but did not significantly alter either the species richness or abundance of other galler species. Compared to control plots, food webs in manipulated plots had significantly lower values of weighted connectance, interaction evenness and robustness (measured as simulated tolerance to secondary extinction), even when B. dracunculifoliae was excluded from calculations. Parasitoid species were almost entirely specialized to individual galler species, so the observed effects of the manipulation on food web structure could not have propagated via the documented trophic links. Instead, they must have spread either through trophic links not included in the webs (e.g. shared predators) or non-trophically (e.g. through changes in habitat availability). Our results highlight that the inclusion of both trophic and non-trophic direct and indirect interactions is essential to understand the structure and dynamics of even apparently discrete ecological communities. PMID- 28000212 TI - Interventions to improve adherence to lipid-lowering medication. AB - BACKGROUND: Lipid-lowering drugs are widely underused, despite strong evidence indicating they improve cardiovascular end points. Poor patient adherence to a medication regimen can affect the success of lipid-lowering treatment. OBJECTIVES: To assess the effects of interventions aimed at improving adherence to lipid-lowering drugs, focusing on measures of adherence and clinical outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and CINAHL up to 3 February 2016, and clinical trials registers (ANZCTR and ClinicalTrials.gov) up to 27 July 2016. We applied no language restrictions. SELECTION CRITERIA: We evaluated randomised controlled trials of adherence-enhancing interventions for lipid-lowering medication in adults in an ambulatory setting with a variety of measurable outcomes, such as adherence to treatment and changes to serum lipid levels. Two teams of review authors independently selected the studies. DATA COLLECTION AND ANALYSIS: Three review authors extracted and assessed data, following criteria outlined by the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the quality of the evidence using GRADEPro. MAIN RESULTS: For this updated review, we added 24 new studies meeting the eligibility criteria to the 11 studies from prior updates. We have therefore included 35 studies, randomising 925,171 participants. Seven studies including 11,204 individuals compared adherence rates of those in an intensification of a patient care intervention (e.g. electronic reminders, pharmacist-led interventions, healthcare professional education of patients) versus usual care over the short term (six months or less), and were pooled in a meta-analysis. Participants in the intervention group had better adherence than those receiving usual care (odds ratio (OR) 1.93, 95% confidence interval (CI) 1.29 to 2.88; 7 studies; 11,204 participants; moderate quality evidence). A separate analysis also showed improvements in long-term adherence rates (more than six months) using intensification of care (OR 2.87, 95% CI 1.91 to 4.29; 3 studies; 663 participants; high-quality evidence). Analyses of the effect on total cholesterol and LDL-cholesterol levels also showed a positive effect of intensified interventions over both short- and long term follow-up. Over the short term, total cholesterol decreased by a mean of 17.15 mg/dL (95% CI 1.17 to 33.14; 4 studies; 430 participants; low-quality evidence) and LDL-cholesterol decreased by a mean of 19.51 mg/dL (95% CI 8.51 to 30.51; 3 studies; 333 participants; moderate-quality evidence). Over the long term (more than six months) total cholesterol decreased by a mean of 17.57 mg/dL (95% CI 14.95 to 20.19; 2 studies; 127 participants; high-quality evidence). Included studies did not report usable data for health outcome indications, adverse effects or costs/resource use, so we could not pool these outcomes. We assessed each included study for bias using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. In general, the risk of bias assessment revealed a low risk of selection bias, attrition bias, and reporting bias. There was unclear risk of bias relating to blinding for most studies. AUTHORS' CONCLUSIONS: The evidence in our review demonstrates that intensification of patient care interventions improves short- and long-term medication adherence, as well as total cholesterol and LDL-cholesterol levels. Healthcare systems which can implement team-based intensification of patient care interventions may be successful in improving patient adherence rates to lipid lowering medicines. PMID- 28000214 TI - Occipital Condyle Syndrome: A Red Flag for Malignancy. Comprehensive Literature Review and New Case Report. AB - OBJECTIVE: To perform a literature review of the epidemiology, clinical presentation, diagnostic evaluation, and clinical course of occipital condyle syndrome, including a new case report. BACKGROUND: Occipital condyle syndrome (OCS) is a rare clinical syndrome, consisting of unilateral occipital headache accompanied by ipsilateral hypoglossal palsy. This headache typically radiates to the temporal region, and is triggered by contralateral head rotation. It is usually associated with skull base metastasis, often unrevealed in basic neuroimaging studies. OCS might be the first manifestation of malignancy, and its unfamiliarity can lead to a delay in the diagnosis. METHODS: We performed a systematic literature review using PubMed and Embase for OCS, along with a new case report. RESULTS: A total of 35 cases (mean age 59 years, range 25-77), 24 (70%) men, presented typical unilateral headache followed by ipsilateral hypoglossal palsy from 0 to 150 days after headache presentation. In 16 patients (46%), initial neuroimaging studies were normal. OCS was due to skull base metastasis in 32 cases (91%). In 18 patients (51%), OCS was the first symptom of disease. CONCLUSIONS: OCS represents a warning sign and requires an exhaustive search for underlying neoplasm. An appropriate clinical evaluation can lead to an earlier diagnosis in patients with consistent headache. PMID- 28000215 TI - Double paddle ulnar perforator free flap in reconstruction of through-and-through and fistulous defects of the head and neck. PMID- 28000216 TI - Vascular structures in dermal nevi: a reappraisal. PMID- 28000218 TI - Supra-Hisian Conduction Block as an Unusual Presenting Feature of Takotsubo Cardiomyopathy. AB - BACKGROUND: Atrioventricular (AV) block is rare in Takotsubo cardiomyopathy (TC). CASE REPORT: A 66-year-old female presented with fatigue. Her electrocardiogram revealed 3:2 Mobitz Type II AV block, confirmed to be supra-Hisian by electrophysiological study. Echocardiogram and left ventricular angiogram showed moderate left ventricular dysfunction and apical ballooning, whereas coronary angiogram revealed mildly ectatic coronaries. At 2 weeks AV block persisted, needing permanent pacemaker implantation. At 1-month follow-up, she had normal ventricular function and no AV block. CONCLUSION: Delayed recovery of AV conduction is possible in TC, thus implying to wait for a longer period before implanting a pacemaker. PMID- 28000217 TI - Thiol/disulfide homeostasis as a novel indicator of oxidative stress in obstructive sleep apnea patients. AB - OBJECTIVES: The aim of the present study was to assess thiol/disulfide (SS) homeostasis as a novel indicator of oxidative stress in patients with obstructive sleep apnea (OSA) and to investigate the effect of continuous positive airway pressure (CPAP) therapy on oxidative parameters. STUDY DESIGN: Prospective clinical study. METHODS: A total of 104 subjects, 44 in an OSA group and 60 in two control groups (control simple snoring group, control OSA group) were included. The levels of parameters were measured using the Erel and Neselioglu method in patients with moderate or severe OSA before and after CPAP therapy. RESULTS: The serum native thiol (SH) and total SH levels as well as the %SH/total SH ratio were significantly lower (P < 0.05) in OSA patients compared to controls, and the SS level and %SS/SH and %SS/total SH ratios were significantly higher (P < 0.05). After CPAP therapy, the native SH level and %SH/total SH ratio were significantly higher (P < 0.05) than before CPAP therapy, and the SS level and %SS/SH and %SS/total SH ratios were significantly lower (P < 0.05). Significant negative correlations were evident between the apnea/hypopnea index (AHI) and the native SH level and %SH/total SH ratio (P < 0.05) before CPAP therapy; and significant positive correlations were seen between the AHI and the %SS/SH and %SS/total SH ratios but not with the SS level. CONCLUSION: We found that oxidative stress was increased and CPAP therapy had a positive effect in patients with moderate or severe OSA. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:E244-E250, 2017. PMID- 28000219 TI - Sex-dependent carry-over effects on timing of reproduction and fecundity of a migratory bird. AB - Life of many organisms flows as a sequence of annual cycles. Timing of cyclical events is shaped by natural selection also via the domino effects that any life history stage has on the stages that follow. Such 'carry-over effects' have major consequences for evolutionary, ecological and demographic processes, but the causes that generate their individual-level variation, including the effect of sex, are poorly understood. We used light-level geolocators to study carry-over effects on the year-round life cycle of the long-distance migratory barn swallow (Hirundo rustica) and sex-dependent variation in their strength. Correlation analyses showed that timing of breeding influenced departure time for autumn migration in females but not in males. In addition, strong, time-mediated carry over effects of timing of departure from the wintering areas in sub-Saharan Africa for spring migration on timing of arrival to the breeding grounds in Italy and Switzerland operated in both sexes. However, carry-over effects of spring migration phenology on breeding date and seasonal fecundity were observed among females but not among males. We used partial least squares path modelling to unveil the complex carry-over effects of phenology during the non-breeding season in combination with the ecological conditions experienced by individual swallows in the wintering area, as gauged by Normalized Difference Vegetation Index values (NDVI), on breeding performance. Phenology during the non-breeding season combined with NDVI during wintering accounted for as much as 65-70% of variation in subsequent seasonal fecundity in females, while such carry-over effects on breeding success of males were weaker. Intense, sex-specific carry-over effects can have impacted on evolutionary processes, including sexual selection, and affected phenological response to climate change, causing the large population decline observed in this species. PMID- 28000220 TI - Odor detection thresholds in a population of older adults. AB - OBJECTIVES/HYPOTHESIS: To measure odor detection thresholds and associated nasal and behavioral factors in an older adult population. STUDY DESIGN: Cross sectional cohort study. METHODS: Odor detection thresholds were obtained using an automated olfactometer on 832 participants, aged 68 to 99 (mean age = 77) years in the 21-year (2013-2016) follow-up visit of the Epidemiology of Hearing Loss Study. RESULTS: The mean odor detection threshold (ODT) score was 8.2 (range = 1 13; standard deviation = 2.54), corresponding to an n-butanol concentration of slightly less than 0.03%. Older participants were significantly more likely to have lower (worse) ODT scores than younger participants (P < .001). There were no significant differences in mean ODT scores between men and women. Older age was significantly associated with worse performance in multivariable regression models, and exercising at least once per week was associated with reduced odds of having a low (<=5) ODT score. Cognitive impairment was also associated with poor performance, whereas a history of allergies or a deviated septum was associated with better performance. CONCLUSIONS: Odor detection threshold scores were worse in older age groups but similar between men and women in this large population of older adults. Regular exercise was associated with better odor detection thresholds, adding to the evidence that decline in olfactory function with age may be partly preventable. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:1257-1262, 2017. PMID- 28000221 TI - Substitution effects in a generalized token economy with pigeons. AB - Pigeons made repeated choices between earning and exchanging reinforcer-specific tokens (green tokens exchangeable for food, red tokens exchangeable for water) and reinforcer-general tokens (white tokens exchangeable for food or water) in a closed token economy. Food and green food tokens could be earned on one panel; water and red water tokens could be earned on a second panel; white generalized tokens could be earned on either panel. Responses on one key produced tokens according to a fixed-ratio schedule, whereas responses on a second key produced exchange periods, during which all previously earned tokens could be exchanged for the appropriate commodity. Most conditions were conducted in a closed economy, and pigeons distributed their token allocation in ways that permitted food and water consumption. When the price of all tokens was equal and low, most pigeons preferred the generalized tokens. When token-production prices were manipulated, pigeons reduced production of the tokens that increased in price while increasing production of the generalized tokens that remained at a fixed price. The latter is consistent with a substitution effect: Generalized tokens increased and were exchanged for the more expensive reinforcer. When food and water were made freely available outside the session, token production and exchange was sharply reduced but was not eliminated, even in conditions when it no longer produced tokens. The results join with other recent data in showing sustained generalized functions of token reinforcers, and demonstrate the utility of token-economic methods for assessing demand for and substitution among multiple commodities in a laboratory context. PMID- 28000222 TI - Infra-His Block during Atrial Pacing-Functional or Pathological? AB - The significance of infra-His conduction abnormalities observed in the electrophysiology lab can be difficult to assess. In this report we show infra His conduction block during programmed atrial stimulation in a patient and discuss if this should be considered functional or pathological. PMID- 28000224 TI - Fabrication and validation of a low-cost, medium-fidelity silicone injection molded endoscopic sinus surgery simulation model. AB - OBJECTIVES/HYPOTHESIS: Develop a low-cost, medium-fidelity model for education in endoscopic sinus surgery techniques. Establish face and content validity of the model based on the feedback of otolaryngology faculty including fellowship trained rhinologists. STUDY DESIGN: Survey. METHODS: A novel silicone injection molded sinus model was constructed. Three fellowship-trained rhinologists and four general otolaryngologists were recruited to perform seven tasks and provide feedback of the model's performance via a 22-question Likert survey. RESULTS: Those surveyed strongly agreed the sinus model is useful for basic endoscopic skill acquisition such as camera skills (86%), hand-eye coordination (100%), nasal endoscopy skills (100%). Ratings of the model for training the specific tasks were consistently high. Neutral or lower were received for inferior turbinoplasty (14%), frontal balloon task (14%), understanding the ethmoid bulla (29%), and advanced sinus techniques (57%). All faculty strongly agreed they would be interested in using the model to train residents. CONCLUSIONS: Simulation models have proven efficacy in endoscopic skill and procedural training. The group developed a novel low-cost, medium-fidelity sinus training model utilizing three-dimensional modeling and printing. Testing of this model revealed high ratings for both face and construct validity for a range of endoscopic procedures. Strong interest in using this model for resident training was unanimous among all survey participants. LEVEL OF EVIDENCE: NA Laryngoscope, 127:781-786, 2017. PMID- 28000225 TI - Topical oral cavity chemoprophylaxis using isotretinoin rinse: A 15-year experience. AB - OBJECTIVES/HYPOTHESIS: To determine the utility of isotretinoin oral rinses as a method of chemoprevention for recurrent oral cavity squamous cell carcinoma (SCC), carcinoma in situ, and dysplasia. STUDY DESIGN: Retrospective cohort study. METHODS: One hundred forty-three patients were initially enrolled in the study; however, 18 were excluded due to inability to tolerate therapy. The included patients were classified into four groups. Group 1 included patients with multiple early stage oral cavity lesions following initial resection. Group 2 included patients with SCC in situ after excision. Group 3 included patients with multifocal dysplasia following initial CO2 laser ablation. Group 4 included patients with a history of treated oral cavity SCC with new leukoplakia lesions proven to be dysplastic. Fifty-three patients in the control group did not use post-treatment isotretinoin rinses due to various reasons, whereas 72 patients completed therapy. Minimum use of isotretinoin rinses was 12 months, and minimum follow-up was 24 months. During the follow-up period, all recurrences of carcinoma, in situ disease, and dysplasia were noted and compared with a Fisher test of fit. A Bonferroni correction was applied to increase accuracy and strength of comparison. RESULTS: Using a Bonferroni correction, the significance threshold was 0.0125. By that cutoff, isotretinoin rinses were found to be associated with lower recurrence in groups 1 and 3 (P = .00014, P = .00002, respectively) but not in groups 2 and 4 (P = .4, P = .3846, respectively). CONCLUSIONS: Oral isotretinoin as chemoprophylaxis for patients treated for oral cavity squamous cell carcinoma, in situ disease, or dysplasia may be beneficial in decreasing recurrence rate. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1595-1599, 2017. PMID- 28000223 TI - Western diet induces colonic nitrergic myenteric neuropathy and dysmotility in mice via saturated fatty acid- and lipopolysaccharide-induced TLR4 signalling. AB - KEY POINTS: A high-fat diet (60% kcal from fat) is associated with motility disorders inducing constipation and loss of nitrergic myenteric neurons in the proximal colon. Gut microbiota dysbiosis, which occurs in response to HFD, contributes to endotoxaemia. High levels of lipopolysaccharide lead to apoptosis in cultured myenteric neurons that express Toll-like receptor 4 (TLR4). Consumption of a Western diet (WD) (35% kcal from fat) for 6 weeks leads to gut microbiota dysbiosis associated with altered bacterial metabolites and increased levels of plasma free fatty acids. These disorders precede the nitrergic myenteric cell loss observed in the proximal colon. Mice lacking TLR4 did not exhibit WD-induced myenteric cell loss and dysmotility. Lipopolysaccharide induced in vitro enteric neurodegeneration requires the presence of palmitate and may be a result of enhanced NO production. The present study highlights the critical role of plasma saturated free fatty acids that are abundant in the WD with respect to driving enteric neuropathy and colonic dysmotility. ABSTRACT: The consumption of a high-fat diet (HFD) is associated with myenteric neurodegeneration, which in turn is associated with delayed colonic transit and constipation. We examined the hypothesis that an inherent increase in plasma free fatty acids (FFA) in the HFD together with an HFD-induced alteration in gut microbiota contributes to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD) (35% kcal from fat enriched in palmitate) or a purified regular diet (16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal lipopolysaccharide (LPS) measurement and metabolomics (linear trap quadrupole-Fourier transform mass spectrometer) analysis. Plasma FFA and LPS levels were assessed, in addition to colonic and ileal nitrergic myenteric neuron quantifications and motility. Compared to regular diet-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding, as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. The numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and this was also associated with delayed colonic transit. WD-fed Toll-like receptor 4 (TLR4)-/- mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS (0.5-2 ng.ml-1 ) and palmitate (20 and 30 MUm) acted synergistically to induce neuronal cell death in vitro, which was prevented by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycaemia or overt endotoxaemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility. PMID- 28000226 TI - Abnormal spontaneous activity in primary myopathic disorders. AB - INTRODUCTION: Reproducible non-insertional spontaneous activity (SA), with the exception of endplate activity, is an unequivocal sign of abnormality and is one of the most useful findings obtained on electromyography. METHODS: In this retrospective study we analyzed occurrence and distribution of abnormal SA in 151 patients with genetically confirmed myopathies. RESULTS: Complex repetitive discharges (CRDs) occurred more frequently than fibrillation potentials (fibs) and positive sharp waves (PSWs) in centronuclear myopathy (CNM) and limb-girdle muscular dystrophy type 2A (LGMD-2A), whereas fibs/PSWs were observed more often in desminopathy and facioscapulohumeral dystrophy (FSHD). Abnormal SA was commonly found in CNM (66.7%) and desminopathy (61.5%), occasionally in Duchenne (DMD) and Becker muscular dystrophy (BMD) (45.2% and 27.6%, respectively), but rarely in FSHD (14.9%) and LGMD-2A (12.0%). CONCLUSIONS: Abnormal SA probably occurs more frequently in disorders associated with structural changes in muscle fibers. Screening for SA may be a valuable tool for diagnosis of non-myotonic myopathies. Muscle Nerve 56: 427-432, 2017. PMID- 28000227 TI - Variants of Brugada Syndrome and Early Repolarization Syndrome: An Expanded Concept of J-Wave Syndrome. AB - BACKGROUND: The role of J-waves in the pathogenesis of ventricular fibrillation (VF) occurring in structurally normal hearts is important. METHODS: We evaluated 127 patients who received an implantable cardioverter-defibrillator (ICD) for Brugada syndrome (BS, n = 53), early repolarization syndrome (ERS, n = 24), and patients with unknown or deferred diagnosis (n = 50). Electrocardiography (ECG), clinical characteristics, and ICD data were analyzed. RESULTS: J-waves were found in 27/50 patients with VF of unknown/deferred diagnosis. The J-waves were reminiscent of those seen in BS or ERS, and this subgroup of patients was termed variants of ERS and BS (VEB). In 12 VEB patients, the J/ST/T-wave morphology was coved, although amplitudes were <0.2 mV. In 15 patients, noncoved-type J/ST/T waves were present in the right precordial leads. In the remaining 23 patients, no J-waves were identified. VEB patients exhibited clinical characteristics similar to those of BS and ERS patients. Phenotypic transition and overlap were observed among patients with BS, ERS, and VEB. Twelve patients with BS had background inferolateral ER, while five ERS patients showed prominent right precordial J-waves. Patients with this transient phenotype overlap showed a significantly lower shock-free survival than the rest of the study patients. CONCLUSIONS: VEB patients demonstrate ECG phenotype similar to but distinct from those of BS and ERS. The spectral nature of J-wave morphology/distribution and phenotypic transition/overlap suggest a common pathophysiologic background in patients with VEB, BS, and ERS. Prognostic implication of these ECG variations requires further investigation. PMID- 28000228 TI - Differential regulation of ssb genes in the nitrogen-fixing cyanobacterium, Anabaena sp. strain PCC71201. AB - Anabaena sp. PCC7120 possesses three genes coding for single-stranded DNA-binding (SSB) protein, of which ssb1 was a single gene, and ssb2 and ssb3 are the first genes of their corresponding operons. Regulation of the truncated ssb genes, ssb1 (alr0088) and ssb2 (alr7559), was unaffected by N-status of growth. They were negatively regulated by the SOS-response regulatory protein LexA, as indicated by the (i) binding of Anabaena LexA to the LexA box of regulatory regions of ssb1 and ssb2, and (ii) decreased expression of the downstream gfp reporter gene in Escherichia coli upon co-expression of LexA. However, the full-length ssb gene, ssb3 (all4779), was regulated by the availability of Fe2+ and combined nitrogen, as indicated by (i) increase in the levels of SSB3 protein on Fe2+ -depletion and decrease under Fe2+ -excess conditions, and (ii) 1.5- to 1.6-fold decrease in activity under nitrogen-fixing conditions compared to nitrogen-supplemented conditions. The requirement of Fe2+ as a co-factor for repression by FurA and the increase in levels of FurA under nitrogen-deficient conditions in Anabaena (Lopez Gomollon et al. 2007) indicated a possible regulation of ssb3 by FurA. This was substantiated by (i) the binding of FurA to the regulatory region of ssb3, (ii) repression of the expression of the downstream gfp reporter gene in E. coli upon co-expression of FurA, and (iii) negative regulation of ssb3 promoter activity by the upstream AT-rich region in Anabaena. This is the first report on possible role of FurA, an important protein for iron homeostasis, in DNA repair of cyanobacteria. PMID- 28000229 TI - Proposed mechanisms of Terminalia catappa in hyperglycaemia and associated diabetic complications. AB - OBJECTIVES: Terminalia catappa has shown potent antidiabetic activity in the past; however, the exact molecular mechanisms by which it acts have not been elucidated. This review aims at exploring several hypotheses which have been proposed to explain its mechanism of action, including reduction in oxidative stress, inflammation, angiogenesis, lipid profile correction and direct hypoglycaemic actions. METHODS: A thorough review of all the articles, research as well as reviews, available regarding the concerned topic was performed. MEDLINE databases were searched using keywords (and their combinations), such as T. catappa, renin oxidative stress, inflammation, angiogenesis, diabetic retinopathy, alpha-glucosidase and alpha-amylase, among several others. English language articles were preferably selected. KEY FINDINGS: Apart from metabolic dysfunctions, several hyperglycaemia-induced pathological conditions come into scene as the after-effects of diabetes. These mainly include inflammation, oxidative stress, angiogenesis and lipid profile alteration, which ultimately result in vascular endothelial dysfunction, hepatic steatosis, lipid peroxidation and apoptosis of endothelial, hepatic and neuronal cells. Terminalia catappa effectively attenuates the progression of diabetic retinopathy and shows significant hypoglycaemic actions. The mechanisms behind these effects were explained. CONCLUSION: Terminalia catappa may provide an effective natural product to treat hyperglycaemia and prevent subsequent diabetic complications. PMID- 28000230 TI - Mitochondrial capacity, muscle endurance, and low energy in friedreich ataxia. AB - INTRODUCTION: In this study we noninvasively evaluated skeletal muscle mitochondrial capacity, muscle-specific endurance, and energy/fatigue feelings in persons with Friedreich ataxia (FRDA) and able-bodied controls (AB). METHODS: Forearm mitochondrial capacity was measured in FRDA (n = 16) and AB (n = 10) study participants using the rate of recovery of oxygen consumption after electrical stimulation with near-infrared spectroscopy. Mechanomyography (MMG) assessed muscle endurance after electrical stimulation for 3 minutes at 2 Hz, 4 Hz, and 6 Hz. Validated scales assessed disease severity and energy/fatigue feelings. RESULTS: Groups did not differ in mitochondrial capacity (FRDA and AB: 1.8 +/- 0.3 L/min). The difference in muscle endurance at 6 Hz was lower by 19.2% in the FRDA group (group effect: P < 0.001). Feelings of physical energy were 34% lower in FRDA group. In FDRA muscle, endurance was positively related to mitochondrial capacity (r = 0.59, P = 0.03), and disease severity was negatively related to mitochondrial capacity (r = -0.55, P = 0.04) and muscle endurance (r = -0.60, P = 0.01). CONCLUSION: Non-invasive measures of skeletal muscle mitochondrial capacity and muscle-specific endurance are useful in monitoring FRDA. Muscle Nerve 56: 773-779, 2017. PMID- 28000231 TI - Duty hour restrictions and surgical complications for head and neck key indicator procedures. AB - OBJECTIVES/HYPOTHESIS: Graduate medical education has traditionally required long work hours, allowing trainees little time for adequate rest. Based on concerns over performance deterioration with sleep deprivation and its effect on patient outcomes, duty hour restrictions have been mandated. We sought to characterize complications from otolaryngology key indicator procedures performed before and after duty hour reform. STUDY DESIGN: Retrospective cross-sectional analysis of National Inpatient Sample (NIS). METHODS: The NIS was queried for procedure codes associated with head and neck key indicator groupings for the years 2000-2002 (45,363 procedures) and 2006-2008 (51,144 procedures). Hospitals were divided into three groups: nonteaching hospitals (NTH), teaching hospitals without otolaryngology programs (TH), and teaching hospitals with otolaryngology programs (TH-OTO). Surgical complication rates, length of stay, and mortality rates were analyzed using logistic and linear regression. RESULTS: The number of procedures increased (12.7%), with TH-OTO contributing more in postrestriction years (21% to 30%). Overall complication rates between the two periods revealed no difference, regardless of hospital setting. Subset analysis showed some variation within each complication within each grouping. Length of stay increased at TH-OTO (2.75 to 2.78 days) and decreased at NTH (2.28 to 2.24 days) and TH (2.39 to 2.36 days). Mortality did not increase among the three hospital types (NTH, P < .58; TH, P < .96; TH-OTO, P < .06). During the latter period, TH-OTO procedures showed lower mortality (P < .0038, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.27 0.77). Increasing Charlson comorbidity index increased overall mortality rate (P < .0001, OR = 2.63, 95% CI = 2.4-2.89). CONCLUSIONS: Overall complication rates did not change for head and neck key indicator procedures. Moreover, concerns about reduced surgical case numbers appear unfounded, especially for otolaryngology programs. LEVEL OF EVIDENCE: 2c Laryngoscope, 127:1797-1803, 2017. PMID- 28000232 TI - Sural neuropathy complicating ankle liposuction. PMID- 28000233 TI - Multifocal sensory demyelinating neuropathy: Report of a case. AB - INTRODUCTION: Multifocal sensory demyelinating neuropathy has not been adequately reported in the literature. METHODS: A 42-year-old man with numbness of the left hand for 3 years and of the right hand for 6 months had a pure multifocal sensory neuropathy involving both hands, most prominently affecting 2-point discrimination, number writing, and object recognition of the left hand. Near nerve needle sensory and mixed nerve conduction studies were performed on the left ulnar nerve. RESULTS: Studies of the left ulnar nerve documented a demyelinating neuropathy characterized by temporal dispersion and marked decrease in the amplitudes of the sensory and mixed compound nerve potentials in the above elbow-axilla segment. With intravenous immunoglobulin treatment, there was improvement in his neuropathic condition. CONCLUSION: In this study I describe a case of multifocal sensory demyelinating neuropathy as a counterpart of multifocal motor neuropathy. Muscle Nerve 56: 825-828, 2017. PMID- 28000234 TI - Eruptive xanthogranuloma in a healthy adult male. AB - Xanthogranuloma is a benign, non-Langerhans cell histiocytosis primarily diagnosed in infants and children, although a subset occurs in adults. Multifocal eruptive presentation of xanthogranuloma is very rare with only 4 previous cases reported in the literature to our knowledge. We describe a case of eruptive xanthogranuloma in a 49-year-old man who presented with sudden onset of numerous asymptomatic, red-yellow to orange papules on the face, scalp, axilla, flank and scrotum. Histologic features were consistent with xanthogranuloma with diffuse mixed infiltrate of foamy histiocytes, Touton giant cells and lymphocytes. Other than temporarily elevated non-fasting triglycerides, lab values have been unremarkable including serum plasma electrophoresis; however, the patient will continue to be monitored for ocular and other extracutaneous involvement and hematologic malignancies. PMID- 28000235 TI - Subcutaneous dirofilariasis: a masquerade of a palisaded granulomatous dermatitis. AB - Dirofilaria species are roundworms responsible for "heartworm" in canines. On occasion, humans are an accidental host, resulting in pulmonary (Dirofilaria immitis) or extrapulmonary (Dirofilaria repens) manifestations. Of the extrapulmonary sites of involvement, subcutaneous involvement is particularly common. We report a case of a 49-year-old female who presented with an erythematous nodule on her shin, which closely resembled necrobiosis lipoidica on histopathologic examination. On closer examination, there were foci of necrosis that harbored segments of the nematode, diagnostic of dirofiliarisis. We present this case to highlight the histopathologic similarities and differences between palisaded necrobiotic conditions and this potentially underrecognized entity. PMID- 28000236 TI - Optimism moderates psychophysiological responses to stress in older people with Type 2 diabetes. AB - Optimism is thought to be beneficial for health, and these effects may be mediated through modifications in psychophysiological stress reactivity. Type 2 diabetes (T2D) is associated with reduced cardiovascular responses to stress and heightened cortisol over the day. This study assessed the relationships between optimism, stress responsivity, and daily cortisol output in people with T2D. A total of 140 participants with T2D were exposed to laboratory stress. Heart rate (HR), systolic (SBP), diastolic blood pressure (DBP), and cortisol were measured throughout the session. Cortisol output over the day was also assessed. Optimism and self-reported health were measured using the revised Life Orientation Test and the Short Form Health Survey. Optimism was associated with heightened SBP and DBP stress reactivity (ps < .047) and lower daily cortisol output (p = .04). Optimism was not related to HR, cortisol stress responses, or the cortisol awakening response (ps > .180). Low optimism was related to poorer self-reported physical and mental health (ps < .01). Optimism could have a protective role in modulating stress-related autonomic and neuroendocrine dysregulation in people with T2D. PMID- 28000237 TI - Predictors of length of stay, reoperation, and readmission following total laryngectomy. AB - OBJECTIVES/HYPOTHESIS: To identify relevant patient and surgical risk factors associated with prolonged length of stay, return to the operating room, and readmission within 30 days following total laryngectomy using the American College of Surgeons National Quality Improvement Program (ACS-NSQIP) STUDY DESIGN: Retrospective database study. Patients undergoing total laryngectomy alone for laryngeal cancer were identified from the ACS-NSQIP database from 2005 to 2014. METHODS: Multivariate logistic regression was used to identify independent predictors for prolonged length of stay, readmissions, and unplanned reoperations within 30 days. RESULTS: Among 871 patients meeting inclusion and exclusion criteria, the median length of stay was 8.0 days (range, 0-130 days). Totally dependent functional status (P < .01; odds ratio [OR]: 32.62), Black or African American race (P = .029; OR: 1.75), and operative time (P < .0001; OR: 1.15) were associated with prolonged length of stay. The overall rate of return to the operating room within 30 days was 12.4%. Contaminated wound status (P = .025; OR: 3.53), operative time (P = .015; OR: 1.10), steroid use (P < .01; OR: 2.92), and smoking (P = .05; OR: 1.60) were significantly associated with return to the operating room. Unplanned readmission rate was 11.9%, and 47.37% of readmissions were due to wound infection/pharyngocutaneous fistula. Dirty/contaminated wound classification (P = .05; OR: 22.5) was associated with readmission on multivariate analysis. CONCLUSIONS: This is the first population level analysis to be performed on length of stay, readmission, and reoperation for total laryngectomy. Assessing and identifying modifiable risk factors on quality metrics may reduce overall cost and the burden on limited hospital resources. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1339-1344, 2017. PMID- 28000238 TI - "Falls prevention among older people and care providers: protocol for an integrative review". AB - AIM: To review the evidence about the role of care providers in fall prevention in older adults aged >= 65 years, this includes their views, strategies, and approaches on falls prevention and effectiveness of nursing interventions. BACKGROUND: Some fall prevention programmes are successfully implemented and led by nurses and it is acknowledged the vital role they play in developing plans for fall prevention. Nevertheless, there has not been a systematic review of the literature that describes this role and care providers' views on fall's prevention initiatives. DESIGN: A convergent synthesis of qualitative, quantitative, and mixed methods studies. The eligibility criteria will be based on participants, interventions/exposure, comparisons, and outcomes for quantitative studies and on population, the phenomena of interest and the context, for qualitative studies. To extract data and assess study qualities members of the research team will work in pairs according to their expertise. The review will follow the guidelines for integrative reviews and the proposed methods will adhere to the PRISMA statement checklist complemented by the ENTREQ framework. As qualitative synthesis are emergent, all procedures and changes in procedure will be documented. DISCUSSION: The review has a constructivist drive as studies that combine methods ought to be paradigmatic driven. Review questions are broad to allow issues emerge and have purposefully left the design flexible to allow for adjustments as the review progresses. The review seeks to highlight the roles that care providers play in fall prevention and their views on fall's prevention initiatives. PMID- 28000239 TI - Aggressive Behaviour Risk Assessment Tool for newly admitted residents of long term care homes. AB - AIM: The aim of this study was to revise the 10-item Aggressive Behaviour Risk Assessment Tool for predicting aggressive events among residents newly admitted to long-term care homes. BACKGROUND: The original tool had acceptable sensitivity and specificity for identifying potentially aggressive patients in acute care medical-surgical units, but its usefulness in long-term care homes is unknown. DESIGN: A retrospective cohort study design was used. METHODS: All residents admitted to 25 long-term care homes in western Canada were assessed for the risk of aggression using the original tool within 24 hours of admission from January 2014 - December 2014 (n = 724). Incident reports of aggressive events occurring within 30 days of admission were collected. Multiple logistic regression and receiver operating characteristics analyses were performed. RESULTS: Fifty-three residents of 724 exhibited aggressive behaviours. The demographic variable of age less than 85 years was found to be a positive predictor of aggressive events in multivariate logistic regression model and was added to the tool. The revised six item Aggressive Behaviour Risk Assessment Tool for Long-Term Care consists of one new item, age less than 85 years and five items from the original tool: History of physical aggression, physically aggressive/threatening, anxiety, confusion/cognitive impairment and threatening to leave. The receiver operating characteristics of the revised tool with weighted scoring showed a good discriminant ability with satisfactory sensitivity and specificity at the recommended cut-off score of 4. CONCLUSION: The revised six-item tool may be useful in identifying potentially aggressive residents newly admitted to long term care homes. PMID- 28000240 TI - Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. AB - Nivolumab is a programmed cell death receptor-1 (PD-1) antibody used in the treatment of metastatic or unresectable melanoma. Cutaneous reactions are the most common adverse events reported with these agents and are rarely severe or life-threatening. Here we present a case report describing the clinicopathological findings of a patient with a fatal toxic epidermal necrolysis (TEN) eruption associated with use of nivolumab for treatment of metastatic melanoma. The patient developed a pruritic, morbiliform eruption, which slowly progressed over 3 months to a tender, exfoliative dermatosis. Histology initially showed interface dermatitis and subsequently revealed full thickness epidermal necrosis. The diagnosis of TEN was made. From initial biopsy to TEN presentation, there was an increase in the number of CD8+ lymphocytes within the dermal epidermal junction and an increase of programmed death ligand 1 (PD-L1) expression in both lymphocytes and keratinocytes. Despite treatment with infliximab, high-dose steroids and intravenous immunoglobulin, the patient expired. Herein we describe what we believe is the second case of TEN associated with anti-PD1 therapy reported in the literature. Increased expression of PD-L1 by immunohistochemistry was observed as the eruption progressed to TEN. Early diagnosis and treatment is necessary in these fatal TEN reactions secondary to the anti-PD-1 antibody therapies. PMID- 28000241 TI - Goals of care: a concept clarification. AB - AIM: To report an analysis and clarification of the concept of goals of care. BACKGROUND: Goals of care have been used by healthcare providers since 1978, but no operationalized, consensual definition exists. DESIGN: Norris's method of concept clarification was used to create an operational definition, conceptual model and testable hypotheses of goals of care from the healthcare provider's perspective. DATA SOURCES: Data came from current research reports, interviews with experts and web sites of professional organizations. Research reports were published between 2003-2013. METHODS: Antecedents, definitions and consequences were systematized and organized into coherent and more abstract groups to define goals of care. A conceptual model and testable hypotheses were created from this process. RESULTS: Goals of care are desired health expectations that are formulated through the thoughtful interaction between a human being seeking medical care and the healthcare team in the healthcare system and are appropriate, agreed on, documented and communicated. CONCLUSIONS: Development of clear goals of care can increase patient satisfaction and quality of care while decreasing costs, hospital length of stay and hospital readmission. Goals of care are dynamic and should be reassessed regularly. How and when goals of care transition from implicit to explicit should be explored further, and what prompts this transition. Nurses, physicians and healthcare providers need education on how to best fill their roles in the development of goals of care. PMID- 28000242 TI - The concept of exposure in environmental health for nursing. AB - AIM: To report an analysis of the concept of exposure in environmental health for nursing. BACKGROUND: The importance of the environment has long been recognized in nursing, although the nature and scope of the concept and how it influences health have varied over time. Exposure is the sufficient and necessary link between environment and health. In nursing practice, the word 'exposure' has been used frequently with no clear standard definition. DESIGN: Concept analysis using Kim's first-level analytics. DATA SOURCES: Chronological review (1980-2015) of the nursing science literature was conducted through ProQuest Dissertations and Theses and CINAHL, followed by a multi-disciplinary search through PubMed (1980 2015), texts and the Internet to compare definitions and measurements of exposure and related concepts. METHODS: Explicit and implicit conceptual definitions and measurements of exposure were identified, categorized and analysed. RESULTS: The newly defined concept of 'exposure' is a process involves three phases: 1, contact is made between a target and one or more agents in the same environment; 2, the agent accesses the target by one or more routes of entry; and 3, the agent enters the target by crossing a barrier or boundary. Existing measurements related to each phase are identified and discussed. Definitions of 'target' and 'agent' were refined for congruency. CONCLUSION: Consistent use of terms as defined is critical to development of nursing knowledge. These concepts should be incorporated into nursing-related research to evaluate their usefulness to nursing. Alignment of this concept with relevant theories should be critically examined. PMID- 28000243 TI - Values in families with young children: Insights from two cultural milieus in Germany. AB - Are children's value priorities different from their parents' generation? We present data from the youngest children's sample that has been included in a comprehensive family study of values so far: Our study is based on self-reported values of 127 six- to eleven-year-old German children (M = 7.89, SD = 1.35) and their mothers and fathers. We further took into account two potentially interacting developmental variables that have been suggested in the literature: (a) family members' gender and (b) cultural milieu (we looked specifically at families with Turkish immigration background and families without immigration background). While values of self-transcendence, self-enhancement and openness to change did not differ significantly between the two generations, children found conservation significantly more important than their parents. This contrasts with findings from previous studies with older participants. We discuss to what extent this effect may be unique to this developmental stage of middle childhood that had not been covered by previous research. Females valued conservation more than males, and conservation was more important in families with as compared to families without Turkish immigration background. There was neither a gender * generation nor a cultural milieu * generation interaction. PMID- 28000244 TI - Sensitivity and specificity of multispectral imaging in detecting central serous chorioretinopathy. AB - BACKGROUND AND OBJECTIVE: Central serous chorioretinopathy (CSCR) is a common and idiopathic retinal disorder that affects young to middle aged adults. The aim of this study was to describe the characteristics of eyes with CSCR using a light emitting diode (LED)-based multispectral imaging (MSI) system and to evaluate the diagnostic reliability of MSI compared to fluorescein angiography (FA) in detecting CSCR. MATERIALS AND METHODS: A total of 56 eyes among 52 patients with 1 or more retinal pigment epithelium (RPE) abnormality were retrospectively enrolled in the study. The patients underwent complete examination, including optical coherence tomography, FA, indocyanine-green angiography, and MSI. MSI images were retrospectively reviewed by experienced masked graders. Diagnoses that were made based on MSI alone were compared with those that were made using FA. Sensitivity and specificity were calculated, and the morphological features on MSI were summarized. RESULTS: Among 56 eyes in 52 patients, MSI detected 22 of 26 true-positive CSCR cases but missed 4 FA-confirmed lesions. Further, it correctly excluded 30 of 30 non-CSCR lesions. The sensitivity and specificity of MSI were 84.6 and 100%, respectively, for identifying CSCR. Using MSI, RPE leakage was observed in 25 (96.2%) of 26 eyes with CSCR, which was comparable to the performance of FA. Dome-shaped areas of signal, which corresponded to fluid accumulation associated with neurosensory retinal detachment or RPE detachment were observed in 23 (88.5%) of 26 eyes. CONCLUSIONS: As a non-invasive technique, MSI permitted the visualization of RPE leakage and neurosensory detachment and allowed good detection of CSCR in this selected clinical population. Lasers Surg. Med. 49:498-505, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000245 TI - Hidradenitis suppurativa association at the time of, or subsequent to, diagnosis of inflammatory bowel disease in a large U.S. patient population. PMID- 28000246 TI - A growing nodule on the forearm of an 84-year-old man. PMID- 28000247 TI - Investigation of nutritional status using the Mini Nutritional Assessment-Short Form and analysis of the relevant factors in patients with head and neck tumour. AB - OBJECTIVE: The aims of this study were to reveal the nutritional status of patients after head and neck tumour treatment by using the Mini Nutritional Assessment-Short Form (MNA-SF) and to analyse the factors affecting nutritional status in patients with head and neck tumour. BACKGROUND: Elderly patients with loss of teeth and maxillary/mandibular bone due to head and neck tumour treatment could be at high risk of malnutrition. However, there are few reports on the nutritional status of these patients. MATERIALS AND METHODS: Forty-six participants (average age 74.7 years) were selected from patients who visited the maxillofacial prosthetics clinic of Tokyo Medical and Dental University Hospital Faculty of Dentistry in Japan. Nutritional status was evaluated using the MNA-SF. Multiple regression analysis was used to identify predictors affecting MNA-SF score. The candidate explanatory variables were age, sex, maxillofacial prosthesis use, number of residual teeth, resection side, neck dissection and treatment option. RESULTS: The results showed that approximately half of the patients were at risk of malnutrition, and a regression equation for MNA-SF score was developed using two predictors: maxillofacial prosthesis use and neck dissection. CONCLUSION: Use of a maxillofacial prosthesis can improve nutritional status. On the other hand, a medical history of neck dissection can decrease nutritional status. PMID- 28000248 TI - The State of The Laryngoscope: 2017. PMID- 28000249 TI - Amicrobial pustulosis of the folds: Report of 4 cases. AB - Amicrobial pustulosis of the folds (APF) is a rare disease characterized by aseptic pustular lesions involving cutaneous folds, typically occurring in the context of an autoimmune disorder. We present 4 patients with APF, focusing on clinical and histopathologic characteristics to improve the recognition of this entity. All 4 patients had intertriginous and extra-intertriginous involvement. Common histopathologic features of skin biopsies in these patients were intracorneal, subcorneal, intraepidermal, perivascular, perifollicular and interstitial neutrophilic inflammation. Pustules overlying adnexal ostium and papillary dermal edema were consistently observed. The pustules were negative for microorganisms on stain testing. In these cases, associated conditions were undifferentiated connective tissue disease, systemic lupus erythematosus, antiphospholipid syndrome, Crohn disease and Hashimoto thyroiditis. The aforementioned clinical and histopathologic characteristics of patients with suspected or diagnosed connective tissue disorders should lead to suspicion for APF. PMID- 28000250 TI - Data-driven region-of-interest selection without inflating Type I error rate. AB - In ERP and other large multidimensional neuroscience data sets, researchers often select regions of interest (ROIs) for analysis. The method of ROI selection can critically affect the conclusions of a study by causing the researcher to miss effects in the data or to detect spurious effects. In practice, to avoid inflating Type I error rate (i.e., false positives), ROIs are often based on a priori hypotheses or independent information. However, this can be insensitive to experiment-specific variations in effect location (e.g., latency shifts) reducing power to detect effects. Data-driven ROI selection, in contrast, is nonindependent and uses the data under analysis to determine ROI positions. Therefore, it has potential to select ROIs based on experiment-specific information and increase power for detecting effects. However, data-driven methods have been criticized because they can substantially inflate Type I error rate. Here, we demonstrate, using simulations of simple ERP experiments, that data-driven ROI selection can indeed be more powerful than a priori hypotheses or independent information. Furthermore, we show that data-driven ROI selection using the aggregate grand average from trials (AGAT), despite being based on the data at hand, can be safely used for ROI selection under many circumstances. However, when there is a noise difference between conditions, using the AGAT can inflate Type I error and should be avoided. We identify critical assumptions for use of the AGAT and provide a basis for researchers to use, and reviewers to assess, data-driven methods of ROI localization in ERP and other studies. PMID- 28000251 TI - Considering ERP difference scores as individual difference measures: Issues with subtraction and alternative approaches. AB - There is growing interest in psychophysiological and neural correlates of psychopathology, personality, and other individual differences. Many studies correlate a criterion individual difference variable (e.g., anxiety) with a psychophysiological measurement derived by subtracting scores taken from two within-subject conditions. These subtraction-based difference scores are intended to increase specificity by isolating variability of interest. Using data on the error-related negativity (ERN) and correct response negativity (CRN) in relation to generalized anxiety disorder (GAD), we highlight several conceptual and practical issues with subtraction-based difference scores and propose alternative approaches based on regression. We show that ERN and CRN are highly correlated, and that the DeltaERN (i.e., ERN - CRN) is correlated in opposite directions both with ERN and CRN. Bivariate analyses indicate that GAD is related to DeltaERN and ERN, but not CRN. We first show that, by using residualized scores, GAD relates both to a larger ERN and smaller CRN. Moreover, by probing the interaction of ERN and CRN, we show that the relationship between GAD and ERN varies by CRN. These latter findings are not evident when using traditional subtraction-based difference scores. We then completed follow-up analyses that suggested that an increased P300 in anxious individuals gave rise to the apparent anxiety/CRN relationship observed. These findings have important conceptual implications for facilitating the interpretability of results from individual difference studies of psychophysiology. PMID- 28000252 TI - Dealing with ocular artifacts on lateralized ERPs in studies of visual-spatial attention and memory: ICA correction versus epoch rejection. AB - The objective of the present study was to assess the robustness and reliability of independent component analysis (ICA) as a method for ocular artifact correction in electrophysiological studies of visual-spatial attention and memory. The N2pc and sustained posterior contralateral negativity (SPCN), electrophysiological markers of visual-spatial attention and memory, respectively, are lateralized posterior ERPs typically observed following the presentation of lateral stimuli (targets and distractors) along with instructions to maintain fixation on the center of the visual search for the entire trial. Traditionally, trials in which subjects may have displaced their gaze are rejected based on a cutoff threshold, minimizing electrophysiological contamination by saccades. Given the loss of data resulting from rejection, we examined ocular correction by comparing results using standard fixation instructions against a condition where subjects were instructed to shift their gaze toward possible targets. Both conditions were analyzed using a rejection threshold and ICA correction for saccade activity management. Results demonstrate that ICA conserves data that would have otherwise been removed and leaves the underlying neural activity intact, as demonstrated by experimental manipulations previously shown to modulate the N2pc and the SPCN. Not only does ICA salvage and not distort data, but also large eye movements had only subtle effects. Overall, the findings provide convincing evidence for ICA correction for not only special cases (e.g., subjects did not follow fixation instruction) but also as a candidate for standard ocular artifact management in electrophysiological studies interested in visual-spatial attention and memory. PMID- 28000253 TI - How to get statistically significant effects in any ERP experiment (and why you shouldn't). AB - ERP experiments generate massive datasets, often containing thousands of values for each participant, even after averaging. The richness of these datasets can be very useful in testing sophisticated hypotheses, but this richness also creates many opportunities to obtain effects that are statistically significant but do not reflect true differences among groups or conditions (bogus effects). The purpose of this paper is to demonstrate how common and seemingly innocuous methods for quantifying and analyzing ERP effects can lead to very high rates of significant but bogus effects, with the likelihood of obtaining at least one such bogus effect exceeding 50% in many experiments. We focus on two specific problems: using the grand-averaged data to select the time windows and electrode sites for quantifying component amplitudes and latencies, and using one or more multifactor statistical analyses. Reanalyses of prior data and simulations of typical experimental designs are used to show how these problems can greatly increase the likelihood of significant but bogus results. Several strategies are described for avoiding these problems and for increasing the likelihood that significant effects actually reflect true differences among groups or conditions. PMID- 28000254 TI - High and dry? Comparing active dry EEG electrodes to active and passive wet electrodes. AB - Dry electrodes are becoming popular for both lab-based and consumer-level electrophysiological-recording technologies because they better afford the ability to move traditional lab-based research into the real world. It is unclear, however, how dry electrodes compare in data quality to traditional electrodes. The current study compared three EEG electrode types: (a) passive-wet electrodes with no onboard amplification, (b) actively amplified, wet electrodes with moderate impedance levels, and low impedance levels, and (c) active-dry electrodes with very high impedance. Participants completed a classic P3 auditory oddball task to elicit characteristic EEG signatures and event-related potentials (ERPs). Across the three electrode types, we compared single-trial noise, average ERPs, scalp topographies, ERP noise, and ERP statistical power as a function of number of trials. We extended past work showing active electrodes' insensitivity to moderate levels of interelectrode impedance when compared to passive electrodes in the same amplifier. Importantly, the new dry electrode system could reliably measure EEG spectra and ERP components comparable to traditional electrode types. As expected, however, dry active electrodes with very high interelectrode impedance exhibited marked increases in single-trial and average noise levels, which decreased statistical power, requiring more trials to detect significant effects. This power decrease must be considered as a trade-off with the ease of application and long-term use. The current results help set constraints on experimental design with novel dry electrodes, and provide important evidence needed to measure brain activity in novel settings and situations. PMID- 28000255 TI - Combating the scientific decline effect with confidence (intervals). AB - A symptom of the need for greater reproducibility in scientific practice is the decline effect-the fact that the size of many experimental effects decline with subsequent study or fail to replicate entirely. A simple way to combat this problem is for scientists to more routinely use confidence intervals (CIs) in their work. CIs provide frequentist bounds on the true size of an effect and can reveal when a statistically significant effect is possibly too small to be reliable or when a large effect might have been missed due to insufficient statistical power. CIs are often lacking in psychophysiological reports, likely due to the large number of dependent variables, which complicates deriving and visualizing CIs. In this article, I explain the value of CIs and show how to compute them for analyses involving multiple variables in various ways that adjust the intervals for the greater uncertainty induced by multiple statistical comparisons. The methods are illustrated using a basic visual oddball ERP dataset and freely available MATLAB software. PMID- 28000256 TI - Reliability of graph metrics derived from resting-state human EEG. AB - It is increasingly appreciated that a complete description of brain functioning will necessarily involve the characterization of large-scale interregional temporal synchronization of neuronal assemblies. The need to capture the dynamic formation of such large-scale networks has yielded a renewed interest in the human EEG in combination with a suite of methods for estimating functional connectivity along with the graph theoretical approaches for characterizing network structure. While initial work has established generally good reproducibility for a limited selection of these graph theoretical measures, there remains an obvious need to document the reproducibility of a more extensive array of commonly used graph metrics. We sought to evaluate the test-retest reliability of a much richer suite of graph theoretic measures as applied to weighted networks derived from high-density resting-state human EEG. Our findings were promising overall, with some important qualifications when considering the frequency bands of interest and the method used to calculate functional connectivity as well as some substantial variance between individual graph metrics. In general, the reliability of networks in the alpha and beta frequency bands was improved when functional connectivity was defined solely on the basis of relative phase distributions. In the delta and theta bands, reliability was substantially better when functional connectivity was based on coherence, which incorporates both phase and amplitude information. PMID- 28000257 TI - Psychometric properties of startle and corrugator response in NPU, affective picture viewing, and resting state tasks by Jesse T. Kaye, Daniel E. Bradford, and John J. Curtin (Erratum). PMID- 28000258 TI - Introduction to the special issue on recentering science: Replication, robustness, and reproducibility in psychophysiology. AB - In recent years, the psychological and behavioral sciences have increased efforts to strengthen methodological practices and publication standards, with the ultimate goal of enhancing the value and reproducibility of published reports. These issues are especially important in the multidisciplinary field of psychophysiology, which yields rich and complex data sets with a large number of observations. In addition, the technological tools and analysis methods available in the field of psychophysiology are continually evolving, widening the array of techniques and approaches available to researchers. This special issue presents articles detailing rigorous and systematic evaluations of tasks, measures, materials, analysis approaches, and statistical practices in a variety of subdisciplines of psychophysiology. These articles highlight challenges in conducting and interpreting psychophysiological research and provide data-driven, evidence-based recommendations for overcoming those challenges to produce robust, reproducible results in the field of psychophysiology. PMID- 28000260 TI - A test-retest reliability analysis of diffusion measures of white matter tracts relevant for cognitive control. AB - Recent efforts to replicate structural brain-behavior correlations have called into question the replicability of structural brain measures used in cognitive neuroscience. Here, we report an evaluation of test-retest reliability of diffusion tensor imaging (DTI) measures, including fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, in several white matter tracts previously shown to be involved in cognitive control. In a data set consisting of 34 healthy participants scanned twice on a single day, we observe overall stability of DTI measures. This stability remained in a subset of participants who were also scanned a third time on the same day as well as in a 2 week follow-up session. We conclude that DTI measures in these tracts show relative stability, and that alternative explanations for the recent failures of replication must be considered. PMID- 28000261 TI - The science pendulum: From programmatic to incremental-and back? AB - The climate in which scientific research is conducted changes over time, and in recent years there has been a shift from a positive view of programmatic science to a more negative evaluation that its contribution to scientific progress is only incremental. In this special issue focusing on the tools of a programmatic approach-replication, reliability and reproducibility-I reflect on changes in scientific practice over my research career, considering some factors contributing to changes in emphasis and highlighting potential pitfalls, particularly in terms of the impact on scientific progress and future scientists. In concluding, I suggest that, as members of the scientific community, we can influence current scientific practices in our day-to-day roles as authors, reviewers, investigators, editors, employers, and educators. PMID- 28000259 TI - Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response. AB - Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response. PMID- 28000262 TI - Optimal measurements of hemodynamic response latency in fNIRS using the jackknife approach. AB - Functional near-infrared spectroscopy (fNIRS) permits measurements of changes in the concentration of oxygenated and deoxygenated hemoglobin, typically with a higher sampling rate than with other imaging methods based on the hemodynamic response. We examined the potential of the fNIRS technique to estimate variations in the latency of hemodynamic responses to experimental events and sought optimal methods to maximize the reliability and reproducibility of latency effects. We used Monte Carlo simulations using subsamples of real fNIRS measures to estimate the statistical power of different approaches (such as fixed threshold, percent of peak, fractional-area latency, for both individual-subject estimates and estimates from jackknife averages) to detect a known simulated latency shift. The simulations used measures of hemodynamic responses in the temporal lobe from two groups of young adult participants who listened to auditory stimuli, one with a blocked presentation design and one with an event-related design. We estimated the relative sensitivity of different latency measures and approaches to the measurement of latency effects of different magnitudes using realistic noise and signal-to-noise characteristics. In general, the jackknife approach provided the greatest statistical power to detect a known latency shift, without inflation of Type I error. PMID- 28000263 TI - Reliability of surface facial electromyography. AB - Data from two studies were used to estimate the reliability of facial EMG when used to index facial mimicry (Study 1) or affective reactions to pictorial stimuli (Study 2). Results for individual muscle sites varied between muscles and depending on data treatment. For difference scores, acceptable internal consistencies were found only for corrugator supercilii, and test-retest reliabilities were low. For contrast measures describing patterns of reactions to stimuli, such as high zygomaticus major combined with low corrugator supercilii, acceptable internal consistencies were found for facial reactions to smiling faces and positive affective reactions to affiliative images (Study 2). Facial reactions to negative emotions (Study 1) and facial reactions to power and somewhat less to achievement imagery (Study 2) showed unsatisfactory internal consistencies. For contrast measures, good temporal stability over 24 months (Study 1) and 15 months (Study 2), respectively, was obtained. In Study 1, the effect of method factors such as mode of presentation was more reliable than the emotion effect. Overall, people's facial reactions to affective stimuli seem to be influenced by a variety of factors other than the emotion-eliciting element per se, which resulted in biased internal consistency estimates. However, the influence of these factors in turn seemed to be stable over time. PMID- 28000265 TI - An evaluation of human ADME and mass balance studies using regular or low doses of radiocarbon. AB - There has been increased interest in conducting human absorption, distribution, metabolism, and excretion (ADME) studies with low doses (up to 0.1 MBq) as opposed to regular doses (1.85-3.7 MBq) of radiocarbon (14 C). This is due to the fact that low-dose human ADME studies may be conducted without dosimetry calculations and will lead to lower human radiation exposure. Here, we sought to compare the outcomes of low-dose versus regular-dose human ADME studies in healthy volunteers. Forty oral human ADME studies conducted at PRA were surveyed, among which 12 were low-dose studies. The fraction of drug material absorbed was 67% +/- 7% in the regular-dose studies (data for 13 studies) versus 39% +/- 16% in the low-dose studies (data for 5 studies). The average total recovery of 14 C in excreta was 93% +/- 5% for regular-dose studies, and 21 of 28 such studies showed recoveries more than 90%. For low-dose studies, average total recovery was 89% +/- 9%, and 6 of 12 studies showed recoveries more than 90%. Metabolite profiling was successful in all cases reported (13 regular-dose studies and 5 low dose studies). There was no obvious relationship between the total recoveries of 14 C in excreta and the proportion of 14 C excreted in feces, or between the total recoveries and the plasma elimination half-lives for parent or total 14 C, neither in the low-dose nor the regular-dose studies. A significant correlation was found between the fraction absorbed and the recovery in feces in the low-dose but not in the regular-dose studies, and no correlation was found between the fractions absorbed and the total recoveries in both types of studies. Low-dose studies were more often conducted on drugs that had a plasma elimination half life of parent drug more than 100 hours (5 of 12 studies) than regular-dose studies (1 of 26 studies). We conclude that both low-dose as well as regular-dose human ADME studies provide adequate data to support decision making for further drug development. PMID- 28000264 TI - Assessing the internal consistency of the event-related potential: An example analysis. AB - ERPs are widely and increasingly used to address questions in psychophysiological research. As discussed in this special issue, a renewed focus on questions of reliability and stability marks the need for intuitive, quantitative descriptors that allow researchers to communicate the robustness of ERP measures used in a given study. This report argues that well-established indices of internal consistency and effect size meet this need and can be easily extracted from most ERP datasets, as demonstrated with example analyses using a representative dataset from a feature-based visual selective attention task. We demonstrate how to measure the internal consistency of three aspects commonly considered in ERP studies: voltage measurements for specific time ranges at selected sensors, voltage dynamics across all time points of the ERP waveform, and the distribution of voltages across the scalp. We illustrate methods for quantifying the robustness of experimental condition differences, by calculating effect size for different indices derived from the ERP. The number of trials contributing to the ERP waveform was manipulated to examine the relationship between signal-to-noise ratio (SNR), internal consistency, and effect size. In the present example dataset, satisfactory consistency (Cronbach's alpha > 0.7) of individual voltage measurements was reached at lower trial counts than were required to reach satisfactory effect sizes for differences between experimental conditions. Comparing different metrics of robustness, we conclude that the internal consistency and effect size of ERP findings greatly depend on the quantification strategy, the comparisons and analyses performed, and the SNR. PMID- 28000266 TI - Zirconia dental implants: where are we now, and where are we heading? AB - Despite decades of titanium as the gold standard in oral implantology, the search for alternatives has been growing. High esthetic standards and increasing incidence of titanium allergies, along with a rising demand for metal-free reconstructions, have led to the proposal of ceramics as potential surrogates. Following numerous experimental studies, zirconium dioxide (zirconia) has earned its place as a potential substitute for titanium in implantology. Yet, despite zirconia's excellent biocompatibility and tissue integration, low affinity to plaque and favorable biomechanical properties, early failures were significantly higher for zirconia implants than for titanium implants. Technical failure as a result of fracture of the material is also a major concern. So far, zirconia implants have been mainly manufactured as one-piece implant systems because of the material's limitations. Nevertheless, various two-piece systems have been progressively emerging with promising results. Screw-retained abutments are desirable but present a major technical challenge. Innovation and technical advances will undoubtedly lead to further improvement in the reliability and strength of zirconia implants, allowing for novel designs, connections and reconstructions. Additional clinical studies are required to identify all relevant technical and biological factors affecting implant success and patients' satisfaction. However, the evidence for a final verdict is, at present, still incomplete. PMID- 28000267 TI - Reliability of periodontal diagnostic tools for monitoring peri-implant health and disease. AB - The prevalence, causes and consequences of crestal bone loss at dental implants are a matter of debate. In recent years, a high prevalence of peri-implant soft tissue inflammation, associated with peri-implant bone loss, has been reported and the need for treatments similar to those offered for natural teeth affected by periodontitis has been proposed. This suggestion is based on the assumption that periodontal indices, such as probing pocket depth and bleeding on probing, are reliable indicators of the peri-implant tissue conditions and good predictors of future bone loss. However, based on a critical review of the literature in the present paper, it is concluded that periodontal indices are not reliable either for identifying peri-implant disease or for predicting future risk for peri implant crestal bone loss and implant failure. The long-term experiences with dental implants, presented in the literature, indicate that the presence of bleeding on probing, probing pocket depths much larger than 4 mm and some bone loss seem to reflect, in most instances, normal conditions of well-functioning dental implants, bearing in mind that healing of dental implants is the result of a foreign body reaction with the formation of scar tissue. Therefore, the use of probing pocket depth and bleeding on probing assessments may lead to over diagnosis and possibly to over-treatment of assumed biofilm-mediated peri implantitis lesions. It is the opinion of the authors of this review that a treatment should only be initiated when a clinical problem is present based on patient's symptoms (discomfort, pain), the presence of swelling, redness and pus, and significant crestal bone loss over time (as verified with radiographs). The treatment should aim at resolving the infection, which could include removal of the implant. PMID- 28000268 TI - Implants for elderly patients. AB - In the developed world, the large birth cohorts of the so-called baby boomer generation have arrived in medical and dental practices. Often, elderly patients are 'young-old' baby boomers in whom partial edentulism is the predominant indication for implant therapy. However, the generation 85+ years of age represents a new challenge for the dental profession, as their lives are frequently dominated by dependency, multimorbidity and frailty. In geriatric implant dentistry, treatment planning is highly individualized, as interindividual differences become more pronounced with age. Nevertheless, there are four typical indications for implant therapy: (i) avoidance of removable partial prostheses; (ii) preservation of existing removable partial prostheses; (iii) stabilization of Kennedy Class I removable partial prostheses; and (iv) stabilization of complete prostheses. From a surgical point of view, two very important aspects must be considered when planning implant surgery in elderly patients: first, the consistent strive to minimize morbidity; and, second, the fact that coexisting medical risk factors are significantly more common in elderly patients. Modern three-dimensional cone beam computed tomography imaging is often indicated in order to plan minimally invasive implant surgery. Computer assisted implant surgery might allow flapless implant surgery, which offers a low level of postoperative morbidity and a minimal risk of postsurgical bleeding. Short and reduced-diameter implants are now utilized much more often than a decade ago. Two-stage surgical procedures should be avoided in elderly patients. Implant restorations for elderly patients should be designed so that they can be modified to become low-maintenance prostheses, or even be removed, as a strategy to facilitate oral hygiene and comfort in the final stage of life. PMID- 28000269 TI - Implant surface roughness and patient factors on long-term peri-implant bone loss. AB - Dental implant placement is a common treatment procedure in current dental practice. High implant survival rates as well as limited peri-implant bone loss has been achieved over the past decades due to continuous modifications of implant design and surface topography. Since the turn of the millennium, implant surface modifications have focused on stronger and faster bone healing. This has not only yielded higher implant survival rates but also allowed modifications in surgical as well as prosthetic treatment protocols such as immediate implant placement and immediate loading. Stable crestal bone levels have been considered a key factor in implant success because it is paramount for long-term survival, aesthetics as well as peri-implant health. Especially during the past decade, clinicians and researchers have paid much attention to peri-implant health and more specifically to the incidence of bone loss. This could furthermore increase the risk for peri-implantitis, the latter often diagnosed as ongoing bone loss and pocket formation beyond the normal biological range in the presence of purulence or bleeding on probing. Information on the effect of surface topography on bone loss or peri-implantitis, a disease process that is to be evaluated in the long-term, is also scarce. Therefore, the current narrative review discusses whether long-term peri-implant bone loss beyond physiological bone adaptation is affected by the surface roughness of dental implants. Based on comparative studies, evaluating implants with comparable design but different surface roughness, it can be concluded that average peri-implant bone loss around the moderately rough and minimally rough surfaces is less than around rough surfaces. However, due to the multifactorial cause for bone loss the clinical impact of surface roughness alone on bone loss and peri-implantitis risk seems rather limited and of minimal clinical importance. Furthermore, there is growing evidence that certain patient factors, such as a history of periodontal disease and smoking, lead to more peri-implant bone loss. PMID- 28000270 TI - Use of cone beam computed tomography in implant dentistry: current concepts, indications and limitations for clinical practice and research. AB - Diagnostic radiology is an essential component of treatment planning in the field of implant dentistry. This narrative review will present current concepts for the use of cone beam computed tomography imaging, before and after implant placement, in daily clinical practice and research. Guidelines for the selection of three dimensional imaging will be discussed, and limitations will be highlighted. Current concepts of radiation dose optimization, including novel imaging modalities using low-dose protocols, will be presented. For preoperative cross sectional imaging, data are still not available which demonstrate that cone beam computed tomography results in fewer intraoperative complications such as nerve damage or bleeding incidents, or that implants inserted using preoperative cone beam computed tomography data sets for planning purposes will exhibit higher survival or success rates. The use of cone beam computed tomography following the insertion of dental implants should be restricted to specific postoperative complications, such as damage of neurovascular structures or postoperative infections in relation to the maxillary sinus. Regarding peri-implantitis, the diagnosis and severity of the disease should be evaluated primarily based on clinical parameters and on radiological findings based on periapical radiographs (two dimensional). The use of cone beam computed tomography scans in clinical research might not yield any evident beneficial effect for the patient included. As many of the cone beam computed tomography scans performed for research have no direct therapeutic consequence, dose optimization measures should be implemented by using appropriate exposure parameters and by reducing the field of view to the actual region of interest. PMID- 28000271 TI - Sinus floor elevation procedures to enable implant placement and integration: techniques, biological aspects and clinical outcomes. AB - Implant treatment in an atrophied edentulous posterior maxilla constitutes a challenge for the therapeutic team. The authors of the present study acknowledge that modern micro-rough surface implants in lengths of about 8-10 mm or longer and of different brands are similarly successful. Consequently, the authors propose that the use of different sinus floor elevation techniques should be considered when < 8 mm of bone is available below the maxillary sinus. The type of sinus floor elevation technique selected is mainly based on residual vertical bone height, marginal bone width, local intrasinus anatomy and the number of teeth to be replaced, although other factors (such as surgical training and surgical experience) may have an impact. It is proposed that a transcrestal sinus floor elevation approach can be considered as a first-choice method for single tooth gaps in situations with sufficient width for implant placement and a residual bone height of 5-8 mm, while lateral sinus floor elevation, with or without grafting materials, is indicated when < 5 mm of bone is available and when several teeth are to be replaced. With regard to time of implant placement, a one-stage procedure is preferred provided that high primary stability can be ensured. PMID- 28000272 TI - Initial and long-term crestal bone responses to modern dental implants. AB - Successful osseointegration is the result of a controlled foreign body reaction to dental implants. Osseointegrated implants have demonstrated excellent long term survivability, although they may be subject to limited marginal bone loss. Marginal bone loss during the first few years after implant placement seldom represents disease, but is instead the result of an adaptive bone response to surgical trauma and implant loading. It is not uncommon for implants with early marginal bone loss to enter a long-lasting state of bone stability. Extensive bone resorption after the first year is generally due to an exacerbation of adverse body reactions caused by non-optimal implant components, adverse surgery or prosthodontics and/or compromised patient factors. Disease in the form of peri implantitis is a late complication that affects some implants with suppuration and rapid loss of crestal bone, and is probably caused by bacterial pathogens and immunological reactions. Unfortunately, the literature is not consistent with respect to the type or magnitude of clinical implant problems, including how they are defined and diagnosed. If the peri-implantitis diagnosis is confined to cases with infection, suppuration and significant bone loss, the frequency of the disease is relatively low, which is in sharp contrast to the frequencies reported with unrealistic definitions of peri-implantitis. We suggest that when modern implants are placed by properly trained individuals, only 1-2% of implants show true peri-implantitis during follow-up periods of 10 years or more. Peri implantitis must be separated from the initial and self-limiting marginal bone loss. PMID- 28000273 TI - Evolution of loading protocols in implant dentistry for partially dentate arches. AB - Better outcomes for patients receiving dental implants as part of oral rehabilitation remains a constant goal. Advances in implant design, clinical protocols and biomaterials provide opportunities to accelerate treatment, increasing efficiency, predictability and patient satisfaction. It is important to understand that these changes can result in negative outcomes and increased risk. This article reviews the existing published evidence relating to accelerated clinical protocols and patient outcomes. Subsequent to the review, clinical recommendations are offered. PMID- 28000274 TI - Digital technology in fixed implant prosthodontics. AB - Digital protocols are increasingly influencing prosthodontic treatment concepts. Implant-supported single-unit and short-span reconstructions will benefit mostly from the present digital trends. In these protocols, monolithic implant crowns connected to prefabricated titanium abutments, which are created based on data obtained from an intraoral scan followed by virtual design and production, without the need of a physical master cast, have to be considered in lieu of conventional manufacturing techniques for posterior implant restorations. No space for storage is needed in the complete digital workflow, and if a remake is required a replica of the original reconstruction can be produced quickly and inexpensively using rapid prototyping. The technological process is split into subtractive methods, such as milling or laser ablation, and additive processing, such as three-dimensional printing and selective laser melting. The dimensions of the supra-implant soft-tissue architecture can be calculated in advance of implant placement, according to the morphologic copy, and consequently are individualized for each patient. All these technologies have to be considered before implementing new digital dental workflows in daily routine. The correct indication and application are prerequisite and crucial for the success of the overall therapy, and, finally, for a satisfied patient. This includes a teamwork approach and equally affects the clinician, the dental assistant and the technician as well. The digitization process has the potential to change the entire dental profession. The major benefits will be reduced production costs, improvement in time efficiency and fulfilment of patients' perceptions of a modernized treatment concept. PMID- 28000275 TI - Current state of the art of computer-guided implant surgery. AB - The invention of computerized axial tomography (now known as computerized tomography) and developments of interactive software to allow virtual planning, with the aim to guide the surgery precisely toward a specific target, has dramatically improved general, as well as oral, surgery. Virtual dental implant planning allows for a prosthetically driven approach, resulting in the best possible design of the prosthesis, better esthetics, optimized occlusion and loading. This approach has also changed the surgical paradigm of using extensive flaps to obtain a proper view of the surgical area because flapless implant surgery, with or without immediate loading, has become more predictable. Two types of guided implant surgery protocols - static and dynamic - are described in the literature. The static approach, better known as computer-guided surgery, refers to the use of a tissue-supported surgical template. This reproduces the virtual implant position directly from computerized tomographic data and this information can be converted to guide templates to be used during surgery, with or without raising a mucoperiosteal flap. Dynamic guided surgery, also called navigation, reproduces the virtual implant position directly from computerized tomographic data and uses motion-tracking technology to guide the implant osteotomy preparation. As the technology developed further, different levels of evidence were presented that showed various degrees of accuracy. Several protocols for guided surgery are available in the literature and are distinguished by different guide production techniques, methods of support and drilling/placement protocols. Currently, implant planning software using cone beam computerized tomography data has made it possible to plan the optical implant position virtually the optimal implant position, taking the surrounding vital anatomic structures and future prosthetic requirements into consideration. This paper summarizes the evolution and ongoing trends in digital and virtual planning and in implant surgery. The purpose of this overview was to clarify the different concepts in guided surgery and their respective advantages, disadvantages and limitations. The outcome of guided surgery is assessed in terms of implant survival, precision and complications. Clinical cases are given to demonstrate briefly the workflow and clinical guidelines for safe use of these approaches. PMID- 28000276 TI - Screw retained vs. cement retained implant-supported fixed dental prosthesis. AB - A fixed dental prosthesis can be secured to an endosseous implant via cementation (using a provisional or definitive cement) on an implant abutment that is screw retained to the implant or directly in the implant via screw retention. The clinical decision as to which retention system best suits the individual patient depends on several factors. The aim of this review is to present a detailed overview of the factors potentially influencing whether to choose screw retention or cement retention. These factors include the individual indication, advantages and disadvantages of the different retention mechanisms, the retention provided, retrievability, provisionalization, esthetics and clinical performance, including failures and complications. The results of recently published systematic reviews on this topic are discussed and an overview is provided. A decision tree is presented to facilitate the clinical selection of the retention type. This overview concludes that the choice of retention type (screw retained or cement retained) might not influence the overall survival of the implant-supported fixed dental prosthesis, but may be responsible for the development of certain complications. The decision may depend on technical feasibility and on weighing the pros and cons. PMID- 28000277 TI - Osseointegration of titanium, titanium alloy and zirconia dental implants: current knowledge and open questions. AB - Bone healing around dental implants follows the pattern and sequence of intramembraneous osteogenesis with formation of woven bone first of all followed later by formation of parallel-fibered and lamellar bone. Bone apposition onto the implant surface starts earlier in trabecular bone than in compact bone. While the first new bone may be found on the implant surface around 1 week after installation, bone remodeling starts at between 6 and 12 weeks and continues throughout life. Bone remodeling also involves the bone-implant interface, thus transiently exposing portions of the implant surface. Surface modifications creating micro-rough implant surfaces accelerate the osseointegration process of titanium implants, as demonstrated in numerous animal experiments. Sandblasting followed by acid-etching may currently be regarded as the gold standard technique to create micro-rough surfaces. Chemical surface modifications, resulting in higher hydrophilicity, further increase the speed of osseointegration of titanium and titanium-zirconium implants in both animals and humans. Surface modifications of zirconia and alumina-toughened zirconia implants also have an influence on the speed of osseointegration, and some implant types reach high bone-to-implant contact values in animals. Although often discussed independently of each other, surface characteristics, such as topography and chemistry, are virtually inseparable. Contemporary, well-documented implant systems with micro-rough implant surfaces, placed by properly trained and experienced clinicians, demonstrate high long-term survival rates. Nevertheless, implant failures do occur. A low percentage of implants are diagnosed with peri-implantitis after 10 years in function. In addition, a low number of implants seem to be lost for primarily reasons other than biofilm-induced infection. Patient factors, such as medications interfering with the immune system and bone cells, may be an element contributing to continuous bone loss and should therefore be monitored and studied in greater detail. PMID- 28000278 TI - Implant placement post extraction in esthetic single tooth sites: when immediate, when early, when late? AB - Implant placement in post-extraction sites of single teeth in the esthetic zone has been a topic of great interest in the field of implant dentistry since 1990. Triggered by the development of guided bone regeneration, the concept of immediate implant placement became quite popular in the 1990s. In the past 12 years, however, the dental community has begun to focus increasingly on the esthetic outcomes of post-extraction implant placement and several studies indicated a significant risk for the development of mucosal recessions with immediate implants. Parallel with this, significant progress has been made in the understanding of tissue biology in terms of hard and soft tissue alterations post extraction, based on preclinical, clinical and radiological studies. This knowledge has helped better to understand the etiology of these esthetic complications with immediate implant placement. The present review first analyzes the various phases of the development of therapeutic strategies over the years for post-extraction implant placement in single tooth sites in the esthetic zone. It presents the current knowledge concerning the terminology with immediate, early and late implant placement, the risk factors for the development of esthetic complications, and the selection criteria for the various treatment options. In the second part, clinical recommendations are given, since a clinician active in this field of implant therapy can use all treatment options depending on the preoperative analysis including a 3D cone beam computed tomography. The selection criteria for all four treatment options are presented and documented with typical case reports to illustrate the current treatment approaches applied in daily practice. PMID- 28000279 TI - Esthetic assessments in implant dentistry: objective and subjective criteria for clinicians and patients. AB - In recent years the scientific community has shown a clear interest in the esthetic outcome of implant treatment. The present paper provides an overview of the esthetic ratings that have been used in implant dentistry. A distinction can be made between objective evaluations by clinicians and subjective evaluations by patients. The former mainly include: midfacial and interproximal soft-tissue levels; two-dimensional/three-dimensional soft-tissue alterations; assessment of the color match between the natural dentition, on the one hand, and the peri implant tissues and the reconstruction, on the other hand; and ordinal indices, such as the pink and white esthetic score. Patient's needs and judgment may differ from objective indicators of implant success and esthetics. As a result, assessing treatment on the basis of patient-reported outcomes measures should be considered important. Validated questionnaires have been used that mainly assess the impact of oral health on the overall well-being of individuals. The esthetic judgment of patients is usually based on nonstandardized questions with varying scoring methods, including visual analog scales, Likert and other category scales and open questions. The heterogeneity in scoring systems between studies may compromise proper comparison of objective and subjective esthetic outcomes between studies and therapeutic concepts. PMID- 28000280 TI - Modern implant dentistry based on osseointegration: 50 years of progress, current trends and open questions. AB - In the 1960s and 1970s, implant-supported prostheses based on subperiosteal or blade implants had a poor reputation because of questionable clinical outcomes and lack of scientific documentation. The change to a scientifically sound discipline was initiated by the two scientific pioneers of modern implant dentistry, Professor P. I. Branemark from the University of Gothenburg in Sweden and Professor Andre Schroeder from the University of Bern in Switzerland. Together with their teams, and independently of each other, they laid the foundation for the most significant development and paradigm shift in dental medicine. The present volume of Periodontology 2000 celebrates 50 years of osseointegration. It reviews the progress of implant therapy over the past 50 years, including the basics of implant surgery required to achieve osseointegration on a predictable basis and evolving innovations. The development of bone-augmentation techniques, such as guided bone regeneration and sinus floor elevation, to correct local bone defects at potential implant sites has increased the indications for implant therapy. The paradigm shift to moderately rough implant surfaces resulted in faster and enhanced bone integration and led to improvements in various treatment protocols, such as immediate and early implant placement in postextraction sites, and made various loading protocols possible, including immediate and early implant loading. In the past 15 years, preoperative analysis and presurgical planning improved as a result of the introduction of three-dimensional imaging techniques. Hereby, cone-beam computed tomography offers better image quality with reduced radiation exposure, when compared with dental computed tomography. This opened the door for digital planning and surgical modifications. Over the last 50 years this evolution has facilitated tremendous progress in esthetic outcomes with implant-supported prostheses and improved patient-centered outcomes. This volume of Periodontology 2000 also discusses the current trends and open questions of implant dentistry, such as the potential of digital implant dentistry in the surgical and prosthetic field, the trend for an increasing average age of implant patients and the related adaptations of treatment protocols, and the second attempt to establish ceramic implants using, this time, zirconia as the implant material. Finally, some of the hottest controversies are discussed, such as recent suggestions on bone integration being a potential foreign-body reaction and the evidence-based appraisal of the peri-implantitis debate. PMID- 28000281 TI - Clinical relevance of dimensional bone and soft tissue alterations post extraction in esthetic sites. AB - The key to achieving pleasing esthetics in implant dentistry is a thorough understanding of the biological processes driving dimensional bone and soft tissue alterations post-extraction. The aim of the present report is first to characterize the extent of bone and soft tissue changes post-extraction and second to identify potential factors influencing tissue preservation in order to facilitate successful treatment outcomes. The facial bone wall thickness has been identified as the most critical factor influencing bone resorption and can be used as a prognostic tool in order to identify sites at risk for future facial bone loss subsequent to tooth extraction. Clinical studies indicated that thin bone wall phenotypes exhibiting a facial bone wall thickness of 1 mm or less revealed progressive bone resorption with a vertical loss of 7.5 mm, whereas thick bone wall phenotypes showed only minor bone resorption with a vertical loss of 1.1 mm. This is in contrast to the dimensional soft tissue alterations. Thin bone wall phenotypes revealed a spontaneous soft tissue thickening after flapless extraction by a factor of seven, whereas thick bone wall phenotypes showed no significant changes in the soft tissue dimensions after 8 weeks of healing. In sites exhibiting a limited bone resorption rate, immediate implant placement may be considered. If such ideal conditions are not present, other timing protocols are recommended to achieve predictable and pleasing esthetics. Socket preservation techniques for ridge preservation utilizing different biomaterials and/or barrier membranes often result in a better maintenance of tissue volumes, although the inevitable biological process of post-extraction bone resorption and bone modeling cannot be arrested. In summary, the knowledge of the biological events driving dimensional tissue alterations post-extraction should be integrated into the comprehensive treatment plan in order to limit tissue loss and to maximize esthetic outcomes. PMID- 28000282 TI - Coverage of mucosal recessions at dental implants. AB - Facial peri-implant mucosal recessions represent an increasing complication in implant dentistry and may negatively affect the esthetic outcome and patient satisfaction. The aim of the present paper is to provide a review on the potential causes of facial peri-implant mucosal recessions and to provide a rationale for treatment along with possible treatment options. The available data indicate that soft tissue augmentation around dental implants is possible, but at present there is no evidence demonstrating that the augmented soft tissues are able to influence the peri-implant bone levels (e.g. to limit peri-implant bone loss). Therefore, the rationale to cover or correct peri-implant mucosal recessions are (i) to optimize the possibility for performing an adequate level of oral hygiene, and (ii) to improve esthetics. At present, there is very limited evidence supporting any specific treatment modality for covering peri-implant soft tissue recessions. The limited available data indicate that only shallow peri-implant mucosal recessions (e.g. up to 2 mm) may be treated successfully by means of a coronally advanced flap and subepithelial connective tissue graft or with guided bone regeneration, while no data are available supporting the possibility of covering deep and large peri-implant mucosal recessions. PMID- 28000283 TI - Maturational and social factors contributing to relative age effects in school sports: Data from the London Youth Games. AB - Few studies have investigated whether relative age effects (RAEs) exist in school sport. None have sought to test the competing maturational and social-agent hypotheses proposed to explain the RAE. We aimed to determine the presence of RAEs in multiple school sports and examine the contribution of maturational and social factors in commonplace school sports. We analyzed birth dates of n=10645 competitors (11-18 years) in the 2013 London Youth Games annual inter-school multisport competition and calculated odds ratio (OR) for students competing based on their yearly birth quarter (Q1-Q4). Multivariate logistic regression was used to determine the relative contribution of constituent year (Grade) and relative age in netball and football which used multiyear age groupings. In girls, RAEs were present in the team sports including hockey, netball, rugby union, cricket and volleyball but not football. In boys, RAEs were stronger in common team sports (football, basketball cricket) as well as athletics and rowing. In netball and football teams with players from two constituent years, birth quarter better-predicted selection than did constituent year. Relatively older players (Q1) from lower constituent years were overrepresented compared with players from Q3 and Q4 of the upper constituent years. RAEs are present in the many sports commonplace in English schools. Selection of relatively older players ahead of chronologically older students born later in the selection year suggests social agents contribute to RAEs in school sports. PMID- 28000284 TI - Synthesis, Characterization, and Catalytic Activities of A Nickel(II) Monoamido Tetradentate Complex: Evidence For NiIII -Oxo and NiIV -Oxo Species. AB - A new mononuclear nickel(II) complex, [NiII (dpaq)Cl] (1), containing a tetradentate monoamido ligand, dpaq (dpaq=2-[bis(pyridin-2-ylmethyl)amino]-N (quinolin-8-yl)acetamide), has been synthesized and characterized by IR spectroscopy, elemental analysis, and UV/Vis spectroscopy. The structure of the nickel complex has been determined by X-ray crystallography. This nonheme NiII complex 1 catalyzed the epoxidation reaction of a wide range of olefins with meta chloroperoxybenzoic acid (m-CPBA) under mild conditions. Olefin epoxidation using this catalytic system has been proposed to involve a new reactive NiIV -oxo (4) species, based on the evidence from a PPAA (peroxyphenylacetic acid) probe, Hammett studies, H218 O exchange experiments, and ESI mass spectroscopic analysis. Moreover, the nature of solvent significantly influenced partitioning between heterolytic and homolytic O-O bond cleavage of the Ni-acylperoxo intermediate (2). The O-O bond of 2 proceeded predominantly through heterolytic cleavage in a protic solvent, such as CH3 OH. These results suggest that possibly a NiIV -oxo species is a common reactive intermediate in protic solvents. The two active oxidants, namely NiIV -oxo (3) and NiIII -oxo (4), which are responsible for stereospecific olefin epoxidation and radical-type oxidations, respectively, operate in aprotic solvents. PMID- 28000285 TI - A defective inflammatory response may underlie cases of atopic dermatitis. PMID- 28000286 TI - Population pharmacokinetics of temsirolimus and sirolimus in children with recurrent solid tumours: a report from the Children's Oncology Group. AB - AIMS: Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Pharmacokinetic (PK) characterization of temsirolimus in children is limited and there is no paediatric temsirolimus population PK model available. The objective of this study was to simultaneously characterize the PK of temsirolimus and its metabolite sirolimus in paediatric patients with recurrent solid or central nervous system tumours and to develop a population PK model. METHODS: The PK data for temsirolimus and sirolimus were collected as a part of a Children's Oncology Group phase I clinical trial in paediatric patients with recurrent solid tumours. Serial blood concentrations obtained from 19 patients participating in the PK portion of the study were used for the analysis. Population PK analysis was performed by nonlinear mixed effect modelling using NONMEM. RESULTS: A three compartment model with zero-order infusion was found to best describe temsirolimus PK. Allometrically scaled body weight was included in the model to account for body size differences. Temsirolimus dose was identified as a significant covariate on clearance. A sirolimus metabolite formation model was developed and integrated with the temsirolimus model. A two-compartment structure model adequately described the sirolimus data. CONCLUSION: This study is the first to describe a population PK model of temsirolimus combined with sirolimus formation and disposition in paediatric patients. The developed model will facilitate PK model-based dose individualization of temsirolimus and the design of future clinical studies in children. PMID- 28000287 TI - The potential role of vascular endothelial growth factor as a new biomarker in severe intracerebral hemorrhage. AB - BACKGROUND: We studied the association between high serum levels of vascular endothelial growth factor (VEGF) and clinical outcomes of intracerebral hemorrhage (ICH) patients. METHODS: Patients were divided into group A (<20 mL), group B (20-30 mL), and group C (>30 mL) based on the bleeding amount. ICH patients were also categorized into the mild group, moderate group (16-30), and severe group (31-45) based on the National Institutes of Health Stroke Scale (NIHSS). The serum levels of VEGF in acute ICH patients detected at 24, 48, and 72 hours were obtained using ELISA kit, and then compared with control group. Main clinical outcomes were evaluated using the modified Rankin scale at 90 days. RESULTS: The serum levels of VEGF were significantly higher than those in the control group. The serum levels of VEGF in group C were specifically higher compared with those in other two groups. The severe group exhibited higher levels of VEGF than the other two groups. NIHSS scores in patients with good outcomes were lower than those with poor outcomes. Besides, VEGF levels in patients with good outcomes were much higher than those in patients with poor outcomes. ROC results indicated that the optimal cut-off value of VEGF at 72 hours for predicting good outcomes was 111.17 pg/mL with 91.5 sensitivity, 98.7 specificity, and an AUC of 0.952 Our results showed that higher serum levels of VEGF were associated with process of ICH. CONCLUSION: VEGF could be a new marker in ICH for severity. PMID- 28000288 TI - The impact of kidney transplantation on insulin sensitivity. AB - To investigate the impact of kidney transplantation (KTx) on insulin sensitivity affecting glucose metabolism. 9 nondiabetic patients awaiting living donor KTx were examined prior to transplantation with an oral glucose tolerance test and a 3-h hyperinsulinaemic-euglycaemic clamp. The clamp was repeated 6 months after KTx. Nine age-, gender- and body mass index (BMI)-matched individuals with normal kidney function served as controls. Endogenous glucose production and glucose disappearance rate (N = 6) were measured in a subgroup of patients with corresponding controls. Results presented as mean [range]. Two patients had pretransplant prediabetes, whereas all others had normal glucose tolerance. After KTx, average glucose infusion rate to maintain euglycaemia during clamp declined significantly from 15.1 [9.1-23.7] to 9.8 [2.8-14.6] MUmol/kg/min (P < 0.01) with 20.2 [9.9-33.7] MUmol/kg/min in controls. Endogenous glucose production increased from 7.0 [4.8-8.5] to 9.4 [7.4-11.8] MUmol/kg/min (P < 0.05) with 7.0 [-3.8 to 10.1] MUmol/kg/min in controls. Glucose disappearance rate was unchanged (18.1 [12.9-24.5] vs. 17.1 [12.2-22.7] MUmol/kg/min, NS) with 22.3 [14.6-34.3] in controls. In conclusion, insulin sensitivity is reduced 6 months after KTx and characterized mainly by impaired suppression of the endogenous glucose production. PMID- 28000289 TI - Trait-demography relationships underlying small mammal population fluctuations. AB - Large-scale fluctuations in abundance are a common feature of small mammal populations and have been the subject of extensive research. These demographic fluctuations are often associated with concurrent changes in the average body mass of individuals, sometimes referred to as the 'Chitty effect'. Despite the long-standing recognition of this phenomenon, an empirical investigation of the underlying coupled dynamics of body mass and population growth has been lacking. Using long-term life-history data combined with a trait-based demographic approach, we examined the relationship between body mass and demography in a small mammal population that exhibits non-cyclic, large-scale fluctuations in abundance. We used data from the male segment of a 25-year study of the monogamous prairie vole, Microtus ochrogaster, in Illinois, USA. Specifically, we investigated how trait-demography relationships and trait distributions changed between different phases of population fluctuations, and the consequences of these changes for both trait and population dynamics. We observed phase-specific changes in male adult body mass distribution in this population of prairie voles. Our analyses revealed that these changes were driven by variation in ontogenetic growth, rather than selection acting on the trait. The resulting changes in body mass influenced most life-history processes, and these effects varied among phases of population fluctuation. However, these changes did not propagate to affect the population growth rate due to the small effect of body mass on vital rates, compared to the overall differences in vital rates between phases. The increase phase of the fluctuations was initiated by enhanced survival, particularly of juveniles and fecundity, whereas the decline phase was driven by an overall reduction in fecundity, survival and maturation rates. Our study provides empirical support, as well as a potential mechanism, underlying the observed trait changes accompanying population fluctuations. Body size dynamics and population fluctuations resulted from different life-history processes. Therefore, we conclude that body size dynamics in our population do not drive the observed population dynamics. This more in-depth understanding of different components of small mammal population fluctuations will help us to better identify the mechanistic drivers of this interesting phenomenon. PMID- 28000290 TI - Comparison between the AC and DC measurement of electrodermal activity. AB - Recording electrodermal activity is a well-accepted physiological measurement for clinical approaches and research. Historically, applying a DC (direct current) signal to the skin to measure the conductance is the most common practice for exogenous recordings. However, this method can be subject to error due to electrode polarization even with "nonpolarizing" electrodes-a problem that can be eliminated with alternating current (AC) methodology. For that reason, Boucsein et al. () called for research demonstrating an AC method that is validated by comparison to standard DC methodology. Additionally, the complex structure of human skin has electrical properties that include both resistance and capacitance, and AC recording enables the measurement of skin susceptance (associated with current flow through capacitors). Finally, AC recording permits the simultaneous recording of the endogenous skin potential. In this paper, the results from a direct comparison between both methods are presented, which has not been reported previously. The results demonstrated excellent agreement between a 20 Hz AC method and a standard DC method, supporting the validity of the AC recording methodology employed. The results also showed that an applied voltage of 0.2 V is sufficient for DC recordings. PMID- 28000291 TI - The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia. AB - FLT3 mutations are present in about one-third of patients with acute myeloid leukemia (AML). Several FLT3 inhibitors have been used in clinical trials, and these include midostaurin, sorafenib, quizartinib, crenolanib, and gilteritinib. Monotherapy with early tyrosine kinase inhibitors (TKIs) did not have much success; however, later generation agents have shown more promising results. Combination with conventional chemotherapy may have benefit as evidenced by recently presented results, and data from ongoing trials are eagerly awaited. Several trials are also evaluating TKI given after HSCT, and a large international randomized trial is planned. We may be close to an era of targeted therapy where the standard of care for this biologically defined subset will involve incorporation of a FLT3 TKI during induction chemotherapy and after HSCT. It is important that our community continues to collaborate to conduct well designed clinical trials to properly define the role of FLT3 TKIs in therapy for FLT3-mutant AML. PMID- 28000292 TI - Microstructural models for diffusion MRI in breast cancer and surrounding stroma: an ex vivo study. AB - The diffusion signal in breast tissue has primarily been modelled using apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) and diffusion tensor (DT) models, which may be too simplistic to describe the underlying tissue microstructure. Formalin-fixed breast cancer samples were scanned using a wide range of gradient strengths, durations, separations and orientations. A variety of one- and two-compartment models were tested to determine which best described the data. Models with restricted diffusion components and anisotropy were selected in most cancerous regions and there were no regions in which conventional ADC or DT models were selected. Maps of ADC generally related to cellularity on histology, but maps of parameters from more complex models suggest that both overall cell volume fraction and individual cell size can contribute to the diffusion signal, affecting the specificity of ADC to the tissue microstructure. The areas of coherence in diffusion anisotropy images were small, approximately 1 mm, but the orientation corresponded to stromal orientation patterns on histology. PMID- 28000293 TI - Do KV 7.1 channels contribute to control of arterial vascular tone? AB - BACKGROUND AND PURPOSE: KV 7.1 voltage-gated potassium channels are expressed in vascular smooth muscle cells (VSMC) of diverse arteries, including mesenteric arteries. Based on pharmacological evidence using R-L3 (KV 7.1 channel opener), HMR1556, chromanol 293B (KV 7.1 channel blockers), stimulation of these channels has been suggested to evoke profound relaxation in various vascular beds of rats. However, the specificity of these drugs in vivo is uncertain. EXPERIMENTAL APPROACH: We used Kcnq1-/- mice and pharmacological tools to determine whether KV 7.1 channels play a role in the regulation of arterial tone. KEY RESULTS: R-L3 produced similar concentration-dependent relaxations (EC50 ~ 1.4 MUM) of arteries from wild-type (Kcnq1+/+ ) and Kcnq1-/- mice, pre-contracted with either phenylephrine or 60 mM KCl. This relaxation was not affected by 10 MUM chromanol 293B, 10 MUM HMR1556 or 30 MUM XE991 (pan-KV 7 channel blocker). The anti contractile effects of the perivascular adipose tissue (PVAT) were normal in Kcnq1-/- arteries. Chromanol 293B and HMR1556 did not affect the anti-contractile effects of (PVAT). Isolated VSMCs from Kcnq1-/- mice exhibited normal peak KV currents. The KV 7.2-5 channel opener retigabine caused similar relaxations in Kcnq1-/- and wild-type vessels. CONCLUSION AND IMPLICATIONS: We conclude that KV 7.1 channels were apparently not involved in the control of arterial tone by alpha1 -adrenoceptor agonists and PVAT. In addition, R-L3 is an inappropriate pharmacological tool for studying the function of native vascular KV 7.1 channels in mice. PMID- 28000295 TI - Drug availability adjustments in population-based studies of prescription opioid abuse. AB - PURPOSE: Population-based prescription opioid abuse studies in which one drug is compared to another, or drugs are compared across time, often account for the availability of those drugs in the community. The objective of this investigation is to assess consistency in the relative abuse ratios (RARs) across different approaches for adjusting for drug availability. METHODS: For the years 2004 through 2010, RARs for each of four prescription opioids (hydrocodone, oxycodone, hydromorphone, and morphine) were calculated using negative binomial regression. Measures of abuse (outcome) were misuse/abuse-related emergency department visits obtained from the Drug Abuse Warning Network. Measures of drug availability (offsets) were drug utilization estimates obtained from IMS Health. Separate regression models were run using each of five measures of drug utilization: unique patients (URDD), prescriptions dispensed (RX), tablets dispensed (TD), kilograms (KGs) sold, and morphine-equivalents (MEs) of kilograms sold. These results were compared for consistency. RESULTS: Aside from oxycodone-combination products, across molecules, RARs adjusted by RXs, TDs, and URDDs were generally similar to each other while RARs adjusted by KGs and MEs were different. For example, compared to hydrocodone, oxycodone had statistically significantly increased RARs of 3.6 (95%CI: 2.0-6.5), 3.5 (95%CI: 1.9-6.4), and 2.7 (95%CI: 1.5 5.0) when adjusted by URDDs, RXs, and TDs, respectively, but not when adjusted by KGs or MEs. CONCLUSIONS: Different drug utilization adjustment approaches may yield inconsistent RAR estimates in population-based prescription opioid abuse analyses. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 28000294 TI - Disrupting a key hydrophobic pair in the oligomerization interface of the actinoporins impairs their pore-forming activity. AB - Crystallographic data of the dimeric and octameric forms of fragaceatoxin C (FraC) suggested the key role of a small hydrophobic protein-protein interaction surface for actinoporins oligomerization and pore formation in membranes. However, site-directed mutagenesis studies supporting this hypothesis for others actinoporins are still lacking. Here, we demonstrate that disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII), and sticholysin II (StII) impairs the pore formation activity of these proteins. Our results allow for the extension of the importance of FraC protein-protein interactions in the stabilization of the oligomeric intermediates of StII and EqtII pointing out that all of these proteins follow a similar pathway of membrane disruption. These findings support the hybrid pore proposal as the universal model of actinoporins pore formation. Moreover, we reinforce the relevance of dimer formation, which appears to be a functional intermediate in the assembly pathway of some different pore-forming proteins. PMID- 28000296 TI - Living with persistent rheumatoid arthritis: a BARFOT study. AB - AIM AND OBJECTIVE: To describe and understand the meaning of living with persistent rheumatoid arthritis. BACKGROUND: A considerable number of patients with rheumatoid arthritis live with an ongoing active and symptomatic illness despite access to potent antirheumatic treatment. There is, however, a lack of knowledge about the meaning of living with this severe long-term illness, defined as persistent rheumatoid arthritis. DESIGN: A descriptive design based on a hermeneutic phenomenological method was used. METHODS: Ten adults with persistent rheumatoid arthritis and at least five years disease duration were interviewed. The interviews were analysed according to van Manen's method. RESULTS: Living with persistent rheumatoid arthritis revealed four overall themes: an existence dominated by painful symptoms and treatment, radical changes and limitations in one's life, a continual struggle to cope with one's life and to master the illness, and a dependency on those who are close by and the world around. The lifeworld was affected to a varying extent and in various ways by the illness but also by the dependence on its treatment and care that was not experienced as sufficiently meeting needs in terms of security, access to and coordination of care as well as team and rehabilitation services. CONCLUSIONS: Persistent rheumatoid arthritis and its treatment entail a radical effect on the person's life and quality of life. Current ordinary rheumatology care does not seem to meet the individual needs of the person with persistent rheumatoid arthritis in an optimal way. RELEVANCE TO CLINICAL PRACTICE: A greater knowledge about and understanding of the person who lives with persistent rheumatoid arthritis is important for facilitating the development of care and the relief of suffering. A holistic alternative to conventional clinical practice, such as person-centred care, could be tested as an innovative model of care. Our findings might serve as material for educational and counselling purposes for healthcare professionals. PMID- 28000297 TI - Use of free tissue transfer in head and neck cancer surgery and risk of overall and serious complication(s): An American College of Surgeons-National Surgical Quality Improvement Project analysis of free tissue transfer to the head and neck. AB - BACKGROUND: The purpose of this article was to assess the rates of head and neck free tissue transfer and variables available in the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) dataset to predict overall and serious complications. METHODS: We conducted a data analysis from 2005 to 2014 on free tissue cases in the head and neck with descriptive and cross sectional analysis to examine correlation of NSQIP variables with complications (p < .05). RESULTS: Of 1643 flaps, 906 complications occurred, such as blood transfusion, return to the operating room, extended ventilator support, pneumonia, and superficial surgical site infection. Insulin-dependent diabetes, operative time, age, white blood cell (WBC) count, and smoking correlated with overall complications. Five hundred one patients experienced 859 serious complications: return to the operating room, pneumonia, deep surgical site infection, sepsis, and unplanned intubation. Operative time, clean contaminated wound status, dirty wound classification, and history of congestive heart failure were predictive. CONCLUSION: Identification of risks for complications is an opportunity for improvement. Extended operative time consistently predicts for both overall and serious complications, suggesting long surgery within contaminated sites risks complication. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 702-707, 2017. PMID- 28000298 TI - The feasibility of using multiple databases to study rare outcomes: the potential effect of long-acting beta agonists with inhaled corticosteroid therapy on asthma mortality. AB - PURPOSE: Long-acting beta agonists (LABAs) when used without concomitant inhaled corticosteroids (ICS) increase the risk of asthma-related deaths, but the effect on asthma-related death of LABA used in combination with ICS therapy is unknown. To address this question, we explored the feasibility of conducting an observational study using multiple US health care data sources. METHODS: Retrospective cohort study to evaluate the likelihood of getting an upper 95% confidence limit <=1.4 for the asthma mortality rate ratio and <=0.40 per 10 000 person-years for the mortality rate difference, assuming no effect of new use of combined LABA + ICS (versus non-LABA maintenance therapy) on asthma mortality. Ten research institutions executed centrally distributed analytic code based on a standard protocol using an extracted (2000-2010) persistent asthma cohort (asthma diagnosis and >=4 asthma medications in 12 months). Pooled results were analyzed by the coordinating center. Asthma deaths were ascertained by linkage with the National Death Index. RESULTS: In a cohort of 994 627 persistent asthma patients (2.4 million person-years; 278 asthma deaths), probabilities of the upper 95% confidence limit for effect estimates being less than targeted values, assuming a null relation, were about 0.05. Modifications in cohort and exposure definitions increased exposed person-time and outcome events, but study size remained insufficient to attain study goals. CONCLUSIONS: Even with 10 data sources and a 10-year study period, the rarity of asthma deaths among patients using certain medications made it infeasible to study the association between combined LABA + ICS and asthma mortality with our targeted level of study precision. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28000299 TI - Prolonged-release minitablets with carbamazepine - preliminary observations in vitro. AB - OBJECTIVE: The aim was to develop prolonged-release minitablets (MT) with carbamazepine (CBZ). METHODS: Matrix-type 3-mm MT (5 mg CBZ) were prepared by direct compression using hydrophilic (hypromellose) or hydrophobic polymers (ethylcellulose, Kollidon SR, glyceryl behenate). Coated prolonged-release MT (2.5 mm/3 mg of CBZ) were produced using ethylcellulose or Eudragit RL/RS. The release tests were performed in a basket apparatus with water or 1% sodium lauryl sulphate solution as dissolution media. KEY FINDINGS: High-viscosity hypromellose used as a matrix polymer resulted in slow release of CBZ (80% released during 12 h). Dissolution was slower from hydrophobic matrices. Non-swelling MT cores were successfully coated with Eudragit RL/RS, which resulted in the prolonged release of CBZ (80%/14 h), depending on the film thickness and Eudragit composition. Careful choice of pore formers in the coating film allowed to reduce lag time. Ethylcellulose was unsuitable as coating polymer due to low permeability to CBZ and unsatisfying mechanical resistance of the films modified with hypromellose. CONCLUSION: Prolonged release of CBZ was obtained from both matrix-type and coated MT. Further development of MT as a single unit or multicompartment prolonged-release new dosage form especially suitable for children has been justified. PMID- 28000300 TI - Nurse-perceived quality of care in intensive care units and associations with work environment characteristics: a multicentre survey study. AB - AIMS: To examine nurse-perceived quality of care, controlling for overall job satisfaction among critical care nurses and to explore associations with work environment characteristics. BACKGROUND: Nurse-perceived quality of care and job satisfaction have been positively linked to quality outcomes for nurses and patients. Much evidence exists on factors contributing to job satisfaction. Understanding specific factors that affect nurse-perceived quality potentially enables for improvements of nursing care quality. DESIGN: A multicentre survey study was conducted in three Dutch intensive care units. METHODS: The Dutch version of the Essentials of Magnetism II questionnaire was used; including the single-item indicators: (i) nurse-perceived quality of care; (ii) overall job satisfaction; and (iii) 58 statements on work environments. Data were collected between October 2013 - June 2014. RESULTS: The majority of 123 responding nurses (response rate 45%) were more than satisfied with quality of care (55%) and with their job (66%). No associations were found with nurse characteristics, besides differences in job satisfaction between the units. After controlling for job satisfaction, nurse-perceived quality was positively associated with the work environment characteristics: adequacy of staffing, patient-centeredness, competent peers and support for education. Patient-centeredness and autonomy were the most important predictors for overall job satisfaction. CONCLUSION: Factors that contribute to nurse-perceived quality of care in intensive care units, independent from the effects of overall job satisfaction, were identified. Hereby, offering opportunities to maximize high quality of care to critically ill patients. Research in a larger sample is needed to confirm our findings. PMID- 28000301 TI - Ferromagnetism at Room Temperature Induced by Spin Structure Change in BiFe1-x Cox O3 Thin Films. AB - The coexistence and coupling of ferromagnetic and ferroelectric orders in a single material is crucial for realizing next-generation multifunctional applications. The coexistence of such orders is confirmed at room temperature in epitaxial thin films of BiFe1-x Cox O3 (x <= 0.15), which manifests a spin structure change from a low-temperature cycloidal one to a high-temperature collinear one with canted ferromagnetism. PMID- 28000302 TI - PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'. AB - AIMS: PD-1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune-type side effects, including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied. METHODS AND RESULTS: We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD-1 or PD-L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra-epithelial neutrophils and increased crypt/gland apoptosis, although intra-epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow-up endoscopies were not performed. CONCLUSIONS: PD-1/PD-L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA-4 inhibitors and PI3Kdelta inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra-epithelial lymphocytes and crypt rupture may help to distinguish PD-1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft versus-host disease, cytomegalovirus infection and autoimmune enteropathy. PMID- 28000303 TI - Primary cutaneous histiocytoid carcinoma with distant metastasis. AB - Distinguishing primary cutaneous adnexal carcinoma from metastatic carcinoma of unknown primary can be a diagnostic challenge due to the frequent overlap of histologic and immunohistochemical features. A 58-year-old man presented with a tender, indurated plaque on axillary skin. Biopsy revealed infiltrating atypical cells throughout the dermis, without connection to the epidermis. Tumor cells had a histiocytoid appearance and displayed mild pleomorphism. The tumor was discohesive and had areas with a single file pattern. Signet ring cells were also present. Cells were reactive with CK7, CK5/6, p63, GATA3, GCDFP-15 and Her 2-neu. Additional studies were negative, including TTF-1, CDX2, E-cadherin, mammaglobin, estrogen receptor and progesterone receptor. Thorough clinical and radiologic evaluation failed to identify an occult primary extracutaneous malignancy; however, regional lymphadenopathy, widespread osteoblastic lesions and multiple subcentimeter liver hypodensities were noted. Considering the clinical and histopathologic features, the diagnosis of primary cutaneous histiocytoid carcinoma with distant metastasis was favored. PMID- 28000304 TI - Discriminating the hemolytic risk of blood type A plasmas using the complement hemolysis using human erythrocytes (CHUHE) assay. AB - BACKGROUND: The agglutination-based cross-matching method is sensitive for antibody binding to red blood cells but is only partially predictive of complement-mediated hemolysis, which is important in many acute hemolytic transfusion reactions. Here, we describe complement hemolysis using human erythrocytes (CHUHE) assays that directly evaluate complement-mediated hemolysis between individual serum-plasma and red blood cell combinations. The CHUHE assay is used to evaluate correlations between agglutination titers and complement mediated hemolysis as well as the hemolytic potential of plasma from type A blood donors. STUDY DESIGN AND METHODS: Plasma or serum from each type A blood donor was incubated with AB or B red blood cells in the CHUHE assay and measured for free hemoglobin release. RESULTS: CHUHE assays for serum or plasma demonstrate a wide, dynamic range and high sensitivity for complement-mediated hemolysis for individual serum/plasma and red blood cell combinations. CHUHE results suggest that agglutination assays alone are only moderately predictive of complement mediated hemolysis. CHUHE results also suggest that plasma from particular type A blood donors produce minimal complement-mediated hemolysis, whereas plasma from other type A blood donors produce moderate to high-level complement-mediated hemolysis, depending on the red blood cell donor. CONCLUSION: The current results indicate that the CHUHE assay can be used to assess complement-mediated hemolysis for plasma or serum from a type A blood donor, providing additional risk discrimination over agglutination titers alone. PMID- 28000305 TI - Parotidectomy under sedation and locoregional anesthesia with monitoring of brain activity. AB - BACKGROUND: Parotidectomy is usually performed while the patient is under general anesthesia, however, sedation with locoregional anesthesia could be an alternative. METHODS: Fifteen adult patients with parotid tumors of the superficial lobe were included in this study. Anesthetic procedure consisted of sedation associated with cervical plexus and auriculotemporal nerve block. Sedation was managed based on the bispectral index. RESULTS: Superficial parotidectomies were performed in 13 patients, and combined partial resections were performed in 2 patients. The mean operative time was 118.2 +/- 16.4 minutes. Conversion to general anesthesia was necessary in only 1 patient. Ten surgeries were performed on an outpatient basis. Definitive facial paralysis occurred in 1 patient. All patients reported total satisfaction with the procedure. CONCLUSION: In selected cases, parotidectomy under sedation plus locoregional anesthesia is feasible and safe. The careful selection of patients and the close collaboration with an anesthesiologist is the key to a successful procedure. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 744-747, 2017. PMID- 28000306 TI - Filaggrin gene mutations and the distribution of filaggrin in oral mucosa of patients with oral lichen planus and healthy controls. AB - BACKGROUND: Lichen planus (LP) is a chronic inflammatory disease of unknown aetiology affecting the skin and oral mucosa. Oral lichenoid lesions (OLLs), like oral contact reactions, may resemble oral lichen planus (OLP) both clinically and histopathologically. As OLP and OLL are hyperkeratotic diseases and filaggrin is essential to keratinization, the distribution of filaggrin may be altered in these lesions. OBJECTIVES: To investigate whether patients with OLP/OLL have (i) altered distribution of filaggrin in the oral mucosa; (ii) a higher incidence of mutations in the filaggrin gene (FLG); (iii) active dermatoses, apart from cutaneous LP, than healthy controls; and (iv) patients with OLP/OLL and a defect in the FLG have more widespread oral lesions and report more symptoms than OLP/OLL patients without a concomitant defect in the FLG. METHODS: Forty-nine Caucasian patients (42 women and 7 men, mean age 61.0 +/- 10.3 years), with symptomatic OLP, OLL or stomatitis, and 29 matched healthy controls underwent a clinical oral and dermatological examination, oral mucosal biopsy and filaggrin genotyping (testing for R2447X, R501X, 2282del4). Smear tests for Candida spp. were performed in all patients to exclude oral candidiasis. Immunohistochemistry were performed using poly- and monoclonal filaggrin antibodies. RESULTS: The immunoreactivity for filaggrin was significantly more intense in the oral mucosa in the patients with OLP/OLL compared with healthy controls (P = 0.000025). No difference was noted in the incidence of defects in the FLG and active dermatoses between patients and healthy controls. No difference was noted in extension and number of symptoms reported by patients with OLP/OLL with or without a concomitant defect in the FLG. CONCLUSION: OLP/OLL is associated with an altered distribution of filaggrin in the oral mucosa independently of defects in the FLG. Patients with OLP/OLL did not display more active dermatoses other than cutaneous LP when compared to healthy controls. PMID- 28000307 TI - Outlook on optimizing ultramicroscopy imaging technique through optical characterization. AB - Here, we present an optically optimized system for static ultramicroscopy imaging technique. The unit for generating an ultra-thin light sheet employs aspheric and meso-optical elements (meso-aspheric system). An analytical as well as an experimental comparison between the light sheet produced by the standard system (using a rectangular slit aperture and one cylindrical lens) and the one produced by our latest optimized system, which converts a symmetrical Gaussian beam into an ultra-thin light sheet is presented. Using the new light sheet in combination with our objective equipped with a modulator unit to compensate the refractive index mismatch between air and mediums with indices of 1.45-1.56, we present high resolution images of various biological samples that were chemically cleared using different methods. They demonstrate a marked improvement in quality, contrast and resolution. PMID- 28000308 TI - Implementation of an e-learning module improves consistency in the histopathological diagnosis of sessile serrated lesions within a nationwide population screening programme. AB - AIMS: Distinguishing premalignant sessile serrated lesions (SSLs) from hyperplastic polyps (HPs) is difficult for pathologists in daily practice. We aimed to evaluate nationwide variability within histopathology laboratories in the frequency of diagnosing an SSL as compared with an HP within the Dutch population-based screening programme for colorectal cancer and to assess the effect of an e-learning module on interlaboratory consistency. METHODS AND RESULTS: Data were retrieved from the Dutch Pathology Registry from the start of the nationwide population screening programme, January 2014, until December 2015. An obligatory e-learning module was implemented among pathologists in October 2014. The ratio between SSL and HP diagnosis was determined per laboratory. Odds ratios (ORs) for the diagnosis of an SSL per laboratory were compared with the laboratory with the median odds (median laboratory), before and after implementation of the e-learning module. In total, 14 997 individuals with 27 879 serrated polyps were included; 6665 (23.9%) were diagnosed as SSLs, and 21 214 as HPs (76.1%). The ratio of diagnosing an SSL ranged from 5% to 47% (median 23%) within 44 laboratories. Half of the laboratories showed a significantly different OR (range 3.47-0.16) for diagnosing an SSL than the median laboratory. Variability decreased after implementation of the e-learning module (P = 0.02). Of all pathology laboratories, 70% became more consistent with the median laboratory after e-learning implementation. CONCLUSIONS: We demonstrated substantial interlaboratory variability in the histopathological diagnosis of SSLs, which significantly decreased after implementation of a structured e learning module. Widespread implementation of education might contribute to more homogeneous practice among pathologists. PMID- 28000309 TI - Utilization of Permanent His-Bundle Pacing for Management of Proarrhythmia Related to Biventricular Pacing. AB - Biventricular pacing has occasionally been associated with ventricular proarrhythmia, which at times can be refractory to conventional antiarrhythmic drug therapy and ablative intervention. Recently, permanent His-bundle pacing has emerged as a reasonable alternative to right ventricular and biventricular pacing. In addition, by maintaining the physiologic pattern of ventricular electrical activation, it is less likely to be arrhythmogenic. We report the use of permanent His-bundle pacing to manage ventricular proarrhythmia that developed after initiation of biventricular pacing and was unresponsive to antiarrhythmic and ablative therapy. PMID- 28000310 TI - Peanut allergy as a family project: social relations and transitions in adolescence. AB - AIMS AND OBJECTIVES: To explore and better understand the impact that peanut allergy can have on family experiences in everyday life through interviews with individual family members. BACKGROUND: Peanut allergy affects adolescents' quality of life through the need to avoid eating peanut-containing food and the risk of anaphylaxis. Adolescence is a period of increasing separation from parents and has the highest risk of food fatalities. DESIGN: A qualitative interview study taking a phenomenological-hermeneutical approach. METHODS: Data were generated through semi-structured individual interviews with the adolescent with peanut allergy, and both parents and a sibling. Five families were interviewed, with 20 participants in total. The theoretical foundation was the family as an interactive system, and data were analysed with Ricoeur's theory of interpretation. RESULTS: The consequences of peanut allergy appeared to affect all family members and required knowledge and understanding, especially in the social network. Siblings took responsibility and had concerns for the well-being of the adolescent with allergy, while parents expressed difficulties with their child's transition to independence and their subsequent loss of control. Social relations with new family members or friends were challenged by lack of knowledge about the potential seriousness of peanut allergy. CONCLUSIONS: Risk and uncertainty were permanent companions for the adolescents with peanut allergy and their families. It takes time to acquire the necessary understanding about peanut allergy and the risk of anaphylaxis. The adolescent's social network also needs this knowledge during the transition to independent living. RELEVANCE TO CLINICAL PRACTICE: In the management of peanut allergy in adolescence, it is important to consider not only the smaller biological family unit (mothers, fathers and siblings) but to also take a wider perspective to include others such as stepfamily and friends. PMID- 28000311 TI - Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: randomized controlled trial study. AB - BACKGROUND AND PURPOSE: Subcutaneous immunoglobulin (SCIG) is effective as maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). We investigated whether multiple subcutaneous infusions are as effective as conventional therapy with intravenous loading doses in treatment-naive patients with CIDP. METHODS: Twenty patients fulfilling the clinical and electrophysiological criteria for CIDP were included and treated with either SCIG (0.4 g/kg/week) for 5 weeks or intravenous immunoglobulin (IVIG) (0.4 g/kg/day) for 5 days. After 10 weeks, patients were switched to the opposite treatment arm and followed for a further 10 weeks. All participants were evaluated at weeks 0, 2, 5 and 10 during both therapies. Primary outcome was combined isokinetic muscle strength (cIKS). Secondary outcomes were disability, clinical evaluation of muscle strength and the performance of various function tests. RESULTS: All participants received both therapies, 14 completing the protocol. Overall, cIKS increased by 7.4 +/- 14.5% (P = 0.0003) during SCIG and by 6.9 +/- 16.8% (P = 0.002) during IVIG, the effect being similar (P = 0.80). Improvement of cIKS peaked 2 weeks after IVIG and 5 weeks after SCIG. Disability improved during SCIG treatment only. Muscle strength determined by manual muscle testing improved after 5 and 10 weeks during SCIG but only after 5 weeks during IVIG. The remaining parameters improved equally during both treatments. Plasma immunoglobulin G levels at baseline and improvement of cIKS were related. CONCLUSION: In treatment-naive patients with CIDP, short-lasting SCIG and IVIG therapy improve motor performance to a similar degree, but with earlier maximal improvement following IVIG than SCIG treatment. PMID- 28000312 TI - Motor adaptations to unilateral quadriceps fatigue during a bilateral pedaling task. AB - This study was designed to investigate how motor coordination adapts to unilateral fatigue of the quadriceps during a constant-load bilateral pedaling task. We first hypothesized that this local fatigue would not be compensated within the fatigued muscles leading to a decreased knee extension power. Then, we aimed to determine whether this decrease would be compensated by between-joints compensations within the ipsilateral leg and/or an increased contribution of the contralateral leg. Fifteen healthy volunteers were tested during pedaling at 350 W before and after a fatigue protocol consisting of 15 minutes of electromyostimulation on the quadriceps muscle. Motor coordination was assessed from myoelectrical activity (22 muscles) and joint powers calculated through inverse dynamics. Maximal knee extension torque decreased by 28.3%+/-6.8% (P<.0005) immediately after electromyostimulation. A decreased knee extension power produced by the ipsilateral leg was observed during pedaling (-22.8+/-12.3 W, -17.0%+/-9.4%; P<.0005). To maintain the task goal, participants primarily increased the power produced by the non-fatigued contralateral leg during the flexion phase. This was achieved by an increase in hip flexion power confirmed by a higher activation of the tensor fascia latae. These results suggest no adjustment of neural drive to the fatigued muscles and demonstrate no concurrent ipsilateral compensation by the non-fatigued muscles involved in the extension pedaling phase. Although interindividual variability was observed, findings provide evidence that participants predominantly adapted by compensating with the contralateral leg during its flexion phase. Both neural (between legs) and mechanical (between pedals) couplings and the minimization of cost functions might explain these results. PMID- 28000314 TI - Quasimolecules in Compressed Lithium. AB - Under high pressure, some materials form electrides, with valence electrons separated from all atoms and occupying interstitial regions. This is often accompanied by semiconducting or insulating behavior. The interstitial quasiatoms (ISQ) that characterize some high pressure electrides have been postulated to show some of the chemical features of atoms, including the potential of forming covalent bonds. It is argued that in the observed high-pressure semiconducting Li phase (oC40, Aba2), an example of such quasimolecules is realized. The theoretical evaluation of electron density, electron localization function, Wannier orbitals, and bond indices forms the evidence for covalently bonded ISQ pairs in this material. The quasimolecule concept thus provides a simple chemical perspective on the unusual insulating behavior of such materials, complementing the physical picture previously presented where the global crystal symmetry of the system plays the major role. PMID- 28000313 TI - A review of the protective role of melatonin during phosphine-induced cardiotoxicity: focus on mitochondrial dysfunction, oxidative stress and apoptosis. AB - OBJECTIVES: Acute poisoning with aluminium phosphide (AlP) is a major cause of mortality in developing countries. AlP mortality is due to cardiac dysfunction leading to cardiomyocyte death. The main mechanism is an inhibition of cytochrome c oxidase in the cardiomyocyte mitochondria, resulting in a decreased ATP production and oxidative stress. Unfortunately, the administration of exogenous drugs does not meet the desired requirements of an effective therapy. Melatonin is an amphiphilic molecule and can easily pass through all cellular compartments with the highest concentration recorded in mitochondria. It is known as a vigorous antioxidant, acting as a potent reactive oxygen species (ROS) scavenger. Our aim is to summarize the mechanisms by which melatonin may modulate the deteriorating effects of AlP poisoning on cardiac mitochondria. KEY FINDINGS: Melatonin not only mitigates the inhibition of respiratory chain complexes, but also increases ATP generation. Moreover, it can directly inhibit the mitochondrial permeability transition pore (mPTP) opening, thus preventing apoptosis. In addition, melatonin inhibits the release of cytochrome c from mitochondria to hinder caspase activation leading to cell survival. SUMMARY: Based on the promising effects of melatonin on mitochondria, melatonin may mitigate AlP-induced cardiotoxicity and might be potentially suggested as cardioprotective in AlP-intoxicated patients. PMID- 28000315 TI - The Mechanism of p53 Rescue by SUSP4. AB - p53 is an important tumor-suppressor protein deactivation of which by mdm2 results in cancers. A SUMO-specific protease 4 (SUSP4) was shown to rescue p53 from mdm2-mediated deactivation, but the mechanism is unknown. The discovery by NMR spectroscopy of a "p53 rescue motif" in SUSP4 that disrupts p53-mdm2 binding is presented. This 29-residue motif is pre-populated with two transient helices connected by a hydrophobic linker. The helix at the C-terminus binds to the well known p53-binding pocket in mdm2 whereas the N-terminal helix serves as an affinity enhancer. The hydrophobic linker binds to a previously unidentified hydrophobic crevice in mdm2. Overall, SUSP4 appears to use two synergizing modules, the p53 rescue motif described here and a globular-structured SUMO binding catalytic domain, to stabilize p53. A p53 rescue motif peptide exhibits an anti-tumor activity in cancer cell lines expressing wild-type p53. A pre structures motif in the intrinsically disordered proteins is thus important for target recognition. PMID- 28000316 TI - Evolutionary potential of morphological traits across different life-history stages. AB - Despite accumulating examples of selection acting on heritable traits in the wild, predicted evolutionary responses are often different from observed phenotypic trends. Various explanations have been suggested for these mismatches. These include within-individual changes across lifespan that can create important variation in genetic architecture of traits and selection acting on them, but also potential problems with the methodological approach used to predict evolutionary responses of traits. Here, we used an 8-year data set on tree swallow (Tachycineta bicolor) to first assess the effects of differences among three nestling life-history stages on the genetic (co)variances of two morphological traits (body mass and primary feather length) and the selection acting on them over three generations. We then estimated the evolutionary potential of these traits by predicting their evolutionary responses using the breeder's equation and the secondary theorem of selection approaches. Our results showed variation in strength and direction of selection and slight changes in trait variance across ages. Predicted evolutionary responses differed importantly between both approaches for half of the trait-age combinations we studied, suggesting the presence of environmentally induced correlations between focal traits and fitness possibly biasing breeder's equation predictions. Our results emphasize that predictions of evolutionary potential for morphological traits are likely to be highly variable, both in strength and direction, depending on the life stage and method used, thus mitigating our capacity to predict adaptation and persistence of wild populations. PMID- 28000317 TI - Combined liver transplant and pancreaticoduodenectomy for inflammatory hilar myofibroblastic tumor: Case report and review of the literature. AB - IMT, previously known as IPT, is a relatively rare tumor that was originally described in the lungs, but case reports have reported the tumor in almost every organ system. Surgical resection is typically the mainstay of therapy; however, tumors have also been shown to respond to chemotherapy or anti-inflammatory therapy and some have spontaneously regressed. We present a literature review and case report representing the first documentation to date of liver transplant combined with PD for surgical resection of a myofibroblastic tumor non-responsive to medical therapy. PMID- 28000318 TI - Dawn of the direct-acting oral anticoagulants: trends in oral anticoagulant prescribing in Wales 2009-2015. AB - WHAT IS KNOWN AND OBJECTIVE: Oral anticoagulants (OACs) have been used for decades for the long-term prevention of arterial and venous thromboembolic disease. These include warfarin and the newer direct-acting OACs (DOACs). Data on 'real-life' prescribing patterns for DOACs are limited. In this commentary, we report the prescribing patterns for OACs in Wales, as a representative country within the UK. COMMENT: A retrospective analysis of anonymized OAC prescribing data in Wales from June 2009 to December 2015. Results reveal that the number of OAC prescription items increased from 40.48 to 65.26 per 1000 prescribing unit (PU). Average cost increased from L87.41 to L529.31 per 1000 PU. The share of warfarin prescribing declined from 100% to 68%, with the a rising share for the DOACs, made up of rivaroxaban (19%), apixaban (9%) and dabigatran (3%) WHAT IS NEW AND CONCLUSION: Analysis of real-life data demonstrates that there has been an increase in the overall numbers and costs of OAC prescriptions, with a rising proportion of DOACs to warfarin prescribing. PMID- 28000319 TI - Dithienyl Acenedithiophenediones as New pi-Extended Quinoidal Cores: Synthesis and Properties. AB - We have synthesized two isomeric pairs of benzo- and naphthodithiophenediones with two flanking thiophenes and characterized them by single-crystal X-ray analysis, cyclic voltammetry, steady-state optical electronic absorption and emission spectroscopies, transient absorption spectroscopy, and vibrational spectroscopies with in situ spectroelectrochemistry techniques, and then compared them with the thieno[3,2-b]thiophene-2,5-dione counterpart that we previously reported. The results show that the central acenedithiophenedione cores have quinoidal conjugation with closed-shell character. The pi-extension of the quinoidal core raises (lowers) the HOMO (LUMO) energy levels of the triads, resulting in the drastic reduction of their energy gaps from approximately 2.0 eV to 1.1 eV. Owing to the electron-withdrawing nature of the carbonyl terminal group at the quinoidal core, the triads have low-lying LUMO energy levels ranging from -3.9 eV to -4.3 eV, and can be regarded as strong electron-acceptor building units. Interestingly, the pairs of structural isomers have similar electronic structures in both the neutral and charged states despite the different shapes (linear and angular) and/or symmetry (C2h and C2v ) of the acenedithiophenedione cores. PMID- 28000320 TI - Is the early course of multiple sclerosis the same in adults and children? PMID- 28000321 TI - Primary care nursing activities with patients affected by physical chronic disease and common mental disorders: a qualitative descriptive study. AB - AIMS AND OBJECTIVES: To describe nursing activities in primary care with patients affected by physical chronic disease and common mental disorders. BACKGROUND: Patients in primary care who are affected by physical chronic disease and common mental disorders such as anxiety and depression require care and follow-up based on their physical and mental health condition. Primary care nurses are increasingly expected to contribute to the care and follow-up of this growing clientele. However, little is known about the actual activities carried out by primary care nurses in providing this service in the Province of Quebec (Canada). METHODS: A qualitative descriptive study was conducted. Data were obtained through semistructured individual interviews with 13 nurses practising among patients with physical chronic disease in seven Family Medicine Groups in Quebec (Canada). RESULTS: Participants described five activity domains: assessment of physical and mental health condition, care planning, interprofessional collaboration, therapeutic relationship and health promotion. CONCLUSION: The full potential of primary care nurses is not always exploited, and some activities could be improved. Evidence for including nurses in collaborative care for patients affected by physical chronic disease and common mental disorders has been shown but is not fully implemented in Family Medicine Groups. Future research should emphasise collaboration among mental health professionals, primary care nurses and family physicians in the care of patients with physical chronic disease and common mental disorders. RELEVANCE TO CLINICAL PRACTICE: Primary care nurses would benefit from gaining more knowledge about common mental disorders and from identifying the resources they need to contribute to managing them in an interdisciplinary team. PMID- 28000322 TI - Head-drop: A frequent feature of late-onset myasthenia gravis. AB - INTRODUCTION: Head-drop is often encountered in myasthenia gravis (MG) patients, but its frequency and clinical course have not been studied systematically. METHODS: In a retrospective study of a cohort of MG patients seen over a period of 11 years in a tertiary medical center, we assessed the clinical characteristics of patients who had head-drop. RESULTS: Of 146 generalized MG patients, 15 had head-drop during the course of their disease. Head-drop patients had older age of onset than those who did not have head-drop (mean age of onset 59.1 vs. 42.3 years) and were predominantly men. Head-drop was present in 23% of patients > 60 versus 6% of those < 60 years, and it improved in 9 of 11 patients with treatment directed to generalized MG. CONCLUSIONS: Head-drop is a common, treatment-responsive manifestation of late-onset MG. Muscle Nerve 56: 441-444, 2017. PMID- 28000323 TI - Large Areal Mass, Mechanically Tough and Freestanding Electrode Based on Heteroatom-doped Carbon Nanofibers for Flexible Supercapacitors. AB - A flexible and freestanding supercapacitor electrode with a N,P-co-doped carbon nanofiber network (N,P-CNFs)/graphene (GN) composite loaded on bacterial cellulose (BC) is first designed and fabricated in a simple, low-cost, and effective approach. The porous structure and excellent mechanical properties make the BC paper an ideal substrate that shows a large areal mass of 8 mg cm-2 . As a result, the flexible N,P-CNFs/GN/BC paper electrode shows appreciable areal capacitance (1990 mF cm-2 in KOH and 2588 mF cm-2 in H2 SO4 electrolytes) without sacrificing gravimetric capacitance (248.8 F g-1 and 323.5 F g-1 ), exhibits excellent cycling ability (without capacity loss after 20 000 cycles), and remarkable tensile strength (42.8 MPa). By direct coupling of two membrane electrodes, the symmetric supercapacitor delivers a prominent areal capacitance of 690 mF cm-2 in KOH and 898 mF cm-2 in H2 SO4 , and remarkable power/energy density (19.98 mW cm-2 /0.096 mW h cm-2 in KOH and 35.01 mW cm-2 /0.244 mW h cm-2 in H2 SO4 ). Additionally, it shows stable behavior in both bent and flat states. These results promote new opportunities for N,P-CNFs/GN/BC paper electrodes as high areal performance, freestanding electrodes for flexible supercapacitors. PMID- 28000324 TI - Mixed-Valence Nickel Bis(azamacrocycle) Compounds with Ghost-Leg-type Sheets. AB - The fabrication of so-called ghost-leg sheets and their electronic properties is reported. This unique sheet structure is composed of one-dimensional mixed valence nickel chains, which are linked with one another by bis(azamacrocycle) ligands. They are also topologically unique NiII /NiIII mixed-valence complexes, as confirmed by X-ray and optical measurements. Moreover, their magnetic susceptibilities indicated two-dimensional antiferromagnetic behavior following the Fisher 1D chain model with interchain interactions, where spins on NiIII sites mutually interact antiferromagnetically in the sheets. PMID- 28000325 TI - Breast conservation in ductal carcinoma in situ (DCIS): what defines optimal margins? AB - The introduction of mammographic screening has resulted in a rise in the detection rate of ductal carcinoma in situ (DCIS), currently accounting for one fifth of screen-detected breast cancers. Although 60-70% of DCIS are treated with breast-conserving surgery (BCS) with or without radiotherapy, the frequency of subsequent surgery to re-excise positive margins in order to reduce the probability of recurrences remains high. DCIS recurrence is associated not only with financial, health and psychological implications; approximately half these recurrences are invasive disease. An appropriate margin width for patients undergoing BCS for invasive breast cancer has been largely agreed. Although there is a perception that such recommendations may be applicable to DCIS, major differences exist which may affect this application. Importantly, DCIS patients often do not receive systemic adjuvant (endocrine) therapy and not all receive radiotherapy in routine practice. There is evidence that wide margins (i.e. >10 mm) confer better protection against recurrence than positive (i.e. 0 mm) margins; however, there remains a debate concerning the optimum margin width between 0 and 10 mm. Previous studies have demonstrated that radiation therapy may not compensate for lack of re-excision in those patients with positive or close margins, while wide margins will inevitably compromise cosmesis and patients' body image perception. This review aims to address the clinical question of the minimal margin width in DCIS treated with BCS that is associated with the lowest recurrence rate and when, therefore, further surgical intervention for re-excision can be safely avoided. A range of clinical circumstances that might affect this are considered. PMID- 28000326 TI - Military to civilian nurse: Personal and professional reconstruction. AB - AIMS AND OBJECTIVES: To examine and describe the transition process of military nurses from military nursing practice to civilian nursing practice. A second aim was to identify challenges and facilitators to this transition. BACKGROUND: Serving in the military, and embodying its values, can have a major impact on a person's worldview. These individuals serve not only as nurses but also as part of a larger military culture with a mission to protect. The decision to separate from the military and transition into the civilian workforce carries many challenges capable of influencing nurses' personal and professional identities. DESIGN: Qualitative descriptive. METHODS: Semi-structured interviews of 10 nurse veterans were conducted in 2015-2016. Data were collected until saturation was reached. RESULTS: The transition includes four major phases from military to civilian nurse: Separating from Military Life, Conflict and Chaos, Shifting Sands and Personal and Professional Reconstruction. Duration and progress through each phase varied slightly for individual nurses. CONCLUSIONS: Both work-role and personal identity transition occur when a nurse leaves the military and enters civilian practice. Military and civilian organisations, in both the USA and other countries, can implement supports to aid these nurses during this personal and professional change. Recommendations from the study group are provided. RELEVANCE TO CLINICAL PRACTICE: The global nursing profession, as well as healthcare organisations that employ nurse veterans, has a commitment and obligation to understand the transition process of nurses who practise within the scope of military nursing and later in civilian nursing environments so that they may be supported and used to the extent of their prior experience. Lessons learned and advice from this group of nurses may positively aid others in their transition experience. PMID- 28000327 TI - JOINT VIRTUAL ISSUE: WHAT IS NEW WITH EQUINE IMAGING? PMID- 28000328 TI - Inorganic and Organometallic Molecular Wires for Single-Molecule Devices. AB - Recent developments of single-molecule conductance measurements allow us to understand fundamental conducting properties of molecular wires. While a wide variety of organic molecular wires have been studied so far, inorganic and organometallic molecular wires have received much less attention. However, molecular wires with transition-metal atoms show interesting features and functions distinct from those of organic wires. These properties originate mainly from metal-ligand dpi-ppi interactions and metal-metal d-d interactions. Thanks to the rich combination of metal atoms and supporting ligands, frontier orbital energies of the molecular wires can be finely tuned to lead to highly conducting molecular wires. Moreover, the unique electronic structures of metal complexes are susceptible to subtle environmental changes, leading to potential functional molecular devices. This article reviews recent advances in the single-molecule conductance study of inorganic and organometallic molecular wires. PMID- 28000330 TI - Substrate Binding by a Parallel Metal Sheet Sandwich Complex: A Unique Role of an Additional Metal Atom. AB - A unique metal addition to the edge of a triangular palladium sandwich cluster is reported. While the edge coordination sites of a parallel sandwich complex are narrow because of two sterically encumbering pi-ligands, association of an additional metal atom to a metal sheet gives a wider coordination site. It was proved that the additional metal atom plays a crucial role in binding of cyclopentadienyl by a Pd3 sheet sandwich complex. PMID- 28000329 TI - Polymerase-Mediated Site-Specific Incorporation of a Synthetic Fluorescent Isomorphic G Surrogate into RNA. AB - An enzyme-mediated approach for the assembly of singly modified RNA constructs in which specific G residues are replaced with th G, an emissive isomorphic G surrogate, is reported. Transcription in the presence of th G and native nucleoside triphosphates enforces initiation with the unnatural analogue, yielding 5'-end modified transcripts that can be mono-phosphorylated and ligated to provide longer site-specifically modified RNA constructs. The scope of this unprecedented enzymatic approach to non-canonical purine-containing RNAs is explored via the assembly of several altered hammerhead (HH) ribozymes and a singly modified HH substrate. By strategically modifying key positions, a mechanistic insight into the ribozyme-mediated cleavage is gained. Additionally, the emissive features of the modified nucleoside and its responsiveness to environmental changes can be used to monitor cleavage in real time by steady state fluorescence spectroscopy. PMID- 28000331 TI - Exploring the potential role of the advanced nurse practitioner within a care path for patients with chronic fatigue syndrome. AB - AIMS: To explore the experiences and expectations of patients with chronic fatigue syndrome and general practitioners to develop the potential role of an advanced nurse practitioner at the diagnostic care path of abnormal fatigue developed for regional transmural implementation in the Belgian provinces of East and West Flanders. BACKGROUND: Patients with chronic fatigue syndrome experience an incapacitating chronic fatigue that is present for at least 6 months. Since many uncertainties exist about the causes and progression of the disease, patients have to cope with disbelief and scepticism. Access to health care may be hampered, which could lead to inappropriate treatments and guidance. DESIGN: Qualitative design. METHODS: Individual semi-structured interviews were conducted with patients with chronic fatigue syndrome and general practitioners in Belgium. Data were collected over 9 months in 2014-2015. All interviews were audio recorded and transcribed for qualitative analysis using open explorative thematic coding. RESULTS: Fifteen patients and 15 general practitioners were interviewed. Three themes were identified: mixed feelings with the diagnosis, lack of one central intermediator and insufficient coordination. Participants stressed the need for education, knowledge and an intermediator to provide relevant information at the right time and to build up a trust relationship. CONCLUSION: This qualitative exploration underscores some clear deficiencies in the guidance of patients suffering from chronic fatigue syndrome and abnormal fatigue. An advanced nurse practitioner as a central intermediator in the transmural care of these patients could promote interdisciplinary/multidisciplinary collaboration and effective communication, provide education and ensure a structured and coordinated approach. PMID- 28000332 TI - Oxidative Intramolecular 1,2-Amino-Oxygenation of Alkynes under AuI /AuIII Catalysis: Discovery of a Pyridinium-Oxazole Dyad as an Ionic Fluorophore. AB - Oxidative intramolecular 1,2-amino-oxygenation reactions, combining gold(I)/gold(III) catalysis, is reported. The reaction provides efficient access to a structurally unique ionic pyridinium-oxazole dyad with tunable emission wavelengths. The application of these fluorophores as potential biomarkers has been investigated. PMID- 28000333 TI - Leveraging Social Capital of Individuals with Intellectual Disabilities through Participation on Facebook. AB - BACKGROUND: Participation in social networking sites has considerable potential to leverage the individual's social capital, including persons with intellectual disabilities, whose real-world social networks are fairly limited. METHOD: This study aimed to understand how individuals with intellectual disabilities use Facebook to access social capital benefits, if at all. Qualitative interviews and observations were conducted with 20 adult Facebook users with intellectual disabilities. RESULTS: The online participation enhanced their bonding social capital as well as contributed to their psychological well-being through increasing their online visibility, popularity and sense of belonging. At the same time, they experienced stress and frustration due to usage difficulties, which prevented them from enhancing their bridging social capital. CONCLUSIONS: Participation in social networking sites may also leverage bridging social capital of persons with intellectual disabilities, but they need a more accessible platform and ongoing support to ensure safe and fruitful participation. PMID- 28000334 TI - Halogen-Bonded Supramolecular Capsules in the Solid State, in Solution, and in the Gas Phase. AB - Supramolecular capsules were assembled by neutral halogen bonding (XB) and studied in the solid state, in solution, and in the gas phase. The geometry of the highly organized capsules is shown by an X-ray crystal structure which features the assembly of two XB hemispheres, geometrically rigidified by H bonding to eight MeOH molecules and encapsulation of two benzene guests. To enhance capsular association strength, tuning the XB donor is more efficient than tuning the XB acceptor, due to desolvation penalties in protic solvents, as shown for a tetraquinuclidine XB acceptor hemisphere. With a tetra(iodoethynyl) XB donor and a tetralutidine XB acceptor, the association in deuterated benzene/acetone/methanol 70:30:1 at 283 K reaches Ka =(2.11+/-0.39)*105 m-1 (DeltaG=-6.9+/-0.1 kcal mol-1 ). The stability of the XB capsules in the gas phase was confirmed by electrospray ionization mass spectrometry (ESI-MS). A new guest binding site was uncovered within the elongated iodoethynyl capsule. PMID- 28000335 TI - Child protection services and parents with intellectual and developmental disabilities. AB - BACKGROUND: Information about parents with intellectual and developmental disabilities (IDD) in the child protection system (CPS) continues to evolve. This study examined characteristics, experiences and representation of parents with IDD across three CPS decision points, as compared to parents with other disabilities and parents without disabilities in the United States. METHODS: The sample consisted of 303,039 individuals: 2,081 were individuals identified as parents in a CPS investigation; 1,101 had children in out-of-home care (OHC); and 308 experienced termination of parental rights (TPR). Descriptive statistics, chi square analysis, disparity indices and logistic regression were employed. RESULTS: Parents with IDD were significantly more likely than parents without disabilities (but not significantly more likely than parents with other types of disabilities) to experience disproportionately representation. CONCLUSIONS: Parents with IDD are generally over-represented within CPS; however, this representation is dependent upon the comparison group utilized and other risk factors. CPS system-level changes are necessary. PMID- 28000336 TI - Inferring human microbial dynamics from temporal metagenomics data: Pitfalls and lessons. AB - The human gut microbiota is a very complex and dynamic ecosystem that plays a crucial role in health and well-being. Inferring microbial community structure and dynamics directly from time-resolved metagenomics data is key to understanding the community ecology and predicting its temporal behavior. Many methods have been proposed to perform the inference. Yet, as we point out in this review, there are several pitfalls along the way. Indeed, the uninformative temporal measurements and the compositional nature of the relative abundance data raise serious challenges in inference. Moreover, the inference results can be largely distorted when only focusing on highly abundant species by ignoring or grouping low-abundance species. Finally, the implicit assumptions in various regularization methods may not reflect reality. Those issues have to be seriously considered in ecological modeling of human gut microbiota. PMID- 28000337 TI - "Helix-in-Helix" Superstructure Formation through Encapsulation of Fullerene Bound Helical Peptides within a Helical Poly(methyl methacrylate) Cavity. AB - A one-handed 310 -helical hexapeptide is efficiently encapsulated within the helical cavity of st-PMMA when a fullerene (C60 ) derivative is introduced at the C-terminal end of the peptide. The encapsulation is accompanied by induction of a preferred-handed helical conformation in the st-PMMA backbone with the same handedness as that of the hexapeptide to form a crystalline st-PMMA/peptide-C60 inclusion complex with a unique optically active helix-in-helix structure. Although the st-PMMA is unable to encapsulate the 310 -helical peptide without the terminal C60 unit, the helical hollow space of the st-PMMA is almost filled by the C60 -bound peptides. This result suggests that the C60 moiety can serve as a versatile molecular carrier of specific molecules and polymers in the helical cavity of the st-PMMA for the formation of an inclusion complex, thus producing unique supramolecular soft materials that cannot be prepared by other methods. PMID- 28000338 TI - Opt-out screening strategy for HIV infection among patients attending emergency departments: systematic review and meta-analysis. AB - OBJECTIVES: International health agencies have promoted nontargeted universal (opt-out) HIV screening tests in different settings, including emergency departments (EDs). We performed a systematic review and meta-analysis to assess the testing uptake of strategies (opt-in targeted, opt-in nontargeted and opt out) to detect new cases of HIV infection in EDs. METHODS: We searched the Pubmed and Embase databases, from 1984 to April 2015, for opt-in and opt-out HIV diagnostic strategies used in EDs. Randomized controlled or quasi experimental studies were included. We assessed the percentage of positive individuals tested for HIV infection in each programme (opt-in and opt-out strategies). The mean percentage was estimated by combining studies in a random-effect meta-analysis. The percentages of individuals tested in the programmes were compared in a random effect meta-regression model. Data were analysed using stata version 12. Quality assessments were performed using the Newcastle-Ottawa Scale. RESULTS: Of the 90 papers identified, 28 were eligible for inclusion. Eight trials used opt-out, 18 trials used opt-in, and two trials used both to detect new cases of HIV infection. The test was accepted and taken by 75 155 of 172 237 patients (44%) in the opt-out strategy, and 73 581 of 382 992 patients (19%) in the opt-in strategy. The prevalence of HIV infection detected by the opt-out strategy was 0.40% (373 cases), that detected by the opt-in nontargeted strategy was 0.52% (419 cases), and that detected by the opt-in targeted strategy was 1.06% (52 cases). CONCLUSIONS: In this meta-analysis, the testing uptake of the opt-out strategy was not different from that of the opt-in strategy to detect new cases of HIV infection in EDs. PMID- 28000339 TI - People with epilepsy receive more statins than the general population but have no higher cardiovascular risk: results from a cross-sectional study. AB - BACKGROUND AND PURPOSE: Epilepsy has been associated with cardiovascular comorbidity. Risk prediction equations are the standard tools in primary prevention of cardiovascular disease. Our aim was to compare the prevalence of cardiovascular risk factors (CVRFs), cardiovascular risk and statin use in people with epilepsy (PWE) and the general population. METHODS: The CVRFs and cardiovascular risk score were compared between 815 PWE from an outpatient register and 5336 participants from a general population cohort. RESULTS: People with epilepsy had less hypertension (43.3% vs. 50.4%), less diabetes (15.8% vs. 19.2%), more dyslipidemia (40.2% vs. 34.6%) and lower cardiovascular risk than the general population (P < 0.01). No etiology was associated with a worse CVRF profile or higher cardiovascular risk. Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) had more dyslipidemia than the general population (41.6% vs. 34.6%) but similar cardiovascular risk. Independently of risk or CVRFs, PWE had 60% more probability of receiving statins than the general population. CONCLUSIONS: People with epilepsy had more dyslipidemia, related to EIAEDs, and lower cardiovascular risk but still took more statins than the general population. Physicians should use clinical judgement to decide on further treatment of CVRFs in PWE who are below the recommended risk threshold for treatment and should consider lipid abnormalities a potential side-effect of EIAEDs. Other therapy options may need to be evaluated before starting lipid lowering treatment. PMID- 28000340 TI - Orientational Disorder in Adamantane and Adamantanecarboxylic Acid. AB - The molecular crystals adamantane, C10 H16 , and adamantanecarboxylic acid, C10 H15 COOH, undergo order-disorder phase transitions at 208 and 250 K, respectively. Reverse Monte Carlo refinement of total neutron scattering data collected from deuterated samples immediately above these phase transitions shows that the high-temperature phases are well described by models in which the adamantyl groups are disordered over two sites. No correlation between the orientations of neighbouring molecules is observed. These results demonstrate that the intermolecular potential energy of these materials depends strongly on the orientation of the reference molecule but only very weakly on the orientations of its neighbours. PMID- 28000341 TI - Heart failure in haemoglobinopathies: pathophysiology, clinical phenotypes, and management. AB - Hereditary haemoglobinopathies, mainly beta-thalassemia and sickle cell disease, constitute the most common monogenic disorders in humans, and although once geographically confined, they are currently globally distributed. They are demanding clinical entities that require multidisciplinary medical management. Despite their genotypic and phenotypic heterogeneity, the haemoglobinopathies share several similarities in pathophysiology, clinical manifestations, therapeutic requirements, and complications, among which heart failure (HF) represents a leading cause of mortality and morbidity. However, haemoglobinopathies have generally been addressed in a rather fragmentary manner. A unifying approach focusing on the underlying similarities of HF attributes in the two main entities might contribute to their better understanding, characterization, and management. In the present review, we attempt such an approach to the pathophysiology, clinical phenotypes, and management of HF in haemoglobinopathies. PMID- 28000342 TI - A new model of short acceleration-based training improves exercise performance in old mice. AB - In order to identify a more appealing exercise strategy for the elderly, we studied a mouse model to determine whether a less time-consuming training program would improve exercise performance, enzyme activities, mitochondrial respiration, and metabolomic parameters. We compared the effects of short-session (acceleration-based) training with those of long-session endurance training in 23 month-old mice. The short-session training consisted of five acceleration-based treadmill running sessions over 2 weeks (the acceleration group), whereas the endurance training consisted of five-one-hour treadmill sessions per week for 4 weeks (the endurance group). A control group of mice was also studied. In the acceleration group, the post-training maximum running speed and time to exhaustion were significantly improved, relative to pretraining values (+8% for speed, P<.05; +10% for time to exhaustion, P<.01). The post-training maximum running speed was higher in the acceleration group than in the endurance group (by 23%; P<.001) and in the control group (by 15%; P<.05). In skeletal muscle samples, the enzymatic activities of citrate synthase, lactate dehydrogenase, and creatine kinase were significantly higher in the acceleration group than in the endurance group. Furthermore, mitochondrial respiratory activity in the gastrocnemius was higher in the acceleration group than in the control group. A metabolomic urine analysis revealed a higher mean taurine concentration and a lower mean branched amino acid concentration in the acceleration group. In old mice, acceleration-based training appears to be an efficient way of increasing performance by improving both aerobic and anaerobic metabolism, and possibly by enhancing antioxidant defenses and maintaining muscle protein balance. PMID- 28000343 TI - Prevalence and clinical significance of cancer cachexia based on time from treatment in advanced-stage head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to identify the prevalence of cancer cachexia and its prognostic impact in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS: The prevalence of cancer cachexia was analyzed according to the follow-up periods during the first year after curative initial treatment. Recurrences, noncancer health events (NCHEs), and cause specific survival outcomes were also analyzed according to the incidence of cancer cachexia during follow-up. RESULTS: Cancer cachexia was identified in 22 (6.1%), 148 (41%), 66 (18.4%), and 65 (18.7%) of 361 enrolled patients at pretreatment, immediately after treatment, 6-months after treatment, and 12 months after treatment, respectively. Sustained or newly developed cachexia at 6 and 12 months showed a significant association with recurrence and NCHE occurrence (p < .05). In cause-specific survival analysis, patients with cachexia had a higher probability of cancer-specific death, noncancerous death, and overall death (p < .05). CONCLUSION: Cachexia prevalence at 6 and 12 months after treatment for HNSCC indicates a higher chance of recurrence, NCHE, and death. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 716-723, 2017. PMID- 28000344 TI - Emergency department utilization by Californians with sickle cell disease, 2005 2014. AB - BACKGROUND: Clinical care for children and adults living with sickle cell disease (SCD) is often provided in the emergency department (ED). Population-based surveillance data can be used to describe the ED utilization patterns of this patient population. PROCEDURE: A cohort of pediatric and adult California patients with SCD was identified from multiple data sources, and 10 years (2005 2014) of their treat-and-release ED utilization data were analyzed. RESULTS: Among a cohort of 4,636 patients with SCD, 4,100 (88%) had one or more treat-and release ED visits. There were 2.1 mean annual visits per person for the cohort (median 0.7; range 0-185). In a single year (2005), 53% had 0 treat-and-release ED visits, 35% had 1-3 visits, 9% had 4-10 visits, and 3% had 11 or more visits; this highest utilization group accounted for 45% of all patients' ED visits. ED utilization in this cohort was highest among young adults and also higher among older adults than pediatric patients. CONCLUSION: The majority of identified patients in each of the 10 years did not go to the ED, but nearly all had one or more such visits over the full span of time. This study highlights the power and utility of a multisource longitudinal data collection effort for SCD. Further study of the segment of the population with highest ED utilization may highlight areas where changes in healthcare and health policy could improve and extend the lives of patients with SCD. PMID- 28000345 TI - Orthopedic and histopathological study on "detritic synovitis" in cases of primary and revision total hip arthroplasty. PMID- 28000346 TI - Diverse Visible-Light-Promoted Functionalizations of Benzotriazoles Inspired by Mechanism-Based Luminescence Screening. AB - Three new visible-light-promoted functionalizations of benzotriazole substrates were discovered using a mechanism-based screening method. ortho-Thiolated, borylated, and alkylated N-arylbenzamide products were obtained under mild reaction conditions in a new denitrogenative synthetic approach to functionalized aniline derivatives. The functional group tolerance of the borylation reaction was further analyzed in the first application of an additive-based robustness screen in a photocatalytic transformation. All the functionalizations proceed via photocatalytically initiated chain mechanisms as indicated by determination of the reaction quantum yields and Stern-Volmer analyses. PMID- 28000347 TI - Response to Professor Kawada. PMID- 28000348 TI - No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case-control study. AB - BACKGROUND AND PURPOSE: Previous studies, mostly case reports and uncontrolled studies, provide a low level of evidence for the hypothesized link between Lyme disease and amyotrophic lateral sclerosis (ALS). In order to make evidence-based recommendations regarding testing for Borrelia burgdorferi antibodies in the diagnostic work-up for ALS, the objective of this study was to explore the evidence for an association between these antibodies and ALS in a case-control design including age-, gender- and residency-matched controls. METHODS: A total of 491 patients with ALS were matched to 982 controls. IgG titers against B. burgdorferi were determined by an enzyme-linked immunosorbent assay and, in the case of positivity or borderline results, a western blot was performed. Conditional logistic regression and Fisher's exact tests were used to compare the antibody titers or positivity between patients and controls. RESULTS: No difference in seroprevalence of Borrelia was found between patients (4.1%) and controls (5.9%). Clinical characteristics and survival were similar between seropositive and seronegative patients. Moreover, patients with a spinal onset were not more frequently seropositive compared with patients with a bulbar onset (P = 0.47), and neither were patients with a short diagnostic delay of <6 months compared with controls (P = 0.69). None of the 20 patients with a diagnostic delay of <3 months tested positive for IgM antibodies, suggestive of a recent infection. CONCLUSION: This large case-control study provides evidence for a lack of association between B. burgdorferi antibodies and ALS, and therefore does not support the inclusion of routine testing for these antibodies in the diagnostic work-up in patients with classical ALS. PMID- 28000349 TI - Response to comment on plasma uric acid and risk of ischaemic stroke in women. PMID- 28000350 TI - Risk factors for onset of amyotrophic lateral sclerosis. PMID- 28000352 TI - A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia. PMID- 28000353 TI - Physical and cognitive fitness in young adulthood and risk of amyotrophic lateral sclerosis at an early age. AB - BACKGROUND AND PURPOSE: There is a clinical impression that patients with amyotrophic lateral sclerosis (ALS) have a higher level of physical fitness and lower body mass index (BMI) than average. However, there is a lack of literature examining the relationship between cognitive fitness and ALS risk. In this study we explored the associations of both physical and cognitive fitness with future risk of ALS. METHODS: Data on physical fitness, BMI, intelligence quotient (IQ) and stress resilience were collected from 1 838 376 Swedish men aged 17-20 years at conscription during 1968-2010. Their subsequent ALS diagnoses were identified through the Swedish Patient Register. Hazard ratios (HRs) and 95% CIs from flexible parametric models were used to assess age-specific associations of physical fitness, BMI, IQ and stress resilience with ALS. RESULTS: We identified 439 incident ALS cases during follow-up (mean age at diagnosis: 48 years). Individuals with physical fitness above the highest tertile tended to have a higher risk of ALS before the age of 45 years (range of HRs: 1.42-1.75; statistically significant associations at age 41-43 years) compared with others. Individuals with BMI >= 25 tended to have a lower risk of ALS at all ages (range of HRs: 0.42-0.80; statistically significant associations at age 42-48 years) compared with those with BMI < 25. Individuals with IQ above the highest tertile had a statistically significantly increased risk of ALS at an age of 56 years and above (range of HRs: 1.33-1.81), whereas individuals with stress resilience above the highest tertile had a lower risk of ALS at an age of 55 years and below (range of HRs: 0.47-0.73). CONCLUSIONS: Physical fitness, BMI, IQ and stress resilience in young adulthood might be associated with the development of ALS at an early age. PMID- 28000354 TI - Evaluation of a Social Network Intervention for People with Mild to Borderline Intellectual Disabilities. AB - BACKGROUND: Little is known about the effectiveness of interventions aimed at enhancing the social networks of people with intellectual disabilities. This study explores the results of such an intervention. How did the clients with mild to borderline intellectual disabilities and their support workers evaluate the intervention? What did they learn from it? Were there any changes in network characteristics, satisfaction and wishes in relation to networks, participation, loneliness, self-determination or self-esteem? METHOD: The evaluation of the intervention was explored from several perspectives (i.e. five clients, their six support workers and three trainers), using mixed methods (i.e. interviews and questionnaires). RESULTS: The intervention was positively evaluated by both clients and support workers. Moreover, the analysis revealed the vulnerability of clients and their networks but also the benefits experienced from the intervention, such as decreased loneliness, enhanced social networks, increased awareness, competence, autonomy and increased participation. CONCLUSION: The indicative level of evidence for the effectiveness of this intervention justifies a larger series of case studies or a larger control trial study. PMID- 28000357 TI - Conceptualizing and Treating Social Anxiety in Autism Spectrum Disorder: A Focus Group Study with Multidisciplinary Professionals. AB - BACKGROUND: Individuals who have autism spectrum disorders (ASD) commonly experience social anxiety (SA). Disentangling SA symptoms from core ASD characteristics is complex, partly due to diagnostic overshadowing and co occurring alexithymia. Causal and maintaining mechanisms for SA in ASD are underexplored, but it is feasible that there is an ASD specificity to the clinical presentation, with implications for the development of targeted treatments. METHODS: Five focus groups were conducted with multidisciplinary professionals to investigate their perspectives about, and approaches to, working with individuals with ASD and SA. Data were analysed thematically. RESULTS: Data analysis revealed two overarching themes: conceptualizing SA in ASD and service provision. Our results suggest that adaptations to service provision are pertinent, so as to accommodate inherent impairments that can mediate assessment and intervention. CONCLUSIONS: Future studies should establish how aspects of the care pathway can be improved for individuals with ASD and SA. PMID- 28000359 TI - Corrigendum. PMID- 28000358 TI - A feasibility study for a clinical decision support system prompting HIV testing. AB - OBJECTIVES: Levels of undiagnosed HIV infection and late presentation remain high globally despite attempts to increase testing. The objective of this study was to evaluate a risk-based prototype application to prompt HIV testing when patients undergo routine blood tests. METHODS: Two computer physician order entry (CPOE) systems were modified using the application to prompt health care workers (HCWs) to add an HIV test when other tests selected suggested that the patient was at higher risk of HIV infection. The application was applied for a 3-month period in two areas, in a large London hospital and in general practices in Teesside/North Yorkshire. At the end of the evaluation period, HCWs were interviewed to assess the usability and acceptability of the prompt. Numbers of HIV tests ordered in the general practice areas were also compared before and after the prompt's introduction. RESULTS: The system was found to be both useable and generally acceptable to hospital doctors, general practitioners and nurse practitioners, with little evidence of prompt/alert fatigue. The issue of the prompt appearing late in the patient consultation did lead to some difficulties, particularly around discussion of the test and consent. In the general practices, around 1 in 10 prompts were accepted and there was a 6% increase in testing rates over the 3 month study period (P = 0.169). CONCLUSIONS: Using a CPOE-based clinical decision support application to prompt HIV testing appears both feasible and acceptable to HCWs. Refining the application to provide more accurate risk stratification is likely to make it more effective. PMID- 28000360 TI - Radical Desulfur-Fragmentation and Reconstruction of Enol Triflates: Facile Access to alpha-Trifluoromethyl Ketones. AB - We report an efficient oxidative radical desulfur-fragmentation and reconstruction of enol triflates for the synthesis of alpha-CF3 ketones. Preliminary mechanistic studies disclosed that oxidative fragmentation to release a CF3 radical from the triflyl group of enol triflate and subsequent addition of the CF3 radical to another enol triflate form the desired alpha-CF3 ketones. This method provides a new approach to alpha-CF3 ketones, featuring the utilization of catalytic amount of oxidants, broad substrate scope, and potential to control the regioselectivity. PMID- 28000362 TI - Modified porous scaffolds of silk fibroin with mimicked microenvironment based on decellularized pulp/fibronectin for designed performance biomaterials in maxillofacial bone defect. AB - Maxillofacial bone defect is a critical problem for many patients. In severe cases, the patients need an operation using a biomaterial replacement. Therefore, to design performance biomaterials is a challenge for materials scientists and maxillofacial surgeons. In this research, porous silk fibroin scaffolds with mimicked microenvironment based on decellularized pulp and fibronectin were created as for bone regeneration. Silk fibroin scaffolds were fabricated by freeze-drying before modification with three different components: decellularized pulp, fibronectin, and decellularized pulp/fibronectin. The morphologies of the modified scaffolds were observed by scanning electron microscopy. Existence of the modifying components in the scaffolds was proved by the increase in weights and from the pore size measurements of the scaffolds. The modified scaffolds were seeded with MG-63 osteoblasts and cultured. Testing of the biofunctionalities included cell viability, cell proliferation, calcium content, alkaline phosphatase activity (ALP), mineralization and histological analysis. The results demonstrated that the modifying components organized themselves into aggregations of a globular structure. They were arranged themselves into clusters of aggregations with a fibril structure in the porous walls of the scaffolds. The results showed that modified scaffolds with a mimicked microenvironment of decellularized pulp/fibronectin were suitable for cell viability since the cells could attach and spread into most of the pores of the scaffold. Furthermore, the scaffolds could induce calcium synthesis, mineralization, and ALP activity. The results indicated that modified silk fibroin scaffolds with a mimicked microenvironment of decellularized pulp/fibronectin hold promise for use in tissue engineering in maxillofacial bone defects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1624-1636, 2017. PMID- 28000361 TI - Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization. AB - Detailed conformational analyses of our previously reported cyclopropane-based peptidomimetics and conformational analysis-driven ligand optimization are described. Computational calculations and X-ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three-dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main-chain and side-chain conformations. Based on these analyses, a lead stereoisomer targeting melanocortin receptors was identified, and its potency and subtype selectivity were improved by further derivatization. The presented strategy is effective not only for designing non-peptidic ligands from a peptide ligand but also for the rational optimization of these ligands based on the plausible target binding conformation without requiring the three- dimensional structural information of the target and its peptide ligands. PMID- 28000363 TI - Native Top-Down Mass Spectrometry of TAR RNA in Complexes with a Wild-Type tat Peptide for Binding Site Mapping. AB - Ribonucleic acids (RNA) frequently associate with proteins in many biological processes to form more or less stable complex structures. The characterization of RNA-protein complex structures and binding interfaces by nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, or strategies based on chemical crosslinking, however, can be quite challenging. Herein, we have explored the use of an alternative method, native top-down mass spectrometry (MS), for probing of complex stoichiometry and protein binding sites at the single-residue level of RNA. Our data show that the electrostatic interactions between HIV-1 TAR RNA and a peptide comprising the arginine-rich binding region of tat protein are sufficiently strong in the gas phase to survive phosphodiester backbone cleavage of RNA by collisionally activated dissociation (CAD), thus allowing its use for probing tat binding sites in TAR RNA by top-down MS. Moreover, the MS data reveal time-dependent 1:2 and 1:1 stoichiometries of the TAR-tat complexes and suggest structural rearrangements of TAR RNA induced by binding of tat peptide. PMID- 28000364 TI - A Specific Activity-Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease. AB - Galactosylceramidase (GALC) is the lysosomal beta-galactosidase responsible for the hydrolysis of galactosylceramide. Inherited deficiency in GALC causes Krabbe disease, a devastating neurological disorder characterized by accumulation of galactosylceramide and its deacylated counterpart, the toxic sphingoid base galactosylsphingosine (psychosine). We report the design and application of a fluorescently tagged activity-based probe (ABP) for the sensitive and specific labeling of active GALC molecules from various species. The probe consists of a beta-galactopyranose-configured cyclophellitol-epoxide core, conferring specificity for GALC, equipped with a BODIPY fluorophore at C6 that allows visualization of active enzyme in cells and tissues. Detection of residual GALC in patient fibroblasts holds great promise for laboratory diagnosis of Krabbe disease. We further describe a procedure for in situ imaging of active GALC in murine brain by intra-cerebroventricular infusion of the ABP. In conclusion, this GALC-specific ABP should find broad applications in diagnosis, drug development, and evaluation of therapy for Krabbe disease. PMID- 28000365 TI - Preoperative platelet-to-lymphocyte ratio can predict recurrence beyond the Milan criteria after hepatectomy for patients with hepatocellular carcinoma. AB - AIM: Postoperative recurrence beyond the Milan criteria is a poor prognostic factor for patients with hepatocellular carcinoma (HCC) treated with various therapies. We investigated the most useful inflammation-based prognostic score for predicting recurrence beyond the Milan criteria after initial liver resection. METHODS: From January 2007 to December 2012, 271 consecutive patients with HCC who underwent curative liver resection were enrolled. Patients were divided according to the initial recurrence pattern: recurrence beyond the Milan criteria; and recurrence within the Milan criteria, or no recurrence. The patients were classified into two groups, low platelet-to-lymphocyte ratio (PLR) (<150) and high PLR (>=150), additionally using other inflammation-based prognostic scores. Then we analyzed the association between the recurrence patterns and the clinicopathological factors including PLR. RESULTS: Fifty-five (20.2%) patients had recurrence beyond the Milan criteria. The 5-year survival rate in patients with recurrence beyond the Milan criteria (41.6%) was significantly lower than in those with other recurrence patterns (79.7%). High PLR level was observed in 15.5% of the patients. Multivariate analysis revealed that PLR was the only independent predictive factor of recurrence patterns (odds ratio, 2.55; 95% confidence interval, 1.17-5.49; P = 0.018). The high PLR level was significantly associated with higher serum des-gamma-carboxy prothrombin level, larger tumor size, and poor histological differentiation. CONCLUSION: Among several inflammatory indices, PLR is a good indicator to predict recurrence beyond the Milan criteria after liver resection for patients with HCC. PMID- 28000366 TI - Hemocompatibility evaluation of poly(1,8-octanediol citrate) blend polyethersulfone membranes. AB - In this study, poly (1,8-octanediol citrate) (POC) was used to modify polyethersulfone (PES)-based membrane to enhance its hemocompatibility. Different compositions of POC (0-3%) were added into the polyethersulfone (PES) dope solutions and polyvinylpyrrolidone (PVP) was used as pore forming agent. The hemocompatible POC modified PES membranes were fabricated through phase-inversion technique. The prepared membranes were characterized using attenuated total reflectance-Fourier transform infrared (ATR-FTIR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), Atomic-force microscopy (AFM), contact angle, Zeta-potential, membrane porosity and pore size and pure water flux (PWF) and BSA rejection. The hemocompatibility of the modified PES membranes was evaluated by human serum fibrinogen (FBG) protein adsorption, platelet adhesion, activated partial thromboplastin time (APTT) and prothrombin time (PT), and thrombin-antithrombin III (TAT), complement (C3a and C5a) activation and Ca2+ absorption on membrane. Results showed that by increasing POC concentration, FBG adsorption was reduced, less platelets adhesion, prolonged APTT and PT, lower TAT, C5a and C3a activation and absorb more Ca2+ ion. These results indicated that modification of PES with POC has rendered improved hemocompatibility properties for potential application in the field of blood purification, especially in hemodialysis. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1510-1520, 2017. PMID- 28000367 TI - Cell adhesive peptides functionalized on CoCr alloy stimulate endothelialization and prevent thrombogenesis and restenosis. AB - Immobilization of bioactive peptide sequences on CoCr surfaces is an effective route to improve endothelialization, which is of great interest for cardiovascular stents. In this work, we explored the effect of physical and covalent immoblization of RGDS, YIGSR and their equimolar combination peptides on endothelial cells (EC) and smooth muscle cell (SMC) adhesion and on thrombogenicity. We extensively investigated using RT-qPCR, the expression by ECs cultured on functionalised CoCr surfaces of different genes. Genes relevant for adhesion (ICAM-1 and VCAM-1), vascularization (VEGFA, VEGFR-1 and VEGFR-2) and anti-thrombogenicity (tPA and eNOS) were over-expressed in the ECs grown to covalently functionalized CoCr surfaces compared to physisorbed and control surfaces. Pro-thrombogenic genes expression (PAI-1 and vWF) decreased over time. Cell co-cultures of ECs/SMCs found that functionalization increased the amount of adhered ECs onto modified surfaces compared to plain CoCr, independently of the used peptide and the strategy of immobilization. SMCs adhered less compared to ECs in all surfaces. All studied peptides showed a lower platelet cell adhesion compared to TCPS. Covalent functionalization of CoCr surfaces with an equimolar combination of RGDS and YIGSR represented prevailing strategy to enhance the early stages of ECs adhesion and proliferation, while preventing SMCs and platelet adhesion. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 973-983, 2017. PMID- 28000368 TI - Extensions of Island Biogeography Theory predict the scaling of functional trait composition with habitat area and isolation. AB - The Theory of Island Biogeography (TIB) predicts how area and isolation influence species richness equilibrium on insular habitats. However, the TIB remains silent about functional trait composition and provides no information on the scaling of functional diversity with area, an observation that is now documented in many systems. To fill this gap, we develop a probabilistic approach to predict the distribution of a trait as a function of habitat area and isolation, extending the TIB beyond the traditional species-area relationship. We compare model predictions to the body-size distribution of piscivorous and herbivorous fishes found on tropical reefs worldwide. We find that small and isolated reefs have a higher proportion of large-sized species than large and connected reefs. We also find that knowledge of species body-size and trophic position improves the predictions of fish occupancy on tropical reefs, supporting both the allometric and trophic theory of island biogeography. The integration of functional ecology to island biogeography is broadly applicable to any functional traits and provides a general probabilistic approach to study the scaling of trait distribution with habitat area and isolation. PMID- 28000369 TI - Arctic and boreal plant species decline at their southern range limits in the Rocky Mountains. AB - Climate change is predicted to cause a decline in warm-margin plant populations, but this hypothesis has rarely been tested. Understanding which species and habitats are most likely to be affected is critical for adaptive management and conservation. We monitored the density of 46 populations representing 28 species of arctic-alpine or boreal plants at the southern margin of their ranges in the Rocky Mountains of Montana, USA, between 1988 and 2014 and analysed population trends and relationships to phylogeny and habitat. Marginal populations declined overall during the past two decades; however, the mean trend for 18 dicot populations was -5.8% per year, but only -0.4% per year for the 28 populations of monocots and pteridophytes. Declines in the size of peripheral populations did not differ significantly among tundra, fen and forest habitats. Results of our study support predicted effects of climate change and suggest that vulnerability may depend on phylogeny or associated anatomical/physiological attributes. PMID- 28000370 TI - Amyloid precursor protein traffics from the Golgi directly to early endosomes in an Arl5b- and AP4-dependent pathway. AB - The intracellular trafficking and proteolytic processing of the membrane-bound amyloid precursor protein (APP) are coordinated events leading to the generation of pathogenic amyloid-beta (Abeta) peptides. The membrane transport of newly synthesized APP from the Golgi to the endolysosomal system is not well defined, yet it is likely to be critical for regulating its processing by beta-secretase (BACE1) and gamma-secretase. Here, we show that the majority of newly synthesized APP is transported from the trans-Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface. We show that Arl5b, a small G protein localized to the TGN, and AP4 are essential for the post-Golgi transport of APP to early endosomes. Arl5b is physically associated with AP4 and is required for the recruitment of AP4, but not AP1, to the TGN. Depletion of either Arl5b or AP4 results in the accumulation of APP, but not BACE1, in the Golgi, and an increase in APP processing and Abeta secretion. These findings demonstrate that APP is diverted from BACE1 at the TGN for direct transport to early endosomes and that the TGN represents a site for APP processing with the subsequent secretion of Abeta. PMID- 28000371 TI - Morphology-Directed Selective Production of Ethylene or Ethane from CO2 on a Cu Mesopore Electrode. AB - The electrocatalytic conversion of CO2 to value-added hydrocarbons is receiving significant attention as a promising way to close the broken carbon-cycle. While most metal catalysts produce C1 species, such as carbon monoxide and formate, the production of various hydrocarbons and alcohols comprising more than two carbons has been achieved using copper (Cu)-based catalysts only. Methods for producing specific C2 reduction outcomes with high selectivity, however, are not available thus far. Herein, the morphological effect of a Cu mesopore electrode on the selective production of C2 products, ethylene or ethane, is presented. Cu mesopore electrodes with precisely controlled pore widths and depths were prepared by using a thermal deposition process on anodized aluminum oxide. With this simple synthesis method, we demonstrated that C2 chemical selectivity can be tuned by systematically altering the morphology. Supported by computational simulations, we proved that nanomorphology can change the local pH and, additionally, retention time of key intermediates by confining the chemicals inside the pores. PMID- 28000372 TI - Azidoimidazolinium Salts: Safe and Efficient Diazo-transfer Reagents and Unique Azido-donors. AB - 2-Azido-1,3-dimethylimidazolinium chloride (ADMC) and its corresponding hexafluorophosphate (ADMP) were found to be efficient diazo-transfer reagents to various organic compounds. ADMC was prepared by the reaction of 2-chloro-1,3 dimethylimidazolinium chloride (DMC) and sodium azide. ADMP was isolated as a crystal having good thermal stability and low explosibility. ADMC and ADMP reacted with 1,3-dicarbonyl compounds under mild basic conditions to give 2-diazo 1,3-dicarbonyl compounds in high yields, which were easily isolated in virtue of the high water solubility of the by-products. ADMP showed high diazo-transfer ability to primary amines even in the absence of metal salt such as Cu(II). Using this diazotization approach, various alkyl/aryl azides were directly obtained from their corresponding primary amines in high yields. Furthermore, naphthols reacted with ADMC to give the corresponding diazonaphthoquinones in good to high yields. In addition, 2-azido-1,3-dimethylimidazolinium salts were employed as azide-transfer and migratory amidation reagents. PMID- 28000373 TI - The care network of the families involved in violence against children and adolescents: the Primary Health Care perspective. AB - AIMS AND OBJECTIVES: To contribute the understanding of the network care provided to families involved in family violence against children and adolescents (FVACA), from the Primary Health Care (PHC) perspective. BACKGROUND: Children and adolescents figure among the main victims of violence around the world, which occurs predominantly in the family context. PHC-guided network care has emerged as a new process that contrasts with traditional approaches, which rely on fragmented, punctual and compensatory actions and produce simplified and segmented interventions in response to complex phenomena like violence. The Paradigm of Complexity interacts with the network care approach and, by articulating the multiple dimensions of the research phenomenon, contributes to its understanding. DESIGN: Qualitative research, based on the Paradigm of Complexity. METHODS: Data were collected through minimal maps of the external institutional social network, focus groups and semi-structured interviews held with 41 PHC professionals in Brazil. The notions of comprehension and contextualisation as well as dialogical, recursive and holographic principles from complexity theory guided the data analysis. RESULTS: The two thematic categories that emerged revealed reduced institutional networks, with low-density and homogeneous bonds, which resulted in fragmented care in all stages of the care process. CONCLUSIONS: Although the network organisation of care for the families involved in FVACA is fundamental, the construction of these networks still represents a great challenge, as it requires the joint work of a multiprofessional team. RELEVANCE TO CLINICAL PRACTICE: For nursing to respond to the contemporary care demands in a contemplative and pertinent manner, a perspective and a reference framework need to be developed, leading to broader and more contextualised actions, with a multidimensional approach to the families and communities of which child and adolescent victims of violence are a part. PMID- 28000374 TI - A Conia-Ene-Type Cyclization under Basic Conditions Enables an Efficient Synthesis of (-)-Lycoposerramine R. AB - An enantioselective total synthesis of the Lycopodium alkaloid lycoposerramine R is presented. It relies on a base-mediated cyclization that resembles the Conia ene reaction of ynones and gold-catalyzed variants thereof. Thus, hydrindanones and other functionalized ring systems bearing an exocyclic alkene can be rapidly accessed at room temperature without noble metal catalysis or substrate preactivation. PMID- 28000376 TI - Structure and Isotope Effects of the beta-H Agostic (alpha-Diimine)Nickel Cation as a Polymerization Intermediate. AB - Single-crystal X-ray characterization of cationic (alpha-diimine)Ni-ethyl and isopropyl beta-agostic complexes, which are key intermediates in olefin polymerization and oligomerization, are presented. The sharp Ni-Calpha -Cbeta angles (75.0(3) degrees and 74.57(18) degrees ) and short Calpha -Cbeta distances (1.468(7) and 1.487(5) A) provide unambiguous evidence for a beta agostic interaction. An inverse equilibrium isotope effect (EIE) for ligand coordination upon cleavage of the agostic bond highlights the weaker bond strength of Ni-H relative to the C-H bond. An Eyring plot for beta-hydride elimination-olefin rotation-reinsertion is constructed from variable-temperature NMR spectra with 13 C-labeled agostic complexes. The enthalpy of activation (DeltaH? ) for beta-H elimination is 13.2 kcal mol-1 . These results offer important mechanistic insight into two critical steps in polymerization: ligand association upon cleavage of the beta-agostic bonds and chain-migration via beta H elimination. PMID- 28000375 TI - Cross calibration of two dual-energy X-ray densitometers and comparison of visceral adipose tissue measurements by iDXA and MRI. AB - OBJECTIVE: Compare total percentage body fat (pfat) measurements between two densitometers and visceral adipose tissue (VAT) estimates between iDXA and magnetic resonance imaging (MRI) from the same defined abdominal region. METHODS: Participants [N = 93 (50 men, 43 women), BMI: 19.1-57.6 kg/m2 ] underwent dual energy X-ray absorptiometry (DXA) scans on two DXA systems (GE Healthcare Lunar iDXA and Lunar Prodigy), and a subgroup underwent abdominal MRI imaging for quantification of VAT. RESULTS: Pfat correlated strongly between both machines (r2 = 0.98, P < 1.0E-14). Bland-Altman plots showed a bias with higher measured pfat on iDXA versus Prodigy in leaner subjects and the opposite in more overweight subjects. The R2 for regression of MRI on iDXA VAT values was 0.948. Bland-Altman bias was +104.1 cm3 with 95% limits of agreement of -681.9 to 890.0 cm3 . For both DXA methods, and iDXA versus MRI determined VAT, comparison using rank regression demonstrated no order bias. CONCLUSIONS: The total pfat measured by both machines was strongly and linearly associated, allowing for conversion (equations are provided) of iDXA for assessment of longitudinal body fat changes. Despite a bias of abdominal VAT measures of iDXA versus MRI, the high rank correlation makes iDXA a good alternative to the more complicated and time consuming MRI for use in larger cross-sectional and longitudinal studies. PMID- 28000377 TI - Randomized, controlled trial of a brief family-centred care programme for hospitalized patients with bipolar disorder and their family caregivers. AB - Family interventions have been emphasized in the treatment of bipolar disorder (BPD) due to the bidirectional and entangled relationships between patients and the family system, and have benefits for patients' symptoms and health; however, the effects of family interventions on family function and caregivers' health related outcomes have not been well investigated. This randomized, controlled trial with 47 hospitalized patients with BPD/family caregiver dyads at a medical centre in northern Taiwan compared the effects of a brief family-centred care (BFCC) programme with treatment as usual (TAU). All of the family caregivers in two groups were invited to attend a routine 60-min family discussion group about violence and suicide prevention. The TAU group without specific family interview for patient and family caregiver dyad. In the BFCC group, four 90-min BFCC programme sessions were additionally provided twice a week for each hospitalized family dyad. We hypothesized that, first, family caregivers in the BFCC group could increase their family function, and second, improve perceived health status and reduce caregiver's burdens compared to the TAU. The results showed that family caregivers in the BFCC group significant interaction effects in overall family function (P = 0.03) and subscale conflict (P = 0.04), communication (P = 0.01), and problem-solving (P = 0.04), but there were no significant interaction effects on the caregivers' perceived health status and caregivers' burdens. Our findings support both the feasibility of using the BFCC programme for inpatients and its specific benefits for family function. An intensive family intervention during hospitalization has been suggested in psychiatric practice to support patients with BPD and family caregivers. PMID- 28000378 TI - The intermediate distance hypothesis of biological invasions. AB - Biological invasions are a worldwide phenomenon, but the global flows between native and alien regions have rarely been investigated in a cross-taxonomic study. We therefore lack a thorough understanding of the global patterns of alien species spread. Using native and alien ranges of 1380 alien species, we show that the number of alien species follows a hump-shaped function of geographic distance. We observe distinct variations in the relationship between alien species exchanges and distance among taxonomic groups, which relate to the taxa specific dispersal modes and their pathways of introduction. We formulate a simple statistical model, combining trade volume and biogeographic dissimilarity, which reproduces the observed pattern in good agreement with reported data and even captures variations among taxonomic groups. This study demonstrates the universality of the intermediate distance hypothesis of alien species spread across taxonomic groups, which will help to improve the predictability of new alien species arrivals. PMID- 28000380 TI - Quercetin inhibits sodium nitrite-induced inflammation and apoptosis in different rats organs by suppressing Bax, HIF1-alpha, TGF-beta, Smad-2, and AKT pathways. AB - The objective of this work is to study the protective effects of Quercetin against sodium nitrite-induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg-1 ,- i.p.) was administrated 24 and 1 h respectively prior to sodium nitrite intoxication, hypoxia significantly decreased hemoglobin concentration, while increased expressions of HIF, Bax, Smad-2, TGF-beta, and AKT. However, administration of Quercetin played a modulatory role against the previous mentioned apoptotic factors protein expressions in all the studied tissues. On the other hand, Bcl-2 was downregulated by NaNO2 , whereas concurrent treatment with Quercetin increased its expression. It was concluded that Quercetin possesses an anti apoptotic action induced by NaNO2 -intoxication via different mechanisms. Quercetin administration is recommended in areas of high altitudes to combat the hazard effect of hypoxia in different organs and in some diseases accompanied by hypoxic stress. PMID- 28000381 TI - Shorter sleep onset latency in patients undergoing hyperbaric oxygen treatment. PMID- 28000379 TI - Rate, correlates and outcomes of repeat pregnancy in HIV-infected women. AB - OBJECTIVES: The aim of the study was to assess the rate, determinants, and outcomes of repeat pregnancies in women with HIV infection. METHODS: Data from a national study of pregnant women with HIV infection were used. Main outcomes were preterm delivery, low birth weight, CD4 cell count and HIV plasma viral load. RESULTS: The rate of repeat pregnancy among 3007 women was 16.2%. Women with a repeat pregnancy were on average younger than those with a single pregnancy (median age 30 vs. 33 years, respectively), more recently diagnosed with HIV infection (median time since diagnosis 25 vs. 51 months, respectively), and more frequently of foreign origin [odds ratio (OR) 1.36; 95% confidence interval (CI) 1.10-1.68], diagnosed with HIV infection in the current pregnancy (OR: 1.69; 95% CI: 1.35-2.11), and at their first pregnancy (OR: 1.33; 95% CI: 1.06-1.66). In women with sequential pregnancies, compared with the first pregnancy, several outcomes showed a significant improvement in the second pregnancy, with a higher rate of antiretroviral treatment at conception (39.0 vs. 65.4%, respectively), better median maternal weight at the start of pregnancy (60 vs. 61 kg, respectively), a higher rate of end-of-pregnancy undetectable HIV RNA (60.7 vs. 71.6%, respectively), a higher median birth weight (2815 vs. 2885 g, respectively), lower rates of preterm delivery (23.0 vs. 17.7%, respectively) and of low birth weight (23.4 vs. 15.4%, respectively), and a higher median CD4 cell count (+47 cells/MUL), with almost no clinical progression to Centers for Disease Control and Prevention stage C (CDC-C) HIV disease (0.3%). The second pregnancy was significantly more likely to end in voluntary termination than the first pregnancy (11.4 vs. 6.1%, respectively). CONCLUSIONS: Younger and foreign women were more likely to have a repeat pregnancy; in women with sequential pregnancies, the second pregnancy was characterized by a significant improvement in several outcomes, suggesting that women with HIV infection who desire multiple children may proceed safely and confidently with subsequent pregnancies. PMID- 28000382 TI - Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells. AB - Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error-free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I-SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR-white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8 days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals. PMID- 28000383 TI - A Facile and Efficient Method to Fabricate Highly Selective Nanocarbon Catalysts for Oxidative Dehydrogenation. AB - Carbon nanotubes (CNTs) were used in oxidative dehydrogenation (ODH) reactions. Quinone groups on the CNT surface were identified as active sites for the dehydrogenation pathway. Liquid-phase oxidation with HNO3 is one way to generate various oxygen functionalities on the CNT surface but it produces a large amount of acid waste, limiting its industrial application. Here, a facile and efficient oxidative method to prepare highly selective CNT catalysts for ODH of n-butane is reported. Magnesium nitrate salts as precursors were used to produce defect-rich CNTs through solid-phase oxidation. Skeleton defects induced on the CNT surface resulted in the selective formation of quinone groups active for the selective dehydrogenation. The as-prepared catalyst exhibited a considerable selectivity (58 %) to C4 olefins, which is superior to that of CNTs oxidized with liquid HNO3 . Through the introduction of MgO nanoparticles on the CNT surface, the desorption of alkenes can be accelerated dramatically, thus enhancing the selectivity. This study provides an attractive way to develop new nanocarbon catalysts. PMID- 28000384 TI - A Robust and Efficient Feature Selection Algorithm for Microarray Data. AB - In the past decades, a few synergistic feature selection algorithms have been published, which includes Cooperative Index (CI) and K-Top Scoring Pair (k-TSP). These algorithms consider the synergistic behavior of features when they are included in a feature panel. Although promising results have been shown for these algorithms, there is lack of a comprehensive and fair comparison with other feature selection algorithms across a large number of microarray datasets in terms of classification accuracy and computational complexity. There is a need in evaluating their performance and reducing the complexity of such algorithms. We compared the performance of synergistic feature selection algorithms with 11 other commonly used algorithms based on 22 microarray gene expression binary class datasets. The evaluation confirms that synergistic algorithms such as CI and k-TSP will gradually increase the classification performance as more features are used in the classifiers. Also, in order to cut down computational cost, we proposed a new feature selection ranking score called Positive Synergy Index (PSI). Testing results show that features selected using PSI as well as synergistic feature selection algorithms provide better performance compared to with all other methods, while PSI has a computational complexity significantly lower than that of other synergistic algorithms. PMID- 28000385 TI - One-Step Annulative pi-Extension of Alkynes with Dibenzosiloles or Dibenzogermoles by Palladium/o-chloranil Catalysis. AB - Reliable and short synthetic routes to polycyclic aromatic hydrocarbons and nanographenes are important in materials science. Herein, we report an efficient one-step annulative pi-extension reaction of alkynes that provides access to diarylphenanthrenes and related nanographene precursors. In the presence of a cationic palladium/o-chloranil catalyst system and dibenzosiloles or dibenzogermoles as pi-extending agents, a variety of diarylacetylenes are transformed successfully into 9,10-diarylphenanthrenes in a single step with good functional-group tolerance. Furthermore, double pi-extension reactions of 1,4 bis(phenylethynyl)benzene and diphenyl-1,3-butadiyne are demonstrated, affording oligoarylene products, which show potential for application in the synthesis of larger polycyclic aromatic hydrocarbons and nanographenes. PMID- 28000386 TI - Chitosan nanofibers for transbuccal insulin delivery. AB - In this work, they aimed at producing chitosan based nanofiber mats capable of delivering insulin via the buccal mucosa. Chitosan was electrospun into nanofibers using poly(ethylene oxide) (PEO) as a carrier molecule in various feed ratios. The mechanical properties and degradation kinetics of the fibers were measured. Insulin release rates were determined in vitro using an ELISA assay. The bioactivity of released insulin was measured in terms of Akt activation in pre-adipocytes. Insulin permeation across the buccal mucosa was measured in an ex vivo porcine transbuccal model. Fiber morphology, mechanical properties, and in vitro stability were dependent on PEO feed ratio. Lower PEO content blends produced smaller diameter fibers with significantly faster insulin release kinetics. Insulin showed no reduction in bioactivity due to electrospinning. Buccal permeation of insulin facilitated by high chitosan content blends was significantly higher than that of free insulin. Taken together, the work demonstrates that chitosan-based nanofibers have the potential to serve as a transbuccal insulin delivery vehicle. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1252-1259, 2017. PMID- 28000387 TI - A Comparison of ddPCR and ARMS for detecting EGFR T790M status in ctDNA from advanced NSCLC patients with acquired EGFR-TKI resistance. AB - A sensitive and convenient method for detecting epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance would be desirable to direct patient sequential treatment strategy. A comparison of two platforms for detecting EGFR mutations in plasma ctDNA was undertaken. Plasma samples and tumor samples were collected from patients with acquired EGFR-TKI resistance in Zhejiang Cancer Hospital from December 2014 to December 2015. Extracted ctDNA was analyzed using two platforms (Droplet Digital PCR and ARMS [dPCR]). A total of 108 patients were enrolled in this study. One hundred and eight patient plasma samples were detected by ddPCR and 75 were detected by ARMS. And 16 patients obtained tissue re-biopsy, using ARMS assay for detecting EGFR T790M mutation. In all, 43.7% (47/108) had acquired T790M mutation by ddPCR. In 75 patient plasma samples, comparing ddPCR with ARMS, the rates of T790M mutation were 46.7% (35/75) and 25.3% (19/75) by ddPCR and ARMS, respectively. Of all, 16 patients both had tumor and plasma samples, the T790M mutation rates were 56.3% (9/16) by ARMS in tissue and 50.5% (8/16) by ddPCR in plasma ctDNA. The progression mode tended to gradual progression in T790M mutation patients (40.4%), but the T790M negative was inclined to the mode of dramatic progression (39.3%). The patients with T790M-positive tumors had a longer time to disease progression after treatment with EGFR-TKIs (median, 13.1 months vs. 10.8 months; P = 0.010) and overall survival (median, 35.3 months vs. 30.3 months; P = 0.214) compared with those with T790M-negative patients. Our study demonstrates ddPCR assay may provide a highly sensitive method to detect EGFR T790M gene in plasma. And T790M-positive patients have better clinical outcomes to EGFR-TKIs than T790M negative patients. PMID- 28000389 TI - Sentence comprehension in Slovak-speaking patients with Alzheimer's disease. AB - BACKGROUND: According to some studies, sentence comprehension is diminished in Alzheimer's disease (AD) patients, but they differ on what underlies the sentence comprehension impairment. Sentence comprehension in AD patients has been studied mainly in the English language. It is less clear how patients with AD speaking a morphologically rich language with grammatical morphemes indicating case and through it even thematic roles process reversible sentences. AIMS: To compare the comprehension of various syntactic constructions in Slovak-speaking AD patients and cognitively intact elderly people. We were concerned with the influence of the following aspects on sentence comprehension: its length, the order of thematic roles and the presence of a morphological cue placed on the first noun (or at the beginning of a sentence). METHODS & PROCEDURES: We used our own Slovak test of sentence comprehension based on matching pictures to spoken sentences. These sentences contain transitive verbs and two nouns (person/animal), one functioning as a subject and the other as an object, which both can perform the action expressed by the verb. We assessed 62 healthy elderly people and two groups of AD patients. The first group consisted of 34 participants with a mild degree of AD and the other group of 43 participants with a moderate degree of AD. OUTCOME & RESULTS: Statistical comparisons showed that the elderly controls were significantly better in the comprehension of simple active OVS (object-verb subject word order) sentences and complex EO sentences (a centre-embedded relative clause with a relative pronoun substituting for an object) than patients with a mild degree of AD. In patients with a moderate degree of AD, comprehension of all tested sentence types was worse than in healthy elderly people. The results also indicated that even mild AD patients have more serious problems with processing sentences with non-canonical order of thematic roles regardless of a morphological cue at the beginning of a sentence. CONCLUSION & IMPLICATIONS: The results point to diminished sentence comprehension in patients with AD. In the group of mild AD patients, the order of thematic roles played a significant role in their sentence comprehension. Even though the grammatical morphemes clearly code the functions of words in the Slovak language, mild AD patients do not process them in sentences with a non-canonical order of thematic roles at the same level as the healthy controls. Patients with moderate AD have significant problems even with the comprehension of sentences with a canonical order of thematic roles. These difficulties seem to be a consequence of insufficient resources for language processing. PMID- 28000388 TI - Venous thromboembolism in metastatic urothelial carcinoma or variant histologies: incidence, associative factors, and effect on survival. AB - Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6-month VTE incidence rates were determined. The association of first-line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing-risk regression model. VTE patients were matched to non-VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non-urotheilal histology (SHR: 2.67; 95% CI: 1.72-4.16, P < 0.001), moderate to severe renal dysfunction (SHR: 2.12; 95% CI: 1.26-3.59, P = 0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49-3.45, P = 0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P < 0.001). Thus, in metastatic UC/VH patients, VTE is common and has a negative impact on survival. We identified multiple associated potential risk factors, although different chemotherapy regimens did not alter risk. PMID- 28000390 TI - An oral formulation of efavirenz-loaded lactoferrin nanoparticles with improved biodistribution and pharmacokinetic profile. AB - OBJECTIVES: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, is a drug that is frequently included in highly active antiretroviral therapy for treatment of HIV infection. Decreased bioavailability and increased toxicity limit its use. We report a formulation of efavirenz-loaded lactoferrin nanoparticles (lacto-EFV-nano) for oral delivery which exhibited significantly improved pharmacological properties coupled with reduced toxicity compared with its free form. METHODS: Lacto-EFV-nano was prepared using the Sol-oil protocol and characterized using various sources of characterization. In vitro and in vivo studies were performed to test the stability, safety, efficacy, biodistribution and pharmacokinetics of lacto-EFV-nano. RESULTS: The nanoparticles prepared for the present study had an average size of 45-60 nm as revealed by field emission scanning electron microscope measurements. Further, dynamic light scattering data showed a hydrodynamic radius of 103 +/- 5.3 nm, a zeta potential of -23 +/- 1.2 mV and a polydispersity index of < 0.341. Lacto-EFV-nano was found to be stable as assessed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. Cell viability studies showed that lacto-EFV-nano was at least 2-fold less toxic to peripheral blood mononuclear cells, Jurkat T cell and B16-F10 cell lines than free EFV. Furthermore, lacto-EFV-nano [50% inhibitory concentration (IC50 ) < 1.1 nM] showed > 2-fold enhanced anti-HIV-1 activity compared with free EFV (IC50 = 2.56 nM). Lacto-EFV-nano exhibited improved oral bioavailability and an improved in vivo pharmacokinetic profile, with a > 3-4 fold increase in the area under the plasma concentration-time curve (AUC), a 6-7 fold increase in the area under the first moment curve (AUMC), a > 30% increase in the peak plasma concentration of the drug after oral administration (Cmax ) and a 2-fold increase in the time to reach Cmax (Tmax ) and the time required for the concentration of the drug to reach half of its original value (t1/2 ). Furthermore, lacto-EFV-nano did not show any organ-related toxicity. A significant decrease in the concentrations of various parameters, elevated concentrations of which are markers of reduced safety, were also observed in rats treated with lacto-EFV-nano. CONCLUSIONS: Compared with free EFV, lacto-EFV-nano is a promising oral nanoformulation with enhanced bioavailability and efficacy of EFV and improved safety. PMID- 28000391 TI - Psychosocial impact on families with an infant with a hypoplastic left heart syndrome during and after the interstage monitoring period - a prospective mixed method study. AB - AIMS AND OBJECTIVES: To investigate parents' experiences, coping ability and quality of life while monitoring their sick child with hypoplastic left heart syndrome at home. BACKGROUND: Interstage home monitoring for children with hypoplastic left heart syndrome reduces interstage mortality between Norwood stages I and II. Little is known about the psychosocial impact of interstage home monitoring. DESIGN: Prospective mixed-method study. METHODS: This study assessed the psychosocial impact on parents during interstage home monitoring. This contains for quantitative assessment the Short Form Health Survey questionnaire and the Impact of Family Scale administered one and five weeks following discharge before and after stage II. For qualitative assessment, semi-structured interviews focussing on the postdischarge coping strategies were conducted twice, five weeks after hospital discharge before and after stage II. RESULTS: Ten infants (eight males) with hypoplastic left heart syndrome (n = 7) or other types of univentricular heart malformations (n = 3), and their parents (nine mother/father two-parent households, one single mother) were included. There were no interstage deaths. Mental Health Composite Summary scores were low in both parents (mothers: 40.45 +/- 9.07; fathers: 40.58 +/- 9.69) and lowest for the item 'vitality' (mothers: 37.0 +/- 19.46; fathers: 43.12 +/- 25.9) before and after stage II. Impact of Family Scale values showed higher daily and social burdens for mothers. 'Becoming a family' was the most important task as coping strategy to equilibrate the fragile emotional balance. The parents judged interstage home monitoring as a protective intervention. CONCLUSIONS: Although psychosocial burden before and after stage II remains high, becoming a family is an essential experience for parents and confirms their parenthood. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals must be aware of parents' needs during this vulnerable interstage period and to provide psychosocial and nursing support. PMID- 28000392 TI - The Antinociceptive Activity of Geraniol. PMID- 28000393 TI - Prediction of hERG Liability - Using SVM Classification, Bootstrapping and Jackknifing. AB - Drug-induced QT prolongation leads to life-threatening cardiotoxicity, mostly through blockage of the human ether-a-go-go-related gene (hERG) encoded potassium ion (K+ ) channels. The hERG channel is one of the most important antitargets to be addressed in the early stage of drug discovery process, in order to avoid more costly failures in the development phase. Using a thallium flux assay, 4,323 molecules were screened for hERG channel inhibition in a quantitative high throughput screening (qHTS) format. Here, we present support vector classification (SVC) models of hERG channel inhibition with the averaged area under the receiver operator characteristics curve (AUC-ROC) of 0.93 for the tested compounds. Both Jackknifing and bootstrapping have been employed to rebalance the heavily biased training datasets, and the impact of these two under sampling rebalance methods on the performance of the predictive models is discussed. Our results indicated that the rebalancing techniques did not enhance the predictive power of the resulting models; instead, adoption of optimal cutoffs could restore the desirable balance of sensitivity and specificity of the binary classifiers. In an external validation set of 66 drug molecules, the SVC model exhibited an AUC-ROC of 0.86, further demonstrating the utility of this modeling approach to predict hERG liabilities. PMID- 28000394 TI - Birth prevalence of congenital talipes equinovarus in low- and middle-income countries: a systematic review and meta-analysis. AB - OBJECTIVE: Congenital talipes equinovarus (CTEV), or clubfoot, is a structural malformation that develops early in gestation. Birth prevalence of clubfoot is reported to vary both between and within low- and middle-income countries (LMICs), and this information is needed to plan treatment services. This systematic review aimed to understand the birth prevalence of clubfoot in LMIC settings. METHODS: Six databases were searched for studies that reported birth prevalence of clubfoot in LMICs. Results were screened and assessed for eligibility using pre-defined criteria. Data on birth prevalence were extracted and weighted pooled estimates were calculated for different regions. Wilcoxon rank-sum test was used to examine changes in birth prevalence over time. Included studies were appraised for their methodological quality, and a narrative synthesis of findings was conducted. RESULTS: Forty-eight studies provided data from 13 962 989 children in 20 countries over 55 years (1960-2015). The pooled estimate for clubfoot birth prevalence in LMICs within the Africa region is 1.11 (0.96, 1.26); in the Americas 1.74 (1.69, 1.80); in South-East Asia (excluding India) 1.21 (0.73, 1.68); in India 1.19 (0.96, 1.42); in Turkey (Europe region) 2.03 (1.54, 2.53); in Eastern Mediterranean region 1.19 (0.98, 1.40); in West Pacific (excluding China) 0.94 (0.64, 1.24); and in China 0.51 (0.50, 0.53). CONCLUSION: Birth prevalence of clubfoot varies between 0.51 and 2.03/1000 live births in LMICs. A standardised approach to the study of the epidemiology of clubfoot is required to better understand the variations of clubfoot birth prevalence and identify possible risk factors. PMID- 28000395 TI - Addressing regional disparities in pediatric oncology: Results of a collaborative initiative across the Mexican-North American border. AB - BACKGROUND: Cancer is emerging as a major cause of childhood mortality in low- and middle-income countries. In Mexico, cancer is the number one cause of death in children aged 5-14. Until recently, many children with cancer from Baja California, Mexico, went untreated. We reasoned that an initiative inspired by the St. Jude Children's Research Hospital (SJCRH) "twinning" model could successfully be applied to the San Diego-Tijuana border region. In 2008, a twinning project was initiated by Rady Children's Hospital, SJCRH, and the General Hospital Tijuana (GHT). Our aim was to establish a pediatric oncology unit in a culturally sensitive manner, adapted to the local healthcare system. PROCEDURE: An initial assessment revealed that despite existence of basic hospital infrastructure at the GHT, the essential elements of a pediatric cancer unit were lacking, including dedicated space, trained staff, and uniform treatment. A 5-year action plan was designed to offer training, support the staff financially, and improve the infrastructure. RESULTS: After 7 years, accomplishments include the opening of a new inpatient unit with updated technology, fully trained staff, and a dedicated, interdisciplinary team. Over 700 children have benefited from accurate diagnosis and treatment. CONCLUSIONS: Initiatives that implement long-term partnerships between institutions along the Mexican-North American border can be highly effective in establishing successful pediatric cancer control programs. The geographic proximity facilitated accelerated training and close monitoring of project development. Similar initiatives across other disciplines may benefit additional patients and synergize with pediatric oncology programs to reduce health disparities in underserved areas. PMID- 28000397 TI - Evolution of the Jugal/Zygomatic Bones. AB - This issue of the Anatomical Record is the second of a two-volume set on the zygoma (also called the cheek bone, the zygomatic bone, the malar, or the jugal, the latter term being used in vertebrates other than mammals). The zygoma is an important component of the craniofacial skeleton, in which the zygoma is a connection between the midfacial and the cranial skeletons; has a functional role as the origin of one of the masticatory muscles, the masseter muscle, and several facial muscles; has been considered as an essential buttress of the facial skeleton for resisting masticatory forces; and has importance for determining phylogenetic relationships. In humans, the zygoma is also of aesthetic significance for facial appearance, and its restoration following trauma has resulted in a large clinical literature. In this second half of the special issue on the zygoma, a series of papers discuss studies related to evolution of the zygoma and related parts of the craniofacial skeleton throughout the vertebrates, and in particular in human evolution. There are also a series of articles discussing variation of the zygoma in modern humans. This article is an overview in which we discuss the primary findings of these studies and some of their implications. Anat Rec, 300:12-15, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000396 TI - The Biomechanics of Bony Facial "Buttresses" in South African Australopiths: An Experimental Study Using Finite Element Analysis. AB - Australopiths exhibit a number of derived facial features that are thought to strengthen the face against high and/or repetitive loads associated with a diet that included mechanically challenging foods. Here, we use finite element analysis (FEA) to test hypotheses related to the purported strengthening role of the zygomatic root and "anterior pillar" in australopiths. We modified our previously constructed models of Sts 5 (Australopithecus africanus) and MH1 (A. sediba) to differ in the morphology of the zygomatic root, including changes to both the shape and positioning of the zygomatic root complex, in addition to creating variants of Sts 5 lacking anterior pillars. We found that both an expanded zygomatic root and the presence of "anterior pillars" reinforce the face against feeding loads. We also found that strain orientations are most compatible with the hypothesis that the pillar evolved to resist loads associated with premolar loading, and that this morphology has an ancillary effect of strengthening the face during all loading regimes. These results provide support for the functional hypotheses. However, we found that an anteriorly positioned zygomatic root increases strain magnitudes even in models with an inflated/reinforced root complex. These results suggest that an anteriorly placed zygomatic root complex evolved to enhance the efficiency of bite force production while facial reinforcement features, such as the anterior pillar and the expanded zygomatic root, may have been selected for in part to compensate for the weakening effect of this facial configuration. Anat Rec, 300:171-195, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000398 TI - Toward Understanding the Mammalian Zygoma: Insights From Comparative Anatomy, Growth and Development, and Morphometric Analysis. AB - The zygoma, or jugum, is a cranial element that was present in Mesozoic tetrapods, well before the appearance of mammals. Although as an entity the zygoma is a primitive retention among mammals, it has assumed myriad configurations as this group diversified. As the zygoma is located at the intersection of the visual, respiratory, and masticatory apparatuses, it is potentially of great importance in systematic, phylogenetic, and functional studies focused on this region. For example, the facial component of the zygoma and its contribution to a postorbital bar (POB) appear to be relevant to the systematics of a number of mammalian subclades, and the formation of a bony postorbital septum (POS) that separates the orbit from the infratemporal fossa is unique to, and thus potentially phylogenetically significant for uniting anthropoid primates, while the zygoma itself appears to serve to resist tension and bending forces during mastication. In order to better understand the zygoma in the context of its contributions to the circumorbital region, we documented its morphological expression in specimens representing 10 orders of mammals. Since the presence of a POB and of a POS has long been used to justify uniting extant primates and anthropoid primates as respective clades, and because postorbital closure (POC) is morphologically more complex than a POB, we provide detail necessary to address these claims. Our taxically broad overview also allowed us to provide for the first time definitions of configurations that can be applied to future studies. Using a different, but also taxically broad sample of mammals, and of primates in particular, we performed two geometric morphometric analyses that were geared toward testing long-held interpretations of the functional role of the zygoma, especially with regard to mastication and in the context of orbital frontation (to which the zygoma contributes). Further, overall, zygomatic morphology tends not to scale with allometry, sexual dimorphism, or angle of orbital convergence, but it does contribute to unique patterns of intraspecies variation. Anat Rec, 300:76-151, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000399 TI - Environment-Related Variation in the Human Mid-Face. AB - Previous studies that have examined mid-facial morphology in geographically dispersed and genetically diverse groups of humans have shown a strong adaptation of the nasal part to extreme cold environments, which was not observed in non Arctic regions. However, it remains unclear whether different parts of the mid face area show independent adaptation to nonpolar climates, and if so, how this adaptation impacted the morphology. To address this question, we investigated potential associations between climatic variables and the mid-facial shape in 14 populations, focusing on four aspects of the morphology: total shape, zygomatic, nasal and alveolar. The results show that when the genetic distance between populations is not considered, all aspects of the morphology are strongly correlated with all climatic variables. When the genetic distance is considered, significant correlations remain only for the zygomatic, and nasal parts with temperature, and for the nasal part and alveolar with sunshine exposure. A strong but probably artificial correlation of the alveolar with atmospheric pressure is also observed. Additionally, partial least square analyses indicate that tropical and subtropical environments are associated with smaller zygomatic and more triangular nose aperture compared to more temperate environments. These findings suggest that temperate and tropical climates have induced adaptation of zygomatic and nasal parts of the mid-face in humans, and that this adaptation was probably driven by temperature and sunlight exposure conditions. Anat Rec, 300:238-250, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000400 TI - Biomechanical Evaluation of Different Musculoskeletal Arrangements in Psittacosaurus and Implications for Cranial Function. AB - The masseter muscle complex is a unique feature of extant mammals and their advanced cynodont precursors, originating from the zygomatic arch and inserting onto the lateral surface of the dentary. This muscle complex is absent in sauropsids, with the exception of the neomorphic m. pseudomasseter complex that is unique to psittaciform birds (parrots and cockatiels). The anterior position and anterodorsally inclined line of action of both muscle groups increases leverage of the jaw and is thought to contribute to increased bite force, particularly in psittaciforms. A corollary is that in mammals at least, the masseter places increased load on the zygomatic arch, which may be withstood by soft tissue temporal fascia. Recently the existence of a m. pseudomasster (mPSM) and m. adductor mandibulae externus ventralis (mAMEV) has been proposed in the ornithischian dinosaur Psittacosaurus. Here we use computed tomography, digital restoration of skull anatomy and adductor musculature and computational biomechanics to test how the presence of anterodorsally inclined muscle loads influences stress, strain, deformation and estimated bite forces in the skull of Psittacosaurus. We find that the m. pseudomasseter and m. amev increases bite force with an associated increase in cranial stress and deformation. There is, however, limited osteological evidence for the existence of these two additional muscles in the psittacosaur skull and geometric morphometric informed sensitivity analysis of our finite element models shows that bite position has a greater effect on loading-induced deformation than muscle loading or material property variation. Anat Rec, 300:49-61, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000401 TI - Opposing Extremes of Zygomatic Bone Morphology: Australopithecus Boisei versus Homo Neanderthalensis. AB - The lateral margin of the zygomatic bone of Australopithecus boisei flares both anteriorly and laterally. As a result, the bone loses the suspensory bracing of the facial frame and is transformed into a visor-like structure that supports itself and gains its rigidity from its shape. The coronally oriented bony plates and the outline of the facial mask help the A. boisei face resist the effect of the visor-like structure, which tends to pull the bone plates of the face away from the midline. On the other hand, the nearly sagittal orientation of the zygomatic bone in Homo neanderthalensis helps the face resist torque and bending forces, which themselves stem from the positioning of the bite point on the anterior teeth. Although the zygomatic bones of these two taxa are highly specialized, they differ fundamentally from each other. Anat Rec, 300:152-159, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000402 TI - A Jugal in the Rough: The Evolutionary Importance of the Zygoma. PMID- 28000403 TI - Morphological Diversity and Evolution of the Jugal in Dinosaurs. AB - In dinosaurs, as in other reptiles, the homologue of the mammalian zygomatic bone is the jugal. The dinosaurian jugal was primitively triradiate, with posterior, dorsal and anterior processes that respectively contacted the quadratojugal, the postorbital, and the maxilla and lacrimal. However, the jugal evolved along different lines in the three major dinosaurian clades. In theropods this cranial element remained relatively conservative in morphology, apart from being reduced to a rod-like structure in most birds and a few non-avians. In sauropodomorphs the jugal eventually became small, plate-like and nearly restricted to the area below the orbit, even being excluded from the ventral margin of the skull in many derived taxa. Among ornithischians the jugal was highly variable, but in many cases became large and/or adorned with ornamental features such as horns, flanges, and rugosities. The jugal does not appear to have been a site of muscle attachment in most non-avian dinosaurs, but represented an important structural element in the akinetic dinosaurian skull. The conspicuous jugal ornaments seen in many ornithischian dinosaurs, like the less striking ones documented in some saurischians, may have played an important role in the social behavior of the species that possessed them. In many cases they have a weapon-like aspect suggesting use in aggressive displays, if not actual combat, adding to the evidence that agonistic behavior was likely widespread among ornithischians in particular. Anat Rec, 300:30-48, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000404 TI - The Anatomical Record Continues Our Special Issue, "Understanding the Zygoma," Now Exploring the Extraordinary Twists and Turns of Its Evolutionary Journey in Our First "Act II" of a Special Issue. PMID- 28000405 TI - Sexual Dimorphism and Population Affinity in the Human Zygomatic Structure Comparing Surface to Outline Data. AB - The human zygomatic structure, consisting of the zygomatic bone and the zygomatic process of the temporal bone, is an essential part of the masticatory apparatus and has been shown to reflect population history and sexual dimorphism to varying degrees. In this study, we analyzed the predictive value of the outlines vs. the complete surface shape of the zygomatic bone in a sample of 98 Chinese (50 ?, 48 ?) and 96 Germans (49 ?, 47 ?). We first applied a surface registration process based on statistical shape modeling. A dense set of 1,480 pseudo-landmarks was then sampled automatically from the surface of the pooled mean shape and three curves were digitized manually along the outlines of the zygomatic bone. Both sets of pseudo-landmarks were automatically transferred to all specimens. Analysis of sex and population affinity showed both factors to be independently significant, but the interaction between them was not. Population affinity could be predicted quite accurately with correct classification of 97.9% using the surface data and 93.3% with the curve data. Sexual dimorphism was less distinct with 89.2% correct sex determination when using surface information compared with 77.8% when using the curve data. Population-related shape differences were captured primarily in the outlines, while sexual dimorphism is distributed more uniformly throughout the entire surface of the zygomatic structure. Anat Rec, 300:226-237, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000406 TI - Zygomatic Root Position in Recent and Fossil Hominids. AB - The relative position of the zygomatic root to the dentition plays a crucial role in determining the overall strength of the face in response to bite forces. The powerful superficial head of the masseter arises there and the zygomaticoalveolar crest (ZAC) is discussed as a buttressing feature of the face. For instance, a more forwardly or backwardly positioned zygomatic root or a lower or higher vertical distance to the dentition could be indicative for evolutionary adaptations to particular loading regimes which are associated with diet. We therefore examined the morphology of the maxilla using state-of-the-art 3D Geometric Morphometric methods. The data set was reduced to a minimum of relevant measurements and includes five landmarks (pr, ol, zm, lingual and buccal midpoint of second molar alveoli) and three curves with semilandmarks along the lingual and buccal alveolar rim and the ZAC. Results show a stunning overlap in shape variation. We find no clear pattern of shape that would allow separating different hominid groups with confidence, except two extreme forms-Paranthropines and Neanderthals. We also find no clear trend over time. Australopithecines, Habilines, Erectines, and Middle Pleistocene Homo can be very similar to modern humans. Even great apes are within or not far from the central shape distribution of Homo, but they separate clearly from gracile and robust Australopithecines. We discuss the shape factors underlying our data. The geometry studied allows simple measurements and analyses and is thus potentially interesting for classification purposes of extreme forms. Anat Rec, 300:160-170, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000407 TI - Zygomaticomaxillary Morphology and Maxillary Sinus Form and Function: How Spatial Constraints Influence Pneumatization Patterns among Modern Humans. AB - Previous research has suggested that the maxillary sinuses may act as "zones of accommodation" for the nasal region, minimizing the impact of climatic-related changes in nasal cavity breadth on surrounding skeletal structures. However, a recent study among modern human crania has identified that, in addition to nasal cavity breadth, sinus morphology also tracks lateral facial form, especially anterior-posterior positioning of the zygomatics. Here, we expand upon this previous study to further investigate these covariation patterns by employing three samples with distinct combinations of nasal and zygomatic morphologies: Northern Asians (n = 28); sub-Saharan Africans (n = 30); and Europeans (n = 29). For each cranium, 30 landmarks were digitized from CT-rendered models and subsequently assigned to either a midfacial or maxillary sinus "block." Two block partial least squares (2B-PLS) analyses indicate that sinus morphology primarily reflects superior-inferior dimensions of the midface, rather than either nasal cavity breadth or zygomatic position. Specifically, individuals with relatively tall midfacial skeletons exhibit more inferiorly and laterally expanded sinuses compared to those with shorter midfaces. Further, separate across-group and within-group 2B-PLS analyses indicate that regional differences between samples primarily build upon a common pattern of midfacial and sinus covariation already present within each regional group. Allometry, while present, only explains a small portion of the midface-sinus covariation pattern. We conclude that previous findings of larger maxillary sinuses among cold-adapted individuals are not predominantly due to possession of relatively narrow nasal cavities, but to greater maxillary and zygomatic heights. Implications for sinus function and midfacial ontogeny are discussed. Anat Rec, 300:209-225, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000408 TI - Ancestral Variations in the Shape and Size of the Zygoma. AB - The variable development of the zygoma, dictating its shape and size variations among ancestral groups, has important clinical implications and valuable anthropological and evolutionary inferences. The purpose of the study was to review the literature regarding the variations in the zygoma with ancestry. Ancestral variation in the zygoma reflects genetic variations because of genetic drift as well as natural selection and epigenetic changes to adapt to diet and climate variations with possible intensification by isolation. Prominence of the zygoma, zygomaxillary tuberosity, and malar tubercle have been associated with Eastern Asian populations in whom these features intensified. Prominence of the zygoma is also associated with groups from Eastern Europe and the rest of Asia. Diffusion of these traits occurred across the Behring Sea to the Arctic areas and to North and South America. The greatest zygomatic projections are exhibited in Arctic groups as an adaptation to extreme cold conditions, while Native South American groups also present with other features of facial robusticity. Groups from Australia, Malaysia, and Oceania show prominence of the zygoma to a certain extent, possibly because of archaic occupations by undifferentiated Southeast Asian populations. More recent interactions with Chinese groups might explain the prominent cheekbones noted in certain South African groups. Many deductions regarding evolutionary processes and diversifications of early groups have been made. Cognisance of these ancestral variations also have implications for forensic anthropological assessments as well as plastic and reconstructive surgery. More studies are needed to improve accuracy of forensic anthropological identification techniques. Anat Rec, 300:196-208, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000409 TI - The Evolution of the Zygomatic Bone From Agnatha to Tetrapoda. AB - Establishing the homology of the zygomatic or jugal bone and tracing its origin and early evolution represents a complex issue because of large morphological gaps between various groups of vertebrates. Using recent paleontological findings, we discuss the deep homology of the zygomatic or jugal bone in stem gnathostomes (placoderms) and examine its homology and modifications in crown gnathostomes (acanthodians, chondrichthyans and osteichthyans). The discovery of the placoderm Entelognathus from the Silurian of China (~423 million years ago) established that the large dermal plates in placoderms and osteichthyans are homologous. In Entelognathus, the jugal was joined by a new set of bones (premaxilla, maxilla, and lachrymal), marking the first appearance of the typical vertebrate face found in tetrapods including humans. In non-Entelognathus placoderms, the jugal (homologized with the suborbital plate) occupied most of the cheek region and covered the palatoquadrate laterally. In antiarch placoderms (the most basal jawed vertebrates), the jugal (represented by the ventrally positioned mental plate) functioned as part of the upper jaw. In osteichthyans, the preopercular arose as a novel bone and separated the jugal from the opercular in piscine osteichthyans. A single bone in basal osteichthyans, the preopercular may have divided into two or three elements (the preopercular, the squamosal and/or the quadratojugal) in several later osteichthyan groups. Subsequent modifications of the jugal in the fish-tetrapod transition (its enlargement leading to its contact with the quadratojugal and the separation of the squamosal from the maxilla) brought the vertebrate face to the typical model we see in living tetrapods. Anat Rec, 300:16-29, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000410 TI - A Comparative Morphological Study of the Jugal and Quadratojugal in Early Birds and Their Dinosaurian Relatives. AB - The zygoma (called jugal bar) in modern birds accounts for a large portion of the ventral margin of the cranium. As a delicate and rod-like element, the jugal bar is functionally integrated into the avian cranial kinesis, a unique property that allows the beak to be elevated or depressed with respect to the braincase and thus distinguishes birds from all other modern vertebrates. Developmental studies show that the jugal bar of modern birds is formed by the fusion of the jugal and quadratojugal that are ossified from separated centers. However, those two bones are unfused and exhibit complicated morphological variations in basal birds and their dinosaurian relatives. Moreover, the jugal and quadratojugal form rigid articulations with the postorbital and squamosal, respectively, consequently hindering the movement of the upper jaw in most non-avian dinosaurs and some basal birds. A comparative study of the jugal and quadratojugal morphology of basal birds and their close relatives such as dromaeosaurids and oviraptorids elucidates how modern birds has achieved its derived jugal bar morphology, and sheds light on the evolution of the postorbital configuration of birds. We propose that numerous morphological modifications of those two elements (morphology changes and reduced articulation with other elements) took place in early bird history, and some of them pertinent to the refinement of the cranial kinesis. Anat Rec, 300:62-75, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28000411 TI - The role of radiation therapy in palliative care of children with advanced cancer: Clinical outcomes and patterns of care. AB - BACKGROUND: There are few published data to guide the use and timing of palliative radiation therapy (RT) in children. We aimed to determine the clinical outcomes of palliative RT in children and the relationship with palliative care and hospice referrals. PROCEDURE: A retrospective chart review was performed on all patients younger than 18 years who received palliative RT in our clinic from January 2005 to January 2015. RESULTS: In the specified time period, 50 children underwent 83 courses of palliative RT. Median survival after treatment was 124 days (range, 1-1141 days). Fifteen courses were delivered to children in the last 30 days of life (dol). Palliative RT was successful in 89% of courses delivered before the last 30 dol versus 28% of courses delivered in the last 30 dol (p < 0.0001, Fisher's exact test). At the time of data collection, 43 children were deceased. Altogether, 88% of children who received palliative RT were also referred to our institution's pediatric palliative care team or to hospice at some time in their course. Of the children who died, 74% were referred to hospice and 34% were on hospice while receiving palliative RT. For children not already on hospice, the median time to hospice referral was 96 days after the last fraction (range, 0-924 days). CONCLUSIONS: Palliative RT is effective in children with advanced cancer, although less so in the last 30 dol. With careful care coordination and multidisciplinary collaboration, RT can be successfully integrated into supportive and end-of-life care for children with advanced cancer. PMID- 28000413 TI - Bacteriostatic behavior of surface modulated silicon nitride in comparison to polyetheretherketone and titanium. AB - Perioperative and latent infections are leading causes of revision surgery for orthopaedic devices resulting in significant increased patient care, comorbidities, and attendant costs. Identifying biomaterial surfaces that inherently resist biofilm adhesion and bacterial expression is an important emerging strategy in addressing implant-related infections. This in vitro study was designed to compare biofilm formation on three biomaterials commonly employed in spinal fusion surgery-silicon nitride (Si3 N4 ), polyetheretherketone (PEEK), and a titanium alloy (Ti6Al4V-ELI) -using one gram-positive and one gram-negative bacterial species. Disc samples from various surface treated Si3 N4 , PEEK, and Ti6Al4V were inoculated with 105 CFU/mm2 Staphylococcus epidermidis (ATCC(r)14990TM) or Escherichia coli (ATCC(r) 25922TM) and cultured in PBS, 7% glucose, and 10% human plasma for 24 and 48 h, followed by retrieval and rinsing. Vortexed solutions were diluted, plated, and incubated at 37 degrees C for 24 to 48 h. Colony forming units (CFU/mm2 ) were determined using applicable dilution factors and surface areas. A two-tailed, heteroscedastic Student's t-test (95% confidence) was used to determine statistical significance. The various Si3 N4 samples showed the most favorable bacterial resistance for both bacilli tested. The mechanisms for the bacteriostatic behavior of Si3 N4 are likely due to multivariate surface effects including submicron-topography, negative charging, and chemical interactions which form peroxynitrite (an oxidative agent). Si3 N4 is a new biomaterial with the apparent potential to inhibit biofilm formation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1521-1534, 2017. PMID- 28000414 TI - Identification of CLK1 Inhibitors by a Fragment-linking Based Virtual Screening. AB - Alternative splicing plays an important role in the regulation of protein biosynthesis. CDC2-like kinases (CLKs) phosphorylate splicing factors rendering them a potential target for treating diseases caused by splicing dysregulation. As selective and potent inhibitors of CLK1 are still lacking, a fragment-linking based virtual screening campaign was successfully applied to identify new inhibitors showing activity on CLK1. These inhibitors exhibit a novel 2,4 substituted 1,3-thiazole scaffold that is suitable for further modification. A subsequently performed docking and protein structure based analysis revealed first hints for inhibitors showing preferred binding activity for CLK1 and DYRK2 over other splicing kinases. PMID- 28000415 TI - Catalytic Enantioselective Arylboration of Alkenylarenes. AB - A method for the catalytic enantioselective arylboration of alkenylarenes is disclosed. The reaction leads to the formation of 1,1-diarylalkanes that also incorporate an additional pinacol boronic ester which can be easily transformed to a variety of groups. The products are formed with excellent diastereoselectivities and enantioselectivities. PMID- 28000416 TI - C-H and C-N Activation at Redox-Active Pyridine Complexes of Iron. AB - Pyridine activation by inexpensive iron catalysts has great utility, but the steps through which iron species can break the strong (105-111 kcal mol-1 ) C-H bonds of pyridine substrates are unknown. In this work, we report the rapid room temperature cleavage of C-H bonds in pyridine, 4-tert-butylpyridine, and 2 phenylpyridine by an iron(I) species, to give well-characterized iron(II) products. In addition, 4-dimethylaminopyridine (DMAP) undergoes room-temperature C-N bond cleavage, which forms a dimethylamidoiron(II) complex and a pyridyl bridged tetrairon(II) square. These facile bond-cleaving reactions are proposed to occur through intermediates having a two-electron reduced pyridine that bridges two iron centers. Thus, the redox non-innocence of the pyridine can play a key role in enabling high regioselectivity for difficult reactions. PMID- 28000418 TI - Expression of type III collagen correlates with poor prognosis in oral squamous cell carcinoma. AB - AIM: The aim of the present study was to evaluate, compare, and correlate the types of collagen fibers seen in different grades of oral cancer. METHODS: Thirty cases of histologically-diagnosed, well-, moderately-, and poorly-differentiated oral squamous cell carcinoma (OSCC) were retrieved from the archives of the Institute. Collagen was evaluated using picrosirius red stain and immunohistochemical analysis of the antibody to type III collagen. A correlation between these findings and the grade of OSCC was evaluated. RESULTS: Collagen fibers showed a change in birefringence ranging from reddish-orange to greenish yellow in well- to poorly-differentiated oral squamous cell carcinoma. The findings were statistically significant for polarizing colors observed in grades of OSCC (P<.001). Immunohistochemical staining intensity of type III collagen changed from weak to strong as grade increased for OSCC, and was also statistically significant (P<.001). CONCLUSION: In the present study, tumor progression reflected a change in collagen present, from type I to type III. Determination of the type of collagen in different grades of OSCC can facilitate therapeutic targeting of molecules responsible for invasion and progression of oral cancer. PMID- 28000417 TI - A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group. AB - BACKGROUND: Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. PROCEDURE: Patients enrolled in the study had high-risk disease defined as >=1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. RESULTS: Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 +/- 6% and 70.2 +/- 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 +/- 6% and 76.6 +/- 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). CONCLUSIONS: Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data. PMID- 28000419 TI - Genomic and physiological analyses of 'Reinekea forsetii' reveal a versatile opportunistic lifestyle during spring algae blooms. AB - Gammaproteobacterial Reinekea spp. were detected during North Sea spring algae blooms in the years 2009-2012, with relative abundances of up to 16% in the bacterioplankton. Here, we explore the ecophysiology of 'R. forsetii' strain Hel1_31_D35 that was isolated during the 2010 spring bloom using (i) its manually annotated, high-quality closed genome, (ii) re-analysis of in situ data from the 2009-2012 blooms and (iii) physiological tests. High resolution analysis of 16S rRNA gene sequences suggested that 'R. forsetii' dominated Reinekea populations during these blooms. This was corroborated by retrieval of almost complete Hel1_31_D35 genomes from 2009 and 2010 bacterioplankton metagenomes. Strain Hel1_31_D35 can use numerous low-molecular weight substrates including diverse sugar monomers, and few but relevant algal polysaccharides such as mannan, alpha glucans, and likely bacterial peptidoglycan. It oxidizes thiosulfate to sulfate, and ferments under anoxic conditions. The strain can attach to algae and thrives at low phosphate concentrations as they occur during blooms. Its genome encodes RTX toxin and secretion proteins, and in cultivation experiments Hel1_31_D35 crude cell extracts inhibited growth of a North Sea Polaribacter strain. Our data suggest that the combination of these traits make strain Hel1_31_D35 a versatile opportunist that is particularly competitive during spring phytoplankton blooms. PMID- 28000420 TI - Hemocompatibility of Superhemophobic Titania Surfaces. AB - The hemocompatibility of superhemophobic surfaces is investigated and compared with that of hemophobic surfaces and hemophilic surfaces. This analysis indicates that only those superhemophobic surfaces with a robust Cassie-Baxter state display significantly lower platelet adhesion and activation. It is envisioned that the understanding gained through this work will lead to the fabrication of improved hemocompatible, superhemophobic medical implants. PMID- 28000421 TI - Job Satisfaction, Quality of Work Life and Work Motivation in Employees with Intellectual Disability: A Systematic Review. AB - BACKGROUND: Current research on employment options for people with Intellectual Disability emphasizes the importance of employee needs and satisfaction. The study aims at systematically reviewing the literature on job satisfaction and related constructs. METHODS: A systematic literature search was conducted. Studies were included if (i) they are specific to effects of work, (ii) assessed variables are related to job satisfaction, QoWL, attitudes towards work or work motivation and if (iii) studies reported intellectual disability-specific results. Twenty-three studies met the inclusion criteria. Findings were classified according to the socio-cognitive model of job satisfaction. RESULTS: Current literature suggests high job satisfaction in people with intellectual disability. Predictors of job satisfaction are similar to people without disabilities, albeit the importance of factors differs. CONCLUSIONS: Stronger consideration of well-established theories and measures from organizational psychology would enhance future research. Findings indicate that high satisfaction ratings might result from lack of control over vocational decisions. PMID- 28000422 TI - Secondary analysis of data can inform care delivery for Indigenous women in an acute mental health inpatient unit. AB - There is a paucity of research exploring Indigenous women's experiences in acute mental health inpatient services in Australia. Even less is known of Indigenous women's experience of seclusion events, as published data are rarely disaggregated by both indigeneity and gender. This research used secondary analysis of pre-existing datasets to identify any quantifiable difference in recorded experience between Indigenous and non-Indigenous women, and between Indigenous women and Indigenous men in an acute mental health inpatient unit. Standard separation data of age, length of stay, legal status, and discharge diagnosis were analysed, as were seclusion register data of age, seclusion grounds, and number of seclusion events. Descriptive statistics were used to summarize the data, and where warranted, inferential statistical methods used SPSS software to apply analysis of variance/multivariate analysis of variance testing. The results showed evidence that secondary analysis of existing datasets can provide a rich source of information to describe the experience of target groups, and to guide service planning and delivery of individualized, culturally secure mental health care at a local level. The results are discussed, service and policy development implications are explored, and suggestions for further research are offered. PMID- 28000423 TI - Anxiety independently contributes to elevated inflammation in humans with obesity. AB - OBJECTIVE: Anxious and depressive states are associated with increased cardiovascular disease (CVD) risk and a proinflammatory phenotype, although the latter appears to be at least partially explained by adiposity. It was hypothesized that depression and anxiety would be associated with elevated inflammation independent of adiposity in persons with obesity at high risk of CVD. METHODS: This study explored the relation between baseline anxiety as measured by the Beck Anxiety Inventory and depression as measured by the Beck Depression Inventory-II and baseline serum c-reactive protein (CRP) in a cross sectional sample of 100 participants [mean (SD) age 57.8 (7.7) years; 64% female] with obesity [mean (SD) body mass index, BMI 37.3 (5.5) kg/m2 ] enrolled in a clinical trial for pharmacological weight loss. RESULTS: Beck Anxiety Inventory, but not Beck Depression Inventory-II, scores were significantly correlated with CRP (rho = 0.28, P = 0.005). BMI was also highly correlated with CRP (rho = 0.42, P < 0.0001). In multivariate models, the relation between anxiety and CRP remained significant (P = 0.038), independent of BMI, age, and sex. CONCLUSIONS: Anxiety, but not depression, was associated with elevated inflammation in persons with obesity beyond that attributable to higher BMI. Further study is warranted to assess whether anxiety represents a potential therapeutic target to mitigate corresponding CVD risk associated with elevated inflammation in persons with obesity. PMID- 28000424 TI - Sleep disturbance and depressive affect in patients treated with haemodialysis. AB - BACKGROUND: Sleep disorders and depression are prevalent conditions in patients with end-stage kidney disease. These co-morbidities have significant overlap and compounded morbidity and mortality burden. This overlap presents challenges to optimal clinical assessment and treatment. The goal of this study was to assess the prevalence of sleep disturbance in patients on maintenance haemodialysis, and to assess the impact of depressive affect. OBJECTIVES: This was a single-site, single group, cross-sectional study of 69 English-speaking patients undergoing maintenance haemodialysis. Self-reported assessments included those of sleep quality (Pittsburgh Sleep Quality Index), depression (Beck Depression Inventory), daytime sleepiness (Epworth's Sleepiness Scale), a dialysis-specific sleep questionnaire, and standard laboratory values. No objective sleep information was collected. METHOD: All participants were well dialysed, and represented all four daily shifts. Fifty-eight per cent reported clinically significant sleep difficulty, with elevated yet sub-threshold daytime sleepiness. Mean depressive affect was also elevated, yet sub-diagnostic and was positively correlated with increased age. RESULTS: Participants scoring above the diagnostic threshold for depression had significantly more disturbed sleep quality, more daytime sleepiness and had more problems sleeping due to restless leg syndrome than people with minimal depressive affect. CONCLUSION: Poor sleep quality is prevalent in patients on maintenance haemodialysis, and is associated with increased daytime sleepiness. Depression further compounds this relationship, and is significantly associated with increased daytime sleepiness and restless leg syndrome. PMID- 28000425 TI - Randomized sham-controlled trial evaluating efficacy and safety of endoscopic gastric plication for primary obesity: The ESSENTIAL trial. AB - OBJECTIVE: Evaluate safety and efficacy of the poseTM procedure for obesity treatment. METHODS: Subjects with Class I to II obesity were randomized (2:1) to receive active or sham procedure, after each investigator performed unblinded lead-in cases. All subjects were provided low-intensity lifestyle therapy. Efficacy end points were the mean difference in percent total body weight loss (%TBWL) at 12 months between randomized groups, and responder rate achieving >=5% TBWL. The primary safety end point was incidence of reported adverse events. RESULTS: Three hundred thirty-two subjects were randomized (active, n = 221; sham, n = 111); thirty-four subjects were included in the unblinded lead-in cohort. Twelve-month results were mean TBWL 7.0 +/- 7.4% in lead-in, 4.95 +/- 7.04% in active, and 1.38 +/- 5.58% in sham groups, respectively. Responder rate was 41.55% in active and 22.11% in sham groups, respectively (P < 0.0001); mean responder result was 11.5% TBWL. The differences observed between active and sham groups for co-primary end points were statistically significant (P < 0.0001); however, super superiority margin as set forth in the study design was not met. No unanticipated adverse events or deaths occurred. Procedure-related serious adverse event rates were 5.0% (active) and 0.9% (sham), P = 0.068. CONCLUSIONS: The pose procedure was safe and resulted in statistically significant and clinically meaningful weight loss over sham through 1 year. PMID- 28000426 TI - Outcome after neoadjuvant chemotherapy in Asian breast cancer patients. AB - We aim to identify clinicopathologic predictors for response to neoadjuvant chemotherapy and to evaluate the prognostic value of pathologic complete response (pCR) on survival in Asia. This study included 915 breast cancer patients who underwent neoadjuvant chemotherapy at five public hospitals in Singapore and Malaysia. pCR following neoadjuvant chemotherapy was defined as 1) no residual invasive tumor cells in the breast (ypT0/is) and 2) no residual invasive tumor cells in the breast and axillary lymph nodes (ypT0/is ypN0). Association between pCR and clinicopathologic characteristics and treatment were evaluated using chi square test and multivariable logistic regression. Kaplan-Meier analysis and log rank test, stratified by other prognostic factors, were conducted to compare overall survival between patients who achieved pCR and patients who did not. Overall, 4.4% of nonmetastatic patients received neoadjuvant chemotherapy. The median age of preoperatively treated patients was 50 years. pCR rates were 18.1% (pCR ypT0/is) and 14.4% (pCR ypT0/is ypN0), respectively. pCR rate was the highest among women who had higher grade, smaller size, estrogen receptor negative, human epidermal growth factor receptor 2-positive disease or receiving taxane-based neoadjuvant chemotherapy. Patients who achieved pCR had better overall survival than those who did not. In subgroup analysis, the survival advantage was only significant among women with estrogen receptor-negative tumors. Patients with poor prognostic profile are more likely to achieve pCR and particularly when receiving taxane-containing chemotherapy. pCR is a significant prognostic factor for overall survival especially in estrogen receptor-negative breast cancers. PMID- 28000427 TI - Incidence and survival of childhood leukemia in Recife, Brazil: A population based analysis. AB - BACKGROUND: Leukemia is the most common pediatric cancer with incidence rates of around 48 per million for children under 15 years of age. The median age-adjusted incidence rate (AAIR) in children aged 0-14 years in Brazil is 53.3 per million. While overall survival rates for children with leukemia have improved significantly, data for incidence, trends, and relative survival among children and adolescents with leukemia in Recife, Brazil, remain incomplete, which hampers our analyses and provision of the best healthcare. The objective of this report is to provide that data. METHODS: Data from the Population-Based Cancer Registry of Recife were analyzed from 1998 to 2007. Our analyses included frequencies and AAIR, together with age-specific incidence rates for all leukemias, acute lymphoblastic leukemia, and acute myeloid leukemia. To evaluate incidence trends, joinpoint regression, including annual average percent change, were analyzed. Relative survival was calculated using the life-table method. RESULTS: One hundred seventy-five cases were identified, 51% in females. The review reduced the not otherwise specified (NOS) leukemia category by 50% and diagnosis by death certificate only from 5.7% to 1.1%. The AAIR for leukemia was 41.1 per million, with a peak among children aged 1-4 (78.3 per million). Incidence trends during the period were stable. The five-year relative survival rate was 69.8%. CONCLUSIONS: These data represent the incidence rate and survival of childhood leukemia in Recife, located in the northeast region of Brazil, using a high quality database. PMID- 28000428 TI - Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance. AB - OBJECTIVE: The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity. METHODS: Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) >=30 kg/m2 , and IR was defined as steady-state plasma glucose (SSPG) >=10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity. RESULTS: Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR. CONCLUSIONS: Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR. PMID- 28000429 TI - Exploring experiences of the quality of nursing care among patients, nurses, caregivers and physicians in a haemodialysis department. AB - BACKGROUND AND OBJECTIVES: Providing high-quality care to patients undergoing haemodialysis (HD) is a priority for nurses. The present study was conducted to explore the experiences of the quality of nursing care among patients, nurses, caregivers and physicians in an HD department in Iran. METHODS: This was a qualitative study, set in the HD department of Kowsar Hospital in Semnan, Iran. A total of 20 participants (patients, caregivers, nurses and doctors) were selected and were invited to semi-structured interviews with open-ended questions. The data obtained were analysed using conventional content analysis. FINDINGS: The analysis of the data led to the extraction of four themes: maintaining health, person/client, nursing responsibility and environment. CONCLUSION: The findings of the present study showed that maintaining health, person/client interaction, nursing responsibility and environment are four important nursing metaparadigms that affect the quality of nursing care in HD departments. PMID- 28000430 TI - Metabolites distinguishing visceral fat obesity and atherogenic traits in individuals with overweight. AB - OBJECTIVE: To screen the metabolomes of both overweight subjects with low visceral fat area (LFO) and high visceral fat area (HFO) to identify potential metabolites that are associated with the different metabolic characteristics. METHODS: The metabolic characteristics of 112 overweight (25 kg/m2 <= BMI < 30 kg/m2 ) Korean individuals aged 30 to 65 years were examined. Plasma metabolomic profiling of HFO [visceral fat area (VFA) at L4 >= 100 cm2 ] and LFO (L4 VFA <100 cm2 ) individuals matched for age, gender, and BMI was performed. RESULTS: HFO subjects showed higher VFA at L1 and L4 than LFO subjects. The HFO group showed higher blood pressure, lipid profile, high-sensitivity C-reactive protein, malondialdehyde, oxidized low-density lipoprotein (LDL), and homeostasis model assessment-insulin resistance and lower high-density lipoprotein-cholesterol levels. In plasma metabolite identification, the HFO group showed significantly higher levels of long-chain (C14:1, C16:1, C16) acylcarnitines (ACs), medium chain (C12:1, C12) ACs, urobilinogen, docosahexaenoic acid (C22:6omega3), lysoPE (22:6), lysoPC (22:6), lysoPC (22:5), methoxybenzenepropanoic acid, and isodesmosine. All five ACs correlated positively with VFA and oxidized LDL levels and negatively with high-density lipoprotein-cholesterol levels and LDL particle size. CONCLUSIONS: Twelve major metabolites, including three long-chain fatty acids and two medium-chain ACs, are important for distinguishing HFO and LFO. Chronic lipid surplus from visceral fat in HFO is likely associated with substantial increases in plasma medium-chain ACs and long-chain fatty acids, which are closely related to atherogenic traits. PMID- 28000431 TI - Detecting spatial regimes in ecosystems. AB - Research on early warning indicators has generally focused on assessing temporal transitions with limited application of these methods to detecting spatial regimes. Traditional spatial boundary detection procedures that result in ecoregion maps are typically based on ecological potential (i.e. potential vegetation), and often fail to account for ongoing changes due to stressors such as land use change and climate change and their effects on plant and animal communities. We use Fisher information, an information theory-based method, on both terrestrial and aquatic animal data (U.S. Breeding Bird Survey and marine zooplankton) to identify ecological boundaries, and compare our results to traditional early warning indicators, conventional ecoregion maps and multivariate analyses such as nMDS and cluster analysis. We successfully detected spatial regimes and transitions in both terrestrial and aquatic systems using Fisher information. Furthermore, Fisher information provided explicit spatial information about community change that is absent from other multivariate approaches. Our results suggest that defining spatial regimes based on animal communities may better reflect ecological reality than do traditional ecoregion maps, especially in our current era of rapid and unpredictable ecological change. PMID- 28000432 TI - Long-term climate and competition explain forest mortality patterns under extreme drought. AB - Rising temperatures are amplifying drought-induced stress and mortality in forests globally. It remains uncertain, however, whether tree mortality across drought-stricken landscapes will be concentrated in particular climatic and competitive environments. We investigated the effects of long-term average climate [i.e. 35-year mean annual climatic water deficit (CWD)] and competition (i.e. tree basal area) on tree mortality patterns, using extensive aerial mortality surveys conducted throughout the forests of California during a 4-year statewide extreme drought lasting from 2012 to 2015. During this period, tree mortality increased by an order of magnitude, typically from tens to hundreds of dead trees per km2 , rising dramatically during the fourth year of drought. Mortality rates increased independently with average CWD and with basal area, and they increased disproportionately in areas that were both dry and dense. These results can assist forest managers and policy-makers in identifying the most drought-vulnerable forests across broad geographic areas. PMID- 28000434 TI - Erratum for Valdovinos et al (2016) DOI: 10.1111/ele.12664. PMID- 28000433 TI - What's your move? Movement as a link between personality and spatial dynamics in animal populations. AB - Recent studies have established the ecological and evolutionary importance of animal personalities. Individual differences in movement and space-use, fundamental to many personality traits (e.g. activity, boldness and exploratory behaviour) have been documented across many species and contexts, for instance personality-dependent dispersal syndromes. Yet, insights from the concurrently developing movement ecology paradigm are rarely considered and recent evidence for other personality-dependent movements and space-use lack a general unifying framework. We propose a conceptual framework for personality-dependent spatial ecology. We link expectations derived from the movement ecology paradigm with behavioural reaction-norms to offer specific predictions on the interactions between environmental factors, such as resource distribution or landscape structure, and intrinsic behavioural variation. We consider how environmental heterogeneity and individual consistency in movements that carry-over across spatial scales can lead to personality-dependent: (1) foraging search performance; (2) habitat preference; (3) home range utilization patterns; (4) social network structure and (5) emergence of assortative population structure with spatial clusters of personalities. We support our conceptual model with spatially explicit simulations of behavioural variation in space-use, demonstrating the emergence of complex population-level patterns from differences in simple individual-level behaviours. Consideration of consistent individual variation in space-use will facilitate mechanistic understanding of processes that drive social, spatial, ecological and evolutionary dynamics in heterogeneous environments. PMID- 28000436 TI - Corrigendum for Lu et al. (2015) DOI: 10.1111/ele.12391. PMID- 28000435 TI - Intraspecific chemical diversity among neighbouring plants correlates positively with plant size and herbivore load but negatively with herbivore damage. AB - Intraspecific plant diversity can modify the properties of associated arthropod communities and plant fitness. However, it is not well understood which plant traits determine these ecological effects. We explored the effect of intraspecific chemical diversity among neighbouring plants on the associated invertebrate community and plant traits. In a common garden experiment, intraspecific diversity among neighbouring plants was manipulated using three plant populations of wild cabbage that differ in foliar glucosinolates. Plants were larger, harboured more herbivores, but were less damaged when plant diversity was increased. Glucosinolate concentration differentially correlated with generalist and specialist herbivore abundance. Glucosinolate composition correlated with plant damage, while in polycultures, variation in glucosinolate concentrations among neighbouring plants correlated positively with herbivore diversity and negatively with plant damage levels. The results suggest that intraspecific variation in secondary chemistry among neighbouring plants is important in determining the structure of the associated insect community and positively affects plant performance. PMID- 28000437 TI - Corrigendum for: Levels of folate receptor autoantibodies in maternal and cord blood and risk of neural tube defects in a Chinese population, 106:685-695 (10.1002/bdra.23517). PMID- 28000438 TI - Gogadget: An R Package for Interpretation and Visualization of GO Enrichment Results. AB - Gene expression profiling followed by gene ontology (GO) term enrichment analysis can generate long lists of significant GO terms. To interpret these results and get biological insight in the data, filtering and rearranging these long lists of GO terms might be desirable. The R package gogadget provides functions to modify GO analysis results, with a simple filter strategy. Furthermore, it groups redundant GO terms with hierarchical clustering and presents the results in a colorful heatmap. The filtered GO term enrichment results can also be exported by the package for subsequent analysis in Cytoscape Enrichment Map. The R package is freely available under the terms of the GNU GPLv3 at https://sourceforge.net/projects/gogadget/. PMID- 28000439 TI - Expediting Combinatorial Data Set Analysis by Combining Human and Algorithmic Analysis. AB - A challenge in combinatorial materials science remains the efficient analysis of X-ray diffraction (XRD) data and its correlation to functional properties. Rapid identification of phase-regions and proper assignment of corresponding crystal structures is necessary to keep pace with the improved methods for synthesizing and characterizing materials libraries. Therefore, a new modular software called htAx (high-throughput analysis of X-ray and functional properties data) is presented that couples human intelligence tasks used for "ground-truth" phase region identification with subsequent unbiased verification by an algorithm to efficiently analyze which phases are present in a materials library. Identified phases and phase-regions may then be correlated to functional properties in an expedited manner. For the functionality of htAx to be proven, two previously published XRD benchmark data sets of the materials systems Al-Cr-Fe-O and Ni-Ti Cu are analyzed by htAx. The analysis of ~1000 XRD patterns takes less than 1 day with htAx. The proposed method reliably identifies phase-region boundaries and robustly identifies multiphase structures. The method also addresses the problem of identifying regions with previously unpublished crystal structures using a special daisy ternary plot. PMID- 28000440 TI - Review of Urban Secondary Organic Aerosol Formation from Gasoline and Diesel Motor Vehicle Emissions. AB - Secondary organic aerosol (SOA) is formed from the atmospheric oxidation of gas phase organic compounds leading to the formation of particle mass. Gasoline- and diesel-powered motor vehicles, both on/off-road, are important sources of SOA precursors. They emit complex mixtures of gas-phase organic compounds that vary in volatility and molecular structure-factors that influence their contributions to urban SOA. However, the relative importance of each vehicle type with respect to SOA formation remains unclear due to conflicting evidence from recent laboratory, field, and modeling studies. Both are likely important, with evolving contributions that vary with location and over short time scales. This review summarizes evidence, research needs, and discrepancies between top-down and bottom-up approaches used to estimate SOA from motor vehicles, focusing on inconsistencies between molecular-level understanding and regional observations. The effect of emission controls (e.g., exhaust aftertreatment technologies, fuel formulation) on SOA precursor emissions needs comprehensive evaluation, especially with international perspective given heterogeneity in regulations and technology penetration. Novel studies are needed to identify and quantify "missing" emissions that appear to contribute substantially to SOA production, especially in gasoline vehicles with the most advanced aftertreatment. Initial evidence suggests catalyzed diesel particulate filters greatly reduce emissions of SOA precursors along with primary aerosol. PMID- 28000441 TI - Synthesis and Characterization of Photo-Cross-Linkable Keratin Hydrogels for Stem Cell Encapsulation. AB - The objective of this work was to synthesize an injectable and photopolymerizable hydrogel based on keratin extracted from poultry feather for encapsulation and delivery of stem cells in tissue regeneration. Since feather keratin is rich in cysteine residue, allylation of sulfhydryl groups was used for functionalization of keratin. Keratin was extracted from feather barbs by reducing the disulfide bonds in cysteine residues to sulfhydryl groups (-SH). Next, the free thiol groups were converted to dehydroalanine (Dha) by oxidative elimination using O (2,4,6-trimethylbenzenesulfonyl) hydroxylamine. Then, the Dha moieties were converted to s-allyl cysteine by reaction with allyl mercaptan to produce keratin allyl thioether (KeratATE) biopolymer. Human mesenchymal stem cell (hMSCs) were suspended in the aqueous solution of KeratATE, injected into a mold, and photopolymerized to generate a KeratATE hydrogel encapsulating hMSCs. The freeze dried photo-cross-linked KeratATE hydrogels had a porous, interconnected, honeycomb microstructure with pore sizes in the 20-60 MUm range. The compressive modulus of the hydrogels ranged from 1 to 8 kPa depending on KeratATE concentration. KeratATE hydrogels had <5% mass loss in collagenase solution after 21 days of incubation, whereas the mass loss was 15% in trypsin solution. Degradation of KeratATE hydrogel was strongly dependent on trypsin concentration but independent of collagenase. hMSCs proliferated and adopted an elongated spindle-shape morphology after seeding on KeratATE hydrogel. KeratATE hydrogel supported differentiation of the encapsulated hMSCs to the osteogenic and chondrogenic lineages to the same extent as those hMSCs encapsulated in gelatin methacryloyl hydrogel. The results suggest that keratin allyl thioether hydrogel with controllable degradation is a viable matrix for encapsulation and delivery of stem cells in tissue regeneration. PMID- 28000442 TI - A Photoactivatable Innate Immune Receptor for Optogenetic Inflammation. AB - Although spatial and temporal elements of immune activation mediate the intensity of the immune response, few tools exist to directly examine these effects. To elucidate the spatiotemporal aspects of innate immune responses, we designed an optogenetic pattern recognition receptor that activates in response to blue light. We demonstrate direct receptor activation, leading to spatial and temporal control of downstream signaling pathways in a variety of relevant cell types. We combined our platform with Bi-molecular Fluorescence Complementation (BiFC), resulting in selective fluorescent labeling of cells in which receptor activation has occurred. PMID- 28000443 TI - Predictors of Serum Polybrominated Diphenyl Ether (PBDE) Concentrations among Children Aged 1-5 Years. AB - Serum concentrations of PBDEs were measured using gas chromatography-tandem mass spectrometry in 80 children aged 15-71 months. Demographic and behavioral data were collected on parental questionnaires; a research nurse recorded anthropometric measures and insurance status. For a subset of children (n = 17), PBDEs were measured in house dust and child handwipes sampled during a home visit. In linear and Tobit regression, log-transformed PBDE congeners were modeled as a function of child characteristics, including neighborhood-level socioeconomic indicators. BDE congeners 47, 99, and 100 were highly correlated and summed for analysis; BDE-153 was examined individually. PBDE serum concentrations were associated with socioeconomic factors; for example, a $20,000 increase in median household income in a child's ZIP code was associated with a 34% decrease (95%CI = 14-49%) in BDE-153 and a 26% decrease (95%CI = 6-42%) in ?BDE-47,-99,-100. Lower body-mass index (BMI) z-score and household smoking were strong predictors of higher BDE-153 levels. Among children who participated in a home visit, serum PBDE was positively correlated with handwipe PBDE (Spearman r ?BDE-47, -99, -100 = 0.48, p = 0.09), but not dust PBDE. Results indicate socioeconomic factors and BMI are strong predictors of serum PBDE levels among young children. PBDEs measured on handwipes are more predictive of serum PBDE levels than vacuum-collected dust. PMID- 28000445 TI - Delphinidin Prevents Muscle Atrophy and Upregulates miR-23a Expression. AB - Delphinidin, one of the major anthocyanidins, shows protective effects against a variety of pathologies, including cancer, inflammation, and muscle atrophy. The purpose of this study was to determine the preventive mechanism of delphinidin on disuse muscle atrophy. In vitro and in vivo models were used to validate the effects of delphinidin on the expression of MuRF1, miR-23a, and NFATc3. Delphinidin suppressed the upregulation of MuRF1 (1.77 +/- 0.05 vs 1.03 +/- 0.17, P < 0.05) expression and inhibited the downregulation of miR-23a (0.56 +/- 0.05 vs 0.94 +/- 0.06, P < 0.05) and NFATc3 (0.61 +/- 0.02 vs 1.02 +/- 0.08, P < 0.01) expression in dexamethasone-treated C2C12 cells. In gastrocnemius, muscle weight loss was prevented by oral administration of delphinidin. Moreover, delphinidin suppressed MuRF1 (3.35 +/- 0.13 vs 2.26 +/- 0.3, P < 0.01) expression and promoted miR-23a (0.58 +/- 0.15 vs 2.25 +/- 0.29, P < 0.001) and NFATc3 (0.85 +/- 0.17 vs 1.54 +/- 0.13, P < 0.001) expressions. Delphinidin intake may prevent disuse muscle atrophy by inducing miR-23a expression and suppressing MuRF1 expression. PMID- 28000446 TI - Simple Physics-Based Analytical Formulas for the Potentials of Mean Force of the Interaction of Amino Acid Side Chains in Water. VII. Charged-Hydrophobic/Polar and Polar-Hydrophobic/Polar Side Chains. AB - The physics-based potentials of side-chain-side-chain interactions corresponding to pairs composed of charged and polar, polar and polar, charged and hydrophobic, and hydrophobic and hydrophobic side chains have been determined. A total of 144 four-dimensional potentials of mean force (PMFs) of all possible pairs of molecules modeling these pairs were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation, and the analytical expressions were then fitted to the PMFs. Depending on the type of interacting sites, the analytical approximation to the PMF is a sum of terms corresponding to van der Waals interactions and cavity-creation involving the nonpolar sections of the side chains and van der Waals, cavity-creation, and electrostatic (charge-dipole or dipole-dipole) interaction energies and polarization energies involving the charged or polar sections of the side chains. The model used in this work reproduces all features of the interacting pairs. The UNited RESidue force field with the new side-chain-side-chain interaction potentials was preliminarily tested with the N-terminal part of the B-domain of staphylococcal protein A (PDBL 1BDD ; a three-alpha-helix bundle) and UPF0291 protein YnzC from Bacillus subtilis (PDB: 2HEP ; an alpha-helical hairpin). PMID- 28000447 TI - Hypocholesterolemic Activity of Curcumin Is Mediated by Down-regulating the Expression of Niemann-Pick C1-like 1 in Hamsters. AB - We previously demonstrated that curcumin reduces cholesterol absorption in Caco-2 cells through down-regulating Niemann-Pick C1-like 1 (NPC1L1) expression, but the in vivo effect of curcumin on intestinal cholesterol absorption remains unknown. The present study aimed to investigate the effects and mechanisms of curcumin consumption on cholesterol absorption in hamsters. Male hamsters were fed a high fat diet supplemented with or without curcumin (0.05% w/w) for 12 weeks. Curcumin supplementation significantly decreased serum total cholesterol (TC) (from 6.86 +/- 0.27 to 3.50 +/- 0.24 mmol/L), triglyceride (TG) (from 5.07 +/- 0.34 to 3.72 +/- 0.40 mmol/L), and low-density lipoprotein cholesterol (from 2.58 +/- 0.19 to 1.71 +/- 0.15 mmol/L) levels as well as liver TC (from 11.6 +/- 0.05 to 7.2 +/- 0.03 mg/g) and TG (from 30.3 +/- 0.22 to 25.2 +/- 0.18 mg/g) levels (P < 0.05 for all). In contrast, curcumin treatment markedly enhanced fecal cholesterol output (P < 0.01). Moreover, curcumin supplementation down-regulated the mRNA and protein expressions of sterol regulatory element binding protein-2 (SREBP-2) and NPC1L1 in the small intestine (P < 0.05). Our current results indicate that curcumin inhibits cholesterol absorption in hamsters by suppressing SREBP-2 and subsequently down-regulating NPC1L1 expression, which may be responsible for the hypocholesterolemic effects of curcumin. PMID- 28000444 TI - Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules. AB - We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development. PMID- 28000449 TI - Breath Figure in Reactive Vapor: A New Route to Nanopore Array. AB - A breath figure (BF)-inspired method for preparing ordered porous films has attracted more and more attention because of its simplicity, low cost, and easy implementation. However, it remains a challenge to use this method to fabricate nanoscale porous structures without designed polymer architecture and auxiliary. Herein, we first report a facile method to fabricate BF arrays with nanopores (nanoBFAs) in reactive vapor. Depending on the chemical reaction between the formic acid (FA) droplet template and the polyvinylpyridine (PVP) segments in copolymer, we successfully create nanoBFAs by casting a PVP-containing copolymer solution in CS2 in FA vapor. The condensed FA droplets can be instantly fixed by the PVP composition, and thus the growth and the aggregation of adjacent droplets are effectively restricted. Eventually, nanoBFAs are achieved in wide range solution concentration. In addition, binary porous structures with both nano- and microscale topology can be formed by using a FA/water mixed vapor with a one-step BF process. The produced nanoBFA films exhibit excellent antireflection performance with 0.5% reflectance, which is well-preserved even after hydrophobic treatment. This modified BF technique not only facilitates the elucidation of BFA formation mechanism but also opens a new way of fabricating nanoporous structures, which may have potential applications in electronic and optical devices. PMID- 28000448 TI - Glycoconjugated Site-Selective DNA-Methylating Agent Targeting Glucose Transporters on Glioma Cells. AB - DNA-alkylating drugs continue to remain an important weapon in the arsenal against cancers. However, they typically suffer from several shortcomings because of the indiscriminate DNA damage that they cause and their inability to specifically target cancer cells. We have developed a strategy for overcoming the deficiencies in current DNA-alkylating chemotherapy drugs by designing a site specific DNA-methylating agent that can target cancer cells because of its selective uptake via glucose transporters, which are overexpressed in most cancers. The design features of the molecule, its synthesis, its reactivity with DNA, and its toxicity in human glioblastoma cells are reported here. In this molecule, a glucosamine unit, which can facilitate uptake via glucose transporters, is conjugated to one end of a bispyrrole triamide unit, which is known to bind to the minor groove of DNA at A/T-rich regions. A methyl sulfonate moiety is tethered to the other end of the bispyrrole unit to serve as a DNA methylating agent. This molecule produces exclusively N3-methyladenine adducts upon reaction with DNA and is an order of magnitude more toxic to treatment resistant human glioblastoma cells than streptozotocin is, a Food and Drug Administration-approved, glycoconjugated DNA-methylating drug. Cellular uptake studies using a fluorescent analogue of our molecule provide evidence of uptake via glucose transporters and localization within the nucleus of cells. These results demonstrate the feasibility of our strategy for developing more potent anticancer chemotherapeutics, while minimizing common side effects resulting from off-target damage. PMID- 28000450 TI - ? AB - Desde hace algun tiempo sabemos que la talla de las poblaciones es un buen instrumento para analizar la evolucion socioeconomica, habiendo dejado de ser motivo de estudio solo por la biomedicina para serlo tambien por los economistas y sociologos. Es lo que han hecho Martinez Carrion y cols., con el trabajo que aparece en este numero de Nutricion Hospitalaria. PMID- 28000451 TI - ? AB - INTRODUCTION: Health-related quality of life (HRQoL) provides a global view of the state of health of a patient receiving home enteral nutrition (HEN). OBJECTIVE: To evaluate the HRQoL of patients receiving HEN using the NutriQoL(r) questionnaire, a specific instrument regardless of the underlying disease and route of administration. MATERIALS AND METHODS: Observational, prospective and multicentre study conducted in the context of the validation and assessment of the NutriQoL(r) questionnaire's psychometric properties. RESULTS: One-hundred-and forty individuals [disease: cancer (58.6%), malabsorption and other (27.1%), neurological (13.6%); HEN: supplement (61.4%), sole source of nutrition (35.7%); administration route: oral (54.3%), ostomy (31.4%), nasoenteric tube (12.1%)] participated. NutriQoL(r) was reliable [ICC: 0.88 (95%CI: 0.80-0.93); Cronbach's alpha: 0.77 (1st visit) and 0.83 (2nd visit)], valid (significant Rho), lowly sensitive to changes (effect size 0.23), can be completed by either patients or caregivers (ICC: 0.82). The mean HRQoL (SD) with NutriQoL(r) was 14.98 (14.86), EQ-5D tariff: 53(0.25), EQ-5D VAS: 54.15 (20.64) and COOP/WONCA charts: 23.32(5.66). HRQoL with NutriQoL(r) was better (p < 0.05) for oral HEN [19.54 (13,23)], than nasoenteric tube [14(11.71)], ostomy [7.02 (15.48)]; administered orally [19.54 (13.23)], than by gravity [10.97 (14.46)], pump [8.5 (19.78)] or syringe bolus [7 (11.40)]; as a supplement [19.33 (13.73)] instead of sole source of nutrition [8.18 (14.23)]. CONCLUSIONS: NutriQoL(r) is valid, reliable, even if lowly sensitive to change, and useful to measure HRQoL in this population. More studies are needed to know HRQoL in routine practice. PMID- 28000452 TI - Phase Angle and Onodera's Prognostic Nutritional Index in critically ill patients. AB - INTRODUCTION: Assessing severity and nutritional prognosis in critical patients has become increasingly important in recent years, since these parameters are related to morbidity/mortality and used to guide therapeutic options. OBJECTIVE: Determine nutritional prognosis through the Phase Angle (PA) and Onodera's Prognostic Nutritional Index (OPNI) and its relationship with severity, hospitalization time and mortality of critically ill patients. METHODS: Descriptive cross-sectional study, involving adult patients hospitalized in an Intensive Care Unit (ICU). Data were collected from the patients' medical records to calculate severity indicators (APACHE II, SOFA and SAPS 3) and determine the length of hospitalization and outcome. Bioimpedance was conducted to calculate the PA, using resistance and reactance data. RESULTS: A total of 35 patients (26% men and 74% women), with mean age of 55.5 +/- 16.7 years, were included. The mortality rate (17%) was similar to that expected by APACHE II and SOFA, but higher than that predicted by SAPS 3. The mean values for the PA (4.2 +/- 1.0) and OPNI (38.7 +/- 8.3) were lower than the reference values adopted. Individuals with PA < 5.1 exhibited significantly lower reactance and albumin and higher APACHE II and SOFA values, in addition to longer hospitalization time and higher mortality. The PA was inversely correlated with all the severity indicators under study (APACHE II, SOFA and SAPS 3), and the length of hospitalization. By contrast, there was no correlation between OPNI and these parameters, or between PA and OPNI. CONCLUSION: The PA proved to be a good tool in assessing nutritional prognosis in critically ill patients. By contrast, more studies using the OPNI with this type of patients are needed. PMID- 28000453 TI - Prognostic value of severity by various visceral proteins in critically ill patients with SIRS during 7 days of stay. AB - INTRODUCTION: Critically ill patients typically develop a catabolic stress state as a result of a systemic inflammatory response (SIRS) that alters clinical nutritional biomarkers, increasing energy demands and nutritional requirements. OBJECTIVE: To evaluate the status of albumin, prealbumin and transferrin in critically ill patients and the association between these clinical-nutritional parameters with the severity during a seven day stay in intensive care unit (ICU). METHOD: Multicenter, prospective, observational and analytical follow-up study. A total of 115 subjects in critical condition were included in this study. Clinical and nutritional parameters and severity were monitored at admission and at the seventh day of the ICU stay. RESULTS: A significant decrease in APACHE II and SOFA (p < 0.05) throughout the evolution of critically ill patients in ICU. In general, patients showed an alteration of most of the parameters analyzed. The status of albumin, prealbumin and transferrin were below reference levels both at admission and the 7th day in ICU. A high percentage of patients presented an unbalanced status of albumin (71.3%), prealbumin (84.3%) and transferrin (69.0%). At admission, 27% to 47% of patients with altered protein parameters had APACHE II above 18. The number of patients with altered protein parameters and APACHE II below 18 were significantly higher than severe ones throughout the ICU stay (p < 0.01). Regarding the multivariate analysis, low prealbumin status was the best predictor of severity critical (p < 0.05) both at admission and 7th day of the ICU stay. CONCLUSION: The results of the present study support the idea of including low prealbumin status as a severity predictor in APACHE II scale, due to the association found between severity and poor status of prealbumin. PMID- 28000454 TI - Mediterranean diet adherence among Catalonian adolescents: socio-economic and lifestyle factors. AB - AIM: This study aims to describe the adherence to the Mediterranean diet (MD), using the KIDMED questionnaire, in a sample of Catalonian adolescents and to assess the association between the MD adherence and socio-economic and lifestyle behaviours. MATERIAL AND METHODS: Data are part of a multi-centre longitudinal study designed for the reduction of risk factors of eating and weight-related problems in adolescents. Here, a cross-sectional analysis was performed with the baseline data, academic period 2010-11. The participants were 1,502 adolescents recruited from 11 schools from the province of Barcelona. RESULTS AND CONCLUSIONS: The results showed a higher level of MD adherence when parents had higher educational level, and when adolescents reported a low level of screen time, and high weekly physical activity. PMID- 28000455 TI - ? AB - Introduccion: a finales del siglo xx, no se conocia con precision si la comida del comedor escolar contribuia adecuadamente a la dieta de la poblacion infantil. Ademas, este servicio complementario no se contemplaba en el proyecto educativo del centro pese a considerarse fundamental en todas sus dimensiones.Objetivo: describir el origen y desarrollo del programa de comedores escolares de la Comunidad de Madrid (CM) en 15 anos desde su implantacion.Metodos: se elaboro una normativa a cumplir por las empresas de restauracion, y que contemplaba aspectos nutricionales y de composicion y variedad de los menus, que se utilizo en los concursos para acceder a la prestacion del servicio de comedor escolar, publicados en los anos 2001, 2002, 2005, 2009 y 2013. Ademas se realizaron visitas acreditadas a los centros sin previo aviso para verifi car el cumplimiento de la documentacion aportada durante el concurso.Resultados: los criterios mas actuales sobre programacion y elaboracion de menus escolares se recogen en el Pliego de Prescripciones Tecnicas del ano 2013 (C-504/001-2013). Un 92% de las empresas de restauracion superaron los cinco concursos habidos en los 15 anos de funcionamiento. Hasta el ano 2014, se han realizado 755 visitas, revisandose un total de 574 centros.Conclusiones: el programa de comedores escolares de la CM, desde su implementacion pionera en Espana, ha contribuido a la mejora del servicio complementario de comedor. En estos anos se han ido incluyendo nuevos requisitos dieteticos y nutricionales que han logrado menus cada vez mas ajustados a las recomendaciones de la poblacion escolar. PMID- 28000456 TI - ? AB - Introduccion y objetivos: los objetivos del presente estudio fueron: a) estimar la prevalencia de sobrepeso/obesidad y delgadez en escolares nacidos en 2007 y 2008 de Castilla-La Mancha, Espana, en los anos 2013 y 2015; y b) analizar la persistencia en las mismas categorias de estatus ponderal entre 2013 y 2015 en esta cohorte de escolares.Material y metodos: estudio de seguimiento en el que se analizaron los datos antropometricos de los escolares nacidos en 2007 y 2008 en los anos 2013 (4-6 anos) y 2015 (6-8 anos). Se invito a participar a todos los escolares de 21 colegios de las provincias de Cuenca y Ciudad Real que cursaban tercero de Educacion Infantil o primero de Educacion Primaria en 2013. En todos ellos se determinaron, ademas de variables sociodemograficas, peso, talla y porcentaje de grasa corporal por bioimpedancia electrica.Resultados: la prevalencia de delgadez, sobrepeso y obesidad en la medicion basal fue de 20,7%, 12% y 8,2% respectivamente. Dos anos despues, la prevalencia de delgadez disminuyo hasta 14,7% y la de sobrepeso y obesidad aumento hasta 15,4% y 8,4% respectivamente. Por otro lado, el 78,8% de los escolares permanecia en 2015 en la misma categoria ponderal que en 2013.Conclusiones: el aumento en la prevalencia de sobrepeso/obesidad de los escolares parece estar remitiendo, al mismo tiempo que el incremento en la prevalencia de bajo peso ha aumentado sustancialmente. Por ultimo, los escolares tienden a mantener el estatus ponderal previo al rebote adiposo durante la edad escolar. PMID- 28000457 TI - Daily physical activity impact in old women bone density and grip strength. AB - INTRODUCTION: Being physically active is related to a better physical functioning in older people, but daily physical activity impact in specific outcomes such as osteoporosis or sarcopenia is still not clear. OBJECTIVE: The main objective of this study is to determine the impact of daily physical activity (DPA) in the bone mineral density and grip strength of old women. The secondary objective is to distinguish between weekday and weekend day scores. METHODS: Forty-two women between 65 and 79 years participated. DPA was monitored with the accelerometer ActiGraph GT3X (Pensacola, FL, USA) placed on the dominant hand wrist. Bone mineral density was measured with dual-energy X-ray absorptiometry (AccuDEXA, SHICK, USA) in the central finger of the dominant hand; and grip strength, with a Takei dynamometer (TKK 5001). RESULTS: There were statistical differences between moderate and vigorous DPA in age, T-score, physical activity counts/min and min/day, and grip strength. Weekend minutes correlated significantly with all the variables. Age was a confounding factor. CONCLUSIONS: Higher DPA intensities accomplished by our old women sample preserve T-score (bone standard deviations respect to young, healthy people) and grip strength in a normal range. These results are strongly influenced by weekend scores. Age should be controlled by shorter ranks. PMID- 28000458 TI - Relationship between social support networks and diabetes control and its impact on the quality of life in older community-dwelling Mexicans. AB - OBJECTIVE: To determine the relationship between social support networks and diabetes control and its impact on quality of life in older community-dwelling Mexicans. METHODS: A cross-sectional study was carried out on a convenience sample of 182 older diabetic people who were active participants in community self-care and mutual help groups in Mexico City for more than one year. All were independents and had medical diagnostics determining that they had diabetes without complications for one year or more. We measured biochemical and anthropometric parameters, social support networks for older people (SSN-Older) and perceived quality of life. Patients with uncontrolled diabetes mellitus had HbA1c (%) >= 8. RESULTS: It was found that 65% (118/182) of the elderly diabetics in the study were controlled. We observed a significantly higher average score in the SSN-Older scale on the extra-familial support subscale in the controlled diabetic group compared with the uncontrolled group (57 +/- 25 vs. 49 +/- 30, p < 0.05). Additionally, the average satisfaction score, as observed from SSN-Older scale data, was significantly higher in the controlled diabetics group compared with the uncontrolled group (51 +/- 21 vs.42 +/- 22, p = 0.01). Likewise, in the quality of life analysis, we observed that 81% of the controlled diabetics perceived a high quality of life compared with 19% of the uncontrolled group (p < 0.001). CONCLUSIONS: Our findings suggest that social support networks, especially community self-help groups, represent a determining social capital for control of diabetes mellitus in older people in the community. PMID- 28000459 TI - ? AB - Objetivo: evaluar la relacion entre la percepcion de las barreras para la practica de la actividad fisica (AF) con la presencia de obesidad abdominal (OA) en universitarios de Colombia.Metodos :estudio descriptivo y transversal en 5.663 sujetos entre 18 y 30 anos de edad (3.348 hombres), pertenecientes a tres ciudades de Colombia. Se midio la circunferencia de cintura (CC) como indicador de OA y el riesgo se clasifico segun valores de referencia internacionales. La autopercepcion de barreras se determino con el cuestionario Barriers to Being Active Quiz (BBAQ-21) validado en Colombia. Se calcularon razones de prevalencia (RP) entre cada dominio del cuestionario y clasificacion de OA.Resultados: la prevalencia de obesidad abdominal fue del 10,4% con diferencias por sexo (7,3% hombres vs.12,6% mujeres p < 0,01). La "falta de tiempo", la "influencia social" y la "falta de habilidades" fueron las barreras mas prevalentes para cesar la practica de AF en el grupo de entrevistados con OA en ambos sexos. Al comparar los estudiantes con CC saludable, la RP de presentar OA fue mayor en el grupo de mujeres que en hombres en los dominios del cuestionario BBAQ-21 "falta de tiempo" (RP = 1,33 [IC 95% 1,11-1,60]) vs.(RP = 1,14 [IC 95% 1,03-1,26]) y "falta de recursos" (RP = 1, 93 [IC 95% 11,67-2,24])vs. (RP = 1,83 [IC 95% 1,68-1,99]), respectivamente.Conclusion: una mayor autopercepcion de las barreras para realizar AF se relaciono con mayor frecuencia en el grupo con OA en universitarios de Colombia. PMID- 28000460 TI - ? AB - Introduccion: el sobrepeso y la obesidad se asocian a una mayor probabilidad de que el parto finalice en cesarea. Dado que dicho incremento del riesgo podria estar sesgado por variables de confusion como la diabetes o la hipertension, en el presente trabajo pretendemos determinar si este riesgo persiste tras ser ajustado por numerosas variables de control.Objetivo: determinar si el sobrepeso y/o la obesidad son factores de riesgo independientes para que el parto finalice en cesarea.Metodos: estudio de cohortes retrospectivo. Se han incluido gestantes adscritas al Hospital Universitario de Puerto Real. Periodo de estudio: 2002 2011. Se incluyeron dos grupos de estudio: sobrepeso al inicio de la gestacion (IMC entre 25 y 29,9) y obesidad al inicio de la gestacion (IMC >= 30). Grupo ontrol: IMC al inicio de la gestacion normal (entre 18,5 y 24,9). El riesgo de cesarea fue analizado mediante un estudio de regresion logistica multiple incluyendo como covariables: edad materna, parto inducido, diabetes gestacional, diabetes pregestacional, macrosomia, hipertension arterial, nuliparidad, cesarea anterior, parto pretermino y parto postermino.Resultados: de los 18.243 partos registrados, el IMC al inicio de la gestacion constaba en 4.711 casos (25,8%). El 26,1% presentaban sobrepeso, el 12,4% obesidad y el 58,9% IMC normal. Sin ajustar por variables control, se asociaron a un incremento del riesgo de cesarea: sobrepeso (OR 1,48; IC95% 1,27-1,73); obesidad grado 1 (OR 2,09; IC95% 1,66 2,64); obesidad grado 2 (OR 3,23; IC95% 2,31-4,53); obesidad grado 3 (OR 2,57; IC95% 1,56-4,22). El riesgo aumentado se mantuvo significativo en el analisis multivariante: sobrepeso (OR 1,51; IC95% 1,24-1,84); obesidad (OR 2,15; IC95% 1,67-2,76).Conclusiones: encontramos una asociacion significativa e independiente entre el sobrepeso/obesidad maternos y la finalizacion del parto mediante cesarea incluso ajustando por numerosas variables de control como: edad materna, nuliparidad, cesarea anterior, hipertension, diabetes, peso al nacer y edad gestacional al parto. PMID- 28000461 TI - ? AB - Objetivo: este estudio tuvo como objetivo probar la eficacia de un programa de danzaterapia en la composicion corporal y calidad de vida en mujeres mayores de 65 anos, que no realizan ejercicio fisico de forma habitual. Metodos: cincuenta y dos mujeres sedentarias (edad media de 69,27 +/- 3,85 anos) fueron asignadas al azar para realizar un programa de danzaterapia (n = 27) o formar parte del grupo control (n = 25). El grupo de danza, participo durante ocho semanas en un programa de danza, tres sesiones semanales de 50 minutos cada una, basado en danza popular espanola (sevillanas) y ballet. Ambos grupos reciben informacion sobre la importancia de la alimentacion y del ejercicio fisico al comienzo y mitad del estudio. La circunferencia de la cintura, la presion arterial, el indice de masa corporal y la calidad de vida se evaluaron al inicio y despues del tratamiento en ambos grupos. El analisis estadistico se realizo con un 2 * 2 ANOVA.Resultados: las mujeres del grupo de danza mostraron reduccion significativa de la circunferencia de la cintura (p = 0,001) en comparacion con las del grupo control. Los cambios en el IMC y la calidad de vida, aunque mejoraron en el grupo de danza, no alcanzaron significacion estadistica. Conclusion: la danzaterapia espanola es una forma de ejercicio fisico eficaz para reducir la grasa visceral y prevenir comorbilidades en mujeres mayores, contribuyendo a cambiar estilos de vida poco saludables. PMID- 28000462 TI - ? AB - Introduccion: existen caracteristicas respecto a los ritmos circadianos (ciclo sueno-vigilia), lo que genera un rasgo denominado cronotipo (madrugador o trasnochador). Se ha asociado el cronotipo vespertino a menos horas de sueno y habitos alimentarios poco saludables. El cronotipo vespertino se asocia con un mayor riesgo de desarrollar obesidad.Objetivo: determinar la asociacion del cronotipo con variables antropometricas en jovenes de 18 a 25 anos.Metodos: jovenes (n = 65) (18 a 25 anos), se les determino el cronotipo (cuestionario de Horne-Ostberg) y mediciones antropometricas (peso, talla, porcentaje de grasa y perimetro de cintura). Resultados: los hombres con cronotipo trasnochador presentaron significativamente mayor perimetro de cintura (p = 0,03). Las mujeres con un porcentaje de grasa < 25% se asocio con cronotipo trasnochador (p = 0,05). Conclusiones: el cronotipo trasnochador se asocia a mayor perimetro de cintura y mayor porcentaje de grasa. El cronotipo constituye un nuevo foco para la prevencion y el tratamiento de la obesidad. PMID- 28000463 TI - Obesity, endothelial function and inflammation: the effects of weight loss after bariatric surgery. AB - OBJECTIVE: Obesity is associated with a high risk for atherosclerotic cardiovascular disease. There is a causal association between obesity, inflammation, insulin resistance (IR) and endothelial dysfunction. The aim of this study was to evaluate changes in IR, proinflammatory state and markers of endothelial dysfunction in morbidly obese patients after weight loss following bariatric surgery. METHODS: In this study, we measured the levels of soluble intracellular adhesion molecule-1 (sICAM1), plasminogen activator inhibitor 1 (PAI-1), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) in 79 morbidly obese patients at baseline and 3, 6 and 12 months after gastric bypass. Also, we evaluated changes in IR. RESULTS: Twelve months after surgery, there was a significant decrease in plasma levels of sICAM1 (p < 0.001), PAI-1 (p < 0.05), hs-CRP (p < 0.001), IL-6 (p < 0.001) and homeostasis model assessment (HOMA) (p < 0.001) and a significant increase of McAuley index (McAuley) (p < 0.001). Baseline levels of hs-PCR were positively correlated with sICAM-1 (r = 0.450, p < 0.01) and IL-6 (r = 0.451, p < 0.01). Significant correlations were also found between the decrease of PAI-1 and the decrease of hs-PCR (r = 0.425, p < 0.01) and tryglicerides (r = 0.351, p < 0.01). CONCLUSIONS: In patients with morbid obesity, substantial surgically induced weight loss is followed by a significant improvement in the endothelial function, inflammatory state and insulin sensitivity, that may reduce their cardiovascular risk. A relationship exists between improved inflammatory profile and endothelial function. PMID- 28000464 TI - A short nutritional intervention in a cohort of hematological inpatients improves energy and protein intake and stabilizes nutritional status. AB - INTRODUCTION: Oncohematological diseases are associated with an important prevalence of malnutrition. AIM: Our aim is to determine if early recognition and treatment of malnourished hematological inpatients can improve their oral intake, nutritional status and reduce the length of hospital stay. METHODS: Prospective 2 year study conducted in a cohort of hematology inpatients. Malnutrition Screening Tool (MST) was carried out on the first day of admission. Patients with a positive screening were recruited to have a complete nutritional evaluation and intervention, following usual clinical practice. Nutritional evaluation was repeated after one week. RESULTS: Six hundred and seventeen hematological patients were screened (37.8% with positive screening). After one week, median diet intake increased from 80% to 90% (p < 0.001), and an increase of 407.36 Kcal (SD 679.37) and 17.58 g of protein (SD 31.97) was also achieved. More patients reached their energy and protein requirements (41.6 vs.% 63.3%, p = 0.009) and nutritional parameters remained stable. A trend to a lower stay (3.5 to 4.5 days less) was detected in the groups of patients who covered their needs. CONCLUSIONS: The implementation of early malnutrition screening and short nutritional interventions improved energy and protein intake, increasing the percentage of patients who meet their requirements and avoiding deterioration of nutritional status. PMID- 28000466 TI - ? AB - Introduccion: la alimentacion constituye el pilar fundamental del soporte nutricional de los pacientes hospitalizados. Evaluar el grado de aceptacion de la dieta es imprescindible en aras de combatir la desnutricion hospitalaria.Objetivos: a) determinar el grado de satisfaccion de los pacientes en relacion con las dietas; y b) analizar posibles variables asociadas a un grado de satisfaccion mayor (apetito y tipo de dieta).Material y metodos: estudio descriptivo de corte transversal. Se emplea una encuesta de 17 preguntas con datos sociodemograficos, datos cualitativos, asi como la valoracion general del paciente. Se comparo el grado de satisfaccion global en funcion del apetito y el tipo de dieta (terapeutica vs.basal; con sal vs.sosa) (Test no parametric o Krustal-Wallis y T-Student para muestras independientes, respectivamente).Resultados: mil cuatrocientos trece pacientes. Edad: 53,9 +/- 19 anos; 51,3% mujeres. Dieta terapeutica (34,9%). Solo el 39,4% tomo dieta con sal. El 66,8% refirio ingresos previos. La alimentacion del hospital para un 43% de pacientes fue ''como esperaba'', mientras que para un 44,1% fue ''mejor de lo que esperaba''. El horario de comidas era adecuado (89,1%) y el tiempo para comer, suficiente (96,4%). En cuanto a las caracteristicas de la comida servida, consideraron como buenas o muy buenas la misma el porcentaje reflejado: sabor/gusto (56.3%), olor (65,5%), cocinado (69,2%), presentacion (80,4%), tamano de racion (75,9%), calidad (73%), cantidad (77,9%), variedad (67,6%), temperatura (70,4%). La valoracion global de la alimentacion en una escala de 1 a 10 fue de 6,8 +/- 2,3. El apetito se asocio a un aumento significativo de la satisfaccion global alimentaria del paciente (p < 0,01). El tipo de dieta o la presencia de sal en la misma no se asociaron a un aumento significativo de la satisfaccion con la dieta de los pacientes (p = 0,99 y 0,35, respectivamente).Conclusiones: aunque el grado de satisfaccion de la dieta de nuestro hospital es aceptable, es preciso introducir mejoras que aumenten su aceptacion. El apetito se asocia a un aumento significativo de la satisfaccion global alimentaria. La presencia de sal y el tipo de dieta (basal versusterapeutica) no se relacionan con una mejoria significativa de la valoracion global de la dieta. PMID- 28000465 TI - Difference in fatty acids composition of breast adipose tissue in women with breast cancer and benign breast disease. AB - INTRODUCTION: Breast cancer is the second most common cancer in the world, and the most frequent cancer among women. Moreover, there are factors that influence the risk for breast cancer including the age, genetic and endocrine factors, and lifestyle. OBJECTIVES: To evaluate the consumption of fatty acids; compare the fatty acids composition in the breast adipose tissue of women with breast cancer and benign breast disease as well as potential risk factors; and describe the genotypic frequency of the Pro12Ala PPARgamma polymorphism. MATERIAL AND METHODS: A hospital-based case-control study was conducted including incident cases (n= 38 breast cancer; n= 75 benign breast disease; n= 166 control). Lifestyle features, socioeconomic issues, dietary intake, anthropometry, and blood and tissue data were assessed. RESULTS: No differences were observed for fatty acids intake. Interestingly, lauric acid (p = 0.001), myristic acid (p = 0.036), stearic acid (p = 0.031), and total saturated fatty acids (SFAs) (p = 0.048) had lower concentrations in BC than in BBD women, while palmitoleic acid (p = 0.022), erucic acid (p = 0.002), total monounsaturated fatty acids (MUFAs) (p = 0.039) and oleic acid/stearic acid ratio (p = 0.015) increased. There was no significant association between PPARgamma polymorphism and studied groups (p = 0.977). The age at first full pregnancy (p = 0.004) was significantly associated with the development BC, whereas BMI (p = 0.005); percentage of body fat (p = 0.024); physical activity (p = 0.036); and age at menarche (p = 0.008), at first full pregnancy (p < 0.001), and of first mammogram (p = 0.018) were significantly associated with the development of BBD. CONCLUSION: The results suggest a different fatty acids composition of breast adipose tissue, a biomarker of long term dietary intake, particularly for SFAs, MUFA and 18: 1 n-9/18: 00 ratio. Our findings also show that are differences in the factors related to the development of BC and BBC. PMID- 28000467 TI - ? AB - : Aim: To assess trends in the biases of self-reported versus measured weight, height, and body mass index (BMI) in adults over the period 2000-2010 in a Mediterranean adult population. METHODS: The sample population consisted of young (18-35) and middle-aged (36-55) adults living in the Balearic Islands, Spain. The data represent 1,089 people during 1999-2000 and 1,081 people during 2000-2010. Weighted-based frequency estimates were used. RESULTS: While no differences between self-reported and measured weight, height and BMI were found in the respondents, it was seen that a decreasing percentage of the population knows their own weight and/or height. A rise in awareness was found in normal-weight men (from 95.0% to 98.9%), and also in normal-weight men and in the middle-aged obese category whose self-reported BMI was not defi ned as "correct" (from 41.2% to 85.7% and from 41.0% to 67.6% respectively). CONCLUSIONS: A substantial proportion of the population does not know their own weight or height. The obtained results suggest the need to develop strategies to enhance awareness of own weight and height. PMID- 28000468 TI - A randomized control trial for reduction of caloric and non-caloric sweetened beverages in young adults: effects in weight, body composition and blood pressure. AB - INTRODUCTION: Recently has been documented that the consumption of sweetened non caloric beverages has increased as an option to weight control, however randomized control trials have demonstrated a modest weight loss. OBJECTIVE: To evaluate the effect of reducing consumption of beverage with caloric and non caloric sweeteners on weight, body composition and blood pressure in young Mexican adults. METHODS: In an experimental study 148 nursing students were randomly assigned to one of 3 groups: 1) no sweetened beverages were permitted, only plain water, tea or coffee without sugar; 2) consumption of beverages with non-caloric sweeteners was allowed; and 3) no restriction of sweetened beverages was imposed. All groups were given individualized isocaloric diets monitored by a 24-hour record of consumption and food frequency questionnaire and blood pressure, weight, waist circumference and body composition by tetrapolar bioelectric impedance were taken at the beginning of the study and three and six months later. RESULTS: Differences between groups were found in body mass index at 3 months that decrease in group 1 and 2 and increase in group 3 (-1.75 vs. 0.61 vs.0.54% of change, p < 0.001). At six months there were also statistical differences in waist circumference (-4.07 vs.-1.23 vs. 0.62% of change, p < 0.001) and sugar consumption (-62.0 vs.-54.61 vs.11.08% of change, p < 0.001) in groups 1, 2 and 3 respectively. CONCLUSIONS: The reduction in consumption of both caloric and non-caloric sweetened beverages contributes to signifi cant body mass index loss and waist circumference. PMID- 28000469 TI - ? AB - Introduccion: Chile en las ultimas decadas ha experimentado un cambio en su perfil epidemiologico nutricional, pasando de una situacion caracterizada por una elevada prevalencia de desnutricion y enfermedades infecciosas/parasitarias a otro completamente distinto, en donde las enfermedades cronicas y degenerativas presentan una elevada prevalencia.Objetivo: el objetivo del estudio es elaborar tablas de referencia de aspectos antropometricos y de condicion fisica en estudiantes varones de 10 a 14 anos de la ciudad de Chillan.Metodo: estudio descriptivo de corte transversal. La muestra se compone de 1250 varones con edades entre los 10 y 14 anos. Para la confeccion de las tablas de referencia se utilizo estadistica descriptiva y estas fueron divididas en cinco clasificaciones desde muy malo, malo, media, bueno y muy bueno, teniendo como parametro la edad.Resultados: observamos niveles importantes de sobrepeso que se asociaron con bajo desempeno fisico, lo que plantea la urgencia de realizar un seguimiento en el tiempo con herramientas de facil aplicacion como la presente bateria; con el fin de detectar a tiempo a los ninos que tienen bajos niveles de condicion fisica y tomar medidas orientadas a estimular o mejorar la capacidad fisica como factores protectores de promocion de la salud y como ayuda en la prevencion de enfermedades cronicas relacionadas con el sobrepeso u obesidad.Conclusion: en este trabajo se han establecido valores de referencia para posteriores estudios en cuanto a la condicion fisica orientada a la salud en estudiantes varones de 10 a 14 anos de la ciudad de Chillan, que permitiran evaluar e interpretar correctamente la condicion fisica orientada a la salud de este grupo etario. PMID- 28000470 TI - ? AB - Introduccion: el trastorno por atracon o "Binge Eating Disorders" (BED) se caracteriza por el consumo de grandes cantidades de comida en un breve periodo de tiempo acompanado de una sensacion de falta de control sobre la ingesta. El BED se relaciona con una alimentacion poco equilibrada, contribuyendo a la aparicion de diversas patologias. La alimentacion y los estilos de vida desempenan un factor clave en la prevencion de estas patologias, siendo la dieta mediterranea (DM) uno de los estandares de la alimentacion saludable.Objetivo: analizar la relacion entre la DM y el BED en una muestra de estudiantes universitarios.Metodo: se realizo un estudio descriptivo transversal en una muestra de 120 estudiantes de la Universidad de Alicante. Para establecer la relacion entre el patron de atracon y el grado de adherencia a la DM se determino el coefi ciente de correlacion r de Pearson. Los resultados se expresaron en odds ratios (OR) e intervalo de confi anza (IC) al 95%.Resultados: los sujetos con un patron de BED presentaron menor adherencia a la DM (OR = 4,03; IC 95%, 1,80 18,69), mayores indices de exceso de peso (OR = 5,31; IC 95%, 1,81-15,64), y vidas mas sedentarias (OR = 1,4; IC 95%, 0,52-4,12). El BED correlaciono negativamente con el grado de adherencia DM (r = -0,3, p < 0,01).Conclusion: el patron de DM se asocia de manera inversa con el riesgo de sufrir trastorno por atracon y ademas dicho patron de atracon se asocia significativamente con el riesgo de sufrir exceso de peso en estudiantes universitarios. Son necesarios estudios que confi rmen que la DM reduce el riesgo de sufrir trastorno por atracon. PMID- 28000471 TI - [Not Available]. AB - Introduction: The assessment of intake and eating habits become increasingly important to relate them to the risk of disease. In this sense, food frequency questionnaires (FFQ) are a common dietary tool used in both clinical practice and nutritional epidemiological studies. Objective: The aim of the study was the validation of a food groups frequency questionnaire (FGFQ) based on an exchange system, in relation to a 7 days food record (FR) used as reference. Methods: A total of 60 healthy adults (males and females) were recruited. To each one a dietitian applied the FGFQ to be validated and then gave instructions for completing the 7 days FR used as a reference standard. Energy and macronutrient distribution were calculated for both methods and appropriate statistical methods were applied. Results: The correlation coeffi cients comparing methods were found between r = 0.3 and r = 0.6 (p < 0.01), and the intraclass correlation coeffi cient between r = 0.2 and r = 0.6 (p < 0.01). The cross-classifi cation analysis revealed that over 80% of individuals were classifi ed into identical and contiguous quartiles from both dietary methods. Conclusions: The proposed FGFQ, based on an exchange system of 19 groups, has obtained comparable results to other similar models for assessing of energy and macronutrient distribution with a more rapid outcome. PMID- 28000472 TI - Abandonment to therapeutic diet on patients at risk cardiovascular in a health care clinic. AB - BACKGROUND: Cardiovascular diseases are the leading cause of death among adults and measures to reverse this situation go through changes in lifestyle, among them adopt healthy eating through professional counseling. To do this we need to keep the patient engaged in treatment, and the abandonment of treatment is an important risk factor in this population. OBJECTIVES: To assess abandonment to dietary treatment of patients with cardiovascular risk treated on an outpatient basis, and identify the reasons for the abandonment of treatment. METHODS: Participants were patients between 18 and 70 years, of both sexes, who held their first nutritional consultation and had two or more cardiovascular risk factors. A telephone contact was made by applying a questionnaire on the withdrawal of reasons for treatment and encouraging them to return to the health service by checking the return after three months of telephone contact. RESULTS: Of the 142 patients with cardiovascular risk, 61.26% did not return to the service after the first visit, a percentage similar to that found in other studies, and contacted by telephone 64.37% of them. Regarding the main reasons for the withdrawal, difficulty following the diet and individual/behavioral characteristics of the patient were the aspects that contributed to the abandonment (57.14%), corroborating the findings that show the influence of cultural and socioeconomic factors on the therapeutic adherence. Although 92.86% of patients have been satisfied with the service and 75% have reported interest in resuming treatment, only 5.36% patients returned to service after the phone contact. CONCLUSION: There was a high drop-out from nutritional treatment, mainly because of the difficulty of organization required to follow the diet. The motivational intervention was not enough to motivate a return to treatment. PMID- 28000473 TI - ? AB - Objetivos: estimar el porcentaje de pacientes con EPOC adiestrados en la consulta para el manejo de inhaladores en la provincia de Leon.Metodos: estudio epidemiologico, transversal, multicentrico (30 centros de salud de la provincia de Leon). Incluyo pacientes mayores de 35 anos diagnosticados y tratados de EPOC. Variables a estudio: edad, sexo, habitat, datos antropometricos, estado nutricional, tabaquismo, espirometria postboroncodilatadora, disnea (mMRC), reagudizaciones, gravedad (Indice Bodex), hospitalizaciones, tratamiento, seguimiento y caracterizacion del fenotipo (GesEOPC 2014). Los resultados se expresan con sus IC al 95,5%.Resultados: se incluyeron 833 pacientes, el 85,8% varones, con edad media de 64,69 (53,66-75,61) anos y 20,65 (4,47-36,8) anos evolucion de la EPOC. Empleaban 1,88 (1,64-2,16) dispositivos inhaladores de media, p = 0,006, (57% de forma correcta, 23% regular y el 20% incorrecta). El 20,9% no recibieron adiestramiento para usar inhaladores frente al 79,1% adiestrados, p < 0,001, (9,4% por neumologos, 20,3% enfermeras y 43,5% medicos familia, p = 0,002). Los pacientes bien adiestrados realizan mejor el tratamiento, en el 60,60% (58,91-62,29), p = 0,002. No hubo diferencias significativas en el adiestramiento por tabaquismo, gravedad, ingresos hospitalarios, ni calidad de vida, obteniendo una reduccion significativa del numero de agudizaciones, siendo de 1,59 (1,12-2,15) reagudizaciones medias en el grupo adiestrado frente a 3,29 (2,50-4,11) en los no adiestrados, p = 0,002.Conclusiones: el nivel de adiestramiento en el uso de inhaladores en los pacientes con EPOC es insuficiente en nuestro medio. La mejor formacion de los profesionales y la simplificacion de los dispositivos contribuiran a que un mayor numero de pacientes realicen el tratamiento de forma adecuada. PMID- 28000474 TI - ? AB - Introduccion: el etiquetado nutricional ayuda a los consumidores a realizar elecciones mas saludables. Sin embargo, este es poco leido, mal interpretado o no usado.Objetivos: evaluar la frecuencia y los factores asociados a la lectura, el uso y la interpretacion de etiquetas nutricionales en usuarios de gimnasios en la ciudad de Huancayo, Peru.Materiales y metodos: estudio de corte transversal en 385 usuarios de una cadena de gimnasios. Se midio la interpretacion con un test a partir de dos etiquetas, lectura reportada (frecuentemente o no) y el uso reportado para elegir un producto (frecuentemente o no), asi como variables demograficas, dieteticas y relacionadas con el gimnasio. Se evaluo la asociacion calculando las razones de prevalencias ajustadas en base a las variables significativas del modelo bivariado.Resultados: los participantes tuvieron una edad media de 27,8 +/- 9,3 anos, 44,7% fueron varones, 49,4% contaron con educacion universitaria. El 27,5% reporta leer frecuentemente y dentro de estos el 55,7% reporta usarlas frecuentemente, asimismo el 17,4% sabe interpretar. La lectura se asocio con factores dieteticos y de uso de gimnasio y la interpretacion con capacitacion previa de lectura de la etiqueta. El uso fue principalmente para seleccionar productos bajos en grasa total (65,1%), alto en proteinas (64,2%) y en menor proporcion, productos bajos en sodio (47,2%).Conclusiones: la frecuencia de lectura, el uso y la interpretacion de etiquetas nutricionales en usuarios de gimnasio de Huancayo es baja. La capacitacion previa de lectura es un factor necesario para una eleccion saludable. Es necesario establecer estrategias educativas para ensenar a interpretar de forma adecuada las etiquetas nutricionales. PMID- 28000475 TI - Effect of grape juice consumption on antioxidant activity and interleukin-6 concentration in lactating rats. AB - OBJECTIVE: This study evaluated the effect of grape juice consumption on the antioxidant capacity and the interleukin-6 blood level of lactating rats. MATERIAL AND METHOD: Eighteen Wistar rats, lactating females adult, were divided into two groups: control group (CG) and grape juice group (GJG). The antioxidant activity was determined by the method of 2,2-diphenyl-1-picrylhydrazyl (DPPH) kidnapping of free radicals (DPPH) and oxygen radical absorbance capacity (ORAC), and the interleukin-6 was determined by Enzyme-Linked Immunosorbent Assay (ELISA) method. The data were presented as mean and standard deviation. RESULTS: The antioxidant capacity was higher (p < 0.05) in the GJG (25.00 +/- 3.08 umol eq. Trolox/g) than in the CG (10.00 +/- 3.11 umol eq. Trolox/g), by the ORAC method. The interleukin-6 (pg/ml) level was lower in the grape juice group than in CG. CONCLUSION: The consumption of grape juice during lactation improves the antioxidant capacity in lactating rats and seems capable to decrease the inflammatory activity. PMID- 28000476 TI - Neuroprotective effect of Sapucaia nuts (Lecythis pisonis)on rats fed with high fat diet. AB - BACKGROUND: Lecythis pisonis Cambess is commonly known as "castanha de sapucaia" in Brazil. Chemical composition studies revealed that this nut is an excellent source of anti-oxidant minerals and of essential lipids. OBJECTIVE: The aim of the present study is to assess the anti-oxidant and anti-inflammatory effect of Lecythis pisonis Cambess on the brain tissue of Wistar rats. MATERIAL AND METHODS: The animals were divided in four experimental groups (n = 6), total of forty-eight rats. Treatments included the standard diet (AIN-93G) and high-fat food, supplemented with Sapucaianut from 14 to 28 days. The gene expression markers TNF-alpha, NFkB, ZnSOD and HSP-72 were defined through reverse transcriptase polymerase chain reaction (rtPCR). The anti-oxidant effect was assessed through the thiobarbituric acid-reactive substances (TBARS) and the measurement of the activity performed by superoxide dismutase enzymes. RESULTS: Accordingly, the gene expression of the inflammatory markers NFkB (p65) and TNF alphawas lower in rats fed on diets supplemented with "sapucaia", and they presented significant difference in the Tukey test (p < 0.05). The heat-shock HSP 72 protein and the ZnSOD enzyme raised the gene expression and showed significant statistical difference (p < 0.05) in both groups fed on Sapucaia nut-based diet. CONCLUSION: Thus, the nutritional properties of the Sapucaia nuts perform important neuroprotective activities because they modulated the anti-oxidant activity and the brain tissue inflammatory process in the assessed animals. PMID- 28000477 TI - Probiotic: effectiveness nutrition in cancer treatment and prevention. AB - Among the neoplasias, colorectal cancer is one of the leading causes of cancer death in men and women. The increasing incidence of this type of cancer is due to the increase in the population's life expectancy, by the increase in chronic inflammatory bowel diseases, primarily ulcerative colitis and Crohn's disease, and the change in eating habits. The American Cancer Society (2011) shows that diet might be responsible for approximately 30% of cancer cases in developed countries, moreover when considering only colorectal cancer, the number can reach 30% to 50%. Probiotics are effective in the prevention and treatment of many bowel diseases as inflammatory bowel disease (IBD), diarrhea, irritable bowel syndrome, gluten intolerance, gastroenteritis, Helicobacter pyloriinfection, and colon cancer. Classical examples are strains from the Lactobacillus, and Bifidobacteriumgenus that have probiotic proprieties with a potential use in the prophylaxis, as well as in the treatment of a variety of gastrointestinal tract disorders. Researchers are focusing on extremely important studies regarding the possibility of using probiotics to promote a balanced microbiota composition, and a sufficient immunological surveillance system as a way to prevent cancer. Considering the fact that the human intestines host 100 trillion bacteria, including more than 1,000 species, there is still need to perform more in depth investigations in order to find probiotics with potential to prevent, and treat cancerous diseases, adding a very promising effect to this already successful panorama. This revision aims to conduct a review of the most recent studies correlating probiotics and its cancer preventing and treatment potential. PMID- 28000478 TI - ? AB - Introduccion: Espana es el tercer pais europeo con mayor prevalencia de obesidad infantil, dando lugar a la aparicion de programas de intervencion destinados a fomentar habitos alimentarios saludables y/o de actividad fisica (AF).Objetivo: el proposito de esta revision sistematica fue conocer aquellos programas de intervencion para la promocion de habitos alimentarios y de AF desarrollados en escolares espanoles de Educacion Primaria (EP) y analizar la influencia que han tenido las intervenciones sobre la composicion corporal, los habitos alimentarios y la AF.Metodo: se revisaron los articulos publicados entre los anos 2000 y 2015 en las siguientes bases de datos: Web of Science, Scopus, Dialnet, PubMed, Eric, Sportdiscus y Psycinfo por dos revisores independientes.Resultados: se contabilizaron un total de 813 articulos, de los cuales tras la eliminacion de duplicados (192), lectura de titulos y resumen (587) y lectura del texto completo (17), tan solo 7 cumplieron con los criterios de inclusion.Conclusiones: los programas de intervencion analizados mostraron cambios positivos en la mejora de la composicion corporal en algo menos de la mitad de los estudios analizados; por otro lado, casi todos los programas de intervencion analizados tuvieron un efecto positivo sobre conductas respecto a ciertos habitos alimentarios, como la ingesta de frutas, y sobre el incremento del nivel de AF. PMID- 28000479 TI - Online platforms to teach Nutrition Education to children: a non-systematic review. AB - INTRODUCTION: Childhood obesity is now considered a worldwide problem. Nutrition Education (NE) has been identified as a key factor in preventing overweight and obesity in children. In recent years, there has been an increase in the interest in innovative ways to teach this knowledge to children, mainly through the use of the Internet. OBJECTIVE: Review and analyze the available evidence about programs focused on NE for children through the use of the Internet. RESULTS: Three different ways were found to deliver NE over the Internet to children: platforms designed to communicate with other peers or professionals; platforms designed to provide NE through the contents included in the web tool; and platforms designed to provide NE through the contents included in the web tool and automated feedback. Most of these programs were effective in achieving the objectives established. CONCLUSION: Although the use of Internet platforms to teach NE to children has been shown to be effective, the amount of evidence is still scarce. Some of the main advantages the Internet provides are: the opportunity to put the children in contact with education and health professionals; children can keep a record of the food consumed; and it is a more attractive and interesting way for children to learn NE, compared to traditional methods. PMID- 28000480 TI - ? AB - La obesidad interfiere con el metabolismo oseo a traves de factores mecanicos, hormonales e inflamatorios. El principal tratamiento de dicha enfermedad es la dieta, modificacion de la cantidad y tipo de alimento. Este tratamiento nutricional tiene una influencia sobre el metabolismo oseo en dos sentidos: modifica el efecto del sobrepeso y la obesidad sobre el hueso e interviene directamente en el turnoveroseo a traves de las caracteristicas de los nutrientes utilizados. Esta revision analiza la evidencia del efecto sobre el hueso del descenso de peso y del patron dietetico utilizado. Por otra parte, se valoraran las modificaciones que se pueden realizar en la dieta indicada en un paciente obeso para prevenir la perdida osea, a corto y largo plazo, y disminuir el riesgo de fractura. PMID- 28000481 TI - ? AB - Introduccion: cambios socioculturales como el incremento en el sedentarismo y el consumo de alimentos ricos en grasas y azucares, sumado a caracteristicas geneticas, han producido un aumento en las cifras de obesidad a nivel mundial. La evaluacion temprana en ninos, mediante el establecimiento de perfi les geneticos asociados a obesidad y a la regulacion metabolica y hedonica de la alimentacion, complementado con estudios de la conducta alimentaria, nos permitiria predecir la predisposicion a la obesidad en etapas adultas.Objetivo: revisar los conceptos asociados a la conducta alimenticia, enfocandose en la regulacion hedonica, que puede convertirse en un parametro predictivo de obesidad en ninos.Material y metodos: se reviso la bibliografia asociada a obesidad infantil y a la regulacion homeostatica y hedonica de la obesidad, como tambien parametros genicos asociados a la obesidad. En la busqueda de articulos se incluyo el trabajo en animales y humanos (adultos y ninos, pero con enfasis en ninos).Resultados: se analizaron los mecanismos celulares de la regulacion de la ingesta, asi como los estudios de conducta alimentaria en ninos, entregando antecedentes y carencias en el desarrollo investigativo para la prediccion de la obesidad infantil.Conclusion: la regulacion hedonica de la ingesta alimenticia en ninos, como perfi les geneticos asociados a receptores de dopamina, puede convertirse en un importante predictor de la obesidad. Es necesario incrementar el numero de estudios que permitan defi nir de mejor forma, cuales son los mejores parametros para predecir el desarrollo de la obesidad adulta. PMID- 28000482 TI - ? AB - Introduccion: si bien el Trastorno por Atracon es un trastorno de la conducta alimentaria que no se da exclusivamente en personas obesas, es mas comun en este grupo que en sujetos con normopeso, sin embargo no todas las personas con malnutricion por exceso presentan Trastorno por Atracon. Objetivo: identificar el conocimiento actual respecto a las diferencias y semejanzas existentes entre personas con malnutricion por exceso con y sin Trastorno por Atracon.Metodo: para lograr el objetivo anterior, se realizo una revision de articulos cientificos en torno al tema.Resultados: primero se analizo la comorbilidad psicopatologica en obesidad y despues se detectaron similitudes y diferencias entre los grupos de interes, tanto en sintomatologia general, como asi tambien en sintomatologia de la conducta alimentaria. Ademas, se identificaron algunos aspectos controversiales, en que existe evidencia contradictoria respecto a la comparacion intergrupal.Conclusion: de esta revision se concluye que en el estudio de la obesidad se hace necesario conocer en mayor profundidad las caracteristicas del subgrupo de pacientes que ademas presenta Trastorno por Atracon, ya que estas personas poseen caracteristicas distintivas cuyo conocimiento permitira ofrecer tratamientos integrales mas adecuados a las necesidades de los pacientes, lo que posibilitara, en consecuencia, disenar intervenciones mas eficaces. PMID- 28000483 TI - ? AB - Objetivo: analizar la geografia del estado nutricional en Espana y su evolucion entre mediados del siglo xixy comienzos del siglo xx, etapa previa a la transicion nutricional con alta prevalencia de malnutricion.Metodos: se utilizan datos antropometricos agregados (promedios provinciales de estatura) del reclutamiento militar en 1858 y 1913, asi como promedios provinciales de estatura y peso procedentes de una revision realizada entre 119.571 soldados en 1903-1906. Con estos datos se elaboran cartografia y estadisticos descriptivos.Resultados: los parametros antropometricos de los espanoles se situaban entre los valores de complexion mas bajos de Europa antes de la transicion nutricional. Entre 1858 y 1913, la altura media crecio solo 1,43 cm. En ese periodo hubo cambios significativos en la geografia antropometrica marcados por la configuracion de una polaridad nutricional a las puertas de la I Guerra Mundial: las provincias del centro y del sur de pais exhiben mayor incidencia de la malnutricion cronica que las provincias del arco Noreste, que disfrutan de ventaja relativa en terminos nutricionales.Conclusion:las desigualdades territoriales que configuraron una geografia polarizada del estado nutricional en Espana pueden asociarse en parte a los cambios ambientales del periodo, caracterizados por el inicio de la modernizacion y la industrializacion y, asimismo, por la privacion derivada de las crisis agrarias, las enfermedades y el relativo atraso tecnologico. Se destaca la relevancia de la historia antropometrica para el estudio de los niveles de vida en poblaciones del pasado y del proceso de transicion nutricional. PMID- 28000484 TI - ? AB - Objetivo: Comunicar los datos del registro de Nutricion Parenteral Domiciliaria (NPD) del grupo de trabajo NADYA-SENPE del anos 2015.Material y metodos: Recopilacion de los datos de NPD del registro "on-line" del grupo de Nutricion Artificial Domiciliaria y Ambulatoria (NADYA) desde el 1 de enero de 2015 al 31 de diciembre de 2015.Resultados: Se registraron 236 pacientes, con 243 episodios de NPD procedentes de 40 hospitales. Lo que representa una tasa de 5,08 pacientes/millon de habitantes/ ano 2015. La patologia mas frecuente en los adultos fue "otros" (26,3%) seguido por "oncologico paliativo" (21,6%). La complicacion mas frecuente fue la septica relacionada con el cateter que presento una tasa de 0,53 infecciones/1000 dias de NPD. Finalizaron 64 episodios, la principal causa fue el fallecimiento (43,7%) y el 'paso a la via oral' (32,8%).Conclusiones: constatamos el aumento de los centros y profesionales colaboradores, dando respuesta a la cantidad progresivamente mayor de pacientes con soporte nutricional parenteral en domicilio. Se mantienen estables las principales indicaciones para el establecimiento de NPD y las causas de finalizacion del tratamiento. PMID- 28000485 TI - Predictive value of SAPS II and APACHE II scoring systems for patient outcome in a medical intensive care unit. AB - OBJECTIVE: The aim is to determine SAPS II and APACHE II scores in medical intensive care unit (MICU) patients, to compare them for prediction of patient outcome, and to compare with actual hospital mortality rates for different subgroups of patients. METHODS: One hundred and seventy-four patients were included in this analysis over a oneyear period in the MICU, Clinical Center, University of Sarajevo. The following patient data were obtained: demographics, admission diagnosis, SAPS II, APACHE II scores and final outcome. RESULTS: Out of 174 patients, 70 patients (40.2%) died. Mean SAPS II and APACHE II scores in all patients were 48.4+/-17.0 and 21.6+/-10.3 respectively, and they were significantly different between survivors and non-survivors. SAPS II >50.5 and APACHE II >27.5 can predict the risk of mortality in these patients. There was no statistically significant difference in the clinical values of SAPS II vs APACHE II (p=0.501). A statistically significant positive correlation was established between the values of SAPS II and APACHE II (r=0.708; p=0.001). Patients with an admission diagnosis of sepsis/septic shock had the highest values of both SAPS II and APACHE II scores, and also the highest hospital mortality rate of 55.1%. CONCLUSION: Both APACHE II and SAPS II had an excellent ability to discriminate between survivors and non-survivors. There was no significant difference in the clinical values of SAPS II and APACHE II. A positive correlation was established between them. Sepsis/septic shock patients had the highest predicted and observed hospital mortality rate. PMID- 28000486 TI - Factors influencing pain therapy for metastatic cancer patients in Bosnia and Herzegovina. AB - OBJECTIVE: To investigate cancer pain management and evaluate factors that could be addressed and lead to potential improvement of pain therapy. MATHERIALS AND METHODS: Two hundred patients with metastatic cancer pain at the Department of Oncology, University Hospital Mostar, completed questionnaires about cancer pain treatment. Thirty oncologists from the Cancer Institute, University of Sarajevo and the Department of Oncology, Clinical Hospital, Mostar were asked to complete the questionnaire about cancer pain management. RESULTS: Compliance for analgesics was statistically better (p=0.013) for patients who were regularly asked about pain than for those patients who were asked periodically. Nearly twice as many patients, whom the doctor always asked about pain, regularly took medication (65.5% versus 32.8%). There was a statistically significant, positive relationship between regular use of analgesics and the interest of the doctor about pain reduction after initiation of analgesic therapy (p=0.008). Almost half of the patients, 47%, stated that their doctor did not devote enough time to their pain problems during the interview. Statistically significantly more patients took analgesic medication regularly if they were not afraid of narcotics (p=0.006). Numerical or VAS scales in description of cancer pain were used by only 30% of interviewed oncologists. The vast majority of doctors, 86.7%, used opiates for the terminal phase of the illness. CONCLUSION: Assessment and the treatment of cancer pain in Bosnia and Herzegovina remains inadequate, emphasizing the need for changes to cancer pain patient care. PMID- 28000487 TI - Risk factors for post-colectomy adhesive small bowel obstruction. AB - OBJECTIVE: The purpose of this study was to assess the risk factors for adhesive small bowel obstruction (SBO) following colectomy for colorectal cancer. PATIENTS AND METHODS: In this retrospective study we analyzed 284 patients who underwent surgery for colorectal cancer at the Department of Surgery University Clinical Center Tuzla in the period from 1st January 2009 until 31st December 2014. All patients underwent open colectomy. The length of follow up was from 6 months to 6 years (median follow up 3 years and 6 months). The study included all patients who underwent surgery due to colon cancer. The study excluded patients with postoperative small bowel obstruction after colon cancer surgery with different comorbidities. RESULTS: In the analyzed sample of 284 patients, a small bowel obstruction occurred in 13.7% patients after surgery for colon cancer. The highest correlation of risk factors and the occurrence of postoperative small bowel obstruction after colectomy for colorectal cancer in multivariate regression analysis was found to be for Tumor-Node-Metastasis >=3 (or =3.680), and postoperative complications (or =30.683). CONCLUSIONS: Postoperative SBO have many causes, but in this study the highest risk factors were the Tumor-Node Metastasis >=3, and postoperative complications. PMID- 28000488 TI - Skeletal maturity assessment using mandibular canine calcification stages. AB - OBJECTIVE: The aims of this study were: to investigate the relationship between mandibular canine calcification stages and skeletal maturity; and to evaluate whether the mandibular canine calcification stages may be used as a reliable diagnostic tool for skeletal maturity assessment. MATERIALS AND METHODS: This study included 151 subjects: 81 females and 70 males, with ages ranging from 9 to 16 years (mean age: 12.29+/-1.86 years). The inclusion criteria for subjects were as follows: age between 9 and 16 years; good general health without any hormonal, nutritional, growth or dental development problems. Subjects who were undergoing or had previously received orthodontic treatment were not included in this study. The calcification stages of the left permanent mandibular canine were assessed according to the method of Demirjian, on panoramic radiographs. Assessment of skeletal maturity was carried out using the cervical vertebral maturation index (CVMI), as proposed by the Hassel-Farman method, on lateral cephalograms. The correlation between the calcification stages of mandibular canine and skeletal maturity was estimated separately for male and female subjects. RESULTS: Correlation coefficients between calcification stages of mandibular canine and skeletal maturity were 0.895 for male and 0.701 for female subjects. CONCLUSIONS: A significant correlation was found between the calcification stages of the mandibular canine and skeletal maturity. The calcification stages of the mandibular canine show a satisfactory diagnostic performance only for assessment of pre-pubertal growth phase. PMID- 28000489 TI - Medical futility treatment in intensive care units. AB - OBJECTIVE: To investigate cases of potential medical futility treatment in intensive care unit (ICU). MATERIALS AND METHODS: Retrospective review of 1567 charts of patients treated during the three-year period (2012 - 2014) in the ICU of the University Hospital Centre Split, Croatia, was conducted. More detailed analysis of the deceased patients' (n=429) charts was performed to identify cases of potential medical futility treatment. There were 99 patients for which ICU treatment was questionable due to their low Glasgow coma scale (GCS) score. For those patients types and duration of treatment were analyzed. RESULTS: Among patients who were treated during that period, 27% had died. Treatment of 99 patients (6.3% of the deceased) was considered a potential medical futility. Mean age of those 99 patients was 68+/-14 years and the mean stay in the ICU was 14+/ 11 days. They spent 1302 patient days in the ICU, of which 52% days they had GCS 3 score. They were treated with catecholamines during 40% of the patient days. Minimal therapy was provided during 44% of the patient days. CONCLUSIONS: Analysis of the deceased patients' charts in the ICU indicated that a certain percentage of patients did not need prolonged ICU treatment. Instead, they were supposed to be treated in a palliative care unit. To avoid medical futility treatment in ICUs, palliative care unit needs to be established, as well as protocols for determining medical futility cases and ethical committee that will decide which patients will be transferred to palliative care. PMID- 28000490 TI - Influence of gender and selection procedures on the academic performance of undergraduate medical students. AB - OBJECTIVES: To determine the impact of gender on success of students studying Medicine in Belgium from the first year (MED1) to the sixth year (MED6) of training, in the context (or not) of a selection process after three years at university. SUBJECTS AND METHOD: Data were evaluated from two cohorts of medical students: students of the first group (n=88) were not submitted to a selection process and students of the second group (n=76) were submitted to a selection process after MED3. Students were enrolled in Brussels Medical School. The variables studied were the grades obtained after the first session of exams, and the student's gender. Variables were put into perspective in relation to the cohort/study year. STATA software was used for statistical analysis. REULTS: Linear regression showed the significant predictability of the grade obtained in MED2 for the grade obtained in MED6 for males and females only in the context of selection (r=0.51; p<0.001). The impact of grades after three years on those after six years was negative in the first group of students (r=-0.17; p=0.005) and positive in the second group (r=0.54; p<0.001). CONCLUSION: These results show a moderate link between success in MED1 and success in MED6, as long as the students undergo selection. A selection system after MED1, based on medical courses, inter alia, could speed up the maturation of students. Further studies with a higher number of candidates are necessary to confirm these results. PMID- 28000491 TI - The forthcoming era of precision medicine. AB - : The aim of this essay is to present the definition and principles of personalized or precision medicine, the perspective and barriers to its development and clinical application. The implementation of precision medicine in health care requires the coordinated efforts of all health care stakeholders (the biomedical community, government, regulatory bodies, patients' groups). Particularly, translational research with the integration of genomic and comprehensive data from all levels of the organism ("big data"), development of bioinformatics platforms enabling network analysis of disease etiopathogenesis, development of a legislative framework for handling personal data, and new paradigms of medical education are necessary for successful application of the concept of precision medicine in health care. CONCLUSION: In the present and future era of precision medicine, the collaboration of all participants in health care is necessary for its realization, resulting in improvement of diagnosis, prevention and therapy, based on a holistic, individually tailored approach. PMID- 28000492 TI - Successful thrombolytic therapy in a patient with congenital corrected transposition of the great arteries. AB - OBJECTIVE: The aim of this report is to emphasize the importance of thrombolytic therapy in selected patients, such as those with congenital heart defects in whom a coronary artery anomaly can be observed. CASE REPORT: We present here a 63 year old female patient who was admitted to our emergency department with ST segment elevation myocardial infarction and a history of a congenital heart defect. We treated the patient successfully with thrombolytic therapy instead of primary percutaneous intervention, because of the suspicion of a coronary artery anomaly. On the following day, we performed coronary angiography on the patient, which revealed the anomalous origin of the coronary arteries, with the left and right coronary arteries originating from the right sinus of Valsalva and the circumflex artery originating from the left sinus of Valsalva. This anomaly in this patient group is described for the first time. CONCLUSION: Coronary artery anomaly may be observed in patients with congenitally corrected transposition of the great arteries, and in the case of requiring emergency reperfusion, thrombolytic treatment can be an alternative strategy in this patient group. PMID- 28000493 TI - Accessory coracobrachialis muscle with two bellies and abnormal insertion - case report. AB - OBJECTIVE: In the current study a brief review is presented of the coracobrachialis muscle's morphological variability, action, embryological development and clinical significance. CASE REPORT: We report a case of a left sided coracobrachialis muscle consisting of two bellies. The deep belly inserts into the usual site in the middle area of the anteromedial aspect of the left humerus, whereas the superficial belly inserts through a muscular slip into the brachial fascia and the medial intermuscular septum, forming a musculo aponeurotic tunnel in the middle region of the left arm, for the passage of the median nerve, brachial artery and veins, medial antebrachial cutaneous nerve and ulnar nerve. CONCLUSION: Awareness of such a muscle variant should be kept in mind by physicians and surgeons during interpretation of neural and vascular disorders of the upper limb, since such a variant may potentially lead to entrapment neuropathy and/or vascular compression, predisposing to neurovascular disorders, as well as during preparation of that muscle in cases of utilizing it as a graft in reconstruction of defects. PMID- 28000494 TI - Twiddler's syndrome. AB - No abstract available. PMID- 28000495 TI - Postal censorship of Bosnian public health institutions during the Second World War: The Independent State of Croatia versus Dr. Stanko Sielski. AB - : This study aims to present evidence of censorship during World War II by the Independent State of Croatia of one of its public health officials, Dr. Stanko Sielski who was a physician trained in epidemiology and public health. During World War II, he directed the Institute for Combating Endemic Syphilis in the Bosnian town Banja Luka. The staff under his direction consisted solely of Jewish physicians. We analyzed two groups of envelopes either sent by or to Dr. Stanko Sielski during the War and found evidence of censorship only in communications with a Jewish physician dated towards the end of the War. Dr. Stanko Sielski would be posthumously recognized for his efforts to shield his Jewish colleagues. CONCLUSION: The newly available, but still limited data, which we present indicates efforts to censor Dr. Stanko Sielski's postal communications towards the War's end. The censors targeted specifically Dr. Stanko Sielski's correspondences with the Jewish physicians he was protecting. This material highlights the many challenges his public health service experienced during the time of armed conflict. PMID- 28000496 TI - From process management towards dynamic capability. AB - No abstract available. PMID- 28000497 TI - Benefits of the EduPlan/EX software platform in managing teaching processes. AB - No abstract available. PMID- 28000498 TI - Information retention among attendees at a traditional poster presentation session. AB - No abstract available. PMID- 28000499 TI - Tiered Pharmacy Copayments for Medications. Final rule. AB - The Department of Veterans Affairs (VA) adopts as a final rule, with changes, a proposal to amend its regulations concerning copayments charged to certain veterans for medication required on an outpatient basis to treat nonservice connected conditions. Prior to this final rule, VA charged non-exempt veterans either $8 or $9 for each 30-day or less supply of medication, and that amount may have changed in future years. This rulemaking replaces those rates and establishes three classes of medications for copayment purposes, identified as Tier 1, Tier 2, and Tier 3. These tiers are defined further in the rulemaking and are distinguished in part based on whether the medications are available from multiple sources or a single source, with some exceptions. Copayment amounts are fixed and would vary depending upon the class of medication. The following medication copayment amounts are applicable on the effective date of this final rule: $5 for a 30-day or less supply of a Tier 1 medication, $8 for a 30-day or less supply of a Tier 2 medication, and $11 for a 30-day or less supply of a Tier 3 medication. For non-exempt veterans these copayment amounts will result in lower out-of-pocket costs, thereby encouraging greater adherence to taking prescribed medications and reducing the risk of fragmented care that results when veterans use non-VA pharmacies to fill their prescriptions. The proposed rule was published on January 5, 2016 and the public comment period closed on March 7, 2016. We received nine comments and respond to these comments here. PMID- 28000500 TI - Evaluation of PCR and high-resolution melt curve analysis for differentiation of Salmonella isolates. AB - Consumption of poultry products contaminated with Salmonella is one of the major causes of foodborne diseases worldwide and therefore detection and differentiation of Salmonella spp. in poultry is important. In this study, oligonucleotide primers were designed from hemD gene and a PCR followed by high resolution melt (HRM) curve analysis was developed for rapid differentiation of Salmonella isolates. Amplicons of 228 bp were generated from 16 different Salmonella reference strains and from 65 clinical field isolates mainly from poultry farms. HRM curve analysis of the amplicons differentiated Salmonella isolates and analysis of the nucleotide sequence of the amplicons from selected isolates revealed that each melting curve profile was related to a unique DNA sequence. The relationship between reference strains and tested specimens was also evaluated using a mathematical model without visual interpretation of HRM curves. In addition, the potential of the PCR-HRM curve analysis was evaluated for genotyping of additional Salmonella isolates from different avian species. The findings indicate that PCR followed by HRM curve analysis provides a rapid and robust technique for genotyping of Salmonella isolates to determine the serovar/serotype. PMID- 28000501 TI - New neolignan glycoside from the root of Aralia echinocaulis Hand. -Mazz. AB - A phytochemical investigation was carried out to the root of Aralia echinocauis, and a new neolignan glycoside, 3-{3,5-dimethoxy-4beta-d-Glucopyranoside-2-[3-(3 beta-d-Glucopyranoside-4-methoxy-phenyl)-allyl]-phenyl}-prop-2-en-1-ol (1), together with a known saponin, araliasaponin II (2) for the first time was obtained. The chemical structure of compound 1 was identified mainly by the analysis of NMR including 1D and 2D NMR in combination with High Resolution Electrospray Ionisation Mass (HR-ESI-MS). This paper herein describes the isolation and structural elucidation of compound 1. PMID- 28000502 TI - Electrochemical monitoring of plastic artefacts degradation. AB - Plastic materials are being used in art: in Italy, for instance, two Art Museums are already presenting only plastic artefacts. As organic matter, plastic suffers degradation and chemical and biological attacks beyond obvious ageing process. Here, we propose an electrochemical approach aiming at the evaluation of the conditions of a plastic object, so giving the opportunity of protection and conservation strategies. The method is very cheap, easy to be handled and absolutely non-invasive, and is based on the monitoring of acidity emitted by a degrading plastic basing on corrosion potential of target metals acting as sensors. PMID- 28000503 TI - Essential oil composition of sweet basil (Ocimum basilicum L.) in symbiotic relationship with Piriformospora indica and paclobutrazol application under salt stress. AB - Essential oil content and oil composition of paclobutrazol treated sweet basil (Ocimum basilicum L.) plant inoculated with Piriformospora indica under salt stress were investigated by GC-MS. The results show a slight increase in essential oil content when basil plants subjected to moderate salinity stress (3 dS m-1 of NaCl). It decreased signifiicantly with increasing salinity level to 9 dS m-1. The findings revealed that leaf area, above ground and leaf dry weights, essential oil content and yield were significantly affected by P. indica inoculation, however paclobutrazol application significantly influenced essential oil yield but not content. Fungal symbiosis as well as paclobutrazol application ameliorated the negative effects of salinity on dry matter and essential oil yield. The main constituents found in the volatile oil of O. basilicum in control treatment were Geranial (26.03%), Neral (24.88%) and Estragole (24.78%). The compounds concentrations showed some differences in P. indica and paclobutrazol treatments. The results demonstrate that micorrhiza-like fungi concomitantly increase essential oil production and biomass in sweet basil, a medicinal herb rich in commercially valuable essential oils. PMID- 28000504 TI - Examination of secondary metabolites and antioxidant capacity of Anthyllis vulneraria, Fuchsia sp., Galium mollugo and Veronica beccabunga. AB - Anthyllis vulneraria L., Fuchsia sp., Galium mollugo L., and Veronica beccabunga L. were selected to analyse the phenolic content and the antioxidant activity by ferric ion reducing antioxidant power (FRAP) and trolox equivalent antioxidant capacity (TEAC) assays. The highest polyphenol, tannin, and flavonoid contents were measured in Fuchsia species (7.40 +/- 0.8, 5.62 +/- 0.7 and 0.72 +/- 0.1 g/100 g dry weight), while the lowest values were detected in Anthyllis vulneraria (0.68 +/- 0.02, 0.17 +/- 0.03 and 0.45 +/- 0.01 g/100 g dry weight) and Galium mollugo (1.77 +/- 0.05, 0.49 +/- 0.04 and 0.16 +/- 0.06 g/100 g dry weight). The leaf extract of Fuchsia sp. had the highest, while the herb of A. vulneraria had the lowest antioxidant effect measured by both methods, which is probably related to total polyphenol, tannin, and flavonoid contents. PMID- 28000505 TI - UV-B radiation increases anthocyanin levels in cotyledons and inhibits the growth of common buckwheat seedlings. AB - The impact of short-term UV-B treatment on the content of individual flavonoids and photosynthetic pigments in cotyledons and the growth of common buckwheat (Fagopyrum esculentum Moench) seedlings was investigated. Seeds of four common buckwheat cultivars were germinated in darkness over a period of 4 days and acclimatized for 2 days under a 16/8 h light/dark photoperiod at 24/18 degrees C day/night, and exposure to 100-120 MUmol ? m-2 ? s-1 of photosynthetically active radiation (PAR). Seedlings were divided into three batches, including two batches subjected to different doses of UV-B (5 W ? m-2 and 10 W ? m-2, one hour per day) for 5 days, and a control group exposed to PAR only. Exposure to UV-B increased anthocyanin levels in the cotyledons of all examined cultivars, it inhibited hypocotyl elongation, but did not affect the content of photosynthetic pigments. Flavone concentrations increased in cv. Red Corolla and Kora, remained constant in cv. Panda and decreased in cv. Hruszowska. Exposure to UV-B decreased rutin levels in cv. Hruszowska, but not in the remaining cultivars. Cultivars Hruszowska, Panda and Kora appeared to be less resistant to UV-B than Red Corolla. Higher resistance to UV-B radiation in Red Corolla can probably be attributed to its higher content of anthocyanins and rutin in comparison with the remaining cultivars. PMID- 28000506 TI - A novel procedure to assess the non-enzymatic hydrogen-peroxide antioxidant capacity of metabolites with high UV absorption. AB - Assays assessing non-enzymatic hydrogen peroxide antioxidant capacities are often hampered by the high UV absorption of the sample itself. This is a typical problem in studies using plant extracts with high polyphenol content. Our assay is based on comparing the 405 nm absorption of the product of potassium iodine and hydrogen peroxide in the presence and absence of a putative hydrogen peroxide reactive antioxidant. This method is free of interference with either hydrogen peroxide or antioxidant self-absorption and it is also suitable for high throughput plate reader applications. PMID- 28000507 TI - Peptaibol profiles of Iranian Trichoderma isolates. AB - Five Iranian Trichoderma isolates from species T. viride, T. viridescens, T. asperellum, T. longibrachiatum and T. citrinoviride - selected from the Fungal Collection of the Bu Ali Sina University, Hamedan, Iran - were investigated for their peptaibol production. All examined isolates showed remarkable antibacterial activities during the screening of their extracts for peptaibol content with a Micrococcus luteus test culture. HPLC-ESI-IT MS was used for identification and elucidation of the amino acid sequences of peptaibols. The detected peptaibol compounds contain 20 or 18 amino acid residues and belong to the trichobrachin and trichotoxin groups of peptaibols, respectively. T. longibrachiatum and T. citrinoviride produced trichobrachins, while trichotoxins could be detected in T. viride, T. viridescens and T. asperellum. Out of 37 sequences detetermined, 26 proved to be new, yet undescribed compounds, while others were identified as previously reported trichotoxins (trichotoxin A-50s and T5D2) and trichobrachins (longibrachins AI, AII, AIII, BII and BIII). Compounds within the two groups of detected peptaibols differed from each other only by a single or just a few amino acid changes. PMID- 28000508 TI - Proteomic insight into the primycin fermentation process of Saccharomonospora azurea. AB - Saccharomonospora azurea SZMC 14600 is a member of the family Pseudonocardiaceae exclusively used for industrial scale production of primycin a large 36-membered non-polyene macrolide lactone antibiotic belonging to the polyketide class of natural products. Even though maximum antibiotic yield has been achieved by empirically optimized two-step fermentation process, little is known about the molecular components and mechanisms underlying the efficient antibiotic production. In order to identify differentially expressed proteins (DEPs) between the pre- and main-fermentation stages of primycin, comparative 2D-PAGE experiments were performed. In total, 98 DEP spots were reproducibly detected, out of which four spots were excised from gels, and identified through MALDI TOF/TOF mass spectrometry. Peptide mass fingerprint analysis revealed peptide matches to HicB antitoxin for the HicAB toxin-antitoxin system (EHK86651), to a nucleoside diphosphate kinase regulator ((Ndk; EHK81899) and two other proteins with unknown function (EHK88946 and EHK86777). PMID- 28000509 TI - ChIP - Does it work correctly? The optimization steps of chromatin immunoprecipitation. AB - The proteins interaction with DNA is one of the key regulatory elements of many biological processes; including gene transcription, epigenetic modification or cell differentiation. Immunoprecipitation of chromatin; ChIP; is a method used to assess the interaction of the protein with a DNA sequence, and determines the localization of specific locus in the genome. The main steps of this method are fixation, sonication, immunoprecipitation and analysis of DNA. Although the immunoprecipitation assay is a multipurpose tool applied in biochemistry and biotechnology, it requires optimization. This paper describes several critical parameters that should be taken into account when immunoprecipitation assay is applied. PMID- 28000510 TI - NADPH-diaphorase histochemistry selectively stains peripheral and central sensory structures of lumbricid earhworms. AB - By means of whole mount NADPH-diaphorase histochemistry the distribution pattern of primary sensory cells (PSC) and the pathway of their central processes in the ventral nerve cord (VNC) ganglia were investigated in the lumbricid earthworms, Eisenia fetida and Lumbricus terrestris. The distribution pattern of the stained structures seemed to be the same in both species investigated. Strong labelling occurred in sensory fibre branches of segmental nerves and in each of the sensory longitudinal axon bundles of VNC ganglia. Based on their anatomical location some NADPH-d positive central sensory cells were identified from among which the putative tactile receptors were characterized by constant, strong staining. PMID- 28000511 TI - The effects of cadmium on the biochemical and physiological parameters of Eruca sativa. AB - In this study, Eruca sativa (Rocket) seedlings were treated with different cadmium (Cd) concentrations (0, 150, 300 and 450 MUg ? g-1). The effects of Cd on lipid peroxidation, enzymatic (APx, CAT, GPX, SOD) and non-enzymatic antioxidants (total ascorbate, dehydroascorbate, ascorbate, non-protein thiol), fresh and dry masses, water content were determined. Also, Cd content of the leaves and the roots were analysed. The highest cadmium accumulation of leaves was at 450 MUg ? g-1 Cd treatment and the accumulation was 2.62 times greater than those in the roots. The translocation factor was 3.89 at 300 MUg ? g-1 Cd treatment. Cd treatments caused decreases of fresh, dry mass and water content of leaves and roots. Malondialdehyde content, which is an index of lipid peroxidation, was increased in proportion with the increase in Cd. While there was not change in the activity of GPX according to control, a decrease in activities of SOD, CAT and APX were observed with the increase of cadmium concentration. Although a significant increase in the amounts of non-protein thiol groups and proline were observed in 450 MUg ? g-1 Cd treated plants, Cd did not lead to a significant change in AsA, DHA and total AsA contents. According to the results of the research, E. sativa may be a Cd hyperaccumulator plant and we suggest that the plant may be a candidate plant for remediation of Cd-contaminated soil. PMID- 28000512 TI - Developmental role of phenylalanine-ammonia-lyase (PAL) and cinnamate 4 hydroxylase (C4H) genes during adventitious rooting of Juglans regia L. microshoots. AB - Phenylalanine-ammonia-lyase and cinnamate-4-hydroxylase play important role in the phenylpropanoid pathway, which produces many biologically important secondary metabolites participating in normal plant development. Flavonol quercetin is the main representant of these compounds that has been identified in numerous Juglans spp. In this survey, the developmental expression patterns of PAL and C4H genes during in vitro rooting of two walnut cultivars 'Sunland' and 'Howard' was examined by RT-PCR. To understand the potential role in rooting, the changing pattern of endogenous content of quercetin was also analyzed by HPLC. The 'Sunland' with better capacity to root had more quercetin content during the "inductive phase" of rooting than 'Howard'. In each cultivar, the level of PAL transcripts showed the same behavior with the changing patterns of quercetin during root formation of microshoots. The positive correlation between the changes of quercetin and PAL-mRNA indicated that PAL gene may have an immediate effect on flavonoid pathway metabolites including quercetin. Although the behavioral change of C4H expression was similar in both cultivars during root formation (with significantly more level for 'Howard'), it was not coincide with the changes of quercerin concentrations. Our results showed that C4H function is important for the normal development, but its transcriptional regulation does not correlate with quercetin as an efficient phenolic compound for walnut rhizogenesis. PMID- 28000513 TI - Anatomical and physiological background permitting spatial odor sensation in stylommatophoran molluscs. AB - Earlier experiments demonstrated that in order to place protracted tentacles and thereby olfactory receptors in an appropriate position for optimal perception of odor stimuli extraordinary complex movements are required. Until recently both large scale tentacle movements and patterned tentacle movements have been attributed to the concerted involvement of the tentacle retractor muscle and muscles of tegumentum. Recently the existence of three novel muscles in the posterior tentacles of Helix has been discovered. The present review, based on experimental data obtained by our research group, outlines the anatomy, physiology and pharmacology of these muscles that enable the tentacles to execute complex movements observed during foraging both in naive and food-conditioned snails. Our findings are also compared as far as possible with earlier and recent data obtained on innervation characteristics and pharmacology of molluscan muscles. PMID- 28000514 TI - Antimicrobial and antioxidant activities of a new metabolite from Quercus incana. AB - Phytochemical investigations of Quercus incana led to the isolation of a new catechin derivative quercuschin (1), along with six known compounds: quercetin (2), methyl gallate (3), gallic acid (4), betulinic acid (5), (Z)-9-octadecenoic acid methyl ester (6) and beta-sitosterol glucoside (7) from the ethyl acetate fraction of methanolic extract of the bark. Compound 1 was screened for its antibacterial, antifungal and antioxidant potential. Antibacterial and antifungal activities of the compound were tested against different bacterial and fungal strains, employing the agar well diffusion methods. The antibacterial activity was the highest against Streptococcus pyogenes with 80.0% inhibition, while the antifungal activity of the compound was the highest against Candida glabrata with 80.5% inhibition. The results of the antioxidant activity indicated that the compound exhibited antioxidant activity comparable to that of standard, butylated hydroxyanisole (51.2 MUg/10 MUl versus 45.9 MUg/10 MUl). PMID- 28000516 TI - Speech perception in children with cochlear implants for continua varying in formant transition duration. AB - PURPOSE: To examine the developmental course of labial and alveolar manner of articulation contrasts, and to determine how that course may be different for typically developing (TD) children with cochlear implants (CI). METHOD: Eight young adults, eight TD 5-8 year-old children, and seven 5-8 year-old children with CIs participated. Labial /ba/-/wa/ and alveolar /da/-/ja/ continua stimuli were presented, with each continuum consisting of nine synthetic stimuli varying in F2 and F3 transition duration. Participants were asked to label the stimuli as either a stop or glide, and responses were analysed for phonetic boundaries and slopes. RESULT: For the /ba/-/wa/ contrast, children with CIs required longer transition durations compared to TD children or adults to cross from one phoneme category to another. The children with CIs demonstrated less confidence in labelling the stimuli (i.e. less steep slopes) than the TD children or the adults. For the /da/-/ja/ contrast, the children with CIs showed less steep slope values than adults. CONCLUSION: These results suggest that there are differences in the way TD children and children with CIs develop and maintain phonetic categories, perhaps differences in phonetic representation or in linking acoustic and phonetic representations. PMID- 28000515 TI - Biological evaluation of phytoconstituents from Polygonum hydropiper. AB - Fourteen compounds including vanicoside B (1), vanicoside F (2), vanicoside E (3) and 5,6-dehydrokawain (4), aniba-dimer-A (5), 6,6'-((1alpha,2alpha,3beta,4beta) 2,4-diphenylcyclobutane-1,3-diyl)bis(4-methoxy-2H-pyran-2-one) (6), (+) ketopinoresinol (7), isorhamnetin (8), 3,7-dihydroxy-5,6-dimethoxy-flavone (9), isalpinin (10), cardamomin (11), pinosylvin (12), 2-desoxy-4-epi-pulchellin (13) and beta-sitosterol (14) were isolated from dichloromethane-soluble portion of Polygonum hydropiper. By using Alamar blue assay, compounds 2, 7, 8, 11 and 12 were found to be active against Trypanosoma brucei with IC50 values in the range of 0.49-7.77 MUg/mL. Cardamomin (11) had most significant activity against T. brucei with IC50/IC90 values of 0.49/0.81 MUg/mL compared to the positive control DFMO (IC50/IC90: 3.02/8.05 MUg/mL). Furthermore, in antimalarial, antimicrobial, anti-inflammatory, PPAR and cytotoxic assays, some compounds have demonstrated moderate inhibitory potentials. PMID- 28000517 TI - Anxiety and depression are associated with long-term outcomes of hepatocellular carcinoma: A nationwide study of a cohort from Taiwan. AB - OBJECTIVES: A natural experimental design was coupled with propensity score matching to assess the risks of anxiety and depression and to assess the longitudinal effects of anxiety and depression on healthcare utilisation and mortality in hepatocellular carcinoma (HCC) patients. METHODS: This nationwide population-based cohort study retrospectively analysed 7304 patients treated for HCC during 1996-2010. Generalised estimating equations were used to estimate differences-in-differences models for examining the effects of anxiety and depression disorders. RESULTS: Independent risk factors for anxiety and depression in the HCC patients were female gender (hazard ratio (HR) 1.45; P < 0.001), Charlson co-morbidity index score (HR 1.12; P = 0.005), and liver cirrhosis (HR 1.35; P = 0.004). Anxiety and depression (differences-in differences value) had a significant (P < 0.001) positive net effect on number of physician visits. Furthermore, the mean overall survival time was 83.4 months (SD 5.4 months) in the anxiety/depression group and 65.4 months (SD 4.8 months) in the non-disorder group. Additionally, the overall survival rate was significantly higher in the anxiety/depression group compared to the non-disorder group during the study period (P = 0.003). CONCLUSIONS: Anxiety disorders and depression disorders are associated with a significantly increased overall survival rate in HCC patients. However, further studies are needed to investigate this association. PMID- 28000518 TI - Artemisinin inhibits inflammatory response via regulating NF-kappaB and MAPK signaling pathways. AB - Artemisinin, isolated from the Chinese plant Artemisia annua, has been used for many years to treat different forms of malarial parasites. In this study, we explored the anti-inflammatory activity of artemisinin and the underlying mechanism of this action. We demonstrated that the anti-inflammatory effects of artemisinin in TPA-induced skin inflammation in mice. Then the artemisinin significantly inhibited the expression of NF-kappaB reporter gene induced by TNF alpha in a dose-dependent manner. Artemisinin also inhibited TNF-alpha induced phosphorylation and degradation of IkappaBalpha, p65 nuclear translocation. Artemisinin also has an impact on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Furthermore, pretreatment of cells with artemisinin prevented the TNF-alpha-induced expression of NF-kappaB target genes, such as anti-apoptosis (c-IAP1, Bcl-2, and FLIP), proliferation (COX-2, cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-alpha, iNOS, and MCP1). We also proved that artemisinin potentiated TNF-alpha-induced apoptosis. Moreover, artemisinin significantly impaired the ROS production and phosphorylation of p38 and ERK, but did not affect the phosphorylation of JNK. Taken together, artemisinin may be a potentially useful therapeutic agent for inflammatory-related diseases. PMID- 28000519 TI - Chamomile reveals to be a potent galactogogue: the unexpected effect. AB - Good habits of breastfeeding have been associated with many long-term health benefits. Nowadays, improvement is seen in the health of children and mothers who practice exclusive breastfeeding for the first six months of life. The search of new potent stimulants for milk production is important to promote lactation, mainly in cases where breastfeeding is a difficult task. This report presents a case of a woman who accidentally realized an abundant amount of milk and had high breast tension, a few hours after consuming chamomile. Although usual consumption of chamomile during pregnancy and lactation are documented for several purposes, the galactogogue effect was never reported. In this case report, we document for the first time the influence of chamomile in a lactating woman by increasing lactogenesis. This article also highlights the need of more research in this field to assure the safety of the intake, by women, of herbal product without the risk for them or the newborns. PMID- 28000520 TI - Small bowel villous atrophy: celiac disease and beyond. AB - INTRODUCTION: Small bowel villous atrophy can represent a diagnostic challenge for gastroenterologists and pathologists. In Western countries small bowel atrophy and mild non-atrophic alterations are frequently caused by celiac disease. However, other pathology can mimic celiac disease microscopically, widening the differential diagnosis. The several novelties on this topic and the introduction of the device-assisted enteroscopy in the diagnostic flowchart make an update of the literature necessary. Areas covered: In this review, a description of the different clinical scenarios when facing with small bowel mucosal damage, particularly small bowel atrophy, is described. The published literature on this subject has been summarized and reviewed. Expert commentary: When an intestinal mucosal alteration is histologically demonstrated, the pathology report forms part of a more complex workup including serological data, clinical presentation and clinical history. A multidisciplinary team, including pathologists and enteroscopy-devoted endoscopists, is frequently required to manage patients with small bowel alterations, especially in cases of severe malabsorption syndrome. PMID- 28000521 TI - Proteomic analysis of irradiated lung tissue of mice using gel-based proteomic approach. AB - PURPOSE: Exposure to radiation causes severe alterations of protein expression level inside the cell, thus it may influence the biological events and stress response. In the present investigation, we have demonstrated the effect of radiation on mice lung tissues. MATERIALS AND METHODS: Two-dimensional gel electrophoresis (2-DE) coupled with MALDI-TOF/TOF was used to check the expression changes in lung proteome profile of strain 'A' female mice after exposure to lethal doses of gamma irradiation at different time periods (24 and 48 h). Identified proteins were analysed for their altered expression and were further validated by Western blotting and enzyme-linked immunosorbent assay (ELISA). RESULTS: Nine significant differentially expressed proteins were identified from irradiated lungs tissues. The expression level of zinc finger protein was found to be up regulated at 24 h irradiation in comparison to 48 h irradiation. CONCLUSIONS: Zinc finger protein may be considered as a radiation responsive protein. Alteration in its expression pattern may primarily affect binding specificity of the protein that can further result in the interference in transcriptional control of multiple stress responsive genes. PMID- 28000522 TI - Targeting the interferon pathway with sifalimumab for the treatment of systemic lupus erythematosus. AB - Dysregulation of the type I interferon (IFN) system is associated with various immunologic diseases, such as systemic lupus erythematosus (SLE). Targeting this dysregulation presents an attractive approach for SLE therapy. Sifalimumab, a fully human immunoglobulin G1 kappa monoclonal antibody that binds to and neutralizes most IFN-alpha subtypes, has been recently evaluated in a Phase IIb study in patients with moderate to severe SLE. Insights gained from earlier studies were used to inform design of the Phase IIb study, to provide a more comprehensive evaluation of sifalimumab. Sifalimumab demonstrated broad efficacy across composite and organ-specific end points, suggesting that targeting of IFN alpha is a promising treatment option for SLE, particularly for those patients whose disease is refractory to current standard of care. PMID- 28000523 TI - CXCR2 inhibition in pancreatic cancer: opportunities for immunotherapy? PMID- 28000524 TI - Modulation of cancer-specific immune responses by amino acid degrading enzymes. AB - To evade immune destruction, tumors exploit a wide range of immune escape mechanisms, including the induction of an immunosuppressive tumor microenvironment. This is mediated, in part, by amino acid degrading enzymes indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, arginase 1 and arginase 2, which have emerged as key players in the regulation of tumor-induced immune tolerance. Here we describe how the expression of tryptophan- and arginine degrading enzymes by tumor and tumor-infiltrating cells can hamper cancer specific immune responses, and discuss how this knowledge is being exploited to develop new strategies for cancer immunotherapy. PMID- 28000525 TI - Inflammatory arthritis due to immune checkpoint inhibitors: challenges in diagnosis and treatment. PMID- 28000526 TI - Tumor-targeting domains for chimeric antigen receptor T cells. AB - Immunotherapy with chimeric antigen receptor (CAR) T cells has been advancing steadily in clinical trials. Since the ability of engineered T cells to recognize intended tumor-associated targets is crucial for the therapeutic success, antigen binding domains play an important role in shaping T-cell responses. Single-chain antibody and T-cell receptor fragments, natural ligands, repeat proteins, combinations of the above and universal tag-specific domains have all been used in the antigen-binding moiety of chimeric receptors. Here we outline the advantages and disadvantages of different domains, discuss the concepts of affinity and specificity, and highlight the recent progress of each targeting strategy. PMID- 28000527 TI - Epigenetic regulation of immune checkpoints: another target for cancer immunotherapy? AB - Epigenetic changes in oncogenes and tumor-suppressor genes contribute to carcinogenesis. Understanding the epigenetic and genetic components of tumor immune evasion is crucial. Few cancer genetic mutations have been linked to direct correlations with immune evasion. Studies on the epigenetic modulation of the immune checkpoints have revealed a critical interaction between epigenetic and immune modulation. Epigenetic modifiers can activate many silenced genes. Some of them are immune checkpoints regulators that turn on immune responses and others turn them off resulting in immune evasion. Many forms of epigenetic inheritance mechanisms may play a role in regulation of immune checkpoints including: covalent modifications, noncoding RNA and histone modifications. In this review, we will show how the potential interaction between epigenetic and immune modulation may lead to new approaches for specific epigenome/immunome targeted therapies for cancer. PMID- 28000529 TI - Corrigendum. PMID- 28000528 TI - Is still there a role for IL-2 for solid tumors other than melanoma or renal cancer? AB - AIM: IL-2 is one of the first immunomodulating cytokines to be tested in the treatment of cancer patients. The effects of this agent in the treatment of solid tumors other than renal cancer and melanoma are poorly understood. MATERIALS & METHODS: We have carried out a meta-analysis of randomized studies. We fixed the response rate as the primary outcome. RESULTS: The pooled risk ratio for an objective response with IL-2 plus chemotherapy versus chemotherapy alone was 1.43 (95% CI: 1.12-1.81; p = 0.004), in favor of colorectal cancer. CONCLUSION: Further investigation in the treatment of patients with colorectal cancer or other solid malignancies with IL-2 is required, alone or in combination with chemotherapy. PMID- 28000530 TI - Welcome to the 9th Volume of Immunotherapy. PMID- 28000532 TI - Maintenance immunosuppressants in the management of antibody-mediated renal allograft rejection: which regimen is best? AB - Antibody-mediated rejection (AMR) is a pivotal cause of long-term graft failure following renal transplantation. De novo donor-specific antibody reduction is essential to prevent AMR and improve long-term graft survival in renal transplant recipients. Although the number of early AMR episodes can be successfully controlled by attenuating de novo donor-specific antibodies, the long-term outcomes are unsatisfactory. Numerous studies have focused on new strategies to reverse AMR, but the available evidence suggests that maintenance immunosuppressive agents play important roles. This article reviews data on the use of various maintenance immunosuppressive strategies in the management of AMR, with a focus on antibody-mediated kidney transplant rejection. Its aim is to help provide options benefitting long-term graft survival in renal transplant recipients. PMID- 28000533 TI - Prospects to improve chimeric antigen receptor T-cell therapy for solid tumors. AB - Adoptive transfer of patient-derived T-cells engineered with a chimeric antigen receptor (CAR) targeting the pan-B-cell marker CD19 has led to complete remission in patients with B-cell leukemias while response rates are more modest for B-cell lymphomas. This can be attributed to the fact that the semi-solid structure of lymphomas impedes T-cell infiltration and that the immune suppressive microenvironment within these tumors dampens the effect of CAR T-cells. These obstacles are even more pronounced for solid tumors where dense and often highly immunosuppressive structures are found. This article focuses on different aspects of how to improve CAR T-cells for solid tumors, primarily by decreasing their sensitivity to the harsh tumor microenvironment, by altering the immunosuppressive microenvironment inside tumors and by inducing bystander immunity. PMID- 28000531 TI - Cytokines and metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy. AB - Recent advances in cancer biology and genetics have fostered precision therapies targeting tumor-specific attributes. Immune-based therapies that elicit cytolytic T cells (CTL) specific for tumor antigens can provide therapeutic benefit to cancer patients, however, cure rates are typically low. This largely results from immunosuppressive mechanisms operating within the tumor microenvironment, many of which inflict metabolic stresses upon CTL. Conversely, immunotherapies can mitigate specific metabolic stressors. For instance, dual costimulation immunotherapy with CD134 (OX40) plus CD137 (4-1BB) agonists appears to mediate tumor control in part by engaging cytokine networks that enable infiltrating CTL to compete for limiting supplies of glucose. Future efforts combining modalities that endow CTL with complimentary metabolic advantages should improve therapeutic efficacies. PMID- 28000534 TI - Adoptive immunotherapy for the treatment of glioblastoma: progress and possibilities. AB - Patients with glioblastoma have a very poor prognosis. Adoptive cellular therapy (ACT) is defined as the collection of circulating or tumor-infiltrating lymphocytes, their selection, modification, expansion and activation, and their re-administration to patients in order to induce antitumor activity. Although various ACTs have been attempted, most failed to improve the outcome. Immune checkpoint blockade antibodies and T cell engineering with tumor-specific chimeric antigen receptors suggest the emergence of a new era of immunotherapy. Here, we summarize approaches with ACTs using genetically modified T cells, which have been improved by enhancing their antitumor activity, and discuss strategies to develop these therapies. The mechanisms by which gliomas modulate and evade the immune system are also discussed. PMID- 28000535 TI - Dermatologic adverse events of checkpoint inhibitors: what an oncologist should know. AB - Immune checkpoint inhibitors (ICI) represent a new revolutionary weapon in the armamentarium of anti-cancer therapies. The side effects of these new agents represent a new challenge for oncologists; they are usually unpredictable and sometimes life threatening, if not managed rapidly and adequately. The most frequent side effects are the dermatologic, but they are usually low grade side effects and consequently easily manageable. Rash, pruritus and vitiligo are the most frequent dermatologic side effects. We aimed in this review to describe first all the dermatologic side effects of ICI according to the subtype of ICI and combination therapies in the clinical trials, then to report all the rare case reports dermatologic side effects, and finally to present the management algorithm of these side effects. PMID- 28000536 TI - Immune checkpoint inhibitors renal side effects and management. AB - The choice of immunotherapy in the treatment of cancer has improved the prognosis of many patients affected by various malignancies. The high expectations foreseen with immunotherapy have led to fast approvals despite the incomplete understanding of the toxicity profiles in the different organs, including the kidneys. The high prevalence of chronic kidney disease in cancer patients complicates the issue further and requires a better knowledge of the renal safety profile to ensure an optimal safe treatment. This review summarizes the present knowledge of renal adverse events secondary to immune checkpoint inhibitors and discusses their pathophysiology, clinical presentation and adequate management. We also advocate the need for a multidisciplinary approach in patients with immune-related toxic adverse events. PMID- 28000538 TI - Mesenchymal stromal cells with enhanced therapeutic properties. AB - Mesenchymal stromal cells (MSC) are connective tissue progenitor cells with interesting immunoregulatory properties and are currently being assessed as cellular therapeutics in a variety of clinical applications. While bone marrow has been the traditional source, adipose tissue and umbilical cord are being used increasingly to generate MSC for therapeutic use as an allogeneic, off-the-shelf product. Although the means by which MSC home to sites of inflammation or tissue damage and exert their beneficial effects remain to be fully elucidated, they have recently been shown to adsorb a number of immunosuppressive and anticancer drugs that may further enhance their therapeutic potential. PMID- 28000537 TI - Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. AB - Immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies have dramatically changed the paradigm of cancer therapy over the past few years. The use of these agents is associated with a unique pattern of autoimmune-like/inflammatory side effects termed immune-related adverse events (irAEs), that may cause collateral damage to normal tissues. Although severe irAEs remain rare, they can become life-threatening if not anticipated and managed appropriately. Improving our knowledge of the mechanisms underlying the development of these toxicities is crucial to optimize clinical efficacy and safety of these new immunotherapeutics. Herein we describe for the first time the pathological features of a severe liver-injury associated with the administration of the anti-PD-1 agent nivolumab in a patient with glioblastoma. PMID- 28000539 TI - Comparison of SMART and WHIM as measurement tools in routine assessment of PDOC patients. AB - BACKGROUND: Royal College of Physicians guidelines on PDOC recommended repeated assessments of patients in PDOC are undertaken by skilled clinicians. The Wessex Head Injury Matrix (WHIM) and the Sensory Modality Assessment and Rehabilitation Technique (SMART) are the most commonly used measures within UK. OBJECTIVE: To evaluate the use of WHIM and SMART to identify potential changes in PDOC patients. METHODS: Twelve PDOC patients admitted to a post-acute regional neuro rehabilitation unit were assessed using WHIM and SMART. Eight of 12 patients were diagnosed with a primary hypoxic ischemic brain injury (HIBI). RESULTS: Overall for the total group there was no significant correlation between patient's highest ranked behaviour and any SMART domain. Initial WHIM total observed behaviour was significantly correlated with SMART tactile domain. Patient's final WHIM and SMART domains were not significantly correlated. Among HIBI subgroup, initial WHIM highest ranked behaviour and WHIM total observed behaviour were significantly correlated with the SMART communication domain. Final WHIM highest ranked behaviour was positively correlated with SMART visual and tactile domains. Final WHIM total observed behaviour was significantly correlated with the SMART visual domain. CONCLUSIONS: Both measures show sensitivity to change in PDOC patients. Larger long-term follow-up of HIBI patients is highlighted. PMID- 28000540 TI - Telomere length in psychiatric disorders: Is it more than an ageing marker? AB - OBJECTIVES: Psychiatric and substance-use disorders have been associated with premature biological ageing. Telomere length (TL), considered an ageing marker, has been analysed in psychiatric disorders, and to a lesser extent in substance use disorders, with recent findings suggesting TL may be related to disease pathology. METHODS: We conducted a critical and non-systematic literature search of TL studies published up to June 2016 in psychiatric and substance-use disorders, focussing on studies describing mechanisms, including studies linking telomere biology with genetic factors, stress and mitochondrial alterations (104 studies selected). RESULTS: Patients with major depressive disorder and anxiety appear to have shorter leukocyte telomeres compared to controls. Inconclusive results are found for other psychiatric disorders and for substance-use disorders. This may be due in part to differences in medication treatment and response, as studies suggest that some psychotropic medications may modulate TL. Importantly, some studies establish a relationship between telomere machinery, stress and mitochondria function in psychiatric and substance-use disorders. CONCLUSIONS: While further longitudinal studies considering telomere genetics are needed to clarify the cause-effect link between telomeres and mitochondria function in psychiatric and substance-use disorders, the recent findings linking these biological processes suggest that telomeres may be more than ageing markers. PMID- 28000541 TI - Involuntary processing of social dominance cues from bimodal face-voice displays. AB - Social-rank cues communicate social status or social power within and between groups. Information about social-rank is fluently processed in both visual and auditory modalities. So far, the investigation on the processing of social-rank cues has been limited to studies in which information from a single modality was assessed or manipulated. Yet, in everyday communication, multiple information channels are used to express and understand social-rank. We sought to examine the (in)voluntary nature of processing of facial and vocal signals of social-rank using a cross-modal Stroop task. In two experiments, participants were presented with face-voice pairs that were either congruent or incongruent in social-rank (i.e. social dominance). Participants' task was to label face social dominance while ignoring the voice, or label voice social dominance while ignoring the face. In both experiments, we found that face-voice incongruent stimuli were processed more slowly and less accurately than were the congruent stimuli in the face-attend and the voice-attend tasks, exhibiting classical Stroop-like effects. These findings are consistent with the functioning of a social-rank bio behavioural system which consistently and automatically monitors one's social standing in relation to others and uses that information to guide behaviour. PMID- 28000542 TI - Cerium oxide nanoparticles: the regenerative redox machine in bioenergetic imbalance. AB - AIM: Owing to their catalytic properties as reactive oxygen species scavengers, cerium oxide nanoparticles (nanoceria) have become an extremely promising candidate for medical applications, especially in the treatment of diseases where oxidative stress has been proposed as one of the main pathogenesis factors. MATERIALS & METHODS: In this work, nanoceria antioxidant power has been tested in primary cultured skin fibroblasts, derived from healthy individuals, by evaluating the mitochondrial function both in basal condition and after an oxidative insult. RESULTS & CONCLUSION: Combined with a clear lack of toxicity, antioxidant activity makes nanoceria promising in a wide range of clinical applications sharing the common signature of a global bioenergetic dysfunction. PMID- 28000543 TI - Allelic variation in dopamine D2 receptor gene is associated with attentional impulsiveness on the Barratt Impulsiveness Scale (BIS-11). AB - OBJECTIVES: Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie individual differences in impulsiveness, however, few have shown this. The current study examined the relationship between catecholamine gene variants and self-reported impulsivity, as measured by the Barratt Impulsiveness Scale (Version 11; BIS-11) Methods: Six hundred and seventy-seven non-clinical adults completed the Barratt Impulsiveness Scale (BIS-11). DNA was analysed for a set of 142 single-nucleotide polymorphisms (SNPs) across 20 autosomal catecholamine genes. Association was tested using an additive regression model with permutation testing used to control for the influence of multiple comparison. RESULTS: Analysis revealed an influence of rs4245146 of the dopamine D2 receptor (DRD2) gene on the BIS-11 attention first order factor, such that self-reported attentional impulsiveness increased in an additive fashion with each copy of the T allele. CONCLUSIONS: These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses. PMID- 28000544 TI - The Complex Inter-Relationship Between Diabetes and Schizophrenia. AB - Schizophrenia is a chronic and debilitating brain disorder. It is associated with increased mortality, primarily due to elevated cardio-metabolic risk. Affected patients have higher rates of obesity, metabolic syndrome and diabetes [1]. Intrinsic factors contributing to this increased risk include a shared underlying pathophysiology between schizophrenia and diabetes mellitus involving stress, inflammation and genetics. Extrinsic contributing factors include diet, lifestyle, health care access, low socioeconomic status and overburden of traditional diabetes risk factors. Antipsychotics are associated with an increased risk of obesity, metabolic syndrome and diabetes mellitus [1]. Appetite regulating hormones, pharmacodynamics and alterations in glucose metabolism may underlie the negative effect of these medications. Reduction in diabetes risk is achieved by mitigating traditional risk factors. Non-pharmacologic and pharmacologic approaches to cardio-metabolic risk reduction may be helpful in these patients. PMID- 28000545 TI - Systemic Cytokines in Type 2 Diabetes Mellitus and Chronic Periodontitis. AB - BACKGROUND: Cytokine dysregulation plays an important role in Type 2 Diabetes Mellitus (T2DM) and Chronic Periodontitis (CP) with a commonality in pathogenic mechanisms. CP is considered the sixth complication of diabetes and may have an increased influence on systemic levels of cytokines in individuals with T2DM. OBJECTIVE: This study investigated two pro-, and two presumed anti-inflammatory cytokines and their ratios in the serum of healthy individuals, in chronic periodontitis with and without T2DM with, and without CP and in CP alone aimed at evaluating the systemic inflammatory burden of a local oral infection. METHODS: Eighty participants were divided equally into four groups as healthy volunteers (H) and patients having T2DM with, and without CP (T2DM+CP, and T2DM) and only CP (CP). Serum samples were collected to measure glycated hemoglobin (HbA1c), Random Blood Sugar (RBS) and also Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL)-4, -6 - 10 were assessed using commercially available ELISA kits. RESULTS: The cytokines were detected in all groups. Significant differences were observed between groups for all the clinical, biochemical parameters and cytokines. Cytokine levels and the ratios showed significant correlations. The ratios of the cytokines differed significantly amongst groups, were highest in T2DM+CP. CONCLUSION: In this study, the cytokine ratios provided a qualitative profile along with the absolute levels in T2DM with periodontitis, indicative of an intensified systemic inflammatory state. PMID- 28000546 TI - Ortho-Methylarylamines as Time-Dependent Inhibitors of Cytochrome P450 1A1 Enzyme. AB - BACKGROUND: Members of the cytochrome P450 1A family metabolize many procarcinogens such as polycyclicaromatic hydrocarbons and heterocyclic amines. Inactivation of these enzymes is a prerequisite for cancer prevention and treatment in certain cases. Mechanism-based inhibition (time and co-factor dependent) is an effective method for the inactivation of these enzymes. Our recent study on emodin analogs revealed an anthraquinone with ortho methylarylamine moiety that exhibited timedependent inhibition of P450 enzymes 1A1 and 1A2. METHODS: To determine whether the amino group or the methyl group or both were responsible for the time-dependent inhibition of these enzymes, a set of eleven compounds containing the orthomethylarylamine moiety were identified through a database search, and studied for the inhibition of the P450 enzymes 1A1, 1A2, 2A6 and 2B1. Our earlier studies on carbazole derivatives provided us with highly selective P450 1A2 inhibitors. Glycine scanning studies were performed on the docked proteinligand complexes of compounds 1-20 in order to understand the contribution of different protein residues towards the ligand binding. RESULTS: Four compounds were found to cause selective time-dependent inhibition of P450 1A1 with KI values ranging from 0.24 to 8.25 mM. These compounds exhibited only direct inhibition of P450 1A2. Molecular modeling studies of these molecules indicated that the shapes of the molecules, their binding modes, and the methyl substituent in close proximity (4.5-5.7 A) to the heme-Fe all contributed to their selective time-dependent inhibition activity on P450 1A1. Glycine scanning studies for P450 1A1 indicated that ligand interaction with Phe123 was the strongest binding contributor and similar studies for P450 1A2 indicated that ligand interactions with the phenylalanine residues 226 and 260 were the largest binding contributors. CONCLUSION: Four compounds have been identified that exhibit selective time-dependent inhibition of P450 1A1. Modeling studies have indicated that the proximity of the aromatic methyl group to the heme-Fe could be the main contributor for time-dependent inhibition. Future studies will focus on the confirmation of the involvement of the aromatic methyl group in enzyme inactivation. PMID- 28000547 TI - Pharmacology and Toxicology of Polyphenols with Potential As Neurotropic Agents in Non-communicable Diseases. AB - BACKGROUND: The central nervous system (CNS) is involved in organic integration. Nervous modulation via bioactive compounds can modify metabolism in order to prevent systemic noncommunicable diseases (NCDs). Concerning this, plant polyphenols are proposed as neurotropic chemopreventive/ therapeutic agents, given their redox and regulating properties. OBJECTIVE: To review polyphenolic pharmacology and potential neurological impact on NCDs. METHOD: First, polyphenolic chemistry was presented, as well as pharmacology, i.e. kinetics and dynamics. Toxicology was particularly described. Then, functional relevance of these compounds was reviewed focusing on the metabolic CNS participation to modulate NCDs, with data being finally integrated. RESULTS: Oxidative stress is a major risk factor for NCDs. Polyphenols regulate the redox biology of different organic systems including the CNS, which participates in metabolic homeostasis. Polyphenolic neurotropism is determined by certain pharmacological characteristics, modifying nervous and systemic physiopathology, acting on several biological targets. Nonetheless, because these phytochemicals can trigger toxic effects, they should not be recommended indiscriminately. CONCLUSION: Summing up, the modulating effects of polyphenols allow for the physiological role of CNS on metabolism and organic integration to be utilized in order to prevent NCDs, without losing sight of the risks. PMID- 28000548 TI - Guide of Hypertensive Crisis Pharmacotherapy. AB - BACKGROUND: Cardiovascular diseases (CVD) are the number one cause of death globally compared to any other cause. CVD accounts for approximately 17.3 million deaths per year and are rising. Hypertension is the leading risk factor for cardiovascular diseases. Approximately, 80 million people suffer from hypertension in the U.S. While, majority of these individuals are on antihypertensive medications only 54% of individuals with hypertension are optimally controlled. Heart failure and stroke are some of the devastating complications of uncontrolled hypertension. Hypertensive crisis can be classified as either an urgency or emergency; difference between the two is the presence of end organ damage, which is noted in hypertensive emergency. Hypertensive crisis is usually treated by parenteral antihypertensive medications. The main drug classes of drugs for treatment are nitrates, calcium channel blockers, dopamine-1 agonists, adrenergic-blocking agents etc. CONCLUSION: In this review, we discuss approach to management of hypertensive crisis and each drug class with its physiology and complications. PMID- 28000549 TI - Vitamin D : Autoimmunity and Gender. AB - BACKGROUND: Vitamin D deficiency is considered a risk factor for autoimmune diseases. Vitamin D and its analogues have been proposed as therapeutic tools in autoimmunity considering their exquisite immunoregulatory effect against over reactivity towards tolerance. Autoimmune diseases, nowadays recognized as emerging non communicable diseases, are characterized by a significant female bias. This sexual dimorphism seems related to sex hormones, which differently affect male and female immune systems. Males show higher immunosuppression, maybe due to androgens; the greater female immunoreactivity and competence, likely related to estrogens, lead to a greater resilience to infections but also to a higher risk for autoimmunity. Higher interest could be given to vitamin D-based supplementation or therapy for autoimmune diseases in relation to gender as well. OBJECTIVE: This review aims to discuss the role of vitamin D in autoimmune diseases with a view inside gender-related differences, in light of the interplay between vitamin D and sex hormones, especially estrogens. RESULTS: Some beneficial effects against autoimmune processes seem to be allowed by vitamin D acting in synergy with estrogens. This observation suggests that possible differences of vitamin D effects depend on the context in which this hormone is active. CONCLUSION: Rather sex-related differences of "absolute" vitamin D levels, the role of gender- dependent factors affecting vitamin D action seems to be critical. Gender and sexual hormones could be included as variables when evaluating the potential power of vitamin D receptor agonists as novel pharmacological tools to approach autoimmune diseases. PMID- 28000550 TI - The Test Your Memory (TYM) Test Outperforms the MMSE in the Detection of MCI and Dementia. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy and clinical usability of a Dutch translation of the Test Your Memory (TYM) test in patients with mild cognitive impairment (MCI) and dementia as compared to the Mini-Mental State Examination (MMSE), in the setting of the memory clinic of a general hospital. METHODS: Fourty-two participants referred to the memory clinic with memory problems and fourty-two healthy controls were assessed using the TYM and the MMSE. We evaluated the sensitivity, specificity and diagnostic accuracy of the TYM and MMSE. Both instruments were tested against recently established clinical diagnostic criteria of MCI, Alzheimer's disease (AD) and vascular dementia (VD). RESULTS: The TYM demonstrated to be more sensitive in detecting dementia than the MMSE. The TYM also was better at discriminating between healthy controls and patients with MCI than the MMSE. CONCLUSION: Our data suggest that the TYM is more suitable as a practical tool for the early detection of dementia than the MMSE. PMID- 28000551 TI - Antimicrobial Evaluation of 5-Substituted Aryl 1H-Tetrazoles. AB - BACKGROUND: Tetrazole derivatives such as 1-substituted dinitrobenzyl tetrazoles and their oxa and selanyl analogs have previously been studied against drug susceptible and multidrug-resistant mycobacteria. In addition, other tetrazole derivatives have been shown to inhibit CTX-M class A b-lactamases. OBJECTIVE: To study the antibacterial activity of 5-substituted aryl 1H-tetrazole derivatives. METHODS: The antibacterial activity of several known 5-substituted aryl 1H tetrazole derivatives was evaluated against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The activity was assessed by determining the minimum inhibitory concentration of these tetrazole derivatives and comparing them to the known antibiotics amoxicillin, trimethoprim and sulfamethoxazole. RESULTS: Some derivatives showed significant antibacterial activity with the most active derivatives exhibiting a minimum inhibitory concentration (MIC) of 125-250 mg/mL against Staphylococcus aureus and Escherichia coli. Using some of these tetrazole compounds in combination with trimethoprim led to a synergistic effect that gave MIC values ranging from 0.24-1.95 mg/mL against Escherichia coli and 3.91-31.3 mg/mL against Staphylococcus aureus. The tetrazole derivatives were prepared in an isopropanol/water mixture using microwave heating at 160 oC for 1 h. The cycloaddition between organonitriles and sodium azide was catalyzed by indium chloride. CONCLUSION: This study shows a significant synergistic effect between the tetrazole compounds tested and trimethoprim which could be used to potentially develop new antibacterial agents. PMID- 28000552 TI - Studies of KP46 and KP1019 and the Hydrolysis Product of KP1019 in Lipiodol Emulsions: Preparation and Initial Characterizations as Potential Theragnostic Agents. AB - BACKGROUND: Lipiodol (iodized poppy seed oil) accumulates predominately in the tumor rather than in the liver tissue [1, 2]. Therefore, mixing anticancer drugs with Lipiodol may enhance the antitumor effect by increasing the local drug concentration. OBJECTIVE: In this pilot study, we made use of Lipiodol as a potential carrier of three promising antitumor metal complexes (tris(8 quinolato)gallium(III) (KP46), tetrachlorobis(indazole)ruthenate(III) (KP1019) and the hydrolysis product of KP1019, mer,trans-[RuCl3(H2O)(Hind)2]. METHODS: The stability of the drugs in Lipiodol and the release profile into the aqueous phase were examined independently by three different analytical techniques (high pressure liquid chromatography, HPLC; atom absorption spectroscopy, AAS; and electron spray ionization mass spectrometry, ESI-MS). RESULTS: The complexes were stable and remained in the Lipiodol emulsion over 3 days. In contrast to KP1019 and KP46, evaluation of Lipiodol emulsions of mer,trans-[RuCl3 (H2O) (Hind) 2] was not possible due to the insolubility of the compound in Lipiodol. KP1019 released rapidly into the aqueous phase in the first week and after 1 month it was not possible to detect the complex in the emulsion. KP46 showed a gradual release with the time resulting in the release of about 6.4 % of KP46 into the aqueous phase after 1 month of incubation. CONCLUSION: The initial results show that Lipiodol can be successfully employed as a carrier of anticancer Ru- or Ga complexes. Furthermore, advantages can overcome the poor water solubility of the metal complexes, opening new perspectives for the use of Lipiodol emulsions in molecular imaging and cancer therapy as theragnostic agents. PMID- 28000553 TI - EDITORIAL New Psychoactive Substances (NPS), a New Global Issue: Neuropharmacological, Chemical and Toxicological Aspects. PMID- 28000554 TI - A Homodimer Model Can Resolve the Conundrum as to How Cytochrome P450 Oxidoreductase and Cytochrome b5 Compete for the Same Binding Site on Cytochrome P450c17. AB - Cytochrome P450 17alpha-hydroxylase, 17,20-lyase (P450c17) is a key enzyme in the synthesis of cortisol in the zona fascicula of the adrenal cortex, and the synthesis of androgen precursors in the adrenal zona reticularis and the gonads. Each of these reactions require electrons transferred by the electron donor cytochrome P450 oxidoreductase. The 17alpha-hydroxylation of its substrate occurs in all cells where P450c17 is expressed. Remarkably, a second, subsequent reaction, namely the 17,20-lyase activity, only occurs in the zona reticularis and gonads. The specificity of the second reaction is due to the interaction with the haem-protein cytochrome b5. Surprisingly, cytochrome b5 and cytochrome P450 oxidoreductase have overlapping sites of interaction on the surface of P450c17. This poses the question as to how cytochrome b5 and cytochrome P450 oxidoreductase interact with P450c17 structurally, functionally and physiologically? This conundrum can be resolved based on the observation that P450c17 can homo-dimerise. A homodimer would allow cytochrome P450 oxidoreductase to bind to one P450c17 monomer of the P450c17 homodimer whilst cytochrome b5 could bind to the other P450c17 monomer simultaneously at the surfaces distal to the dimer interface. This structure is likely to be dynamic in vivo. Our modelling predicts that the proteins can assemble as a stable tetramer and is fully consistent with extensive experimental data that have been published over the last two decades. Predictions derived from this structural model are currently being tested by a range of in vitro and in vivo experimental approaches. PMID- 28000555 TI - Physicochemical Characteristics of Brazilian Green Propolis Evaluated During a Six-Year Period. AB - BACKGROUND: Propolis has been used as a natural health product mainly due to the presence of polyphenols, flavonoids, phenolic aldehydes, amino acids, vitamins and others bioactive constituents. To this natural substance are attributed different biological and pharmacological properties which are influenced by its chemical composition and organoleptic properties. The aim of this work was to evaluate the physicochemical properties and parameters of green propolis collected during a period of six years (2008-2013) in the state of Minas Gerais, located at the southeastern region of Brazil. METHODS: The methodology were in accordance with Brazilian legislation on the identity and quality standards of propolis. The evaluated parameters of hydroalcoholic from green propolis were total flavonoids, antioxidant activity - DPPH method, oxidation index, wax content, humidity and insoluble impurities. RESULTS: Propolis samples collected in different seasons during the years 2008 to 2013 presented mean values of total flavonoids (3.4 +/- 0.11 mg/g), antioxidant activity DPPH (4.76 +/- 0.16 MUg/mL), oxidation index (3, 4 +/- 0.33 seconds) and wax (15.14 +/- 0.78% m/m), which are in accordance with Brazilian legislation. CONCLUSION: Green propolis did not show abrupt seasonal changes during the six years of investigation, and may be considered as an adequate functional ingredient. PMID- 28000556 TI - Therapeutic Approaches Blocking Glycan Synthesis as Targeting Strategy for Malaria. AB - Over one million people die from malaria each year, mainly in the world's tropical and sub-tropical areas. Several research efforts have been devoted to the design of new therapeutic targets for disease control, as drug resistance is one of the greatest challenges in malaria eradication. Carbohydrate recognition in Plasmodium-host interactions is one area for potential targets against disease. The glycan derivatives interfere with replication and invasion of Plasmodium falciparum. Sulfated glycosaminoglycans (GAGs) are known to block merozoite and sporozoite invasion. Heparin is a GAG that has been shown blocking the invasion by binding to the specific domain of merozoites surface (MSP) termed MSP-1. Although MSP does not bind to heparin-like GAG oligosaccharides, its ability to bind to small molecules has not yet been investigated. Besides this, the red blood cell also has glycans on the surface that mediate parasites-cell and cell-cell interactions. In this review, we aim to discuss drug mechanisms that act in carbohydrate synthesis targets in malaria disease. PMID- 28000557 TI - The Resting-State Functional Connectivity of the Default Mode Networks in Patients With Obstructive Sleep Apnea-Hypopnea Syndrome. AB - Obstructive sleep apnea-hypopnea syndrome (OSAHS) is normally linked to cognitive and functional dysfunctions. In this study, we explored the resting-state functional connectivity (rsFC) in the default mode network (DMN) to show the mechanism of neurophysiology in patients with OSAHS. Resting-state structural and functional Magnetic Resonance Imaging data were obtained from sixteen male moderate-to- severe patients with untreated OSAHS and 15 male matched healthy control subjects. The rsFC in the DMN was analyzed between OSAHS and healthy controls by the CONN software. Compared with the controls, the rsFC showed a significant decrease in the the medial prefrontal cortex, anterior cingulate and posterior cingulate, and showed an increase in the left inferior parietal lobule in OSAHS patients. The results indicated that the OSAHS patients presented alternatives of rsFC in the DMN compared with the controls. PMID- 28000558 TI - Coarse Classification to Region-Scalable Refining for White Matter Lesions Segmentation in Multi-Channel MRI. AB - Brain lesions, especially White Matter Lesions (WMLs) that mostly found on magnetic resonance images of elderly people, are not only associated with normal aging, but also with various geriatric disorders including cardiovascular diseases, vascular disease, psychiatric disorders and dementia. Quantitative analysis of WMLs in large clinical trials is crucial in scientific investigations of such neurological diseases as well as in studying aging processes. Exploiting the different appearances of WMLs in multiple modalities, we propose a novel coarse classification to region-scalable refining method to segment WMLs in Magnetic Resonance Imaging (MRI) sequences without user intervention. Specifically, a nonlinear voxel-wise classifier is trained based on intensity features extracted from multimodality MRI sequences, and tissues' probabilistic prior provided by partial volume estimate images in native space. By considering the prior that the WMLs almost exist in white matter, a rejection algorithm is then used to eliminate the false-positive labels from the initial coarse classification. To further segment precise lesions boundary and detect missing lesions, a region-scalable refining is finally employed to effectively segment the WMLs based on the previous initial contour. Compared with the manual segmentation results from an experienced neuroradiologist, the segmentations for real images of our proposal show desirable performances and high accuracy and provide competitive solution with stateof- the-art methods. PMID- 28000560 TI - Ligand Based-Pharmacophore Modeling and Extended Bi oactivity Prediction for Salinosporamide A, B and C from Marine Actino mycetes Salinispora tropica. AB - AIM AND OBJECTIVE: Actinomycetes produce structurally unique secondary metabolites with pharmaceutically essential bioactivities. Salinispora, an obligate marine actinomycete, produces structurally varied and unique secondary metabolites. There is plenty of scope for development of drugs from the novel compounds isolated from Salinispora. Anticancer, antibacterial and anti-protozoa activities have been shown for Salinosporamides A, B and C, the secondary metabolites identified from Salinispora, which make them interesting subjects for further extended biological activity prediction. MATERIAL AND METHODS: An in silico ligand based-pharmacophore approach was used for the prediction of extended biological targets for salinosporamide A, B and C. Pharmacophore models of salinosporamide A, B and C were generated individually and screened against known drug databases. The drugs with best fitness score were shortlisted, and their respective targets pertaining to their bioactivity were retrieved. The predicted biological drug targets were docked with salinosporamide A, B and C for validation. RESULTS: The glucocorticoid receptor and methionine aminopeptidase 2 showed good docking score and binding energy with salinosporamide A, B and C. Molecular dynamics studies of the protein-ligand complexes showed stable interactions suggesting that the predicted new targets for salinosporamides might be promising. CONCLUSIONS: The glucocorticoid receptor and methionine aminopeptidase 2 could be possible new drug targets of bioactivity of salinosporamides. These proteins could be the druggable targets for antiinflammatory and anticancer activity of salinosporamides. PMID- 28000561 TI - Protein Modeling and Molecular Dynamics Simulation of Cloned Regucalcin (RGN) Gene from Bubalus bubalis. AB - BACKGROUND: Regucalcin (RGN), a calcium regulating protein having anti-prolific, antiapoptotic functions, plays important part in the biosynthesis of ascorbic acid. It is a highly conserved protein that has been reported from many tissue types of various vertebrate species. Employing its effect of regulating enzyme activities through reaction with sulfhydryl group (-SH) and calcium, structural level study believed to offer a better understanding of binding properties and regulatory mechanisms of RGN, was performed. MATERIAL AND METHOD: Using sample from testis of Bubalus bubalis, amplification of regucalcin (RGN) gene was subjected to characterization by performing digestion using different restriction endonucleases (RE). Alongside, cDNA was cloned into pPICZalphaC vector and transformed in DH5alpha host for custom sequencing. To get a better insight of its structural characteristics, three dimensional (3D) structure of protein sequence was generated using in silico molecular modelling approach. The full trajectory analysis of structure was achieved by the Molecular Dynamics (MD) that explains the stability, flexibility and robustness of protein during simulation in a time of 50ns. Molecular docking against 1,5-anhydrosorbitol was performed for functional characterization of RGN. RESULTS: Preliminary screening of amplified products on Agarose gel showed expected size of ~893 bp of PCR product corresponding to RGN. Following sequencing, BLASTp search of the target sequence revealed that it shares 91% similarity score with human senescence marker protein 30 (pdb id: 3G4E). Molecular docking of 1,5-anhydrosorbitol reveals information regarding important binding site residues of RGN. 1,5-anhydrosorbitol was found to interact with binding free energy of - 6.01 Kcal/mol. RMSD calculation of subunits A, B and D-F might be responsible for functional and conserved regions of modeled protein. CONCLUSION: Three dimensional structure of RGN was generated and its interactions with 1,5- anhydrosorbitol, demonstrates the role of key binding residues. Until now, no structural details were available for buffalo RGN proteins, hence this study will broaden the horizon towards understanding the structural and functional aspects of different proteins in cattle. PMID- 28000562 TI - Synchronized Fast SPE and UFLC Methods for the Analyses of Eight Antidiabetic Drugs in Human Plasma. AB - AIM AND OBJECTIVE: The population of diabetic patients is rapidly increasing globally. The treatment of these patients is a complex phenomenon due to the use of the different drugs. The present article reports a synchronized fast SPE-UFLC separation of eight antidiabetic drugs in human plasma. Inexpensive solid phase extraction (SPE) and ultra fast liquid chromatography (UFLC) methods were presented for monitoring of eight antidiabetic drugs in human plasma. The separated drugs include metformin HCl, vildagliptin, gliclazide, linagliptin, sitagliptin, pioglitazone, glimepiride and repaglinide plasma sample. MATERIAL AND METHOD: The column used was a Sunshell C18 (150 x 4.6 mm, 2.6 MU) with eluent of acetate buffer (0.05% TEA in 0.05 M NH4Ac of pH 7.0 with H 3PO4) - ACN (60 : 40, v/v). The flow rate was 1.0 mL/min with a detection wavelength of 210 nm and column temp. of 45+/-1oC. These drugs were extracted from human plasma using Sep Pac C18 cartridge. Phosphate buffer (25 mM; pH 7.0) containing these drugs were allowed to pass through cartridge at 0.1 mL/min flow rate. The adsorbed drugs on C18 cartridge were eluted by methanol at 1.0 mL/min flow rate. RESULTS: The values for the retention, separation and resolution factors were ranged from 0.072 to 9.140, 1.443 to 4.208 and 2.147 to 18.652, correspondingly. The percent recoveries for these drugs in the standard laboratory samples prepared in water ranged from 77 to 88%. These values in plasma samples ranged from 10 to 22%. CONCLUSION: The validated method was fruitfully adopted to analyze these drugs in human plasma for the clinical monitoring of these drugs. PMID- 28000564 TI - A Two-layer Model to Identify Hepatitis B Virus Related Chronic Hepatitis and Liver Cirrhosis Based on Plasma microRNA Biomarkers. AB - BACKGROUND: Accurate diagnosis of chronic Hepatitis B virus (HBV) infection related diseases is crucial to guide the therapy and to understand the mechanisms of disease progression. Plasma microRNAs, as stable biomarkers, have drawn significant attentions for distinguishing HBVrelated diseases. METHODS: In this study, a new HBV-related disease identification method based on a two-layer logistic regression model was presented. A total of nine effective plasma microRNA biomarkers were selected through sample collection, data processing, model selection, feature selection and model optimization to distinguish HBV related chronic hepatitis and cirrhosis samples as well as healthy controls. The first layer utilized three microRNAs to distinguish HBV-related disease samples from healthy controls. Then the second layer divided the HBV-related disease samples into cirrhosis and chronic hepatitis samples by using eight microRNAs. RESULT: Test on two independent cohorts showed high accuracy and robustness of our model. Functional analysis of the selected microRNAs and their target genes confirmed that they were significantly associated with HBV-related diseases and related functional pathways. CONCLUSION: Compared with previous models, the two layer model was more consistent with the underlying pathological progress of HBV related diseases from health to chronic hepatitis and further to liver cirrhosis. It could also take the results of other diagnostic tests into account, which could be useful in both physical examination and disease diagnosis. PMID- 28000563 TI - Metabolomics as a Functional Tool in Screening Gastro Intestinal Diseases: Where are we in High Throughput Screening? AB - Identifying novel bio markers in gastro intestinal disease is a promising method where a comprehensive analysis of the metabolome is performed. Metabolomics has evolved enormously in the past decade, paving a path in gastro intestinal disease research, especially diseases which lead to high morbidity and mortality. Metabolomics involves identifying metabolites such as anti-oxidants, and amino acids etc., which are screened in the urine, feces and tissue samples. Certain cases employ advanced tools like GC-MS, 1HNMR and GC-MS/SPME which reveal valuable information concerning disease severity and differentiation. In light of escalating health care costs and risky invasive procedures, metabolomics can be chosen as a safe yet precise method for screening diseases like ulcerative colitis, Crohns' disease, celiac disease, and gastro intestinal cancers. The present review focuses on major advancements in gastro intestinal metabolomics, giving attention to which parameters are assessed, and to recent changes in metabolite analysis. PMID- 28000565 TI - Towards Tyrosine Metabolism in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Esophageal Squamous Cell Carcinoma (ESCC) is a common malignant tumor in China, which causes about 200,000 deaths each year. Sensitive biomarkers are helpful to diagnose the disease in early stage. METHODS: To identify biomarkers of ESCC and elucidate underlying mechanism of the disease, a targeted metabolomics strategy based on liquid chromatography-tandem mass spectrometry (LCMS/ MS) has been implemented to explore tyrosine metabolism from 40 ESCC patients and 27 healthy controls. RESULTS: Four metabolites, i.e. phenylalanine, 4-hydroxyphenyllactic acid, 3,4-dihydroxyphenylalanine, and 3,4 dihydroxyphenylacetic acid were identified as diagnostic biomarkers for ESCC patients. Based on these biomarkers, a prediction model was constructed for ESCC diagnosis. The analysis of receiver operating characteristic (ROC) curve confirmed its effectiveness of the model. CONCLUSION: Our results reveal that tyrosine metabolism is disturbed in ESCC patients and the metabolites involved in tyrosine pathway can be used as diagnostic biomarkers of the disease. Findings of this study can help investigate pathogenesis of ESCC and facilitate understanding mechanism of the disease. PMID- 28000566 TI - Inferring Alcoholism SNPs and Regulatory Chemical Compounds Based on Ensemble Bayesian Network. AB - AIM AND OBJECTIVE: The disturbance of consciousness is one of the most common symptoms of those have alcoholism and may cause disability and mortality. Previous studies indicated that several single nucleotide polymorphisms (SNP) increase the susceptibility of alcoholism. In this study, we utilized the Ensemble Bayesian Network (EBN) method to identify causal SNPs of alcoholism based on the verified GAW14 data. MATERIALS AND METHODS: We built a Bayesian network combining random process and greedy search by using Genetic Analysis Workshop 14 (GAW14) dataset to establish EBN of SNPs. Then we predicted the association between SNPs and alcoholism by determining Bayes' prior probability. RESULTS AND CONCLUSION: Thirteen out of eighteen SNPs directly connected with alcoholism were found concordance with potential risk regions of alcoholism in OMIM database. As many SNPs were found contributing to alteration on gene expression, known as expression quantitative trait loci (eQTLs), we further sought to identify chemical compounds acting as regulators of alcoholism genes captured by causal SNPs. Chloroprene and valproic acid were identified as the expression regulators for genes C11orf66 and SALL3 which were captured by alcoholism SNPs, respectively. PMID- 28000567 TI - Analysis and Prediction of Myristoylation Sites Using the mRMR Method, the IFS Method and an Extreme Learning Machine Algorithm. AB - BACKGROUND: Myristoylation is an important hydrophobic post-translational modification that is covalently bound to the amino group of Gly residues on the N terminus of proteins. The many diverse functions of myristoylation on proteins, such as membrane targeting, signal pathway regulation and apoptosis, are largely due to the lipid modification, whereas abnormal or irregular myristoylation on proteins can lead to several pathological changes in the cell. OBJECTIVE: To better understand the function of myristoylated sites and to correctly identify them in protein sequences, this study conducted a novel computational investigation on identifying myristoylation sites in protein sequences. MATERIALS AND METHODS: A training dataset with 196 positive and 84 negative peptide segments were obtained. Four types of features derived from the peptide segments following the myristoylation sites were used to specify myristoylatedand non myristoylated sites. Then, feature selection methods including maximum relevance and minimum redundancy (mRMR), incremental feature selection (IFS), and a machine learning algorithm (extreme learning machine method) were adopted to extract optimal features for the algorithm to identify myristoylation sites in protein sequences, thereby building an optimal prediction model. RESULTS: As a result, 41 key features were extracted and used to build an optimal prediction model. The effectiveness of the optimal prediction model was further validated by its performance on a test dataset. Furthermore, detailed analyses were also performed on the extracted 41 features to gain insight into the mechanism of myristoylation modification. CONCLUSION: This study provided a new computational method for identifying myristoylation sites in protein sequences. We believe that it can be a useful tool to predict myristoylation sites from protein sequences. PMID- 28000568 TI - Plant Peptides: Bioactivity, Opportunities and Challenges. AB - Bioactive peptides from plants are an underexplored domain in the field of proteomics and peptidomics. Recent evidences of plant peptides being more than chemical signals and indeed, functioning in the responses of plants to diverse environmental cues such as stress and infection by pathogens, suggests their potentially wide applicability in agrochemical and pharmaceutical industries. With cutting-edge technologies available, studies on plant peptides still lag behind those from food or microorganisms. The current mini-review provides an overview of the major bioactivity documented of plant-based peptides. It further underlines the techniques associated with isolation and identification of peptides, the limitations associated with these techniques and the '-omics' revolution that is playing a major part in better understanding of these peptides. PMID- 28000569 TI - Antimicrobial Peptides of Meat Origin - An In silico and In vitro Analysis. AB - The aim of this study was to evaluate the antimicrobial activity of meat protein derived peptides against selected Gram-positive and Gram-negative bacteria. The in silico and in vitro approach was combined to determine the potency of antimicrobial peptides derived from pig (Sus scrofa) and cow (Bos taurus) proteins. The in silico studies consisted of an analysis of the amino acid composition of peptides obtained from the CAMPR database, their molecular weight and other physicochemical properties (isoelectric point, molar extinction coefficient, instability index, aliphatic index, hydropathy index and net charge). The degree of similarity was estimated between the antimicrobial peptide sequences derived from the slaughtered animals and the main meat proteins. Antimicrobial activity of peptides isolated from dry-cured meat products was analysed (in vitro) against two strains of pathogenic bacteria using the disc diffusion method. There was no evidence of growthinhibitory properties of peptides isolated from dry-cured meat products against Escherichia coli K12 ATCC 10798 and Staphylococcus aureus ATCC 25923. PMID- 28000570 TI - Structural, Functional and Evolutionary Aspects of Seed Globulins. AB - Globulins are a major class of seed storage proteins which were thought to be enzymatically inactive. These proteins belong to the most ancient cupin superfamily. They can be graded into 11S legumin type and 7S vicilin type based on their sedimentation coefficients. Members from both classes share structural homology are thought to have evolved from either one-domain germin predecessor by duplication or by horizontal gene transfer of two-domain gene from bacteria to eukaryotes. Globulins are known to define the nutritional quality of the seeds, however, they are also involved in sucrose binding, desiccation, defense against microbes, hormone binding and oxidative stress etc. Major drawback with globulins is their tendency to bind to IgE. Studying structural-functional behavior of such protein can help in modifying proteins for enhanced functionality in food processing industries. PMID- 28000571 TI - Immuno-Stimulating Peptide Derived from HMGB1 is More Effective Than the N Terminal Domain of Gp96 as an Endogenous Adjuvant for Improvement of Protein Vaccines. AB - Up to now, different protein vaccine modalities against human papillomavirus (HPV) have been designed to control cervical cancer. The important issue is to increase their immunogenicity using appropriate adjuvants. Among heat shock proteins (HSPs), glycoprotein 96 (Gp96) and its Nterminal region (NT-gp96) have attracted a specific interest in stimulation of antigen-specific immune responses in vivo. Furthermore, the potency of high mobility group box 1 (HMGB1) protein and its fragment (Hp91) was reported to enhance the desired immune responses against various disorders. In this study, the recombinant (r) HPV16 E7 and rNT gp96 proteins were generated in bacterial expression system. Mice were vaccinated three times with E7 antigen mixed with Montanide, Hp91, and NT-gp96 as the adjuvant and their preventive and therapeutic efficiencies were evaluated in a murine tumor model. Mice vaccinated with E7 co-delivered by Hp91 peptide induced higher IgG2a and IFN-gamma responses in comparison with E7 co-injected with Montanide and NT-gp96 protein suggesting a strong Th1 cellular immune response. The data showed that vaccination with noncovalent rE7 + rNT-gp96 complex delayed the tumor growth as compared to control groups. Mice immunized with rE7 + Montanide and rE7 + Hp91 protected 100% of mice versus 75% survival in groups vaccinated with rE7 + rNT-gp96 after TC-1 tumor challenge. The percentage of tumor free mice was decreased in group immunized with rE7 + rNT-gp96 in therapeutic experiments (~ 50%). These results demonstrated that Hp91 peptide is a safe and strong adjuvant against rNT-gp96 with the potent anti-tumor effects similar to Montanide adjuvant. PMID- 28000572 TI - [Vismodegib for basal cell carcinoma: targeted therapy in case of locally advanced or metastasised disease]. AB - The development of the hedgehog pathway inhibitor vismodegib provides a new treatment option for metastasised and locally advanced basal cell carcinoma in which surgical excision or radiotherapy is contraindicated. Only a fraction of patients with basal cell carcinoma are eligible for this therapy, but it is effective in the majority of those who do receive vismodegib. However, development of tumour resistance is quite common and adverse events frequently lead to discontinuation of therapy. Intermittent treatment or combination therapy could reduce the occurrence of tumour resistance and diminish toxicity. We present three patients who were successfully treated with vismodegib: a 73-year old man with locally advanced basal cell carcinoma, an 82-year-old man with basal cell carcinoma that had metastasised to the lungs, and a 42-year-old man with Gorlin syndrome. PMID- 28000573 TI - [Immunogenicity of biosimilars]. AB - Biosimilars of more complex recombinant protein drugs, such as monoclonal antibodies and fusion proteins, are entering the market. The manufacturer should demonstrate that its product does not show any relevant differences in terms of quality characteristics, biological activity, safety and efficacy compared to the reference product, as outlined in EMA guidelines. This should be established with an extensive comparability exercise. One aspect that is subject to particular scrutiny is the immunogenicity of the biosimilar and the reference medicinal product. For three cases, one etanercept and two infliximab biosimilars, we describe how data are assessed and an opinion is reached by authorities. Not in all cases unanimity exists whether all remaining uncertainties on biosimilarity have been resolved satisfactorily before marketing authorisation. The Dutch Medicines Evaluation Board therefore emphasises that even after marketing authorisation, biosimilars and other biologicals should be properly monitored. PMID- 28000574 TI - [Legal aspects of post-mortem radiology in the Netherlands]. AB - In the Netherlands, the application of post-mortem radiology (virtual autopsy) is on the rise. Contrary to conventional autopsy, with post-mortem radiology the body remains intact. There is uncertainty concerning the legal admissibility of post-mortem radiology, since the Dutch Corpse Disposal Act does not contain any specific regulations for this technique. Autopsy and post-mortem radiology differ significantly from a technical aspect, but these differences do not have far reaching legal consequences from a legal perspective. Even though the body remains intact during post-mortem radiology, the bodily integrity of a deceased person is breached if it would be applied without previously obtained consent. This permission can only be obtained after the relatives are fully informed about the proposed activity. In this respect, it is not relevant which technique is used, be it post-mortem radiology or autopsy. Therefore, the other legal conditions for post-mortem radiology are essentially identical to those for autopsy. PMID- 28000575 TI - [National developments in Emergency Departments in the Netherlands: numbers and origins of patients in the period from 2012 to 2015]. AB - OBJECTIVE: Gaining insight into key figures of emergency departments (EDs) in the Netherlands and developments in these figures. DESIGN: Longitudinal survey study. METHOD: Over the period from 2012 up to and including 2015, the following key data were surveyed: number of EDs, number of ED patients, ED patients' origin, number of hospital admissions from the ED and form of cooperation between ED and a general practitioner centre (GPC). RESULTS: An average of 96% of all EDs responded. The number of EDs decreased from 93 to 87. The percentage of EDs that maintained a form of cooperation with a GPC in the hospital rose from 49% to 79%. The total number of patients seen annually in an ED in the Netherlands decreased by 128,000 to 1.951 million. The proportion of patients presenting in the ED via ambulance, mobile medical team or 112 (emergency number) increased by 2.6% to 16.0%. The proportion of patients referred from their own GP or GPCs increased by 7.8% to an average of 50.3%. The proportion of self-referrals decreased by 12.6% to 17.4%. The proportion of patients who came up to the ED through a different route remained constant at around 14%. The nationwide variation in the origin of patients remained high. The average percentage of hospital admissions from the ED increased by 5.6% to 37.2%. CONCLUSION: The number of EDs is decreasing and the cooperation between EDs and GPCs has intensified. The number of patients seen in the ED has decreased. The percentage of self-referrals has decreased and the number of hospital admissions from the ED has increased significantly. For a successful and consistent policy, more substantive data on the nature and extent of emergency care in the ED are needed. This requires a national registry. PMID- 28000576 TI - [Power in the PhD programme]. AB - This article describes the role of power in the world of biomedical research. On the basis of some examples, I intend to demonstrate the influence of power, or its misuse, on PhD students and supervisors, and how this may have a negative effect on the research of PhD students. I will then outline how the biomedical research field can prevent these practices, and how it can create a better and more inspiring atmosphere for young, enthusiastic and talented researchers. PMID- 28000577 TI - [Do healthcare insurers have too much power?] AB - In the Dutch healthcare system, healthcare insurers act as purchasers of care on behalf of their insured clients. To this end, the insurers form contractual agreements with healthcare providers. In the interest of balanced negotiations regarding price and quality, it is important that neither of the two parties has a disproportionate position of power. This paper discusses whether healthy power relationships exist between healthcare insurers and healthcare providers. PMID- 28000578 TI - [Power in the consulting room]. AB - Three physicians reflect on the theme 'power in the consulting room', but in fact they are mostly discussing disempowerment. In this article we discuss strategies involved in the physician's power over patients and factors that limit these powers. PMID- 28000579 TI - [The patient rules; the power of transference in the doctor-patient relationship]. AB - The challenge of the doctor-patient relationship for the participants is maintaining their equivalence while respecting the needs of both sides. As the doctor has the expert power ('authority'), the patient reacts in different ways when he or she cannot release the control over the diagnostic situation. Regressive power can be exercised in three forms of transference relationships: the power of dependency, the power of dominance and the power of desorganisation. Doctors should recognize these forms of relationship but not engage in them. This implies that doctors should be educated in meta-communication with the patient and trained to keep up their warm interested neutrality and their ability to communicate from a scientific background. PMID- 28000580 TI - [Who may place the first donor heart? Conflict surrounding the first heart transplant in the Netherlands]. AB - On Friday 22 June 1984 a patient was waiting in Rotterdam to be moved to Brussels for a heart transplant. The Dutch heart surgery centres tried to mutually agree on the place where the first heart transplant should be performed. When this proved impossible, the decision was made by the cardiac surgeons from Rotterdam and Leiden. In this article we will reconstruct the events that took place at that time, partly on the basis of a recent 'witness seminar'. PMID- 28000581 TI - Tuberculosis clinical units improve contact tracing. AB - INTRODUCTION: The Barcelona Tuberculosis Programme was established in 1987, and in 2007 five tuberculosis (TB) clinical units were created to improve the follow up of cases and contacts. This included the designation of a nurse for case management. OBJECTIVE: To assess the impact of the TB clinical units on the screening programme for TB contacts. METHODS: Before-after population-based study before (2003-2007) and after (2008-2013) the creation of the clinical units. To determine which factors were related to contact tracing, we fitted a multivariate logistic regression model to estimate odds ratios (OR) with their 95% confidence intervals (CIs). RESULTS: Following the creation of the clinical units, the proportion of prescriptions for latent tuberculous infection among contacts in the clinical units increased from 40.7% to 57.4% (P < 0.001), and treatment adherence from 75.9% to 80.3% (P = 0.035). One factor associated with contact tracing was receiving care after the creation of the clinical units (2008-2013) (OR 1.2, 95%CI 1.0-1.3). During the second period, receiving care outside the clinical units reduced the probability of contact tracing (OR 0.7, 95%CI 0.5 0.9). CONCLUSION: The creation of the TB clinical units represents an organisational improvement for the study and management of contacts of patients with TB. PMID- 28000582 TI - Seasonality of tuberculosis in Israel, 2001-2011. AB - BACKGROUND: Several studies have suggested that the incidence of tuberculosis (TB) varies with the seasons. OBJECTIVE: To determine the seasonality of TB in Israel and to explore possible associations with climatic variables. METHODS: Laboratory-confirmed TB cases reported between 2001 and 2011 in individuals resident in Israel for at least 1 year before diagnosis were included in the study. Climatic variables included average temperature and average ultraviolet radiation. The mean serum 25-hydroxyvitamin D level of the population was also recorded. RESULTS: Of all 2653 TB cases, incidence peaked during spring (n = 712) and reached its nadir during the fall (n = 577), with a case proportion amplitude (CPA) of 5.1% (P = 0.036). Individuals born in the Horn of Africa exhibited a CPA of 9.5% (P = 0.077). Mean population 25-hydroxyvitamin D level was significantly correlated with the seasonal pattern of the disease. Southern Israel had the highest global radiation and, counter-instinctively, the highest TB incidence. CONCLUSIONS: TB exhibited a seasonal tendency in Israel, with the spring peak/fall nadir pattern found elsewhere. Vitamin D is suspected to be an explanatory variable for this seasonal phenomenon. The finding that the highest incidence is in the area receiving the highest global radiation suggests population-related vulnerability to vitamin D deficiency. PMID- 28000583 TI - Clinical characteristics and outcomes of tuberculosis in Douala, Cameroon: a 7 year retrospective cohort study. AB - SETTING: Tuberculosis (TB) clinic, Douala Laquintinie Hospital, Douala, Cameroon. OBJECTIVE: To describe the clinical characteristics of TB and to investigate predictors of poor treatment outcomes. DESIGN: A registry-based, retrospective cohort study of all TB cases recorded from 2007 to 2013 was conducted. Multinomial logistic regression models were used to identify predictors of poor outcomes. RESULTS: Of 8902 TB cases included, 5110 (57.4%) were males. The median age was 33 years. The prevalence of human immunodeficiency virus (HIV) infection was 37.6%, with a significant decline over the study years (P = 0.000). The main clinical form of TB was smear-positive TB (50.5%). The treatment success rate was 75.2%, while the mortality rate was 8.1%. The year of TB diagnosis, retreatment cases, sputum non-conversion at the end of month 2, HIV infection and HIV testing not done were associated with death. Retreatment and non-conversion of sputum were associated with treatment failure, while male sex, age, sputum non conversion, HIV infection and HIV testing not done were associated with loss to follow-up. CONCLUSION: TB management objectives may be attained by focusing specifically on higher risk groups to prevent poor treatment outcomes. PMID- 28000585 TI - IFN-gamma promoter polymorphisms do not affect QuantiFERON(r) TB Gold In-Tube test results in a Canadian population. AB - BACKGROUND: Several studies have shown polymorphisms within the interferon-gamma (IFN-gamma) promoter influence cytokine expression. The interferon-gamma release assay (IGRA) relies on the ability to produce IFN-gamma in response to tuberculosis (TB) specific antigens. This study determined the relationship between the IFN-gamma +874 A/T promoter polymorphism and the performance of the QuantiFERON(r)-TB Gold In-Tube (QFT-GIT) test in an ethnically diverse Canadian population. METHODS: A total of 190 participants were categorised into three groups based on history of and exposure to TB: active TB (n = 55), TB exposed (n = 55) and presumably TB unexposed controls (n = 80). All participants underwent QFT-GIT testing, and DNA was extracted from whole blood and probed for polymorphism at position +874 (T/A) of intron 1 of IFN-gamma. Statistical relationships between the QFT-GIT results, polymorphisms and demographic data were evaluated. RESULTS: IFN-gamma +874 genotype frequencies among the entire study population (n = 190) were A/A (45.8%), T/A (39.5%), and T/T (14.7%). Among the three study groups, there was no correlation between QFT-GIT results and the IFN-gamma +874 A/T genotype, and no correlation of genotype with IFN-gamma production in response to either Mycobacterium tuberculosis antigens or mitogenic stimulation. CONCLUSION: Our results indicate that the IFN-gamma +874 promoter polymorphism does not influence QFT-GIT performance in this study population. PMID- 28000586 TI - Evaluation of OMNIgene(r)*SPUTUM-stabilised sputum for long-term transport and Xpert(r) MTB/RIF testing in Nepal. AB - SETTING: German Nepal TB Project, National Tuberculosis Reference Laboratory, Kathmandu, Nepal. OBJECTIVE: To evaluate whether transporting samples in OMNIgene(r)*SPUTUM (OM-S) reagent from a peripheral collection site to a central laboratory in Nepal can improve tuberculosis (TB) detection and increase the sensitivity of Xpert(r) MTB/RIF testing. DESIGN: One hundred sputum samples were split manually. Each portion was assigned to the OM-S group (OM-S added at collection, airline-couriered without cold chain, no other processing required) or the standard-of-care (SOC) group (samples airline-couriered on ice, sodium hydroxide + N-acetyl-L-cysteine processing required at the laboratory). Smear microscopy and Xpert testing were performed. RESULTS: Transport time was 2-13 days. Overall smear results were comparable (respectively 58% and 56% smear negative results in the OM-S and SOC groups). The rate of smear-positive, Mycobacterium tuberculosis-positive (MTB+) sample detection was identical for both treatment groups, at 95%. More smear-negative MTB+ samples were detected in the OM-S group (17% vs. 13%, P = 0.0655). CONCLUSION: Sputum samples treated with OM-S can undergo multiday ambient-temperature transport and yield comparable smear and Xpert results to those of SOC samples. Further investigation with larger sample sizes is required to assess whether treating sputum samples with OM S could increase the sensitivity of Xpert testing in smear-negative samples. PMID- 28000587 TI - The clinical utility of Xpert(r) MTB/RIF testing in induced sputum. AB - We performed a prospective clinical audit in hospitalised patients with suspected pulmonary tuberculosis (PTB) with the objective of evaluating the accuracy and clinical utility of Xpert(r) MTB/RIF in induced sputum in an intermediate-burden setting. Of 450 patients audited, 61 (13.6%) were diagnosed with PTB based on positive culture. The sensitivity, specificity and positive and negative predictive values for Xpert in smear-negative cases for induced sputum were respectively 75%, 99.5%, 94.7% and 97.0%. Xpert in induced sputum may facilitate diagnostic yield and expedite treatment in up to a quarter of PTB patients. PMID- 28000588 TI - Active tuberculosis patients have high levels of IgA anti-alpha-crystallin and isocitrate lyase proteins. AB - SETTING: Mexico City, Mexico. OBJECTIVE: To identify proteins synthetised by Mycobacterium tuberculosis in hypoxic culture, which resemble more closely a granuloma environment than aerobic culture, and to determine if they are recognised by antibodies from patients with active pulmonary tuberculosis (PTB). DESIGN: Soluble extracts from M. tuberculosis H37Rv cultured under aerobic or hypoxic conditions were analysed using two-dimensional polyacrylamide gel electrophoresis, and proteins over-expressed under hypoxia were identified by mass spectrometry. The presence of immunoglobulin (Ig) G, IgA and IgM antibodies against these proteins was determined in the serum of 42 patients with active PTB and 42 healthy controls. RESULTS: We selected three M. tuberculosis H37Rv proteins (alpha-crystallin protein [Acr, Rv2031c], universal stress protein Rv2623 and isocitrate lyase [ICL, RV0467]) that were over-expressed under hypoxia. Titres of anti-Acr and anti-ICL IgA antibodies were higher in patients than in healthy controls, with an area under the receiver operating characteristic curve of 0.71 for anti-ICL IgA antibodies. CONCLUSION: ICL could be used in combination with other M. tuberculosis antigens to improve the sensitivity and specificity of current serological TB diagnostic methods. PMID- 28000590 TI - Parasitoids of the eucalyptus gall wasp Leptocybe invasa (Hymenoptera: Eulophidae) in China. AB - Leptocybe invasa Fisher & La Salle (Hymenoptera, Eulophidae) is an invasive pest in Eucalyptus plantations throughout the world. Potential biological control agents for L. invasa were investigated in the Fujian, Guangdong, Hainan, Guangxi, Jiangxi, and Sichuan provinces of China, where Eucalyptus spp. have been severely damaged by the eucalyptus gall wasp. Three hymenopteran parasitoids of L. invasa were identified: Quadrastichus mendeli Kim & La Salle (Eulophidae), Aprostocetus causalis La Salle & Wu (Eulophidae), and Megastigmus viggianii Narendran & Sureshan (Torymidae); M. viggianii is newly recorded in China. The percentages of parasitization by Q. mendeli, A. causalis, and M. viggianii were 2.96%-19.53%, 2.30%-26.38%, and 24.93%, respectively. The longevity and body length of females were significantly greater than for males in A. causalis and M. viggianii. No males of Q. mendeli were found in China. These parasitoids could be used as biological agents for L. invasa in China. PMID- 28000591 TI - Relative importance of meteorological and geographical factors in the distribution of Fasciola hepatica infestation in farmed sheep in Qinghai province, China. AB - Fasciola hepatica is an important trematode parasite of economic importance that infests sheep and cattle worldwide. We conducted a detailed investigation into the spatial distribution of F. hepatica infestation in farmed sheep in Qinghai (Wutumeiren) province, Mainland China. Mathematical modelling was used to assess the inter-relationships between meteorological and geographical factors and the risk of F. hepatica infestation across the province. A capture enzyme-linked immunosorbent assay (ELISA) test (MM3-SERO) was used to detect F. hepatica infestation. A niche model based on the maximum entropy method (MaxEnt) was used to estimate the influence of meteorological and geographical factors on the observed spatial distribution of F. hepatica infestation. Results of jackknife analysis indicated that temperature, precipitation, solar radiation, digital elevation and slope were associated with the occurrence of F. hepatica infestation, and that infestation rates were significantly higher among animals from districts with a high percentage of grassland habitat. The findings indicate that meteorological and geographical factors may be important variables affecting the distribution of F. hepatica infestation and should be taken into account in the development of future surveillance and control programmes for fascioliasis. PMID- 28000592 TI - The respiratory landscape in China: a focus on air pollution. PMID- 28000593 TI - Chronic obstructive pulmonary disease (COPD). PMID- 28000594 TI - Dante Alighieri: evidence for sleep disorder-related cardiac autonomic dysfunctions. PMID- 28000595 TI - Respiratory syncytial virus-induced paediatric ARDS: why we should unpack the syndrome. PMID- 28000596 TI - N-acetylcysteine for idiopathic pulmonary fibrosis: the door is still open. PMID- 28000597 TI - N-acetylcysteine for idiopathic pulmonary fibrosis: the door is still open Authors' reply. PMID- 28000598 TI - Baseline use of antiarrhythmics in patients given adaptive servoventilation: SERVE-HF. PMID- 28000599 TI - Baseline use of antiarrhythmics in patients given adaptive servoventilation: SERVE-HF-Authors' reply. PMID- 28000600 TI - Community-based management of COPD in Nepal. PMID- 28000601 TI - Isolation of Tasmanian Rickettsia-like organism (RLO) from farmed salmonids: identification of multiple serotypes and confirmation of pathogenicity. AB - Atlantic salmon Salmo salar L. farmed in south-east Tasmania, Australia, are susceptible to infection by the Tasmanian Rickettsia-like organism (TRLO), a Gram negative bacterium. Here, we report the first isolation of TRLO from south-east Tasmania in pure culture and show that the bacterium is culturable on both specialised enriched agar and in cell culture using the CHSE-214 cell line. In vitro cultured TRLO was used to reproducibly elicit disease in Atlantic salmon parr held in fresh water. In inoculated fish, TRLO was observed intracytoplasmically in peripheral blood leucocytes, suggesting that these cells are responsible for haematogenous dispersal of the bacterium within the host. Fish with experimentally induced disease presented with gross and histopathological changes similar to TRLO-infected fish at commercial marine farms. TRLO was also isolated in culture from farmed Atlantic salmon in the Tamar River and Macquarie Harbour production areas in Tasmania, both of which have no history of TRLO-associated disease. These TRLO isolates appear to be serologically distinct from each other as well as from isolates obtained from south-east Tasmania, linking each serotype to a specific geographical location within Tasmania. Despite the lack of clinical evidence of TRLO-linked disease in fish grown in the Tamar River and Macquarie Harbour, experimental infection trials demonstrably showed the pathogenic potential of these TRLO serovars. Together, these data provide evidence that TRLO is a fastidious, facultative intracellular bacterium and confirm TRLO as a pathogen of Atlantic salmon, causing a disease designated Tasmanian salmonid rickettsiosis. PMID- 28000602 TI - Detection of infectious spleen and kidney necrosis virus (ISKNV) and turbot reddish body iridovirus (TRBIV) from archival ornamental fish samples. AB - Although infections caused by megalocytiviruses have been reported from a wide range of finfish species for several decades, molecular characterisation of the viruses involved has been undertaken only on more recent cases. Sequence analysis of the major capsid protein and adenosine triphosphatase genes is reported here from formalin-fixed, paraffin-embedded material from 2 archival ornamental fish cases from 1986 and 1988 in conjunction with data for a range of genes from fresh frozen tissues from 5 cases obtained from 1991 through to 2010. Turbot reddish body iridovirus (TRBIV) genotype megalocytiviruses, previously not documented in ornamental fish, were detected in samples from 1986, 1988 and 1991. In contrast, megalocytiviruses from 1996 onwards, including those characterised from 2002, 2006 and 2010 in this study, were almost indistinguishable from infectious spleen and kidney necrosis virus (ISKNV). Three of the species infected with TRBIV-like megalocytiviruses from 1986 to 1991, viz. dwarf gourami Trichogaster lalius (formerly Colisa lalia), freshwater angelfish Pterophyllum scalare and oscar Astronotus ocellatus, were infected with ISKNV genotype megalocytiviruses from 2002 to 2010. The detection of a TRBIV genotype isolate in ornamental fish from 1986 represents the index case, confirmed by molecular sequence data, for the genus Megalocytivirus. PMID- 28000603 TI - Development of quantitative PCR assay for detection of the trematode parasite Proctoeces maculatus in the blue mussel Mytilus edulis. AB - The digenean trematode Proctoeces maculatus is an important parasite of the blue mussel Mytilus edulis. The parasite reduces mussel quality and yield, negatively impacting mussel aquaculture efforts. Typically, the trematode is detected by visual observation. To provide a better diagnostic tool able to detect this parasite at any life stage and at low intensities, we designed a species-specific molecular assay to detect P. maculatus in M. edulis tissue. Primers targeting the 18S nuclear ribosomal DNA (rDNA) from P. maculatus were used to develop an end point polymerase chain reaction assay and a quantitative polymerase chain reaction (qPCR) assay. Analytical specificity of the assays was demonstrated using DNA from 4 other digenean trematodes. The qPCR assay was linear from 6.79 * 102 to 6.79 * 107 copies of the cloned target DNA and had a conservative detection limit of 68 copies. The qPCR assay detected single cercariae, and the number of isolated cercariae was linearly correlated with the threshold cycle (CT). Diagnostic sensitivity of the PCR-based methods was 100%. The assays also detected the parasite in 6 additional samples from the 57 tested through microscopy. We used the assays to verify the presence of encapsulated sporocysts in the mantle and to document infected mussels from Dover, New Hampshire, extending the previously described northern range of the species. Thus, this work has important implications for detection of the parasite in aquaculture and in monitoring its potential spread with climate change. PMID- 28000604 TI - Parasites, pathological conditions and resistance to Marteilia cochillia in lagoon cockle Cerastoderma glaucum from Galicia (NW Spain). AB - A histopathological survey revealed parasites and pathological conditions affecting lagoon cockles Cerastoderma glaucum along the Galician coast; serious pathological threats were not detected because the potentially pathogenic conditions (infections with a Marteilia-like parasite and bucephalid sporocysts, disseminated neoplasia and a condition involving large foci of heavy haemocytic reaction) were rare, while more prevalent parasites had negligible or limited pathogeny. Considering that C. edule and C. glaucum are sympatric in some Galician rias, it is remarkable that C. glaucum was not seriously affected by Marteilia cochillia while C. edule suffered an intense outbreak of this parasite associated with massive mortality. Comparison of the digestive gland between cockle species showed co-occurrence of digestive tubules in different phases, with abundant disintegrated tubules, in the case of C. glaucum, while C. edule showed synchronicity and absence of fully disintegrated tubules; these differences could influence their susceptibility to M. cochillia because the main location of this parasite in common cockles is the epithelia of the digestive gland. Moreover, the observation of histological sections through the digestive gland easily allows differentiating the 2 cockle species. PMID- 28000605 TI - Possible links between white plague-like disease, scleractinian corals, and a cryptochirid gall crab. AB - White plague (WP) is a highly destructive coral disease that rapidly kills susceptible coral species by mass tissue lysis. The pathogen and underlying causes of this disease are not known. In this laboratory-based study, we examined a small coral-associated gall crab from the family Cryptochiridae in terms of a possible association with WP-like lesions. A series of experiments was conducted after observations that 2 scleractinian coral species, Diploria labyrinthiformis and Pseudodiploria strigosa, developed signs of WP-like disease within a laboratory holding aquarium and that small gall crabs were physically present in the center of each lesion. Using fragments of D. labyrinthiformis, a crab from one of the lesions was sequentially removed and placed, under controlled conditions, onto apparently healthy coral colonies, resulting in the development of similar lesions. Next-generation sequencing of the 16S rRNA gene was performed to profile the bacterial communities associated with the crab, lesions, and healthy corals. The microbiota of the crab and lesions were highly similar while that of apparently healthy colonies were significantly different. Significant differences were largely due to an increase in Alphaproteobacteria in crab and lesion communities. In particular, the Roseobacter clade had a higher relative abundance in the crab and WP-like lesions. This study suggests that the cryptochirid gall crab may be associated with development of WP-like lesions. PMID- 28000606 TI - Development of Streptococcus agalactiae vaccines for tilapia. AB - Vaccination is a widely accepted and effective method to prevent most pathogenic diseases in aquaculture. Various species of tilapia, especially Nile tilapia Oreochromis niloticus, are farmed worldwide because of their high consumer demand. Recently, the tilapia-breeding industry has been hampered by outbreaks of Streptococcus agalactiae infection, which cause high mortality and huge economic losses. Many researchers have attempted to develop effective S. agalactiae vaccines for tilapia. This review provides a summary of the different kinds of S. agalactiae vaccines for tilapia that have been developed recently. Among the various vaccine types, inactivated S. agalactiae vaccines showed superior protection efficiency when compared with live attenuated, recombinant and DNA vaccines. With respect to vaccination method, injecting the vaccine into tilapia provided the most effective immunoprotection. Freund's incomplete adjuvant appeared to be suitable for tilapia vaccines. Other factors, such as immunization duration and number, fish size and challenge dose, also influenced the vaccine efficacy. PMID- 28000607 TI - Polychromatic SSVEP stimuli with subtle flickering adapted to brain-display interactions. AB - OBJECTIVE: Interactive displays armed with natural user interfaces (NUIs) will likely lead the next breakthrough in consumer electronics, and brain-computer interfaces (BCIs) are often regarded as the ultimate NUI-enabling machines to respond to human emotions and mental states. Steady-state visual evoked potentials (SSVEPs) are a commonly used BCI modality due to the ease of detection and high information transfer rates. However, the presence of flickering stimuli may cause user discomfort and can even induce migraines and seizures. With the aim of designing visual stimuli that can be embedded into video images, this study developed a novel approach to induce detectable SSVEPs using a composition of red/green/blue flickering lights. APPROACH: Based on the opponent theory of colour vision, this study used 32 Hz/40 Hz rectangular red-green or red-blue LED light pulses with a 50% duty cycle, balanced/equal luminance and 0 degrees /180 degrees phase shifts as the stimulating light sources and tested their efficacy in producing SSVEP responses with high signal-to-noise ratios (SNRs) while reducing the perceived flickering sensation. MAIN RESULTS: The empirical results from ten healthy subjects showed that dual-colour lights flickering at 32 Hz/40 Hz with a 50% duty cycle and 180 degrees phase shift achieved a greater than 90% detection accuracy with little or no flickering sensation. SIGNIFICANCE: As a first step in developing an embedded SSVEP stimulus in commercial displays, this study provides a foundation for developing a combination of three primary colour flickering backlights with adjustable luminance proportions to create a subtle flickering polychromatic light that can elicit SSVEPs at the basic flickering frequency. PMID- 28000608 TI - CP violation in the B system. AB - The phenomenon of CP violation is crucial to understand the asymmetry between matter and antimatter that exists in the Universe. Dramatic experimental progress has been made, in particular in measurements of the behaviour of particles containing the b quark, where CP violation effects are predicted by the Kobayashi Maskawa mechanism that is embedded in the standard model. The status of these measurements and future prospects for an understanding of CP violation beyond the standard model are reviewed. PMID- 28000609 TI - An in vitro 3D model using collagen coated gelatin nanofibers for studying breast cancer metastasis. AB - The study of breast cancer metastasis is limited due to poor knowledge of molecular progression of breast tumor and varied heterogeneity. For a better understanding of tumor metastasis, a reliable 3D in vitro model bridging the gap between 2D cultures and in vivo animal model studies is essential. Our study is focused on two key points: (i) designing a 3D microenvironment for studying metastasis and (ii) simulating the metastasis milieu by inducing epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET). An electrospun gelatin nanofiber matrix (EGNF) was fabricated using electrospinning and further dip coated with different concentrations of collagen to obtain surface complexity and mechanical properties, similar to connective tissues. Nanofiber matrices were physically characterized by Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and field-emission scanning electron microscopy (FESEM). The FTIR, AFM, and FESEM results indicated the crosslinking and confirmed the presence of pores in the nanofiber matrices. Comparative studies on biocompatibility, cell attachment, and the proliferation of MCF-7 cells on EGNF and collagen coated gelatin nanofibrous matrix (CCGM) revealed higher cellular attachment and proliferation in CCGM. CCGM with human metastatic breast cancer cell line (MCF-7) was taken to study breast cancer metastasis using estrogen (induces EMT) and progesterone (induces MET) hormones for 24 h. Quantitative real-time PCR was used for quantifying the expression of metastasis related genes, and fluorescence microscopy for verifying the invasion of cells to the matrices. The expression of E-cadherin and matrix metalloproteinase 2 (MMP 2) confirmed the occurrence of EMT and MET. Live cell imaging and cellular attachment showed significant increase of cellular invasion in crosslinked 0.15% CCGM that serves as a suitable non-toxic, biocompatible, and affordable scaffold for studying breast cancer metastasis. Our findings suggested that CCGM can be used as a tissue-like 3D model for studying breast cancer metastatic events in vitro. PMID- 28000610 TI - Growth and optical investigations of high quality individual CdTe/(Cd,Mg)Te core/shell nanowires. AB - CdTe nanowires with the average diameter of only 40 nm coated with (Cd,Mg)Te shells are grown using Au-catalyzed vapor-liquid-solid growth mechanism in a system for molecular beam epitaxy. High optical quality of individual nanowires is revealed by means of low temperature cathodoluminescence and micro luminescence. It is found that, the optical emission spectrum consists mostly of the near band edge emission without any significant contribution of defect related luminescence. Moreover, the importance of surface passivation with (Cd,Mg)Te coating shells is demonstrated. PMID- 28000611 TI - Micromechanical contact stiffness devices and application for calibrating contact resonance atomic force microscopy. AB - This paper reports the design, fabrication, and characterization of micromechanical devices that can present an engineered contact stiffness to an atomic force microscope (AFM) cantilever tip. These devices allow the contact stiffness between the AFM tip and a substrate to be easily and accurately measured, and can be used to calibrate the cantilever for subsequent mechanical property measurements. The contact stiffness devices are rigid copper disks of diameters 2-18 MUm integrated onto a soft silicone substrate. Analytical modeling and finite element simulations predict the elastic response of the devices. Measurements of tip-sample interactions during quasi-static force measurements compare well with modeling simulation, confirming the expected elastic response of the devices, which are shown to have contact stiffness 32-156 N m-1. To demonstrate one application, we use the disk sample to calibrate three resonant modes of a U-shaped AFM cantilever actuated via Lorentz force, at approximately 220, 450, and 1200 kHz. We then use the calibrated cantilever to determine the contact stiffness and elastic modulus of three polymer samples at these modes. The overall approach allows cantilever calibration without prior knowledge of the cantilever geometry or its resonance modes, and could be broadly applied to both static and dynamic measurements that require AFM calibration against a known contact stiffness. PMID- 28000612 TI - Post-translational modifications of linker histone H1 variants in mammals. AB - The covalent modifications of the linker histone H1 and the core histones are thought to play an important role in the control of chromatin functioning. Histone H1 variants from K562 cell line (hH1), mouse (mH1) and calf (cH1) thymi were studied by matrix-activated laser desorption/ionization fourier transform ion cyclotron resonance mass-spectroscopy (MALDI-FT-ICR-MS). The proteomics analysis revealed novel post-translational modifications of the histone H1, such as meK34-mH1.4, meK35-cH1.1, meK35-mH1.1, meK75-hH1.2, meK75-hH1.3, acK26-hH1.4, acK26-hH1.3 and acK17-hH1.1. The comparison of the hH1, mH1 and cH1 proteins has demonstrated that the types and positions of the post-translational modifications of the globular domains of the H1.2-H1.4 variants are very conservative. However, the post-translational modifications of the N- and C-terminal tails of H1.2, H1.3 and H1.4 are different. The differences of post-translational modifications in the N- and C-terminal tails of H1.2, H1.3 and H1.4 likely lead to the differences in DNA-H1 and H1-protein interactions. PMID- 28000613 TI - A depth-of-interaction PET detector using a stair-shaped reflector arrangement and a single-ended scintillation light readout. AB - Positron emission tomography (PET) detectors with the ability to encode depth-of interaction (DOI) information allow us to simultaneously improve the spatial resolution and sensitivity of PET scanners. In this study, we propose a DOI PET detector based on a stair-pattern reflector arrangement inserted between pixelated crystals and a single-ended scintillation light readout. The main advantage of the proposed method is its simplicity; DOI information is decoded from a flood map and the data can be simply acquired by using a single-ended readout system. Another potential advantage is that the two-step DOI detectors can provide the largest peak position distance in a flood map because two dimensional peak positions can be evenly distributed. We conducted a Monte Carlo simulation and obtained flood maps. Then, we conducted experimental studies using two-step DOI arrays of 5 * 5 Lu1.9Y0.1SiO5:Ce crystals with a cross-section of 1.7 * 1.7 mm2 and different detector configurations: an unpolished single-layer (US) array, a polished single-layer (PS) array and a polished stacked two-layer (PT) array. For each detector configuration, both air gaps and room-temperature vulcanization (RTV) silicone gaps were tested. Detectors US and PT showed good peak separation in each scintillator with an average peak-to-valley ratio (PVR) and distance-to-width ratio (DWR) of 2.09 and 1.53, respectively. Detector PSRTV showed lower PVR and DWR (1.65 and 1.34, respectively). The configuration of detector PTAir is preferable for the construction of time-of-flight-DOI detectors because timing resolution was degraded by only about 40 ps compared with that of a non-DOI detector. The performance of detectors USAir and PSRTV was lower than that of a non-DOI detector, and thus these designs are favorable when the manufacturing cost is more important than timing performance. The results demonstrate that the proposed DOI-encoding method is a promising candidate for PET scanners that require high resolution and sensitivity and operate with conventional acquisition systems. PMID- 28000614 TI - Self-supported Cu(OH)2@Co2CO3(OH)2 core-shell nanowire array as a robust catalyst for ammonia-borane hydrolysis. AB - High hydrogen content and long-term stability in aqueous solutions make ammonia borane (AB) a promising hydrogen-storage material. It is highly attractive but still challenging to develop efficient catalysts for real-time and controllable hydrogen release from AB solution under mild conditions. Herein, we describe the use of a three-dimensional hierarchical Cu(OH)2@Co2CO3(OH)2 core-shell nanowire array on copper foam (denoted as Cu(OH)2@Co2CO3(OH)2/CF) as a highly efficient catalyst for hydrolytic dehydrogenation of AB. The Cu(OH)2@Co2CO3(OH)2/CF works as an on/off switch for on-demand hydrogen generation with a low activation energy of 44.3 KJ mol-1 and a turnover frequency of 39.72 mol(H2)/mol(cat.)/min. It also maintains activity and integration after long-term usage. PMID- 28000615 TI - Beneficial aerodynamic effect of wing scales on the climbing flight of butterflies. AB - It is hypothesized that butterfly wing scale geometry and surface patterning may function to improve aerodynamic efficiency. In order to investigate this hypothesis, a method to measure butterfly flapping kinematics optically over long uninhibited flapping sequences was developed. Statistical results for the climbing flight flapping kinematics of 11 butterflies, based on a total of 236 individual flights, both with and without their wing scales, are presented. Results show, that for each of the 11 butterflies, the mean climbing efficiency decreased after scales were removed. Data was reduced to a single set of differences of climbing efficiency using are paired t-test. Results show a mean decrease in climbing efficiency of 32.2% occurred with a 95% confidence interval of 45.6%-18.8%. Similar analysis showed that the flapping amplitude decreased by 7% while the flapping frequency did not show a significant difference. Results provide strong evidence that butterfly wing scale geometry and surface patterning improve butterfly climbing efficiency. The authors hypothesize that the wing scale's effect in measured climbing efficiency may be due to an improved aerodynamic efficiency of the butterfly and could similarly be used on flapping wing micro air vehicles to potentially achieve similar gains in efficiency. PMID- 28000616 TI - Use of spatiotemporal templates for pathway discrimination in peripheral nerve recordings: a simulation study. AB - OBJECTIVE: Extraction of information from the peripheral nervous system can provide control signals in neuroprosthetic applications. However, the ability to selectively record from different pathways within peripheral nerves is limited. We investigated the integration of spatial and temporal information for pathway discrimination in peripheral nerves using measurements from a multi-contact nerve cuff electrode. APPROACH: Spatiotemporal templates were established for different neural pathways of interest, and used to obtain tailored matched filters for each of these pathways. Simulated measurements of compound action potentials propagating through the nerve in different test cases were used to evaluate classification accuracy, percentage of missed spikes, and ability to reconstruct the original firing rates of the neural pathways. MAIN RESULTS: The mean Pearson correlation coefficients between the original firing rates and estimated firing rates over all tests cases was found to be 0.832 +/- 0.161, 0.421 +/- 0.145, 0.481 +/- 0.340 for our algorithm, Bayesian spatial filters, and velocity selective recordings respectively. SIGNIFICANCE: The proposed method shows that the spatiotemporal templates were able to provide more robust spike detection and reliable pathway discrimination than these existing algorithms. PMID- 28000617 TI - Ex vivo detection of macrophages in atherosclerotic plaques using intravascular ultrasonic-photoacoustic imaging. AB - Macrophages are excellent imaging targets for detecting atherosclerotic plaques as they are involved in all the developmental stages of atherosclerosis. However, no imaging technique is currently capable of visualizing macrophages inside blood vessel walls. The current study develops an intravascular ultrasonic photoacoustic (IVUP) imaging system combined with indocyanine green (ICG) as a contrast agent to provide morphological and compositional information about the targeted samples. Both tissue-mimicking vessel phantoms and atherosclerotic plaque-mimicking porcine arterial tissues are used to demonstrate the feasibility of mapping macrophages labeled with ICG by endoscopically applying the proposed hybrid technique. A delay pulse triggering technique is able to sequentially acquire photoacoustic (PA) and ultrasound (US) signals from a single scan without using any external devices. The acquired PA and US signals are used to reconstruct 2D cross-sectional and 3D volumetric images of the entire tissue with the ICG-loaded macrophages injected. Due to high imaging contrast and sensitivity, the IVUP imaging vividly reveals structural information and detects the spatial distribution of the ICG-labeled macrophages inside the samples. ICG assisted IVUP imaging can be a feasible imaging modality for the endoscopic detection of atherosclerotic plaques. PMID- 28000618 TI - Effects of image noise, respiratory motion, and motion compensation on 3D activity quantification in count-limited PET images. AB - The aims of this study were to evaluate the effects of noise, motion blur, and motion compensation using quiescent-period gating (QPG) on the activity concentration (AC) distribution-quantified using the cumulative AC volume histogram (ACVH)-in count-limited studies such as 90Y-PET/CT. An International Electrotechnical Commission phantom filled with low 18F activity was used to simulate clinical 90Y-PET images. PET data were acquired using a GE-D690 when the phantom was static and subject to 1-4 cm periodic 1D motion. The static data were down-sampled into shorter durations to determine the effect of noise on ACVH. Motion-degraded PET data were sorted into multiple gates to assess the effect of motion and QPG on ACVH. Errors in ACVH at AC90 (minimum AC that covers 90% of the volume of interest (VOI)), AC80, and ACmean (average AC in the VOI) were characterized as a function of noise and amplitude before and after QPG. Scan time reduction increased the apparent non-uniformity of sphere doses and the dispersion of ACVH. These effects were more pronounced in smaller spheres. Noise related errors in ACVH at AC20 to AC70 were smaller (<15%) compared to the errors between AC80 to AC90 (>15%). The accuracy of ACmean was largely independent of the total count. Motion decreased the observed AC and skewed the ACVH toward lower values; the severity of this effect depended on motion amplitude and tumor diameter. The errors in AC20 to AC80 for the 17 mm sphere were -25% and -55% for motion amplitudes of 2 cm and 4 cm, respectively. With QPG, the errors in AC20 to AC80 of the 17 mm sphere were reduced to -15% for motion amplitudes <4 cm. For spheres with motion amplitude to diameter ratio >0.5, QPG was effective at reducing errors in ACVH despite increases in image non-uniformity due to increased noise. ACVH is believed to be more relevant than mean or maximum AC to calculate tumor control and normal tissue complication probability. However, caution needs to be exercised when using ACVH in post-therapy 90Y imaging because of its susceptibility to image degradation from both image noise and respiratory motion. PMID- 28000619 TI - Magnetic order and Mott transition on the checkerboard lattice. AB - The checkerboard lattice, with alternating 'crossed' plaquettes, serves as the two dimensional analog of the pyrochlore lattice. The corner sharing plaquette structure leads to a hugely degenerate ground state, and no magnetic order, for classical spins with short range antiferromagnetic interaction. For the half filled Hubbard model on this structure, however, we find that the Mott insulating phase involves virtual electronic processes that generate longer range and multispin couplings. These couplings lift the degeneracy, selecting a 'flux like' state in the Mott insulator. Increasing temperature leads, strangely, to a sharp crossover from this state to a '120 degree' correlated state and then a paramagnet. Decrease in the Hubbard repulsion drives the system towards an insulator-metal transition-the moments reduce, and a spin disordered state wins over the flux state. Near the insulator-metal transition the electron system displays a pseudogap extending over a large temperature window. PMID- 28000620 TI - Aerobic exercise in polluted urban environments: effects on airway defense mechanisms in young healthy amateur runners. AB - In this study, the effects of aerobic exercise on the upper airways and their defense mechanisms were investigated in athletes. The athletes ran in two different environments: the downtown streets of the city of Sao Paulo (Street), more polluted, and an urban forest (Forest), less polluted. Thirty-eight young healthy athletes ran for 45 min d-1 randomly during five consecutive days, with an interval of 48 h before changing environment. Clinical parameters and respiratory tract defense markers were evaluated before and after the first run on Mondays (1 d) and on Fridays (5 d). Street presented higher mean PM2.5 concentrations (65.1 +/- 39.1 ug m-3, p < 0.001) and lower temperature (22.0 degrees C, p = 0.010) than Forest (22.6 +/- 15.3 ug m-3 and 22.8 degrees C). After 1 d Street running, subjects showed an increment in heart rate (p < 0.001). At day 5, there was twice the number of athletes with impaired nasal mucociliary clearance (MCC) in the Street runners group when compared to the Forest runners group. Exhaled breath condensate pH values increased in the Forest group, with significant differences between groups in day 1 (p = 0.006) and day 5 (p < 0.001), despite the fact that both groups showed values within the normal range. After exposure to both environments, the number of cells in the nasal lavage fluid was reduced after exercise (p = 0.014), without alterations in cell type and IL-8 and IL-10 concentrations. Aerobic exercise can either maintain or acutely enhance MCC and it may help to regulate inflammatory responses in the airways. Here we show that exercise practice in polluted outdoor environment, over a 5 d period, impairs MCC. In contrast, athletes running in the less polluted environment (Forest) show higher exhaled breath condensate pH values when compared to those who exercised in a more polluted environment (Street). PMID- 28000621 TI - Construction of three-dimensional graphene interfaces into carbon fiber textiles for increasing deposition of nickel nanoparticles: flexible hierarchical magnetic textile composites for strong electromagnetic shielding. AB - Since manipulating electromagnetic waves with electromagnetic active materials for environmental and electric engineering is a significant task, here a novel prototype is reported by introducing reduced graphene oxide (RGO) interfaces in carbon fiber (CF) networks for a hierarchical carbon fiber/reduced graphene oxide/nickel (CF-RGO-Ni) composite textile. Upon charaterizations of the microscopic morphologies, electrical and magnetic properties, the presence of three-dimensional RGO interfaces and bifunctional nickel nanoparticles substantially influences the related physical properties in the resulting hierarchical composite textiles. Eletromagnetic interference (EMI) shielding performance suggests that the hierarchical composite textiles hold a strong shielding effectiveness greater than 61 dB, showing greater advantages than conventional polymeric and foamy shielding composites. As a polymer-free lightweight structure, flexible CF-RGO-Ni composites of all electromagnetic active components offer unique understanding of the multi-scale and multiple mechanisms in electromagnetic energy consumption. Such a novel prototype of shielding structures along with convenient technology highlight a strategy to achieve high-performance EMI shielding, coupled with a universal approach for preparing advanced lightweight composites with graphene interfaces. PMID- 28000622 TI - Finite-size effects on electronic structure and local properties in passivated AA stacked bilayer armchair-edge graphene nanoribbons. AB - Based on the tight-binding model and dual-probe scanning tunneling microscopy technology, we theoretically investigate the electronic structure and local property in the passivated AA-stacked bilayer armchair-edge graphene nanoribbons (AABLAGNRs). We show that they are highly sensitive to the size of the ribbons, which is evidently different from the single-layer armchair-edge graphene nanoribbons. The '3p' rule only applies to the narrow AABLGNRs. Namely, in the passivated 3p- and (3p + 1)-AABLGNRs, the narrow ribbons are semiconducting while the medium and wide ribbons are metallic. Although the passivated (3p + 2)-AABLGNRs are metallic, the '3j' rule only applies to the narrow and medium ribbons. Namely, electrons are in the semiconducting states at sites of line 3j while they are in the metallic states at other sites. This induces a series of parallel and discrete metallic channels, consisting of lines 3j - 1 and 3j - 2, for the low-energy electronic transports. In the passivated wide (3p + 2) AABLGNRs, all electrons are in the metallic states. Additionally, the '3p' and '3j' rules are controllable to disappear and reappear by applying an external perpendicular electric field. Resultantly, an electric filed-driven current switch can be realized in the passivated narrow and medium (3p + 2)-AABLGNRs. PMID- 28000623 TI - Attenuation measuring ultrasound shearwave elastography and in vivo application in post-transplant liver patients. AB - Ultrasound and magnetic resonance elastography techniques are used to assess mechanical properties of soft tissues. Tissue stiffness is related to various pathologies such as fibrosis, loss of compliance, and cancer. One way to perform elastography is measuring shear wave velocity of propagating waves in tissue induced by intrinsic motion or an external source of vibration, and relating the shear wave velocity to tissue elasticity. All tissues are inherently viscoelastic and ignoring viscosity biases the velocity-based estimates of elasticity and ignores a potentially important parameter of tissue health. We present attenuation measuring ultrasound shearwave elastography (AMUSE), a technique that independently measures both shear wave velocity and attenuation in tissue and therefore allows characterization of viscoelasticity without using a rheological model. The theoretical basis for AMUSE is first derived and validated in finite element simulations. AMUSE is validated against the traditional methods for assessing shear wave velocity (phase gradient) and attenuation (amplitude decay) in tissue mimicking phantoms and excised tissue. The results agreed within one standard deviation. AMUSE was used to measure shear wave velocity and attenuation in 15 transplanted livers in patients with potential acute rejection, and the results were compared with the biopsy findings in a preliminary study. The comparison showed excellent agreement and suggests that AMUSE can be used to separate transplanted livers with acute rejection from livers with no rejection. PMID- 28000624 TI - Plant leaves as natural green scaffolds for palladium catalyzed Suzuki-Miyaura coupling reactions. AB - This work presents a novel approach of using natural plant leaf surfaces having intricate hierarchical structures as scaffolds for Pd nanoparticles and demonstrated it as a Green dip catalyst for Suzuki-Miyaura coupling reactions in water. The influence of the topographical texture of the plant leaves on the deposition and catalytic properties of Pd nanoparticles are presented and discussed. The catalytic activity can be correlated to the surface texture of the leaves, wherein it has been found that the micro/nanostructures present on the surface strongly influence the assembly and entrapment of the nanoparticles, and thereby control aggregation and leaching of the catalysts. This approach can provide insights for the future design and fabrication of bioinspired supports for catalysis, based on replication of leaf surfaces. PMID- 28000625 TI - Contrast-enhanced harmonic endoscopic ultrasound: Future perspectives. PMID- 28000626 TI - Role of contrast-enhanced harmonic endoscopic ultrasound in submucosal tumors. AB - With the widespread use of endoscopy, gastrointestinal submucosal lesions are now more commonly discovered. Although endoscopic ultrasound (EUS) is superior to all other imaging techniques for the diagnosis of submucosal tumors (SMTs), it is still suboptimal for differentiating hypoechoic lesions arising from the fourth sonographic gastrointestinal wall layer, which encompass tumors with very different prognosis. EUS tissue acquisition has provided with the unique opportunity to obtain histological confirmation, but it is not accurate enough to evaluate the malignant potential of gastrointestinal stromal tumors (GISTs). In the last years, contrast-enhanced harmonic EUS (CH-EUS) emerged as a powerful imaging modality to assess the microperfusion patterns of pancreatic tumors. Based on the distinct microvascularity of malignant SMTs, it was hypothesized that CH-EUS might also assist in the differential diagnosis of SMTs. Preliminary experience in this field is now available and suggests CH-EUS as a performant modality to distinguish between benign SMTs and GISTs and to evaluate the malignant potential of GISTs. High expectations are also relied on CH-EUS for the monitoring of antiangiogenic treatments of GISTs and the evaluation of gastrointestinal neuroendocrine tumors (NETs). PMID- 28000627 TI - The role of contrast-enhanced endoscopic ultrasound in pancreatic adenocarcinoma. AB - Contrast-enhanced endoscopic ultrasound (CE-EUS) allows characterization, differentiation, and staging of focal pancreatic masses. The method has a high sensitivity and specificity for the diagnosis of pancreatic adenocarcinoma which is visualized as hypo-enhanced as compared to the rest of the parenchyma while chronic pancreatitis and neuroendocrine tumors are generally either iso-enhanced or hyper-enhanced. The development of contrast-enhanced low mechanical index harmonic imaging techniques used in real time during endoscopic ultrasound (EUS) allowed perfusion imaging and the quantification of intensity of the contrast signal through time-intensity curve analysis. Thus, contrast harmonic imaging-EUS has been used to differentiate pancreatic adenocarcinoma based on lower values of the peak enhancement. Future applications of CE-EUS in pancreatic adenocarcinoma include not only use of targeted contrast agents for early detection, tridimensional and fusion techniques for enhanced staging and resectability assessment but also novel applications of perfusion imaging for monitoring ablative therapy, improved local detection through EUS-guided sampling of portal vein flow or enhanced drug delivery through sonoporation and ultrasound-induced release of the drugs locally. PMID- 28000628 TI - Role of contrast harmonic endoscopic ultrasonography in other pancreatic solid lesions: Neuroendocrine tumors, autoimmune pancreatitis and metastases. AB - Contrast harmonic endoscopic ultrasonography (CH-EUS) is a new technique which allows the dynamic study of the microvascularization of a target tissue. Its application is validated for the diagnosis of pancreatic adenocarcinoma but remains unclear for other solid pancreatic tumors (neuroendocrine tumors [NETs], autoimmune pancreatitis [AIP], metastases). The purpose of this review is to outline the potential role of the CH-EUS in these indications. NETs are typically iso/hyperenhanced at CH-EUS, and a heterogeneous enhancement seems a good predictor of malignancy in neuroendocrine pancreatic tumor. AIP is often iso/hyperenhanced at CH-EUS. Quantitative analysis of time-intensity parameters is promising for the distinction between pancreatic adenocarcinoma and AIP. The appearance of pancreatic metastases at CH-EUS is various depending on the origin of the primary tumor. Data from the literature remain to this day weak to determine the role of the CH-EUS in the management of rare solid tumor of the pancreas (NETs, AIP, and metastases). Specific studies are expected to further clarify the impact of this procedure in this field. PMID- 28000629 TI - Effectiveness of contrast-enhanced endoscopic ultrasound for detecting mural nodules in intraductal papillary mucinous neoplasm of the pancreas and for making therapeutic decisions. AB - BACKGROUND AND OBJECTIVES: There have been few studies to date evaluating the effectiveness of contrast-enhanced endoscopic ultrasound (CE-EUS) for detecting mural nodules in patients with branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN) of the pancreas. We aim to evaluate the effectiveness of CE EUS for detecting mural nodules in BD-IPMN. PATIENTS AND METHODS: Of the 427 BD IPMN patients, 21 patients (4.9%) in whom the presence of mural nodules was suggested by CE computed tomography (CT) or magnetic resonance imaging (MRI), or in whom the presence of nodule-like lesions as shown by fundamental EUS, were examined by CE-EUS. RESULTS: The mean diameter of cystic lesions was 29.8 +/- 12.8 mm. The mean diameter of mural nodules was 9.5 +/- 5.7 mm. BD-IPMN was detected in the pancreatic head in 16 cases, pancreatic body in 2 cases, and pancreatic tail in 3 cases. The mean follow-up period was 17.2 +/- 11.9 months. The detection rates of mural nodule-like lesions in BD-IPMN patients on CT, MRI, and fundamental EUS were 36.8%, 63.2%, and 100%, respectively. The detection rates of true mural nodules in BD-IPMN patients on CT, MRI, and fundamental EUS were 85.7%, 71.4%, and 100%, respectively. The echo levels of mural nodule-like lesions on fundamental EUS were hyperechoic in 6 patients, isoechoic in 9 patients, and hypoechoic in 6 patients. The final diagnosis was mucus lumps in 14 patients and mural nodules in 7 patients. The contrast patterns observed were avascular, isovascular, and hypervascular in 14, 3, and 4 patients, respectively. No patients showed a hypovascular pattern. Fourteen patients showing an avascular pattern were diagnosed as having mucus lumps, and they were able to avoid surgical resection. Of the 7 patients who were diagnosed as having mural nodules, 5 underwent surgical resection. The pathological findings were adenocarcinoma in 2 patients and adenoma in 3 patients. Of the 3 adenoma patients, fundamental EUS demonstrated a hypoechoic area in 1 patient and an isoechoic area in 2 patients. Of the 2 adenocarcinoma patients, 1 each showed a hypoechoic area and a hyperechoic area. It was difficult to distinguish between patients with adenoma and patients with adenocarcinoma using the echo levels obtained from fundamental EUS. CONCLUSIONS: CE-EUS may be useful for avoiding the overdiagnosis of BD-IPMN with mural nodule-like lesions. However, it has difficulty in distinguishing between clearly benign and malignant lesions in BD-IPMN. PMID- 28000630 TI - Can contrast-enhanced harmonic endosonography predict malignancy risk in gastrointestinal subepithelial tumors? AB - BACKGROUND AND OBJECTIVES: Contrast-enhanced harmonic endoscopic ultrasound (CEH EUS) is a novel technology that can identify subepithelial tumors (SETs) by detecting the degree of enhancement, but whether CEH-EUS can predict the malignancy risk of gastrointestinal stromal tumors (GISTs) remains unclear. The aim of our study was to evaluate the diagnostic accuracy of CEH-EUS and its ability to discriminate among SETs and predict the malignancy risk of GISTs. MATERIALS AND METHODS: We retrospectively included patients with suspected subepithelial lesions who underwent CEH-EUS preoperatively. Thirty-five patients with histologically proven GISTs and benign neoplasms were enrolled in the study. The images of CEH-EUS were categorized in accordance with microvasculature, parenchymal perfusion, and nonenhancing spots. The diagnostic performance of CEH EUS was evaluated by comparing these findings with the histological diagnosis. RESULTS: When we divided the enrolled patients into high- and low-grade malignancy and benign groups, nonenhancing spots on CEH-EUS were found more frequently in the high-grade malignancy group (63.6%), followed by the low-grade malignancy (46.7%) and benign groups (25.7%) (P = 0.022). However, based on the statistical validity of the CEH-EUS findings for the discrimination of SETs, the sensitivity was 53.8% for diagnostic performance and 63.6% for prediction of malignancy risk of GISTs. CONCLUSIONS: From our study results, it is unclear whether CEH-EUS alone has a diagnostic role in the discrimination of SETs and the prediction of malignancy risk of GISTs. Further studies with larger samples from multiple centers and use of other imaging analysis modalities are needed. PMID- 28000631 TI - Evaluation of the viability of hepatocellular carcinoma in the caudate lobe using contrast-enhanced endoscopic ultrasonography after transarterial chemoembolization. AB - A 71-year-old female was diagnosed with hepatocellular carcinoma (HCC). The tumor measured 65 mm in diameter and was located in the caudate lobe. Transarterial chemoembolization (TACE) was performed repeatedly; however, a follow-up dynamic computed tomography (CT) scan showed that the tumor remained viable. Thus, TACE was performed using drug-eluting beads that had been preloaded with epirubicin. Contrast-enhanced endoscopic ultrasonography (CE-EUS) was conducted for evaluating the treatment effects. First, we detected the internal part of the tumor. Then, a perflubutane suspension was injected intravenously. Next, CE-EUS was performed for the external ventral part of the tumor in the same manner. The perflubutane flowed into the tumor and spread into both its internal and external ventral regions. Thus, we considered that the tumor was still viable and planned to carry out TACE again. CE-EUS could be a useful tool for evaluating the treatment effects of TACE on HCC deep inside the liver. PMID- 28000632 TI - An unusual cause of dysphagia: Isolated IgG 4-related esophageal disease. PMID- 28000633 TI - Endoscopic ultrasound features of pancreatic schwannoma. PMID- 28000634 TI - Closure of echoendoscope-related duodenal free wall perforation by placement of a covered metallic stent. PMID- 28000635 TI - The health of internally displaced persons. PMID- 28000636 TI - A review of the health problems of the internally displaced persons in Africa. AB - Globally, over 40 million people were displaced as a result of wars and violence due to religious and ethnic conflicts in 2015 while 19.2 million were displaced by natural disasters such as famine and floods. In Africa, 12 million people were displaced by armed conflict and violence and there were hundreds of thousands of people displaced by natural disasters. Despite these large numbers of internally displaced persons (IDPs) in Sub-Saharan African countries and the potentially negative impact of displacement on the health of these populations, there is limited information on the health problems of IDPs in the region. The previous studies have mainly focused on the health problems of refugees and single disease entities among IDPs. However, a more comprehensive picture is required to inform the provision of adequate healthcare services for this vulnerable population. The objective of this review was to fill this knowledge gap. Bibliographic databases were searched and screened, and nine studies were selected and reviewed. The major physical health problems and symptoms were fever/malaria (85% in children and 48% in adults), malnutrition in children (stunting 52% and wasting 6%), malnutrition in adult males (24%), diarrhoea (62% in children and 22% in adults) and acute respiratory infections (45%). The prevalent mental health problems were post-traumatic stress disorder (range: 42%-54%) and depression (31%-67%). Most of the studies reviewed focused on mental health problems. Limited evidence suggests that IDPs experience various health problems but more research is required to inform the provision of adequate and comprehensive healthcare services for this group of individuals. PMID- 28000637 TI - Cohort event monitoring of patients treated for uncomplicated malaria with artemisinin-based combination therapies in selected hospitals and community pharmacies in Nigeria. AB - AIMS AND OBJECTIVES: The study was designed with the broad objective of determining the safety profile of artemisinin-based combination therapies amongst Nigerian population. PATIENTS AND METHODS: This was a cohort event monitoring (CEM) programme involving monitoring adverse events (AEs) in malaria patients treated with either artemether-lumefantrine (AL) or artesunate-amodiaquine (AA) in healthcare facilities in Nigeria. The study involved continuous enrolment of patients with malaria and treated with either AL or AA at the various sites until a total cohort of 600 patients were enrolled at each site. Patients were monitored from the onset of therapy, and on days 3 and 7 from the first day of treatment to identify AEs that may occur. RESULTS: A total of 6102 AEs were recorded in 10,259 patients monitored during the programme. Of 4896 patients who received AA, 4233 (86.5%) patients reported at least one AE while 1869 (34.8%) AEs out of 5363 patients who received AL were reported (P = 0.010). The predominant incidence of each specific AE reported in each group among the patients who received AA and AL includes body weakness 30.8%/7.5%, dizziness 10.3%/3.9%, restlessness 5.02/1.12%, vomiting 3.5/1.03% and drowsiness 3.1/1.5% for AA and AL, respectively. There were more AEs among patients with co-morbid conditions and patients in the younger age groups (9-<15 years), P = 0.000. CONCLUSIONS: Various types of AEs were seen and documented during the CEM programme. The findings suggested that the AA/AL monitored during this programme was generally safe and remarkably well tolerated among the Nigerian populations. PMID- 28000638 TI - Pattern and predictive factors of health-related quality of life of patients with hypertension, diabetes and concomitant hypertension with diabetes in Ilorin, Nigeria. AB - BACKGROUND: Hypertension and diabetes are the two most important modifiable risk factors for cardiovascular disease (CVD) among Nigerian population. Because of the lifelong nature of the two diseases and the attendant long treatment regimen required, assessing the health-related quality of life (HRQoL) is an important outcome of these diseases. OBJECTIVE: This study assessed the pattern and predictive factors of HRQoL among patients with hypertension, diabetes and concomitant hypertension and diabetes using the 36-item short-form version 2. PATIENTS AND METHODS: A cross-sectional study of 1203 patients attending the outpatient clinics of the University of Ilorin Teaching Hospital, Ilorin; the patients were sampled using systematic random sampling methods. Patients were divided into those with hypertension, diabetes and both diseases. The predictors of physical and mental component summaries of HRQoL were analysed using Norm based Scoring. The level of significance was set at P < 0.05 and 95% confidence interval. RESULTS: The patients with both diseases have lowest physical HRQoL (45.6), while the diabetic patients have the worst mental HRQoL (39.5). Negative predictors of physical HRQoL across the three groups were: drug regimen (hypertension P < 0.001, diabetes P < 0.001, both P = 0.005), CVD complication (hypertension P < 0.001, diabetes P = 0.025) and accompanying persons (P < 0.001). The positive predictors of physical HRQoL across the three groups were medication adherence (hypertension P < 0.001, diabetes P < 0.001 and both P = 0.002). Similarly, medication adherence was the positive predictor for mental HRQoL across the three groups of patients (hypertension P < 0.001, diabetes P = 0.001 and both P < 0.001). CONCLUSION: This study provided evidence to show that HRQoL across the three categories of patients in Ilorin, Nigeria, is suboptimal. Drug regimen, medication adherence and support from accompanying persons were important predictive factors of HRQoL. PMID- 28000639 TI - Relationship between gross placental characteristics and perinatal outcome of low risk singleton deliveries. AB - BACKGROUND: Gross examination of the placenta may provide useful insight into the aetiology of newborn and maternal complications. A review of literature revealed only a few epidemiological studies that determined the relationships between placental abnormalities, gestational age and occurrence of adverse outcome in babies of healthy pregnant women in our region. PATIENTS AND METHODS: A prospective cross-sectional study was conducted at the Department of Obstetrics and Gynecology of University of Ilorin Teaching Hospital, between 1 st February and August 2013. Pregnant women in labour at >=28 weeks' gestational age with singleton pregnancies were recruited. Gross examination of the placenta and umbilical cord after delivery were performed. RESULTS: Four hundred and twenty eight singleton deliveries were studied. The average placental weight was 580.8 +/- 130.6 g (range = 125-1500 g). The mean values of the umbilical cord length and width were 52.7 +/- 10.5 cm and 1.96 +/- 1.11 cm, respectively. Placental abnormalities occurred in 1.2%. The umbilical cord was centrally inserted in 290 (67.8%), marginally in 31% of cases. There was significant but weak positive correlation between the placental weight, birth weight and gestational age at 40 weeks (P <= 0.001, r = 0.356). Placental weight was directly related to birth weight (P < 0.0001, r = 0.244) and greater in babies with congenital abnormalities (P = 0.002). CONCLUSIONS: There was an association between placental parameters and foetal outcome at birth. Placental weight was positively correlated with birth weight, gestational age and occurrence of congenital abnormalities. PMID- 28000640 TI - Prevalence and pattern of amblyopia among primary school pupils in Kosofe town, Lagos state, Nigeria. AB - OBJECTIVE: The objective of this study was to determine the prevalence and pattern of amblyopia in primary school pupils in Kosofe town of Lagos State with a view to providing baseline data that may facilitate the establishment of routine school eye screening programs in primary schools in Lagos State. MATERIALS AND METHODS: A descriptive, cross-sectional study was conducted among pupils from public and private primary schools in Kosofe town. The pupils underwent visual acuity assessment with the HOTV charts, detailed ocular examinations and cycloplegic refractions. Data obtained were analysed using the Statistical Package for Social Sciences version 20.0. RESULTS: A total of 1702 pupils participated in the study, out of which 899 (52.8%) were males. The age range was 4-16 years with 1630 (95.8%) pupils within the ages of 4 and 10. Amblyopia was detected in 24 (1.4%) of the screened pupils (95% confidence interval = 0.610-0.914). There was no significant sex predilection (P = 0.367) or age trend (P = 0.158) in this study although amblyopia occurred more in boys (54.2%). Refractive amblyopia (58.4%) was the most common type of amblyopia out of which anisometropic amblyopia accounted for 78.6%. Unilateral amblyopia was observed in 87.5% of the amblyopic pupils, and the left eye was more commonly affected than the right eye. All the types of amblyopia were more common within the age group of 4-10 years and in public school children (P = 0.039 and P = 0.015, respectively). CONCLUSION: The prevalence of amblyopia in this study was low and it falls within the general prevalence range for amblyopia in Nigeria. PMID- 28000641 TI - Difference in occurrence of muscle-related adverse effects of statins among male and female geriatric patients: A cross-sectional observational study. AB - BACKGROUND: Statins are the most widely used agents for the treatment of dyslipidaemias in geriatric patients. Muscle-related adverse effects (MRAE) are one of the most common toxicities of statins. Female gender has been mentioned as the risk factor for the development of MRAE of statins; however, there are inconclusive data regarding the difference in the occurrence of MRAE among male and female geriatric users. OBJECTIVES: The main objective was to find the difference in the occurrence of MRAE of statins among male and female geriatric statin users. METHODS: In this cross-sectional, observational, comparative study, relevant patient information and MRAE associated with statin use were noted. Creatine phosphokinase (CPK) levels were obtained for all patients as this is considered as the marker for statin-induced muscle damage. The parameters were compared among male and female geriatric statin users. RESULTS: 172 geriatric patients (86 male and 86 female statin users) were enrolled in the study. 38 (22%) geriatric statin users were found to have MRAE and significantly more number of female patients had MRAE as compared to male patients (25 vs. 13 P = 0.02). Significantly more number of female patients had elevated CPK as compared to male patients (20 vs. 8, P = 0.01). No significant difference was observed in CPK levels among male and female statin users. CONCLUSIONS: Statin-induced MRAE tend to occur with more frequency in geriatric female patients as compared to male geriatric patients; however, further research in the form of prospective studies is warranted. PMID- 28000642 TI - Evaluation of seroprevalence of Hepatitis B virus infection among patients attending a hospital of semi-urban North India using rapid immunoassay test. AB - BACKGROUND: Viral hepatitis is a serious public health problem with hepatitis B virus (HBV) being one of its principle causes affecting billions of people globally. The laboratory diagnosis of HBV infection is made by detection of hepatitis B surface antigen (HBsAg) in serum. OBJECTIVE: The present study was done to evaluate the seroprevalence of hepatitis B infection among patients attending a hospital at a semi-urban North India using rapid immunoassay test kit. MATERIALS AND METHODS: A total of 1537 patients were included in the study whose venous blood samples were collected, and serum was tested for the presence of HBsAg using a rapid one-step immunoassay test kit. RESULTS: Out of 1537 patients whose blood samples were tested, 61 were found to be reactive to HBsAg giving the prevalence to be 3.9%, with 49 males and 12 females. Out of 61 reactive patient's majority belonged to inpatient (82.0%) as compared to outpatient department (18.0%). The majority of the reactive patients belonged to age group 28-37 years (37.7%), belonged to rural areas (86.9%), were illiterate (67.2%), were skilled workers (63.9%) and belonged to socioeconomic Class 4 (50.8%). Among the reactive patients, the most frequent suspected risk factor for hepatitis B infection was found to be visiting a community barber (19.7%). CONCLUSION: HBV infection is a dreadful disease, and its accurate and timely diagnosis using rapid immunoassay test kit is useful as it gives an indication about its seroprevalence in a given geographical area even with limited resources. PMID- 28000643 TI - Pattern of presentation and outcome of routine dental interventions in patients with halitosis. AB - AIMS: The aims of this study were to describe the pattern of presentation of halitosis and to evaluate the success rate following routine dental intervention irrespective of the type of halitosis. PATIENTS AND METHODS: This cross-sectional study was conducted among sixty consecutive patients who presented in our Oral Diagnosis and Oral Medicine Clinic, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, on account of halitosis from May 2015 to April 2016. Diagnosis of halitosis was made using the organoleptic method from a whole mouth breath test as described by Miyazaki et al., 1999. Halitosis was assessed before treatment, 2 and 6 weeks after treatment. The results were analysed with STATA statistical software version 11. RESULTS: Sixty out of 305 patients seen in the clinics during the study period had halitosis, with a prevalence of 19.5%. Fourteen (23%) patients had pseudohalitosis while 46 (77%) had genuine halitosis; no case of halitophobia was seen. Majority (71.6%) brush their teeth once daily. The predominant extra-oral etiologic factors were respiratory 2 (3.3%) and ear, nose and throat disorders 1 (1.6%). Twenty-nine (63%) patients with genuine halitosis who had organoleptic scores of >=4 had no perceivable odour, following routine dental interventions (P < 0.001); the remaining 17 (37%) patients only had slight malodour. Similarly, all the 14 (100%) patients with pseudohalitosis had complete remission after the treatment. CONCLUSIONS: The prevalence of halitosis was 19.5%, with male predilection. Routine dental interventions achieved >90% success rate. Preventive oral care is recommended for all halitosis patients. PMID- 28000644 TI - Comparative analysis of cleaning ability of three nickel-titanium rotary systems: ProTaper universal, K3 and Mtwo: An in vitro scanning electron microscopic study. AB - BACKGROUND: Endodontic instruments including the nickel-titanium (NiTi) instruments produce debris and smear layer during instrumentation. The study was carried out to evaluate and compare the cleaning effectiveness of root canal preparation using three different rotary NiTi instrumentation systems - ProTaper Universal, K3 and Mtwo by means of scanning electron microscopy (SEM). METHODS: Thirty-six freshly extracted permanent mandibular molars were randomly divided into four groups: ProTaper Universal, K3, Mtwo system and control group. The mesiobuccal canal was cleaned and shaped with rotary instruments. The intracanal irrigant used after each instrument was 3 mL of 3% sodium hypochlorite (NaOCl). After the cleaning and shaping was completed, a 1-min 17% ethylenediaminetetraacetic acid rinse was followed by a final NaOCl rinse. All samples were decoronated. Mesial roots were sectioned buccolingually and examined under SEM at 500* magnification in three areas of root canal. Canal walls were quantitatively evaluated using a five-score evaluation scale. Statistical analysis was done using Kruskal-Wallis test, Fisher's exact test and weighted kappa. RESULTS: Completely clean canals were not found in any of the groups. The mean value of debris score for ProTaper, K3 and Mtwo was 2.35, 2.41 and 2.22 respectively. There was no statistically significant difference between the three tested groups (P = 0.237). The apical thirds of the canal was found to be significantly less clean than coronal and middle thirds irrespective of the system used. CONCLUSIONS: There was no statistically significant difference between the three tested groups - ProTaper, K3 and Mtwo in cleaning different regions of the canal - coronal, middle and apical. PMID- 28000645 TI - Assessment of satisfaction levels of patients during dental outreach programs in rural part of Udaipur, India. AB - BACKGROUND: The community-based dental outreach programs play a very crucial role in declining discovery-delivery disconnect by introducing awareness through health education and dental adumbrating services to the community members. However, the success of any oral health programme depends largely on how it meets the needs and expectations of the target community. Therefore, the present study was designed for the assessment of patient satisfaction at various rural outreach dental camps conducted over a period of 2 months. MATERIALS AND METHODS: The present study was conducted on patients visiting weekly and monthly outreach dental programmes organised by the Department of Public Health Dentistry. Data were obtained from a total of 298 patients using a pre-tested questionnaire as a survey instrument. The questionnaire consisted of nine questions, measuring the patient satisfaction levels on a five-point Likert scale. RESULTS: The highest mean satisfaction score (4.97 +/- 0.59) was observed for the question on the overall performance of camp, whereas waiting time for treatment, quality of the treatment and explanation of need for referral exhibited lowest mean scores. The mean satisfaction scores for the monthly camp (4.55 +/- 0.52) were significantly higher as compared to the weekly camps (4.38 +/- 0.55) (P = 0.013). CONCLUSION: The results of the study showed that the patient satisfaction scores were satisfactory to good for various aspects of the weekly and monthly dental outreach programmes. Such programmes should be conducted on regular basis, and comprehensive oral care should be provided. PMID- 28000646 TI - Renal cell carcinoma in a horseshoe kidney: Report of a rare disease. AB - A horseshoe kidney (HSK) is the most common congenital renal fusion anomaly. HSKs are more likely than normal kidneys to have associated problems of stones, ureteropelvic junction obstruction, stasis and infection. However, they do not have an increased incidence of renal cell carcinoma when compared to normal kidneys. Due to its rarity, accurate diagnosis may be difficult. Of similar significance is the fact that problems may arise during surgery on these kidneys due to altered anatomy and aberrant blood supply. We report a case of HSK with a renal tumour in a 69-year-old woman and highlight our challenges in the management of the case. To the best of our knowledge, this is the first reported case of a tumour in an HSK in West Africa. PMID- 28000648 TI - Robotics in general surgery: A systematic cost assessment. AB - The utilisation of robotic-assisted techniques is a novelty in the field of general surgery. Our intention was to examine the up to date available literature on the cost assessment of robotic surgery of diverse operations in general surgery. PubMed and Scopus databases were searched in a systematic way to retrieve the included studies in our review. Thirty-one studies were retrieved, referring on a vast range of surgical operations. The mean cost for robotic, open and laparoscopic ranged from 2539 to 57,002, 7888 to 16,851 and 1799 to 50,408 Euros, respectively. The mean operative charges ranged from 273.74 to 13,670 Euros. More specifically, for the robotic and laparoscopic gastric fundoplication, the cost ranged from 1534 to 2257 and 657 to 763 Euros, respectively. For the robotic and laparoscopic colectomy, it ranged from 3739 to 17,080 and 3109 to 33,865 Euros, respectively. For the robotic and laparoscopic cholecystectomy, ranged from 1163.75 to 1291 and from 273.74 to 1223 Euros, respectively. The mean non-operative costs ranged from 900 to 48,796 from 8347 to 8800 and from 870 to 42,055 Euros, for robotic, open and laparoscopic technique, respectively. Conversions to laparotomy were present in 34/18,620 (0.18%) cases of laparoscopic and in 22/1488 (1.5%) cases of robotic technique. Duration of surgery robotic, open and laparoscopic ranged from 54.6 to 328.7, 129 to 234, and from 50.2 to 260 min, respectively. The present evidence reveals that robotic surgery, under specific conditions, has the potential to become cost-effective. Large number of cases, presence of industry competition and multidisciplinary team utilisation are some of the factors that could make more reasonable and cost effective the robotic-assisted technique. PMID- 28000650 TI - Systematic review and meta-analysis of single-incision versus conventional multiport laparoscopic splenectomy. AB - BACKGROUND: There is no consensus that single-incision laparoscopic surgery splenectomy (SILS-SP) is on a par with conventional multiport laparoscopic surgery splenectomy (CMLS-SP). AIMS: The aim of this systematic review and meta analysis was to assess feasibility and safety of SILS-SP when compared with CMLS SP. MATERIALS AND METHODS: Eligible articles were identified by searching several databases including PubMed, EMBASE, CNKI (China) and the Cochrane Library, up until February 2016. Studies were reviewed independently and rated by Newcastle Ottawa Quality Assessment Scale. Evaluated outcomes were complications, operative time, post-operative hospital stay, blood loss, starting diet, post-operative pain scores, conversion and analgesic requirements. RESULTS: Ten retrospective studies met the eligibility criteria. Overall, there was no significant difference between SILS-SP and CMLS-SP in complications, operative time, post operative hospital stay, blood loss, starting diet, post-operative pain scores, conversion and analgesic requirements. CONCLUSIONS: SILS-SP is feasible and safe in certain patients, with no obvious advantages over CMLS-SP. Therefore, it may be considered an alternative to CMLS-SP. We await high-quality, double-blind RCTs. These should include clear statements on standard scores of post-operative pain and cosmetic results, longer follow-up assessment and cost-benefit analysis. PMID- 28000658 TI - Evaluation of Left Ventricular Ejection Fractions in Breast Cancer Patients Undergoing Long-Term Trastuzumab Treatment. AB - BACKGROUND The aim of this study was to assess the long-term clinical tolerance and cardiac safety during trastuzumab treatment for patients diagnosed as having breast cancer with human epidermal growth factor receptor 2 (HER2) overexpression. MATERIAL AND METHODS A total 105 female cases diagnosed as having breast cancer with high expression of Her2, were treated with trastuzumab (T). All of them underwent electrocardiography monitoring in the process of T treatment. Left ventricular ejection fractions (LVEFs) were estimated using echocardiography before the T treatment and every 3 months. General clinical data and above parameters were collected and reviewed as analysis. RESULTS The mean value of LVEFs with baseline was higher than those at other time points. All LVEFs were more than 50% during the course of trastuzumab treatment. The decline scope >=15% of LVEFs ranged from 2 months to 16 months, and the ratios were counted for 3.1% at 2 months, 4.3% at 6 months, 3.8% at 10 months, and 5.4% at 16 months. Furthermore, a larger decrease of LVEF during the course occurred mainly in the patients with cumulative dose of A >300 mg/m2, without CPD and 16-month duration of T treatment. There was a strong correlation between cumulative dose of A, cyto/cardio-protection drugs (CPD), duration of T, and the change of LVEF (P=0.82, P=0.744, and P=0.717, respectively), which indicated that 3 factors may be associated with the change in LVEF (P<0.05). CONCLUSIONS The LVEF in patients with trastuzumab treatment was significantly decreased, which may be seen as a favorable benefit-risk ratio for patients undergoing long-term trastuzumab treatment. PMID- 28000659 TI - Highly conserved Z and molecularly diverged W chromosomes in the fish genus Triportheus (Characiformes, Triportheidae). AB - The main objectives of this study were to test: (1) whether the W-chromosome differentiation matches to species' evolutionary divergence (phylogenetic concordance) and (2) whether sex chromosomes share a common ancestor within a congeneric group. The monophyletic genus Triportheus (Characiformes, Triportheidae) was the model group for this study. All species in this genus so far analyzed have ZW sex chromosome system, where the Z is always the largest chromosome of the karyotype, whereas the W chromosome is highly variable ranging from almost homomorphic to highly heteromorphic. We applied conventional and molecular cytogenetic approaches including C-banding, ribosomal DNA mapping, comparative genomic hybridization (CGH) and cross-species whole chromosome painting (WCP) to test our questions. We developed Z- and W-chromosome paints from T. auritus for cross-species WCP and performed CGH in a representative species (T. signatus) to decipher level of homologies and rates of differentiation of W chromosomes. Our study revealed that the ZW sex chromosome system had a common origin, showing highly conserved Z chromosomes and remarkably divergent W chromosomes. Notably, the W chromosomes have evolved to different shapes and sequence contents within ~15-25 Myr of divergence time. Such differentiation highlights a dynamic process of W-chromosome evolution within congeneric species of Triportheus. PMID- 28000661 TI - Temporal stability and molecular persistence of the bone marrow plasma cell antibody repertoire. AB - Plasma cells in human bone marrow (BM) are thought to be responsible for sustaining lifelong immunity, but its underlying basis is controversial. Here we use high-throughput sequence analysis of the same individual across 6.5 years to show that the BM plasma cell immunoglobulin heavy chain repertoire is remarkably stable over time. We find a nearly static bias in individual and combinatorial gene usage across time. Analysis of a second donor corroborates these observations. We also report the persistence of numerous BM plasma cell clonotypes (~2%) identifiable at all points assayed across 6.5 years, supporting a model of serological memory based upon intrinsic longevity of human plasma cells. Donors were adolescents who completely recovered from neuroblastoma prior to the start of this study. Our work will facilitate differentiation between healthy and diseased antibody repertoires, by serving as a point of comparison with future deep-sequencing studies involving immune intervention. PMID- 28000660 TI - A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units. AB - Type I modular polyketide synthases assemble diverse bioactive natural products. Such multienzymes typically use malonyl and methylmalonyl-CoA building blocks for polyketide chain assembly. However, in several cases more exotic alkylmalonyl-CoA extender units are also known to be incorporated. In all examples studied to date, such unusual extender units are biosynthesized via reductive carboxylation of alpha, beta-unsaturated thioesters catalysed by crotonyl-CoA reductase/carboxylase (CCRC) homologues. Here we show using a chemically synthesized deuterium-labelled mechanistic probe, and heterologous gene expression experiments that the unusual alkylmalonyl-CoA extender units incorporated into the stambomycin family of polyketide antibiotics are assembled by direct carboxylation of medium chain acyl-CoA thioesters. X-ray crystal structures of the unusual beta-subunit of the acyl-CoA carboxylase (YCC) responsible for this reaction, alone and in complex with hexanoyl-CoA, reveal the molecular basis for substrate recognition, inspiring the development of methodology for polyketide bio-orthogonal tagging via incorporation of 6 azidohexanoic acid and 8-nonynoic acid into novel stambomycin analogues. PMID- 28000662 TI - Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow. AB - Hematopoietic stem cells (HSCs) in the endosteum of mesoderm-derived appendicular bones have been extensively studied. Neural crest-derived bones differ from appendicular bones in developmental origin, mode of bone formation and pathological bone resorption. Whether neural crest-derived bones harbor HSCs is elusive. Here, we discovered HSC-like cells in postnatal murine mandible, and benchmarked them with donor-matched, mesoderm-derived femur/tibia HSCs, including clonogenic assay and long-term culture. Mandibular CD34 negative, LSK cells proliferated similarly to appendicular HSCs, and differentiated into all hematopoietic lineages. Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Remarkably, mandibular HSCs reconstituted irradiated hematopoietic bone marrow in vivo, just as appendicular HSCs. Genomic profiling of osteoblasts from mandibular and femur/tibia bone marrow revealed deficiencies in several HSC niche regulators among mandibular osteoblasts including Cxcl12. Neural crest derived bone harbors HSCs that function similarly to appendicular HSCs but are deficient in the lymphoid lineage. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw. PMID- 28000663 TI - Robust fractional quantum Hall effect in the N=2 Landau level in bilayer graphene. AB - The fractional quantum Hall effect is a canonical example of electron-electron interactions producing new ground states in many-body systems. Most fractional quantum Hall studies have focussed on the lowest Landau level, whose fractional states are successfully explained by the composite fermion model. In the widely studied GaAs-based system, the composite fermion picture is thought to become unstable for the N>=2 Landau level, where competing many-body phases have been observed. Here we report magneto-resistance measurements of fractional quantum Hall states in the N=2 Landau level (filling factors 4<|nu|<8) in bilayer graphene. In contrast with recent observations of particle-hole asymmetry in the N=0/N=1 Landau levels of bilayer graphene, the fractional quantum Hall states we observe in the N=2 Landau level obey particle-hole symmetry within the fully symmetry-broken Landau level. Possible alternative ground states other than the composite fermions are discussed. PMID- 28000664 TI - Endothelial-specific inhibition of NF-kappaB enhances functional haematopoiesis. AB - Haematopoietic stem cells (HSCs) reside in distinct niches within the bone marrow (BM) microenvironment, comprised of endothelial cells (ECs) and tightly associated perivascular constituents that regulate haematopoiesis through the expression of paracrine factors. Here we report that the canonical NF-kappaB pathway in the BM vascular niche is a critical signalling axis that regulates HSC function at steady state and following myelosuppressive insult, in which inhibition of EC NF-kappaB promotes improved HSC function and pan-haematopoietic recovery. Mice expressing an endothelial-specific dominant negative IkappaBalpha cassette under the Tie2 promoter display a marked increase in HSC activity and self-renewal, while promoting the accelerated recovery of haematopoiesis following myelosuppression, in part through protection of the BM microenvironment following radiation and chemotherapeutic-induced insult. Moreover, transplantation of NF-kappaB-inhibited BM ECs enhanced haematopoietic recovery and protected mice from pancytopenia-induced death. These findings pave the way for development of niche-specific cellular approaches for the treatment of haematological disorders requiring myelosuppressive regimens. PMID- 28000665 TI - A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan. AB - In gonadal tissues, the Piwi-interacting (piRNA) pathway preserves genomic integrity by employing 23-29 nucleotide (nt) small RNAs complexed with argonaute proteins to suppress parasitic mobile sequences of DNA called transposable elements (TEs). Although recent evidence suggests that the piRNA pathway may be present in select somatic cells outside the gonads, the role of a non-gonadal somatic piRNA pathway is not well characterized. Here we report a functional somatic piRNA pathway in the adult Drosophila fat body including the presence of the piRNA effector protein Piwi and canonical 23-29 nt long TE-mapping piRNAs. The piwi mutants exhibit depletion of fat body piRNAs, increased TE mobilization, increased levels of DNA damage and reduced lipid stores. These mutants are starvation sensitive, immunologically compromised and short-lived, all phenotypes associated with compromised fat body function. These findings demonstrate the presence of a functional non-gonadal somatic piRNA pathway in the adult fat body that affects normal metabolism and overall organismal health. PMID- 28000666 TI - Ultrafast electronic response of graphene to a strong and localized electric field. AB - The way conduction electrons respond to ultrafast external perturbations in low dimensional materials is at the core of the design of future devices for (opto)electronics, photodetection and spintronics. Highly charged ions provide a tool for probing the electronic response of solids to extremely strong electric fields localized down to nanometre-sized areas. With ion transmission times in the order of femtoseconds, we can directly probe the local electronic dynamics of an ultrathin foil on this timescale. Here we report on the ability of freestanding single layer graphene to provide tens of electrons for charge neutralization of a slow highly charged ion within a few femtoseconds. With values higher than 1012 A cm-2, the resulting local current density in graphene exceeds previously measured breakdown currents by three orders of magnitude. Surprisingly, the passing ion does not tear nanometre-sized holes into the single layer graphene. We use time-dependent density functional theory to gain insight into the multielectron dynamics. PMID- 28000667 TI - Folding of xylan onto cellulose fibrils in plant cell walls revealed by solid state NMR. AB - Exploitation of plant lignocellulosic biomass is hampered by our ignorance of the molecular basis for its properties such as strength and digestibility. Xylan, the most prevalent non-cellulosic polysaccharide, binds to cellulose microfibrils. The nature of this interaction remains unclear, despite its importance. Here we show that the majority of xylan, which forms a threefold helical screw in solution, flattens into a twofold helical screw ribbon to bind intimately to cellulose microfibrils in the cell wall. 13C solid-state magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, supported by in silico predictions of chemical shifts, shows both two- and threefold screw xylan conformations are present in fresh Arabidopsis stems. The twofold screw xylan is spatially close to cellulose, and has similar rigidity to the cellulose microfibrils, but reverts to the threefold screw conformation in the cellulose deficient irx3 mutant. The discovery that induced polysaccharide conformation underlies cell wall assembly provides new principles to understand biomass properties. PMID- 28000668 TI - Demarcation of Prime Farmland Protection Areas around a Metropolis Based on High Resolution Satellite Imagery. AB - Prime farmland (PF) is defined as high-quality farmland and a prime farmland protection area (PFPA, including related roads, waters and facilities) is a region designated for the special protection of PF. However, rapid urbanization in China has led to a tremendous farmland loss and to the degradation of farmland quality. Based on remote sensing and geographic information system technology, this study developed a semiautomatic procedure for designating PFPAs using high resolution satellite imagery (HRSI), which involved object-based image analysis, farmland composite evaluation, and spatial analysis. It was found that the HRSIs can provide elaborate land-use information, and the PFPA demarcation showed strong correlation with the farmland area and patch distance. For the benefit of spatial planning and management, different demarcation rules should be applied for suburban and exurban areas around a metropolis. Finally, the overall accuracy of HRSI classification was about 80% for the study area, and high-quality farmlands from evaluation results were selected as PFs. About 95% of the PFs were demarcated within the PFPAs. The results of this study will be useful for PFPA planning and the methods outlined could help in the automatic designation of PFPAs from the perspective of the spatial science. PMID- 28000670 TI - Strong confinement-induced engineering of the g factor and lifetime of conduction electron spins in Ge quantum wells. AB - Control of electron spin coherence via external fields is fundamental in spintronics. Its implementation demands a host material that accommodates the desirable but contrasting requirements of spin robustness against relaxation mechanisms and sizeable coupling between spin and orbital motion of the carriers. Here, we focus on Ge, which is a prominent candidate for shuttling spin quantum bits into the mainstream Si electronics. So far, however, the intrinsic spin dependent phenomena of free electrons in conventional Ge/Si heterojunctions have proved to be elusive because of epitaxy constraints and an unfavourable band alignment. We overcome these fundamental limitations by investigating a two dimensional electron gas in quantum wells of pure Ge grown on Si. These epitaxial systems demonstrate exceptionally long spin lifetimes. In particular, by fine tuning quantum confinement we demonstrate that the electron Lande g factor can be engineered in our CMOS-compatible architecture over a range previously inaccessible for Si spintronics. PMID- 28000669 TI - A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation. AB - Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization and there remains no pediatric vaccine. RSV live-attenuated vaccines (LAVs) have a history of safe testing in infants; however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we seek to engineer an RSV LAV with enhanced immunogenicity. Genetic mapping identifies strain line 19 fusion (F) protein residues that correlate with pre-fusion antigen maintenance by ELISA and thermal stability of infectivity in live RSV. We generate a LAV candidate named OE4 which expresses line 19F and is attenuated by codon deoptimization of non-structural (NS1 and NS2) genes, deletion of the small hydrophobic (SH) gene, codon-deoptimization of the attachment (G) gene and ablation of the secreted form of G. OE4 (RSV-A2-dNS1-dNS2-DeltaSH-dGm-Gsnull line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats. PMID- 28000671 TI - Local synthesis of dynein cofactors matches retrograde transport to acutely changing demands. AB - Cytoplasmic dynein mediates retrograde transport in axons, but it is unknown how its transport characteristics are regulated to meet acutely changing demands. We find that stimulus-induced retrograde transport of different cargos requires the local synthesis of different dynein cofactors. Nerve growth factor (NGF)-induced transport of large vesicles requires local synthesis of Lis1, while smaller signalling endosomes require both Lis1 and p150Glued. Lis1 synthesis is also triggered by NGF withdrawal and required for the transport of a death signal. Association of Lis1 transcripts with the microtubule plus-end tracking protein APC is required for their translation in response to NGF stimulation but not for their axonal recruitment and translation upon NGF withdrawal. These studies reveal a critical role for local synthesis of dynein cofactors for the transport of specific cargos and identify association with RNA-binding proteins as a mechanism to establish functionally distinct pools of a single transcript species in axons. PMID- 28000672 TI - A small electron donor in cobalt complex electrolyte significantly improves efficiency in dye-sensitized solar cells. AB - Photoelectrochemical approach to solar energy conversion demands a kinetic optimization of various light-induced electron transfer processes. Of great importance are the redox mediator systems accomplishing the electron transfer processes at the semiconductor/electrolyte interface, therefore affecting profoundly the performance of various photoelectrochemical cells. Here, we develop a strategy-by addition of a small organic electron donor, tris(4 methoxyphenyl)amine, into state-of-art cobalt tris(bipyridine) redox electrolyte to significantly improve the efficiency of dye-sensitized solar cells. The developed solar cells exhibit efficiency of 11.7 and 10.5%, at 0.46 and one-sun illumination, respectively, corresponding to a 26% efficiency improvement compared with the standard electrolyte. Preliminary stability tests showed the solar cell retained 90% of its initial efficiency after 250 h continuous one-sun light soaking. Detailed mechanistic studies reveal the crucial role of the electron transfer cascade processes within the new redox system. PMID- 28000673 TI - The Crystal Structure of Monovalent Streptavidin. AB - The strong interaction between streptavidin (SA) and biotin is widely utilized in biotechnological applications. A SA variant, monovalent SA, was developed with a single and high affinity biotin-binding site within the intact tetramer. However, its structural characterization remains undetermined. Here, we seek to determine the crystal structure of monovalent SA at 1.7-A resolution. We show that, in contrast to its 'close-state' in the only wild-type subunit, the L3,4 loops of three Dead SA subunits are free from crystal packing and remain in an 'open state', stabilized by a consistent H-bonding network involving S52. This H bonding network also applies to the previously reported open state of the wild type apo-SA. These results suggest that specific substitutions (N23A/S27D/S45A) at biotin-binding sites stabilize the open state of SA L3,4 loop, thereby further reducing biotin-binding affinity. The general features of the 'open state' SA among different SA variants may facilitate its rational design. The structural information of monovalent SA will be valuable for its applications across a wide range of biotechnological areas. PMID- 28000674 TI - Observing coherence effects in an overdamped quantum system. AB - It is usually considered that the spectrum of an optical cavity coupled to an atomic medium does not exhibit a normal-mode splitting unless the system satisfies the strong coupling condition, meaning the Rabi frequency of the coherent coupling exceeds the decay rates of atom and cavity excitations. Here we show that this need not be the case, but depends on the way in which the coupled system is probed. Measurements of the reflection of a probe laser from the input mirror of an overdamped cavity reveal an avoided crossing in the spectrum that is not observed when driving the atoms directly and measuring the Purcell-enhanced cavity emission. We understand these observations by noting a formal correspondence with electromagnetically induced transparency of a three-level atom in free space, where our cavity acts as the absorbing medium and the coupled atoms play the role of the control field. PMID- 28000675 TI - Suppressed ion-scale turbulence in a hot high-beta plasma. AB - An economic magnetic fusion reactor favours a high ratio of plasma kinetic pressure to magnetic pressure in a well-confined, hot plasma with low thermal losses across the confining magnetic field. Field-reversed configuration (FRC) plasmas are potentially attractive as a reactor concept, achieving high plasma pressure in a simple axisymmetric geometry. Here, we show that FRC plasmas have unique, beneficial microstability properties that differ from typical regimes in toroidal confinement devices. Ion-scale fluctuations are found to be absent or strongly suppressed in the plasma core, mainly due to the large FRC ion orbits, resulting in near-classical thermal ion confinement. In the surrounding boundary layer plasma, ion- and electron-scale turbulence is observed once a critical pressure gradient is exceeded. The critical gradient increases in the presence of sheared plasma flow induced via electrostatic biasing, opening the prospect of active boundary and transport control in view of reactor requirements. PMID- 28000676 TI - Pressure induced enhancement of the magnetic ordering temperature in rhenium(IV) monomers. AB - Materials that demonstrate long-range magnetic order are synonymous with information storage and the electronics industry, with the phenomenon commonly associated with metals, metal alloys or metal oxides and sulfides. A lesser known family of magnetically ordered complexes are the monometallic compounds of highly anisotropic d-block transition metals; the 'transformation' from isolated zero dimensional molecule to ordered, spin-canted, three-dimensional lattice being the result of through-space interactions arising from the combination of large magnetic anisotropy and spin-delocalization from metal to ligand which induces important intermolecular contacts. Here we report the effect of pressure on two such mononuclear rhenium(IV) compounds that exhibit long-range magnetic order under ambient conditions via a spin canting mechanism, with Tc controlled by the strength of the intermolecular interactions. As these are determined by intermolecular distance, 'squeezing' the molecules closer together generates remarkable enhancements in ordering temperatures, with a linear dependence of Tc with pressure. PMID- 28000677 TI - Nutrient enrichment modifies temperature-biodiversity relationships in large scale field experiments. AB - Climate effects and human impacts, that is, nutrient enrichment, simultaneously drive spatial biodiversity patterns. However, there is little consensus about their independent effects on biodiversity. Here we manipulate nutrient enrichment in aquatic microcosms in subtropical and subarctic regions (China and Norway, respectively) to show clear segregation of bacterial species along temperature gradients, and decreasing alpha and gamma diversity toward higher nutrients. The temperature dependence of species richness is greatest at extreme nutrient levels, whereas the nutrient dependence of species richness is strongest at intermediate temperatures. For species turnover rates, temperature effects are strongest at intermediate and two extreme ends of nutrient gradients in subtropical and subarctic regions, respectively. Species turnover rates caused by nutrients do not increase toward higher temperatures. These findings illustrate direct effects of temperature and nutrients on biodiversity, and indirect effects via primary productivity, thus providing insights into how nutrient enrichment could alter biodiversity under future climate scenarios. PMID- 28000678 TI - The effects of prebiotics on microbial dysbiosis, butyrate production and immunity in HIV-infected subjects. AB - Altered interactions between the gut mucosa and bacteria during HIV infection seem to contribute to chronic immune dysfunction. A deeper understanding of how nutritional interventions could ameliorate gut dysbiosis is needed. Forty-four subjects, including 12 HIV+ viremic untreated (VU) patients, 23 antiretroviral therapy-treated (ART+) virally suppressed patients (15 immunological responders and 8 non-responders) and 9 HIV- controls (HIV-), were blindly randomized to receive either prebiotics (scGOS/lcFOS/glutamine) or placebo (34/10) over 6 weeks in this pilot study. We assessed fecal microbiota composition using deep 16S rRNA gene sequencing and several immunological and genetic markers involved in HIV immunopathogenesis. The short dietary supplementation attenuated HIV-associated dysbiosis, which was most apparent in VU individuals but less so in ART+ subjects, whose gut microbiota was found more resilient. This compositional shift was not observed in the placebo arm. Significantly, declines in indirect markers of bacterial translocation and T-cell activation, improvement of thymic output, and changes in butyrate production were observed. Increases in the abundance of Faecalibacterium and Lachnospira strongly correlated with moderate but significant increases of butyrate production and amelioration of the inflammatory biomarkers soluble CD14 and high-sensitivity C-reactive protein, especially among VU. Hence, the bacterial butyrate synthesis pathway holds promise as a viable target for interventions. PMID- 28000680 TI - Pretreatment with antibiotics may enhance the efficacy of fecal microbiota transplantation in ulcerative colitis: a meta-analysis. PMID- 28000679 TI - Mycobacterium tuberculosis cell wall released fragments by the action of the human lung mucosa modulate macrophages to control infection in an IL-10-dependent manner. AB - Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, is a major public health challenge facing the world. During infection, M.tb is deposited in the lung alveolar space where it comes in contact with the lung mucosa, known as alveolar lining fluid (ALF), an environment that M.tb encounters at different stages of the infection and disease. ALF is abundant in homeostatic and antimicrobial hydrolytic enzymes, also known as hydrolases. Here we demonstrate that ALF hydrolases, at their physiological concentrations and upon contact with M.tb, release M.tb cell envelope fragments into the milieu. These released fragments are bioactive, but non-cytotoxic, regulate the function of macrophages, and thus are capable of modulating the immune response contributing to the control of M.tb infection by human macrophages. Specifically, macrophages exposed to fragments derived from the exposure of M.tb to ALF were able to control the infection primarily by increasing phagosome-lysosome fusion and acidification events. This enhanced control was found to be dependent on fragment induced interleukin-10 (IL-10) production but also involves the STAT3 signaling pathway in an IL-10-independent manner. Collectively our data indicate that M.tb fragments released upon contact with lung mucosa hydrolases participate in the host immune response to M.tb infection through innate immune modulation. PMID- 28000681 TI - The dynamics of filament assembly define cytoskeletal network morphology. AB - The actin cytoskeleton is a key component in the machinery of eukaryotic cells, and it self-assembles out of equilibrium into a wide variety of biologically crucial structures. Although the molecular mechanisms involved are well characterized, the physical principles governing the spatial arrangement of actin filaments are not understood. Here we propose that the dynamics of actin network assembly from growing filaments results from a competition between diffusion, bundling and steric hindrance, and is responsible for the range of observed morphologies. Our model and simulations thus predict an abrupt dynamical transition between homogeneous and strongly bundled networks as a function of the actin polymerization rate. This suggests that cells may effect dramatic changes to their internal architecture through minute modifications of their nonequilibrium dynamics. Our results are consistent with available experimental data. PMID- 28000682 TI - Electronic single-molecule identification of carbohydrate isomers by recognition tunnelling. AB - Carbohydrates are one of the four main building blocks of life, and are categorized as monosaccharides (sugars), oligosaccharides and polysaccharides. Each sugar can exist in two alternative anomers (in which a hydroxy group at C-1 takes different orientations) and each pair of sugars can form different epimers (isomers around the stereocentres connecting the sugars). This leads to a vast combinatorial complexity, intractable to mass spectrometry and requiring large amounts of sample for NMR characterization. Combining measurements of collision cross section with mass spectrometry (IM-MS) helps, but many isomers are still difficult to separate. Here, we show that recognition tunnelling (RT) can classify many anomers and epimers via the current fluctuations they produce when captured in a tunnel junction functionalized with recognition molecules. Most importantly, RT is a nanoscale technique utilizing sub-picomole quantities of analyte. If integrated into a nanopore, RT would provide a unique approach to sequencing linear polysaccharides. PMID- 28000683 TI - Elemental analysis of infant airborne particulate exposures. AB - Air pollution is hypothesized to have negative impacts on infant pulmonary health because of infants' increased rates of respiration and ongoing lung development. The severity and type of impact may differ depending on elemental concentrations. We conducted a study of 21 infants <6 months old whose parents carried a small personal particulate monitoring device (RTI MicroPEM) and GPS unit with the infant for 7 days in January and February 2015. The study area was Utah County, UT, USA. Real-time particulate exposure levels, as well as optical density and elemental analysis of the particulate matter (PM), were compared with levels from an outdoor stationary monitor. Infants spent an average of 87.4% of their time indoors. PM levels varied widely by infant and time of day (average=19.07 MUg/m3, range=0.63-170.25 MUg/m3). Infant particulate exposures were not well approximated by the outdoor monitor. Infants had lower exposures to Sb, Mn, Pb, W and Fe than the outdoor monitor and higher exposures to Cd, Ni and Na. Differences were most pronounced for Na. Brown carbon was only detected by personal monitors and not by the outdoor monitor. Further research is needed to understand the potential implications of indoor elemental exposures on early respiratory development. PMID- 28000684 TI - Levels and determinants of tree pollen in New York City. AB - Exposure to allergenic tree pollen is a risk factor for multiple allergic disease outcomes. Little is known about how tree pollen levels vary within cities and whether such variation affects the development or exacerbation of allergic disease. Accordingly, we collected integrated pollen samples at uniform height at 45 sites across New York City during the 2013 pollen season. We used these monitoring results in combination with adjacent land use data to develop a land use regression model for tree pollen. We evaluated four types of land use variables for inclusion in the model: tree canopy, distributed building height (a measure of building volume density), elevation, and distance to water. When included alone in the model, percent tree canopy cover within a 0.5 km radial buffer explained 39% of the variance in tree pollen (1.9% increase in tree pollen per one-percentage point increase in tree canopy cover, P<0.0001). The inclusion of additional variables did not improve model fit. We conclude that intra-urban variation in tree canopy is an important driver of tree pollen exposure. Land use regression models can be used to incorporate spatial variation in tree pollen exposure in studies of allergic disease outcomes. PMID- 28000685 TI - Update on dietary intake of perchlorate and iodine from U.S. food and drug administration's total diet study: 2008-2012. AB - The U.S. Food and Drug Administration's (FDA) Total Diet Study (TDS) monitors the US food supply for pesticide residues, industrial chemicals, radionuclides, nutrients, and toxic elements. Perchlorate and iodine intakes based on concentrations in TDS samples collected between 2008 and 2012 were estimated in order to update an earlier TDS dietary assessment. Perchlorate is used as an oxidizing agent in rocket and missile fuel, is formed naturally in the atmosphere, and occurs naturally in some soils. Because of perchlorate's presence in soil, and in irrigation, processing, and source water, it is widely found in food. Iodine was included in the study because perchlorate at high doses interferes with iodide uptake in the thyroid. Iodine (the elemental form of iodide) is essential for growth and development, and metabolism. This study uses a novel statistical method based on a clustered zero-inflated lognormal distribution model to estimate mean and 95th percentile confidence interval concentrations for perchlorate and iodine in US foods. These estimates were used to estimate mean perchlorate and iodine exposures for the total US population and for 14 age/sex groups in the US population. Estimated mean perchlorate intake for the total US population was 0.13 MUg/kg bw/day, with mean intakes for the 14 age/sex groups between 0.09 and 0.43 MUg/kg bw/day. The estimated mean intakes of perchlorate for all age/sex groups were below EPA's reference dose (RfD) of 0.7 MUg/kg bw/day. The estimated mean iodine intake for the total US population was 216.4 MUg/person/day, with mean intakes ranging from 140.9 to 296.3 MUg/person/day for the 14 age/sex groups, with all age/sex groups exceeding their respective estimated average requirements (EARs). PMID- 28000686 TI - An accurate filter loading correction is essential for assessing personal exposure to black carbon using an Aethalometer. AB - The AE51 micro-Aethalometer (microAeth) is a popular and useful tool for assessing personal exposure to particulate black carbon (BC). However, few users of the AE51 are aware that its measurements are biased low (by up to 70%) due to the accumulation of BC on the filter substrate over time; previous studies of personal black carbon exposure are likely to have suffered from this bias. Although methods to correct for bias in micro-Aethalometer measurements of particulate black carbon have been proposed, these methods have not been verified in the context of personal exposure assessment. Here, five Aethalometer loading correction equations based on published methods were evaluated. Laboratory generated aerosols of varying black carbon content (ammonium sulfate, Aquadag and NIST diesel particulate matter) were used to assess the performance of these methods. Filters from a personal exposure assessment study were also analyzed to determine how the correction methods performed for real-world samples. Standard correction equations produced correction factors with root mean square errors of 0.10 to 0.13 and mean bias within +/-0.10. An optimized correction equation is also presented, along with sampling recommendations for minimizing bias when assessing personal exposure to BC using the AE51 micro-Aethalometer. PMID- 28000687 TI - Long-term recall accuracy for mobile phone calls in young Japanese people: A follow-up validation study using software-modified phones. AB - This study examined changes in recall accuracy for mobile phone calls over a long period. Japanese students' actual call statuses were monitored for 1 month using software-modified phones (SMPs). Three face-to-face interviews were conducted to obtain information regarding self-reported call status during the monitoring period: first interview: immediately after the monitoring period; second interview: after 10-12 months; third interview: after 48-55 months. Using the SMP records as the "gold standard", phone call recall accuracy was assessed for each interview. Data for 94 participants were analyzed. The number of calls made was underestimated considerably and the duration of calls was overestimated slightly in all interviews. Agreement between self-report and SMP records regarding the number of calls, duration of calls and laterality (i.e., use of the dominant ear while making calls) gradually deteriorated with the increase in the interval following the monitoring period (number of calls: first interview: Pearson's r=0.641, third interview: 0.396; duration of calls: first interview: Pearson's r=0.763, third interview: 0.356; laterality: first interview: weighted kappa=0.677, third interview: 0.448). Thus, recall accuracy for mobile phone calls would be consistently imperfect over a long period, and the results of related epidemiological studies should be interpreted carefully. PMID- 28000688 TI - Direct observation of exceptional points in coupled photonic-crystal lasers with asymmetric optical gains. AB - Although counter-intuitive features have been observed in non-Hermitian optical systems based on micrometre-sized cavities, the achievement of a simplified but unambiguous approach to enable the efficient access of exceptional points (EPs) and the phase transition to desired lasing modes remains a challenge, particularly in wavelength-scale coupled cavities. Here, we demonstrate coupled photonic-crystal (PhC) nanolasers with asymmetric optical gains, and observe the phase transition of lasing modes at EPs through tuning of the area of graphene cover on one PhC cavity and systematic scanning photoluminescence measurements. As the gain contrast between the two identical PhC cavities exceeds the intercavity coupling, the phase transition occurs from the bonding/anti-bonding lasing modes to the single-amplifying lasing mode, which is confirmed by the experimental measurement of the mode images and the theoretical modelling of coupled cavities with asymmetric gains. In addition, we demonstrate active tuning of EPs by controlling the optical loss of graphene through electrical gating. PMID- 28000689 TI - Comparison of flax (Linum usitatissimum) and Salba-chia (Salvia hispanica L.) seeds on postprandial glycemia and satiety in healthy individuals: a randomized, controlled, crossover study. AB - BACKGROUND/OBJECTIVES: Flax and Salba-chia seeds have risen in popularity owing to their favorable nutrient composition, including a high fiber content. Despite having comparable nutritional profiles, preliminary observations suggest differences in gelling properties, an attribute that may alter the kinetics of food digestion. Thus, we compared the effect of two seeds on postprandial glycemia and satiety scores. SUBJECTS/METHODS: Fifteen healthy participants (M/F: 5/10; age: 23.9+/-3 years; BMI: 22.2+/-0.8 kg/m2) were randomized to receive a 50 g glucose challenge, alone or supplemented with either 25 g ground Salba-chia or 31.5 g flax, on three separate occasions. Blood glucose samples and satiety ratings were collected at fasting and over 2-h postprandially. In addition, in vitro viscosity of the beverages was assessed utilizing standard rheological methodology. RESULTS: Both Salba-chia and flax reduced blood glucose area under the curve over 120 min by 82.5+/-19.7 mmol/l (P<0.001) and 60.0+/-19.7 mmol/l (P=0.014), respectively, relative to a glucose control. Salba-chia reduced peak glucose (-0.64+/-0.24 mmol/l; P=0.030) and increased time to peak (11.3+/-3.8 min; P=0.015) compared with flax. Salba-chia significantly reduced the mean ratings of desire to eat (-7+/-2 mm; P=0.005), prospective consumption (-7+/-2 mm; P=0.010) and overall appetite score (-6+/-2 mm; P=0.012), when compared with flax. The viscosity of Salba-chia, flax and control was 49.9, 2.5, and 0.002 Pa.s, respectively. CONCLUSIONS: Despite the similarities in nutritional composition, Salba-chia appears to have the ability to convert glucose into a slow-release carbohydrate and affect satiety to a greater extent than flax, possibly due to the higher fiber viscosity. Incorporation of either flax or Salba chia into the diet may be beneficial, although use of Salba-chia may confer additional benefit. PMID- 28000690 TI - The need to standardize ad libitum eating protocols in dietary fibre appetite research. PMID- 28000691 TI - Consultation with registered dietitian to prevent accidental reactions to food: insight from an egg allergy influenza vaccination cohort. AB - Egg is an ubiquitous allergen found in many food products. Current food allergy guidelines recognize the importance of consultation with a registered dietitian to ensure nutritional adequacy. However, there is a lack of evidence on its impact on the implementation of allergen avoidance strategies. Taking advantage of a well-characterized cohort of influenza vaccination in egg-allergic children (n=397), we tested the hypothesis that real-life professional dietary advice was associated with a decrease in accidental reactions to egg in allergic children with retrospective questionnaires. Lack of consultation with a dietitian was associated with a 1.89-fold increase in the risk of accidental reactions to egg (confidence interval: 1.47-2.42). The only other independent variable that predicted reactions was having had a history of acute reaction to egg prior diagnosis (relative risk=2.02; confidence interval: 1.64-3.00). These findings support the usefulness of referral to a food allergy-specialized dietitian at time of diagnosis in order to prevent future accidental reactions to egg. PMID- 28000692 TI - Impact of maternal, antenatal and birth-associated factors on iron stores at birth: data from a prospective maternal-infant birth cohort. AB - BACKGROUND/OBJECTIVES: Low serum ferritin concentrations at birth, which reflect neonatal iron stores, track through to early childhood and have been associated with poorer neurodevelopmental outcomes. We aimed to identify maternal, antenatal and birth-associated factors that influence iron stores at birth in a prospective maternal-infant birth cohort. SUBJECTS/METHODS: In a population-based, longitudinal, birth cohort in Ireland, 413 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks' gestation had umbilical cord serum ferritin concentrations measured. Regression models were developed to identify independent factors associated with cord ferritin concentrations. RESULTS: Median (IQR) cord ferritin concentrations were 185.7 (131.7, 385.5) MUg/l, and 8% (n=33) of infants had low iron stores (ferritin <76 MUg/l) at birth. Maternal obesity (BMI ?30 kg/m2) at 15 weeks' gestation (adj. estimate (95% confidence interval (CI)): -66.4 (-106.9, -25.9) MUg/l, P<0.0001) and delivery by caesarean section (-38.8 (-70.2, -7.4) MUg/l, P=0.016) were inversely associated with cord ferritin concentrations. In addition, maternal smoking at 15 weeks' gestation (adj. odds ratio (95% CI): 2.9 (1.2, 7), P=0.020) and being born small-for-gestational age (3.4 (1.3, 8.9), P=0.012) were associated with an increased risk of low iron stores (ferritin <76 MUg/l) at birth. CONCLUSIONS: We have identified a number of potentially modifiable lifestyle factors that influence iron stores at birth, with the important role of overall maternal health and lifestyle during pregnancy highlighted. Public health policies targeting women of child-bearing age to improve nutrition and health outcomes should be prioritised for the health of the next generation. PMID- 28000694 TI - Access policies in biobank research: what criteria do they include and how publicly available are they? A cross-sectional study. AB - Access policies of biobanks specify the governance of sample and data sharing. Basic guidance on relevant access criteria exists, but so far little is known about their public availability and what criteria for access and prioritization they actually include. Access policies were gathered by hand searching the websites of biobanks identified via registries (eg, BBMRI and P3G), and by additional search strategies. Criteria for access and prioritization were synthesized by thematic analysis. Of 523 biobank websites screened, 9% included a publicly available access policy. With all applied search strategies, we finally retrieved 74 access policies. Thematic analysis resulted in 62 different access criteria in three main categories: (a) scientific quality, (b) value and (c) ethical soundness. 'Scientific quality' criteria were mentioned in 70% of all policies, 'value' criteria in 33% and 'ethical soundness' criteria in 73%. Criteria for prioritization were specified in 27% of all policies. Access policies differed broadly in number, specification and operationalization of the included access criteria. In order to make biobank research more effective, efficient and trustworthy, access policies should be more available to the public. Furthermore, access policies should aim for precise and more harmonized wording of access criteria. From a public and governance perspective, the issue of how to prioritize access to scarce samples should form part of access policies. PMID- 28000693 TI - Consumption of a high-fat breakfast on consecutive days alters preclinical biomarkers for atherosclerosis. AB - BACKGROUND/OBJECTIVES: Recent research has speculated that the risk of developing atherosclerosis is due to the accumulation of the effects of daily diet choices. The purpose of this study was to examine which of our previously identified preclinical disease risk biomarkers were further elevated when consuming a high fat (644+/-50 kcal; 100% recommended dietary allowance for fat), high-calorie (1118+/-100 kcal; 70% daily caloric needs) breakfast on consecutive days. Young, normal weight females (N=7) participated in this study. SUBJECTS/METHODS: Blood samples were taken premeal and hourly for 5-h postprandial. Serum biomarkers (C peptide, eotaxin, gastric inhibitory polypeptide, granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), insulin, leptin, monocyte chemoattractant protein 1, pancreatic polypeptide (PPY) and tumor necrosis factor-alpha), monocyte concentration, and adhesion molecule expression (CD11a, CD18 and CD54) were measured. Area under the curve was calculated for each outcome variable as a function of day and data were analyzed for significance. RESULTS: We found significant (P<0.05) increases on Day 2 for: GM-CSF (+47%; P=0.041), G-CSF (+31%; P=0.012), PPY (+51%; P=0.049), total monocyte (+110%; P=0.043), pro-inflammatory (PI) monocyte (+60%; P=0.012), PI monocyte CD18 (+960%; P=0.003), PI monocyte CD11a (+230%; P=0.006), and PI monocyte CD54 (+208%; P=0.015). CONCLUSIONS: To our knowledge, the present study is the first to report changes in selected biomarkers and monocytes following eating a high-fat, high-calorie breakfast on consecutive days in humans. More research is needed to determine how transient the observed changes are and what the long-term implications for disease risk are. PMID- 28000695 TI - A two-stage inter-rater approach for enrichment testing of variants associated with multiple traits. AB - Shared genetic aetiology may explain the co-occurrence of diseases in individuals more often than expected by chance. On identifying associated variants shared between two traits, one objective is to determine whether such overlap may be explained by specific genomic characteristics (eg, functional annotation). In clinical studies, inter-rater agreement approaches assess concordance among expert opinions on the presence/absence of a complex disease for each subject. We adapt a two-stage inter-rater agreement model to the genetic association setting to identify features predictive of overlap variants, while accounting for their marginal trait associations. The resulting corrected overlap and marginal enrichment test (COMET) also assesses enrichment at the individual trait level. Multiple categories may be tested simultaneously and the method is computationally efficient, not requiring permutations to assess significance. In an extensive simulation study, COMET identifies features predictive of enrichment with high power and has well-calibrated type I error. In contrast, testing for overlap with a single-trait enrichment test has inflated type I error. COMET is applied to three glycaemic traits using a set of functional annotation categories as predictors, followed by further analyses that focus on tissue-specific regulatory variants. The results support previous findings that regulatory variants in pancreatic islets are enriched for fasting glucose-associated variants, and give insight into differences/similarities between characteristics of variants associated with glycaemic traits. Also, despite regulatory variants in pancreatic islets being enriched for variants that are marginally associated with fasting glucose and fasting insulin, there is no enrichment of shared variants between the traits. PMID- 28000696 TI - Meta-analysis of quantitative pleiotropic traits for next-generation sequencing with multivariate functional linear models. AB - To analyze next-generation sequencing data, multivariate functional linear models are developed for a meta-analysis of multiple studies to connect genetic variant data to multiple quantitative traits adjusting for covariates. The goal is to take the advantage of both meta-analysis and pleiotropic analysis in order to improve power and to carry out a unified association analysis of multiple studies and multiple traits of complex disorders. Three types of approximate F distributions based on Pillai-Bartlett trace, Hotelling-Lawley trace, and Wilks's Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants. Simulation analysis is performed to evaluate false-positive rates and power of the proposed tests. The proposed methods are applied to analyze lipid traits in eight European cohorts. It is shown that it is more advantageous to perform multivariate analysis than univariate analysis in general, and it is more advantageous to perform meta analysis of multiple studies instead of analyzing the individual studies separately. The proposed models require individual observations. The value of the current paper can be seen at least for two reasons: (a) the proposed methods can be applied to studies that have individual genotype data; (b) the proposed methods can be used as a criterion for future work that uses summary statistics to build test statistics to meta-analyze the data. PMID- 28000697 TI - The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America. AB - Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. HD occurs worldwide, but the causative mutation is found on different HTT haplotypes in distinct ethnic groups. In Latin America, HD is thought to have European origins, but indigenous Amerindian ancestry has not been investigated. Here, we report dense HTT haplotypes in 62 mestizo Peruvian HD families, 17 HD families from across Latin America, and 42 controls of defined Peruvian Amerindian ethnicity to determine the origin of HD in populations of admixed Amerindian and European descent. HD in Peru occurs most frequently on the A1 HTT haplotype (73%), as in Europe, but on an unexpected indigenous variant also found in Amerindian controls. This Amerindian A1 HTT haplotype predominates over the European A1 variant among geographically disparate Latin American controls and in HD families from across Latin America, supporting an indigenous origin of the HD mutation in mestizo American populations. We also show that a proportion of HD mutations in Peru occur on a C1 HTT haplotype of putative Amerindian origin (14%). The majority of HD mutations in Latin America may therefore occur on haplotypes of Amerindian ancestry rather than on haplotypes resulting from European admixture. Despite the distinct ethnic ancestry of Amerindian and European A1 HTT, alleles on the parent A1 HTT haplotype allow for development of identical antisense molecules to selectively silence the HD mutation in the greatest proportion of patients in both Latin American and European populations. PMID- 28000698 TI - Mosaicism and prenatal diagnosis options: insights from retinoblastoma. AB - In sporadic cases, a post-zygotic mutational event signifies a somatic mosaicism in the affected child only, which implies that these mutations affect only a portion of the body. Therefore siblings do not need follow-up. On the other hand, a pre-zygotic mutation transmitted by an unaffected mosaic parent implies recurrent risks in offspring. To better estimate the contribution of pre- and post-zygotic events, we analysed 124 consecutive bilateral retinoblastoma probands, carrying a heterozygous RB1 pathogenic variant and their unaffected, non-carrier parents. In order to evaluate somatic mosaicism in blood, the deleterious RB1 pathogenic variant identified in the proband, was searched for in the unaffected parents, using targeted deep sequencing. Observed recurrences, which represent an estimation of germline and somatic mosaicisms, were recorded and computed in the sibships. Deep sequencing revealed one mosaic-unaffected parent out of 124 tested couples, which provides an estimation of the maximal risk of recurrence, due to parental mosaicism, at 0.4%. Follow-up in the sibships showed one recurrence, providing a maximal recurrence risk, due to parental mosaicism, at 0.8%. Two different statistical strategies led to close estimates (0.4 and 0.8% risks) which appeared 266-533-fold higher, as compared with the general population. These recurrence estimates could be considered when counselling couples with retinoblastoma or diseases with a high de novo mutation rate. PMID- 28000699 TI - Absence of Hikeshi, a nuclear transporter for heat-shock protein HSP70, causes infantile hypomyelinating leukoencephalopathy. AB - Genetic leukoencephalopathies are a heterogeneous group of central nervous system disorders with white matter involvement. In a Finnish patient, we identified a novel homozygous disease-causing variant in HIKESHI, c.11G>C, p.(Cys4Ser), leading to hypomyelinating leukoencephalopathy with periventricular cysts and vermian atrophy. A founder Ashkenazi-Jewish disease-causing variant recently linked Hikeshi and its heat-shock protective function to leukoencephalopathy. In our patient, clinical features of lower limb spasticity, optic atrophy, nystagmus, and severe developmental delay were similar to reported patients. Additional features included vermian atrophy, epileptic seizures, and an ovarian tumor. Structural modeling and protein analyses revealed that modified interactions inside Hikeshi's hydrophobic pockets induce protein instability. The patient's cells showed impaired nuclear translocation of HSP70 during heat shock, and decreased ERO1-Lalpha, an endoplasmic reticulum (ER) oxidoreductase. Overall, we show that: (1) the clinical spectrum associated with Hikeshi deficiency extends to leukoencephalopathy with vermian atrophy and epilepsy; (2) the cellular disease process involves both nuclear chaperone and ER functions. PMID- 28000700 TI - Different kinds of genetic markers permit inference of Paleolithic and Neolithic expansions in humans. AB - Recent population genetic studies have provided valuable insights on the demographic history of our species. However, some issues such as the dating of the first demographic expansions in human populations remain puzzling. Indeed, although a few genetic studies argued that the first human expansions were concomitant with the Neolithic transition, many others found signals of expansion events starting during the Palaeolithic. Here we performed a simulation study to show that these contradictory findings may result from the differences in the genetic markers used, especially if two successive expansion events occurred. For a large majority of replicates for each scenario tested, microsatellite data allow only detecting the recent expansion event in that case, whereas sequence data allow only detecting the ancient expansion. Combined with previous real data analyses, our results bring support to the ideas that (i) a first human expansions started during the Palaeolithic period, (ii) a second expansion event occurred later, concomitantly with the Neolithic transition. PMID- 28000701 TI - The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands. AB - Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES. PMID- 28000702 TI - Fading competency of cytogenetic diagnostic laboratories: the alarm bell has started to ring. PMID- 28000703 TI - Characterization of Pseudomonas aeruginosa Phage C11 and Identification of Host Genes Required for Virion Maturation. AB - The underlying mechanisms of phage-host interactions largely remained to be elucidated. In this work, Pseudomonas aeruginosa phage C11 was first characterized as a Myoviridae virus having a linear dsDNA molecule of 94109 bp with 1173 bp identical terminal direct repeats (TDR). Then the mutants resistant to phage C11 were screened in a Tn5G transposon mutant library of P. aeruginosa PAK, including two mutants with decreased adsorption rates (DAR) and five mutants with wild-type adsorption rates (WAR). When the WAR mutants were incubated with phage C11, their growth rates were significantly inhibited; the replication of the phage genomic DNA was detected in all the WAR mutants with the real-time quantitative PCR analysis; and the synthesized phage genomic DNA was processed into monomers for packaging evidenced by the southern blot analysis. Moreover, with strain PAK as indicator, small quantities of phage C11 were synthesized in the WAR mutants. Taken together, these data suggested the identified genes of the WAR mutants are necessary for efficient synthesis of the infectious phage particles. Finally, the WAR mutants were detected sensitive to two other Pseudomonas phages closely related with C11, further implying the evolved diversity and complexity of the phage-host interactions in both sides. PMID- 28000704 TI - Systematic Assessment of Seven Solvent and Solid-Phase Extraction Methods for Metabolomics Analysis of Human Plasma by LC-MS. AB - The comparison of extraction methods for global metabolomics is usually executed in biofluids only and focuses on metabolite coverage and method repeatability. This limits our detailed understanding of extraction parameters such as recovery and matrix effects and prevents side-by-side comparison of different sample preparation strategies. To address this gap in knowledge, seven solvent-based and solid-phase extraction methods were systematically evaluated using standard analytes spiked into both buffer and human plasma. We compared recovery, coverage, repeatability, matrix effects, selectivity and orthogonality of all methods tested for non-lipid metabolome in combination with reversed-phased and mixed-mode liquid chromatography mass spectrometry analysis (LC-MS). Our results confirmed wide selectivity and excellent precision of solvent precipitations, but revealed their high susceptibility to matrix effects. The use of all seven methods showed high overlap and redundancy which resulted in metabolite coverage increases of 34-80% depending on LC-MS method employed as compared to the best single extraction protocol (methanol/ethanol precipitation) despite 7x increase in MS analysis time and sample consumption. The most orthogonal methods to methanol-based precipitation were ion-exchange solid-phase extraction and liquid liquid extraction using methyl-tertbutyl ether. Our results help facilitate rational design and selection of sample preparation methods and internal standards for global metabolomics. PMID- 28000705 TI - The presence of T cell epitopes is important for induction of antibody responses against antigens directed to DEC205+ dendritic cells. AB - In vivo antigen targeting to dendritic cells (DCs) has been used as a way to improve immune responses. Targeting is accomplished with the use of monoclonal antibodies (mAbs) to receptors present on the DC surface fused with the antigen of interest. An anti-DEC205 mAb has been successfully used to target antigens to the DEC205+CD8alpha+ DC subset. The administration of low doses of the hybrid mAb together with DC maturation stimuli is able to activate specific T cells and induce production of high antibody titres for a number of different antigens. However, it is still not known if this approach would work with any fused protein. Here we genetically fused the alphaDEC205 mAb with two fragments (42-kDa and 19-kDa) derived from the ~200 kDa Plasmodium vivax merozoite surface protein 1 (MSP1), known as MSP142 and MSP119, respectively. The administration of two doses of alphaDEC-MSP142, but not of alphaDEC-MSP119 mAb, together with an adjuvant to two mouse strains induced high anti-MSP119 antibody titres that were dependent on CD4+ T cells elicited by peptides present in the MSP133 sequence, indicating that the presence of T cell epitopes in antigens targeted to DEC205+ DCs increases antibody responses. PMID- 28000706 TI - Identification of a TNF-alpha inducer MIC3 originating from the microneme of non cystogenic, virulent Toxoplasma gondii. AB - Toxoplasma gondii is an opportunistic parasite with avirulent cystogenic and highly virulent non-cystogenic isolates. Although non-cystogenic strains are considered the most virulent, there are also marked genetic and virulence differences among these strains. Excretory-secretory antigens (ESAs) of T. gondii are critical for the invasion process and the immune response of the host. To better understand the differences in virulence between non-cystogenic T. gondii isolates, we studied ESAs of the RH strain (Type I), and the very prevalent in China, but less virulent TgCtwh3 strain (Chinese 1). ESAs of RH and TgCtwh3 triggered different levels of TNF-alpha production and macrophage M1 polarization. Using iTRAQ analysis, 27 differentially expressed proteins originating from secretory organelles and surface were quantified. Of these proteins, 11 microneme-associated proteins (MICs), 6 rhoptry proteins, 2 dense granule proteins and 5 surface proteins were more abundant in RH than in TgCtwh3. The protein-protein correlation network was employed to identify the important functional node protein MIC3, which was upregulated 5-fold in RH compared with TgCtwh3. MIC3 was experimentally confirmed to evoke a TNF-alpha secretory response, and it also induced macrophage M1 polarization. This result suggests that MIC3 is a potentially useful immunomodulator that induces TNF-alpha secretion and macrophage M1 polarization. PMID- 28000707 TI - Sustained Elevation of Intraocular Pressure Associated with Intravitreal Administration of Anti-vascular Endothelial Growth Factor: A Systematic Review and Meta-Analysis. AB - This study aimed to assess whether repetitive intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) cause sustained elevation of intraocular pressure (SE-IOP). We conducted a systematic review and meta-analysis based on five randomized controlled trials (RCTs) assessing 1428 subjects and 17 non-RCTs evaluating 8358 cases. In the RCTs, an increased risk of SE-IOP was found in the anti-VEGF group (summary risk ratio [RR] = 3.00, 95% confidence interval [CI]: 1.63-5.53) compared with the sham injection or laser group. The increased risk of SE-IOP was correlated with follow-up duration (RR = 2.14, 95% CI 0.69-6.57 at 6 months; RR = 3.15, 95% CI 0.99-10.09 at 12 months; RR = 3.48, 95% CI 1.38-8.78 at 23 months). The risk of SE-IOP after non-exclusion of pre existing glaucoma patients (RR = 3.48, 95% CI 1.38-8.78) was higher than that obtained after excluding pre-existing glaucoma patients (RR = 2.6, 95% CI 1.16 5.81). In non-RCTs, the pooled prevalence of SE-IOP was 4.7% (95% CI 3.7-5.8) regardless of diagnosis criteria. In conclusion, repeated intravitreal injections of anti-VEGF agents cause a 2-fold elevation in SE-IOP risk. PMID- 28000708 TI - Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1. AB - It is known that the LIM homeodomain transcription factor Isl1 is highly expressed in all pancreatic endocrine cells and functions in regulating pancreatic development and insulin secretion. The Isl1 mutation has been found to be associated with type 2 diabetes, but the mechanism responsible for Isl1 regulation of insulin synthesis and secretion still needs to be elucidated. In the present study, the protein inhibitor of activated STAT Y (PIASy) was identified as a novel Isl1-interacting protein with a yeast two-hybrid system, and its interaction with Isl1 was further confirmed by a co-immunoprecipitation experiment. PIASy and Isl1 colocalize in human and mouse pancreas and NIT beta cells. Furthermore, PIASy and Isl1 upregulate insulin gene expression and insulin secretion in a dose-dependent manner by activating the insulin promoter. PIASy and Isl1 mRNA expression levels were also increased in type 2 diabetic db/db mice. In addition, our results demonstrate that PIASy and Isl1 cooperate to activate the insulin promoter through the Isl1 homeodomain and PIASy ring domain. These data suggest that that PIASy regulates insulin synthesis and secretion by interacting with Isl1 and provide new insight into insulin regulation, although the detailed molecular mechanism needs to be clarified in future studies. PMID- 28000710 TI - The application of homemade Neosinocalamus affinis AC in electrokinetic removal technology on heavy metal removal from the MSWI fly ash. AB - This present paper was focused on the manufacture of activated carbon (AC) and its application in the electrokinetic remediation (EKR) technology on removal of the heavy metals (HMs) from the municipal solid waste incineration fly ash. AC was produced from Neosinocalamus affinis (NF) by chemical activation with H3PO4 in N2 atmosphere, the effects of activation temperatures, soaking time and impregnation ratios on the adsorption capacity of AC on HMs were examined through equilibrium adsorption experiments. The AC produced under the condition of 450 degrees C of activation temperature, 10 h of soaking time and 1.5 of impregnation ration was applied in the EKR experiment. The addition of AC in the S3-region of the electrolyzer could effectively improve the removal efficiencies of HMs. The technical parameters of voltage gradient, processing time and proportion were further optimized in the coupled experiments, the maximum removal of Cu, Zn, Cd, and Pb was 84.93%, 69.61%, 79.57%, and 78.55% respectively obtained under the optimal operating conditions of 2 V/cm of voltage gradient, 8 d of processing time and 20% of proportion. PMID- 28000709 TI - Characterization of a novel inhibitory human monoclonal antibody directed against Plasmodium falciparum Apical Membrane Antigen 1. AB - Malaria remains a major challenge to global health causing extensive morbidity and mortality. Yet, there is no efficient vaccine and the immune response remains incompletely understood. Apical Membrane Antigen 1 (AMA1), a leading vaccine candidate, plays a key role during merozoite invasion into erythrocytes by interacting with Rhoptry Neck Protein 2 (RON2). We generated a human anti-AMA1 antibody (humAbAMA1) by EBV-transformation of sorted B-lymphocytes from a Ghanaian donor and subsequent rescue of antibody variable regions. The antibody was expressed in Nicotiana benthamiana and in HEK239-6E, characterized for binding specificity and epitope, and analyzed for its inhibitory effect on Plasmodium falciparum. The generated humAbAMA1 shows an affinity of 106-135 pM. It inhibits the parasite strain 3D7A growth in vitro with an expression system independent IC50-value of 35 MUg/ml (95% confidence interval: 33 MUg/ml-37 MUg/ml), which is three to eight times lower than the IC50-values of inhibitory antibodies 4G2 and 1F9. The epitope was mapped to the close proximity of the RON2 peptide binding groove. Competition for binding between the RON2-peptide and humAbAMA1 was confirmed by surface plasmon resonance spectroscopy measurements. The particularly advantageous inhibitory activity of this fully human antibody might provide a basis for future therapeutic applications. PMID- 28000711 TI - The matrix protein of rabies virus binds to RelAp43 to modulate NF-kappaB dependent gene expression related to innate immunity. AB - The matrix (M) protein of wild isolates of rabies virus such as Tha (M-Tha) was previously shown to be able to interact with RelAp43, a protein of the NF-kappaB family, and to efficiently suppress NF-kappaB-dependent reporter gene expression, in contrast with the vaccine strain SAD. Here, we analyze the mechanisms involved in RelAp43-M protein interaction. We demonstrate that the central part of M-Tha, and the specific C-terminal region of RelAp43 are required for this interaction. Four differences in the corresponding amino acid sequences of the M-Tha and M-SAD are shown to be crucial for RelAp43 interaction and subsequent modulation of innate immune response. Furthermore, the capacity of M-Tha to interact with RelAp43 was shown to be crucial for the control of the expression of four genes (IFN, TNF, IL8 and CXCL2) during viral infection. These findings reveal that RelAp43 is a potent regulator of transcription of genes involved in innate immune response during rabies virus infection and that the M protein of wild isolates of rabies virus is a viral immune-modulatory factor playing an important role in this RelAp43-mediated host innate immunity response in contrast to M protein of vaccine strains, which have lost this property. PMID- 28000712 TI - Genetic polymorphisms -137 (rs187238) and -607 (rs1946518) in the interleukin-18 promoter may not be associated with development of hepatocellular carcinoma. AB - This study meta-analyzed the literature on possible association of polymorphisms 137 (rs187238) and -607 (rs1946518) in the interleukin-18 (IL-18) promoter with risk of hepatocellular carcinoma (HCC). The analysis included 8 case-control studies on the -137 polymorphism (1,318 cases, 2,254 controls) and 7 case-control studies on the -607 polymorphism (1,262 cases, 1,696 controls). None of the five genetic models suggested a significant association between the -137 polymorphism and HCC risk: allelic model, OR 0.99, 95% CI 0.74-1.34, P = 0.97; recessive model, OR 0.98, 95% CI 0.65-1.46, P = 0.91; dominant model, OR 1.35, 95% CI 0.73 2.52, P = 0.34; homozygous model, OR 0.99, 95% CI 0.65-1.49, P = 0.95; heterozygous model, OR 0.99, 95% CI 0.66-1.48, P = 0.94. Similar results were obtained in subgroup analyses of Asian patients, Chinese patients, or patients with hepatitis B virus (HBV)-related HCC. Similar results were also obtained for the -607 polymorphism across the entire study population as well as in the three subgroups. The available evidence suggests no significant association of the -137 or -607 polymorphisms with risk of HCC in general or specifically of HBV-related HCC. These conclusions should be verified in large, well-designed studies. PMID- 28000713 TI - Use of PEG-asparaginase in newly diagnosed adults with standard-risk acute lymphoblastic leukemia compared with E. coli-asparaginase: a retrospective single center study. AB - Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, and the long-term survival varies with different ages. We performed a retrospective analysis of 122 newly diagnosed adults with standard-risk ALL treated with Escherichia coli asparaginase (E. coli-asparaginase, n = 50) and polyethylene glycol-conjugated asparaginase (PEG-asparaginase, n = 72). No treatment-related mortality (TRM) occurred in the E. coli-asparaginase group, and 3 TRM events occurred in the PEG asparaginase group without relation to asparaginase. In addition, 22 (44.0%) and 48 (66.7%) patients achieved a complete response (CR) on day 14 in the E. coli asparaginase and PEG-asparaginase groups, respectively (P = 0.032). No different 5-year event-free survival (EFS) or overall survival (OS) rate (P = 0.632 and 0.769) was observed. Multivariate analysis revealed later CR (P = 0.008) and older age (P = 0.049) as adverse prognostic factors for both EFS and OS. In addition, we specifically monitored the known adverse effects of asparaginase, and no asparaginase-related death was observed. Allergy occurred in 9 patients using E. coli-asparaginase, and no patient in the PEG-asparaginase group suffered from allergies (P < 0.001). The incidence of other asparaginase-related toxicities was similar. We conclude that PEG-asparaginase can be safely and effectively used as asparaginase in adults with newly diagnosed standard-risk ALL. PMID- 28000714 TI - Mechanical splitting of microtubules into protofilament bundles by surface-bound kinesin-1. AB - The fundamental biophysics of gliding microtubule (MT) motility by surface tethered kinesin-1 motor proteins has been widely studied, as well as applied to capture and transport analytes in bioanalytical microdevices. In these systems, phenomena such as molecular wear and fracture into shorter MTs have been reported due the mechanical forces applied on the MT during transport. In the present work, we show that MTs can be split longitudinally into protofilament bundles (PFBs) by the work performed by surface-bound kinesin motors. We examine the properties of these PFBs using several techniques (e.g., fluorescence microscopy, SEM, AFM), and show that the PFBs continue to be mobile on the surface and display very high curvature compared to MT. Further, higher surface density of kinesin motors and shorter kinesin-surface tethers promote PFB formation, whereas modifying MT with GMPCPP or higher paclitaxel concentrations did not affect PFB formation. PMID- 28000715 TI - The mechanism of a chitosan-collagen composite film used as biomaterial support for MC3T3-E1 cell differentiation. AB - Natural composite biomaterials are good structural supports for bone cells to regenerate lost bone. Here, we report that a chitosan-collagen composite film accelerated osteoblast proliferation, differentiation and matrix mineralization in MC3T3-E1 cells. Intriguingly, we observed that the film enhanced the phosphorylation of Erk1/2. We showed that the chitosan-collagen composite film increased the transcriptional activity of Runx2, which is an important factor regulating osteoblast differentiation downstream of phosphorylated Erk1/2. Consistent with this observation, we found that the chitosan-collagen composite film increased the expression of osteoblastic marker genes, including Type I Collagen and Runx2 in MC3T3-E1 cells. We conclude that this film promoted osteoblast differentiation and matrix mineralization through an Erk1/2-activated Runx2 pathway. Our findings provide new evidence that chitosan-collagen composites are promising biomaterials for bone tissue engineering in bone defect related diseases. PMID- 28000716 TI - beta-subunit myristoylation functions as an energy sensor by modulating the dynamics of AMP-activated Protein Kinase. AB - The heterotrimeric AMP-activated protein kinase (AMPK), consisting of alpha, beta and gamma subunits, is a stress-sensing enzyme that is activated by phosphorylation of its activation loop in response to increases in cellular AMP. N-terminal myristoylation of the beta-subunit has been shown to suppress Thr172 phosphorylation, keeping AMPK in an inactive state. Here we use amide hydrogen deuterium exchange mass spectrometry (HDX-MS) to investigate the structural and dynamic properties of the mammalian myristoylated and non-myristoylated inactivated AMPK (D139A) in the presence and absence of nucleotides. HDX MS data suggests that the myristoyl group binds near the first helix of the C-terminal lobe of the kinase domain similar to other kinases. Our data, however, also shows that ATP.Mg2+ results in a global stabilization of myristoylated, but not non myristoylated AMPK, and most notably for peptides of the activation loop of the alpha-kinase domain, the autoinhibitory sequence (AIS) and the betaCBM. AMP does not have that effect and HDX measurements for myristoylated and non-myristoylated AMPK in the presence of AMP are similar. These differences in dynamics may account for a reduced basal rate of phosphorylation of Thr172 in myristoylated AMPK in skeletal muscle where endogenous ATP concentrations are very high. PMID- 28000717 TI - A quantitative comparison of micro-CT preparations in Dipteran flies. AB - X-ray-based 3D-imaging techniques have gained fundamental significance in research areas ranging from taxonomy to bioengineering. There is demand for the characterisation of species-specific morphological adaptations, micro-CT (MUCT) being the method of choice in small-scale animals. This has driven the development of suitable staining techniques to improve absorption-based tissue contrast. A quantitative account on the limits of current staining protocols for preparing MUCT specimen, however, is still missing. Here we present a study that quantifies results obtained by combining a variety of different contrast agents and fixative treatments that provides general guidance for MUCT applications, particularly suitable for insect species. Using a blowfly model system (Calliphora), we enhanced effective spatial resolution and, in particular, optimised tissue contrast enabling semi-automated segmentation of soft and hard tissue from MUCT data. We introduce a novel probabilistic measure of the contrast between tissues: PTC. Our results show that a strong iodine solution provides the greatest overall increase in tissue contrast, however phosphotungstic acid offers better inter-tissue discriminability. We further show that using paraformaldehyde as a fixative as opposed to ethanol, slows down the uptake of a staining solution by approximately a factor of two. PMID- 28000718 TI - Broadband near-infrared metamaterial absorbers utilizing highly lossy metals. AB - Radiation absorbers have increasingly been attracting attention as crucial components for controllable thermal emission, energy harvesting, modulators, etc. However, it is still challenging to realize thin absorbers which can operate over a wide spectrum range. Here, we propose and experimentally demonstrate thin, broadband, polarization-insensitive and omnidirectional absorbers working in the near-infrared range. We choose titanium (Ti) instead of the commonly used gold (Au) to construct nano-disk arrays on the top of a silicon dioxide (SiO2) coated Au substrate, with the quality (Q) factor of the localized surface plasmon (LSP) resonance being decreased due to the intrinsic high loss of Ti. The combination of this low-Q LSP resonance and the propagating surface plasmon (PSP) excitation resonance, which occur at different wavelengths, is the fundamental origin of the broadband absorption. The measured (at normal light incidence) absorption is over 90% in the wavelength range from 900 nm to 1825 nm, with high absorption persisting up to the incident angle of ~40 degrees . The demonstrated thin-film absorber configuration is relatively easy to fabricate and can be realized with other properly selected materials. PMID- 28000719 TI - Association between low-grade albuminuria and frailty among community-dwelling middle-aged and older people: a cross-sectional analysis from I-Lan Longitudinal Aging Study. AB - Frailty is characterized by decreased physiological reserve and increased vulnerability to atherosclerosis and subsequent mortality. Recently, low-grade albuminuria has been proposed as an atherosclerotic risk factor. We aimed to investigate the relationship between low-grade albuminuria and frailty by using cross-sectional data among community-dwelling middle-aged and older people. Totally, 1,441 inhabitants of I-Lan County with normal urinary albumin excretion (urine albumin to urine creatinine ratio [UACR] <30 mg/g) were enrolled (677 men; mean age 63 +/- 9 years, range from 50 to 91 years old). Assessment of frailty was based on the 'Fried frailty phenotype' criteria, including weight loss, grip strength, exhaustion, slowness and low physical activity. The study population was stratified into quartiles according to UACR levels. Age, body mass index, hypertension, diabetes, systolic blood pressure, insulin resistance, fasting glucose and high-sensitivity C-reactive protein levels were increased with the increment of UACR (P for trend <0.05). The prevalence of prefrailty/frailty and its components increased across the UACR quartiles. A multivariate stepwise logistic regression analysis revealed that UACR was independently associated with the likelihood of prefrailty/frailty (odds ratio 1.13, 95% CI 1.01-1.27). In conclusion, low-grade albuminuria is associated with the increased prevalence of prefrailty/frailty. PMID- 28000720 TI - Extraction of nano-silicon with activated carbons simultaneously from rice husk and their synergistic catalytic effect in counter electrodes of dye-sensitized solar cells. AB - The extraction of renewable energy resources particularly from earth abundant materials has always been a matter of significance in industrial products. Herein, we report a novel simultaneous extraction of nano-silicon with activated carbons (nano-Si@ACs) from rice husk (RH) by chemical activation method. As extracted nano-Si@ACs is then used as an energy harvesting materials in counter electrodes (CEs) of dye-sensitized solar cells (DSSCs). The morphology, structure and texture studies confirm the high surface area, abundant active sites and porous structure of nano-Si@ACs. Electrochemical impedance spectroscopy and cyclic voltammetry analyses reveal that the nano-Si@ACs is highly beneficial for fast I3- reduction and superior electrolyte diffusion capability. The nano-Si@ACs CE based DSSC exhibits enhanced power conversion efficiency of (8.01%) in contrast to pristine Pt CE (7.20%). These favorable results highlight the potential application of RH in low-cost, high-efficiency and Pt-free DSSCs. PMID- 28000721 TI - Overexcited MaxiK and KATP channels underlie obstructive jaundice-induced vasoconstrictor hyporeactivity of arterial smooth muscle. AB - Substantial evidence has shown that obstructive jaundice can induce vascular hyporesponsiveness. The present study was designed to investigate mechanisms of MaxiK channel and KATP underlying cholestasis-induced vascular dysfunction. The isolated thoracic aorta was used to explore norepinephrine (NE)-induced contraction. The function of MaxiK and KATP channels were investigated using whole-cell patch clamp recording. Compared with Sham group, NE-induced vascular contraction was blunted after bile duct ligation (BDL), which could not be ameliorated significantly after endothelial denudation. Charybdotoxin and glibenclamide induced a more pronounced recovery from vascular hyporesponsiveness to NE in BDL group compared with Sham group. BDL significantly promoted the charybdotoxin sensitive MaxiK current and KATP current in isolated aortic smooth muscle cells. In addition, the expression of auxiliary subunits (MaxiK-beta1 and SUR2B) rather pore-forming subunits (MaxiK-alpha and Kir6.1) was significantly up regulated after BDL. These findings suggest that MaxiK and KATP channels play an important role in regulating vascular hyporesponsiveness in BDL rats. PMID- 28000722 TI - An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets. AB - The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFNlambda1 and IFNlambda2, linking rs1990760 to the expression of type III IFNs. In the high-responding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positive-feedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs. PMID- 28000724 TI - Corrigendum: miR-200 family controls late steps of postnatal forebrain neurogenesis via Zeb2 inhibition. PMID- 28000723 TI - Plasma DPP4 activity is associated with no-reflow and major bleeding events in Chinese PCI-treated STEMI patients. AB - Dipeptidyl peptidase-4 (DPP4) is an important regulator of incretins and inflammation, and it is involved in the pathophysiological process of myocardial infarction (MI). This study investigated the role of plasma DPP4 activity (DPP4a) in patients with ST-segment elevation myocardial infarction (STEMI) who had undergone percutaneous coronary intervention (PCI). We recruited 747 consecutive PCI-treated STEMI patients from a tertiary referral center from January 2014 to October 2015. The outcomes of interest were the rates of no-reflow, in-hospital major adverse cardiac or cerebrovascular events (iMACCE), in-hospital complications (IHC) and in-hospital major bleeding. The DPP4a was lower in STEMI patients compared with the controls (p < 0.0001). Multivariate logistic regression analyses (adjusted for confounding variables) showed that a 1 U/L increase in DPP4a was associated with an increased rate of no-reflow events (odds ratio [OR]: 1.07; 95% CI: 1.02-1.11; p < 0.01) and a decreased rate of major bleeding events (OR: 0.90; 95% CI: 0.82-0.98; p = 0.02). There were no associations between DPP4a and either iMACCE or IHC. In conclusions, high levels of DPP4a are independently associated with an increased rate of no-reflow events and a decreased rate of major bleeding events in PCT-treated STEMI patients. PMID- 28000725 TI - Nonlinear characterization of GeSbS chalcogenide glass waveguides. AB - GeSbS ridge waveguides have recently been demonstrated as a promising mid - infrared platform for integrated waveguide - based chemical sensing and photodetection. To date, their nonlinear optical properties remain relatively unexplored. In this paper, we characterize the nonlinear optical properties of GeSbS glasses, and show negligible nonlinear losses at 1.55 MUm. Using self - phase modulation experiments, we characterize a waveguide nonlinear parameter of 7 W-1/m and nonlinear refractive index of 3.71 * 10-18 m2/W. GeSbS waveguides are used to generate supercontinuum from 1280 nm to 2120 nm at the -30 dB level. The spectrum expands along the red shifted side of the spectrum faster than on the blue shifted side, facilitated by cascaded stimulated Raman scattering arising from the large Raman gain of chalcogenides. Fourier transform infrared spectroscopic measurements show that these glasses are optically transparent up to 25 MUm, making them useful for short - wave to long - wave infrared applications in both linear and nonlinear optics. PMID- 28000726 TI - Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging. AB - The penetration of anticancer drugs in solid tumors is important to ensure the therapeutic effect, so methods are needed to understand drug distribution in different parts of the tumor. Mass spectrometry imaging (MSI) has great potential in this field to visualize drug distribution in organs and tumor tissues with good spatial resolution and superior specificity. We present an accurate and reproducible imaging method to investigate the variation of drug distribution in different parts of solid tumors. The method was applied to study the distribution of paclitaxel in three ovarian cancer models with different histopathological characteristics and in colon cancer (HCT116), breast cancer (MDA-MB-231) and malignant pleural mesothelioma (MPM487). The heterogeneous drug penetration in the tumors is evident from the MALDI imaging results and from the images analysis. The differences between the various models do not always relate to significant changes in drug content in tumor homogenate examined by classical HPLC analysis. The specificity of the method clarifies the heterogeneity of the drug distribution that is analyzed from a quantitative point of view too, highlighting how marked are the variations of paclitaxel amounts in different part of solid tumors. PMID- 28000727 TI - Evidence of Cnidarians sensitivity to sound after exposure to low frequency underwater sources. AB - Jellyfishes represent a group of species that play an important role in oceans, particularly as a food source for different taxa and as a predator of fish larvae and planktonic prey. The massive introduction of artificial sound sources in the oceans has become a concern to science and society. While we are only beginning to understand that non-hearing specialists like cephalopods can be affected by anthropogenic noises and regulation is underway to measure European water noise levels, we still don't know yet if the impact of sound may be extended to other lower level taxa of the food web. Here we exposed two species of Mediterranean Scyphozoan medusa, Cotylorhiza tuberculata and Rhizostoma pulmo to a sweep of low frequency sounds. Scanning electron microscopy (SEM) revealed injuries in the statocyst sensory epithelium of both species after exposure to sound, that are consistent with the manifestation of a massive acoustic trauma observed in other species. The presence of acoustic trauma in marine species that are not hearing specialists, like medusa, shows the magnitude of the problem of noise pollution and the complexity of the task to determine threshold values that would help building up regulation to prevent permanent damage of the ecosystems. PMID- 28000728 TI - Detailed analysis of charge transport in amorphous organic thin layer by multiscale simulation without any adjustable parameters. AB - Hopping-type charge transport in an amorphous thin layer composed of organic molecules is simulated by the combined use of molecular dynamics, quantum chemical, and Monte Carlo calculations. By explicitly considering the molecular structure and the disordered intermolecular packing, we reasonably reproduce the experimental hole and electron mobilities and their applied electric field dependence (Poole-Frenkel behaviour) without using any adjustable parameters. We find that the distribution of the density-of-states originating from the amorphous nature has a significant impact on both the mobilities and Poole Frenkel behaviour. Detailed analysis is also provided to reveal the molecular level origin of the charge transport, including the origin of Poole-Frenkel behaviour. PMID- 28000729 TI - Systemic Immune-Inflammation Index Predicts Prognosis of Patients with Esophageal Squamous Cell Carcinoma: A Propensity Score-matched Analysis. AB - Systemic immune-inflammation index (SII), based on peripheral lymphocyte, neutrophil, and platelet counts, was recently investigated as a prognostic marker in several tumors. However, SII has not been reported in esophageal squamous cell carcinoma (ESCC). We evaluated the prognostic value of the SII in 916 patients with ESCC who underwent radical surgery. Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model. The time dependent receiver operating characteristics (ROC) curve was used to compare the discrimination ability for OS. PSM (propensity score matching) was carried out to imbalance the baseline characteristics. Our results showed that SII, PLR, NLR and MLR were all associated with OS in ESCC patients in the Kaplan-Meier survival analysis. However, only SII was an independent risk factor for OS (HR = 1.24, 95% CI 1.01-1.53, P = 0.042) among these systemic inflammation scores. The AUC for SII was bigger than PLR, NLR and MLR. In the PSM analysis, SII still remained an independent predictor for OS (HR = 1.30, CI 1.05-1.60, P = 0.018). SII is a novel, simple and inexpensive prognostic predictor for patients with ESCC undergoing radical esophagectomy. The prognostic value of SII is superior to PLR, NLR and MLR. PMID- 28000731 TI - Electronic Structure of the Kitaev Material alpha-RuCl3 Probed by Photoemission and Inverse Photoemission Spectroscopies. AB - Recently, alpha-RuCl3 has attracted much attention as a possible material to realize the honeycomb Kitaev model of a quantum-spin-liquid state. Although the magnetic properties of alpha-RuCl3 have been extensively studied, its electronic structure, which is strongly related to its Kitaev physics, is poorly understood. Here, the electronic structure of alpha-RuCl3 was investigated by photoemission (PE) and inverse-photoemission (IPE) spectroscopies. The band gap was directly measured from the PE and IPE spectra and was found to be 1.9 eV, much larger than previously estimated values. Local density approximation (LDA) calculations showed that the on-site Coulomb interaction U could open the band gap without spin-orbit coupling (SOC). However, the SOC should also be incorporated to reproduce the proper gap size, indicating that the interplay between U and SOC plays an essential role. Several features of the PE and IPE spectra could not be explained by the results of LDA calculations. To explain such discrepancies, we performed configuration-interaction calculations for a RuCl63- cluster. The experimental data and calculations demonstrated that the 4d compound alpha-RuCl3 is a Jeff = 1/2 Mott insulator rather than a quasimolecular-orbital insulator. Our study also provides important physical parameters required for verifying the proposed Kitaev physics in alpha-RuCl3. PMID- 28000730 TI - An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with aggregation of TAR DNA-binding protein-43 (TDP-43) in neuronal cells and manifests as motor neuron dysfunction &muscle atrophy. The carboxyl terminal prion-like domain of TDP-43 can aggregate in vitro into toxic beta-sheet rich amyloid-like structures. So far, treatment options for ALS are very limited and Riluzole, which targets glutamate receptors, is the only but highly ineffective drug. Therefore, great interest exists in developing molecules for ALS treatment. Here, we have examined certain derivatives of acridine containing same side chains at position 4 &5, for inhibitory potential against TDP-43 aggregation. Among several acridine derivatives examined, AIM4, which contains polar carboxyl groups in the side arms, significantly reduces TDP-43-YFP aggregation in the powerful yeast model cell and also abolishes in vitro amyloid like aggregation of carboxyl terminal domain of TDP-43, as observed by AFM imaging. Thus, AIM4 can be a lead molecule potentiating further therapeutic research for ALS. PMID- 28000732 TI - Allocation strategies of savanna and forest tree seedlings in response to fire and shading: outcomes of a field experiment. AB - The forest-savanna ecotone may be very sharp in fire-prone areas. Fire and competition for light play key roles in its maintenance, as forest and savanna tree seedlings are quickly excluded from the other ecosystem. We hypothesized a tradeoff between seedling traits linked to fire resistance and to competition for light to explain these exclusions. We compared growth- and survival-related traits of two savanna and two forest species in response to shading and fire in a field experiment. To interpret the results, we decomposed our broad hypothesis into elementary tradeoffs linked to three constraints, biomass allocation, plant architecture, and shade tolerance, that characterize both savanna and adjacent forest ecosystems. All seedlings reached similar biomasses, but forest seedlings grew taller. Savanna seedlings better survived fire after topkill and required ten times less biomass than forest seedlings to survive. Finally, only savanna seedlings responded to shading. Although results were consistent with the classification of our species as mostly adapted to shade tolerance, competition for light in the open, and fire tolerance, they raised new questions: how could savanna seedlings survive better with a 10-times lower biomass than forest seedlings? Is their shade intolerance sufficient to exclude them from forest understory? PMID- 28000734 TI - Multi-beam reflections with flexible control of polarizations by using anisotropic metasurfaces. AB - We propose a method to convert linearly polarized incident electromagnetic waves fed by a single source into multi-beam reflections with independent control of polarizations based on anisotropic metasurface at microwave frequencies. The metasurface is composed of Jerusalem Cross structures and grounded plane spaced by a dielectric substrate. By designing the reflection-phase distributions of the anisotropic metasurface along the x and y directions, the x- and y-polarized incident waves can be manipulated independently to realize multi-beam reflections. When the x- and y-polarized reflected beams are designed to the same direction with equal amplitude, the polarization state of the beam will be only controlled by the phase difference between the x- and y-polarized reflected waves. Three examples are presented to show the multi-beam reflections with flexible control of polarizations by using anisotropic metasurfaces and excellent performance. Particularly, we designed, fabricated, and measured an anisotropic metasurface for two reflected beams with one linearly polarized and the other circularly polarized. The measurement results have good agreement with the simulations in a broad bandwidth. PMID- 28000733 TI - Additive and Photochemical Manufacturing of Copper. AB - In recent years, 3D printing technologies have been extensively developed, enabling rapid prototyping from a conceptual design to an actual product. However, additive manufacturing of metals in the existing technologies is still cost-intensive and time-consuming. Herein a novel platform for low-cost additive manufacturing is introduced by simultaneously combining the laser-induced forward transfer (LIFT) method with photochemical reaction. Using acrylonitrile butadiene styrene (ABS) polymer as the sacrificial layer, sufficient ejection momentum can be generated in the LIFT method. A low-cost continuous wave (CW) laser diode at 405 nm was utilized and proved to be able to transfer the photochemically synthesized copper onto the target substrate. The wavelength-dependent photochemical behaviour in the LIFT method was verified and characterized by both theoretical and experimental studies compared to 1064 nm fiber laser. The conductivity of the synthesized copper patterns could be enhanced using post electroless plating while retaining the designed pattern shapes. Prototypes of electronic circuits were accordingly built and demonstrated for powering up LEDs. Apart from pristine PDMS materials with low surface energies, the proposed method can simultaneously perform laser-induced forward transfer and photochemical synthesis of metals, starting from their metal oxide forms, onto various target substrates such as polyimide, glass and thermoplastics. PMID- 28000735 TI - Reconfigurable SDM Switching Using Novel Silicon Photonic Integrated Circuit. AB - Space division multiplexing using multicore fibers is becoming a more and more promising technology. In space-division multiplexing fiber network, the reconfigurable switch is one of the most critical components in network nodes. In this paper we for the first time demonstrate reconfigurable space-division multiplexing switching using silicon photonic integrated circuit, which is fabricated on a novel silicon-on-insulator platform with buried Al mirror. The silicon photonic integrated circuit is composed of a 7 * 7 switch and low loss grating coupler array based multicore fiber couplers. Thanks to the Al mirror, grating couplers with ultra-low coupling loss with optical multicore fibers is achieved. The lowest total insertion loss of the silicon integrated circuit is as low as 4.5 dB, with low crosstalk lower than -30 dB. Excellent performances in terms of low insertion loss and low crosstalk are obtained for the whole C-band. 1 Tb/s/core transmission over a 2-km 7-core fiber and space-division multiplexing switching is demonstrated successfully. Bit error rate performance below 10-9 is obtained for all spatial channels with low power penalty. The proposed design can be easily upgraded to reconfigurable optical add/drop multiplexer capable of switching several multicore fibers. PMID- 28000736 TI - Unraveling the genetic basis of xylose consumption in engineered Saccharomyces cerevisiae strains. AB - The development of biocatalysts capable of fermenting xylose, a five-carbon sugar abundant in lignocellulosic biomass, is a key step to achieve a viable production of second-generation ethanol. In this work, a robust industrial strain of Saccharomyces cerevisiae was modified by the addition of essential genes for pentose metabolism. Subsequently, taken through cycles of adaptive evolution with selection for optimal xylose utilization, strains could efficiently convert xylose to ethanol with a yield of about 0.46 g ethanol/g xylose. Though evolved independently, two strains carried shared mutations: amplification of the xylose isomerase gene and inactivation of ISU1, a gene encoding a scaffold protein involved in the assembly of iron-sulfur clusters. In addition, one of evolved strains carried a mutation in SSK2, a member of MAPKKK signaling pathway. In validation experiments, mutating ISU1 or SSK2 improved the ability to metabolize xylose of yeast cells without adaptive evolution, suggesting that these genes are key players in a regulatory network for xylose fermentation. Furthermore, addition of iron ion to the growth media improved xylose fermentation even by non evolved cells. Our results provide promising new targets for metabolic engineering of C5-yeasts and point to iron as a potential new additive for improvement of second-generation ethanol production. PMID- 28000737 TI - Development of an in-vivo active reversible butyrylcholinesterase inhibitor. AB - Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD. PMID- 28000738 TI - Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib. AB - As new treatment approaches, both immunotherapy and targeted treatments have been used in the clinical treatment of cancers. These therapies are different from traditional surgery, chemotherapy and radiotherapy. Use of a combination of immunotherapy and targeted treatments may improve tumor clearance. We investigated the feasibility of combining tyrosine kinase inhibitors (TKIs, targeted drugs) and SZU-101 (a novel TLR7 agonist synthesized by our laboratory). Thirteen different TKIs were combined with or without SZU-101 and studied to determine their effects on immunocytes. On the basis of the distinctive results, lapatinib and sunitinib were selected for further tumor-inhibition investigation and determination of the underlying mechanism. Interestingly, we found lapatinib to work better with SZU-101, enhancing tumor clearance in vivo, without affecting the TLR7-NF-kappaB pathway activated by the TLR7 agonist in mouse spleen lymphocytes and bone marrow dendritic cells (BMDCs). PMID- 28000739 TI - Drivers of U.S. toxicological footprints trajectory 1998-2013. AB - By exploiting data from the Toxic Release Inventory of the United States, we have established that the toxicological footprint (TF) increased by 3.3% (88.4 Mt) between 1998 and 1999 and decreased by 39% (1088.5 Mt) between 1999 and 2013. From 1999 to 2006, the decreasing TF was driven by improvements in emissions intensity (i.e. gains in production efficiency) through toxic chemical management options: cleaner production; end of pipe treatment; transfer for further waste management; and production scale. In particular, the mining sector reduced its TF through outsourcing processes. Between 2006 and 2009, decreasing TF was due to decrease in consumption volume triggered by economic recession. Since 2009, the economic recovery increased TF, overwhelming the influence of improved emissions intensity through population growth, consumption and production structures. Accordingly, attaining a less-toxic economy and environment will be influenced by a combination of gains in production efficiency through improvement in emissions mitigation technologies and changes in consumption patterns. Overall, the current analysis highlights the structural dynamics of toxic chemical release and would inform future formulation of effective mitigation standards and management protocols towards the detoxification of the environment. PMID- 28000741 TI - Investigation of switching mechanism in HfOx-ReRAM under low power and conventional operation modes. AB - Low-power resistive random access memory (LP-ReRAM) devices have attracted increasing attention owing to their advantages of low operation power. In this study, a vertical-type LP-ReRAM consisting of TiN/Ti/HfO2/TiN structure was fabricated. The switching mechanism for LP-ReRAM was elucidated as the conductive filament mechanism for conventional mode, and an interface-type switching mechanism for low power mode was proposed. The analysis of low frequency noise shows that power spectral density (PSD) is approximately proportional to 1/f for conventional operation mode. Nevertheless, for low power mode, the PSD of low resistance state (LRS) is proportional to 1/f, while that of high resistance state (HRS) is clear proportional to 1/f2. The envelope of multiple Lorentzian spectra of 1/f2 characteristics due to different traps reveals the characteristics of 1/f. For HRS of low power mode, a limited number of traps results in a characteristic of 1/f2. During the set process, the number of oxygen vacancies increases for LRS. Therefore, the PSD value is proportional to 1/f. Owing to the increase in the number of traps when the operation mode changes to conventional mode, the PSD value is proportional to 1/f. To the best of our knowledge, this is the first study that reveals the different noise characteristics in the low power operation mode from that in the conventional operation mode. PMID- 28000740 TI - Physico-chemical properties based differential toxicity of graphene oxide/reduced graphene oxide in human lung cells mediated through oxidative stress. AB - Graphene derivatives (GD) are currently being evaluated for technological and biomedical applications owing to their unique physico-chemical properties over other carbon allotrope such as carbon nanotubes (CNTs). But, the possible association of their properties with underlying in vitro effects have not fully examined. Here, we assessed the comparative interaction of three GD - graphene oxide (GO), thermally reduced GO (TRGO) and chemically reduced GO (CRGO), which significantly differ in their lateral size and functional groups density, with phenotypically different human lung cells; bronchial epithelial cells (BEAS-2B) and alveolar epithelial cells (A549). The cellular studies demonstrate that GD significantly ineternalize and induce oxidative stress mediated cytotoxicity in both cells. The toxicity intensity was in line with the reduced lateral size and increased functional groups revealed more toxicity potential of TRGO and GO respectively. Further, A549 cells showed more susceptibility than BEAS-2B which reflected cell type dependent differential cellular response. Molecular studies revealed that GD induced differential cell death mechanism which was efficiently prevented by their respective inhibitors. This is prior study to the best of our knowledge involving TRGO for its safety evaluation which provided invaluable information and new opportunities for GD based biomedical applications. PMID- 28000742 TI - Pentacle gold-copper alloy nanocrystals: a new system for entering male germ cells in vitro and in vivo. AB - Gold-based nanocrystals have attracted considerable attention for drug delivery and biological applications due to their distinct shapes. However, overcoming biological barriers is a hard and inevitable problem, which restricts medical applications of nanomaterials in vivo. Seeking for an efficient transportation to penetrate biological barriers is a common need. There are three barriers: blood testis barrier, blood-placenta barrier, and blood-brain barrier. Here, we pay close attention to the blood-testis barrier. We found that the pentacle gold copper alloy nanocrystals not only could enter GC-2 cells in vitro in a short time, but also could overcome the blood-testis barrier and enter male germ cells in vivo. Furthermore, we demonstrated that the entrance efficiency would become much higher in the development stages. The results also suggested that the pentacle gold-copper alloy nanocrystals could easier enter to germ cells in the pathological condition. This system could be a new method for theranostics in the reproductive system. PMID- 28000743 TI - Multi-Scale-Porosity TiO2 scaffolds grown by innovative sputtering methods for high throughput hybrid photovoltaics. AB - We propose an up-scalable, reliable, contamination-free, rod-like TiO2 material grown by a new method based on sputtering deposition concepts which offers a multi-scale porosity, namely: an intra-rods nano-porosity (1-5 nm) arising from the Thornton's conditions and an extra-rods meso-porosity (10-50 nm) originating from the spatial separation of the Titanium and Oxygen sources combined with a grazing Ti flux. The procedure is simple, since it does not require any template layer to trigger the nano-structuring, and versatile, since porosity and layer thickness can be easily tuned; it is empowered by the lack of contaminations/solvents and by the structural stability of the material (at least) up to 500 degrees C. Our material gains porosity, stability and infiltration capability superior if compared to conventionally sputtered TiO2 layers. Its competition level with chemically synthesized reference counterparts is doubly demonstrated: in Dye Sensitized Solar Cells, by the infiltration and chemisorption of N-719 dye (~1 * 1020 molecules/cm3); and in Perovskite Solar Cells, by the capillary infiltration of solution processed CH3NH3PbI3 which allowed reaching efficiency of 11.7%. Based on the demonstrated attitude of the material to be functionalized, its surface activity could be differently tailored on other molecules or gas species or liquids to enlarge the range of application in different fields. PMID- 28000744 TI - Mechanical unfolding kinetics of the SRV-1 gag-pro mRNA pseudoknot: possible implications for -1 ribosomal frameshifting stimulation. AB - Minus-one ribosomal frameshifting is a translational recoding mechanism widely utilized by many RNA viruses to generate accurate ratios of structural and catalytic proteins. An RNA pseudoknot structure located in the overlapping region of the gag and pro genes of Simian Retrovirus type 1 (SRV-1) stimulates frameshifting. However, the experimental characterization of SRV-1 pseudoknot (un)folding dynamics and the effect of the base triple formation is lacking. Here, we report the results of our single-molecule nanomanipulation using optical tweezers and theoretical simulation by steered molecular dynamics. Our results directly reveal that the energetic coupling between loop 2 and stem 1 via minor groove base triple formation enhances the mechanical stability. The terminal base pair in stem 1 (directly in contact with a translating ribosome at the slippery site) also affects the mechanical stability of the pseudoknot. The -1 frameshifting efficiency is positively correlated with the cooperative one-step unfolding force and inversely correlated with the one-step mechanical unfolding rate at zero force. A significantly improved correlation was observed between -1 frameshifting efficiency and unfolding rate at forces of 15-35 pN, consistent with the fact that the ribosome is a force-generating molecular motor with helicase activity. No correlation was observed between thermal stability and -1 frameshifting efficiency. PMID- 28000745 TI - Social conformity persists at least one day in 6-year-old children. AB - Humans have a tendency to forgo their own attitudes or beliefs in order to better align with the interests of a majority, a behavioral process known as conformity. Social conformity has been widely studied among adults and adolescents, whereas experimental studies on the impact of peer influence among young children have been relatively limited. The current study aims to investigate both short-term and sustained conforming behaviors among children in situations of relatively low social pressure. Forty-one children aged 5 to 6 years rated the attractiveness of 90 faces presented serially followed by witnessing a group rating in the absence of peers. Subsequently, second judgement was made after 30 minutes (Experiment 1). Results show that 6-year-old children tended to conform to their peers when group ratings differed from their own ratings, while younger children did not. In Experiment 2, children were required to make the second judgment one day after exposure to group ratings. Similarly, children aged 6 years exhibited a sustained conformity effect even after one day. Our findings suggest that 6-year-old children spontaneously change their private opinions under implicit social influence from peers. PMID- 28000746 TI - Initiation and propagation of cloud-to-ground lightning observed with a high speed video camera. AB - Complete evolution of a lightning discharge, from its initiation at an altitude of about 4 km to its ground attachment, was optically observed for the first time at the Lightning Observatory in Gainesville, Florida. The discharge developed during the late stage of a cloud flash and was initiated in a decayed branch of the latter. The initial channel section was intermittently illuminated for over 100 ms, until a bidirectionally extending channel (leader) was formed. During the bidirectional leader extension, the negative end exhibited optical and radio frequency electromagnetic features expected for negative cloud-to-ground strokes developing in virgin air, while the positive end most of the time appeared to be inactive or showed intermittent channel luminosity enhancements. The development of positive end involved an abrupt creation of a 1-km long, relatively straight branch with a streamer corona burst at its far end. This 1-km jump appeared to occur in virgin air at a remarkably high effective speed of the order of 106 m/s. The positive end of the bidirectional leader connected to another bidirectional leader to form a larger bidirectional leader, whose negative end attached to the ground and produced a 36-kA return stroke. PMID- 28000748 TI - Amendments to Accreditation of Third-Party Certification Bodies To Conduct Food Safety Audits and To Issue Certifications To Provide for the User Fee Program. Final rule. AB - The Food and Drug Administration (FDA, the Agency, or we) is amending its regulations on accreditation of third-party certification bodies to conduct food safety audits and to issue certifications to provide for a reimbursement (user fee) program to assess fees for the work FDA performs to establish and administer the third-party certification program under the FDA Food Safety Modernization Act (FSMA). PMID- 28000747 TI - Structure-based rationale for differential recognition of lacto- and neolacto- series glycosphingolipids by the N-terminal domain of human galectin-8. AB - Glycosphingolipids are ubiquitous cell surface molecules undertaking fundamental cellular processes. Lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) are the representative core structures for lacto- and neolacto-series glycosphingolipids. These glycolipids are the carriers to the blood group antigen and human natural killer antigens mainly found on blood cells, and are also principal components in human milk, contributing to infant health. The beta-galactoside recognising galectins mediate various cellular functions of these glycosphingolipids. We report crystallographic structures of the galectin-8 N-terminal domain (galectin 8N) in complex with LNT and LNnT. We reveal the first example in which the non reducing end of LNT binds to the primary binding site of a galectin, and provide a structure-based rationale for the significant ten-fold difference in binding affinities of galectin-8N toward LNT compared to LNnT, such a magnitude of difference not being observed for any other galectin. In addition, the LNnT complex showed that the unique Arg59 has ability to adopt a new orientation, and comparison of glycerol- and lactose-bound galectin-8N structures reveals a minimum atomic framework for ligand recognition. Overall, these results enhance our understanding of glycosphingolipids interactions with galectin-8N, and highlight a structure-based rationale for its significantly different affinity for components of biologically relevant glycosphingolipids. PMID- 28000750 TI - Direct observation of atomic-scale origins of local dissolution in Al-Cu-Mg alloys. AB - Atomistic chemical inhomogeneities are anticipated to induce dissimilarities in surface potentials, which control corrosion initiation of alloys at the atomic scale. Precise understanding of corrosion is therefore hampered by lack of definite information describing how atomistic heterogeneities regulate the process. Here, using high-angle annular dark-field (HAADF) scanning transmission electron microscope (STEM) and electron energy loss spectroscopy (EELS) techniques, we systematically analyzed the Al20Cu2Mn3 second phase of 2024Al and successfully observed that atomic-scale segregation of Cu at defect sites induced preferential dissolution of the adjacent zones. We define an "atomic-scale galvanic cell", composed of zones rich in Cu and its surrounding matrix. Our findings provide vital information linking atomic-scale microstructure and pitting mechanism, particularly for Al-Cu-Mg alloys. The resolution achieved also enables understanding of dealloying mechanisms and further streamlines our comprehension of the concept of general corrosion. PMID- 28000749 TI - High resolution crystal structure of the catalytic domain of MCR-1. AB - The newly identified mobile colistin resistant gene (mcr-1) rapidly spread among different bacterial strains and confers colistin resistance to its host, which has become a global concern. Based on sequence alignment, MCR-1 should be a phosphoethanolamine transferase, members of the YhjW/YjdB/YijP superfamily and catalyze the addition of phosphoethanolamine to lipid A, which needs to be validated experimentally. Here we report the first high-resolution crystal structure of the C-terminal catalytic domain of MCR-1 (MCR-1C) in its native state. The active pocket of native MCR-1C depicts unphosphorylated nucleophilic residue Thr285 in coordination with two Zinc ions and water molecules. A flexible adjacent active site loop (aa: Lys348-365) pose an open conformation compared to its structural homologues, suggesting of an open substrate entry channel. Taken together, this structure sets ground for further study of substrate binding and MCR-1 catalytic mechanism in development of potential therapeutic agents. PMID- 28000751 TI - Suppression of NLRP3 Inflammasome Activation Ameliorates Chronic Kidney Disease Induced Cardiac Fibrosis and Diastolic Dysfunction. AB - Cardiac fibrosis is a common finding in patients with chronic kidney disease. Here, we investigate the cardio-renal effects of theracurmin, a novel formulation of the polyphenolic compound curcumin, in a rat model of chronic kidney disease. Briefly, Sprague-Dawley rats were randomized to undergo sham or subtotal nephrectomy (SNx) surgery. At 3 weeks post surgery, SNx animals were further randomized to received theracurmin via once daily oral gavage or vehicle for 5 consecutive weeks. At 8 weeks post surgery, cardiac function was assessed via echocardiography and pressure volume loop analysis, followed by LV and renal tissue collection for analysis. SNx animals developed key hallmarks of renal injury including hypertension, proteinuria, elevated blood urea nitrogen, and glomerulosclerosis. Renal injury in SNx animals was also associated with significant diastolic dysfunction, macrophage infiltration, and cardiac NLRP3 inflammasome activation. Treatment of SNx animals with theracurmin improved structural and functional manifestations of cardiac injury associated with renal failure and also attenuated cardiac NLRP3 inflammasome activation and mature IL 1beta release. Taken together, our findings suggest a significant role for the NLRP3 inflammasome in renal injury-induced cardiac dysfunction and presents inflammasome attenuation as a unique strategy to prevent adverse cardiac remodeling in the setting of chronic kidney disease. PMID- 28000752 TI - Infergen Stimulated Macrophages Restrict Mycobacterium tuberculosis Growth by Autophagy and Release of Nitric Oxide. AB - IFN alfacon-1 (Infergen) is a synthetic form of Interferon (IFN)-alpha2b. Infergen has immunomodulatory activity and is effective against hepatitis C virus. However, the effect of Infergen (IFG) on Mycobacterium tuberculosis (Mtb) has not yet been reported. Therefore, for the first time, we have studied the influence of IFG in constraining the survival of Mtb in human macrophages. We observed that IFG significantly enhanced the maturation and activation of macrophages. Further, it substantially augmented the secretion of IL-6, nitric oxide (NO) and antigen uptake. Moreover, macrophages exhibited remarkably higher bactericidal activity, as evidenced by reduction in the Mtb growth. Infergen mediated mechanism was different from the type-1 interferons; since it worked through the activation of NF-kappaB, phosphorylation of STAT-3 and Akt-PI3K that improved the bactericidal activity through autophagy and NO release. In future, IFG immunotherapy can be a novel strategy for treating patients and controlling TB. PMID- 28000753 TI - Plasmodium falciparum malaria importation from Africa to China and its mortality: an analysis of driving factors. AB - Plasmodium falciparum malaria importation from Africa to China is rising with increasing Chinese overseas investment and international travel. Identifying networks and drivers of this phenomenon as well as the contributors to high case fatality rate is a growing public health concern to enable efficient response. From 2011-2015, 8653 P. falciparum cases leading to 98 deaths (11.3 per 1000 cases) were imported from 41 sub-Saharan countries into China, with most cases (91.3%) occurring in labour-related Chinese travellers. Four strongly connected groupings of origin African countries with destination Chinese provinces were identified, and the number of imported cases was significantly associated with the volume of air passengers to China (P = 0.006), parasite prevalence in Africa (P < 0.001), and the amount of official development assistance from China (P < 0.001) with investment in resource extraction having the strongest relationship with parasite importation. Risk factors for deaths from imported cases were related to the capacity of malaria diagnosis and diverse socioeconomic factors. The spatial heterogeneity uncovered, principal drivers explored, and risk factors for mortality found in the rising rates of P. falciparum malaria importation to China can serve to refine malaria elimination strategies and the management of cases, and high risk groups and regions should be targeted. PMID- 28000754 TI - Genetically regulated hepatic transcripts and pathways orchestrate haematological, biochemical and body composition traits. AB - The liver is the central metabolic organ and exhibits fundamental functions in haematological traits. Hepatic expression, haematological, plasma biochemical, and body composition traits were assessed in a porcine model (n = 297) to establish tissue-specific genetic variations that influence the function of immune-metabolism-correlated expression networks. At FDR (false discovery rate) <1%, more than 3,600 transcripts were jointly correlated (r = |0.22-0.48|) with the traits. Functional enrichment analysis demonstrated common links of metabolic and immune traits. To understand how immune and metabolic traits are affected via genetic regulation of gene expression, eQTLs were assessed. 20517 significant (FDR < 5%) eQTLs for 1401 transcripts were identified, among which 443 transcripts were associated with at least one of the examined traits and had cis eQTL (such as ACO1 (6.52 * 10-7) and SOD1 (6.41 * 10-30). The present study establishes a comprehensive view of hepatic gene activity which links together metabolic and immune traits in a porcine model for medical research. PMID- 28000755 TI - The balance of metagenomic elements shapes the skin microbiome in acne and health. AB - Studies have emphasized the importance of disease-associated microorganisms in perturbed communities, however, the protective roles of commensals are largely under recognized and poorly understood. Using acne as a model disease, we investigated the determinants of the overall virulence property of the skin microbiota when disease- and health-associated organisms coexist in the community. By ultra-deep metagenomic shotgun sequencing, we revealed higher relative abundances of propionibacteria and Propionibacterium acnes phage in healthy skin. In acne patients, the microbiome composition at the species level and at P. acnes strain level was more diverse than in healthy individuals, with enriched virulence-associated factors and reduced abundance of metabolic synthesis genes. Based on the abundance profiles of the metagenomic elements, we constructed a quantitative prediction model, which classified the clinical states of the host skin with high accuracy in both our study cohort (85%) and an independent sample set (86%). Our results suggest that the balance between metagenomic elements, not the mere presence of disease-associated strains, shapes the overall virulence property of the skin microbiota. This study provides new insights into the microbial mechanism of acne pathogenesis and suggests probiotic and phage therapies as potential acne treatments to modulate the skin microbiota and to maintain skin health. PMID- 28000757 TI - Perfluorocyclobutyl Aryl Ether-Based ABC Amphiphilic Triblock Copolymer. AB - A series of fluorine-containing amphiphilic ABC triblock copolymers comprising hydrophilic poly(ethylene glycol) (PEG) and poly(methacrylic acid) (PMAA), and hydrophobic poly(p-(2-(4-biphenyl)perfluorocyclobutoxy)phenyl methacrylate) (PBPFCBPMA) segments were synthesized by successive atom transfer radical polymerization (ATRP). First, PEG-Br macroinitiators bearing one terminal ATRP initiating group were prepared by chain-end modification of monohydroxy terminated PEG via esterification reaction. PEG-b-PBPFCBPMA-Br diblock copolymers were then synthesized via ATRP of BPFCBPMA monomer initiated by PEG-Br macroinitiator. ATRP polymerization of tert-butyl methacrylate (tBMA) was directly initiated by PEG-b-PBPFCBPMA-Br to provide PEG-b-PBPFCBPMA-b-PtBMA triblock copolymers with relatively narrow molecular weight distributions (Mw/Mn <= 1.43). The pendant tert-butyoxycarbonyls were hydrolyzed to carboxyls in acidic environment without affecting other functional groups for affording PEG-b PBPFCBPMA-b-PMAA amphiphilic triblock copolymers. The critical micelle concentrations (cmc) were determined by fluorescence spectroscopy using N-phenyl 1-naphthylamine as probe and the self-assembly behavior in aqueous media were investigated by transmission electron microscopy. Large compound micelles and bowl-shaped micelles were formed in neutral aqueous solution. Interestingly, large compound micelles formed by triblock copolymers can separately or simultaneously encapsulate hydrophilic Rhodamine 6G and hydrophobic pyrene agents. PMID- 28000756 TI - A Magnetic Soft Endoscopic Capsule-Inflated Intragastric Balloon for Weight Management. AB - Overweight and obesity have been identified as a cause of high risk diseases like diabetes and cancer. Although conventional Intragastric Balloons (IGBs) have become an efficient and less invasive method for overweight and obesity treatment, the use of conventional tools such as catheter or endoscope to insert and remove the IGBs from the patient's body causes nausea, vomiting, discomfort, and even gastric mucous damage. To eliminate these drawbacks, we develop a novel magnetic soft capsule device with gas-filled balloon inflation. The balloon is made from a thin and biocompatible material that can be inflated to a desired volume using biocompatible effervescent chemicals. In addition, both the outer balloon and inner capsule are designed to be soft and chemical resistance. The soft capsule shell is fabricated using scaffold-solvent approach while the outer balloon utilizes a novel fabrication approach for 3D spherical structure. A prototype of the proposed capsule and balloon is given. Experiments are successfully carried out in stimulated gastric environment and fresh porcine stomach to validate the effectiveness and reliability of the proposed approach. PMID- 28000758 TI - Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation. AB - The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV-induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV-induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV associated immune dysregulation and liver fibrosis. PMID- 28000759 TI - One-pot synthesis of carbon supported calcined-Mg/Al layered double hydroxides for antibiotic removal by slow pyrolysis of biomass waste. AB - A biochar supported calcined-Mg/Al layered double hydroxides composite (CLDHs/BC) was synthesized by a one-pot slow pyrolysis of LDHs preloaded bagasse biomass. Multiple characterizations of the product illustrated that the calcined-Mg/Al layered double hydroxides (CLDHs) were successfully coated onto the biochar in slow pyrolysis of pre-treated biomass. The as-synthesized CLDHs/BC could efficiently remove antibiotic tetracycline from aqueous solutions. The coating of CLDHs significantly increased the adsorption ability of biochar, and CLDHs/BC exhibited more than 2 times higher adsorption capacity than that of the pristine biochar (BC) in the tested pH range. The maximum adsorption capacity of CLDHs/BC for tetracycline was 1118.12 mg/g at 318 K. The experimental results suggested that the interaction with LDHs on biochar played a dominant role in tetracycline adsorption, accompanied with pi-pi interaction and hydrogen bond. This study provides a feasible and simple approach for the preparation of high-performance material for antibiotics contaminated wastewater treatment in a cost-effective way. PMID- 28000761 TI - BTeam, a Novel BRET-based Biosensor for the Accurate Quantification of ATP Concentration within Living Cells. AB - ATP levels may represent fundamental health conditions of cells. However, precise measurement of intracellular ATP levels in living cells is hindered by the lack of suitable methodologies. Here, we developed a novel ATP biosensor termed "BTeam". BTeam comprises a yellow fluorescent protein (YFP), the ATP binding domain of the epsilon subunit of the bacterial ATP synthase, and an ATP nonconsuming luciferase (NLuc). To attain emission, BTeam simply required NLuc substrate. BTeam showed elevated bioluminescence resonance energy transfer efficiency upon ATP binding, resulted in the emission spectra changes correlating with ATP concentrations. By using values of YFP/NLuc emission ratio to represent ATP levels, BTeam achieved steady signal outputs even though emission intensities were altered. With this biosensor, we succeeded in the accurate quantification of intracellular ATP concentrations of a population of living cells, as demonstrated by detecting the slight distribution in the cytosol (3.7-4.1 mM) and mitochondrial matrix (2.4-2.7 mM) within some cultured cell lines. Furthermore, BTeam allowed continuous tracing of cytosolic ATP levels of the same cells, as well as bioluminescent imaging of cytosolic ATP dynamics within individual cells. This simple and accurate technique should be an effective method for quantitative measurement of intracellular ATP concentrations. PMID- 28000760 TI - Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo. AB - Tail-anchored (TA) proteins are post-translationally inserted into membranes. The TRC40 pathway targets TA proteins to the endoplasmic reticulum via a receptor comprised of WRB and CAML. TRC40 pathway clients have been identified using in vitro assays, however, the relevance of the TRC40 pathway in vivo remains unknown. We followed the fate of TA proteins in two tissue-specific WRB knockout mouse models and found that their dependence on the TRC40 pathway in vitro did not predict their reaction to receptor depletion in vivo. The SNARE syntaxin 5 (Stx5) was extremely sensitive to disruption of the TRC40 pathway. Screening yeast TA proteins with mammalian homologues, we show that the particular sensitivity of Stx5 is conserved, possibly due to aggregation propensity of its cytoplasmic domain. We establish that Stx5 is an autophagy target that is inefficiently membrane-targeted by alternative pathways. Our results highlight an intimate relationship between the TRC40 pathway and cellular proteostasis. PMID- 28000762 TI - Axonal branching in lateral olfactory tract is promoted by Nogo signaling. AB - Mitral cells are major projection neurons of the olfactory bulb (OB) that form an axonal bundle known as the lateral olfactory tract (LOT). After axonal bundle formation, collateral branches sprout from primary axons of the LOT. Recently, we identified LOT usher substance (LOTUS) as an endogenous Nogo receptor-1 (NgR1) antagonist and demonstrated that LOTUS contributes to the formation of the LOT axonal bundle. Immunoblots revealed that the expression level of Nogo-A in the OB developmentally increased during axonal collateral formation. Next, we found that the axonal collateral branches were increased in cultured OB neurons from LOTUS knockout (KO) mice, whereas they were decreased in cultured OB neurons from NgR1 KO mice. Knockdown of Nogo-A in cultured OB neurons reduced the number of axonal collateral branches, suggesting that endogenous Nogo-A induces axonal branching. Finally, the collateral branches of the LOT were increased in LOTUS-KO mice, whereas those in NgR1-KO mice were decreased. Moreover, the abnormal increase of axonal branching observed in LOTUS-KO mice was rescued in the double mutant of LOTUS- and NgR1-KO mice. These findings suggest that Nogo-A and NgR1 interactions may contribute to axonal branching in LOT development. PMID- 28000763 TI - Height and prevalence of hypertension in a middle-aged and older Chinese population. AB - Evidence from epidemiological studies reported that height was inversely associated with cardiovascular diseases, but the association between height and hypertension was unclear. The purpose of this study was to explore the association between height and blood pressure or prevalence of hypertension in a middle-aged and older Chinese population. A total of 33,197 participants aged 37 to 94 years were recruited from the Dongfeng-Tongji cohort study in Hubei province, China. All participants completed baseline questionnaires, medical examinations and provided blood samples. Hypertension was define as a systolic blood pressure (SBP) over 140 mmHg or/and a diastolic blood pressure (DBP) over 90 mmHg, or current use of antihypertensive medication, or participants with self reported physician diagnosis of hypertension. Multivariate linear and logistic regression models were used. The prevalence of hypertension was 69.1% for men and 58.0% for women. Pulse pressure (PP) and SBP, but not DBP decreased linearly with increasing height among men and women. Comparing the highest with the shortest quartile of height, the multivariate-adjusted odds ratios were 0.80 (95% confidence interval, 0.71, 0.91) for men and 0.83 (0.74, 0.92) for women. In conclusion, height was associated with reduced SBP, PP and prevalence of hypertension in a middle-aged and older Chinese population. PMID- 28000764 TI - Statistically validated network of portfolio overlaps and systemic risk. AB - Common asset holding by financial institutions (portfolio overlap) is nowadays regarded as an important channel for financial contagion with the potential to trigger fire sales and severe losses at the systemic level. We propose a method to assess the statistical significance of the overlap between heterogeneously diversified portfolios, which we use to build a validated network of financial institutions where links indicate potential contagion channels. The method is implemented on a historical database of institutional holdings ranging from 1999 to the end of 2013, but can be applied to any bipartite network. We find that the proportion of validated links (i.e. of significant overlaps) increased steadily before the 2007-2008 financial crisis and reached a maximum when the crisis occurred. We argue that the nature of this measure implies that systemic risk from fire sales liquidation was maximal at that time. After a sharp drop in 2008, systemic risk resumed its growth in 2009, with a notable acceleration in 2013. We finally show that market trends tend to be amplified in the portfolios identified by the algorithm, such that it is possible to have an informative signal about institutions that are about to suffer (enjoy) the most significant losses (gains). PMID- 28000765 TI - Dipentaerythritol penta-acrylate phosphate - an alternative phosphate ester monomer for bonding of methacrylates to zirconia. AB - The present work examined the effects of dipentaerythritol penta-acrylate phosphate (PENTA) as an alternative phosphate ester monomer for bonding of methacrylate-based resins to yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) and further investigated the potential bonding mechanism involved. Shear bond strength testing was performed to evaluate the efficacy of experimental PENTA-containing primers (5, 10, 15, 20 or 30 wt% PENTA in acetone) in improving resin-Y-TZP bond strength. Bonding without the use of a PENTA-containing served as the negative control, and a Methacryloyloxidecyl dihydrogenphosphate(MDP) containing primer was used as the positive control. Inductively coupled plasma mass spectrometry (ICP-MS), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) were used to investigate the potential existence of chemical affinity between PENTA and Y-TZP. Shear bond strengths were significant higher in the 15 and 20 wt% PENTA groups. The ICP-MS, XPS and FTIR data indicated that the P content on the Y-TZP surface increased as the concentration of PENTA increased in the experimental primers, via the formation of Zr-O-P bond. Taken together, the results attest that PENTA improves resin bonding of Y-TZP through chemical reaction with Y-TZP. Increasing the concentration of PENTA augments its binding affinity but not its bonding efficacy with zirconia. PMID- 28000766 TI - Associations of five polymorphisms in the CD44 gene with cancer susceptibility in Asians. AB - CD44 polymorphisms have been previously associated with cancer risk. However, the results between independent studies were inconsistent. Here, a meta-analysis was performed to systematically evaluate associations between CD44 polymorphisms and cancer susceptibility. A comprehensive literature search conducted in PubMed, Embase, and Web of Science databases through August 10, 2016 yielded 11 eligible publications consisting of 5,788 cancer patients and 5,852 controls. Overall, odds ratios (OR) calculated with 95% confidence intervals (CI) identified a significant association between CD44 polymorphism rs13347 and cancer susceptibility under all genetic models. Additionally, the minor allele of polymorphism rs11821102 was associated with a decreased susceptibility to cancer in allele contrast, dominant, and heterozygous models, while no significant association was identified for polymorphisms rs10836347, rs713330, or rs1425802. Subgroup analysis by ethnicity revealed rs13347 was significantly associated with cancer susceptibility for Chinese but not for Indians. Linkage disequilibrium (LD) between different polymorphisms varied across diverse ethnic populations. In conclusion, the results indicate that CD44 polymorphism rs13347 acts as a risk factor for cancer, especially in Chinese, while the minor allele of polymorphism rs11821102 may be associated with a decreased susceptibility to cancer. Nevertheless, further studies on a larger population covering different ethnicities are warranted. PMID- 28000767 TI - A diketopiperazine factor from Rheinheimera aquimaris QSI02 exhibits anti-quorum sensing activity. AB - An ethyl acetate (EtOAc) extract isolated from the marine bacterium, Rheinheimera aquimaris QSI02, was found to exhibit anti-quorum sensing (anti-QS) activity. A subsequent bioassay-guided isolation protocol led to the detection of an active diketopiperazine factor, cyclo(Trp-Ser). Biosensor assay data showed that the minimum inhibitory concentration (MIC) of cyclo(Trp-Ser) ranged from 3.2 mg/ml to 6.4 mg/m for several microorganisms, including Escherichia coli, Chromobacterium violaceum CV026, Pseudomonas aeruginosa PA01, Staphylococcus aureus, and Candida albicans. Additionally, sub-MICs of cyclo(Trp-Ser) decreased the QS-regulated violacein production in C. violaceum CV026 by 67%. Furthermore, cyclo(Trp-Ser) can decrease QS-regulated pyocyanin production, elastase activity and biofilm formation in P. aeruginosa PA01 by 65%, 40% and 59.9%, respectively. Molecular docking results revealed that cyclo(Trp-Ser) binds to CviR receptor more rigidly than C6HSL with lower docking energy -8.68 kcal/mol, while with higher binding energy of -8.40 kcal/mol than 3-oxo-C12HSL in LasR receptor. Molecular dynamics simulation suggested that cyclo(Trp-Ser) is more easy to bind to CviR receptor than natural signaling molecule, but opposite in LasR receptor. These results suggest that cyclo(Trp-Ser) can be used as a potential inhibitor to control QS systems of C. violaceum and P. aeruginosa and provide increased the understanding of molecular mechanism that influences QS-regulated behaviors. PMID- 28000768 TI - Knowledge-Guided Bioinformatics Model for Identifying Autism Spectrum Disorder Diagnostic MicroRNA Biomarkers. AB - Autism spectrum disorder (ASD) is a severe neurodevelopmental disease with a high incidence and effective biomarkers are urgently needed for its diagnosis. A few previous studies have reported the detection of miRNA biomarkers for autism diagnosis, especially those based on bioinformatics approaches. In this study, we developed a knowledge-guided bioinformatics model for identifying autism miRNA biomarkers. We downloaded gene expression microarray data from the GEO Database and extracted genes with expression levels that differed in ASD and the controls. We then constructed an autism-specific miRNA-mRNA network and inferred candidate autism biomarker miRNAs based on their regulatory modes and functions. We defined a novel parameter called the autism gene percentage as autism-specific knowledge to further facilitate the identification of autism-specific biomarker miRNAs. Finally, 11 miRNAs were screened as putative autism biomarkers, where eight miRNAs (72.7%) were significantly dysregulated in ASD samples according to previous reports. Functional enrichment results indicated that the targets of the identified miRNAs were enriched in autism-associated pathways, such as Wnt signaling (in KEGG and IPA), cell cycle (in KEGG), and glioblastoma multiforme signaling (in IPA), thereby supporting the predictive power of our model. PMID- 28000770 TI - Angle- and Polarization-Insensitive Metamaterial Absorber using Via Array. AB - In this paper, we propose an angle- and polarization-insensitive metamaterial absorber. We design a metamaterial unit cell that is based on a split ring cross resonator (SRCR). We observe that the absorption frequency and absorption ratio are insensitive to incident angles when a via array surrounds the SRR. We demonstrate the effect of the via array using full-wave simulations by comparing the absorptivity of the SRCR with and without the via array. Because of the symmetric geometry, we also realize polarization insensitivity. We build the proposed absorber on a printed-circuit-board with 30 * 30 unit cells, and we demonstrate its performance experimentally in free space. Under normal incidence, the fabricated absorber shows 99.6% absorptivity at 11.3 GHz for all polarization angles, while for oblique incidence, the fabricated absorber maintains an absorptivity higher than 90% for incident angles up to 70 degrees and 60 degrees for transverse magnetic (TM) and transverse electric (TE) modes, respectively. PMID- 28000769 TI - Characterization of blunt chest trauma in a long-term porcine model of severe multiple trauma. AB - Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics. PMID- 28000771 TI - The pan-cancer pathological regulatory landscape. AB - Dysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer. Detecting the specific perturbed regulators that have an effect on the generation and the development of the disease is crucial for understanding the disease mechanism and for taking decisions on efficient preventive and curative therapies. Moreover, detecting such perturbations at the patient level is even more important from the perspective of personalized medicine. We applied the Transcription Factor Target Enrichment Analysis, a method that detects the activity of transcription factors based on the quantification of the collective transcriptional activation of their targets, to a large collection of 5607 cancer samples covering eleven cancer types. We produced for the first time a comprehensive catalogue of altered transcription factor activities in cancer, a considerable number of them significantly associated to patient's survival. Moreover, we described several interesting TFs whose activity do not change substantially in the cancer with respect to the normal tissue but ultimately play an important role in patient prognostic determination, which suggest they might be promising therapeutic targets. An additional advantage of this method is that it allows obtaining personalized TF activity estimations for individual patients. PMID- 28000772 TI - Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients. AB - The relevance of blood-based assays to monitor minimal residual disease (MRD) in non-metastatic prostate cancer (PCa) remains unclear. Proving that clinically relevant circulating tumor cells (CTCs) can be detected with available technologies could address this. This study aimed to improve CTC detection in non metastatic PCa patients by combining three independent CTC assays: the CellSearch system, an in vivo CellCollector and the EPISPOT. Peripheral blood samples from high-risk PCa patients were screened for CTCs before and three months after radical prostatectomy (RP). Combining the results of both time points, CTCs were detected in 37%, 54.9% and 58.7% of patients using CellSearch, CellCollector and EPISPOT, respectively. The cumulative positivity rate of the three CTC assays was 81.3% (87/107) with 21.5% (23/107) of patients harboring >=5 CTCs/7.5 ml blood. Matched pair analysis of 30 blood samples taken before and after surgery indicated a significant decrease in CTCs captured by the CellCollector from 66% before RP to 34% after therapy (p = 0.031). CTC detection by EPISPOT before RP significantly correlated with PSA serum values (p < 0.0001) and clinical tumor stage (p = 0.04), while the other assays showed no significant correlations. In conclusion, CTC-based liquid biopsies have the potential to monitor MRD in patients with non-metastatic prostate cancer. PMID- 28000773 TI - Bioorthogonal chemical imaging of metabolic activities in live mammalian hippocampal tissues with stimulated Raman scattering. AB - Brain is an immensely complex system displaying dynamic and heterogeneous metabolic activities. Visualizing cellular metabolism of nucleic acids, proteins, and lipids in brain with chemical specificity has been a long-standing challenge. Recent development in metabolic labeling of small biomolecules allows the study of these metabolisms at the global level. However, these techniques generally require nonphysiological sample preparation for either destructive mass spectrometry imaging or secondary labeling with relatively bulky fluorescent labels. In this study, we have demonstrated bioorthogonal chemical imaging of DNA, RNA, protein and lipid metabolism in live rat brain hippocampal tissues by coupling stimulated Raman scattering microscopy with integrated deuterium and alkyne labeling. Heterogeneous metabolic incorporations for different molecular species and neurogenesis with newly-incorporated DNA were observed in the dentate gyrus of hippocampus at the single cell level. We further applied this platform to study metabolic responses to traumatic brain injury in hippocampal slice cultures, and observed marked upregulation of protein and lipid metabolism particularly in the hilus region of the hippocampus within days of mechanical injury. Thus, our method paves the way for the study of complex metabolic profiles in live brain tissue under both physiological and pathological conditions with single-cell resolution and minimal perturbation. PMID- 28000774 TI - The levels of the sex hormones are not different between type 1 and type 2 endometrial cancer. AB - The involvement of hormonal factors in developing endometrial cancer is well documented. In particular, excess or unopposed estrogen is a major risk factor. Endometrial cancer is divided into estrogen-dependent and estrogen-independent types. Studies suggested that the subtypes of endometrial cancer share many common risk factors. Whether the levels of sex hormones differ between types 1 and 2 endometrial cancer has not been investigated. In this study, levels of estrogen, progesterone, testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were investigated between type 1 and type 2 endometrial cancer taking into account menopausal status and parity. The sex hormones levels and estrogen and progesterone receptors were measured in 187 women with endometrial cancer. The levels of estradiol (E2), progesterone, testosterone, FSH and LH were not different between the subtypes of endometrial cancer regardless of menopausal status. In addition, the sex hormones were not different between patients of different party regardless of the menopausal status. The majority of type 1 (96%) and type 2 (82%) endometrial cancers were estrogen and progesterone receptor positive. Our data suggest that type 2 endometrial cancer is not completely estrogen independent, and type 1 and type 2 endometrial cancers may have a similar pathogenesis. PMID- 28000775 TI - Structural basis of the substrate preference towards CMP for a thymidylate synthase MilA involved in mildiomycin biosynthesis. AB - Modified pyrimidine monophosphates such as methyl dCMP (mdCMP), hydroxymethyl dUMP (hmdUMP) and hmdCMP in some phages are synthesized by a large group of enzymes termed as thymidylate synthases (TS). Thymidylate is a nucleotide required for DNA synthesis and thus TS is an important drug target. In the biosynthetic pathway of the nucleoside fungicide mildiomycin isolated from Streptomyces rimofaciens ZJU5119, a cytidylate (CMP) hydroxymethylase, MilA, catalyzes the conversion of CMP into 5'-hydroxymethyl CMP (hmCMP) with an efficiency (kcat/KM) of 5-fold faster than for deoxycytidylate (dCMP). MilA is thus the first enzyme of the TS superfamily preferring CMP to dCMP. Here, we determined the crystal structures of MilA and its complexes with various substrates including CMP, dCMP and hmCMP. Comparing these structures to those of dCMP hydroxymethylase (CH) from T4 phage and TS from Escherichia coli revealed that two residues in the active site of CH and TS, a serine and an arginine, are respectively replaced by an alanine and a lysine, Ala176 and Lys133, in MilA. Mutation of A176S/K133R of MilA resulted in a reversal of substrate preference from CMP to dCMP. This is the first study reporting the evolution of the conserved TS in substrate selection from DNA metabolism to secondary nucleoside biosynthesis. PMID- 28000776 TI - Cpf1 Is A Versatile Tool for CRISPR Genome Editing Across Diverse Species of Cyanobacteria. AB - Cyanobacteria are the ideal organisms for the production of a wide range of bioproducts as they can convert CO2 directly into the desired end product using solar energy. Unfortunately, the engineering of cyanobacteria to create efficient cell factories has been impaired by the cumbersome genetic tools that are currently available for these organisms; especially when trying to accumulate multiple modifications. We sought to construct an efficient and precise tool for generating numerous markerless modifications in cyanobacteria using CRISPR technology and the alternative nuclease, Cpf1. In this study we demonstrate rapid engineering of markerless knock-ins, knock-outs and point mutations in each of three model cyanobacteria; Synechococcus, Synechocystis and Anabaena. The markerless nature of cpf1 genome editing will allow for complex genome modification that was not possible with previously existing technology while facilitating the development of cyanobacteria as highly modified biofactories. PMID- 28000777 TI - BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53. AB - The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance. PMID- 28000778 TI - New Potassium Sodium Niobate Single Crystal with Thickness-independent High performance for Photoacoustic Angiography of Atherosclerotic Lesion. AB - The synthesis of (K0.45Na0.55)0.96Li0.04NbO3 (KNLN) single crystals with a <100> orientation, using a seed-free solid state crystal growth method, is described here. With the thickness of the crystals decreasing down to the order of tens of micrometers, this new lead-free single crystal exhibits thickness-independent electrical behavior, and maintains superior piezoelectric constant (d33 = 670 pC N-1) and electromechanical coupling factor (kt = 0.55). The successful fabrication of a tiny intravascular photoacoustic probe, with a 1 mm outside diameter, is achieved using a single crystal with a thickness of around 60 MUm, in combination with a 200 MUm core multimode fiber. Wire phantom photoacoustic images show that the axial resolution and lateral resolution of the single crystal based probe are 60 and 220 MUm, respectively. In addition, intravascular photoacoustic imaging of the atherosclerotic lesion of a human artery is presented. In the time-domain and frequency-domain images, calcified regions are clearly distinguishable from surrounding tissue. These interesting results demonstrate that KNN-based lead-free piezoelectric single crystals are a promising candidate to substitute for lead-based piezoelectric materials for photoacoustic imaging in the future. PMID- 28000779 TI - Generation of flower high-order Poincare sphere laser beams from a spatial light modulator. AB - We propose and experimentally demonstrate a new complex laser beam with inhomogeneous polarization distributions mapping onto high-order Poincare spheres (HOPSs). The complex laser mode is achieved by superposition of Laguerre-Gaussian modes and manifests exotic flower-like localization on intensity and phase profiles. A simple optical system is used to generate a polarization-variant distribution on the complex laser mode by superposition of orthogonal circular polarizations with opposite topological charges. Numerical analyses of the polarization distribution are consistent with the experimental results. The novel flower HOPS beams can act as a new light source for photonic applications. PMID- 28000780 TI - The Nature of Metastable AA' Graphite: Low Dimensional Nano- and Single Crystalline Forms. AB - Over the history of carbon, it is generally acknowledged that Bernal AB stacking of the sp2 carbon layers is the unique crystalline form of graphite. The universal graphite structure is synthesized at 2,600~3,000 degrees C and exhibits a micro-polycrystalline feature. In this paper, we provide evidence for a metastable form of graphite with an AA' structure. The non-Bernal AA' allotrope of graphite is synthesized by the thermal- and plasma-treatment of graphene nanopowders at ~1,500 degrees C. The formation of AA' bilayer graphene nuclei facilitates the preferred texture growth and results in single-crystal AA' graphite in the form of nanoribbons (1D) or microplates (2D) of a few nm in thickness. Kinetically controlled AA' graphite exhibits unique nano- and single crystalline feature and shows quasi-linear behavior near the K-point of the electronic band structure resulting in anomalous optical and acoustic phonon behavior. PMID- 28000781 TI - Direct synthesis of graphitic mesoporous carbon from green phenolic resins exposed to subsequent UV and IR laser irradiations. AB - The design of mesoporous carbon materials with controlled textural and structural features by rapid, cost-effective and eco-friendly means is highly demanded for many fields of applications. We report herein on the fast and tailored synthesis of mesoporous carbon by UV and IR laser assisted irradiations of a solution consisting of green phenolic resins and surfactant agent. By tailoring the UV laser parameters such as energy, pulse repetition rate or exposure time carbon materials with different pore size, architecture and wall thickness were obtained. By increasing irradiation dose, the mesopore size diminishes in the favor of wall thickness while the morphology shifts from worm-like to an ordered hexagonal one. This was related to the intensification of phenolic resin cross linking which induces the reduction of H-bonding with the template as highlighted by 13C and 1H NMR. In addition, mesoporous carbon with graphitic structure was obtained by IR laser irradiation at room temperature and in very short time periods compared to the classical long thermal treatment at very high temperatures. Therefore, the carbon texture and structure can be tuned only by playing with laser parameters, without extra chemicals, as usually required. PMID- 28000782 TI - Local-scale projections of coral reef futures and implications of the Paris Agreement. AB - Increasingly frequent severe coral bleaching is among the greatest threats to coral reefs posed by climate change. Global climate models (GCMs) project great spatial variation in the timing of annual severe bleaching (ASB) conditions; a point at which reefs are certain to change and recovery will be limited. However, previous model-resolution projections (~1 * 1 degrees ) are too coarse to inform conservation planning. To meet the need for higher-resolution projections, we generated statistically downscaled projections (4-km resolution) for all coral reefs; these projections reveal high local-scale variation in ASB. Timing of ASB varies >10 years in 71 of the 87 countries and territories with >500 km2 of reef area. Emissions scenario RCP4.5 represents lower emissions mid-century than will eventuate if pledges made following the 2015 Paris Climate Change Conference (COP21) become reality. These pledges do little to provide reefs with more time to adapt and acclimate prior to severe bleaching conditions occurring annually. RCP4.5 adds 11 years to the global average ASB timing when compared to RCP8.5; however, >75% of reefs still experience ASB before 2070 under RCP4.5. Coral reef futures clearly vary greatly among and within countries, indicating the projections warrant consideration in most reef areas during conservation and management planning. PMID- 28000784 TI - All-into-one strategy to synthesize mesoporous hybrid silicate microspheres from naturally rich red palygorskite clay as high-efficient adsorbents. AB - A mesoporous hybrid silicate microsphere with superior adsorption performance has been successfully synthesized by employing an "all-into-one" strategy and a simple one-pot hydrothermal process using naturally abundant low-grade red palygorskite (PAL) clay as raw material in the presence of non-toxic SiO32- and Mg2+ ions. As is expected, both the PAL and associated minerals transformed into a new amorphous mesoporous hybrid silicate microsphere without using any additional pore-forming template. The mesoporous silicate microsphere shows a large pore size of 37.74 nm, high specific surface area of 489.81 m2/g (only 54.67 m2/g for raw PAL) and negative surface potential of -43.3 mV, and its maximum adsorption capabilities for Methylene bule (MB) and Crystal violet (CV) reach 407.95 mg/g and 397.22 mg/g, respectively. Meanwhile, 99.8% of MB (only 53% for raw PAL) and 99.7% of CV (only 43% for raw PAL) were sucessfully removed from 200 mg/L of initial dye solution by only using 1 g/L of the adsorbent. In addition, the spent adsorbent can be easily regenerated and repeatly reused for muptiple cycles. The study on adsorption mechanism revealed that electrostatic attraction, hydrogen bonding and chemical complexing interactions are the main factors contributed to the high dye adsorption. PMID- 28000783 TI - Illegitimate translation causes unexpected gene expression from on-target out-of frame alleles created by CRISPR-Cas9. AB - CRISPR-Cas9 is efficient enough to knock out both alleles directly by introducing out-of-frame mutations. We succeeded in making biallelic on-target frameshift mutations of the endogenous Gli3 gene; however, the GLI3 protein was expressed in all six of the established cell lines carrying homozygous out-of-frame mutations. We developed a dual-tagged expression vector and proved that illegitimate translation (ITL) was the cause of the unexpected Gli3 expression. Thus, gene expression must be examined even if designed on-target out-of-frame sequences are introduced by genome editing. In addition, it is highly recommended to pre examine the occurrence of ITL in vitro prior to the design and construction of any genome-editing vectors. In vitro assay systems such as the dual-tagged ITL assay system developed in this study should aid the identification and elucidation of ITL-based human diseases and gene expression. PMID- 28000785 TI - Cross-regulation by CrcZ RNA controls anoxic biofilm formation in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (PA) can thrive in anaerobic biofilms in the lungs of cystic fibrosis (CF) patients. Here, we show that CrcZ is the most abundant PA14 RNA bound to the global regulator Hfq in anoxic biofilms grown in cystic fibrosis sputum medium. Hfq was crucial for anoxic biofilm formation. This observation complied with an RNAseq based transcriptome analysis and follow up studies that implicated Hfq in regulation of a central step preceding denitrification. CrcZ is known to act as a decoy that sequesters Hfq during relief of carbon catabolite repression, which in turn alleviates Hfq-mediated translational repression of catabolic genes. We therefore inferred that CrcZ indirectly impacts on biofilm formation by competing for Hfq. This hypothesis was supported by the findings that over-production of CrcZ mirrored the biofilm phenotype of the hfq deletion mutant, and that deletion of the crcZ gene augmented biofilm formation. To our knowledge, this is the first example where competition for Hfq by CrcZ cross regulates an Hfq-dependent physiological process unrelated to carbon metabolism. PMID- 28000786 TI - Solid-state NMR Study of Ion Adsorption and Charge Storage in Graphene Film Supercapacitor Electrodes. AB - Graphene film has been demonstrated as promising active materials for electric double layer capacitors (EDLCs), mainly due to its excellent mechanical flexibility and freestanding morphology. In this work, the distribution and variation pattern of electrolyte ions in graphene-film based EDLC electrodes are investigated with a 11B magic-angle spinning nuclear magnetic resonance (MAS-NMR) spectroscopy. For neutral graphene films soaked with different amounts of electrolytes (1 M TEABF4/ACN), weakly and strongly adsorbed anions are identified based on the resonances at different 11B chemical shifts. Unlike other porous carbonaceous materials, the strongly adsorbed anions are found as the major electrolyte anions components in graphene films. Further measurements on the ion population upon charging are carried out with applying different charging voltages on the graphene films. Results indicate that the charging process of graphene-film based EDLCs can be divided into two distinct charge storage stages (i.e., ejection of co-ions and adsorption of counter-ions) for different voltages. The as-obtained results will be useful for the design and fabrication of high performance graphene-film based EDLCs. PMID- 28000787 TI - Establishment of a New Drug Code for Marihuana Extract. Final rule. AB - The Drug Enforcement Administration is creating a new Administration Controlled Substances Code Number for "Marihuana Extract." This code number will allow DEA and DEA-registered entities to track quantities of this material separately from quantities of marihuana. This, in turn, will aid in complying with relevant treaty provisions. Under international drug control treaties administered by the United Nations, some differences exist between the regulatory controls pertaining to marihuana extract versus those for marihuana and tetrahydrocannabinols. The DEA has previously established separate code numbers for marihuana and for tetrahydrocannabinols, but not for marihuana extract. To better track these materials and comply with treaty provisions, DEA is creating a separate code number for marihuana extract with the following definition: "Meaning an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin (whether crude or purified) obtained from the plant." Extracts of marihuana will continue to be treated as Schedule I controlled substances. PMID- 28000788 TI - In vivo label-free photoacoustic flow cytography and on-the-spot laser killing of single circulating melanoma cells. AB - Metastasis causes as many as 90% of cancer-related deaths, especially for the deadliest skin cancer, melanoma. Since hematogenous dissemination of circulating tumor cells is the major route of metastasis, detection and destruction of circulating tumor cells are vital for impeding metastasis and improving patient prognosis. Exploiting the exquisite intrinsic optical absorption contrast of circulating melanoma cells, we developed dual-wavelength photoacoustic flow cytography coupled with a nanosecond-pulsed melanoma-specific laser therapy mechanism. We have successfully achieved in vivo label-free imaging of rare single circulating melanoma cells in both arteries and veins of mice. Further, the photoacoustic signal from a circulating melanoma cell immediately hardware triggers a lethal pinpoint laser irradiation to kill it on the spot in a thermally confined manner without causing collateral damage. A pseudo-therapy study including both in vivo and in vitro experiments demonstrated the performance and the potential clinical value of our method, which can facilitate early treatment of metastasis by clearing circulating tumor cells from vasculature. PMID- 28000789 TI - Earliest known unequivocal rhinocerotoid sheds new light on the origin of Giant Rhinos and phylogeny of early rhinocerotoids. AB - Forstercooperiines are a group of primitive rhinocerotoids with a relatively large body size in the Eocene, and normally considered to be closely related to Giant Rhinos. Here we report a new forstercooperiine, Pappaceras meiomenus sp. nov., from the late Early Eocene Arshanto Formation, Erlian Basin, Nei Mongol, China. Pappaceras is the earliest known unequivocal rhinocerotoid, and the holotype of the new species, represented by the most complete cranium of forstercooperiines known to date, shows the earliest evidence of reduction of the first upper premolar in rhinocerotoids, and resembles paraceratheriine Juxia in basicranial features, supporting the interpretation that the forstercooperiine clade is ancestral to paraceratheriines. The new species also displays some similarities with amynodontids in craniodental structures. Phylogenetic analysis identifies P. meiomenus as a basal taxon of the monophyletic forstercooperiines. It also reveals novel phylogenetic relationships of early rhinocerotoids that indicates Uintaceras is the sister group of paraceratheriids, to which amynodontids are more closely related than to any other group of rhinocerotoids. Furthermore, the eggysodontid clade is excluded from hyracodontids and placed as the sister group of rhinocerotids. Hyracodontidae, excluding paraceratheriids and eggysodontids, is placed as the most basal group of the rhinocerotoids. PMID- 28000790 TI - A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies. Currently, the only therapeutic option for advanced HCC is Sorafenib, an inhibitor whose targets include RAF. Unexpectedly, RAF1 expression is reduced in human HCC samples. Modelling RAF1 downregulation by RNAi increases the proliferation of human HCC lines in xenografts and in culture; furthermore, RAF1 ablation promotes chemical hepatocarcinogenesis and the proliferation of cultured (pre)malignant mouse hepatocytes. The phenotypes depend on increased YAP1 expression and STAT3 activation, observed in cultured RAF1-deficient cells, in HCC xenografts, and in autochthonous liver tumours. Thus RAF1, although essential for the development of skin and lung tumours, is a negative regulator of hepatocarcinogenesis. This unexpected finding highlights the contribution of the cellular/tissue environment in determining the function of a protein, and underscores the importance of understanding the molecular context of a disease to inform therapy design. PMID- 28000791 TI - Observing eruptions of gas-rich compressible magmas from space. AB - Observations of volcanoes from space are a critical component of volcano monitoring, but we lack quantitative integrated models to interpret them. The atmospheric sulfur yields of eruptions are variable and not well correlated with eruption magnitude and for many eruptions the volume of erupted material is much greater than the subsurface volume change inferred from ground displacements. Up to now, these observations have been treated independently, but they are fundamentally linked. If magmas are vapour-saturated before eruption, bubbles cause the magma to become more compressible, resulting in muted ground displacements. The bubbles contain the sulfur-bearing vapour injected into the atmosphere during eruptions. Here we present a model that allows the inferred volume change of the reservoir and the sulfur mass loading to be predicted as a function of reservoir depth and the magma's oxidation state and volatile content, which is consistent with the array of natural data. PMID- 28000792 TI - Mechanistic Study of Tetrahydrofuran- acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma. AB - For past three decades, numerous studies have elucidated the antiproliferative effects of acetogenins in hopes of developing a new class of clinical anticancer agents. However, clear and definitive action mechanisms of acetogenins were less clarified. In the present study, three tetrahydrofuran (THF)-containing acetogenins were found to have potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate resistant counterparts. The THF-containing acetogenins induced G2/M phase arrest, mitochondrial damage and apoptosis, and increased cytosolic and mitochondrial Ca2+ in NPCs. Microarray analysis of NPC-TW01 cells treated with squamostatin A, a non-adjacent bis-THF acetogenin, demonstrated an increased endoplasmic reticulum (ER)-stress response (ESR). Enhanced ESR in squamostatin A-treated cells was confirmed by real-time PCR, Western blot and shRNA gene knockdown experiments. Although our results showed that squamostatin A-induced ESR was independent of extracellular Ca2+, the presence of extracellular Ca2+ enhanced the antiproliferative effect of acetogenins. In vivo analyses demonstrated that squamostatin A showed good pharmacokinetic properties and significantly retarded NPC tumor growth in the xenograft mouse model. Conclusively, our work demonstrates that acetogenins are effective and selective inducers of the ESR that can block NPC proliferation, and illustrate a previously unappreciated antitumor mechanism of acetogenins that is effective against nasopharyngeal malignancies. PMID- 28000793 TI - Root transcriptome of two contrasting indica rice cultivars uncovers regulators of root development and physiological responses. AB - The huge variation in root system architecture (RSA) among different rice (Oryza sativa) cultivars is conferred by their genetic makeup and different growth or climatic conditions. Unlike model plant Arabidopsis, the molecular basis of such variation in RSA is very poorly understood in rice. Cultivars with stable variation are valuable resources for identification of genes involved in RSA and related physiological traits. We have screened for RSA and identified two such indica rice cultivars, IR-64 (OsAS83) and IET-16348 (OsAS84), with stable contrasting RSA. OsAS84 produces robust RSA with more crown roots, lateral roots and root hairs than OsAS83. Using comparative root transcriptome analysis of these cultivars, we identified genes related to root development and different physiological responses like abiotic stress responses, hormone signaling, and nutrient acquisition or transport. The two cultivars differ in their response to salinity/dehydration stresses, phosphate/nitrogen deficiency, and different phytohormones. Differential expression of genes involved in salinity or dehydration response, nitrogen (N) transport, phosphate (Pi) starvation signaling, hormone signaling and root development underlies more resistance of OsAS84 towards abiotic stresses, Pi or N deficiency and its robust RSA. Thus our study uncovers gene-network involved in root development and abiotic stress responses in rice. PMID- 28000794 TI - Parental life events cause behavioral difference among offspring: Adult pre gestational restraint stress reduces anxiety across generations. AB - While effects of gestational, neonatal or adolescent stress on psychological alterations in progeny have been extensively studied, much less is known regarding the effects of adult pre-gestational life events on offspring behavior. Although full siblings often display behavioral differences, whether the different parental life events prior to different pregnancies contribute to these behavioral differences among siblings is worth studying. In this study, male and female adult mice were restrained for 60 days before mating with unstressed or stressed partners. F1 offspring were examined for anxiety or mated to generate F2. Both F1 females and males from restrained mothers and/or fathers showed significantly reduced anxiety and serum cortisol and increased mRNA levels of glucocorticoid receptor and brain-derived neurotrophic factor compared to control offspring from unstressed parents. Similar behavioral and molecular changes were also observed in F2 females and males. Although restraint of adolescent mice reduced anxiety in F1 of both sexes, social instability of them increased anxiety predominantly in F1 females. Thus, adult pre-gestational restraint reduced offspring's anxiety across generations; different stressors on parents may cause different phenotypes in offspring; individual behaviors can depend on adult life experiences of parents. PMID- 28000795 TI - Fabrication of Sesame Sticks-like Silver Nanoparticles/Polystyrene Hybridnanotubes and Their Catalytic Effects. AB - A novel and efficient catalyst is one of the goals in the material field, and the involvement of nanoscience and technology has brought new vigor to the development of catalyst. This research aimed to develop a simple two-step route to fabricate Fe3O4@PS/PDA-Ag hybridnanotubes with size-controllable and highly dispersed silver nanoparticles (NPs). First, Fe3O4@PS nanotubes of a sound mechanical property were prepared using polystyrene (PS)/toluene solution containing highly dispersed oleic acid modified Fe3O4 particles in a commercial AAO template. Next, the facile technique was used to form in situ silver NPs on the surface of magnetic PS (Fe3O4@PS) nanotubes through dopamine coating. The catalytic effects of the prepared Fe3O4@PS/PDA-Ag hybridnanotubes with highly dispersed AgNPs were characterized using a range of analytical methods, including transmission electron microscopy, thermogravimetric analysis, UV-Visible spectroscopy, and X-ray diffraction. It was found that such prepared Fe3O4@PS/PDA Ag hybridnanotubes had a large specific surface area. They possessed excellent activities in catalyzing the reduction of 4-nitrophenol (4-NP) by NaBH4 in the aqueous phase. Furthermore, they were readily separated from fluid and retrieved by an external magnet. Their catalyst activity and recyclability demonstrated that this approach we proposed had the potential to become a new idea and route for catalytic platform. PMID- 28000797 TI - Mid-Cretaceous carbon cycle perturbations and Oceanic Anoxic Events recorded in southern Tibet. AB - The organic carbon isotope (delta13Corg) curve for ~1.7-km-thick mid-Cretaceous strata of the Chaqiela section in Gamba area, southern Tibet is presented in this study. C-isotopic chemostratigraphic correlation combined with biostratigraphic constraints show that the Chaqiela section spans early Aptian through early Campanian period, and that almost all of the carbon cycle perturbations and Oceanic Anoxic Events during the mid-Cretaceous period are well recorded in the continental margin area of the southeastern Tethys Ocean. Significantly, two levels of methane-derived authigenic carbonates were identified at the onset of OAE1b near the Aptian-Albian boundary. We suggest that an increase in methane release from gas hydrates, potentially driven by sea-level fall and bottom water temperature increase, may have contributed to the large negative delta13Corg excursions and global warming during OAE1b. PMID- 28000799 TI - Invited Commentary: Epipericardial fat necrosis: a unique clinicoradiologic disease. PMID- 28000796 TI - Identification of DEP domain-containing proteins by a machine learning method and experimental analysis of their expression in human HCC tissues. AB - The Dishevelled/EGL-10/Pleckstrin (DEP) domain-containing (DEPDC) proteins have seven members. However, whether this superfamily can be distinguished from other proteins based only on the amino acid sequences, remains unknown. Here, we describe a computational method to segregate DEPDCs and non-DEPDCs. First, we examined the Pfam numbers of the known DEPDCs and used the longest sequences for each Pfam to construct a phylogenetic tree. Subsequently, we extracted 188 dimensional (188D) and 20D features of DEPDCs and non-DEPDCs and classified them with random forest classifier. We also mined the motifs of human DEPDCs to find the related domains. Finally, we designed experimental verification methods of human DEPDC expression at the mRNA level in hepatocellular carcinoma (HCC) and adjacent normal tissues. The phylogenetic analysis showed that the DEPDCs superfamily can be divided into three clusters. Moreover, the 188D and 20D features can both be used to effectively distinguish the two protein types. Motif analysis revealed that the DEP and RhoGAP domain was common in human DEPDCs, human HCC and the adjacent tissues that widely expressed DEPDCs. However, their regulation was not identical. In conclusion, we successfully constructed a binary classifier for DEPDCs and experimentally verified their expression in human HCC tissues. PMID- 28000798 TI - Identification and Evaluation of Novel Drug Targets against the Human Fungal Pathogen Aspergillus fumigatus with Elaboration on the Possible Role of RNA Binding Protein. AB - BACKGROUND: Aspergillus fumigatus is an airborne opportunistic fungal pathogen that can cause fatal infections in immunocompromised patients. Although the current anti-fungal therapies are relatively efficient, some issues such as drug toxicity, drug interactions, and the emergence of drug-resistant fungi have promoted the intense research toward finding the novel drug targets. METHODS: In search of new antifungal drug targets, we have used a bioinformatics approach to identify novel drug targets. We compared the whole proteome of this organism with yeast Saccharomyces cerevisiae to come up with 153 specific proteins. Further screening of these proteins revealed 50 potential molecular targets in A. fumigatus. Amongst them, RNA-binding protein (RBP) was selected for further examination. The aspergillus fumigatus RBP (AfuRBP), as a peptidylprolyl isomerase, was evaluated by homology modeling and bioinformatics tools. RBP deficient mutant strains of A. fumigatus were generated and characterized. Furthermore, the susceptibility of these strains to known peptidylprolyl isomerase inhibitors was assessed. RESULTS: AfuRBP-deficient mutants demonstrated a normal growth phenotype. MIC assay results using inhibitors of peptidylprolyl isomerase confirmed a higher sensitivity of these mutants compared to the wild type. CONCLUSION: Our bioinformatics approach revealed a number of fungal specific proteins that may be considered as new targets for drug discovery purposes. Peptidylprolyl isomerase, as a possible drug target, was evaluated against two potential inhibitors and the promising results were investigated mechanistically. Future studies would confirm the impact of such target on the antifungal discovery investigations. PMID- 28000800 TI - Laparoscopic resection of rectal cancer in the elderly. AB - Recent published trials have failed to demonstrate that laparoscopic resection is not inferior to open resection of rectal cancer in terms of pathologic outcomes. However, there have been numerous studies showing the benefit of laparoscopic resection in terms of short-term complications and quality of life. Fewer complications and shorter hospital stays improve the chance of maintaining functional status, which is very important for the elderly population. Thus, laparoscopic resection of rectal cancer remains a viable option for the elderly. PMID- 28000801 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000448009.]. PMID- 28000802 TI - Metal nanofoams via a facile microwave-assisted solvothermal process. AB - A novel, facile, non-hazardous, low temperature/pressure microwave solvothermal method of producing pure copper, silver, and nickel metal nanofoams is presented. The nanofoams have been produced using inexpensive metal acetates and polyglycol solvent. The nanofoam formation proceeds in two steps within a single-pot synthesis: formation of metal nanoparticles, followed by the sintering of nanoparticles into nanofoams. The nanofoams have many potential uses in clean energy applications, particularly lithium-ion batteries. PMID- 28000803 TI - Efficacious fluorescence turn-on probe for high-contrast imaging of human cells overexpressing quinone reductase activity. AB - We report a new turn-on substrate probe whose intense fluorescent reporter signature is selectively provided upon probe activation by the cancer-associated oxidoreductase, hNQO1. The extremely high fluorescence turn-on of the probe was utilized to generate fluorescence microscope images of hNQO1-expressing, tumor derived colorectal and ovarian cancer cells with unprecedented positive signal-to negative background ratios (PNRs), a key step toward probe application in guided surgical removal of diseased tissues. PMID- 28000804 TI - A five-fold interpenetrated metal-organic framework showing a large variation in thermal expansion behaviour owing to dramatic structural transformation upon dehydration-rehydration. AB - A five-fold interpenetrated metal organic framework (MOF) has been shown to exhibit anomalous thermal expansion due to the combined effect of hinge-like motion and sliding of individual diamondoid networks. Upon dehydration, the MOF undergoes dramatic structural changes, thereby altering its thermal expansion behaviour to a large extent. PMID- 28000805 TI - Computational prediction of hetero-interpenetration in metal-organic frameworks. AB - We present a computational algorithm that can screen through a database of metal organic framework structures and identify materials that lead to hetero interpenetration with targeted porous materials. Two MOFs (IRMOF-1 and IRMOF-8) were selected as target materials and our algorithm identified PCN-68 and PCN-610 as matching candidates for interpenetration. Molecular simulation results indicate that the interpenetrated MOFs possess enhanced methane and hydrogen adsorption properties compared to the parent materials. PMID- 28000806 TI - Colloidal atomic layer deposition growth of PbS/CdS core/shell quantum dots. AB - Traditionally, PbS/CdS quantum dots (QDs) have been synthesized via a cation exchange method, making fine control over shell growth challenging. We show here that colloidal atomic layer deposition (c-ALD) allows for the sequential growth of single monolayers of the shell, thus creating a 'true' CdS shell on PbS QDs. PMID- 28000807 TI - A semi-classical approach to the calculation of highly excited rotational energies for asymmetric-top molecules. AB - We report a new semi-classical method to compute highly excited rotational energy levels of an asymmetric-top molecule. The method forgoes the idea of a full quantum mechanical treatment of the ro-vibrational motion of the molecule. Instead, it employs a semi-classical Green's function approach to describe the rotational motion, while retaining a quantum mechanical description of the vibrations. Similar approaches have existed for some time, but the method proposed here has two novel features. First, inspired by the path integral method, periodic orbits in the phase space and tunneling paths are naturally obtained by means of molecular symmetry analysis. Second, the rigorous variational method is employed for the first time to describe the molecular vibrations. In addition, we present a new robust approach to generating rotational energy surfaces for vibrationally excited states; this is done in a fully quantum-mechanical, variational manner. The semi-classical approach of the present work is applied to calculating the energies of very highly excited rotational states and it reduces dramatically the computing time as well as the storage and memory requirements when compared to the fullly quantum-mechanical variational approach. Test calculations for excited states of SO2 yield semi classical energies in very good agreement with the available experimental data and the results of fully quantum-mechanical calculations. PMID- 28000808 TI - The synergistic effect achieved by combining different nitrogen-doped carbon shells for high performance capacitance. AB - Ellipsoid nitrogen-doped hollow carbon shells with different nitrogen contents and electrical conductivities were prepared using a simple calcination method by regulating the calcination temperature. Although a high nitrogen content promotes pseudocapacitance, it reduces the electrical conductivity of carbon, causing loss of capacitance. The best rate performance was achieved by a mixture of two types of ellipsoid nitrogen-doped hollow carbon shells, in which one contains a higher level of nitrogen with lower conductivity and higher pseudocapacitance, while the other contains a relatively lower level of nitrogen with higher conductivity. The enhanced performance can be explained by the synergistic effect of one component providing high pseudocapacitance and the other component serving as a highly electrically conductive network, which leads to activation of "nitrogen" to enhance pseudocapacitance performance. The mixed material showed a specific capacitance of 156.9 F g-1 at a high current density of 10 A g-1, with no degradation after 10 000 cycles. PMID- 28000810 TI - Comment on "trans-1,2-Disiloxybenzocyclobutene, an adequate partner for the auto oxidation: EPR/spin trapping and theoretical studies" by J. Drujon et al., Phys. Chem. Chem. Phys., 2014, 16, 7513. AB - Despite the claim of the contrary, (i) the facile formation of a ring-opened cyclic peroxide from reaction of a 1,2-disubstituted benzocyclobutene with molecular oxygen has been reported before, and (ii) the analysis of the mechanistic steps of this process is incomplete, as only the symmetry-allowed conrotatory ring-opening of the benzocyclobutene has been considered. The probable involvement of biradical intermediates/biradicaloid transition states in a formally symmetry-forbidden reaction sequence has not been taken into account. PMID- 28000809 TI - Long range electrostatic forces in ionic liquids. AB - Ionic liquids are pure salts that are liquid under ambient conditions. As liquids composed solely of ions, the scientific consensus has been that ionic liquids have exceedingly high ionic strengths and thus very short Debye screening lengths. However, several recent experiments from laboratories around the world have reported data for the approach of two surfaces separated by ionic liquids which revealed remarkable long range forces that appear to be electrostatic in origin. Evidence has accumulated demonstrating long range surface forces for several different combinations of ionic liquids and electrically charged surfaces, as well as for concentrated mixtures of inorganic salts in solvent. The original interpretation of these forces, that ionic liquids could be envisioned as "dilute electrolytes," was controversial, and the origin of long range forces in ionic liquids remains the subject of discussion. Here we seek to collate and examine the evidence for long range surface forces in ionic liquids, identify key outstanding questions, and explore possible mechanisms underlying the origin of these long range forces. Long range surface forces in ionic liquids and other highly concentrated electrolytes hold diverse implications from designing ionic liquids for energy storage applications to rationalizing electrostatic correlations in biological self-assembly. PMID- 28000811 TI - N-Doping of graphene oxide at low temperature for the oxygen reduction reaction. AB - Nitrogen doping of graphene oxide was demonstrated for the first time at a temperature as low as 5 degrees C in ammonia solution with the aid of ultrasonication. Controlling the ultrasonication time and bath temperature permitted tuning of the N doping level. The resulting N doped graphene oxide showed high activity towards the oxygen reduction reaction. PMID- 28000812 TI - N-terminal lipid conjugation of amyloid beta(1-40) leads to the formation of highly ordered N-terminally extended fibrils. AB - Fibril formation of amyloid beta(1-40) (Abeta(1-40)) peptides N-terminally lipid modified with saturated octanoyl or palmitoyl lipid chains was investigated. Lipid modification of Abeta(1-40) significantly accelerates the fibrillation kinetics of the Abeta peptides as revealed by ThT fluorescence. Electron microscopy and X-ray diffraction results indicate a heterogeneous cross-beta structure of the fibrils formed by the lipid-conjugated peptides. Solid-state NMR was used to investigate structural features of these fibrils. The lipid moieties form dynamic and loosely structured heterogeneous lipid assemblies as inferred from 2H NMR of the deuterated lipid chains. 13C NMR studies of selected isotopic labels reveals that in addition to Phe19 and Val39, which are part of the canonical cross-beta structure, also N-terminal residues (Ala2, Phe4, Val12) are found in beta-strand conformation. This suggests that the increased hydrophobicity induced by the lipid modification, alters the energy landscape rendering an N-terminal extension of the beta-sheet structure favorable. Furthermore, the fibrils formed by the Abeta-lipid hybrids are much more rigid than wildtype Abeta fibrils as inferred from NMR order parameter measurements. Taken together, increasing the local hydrophobicity of the Abeta N-terminus results in highly ordered but heterogeneous amyloid fibrils with extended N terminal beta-sheet structure. PMID- 28000813 TI - Dual aggregation-induced emission for enhanced fluorescence sensing of furin activity in vitro and in living cells. AB - The aggregation-induced emission (AIE) effect has recently been widely applied for biomarker sensing. But developing "smart" strategies to effectively aggregate the AIE fluorogen and additionally enhance the fluorescence emission remain challenging. In this work, by integrating a biocompatible condensation reaction with an AIE fluorogen, we rationally designed a "smart" dual AIE probe Ac-Arg-Val Arg-Arg-Cys(StBu)-Lys(TPE)-CBT (1) for enhanced fluorescence sensing furin activity in vitro and in living cells. Compared with the single AIE probe Ac-Arg Val-Arg-Arg-Lys(TPE)-OH (1-Ctrl) which also subjects to furin cleavage, fluorescence emissions of 1 were additionally enhanced 1.7 fold and 3.4 fold in vitro and in living cells, respectively. We envision that, in the near future, our "smart" strategy of enzyme-instructed dual AIE could be widely applied for sensing (or imaging) enzyme activity in vitro and even in vivo with dramatically enhanced sensitivity. PMID- 28000814 TI - Modulating the photocatalytic redox preferences between anatase TiO2 {001} and {101} surfaces. AB - It is widely believed that anatase TiO2 {001} and {101} surfaces acts as the oxidative and reductive sites in photocatalytic reactions, respectively, which is attributed to their different intrinsic surface structures. However, we demonstrate that the photocatalytic redox preferences of TiO2 {001} and {101} surfaces are determined by the adsorbate-reconstructed surface structure instead of their intrinsic surface structures, which can be modulated by surface protonation/deprotonation. PMID- 28000815 TI - Induced core-shell structure and the electric properties of (K0.48Na0.52)0.95Li0.05Nb0.95Sb0.05O3 ceramics. AB - The relationship among dielectric anomaly, ferroelectric response, defects, and microstructures was established for (K0.48(1+x)Na0.52)0.95Li0.05Nb0.95Sb0.05O3 (x = 0.04, 0.00, -0.02, -0.04 and -0.08) ceramics. For x = -0.02 and -0.04, larger coercive fields and lower remnant polarizations were obtained; besides, an additional dielectric relaxation behavior was observed with the activation energy Ea being about 2.19 eV and 1.92 eV, respectively. Furthermore, the grain and grain boundary contributions to the capacitance were separated using impedance spectroscopy, which, combined with back-scattering characterization, firmly indicates the core-shell structure of K-deficient samples (x = -0.02 and -0.04). Unlike the cores, the shells possess a large amount of K+ vacancies (). This work paves a way for regulating the fine structure and more on the electrical properties of KNN-based materials. PMID- 28000816 TI - First kinetic study of the atmospherically important reactions BrHg + NO2 and BrHg + HOO. AB - We use computational chemistry to determine the rate constants and product yields for the reactions of BrHg with the atmospherically abundant radicals NO2 and HOO. The reactants, products, and well-defined transition states are characterized using CCSD(T) with large basis sets. The potential energy profiles for the barrierless addition of HOO and NO2 to BrHg are characterized using CASPT2 and RHF-CCSDT, and the rate constants are computed as a function of temperature and pressure using variational transition state theory and master equation simulations. The calculated rate constant for the addition of NO2 to BrHg is larger than that for the addition of HOO by a factor of up to two under atmospheric conditions. For the reaction of HOO with BrHg the addition reaction entirely dominates competing HOO + BrHg reaction channels. The addition of NO2 to BrHg initially produces both BrHgNO2 and BrHgONO, but after a few seconds under atmospheric conditions the sole product is syn-BrHgONO. A previously unsuspected reaction channel for BrHg + NO2 competes with the addition to yield Hg + BrNO2. This reaction reduces the mercury oxidation state in BrHg from Hg(i) to Hg(0) and slows the atmospheric oxidation of Hg(0). While the rate constant for this reduction channel is not well-constrained by the present calculations, it may be as much as 18% as large as the oxidation channel under some atmospheric conditions. As no experimental kinetic or product yield data are available for the reactions studied here, this work will provide guidance for atmospheric modelers and experimental kineticists. PMID- 28000817 TI - Modeling the abnormally slow infiltration rate in mesoporous films. AB - Mesoporous films have been shown to exhibit striking behaviors in capillary driven infiltration experiments. The process has been shown to follow classical Lucas-Washburn dynamics, but the effective pore radius has been calculated from hydrodynamic resistance considerations to be orders of magnitude lower than measured pore dimensions. In addition, the infiltration rate has been observed to decrease with increasing pore diameter, in contrast to the expected trend for capillary-like pores. Here, we present a simple model accounting for the mechanism behind these anomalous effects. We found the infiltration rate to be inversely proportional to the cubed ratio of pore to neck size. This physical scaling correctly modeled both the magnitude of the infiltration rate and its variation with pore diameters, for a wide range of experimental data. The model established a connection between capillary filling dynamics and nanoscale pore structure, which is of practical interest for the design and characterization of mesoporous films. PMID- 28000818 TI - Diffusive dynamics of polymer chains in an array of nanoposts. AB - We present a dynamic density functional approach to study polymer chain diffusion in a good solvent in the confinement of a nanopost array. Three key results emerge from our study. First, we show different scaling laws of the chains moving toward, close to, and around the posts. Second, in the flux process of polymer chains, the head, side, and middle segments display different scaling laws. As the chains come in contact with the posts, an enlarged motion discrepancy emerges between the head and middle segments perpendicular to the posts. For instance, the motion of head segments transforms from Zimm to reputation type, whereas the middle segments almost retain the Zimm motion. Third, as the spacing crack between two posts narrows down, a climbing effect along the posts can be clearly observed in the polymer motion. PMID- 28000819 TI - Zeolite molecular accessibility and host-guest interactions studied by adsorption of organic probes of tunable size. AB - A series of fluorescent probe molecules based on the commercially available trans 4-(4-(diethylamino)styryl)-N-methylpyridinium iodide (DAMPI) scaffold has been developed. The dynamic radii of these DAMPI-type probes covered a range of 5.8 to 10.1 A and could be changed by varying the alkyl substituents on the amine donor group, with limited effect on the electronic properties. These probe molecules allow for the direct evaluation of the molecular accessibility into confined spaces, more specifically the micropore architecture of zeolite materials. Evaluation of industrially relevant zeolite materials with 8- (CHA), 10- (MFI) and 12-membered ring pores (FAU) showed that steric bulk influences the rate of adsorption, the amount of probe molecule taken up by the zeolite as well as the interaction of the probe molecule with the zeolite material. Furthermore, a positive linear correlation is found between the pore-probe size difference and total probe uptake by the zeolite. The absorption spectra of each probe molecule within the zeolites show that this DAMPI-type compound is chemically bound to the zeolite's acid sites. The new approach shows the general principle of determining size-accessibility relationships in microporous solids with a series of fluorescent probes of systematically tunable size. PMID- 28000820 TI - Stability of 2',3' and 3',5' cyclic nucleotides in formamide and in water: a theoretical insight into the factors controlling the accumulation of nucleic acid building blocks in a prebiotic pool. AB - Synthesis of the first RNAs represents one of the cornerstones of the emergence of life. Recent studies demonstrated powerful scenarios of prebiotic synthesis of cyclic nucleotides in aqueous and formamide environments. This raised a question about their thermodynamic stability, a decisive factor determining their accumulation in a prebiotic pool. Here we performed ab initio molecular dynamics simulations at various temperatures in formamide and water to study the relative stabilities of the 2',3' and 3',5' isomers of cyclic nucleotides. The computations show that in an aqueous environment 2',3' cyclic nucleotides are more stable than their 3',5' counterparts at all temperatures up to the boiling point. In contrast, in formamide higher temperatures favor the accumulation of the 3',5' cyclic form, whereas below about 400 K the 2',3' cyclic form becomes more stable. The latter observation is consistent with a formamide-based origin scenario, suggesting that 3',5' cyclic nucleotides accumulated at higher temperatures subsequently allowed oligomerization reactions after fast cooling to lower temperatures. A statistical analysis of the geometrical parameters of the solutes indicates that thermodynamics of cyclic nucleotides in aqueous and formamide environments are dictated by the floppiness of the molecules rather than by the ring strain of the cyclic phosphodiester linkages. PMID- 28000822 TI - Ionic current modulation from DNA translocation through nanopores under high ionic strength and concentration gradients. AB - Ion transport through nanopores is an important process in nature and has important engineering applications. To date, most studies of nanopore ion transport have been carried out with electrolytes of relatively low concentrations. In this paper, we report on ionic current modulation from the translocation of dsDNA through a nanopore under high ionic strength and with an electrolyte concentration gradient across the nanopore. Results show that in this case, DNA translocation can induce either negative or positive ionic current modulation, even though usually only downward peaks are expected under this high ion concentration. Through a series of experiments and numerical simulations with nanopores of different diameters and concentration gradients, it is found that the positive pulse is due to extra ions outside the electric double layer of the DNA that are brought into the nanopore by the enhanced electroosmotic flow (EOF) with the negatively charged DNA inside the nanopore. PMID- 28000823 TI - Internal potential mapping of charged solid-state-lithium ion batteries using in situ Kelvin probe force microscopy. AB - Solid-state-lithium ion batteries (SS-LIBs) are a promising candidate for next generation energy storage devices. Novel methods for characterizing electrochemical reactions occurring during battery operation at the nanoscale are highly required for understanding the fundamental working principle and improving the performance of the devices. In this work, we combined Ar ion milling under non-atmospheric conditions with in situ cross-sectional Kelvin probe force microscopy (KPFM) for direct imaging of the internal electrical potential distribution of the SS-LIBs. We succeeded in the direct visualization of the change in the potential distribution of a cathode composite electrode (a mixture of the active materials, solid electrolytes, and conductive additives) arising from battery charging (electrochemical reaction). The observed results provided several insights into battery operation, such as the behavior of Li ions and inhomogeneity of electrochemical reactions in the electrode. Our method paves the way to characterize the fundamental aspects of SS-LIBs for the improvement of device performance, including the evaluation of the distribution of the Li ion depleted regions, visualization of the conductive paths, and analysis of the cause of degradation. PMID- 28000825 TI - Micro-structured inverted pyramid texturization of Si inspired by self-assembled Cu nanoparticles. AB - A superior micron-sized inverted pyramid structure has been successfully achieved by one-step copper nanoparticles assisted chemical etching in Si/Cu(NO3)2/HF/H2O2 solution for light trapping in silicon solar cells. The detailed mechanisms of such a novel method have been systematically demonstrated. The charge transfer during the reaction has been revealed by the simplified energy band diagram of the system as well. In order to form micro-structured inverted pyramids, the generation and dissolution of Cu nanoparticles should keep in balance during the reaction, which depends on the concentration of the etchant, the doping type and the doping level of the silicon substrate. With the investigation of the intrinsic properties of the silicon substrate, the etching rate is found out as a combined result of the electron concentration and the defect density of the substrate, as well as the potential barrier on the interface of Si/Cu nanoparticles. Furthermore, the anisotropic nature of Cu assisted chemical etching has also been investigated. PMID- 28000830 TI - Semimetal to semiconductor transition and polymer electrolyte gate modulation in single-crystalline bismuth nanowires. AB - A semimetal to semiconductor transition in low-dimensional Bi nanowires is theoretically predicted based on the quantum confinement effect, which results in the enhancement of the thermoelectric performance. However, this transition has rarely been observed in the transport properties of gate modulation because of there being too few charge carriers induced by a typical electric field effect. In this paper, we report on our observations of the on-off state in a Bi nanowire using a polyethylene oxide/LiClO4 electrolyte gate, which produces a much larger effect than a back-gate. The carrier density of the surface state was found to be consistent with previously reported results. The intrinsic properties of the Bi nanowires, as obtained by temperature- and diameter-dependent gate modulations, are also discussed. PMID- 28000831 TI - Formylation of phenols using formamidine acetate. AB - We report a new method to formylate phenol derivatives using formamidine acetate and acetic anhydride. This general-purpose transformation is a significant improvement over many other methods and does not require high temperatures or the addition of strong acid or base. Mono-, di-, and tri-formylated product can be obtained, depending on the substrate and conditions used. PMID- 28000832 TI - Autocatalytic synthesis of multifunctional precursors for fabricating silica microspheres with well-dispersed Ag and Co3O4 nanoparticles. AB - Herein, an autocatalytic route to fabricate dual metal ion-equipped organic/inorganic hybrid silica, an ideal precursor for multifunctional silica based composites integrated with well-dispersed Ag and Co3O4 nanoparticles was demonstrated. Significantly, by rational selection of reactants, such dual metal ion-equipped organic/inorganic hybrid silica can be synthesized through successive spontaneous reactions under near neutral conditions without an additional catalyst. Both the Ag+ and Co2+ ions are introduced into silica by chemical bonds, which favor the formation of small-sized and well-dispersed Ag and Co3O4 nanoparticles without aggregation in the entire silica matrix. After calcination, multifunctional silica composites equipped with well-dispersed Ag and Co3O4 nanoparticles were obtained. The as-obtained silica composites, as indicated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), have a spherical morphology and smooth surface. TEM tests also reveal the well dispersed fashion of Ag and Co3O4 nanoparticles. In addition, the obtained Ag-Co3O4@SiO2 composites exhibit good catalytic performance in the reduction of methylene blue (MB) with NaBH4 as a reducing agent, and can be readily recycled by an external magnetic field due to their superparamagnetic properties. PMID- 28000833 TI - Boosting infrared energy transfer in 3D nanoporous gold antennas. AB - The applications of plasmonics to energy transfer from free-space radiation to molecules are currently limited to the visible region of the electromagnetic spectrum due to the intrinsic optical properties of bulk noble metals that support strong electromagnetic field confinement only close to their plasma frequency in the visible/ultraviolet range. In this work, we show that nanoporous gold can be exploited as a plasmonic material for the mid-infrared region to obtain strong electromagnetic field confinement, co-localized with target molecules into the nanopores and resonant with their vibrational frequency. The effective optical response of the nanoporous metal enables the penetration of optical fields deep into the nanopores, where molecules can be loaded thus achieving a more efficient light-matter coupling if compared to bulk gold. In order to realize plasmonic resonators made of nanoporous gold, we develop a nanofabrication method based on polymeric templates for metal deposition and we obtain antenna arrays resonating at mid-infrared wavelengths selected by design. We then coat the antennas with a thin (3 nm) silica layer acting as the target dielectric layer for optical energy transfer. We study the strength of the light matter coupling at the vibrational absorption frequency of silica at 1240 cm-1 through the analysis of the experimental Fano lineshape that is benchmarked against identical structures made of bulk gold. The boost in the optical energy transfer from free-space mid-infrared radiation to molecular vibrations in nanoporous 3D nanoantenna arrays can open new application routes for plasmon enhanced physical-chemical reactions. PMID- 28000834 TI - Self-assembled Co3O4 hexagonal plates by solvent engineering and their dramatically enhanced electrochemical performance. AB - In this study, a facile two-phase solvothermal method was used to synthesize Co3O4 nanocubes with high crystallinity and narrow size distribution (~49 nm) for use in lithium-ion batteries. Here, oleylamine (OAm) was chosen as the solvent, surfactant, and reducing agent. After washing with the appropriate organic solvent, the Co3O4 nanocubes self-assembled into hexagonal plates with a diameter and thickness of approximately 2.5 MUm and 550 nm, respectively. Moreover, with the assistance of dipole-dipole and van der Waals interactions, the Co3O4 nanocubes stacked along the [111] direction with their exposed facets attached, leading to their final exposed cross-sectional facet being (111). A possible assembling mechanism is proposed and explained in detail. Furthermore, the self assembled (111) faceted Co3O4 plates exhibited superior electrochemical capacity and stability to those original (001) faceted Co3O4 nanocubes for Li+ ion storage. Therefore, the solvent engineered self-assembly into secondary structures has proven to be a potential strategy for energy applications. PMID- 28000839 TI - IL-1beta impedes the chondrogenic differentiation of synovial fluid mesenchymal stem cells in the human temporomandibular joint. AB - Mesenchymal stem cell-based therapy has great therapeutic potential for temporomandibular joint (TMJ) cartilage repair. However, the behavior of mesenchymal stem cells in the inflammatory milieu following their delivery remains poorly understood. Synovial fluid-derived mesenchymal stem cells (SFMSCs) are a promising resource for TMJ cartilage repair, as they are easily obtained from patients with TMJ disorders (TMD). In this study, we obtained SFMSCs from patients with TMD and expanded them in vitro; we then stimulated the cells with interleukin (IL)-8, IL-1beta, IL-6, IL-10, tumor necrosis factor (TNF)-alpha and IL-12p. The cells expressed CD90, CD44, CD105 and CD73, and were negative for CD45, CD34, CD11b, CD19 and HLA-DR. They could be induced to differentiate into osteogenic, chondrogenic, adipogenic and neurogenic lineages in vitro. Only the levels of IL-6 and IL-8 were upregulated significantly following stimulation with IL-8, IL-1beta, IL-6, IL-10, TNF-alpha and IL-12p. Furthermore, IL-6 and IL-8 expression was driven mainly by IL-1beta-dependent nuclear factor-kappaB (NF kappaB) pathway activation, and was independent of IL-8, IL-6, IL-10, TNF-alpha and IL-12p. IL-6 and IL-8 expression was inhibited completely by treatment with the NF-kappaB inhibitor, BAY11-7082. SRY-box 9 (SOX9) was downregulated and matrix metalloproteinase (MMP)13 was upregulated upon chondrogenic differentiation induced in the cells also exposed to IL-1beta. Sulfated glycosaminoglycan production was also reduced upon chondrogenic differentiation in the presence of IL-6, but not IL-8. Thus, IL-1beta in the inflammatory milieu is crucial in regulating SFMSCs. In doing so, IL-1beta impedes the chondrogenic differentiation of SFMSCs. The upregulation of IL-6 and NF-kappaB pathway activation also contribute to this biological behavior. The findings of our study indicate the potential adverse effects of IL-1beta on the chondrogenic differentiation of SFMSCs, and may thus provide new insight into the pathogenesis of TMD. PMID- 28000840 TI - Identification of potential drug targets based on a computational biology algorithm for venous thromboembolism. AB - Venous thromboembolism (VTE) is a common, fatal and frequently recurrent disease. Changes in the activity of different coagulation factors serve as a pathophysiological basis for the recurrent risk of VTE. Systems biology approaches provide a better understanding of the pathological mechanisms responsible for recurrent VTE. In this study, a novel computational method was presented to identify the recurrent risk modules (RRMs) based on the integration of expression profiles and human signaling network, which hold promise for achieving new and deeper insights into the mechanisms responsible for VTE. The results revealed that the RRMs had good classification performance to discriminate patients with recurrent VTE. The functional annotation analysis demonstrated that the RRMs played a crucial role in the pathogenesis of VTE. Furthermore, a variety of approved drug targets in the RRM M5 were related to VTE. Thus, the M5 may be applied to select potential drug targets for combination therapy and the extended treatment of VTE. PMID- 28000841 TI - Genome-wide association scans for idiopathic osteonecrosis of the femoral head in a Korean population. AB - Osteonecrosis of the femoral head (ONFH) is a multifactorial disease and is associated with genetic predisposition, and exposure to certain risk factors. In particular, idiopathic ONFH in twins and the clustering of cases in families have indicated that genetic factors are involved. However, the majority of cases of ONFH are sporadic and various studies have demonstrated that differences in the study design and/or the ethnic groups analyzed leads to different results. The present study performed one of the first genome-wide association studies to identify genetic loci that may increase the risk of idiopathic ONFH. In total, 217 patients with idiopathic ONFH and 217 control samples, without ONFH, were genotyped using AxiomTM chips. Following quality control, 509,886 single nucleotide polymorphisms (SNPs) were included in the association analysis to identify genetic variants that may influence susceptibility to idiopathic ONFH. The lowest P-value identified by the current study was for an association with rs220324 (P=3.57x10-7), an SNP that is located near to the uromodulin-like 1 gene region on chromosome 21q22.3, although none of the SNPs reached the traditional genome-wide significance level of 5x10-8. However, the DnaJ heat shock protein family (Hsp40) member C6 (DNAJC6) locus, a region between 65.37 and 65.67 Mb located on chromosome 1p31.3, harbored a cluster of SNPs that were associated with idiopathic ONFH at a significance level of P<1x10-5. Four variants, rs10493374, rs12032616, rs17127529 and rs6679032, with marginal associations were located in and around the DNAJC6 locus and were in strong linkage disequilibrium with each other. In conclusion, the current study did not identify any SNPs that were associated with idiopathic ONFH at a genome-wide significance level, however, the results suggest that future studies should investigate the effects of SNPs in the DNAJC6 gene on the idiopathic ONFH risk. PMID- 28000842 TI - The anti-angiogenic role of soluble-form VEGF receptor in malignant gliomas. AB - Anti-angiogenic therapy represents a promising, new therapeutic modality for malignant gliomas. The present study was designed to define the malignant glioma cases most suitable for anti-angiogenic therapy and to demonstrate the efficacy of anti-angiogenic therapy using soluble-form Flt1 (sFlt1) gene delivery in mice. In human malignant glioma samples (39 glioblastomas, 21 anaplastic astrocytomas and 4 anaplastic oligoastrocytomas), protein expression of VEGF, and its specific natural inhibitor, sFlt1, as well as vessel architecture were assessed. Among these variables, VEGF >1000 ng/ml, VEGF/sFlt1 ratio >1, vessel density >30, and vessel area >7% were prognostic factors for malignant gliomas. VEGF/sFlt1 ratio >1 was the most powerful prognostic marker for survival in multivariate analysis. The sFlt1 gene was also successfully introduced into U87 glioma cells in vitro, resulting in 31% tumor growth inhibition in vivo. sFlt1-transfected tumor demonstrated high sFlt-1 expression along with diminished vessel density and area compared with the control tumor. In transfected tumor, VEGF expression was decreased in the viable area, but still high in the hypoxic area. sFlt1 and VEGF expression was re-evaluated in vitro using glioma cells under normoxic and hypoxic conditions. For sFlt1-transfected cells, VEGF expression was upregulated, but sFlt1 expression was downregulated, resulting in an increase of VEGF/sFlt1 ratio in hypoxic conditions. We conclude that malignant gliomas with a high VEGF/sFlt1 ratio and large vessel area are good candidates for anti-angiogenic therapy. Soluble Flt1 gene delivery was demonstrated to inhibit glioma growth, but this was limited in hypoxic areas. PMID- 28000843 TI - Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice. AB - Whole-wheat intake is known to reduce the risk of metabolic syndrome. However, the active component remains unclear. Recently, we identified bioactive peptides [leucine-arginine-proline (LRP) and leucine-glutamine-proline (LQP)] from wheat bran autolytic hydrolysate. The present study aimed to investigate the effects of LRP and LQP on non-alcoholic steatohepatitis (NASH) in a mouse model. We also evaluated the effects of these peptides on oxidative stress and on the AMP activated protein kinase (AMPK) signaling pathway, two major pathogenic factors of NASH. Seven-week-old male C57BL/6 mice were fed a high-fat diet for 10 weeks and administered water supplemented with 0.05% LRP, 0.20% LRP, 0.05% LQP, or 0.20% LQP (each n=5) or distilled water (control; n=5) ad libitum. Oxidative stress was evaluated by measuring the serum levels of diacron reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP). Hepatic expression of phosphorylated AMPK and phosphorylated acetyl-CoA carboxylase (ACC) were evaluated by immunoblotting. The result showed that non-alcoholic fatty liver disease activity score was significantly decreased in all types of treatment. Serum d-ROM levels were significantly decreased in the 0.20% LRP group, but not in the 0.05% LRP, 0.05% LQP, and 0.20% LQP groups. Serum BAP levels were significantly increased in the 0.05% LRP and 0.20% LRP groups, but not in the 0.05% LQP and 0.20% LQP groups. Immunoblotting analysis revealed that the expression of phospho-AMPK was increased whereas that of phospho-ACC was decreased in the 0.20% LQP group. In conclusion, we demonstrated that both LRP and LQP alleviated the severity of NASH in a high-fat diet-induced NASH mouse model. In addition, we showed that LRP and LQP modulated oxidative stress and upregulated AMPK/ACC, respectively. Thus, LRP and LQP may constitute clinically applicable therapeutic agents for NASH. PMID- 28000845 TI - Long non-coding RNA NEAT1 promotes malignant progression of thyroid carcinoma by regulating miRNA-214. AB - The long non-coding RNA nuclear enrich abundant transcript 1 (NEAT1) has been identified to be carcinogenic in various cancers and elevated NEAT1 expression was tightly linked to tumorigenesis and progression. However, the mechanism has not been revealed in progression of thyroid cancer. Tumor xenograft mouse model was established and tumor size was evaluated. Arg-1, NEAT1 and miR-214 expression in CBMs, TAMs, BMDMs and RAW 264.7 cell lines were detected. TPC-1 cells were subjected to si-NEAT1 transfection in vitro for cell viability study. A direct target of miRNA-214 (beta-catenin) was assessed, cell survival and invasion in TAMs were investigated. NEAT1, Arg-1 was highly expressed and miRNA-214 had lower expression in patients with thyroid cancer. NEAT1 knockout inhibited thyroid cancer cell survival, migration and invasion, along with reduced beta-catenin (a direct target of miRNA-214) protein expression. Furthermore, NEAT1 significantly accelerated thyroid cancer cell growth and metastasis in vitro and increased tumor size in vivo. Upregulation of NEAT1 decreased the expression of miRNA-214, presenting a reciprocal repression correlation. In conclusion, these results suggest that high expression of NEAT1 promoted the onset of thyroid carcinoma. In addition, NEAT1 promoted the malignant progression of thyroid cancer through regulating miRNA-214 expression, which adds to our understanding of the molecular mechanisms in thyroid carcinoma. PMID- 28000844 TI - Cytoprotective effects of esculetin against oxidative stress are associated with the upregulation of Nrf2-mediated NQO1 expression via the activation of the ERK pathway. AB - Esculetin, a coumarin derivative isolated from a variety of medicinal herbs, has been reported to possess multiple therapeutic and pharmacological actions. Although several studies have demonstrated the antioxidant activity of esculetin, its mechanisms of action have not been clearly established. The aim of this study was to evaluate the effects of esculetin against hydrogen peroxide (H2O2)-induced oxidative stress in C2C12 myoblasts and to investigate the mechanisms involved in this process. Our data indicated that esculetin preconditioning significantly attenuated H2O2-induced growth inhibition and DNA damage and the apoptosis of C2C12 cells by suppressing intracellular reactive oxygen species (ROS) accumulation. Treatment with esculetin effectively increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1). Esculetin treatment also activated extracellular signal-regulated kinase (ERK), and pre-treatment with PD98059, an ERK-specific inhibitor, blocked esculetin-mediated phosphorylation of Nrf2 and the induction of NQO1 expression. In addition, the protective effects of esculetin against H2O2-induced ROS accumulation, apoptosis and growth inhibition were abrogated in the C2C12 cells pre-treated with PD98059. Thus, the present study demonstrates that esculetin protects C2C12 cells against oxidative stress induced injury, possibly through the activation of the Nrf2/NQO1 pathway. PMID- 28000846 TI - Reduced miR-26a and miR-26b expression contributes to the pathogenesis of osteoarthritis via the promotion of p65 translocation. AB - Osteoarthritis (OA) is a common chronic joint disease, the etiology of which is complex. Disturbance to proinflammatory and anti-inflammatory signaling pathways is a major cause of OA. MicroRNAs (miRNAs/miR) are a group of endogenous, short, non-coding RNAs, the expression profile of which is disturbed in the cartilage of patients with OA. To determine the function of miRNAs during the progression of OA, the present study detected the expression levels of nine candidate miRNAs in cartilage samples from 33 patients with OA. The results demonstrated that miR 26a, miR-26b, miR-138 and miR-140 were downregulated in patients with OA. As predicted by a bioinformatics analysis and confirmed by luciferase assay and western blotting, the present study revealed that miR-26a and miR-26b are able to suppress karyopherin subunit alpha 3 (KPNA3) expression by targeting its 3' untranslated region. Since KPNA3 is an important mediator that modulates nuclear factor (NF)-kappaB p65 translocation, the present study examined the impact of miR-26a and miR-26b on NF-kappaB signaling. The results indicated that transfection of cells with a miR-26a or miR-26b inhibitor may promote NF-kappaB p65 translocation from the cytoplasm to the nucleus via the upregulation of KPNA3. Furthermore, the expression levels of matrix metalloproteinase-3, -9, -13 and cyclooxygenase-2 were upregulated following transfection with a miR-26a or miR-26b inhibitor. These results indicate that downregulation of miR-26a and miR 26b may contribute to the pathogenesis of OA via promotion of the NF-kappaB signaling pathway. The present study sheds light on the pathogenesis of OA and may provide a target for the development of therapeutic methods for the treatment of OA. PMID- 28000847 TI - PI3K/AKT signaling mediated by G protein-coupled receptors is involved in neurodegenerative Parkinson's disease (Review). AB - Parkinson's disease (PD) is a common progressive and multifactorial neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons. Numerous pathological processes including, inflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalance, and apoptosis as well as genetic factors may lead to neuronal degeneration. Motor deficits in PD are due mostly to the progressive loss of nigrostriatal dopaminergic neurons. Neuroprotection of functional neurons is of significance in the treatment of PD. G protein-coupled receptors (GPCRs) have been implicated in the neuroprotection against PD through the survival of dopaminergic neurons. In addition, phosphatidyl-inositol-3-kinase (PI3K)/AKT signaling has also been demonstrated to be neuroprotective. Knowledge of the mechanisms involved in this cellular protection could be critical for developing treatments to prevent this neurodegenerative disorder. In this review, we highlight the protective roles of the PI3K/AKT signaling pathway in the function of representative serotonin GPCRs. Particular attention is given to the molecular mechanisms of this pathway proposed to explain the favorable effects of food ingredients against neurodegenerative disease. PMID- 28000848 TI - Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia. AB - High altitude-associated polycythemia (HAPC) is a very common disease. However, it the disease is still unmanageable and the related molecular mechanisms remain largely unclear. In the present study, we aimed to explore the molecular mechanisms responsible for the development of HAPC using transcriptome analysis. Transcriptome analysis was conducted in 3 pairs of gastric mucosa tissues from patients with HAPC and healthy residents at a similar altitude. Endoscopy and histopathological analyses were used to examine the injury to gastric tissues. Molecular remodeling was performed for the interaction between different KLK members and cholesterol. HAPC was found to lead to morphological changes and pathological damage to the gastric mucosa of patients. A total of 10,304 differentially expressed genes (DEGs) were identified. Among these genes, 4,941 DEGs were upregulated, while 5,363 DEGs were downregulated in the patients with HAPC (fold change >=2, P<0.01 and FDR <0.01). In particular, the kallikrein gene cluster (KLK1/3/7/8/12) was upregulated >17-fold. All the members had high-score binding cholesterol, particularly for the polymers of KLK7. The kallikrein gene cluster (KLK1/3/7/8/12) is on chromosome 19q13.3-13.4. The elevated levels of KLK1, KLK3, KLK7, KLK8 and KLK12 may be closely associated with the hypertension, inflammation, obesity and other gastric injuries associated with polycythemia. The interaction of KLKs and cholesterol maybe play an important role in the development of hypertension. The findings of the present study revealed that HAPC induces gastric injury by upregulating the kallikrein gene cluster (KLK1/3/7/8/12), which can bind cholesterol and result in kallikrein hypertension. These findings provide some basic information for understanding the molecular mechanisms responsible for HAPC and HAPC-related diseases. PMID- 28000849 TI - Comparative analysis of gene regulatory networks of highly metastatic breast cancer cells established by orthotopic transplantation and intra-circulation injection. AB - Metastasis signature genes in breast cancer have been studied comparing transcriptomic profiles of highly metastatic cancer cell lines established by intra-circulation injection with that of their parental cell line. However, this method is not suitable to analyze the initial steps of metastasis including invasion into local tissues and the circulatory system. To characterize the molecular mechanisms of early metastasis, we established highly metastatic MDA-MB 231 cell lines that metastasized to lung by the two animal transplantation models: the orthotopic transplantation method, which mimics all steps of metastasis, or intra-circulation injection method. We then performed data-mining and network analysis of gene expression profiles of metastatic cell lines established by each transplantation method. Transcriptome analysis of seven metastatic cell lines revealed novel lung metastasis signature genes, including known metastasis promoting genes and signature genes. In the OXconc (orthotopic xenograft concentration) signature, 'chemotaxis' and 'cell adhesion' terms were enriched. In the TVIconc (tail vein injection concentration) signature, 'antigen recognition' and 'cell adhesion' were enriched. Furthermore, network analysis of the metastasis signature genes highlighted hub genes in the gene regulatory network. Our findings show that expression profiles of highly metastatic cell lines were different between the orthotopic transplantation and intra-circulation injection method. It also indicates that some metastatic signature genes have been missed in previous studies. Characterization of metastasis genes using the orthotopic transplantation method will be helpful in understanding the multi-step mechanisms of metastasis. Signature genes in OXconc may have the potential to become prognostic markers. PMID- 28000850 TI - Fas expression is downregulated in gastric cancer. AB - The aim of the present study was to investigate Fas expression in tumor samples from patients with gastric cancer, in order to determine the involvement of the Fas signaling pathway. The protein expression levels of Fas, caspase-8, caspase-3 and poly (adenosine diphosphate-ribose) polymerase 1 (PARP1) were examined in gastric cancer specimens and their associations with clinical pathological parameters were analyzed with immunohistochemical staining and western blot analysis. The mRNA expression was quantified with quantitative PCR and apoptosis was examined with a FACScan flow cytometer. The results demonstrated that the downregulation of Fas expression was correlated with less histological differentiation, gender (male), and increased lymph node and distant metastases (P<0.05). In the AGS established gastric cancer cell line, upregulation of the Fas signaling pathway promoted the apoptosis of gastric cancer cells by upregulating the expression of caspase-8 and caspase-3, and downregulating the expression of PARP1. The present study demonstrated that Fas was associated with gastric cancer and promoted the apoptosis of gastric cancer cells via caspase-8, caspase-3 and PARP1. These results suggested that caspase-8, caspase-3 and PARP1 may be triggers of gastric cancer, and upregulation of caspase-8 and caspase-3 expression, or inhibition of PARP1 expression may improve the therapeutic outcome in patients with gastric cancer. PMID- 28000851 TI - Three-dimensional simulated microgravity culture improves the proliferation and odontogenic differentiation of dental pulp stem cell in PLGA scaffolds implanted in mice. AB - Tooth regeneration through stem cell-based therapy is a promising treatment for tooth decay and loss. Human dental pulp stem cells (hDPSCs) have been widely identified as the stem cells with the most potential for tooth tissue regeneration. However, the culture of hDPSCs in vitro for tissue engineering is challenging, as cells may proliferate slowly or/and differentiate poorly in vivo. Dynamic three-dimensional (3D) simulated microgravity (SMG) created using the rotary cell culture system is considered to an effective tool, which contributes to several cell functions. Thus, the present study aimed to investigate the effect of dynamic 3D SMG culture on the proliferation and odontogenic differentiation abilities of hDPSCs in poly (lactic-co-glycolic acid) (PLGA) scaffolds in nude mice. The hDPSCs on PLGA scaffolds were maintained separately in the 3D SMG culture system and static 3D cultures with osteogenic medium for 7 days in vitro. Subsequently, the cell-PLGA complexes were implanted subcutaneously on the backs of nude mice for 4 weeks. The results of histological and immunohistochemical examinations of Ki-67, type I collagen, dentin sialoprotein and DMP-1 indicated that the proliferation and odontogenic differentiation abilities of the hDPSCs prepared in the 3D SMG culture system were higher, compared with those prepared in the static culture system. These findings suggested that dynamic 3D SMG culture likely contributes to tissue engineering by improving the proliferation and odontogenic differentiation abilities of hDPSCs in vivo. PMID- 28000853 TI - Matrine suppresses invasion of castration-resistant prostate cancer cells by downregulating MMP-2/9 via NF-kappaB signaling pathway. AB - Matrine is an alkaloid from Sophora flavescens that exhibits multiple protective effects on cancers. However, the molecular mechanisms of anti-metastatic effects of matrine on castration-resistant prostate cancer (CRPC) remain unknown. This study investigated the anti-metastatic effects of matrine on CRPC to identify the underlying mechanisms. The effects of matrine on the cell viability of DU145 and PC-3 cells were measured using MTS assay. The impact of matrine on expression levels of matrix metalloproteinase (MMP)-9, MMP-2, nuclear factor-kappaB (NF kappaB) subunit p65 and phosphorylated p65 in cells untreated or treated with matrine were analyzed by western blotting. The inhibitory effects of matrine on cell migration and invasion were examined by Transwell assay. The impact of matrine on tumorigenesis in male Balb/c nude mice inoculated subcutaneously with cells were investigated in vivo. We found that matrine inhibited the growth of DU145 and PC3 cells time- and dose-dependently both in vitro and in vivo. Migration and invasion capabilities of cells were also suppressed by matrine. At the same time, matrine markedly reduced the expression levels of MMP-9, MMP-2 and p-p65 in both cell lines. Further experiments revealed that matrine exhibited inhibitory effects of migration and invasion of CRPC by downregulating MMP-2/9 through NF-kappaB pathway. Matrine inhibits invasion of CRPC by reducing levels of MMP-9 and MMP-2 through NF-kappaB pathway. Therefore, it may be a potential anti-metastatic therapeutic agent for CRPC. PMID- 28000852 TI - Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review). AB - miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3'-untranslated regions of the downstream gene mRNAs to repress mRNA expression. Mounting investigations forcefully document that not only does miR-22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR-22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR 22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR-22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis. PMID- 28000854 TI - Identification of microRNA-487b as a negative regulator of liver metastasis by regulation of KRAS in colorectal cancer. AB - Recent studies have shown that microRNAs (miRNAs) are involved in the progression of colorectal cancer (CRC). The aim of this study is to identify a novel miRNA that especially relates to liver metastasis and to explore the underlying mechanism. Differentially expressed miRNAs were analyzed using microarray, in primary CRC tumors without metastasis (n=16), those with liver metastasis (n=12), and liver metastatic lesions (n=8). We found that miR-487b level decreased in liver metastatic lesions, and qRT-PCR confirmed the results in the validating cohort (n=134). Survival analysis indicated that high expression of miR-487b was associated with better prognosis. In vitro studies were also performed to investigate the functional significance of miR-487b in human CRC cell lines. miR 487b showed an inhibitory effect on cell proliferation and invasion of CRC cells. miR-487b downregulated KRAS and inhibited its downstream signal pathways, and the luciferase reporter assay revealed that miR-487b directly targeted LRP6, a receptor for WNT/beta-catenin signaling. These findings showed that decrease in miR-487b was related with liver metastasis. Our data suggest a possibility that miR-487b may suppress metastasis of CRC progression through inhibition of KRAS. PMID- 28000855 TI - Involvement of interleukin-23 induced by Porphyromonas endodontalis lipopolysaccharide in osteoclastogenesis. AB - Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin-23 (IL-23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL-23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL-23 in periodontal ligament (PDL) cells. Reverse transcription- quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL-23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL-23 in the SH-9 human PDL cell line. BAY11-7082, a nuclear factor kappaB inhibitor, suppressed P. endodontalis LPS-induced IL-23 expression in SH-9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS-treated SH-9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL-23-knockdown SH-9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL-23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process. PMID- 28000856 TI - CYP2J2 participates in atherogenesis by mediating cell proliferation, migration and foam cell formation. AB - Atherosclerosis (AS) is a common pathological basis for the development of various cardiovascular and cerebrovascular diseases, however, currently, no effective treatment against AS has been established. It has previously been suggested that intravascular cytochrome P450 (CYP) oxidase is involved in the pathogenesis of AS. The present study investigated the role of cytochrome P450, family 2, subfamily J, polypeptide 2 (CYP2J2), the most common subtype of CYP oxidase in the human body, in the occurrence and development of AS. CYP2J2 was overexpressed in human umbilical vein endothelial cells (HUVECs), human arterial smooth muscle cells (HASMCs), and human peripheral monocyte-derived foam cells by lentiviral infection. The mRNA and protein levels were measured by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Cell proliferation and migration were determined by MTS and Transwell assays, respectively. Furthermore, lipid accumulation was detected with Oil red O staining. The concentrations of total and free cholesterol were measured using a quantitation kit. Following lentiviral infection, CYP2J2 was successfully overexpressed in HUVEC, HASMC and foam cells. CYP2J2 overexpression promoted proliferation and migration in HUVECs and suppressed these actions in HASMCs. In addition, it suppressed oxidized low-density lipoprotein-induced foam cell formation. In conclusion, it was hypothesized that CYP2J2 may have a protective role in AS, as proliferation of HASMCs and the formation of foam cells are notable characteristics of AS. PMID- 28000857 TI - Hypomethylation of Agtrap is associated with long-term inhibition of left ventricular hypertrophy in prehypertensive losartan-treated spontaneously hypertensive rats. AB - Prehypertensive losartan treatment may lead to long-term inhibition of the development of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the expression of angiotensin type 1 receptor-associated protein (ATRAP/Agtrap) and methylation of the Agtrap gene in the myocardium following the withdrawal of treatment. Four-week-old SHRs were randomly divided into three groups, and were treated with saline, amlodipine or losartan, respectively, for 6 weeks. Wistar Kyoto rats (WKYs) were used as a control. All rats were followed up regularly until they reached the age of 32 weeks. Systolic blood pressure (SBP), left ventricular mass/body weight (LVM/BW), and cardiac fibrosis and structure were measured. The mRNA and protein expression of ATRAP in the myocardium were determined using reverse transcription quantitative polymerase chain reaction and western blot analysis. Methylation of the Agtrap promoter was detected by bisulfite pyrosequencing. Reduced levels of SBP, LVM/BW, cardiac fibrosis and interventricular septum thickness were determined to be maintained only in prehypertensive losartan-treated SHRs. Whereas, an increased expression of ATRAP mRNA and protein, and hypomethylation of the Agtrap promoter in the myocardium, were demonstrated only in the losartan treated SHRs. In conclusion, the results of the present study suggested that the hypomethylation of Agtrap accompanying upregulation of ATRAP expression in the myocardium is associated with the long-term inhibition of LVH in SHRs with prehypertensive losartan treatment. PMID- 28000858 TI - Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis. AB - Hypoxia is an essential feature of cancer malignancy, but there are no methods for the routine detection of hypoxia-inducible prognostic factors and potential therapeutic targets. We reported previously that the hypoxic tumor cells of metastatic liver tissue from patients with colorectal cancer (CRC) could be used as an 'in vivo' hypoxia culture model. Several potential hypoxia-inducible genes were identified using this model. Among them, one glycolytic enzyme was of special interest. There is currently increasing attention on glycolytic enzymes as potential therapeutic targets due to their association with cancer-specific metabolism. To better understand the molecular mechanisms of cancer malignancy, we investigated the expression of fructose-bisphosphate aldolase A (ALDOA) and its relationship with cancer metabolism. We found that ALDOA was induced by hypoxia in CRC-derived cell lines, and univariate and multivariate analyses of microarray data from the resected CRC samples of 222 patients revealed that ALDOA was an independent prognostic factor for CRC. We also analyzed the malignant potential of ALDOA in vitro using overexpression and knockdown assays. We found that ALDOA was negatively related to chemosensitivity and radiosensitivity and positively associated with proliferation, sphere formation and invasion in both normoxia and hypoxia. These associations were due to the roles of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle. These findings demonstrate that ALDOA is a hypoxia-inducible prognostic factor that is closely related to CRC malignancy, and also provide new insights into the importance of ALDOA and glycolysis in cancer and suggest new targets for anticancer therapies. PMID- 28000859 TI - 131I-labeled monoclonal antibody targeting neuropilin receptor type-2 for tumor SPECT imaging. AB - As a co-receptor for vascular endothelial growth factor-3 (VEGF-3), neuropilin receptor type-2 (NRP-2) plays a central role in lymphangiogenesis and angiogenesis. Recently, mounting data of evidence show that NRP-2 is overexpressed in several human cancers, and its overexpression is often associated with poor prognosis. Therefore, it is necessary for us to develop an affinity reagent for noninvasive imaging of NRP-2 expression because it may be possible to provide early cancer diagnosis, more accurate prognosis, and better treatment planning. Due to their high affinity, and specificity, monoclonal antibodies (mAbs) have been considered attractive candidates for targeted cancer therapy and diagnostics. We recently generated and validated a monoclonal antibody that specifically binds NRP-2 b1b2 domain with no cross-reactivity to NRP-1 b1b2 domain, also known to be overexpressed in a variety of cancers. Here, we developed a single photon emission computed tomography (SPECT) probe for imaging NRP-2- positive tumors. Anti-NRP-2 monoclonal antibodies were prepared by hybridomas and were labeled with iodine-131 by chloramine-T method. The in vitro physicochemical properties of 131I-anti-NRP-2 mAb was determined. Binding affinity and specificity of 131I-anti-NRP-2 mAb to NRP-2 were assessed using human lung adenocarcinoma A549 cells. Biodistribution and SPECT studies were performed in mice bearing A549 tumor xenografts to evaluate the in vivo performance of 131I-anti-NRP-2 mAb. The preparation of anti-NRP-2 mAb was completed successfully by hybridoma with high purity (>95%) and specific for NRP 2 b1b2 domain, but not NRP-1 b1b2 domain. The radiosynthesis of 131I-anti-NRP-2 mAb was completed successfully within 60 min with high labelling efficiency (94.69+/-3.63%), and radiochemical purity (98.56+/-0.48%). The resulting probe, 131I-anti-NRP-2 mAb displayed excellent stability in PBS solution during 24-72 h. 131I-anti-NRP-2 mAb showed high binding affinity with A549 cells (96.6+/-1.44 nM). In vivo biodistribution and SPECT studies demonstrated targeting of A549 glioma xenografts was NRP-2 specific. The tumor uptake was 5.86+/-0.27% ID/g at 6 h, and kept at high level of 4.64+/-0.82% ID/g at 72 h-post-injection. The tumor to contralateral muscle ratio (T/NT) was 2.08+/-0.33 at 6 h, and reached the highest level of 3.83+/-0.18 at 72 h after injection. SPECT imaging studies revealed that 131I-anti-NRP-2 mAb could clearly identify A549 tumors with good contrast, especially at 48-72 h after injection. In conclusion, this study demonstrates that 131I-anti-NRP-2 mAb exhibited highly selective uptake in NRP-2 expressing tumors, and may provide a promising SPECT probe for imaging NRP-2 positive tumors. PMID- 28000860 TI - Downregulation of the beta1 adrenergic receptor in the myocardium results in insensitivity to metoprolol and reduces blood pressure in spontaneously hypertensive rats. AB - The beta1-adrenergic receptor (AR) is the primary beta-AR subtype in the heart and is the target of metoprolol (Met), which is commonly used to treat angina and hypertension. Previous studies have revealed a positive correlation between the methylation levels of the adrenoreceptor beta1 gene (Adrb1) promoter in the myocardium with the antihypertensive activity of Met in spontaneously hypertensive rats (SHR), which affects beta1-AR expression in H9C2 cells. The aim of the present study was to investigate the effects of myocardial beta1-AR downregulation using short-hairpin RNA (shRNA) against Adrb1 on the antihypertensive activity of Met in SHR. Recombinant adeno-associated virus type 9 (rAAV9) vectors carrying Adrb1 shRNA (rAAV9-Adrb1) or a negative control sequence (rAAV9-NC) were generated and used to infect rat hearts via the pericardial cavity. The results of reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting analyses demonstrated that cardiac beta1-AR expression in the rAAV9-Adrb1 group was significantly downregulated when compared with the rAAV9-NC group (P<0.001, P<0.001 and P=0.032, respectively). In addition, a greater reduction in systolic blood pressure (SBP) was observed in the rAAV9-NC group compared with the rAAV9-Adrb1 group following Met treatment (P=0.035). Furthermore, downregulation of myocardial beta1-AR was associated with a significant decrease in SBP (P<0.001). In conclusion, these data suggest that suppression of beta1-AR expression in the myocardium reduces SBP and sensitivity to Met in SHR. PMID- 28000861 TI - CXCR4 is involved in CD133-induced EMT in non-small cell lung cancer. AB - Metastasis is the major cause of death in patients with non-small cell lung cancer (NSCLC), and epithelial-mesenchymal transition (EMT) has been observed to be one of the key regulators of metastasis in certain cancers as it confers an invasive phenotype. CD133 is a widely used cancer stem cell (CSC) marker, and CD133-positive cancer cells are thought to be tumor-initiating cells with CSC characteristics, while CXCR4, a stromal-derived-factor-1 specific chemokine receptor, is highly expressed in NSCLC tissues and participates in cancer progression by regulating cell anti-apoptosis. We previously demonstrated that CXCR4 promotes NSCLC chemoresistance by upregulating CYP1B1, however, the relationship of CD133, CXCR4 and EMT processes in NSCLC metastasis are unclear. In this study, we detected a CD133 and CXCR4 high expression in tissue specimens from 64 NSCLC patients by immunohistochemistry, of which CD133 and CXCR4 were found to be positively associated with metastatic NSCLC patients. CD133 was found to promote NSCLC tumorigenesis and mediated the expression of CXCR4. Furthermore, CD133/CXCR4 co-expression was found to be an independent prognostic factor as shown by univariate and multivariate Cox regression analysis, and was observed to regulate the expression of EMT-related molecules and transcriptional factors in NSCLC. In addition, our results showed that E-cadherin and Vimentin were simultaneously downregulated and upregulated, in CD133+CXCR4+ A549 cells, respectively. While E-cadherin was upregulated and Vimentin was downregulated in metastatic NSCLC patients. Vimentin expression was also observed to have a positive correlation with CD133/CXCR4 co-expression in NSCLC patients and survival analysis results suggested that Vimentin high expression might be significantly associated with poor survival rates of the patients. Thus, these results suggest that the CD133/CXCR4/EMT axis may be a prognostic marker and may provide novel targets for combinational therapies in the treatment of NSCLC. PMID- 28000862 TI - SIRT1-mediated regulation of oxidative stress induced by Pseudomonas aeruginosa lipopolysaccharides in human alveolar epithelial cells. AB - Sirtuin1 (SIRT1) is an NAD+-dependent deacetylase that exhibits multiple biological functions, including cell differentiation inhibition, transcription regulation, cell cycle regulation and anti-apoptosis. Lipopolysaccharides (LPS) are crucial virulence factors produced by Pseudomonas aeruginosa and serve an important role in adjusting the interactions between the host and the pathogen. However, the effect of SIRT1 in the regulation of LPS-induced A459 human alveolar epithelial cells (AECs) oxidative stress remains unclear. The cellular reactive oxygen species (ROS) production was examined in A549 cells that were supplemented with LPS. Relative cell signaling pathway proteins were further investigated by western blot analysis. It was identified that LPS downregulated SIRT1 expression, however, upregulated ROS generation, which was associated with the increase of nuclear factor (NF)-kappaB and acetyl-NF-kappaB. Activation of SIRT1 by resveratrol significantly reversed the effects of LPS on A549 cells. By contrast, inhibition of SIRT1 by nicotinamide had the opposite effects that enhance cell ROS production. Thus, the results indicated that SIRT1 serves an important role in the regulation of oxidative stress induced by LPS in human AECs. PMID- 28000863 TI - Differential expression of microRNA in the lungs of rats with pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic disorder of the small pulmonary arteries, and the efficacy of the therapies and the prognosis remain poor. The pathobiology of PAH is complex, and needs to be elucidated by multiple approaches. The present study used a monocrotaline-induced PAH rat model to perform a comprehensive microRNA (miRNA) microarray screening in the lungs and identified 16 downregulated miRNAs in the lungs from PAH rats. High-enrichment gene ontology (GO) analysis identified several sets of genes, and established the miRNA-mRNA network by outlining the interactions of miRNA and GO-associated genes. Three downregulated miRNAs [miRNA 125-3p (miR-125-3p), miR-148-3p and miR 193] displayed the most marked regulatory function, and miR-148-3p and miR-193 were observed to have the highest number of target mRNAs. Signaling pathway analysis demonstrated 26 signal transduction pathways, with MAPK, TGF-beta and cell cycle signaling as the most prominent. In addition, 342 genes were identified as the potential targets of these 16 miRNAs. Thus, a set of miRNAs in the lungs from rats with PAH and novel associations between biological events and PAH pathogenesis were identified, providing potential therapeutic targets for this disorder. PMID- 28000864 TI - Identification of therapeutic targets for Parkinson's disease via bioinformatics analysis. AB - The present study aimed to identify molecular targets that have important roles in the progression of Parkinson's disease. The gene expression profile dataset GSE7621 and the microRNA (miRNA) expression profile dataset GSE16658 were downloaded from the Gene Expression Omnibus database. R programing software was used to identify differentially expressed genes and miRNAs. Subsequently, enriched Gene Ontology terms of differentially expressed genes were obtained using the Database for Annotation, Visualization and Integrated Discovery. Target genes of differentially expressed miRNAs were identified using the starBase database and a miRNA-gene regulatory network was constructed using Cytoscape software. A total of 391 differentially expressed genes and 88 differentially expressed miRNAs were identified. Gene Ontology terms that were associated with nervous system activity, including synapse and dopamine metabolic process, were shown to be enriched in the differentially expressed genes. A total of 620 target genes were identified from the differentially expressed miRNAs, and 10 overlaps were identified between these target genes and differentially expressed genes. Furthermore, 10 miRNA-gene regulation pairs were obtained between the overlaps and differentially expressed miRNAs. In conclusion, the present study used bioinformatics analysis of gene and miRNA expression profile datasets, and identified potential therapeutic targets for Parkinson's disease. PMID- 28000865 TI - PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. AB - LY294002 and wortmannin are chemical compounds that act as potent inhibitors of phosphoinositide 3-kinases (PI3Ks). Both of them are generally used to inhibit cell proliferation as cancer treatment by inhibiting the PI3K/protein kinase B (AKT) signaling pathway. In this study, LY294002 (but not wortmannin) showed an abnormal ability to enhance AKT phosphorylation (at Ser472) specifically in gemcitabine (GEM)-resistant pancreatic cancer (PC) cell lines PK59 and KLM1-R. LY294002 was shown to activate AKT and accumulate phospho-AKT at the intracellular membrane in PK59, which was abolished by treatment with AKTi-1/2 or wortmannin. Inhibiting AKT phosphorylation by treatment with AKTi-1/2 or wortmannin further enhanced LY294002-induced cell death in PK59 and KLM1-R cells. In addition, treatment with wortmannin alone failed to inhibit cell proliferation in both PK59 and KLM1-R cells. Thus, our results reveal that LY294002 displays the opposite effect on PI3K-dependent AKT phosphorylation, which maintains cell survival from the cytotoxicity introduced by LY294002 itself in GEM-resistant pancreatic cancer cells. We suggest that targeting the PI3K/AKT signaling pathway with inhibitors may be counterproductive for patients with PC who have acquired GEM-resistance. PMID- 28000866 TI - Testin is a tumor suppressor in non-small cell lung cancer. AB - The Testin gene was previously identified in the fragile chromosomal region FRA7G at 7q31.2. It has been implicated in several types of cancers including prostate, ovarian, breast and gastric cancer. In the present study, we investigated the function of the candidate tumor-suppressor Testin gene in non-small cell lung cancer (NSCLC). In NSCLC cell lines, we observed lower expression of Testin compared to that noted in normal human bronchial epithelial cells. MTT assays, flow cytometry, clonogenic assay and invasion assay showed that the overexpression of the Testin gene inhibited cancer cell proliferation, invasion and colony formation. In tumor xenograft models, Testin markedly inhibited lung cancer cell xenograft formation and growth in athymic nude mice. Taken together, these data suggest that Testin plays an important role in the development and progression of NSCLC. Testin may be an effective novel target in NSCLC prevention and treatment. PMID- 28000867 TI - Dexmedetomidine may upregulate the expression of caveolin-1 in lung tissues of rats with sepsis and improve the short-term outcome. AB - Dexmedetomidine (DXM) is a selective alpha2-adrenoceptor (alpha2-AR) and imidazoline receptor (IR) agonist that has been reported to regulate inflammatory responses mediated by diverse signaling pathways through alpha2-AR. The majority of the reported receptors or downstream molecules have been demonstrated to locate with caveolin-1, a protein suggested to participate in regulating Toll like receptor 4 (TLR4)-mediated inflammatory responses and the pathogen endocytosis capability of macrophages. The present study hypothesized that DXM may influence these pathways by regulating the expression of caveolin-1 and mediating the subsequent effects. Using a cecal-ligation and puncture-induced rat sepsis model, it was initially observed that pre-emptive DXM is able to upregulate and stabilize the amount of caveolin-1 expression, which may be partly antagonized by both alpha2-AR and the IR antagonist atepamezole (APZ). The pathophysiological parameters indicated that DXM is able to inhibit secondary lung injury, in addition to the rise of body temperature and arterial lactate accumulation, however it marginally increased arterial glucose and the murine sepsis score, which can be largely antagonized by APZ. The overall effect was beneficial and improved the 24-h cumulative survival rate of rats with sepsis. In conclusion, preemptive clinical sedative doses of DXM may upregulate the expression of caveolin-1 downregulated by sepsis, which may contribute to the inhibition of inflammatory pathways such as TLR4-mediated pathways. Furthermore, DXM may favor the improvement of short-term outcomes by the regulation of other metabolic pathways. PMID- 28000868 TI - Methyl jasmonate induces the apoptosis of human colorectal cancer cells via downregulation of EZH2 expression by microRNA-101. AB - Methyl jasmonate is found universally in the plant kingdom and functions to regulate plant growth and development, as well as in stress responses through signal transduction pathways. The present study aimed to investigate the anticancer effect of methyl jasmonate on SW620 human colorectal cancer cells and its potential underlying mechanism. SW620 cells were treated with 0, 0.5, 0.75, 1.5 and 2.0 mM methyl jasmonate for 12, 24 and 48 h. Methyl jasmonate was shown to be able to inhibit cell growth and induce apoptosis of SW620 cells in a concentration and time-dependent manner, whilst promoting an increase in caspase 3 protein expression. Compared with control, the anticancer effect of methyl jasmonate inhibited Enhancer of zeste homolog 2 (EZH2) protein expression and activated microRNA (miR)-101 expression in SW620 cells. However, knockdown of miR 101 suppresses methyl jasmonate-induced cell growth inhibition, activation of caspase-3 expression and inhibition of EZH2 expression in SW620 cells. These results demonstrate that methyl jasmonate induced the apoptosis of human colorectal cancer cells via downregulation of EZH2 expression by miR-101. PMID- 28000869 TI - Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation. AB - Advanced oxidation protein products (AOPPs) are recognized as novel markers of oxidative stress and contribute to various medical conditions, which are associated with secondary osteoporosis. However, little is currently known regarding the role of AOPPs in the development of secondary osteoporosis. As the commander cells of bone remodeling, osteocytes are involved in the pathogenesis of osteoporosis. The present study aimed to determine the cytotoxic mechanisms of AOPPs on osteocytic MLO-Y4 cells. The results demonstrated that treatment with AOPPs significantly triggered apoptosis of MLO-Y4 cells, in a dose- and time dependent manner. Furthermore, exposure to AOPPs induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK). Conversely, N-acetylcysteine inhibited the activation of JNK and p38 MAPK, thus suggesting that the AOPPs-induced activation of JNK/p38 MAPK is reactive oxygen species (ROS)-dependent. In addition, SB203580 and SP600125 suppressed apoptosis, but did not affect ROS production, following AOPPs treatment. Notably, AOPPs also induced a significant upregulation in the expression levels of sclerostin and receptor activator of nuclear factor kappa-B ligand (RANKL) in a JNK/p38 MAPK dependent manner. These findings provide novel insights into the molecular mechanisms underlying AOPPs-mediated cell death, and suggest that modulation of apoptotic pathways via the MAPK signaling cascade may be considered a therapeutic strategy for the prevention and treatment of secondary osteoporosis. PMID- 28000870 TI - Quercetin alleviates cell apoptosis and inflammation via the ER stress pathway in vascular endothelial cells cultured in high concentrations of glucosamine. AB - Glucosamine is a possible cause of vascular endothelial injury in the initial stages of atherosclerosis, through endoplasmic reticulum (ER) stress resulting in fatty streaks in the vascular wall. Quercetin is an anti-diabetic and cardiovascular protective agent that has previously been demonstrated to reduce ER stress in human umbilical vein endothelial cells (HUVECs). The present study aimed to investigate whether quercetin prevents glucosamine-induced apoptosis and inflammation via ER stress pathway in HUVECs. The effect of quercetin on cell viability, apoptosis, and protein expression levels of inflammatory cytokines and ER stress markers was investigated in glucosamine-supplemented HUVECs. Quercetin was demonstrated to protect against glucosamine-induced apoptosis, improved cell viability, and inhibited expression of pro-inflammatory factors and endothelin-1. Quercetin treatment also reduced the expression levels of glucose-regulated protein 78, phosphorylated protein kinase-like ER kinase, phosphorylated c-Jun N terminal kinase and C/EBP homologous protein. In conclusion, quercetin may have auxiliary therapeutic potential against glucosamine-induced cell apoptosis and inflammation, which may be partially due to alleviation of ER stress. PMID- 28000871 TI - Mechanical stress influences the viability and morphology of human parametrial ligament fibroblasts. AB - The present study aimed to investigate damage to human parametrial ligament fibroblasts by detecting cell proliferation, cytoskeletal structure, cellular alterations and senescence. Uterosacral and cardinal ligaments were obtained from 10 patients with cervical intraepithelial neoplasia grade II-III, who had received total vaginal hysterectomies, and fibroblasts were derived from this tissue. Fibroblasts were stretched using a four-point bending system with a force of 0 (control), 1,333 u strain (1 mm) or 5,333 u strain (4 mm) for 4 h. The present study revealed that mechanical force significantly reduced cell proliferation and increased cell senescence. As mechanical force increased, the mitochondria of fibroblasts began to exhibit vacuolization, and the cell cytoskeleton began to depolymerize and rearrange. In conclusion, the present study demonstrated that mechanical forces within a certain range may induce cell damage via mitochondrial injury, cytoskeletal alterations and increased cell senescence, resulting in decreased cell viability of pelvic fibroblasts. PMID- 28000872 TI - Inhibitory effects of resveratrol on the adhesion, migration and invasion of human bladder cancer cells. AB - Resveratrol is a polyphenolic compound, which has been revealed to induce apoptosis in numerous human cancer cells; however, the effects of resveratrol on the migration and invasion of human bladder cancer cells have not been reported. The present study aimed to evaluate the anti-metastatic potential of resveratrol against bladder cancer and its mechanism of action. The results indicated that resveratrol inhibits the adhesion, migration and invasion of bladder cancer cells in a dose-dependent manner. Resveratrol was shown to significantly inhibit the expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9 in bladder cancer cells. Furthermore, resveratrol suppressed the phosphorylation of c-Jun N terminal kinase and extracellular signal-regulated protein kinase. In conclusion, the present study is the first, to the best of our knowledge, to demonstrate that resveratrol may be considered a novel anticancer agent for the treatment of bladder cancer via the inhibition of migration and invasion. PMID- 28000873 TI - Salvianolic acid B reverses multidrug resistance in HCT-8/VCR human colorectal cancer cells by increasing ROS levels. AB - Salvianolic acid B (SalB) a water-soluble phenolic compound, extracted from Salvia miltiorrhiza, has previously been demonstrated to reverse tumor multidrug resistance (MDR), including in colorectal cancer. Reactive oxygen species (ROS) are oxygen radicals generated during aerobic metabolism (superoxide and hydroxyl radicals) and superoxide easily generating free radicals (H2O2). The concept that increased ROS levels can lead to augmented tumor cell-sensitivity to chemotherapy drugs has become notable. The aim of the present study was to elucidate the role of ROS in mediating the effect of SalB on drug resistance and the correlation with drug resistance-associated protein, P-glycoprotein (P-gp), and apoptosis associated proteins, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). In the current study, through utilizing the multidrug resistant colorectal cancer cell line, HCT-8/VCR, it was demonstrate that SalB reversed MDR in HCT-8/VCR. In addition, SalB significantly increased ROS levels, which may have accelerated the apoptosis of HCT-8/VCR cells by downregulating Bcl-2 and increasing Bax protein expression. Furthermore the increased intracellular ROS levels may have inhibited P-gp expression at the gene and protein levels. In conclusion, the data of the current study demonstrate that SalB reversed MDR in HCT-8/VCR cells, and the effect is associated with increased ROS levels, which may downregulate P-gp expression and promote tumor cell apoptosis, which in turn increases the sensitivity of drug-resistant cells to chemotherapy drugs. PMID- 28000874 TI - Changes in TL1A levels and associated cytokines during pathogenesis of diabetic retinopathy. AB - Tumor necrosis factor (TNF) ligand related molecule 1A (TL1A), also termed TNF superfamily member 15 and vascular endothelial growth inhibitor is important for tumorigenicity and autoimmunity. However, the function of TL1A in diabetic retinopathy (DR) remains to be elucidated. The present study established a diabetes mellitus (DM) rat model to investigate TL1A, vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL 1beta) expression levels in the retina, vitreous and serum of rats with DM at different stages (1 month group, 3 month group and 6 month group). The present study determined that TL1A expression levels in the retina and vitreous from the DM 1 month group were significantly lower compared with the control group. However, TL1A levels in the retina and vitreous were significantly increased in advanced stages of DM compared with the control group. Furthermore, the levels of VEGF in the retina and vitreous were significantly higher in the DM groups compared with the control group. The expression levels of TNF-alpha and IL-1beta in the retina and vitreous were significantly higher in DM 3 month and 6 month groups compared with the control group. It is of note that the expression levels of TL1A were significantly lower in the DM 1 and 3 month groups compared with the control group; however, they were significantly increased in the DM 6 month group compared with the DM 3 month group. The expression levels of VEGF, TNF-alpha and IL-1beta in blood serum have been observed to exhibit similar expression change dynamics as those of the retina and vitreous. Therefore, these findings suggest that TL1A may be a protective factor of DR, and may provide a rationale for the development of novel therapeutic strategies to treat DR. PMID- 28000875 TI - Fulvestrant reverses doxorubicin resistance in multidrug-resistant breast cell lines independent of estrogen receptor expression. AB - Drug resistance, a major obstacle to successful cancer chemotherapy, frequently occurs in recurrent or metastatic breast cancer and results in poor clinical response. Fulvestrant is a new type of selective estrogen receptor (ER) downregulator and a promising endocrine therapy for breast cancer. In this study, we evaluated the combination treatment of fulvestrant and doxorubicin in ER negative multidrug-resistant (MDR) breast cancer cell lines Bads-200 and Bats-72. Fulvestrant potentiated doxorubicin-induced cytotoxicity, apoptosis and G2/M arrest with upregulation of cyclin B1. It functioned as a substrate for P glycoprotein (P-gp) without affecting its expression. Furthermore, fulvestrant not only restored the intracellular accumulation of doxorubicin but also relocalized it to the nuclei in Bats-72 and Bads-200 cells, which may be another potential mechanism of reversal of P-gp mediated doxorubicin resistance. These results indicated that the combination of fulvestrant and doxorubicin-based chemotherapy may be feasible and effective for patients with advanced breast cancer. PMID- 28000876 TI - miR-196b/miR-1290 participate in the antitumor effect of resveratrol via regulation of IGFBP3 expression in acute lymphoblastic leukemia. AB - MicroRNAs play critical roles in the progression of acute lymphoblastic leukemia (ALL). Previous studies have indicated that miR-196b and miR-1290 play critical roles in T-cell ALL (T-ALL) and B-cell ALL (B-ALL), respectively. Resveratrol, a natural edible polyphenolic phytoalexin, possesses certain anticancer activities. Nevertheless, the mechanism involved in the regulation of ALL by resveratrol is still poorly understood. The present study aimed to reveal the potential mechanism underlying the antitumor effect of resveratrol in ALL focusing on miRNAs. Research indicates that insulin-like growth factor binding protein 3 (IGFBP3) plays a critical role in the aetiology of ALL. In the present study, we first demonstrated that the expression of IGFBP3 was decreased in ALL patients. We further identified that miR-196b and miR-1290 were overexpressed in T-ALL TALL 104 and B-ALL SUP-B15 cell lines, respectively. Moreover, resveratrol markedly decreased the overexpression of miR-196b/miR-1290 and elevated IGFBP3 expression in the ALL cell lines. As an miR-196b/miR-1290 inhibitor, resveratrol was further demonstrated to exert antitumor effects on ALL cells including antiproliferation, cell cycle arrest, apoptosis and inhibition of migration. Dual-luciferase reporter assay revealed that miR-196b/miR-1290 directly bound to the 3' untranslated (3'-UTR) region of IGFBP3 mRNA. Moreover, we observed that IGFBP3 short interfering RNA reversed the antitumor activity of resveratrol against ALL cells. Taken together, the present study provides evidence that resveratrol targets miR-196b and miR-1290 for its antitumor activity in T-ALL and B-ALL, respectively. The present study also confirms that both miR-196b and miR-1290 target the IGFBP3 3'-UTR and are potential therapeutic targets for ALL. PMID- 28000877 TI - Low-molecular weight fucoidan inhibits the differentiation of osteoclasts and reduces osteoporosis in ovariectomized rats. AB - Fucoidan is a type of sulfated polysaccharide isolated from seaweed. The present study used ovariectomized Sprague-Dawley rats, which were treated with fucoidan. The effects of fucoidan on bone metabolism, density and microarchitecture were assessed using micro-computed tomography (CT), histomorphometric analysis, biochemical markers of bone metabolism (Serum procollagen type I N propeptide and C-terminal telopeptide-1) and tests of mechanical competence of the femur. In addition, the effects of low-molecular weight fucoidan (LMWF) on in vitro cultured osteoclasts were examined, in order to determine the mechanisms underlying LMWF-induced osteoclastic inhibition. In ovariectomized rats, LMWF increased femoral bone density. Micro-CT scan also revealed that LMWF prevented microarchitectural deterioration and histomorphometric analysis determined that LMWF increased trabecular bone number and reduced the surface of bone resorption. In addition, LMWF reduced the high bone turnover rate, and improved the mechanical properties of the femur in ovariectomized rats. In vitro experiments revealed that LMWF inhibited the receptor activator of nuclear factor kappaB ligand (RANKL) and macrophage colony-stimulating factor-induced differentiation of RAW264.7 cells into tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and reduced the bone resorption surface of the osteoclasts. Reverse transcription-quantitative polymerase chain reaction demonstrated that LMWF inhibited mRNA expression of TRAP, matrix metallopeptidase-9, nuclear activator of activated T-cells 1, and osteoclast-associated immunoglobulin-like receptor, which are components of the signaling pathway for osteoclast differentiation. LMWF had no effect on RANK mRNA expression. In conclusion, the present study confirmed that LMWF inhibited osteoclast differentiation and bone resorption, and may be a potential treatment for osteoporosis in ovariectomized rats. PMID- 28000878 TI - Elevated expression of TrpC5 and GLUT1 is associated with chemoresistance in colorectal cancer. AB - Reprogramming of energy metabolism (aerobic glycolysis) is thought to play an essential role in cancer. Compared to oxidative phosphorylation, aerobic glycolysis consumes more glucose through the upregulation of glucose transporters, notably glucose transporter 1 (GLUT1). Elevated glycolysis occurs in chemoresistant cancer cells, but the detailed mechanism is not well understood. The upregulation of the Ca2+-permeable transient receptor potential channel 5 (TrpC5) activates the Wnt/beta-catenin signaling pathway in 5 fluorouracil (5-Fu)-resistant human colorectal cancer (CRC) HCT-8 (HCT-8/5-Fu) cells. In the present study, TrpC5 was overexpressed at the mRNA and protein levels along with GLUT1 in HCT-8/5-Fu cells. Suppression of TrpC5 expression with a TrpC5-specific shRNA reduced the induction of GLUT1 in the HCT-8 cells. The inhibition of the Wnt/beta-catenin signaling pathway with XAV939 resulted in a decreased GLUT1 and nuclear c-Myc expression. Further study using clinical specimens validated the positive correlation between TrpC5 and GLUT1 protein levels and showed that a high TrpC5/GLUT1 expression was significantly correlated with chemoresistance. Taken together, we demonstrated the essential role of TrpC5 in GLUT1 induction and revealed that a high TrpC5/GLUT1 expression is associated with chemoresistance in human CRC. PMID- 28000879 TI - High-mobility group box 1 is overexpressed in cervical carcinoma and promotes cell invasion and migration in vitro. AB - The present study aimed to investigate the expression of high-mobility group box 1 protein (HMGB1) in cervical carcinoma and explore whether or not HMGB1 promotes cervical carcinoma cell invasion and migration in vitro and the related mechanism. HMGB1, nuclear factor-kappaB (NF-kappaB), E-cadherin and N-cadherin protein expression was analyzed in tissues from 48 cervical carcinomas, 51 cervical intraepithelial neoplasia (CIN) and tissues from 24 healthy controls using immunohistochemistry. HeLa cells were treated with different concentrations of HMGB1 (0, 10, 100, and 1,000 ng/ml) at different time-points (0, 24, 48 and 72 h), and changes in cell morphology and biological behaviors were observed. Changes in the expression levels of E-cadherin, N-cadherin, NF-kappaB and the inhibitor kappaB (IkappaB) in the treated cells were detected by western blot analysis and real-time PCR. HMGB1 expression exhibited a gradually increasing trend in the normal cervical tissues, CIN and cervical cancer, and there was statistical significance between the three groups (P<0.05). HMGB1 expression level was associated with FIGO stage, lymph node metastasis and differentiation (P<0.05). HMGB1 expression was positively related to N-cadherin and NF-kappaB; and HMGB1 had a negative relationship with E-cadherin. HMGB1 stimulation caused HeLa cells to lose cell polarity and transition from epithelial cells into spindle-shaped cells with sparse cell-cell junctions. The expression levels of E cadherin and IkappaB in the cytoplasm were reduced, while N-cadherin expression was increased. The level of NF-kappaB expression in the nucleus was also increased. Treatment with NF-kappaB inhibitor (BAY11-7082) and receptor for advanced glycation end products (RAGE) antagonist (anti-RAGE) significantly suppressed HMGB1-mediated epithelial-to-mesenchymal transition in the HeLa cervical cancer cells. The results suggest that HMGB1 is associated with outcomes of cervical cancer and promotes subsequent invasion and metastasis of cervical cancer cells by activating the NF-kappaB signaling pathway. This potential mechanism could be an important determinant of cervical cancer metastasis. PMID- 28000880 TI - MicroRNA-302a targets GAB2 to suppress cell proliferation, migration and invasion of glioma. AB - Glioma is the most frequent and aggressive primary tumor of the brain in humans. Over the last few decades, significant progress has been made in early detection and multi-mode treatments, but the prognosis of gliomas is still extremely poor. MicroRNAs are endogenously expressed non-coding, single strand and short RNA molecules. Increasing number of studies demonstrated that microRNAs are dysregulated in a variety of human cancers, and play significant roles in tumorigenesis and tumor development, including glioma. In the present study, we for the first time found that microRNA-302a (miR-302a) was significantly downregulated in both glioma tissues and cell lines. In glioma patients, low miR 302a expression was correlated with KPS score and WHO grade. Restoration of miR 302a expression inhibited cell proliferation, migration and invasion of glioma in vitro. In addition, GAB2 was identified as a direct target of miR-320a. In clinical glioma tissues, GAB2 was upregulated and in-versely correlated with miR 302a expression. GAB2 underexpression had similar biological roles with miR-302a overexpression in glio-ma cells, further confirming that GAB2 was a functional downstream target of miR-302a. Moreover, rescue experiments showed that upregulation of GAB2 effectively reversed the inhibition effects of miR-302a on glioma cells proliferation, migration and invasion. These findings suggested that miR-302a is an important tumor suppressor of glioma progression by directly targeting GAB2, thus providing new insight into the molecular mechanisms underlying glioma occurrence, development and evolution of glioma. PMID- 28000881 TI - Expression and clinical significance of C14orf166 in esophageal squamous cell carcinoma. AB - C14orf166, a 28 kD protein regulating RNA transcription and translation, may serve a critical role in oncogenesis. The aim of the current study was to explore the association between C14orf166 expression and esophageal squamous cell carcinoma (ESCC) and to draw attention to the association between C14orf166 and the initiation, progression and prognosis of ESCC. C14orf166 expression in ESCC and paired normal tissues was detected by immunohistochemical staining, western blotting and reverse transcription-quantitative polymerase chain reaction, and the association between C14orf166 expression and clinicopathological characters of ESCC was analyzed. Survival analysis was used to assess the prognostic significance of C14orf166 and it was observed that C14orf166 expression was higher in the ESCC tissues when compared with adjacent non-cancerous tissues at protein (P<0.001) and mRNA levels (P<0.001). There was a significant difference in T stage, lymph node metastasis and TNM stage in patients categorized according to different C14orf166 expression levels. The overexpression of C14orf166 was associated with a shorter overall survival and disease-free survival, and multivariate analysis indicated that C14orf166 was an independent prognostic indicator. The present study indicates that the expression of C14orf166 is elevated in ESCC, and is potentially a valuable prognostic predictor for ESCC. PMID- 28000882 TI - Modulation of low shear stress-induced eNOS multi-site phosphorylation and nitric oxide production via protein kinase and ERK1/2 signaling. AB - Physiological shear stress has been demonstrated to serve an atheroprotective function by stimulating endothelial nitric oxide synthase (eNOS) multi-site phosphorylation. Low shear stress (LSS) serves an atheroprone role by increasing endothelial cell apoptosis and inflammation. The present study assessed whether LSS inhibited nitric oxide (NO) production in human umbilical vein endothelial cells by modulating eNOS phosphorylation and potential signaling pathways. A parallel flow chamber imposed with 2 dyn/cm2 shear stress on endothelial cells was used. Western blotting and 4,5-diaminofluorescein diacetate were used to analyze the protein expression levels and NO production. LSS activated eNOS Ser1177 and eNOS-Thr495, but inhibited eNOS-Ser633. NO production was decreased after a transient increase at 5 min. LSS-stimulated phosphorylation of eNOS Ser1177 and -Thr495 were suppressed by the Akt inhibitor, perifosine, and extracellular signal regulated kinases1/2 (ERK1/2) inhibitor, PD98059, respectively. Additionally, the phosphorylation of eNOS-Ser633 inhibited by LSS was restored by the protein kinase A activator, 8-Bromo-cAMP. PD98059 completely inhibited the LSS-induced downregulation of NO production. NO downregulation in response to LSS was intensified by perifosine and was partly inhibited by 8-Bromo cAMP. These results indicated that LSS-induced activation of ERK1/2/eNOS-Thr495 serves a major role in inhibiting endothelial NO synthase, which may explain the proinflammatory and proatherosclerotic properties of LSS. PMID- 28000883 TI - 2-Methoxyestradiol inhibits the proliferation and migration and reduces the radioresistance of nasopharyngeal carcinoma CNE-2 stem cells via NF-kappaB/HIF-1 signaling pathway inactivation and EMT reversal. AB - Accumulating evidence indicates that cancer stem cells (CSCs) are a source of resistance to radiation therapy (RT); however, the mechanism of this resistance remains unclear. 2-Methoxyestradiol (2-ME2) is a metabolic product of estrogen in the body. Recent studies have found that 2-ME2 regulates the activation of transcription factors, including nuclear factor (NF)-kappaB/hypoxia-inducible factor-1 (HIF-1), thus contributing to tumor cell apoptosis and chemosensitivity. Therefore, 2-ME2 is being studied as a potential anticancer drug. The purpose of this study was to determine the effect and mechanism by which 2-ME2 inhibits nasopharyngeal carcinoma CNE-2 stem-like cell (NPCSC) proliferation and migration and reduces NPCSC radioresistance. This study has important significance for reducing the radioresistance of these cells to improve the cure rate of NPC. First, the NPCSCs were collected in a serum-free culture system and then identified by relevant experiments. The NPCSCs were treated with 2-ME2 (0-8 uM) combined with X-ray exposure and Cell Counting Kit-8 (CCK-8), Transwell assay, colony formation assay, western blot analysis, RT-PCR, flow cytometry and RNA interference technology were used to explore the effect and mechanism of 2-ME2 on NPCSCs. The results showed that the microspheres collected in the serum-free culture system possessed CSC traits and radioresistance. 2-ME2 obviously inhibited NPCSC growth and migration and reduced NPCSC radioresistance. 2-ME2 decreased NF-kappaB p65 and HIF-1alpha protein expression, downregulated NF kappaB p65 nuclear localization, and reversed epithelial-mesenchymal transition (EMT). NF-kappaB p65 knockdown reduced HIF-1alpha expression, reversed EMT, and enhanced the suppressive effect of 2-ME2 on NPCSCs. Collectively, these data indicate that 2-ME2 inhibits NPCSC proliferation and migration and reduces the radioresistance of NPCSCs via NF-kappaB/HIF-1 signaling pathway inactivation and EMT reversal. PMID- 28000884 TI - Thioridazine elicits potent antitumor effects in colorectal cancer stem cells. AB - As a member of the phenothiazine family, thioridazine (THIO) is a potent anti anxiety and anti-psychotic drug. Recent studies have reported that THIO could suppress the growth of several types of cancer cells. However, the effect of THIO on colorectal cancer stem cells (CSCs) has not been investigated. In the present study, we examined the effect of THIO on viability of CSCs isolated from the human colon cancer cell line HCT116 and its colony-formation ability, along with its stem cell-specific gene expression. The CSCs, EpCAM+ and CD44+ subpopulations from HCT116 cells were isolated using immunomagnetic beads. After incubation with several concentrations of THIO, we evaluated the proliferation and invasion ability of colon CSCs, as well as cell apoptosis. We found that THIO significantly suppressed the proliferation and invasion of colon CSCs and induced cell apoptosis in a concentration-dependent manner. The expression of some apoptosis genes (Bax and caspase-3) was upregulated after treatment with THIO, while that of the anti-apoptosis gene Bcl-2 was downregulated. Moreover, the CSC mitochondrial membrane potential was downregulated. Overall, this study showed that THIO inhibits the proliferation of CSCs derived from the HCT116 cell line through induction of apoptosis, and thus, could be a promising agent for the treatment of colon cancer and worthy of exploring in prospective clinical studies. PMID- 28000885 TI - MicroRNA-152 inhibits cell proliferation, migration and invasion by directly targeting MAFB in nasopharyngeal carcinoma. AB - Aberrant expression of microRNAs (miRs) has been reported to be involved in nasopharyngeal carcinoma (NPC) carcinogenesis and development. The expression and functions of miR-152 have previously been studied in several types of cancer. However, to the best of our knowledge, no previous studies have investigated the effects of miR-152 on NPC. The present study aimed to explore the expression, functions and molecular mechanisms of miR-152 in NPC. The expression levels of miR-152 were detected in NPC tissues and cell lines using quantitative polymerase chain reaction (qPCR). Cell proliferation, migration and invasion were measured by MTT, cell migration and invasion assays, respectively. Dual-luciferase reporter assay was used to determine whether V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) was a direct target gene of miR-152. qPCR and western blotting were used to detect the mRNA and protein expression levels of MAFB. In addition, functional assays were performed to explore the effects of endogenous MAFB on NPC. The results of the present study demonstrated that miR 152 was significantly downregulated in NPC tissues and cell lines. Furthermore, ectopic expression of miR-152 suppressed cell proliferation, migration and invasion of NPC cells. Dual-luciferase reporter assay demonstrated that MAFB was a direct target gene of miR-152, and qPCR and western blotting indicated that miR 152 negatively regulated MAFB expression at the mRNA and protein level. Knockdown of MAFB expression markedly suppressed NPC cell proliferation, migration and invasion. These findings suggested that miR-152 may target MAFB to regulate NPC initiation and progression; therefore, it may be investigated as a target for the treatment of NPC. PMID- 28000886 TI - hsa-miR-631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10. AB - Although bortezomib (BTZ) remains a first-line agent for multiple myeloma (MM) therapy, the development of BTZ resistance has become an indicator of poor prognosis in MM patients. It is thus urgent to develop strategies to restore the vulnerability of MM to BTZ. This study demonstrated, for the first time, that UbcH10 is highly expressed in BTZ-resistant myeloma cell lines U-266/BTZ, NCI H929/BTZ and RPMI-8226/BTZ, which is attributed to the inactivation of post transcriptional control. The in-depth study revealed that during the development of BTZ resistance in these cells, the hsa-miR-631 levels were decreased, which resulted in the increased expression of the target gene UbcH10. We also found that the multiple drug-resistant protein MDR1 exhibited a positive correlation with UbcH10 due to the reduced ubiquitination of MDR1, which was caused by high UbcH10 expression. Following overexpression of miR-631, both BTZ sensitivity and BTZ-induced apoptosis were enhanced in the resistant cells. Meanwhile, resensitization by miR-631 overexpression was blocked by exogenous expression of UbcH10, which was not regulated by intracellular miR-631. In conclusion, the miR 631/UbcH10/MDR1 pathway is closely associated with the development of BTZ resistance in myeloma cells, and the overexpression of miR-631 can significantly improve BTZ sensitivity in resistant myeloma cells. PMID- 28000887 TI - Lentiviral-mediated overexpression of KCTD12 inhibits the proliferation of human uveal melanoma OCM-1 cells. AB - Human potassium channel tetramerization domain containing 12 (KCTD12, also known as Pfetin) is a member of the KCTD family which consists of 26 members. It has been reported that KCTD12 regulates agonist potency and kinetics of GABAB receptor signaling. Proteomic analysis indicates that KCTD12 may be a potential biomarker for the diagnosis and prognosis of gastrointestinal stromal tumors. However, little has been reported concerning the role of KCTD12 in the other tumor types. In the present study, we designed and subcloned N-terminally Flag tagged human KCTD12 into the pLVX-Puro vector. We then generated a human uveal melanoma cell line (OCM-1) stably expressing KCTD12. Using this stable cell line, we performed a series of experiments including colony formation, invasion, migration and wound-healing assays, flow cytometry and western blotting. Based on the experimental results, we first demonstrated that KCTD12 effectively suppressed the proliferation of OCM-1 cells and limited the spread of OCM-1 cells. In the flow cytometric analysis, prolongation of the progression of G2/M to G1 phase in the KCTD12-overexpressing OCM-1 cells was observed. In addition, inhibition of KCTD12-overexpressing OCM-1 cell xenograft growth in nude mice was observed. Taken together, KCTD12 may serve as a novel therapeutic target for patients with uveal melanoma. PMID- 28000888 TI - Genetic heterogeneity in patients with Bartter syndrome type 1. AB - Bartter syndrome (BS) type 1 is an autosomal recessive kidney disorder caused by loss-of-function mutations in the solute carrier family 12 member 1 (SLC12A1) gene. To date, 72 BS type 1 patients harboring SLC12A1 mutations have been documented. Of these 144 alleles studied, 68 different disease-causing mutations have been detected in 129 alleles, and no mutation was detected in the remaining 15 alleles. The mutation types included missense/nonsense mutations, splicing mutations and small insertions and deletions ranging from 1 to 4 nucleotides. A large deletion encompassing a whole exon in the SLC12A1 gene has not yet been reported. The current study initially identified an undocumented homozygous frameshift mutation (c.1833delT) by Sanger sequencing analysis of a single infant with BS type 1. However, in a subsequent analysis, the mutation was detected only in the father's DNA. Upon further investigation using a next-generation sequencing approach, a deletion in exons 14 and 15 in both the patient and patient's mother was detected. The deletion was subsequently confirmed by use of a long-range polymerase chain reaction and was determined to be 3.16 kb in size based on sequencing of the junction fragment. The results of the present study demonstrated that pathogenic variants of SLC12A1 are heterogeneous. Large deletions appear to serve an etiological role in BS type 1, and may be more prevalent than previously thought. PMID- 28000889 TI - High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases. AB - Genetic testing is needed for the treatment of colorectal cancer (CRC), especially molecular-targeted therapy. The effects of anti-EGFR therapy and prognosis are affected by the presence of KRAS mutations. However, whether primary CRC or metastatic tissues are appropriate in the analysis is still unclear. In the present study, we assessed the concordance of KRAS/BRAF mutation status and microsatellite instability (MSI) in primary CRC and corresponding metastases. This study enrolled 457 patients with surgically resected primary and corresponding metastatic CRC (499 synchronous metastases and 57 metachronous metastases) and seven local recurrences, and KRAS/BRAF mutation and MSI status were analysed for these tumours. The concordance rates of KRAS mutation, BRAF mutation, wild-type, MSI-H and MSS between primary CRC and corresponding metastases were 93.9% (214/228), 100% (30/30), 99.3% (304/306), 87.5% (21/24) and 100% (137/137), respectively. These high concordance rates were not different between synchronous and metachronous metastases. In conclusion, a high concordance of KRAS/BRAF mutation status and MSI status was observed between primary CRC and corresponding metastases in this study. Either primary CRC or metastatic tissues can be used for testing KRAS/BRAF mutation status and MSI status. PMID- 28000890 TI - Combined analysis of gene expression, miRNA expression and DNA methylation profiles of osteosarcoma. AB - Osteosarcoma (OS) is a common primary malignancy in children and adolescents with relative high survival rate after chemotherapy. While the toxicity of chemotherapy and personalized different response to chemotherapy makes it difficult for the selection of therapeutics and improvement of diagnosis. In this study, we conducted a combined analysis of three types of microarray datasets (gene expression, microRNA (miRNA) expression and DNA methylation) from the Gene Expression Omnibus (GEO). The differential expression genes (DEGs) and miRNAs (DEMI) were screened out via the limma package and differential methylation sites (DMS) were identified by the IMA package. Enriched functions of DEGs and genes contained DMS (DEMs) were obtained through the Database for Annotation, Visualization and Integrated Discovery (DAVID). Besides, miRNA-gene regulation network was obtained based on the pairs of involved DEMIs and overlapping genes between DEMs and DEGs and visualized through Cytoscape software. A total of 583 DEGs and 1051 DMS (corresponding to 827 DEMs) were identified and 56 overlaps were obtained. As expected, most of the expression and methylation profiles of the overlaps exhibited significant negative correlation. The DEGs were mainly enriched in the biological processes related to inflammatory/immune response, cell proliferation, while DEMs were involved in the regulation of gene expression, tissue/organ development. Based on the correlation and network analysis, some novel targets were identified for OS and many known biomarkers were proved in this study, which would be helpful in its early diagnosis and treatment. PMID- 28000891 TI - Expression of miR-26a exhibits a negative correlation with HMGA1 and regulates cancer progression by targeting HMGA1 in lung adenocarcinoma cells. AB - Lung cancer is the most common cause of cancer-associated mortality worldwide, and the number of cases is increasing annually. Several studies have shown that microRNAs (miRNAs) control proliferation, differentiation, and apoptosis in various cell types, and increasing evidence indicates the presence of aberrant miRNA expression profiles and unique miRNA signaling pathways in several types of cancer. The present study aimed to identify miRNAs, which correlated specifically with the progression of lung cancer through the analysis of 57,100 transcripts and 1,341 small RNA expression profiles in 26 lung adenocarcinoma cell lines using next-generation sequencing. The most marked negative correlation was found between the expression of hsa-miR-26a-1 and messenger RNA (mRNA), and a list of mRNAs, which exhibited negative correlation with hsa-miR-26a-1 were investigated. The most marked negative correlation was observed between the expression levels of hsa-miR-26a-1 and high mobility group A1 (HMGA1). Using a lung adenocarcinoma cell line, the present study analyzed the effect of the overexpression of miR-26a on the expression of HMGA1 and found that miR-26a repressed the expression of HMGA1 by reducing the mRNA levels of HMGA1. Furthermore, it was demonstrated that the overexpression of miR-26a in a lung adenocarcinoma cell line repressed cell migration, invasion and growth by targeting HMGA1. Taken together, the present study showed a significant negative correlation between the expression of miR-26a and HMGA1 in 26 lung adenocarcinoma cell lines, and provided evidence that the suppression of miR-26a supports the progression of cancer by stimulating the expression of HMGA1. PMID- 28000893 TI - Hyperlipidemia-induced apoptosis of hippocampal neurons in apoE(-/-) mice may be associated with increased PCSK9 expression. AB - Hyperlipidemia is a risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a lipid regulatory gene involved in cell apoptosis. However, the function and mechanism of PCSK9 in neuronal apoptosis following hyperlipidemia remains to be elucidated. The present study established a hyperlipidemic mouse model by feeding a high-fat diet (HFD) to 6-week-old apoE(-/-) mice. Plasma lipid levels, hippocampal lipid accumulation, hippocampal histology, and hippocampal neuronal apoptosis were all monitored for changes. The expression levels of PCSK9, beta secretase 1 (BACE1), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase-3 in hippocampal CA3 and CA1 neurons were also measured. Results demonstrated that a HFD increased the lipid accumulation in the CA3 hippocampus and the levels of plasma lipids, including triglycerides, total cholesterol, low density lipoprotein, and high-density lipoprotein. In addition, CA3 neurons in the HFD group indicated apparent injuries and increased neuronal apoptosis, which are associated with the expression of Bcl-2, Bax, and caspase-3. A HFD also increased the expression levels of PCSK9 and BACE1. BACE1 promotes cleavage of amyloid precursor proteins to generate beta-amyloid peptide (Abeta), which induces neuronal apoptosis. Protein levels of Abeta are associated with the observation of amyloid plaques in the hippocampus of the HFD group. The results suggest that hyperlipidemia regulates neuronal apoptosis by increasing PCSK9 and BACE1 expression. Overall, the current study may elucidate the role of lipid metabolism disorder in AD pathogenesis. PMID- 28000894 TI - Berberine affects osteosarcoma via downregulating the caspase-1/IL-1beta signaling axis. AB - Osteosarcoma is one of the most devastating cancers with associated poor prognosis. Chronic bone inflammation frequently predisposes to tumorigenesis and progression of osteosarcoma. In the tumor inflammatory microenvironment, caspase 1 and its processed cytokines such as interleukin 1beta (IL-1beta) play an important role in the occurrence and development of cancer. Berberine is an isoquinoline alkaloid extracted from the dry root of Coptidis Rhizoma, which has been found to exhibit significant anticancer effects on a wide spectrum of carcinomas including osteosarcoma. However, the mechanisms underlying the anticancer effects of berberine in osteosarcoma remain poorly understood and their elucidation is critical for developing improved therapies. In the present study, we investigated the potential mechanism underlying the anticancer effect of berberine in osteosarcoma. We found that the expression of caspase-1 and its downstream target IL-1beta were higher in osteosarcoma cells compared with normal cells both in vitro and in vivo. Furthermore, administration of berberine is capable of reducing the expression of caspase-1 and IL-1beta in osteosarcoma cells and inhibiting the growth of tumor cells. Based on the above, for the first time, we propose the hyposis that berberine could gengerate an anti-osteosarcoma property through downregulating caspase-1/IL-1beta inflammatory signaling axis. PMID- 28000895 TI - HELQ reverses the malignant phenotype of osteosarcoma cells via CHK1-RAD51 signaling pathway. AB - HELQ is a DNA helicase important for repair of DNA lesions and has been linked to several types of cancer. However, little is known about its relationship with osteosarcoma (OS) and its mechanism. In the present study, the expression of HELQ and its downstream mediators in OS cells was assayed by quantitative PCR and western blot analysis. The function of HELQ in OS cells was investigated by Transwell invasion, wound healing, CCK8 assays and Comet assay. The results demonstrated that HELQ gene and protein were expressed in OS cells. OS cell invasion, migration, proliferation and DNA damage repair were enhanced by HELQ knock-down with shRNA-lentivirus and inhibited by HELQ overexpression with lentivirus transfection. Furthermore, the antitumor activities of HELQ may be associated with upregulated expression of the DNA damage-related proteins CHK1 and RAD51. Our findings indicated that HELQ confers an anti-invasive phenotype on OS cells by activating the CHK1-RAD51 signaling pathway and suggested that HELQ could be recognized as a promising therapeutic target for OS and other types of malignant tumors. PMID- 28000896 TI - miR-223-3p regulates cell growth and apoptosis via FBXW7 suggesting an oncogenic role in human testicular germ cell tumors. AB - miR-223-3p is deregulated in several tumor types and plays an important role in tumorigenesis and progression. However, its role in the pathogenesis of testicular germ cell tumor (TGCT) remains uncharacterized. We previously demonstrated that miR-223-3p expression was increased in TGCTs compared with normal testes (NT), suggesting that miR-223-3p may have an oncogenic role in TGCT. Using published dataset and The Cancer Genome Atlas database, we validated higher miR-223-3p expression in TGCTs than NT, and found a negative correlation between miR-223-3p and FBXW7 mRNA expression levels. Using both gain- and loss-of function experiments, we show that miR-223-3p regulates FBXW7 protein expression, cell growth and apoptosis in TGCT cell lines. Additionally, we demonstrate that ectopic expression of the full-length coding sequence of FBXW7 could rescue the cell growth and apoptotic effects mediated by miR-223-3p. Our findings suggest an oncogenic role for miR-223-3p in TGCT, which promotes cell growth and inhibits apoptosis through repression of FBXW7. PMID- 28000897 TI - Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma. AB - Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors. PMID- 28000898 TI - Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-kappaB activation in hepatocellular carcinoma cells. AB - The aim of the present study was to investigate the role of NF-kappaB inactivation in regorafenib-induced apoptosis in human hepatocellular carcinoma SK-HEP-1 cells. SK-HEP-1 cells were treated with different concentrations of the NF-kappaB inhibitor 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) or regorafenib for different periods. The effects of QNZ and regorafenib on cell viability, expression of NF-kappaB-modulated anti-apoptotic proteins and apoptotic pathways were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, western blotting, DNA gel electrophoresis, flow cytometry and NF-kappaB reporter gene assay. Inhibitors of various kinases including AKT, c-Jun N-terminal kinase (JNK), P38 and extracellular signal-regulated kinase (ERK) were used to evaluate the mechanism of regorafenib-induced NF-kappaB inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of anti-apoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-kappaB activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-kappaB activation in SK-HEP-1 cells. PMID- 28000892 TI - Non-infective occupational risk factors for hepatocellular carcinoma: A review (Review). AB - Liver cancer is the second leading worldwide cause of cancer-associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well-established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non-specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem. PMID- 28000900 TI - miR-24-3p regulates bladder cancer cell proliferation, migration, invasion and autophagy by targeting DEDD. AB - microRNAs (miRNAs), a class of small non-coding RNA molecules, can regulate gene expression by interacting with the 3'-untranslated regions (3'UTR) of target genes and influence various biological processes. We investigated the potential role of miR-24-3p in the development of bladder cancer by regulating DEDD, a member of the death effector domain-containing protein family. First, we found that miR-24-3p was highly expressed and that DEDD was expressed at a low level in bladder cancer tissues compared with that in adjacent bladder tissues by qRT-PCR (P<0.0001). Second, we found that miR-24-3p promoted the proliferation ability of bladder cancer cells using the MTT assay and colony forming assay; and showed that miR-24-3p accelerated the migration and invasion of bladder cancer cells using migration and invasion assays (P<0.05). Moreover, miR-24-3p inhibited apoptosis of bladder cancer cells, as shown by flow cytometry (P<0.05). Western blot results demonstrated that miR-24-3p participated in autophagy of bladder cancer cells by DEDD. In addition, the tumor formation assay showed that miR-24 3p promoted the growth of bladder tumor in vivo. Furthermore, the luciferase reporter gene assay indicated that miR-24-3p suppressed DEDD gene transcription. Therefore, our study indicated that miR-24-3p promoted bladder cancer progression by inhibiting DEDD. PMID- 28000899 TI - miR-367 promotes the proliferation and invasion of non-small cell lung cancer via targeting FBXW7. AB - The involvement of miR-367 in lung cancer development remains unclear. In the present study, we analyzed the expression of miR-367 in tumor and adjacent tissue samples from 113 patients with non-small cell lung cancer (NSCLC) utilizing real time PCR. miR-367 expression was significantly upregulated in the cancer tissues compared with non-cancer controls. Based on the median value of the miR-367 expression level, we divided the NSCLC patients into miR-367 high-expression and miR-367 low-expression groups. Overexpression of miR-367 was correlated with a poorer prognosis of NSCLC patients Chi-square (chi2) test showed a significant statistical correlation between tumor size, tumor stage, metastasis and miR-367 expression. Additionally, miR-367 expression was found to be negatively correlated with FBXW7 expression. Based on the above correlations, we performed a series of functional experiments to further confirm the effect of miR-367 on NSCLC. Our results indicated that miR-367 may be involved in the development and progression of NSCLC by promoting proliferation and invasion and impeding apoptosis in NSCLC cells. Furthermore, FBXW7 was identified as a potential target of miR-367, and FBXW7 silencing partially compromised the invasive, proliferative and migratory capacities in the cells with low miR-367 expression. Thus, the miR 367/FBXW7 axis may be involved in the development and progression of NSCLC and may be valuable as a therapeutic target for the treatment of human NSCLC, especially cancers with high invasive potential. PMID- 28000901 TI - Identification of key genes in colorectal cancer using random walk with restart. AB - As the most common type of cancer and the second leading cause of cancer associated mortality, colorectal cancer (CRC) has received increasing attention. The aim of the present study was to investigate the mechanisms of CRC by analyzing the microarray dataset, GSE32323. The GSE32323 dataset was downloaded from the Gene Expression Omnibus, and included 17 pairs of matched cancer and normal colorectal tissue samples. The differentially expressed genes (DEGs) were screened using the Linear Models for Microarray Data package and a search of CRC genes, also denoted as seed genes, was performed using the Online Mendelian Inheritance in Man database. Subsequently, the protein-protein interaction (PPI) network was downloaded from the Search Tool for the Retrieval of Interacting Genes database and the sub-network (CRC.PPI) of the DEGs and seed genes were obtained. In addition, the top 50 nodes with highest affinity scores in the CRC.PPI were identified using random walk with restart analysis. The potential functions of the DEGs included in the top 50 nodes were analyzed using the Database for Annotation, Visualization and Integrated Discovery online tool. Using the Drug Gene Interaction database, drug-gene interaction analysis was performed to identify antineoplastic drug interacts with genes. A total of 1,640 DEGs between the CRC and normal samples were screened. The obtained seed genes included cyclin D1 (CCND1) and aurora kinase A (AURKA). The enriched functions for the 31 DEGs in the PPI network of the top 50 nodes were predominantly associated with cell cycle. The DEGs may function in CRC by interacting with other genes in the PPI network of the top 50 nodes, for example, DEP domain containing MTOR-interacting protein (DEPTOR)-CCND1, AURKA-breast carcinoma amplified sequence-1 (BCAS1), CCND1-BCAS1, CCND1-neural precursor cell expressed developmentally downregulated 9 (NEDD9) and CCND1-mitogen-activated protein kinase kinase 2 (MAP2K2). Only three DEGs (CCND1, AURKA and DEPTOR) had interactions with their corresponding antineoplastic drugs. Taken together, DEPTOR, AURKA, CCND1, BCAS1, NEDD9 and MAP2K2 may act in CRC. PMID- 28000902 TI - MicroRNA-375 inhibits oral squamous cell carcinoma cell migration and invasion by targeting platelet-derived growth factor-A. AB - MicroRNA-375 (miR-375) serves an important role in cancer development and growth. However, little is known about the role of miR-375 in the regulation of oral squamous cell carcinoma (OSCC) metastasis and invasion. The present study measured the expression levels of miR-375 in Tca8113, UM2, UM1 and CAL-27 cell lines, using reverse transcription-quantitative polymerase chain reaction. The results demonstrated that miR-375 expression levels were significantly reduced in UM1 and CAL-27 (highly metastatic) compared with Tca8113 and UM2 (less aggressive) OSCC cell lines. Furthermore, it was revealed that overexpression of miR-375 suppressed the migration and invasion of UM1 cells. Based on a luciferase reporter assay, platelet-derived growth factor-A (PDGF-A) was identified as a direct target gene of miR-375. Additionally, overexpression of PDGF-A significantly reversed the effect of miR-375 on cell migration and invasion in UM1 cells. These data demonstrated that miR-375 suppressed OSCC cell migration and invasion by targeting PDGF-A, which may be a potential therapeutic target for the treatment of OSCC. PMID- 28000903 TI - Pluripotent human stem cells: Standing on the shoulders of giants. AB - The advent of human pluripotent stem cells, with the first derivation of human embryonic stem cells in 1998, and of human induced pluripotent stem cells in 2007, has ushered in an era of considerable excitement about the prospects of using these cells to develop new opportunities for healthcare, from their potential for regenerative medicine to their use as tools for studying the cellular basis of many diseases and the discovery of new drugs. But as with the flowering of many new areas in science, the biology of human pluripotent stem cells has its roots in a long history of, sometimes, less feted research. In a period when research funding is frequently driven by a desire to meet specific clinical or economic goals, it is salutary to remember that the opportunities offered by human pluripotent stem cells have their origins in curiosity driven research without any of those goals in mind. In this case, that research focused on the relatively rare gonadal cancers known as teratomas, tumors that have fascinated people since antiquity because their sometime grotesque manifestations with haphazard collections of tissues and sometimes recognizable body parts. Although well known to clinical pathologists it was the pioneering work of Leroy Stevens, who first discovered that teratomas occur at a significant rate in the 129 strain of the laboratory mouse and could be produced experimentally, that laid the foundations for our understanding of the biology of these tumors and the central role of the embryonal carcinoma cell, one of the archetypal tumor stem cells. PMID- 28000904 TI - Honoring the work and life of Leroy C. Stevens. A symposium as part of the International Stem Cell Initiative Workshop. AB - In 2016, a symposium was convened in Leroy C. Stevens' honor, in association with a meeting of the International Stem Cell Initiative (ISCI). ISCI, funded internationally, is composed of a group of ~100 scientists from many countries, under the leadership of Peter Andrews, who have worked together to characterize a significant number of human pluripotent stem cell lines, to monitor their genetic stability and their differentiation into mature cell types and tissues in vitro and in vivo. Those at the ISCI meeting puzzled through one of the thorniest problems in the therapeutic use of the differentiated derivatives of pluripotent stem cells for human therapy; namely, pluripotent stem cells can differentiate into any cell type in the adult organism, but they also have the capacity for unlimited self-renewal, hence if mutated they may have tumorigenic potential. The meeting considered how these cells might become genetically or epigenetically abnormal and how the safety of these cells for human therapeutic uses could be assessed and assured. The symposium was an opportunity to pay tribute to Leroy Stevens and to the basic science origins of this newest aspect of regenerative medicine. It was a time to reflect on the past and on how it can influence the future of our field. PMID- 28000905 TI - Teratomas produced from human pluripotent stem cells xenografted into immunodeficient mice - a histopathology atlas. AB - This atlas illustrates the microscopic features of tumors produced from human pluripotent stem cells (hPSCs) xenografted into immunosuppressed mice, according to the generally accepted protocols for performing this teratoma assay of stem cell pluripotency. Microphotographs depict various hematoxylin and eosin (H&E) stained tissues derived from all three embryonic germ layers (ectoderm, mesoderm and endoderm). The appearance of persistent hPSC in teratomas is also described with special emphasis on the morphogenesis of embryoid bodies and yolk sac components surrounding them. The use of immunohistochemistry for analyzing hPSC derived teratomas is also illustrated. PMID- 28000906 TI - [Clinical characteristics of vestibular migraine: considerations in a series of 41 patients]. AB - INTRODUCTION: After years of debate about its being approached from headaches and its denomination, vestibular migraine has recently been included in the research appendix of the 3rd edition of the International Headache Classification. AIM: To analyse the characteristics of a series of patients with vestibular migraine who visited because of headaches. PATIENTS AND METHODS: Our sample consisted of patients who were attended in a headache unit between January 2014 and December 2015. The demographic variables and the characteristics of both migraine and vestibular symptoms were considered, and cases with other otorhinolaryngological conditions were excluded. RESULTS: The sample was finally made up of 41 patients (11 males, 30 females) with a mean age of 31.8 +/- 13.3 years at the time they were included in the study. Sixteen patients (39%) met criteria for chronic migraine and two (4.9%) presented visual auras. The vestibular symptoms were considered severe in eight cases (19.5%) and occurred in 74.6% of the migraine attacks. Vertigo was described as internal in 18 cases (43.9%), external in 22 (53.7%) and mixed in one case (2.4%). The most frequent symptom was positional vertigo (n = 25; 61%), followed by that induced by head movements (n = 18; 43.9%) and spontaneous (n = 15; 36.6%). Accompanying symptoms included tinnitus (n = 12; 29.3%) and a feeling of fullness in the ear (n = 8; 19.5%). CONCLUSION: It is not uncommon to identify symptoms consistent with vestibular migraine in patients who visit a headache unit; they are patients whose day-to-day activities are not usually affected by their vertigo. PMID- 28000907 TI - [Cognitive Reserve Scale: testing the theoretical model and norms]. AB - INTRODUCTION: The cognitive reserve theory may contribute to explain cognitive performance differences among individuals with similar cognitive decline and among healthy ones. However, more psychometric analysis are needed to guarantee the usage of tests for assessing cognitive reserve. AIMS: To study validity evidences in relation to the structure of the Cognitive Reserve Scale (CRS) and to create reference norms to interpret the scores. SUBJECTS AND METHODS: A total of 172 participants completed the scale and they were classified into two age groups: aged 36-64 years (n = 110) and 65-88 years (n = 62). RESULTS: The exploratory factor analysis using ESEM revealed that the data fitted the proposed model. Overall, the discriminative indices were acceptable (between 0.21 and 0.50) and congruence was observed in the periods of young adulthood, adulthood and late adulthood, in both age group. Besides, the index of reliability (Cronbach's alpha: 0.80) and the typical mean error test (mean: 51.40 +/- 11.11) showed adequate values for this type of instrument. CONCLUSION: The CRS seemed to be set under the hypothetical theoretical model, and the scores might be interpreted by the norms showed. This study provided guarantees for the usage of the CRS in research. PMID- 28000908 TI - [Knowledge of cerebrovascular disease in the population of Zaragoza]. AB - INTRODUCTION: Acute cerebrovascular disease is a major cause of disability and mortality, with important socio-economic and health impacts. Early stroke care can reduce mortality and improve prognosis. Right now, we can apply treatments in the acute phase, with capacity to reverse the symptoms, but few patients who benefit not reach the hospital soon. One reason for this delay is the lack of recognition of symptoms and poor perception of gravity. AIM: To find out the knowledge of the public about the stroke. SUBJECTS AND METHODS: The sample analyzed was the population of Sector III of Zaragoza, with random selection. The tool used was a telephone survey structured. We analyzed 583 surveys. RESULTS: 63.5% of respondents did not know any symptoms of stroke. 48% do not know any vascular risk factor. Only 9% recognized at least two symptoms and two risk factors. Regarding the attitude, 56% act properly against 44% who do not. Multivariate analysis showed that the factors more related to knowledge are the cultural level and young age. Living in town, and female, they are associated with the best attitude. CONCLUSIONS: Knowledge about stroke is poor, with a low sense of urgency. The factors most associated with the best knowledge are young age and cultural level. PMID- 28000909 TI - [Language disorders in acute cerebellitis: beyond dysarthria]. AB - INTRODUCTION: Acute cerebellitis is one of the main causes of cerebellar syndrome in infancy. Among the wide range of manifestations, headache and ataxia being the most predominant, we can find other less frequent, although nonetheless interesting, ones, such as language disorders, which go beyond the well-known cerebellar dysarthria. The different combinations in which the symptoms can appear, especially when not accompanied by ataxia, make the condition a real challenge for the clinician. CASE REPORTS: Two patients, aged 2 and 4 years, with clinical features, lab tests and neuroimaging results consistent with parainfectious acute cerebellitis. Both of them also presented a striking language disorder, one in the form of cerebellar mutism and the other in the form of hypofluency and agrammatism, the latter also developing in the absence of ataxia. Both cases progressed favourably, and mild speech alterations persisted in the follow-up visits. CONCLUSIONS: Cases such as these expand the range of clinical manifestations of acute cerebellitis. The involvement of the cerebellum in neurocognitive processes like language is becoming increasingly more important and, although many aspects are still only speculations, managing to define its true role will have important repercussions on the diagnosis, treatment and long term prognosis of these patients. PMID- 28000910 TI - [Environmental and genetic variables related with alterations in language acquisition in early childhood]. AB - INTRODUCTION: A great deal of research has addressed problems in the correct acquisition of language, but with few overall conclusions. The reasons for this lie in the individual variability, the existence of different measures for assessing language and the fact that a complex network of genetic and environmental factors are involved in its development. AIM: To review the environmental and genetic variables that have been studied to date, in order to gain a better under-standing of the causes of specific language impairment and create new evidence that can help in the development of screening systems for the early detection of these disorders. DEVELOPMENT: The environmental variables related with poorer early child language development include male gender, low level of education of the mother, familial history of problems with language or psychiatric problems, perinatal problems and health problems in early childhood. Bilingualism seems to be a protective factor. Temperament and language are related. Within the genetic factors there are several specific genes associated with language, two of which have a greater influence on its physiological acquisition: FOXP2 and CNTNAP2. The other genes that are most related with specific language disorders are ATP2C2, CMIP, ROBO2, ZNF277 and NOP9. CONCLUSIONS: The key to comprehending the development of specific language disorders lies in reaching an understanding of the true role played by genes in the ontogenesis, in the regulation of the different developmental processes, and how this role is modulated by the environment. PMID- 28000911 TI - [41.a Reunion de la Sociedad de Neurofisiologia Clinica de las Comunidades de Valencia y Murcia. Communications]. PMID- 28000912 TI - [Hereditary distal motor neuropathy due to mutation of BSCL2]. PMID- 28000913 TI - [Clinical and immunological improvement of myasthenia gravis following treatment with denosumab]. PMID- 28000914 TI - Inclusion of Hermetia illucens larvae meal on rainbow trout (Oncorhynchus mykiss) feed: effect on sensory profile according to static and dynamic evaluations. AB - BACKGROUND: Diet implementation with insect meal has aroused increased attention in aquaculture considering the advantages of this new protein source. The effect of Hermetia illucens meal (HI) inclusion in diets on rainbow trout physical chemical and sensory properties was evaluated. Three diets were prepared: HI0, HI25, HI50, with 0, 25 and 50% of HI replacing fish meal, respectively. Fillet sensory profiles were described by descriptive analysis and temporal dominance of sensation methods. Cooking loss, Warner-Bratzler shear force, proximate analysis, and fatty acid composition were also determined. RESULTS: Diets significantly affected fillets sensory profile. Descriptive analysis indicated significant changes in perceived intensity of aroma, flavour and texture descriptors as a function of diet composition. Temporal dominance of sensation evaluations provided information on dominance and evolution of sensations perceived in fillets from different diets. The first sensations perceived as dominant were related to texture attributes, followed by flavours. Dominance of fibrousnesses decreased with the increase of HI in the diet. Boiled fish, algae flavours and umami taste clearly dominated the HI0 dynamic profile. The onset of metallic flavour dominance characterised HI25 and HI50. No differences in physical parameters were detected. Principal component analysis highlighted the relationship between sensory attributes and physico-chemical parameters. CONCLUSION: The sensory description of fillets indicated that HI inclusion induces significant differences in the perceived profile. (c) 2016 Society of Chemical Industry. PMID- 28000915 TI - Experimental evolution of slowed cognitive aging in Drosophila melanogaster. AB - Reproductive output and cognitive performance decline in parallel during aging, but it is unknown whether this reflects a shared genetic architecture or merely the declining force of natural selection acting independently on both traits. We used experimental evolution in Drosophila melanogaster to test for the presence of genetic variation for slowed cognitive aging, and assess its independence from that responsible for other traits' decline with age. Replicate experimental populations experienced either joint selection on learning and reproduction at old age (Old + Learning), selection on late-life reproduction alone (Old), or a standard two-week culture regime (Young). Within 20 generations, the Old + Learning populations evolved a slower decline in learning with age than both the Old and Young populations, revealing genetic variation for cognitive aging. We found little evidence for a genetic correlation between cognitive and demographic aging: although the Old + Learning populations tended to show higher late-life fecundity than Old populations, they did not live longer. Likewise, selection for late reproduction alone did not result in improved late-life learning. Our results demonstrate that Drosophila harbor genetic variation for cognitive aging that is largely independent from genetic variation for demographic aging and suggest that these two aspects of aging may not necessarily follow the same trajectories. PMID- 28000916 TI - Pathological changes of adipose tissue in secondary lymphoedema. AB - BACKGROUND: The pathophysiology of lymphoedema is poorly understood. Current treatment options include compression therapy, resection, liposuction and lymphatic microsurgery, but determining the optimal treatment approach for each patient remains challenging. OBJECTIVES: We characterized skin and adipose tissue alterations in the setting of secondary lymphoedema. METHODS: Morphological and histopathological evaluations were conducted for 70 specimens collected from 26 female patients with lower-extremity secondary lymphoedema following surgical intervention for gynaecological cancers. Indocyanine green lymphography was performed for each patient to assess lymphoedema severity. RESULTS: Macroscopic and ultrasound findings revealed that lymphoedema adipose tissue had larger lobules of adipose tissue, with these lobules surrounded by thick collagen fibres and interstitial lymphatic fluid. In lymphoedema specimens, adipocytes displayed hypertrophic changes and more collagen fibre deposits when examined using electron microscopy, whole-mount staining and immunohistochemistry. The number of capillary lymphatic channels was also found to be increased in the dermis of lymphoedema limbs. Crown-like structures (dead adipocytes surrounded by M1 macrophages) were less frequently seen in lymphoedema samples. Flow cytometry revealed that, among the cellular components of adipose tissue, adipose-derived stem/stromal cells and M2 macrophages were decreased in number in lymphoedema adipose tissue compared with normal controls. CONCLUSIONS: These findings suggest that long-term lymphatic volume overload can induce chronic tissue inflammation, progressive fibrosis, impaired homeostasis, altered remodelling of adipose tissue, impaired regenerative capacity and immunological dysfunction. Further elucidation of the pathophysiological mechanisms underlying lymphoedema will lead to more reliable therapeutic strategies. PMID- 28000918 TI - New insight on vertebral anomalies in cultured Senegalese sole (Solea senegalensis, Kaup) at early stages of development. AB - Senegalese sole (Solea senegalensis, Kaup) is a promising flatfish species in aquaculture. However, skeletal anomalies are still a great concern in sole farming. Investigation of this issue is crucial to improving larval quality and optimizing production. The aim of this study was to thoroughly assess anomalies in the rachis of reared sole at early developmental stages. Sole (n = 507) were sampled at 31 or 32 days after hatching (dah). The specimens were stained with alcian blue and alizarin red and evaluated for the detection of vertebral deformities. Most fish presented 9:34:3 vertebrae in abdominal, caudal and caudal complex regions, respectively. Remarkably, all specimens showed at least one spinal anomaly. Alterations of neural/haemal elements, as well as deformities of hypurals, parhypural and epural, were recurrent. Vertebral body anomalies and/or vertebral column deviations were identified in 52% of the individuals. Vertebral deformations and fusions were common, especially in caudal complex. 'Minor' anomalies were predominant, and some of the detected disorders might be a result of non-/low-pathological processes. These results contribute a new insight into the main skeletal anomalies affecting cultured sole larvae. Further research is required to determine their impact on fish welfare and external appearances at commercial stages. PMID- 28000917 TI - Simulating demand for cigarettes among pregnant women: A Low-Risk method for studying vulnerable populations. AB - A substantive obstacle to experimentally studying cigarette smoking and use of other tobacco products in pregnant women is the risk of adverse effects on mother and fetus from experimenter administration of the product of interest. The purpose of this study is to investigate bypassing that obstacle by using behavioral economic simulation tasks. In the present study we used the Cigarette Purchase Task (CPT) to simulate changes in demand for hypothetical cigarettes as a function of varying cigarette prices. Participants were 95 pregnant women who completed the CPT prior to participation in a smoking-cessation trial. Aggregate and individual participant demand varied as an orderly function of price and those changes were well fitted by an exponential equation. Demand also varied in correspondence to two well-validated predictors of individual differences in smoking cessation among pregnant women (cigarettes smoked per day, pre-pregnancy quit attempts). Moreover, CPT indices were more effective than these two conventional variables in predicting individual differences in whether women made a quit attempt during the current pregnancy. Overall, these results represent a promising step in demonstrating the validity and utility of the CPT for experimentally examining demand for cigarettes, and potentially other tobacco and nicotine delivery products, among pregnant women. PMID- 28000919 TI - Antibiotic treatment for nontuberculous mycobacteria lung infection in people with cystic fibrosis. AB - BACKGROUND: Nontuberculous mycobacteria are mycobacteria, other than those in the Mycobacterium tuberculosis complex, and are commonly found in the environment. Nontuberculous mycobacteria species (most commonly Mycobacterium avium complex and Mycobacterium abscessus) are isolated from the respiratory tract of approximately 5% to 40% of individuals with cystic fibrosis; they can cause lung disease in people with cystic fibrosis leading to more a rapid decline in lung function and even death in certain circumstances. Although there are guidelines for the antimicrobial treatment of nontuberculous mycobacteria lung disease, these recommendations are not specific for people with cystic fibrosis and it is not clear which antibiotic regimen may be the most effective in the treatment of these individuals. This is an update of a previous review. OBJECTIVES: The objective of our review was to compare antibiotic treatment to no antibiotic treatment, or to compare different combinations of antibiotic treatment, for nontuberculous mycobacteria lung infections in people with cystic fibrosis. The primary objective was to assess the effect of treatment on lung function and pulmonary exacerbations and to quantify adverse events. The secondary objectives were to assess treatment effects on the amount of bacteria in the sputum, quality of life, mortality, nutritional parameters, hospitalizations and use of oral antibiotics. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search: 02 September 2016.We also searched a register of ongoing trials and the reference lists of relevant articles and reviews. Date of last search: 03 November 2016. SELECTION CRITERIA: Any randomized controlled trials comparing nontuberculous mycobacteria antibiotics to no antibiotic treatment, as well as one nontuberculous mycobacteria antibiotic regimen compared to another nontuberculous mycobacteria antibiotic regimen, in individuals with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Data were not collected because in the one trial identified by the search, data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. MAIN RESULTS: One completed trial was identified by the searches, but data specific to individuals with cystic fibrosis could not be obtained from the pharmaceutical company. AUTHORS' CONCLUSIONS: This review did not find any evidence for the effectiveness of different antimicrobial treatment for nontuberculous mycobacteria lung disease in people with cystic fibrosis. Until such evidence becomes available, it is reasonable for clinicians to follow published clinical practice guidelines for the diagnosis and treatment of nodular or bronchiectatic pulmonary disease due to Mycobacterium avium complex or Mycobacterium abscessus in patients with cystic fibrosis. PMID- 28000920 TI - On fascination and fear of annihilation. AB - In this paper fascination phenomenologically is described as a state of radically being captured by an imposing object. What is left of the impoverished and paralysed subject clings to the exclusive fascinating object. Fascination is the eye of the storm of extreme ambivalence towards an exclusive object: being the only remaining object it is necessary for living in an object world, but at the same time it is threatening to life by absorbing the subject totally. So the subject is sucked in by a yet frightening object. From a metapsychological point of view fascination is understood as the congealed result of excessive projective identification and a strong confusional state connected with it: the subject empties itself so much in the object that it comes to stand for the subject. The fascinating object embodies in a condensed way - as a special form of a bizarre object - split off unconscious threatening material. So fascination is linked to the Kleinian theory of anxiety. Two clinical vignettes illustrate how states of fascination can be understood as an ultimate defence against unconscious menacing material welling up. The hypothesis is developed that fascination points to a revelation of fundamental psychic truth that promptly cramps the subject because the reintegration of it is felt as annihilating. In the vignettes this takes the form of a 'transformation in hallucinosis'. Fascination is at the same time 'the moment of truth' and possibly a serious obstruction of the analytic process. This unconscious truth seems to concern primitive 'superego violence'. The challenge consists in thawing the frozen fascinating object by linking it to other material. PMID- 28000921 TI - Comparative evaluation of performance measures for shading correction in time lapse fluorescence microscopy. AB - Time-lapse fluorescence microscopy is a valuable technology in cell biology, but it suffers from the inherent problem of intensity inhomogeneity due to uneven illumination or camera nonlinearity, known as shading artefacts. This will lead to inaccurate estimates of single-cell features such as average and total intensity. Numerous shading correction methods have been proposed to remove this effect. In order to compare the performance of different methods, many quantitative performance measures have been developed. However, there is little discussion about which performance measure should be generally applied for evaluation on real data, where the ground truth is absent. In this paper, the state-of-the-art shading correction methods and performance evaluation methods are reviewed. We implement 10 popular shading correction methods on two artificial datasets and four real ones. In order to make an objective comparison between those methods, we employ a number of quantitative performance measures. Extensive validation demonstrates that the coefficient of joint variation (CJV) is the most applicable measure in time-lapse fluorescence images. Based on this measure, we have proposed a novel shading correction method that performs better compared to well-established methods for a range of real data tested. PMID- 28000922 TI - Pseudocyst formation in the marine parasitic amoeba Neoparamoeba perurans: a short-term survival strategy to abrupt salinity variation. PMID- 28000923 TI - Core principles characterizing immune function. AB - The immune system is an anticipatory mechanism designed by evolution to protect the individual against noxious agents and harmful cellular debris. In order to recognize substances that it has never encountered, the immune system somatically generates an appropriately sized random (with respect to self and nonself [NS]) recognitive repertoire that is coupled to a biodestructive and ridding output. Consequently, a Self-NS discrimination is required in order to avoid autoimmunity. This essay is an attempt to highlight the core principles upon which this anticipatory mechanism depends in order to function. PMID- 28000924 TI - Streptococcus agalactiae outbreaks in cultured golden pomfret, Trachinotus blochii (Lacepede), in Singapore. PMID- 28000925 TI - A Concept Analysis of Systems Thinking. AB - PURPOSE: This concept analysis, written by the National Quality and Safety Education for Nurses (QSEN) RN-BSN Task Force, defines systems thinking in relation to healthcare delivery. METHODS: A review of the literature was conducted using five databases with the keywords "systems thinking" as well as "nursing education," "nursing curriculum," "online," "capstone," "practicum," "RN BSN/RN to BSN," "healthcare organizations," "hospitals," and "clinical agencies." Only articles that focused on systems thinking in health care were used. The authors identified defining attributes, antecedents, consequences, and empirical referents of systems thinking. FINDINGS: Systems thinking was defined as a process applied to individuals, teams, and organizations to impact cause and effect where solutions to complex problems are accomplished through collaborative effort according to personal ability with respect to improving components and the greater whole. Four primary attributes characterized systems thinking: dynamic system, holistic perspective, pattern identification, and transformation. CONCLUSION: Using the platform provided in this concept analysis, interprofessional practice has the ability to embrace planned efforts to improve critically needed quality and safety initiatives across patients' lifespans and all healthcare settings. PMID- 28000926 TI - Virtual reality for rehabilitation in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is best managed by a combination of medication and regular physiotherapy. In this context, virtual reality (VR) technology is proposed as a new rehabilitation tool with a possible added value over traditional physiotherapy approaches. It potentially optimises motor learning in a safe environment, and by replicating real-life scenarios could help improve functional activities of daily living. OBJECTIVES: The objective of this review was to summarise the current best evidence for the effectiveness of VR interventions for the rehabilitation of people with PD in comparison with 1) active interventions, and 2) passive interventions. Our primary goal was to determine the effect of VR training on gait and balance. Secondary goals included examining the effects of VR on global motor function, activities of daily living, quality of life, cognitive function, exercise adherence, and the occurrence of adverse events. SEARCH METHODS: We identified relevant articles through electronic searches of the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, Embase, CINAHL, the Physiotherapy Evidence Database (PEDro), online trials registers, and by handsearching reference lists. We carried out all searches up until 26 November 2016. SELECTION CRITERIA: We searched for randomised and quasi-randomised controlled trials of VR exercise interventions in people with PD. We included only trials where motor rehabilitation was the primary goal. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for trials that corresponded to the predefined inclusion criteria. We independently extracted and assessed all data for methodological quality. A third review author was responsible for conflict resolution when required. MAIN RESULTS: We included 8 trials involving 263 people with PD in the review. Risk of bias was unclear or high for all but one of the included studies. Study sample sizes were small, and there was a large amount of heterogeneity between trials with regard to study design and the outcome measures used. As a result, we graded the quality of the evidence as low or very low. Most of the studies intended to improve motor function using commercially available devices, which were compared with physiotherapy. The interventions lasted for between 4 and 12 weeks.In comparison to physiotherapy, VR may lead to a moderate improvement in step and stride length (standardised mean difference (SMD) 0.69, 95% confidence interval (CI) 0.30 to 1.08; 3 studies; 106 participants; low-quality evidence). VR and physiotherapy interventions may have similar effects on gait (SMD 0.20, 95% CI -0.14 to 0.55; 4 studies; 129 participants; low-quality evidence), balance (SMD 0.34, 95% CI -0.04 to 0.71; 5 studies; 155 participants; low-quality evidence), and quality of life (mean difference 3.73 units, 95% CI -2.16 to 9.61; 4 studies; 106 participants). VR interventions did not lead to any reported adverse events, and exercise adherence did not differ between VR and other intervention arms.The evidence available comparing VR exercise with a passive control was more limited. The evidence for the main outcomes of interest was of very low quality due to the very small sample sizes of the two studies available for this comparison. AUTHORS' CONCLUSIONS: We found low-quality evidence of a positive effect of short-term VR exercise on step and stride length. VR and physiotherapy may have similar effects on gait, balance, and quality of life. The evidence available comparing VR with passive control interventions was more limited. Additional high-quality, large scale studies are needed to confirm these findings. PMID- 28000927 TI - Does detection of DDX4 mRNA in cell-free seminal plasma represents a reliable noninvasive germ cell marker in patients with nonobstructive azoospermia? AB - This study aimed to investigate the potential application of DDX4 gene expression in cell-free seminal mRNA as a noninvasive biomarker for the identification of the presence of germ cells in men with nonobstructive azoospermia and to correlate this factor with testicular biopsy. Male reproductive organ-specific genes were chosen: DDX4, which is a germ cell-specific gene and transglutaminase 4, which is a prostate-specific gene that was used as a control gene. Thirty-nine azoospermic males and twenty-eight normospermic fertile males (serving as a control group) participated in the study. Histopathological examination of testicular biopsies categorised azoospermic males into 20.5% with maturation arrest, 17.9% with incomplete Sertoli cell-only syndrome and 61.5% with complete Sertoli cell-only syndrome. Using real-time polymerase chain reaction, positivity for DDX4 gene was detected in 17 of 39 males with NOA which was due to maturation arrest in 35.3% (n = 6/17) of cases, due to incomplete Sertoli cell only in 23.5% (n = 4/17) and due to complete Sertoli cell only in 41.2% (n = 7/17). The study recommends joint utilisation of molecular transcripts as noninvasive biomarkers and histopathological examination of testicular biopsies in management of cases with azoospermia of the nonobstructive type. PMID- 28000928 TI - Evacuation from Natural Disasters: A Systematic Review of the Literature. AB - Research on evacuation from natural disasters has been published across the peer reviewed literature among several disparate disciplinary outlets and has suggested a wide variety of predictors of evacuation behavior. We conducted a systematic review to summarize and evaluate the current literature on demographic, storm-related, and psychosocial correlates of natural disaster evacuation behavior. Eighty-three eligible papers utilizing 83 independent samples were identified. Risk perception was a consistent positive predictor of evacuation, as were several demographic indicators, prior evacuation behavior, and having an evacuation plan. The influence of prior experiences, self-efficacy, personality, and links between expected and actual behavior were examined less frequently. Prospective, longitudinal designs are relatively uncommon. Although difficult to conduct in postdisaster settings, more prospective, methodologically rigorous studies would bolster inferences. Results synthesize the current body of literature on evacuation behavior and can help inform the design of more effective predisaster evacuation warnings and procedures. PMID- 28000929 TI - In vitro reprotoxicity of carboxyl-functionalised single- and multi-walled carbon nanotubes on human spermatozoa. AB - Reproductive toxicity of carboxyl-functionalised carbon nanotubes (CNT-COOH), as the most commonly used form of water-soluble CNTs, is not clearly studied. The aim of this study was to investigate in vitro toxicity of carboxylated single walled and multi-walled CNTs (SWCNT-COOH and MWCNT-COOH) against human spermatozoa. Sperm cells from healthy donors were incubated with 0.1-100 MUg/ml of SWCNT-COOH or MWCNT-COOH at 37 degrees C for up to 5 hr. Viability of sperm cells was assessed using MTT test, and sperm motility was evaluated following World Health Organization guideline. Production of reactive oxygen species (ROS) and nitric oxide (NO) in sperm was also assessed. We showed that both MWCNT-COOH and SWCNT-COOH following incubation in vitro with human spermatozoa did not exert negative effect on viability while motility was significantly (p < .05) dropped in a dose-dependent manner. Moreover, there was no significant effect of the type, dose and exposure time of the CNT-COOH on NO production. Exposure of sperm cells to both examined types of CNTs at concentrations as low as 0.1 MUg/ml caused a significant increase in ROS levels. In conclusion, carboxylated forms of CNTs seem to be harmful for human spermatozoa. Further studies, especially using in vivo models, are needed to decide about reprotoxicity of carboxylated forms of CNTs. PMID- 28000930 TI - Adolescent Communal Narcissism and Peer Perceptions. AB - OBJECTIVE: The present study extended recent work on communal narcissism to a sample of at-risk adolescents. Although narcissism is widely considered an agentic personality construct, Gebauer and colleagues (Gebauer, Sedikides, Verplanken, & Maio, 2012) demonstrated the existence and utility of a communal narcissism construct in adults. The extent to which this variant of narcissism applies to adolescents is not yet known. Because communal narcissism (e.g., feeling that one is the most helpful, is a great influence on others, will bring about world peace) may actually be aversive to others, we investigated the associated self- and peer perceptions of adolescent communal narcissism. METHOD: Participants were 136 adolescents (104 males, 32 females; 52.2% White, 42.2% Black, 5.6% Other) aged 16-19, who were attending a 22-week residential program together. Participants completed self-report measures of narcissism and interpersonal behavior, as well as a peer nomination procedure. RESULTS: Self reported communal narcissism was significantly related to self-reported pro social behavior but was associated with peer-reported aggression, similar to the findings for nonpathological narcissism, which is considered agentic. CONCLUSIONS: Adolescent communal narcissism appears to be tied to negative peer perceptions. The implications for understanding the interpersonal consequences of adolescent grandiosity in communal domains are discussed. PMID- 28000931 TI - Network meta-analysis of the effect of preoperative carbohydrate loading on recovery after elective surgery. AB - BACKGROUND: Three meta-analyses have summarized the effects of preoperative carbohydrate administration on postoperative outcomes in adult patients undergoing elective surgery. However, these studies could not account for the different doses of carbohydrate administered and the different controls used. Multiple-treatments meta-analysis allows robust synthesis of all available evidence in these situations. METHODS: Article databases were searched systematically for RCTs comparing preoperative carbohydrate administration with water, a placebo drink, or fasting. A four-treatment multiple-treatments meta analysis was performed comparing two carbohydrate dose groups (low, 10-44 g; high, 45 g or more) with two control groups (fasting; water or placebo). Primary outcomes were length of hospital stay and postoperative complication rate. Secondary outcomes included postoperative insulin resistance, vomiting and fatigue. RESULTS: Some 43 trials involving 3110 participants were included. Compared with fasting, preoperative low-dose and high-dose carbohydrate administration decreased postoperative length of stay by 0.4 (95 per cent c.i. 0.03 to 0.7) and 0.2 (0.04 to 0.4) days respectively. There was no significant decrease in length of stay compared with water or placebo. There was no statistically significant difference in the postoperative complication rate, or in most of the secondary outcomes, between carbohydrate and control groups. CONCLUSION: Carbohydrate loading before elective surgery conferred a small reduction in length of postoperative hospital stay compared with fasting, and no benefit in comparison with water or placebo. PMID- 28000933 TI - Disentangling the complexities of how legumes and their symbionts regulate plant nitrogen access and storage. PMID- 28000932 TI - Clonal structure in Ichthyobacterium seriolicida, the causative agent of bacterial haemolytic jaundice in yellowtail, Seriola quinqueradiata, inferred from molecular epidemiological analysis. AB - Bacterial haemolytic jaundice caused by Ichthyobacterium seriolicida has been responsible for mortality in farmed yellowtail, Seriola quinqueradiata, in western Japan since the 1980s. In this study, polymorphic analysis of I. seriolicida was performed using three molecular methods: amplified fragment length polymorphism (AFLP) analysis, multilocus sequence typing (MLST) and multiple-locus variable-number tandem repeat analysis (MLVA). Twenty-eight isolates were analysed using AFLP, while 31 isolates were examined by MLST and MLVA. No polymorphisms were identified by AFLP analysis using EcoRI and MseI, or by MLST of internal fragments of eight housekeeping genes. However, MLVA revealed variation in repeat numbers of three elements, allowing separation of the isolates into 16 sequence types. The unweighted pair group method using arithmetic averages cluster analysis of the MLVA data identified four major clusters, and all isolates belonged to clonal complexes. It is likely that I. seriolicida populations share a common ancestor, which may be a recently introduced strain. PMID- 28000934 TI - Plants anticipating rain - a challenge for modelling climate change impacts. PMID- 28000935 TI - Double trouble: taxonomy and definitions of polyploidy. PMID- 28000937 TI - Meta-analysis of operative experiences of general surgery trainees during training. AB - BACKGROUND: General surgical training curricula around the world set defined operative numbers to be achieved before completion of training. However, there are few studies reporting total operative experience in training. This systematic review aimed to quantify the published global operative experience at completion of training in general surgery. METHODS: Electronic databases were searched systematically for articles in any language relating to operative experience in trainees completing postgraduate general surgical training. Two reviewers independently assessed citations for inclusion using agreed criteria. Studies were assessed for quantitative data in addition to study design and purpose. A meta-analysis was performed using a random-effects model of studies with appropriate data. RESULTS: The search resulted in 1979 titles for review. Of these, 24 studies were eligible for inclusion in the review and data from five studies were used in the meta-analysis. Studies with published data of operative experience at completion of surgical training originated from the USA (19), UK (2), the Netherlands (1), Spain (1) and Thailand (1). Mean total operative experience in training varied from 783 procedures in Thailand to 1915 in the UK. Meta-analysis produced a mean pooled estimate of 1366 (95 per cent c.i. 1026 to 1707) procedures per trainee at completion of training. There was marked heterogeneity between studies (I2 = 99.6 per cent). CONCLUSION: There is a lack of robust data describing the operative experiences of general surgical trainees outside the USA. The number of surgical procedures performed by general surgeons in training varies considerably across the world. PMID- 28000938 TI - Spurious findings. PMID- 28000939 TI - As one door closes, another opens. PMID- 28000940 TI - An approach to randomization into surgical clinical trials. PMID- 28000941 TI - Cost analysis of laparoscopic lavage compared with sigmoid resection for perforated diverticulitis in the Ladies trial. AB - BACKGROUND: Laparoscopic peritoneal lavage is an alternative to sigmoid resection in selected patients presenting with purulent peritonitis from perforated diverticulitis. Although recent trials have lacked superiority for lavage in terms of morbidity, mortality was not compromised, and beneficial secondary outcomes were shown. These included shorter duration of surgery, less stoma formation and less surgical reintervention (including stoma reversal) for laparoscopic lavage versus sigmoid resection respectively. The cost analysis of laparoscopic lavage for perforated diverticulitis in the Ladies RCT was assessed in the present study. METHODS: This study involved an economic evaluation of the randomized LOLA (LaparOscopic LAvage) arm of the Ladies trial (comparing laparoscopic lavage with sigmoid resection in patients with purulent peritonitis due to perforated diverticulitis). The actual resource use per individual patient was documented prospectively and analysed (according to intention-to-treat) for up to 1 year after randomization. RESULTS: Eighty-eight patients were randomized to either laparoscopic lavage (46) or sigmoid resection (42). The total medical costs for lavage were lower (mean difference ? - 3512, 95 per cent bias-corrected and accelerated c.i. -16 020 to 8149). Surgical reintervention increased costs in the lavage group, whereas stoma reversal increased costs in the sigmoid resection group. Differences in favour of laparoscopy were robust when costs were varied by +/-20 per cent in a sensitivity analysis (mean cost difference ? - 2509 to 4438). CONCLUSION: Laparoscopic lavage for perforated diverticulitis is more cost effective than sigmoid resection. PMID- 28000943 TI - Effects of treatment with Hypoxis hemerocallidea extract on sexual behaviour and reproductive parameters in male rats. AB - Hypoxis hemerocallidea is used in traditional medicine in South Africa, for the treatment of male reproductive ailments and various chronic illnesses. Despite chronic use, its effects on male reproductive system are unknown. Male Wistar rats were treated orally daily for 28 (n = 18) and 56 days (n = 18). Treatment groups (n = 6/group) per treatment period were as follows: untreated control, 150 mg/kg and 300 mg/kg 70% ethanolic extract of H. hemerocallidea. Sexual behaviour observations were performed on days 17 and 42 of the study. Sperm, biochemical and testicular histopathological studies were carried out. Arousal and libido and serum testosterone increased after 56 days of treatment. There was an increase in epididymal sperm count at both treatment doses, with the 300 mg/kg dose showing a higher sperm count (p < .05) compared to the 150 mg/kg treatment group. The higher 300 mg/kg dose also showed an increase (p < .05) in sperm motility after 56 days of treatment. Histology showed an increase in germinal layer thickness, consistent with the observed increase in sperm count. Testicular oxidative status improved after 56 days of treatment. Results suggest that chronic treatment with H. hemerocallidea may improve male sexual function and fertility parameters and may protect testes from oxidative damage. PMID- 28000944 TI - Learning to Be (In)variant: Combining Prior Knowledge and Experience to Infer Orientation Invariance in Object Recognition. AB - How does the visual system recognize images of a novel object after a single observation despite possible variations in the viewpoint of that object relative to the observer? One possibility is comparing the image with a prototype for invariance over a relevant transformation set (e.g., translations and dilations). However, invariance over rotations (i.e., orientation invariance) has proven difficult to analyze, because it applies to some objects but not others. We propose that the invariant transformations of an object are learned by incorporating prior expectations with real-world evidence. We test this proposal by developing an ideal learner model for learning invariance that predicts better learning of orientation dependence when prior expectations about orientation are weak. This prediction was supported in two behavioral experiments, where participants learned the orientation dependence of novel images using feedback from solving arithmetic problems. PMID- 28000945 TI - Histopathological and biochemical comparisons of the protective effects of amifostine and l-carnitine against radiation-induced acute testicular toxicity in rats. AB - The aim of this study was to compare the radioprotective efficacies of amifostine (AMI) and l-carnitine (LC) against radiation-induced acute testicular damage. Thirty Wistar albino rats were randomly assigned to four groups: control (n = 6), AMI plus radiotherapy (RT) (n = 8), LC plus RT (n = 8) and RT group (n = 8). The rats were irradiated with a single dose of 20 Gy to the scrotal field. LC (300 mg/kg) and AMI (200 mg/kg) were given intraperitoneally 30 min before irradiation. The mean seminiferous tubule diameters (MSTDs) were calculated. Testicular damage was evaluated histopathologically using Johnsen's mean testicular biopsy score criteria. Malondialdehyde (MDA) and glutathione levels were measured in tissue samples. AMI plus RT and LC plus RT groups had significantly higher MSTDs than those in the RT group (p = .003 and p = .032 respectively). MDA values of both AMI plus RT and LC plus RT groups were significantly lower than those in RT group (p < .004 and p < .012 respectively). As a result, AMI and LC have a similar radioprotective effect against radiation induced acute testicular damage, histopathologically and biochemically. PMID- 28000946 TI - Direct chiral separations of the enantiomers of phenylpyrazole pesticides and the metabolites by HPLC. AB - The enantiomeric separation of the enantiomers of three phenylpyrazole pesticides (fipronil, flufiprole, ethiprole) and two fipronil metabolites (amide-fipronil and acid-fipronil) were investigated by high-performance liquid chromatography (HPLC) with a CHIRALPAK(r) IB chiral column. The mobile phase was n-hexane or petroleum ether with 2-propanol or ethanol as modifier at a flow rate of 1.0 mL/min. The influences of mobile phase composition and column temperature between 15 and 35 degrees C on the separations were studied. All the analytes except ethiprole obtained complete enantiomeric separation after chromatographic condition optimization. Fipronil, flufiprole, amide-fipronil, and acid-fipronil obtained complete separation with the best resolution factors of 2.40, 3.40, 1.67, and 16.82, respectively, but ethiprole showed no enantioselectivity under the optimized conditions. In general, n-hexane with 2-propanol gave better separations in most cases. The results showed decreasing temperature and content of modifier in the mobile phase resulted in better separation and longer analysis time as well. The thermodynamic parameters calculated according to linear the Van't Hoff equation indicated the chiral separations in the study were enthalpy driven. Fipronil and its two chiral hydrolyzed metabolites obtained baseline separation simultaneously under optimized conditions. PMID- 28000947 TI - A potential mechanism associated with lead-induced testicular toxicity in rats. AB - This study was conducted to investigate the mechanism of lead (Pb)-induced testicular toxicity. We examined the impact of Pb toxicity on 17beta-oestradiol (E2), oestrogen receptors (ERs) and aromatase P450 which are key factors in spermatogenesis. Treatment of rats with Pb acetate (PbAc, 50 mg/L in drinking water) significantly reduced sperm count, motility, viability and increased sperm abnormalities along with degenerative changes in seminiferous tubules and Leydig cells. Additionally, administration of PbAc resulted in a significant reduction in serum testosterone, serum and testicular E2 as well as increased level of testicular testosterone. Pb also induced testicular oxidative stress as evidenced by a significant decrease in the activities of superoxide dismutase, glutathione peroxidase and catalase antioxidant enzymes, and increased malondialdehyde level in the testis. At the molecular level, Pb treatment downregulated the mRNA expression of P450 arom (Cyp19) and ERalpha. In conclusion, Pb induces testicular oxidative damage and disrupts spermatogenesis, at least in part, via downregulation of Cyp19 and ERalpha expression, which further decrease E2 level. These data, therefore, provide insight into the mechanism of lead-induced testicular toxicity. PMID- 28000948 TI - The expression patterns of the clock genes period and timeless are affected by photoperiod in the Mediterranean corn stalk borer, Sesamia nonagrioides. AB - To obtain clues to the link between the molecular mechanism of circadian and photoperiod clocks, we cloned two circadian clock genes, period (per) and timeless (tim) from the moth Sesamia nonagrioides, which undergoes facultative diapause controlled by photoperiod. Sequence analysis revealed a high degree of conservation among the compared insects fomicronr both genes. We also investigated the expression patterns of per and tim in brains of larvae growing under 16L:8D (long days), constant darkness (DD) and 10L:14D (short days) conditions by qPCR assays. The results showed that mRNA accumulations encoding both genes exhibited diel oscillations under different photoperiods. The oscillation of per and tim mRNA, under short-day photoperiod differed from long day. The difference between long-day and short-day conditions in the pattern of mRNA levels of per and tim appears to distinguish photoperiodic conditions clearly and both genes were influenced by photoperiod in different ways. We infer that not all photoperiodic clocks of insects interact with circadian clocks in the same fashion. Our results suggest that transcriptional regulations of the both clock genes act in the diapause programing in S. nonagrioides. The expression patterns of these genes are affected by photoperiod but runs with 24 h by entrainment to daily environmental cues. PMID- 28000950 TI - Knowledge Attributions and Behavioral Predictions. AB - Recent work has shown that knowledge attributions affect how people think others should behave, more so than belief attributions do. This paper reports two experiments providing evidence that (a) knowledge attributions also affect behavioral predictions more strongly than belief attributions do, and (b) knowledge attributions facilitate faster behavioral predictions than belief attributions do. Thus, knowledge attributions play multiple critical roles in social cognition, guiding judgments about how people should and will behave. PMID- 28000949 TI - IL-3 up-regulates and activates human eosinophil CD32 and alphaMbeta2 integrin causing degranulation. AB - BACKGROUND: Eosinophils contribute to the pathogenesis of multiple diseases, including asthma. Treatment with antibodies targeting IL-5 or IL-5 receptor alpha reduces the frequency of asthma exacerbations. Eosinophil receptors for IL-5 share a common beta-chain with IL-3 and GM-CSF receptors. We recently reported that IL-3 is more potent than IL-5 or GM-CSF in maintaining the ERK/p90S6K/RPS6 ribosome-directed signaling pathway, leading to increased protein translation. OBJECTIVE: We aimed to determine disease-relevant consequences of prolonged eosinophil stimulation with IL-3. RESULTS: Human blood eosinophils were used to establish the impact of activation with IL-3 on IgG-driven eosinophil degranulation. When compared to IL-5, continuing exposure to IL-3 further induced degranulation of eosinophils on aggregated IgG via increased production and activation of both CD32 (low affinity IgG receptor) and alphaMbeta2 integrin. In addition, unlike IL-5 or GM-CSF, IL-3 induced expression of CD32B/C (FCGRIIB/C) subtype proteins, without changing CD32A (FCGRIIA) protein and CD32B/C mRNA expression levels. Importantly, these in vitro IL-3-induced modifications were recapitulated in vivo on airway eosinophils. CONCLUSIONS AND CLINICAL RELEVANCE: We observed for the first time upregulation of CD32B/C on eosinophils, and identified IL-3 as a potent inducer of CD32- and alphaMbeta2-mediated eosinophil degranulation. PMID- 28000951 TI - Subpollen particles are rich carriers of major short ragweed allergens and NADH dehydrogenases: quantitative proteomic and allergomic study. AB - BACKGROUND: Short ragweed (Ambrosia artemisiifolia) allergies affect more than 36 million people annually. Ragweed pollen grains release subpollen particles (SPP) of respirable size upon hydration or a change in air electrical conditions. The aim of this study was to characterize the proteomes and allergomes of short ragweed SPP and total pollen protein extract (TOT), and compare their effects with those of standard aqueous pollen protein extract (APE) using sera from short ragweed pollen-sensitized patients. METHODS: Quantitative 2D gel-based and shotgun proteomics, 1D and 2D immunoblotting, and quantitative ELISA were applied. Novel SPP extraction and preparation protocols enabled appropriate sample preparation and further downstream analysis by quantitative proteomics. RESULTS: The SPP fraction contained the highest proportion (94%) of the allergome, with the largest quantities of the minor Amb a 4 and major Amb a 1 allergens, and as unique, NADH dehydrogenases. APE was the richest in Amb a 6, Amb a 5 and Amb a 3, and TOT fraction was the richest in the Amb a 8 allergens (89% and 83% of allergome, respectively). Allergenic potency correlated well among the three fractions tested, with 1D immunoblots demonstrating a slight predominance of IgE reactivity to SPP compared to TOT and APE. However, the strongest IgE binding in ELISA was noted against APE. New allergenic candidates, phosphoglycerate mutase and phosphoglucomutase, were identified in all the three pollen fractions. Enolase, UTP-glucose-1-phosphate uridylyltransferase and polygalacturonase were observed in SPP and TOT fractions as novel allergens of the short ragweed pollen, as previously described. CONCLUSION AND CLINICAL RELEVANCE: We demonstrated that the complete major (Amb a 1 and 11) and almost all minor (Amb a 3, 4, 5, 6, 8 and 9) short ragweed pollen allergen repertoire as well as NADH oxidases are present in SPP, highlighting an important role for SPP in allergic sensitization to short ragweed. PMID- 28000952 TI - Human basophils are a source of - and are differentially activated by - IL-31. AB - BACKGROUND: Basophils are important effector cells involved in the pathogenesis of inflammatory skin diseases including chronic urticaria which is associated by increased IL-31 serum levels. So far the effects of IL-31 on human basophils are unknown. OBJECTIVE: To analyse the functional role of IL-31 in basophil biology. METHODS: IL-31 expression was evaluated in skin samples derived from chronic spontaneous urticaria patients. Oncostatin M receptor (OSMR), IL-31 receptor A (RA) and IL-31 protein expressions were analysed on human basophils from healthy donors. Basophil responses to IL-31 were assessed for chemotaxis, externalization of CD63 and CD203c as well as the release of histamine, IL-4 and IL-13. RESULTS: IL-31RA and OSMR were expressed on human basophils. IL-31 was strongly expressed in the skin of patients with chronic spontaneous urticaria and was released from isolated basophils following either anti-IgE, IL-3 or fMLP stimulation. IL-31 induced chemotaxis and the release of IL-4 and IL-13 which was specifically inhibited by anti-IL-31RA and anti-OSMR. Conversely, IL-31 had no effect on CD63 and CD203c externalization or histamine release. CONCLUSIONS AND CLINICAL RELEVANCE: Human basophils are a source of -and are activated by - IL-31 with the release of pro-inflammatory cytokines and the induction of chemotaxis indicating an important novel function of IL-31 in basophil biology. PMID- 28000953 TI - Heavy metal concentrations in female wild mink (Neovison vison) in Sweden: Sources of variation and associations with internal organ weights. AB - The American mink is an invasive species in Sweden, and it is legally hunted all year. Therefore, the mink is well suited as a sentinel species for environmental monitoring. In the present study female mink (n = 91) from 6 different areas in Sweden were analyzed for the concentrations of silver, cadmium, mercury and lead in liver tissue using inductively coupled plasma mass spectrometry. The wet concentrations in liver tissue were 42.6 +/- 52.7 ng/g for silver, 99.5 +/- 100 ng/g for cadmium, 652 +/- 537 ng/g for mercury, and 196 +/- 401 ng/g for lead (expressed as mean +/- standard deviation). There were associations between the sample area and the concentrations of silver, lead, and mercury. The concentrations of lead and cadmium varied with season of capture and lead, cadmium, and mercury were positively associated with increasing age. Relative liver weight was positively associated with concentrations of mercury and negatively associated with lead and cadmium. Relative kidney weight was negatively associated with lead concentrations. In summary, it is of importance to take age and season of capture into account when assessing levels of heavy metals in wild mink. Also, liver and kidneys seem to be potential targets for heavy metal toxicity in wild female mink in Sweden. Environ Toxicol Chem 2017;36:2030-2035. (c) 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28000954 TI - Do Americans Have a Preference for Rule-Based Classification? AB - Six experiments investigated variables predicted to influence subjects' tendency to classify items by a single property (rule-based responding) instead of overall similarity, following the paradigm of Norenzayan et al. (, Cognitive Science), who found that European Americans tended to give more "logical" rule-based responses. However, in five experiments with Mechanical Turk subjects and undergraduates at an American university, we found a consistent preference for similarity-based responding. A sixth experiment with Korean undergraduates revealed an effect of instructions, also reported by Norenzayan et al., in which classification instructions led to majority rule-based responding but similarity instructions led to overall similarity grouping. Our American subjects showed no such difference and used similarity more overall. We conclude that Americans do not have a preference for rule responding in classification and discuss the differences between tasks that reliably show strong rule or unidimensional preferences (category construction and category learning) in contrast to this classification paradigm. PMID- 28000956 TI - Blood and semen paraoxonase-arylesterase activities in normozoospermic and azoospermic men. AB - Paraoxonase and arylesterase enzymes are corner stones of antioxidant defence. We aimed to compare azoospermic infertile men and normozoospermic individuals with respect to total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), paraoxonase and arylesterase levels in the blood and seminal plasma. Two-hundred consecutive infertility patients and voluntarily participated were included. In the normozoospermic group, TAS, PON, arylesterase values were statistically significantly higher when compared with those in the azoospermic group, while lower TOS and OSI levels were observed in the blood and seminal plasma of azoospermic group. In the semen analyses of normozoospermic group, the correlation between semen volume, sperm concentration, sperm motility and morphology and TAS, TOS, OSI, PON and arylesterase values was examined. A negative correlation was determined between semen volume and OSI. Levels of serum oxidative parameters were higher in the azoospermic group relative to normozoospermic group, but antioxidant parameters were lower than those of the normozoospermic group. Oxidative stress performs an essential role in the aetiology of male infertility by negatively influencing sperm quality and function. Assessment of blood and seminal plasma oxidative profiles might be an important tool to better evaluation of sperm reproductive capacity and functional competence. PMID- 28000955 TI - Chronic airway inflammation provides a unique environment for B cell activation and antibody production. AB - BACKGROUND: B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways. OBJECTIVE: We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation. METHODS: We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody-secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT-PCR. RESULTS: NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein Barr virus-induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC-mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell-targeted therapies may provide new treatment options for CRSwNP. PMID- 28000957 TI - Bacteriocins and the assembly of natural Pseudomonas fluorescens populations. AB - When competing for space and resources, bacteria produce toxins known as bacteriocins to gain an advantage over competitors. Recent studies in the laboratory have confirmed theoretical predictions that bacteriocin production can determine coexistence, by eradicating sensitive competitors or driving the emergence of resistant genotypes. However, there is currently limited evidence that bacteriocin-mediated competition influences the coexistence and distribution of genotypes in natural environments, and what factors drive interactions towards inhibition remain unclear. Using natural soil populations of Pseudomonas fluorescens, we assessed the ability of the isolates to inhibit one another with respect to spatial proximity in the field, genetic similarity and niche overlap. The majority of isolates were found to produce bacteriocins; however, widespread resistance between coexisting isolates meant relatively few interactions resulted in inhibition. When inhibition did occur, it occurred more frequently between ecologically similar isolates. However, in contrast with results from other natural populations, we found no relationship between the frequency of inhibition and the genetic similarity of competitors. Our results suggest that bacteriocin production plays an important role in mediating competition over resources in natural settings and, by selecting for isolates resistant to local bacteriocin production, can influence the assembly of natural populations of P. fluorescens. PMID- 28000958 TI - Quality of reporting of diagnostic accuracy studies on pelvic floor three dimensional transperineal ultrasound: a systematic review. AB - OBJECTIVE: In recent years, a large number of studies have been published on the clinical relevance of pelvic floor three-dimensional (3D) transperineal ultrasound. Several studies compare sonography with other imaging modalities or clinical examination. The quality of reporting in these studies is not known. The objective of this systematic review was to determine the compliance of diagnostic accuracy studies investigating pelvic floor 3D ultrasound with the Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. METHODS: Published articles on pelvic floor 3D ultrasound were identified by a systematic literature search of MEDLINE, Web of Science and Scopus databases. Prospective and retrospective studies that compared pelvic floor 3D ultrasound with other clinical and imaging diagnostics were included in the analysis. STARD compliance was assessed and quantified by two independent investigators, using 22 of the original 25 STARD checklist items. Items with the qualifier 'if done' (Items 13, 23 and 24) were excluded because they were not applicable to all papers. Each item was scored as reported (score = 1) or not reported (score = 0). Observer variability, the total number of reported STARD items per article and summary scores for each item were calculated. The difference in total score between STARD-adopting and non-adopting journals was tested statistically, as was the effect of year of publication. RESULTS: Forty studies published in 13 scientific journals were included in the analysis. Mean +/- SD STARD checklist score of the included articles was 16.0 +/- 2.5 out of a maximum of 22 points. The lowest scores (< 50%) were found for reporting of handling of indeterminate results or missing responses, adverse events and the time interval between tests. Interobserver agreement for rating the STARD items was excellent (intraclass correlation coefficient, 0.77). An independent t-test showed no significant mean difference +/- SD in total STARD checklist score between STARD-adopting and non-adopting journals (16.4 +/- 2.2 vs 15.9 +/- 2.6, respectively). Mean +/- SD STARD checklist score for articles published in 2003-2009 was lower, but not statistically different, compared with those published in 2010-2015 (15.2 +/- 2.5 vs 16.6 +/- 2.4, respectively). CONCLUSION: The overall compliance with reporting guidelines of diagnostic accuracy studies on pelvic floor 3D transperineal ultrasound is relatively good compared with other fields of medicine. However, specific checklist items require more attention when reported. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28000959 TI - A "Molecular Water Pipe": A Giant Tubular Cluster {Dy72 } Exhibits Fast Proton Transport and Slow Magnetic Relaxation. AB - A lanthanide cluster, PCC-72, which is the second largest, with 72 Dy(III) ions assembled into an unprecedented tubular structure, is synthesized. Remarkably, PCC-72 exhibits superionic proton conductivity (>10-4 S cm-1 ) under both ambient (with relative humidity RH < 75%) and hot (T > 90 degrees C, RH = 95%) conditions. Moreover, slow magnetic relaxation is observed, making PCC-72 the largest Dy(III) cluster that is a single-molecule magnet. PMID- 28000960 TI - Neuroimaging Findings in Pediatric Genetic Skeletal Disorders: A Review. AB - Genetic skeletal disorders (GSDs) are a heterogeneous group characterized by an intrinsic abnormality in growth and (re-)modeling of cartilage and bone. A large subgroup of GSDs has additional involvement of other structures/organs beside the skeleton, such as the central nervous system (CNS). CNS abnormalities have an important role in long-term prognosis of children with GSDs and should consequently not be missed. Sensitive and specific identification of CNS lesions while evaluating a child with a GSD requires a detailed knowledge of the possible associated CNS abnormalities. Here, we provide a pattern-recognition approach for neuroimaging findings in GSDs guided by the obvious skeletal manifestations of GSD. In particular, we summarize which CNS findings should be ruled out with each GSD. The diseases (n = 180) are classified based on the skeletal involvement (1. abnormal metaphysis or epiphysis, 2. abnormal size/number of bones, 3. abnormal shape of bones and joints, and 4. abnormal dynamic or structural changes). For each disease, skeletal involvement was defined in accordance with Online Mendelian Inheritance in Man. Morphological CNS involvement has been described based on extensive literature search. Selected examples will be shown based on prevalence of the diseases and significance of the CNS involvement. CNS involvement is common in GSDs. A wide spectrum of morphological abnormalities is associated with GSDs. Early diagnosis of CNS involvement is important in the management of children with GSDs. This pattern-recognition approach aims to assist and guide physicians in the diagnostic work-up of CNS involvement in children with GSDs and their management. PMID- 28000961 TI - Adiabatic excitation for 31 P MR spectroscopy in the human heart at 7 T: A feasibility study. AB - PURPOSE: Phosphorus magnetic resonance spectroscopy (31 P-MRS) provides a unique tool for assessing cardiac energy metabolism, often quantified using the phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. Surface coils are typically used for excitation for 31 P-MRS, but they create an inhomogeneous excitation field across the myocardium, producing undesirable, spatially varying partial saturation. Therefore, we implemented adiabatic excitation in a 3D chemical shift imaging (CSI) sequence for cardiac 31 P-MRS at 7 Tesla (T). METHODS: We optimized an adiabatic half passage pulse with bandwidth sufficient to excite PCr and gamma-ATP together. In addition, the CSI sequence was modified to allow interleaved excitation of PCr and gamma-ATP, then 2,3-DPG, to enable PCr/ATP determination with blood correction. Nine volunteers were scanned at 2 transmit voltages to confirm that measured PCr/ATP was independent of B1+ (i.e. over the adiabatic threshold). Six septal voxels were evaluated for each volunteer. RESULTS: Phantom experiments showed that adiabatic excitation can be reached at the depth of the heart using our pulse. The mean evaluated cardiac PCr/ATP ratio from all 9 volunteers corrected for blood signal was 2.14 +/- 0.16. Comparing the two acquisitions with different voltages resulted in a minimal mean difference of -0.005. CONCLUSION: Adiabatic excitation is possible in the human heart at 7 T, and gives consistent PCr/ATP ratios. Magn Reson Med 78:1667-1673, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28000962 TI - Hypoxia causes IL-8 secretion, Charcot Leyden crystal formation, and suppression of corticosteroid-induced apoptosis in human eosinophils. AB - BACKGROUND: Inflamed environments are typically hypercellular, rich in pro inflammatory cytokines, and profoundly hypoxic. While the effects of hypoxia on neutrophil longevity and function have been widely studied, little is known about the consequences of this stimulus on eosinophils. OBJECTIVE: We sought to investigate the effects of hypoxia on several key aspects of eosinophil biology, namely secretion, survival, and their sensitivity to glucocorticosteroids (GCS), agents that normally induce eosinophil apoptosis. METHODS: Eosinophils derived from patients with asthma/atopy or healthy controls were incubated under normoxia and hypoxia, with or without glucocorticoids. Activation was measured by flow cytometry, ELISA of cultured supernatants, and F-actin staining; apoptosis and efferocytosis by morphology and flow cytometry; and GCS efficacy by apoptosis assays and qPCR. RESULTS: Hypoxic incubation (3 kPa) caused (i) stabilization of HIF-2alpha and up-regulation of hypoxia-regulated genes including BNIP3 (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3) and GLUT1 (glucose transporter 1); (ii) secretion of pre-formed IL-8, and Charcot Leyden crystal (CLC) formation, which was most evident in eosinophils derived from atopic and asthmatic donors; (iii) enhanced F-actin formation; (iv) marked prolongation of eosinophil lifespan (via a NF-kappaB and Class I PI3-kinase-dependent mechanism); and (v) complete abrogation of the normal pro-apoptotic effect of dexamethasone and fluticasone furoate. This latter effect was evident despite preservation of GCS-mediated gene transactivation under hypoxia. CONCLUSION AND CLINICAL RELEVANCE: These data indicate that hypoxia promotes an eosinophil pro inflammatory phenotype by enhancing eosinophil secretory function, delaying constitutive apoptosis, and importantly, antagonizing the normal pro-apoptotic effect of GCS. As eosinophils typically accumulate at sites that are relatively hypoxic, particularly during periods of inflammation, these findings may have important implications to understanding the behaviour of these cells in vivo. PMID- 28000964 TI - In vitro to in vivo extrapolation of biotransformation rates for assessing bioaccumulation of hydrophobic organic chemicals in mammals. AB - Incorporating biotransformation in bioaccumulation assessments of hydrophobic chemicals in both aquatic and terrestrial organisms in a simple, rapid, and cost effective manner is urgently needed to improve bioaccumulation assessments of potentially bioaccumulative substances. One approach to estimate whole-animal biotransformation rate constants is to combine in vitro measurements of hepatic biotransformation kinetics with in vitro to in vivo extrapolation (IVIVE) and bioaccumulation modeling. An established IVIVE modeling approach exists for pharmaceuticals (referred to in the present study as IVIVE-Ph) and has recently been adapted for chemical bioaccumulation assessments in fish. The present study proposes and tests an alternative IVIVE-B technique to support bioaccumulation assessment of hydrophobic chemicals with a log octanol-water partition coefficient (KOW ) >= 4 in mammals. The IVIVE-B approach requires fewer physiological and physiochemical parameters than the IVIVE-Ph approach and does not involve interconversions between clearance and rate constants in the extrapolation. Using in vitro depletion rates, the results show that the IVIVE-B and IVIVE-Ph models yield similar estimates of rat whole-organism biotransformation rate constants for hypothetical chemicals with log KOW >= 4. The IVIVE-B approach generated in vivo biotransformation rate constants and biomagnification factors (BMFs) for benzo[a]pyrene that are within the range of empirical observations. The proposed IVIVE-B technique may be a useful tool for assessing BMFs of hydrophobic organic chemicals in mammals. Environ Toxicol Chem 2017;36:1934-1946. (c) 2016 SETAC. PMID- 28000963 TI - A Neurocomputational Model of the N400 and the P600 in Language Processing. AB - Ten years ago, researchers using event-related brain potentials (ERPs) to study language comprehension were puzzled by what looked like a Semantic Illusion: Semantically anomalous, but structurally well-formed sentences did not affect the N400 component-traditionally taken to reflect semantic integration-but instead produced a P600 effect, which is generally linked to syntactic processing. This finding led to a considerable amount of debate, and a number of complex processing models have been proposed as an explanation. What these models have in common is that they postulate two or more separate processing streams, in order to reconcile the Semantic Illusion and other semantically induced P600 effects with the traditional interpretations of the N400 and the P600. Recently, however, these multi-stream models have been called into question, and a simpler single stream model has been proposed. According to this alternative model, the N400 component reflects the retrieval of word meaning from semantic memory, and the P600 component indexes the integration of this meaning into the unfolding utterance interpretation. In the present paper, we provide support for this "Retrieval-Integration (RI)" account by instantiating it as a neurocomputational model. This neurocomputational model is the first to successfully simulate the N400 and P600 amplitude in language comprehension, and simulations with this model provide a proof of concept of the single-stream RI account of semantically induced patterns of N400 and P600 modulations. PMID- 28000965 TI - The Generalized Quantum Episodic Memory Model. AB - Recent evidence suggests that experienced events are often mapped to too many episodic states, including those that are logically or experimentally incompatible with one another. For example, episodic over-distribution patterns show that the probability of accepting an item under different mutually exclusive conditions violates the disjunction rule. A related example, called subadditivity, occurs when the probability of accepting an item under mutually exclusive and exhaustive instruction conditions sums to a number >1. Both the over-distribution effect and subadditivity have been widely observed in item and source-memory paradigms. These phenomena are difficult to explain using standard memory frameworks, such as signal-detection theory. A dual-trace model called the over-distribution (OD) model (Brainerd & Reyna, 2008) can explain the episodic over-distribution effect, but not subadditivity. Our goal is to develop a model that can explain both effects. In this paper, we propose the Generalized Quantum Episodic Memory (GQEM) model, which extends the Quantum Episodic Memory (QEM) model developed by Brainerd, Wang, and Reyna (2013). We test GQEM by comparing it to the OD model using data from a novel item-memory experiment and a previously published source-memory experiment (Kellen, Singmann, & Klauer, 2014) examining the over-distribution effect. Using the best-fit parameters from the over distribution experiments, we conclude by showing that the GQEM model can also account for subadditivity. Overall these results add to a growing body of evidence suggesting that quantum probability theory is a valuable tool in modeling recognition memory. PMID- 28000966 TI - Dirty Money: The Role of Moral History in Economic Judgments. AB - Although traditional economic models posit that money is fungible, psychological research abounds with examples that deviate from this assumption. Across eight experiments, we provide evidence that people construe physical currency as carrying traces of its moral history. In Experiments 1 and 2, people report being less likely to want money with negative moral history (i.e., stolen money). Experiments 3-5 provide evidence against an alternative account that people's judgments merely reflect beliefs about the consequences of accepting stolen money rather than moral sensitivity. Experiment 6 examines whether an aversion to stolen money may reflect contamination concerns, and Experiment 7 indicates that people report they would donate stolen money, thereby counteracting its negative history with a positive act. Finally, Experiment 8 demonstrates that, even in their recall of actual events, people report a reduced tendency to accept tainted money. Altogether, these findings suggest a robust tendency to evaluate money based on its moral history, even though it is designed to participate in exchanges that effectively erase its origins. PMID- 28000967 TI - Decrease in bovine in vitro embryo production efficiency during winter season in a warm-summer Mediterranean climate. AB - Retrospective analysis of monthly embryo production from December 2011 to May 2015 and its correlation with meteorological data in our geographic zone was made. We had observed that in certain time of the year, in vitro blastocyst production decreases. Accordingly, was examined the association between blastocyst production and climatological parameters. Cleavage rates correlate positively with blastocyst rates (p < .05). Significant differences in cleavage rates between autumn and summer (79.8%; 71.5%), and between winter and autumn (71.8%; 79.8%), were found. Blastocyst production had lower efficiency in June (9 +/- 12%) and July (4.9 +/- 5.7%), which coincides with winter season. In contrast, higher embryo production was obtained in February (22.2 +/- 9.7%), March (22.9 +/- 14%) and September (25.2 +/- 6.6%), which coincides with autumn and spring season. Similarly, embryo production correlates with meteorological parameters: blastocyst production positively correlates with sunshine hours, maximum temperature and average temperature. Similarly, blastocyst production inversely correlates with total precipitation and days >1 mm precipitation (p < .05). There is a significant decrease in bovine in vitro embryo production efficiency during winter season in our warm-summer Mediterranean climate zone. It remains to be investigated the direct effect of environmental factors on oocyte quality and its impact on in vitro production efficiency. PMID- 28000968 TI - Guest-Induced Folding and Self-Assembly of Conformationally Adaptive Macrocycles into Nanosheets and Nanotubes. AB - A conformationally adaptive macrocycle is presented, namely zorb[4]arene, which exists in multiple conformations in the uncomplexed state. The binding cavity of zorb[4]arene is concealed, either due to a collapsed conformation or by self inclusion. The zorb[4]arene with long alkyl chains manifests itself with surprisingly low melting point and thus exist as an oil at room temperature. Binding of a guest molecule induces the folding and conformational rigidity of zorb[4]arene and leads to well-defined three-dimensional structures, which can further self-assemble into nanosheets or nanotubes upon solvent evaporation, depending on guest molecules and the conformations they can induce. PMID- 28000969 TI - High-Performance Color-Tunable Perovskite Light Emitting Devices through Structural Modulation from Bulk to Layered Film. AB - Adding 2-phenoxyethylamine (POEA) into a CH3 NH3 PbBr3 precursor solution can modulate the organic-inorganic hybrid perovskite structure from bulk to layered, with a photoluminescence and electroluminescence shift from green to blue. Meanwhile, POEA can passivate the CH3 NH3 PbBr3 surface and help to obtain a pure CH3 NH3 PbBr3 phase, leading to an improvement of the external quantum efficiency to nearly 3% in CH3 NH3 PbBr3 LED. PMID- 28000970 TI - Evaluation of serum level of Osteocalcin hormone in male infertility. AB - The suggested concept of "bone as an endocrine organ" had shed the light on the role of osteocalcin, an osteoblast secreted hormone, in regulation of testosterone production. This study aimed to assess the association between the active undercarboxylated form of osteocalcin (ucOC) and semen parameters and hormonal levels in infertile male patients. The study was carried on 34 infertile male patients and 20 fertile healthy control males. Semen analysis and serum level of testosterone, LH and FSH were performed in addition to serum level of ucOC in cases and controls. The results revealed significant differences between cases and controls in all measured semen and hormonal parameters. In addition, significant higher level of ucOC in cases than control group (p = .019). On the other hand, ucOC was not related significantly to any of the measured hormones or semen parameters. There was no significant correlation between ucOC and sperm concentration, total motility, morphology (p = .594, .640, .940 respectively) and similarly between ucOC and testosterone level or LH level (p = .275, .954 respectively). The significant higher level of ucOC in infertile cases cannot be used as a predictor of male reproductive parameters. PMID- 28000971 TI - Safety and Tolerability of SonoVue(r) in Patients with Large Artery Anterior Circulation Acute Stroke. AB - BACKGROUND AND PURPOSE: Ultrasound contrast agents (UCAs) are routinely used to improve the visualization of intracranial arteries. Since a higher rate of intracranial hemorrhage (ICH) has been observed in patients undergoing sonothrombolysis in combination with UCAs, we conducted this study with the aim of assessing safety and tolerability of SonoVue(r) in patients with acute ischemic stroke due to anterior circulation large artery occlusion (LAO) and eligible to intravenous thrombolysis and/or mechanical thrombectomy. METHODS: Among 474 patients consecutively admitted to our Stroke Unit with anterior circulation ischemic stroke, SonoVue(r) was administered during transcranial ultrasound evaluation to 48 patients with suspected LAO for diagnostic confirmation (group I) and to 44 patients with inadequate temporal bone window. Forty-eight stroke patients with LAO diagnosed only by computed tomography (CT) angiography /magnetic resonance (MR) angiography and matched for age, gender, and National Institutes of Health Stroke Scale score with group I represented the control group (group II). Thrombolysis, thrombectomy, or combined treatment were offered to all eligible patients. Brain MR imaging/CT was performed in both groups in case of neurological deterioration or after 1 week to check for ICH. RESULTS: SonoVue(r) did not cause any serious adverse event; only mild and transient side effects were reported in six cases (6.5%). Among patients in groups I and II, there were 31 (32.3%) secondary cerebral bleedings with no statistically significant difference between the groups, but only 2 (2.1%) were symptomatic. CONCLUSIONS: According to our study, SonoVue(r) can be safely administered to acute ischemic stroke patients with suspected anterior circulation LAO and/or inadequate temporal bone window. PMID- 28000972 TI - Constructing Hierarchical Tectorum-like alpha-Fe2 O3 /PPy Nanoarrays on Carbon Cloth for Solid-State Asymmetric Supercapacitors. AB - The design of complex heterostructured electrode materials that deliver superior electrochemical performances to their individual counterparts has stimulated intensive research on configuring supercapacitors with high energy and power densities. Herein we fabricate hierarchical tectorum-like alpha-Fe2 O3 /polypyrrole (PPy) nanoarrays (T-Fe2 O3 /PPy NAs). The 3D, and interconnected T Fe2 O3 /PPy NAs are successfully grown on conductive carbon cloth through an easy self-sacrificing template and in situ vapor-phase polymerization route under mild conditions. The electrode made of the T-Fe2 O3 /PPy NAs exhibits a high areal capacitance of 382.4 mF cm-2 at a current density of 0.5 mA cm-2 and excellent reversibility. The solid-state asymmetric supercapacitor consisting of T-Fe2 O3 /PPy NAs and MnO2 electrodes achieves a high energy density of 0.22 mWh cm-3 at a power density of 165.6 mW cm-3 . PMID- 28000973 TI - Quality of life and recreational cannabis use. AB - INTRODUCTION: Cannabis is now the most commonly used illicit drug in the United States and use is increasing. Frequent cannabis use has been associated with adverse social and health effects. We sought to evaluate the relationship between recreational cannabis use and Quality of Life (QoL), a person-centered measure that characterizes the overall sense of health and wellbeing. We hypothesized that QoL would be unchanged or increased among recreational cannabis users, who did not meet criteria for a Cannabis Use Disorder (CUD) and that QoL would be lower among those who met criteria for a CUD. METHODS: We conducted a systematic review, employing guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The results were categorized into tables and identified trends. RESULTS: Fourteen studies met our pre-defined selection criteria. The studies were heterogeneous and their quality was low. With one exception, we did not identify any population for whom cannabis use was associated with improved QoL. QoL was lower in persons who used cannabis heavily, or who met criteria for CUD. However, this association was inconsistent and the magnitude was weaker than the relationship between QoL and use of other addictive substances (including tobacco and illicit drugs). CONCLUSION: In this systematic review, heavy cannabis use or CUD was associated with reduced QoL. It is unknown whether reduced QoL drives cannabis use, or whether cannabis use can lead to reduced QoL. Prospective studies are needed to evaluate the causal relationship between cannabis and QoL. SCIENTIFIC SIGNIFICANCE: Furthering the understanding of the relationship between cannabis and QoL can inform public policy, prevention efforts, outcomes, and an objective understanding of the effects of cannabis users. (Am J Addict 2017;26:8-25). PMID- 28000974 TI - Amino Acid-Specific, Ribonucleotide-Promoted Peptide Formation in the Absence of Enzymes. AB - Nucleic acids and polypeptides are at the heart of life. It is interesting to ask whether the monomers of these biopolymers possess intrinsic reactivity that favors oligomerization in the absence of enzymes. We have recently observed that covalently linked peptido RNA chains form when mixtures of monomers react in salt rich condensation buffer. Here, we report the results of a screen of the 20 proteinogenic amino acids and four ribonucleotides. None of the amino acids prevent phosphodiester formation, so all of them are compatible with genetic encoding through RNA chain growth. A reactivity landscape was found, in which peptide formation strongly depends on the structure of the amino acid, but less on the nucleobase. For example, proline gives ribonucleotide-bound peptides most readily, tyrosine favors pyrophosphate and phosphodiester formation, and histidine gives phosphorimidazolides as dominant products. When proline and aspartic acid were allowed to compete for incorporation, only proline was found at the N-terminus of peptido chains. The reactivity described here links two fundamental classes of biomolecules through reactions that occur without enzymes, but with amino acid specificity. PMID- 28000975 TI - Hypointense Vessels Detected by Susceptibility-Weighted Imaging Identifies Tissue at Risk of Infarction in Anterior Circulation Stroke. AB - BACKGROUND AND PURPOSE: The diagnostic value of susceptibility-weighted magnetic resonance imaging of acute stroke patients has shown potential as a surrogate marker of impaired hemodynamics. We investigate the value of asymmetrical hypointense cerebral vessels (HV) for the identification of vessel status and tissue at risk of infarction (TaR). METHODS: Symmetry of HV was visually rated on SWI data from a well-defined population of acute anterior circulation stroke with onset <24 hours. MRI perfusion data was analyzed and volumes of tissue at risk segmented using a delay threshold of Tmax> 6 seconds. Status of the extra- and intracranial arteries was assessed by ultrasound and MR angiography. RESULTS: 35 patients were included (12 women; median age 69 years, IQR 61-77; median NIHSS at admission 10, IQR 6-20). Asymmetrically distributed HV were detected at the stroke hemisphere in 25 patients (71%). Of those, 12 patients displayed occlusion of the middle cerebral artery, whereas occlusion of the extracranial ICA was detected in 6 patients. TaR was larger, yet not significantly different in patients with asymmetrically HV (mean volume 38.9 ml, SD 52.9 ml) compared to patients showing symmetrical HV (4.2 ml; SD 10.7 ml, p-value 0.081). Significant differences where, however, found after excluding patients with extracranial ICA occlusions (42.9 ml; SD 50.4 ml vs. 4.2 ml, SD 10.8 ml, p-value 0.025). CONCLUSION: Visual analysis of HV in SWI identifies tissue at risk in patients with anterior circulation stroke. Potentially pre-existing extracranial ICA occlusions leading to prominent HV have to be considered as a confounding factor. PMID- 28000976 TI - Gold-Catalyzed Direct Oxidative Arylation with Boron Coupling Partners. AB - An efficient synthesis of biaryls through a gold-catalyzed oxidative cross coupling of arenes with strong electron-deprived aryl boronates is presented herein. Regio- and chemocontrol are achieved by the selective activation of these coupling partners by gold at different oxidation states. Under reaction conditions devoid of basic additives or directing groups, the role of acetato ligand as an internal base has been revealed as a key parameter for expanding the reaction scope in these transformations. PMID- 28000977 TI - SILAC-based quantitative proteomic analysis reveals widespread molecular alterations in human skin keratinocytes upon chronic arsenic exposure. AB - Chronic exposure to arsenic is associated with dermatological and nondermatological disorders. Consumption of arsenic-contaminated drinking water results in accumulation of arsenic in liver, spleen, kidneys, lungs, and gastrointestinal tract. Although arsenic is cleared from these sites, a substantial amount of residual arsenic is left in keratin-rich tissues including skin. Epidemiological studies suggest the association of skin cancer upon arsenic exposure, however, the mechanism of arsenic-induced carcinogenesis is not completely understood. We developed a cell line based model to understand the molecular mechanisms involved in arsenic-mediated toxicity and carcinogenicity. Human skin keratinocyte cell line, HaCaT, was chronically exposed to 100 nM sodium arsenite over a period of 6 months. We observed an increase in basal ROS levels in arsenic-exposed cells. SILAC-based quantitative proteomics approach resulted in identification of 2111 proteins of which 42 proteins were found to be overexpressed and 54 downregulated (twofold) upon chronic arsenic exposure. Our analysis revealed arsenic-induced overexpression of aldo-keto reductase family 1 member C2 (AKR1C2), aldo-keto reductase family 1 member C3 (AKR1C3), glutamate cysteine ligase catalytic subunit (GCLC), and NAD(P)H dehydrogenase [quinone] 1 (NQO1) among others. We observed downregulation of several members of the plakin family including periplakin (PPL), envoplakin (EVPL), and involucrin (IVL) that are essential for terminal differentiation of keratinocytes. MRM and Western blot analysis confirmed differential expression of several candidate proteins. Our study provides insights into molecular alterations upon chronic arsenic exposure on skin. PMID- 28000979 TI - Combination of Cp*RhIII -Catalyzed C-H Activation and a Wagner-Meerwein-Type Rearrangement. AB - A combination of Cp*RhIII -catalyzed C-H activation and Wagner-Meerwein-type rearrangement was successfully achieved for the first time. Thus, bridged polycyclic molecules that are not readily accessible by other means were accessed under mild conditions with high efficiency (as low as 0.5 mol % Rh catalyst) in the coupling of N-phenoxyacetamide with 7-azabenzonorbornadiene. PMID- 28000978 TI - Co-immobilized Phosphorylated Cofactors and Enzymes as Self-Sufficient Heterogeneous Biocatalysts for Chemical Processes. AB - Enzyme cofactors play a major role in biocatalysis, as many enzymes require them to catalyze highly valuable reactions in organic synthesis. However, the cofactor recycling is often a hurdle to implement enzymes at the industrial level. The fabrication of heterogeneous biocatalysts co-immobilizing phosphorylated cofactors (PLP, FAD+ , and NAD+ ) and enzymes onto the same solid material is reported to perform chemical reactions without exogeneous addition of cofactors in aqueous media. In these self-sufficient heterogeneous biocatalysts, the immobilized enzymes are catalytically active and the immobilized cofactors catalytically available and retained into the solid phase for several reaction cycles. Finally, we have applied a NAD+ -dependent heterogeneous biocatalyst to continuous flow asymmetric reduction of prochiral ketones, thus demonstrating the robustness of this approach for large scale biotransformations. PMID- 28000980 TI - Qualitative study of peer workers within the 'Partners in Recovery' programme in regional Australia. AB - In Australia and internationally, Peer Workers are increasingly being incorporated into the mental health workforce. Underpinning this trend is the conviction that the inclusion of workers with lived experience in overcoming mental health challenges is central to transforming service delivery. Given there are few identified Australian studies into the experiences of Peer Workers, this paper reports findings from qualitative interviews conducted in a Partners In Recovery programme in one regional area in Australia. The interviews formed part of a larger mixed-method study evaluating Peer Worker roles in the programme. Thematic analysis of interview transcripts with Peer Workers and other staff employed in the programme (n = 22) was undertaken. Central to the five themes that emerged was the concept of lived experience expertise in overcoming mental health challenges. The themes were: (i) role variance, (ii) the challenges and opportunities for Peer Worker, (iii) the processes Peer Workers employed as they attempted to shape an identify and language, (iv) the inconsistencies and challenges of employing lived experience as a defining feature of the peer worker role, and (v) the nature of trust arising from lived experience relationships. From this study, it is evident that the Peer Worker role remains underdeveloped. The difficulties experienced by Peer Workers in establishing a homogenous identity and role is not unique. The process and lack of clarity around role identity revealed from the narratives, parallels the experiences of Mental Health Nursing. PMID- 28000981 TI - Palladium-Mediated Labeling of Nucleic Acids. AB - New applications of Pd-catalyzed coupling reactions (Suzuki-Miyaura, Sonogashira, and Stille-Migita coupling) for post-conjugation of nucleic acids have been developed recently. Breakthroughs in this area might now pave the way for the development of sophisticated DNA probes, which might be of great interest in chemical biology, nanotechnology, and bioanalysis, as well as in diagnostic domains. PMID- 28000982 TI - Prognostication in MELAS syndrome and other m.3243A-G mutation-associated disorders. PMID- 28000983 TI - Visual function and retinal vessel diameters during hyperthermia in man. AB - PURPOSE: To assess the effect of elevated core body temperature on temporal and spatial contrast sensitivity and retinal vessel diameters. METHODS: The study included 13 healthy volunteers aged 20-37 years. Core body temperature elevation (target +1.1 degrees C) was induced by wrapping the participants in cling film, tinfoil and warming blankets. Subsequent cooling was achieved by undressing. Flicker sensitivity (critical flicker fusion frequency) was chosen to assess temporal resolution, while the Freiburg Vision Test was used to determine spatial contrast sensitivity at 1.5 cycles per degree. Scanning laser ophthalmoscopy was used to measure retinal trunk vessel diameters. Assessment was made at baseline, during hyperthermia and after cooling. RESULTS: The induction of a mean increase in core body temperature of 1.02 degrees C was associated with a 7.15-mmHg mean reduction in systolic blood pressure (p < 0.01), a 10.6-mmHg mean reduction in diastolic blood pressure (p < 0.01), a mean increase in pulse rate of 36.3 bpm (p < 0.0001), a 2.66% improvement in flicker sensitivity (CI95 1.37-3.94, p < 0.001), a 2.80% increase in retinal artery diameters (CI95 1.09-4.51, p < 0.01) and a 2.95% increase in retinal vein diameters (CI95 0.96-4.94, p < 0.01). There was no detectable effect of temperature on spatial contrast sensitivity. All ocular test parameters returned to baseline levels after cooling. CONCLUSION: Increased core body temperature was accompanied by improved temporal visual resolution and retinal trunk vessel dilation. The results suggest that hyperthermia is associated with enhanced retinal function and increased retinal metabolism. PMID- 28000984 TI - Molding young minds: The importance of residency training in shaping residents' attitudes toward substance use disorders. PMID- 28000985 TI - The Myth of Color Sensations, or How Not to See a Yellow Banana. AB - I argue against a class of philosophical views of color perception, especially insofar as such views posit the existence of color sensations. I argue against the need to posit such nonconceptual mental intermediaries between the stimulus and the eventual conceptualized perceptual judgment. Central to my arguments are considerations of certain color illusions. Such illusions are best explained by reference to high-level, conceptualized knowledge concerning, for example, object identity, likely lighting conditions, and material composition of the distal stimulus. Such explanations obviate the need to appeal to nonconceputal mental links in the causal chains eventuating in conceptualized color discriminations. PMID- 28000986 TI - Cortical Color and the Cognitive Sciences. AB - Back when researchers thought about the various forms that color vision could take, the focus was primarily on the retinal mechanisms. Since that time, research on human color vision has shifted from an interest in retinal mechanisms to cortical color processing. This has allowed color research to provide insight into questions that are not limited to early vision but extend to cognition. Direct cortical connections from higher-level areas to lower-level areas have been found throughout the brain. One of the classic questions in cognitive science is whether perception is influenced, and if so to what extent, by cognition and whether a clear distinction can be drawn between perception and cognition. Since perception is seen as providing justification for our beliefs about properties in the external world, these questions also have metaphysical and epistemological significance. The aim of this paper is to highlight some of the areas where research on color perception can shed new light on questions in the cognitive sciences. A further aim of the paper is to raise some questions about color research that are in dire need of further reflection and investigation. PMID- 28000987 TI - Prognostic value of prostate biopsy grade: forever a product of sampling. PMID- 28000989 TI - Circulating biomarkers of neuroendocrine prostate cancer: an unmet challenge. PMID- 28000990 TI - Quality improvement in cystectomy care with enhanced recovery (QUICCER) study. PMID- 28000991 TI - Laparoscopic adrenalectomy: the 'gold standard' when performed appropriately. PMID- 28000992 TI - Infographics. PMID- 28000993 TI - Towards Modeling False Memory With Computational Knowledge Bases. AB - One challenge to creating realistic cognitive models of memory is the inability to account for the vast common-sense knowledge of human participants. Large computational knowledge bases such as WordNet and DBpedia may offer a solution to this problem but may pose other challenges. This paper explores some of these difficulties through a semantic network spreading activation model of the Deese Roediger-McDermott false memory task. In three experiments, we show that these knowledge bases only capture a subset of human associations, while irrelevant information introduces noise and makes efficient modeling difficult. We conclude that the contents of these knowledge bases must be augmented and, more important, that the algorithms must be refined and optimized, before large knowledge bases can be widely used for cognitive modeling. PMID- 28000994 TI - Lithium Dihydropyridine Dehydrogenation Catalysis: A Group 1 Approach to the Cyclization of Diamine Boranes. AB - In reactions restricted previously to a ruthenium catalyst, a 1-lithium-2-alkyl 1,2-dihydropyridine complex is shown to be a competitive alternative dehydrogenation catalyst for the transformation of diamine boranes into cyclic 1,3,2-diazaborolidines, which can in turn be smoothly arylated in good yields. This study established the conditions and solvent dependence of the catalysis through NMR monitoring, with mechanistic insight provided by NMR (including DOSY) experiments and X-ray crystallographic studies of several model lithio intermediates. PMID- 28000995 TI - Ribonucleotides and RNA Promote Peptide Chain Growth. AB - All known forms of life use RNA-mediated polypeptide synthesis to produce the proteins encoded in their genes. Because the principal parts of the translational machinery consist of RNA, it is likely that peptide synthesis was achieved early in the prebiotic evolution of an RNA-dominated molecular world. How RNA attracted amino acids and then induced peptide formation in the absence of enzymes has been unclear. Herein, we show that covalent capture of an amino acid as a phosphoramidate favors peptide formation. Peptide coupling is a robust process that occurs with different condensation agents. Kinetics show that covalent capture can accelerate chain growth over oligomerization of the free amino acid by at least one order of magnitude, so that there is no need for enzymatic catalysis for peptide synthesis to begin. Peptide chain growth was also observed on phosphate-terminated RNA strands. Peptide coupling promoted by ribonucleotides or ribonucleotide residues may have been an important transitional form of peptide synthesis that set in when amino acids were first captured by RNA. PMID- 28000996 TI - Increased fall risk in patients with neovascular age-related macular degeneration: a three-year follow-up study. PMID- 28000998 TI - The role of objective cognitive dysfunction in subjective cognitive complaints after stroke. AB - BACKGROUND AND PURPOSE: Objective cognitive performance (OCP) is often impaired in patients post-stroke but the consequences of OCP for patient-reported subjective cognitive complaints (SCC) are poorly understood. We performed a detailed analysis on the association between post-stroke OCP and SCC. METHODS: Assessments of OCP and SCC were obtained in 208 patients 3 months after stroke. OCP was evaluated using conventional and ecologically valid neuropsychological tests. Levels of SCC were measured using the CheckList for Cognitive and Emotional (CLCE) consequences following stroke inventory. Multivariate hierarchical regression analyses were used to evaluate the association of OCP with CLCE scores adjusting for age, sex and intelligence quotient. Analyses were performed to examine the global extent of OCP dysfunction (based on the total number of impaired neuropsychological tests, i.e. objective cognitive impairment index) and for each OCP test separately using the raw neuropsychological (sub)test scores. RESULTS: The objective cognitive impairment index for global OCP was positively correlated with the CLCE score (Spearman's rho = 0.22, P = 0.003), which remained significant in multivariate adjusted models (beta = 0.25, P = 0.01). Results for the separate neuropsychological tests indicated that only one task (the ecologically valid Rivermead Behavioural Memory Test) was independently associated with the CLCE in multivariate adjusted models (beta = 0.34, P < 0.001). CONCLUSIONS: Objective neuropsychological test performance, as measured by the global dysfunction index or an ecologically valid memory task, was associated with SCC. These data suggest that cumulative deficits in multiple cognitive domains contribute to subjectively experienced poor cognitive abilities in daily life in patients post-stroke. PMID- 28000997 TI - In-Cell Activation of Organo-Osmium(II) Anticancer Complexes. AB - The family of iodido OsII arene phenylazopyridine complexes [Os(eta6 -p-cym)(5-R1 -pyridylazo-4-R2 -phenyl))I]+ (where p-cym=para-cymene) exhibit potent sub micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I- ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R1 =OEt, R2 =H) and 2-I (R1 =H, R2 =NMe2 ). They were labelled with the radionuclide 131 I (beta- /gamma emitter, t1/2 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[131 I] and 2-[131 I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2 O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes. PMID- 28000999 TI - N/OFQ system in brain areas of nerve-injured mice: its role in different aspects of neuropathic pain. AB - Several studies showed that chronic pain causes reorganization and functional alterations of supraspinal brain regions. The nociceptin-NOP receptor system is one of the major systems involved in pain control and much evidence also suggested its implication in stress, anxiety and depression. Therefore, we investigated the nociceptin-NOP system alterations in selected brain regions in a neuropathic pain murine model. Fourteen days after the common sciatic nerve ligature, polymerase chain reaction (PCR) analysis indicated a significant decrease of pronociceptin and NOP receptor mRNA levels in the thalamus; these alterations could contribute to the decrease of the thalamic inhibitory function reported in neuropathic pain condition. Nociceptin peptide and NOP mRNA increased in the anterior cingulate cortex (ACC) and not in the somatosensory cortex, suggesting a peculiar involvement of this system in pain regulating circuitry. Similarly to the ACC, an increase of nociceptin peptide levels was observed in the amygdala. Finally, the pronociceptin and NOP mRNAs decrease observed in the hypothalamus reflects the lack of hypothalamus-pituitary-adrenal axis activation, already reported in neuropathic pain models. Our data indicate that neuropathic pain conditions affect the supraspinal nociceptin-NOP system which is also altered in regions known to play a role in emotional aspects of pain. PMID- 28001001 TI - CO2 Capture from Ambient Air by Crystallization with a Guanidine Sorbent. AB - Carbon capture and storage is an important strategy for stabilizing the increasing concentration of atmospheric CO2 and the global temperature. A possible approach toward reversing this trend and decreasing the atmospheric CO2 concentration is to remove the CO2 directly from air (direct air capture). Herein we report a simple aqueous guanidine sorbent that captures CO2 from ambient air and binds it as a crystalline carbonate salt by guanidinium hydrogen bonding. The resulting solid has very low aqueous solubility (Ksp =1.0(4)*10-8 ), which facilitates its separation from solution by filtration. The bound CO2 can be released by relatively mild heating of the crystals at 80-120 degrees C, which regenerates the guanidine sorbent quantitatively. Thus, this crystallization based approach to CO2 separation from air requires minimal energy and chemical input, and offers the prospect for low-cost direct air capture technologies. PMID- 28001000 TI - Echocardiographic abnormalities and their impact on health status in patients with COPD referred for pulmonary rehabilitation. AB - BACKGROUND AND OBJECTIVE: Both patients with cardiac diseases as well as those with COPD report an impaired health status. The frequencies of objectively assessed co-morbid cardiac diseases and their impact on health status in patients with COPD are unknown. We aimed to investigate echocardiographic abnormalities and their impact on health status in a large cohort of patients with COPD referred for pulmonary rehabilitation (PR). METHODS: In this cross-sectional, observational analyses, demographic and clinical characteristics were assessed during an inpatient pre-PR assessment. All patients underwent Doppler echocardiographic evaluation. Health status was assessed using the COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 514 patients (55.3% males, age: 64.1 (9.1) years, forced expiratory volume in 1 s (FEV1 ): 48.6 (20.0) % predicted) were included for analyses. Two hundred and seventy-six patients (53.7%) were diagnosed with one or more echocardiographic abnormalities. Most prevalent were left ventricular (LV) hypertrophy (LVH, 31.0%), increased right ventricular systolic pressure (RVSP, 20.4%) and impaired LV ejection fraction (LVEF, 16.5%). Of the 276 patients, 176 (63.8%) with echocardiographic abnormalities did not have these recorded in their medical history. Patients with echocardiographic abnormalities reported a worse health status as assessed with the SGRQ total score (62.5 (17.1) vs 59.3 (17.6) points, P = 0.044). CCQ and CAT did not differ between groups. CONCLUSION: More than half of the patients referred to PR had echocardiographic abnormalities of which two-third did not have them recorded in their medical history. We detected a limited impact of echocardiographic abnormalities on health status. PMID- 28001002 TI - The Effects of Guanfacine and Phenylephrine on a Spiking Neuron Model of Working Memory. AB - We use a spiking neural network model of working memory (WM) capable of performing the spatial delayed response task (DRT) to investigate two drugs that affect WM: guanfacine (GFC) and phenylephrine (PHE). In this model, the loss of information over time results from changes in the spiking neural activity through recurrent connections. We reproduce the standard forgetting curve and then show that this curve changes in the presence of GFC and PHE, whose application is simulated by manipulating functional, neural, and biophysical properties of the model. In particular, applying GFC causes increased activity in neurons that are sensitive to the information currently being remembered, while applying PHE leads to decreased activity in these same neurons. Interestingly, these differential effects emerge from network-level interactions because GFC and PHE affect all neurons equally. We compare our model to both electrophysiological data from neurons in monkey dorsolateral prefrontal cortex and to behavioral evidence from monkeys performing the DRT. PMID- 28001003 TI - Intrinsic Thermodynamics and Structures of 2,4- and 3,4-Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases. AB - The goal of rational drug design is to understand structure-thermodynamics correlations in order to predict the chemical structure of a drug that would exhibit excellent affinity and selectivity for a target protein. In this study we explored the contribution of added functionalities of benzenesulfonamide inhibitors to the intrinsic binding affinity, enthalpy, and entropy for recombinant human carbonic anhydrases (CA) CA I, CA II, CA VII, CA IX, CA XII, and CA XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from 90 to +10 kJ mol-1 , and are compensated by a similar opposing entropy contribution. The intrinsic parameters of binding were determined by subtracting the linked protonation reactions. The sulfonamide group pKa values of the compounds were measured spectrophotometrically, and the protonation enthalpies were measured by isothermal titration calorimetry (ITC). Herein we describe the development of meta- or ortho-substituted fluorinated benzenesulfonamides toward the highly potent compound 10 h, which exhibits an observed dissociation constant value of 43 pm and an intrinsic dissociation constant value of 1.1 pm toward CA IX, an anticancer target that is highly overexpressed in various tumors. Fluorescence thermal shift assays, ITC, and X-ray crystallography were all applied in this work. PMID- 28001006 TI - Intracameral antibiotic: the Vancomycin conundrum. PMID- 28001004 TI - Quantitative Structure-activity Relationship (QSAR) Models for Docking Score Correction. AB - In order to improve docking score correction, we developed several structure based quantitative structure activity relationship (QSAR) models by protein-drug docking simulations and applied these models to public affinity data. The prediction models used descriptor-based regression, and the compound descriptor was a set of docking scores against multiple (~600) proteins including nontargets. The binding free energy that corresponded to the docking score was approximated by a weighted average of docking scores for multiple proteins, and we tried linear, weighted linear and polynomial regression models considering the compound similarities. In addition, we tried a combination of these regression models for individual data sets such as IC50 , Ki , and %inhibition values. The cross-validation results showed that the weighted linear model was more accurate than the simple linear regression model. Thus, the QSAR approaches based on the affinity data of public databases should improve docking scores. PMID- 28001007 TI - Fungal keratitis: dealing with a diverse kingdom of ocular assailants. PMID- 28001008 TI - Continuing professional development. PMID- 28001009 TI - A Perfect Ten. AB - The X files: This Editorial welcomes you to Volume 10 of ChemSusChem! It contains a look at some of the statistics and highlights from 2016, as well as some of our plans for 2017. The truth is in here! PMID- 28001010 TI - Adipocyte lipopolysaccharide binding protein (LBP) is linked to a specific lipidomic signature. AB - OBJECTIVE: Lipopolysaccharide binding protein (LBP) is part of a family of structurally and functionally related lipid transfer proteins. This study aimed to investigate the associations of LBP with the lipid composition of human adipose tissue. METHODS: Lipidomic analysis was performed in whole adipose tissue. To validate the associations found, LBP was knocked down (KD) in 3T3-L1 adipocytes, and lipidomic profile was evaluated by nontargeted lipidomics. RESULTS: LBP gene expression was negatively associated with phosphatidylcholine, phosphatidylserine, and sphingomyelin relative abundance in vivo. LBP expression was also decreased in those samples with the highest docosahexanoic content, implicated in the resolution of inflammation. The KD of LBP (by ~70%) led to sharp changes in the lipidome of adipocytes. Of note, specific plasmalogen species PE(O-16:0/22:5), PE(38:2), odd chain glycerolipids, and cholesteryl linoleate were upregulated by LBP KD. In contrast, GM3 gangliosides, several ceramides, a triacylglycerol potentially containing arachidonate, and cholesteryl palmitate were downregulated by LBP KD. CONCLUSIONS: LBP seems to play a role in the regulation of lipid composition of adipose tissue linked to resilience to inflammation. PMID- 28001011 TI - Deterioration of endothelial function of micro- and macrocirculation in patients with diabetes type 1 and 2. AB - BACKGROUND: Vascular complications are an important cause of morbidity in patients with diabetes mellitus (DM). Endothelial dysfunction is an early marker of atherosclerosis and has already been shown in macrocirculation of diabetic patients; however, data on endothelial function of microcirculation is scarce. Our aim was to evaluate endothelial function in macro- and microcirculation and their interrelationship in patients with type 1 and 2 DM. METHODS: The study included 30 patients with type 1 DM, 30 patients with type 2 DM and 25 healthy controls. The endothelial function of large arteries was studied measuring flow mediated dilation (FMD). Peripheral arterial tonometry was used for investigation of the endothelial function of microcirculation, measuring Reactive Hyperemia Index (RHI) and Augmentation Index (AI). RESULTS: In comparison to controls, both DM groups had decreased FMD: type 1 (4.0+/-5.0% vs. 10.0+/-7.8%, P=0.005) and type 2 (5.0+/-0.6% vs. 10.0+/-7.8%, P=0.007). However, only type 2 DM group had a lower RHI (1.71+/-0.44 vs. 2.05+/-0.54, P=0.017) in comparison to controls. CONCLUSIONS: Patients with type 1 and 2 DM had deteriorated functional capability of macrocirculation. However, endothelial dysfunction of microcirculation was present only in type 2 DM patients. Type 2 DM patients were also at higher risk for atherosclerosis because of the more frequent presence of risk factors. PMID- 28001012 TI - Iodine deficiency and nutrition in Scandinavia. AB - Iodine nutrition is a result of geological conditions, iodine fortification and monitoring strategies within a country together with the dietary habits of the population. This review summarizes the basis for the current iodine situation in the Scandinavian countries in order to identify gaps in knowledge, determine necessary future steps, highlight landmarks in Scandinavian iodine research and consider ongoing studies in Scandinavian countries with high international impact. Historically, iodine deficiency disorders such as goiter were common in Norway and Sweden, but not in Denmark. Different strategies have been used in Scandinavia to improve iodine nutrition. The major source of iodine is iodized salt in Sweden and from milk and dairy products in Norway. In Denmark, drinking water, milk, dairy products and iodized salt used in commercial production of bread are the important sources of iodine. The current iodine status in Scandinavia is not optimal and action is ongoing to increase iodination in Denmark, where there is mild iodine deficiency in the general population. Data from all three countries indicate insufficient iodine nutrition during pregnancy and there is a need for data from children, adolescents and young women. Monitoring a population's iodine status and dietary iodine sources is necessary to secure iodine nutrition in Scandinavia. Ongoing studies in Scandinavia will contribute significantly to the knowledge about the effects of mild to moderate iodine deficiency. PMID- 28001013 TI - Management and prevention of occupational asthma. AB - Occupational asthma is a potential preventable form of asthma. This review of diagnosis, management and prevention focuses mainly on publications from the past three years. Early suspicion of the diagnosis is essential for a timely diagnosis and management and the possibility may first be raised by the patient or may need to be elicited by careful history by the health care provider. Objective diagnostic steps are needed, as have been detailed in consensus statements and guidelines. A combination of tests is often needed for diagnosis and these are most easily obtained while the patient is still employed. Management includes consideration of safe future workplace accommodation and of preventive measures for the patient and for other workers. PMID- 28001014 TI - Stroke prevention in atrial fibrillation with left atrial appendage closure. AB - Patients with atrial fibrillation (AF) are at risk for stroke and thromboembolism. Oral anticoagulants (OAC) are effective therapies to reduce the risk of stroke; however, these agents also increase the risk of bleeding complications. Concerns over bleeding contribute to significant under treatment and leave a substantial proportion of patients at risk for a serious or life threatening stroke. Identification of the left atrial appendage (LAA) as the major site of pathogenic thrombus formation in AF patients has led to the development of devices which exclude the appendage from the systemic circulation. These devices offer a potential alternative treatment for some AF patients who cannot tolerate long term OAC. This article will review the pathogenesis of LAA thrombus formation and identify the patient population most likely to benefit from LAA closure devices. Finally, we will review LAA closure techniques (both surgical and percutaneous), evaluate published outcomes data, and discuss the indications and risk/benefit considerations of each approach. PMID- 28001015 TI - Procedures for Handling Retaliation Complaints Under Section 31307 of the Moving Ahead for Progress in the 21st Century Act (MAP-21). Final rule. AB - On March 16, 2016, the Occupational Safety and Health Administration (OSHA) of the U.S. Department of Labor (Department) issued an interim final rule (IFR) that provided procedures for the Department's processing of complaints under the employee protection (retaliation or whistleblower) provisions of Section 31307 of the Moving Ahead for Progress in the 21st Century Act (MAP-21). The IFR established procedures and time frames for the handling of retaliation complaints under MAP-21, including procedures and time frames for employee complaints to OSHA, investigations by OSHA, appeals of OSHA determinations to an administrative law judge (ALJ) for a hearing de novo, hearings by ALJs, review of ALJ decisions by the Administrative Review Board (ARB) (acting on behalf of the Secretary of Labor) and judicial review of the Secretary's final decision. It also set forth the Department's interpretations of the MAP-21 whistleblower provisions on certain matters. This final rule adopts, without change, the IFR. PMID- 28001016 TI - Effect of dapagliflozin administration on metabolic syndrome, insulin sensitivity, and insulin secretion. AB - BACKGROUND: The aim of this paper was to evaluate the effect of dapagliflozin on metabolic syndrome (MetS), insulin sensitivity and insulin secretion. METHODS: A randomized, double blind, placebo-controlled clinical trial was carried out in 24 patients with MetS. Glucose and insulin levels were measured every 30 minutes for 2 hours after a 75-g dextrose load. Metabolic profile was also evaluated before and after the pharmacological intervention. Twelve patients received dapagliflozin (10 mg) before breakfast for 90 days. The remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion and insulin sensitivity were calculated. Data were tested using the Wilcoxon signed-rank, Mann-Whitney U and chi2 tests. The Ethics Committee approved the study protocol. RESULTS: After dapagliflozin, there were significant decreases in body weight (82.8+/-12.9 vs. 81.2+/-12.9 kg, P<0.001), BMI (33.4+/-3.6 vs. 32.7+/-3.7 kg/m2, P<0.001), waist circumference (102+/-10 vs. 98+/-9 cm, P<0.001), total cholesterol (5.4+/-0.7 vs. 5.2+/-0.7 mmol/L, P=0.049), triglycerides (2.7+/-1.4 vs. 1.7+/-0.8 mmol/L, P=0.003), AUC of insulin (103,914+/-55,170 vs. 45,018+/-22,146 pmol/L, P<0.001) and total insulin secretion (0.84+/-0.64 vs. 0.35+/-0.11, P<0.001). Seven patients (58.3%) in the dapagliflozin group showed remission of MetS (P=0.027). CONCLUSIONS: Dapagliflozin decreased body weight, BMI, waist circumference, total cholesterol, triglycerides, AUC of insulin and total insulin secretion, with a remission of MetS in 58.3%. PMID- 28001017 TI - Improvement of bone turnover markers and bone mineral density following treatment of primary aldosteronism. AB - BACKGROUND: Recent studies showed association between hyperaldosteronism and low bone density among patients with primary aldosteronism (PA) due to secondary hyperparathyroidism. Our objective is to assess bone turnover markers (BTM) and bone mineral density (BMD) of PA patients compared to essential hypertension. METHODS: This was an open-label, prospective, case-controlled study, conducted over 12 months. Fifty-two consecutive patients referred for secondary hypertension were screened. Eighteen patients with confirmed PA (diagnosis based on the Endocrine Society clinical guideline) and seventeen matched controls with essential hypertension were recruited. BTM (CTX and P1NP), BMD, intact parathyroid hormone (iPTH), and bone profile were assessed at baseline and three months following treatment among the PA patients. Calcium intake was assessed using a validated questionnaire. Primary outcomes were the changes of bone markers and BMD following treatment of PA, and their relation to other parameters. RESULTS: PA patients had significantly lower serum calcium and higher iPTH despite comparable vitamin D levels with control group. Both BTM were significantly higher among the PA group. BMD of lumbar spine, neck of femur and distal radius did not differ between groups. Three months following treatment, there were significant: 1) reduction in BTM; 2) improvement in the lumbar spine BMD; 3) reduction in iPTH level; and 4) increment of serum 25-OH vitamin D level. CONCLUSIONS: Our findings support that bone loss and potential fracture risk among PA patients are likely a result of aldosterone-mediated secondary hyperparathyroidism. Patients with early PA may already exhibit increased bone turnover despite no significant changes in BMD. PMID- 28001018 TI - Advanced Practice Registered Nurses. Final rule with comment period. AB - The Department of Veterans Affairs (VA) is amending its medical regulations to permit full practice authority of three roles of VA advanced practice registered nurses (APRN) when they are acting within the scope of their VA employment. Certified Registered Nurse Anesthetists (CRNA) will not be included in VA's full practice authority under this final rule, but comment is requested on whether there are access issues or other unconsidered circumstances that might warrant their inclusion in a future rulemaking. The final rulemaking establishes the professional qualifications an individual must possess to be appointed as an APRN within VA, establishes the criteria under which VA may grant full practice authority to an APRN, and defines the scope of full practice authority for each of the three roles of APRN. The services provided by an APRN under full practice authority in VA are consistent with the nursing profession's standards of practice for such roles. This rulemaking increases veterans' access to VA health care by expanding the pool of qualified health care professionals who are authorized to provide primary health care and other related health care services to the full extent of their education, training, and certification, without the clinical supervision of physicians, and it permits VA to use its health care resources more effectively and in a manner that is consistent with the role of APRNs in the non-VA health care sector, while maintaining the patient-centered, safe, high-quality health care that veterans receive from VA. PMID- 28001019 TI - Medicare Program; Conditions for Coverage for End-Stage Renal Disease Facilities- Third Party Payment. Interim final rule with comment period. AB - This interim final rule with comment period implements new requirements for Medicare-certified dialysis facilities that make payments of premiums for individual market health plans. These requirements apply to dialysis facilities that make such payments directly, through a parent organization, or through a third party. These requirements are intended to protect patient health and safety; improve patient disclosure and transparency; ensure that health insurance coverage decisions are not inappropriately influenced by the financial interests of dialysis facilities rather than the health and financial interests of patients; and protect patients from mid-year interruptions in coverage. PMID- 28001020 TI - Continuous successful re-aspirating a large obstructive pelvic cystic mass of low grade serous carcinoma after failed sclerotherapy. PMID- 28001021 TI - Outcomes of first IVF/ICSI in young women with diminished ovarian reserve. AB - BACKGROUND: There is no consensual definition of diminished ovarian reserve and the best therapeutic strategy has not yet been demonstrated. METHODS: We performed a retrospective study to evaluate outcomes following a first in-vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) cycle in young women with diminished ovarian reserve. Women with tubal factor, endometriosis or previous stimulation cycle were excluded. We defined diminished ovarian reserve as women <=38 years with an AMH <=1.1 ng/mL or antral follicular count <=7. RESULTS: Among 59 IVF/ICSI cycles (40% IVF/60% ICSI), the pregnancy rate was 17% (10/59) and live birth rate 8.5% (5/59). Miscarriage rate was 50%. Baseline characteristics and IVF outcomes of the pregnant and not pregnant women were compared. No differences in age, antral follicular count, AMH, protocol used or number of harvested oocytes were found between the groups. A higher gonadotropin starting dose in the pregnancy group (397.5+/-87 IU vs. 314.8+/-103 IU; P=0.02) and a trend to a higher total dose received (4720+/-1349 IU vs. 3871+/-1367 IU; P=0.07) were noted. CONCLUSIONS: The present study confirms that women with diminished ovarian reserve have low live birth rates after a first IVF-ICSI cycle and that a higher gonadotropin starting dose might be associated with better outcomes. PMID- 28001022 TI - Lifetime risk of surgery for stress urinary incontinence or pelvic organ prolapse. AB - Understanding and applying the epidemiology and lifetime risk of surgery for stress urinary incontinence (SUI) and pelvic organ prolapse (POP) is necessary to provide quality care to a growing and aging female population. Both SUI and POP are prevalent medical conditions, affecting 15-17% and 3-6% of women respectively. While generally not life-threatening, they represent a significant public health burden as they are associated with a decreased quality of life and significant economic impact. Although treatment is considered elective, for many women, the decision to address SUI or POP is necessary in order to regain a normal lifestyle and the lifetime risk for undergoing surgery to address either stress urinary incontinence or pelvic organ prolapse is 20.5%. This review includes a brief overview of the epidemiology of both disorders, followed by discussion of both landmark and recent literature regarding the lifetime risk of surgery for either disorder. Additionally, we will review re-operation rates, trends in management, and future care needs. PMID- 28001023 TI - Modified Glasgow prognostic score might be a prognostic factor for hepatocellular carcinoma: a meta-analysis. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is the fifth-most common cancer. Recent studies have demonstrated that there was a relationship between modified Glasgow prognostic score (mGPS) and survival of HCC. However, the results were inconsistent. EVIDENCE ACQUISITION: The following databases were searched for relevant articles published until June 2016: PubMed; EMBASE; Web of Science and the China National Knowledge Infrastructure. The strength of association between mGPS and OS of HCC was estimated by pooled HRs with corresponding 95% CIs. EVIDENCE SYNTHESIS: Seven studies with 2047 HCC patients were included in this meta-analysis. The mGPS was an independent marker of poor prognosis in patients with HCC (HR=2.21; 95% CI: 1.73-2.82; I2=51%). In the subgroup analysis of study design, both prospective studies (HR=1.68; 95% CI: 1.35-2.11; I2=0%) and retrospective studies (HR=2.64; 95% CI: 1.92-3.62; I2=39%) with higher mGPS had shorter OS. The patients with resectable HCC and high mGPS also showed shorter OS (HR=2.33; 95% CI: 1.65-3.29; I2=63%). In the subgroup analysis by sample size, both large sample size studies (HR=2.56; 95% CI: 1.50-4.38; I2=72%) and small sample size studies (HR=2.00; 95% CI: 1.62-2.48; I2=0%) showed the same results. CONCLUSIONS: In conclusion, this meta-analysis suggested that mGPS might be an independent prognostic factor for HCC. PMID- 28001024 TI - Microbiota and prebiotics modulation of uremic toxin generation. AB - Recent data have shown that the host-intestinal microbiota interaction is intrinsically linked with overall health. Chronic kidney disease (CKD) could influence intestinal microbiota and gut dysbiosis is also considered as a cause of progression of kidney disease. An increasing body of evidence indicates that dysbiosis is a key contributor of uremic retention solutes (URS) accumulating in patients with CKD. The discovery of the kidney-gut axis has created new therapeutic opportunities for nutritional intervention in order to prevent adverse outcomes. One of these strategies is prebiotics, which refers to nondigestible food ingredients or substances that beneficial affect growth and/or activity of limited health-promoting bacteria in the gastrointestinal tract. The influence of prebiotics on the production and concentration of URS have been investigated in various animal and human CKD studies. However, to date, there is still paucity of high-quality intervention trials. Randomized controlled trials and adequately powered intervention studies are needed before recommending prebiotics in clinical practice. This review will outline the interconnection between CKD progression, dysbiosis and URS production and will discuss mechanisms of action and efficacy of prebiotics as a new CKD management tool, with a particular emphasis on URS generation. PMID- 28001025 TI - Clinical benefits of phosphate control in progression of end stage renal disease. AB - It is largely agreed that preservation of residual kidney function (RKF) has a directly proportional affect on general, and in particular cardiovascular, mortality. During evaluation of patients on infrequent hemodialysis (ID) as both as once-weekly or twice-weekly hemodialysis it has been frequently underestimated the importance of phosphaturia, Indeed, the native kidney preserves the ability to eliminate not only toxic molecules but also a significative output of phosphate despite of a severe decrease of RKF. This task the modern membranes are as yet not very efficient of reproducing. The hemodialysis patients on ID who adhere accurately to a low protein diet of 0.6-0.8 g/kg/day could reach a draw in the balance of phosphates. In view of the significant impact produced by poor phosphate control on both RKF and the frequency of even severe cardiovascular effects, infrequent dialysis with its negative or neutral weekly phosphate balance, may constitute a valid "bridging" treatment even in the long-term, thus explaining the improved survival rates compared to patients receiving conventional triweekly hemodialysis. PMID- 28001026 TI - Keto-analogues and essential aminoacids and other supplements in the conservative management of chronic kidney disease. AB - The manipulation of dietary protein intake is the mainstay of nutritional treatment of patients affected by chronic renal insufficiency, with the aim to reduce the burden of uremic toxins in order to decrease uremic toxicity and delay the need for dialysis. Consensus exists regarding the benefit of progressive protein restriction towards delaying the progression of renal failure and the need for dialysis, provided adequate energy supply. Although pivotal, protein restriction is only one aspect of the dietary management of chronic kidney disease (CKD) patients. Additional features, though strictly related to proteins, include modifications in sodium, phosphorus and energy intake, as well as in the source (animal or plant derived) of protein and lipids. In addition, supplements play an important role as a means to obtain both beneficial effects and nutritional safety in the renal patient. Essential amino acid and ketoacid mixtures are the most utilized types of supplementation in CKD patients on restricted protein regimens. The essential amino acids plus ketoacid supplementation is mandatory in conjunction with a very low-protein diet in order to assure an adequate essential amino acid supply. It is needed to safely implement a very low protein (and phosphorus) intake, so as to obtain the beneficial effect of a severe protein restriction while preventing malnutrition. Protein-free products and energy supplements are also crucial for the prevention of protein-energy wasting in CKD patients. Calcium, iron, native vitamin D and omega-3 PUFAs are other types of supplementation of potential benefits in the CKD patients on conservative management. PMID- 28001027 TI - Sustainable Electronic Materials: Reversible Phototuning of Conductance in a Noncovalent Assembly of MWCNT and Bioresource-Derived Photochromic Molecule. AB - Tuning the microstructure, conductance, band gap of a single molecule with an external stimuli such as light have vital importance in nanoscale molecular electronics. Azobenzene systems are inimitable light responsive molecules suitable for the development of optically modulated materials. In this work we have demonstrated the development of an optically active Multiwalled Carbon Nanotube (MWCNT)-hybrid material by the noncovalent functionalization of azo based chromophore derived from cardanol, a bioresource material. This photoresponsive noncovalent hybrid shows trans-cis photoisomerization induced switching of conductance. We report this as the first example in which the photochromic assembly developed from a bioresource material exhibited tunable conductivity. We expect that this novel photoswitchable hybrid with reversible conductance may have potential applications in nanoscale molecular electronics, solar cells, OLEDs, etc. PMID- 28001028 TI - Preparation of a Thermally Light-Transmittance-Controllable Film from a Coexistent System of Polymer-Dispersed and Polymer-Stabilized Liquid Crystals. AB - Polymer-dispersed liquid crystal (PDLC) and polymer-stabilized liquid crystal (PSLC) systems are the two primary distinct systems in the field of liquid crystal (LC) technology, and they are differentiated by their unique microstructures. Here, we present a novel coexistent system of polymer-dispersed and polymer-stabilized liquid crystals (PD&SLCs), which forms a homeotropically aligned polymer network (HAPN) within the LC droplets after a microphase separation between the LC and polymer matrix and combines the advantages of both the PDLC and PSLC systems. Then, we prepare a novel thermally light-transmittance controllable (TLTC) film from the PD&SLC system, where the transmittance can be reversibly changed through thermal control from a transparent to a light scattering state. The film also combines the advantageous features of flexibility and a potential for large-scale manufacturing, and it shows significant promise in future applications from smart windows to temperature sensors. PMID- 28001029 TI - Efficient Photocurrent Enhancement from Porphyrin Molecules on Plasmonic Copper Arrays: Beneficial Utilization of Copper Nanoanntenae on Plasmonic Photoelectric Conversion Systems. AB - We demonstrated the usefulness of Cu light-harvesting plasmonic nanoantennae for the development of inexpensive and efficient artificial organic photoelectric conversion systems. The systems consisted of the stacked structures of layers of porphyrin as a dye molecule, oxidation-suppressing layers, and plasmonic Cu arrayed electrodes. To accurately evaluate the effect of Cu nanoantenna on the porphyrin photocurrent, the production of Cu2O by the spontaneous oxidation of the electrode surfaces, which can act as a photoexcited species under visible light irradiation, was effectively suppressed by inserting the ultrathin linking layers consisting of 16-mercaptohexadecanoic acid, titanium oxide, and poly(vinyl alcohol) between the electrode surface and porphyrin molecules. The reflection spectra in an aqueous environment of the arrayed electrodes, which were prepared by thermally depositing Cu on two-dimensional colloidal crystals of silica with diameters of 160, 260, and 330 nm, showed clear reflection dips at 596, 703, and 762 nm, respectively, which are attributed to the excitation of localized surface plasmon resonance (LSPR). While the first dip lies within the wavelengths where the imaginary part of the Cu dielectric function is moderately large, the latter two dips lie within a region of a quite small imaginary part. Consequently, the LSPR excited at the red region provided a particularly large enhancement of porphyrin photocurrent at the Q-band (ca. 59-fold), compared to that on a Cu planar electrode. These results strongly suggest that the plasmonic Cu nanoantennae contribute to the substantial improvement of photoelectric conversion efficiency at the wavelengths, where the imaginary part of the dielectric function is small. PMID- 28001030 TI - Visible Light Responsive Liquid Crystal Polymers Containing Reactive Moieties with Good Processability. AB - Two types of novel reactive linear liquid crystal polymers (LLCPs) with different azotolene concentrations have been synthesized and processed into films and fibers by solution and melting processing methods. Then, the LLCPs in the obtained monodomain fiber and polydomain film were easily cross-linked with difunctional primary amines. The resulted cross-linked liquid crystal polymers (CLCPs) underwent reversible photoinduced bending and unbending behaviors in response to 445 and 530 nm visible light at room temperature, respectively. The post-cross-linking method provides a facile way to prepare the CLCP films and fibers with different shapes from LLCPs, which can be processed by traditional melting and solution methods. PMID- 28001031 TI - Molecular Dynamics Simulation and Experimental Studies of Gold Nanoparticle Templated HDL-like Nanoparticles for Cholesterol Metabolism Therapeutics. AB - High-density lipoprotein (HDL) plays an important role in the transport and metabolism of cholesterol. Mimics of HDL are being explored as potentially powerful therapeutic agents for removing excess cholesterol from arterial plaques. Gold nanoparticles (AuNPs) functionalized with apolipoprotein A-I and with the lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] have been demonstrated to be robust acceptors of cellular cholesterol. However, detailed structural information about this functionalized HDL AuNP is still lacking. In this study, we have used X-ray photoelectron spectroscopy and lecithin/cholesterol acyltransferase activation experiments together with coarse grained and all-atom molecular dynamics simulations to model the structure and cholesterol uptake properties of the HDL AuNP construct. By simulating different apolipoprotein-loaded AuNPs, we find that lipids are oriented differently in regions with and without apoA-I. We also show that in this functionalized HDL AuNP, the distribution of cholesteryl ester maintains a reverse concentration gradient that is similar to the gradient found in native HDL. PMID- 28001032 TI - Pt-Enhanced Mesoporous Ti3+/TiO2 with Rapid Bulk to Surface Electron Transfer for Photocatalytic Hydrogen Evolution. AB - Pt-doped mesoporous Ti3+ self-doped TiO2 (Pt-Ti3+/TiO2) is in situ synthesized via an ionothermal route, by treating metallic Ti in an ionic liquid containing LiOAc, HOAc, and a H2PtCl6 aqueous solution under mild ionothermal conditions. Such Ti3+-enriched environment, as well as oxygen vacancies, is proven to be effective for allowing the in situ reduction of Pt4+ ions uniformly located in the framework of the TiO2 bulk. The photocatalytic H2 evolution of Pt-Ti3+/TiO2 is significantly higher than that of the photoreduced Pt loaded on the original TiO2 and commercial P25. Such greatly enhanced activity is due to the various valence states of Pt (Ptn+, n = 0, 2, or 3), forming Pt-O bonds embedded in the framework of TiO2 and ultrafine Pt metal nanoparticles on the surface of TiO2. Such Ptn+-O bonds could act as the bridges for facilitating the photogenerated electron transfer from the bulk to the surface of TiO2 with a higher electron carrier density (3.11 * 1020 cm-3), about 2.5 times that (1.25 * 1020 cm-3) of the photoreduced Pt-Ti3+/TiO2 sample. Thus, more photogenerated electrons could reach the Pt metal for reducing protons to H2. PMID- 28001033 TI - Colorful Superamphiphobic Coatings with Low Sliding Angles and High Durability Based on Natural Nanorods. AB - Superamphiphobic coatings with low sliding angles (SAs) and high durability are very attractive in academic and industrial areas but are very challenging to invent. Here, inspired by Maya Blue, we report for the first time colorful superamphiphobic coatings with low SAs and high durability by the combination of natural palygorskite (PAL) nanorods and organosilanes. The coatings were characterized using a wide range of electron microscopy and other analytical techniques. Different from the previously reported methods, the micro/nanostructure of the superamphiphobic coatings were constructed by using the abundant natural PAL nanorods as the building blocks. Superamphiphobicity of the coatings depends on surface morphology and chemical composition of the coatings, which can be regulated by the concentrations of PAL and organosilanes. The colorful superamphiphobic coatings feature high contact angles and low SAs for various liquids, including water and n-decane. The coatings also showed high mechanical, environmental, chemical, and thermal durability even under harsh conditions. Moreover, the coatings in different colors with comparable superamphiphobicity and durability can be prepared using different cationic dyes applied onto various substrates via the same approach. The colorful superamphiphobic coatings with low SAs and high durability may be useful in various fields, e.g., anticreeping of oils and restoration of cultural relics. PMID- 28001034 TI - The O2-Evolving Complex of Photosystem II: Recent Insights from Quantum Mechanics/Molecular Mechanics (QM/MM), Extended X-ray Absorption Fine Structure (EXAFS), and Femtosecond X-ray Crystallography Data. AB - Efficient photoelectrochemical water oxidation may open a way to produce energy from renewable solar power. In biology, generation of fuel due to water oxidation happens efficiently on an immense scale during the light reactions of photosynthesis. To oxidize water, photosynthetic organisms have evolved a highly conserved protein complex, Photosystem II. Within that complex, water oxidation happens at the CaMn4O5 inorganic catalytic cluster, the so-called oxygen-evolving complex (OEC), which cycles through storage "S" states as it accumulates oxidizing equivalents and produces molecular oxygen. In recent years, there has been significant progress in understanding the OEC as it evolves through the catalytic cycle. Studies have combined conventional and femtosecond X-ray crystallography with extended X-ray absorption fine structure (EXAFS) and quantum mechanics/molecular mechanics (QM/MM) methods and have addressed changes in protonation states of MU-oxo bridges and the coordination of substrate water through the analysis of ammonia binding as a chemical analog of water. These advances are thought to be critical to understanding the catalytic cycle since protonation states regulate the relative stability of different redox states and the geometry of the OEC. Therefore, establishing the mechanism for substrate water binding and the nature of protonation/redox state transitions in the OEC is essential for understanding the catalytic cycle of O2 evolution. The structure of the dark-stable S1 state has been a target for X-ray crystallography for the past 15 years. However, traditional X-ray crystallography has been hampered by radiation-induced reduction of the OEC. Very recently, a revolutionary X-ray free electron laser (XFEL) technique was applied to PSII to reveal atomic positions at 1.95 A without radiation damage, which brought us closer than ever to establishing the ultimate structure of the OEC in the S1 state. However, the atom positions in this crystal structure are still not consistent with high-resolution EXAFS spectroscopy, partially due to the poorly resolved oxygen positions next to Mn centers and partial reduction due to extended dark adaptation of the sample. These inconsistencies led to the new models of the OEC with an alternative low oxidation state and raised questions on the protonation state of the cluster, especially the O5 MU-oxo bridge. This Account summarizes the most recent models of the OEC that emerged from QM/MM, EXAFS and femtosecond X-ray crystallography methods. When PSII in the S1 state is exposed to light, the S1 state is advanced to the higher oxidation states and eventually binds substrate water molecules. Identifying the substrate waters is of paramount importance for establishing the water-oxidation mechanism but is complicated by a large number of spectroscopically similar waters. Water analogues can, therefore, be helpful because they serve as spectroscopic markers that help to track the motion of the substrate waters. Due to a close structural and electronic similarity to water, ammonia has been of particular interest. We review three competing hypotheses on substrate water/ammonia binding and compile theoretical and experimental evidence to support them. Binding of ammonia as a sixth ligand to Mn4 during the S1 -> S2 transition seems to satisfy most of the criteria, especially the most compelling recent EPR data on D1-D61A mutated PSII. Such a binding mode suggests delivery of water from the "narrow" channel through a "carousel" rearrangement of waters around Mn4 upon the S2 -> S3 transition. An alternative hypothesis suggests water delivery through the "large" channel on the Ca side. However, both water delivery paths lead to a similar S3 structure, seemingly reaching consensus on the nature of the last detectable S-state intermediate in the Kok cycle before O2 evolution. PMID- 28001035 TI - Serotonin in Space: Understanding Single Fibers. AB - All brain regions contain fibers that store and release 5-hydroxytryptamine (5 HT, serotonin). Since these fibers often do not have well-defined trajectories, most studies have focused on their overall densities, a measure that can be associated with local 5-HT tone in heathy and diseased brains. However, the observed fiber densities are the consequence of the behavior of single fibers. Evidence is presented as to why understanding single-fiber trajectories is important for basic and clinical neuroscience. In particular, serotonergic fibers can be viewed as natural, readily detectable stochastic probes that sample the invisible microarchitecture of brain tissue. PMID- 28001036 TI - High-Performance Solution-Processed Single-Junction Polymer Solar Cell Achievable by Post-Treatment of PEDOT:PSS Layer with Water-Containing Methanol. AB - PEDOT: PSS (poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)) is widely used as the hole-transporting layer for fabrication of new-generation solar cells. Herein, we utilize water-containing methanol to post-treat the PEDOT:PSS surface, by which the insulating PSS component is partially washed out with the PEDOT-to-PSS weight ratio increasing from 1:6.79 to 1:2.93. As a result, the surface becomes more covered with the electrically conductive PEDOT nanodomains, and again the mean current of the conductive nanodomains increases slightly from 6.68 to 7.28 pA, as demonstrated with conductive atomic force microscopy images. The electrical conductivity of the bulk PEDOT:PSS layer increases from 5.51 * 10 4 to 4.04 * 10-2 S/cm. The improvement in the surface conductivity allows for more efficient collection of mobile holes with a bit higher value of the hole mobility (5.56 vs 6.78 * 10-4 cm2 V-1 s-1). The solution-processed single junction polymer solar cell fabricated on the treated PEDOT:PSS surface shows a higher mean short-circuit current-density (14.46 vs 16.48 mA cm-2) and, hence, a higher mean power conversion efficiency (8.23% vs 9.28%) than that on the untreated surface, as calculated from over 200 cells. PMID- 28001037 TI - Photoinitiation and Inhibition under Monochromatic Green Light for Storage of Colored 3D Images in Holographic Polymer-Dispersed Liquid Crystals. AB - Holographic photopolymer composites have garnered a great deal of interest in recent decades, not only because of their advantageous light sensitivity but also due to their attractive capabilities of realizing high capacity three-dimensional (3D) data storage that is long-term stable within two-dimensional (2D) thin films. For achieving high performance holographic photopolymer composites, it is of critical importance to implement precisely spatiotemporal control over the photopolymerization kinetics and gelation during holographic recording. Though a monochromatic blue light photoinitibitor has been demonstrated to be useful for improving the holographic performance, it is impractical to be employed for constructing holograms under green light due to the severe restriction of the First Law of Photochemistry, while holography under green light is highly desirable considering the relatively low cost of laser source and high tolerance to ambient vibration for image reconstruction. Herein, we disclose the concurrent photoinitiation and inhibition functions of the rose bengal (RB)/N-phenylglycine (NPG) system upon green light illumination, which result in significant enhancement of the diffraction efficiency of holographic polymer-dispersed liquid crystal (HPDLC) gratings from zero up to 87.6 +/- 1.3%, with an augmentation of the RB concentration from 0.06 * 10-3 to 9.41 * 10-3 mol L-1. Interestingly, no detectable variation of the phi1/2kp/kt1/2, which reflects the initiation efficiency and kinetic constants, is given when increasing the RB concentration. The radical inhibition by RBH* is believed to account for the greatly improved phase separation and enhanced diffraction efficiency, through shortening the weight-average polymer chain length and subsequently delaying the photopolymerization gelation. The reconstructed colored 3D images that are easily identifiable to the naked eye under white light demonstrate great potential to be applied for advanced anticounterfeiting. PMID- 28001038 TI - Scalable 3-D Carbon Nitride Sponge as an Efficient Metal-Free Bifunctional Oxygen Electrocatalyst for Rechargeable Zn-Air Batteries. AB - Rational design of efficient and durable bifunctional oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) electrocatalysts is critical for rechargeable metal-air batteries. Here, we developed a facile strategy for fabricating three-dimensional phosphorus and sulfur codoped carbon nitride sponges sandwiched with carbon nanocrystals (P,S-CNS). These materials exhibited high surface area and superior ORR and OER bifunctional catalytic activities than those of Pt/C and RuO2, respectively, concerning its limiting current density and onset potential. Further, we tested the suitability and durability of P,S-CNS as the oxygen cathode for primary and rechargeable Zn-air batteries. The resulting primary Zn-air battery exhibited a high open-circuit voltage of 1.51 V, a high discharge peak power density of 198 mW cm-2, a specific capacity of 830 mA h g-1, and better durability for 210 h after mechanical recharging. An extraordinary small charge-discharge voltage polarization (~0.80 V at 25 mA cm-2), superior reversibility, and stability exceeding prolonged charge-discharge cycles have been attained in rechargeable Zn-air batteries with a three-electrode system. The origin of the electrocatalytic activity of P,S-CNS was elucidated by density functional theory analysis for both oxygen reactions. This work stimulates an innovative prospect for the enrichment of rechargeable Zn-air battery viable for commercial applications such as armamentaria, smart electronics, and electric vehicles. PMID- 28001039 TI - Cell-Penetrating Cross-beta Peptide Assemblies with Controlled Biodegradable Properties. AB - Although self-assembled peptide nanostructures (SPNs) have shown potential as promising biomaterials, there is a potential problem associated with the extremely slow hydrolysis rate of amide bonds. Here, we report the development of cell-penetrating cross-beta SPNs with a controllable biodegradation rate. The designed self-assembling beta-sheet peptide incorporating a hydrolyzable ester bond (self-assembling depsipeptide; SADP) can be assembled into bilayer beta sandwich one-dimensional (1D) fibers similarly to conventional beta-sheet peptides. The rate of hydrolysis can be controlled by the pH, temperature, and structural characteristics of the ester unit. The 1D fiber of the SADP transforms into vesicle-like 3D structures when the hydrophilic cell-penetrating peptide segment is attached to the SADP segment. Efficient cell internalization of the 3D nanostructures was observed, and we verified the intracellular degradation and disassembly of the biodegradable nanostructures. This study illustrates the potential of biodegradable cross-beta SPNs and provides a valuable toolkit that can be used with self-assembling peptides. PMID- 28001040 TI - Nanocomposite Membranes via the Codeposition of Polydopamine/Polyethylenimine with Silica Nanoparticles for Enhanced Mechanical Strength and High Water Permeability. AB - A defect-free and stable selective layer is of critical significance for thin film composite membrane with excellent separation performance and service durability. We report a facial strategy for fabricating thin film nanocomposite (TFN) nanofltration membranes (NFMs) based on the codeposition of polydopamine, polyetheylenimine, and silica nanoparticles. Tripled water flux can be obtained from the TFN NFMs as compared with those NFMs without silica nanoparticles. This is ascribed to the improved wettability of the membrane surfaces and the enlarged pore sizes of the selective layer. The interfacial compatibility of the inorganic fillers and the polymer matrices can be enhanced by the electrostatic interactions of silica nanoparticles with polyethylenimine and the adhesive characteristics of polydopamine, resulting in a defect-free selective layer and then good rejection for both bivalent cations and neutral solutes. The rigid silica nanoparticles also improve the surface mechanical strength of the TFN NFMs effectively and lead to structural stability and compaction resistance during the long-term filtration process. PMID- 28001041 TI - Ultrasound Responsive Macrophase-Segregated Microcomposite Films for in Vivo Biosensing. AB - Ultrasound imaging is a safe, low-cost, and in situ method for detecting in vivo medical devices. A poly(methyl-2-cyanoacrylate) film containing 2 MUm boron doped, calcined, porous silica microshells was developed as an ultrasound imaging marker for multiple medical devices. A macrophase separation drove the gas-filled porous silica microshells to the top surface of the polymer film by controlled curing of the cyanoacrylate glue and the amount of microshell loading. A thin film of polymer blocked the wall pores of the microshells to seal air in their hollow core, which served as an ultrasound contrast agent. The ultrasound activity disappeared when curing conditions were modified to prevent the macrophase segregation. Phase segregated films were attached to multiple surgical tools and needles and gave strong color Doppler signals in vitro and in vivo with the use of a clinical ultrasound imaging instrument. Postprocessing of the simultaneous color Doppler and B-mode images can be used for autonomous identification of implanted surgical items by correlating the two images. The thin films were also hydrophobic, thereby extending the lifetime of ultrasound signals to hours of imaging in tissues by preventing liquid penetration. This technology can be used as a coating to guide the placement of implantable medical devices or used to image and help remove retained surgical items. PMID- 28001043 TI - Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor. AB - The dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [3H](+)-4-propyl-3,4,4a,5,6,10b hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO) revealed Ki values of 32 nM for the D2highR and 52 MUM for the D2lowR. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2highR were -9.46 and 8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2highR is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2highR conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R. PMID- 28001042 TI - Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron-Sulfur Cluster Biosynthesis. AB - Ferredoxins play an important role as an electron donor in iron-sulfur (Fe-S) cluster biosynthesis. Two ferredoxins, human mitochondrial ferredoxin 1 (FDX1) and human mitochondrial ferredoxin 2 (FDX2), are present in the matrix of human mitochondria. Conflicting results have been reported regarding their respective function in mitochondrial iron-sulfur cluster biogenesis. We report here biophysical studies of the interaction of these two ferredoxins with other proteins involved in mitochondrial iron-sulfur cluster assembly. Results from nuclear magnetic resonance spectroscopy show that both FDX1 and FDX2 (in both their reduced and oxidized states) interact with the protein complex responsible for cluster assembly, which contains cysteine desulfurase (NFS1), ISD11 (also known as LYRM4), and acyl carrier protein (Acp). In all cases, ferredoxin residues close to the Fe-S cluster are involved in the interaction with this complex. Isothermal titration calorimetry results showed that FDX2 binds more tightly to the cysteine desulfurase complex than FDX1 does. The reduced form of each ferredoxin became oxidized in the presence of the cysteine desulfurase complex when l-cysteine was added, leading to its conversion to l-alanine and the generation of sulfide. In an in vitro reaction, the reduced form of each ferredoxin was found to support Fe-S cluster assembly on ISCU; the rate of cluster assembly was faster with FDX2 than with FDX1. Taken together, these results show that both FDX1 and FDX2 can function in Fe-S cluster assembly in vitro. PMID- 28001044 TI - Formation and Controlled Growth of Bismuth Titanate Phases into Mesoporous Silica Nanoparticles: An Efficient Self-Sealing Nanosystem for UV Filtering in Cosmetic Formulation. AB - The application of nanosized inorganic UV filters in cosmetic field is limited by their high photocatalytic properties that could induce the degradation or dangerous transformation of the organic molecules in sunscreen formulations. To overcome this problem and simultaneously enlarge the window of filter's absorption, we propose the growth of bismuth titanates BixTiyOz into mesoporous silica nanoparticles (MSN). We investigated the chemical-physical properties by means of XRPD, TEM, UV-vis spectroscopy, N2 physisorption, XPS, and SF-ICP-MS analysis, while the influence on the environment was evaluated through photocatalytic tests. The growing process of this new nanosystem is discussed underlining the key role of the Bi3+ ion that, acting as a low-melting point agent for the silica framework, led to a self-sealing mechanism. The excellent UV shielding properties combined with a radical suppression of the photocatalytic activity make the proposed nanosystem a perfect candidate for the development of the next generation nanomaterials for sunscreen formulations. PMID- 28001045 TI - Are All-Solid-State Lithium-Ion Batteries Really Safe?-Verification by Differential Scanning Calorimetry with an All-Inclusive Microcell. AB - Although all-solid-state lithium-ion batteries (ALIBs) have been believed as the ultimate safe battery, their true character has been an enigma so far. In this paper, we developed an all-inclusive-microcell (AIM) for differential scanning calorimetry (DSC) analysis to clarify the degree of safety (DOS) of ALIBs. Here AIM possesses all the battery components to work as a battery by itself, and DOS is determined by the total heat generation ratio (DeltaH) of ALIB compared with the conventional LIB. When DOS = 100%, the safety of ALIB is exactly the same as that of LIB; when DOS = 0%, ALIB reaches the ultimate safety. We investigated two types of LIB-AIM and three types of ALIB-AIM. Surprisingly, all the ALIBs exhibit one or two exothermic peaks above 250 degrees C with 20-30% of DOS. The exothermic peak is attributed to the reaction between the released oxygen from the positive electrode and the Li metal in the negative electrode. Hence, ALIBs are found to be flammable as in the case of LIBs. We also attempted to improve the safety of ALIBs and succeeded in decreasing the DOS down to ~16% by incorporating Ketjenblack into the positive electrode as an oxygen scavenger. Based on DeltaH as a function of voltage window, a safety map for LIBs and ALIBs is proposed. PMID- 28001046 TI - Translocation of an Intracellular Protein via Peptide-Directed Ligation. AB - Ligand-directed reactions allow chemical transformations at very low reactant concentrations and can thus provide access to efficient approaches for the post translational modification of proteins. The development of these proximity induced reactions is hampered by the number of appropriate ligands and the lack of design principles. Addressing these limitations, we report a proximity-induced labeling system which applies a moderate affinity peptide ligand. The design process was structure-guided and supported by molecular dynamics simulations. We show that selective protein labeling can be performed inside living cells enabling the subcellular translocation of a protein via ligand-directed chemistry for the first time. PMID- 28001047 TI - Correction to Peptide Tag-Induced Horseradish Peroxidase-Mediated Preparation of a Streptavidin-Immobilized Redox-Sensitive Hydrogel. PMID- 28001048 TI - Importance of the Active Site "Canopy" Residues in an O2-Tolerant [NiFe] Hydrogenase. AB - The active site of Hyd-1, an oxygen-tolerant membrane-bound [NiFe]-hydrogenase from Escherichia coli, contains four highly conserved residues that form a "canopy" above the bimetallic center, closest to the site at which exogenous agents CO and O2 interact, substrate H2 binds, and a hydrido intermediate is stabilized. Genetic modification of the Hyd-1 canopy has allowed the first systematic and detailed kinetic and structural investigation of the influence of the immediate outer coordination shell on H2 activation. The central canopy residue, arginine 509, suspends a guanidine/guanidinium side chain at close range above the open coordination site lying between the Ni and Fe atoms (N-metal distance of 4.4 A): its replacement with lysine lowers the H2 oxidation rate by nearly 2 orders of magnitude and markedly decreases the H2/D2 kinetic isotope effect. Importantly, this collapse in rate constant can now be ascribed to a very unfavorable activation entropy (easily overriding the more favorable activation enthalpy of the R509K variant). The second most important canopy residue for H2 oxidation is aspartate 118, which forms a salt bridge to the arginine 509 headgroup: its mutation to alanine greatly decreases the H2 oxidation efficiency, observed as a 10-fold increase in the potential-dependent Michaelis constant. Mutations of aspartate 574 (also salt-bridged to R509) to asparagine and proline 508 to alanine have much smaller effects on kinetic properties. None of the mutations significantly increase sensitivity to CO, but neutralizing the expected negative charges from D118 and D574 decreases O2 tolerance by stabilizing the oxidized resting NiIII-OH state ("Ni-B"). An extensive model of the catalytic importance of residues close to the active site now emerges, whereby a conserved gas channel culminates in the arginine headgroup suspended above the Ni and Fe. PMID- 28001049 TI - Nitrogen is Not a 'House of Cards'. PMID- 28001050 TI - Strained Cyclic Disulfides Enable Cellular Uptake by Reacting with the Transferrin Receptor. AB - In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure efficient cellular uptake and intracellular distribution of fully unprotected peptides. We apply this new delivery method to induce apoptotic response in cancer cells using long (up to 20mer) BH3 domain peptides. Moreover, to understand the molecular mechanism of the cellular uptake, we perform chemical proteomics experiments and identify the direct molecular targets of the asparagusic acid tag. Our findings document covalent bond formation between the asparagusic acid moiety and the cysteines 556 and 558 on the surface of the transferrin receptor resulting in subsequent endocytic uptake of the payload. We believe that the small size, low cellular toxicity and the efficient transferrin receptor-mediated uptake render the AspA tag highly attractive for various life science applications. PMID- 28001051 TI - Soil-Bacterium Compatibility Model as a Decision-Making Tool for Soil Bioremediation. AB - Bioremediation of organic pollutant contaminated soil involving bioaugmentation with dedicated bacteria specialized in degrading the pollutant is suggested as a green and economically sound alternative to physico-chemical treatment. However, intrinsic soil characteristics impact the success of bioaugmentation. The feasibility of using partial least-squares regression (PLSR) to predict the success of bioaugmentation in contaminated soil based on the intrinsic physico chemical soil characteristics and, hence, to improve the success of bioaugmentation, was examined. As a proof of principle, PLSR was used to build soil-bacterium compatibility models to predict the bioaugmentation success of the phenanthrene-degrading Novosphingobium sp. LH128. The survival and biodegradation activity of strain LH128 were measured in 20 soils and correlated with the soil characteristics. PLSR was able to predict the strain's survival using 12 variables or less while the PAH-degrading activity of strain LH128 in soils that show survival was predicted using 9 variables. A three-step approach using the developed soil-bacterium compatibility models is proposed as a decision making tool and first estimation to select compatible soils and organisms and increase the chance of success of bioaugmentation. PMID- 28001052 TI - Modeling Remobilization of Neonicotinoid Residues from Tree Foliage in Streams-A Relevant Exposure Pathway in Risk Assessment? AB - Systemic neonicotinoid insecticides are increasingly used as a crop protection measure to suppress insect pests on trees. However, senescent foliage falling from treated trees represents a rarely studied pathway through which neonicotinoids may enter nontarget environments, e.g., surface waters. To estimate risk posed by this pathway, neonicotinoid residues were analyzed in foliage from black alder trees treated with one of three neonicotinoid insecticides (imidacloprid, thiacloprid, or acetamiprid) at five concentrations, each ranging from 0.0375-9.6 g active ingredient/cm trunk diameter at breast height (n = 3). Foliar residues measured at the time of leaf fall were used as input parameters for a model predicting imidacloprid water concentrations over a 100-m-long stream stretch as a consequence of remobilization from introduced foliage (input: 600 g foliage/m2 containing 80 MUg imidacloprid/g). The water concentration (up to ~250 ng/L) predicted by the model exceeded the recently proposed Maximum Permissible Concentration of 8.3 ng/L for ~6.5 days. Moreover, dietary uptake was identified as an additional exposure route for aquatic organisms. The alternative pathway (i.e., introduction via leaf fall) and exposure route (i.e., dietary uptake) associated with the systemic nature of neonicotinoids should be accounted for during their registration process in order to safeguard ecosystem integrity. PMID- 28001053 TI - Low-Dose Effects: Nonmonotonic Responses for the Toxicity of a Bacillus thuringiensis Biocide to Daphnia magna. AB - Currently, there is a trend toward an increasing use of biopesticides assumed to be environmentally friendly, such as Bacillus thuringiensis (Bt). Studies of the Bt toxicity to nontarget organisms have reported low effects at high exposure levels, which is interpreted as indicating negligible risk to nontarget organisms. We investigated the response of the nontarget organism Daphnia magna to waterborne DiPel ES, a globally used Bt formulation. Neonates and adults were exposed for 48 h to a wide range of concentrations, and immobilization and mortality were monitored. Whole body biomarkers (body weight, protein, chitobiase, catalase, xenobiotic metabolism, and acetylcholinesterase) were measured in the adults. The immobilization and mortality of the neonates were affected in a nonmonotonic and inverted U-shaped pattern with EC50s that were ~105-fold lower than those reported by the manufacturer. The immobilization of adults demonstrated a similar pattern, but significant mortality was not observed. The biomarker results revealed multiphasic dose-response curves, which suggested toxicity mechanisms that affected various physiological pathways. The main particle size in exposure media was in the size range of bacterial spores and crystal toxins. However, the chemical heterogeneity was nonmonotonic, with a change in the phase at the maximum of toxicity (~5 MUL L-1), which might explain the observed nonmonotonic effects. These results demonstrate the vulnerability of a nontarget organism to a biopesticide that is considered to be safe, while challenging the universal applicability of the central ecotoxicological assumption of monotonicity. PMID- 28001054 TI - Effect of Simultaneous Amphibian Exposure to Pesticides and an Emerging Fungal Pathogen, Batrachochytrium dendrobatidis. AB - Amphibian declines have been linked to numerous factors, including pesticide use and the fungal pathogen Batrachochytrium dendrobatidis (Bd). Moreover, research has suggested a link between amphibian sensitivity to Bd and pesticide exposure. We simultaneously exposed postmetamorphic American toads (Anaxyrus americanus), western toads (A. boreas), spring peepers (Pseudacris crucifer), Pacific treefrogs (P. regilla), leopard frogs (Lithobates pipiens), and Cascades frogs (Rana cascadae) to a factorial combination of two pathogen treatments (Bd+, Bd-) and four pesticide treatments (control, ethanol vehicle, herbicide mixture, and insecticide mixture) for 14 d to quantify survival and infection load. We found no interactive effects of pesticides and Bd on anuran survival and no effects of pesticides on infection load. Mortality following Bd exposure increased in spring peepers and American toads and was dependent upon snout-vent length in western toads, American toads, and Pacific treefrogs. Previous studies reported effects of early sublethal pesticide exposure on amphibian Bd sensitivity and infection load at later life stages, but we found simultaneous exposure to sublethal pesticide concentrations and Bd had no such effect on postmetamorphic juvenile anurans. Future research investigating complex interactions between pesticides and Bd should employ a variety of pesticide formulations and Bd strains and follow the effects of exposure throughout ontogeny. PMID- 28001055 TI - Tandem Addition of Phosphite Nucleophiles Across Unsaturated Nitrogen-Containing Systems: Mechanistic Insights on Regioselectivity. AB - The addition of phosphite nucleophiles across linear unsaturated imines is a powerful and atom-economical methodology for the synthesis of aminophosphonates. These products are of interest from both a biological and a synthetic point of view: they act as amino acid transition state analogs and Horner-Wadsworth-Emmons reagents, respectively. In this work the reaction between dialkyl trimethylsilyl phosphites and alpha,beta,gamma,delta-diunsaturated imines was evaluated as a continuation of our previous efforts in the field. As such, the first conjugate 1,6-addition of a phosphite nucleophile across a linear unsaturated N-containing system is reported herein. Theoretical calculations were performed to rationalize the observed regioselectivites and to shed light on the proposed mechanism. PMID- 28001056 TI - Site-Selective Oxidative Coupling Reactions for the Attachment of Enzymes to Glass Surfaces through DNA-Directed Immobilization. AB - Enzymes are able to maintain remarkably high selectivity toward their substrates while still retaining high catalytic rates. By immobilizing enzymes onto surfaces we can heterogenize these biological catalysts, making it practical to study, use, and combine them in an easily controlled system. In this work, we developed a platform that allows for the simple and oriented immobilization of proteins through DNA-directed immobilization. First, we modified a glass surface with single-stranded DNA. We then site-selectively attached the complementary DNA strand to the N-terminus of a protein. Both DNA modifications were carried out using an oxidative coupling strategy, and the DNA strands served as easily tunable and reversible chemical handles to hybridize the protein-DNA conjugates onto the surface. We have used the aldolase enzyme as a model protein to conduct our studies. We characterized each step of the protein immobilization process using fluorescent reporters as well as atomic force microscopy. We also conducted activity assays on the surfaces with DNA-linked aldolase to validate that, despite being modified with DNA and undergoing subsequent immobilization, the enzyme was still able to retain its catalytic activity and the surfaces were reusable in subsequent cycles. PMID- 28001057 TI - Emissions and Economics of Behind-the-Meter Electricity Storage. AB - Annual installations of behind-the-meter (BTM) electric storage capacity are forecast to eclipse grid-side electrochemical storage by the end of the decade. Here, we characterize the economic payoff and regional emission consequences of BTM storage without colocated generation under different tariff conditions, battery characteristics, and ownership scenarios using metered loads for several hundred commercial and industrial customers. Net emissions are calculated as increased system emissions from charging minus avoided emissions from discharging. Net CO2 emissions range from 75 to 270 kg/MWh of delivered energy depending on location and ownership perspective, though in New York, these emissions can be reduced with careful tariff design. Net NOx emissions range from -0.13 to 0.24 kg/MWh, and net SO2 emissions range from -0.01 to 0.58 kg/MWh. Emission rates are driven primarily by energy losses, not by the difference between marginal emission rates during battery charging and discharging. Economics are favorable for many buildings in regions with high demand charges like California and New York, even without subsidies. Future penetration into regions with average charges like Pennsylvania will depend greatly on installation cost reductions and wholesale prices for ancillary services. PMID- 28001058 TI - pH-Triggered, Macromolecule-Sized Poration of Lipid Bilayers by Synthetically Evolved Peptides. AB - pH-triggered membrane-permeabilizing peptides could be exploited in a variety of applications, such as to enable cargo release from endosomes for cellular delivery, or as cancer therapeutics that selectively permeabilize the plasma membranes of malignant cells. Such peptides would be especially useful if they could enable the movement of macromolecules across membranes, a rare property in membrane-permeabilizing peptides. Here we approach this goal by using an orthogonal high-throughput screen of an iterative peptide library to identify peptide sequences that have the following two properties: (i) little synthetic lipid membrane permeabilization at physiological pH 7 at high peptide concentration and (ii) efficient formation of macromolecule-sized defects in synthetic lipid membranes at acidic pH 5 and low peptide concentration. The peptides we selected are remarkably potent macromolecular sized pore-formers at pH 5, while having little or no activity at pH 7, as intended. The action of these peptides likely relies on tight coupling between membrane partitioning, alpha-helix formation, and electrostatic repulsions between acidic side chains, which collectively drive a sharp pH-triggered transition between inactive and active configurations with apparent pKa values of 5.5-5.8. This work opens new doors to developing applications that utilize peptides with membrane permeabilizing activities that are triggered by physiologically relevant decreases in pH. PMID- 28001059 TI - Transition Metal Dichalcogenide Atomic Layers for Lithium Polysulfides Electrocatalysis. AB - Lithium-sulfur (Li-S) chemistry is projected to be one of the most promising for next-generation battery technology, and controlling the inherent "polysulfide shuttle" process has become a key research topic in the field. Regulating intermediary polysulfide dissolution by understanding the metamorphosis is essential for realizing stable and high-energy-density Li-S batteries. As of yet, a clear consensus on the basic surface/interfacial properties of the sulfur electrode has not been achieved, although the catalytic phenomenon has been shown to result in enhanced cell stability. Herein, we present evidence that the polysulfide shuttle in a Li-S battery can be stabilized by using electrocatalytic transition metal dichalcogenides (TMDs). Physicochemical transformations at the electrode/electrolyte interface of atomically thin monolayer/few-layer TMDs were elucidated using a combination of spectroscopic and microscopic analysis techniques. Preferential adsorption of higher order liquid polysulfides and subsequent conversion to lower order solid species in the form of dendrite-like structures on the edge sites of TMDs have been demonstrated. Further, detailed electrochemical properties such as activation energy, exchange current density, rate capabilities, cycle life, etc. have been investigated by synthesizing catalytically active nanostructured TMDs in bulk quantity using a liquid-based shear-exfoliation method. Unveiling a specific capacity of 590 mAh g-1 at 0.5 C rate and stability over 350 cycles clearly indicates yet another promising application of two-dimensional TMDs. PMID- 28001060 TI - Biosynthesis of Antroquinonol and 4-Acetylantroquinonol B via a Polyketide Pathway Using Orsellinic Acid as a Ring Precursor in Antrodia cinnamomea. AB - Antroquinonol (AQ) and 4-acetylantroquinonol B (4-AAQB), isolated from the mycelium of Antrodia cinnamomea, have a similar chemical backbone to coenzyme Q (CoQ). Based on the postulation that biosynthesis of both AQ and 4-AAQB in A. cinnamomea starts from the polyketide pathway, we cultivated this fungus in a culture medium containing [U-13C]oleic acid, and then we analyzed the crude extracts of the mycelium using UHPLC-MS. We found that AQ and 4-AAQB follow similar biosynthetic sequences as CoQ. Obvious [13C2] fragments on the ring backbone were detected in the mass spectrum for [13C2]AQ, [13C2]4-AAQB, and their [13C2] intermediates found in this study. The orsellinic acid, formed from acetyl CoA and malonyl-CoA via the polyketide pathway, was found to be a novel benzoquinone ring precursor for AQ and 4-AAQB. The identification of endogenously synthesized farnesylated intermediates allows us to postulate the routes of AQ and 4-AAQB biosynthesis in A. cinnamomea. PMID- 28001061 TI - Atomistic Mechanisms Underlying Selectivities in C(1) and C(2) Products from Electrochemical Reduction of CO on Cu(111). AB - Practical environmental and energy applications of the electrochemical reduction of CO2 to chemicals and fuels require far more efficient and selective electrocatalysts beyond the only working material Cu, but the wealth of experimental data on Cu can serve to validate any proposed mechanisms. To provide design guidelines, we use quantum mechanics to predict the detailed atomistic mechanisms responsible for C1 and C2 products on Cu. Thus, we report the pH dependent routes to the major products, methane and ethylene, and identify the key intermediates where branches to methanol, ketene, ethanol, acetylene, and ethane are kinetically blocked. We discovered that surface water on Cu plays a key role in the selectivity for hydrocarbon products over the oxygen-containing alcohol products by serving as a strong proton donor for electrochemical dehydration reductions. We suggest new experiments to validate our predicted mechanisms. PMID- 28001062 TI - Effects of Imidazole-Type Ligands in CuI/TEMPO-Mediated Aerobic Alcohol Oxidation. AB - Selective aerobic oxidation of benzyl alcohol to benzaldehyde by a (bpy)CuI(IM)/TEMPO catalyst (IM represents differently substituted imidazoles) has been studied by simultaneous operando electron paramagnetic resonance/UV vis/attentuated total reflectance infrared spectroscopy in combination with cyclic voltammetry to explore the particular role of imidazole in terms of ligand and/or base as well as of its substitution pattern on the catalytic performance. For molar ratios of IM/Cu >= 2, a (bpy)CuI/II(IM)a(IM)b complex is formed, in which the Cu-N distances and/or angles for the two IM ligands a and b are different. The coordination of a second IM molecule boosts the oxidation of CuI to CuII and, thus, helps to activate O2 by electron transfer from CuI to O2. The rates of CuI oxidation and CuII reduction and, thus, the rates of benzaldehyde formation depend on R of the R-N moiety in the IM ligand. Oxidation is fastest for R = H and alkyl, while reduction is slowest for R = H. The CuI/CuII interplay leads to decreasing total benzaldehyde formation rates in the order R (I+ effect) > R (conjugated system) > R = H. PMID- 28001063 TI - More Than 50 Years after Its Discovery in SiO2 Octahedral Coordination Has Also Been Established in SiS2 at High Pressure. AB - SiO2 exhibits a high-pressure-high-temperature polymorphism, leading to an increase in silicon coordination number and density. However, for the related compound SiS2 such pressure-induced behavior has not been observed with tetrahedral coordination yet. All four crystal structures of SiS2 known so far contain silicon with tetrahedral coordination. In the orthorhombic, ambient pressure phase these tetrahedra share edges and achieve only low space filling and density. Up to 4 GPa and 1473 K, three phases can be quenched as metastable phases from high-pressure high-temperature to ambient conditions. Space occupancy and density are increased first by edge and corner sharing and then by corner sharing alone. The structural situation of SiS2 up to the current study resembles that of SiO2 in 1960: Then, in its polymorphs only Si-O4 tetrahedra were known. But in 1961, a polymorph with rutile structure was discovered: octahedral Si-O6 coordination was established. Now, 50 years later, we report here on the transition from 4-fold to 6-fold coordination in SiS2, the sulfur analogue of silica. PMID- 28001064 TI - Recent Advances in Scaffold Hopping. AB - Scaffold hopping refers to the computer-aided search for active compounds containing different core structures, which is a topic of high interest in medicinal chemistry. Herein foundations and caveats of scaffold hopping approaches are discussed and recent methodological developments analyzed. Despite the conceptual prevalence of pharmacophore methods for scaffold hopping, a variety of computational approaches have been successfully applied. In recent years, scaffold hopping calculations are increasingly carried out at the level of scaffolds rather than compounds, and scaffold queries increasingly abstract from chemical structures. In addition, relationships between compounds, scaffolds, and biological activities are beginning to be globally explored, beyond individual applications. Going forward, computational scaffold hopping is thought to benefit from the consideration of new scaffold concepts and the development of methods capable of guiding search calculations toward scaffolds that are likely to represent potent compounds. PMID- 28001065 TI - Prunella vulgaris L., an Edible and Medicinal Plant, Attenuates Scopolamine Induced Memory Impairment in Rats. AB - Prunella vulgaris L. is as a major plant in the Chinese traditional functional beverage Guangdong herbal tea for the treatment of fevers, diarrhea, and sore mouth. In this study, ethyl acetate parts of aqueous extracts from P. vulgaris L. (EtOAc-APV) were found to demonstrate potent acetylcholinesterase (AChE) inhibition in vitro. Therefore, this study was designed to further investigate the effects of EtOAc-APV on scopolamine (SCOP)-induced aging rats. Male Wistar rats were randomly divided into four groups (n = 12) and given orally by gavage EtOAc-APV (100 mg/kg) for 3 weeks. SCOP (1 mg/kg, ip) was administered to rats 30 min before starting behavioral tests consecutively for 3 days. EtOAc-APV could attenuate SCOP-induced brain senescence in rats by improving behavioral performance and decreasing brain cell damage, which was associated with a notable reduction in AChE activity and MDA level, as well as an increase in SOD and GPx activities. Additionally, EtOAc-APV administration could reduce the expression of NF-kappaB and GFAP, which showed an anti-neuroinflammatory effect on the SCOP treated rat. Overall, the current study highlights P. vulgaris L. as an antidementia dietary supplement. PMID- 28001066 TI - Preparation of S-Allylcysteine-Enriched Black Garlic Juice and Its Antidiabetic Effects in Streptozotocin-Induced Insulin-Deficient Mice. AB - S-Allylcysteine (SAC), produced in large amounts during the aging process of garlic via enzymatic hydrolysis, is known as a key compound responsible for the multiple pharmacological activities of aged black garlic. This study investigated the effects of enzyme- and high hydrostatic pressure (HHP)-assisted extraction on the content of the bioactive compounds, including SAC, in black garlic juice (BGJ) and evaluated the antidiabetic effects of SAC-enriched BGJ in streptozotocin (STZ)-treated mice. The aging process increased the contents of SAC, total polyphenols, and total flavonoids in garlic juice. More importantly, pretreatment of pectinase cocktail with HHP resulted in a greater increase in those compounds during aging. Enzyme-treated BGJ reduced hyperglycemia and improved islet architecture and beta-cell function in STZ-treated mice. Moreover, these effects were more potent than those of BGJ prepared by the conventional aging process. These findings provide useful information for the production of black garlic with improved bioactivities. PMID- 28001067 TI - Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves. AB - Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A-F (6-11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15-21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2-40 MUM, and against HEK293 mammalian cells (IC50 2.7-3.6 MUM). While the crude extract was inactive at 100 MUg/mL against the MDA-MB-231 triple negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03-8.2 MUM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 MUM) and cytotoxic (IC50 0.03 MUM, MDA MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 MUM. PMID- 28001068 TI - Excited-State Intramolecular Proton Transfer and Global Aromaticity. AB - A general survey of excited-state intramolecular proton transfer (ESIPT) processes was made from the viewpoint of global aromaticity. For most ESIPT processes studied, a tautomeric product in the first excited electronic state was found to have a larger topological resonance energy (TRE) than the reactant in the same excited state. Conversely, if a transient tautomer is much less aromatic in the excited state than the reactant, an appreciable aromaticity-imposed energy barrier to the reaction will result. Thus, excited-state aromaticity is a very important factor, although not a definitive one, in determining the allowedness of ESIPT. PMID- 28001069 TI - Ligand Binding Swaps between Soft Internal Modes of alpha,beta-Tubulin and Alters Its Accessible Conformational Space. AB - The dynamic instability of the microtubule originates from the conformational switching of its building block, that is, the alpha, beta-tubulin dimer. Ligands occupying the interface of the alpha-beta dimer bias the switch toward the disintegration of the microtubule, which in turn controls the cell division. A little loop of tubulin is structurally encoded as a biophysical "gear" that works by changing its structural packing. The consequence of such change propagates to the quaternary level to alter the global dynamics and is reflected as a swapping between the relative contributions of dominating internal modes. Simulation shows that there is an appreciable separation between the conformational space accessed by the liganded and unliganded systems; the clusters of conformations differ in their intrinsic tendencies to "bend" and "twist". The correlation between the altered breathing modes and conformational space rationally hypothesizes a mechanism of straight-bent interconversion of the system. In this mechanism, a ligand is understood to bias the state of the "gear" that detours the conformational equilibrium away from its native preference. Thus, a fundamental biophysical insight into the mechanism of the conformational switching of tubulin is presented as a multiscale process that also shows promise to yield newer concept of ligand design. PMID- 28001070 TI - Solvation Dynamics and Proton Transfer in Diethylaminohydroxyflavone. AB - 4'-N,N-Diethylamino-3-hydroxyflavone (DEAHF) exhibits dual fluorescence in most solvents as a result of a rapid excited-state intramolecular proton transfer reaction. The high sensitivity of its dual emission to solvent polarity and hydrogen bonding make DEAHF of interest as a ratiometric fluorescence sensor. In addition, prior work has suggested that the rate of this proton transfer should depend on solvent relaxation in an unusual manner. It has been proposed that rapid solvation of the initially excited reactant should retard reaction. The present work tests this idea by using femtosecond Kerr-gated emission spectroscopy to measure the reaction kinetics of DEAHF in mixtures of propylene carbonate (PC) + acetonitrile (ACN). This mixture was chosen to maintain constant solvent polarity and thereby constant reaction energies while varying solvation times ~10-fold with composition. The reaction kinetics observed in these mixtures are multiexponential, consisting of resolvable components of ~2 and ~30 ps and a small fraction of reaction faster than detectable by the 400 fs resolution of the experiment. Average reaction times increase by approximately a factor of 2 as a function of ACN mole fraction, primarily as a result of changes to the slower kinetic component. This trend is opposite to the composition dependence of solvation times, thereby supporting the unusual role of polar solvation dynamics in this proton transfer. In n-alkane solvents, where electrostatic coupling is minimized, frictional properties of the solvent do not influence reaction rates. PMID- 28001071 TI - Tensile Fracture of Molecular Glasses Studied by Differential Scanning Calorimetry: Reduction of Heat Capacity by Lateral Constraint. AB - Molecular glasses indomethacin and ortho-terphenyl were formed and fractured by cooling a liquid on a less thermally expansive substrate. In-plane tension was created by the mismatch of thermal expansion coefficients and accumulated to cause catastrophic network fracture. Differential scanning calorimetry was used to characterize the process. The heat of fracture exceeds by 10 times the strain energy released, and matches the excess enthalpy stored by an elastic film that is cooled under lateral constraint. The constrained film has a smaller heat capacity than a free-standing film, by approximately 0.01 J/g/K or 1%. This allows the constrained film to reach higher enthalpy on cooling and the excess enthalpy is released at fracture. PMID- 28001072 TI - Revealing the Size-Dependent d-d Excitations of Cobalt Nanoparticles Using Soft X ray Spectroscopy. AB - Cobalt-based catalysts are widely used to produce liquid fuels through the Fischer-Tropsch (FT) reaction. However, the cobalt nanocatalysts can exhibit intriguing size-dependent activity whose origin remains heavily debated. To shed light on this issue, the electronic structures of cobalt nanoparticles with size ranging from 4 to 10 nm are studied using soft X-ray absorption (XAS) and resonant inelastic X-ray scattering (RIXS) spectroscopies. The RIXS measurements reveal the significant size-dependent d-d excitations, from which we determine that the crystal-field splitting energy 10Dq changes from 0.6 to 0.9 eV when the particle size is reduced from 10 to 4 nm. The finding that larger Co nanoparticles have smaller 10Dq value is further confirmed by the Co L-edge RIXS simulations with atomic multiplet code. Our RIXS results demonstrate a stronger Co-O bond in smaller Co nanoparticles, which brings in further insight into their size-dependent catalytic performance. PMID- 28001073 TI - Calculation of Positron Binding Energies and Electron-Positron Annihilation Rates for Atomic Systems with the Reduced Explicitly Correlated Hartree-Fock Method in the Nuclear-Electronic Orbital Framework. AB - Although the binding of a positron to a neutral atom has not been directly observed experimentally, high-level theoretical methods have predicted that a positron will bind to a neutral atom. In the present study, the binding energies of a positron to lithium, sodium, beryllium, and magnesium, as well as the electron-positron annihilation rates for these systems, are calculated using the reduced explicitly correlated Hartree-Fock (RXCHF) method within the nuclear electronic orbital (NEO) framework. Due to the lack of explicit electron-positron correlation, NEO Hartree-Fock and full configuration interaction calculations with reasonable electronic and positronic basis sets do not predict positron binding to any of these atoms. In contrast, the RXCHF calculations predict positron binding energies and electron-positron annihilation rates in qualitative agreement with previous highly accurate but computationally expensive stochastic variational method calculations. These results illustrate that the RXCHF method can successfully describe the binding of a positron to a neutral species with no dipole moment. Moreover, the RXCHF method will be computationally tractable for calculating positron binding to molecular systems. The RXCHF approach offers a balance of accuracy and computational tractability for studying these types of positronic systems. PMID- 28001074 TI - Mesoscopic Correlation Functions in Heterogeneous Ionic Liquids. AB - A common feature of ionic liquids composed of cations with long aliphatic side chains is structural heterogeneities on the nanometer length scale. This so called microphase separation arises from the clustering of aliphatic moieties. The temperature dependence of the liquid bulk structure was studied by small angle X-ray and neutron scattering for a set of methylimidazolium ([C18C1im]+, [C22C1im]+) based ionic liquids with tris(pentafluoroethyl)trifluorophosphate ([FAP]-), bis(trifluoromethylsulfonyl)imide ([NTf2]-), and bis(nonafluorobutylsulfonyl)imide ([NNf2]-) anions. The experimental data is quantitatively analyzed using a generalized Teubner-Strey model. Discussion of the resulting periodicity d and correlation length xi shows that the structural heterogeneities are governed by the interplay between the alkyl chain length, the geometry of the anion, and entropic effects. Connections between the mesoscopic correlation functions, density, and entropy of fusion are discussed in comparison to alcohols. The observed dependencies allow predictions on the mesoscopic correlation functions based on macroscopic bulk quantities. PMID- 28001075 TI - Microsolvation within the Systematic Molecular Fragmentation by Annihilation Approach. AB - We have applied the systematic molecular fragmentation by annihilation (SMFA) fragmentation technique to glycine and DNA base pairs in water clusters, systems for which explicit solvation is believed to be important. The SMFA method was found to be capable of describing the structures, especially in handling the complexity of hydrogen bonding, with energies produced being comparable with those from full molecule results. Thus, the ability to break down large calculations into a manageable time without loss of accuracy shows promise for application to real biological systems for which these effects are relevant. PMID- 28001076 TI - Simulation of Vertical Surfactant Distributions in Drying Latex Films. AB - Following our previous contribution ( Gromer, A. et al. Langmuir 2015 , 31 , 10983 - 10994 ) presenting a new simulation tool devoted to particle distributions in drying latex films, this Article describes the prediction of surfactant concentration profiles in the vertical direction during the complete film formation process. The simulation is inspired by cellular automata and equations by Routh and co-workers. It includes effects that were not considered before: surfactant convection by water and surfactant desorption upon particle deformation. It is based on five parameters describing the nature of the polymer/surfactant system and on film formation conditions. In particular, the viscoelastic properties of the polymer were taken into account through the lambda parameter introduced by Routh and Russel. Results show the importance of convection by water and the influence of the particular deformation mechanism on the final surfactant distribution. Excesses or depletions can be predicted either on the surface or on the substrate sides, in qualitative agreement with the numerous existing experimental studies. The complex interplay between parameters governing surfactant distributions makes the results unpredictable without the help of such a simulation tool. Therefore, it should be of interest to both industrial and academic scientists. PMID- 28001077 TI - Interaction Forces between Lipid Rafts. AB - Cellular membranes containing sphingolipids and cholesterol have been shown to self-organize into lipid rafts-specialized domains that host integral membrane proteins and modulate the bioactivity of cells. In this work, force-distance profiles between raft membranes in the liquid-ordered phase consisting of singly unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a complex mixture of brain sphingomyelin (BSM), and cholesterol were measured using the surface force apparatus (SFA). Two distinct force profiles were detected corresponding to uniform raft membranes and raft membranes with a higher level of topological membrane defects (heterogeneous) as corroborated by atomic force microscopy (AFM) scans. In all cases a weak, long-range electrostatic repulsion was observed with some variation in the surface charge density. The variation in electrostatic repulsion was attributed to charged lipid species primarily from the constituent lipids in the BSM mixture. The adhesion between the uniform raft membranes was comparable to our previous work with pure component, liquid-ordered POPC-DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine)-cholesterol membranes. Raft membranes with more topological defects adhered more strongly owing to hydrophobic attraction between exposed acyl chains. Even though the rafts were in the liquid-ordered phase and membrane defects were present in the contact region, the raft membranes were stable, and no structural rearrangement was observed throughout the measurements. Our findings demonstrate that liquid-ordered membranes are stable to mechanical loading and not particularly sensitive to compositional variation. PMID- 28001078 TI - Effect of Ablation Rate on the Microstructure and Electrochromic Properties of Pulsed-Laser-Deposited Molybdenum Oxide Thin Films. AB - Molybdenum trioxide (MoO3) is a well-known electrochromic material. In the present work, n-type alpha-MoO3 thin films with both direct and indirect band gaps were fabricated by varying the laser repetition (ablation) rate in a pulsed laser deposition (PLD) system at a constant reactive O2 pressure. The electrochromic properties of the films are compared and correlated to the microstructure and molecular-level coordination. Mixed amorphous and textured crystallites evolve at the microstructural level. At the molecular level, using NMR and EPR, we show that the change in the repetition rate results in a variation of the molybdenum coordination with oxygen: at low repetition rates (2 Hz), the larger the octahedral coordination, and greater the texture, whereas at 10 Hz, tetrahedral coordination is significant. The anion vacancies also introduce a large density of defect states into the band gap, as evidenced by XPS studies of the valence band and supported by DFT calculations. The electrochromic contrast improved remarkably by almost 100% at higher repetition rates whereas the switching speed decreased by almost 6-fold. Although the electrochromic contrast and coloration efficiency were better at higher repetition rates, the switching speed, reversibility, and stability were better at low repetition rates. This difference in the electrochromic properties of the two MoO3 films is attributed to the variation in the defect and molecular coordination states of the Mo cation. PMID- 28001079 TI - Profiling of Histone Post-Translational Modifications in Mouse Brain with High Resolution Top-Down Mass Spectrometry. AB - As histones play central roles in most chromosomal functions including regulation of DNA replication, DNA damage repair, and gene transcription, both their basic biology and their roles in disease development have been the subject of intense study. Because multiple post-translational modifications (PTMs) along the entire protein sequence are potential regulators of histones, a top-down approach, where intact proteins are analyzed, is ultimately required for complete characterization of proteoforms. However, significant challenges remain for top down histone analysis primarily because of deficiencies in separation/resolving power and effective identification algorithms. Here we used state-of-the-art mass spectrometry and a bioinformatics workflow for targeted data analysis and visualization. The workflow uses ProMex for intact mass deconvolution, MSPathFinder as a search engine, and LcMsSpectator as a data visualization tool. When complemented with the open-modification tool TopPIC, this workflow enabled identification of novel histone PTMs including tyrosine bromination on histone H4 and H2A, H3 glutathionylation, and mapping of conventional PTMs along the entire protein for many histone subunits. PMID- 28001080 TI - Asymmetric Total Synthesis of Lepadiformine C Using Memory of Chirality in an Intramolecular Ester Enolate Michael Addition. AB - The asymmetric synthesis of lepadiformine C was achieved using d-proline as the only chiral source. The synthetic strategy features the use of the principle of "memory of chirality" in an intramolecular Michael addition to construct the bicyclic intermediate without the aid of external chiral sources. A brief mechanistic rationale is presented to account for the stereochemical outcome. PMID- 28001081 TI - Computer Simulation Studies on the pH-Responsive Self-Assembly of Amphiphilic Carboxy-Terminated Polyester Dendrimers in Aqueous Solution. AB - This paper investigates the pH-responsive self-assembly of an amphiphilic carboxyl-terminated polyester dendrimer, H20-COOH, in aqueous solution using the dissipative particle dynamics method. The electrostatic interactions were described by introducing the explicit interaction between the smeared charges on ionized polymer beads and the counterions. The results show that the self assemblies could change from unimolecular micelles, microphase-separated small micelles, wormlike micelles, sheetlike micelles, and small vesicles to large vesicles with the decrease in the degree of ionization (alpha) of carboxylic acid groups. In addition, the detailed self-assembly mechanisms and the molecular packing models have also been disclosed for each self-assembly stages. Interestingly, the wormlike micelles are found to change from linear to branched when alpha decreases from 0.182 to 0.109. The current work might serve as a comprehensive understanding on the effect of carboxylic acid groups on the self assembly behaviors of dendritic polymers. PMID- 28001082 TI - Impact of human Campylobacter infections in Southeast Asia: The contribution of the poultry sector. AB - Campylobacter is globally recognized as a major cause of foodborne infection in humans, whilst the development of antimicrobial resistance and the possibility of repelling therapy increase the threat to public health. Poultry is the most frequent source of Campylobacter infection in humans, and southeast Asia is a global leader in poultry production, consumption, and exports. Though three of the world's top 20 most populated countries are located in southeast Asia, the true burden of Campylobacter infection in the region has not been fully elucidated. Based on published data, Campylobacter has been reported in humans, animals, and food commodities in the region. To our knowledge, this study is the first to review the status of human Campylobacter infection in southeast Asia and to discuss future perspectives. Gaining insight into the true burden of the infection and prevalence levels of Campylobacter spp. in the southeast Asian region is essential to ensuring global and regional food safety through facilitating improvements in surveillance systems, food safety regulations, and mitigation strategies. PMID- 28001084 TI - Resveratrol as an anti-cancer agent: A review. AB - Owing to their antimicrobial, antioxidant, and anti-inflammatory activity, grapes (Vitis vinifera L.) are the archetypal paradigms of fruits used not only for nutritional purposes, but also for exclusive therapeutics. Grapes are a prominent and promising source of phytochemicals, especially resveratrol, a phytoalexin antioxidant found in red grapes which has both chemopreventive and therapeutic effects against various ailments. Resveratrol's role in reducing different human cancers, including breast, cervical, uterine, blood, kidney, liver, eye, bladder, thyroid, esophageal, prostate, brain, lung, skin, gastric, colon, head and neck, bone, ovarian, and cervical, has been reviewed. This review covers the literature that deals with the anti-cancer mechanism of resveratrol with special reference to antioxidant potential. Furthermore, this article summarizes the literature pertaining to resveratrol as an anti-cancer agent. PMID- 28001083 TI - Nrf2 targeting by sulforaphane: A potential therapy for cancer treatment. AB - In the past decades, extensive studies have reported the potential chemopreventive activity of sulforaphane, an isothiocyanate derived from glucoraphanin, occurring in large amounts in Brassica genus plants. Sulforaphane was found to be active against several forms of cancer. A growing body of data shows that sulforaphane acts against cancer at different levels, from development to progression, through pleiotropic effects. In this review, we discuss the available experimental and clinical data on the potential therapeutic role of sulforaphane against cancer. Its effects range from the protection of cells from DNA damage to the modulation of the cell cycle via pro-apoptotic, anti angiogenesis and anti-metastasis activities. At molecular level, sulforaphane modulates cellular homeostasis via the activation of the transcription factor Nrf2. Although data from clinical studies are limited, sulforaphane remains a good candidate in the adjuvant therapy based on natural molecules against several types of cancer. PMID- 28001085 TI - Biomarkers of dairy fat intake and risk of cardiovascular disease: A systematic review and meta analysis of prospective studies. AB - BACKGROUND: Circulating biomarkers of dairy fat provide objective measures of dairy fat intake and facilitate conclusions relevant to populations with different diets and susceptibility to cardiovascular diseases (CVD). OBJECTIVE: To assess the relationship between circulating pentadecanoic acid (15:0), heptadecanoic acid (17:0) and trans-palmitoleic acid (trans-16:1n-7) and the risk of CVD. METHODS: Pubmed, Medline and Embase were searched for prospective cohort studies of the relationship between biomarkers of dairy fat and CVD risk, which included coronary heart disease (CHD), stroke, heart failure and CVD mortality, supplemented by bibliographies of retrieved articles and previous reviews. For each study, relative risks (RR) and 95% confidence intervals (CI) were extracted and pooled with the random effect model. RESULTS: Thirteen studies involving 7,680 CVD cases were included. The pooled RRs of the risk of CVD for the top third vs. bottom third 15:0, 17:0 and trans-16:1n-7 level were 0.94 (95%CI: 0.77 1.15), 0.82 (95% CI: 0.68-0.99) and 0.82 (95% CI: 0.67-1.02), respectively. Subgroup analysis indicated that there were no associations between the concentration of 15:0 with CHD and stroke, but a negative relationship with heart failure (RR = 0.72, 95% CI: 0.55-0.95). Null association was observed between circulating 17:0 and trans-16:1n-7 level and subtypes of CVD except for only one study which reported a negative relationship between 17:0 and heart failure. CONCLUSION: Higher dairy fat exposure is not associated with an increased risk of CVD. PMID- 28001086 TI - Bioactive whey peptide particles: An emerging class of nutraceutical carriers. AB - Whey-based diets have been linked with prolonged life expectancy and improved physical performance. These observations based on numerous clinical and simulated studies are attributed to diverse biological activities of whey peptides. Recently, bioactive whey peptides were exploited for enveloping nutraceuticals and drugs in view of fabricating capsules that the carrier matrix is also bioactive. Some of the most considered bioactivities of whey peptides including antihypertension, antioxidant, anti-obesity, anti-diabetes, and hypocholesterolemic properties with corresponding underlying mechanisms are briefly discussed. Then, we overview the supramolecular and gelation-prompted encapsulation of nutraceuticals with whey proteins, followed by summarizing recent developments in utilization of synthetic peptides for gene and drug delivery. Finally, particulation of bioactive whey peptides are communicated. Whey peptides may exert both biologically beneficial and technologically appreciated activities. Two procedures including desolvation and internal gelation have been so far employed for bioactive peptides particulation. Crosslinking is a prerequisite to confer acid-induced cold-set gelation to bioactive peptides. It also increases peptides Fe3+-reducing power. Surface activity of a population of peptides in whey protein hydrolysate may result in co adsorption of the peptides together with small molecule surfactants onto oil water interface, leading to modulated interfacial architecture and particle morphology. PMID- 28001087 TI - Extraction and purification of high added value compounds from by-products of the winemaking chain using alternative/nonconventional processes/technologies. AB - Grape byproducts are today considered as a cheap source of valuable compounds since existent technologies allow the recovery of target compounds and their recycling. The goal of the current article is to explore the different recovery stages used by both conventional and alternative techniques and processes. Alternative pre-treatments techniques reviewed are: ultrasounds, pulsed electric fields and high voltage discharges. In addition, nonconventional solvent extraction under high pressure, specifically, supercritical fluid extraction and subcritical water extraction are discussed. Finally alternative purification technologies, for example membrane processing were also examined. The intent is to describe the mechanisms involved by these alternative technologies and to summarize the work done on the improvement of the extraction process of phenolic compounds from winery by-products. With a focus on the developmental stage of each technology, highlighting the research need and challenges to be overcome for an industrial implementation of these unitary operations in the overall extraction process. A critical comparison of conventional and alternative techniques will be reviewed for ethe pre-treatment of raw material, the diffusion of polyphenols and the purification of these high added value compounds. This review intends to give the reader some key answers (costs, advantages, drawbacks) to help in the choice of alternative technologies for extraction purposes. PMID- 28001088 TI - Glioblastoma in the elderly: treatment patterns and survival. AB - AIM: The optimal treatment for elderly glioblastoma patients is unclear. We conducted a retrospective review of the California Cancer Registry to examine treatment patterns and survival by age. METHODS: We identified 2670 adult patients from the California Cancer Registry with glioblastoma. We compared the extent of resection, treatment type and modality. RESULTS: Elderly patients had the greatest overall survival (OS) with combined surgery, radiation and chemotherapy. However, they were more likely to undergo biopsy and less likely to receive combined radiation and chemotherapy than patients <70. CONCLUSION: OS was maximized in elderly patients who were able to get some surgical resection and undergo combined radiation and chemotherapy. OS survival in some elderly patients may be improved by more extensive therapy. PMID- 28001089 TI - The role of the immune system in neurofibromatosis type 1-associated nervous system tumors. AB - With the recent development of new anticancer therapies targeting the immune system, it is important to understand which immune cell types and cytokines play critical roles in suppressing or promoting tumorigenesis. The role of mast cells in promoting neurofibroma growth in neurofibromatosis type 1 (NF1) patients was hypothesized decades ago. More recent experiments in mouse models have demonstrated the causal role of mast cells in neurofibroma development and of microglia in optic pathway glioma development. We review here what is known about the role of NF1 mutation in immune cell function and the role of immune cells in promoting tumorigenesis in NF1. We also review the therapies targeting immune cell pathways and their promise in NF1 tumors. PMID- 28001090 TI - Recent technological advances in pediatric brain tumor surgery. AB - X-rays and ventriculograms were the first imaging modalities used to localize intracranial lesions including brain tumors as far back as the 1880s. Subsequent advances in preoperative radiological localization included computed tomography (CT; 1971) and MRI (1977). Since then, other imaging modalities have been developed for clinical application although none as pivotal as CT and MRI. Intraoperative technological advances include the microscope, which has allowed precise surgery under magnification and improved lighting, and the endoscope, which has improved the treatment of hydrocephalus and allowed biopsy and complete resection of intraventricular, pituitary and pineal region tumors through a minimally invasive approach. Neuronavigation, intraoperative MRI, CT and ultrasound have increased the ability of the neurosurgeon to perform safe and maximal tumor resection. This may be facilitated by the use of fluorescing agents, which help define the tumor margin, and intraoperative neurophysiological monitoring, which helps identify and protect eloquent brain. PMID- 28001091 TI - Treatment options for recurrent high-grade gliomas. AB - High-grade gliomas are aggressive brain tumors encompassing Grade III and IV classifications. Of these, glioblastoma (GB) is the most malignant with a high rate of recurrence after initial resection. Although standard treatment does exist for newly diagnosed GBs, therapeutic strategies for recurrent GB are less solidified. However, mounting evidence describes the role of re-resection, bevacizumab, chemotherapy, targeted molecular therapies, immunotherapeutic approaches and radiotherapy in recurrent GB management. This review article provides analysis of the aforementioned therapies, through assessing their effect on overall survival. Because GB tumor heterogeneity is prevalent there is a constant need to investigate therapies targeting recurrence. Studies evaluating both therapeutic targets and strategies for high-grade gliomas are and will remain invaluable. PMID- 28001092 TI - Familial Mediterranean fever with P369S/R408Q exon3 variant in pyrin presenting as symptoms of PFAPA. AB - Familial Mediterranean fever (FMF) can be classified into typical and incomplete/atypical types. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome-like symptoms have been found in atypical type carrying P369S-R408Q mutations in the responsible gene MEFV. A 28-year-old female with recurrent fever and her young sisters and mother, all of whom had tonsillectomy for tonsillitis, carried heterozygous alterations involving E148Q/P369S/R408Q. A diagnosis of atypical FMF, MEFV exon3 variants with PFAPA syndrome-like symptoms, was made. PMID- 28001093 TI - GABA (gamma-Aminobutyric Acid) Uptake Via the GABA Permease GabP Represses Virulence Gene Expression in Pseudomonas syringae pv. tomato DC3000. AB - The nonprotein amino acid gamma-aminobutyric acid (GABA) is the most abundant amino acid in the tomato (Solanum lycopersicum) leaf apoplast and is synthesized by Arabidopsis thaliana in response to infection by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (hereafter called DC3000). High levels of exogenous GABA have previously been shown to repress the expression of the type III secretion system (T3SS) in DC3000, resulting in reduced elicitation of the hypersensitive response (HR) in the nonhost plant tobacco (Nicotiana tabacum). This study demonstrates that the GABA permease GabP provides the primary mechanism for GABA uptake by DC3000 and that the gabP deletion mutant DeltagabP is insensitive to GABA-mediated repression of T3SS expression. DeltagabP displayed an enhanced ability to elicit the HR in young tobacco leaves and in tobacco plants engineered to produce increased levels of GABA, which supports the hypothesis that GABA uptake via GabP acts to regulate T3SS expression in planta. The observation that P. syringae can be rendered insensitive to GABA through loss of gabP but that gabP is retained by this bacterium suggests that GabP is important for DC3000 in a natural setting, either for nutrition or as a mechanism for regulating gene expression. [Formula: see text] Copyright (c) 2016 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license . PMID- 28001095 TI - Antileukemic effects of midostaurin in acute myeloid leukemia - the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells. AB - INTRODUCTION: Midostaurin is a multikinase inhibitor that inhibits receptor tyrosine kinases (Flt3, CD117/c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor 2) as well as non-receptor tyrosine kinases (Frg, Src, Syk, Protein kinase C). Combination of midostaurin with conventional intensive chemotherapy followed by one year maintenance monotherapy was recently reported to improve the survival of acute myeloid leukemia (AML) patients with Flt3 mutations. Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies; (ii) published articles describing the importance of midostaurin-inhibited kinases for leukemogenesis and chemosensitivity. Expert opinion: Midostaurin monotherapy is well tolerated, combined with conventional chemotherapy gastrointestinal toxicity increases significantly. Midostaurin alters anthracycline pharmacokinetics. Furthermore, its antileukemic effects may not only be mediated through Flt3 inhibition alone; the inhibition of other kinases may also be important for the overall antileukemic effect. Midostaurin may then have direct effects on the leukemic cells but also indirect antileukemic effects through inhibition of the AML-supporting effects of neighboring stromal cells in the bone marrow microenvironment. Midostaurin may thus be used in combination with intensive chemotherapy, as maintenance treatment or as disease-stabilizing treatment for elderly unfit patients. PMID- 28001096 TI - Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development. AB - INTRODUCTION: Opioids are widely used to treat severe pain. Most clinically used opioids activate u-opioid receptors (MOR). Their ligands induce potent analgesia but also adverse effects. The delta-opioid receptor (DOR) is another member of the opioid receptor family that has been under intense investigation with the aim to avoid MOR-induced side effects. Areas covered: This article reviews DOR ligands which appeared to be promising after preclinical evaluation. A literature search using Pubmed, Cochrane library, ClinicalTrials.gov, EudraCT, AdisInsight database and EBSCO Online Library was conducted. Out of numerous newly synthesized molecules, only few candidates entered phase I and/or II clinical investigation. The publicly accessible results are presented here. Expert opinion: Many compounds showed potent DOR-specific pain inhibition in preclinical studies. ADL5859 and ADL5747 entered clinical trials and successfully passed phase I. However, in phase II studies the primary endpoint (pain reduction) was not met and further investigation was terminated. A third compound, NP2, is in phase II clinical evaluation and results are pending. These findings suggest a potential of DOR ligands according to preclinical studies. Further clinical research and secondary analysis of unpublished data is needed to identify molecules which are useful in humans. PMID- 28001094 TI - Prevalence of Substance Use Among Patients of Community Health Centers in East Los Angeles and Tijuana. AB - BACKGROUND: Given the increased use of psychoactive substances on the United States-Mexico border, a binational study (Tijuana, Mexico-Los Angeles, USA) was conducted to identify the prevalence of substance use in primary care settings. OBJECTIVES: To compare the prevalence and characteristics of patients at risk for substance use disorders in Tijuana and East Los Angeles (LA) community clinics with special attention paid to drug use. METHODS: This was an observational, cross-sectional, analytical study, comparing substance use screening results from patients in Tijuana and LA. The settings were 2 community clinics in LA and 6 in Tijuana. Participants were 2,507 adult patients in LA and 2,890 in Tijuana eligible for WHO Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) screening during March-October 2013. Patients anonymously self administered the WHO ASSIST on a tablet PC in the clinic waiting rooms. RESULTS: Of eligible patients, 96.4% completed the ASSIST in Tijuana and 88.7% in LA (mean 1.34 minutes and 4.20 minutes, respectively). The prevalence of patients with moderate-to-high substance use was higher in LA than Tijuana for each substance: drugs 19.4% vs. 5.7%, alcohol 15.2% vs. 6.5%, tobacco 20.4% vs. 16.2%. LA patients born in Mexico had 2x the odds and LA patients born in the United States had 6x the odds of being a moderate-to-high drug user compared to Tijuana patients born in Mexico. CONCLUSIONS: Moderate-to-high drug use is higher in LA than in Tijuana but rates are sufficiently high in both to suggest that screening for drug use (along with alcohol and tobacco use) should be integrated into routine primary care of community clinics in both cities. PMID- 28001097 TI - Perirenal Hematoma After Ureteroscopy: A Systematic Review. AB - INTRODUCTION: With the broadening indications of ureteroscopy (URS) for complex stones and high-risk patients, more URS is being performed and hence there is an increasing risk of major potentially life-threatening complications. We wanted to define the incidence, predisposing factors, management, and long-term sequelae for post-URS perirenal hematoma (PRH). MATERIAL AND METHODS: We conducted a systematic review of literature according to Cochrane and preferred reporting items for systematic reviews and meta-analysis guidelines for all studies reporting on post-URS PRH from 1980 to September 2016. A literature search was conducted through PubMed, EMBASE, CINAHL, and Cochrane Library for all English language articles. RESULTS: Based on a literature search of 210 articles, seven studies (8929 patients) met the inclusion criteria with an incidence of post-URS PRH reported as 0.45% (40 patients, range: 0.15%-8.9% per study) with a mean age of 53 years and a mean stone size of 1.7 cm. The predisposing factors were moderate-severe hydronephrosis, thin renal cortex, prolonged operative duration, hypertension, and preoperative urinary tract infection (UTI). The management strategy varied from conservative management with blood transfusion and antibiotics (n = 22, 55%) to percutaneous drainage (n = 11, 27.5%). Surgical intervention was needed in seven (17.5%) patients. Two of these were emergency angiography of which one proceeded to open nephrectomy. Open surgery with clot removal was done in three patients, nephrostomy for severe hydronephrosis in one patient, and surgery to correct malpositioned stent in one patient. There was one mortality reported, wherein a patient who had postangiography nephrectomy died of multiple organ failure after the intervention. CONCLUSION: URS related PRH is a rare, but potentially life threatening complication with a small risk of renal loss. Although most cases may be managed conservatively, incidence of PRH can be minimized by control of blood pressure, treatment of preoperative UTI, and reduction in intrarenal pressures and operative time duration. PMID- 28001098 TI - Pre-eclampsia and risk of subsequent hypertension: in an American Indian population. AB - BACKGROUND AND OBJECTIVES: Pre-eclampsia (PE) shares a number of proposed pathophysiologic mechanisms related to those implicated in cardiovascular disease (CVD), such as endothelial dysfunction, inflammation, insulin resistance, and impaired renal regulation. PE has also been associated with subsequent hypertension, CVD, and related mortality in later life. METHODS: At follow-up, the four most recent blood pressures, body mass index (BMI), and use of hypertensive medications were recorded from clinic visits of 130 PE cases and 289 normal pregnancies. Student's t test, Chi-square testing, multivariate linear, and logistic regression were used in analysis. RESULTS: Follow-up measurements occurred a mean of 13.11 years post PE pregnancy. Multivariate linear regression showed a significant and independent association between current systolic blood pressure and previous history of PE (beta = 4.47, p = 0.04), while adjusting for age, BMI, and blood pressure from 1 year prior to and up to the 20th week of gestation. A similarly adjusted multivariate logistic regression model found an odds ratio of 3.43, 95% CI 1.83-6.43, p = 0.001 for subsequent hypertension. Logistic regression analysis of the quartile with follow-up of less than 7.19 years also shows independent association of prior PE with subsequent hypertension. DISCUSSION AND CONCLUSIONS: PE appears to confer risk of subsequent hypertension on this cohort of American Indian women within as little as 8 years. This risk is independent of additional risk factors such as increased age, BMI, and blood pressure prior to 20 weeks of gestation. There is evidence of increased risk among those with more severe PE. PMID- 28001099 TI - Inhibitory effects of veterinary antibiotics on anammox activity: short- and long term tests. AB - The suitability of the anammox process for the treatment of swine digester liquor was assessed through the evaluation of the short- and long-term inhibitory effect of three veterinary antibiotics commonly administered to Italian swine livestock. The toxicity of doxycycline, tiamulin and enrofloxacin was evaluated through batch tests designed to estimate specific anammox activity. Moreover, the short term toxicity of combined concentrations of doxycycline and enrofloxacin was evaluated so as to verify whether a synergistic effect could be established. According to the inhibition recorded in the presence of the maximum antibiotics concentrations predicted for digester liquor, target compounds do not seem to represent a real hazard for anammox bacteria because at those concentration levels, the activity was just slightly reduced. Moreover, in granular systems, inhibition could be easily counterbalanced by increasing the biomass concentration in the reactor, thus assuring the design treatment capacity for antibiotic-rich wastewaters. PMID- 28001100 TI - Content Validity of Patient-Reported Outcome Instruments used with Pediatric Patients with Facial Differences: A Systematic Review. AB - OBJECTIVE: The aim of this systematic review was to identify patient-reported outcome (PRO) instruments used in research with children/youth with conditions associated with facial differences to identify the health concepts measured. DESIGN: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from 2004 to 2016 to identify PRO instruments used in acne vulgaris, birthmarks, burns, ear anomalies, facial asymmetries, and facial paralysis patients. We performed a content analysis whereby the items were coded to identify concepts and categorized as positive or negative content or phrasing. RESULTS: A total of 7,835 articles were screened; 6 generic and 11 condition-specific PRO instruments were used in 96 publications. Condition-specific instruments were for acne (four), oral health (two), dermatology (one), facial asymmetries (two), microtia (one), and burns (one). The PRO instruments provided 554 items (295 generic; 259 condition specific) that were sorted into 4 domains, 11 subdomains, and 91 health concepts. The most common domain was psychological (n = 224 items). Of the identified items, 76% had negative content or phrasing (e.g., "Because of the way my face looks I wish I had never been born"). Given the small number of items measuring facial appearance (n = 19) and function (n = 22), the PRO instruments reviewed lacked content validity for patients whose condition impacted facial function and/or appearance. CONCLUSIONS: Treatments can change facial appearance and function. This review draws attention to a problem with content validity in existing PRO instruments. Our team is now developing a new PRO instrument called FACE-Q Kids to address this problem. PMID- 28001101 TI - Palatal Fistula Risk after Primary Palatoplasty: A Retrospective Comparison of a Humanitarian Organization and Tertiary Hospitals. AB - BACKGROUND: Humanitarian surgical organizations provide palatoplasties for patients without access to surgical care. Few organizations have evaluated the outcomes of these trips. This study evaluates the palatal fistula rate in patients from two cohorts in rural China and one in the United States. METHODS: This study compared the odds of fistula formation among three cohorts whose palates were repaired between 2005 and 2009. One cohort included 97 Chinese patients operated on by teams from the United States and Canada under the auspices of Resurge International. They were compared to cohorts at Huaxi Stomatology Hospital and the University of California San Francisco (UCSF). Age, fistula presence, and Veau class were compared among cohorts using Chi-square tests. Logistic regression was used to analyze predictors of fistula formation. RESULTS: The fistula risk was 35.4% in patients treated by humanitarian teams, 12.8% at Huaxi University Hospital and 2.5% at UCSF ( P < 0.001). Age and Veau class were associated with fistula formation (Age P = 0.0015; Veau P < 0.001). ReSurge and Huaxi patients had 20.2 and 5.6 times the odds of developing a fistula, respectively, compared to UCSF patients ( P < 0.01, both). A multivariable model controlling for surgical group, age, and gender showed an association between Veau class and the odds of fistula formation. CONCLUSIONS: Chinese children undergoing palatoplasty by international teams had higher odds of palatal fistula than children treated by Chinese surgeons in established institutions and children treated in the United States. More research is required to identify factors affecting complication rates in low-resource environments. PMID- 28001102 TI - Transforming Growth Factor Alpha Taq I Polymorphisms and Nonsyndromic Cleft Lip and/or Palate Risk: A Meta-Analysis. AB - BACKGROUND: A series of epidemiological studies were conducted to investigate the association between transforming growth factor alpha ( TGFA) polymorphism and nonsyndromic cleft lip and/or palate (CL/P) risk, but the findings remain conflicting. The present meta-analysis summarizes the association between the TGFA Taq I polymorphisms and nonsyndromic CL/P risk. METHODS: We searched PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature databases from their inception to May 1, 2015. Fixed-effects or random-effects models were used to calculate the pooled odds ratio for two genetic comparisons (heterozygous mutation versus wild type, homozygous mutation versus wild type). All of the statistical tests were conducted by STATA 10.0 (StataCorp, College Station, TX). RESULTS: A total of 26 case-control studies were identified for this meta analysis. There was evidence of a significant association between the TGFA Taq I polymorphism and nonsyndromic CL/P risk in the overall population. The TGFA polymorphism was associated with nonsyndromic CL/P susceptibility in Asian populations under any of genetic models. However, in subgroup analysis, we did not find a significant association of TGFA gene polymorphisms with a reduced cancer risk in White and other populations and (recessive model, odds ratio = 2.37, 95% confidence intervals = 0.92-6.07; odds ratio = 3.45, 95% confidence intervals = 1.07-11.09, respectively). CONCLUSION: Our study indicates that the TGFA gene polymorphism might be associated with nonsyndromic CL/P susceptibility. However, these findings still need to be confirmed by single, large, well designed prospective studies. PMID- 28001105 TI - Letters to the Editor. PMID- 28001104 TI - What Is Your Diagnosis? PMID- 28001106 TI - Evaluation of potential risk factors for development of primary angle-closure glaucoma in Bouviers des Flandres. AB - OBJECTIVE To evaluate potential risk factors for development of primary angle closure glaucoma (PACG) in Bouviers des Flandres. DESIGN Prospective, observational study. ANIMALS 98 Bouviers des Flandres. PROCEDURES All dogs underwent slit-lamp biomicroscopy, indirect ophthalmoscopy, gonioscopy, applanation tonometry, streak retinoscopy, and A-scan, B-scan, and high resolution ultrasonography. Iridocorneal angles and degree of pectinate ligament dysplasia sheeting were graded, and an angle index was mathematically derived for each eye on the basis of these values. Ciliary clefts evaluated by high resolution ultrasonography were classified as open, narrow, or closed. Owners were contacted by telephone 7 to 9 years after the initial examination to determine whether dogs had a subsequent diagnosis of PACG. Relationships between previously recorded variables and the development of PACG were evaluated by logistic regression methods. Available pedigrees were reviewed to assess genetic relationships among affected dogs. RESULTS 9 of 92 (9.8%) dogs with follow-up information available developed PACG. An angle index < 1 and presence of a narrow or closed ciliary cleft in 1 or both eyes were each significantly associated with development of PACG. Odds of developing PACG for dogs with an angle index < 1 (indicating marked reduction in outflow capacity through the iridocorneal angle), a narrow or closed ciliary cleft in > 1 eye, or both findings were 13, 20, and 28 times those for dogs that did not have these findings, respectively. All dogs that developed PACG shared 1 common male sire or grandsire. CONCLUSIONS AND CLINICAL RELEVANCE Several anatomic factors were significant risk factors for development of PACG in this population of dogs. Results also suggested a genetic component for the disease. PMID- 28001107 TI - Taking action to address member concerns about cyberbullying. PMID- 28001108 TI - Pathology in Practice. PMID- 28001110 TI - In This Issue * January 1, 2017. PMID- 28001111 TI - Radiographic evaluation and comparison of the patellar ligament following tibial plateau leveling osteotomy and tibial tuberosity advancement in dogs: 106 cases (2009-2012). AB - OBJECTIVE To radiographically evaluate and compare changes in the patellar ligament of dogs following tibial plateau leveling osteotomy (TPLO) and tibial tuberosity advancement (TTA). DESIGN Retrospective case series. ANIMALS 106 dogs that underwent TPLO (n = 59) or TTA (n = 47) for unilateral rupture of the cranial cruciate ligament at a private veterinary hospital from August 2009 through September 2012. PROCEDURES Medical records were reviewed to collect information on dog signalment, surgical procedure, whether arthrotomy had been performed, pre- and postoperative measurements of patellar ligament angle (PLA) and tibial plateau angle (TPA), and preoperative and follow-up measurements of patellar ligament thickness. RESULTS For dogs that underwent TTA, thickening of the distal portion of the patellar ligament was identified radiographically in 43 (92%) dogs at the first follow-up examination and 36 (77%) at the second follow up examination. For dogs that underwent TPLO, these numbers were 57 (97%) and 54 (92%), respectively. A significant decrease in patellar ligament thickness was identified between the first and second follow-up examinations for TTA but not TPLO. Mean +/- SD PLA following TTA was 89.46 +/- 5.54 degrees , representing a mean difference from the preoperative PLA of 11.86 +/- 5.3 degrees ; following TPLO, mean TPA was 12.61 +/- 4.03 degrees , representing a mean difference from the preoperative TPA of 16.74 +/- 7.13 degrees . CONCLUSIONS AND CLINICAL RELEVANCE Patellar ligament thickening occurred following TPLO and TTA in dogs. The clinical relevance of this thickening remains unknown. PMID- 28001112 TI - Microwave ablation for treatment of hepatic neoplasia in five dogs. AB - CASE DESCRIPTION 5 dogs between 9 and 11 years of age were evaluated for treatment of primary (n = 2) or metastatic (3) hepatic neoplasia. CLINICAL FINDINGS Patients were evaluated on an elective (n = 3) or emergency (2) basis. Two dogs with primary hepatic neoplasia were evaluated because of lethargy and inappetence. One dog was referred after an enlarged anal sac was detected via palpation per rectum during a routine physical examination. Two dogs were evaluated on an emergency basis because of lethargy and weakness, and hemoabdomen in the absence of a history of trauma was detected. All 5 dogs underwent thoracic radiography and abdominal ultrasonography, with CT performed in both dogs with primary hepatic neoplasia. All dogs had preoperative evidence of abdominal neoplasia, and none had evidence of thoracic metastasis. TREATMENT AND OUTCOME All dogs underwent ventral midline laparotomy and had diffuse hepatic neoplasia that precluded complete resection. Locoregional treatment with MWA was applied to hepatic lesions (0.5 to 2.5 cm diameter) without procedural complications. Histopathologic diagnoses were biliary adenocarcinoma (n = 1), hemangiosarcoma (2), hepatocellular carcinoma (1), and apocrine gland adenocarcinoma (1). CLINICAL RELEVANCE MWA is being increasingly used as an adjunct in the surgical treatment of human patients with primary and metastatic liver disease. Results of the present small case series suggested that MWA is feasible and potentially effective as an adjunctive treatment for appropriately selected dogs with nonresectable hepatic tumors. Further investigation is indicated. PMID- 28001113 TI - Pathology in Practice. PMID- 28001114 TI - Strategies veterinary practices can use to address the problem of intimate partner violence. PMID- 28001115 TI - Attitudes of small animal practitioners toward participation in veterinary clinical trials. AB - OBJECTIVE To determine attitudes of small animal practitioners toward veterinary clinical trials and variables influencing their likelihood of participating in such trials. DESIGN Cross-sectional survey. SAMPLE Small animal practitioners with membership in 1 of 2 online veterinary communities (n = 163 and 652). PROCEDURES An online survey was developed for each of 2 veterinary communities, and invitations to participate were sent via email. Each survey included questions designed to collect information on the respondents' willingness to enroll their patients in clinical trials and to recommend participation to clients for their pets. RESULTS More than 80% of respondents to each survey indicated that they spend no time in clinical research. A high proportion of respondents were likely or extremely likely to recommend clinical trial participation to clients for their pets when those trials involved treatments licensed in other countries, novel treatments, respected investigators, or sponsoring by academic institutions, among other reasons. Reasons for not recommending participation included distance, time restrictions, and lack of awareness of ongoing clinical trials; 28% of respondents indicated that they did not usually learn about such clinical trials. Most respondents (79% to 92%) rated their recommendation of a trial as important to their client's willingness to participate. CONCLUSIONS AND CLINICAL RELEVANCE Participation in veterinary clinical trials by small animal practitioners and their clients and patients appeared low. Efforts should be increased to raise practitioner awareness of clinical trials for which patients might qualify. Specific elements of trial design were identified that could be modified to increase participation. PMID- 28001117 TI - Introducing Volume 6 of the Journal of Comparative Effectiveness Research. PMID- 28001116 TI - Features of stimulus-specific seizures in dogs with reflex epilepsy: 43 cases (2000-2014). AB - OBJECTIVE To describe the occurrence and management of reflex epilepsy (ie, seizure activity triggered by exposure to specific locations or situations) in dogs. DESIGN Retrospective case series. ANIMALS 43 client-owned dogs. PROCEDURES Discussions by veterinarians participating in the Veterinary Information Network online community for the years 2000 through 2014 were reviewed to identify dogs with a diagnosis of reflex epilepsy and seizure activity in response to stimuli. History, signalment (including age at onset), the specific stimulus or stimuli that provoked seizures, treatments, and any concurrent neurologic diagnoses were recorded. RESULTS A variety of breeds were affected. Median age at onset was 5 years (range, 3 months to 11 years). Reflex seizures were reported as being repeatedly triggered by visits to a veterinary clinic (35/43 dogs), grooming facility (24/43 dogs), or boarding facility (13/43 dogs) and, less commonly, by other situations (eg, pet store or car ride). Over half of the dogs (24/43) had multiple triggers. Eight (19%) dogs had seizures at other times that were not induced by location or a specific situation. A variety of sedatives and maintenance antiepileptic drugs administered to affected dogs failed to prevent the stimulus-specific seizure activity. CONCLUSIONS AND CLINICAL RELEVANCE Results of the present study suggested that seizures provoked by specific situations or locations occur in dogs with reflex epilepsy and that common triggers were visits to veterinary and grooming facilities. Further studies are necessary to elucidate the characteristics of reflex epilepsy in dogs and to determine the most effective means to manage these patients. PMID- 28001118 TI - The expression of VEGF receptor genes is concurrently influenced by epigenetic gene silencing of the genes and VEGF activation. AB - Vascular endothelial growth factor (VEGF) activates the VEGF-VEGF receptor (VEGFR) signaling pathway in angiogenesis. Some cancer cell lines show decreased expression of the two VEGFRs, Flt-1 and KDR, even though VEGF is uniformly expressed in cancer cell lines. Promoter methylation is a well-known cause of epigenetic gene silencing in cancer cells. Although VEGF, Flt-1 and KDR have typical CpG islands in their promoter regions, the epigenetic transcriptional alterations of these genes have not yet been described. The present study evaluated the epigenetic gene silencing of VEGF and VEGFR genes in cancer tissues. We also analyzed whether the epigenetic alterations of VEGFR genes influence VEGFR expression concurrently with VEGF activation in cancer tissues. All cancer tissues we tested showed no methylation of VEGF, and variable promoter hypermethylation of Flt-1 and KDR. The promoter hypermethylation of Flt-1 and KDR was correlated with decreasing expression of the respective genes. In contrast, an increase in VEGF expression was positively correlated with Flt-1 and KDR expression in primary cancer tissues. The opposing influences of promoter methylation of VEGFR and increased VEGF expression concurrently influence Flt-1 and KDR expression in stomach cancer, colon cancer and hepatocellular carcinoma. The findings we observed showed that the epigenetic alteration developing in VEGFR genes might be an important factor to concurrently modulate expressions of the genes in addition to VEGF stimulation in cancer tissues. The epigenetic silencing of VEGFR genes should be considered in the activation of VEGF-VEGFR signaling pathway in the cancer cells. PMID- 28001119 TI - Epigenetic disruption of the WNT/beta-catenin signaling pathway in human cancers. AB - Aberrant activation of the WNT/beta-catenin signaling pathway is frequently involved in a broad spectrum of human malignancies. Alternative to genetic deletions and point mutations, epigenetic inactivation of negative WNT regulators, through DNA methylation of promoter CpG islands and/or histone modification, leads to the activation or amplification of aberrant WNT/beta catenin signaling. In this review, we summarized the contribution of epigenetic dysregulation of WNT/beta-catenin signaling to tumorigenesis and highlighted the importance of epigenetic identification of negative regulators of this pathway as putative tumor suppressors. The reversal of these silenced regulators may be developed as potential cancer therapeutics. PMID- 28001120 TI - Epigenetics of imprinted long non-coding RNAs. AB - It is becoming increasingly evident that noncoding RNA (ncRNA) constitutes an important component of chromatin and that ncRNA has a critical role in organizing the chromatin architecture and epigenetic memory by acting as an interface with the chromatin modifying machinery. Xist is the only RNA that has been shown to regulate gene expression by modulating chromatin structure using a multilayered silencing pathway. Recent emerging evidence indicates that long ncRNAs such as Kcnq1ot1 and Air which map to the Kcnq1 and Igf2r imprinted gene clusters, respectively, mediate the transcriptional silencing of multiple genes by interacting with chromatin and recruiting the chromatin modifying machinery. Though there are some parallels in the mechanistic actions of Kcnq1ot1 and Air, they seem to differ greatly in the way they achieve the silencing of overlapping and nonoverlapping genes. By reviewing the latest available evidence, we propose that Kcnq1ot1 RNA itself seems to play a critical role in the bidirectional silencing of genes in the Kcnq1 domain, thus resembling the Xist RNA; whereas in the case of Air, the act of transcription plays a critical role in the silencing of the overlapping gene, whilst Air RNA itself mediates the silencing of nonoverlapping genes in a fashion similar to Kcnq1ot1 and Xist RNAs. PMID- 28001121 TI - The Second Antithyroid Drug Treatment Is Effective in Relapsed Graves' Disease Patients: A Median 11-Year Follow-Up Study. AB - BACKGROUND: Antithyroid drug (ATD) is a widely used treatment for Graves' disease (GD). However, its long-term efficiency remains unclear. This study investigated the long-term disease prognosis and predictive factors for relapse in ATD-treated GD patients. METHODS: Newly diagnosed, ATD-treated GD patients with at least four years of follow-up were recruited (n = 187). Remission was defined as maintaining a euthyroid status for more than one year after ATD withdrawal. RESULTS: During 11.1 years (range 4.0-23.7 years) of median follow-up, overall, 51.9% of the newly diagnosed ATD-treated GD patients achieved remission, 32.1% continued ATD treatment, and 13.4% underwent other ablation treatments. The 10-year remission rates were higher in the first (34.2%) and second (25.5%) ATD courses than in any of the other subsequent ATD courses, and decreased as ATD treatments were repeated. The 10-year relapse rate was the highest after the third ATD treatment (71.4%) compared with that after the first (60.5%) and second (58.3%) courses. Longer duration of ATD treatment (odds ratio [OR] = 1.4 [confidence interval (CI) 1.2-1.7], p < 0.001), higher number of relapses (OR = 4.7 [CI 2.3-9.8], p < 0.001), and moderate to severe Graves' ophthalmopathy (OR = 4.1 [CI 1.1-15.2], p = 0.032) were associated with persistent disease status. CONCLUSIONS: A second course of ATD can be considered for GD patients after the first relapse because the chance of remission and the relapse rate are similar to the one after the first ATD treatment course. For GD patients with more than two relapses, or with an ATD treatment duration of more than four to five years, low-dose maintenance of ATD or ablative treatment needs to be considered. PMID- 28001122 TI - Spatial and temporal variability in desert dust and anthropogenic pollution in Iraq, 1997-2010. AB - : Satellite imaging has emerged as a method for monitoring regional air pollution and detecting areas of high dust concentrations. Unlike ground observations, continuous data monitoring is available with global coverage of terrestrial and atmospheric components. In this study we test the utility of different sources of satellite data to assess air pollution concentrations in Iraq. SeaWiFS and MODIS Deep Blue (DB) aerosol optical depth (AOD) products were evaluated and used to characterize the spatial and temporal pollution levels from the late 1990s through 2010. The AOD and Angstrom exponent (an indicator of particle size, since smaller Angstrom exponent values reflect a source that includes larger particles) were correlated on 50 * 50 km spatial resolution. Generally, AOD and Angstrom exponent were inversely correlated, suggesting a significant contribution of coarse particles from dust storms to AOD maxima. Although the majority of grid cells exhibited this trend, a weaker relationship in other locations suggested an additional contribution of fine particles from anthropogenic sources. Tropospheric NO2 densities from the OMI satellite were elevated over cities, also consistent with a contribution from anthropogenic sources. Our analysis demonstrates the use of satellite imaging data to estimate relative pollution levels and source contributions in areas of the world where direct measurements are not available. IMPLICATIONS: The authors demonstrated how satellite data can be used to characterize exposures to dust and to anthropogenic pollution for future health related studies. This approach is of a great potential to investigate the associations between subject-specific exposures to different pollution sources and their health effects in inaccessible regions and areas where ground monitoring is unavailable. PMID- 28001124 TI - Introduction to a Special Issue of JA&WMA on Exposure Assessment. PMID- 28001125 TI - Taking stories to the mountains. PMID- 28001123 TI - Fine-scale spatial and temporal variation in temperature and arrhythmia episodes in the VA Normative Aging Study. AB - : Many studies have demonstrated that cold and hot temperatures are associated with increased deaths and hospitalization rates; new findings indicate also an association with more specific cardiac risk factors. Most of these existing studies have relied on few weather stations to characterize exposures; few have used residence-specific estimates of temperature, or examined the exposure response function. We investigated the association of arrhythmia episodes with spatial and temporal variation in temperature. We also evaluated the association btween monitored ambient temperature (central) and the same outcome. This longitudinal analysis included 701 older men participating in the VA Normative Aging Study. Arrhythmia episodes were measured as ventricular ectopy (VE) (bigeminy, trigeminy, or couplets episodes) by 4-min electrocardiogram (ECG) monitoring in repeated visits during 2000-2010. The outcome was defined as having or not VE episodes during a study visit. We applied a mixed-effect logistic regression model with a random intercept for subject, controlling for seasonality, weekday, medication use, smoking, diabetes status, body mass index, and age. We also examined effect modification by personal characteristics, confounding by air pollution, and the exposure-response function. For 1 degrees C increase in the same day residence-specific temperature, the odds of having VE episodes was 1.10 (95% confidence interval [CI]: 1.04-1.17). The odds associated with 1 degrees C increase in central temperature was 1.05 (95% CI: 1.02-1.09). The exposure-response function was nonlinear for averages of temperature, presenting a J-shaped pattern, suggesting greater risk at lower and higher temperatures. Increased warm temperature and decreased cold temperature may increase the risk of ventricular arrhythmias. IMPLICATIONS: This is the first study to provide evidence that residence-specific temperature exposure is associated with increased risk of ventricular arrhythmias in cohort of elderly subjects without known chronic medical conditions; that the delayed effect of temperature has a nonlinear relationship; and therefore that both warm and cold temperature increase the risk of having ventricular arrhythmias. Moreover, we show that the use of residence-specific temperature data reduces downward bias due to exposure error, by comparing the estimated health effect based on our spatiotemporal exposure prediction model to those based on a single local weather monitor. PMID- 28001126 TI - A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory. AB - The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway. PMID- 28001127 TI - Cryo-EM structures of the autoinhibited E. coli ATP synthase in three rotational states. AB - A molecular model that provides a framework for interpreting the wealth of functional information obtained on the E. coli F-ATP synthase has been generated using cryo-electron microscopy. Three different states that relate to rotation of the enzyme were observed, with the central stalk's epsilon subunit in an extended autoinhibitory conformation in all three states. The Fo motor comprises of seven transmembrane helices and a decameric c-ring and invaginations on either side of the membrane indicate the entry and exit channels for protons. The proton translocating subunit contains near parallel helices inclined by ~30 degrees to the membrane, a feature now synonymous with rotary ATPases. For the first time in this rotary ATPase subtype, the peripheral stalk is resolved over its entire length of the complex, revealing the F1 attachment points and a coiled-coil that bifurcates toward the membrane with its helices separating to embrace subunit a from two sides. PMID- 28001129 TI - A multispectral microscope for in vivo oximetry of rat dorsal spinal cord vasculature. AB - Quantification of blood oxygen saturation (SO2) in vivo is essential for understanding the pathogenesis of diseases in which hypoxia is thought to play a role, including inflammatory disorders such as multiple sclerosis (MS) and rheumatoid arthritis (RA). We describe a low-cost multispectral microscope and oximetry technique for calibration-free absolute oximetry of surgically exposed blood vessels in vivo. We imaged the vasculature of the dorsal spinal cord in healthy rats, and varied inspired oxygen (FiO2) in order to evaluate the sensitivity of the imaging system to changes in SO2. The venous SO2 was calculated as 67.8 +/- 10.4% (average +/- standard deviation), increasing to 83.1 +/- 11.6% under hyperoxic conditions (100% FiO2) and returning to 67.4 +/ 10.9% for a second normoxic period; the venous SO2 was 50.9 +/- 15.5% and 29.2 +/- 24.6% during subsequent hypoxic states (18% and 15% FiO2 respectively). We discuss the design and performance of our multispectral imaging system, and the future scope for extending this oximetry technique to quantification of hypoxia in inflamed tissue. PMID- 28001128 TI - Coincidence detection and bi-directional transmembrane signaling control a bacterial second messenger receptor. AB - The second messenger c-di-GMP (or cyclic diguanylate) regulates biofilm formation, a physiological adaptation process in bacteria, via a widely conserved signaling node comprising a prototypical transmembrane receptor for c-di-GMP, LapD, and a cognate periplasmic protease, LapG. Previously, we reported a structure-function study of a soluble LapD*LapG complex, which established conformational changes in the receptor that lead to c-di-GMP-dependent protease recruitment (Chatterjee et al., 2014). This work also revealed a basal affinity of c-di-GMP-unbound receptor for LapG, the relevance of which remained enigmatic. Here, we elucidate the structural basis of coincidence detection that relies on both c-di-GMP and LapG binding to LapD for receptor activation. The data indicate that high-affinity for LapG relies on the formation of a receptor dimer-of dimers, rather than a simple conformational change within dimeric LapD. The proposed mechanism provides a rationale of how external proteins can regulate receptor function and may also apply to c-di-GMP-metabolizing enzymes that are akin to LapD. PMID- 28001130 TI - Site dilution in SrRuO3: effects on structural and magnetic properties. AB - We have investigated the effect of site dilution with substitution of nonmagnetic element in SrRu1-x Ti x O3 (x ? 0.7). The nature of ferromagnetic state in SrRuO3 is believed to be of itinerant type with transition temperature [Formula: see text] K. Crystallographically, SrRuO3 has a distorted orthorhombic structure. Substitution of [Formula: see text] (3d 0) for Ru+4 (4d 4), however, does not introduce significant structural modification due to their matching ionic radii. This substitution, on the other hand, is expected to tune the electronic correlation effect and the d electron density in the system. With Ti substitution, we find that magnetic moment and Curie temperature decreases but T c remains unchanged which has been attributed to opposite tuning of electron correlation effect and density of states within the framework of itinerant ferromagnetism. The estimated critical exponent (beta) related to magnetization implies a mean-field type of magnetic nature in SrRuO3. The value of beta further increases with x which is understood from the dilution effect of magnetic lattice. The system evolves to exhibit Griffiths phase like behavior above T c which is usually realized in diluted ferromagnet following local moment model of magnetism. Our detail analysis of magnetization data indicates that magnetic state in SrRuO3 has contribution from both itinerant and local moment model of magnetism. PMID- 28001131 TI - The effect of temperature, interaction range, and pair potential on the formation of dodecagonal quasicrystals in core-corona systems. AB - A two-dimensional dodecagonal quasicrystal was previously reported by Dotera et al (2014 Nature 506 208) in a system of particles interacting with a hard core of diameter sigma and a repulsive square shoulder of diameter [Formula: see text]. In the current work, we examine the formation of this quasicrystal using bond orientational order parameters, correlation functions and tiling distributions. We find that this dodecagonal quasicrystal forms from a fluid phase. We further study the effect of the width of the repulsive shoulder by simulating the system over a range of values of delta. For the range of densities and temperatures considered, we observe the formation of the dodecagonal quasicrystal between [Formula: see text] and [Formula: see text]. We also study the effect of shape of the interaction potential by simulating the system using three other interaction potentials with two length scales, namely hard-core plus a linear ramp, modified exponential, or Buckingham (exp-6) potential. We observe the presence of the quasicrystal in all three systems. However, depending on the shape of the potential, the formation of the quasicrystal takes place at lower temperatures (or higher interaction strengths). Using free-energy calculations, we demonstrate that the quasicrystal is thermodynamically stable in the square-shoulder and linear-ramp system. PMID- 28001132 TI - Geometrical control of pure spin current induced domain wall depinning. AB - We investigate the pure spin-current assisted depinning of magnetic domain walls in half ring based Py/Al lateral spin valve structures. Our optimized geometry incorporating a patterned notch in the detector electrode, directly below the Al spin conduit, provides a tailored pinning potential for a transverse domain wall and allows for a precise control over the magnetization configuration and as a result the domain wall pinning. Due to the patterned notch, we are able to study the depinning field as a function of the applied external field for certain applied current densities and observe a clear asymmetry for the two opposite field directions. Micromagnetic simulations show that this can be explained by the asymmetry of the pinning potential. By direct comparison of the calculated efficiencies for different external field and spin current directions, we are able to disentangle the different contributions from the spin transfer torque, Joule heating and the Oersted field. The observed high efficiency of the pure spin current induced spin transfer torque allows for a complete depinning of the domain wall at zero external field for a charge current density of [Formula: see text] A m-2, which is attributed to the optimal control of the position of the domain wall. PMID- 28001133 TI - Spin Seebeck effect in quantum dot side-coupled to topological superconductor. AB - The spin-resolved thermoelectric transport properties of a quantum dot coupled to ferromagnetic leads and side-coupled to a topological superconductor wire hosting Majorana zero-energy modes are studied theoretically. The calculations are performed in the linear response regime by using the numerical renormalization group method. It is shown that transport characteristics are determined by the interplay of Kondo correlations, exchange field due to the presence of ferromagnets and the strength of coupling to Majorana wire. These different energy scales are revealed in the behavior of the Seebeck and spin Seebeck coefficients, which exhibit an enhancement for temperatures of the order of the coupling strength to topological wire. Moreover, it is demonstrated that additional sign changes of the thermopower can occur due to the presence of Majorana zero-energy modes. These findings may provide additional fingerprints of the presence of Majorana fermions. PMID- 28001134 TI - New Paradigms in Medical Ethics. AB - As new technologies develop, new ethical paradigms may be needed. This article considers several examples, such as stopping venoarterial extracorporeal membrane oxygenation (VA-ECMO), treating patients who are in a locked-in-like state who have awareness, purposefully deceiving patients who have dementia, meeting the needs of transgender persons, showing loved ones patients' wounds, and doing research on controlled substances. I suggest that clinicians should identify the practices underlying their value assumptions so they can alter their assumptions when this might improve the care they offer to their patients. PMID- 28001136 TI - Covert Administration of Medication to Persons with Dementia: Exploring Ethical Dimensions. AB - The literature, although sparse, reports that covert administration of all types of medications is prevalent in nursing homes. Whether it is ever ethically defensible, however, to administer medications covertly to persons with significant dementia is a complex and contentious question. Some scholars contend that deception is inherently wrong and is never acceptable, while others believe that deception is intrinsic to providing care to persons with dementia. With an aim to begin to reconcile these polarized positions and to objectively study this contentious issue, the authors undertake an ethical analysis of the covert administration of medications by utilizing the principles of respect for autonomy, nonmaleficence, beneficence, and justice. Our approach examines covert administration within the context of all persons with significant dementia who are administered medications, and is aimed at providing ethical and practical guidance to clinicians who, when confronted with a patient who refuses medication, must choose the "least bad" option from among various courses of action, all of which have ethical implications. Components of a possible guideline for practice are proposed. PMID- 28001135 TI - A Survey of Physicians' Attitudes toward Decision-Making Authority for Initiating and Withdrawing VA-ECMO: Results and Ethical Implications for Shared Decision Making. AB - OBJECTIVE: Although patients exercise greater autonomy than in the past, and shared decision making is promoted as the preferred model for doctor-patient engagement, tensions still exist in clinical practice about the primary locus of decision-making authority for complex, scarce, and resource-intensive medical therapies: patients and their surrogates, or physicians. We assessed physicians' attitudes toward decisional authority for adult venoarterial extracorporeal membrane oxygenation (VA-ECMO), hypothesizing they would favor a medical locus. DESIGN, SETTING, PARTICIPANTS: A survey of resident/fellow physicians and internal medicine attendings at an academic medical center, May to August 2013. MEASUREMENTS: We used a 24-item, internet-based survey assessing physician respondents' demographic characteristics, knowledge, and attitudes regarding decisional authority for adult VA-ECMO. Qualitative narratives were also collected. MAIN RESULTS: A total of 179 physicians completed the survey (15 percent response rate); 48 percent attendings and 52 percent residents/fellows. Only 32 percent of the respondents indicated that a surrogate's consent should be required to discontinue VA-ECMO; 56 percent felt that physicians should have the right to discontinue VA-ECMO over a surrogate's objection. Those who self reported as "knowledgeable" about VA-ECMO, compared to those who did not, more frequently replied that there should not be presumed consent for VA-ECMO (47.6 percent versus 33.3 percent, p = 0.007), that physicians should have the right to discontinue VA-ECMO over a surrogate's objection (76.2 percent versus 50 percent, p = 0.02) and that, given its cost, the use of VA-ECMO should be restricted (81.0 percent versus 54.4 percent, p = 0.005). CONCLUSIONS: Surveyed physicians, especially those who self-reported as knowledgeable about VA-ECMO and/or were specialists in pulmonary/critical care, favored a medical locus of decisional authority for VA-ECMO. VA-ECMO is complex, and the data may (1) reflect physicians' hesitance to cede authority to presumably less knowledgeable patients and surrogates, (2) stem from a stewardship of resources perspective, and/or (3) point to practical efforts to avoid futility and utility disputes. Whether these results indicate a more widespread reversion to paternalism or a more circumscribed usurping of decisional authority occasioned by VA-ECMO necessitates further study. PMID- 28001137 TI - Covert Medications: Act of Compassion or Conspiracy of Silence? AB - As the population in the United States gets older, more people suffer from dementia, which often causes neuropsychiatric symptoms such as agitation and paranoia. This can lead patients to refuse medications, prompting consideration of covert administration (that is, concealing medication in food or drink). While many condemn this practice as paternalistic, deceptive, and potentially harmful, the end result of assuming the "moral high ground" can be increased suffering for patients and families. This article addresses common criticisms of covert medication and presents a detailed algorithm by which to determine whether the practice is ethically permissible in specific cases. It also explores why so little attention has been paid in the U.S. to this presumably common practice, and reviews professional statements from Europe that endorse the practice. Finally, it presents a compelling argument for the role of Ulysses clauses in advance care planning, not only for patients with psychiatric illness but also for those who may suffer from dementia, which is far more common. PMID- 28001138 TI - Stakeholders' Views on Barriers to Research on Controversial Controlled Substances. AB - Many diseases and disease symptoms still lack effective treatment. At the same time, certain controversial Schedule I drugs, such as heroin and cannabis, have been reputed to have considerable therapeutic potential for addressing significant medical problems. Yet, there is a paucity of U.S. clinical studies on the therapeutic uses of controlled drugs. For example, people living with HIV/AIDS experience a variety of disease- and medication-related symptoms. Their chronic pain is intense, frequent, and difficult to treat. Nevertheless, clinical trials of compassionate management for their chronic symptoms, which should be a research priority, are stymied. We employed qualitative methods to develop an understanding of the barriers to research on potential therapeutic uses of Schedule I drugs so that they might be addressed. We elicited the perspectives of key stakeholder groups that would be involved in such studies: people living with HIV/AIDS, clinicians, and members of institutional review boards. As we identified obstacles to research, we found that all of the stakeholder groups arrived at the same conclusion, that clinical research on the therapeutic potential of these drugs is ethically required. PMID- 28001139 TI - The Evolution of American Hospital Ethics Committees: A Systematic Review. AB - During the 1970s and 1980s, legal precedent, governmental recommendations, and professional society guidelines drove the formation of hospital ethics committees (HECs). The Joint Commission on Accreditation of Health Care Organization's requirements in the early 1990s solidified the role of HECs as the primary mechanism to address ethical issues in patient care. Because external factors drove the rapid growth of HECs on an institution-by-institution basis, however, no initial consensus formed around the structure and function of these committees. There are now almost 40 years of empirical studies on the composition, administration, and activities of HECs in the United States. We conducted a systematic review of the available empirical literature on HECs to describe their evolution. As HECs changed over time, they increased their total number of members and percentage of members from nursing and the community. Although physicians increasingly chaired these committees, their presence as a percentage of overall members declined. The percentage of administrative members remained steady, although committees became increasingly likely to have at least one administrative member. HECs were also increasingly likely to report to an administrative body or to the board of trustees or directors rather than to the medical staff. Finally, consultation volume increased steadily over time. There has not, however, been a national survey of the composition of ethics committees, their administration, or volume of consultation in more than 10 years, despite increasing calls for professional standards and quality improvement assessments among HECs. PMID- 28001140 TI - Cultivating Administrative Support for a Clinical Ethics Consultation Service. AB - Hospital administrators may lack familiarity with what clinical ethicists do (and do not do), and many clinical ethicists report receiving inadequate financial support for their clinical ethics consultation services (CECSs). Ethics consultation is distinct in that it is not reimbursable by third parties, and its financial benefit to the hospital may not be quantifiable. These peculiarities make it difficult for clinical ethicists to resort to tried-and-true outcome centered evaluative strategies, like cost reduction or shortened length of stay for patients, to show a "need" for ethics consultation. Likewise, it can be difficult for clinical ethicists to "speak the same language" as healthcare administrators and managers, which, in turn, means that CECSs run the risk of being unable to demonstrate value to those who pay for the service. The purpose of this descriptive article is to provide practical guidance to clinical ethicists and program directors on how to cultivate administrative support for a CECS. Specifically, we discuss two elements that clinical ethics leaders must critically appraise and successfully argue to meet the expectations of administrators-the value of a CECS and its fit in clinical workflow. PMID- 28001141 TI - Cases from the Cleveland Clinic Foundation: What's Knowledge Got to Do with It? Ethics, Epistemology, and Intractable Conflicts in the Medical Setting. AB - This article utilizes the case of Ms H. to examine the contrasting ways that surrogate decision makers move from simply hearing information about the patient to actually knowing and understanding the patient's medical condition. The focus of the case is on a family's request to actually see the patient's wounds instead of being told about the wounds, and the role of clinical ethicists in facilitating this request. We argue that clinical ethicists have an important role to play in the work of converting information into knowledge and that this can serve as a valuable way forward in the midst of seemingly intractable conflicts in the medical setting. PMID- 28001142 TI - Perspective: Medical Futility: A Contemporary Review. AB - As medical technology has advanced, the question of medical futility has become a topic of intense debate both within the medical community and within society as a whole. However, a unanimous definition thereof is yet to be decided-some commentators are sceptical as to whether an agreement will ever be reached-and this continues to lead to difficulties, tension, and even legal action when a treating physician disagrees with a patient and/or a patient's family regarding care and treatment options. Although living in a pluralistic society presents one of the major reasons as to why, despite 30 years of intense discussion, no consensus has been made; the issue of medical futility will always be complex as it is, by nature, multifaceted, and numerous elements-including possible risks, evidence of the probability of benefit, the wishes of the patient (and family), professional standards, and cost-interact. Nevertheless, the global medical community has seen the development of two distinctly different approaches to medical futility: one in which the autonomy of patients is of paramount importance in the decision whether or not to pursue a treatment; and one in which beneficence and primum non nocere-first do no harm-are almost entirely the clinician's prerogative, and whereby he/she has a duty to refuse any treatment for which the potential risks outweigh the potential benefits for the patient. Recently, however, there has been a rejection of this dichotomous view of medical futility and the apparent "power struggle" between physician and patient, and a positive movement towards a more collaborative decision-making process that highlights the necessity of communication, aiming to result in the obtainment of the best possible outcome for each patient as an individual. PMID- 28001144 TI - Thermal, vibrational and optical properties of PrLuO3 interlanthanides from hydrothermally-derived precursors. AB - PrLuO3 interlanthanides were prepared at temperatures ranging from 800 degrees C to 1600 degrees C using hydrothermally-derived precursors. The chemical reactions observed include the conversion and segregation of Pr(OH)3 and LuO(OH), respectively, into PrO2 and Lu2O3 cubic oxides below 1200 degrees C, followed by the production of a mixture of hexagonal P63/mmc and orthorhombic Pnma PrLuO3 phases at 1400 degrees C. Phase-pure orthorhombic PrLuO3 was obtained at 1600 degrees C, which was corroborated by Raman and micro far-infrared spectroscopic analyses. Photoluminescence, colorimetric and lifetime measurements were carried out in PrLuO3 samples. Dominant emission verified in samples calcined at 1400 degrees C corresponds to the hypersensitive 3P0 -> 3F2 transition with a color purity of 97% (decay times of 12 MUs and 3 MUs), while emissions for the phase pure samples correspond to the 3P0 -> 3H6 and 3P0 -> 3H5 transitions with a color purity of 94% (a single luminescence lifetime of 12 MUs). The optical properties of PrLuO3 interlanthanides thereby suggest that they can be used as luminescent materials in both structural arrangements. PMID- 28001143 TI - Vital signs and their cross-correlation in sepsis and NEC: a study of 1,065 very low-birth-weight infants in two NICUs. AB - BACKGROUND: Subtle changes in vital signs and their interactions occur in preterm infants prior to overt deterioration from late-onset septicemia (LOS) or necrotizing enterocolitis (NEC). Optimizing predictive algorithms may lead to earlier treatment. METHODS: For 1,065 very-low-birth-weight (VLBW) infants in two neonatal intensive care units (NICUs), mean, SD, and cross-correlation of respiratory rate, heart rate (HR), and oxygen saturation (SpO2) were analyzed hourly (131 infant-years' data). Cross-correlation (cotrending) between two vital signs was measured allowing a lag of +/- 30 s. Cases of LOS and NEC were identified retrospectively (n = 186) and vital sign models were evaluated for ability to predict illness diagnosed in the ensuing 24 h. RESULTS: The best single illness predictor within and between institutions was cross-correlation of HR-SpO2. The best combined model (mean SpO2, SDHR, and cross-correlation of HR SpO2,) trained at one site with ROC area 0.695 had external ROC area of 0.754 at the other site, and provided additive value to an established HR characteristics index for illness prediction (Net Reclassification Improvement: 0.205; 95% confidence interval (CI): 0.113, 0.328). CONCLUSION: Despite minor inter institutional differences in vital sign patterns of VLBW infants, cross correlation of HR-SpO2 and a 3-variable vital sign model performed well at both centers for preclinical detection of sepsis or NEC. PMID- 28001145 TI - DNA biosensing with 3D printing technology. AB - 3D printing, an upcoming technology, has vast potential to transform conventional fabrication processes due to the numerous improvements it can offer to the current methods. To date, the employment of 3D printing technology has been examined for applications in the fields of engineering, manufacturing and biological sciences. In this study, we examined the potential of adopting 3D printing technology for a novel application, electrochemical DNA biosensing. Metal 3D printing was utilized to construct helical-shaped stainless steel electrodes which functioned as a transducing platform for the detection of DNA hybridization. The ability of electroactive methylene blue to intercalate into the double helix structure of double-stranded DNA was then exploited to monitor the DNA hybridization process, with its inherent reduction peak serving as an analytical signal. The designed biosensing approach was found to demonstrate superior selectivity against a non-complementary DNA target, with a detection range of 1-1000 nM. PMID- 28001146 TI - Development of a high throughput (HT) Raman spectroscopy method for rapid screening of liquid blood plasma from prostate cancer patients. AB - Extensive research has been undertaken on the examination of tissue biopsies using vibrational spectroscopic techniques. However, fewer studies have focused on less invasive and commonly acquired blood samples. Recent studies have shown the ability of Raman and Fourier transform infrared (FTIR) spectroscopy to discriminate between non-cancer controls and cancer cases using blood serum or plasma. Even though many studies have proposed Raman spectroscopy as a potential diagnostic tool in various cancers, the Raman spectroscopic technique has not been introduced as a routine clinical technology. This is due to multiple drawbacks with the application of the technique, including sample preparation, the requirement for expensive substrates and long acquisition times. The current study aims to overcome these limitations and focuses on the translation of Raman spectroscopy into a high throughput clinical diagnostic tool for prostate cancer. In this study, the effect of different instrumental and sample preparation parameters were investigated, with the aim of identifying a combination that would reduce the overall acquisition time for spectra from peripheral blood plasma, reduce the complexity of sample preparation and retain the classification accuracy from Raman spectroscopic diagnostics. A high throughput (HT) system was developed and Raman spectroscopic measurements were performed on plasma samples from 10 prostate cancer patients and 10 healthy volunteers. The spectra were pre processed and classified by principal component analysis - linear discriminant analysis (PCA-LDA) in the R environment. Statistically significant differences were observed between Raman spectra of prostate cancer patients and non-cancer controls. The (HT) classification resulted in a sensitivity and specificity of 96.5% and 95% respectively. Overall, this study has overcome some of the limitations associated with clinical translation of Raman spectroscopy. The HT Raman spectroscopy method developed in this study can be used for rapid and accurate diagnosis of prostate cancer using liquid plasma samples. PMID- 28001147 TI - Effects of weight loss using supplementation with Lactobacillus strains on body fat and medium-chain acylcarnitines in overweight individuals. AB - Our previous study showed that supplementation with a combination of Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 reduced the body weight, body fat percentage, body fat mass and L1 subcutaneous fat area in overweight subjects. We aimed to evaluate whether the changes in adiposity after supplementation with Lactobacillus strains were associated with metabolic intermediates. A randomized, double-blind, placebo controlled study was conducted on 66 non-diabetic and overweight individuals. Over a 12-week period, the probiotic group consumed 2 g of probiotic powder, whereas the placebo group consumed the same product without the probiotics. To investigate metabolic alterations, we performed plasma metabolomics using ultra performance liquid chromatography and mass spectrometry (UPLC-LTQ/Orbitrap MS). Probiotic supplementation significantly increased the levels of octenoylcarnitine (C8:1), tetradecenoylcarnitine (C14:1), decanoylcarnitine (C10) and dodecenoylcarnitine (C12:1) compared with the levels from placebo supplementation. In the probiotic group, the changes in the body weight, body fat percentage, body fat mass and L1 subcutaneous fat area were negatively associated with changes in the levels of C8:1, C14:1, C10 and C12:1 acylcarnitines. In overweight individuals, probiotic-induced weight loss and adiposity reduction from the probiotic supplementation were associated with an increase in medium chain acylcarnitines. PMID- 28001148 TI - A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier. AB - The neurovascular unit is a complex, interdependent system composed of neurons and neural supporting cells, such as astrocytes, as well as cells that comprise the vascular system including endothelial cells, pericytes, and smooth muscle cells. Each cell type in the neurovascular unit plays an essential role, either in transmitting and processing neural signals or in maintaining the appropriate microenvironmental conditions for healthy neural function. In vitro neurovascular models can be useful for understanding the different roles and functions of the cells composing the neurovascular unit, as well as for assessing the effects on neural function of therapeutic compounds after crossing the endothelial barrier. Here, we report a novel three-dimensional neurovascular microfluidic model consisting of primary rat astrocytes and neurons together with human cerebral microvascular endothelial cells. These three cell types in our neurovascular chip (NVC) show distinct cell type-specific morphological characteristics and functional properties. In particular, morphological and functional analysis of neurons enables quantitative assessment of neuronal responses, while human cerebral endothelial cells form monolayers with size-selective permeability similar to existing in vitro blood-brain barrier (BBB) models. PMID- 28001150 TI - Two hybrid transition metal triphosphonates decorated with a tripodal imidazole ligand: synthesis, structures and properties. AB - Two isostructural transition-metal (TM) triphosphonates decorated with neutral rigid N-containing ligands 1,3,5-tris(1-imidazolyl)benzene (tib), [Zn3(L1)(tib)].8H2O (1) and [Co3(L1)(tib)].9H2O (2) (H6L1 = N(CH2PO3H2)3), nitrilotris(methylenephosphonic acid), have been solvothermally prepared and structurally characterized by infrared spectroscopy, elemental analysis, thermogravimetric analysis and single-crystal/powder X-ray diffraction. The title compounds exhibit a pillar-layer structure with the TM-triphosphonates as layers and the rigid tib ligand as a pillar. The luminescence and magnetic properties have been investigated. Compound 1 exhibits intense blue luminescence, while compound 2 shows weak ferromagnetic behaviour. PMID- 28001149 TI - Patterning of sharp cellular interfaces with a reconfigurable elastic substrate. AB - Micropatterned cocultures are a useful experimental tool for the study of cell cell interactions. Patterning methods often rely on sequential seeding of different cell types or removal of a barrier separating two populations, but it is difficult to pattern sharp interfaces between pure populations with low cross contamination when using these approaches. Patterning by the use of reconfigurable substrates can overcome these limitations, but such methods can be costly and challenging to employ in a typical biology laboratory. Here, we describe a low-cost and simple-to-use reconfigurable substrate comprised of a transparent elastic material that is partially cut to form a slit that opens when the device is stretched. The slit seals back up when released, allowing two initially separate, adherent cell populations to be brought together to form a contact interface. Fluorescent imaging of patterned cocultures demonstrates the early establishment of a sharp cellular interface. As a proof of principle, we demonstrate the use of this device to study competition at the interface of two stem cell populations. PMID- 28001151 TI - Evaluation of clinical safety and beneficial effects of stachyose-enriched alpha galacto-oligosaccharides on gut microbiota and bowel function in humans. AB - Deshipu stachyose granules (DSG) is a mixture of alpha-galacto-oligosaccharides derived from the dietary roots of Lycopus lucidus Turcz. Our previous study showed that DSG could improve the faecal microbial composition, and facilitate intestinal peristalsis and fecal excretion in mice. This study was designed to investigate the effect of DSG on gut microbiota and bowel function in humans. Two human intervention studies were conducted. In the first study, 100 healthy adults were treated without or with 5 g per day of DSG for 14 days. The microbiota composition in fecal samples was quantitatively analyzed before and after DSG supplementation. We found that DSG consumption significantly elevated the fecal bifidobacteria and lactobacilli levels, and also decreased the fecal Clostridium perfringens concentration. In the second study, 103 constipated patients were treated with 5 g per day of placebo or DSG for 30 days, and subsequently subjected to bowel function evaluation. As a result, dietary intake of DSG effectively improved the bowel function of constipated patients, as evidenced by the increased defecation frequency, softer stools and easier defecation. Moreover, clinical safety assessment showed that DSG at 5 g per day did not cause significant adverse effects in both healthy and constipated volunteers. In conclusion, DSG at 5 g d-1 beneficially modulated the gut microbiota in healthy adults and potently improved the bowel function of constipated patients without consequent adverse events. This study suggests that DSG holds promising potential for safe treatment of functional constipation. PMID- 28001152 TI - PEG-peptide hydrogels reveal differential effects of matrix microenvironmental cues on melanoma drug sensitivity. AB - Metastatic melanoma is highly drug resistant, though the exact mechanisms of this resistance are not completely understood. One method to study melanoma drug responsiveness in vitro is through the use of multicellular spheroids, which have been found to exhibit decreased drug sensitivity compared to traditional 2D culture on various substrates. Because it is unclear whether dimensionality, cell matrix interactions, and/or cell-cell contacts may influence melanoma drug responsiveness, we utilized a synthetic PEG-based hydrogel to compare the responses of cells cultured on top of or encapsulated within matrices with the same adhesive ligand density, polymer density, and material properties. We found that depending on the stage of progression at which the melanoma cells were derived, the cells responded differently to PLX4032 treatment, a commercially available melanoma drug. In particular, early stage WM35 cells were insensitive to dimensionality (i.e., 2D versus 3D culture), while metastatic A375 cells exhibited decreased responsiveness in 3D compared to 2D. To further understand the role of the microenvironment in early stage melanoma cells, we tested single WM35 cells and multicellular WM35 spheroids in 3D. The results revealed that the spheroids were similarly sensitive to PLX4032 treatment compared to single cell encapsulations. Collectively, this study implicates the role that 3D microenvironments (i.e., dimensionality) may play in observed melanoma drug responsiveness, and the potential lack of influence of cell-matrix interactions over cell-cell contacts in early stages of melanoma resistance to PLX4032-induced apoptosis. PMID- 28001153 TI - Digital de-waxing on FTIR images. AB - This paper presents a procedure that digitally neutralizes the contribution of paraffin to FTIR hyperspectral images. A brief mathematical derivation of the procedure is demonstrated and applied on one normal human colon sample to exemplify the de-waxing procedure. The proposed method includes construction of a paraffin model based on PCA, EMSC normalization and application of two techniques for spectral quality control. We discuss every step in which the researcher needs to take a subjective decision during the de-waxing procedure, and we explain how to make an adequate choice of parameters involved. Application of this procedure to 71 hyperspectral images collected from 55 human colon biopsies (20 normal, 17 ulcerative colitis, and 18 adenocarcinoma) showed that paraffin was appropriately neutralized, which made the de-waxed images adequate for analysis by pattern recognition techniques such as k-means clustering or PCA-LDA. PMID- 28001154 TI - Synthetic investigation, structural analysis and photocatalytic study of a carboxylate-phosphonate bridged Ti18-oxo cluster. AB - By the combination of carboxylate and phosphonate ligands, we herein report a nanosized H2[Ti18(MU3-O)14(MU2-O)6(O3P-Phen)2(PA)16(OPri)14] (PTC-51) (HPA = propionic acid, O3P-Phen = phenyl phosphonate), whose structure can be observed as the linkage of independent phosphonate supporting and carboxylate bridging hexanuclear Ti(iv) clusters. We also demonstrate a concise crystalline phase diagram, which shows the important effect of phosphonate and carboxylate ligand ratio during synthetic reactions. The photocatalytic H2 evolution activities of the obtained polyoxotitanate materials have been studied, with carboxylate-Ti6 presenting the maximum H2 production rate up to 267.78 MUmol g-1 h-1. PMID- 28001155 TI - Microporous rod metal-organic frameworks with diverse Zn/Cd-triazolate ribbons as secondary building units for CO2 uptake and selective adsorption of hydrocarbons. AB - The synthetic design of new porous open-framework materials with pre-designed pore properties for desired applications such as gas adsorption and separation remains challenging. We proposed one such class of materials, rod metal-organic frameworks (rod MOFs), which can be tuned by using rod secondary building units (rod SBUs) with different geometrical and chemical features. Our approach takes advantage of the readily accessible metal-triazolate 1-D motifs as rod SBUs to combine with dicarboxylate ligands to prepare target rod MOFs. Herein we report three such metal-triazolate-dicarboxylate frameworks (SNNU-21, -22 and -23). During the formation of these three MOFs, Cd or Zn ions are firstly connected by 1,2,4-triazole through the N1,N2,N4-mode to form 1-D metal-organic ribbon-like rod SBUs, which further joint four adjacent rod SBUs via eight BDC linkers to give 3-D microporous frameworks. However, tuned by the different NH2 groups from metal-triazolate rod SBUs, different space groups, pore sizes and shapes are observed for SNNU-21-23. All of these rod MOFs show not only remarkable CO2 uptake capacity, but also high CO2 over CH4 and C2-hydrocarbons over CH4 selectivity under ambient conditions. Specially, SNNU-23 exhibits a very high isosteric heat of adsorption (Qst) for C2H2 (62.2 kJ mol-1), which outperforms the values of all MOF materials reported to date including the famous MOF-74-Co. PMID- 28001156 TI - An integral study of cyclodextrins as solubility enhancers of alpha methylstilbene, a resveratrol analogue. AB - trans-alpha-Methylstilbene (tMS), a resveratrol analogue, has recently been studied in a search for new bioactivities. However, such studies do not take into account that the poor solubility of tMS in aqueous solutions could affect its bioactivity. For this reason, we propose, for the first time, using cyclodextrins (CDs) as solubilizers to increase tMS solubility, in aqueous solutions. The HPLC RP results obtained, point to a 1 : 1 stoichiometry for all the natural (alpha-, beta- and gamma-CD) and modified (HPbetaCD and MbetaCD) CDs tested. The KFapp (apparent formation constant) for the tMS-CD complexes was seen to be closely dependent on several factors, including the temperature and type of CD. Indeed, the highest KFapp value was obtained for MbetaCD, while the KFapp decreased with increasing temperature. In addition, the results showed negative entropy (-8.86 * 10-3 +/- 0.40 kJ mol-1 K-1) and enthalpy (-16.70 +/- 0.98 kJ mol-1) changes and a negative Gibbs free energy value at 25 degrees C (-14.00 +/- 0.55 kJ mol-1) for the encapsulation process. A computational study carried out using molecular docking calculations showed a high degree of correlation between the computed scores and experimental values. Finally, the complexation of trans-stilbene and pinosylvin with HPbetaCD was compared with tMS. PMID- 28001157 TI - Multidentate 2-pyridyl-phosphine ligands - towards ligand tuning and chirality. AB - In the current work a range of multidentate pyridyl-phosphine ligands are synthesised with tuneable electronic and steric character, through the incorporation of a variety of alcohols into (amino)pyridyl-phosphine frameworks. The stoichiometric reactions of compounds of the type (R2N)xP(2-py)3-x (2-py = 2 pyridyl) with alkyl as well as aryl alcohols result in the formation of (alkoxy)pyridyl-phosphines (RO)xP(2-py)3-x (R = Me, 2-Bu, Ph). This synthetic procedure also allows the introduction of enantiomerically pure alcohols, like (R)-(-)-2-BuOH and (S)-(+)-2-BuOH, and as such provides a very convenient two step route to chiral multidentate pyridyl-phosphine ligand sets. Using the bis amino-phosphine (Et2N)2P(2-py), the stepwise introduction of alcohols enables the synthesis of racemic alkoxy-amino-phosphines (R2N)(RO)P(2-py), as well as alkoxy phosphines (RO)2P(2-py) and therefore offers easy access to a library of different pyridyl-phosphine ligands. Coordination studies of the (amino)pyridyl phosphines and (alkoxy)pyridyl-phosphines with copper(i) reveal that ligands with two N donor atoms form dimeric arrangements, while (PhO)2P(2-py), in-corporating only one N donor atom, shows completely different coordination behaviour. PMID- 28001158 TI - Water-head-driven microfluidic oscillators for autonomous control of periodic flows and generation of aqueous two-phase system droplets. AB - Generating periodic flows with an oscillator driven only by water-head pressure has potential for the operation of microfluidic systems without any dynamic off chip controllers. However, its operational characteristic is not well understood due to complex dynamic interactions of the microfluidic components. Here, we focus on the mechanism of a water-head-driven oscillator and analyze the functions of its flow-switching period (T) and flow rate (Q) in a wide range (0.1 s-5.9 h and 2 MUL min-1-2 mL min-1). We show linear control of T and Q by their corresponding fluidic resistors even with the complex and nonlinear relation of the microfluidic components. This allows independent regulation of T and Q within their operational ranges but we found the two parameters mutually constrain their ranges via fluidic resistance. Also, we characterize the control of T by water head pressure and present operational ranges of input water-head pressure decrease with increasing output water-head pressure. To show its utility, we apply the oscillator to generate droplets with low interfacial tension aqueous two-phase systems. Our study would be useful and provide the foundation for various functions of water-head-driven microfluidic circuits. PMID- 28001159 TI - Effect of Cu(ii) on in vitro glycation of human serum albumin by methylglyoxal: a LC-MS-based proteomic approach. AB - It has been reported that glycation of human serum albumin (HSA) changes its capability for copper binding whereas the increase of free copper might have an impact on protein glycation - a key process in diabetes progression. In this work, proteomic analysis of non-glycated HSA and HSA glycated with methylglyoxal (MGo) in the absence or in the presence of Cu(ii) (0.1; 1.0; 5.0 mg Cu L-1) has been undertaken. Trypsin hydrolysates were subjected to capillary HPLC-ESI-QTOF MS and MS/MS. Raw data were analyzed using two proteomic platforms: MaxQuant () and ProteinScape (Bruker). Considering seven MGo-derived modifications, the sequence coverage was 98% for non-modified HSA and >=93% for HSA incubated with MGo or MGo + Cu(ii). Peptide mapping yielded 76 identical peptides in all samples though important differences were found between non-modified HSA and protein glycated with or without Cu(ii). Overall, 46 peptides with residues from 1 to 3 modified were detected/sequenced; the MGo-derived modifications found were: hydroimidazolone, argpyrimidine, Nepsilon-carboxyethyl-lysine and S-carboxyethyl cysteine; 39 modified sites were identified (22 on arginine, 12 on lysine, and 5 on cysteine) and among them, 27 were common for ProteinScape and MaxQuant. The count of the modified peptides and the comparative analysis of their abundance in different samples indicated that Cu(ii) at physiological and sub-physiological concentrations inhibited HSA glycation as compared to the glycation of the Cu devoid protein; at higher concentrations (5 mg Cu L-1), this inhibitory effect tends to be inverted. The results obtained suggest that increased protein glycation might be associated with Cu-deficiency and with excessive Cu(ii) concentrations, calling for more detailed studies performed on real-world samples with a strict control of copper concentration. PMID- 28001160 TI - Photoluminescence and electroluminescence of cationic PtAu2 heterotrinuclear complexes with aromatic acetylides. AB - Cationic PtAu2 heterotrinuclear complexes [PtAu2(dpmp)2(C[triple bond, length as m-dash]CR)2]2+ (dpmp = bis(diphenylphosphinomethyl)phenylphosphine, R = aryl) of aromatic acetylides were prepared. The PtAu2 structures are supported through doubly bridging dpmp and stabilized by a significant Pt-Au interaction. They are highly phosphorescent in fluid CH2Cl2 solution (Phiem = 23.5%-78.9%), the solid state (Phiem = 15.4%-70.2%), the PMMA film (Phiem = 39.9%-71.7%) and the doping film of 61% TCTA : 31% OXD-7 : 8% PtAu2 complex (Phiem = 16.9%-67.9%). The phosphorescence arises mainly from 3[pi (C[triple bond, length as m-dash]CR) -> pi* (dpmp)] 3LLCT and 3[pi (C[triple bond, length as m-dash]CR) -> s/p (PtAu2)] 3LMCT triplet excited states for carbazole-acetylide complexes, whereas other complexes display a 3LLCT character mixed with noticeable PtAu2 centered 3[d -> s/p] parentage. Utilizing a mixed host composed of hole-transporting TCTA and electron-transporting OXD-7 doped with 8% PtAu2 species as a light-emitting layer and CuSCN as a hole-transporting layer through an orthogonal solution process, the devices exhibit highly efficient electrophosphorescence with the highest current efficiency (CEmax) of 51.7 cd A-1 and external quantum efficiency (EQEmax) of 14.5%. The efficiency roll-off is small in the practical brightness range of 500-5000 cd m-2. The PtAu2 complexes with carbazole-acetylides display a higher electroluminescence efficiency ascribed to their better hole-transporting character as well as more facile energy transfer from mixed host materials. PMID- 28001161 TI - Magnetic separation of microparticles by shape. AB - Accurate separation of microparticles by shape has diverse applications in biology and biotechnology, but is a significant challenge in separation science and engineering. We demonstrate a simple and effective mechanism that can achieve shape-based separation of magnetic particles in microscale flows. In this method, a uniform magnetic field is applied perpendicularly to the flow direction, and causes shape-dependent lateral migration of the particles. Using high-speed imaging, we studied the rotational dynamics of the ellipsoidal particles. It is found that the lateral migration is correlated with the asymmetric rotation of the particles. Different from existing techniques that use magnetic forces, our method uses shape-dependent magnetic torque but zero magnetic force. PMID- 28001162 TI - Diversity of reactivity modes upon interplay between Au(iii)-bound isocyanides and cyclic nitrones: a theoretical consideration. AB - Metal-bound isocyanides demonstrate a very rich chemistry towards 1,3-dipoles of the allyl anion type such as nitrones. Depending on the metal centre, dipole nature and substituent in isocyanides, cycloadducts, imine + isocyanates or metallacycles may be formed. In this work, the reasons for such diversity, intimate details of the reaction mechanism and main factors determining the chemoselectivity in the reaction between Au(iii)-bound isocyanides ([AuCl3(C[triple bond, length as m-dash]NR)]) and cyclic nitrones -O-N[combining low line]+[double bond, length as m-dash]C(H)XXX[combining low line] (XXX = CH2CH2CMe2, CH2CH2CH2, OCH2CMe2, CH2OCMe2 and CH2CH2O) are analysed in detail by theoretical (DFT) methods. The formation of cycloadducts is controlled by the LUMOpi*(C[triple bond, length as m-dash]N) of isocyanides and it occurs in a stepwise manner via the initial nucleophilic addition of nitrone at the C atom of C[triple bond, length as m-dash]NR (except for nitronate -O-N[combining low line]+[double bond, length as m-dash]C(H)CH2CH2O[combining low line]). The imine + isocyanate products are formed upon oxygen transfer from nitrones to isocyanides, and N-O bond cleavage is the main factor determining this process. A metallacycle is formed upon decomposition of the cycloadduct, and this process includes deprotonation of the oxadiazoline CH group/N-O bond cleavage and Cl- elimination/cyclization. The main factor controlling the metallacycle formation is the acidity of the endocyclic CH group in the cycloadduct. Effects of the substituent R in C[triple bond, length as m-dash]NR and the nitrone nature on the reactivity are analysed. PMID- 28001163 TI - Aryl-NHC-group 13 trimethyl complexes: structural, stability and bonding insights. AB - Treatment of aromatic N-substituted N-heterocyclic carbenes (NHCs) with trimethyl gallium and -indium yielded the new Lewis acid-base adducts, IMes.GaMe3 (1), SIMes.GaMe3 (2), IPr.GaMe3 (3), SIPr.GaMe3 (4), IMes.InMe3 (5), SIMes.InMe3 (6), IPr.InMe3 (7), and SIPr.InMe3 (8), with all complexes being identified by X-ray diffraction, IR, and multinuclear NMR analyses. Complex stability was found to be largely dependent on the nature of the constituent NHC ligands. Percent buried volume (%VBur) and topographic steric map analyses were employed to quantify and elucidate the observed trends. Additionally, a detailed bond snapping energy (BSE) decomposition analysis focusing on both steric and orbital interactions of the M-NHC bond (M = Al, Ga and In) has been performed. PMID- 28001164 TI - Photoluminescence and electroluminescence of iridium(iii) complexes with 2',6' bis(trifluoromethyl)-2,4'-bipyridine and 1,3,4-oxadiazole/1,3,4-thiadiazole derivative ligands. AB - Using 2',6'-bis(trifluoromethyl)-2,4'-bipyridine as a monoanionic cyclometalated ligand, 2-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)phenol and 2-(5-(4 (trifluoromethyl) phenyl)-1,3,4-thiadiazol-2-yl)phenol as ancillary ligands, two new heteroleptic iridium(iii) complexes (Ir1 and Ir2) were prepared and investigated. The ancillary ligand variations affected their emissions greatly, and the complexes Ir1 and Ir2 emitted green (503 nm) and orange (579 nm) lights, respectively. Moreover, the electron mobility of the two complexes is as high as that of the electron transport material Alq3 (tris-(8 hydroxyquinoline)aluminium), which is useful for their performances in organic light-emitting diodes (OLEDs). The OLEDs with Ir1 as the emitter showed excellent performances with a maximum current efficiency of 74.8 cd A-1, a maximum external quantum efficiency of 27.0%, a maximum power efficiency of 33.4 lm W-1, and the efficiency roll-off is mild. These results suggest that complexes with 1,3,4 oxadiazole/1,3,4-thiadiazole derivatives have potential application as efficient emitters in OLEDs. PMID- 28001165 TI - Pinch-off dynamics and dripping-onto-substrate (DoS) rheometry of complex fluids. AB - Liquid transfer and drop formation/deposition processes involve complex free surface flows including the formation of columnar necks that undergo spontaneous capillary-driven instability, thinning and pinch-off. For simple (Newtonian and inelastic) fluids, a complex interplay of capillary, inertial and viscous stresses determines the nonlinear dynamics underlying finite-time singularity as well as self-similar capillary thinning and pinch-off dynamics. In rheologically complex fluids, extra elastic stresses as well as non-Newtonian shear and extensional viscosities dramatically alter the nonlinear dynamics. Stream-wise velocity gradients that arise within the thinning columnar neck create an extensional flow field, and many complex fluids exhibit a much larger resistance to elongational flows than Newtonian fluids with similar shear viscosity. Characterization of pinch-off dynamics and the response to both shear and extensional flows that influence drop formation/deposition in microfluidic and printing applications requires bespoke instrumentation not available, or easily replicated, in most laboratories. Here we show that dripping-onto-substrate (DoS) rheometry protocols that involve visualization and analysis of capillary-driven thinning and pinch-off dynamics of a columnar neck formed between a nozzle and a sessile drop can be used for measuring shear viscosity, power law index, extensional viscosity, relaxation time and the most relevant processing timescale for printing. We showcase the versatility of DoS rheometry by characterizing and contrasting the pinch-off dynamics of a wide spectrum of simple and complex fluids: water, printing inks, semi-dilute polymer solutions, yield stress fluids, food materials and cosmetics. We show that DoS rheometry enables characterization of low viscosity printing inks and polymer solutions that are beyond the measurable range of commercially-available capillary break-up extensional rheometer (CaBER). We show that for high viscosity fluids, DoS rheometry can be implemented relatively inexpensively using an off-the-shelf digital camera, and for many complex fluids, similar power law scaling exponent describes both neck thinning dynamics and the shear thinning response. PMID- 28001172 TI - Pregnancy after kidney transplantation: high rates of maternal complications. AB - INTRODUCTION: Women regain fertility a few time after renal transplantation. However, viability of pregnancy and maternal complications are still unclear. OBJECTIVE: To describe the outcomes of pregnancies in kidney transplanted patients, focusing on maternal complications. METHODS: Retrospective study of pregnancies in kidney transplanted patients between 2004 and 2014, followed up 12 months after delivery. Each pregnancy was considered an event. RESULTS: There were 53 pregnancies in 36 patients. Mean age was 28 +/- 5years. Pregnancy occurred 4.4 +/- 3.0 years post-transplant. Immunosuppression before conception was tacrolimus, azathioprine, and prednisone in 74% of the cases. There were 15% miscarriages in the 1st trimester and 8% in 2nd trimester. In 41% of the cases, it was necessary to induce labor. From all births, 22% were premature and 17% very premature. There were 5% stillbirths and 5% of neonatal deaths. De novo proteinuria occurred in 60%, urinary tract infection in 23%, preeclampsia in 11%, acute rejection in 6%, and graft loss in 2% of the cases. It was observed a significant increase in creatinine at preconception comparing to 3rd trimester and follow-up (1.17 vs. 1.46 vs. 1.59 mg/dL, p < 0.001). CONCLUSION: Although the sample is limited, the number of miscarriages was higher than in the general population, with high rates of maternal complications. Sustained increase of creatinine suggests increased risk of graft loss in long-term. PMID- 28001171 TI - Anisakid larva parasitizing Plagioscion squamosissimus in Marajo Bay and Tapajos River, state of Para, Brazil. AB - In November 2014 and May 2015, a total of 44 specimens of the South American silver croaker Plagioscion squamosissimus were collected: 30 in Marajo Bay and 14 in the Tapajos River, state of Para, Brazil. The aim was to investigate the presence of anisakid nematodes and determine their parasitism indices and sites of infection, because of their importance regarding health inspection. Sixty-nine Anisakis sp. larvae were found; among them, 16 larvae in seven fish collected in Marajo Bay and 53 larvae in four fish in the Tapajos River. The parasitism indices of the nematodes collected from the fish in Marajo Bay comprised prevalence (P) of 23%, mean infection intensity (MI) of 2.28, mean abundance (MA) of 0.53, range of infection (RI) of 1-4, and infection site (IS) in the mesentery. The fish from the Tapajos River showed P = 28%, MI = 13.2, MA = 3.8, RI = 1-22, and IS = mesentery and intestine. To assist in taxonomic identification, images of the specimens obtained through optical microscopy with Nomarski's interferential contrast system and scanning electron microscopy were used. This is the first record of Anisakis sp. parasitizing P. squamosissimus. PMID- 28001173 TI - Patient in chronic hemodialysis with right atrial mass: thrombus, fungal endocarditis or atrial myxoma? AB - We present the case report of a 19-year-old patient with chronic kidney disease due to chronic glomerulonephritis, in hemodialysis (HD) by central catheter, with the incidental finding of a mass of 28x16 mm in right atrium (RA). The diagnosis of thrombus, infective endocarditis or myxoma were considered. Given the context of immunosuppression and difficult access vascular therapeutic practice has proved complex. Although Doppler echocardiography suggested thrombus in RA, nuclear magnetic resonance imaging (MRI) indicated for the diagnosis of myxoma in RA. In both conditions, the proposed surgical approach was limited by intense immunosuppression history and the risk of infectious complications. Throughout the treatment, the general state of K.M.F. remained satisfactory and revealed no signs or symptoms related to atrial dysfunction. The absence of fever and negative blood cultures excluded infective endocarditis. Prior echocardiogram report without masses in the RA decreased the chance of cardiac myxoma. The therapeutic response to anticoagulation confirmed the diagnosis of thrombosis. After 180 days of anticoagulation, there was significant reduction in mass. The patient developed asymptomatic. The diagnosis of mass in RA can be a challenge and only the evolution of the case was able to guide the appropriate conduit. While MRI has high sensitivity and specificity for the diagnosis of cardiac myxoma, the interpretation of images can be subjective. Controversial point is the removal of the catheter in such cases, which is subject discussed throughout the report. PMID- 28001174 TI - Impact of gender in early structural changes of contrast induced nephropathy in rats. AB - INTRODUCTION: Contrast-induced nephropathy (CIN) is a major iatrogenic cause of acute kidney injury. Experimental studies have shown that intravascular injection causes intense vacuolization of the contrast agent in the proximal renal tubules cells, preceding the increase in serum creatinine, and that the female may be at a higher risk for CIN. OBJECTIVE: To study the early kidney histomorphometric changes in contrast-induced nephropathy according to the gender. METHODS: Twenty previously uninephrectomized Wistar rats were divided into 4 groups (n = 5): control males; control females; contrast exposed males; and contrast exposed females. The animals were sacrificed immediately after contrast administration and kidney tissue samples were collected for histomorphometric analysis. The research project was approved by the Research Ethics Committee of the School of Medicine of Universidade Federal Fluminense. RESULTS: There was a more intense presence of microvacuoles in proximal tubules in the rats exposed to contrast than in the control groups. Such proximal tubular vacuolation was more intensive in the female rats (p = 0.001). CONCLUSION: Proximal tubular vacuolation is a very early change in CIN and is more intensive in female than in male rats. PMID- 28001175 TI - Nodular glomerulosclerosis in a non-diabetic hypertensive, dyslipidemic, smoker patient: a case report. AB - INTRODUCTION: This is a case report of a patient with idiopathic nodular glomerulosclerosis whose pathogenesis and morphology are similar to diabetic nephropathy. CASE PRESENTATION: A 64-year-old Brazilian man, leukoderma, dyslipidemic, obese with chronic obstructive pulmonary disease secondary to tobacco smoking, known to be hypertensive for five years and he had no history of diabetes. He was admitted with sudden anasarca, rapid loss of renal function and needed to start hemodialysis immediately. Renal biopsy was performed, and the sections were examined by light microscopy, immunofluorescence and electron microscopy. Morphological and ultrastructural findings showed that the profile of the disease studied herein strongly resembles diabetic nephropathy. However, the absence of diabetes mellitus, the presence of arteriolar hyalinosis in renal arterioles, tobacco smoking, and other clinical factors observed can play a significant role in nodular formation. CONCLUSION: The clinical features of the patient, and most importantly, the fact that he is a smoker, favor the diagnosis of "nodular glomerulosclerosis associated with smoking", a nomenclature proposed by some authors as an alternative to the term idiopathic nodular glomerulosclerosis. This clinical case report highlights idiopathic nodular glomerulosclerosis as a rare disease of little known etiopathogenesis; thus, further studies are necessary in order to elucidate the causes of this disease. PMID- 28001176 TI - Hyperuricemia as a potential risk factor for type 2 diabetes and diabetic nephropathy. PMID- 28001177 TI - Uromodulin: a new biomarker of fetal renal function? AB - INTRODUCTION: Obstructive uropathies are main diseases affecting the fetus. Early diagnosis allows to establish the appropriate therapy to minimize the risk of damage to kidney function at birth. Biochemical markers have been used to predict the prognosis of renal function in fetuses. Uromodulin, also known by Tamm Horsfall protein (THP) is exclusively produced in the kidneys and in normal conditions is the protein excreted in larger amounts in human urine. It plays important roles in kidneys and urinary tract. Also it participates in ion transport processes, interact with various components of the immune system and has a role in defense against urinary tract infections. Moreover, this protein was proved to be a good marker of renal function in adult patients with several renal diseases. OBJECTIVE: To evaluate if uromodulin is produced and eliminated by the kidneys during fetal life by analyzing fetal urine and amniotic fluid and to establish correlation with biochemical parameter of renal function already used in Fetal Medicine Center at the Clinic Hospital of UFMG (CEMEFE/HC). METHODS: Between 2013 and 2015, were selected 29 fetuses with indication of invasive tests for fetal diagnosis in monitoring at the CEMEFE/HC. RESULTS: The determination of uromodulin was possible and measurable in all samples and showed statistically significant correlation with the osmolarity. CONCLUSION: There was a tendency of lower levels of Uromodulin values in fetuses with severe renal impairment prenatally. Thus, high levels of this protein in fetal amniotic fluid or fetal urine dosages possibly mean kidney function preserved. PMID- 28001178 TI - Careful selection of predictor variables of AKI for robust regression model in Intensive Care Unit. PMID- 28001179 TI - Lupus cystitis presenting with hidronephrosis and gastrointestinal involvement. AB - INTRODUCTION: Lupus cystitis is a rare manifestation of systemic lupus erythematosus, characterized by thickening of the bladder wall, associated with ureterohydronephrosis. In several cases gastrointestinal symptoms are the main manifestation. The optimal immunosuppressive regimen is still unknown. METHODS: 16-year-old girl with systemic lupus erythematosus was admitted with dysuria, renal impairment, diarrhea, abdominal pain, nausea and vomiting. An abdominal CT scan demonstrated moderate bilateral dilation from the pelvis to the ureterovesical junction, and the bladder exhibited reduced capacity and diffusely thickened walls. A diagnosis of chronic interstitial cystitis was performed and treatment with high dose methylprednisolone resulted in a significant relief of gastrointestinal and urinary symptoms and a reduction of the bladder thickness with improvement of their capacity. CONCLUSION: Lupus cystitis is a rare and underdiagnosed urinary manifestation of LES and the presence of mild urinary symptoms and abdominal pain may alert about this possibility. PMID- 28001180 TI - Is there a relationship between tryptophan dietary intake and plasma levels of indoxyl sulfate in chronic kidney disease patients on hemodialysis? AB - INTRODUCTION: Gut microbiota is involved in generation of uremic toxins in chronic kidney disease (CKD) patients on hemodialysis (HD), like indoxyl sulfate (IS) that is originated from tryptophan amino acid fermentation. OBJECTIVE: To evaluate the tryptophan intake by chronic renal failure patients on HD and its possible relationship with IS plasma levels. METHODS: Participated of the study 46 patients with CKD on HD regular program (56.5% men; 52.7 +/- 10.3 years; 63 (32.2-118.2) months on HD; BMI 25.6 +/- 4.9 kg/m2). The tryptophan intake was evaluated by a 24-hours dietary recall (R-24h) performed on 3 different days. Routine biochemical tests and anthropometric measurements were evaluated. IS plasma levels were determined by High Performance Liquid Chromatography (HPLC) with fluorescent detection and the interleukin-6 (IL-6) plasma levels by immunoenzymatic method (ELISA, Enzyme Linked Immunosorbent Assay). RESULTS: The average of tryptophan intake was according to recommendation, but IS plasma levels (35.0 +/- 11.9 mg/L) were elevated, however according to the EUTox values for uremic individuals. There was no correlation between the tryptophan intake and IS plasma levels. However, there was positive correlation between protein intake and tryptophan and variables used to evaluate lean body mass, and moreover, IS levels were positively associated with IL-6 (r = 0.6: p = 0.01). CONCLUSION: The present study suggests that tryptophan dietary intake may not be a determinant factor to IS levels. However, it suggests that gut microbiota may play an important role in systemic inflammation in patients with CKD. PMID- 28001181 TI - Errata. PMID- 28001182 TI - Contrast induced nephropathy. PMID- 28001183 TI - Quality of life in hemodialysis patients and the relationship with mortality, hospitalizations and poor treatment adherence. AB - INTRODUCTION: Chronic kidney disease (CKD) causes sudden changes in the daily lives of patients, creates limitations to perform activities of daily life and creates a great impact on emotions and quality of life (QOL) of patients. OBJECTIVE: To understand the relationship between QOL of patients on dialysis and mortality rates, hospitalization and absences. METHODS: A prospective descriptive study with 286 patients on hemodialysis, by applying demographic questionnaire, KDQOL SF-36 and electronic medical record analysis Dialsist. RESULTS: The mean age was 54.71 +/- 14.12 years, with a mean score of QOL 60.53 having as higher factor encouraging the support team (85.03) and lowest in work status (21.11). The days of hospitalization is negatively correlated to the compounds of the instrument, particularly in physical functioning (p = 0.000), mean score (p = 0.001) and emotional well-being (p = 0.005). Women had lower QOL in physical role scores, symptoms/problems, physical functioning, emotional well-being, energy and fatigue mean score (p <= 0.05). The lowest score was found to be related to treatment of patients in 1 year and 7 months and 5 years (59.93) and higher in patients with more than five years and one month (61.39). CONCLUSION: Hospitalizations decrease QV emotional and physical scores and absences are directly related to social support and age. The study looked through the data raise subsidies for the work of the aspects that need stimulation and adaptation in the lives of patients, providing a better balance in the individual's life. PMID- 28001184 TI - Mental disorders in children and adolescents with lower urinary tract dysfunction. AB - Lower urinary tract dysfunction (LUTD) affects about 2-25% of the pediatric population and is associated with the presence of emotional and behavioral disorders. The purpose of this literature review was to identify studies focusing on mental disorders in children and adolescents with LUTD. The prevalence of these disorders is high - ranging from about 20 to 40% - in children with symptoms of LUTD and comorbidities. The presence of emotional and behavioral symptoms impact in the treatment of the dysfunction, self-esteem of patients and caregivers. Despite the association between mental/behavioral disorders and LUTD be well documented in the literature, the investigation of psychiatric symptoms in clinical practice is still not common and should be stimulated. PMID- 28001185 TI - Serum uric acid and its association with hypertension, early nephropathy and chronic kidney disease in type 2 diabetic patients. AB - INTRODUCTION: Early detection diabetic nephropathy (DN) is important. Whether serum uric acid (SUA) has a role in the development of DN is not known. OBJECTIVE: To study the relationship between SUA and hypertension, early nephropathy and progression of chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM). METHODS: The total number of the study was 986 participants, according to presence and duration of diabetes were classified into three groups. Group I; including 250 healthy participants. Group II; including 352 with onset of diabetes < 5 years. Group III; including 384, with the onset of diabetes > 5 years. All participants were submitted to complete clinical examination, anthropometric measurements, laboratory investigations, including glycosylated hemoglobin (HbA1C), as well triglycerides to high-density lipoprotein ratios (TG/HDL-C), SUA, urinary albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). RESULTS: SUA, BP, HbA1c, TG/HDL-C ratio, and ACR levels were significantly higher in group III than group I, II and in II than I. eGFR significantly lower in group III than group I, II and in II than I (p < 0.001). Age, BMI, BP, HbA1c, TG/HDL-C, ACR, were positively correlated with SUA, while GFR negatively correlated. SUA at level of > 6.1 mg/dl, > 6.2 mg/dl and > 6.5 mg/dl had a greater sensitivity and specificity for identifying hypertension, early nephropathy and decline eGFR respectively. CONCLUSION: Even high normal SUA level, was associated with the risk of hypertension, early nephropathy and decline of eGFR. Moreover SUA level may identify the onset of hypertension, early nephropathy and progression of CKD in T2DM. PMID- 28001186 TI - Hypercalcemia and renal function impairment associated with vitamin D toxicity: case report. AB - Nowadays vitamin D (25-OHD) deficiency is supposed to be a global epidemic condition. Expectedly, vitamin D measurement and intake exponentially increased in Brazil in this decade. Although the benefit of vitamin D to general health is still in debate, its indiscriminate use potentially may lead to enhance the incidence of vitamin D intoxication, which is considered a rare disorder. We report a case of a 70 year old diabetic male with chronic renal disease (blood creatinine of 1.6 mg/dL) who progressed suddenly to acute kidney injury (blood creatinine of 5.7 mg/dL) associated with hypercalcemia and high blood levels of vitamin D. Vitamin D and calcitriol were discontinued and hypercalcemia was managed by hydration followed by furosemide. Thereafter, disodium pamidronate was administered and the patient did not undergo on dialysis. It took approximately 14 months to normalize 25-OHD levels and blood creatinine returned to basal levels only after 24 months. The indicated labeling dosage was 2000 IU, but most likely the vitamin D manipulated preparation was higher as the vitamin D blood levels were very high. Although rare, vitamin D intoxication is becoming more frequent as the patients use frequently manipulated preparations that could be subject to errors in the manufacturing and labeling of the tablets or capsules. The present report alerts to the potential increase in the incidence of severe vitamin D intoxication due to the frequent use of this secosteroid as a nutritional supplement. At the same time, it is necessary to improve regulation on the nutrient supplement market. PMID- 28001188 TI - Author's response. PMID- 28001187 TI - Treatment of idiopathic light chain deposition disease: complete remission with bortezomib and dexamethasone. AB - Light chain deposition disease (LCDD) is a rare clinical entity characterized by the deposition of light chain immunoglobulins in different tissues and primarily affects the kidneys, followed by the liver and heart. This disease often manifests as nephrotic syndrome with marked proteinuria and rapid deterioration of renal function. More than 50% of cases are secondary to multiple myeloma or other lymphoproliferative diseases, with a well-established treatment aimed at controlling the underlying disease. In rare cases, there is no detection of an associated hematological disease, referred to as idiopathic LCDD. In these cases, there is no evidence-based consensus on the therapeutic approach, and management is based on the clinical experience of reported cases. Here we report a case of idiopathic LCDD treated with bortezomib and dexamethasone with complete hematologic responses, significant reduction of proteinuria, and improved renal function. PMID- 28001189 TI - Acute myeloid leukemia after kidney transplantation: a case report and literature review. AB - The incidence of malignancy is greater in kidney transplant recipients compared to the general population, though the higher risk is not equally distributed to all types of cancers. In face of the increased longevity of renal transplant recipients, certain cancers, such as acute leukemias, are becoming more prevalent. Acute myeloid leukemia (AML) typically presents with cytopenias and infections, both common findings after kidney transplantation. Therefore, the diagnosis of AML may be initially overlooked in these patients. We report the case of a 33-year-old man who presented with fever, pancytopenia and acute worsening of his renal allograft function 9 years after a living unrelated kidney transplant. After initial negative infectious work-up, a kidney biopsy revealed C4d-positive antibody-mediated rejection in combination with scattered atypical inflammatory cells. A subsequent bone marrow biopsy confirmed AML. He underwent successful induction chemotherapy with daunorubucin and cytarabine and ultimately achieved a complete remission. However, he developed a Page kidney with worsening renal function and abdominal pain three weeks after biopsy in the setting of chemotherapy-induced thrombocytopenia. Herein, we discuss the prevalence, risk factors, presentation and management of leukemia after kidney transplantation. PMID- 28001190 TI - An update on pathology of IgA nephropathy. AB - IgA Nephropathy (IgAN) is the commonest of the glomerular diseases in the world. Its progression rate of 30-40% of the cases em 20-30 years makes IgAN an important healthcare issue in Nephrology. Diagnosis of IgAN depends on biopsy findings, particularly at immunofluorescence microscopy. The frequence of IgAN diagnosis is variable in different populations and depends on screening and biopsy indication policies. IgAN pathogenesis is considered multifactorial; its primordial defect is the production of galactosis-deficient IgA molecules. This review paper discusses the most uptodate aspects of the pathogenesis, pathological classification and clinical implications of IgAN. PMID- 28001191 TI - Purple urine bag syndrome: case report for Streptoccocus agalactiae and literature review. AB - We report a case of purple urine bag syndrome, associated to Streptococcus agalactiae urinary tract infection, progressing to septic shock and death. We present a review of the literature on the subject and take the opportunity to attend readers about increasing incidence with population aging and its potential bad outcome. PMID- 28001192 TI - Curbing the tobacco epidemic in the Americas. PMID- 28001193 TI - The case of tobacco taxation: where we are and how to accelerate its use for public health. PMID- 28001194 TI - Addressing the evidence gap to stimulate tobacco control in Latin America and the Caribbean. PMID- 28001195 TI - [Burden of disease attributable to tobacco use in Argentina and potential impact of price increases through taxes]. AB - Objective: Evaluate burden of disease associated with tobacco use in Argentina and estimate health and economic impacts of cigarette price increases through taxes. Methods: A microsimulation model was used to quantify smoking-attributable impact on mortality, quality of life, and costs for cardiovascular, cerebrovascular, and chronic obstructive pulmonary disease; pneumonia; and ten cancers. Modeling was done for effect of different price increase scenarios on tobacco use and their impact on health and economics. Results: In Argentina, 44 851 deaths, 20 620 cancer diagnoses, 14 405 strokes, and 68 100 hospital admissions for cardiovascular disease can be attributed to smoking every year. Every year, 998 881 years of life are lost from premature death and disability. The cost of treating tobacco-attributable health problems amounts to 33 billion Argentine pesos (ARS). Tobacco taxes only cover 67.3% of this expense. If Argentina increases cigarettes prices by 50% in the next 10 years, 25 557 deaths, 42 560 cardiovascular events, and 11 222 cancers could be prevented, with an economic benefit of 122 billion ARS from savings on health costs and from increasing tax revenues (1 US$ = 8.8096 ARS). Conclusions: Smoking-attributable burden of disease and costs to the health system are very high in Argentina. An increase in cigarette taxes could have considerable health and economic benefits. PMID- 28001196 TI - [Financial impact of smoking on health systems in Latin America: A study of seven countries and extrapolation to the regional level]. AB - Objective: Estimate smoking-attributable direct medical costs in Latin American health systems. Methods: A microsimulation model was used to quantify financial impact of cardiovascular and cerebrovascular disease, chronic obstructive pulmonary disease (COPD), pneumonia, lung cancer, and nine other neoplasms. A systematic search for epidemiological data and event costs was carried out. The model was calibrated and validated for Argentina, Bolivia, Brazil, Chile, Colombia, Mexico, and Peru, countries that account for 78% of Latin America's population; the results were then extrapolated to the regional level. Results: Every year, smoking is responsible for 33 576 billion dollars in direct costs to health systems. This amounts to 0.7% of the region's gross domestic product (GDP) and 8.3% of its health budget. Cardiovascular disease, COPD, and cancer were responsible for 30.3%, 26.9%, and 23.7% of these expenditures, respectively. Smoking-attributable costs ranged from 0.4% (Mexico and Peru) to 0.9% (Chile) of GDP and from 5.2% (Brazil) to 12.7% (Bolivia) of health expenditures. In the region, tax revenues from cigarette sales barely cover 37% of smoking attributable health expenditures (8.1% in Bolivia and 67.3% in Argentina). Conclusions: Smoking is responsible for a significant proportion of health spending in Latin America, and tax revenues from cigarette sales are far from covering it. The region's countries should seriously consider stronger measures, such as an increase in tobacco taxes. PMID- 28001197 TI - [Price elasticity of demand for cigarettes and alcohol in Ecuador, based on household data]. AB - Objective: Estimate price elasticity of demand for cigarettes and alcohol in Ecuador using cross-sectional data from the National Survey of Urban and Rural Household Income and Expenditures (ENIGHUR is the acronym in Spanish) 2011-2012. Methods: ENIGHUR 2011-2012 data were used with Deaton's (1, 2) methodology to estimate price elasticity of demand for cigarettes and alcohol with expenditure and quantity information. Household socioeconomic variables were also included. Results: Price elasticity of demand for cigarettes is -0.87, meaning that a 10% price increase could lead to an 8.7% decrease in consumption. Results for cross price elasticities of alcohol on cigarette demand are negative, as expected, indicating that they are complementary goods; however, the results are not statistically significant. Furthermore, it was found that price elasticity of demand for alcohol is -0.44, meaning that a 10% increase in the price of alcohol would produce a 4.4% decrease in consumption. Conclusions: A policy of price increases, for example, with a tax increase, applied to both cigarettes and alcohol, could have a positive effect on public health through reductions in consumption of both goods. However, this measure would not be sufficient to bridge gaps in prevalence measures and health outcomes between sex and other population groups, given the observed difference in the sensitivity of consumption to price variations. PMID- 28001198 TI - [Cigarette taxes and demand in Colombia]. AB - Objective: Estimate price and income elasticities of aggregate demand for cigarettes in Colombia, by controlling for structural market changes since the late 1990s, to identify policy opportunities for taxes that could improve public health and increase tax revenues. Methods: Measurement of aggregate demand for cigarettes using gross income reported on value-added tax returns submitted to Colombia's National Tax and Customs Office (DIAN is the acronym in Spanish) by the tobacco product manufacturing industry, subtracting exports. A quarterly time series was obtained for the period 1994-2014. The econometric estimation using two-stage least squares controls for price endogeneity and uses a set of dummy variables to control for structural changes in the market and in its regulation. Results: Demand is, from a statistical standpoint, sensitive to price and to income. Price elasticity of demand is -0.78 and income elasticity is 0.61. Conclusions: Inelastic demand implies that it is possible, through cigarette excise taxes, to meet public health targets and increase revenues simultaneously. The results also suggest that the considerable increase in household income in Colombia in the first decade of the 21st century increased purchasing power, which, lacking an accompanying tax increase, promoted cigarette consumption, with negative effects on public health, and wasted an opportunity to increase tax revenues. PMID- 28001199 TI - [Demand for cigarettes and tax increases in El Salvador]. AB - Objective: Analyze short- and long-term elasticities of demand for cigarettes in El Salvador as a tool for supporting recommendations on tax increases to reduce prevalence and consumption through price increases. Methods: Demand for cigarettes in El Salvador was analyzed through an econometric time-series model using a database from El Salvador's General Directorate of Internal Taxes (DGII) and the General Directorate of Statistics and Census (DIGESTYC). The analysis period was quarterly: 2000Q1-2012Q4. The usual tests were done to prevent a spurious econometric estimation. It was found that the variables volume sales, actual sale prices, and actual per capita income exhibited first-order cointegration; this result makes it possible to use an error correction model with short- and long-term elasticity estimates. Results: Only long-term elasticities were found to be statistically significant to 5%. Results show long term price elasticity (5 quarters) of -0.9287 and income price elasticity of 0.9978. Conclusions: Absolute price elasticity is somewhat high, although it is within the levels estimated in other studies in low per-capita income countries. A tax increase from a base amount of US$1.04 per pack of 20 cigarettes to US$1.66 within three years would reduce demand by 20% to 31% and would increase tax revenues by 9% to 22%. PMID- 28001200 TI - Increasing excise taxes in the presence of an illegal cigarette market: the 2011 Brazil tobacco tax reform. AB - The Brazilian cigarette excise tax reform of 2011 increased tax rates significantly in the presence of a high proportion of illegal and cheap cigarettes contributing to total consumption. Prior to 2011, tobacco tax policy in Brazil had reduced excise tax share on consumer prices, for fear of smuggling. This report examines two hypotheses explaining why tax authorities changed direction. The first is related to lack of concern regarding smuggling in tobacco industry pricing behavior before 2011 (rather than reducing prices following tax reduction, legal companies increased net of tax prices above inflation and key costs). The second hypothesis regards inconsistent industry assessments of the size of the illicit market, which ultimately undermined the credibility of the industry with tax authorities. The author concludes that the 2011 reform was designed to revert the weakness of previous policies, and did indeed succeed. The post-2011 experience in Brazil indicates that increased cigarette excise taxes can increase government revenues and reduce smoking prevalence and consumption despite widespread smuggling of tobacco products. PMID- 28001201 TI - Implications of raising cigarette excise taxes in Peru. AB - Objective: To assess how raising cigarette excise taxes in Peru might impact cigarette consumption, and to determine if higher taxes would be regressive. Methods: Total demand price elasticity was estimated by income groups using two datasets: quarterly time-series data from 1993 - 2012 and data from a cross sectional survey of income and expenses conducted in 2008 - 2009 . A functional form of the cigarette demand in Peru was specified using the quarterly data set, and the demand price elasticity was estimated for the short and long run. Using the second data set and Deaton methodology, the implementation of elasticity estimation and by groups' elasticity was done in a two-step procedure. Results: Demand price elasticity was -0.7, implying that a 10% price increase via a new tax would reduce consumption by 7%. Demand price elasticity estimations by income group suggested that poorer families are not more price sensitive than richer ones, which implies that increasing cigarette taxes could be regressive. Conclusions: Increasing cigarette taxes is the most efficient policy for inducing a reduction in smoking. However, in the case of Peru, an increase in cigarette taxes could be regressive. PMID- 28001202 TI - [Evaluation of Uruguay's antismoking campaign: progress and challenges at ten years]. AB - In 2005, shortly after ratifying the Framework Convention on Tobacco Control (FCTC), Uruguay began an ambitious tobacco control campaign that brought the country to the global forefront in the fight against smoking. The wide range of measures implemented in a relatively short period and the rigorousness with which policies were implemented and enforced have few precedents, even in the most developed countries. This paper presents a synthesis and update of several papers by the authors that evaluate different aspects of the campaign ten years following ratification of the FCTC. In particular, these research studies highlight the campaign's aggregate impact on the drop in prevalence of current tobacco consumption in adult and youth populations, and on decisions by pregnant women to quit smoking (1, 2), as well as the relative impact of tax policies in relation to non-price tobacco control measures. The analyses are based on observational studies (at the population or individual level) that use external (Argentina and Chile) and internal (nonsmokers) control groups. Pending challenges in the design of antismoking policies are also discussed. PMID- 28001204 TI - [The Impact of Prices and Taxes on the Use of Tobacco Products in Latin America and the Caribbean]. AB - We examined the impact of tobacco prices or taxes on tobacco use in Latin America and Caribbean countries. We searched MEDLINE, EconLit, LILACS, unpublished literature, 6 specialty journals, and reviewed references. We calculated pooled price elasticities using random-effects models. The 32 studies we examined found that cigarette prices have a negative and statistically significant effect on cigarette consumption. A change in price is associated with a less than proportional change in the quantity of cigarettes demanded. In most Latin American countries, own-price elasticity for cigarettes is likely below -0.5 (pooled elasticities, shortrun: -0.31; 95% confidence interval = -0.39, -0.24; longrun: -0.43; 95% CI = -0.51, -0.35). Tax increases effectively reduce cigarette use. Lack of studies using household- or individual-level data limits research's policy relevance. PMID- 28001203 TI - [Income and smoking prevalence in Latin America: a systematic review and meta analysis]. AB - Objective: Determine the relationship between tobacco-use prevalence and smoker income level in Latin America and the Caribbean (LAC). Methods: A systematic search was carried out in MEDLINE, EMBASE, CENTRAL, SOCINDEX, and LILACS databases. Studies from LAC published from January 1989 to December 2015 were included and were analyzed by subgroups disaggregated by decade of data, country, bias risk, sex, and age group. Results: Of 1 254 studies evaluated by full text, 29 articles were included, of which 25 were chosen for meta-analysis. All included studies were cross-sectional or surveillance, primarily from Brazil and Mexico.Low income was associated with higher prevalence of active smoking (odds ratio [OR] 1.62; 95% confidence interval [95%CI] 1.34-1.96) than high income (reference). A dose-response effect trend was observed: middle income (OR 1.23; 95%CI 1.00-1.52) and low income (OR 1.64; 95%CI 1.17-2.30). This association was greater in men (OR 2.22; 95%CI 1.77-2.78) than in women (OR 1.6; 95%CI 1.11 2.47). Conclusions: An inverse relationship was observed between income and tobacco-use prevalence. Further efforts are required to determine this relationship in special populations, such as adolescents and pregnant women. This research can be useful for policymakers by improving tobacco control strategies and for characterizing public health equity issues. PMID- 28001205 TI - [Integrated tobacco production: health, labor, and working conditions of tobacco farmers in Southern Brazil]. AB - This study aimed to analyze the tobacco farming and marketing process in an integrated system and tobacco farmers' living and working conditions in Southern Brazil. A qualitative study was conducted from December 2010 to August 2011, with 31 semi-structured interviews with tobacco farmers and key informants, besides participant observation. The principal analytical reference was the ergological perspective. The integrated system allows the tobacco industry to control the amounts paid and the tobacco's quality. Tobacco growing features high cost of inputs, farmers' indebtedness, insufficient crop insurance, and intensive use of family labor. Accident and disease risks were associated with work in tobacco farming. According to the dynamic three-pole model proposed by ergology, dealing with these problems requires confronting the workers' knowledge with technical and scientific knowledge, linked with ethical and social responsibility. PMID- 28001206 TI - Independent effect of type of breastfeeding on overweight and obesity in children aged 12-24 months. AB - This study aimed to analyze the effect of type of breastfeeding on the nutritional status of children between 12-24 months of age. This cohort study included 435 children born in 2012 in a public hospital in Joinville, Santa Catarina State, Brazil. Two years after delivery the mothers and their children were contacted in their homes for a new investigation of demographic, economic, nutritional, and anthropometric data. In the unadjusted analysis, children who were not exclusively breastfed were more likely to be overweight (including obesity) at 2 years of age (OR = 1.6; p = 0.049) than exclusively breastfed children. After adjusting for several covariates, children who were not exclusively breastfed had a 12% higher risk of overweight including obesity compared to unadjusted analysis (OR = 2.6 vs. OR = 1.8; p = 0.043). In addition, birthweight was also an independent determinant of overweight including obesity (OR = 2.5; p = 0.002). The practice of exclusive breastfeeding can reduce the risk of overweight in children from developing countries such as Brazil. PMID- 28001207 TI - Diet quality among adolescents has deteriorated: a panel study in Niteroi, Rio de Janeiro State, Brazil, 2003-2008. AB - This study aimed to analyze changes in the diet quality of adolescents from public schools in Niteroi, Rio de Janeiro State, Brazil, over a five-year period. Data on the food consumption of adolescents (12-19 years) were obtained by means of two sets of 3-day food records in two school-based, cross-sectional studies conducted in 2003 and 2008. The Brazilian Revised Healthy Eating Index (BHEI-R) was used to estimate dietary quality. From 2003 to 2008 there was an overall decrease in the scores attributed to "total vegetables", "dark green and orange vegetables", and "meat, eggs, and legumes", but there was an increase in the score for "milk and dairy" (4.0 vs. 5.2; p < 0.01). Among female adolescents, the BHEI-R decreased (64.1 vs. 62.4; p = 0.04), as did the scores attributed to "total vegetables", "dark green and orange vegetables", "meat, eggs, and legumes", and "solid fat, alcohol, and added sugar". In contrast, among males, only the "whole grains" score decreased (0.2 vs. 0.1; p = 0.04). From 2003 to 2008, the diet quality of female public school students declined in Niteroi. PMID- 28001208 TI - [Occupational exposure to benzene in Brazil: estimates based on an occupational exposure matrix]. AB - This study estimates the number of exposed workers and the prevalence of occupational benzene exposure in Brazil. Due to the lack of available local measurements for the study, data were used from an occupational exposure matrix, the Finnish National Job-Exposure Matrix (FINJEM), which covers proportions of individuals exposed to benzene, calculated as environmental measures. In Brazil, the 2010 Demographic Census identified 86,353,839 workers in the workforce and employed. Applying the FINJEM parameters, an estimated 7,376,761 (8.5%) belonged to potentially exposed occupational groups, while 770,212 were considered exposed to benzene, corresponding to an occupational group-weighted prevalence of 0.9%, higher in men (1.1%) than in women (0.6%). Exposed individuals were concentrated in the category of Machine and Motor Operators and Mechanics (62%). The number of exposed and prevalence of occupational exposure to benzene are high, even when compared to Finnish parameters, suggesting the need for monitoring and control of this carcinogen in Brazil. PMID- 28001209 TI - Quality of life and its association with work, the Internet, participation in groups and physical activity among the elderly from the EpiFloripa survey, Florianopolis, Santa Catarina State, Brazil. AB - The study aimed to investigate the association between changes in social relations and physical activity on the quality of life of the elderly in the city of Florianopolis, Santa Catarina state, Brazil. Data on 1,197 elderly from two waves of the population and household survey, EpiFloripa Idoso, were analyzed. Multiple linear regression was performed to estimate association of social change variables and lifestyle on quality of life score (QoL; measured by CASP-16 Brazil, score can range from 0, which represents no QoL to 48, total satisfaction in all domains of CASP). The average QoL score in the sample was 37.6 (95%CI: 37.2; 38.1). The social relations that were associated with positive QoL score were to start to work, to continue to use the Internet, to start participating in religious or lifestyle groups, to remain and to become physically active, and for those who were physically active, but became inactive in the second wave. To remain living with family had a negative effect on QoL score for the elderly. Some changes in social relations had a positive effect on QoL, and results reaffirmed the importance of physical activity to healthy aging, since to pursue it in some of the waves was better than to remain inactive. PMID- 28001210 TI - Social support network, mental health and quality of life: a cross-sectional study in primary care. AB - The objective of this study was to identify the association between emotional distress and social support networks with quality of life in primary care patients. This was a cross-sectional study involving 1,466 patients in the cities of Sao Paulo and Rio de Janeiro, Brazil, in 2009/2010. The General Health Questionnaire, the Hospital Anxiety and Depression Scale and the brief version of the World Health Organization Quality of Life Instrument were used. The Social Support Network Index classified patients with the highest and lowest index as socially integrated or isolated. A bivariate analysis and four multiple linear regressions were conducted for each quality of life outcome. The means scores for the physical, psychological, social relations, and environment domains were, respectively, 64.7; 64.2; 68.5 and 49.1. In the multivariate analysis, the psychological domain was negatively associated with isolation, whereas the social relations and environment domains were positively associated with integration. Integration and isolation proved to be important factors for those in emotional distress as they minimize or maximize negative effects on quality of life. PMID- 28001211 TI - How are so many foreign arboviruses introduced in Brazil? PMID- 28001212 TI - Pharmacologic management of pain in patients with Chikungunya: a guideline. AB - From the arrival of Chikungunya virus in the Americas in 2013 until March 2016, approximately two million cases of the disease have been reported. In Brazil, the virus was identified in 2014 and thousands of people have been affected. The disease has high attack rates, infecting 50% of a population within a few months. Approximately 50% of infected people develop chronic symptoms lasting for months or years. Joint involvement is the main clinical manifestation of Chikungunya. It is characterized by swelling and intense pain that is poorly responsive to analgesics, both in the acute and chronic phase of the disease. This significantly compromises quality of life and may have immeasurable psychosocial and economic repercussions, constituting therefore, a serious public health problem requiring a targeted approach. Physicians are often not familiar with how to approach the management of pain, frequently prescribing limited analgesics, such as dipyrone, in sub-therapeutic doses. In addition, there are few published studies or guidelines on the approach to the treatment of pain in patients with Chikungunya. Some groups of specialists from different fields have thus developed a protocol for the pharmacologic treatment of Chikungunya-associated acute and chronic joint pain; this will be presented in this review. PMID- 28001213 TI - An overview of Bothrops erythromelas venom. AB - This review discusses studies on the venom of Bothrops erythromelas published over the past 36 years. During this period, many contributions have been made to understand the venomous snake, its venom, and its experimental and clinical effects better. The following chronological overview is based on 29 articles that were published between 1979 and 2015, with emphasis on diverse areas. The complexity of this task demands an integration of multidisciplinary research tools to study toxinology. This science is in need of renewed conceptual and experimental platforms aimed at obtaining a profound understanding of the highly complex pathophysiology of snakebite envenoming and toxins isolated from snakes. PMID- 28001214 TI - A biodegradable device for the controlled release of Piper nigrum (Piperaceae) standardized extract to control Aedes aegypti (Diptera, Culicidae) larvae. AB - INTRODUCTION:: The significant increase in dengue, Zika, and chikungunya and the resistance of the Aedes aegypti mosquito to major insecticides emphasize the importance of studying alternatives to control this vector. The aim of this study was to develop a controlled-release device containing Piper nigrum extract and to study its larvicidal activity against Aedes aegypti. METHODS:: Piper nigrum extract was produced by maceration, standardized in piperine, and incorporated into cotton threads, which were inserted into hydrogel cylinders manufactured by the extrusion of carrageenan and carob. The piperine content of the extract and thread reservoirs was quantified by chromatography. The release profile from the device was assessed in aqueous medium and the larvicidal and residual activities of the standardized extract as well as of the controlled-release device were examined in Aedes aegypti larvae. RESULTS: The standardized extract contained 580mg/g of piperine and an LC50 value of 5.35ppm (24h) and the 3 cm thread reservoirs contained 13.83 +/- 1.81mg of piperine. The device showed zero-order release of piperine for 16 days. The P. nigrum extract (25ppm) showed maximum residual larvicidal activity for 10 days, decreasing progressively thereafter. The device had a residual larvicidal activity for up to 37 days. CONCLUSIONS:: The device provided controlled release of Piper nigrum extract with residual activity for 37 days. The device is easy to manufacture and may represent an effective alternative for the control of Aedes aegypti larvae in small water containers. PMID- 28001215 TI - In vitro evaluation of the effect of botanical formulations used in the control of Aedes aegypti L. (Diptera: Culicidae) on liver enzymes. AB - INTRODUCTION: : Dengue fever is a viral disease transmitted by the Aedes aegypti Linn. (1792) (Diptera: Culicidae) mosquito, which is endemic in several regions of Brazil. Alternative methods for the control of the vector include botanical insecticides, which offer advantages such as lower environmental contamination levels and less likelihood of resistant populations. Thus, in this study, the ability of botanical insecticide formulations to inhibit the activity of the liver enzymes serum cholinesterase and malate dehydrogenase was evaluated. METHODS: : Inhibition profiles were assessed using in vitro assays for cholinesterase and malate dehydrogenase activity and quantitated by ultraviolet visible spectroscopy at 410nm to 340nm. RESULTS: Insecticide products formulated from cashew nutshell liquid [A] and ricinoleic acid [B] showed cholinesterase activity levels of 6.26IU/mL and 6.61IU/mL, respectively, while the control level for cholinesterase was 5-12IU/mL. The products did not affect the level of 0.44IU/mL established for malate dehydrogenase, as the levels produced by [A] and [B] were 0.43IU/mL and 0.45IU/mL, respectively. CONCLUSIONS: Our findings show that in vitro testing of the formulated products at concentrations lethal to A. aegypti did not affect the activity of cholinesterase and malate dehydrogenase, indicating the safety of these products. PMID- 28001216 TI - Sandflies (Diptera: Psychodidae) in an urban area of Northeastern Brazil. AB - INTRODUCTION:: The sandfly fauna is well studied globally. In Brazil, sandfly fauna is very diverse in the Northeast region, especially in states such as Maranhao, Ceara, and Bahia. However, in the State of Pernambuco, the distribution of these insects is still not well known. Therefore, the objective of this study was to identify the different species that constitute the sandfly fauna in an urban area in the Northeast region of Brazil, where an outbreak of visceral leishmaniasis (VL) was recently reported. METHODS:: The sandflies were collected from an urban area endemic for VL, at five collection points. The collection of samples was carried out from November 2014 to December 2015, using CDC light traps installed in intradomiciliary and peridomiciliary fashion. RESULTS:: The collected sandflies (n = 297) belonged to eight species: Lutzomyia lenti, Lutzomyia longipalpis, Lutzomyia sallesi, Lutzomyia migonei, Lutzomyia walkeri, Lutzomyia capixaba, Lutzomyia carmelinoi, and Lutzomyia whitmani. Most of the specimens collected were peridomiciliary (247/297, 83%). L. lenti (154/297, 52%) was the most frequently sampled species, followed by L. longipalpis (88/297, 29.6%), and L. sallesi (42/297, 14.1%), which together accounted for over 90% of the collected sandfly specimens. CONCLUSIONS:: The continued presence of L. longipalpis in urban areas, including that in intradomiciliary areas, with a predominance of females, is crucial because of the high possibility of them causing VL outbreaks, since this species is the main vector of Leishmania infantum in Brazil. PMID- 28001217 TI - Biofilm inhibition activity of traditional medicinal plants from Northwestern Argentina against native pathogen and environmental microorganisms. AB - INTRODUCTION:: Plants have been commonly used in popular medicine of most cultures for the treatment of disease. The in vitro antimicrobial activity of certain Argentine plants used in traditional medicine has been reported. The aim of this study was to investigate the antimicrobial, anti-biofilm, and anti-cell adherence activities of native plants (Larrea divaricata, Tagetes minuta, Tessaria absinthioides, Lycium chilense, and Schinus fasciculatus) collected in northwestern Argentina. METHODS:: The activities of the five plant species were evaluated in Bacillus strains and clinical strains of coagulase-negative Staphylococcus isolated from northwestern Argentina and identified by 16S rDNA. RESULT:: Lycium chilense and Schinus fasciculatus were the most effective antimicrobial plant extracts (15.62ug/ml and 62.50ug/ml for Staphylococcus sp. Mcr1 and Bacillus sp. Mcn4, respectively). The highest (66%) anti-biofilm activity against Bacillus sp. Mcn4 was observed with T. absinthioides and L. divaricate extracts. The highest (68%) anti-biofilm activity against Staphylococcus sp. Mcr1 was observed with L. chilense extract. T. minuta, T. absinthioides, and L. divaricata showed percentages of anti-biofilm activity of between 55% and 62%. The anti-adherence effects of T. minuta and L. chilense observed in Bacillus sp. Mcn4 reflected a difference of only 22% and 10%, respectively, between anti-adherence and biofilm inhibition. Thus, the inhibition of biofilm could be related to cell adherence. In Staphylococcus sp. Mcr1, all plant extracts produced low anti-adherence percentages. CONCLUSION:: These five species may represent a source of alternative drugs derived from plant extracts, based on ethnobotanical knowledge from northwest Argentina. PMID- 28001218 TI - Benznidazole therapy for Chagas disease in asymptomatic Trypanosoma cruzi seropositive former blood donors: evaluation of the efficacy of different treatment regimens. AB - INTRODUCTION: : Chagas disease currently affects 5.7 million people in Latin America and is emerging in non-endemic countries. There is no consensus concerning the efficacy of trypanocidal therapy for patients with the chronic form of the disease. We evaluated cardiac function and sociodemographic, clinical, and serologic characteristics of a group of asymptomatic Trypanosoma cruzi-seropositive former blood donors, and compared the effects of benznidazole treatment applied for different lengths of time. METHODS: : Blood donors who screened positive for T. cruzi between 1998 and 2002 were recruited 10 years later for follow-up (n = 244); 46 individuals had received treatment. Three subjects had terminated treatment prematurely. The remaining 43 individuals were divided into two groups: individuals who had received benznidazole therapy for 50 60 days (n = 28; BT <=60 group) or more than 60 days (n = 15; BT >60). Serologic assays, biochemical tests, electrocardiographic, echocardiographic, and clinical examinations were performed on all participants. Parasite loads were determined by qualitative and quantitative polymerase chain reaction. RESULTS: : Parasitemia was significantly reduced in the BT <=60 and BT >60 groups compared with the untreated group. There were no differences in epidemiologic profiles or clinical, biochemical, electrocardiographic, or echocardiographic data between any of the groups. CONCLUSIONS:: Despite elimination or significant reduction in parasitemia in patients with chronic Chagas disease who received benznidazole, there was no clinical difference between those who were treated for >60 days and those treated for a shorter duration. Furthermore, the adverse effects of benznidazole appear to be less severe than previous reports would suggest. PMID- 28001220 TI - Predicting death from kala-azar: construction, development, and validation of a score set and accompanying software. AB - INTRODUCTION: Early identification of patients at higher risk of progressing to severe disease and death is crucial for implementing therapeutic and preventive measures; this could reduce the morbidity and mortality from kala-azar. We describe a score set composed of four scales in addition to software for quick assessment of the probability of death from kala-azar at the point of care. METHODS:: Data from 883 patients diagnosed between September 2005 and August 2008 were used to derive the score set, and data from 1,031 patients diagnosed between September 2008 and November 2013 were used to validate the models. Stepwise logistic regression analyses were used to derive the optimal multivariate prediction models. Model performance was assessed by its discriminatory accuracy. A computational specialist system (Kala-Cal(r)) was developed to speed up the calculation of the probability of death based on clinical scores. RESULTS:: The clinical prediction score showed high discrimination (area under the curve [AUC] 0.90) for distinguishing death from survival for children <=2 years old. Performance improved after adding laboratory variables (AUC 0.93). The clinical score showed equivalent discrimination (AUC 0.89) for older children and adults, which also improved after including laboratory data (AUC 0.92). The score set also showed a high, although lower, discrimination when applied to the validation cohort. CONCLUSIONS:: This score set and Kala-Cal(r) software may help identify individuals with the greatest probability of death. The associated software may speed up the calculation of the probability of death based on clinical scores and assist physicians in decision-making. PMID- 28001219 TI - High seroconversion rates in Trypanosoma cruzi chronic infection treated with benznidazole in people under 16 years in Guatemala. AB - INTRODUCTION: : Geographical, epidemiological, and environmental differences associated with therapeutic response to Chagas etiological treatment have been previously discussed. This study describes high seroconversion rates 72 months after benznidazole treatment in patients under 16 years from a project implemented by Doctors without Borders in Guatemala. METHODS: : An enzyme-linked immunosorbent assay was used to detect Trypanosoma cruzi IgG antibodies in capillary blood samples from patients 72 months after treatment. Fisher's exact test was used to establish association between characteristics, such as sex, age, and origin of patients, and final seroconversion. Kappa index determined concordance between laboratory tests. The level of significance was set to 5%. RESULTS: : Ninety-eight patients, aged 6 months to 16 years, were available for follow-up. Sex and origin were not associated with seroconversion. Individuals older than 13 were more prone to maintain a positive result 72 months after treatment, although results were not highly significant. Laboratory tests presented elevated Kappa concordance (95% CI) = 0.8290 (0.4955-1), as well as high (97%) seroconversion rates. CONCLUSIONS: : The high seroconversion rate found in this study emphasizes the importance of access to diagnosis, treatment, and follow-up of individuals affected by Chagas disease. Moreover, it contradicts the idea that it is not possible to achieve a cure with the currently available drugs. This study strongly supports expanding programs for patients infected with T. cruzi in endemic and non-endemic countries. PMID- 28001221 TI - Number of leprosy reactions during treatment: clinical correlations and laboratory diagnosis. AB - INTRODUCTION: : The occurrence of leprosy reactions, a common event during treatment, may be mostly related to the action of multidrug therapy on Mycobacterium leprae. The clinical and laboratory monitoring of patients with reactions is important, since collecting data that assists in predicting the risk of reactions may help to prevent disability. METHODS: : This was a sectional study, in order to correlate clinical and laboratory diagnosis with the number of reactions during treatment. Spearman's correlation was used to verify the degree of association between the assessed variables. RESULTS: : This study was conducted with 211 patients with leprosy reactions during treatment of M. leprae. The borderline tuberculoid group was the most prevalent clinical form (74/211; 35.1%) and the type one reaction showed the highest frequency (136/211; 64.5%). It was observed that 73.5% (155/211) of reactions occurred within 3 months of the initiation of multidrug therapy. The diagnostic values, including the bacterial indices (BIs) of dermal smears (r = 0.21, p < 0.05) and skin biopsies (r = 0.20; p < 0.05), showed a positive correlation with the number of reactions during treatment. CONCLUSIONS: : This research showed a positive correlation between bacillary load markers and the number of leprosy reactions. This study provided scientific support to future research aiming to elucidate the influence of antigenic load on the number of leprosy reactions during treatment. PMID- 28001222 TI - Secondary bacterial isolates from previously untreated Buruli ulcer lesions and their antibiotic susceptibility patterns in Southern Nigeria. AB - INTRODUCTION: : Mycolactones, secreted by Mycobacterium ulcerans, were previously believed to prevent super infection in Buruli ulcer lesions. However, little is known about secondary bacterial infections in these lesions. This study evaluated contaminating bacterial flora and their antibiotic susceptibility patterns in cases of previously untreated Buruli ulcer disease from three states in Southern Nigeria. METHODS: A prospective analysis was conducted between January and June of 2015 using wound swabs from eligible patients with Buruli ulcer disease, confirmed by quantitative-polymerase chain reaction, with active ulcers. Microbiological analyses including isolation of bacteria, species identification of isolates, and drug susceptibility tests were performed. RESULTS: Of 51 patients, 27 (52.9%) were female. One or more bacterial species of clinical importance was isolated from each patient. A total of 17 different microbial species were isolated; 76.4% were Gram-negative and 23.6% were Gram-positive isolates. The most common bacterial species detected was Staphylococcus aureus (24%), followed by Aeromonas hydrophila (13%), Pseudomonas aeruginosa (13%), and Klebsiella pneumoniae (11%). Drug susceptibility tests showed a particularly high frequency of resistance to commonly used antimicrobials in Nigeria for Staphylococcus aureus. CONCLUSIONS: Super bacterial infections occur in Buruli ulcer lesions in Nigeria, and these infections are associated with high rates of resistance to commonly used antibiotics in the country. PMID- 28001223 TI - In vitro antischistosomal activity of venom from the Egyptian snake Cerastes cerastes. AB - INTRODUCTION:: We studied the potential in vitro antischistosomal activity of Cerastes cerastes venom on adult Schistosoma mansoni worms. METHODS:: Live specimens of the horned viper snake, C. cerastes were collected from the Aswan Governorate (Egypt). Venom was collected from snakes by manual milking. Worms of S. mansoni were obtained from infected hamsters by perfusion and isolated from blood using phosphate buffer. Mortality rates of worms were monitored after 3 days of exposure to snake venom at LC50 and various sublethal concentrations (10, 5, 2.5ug/ml). Scanning electron microscopy was used to investigate tegumental changes in treated worms after exposure to LC50 doses of venom. RESULTS: : The LC50 of C. cerastes venom was 21.5ug/ml. The effect of C. cerastes venom on Schistosoma worms varied according to their sex. The mortality rate of male and female worms after 48-h exposure was 83.3% and 50%, respectively. LC50 of C. cerastes venom induced mild to severe tegumental damage in Schistosoma worms in the form of destruction of the oral sucker, shrinkage and erosion of the tegument, and loss of some tubercle spines. CONCLUSIONS:: The present study demonstrated that C. cerastes venom exerts potential in vitro antischistosomal activity in a time and dose-dependent manner. These results may warrant further investigations to develop novel schistosomicidal agents from C. cerastes snake venom. PMID- 28001224 TI - High incidence of hypertriglyceridemia in a Brazilian cohort of people living with HIV/AIDS undergoing antiretroviral treatment in Belo Horizonte, 2001-2010. AB - INTRODUCTION: : Hypertriglyceridemia incidence should be estimated in HIV infected patients after antiretroviral therapy (ART) initiation. METHODS: : We retrospectively analyzed clinical data of HIV-infected adults at 3 public referral centers. Cumulative and person-time incidences were estimated for patients without hypertriglyceridemia. Survival time and hazard ratio (HR) were estimated by Kaplan-Meier analysis and Cox proportional regression, respectively. RESULTS: : Cumulative and person-time incidences were 40.4% and 1.4 cases/100 person-months, respectively. The median period for hypertriglyceridemia occurrence was 47 months. Men and patients with switched ART regimens had increased hypertriglyceridemia risk (HR=3.05 and 3.34, respectively). CONCLUSIONS: : Hypertriglyceridemia incidence is high in HIV-infected patients undergoing ART. PMID- 28001225 TI - Adverse drug reactions among patients admitted with infectious diseases at a Brazilian hospital. AB - INTRODUCTION: : Despite the therapeutic benefits of drugs, adverse drug reactions (ADRs) occur. Method: We assessed a series of suspected ADRs identified from notifications and intensive monitoring of inpatients from March 2013 to March 2014. RESULTS:: Skin reactions predominated (31%). Systemic anti-infective agents were implicated in 16 (72%) reactions. Fifteen (68%) ADRs were classified as possible. The implicated drug was not correctly identified by the healthcare team in 12 cases. CONCLUSIONS: : Some reactions were not correctly attributed to the causative drug(s), suggesting that the use of a validated evaluation method can promote successful identification of causal links between ADRs and drugs. PMID- 28001226 TI - Trypanosoma cruzi seroprevalence and associated risk factors in cancer patients from Southern Brazil. AB - INTRODUCTION: : The aim of this study was to investigate the prevalence of Chagas disease in patients treated at a Public Oncology Service in the City of Pelotas, Southern Brazil. METHODS: : This study included 200 individuals undergoing cancer treatment and involved the use of a questionnaire and venous blood collection for the detection of anti-Trypanosoma cruzi antibody. RESULTS: : The study found a 5% prevalence of patient seropositivity. Significant variables are presented and discussed in the article. CONCLUSIONS: : Serological T. cruzi checks are recommended in cancer patients, especially individuals from endemic areas in Brazil and other Latin American countries. PMID- 28001227 TI - Increasing potential risk for American visceral leishmaniasis in Amapa, Brazil. AB - INTRODUCTION:: The present note discusses some evidence on the increasing potential risk for American visceral leishmaniasis (AVL) transmission in the Northern Brazilian State of Amapa, the Guianan-Amazon biome. METHODS: Early and present data about AVL were collected, including our recent entomological findings. RESULTS: : The spread of the sand fly vector Lutzomyia longipalpis, and a sylvatic reservoir host, the crab-eating fox Cerdocyon thous in that region represents important findings related to the epidemiology of AVL in the Guianan Amazon biome. CONCLUSIONS:: These observations suggest that Brazilian authorities need to develop surveillance strategies in these risk areas. PMID- 28001228 TI - Standardization of intralesional meglumine antimoniate treatment for cutaneous leishmaniasis. AB - INTRODUCTION: : Intralesional treatment for cutaneous leishmaniasis has been applied for over 30 years at the Oswaldo Cruz Foundation, Rio de Janeiro, with good therapeutic results and without relevant systemic toxicity. METHODS: Meglumine antimoniate was injected subcutaneously, using a long medium-caliber needle (for example, 30mm * 0.8mm); patients received 1-3 injections, with 15-day intervals. RESULTS: The technique is described in detail sufficient to enable replication. CONCLUSIONS: : The treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate is a simple, effective, and safe technique, which may be used in basic healthcare settings. PMID- 28001229 TI - Sociodemographic and epidemiological profile of leprosy patients in an endemic region in Brazil. AB - INTRODUCTION:: The incidence of Hansen's disease is high in overlooked populations. METHODS: : Data of Hansen's disease cases reported in the information system of the Department of Informatics, Brazilian Unified Health System, from 2013 to 2014 were analyzed. RESULTS: : Among 434 studied cases of Hansen's disease, the female sex (52.5%), adult age (73.7%), low educational level (61.8%), and multibacillary form were associated with higher prevalence rates. CONCLUSIONS: : Hansen's disease is more frequent among female adults with a low educational level, and the prevalence of multibacillary leprosy reflects disease detection at late stages. PMID- 28001230 TI - There is no evident correlation between interleukin-10 gene polymorphisms and periportal fibrosis regression after specific treatment. AB - INTRODUCTION:: We evaluated the associations between interleukin-10 (IL-10) gene polymorphisms -G1082A/-C819T/-C592A and periportal fibrosis regression after specific treatment for schistosomiasis. METHODS:: This retrospective cohort study involved 125 Brazilian patients infected with Schistosomiasis mansoni, who were followed up for 2 years after specific treatment to estimate the probability of periportal fibrosis regression. RESULTS:: There was no evidence of associations between IL-10 polymorphisms and periportal fibrosis regression after treatment. CONCLUSIONS:: There was no evidence of associations between gene promoter polymorphisms of IL-10 and the regression of periportal fibrosis in this Brazilian population. PMID- 28001231 TI - Arachnidism, scorpionism and ophidism in Ouro Preto Municipality, Minas Gerais State, Brazil. AB - INTRODUCTION: This retrospective study shows the profile of arachnidism, ophidism, and scorpionism in the Ouro Preto Municipality, Brazil, from January 2007 to December 2013. METHODS: The data were gathered from forms of the Epidemiological Surveillance Sector of the town's Health's Municipal Secretary. RESULTS: Of the 412 envenomations, 308 were caused by spiders, 78 by scorpions, and 26 by snakes. The highest number of incidents involved people aged 20-34 years. Females were more affected than males. There were no reports of death. CONCLUSIONS: The results show that envenomations caused by spiders, scorpions and snakes have decreased in recent years. PMID- 28001232 TI - A case of chikungunya virus disease presenting with remarkable acute arthritis of a previously damaged finger joint. AB - Chikungunya virus (CHIKV) is a mosquito-borne arthritogenic alphavirus that has recently been introduced to Brazil. We report the case of a 36-year-old male patient from the City of Rio de Janeiro who developed molecularly-confirmed CHIKV disease and whose clinical picture was remarkable because of acute arthritis of an interphalangeal joint that had been damaged by trauma 8 years previously. This case illustrates that acute CHIKV disease may preferentially target previously damaged joints. Careful study of individual cases may provide valuable information on the presentation and management of this emerging zoonosis in Brazil. PMID- 28001233 TI - Candida arthritis in a patient diagnosed with spondyloarthritis. AB - Candida arthritis is an unusual manifestation that usually affects the knees. A 35-year-old man presented with a 2-month history of pain and swelling in the right knee. Swelling persisted after anti-inflammatory treatment. Peripheric spondyloarthritis was considered, but methotrexate, sulfasalazine, and methylprednisolone did not reduce the swelling. Direct examination of synovial fluid and a culture were positive for Candida albicans. Intravenous and intra articular amphotericin-B were administered. The arthritis regressed and a culture and direct staining showed negative results. Candida arthritis should be considered in patients with arthritis that is resistant to treatment and prolonged, even if risk factors are absent. PMID- 28001234 TI - Abdominal mucormycosis in a child: a case report. AB - A 2-year-old Brazilian female child from the countryside in Bahia State presented with pain in the right flank of the abdomen, accompanied by a daily fever for about 2 weeks before admission. A large mass in the abdomen was resected by the surgical team. The biopsies revealed the mass was an intra-abdominal mucormycosis. However, the diagnosis was late, and despite treatment (amphotericin B) initiation, the patient eventually died. PMID- 28001235 TI - Dermatitis after contact with Pheropsophus sp (Coleoptera, Carabidae, Brachininae) in the Para State, Brazilian Amazon. AB - Dermatitis caused by bombardier beetles is rarely reported. Here, we report a case of beetle-caused dermatitis that occurred in Para State, the Brazilian Amazon. A female patient while putting on her shoes, felt a burning pain in the right hallux and noticed a beetle inside the shoe. During medical consultation, the physician observed that the injury site was brown and discolored. The patient complained of localized burning pain and blurred vision. The beetle responsible for the injury was identified as Pheropsophus sp. Administered treatment included cleaning with saline, analgesics, and topical hydrocortisone acetate and the patient was discharged without complaints. PMID- 28001236 TI - Meloidogyne eggs in human stool in Northeastern Brazil. PMID- 28001237 TI - Natural history of liver fibrosis progression in patients confected with hepatitis c virus and human immunodeficiency virus type 1. PMID- 28001238 TI - Fibrosis progression in chronic hepatitis C in patients coinfected with human immunodeficiency virus and hepatitis C virus. PMID- 28001239 TI - Patients with dental calculus have increased saliva and gingival crevicular fluid fetuin-A levels but no association with fetuin-A polymorphisms. AB - Fetuin-A is a potent inhibitor of calcium-phosphate precipitation and of the calcification process, therefore it can also be related with dental calculus. Thus, we aimed to investigate a possible relationship between fetuin-A gene polymorphism and the presence of dental calculus. A possible relationship between serum, saliva and gingival crevicular fluid (GCF) levels of fetuin-A was also investigated. Fetuin-A c.742C > T and c.766C > G polymorphisms were investigated in 103 patients with or without dental calculus. Additionally, serum, saliva and GCF fetuin-A levels of patients were compared according to dental calculus presence. A significant difference was not observed in the distribution of the fetuin-A c.742C > T and c.766C > G polymorphisms between patients with or without dental calculus. Saliva and GCF fetuin-A concentrations of patients with dental calculus were statistically higher than those without dental calculus (P=0.001, P=0.036 respectively). According to our results, fetuin-A c.742C > T and c.766C > G polymorphisms were not associated with presence of dental calculus. However, higher GCF and saliva fetuin-A levels were detected in patients with dental calculus than in patients without dental calculus, which may result from an adaptive mechanism to inhibit mineral precipitation and eventually calculus formation. PMID- 28001240 TI - Immunohistochemical analysis of FoxP3+ regulatory T cells in lower lip squamous cell carcinomas. AB - The aim of this study was to determine the number of FoxP3+ regulatory T (Treg) cells in the microenvironment of lower lip squamous cell carcinomas (LLSCCs) and to correlate the findings with clinicopathological parameters (tumor size/extent, regional lymph node metastasis, clinical stage, and histopathological grade of malignancy). Fifty cases of LLSCC were selected. Lymphocytes exhibiting nuclear immunostaining for FoxP3 were quantified in 10 microscopic fields at the deep invasive front of LLSCCs. The results were analyzed statistically using the nonparametric Mann-Whitney test and Fisher's exact test. FoxP3+ lymphocytes were observed in all cases studied. The number of these cells tended to be higher in smaller tumors, tumors without regional lymph node metastasis, and tumors in early clinical stages, but the difference was not statistically significant (p > 0.05). Low-grade tumors contained a larger number of FoxP3+ lymphocytes than high grade tumors (p = 0.019). Tumors with an intense inflammatory infiltrate exhibited a larger number of Treg cells (p = 0.035). On the other hand, the number of FoxP3+ lymphocytes was smaller in tumors arranged in small cell clusters (p = 0.003). No significant differences in the number of FoxP3+ lymphocytes were observed according to the degree of keratinization (p = 0.525) or nuclear pleomorphism (p = 0.343). The results suggest the participation of Treg cells in immune and inflammatory responses in the microenvironment of LLSCCs. These cells may play a more important role in early stages rather than in advanced stages of lip carcinogenesis. PMID- 28001241 TI - Effect of EDTA on TGF-beta1 released from the dentin matrix and its influence on dental pulp stem cell migration. AB - Bioactive molecules stored in dentin, such as transforming growth factor beta1 (TGF-b1), may be involved in the signaling events related to dental tissue repair. The authors conducted an in vitro evaluation of the amount of TGF-b1 released from dentin slices after treatment with 10% ethylenediaminetetraacetic acid (EDTA), 2.5% sodium hypochlorite (NaOCl) or phosphate-buffered saline (PBS), and the effect of this growth factor on stem cell migration from human exfoliated deciduous teeth (SHED). Sixty 1-mm-thick tooth slices were prepared with or without the predentin layer, and treated with either 10% EDTA for 1 minute, 2.5% NaOCl for 5 days or kept in PBS. Tooth slice conditioned media were prepared and used for TGF-b1 ELISA and migration assays. Culture medium with different concentrations of recombinant human TGF-b1 (0.5, 1.0, 5.0 or 10.0 ng/mL) was also tested by migration assay. The data were evaluated by ANOVA and Tukey's test. Optical density values corresponding to media conditioned by tooth slices either containing or not containing the predentin layer and treated with 10% EDTA were statistically greater than the other groups and close to 1 ng/mL. Increased rates of migration toward media conditioned by tooth slices containing the predentin layer and treated with PBS, 10% EDTA or 2.5% NaOCl were observed. Recombinant human TGF-b1 also stimulated migration of SHED, irrespective of the concentration used. EDTA may be considered an effective extractant of TGF-b1 from the dentin matrix. However, it does not impact SHED migration, suggesting that other components may account for the cell migration. PMID- 28001242 TI - Effect of the time-point of acid etching on the persistence of sealer residues after using different dental cleaning protocols. AB - Endodontic sealer residues remaining within the pulp chamber dentin after root canal obturation and cleaning with various solvents may compromise the appearance and the durability of dental restorations. Acid etching is routinely performed prior to application of dentine adhesive systems, but is effect on residual sealer material and the optimal time-point for performing etching, are unknown. Here, we evaluated the effect of acid etching on the dentin surface when performed either immediately or 7 days after removal of the endodontic sealer with two solvents, i.e., 95% ethanol or xylol. Forty crowns fragments from bovine incisors were impregnated with sealer and divided into 4 groups (n = 10 each), according to the dentin cleaning protocol and to the acid etching time-point: G1, 95.0% ethanol and immediate acid etching; G2, xylol and immediate acid etching; G3, 95.0% ethanol and acid etching after 7 days; and G4, xylol and acid etching after 7 days. Scanning electron microscopy (SEM) images (2000 *) were obtained from each specimen and the number of open dentinal tubules counted and compared. Another 40 fragments were similarly prepared, and SEM images were obtained (500 *) to score and compare the persistence of sealer residues on the dentin. G4 showed the most open dentinal tubules and the least epoxy resin-based sealer residues on the dentin surface (p < 0.05). The least epoxy resin-based sealer residues was obtained when acid etching, using 37% phosphoric acid, was performed after 7 days after cleaning the dentin with xylol. PMID- 28001243 TI - Accuracy of clinical diagnosis for the identification of potentially malignant disorders and malignant lip lesions. AB - The aim of this study was to assess the accuracy of clinical diagnosis for lip lesions based on sensitivity and specificity. The retrospective analysis focused on the detection of lesions caused by potentially malignant disorders (PMDs) and malignant lesions (n = 1195). All cases were classified as benign, PMD, and malignant lesions. Concordance between diagnoses based on clinical examination and those based on histopathological analysis was assessed, and accuracy for the identification of PMD and malignant lesions was calculated. Histopathological analysis revealed 44 lesion types; PMD and malignant lesions comprised 8.3% of all cases. Compared with histopathological analysis, clinical examination showed 97.4% accuracy for the identification of non-malignant and potentially malignant/malignant cases. Degrees of specific sensitivity ranged from 34% to 77% for different lesions, and were highest for autoimmune (77%) and reactive (72%) lesions. Positive and negative predictive values for the identification of PMD and malignant lesions were 81.9% and 98.9%, respectively. Clinical examination showed a high degree of accuracy for the detection of PMD and malignant lip lesions, indicating good reliability. PMID- 28001244 TI - Survival analysis of banding and bonding molar tubes in adult patients over a 12 month period: a split-mouth randomized clinical trial. AB - This split-mouth randomized clinical trial aimed to compare the survival rate of bonding and banding molar tubes in adult orthodontic patients. Eligibility criteria included adults (aged >18 years), no active caries, restorations, or fractures in the upper and lower molars. The main outcome was any type of first time failure in molar tubes. A computer-generated randomization scheme was used in a 1:1 ratio. The survival rate was estimated for 32 adult patients, in whom a tube was bonded to a molar tooth using composite resin on one side and a band was cemented with glass ionomer onto the same tooth in the contralateral arch. A total of 59 banded and 59 bonded molars were followed up for 12 months. Blinding was not applicable. Survival analysis including Cox regression was used at p < 0.05. The survival rate of bonded molars was not statistically different from that of banded molars (log-rank test, p = 0.97). Hazard ratio (HR) was 0.72 (95%CI, 0.38-1.31). Bonded upper molars yielded a survival rate of 81.25% (26 out of 32) compared to 71.87% (23 out of 32) for banded upper molars. The survival rate was 66.66% (18 out of 27) for banded lower molars and 59.25% for bonded lower molars (16 out of 27). The HR for lower vs. upper arch was 2.16 (95%CI, 1.18-3.98). No serious problem was observed other than gingivitis associated with plaque accumulation. In contrast to previous studies in young patients, in adults, bonding orthodontic tubes to molars is similar to molar banding. However, both procedures had a high failure rate in the lower arch. PMID- 28001245 TI - The effect of standardised implantoplasty protocol on titanium surface roughness: an in-vitro study. AB - To analyse the changes of surface characteristics of machined and moderately roughened titanium disks following a standardised implantoplasty protocol. Forty titanium discs (machined: n = 20; moderately roughened: n = 20) were instrumented with one half of each disc maintained as the control (non-instrumented). The standardised implantoplasty protocol was carried out using a custom jig with the sequential change of burs: 1) Regular grit diamond [10s], 2) Super-fine grit diamond [10s], 3) Brownie(tm) silicone polisher [15s], 4) Greenie(tm) silicone polisher [15s]. Surface topography was analysed using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Energy dispersive x-ray spectroscopy (EDS) was used to measure the elemental profiles of each disc. Quantitative analysis showed similar changes in level of roughness between the machined and moderately roughened titanium discs. CLSM demonstrated an increased roughness (Ra and Sa values) after polishing with a regular grit diamond bur when compared to the uninstrumented surfaces. Although the roughness decreased after the further polishing with the super-fine grit diamond bur, subsequent instrumentation using silicon burs tended to increase the roughness, albeit being statistically insignificant. There was a residue of silicon particles despite the irrigation after each polishing stage. The proposed implantoplasty protocol did not achieve a sufficient level of smoothness on the machined or moderately roughened titanium surfaces when compared to the Ra threshold. Further research is recommended to test the efficacy of each bur on titanium surfaces with longer duration using actual oral implants to allow better comparison. PMID- 28001246 TI - Validation and Invariance of the Dental Anxiety Scale in a Brazilian sample. AB - The aim of this study was to evaluate the properties of the Dental Anxiety Scale (DAS) when applied to Brazilian adults and to test its invariance across independent samples and different sociodemographic groups. Sociodemographic data, reports on previous unpleasant dental experiences and DAS responses were collected through telephone interviews. Metric properties of the one and two factor models were evaluated using confirmatory factor analysis. The analysis included the chi-square ratio divided by degrees of freedom (chi2/df), the comparative fit index (CFI), the goodness of fit index (GFI) and the root mean square error of approximation (RMSEA). Convergent validity was evaluated using the average variance extracted (AVE). Cronbach's alpha (alpha) and composite reliability (CR) were calculated. In the two-factor model, discriminant validity was evaluated. The invariance of the models was evaluated using a multigroup analysis of the independent samples (pDeltachi2lambda, pDeltachi2 i and pDeltachi2 Res >= 0.05). Telephone interviews were held with 350 individuals (74.3% women). Of the participants, 135 (38.6%) had previous unpleasant dental experiences, and 117 (33.4%) knew someone who had had this type of experience. The one- and two-factor model (chi2/df < 2.0; CFI,GFI > 0.90; RMSEA < 0.10; AVE > 0.50; alpha,CR > 0.70) were adjusted to the data. Discriminant validity was limited (rho2 = 0.66). Both models presented strong invariance across independent samples, but the invariance was weak (pDeltachi2i < 0.05) when samples were defined by socioeconomic variables. In conclusion, both DAS models were valid and reliable when applied to a sample of Brazilian adults. However, the weak invariance of the models suggests that sample characteristics interfered with the measurement of dental anxiety. PMID- 28001247 TI - Impact of a dental care program on the quality of life of children with and without caries. AB - The aim of the present study was to evaluate the long-term effects of the caries treatment provided by a dental care program on changes in schoolchildren's OHRQoL. A one-year follow-up was conducted with a sample of 372 children aged 8 to 10 years which were clinically examined and divided into two matched groups according to their caries experience: dental treatment group (DTG) and group without caries (GWC). Both groups were assessed three times (at baseline, at 4 weeks, and at 1 year) using the Child Perceptions Questionnaire (CPQ8-10). The normality test was performed for the statistical analyses; the Friedman test was used for the dependent variables (longitudinal assessment repeated three times for the same group); and the Mann-Whitney test was used for the independent variables (test and control groups in each time period). There was improvement in all domains and in overall CPQ8-10 (p < 0.0001) in the DTG over time, but no significant changes (p > 0.05) were observed at baseline for overall CPQ8-10 and for the emotional well-being domain in the GWC. The comparison between groups demonstrated that OHRQoL was persistently better for the GWC (p < 0.05) over time. In conclusion, dental caries treatment has a long-term positive impact on schoolchildren's OHRQoL, highlighting the importance of health policies that promote access to dental care for this population. PMID- 28001248 TI - Effect of lectin (ScLL) on fibroblasts stimulated with LPS - an in vitro study. AB - The lectin (ScLL) extracted from the Synadenium carinatum plant has been evaluated as an immunomodulator in diseases such as asthma, neosporosis and leishmaniasis. However, it has not yet been evaluated in the oral cavity. This study evaluated the effect of ScLL on viability, proliferation and release of IL 10 in human gingival fibroblasts (HGF) stimulated with lipopolysaccharide (LPS). HGF were stimulated with LPS 1 ug/ml and treated with ScLL in concentrations of 10, 5 and 2 ug/ml for 1 and 5 h, and evaluated by flow cytometry for viability, apoptosis (initial/advanced) and necrosis. The supernatant was collected to detect release of IL-10 by ELISA. The proliferation was assessed with the BrdU assay. Positive control consisted of cells maintained in Dulbecco's Modified Eagles Medium (DMEM), and the negative control, of those kept in tap water. Data were analyzed by ANOVA and Dunnett's test (alpha = 0.05). No significant difference was found for ScLL concentrations regarding viability or initial and advanced apoptosis (p=0.455). All the groups, including the positive control, had a significantly lower necrosis parameter than negative control at 5 h (p < 0.001). No difference was found for proliferation among the experimental groups (p = 0.832). ScLL at 5 and 2 ug/ml resulted in a lower release of IL-10 than positive and negative controls at 5 h (p = 0.047). The results indicated that ScLL concentrations tested were not cytotoxic, and had no effect on proliferation and release of IL-10 parameters. A thorough understanding of ScLL, regarding its immunomodulatory potential, may open the door to new perspectives for dentistry. PMID- 28001249 TI - Cheers!!! PMID- 28001250 TI - Nutritional therapy assessment - Outpatient mobility monitoring (MAM). PMID- 28001251 TI - Primary cutaneous histoplasmosis in an immunocompromised patient with long standing rheumatoid arthritis. PMID- 28001252 TI - Endoscopic ultrasound in the diagnosis of foreign bodies of the colon and rectum. AB - Although the ingestion of foreign bodies is a common clinical problem, severe complications such as perforation are rare and occur in less than 1% of cases. Different types of foreign bodies and the various affected regions within the gastrointestinal tract make foreign body ingestion a complex entity, with a wide range of presentation requiring different diagnostic modalities. We report two cases of patients who underwent endoscopic ultrasound for evaluation of sub epithelial lesions consisting of foreign body granulomas in the colon and rectum. Colorectal foreign body granuloma is a rare complication after accidental ingestion. Endoscopic ultrasound can be a useful diagnostic tool and can avoid the need for more invasive procedures. PMID- 28001253 TI - Black coated tongue in integrative medicine: An alarm signal. PMID- 28001254 TI - Imaging aspects of Camurati-Engelmann disease. PMID- 28001255 TI - Giant scalp arteriovenous malformation. AB - Arteriovenous malformations (AVMs) of the scalp are rare lesions. The clinical picture presents with complaints of increased scalp, scalp disfigurement, pain and neurological symptoms. Its origin can be congenital or traumatic. We present a case of giant scalp AVMs and its management, followed by a brief literature review on the subject. The diagnosis of scalp AVMs is based on physical examination and confirmed by internal and external carotid angiography or computed tomographic angiography (CTA). Surgical excision is especially effective in scalp AVMs, and is the most frequently used treatment modality. PMID- 28001256 TI - Body composition in adults with neurofibromatosis type 1. AB - Objective: To evaluate the body composition and nutritional status of neurofibromatosis type 1 (NF1) adult patients. Method: A cross-sectional study of 60 NF1 patients (29 men, 31 women) aged >= 18 years who were evaluated from September 2012 to September 2013 in a Neurofibromatosis Outpatient Reference Center. Patients underwent nutritional assessment including measurements of weight, stature, waist circumference (WC), upper-arm circumference (UAC), and skinfolds (biceps, triceps, subscapular, suprailiac). Body mass index (BMI), upper-arm total area (UATA), upper-arm muscle area (UAMA), upper-arm fat area (UAFA), body fat percentage (BFP), fat mass, fat-free mass, fat mass index, and fat-free mass index were also calculated. Results: The mean age of the study population was 34.48+/-10.33 years. The prevalence of short stature was 28.3%. Low weight was present in 10% of the sample and 31.7% of patients had a BMI >= 25 kg/m2. Reduced UAMA (<5th percentile) was present in 43.3% and no difference was found in UAFA between the sexes. The BFP was considered high in 30% and 17 (28.3%) patients had a WC above the World Health Organization cutoffs. Conclusion: In this study, NF1 patients had a high prevalence of underweight, short stature, and reduced UAMA, with no difference between the sexes. Reduced UAMA was more prevalent in underweight patients; however, this was also observed in the normal and overweight patients. Further studies should investigate the distribution of body tissues in NF1 patients, including differences between men and women, and the influence of diet and nutrition on clinical features in NF1. PMID- 28001257 TI - Pregnancy outcomes after chemotherapy for trophoblastic neoplasia. AB - Introduction: The successful development of chemotherapy enabled a fertilitysparing treatment for patients with trophoblastic neoplasia. After disease remission, the outcome of a subsequent pregnancy becomes a great concern for these women. Objective: To analyze existing studies in the literature that describe the reproductive outcomes of patients with trophoblastic neoplasia treated with chemotherapy. Method: Systematic review was performed searching for articles on Medline/ Pubmed, Lilacs and Cochrane Library databases, using the terms "gestational trophoblastic disease" and "pregnancy outcome". Results: A total of 18 articles were included. No evidence of decreased fertility after chemotherapy for trophoblastic neoplasia was observed. The abortion rates in patients who conceived within 6 months after chemotherapy was higher compared to those who waited longer. Some studies showed increased rates of stillbirth and repeat hydatidiform moles. Only one work showed increased congenital abnormalities. Conclusion: The pregnancies conceived after chemotherapy for trophoblastic neoplasia should be followed with clinical surveillance due to higher rates of some pregnancy complications. However, studies in the literature provide reassuring data about reproductive outcomes of these patients. PMID- 28001258 TI - Translation and validation of Hyperhidrosis Disease Severity Scale. AB - Introduction: The evaluation of patients with hyperhidrosis (HH) can be accomplished, among other ways, through questionnaires and scales. The Hyperhidrosis Disease Severity Scale (HDSS) has been used as a simple and quick tool to perform this evaluation. Although HDSS has been well established in several languages, it has not been translated into Portuguese, restricting its specific use for Brazilian patients. The aim of this study was to translate HDSS into Portuguese and validate it in a sample of Brazilian subjects. Method: 290 Brazilian patients (69% women, with a mean age of 28.7+/-9.6 years and BMI 22.4+/ 3.9 kg/m2) diagnosed with HH were evaluated using HDSS, Quality of Life Questionnaire (QLQ) and Sweating Evolution Questionnaire (SEQ) before and after a five-week oxybutynin treatment. Regarding validation, an association between HDSS results and two other questionnaires was performed. To analyze HDSS sensitivity, evaluation of effects pre- and post-treatment with oxybutynin was conducted. Furthermore, HDSS reproducibility was analyzed in a subsample in which the scale was applied again after 7 days of the first follow-up appointment. Results: There was statistical correlation between HDSS and QLQ and between HDSS and SEQ before treatment and after 5 weeks. Additionally, HDSS was reproducible and sensitive to clinical changes after the treatment period. Conclusion: The Portuguese version of HDSS has been validated and shown to be reproducible in a Brazilian sample. Therefore it can be used as a tool to improve medical assistance in patients with HH. PMID- 28001259 TI - Health-related quality of life in Brazilian community-dwelling and institutionalized elderly: Comparison between genders. AB - Objective: To compare the health-related quality of life (HRQL) indicators between institutionalized and community-dwelling elderly men and women. Method: This was a cross-sectional study with a sample of 496 elderly men and women, surveyed by researchers at a private hospital that attends institutionalized and community-dwelling elderly. HRQL (World Health Organization Quality of Life), daily living activities (Katz questionnaire), and instrumental daily living activities (Lawton questionnaire), mini-mental state examination, handgrip strength test, and function capacity (timed up and go test) were obtained. Results: Institutionalized men presented higher scores in physical and psychological domains of HRQL compared to elderly men living alone (p<0.05). Among women, the scores in all domains (physical, psychological, relationship, and environment) were similar between institutionalized and community-dwelling individuals. Conclusion: Institutionalized elderly men reported better scores in physical and psychological domains of HRQL compared to their community-dwelling pairs, while both institutionalized and community-dwelling elderly women presented similar HRQL. PMID- 28001260 TI - Reasons for choosing the profession and profile of newly qualified physicians in Brazil. AB - Objective: To evaluate the socio-demographic profile, path to medical school admission and factors affecting the choice of becoming a physician in Brazil. Method: Application of a structured questionnaire to 4,601 participants among the 16,323 physicians who graduated between 2014 and 2015 that subsequently registered with one of the 27 Regional Boards of Medicine (CRMs). Results: The average age of participants is 27 years, 77.2% are white, 57% come from families with a monthly income greater than ten times the minimum wage, 65% have fathers who have completed higher education, 79.1% attended a private high school, and 63.5% selected the "will to make a difference in people's lives or do good" as their main reason for choosing medicine, with some differences between the sexes and matriculation at a public or private medical school. Conclusion: The recent politics for educational diversity and the opening of additional medical schools has not yet had an impact on the socio-demographic profile of graduates, who are mainly white, wealthy individuals. PMID- 28001261 TI - Evidences of autologous fat grafting for the treatment of keloids and hypertrophic scars. AB - Introduction: Since the 1980s, the use of autologous fat grafting has been growing in plastic surgery. Recently, this procedure has come to be used as a treatment for keloids and hypertrophic scars mainly due to the lack of satisfactory results with other techniques. So far, however, it lacks more consistent scientific evidence to recommend its use. The aim of this study was to review the current state of autologous fat grafting for the treatment of keloids and hypertrophic scars, their benefits and scientific evidences in the literature. Method: A review in the Pubmed database was performed using the keywords "fat grafting and scar", "fat grafting and keloid scar" and "fat grafting and hypertrophic scar." Inclusion criteria were articles written in English and published in the last 10 years, resulting in 15 studies. Results: These articles indicate that autologous fat grafting carried out at sites with pathological scars leads to a reduction of the fibrosis and pain, an increased range of movement in areas of scar contraction, an increase in their flexibility, resulting in a better quality of scars. Conclusion: So far, evidences suggest that autologous fat grafting for the treatment of keloids and hypertrophic scars is associated with a better quality of scars, leading to esthetic and functional benefits. However, this review has limitations and these findings should be treated with reservations, since they mostly came from studies with low levels of evidence. PMID- 28001262 TI - Current aspects of polycystic ovary syndrome: A literature review. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with variable prevalence, affecting about one in every 15 women worldwide. The diagnosis of polycystic ovary syndrome requires at least two of the following criteria: oligoovulation and/or anovulation, clinical and/or biochemical evidence of hyperandrogenism and morphology of polycystic ovaries. Women with PCOS appear to have a higher risk of developing metabolic disorders, hypertension and cardiovascular disorders. The aim of this article was to present a review of the literature by searching the databases Pubmed and Scielo, focusing on publications related to polycystic ovaries, including its pathogenesis, clinical manifestations, diagnosis and therapeutic aspects, as well as its association with cardiovascular and arterial hypertensive disorders. PMID- 28001263 TI - Current management of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipid in patients who do not consume alcohol in amounts generally considered harmful to the liver. NAFLD is becoming a major liver disease in Eastern countries and it is related to insulin resistance and metabolic syndrome. Treatment has focused on improving insulin sensitivity, protecting the liver from oxidative stress, decreasing obesity and improving diabetes mellitus, dyslipidemia, hepatic inflammation and fibrosis. Lifestyle modification involving diet and enhanced physical activity associated with the treatment of underlying metabolic are the main stain in the current management of NAFLD. Insulin sensitizing agents and antioxidants, especially thiazolidinediones and vitamin E, seem to be the most promising pharmacologic treatment for non-alcoholic steatohepatitis, but further long-term multicenter studies to assess safety are recommended. PMID- 28001264 TI - Atrial fibrillation with high ventricular rate in emergency room: What's the best strategy for treatment? AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and can lead to significant decline in functional status and quality of life among affected patients. The risk of developing AF increases with age and the presence of structural heart disease. Thus, the attendance of patients with high ventricular response to AF is common, which makes knowledge of its management mandatory. In this context, the choice of heart rate and/or rhythm control therapy is fundamental and complex, with multiple possibilities. Thus, this review aims to assist in the management of these patients, systematizing their care. PMID- 28001265 TI - Management of degenerative cervical myelopathy - An update. AB - Introduction: Degenerative cervical myelopathy (DCM) is the most common cause of spinal cord dysfunction in adult patients. Patients generally present with a slow, progressive neurological decline or a stepwise deterioration pattern. In this paper, we discuss the most important factors involved in the management of DCM, including a discussion about the surgical approaches. Method: The authors performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives. Results: Although the diagnosis is clinical, magnetic resonance imaging (MRI) is the study of choice to confirm stenosis and also to exclude the differential diagnosis. The severity the clinical symptoms of DCM are evaluated by different scales, but the modified Japanese Orthopedic Association (mJOA) and the Nurick scale are probably the most commonly used. Spontaneous clinical improvement is rare and surgery is the main treatment form in an attempt to prevent further neurological deterioration and, potentially, to provide some improvement in symptoms and function. Anterior, posterior or combined cervical approaches are used to decompress the spinal cord, with adjunctive fusion being commonly performed. The choice of one approach over the other depends on patient characteristics (such as number of involved levels, site of compression, cervical alignment, previous surgeries, bone quality, presence of instability, among others) as well as surgeon preference and experience. Conclusion: Spine surgeons must understand the advantages and disadvantages of all surgical techniques to choose the best procedure for their patients. Further comparative studies are necessary to establish the superiority of one approach over the other when multiple options are available. PMID- 28001266 TI - Microscopic colitis: A literature review. AB - Microscopic colitis (MC) refers to chronic inflammation of the colon which is characterized by histologic changes at the level of a radiologically and endoscopically normal mucosa. It is a common cause of chronic non-bloody diarrhea that occurs primarily in older individuals; however, there are few studies in the literature with strong scientific evidence compared to other inflammatory bowel diseases (IBD), which limits the knowledge of physicians and pathologists. This article aims to review the information on MC, describing diagnostic methods and drugs available for treatment. We conducted a search of the Pubmed database and CAPES Portal using the keywords "microscopic colitis", "collagenous colitis", "lymphocytic colitis", and "review" for selection of articles published between 1996 and 2015 related to the topic. Based on the studies discussed in this review, we conclude that MC is a relatively new gastrointestinal disorder, most studies are incipient particularly with respect to pathophysiology and immunology, and budesonide is the best documented short-term treatment. However, further studies are needed to elucidate the best strategy for treatment in the long term. PMID- 28001267 TI - The Brazilian Journal of Physical Therapy is now published by Elsevier: a step forward. PMID- 28001269 TI - Editorial. PMID- 28001268 TI - The evolving role of physical therapists in the long-term management of chronic low back pain: longitudinal care using assisted self-management strategies. AB - Background: Longitudinal studies have shown that the symptoms of chronic low back pain (CLBP) will follow an episodic trajectory characterized by periods of high and low pain intensity that can persist for many years. There is a growing belief that the contemporary approach of limiting physical therapy to short, but intense courses of treatment for (CLBP) may be sub-optimal because these limited "windows" of clinical care are not congruent with the natural history of this condition. Recent research has suggested that people with CLBP undergo substantial, and individualized long-term variations in the neural processing of nociception over time. This has led to the concept of a "unique biosignature of pain" that may explain much of the variation in a person's clinical picture. These and other findings have led to the reconceptualization of CLBP as an individualized, and continually evolving condition that may be more suitably managed by empowering the patient toward self-management strategies that can be modified as needed over time by the PT. Objectives: The purpose of this Master Class Paper is to describe an emerging approach for the treatment of CLBP that emphasizes the formation of a long-term therapeutic alliance between the patient and the PT with an emphasis on individualized, patient-preferred approaches for activity-based self-management as an alternative to the contemporary approach of short, intense episodes of care directed toward pain reduction. Conclusion: Longitudinal care using assisted self-management strategies is more congruent with the natural history of CLBP than are traditional approaches for PT intervention. This approach may empower patients to undergo lifestyle changes that will favorably influence long-term outcomes; however additional research is needed. PMID- 28001270 TI - Speech-language pathology assessment for tracheal decannulation in patients suffering from traumatic brain injury. AB - Purpose: To describe the effect of Speech-Language Pathology (SLP) management on the tracheal decannulation process in patients with traumatic brain injury (TBI). Methods: Prospective controlled clinical study. Two groups of patients with TBI confirmed by computed axial tomography were included in the study group (G1) and control group (G2) composed of 30 individuals each, with 25 (83.3%) male and 5 (16.7%) female individuals in both groups. Patients' age ranged from 18 to 53 years old - mean age was 32 years. A SPL assessment tool was developed for tracheostomized patients with TBI, composed of investigation of awareness level, cognition and swallowing (annex 1) and conduct. G1 underwent the assessment proposed by the study, and G2 was assessed by retrospective analysis of medical records without SLP evaluation. In this population, the variables time with tracheostomy and total days of hospitalization were the measurement markers for the effect of SLP conduct with this instrument. Results: It was verified that G1 presented mean reduction of 4.2 days with tracheostomy and of 4.4 days in length of hospital stay when compared to G2. However, these figures are not statistically significant (p = 0.2031). Conclusion: The group that was evaluated and received the SLP conduct proposed in the instrument presented a reduction in the time of permanence with tracheostomy, as well as in hospital stay. PMID- 28001271 TI - Validation of risk indicators for the constitution of the reader/scribe. AB - Purpose: To evaluate risk factors for the constitution of the reader/scribe. Methods: This is an exploratory study in which a retrospective questionnaire about the child before entering elementary school, based on preliminary indicators for the constitution of the subject reader/scribe, was applied to a population of 293 parents of elementary school students from a public school in Sao Paulo. The findings were crossed with the diagnostic survey of writing of students from the 1st to the 5th grade and with the evaluation of text production of students from the 3rd to the 5th grade. Data was statistically analyzed. Results and discussion: The questionnaire showed acceptable reliability and the analysis of convergent validity presented positive correlation considered valid, statistically significant with the diagnostic survey of writing, that is, the higher the score the better the performance in the survey questionnaire. There was statistically positive correlation between the questionnaire and the performance of the students on text production in cases where parents had complaints regarding the reading and writing of their children. Exploratory factor analysis validated the proposed construct. Conclusion: The questionnaire is easy to apply and inexpensive, and the results showed acceptance by the respondents -- fundamental characteristics of instruments that serve public health and education. The research allowed validating 8 of 15 risk indicators initially proposed for the constitution of the reader/scribe. This validation confers quality to the construct and opens possibilities for its use in health promotion, prevention and rehabilitation in reading, writing and therapy. PMID- 28001272 TI - Change in the nose areas in children with mouth breathing after nasal cleansing and massage. AB - Purpose: To analyze the changes occurred in the nasal cavity geometry, before and after nasal cleansing, through nasal aeration and acoustic rhinometry in children with oral breathing. Methods: Twenty children aged four to 12 years were included in the study. The gathering of participants was conducted at the Multifunctional Laboratory of the Speech Pathology Department of the Federal University of Pernambuco - UFPE. The following procedures were conducted: Identification Index of Signs and Symptoms of Oral Breathing; marking of nasal expiratory airflow using the graded mirror of Altmann, and examination of the Nasal Geometry by Acoustic Rhinometry. The same procedures were performed after nasal massage and cleansing with saline solution. Results: Significant change was observed in the areas with respect to the nasal airflow on both sides after nasal cleansing and massage. As for nasal geometry, measured by acoustic rhinometry, comparison between the nostrils showed that the effect of cleansing and massage was discrete. Conclusion: Nasal aeration measures showed sensitivity to the cleansing and massage technique and measures of nasal geometry confirmed its effect on respiratory physiology. PMID- 28001273 TI - Effect of speech-language therapy after low-level laser therapy in patients with TMD: a descriptive study. AB - Increased pain and/or discomfort during chewing, speaking, and swallowing have been commonly reported by patients with Temporomandibular Dysfunction (TMD). Speech-language pathology therapy (orofacial myofunctional therapy - OMT) has been proposed as part of the treatment for this condition; however, it is a modality that should be introduced when the TMD context and the pain are not accentuated, so that they do not prevent or hinder the performance of exercises. The aim of this study was to analyze the effect of OMT on the treatment of patients with TMD, according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), after analgesia with low-level laser therapy (LLLT), regarding orofacial myofunctional conditions (OMC) and the perception of TMD symptoms. Five patients aged 50 to 61 years were evaluated 30 days after completion of LLLT. An experienced speech-language pathologist conducted, pre- and post-OMT, the application of the ProDTM Multi-questionnaire - to investigate the self-perception of TMD symptomatology, and the Orofacial Myofunctional Evaluation with Scores (OMES) clinical examination - to confirm the orofacial myofunctional conditions. OMC presented increased OMT scores, indicating an increase in myofunctional orofacial balance. According to the patients' perception, TMD signs and symptoms were relieved after the application of OMT. According to the self-perception of the treated patients, introduction of OMT after LLLT analgesia promoted a balance of the orofacial functions of the sample studied, as well as a decrease in the remaining TMD signs and symptoms. PMID- 28001274 TI - Language, behavior and neurodevelopment in Joubert syndrome: a case report. AB - The Joubert syndrome (JS) is a rare, heterogeneous genetic condition among the ciliopathies. More than 20 genes have been identified associated with this phenotype. The main manifestations include hypotonia, ataxia, psychomotor retardation, ocular-motor apraxia and neonatal respiratory abnormalities. The objective of this paper was to present language and neurodevelopmental findings of an individual diagnosed with JS. The following procedures were performed: anamnesis, clinical genetic evaluation observation of communicative behavior, evaluation of language, the Denver Developmental Screening Test II (DDST-II) and the Early Language Milestone Scale (ELMS). The main findings of the MRI brain showed severe hypoplasia of the cerebellar vermis, "molar tooth sign", hypoplastic brain stem and atrophy of the cerebellar hemispheres. The observation and evaluation of the language showed no oral, impaired reception of language, confirming the diagnosis of language disorder with severe degree of impairment. The DDST-II and the ELMS confirmed the observation and clinical assessment and indicated serious delay in motor domains, self-care and receptive and expressive language. Given the presence of hypotonia, ataxia, delayed psychomotor and neonatal respiratory abnormalities it is essential to carry out examination imaging and genetic evaluation for the diagnosis of this condition, so complex, with unique therapeutic needs. This set of findings, along with the familial history and unique phenotypic characteristics reinforce the clinical genetic diagnosis JS. This genetic syndrome is rarely recognized and deserves to be presented to the recognition of the scientific community, targeting the correct diagnosis and treatment planning that minimizes the deleterious effects of this condition. PMID- 28001275 TI - Speech-language pathology findings in Attention Deficit Hyperactivity Disorder: a systematic literature review. AB - Purpose: To systematically review the scientific production on the relationship between Attention Deficit Hyperactivity Disorder (ADHD) and Speech-language Pathology and to methodologically analyze the observational studies on the theme. Research strategies: Systematic review of the literature conducted at the databases Medical Literature Analysis and Retrieval System online (MEDLINE, USA), Literature of Latin America and the Caribbean Health Sciences (LILACS, Brazil) and Spanish Bibliographic Index of Health Sciences (IBECS, Spain) using the descriptors: "Language", "Language Development", "Attention Deficit Hyperactivity Disorder", "ADHD" and "Auditory Perception". Selection criteria: Articles published between 2008 and 2013. Inclusion criteria: full articles published in national and international journals from 2008 to 2013. Exclusion criteria: articles not focused on the speech-language pathology alterations present in the attention deficit hyperactivity disorder. Data analysis: The articles were read in full and the data were extracted for characterization of methodology and content. Results: The 23 articles found were separated according to two themes: Speech-language Pathology and Attention Deficit Hyperactivity Disorder. Conclusion: The study of the scientific production revealed that the alterations most commonly discussed were reading disorders and that there are few reports on the relationship between auditory processing and these disorders, as well as on the role of the speech-language pathologist in the evaluation and treatment of children with Attention Deficit Hyperactivity Disorder. PMID- 28001276 TI - Effects of prematurity on language acquisition and auditory maturation: a systematic review. AB - Purpose: To verify which damages prematurity causes to hearing and language. Research strategies: We used the decriptors language/linguagem, hearing/audicao, prematurity/prematuridade in databases LILACS, MEDLINE, Cochrane Library and Scielo. Selection criteria: randomized controlled trials, non-randomized intervention studies and descriptive studies (cross-sectional, cohort, case control projects). Data analysis: The articles were assessed independently by two authors according to the selection criteria. Twenty-six studies were selected, of which seven were published in Brazil and 19 in international literature. Results: Nineteen studies comparing full-term and preterm infants. Two of the studies made comparisons between premature infants small for gestational age and appropriate for gestational age. In four studies, the sample consisted of children with extreme prematurity, while other studies have been conducted in children with severe and moderate prematurity. To assess hearing, these studies used otoacoustic emissions, brainstem evoked potentials, tympanometry, auditory steady state response and visual reinforcement audiometry. For language assessment, most of the articles used the Bayley Scale of Infant and Toddler Development. Most studies reviewed observed that prematurity is directly or indirectly related to the acquisition of auditory and language abilities early in life. Conclusion: Thus, it could be seen that prematurity, as well as aspects related to it (gestational age, low weight at birth and complications at birth), affect maturation of the central auditory pathway and may cause negative effects on language acquisition. PMID- 28001278 TI - End of an Era. PMID- 28001277 TI - Optimization and characterization of the endogenous production of protoporphyrin IX in a yeast model. AB - The availability of reproducible, convenient, and inexpensive model organisms able to generate predictable levels of endogenous porphyrins, including protoporphyrin IX (PpIX), is essential in photomedicine research. Saccharomyces cerevisiae produces endogenous PpIX and was used as a model organism for this study with the aim to maximize endogenous PpIX fluorescence intensity. It was found that PpIX fluorescence was significantly enhanced by administration of 5 aminolevulinic acid (ALA) and 2,2?-bipyridyl. Fluorescence intensity and spectroscopy of PpIX produced endogenously were measured in diluted yeast solutions under various conditions. The optimal protocol was: 5 ?? ? M ALA and 1 mM 2,2?-bipyridyl administered synchronously at 32 degrees C. After 3 h, PpIX in yeast demonstrated similar steady-state and time-resolved spectroscopy as that of PpIX in DMSO. Moreover, under hypoxic conditions, the reciprocal lifetime of PpIX delayed fluorescence measured in real time was correlated to the partial pressure of oxygen ( pO 2 ) measured concomitantly with a commercially available pO 2 probe. These data show that yeast can, in optimal conditions, reproducibly generate PpIX. This is of interest in various fields such as photodiagnosis, photodynamic therapy, and photobiomodulation. Use of this model organism focuses on essential mechanisms, without the complexity of a multicellular organism. PMID- 28001282 TI - FDA-Approved Drugs to Treat Schizophrenia. PMID- 28001279 TI - Psychosis. PMID- 28001283 TI - Hey Mister Tambourine Man, Play a Drug for Me: Music as Medication. AB - Listening to music may be thought of as noninvasive and nonpharmacological, but music should be considered a drug therapy. Music exposure has measurable neurobiological effects that are linked to systems regulating reward, motivation, and pleasure; stress and arousal; and immunity. Functional neuroimaging and lesion studies demonstrate that music-evoked emotions are associated with modulation of linked limbic and paralimbic brain regions. Some of these regions are involved in reward, motivation, and pleasure, and there are additional projections to brain structures regulating autonomic, emotional, and cognitive function. Controlled clinical studies have found significant benefits with the use of music for depression and anxiety, pain relief, stroke recovery, schizophrenia, and behavioral and psychological symptoms of dementia. Because music is not associated with significant adverse effects, it is a viable adjunctive treatment option for patients in many different clinical settings. [Journal of Psychosocial Nursing and Mental Health Services, 54(12), 23-27.]. PMID- 28001284 TI - Irritability in Childhood and Adolescence. AB - Irritability is common among children 5 and younger and is defined as a marked predisposition to anger. Irritability in childhood is associated with later psychopathology, suicide, and financial instability. Its persistence through later childhood may be associated with mood, anxiety, and substance use disorders. Assessment of irritability and psychiatric nursing implications are discussed. [Journal of Psychosocial Nursing and Mental Health Services, 54(12), 28-31.]. PMID- 28001285 TI - The Effect of Respite Services on Carers of Individuals With Severe Mental Illness. AB - Many individuals with severe mental illness (SMI) require the support of an informal carer, such as a family member or close friend, to assist with everyday living. The difficulties and altered life circumstances experienced by individuals with SMI result in carers taking on significant responsibilities. The current study aimed to address the benefits to carers of several days relief from their caring responsibilities. Carers (N = 9) of a cohort of individuals with SMI who attended a therapeutic recreation initiative, Recovery Camp, were surveyed in late May 2015. A custom-designed instrument using open and closed questions was administered. Data were analyzed using the constant-comparative method. Participants reported negative health effects that they directly associated with their caring responsibilities. The experience of having a break when their care recipient attended Recovery Camp was positive for all participants, highlighting the need for respite services. Further research is required to explore the specific respite needs of individuals who provide care to those with SMI to reduce the burden experienced by these vulnerable populations. [Journal of Psychosocial Nursing and Mental Health Services, 54 (12), 33-38.]. PMID- 28001286 TI - Charting the Course of Electroconvulsive Therapy: Where Have We Been and Where Are We Headed? AB - Electroconvulsive therapy (ECT) is one of the oldest and best treatments for severe mental illness. A safe and highly effective option for treatment-resistant mood disorders, ECT can be a lifesaving treatment for people suffering from catatonia and acute suicidality. Less recognized are the benefits of ECT in the treatment of primary psychotic disorders, Parkinson's disease, and status epilepticus. Evidence from multisite clinical trials in the past decade shows an evolving standard for the delivery of ECT to achieve and maintain remission and quality of life. Today, the optimal practice of ECT is defined by evidence-based treatment planning, including patient selection, choice of electrode placement and stimulus parameters, augmentation with pharmacotherapy, and the use of continuation/maintenance treatment. Research into biomarkers and neuroplasticity related to ECT response, as well as new investigational methods of delivering ECT, provide a glimpse into the future of this time-tested treatment. [Journal of Psychosocial Nursing and Mental Health Services, 54 (12), 39-43.]. PMID- 28001287 TI - Mental Health and the Transgender Population. AB - Although research into the physical and mental health disparities faced by transgender and gender nonconforming (TGNC) populations is becoming more popular, historically it has been limited. It is now recognized that TGNC people experience disproportionate rates of negative mental health outcomes relative to both their gender-normative, heterosexual peers, as well as their gender normative lesbian, gay, and bisexual (LGB) peers. The theoretical basis of current transgender mental health research is rooted in the Minority Stress Model, which postulates that we live in a hetero-centric, gender-normative society that stigmatizes and discriminates against lesbian, gay, bisexual, and transgender (LGBT) people, subjecting them to chronic stress (Hendricks & Testa, 2012; Meyer, 1995). This chronic, potentially compounding stress, is responsible for the increased risk of negative mental health outcomes in LGBT populations. TGNC people, in particular, may experience more adverse outcomes than their LGB peers due to rejection and discrimination within society at large as well as within the LGB community. [Journal of Psychosocial Nursing and Mental Health Services, 54(12), 44-48.]. PMID- 28001289 TI - Use of Precision Medicine Molecular Profiling of Baseline Tumor Specimen May Not Benefit Outcomes in Children With Relapsed or Refractory Pediatric Sarcomas. PMID- 28001290 TI - Reconciling inconsistencies in precipitation-productivity relationships: implications for climate change. AB - Contents 41 I. 41 II. 42 III. 43 IV. 44 V. 45 Acknowledgements 46 References 46 SUMMARY: Precipitation (PPT) is a primary climatic determinant of plant growth and aboveground net primary production (ANPP) over much of the globe. Thus, PPT ANPP relationships are important both ecologically and to land-atmosphere models that couple terrestrial vegetation to the global carbon cycle. Empirical PPT-ANPP relationships derived from long-term site-based data are almost always portrayed as linear, but recent evidence has accumulated that is inconsistent with an underlying linear relationship. We review, and then reconcile, these inconsistencies with a nonlinear model that incorporates observed asymmetries in PPT-ANPP relationships. Although data are currently lacking for parameterization, this new model highlights research needs that, when met, will improve our understanding of carbon cycle dynamics, as well as forecasts of ecosystem responses to climate change. PMID- 28001291 TI - Ion recombination and polarity corrections for small-volume ionization chambers in high-dose-rate, flattening-filter-free pulsed photon beams. AB - PURPOSE: To investigate ion recombination and polarity effects in scanning and microionization chambers when used with digital electrometers and high-dose-rate linac beams such as flattening-filter-free (FFF) fields, and to compare results against conventional pulsed and continuous photon beams. METHODS: Saturation curves were obtained for one Farmer-type ionization chamber and eight small volume chamber models with volumes ranging from 0.01 to 0.13 cm3 using a Varian TrueBeamTM STx with FFF capability. Three beam modes (6 MV, 6 MV FFF, and 10 MV FFF) were investigated, with nominal dose-per-pulse values of 0.0278, 0.0648, and 0.111 cGy/pulse, respectively, at dmax . Saturation curves obtained using the Theratronics T1000 60 Co unit at the UWADCL and a conventional linear accelerator (Varian Clinac iX) were used to establish baseline behavior. Jaffe plots were fitted to obtain Pion , accounting for exponential effects such as charge multiplication. These values were compared with the two-voltage technique recommended in TG-51, and were plotted as a function of dose-per-pulse to assess the ability of small-volume chambers to meet reference-class criteria in FFF beams. RESULTS: Jaffe- and two-voltage-determined Pion values measured for high dose-rate beams agreed within 0.1% for the Farmer-type chamber and 1% for scanning and microionization chambers, with the exception of the CC01 which agreed within 2%. With respect to ion recombination and polarity effects, the Farmer-type chamber, scanning chambers and the Exradin A26 microchamber exhibited reference-class behavior in all beams investigated, with the exception of the IBA CC04 scanning chamber, which had an initial recombination correction that varied by 0.2% with polarity. All microchambers investigated, with the exception of the A26, exhibited anomalous polarity and ion recombination behaviors that make them unsuitable for reference dosimetry in conventional and high-dose-rate photon beams. CONCLUSIONS: The results of this work demonstrate that recombination and polarity behaviors seen in conventional pulsed and continuous photon beams trend accordingly in high-dose-rate FFF linac beams. Several models of small-volume ionization chambers used with a digital electrometer have been shown to meet reference-class requirements with respect to ion recombination and polarity, even in the high-dose-rate environment. For such chambers, a two-voltage technique agreed well with more rigorous methods of determining Pion . However, the results emphasize the need for careful reference detector selection, and indicate that ionization chambers ought to be extensively tested in each beam of interest prior to their use for reference dosimetry. PMID- 28001292 TI - Predictors for Unplanned Hospitalization of New Home Care Clients. AB - OBJECTIVES: To identify factors predicting unplanned hospitalization of new home care clients using the Resident Assessment Instrument for Home Care (RAI-HC). DESIGN: A register-based study based on RAI-HC assessments and nationwide hospital discharge records. SETTING: Municipal home care services in Finland. PARTICIPANTS: New Finnish home care clients aged 63 and older (N = 15,700). MEASUREMENTS: Information from home care clients' first RAI-HC assessment was connected to information regarding their first hospitalization over 1 year of follow-up. Multivariate regression analyses were used to evaluate the independent risk factors for hospitalization. RESULTS: Forty-three percent (n = 6,812) of participants were hospitalized at least once. The strongest independent risk factors were hospitalization during the year preceding the RAI-HC assessment (odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.87-2.16), aged 90 and older (OR = 1.69, 95% CI = 1.48-1.92), renal insufficiency (OR = 1.44, 95% CI = 1.22-1.69) and using 10 or more drugs (OR = 1.41, 95% CI = 1.26-1.58). Other independent risk factors were male sex, previous emergency department visits or other acute outpatient care use, daily urinary incontinence, fecal incontinence, history of falls, cognitive impairment, chronic skin ulcer, pain, unstable health status, housing-related problems, and poor self-rated health. Parkinson's disease, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, and cancer were independent prognostic indicators. A body mass index of 24 kg/m2 or greater and the client's own belief that functional capacity could improve had a protective role. CONCLUSION: Assessing new home care clients using the RAI-HC reveals modifiable risk factors for unplanned hospitalization. Systematic assessment by a multidisciplinary team at the beginning of the service and targeting modifiable risk factors could reduce the risk of unplanned hospitalization. PMID- 28001293 TI - Experiences with semi-routine production of riboflavin and UV-B pathogen inactivated platelet concentrates in three blood centres. AB - BACKGROUND: For a clinical platelet (PLT) transfusion trial conducted in three countries, the production of PLT concentrates (PCs) that were pathogen inactivated with the Mirasol technology was set up and validated. While the Mirasol procedure is applied to an established PLT product, the PLT processing procedure still had to be modified to ensure a treated PC was of sufficient quality. Further, the effect of simulated transport conditions and the effect of ambient light on Mirasol-treated PCs was determined. STUDY DESIGN AND METHODS: Platelet concentrates in plasma were made from pooled buffy coats followed by Mirasol treatment. To mimic transport conditions, units were left unagitated for 6 h at room temperature. To mimic ambient light exposure, units were held unagitated for 4 h in direct fluorescent tube light. RESULTS: Measures had to be taken to allow 7-day storage of treated concentrates. In one site, PCs made from five buffy coats with >450 * 109 PLTs were removed from inventory. Another site went from five to four buffy coats per pool. Interruption of agitation for 6 h on day 3 did not induce meaningful changes in in vitro measures, even when stored up to 7 days. Exposure to ambient light for 4 h, either on day 3 or 6, had no effect on in vitro measures. CONCLUSION: The Mirasol pathogen inactivation process can be implemented in routine, but changes to current PLT processing methods might be needed. Transport conditions and 4-h-long ambient light exposure have no negative effect on the in vitro quality of Mirasol-treated PCs. PMID- 28001294 TI - Longitudinal analysis of reporting and quality of systematic reviews in high impact surgical journals. AB - BACKGROUND: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) Statement aims to optimize the reporting of systematic reviews. The performance of the PRISMA Statement in improving the reporting and quality of surgical systematic reviews remains unclear. METHODS: Systematic reviews published in five high-impact surgical journals between 2007 and 2015 were identified from online archives. Manuscripts blinded to journal, publication year and authorship were assessed according to 27 reporting criteria described by the PRISMA Statement and scored using a validated quality appraisal tool (AMSTAR, Assessing the Methodological Quality of Systematic Reviews). Comparisons were made between studies published before (2007-2009) and after (2011-2015) its introduction. The relationship between reporting and study quality was measured using Spearman's rank test. RESULTS: Of 281 eligible manuscripts, 80 were published before the PRISMA Statement and 201 afterwards. Most manuscripts (208) included a meta-analysis, with the remainder comprising a systematic review only. There was no meaningful change in median compliance with the PRISMA Statement (19 (i.q.r. 16-21) of 27 items before versus 19 (17-22) of 27 after introduction of PRISMA) despite achieving statistical significance (P = 0.042). Better reporting compliance was associated with higher methodological quality (rs = 0.70, P < 0.001). CONCLUSION: The PRISMA Statement has had minimal impact on the reporting of surgical systematic reviews. Better compliance was associated with higher quality methodology. PMID- 28001295 TI - Gradients in cytoarchitectural landscapes of the isocortex: Diprotodont marsupials in comparison to eutherian mammals. AB - Although it has been claimed that marsupials possess a lower density of isocortical neurons compared with other mammals, little is known about cross cortical variation in neuron distributions in this diverse taxonomic group. We quantified upper-layer (layers II-IV) and lower-layer (layers V-VI) neuron numbers per unit of cortical surface area in three diprotodont marsupial species (two macropodiformes, the red kangaroo and the parma wallaby, and a vombatiform, the koala) and compared these results to eutherian mammals (e.g., xenarthrans, rodents, primates). In contrast to the notion that the marsupial isocortex contains a low density of neurons, we found that neuron numbers per unit of cortical surface area in several marsupial species overlap with those found in eutherian mammals. Furthermore, neuron numbers vary systematically across the isocortex of the marsupial mammals examined. Neuron numbers under a unit of cortical surface area are low toward the frontal cortex and high toward the caudo medial (occipital) pole. Upper-layer neurons (i.e., layers II-IV) account for most of the variation in neuron numbers across the isocortex. The variation in neuron numbers across the rostral to the caudal pole resembles primates. These findings suggest that diprotodont marsupials and eutherian mammals share a similar cortical architecture despite their distant evolutionary divergence. PMID- 28001296 TI - Spatial distribution of intermingling pools of projection neurons with distinct targets: A 3D analysis of the commissural ganglia in Cancer borealis. AB - Projection neurons play a key role in carrying long-distance information between spatially distant areas of the nervous system and in controlling motor circuits. Little is known about how projection neurons with distinct anatomical targets are organized, and few studies have addressed their spatial organization at the level of individual cells. In the paired commissural ganglia (CoGs) of the stomatogastric nervous system of the crab Cancer borealis, projection neurons convey sensory, motor, and modulatory information to several distinct anatomical regions. While the functions of descending projection neurons (dPNs) which control downstream motor circuits in the stomatogastric ganglion are well characterized, their anatomical distribution as well as that of neurons projecting to the labrum, brain, and thoracic ganglion have received less attention. Using cell membrane staining, we investigated the spatial distribution of CoG projection neurons in relation to all CoG neurons. Retrograde tracing revealed that somata associated with different axonal projection pathways were not completely spatially segregated, but had distinct preferences within the ganglion. Identified dPNs had diameters larger than 70% of CoG somata and were restricted to the most medial and anterior 25% of the ganglion. They were contained within a cluster of motor neurons projecting through the same nerve to innervate the labrum, indicating that soma position was independent of function and target area. Rather, our findings suggest that CoG neurons projecting to a variety of locations follow a generalized rule: for all nerve pathway origins, the soma cluster centroids in closest proximity are those whose axons project down that pathway. PMID- 28001297 TI - Impact of platelet pathogen inactivation on blood component utilization and patient safety in a large Austrian Regional Medical Centre. AB - BACKGROUND: In clinical studies, pathogen inactivation (PI) of platelet concentrates (PC) with amotosalen and UVA light did not impact patient risk for haemorrhage but may affect transfusion frequency and component utilization. We evaluated the influence of platelet PI on PC, red cell concentrate (RCC) and plasma use and safety in routine practice in a large regional hospital. STUDY DESIGN AND METHODS: Comparative effectiveness of conventional vs. PI-treated PC was analysed during two 21-month periods, before and after PI implementation. RESULTS: Similar numbers of patients were transfused in the pre-PI (control, 1797) and post-PI (test, 1694) periods with comparable numbers of PC (8611 and 7705, respectively). The mean numbers of PC per patient transfused (4.8 vs. 4.5, P = 0.43) were not different but days of PC support (5.9 vs. 5.0, P < 0.01) decreased. Most patients received RCC (86.8% control vs. 84.8% test, P = 0.90) with similar mean numbers transfused (10.8 vs. 10.2 RCC, P = 0.22), and fewer patients (55.4% control vs. 44.7% test, P < 0.01) received less plasma units (mean 9.9 vs. 7.8, respectively, P < 0.01) in the test period. The frequencies of transfusion-related adverse events (AE) were comparable (1.3% vs. 1.4%, P = 0.95). Analysis of haematology-oncology (522 control, 452 test), cardiac surgery (739 control, 711 test), paediatric (157 control, 130 test) and neonate (23 control, 20 test) patients revealed no increase in PC, plasma and RCC utilization, or AE. CONCLUSION: Component utilization and patient safety were not impacted by adoption of PI for PC. RCC use per patient was comparable, suggestive of no increase in significant bleeding. PMID- 28001298 TI - Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: European regulators' perspective. AB - Progressive multifocal leukoencephalopathy (PML) has been associated with the use of a number of multiple sclerosis (MS) immunomodulatory therapies and has assumed a critical place in the evaluation of their benefit/risk. In this review, we discuss the European Union regulatory approach to drug-induced PML in MS, highlight a number of key issues related to the current knowledge on PML, and outline possible paths to help progress the risk management of patients with MS at risk of PML. PMID- 28001299 TI - Organization of the antennal lobes in the praying mantis (Tenodera aridifolia). AB - Olfaction in insects plays pivotal roles in searching for food and/or for sexual partners. Although many studies have focused on the olfactory processes of nonpredatory insect species, little is known about those in predatory insects. Here, we investigated the anatomical features of the primary olfactory center (antennal lobes) in an insect predator whose visual system is well developed, the praying mantis Tenodera aridifolia. Both sexes of T. aridifolia were found to possess 54 glomeruli, and each glomerulus was identified based on its location and size. Moreover, we found a sexual dimorphism in three glomeruli (macroglomeruli) located at the entrance of the antennal nerves, which are 15 times bigger in males than their homologs in females. We additionally deduced the target glomeruli of olfactory sensory neurons housed in cognate types of sensilla by degenerating the sensory afferents. The macroglomeruli received sensory inputs from grooved peg sensilla, which are present in a large number at the proximal part of the males' antennae. Furthermore, our findings suggest that glomeruli at the posteriodorsal part of the antennal lobes receive sensory information from putative hygro- and thermosensitive sensilla. The origins of projections connected to the protocerebrum are also discussed. J. Comp. Neurol. 525:1685 1706, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28001301 TI - Tumor response to neoadjuvant chemotherapy predicts long-term survival outcomes in patients with locoregionally advanced nasopharyngeal carcinoma: A secondary analysis of a randomized phase 3 clinical trial. AB - BACKGROUND: Tumor response to neoadjuvant chemotherapy using the regimen of cisplatin and 5-fluorouracil could define high-risk patients with locoregionally advanced nasopharyngeal carcinoma (NPC). However, the regimen of docetaxel, cisplatin, and 5-fluorouracil (TPF) appears to be more effective than the regimen of cisplatin and 5-fluorouracil. Therefore, one needs to redefine the high-risk subpopulation of patients receiving neoadjuvant chemotherapy with TPF. METHODS: A total of 231 patients from a randomized phase 3 trial with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC (except T3-T4N0 disease) who were receiving treatment with the TPF regimen were enrolled. Patient survival rates between different groups were compared. RESULTS: Of the 231 patients, the overall response to neoadjuvant chemotherapy was a complete response (CR) for 26 (11.3%), a partial response (PR) for 184 patients (79.6%), and stable disease (SD) for 21 patients (9.1%). Univariate analysis revealed the 3-year failure-free survival (FFS) rates in the CR (88.5% vs 61.9%; P =.017) and PR (81.2% vs 61.9%; P = .01) groups, and the 3-year overall survival rates for the CR (96.2% vs 76.2%; P =.048) and PR (93.4% vs 76.2%; P =.025) groups were obviously higher compared with that of the SD group. In multivariate analysis, CR was established as a favorable prognostic factor for FFS (hazard ratio [HR], 0.210; 95% confidence interval [95% CI], 0.057-0.779 [P =.02]), and PR for FFS (HR, 0.447; 95% CI, 0.213-0.936 [P =.033]) and OS (HR, 0.361; 95% CI, 0.132-0.986 [P =.047]) when compared with SD. No survival difference was observed between the CR and PR groups. CONCLUSIONS: Tumor response to TPF may be a properly powerful prognosis predictor and help to develop individualized treatment strategies for patients with locoregionally advanced NPC. Cancer 2017;123:1643-1652. (c) 2017 American Cancer Society. PMID- 28001302 TI - Impact of concomitant chemoradiation on survival for patients with T1-2N1 head and neck cancer. AB - BACKGROUND: Single-modality radiotherapy is considered a standard-of-care option for certain stage III, T1-2N1 head and neck squamous cell carcinomas (HNSCCs). The role of concomitant chemoradiation is not well established because there have been no studies comparing chemoradiation with radiation alone in this population. METHODS: This study analyzed patients in the National Cancer Data Base with cT1 2N1M0 invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx who were diagnosed between 2004 and 2012 and were undergoing definitive radiation. Patients who were undergoing surgery before radiation with unknown follow-up or for whom either the receipt or timing of chemotherapy was unknown were excluded. RESULTS: In all, 5030 patients with T1-2N1 oropharyngeal, laryngeal, or hypopharyngeal cancer were included. The median follow-up was 56.8 months (95% confidence interval [CI], 55.7-58.6 months). Overall, 68% of the patients received concomitant chemoradiation (CCRT). The use of CCRT significantly increased during the time period of this study from 53% in 2004 to 78% in 2012 (P < .001). CCRT was associated with improved overall survival (OS) in comparison with radiation alone in a multivariate analysis (hazard ratio [HR], 0.80; 95% CI, 0.72-0.88; P < .001). In propensity score-adjusted analyses, CCRT remained significantly associated with improved OS, with 5-year OS rates of 63.5% (95% CI, 60.7%-66.2%) and 55.6% (95% CI, 52.7%-58.4%; P < .001) with CCRT and radiation alone, respectively. Subgroup analyses showed a benefit across the majority of subgroups, including patients with oropharyngeal cancer (HR, 0.74; 95% CI, 0.65-0.85; P < .001). CONCLUSIONS: Concomitant chemoradiation is associated with improved survival for patients with T1-2N1 HNSCC. Prospective trials in this population should be pursued. Cancer 2017;123:1555-1565. (c) 2017 American Cancer Society. PMID- 28001303 TI - Predictors of multidomain decline in health-related quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) for localized prostate cancer involves high-dose-per-fraction radiation treatments. Its use is increasing, but concerns remain about treatment-related toxicity. The authors assessed the incidence and predictors of a global decline in health-related quality of life (HRQOL) after prostate SBRT. METHODS: From 2008 to 2014, 713 consecutive men with localized prostate cancer received treatment with SBRT according to a prospective institutional protocol. Expanded Prostate Cancer Index Composite (EPIC-26) HRQOL data were collected at baseline and longitudinally for 5 years. EPIC-26 is comprised of 5 domains. The primary endpoint was defined as a decline exceeding the clinically detectable threshold in >=4 EPIC-26 domains, termed multidomain decline. RESULTS: The median age was 69 years, 46% of patients had unfavorable intermediate-risk or high-risk disease, and 20% received androgen deprivation therapy. During 1 to 3 months and 6 to 60 months after SBRT, 8% to 15% and 10% to 11% of patients had multidomain declines, respectively. On multivariable analysis, lower baseline bowel HRQOL (odds ratio, 1.8; 95% confidence interval, 1.2-2.7; P < .01) and baseline depression (odds ratio, 5.7; 95% confidence interval, 1.3-24.3; P = .02) independently predicted for multidomain decline. Only 3% to 4% of patients had long-term multidomain declines exceeding twice the clinical threshold, and 30% of such declines appeared to be related to prostate cancer treatment or progression of disease. CONCLUSIONS: Prostate SBRT has minimal long-term impact on multidomain decline, and the majority of more significant multidomain declines appear to be unrelated to treatment. This emphasizes the importance of focusing not only on the side effects of prostate cancer treatment but also on other comorbid illnesses that contribute to overall HRQOL. Cancer 2017;123:1635-1642. (c) 2017 American Cancer Society. PMID- 28001304 TI - Text message reminders increased colorectal cancer screening in a randomized trial with Alaska Native and American Indian people. AB - BACKGROUND: Alaska Native and American Indian people (AN/AIs) have a high incidence of colorectal cancer (CRC) and CRC-related mortality. Screening can prevent death from CRC, but screening rates are low in racially and ethnically diverse populations. The authors conducted a randomized controlled trial using text messaging to increase CRC screening among unscreened AN/AIs in a tribal health care system in Anchorage, Alaska. METHODS: The intervention entailed up to 3 text messages sent 1 month apart. The authors randomized 2386 AN/AIs aged 40 to 75 years who were eligible for CRC screening to the intervention or usual-care control conditions. Screening status was ascertained from electronic health records 3 months and 6 months after the last text message. Hazard ratios (HRs) were estimated to evaluate the effectiveness of the intervention, stratified by age and sex. RESULTS: The intervention increased CRC screening for AN/AIs aged 50 to 75 years (HR, 1.42; 95% confidence interval [95% CI], 0.97-2.09) and aged 40 to 49 years (HR, 1.24; 95% CI, 0.95-1.62). Within both age groups, the HRs were higher for women (HR, 1.69 [95% CI, 1.02-2.80] and HR, 1.37 [95% CI, 1.01-1.88]) compared with men (HR, 1.09 [95% CI, 0.59-1.99] and HR, 0.90 [95% CI, 0.54 1.53]). Interaction analysis yielded P values of .55 and .09, respectively, for age and sex. CONCLUSIONS: A simple text messaging intervention was found to increase CRC screening rates in AN/AIs, a group with high CRC morbidity and mortality. Text messaging may be a cost-effective means of reducing CRC screening disparities in AN/AIs and other populations. Cancer 2017;123:1382-1389. (c) 2016 American Cancer Society. PMID- 28001306 TI - Doxapram-mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic-Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers. AB - Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K+ -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety. PMID- 28001305 TI - An entertainment-education colorectal cancer screening decision aid for African American patients: A randomized controlled trial. AB - BACKGROUND: Colorectal cancer screening rates for African American patients remain suboptimal. Patient decision aids designed with an entertainment-education approach have been shown to improve saliency and foster informed decision making. The purpose of this study was to assess whether an entertainment-education decision aid tailored for African American patients improved patients' decision making, attitudes, intentions, or colorectal cancer screening behavior. METHODS: Eighty-nine participants were randomized to view 1) a patient decision aid video containing culturally tailored information about colorectal cancer screening options and theory-based support in decision making presented in an entertainment education format or 2) an attention control video about hypertension that contained similarly detailed information. Participants met with their clinician and then completed follow-up questionnaires assessing their knowledge, decisional conflict, self-advocacy, attitudes, perceived social norms, and intentions. At 3 months, completion of screening was assessed by chart review. RESULTS: Viewing the culturally tailored decision aid significantly increased African American patients' knowledge of colorectal cancer screening recommendations and options. It also significantly reduced their decisional conflict and improved their self advocacy. No significant differences were observed in participants' attitudes, norms, or intentions. At three months, 23% of all patients had completed a colonoscopy. CONCLUSIONS: Designing targeted, engaging patient decision aids for groups that receive suboptimal screening holds promise for improving patient decision making and self-advocacy. Additional research is warranted to investigate the effectiveness of such aids in clinical practices with suboptimal screening rates and on downstream behaviors (such as repeat testing). Cancer 2017;123:1401-1408. (c) 2016 American Cancer Society. PMID- 28001308 TI - Heterogeneous multiscale Monte Carlo simulations for gold nanoparticle radiosensitization. AB - PURPOSE: To introduce the heterogeneous multiscale (HetMS) model for Monte Carlo simulations of gold nanoparticle dose-enhanced radiation therapy (GNPT), a model characterized by its varying levels of detail on different length scales within a single phantom; to apply the HetMS model in two different scenarios relevant for GNPT and to compare computed results with others published. METHODS: The HetMS model is implemented using an extended version of the EGSnrc user-code egs_chamber; the extended code is tested and verified via comparisons with recently published data from independent GNP simulations. Two distinct scenarios for the HetMS model are then considered: (a) monoenergetic photon beams (20 keV to 1 MeV) incident on a cylinder (1 cm radius, 3 cm length); (b) isotropic point source (brachytherapy source spectra) at the center of a 2.5 cm radius sphere with gold nanoparticles (GNPs) diffusing outwards from the center. Dose enhancement factors (DEFs) are compared for different source energies, depths in phantom, gold concentrations, GNP sizes, and modeling assumptions, as well as with independently published values. Simulation efficiencies are investigated. RESULTS: The HetMS MC simulations account for the competing effects of photon fluence perturbation (due to gold in the scatter media) coupled with enhanced local energy deposition (due to modeling discrete GNPs within subvolumes). DEFs are most sensitive to these effects for the lower source energies, varying with distance from the source; DEFs below unity (i.e., dose decreases, not enhancements) can occur at energies relevant for brachytherapy. For example, in the cylinder scenario, the 20 keV photon source has a DEF of 3.1 near the phantom's surface, decreasing to less than unity by 0.7 cm depth (for 20 mg/g). Compared to discrete modeling of GNPs throughout the gold-containing (treatment) volume, efficiencies are enhanced by up to a factor of 122 with the HetMS approach. For the spherical phantom, DEFs vary with time for diffusion, radionuclide, and radius; DEFs differ considerably from those computed using a widely applied analytic approach. CONCLUSIONS: By combining geometric models of varying complexity on different length scales within a single simulation, the HetMS model can effectively account for both macroscopic and microscopic effects which must both be considered for accurate computation of energy deposition and DEFs for GNPT. Efficiency gains with the HetMS approach enable diverse calculations which would otherwise be prohibitively long. The HetMS model may be extended to diverse scenarios relevant for GNPT, providing further avenues for research and development. PMID- 28001307 TI - Storage of red blood cells in a novel polyolefin blood container: a pilot in vitro study. AB - BACKGROUND AND OBJECTIVES: The present general plasticizer di-2-ethylhexyl phthalate in polyvinylchloride (PVC) blood bags is only physically dispersed in PVC and will therefore leach into blood components. The objective of this study was to perform a first preliminary red blood cell (RBC) storage evaluation in a new blood bag manufactured of polyolefin without any inclusion of potentially migrating substances. STUDY DESIGN AND METHODS: This is a RBC storage study for 42 days. Blood collection was performed in a polyolefin-based PVC-free blood bag. RBCs were prepared within 8 h. Two different RBC additive solutions were used, either PAGGS-M or PAGGG-M. We weekly measured pH, K+ , glucose, lactate, haemolysis, red cell ATP and 2,3-DPG. RESULTS: RBC storage in PAGGS-M resulted in high haemolysis levels already after 21 days, exceeding the European maximum limit of 0.8%, and low ATP levels by the end of the storage period. With PAGGG-M, haemolysis exceeded 0.8% after 28 days of storage. For additional parameters, the results were comparable to those of previous studies in conventional blood bags. CONCLUSION: This is a first preliminary study of RBC storage in a new type of blood bags. PAGGG-M gave encouraging results except for its inability to prevent increased haemolysis. There will be room for further development of RBC additive solutions to address the haemolysis problems. Plasma should also be tested regarding the stability of coagulation and activation pathway variables. There may also be a potential for future use of the bag for preparation of pooled buffy coat-derived platelets. PMID- 28001309 TI - Platelet responses to agonists in a cohort of highly characterised platelet donors are consistent over time. AB - BACKGROUND AND OBJECTIVES: Platelet function shows significant inheritance that is at least partially genetically controlled. There is also evidence that the platelet response is stable over time, but there are few studies that have assessed consistency of platelet function over months and years. We aimed to measure platelet function in platelet donors over time in individuals selected from a cohort of 956 donors whose platelet function had been previously characterised. MATERIALS AND METHODS: Platelet function was assessed by flow cytometry, measuring fibrinogen binding and P-selectin expression after stimulation with either cross-linked collagen-related peptide or adenosine 5' diphosphate. Eighty-nine donors from the Cambridge Platelet Function Cohort whose platelet responses were initially within the lower or upper decile of reactivity were retested between 4 months and five and a half years later. RESULTS: There was moderate-to-high correlation between the initial and repeat platelet function results for all assays (P <= 0.007, r2 0.2961-0.7625); furthermore, the range of results observed in the initial low and high responder groups remained significantly different at the time of the second test (P <= 0.0005). CONCLUSION: Platelet function remains consistent over time. This implies that this potential influence on quality of donated platelet concentrates will remain essentially constant for a given donor. PMID- 28001310 TI - The association of fever with transfusion-associated circulatory overload. AB - BACKGROUND: Fever is described in transfusion-associated circulatory overload (TACO), reflecting either comprehensive haemovigilance or an inflammatory pathobiology (such as congestion-associated atheroma disruptions). METHODS: Hospital haemovigilance data (1/1/2010-31/12/2012) were reviewed for TACO cases (frequency and mode of referral). TACO with or without fever (TACO+F/-F) was examined for its association with patient age (as a surrogate for atheroma burden) and product age (as a surrogate for storage-related pyrogens). Fever in allergic transfusion reactions was also compared. RESULTS: Of 972 reactions, 107 suspected cases of TACO (11%) were seen. TACO+F vs. TACO-F occurred in 42.1 vs. 57.9%, respectively. TACO+F cases were discovered in referrals to investigate either a fever (in 47.1%) or dyspnoea (in 52.9%). Among TACO+F cases, 24.4% had already been febrile, whereas 75.6% exhibited a new reaction-associated fever. After excluding preexisting fevers, TACO+F occurred in 31.8% of TACO, compared with 8.2% of allergic reactions with fever, for an odds ratio of 5.2 (2.9-9.4 [95% CI]), P < 0.001. TACO+F/TACO-F showed no difference in median host age (69 vs. 64 years, P = 0.3), RBC age (22 days +F/-F, P = 0.9) or severity. CONCLUSION: Transfusion-associated circulatory overload disproportionately exhibits fever compared with allergic reactions. However, TACO+F did not associate with patient or product age, nor reflect severity. To better understand TACO+F, the fever congestion sequence merits attention. Further study is needed to see whether TACO+F occurs as reproducibly elsewhere, and in association with atherosclerosis in a better characterized cohort. PMID- 28001311 TI - Extreme lymphocytosis with myelomonocytic morphology in a horse with diffuse large B-cell lymphoma. AB - An 11-year-old, 443-kg Haflinger mare was presented to the North Carolina State University Veterinary Teaching Hospital with a 2-week history of lethargy and a 3 day duration of anorexia, pyrexia, tachycardia, and ventral edema. Severe pitting edema, peripheral lymphadenopathy, and a caudal abdominal mass were noted on physical examination. An extreme leukocytosis (154.3 * 103 /MUL) and microscopic hematologic findings suggestive of myelomonocytic leukemia were observed. Serum protein electrophoresis revealed a monoclonal gammopathy and urine protein electrophoresis revealed a monoclonal light chain proteinuria. Necropsy and histopathology confirmed widespread neoplastic infiltration in many organs with a heterogenous population of cells; there was no apparent evidence of bone marrow involvement. Immunohistochemistry confirmed presence of a majority of B cells with a limited antigen expression, admixed with a lower number of T cells. Molecular clonality analysis of IgH2, IgH3, and kappa-deleting element (KDE, B cell) on whole blood and KDE on infiltrated tissues revealed clonal rearrangements, and the KDE intron clones that amplified in blood and in infiltrated tissue were identical. In contrast, the clonality analysis of T-cell receptor gamma revealed no clonality on blood cells and infiltrated tissues. In conjunction with the histopathologic changes, the lesion was interpreted to be composed of neoplastic B cells with a reactive T-cell population. Polymerase chain reaction testing for equine herpes virus 5 was negative. The final diagnosis was diffuse large B-cell lymphoma with a marked hematogenous component. PMID- 28001312 TI - Critical re-appraisal of blood component quality after overnight hold of whole blood outside current room temperature limits. AB - BACKGROUND AND OBJECTIVES: According to European guidelines, the temperature of whole blood (WB) has to be maintained at 20-24 degrees C until processing within 24 h, but in blood bank practice, WB is frequently held at temperatures between 18-25 degrees C. We aimed to assess the impact of these small temperature deviations on the quality of the blood components. MATERIALS AND METHODS: After rapid cooling, 7 WB units were held overnight at 18 degrees C and 8 units at 25 degrees C, reflecting worst case holding conditions, and separated into a red cell concentrate (RCC), plasma and buffy coat (BC). RCCs were filtered at test temperature and stored for 42 days at 2-6 degrees C. BCs were processed to single BC platelet concentrates (sPC) and stored up to Day 8 at 20-24 degrees C. RESULTS: After overnight hold at 18 degrees C, 2,3-DPG in WB decreased by 34 +/- 9%, while at 25 degrees C the decrease was 82 +/- 6%. Accordingly, the 2,3-DPG levels in the RCCs in the 25 degrees C group were significantly lower than in the 18 degrees C group (2.2 +/- 1.4 vs. 10.4 +/- 2.9 MUmol/g Hb). RCCs and sPCs in the 25 degrees C group showed higher initial lactate levels and lower pH compared to the 18 degrees C group, but these differences levelled off at the end of storage. RCCs showed small differences in ATP levels and haemolysis. Plasma in both groups showed comparable Factor VIII:C levels. CONCLUSION: The temperature of WB during overnight hold strongly affects initial 2,3-DPG levels of RCCs and supports the maintenance of temperature limits between 20 and 24 degrees C. Other in vitro effects of the temperature deviations were small and of no practical relevance. PMID- 28001313 TI - Incidence and clinical characteristics of transfusion-associated circulatory overload using an active surveillance algorithm. AB - BACKGROUND: The concordance of haemovigilance criteria developed for surveillance of transfusion-associated circulatory overload (TACO) with its clinical diagnosis has not been assessed. In a pilot study to evaluate an electronic screening algorithm, we sought to examine TACO incidence and application of haemovigilance criteria in patients with post-transfusion pulmonary oedema. STUDY DESIGN AND METHODS: From June to September 2014, all transfused adult inpatients at four academic hospitals were screened with an algorithm identifying chest radiographs ordered within 12 h of blood component release. Patients with post-transfusion pulmonary oedema underwent case adjudication by an expert panel. TACO incidence was calculated, and clinical characteristics were compared with other causes of post-transfusion pulmonary oedema. RESULTS: Among 4932 transfused patients, there were 3412 algorithm alerts, 50 cases of TACO and 47 other causes of pulmonary oedema. TACO incidence was 1 case per 100 patients transfused. TACO classification based on two sets of haemovigilance criteria (National Healthcare Safety Network and proposed revised International Society for Blood Transfusion) was concordant with expert panel diagnosis in 57% and 54% of reviewed cases, respectively. Although the majority of clinical parameters did not differentiate expert panel adjudicated TACO from other cases, improved oxygenation within 24 h of transfusion did (P = 0.01). CONCLUSIONS: The incidence of TACO was similar to that observed in prior studies utilizing active surveillance. Case classification by haemovigilance criteria was frequently discordant with clinical diagnoses of TACO in patients with post-transfusion pulmonary oedema. Improvements in oxygenation within 24 h of transfusion merit further evaluation in the diagnosis of TACO. PMID- 28001314 TI - New aspects on the efficacy of high-dose intravenous immunoglobulins in patients with autoimmune thrombocytopenia. AB - BACKGROUND AND OBJECTIVES: The clinical significance of autoimmune thrombocytopenia (ITP) is reflected by bleeding and/or an increased bleeding risk due to low platelet counts. In most cases, treatment with high-dose (1-2 g/kg body weight) intravenous immunoglobulin has been demonstrated to result in an increase in platelet counts after one day of treatment. Until now, there is little information on the true beginning of therapy effect in patients treated with high-dose intravenous immunoglobulin. In this study, we focused on the kinetic of platelet counts and cessation of bleeding within the first 24 h of treatment. MATERIALS AND METHODS: Nineteen patients with chronic ITP were treated with high-dose intravenous immunoglobulin due to clinically relevant bleeding and/or for increased bleeding risk. RESULTS: Although the response was variable in treated patients, cessation of bleeding was observed within 12 h in all such affected patients (n = 7), even in patients with platelet counts that were not increased (n = 3). Furthermore, platelet counts were observed to increase already within 1 h in 10 (53%) patients and within 8 h in 12 (63%) patients. CONCLUSIONS: From a clinical perspective, the onset of therapeutic effects of intravenous immunoglobulin in patients with ITP may occur at an earlier stage and be superior to that previously expected. Failure to measure an increase in platelets in the circulation of 'non-responders' may be explained by an increased consumption of platelets due to recognizable or unrecognizable bleeding in such affected patients. PMID- 28001315 TI - GLANDULAR TRICHOME-SPECIFIC WRKY 1 promotes artemisinin biosynthesis in Artemisia annua. AB - Artemisinin is a type of sesquiterpene lactone well known as an antimalarial drug, and is specifically produced in glandular trichomes of Artemisia annua. However, the regulatory network for the artemisinin biosynthetic pathway remains poorly understood. Exploration of trichome-specific transcription factors would facilitate the elucidation of regulatory mechanism of artemisinin biosynthesis. The WRKY transcription factor GLANDULAR TRICHOME-SPECIFIC WRKY 1 (AaGSW1) was cloned and analysed in A. annua. AaGSW1 exhibited similar expression patterns to the trichome-specific genes of the artemisinin biosynthetic pathway and AP2/ERF transcription factor AaORA. A beta-glucuronidase (GUS) staining assay further demonstrated that AaGSW1 is a glandular trichome-specific transcription factor. AaGSW1 positively regulates CYP71AV1 and AaORA expression by directly binding to the W-box motifs in their promoters. Overexpression of AaGSW1 in A. annua significantly improves artemisinin and dihydroartemisinic acid contents; moreover, AaGSW1 can be directly regulated by AaMYC2 and AabZIP1, which are positive regulators of jasmonate (JA)- and abscisic acid (ABA)-mediated artemisinin biosynthetic pathways, respectively. These results demonstrate that AaGSW1 is a glandular trichome-specific WRKY transcription factor and a positive regulator in the artemisinin biosynthetic pathway. Moreover, we propose that two trifurcate feed-forward pathways involving AaGSW1, CYP71AV1 and AaMYC2/AabZIP1 function in the JA/ABA response in A. annua. PMID- 28001316 TI - Computed tomography-based quantification of lesion water uptake identifies patients within 4.5 hours of stroke onset: A multicenter observational study. AB - OBJECTIVE: Many patients with stroke cannot receive intravenous thrombolysis because the time of symptom onset is unknown. We tested whether computed tomography (CT)-based quantification of water uptake in the ischemic tissue can identify patients with stroke onset within 4.5 hours, the time window of thrombolysis. METHODS: Perfusion CT was used to identify ischemic brain tissue, and its density was measured in native CT and related to the density of the corresponding area of the contralateral hemisphere to quantify lesion water uptake. The optimal cutoff value of water uptake distinguishing stroke onset within and beyond 4.5 hours was calculated in patients with proximal middle cerebral artery occlusion (derivation cohort) with known time of symptom onset. The so-derived cutoff value was validated in a prospective cohort from other stroke centers. RESULTS: Of 178 patients of the derivation cohort, 147 (82.6%) had CT within 4.5 hours. Percentage water uptake was significantly lower in patients with stroke onset within compared to beyond 4.5 hours. The area under the receiver operating characteristic curve for distinguishing these patient groups according to percentage water uptake was 0.999 (95% confidence interval = 0.996-1.000, p < 0.001) with an optimal cutoff value of 11.5%. Applying this cutoff to the validation cohort of 240 patients, sensitivity was 98.6%, specificity 90.5%, positive predictive value 99.1%, and negative predictive value 86.4%. INTERPRETATION: Quantification of brain water uptake identifies stroke patients with symptom onset within 4.5 hours with high accuracy and may guide the decision to use thrombolysis in patients with unknown time of stroke onset. Ann Neurol 2016;80:924-934. PMID- 28001317 TI - LRSAM1 lessons. PMID- 28001318 TI - Carbon Dioxide Capture Adsorbents: Chemistry and Methods. AB - Excess carbon dioxide (CO2 ) emissions and their inevitable consequences continue to stimulate hard debate and awareness in both academic and public spaces, despite the widespread lack of understanding on what really is needed to capture and store the unwanted CO2 . Of the entire carbon capture and storage (CCS) operation, capture is the most costly process, consisting of nearly 70 % of the price tag. In this tutorial review, CO2 capture science and technology based on adsorbents are described and evaluated in the context of chemistry and methods, after briefly introducing the current status of CO2 emissions. An effective sorbent design is suggested, whereby six checkpoints are expected to be met: cost, capacity, selectivity, stability, recyclability, and fast kinetics. PMID- 28001319 TI - Fifteen years of quantitative trait loci studies in fish: challenges and future directions. AB - Understanding the genetic basis of phenotypic variation is a major challenge in biology. Here, we systematically evaluate 146 quantitative trait loci (QTL) studies on teleost fish over the last 15 years to investigate (i) temporal trends and (ii) factors affecting QTL detection and fine-mapping. The number of fish QTL studies per year increased over the review period and identified a cumulative number of 3632 putative QTLs. Most studies used linkage-based mapping approaches and were conducted on nonmodel species with limited genomic resources. A gradual and moderate increase in the size of the mapping population and a sharp increase in marker density from 2011 onwards were observed; however, the number of QTLs and variance explained by QTLs changed only minimally over the review period. Based on these findings, we discuss the causative factors and outline how larger sample sizes, phenomics, comparative genomics, epigenetics and software development could improve both the quantity and quality of QTLs in future genotype-phenotype studies. Given that the technical limitations on DNA sequencing have mostly been overcome in recent years, a renewed focus on these and other study design factors will likely lead to significant improvements in QTL studies in the future. PMID- 28001320 TI - Dynamic multi-echo DCE- and DSC-MRI in rectal cancer: Low primary tumor Ktrans and DeltaR2* peak are significantly associated with lymph node metastasis. AB - PURPOSE: To implement a dynamic contrast-based multi-echo MRI sequence in assessment of rectal cancer and evaluate associations between histopathologic data and the acquired dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) -MRI parameters. MATERIALS AND METHODS: This pilot study reports results from 17 patients with resectable rectal cancer. Dynamic contrast-based multi-echo MRI (1.5T) was acquired using a three-dimensional multi-shot EPI sequence, yielding both DCE- and DSC-data following a single injection of contrast agent. The Institutional Review Board approved the study and all patients provided written informed consent. Quantitative analysis was performed by pharmacokinetic modeling on DCE data and tracer kinetic modeling on DSC data. Mann-Whitney U-test and receiver operating characteristics curve statistics was used to evaluate associations between histopathologic data and the acquired DCE- and DSC-MRI parameters. RESULTS: For patients with histologically confirmed nodal metastasis, the primary tumor demonstrated a significantly lower Ktrans and peak change in R2*, R2*-peakenh , than patients without nodal metastasis, showing a P value of 0.010 and 0.005 for reader 1, and 0.043 and 0.019 for reader 2, respectively. CONCLUSION: This study shows the feasibility of acquiring DCE- and DSC-MRI in rectal cancer by dynamic multi-echo MRI. A significant association was found between both Ktrans and R2*-peakenh in the primary tumor and histological nodal status of the surgical specimen, which may improve stratification of patients to intensified multimodal treatment. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:194-206. PMID- 28001321 TI - Complexities of emergency communication: clinicians' perceptions of communication challenges in a trilingual emergency department. AB - AIMS AND OBJECTIVES: To understand the challenges that clinicians face in communicating with patients and other clinicians within a Hong Kong trilingual emergency department. BACKGROUND: Effective communication has long been recognised as fundamental to the delivery of quality health care, especially in high-risk and time-constrained environments such as emergency departments. The issue of effective communication is particularly relevant in Hong Kong emergency departments, due to the high volume of patients and the linguistic complexity of this healthcare context. In Hong Kong, emergency department clinicians are native speakers of Chinese, but have received their medical training in English. The clinicians read and record virtually all of their medical documentation in English, yet they communicate verbally with patients in Cantonese and Mandarin. In addition, communication between clinicians occurs in spoken Cantonese, mixed with medical English. Thus, medical information is translated numerous times within one patient journey. This complex linguistic environment creates the potential for miscommunication. DESIGN: A mixed-methods design consisting of a quantitative survey with a sequential qualitative interview. METHODS: Data were collected in a survey from a purposive sample of 58 clinicians and analysed through descriptive statistics. Eighteen of the clinicians were then invited to take part in semi-structured interviews, the data from which were then subjected to a manifest content analysis. RESULTS: Nearly half of the clinicians surveyed believed that medical information may be omitted or altered through repeated translation in a trilingual emergency department. Eighty-three per cent of clinicians stated that there are communication problems at triage. Over 40% said that they have difficulties in documenting medical information. Around 50% believed that long work hours reduced their ability to communicate effectively with patients. In addition, 34% admitted that they rarely or never listen to patients during a consultation. CONCLUSION: The findings reveal that the quality of communication in this Hong Kong emergency department is compromised by specific factors inherent in the linguistic complexity of Hong Kong emergency departments. These factors include the constant translation of medical information, inadequate documentation of medical information and significant professional and cultural pressures. Each of these issues increases the likelihood that healthcare communication will be difficult, incomplete or incorrect. This research provides empirical evidence for, and justifies the development of, an effective framework to enable clinicians to overcome communication challenges. RELEVANCE TO CLINICAL PRACTICE: The findings of this study may shed light on the unique conditions faced by clinicians, particularly in relation to communication, in the complex trilingual healthcare context of an emergency department similar to those in Hong Kong, and provide potential policy solutions for barriers to improve communication in such settings. PMID- 28001322 TI - "Giving us hope": Parent and neonatal staff views and expectations of a planned family-centred discharge process (Train-to-Home). AB - BACKGROUND: Preparing families and preterm infants for discharge is relatively unstructured in many UK neonatal units (NNUs). Family-centred neonatal care and discharge planning are recommended but variable. DESIGN AND PARTICIPANTS: Qualitative interviews with 37 parents of infants in NNUs, and 18 nursing staff and 5 neonatal consultants explored their views of discharge planning and perceptions of a planned family-centred discharge process (Train-to-Home). Train to-Home facilitates communication between staff and parents throughout the neonatal stay, using a laminated train and parent booklets. RESULTS: Parents were overwhelmingly positive about Train-to-Home. They described being given hope, feeling in control and having something visual to show their baby's progress. They reported positive involvement of fathers and families, how predicted discharge dates helped them prepare for home and ways staff engaged with Train-to Home when communicating with them. Nursing staff reactions were mixed-some were uncertain about when to use it, but found the visual images powerful. Medical staff in all NNUs were positive about the intervention recognizing that it helped in communicating better with parents. CONCLUSIONS: Using a parent-centred approach to communication and informing parents about the needs and progress of their preterm infant in hospital is welcomed by parents and many staff. This approach meets the recommended prioritization of family-centred care for such families. Predicted discharge dates helped parents prepare for home, and the ways staff engaged with Train-to-Home when communicating with them helped them feel more confident as well as having something visual to show their baby's progress. PMID- 28001323 TI - Prenatal transplantation of epidermal neural crest stem cells in malformation of cortical development mouse model. AB - Prenatal interventions may offer an immense opportunity in therapeutic protocols of malformations of cortical development (MCD). Epidermal neural crest stem cells (EPI-NCSCs) of the hair follicle bulge exhibit features of both embryonic and adult stem cells; these cells maintain their neurologic differentiation capability because of their neural crest origin. However, it is unknown if prenatal use of EPI-NCSCs could be beneficial in targeting methylazoxymethanol (MAM)-induced MCD, which further addressed in the present work. EPI-NCSCs were prenatally infused to the MAM-exposed mice. Thicknesses of various cerebral cortex areas as well as corpus callosum was measured; there were markedly decrease in MAM group (p < .001 vs. untreated), but a significant increase in EPI NCSC group (p < .05 vs. MAM), except for corpus callosum. Real-time PCR analysis showed high expressions for absent, small, or homeotic 2-like protein, nestin, doublecortin (DCX), neuronal specific nuclei protein (NeuN), and glial fibrillary acidic protein (GFAP) in MAM group (p < .001 vs. untreated), except for G-protein coupled C-X-C chemokine receptor type 4 (CXCR4) and CXC motif ligand 12 (CXCL12), whereas there were low expressions in EPI-NCSCs group (p < .01 vs. MAM). Immunohistochemistry of NeuN, GFAP, ionized calcium-binding adapter molecule (Iba1), and oligodendrocyte lineage transcription factor 2 (Olig2) was also revealed the same pattern as real-time PCR (p < .001 MAM vs. untreated, and p < .05 EPI-NCSCs vs. MAM). Our findings suggest prenatal use of EPI-NCSCs as a possible candidate for cell-based therapy of cortical injury through affecting neural markers and their relationship with glial. PMID- 28001324 TI - Smart Microbubble Eluting Theranostic Stent for Noninvasive Ultrasound Imaging and Prevention of Restenosis. AB - A pH-responsive microbubble-eluting theranostic stent is developed for real-time ultrasound imaging of stent implanted blood vessels and dissolution of fat-rich plaques to prevent the blocking of blood vessels in rats. This smart theranostic stent can be effectively applied to facilitate noninvasive monitoring and prevent restenosis after stent implantation. PMID- 28001325 TI - First Example of Nonlinear Optical Materials Based on Nanoconjugates of Sandwich Phthalocyanines with Quantum Dots. AB - We report original, selective, and efficient approaches to novel nonlinear optical (NLO) materials, namely homoleptic double- and triple-decker europium(III) complexes 2 and 3 with the A3 B-type phthalocyanine ligand (2,3 bis[2'-(2''-hydroxyethoxy)ethoxy]-9,10,16,17,23,24-hexa-n-butoxyphthalocyanine 1) bearing two anchoring diethyleneglycol chains terminated with OH groups. Their covalently linked nanoconjugates with mercaptosuccinic acid-capped ternary CdSeTe/CdTeS/ZnSeS quantum dots are prepared in the presence of an ethyl(dimethylaminopropyl)carbodiimide activating agent. Optical limiting (OL) properties of the obtained low-symmetry complexes and their conjugates with quantum dots (QDs) are measured for the first time by the open-aperture Z-scan technique (532 nm laser and pulse rate of 10 ns). For comparison, symmetrical double- and triple-decker EuIII octa-n-butoxyphthalocyaninates 5 and 6 and their mixtures with trioctylphosphine oxide-capped QDs are also synthesized and studied. It is revealed that both lowering of molecular symmetry and expansion of the pi-electron system upon moving from double- to triple-decker complexes significantly improves the OL characteristics, making the low-symmetry triple decker complex 3 the most efficient optical limiter in the studied family of sandwich complexes, affording 50 % lowering of light transmittance below 0.5 J cm 2 input fluence. Conjugation (both covalent and noncovalent) with QDs affords further enhancement of the OL properties of both double- and triple-decker complexes. Altogether, the obtained results contribute to the development of novel nonlinear optical materials for future nanoelectronic and optical device applications. PMID- 28001326 TI - 3D Interconnected Carbon Fiber Network-Enabled Ultralong Life Na3 V2 (PO4 )3 @Carbon Paper Cathode for Sodium-Ion Batteries. AB - Sodium-ion batteries (NIBs) are an emerging technology, which can meet increasing demands for large-scale energy storage. One of the most promising cathode material candidates for sodium-ion batteries is Na3 V2 (PO4 )3 due to its high capacity, thermal stability, and sodium (Na) Superionic Conductor 3D (NASICON) type framework. In this work, the authors have significantly improved electrochemical performance and cycling stability of Na3 V2 (PO4 )3 by introducing a 3D interconnected conductive network in the form of carbon fiber derived from ordinary paper towel. The free-standing Na3 V2 (PO4 )3 -carbon paper (Na3 V2 (PO4 )3 @CP) hybrid electrodes do not require a metallic current collector, polymeric binder, or conducting additives to function as a cathode material in an NIB system. The Na3 V2 (PO4 )3 @CP cathode demonstrates extraordinary long term cycling stability for 30 000 deep charge-discharge cycles at a current density of 2.5 mA cm-2 . Such outstanding cycling stability can meet the stringent requirements for renewable energy storage. PMID- 28001328 TI - Transcriptome and proteome analyses reveal complex mechanisms of reproductive diapause in the two-spotted spider mite, Tetranychus urticae. AB - Although a variety of factors underlying diapause have been identified in arthropods and other organisms, the molecular mechanisms regulating diapause are still largely unknown. Here, to better understand this process, we examined diapause-associated genes in the two-spotted spider mite, Tetranychus urticae, by comparing the transcriptomes and proteomes of early diapausing and reproductive adult females. Amongst genes underlying diapause revealed by the transcriptomic and proteomic data sets, we described the noticeable change in Ca2+ -associated genes, including 65 Ca2+ -binding protein genes and 23 Ca2+ transporter genes, indicating that Ca2+ signalling has a substantial role in diapause regulation. Other interesting changes in diapause included up-regulation of (1) glutamate receptors that may be involved in synaptic plasticity changes, (2) genes involved in cytoskeletal reorganization including genes encoding each of the components of thick and thin filaments, tubulin and members of integrin signalling and (3) genes involved in anaerobic energy metabolism, which reflects a shift to anaerobic energy metabolism in early diapausing mites. PMID- 28001327 TI - Supraspinatus tendon overuse results in degenerative changes to tendon insertion region and adjacent humeral cartilage in a rat model. AB - The etiology of rotator cuff tendon overuse injuries is still not well understood. Furthermore, how this overuse injury impacts other components of the glenohumeral joint, including nearby articular cartilage, is also unclear. Therefore, this study sought to better understand the time course of tendon protease activity in a rat model of supraspinatus overuse, as well as determine effects of 10 weeks of overuse on humeral head articular cartilage. For these studies, multiplex gelatin zymography was used to characterize protease activity profiles in tendon and cartilage, while histological scoring/mechanical testing and micro-computed tomography (MUCT) imaging were used to quantify structural damage in the supraspinatus tendon insertion and humeral articular cartilage, respectively. Histological scoring of supraspinatus tendon insertions revealed tendinopathic cellular and collagen fiber changes after 10 weeks of overuse when compared to controls, while mechanical testing revealed no significant differences between tensile moduli (overuse: 24.5 +/- 11.5 MPa; control: 16.3 +/- 8.7 MPa). EPIC-MUCT imaging on humeral articular cartilage demonstrated significant cartilage thinning (overuse: 119.6 +/- 6.34 MUm; control: 195.4 +/- 13.4MUm), decreased proteoglycan content (overuse: 2.1 +/- 0.18 cm-1 ; control: 1.65 +/- 0.14 cm-1 ), and increased subchondral bone thickness (overuse: 216.2 +/ 10.9 MUm; control: 192 +/- 17.8MUm) in the overuse animals. Zymography results showed no significant upregulation of cathepsins or matrix metalloproteinases in tendon or cartilage at 2 or 10 weeks of overuse compared to controls. These results have further elucidated timing of protease activity over 10 weeks and suggest that damage occurs to other tissues in addition to the supraspinatus tendon in this overuse injury model. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1910-1918, 2017. PMID- 28001329 TI - FNA biopsy of secondary nonlymphomatous malignancies in salivary glands: A multi institutional study of 184 cases. AB - BACKGROUND: Secondary malignancies of salivary glands (SMSGs) are among the most common malignant neoplasms to involve the salivary glands. Fine-needle aspiration biopsy (FNAB) of SMSG can present diagnostic challenges. The current report presents the largest such FNAB series to date. METHODS: A search of the pathology database from 6 academic institutions identified 184 FNAB cases of nonlymphomatous SMSG. RESULTS: Of the 184 cases, 171 were of the parotid glands, and 13 were of the submandibular glands; 130 patients were men, and 54 were women, and the mean patient age at diagnosis was 68 years. Metastatic squamous cell carcinoma (SCC) from all sites (n = 87) and melanoma (n = 67) constituted the majority of SMSGs. Less frequent SMSGs were comprised of metastatic carcinomas from distant organs (n = 16), including sites in the breast, lung, kidney, thyroid, pancreatobiliary, prostate, and bladder. Other uncommon SMSGs, including nasopharyngeal carcinoma (n = 3), sarcoma (n = 4), other metastatic skin-derived carcinomas (n = 6), and metastatic chordoma (n = 1), also were observed. Ancillary tests were performed on 37 FNAB specimens (20.1%) to aid the evaluation. One hundred forty-seven specimens (79.9%) had a definitive diagnosis with accurate tumor subtyping, 21 (11.4%) had a definitive malignant diagnosis but without specifying subtype, 9 (4.9%) had an indeterminate diagnosis, and 7 (3.8%) had a false-negative diagnosis. CONCLUSIONS: SMSGs originate predominately from the head and neck and are more common in older men. Overall, the FNAB diagnosis of SMSG is accurate, but diagnostic challenges can be encountered, especially in SCC types of SMSG. Ancillary studies are needed for the definitive diagnosis of challenging cases. Cancer Cytopathol 2017;125:91-103. (c) 2016 American Cancer Society. PMID- 28001331 TI - Compartmentalising time and space: a phenomenological interpretation of the temporal experience of commencing haemodialysis. AB - AIMS AND OBJECTIVES: To interpret the spatio-temporal experience of people with end-stage kidney disease and their families in the first months of haemodialysis. BACKGROUND: While dialysis is the mainstay of end-stage kidney disease management, the actual initiation of treatment is often unexpected by people and families. Poor biopsychosocial preparation means haemodialysis commencement is experienced as a crisis. While previous phenomenological studies suggest that over time, a habitual incorporation of dialysis into one's self-concept is possible, the spatio-temporal experience of people new to haemodialysis is not well understood. DESIGN: A phenomenological study. METHODS: Following purposive sampling, 18 participants were recruited either during an inpatient admission or while attending a public hospital-based haemodialysis unit in Sydney, Australia. Eleven people who had commenced haemodialysis within the previous three months and five close family members were separately engaged in semistructured interviews. Hermeneutic interpretation within a Heideggerian framework occurred through a backward-and-forward analysis between the early haemodialysis experience and its relationship to Being. RESULTS: Themes that related to a temporal and spatial understanding of Being-in-the-world as a new haemodialysis patient or carer included the following: 'compartmentalising life into dialysis and non-dialysis days' (lost time, clock time and lived time); 'compartmentalising before, now and future' (normalising the 'before', dealing with the 'now' and the 'foreverness' of dialysis); and finally, 'compartmentalising space'. CONCLUSIONS: In the months after dialysis commencement, patients and family carers compartmentalise time and space with a loss of continuity of meaningful, lived time that had framed people's past sense of normal. RELEVANCE TO CLINICAL PRACTICE: Resource enhancement activities should focus on social connectivity and provision of personnel and/or infrastructure to reduce boredom, to facilitate engagement with meaningful tasks and, where appropriate, to support the continuation of work activities during the dialysis period. PMID- 28001330 TI - 'Kids need to talk too': inclusive practices for children's healthcare education and participation. AB - AIMS AND OBJECTIVES: To examine how children with chronic medical conditions view healthcare education and decision-making and to propose the application of the universal design for learning in paediatric settings. BACKGROUND: Children and adolescents with chronic medical conditions tend to be excluded from healthcare decision-making. In schools, the universal design for learning promotes access to education and participation in school communities for all children, regardless of their disabilities or medical needs, rendering it an appropriate model for children's participation in healthcare decision-making. DESIGN: This article presents findings from a qualitative study with 26 children and adolescents with chronic medical conditions about their views and experiences with healthcare education and decision-making. METHODS: Twenty-six children and adolescents with chronic medical conditions were interviewed using semi-structured interviews. RESULTS: Findings provide evidence that clinical practices often fail to provide equal opportunities for paediatric patients to understand their condition, share their views and/or participate in decisions regarding their care. CONCLUSIONS: In response to ongoing concerns about paediatric decision-making, we propose that the universal design for learning be adapted in paediatrics. The model presents exemplary programmes as inclusive, accounting for the needs of all children through multiple means of engagement and expression. RELEVANCE TO CLINICAL PRACTICE: A discussion of how the principles of universal design for learning could be applied in paediatric settings is offered for the purpose of advancing ethical and psychosocial care for all children regardless of their age, developmental capacity or condition. PMID- 28001332 TI - Patients experiences of negative pressure wound therapy at home for the treatment of deep perivascular groin infection after vascular surgery. AB - AIMS AND OBJECTIVES: To explore experiences of negative pressure wound therapy at home, in patients with deep perivascular groin infection after vascular surgery and management in daily life. BACKGROUND: Deep surgical site infection after vascular surgery with exposed vessels often requires long-term treatment with negative pressure wound therapy, and continued therapy at home has become routine. DESIGN: An explorative qualitative study. METHODS: Nine men and six women with a deep surgical site infection in the groin after vascular surgery, treated in their home with negative pressure wound therapy, were interviewed. The interviews were analysed using manifest and latent content analysis. RESULTS: Undergoing negative pressure wound therapy at home meant a transition from being a dependent patient to a person who must have self-care competence and be involved in their own care. A need to feel prepared for this before discharge from hospital was expressed. Lack of information and feelings of uncertainty prolonged the time before feeling confident in managing the treatment. The informants gradually accepted the need to be tied up to a machine, became competent in its management and found solutions to perform everyday tasks. Overall, it was a relief to be treated at home. CONCLUSIONS: Several benefits of negative pressure wound therapy at home were expressed. However, unnecessary stress and anxiety were experienced due to a lack of information on the treatment and instruction concerning the equipment. Adequate information and education must therefore be provided to facilitate the transition from a patient to a person with self-care competence and ability to manage this treatment at home. RELEVANCE TO CLINICAL PRACTICE: The findings revealed a need for more support and knowledge in their transition from hospital care to home care with negative pressure wound therapy. Routines must be established that ensure patient safety and security in treatment at home. PMID- 28001333 TI - Breast-related stereotype threat contributes to a symptom cluster in women with breast cancer. AB - AIMS AND OBJECTIVES: To investigate the prevalence of breast-related stereotype threat and its effects on a symptom cluster consisting of anxiety, depression and fatigue and on each symptom. BACKGROUND: The stereotype that breasts are a sign of women's femininity results in patients with breast cancer fearing diminished femininity and rejection, which may induce psychological problems that co-occur as a symptom cluster. DESIGN: Cross-sectional study. METHODS: A total of 131 patients with breast cancer postmastectomy completed the study. A question measuring breast-related stereotype threat, the Hospital Anxiety and Depression Scale and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale were used to assess their breast-related stereotype threat and symptoms of anxiety, depression and fatigue. RESULTS: Of the 131 patients who answered the breast related stereotype threat question, 86 (65.6%) reported breast-related stereotype threat. They did not differ significantly in social and clinical characteristics compared with those without the stereotype, but did report significantly higher levels of the symptom cluster and each symptom (anxiety, depression and fatigue). The odds ratios of the stereotype were significant for the symptom cluster, depression and fatigue (odds ratios = 2.52-3.98, p < 0.05). CONCLUSION: The breast-related stereotype threat was common in patients with breast cancer. There was about a twofold increase in their risk of experiencing the symptom cluster and symptoms of depression and fatigue. RELEVANCE TO CLINICAL PRACTICE: In clinical practice, breast-related stereotype threat should be measured together with prevalent symptoms (e.g. anxiety, depression and fatigue) in patients with breast cancer. Our findings will aid the development of interventions for improving the mental health of women with breast cancer. PMID- 28001334 TI - Coping strategies of Taiwanese children with autism spectrum disorders. AB - AIMS AND OBJECTIVES: To explore and describe the coping experiences of children with autism spectrum disorders in Taiwan. BACKGROUND: Children with autism spectrum disorders are faced with daily social and living challenges, which can cause stress. Chinese culture emphasises discipline and obedience, which may influence coping strategies of children with autism spectrum disorders in Taiwan. DESIGN: This qualitative study employed an exploratory descriptive design. METHOD: Data were collected from in-depth, face-to-face structured interviews. Interviews explored coping strategies of Taiwanese school-aged children (aged 6 19) with autism spectrum disorders. Children (N = 17) and their caregivers were recruited by purposive sampling. Transcribed interview data were thematically analysed using the procedure of Miles and Huberman. RESULT: Five themes emerged from the analysis of the data, which described the coping strategies of the children: (1) problem-solving, (2) acting-out, (3) avoidance, (4) seeking help and (5) self-regulation. These themes included multiple coping strategies, which employed the concepts of engagement and disengagement. CONCLUSIONS: The children with autism spectrum disorder used many strategies to cope with the stresses resulting from behaviours and symptoms associated with the disorder. Most of the Taiwanese children use both problem-solving and emotional-focused coping strategies. RELEVANCE TO CLINICAL PRACTICE: Understanding coping strategies of children with autism spectrum disorder could help caregivers (parents, teachers) and medical professionals develop interventions to reduce these challenges, which could alleviate stress and improve social functioning for these children. PMID- 28001335 TI - Climate change and the eco-hydrology of fire: Will area burned increase in a warming western USA? AB - Wildfire area is predicted to increase with global warming. Empirical statistical models and process-based simulations agree almost universally. The key relationship for this unanimity, observed at multiple spatial and temporal scales, is between drought and fire. Predictive models often focus on ecosystems in which this relationship appears to be particularly strong, such as mesic and arid forests and shrublands with substantial biomass such as chaparral. We examine the drought-fire relationship, specifically the correlations between water-balance deficit and annual area burned, across the full gradient of deficit in the western USA, from temperate rainforest to desert. In the middle of this gradient, conditional on vegetation (fuels), correlations are strong, but outside this range the equivalence hotter and drier equals more fire either breaks down or is contingent on other factors such as previous-year climate. This suggests that the regional drought-fire dynamic will not be stationary in future climate, nor will other more complex contingencies associated with the variation in fire extent. Predictions of future wildfire area therefore need to consider not only vegetation changes, as some dynamic vegetation models now do, but also potential changes in the drought-fire dynamic that will ensue in a warming climate. PMID- 28001336 TI - Decadal shifts in autumn migration timing by Pacific Arctic beluga whales are related to delayed annual sea ice formation. AB - Migrations are often influenced by seasonal environmental gradients that are increasingly being altered by climate change. The consequences of rapid changes in Arctic sea ice have the potential to affect migrations of a number of marine species whose timing is temporally matched to seasonal sea ice cover. This topic has not been investigated for Pacific Arctic beluga whales (Delphinapterus leucas) that follow matrilineally maintained autumn migrations in the waters around Alaska and Russia. For the sympatric Eastern Chukchi Sea ('Chukchi') and Eastern Beaufort Sea ('Beaufort') beluga populations, we examined changes in autumn migration timing as related to delayed regional sea ice freeze-up since the 1990s, using two independent data sources (satellite telemetry data and passive acoustics) for both populations. We compared dates of migration between 'early' (1993-2002) and 'late' (2004-2012) tagging periods. During the late tagging period, Chukchi belugas had significantly delayed migrations (by 2 to >4 weeks, depending on location) from the Beaufort and Chukchi seas. Spatial analyses also revealed that departure from Beaufort Sea foraging regions by Chukchi whales was postponed in the late period. Chukchi beluga autumn migration timing occurred significantly later as regional sea ice freeze-up timing became later in the Beaufort, Chukchi, and Bering seas. In contrast, Beaufort belugas did not shift migration timing between periods, nor was migration timing related to freeze-up timing, other than for southward migration at the Bering Strait. Passive acoustic data from 2008 to 2014 provided independent and supplementary support for delayed migration from the Beaufort Sea (4 day yr-1 ) by Chukchi belugas. Here, we report the first phenological study examining beluga whale migrations within the context of their rapidly transforming Pacific Arctic ecosystem, suggesting flexible responses that may enable their persistence yet also complicate predictions of how belugas may fare in the future. PMID- 28001337 TI - Precipitation and Crystallization Kinetics in Silica Gardens. AB - Silica gardens are extraordinary plant-like structures resulting from the complex interplay of relatively simple inorganic components. Recent work has highlighted that macroscopic self-assembly is accompanied by the spontaneous formation of considerable chemical gradients, which induce a cascade of coupled dissolution, diffusion, and precipitation processes occurring over timescales as long as several days. In the present study, this dynamic behavior was investigated for silica gardens based on iron and cobalt chloride by means of two synchrotron based techniques, which allow the determination of concentration profiles and time-resolved monitoring of diffraction patterns, thus giving direct insight into the progress of dissolution and crystallization phenomena in the system. On the basis of the collected data, a kinetic model is proposed to describe the relevant reactions on a fundamental physicochemical level. The results show that the choice of the metal cations (as well as their counterions) is crucial for the development of silica gardens in both the short and long term (i.e. during tube formation and upon subsequent slow equilibration), and provide important clues for understanding the properties of related structures in geochemical and industrial environments. PMID- 28001338 TI - WDPCP regulates the ciliogenesis of human sinonasal epithelial cells in chronic rhinosinusitis. AB - Damage to the mucociliary clearance system is a typical change in the pathogenesis in chronic rhinosinusitis. However, the mechanisms underlying cilia loss remain unclear. WDPCP is a key protein essential for ciliogenesis, and is also an effector of the planar cell polarity signaling system. In this study, we sought to determine the role of WDPCP in cilia loss in patients with chronic rhinosinusitis. We demonstrated the expression of WDPCP in human sinonasal epithelium from patients with chronic rhinosinusitis and control subjects. We also used air-liquid interface to culture primary human sinonasal epithelial cells in-vitro model and to investigate WDPCP function. We then explored links between rhinosinusitis, WDPCP and inflammation. Accompanied with cilia loss, expression of WDPCP in human sinonasal epithelium from patients with chronic rhinosinusitis was decreased significantly compared with control subjects. In vitro study, we found that WDPCP level increased at first, and then decreased. Inhibiting WDPCP expression could lead to the poor quantity and length of cilia with reduced expression of Septin7. Also, Th1 type inflammatory mediators could decrease the expression of WDPCP. In conclusion, inflammatory cytokines cause reduced WDPCP expression, which contributes to impaired ciliogenesis in human rhinosinusitis. PMID- 28001339 TI - An integrative literature review to examine the provision of self-management support following transient ischaemic attack. AB - AIMS AND OBJECTIVES: To identify the types of self-management support that have been provided to persons with transient ischaemic attack and the evidence for the effectiveness of these programmes. BACKGROUND: Self-management is a key element for the effective management of chronic conditions. For persons with transient ischaemic attack, secondary stroke prevention is a recognised standard of care. Best practice guidelines indicate that persons who have experienced transient ischaemic attack should be supported to develop self-management skills. However, it is not clear how best to support the development of these skills. DESIGN: An integrative literature review was conducted. METHODS: A search was conducted using Medline, Embase, HealthSTAR, CINAHL and PsycINFO. Published quantitative and qualitative studies, abstracts or dissertations describing the provision, experience or outcomes of self-management interventions for people with transient ischaemic attack, and published in English before March 2016, were included. Articles were selected and rated separately by two reviewers. The American Academy for Cerebral Palsy and Developmental Medicine Level of Evidence and Conduct Rating tools were used for rating. Interventions were described and compared, and evidence was presented using the traffic lighting system. RESULTS: Sixteen interventions representing a variety of group- and individual-based interventions were identified. Interventions differed in target population, content, structure, duration and outcomes. Only four interventions were specifically designed for persons with transient ischaemic attack. While evidence to support self-management interventions is promising, there is limited evidence to support any one intervention. However, one good-quality randomised controlled trial supports the provision of a group self-management programme for improving blood pressure control. CONCLUSIONS: There are numerous interventions to support self-management by persons with transient ischaemic attack. More research is needed to determine which approaches are most effective. Given the limited evidence to support any one program for persons with TIA, clinicians and programs that provide self-management support should evaluate and monitor outcomes to ensure client needs are being met. PMID- 28001341 TI - Graphitic C3 N4 Decorated with CoP Co-catalyst: Enhanced and Stable Photocatalytic H2 Evolution Activity from Water under Visible-light Irradiation. AB - In this work, graphitic C3 N4 decorated with a CoP co-catalyst (g-C3 N4 /CoP) is reported for photocatalytic H2 evolution reaction based on two-step hydrothermal and phosphidation method. The structure of g-C3 N4 /CoP is well confirmed by XRD, FTIR, TEM, XPS, and UV/Vis diffuse reflection spectra techniques. When the weight percentage of CoP loading is 3.4 wt % (g-C3 N4 /CoP-3.4 %), the highest H2 evolution amount of 8.4*102 MUmol g-1 is obtained, which is 1.1*103 times than that over pure g-C3 N4 . This value also is comparable with that of g-C3 N4 loaded by the same amount of Pt. In cycling experiments, g-C3 N4 /CoP-3.4 % shows a stable photocatalytic activity. In addition, g-C3 N4 /CoP-3.4 % is an efficient photocatalyst for H2 evolution under irradiation with natural solar light. Based on comparative photoluminescence emission spectra, photoelectrochemical I-t curves, EIS Nyquist plots, and polarization curves between g-C3 N4 /CoP-3.4 % and pure g-C3 N4 , it is concluded that the presence of the CoP co-catalyst accelerates the separation and transfer of photogenerated electrons of g-C3 N4 , thus resulting in improved photocatalytic activity in the H2 evolution reaction. PMID- 28001340 TI - Quantitative approaches for investigating the spatial context of gene expression. AB - The spatial information associated with gene expression is important for elucidating the context-dependent transcriptional regulation during development. Recently, high-resolution sampling approaches, such as RNA tomography or single cell RNA-seq combined with fluorescence in situ hybridization (FISH), have provided indirect ways to view global gene expression patterns in three dimensions. Now in situ sequencing technologies, such as fluorescent in situ sequencing (FISSEQ), are attempting to visualize the genetic signature directly in microscope images. This article will examine the basic principle of modern in situ and single-cell genetic methods, hurdles in quantifying intrinsic and extrinsic forces that influence cell decision-making, and technological requirements for making a visual map of gene regulation, form, and function. Successfully addressing these challenges will be essential for investigating the functional evolution of regulatory sequences during growth, development, and cancer progression. WIREs Syst Biol Med 2017, 9:e1369. doi: 10.1002/wsbm.1369 For further resources related to this article, please visit the WIREs website. PMID- 28001345 TI - Erratum. PMID- 28001342 TI - Triggering Mechanisms and Inflammatory Effects of Combustion Exhaust Particles with Implication for Carcinogenesis. AB - A number of biological responses may contribute to the carcinogenic effects of combustion-derived particulate matter (CPM). Here, we focus on mechanisms that trigger CPM-induced pro-inflammatory responses. Inflammation has both genotoxic and non-genotoxic implications and is considered to play a central role in development of various health outcome associated with CPM exposure, including cancer. Chronic, low-grade inflammation may cause DNA damage through a persistent increased level of reactive oxygen species (ROS) produced and released by activated immune cells. Moreover, a number of pro-inflammatory cytokines and chemokines display mitogenic, motogenic, morphogenic and/or angiogenic properties and may therefore contribute to tumour growth and metastasis. The key triggering events involved in activation of pro-inflammatory responses by CPM and soluble CPM components can be categorized into (i) formation of ROS and oxidative stress, (ii) interaction with the lipid layer of cellular membranes, (iii) activation of receptors, ion channels and transporters on the cell surface and (iv) interactions with intracellular molecular targets including receptors such as the aryl hydrocarbon receptor (AhR). In particular, we will elucidate the effects of diesel exhaust particles (DEP) using human lung epithelial cells as a model system. PMID- 28001346 TI - Analgesic Microneedle Patch for Neuropathic Pain Therapy. AB - Neuropathic pain caused by nerve injury is debilitating and difficult to treat. Current systemic pharmacological therapeutics for neuropathic pain produce limited pain relief and have undesirable side effects, while current local anesthetics tend to nonspecifically block both sensory and motor functions. Calcitonin gene related peptide (CGRP), a neuropeptide released from sensory nerve endings, appears to play a significant role in chronic neuropathic pain. In this study, an analgesic microneedle (AMN) patch was developed using dissolvable microneedles to transdermally deliver selective CGRP antagonist peptide in a painless manner for the treatment of localized neuropathic pain. Local analgesic effects were evaluated in rats by testing behavioral pain sensitivity in response to thermal and mechanical stimuli using neuropathic pain models such as spared nerve injury and diabetic neuropathy pain, as well as neurogenic inflammatory pain model induced by ultraviolet B (UVB) radiation. Unlike several conventional therapies, the AMN patches produced effective analgesia on neuropathic pain without disturbing the normal nociception and motor function of the rat, resulting from the high specificity of the delivered peptide against CGRP receptors. The AMN patches did not cause skin irritation or systemic side effects. These results demonstrate that dissolvable microneedle patches delivering CGRP antagonist peptide provide an effective, safe, and simple approach to mitigate neuropathic pain with significant advantages over current treatments. PMID- 28001347 TI - Microencapsulated Phase Change Materials in Solar-Thermal Conversion Systems: Understanding Geometry-Dependent Heating Efficiency and System Reliability. AB - The performance of solar-thermal conversion systems can be improved by incorporation of nanocarbon-stabilized microencapsulated phase change materials (MPCMs). The geometry of MPCMs in the microcapsules plays an important role for improving their heating efficiency and reliability. Yet few efforts have been made to critically examine the formation mechanism of different geometries and their effect on MPCMs-shell interaction. Herein, through changing the cooling rate of original emulsions, we acquire MPCMs within the nanocarbon microcapsules with a hollow structure of MPCMs (h-MPCMs) or solid PCM core particles (s-MPCMs). X-ray photoelectron spectroscopy and atomic force microscopy reveals that the capsule shell of the h-MPCMs is enriched with nanocarbons and has a greater MPCMs shell interaction compared to s-MPCMs. This results in the h-MPCMs being more stable and having greater heat diffusivity within and above the phase transition range than the s-MPCMs do. The geometry-dependent heating efficiency and system stability may have important and general implications for the fundamental understanding of microencapsulation and wider breadth of heating generating systems. PMID- 28001348 TI - Two Lanthanide Metal-Organic Frameworks as Remarkably Selective and Sensitive Bifunctional Luminescence Sensor for Metal Ions and Small Organic Molecules. AB - Two lanthanide metal-organic frameworks (Ln-MOFs) with similar structures have been synthesized through objective synthesis. The two compounds are both 2-fold interpenetrating 3D frameworks. Topological analyses reveal that complexes 1 and 2 are 6-connected pcu net. In addition, both structures were embedded in uncoordinated nitrogen atoms. As the uncoordinated pyridine groups can be used as functional groups, we tested their sensing ability toward metal ions and small organic molecules. To our delight, fluorescence measurements show the two complexes can selectively and sensitively detect for Fe3+ ion and nitromethane, which suggests that the two Ln-MOFs are promising bifunctional luminescence sensor materials with sensing metal ions and small organic molecules. PMID- 28001349 TI - In Situ Hydrothermally Grown TiO2@C Core-Shell Nanowire Coating for Highly Sensitive Solid Phase Microextraction of Polycyclic Aromatic Hydrocarbons. AB - Nanostructured materials have great potential for solid phase microextraction (SPME) on account of their tiny size, distinct architectures and superior physical and chemical properties. Herein, a core-shell TiO2@C fiber for SPME was successfully fabricated by the simple hydrothermal reaction of a titanium wire and subsequent amorphous carbon coating. The readily hydrothermal procedure afforded in situ synthesis of TiO2 nanowires on a titanium wire and provided a desirable substrate for further coating of amorphous carbon. Benefiting from the much larger surface area of subsequent TiO2 and good adsorption property of the amorphous carbon coating, the core-shell TiO2@C fiber was utilized for the SPME device for the first time and proved to have better performance in extraction of polycyclic aromatic hydrocarbons. In comparison to the polydimethylsiloxane (PDMS) and PDMS/divinylbenzene (DVB) fiber for commercial use, the TiO2@C fiber obtained gas chromatography responses 3-8 times higher than those obtained by the commercial 100 MUm PDMS and 1-9 times higher than those obtained by the 65 MUm PDMS/DVB fiber. Under the optimized extraction conditions, the low detection limits were obtained in the range of 0.4-7.1 ng L-1 with wider linearity in the range of 10-2000 ng L-1. Moreover, the fiber was successfully used for the determination of polycyclic aromatic hydrocarbons in Pearl River water, which demonstrated the applicability of the core-shell TiO2@C fiber. PMID- 28001350 TI - Ionic Conductor of Li2SiO3 as an Effective Dual-Functional Modifier To Optimize the Electrochemical Performance of Li4Ti5O12 for High-Performance Li-Ion Batteries. AB - Ionic conductor of Li2SiO3 (LSO) was used as an effective modifier to fabricate surface-modified Li4Ti5O12 (LTO) via simply mixing followed by sintering at 750 degrees C in air. The electrochemical performance of LTO was enhanced by merely adjusting the mass ratio of LTO/LSO, and the LTO/LSO composite with 0.51 wt % LSO exhibited outstanding rate capabilities (achieving reversible capacities of 163.8, 157.6, 153.1, 147.0, and 137.9 mAh g-1 at 100, 200, 400, 800, and 1600 mA g-1, respectively) and remarkable long-term cycling stability (120.2 mAh g-1 after 2700 cycles with a capacity fading rate of only 0.0074% per cycle even at 500 mA g-1). Combining structural characterization with electrochemical analysis, the LSO coating coupled with the slight doping effect adjacent to the LTO surface contributes to the enhancement of both electronic and ionic conductivities of LTO. PMID- 28001352 TI - High-Flux Graphene Oxide Membranes Intercalated by Metal-Organic Framework with Highly Selective Separation of Aqueous Organic Solution. AB - Graphene oxide (GO) membranes assembled by single-atom thick GO nanosheets have displayed huge potential application both in gas and liquid separation processes due to its facile and large-scale preparation resulting from various functional groups, such as hydroxyl, carboxyl, and epoxide groups. Taking advantage of these characters, GO membranes intercalated by superhydrophilic metal-organic frameworks (MOFs) as strengthening separation fillers were prepared on modified polyacrylonitrile (PAN) support by a novel pressure-assisted self-assembly (PASA) filtration technique instead of traditional vacuum filtration method for the first time. The synthesized MOF@GO membranes were characterized with several spectroscopic techniques including X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS), as well as scanning electron microscopy (SEM). Compared with GO membrane, these MOF@GO membranes combine the unique properties of MOF and GO and thus have significant enhancements of pervaporation (PV) permeation flux and separation factor simultaneously for ethyl acetate/water mixtures (98/2, w/w) through the PV process, which are also superior to the reported other kinds of membranes. Especially, for MOF@GO-0.3 membrane (corresponding MOF loading: 23.08 wt %), the increments are 159% and 244%, respectively, at 303 K, and the permeate water content can reach as high as 99.5 wt % (corresponding separation factor, 9751) with a high permeation flux of 2423 g m-2 h-1. Moreover, the procedures of both the synthesis of MOF and membranes preparation are environmentally friendly that only water was used as solvent. Such a nanosized MOF-intercalating approach may be also extended to other laminated membranes, providing valuable insights in designing and developing of advanced membranes for effective separation of aqueous organic solution through nanostructure manipulation of the nanomaterials. PMID- 28001351 TI - Proteoform-Specific Protein Binding of Small Molecules in Complex Matrices. AB - Characterizing the specific binding between protein targets and small molecules is critically important for drug discovery. Conventional assays require isolation and purification of small molecules from complex matrices through multistep chromatographic fractionation, which may alter their original bioactivity. Most proteins undergo posttranslational modification, and only certain proteoforms have the right conformation with accessible domains and available residues for small molecule binding. We developed a top-down mass spectrometry (MS) centric workflow for rapid evaluation of the bioactivity of crude botanical extracts after a one-step reaction. Our assay distinguished covalent from noncovalent binding and mapped the residue for covalent binding between bioactive constituents and specific proteoforms of the target protein. We augmented our approach with a nanoflow liquid chromatography-selected reaction monitoring (SRM) MS assay for simultaneous identification and label-free multiplex quantitation of small molecules in the crude botanical extracts. Our assay was validated for various proteoforms of human serum albumin, which plays a key role in pharmacokinetics of small molecules in vivo. We demonstrated the utility of our proteoform-specific assay for evaluating thymoquinone in crude botanical extracts, studying its pharmacokinetics in human blood, and interpreting its toxicity to human breast cancer cells in tissue culture. PMID- 28001353 TI - Bioengineered Osteoinductive Broussonetia kazinoki/Silk Fibroin Composite Scaffolds for Bone Tissue Regeneration. AB - In this article, Broussonetia kazinoki (BK) powdery extract is utilized to modify the silk fibroin (SF) scaffold and applied to the bone defect area. The BK/SF scaffold is an efficient cell carrier which promotes cell proliferation and osteogenic differentiation of rBMSCs (bone marrow derived mesenchymal stem cells). We confirmed biocompatibility and osteogenic differentiation capacity of BK/SF scaffolds compared to pristine SF scaffold in both in vitro and in vivo evaluation. Gene expression related to osteogenic differentiation and bone regeneration significantly upregulated in the BK/SF scaffold group. The implanted scaffolds were attached well to the surface of the bone defect region and integrated with surrounding tissues without significant inflammatory reaction. Furthermore, almost 45% of bone volume has been recovered at 8 weeks postsurgery, while the SF and control group showed 20% recovery. These results suggest that BK powdery extract incorporated with an SF scaffold might be a suitable substitute for an alternative bone graft for bone regeneration. PMID- 28001354 TI - Mechanism of Kinetically Controlled Capillary Condensation in Nanopores: A Combined Experimental and Monte Carlo Approach. AB - We find the rule of capillary condensation from the metastable state in nanoscale pores based on the transition state theory. The conventional thermodynamic theories cannot achieve it because the metastable capillary condensation inherently includes an activated process. We thus compute argon adsorption isotherms on cylindrical pore models and atomistic silica pore models mimicking the MCM-41 materials by the grand canonical Monte Carlo and the gauge cell Monte Carlo methods and evaluate the rate constant for the capillary condensation by the transition state theory. The results reveal that the rate drastically increases with a small increase in the chemical potential of the system, and the metastable capillary condensation occurs for any mesopores when the rate constant reaches a universal critical value. Furthermore, a careful comparison between experimental adsorption isotherms and the simulated ones on the atomistic silica pore models reveals that the rate constant of the real system also has a universal value. With this finding, we can successfully estimate the experimental capillary condensation pressure over a wide range of temperatures and pore sizes by simply applying the critical rate constant. PMID- 28001355 TI - Dual Cation- and Anion-Based Redox Process in Lithium Titanium Oxysulfide Thin Film Cathodes for All-Solid-State Lithium-Ion Batteries. AB - A dual redox process involving Ti3+/Ti4+ cation species and S2-/(S2)2- anion species is highlighted in oxygenated lithium titanium sulfide thin film electrodes during lithium (de)insertion, leading to a high specific capacity. These cathodes for all-solid-state lithium-ion microbatteries are synthesized by sputtering of LiTiS2 targets prepared by different means. The limited oxygenation of the films that is induced during the sputtering process favors the occurrence of the S2-/(S2)2- redox process at the expense of the Ti3+/Ti4+ one during the battery operation, and influences its voltage profile. Finally, a perfect reversibility of both electrochemical processes is observed, whatever the initial film composition. All-solid-state lithium microbatteries using these amorphous lithiated titanium disulfide thin films and operated between 1.5 and 3.0 V/Li+/Li deliver a greater capacity (210-270 mAh g-1) than LiCoO2, with a perfect capacity retention (-0.0015% cycle-1). PMID- 28001357 TI - Tribotronic Tuning Diode for Active Analog Signal Modulation. AB - Realizing active interaction with external environment/stimuli is a great challenge for current electronics. In this paper, a tribotronic tuning diode (TTD) is proposed by coupling a variable capacitance diode and a triboelectric nanogenerator in free-standing sliding mode. When the friction layer is sliding on the device surface for electrification, a reverse bias voltage is created and applied to the diode for tuning the junction capacitance. When the sliding distance increases from 0 to 25 mm, the capacitance of the TTD decreases from about 39 to 8 pF. The proposed TTD has been integrated into analog circuits and exhibited excellent performances in frequency modulation, phase shift, and filtering by sliding a finger. This work has demonstrated tunable diode and active analog signal modulation by tribotronics, which has great potential to replace ordinary variable capacitance diodes in various practical applications such as signal processing, electronic tuning circuits, precise tuning circuits, active sensor networks, electronic communications, remote controls, flexible electronics, etc. PMID- 28001358 TI - Additively Manufactured and Surface Biofunctionalized Porous Nitinol. AB - Enhanced bone tissue regeneration and improved osseointegration are among the most important goals in design of multifunctional orthopedic biomaterials. In this study, we used additive manufacturing (selective laser melting) to develop multifunctional porous nitinol that combines superelasticity with a rationally designed microarchitecture and biofunctionalized surface. The rational design based on triply periodic minimal surfaces aimed to properly adjust the pore size, increase the surface area (thereby amplifying the effects of surface biofunctionalization), and resemble the curvature characteristics of trabecular bone. The surface of additively manufactured (AM) porous nitinol was biofunctionalized using polydopamine-immobilized rhBMP2 for better control of the release kinetics. The actual morphological properties of porous nitinol measured by microcomputed tomography (e.g., open/close porosity, and surface area) closely matched the design values. The superelasticity originated from the austenite phase formed in the nitinol porous structure at room temperature. Polydopamine and rhBMP2 signature peaks were confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy tests. The release of rhBMP2 continued until 28 days. The early time and long-term release profiles were found to be adjustable independent of each other. In vitro cell culture showed improved cell attachment, cell proliferation, cell morphology (spreading, spindle-like shape), and cell coverage as well as elevated levels of ALP activity and increased calcium content for biofunctionalized surfaces as compared to as-manufactured specimens. The demonstrated functionalities of porous nitinol could be used as a basis for deployable orthopedic implants with rationally designed microarchitectures that maximize bone tissue regeneration performance by release of biomolecules with adjustable and well-controlled release profiles. PMID- 28001356 TI - Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs. AB - Both historical clinical and recent preclinical data suggest that the M1 muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1 activation. Efforts then shifted to focus on selective activation of M1 via either allosteric agonists or positive allosteric modulators (PAMs). While M1 PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M1 ago-PAMs. Our data demonstrate that closely related M1 PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M1 PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M1 responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M1 PAMs. PMID- 28001359 TI - Multiconfiguration Pair-Density Functional Theory: A New Way To Treat Strongly Correlated Systems. AB - The electronic energy of a system provides the Born-Oppenheimer potential energy for internuclear motion and thus determines molecular structure and spectra, bond energies, conformational energies, reaction barrier heights, and vibrational frequencies. The development of more efficient and more accurate ways to calculate the electronic energy of systems with inherently multiconfigurational electronic structure is essential for many applications, including transition metal and actinide chemistry, systems with partially broken bonds, many transition states, and most electronically excited states. Inherently multiconfigurational systems are called strongly correlated systems or multireference systems, where the latter name refers to the need for using more than one ("multiple") configuration state function to provide a good zero-order reference wave function. This Account describes multiconfiguration pair-density functional theory (MC-PDFT), which was developed as a way to combine the advantages of wave function theory (WFT) and density functional theory (DFT) to provide a better treatment of strongly correlated systems. First we review background material: the widely used Kohn-Sham DFT (which uses only a single Slater determinant as reference wave function), multiconfiguration WFT methods that treat inherently multiconfigurational systems based on an active space, and previous attempts to combine multiconfiguration WFT with DFT. Then we review the formulation of MC-PDFT. It is a generalization of Kohn-Sham DFT in that the electron kinetic energy and classical electrostatic energy are calculated from a reference wave function, while the rest of the energy is obtained from a density functional. However, there are two main differences with respent to Kohn-Sham DFT: (i) The reference wave function is multiconfigurational rather than being a single Slater determinant. (ii) The density functional is a function of the total density and the on-top pair density rather than being a function of the spin-up and spin-down densities. In work carried out so far, the multiconfigurational wave function is a multiconfiguration self-consistent-field wave function. The new formulation has the advantage that the reference wave function has the correct spatial and spin symmetry and can describe bond dissociation (of both single and multiple bonds) and electronic excitations in a formally and physically correct way. We then review the formulation of density functionals in terms of the on-top pair density. Finally we review successful applications of the theory to bond energies and bond dissociation potential energy curves of main group and transition metal bonds, to barrier heights (including pericyclic reactions), to proton affinities, to the hydrogen bond energy of water dimer, to ground- and excited-state charge transfer, to valence and Rydberg excitations of molecules, and to singlet-triplet splittings of radicals. We find that that MC PDFT can give accurate results not only with complete-active-space multiconfiguration wave functions but also with generalized-active-space multiconfiguration wave functions, which are practical for larger numbers of active electrons and active orbitals than are complete-active-space wave functions. The separated-pair approximation, which is a special case of generalized active space self-consistent-field theory, is especially promising. MC-PDFT, because it requires much less computer time and storage than pure WFT methods, has the potential to open larger and more complex strongly correlated systems to accurate simulation. PMID- 28001360 TI - Diamond-Graphite Nanoplatelet Surfaces as Conductive Substrates for the Electrical Stimulation of Cell Functions. AB - The nanocarbon allotropes constitute valid alternatives when designing control and actuation devices for electrically assisted tissue regeneration purposes, gathering among them important characteristics such as chemical inertness, biocompatibility, extreme mechanical properties, and, importantly, low and tailorable electrical resistivity. In this work, coatings of thin (100 nm) vertically aligned nanoplatelets composed of diamond (5 nm) and graphite were produced via a microwave plasma chemical vapor deposition (MPCVD) technique and used as substrates for electrical stimulation of MC3T3-E1 preosteoblasts. Increasing the amount of N2 up to 14.5 vol % during growth lowers the coatings' electrical resistivity by over 1 order of magnitude, triggers the nanoplatelet vertical growth, and leads to the higher crystalline quality of the nanographite phase. When preosteoblasts were cultured on these substrates and subjected to two consecutive daily cycles of 3 MUA direct current stimulation, enhanced cell proliferation and metabolism were observed accompanied by high cell viability. Furthermore, in the absence of DC stimulation, alkaline phosphatase (ALP) activity is increased significantly, denoting an up-regulating effect of preosteoblastic maturation intrinsically exerted by the nanoplatelet substrates. PMID- 28001361 TI - Flexible Organic/Inorganic Hybrid Field-Effect Transistors with High Performance and Operational Stability. AB - The production of high-quality semiconducting nanostructures with optimized electrical, optical, and electromechanical properties is important for the advancement of next-generation technologies. In this context, we herein report on highly obliquely aligned single-crystalline zinc oxide nanosheets (ZnO NSs) grown via the vapor-liquid-solid approach using r-plane (01-12) sapphire as the template surface. The high structural and optical quality of as-grown ZnO NSs has been confirmed using high-resolution transmission electron microscopy and temperature-dependent photoluminescence, respectively. To assess the potential of our NSs as effective building materials in high-performance flexible electronics, we fabricate organic (parylene C)/inorganic (ZnO NS) hybrid field-effect transistor (FET) devices on flexible substrates using room-temperature assembly processes. Extraction of key FET performance parameters suggests that as-grown ZnO NSs can successfully function as excellent n-type semiconducting modules. Such devices are found to consistently show very high on-state currents (Ion) > 40 MUA, high field-effect mobility (MUeff) > 200 cm2/(V s), exceptionally high on/off current modulation ratio (Ion/off) of around 109, steep subthreshold swing (s-s) < 200 mV/decade, very low hysteresis, and negligible threshold voltage shifts with prolonged electrical stressing (up to 340 min). The present study delivers a concept of integrating high-quality ZnO NS as active semiconducting elements in flexible electronic circuits. PMID- 28001362 TI - Reduced Ensemble Plasmon Line Widths and Enhanced Two-Photon Luminescence in Anodically Formed High Surface Area Au-TiO2 3D Nanocomposites. AB - Localized surface plasmon resonances (LSPR) in TiO2 nanorod and nanotube arrays decorated by gold nanoparticles can be exploited to improve photocatalytic activity, enhance nonlinear optical coefficients, and increase light harvesting in solar cells. However, the LSPR typically has a low quality factor, and the resonance is often obscured by the Urbach tail of the TiO2 band gap absorption. Attempts to increase the LSPR extinction intensity by increasing the density of gold nanoparticles on the surface of the TiO2 nanostructures invariably produce peak broadening due to the effects of either agglomeration or polydispersity. We present a new class of hybrid nanostructures containing gold nanoparticles (NPs) partially embedded in nanoporous/nanotubular TiO2 by performing the anodization of cosputtered Ti-Au thin films containing a relatively high ratio of Au:Ti. Our method of anodizing thin film stacks containing alternate layers of Ti and TiAu results in very distinctive LSPR peaks with quality factors as high as 6.9 and ensemble line widths as small as 0.33 eV even in the presence of an Urbach tail. Unusual features in the anodization of such films are observed and explained, including oscillatory current transients and the observation of coherent heterointerfaces between the Au NPs and anatase TiO2. We further show that such a plasmonic NP-embedded nanotube structure dramatically outperforms a plasmonic NP decorated anodic nanotube structure in terms of the extinction coefficient, and achieves a strongly enhanced two-photon fluorescence due to the high density of gold nanoparticles in the composite film and the plasmonic local field enhancement. PMID- 28001363 TI - Mass Spectrometry Imaging of Complex Microbial Communities. AB - In the two decades since mass spectrometry imaging (MSI) was first applied to visualize the distribution of peptides across biological tissues and cells, the technique has become increasingly effective and reliable. MSI excels at providing complementary information to existing methods for molecular analysis-such as genomics, transcriptomics, and metabolomics-and stands apart from other chemical imaging modalities through its capability to generate information that is simultaneously multiplexed and chemically specific. Today a diverse family of MSI approaches are applied throughout the scientific community to study the distribution of proteins, peptides, and small-molecule metabolites across many biological models. The inherent strengths of MSI make the technique valuable for studying microbial systems. Many microbes reside in surface-attached multicellular and multispecies communities, such as biofilms and motile colonies, where they work together to harness surrounding nutrients, fend off hostile organisms, and shield one another from adverse environmental conditions. These processes, as well as many others essential for microbial survival, are mediated through the production and utilization of a diverse assortment of chemicals. Although bacterial cells are generally only a few microns in diameter, the ecologies they influence can encompass entire ecosystems, and the chemical changes that they bring about can occur over time scales ranging from milliseconds to decades. Because of their incredible complexity, our understanding of and influence over microbial systems requires detailed scientific evaluations that yield both chemical and spatial information. MSI is well-positioned to fulfill these requirements. With small adaptations to existing methods, the technique can be applied to study a wide variety of chemical interactions, including those that occur inside single-species microbial communities, between cohabitating microbes, and between microbes and their hosts. In recognition of this potential for scientific advancement, researchers have adapted MSI methodologies for the specific needs of the microbiology research community. As a result, workflows exist for imaging microbial systems with many of the common MSI ionization methods. Despite this progress, there is substantial room for improvements in instrumentation, sample preparation, and data interpretation. This Account provides a brief overview of the state of technology in microbial MSI, illuminates selected applications that demonstrate the potential of the technique, and highlights a series of development challenges that are needed to move the field forward. In the coming years, as microbial MSI becomes easier to use and more universally applicable, the technique will evolve into a fundamental tool widely applied throughout many divisions of science, medicine, and industry. PMID- 28001365 TI - Redox Roll-Front Mobilization of Geogenic Uranium by Nitrate Input into Aquifers: Risks for Groundwater Resources. AB - Redox conditions are seen as the key to controlling aqueous uranium concentrations (cU(aq)). Groundwater data collected by a state-wide groundwater quality monitoring study in Mecklenburg-Western Pomerania (Germany) reveal peak cU(aq) up to 75 MUg L-1 but low background uranium concentrations (median cU(aq) < 0.5 MUg L-1). To characterize the hydrogeochemical processes causing such groundwater contamination by peak cU(aq), we reanalyzed measured redox potentials and total concentrations of aqueous uranium, nitrate, and sulfate species in groundwater together with their distribution across the aquifer depth and performed semigeneric 2D reactive mass transport modeling which is based on chemical thermodynamics. The combined interpretation of modeling results and measured data reveals that high cU(aq) and its depth-specific distribution depending on redox conditions is a result of a nitrate-triggered roll-front mobilization of geogenic uranium in the studied aquifers which are unaffected by nuclear activities. The modeling results show that groundwater recharge containing (fertilizer-derived) nitrate drives the redox shift from originally reducing toward oxidizing environments, when nitrate input has consumed the reducing capacity of the aquifers, which is present as pyrite, degradable organic carbon, and geogenic U(IV) minerals. This redox shift controls the uranium roll front mobilization and results in high cU(aq) within the redoxcline. Moreover, the modeling results indicate that peak cU(aq) occurring at this redox front increase along with the temporal progress of such redox conversion within the aquifer. PMID- 28001364 TI - 111In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues. AB - Targeted delivery of drug-encapsulated nanoparticles is a promising new approach to safe and effective therapeutics for cancer. Here we investigate the pharmacokinetics and biodistribution of a prostate-specific membrane antigen (PSMA)-targeted nanoparticle based on a poly(lactic acid)-polyethylene glycol copolymer by utilizing single photon emission computed tomography (SPECT) and fluorescence imaging of a low-molecular-weight, PSMA-targeting moiety attached to the surface and oriented toward the outside environment. Tissue biodistribution of the radioactive, PSMA-targeted nanoparticles in mice containing PSMA(+) PC3 PIP and PSMA(-) PC3 flu (control) tumors demonstrated similar accumulation compared to the untargeted particles within all tissues except for the tumor and liver by 96 h postinjection. For PSMA(+) PC3 PIP tumor, the targeted nanoparticle demonstrated retention of 6.58% injected dose (ID)/g at 48 h and remained nearly at that level out to 96 h, whereas the untargeted nanoparticle showed a 48 h retention of 8.17% ID/g followed by a significant clearance to 2.37% ID/g at 96 h (P < 0.02). On the other hand, for control tumor, both targeted and untargeted particles displayed similar 48 h retentions and rates of clearance over 96 h. Ex vivo microscopic analysis with near-infrared versions of the nanoparticles indicated retention within PSMA(+) tumor epithelial cells as well as tumor associated macrophages for targeted particles and primarily macrophage-associated uptake for the untargeted particles. Retention in control tumor was primarily associated with tumor vasculature and macrophages. The data demonstrate the utility of radioimaging to assess nanoparticle biodistribution and suggest that active targeting has a modest positive effect on tumor localization of PSMA targeted PLA-PEG nanoparticles that have been derivatized for imaging. PMID- 28001366 TI - Metal Selectivity of a Cd-, Co-, and Zn-Transporting P1B-type ATPase. AB - The P1B-ATPases, a family of transmembrane metal transporters important for transition metal homeostasis in all organisms, are subdivided into classes based on sequence conservation and metal specificity. The multifunctional P1B-4-ATPase CzcP is part of the cobalt, zinc, and cadmium resistance system from the metal tolerant, model organism Cupriavidus metallidurans. Previous work revealed the presence of an unusual soluble metal-binding domain (MBD) at the CzcP N-terminus, but the nature, extent, and selectivity of the transmembrane metal-binding site (MBS) of CzcP have not been resolved. Using homology modeling, we show that four wholly conserved amino acids from the transmembrane (TM) domain (Met254, Ser474, Cys476, and His807) are logical candidates for the TM MBS, which may communicate with the MBD via interactions with the first TM helix. Metal-binding analyses indicate that wild-type (WT) CzcP has three MBSs, and data on N-terminally truncated (DeltaMBD) CzcP suggest the presence of a single TM MBS. Electronic absorption and electron paramagnetic resonance spectroscopic analyses of DeltaMBD CzcP and variant proteins thereof provide insight into the details of Co2+ coordination by the TM MBS. These spectroscopic data, combined with in vitro functional studies of WT and variant CzcP proteins, show that the side chains of Met254, Cys476, and His807 contribute to Cd2+, Co2+, and Zn2+ binding and transport, whereas the side chain of Ser474 appears to play a minimal role. By comparison to other P1B-4-ATPases, we suggest that an evolutionarily adapted flexibility in the TM region likely afforded CzcP the ability to transport Cd2+ and Zn2+ in addition to Co2+. PMID- 28001368 TI - Biochemical Validation of a Second Guanidine Riboswitch Class in Bacteria. AB - Recently, it was determined that representatives of the riboswitch candidates called ykkC and ykkC-III directly bind free guanidine. Guanidine-binding ykkC motif RNAs, now renamed guanidine-I riboswitches, were demonstrated to commonly regulate the expression of genes encoding guanidine carboxylases, as well as others encoding guanidine efflux proteins such as EmrE and SugE. Likewise, genes encoding similar efflux proteins are associated with ykkC-III motif RNAs, which have now been renamed guanidine-III riboswitches. Prior to the validation of guanidine as the ligand for these newly established riboswitch classes, another RNA motif was discovered by comparative genomic analysis and termed mini-ykkC because of its small size and gene associations similar to those of the original ykkC motif. It was hypothesized that these distinct RNA structures might respond to the same ligand. However, the small size and repetitive nature of mini-ykkC RNAs suggested that it might respond to ligand via the action of a protein factor. Herein, we demonstrate that, despite its extremely simple architecture, mini-ykkC motif RNAs constitute a distinct class of guanidine-sensing RNAs, called guanidine-II riboswitches. Surprisingly, each of the two stem-loop structures that comprise the mini-ykkC motif appears to directly bind free guanidine in a cooperative manner. These findings reveal that bacteria make extensive use of diverse guanidine-responsive riboswitches to overcome the toxic effects of this compound. PMID- 28001367 TI - Prolyl 4-Hydroxylase: Substrate Isosteres in Which an (E)- or (Z)-Alkene Replaces the Prolyl Peptide Bond. AB - Collagen prolyl 4-hydroxylases (CP4Hs) catalyze a prevalent posttranslational modification, the hydroxylation of (2S)-proline residues in protocollagen strands. The ensuing (2S,4R)-4-hydroxyproline residues are necessary for the conformational stability of the collagen triple helix. Prolyl peptide bonds isomerize between cis and trans isomers, and the preference of the enzyme is unknown. We synthesized alkene isosteres of the cis and trans isomers to probe the conformational preferences of human CP4H1. We discovered that the presence of a prolyl peptide bond is necessary for catalysis. The cis isostere is, however, an inhibitor with a potency greater than that of the trans isostere, suggesting that the cis conformation of a prolyl peptide bond is recognized preferentially. Comparative studies with a Chlamydomonas reinhardtii P4H, which has a similar catalytic domain but lacks an N-terminal substrate-binding domain, showed a similar preference for the cis isostere. These findings support the hypothesis that the catalytic domain of CP4Hs recognizes the cis conformation of the prolyl peptide bond and inform the use of alkenes as isosteres for peptide bonds. PMID- 28001370 TI - Techno-Economic Evaluation of Technologies to Mitigate Greenhouse Gas Emissions at North American Refineries. AB - A petroleum refinery model, Petroleum Refinery Life-cycle Inventory Model (PRELIM), that estimates energy use and CO2 emissions was modified to evaluate the environmental and economic performance of a set of technologies to reduce CO2 emissions at refineries. Cogeneration of heat and power (CHP), carbon capture at fluid catalytic cracker (FCC) and steam methane reformer (SMR) units, and alternative hydrogen production technologies were considered in the analysis. The results indicate that a 3-44% reduction in total annual refinery CO2 emissions (2 24% reductions in the CO2 emissions on a per barrel of crude oil processed) can be achieved in a medium conversion refinery that processes a typical U.S. crude slate obtained by using the technologies considered. A sensitivity analysis of the quality of input crude to a refinery, refinery configuration, and prices of natural gas and electricity revealed how the magnitude of possible CO2 emissions reductions and the economic performance of the mitigation technologies can vary under different conditions. The analysis can help inform decision making related to investment decisions and CO2 emissions policy in the refining sector. PMID- 28001369 TI - Stem Cell Transcriptome Responses and Corresponding Biomarkers That Indicate the Transition from Adaptive Responses to Cytotoxicity. AB - Analysis of transcriptome changes has become an established method to characterize the reaction of cells to toxicants. Such experiments are mostly performed at compound concentrations close to the cytotoxicity threshold. At present, little information is available on concentration-dependent features of transcriptome changes, in particular, at the transition from noncytotoxic concentrations to conditions that are associated with cell death. Thus, it is unclear in how far cell death confounds the results of transcriptome studies. To explore this gap of knowledge, we treated pluripotent stem cells differentiating to human neuroepithelial cells (UKN1 assay) for short periods (48 h) with increasing concentrations of valproic acid (VPA) and methyl mercury (MeHg), two compounds with vastly different modes of action. We developed various visualization tools to describe cellular responses, and the overall response was classified as "tolerance" (minor transcriptome changes), "functional adaptation" (moderate/strong transcriptome responses, but no cytotoxicity), and "degeneration". The latter two conditions were compared, using various statistical approaches. We identified (i) genes regulated at cytotoxic, but not at noncytotoxic, concentrations and (ii) KEGG pathways, gene ontology term groups, and superordinate biological processes that were only regulated at cytotoxic concentrations. The consensus markers and processes found after 48 h treatment were then overlaid with those found after prolonged (6 days) treatment. The study highlights the importance of careful concentration selection and of controlling viability for transcriptome studies. Moreover, it allowed identification of 39 candidate "biomarkers of cytotoxicity". These could serve to provide alerts that data sets of interest may have been affected by cell death in the model system studied. PMID- 28001371 TI - Intracellular Delivery of Luminescent Quantum Dots Mediated by a Virus-Derived Lytic Peptide. AB - We describe a new quantum dot (QD)-conjugate prepared with a lytic peptide, derived from a nonenveloped virus capsid protein, capable of bypassing the endocytotic pathways and delivering large amounts of QDs to living cells. The polypeptide, derived from the Nudaurelia capensis Omega virus, was fused onto the C-terminus of maltose binding protein that contained a hexa-HIS tag at its N terminus, allowing spontaneous self-assembly of controlled numbers of the fusion protein per QD via metal-HIS interactions. We found that the efficacy of uptake by several mammalian cell lines was substantial even for small concentrations (10 100 nM). Upon internalization the QDs were primarily distributed outside the endosomes/lysosomes. Moreover, when cells were incubated with the conjugates at 4 degrees C, or in the presence of chemical endocytic inhibitors, significant intracellular uptake continued to occur. These findings indicate an entry mechanism that does not involve endocytosis, but rather the perforation of the cell membrane by the lytic peptide on the QD surfaces. PMID- 28001372 TI - Biochemical Validation of a Third Guanidine Riboswitch Class in Bacteria. AB - Recently, it was determined that representatives of the riboswitch candidates called ykkC and mini-ykkC directly bind free guanidine. These riboswitches regulate the expression of genes whose protein products are implicated in overcoming the toxic effects of this ligand. Thus, the relevant ykkC motif and mini-ykkC motif RNAs have been classified as guanidine-I and guanidine-II riboswitch RNAs, respectively. Moreover, we had previously noted that a third candidate riboswitch class, called ykkC-III, was associated with a distribution of genes similar to those of the other two motifs. Therefore, it was predicted that ykkC-III motif RNAs would sense and respond to the same ligand. In this report, we present biochemical data supporting the hypothesis that ykkC-III RNAs represent a third class of guanidine-sensing RNAs called guanidine-III riboswitches. Members of the guanidine-III riboswitch class bind their ligand with an affinity similar to that observed for members of the other two classes. Notably, there are some sequence similarities between guanidine-II and guanidine III riboswitches. However, the characteristics of ligand discrimination by guanidine-III RNAs are different from those of the other guanidine-binding motifs, suggesting that the binding pockets have distinct features among the three riboswitch classes. PMID- 28001373 TI - Direct Measurement of Trafficking of the Cystic Fibrosis Transmembrane Conductance Regulator to the Cell Surface and Binding to a Chemical Chaperone. AB - Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in the disease cystic fibrosis. Deletion of Phe508, the most prevalent mutation associated with this disease, disrupts trafficking of the protein. Small molecule correctors yield moderate improvements in the trafficking of DeltaF508 CFTR to the plasma membrane. It is currently not known if correctors increase the level of trafficking through improved cargo loading of transport vesicles or through direct binding to CFTR. Real-time measurements of trafficking were utilized to identify the mechanistic details of chemical, biochemical, and thermal factors that impact CFTR correction, using the corrector molecule VX-809, a secondary mutation (I539T), and low-temperature conditions. Each individually improved trafficking of DeltaF508-CFTR to approximately 10% of wild-type levels. The combination of VX-809 with either low temperature or the I539T mutation increased the amount of CFTR on the plasma membrane to nearly 40%, indicating synergistic activity. The number of vesicles reaching the surface was significantly altered; however, the amount of channel in each vesicle remained the same. Direct binding measurements of VX-809 in native membranes using backscattering interferometry indicate tight binding to CFTR, which occurred in a manner independent of mutation. The similar values obtained for all forms of the channel indicate that the binding site is not compromised or enhanced by these mutations. PMID- 28001374 TI - Nanoscale Structural Features in Major Ampullate Spider Silk. AB - Spider major ampullate silk is often schematically represented as a two-phase material composed of crystalline nanodomains in an amorphous matrix. Here we are interested in revealing its more complex nanoscale organization by probing Argiope bruennichi dragline-type fibers using scanning X-ray nanodiffraction. This allows resolving transversal structural features such as an about 1 MUm skin layer composed of around 100 nm diameter nanofibrils serving presumably as an elastic sheath. The core consists of a composite of several nm size crystalline nanodomains with poly(l-alanine) microstructure, embedded in a polypeptide network with short-range order. Stacks of nanodomains separated by less ordered nanosegments form nanofibrils with a periodic axial density modulation which is particularly sensitive to radiation damage. The precipitation of larger beta-type nanocrystallites in the outer core-shell is attributed to MaSp1 protein molecules. PMID- 28001375 TI - Novel Kinetic Intermediates Populated along the Folding Pathway of the Transmembrane beta-Barrel OmpA. AB - We examined the folding of the beta-barrel membrane protein OmpA from Escherichia coli. Although previous studies identified several intermediate states followed by a concerted translocation mechanism across the bilayer, some aspects of the pathway were still unclear, including the extent of secondary structure formation in the intermediate states and how the mechanism gave rise to multiple exponential phases in the folding kinetics. We addressed these questions by investigating the folding kinetics of the OmpA transmembrane beta-barrel domain over a range of bilayer thicknesses, allowing us to observe different regions of the folding pathway. The fastest folding into the thinnest bilayers provided information about the later stages of the process, and the slowest folding into thicker bilayers revealed early kinetic steps. Folding was monitored using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and circular dichroism spectroscopy, which provide complementary information about tertiary and secondary structure formation. We globally fit the folding data to kinetic schemes and found that the same core pathway was followed under all lipid conditions. We propose a multistep folding mechanism for OmpA that includes unstructured surface-adsorbed states converting through a partially inserted state with substantial beta-sheet structure to the final natively inserted barrel. Kinetic models show that all steps of the main folding pathway are accelerated by membrane defects that occur as a result of thinning the bilayer or incubation of lipids at the phase transition temperature. In addition to suppressing off-pathway states, beta-barrel assembly machinery-catalyzed folding in vivo could accelerate any or all of these main folding steps to ensure efficient outer membrane protein biogenesis in vivo. PMID- 28001377 TI - Impact of Mineral Precipitation on Flow and Mixing in Porous Media Determined by Microcomputed Tomography and MRI. AB - Precipitation reactions influence transport properties in porous media and can be coupled to advective and dispersive transport. For example, in subsurface environments, mixing of groundwater and injected solutions can induce mineral supersaturation of constituents and drive precipitation reactions. Magnetic resonance imaging (MRI) and microcomputed tomography (MU-CT) were employed as complementary techniques to evaluate advection, dispersion, and formation of precipitate in a 3D porous media flow cell. Two parallel fluids were flowed concentrically through packed glass beads under two relative flow rates with Na2CO3 and CaCl2 in the inner and outer fluids, respectively. CaCO3 became supersaturated and formed a precipitate at the mixing interface between the two solutions. Spatial maps of changing local velocity fields and dispersion in the flow cell were generated from MRI, while high resolution MU-CT imaging visualized the precipitate formed in the porous media. Formation of a precipitate minimized dispersive and advective transport between the two fluids and the shape of the precipitation front was influenced by the relative flow rates. This work demonstrates that the combined use of MRI and MU-CT can be highly complementary in the study of reactive transport processes in porous media. PMID- 28001378 TI - The Economic Merits of Flexible Carbon Capture and Sequestration as a Compliance Strategy with the Clean Power Plan. AB - Carbon capture and sequestration (CCS) may be a key technology for achieving large CO2 emission reductions. Relative to "normal" CCS, "flexible" CCS retrofits include solvent storage that allows the generator to temporarily reduce the CCS parasitic load and increase the generator's net efficiency, capacity, and ramp rate. Due to this flexibility, flexible CCS generators provide system benefits that normal CCS generators do not, which could make flexible CCS an economic CO2 emission reduction strategy. Here, we estimate the system-level cost effectiveness of reducing CO2 emissions with flexible CCS compared to redispatching (i.e., substituting gas- for coal-fired electricity generation), wind, and normal CCS under the Clean Power Plan (CPP) and a hypothetical more stringent CO2 emission reduction target ("stronger CPP"). Using a unit commitment and economic dispatch model, we find flexible CCS achieves more cost-effective emission reductions than normal CCS under both reduction targets, indicating that policies that promote CCS should encourage flexible CCS. However, flexible CCS is less cost effective than wind under both reduction targets and less and more cost effective than redispatching under the CPP and stronger CPP, respectively. Thus, CCS will likely be a minor CPP compliance strategy but may play a larger role under a stronger emission reduction target. PMID- 28001376 TI - Thirdhand Smoke: New Evidence, Challenges, and Future Directions. AB - Thirdhand smoke (THS) is the contamination that persists after secondhand tobacco smoke has been emitted into air. It refers to the tobacco-related gases and particles that become embedded in materials, such as the carpet, walls, furniture, blankets, and toys. THS is not strictly smoke, but chemicals that adhere to surfaces from which they can be released back into the air, undergo chemical transformations and/or accumulate. Currently, the hazards of THS are not as well documented as the hazards of secondhand smoke (SHS). In this Perspective, we describe the distribution and chemical changes that occur as SHS is transformed into THS, studies of environmental contamination by THS, human exposure studies, toxicology studies using animal models and in vitro systems, possible approaches for avoiding exposure, remediation of THS contamination, and priorities for further research. PMID- 28001380 TI - Assembly of the Limonoid Architecture by a Divergent Approach: Total Synthesis of (+/-)-Andirolide N via (+/-)-8alpha-Hydroxycarapin. AB - We report the first total synthesis of the limonoid andirolide N using a 12-step sequence from commercially available materials. The final step of this route demonstrates the chemical feasibility of our biosynthetic proposal that andirolide N arises from 8alpha-hydroxycarapin. The strategic use of a degraded limonoid as a platform for the synthesis of more structurally complex congeners may be a general approach to obtain limonoids with diverse functional properties. PMID- 28001379 TI - The Two Faces of Tetramethylcyclam in Iron Chemistry: Distinct Fe-O-M Complexes Derived from [FeIV(Oanti/syn)(TMC)]2+ Isomers. AB - Tetramethylcyclam (TMC, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) exhibits two faces in supporting an oxoiron(IV) moiety, as exemplified by the prototypical [(TMC)FeIV(Oanti)(NCCH3)](OTf)2, where anti indicates that the O atom is located on the face opposite all four methyl groups, and the recently reported syn isomer [(TMC)FeIV(Osyn)(OTf)](OTf). The ability to access two isomers of [(TMC)FeIV(Oanti/syn)] raises the fundamental question of how ligand topology can affect the properties of the metal center. Previously, we have reported the formation of [(CH3CN)(TMC)FeIII-Oanti-CrIII(OTf)4(NCCH3)] (1) by inner-sphere electron transfer between Cr(OTf)2 and [(TMC)FeIV(Oanti)(NCCH3)](OTf)2. Herein we demonstrate that a new species 2 is generated from the reaction between Cr(OTf)2 and [(TMC)FeIV(Osyn)(NCCH3)](OTf)2, which is formulated as [(TMC)FeIII-Osyn-CrIII(OTf)4(NCCH3)] based on its characterization by UV-vis, resonance Raman, Mossbauer, and X-ray absorption spectroscopic methods, as well as electrospray mass spectrometry. Its pre-edge area (30 units) and Fe-O distance (1.77 A) determined by X-ray absorption spectroscopy are distinctly different from those of 1 (11-unit pre-edge area and 1.81 A Fe-O distance) but more closely resemble the values reported for [(TMC)FeIII-Osyn-ScIII(OTf)4(NCCH3)] (3, 32-unit pre-edge area and 1.75 A Fe-O distance). This comparison suggests that 2 has a square pyramidal iron center like 3, rather than the six-coordinate center deduced for 1. Density functional theory calculations further validate the structures for 1 and 2. The influence of the distinct TMC topologies on the coordination geometries is further confirmed by the crystal structures of [(Cl)(TMC)FeIII-Oanti-FeIIICl3] (4Cl) and [(TMC)FeIII-Osyn-FeIIICl3](OTf) (5). Complexes 1-5 thus constitute a set of complexes that shed light on ligand topology effects on the coordination chemistry of the oxoiron moiety. PMID- 28001381 TI - Treatment of Sepsis Pathogenesis with High Mobility Group Box Protein 1 Regulating Anti-inflammatory Agents. AB - Sepsis is one of the major causes of death worldwide when associated with multiple organ failure. However, there is a critical lack of adequate sepsis therapies because of its diverse patterns of pathogenesis. The pro-inflammatory cytokine cascade mediates sepsis pathogenesis, and high mobility group box proteins (HMGBs) play an important role as late-stage cytokines. We previously reported the small-molecule modulator, inflachromene (1d), which inhibits the release of HMGBs and, thereby, reduces the production of pro-inflammatory cytokines. In this context, we intraperitoneally administered 1d to a cecal ligation and puncture (CLP)-induced mouse model of sepsis and confirmed that it successfully ameliorated sepsis pathogenesis. On the basis of a structure activity relationship study, we discovered new candidate compounds, 2j and 2l, with improved therapeutic efficacy in vivo. Therefore, our study clearly demonstrates that the regulation of HMGB1 release using small molecules is a promising strategy for the treatment of sepsis. PMID- 28001382 TI - Bifunctional Photocatalysts for Enantioselective Aerobic Oxidation of beta Ketoesters. AB - A novel visible-light-responsive chiral ligand has been developed by grafting a triplet state photosensitizer to chiral bisoxazoline ligands. Complexation of this ligand with Ni(acac)2 results in a powerful catalyst for the asymmetric oxidation reaction of beta-ketoesters, which uses oxygen or air as the green oxidant and visible light or sunlight as the ideal driving force. Using this protocol, products containing the alpha-hydroxy-beta-dicarbonyl motif are produced in high yields and with excellent enantiopurities. PMID- 28001383 TI - Luminescent Lanthanide Cyclen-Based Enzymatic Assay Capable of Diagnosing the Onset of Catheter-Associated Urinary Tract Infections Both in Solution and within Polymeric Hydrogels. AB - Herein we present a supramolecular (delayed luminescent) Eu(III)-based pH responsive probe/sensor with the ability to detect the urease-mediated hydrolysis of urea in aqueous solution. A series of photophysical titrations show this Eu(III) chelate behaves as an "on-off" luminescent switching probe, with its luminescence being quenched upon urea being enzymatically converted into ammonia and carbon dioxide. Calculation of the rate constant (k) and activation energy (Ea) for this hydrolysis reaction are detailed; the results demonstrate a direct observation of enzymatic activity in solution by the sensor. The potential application of this probe in detecting the onset of catheter-associated urinary tract infections (CAUTIs) is also demonstrated by incorporating 1.Eu into water permeable hydrogels that can be utilized as an alternative coating for catheters. PMID- 28001385 TI - Covalent and Ionic Functionalization of HLN Layered Perovskite by Sonochemical Methods. AB - We describe the functionalization of the layered perovskite HLaNb2O7 with n propanol, n-decanol, 3-mercaptopropyl-trimethoxysilane, imidazole, n-decylamine, and histamine. The use of sonication is found to significantly improve the reaction yield and to reduce the reaction time, compared to conventional thermal treatment under reflux. The obtained intercalates are thoroughly characterized through the use of several complementary experimental techniques (scanning electron microscopy, IR spectroscopy, X-ray diffraction, thermogravimetric analysis, magic-angle spinning NMR), clarifying their structure and chemical bonding. The implications for the design of inorganic-organic composite materials are discussed. PMID- 28001386 TI - Assessment and Optimization of Configurational-Bias Monte Carlo Particle Swap Strategies for Simulations of Water in the Gibbs Ensemble. AB - Particle swap moves between phases are usually the rate-limiting step for Gibbs ensemble Monte Carlo (GEMC) simulations of fluid phase equilibria at low reduced temperatures because the acceptance probabilities for these moves can become very low for molecules with articulated architecture and/or highly directional interactions. The configurational-bias Monte Carlo (CBMC) technique can greatly increase the acceptance probabilities, but the efficiency of the CBMC algorithm is influenced by multiple parameters. In this work we assess the performance of different CBMC strategies for GEMC simulations using the SPC/E and TIP4P water models at 283, 343, and 473 K, demonstrate that much higher acceptance probabilities can be achieved than previously reported in the literature, and make recommendations for CBMC strategies leading to optimal efficiency. PMID- 28001384 TI - Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. AB - Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects. PMID- 28001387 TI - Structural Determinants of Constitutive Activation of Galpha Proteins: Transducin as a Paradigm. AB - Heterotrimeric guanine nucleotide-binding proteins (Galpha proteins) are intracellular nanomachines deputed to signal transduction. The switch-on process requires the release of bound GDP from a site at the interface between GTPase and helical domains. Nucleotide release is catalyzed by G protein Coupled Receptors (GPCRs). Here we investigate the functional dynamics of wild type (WT) and six constitutively active mutants (CAMs) of the Galpha protein transducin (Gt) by combining atomistic molecular dynamics (MD) simulations with Maxwell-Demod discrete MD (MDdMD) simulations of the receptor-catalyzed transition between GDP bound and nucleotide-free states. Compared to the WT, Gt CAMs increase the overall fluctuations of nucleotide and its binding site. This is accompanied by weakening of native links involving GDP, alpha1, the G boxes, beta1-beta3, and alpha5. Collectively, constitutive activation by the considered mutants seems to associate with weakening of the interfaces between alpha5 and the surrounding portions and the interface between GTPase (G) and helical (H) domains. These mutational effects associate with increases in the overall fluctuations of the G and H domains, which reflect on the collective motions of the protein. Gt CAMs, with prominence to G56P, T325A, and F332A, prioritize collective motions of the H domain overlapping with the collective motions associated with receptor-catalyzed nucleotide release. In spite of different local perturbations, the mechanisms of nucleotide exchange catalyzed by activating mutations and by receptor are expected to employ similar molecular switches in the nucleotide binding site and to share the detachment of the H domain from the G domain. PMID- 28001388 TI - The Distinctive Electronic Structures of Rhenium Tris(thiolate) Complexes, an Unexpected Contrast to the Valence Isoelectronic Ruthenium Tris(thiolate) Complexes. AB - The noninnocent 2-diphenylphosphino-benzenethiolate (DPPBT) ligand containing both phosphorus and sulfur donors delocalizes the electron density in a manner reminiscent of dithiolenes. The electronic structure of the [ReL3]n (L = DPPBT, n = 0, 1+, 2+) complexes was probed with density-functional theory (DFT) and high level ab initio methods including complete active space self-consistent field (CASSCF and CASPT2) and coupled cluster (CCSD and CCSD(T)). DFT predicts a slight preference for a closed-shell (CS) singlet ground state for the neutral [ReL3]0 and stronger preferences for low-spin ground states for the oxidized [ReL3]+ and [ReL3]2+. High-level ab initio methods confirm a CS singlet with a Re(III) (d4, S = 0) center as the ground state of [ReL3]0. Thus, this neutral Re species has considerably less thiyl radical character than the valence isoelectronic [RuL3]+, which is mainly a Ru(III) (d5, S = 1/2) anti-ferromagnetically (AF) coupled to a thiyl radical (S = 1/2). However, the oxidized derivatives [ReL3]+ and [ReL3]2+ show significant metal-stabilized thiyl radical character like [RuL3]+. Both [ReL3]+ and [ReL3]2+ have major contributions from Re(III) (d4, S = 1) centers AF coupled to thiyl and dithiyl DPPBT ligands. These findings are consistent with the experimental chemistry as [RuL3]+, [ReL3]+, and [ReL3]2+ can add ethylene to form the new C-S bonds, but [ReL3]0 cannot. The thiyl radicals on the S2 position (the S trans to a P donor) serve as the intrinsic electron acceptors in the actual ethylene addition reactions with Ru and Re tris(thiolate) complexes. PMID- 28001389 TI - Synthesis and Characterization of 0D-3D Copper-Containing Tungstobismuthates Obtained from the Lacunary Precursor Na9[B-alpha-BiW9O33]. AB - The reaction of the lacunary polyoxometalate precursor Na9[B-alpha BiW9O33].19.5H2O with Cu(II) ions was explored in search of new economic ways to copper tungstobismuthates as interesting prototypes for water oxidation and reduction catalysts. The emerging series of new 0D-3D polyoxometalate architectures with distinct copper cores was structurally characterized. Na6Rb6[Cu3(H2O)3(BiW9O33)2] (Cu-4) and 3D K6.56Cu0.43H2.20[(Cu3Cl)(K2.62Cu0.38(H2O)3)(B-alpha-BiW9O33)2].13H2O (Cu-5) display a Cu3(H2O)3 core. The 2D representatives Na12[Cu2(H2O)4Cl2(BiW10O35)2] (Cu-1a), Na10[Cu2(H2O)6(BiW10O35)2] (Cu-1b), 2D Na7K3Cu0.5Cl[Cu2(H2O)4(BiW10O35)2] (Cu-2), and 2D Na5.5K2.5Cu[Cu2(H2O)4(BiW10O35)2] (Cu-3) contain Cu2(H2O)nW2O4 cores. Interestingly, the bismuth-free 1D paratungstate B Na4K4Cu[H2W12O42] (Cu-6) is formed through reassembly of the precursor. Cu-5 displays a disordered transition metal core, implying the presence of the polyanions [Cu4(H2O)4(BiW9O33)2]10- and [Cu5(H2O)5(BiW9O33)2]8-. The magnetic properties of Cu-5 as well as its activity as visible-light-driven H2 and O2 evolution catalyst were evaluated. PMID- 28001390 TI - Predicting Bond Dissociation Energies of Transition-Metal Compounds by Multiconfiguration Pair-Density Functional Theory and Second-Order Perturbation Theory Based on Correlated Participating Orbitals and Separated Pairs. AB - We study the performance of multiconfiguration pair-density functional theory (MC PDFT) and multireference perturbation theory for the computation of the bond dissociation energies in 12 transition-metal-containing diatomic molecules and three small transition-metal-containing polyatomic molecules and in two transition-metal dimers. The first step is a multiconfiguration self-consistent field calculation, for which two choices must be made: (i) the active space and (ii) its partition into subspaces, if the generalized active space formulation is used. In the present work, the active space is chosen systematically by using three correlated-participating-orbitals (CPO) schemes, and the partition is chosen by using the separated-pair (SP) approximation. Our calculations show that MC-PDFT generally has similar accuracy to CASPT2, and the active-space dependence of MC-PDFT is not very great for transition-metal-ligand bond dissociation energies. We also find that the SP approximation works very well, and in particular SP with the fully translated BLYP functional SP-ftBLYP is more accurate than CASPT2. SP greatly reduces the number of configuration state functions relative to CASSCF. For the cases of FeO and NiO with extended-CPO active space, for which complete active space calculations are unaffordable, SP calculations are not only affordable but also of satisfactory accuracy. All of the MC-PDFT results are significantly better than the corresponding results with broken-symmetry spin-unrestricted Kohn-Sham density functional theory. Finally we test a perturbation theory method based on the SP reference and find that it performs slightly worse than CASPT2 calculations, and for most cases of the nominal-CPO active space, the approximate SP perturbation theory calculations are less accurate than the much less expensive SP-PDFT calculations. PMID- 28001391 TI - Microwave-Assisted Synthesis, Microstructure, and Magnetic Properties of Rare Earth Cobaltites. AB - The series of perovskite rare-earth (RE) doped cobaltites (RE)CoO3 (RE = La-Dy) was prepared by microwave-assisted synthesis. The crystal structure undergoes a change of symmetry depending on the size of the RE cation. LaCoO3 is rhombohedral, S.G. R3c (No. 167), while, for the rest of the RE series (Pr-Dy), the symmetry is orthorhombic, S.G. Pnma (No. 62). The crystal structure obtained by X-ray diffraction was confirmed by high-resolution transmission electron microscopy, which yielded a good match between experimental and simulated images. It is further shown that the well-known magnetism in LaCoO3, which involves a thermally induced Co3+ (d6) low spin to intermediate or high spin state transition, is strongly modified by the RE cation, and a rich variety of magnetic order has been detected across the series. PMID- 28001392 TI - Stabilization, Assembly, and Toxicity of Trimers Derived from Abeta. AB - Oligomers of the beta-amyloid peptide Abeta have emerged as important contributors to neurodegeneration in Alzheimer's disease. Mounting evidence suggests that Abeta trimers and higher-order oligomers derived from trimers have special significance in the early stages of Alzheimer's disease. Elucidating the structures of these trimers and higher-order oligomers is paramount for understanding their role in neurodegeneration. This paper describes the design, synthesis, X-ray crystallographic structures, and biophysical and biological properties of two stabilized trimers derived from the central and C-terminal regions of Abeta. These triangular trimers are stabilized through three disulfide cross-links between the monomer subunits. The X-ray crystallographic structures reveal that the stabilized trimers assemble hierarchically to form hexamers, dodecamers, and annular porelike structures. Solution-phase biophysical studies reveal that the stabilized trimers assemble in solution to form oligomers that recapitulate some of the higher-order assemblies observed crystallographically. The stabilized trimers share many of the biological characteristics of oligomers of full-length Abeta, including toxicity toward a neuronally derived human cell line, activation of caspase-3 mediated apoptosis, and reactivity with the oligomer-specific antibody A11. These studies support the biological significance of the triangular trimer assembly of Abeta beta-hairpins and may offer a deeper understanding of the molecular basis of Alzheimer's disease. PMID- 28001393 TI - Palladium-Catalyzed Suzuki-Miyaura Coupling of Aryl Esters. AB - The Suzuki-Miyaura coupling is among the most important C-C bond-forming reactions available due to its reliability, chemoselectivity, and diversity. Aryl halides and pseudohalides such as iodides, bromides, and triflates are traditionally used as the electrophilic coupling partner. The expansion of the reaction scope to nontraditional electrophiles is an ongoing challenge to enable an even greater number of useful products to be made from simple starting materials. Herein, we present how an NHC-based Pd catalyst can enable Suzuki Miyaura coupling where the C(acyl)-O bond of aryl esters takes on the role of electrophile, allowing the synthesis of various ketone-containing products. This contrasts known reactions of similar esters that provide biaryls via nickel catalysis. The underlying cause of this mechanistic divergence is investigated by DFT calculations, and the robustness of esters compared to more electrophilic acylative coupling partners is analyzed. PMID- 28001394 TI - Predicting the Kinetics of RNA Oligonucleotides Using Markov State Models. AB - Nowadays different experimental techniques, such as single molecule or relaxation experiments, can provide dynamic properties of biomolecular systems, but the amount of detail obtainable with these methods is often limited in terms of time or spatial resolution. Here we use state-of-the-art computational techniques, namely, atomistic molecular dynamics and Markov state models, to provide insight into the rapid dynamics of short RNA oligonucleotides, to elucidate the kinetics of stacking interactions. Analysis of multiple microsecond-long simulations indicates that the main relaxation modes of such molecules can consist of transitions between alternative folded states, rather than between random coils and native structures. After properly removing structures that are artificially stabilized by known inaccuracies of the current RNA AMBER force field, the kinetic properties predicted are consistent with the time scales of previously reported relaxation experiments. PMID- 28001395 TI - Povarov Reaction of Cycloiminium Formed in Situ via Hydroamination Cycloisomerization of Homopropargylic Amines with Electron-Rich Olefins. AB - A new, one-pot cascade reaction of homopropargylic amines with electron-rich olefins is developed in the presence of Cu(OTf)2 and affords a series of octahydrofuro[3,2-c]pyrrolo[1,2-a]quinoline derivatives in yields of 38-80%. This reaction proceeds through an intramolecular hydroamination cyclization of homopropargylic amine to generate a highly reactive cycloenamine intermediate in situ that subsequently isomerizes to the cycloiminium cation followed by the Povarov-type reaction with dihydrofuran, dihydropyran, or dihydropyrrole. Notably, the Al2O3 additive plays a key role for the effective inhibition of competitive self-dimerization of homoproargylic amines. PMID- 28001396 TI - Photoprotolytic Processes of Lumazine. AB - Steady-state and time-resolved UV-vis spectroscopies were used to study the photoprotolytic properties of lumazine, which belongs to a class of biologically important compounds-the petridines. We found that in water an excited-state proton transfer occurs with a time constant of ~70 ps and competes with a nonradiative rate of about the same value. The nonradiative rate of the protonated form of lumazine in polar and nonpolar solvents is large knr >= 1.5 * 1010s-1. The fluorescence properties indicate that in water, the ground-state neutral form of lumazine is already stable in two tautomeric forms. The fluorescence of the deprotonated form is quenched by protons in acidic solutions with a diffusion-controlled reaction rate. We conclude that the neutral form of lumazine is an irreversible mild photoacid. PMID- 28001397 TI - Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High Temperature and High-Pressure Flow Reactor. AB - Fused pyrimidinone and quinolone derivatives that are of potential interest to pharmaceutical research were synthesized within minutes in up to 96% yield in an automated Phoenix high-temperature and high-pressure continuous flow reactor. Heterocyclic scaffolds that are either hard to synthesize or require multisteps are readily accessible using a common set of reaction conditions. The use of low boiling solvents along with the high conversions of these reactions allowed for facile workup and isolation. The methods reported herein are highly amenable for fast and efficient heterocycle synthesis as well as compound scale-ups. PMID- 28001398 TI - Excitonic Splitting and Vibronic Coupling Analysis of the m-Cyanophenol Dimer. AB - The S1/S2 splitting of the m-cyanophenol dimer, (mCP)2 and the delocalization of its excitonically coupled S1/S2 states are investigated by mass-selective two color resonant two-photon ionization and dispersed fluorescence spectroscopy, complemented by a theoretical vibronic coupling analysis based on correlated ab initio calculations at the approximate coupled cluster CC2 and SCS-CC2 levels. The calculations predict three close-lying ground-state minima of (mCP)2: The lowest is slightly Z-shaped (Ci-symmetric); the second-lowest is <5 cm-1 higher and planar (C2h). The vibrational ground state is probably delocalized over both minima. The S0 -> S1 transition of (mCP)2 is electric-dipole allowed (Ag -> Au), while the S0 -> S2 transition is forbidden (Ag -> Ag). Breaking the inversion symmetry by 12C/13C- or H/D-substitution renders the S0 -> S2 transition partially allowed; the excitonic contribution to the S1/S2 splitting is Deltaexc = 7.3 cm-1. Additional isotope-dependent contributions arise from the changes of the m-cyanophenol zero-point vibrational energy upon electronic excitation, which are Deltaiso(12C/13C) = 3.3 cm-1 and Deltaiso(H/D) = 6.8 cm-1. Only partial localization of the exciton occurs in the 12C/13C and H/D substituted heterodimers. The SCS-CC2 calculated excitonic splitting is Deltael = 179 cm-1; when multiplying this with the vibronic quenching factor Gammavibronexp = 0.043, we obtain an exciton splitting Deltavibronexp = 7.7 cm-1, which agrees very well with the experimental Deltaexc = 7.3 cm-1. The semiclassical exciton hopping times range from 3.2 ps in (mCP)2 to 5.7 ps in the heterodimer (mCP-h).(mCP-d). A multimode vibronic coupling analysis is performed encompassing all the vibronic levels of the coupled S1/S2 states from the v = 0 level to 600 cm-1 above. Both linear and quadratic vibronic coupling schemes were investigated to simulate the S0 -> S1/S2 vibronic spectra; those calculated with the latter scheme agree better with experiment. PMID- 28001399 TI - The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors. AB - Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices. Further improvement of potency and pharmacokinetics produced in vivo proof-of-concept tool molecule 20 (AM-1488), which reversed tactile allodynia in a mouse spared-nerve injury (SNI) model. Additional structural optimization provided highly potent potentiator 32 (AM 3607), which was cocrystallized with human GlyRalpha3cryst to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand gated ion channels (LGICs). PMID- 28001400 TI - Global Sensitivity Analysis with Small Sample Sizes: Ordinary Least Squares Approach. AB - A new version of global sensitivity analysis is developed in this paper. This new version coupled with tools from statistics, machine learning, and optimization can devise small sample sizes that allow for the accurate ordering of sensitivity coefficients for the first 10-30 most sensitive chemical reactions in complex chemical-kinetic mechanisms, and is particularly useful for studying the chemistry in realistic devices. A key part of the paper is calibration of these small samples. Because these small sample sizes are developed for use in realistic combustion devices, the calibration is done over the ranges of conditions in such devices, with a test case being the operating conditions of a compression ignition engine studied earlier. Compression-ignition engines operate under low-temperature combustion conditions with quite complicated chemistry making this calibration difficult, leading to the possibility of false positives and false negatives in the ordering of the reactions. So an important aspect of the paper is showing how to handle the trade-off between false positives and false negatives using ideas from the multiobjective optimization literature. The combination of the new global sensitivity method and the calibration are sample sizes a factor of approximately 10 times smaller than were available with our previous algorithm. PMID- 28001401 TI - Palladium Catalyzed Carbonylative Coupling for Synthesis of Arylketones and Arylesters Using Chloroform as the Carbon Monoxide Source. AB - We describe a modular, palladium catalyzed synthesis of aryl(hetero)aryl benzophenones and aryl benzoates from aryl(hetero)aryl halides using CHCl3 as the carbonyl source in the presence of KOH. The reaction occurs in tandem through an initial carbonylation to generate an aroyl halide, which undergoes coupling with arylboronic acids, bornonates, and phenols. Direct carbonylative coupling of indoles at the third position has also been accomplished under slightly modified reaction conditions by in situ activation of the C-H bond. Notably, CHCl3 is a convenient and safe alternation of CO gas, provides milder reaction conditions with high functional group tolerance, and gives the products in moderate to good yields. PMID- 28001402 TI - Anticancer and Antiangiogenic Iron(II) Complexes That Target Thioredoxin Reductase to Trigger Cancer Cell Apoptosis. AB - Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment. PMID- 28001403 TI - Ferrofluids of Thermotropic Liquid Crystals by DNA-Lipid Hybrids. AB - Here is the first report the creation of ferrofluids of thermotropic liquid crystals in the absence of any solvent or nanoparticle. These ferrofluids were prepared by the electrostatic coupling of single-strand (ss) DNA with paramagnetic lipids. DNA molecules, as rigid parts, offer the orientational anisotropy and lipids (surfactants) due to the flexible hydrocarbon chains suppress crystallization, hybrids with DNA significantly increase the Cure temperature (Tc) of the lipids. The ferrofluids possess good fluidity and low viscosity. They serve as excellent solvents for both hydrophilic and lipophilic compounds. Their strong magnetism further allows the solutes to be controlled by external magnetic force. The DNA-lipid hybrid ferrofluids show liquid crystal (LC) behavior at low temperatures, and the LC phase is made of ordered multilamellar structures. Compared with conventional magnetic nanoparticle dispersions, the solvent-free lipoplex ferrofluids provide potential applications for nanotechnology, material science, and biotechnology. PMID- 28001404 TI - Hydroxyacetone Production From C3 Criegee Intermediates. AB - Hydroxyacetone (CH3C(O)CH2OH) is observed as a stable end product from reactions of the (CH3)2COO Criegee intermediate, acetone oxide, in a flow tube coupled with multiplexed photoionization mass spectrometer detection. In the experiment, the isomers at m/z = 74 are distinguished by their different photoionization spectra and reaction times. Hydroxyacetone is observed as a persistent signal at longer reaction times at a higher photoionization threshold of ca. 9.7 eV than Criegee intermediate and definitively identified by comparison with the known photoionization spectrum. Complementary electronic structure calculations reveal multiple possible reaction pathways for hydroxyacetone formation, including unimolecular isomerization via hydrogen atom transfer and -OH group migration as well as self-reaction of Criegee intermediates. Varying the concentration of Criegee intermediates suggests contributions from both unimolecular and self reaction pathways to hydroxyacetone. The hydroxyacetone end product can provide an effective, stable marker for the production of transient Criegee intermediates in future studies of alkene ozonolysis. PMID- 28001405 TI - Development of Site-Specific Mg(2+)-RNA Force Field Parameters: A Dream or Reality? Guidelines from Combined Molecular Dynamics and Quantum Mechanics Simulations. AB - The vital contribution of Mg2+ ions to RNA biology is challenging to dissect at the experimental level. This calls for the integrative support of atomistic simulations, which at the classical level are plagued by limited accuracy. Indeed, force fields intrinsically neglect nontrivial electronic effects that Mg2+ exerts on its surrounding ligands in varying RNA coordination environments. Here, we present a combined computational study based on classical molecular dynamics (MD) and Density Functional Theory (DFT) calculations, aimed at characterizing (i) the performance of five Mg2+ force field (FF) models in RNA systems and (ii) how charge transfer and polarization affect the binding of Mg2+ ions in different coordination motifs. As a result, a total of ~2.5 MUs MD simulations (100/200 ns for each run) for two prototypical Mg2+-dependent ribozymes showed remarkable differences in terms of populations of inner-sphere coordination site types. Most importantly, complementary DFT calculations unveiled that differences in charge transfer and polarization among recurrent Mg2+-RNA coordination motifs are surprisingly small. In particular, the charge of the Mg2+ ions substantially remains constant through different coordination sites, suggesting that the common philosophy of developing site-specific Mg2+ ion parameters is not in line with the physical origin of the Mg2+-RNA MD simulations inaccuracies. Overall, this study constitutes a guideline for an adept use of current Mg2+ models and provides novel insights for the rational development of next-generation Mg2+ FFs to be employed for atomistic simulations of RNA. PMID- 28001406 TI - Ruthenium-Catalyzed Addition of Aromatic Amides to Internal Alkynes and Subsequent Intramolecular Cyclization for the Atom-Economical Synthesis of Isoindolinones. AB - A selective and atom-economical synthesis of isoindolinones is described. This novel synthetic strategy involves two catalytic reactions: the ruthenium catalyzed regioselective alkenylation of aromatic C-H bond of aromatic amides with internal alkynes, and subsequent intramolecular cyclization of the resulting alkene with amide functionalities. The addition of only a catalytic amount of bases is required for efficient construction of the desired isoindolinones, and no byproducts are formed in the tandem catalytic reactions. Various kinds of aromatic amides and internal alkynes can be used in the present reactions, and the corresponding isoindolinones bearing a quaternary carbon at the C3 position are obtained in good to high yields. PMID- 28001407 TI - Microhydration of Neutral and Charged Acetic Acid. AB - A systematic theoretical study has been carried out on the effect of sequential addition of water molecules to neutral and mono positively charged acetic acid molecules by applying first principle based electronic structure theory. Geometry, dipole moment, and polarizability of hydrated clusters of neutral and mono positively charged acetic acid of the type CH3COOH.nH2O (n = 1-8) and [CH3COOH.nH2O]+ (n = 1, 2) are calculated at the omegaB97X-D/aug-cc-pVDZ level of theory. Free energies of formation of the hydrated acid clusters, at different temperatures and pressures are determined. Solvent stabilization energy and interaction energy are also calculated at the CCSD(T)/6-311++G(d,p) level of theory. It is observed that in the case of neutral acetic acid, proton transfer from the acid molecule to solvent water molecules does not occur even with eight water molecules and the acid molecule remains in the undissociated form. High energy equilibrium structures showing dissociation of acetic acid are obtained in case of hexahydrated and larger hydrated clusters only. However, dissociation of mono positively charged acetic acid occurs with just two water molecules. Interestingly, it is noted that in the case of dissociation, calculated bond dipole moments of the dissociating bonds of acetic acid in microhydated clusters shows a characteristic feature. IR spectra of CH3COOH.nH2O (n = 1-8) and [CH3COOH.nH2O]+ (n = 1-3) clusters are simulated and compared with the available experimental data. PMID- 28001408 TI - Ultrathin Monomolecular Films and Robust Assemblies Based on Cyclic Catechols. AB - We introduce a newly designed catechol-based compound and its application for the preparation of homogeneous monomolecular layers as well as for robust assemblies on various substrates. The precisely defined cyclic catechol material (CyCat) was prepared from ortho-dimethoxybenzene in a phenolic resin-like synthesis and subsequent deprotection, featuring molecules with up to 32 catechol units. The CyCat's chemical structure was carefully assessed via matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF), proton nuclear magnetic resonance (1H NMR), diffusion ordered spectroscopy (2D DOSY) and high resolution electrospray ionization mass spectrometry (ESI MS) experiments. The formation of colloidal aggregates of the CyCat material in alkaline solution was followed by dynamic light scattering (DLS) and further verified by dropcasting CyCat from solution on highly oriented pyrolytic graphite (HOPG), which was examined by Kelvin probe force microscopy (KPFM). The adsorption behavior of the CyCat to form monomolecular layers was investigated in real time by surface plasmon resonance (SPR). Formation of these thin CyCat layers (1.6-2.1 nm) on Au, SiO2 and TiO2 substrates was corroborated by spectroscopic ellipsometry (SE) and X-ray photoelectron spectroscopy (XPS). The prepared coating perfectly reflects the surface structure of the underlying substrate and does not exhibit CyCat colloidal aggregates as verified by atomic force microscopy (AFM). The functional nature of the prepared catechol monolayers was evidenced by reaction with 4-bromophenethylamine and bis(3-aminopropyl) terminated poly(ethylene oxide) (PEO). Multilayer assemblies were prepared by a simple procedure of iterative immersion in solutions of CyCat and a multifunctional amine on Au, SiO2 and TiO2 substrates forming thicker coatings (up to 12 nm). Postmodification with small organic molecules was performed to covalently attach trifluoroacetyl, tetrazole and 2-bromo-2-methylpropanoyl moieties to the amine groups of the multilayer assembly coating. Furthermore, the versatility of the novel multilayer coating was underpinned by "grafting-to" of phenacyl sulfide-terminated PEO and "grafting-from" of poly(methyl methacrylate) via surface-initiated atom transfer radical polymerization (ATRP). PMID- 28001409 TI - Shape Engineering Driven by Selective Growth of SnO2 on Doped Ga2O3 Nanowires. AB - Tailoring the shape of complex nanostructures requires control of the growth process. In this work, we report on the selective growth of nanostructured tin oxide on gallium oxide nanowires leading to the formation of SnO2/Ga2O3 complex nanostructures. Ga2O3 nanowires decorated with either crossing SnO2 nanowires or SnO2 particles have been obtained in a single step treatment by thermal evaporation. The reason for this dual behavior is related to the growth direction of trunk Ga2O3 nanowires. Ga2O3 nanowires grown along the [001] direction favor the formation of crossing SnO2 nanowires. Alternatively, SnO2 forms rhombohedral particles on [110] Ga2O3 nanowires leading to skewer-like structures. These complex oxide structures were grown by a catalyst-free vapor-solid process. When pure Ga and tin oxide were used as source materials and compacted powders of Ga2O3 acted as substrates, [110] Ga2O3 nanowires grow preferentially. High resolution transmission electron microscopy analysis reveals epitaxial relationship lattice matching between the Ga2O3 axis and SnO2 particles, forming skewer-like structures. The addition of chromium oxide to the source materials modifies the growth direction of the trunk Ga2O3 nanowires, growing along the [001], with crossing SnO2 wires. The SnO2/Ga2O3 junctions does not meet the lattice matching condition, forming a grain boundary. The electronic and optical properties have been studied by XPS and CL with high spatial resolution, enabling us to get both local chemical and electronic information on the surface in both type of structures. The results will allow tuning optical and electronic properties of oxide complex nanostructures locally as a function of the orientation. In particular, we report a dependence of the visible CL emission of SnO2 on its particular shape. Orange emission dominates in SnO2/Ga2O3 crossing wires while green-blue emission is observed in SnO2 particles attached to Ga2O3 trunks. The results show that the Ga2O3-SnO2 system appears to be a benchmark for shape engineering to get architectures involving nanowires via the control of the growth direction of the nanowires. PMID- 28001410 TI - Synthesis of Aryl(2,4,6-trimethoxyphenyl)iodonium Trifluoroacetate Salts. AB - The direct synthesis of aryl(2,4,6-trimethoxyphenyl)iodonium trifluoroacetate salts from aryl iodides is described. Stoichiometric quantities of trifluoroacetic acid and trimethoxybenzene are used as the counteranion and auxiliary precursors, respectively, under oxidizing conditions. The reaction occurs at mild temperature, is broad in scope, and does not require a separate anion exchange step to install the trifluoroacetate group. The intermediacy of two distinct dicarboxy aryl-lambda3-iodanes is hypothesized in the mechanism. PMID- 28001411 TI - NHC as the Guiding Factor in a Copper-Catalyzed Intramolecular C Arylation of Pyrrolylimidazolium Salts: Synthesis of Luminescent Heterotetracyclic Frameworks. AB - 3-(2/4-(2-Bromophenyl)-1H-pyrrol-3-yl)-1H-imidazol-3-ium bromides undergo a copper-catalyzed intramolecular direct C arylation under mild conditions to give new heterocyclic frameworks. The cyclizations involve the formation of betaines (imidazoliumylpyrrolides) under basic conditions and the tautomerizaton of the betaines to the corresponding NHCs, which are the reactive species responsible for the selectivity of the arylation via the formation of NHC-Cu complexes. The primary salt arylation products were dehydrohalogenated to obtain the first representatives of 7H-imidazo[2,1-a]pyrrolo[3,2-c]isoquinoline and 1H-imidazo[2,1 a]pyrrolo[3,4-c]isoquinoline heterocyclic skeletons, which were further transformed into thermodynamically more stable 1H- and 6H-tautomers, respectively, by removing of the benzyl-PG. The new heterotetracyclic systems are fluorescent in solutions with high quantum yields. PMID- 28001412 TI - Facet-Dependent Photoreduction on Single ZnO Crystals. AB - Photocatalytic reactions occur at the crystal-solution interface, and hence specific crystal facet expression and surface defects can play an important role. Here we investigate the structure-related photoreduction at zinc oxide (ZnO) microparticles via integrated light and electron microscopy in combination with silver metal photodeposition. This enables a direct visualization of the photoreduction activity at specific crystallographic features. It is found that silver nanoparticle photodeposition on dumbbell-shaped crystals mainly takes place at the edges of O-terminated (0001) polar facets. In contrast, on ZnO microrods photodeposition is more homogeneously distributed with an increased activity at {1011} facets. Additional time-resolved measurements reveal a direct spatial link between the enhanced photoactivity and increased charge carrier lifetimes. These findings contradict previous observations based on indirect, bulk-scale experiments, assigning the highest photocatalytic activity to polar facets. The presented research demonstrates the need for advanced microscopy techniques to directly probe the location of photocatalytic activity. PMID- 28001413 TI - Correction to Coupled Cluster Method with Single and Double Excitations Tailored by Matrix Product State Wave Functions. PMID- 28001414 TI - Syn Selective Vinylogous Mukaiyama Aldol Reaction Using Z,E-Vinylketene N,O Acetal with Acetals. AB - Stereoselective vinylogous Mukaiyama aldol reactions using the Z,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary, derived from (E)-3-pentenoic acid and l-valine, have been achieved. The reaction proceeded smoothly to give a syn adduct in high stereoselectivity. Since the products possess structures including delta-alkoxy-gamma-methyl-alpha,beta-unsaturated imide, this reaction would be applicable to synthesize polyketides in a short procedure. PMID- 28001415 TI - Why Is Direct Glycosylation with N-Acetylglucosamine Donors Such a Poor Reaction and What Can Be Done about It? AB - The monosaccharide N-acetyl-d-glucosamine (GlcNAc) is an abundant building block in naturally occurring oligosaccharides, but its incorporation by chemical glycosylation is challenging since direct reactions are low yielding. This issue, generally agreed upon to be caused by an intermediate 1,2-oxazoline, is often bypassed by introducing extra synthetic steps to avoid the presence of the NHAc functional group during glycosylation. The present paper describes new fundamental mechanistic insights into the inherent challenges of performing direct glycosylation with GlcNAc. These results show that controlling the balance of oxazoline formation and glycosylation is key to achieving acceptable chemical yields. By applying this line of reasoning to direct glycosylation with a traditional thioglycoside donor of GlcNAc, which otherwise affords poor glycosylation yields, one may obtain useful glycosylation results. PMID- 28001417 TI - Palladium-Catalyzed Three-Component Reaction of Propargyl Carbonates, Isocyanides, and Alcohols or Water: Switchable Synthesis of Pyrroles and Its Bicyclic Analogues. AB - In the presence of a catalytic amount of Pd(OAc)2 and a stoichiometric amount of tert-butylamine, the reaction of propargyl carbonates, isocyanides, and alcohols afforded polysubstituted aminopyrroles in good yields. Using water as a nucleophile instead of alcohol, the same reaction provided 1,4-dihydro-6H furo[3,4-b]pyrrol-6-imines. A triple isocyanide insertion to the hypothetic (sigma-allenyl)palladium(II) intermediate was involved in these ABC3-type multicomponent reactions. The key role of tert-butylamine was accounted for by its reaction with in situ generated carbon dioxide to form the carbamic acid, which in turn served as a nucleophile to trap the nitrilium intermediate. PMID- 28001416 TI - Tobacco-Specific Nitrosamines in the Tobacco and Mainstream Smoke of U.S. Commercial Cigarettes. AB - Tobacco-specific nitrosamines (TSNAs) are N-nitroso-derivatives of pyridine alkaloids (e.g., nicotine) present in tobacco and cigarette smoke. Two TSNAs, N' nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are included on the Food and Drug Administration's list of harmful and potentially harmful constituents (HPHCs) in tobacco products and tobacco. The amounts of four TSNAs (NNK, NNN, N-nitrosoanabasine (NAB), and N' nitrosoanatabine (NAT)) in the tobacco and mainstream smoke from 50 U.S. commercial cigarette brands were measured from November 15, 2011 to January 4, 2012 using a validated HPLC/MS/MS method. Smoke samples were generated using the International Organization of Standardization (ISO) and Canadian Intense (CI) machine-smoking regimens. NNN and NAT were the most abundant TSNAs in tobacco filler and smoke across all cigarette brands, whereas NNK and NAB were present in lesser amounts. The average ratios for each TSNA in mainstream smoke to filler content is 29% by the CI smoking regimen and 13% for the ISO machine-smoking regimen. The reliability of individual TSNAs to predict total TSNA amounts in the filler and smoke was examined. NNN, NAT, and NAB have a moderate to high correlation (R2 = 0.61-0.98, p < 0.0001), and all three TSNAs individually predict total TSNAs with minimal difference between measured and predicted total TSNA amounts (error < 7.4%). NNK has weaker correlation (R2 = 0.56-0.82; p < 0.0001) and is a less reliable predictor of total TSNA quantities. Tobacco weight and levels of TSNAs in filler influence TSNA levels in smoke from the CI machine smoking regimen. In contrast, filter ventilation is a major determinant of levels of TSNAs in smoke by the ISO machine-smoking regimen. Comparative analysis demonstrates substantial variability in TSNA amounts in tobacco filler and mainstream smoke yields under ISO and CI machine-smoking regimens among U.S. commercial cigarette brands. PMID- 28001419 TI - Secondary Amides as Hydrogen Atom Transfer Promoters for Reactions of Samarium Diiodide. AB - Two secondary amides (N-methylacetamide and 2-pyrrolidinone) were used as additives with SmI2 in THF to estimate the extent of N-H bond weakening upon coordination. Mechanistic and synthetic studies demonstrate significant bond weakening, providing a reagent system capable of reducing a range of substrates through formal hydrogen atom transfer. PMID- 28001418 TI - Toward Closing the Gap: Quantum Mechanical Calculations and Experimentally Measured Chemical Shifts of a Microcrystalline Lectin. AB - NMR chemical shifts are exquisitely sensitive probes for conformation and dynamics in molecules and supramolecular assemblies. Although isotropic chemical shifts are easily measured with high accuracy and precision in conventional NMR experiments, they remain challenging to calculate quantum mechanically, particularly in inherently dynamic biological systems. Using a model benchmark protein, the 133-residue agglutinin from Oscillatoria agardhii (OAA), which has been extensively characterized by us previously, we have explored the integration of X-ray crystallography, solution NMR, MAS NMR, and quantum mechanics/molecular mechanics (QM/MM) calculations for analysis of 13Calpha and 15NH isotropic chemical shifts. The influence of local interactions, quaternary contacts, and dynamics on the accuracy of calculated chemical shifts is analyzed. Our approach is broadly applicable and expected to be beneficial in chemical shift analysis and chemical-shift-based structure refinement for proteins and protein assemblies. PMID- 28001420 TI - Modifying the Interface Edge to Control the Electrical Transport Properties of Nanocontacts to Nanowires. AB - Selecting the electrical properties of nanomaterials is essential if their potential as manufacturable devices is to be reached. Here, we show that the addition or removal of native semiconductor material at the edge of a nanocontact can be used to determine the electrical transport properties of metal-nanowire interfaces. While the transport properties of as-grown Au nanocatalyst contacts to semiconductor nanowires are well-studied, there are few techniques that have been explored to modify the electrical behavior. In this work, we use an iterative analytical process that directly correlates multiprobe transport measurements with subsequent aberration-corrected scanning transmission electron microscopy to study the effects of chemical processes that create structural changes at the contact interface edge. A strong metal-support interaction that encapsulates the Au nanocontacts over time, adding ZnO material to the edge region, gives rise to ohmic transport behavior due to the enhanced quantum mechanical tunneling path. Removal of the extraneous material at the Au-nanowire interface eliminates the edge-tunneling path, producing a range of transport behavior that is dependent on the final interface quality. These results demonstrate chemically driven processes that can be factored into nanowire-device design to select the final properties. PMID- 28001421 TI - Apparent Contact Angle Calculated from a Water Repellent Model with Pinning Effect. AB - A set of new theoretical equations for apparent contact angles is proposed. The equations are derived from an equilibrium of interfacial tensions of a three phase contact line pinned at the edges of a fine structure. These equations are validated by comparison with contact-angle measurement results for 2 MUL water droplets on poly(methyl methacrylate) microstructured samples with square pillars or holes. The equilibrium contact angles predicted by the new equations reasonably agree with the experimental results. In contrast, the values predicted by the Cassie-Baxter equation or the Wenzel equation do not qualitatively agree with the experimental results in pillar pattern cases because the Cassie-Baxter equation and the Wenzel equation do not account for the pinning effect. PMID- 28001422 TI - Iodocyclization of N-Arylpropynamides Mediated by Hypervalent Iodine Reagent: Divergent Synthesis of Iodinated Quinolin-2-ones and Spiro[4,5]trienones. AB - PhI(OCOCF3)2 acts as both a nonmetal oxidant and an iodination reagent to trigger iodocyclization of N-arylpropynamides while selectively affording iodinated quinolin-2-ones or the spiro[4,5]trienone skeleton, depending on the substituent pattern. In cases where the N-arylpropynamide bears a para-fluorine on the aniline ring, the spiro compound is formed via an exclusive defluorination process; otherwise, the product was quinolin-2-one. PMID- 28001423 TI - Modeling of Transient Absorption Spectra in Exciton-Charge-Transfer Systems. AB - Time-resolved spectroscopy provides the main tool for analyzing the dynamics of excitonic energy transfer in light-harvesting complexes. Inferring the time scales and effective coupling parameters from experimental data requires the development of numerically exact theoretical models. The finite duration of the laser-molecule interactions and the reorganization process during the exciton migration affect the location and strength of spectroscopic signals. We show that the nonperturbative hierarchical equations of motion method captures these processes in a model exciton system, including the charge-transfer state. PMID- 28001424 TI - Beyond the Five and Six: Evaluation of Seven-Membered Cyclic Anhydrides in the Castagnoli-Cushman Reaction. AB - The Castagnoli-Cushman reaction with benzo[d]oxepine-2,4(1H,5H)-dione as an anhydride component allowed for preparation of 2,3-disubstituted 4-oxo-2,3,4,5 tetrahydro-1H-benzo[d]azepine-1-carboxylic acids in 21-75% yields and with good trans diastereoselectivity. The method worked with imines generated from aromatic or alpha-branched aliphatic aldehydes and is amenable for both parallel synthesis and scale-up. The procedure for epimerization of the resulting trans disubstituted tetrahydrobenzo[d]azepines to their cis isomers was also developed. PMID- 28001425 TI - Gold-Catalyzed Intramolecular Regioselective 7-exo-dig Cyclization To Access 3 Methylene-3,4-dihydrobenzo[b]oxepinones. AB - An efficient gold-catalyzed synthesis of substituted 3-methylene-3,4 dihydrobenzo[b]oxepinones from ortho-O-propargyl substituted aryl enaminones has been achieved. In this transformation a new C-C bond formation occurred regioselectively via 7-exo-dig cyclization. Benzooxepinone derivatives were obtained in good to excellent yields in a one-pot synthesis at ambient temperature. PMID- 28001426 TI - One-Pot Synthesis and Structure-Property Relationship of Aminomaleimides: Fluorescence Efficiencies in Monomers and Aggregates Easily Tuned by Switch of Aryl and Alkyl. AB - Organic fluorophores have attracted great interest owing to their wide applications. They usually contain an electron-conjugated system with an aromatic moiety and show high emission in dilute solutions but weaker or even no emission upon aggregation. Here, a simple one-pot, three-component reaction (3CR) (method I) for the synthesis of various di- and monosubstituted aminomaleimides (DAMIs and MAMIs) has been developed, and the reported 3CR (method II) has been found to be efficient only for the synthesis of MAMIs with R2 = alkyl. Twelve AMIs were designed and synthesized for investigation of the influence of structures on their optical properties in monomers and aggregates. It was found that alkyl MAMIs, alkyl DAMIs, and aryl AMIs/DAMIs show very different fluorescence efficiencies in different solvents, and only MAMIs with butyl and oleyl show high emissions in powders similar to those in nonpolar solutions. Single-crystal structures indicate that their fluorescence efficiencies in aggregates mainly correlate with molecular packing modes. The efficient synthesis method, the sensitive fluorescence on-off response to protic solvents or polar solvents, and the unusual high emissions of AMI without any aromatic moiety in both monomer and aggregates are expected to attract great interest in the fields of application and theory. PMID- 28001428 TI - Energy Dissipation of Moving Drops on Superhydrophobic and Superoleophobic Surfaces. AB - A water drop moving on a superhydrophobic surface or an oil drop moving on a superoleophobic surface dissipates energy by pinning/depinning at nano- and microprotrusions. Here, we calculate the work required to form, extend, and rupture capillary bridges between the protrusions and the drop. The energy dissipated at one protrusion WS is derived from the observable apparent receding contact angle Thetarapp and the density of protrusions n by Ws = gamma(cos Thetarapp + 1)/n, where gamma is the surface tension of the liquid. To derive an expression for Ws that links the microscopic structure of the surface to apparent contact angles, two models are considered: A superhydrophobic array of cylindrical micropillars and a superoleophobic array of stacks of microspheres. For a radius of a protrusion R and a receding materials contact angle Thetar, we calculate the energy dissipated per protrusion as Ws = pigammaR2[A - ln(R/kappa)]f(Thetar). Here, A = 0.60 for cylindrical micropillars and 2.9 for stacks of spheres. kappa is the capillary length. f(Thetar) is a function which depends on Thetar and the specific geometry, f ranges from ~0.25 to 0.96. Combining both equations above, we can correlate the macroscopically observed apparent receding contact angle with the microscopic structure of the surface and its material properties. PMID- 28001427 TI - O-Acetyl Side-Chains in Monosaccharides: Redundant NMR Spin-Couplings and Statistical Models for Acetate Ester Conformational Analysis. AB - alpha- and beta-d-glucopyranose monoacetates 1-3 were prepared with selective 13C enrichment in the O-acetyl side-chain, and ensembles of 13C-1H and 13C-13C NMR spin-couplings (J-couplings) were measured involving the labeled carbons. Density functional theory (DFT) was applied to a set of model structures to determine which J-couplings are sensitive to rotation of the ester bond theta. Eight J couplings (1JCC, 2JCH, 2JCC, 3JCH, and 3JCC) were found to be sensitive to theta, and four equations were parametrized to allow quantitative interpretations of experimental J-values. Inspection of J-coupling ensembles in 1-3 showed that O acetyl side-chain conformation depends on molecular context, with flanking groups playing a dominant role in determining the properties of theta in solution. To quantify these effects, ensembles of J-couplings containing four values were used to determine the precision and accuracy of several 2-parameter statistical models of rotamer distributions across theta in 1-3. The statistical method used to generate these models has been encoded in a newly developed program, MA'AT, which is available for public use. These models were compared to O-acetyl side-chain behavior observed in a representative sample of crystal structures, and in molecular dynamics (MD) simulations of O-acetylated model structures. While the functional form of the model had little effect on the precision of the calculated mean of theta in 1-3, platykurtic models were found to give more precise estimates of the width of the distribution about the mean (expressed as circular standard deviations). Validation of these 2-parameter models to interpret ensembles of redundant J-couplings using the O-acetyl system as a test case enables future extension of the approach to other flexible elements in saccharides, such as glycosidic linkage conformation. PMID- 28001429 TI - Single-Crystalline Hexagonal Silicon-Germanium. AB - Group IV materials with the hexagonal diamond crystal structure have been predicted to exhibit promising optical and electronic properties. In particular, hexagonal silicon-germanium (Si1-xGex) should be characterized by a tunable direct band gap with implications ranging from Si-based light-emitting diodes to lasers and quantum dots for single photon emitters. Here we demonstrate the feasibility of high-quality defect-free and wafer-scale hexagonal Si1-xGex growth with precise control of the alloy composition and layer thickness. This is achieved by transferring the hexagonal phase from a GaP/Si core/shell nanowire template, the same method successfully employed by us to realize hexagonal Si. We determine the optimal growth conditions in order to achieve single-crystalline layer-by-layer Si1-xGex growth in the preferred stoichiometry region. Our results pave the way for exploiting the novel properties of hexagonal Si1-xGex alloys in technological applications. PMID- 28001430 TI - Anomalous Strain Relaxation in Core-Shell Nanowire Heterostructures via Simultaneous Coherent and Incoherent Growth. AB - Nanoscale substrates such as nanowires allow heterostructure design to venture well beyond the narrow lattice mismatch range restricting planar heterostructures, owing to misfit strain relaxing at the free surfaces and partitioning throughout the entire nanostructure. In this work, we uncover a novel strain relaxation process in GaAs/InxGa1-xAs core-shell nanowires that is a direct result of the nanofaceted nature of these nanostructures. Above a critical lattice mismatch, plastically relaxed mounds form at the edges of the nanowire sidewall facets. The relaxed mounds and a coherent shell grow simultaneously from the beginning of the deposition with higher lattice mismatches increasingly favoring incoherent mound growth. This is in stark contrast to Stranski-Krastanov growth, where above a critical thickness coherent layer growth no longer occurs. This study highlights how understanding strain relaxation in lattice mismatched nanofaceted heterostructures is essential for designing devices based on these nanostructures. PMID- 28001431 TI - The relationship between family functioning and caregiving appraisal of dementia family caregivers: caregiving self-efficacy as a mediator. AB - OBJECTIVES: The aim of this study was to explore caregiving self-efficacy as a mediator for the association between family functioning and caregiving appraisal of dementia family caregivers in Taiwan. METHOD: This study adopted a cross sectional correlational design. Purposive sampling was used to recruit 115 dyads of dementia patients and family caregivers from the outpatient neurological clinics of two hospitals in northern Taiwan. Data were gathered through interviews with a structured questionnaire, which included demographic characteristics for caregivers and patients, family functioning, caregiving self efficacy, as well as positive and negative aspects of caregiving appraisal. RESULTS: Family functioning, patients' activities of daily living score, Neuropsychiatric Inventory caregiver distress, and three domains of self-efficacy were significantly associated with caregiver burden. Hierarchical multiple regression analyses indicated that self-efficacy for obtaining respite (SE-OR) significantly explained 20.5% of the variance in caregiver esteem. Caregiver perceived worsened health status, family functioning, and SE-OR significantly explained 59% of the variance in caregiver burden. The mediation test only supported the partially mediating role of SE-OR on the relationship between family functioning and caregiver burden, while the mediating effect of self efficacy for responding to disruptive behaviours and controlling upsetting thoughts were insignificant. CONCLUSION: Our findings provided preliminary evidence for health professionals recommending that future studies should assess the family dynamic and health problems of caregivers, and develop appropriate family-centred interventions that focus on strengthening interfamily support and respite services to alleviate caregiver burden. PMID- 28001432 TI - Avi Sadeh, DSc (1957-2016). PMID- 28001433 TI - Capsaicin and capsiate could be appropriate agents for treatment of obesity: A meta-analysis of human studies. AB - Consumption of capsaicin or its nonpungent analogues, capsinoids has been reported to affect energy expenditure and fat oxidation, although available data are still controversial. The aim of the present study was to conduct a meta analysis regarding the effects of these substances on energy expenditure and respiratory quotient, with special emphasis on the role of body mass index (BMI) of the participants. Medical databases were systematically searched for papers. Of the 627 trials identified, 9 provided results suitable to be included in analysis. Data analysis showed that after ingestion of capsaicin or capsinoids the energy expenditure increased (245 kJ/day, 58.56 kcal/day, p = 0.030) and the respiratory quotient decreased (by 0.216; p = 0.031) indicating a rise in fat oxidation. Studies with mean BMI of the participants below 25 kg/m2 failed to report any effect of capsaicin or capsinoids on the energy expenditure (p = 0.718) or on the respiratory quotient (p = 0.444), but studies with mean BMI exceeding 25 kg/m2 demonstrated an increase in energy expenditure (292 kJ/day, 69.79 kcal/day, p = 0.023) and a marked decrease in respiratory quotient (-0.257, p = 0.036). Our data clearly suggest that capsaicin or capsiate could be a new therapeutic approach in obesity promoting a negative energy balance and increased fat oxidation. PMID- 28001434 TI - Efficacy and Safety of Insulin Therapy in Patients with Type 2 Diabetes Treated at Different Grades of Hospitals in China: Subgroup Analysis of the Real-World SEAS Study. AB - BACKGROUNDS: As patients attending hospitals of different grades in China may receive different medical care, we investigated the clinical efficacy and safety of routine insulin therapy in patients with type 2 diabetes who were treated at grade 2 and grade 3 (highest grade) hospitals in China. METHODS: 2683 patients with type 2 diabetes were enrolled in a multicenter, nonrandomized, open-label, noninterventional, 12-week clinical trial performed at 62 Chinese hospitals. Patients were divided into two groups according to the hospitals' grading. Data were analyzed for efficacy (changes and normalization of glycated hemoglobin [HbA1c] and changes in fasting plasma glucose and 2-h postprandial blood glucose [PBG] levels from baseline to the final visit) and for safety (hypoglycemia). RESULTS: After 12 weeks of routine human insulin (SciLin) therapy, decreases in mean HbA1c and PBG levels were significantly greater in patients treated at second-grade hospitals (all P < 0.001 vs. third-grade hospitals), and the HbA1c success rate (<7%) was significantly higher (46.94% vs. 38.85%; P = 0.0002). However, patients treated at second-grade hospitals had more weight gain (0.29 kg vs. 0.04 kg; P < 0.0001) and a higher incidence of total hypoglycemic events (21.82% vs. 16.79%; P = 0.0002). CONCLUSIONS: Routine insulin treatment of patients with type 2 diabetes in China demonstrates acceptable safety and effectiveness, improving blood glucose control with a low incidence of severe hypoglycemia. Patients treated at second-grade hospitals had a greater HbA1c success rate than those treated at third-grade hospitals, but with more weight gain and more hypoglycemic events. PMID- 28001435 TI - How should physical exercise be used in schizophrenia treatment? PMID- 28001436 TI - Teaching Resident Self-Assessment Through Triangulation of Faculty and Patient Feedback. AB - PROBLEM: To accurately determine one's ability in any clinical competency, an individual must be able to self-assess performance and identify personal limitations. Existing research demonstrates that physicians of all levels are unreliable self-assessors. This poses a concern in medical practice, which requires continuous updates to clinical competencies and awareness of personal limitations. Few published studies examine graduate medical education curricula designed to develop self-assessment skills. INTERVENTION: Conceptual models, such as self-determination theory, suggest that self-assessment is most effectively learned through reflective processes. The Family Medicine Residency Program at Lehigh Valley Health Network developed a learner-centered competency assessment process that integrates advising and performance review. The multisource, observable behavior-based process encourages conversation between resident and advisor. Utilizing feedback from clinical preceptors and patient surveys, advisors guide residents in determining individual learning needs in core competency areas, including relationship-centered care. Development of medical learners' capacity to form relationships is one means to improving the patient experience. CONTEXT: This retrospective case study evaluates the accuracy of senior residents' self-assessment in relationship-centered care compared with that of junior residents. The study population includes the 34 residents enrolled from AY 2009-2012. Data sets represent specific 6-month periods and have 3 component scores-Self, Faculty, and Patient-which were triangulated to determine concordance rates by postgraduate year level. OUTCOME: The concordance rate among first-years was 26.7%, whereas third-years saw 60.0% concordance. A discordance analysis found the Patient score most often deviated from the other 2 scores, whereas the Faculty score was never the sole dissenter. When all 3 scores differed, the Self score frequently fell between the other 2 scores. LESSONS LEARNED: The principles of self-determination theory provide a valuable framework for understanding the development of residents' intrinsic motivation to become lifelong learners. The trend in improved concordance rates among senior residents suggests that prompting learners to triangulate feedback from multiple sources can lead to a shift in perspective about competency. Further study is needed to determine whether our results are generalizable to other competencies and educational settings. PMID- 28001437 TI - Garp as a therapeutic target for modulation of T regulatory cell function. AB - INTRODUCTION: Foxp3+ T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-beta. As Treg-derived TGF-beta may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity. Areas covered: This article will focus on 1) the role of Treg-derived TGF-beta in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-beta/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-beta/GARP complex. Expert opinion: Two approaches are outlined for targeting the L-TGF-beta1/GARP complex for therapeutic purposes. Tregs play a major role in suppressive effector T cell responses to tumors and TGF-beta1 may be a major contributor to this process. One approach is to specifically block the production of active TGF-beta1 from Tregs as an adjunct to tumor immunotherapy. The second approach in autoimmunity is to selectively enhance the production of TGF-beta by Tregs at sites of chronic inflammation. PMID- 28001438 TI - Isolation and characterization of wetland VSW-3, a novel lytic cold-active bacteriophage of Pseudomonas fluorescens. AB - Wetlands are often called the "kidneys of the Earth" and contribute substantially to environmental improvement. Pseudomonas fluorescens is a major contaminant of milk products and causes the spoilage of refrigerated foods and fresh poultry. In this study, we isolated and characterized a lytic cold-active bacteriophage named VSW-3 together with P. fluorescens SW-3 cells from the Napahai wetland in China. Electron microscopy showed that VSW-3 had an icosahedral head (56 nm) and a tapering tail (20 nm * 12 nm) and a genome size of approximate 40 kb. On the basis of the top-scoring hits in the BLASTP analysis, VSW-3 showed a high degree of module similarity to the Pseudomonas phages Andromeda and Bf7. The latent and burst periods were 45 and 20 min, respectively, with an average burst size of 90 phage particles per infected cell. The pH and thermal stability of VSW-3 were also explored. The optimal pH was found to be 7.0 and the activity decreased rapidly when the temperature exceeded 60 degrees C. VSW-3 is a cold-active bacteriophage, hence, it is important to research its ability to prevent product contamination caused by P. fluorescens and to characterize its relationship with its host P. fluorescens in the future. PMID- 28001439 TI - Tackling myocardial ischemic injury: the signal transducer and activator of transcription 3 (STAT3) at a good site. AB - INTRODUCTION: Myocardial ischemia is one of the main causes of cardiac remodeling and heart failure. As a highly evolutionarily conserved pathway, the signal transducer and activator of transcription 3 (STAT3) signaling controls intercellular communication, signaling transduction and gene transcription. Interestingly, STAT3 signaling has been demonstrated to take part in myocardial ischemia. Furthermore, activation of STAT3 signaling contributes to the protective efficacy of various interventions, including pharmacological and non pharmacological treatment of myocardial ischemic injury. Areas covered: We first introduce the protective mechanisms of STAT3. We then discuss STAT3 signaling in various cells and the roles of STAT3 in myocardial processes during myocardial ischemia. Finally, the roles of STAT3 in myocardial ischemia and the upstream regulators of STAT3 activation are summarized. Expert opinion: In various animal experiments, STAT3 has been demonstrated to take part in myocardial responses to myocardial ischemic injury and to be activated during various modes of protection against myocardial ischemia and ischemia/reperfusion (I/R) injury. However, further clinical evidence on the role of STAT3 in such protection is needed. Treatments targeting STAT3 as a means of reducing myocardial ischemic injury need to be tested in a clinical setting. Furthermore, biotechnology can be used to develop effective drugs for this purpose. PMID- 28001440 TI - Who Believes in the Storybook Image of the Scientist? AB - Do lay people and scientists themselves recognize that scientists are human and therefore prone to human fallibilities such as error, bias, and even dishonesty? In a series of three experimental studies and one correlational study (total N = 3,278) we found that the "storybook image of the scientist" is pervasive: American lay people and scientists from over 60 countries attributed considerably more objectivity, rationality, open-mindedness, intelligence, integrity, and communality to scientists than to other highly-educated people. Moreover, scientists perceived even larger differences than lay people did. Some groups of scientists also differentiated between different categories of scientists: established scientists attributed higher levels of the scientific traits to established scientists than to early-career scientists and Ph.D. students, and higher levels to Ph.D. students than to early-career scientists. Female scientists attributed considerably higher levels of the scientific traits to female scientists than to male scientists. A strong belief in the storybook image and the (human) tendency to attribute higher levels of desirable traits to people in one's own group than to people in other groups may decrease scientists' willingness to adopt recently proposed practices to reduce error, bias and dishonesty in science. PMID- 28001441 TI - Developing a Motion Comic for HIV/STD Prevention for Young People Ages 15-24, Part 1: Listening to Your Target Audience. AB - Young people (15-24 years) in the United States are disproportionately affected by infection with human immunodeficiency virus (HIV) and sexually transmitted diseases (STD). Shortfalls in HIV/STD-related knowledge, attitudes, beliefs, and behavioral intentions (KABI) likely contribute to this discrepancy. In this report we describe our experience developing a novel means of health communication combining entertainment-education theory and recent technological advances to create a HIV/STD-focused "motion comic." We also report the audience satisfaction and acceptance of the intervention. We used the Health Belief Model (HBM), entertainment-education (EE) principles, and the Sabido Method (SM) and conducted three rounds of focus groups to develop a 38-minute HIV/STD focused motion comic for young people between the ages 15 and 24 years. Participants indicated that motion comics were an acceptable method of delivering HIV/STD prevention messages. They also expressed satisfaction with motion comics plot, story settings, the tone of humor, and drama. Our results suggest that motion comics are a viable new method of delivering health communication messages about HIV/STD and other public health issues, and warrant further development and broader evaluation. PMID- 28001442 TI - "It's Just Not the Culture": A Qualitative Study Exploring Residents' Perceptions of the Impact of Institutional Culture on Feedback. AB - : Phenomenon: Competency-based medical education requires ongoing performance based feedback for professional growth. In several studies, medical trainees report that the quality of faculty feedback is inadequate. Sociocultural barriers to feedback exchanges are further amplified in graduate and postgraduate medical education settings, where trainees serve as frontline providers of patient care. Factors that affect institutional feedback culture, enhance feedback seeking, acceptance, and bidirectional feedback warrant further exploration in these settings. APPROACH: Using a constructivist grounded theory approach, we sought to examine residents' perspectives on institutional factors that affect the quality of feedback, factors that influence receptivity to feedback, and quality and impact of faculty feedback. Four focus group discussions were conducted, with two investigators present at each. One facilitated the discussion, and the other observed the interactions and took field notes. We audiotaped and transcribed the discussions, and performed a thematic analysis. Measures to ensure rigor included thick descriptions, independent coding by two investigators, and attention to reflexivity. FINDINGS: We identified five key themes, dominated by resident perceptions regarding the influence of institutional feedback culture. The theme labels are taken from direct participant quotes: (a) the cultural norm lacks clear expectations and messages around feedback, (b) the prevailing culture of niceness does not facilitate honest feedback, (c) bidirectional feedback is not part of the culture, (d) faculty-resident relationships impact credibility and receptivity to feedback, and (e) there is a need to establish a culture of longitudinal professional growth. Insights: Institutional culture could play a key role in influencing the quality, credibility, and acceptability of feedback. A polite culture promotes a positive learning environment but can be a barrier to honest feedback. Feedback initiatives focusing solely on techniques of feedback giving may not enhance meaningful feedback. Further research on factors that promote feedback seeking, receptivity to constructive feedback, and bidirectional feedback would provide valuable insights. PMID- 28001443 TI - Restoring BMPRII functions in pulmonary arterial hypertension: opportunities, challenges and limitations. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in pulmonary arterial pressures. The discovery of heterozygous BMPR2 germline mutations as critical predisposing factors together with a remarkable progress in our understanding of the pathogenic mechanisms have helped identify the significant and complex roles of the BMPRII axis in PAH. However, their precise contributions to the condition are still incompletely understood. Areas covered: This review aims to assemble and discuss the cellular actions of BMPs together with the possible clinical applications and prospects for their use in the near future. Expert opinion: Although major advances have been made, several questions remain unanswered regarding development of efficacious therapies targeting the BMPRII axis in PAH. Specifically, the reasons why BMPRII signaling is reduced in PAH and how the alterations influence or even drive the pathogenesis need to be understood. Because the BMPRII axis is ubiquitously expressed and exhibits a wide variety of functions in organ regeneration and homeostasis, a better understanding of the overall risk-benefit ratio of these strategies with long-term follow-up is needed. This knowledge will lay the foundation for discovery of innovative therapeutics for PAH. PMID- 28001445 TI - Long-Term Efficacy and Safety of Sensor Augmented Insulin Pump Therapy with Low Glucose Suspend Feature in Patients with Type 1 Diabetes. AB - BACKGROUND: Literature supports short-term efficacy and safety of Sensor Augmented Insulin Pump (SAP) therapy in patients with type 1 diabetes (T1D). However, no data are available showing long-term outcomes. Our study describes the long-term outcomes of SAP therapy with low-glucose suspend feature (SAP+LGS) in hypoglycemia in a Colombian population with T1D and hypoglycemia. METHODS: A cohort study was conducted with T1D patients receiving SAP+LGS therapy who initiated this therapy because of hypoglycemia at San Ignacio University Hospital diabetes center in Bogota, Colombia. Glycated hemoglobin (A1c) was assessed at least every 6 months, severe hypoglycemia (SH) and hypoglycemia unawareness (HU) incidence yearly. Adherence to therapy was also evaluated. RESULTS: One hundred eleven patients were included in the analysis. Total daily insulin dose was reduced during follow-up (mean difference -0.22 U/kg; 95% confidence interval [CI] -0.18 to -0.26; P < 0.001). A1c levels were reduced from a baseline value of 8.8% +/- 1.9% to 7.5% +/- 1.0% at 5 months (mean difference -1.3%; 95% CI -1.09 to -1.50; P < 0.001) and 7.1% +/- 0.8% (mean difference -1.7%; 95% CI -1.59 to 1.90; P < 0.001) at the end of follow-up (47 months on average). The incidence of SH and HU episodes decreased significantly since the first year, and this effect was maintained over time (P < 0.001). CONCLUSIONS: SAP+LGS therapy in T1D patients with hypoglycemia led to a significant and sustained decrease in A1c during long periods of follow-up, as well as a significant reduction in SH and HU. Future randomized clinical trials are desired. PMID- 28001446 TI - Evidence-Based Treatments for Youths Who Engage in Illegal Sexual Behaviors. AB - Effective treatments for youths who have engaged in illegal sexual behaviors are needed to reduce the societal impact of sexual crimes. This article reviews the state of the evidence base for treatments that target this clinical population. We conducted a comprehensive literature review to identify studies that evaluated outcomes of treatments for youths who have engaged in illegal sexual behaviors. Based on the results of our review, we characterized each treatment using established criteria for five evidence-based treatment classifications. We identified 10 treatment studies that met inclusion criteria. We classified one treatment-multisystemic therapy for problem sexual behaviors-as Probably Efficacious (Level 2), and two treatments-cognitive-behavioral therapy and behavior management through adventure-as Experimental (Level 4). Cognitive behavioral therapy has limited research support with youths who have engaged in illegal sexual behaviors, but it is widely used in the United States and Canada. In contrast, multisystemic therapy for problem sexual behaviors had the highest level of research support but is used much less extensively with this population. We discuss implications of the present findings for treatment providers, policymakers, and researchers who seek to improve clinical services in this area. PMID- 28001444 TI - Vitamin D Receptor Expression in Plasmablastic Lymphoma and Myeloma Cells Confers Susceptibility to Vitamin D. AB - Plasmablastic B-cell malignancies include plasmablastic lymphoma and subsets of multiple myeloma and diffuse large B-cell lymphomaDLBCL. These diseases can be difficult to diagnose and treat, and they lack well-characterized cell line models. Here, immunophenotyping and FOXP1 expression profiling identified plasmablastic characteristics in DLBCL cell lines HLY-1 and SU-DHL-9, associated with CTNNAL1, HPGD, RORA, IGF1, and/or vitamin D receptor (VDR) transcription. We demonstrated VDR protein expression in primary plasmablastic tumor cells and confirmed in cell lines expression of both VDR and the metabolic enzyme CYP27B1, which catalyzes active vitamin D3 production. Although Vdr and Cyp27b1 transcription in normal B cells were activated by interleukin 4 (IL-4) and CD40 signaling, respectively, unstimulated malignant plasmablastic cells lacking IL-4 expressed both VDR and CYP27B1. Positive autoregulation evidenced intact VDR function in all plasmablastic lines, and inhibition of growth by active vitamin D3 was both dependent on MYC protein inhibition and could be enhanced by cotreatment with a synthetic ROR ligand SR-1078. Furthermore, a VDR polymorphism, FOK1, was associated with greater vitamin D3-dependent growth inhibition. In summary, HLY-1 provides an important model of strongly plasmablastic lymphoma, and disruption of VDR pathway activity may be of therapeutic benefit in both plasmablastic lymphoma and myeloma. PMID- 28001447 TI - Mirabegron for the treatment of overactive bladder: a review of efficacy, safety and tolerability with a focus on male, elderly and antimuscarinic poor-responder populations, and patients with OAB in Asia. AB - INTRODUCTION: Mirabegron is established as an alternative monotherapy to antimuscarinics for the treatment of overactive bladder (OAB) symptoms. Initial studies focused on Western populations, but over the past few years other populations and subpopulations have been evaluated. Areas covered: The authors' knowledge of the literature was used to develop the manuscript alongside a PubMed search ('mirabegron and clinical trial' and 'overactive bladder') to select independent studies of mirabegron. Up-to-date information is provided about the most recent mirabegron clinical trial and real-world efficacy, safety and tolerability data in a variety of patient populations with OAB, including those from different geographic areas, men, the elderly, and those with poor tolerability to antimuscarinics. Expert commentary: Improvements in efficacy parameters in patients with OAB at mirabegron doses approved for clinical use (25 and 50 mg/day) are also associated with clinically meaningful benefits according to patient-reported outcomes. Mirabegron has a favorable safety and tolerability profile, particularly compared with antimuscarinics, for dry mouth, constipation, and many CNS effects, which is maintained over 1 year. A growing body of evidence suggests that mirabegron represents a new treatment option for a broad range of patients with OAB. PMID- 28001448 TI - Following the Interstellar History of Carbon: From the Interiors of Stars to the Surfaces of Planets. AB - The chemical history of carbon is traced from its origin in stellar nucleosynthesis to its delivery to planet surfaces. The molecular carriers of this element are examined at each stage in the cycling of interstellar organic material and their eventual incorporation into solar system bodies. The connection between the various interstellar carbon reservoirs is also examined. Carbon has two stellar sources: supernova explosions and mass loss from evolved stars. In the latter case, the carbon is dredged up from the interior and then ejected into a circumstellar envelope, where a rich and unusual C-based chemistry occurs. This molecular material is eventually released into the general interstellar medium through planetary nebulae. It is first incorporated into diffuse clouds, where carbon is found in polyatomic molecules such as H2CO, HCN, HNC, c-C3H2, and even C60+. These objects then collapse into dense clouds, the sites of star and planet formation. Such clouds foster an active organic chemistry, producing compounds with a wide range of functional groups with both gas-phase and surface mechanisms. As stars and planets form, the chemical composition is altered by increasing stellar radiation, as well as possibly by reactions in the presolar nebula. Some molecular, carbon-rich material remains pristine, however, encapsulated in comets, meteorites, and interplanetary dust particles, and is delivered to planet surfaces. Key Words: Carbon isotopes Prebiotic evolution-Interstellar molecules-Comets-Meteorites. Astrobiology 16, 997-1012. PMID- 28001449 TI - Corrigendum. PMID- 28001450 TI - SDF-1/CXCL12 and CXCR4 gene variants, and elevated serum SDF-1 levels are associated with preeclampsia. AB - OBJECTIVE: We aimed to compare the frequencies of stromal cell-derived factor-1 (SDF-1) 3'A and CXCR4 single-nucleotide polymorphisms (SNPs) and serum SDF-1 levels in patients with preeclampsia (PE). METHODS: In total, 89 women with PE and 89 control women were included in the study. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method. Enzyme linked immunosorbent assay method was used to measure serum SDF-1 level. RESULTS: For SDF-1 3'A SNP, the frequency of GA genotype, total number of GA and AA genotypes, and the A allele frequency was higher in PE patients than controls (p = 0.04, 0.023, and 0.029, respectively). For CXCR4 SNP, the frequency of CT genotype, total number of CT and TT genotypes, and the T allele frequency were higher in PE patients than controls (p = 0.04, 0.006, and 0.005, respectively). SDF-1 serum level was detected higher in preeclamptic women compared with controls (p = 0.001). In PE patients, there was no significant association between serum SDF-1 levels and genotypes of SDF-1 3'A SNP. SDF-1 level was significantly higher in patients bearing CXCR4 CT genotype than CC genotype (p = 0.001). Furthermore, SDF-1 levels in patients bearing CT+TT genotype were found higher than that of patients with CC genotypes (p = 0.001). CONCLUSION: Results of our study suggest that SDF-1 3'A and CXCR4 polymorphisms and elevated serum SDF-1 levels may have a role in the development of PE. PMID- 28001451 TI - MGMT hypomethylation is associated with DNA damage in workers exposed to low-dose benzene. AB - OBJECTIVE: This study aims to assess the effects of low-dose benzene on DNA damage and O6-methylguanine-DNA methyltransferase (MGMT) methylation in occupational workers. MATERIALS AND METHODS: We recruited 96 nonsmoking male petrochemical industry workers exposed to low-dose benzene and 100 matched control workers. Urinary S-phenylmercapturic acid (SPMA) and S-benzylmercapturic acid (SBMA) were measured for indicating internal exposure of benzene and toluene. The degree of DNA damage was determined by the Comet assay. The levels of MGMT methylation were detected quantitatively by bisulphite-PCR pyrosequencing assay. RESULTS: The benzene-exposed workers had significantly higher levels of urinary SPMA, degree of DNA damage but decreased MGMT methylation than the controls (all p < 0.05). In contrast, the level of urinary SBMA does not differ between benzene-exposed workers and the controls. In all participants, MGMT methylation was negatively associated with the urinary SPMA and the degree of DNA damage, indicating that epigenetic regulation might be involved in response to low-dose benzene exposure-induced genetic damage. DISCUSSION AND CONCLUSION: MGMT methylation could be a potent biomarker associated with low-dose benzene exposure and benzene-induced DNA damage. PMID- 28001452 TI - Test-retest reliability of five frequently used executive tasks in healthy adults. AB - Executive tasks are important instruments for neuropsychological and cognitive research, but only a limited number of studies have investigated the test-retest reliability of these tasks. Such information is needed for optimizing task usage, for example, in longitudinal and intervention studies. In this study with healthy adults, we investigated the temporal stability of five executive tasks: the Simon task, a visuoverbal N-back task, a visuospatial N-back task, a running memory task, and the Number-letter task. These five tasks are frequently used in research, but previously published reliability data is very limited or totally lacking. The results from the present study showed considerable variability with the highest test-retest reliabilities amongst the three working memory tasks. Furthermore, reaction time measures indicated practice effects between the two sessions across the tasks. The present results set constraints to the interpretation of the results of longitudinal and intervention studies using these tasks. PMID- 28001453 TI - Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass. AB - Context: In type 2 diabetes mellitus, fracture risk is increased despite preserved areal bone mineral density. Although this apparent paradox may in part be explained by insulin resistance affecting bone structure and/or material properties, few studies have investigated the association between insulin resistance and bone geometry. Objective: We aimed to explore this association in a cohort of nondiabetic men at the age of peak bone mass. Design, Setting, and Participants: Nine hundred ninety-six nondiabetic men aged 25 to 45 years were recruited in a cross-sectional, population-based sibling pair study at a university research center. Main Outcome Measures: Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR), with insulin and glucose measured from fasting serum samples. Bone geometry was assessed using peripheral quantitative computed tomography at the distal radius and the radial and tibial shafts. Results: In age-, height-, and weight-adjusted analyses, HOMA-IR was inversely associated with trabecular area at the distal radius and with cortical area, periosteal and endosteal circumference, and polar strength strain index at the radial and tibial shafts (beta <= -0.13, P < 0.001). These associations remained essentially unchanged after additional adjustment for dual-energy X-ray absorptiometry-derived body composition, bone turnover markers, muscle size or function measurements, or adiponectin, leptin, insulin-like growth factor 1, or sex steroid levels. Conclusion: In this cohort of nondiabetic men at the age of peak bone mass, insulin resistance is inversely associated with trabecular and cortical bone size. These associations persist after adjustment for body composition, muscle size or function, or sex steroid levels, suggesting an independent effect of insulin resistance on bone geometry. PMID- 28001454 TI - Metabolic Health and Long-Term Safety of Growth Hormone Treatment in Silver Russell Syndrome. AB - Context: Children with Silver-Russell syndrome (SRS) are born small for gestational age (SGA) and remain short. Growth hormone (GH) treatment improves height in short SGA children, including those with SRS. Data on metabolic health and long-term safety of GH treatment in SRS are lacking. Objective: To investigate metabolic health in SRS patients during and until 2 years after discontinuation of GH treatment. Design: Metabolic health was assessed longitudinally at GH-start, GH-stop, 6 months, and 2 years thereafter. Patients: Twenty-nine SRS patients vs 171 non-SRS subjects born SGA. Main Outcome Measures: Lean body mass (LBM), fat mass percentage (FM%), insulin sensitivity (Si), beta cell function, blood pressure, and serum lipids. Results: At GH-start [mean age (standard deviation) 5.4 (2.1) years in SRS and 6.7 (2.0) years in non-SRS (P = 0.003)], blood pressure, serum lipids, glucose, and insulin levels were similar and within normal ranges in SRS and non-SRS. LBM standard deviation score (SDS) and FM% SDS were lower than average in both groups. During treatment, LBM SDS remained stable whereas FM% SDS increased in both groups. During the 2 years after GH-stop, LBM decreased and FM% increased, whereas Si and beta-cell function improved. At 2 years after GH-stop (mean age 18 years), all parameters were similar and within normal ranges in SRS and non-SRS. None of the SRS patients developed metabolic syndrome, diabetes mellitus type 2, or adverse events. Conclusion: GH-treated SRS patients have a similar metabolic health and safety profile as non-SRS subjects born SGA, both during and until 2 years after GH stop. PMID- 28001455 TI - Assessment of efficacy and safety of a fractionated bipolar radiofrequency device for the treatment of lower face wrinkles and laxity. AB - Skin aging, as a natural course, is a gradual process. It can be classified as either intrinsic or photo-aging. In recent years, as the attention to lower face wrinkles and laxity has raised significantly, the demands to facial rejuvenation also increased, along with a variety of technologies coming into being. Fractional bipolar RF as a novel means of rejuvenation has been used in clinical practice, but questions remain in terms of its efficacy and safety. Considering a large population in our country and huge demands for skin tightening, we did this research to evaluate the efficacy and safety of fractional bipolar radiofrequency. PMID- 28001456 TI - Measurement Properties of the Persian Translated Version of Graves Orbitopathy Quality of Life Questionnaire: A Validation Study. AB - PURPOSE: To determine the measurement properties of the Persian language version of the Graves orbitopathy quality of life questionnaire (GO-QOL). METHODS: Following a systematic translation and cultural adaptation process, 141 consecutive unselected thyroid eye disease (TED) patients answered the Persian GO QOL and underwent complete ophthalmic examination. The questionnaire was again completed by 60 patients on the second visit, 2-4 weeks later. Construct validity (cross-cultural validity, structural validity and hypotheses testing), reliability (internal consistency and test-retest reliability), and floor and ceiling effects of the Persian version of the GO-QOL were evaluated. Furthermore, Rasch analysis was used to assess its psychometric properties. RESULTS: Cross cultural validity was established by back-translation techniques, committee review and pretesting techniques. Bi-dimensionality of the questionnaire was confirmed by factor analysis. Construct validity was also supported through confirmation of 6 out of 8 predefined hypotheses. Cronbach's alpha and intraclass correlation coefficient (ICC) were 0.650 and 0.859 for visual functioning and 0.875 and 0.896 for appearance subscale, respectively. Mean quality of life (QOL) scores for visual functioning and appearance were 78.18 (standard deviation, SD, 21.57) and 56.25 (SD 26.87), respectively. Person reliabilities from the Rasch rating scale model for both visual functioning and appearance revealed an acceptable internal consistency for the Persian GO-QOL. CONCLUSION: The Persian GO-QOL questionnaire is a valid and reliable tool with good psychometric properties in evaluation of Persian-speaking patients with TED. Applying Rasch analysis to future versions of the GO-QOL is recommended in order to perform tests for linearity between the estimated item measures in different versions. PMID- 28001457 TI - Illustrating and Analyzing the Processes of Interprofessional Collaboration: A Lesson Learned from Palliative Care in Deconstructing the Concept. AB - BACKGROUND: A basic tenet of palliative care is interprofessional collaboration. Palliative care educators and practitioners lead the way in responding to the Institute of Medicine's (2003) challenge to transform educational and health care systems through interprofessional collaboration. Through exemplary commitment to interprofessional collaboration, a college's academic and palliative care leader, in collaboration with Department Chairs and Directors of nursing and allied health professions, can illustrate and analyze the processes of interprofessional collaboration through the development of a simulated case study of a combat veteran with traumatic brain injury. METHODS: Methodologic components: (1) interprofessional development of a palliative care case study and (2) debriefing interviews regarding the experience of collaboration of interprofessional team members. RESULTS: The results provide the identification of steps of the interprofessional process and the shared and unique disciplinary competencies in determining a comprehensive health history, physical examination, identifying and prioritizing diagnoses, and determining collaborative discipline-specific interventions. Content analysis of debriefing team interviews provides a description of group composition, structure, process, development, and performance, as well as team member's perceptions of what fosters and challenges collaboration, benefits, and drawbacks, and what could have been done differently in developing an interprofessional initiative. DISCUSSION: Transformative change in healthcare education and clinical practice involves interprofessional collaboration of colleagues within, across, and beyond universities/colleges and healthcare systems and agencies. Advocating for teamwork has to go beyond talking about being a team player or not to having the language and behaviors we need to observe and measure. This article not only provides key processes in interprofessional collaboration but also identifies key attitudes and behaviors critical to teamwork. It provides a starting point to determine observable and measurable outcomes for interprofessional education, practice, and research. This article highlights expert behavior to move professionals from being novices in interprofessional collaboration to mastering the skills. PMID- 28001458 TI - Similarity and Difference in Drug Addiction Process Between Heroin- and Methamphetamine-Dependent Users. AB - OBJECTIVES: This study aimed to compare the drug addiction process between Chinese heroin- and methamphetamine (MA)-dependent users via a modified 4-stage addiction model (experimentation, occasional use, regular use, and compulsive use). METHODS: A descriptive study was conducted among 683 eligible participants. In the statistical analysis, we selected 340 heroin- and 295 MA-dependent users without illicit drug use prior to onset of heroin or MA use. RESULTS: The addiction process of heroin-dependent users was shorter than that of MA-dependent users, with shorter transitions from the onset of drug-use to the first drug craving (19.5 vs. 50.0 days), regular use (30.0 vs. 60.0 days), and compulsive use (50.0 vs. 85.0 days). However, no significant differences in the addiction process were observed in frequency of drug administration, except that heroin users reported more administrations of the drug (20.0 vs. 15.0) before progressing to the stage of compulsive drug use. A larger proportion of regular heroin users progressed to use illicit drugs recklessly than did MA users. Most heroin and MA users reported psychological dependence as their primary motivation for compulsive drug use, but more heroin users selected uncomfortable symptoms upon ceasing drug use as further reason to continue. CONCLUSION: Our results suggest that typical heroin and MA users may experience a similar four-stage addiction process, but MA users might undergo a longer addiction process (in days). More research is necessary to further explore factors influencing the drug addiction process. PMID- 28001459 TI - Long-Term Effect of Adrenalectomy on Cardiovascular Remodeling in Patients With Pheochromocytoma. AB - Context: Catecholamines may contribute to the accumulation of collagen fibers and extracellular matrix in the arterial and myocardial wall due to various mechanisms. Reversibility of this process has not been studied on both structures simultaneously. Objective: To clarify the long-term effect of excess normalization of catecholamines on carotid and myocardial wall changes in patients with pheochromocytoma or functional paraganglioma (PHEO) after tumor removal. Design, Settings, and Patients: Carotid intima-media thickness (IMT) and the left ventricular (LV) mass index were studied in 50 patients with PHEO before tumor removal and 5 years after tumor removal, and in 50 blood pressure- and age matched essential hypertensive patients before follow-up and after 5 years of follow-up. Main Outcome Measures: Common carotid artery (CCA)-IMT and LV mass indexed to lean body mass (LBM). Results: Elimination of catecholamine excess in the PHEO group resulted in a significant decrease in CCA-IMT and LV mass index from 0.86 +/- 0.17 to 0.83 +/- 0.18 mm (P < 0.05) and from 3.2 +/- 0.9 to 2.9 +/- 0.9 g/LBM (P < 0.001), respectively. In contrast, CCA-IMT and LV mass index increased significantly from 0.78 +/- 0.14 to 0.81 +/- 0.15 mm (P < 0.05) and from 3.1 +/- 0.7 to 3.2 +/- 0.6 g/LBM (P < 0.05), respectively, in patients with essential hypertension. Conclusion: In patients with PHEO, carotid IMT and LV mass index can significantly regress after tumor removal, in contrast to the impairment of these parameters in essential hypertensive patients during the same long-term period. PMID- 28001460 TI - High Frequency of Antimicrobials Use in Palliative Care: Are We Moving in the Right Direction? PMID- 28001461 TI - Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults. AB - Tobacco smoking is a preventable environmental factor that contributes to a wide spectrum of age-related health outcomes; however, its association with the development of frailty is not yet well established. We examined the associations of self-reported smoking indicators, serum cotinine levels and smoking-related DNA methylation biomarkers with a quantitative frailty index (FI) in 2 independent subsets of older adults (age 50-75) recruited in Saarland, Germany in 2000 - 2002 (discovery set: n = 978, validation set: n = 531). We obtained DNA methylation profiles in whole blood samples by Illumina HumanMethylation450 BeadChip and calculated the FI according to the method of Mitnitski and Rockwood. Mixed linear regression models were implemented to assess the associations between smoking indicators and the FI. After controlling for potential covariates, current smoking, cumulative smoking exposure (pack-years), and time after smoking cessation (years) were significantly associated with the FI (P value < 0.05). In the discovery panel, 17 out of 151 previously identified smoking-related CpG sites were associated with the FI after correction for multiple testing (FDR < 0.05). Nine of them survived in the validation phase and were designated as frailty-associated loci. A smoking index (SI) based on the 9 loci manifested a monotonic association with the FI. In conclusion, this study suggested that epigenetic alterations could play a role in smoking-associated development of frailty. The identified CpG sites have the potential to be prognostic biomarkers of frailty and frailty-related health outcomes. Our findings and the underlying mechanisms should be followed up in further, preferably longitudinal studies. PMID- 28001462 TI - Comparative pharmacokinetics between madecassoside and asiaticoside presented in a standardised extract of Centella asiatica, ECa 233 and their respective pure compound given separately in rats. AB - 1. ECa 233, the standardised extract of Centella asiatica, contains not less than 80% triterpenoid glycosides, in a madecassoside:asiaticoside ratio of 1.5 (+/ 0.5):1. 2. The pharmacokinetic comparison of madecassoside and asiaticoside was performed in rats following intravenous and oral administration of ECa 233, or an equivalent dose of the individual compounds. Blood, tissues, urine and faeces were collected after dosing to determine drug and metabolite levels using liquid chromatography-tandem mass spectrometry. 3. Our study demonstrated that plasma levels of madecassoside, and to a lesser extent asiaticoside, were higher after administration of ECa 233 than the corresponding values for the pure compounds. There was a bidirectional interconversion between asiaticoside and madecassoside consistent with the increased exposure of madecassoside and asiaticoside in ECa 233. 4. Both madecassoside and asiaticoside appeared to be widely distributed in several organs and metabolized extensively; following intravenous administration of either compound, approximately 80-90% of the dose was recovered as madecassic acid and asiatic acid in the faeces. PMID- 28001463 TI - To Trigger or Not: That Is the Question! PMID- 28001464 TI - Differences by Gender in Predictors of Motivation Among Substance Abuse Treatment Participants. AB - BACKGROUND: Substance-involved females tend to have different clinical profiles than men (Adams, Leukefeld, & Peden, 2008 ); yet they do not appear to have worse treatment outcomes (Green, 2006 ; Hser, Huang, Teruya, & Anglin, 2003 ). As motivation for treatment is considered essential in the substance abuse treatment context (Cahill, Adinoff, Hosig, Muller, & Pulliam, 2003 ; Longshore & Teruya, 2006 ), it is possible that higher motivation among females could potentially counteract the negative effect of more risk factors. OBJECTIVE: The purpose of the current study was to examine if females differ from males in their motivation for treatment using the Texas Christian University Motivation Form scales: desire for help, problem recognition, treatment readiness, pressure for treatment, and treatment needs; and whether factors predicting motivation for treatment differed between male and female participants of substance abuse treatment. METHODS: The sample included 2,989 substance-involved males and 982 substance-involved females who were referred to substance abuse treatment through a case management program. Linear regression models predicting each motivation scale were analyzed, followed by gender-specific models. RESULTS: Overall, the results did not demonstrate a significant gender difference in the motivation scales. However, among male participants, the findings did show that Hispanic significantly predicted desire for help and alcohol as a primary drug of choice predicted treatment readiness. CONCLUSION: Findings suggest that motivation for treatment may be a gender neutral construct, and that there is a need to better understand sociodemographic predictors of motivation. PMID- 28001465 TI - Posterior Capsule Opacification and Nd:YAG Rates with Two Acrylic Intraocular Lenses after Age-Related Cataract Treatment: Three-year Results. AB - OBJECTIVE: To compare the incidence and intensity of posterior capsule opacification (PCO) between two intraocular lenses (IOLs) over three years. METHODS: Eighty-three patients underwent cataract surgery with implantation of Acreos Adapt AO or Acrysof SA60AT. PCO values were assessed using a photographic image analysis system (EPCO 2000) and the amount of PCO at the slit lamp. RESULTS: Mean PCO score was 2.78 +/- 1.55 for the Acreos Adapt AO and 2.32 +/- 1.20 for the Acrysof SA60AT (P=.229). There were no significant differences in the median EPCO values in the entire IOL optics area (0.60 +/- 0.26 vs 0.58 +/- 0.23; P=.745) and in the central 3-mm zone (0.28 +/- 0.13 vs 0.27 +/- 0.12; P=.638). Neodymium:YAG capsulotomy was performed in 28% of eyes with Acreos Adapt AO and 23.33% with Acrysof SA60AT (P=.692). CONCLUSION: Both IOLs had comparable PCO and Nd:YAG rates three years postoperatively. PMID- 28001466 TI - The Intensive Palliative Care Unit: Changing Outcomes for Hospitalized Cancer Patients in an Academic Medical Center. AB - BACKGROUND: Patients with advanced cancer often require complex symptom management. At Dana-Farber/Brigham and Women's Cancer Center, the intensive palliative care unit (IPCU) admits symptomatic oncology patients with uncontrolled symptoms throughout the trajectory of illness. Patients are uniquely managed by an interdisciplinary team of clinicians who focus on symptom management and advance care planning. OBJECTIVE: The purpose of our analysis was to investigate goals-of-care outcomes and healthcare utilization after admission to the IPCU. DESIGN: We retrospectively reviewed 74 oncology patients admitted to the IPCU in August and September, 2013. RESULTS: A total of 67 IPCU patients who were admitted received palliative intent treatment, whereas 7 patients received curative intent care. All patients were engaged in a goals-of-care discussion during admission. Of the palliative intent patients, 58% were transferred to the IPCU from medical oncology and 42% were directly admitted. Forty-eight percent of the patients were diagnosed with metastatic lung, genitourinary, or gastrointestinal cancer. Eighty-seven percent of patients reported pain as the chief complaint at admission. Twenty-five patients experienced a change in code status from Full Code to do-not-resuscitate/do-not-incubate. A total of eight patients died in the IPCU, and 50% experienced a code status change. Eighty-eight percent of patients were discharged alive. Of those, 49% were discharged to home hospice, general inpatient hospice, or an inpatient hospice facility. The risk of 30-day readmission was 4%. CONCLUSIONS: Among advanced cancer patients, our findings suggest that an inpatient palliative care unit helps clarify goals of care, aids in appropriate hospice referrals, and decreases hospital readmissions. PMID- 28001467 TI - Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: A promising treatment approach. AB - Severe and severe-complicated Clostridium difficile infection (CDI) is associated with high morbidity and mortality. Colectomy is standard of care; however, post surgical mortality rates approach 50%. Case reports suggest fecal microbiota transplant (FMT) is a promising treatment of severe and severe-complicated disease but there is a paucity of data. Here, we present a single center experience with a novel sequential FMT protocol for patients refractory to maximal medical therapy. This approach consists of at least one FMT delivered via colonoscopy with criteria for repeat FMT and continued vancomycin therapy based on clinical response and pseudomembranes. Our cohort included 57 consecutive inpatients diagnosed with severe or severe-complicated CDI and treated with FMT. Overall, 91% (52/57) experienced clinical cure at 1 month with a 100% cure rate among severe CDI (n = 19) patients and an 87% cure rate for severe-complicated CDI (n = 33) patients. For the cohort, the survival rate was 94.7% at 1 month and 78.6% at 3 months. There were no serious adverse events related to FMT including no procedure-related complications or perforation. There was no difference in outcome between fresh or frozen fecal material. Sequential FMT for inpatients with severe or severe-complicated CDI is promising and may be preferred over colectomy in certain patients. PMID- 28001469 TI - A cross-sectional assessment of the prevalence and burden of mild asthma in urban China using the 2010, 2012, and 2013 China National Health and Wellness Surveys. AB - OBJECTIVE: To estimate the prevalence of mild asthma in urban China and to measure the association between asthma severity and quality of life (QOL), work productivity, and healthcare resource use. METHODS: Data were from the China National Health and Wellness Surveys (NHWS) conducted between 2010 and 2013 (N = 59,935), Internet-based surveys of adults in urban China. Patients were categorized by asthma severity according to self-report and Global Initiative for Asthma (GINA2014) guidelines via self-reported medication use (mild [GINA 1-2] vs moderate/severe [GINA 3-4]). Propensity scores were used to identify matched controls without asthma. These three groups (mild vs. moderate/severe vs. matched control) were compared with respect to QOL (revised Short Form-12/36), work productivity (WPAI questionnaire), and healthcare use using generalized linear models. RESULTS: 1,191 respondents reported an asthma diagnosis (1.99%). Then 455 (0.77% and 76.86% of the total sample and asthma sample which could be categorized based on GINA2014 guidelines, respectively) and 897 (1.50% and 75.31% of the total and asthma sample, respectively) had mild asthma based on GINA2014 guidelines and self-report, respectively. Compared with matched controls, mild patients based on GINA2014 guidelines reported worse QOL (Physical Component Summary = 44.67 vs. 48.97), more overall work impairment (54.51% vs. 34.35%), and more all-cause emergency room visits in the past 6 months (1.95 vs. 0.63 visits) (all p <.05). Similar results were observed using self-reported severity. CONCLUSIONS: Most patients with asthma in the China NHWS are mild according to either definition. Asthma patients experience significant burden to QOL, work productivity, activity impairment, and healthcare resource use. PMID- 28001468 TI - Long-Term Quality of Life in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma. AB - Context: Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer specific HRQoL in survivors only. Design: Survivors diagnosed between 1970 and 2013 at age <=18 years, were included. Exclusion criteria were a follow-up <5 years, attained age <18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer specific HRQoL questionnaire. Results: Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL. Conclusions: Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer-specific complaints). Factors possibly affecting QoL need further exploration. PMID- 28001470 TI - The EU legislation on "GMOs" between nonsense and protectionism: An ongoing Schumpeterian chain of public choices. AB - The EU regulation of agricultural biotechnology is botched and convoluted: the pseudo-concept of "Genetically Modified Organisms" has no coherent semantic or scientific content. The reasons of the paradox by which the cultivation of "GMOs" is substantially banned in Europe, while enormous quantities of recombinant-DNA cereals and legumes are imported to be used as feedstuff, are explained. The Directive 2015/412, giving Member states the choice to refuse the cultivation of genetically engineered crops at a national or local level, paves the way for a mosaic-like, Harlequinesque form of protectionism: nothing resembling a well regulated free market. In the meantime, importation of "GMO" feed goes on at full speed all over Europe. A proposal by the Commission to adjust the rules on importation according to those for cultivation has been rejected by the Parliament.This dynamics may be seen as an ongoing "Schumpeterian" chain of public choices: the calculus of consent drives politicians more than a science based approach to law-making. The EU should restart from scratch with the right concept, i.e. the careful examination of the pros and cons, the costs and benefits of each new agricultural product ("GMO" or otherwise), freely cultivated and/or imported, assessed case by case, at last acknowledging that the biotech processes used to create new varieties are of no practical or legal relevance. In doing so, the EU would pursue its stated "better regulation" approach, cancelling any sectoral and sectarian regulation. PMID- 28001471 TI - Pediatric Cancer Patients' Important End-of-Life Issues, Including Quality of Life: A Survey of Pediatric Oncologists and Nurses in Japan. AB - BACKGROUND: Research into the key themes and concepts of quality of life (QOL) relevant to the end-of-life (EOL) care of pediatric cancer patients in the Japanese context is imperative. OBJECTIVE: This study aimed at identifying the key items and constructive concepts of QOL at EOL of pediatric cancer patients. DESIGN: In 2015, pediatricians and nurses were recruited from 163 pediatric oncology treatment facilities in Japan. The questionnaire was developed on the basis of a previous qualitative study. Items that were rated as "very important" or "important" by at least 80% of the respondents were considered as "common and important" QOL items. Exploratory factor analysis was performed to conceptualize QOL of the pediatric cancer patients during EOL care. RESULTS: A total of 157 pediatricians and 270 nurses participated in this study. Fifty-five items were refined to 35 "common and important" QOL items. On factor analysis, 12 domains (containing 29 items) were identified: playing and learning; fulfilling wishes; spending time with family; receiving relief from physical and psychological suffering; making many wonderful memories; having a good relationship with the medical staff; having a peaceful death in the presence of family; spending time with a minimum of medical treatment; living one's life as usual; spending time in a calm hospital environment; being oneself; and having a close family. CONCLUSIONS: Although the respondents in this study were medical care providers rather than the patients or their family members, findings should help medical staff provide better palliative care to Japanese pediatric cancer patients. PMID- 28001472 TI - Two sulfonate metabolites of physalin A in rats. AB - 1. Physalin A is a bioactive withanolide isolated from the natural plant Physalis alkekengi var. franchetii (Solanaceae), a common traditional Chinese herbal medicine. This study aims to investigate the metabolites of physalin A in vivo. 2. Two metabolites (M1 and M2) were characterized as sulfonate metabolites in the feces obtained from rats treated with physalin A orally at a dose of 15 mg/kg/day for 3 days, by application of a UPLC-Q/TOF-MS method. Furthermore, formation of the two sulfonate metabolites was verified by chemical synthesis and NMR, including 1H NMR, 13C NMR and two-dimensional NMR. The structures of M1 and M2 were identified to be 3alpha-sulfo-2,25beta,27-trihydrophysalin A and 3alpha,27 disulfo-2,25alpha-dihydrophysalin A, respectively. 3. In summary, this study indicated that physalin A could be biotransformed to sulfonate metabolites with strong polarity, which contributed to the elimination of physalin A. A rare metabolic pathway has been revealed in this study. PMID- 28001473 TI - Care for the Vulnerable vs. Cash for the Powerful - Trump's Pick for HHS. PMID- 28001474 TI - Effects of resistance training in HIV-infected patients: A meta-analysis of randomised controlled trials. AB - The relative effects of resistance training (RT) upon muscle fitness and immune function among HIV-infected patients are uncertain. The purpose of this study was to perform a meta-analysis to determine the effects of RT upon muscle strength, muscle mass and CD4 cells count and to identify potential moderators of those outcomes in HIV-infected patients. Meta-analyses use random or fixed-effects model depending on the heterogeneity of effect sizes, complemented with Hedge's g correction factor. Thirteen trials were meta-analysed. Overall, RT increased muscle strength (35.5%, P < 0.01) and CD4 cell count (26.1%, P = 0.003) versus controls (P < 0.03), but not muscle mass (P = 0.051). Meta-regression followed by subgroup moderator analysis showed that gains in muscle strength followed a dose response pattern with largest increase detected among trials with longer (24 weeks; 49.3%) than shorter intervention (<12 weeks; 39%), higher (Physiotherapy Evidence-Based Database [PEDro] scale = 6; 38.3%) than lower (PEDro = 5; 28.1%) quality, and longer (12 months; 59.7%) than shorter time under highly active antiretroviral therapy (HAART) (<6 months; 37.1%), (P < 0.01). RT appears to be efficacious to improve muscular strength (~35.5%) and CD4 cell count (~26.1%), but not muscle mass of HIV-infected patients. Effects upon strength were greater in studies with higher quality and among trials with longer RT and HAART. PMID- 28001481 TI - Vertical Finger Displacement Is Reduced in Index Finger Tapping During Repeated Bout Rate Enhancement. AB - The present study analyzed (a) whether a recently reported phenomenon of repeated bout rate enhancement in finger tapping (i.e., a cumulating increase in freely chosen finger tapping frequency following submaximal muscle activation in the form of externally unloaded voluntary tapping) could be replicated and (b) the hypotheses that the faster tapping was accompanied by changed vertical displacement of the fingertip and changed peak force during tapping. Right handed, healthy, and recreationally active individuals (n = 24) performed two 3 min index finger tapping bouts at freely chosen tapping frequency, separated by 10-min rest. The recently reported phenomenon of repeated bout rate enhancement was replicated. The faster tapping (8.8 +/- 18.7 taps/min, corresponding to 6.0 +/- 11.0%, p = .033) was accompanied by reduced vertical displacement (1.6 +/- 2.9 mm, corresponding to 6.3 +/- 14.9%, p = .012) of the fingertip. Concurrently, peak force was unchanged. The present study points at separate control mechanisms governing kinematics and kinetics during finger tapping. PMID- 28001482 TI - Thermodynamic Effects of 3 Different Diode Lasers on an Implant-Bone Interface: An Ex-Vivo Study With Review of the Literature. AB - The aim of this study is to assess the increase of temperature following laser irradiation with 810 nm, 980 nm, and 1064 nm diode laser wavelengths, of an implant under conditions that more closely replicate those of the human body. A 4 * 14 mm machined surface implant was placed in a porcine rib to replicate the conductivity of heat given by the bone. A peri-implant vertical defect was made that was 2 mm wide and 2 mm deep to simulate bone resorption. Two thermocouples were positioned crestally and apically on the implant surface. The tip of the laser was kept 3 mm away from the surface and continuously moved in an up-and down and side-to-side fashion, inside the defect for 60 seconds. Initial temperatures and the time needed to reach an increase of 10 degrees C were recorded. The experiment was repeated at room temperature and in a 37 degrees C water bath with the following settings: 0.6 W, 0.8 W, 1 W continuous and repeated in pulsed. A critical increase of temperature of more than 10 degrees C is reached with all lasers at 0.8 W and 1 W in continuous mode at room temperature. Only the 1064 nm diode laser reached the critical increase at 0.8 W in pulsed mode. No critical increase of temperature was registered with other settings and when the bone block was placed in a 37 degrees C water bath. The results of this study suggest that use of these diode lasers does not cause a harmful increase in temperature when used under conditions similar to those of the human body. PMID- 28001483 TI - Bayesian isotonic regression dose-response model. AB - Understanding dose-response relationship is a crucial step in drug development. There are a few parametric methods to estimate dose-response curves, such as the Emax model and the logistic model. These parametric models are easy to interpret and, hence, are widely used. However, these models often require the inclusion of patients on high-dose levels; otherwise, the model parameters cannot be reliably estimated. To have robust estimation, nonparametric models are used. However, these models are not able to estimate certain important clinical parameters, such as ED50 and Emax. Furthermore, in many therapeutic areas, dose-response curves can be assumed as nondecreasing functions. This creates an additional challenge for nonparametric methods. In this paper, we propose a new Bayesian isotonic regression dose-response (BIRD) which features advantages from both parametric and nonparametric models. The ED50 and Emax can be derived from this model. Simulations are provided to evaluate the BIRD model performance against two parametric models. We apply this model to a dataset from a diabetes dose-finding study. PMID- 28001484 TI - Assessment via the Oculus of Visual "Weighting" and "Reweighting" in Young Adults. AB - Substantial advances in virtual reality technology open an exciting window toward better understanding of subdomains of balance control. Here, we studied whether a portable virtual reality headset can be used to test sensory integration for balance. Twenty young adults stood on a both-sides-up ball or floor. Moving spheres were projected from an Oculus Development Kit 2 at various amplitudes and frequencies. Participants' gains indicated visual "weighting" when standing on both-sides-up but not on the floor and "reweighting" with increased visual amplitude. Intraclass correlations showed acceptable to good reliability for all floor conditions and for some of the both-sides-up conditions when we repeated the protocol a week later. Future steps to further develop our paradigm into a clinical assessment of sensory integration for postural control are discussed. PMID- 28001485 TI - Optimizing assembly and production of native bispecific antibodies by codon de optimization. AB - When production of bispecific antibodies requires the co-expression and assembly of three or four polypeptide chains, low expression of one chain can significantly limit assembly and yield. kappalambda bodies, fully human bispecific antibodies with native IgG structure, are composed of a common heavy chain and two different light chains, one kappa and one lambda. No engineering is applied to force pairing of the chains, thus both monospecific and bispecific antibodies are secreted in the supernatant. In this context, stoichiometric expression of the two light chains allows for maximal assembly of the bispecific antibody. In this study, we selected a kappalambda body with suboptimal characteristics due to low kappa chain expression. Codon optimization to increase expression of the kappa chain did not improve bispecific yield. Surprisingly, progressive introduction of non-optimal codons into the sequence of the lambda chain resulted in lowering its expression for an optimal tuning of the relative distribution of monospecific and bispecific antibodies. This codon de optimization led to doubling of the kappalambda body yield. These results indicate that assembly of different proteins into a recombinant complex is an interconnected process and that reducing the expression of one polypeptide can actually increase the overall yield. PMID- 28001486 TI - B-Cell Depletion - A Frontier in Monoclonal Antibodies for Multiple Sclerosis. PMID- 28001487 TI - Impact of SPR biosensor assay configuration on antibody: Neonatal Fc receptor binding data. AB - Binding interactions with the neonatal Fc receptor (FcRn) are one determinant of pharmacokinetic properties of recombinant human monoclonal antibody (rhumAb) therapeutics, and a conserved binding motif in the crystallizable fragment (Fc) region of IgG molecules interacts with FcRn. Surface plasmon resonance (SPR) biosensor assays are often used to characterize interactions between FcRn and rhumAb therapeutics. In such assays, generally either the rhumAb (format 1) or the FcRn protein (format 2) is immobilized on a biosensor chip. However, because evidence suggests that, in some cases, the variable domains of a rhumAb may also affect FcRn binding, we evaluated the effect of SPR assay configuration on binding data. We sought to assess FcRn binding properties of 2 rhumAbs (rhumAb1 and rhumAb2) to FcRn proteins using these 2 biosensor assay formats. The two rhumAbs have greater than 99% sequence identity in the Fc domain but differ in their Fab regions. rhumAb2 contains a positively charged patch in the variable domain that is absent in rhumAb1. Our results showed that binding of rhumAb1 to FcRn was independent of biosensor assay configuration, while binding of rhumAb2 to FcRn was highly SPR assay configuration dependent. Further investigations revealed that the format dependency of rhumAb2-FcRn binding is linked to the basic residues that form a positively charged patch in the variable domain of rhumAb2. Our work highlights the importance of analyzing rhumAb-FcRn binding interactions using 2 alternate SPR biosensor assay configurations. This approach may also provide a simple way to identify the potential for non-Fc-driven FcRn binding interactions in otherwise typical IgGs. PMID- 28001489 TI - The Influence of eHealth Literacy on Perceived Trust in Online Health Communication Channels and Sources. AB - Disparities in online health information accessibility are partially due to varying levels of eHealth literacy and perceived trust. This study examined the relationship between eHealth literacy and perceived trust in online health communication channels and sources among diverse sociodemographic groups. A stratified sample of Black/African Americans (n = 402) and Caucasians (n = 409) completed a Web-based survey that measured eHealth literacy and perceived trustworthiness of online health communication channels and information sources. eHealth literacy positively predicted perceived trust in online health communication channels and sources, but disparities existed by sociodemographic factors. Segmenting audiences according to eHealth literacy level provides a detailed understanding of how perceived trust in discrete online health communication channels and information sources varies among diverse audiences. Black/African Americans with low eHealth literacy had high perceived trust in YouTube and Twitter, whereas Black/African Americans with high eHealth literacy had high perceived trust in online government and religious organizations. Older adults with low eHealth literacy had high perceived trust in Facebook but low perceived trust in online support groups. Researchers and practitioners should consider the sociodemographics and eHealth literacy level of an intended audience when tailoring information through trustworthy online health communication channels and information sources. PMID- 28001490 TI - Severity factors associated with borderline personality disorder among misusers in an outpatient sample in Spain. AB - The comorbidity between substance-use disorders and borderline personality disorder (SUD-BPD) with other psychiatric disorders has been little studied. A total of 937 drug-dependent patients were evaluated using semistructured interviews and 13.7% were SUD-BPD patients. After multivariate analysis, gender, Affective Disorder (OR 2.59), Anxiety Disorder (OR 1.90), Eating Disorders (OR 4.29), Cocaine (OR 2.16), benzodiazepine dependence (OR 1.90), early age of onset of drug consumption (OR 0.94), and dependent (OR 4.04), paranoid (OR 3.70) and antisocial personality disorders (OR 3.46) were associated with SUD-BPD. Several psychiatric comorbidities are the norm in SUD-BPD patients; therefore these patients are a challenge for clinicians. PMID- 28001492 TI - Effects of Temporal Framing on Response to Antismoking Messages: The Mediating Role of Perceived Relevance. AB - This study tested the effect of temporal framing on young adult smokers' response to antismoking communication messages. In two studies using largely identical designs, young adult smokers recruited from a large university (n = 52) and Amazon Mechanical Turk (n = 210) were exposed to either no messages or messages featuring different temporal frames. Analysis of the combined data (N = 262) showed that framing the health consequences of smoking in a proximal (vs. distal) time frame led to greater perceived message relevance, less use of heuristic processing, greater use of systematic processing, greater positive affect, and more intense fear. Mediation analysis showed that perceived relevance was a significant mediator of the effect of temporal framing on message processing and emotional responses. In separate analysis of the Amazon Mechanical Turk data, the proximal frame also showed a consistent pattern of stronger impact on behavioral intentions compared to the distal frame, but the difference was only significant on the measure of intending to try to quit. Overall, findings of this study suggest that using proximal (vs. distal) frames may enhance receptivity to antismoking messages among young adult smokers, although the behavioral impact of this framing strategy still awaits further research. PMID- 28001493 TI - Enhancing conflict negotiation strategies of adolescents with autism spectrum disorder using video modeling. AB - Adolescents with autism spectrum disorder (ASD) have particular difficulty in negotiating conflict. A randomized control trial (RCT) was carried out to determine whether the negotiation strategies of adolescents with ASD would be enhanced via a 6-week intervention based on a video modeling application. Adolescents with ASD, aged 12-18 years, were randomly divided into an intervention group (n = 36) and a non-treatment control group (n = 25). Participants' negotiating strategies prior to and following the intervention were measured using the Five Factor Negotiation Scale (FFNS; Nakkula & Nikitopoulos, 1999) and the ConflicTalk questionnaire (Kimsey & Fuller, 2003). The results suggest that video modeling is an effective intervention for improving and maintaining conflict negotiation strategies of adolescents with ASD. PMID- 28001494 TI - Practitioner Perspectives on Child Sexual Exploitation: Rapport Building With Young People. AB - Young people suspected of being sexually exploited are unlikely to have made prior disclosures before being approached by authorities, and this can make them especially uncomfortable when involved in investigations. Semistructured interviews were conducted with frontline social workers and law enforcement practitioners about their experiences interacting with youth during child sexual exploitation investigations. The findings provided some tentative insights into the processes by which practitioners sought to establish rapport with young people who have been exploited and establish themselves as trustworthy abuse disclosure recipients. Practitioners reported that rapport building in child sexual exploitation cases not only occurred over lengthy periods of time (e.g., months or years) but also required repeated contacts between the practitioners and young people, during which practitioners minimized their roles as authorities and maximized their authenticity as caring people. Practitioners mentioned the importance of dependability, lightheartedness, and having a casual demeanor. Findings have implications for managing reluctance and understanding rapport building when working with possible victims. PMID- 28001495 TI - The ecstasy of death. PMID- 28001497 TI - Physiologically based pharmacokinetic model for quinocetone in pigs and extrapolation to mequindox. AB - Physiologically based pharmacokinetic (PBPK) models are scientific methods used to predict veterinary drug residues that may occur in food-producing animals, and which have powerful extrapolation ability. Quinocetone (QCT) and mequindox (MEQ) are widely used in China for the prevention of bacterial infections and promoting animal growth, but their abuse causes a potential threat to human health. In this study, a flow-limited PBPK model was developed to simulate simultaneously residue depletion of QCT and its marker residue dideoxyquinocetone (DQCT) in pigs. The model included compartments for blood, liver, kidney, muscle and fat and an extra compartment representing the other tissues. Physiological parameters were obtained from the literature. Plasma protein binding rates, renal clearances and tissue/plasma partition coefficients were determined by in vitro and in vivo experiments. The model was calibrated and validated with several pharmacokinetic and residue-depletion datasets from the literature. Sensitivity analysis and Monte Carlo simulations were incorporated into the PBPK model to estimate individual variation of residual concentrations. The PBPK model for MEQ, the congener compound of QCT, was built through cross-compound extrapolation based on the model for QCT. The QCT model accurately predicted the concentrations of QCT and DQCT in various tissues at most time points, especially the later time points. Correlation coefficients between predicted and measured values for all tissues were greater than 0.9. Monte Carlo simulations showed excellent consistency between estimated concentration distributions and measured data points. The extrapolation model also showed good predictive power. The present models contribute to improve the residue monitoring systems of QCT and MEQ, and provide evidence of the usefulness of PBPK model extrapolation for the same kinds of compounds. PMID- 28001498 TI - Evaluation of the osteoconductive potential of poly(propylene carbonate)/nano hydroxyapatite composites mimicking the osteogenic niche for bone augmentation. AB - Nano-hydroxyapatite (n-HA) reinforced poly(propylene carbonate) (PPC) composites were prepared for bone repair and reconstruction. The effects of reinforcement on the morphology, mechanical properties and biological performance of n-HA/PPC composites were investigated. The surface morphology and mechanical properties of the composites were characterized by scanning electron microscopy (SEM) and universal material testing machine. The analytical data showed that good incorporation and dispersion of n-HA crystals could be obtained in the PPC matrix at a 30:70 weight ratio. With the increase of n-HA content, the tensile strength increased and the fracture elongation rate decreased. In vitro cell culture revealed that the composite was favorable template for cell attachment and growth. In vivo implantation in femoral condyle defects of rabbits confirmed that the n-HA/PPC composite had good biocompatibility and gradual biodegradability, exhibiting good performance in guided bone regeneration. The results demonstrates that the incorporation of n-HA crystals into PPC matrix provides a practical way to produce biodegradable and cost-competitive composites mimicking the osteogenic niche for bone augmentation. PMID- 28001499 TI - Effectiveness and safety of Methotrexate in psoriasis: an eight-year experience with 218 patients. AB - BACKGROUND: Methotrexate (MTX), a traditional antipsoriatic drug, is very frequently used either as monotherapy or in combination with other systemic drugs. OBJECTIVES: To assess the effectiveness and safety of MTX in psoriasis in usual clinical practice. METHODS: We conducted a retrospective study. We performed an electronic and manual chart review of patients treated with MTX in the Psoriasis Unit of our Hospital from January 2007 to December 2014. Demographic and clinical data, PASI/DLQI scores and reasons for suspension of all patients treated with MTX in usual clinical practice were recorded. RESULTS: Two hundred and eighteen patients were included. MTX was administered in 67% of cases as the first systemic treatment. The average treatment duration was 17.2 +/- 13.6 months. All patients were subjected to clinical and laboratory monitoring. About 33.5% of them achieved a reduction of 75% or more of the initial PASI at week 12, 34.9% at week16, 44.7% at week 24, and 52.8% at week 48. A 3.3% had to discontinue the therapy due to analytical hepatic (2.8%) or renal (0.5%) abnormalities. Only one patient experienced severe interstitial pneumonitis and none required liver biopsy. CONCLUSIONS: MTX is an effective and safe option for the treatment of psoriasis in the real-world clinical practice. PMID- 28001500 TI - "Unnatural Fornication" Cases Under State-Socialism: A Hungarian-Slovenian Comparative Social-Historical Approach. AB - This comparative social-historical study examines different versions of state socialist body politics manifested in Hungary and Slovenia mainly during the 1950s by using archive material of "unnatural fornication" court cases. By analyzing the available Hungarian "termeszet elleni fajtalansag" and Slovenian "nenaravno obcevanje" court cases, we can shed light on how the defendants were treated by the police and the judiciary. On the basis of these archive data that have never been examined before from these angles, we can construct an at least partial picture of the practices and consequences of state surveillance of same sex-attracted men during state-socialism. The article explores the functioning of state-socialist social control mechanisms directed at nonnormative sexualities that had long-lasting consequences on the social representation of homosexuality in both countries. PMID- 28001501 TI - The small GTPase ARF6 regulates protein trafficking to control cellular function during development and in disease. AB - The activation of the small GTPase ARF6 has been implicated in promoting several pathological processes related to vascular instability and tumor formation, growth, and metastasis. ARF6 also plays a vital role during embryonic development. Recent studies have suggested that ARF6 carries out these disparate functions primarily by controlling protein trafficking within the cell. ARF6 helps direct proteins to intracellular or extracellular locations where they function in normal cellular responses during development and in pathological processes later in life. This transport of proteins is accomplished through a variety of mechanisms, including endocytosis and recycling, microvesicle release, and as yet uncharacterized processes. This Commentary will explore the functions of ARF6, while focusing on the role of this small GTPase in development and postnatal physiology, regulating barrier function and diseases associated with its loss, and tumor formation, growth, and metastasis. PMID- 28001644 TI - Music on the Mind: an introduction to this special issue of Neurocase. PMID- 28001645 TI - Corrigendum. PMID- 28001646 TI - Effects of vocal training in a musicophile with congenital amusia. AB - Congenital amusia is a condition in which an individual suffers from a deficit of musical pitch perception and production. Individuals suffering from congenital amusia generally tend to abstain from musical activities. Here, we present the unique case of Tim Falconer, a self-described musicophile who also suffers from congenital amusia. We describe and assess Tim's attempts to train himself out of amusia through a self-imposed 18-month program of formal vocal training and practice. We tested Tim with respect to music perception and vocal production across seven sessions including pre- and post-training assessments. We also obtained diffusion-weighted images of his brain to assess connectivity between auditory and motor planning areas via the arcuate fasciculus (AF). Tim's behavioral and brain data were compared to that of normal and amusic controls. While Tim showed temporary gains in his singing ability, he did not reach normal levels, and these gains faded when he was not engaged in regular lessons and practice. Tim did show some sustained gains with respect to the perception of musical rhythm and meter. We propose that Tim's lack of improvement in pitch perception and production tasks is due to long-standing and likely irreversible reduction in connectivity along the AF fiber tract. PMID- 28001756 TI - Transcranial, Red/Near-Infrared Light-Emitting Diode Therapy to Improve Cognition in Chronic Traumatic Brain Injury. AB - OBJECTIVE: We review the general topic of traumatic brain injury (TBI) and our research utilizing transcranial photobiomodulation (tPBM) to improve cognition in chronic TBI using red/near-infrared (NIR) light-emitting diodes (LEDs) to deliver light to the head. tPBM improves mitochondrial function increasing oxygen consumption, production of adenosine triphosphate (ATP), and improving cellular energy stores. Nitric oxide is released from the cells increasing regional blood flow in the brain. Review of published studies: In our previously published study, 11 chronic TBI patients with closed-head TBI caused by different accidents (motor vehicle accident, sports-related, improvised explosive device blast injury) and exhibiting long-lasting cognitive dysfunction received 18 outpatient treatments (Monday, Wednesday, Friday for 6 weeks) starting at 10 months to 8 years post-TBI. LED therapy is nonthermal, painless, and noninvasive. An LED based device classified as nonsignificant risk (FDA cleared) was used. Each LED cluster head (5.35 cm diameter, 500 mW, 22.2 mW/cm2) was applied for 9 min 45 sec (13 J/cm2) using 11 locations on the scalp: midline from front-to-back hairline and bilaterally on frontal, parietal, and temporal areas. Testing was performed before and after transcranial LED (tLED; at 1 week, 1 month, and at 2 months after the 18th treatment) and showed significant improvements in executive function and verbal memory. There were also fewer post-traumatic stress disorder (PTSD) symptoms reported. Ongoing studies: Ongoing, current studies involve TBI patients who have been treated with tLED using either 26 J/cm2 per LED location on the head or treated with intranasal only (iLED) using red (633 nm) and NIR (810 nm) diodes placed into the nostrils. The NIR iLED is hypothesized to deliver photons to the hippocampus, and the red 633 nm iLED is believed to increase melatonin. Results have been similar to the previously published tLED study. Actigraphy sleep data showed increased time asleep (on average one additional hour per night) after the 18th tLED or iLED treatment. LED treatments may be performed in the home. Sham-controlled studies with veterans who have cognitive dysfunction from Gulf War Illness, blast TBI, and TBI/PTSD are currently ongoing. PMID- 28001757 TI - Photobiomodulation Triple Treatment in Peripheral Nerve Injury: Nerve and Muscle Response. AB - BACKGROUND: Muscle preservation or decrease in muscle degeneration and progressive atrophy are major challenges in patients with severe peripheral nerve injury (PNI). Considerable interest exists in the potential therapeutic value of laser phototherapy (photobiomodulation) for restoring denervated muscle atrophy and for enhancing regeneration of severely injured peripheral nerves. As previously published, the laser phototherapy has a protective and immediate effect in PNI. Laser phototherapy in the early stages of muscle atrophy may preserve the denervated muscle by maintaining creatinine kinase (CK) activity and the amount of acetylcholine receptor (AChR). OBJECTIVE AND METHODS: In the present study, the effectiveness of triple treatment laser phototherapy, namely, applied simultaneously at three areas: injured area of the peripheral nerve, corresponding segments of the spinal cord, and corresponding denervated muscle (triple treatment), was evaluated for the treatment of incomplete PNI in rats with the ultimate goal of achieving improved limb function. RESULTS: Forty-five days after the sciatic nerve insult, all rats regained normal walking (functional sciatic index values returned to baseline); however, the long laser irradiation (7 min) group presented the fastest recovery as opposed to short laser irradiation (3 min). A histological evaluation of the nerves revealed that long laser irradiation led to a higher amount of neuronal fibers that were larger than 4 MUm (543 +/- 76.8, p < 0.01) than short irradiation (283 +/- 35.36). A histological evaluation of muscular atrophy showed that long laser irradiation evolved with significantly less muscle atrophy (8.06% +/- 1.23%, p < 0.05) than short irradiation (24.44% +/- 7.26%). CONCLUSIONS: The present study and our previous investigations showed that the laser phototherapy increases biochemical activity and improves morphological recovery in muscle and, thus, could have direct therapeutic applications on muscle, especially during progressive atrophy resulting from PNI. PMID- 28001758 TI - Correction to: Photomedicine and Laser Surgery 2016;34:483-486; DOI: 10.1089/pho.2014.3868. PMID- 28001759 TI - Transcranial Low-Level Laser (Light) Therapy for Brain Injury. AB - BACKGROUND: Low-level laser therapy (LLLT) or photobiomodulation (PBM) is a possible treatment for brain injury, including traumatic brain injury (TBI). METHODS: We review the fundamental mechanisms at the cellular and molecular level and the effects on the brain are discussed. There are several contributing processes that have been proposed to lead to the beneficial effects of PBM in treating TBI such as stimulation of neurogenesis, a decrease in inflammation, and neuroprotection. Both animal and clinical trials for ischemic stroke are outlined. A number of articles have shown how transcranial LLLT (tLLLT) is effective at increasing memory, learning, and the overall neurological performance in rodent models with TBI. RESULTS: Our laboratory has conducted three different studies on the effects of tLLLT on mice with TBI. The first studied pulsed against continuous laser irradiation, finding that 10 Hz pulsed was the best. The second compared four different wavelengths, discovering only 660 and 810 nm to have any effectiveness, whereas 732 and 980 nm did not. The third looked at varying regimens of daily laser treatments (1, 3, and 14 days) and found that 14 laser applications was excessive. We also review several studies of the effects of tLLLT on neuroprogenitor cells, brain-derived neurotrophic factor and synaptogenesis, immediate early response knockout mice, and tLLLT in combination therapy with metabolic inhibitors. CONCLUSIONS: Finally, some clinical studies in TBI patients are covered. PMID- 28001907 TI - Ionizing Radiation Induces Innate Immune Responses in Macrophages by Generation of Mitochondrial Reactive Oxygen Species. AB - During radiotherapy for tumors, the innate immune system also responds to ionizing radiation and induces immune modulation. However, little is known about the molecular mechanisms by which radiation modulates innate immune responses. In this study, we observed that radiation triggered the generation of mitochondrial reactive oxygen species (mROS), leading to innate immune responses in murine bone marrow-derived macrophages (BMDM). Radiation-induced mROS was essential for robust induction of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-12p40 mRNA and protein in BMDM. Exposure to radiation also led to rapid activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF) kappaB pathways in BMDM. Notably, radiation-induced MAPK activation and NF-kappaB signaling were regulated by mROS in macrophages. Additionally, radiation-induced expression of TNF-alpha, IL-6 and IL-12p40 was dependent on JNK, p38 and NF kappaB activation in BMDM. These data suggest a key role for radiation-induced pro-inflammatory responses and activation of the MAPK and NF-kappaB pathways through a triggering mechanism involving mROS generation. PMID- 28001909 TI - NEUDOSE: A CubeSat Mission for Dosimetry of Charged Particles and Neutrons in Low Earth Orbit. AB - During space missions, astronauts are exposed to a stream of energetic and highly ionizing radiation particles that can suppress immune system function, increase cancer risks and even induce acute radiation syndrome if the exposure is large enough. As human exploration goals shift from missions in low-Earth orbit (LEO) to long-duration interplanetary missions, radiation protection remains one of the key technological issues that must be resolved. In this work, we introduce the NEUtron DOSimetry & Exploration (NEUDOSE) CubeSat mission, which will provide new measurements of dose and space radiation quality factors to improve the accuracy of cancer risk projections for current and future space missions. The primary objective of the NEUDOSE CubeSat is to map the in situ lineal energy spectra produced by charged particles and neutrons in LEO where most of the preparatory activities for future interplanetary missions are currently taking place. To perform these measurements, the NEUDOSE CubeSat is equipped with the Charged & Neutral Particle Tissue Equivalent Proportional Counter (CNP-TEPC), an advanced radiation monitoring instrument that uses active coincidence techniques to separate the interactions of charged particles and neutrons in real time. The NEUDOSE CubeSat, currently under development at McMaster University, provides a modern approach to test the CNP-TEPC instrument directly in the unique environment of outer space while simultaneously collecting new georeferenced lineal energy spectra of the radiation environment in LEO. PMID- 28001908 TI - Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism. AB - In this study we used magnetic resonance imaging (MRI) biomarkers to monitor the acute temporal changes in tumor vascular physiology with the aim of identifying the vascular signatures that predict response to combined anti-angiogenic and radiation treatments. Forty-three athymic rats implanted with orthotopic U-251 glioma cells were studied for approximately 21 days after implantation. Two MRI studies were performed on each animal, pre- and post-treatment, to measure tumor vascular parameters. Two animal groups received treatment comprised of Cilengitide, an anti-angiogenic agent and radiation. The first group received a subcurative regimen of Cilengitide 1 h before irradiation, while the second group received a curative regimen of Cilengitide 8 h before irradiation. Cilengitide was given as a single dose (4 mg/kg; intraperitoneal) after the pretreatment MRI study and before receiving a 20 Gy radiation dose. After irradiation, the post treatment MRI study was performed at selected time points: 2, 4, 8 and 12 h (n = >=5 per time point). Significant changes in vascular parameters were observed at early time points after combined treatments in both treatment groups (1 and 8 h). The temporal changes in vascular parameters in the first group (treated 1 h before exposure) resembled a previously reported pattern associated with radiation exposure alone. Conversely, in the second group (treated 8 h before exposure), all vascular parameters showed an initial response at 2-4 h postirradiation, followed by an apparent lack of response at later time points. The signature time point to define the "synergy" of Cilengitide and radiation was 4 h postirradiation. For example, 4 h after combined treatments using a 1 h separation (which followed the subcurative regimen), tumor blood flow was significantly decreased, nearly 50% below baseline (P = 0.007), whereas 4 h after combined treatments using an 8 h separation (which followed the curative regimen), tumor blood flow was only 10% less than baseline. Comparison between the first and second groups further revealed that most other vascular parameters were maximally different 4 h after combined treatments. In conclusion, the data are consistent with the assertion that the delivery of radiation at the vascular normalization time window of Cilengitide improves radiation treatment outcome. The different vascular responses after the different delivery times of combined treatments in light of the known tumor responses under similar conditions would indicate that timing has a crucial influence on treatment outcome and long-term survival. Tracking acute changes in tumor physiology after monotherapy or combined treatments appears to aid in identifying the beneficial timing for administration, and perhaps has predictive value. Therefore, judicial timing of treatments may result in optimal treatment response. PMID- 28001910 TI - Substance Use, Health, and Functioning Characteristics of Medical Marijuana Program Participants Compared to the General Adult Population in Ontario (Canada). AB - Existent profiles of Medical Marijuana Program (MMP) participants indicate common and co-morbid chronic diseases, yet evidence on disability or functioning as well as comparisons with general populations are largely lacking. This study compared health, substance use, and functioning status among formally approved MMP participants with the general adult population in Ontario (Canada). A community recruited sample (n = 53) of MMP participants was compared to a sub-sample (n = 510) of the representative Centre for Addiction and Mental Health (CAMH) Monitor (2015 cycle) survey of Ontario general population adults (ages 18+) based on identical telephone-based interviews regarding substance use, health, and functioning measures. Means and standard deviations for all indicators were computed by sex, controlled for age and education, and compared by regression techniques. MMP participants were more likely to be male, younger, and less socio economically integrated; they indicated more common psychoactive substance (e.g., tobacco, daily cannabis) and psychotropic medication use, as well as overall worse physical and mental health and functioning status. Marked differences between MMP participants and general population adults were observed. MMPs appear to attract individuals with complex chronic health problems; however, little is known about the impact of MMP participation on these. PMID- 28001911 TI - Sustained Professional Development on Cooperative Learning: Impact on Six Teachers' Practices and Students' Learning. AB - PURPOSE: It has been argued, extensively and internationally, that sustained school-based continuous professional development (CPD) has the potential to overcome some of the shortcomings of traditional one-off CPD programs. Yet, the evidence base on more effective or less effective forms of CPD is contradictory. The mechanisms by which sustained support should be offered are unclear, and the impacts on teachers' and students' learning are complex and difficult to track. The purpose of this study was to examine the impact of a sustained school-based, tailored, and supported CPD program on teachers' practices and students' learning. METHOD: Data are reported from 6 case studies of individual teachers engaged in a yearlong CPD program focused on cooperative learning. The CPD program involved participatory action research and frequent interaction/support from a boundary spanner (researcher/facilitator). Data were gathered from 29 video-recorded lessons, 108 interviews, and 35 field journal entries. RESULTS: (a) Individualized (external) support, (b) departmental (internal) support, and (c) sustained support impacted teachers' practices of cooperative learning. The teachers adapted their practices of cooperative learning in response to their students' learning needs. Teachers began to develop a level of pedagogical fluency, and in doing so, teachers advanced students' learning. CONCLUSIONS: Because this study demonstrates impact, it contributes to international literature on effective CPD. The key contribution is the detailed evidence about how and why CPD supported 6 individual teachers to learn-differently-and the complexity of the learning support required to engage in ongoing curriculum development to positively impact student learning. PMID- 28001912 TI - Air Force Chaplains' Perceived Effectiveness on Service Member's Resilience and Satisfaction. AB - This study examined how 3,777 active duty male United States Air Force service members' (SMs) rank and residence location moderated the associations between perceived chaplain effectiveness, SMs' resilience, family coping, marital satisfaction, and satisfaction with the Air Force (AF). A multiple-sample structural equation model was conducted with four subgroups of SMs who had received chaplain support: enlisted members living on base, enlisted members living off base, officers living on base, and officers living off base. Chaplain effectiveness was significantly related, both directly and indirectly, to SM's spirituality, resilience, family coping, marital satisfaction, and AF satisfaction. Resilience was significantly associated with increased AF satisfaction for all SMs, except for those living on base. However, living on base was found to strengthen the protective factor between family coping and relationship satisfaction. Rank was found to moderate the link between resilience and family coping. Family coping was significantly related to increased relationship satisfaction. PMID- 28001963 TI - Second in a Series on Neighborhoods and Communities: Focus on Community Development. PMID- 28001962 TI - Benzodiazepine Dependence among Young Adult Participants in the Club Scene Who Use Drugs. AB - Young adults ages 18-29 report the highest rates of benzodiazepine (BZD) misuse in the United States. The majority of club drug users are also in this age group, and BZD misuse is prevalent among participants in club scenes. This article examines BZD dependence and its correlates among young adult participants in the electronic dance music (EDM) culture in Miami, Florida, who use drugs. Structured interviews were with men and women (N = 356) ages 18 to 29 who reported regular attendance at EDM venues and recent use of both club drugs and BZDs. Prevalences of BZD-related problems were 12.6% for BZD dependence, 21.1% BZD abuse, and 24.2% BZD abuse and/or dependence. In a multivariate logistic regression model, younger age (OR 0.85; 95% CI 0.76, 0.96), severe mental distress (OR 8.30; 95% CI 3.07, 22.49), daily marijuana use (OR 2.10; 95% CI 1.03, 4.27), and heavy opioid use (OR 2.33; 95% CI 1.12, 4.83) were associated with BZD dependence. BZD dependence was higher in this sample than in other populations described in the literature. The links between BZD dependence, overdose history, and heavy opioid misuse are especially worrisome among this young sample. Recommendations for intervention and research are discussed. PMID- 28001965 TI - Senseless Violence: A Global Problem With Psychological Ramifications. PMID- 28001966 TI - Senseless Violence: An Overview. AB - In this epilogue I review some of the existing literature on senseless violence, highlighting the phenomenon, examining the factors that cause people to commit such horrific deeds, and the complex thoughts, feelings, and acts that precede such senseless violence. The article ends with some reflections on what we should do as a profession and as a society to help curb this life shattering violence. PMID- 28002019 TI - Lysosomes in programmed cell death pathways: from initiators to amplifiers. AB - Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it. PMID- 28002020 TI - Novel domain architectures and functional determinants in atypical annexins revealed by phylogenomic analysis. AB - The fundamental cellular role and molecular interactions of annexins in vesicle trafficking and membrane remodeling remain to be further clarified in order to better understand and exploit their contributions to health and disease. We focused on distinctive features of atypical annexins from all domains of life using phylogenomic, molecular systematic and experimental approaches, to extend the current paradigm and better account for annexin diversity of structure, function and mechanistic role in membrane homeostasis. The analysis of gene duplications, organization of domain architectures and profile hidden Markov models of subfamily orthologs defined conserved structural features relevant to molecular interactions and functional divergence of seven family clades ANXA-G. Single domain annexins of bacteria, including cyanobacteria, were frequently coupled to enzymatic units conceivably related to membrane metabolism and remodeling. Multiple ANX domains (up to 20) and various distinct functional domains were observed in unique annexins. Canonical type 2 calcium binding ligands were well-preserved in roughly half of all ANX domains, but alternative structural motifs comprised of 'KGD', cysteine or tryptophan residues were prominently conserved in the same strategic interhelical loops. Selective evolutionary constraint, site-specific location and co-occurrence in all kingdoms identify alternative modes of fundamental binding interactions for annexins. PMID- 28002021 TI - Proteases and cytokines as mediators of interactions between cancer and stromal cells in tumours. AB - Proteolytic enzymes are highly relevant in different processes of cancer progression. Their interplay with other signalling molecules such as cytokines represents important regulation of multicellular cross-talk. In this review, we discuss protease regulation mechanisms of cytokine signalling in various types of cancer. Additionally, we highlight the reverse whereby cytokines have an impact on protease expression in an autocrine and paracrine manner, representing complex feedback mechanisms among multiple members of these two protein families. The relevance of the protease-cytokine axis is illustrated in glioblastoma, where interactions between normal mesenchymal stem cells and cancer cells play an important role in this very malignant form of brain cancer. PMID- 28002022 TI - Interface analysis of small GTP binding protein complexes suggests preferred membrane orientations. AB - Crystal structures of small GTP binding protein complexes with their effectors and regulators reveal that one particularly flat side of the G domain that contains helix alpha4 and the C-terminal helix alpha5 is practically devoid of contacts. Although this observation seems trivial as the main binding targets are the switch I and II regions opposite of this side, the fact that all interacting proteins, even the largest ones, seem to avoid occupying this area (except for Ran, that does not localize to membranes) is very striking. An orientation with this 'flat' side parallel to the membrane was proposed before and would allow simultaneous interaction of the lipidated C-terminus and positive charges in the alpha4 helix with the membrane while being bound to effector or regulator molecules. Furthermore, this 'flat' side might be involved in regulatory mechanisms: a Ras dimer that is found in different crystal forms interacts exactly at this side. Additional interface analysis of GTPase complexes nicely confirms the effect of different flexibilities of the GTP and GDP forms. Besides Ran proteins, guanine nucleotide exchange factors (GEFs) bury the largest surface areas to provide the binding energy to open up the switch regions for nucleotide exchange. PMID- 28002023 TI - Valproic acid (VPA) enhances cisplatin sensitivity of non-small cell lung cancer cells via HDAC2 mediated down regulation of ABCA1. AB - Valproic acid (VPA) has been suggested to be a histone deacetylase inhibitor (HDACI). Our present study revealed that VPA at 1 mm, which had no effect on cell proliferation, can significantly increase the sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin (DDP). VPA treatment markedly decreased the mRNA and protein levels of ABCA1, while had no significant effect on ABCA3, ABCA7 or ABCB10. Luciferase reporter assays showed that VPA can decrease the ABCA1 promoter activity in both A549 and H358 cells. VPA treatment also decreased the phosphorylation of SP1, which can bind to -100 and -166 bp in the promoter of ABCA1. While the phosphorylation of c-Fos and c-Jun were not changed in VPA treated NSCLC cells. Over expression of HDAC2 attenuated VPA induced down regulation of ABCA1 mRNA expression and promoter activities. Over expression of HDAC2 also attenuated VPA induced DDP sensitivity of NSCLC cells. These data revealed that VPA can increase the DDP sensitivity of NSCLC cells via down regulation of ABCA1 through HDAC2/SP1 signals. It suggested that combination of VPA and anticancer drugs such as DDP might be great helpful for treatment of NSCLC patients. PMID- 28002024 TI - The cancer cell adhesion resistome: mechanisms, targeting and translational approaches. AB - Cell adhesion-mediated resistance limits the success of cancer therapies and is a great obstacle to overcome in the clinic. Since the 1990s, where it became clear that adhesion of tumor cells to the extracellular matrix is an important mediator of therapy resistance, a lot of work has been conducted to understand the fundamental underlying mechanisms and two paradigms were deduced: cell adhesion mediated radioresistance (CAM-RR) and cell adhesion-mediated drug resistance (CAM DR). Preclinical work has evidently demonstrated that targeting of integrins, adapter proteins and associated kinases comprising the cell adhesion resistome is a promising strategy to sensitize cancer cells to both radiotherapy and chemotherapy. Moreover, the cell adhesion resistome fundamentally contributes to adaptation mechanisms induced by radiochemotherapy as well as molecular drugs to secure a balanced homeostasis of cancer cells for survival and growth. Intriguingly, this phenomenon provides a basis for synthetic lethal targeted therapies simultaneously administered to standard radiochemotherapy. In this review, we summarize current knowledge about the cell adhesion resistome and highlight targeting strategies to override CAM-RR and CAM-DR. PMID- 28002025 TI - Increased beat-to-beat T-wave variability in myocardial infarction patients. AB - The purpose of this study was to investigate the beat-to-beat variability of T waves (TWV) and to assess the diagnostic capabilities of T-wave-based features for myocardial infarction (MI). A total of 148 recordings of standard 12-lead electrocardiograms (ECGs) from 79 MI patients (22 females, mean age 63+/-12 years; 57 males, mean age 57+/-10 years) and 69 recordings from healthy subjects (HS) (17 females, 42+/-18 years; 52 males, 40+/-13 years) were studied. For the quantification of beat-to-beat QT intervals in ECG signal, a template-matching algorithm was applied. To study the T-waves beat-to-beat, we measured the angle between T-wave max and T-wave end with respect to Q-wave (?alpha) and T-wave amplitudes. We computed the standard deviation (SD) of beat-to-beat T-wave features and QT intervals as markers of variability in T-waves and QT intervals, respectively, for both patients and HS. Moreover, we investigated the differences in the studied features based on gender and age for both groups. Significantly increased TWV and QT interval variability (QTV) were found in MI patients compared to HS (p<0.05). No significant differences were observed based on gender or age. TWV may have some diagnostic attributes that may facilitate identifying patients with MI. In addition, the proposed beat-to-beat angle variability was found to be independent of heart rate variations. Moreover, the proposed feature seems to have higher sensitivity than previously reported feature (QT interval and T-wave amplitude) variability for identifying patients with MI. PMID- 28002026 TI - Validation and comparison of shank and lumbar-worn IMUs for step time estimation. AB - Gait assessment is frequently used as an outcome measure to determine changes in an individual's mobility and disease processes. Inertial measurement units (IMUs) are quickly becoming commonplace in gait analysis. The purpose of this study was to determine and compare the validity of shank and lumbar IMU mounting locations in the estimation of temporal gait features. Thirty-seven adults performed 20 walking trials each over a gold standard force platform while wearing shank and lumbar-mounted IMUs. Data from the IMUs were used to estimate step times using previously published algorithms and were compared with those derived from the force platform. There was an excellent level of correlation between the force platform and shank (r=0.95) and lumbar-mounted (r=0.99) IMUs. Bland-Altman analysis demonstrated high levels of agreement between the IMU and the force platform step times. Confidence interval widths were 0.0782 s for the shank and 0.0367 s for the lumbar. Both IMU mounting locations provided accurate step time estimations, with the lumbar demonstrating a marginally superior level of agreement with the force platform. This validation indicates that the IMU system is capable of providing step time estimates within 2% of the gold standard force platform measurement. PMID- 28002028 TI - Within-day biological variation and hour-to-hour reference change values for hematological parameters. AB - BACKGROUND: Middle- and long-term biological variation data for hematological parameters have been reported in the literature. Within-day 24-h variability profiles for hematological parameters are currently lacking. However, comprehensive hour-to-hour variability data are critical to detect diurnal cyclical rhythms, and to take into account the 'time of sample collection' as a possible determinant of natural fluctuation. In this study, we assessed 24-h variation profiles for 20 hematological parameters. METHODS: Blood samples were collected under standardized conditions from 24 subjects every hour for 24 h. At each measurement, 20 hematological parameters were determined in duplicate. Analytical variation (CVA), within-subject biological variation (CVI), between subject biological variation (CVG), index of individuality (II), and reference change values (RCVs) were calculated. For the parameters with a diurnal rhythm, hour-to-hour RCVs were determined. RESULTS: All parameters showed higher CVG than CVI. Highest CVG was found for eosinophils (46.6%; 95% CI, 34.9%-70.1%) and the lowest value was mean corpuscular hemoglobin concentration (MCHC) (3.2%; 95% CI, 2.4%-4.8%). CVI varied from 0.4% (95% CI, 0.32%-0.42%) to 20.9% (95% CI, 19.4% 22.6%) for red cell distribution width (RDW) and eosinophils, respectively. Six hematological parameters showed a diurnal rhythm. CONCLUSIONS: We present complete 24-h variability profiles for 20 hematological parameters. Hour-to-hour reference changes values may help to better discriminate between random fluctuations and true changes in parameters with rhythmic diurnal oscillations. PMID- 28002027 TI - Coexistence of anti-beta2-glycoprotein I domain I and anti phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk. AB - BACKGROUND: Highly specific assays for measuring antiphospholipid antibodies (aPLs) are required for accurate assessment of thrombotic risk. aPLs against beta2-glycoprotein I domain I (anti-beta2GPIdI) and against prothrombin complexed with phosphatidylserine (anti-PS/PT) have been recently identified as being associated with a hypercoagulable state. This study evaluated the synergism between anti-beta2GPIdI and anti-PS/PT for predicting thrombotic events. METHODS: A total of 180 patients with clinical suspicion of hypercoagulability were evaluated. The plasma levels of lupus anticoagulant (LA) and antibodies against anticardiolipin (anti-CL) (IgG and IgM), beta2GPI (IgG and IgM), PS/PT (IgG and IgM), and beta2GPI dI (IgG) were measured. RESULTS: IgG anti-beta2GPIdI and LA were highly associated with thrombosis. Mean values and positivity rates of IgG anti-beta2GPI dI and IgG anti-PS/PT were significantly higher in the triple positive group (LA+, IgG anti-CL+, IgG anti-beta2GPI+) than in the other groups. Interestingly, the thrombotic risk [odds ratio (OR) 24.400, 95% confidence interval (CI) 1.976-63.273, p<0.001] of the newly defined triple positive group (LA+, IgG anti-CL+, IgG anti-beta2GPIdI+; OR 11.182, 95% CI 1.976-63.273, p=0.006) was more than twice that of the triple-positive group (LA+, IgG anti CL+, IgG anti-beta2GPI+). Double positivity for IgG anti-PS/PT and IgG anti beta2GPI also indicated significant thrombotic risk (OR 7.467, 95% CI 2.350 23.729, p=0.001). Furthermore, the thrombotic risk associated with double positivity for IgG anti-PS/PT and IgG anti-beta2GPIdI was markedly elevated (OR 33.654, 95% CI 6.322-179.141, p<0.001). CONCLUSIONS: Our data suggest that simultaneous measurement of IgG anti-beta2GPIdI and IgG anti-PS/PT may improve clinical decision-making for aPL-positive patients. PMID- 28002029 TI - QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions. AB - BACKGROUND: Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. METHODS: After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. RESULTS: The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86 1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. CONCLUSIONS: The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice. PMID- 28002030 TI - Anti-hyperglycemic activity of Aegle marmelos (L.) corr. is partly mediated by increased insulin secretion, alpha-amylase inhibition, and retardation of glucose absorption. AB - BACKGROUND: Aegle marmelos (commonly known as Bael, golden apple) was formerly described to have anti-hyperglycemic activity. The present study aimed to explore the possible effects, in depth, of A. marmelos extracts on carbohydrate absorption, glucose utilization, and alpha-amylase inhibition and insulin content in pancreases of type 2 diabetic rats. METHODS: This research begins with fasting blood glucose and oral glucose tolerance test (OGTT) to evaluate the primary anti hyperglycemic effect in chemically induced type 2 diabetic rats. Furthermore, the plasma insulin concentration and serum glucose level were studied, which include measuring the sucrose content in six different segments of the gastrointestinal (GI) tract of the rats following oral sucrose feeding. An in situ, perfused, intestinal model in rats and glucose-fiber binding assay were conducted to find the effects of A. marmelos extracts on glucose absorption. Extract effects on carbohydrate breakdown, intestinal disaccharidase enzyme activity, and alpha amylase inhibition were assessed. Effect on GI motility was evaluated using BaSO4 milk traverse test. RESULTS: Treatment of extracts suppressed blood glucose elevation after oral sucrose (2.5 g/kg) administration and significantly (p<0.05) improved oral glucose tolerance in type 2 diabetic rats. Aegle marmelos extracts showed remarkable (p<0.05) changes in plasma insulin secretion at 30 min and 60 min, respectively. A noticeable reduction in glucose absorption was observed in the in situ perfused rat intestinal model at two different doses (250 and 500 mg/kg). The extract was also found to inhibit the action of both alpha-amylase and intestinal disaccharidase enzyme, and this study was affirmed again by the sucrose malabsorption test, where sucrose digestion was inhibited throughout the length of the GI tract. During this chronic study, body mass of rats became normal and their polydipsic and polyphagic conditions were ameliorated also. CONCLUSIONS: The findings demonstrate that anti-hyperglycemic activity of A. marmelos is mediated by the inhibition of carbohydrate digestion and absorption, and improvement of insulin action to uptake glucose in peripheral tissue. Additional study is required to correlate A. marmelos extracts' specific mechanism of glucose-fiber binding capacity and glucose transporters. PMID- 28002031 TI - Intentional Long-Term Repeated Insulin Overdosing for 15 years in a 55-year Old Male with Compulsive Personality Traits. PMID- 28002032 TI - Hyponatremia - unfavourable prognostic factor in hepatic cirrhosis. AB - Hyponatremia is defined by a level of Na in serum below or equal to 136 mEq/L while in hepatic cirrhosis it is classically considered as relevant only at a level of Na below 130 mEq/L. Hyponatremia frequently occurs in patients with end stage hepatic disease. The frequency and severity are variable but it has been estimated that it occurs with a frequency of 57% in hospitalized patients with cirrhosis and in those on waiting lists for hepatic transplants. Signs and symptoms of hyponatremia are related to dysfunctions of the central nervous system, due to migration of the water from intravascular space to the brain cells, resulting in the occurrence of cerebral edema. Therapeutic options in hyponatremia are limited and are based on restriction of water consumption, exclusion of diuretics and vaptans. Hepatic transplant remains the only definitive treatment for end-stage hepatic diseases in which hyponatremia has occurred. PMID- 28002033 TI - Depression and Hypothyroidism in a Population-Based Study of Iranian Women. AB - BACKGROUND: Recent biochemical and physiological investigations have focused on the fundament of mood disorders in thyroid dysfunction. The present study aimed to address depressive disorder in a sample of Iranian hypothyroid women compared to euthyroid individuals. METHODS: Thirty consecutive hypothyroid female patients aged 25 to 40 years who referred to the Endocrinology and Metabolism Clinic at Rasoul-e-Akram Hospital in Tehran within a four-month period in 2015 were assessed. Thirty healthy euthyroid subjects matched for sex, age, and educational level were selected as the control. For assessment of depression status, Depression Anxiety Stress Scale-21 (DASS-21) was employed. RESULTS: The study showed higher mean depression score in hypothyroid patients when compared to euthyroid ones (13.8 +/- 9.5 versus 5.8 +/- 5.2, p = 0.010). No significant association was revealed between mean depression score and patients' education level (p = 0.627), age (p = 0.967), occupation status (p = 0.211), and marital status (p = 0.556). CONCLUSION: Hypothyroid women are predisposed to depressive symptoms independent of their baseline demographic and socioeconomic characteristics. PMID- 28002034 TI - Serum Progranulin Levels in Type 2 Diabetic Patients with Metabolic Syndrome. AB - INTRODUCTION: The role of progranulin in individuals with metabolic syndrome is not exactly clear.We aimed to assess the serum level of progranulin in type 2 diabetic patients with and without metabolic syndrome and compare them with healthy controls. METHODS: The study included 60 patients with type 2 diabetes and 30 healthy individuals as control groups. Biochemical parameters and progranulin levels were determined. RESULTS: Subjects with metabolic syndrome showed significantly higher levels of triglyceride, waist circumference, BMI, systolic and diastolic blood pressure than subjects without metabolic syndrome and the control groups, while HDL-cholesterol level was significantly lower in subjects with metabolic syndrome. Fasting blood sugar was significantly higher in type 2 diabetic patients than in the control groups. Serum level of progranulin was slightly increased in subjects with metabolic syndrome. Serum progranulin level had no significant relationship with metabolic syndrome components. CONCLUSIONS: Serum progranulin was also not dependent on cardiometabolic risk factors for subjects with metabolic syndrome, but it could be considered for the management of type 2 diabetes mellitus. Further studies are recommended to explain the effect of progranulin on the pathogenesis of metabolic risk factors. PMID- 28002035 TI - The Effect of Omega-3 Supplement on Serum Lipid Profile in Patients Undergoing Hemodialysis: A Randomized Clinical Trial. AB - BACKGROUND: Some recent suggestions could show omega-3 condition deficiency following prolonged hemodialysis; however, these claims and speculations have not been well demonstrated with sufficient evidences. Hence, we attempted to assess the beneficial effects of omega-3 on lipid profile in patients with end-stage renal disease (ESRD) undergoing hemodialysis. METHODS: One hundred and seventeen ESRD patients who were on maintenance dialysis in Rasoul-e-Akram and Madaen Hospitals were enrolled in this randomized clinical trial. These patients were divided into two groups randomly using block randomization method (57 patients as the case group receiving omega-3 for 12 weeks and 60 as the control group). Blood sample was taken from all patients for measurement of lipid profile, serum hemoglobin, and C-reactive protein at baseline as well as after the completion of interventions (after 12 weeks). RESULTS: The average change in the value of HDL-C was significantly more in the patients who received omega-3 than in the control group (MD, -7 mg/dL; 95% CI, -11 to 0 p = 0.000). Also, the reduction in serum creatinine level was more in the omega-3 group than in the control group (MD, 0.7 mg/dL; 95% CI, -0.4 to 2.1 p = 0.023). The change in other indices including serum triglyceride, total cholesterol, and serum hemoglobin levels was not different between the two groups. The multivariable linear regression analysis showed no difference in serum HDL level between the two groups adjusted for sex, age, and time of dialysis, while the level of serum HDL-C could be adversely predicted by duration time. Similar regression model showed a between-group difference in serum creatinine in the presence of potential confounders. CONCLUSION: The change in serum HDL level following use of omega-3 supplement is influenced by time of dialysis, not by drug effect. However, consumption of omega 3 can significantly reduce serum creatinine. PMID- 28002036 TI - Serum Levels of Oxidative Stress Markers in Patients with Type 2 Diabetes Mellitus and Non-alcoholic Steatohepatitis. AB - INTRODUCTION: Oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. The aim of this study was to evaluate the serum levels of oxidative stress markers in patients with type 2 diabetes mellitus (DMT2) and non-alcoholic steatohepatitis (NASH) and test their relationships with clinical and biochemical patient characteristics, compared to patients with DMT2 without non-alcoholic fatty liver disease (NAFLD), and controls. MATERIALS AND METHODS: In all, 60 consecutive patients with DMT2 and NASH, 55 with DMT2 without NAFLD, and 50 age-and-gender-matched healthy subjects participated in the study. The serum levels of protein carbonyls and 8 isoprostane were determined by ELISA methods, while the serum levels of malondialdehyde (MDA) were detected by means of the spectrophotometric method. Clinical, demographic, and laboratory parameters were examined for all the subjects included in the study. Multivariate logistic regression was used to test the independent predictive factors in the relationships investigated here. RESULTS: Patients with DMT2 and NASH displayed significantly higher serum levels of protein carbonyls (1.112 +/- 0.42 nmol/dL), MDA (6.181 +/- 1.81 ng/mL), and 8 isoprostane (338.6 +/- 98.5 pg/mL) compared to patients with DMT2 without NAFLD, and controls. Results of multivariate logistic regression analyses indicate that in patients with DMT2 and NASH, the serum levels of oxidative stress markers were independently and positively associated with: HbA1c, duration of diabetes, the UKPDS cardiovascular risk score (for protein carbonyls); age, LDL-cholesterol (for 8-isoprostane); and triglycerides serum levels (for MDA). CONCLUSIONS: Our findings indicate that the process of oxidative stress tends to increase in patients with DMT2 and NASH, compared to patients with DMT2 without NAFLD, and controls. This evidence suggests that an antioxidant therapy might prove useful in the treatment of patients with DMT2 and NASH. PMID- 28002037 TI - Electronic structure of K-doped picene film on HOPG. AB - We have performed potassium (K)-doping dependent photoemission (PES) measurements of picene film on highly oriented pyrolytic graphite (HOPG). K-doping dependent valence band PES data exhibits a shift of the valence band to a higher binding energy, indicative of the charge transfer from the K atoms to the picene film. K doping dependent PES spectra near the Fermi level (E F) show the appearance and disappearance of a Fermi edge, indicating the metallic properties of the film at certain K concentrations. High-resolution PES spectrum at the lowest measured temperature does not show an opening of the superconducting gap, requesting further studies to explore the superconducting properties of the K-doped picene film. The results will be discussed by comparison with previous and recent spectroscopic studies. PMID- 28002038 TI - Colloidal liquid crystals in square confinement: isotropic, nematic and smectic phases. AB - We report on the confinement of colloidal liquid crystals in three dimensional chambers with a square footprint. To this end we use colloidal silica rods and exploit their relatively large density difference with respect to the dispersing solvent to study isotropic, nematic and smectic phases confined into a single chamber. Combining laser scanning confocal microscopy and soft-lithography techniques enables us to characterize the configurations down to the single particle level. We will focus on the smectic phase and compare to recent theories and simulations. PMID- 28002040 TI - Optical response of correlated electron systems. AB - Recent progress in experimental techniques has made it possible to extract detailed information on dynamics of carriers in a correlated electron material from its optical conductivity, [Formula: see text]. This review consists of three parts, addressing the following three aspects of optical response: (1) the role of momentum relaxation; (2) [Formula: see text] scaling of the optical conductivity of a Fermi-liquid metal, and (3) the optical conductivity of non Fermi-liquid metals. In the first part (section 2), we analyze the interplay between the contributions to the conductivity from normal and umklapp electron electron scattering. As a concrete example, we consider a two-band metal and show that although its optical conductivity is finite it does not obey the Drude formula. In the second part (sections 3 and 4), we re-visit the Gurzhi formula for the optical scattering rate, [Formula: see text], and show that a factor of [Formula: see text] is the manifestation of the 'first-Matsubara-frequency rule' for boson response, which states that [Formula: see text] must vanish upon analytic continuation to the first boson Matsubara frequency. However, recent experiments show that the coefficient b in the Gurzhi-like form, [Formula: see text], differs significantly from b = 4 in most of the cases. We suggest that the deviations from Gurzhi scaling may be due to the presence of elastic but energy-dependent scattering, which decreases the value of b below 4, with b = 1 corresponding to purely elastic scattering. In the third part (section 5), we consider the optical conductivity of metals near quantum phase transitions to nematic and spin-density-wave states. In the last case, we focus on 'composite' scattering processes, which give rise to a non-Fermi-liquid behavior of the optical conductivity at T = 0: [Formula: see text] at low frequencies and [Formula: see text] at higher frequencies. We also discuss [Formula: see text] scaling of the conductivity and show that [Formula: see text] in the same model scales in a non-Fermi-liquid way, as [Formula: see text]. PMID- 28002039 TI - Pulse wave imaging using coherent compounding in a phantom and in vivo. AB - Pulse wave velocity (PWV) is a surrogate marker of arterial stiffness linked to cardiovascular morbidity. Pulse wave imaging (PWI) is a technique developed by our group for imaging the pulse wave propagation in vivo. PWI requires high temporal and spatial resolution, which conventional ultrasonic imaging is unable to simultaneously provide. Coherent compounding is known to address this tradeoff and provides full aperture images at high frame rates. This study aims to implement PWI using coherent compounding within a GPU-accelerated framework. The results of the implemented method were validated using a silicone phantom against static mechanical testing. Reproducibility of the measured PWVs was assessed in the right common carotid of six healthy subjects (n = 6) approximately 10-15 mm before the bifurcation during two cardiac cycles over the course of 1-3 d. Good agreement of the measured PWVs (3.97 +/- 1.21 m s-1, 4.08 +/- 1.15 m s-1, p = 0.74) was obtained. The effects of frame rate, transmission angle and number of compounded plane waves on PWI performance were investigated in the six healthy volunteers. Performance metrics such as the reproducibility of the PWVs, the coefficient of determination (r 2), the SNR of the PWI axial wall velocities ([Formula: see text]) and the percentage of lateral positions where the pulse wave appears to arrive at the same time-point, indicating inadequacy of the temporal resolution (i.e. temporal resolution misses) were used to evaluate the effect of each parameter. Compounding plane waves transmitted at 1 degrees increments with a linear array yielded optimal performance, generating significantly higher r 2 and [Formula: see text] values (p ? 0.05). Higher frame rates (?1667 Hz) produced improvements with significant gains in the r 2 coefficient (p ? 0.05) and significant increase in both r 2 and [Formula: see text] from single plane wave imaging to 3-plane wave compounding (p ? 0.05). Optimal performance was established at 2778 Hz with 3 plane waves and at 1667 Hz with 5 plane waves. PMID- 28002041 TI - Pattern-induced anchoring transitions in nematic liquid crystals. AB - In this paper we revisit the problem of a nematic liquid crystal in contact with patterned substrates. The substrate is modelled as a periodic array of parallel infinite grooves of well-defined cross-section sculpted on a chemically homogeneous substrate which favours local homeotropic anchoring of the nematic. We consider three cases: a sawtooth, a crenellated and a sinusoidal substrate. We analyse this problem within the modified Frank-Oseen formalism. We argue that, for substrate periodicities much larger than the extrapolation length, the existence of different nematic textures with distinct far-field orientations, as well as the anchoring transitions between them, are associated with the presence of topological defects either on or close to the substrate. For the sawtooth and sinusoidal cases, we observe a homeotropic to planar anchoring transition as the substrate roughness increases. On the other hand, a homeotropic to oblique anchoring transition is observed for crenellated substrates. In this case, the anchoring phase diagram shows a complex dependence on the substrate roughness and substrate anchoring strength. PMID- 28002042 TI - The linear and non-linear magnetic response of a tri-uranium single molecule magnet. AB - We report here low temperature magnetization isotherms for the single molecule magnet, (UO2-L)3. By analyzing the low temperature magnetization in terms of M = chi 1 B + chi 3 B 3 we extract the linear susceptibility chi 1 and the leading order nonlinear susceptibility chi 3. We find that chi 1 exhibits a peak at a temperature of T 1 = 10.4 K with chi 3 also exhibiting a peak but at a reduced temperature T 3 = 5 K. At the lowest temperatures the isotherms exhibit a critical field B c = 11.5 T marked by a clear point of inflection. A minimal Hamiltonian employing S = 1 (pseudo) spins with only a single energy scale (successfully used to model the behavior of bulk f-electron metamagnets) is shown to provide a good description of the observed linear scaling between T 1, T 3 and B c. We further show that a Heisenberg Hamiltonian previously employed by Carretta et al (2013 J. Phys.: Condens. Matter 25 486001) to model this single molecule magnet gives formulas for the angle averaged susceptibilities (in the Ising limit) very similar to those of the minimal model. PMID- 28002043 TI - Radiation dose due to radon and thoron progeny inhalation in high-level natural radiation areas of Kerala, India. AB - In order to evaluate internal exposure to radon and thoron, concentrations for radon, thoron, and thoron progeny were measured for 259 dwellings located in high background radiation areas (HBRAs, outdoor external dose: 3-5 mGy y-1) and low background radiation areas (control areas, outdoor external dose: 1 mGy y-1) in Karunagappally Taluk, Kerala, India. The measurements were conducted using passive-type radon-thoron detectors and thoron progeny detectors over two six month measurement periods from June 2010 to June 2011. The results showed no major differences in radon and thoron progeny concentrations between the HBRAs and the control areas. The geometric mean of the annual effective dose due to radon and thoron was calculated as 0.10 and 0.44 mSv, respectively. The doses were small, but not negligible compared with the external dose in the two areas. PMID- 28002044 TI - DOS cones along atomic chains. AB - The electron transport properties of a linear atomic chain are studied theoretically within the tight-binding Hamiltonian and the Green's function method. Variations of the local density of states (DOS) along the chain are investigated. They are crucial in scanning tunnelling experiments and give important insight into the electron transport mechanism and charge distribution inside chains. It is found that depending on the chain parity the local DOS at the Fermi level can form cone-like structures (DOS cones) along the chain. The general condition for the local DOS oscillations is obtained and the linear behaviour of the local density function is confirmed analytically. DOS cones are characterized by a linear decay towards the chain which is in contrast to the propagation properties of charge density waves, end states and Friedel oscillations in one-dimensional systems. We find that DOS cones can appear due to non-resonant electron transport, the spin-orbit scattering or for chains fabricated on a substrate with localized electrons. It is also shown that for imperfect chains (e.g. with a reduced coupling strength between two neighboring sites) a diamond-like structure of the local DOS along the chain appears. PMID- 28002046 TI - Cooperative Jahn-Teller phase transition of icosahedral molecular units. AB - Non-linear molecules undergo distortions when the orbital degeneracy of the highest occupied level is lifted by the Jahn-Teller effect. If such molecules or clusters of atoms are coupled to one another, the system may experience a cooperative Jahn-Teller effect (CJTE). In this paper, we describe a model of how the CJTE leads to the crystallization of the disordered phase. The model Hamiltonian is based on a normal mode decomposition of the clusters in order to maintain the symmetry labels. We take account of the electron-strain and the electron-phonon couplings and, by displacing the coordinates of the oscillators, obtain a term that explicitly couples the Jahn-Teller centers, enabling us to perform a mean-field analysis. The calculation of the free energy then becomes straightforward, and obtaining phase diagrams in various regimes follows from the minimization of this free energy. The results show that the character of the phase transition may change from strong to weak first order and even to second order, depending on the coupling to the vibrational modes. Taken together, these results may serve as a paradigm for crystallization near the transition temperature, where the atoms tend to form clusters of icosahedral symmetry. PMID- 28002045 TI - Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI. AB - Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver DCE MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7 +/- 1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n = 9) measured at 7 d. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and 7 d reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p = 0.066), total liver blood flow (TLBF) (p = 0.101), hepatic arterial (HA) fraction (p = 0.895), mean transit time (MTT) (p = 0.646), distribution volume (DV) (p = 0.890) were not significantly different. Seven day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland-Altman 95% limits-of-agreement (BA95%LoA) +/-27.9%, coefficient of variation (CoV) 61.4% versus 9.3%, +/-35.5%, 81.7% respectively without correction). Seven day uncorrected PV perfusion was also improved (mean difference 9.3 ml min-1/100 g, BA95%LoA +/-506.1 ml min-1/100 g, CoV 64.1% versus 0.9 ml min-1/100 g, +/-562.8 ml min-1/100 g, 65.1% respectively with correction) as was uncorrected TLBF (mean difference 43.8 ml min-1/100 g, BA95%LoA +/-586.7 ml min-1/ 100 g, CoV 58.3% versus 13.3 ml min-1/100 g, +/ 661.5 ml min-1/100 g, 60.9% respectively with correction). Reproducibility of uncorrected MTT was similar (uncorrected mean difference 2.4 s, BA95%LoA +/-26.7 s, CoV 60.8% uncorrected versus 3.7 s, +/-27.8 s, 62.0% respectively with correction), as was and DV (uncorrected mean difference 14.1%, BA95%LoA +/ 48.2%, CoV 24.7% versus 10.3%, +/-46.0%, 23.9% respectively with correction). Cardiac output AIF correction does not significantly affect the estimation of hepatic perfusion parameters but demonstrates improvements in normal volunteer 7 d HA fraction reproducibility, but deterioration in PV perfusion and TLBF reproducibility. Improved HA fraction reproducibility maybe important as arterialisation of liver perfusion is increased in chronic liver disease and within malignant liver lesions. PMID- 28002047 TI - The modified Langevin description for probes in a nonlinear medium. AB - When the motion of a probe strongly disturbs the thermal equilibrium of the solvent or bath, the nonlinear response of the latter must enter the probe's effective evolution equation. We derive that induced stochastic dynamics using second order response around the bath thermal equilibrium. We discuss the nature of the new term in the evolution equation which is no longer purely dissipative, and the appearance of a novel time-scale for the probe related to changes in the dynamical activity of the bath. A major application for the obtained nonlinear generalized Langevin equation is in the study of colloid motion in a visco elastic medium. PMID- 28002048 TI - Exchange anisotropy in the skyrmion host GaV4S8. AB - Using ferromagnetic resonance spectroscopy at 34 GHz we explored the magnetic anisotropy of single-crystalline GaV4S8 in the field-polarized magnetic state. We describe the data in terms of an easy-axis type uniaxial anisotropy with an anisotropy constant [Formula: see text] erg cm-3 at 2 K, corresponding to a relative exchange anisotropy [Formula: see text]%, and about [Formula: see text]erg cm-3 near 11 K, i.e. at temperatures where the skyrmion-lattice phase was recently discovered. The relatively large value of K 1 explains the confinement of the skyrmion tubes to the [Formula: see text] easy axes. A distinct set of resonances in the spectra is attributed to the co-existence of different rhombohedral domains. Complementary broadband spectroscopy demonstrates that non-collinear spin states may sensitively be detected by electron spin resonance techniques. PMID- 28002049 TI - Ab initio study of the strain dependence of thermopower in electron-doped SrTiO3. AB - In this paper we explore the different mechanisms that affect the thermopower of a band insulating perovskite (in this case, SrTiO3) when subject to strain (both compressive or tensile). We analyze the high temperature, entropy-dominated limit and the lower temperature, energy-transport regime. We observe that the effect of strain in the high-temperature Seebeck coefficient is small at the concentration levels of interest for thermoelectric applications. However, the effective mass changes substantially with strain, which produces an opposite effect to that of the degeneracy breakups brought about by strain. In particular, we find that the thermopower can be enhanced by applying tensile strain in the adequate regime. We conclude that the detrimental effect of strain in thermopower due to band splitting is a minor effect that will not hamper the optimization of the thermoelectric properties of oxides with t 2g -active bands by applying strain. PMID- 28002050 TI - Fluctuation-induced forces in nematics with a foreign anisotropy in the bulk. AB - Within a linear coupling between orientational order of nematic liquid crystal and anisotropic mesoscopic particles immeresed in the nematic, the pseudo-Casimir effect is investigated. A quenched disorder in the alignment of the particles, which is on average in the direction of the nematic director, induces an inter substrate force as this composite is confined by two flat parallel surfaces a distance d apart. The disorder-induced force decays as -d -1 in the weak coupling regime. The force magnitude increases with the variance of the disorder and decreases on increasing the correlation length of the disorder. If the disorder is considered to be annealed, the disorder effects are not decoupled from the thermal effects and thus the form of the nematic fluctuation-induced force does not alter. The force is affected by the disorder only through a re-normalization of the mean particles' pinning strength. The trend for this modified thermal induced force with respect to the variance and the correlation length of the disorder remains as in the quenched case, where the pseudo-Casimir force was decomposed into two distinct thermal- and disorder-induced components. PMID- 28002051 TI - Macrotextured spoked surfaces reduce the residence time of a bouncing Leidenfrost drop. AB - Liquid drops can bounce when they impact non-wetting surfaces. Recently, studies have demonstrated that the time that the bouncing drop contacts a superhydrophobic surface can be reduced by incorporating ridged macrotextures on the surface. Yet the existing models aimed at explaining this phenomenon offer incompatible predictions of the contact time when a drop impacts multiple intersecting macrotextures, or spokes. Furthermore, it is unclear whether the effects of the macrotexture on the drop hydrodynamics extend to non-wetting surfaces in which direct contact is avoided by a thin vapor layer. Here we demonstrate that the phenomenon observed for macrotextured, superhydrophobic surfaces extends to macrotextured, wettable surfaces above the Leidenfrost temperature. We show that the number of droplets and overall residence time both depend on the number of intersecting spokes. Finally, we compare and contrast our results with mechanistic models to rationalize various elements of the phenomenon. PMID- 28002052 TI - The role of sample height in the stacking diagram of colloidal mixtures under gravity. AB - Bulk phase separation is responsible for the occurrence of stacks of different layers in sedimentation of colloidal mixtures. A recently proposed theory (de las Heras and Schmidt 2013 Soft Matter 9 8636) establishes a unique connection between the bulk phase behaviour and sedimentation-diffusion-equilibrium. The theory constructs a stacking diagram of all possible sequences of stacks under gravity in the limit of very high (infinite) sample heights. Here, we study the stacking diagrams of colloidal mixtures at finite sample height, h. We demonstrate that h plays a vital role in sedimentation-diffusion-equilibrium of colloidal mixtures. The region of the stacking diagram occupied by a given sequence of stacks depends on h. Hence, two samples with different heights but identical colloidal concentrations can develop different stacking sequences. In addition, the stacking diagrams for different heights can be qualitatively different since some stacking sequences occur only in a given interval of sample heights. We use the theory to investigate the stacking diagrams of both model bulk systems and mixtures of patchy particles that differ either by the number or by the types of patches. PMID- 28002054 TI - Electronic and structural properties of rhombohedral [1 1 1] and [1 1 0] oriented ultra-thin bismuth nanowires. AB - Structures and electronic properties of rhombohedral [1 1 1] and [1 1 0] bismuth nanowires are calculated with the use of density functional theory. The formation of an energy band gap from quantum confinement is studied and to improve estimates for the band gap the GW approximation is applied. The [1 1 1] oriented nanowires require surface bonds to be chemically saturated to avoid formation of metallic surface states, whereas the surfaces of the [1 1 0] nanowires do not support metallic surface states. It is found that the onset of quantum confinement in the surface passivated [1 1 1] nanowires occurs at larger critical dimensions than for the [1 1 0] nanowires. For the [1 1 1] oriented nanowires it is predicted that a band gap of ~0.5 eV can be formed at a diameter of approximately 6 nm, whereas for the [1 1 0] oriented nanowires a diameter of approximately 3 nm is required to achieve a similar band gap energy. The GW correction is also applied to estimates of the electron affinity, ionisation potentials and work functions for both orientations of the nanowires for various diameters below 5 nm. The magnitude of the energy band gaps that arise in bismuth at critical dimensions of a few nanometers are of the same order as for conventional bulk semiconductors. PMID- 28002053 TI - In vitro thrombolytic efficacy of echogenic liposomes loaded with tissue plasminogen activator and octafluoropropane gas. AB - Echogenic liposomes loaded with the thrombolytic recombinant tissue-type plasminogen activator (rt-PA) are under development for the treatment of ischemic stroke. These agents are designed to co-encapsulate cavitation nuclei to promote bubble activity in response to ultrasound exposure, and to enable localized delivery of thrombolytic. Stable cavitation improves the efficacy of the thrombolytic through enhanced fluid mixing. Echogenic liposomes that encapsulate air-filled microbubbles nucleate scant stable cavitation activity in response to 120 kHz intermittent ultrasound exposure, and have demonstrated thrombolytic efficacy equivalent to rt-PA alone. It was hypothesized that encapsulating octafluoropropane (OFP) gas within rt-PA-loaded liposomes instead of air will enhance ultrasound-mediated stable cavitation activity and increase thrombolytic efficacy compared to previous studies. The thrombolytic efficacy and cavitation activity nucleated from liposomes that encapsulate OFP microbubbles and rt-PA (OFP t-ELIP) was evaluated in vitro. Human whole blood clots were exposed to human fresh-frozen plasma alone, rt-PA (0, 0.32, 1.58, and 3.15 ug ml-1), or OFP t-ELIP at equivalent enzymatic activity, with and without exposure to intermittent ultrasound. Further, numerical simulations were performed to gain insight into the mechanisms of cavitation nucleation. Sustained ultraharmonic activity was nucleated from OFP t-ELIP when exposed to ultrasound. Furthermore, the thrombolytic efficacy was enhanced compared to rt-PA alone at concentrations of 1.58 ug ml-1 and 3.15 ug ml-1 (p < 0.05). These results indicate that OFP t ELIP can nucleate sustained stable cavitation activity and enhance the efficacy of thrombolysis. PMID- 28002055 TI - Sliding friction in the hydrodynamic lubrication regime for a power-law fluid. AB - A scaling analysis is undertaken for the load balance in sliding friction in the hydrodynamic lubrication regime, with a particular emphasis on power-law shear thinning typical of a structured liquid. It is argued that the shear-thinning regime is mechanically unstable if the power-law index n < 1/2, where n is the exponent that relates the shear stress to the shear rate. Consequently the Stribeck (friction) curve should be discontinuous, with possible hysteresis. Further analysis suggests that normal stress and flow transience (stress overshoot) do not destroy this basic picture, although they may provide stabilising mechanisms at higher shear rates. Extensional viscosity is also expected to be insignificant unless the Trouton ratio is large. A possible application to shear thickening in non-Brownian particulate suspensions is indicated. PMID- 28002056 TI - Radionulide analyses of ingested water from some estuaries within the coastal area of Akwa Ibom State, Nigeria. AB - Radionuclide analyses of ingested water from three selected estuaries within the coastal areas of Akwa Ibom State, Nigeria have been carried out. Fifteen water samples collected at strategic points from the estuaries were pre-treated and each placed on the sodium iodide NaI (Tl) -model 802 detector for 3600 s to obtain the gamma radiation count rate. The activity concentrations and other radiological risk parameters were computed. The effective dose rate of radiation due to ingested water (E.D.I.W.) ranged between 0.25 and 1.86 mSv yr-1, the effective equivalent dose rate due to absorbed radiation in air (Deq) ranged between 0.0065 and 0.0369 mSv yr-1 and the total equivalent dose rate of radiation ranged between 0.257 and 1.87 mSv yr-1. The E.D.I.W exceeded the International Commission on Radiological Protection (ICRP) permissible limit of 0.1 mSv yr-1 set for ingested radionuclides from food. Most surveyed points had their total equivalent dose rate of radiation greater than the ICRP permissible dose limit of 1 mSv yr-1 for radiation exposure from all internal and external sources. The annual gonadal dose equivalent ranged between 0.008 and 0.041 mSv yr 1 and are below the world average value of 0.3 mSv yr-1. The excess lifetime cancer risk ranged between 0.7 * 10-3 and 5.07 * 10-3 and are above the world average value of 0.29 * 10-3. The elevation of most of the radiation risk parameters over the standard limits shows that oil production activities may have raised the background radiation levels of the area. This research also revealed that computing only the Deq and neglecting the E.D.I.W would mean under estimating the radiation doses received by an impacted person by 97.4%-98.3%. Water consumed from these sources could enhance the radionuclide content and the percentage probabilities of developing cancer by impacted persons. PMID- 28002057 TI - Magnetic transition temperatures follow crystallographic symmetry in samarium under high-pressures and low-temperatures. AB - Magnetic ordering temperatures in rare earth metal samarium (Sm) have been studied using an ultrasensitive electrical transport measurement technique in a designer diamond anvil cell to high-pressure up to 47 GPa and low-temperature to 10 K. The two magnetic transitions at 106 K and 14 K in the alpha-Sm phase, attributed to antiferromagnetic ordering on hexagonal and cubic layers respectively, collapse in to one magnetic transition near 10 GPa when Sm assumes a double hexagonal close packed (dhcp) phase. On further increase in pressure above 34 GPa, the magnetic transitions split again as Sm adopts a hexagonal-hP3 structure indicating different magnetic transition temperatures for different crystallographic sites. A model for magnetic ordering for the hexagonal-hP3 phase in samarium has been proposed based on the experimental data. The magnetic transition temperatures closely follow the crystallographic symmetry during alpha Sm -> dhcp -> fcc/dist.fcc -> hP3 structure sequence at high-pressures and low-temperatures. PMID- 28002058 TI - Canted magnetic ground state of quarter-doped manganites R 0.75Ca0.25MnO3 (R = Y, Tb, Dy, Ho, and Er). AB - Polycrystalline samples of the quarter-doped manganites R 0.75Ca0.25MnO3 (R = Y, Tb, Dy, Ho, and Er) were studied by x-ray diffraction and AC/DC susceptibility measurements. All five samples are orthorhombic and exhibit similar magnetic properties: enhanced ferromagnetism below T 1 (~80 K) and a spin glass (SG) state below T SG (~30 K). With increasing R 3+ ionic size, both T 1 and T SG generally increase. The single crystal neutron diffraction results on Tb0.75Ca0.25MnO3 revealed that the SG state is mainly composed of a short-range ordered version of a novel canted (i.e. noncollinear) antiferromagnetic spin state. Furthermore, calculations based on the double exchange model for quarter-doped manganites reveal that this new magnetic phase provides a transition state between the ferromagnetic state and the theoretically predicted spin-orthogonal stripe phase. PMID- 28002059 TI - ImmunoScore Signature: A Prognostic and Predictive Tool in Gastric Cancer. AB - OBJECTIVE: We postulated that the ImmunoScore (IS) could markedly improve the prediction of postsurgical survival and chemotherapeutic benefits in gastric cancer (GC). SUMMARY BACKGROUND DATA: A prediction model for GC patients was developed using data from 879 consecutive patients. METHODS: The expression of 27 immune features was detected in 251 specimens by using immunohistochemistry, and a 5-feature-based ISGC was then constructed using the LASSO Cox regression model. Testing and validation cohorts were included to validate the model. RESULTS: Using the LASSO model, we established an ISGC classifier based on 5 features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. Significant differences were found between the high-ISGC and low-ISGC patients in the training cohort in 5-year disease-free survival (45.0% vs. 4.4%, respectively; P <0.001) and 5-year overall survival (48.8% vs. 6.7%, respectively; P <0.001). Multivariate analysis revealed that the ISGC classifier was an independent prognostic factor. A combination of ISGC and tumor, node, and metastasis (TNM) had better prognostic value than TNM stage alone. Further analysis revealed that stage II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. Finally, we constructed 2 nomograms to predict which patients with stages II and III GC might benefit from adjuvant chemotherapy after surgery. CONCLUSIONS: The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value of the TNM staging system. Moreover, the ISGC might be a useful predictive tool to identify stage II and III GC patients who would benefit from adjuvant chemotherapy. PMID- 28002061 TI - Reply to Letter to The Editor Regarding the COBRA Trial: What Will it Take to Perform High-quality Hernia Research? PMID- 28002060 TI - Embryonic Origin of Primary Colon Cancer Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colon Cancer Liver Metastases. AB - BACKGROUND: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). METHODS: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. RESULTS: Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value >=5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003). CONCLUSIONS: Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status. PMID- 28002062 TI - Nonopioid Management of Neonatal Abstinence Syndrome. AB - BACKGROUND: Current standard therapy for moderate to severe neonatal abstinence syndrome (NAS) includes opioid administration and often results in separation of mother and infant. Impaired maternal-infant bonding and extended neonatal opiate exposure may be associated with adverse developmental outcomes. Increased use of nonopioid adjunctive NAS therapies may decrease postnatal opioid exposure and length of stay (LOS), thereby promoting positive developmental outcomes for NAS affected infants. PURPOSE: To review the efficacy of rooming-in care and acupuncture as nonpharmacologic adjunctive agents to reduce the magnitude of postnatal opioid exposure and LOS. METHODS: PubMed, Ovid Medline, Embase, and CINAHL databases were searched for primary studies on rooming-in care and acupuncture as adjunctive treatments for NAS; 8 are included in this review. FINDINGS: Rooming-in care may decrease postnatal opioid exposure and LOS in NAS affected infants. Acupuncture is safe in NAS patients; however, its definitive effect on narcotic use and length of hospitalization are inconclusive. IMPLICATIONS FOR PRACTICE: Rooming-in care should be offered to NAS patients. Strong evidence does not exist to recommend acupuncture as a routine NAS treatment. IMPLICATIONS FOR RESEARCH: Additional randomized clinical trials are necessary to assess the efficacy of acupuncture and to confirm the effect of rooming-in care on NAS outcomes, and delineate optimal elements of a rooming-in care model. PMID- 28002064 TI - Antibody therapy paired with antiretroviral therapy suppresses viral load long term in SIV+ macaques, even after treatment stops. PMID- 28002065 TI - To break patent or not to break patent: what is in the best interests of HIV patients in low-income countries? PMID- 28002066 TI - Do HIV-infected children who do not develop AIDS hold clues to a cure? PMID- 28002067 TI - New mouse models provide insights into how to design a more effective HIV vaccine. PMID- 28002063 TI - Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation. AB - OBJECTIVE: Gut microbial translocation is a major driving force behind chronic immune activation during HIV-1 infection. HIV-1-related intestinal dysbiosis, including increases in mucosa-associated pathobionts, may influence microbial translocation and contribute to mucosal and systemic inflammation. Thus, it is critical to understand the mechanisms by which gut microbes and their metabolic products, such as butyrate, influence immune cell function during HIV-1 infection. DESIGN: A cross-sectional study was performed to compare the relative abundance of butyrate-producing bacterial (BPB) species in colonic biopsies and stool of untreated, chronic HIV-1-infected (n = 18) and HIV-1-uninfected (n = 14) study participants. The effect of exogenously added butyrate on gut T-cell activation and HIV-1 infection was evaluated using an ex-vivo human intestinal cell culture model. METHODS: Species were identified in 16S ribosomal RNA sequence datasets. Ex-vivo isolated lamina propria mononuclear cells were infected with C-C chemokine receptor type 5-tropic HIV-1Bal, cultured with enteric gram-negative bacteria and a range of butyrate doses, and lamina propria T-cell activation and HIV-1 infection levels measured. RESULTS: Relative abundance of total BPB and specifically of Roseburia intestinalis, were lower in colonic mucosa of HIV-1-infected versus HIV-1-uninfected individuals. In HIV-1 infected study participants, R. intestinalis relative abundance inversely correlated with systemic indicators of microbial translocation, immune activation, and vascular inflammation. Exogenous butyrate suppressed enteric gram negative bacteria-driven lamina propria T-cell activation and HIV-1 infection levels in vitro. CONCLUSION: Reductions in mucosal butyrate from diminished colonic BPB may exacerbate pathobiont-driven gut T-cell activation and HIV replication, thereby contributing to HIV-associated mucosal pathogenesis. PMID- 28002068 TI - An acute bout of aerobic exercise alters interarm systolic blood pressure difference. AB - BACKGROUND: Clinically, when a difference of at least 10 mmHg in systolic blood pressure (SBP) between arms exists, it is identified as an interarm systolic blood pressure difference (ISBPD). At rest, ISBPD is linked with hypertension, peripheral vascular disease, and increased premature mortality. Exercise may reveal underlying cardiovascular pathologies otherwise absent at rest. However, there have been no investigations to examine the effect of exercise on ISBPD. AIM: The aim of this investigation was to determine whether exercise may alter ISBPD when detected at rest or reveal ISBPD when it was not observed in the resting condition. METHODS: An experienced investigator sequentially measured SBP using standard auscultation in each arm (alternating order) in 85 normotensive individuals (22+/-6 years, 39 male, 46 female). ISBPD was quantified before exercise (PRE). Participants then completed a three-stage protocol on a cycle ergometer. A cadence of 50 rpm was maintained at a workload of 3 (EX-3; light) and 6 (EX-6; moderate) METS and during an active recovery (REC). At each stage, SBP was measured upon achieving steady-state heart rate. A logistic regression analysis was used to determine the change in odds ratio of ISBPD when exposed to exercise. RESULTS: Thirteen percent (n=11) of patients presented with ISBPD during PRE and the degree of ISBPD was lower (3.81 mmHg; P<0.05) in REC than PRE. In individuals who did not present with ISBPD during PRE (n=74), progression from EX-3 to EX-6 significantly increased the odds of developing ISBPD (4.31; P<0.05). CONCLUSION: In individuals with ISBPD at PRE, active recovery from exercise attenuated the difference between interarm SBP. Moderate-intensity exercise resulted in ISBPD not otherwise present at rest. PMID- 28002069 TI - Assessment of a smartphone app (Capstesia) for measuring pulse pressure variation: agreement between two methods: A Cross-sectional study. AB - BACKGROUND: Less invasive and noninvasive methods are emerging for haemodynamic monitoring. Among them is Capstesia, a smartphone app that, from photographs of a patient monitor showing invasive arterial pressure, estimates advanced haemodynamic variables after digitising and analysing the pressure curves. OBJECTIVE: The aim of this study was to compare the level of agreement between the analysis of the signals obtained from the patient monitor and a photograph of the same images using the Capstesia app. DESIGN: Cross-sectional study. SETTING: Araba University hospital (Txagorritxu), Vitoria-Gasteiz, Alava, Spain, from January to February 2015. PATIENTS: Twenty patients (229 images) who had an arterial catheter (radial or femoral artery) inserted for haemodynamic monitoring. INTERVENTION: Snapshots obtained from the patient monitor and a photograph of these same snapshots using the Capstesia application were assessed with the same software (MATLAB, Mathworks, Natick, Massachusetats, USA) for evaluating the level of concordance of the following variables: pulse pressure variation (PPV), cardiac output (CO) and maximum slope of the pressure curve (dP/dt). Comparison was made using interclass correlation coefficients with corresponding 95% confidence intervals, and Bland-Altman plots with the corresponding percentages of error. MAIN OUTCOME MEASURES: (PPV). Secondary outcome: CO and maximum slope of the pressure curve [dP/dt]. RESULTS: The interclass correlation coefficients for PPV, CO and max dP/dt were 0.991 (95% confidence interval 0.988 to 0.993), 0.966 (95% confidence interval 0.956 to 0.974) and 0.962 (95% confidence interval 0.950 to 0.970), respectively. In the Bland-Altman analysis, bias and limits of agreement of PPV were (0.50% +/- 1.42) resulting in a percentage of error of 20% for PPV. For CO they were 0.19 +/- 0.341, with a 13.8% of error. Finally bias and limits of agreement for max dP/dt were 1.33 +/- 77.71, resulting in an error of 14.20% CONCLUSIONS: Photograph of the screenshots obtained with the Capstesia app show a good concordance with analysis of the original screenshots. Either approach could be used to monitor the haemodynamic variables assessed. PMID- 28002070 TI - Retrospective validation of the pulmonary embolism rule-out criteria rule in 'PE unlikely' patients with suspected pulmonary embolism. AB - INTRODUCTION: Patients presenting to emergency departments (EDs) with suspected pulmonary embolism (PE) can be risk stratified and those who are deemed to be at low risk for PE usually undergo D-dimer testing. A negative D-dimer in this low risk group rules out PE with a high degree of certainty because of its high sensitivity. The D-dimer is, however, a poorly specific test and positive results often lead to unnecessary radiological imaging (notably computed tomography pulmonary angiography). The Pulmonary Embolism Rule-Out Criteria (PERC) rule has been suggested as an alternative to D-dimer testing in these patients. This study looked at whether the PERC rule could safely replace the use of D-dimer in patients suspected of PE, but deemed 'PE unlikely' by the dichotomized Wells score in a UK ED setting. PATIENTS AND METHODS: This was a retrospective review of 986 patients with suspected PE who had a blood sample for D-dimer level taken. In patients deemed 'PE unlikely' (using the dichotomized Wells score), the diagnostic performance of the PERC rule was compared with a standard D-dimer level in the detection of PE at index presentation and up to 3 months afterwards. RESULTS: Of the 986 patients, 940 patients were deemed 'PE unlikely' using the dichotomized Wells score. Three patients with confirmed PE would have been missed by the PERC rule compared with only one missed by the D-dimer test. In these patients, the sensitivity of the PERC rule for detecting PE was 91.4% [95% confidence interval (CI): 76.9-98.2%], with a negative likelihood ratio of 0.25 (95% CI: 0.08-0.73). However, the negative predictive value of the PERC rule was 99.1% (95% CI: 97.3-99.8%). In comparison, the sensitivity for the standard D dimer test was 97.1% (95% CI: 85.1-99.9%), with a negative likelihood ratio of 0.04 (95% CI: 0.01-0.27). The negative predictive value for the standard D-dimer test was 99.8% (95% CI: 99.2-100%). CONCLUSION: The PERC rule has a high negative predictive value for excluding PE in patients presenting with suspected PE to the ED. However, the PERC rule may still miss around 8% of confirmed PE in patients who are deemed 'PE unlikely' by a dichotomized Wells score. Caution is advised in using the PERC rule as a substitute for the standard D-dimer test in all these patients. PMID- 28002071 TI - Occupational Hydrogen Sulfide Fatalities and Thiosulfate Levels. PMID- 28002072 TI - The 100 Top-Cited Articles in Pulmonary Imaging: A Bibliometric Analysis. AB - PURPOSE: The purpose of this study was to identify and characterize the 100 top cited articles in pulmonary imaging. MATERIALS AND METHODS: From the database of Journal Citation Reports, 274 journals whose scope included pulmonary imaging were selected. The Web of Science search tools were then used to identify the 100 top-cited articles in the subject of pulmonary imaging published in these journals. The parameters used to analyze the characteristics of the 100 top-cited articles were journal (including subject category and impact factor), publication year, number of citations and annual citations, department and institution of authors, country of origin, article type, imaging technique, and topic. RESULTS: The 100 top-cited articles in pulmonary imaging were published between 1953 and 2012, with 43 published between 2000 and 2009. Citations ranged from 199 to 1447, and annual citations ranged from 5.1 to 314. The majority of articles were published in radiology or imaging journals (n=64), originated in the United States (n=49), were original articles (n=87), used computed tomography (n=66), and were based on the topic of pulmonary thromboembolism (n=18). Department of Radiology, Mayo Clinic (n=7), and Department of Radiology, University of British Columbia and Vancouver General Hospital (n=7), were the leading institutions, and Muller NL (n=11) was the most prolific author. CONCLUSIONS: Our study lists the 100 top-cited articles in pulmonary imaging, provides an insight into historical developments, and allows for recognition of advances in this field. PMID- 28002073 TI - The Progressive Advances of Sentinel Lymph Node Biopsy Technique in Head and Neck Cancer. AB - In this short review, the technical and clinical improvements of the sentinel lymph node biopsy in head and neck cancer are presented. PMID- 28002075 TI - What factors influence protein synthesis and degradation in critical illness? AB - PURPOSE OF REVIEW: The optimal approach to improve protein metabolism in critical illness is not yet fully defined. Here, we have summarized recent literature dealing with the main catabolic and anabolic factors influencing protein kinetics in acute hypercatabolic patients. RECENT FINDINGS: Protein/amino acid intake levels should be adapted to type and severity of illness, keeping in mind that energy overfeeding is associated with poor outcome. A number of anticatabolic nutraceuticals and drugs have been tested in acute patients. The encouraging results have been obtained with beta-hydroxy-beta-methylbutyrate, omega-3 fatty acids, oxandrolone, propranolol, and metformin. Their efficacy and lack of side effects need to be confirmed. Physical therapy, including muscle electro stimulation, appears a very promising intervention, both effective and safe. SUMMARY: Protein catabolism can be minimized in acute patients by adequate nutritional support, early mobilization, and, possibly, pharmacological and nutraceutical interventions. A combination of these strategies should be tested in randomized controlled trials. PMID- 28002074 TI - Resolving inflammation by using nutrition therapy: roles for specialized proresolving mediators. AB - PURPOSE OF REVIEW: Inflammation is a unifying component of many of the diseases that afflict Western civilizations. Nutrition therapy and, in particular, essential fatty acid supplementation is one of the approaches that is currently in use for the treatment and management of many inflammatory conditions. The purpose of the present review is to discuss the recent literature in light of the discovery that essential fatty acids are converted by the body to a novel genus of lipid mediators, termed specialized proresolving mediators (SPMs). RECENT FINDINGS: The SPM genus is composed of four mediator families - the lipoxins, resolvins, protectins, and maresins. These molecules potently and stereoselectively promote the termination of inflammation, tissue repair, and regeneration. Recent studies indicate that in disease, SPM production becomes dysregulated giving rise to a status of failed resolution. Of note, several studies found that omega-3 fatty acid supplementation, at doses within the recommended daily allowance, led to increases in several SPM families that correlate with enhanced white blood cell responses in humans and reduced inflammation in mice. SUMMARY: Given the potent biological actions of SPM in organ protection and promoting bacterial clearance, nutritional therapies enriched in omega-3 fatty acids hold promise as a potential co-therapy approach when coupled with functional lipid mediator profiling. PMID- 28002076 TI - What Do Participants of the Crohn's and Colitis UK (CCUK) Annual York Walk Think of Their Inflammatory Bowel Disease Care? A Short Report on a Survey. AB - There has been a growing interest in a patient-centered model of care in inflammatory bowel disease; however, no relevant study using a mixed methodology has been conducted to date. Thus, our multidisciplinary group aimed to explore the issue of patient involvement in care among the inflammatory bowel disease community. A mixed-methods anonymous survey was conducted during the Crohn's and Colitis UK annual event. Summary statistics were used to describe the sample, and a simple thematic analysis identified key themes in qualitative responses. There were 64 survey respondents, representing 73% of the total family/friend groups participating (N = 87). Overall, 75% of respondents answered that they had the opportunity to discuss their care with their inflammatory bowel disease practitioner and 81% felt their opinions were taken on board and valued. A clear majority (84%) had at some point been treated by a gastroenterologist. In contrast, less than half (44%) had the opportunity for a dietician consultation and only 28% had the opportunity for a psychologist/counselor consultation. Although satisfaction with inflammatory bowel disease care was high, access to specialty services was concerning. Efforts should be made to provide access to mental health practitioners for those with clinically significant anxiety and/or depression. PMID- 28002077 TI - SUCCESSFUL CONSERVATIVE TREATMENT OF AN ELDERLY PATIENT WITH AN ERCP-RELATED DUODENAL PERFORATION ASSOCIATED WITH WIDESPREAD SUBCUTANEOUS EMPHYSEMA. PMID- 28002078 TI - Nurse Counseling for Physical Activity in Patients Undergoing Esophagectomy. AB - Strong evidence exists regarding multiple benefits of physical activity among cancer patients. Patients undergoing esophagectomy received counseling for physical activity by a nurse and instructions to keep a diary of physical activities before surgery, followed by 2 counseling sessions after surgery. Physical activity, body mass index, psychological distress, and quality of life were measured at baseline, 2-4 weeks, and 3 and 6 months after discharge. Of 29 participants (mean age = 65.9 years), 72.5% underwent thoracoscopic esophagectomy in the prone position with 3-field lymphadectomy. The results of the International Physical Activity Questionnaire indicated that postoperative physical activity returned to nearly preoperative level, and the number of inactive patients gradually decreased by half at 6 months after discharge. Quality of life scores, except those for role function and social function, tended to return to the baseline at 6 months after discharge. Psychological distress measured by the Kessler 6 remained lower than the baseline, whereas the mean score of body mass index gradually declined after discharge. Patients undergoing esophagectomy and receiving nurse counseling can return to preoperative physical activity level in their daily lives after surgery. Nurses should integrate physical activity promotion into cancer care. PMID- 28002079 TI - Unbiased and targeted mass spectrometry for the HDL proteome. AB - PURPOSE OF REVIEW: Mass spectrometry is an ever evolving technology that is equipped with a variety of tools for protein research. Some lipoprotein studies, especially those pertaining to HDL biology, have been exploiting the versatility of mass spectrometry to understand HDL function through its proteome. Despite the role of mass spectrometry in advancing research as a whole, however, the technology remains obscure to those without hands on experience, but still wishing to understand it. In this review, we walk the reader through the coevolution of common mass spectrometry workflows and HDL research, starting from the basic unbiased mass spectrometry methods used to profile the HDL proteome to the most recent targeted methods that have enabled an unprecedented view of HDL metabolism. RECENT FINDINGS: Unbiased global proteomics have demonstrated that the HDL proteome is organized into subgroups across the HDL size fractions providing further evidence that HDL functional heterogeneity is in part governed by its varying protein constituents. Parallel reaction monitoring, a novel targeted mass spectrometry method, was used to monitor the metabolism of HDL apolipoproteins in humans and revealed that apolipoproteins contained within the same HDL size fraction exhibit diverse metabolic properties. SUMMARY: Mass spectrometry provides a variety of tools and strategies to facilitate understanding, through its proteins, the complex biology of HDL. PMID- 28002081 TI - Children With Cochlear Implants and Their Parents: Relations Between Parenting Style and Children's Social-Emotional Functioning. AB - OBJECTIVES: Parenting a child who has a severe or profound hearing loss can be challenging and at times stressful, and might cause parents to use more adverse parenting styles compared with parents of hearing children. Parenting styles are known to impact children's social-emotional development. Children with a severe to profound hearing loss may be more reliant on their parents in terms of their social-emotional development when compared with their hearing peers who typically have greater opportunities to interact with and learn from others outside their family environment. Identifying the impact which parenting styles pertain on the social-emotional development of children who have cochlear implants (CIs) could help advance these children's well-being. Therefore, the authors compared parenting styles of parents with hearing children and of parents with children who have a CI, and examined the relations between parenting styles and two key aspects of children's social-emotional functioning: emotion regulation and empathy. DESIGN: Ninety-two hearing parents and their children (aged 1 to 5 years old), who were either hearing (n = 46) or had a CI (n = 46), participated in this cross-sectional study. Parents completed questionnaires concerning their parenting styles (i.e., positive, negative and uninvolved), and regarding the extent to which their children expressed negative emotions (i.e., anger and sadness) and empathy. Furthermore, an emotion-regulation task measuring negative emotionality was administered to the children. RESULTS: No differences in reported parenting styles were observed between parents of hearing children and parents of children with a CI. In addition, negative and uninvolved parenting styles were related to higher levels of negative emotionality in both groups of children. No relation was found between positive parenting and children's social emotional functioning. Hearing status did not moderate these relationships. Language mediated the relationship between parenting styles and children's social emotional functioning. CONCLUSIONS: Children's hearing status did not impact parenting styles. This may be a result of the support that parents of children with a CI receive during their enrollment in the rehabilitation program preceding and after implantation. Rehabilitation programs should dedicate more attention to informing parents about the impact of parenting behaviors on children's social emotional functioning. Offering parenting courses as part of the program could promote children's well-being. Future longitudinal research should address the directionality of the relations between parenting styles and children's social emotional functioning. PMID- 28002082 TI - Long-Term Synergistic Interaction of Cisplatin- and Noise-Induced Hearing Losses. AB - OBJECTIVE: Past experiments in the literature have shown that cisplatin interacts synergistically with noise to create hearing loss. Much of the previous work on the synergistic interaction of noise and cisplatin tested exposures that occurred very close together in time. The present study assessed whether rats that have been exposed to cisplatin continue to show increased susceptibility to noise induced hearing loss months after conclusion of the cisplatin exposure. DESIGN: Thirty-two Fischer 344/NHsd rats were exposed to one of five conditions: (1) cisplatin exposure followed by immediate cochlear tissue harvest, (2) cisplatin exposure and a 20-week monitoring period before tissue harvest, (3) cisplatin exposure followed immediately by noise exposure, (4) cisplatin exposure followed by noise exposure 16 weeks later, and (5) noise exposure without cisplatin exposure. The cisplatin exposure was an 8-week interval in which cisplatin was given every 2 weeks. Cochlear injury was evaluated using auditory brainstem response thresholds, P1 wave amplitudes, and postmortem outer hair cell counts. RESULTS: The 8-week cisplatin exposure induced little threshold shift or P1 amplitude loss, and a small lesion of missing outer hair cells in the basal half of the cochlea. The rats exposed to noise immediately after the cisplatin exposure interval showed a synergistic interaction of cisplatin and noise. The group exposed to noise 16 weeks after the cisplatin exposure interval also showed more severe threshold shift and outer hair cell loss than control subjects. The controls exposed to cisplatin and monitored for 20 weeks showed little threshold shift or outer hair cell loss, but did show P1 wave amplitude changes over the 20 week monitoring period. CONCLUSIONS: The results from the groups exposed to cisplatin followed by noise, combined with the findings from the cisplatin- and noise-only groups, suggest that the cisplatin induced cochlear injuries that were not severe enough to result in threshold shift, but left the cochlea in a state of heightened susceptibility to future injury. The heightened susceptibility to noise injury was still present 16 weeks after the conclusion of the cisplatin exposure. PMID- 28002083 TI - The Effect of Interaural Mismatches on Contralateral Unmasking With Single-Sided Vocoders. AB - OBJECTIVES: Cochlear-implant (CI) users with single-sided deafness (SSD)-that is, one normal-hearing (NH) ear and one CI ear-can obtain some unmasking benefits when a mixture of target and masking voices is presented to the NH ear and a copy of just the masking voices is presented to the CI ear. NH listeners show similar benefits in a simulation of SSD-CI listening, whereby a mixture of target and masking voices is presented to one ear and a vocoded copy of the masking voices is presented to the opposite ear. However, the magnitude of the benefit for SSD CI listeners is highly variable across individuals and is on average less than for NH listeners presented with vocoded stimuli. One possible explanation for the limited benefit observed for some SSD-CI users is that temporal and spectral discrepancies between the acoustic and electric ears might interfere with contralateral unmasking. The present study presented vocoder simulations to NH participants to examine the effects of interaural temporal and spectral mismatches on contralateral unmasking. DESIGN: Speech-reception performance was measured in a competing-talker paradigm for NH listeners presented with vocoder simulations of SSD-CI listening. In the monaural condition, listeners identified target speech masked by two same-gender interferers, presented to the left ear. In the bilateral condition, the same stimuli were presented to the left ear, but the right ear was presented with a noise-vocoded copy of the interfering voices. This paradigm tested whether listeners could integrate the interfering voices across the ears to better hear the monaural target. Three common distortions inherent in CI processing were introduced to the vocoder processing: spectral shifts, temporal delays, and reduced frequency selectivity. RESULTS: In experiment 1, contralateral unmasking (i.e., the benefit from adding the vocoded maskers to the second ear) was impaired by spectral mismatches of four equivalent rectangular bandwidths or greater. This is equivalent to roughly a 3.6-mm mismatch between the cochlear places stimulated in the electric and acoustic ears, which is on the low end of the average expected mismatch for SSD-CI listeners. In experiment 2, performance was negatively affected by a temporal mismatch of 24 ms or greater, but not for mismatches in the 0 to 12 ms range expected for SSD-CI listeners. Experiment 3 showed an interaction between spectral shift and spectral resolution, with less effect of interaural spectral mismatches when the number of vocoder channels was reduced. Experiment 4 applied interaural spectral and temporal mismatches in combination. Performance was best when both frequency and timing were aligned, but in cases where a mismatch was present in one dimension (either frequency or latency), the addition of mismatch in the second dimension did not further disrupt performance. CONCLUSIONS: These results emphasize the need for interaural alignment-in timing and especially in frequency-to maximize contralateral unmasking for NH listeners presented with vocoder simulations of SSD-CI listening. Improved processing strategies that reduce mismatch between the electric and acoustic ears of SSD-CI listeners might improve their ability to obtain binaural benefits in multitalker environments. PMID- 28002080 TI - On the Etiology of Listening Difficulties in Noise Despite Clinically Normal Audiograms. AB - Many people with difficulties following conversations in noisy settings have "clinically normal" audiograms, that is, tone thresholds better than 20 dB HL from 0.1 to 8 kHz. This review summarizes the possible causes of such difficulties, and examines established as well as promising new psychoacoustic and electrophysiologic approaches to differentiate between them. Deficits at the level of the auditory periphery are possible even if thresholds remain around 0 dB HL, and become probable when they reach 10 to 20 dB HL. Extending the audiogram beyond 8 kHz can identify early signs of noise-induced trauma to the vulnerable basal turn of the cochlea, and might point to "hidden" losses at lower frequencies that could compromise speech reception in noise. Listening difficulties can also be a consequence of impaired central auditory processing, resulting from lesions affecting the auditory brainstem or cortex, or from abnormal patterns of sound input during developmental sensitive periods and even in adulthood. Such auditory processing disorders should be distinguished from (cognitive) linguistic deficits, and from problems with attention or working memory that may not be specific to the auditory modality. Improved diagnosis of the causes of listening difficulties in noise should lead to better treatment outcomes, by optimizing auditory training procedures to the specific deficits of individual patients, for example. PMID- 28002084 TI - Use of visual inspection with acetic acid, Pap smear, or high-risk human papillomavirus testing in women living with HIV/AIDS for posttreatment cervical cancer screening: same tests, different priorities. AB - OBJECTIVES: Few studies have addressed optimal follow-up for HIV-infected women after cervical treatment. This study aimed to compare performance of three available tests to detect posttreatment cervical disease in HIV-infected women in Kenya. DESIGN: This is a prospective cohort study. METHODS: At least 6 months following cryotherapy, 517 HIV-infected women were evaluated concurrently with visual inspection with acetic acid (VIA), papanicolaou (Pap) smear, and high-risk human papillomavirus (HR-HPV) testing. Women positive by any test (>=low-grade squamous intraepithelial lesion for Pap) were scheduled for colposcopy and biopsy. Among 248 with histological confirmation [and 174 assumed to be truly negative for cervical intraepithelial neoplasia (CIN)2+ after testing negative by all three tests], the ability of each test alone, or in combination, to detect CIN2+ was calculated to determine their utility in posttreatment follow-up. RESULTS: The median age of women was 35 years, 68% were WHO stage 1-2, with a median CD4 cell count of 410 cells/MUl, and 87% were on combination antiretroviral therapy. At a median of 6.3 months posttreatment, 64% had an abnormal screen by VIA, Pap, and/or HR-HPV. Among women with histological confirmation, 72 (30%) had persistent/recurrent CIN2+. As single tests, Pap correctly classified the most cases (83%) and had the highest specificity [91% (88 and 95%); sensitivity 44% (35 and 53%)], whereas HR-HPV had the highest sensitivity [85% (75 and 96%); specificity 54% (49 and 58%)]. VIA was not sensitive [27% (18 and 36%)] for the detection of posttreatment CIN2+ [specificity 82% (79 and 86%)]. CONCLUSION: With the goal to minimize the number of false negatives (e.g. not miss CIN2+ posttreatment) in this population that is high-risk due to both prior cervical disease and HIV infection, HR-HPV-based algorithms are recommended. PMID- 28002085 TI - Rates and predictors of injury in a population-based cohort of people living with HIV. AB - OBJECTIVES: Injuries are responsible for 10% of the global burden of disease; however, the epidemiology of injury among people living with HIV (PLHIV) has not been well elucidated. This study seeks to characterize rates and predictors of injury among PLHIV compared to the general population in British Columbia (BC), Canada. DESIGN: A population-based dataset was created via linkage between the BC Centre for Excellence in HIV/AIDS and PopulationDataBC. METHODS: PLHIV aged 20 years and older were compared to a random 10% sample of the adult general population. The International Classification of Diseases 9 and 10 codes were used to classify unintentional and intentional injuries based on the external cause of the injury from 1996 to 2013. Generalized estimating equation (GEE) Poisson regression models were fit to estimate the effect of HIV status on rates of unintentional and intentional injury, and to identify correlates of injury among PLHIV. RESULTS: The crude incidence rate of unintentional injury was 18.56/1000 person-years [95% confidence interval (CI) 17.77-19.39] among PLHIV and 8.51/1000 person-years (95% CI 8.42-8.59) in the general population. Among PLHIV, 13.45% of deaths were due to injury, compared to 5.52% of deaths in the general population. In adjusted models, PLHIV were more likely to report unintentional (incidence rate ratio 1.42, 95% CI 1.32-1.52) and intentional injury (incidence rate ratio 1.93, 95% CI 1.70-2.18) compared to the general population. CONCLUSIONS: We identified elevated rates of intentional and unintentional injury among PLHIV. Injuries are largely preventable; as such, targeted efforts are needed to decrease the burden of injury-related disability and death among PLHIV. PMID- 28002086 TI - Educational attainment and intersectionality in the response to HIV antiretroviral treatment in Europe. PMID- 28002087 TI - Protecting the health of our AIDS-free generation: beyond prevention of mother-to child HIV transmission. PMID- 28002088 TI - Prioritizing health outcomes of HIV-exposed, uninfected children in low and middle-income countries: response to Powis et al. PMID- 28002089 TI - Kaposi's sarcoma in Malawi: a continued problem for HIV-positive and HIV-negative individuals. PMID- 28002090 TI - Prognostic value of infrared thermography in an emergency department. AB - OBJECTIVE: In this study, we aimed to investigate the prognostic potential of infrared thermography in a population of medical patients admitted to the emergency department. Central-to-peripheral temperature gradients were analyzed for association with 30-day mortality. METHODS: This prospective observational study included 198 medical patients admitted to the Emergency Department, at Odense University Hospital. A standardized thermal picture was taken and temperatures of the inner canthus, the earlobe, the nose tip, and the tip of the third finger were reported. The inner canthus was chosen as a marker for central temperature and the three others as markers for peripheral temperatures, resulting in three gradients per patient. Thirty-day follow-up was performed and 30-day mortality was reported. RESULTS: One hundred and ninety-eight patients were included and the number of events was nine. The gradient between the inner canthus and the nose tip (DeltaN) and the gradient between the inner canthus and the fingertip (DeltaF) showed a significant association with 30-day mortality (DeltaN: odds ratio: 1.31; 95% confidence interval: 1.05-1.64 and DeltaF: odds ratio: 1.27; 95% confidence interval: 1.02-1.57). CONCLUSION: DeltaN and DeltaF showed a significant association with 30-day mortality, suggesting a prognostic value. However, this was a small pilot study with few events. Larger studies are warranted for confirmation of these findings. PMID- 28002091 TI - Vector Analysis of 1-Year Astigmatic Outcomes From a Randomized Fellow Eye Comparison of Photorefractive Keratectomy Using 2 Excimer Laser Platforms. AB - OBJECTIVE: To compare the astigmatic outcomes of photorefractive keratectomy (PRK) with a wavefront-guided (WFG) and a wavefront-optimized (WFO) excimer laser performed on two different platforms. METHODS: Setting: institutional. DESIGN: Prospective, randomized, fellow eye comparison clinical trial. PARTICIPANTS: A total of 142 eyes of 71 patients with myopia of 12 diopters (D) or less and astigmatism of 3D or less were enrolled at the Byers Eye Institute at Stanford between April 2009 and March 2011. INTERVENTION: One eye of each patient underwent WFG-PRK with the VISX CustomVue Star S4 IR (Abbott Medical Optics, Abbott Park, IL) and the contralateral eye underwent WFO-PRK with the Wavelight Allegretto Eye-Q 400-Hz laser platform (Alcon, Inc., Huenberg, Switzerland). Alpins vector analysis of astigmatism was performed using manifest refraction measured preoperatively and 12 months postoperatively and vertexed to the corneal plane. Eyes were stratified for subgroup analysis based on preoperative manifest astigmatism. RESULTS: WFG-PRK and WFO-PRK were similar regarding surgically induced astigmatism, difference vector, magnitude of error, correction index, flattening index, and index of success. The angle of error was 60% less in the WFG group compared with the WFO group (4.9+/-1.1 degrees vs. 11.8+/-2.4 degrees , P=0.01). CONCLUSIONS: WFG-PRK with the VISX CustomVue Star S4 IR and WFO-PRK with the Alcon WaveLight Allegretto Eye-Q 400-Hz excimer laser platform produce similar astigmatic results in myopic patients; however, the WFG mode may produce slightly more predictable astigmatic corrections. PMID- 28002092 TI - Treatment Practices and Outcomes of Meibomian Gland Dysfunction at a Tertiary Center in Southern India. AB - OBJECTIVE: To describe the current treatment practices for meibomian gland dysfunction (MGD) at a tertiary eye center, together with the subjective outcomes and compliance behaviors of patients. METHODS: This retrospective cohort study reviewed medical records for MGD severity grading, treatment prescribed, and follow-up schedule. In addition, participants were surveyed to gauge subjective outcomes and treatment adherence. RESULTS: Eight hundred ten patients were diagnosed with "MGD" or "meibomitis" and had a total of 14 different treatment combinations prescribed. In 3.0% of cases, there was no treatment specified. As MGD severity increased, it became more likely that management would be applied and this was also associated with significantly longer treatment durations (P=0.02) and shorter follow-up periods (P<0.001). Posttreatment subjective outcomes and treatment adherence surveys had a response rate of 36.7% and 24.1% respectively. Overall, 53.5% reported sustained improvement, 40.7% no improvement, and 5.7% experienced temporary relief. Although no treatment regimen seemed to be more efficacious than others, patients showed greater adherence when using topical reagents compared with lid hygiene measures (P<=0.002). CONCLUSION: Clinicians, in this large tertiary eye center, use a wide range of treatment regimens to manage MGD. This suggests the need for development of standard management protocols. Whether alone, or in combination, no MGD treatment significantly improved subjective symptoms, a result that may be influenced by compliance behaviors. Use of topical reagents (eye drops or ointment) seemed to be associated with the best compliance. Future focus on more effective MGD treatments is needed to improve practical outcomes. PMID- 28002093 TI - Postoperative Analgesia by a Transversus Abdominis Plane Block Using Different Concentrations of Ropivacaine for Abdominal Surgery: A Meta-Analysis. AB - BACKGROUND: Transversus abdominis plane block (TAPB) has been proven to be an effective means of postoperative anesthesia, but the optimum effective concentration of ropivacaine warrants further research. OBJECTIVE: This study aimed to identify the optimal ropivacaine concentration of TAPB using a meta analysis. MATERIALS AND METHODS: This study consisted of a meta-analysis of randomized controlled trials (RCTs). We searched online databases, including PubMed, Embase, the Cochrane Database of Systematic Reviews, and Web of Science. RCTs investigating the 24-hour postoperative opioid consumption and the rest and dynamic pain scores 2, 12, and 24 hours after surgery were included in this analysis. We also assessed opioid-related side-effects and patient satisfaction 24 hours after surgery. RESULTS: Nineteen RCTs (1217 patients) were included in this meta-analysis, which showed that only TAPB with 0.375% and 0.5% ropivacaine was able to reduce opioid consumption 24 hours after surgery by weighted mean differences of -6.55 and -4.44 mg (morphine IV equivalents), respectively (P<0.05). A meta-regression analysis did not reveal an association between the local anesthetic dose (in mg), surgery, anesthesia, block timing, and the TAPB effect on opioid consumption. Ropivacaine concentrations of 0.375% and 0.5% reduced the 2-hour postoperative pain score and reduced the incidence of nausea and vomiting, but this analgesic effect disappeared at 12 and 24 hours. Only TAPB with 0.375% ropivacaine improved the degree of satisfaction 24 hours after surgery (weighted mean difference of 0.87 [0.08-1.66], P=0.03). CONCLUSION: In terms of efficacy and safety, the use of 0.375% ropivacaine for TAPB is preferred in the clinical work. PMID- 28002095 TI - Assessing Prescribing Trends of Adjuvant Medication Therapy in Outpatients With a Diagnosis of Noncancer Chronic Pain. AB - BACKGROUND: Chronic pain affects over 100 million adults in the United States, yet continues to be difficult to treat. Concerns continue to mount over the use of opioids to treat noncancer chronic pain (NCCP). Guidelines support the use of adjuvant medications as one of the preferred options for treating chronic pain over opioids. OBJECTIVES: To examine reported usage of adjuvants in the treatment of chronic pain via the National Ambulatory Medical Care Survey (NAMCS). MATERIALS AND METHODS: A retrospective, cross-sectional study evaluating reported usage of adjuvant pain medications for the treatment of NCCP was conducted using NAMCS data from 2000 to 2007. Weighted samples were analyzed with regard to several patient variables. Logistic regression models provided 95% confidence intervals and an adjusted odds ratio to determine statistically significant differences in reported usage for the evaluated patient variables. RESULTS: In total, 244,797,406 weighted visits were included for analysis. The analysis showed an almost 2-fold increase in adjuvant use during the study period. Statistically significant differences were identified for several factors evaluated. Younger age, female sex, care from a nonprimary care physician, comorbidities with pain, and >5 current medications were associated with higher rates adjuvant therapy use. DISCUSSION: Overall adjuvant usage dramatically increased during the study period. Analysis of data demonstrated adjuvant use in chronic pain varied based patient-specific characteristics. These results may allow clinicians, policy makers, and medical educators to identify potential gaps in adjuvant use in certain populations and target areas for clinical, populations based, and educational improvements in managing NCCP. PMID- 28002094 TI - The Association Between Headaches and Temporomandibular Disorders is Confounded by Bruxism and Somatic Symptoms. AB - OBJECTIVES: The objective of this observational study was to establish the possible presence of confounders on the association between temporomandibular disorders (TMD) and headaches in a patient population from a TMD and Orofacial Pain Clinic. MATERIALS AND METHODS: Several subtypes of headaches have been diagnosed: self-reported headache, (probable) migraine, (probable) tension-type headache, and secondary headache attributed to TMD. The presence of TMD was subdivided into 2 subtypes: painful TMD and function-related TMD. The associations between the subtypes of TMD and headaches were evaluated by single regression models. To study the influence of possible confounding factors on this association, the regression models were extended with age, sex, bruxism, stress, depression, and somatic symptoms. RESULTS: Of the included patients (n=203), 67.5% experienced headaches. In the subsample of patients with a painful TMD (n=58), the prevalence of self-reported headaches increased to 82.8%. The associations found between self-reported headache and (1) painful TMD and (2) function-related TMD were confounded by the presence of somatic symptoms. For probable migraine, both somatic symptoms and bruxism confounded the initial association found with painful TMD. DISCUSSION: The findings of this study imply that there is a central working mechanism overlapping TMD and headache. Health care providers should not regard these disorders separately, but rather look at the bigger picture to appreciate the complex nature of the diagnostic and therapeutic process. PMID- 28002096 TI - Duloxetine as an Analgesic Reduces Opioid Consumption After Spine Surgery: A Randomized, Double-Blind, Controlled Study. AB - OBJECTIVES: Multimodal analgesia is widely advocated for the control of perioperative pain in an effort to reduce the use of opioid. Duloxetine is a selective inhibitor of serotonin and norepinephrine reuptake with efficacy for chronic pain conditions. The primary objective of this study was to evaluate the efficacy of two 60 mg oral doses of duloxetine in terms of fentanyl consumption during the postoperative period in patients undergoing elective spine surgery. MATERIALS AND METHODS: This study was prospective, double-blind, randomized, and placebo controlled. Patients received either 60 mg duloxetine or an identical placebo 1 hour before surgery and again the following morning. The study participants were allocated into 2 groups: Group C (control) participants received the placebo and Group D (duloxetine) participants received 60 mg duloxetine. The total consumption of fentanyl 48 hours after surgery was measured. Secondary end points were pain scores and the presence or absence of adverse effects, such as headache, nausea, vomiting, itching, dizziness, and drowsiness. RESULTS: Demographic characteristics did not differ between groups. There was a significant difference in fentanyl consumption in the first 24 hours between Groups C and D (mean difference, 223.11+/-39.32 ug; P<0.001). Fentanyl consumption also differed between Groups C and D after 48 hours (mean difference, 179.35+/-32.55 ug; P<0.000). The pain scores over 48 hours did not significantly differ between groups. The incidence of side-effects was similar in both groups. DISCUSSION: Duloxetine was effective as an adjunct for postoperative analgesia and reduced opioid consumption. PMID- 28002097 TI - Associations Between Spatial and Temporal Contrast Sensitivity and Reading. AB - PURPOSE: To gain insight into the association between optical and neural components of contrast sensitivity (CS), operationalized as spatial CS (optical and neural) or temporal CS (solely neural), and reading speed in a clinical sample of healthy adults of various ages. Furthermore, precision and agreement of the two methods were assessed. METHODS: The Mars test and the temporal CS implementation of the C-Quant device were used to measure spatial CS and temporal CS, respectively. Tests were performed with 71 normally sighted adults: mean age 55 (range 18-86) years. Pearson's correlation analyses were performed between spatial CS or temporal CS, and reading speed and partial correlations controlled for age are presented. Precision of the measurement was defined by the coefficient of repeatability and repeated measures standard deviations. Differences between spatial CS and temporal CS values were determined with 95% limits of agreement. RESULTS: A correlation was found between reading speed and both spatial CS (r = 0.470; P < .001) and temporal CS (r = 0.258; P = .04); partial correlations controlled for age were r = 0.175 (P = .17) and r = 0.152 (P = .24), respectively. Coefficient of repeatability was 0.13 log units and 0.24 log units for spatial CS and temporal CS test, respectively. A proportional difference of 0.1 log units was found between spatial CS and temporal CS measurements. CONCLUSIONS: A significant correlation was found between both spatial CS and temporal CS and reading speed indicating that, besides optical components, neural aspects may be important in defining reading speed. The stronger correlation between spatial CS and reading speed is suggested to reflect a deterioration of both optical and neural factors with increasing age. The coefficients of repeatability for spatial CS and temporal CS found in the present study are in agreement with previous research, and the difference found between the two methods might be attributed to the psychometric differences between the methods. PMID- 28002098 TI - Superficial Acral Fibromyxoma of the Toe: Unusual Location of the Mixoid Variant. AB - Superficial acral fibromyxoma (SAFM) is a rare soft tissue tumor that frequently involves the periungual and subungual regions of acral surfaces. Macroscopically, it appears as a flesh-colored dome-shaped solitary mass; microscopically, it consists of a moderately cellular proliferation of spindle-shaped fibroblast-like cells embedded in a myxocollagenous stroma and arranged in a loose storiform and focally fascicular pattern. The tumor cells are immunoreactive for CD34, epithelial membrane antigen, CD99, and CD10. In this study, we describe a case of SAFM on the fourth toe with predominantly myxoid stroma. Our case, in contrast of those reported in the literature, showed an unusual location for the myxoid variant. SAFM is often not recognized; it may resemble some benign and malignant mesenchymal neoplasm. The gold standard treatment is surgery. The tumor was completely excised, and no recurrence was evident at 1-year follow-up. Awareness of this entity facilitates its diagnosis and management, avoiding unwarranted concerns and additional procedures for the patient. PMID- 28002099 TI - Achille Civatte: A Master of the Microscope. AB - Achille Civatte (1877-1956) was one of the most highly regarded dermatologists of the 20th century. We provide a succinct account of Civatte's academic life and contributions to the field of dermatopathology, in addition to briefly discussing his son, Jean Civatte, who himself became a highly regarded dermatologist. PMID- 28002100 TI - Revisiting PAX-8's Labeling of Merkel Cell Carcinoma. PMID- 28002101 TI - Development of Basal Cell Carcinoma With Squamous Differentiation During Vismodegib Treatment. PMID- 28002102 TI - 755-nm Q-Switched Alexandrite Laser as a Treatment for Melanonychia Caused by Onychomycosis. PMID- 28002103 TI - Total Matricectomy and V-Y Advancement Flap Technique in the Treatment of Onychogryphosis. AB - BACKGROUND: Onychogryphosis is manifested by irregular thickening and curving of nails and the nailfold, resulting in ram horn appearance. No therapeutic modality that can normalize nails with onychogryphosis is yet available. Recommended therapies include palliative measures and various surgical interventions. OBJECTIVE: The authors reviewed the outcomes of total matricectomy and V-Y advancement flap technique used for nail removal in patients with onychogryphosis at the big toe. MATERIALS AND METHODS: The authors evaluated 14 patients with onychogryphosis, including 8 men and 6 women (15 big toes; 10 at the right foot and 5 at the left foot), who underwent total matricectomy and V-Y advancement flap technique. The general complaints included repeated nail removal, pain, cosmetic complaints, and difficulty in wearing shoe and footwear. RESULTS: Mean age of the patients was 42.4 years. Mean follow-up was 13.5 months. Clinical history revealed at least 2 previous nail removals. No complications were observed during the follow-up period. Mean time to return to daily activities was 4.5 weeks. Patient satisfaction was rated as very good in 9 patients and good in 5 patients. CONCLUSION: The surgical technique employed in patients with onychogryphosis is a safe treatment option with a high success rate. PMID- 28002104 TI - Laser Treatment of Keloid Scars. PMID- 28002105 TI - Variables in Cryosurgery Technique Associated With Clearance of Actinic Keratosis. AB - BACKGROUND: Cryosurgery is the most commonly used method to treat actinic keratosis (AK). Cryosurgical methods are not standardized. OBJECTIVE: To examine differences in the spray techniques used for liquid nitrogen cryosurgery when treating AKs of the head, and the effect of these variations in technique on rates of complete clearance of AKs. MATERIALS AND METHODS: Patients were those from the FIELD-1 study, who received cryosurgery as per the investigators' usual practice to all AKs. This was followed by topical treatment with either vehicle gel or ingenol mebutate gel, 0.015%, after 3 weeks. The investigator recorded the average duration of cryosurgery spray used, the number of freeze-thaw cycles, and the distance from the tip of the spray device to the AK. Clearance rates were determined at Week 11. RESULTS: Less-aggressive freezing techniques were used for AKs on the face than for those on the scalp. However, higher rates of complete clearance on the face and scalp were associated with more-aggressive freezing techniques. CONCLUSION: Patients with AKs on the face receive less-aggressive cryosurgery than do patients with AKs on the scalp. PMID- 28002106 TI - The application of lipidomics to biomarker research and pathomechanisms in Alzheimer's disease. AB - PURPOSE OF REVIEW: Alzheimer's disease is the most common cause of dementia. There are still no disease modifying treatments that can cure or slow disease progression. Recently, Alzheimer's disease researchers have attempted to improve early detection and diagnostic criteria for Alzheimer's disease, with the rationale that treatment of disease, or even prevention, may be more successful during the early preclinical stages of Alzheimer's disease when neurodegenerative damage is not as widespread. As the brain has a high lipid content, lipidomics may offer novel insights into the underlying pathogenesis of Alzheimer's disease. This review reports on recent developments in the relatively unexplored field of lipidomics in Alzheimer's disease, including novel biomarkers and pathomechanisms of Alzheimer's disease. RECENT FINDINGS: Numerous biomarker panels involving phospholipids and sphingolipids have been proposed, indicating perturbed lipid metabolism in early stages of Alzheimer's disease. Future strategies targeting these metabolic changes through dietary supplementation could have therapeutic benefits in at-risk individuals. SUMMARY: Dysregulated lipid metabolism could reflect pathological changes in synaptic function and neuronal membranes, leading to cognitive decline. However, extensive validation in large independent cohorts is required before lipid biomarkers can be used clinically to assess Alzheimer's disease risk and progression. PMID- 28002107 TI - Astigmatism Correction With Toric Intraocular Lenses in Descemet Membrane Endothelial Keratoplasty Triple Procedures. AB - PURPOSE: To report the clinical efficacy of astigmatism correction with toric intraocular lenses (IOLs) in patients undergoing the Descemet membrane endothelial keratoplasty (DMEK) triple procedure and to evaluate the accuracy of the correction. METHODS: Fifteen eyes of 10 patients who received cataract extraction, toric IOL placement, and DMEK surgery for Fuchs corneal dystrophy and cataracts were evaluated. The cylinder power of toric IOLs was determined by an online toric calculator with keratoscopy measurements obtained using Scheimpflug corneal imaging. Prediction errors were assessed as a difference vector between the anticipated minus postoperative residual astigmatism. RESULTS: At 10.1 +/- 4.9 months postoperatively, 8/13 (61.5%) of eyes achieved uncorrected distance visual acuity better than 20/40. Mean best spectacle-corrected distance visual acuity (logMAR) improved from 0.21 +/- 0.15 preoperatively to 0.08 +/- 0.12 postoperatively (P < 0.01). The magnitude of refractive astigmatism was also significantly decreased from 2.23 +/- 1.10 D (range 0.75-4.25 D) preoperatively to 0.87 +/- 0.75 D (range 0.00-3.00 D) postoperatively (P < 0.01). In 1 eye with rotational misalignment by 43 degrees, we found no improvement of astigmatism. The prediction error of astigmatism at the corneal plane was 0.77 +/- 0.54 D (range 0.10-1.77 D). Four eyes with preoperative "with-the-rule" corneal astigmatism had postoperative "against-the-rule" refractive astigmatism. CONCLUSIONS: For patients with Fuchs corneal dystrophy and cataracts, use of toric IOLs might be a valuable option in triple DMEK surgery. Additionally, care should be taken to prevent excessive IOL rotation. PMID- 28002108 TI - Corneal Biomechanical Properties After Penetrating Keratoplasty or Deep Anterior Lamellar Keratoplasty Using the Ocular Response Analyzer: A Meta-Analysis. AB - PURPOSE: To evaluate the corneal biomechanical properties of patients who have undergone penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) using the ocular response analyzer. METHODS: Stata 13.0 SE was used for this meta-analysis. Studies in the literature that focused on corneal hysteresis (CH) or corneal resistance factor (CRF) after PK or DALK were retrieved by searching PubMed, Embase, Ovid, and Cochrane databases. We present the results as weighted mean difference (WMD) with a corresponding 95% confidence interval (CI). RESULTS: Eight studies with a total of 750 eyes were included in the post-PK versus control group, and 4 studies with a total of 218 eyes were included in the post-DALK versus control group. The pooled results showed that CH and CRF were significantly reduced (P < 0.00001) for patients who have undergone PK (WMD = 1.16, 95% CI: -1.73 to -0.60 and WMD = -1.00, 95% CI: -1.61 to -0.40). No significant differences were found in both CH and CRF for patients who have undergone DALK (WMD = -0.27, 95% CI: -0.64 to -0.09 and WMD = -0.15, 95% CI: 0.53 to 0.23). CONCLUSIONS: This meta-analysis suggested that both CH and CRF had better recovery after corneal transplantation with DALK than PK. PMID- 28002109 TI - Neonatal Bacterial Conjunctivitis in Korea in the 21st Century. AB - PURPOSE: To investigate the microbial cause and antibiotic susceptibility of neonatal bacterial conjunctivitis in Korean patients in the 21st century. METHODS: We retrospectively reviewed the medical records of patients diagnosed with neonatal bacterial conjunctivitis between January 2000 and December 2015. We recorded the organism, antibiotic susceptibility, and antibiotics used. RESULTS: A total of 82 neonates were included in the study (53 males and 29 females), with a mean age of 17.5 +/- 7.1 days. The most commonly isolated organisms were Staphylococcus aureus (43 cases, 52.4%), coagulase-negative staphylococci (11 cases, 13.4%), Staphylococcus epidermidis (11 cases, 13.4%), Serratia marcescens (4 cases, 4.9%), Pseudomonas aeruginosa (4 cases, 4.9%), and Enterobacter cloacae (3 cases, 3.7%). We found no cases of Neisseria gonorrhoeae or Chlamydia trachomatis infection. Resistance to methicillin (83.7%), macrolide (81.4%), and aminoglycoside (23.3%) was observed in patients with S. aureus infection. Conjunctivitis that did not improve with erythromycin or tobramycin generally improved with the additional use of tosufloxacin. CONCLUSIONS: The prevalence of neonatal gonococcal or chlamydial conjunctivitis has decreased in the 21st century. However, methicillin-resistant S. aureus has been increasing, but these cases are responsive to tosufloxacin. PMID- 28002110 TI - Total Corneal Astigmatism Measurements: Agreement Between 2 Rotating Scheimpflug Cameras. AB - PURPOSE: To investigate agreement between rotating Scheimpflug camera (Pentacam HR, Oculus) and rotating Scheimpflug camera combined with Placido disc corneal topography (Sirius, CSO) in measuring total corneal astigmatism (TCA). METHODS: In this observational study, all patients undergoing cataract surgery with preoperative measurement of TCA by both devices and a validated corneal topographer (Keratron, Optikon 2000) were retrospectively evaluated. Astigmatism analysis was performed with and without vector analysis separately in eyes with with-the-rule, against-the-rule, and oblique astigmatism. Vector analysis was performed using the Naeser polar system. RESULTS: In 130 eyes of 130 subjects, nonvectorial analysis revealed that the mean TCA values obtained with the Sirius were higher than the corresponding values given by the Pentacam HR in all subgroups, although the difference was statistically significant only in eyes with against-the-rule astigmatism (P = 0.0009). This finding was confirmed by vector analysis. A TCA magnitude difference greater than 0.5 diopters was observed in 20.8% of cases, and a TCA axis difference greater than 10 degrees was observed in 45.4% of cases. Axis differences dropped to 18.5% when only eyes with astigmatism >0.75 diopters were analyzed and 3 measurements were averaged. The mean difference in the meridional and torsional power of TCA was close to zero in all subgroups, but with relatively large standard deviations (approximately 0.5 D). CONCLUSIONS: Agreement between both devices in measuring TCA is only moderate with respect to both magnitude and axis orientation. PMID- 28002111 TI - Outcome of Therapeutic Penetrating Keratoplasty Using Glycerol-Preserved Donor Corneas in Infectious Keratitis. PMID- 28002112 TI - Wet-Peeling Technique of Deep Anterior Lamellar Keratoplasty With Hypotonic Water and Blunt Dissection for Healed Hydrops. AB - PURPOSE: To describe the surgical technique and outcomes of "wet-peeling" deep anterior lamellar keratoplasty (DALK) using sterile water and blunt dissection in cases with corneal scarring after healed corneal hydrops. METHODS: Manual DALK using a "wet-peeling" technique was performed in 20 eyes of 20 consecutive patients with healed corneal hydrops between June 2011 and October 2013. RESULTS: Intraoperative microperforations were encountered in 2 (10%) cases. None of the cases required conversion to penetrating keratoplasty. There was significant improvement in mean best-corrected visual acuity at the end of 24 months postoperatively (0.99 +/- 0.30 logMAR vs. 0.20 +/- 0.11 logMAR; P < 0.001). The postoperative mean residual stromal bed thickness was 48.9 +/- 5.9 MUm, and mean central corneal thickness was 557.2 +/- 50.3 MUm. The mean endothelial density was 2021 +/- 236 cells/mm at the final follow-up. CONCLUSIONS: Manual DALK using sterile water can be successfully performed in corneas with healed hydrops. Favorable visual outcomes may be attributed to thin residual bed thickness postoperatively. PMID- 28002113 TI - Techniques for Learning Descemet Membrane Endothelial Keratoplasty for Eyes of Asian Patients With Shallow Anterior Chamber. AB - PURPOSE: To describe several essential surgical techniques that overcome difficulties in performing Descemet membrane endothelial keratoplasty (DMEK) for inexperienced surgeons, especially those who perform DMEK on eyes of Asian patients. METHODS: Nine eyes of 9 Asian patients with bullous keratopathy who underwent DMEK were analyzed retrospectively. All patients were given a diuretic such as D-mannitol or acetazolamide shortly before surgery, with retrobulbar anesthesia and a Nadbath facial nerve block. Core vitrectomy before DMEK was performed in several cases in which a high vitreous pressure during surgery was predicted. The donor graft was stained with trypan blue, and a 25-G anterior chamber maintenance cannula was used to maintain the anterior chamber depth during graft insertion in all eyes. RESULTS: The cornea became clear in all eyes. The best spectacle-corrected visual acuity had improved significantly 6 months after the surgery compared with preoperative values (P = 0.026). The corneal endothelial cell density was 1371 cells per square millimeter at postoperative 6 months. CONCLUSIONS: Although DMEK is technically difficult, especially for inexperienced surgeons who operate on eyes of Asian patients, controlling anterior chamber pressure using various manipulations may help to prevent iatrogenic primary graft failure and lead to successful DMEK. PMID- 28002114 TI - Treatment of Pseudomonas Keratitis by Continuous Infusion of Topical Antibiotics With the Morgan Lens. AB - PURPOSE: Despite following standard treatment, Pseudomonas keratitis can continue to progress and result in loss of vision or of the eye. Our cases demonstrate that the Morgan Lens can be an effective topical antibiotic delivery vehicle in advanced keratitis. METHODS: Two patients (3 eyes) with Pseudomonas keratitis were included in this report after failing to respond to intense inpatient topical treatment. Because loss of the eyes was imminent, the Morgan Lenses were used for continuous lavage with ceftazidime (50 mg/mL), in conjunction with other conventional treatment. RESULTS: Three days after lavage, corneal cultures became negative in all eyes. Infusion was continued for at least a week to ensure sterilization of the infection before switching to standard topical therapy. The infection in both cases was promptly eradicated and the eyes were rescued. CONCLUSIONS: The Morgan Lens can be a viable alternative in treating severe and aggressive infectious keratitis or sclerokeratitis. Application of the Morgan Lens is noninvasive and requires minimal training. Intravenous tubing connectors allow for easy swapping between medications, simultaneous administration of multiple medications, and titration of dosing. Additionally, it is cost-effective as the low demand for nursing care essentially eliminates the need for intensive care unit admission. PMID- 28002115 TI - Pilot Testing a Web-Based System for the Assessment and Management of Chemotherapy-Induced Peripheral Neuropathy. AB - Because numerous barriers hinder the assessment and management of chemotherapy induced peripheral neuropathy in clinical practice, the Carevive Care Planning System, a novel Web-based platform, was developed to address these barriers. It provides patients an opportunity to report their symptoms before their clinic visit and generates customizable care plans composed of evidence-based management strategies. The purpose of this study was to evaluate patient and provider perspectives of feasibility, usability, acceptability, and satisfaction with the Carevive platform. We used a single-arm, pretest/posttest, prospective design and recruited 25 women with breast cancer who were receiving neurotoxic chemotherapy and six advanced practice providers from an academic hospital. At three consecutive clinical visits, patients reported their neuropathy symptoms on a tablet via the Carevive system. The Diffusion of Innovations Theory served as an overarching evaluation framework. The Carevive platform was feasible to use. However, patients had higher ratings of usability, acceptability, and satisfaction with the platform than did the providers, who disliked the amount of time required to use the platform and had difficulty logging into Carevive. If issues regarding provider dissatisfaction can be addressed, the Carevive platform may aid in the screening of neuropathy symptoms and facilitate the use of evidence-based management strategies. PMID- 28002116 TI - Crossing Borders: An Online Interdisciplinary Course in Health Informatics for Students From Two Countries. AB - A cross-countries and interprofessional novel approach for delivering an international interdisciplinary graduate health informatics course online is presented. Included in this discussion are the challenges, lessons learned, and pedagogical recommendations from the experiences of teaching the course. Four professors from three different fields and from three universities collaborated in offering an international health informatics course for an interdisciplinary group of 18 US and seven Norwegian students. Highly motivated students and professors, an online technology infrastructure that supported asynchronously communication and course delivery, the ability to adapt the curriculum to meet the pedagogy requirements at all universities, and the support of higher administration for international collaboration were enablers for success. This project demonstrated the feasibility and advantages of an interdisciplinary, interprofessional, and cross-countries approach in teaching health informatics online. Students were able to establish relationships and conduct professional conversations across disciplines and international boundaries using content management software. This graduate course can be used as a part of informatics, computer science, and/or health science programs. PMID- 28002118 TI - Hemodynamic response to primary prophylactic therapy with nonselective beta blockers is related to a reduction of first variceal bleeding risk in liver cirrhosis: a meta-analysis. AB - The current primary prophylaxis for esophageal variceal bleeding in cirrhotic patients consists of nonselective beta-blocker (NSBB) therapy. However, only approximately half of the patients achieve a sufficient hemodynamic response to NSBB therapy. Clinical application of hemodynamic response monitoring is still under debate. The aim of this meta-analysis is to assess the potential clinical value of monitoring the hemodynamic response to NSBB therapy using hepatic venous pressure gradient (HVPG) measurements in the primary prophylaxis for variceal bleeding. A systematic literature search was performed in PubMed, Embase, Web of Science, and the COCHRANE Library. Randomized-controlled trials and case series that included cirrhotic patients receiving primary prophylaxis for variceal bleeding with NSBBs and hemodynamic response monitoring using HVPG measurements were included for analysis. The primary outcome measure was variceal bleeding. A fixed-effect analysis was carried out using the Mantel-Haenszel method for relative risks. Six of the 1172 papers found were selected on the basis of stringent selection criteria. Hemodynamic response (HVPG <=12 mmHg and/or a reduction of >=20%, or >=10% in one study, from baseline) to beta-blocker therapy was associated significantly with a lower risk of variceal bleeding (relative risk=0.13, 95% confidence interval=0.06-0.29) compared with a nonresponse. Patients achieving a hemodynamic response to NSBB therapy have a lower risk of variceal bleeding than hemodynamic nonresponders. Hemodynamic monitoring in primary prophylaxis is of potential clinical value and requires further assessment in large cohort randomized-controlled trials. PMID- 28002119 TI - Rat Bite Fever: A Case Report and Review of the Literature. AB - Cases of rat-bite fever (RBF) were reported in the literature for more than 2000 years. Not until recently, however, were attempts made to differentiate between RBF and Streptobacillus moniliformis septic arthritis, 2 arguably different clinical entities. There are limited data regarding S moniliformis septic arthritis and the features that distinguish it from RBF, and most conclude that although clinically disparate diseases, it is difficult to differentiate between them. We report a case of a 17-year-old girl who presented with S moniliformis bacteremia and symptoms that spanned both RBF and S moniliformis septic arthritis. This case emphasizes the difficulty in differentiating the 2 clinical entities and the importance of early diagnosis, proper clinical suspicion, and prompt treatment to achieve positive outcomes. PMID- 28002117 TI - Quantitative Assessment of Liver Function Using Gadoxetate-Enhanced Magnetic Resonance Imaging: Monitoring Transporter-Mediated Processes in Healthy Volunteers. AB - OBJECTIVE: The objective of this study was to use noninvasive dynamic contrast enhanced magnetic resonance imaging (MRI) techniques to study, in vivo, the distribution and elimination of the hepatobiliary contrast agent gadoxetate in the human body and characterize the transport mechanisms involved in its uptake into hepatocytes and subsequent efflux into the bile using a novel tracer kinetic model in a group of healthy volunteers. MATERIALS AND METHODS: Ten healthy volunteers (age range, 18-29 years), with no history of renal or hepatic impairment, were recruited via advertisement. Participants attended 2 MRI visits (at least a week apart) with gadoxetate as the contrast agent. Dynamic contrast enhanced MRI data were acquired for approximately 50 minutes with a 3-dimensional gradient-echo sequence in the axial plane, at a temporal resolution of 6.2 seconds. Data from regions of interest drawn in the liver were analyzed using the proposed 2-compartment uptake and efflux model to provide estimates for the uptake rate of gadoxetate in hepatocytes and its efflux rate into the bile. Reproducibility statistics for the 2 visits were obtained to examine the robustness of the technique and its dependence in acquisition time. RESULTS: Eight participants attended the study twice and were included into the analysis. The resulting images provided the ability to simultaneously monitor the distribution of gadoxetate in multiple organs including the liver, spleen, and kidneys as well as its elimination through the common bile duct, accumulation in the gallbladder, and excretion in the duodenum. The mean uptake (ki) and efflux (kef) rates in hepatocytes, for the 2 visits using the 50-minute acquisition, were 0.22 +/- 0.05 and 0.017 +/- 0.006/min, respectively. The hepatic extraction fraction was estimated to be 0.19 +/- 0.04/min. The variability between the 2 visits within the group level (95% confidence interval; ki: +/-0.02/min, kef: +/ 0.004/min) was lower compared with the individual variability (repeatability; ki: +/-0.06/min, kef: +/-0.012/min). Data truncation demonstrated that the uptake rate estimates retained their precision as well as their group and individual reproducibility down to approximately 10 minutes of acquisition. Efflux rate estimates were underestimated (compared with the 50-minute acquisition) as the duration of the acquisition decreased, although these effects were more pronounced for acquisition times shorter than approximately 30 minutes. CONCLUSIONS: This is the first study that reports estimates for the hepatic uptake and efflux transport process of gadoxetate in healthy volunteers in vivo. The results highlight that dynamic contrast-enhanced MRI with gadoxetate can provide novel quantitative insights into liver function and may therefore prove useful in studies that aim to monitor liver pathology, as well as being an alternative approach for studying hepatic drug-drug interactions. PMID- 28002121 TI - Symptomatic carotid stenosis: is stenting as safe and effective as carotid endarterectomy? AB - PURPOSE OF REVIEW: Reviewing current evidence on carotid artery stenting (CAS) compared with carotid endarterectomy (CEA) in the prevention of ipsilateral stroke in patients with a symptomatic carotid stenosis. RECENT FINDINGS: Randomized clinical trials and registries have consistently shown that CAS is associated with a higher risk of procedural stroke or death and a lower risk of procedural myocardial infarction and local complications compared with CEA. Both procedures are equally effective to prevent late recurrent ipsilateral stroke and are associated with similar low risk of restenosis.Individual patient data analyses of the Carotid Stenosis Trialists' Collaboration recently showed that CAS is as safe and as effective in patients younger than 70. SUMMARY: Although CEA remains the standard treatment in patients with recently symptomatic carotid stenosis, CAS is a safe and effective alternative option in patients younger than 70 and can be also considered when a contraindication to CEA exists. PMID- 28002122 TI - Neuroplasticity and amblyopia: vision at the balance point. AB - PURPOSE OF REVIEW: New insights into triggers and brakes of plasticity in the visual system are being translated into new treatment approaches which may improve outcomes not only in children, but also in adults. RECENT FINDINGS: Visual experience-driven plasticity is greatest in early childhood, triggered by maturation of inhibitory interneurons which facilitate strengthening of synchronous synaptic connections, and inactivation of others. Normal binocular development leads to progressive refinement of monocular visual acuity, stereoacuity and fusion of images from both eyes. At the end of the 'critical period', structural and functional brakes such as dampening of acetylcholine receptor signalling and formation of perineuronal nets limit further synaptic remodelling. Imbalanced visual input from the two eyes can lead to imbalanced neural processing and permanent visual deficits, the commonest of which is amblyopia. SUMMARY: The efficacy of new behavioural, physical and pharmacological interventions aiming to balance visual input and visual processing have been described in humans, and some are currently under evaluation in randomised controlled trials. Outcomes may change amblyopia treatment for children and adults, but the safety of new approaches will need careful monitoring, as permanent adverse events may occur when plasticity is re-induced after the end of the critical period.Video abstracthttp://links.lww.com/CONR/A42. PMID- 28002123 TI - Functional dizziness: from phobic postural vertigo and chronic subjective dizziness to persistent postural-perceptual dizziness. AB - PURPOSE OF REVIEW: Functional dizziness is the new term for somatoform or psychogenic dizziness. The aim of this study is to review arguments for the new nomenclature, clinical features, possible pathomechanisms, and comorbidities of functional dizziness. RECENT FINDINGS: The prevalence of functional dizziness as a primary cause of vestibular symptoms amounts to 10% in neuro-otology centers. Rates of psychiatric comorbidity in patients with structural vestibular syndromes are much higher with nearly 50% and with highest rates in patients with vestibular migraine, vestibular paroxysmia, and Meniere's disease. Pathophysiologic processes seem to include precipitating events that trigger anxiety-related changes in postural strategies with an increased attention to head and body motion and a cocontraction of leg muscles. Personality traits with high levels of neuroticism and low levels of extraversion appear as risk factors for anxiety and depressive disorders and increased morbidity in functional disorders. SUMMARY: Correct and early diagnosis of functional dizziness, as primary cause or secondary disorder after a structural vestibular syndrome, is very important to prevent further chronification and enable adequate treatment. Treatment plans that include patient education, vestibular rehabilitation, cognitive and behavioral therapies, and medications substantially reduce morbidity and offer the potential for sustained remission when applied systematically. PMID- 28002124 TI - Our Vision for the Future of Inflammatory Bowel Diseases: Research, Innovations, and Controversies. PMID- 28002125 TI - Bowel Thickening in Crohn's Disease: Fibrosis or Inflammation? Diagnostic Ultrasound Imaging Tools. AB - The high frequency of intestinal strictures in patients with Crohn's disease and the different treatment approaches specific for each type of stenosis make the differentiation between fibrotic and inflammatory strictures crucial in management of the disease. However, there is no standardized approach to evaluate and discriminate intestinal strictures, and until now, there was no established cross-sectional imaging modality to detect fibrosis. New techniques, such as contrast-enhanced ultrasound and sonoelastography allow the assessment of vascularization and mechanical properties of stenotic bowel tissue, respectively. These techniques have shown great potential to characterize strictures in Crohn's disease. The aim of this review is to sum up the current knowledge on bowel ultrasound tools to discriminate inflammatory from fibrotic stenosis in Crohn's disease considering the most recent published studies in the field. PMID- 28002127 TI - Sex Is Associated with Adalimumab Side Effects and Drug Survival in Patients with Crohn's Disease. AB - BACKGROUND: Adalimumab (ADA) is an effective treatment for Crohn's disease (CD). In rheumatology, sex differences concerning the response to ADA therapy have been described. However, such differences have not yet been reported for patients with CD. As such, the aim of this study was to compare ADA treatment outcomes in male and female patients with CD. METHODS: A clinical cohort was formed of consecutive patients with CD starting ADA in a single tertiary center between March 2006 and February 2011. The cohort was followed up to August 2015. Clinical outcomes were primary nonresponse, secondary nonresponse, and drug survival (ongoing ADA use). Reasons for stopping ADA were recorded. Kaplan-Meier analysis and Cox regression were used to assess drug survival. RESULTS: The cohort consisted of 107 female and 81 male patients. Median follow-up was 6.0 years (range 0.3-9.2). Drug survival was higher in male than female patients (48.1% versus 30.8%, P = 0.016). Side effects were reported more often by female patients (81.3% versus 64.2%, P = 0.008), and female patients ceased ADA more often due to side effects (35.4% versus 18.4%, P = 0.017). In survival analysis, female sex was associated with higher cessation rates (P = 0.006). Cox regression also identified female sex (P = 0.020), along with higher baseline CD Activity Index (P = 0.003), as predictors of ADA cessation. CONCLUSIONS: Female sex is negatively associated with ADA drug survival. Female patients report more side effects and cease ADA because of side effects more often. A more personalized and sex-specific approach seems warranted to increase drug survival in female patients. PMID- 28002128 TI - What Teens Do Not Know Can Hurt Them: An Assessment of Disease Knowledge in Adolescents and Young Adults with IBD. AB - BACKGROUND: Although adequate disease-related knowledge is recognized as an important component of transition readiness, little empirical attention has been directed toward understanding the levels of disease knowledge of adolescents and young adults (AYAs) with inflammatory bowel diseases (IBDs) or factors associated with higher levels of knowledge. This study described disease knowledge in a sample of AYAs with IBDs and examined individual, family, and patient-provider relationship factors associated with higher knowledge. METHODS: Seventy-five AYAs (ages 16-20) and their parents participated. AYAs and parents reported on demographics, parent autonomy granting behaviors, health care satisfaction, patient-provider transition-related communication, and disease knowledge. AYAs self-reported on disease self-efficacy. Disease information was abstracted from the medical record. RESULTS: On average, AYAs answered 8.20 (SD = 1.75) of 12 knowledge questions correctly. Over 85% of AYAs correctly identified their type of IBD, number and type of IBD-related surgeries, and name of their current IBD medical provider. In contrast, knowledge about frequency of medication refills, effects of drugs and alcohol on IBD, and number to call to schedule medical appointments was suboptimal (i.e., 50% or fewer provided a correct response). Older AYA age, greater AYA health care satisfaction, higher AYA self-efficacy, and more frequent patient-provider transition-related communication were each associated with higher IBD-related knowledge. CONCLUSIONS: To promote disease knowledge, providers should foster AYA self-efficacy by encouraging age appropriate involvement in IBD management and make discussion of transition related issues a priority during clinical appointments. Moreover, fostering collaborative and positive relationships with patients will improve satisfaction and may also enhance knowledge. PMID- 28002129 TI - Development and Internal Validation of a Model Using Fecal Calprotectin in Combination with Infliximab Trough Levels to Predict Clinical Relapse in Crohn's Disease. AB - BACKGROUND: The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohn's disease. METHODS: All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single center study. The Crohn's Disease Activity Index (CDAI), fecal calprotectin, C reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 MUg/mL) and calprotectin (50 versus 250 MUg/g stools) were identified across four logistic regression models. RESULTS: One hundred nineteen patients (mean age: 34 +/- 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin >250 MUg/g stools (OR: 4.09; 95% CI, 1.01-16.21; P = 0.049) and TLI <2 MUg/mL (OR: 14.85; 95% CI, 3.67 60; P < 0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI <2 MUg/mL and a fecal calprotectin level >250 MUg/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97). CONCLUSIONS: In IFX-treated patients with CD in clinical remission, a combination of TLI (<2 MUg/mL) and fecal calprotectin (>250 MUg/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 MUg/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment. PMID- 28002130 TI - A Pooled Analysis of Efficacy, Safety, and Long-term Outcome of Endoscopic Balloon Dilation Therapy for Patients with Stricturing Crohn's Disease. AB - BACKGROUND: Endoscopic balloon dilation (EBD) is widely used to manage Crohn's disease-associated strictures. However, most studies of the safety and efficacy are small and heterogenous. We performed a combined analysis of published studies and evaluated 676 comprehensive individual participant data sets to determine the overall effects of EBD. METHODS: Citations from the Embase, MEDLINE, and the Cochrane library from 1991 through 2013 were systematically reviewed, and references of cited articles were assessed for relevant publications. We collected data from studies including >=15 patients and additionally generated a unique individual patient database containing 676 individual data sets derived from 12 studies. Technical feasibility, short-term and long-term efficacies, and safety were evaluated. RESULTS: In 1463 patients with Crohn's disease who underwent 3213 EBD procedures, 98.6% of strictures were ileal and 62% anastomotic. The technical success rate of the EBDs was 89.1% with a clinical efficacy of 80.8%. Complications occurred in 2.8% per procedure. After 24 months of follow-up, 73.5% of subjects underwent redilation and 42.9% surgical resection. In a multivariate analysis of 676 individual patients, a stricture length of <=5 cm was associated with a surgery-free outcome; every 1 cm increase of stricture length increased the hazard of need for surgery by 8% (P = 0.008). Inflammation did not affect outcomes or rate of complications. CONCLUSIONS: Based on a systematic literature review and analysis of data sets from 676 patients, EBD has a high rate of short-term technical and clinical efficacies, with substantial long-term efficacy and acceptable rates of complication. PMID- 28002131 TI - Premedication Use Before Infliximab Administration: A Cross-sectional Analysis. AB - BACKGROUND: Premedications are commonly given to patients with inflammatory bowel disease before intravenous infliximab administration. We aimed to (1) describe practice variability; and (2) determine clinician rationale for premedicating patients with inflammatory bowel disease before infliximab administration. METHODS: We developed a cross-sectional electronic survey after comprehensive literature review to assess practice variability and clinician rationale for premedication use before infliximab. An optional postsurvey quiz assessed clinicians' understanding of the available literature. The survey was distributed through members-only NASPGHAN and Crohn's and Colitis Foundation of America (CCFA) listservs and American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) web-based discussion boards. RESULTS: Three hundred seventy-nine unique respondents with a 93.3% survey completion rate comprised 331 (87%) and 45 (12%) pediatric and adult gastroenterologists. Among numerous options for premedications, acetaminophen (66%) and diphenhydramine (64%) were most often given before each infliximab infusion. Only 20% did not routinely use premedications. There was heterogeneity of premedication use between gastroenterologists within the same clinical practice. Of 328 (87%) respondents who completed the knowledge assessment quiz, only 18% identified the association of diphenhydramine use with increased reaction. CONCLUSIONS: There is high interpractice and intrapractice variability for premedication use before infliximab administration. Clinician rationale for premedicating patients seems to be driven by individual preference or group practice habit. Improved knowledge of the evidence may assist in decreasing overuse of premedications, particularly diphenhydramine. PMID- 28002132 TI - Reply. PMID- 28002133 TI - Reply. PMID- 28002141 TI - A new beginning: Stay informed! PMID- 28002142 TI - Diagnosis and management of pityriasis rosea. PMID- 28002143 TI - Improving breast cancer screening in a federally qualified health center with a team of nursing leaders. PMID- 28002144 TI - 29th Annual APRN Legislative Update. AB - The Annual Legislative Update describes the legislative issues that have the most impact on NPs and other advanced practice nurses across the country. PMID- 28002145 TI - HPV knowledge and vaccination rates in college-aged males: Implications for practice. AB - Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States and is linked to anogenital cancers. College-aged males are at high risk for contracting HPV due to a lack of HPV knowledge and low vaccination rates. NPs are responsible for providing this education and in return can help reduce infection transmission. PMID- 28002147 TI - Cardiac-related prodromal symptoms: A complicated clinical challenge. PMID- 28002148 TI - Hematuria: Incidental finding or a problem? PMID- 28002149 TI - The Effect of Allopurinol on Renal Function. AB - BACKGROUND: Hyperuricemia is associated with development of gout, hypertension, and renal disease. The impact of allopurinol, a urate-lowering therapy, on renal function is unclear, especially in patients with chronic kidney disease who are at higher risk of hypersensitivity reaction. OBJECTIVES: The aim of this study was to determine the effect of allopurinol on kidney function in hyperuricemic male veterans. METHODS: This is a retrospective cohort study using pharmacy, medical, and laboratory records of veterans enrolled at the Veterans Administration New York Harbor Healthcare System, Brooklyn campus. Fifty patients with hyperuricemia defined as a serum uric acid greater than 7 mg/dL (average of ~9 mg/dL), newly started on allopurinol for any reason, with evidence of treatment compliance, were matched by age, race, sex, and estimated glomerular filtration rate (EGFR) to 50 hyperuricemic control subjects. The retrospective cases were observed from October 2000 until November 2006, at which time there was a change in the laboratory analyzer, making further comparisons inappropriate. RESULTS: On average, patients treated with a mean 221 (SD, 96) mg/d dose of allopurinol achieved 11.9 mL/min higher GFR (95% confidence interval, 4.8-11.9 mg/d dose; P = 0.01) than did the control group. Treatment effect was found to depend on the initial EGFR, as indicated by the significant treatment by initial EGFR interaction (P = 0.004) and increased with a higher initial EGFR. The allopurinol-treated group had a 0.10 mg/dL lower final creatinine level (95% confidence interval, 0.003-0.20 mg/dL; P = 0.04) than did the control subjects, adjusted for initial creatinine and age. The average length of follow-up was 3.4 years. There were 5 mild adverse events in the treated cases. CONCLUSIONS: Treatment of hyperuricemic patients with allopurinol over an average of 3.4 years resulted in a significant improvement of kidney function in this male cohort from the Veterans Administration Healthcare System. Clinicians should consider this potential benefit of allopurinol in the treatment of patients with hyperuricemia, those with overall maintained renal function. PMID- 28002150 TI - Screening and Treatment of Latent Tuberculosis Among Patients Receiving Biologic Agents: A National and International Survey of Rheumatologists. AB - OBJECTIVE: We sought to understand the current practice patterns of both US and international members of the American College of Rheumatology (ACR) in this regard. METHODS: A set of questionnaires developed by a focus group of faculties and fellows of the Rheumatology Division of University of Tennessee Health Science Center, Memphis, TN, was sent electronically using an online survey tool to 4433 rheumatologists who are ACR members in the United States and internationally. RESULTS: Seven hundred sixty-eight physicians out of 4433 ACR members responded to the electronic survey, with a response rate of 17.32%. The preferred screening method by most of the respondents was either tuberculin skin test (19%) or interferon gamma release assay (32%) or both. For treatment of latent tuberculosis infection (LTBI) overall, 49% of the respondents would refer management to infectious disease specialist or the health department, 37% would initiate isoniazid for 9 or 12 months, and 14% would use isoniazid for 6 months. Approximately 60% of respondents would initiate anti-tumor necrosis factor therapy after being on LTBI treatment for 1 month. The other respondents were almost equally divided among the 3 responses: 2, 3, 6, or 9 months. CONCLUSIONS: There is a large disagreement regarding the method used and how often to screen for LTBI after initiating biologic therapy and how soon biologic treatment would be started after initiating LTBI therapy. Another disagreement exists regarding the duration of LTBI therapy. The information obtained from the survey can be taken into account when ACR or other international member organizations formulate future recommendations regarding screening and treatment of LTBI. PMID- 28002151 TI - Use of Biologic Therapy in Racial Minorities With Rheumatoid Arthritis From 2 US Health Care Systems. AB - BACKGROUND: In the United States, there is racial/ethnic disparity in the care of rheumatoid arthritis (RA), yet there are limited data regarding the impact of varied health care systems on treatment outcomes. OBJECTIVE: The aim fo this study was to compare the frequencies of use of disease-modifying antirheumatic drugs and biologic agents in racial minorities with RA in a single-payer and variable-access health systems. METHODS: Rheumatoid arthritis disease status was examined in the Ethnic Minority Rheumatoid Arthritis Consortium (EMRAC) and Veterans Affairs Rheumatoid Arthritis Registry (VARA); frequencies of prednisone and disease-modifying antirheumatic drugs and biologic agent use at enrollment were documented. Comparisons in frequencies of RA therapies between RA cohorts and white and nonwhite racial subsets were evaluated. RESULTS: The combined cohorts provided 2899 subjects for analysis (EMRAC = 943, VARA = 1956). Routine Assessment of Patient Index Data 3 and Disease Activity Score in 28 Joints scores were equivalent (cohort, racial subsets), as was biologic agent use (26% vs. 28%) between whites and nonwhites. Disease-modifying antirheumatic drug use was greater in EMRAC nonwhites compared with their white counterparts, but similar to all VARA patients (33% vs. 22% [P < 0.001], 36%, 39%, respectively). However, biologic agent use was significantly greater in EMRAC versus VARA patients (37% vs. 22%, P < 0.001). In VARA patients, there was no difference in biologic agent use among racial subsets (22% vs. 21%). In EMRAC patients, biologic agent use was greater in whites than in nonwhites (EMRAC white 45% vs. EMRAC nonwhite 33%, P < 0.001; odds ratio, 1.66) and compared with all VARA subjects (EMRAC white 45% vs. all VARA 22%, P < 0.001; odds ratio, 2.91). Younger age, advanced education, longstanding disease, and severe disease were associated with biologic agent use. CONCLUSIONS: When compared with more variable-access systems, a VA system of care that includes a single-payer insurance may afford equality in use of biologic agents among different racial subsets. PMID- 28002152 TI - Comorbid Conditions are Associated With Emergency Department Visits, Hospitalizations, and Medical Charges of Patients With Systemic Lupus Erythematosus. AB - BACKGROUND/OBJECTIVES: In addition to increase mortality, comorbidities can increase medical costs for systemic lupus erythematosus (SLE). Healthcare utilization can dramatically increase medical costs. It is essential to better understand the comorbidities that can lead to healthcare utilization, such as emergency department visit and/or hospitalization, for SLE patients. Therefore, the objective of this study was to examine the associations between comorbidities and healthcare utilization and medical charges of patients with SLE. METHODS: Nebraska statewide emergency departments (ED) discharge and hospitals discharge data from 2007 to 2012 were used to study the comorbid conditions of patients with SLE. SLE was defined using the standard International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes (710.0). RESULTS: There were more comorbid conditions in patients with SLE than patients without SLE. Comorbid conditions were majorly related to ED visits and hospitalizations of patients with SLE. Chest pain, abdominal pain, injury, acute respiratory infections, symptoms of digestive systems, headache, myalgia and myositis, noninfectious gastroenteritis and colitis, and symptoms of skin and other integumentary systems are common comorbid conditions for ED visits. Infections, cardiovascular diseases, fractures, chronic obstructive pulmonary disease (COPD) and allied conditions, cerebrovascular diseases, and episodic mood disorder are common comorbid conditions for hospitalizations of patients with SLE. In addition, the numbers of comorbid conditions were significantly associated with the length of hospital stay and hospital charges for SLE patients. CONCLUSION: The findings in this study indicated that comorbid conditions are associated with healthcare utilization and medical charges of patients with SLE. PMID- 28002153 TI - Do Inactive Older Adults Who Increase Physical Activity Experience Less Disability: Evidence From the Osteoarthritis Initiative. AB - BACKGROUND: Physical inactivity is a leading risk factor for developing disability. Although randomized clinical trials have demonstrated improving physical activity can reduce this risk in older adults with arthritis, these studies did not specifically evaluate inactive adults. OBJECTIVES: The aim of this study was to evaluate the relationship of changes in physical activity with disability changes among initially inactive adults with or at high risk of knee osteoarthritis from Osteoarthritis Initiative. METHODS: Inactive persons were identified at baseline based on the US Department of Health and Human Services classification (no [zero] 10-minute session of moderate-to-vigorous [MV] activity over 1 week) from objective accelerometer monitoring. Two years later, physical activity change status was classified as follows: (1) met Federal physical activity guidelines (>=150 MV minutes/week acquired in bouts >=10 minutes), (2) insufficiently increased activity (some but <150 MV bout minutes/week), or (3) remained inactive. Disability at baseline and 2 years was assessed by Late Life Disability Instrument limitation and frequency scores. Multiple regression evaluated the relationship of physical activity change status with baseline-to-2 year changes in disability scores adjusting for socioeconomics, health factors, and baseline disability score. RESULTS: Increased physical activity showed a graded relationship with improved disability scores in Late Life Disability Instrument limitation (P < 0.001) and frequency scores (P = 0.027). While increasing MV activity to guideline levels showed the greatest reduction, even insufficiently increased physical activity was related to reduced disability. CONCLUSIONS: Findings support advice to increase MV physical activity to reduce disability among inactive adults with or at high risk of knee osteoarthritis, even when guidelines are not met. PMID- 28002154 TI - The Role of 25-Hydroxyvitamin D as a Predictor of Clinical and Radiological Outcomes in Early Onset Rheumatoid Arthritis. AB - OBJECTIVE: The aims of this study were to compare the levels of 25-hydroxyvitamin D (25(OH)D) in patients with early-onset rheumatoid arthritis (EORA) versus a healthy control group and to assess the association of 25(OH)D deficiency and the BsmI polymorphism of the vitamin D receptor gene with clinical, radiological, and laboratory parameters. METHODS: Early-onset RA Colombian patients were enrolled in a 3-year follow-up study. Vitamin D deficiency was diagnosed for 25(OH)D levels of less than 20 ng/mL. Pearson and Spearman correlation coefficients were used to assess data. RESULTS: Seventy patients and 70 matched healthy subjects were included. 25-Hydroxyvitamin D was lower in the EORA group (27.13 [SD, 13.4] ng/mL vs. 33.74 [SD, 16.7] ng/mL; P = 0.01); 31.4% of EORA patients were vitamin D deficient. Remission was higher in subjects without 25(OH)D deficiency (22.7% vs. 47.9%; P = 0.04). Patients with 25(OH)D deficiency at baseline had higher Health Assessment Questionnaire and Physician Global Disease Activity Assessment scores, fatigue levels, erythrocyte sedimentation rate, and morning stiffness after 3 years. At disease onset, only a relationship between 25(OH)D deficiency with fatigue and morning stiffness was found. Neither radiographic progression nor Sharp van der-Heidje score was associated to hypovitaminosis D after 36-month follow-up. The bb genotype was less frequent in patients with vitamin D deficiency (0% vs. 16.6%; P = 0.04). Patients with BB-Bb genotype had lower 25(OH)D and a propensity to more severe disease. CONCLUSIONS: Our data provide further support for a role of vitamin D as a clinical biomarker for RA. Baseline 25(OH)D could have potential as a predictor of disease severity in EORA. PMID- 28002155 TI - Multifocal Osteonecrosis in an Adolescent Patient With Systemic Lupus Erythematosus and Ankle Pain. PMID- 28002157 TI - Lupus is Hard to Dx. PMID- 28002156 TI - Technetium-99m Albumin Scintigraphy in Protein-Losing Gastroenteropathy With Systemic Lupus Erythematosus: Typical Diagnostic Pattern of Radiotracer Leakage and Chronological Improvement by Treatment. PMID- 28002158 TI - Immunoglobulin G4-Related Disease Involving the Sclera. PMID- 28002159 TI - Hypertrophic Osteoarthropathy Secondary to Lung Cancer: Beneficial Effect of Anti vascular Endothelial Growth Factor Antibody. PMID- 28002160 TI - Comparison Between Anterior and Posterior Approaches for Ultrasound-Guided Glenohumeral Steroid Injection in Primary Adhesive Capsulitis: A Randomized Controlled Trial. PMID- 28002161 TI - Henoch-Schonlein Purpura With Muscle Involvement, Presenting as Myositis. PMID- 28002162 TI - Plantar Fascial Fibromatosis: Two Cases Treated With Low-Energy Focused Shock Waves. PMID- 28002163 TI - A Quality Improvement Approach to Rheumatoid Arthritis Management With Biologic Disease-Modifying Antirheumatic Drugs: Assessing Variability in a Treatment Pathway. PMID- 28002164 TI - "Rituximab: A Safe Treatment in a Patient With Refractory Felty Syndrome and Recurrent Infections". PMID- 28002165 TI - Improving Prediction of Postoperative Myocardial Infarction With High-Sensitivity Cardiac Troponin T and NT-proBNP. AB - BACKGROUND: This study sought to determine whether preoperatively measured high sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) improve cardiac risk prediction in patients undergoing major noncardiac surgery compared with the standard risk indices. METHODS: In this ancillary study to the Vitamins in Nitrous Oxide trial, patients were included who had preoperative hs-cTnT and NT-proBNP measured (n = 572). Study outcome was the incidence of postoperative myocardial infarction (MI) within the first 3 postoperative days. hs-cTnT was considered elevated if >14 ng/L and NT-proBNP if >300 ng/L. Additional cutoff values were investigated on the basis of receiver operating characteristic statistics. Biomarker risk prediction was compared with Lee's Revised Cardiac Risk Index (RCRI) with the use of standard methods and net reclassification index. RESULTS: The addition of hs-cTnT (>14 ng/L) and NT-proBNP (>300 ng/L) to RCRI significantly improved the prediction of postoperative MI (event rate 30/572 [5.2%], Area under the receiver operating characteristic curve increased from 0.590 to 0.716 with a 0.66 net reclassification index [95% confidence interval 0.32-0.99], P < .001). The use of 108 ng/L as a cutoff for NT proBNP improved sensitivity compared with 300 ng/L (0.87 vs 0.53). Sensitivity, specificity, positive, and negative predictive value for hs-cTnT were 0.70, 0.60, 0.09, and 0.97 and for NT-proBNP were 0.53, 0.68, 0.08, and 0.96. CONCLUSIONS: The addition of cardiac biomarkers hs-cTnT and NT-proBNP to RCRI improves the prediction of adverse cardiac events in the immediate postoperative period after major noncardiac surgery. The high negative predictive value of preoperative hs cTnT and NT-proBNP suggest usefulness as a "rule-out" test to confirm low risk of postoperative MI. PMID- 28002167 TI - Haloperidol Versus Ondansetron for Treatment of Established Nausea and Vomiting Following General Anesthesia: A Randomized Clinical Trial. AB - BACKGROUND: Haloperidol is an antipsychotic. At low doses, it is a useful agent for the prophylaxis of postoperative nausea and vomiting (PONV). However, its use for treating established PONV has not been well studied. METHODS: This randomized double-blinded trial tested whether haloperidol is noninferior to ondansetron for the early treatment of established PONV in adult patients undergoing general anesthesia. The primary outcome is whether patients were PONV free during the first 4 hours. The noninferiority margin was set at 15%. One hundred twenty patients with PONV received either haloperidol 1 mg intravenously (n = 60) or ondansetron 4 mg intravenously (n = 60). RESULTS: Data from 112 patients (59 in the haloperidol group and 53 in the ondansetron group) were analyzed. Thirty-five patients (52%) in the haloperidol group received 1 or 2 prophylactic antiemetics compared with 42 (79%) in the ondansetron group. Haloperidol was noninferior to ondansetron for the end point of complete response to treatment (defined as the rate of PONV-free patients) for the early (0-4 hour) and the 0- to 24-hour postoperative periods by both the per-protocol and intention-to-treat analyses. In the per-protocol analysis, complete responses in the early period were noted in 35 of 59 patients (59%) and 29 of 53 patients (55%) for the haloperidol and ondansetron groups, respectively (difference 5%; 95% confidence interval [CI]: 13% to 22 %), and in the 0- to 24-hour period in 31 of 59 patients (53%) and 26 of 53 patients (49%) for the haloperidol and ondansetron groups, respectively (difference 4%; 95% CI of the difference: -15% to 21%). In the intention-to-treat analysis, complete responses in the early period were noted in 35 of 60 patients (58%) and 29 of 60 patients (48%) for the haloperidol and ondansetron groups, respectively (difference 10%; 95% CI of difference: -8% to 27%) and in the 0- to 24-hour period in 31 of 60 patients (52%) and 26 of 60 patients (43%) for the haloperidol and ondansetron groups, respectively (difference 8%; 95% CI of the difference: -9% to 25%). All other PONV secondary outcomes were comparable. Twenty-five percent of patients in the haloperidol group were sedated versus 2% in the ondansetron group (P < .001; difference 23%; 95% CI of the difference: 11% 36%). Pain, satisfaction scores, need for analgesics, and changes in QTc intervals were not different between the 2 groups. CONCLUSIONS: Haloperidol is at worst 13% and 8% less effective than ondansetron by per-protocol analysis and by intention-to-treat analysis, respectively. Thus, it is noninferior to ondansetron for the early treatment of established PONV, but is associated with sedation. PMID- 28002166 TI - The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1 azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain. AB - BACKGROUND: Both pharmacologic and genetic approaches have been used to study the involvement of the muscarinic acetylcholine system in the regulation of chronic pain. Previous studies suggest that the M2 and M4 subtypes of muscarinic acetylcholine receptors (mAChRs) are important targets for the development of chronic pain. (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] octane (PTAC) has agonist effects on muscarinic M2 and M4 receptors and antagonist effects on muscarinic M1, M3, and M5 receptors. However, its analgesic effects have been less studied. METHODS: Male C57B L/6 mice were anesthetized, and left common peroneal nerve (CPN) ligation was performed to induce neuropathic pain. Before and after the application of PTAC systemically or specifically to the anterior cingulate cortex (ACC), the withdrawal thresholds to mechanical stimulation and static weight balance were measured, and the effects of PTAC on the conditioned place preference (CPP) were further evaluated. Western blotting was used to examine the expression of M1 and M2 in the striatum, ACC, and ventral tegmental area. RESULTS: The application of PTAC ([i.p.] intraperitoneal injection) increased the paw withdraw threshold in both the early (0.05 mg/kg, mean difference [95% confidence interval, CI]: 0.19 [0.05-0.32]; 0.10 mg/kg: mean difference [95% CI]: 0.34 [0.22-0.46]) and the late phases (0.05 mg/kg: mean difference [95% CI]: 0.45 [0.39-0.50]; 0.1 mg/kg: mean difference [95% CI]: 0.44 [0.37-0.51]) after nerve injury and rebalanced the weight distribution on the hind paws of mice (L/R ratio: before, 0.56 +/- 0.03. 0.05 mg/kg, 1.00 +/- 0.04, 0.10 mg/kg, 0.99 +/- 0.03); however, it failed to induce place preference in the CPP (0.05 mg/kg, 2-way analysis of variance, P > .05; 0.2 mg/kg, 2-way analysis of variance, P > .05,). At the same doses, the analgesic effects at D3-5 lasted longer than the effects at D14-16. This may be due to the down-regulation of the M2 and M1 in tested brain regions. CONCLUSIONS: These observations suggested that PTAC has analgesic effects on the neuropathic pain induced by nerve injury. PMID- 28002168 TI - Nitrous Oxide During Labor: Maternal Satisfaction Does Not Depend Exclusively on Analgesic Effectiveness. AB - BACKGROUND: Evidence on the analgesic effectiveness of nitrous oxide for labor pain is limited. Even fewer studies have looked at patient satisfaction. Although nitrous oxide appears less effective than neuraxial analgesia, it is unclear whether labor analgesic effectiveness is the most important factor in patient satisfaction. We sought to compare the relationship between analgesic effectiveness and patient satisfaction with analgesia in women who delivered vaginally using nitrous oxide, neuraxial analgesia (epidural or combined spinal epidural [CSE]), or both (neuraxial after a trial of nitrous oxide). METHODS: A standardized survey was recorded on the first postpartum day for all women who received anesthetic care for labor and delivery. Data were queried for women who delivered vaginally with nitrous oxide and/or neuraxial labor analgesia over a 34 month period in 2011 to 2014. Parturients with complete data for analgesia quality and patient satisfaction were included. Analgesia and satisfaction scores were grouped into 8 to 10 high, 5 to 7 intermediate, and 0 to 4 low. These scores were compared with the use of ordinal logistic regression across 3 groups: nitrous oxide alone, epidural or CSE alone, or nitrous oxide followed by neuraxial (epidural or CSE) analgesia. RESULTS: A total of 6507 women received anesthesia care and delivered vaginally. Complete data were available for 6242 (96%) women; 5261 (81%) chose neuraxial analgesia and 1246 (19%) chose nitrous oxide. Of the latter, 753 (60%) went on to deliver with nitrous oxide alone, and 493 (40%) switched to neuraxial analgesia. Most parturients who received neuraxial analgesia (>90%) reported high analgesic effectiveness. Those who used nitrous oxide alone experienced variable analgesic effectiveness, with only one half reporting high effectiveness. Among all women who reported poor analgesia effectiveness (0-4; n = 257), those who received nitrous oxide alone were more likely to report high satisfaction (8-10) than women who received epidural analgesia alone (OR 2.5; 95% CI 1.4-4.5; P = .002). Women who reported moderate analgesia (5-7) and received nitrous oxide only were more likely to report high satisfaction compared with the other groups. Among women who reported a high level of analgesic effectiveness, satisfaction with anesthesia was high and not different among groups. CONCLUSIONS: Patients who received nitrous oxide alone were as likely to express satisfaction with anesthesia care as those who received neuraxial analgesia, even though they were less likely to report excellent analgesia. Although pain relief contributes to the satisfaction with labor analgesia care, our results suggest that analgesia is not the only contributor to maternal satisfaction. PMID- 28002169 TI - Fluoroscopic-Guided Lumbar Spinal Drain Insertion for Thoracic Aortic Aneurysm Surgery. AB - We retrospectively reviewed the medical records of 11 patients who were referred by anesthesiologists to an interventional neuroradiologist for fluoroscopy-guided lumbar spinal drain insertion for thoracic aortic aneurysm repair between January 2010 and June 2015. Successful drain insertion was achieved in all patients. Three (27.3%) patients developed drain-related complications. Fluoroscopy-guided spinal drain insertion is an alternative to the conventional, nonimage-guided, blind technique used by anesthesiologists when they expect to encounter difficulty with insertion or in cases of failed insertion. PMID- 28002170 TI - Retained Seton Presenting as a Perineal Abscess. PMID- 28002171 TI - National utilization of different biliary decompression procedures in septic shock due to cholangitis. PMID- 28002173 TI - Higher preablative serum thyroid-stimulating hormone level predicts radioiodine ablation effectiveness in patients with differentiated thyroid carcinoma. AB - INTRODUCTION: Radioiodine ablation of remnant thyroid tissue is an important adjuvant therapy of differentiated thyroid carcinoma (DTC) after thyroidectomy. Elevated serum thyroid-stimulating hormone (TSH) level is necessary for successful ablation. The optimum level of serum TSH level necessary for successful radioiodine ablation of well-DTC is, however, yet to be defined. We aimed to determine whether higher serum TSH level will result in a better rate of complete ablation of well-DTC using iodine-131 (I) following initial thyroidectomy. PATIENTS AND METHODS: A total of 109 patients with differentiated thyroid cancer were divided into four treatment groups on the basis of serum TSH levels. They were followed up from 6 to 12 months after treatment with stimulated serum thyroglobulin level and a diagnostic whole-body scan with radioactive iodine I to determine early response. RESULTS: Sixty-four patients had papillary thyroid carcinoma, whereas 45 patients had follicular carcinoma. An excellent response was observed in 66.7% of patients with TSH level more than 90 MUIU/ml, 72.2% in the group with TSH level of 60-89 MUIU/ml, 48.5% when TSH was 30-59 MUIU/ml and 26.7% when TSH was less than 30 MUIU/ml (P=0.002). CONCLUSION: Higher preablative serum TSH predicts a better rate of ablation in patients with differentiated thyroid cancer treated with I after thyroidectomy. PMID- 28002174 TI - Use of Convexity in Ostomy Care: Results of an International Consensus Meeting. AB - Ostomy skin barriers that incorporate a convexity feature have been available in the marketplace for decades, but limited resources are available to guide clinicians in selection and use of convex products. Given the widespread use of convexity, and the need to provide practical guidelines for appropriate use of pouching systems with convex features, an international consensus panel was convened to provide consensus-based guidance for this aspect of ostomy practice. Panelists were provided with a summary of relevant literature in advance of the meeting; these articles were used to generate and reach consensus on 26 statements during a 1-day meeting. Consensus was achieved when 80% of panelists agreed on a statement using an anonymous electronic response system. The 26 statements provide guidance for convex product characteristics, patient assessment, convexity use, and outcomes. PMID- 28002175 TI - Executive Summary: Enhanced Recovery After Surgery: Best Practice Guideline for Care of Patients With a Fecal Diversion. AB - Enhanced Recovery After Surgery (ERAS) is a multimodal program developed to decrease postoperative complications, improve patient safety and satisfaction, and promote early discharge. In the province of Ontario, Canada, a standardized approach to the care of adult patients undergoing elective colorectal surgery (including benign and malignant diseases) was adopted by 15 hospitals in March 2013. All colorectal surgery patients with or without an ostomy were included in the ERAS program targeting a length of stay of 3 days for colon surgery and 4 days for rectal surgery. To ensure the individual needs of patients requiring an ostomy in an ERAS program were being met, a Provincial ERAS Enterostomal Therapy Nurse Network was established. Our goal was to develop and implement an evidence based, ostomy-specific best practice guideline addressing the preoperative, postoperative, and discharge phases of care. The guideline was developed over a 3 year period. It is based on existing literature, guidelines, and expert opinion. This article serves as an executive summary for this clinical resource; the full guideline is available as Supplemental Digital Content 1 (available at: http://links.lww.com/JWOCN/A36) to this executive summary. PMID- 28002176 TI - Effects of Synergist vs. NonSynergist Split Resistance Training Routines on Acute Neuromuscular Performance in Resistance-Trained Men. AB - Castanheira, RPM, Ferreira-Junior, JB, Celes, RS, Rocha-Junior, VA, Cadore, EL, Izquierdo, M, and Bottaro, M. Effects of synergist vs. nonsynergist split resistance training routines on acute neuromuscular performance in resistance trained men. J Strength Cond Res 31(12): 3482-3488, 2017-The aim of this study was to evaluate the effects of synergist (SN) vs. nonsynergist (NS) split resistance training routines on the acute neuromuscular performance of the elbow flexors in resistance-trained men. Fifteen resistance-trained men (age: 23.2 +/- 4.0 years, height: 173.0 +/- 0.08 cm, and body mass: 78.38 +/- 9.31 kg) randomly performed 3 training routines separated by an interval of 7 days: (a) pull-pull exercises (SN), which included 6 sets of 10 repetition maximum (RM) of a seated row exercise followed by 4 sets of 10RM of the preacher biceps curl exercise; (b) push-pull exercises (NS), which included 6 sets of 10RM of the bench press exercise followed by 4 sets of 10RM of the preacher biceps curl exercise; and (c) Control, which included 4 sets of 10RM of the preacher biceps curl exercise. Elbow flexors peak torque, total work, and the amplitude of electromyography signal (EMG root mean square) were measured during the elbow flexor isokinetic exercise. Peak torque was 10.2 and 3.9% higher during Control condition when compared with the SN and NS conditions, respectively (p <= 0.05). Peak torque was also 6.0% greater in the NS condition than the SN condition (p <= 0.05). Moreover, total work was 5.1% greater in the NS condition than the SN condition. Additionally, EMG findings did not differ among conditions (p > 0.05). In conclusion, a push and pull NS split routine is recommended to maximize elbow flexor training performance (i.e., lower acute loading effect) in trained subjects. PMID- 28002177 TI - Selected Physiological, Perceptual, and Physical Performance Changes During Two Bouts of Prolonged High-Intensity Intermittent Running Separated by 72 Hours. AB - Dobbin, N, Lamb, KL, and Twist, C. Selected physiological, perceptual, and physical performance changes during two bouts of prolonged high-intensity intermittent running separated by 72 hours. J Strength Cond Res 31(12): 3474 3481, 2017-This study investigated the effects of performing a second 90-minute intermittent running protocol 72 hours after an initial trial on selected physiological, perceptual, and sprint running measures. Eight subelite soccer players provided measures of isokinetic muscle function, countermovement jump (CMJ), 10-m sprinting, and muscle soreness before, and at 0, 24, 48, and 72 hours after a 90-minute intermittent high-intensity running bout (IHIR-1). A second 90 minute IHIR bout (IHIR-2) was performed 72 hours after the first. Heart rates, ratings of perceived exertion (RPE), blood lactate concentration [Bla], and 10-m sprint times were recorded periodically during both IHIR. Analysis of effects revealed that in the 72-hour period after IHIR-1, there were most likely increases in muscle soreness and likely to very likely deteriorations in CMJ, 10 m sprint, and isokinetic muscle function. During IHIR-2, heart rates (possibly to likely) and [Bla] (possibly to very likely) were lower than IHIR-1, whereas RPE remained unchanged. Sprint times during IHIR-2 were also likely to very likely higher than in IHIR-1. It was evident that these team sport players exposed to repeat bouts of prolonged high-intensity running within 72 hours downregulated their sprint performances in the second bout despite no change in perceived effort. These findings have implications for managing training and match loads during periods of intense scheduling. PMID- 28002178 TI - Effect of Different Onset Thresholds on Isometric Midthigh Pull Force-Time Variables. AB - Dos'Santos, T, Jones, PA, Comfort, P, and Thomas, C. Effect of different onset thresholds on isometric midthigh pull force-time variables. J Strength Cond Res 31(12): 3463-3473, 2017-Various thresholds have been used to identify the onset of contraction during isometric midthigh pull (IMTP); however, no agreed onset threshold exists for this assessment. The purpose of this study was to compare relative body weight (BW) and arbitrary onset thresholds to a criterion onset threshold 5 SDs of BW for IMTP force-time variables; force at each threshold, peak force, time-specific force values (100, 150, and 200 ms), and rate of force development (RFD) during 0-100, 0-150, 0-200 ms. Academy rugby league players (n = 9, age: 18.5 +/- 0.4 years; height: 1.82 +/- 0.09 m; mass: 91.2 +/- 13.1 kg) performed 2 IMTP trials on a force platform sampling at 1,000 Hz. The neutral force-time data pool (18 trials) was analyzed with five different thresholds and compared with criterion threshold to determine any variance in force-time variables. Five SDs of BW were significantly lower than 10% BW and 75 N for threshold force which led to significantly greater time-specific force values at 100 and 150 ms and unacceptable limits of agreements (LOA) for all force-time variables. No significant differences (p > 0.05) were observed between 2.5% and 5 SDs of BW; and between 5% and 5 SDs of BW for threshold force and all force-time variables with acceptable LOA. The 5 SDs of BW and 2.5% BW onset thresholds consistently resulted in the lowest values for threshold force, time-specific force values, and RFD, attributed to a lower onset bias. Therefore, scientists and practitioners are recommended to use a 5 SD of BW onset threshold for time specific force values and RFD for accurate data because it accounts for signal noise during the weighing period. Subsequently, there is greater certainty that the onset of contraction identifies a true meaningful change in force, in contrast to relative BW thresholds. PMID- 28002179 TI - Game Profile-Based Training in Soccer: A New Field Approach. AB - Dello Iacono, A, Martone, D, Cular, D, Milic, M, and Padulo, J. Game profile based training in soccer: a new field approach. J Strength Cond Res 31(12): 3333 3342, 2017-The aim of the study was to profile and compare the time-motion, physiological, and neuromuscular responses of both National Youth League (NYL) and UEFA Youth League (UYL) matches with those of an experimental game profile based training (GPBT) protocol. Time-motion traits and physiological, perceptual, and neuromuscular responses were investigated in 24 male soccer players across 14 matches and 6 GPBT training sessions, for a total of 420 samples. The GPBT had a greater influence on time-motion traits and perceptual responses than the NYL and UYL matches (all p < 0.001). No significant GPBT vs. match differences were found for mean heart rate or blood lactate (F = 1.228, p = 0.304, and F = 0.978, p = 0.385, respectively). Finally, the GPBT protocol led to greater impairment of the neuromuscular explosive performances when compared with those of the postmatch scores (squat jump: F = 19.991, p < 0.001; countermovement jump: F = 61.703, p < 0.001). Results identified the GPBT protocol as characterized by relatively greater high-intensity workloads than official NYL and UYL matches, requiring increased demanding efforts. In light of these outcomes, the GPBT protocol can be considered an advantageous training method for elite soccer players, capable of stimulating the physical effort and physiological capabilities required during a match. This approach is favorable when designing a training intervention according to the principle of sport specificity, as it is based on the specific metabolic demands. PMID- 28002180 TI - Effect of Whole-Body Vibration on Neuromuscular Activation of Leg Muscles During Dynamic Exercises in Individuals With Stroke. AB - Liao, L-R, and Pang, MYC. Effect of whole-body vibration on neuromuscular activation of leg muscles during dynamic exercises in individuals with stroke. J Strength Cond Res 31(7): 1954-1962, 2017-This study examined the leg muscle activity during exposure to different whole-body vibration (WBV) intensities while performing various dynamic exercises in patients with chronic stroke. Thirty patients with chronic stroke performed a series of dynamic exercises under 3 conditions: (a) low-intensity WBV (peak acceleration: 0.96 units of gravity of Earth [g]), (b) high-intensity WBV (1.61 g), and (c) no WBV. Neuromuscular activation was recorded with surface electromyography (EMG) on bilateral biceps femoris (BF), vastus lateralis, tibialis anterior (TA), and gastrocnemius (GS) in both legs and was reported as EMGrms (root mean square) normalized to % maximal voluntary contraction. The EMG amplitude of all tested muscles was significantly increased by adding WBV during dynamic exercise (p <= 0.05). The EMG amplitude of BF, TA, and GS during exposure to high-intensity WBV was significantly greater than low-intensity WBV (p <= 0.05). The increase in EMG amplitude caused by WBV was exercise dependent in GS and TA (p <= 0.05). The EMG response to WBV in GS and BF in the affected leg was significantly greater than the corresponding muscles in the unaffected leg (p <= 0.05). The extent of WBV-induced muscle activity was dependent on the dynamic exercise, WBV intensity, and muscle trained among patients with chronic stroke. PMID- 28002181 TI - Effects of Caffeine Ingestion on Skill Performance During an International Female Rugby Sevens Competition. AB - Portillo, J, Del Coso, J, and Abian-Vicen, J. Effects of caffeine ingestion on skill performance during an international female rugby sevens competition. J Strength Cond Res 31(12): 3351-3357, 2017-The aim of this study was to establish the effects of a caffeine-containing energy drink on skills and technical performance during a match in female elite rugby sevens players. On 2 nonconsecutive days of a friendly tournament, 16 women from the Spanish national rugby sevens team (mean age = 23 +/- 2 years) ingested 3 mg of caffeine per kilogram of body mass in the form of an energy drink or the same drink without caffeine (placebo drink). After 60 minutes for caffeine absorption, participants played 3 rugby sevens matches against another national team. Body impacts during the matches were assessed by triaxial accelerometers. The matches were videotaped, and each individual technical action was notated afterward by 2 experienced observers. In comparison with the placebo drink, the ingestion of the caffeinated energy drink increased the rate of body impacts in zone 1 (16.1 +/- 4.9 vs. 20.8 +/- 9.9 impacts/min, p < 0.05), zone 2 (12.2 +/- 10.6 vs. 16.2 +/- 15.2 impacts/min, p < 0.05), zone 3 (3.8 +/- 1.5 vs. 4.7 +/- 2.6 impacts/min, p < 0.05), and zone 5 (0.8 +/- 0.4 vs. 1.1 +/- 0.6 impacts/min, p < 0.05). The pre exercise ingestion of the caffeinated energy drink did not affect the frequency or the quality of any rugby-specific technical actions during the games. In conclusion, the ingestion of 3 mg.kg of caffeine in the form of an energy drink increased the number of body impacts during a rugby sevens international competition which suggests a higher engagement of the players during the game. However, the caffeine ingestion did not influence the quality of the technical actions performed during the competition. PMID- 28002183 TI - Relationship Between Time to Initiation of Antiretroviral Therapy and Treatment Outcomes: A Cohort Analysis of ART Eligible Adolescents in Zimbabwe. AB - BACKGROUND: Age-specific retention challenges make antiretroviral therapy (ART) initiation in adolescents difficult, often requiring a lengthy preparation process. This needs to be balanced against the benefits of starting treatment quickly. The optimal time to initiation duration in adolescents is currently unknown. OBJECTIVE: To assess the effect of time to ART initiation on mortality and loss to follow-up (LTFU) among treatment eligible adolescents. METHODS: We conducted a retrospective cohort analysis among 1499 ART eligible adolescents aged >=10 to <19 years registered in a public sector HIV program in Bulawayo, Zimbabwe, between 2004 and 2011. Hazard ratios (HR) for mortality and LTFU were calculated for different time to ART durations using multivariate Cox regression models. RESULTS: Median follow-up duration was 1.6 years. Mortality HRs of patients who initiated at 0 to <=7 days, >14 days to <=1 month, >1 to <=2 months, >2 months, and before initiation were 1.59, 1.19, 1.56, 1.08, and 0.94, respectively, compared with the reference group of >7 to <=14 days. LTFU HRs were 1.02, 1.07, 0.85, 0.97, and 3.96, respectively. Among patients not on ART, 88% of deaths and 85% of LTFU occurred during the first 3 months after becoming ART eligible, but only 37% and 29% among adolescents on ART, respectively. CONCLUSIONS: Neither mortality or LTFU was associated with varying time to ART. The initiation process can be tailored to the adolescents' needs and individual life situations without risking to increase poor treatment outcomes. Early mortality was high despite rapid ART initiation, calling for earlier rather than faster initiation through HIV testing scale-up. PMID- 28002182 TI - Sex Differences in Tobacco Use Among Persons Living With HIV/AIDS: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Persons living with HIV/AIDS (PLWH) smoke at higher rates than other adults and experience HIV-related and non-HIV-related adverse smoking consequences. This study conducted a systematic review to synthesize current knowledge about sex differences in smoking behaviors among PLWH. METHODS: Over 3000 abstracts from MEDLINE were reviewed and 79 publications met all the review inclusion criteria (ie, reported data on smoking behaviors for PLWH by sex). Sufficient data were available to conduct a meta-analysis for one smoking variable: current smoking prevalence. RESULTS: Across studies (n = 51), the meta analytic prevalence of current smoking among female PLWH was 36.3% (95% confidence interval [CI]: 28.0% to 45.4%) and male PLWH was 50.3% (95% CI: 44.4% to 56.2%; meta-analytic odds ratio = 1.78, 95% CI: 1.29 to 2.45). When analyses were repeated just on the US studies (n = 23), the prevalence of current smoking was not significantly different for female PLWH (55.1%, 95% CI: 47.6% to 62.5%) compared with male PLWH (55.5%, 95% CI: 48.2% to 62.5%; meta-analytic odds ratio = 1.04, 95% CI: 0.86 to 1.26). Few studies reported data by sex for other smoking variables (eg, quit attempts, noncigarette tobacco product use) and results for many variables were mixed. DISCUSSION: Unlike the general US population, there was no difference in smoking prevalence for female versus male PLWH (both >50%) indicating that HIV infection status was associated with a greater relative increase in smoking for women than men. More research is needed in all areas of smoking behavior of PLWH to understand similarities and differences by sex to provide the best interventions to reduce the high smoking prevalence for all sexes. PMID- 28002184 TI - Prevalence and Predictors of Hospitalizations Among HIV-Infected and At-Risk HIV Uninfected Women. AB - OBJECTIVES: We evaluated the Veterans Aging Cohort Study (VACS) Index score, an index composed of age, CD4 count, viral load, hemoglobin, Hepatitis C coinfection, Fibrosis Index-4, and estimated glomerular filtration rate, and psychosocial and clinical risk factors for all-cause hospitalization among HIV infected women on highly active antiretroviral therapy and HIV-uninfected women. METHODS: Data were collected from 2008 to 2014 from 1585 highly active antiretroviral therapy-experienced HIV infected and 692 uninfected women. Cox proportional hazards regression evaluated predictors of first hospitalization over 2 years. RESULTS: Among HIV-infected women, VACS Index score (per 5 points) [adjusted hazard ratio (aHR) 1.08; 95% confidence interval (CI): 1.06 to 1.11], Centers for Epidemiologic Studies-Depression (CESD) scores >=16 (aHR 1.61; 95% CI: 1.30 to 1.99), smoking (aHR 1.26; 95% CI: 1.02 to 1.55), abuse history (aHR 1.52; 95% CI: 1.20 to 1.93), diabetes (aHR 1.63; 95% CI: 1.31 to 2.04), and black race (aHR 1.28; 95% CI: 1.03 to 1.59) increased risk of hospitalization. Among HIV-uninfected women, VACS Index score (aHR 1.08; 95% CI: 1.03 to 1.13), CESD scores >=16 (aHR 1.38; 95% CI: 1.02 to 1.86), diabetes (aHR 2.15; 95% CI: 1.57 to 2.95), and black race (aHR 1.61; 95% CI: 1.15 to 2.24) predicted subsequent hospitalization. CONCLUSIONS: Psychosocial and clinical factors were associated with risk of hospitalization independently of the VACS Index score. Additional research on contextual and psychosocial influences on health outcomes among women is needed. PMID- 28002185 TI - Field Evaluation of Dried Blood Spots for HIV-1 Viral Load Monitoring in Adults and Children Receiving Antiretroviral Treatment in Kenya: Implications for Scale up in Resource-Limited Settings. AB - BACKGROUND: The World Health Organization recommends viral load (VL) as the preferred method for diagnosing antiretroviral therapy failure; however, operational challenges have hampered the implementation of VL monitoring in most resource-limited settings. This study evaluated the accuracy of dried blood spot (DBS) VL testing under field conditions as a practical alternative to plasma in determining virologic failure (VF). METHODS: From May to December 2013, paired plasma and DBS specimens were collected from 416 adults and 377 children on antiretroviral therapy for >=6 months at 12 clinics in Kenya. DBSs were prepared from venous blood (V-DBS) using disposable transfer pipettes and from finger prick capillary blood using microcapillary tubes (M-DBS) and directly spotting (D DBS). All samples were tested on the Abbott m2000 platform; V-DBS was also tested on the Roche COBAS Ampliprep/COBAS TaqMan (CAP/CTM) version 2.0 platform. VF results were compared at 3 DBS thresholds (>=1000, >=3000, and >=5000 copies/mL) and a constant plasma threshold of >=1000 copies/mL. RESULTS: On the Abbott platform, at >=1000-copies/mL threshold, sensitivities, specificities, and kappa values for VF determination were >=88.1%, >=93.1%, and >=0.82%, respectively, for all DBS methods, and it had the lowest percentage of downward misclassification compared with higher thresholds. V-DBS performance on CAP/CTM had significantly poorer specificity at all thresholds (1000%-33.0%, 3000%-60.9%, and 5000%-77.0%). No significant differences were found between adults and children. CONCLUSIONS: VL results from V-DBS, M-DBS, and D-DBS were comparable with those from plasma for determining VF using the Abbott platform but not with CAP/CTM. A 1000 copies/mL threshold was optimal and should be considered for VF determination using DBS in adults and children. PMID- 28002186 TI - Barriers to Universal Prescribing of Antiretroviral Therapy by HIV Care Providers in the United States, 2013-2014. AB - INTRODUCTION: HIV treatment guidelines recommend initiating antiretroviral therapy (ART) regardless of CD4 cell (CD4) count, barring contraindications or barriers to treatment. An estimated 6% of persons receiving HIV care in 2013 were not prescribed ART. We examined reasons for this gap in the care continuum. METHODS: During 2013-2014, we surveyed a probability sample of HIV care providers, of whom 1234 returned surveys (64.0% adjusted response rate). We estimated percentages of providers who followed guidelines and their characteristics, and who deferred ART prescribing for any reason. RESULTS: Barring contraindications, 71.2% of providers initiated ART regardless of CD4 count. Providers less likely to initiate had caseloads <=20 vs. >200 patients [adjusted prevalence ratios (aPR) 0.69, 95% confidence interval (CI): 0.47 to 1.02, P = 0.03], practiced at non-Ryan White HIV/AIDS Program-funded facilities (aPR 0.85, 95% CI: 0.74 to 0.98, P = 0.02), or reported pharmaceutical assistance programs provided insufficient medication to meet patients' needs (aPR 0.79, 95% CI: 0.65 to 0.98, P = 0.02). In all, 17.0% never deferred prescribing ART, 69.6% deferred for 1%-10% of patients, and 13.3% deferred for >10%. Among providers who had deferred ART, 59.4% cited patient refusal as a reason in >50% of cases, 31.1% reported adherence concerns because of mental health disorders or substance abuse, and 21.4% reported adherence concerns because of social problems, eg, homelessness, as factors in >50% of cases when deferring ART. CONCLUSIONS: An estimated 29% of HIV care providers had not adopted recommendations to initiate ART regardless of CD4 count, barring contraindications, or barriers to treatment. Low-volume providers and those at non-Ryan White HIV/AIDS Program-funded facilities were less likely to follow this guideline. Among all providers, leading reasons for deferring ART included patient refusal and adherence concerns. PMID- 28002187 TI - Early Reoperation Rate, Complication, and Outcomes in Resident-performed Glaucoma Surgery. AB - PURPOSE OF THE STUDY: The purpose of the study was to examine reoperation rate and complications of resident-performed glaucoma surgeries within the first 90 postoperative days. MATERIALS AND METHODS: A retrospective study of resident performed glaucoma filtering surgeries at the San Francisco Veterans Affairs Medical Center between 2002 and 2014 was performed. Patients requiring reoperation within 90 days of the initial surgery were included in our study. Combined surgeries were excluded. Complications and the rates of reoperation within the first 90 days were evaluated. Clinical outcomes for those who needed reoperations were evaluated at the 1-year follow-up. RESULTS: Total of 180 cases were reviewed [34 trabeculectomy, 85 Ex-PRESS shunt, and 61 Ahmed glaucoma valve (AGV)]. One hundred and four eyes developed complications, most commonly choroidal effusion (65.3%), followed by hypotony (45.2%) and wound leak (32.7%). Complications were comparable among the 3 groups, except that filtering surgery had significantly more wound leak than AGV (P<0.001). Seven (3.9%) cases required reoperation within first 90 days. There was no reoperation for trabeculectomy group. Reoperation rate was 4.7% for Ex-PRESS and 4.9% for AGV (P=0.74). Indications for reoperation were persistent wound leak (4 cases) and tube occlusion/revision (3 cases). For the 7 patients who required reoperations, their intraocular pressure at 1-year postreoperation was significantly decreased compared with intraocular pressure before the initial glaucoma surgery (P<0.001) with similar number of glaucoma medications and stable visual acuity. CONCLUSIONS: Glaucoma incisional surgeries performed by third-year ophthalmology residents had acceptable and comparable reoperation rates and complication rates for patients with trabeculectomy, Ex-PRESS, and AGV. Clinical outcomes for the patients requiring reoperation were favorable. PMID- 28002188 TI - Orbital Cellulitis Following Uncomplicated Aqueous Shunt Surgery. AB - PURPOSE: To date, there have only been 5 reported cases of orbital cellulitis following implantation of an aqueous tube shunt for glaucoma. Previously reported cases have involved eyes with significant comorbidities and successful management has often required the removal of the device alongside systemic antibiotic therapy. PATIENTS AND METHODS: We present a 53-year-old man with severe orbital cellulitis, 3 months after routine implantation of a Baerveldt tube shunt for primary open angle glaucoma. The patient was managed medically, with topical and systemic antibiotic therapy. The patient went on to make a full recovery with the tube in situ. RESULTS AND CONCLUSIONS: We report that a more conservative approach (without tube removal) to be successful in a case where there is no evidence of tube exposure. It is important to appreciate that in some cases of orbital cellulitis without clear signs of intraocular involvement, a tube can be left in situ. PMID- 28002189 TI - To Study the Efficacy of Laser Peripheral Iridoplasty in the Treatment of Eyes With Primary Angle Closure and Plateau Iris Syndrome, Unresponsive to Laser Peripheral Iridotomy, Using Anterior-Segment OCT as a Tool: Comment. PMID- 28002190 TI - A Comment on "Juvenile-onset Normal Tension Glaucoma From Chronic, Recurrent Low Cerebrospinal Fluid Pressure." J Glaucoma. 2016;25: e738-e740. PMID- 28002191 TI - Sekundo's Applanator: 5 Years of Experience With Transconjunctival Suturing. AB - Sekundo's Applanator is a new surgical instrument used mainly in transconjunctival scleral flap suturing in cases of postoperative hypotony after trabeculectomy. In contrast to Hoskins lens, it offers better visualization of the border of the scleral flap with good intraoperative stabilization of the globe; thus, it increases the effectiveness and decreases the time of the surgical procedure. Sekundo's Applanator was also found to be useful in reducing the size of an oversized bleb after trabeculectomy and in the closure of leaking sutureless sclerotomies after vitrectomies. In this report, we present and discuss the properties, uses, and advantages of this new instrument to the ophthalmic community. PMID- 28002192 TI - Long-term Outcomes and Complications of Pars Plana Baerveldt Implantation in Children. AB - PURPOSE OF THE STUDY: The purpose of the study was to report long-term outcomes and complications of Baerveldt glaucoma implant (BGI) surgery with pars plana tube insertion in children. MATERIALS AND METHODS: The medical records of consecutive aphakic and pseudophakic children (<16 y of age) who underwent BGI surgery with pars plana tube insertion between 1990 and 2013 were retrospectively reviewed. Main outcome measures were intraocular pressure and number of glaucoma medications. Postoperative complications were recorded. Failure was defined as an intraocular pressure <5 or >=21 mm Hg (with or without glaucoma medications), loss of light perception, or need for additional glaucoma surgery. RESULTS: Thirty-seven children were identified with a mean age of 6.0+/-4.7 years (range, 4 mo to 14.5 y). Mean follow-up after pars plana BGI surgery was 6.5+/-3.4 years (range, 9 mo to 12.8 y) for patients who met success criteria. Mean intraocular pressure and mean number of glaucoma medications at most recent follow-up for patients with successful intraocular pressure control were 13.8+/-4.1 and 2.3+/ 1.9 mm Hg, respectively. The Kaplan-Meier survival analysis revealed 1-, 3-, 5-, and 7-year success rates of 94.5%, 74.6%, 65.0%, and 45.8%, respectively. Complications included tube exposure in 1 patient (2.7%), tube obstruction in 8 patients (21.6%), and retinal detachment in 9 patients (24.3%). Seventeen patients (45.9%) failed due to inadequate intraocular pressure control, of whom 9 (24.3%) required additional glaucoma surgery. CONCLUSIONS: Although pars plana BGI surgery is a reasonable option for managing refractory glaucoma in aphakic and pseudophakic children, surgeons must be aware of the potential need for additional glaucoma surgery and/or posterior segment complications with extended follow-up. PMID- 28002194 TI - Spontaneous Dislocation of Trabeculectomy Scleral Flap in the Anterior Chamber in a Patient With Pseudoxanthoma Elasticum. AB - We report a case of a 54-year-old man, known to have pseudoxanthoma elasticum (PXE), who had a trabeculectomy in his left eye for secondary glaucoma following blunt trauma. Ten years after augmented trabeculectomy, the patient presented to casualty clinic with an inferiorly dislocated, anterior chamber (AC), scleral trabeculectomy flap. Corrected vision was hand movement with an intraocular pressure of 17 mm Hg. There was significant AC inflammation (cells 2+). Gonioscopy revealed a residual mobile scleral flap. The bleb was cystic with no leak. To our knowledge this is the first report of a trabeculectomy scleral flap dislocation into the AC in a patient with PXE. Ophthalmologists should be aware of this complication in patients with PXE. PMID- 28002196 TI - Transcatheter mitral valve repair and replacement. PMID- 28002197 TI - Triple antithrombotic therapy, including NAO, in patients after coronary stenting. PMID- 28002198 TI - Relation between weight loss and causes of death in patients with cardiovascular disease: finding from the SCOUT trial. AB - AIMS: Obesity is associated with an increased incidence of mortality. The Sibutramine Cardiovascular Outcomes (SCOUT) trial can provide the first evidence of the effect of intentional weight loss on mortality in an obese population at high risk. METHODS: SCOUT was a randomized, double-blind, placebo-controlled trial testing sibutramine vs. placebo. Eligibility for the trial required both men and women aged at least 55 years, with BMI of at least 27 kg/m and 45 kg/m or less. Study participants with type 2 diabetes mellitus (T2DM) only should have at least one other risk factor defined as hypertension, dyslipidaemia, smoking, or diabetic nephropathy, and/or they had a history of cardiovascular disease. Study participants were stratified in three groups: patients with T2DM, patients with a prior cardiovascular event but without diabetes, and patients with both T2DM and a prior cardiovascular event.The relationship between weight loss and mortality (all-cause, cardiovascular, and noncardiovascular) was investigated with Cox regression models. RESULTS: The main study showed that all-cause mortality was not different in patients allocated to sibutramine or placebo. This ancillary analysis demonstrates that there is a general trend showing higher mortality in patients with the greatest weight loss (weight reduction >10 kg) and in those with increasing weight (>1 kg). If integrated weight loss (area under the curve from baseline to 12 months) is used, these observations are confirmed. The impact of substantial weight loss on mortality is marked in those dying of noncardiovascular causes, specifically cancer. CONCLUSION: The relationship between weight change and mortality differs for cardiovascular and noncardiovascular mortality. PMID- 28002199 TI - Low-density lipoprotein cholesterol variability increases the risk of cardiovascular events: the importance of keeping constant low cholesterol levels. PMID- 28002200 TI - Association between expression of inflammatory markers in normal breast tissue and mammographic density among premenopausal and postmenopausal women. AB - OBJECTIVE: Inflammatory markers may be associated with breast cancer risk. We assessed the association between expression levels of proinflammatory (interleukin 6, tumor necrosis factor-alpha, C-reactive protein, cyclooxygenase 2, leptin, serum amyloid A1, interleukin 8, and signal transducer and activator of transcription 3) and anti-inflammatory markers (transforming growth factor beta, interleukin 10, and lactoferrin) in normal breast tissue with mammographic density, a strong breast cancer risk indicator, among 163 breast cancer patients. METHODS: The expression of inflammatory markers was visually evaluated on immunohistochemistry stained slides. The percent mammographic density (PMD) was estimated by a computer-assisted method in the contralateral cancer-free breast. We used generalized linear models to estimate means of PMD by median expression levels of the inflammatory markers while adjusting for age and waist circumference. RESULTS: Higher expression levels (above median) of the proinflammatory marker interleukin 6 were associated with higher PMD among all women (24.1% vs 18.5%, P = 0.007). Similarly, higher expression levels (above median) of the proinflammatory markers (interleukin 6, tumor necrosis factor alpha, C-reactive protein, and interleukin 8) were associated with higher PMD among premenopausal women (absolute difference in the PMD of 8.8% [P = 0.006], 7.7% [P = 0.022], 6.7% [P = 0.037], and 16.5% [P = 0.032], respectively). Higher expression levels (above median) of the anti-inflammatory marker transforming growth factor-beta were associated with lower PMD among all (18.8% vs 24.3%, P = 0.005) and postmenopausal women (14.5% vs 20.7%, P = 0.013). CONCLUSIONS: Our results provide support for the hypothesized role of inflammatory markers in breast carcinogenesis through their effects on mammographic density. Inflammatory markers could be targeted in future breast cancer prevention interventions. PMID- 28002201 TI - TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. AB - OBJECTIVE: To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy. METHODS: A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-MUg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates. RESULTS: Seventy-two women (mean 59 y) participated. TX-004HR 4 MUg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 MUg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 MUg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 MUg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed. CONCLUSIONS: Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 MUg, and only minor increases were observed with 25 MUg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure. PMID- 28002202 TI - BH4 improves postprandial endothelial function after a high-fat meal in men and postmenopausal women. AB - OBJECTIVE: The timing and duration of menopause is important when evaluating the risk for cardiovascular disease in postmenopausal women, likely related in part to nitric oxide (NO) bioavailability. The flow-mediated dilation (FMD) test is a noninvasive assessment of NO bioavailability in humans, and tetrahydrobiopterin (BH4) is essential for NO synthesis. A high-fat meal (HFM) has been used to increase lipemia and reduce NO bioavailability. Thus, this study sought to determine if menopausal transition has any impact on the postprandial endothelial function response to a HFM, and evaluate the effect of BH4 on postprandial endothelial function in postmenopausal women and men. METHODS: Utilizing a randomized, double-blind, placebo-controlled design, sex-steroid hormones and FMD were determined in 30 older adults (10 postmenopausal women aged below 3 y [W < 3], 10 postmenopausal women aged above 10 y [W > 10], and 10 men) at baseline and 4 hours after the ingestion of a HFM alone or a HFM with BH4 (HFM + BH4; 5 mg/kg). RESULTS: Data are presented as mean +/- SEM. Independent of treatment, postprandial testosterone was significantly (P < 0.05) decreased in men (-64 +/- 11 ng/dL), whereas no changes were observed in W < 3 or W > 10 group. In addition, concentrations of progesterone were higher (P = 0.019) and the testosterone/estradiol ratio was lower (P = 0.026) in all groups after the ingestion of HFM + BH4 compared with the ingestion of HFM alone. Overall, an increase in FMD was observed after the ingestion of HFM + BH4 (Delta1.9% +/- 0.6%), whereas no change in FMD was observed after the ingestion of HFM alone (Delta-0.7% +/- 0.6%). CONCLUSIONS: Co-ingestion of BH4 with a HFM not only alters the sex-steroid hormone ratio, it improves postprandial FMD after a HFM regardless of postmenopause status or sex. PMID- 28002203 TI - Differences in Hospital Risk-standardized Mortality Rates for Acute Myocardial Infarction When Assessed Using Transferred and Nontransferred Patients. AB - BACKGROUND: One in 5 patients with acute myocardial infarction (AMI) are transferred between hospitals. However, current hospital performance measures based on AMI mortality exclude these patients from the evaluation of referral hospitals. OBJECTIVE: To determine the relationship between risk-standardized mortality for transferred and nontransferred patients at referral hospitals. RESEARCH DESIGN: This is a retrospective cohort study. SUBJECTS: Fee-for-service Medicare claims from 2011 for patients hospitalized with a primary diagnosis of AMI, at hospitals admitting at least 15 patients in transfer. MEASURES: Hospital specific risk-standardized 30-day mortality rates (RSMRs) for 2 groups of patients: those admitted through transfer from another hospital, and those natively admitted without a preceding or subsequent interhospital transfer. RESULTS: There were 304 hospitals admitting at least 15 patients in transfer. These hospitals cared for 77,711 natively admitted patients (median, 254; interquartile range, 162-321), and 11,829 patients admitted in transfer (median, 26; interquartile range, 19-46). Risk-standardized mortality rates were higher for natively admitted patients than for those admitted in transfer (mean, 11.5%+/ 1.2% vs. 7.2%+/-1.1%). There was weak correlation between hospital performance as assessed by RSMR for patients natively admitted versus those admitted in transfer (Pearson r=0.24, P<0.001); when performance was arrayed by quartile, 102 hospitals (33.6%) differed at least 2 quartiles of performance across the 2 patient groups. CONCLUSIONS: For Medicare patients with AMI, hospital-specific RSMRs for natively admitted patients are only weakly associated with RSMRs for patients transferred in from another hospital. Current AMI performance metrics may fail to provide guidance about hospital quality for transferred patients. PMID- 28002204 TI - Anesthesia Service Use and the Uptake of Screening Colonoscopies. AB - BACKGROUND: The Center for Medicare & Medicaid Services recently defined "screening colonoscopy" to include separately furnished anesthesia services. OBJECTIVE: To examine the relationship between anesthesia service use and the uptake of screening colonoscopies. STUDY DESIGN: We correlated metropolitan statistical area (MSA) level anesthesia service use rates, derived from the 2008, 2010, and 2012 Medicare and MarketScan claims data, with the presence of individual level guideline concordant screening colonoscopy using the Behavioral Risk Factor Surveillance System data for the same years. MEASURES: Proportion of colonoscopies with anesthesia service was calculated at the MSA level. A guideline concordant screening colonoscopy was defined as a colonoscopy received within the past 10 years. RESULTS: The average MSA level anesthesia service use rate in colonoscopy significantly increased from 25.34% in 2008 to 44.25% in 2012; but only a moderate increase in the rate of guideline concordant colonoscopies was observed, from 57.36% in 2008 to 65.32% in 2012. After adjusting for patient characteristics, we found a nonsignificant negative association between anesthesia service use rate and colonoscopy screening rate, with an odds ratio of 0.90 for receiving a guideline concordant colonoscopy for each percentage point increase in anesthesia service use rate (P=0.27). The relationship between anesthesia service use and the overall colorectal cancer screening rate followed the same pattern and was also not statistically significant. CONCLUSIONS: No significant association between anesthesia service use and colonoscopy screening or colorectal cancer screening rates was found, suggesting that more evidence is needed to support the Center for Medicare & Medicaid Services rule change. PMID- 28002205 TI - The Role of Public and Private Insurance Expansions and Premiums for Low-income Parents: Lessons From State Experiences. AB - BACKGROUND: Numerous states have implemented policies expanding public insurance eligibility or subsidizing private insurance for parents. OBJECTIVES: To assess the impact of parental health insurance expansions from 1999 to 2012 on the likelihood that parents are insured; their children are insured; both the parent and child within a family unit are insured; and the type of insurance. DESIGN: Cross-sectional analysis of the 2000-2013 March supplements to the Current Population Survey, with data from the Medical Expenditure Panel Survey-Insurance Component and the Area Resource File. METHODS: Cross-state and within-state multivariable regression models estimated the effects of health insurance expansions targeting parents using 2-way fixed effect modeling and difference-in difference modeling. All analyses controlled for household, parent, child, and local area characteristics that could affect insurance status. RESULTS: Expansions increased parental coverage by 2.5 percentage points, and increased the likelihood of both parent and child being insured by 2.1 percentage points. Substantial variation was observed by type of expansion. Public expansions without premiums and special subsidized plan expansions had the largest effects on parental coverage and increased the likelihood of jointly insuring both the parent and child. Higher premiums were a substantial deterrent to parents' insurance. CONCLUSIONS: Our findings suggest that premiums and the type of insurance expansion can have a substantial impact on the insurance status of the family. These findings can help inform states as they continue to make decisions about expanding Medicaid under the Affordable Care Act to cover all family members. PMID- 28002206 TI - January Editorial. PMID- 28002207 TI - Correspondence: Premature Stop of the SOCceR Trial, a Multicenter Randomized Controlled Trial on Secondary Cytoreductive Surgery: Netherlands Trial Register Number: NTR3337. PMID- 28002208 TI - Ovarian Cancer Follow-up: A Preliminary Comparison of 2 Approaches. AB - OBJECTIVE: The aim of the study was to perform a preliminary comparison of quality of life (QoL) and patient satisfaction in individualized nurse-led follow up versus conventional medical follow-up in ovarian cancer. METHODS: One hundred twelve women who received a diagnosis of ovarian, fallopian tube, or peritoneal cancer, completed primary treatment by surgery alone or with chemotherapy, irrespective of outcome with regard to remission, and expected survival of more than 3 months. Fifty-seven participants were randomized to individualized follow up and 55 patients to conventional follow-up. Well-being was measured at baseline and at 3, 6, 12, and 24 months after randomization for QoL (QLQ-C30 [European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire], QLQ-Ov28), the Hospital Anxiety and Depression Scale (HADS), and a Patient Satisfaction Questionnaire (PSQ-III). The primary endpoints were the effects of follow-up on each of the scores (via hierarchical mixed-effects model) and on relapse-free time (via Cox model). The total cost of follow-up was compared between each group. RESULTS: There was evidence for a QoL and patient satisfaction benefit for individualized versus standard follow-up (QLQ-C30, P = 0.013; 95% confidence interval, -0.03 to -0.001; PSQ-III P = 0.002; 95% confidence interval, -0.003 to -0.015; QLQ-Ov28, P = 0.14). Hospital Anxiety and Depression Scale data provided no evidence in favor of either treatment (P = 0.42). Delivered to protocol individualized follow-up resulted in a delay in the presentation of symptomatic relapse (P = 0.04), although the effect on survival in this study is unknown. Cost was L700 lower on average for the individualized follow-up group, but the difference was not statistically significant at the 5% level (P = 0.07). CONCLUSIONS: Individualized follow-up was superior to conventional follow-up in 3 of the 4 QoL and patient satisfaction surveys in this preliminary study. Further prospective studies are needed in a larger population.Trial registration number is ISRCTN59149551. PMID- 28002209 TI - Value of Specialist Pathology Review in a Single Statewide Gynecologic Cancer Service. AB - OBJECTIVE: A case review by specialist diagnostic pathologists as part of a Gynecologic Oncology Multi-disciplinary Tumor group has the potential to influence the management of patients with cancer. The primary aim of this study was to determine the frequency of diagnostic discrepancies between the initial (nonspecialist) and final pathological diagnoses in cases referred to the Gynecologic Oncology Tumor Conference (TC) in Western Australia and the impact of such revised diagnosis on clinical management. A secondary aim was to assess the evolving workload encountered by the TC during a 5-year interval. METHODS: The records of the weekly TC for the 2 calendar years 2008 and 2013 were examined, and histological and cytological specimens that had been initially assessed by "outside" (nonspecialist) pathology departments, and subsequently reviewed by specialist pathologists, were assessed. The initial and final diagnoses were compared, and where the pathological findings were amended upon review, it was determined whether the change affected clinical management. Diagnostic discrepancies that resulted in a change in patient management were classified as major, whereas discrepancies that did not affect patient management were classified as minor. RESULTS: A total of 481 outside cases were included among 2387 cases presented for histological review at the TC during the 2 years. For outside cases alone, the incidence of major diagnostic discrepancies was 3.4% in 2008, 5.5% in 2013 (no significant difference, P = 0.3787), and 4.6% for the 2 years combined. A recommendation for surgery was the most common change in clinical management as a result of major discrepancy. The minor discrepancy rate was 4.4% of outside cases for both years combined. Pathological discrepancies (major and minor) of the uterine corpus and cervix were most frequent, followed by those of the vulva and ovary. There was a 48.4% increase in total case discussions at the TC during the interval period with a significant rise in nonmalignant cases, 29.8% of the total cases in 2008 compared with 36.8% in 2013 (P = 0.0004). CONCLUSIONS: Nonspecialist pathology departments maintained a high level of reporting accuracy during the interval period, with the major discrepancy rate not changing significantly between 2008 and 2013. Specimens from the uterine corpus and cervix in particular may prove diagnostically challenging on occasion. A pathology review of outside cases by a tertiary-based laboratory in conjunction with a TC can identify a small but clinically significant number of cases that lead to a change in clinical management. It is uncertain whether this affects patient outcomes. PMID- 28002210 TI - European Society of Gynecological Oncology Statement on Fibroid and Uterine Morcellation. AB - Recently, there has been an intense discussion about the issue of fibroid and uterine morcellation in relation to the risk of unrecognized uterine sarcoma spread. Morcellation can negatively influence the prognosis of patients, and transecting the specimen into pieces prevents the pathologist from performing proper disease staging. Many societies have published their statements regarding this issue. The European Society for Gynecological Oncology has established a working group of clinicians involved in diagnostics and treatment of oncogynecological patients to provide a statement from the oncological point of view. Leiomyosarcomas and undifferentiated endometrial sarcomas have generally dismal prognosis, whereas low-grade endometrial stromal sarcomas and adenosarcomas have variable prognosis based on their stage. A focus on the detection of patients at risk of having a sarcoma should be mandatory before every surgery where morcellation is planned by evaluation of risk factors (African American descent, previous pelvic irradiation, use of tamoxifen, rapid lesion growth particularly in postmenopausal patients) and exclusion of patients with any suspicious ultrasonographic signs. Preoperative endometrial biopsy should be mandatory, although the sensitivity to detect sarcomas is low. An indication for myomectomy should be used only in patients with pregnancy plans; otherwise en bloc hysterectomy is preferred in both symptomatic and postmenopausal patients. Eliminating the technique of morcellation could lead to an increased morbidity in low-risk patients; therefore, after thorough preoperative evaluation and discussion with patients, morcellation still has its place in the armamentarium of gynecologic surgery. PMID- 28002211 TI - JAAOS: A Global Presence. PMID- 28002212 TI - Ambulatory Surgical Centers: A Review of Complications and Adverse Events. AB - An increasing number of orthopaedic surgeries are performed at ambulatory surgical centers (ASCs), as is exemplified by the 272% population-adjusted increase in outpatient rotator cuff repairs from 1996 to 2006. Outpatient surgery is convenient for patients and cost effective for the healthcare system. The rate of complications and adverse events following orthopaedic surgeries at ASCs ranges from 0.05% to 20%. The most common complications are pain and nausea, followed by infection, impaired healing, and bleeding; these are affected by surgical and patient risk factors. The most important surgeon-controlled factors are surgical time, type of anesthesia, and site of surgery, whereas the key patient comorbidities are advanced age, female sex, diabetes mellitus, smoking status, and high body mass index. As the use of ASCs continues to rise, an understanding of risk factors and outcomes becomes increasingly important to guide indications for and management of orthopaedic surgery in the outpatient setting. PMID- 28002213 TI - Assessment of the Pediatric Foot Mass. AB - Masses in the pediatric foot are relatively uncommon and can present a diagnostic challenge. The literature lacks a comprehensive overview of these types of lesions. Most are benign soft-tissue lesions that can be diagnosed on the basis of history and physical examination. However, some rare malignant neoplasms can mimic benign masses. It is imperative to recognize these lesions because the consequences of a delayed or missed diagnosis can be substantial. A thorough history and physical examination of all pediatric patients with foot lesions are crucial to ensure that any lesion not readily identified as benign is appropriately managed. PMID- 28002214 TI - Management of Acute Proximal Humeral Fractures. AB - Proximal humeral fractures, which typically occur in elderly persons, are among the most common fractures. A myriad of nonsurgical and surgical treatment options exist for these injuries, including short-term immobilization and early physical therapy, percutaneous fixation, plate osteosynthesis, intramedullary nailing, hemiarthroplasty, and reverse shoulder arthroplasty. The choice of treatment depends on the fracture type and severity, surgeon expertise, patient age, and patient health status. PMID- 28002215 TI - Orthopaedic Surgery Residency: Perspectives of Applicants and Program Directors on Medical Student Away Rotations. AB - INTRODUCTION: Senior medical students frequently rotate at orthopaedic residency programs away from their home medical schools. However, to our knowledge, the perspective of program directors (PDs) and applicants on the value, objectives, and costs of these rotations has not been studied. METHODS: Surveys evaluating the frequency, costs, benefits, and objectives of away rotations were distributed to all orthopaedic residency PDs in the United States and applicants in the 2014 2015 Match cycle. Data analysis was conducted to perform inferential and descriptive statistics; comparisons were made between and among PD and applicant groups using two-tailed means Student t-test and analysis of variance. RESULTS: A total of 74 PD (46.0%) and 524 applicant (49.3%) responses were obtained from a national distribution. Applicants completed an average of 2.4 away rotations, with an average cost of $2,799. When stratified on self-reported likelihood of Matching, there were no substantial differences in the total number of rotations performed. The only marked differences between these groups were the United States Medical Licensing Examination Step 1 score and the number of applications to residency programs. PDs reported that significantly fewer rotations should be allowed, whereas applicants suggested higher limits (2.42 rotations versus 6.24, P < 0.001). PDs and applicants had similar perspectives on the value of away rotations; both groups reported more value in finding a "good fit" and making a good impression at the program and placed less value on the educational impact. DISCUSSION: The value of orthopaedic away rotations appears more utilitarian than educational for both PDs and applicants. Rotations are performed regardless of perceived likelihood of Matching and are used by students and programs to identify a "good fit." Therefore, given the portion of an academic year that is spent on orthopaedic rotations, findings showing perceived low educational value and marked discrepancies between the expected number of rotations by PDs and applicants indicate that the current structure of away rotations may not be well aligned with the mission of undergraduate medical education. LEVEL OF EVIDENCE: V. PMID- 28002216 TI - Appropriate Use Criteria: Postoperative Rehabilitation of Low Energy Hip Fractures in the Elderly. PMID- 28002217 TI - The Meniscus. PMID- 28002218 TI - Color Analysis of Periimplant Soft Tissues Focusing on Implant System: A Case Series. AB - PURPOSE: To assess the impact of implant system on color harmonization of periimplant mucosa. MATERIALS AND METHODS: In this case series, color of periimplant mucosa was compared with color of natural tooth gingiva. Seventeen intercanine implants were analyzed (11 bone level [BL], 6 tissue level [TL] implants). Colorimetric data, at 2, 4, and 6 mm from gingival margin, were collected through fiber optics reflectance spectroscopy, and color differences calculated as DeltaE. Dentists, dental students, and lay people, in blind, performed an additional visual color analysis on clinical images. RESULTS: Independently from implant system, the color of periimplant mucosa was significantly different from gingiva (DeltaE = 8.2 +/- 0.7), resulting darker at L* comparison (P <= 0.05). TL periimplant mucosa showed higher DeltaE than BL (9.0 +/- 1.0 vs 6.6 +/- 0.8, respectively; P <= 0.05). Observers correctly identified where the implant was placed in about half of the cases, with no significant difference between implant systems. CONCLUSION: Within the limitations of this study, the color of periimplant soft tissues appears different from gingiva, at spectroscopic analysis. Color discrepancy results higher in the presence of TL implants than in BL implants, although the difference may not be clinically significant. PMID- 28002219 TI - Do Transcortical Screws in a Locking Plate Construct Improve the Stiffness in the Fixation of Vancouver B1 Periprosthetic Femur Fractures? A Biomechanical Analysis of 2 Different Plating Constructs. AB - OBJECTIVES: This biomechanical study compared Vancouver B1 periprosthetic femur fractures fixed with either a locking plate and anterior allograft strut construct or an equivalent locking plate with locking attachment plates construct in paired cadaveric specimens. METHODS: After 9 pairs of cadaveric femora were implanted with a cemented primary total hip arthroplasty, an oblique osteotomy was created distal to the cement mantle. Femora underwent fixation with either: (1) a locking plate with anterior strut allograft (locking compression plating (LCP)-Allograft) or (2) a locking plate with 2 locking attachment plates (LAPs) (LCP-LAP). Construct stiffness was compared in nondestructive mechanical testing for 2 modes of compression (20 degrees abduction and 20 degrees flexion), 2 four point bending directions (anterior-posterior and medial-lateral), and torsion. A final load to failure test evaluated the axial compression required to achieve fracture gap closure or construct yield. Fixation was compared through paired t tests (alpha = 0.05). RESULTS: The LCP-Allograft construct demonstrated higher stiffness values in compressive abduction (207 +/- 57 vs.151 +/- 40 N/mm), torsion (1666 +/- 445 vs. 1125 +/- 160 N mm/degree) and medial-lateral four-point bending (413 +/- 135 vs. 167 +/- 68 N/mm) compared with the LCP-LAP construct (P < 0.05). No differences were identified between the 2 constructs in compressive flexion, anterior-posterior bending, or the load to failure test (P > 0.05). CONCLUSION: Use of the anterior allograft strut created a stiffer construct compared with the LCP-LAP for the treatment of a Vancouver B1 periprosthetic femur fracture only in loading modes with increased medial-lateral bending. Although these static load results are indicative of the early postoperative environment, further fatigue testing is required to better understand the importance of the reduced medial-lateral stiffness over a longer period. PMID- 28002220 TI - Postoperative Computed Tomography for Articular Fractures: A Systematic Review. AB - OBJECTIVES: To determine the current published patterns of computed tomography (CT) use postoperatively in peri-articular fractures and identify those populations whereby postoperative CT changes management or results in better clinical outcomes. DATA SOURCES: Systematic review of MEDLINE and Cochrane using a combination of key words, including fracture fixation, fracture healing, and computed tomography. The final update search was performed on May 20, 2015. The search was limited to English language publications of human studies from the past 20 years. STUDY SELECTION: Eligible studies enrolled internally fixed peri articular fractures in adults imaged routinely with postoperative CT. Facial and spinal fracture studies were excluded. DATA EXTRACTION: One thousand five hundred thirty-seven articles were identified using the search strategy. One thousand two hundred ninty-seven articles were excluded by title. One hundred eighty-three studies were excluded by abstract. Fifty-seven full text articles were assessed for eligibility, 31 studies were eligible for study inclusion. DATA SYNTHESIS: There was no intention to perform combined statistical analysis in the form of a meta-analysis as disparity was anticipated between study populations, interventions, and outcome measures. Routine CT use postoperatively in peri articular fractures is limited to countries within the developed world, predominantly imaging the lower limb. Only 5 studies detailed postoperative CT leading to a change in patient management; within this pool, only 8 of the 361 individual patients received management changes due to CT scan findings. CONCLUSIONS: Use of postoperative CT in peri-articular fracture fixation has been demonstrated with minimal evidence, this leads to improved clinical outcomes. Based on available literature, postoperative CT scan use is questionable without convincing evidence of benefit. More research is required to identify selected patients who benefit from postoperative CT imaging. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002221 TI - Gartland Type 3 Supracondylar Humeral Fractures in Children: Which Open Reduction Approach Should Be Used After Failed Closed Reduction? AB - OBJECTIVES: For displaced supracondylar humeral fractures in children, in the event of closed reduction failure, anatomic reduction is achieved via open reduction techniques; however, there are no confirmative reports among the published open reduction approaches that deliver the best functional and cosmetic results. Here, we compared long-term functional and cosmetic results of different surgical approaches. DESIGN: Retrospective cohort study. SETTING: Ankara Education and Research Hospital/Turkey. Secondary care hospital and trauma center. PATIENTS/PARTICIPANTS: We evaluated 70 surgically treated Gartland type 3 supracondylar humeral fractures. Patients, with detailed history record, were divided into 5 groups with respect to surgery methods. INTERVENTION: All patients were treated surgically using closed reduction and percutaneous pinning or 4 different open reduction approaches and percutaneous pinning. MAIN OUTCOME MEASURES: Flynn cosmetic and functional score results were compared between surgical groups. RESULTS: Posterior open reduction and triceps transection groups showed worst results, whereas medial and lateral open reduction groups showed good to excellent results similar to closed reduction group. CONCLUSION: Medial and lateral approaches demonstrated better functional results than posterior and triceps transection approaches. Posterior approaches lead to restrictions in extension and poor functional results. In the posterior approach, transecting triceps from olecranon does not benefit from fracture reduction but results in loss of triceps strength and should be avoided. In failed closed reduction, medial and lateral open reduction approaches lead to similar cosmetic outcomes and functional results that are only slightly worse compared with those in closed reduction. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002222 TI - Contact Lens Discomfort: Can We Prevent Dropout? PMID- 28002223 TI - Is There a Role for Inflammation in Contact Lens Discomfort? AB - PURPOSE: The aim of this study was to examine the literature with respect to inflammation of the ocular surface and the presence of inflammatory mediators in the tear film during contact lens wear. METHODS: The literature on contact lens discomfort that relates to signs of inflammation was searched. Reference was paid to the cardinal signs of inflammation (pain, heat, redness, and swelling) as well as the appearance of inflammatory mediators in the tear film during contact lens wear. RESULTS: Contact lens wear does induce discomfort, which is a mild form of pain, and wearing of lenses can induce increases in limbal and conjunctival redness. However, there is little evidence for a direct relationship between limbal or conjunctival redness and contact lens discomfort. Contact lenses may increase the temperature of the ocular surface by a small amount (<=2.1 degrees C). Corneal or conjunctival swelling has not been associated with contact lens discomfort. Complement or kinin breakdown products or histamine in tears are not associated with contact lens discomfort. Cytokines are generally not related to discomfort, although nerve growth factor levels were increased in tears of symptomatics in one report. The presence of degraded lipids, leukotriene B4 and peroxidation products, and the enzyme secretory phospholipase A2 in tears has been associated with contact lens discomfort, and this area is worthy of further research. CONCLUSIONS: There have been only a few studies that have investigated a role for inflammation in contact lens-induced discomfort, and the strongest associations have been found with lipid degradation processes. PMID- 28002224 TI - Meibomian Gland Dysfunction and Contact Lens Discomfort. AB - Meibomian glands are located in the eyelids and secrete meibum, which gives rise to the lipid layer of the tear film. Changes to these glands can lead to the development of meibomian gland dysfunction (MGD), which is associated with various ocular symptoms such as fatigue, dryness, burning sensation, and heavy sensation. The diagnosis of MGD thus relies on evaluation of ocular symptoms, meibum condition, and lid margin abnormalities. The recent development of noninvasive meibography and tear interferometry has provided important insight into meibomian gland structure and function, respectively. Wearers of contact lenses complain of ocular symptoms that are thought to be attributable to a variety of causes, such as a diminished aqueous or mucin layer of the tear film, changes in tear protein concentration, and altered meibomian gland structure or function. Many studies have examined the relation between contact lens wear and meibomian gland changes. Such studies have found that lens wear is associated with adverse changes in meibomian gland morphology and in the condition of the lid margin and meibum, suggesting that contact lenses negatively affect meibomian glands. Meibomian gland dysfunction-like changes in meibomian glands induced by contact lens wear may thus be responsible for at least some of the ocular symptoms in lens wearers. PMID- 28002225 TI - Impact of Contact Lens Material, Design, and Fitting on Discomfort. AB - OBJECTIVE: To review the effect of contact lens (CL) material, design, and fitting characteristics on CL discomfort. METHODS: A PubMed search identified publications describing subjective comfort and CL material, fitting, and design parameters. The review included clinical signs associated with discomfort that may be a consequence of these parameters. RESULTS: Reduced lens movement or more CL tightness were associated with improved comfort. Increased lens-induced paralimbal conjunctival staining and indentation, considered as quasi-indicators of CL fitting or edge design, were also associated with better comfort. No recent studies have evaluated varying CL design parameters and subjective comfort. Silicone hydrogel CLs are no different in comfort compared with hydrogel CLs. Lower equilibrium water content is associated with improved comfort in hydrogel CL wear. Coefficient of friction shows promise as a material factor potentially associated with comfort. Lid wiper epitheliopathy and lid-parallel conjunctival folds have been linked with comfort in established wearers. CONCLUSIONS: Recent studies have confirmed the association between more mobile CLs and more discomfort, whereas closer conformity of the CL to the bulbar conjunctiva improved subjective comfort. There is no evidence to support the perceived comfort difference between silicone hydrogel and hydrogel CL. There has been limited progress in understanding the impact of varying specific CL design parameters. Although specific clinical signs may be predictive of discomfort, their role in the natural history of discomfort remains unclear. A better understanding of the relationship between coefficient of friction and comfort and strategies to improve lubricity may hold promise for limiting CL discomfort. PMID- 28002226 TI - Correctional Nursing: Caring for the Least of These. AB - The purpose of this article is to give insights into challenges faced by inmates, many of whom may be struggling with substance abuse, while almost all deal with physical and emotional problems-and offer a Christian nursing response. Resources for exploring correctional nursing are provided. PMID- 28002227 TI - Using Reflective Practice to Understand LGBTQ Client Needs. AB - Nurse practitioners as well as all nurses need to assess their values, be knowledgeable of Lesbian, Gay, Bisexual, Transgender, and Queer issues and current guidelines of care, and communicate with clients and their families in such a way as to create trusting and safe environments, free from barriers for quality healthcare. Nursing literature supports reflective practice as a means of reducing bias, as well as improving patient-provider trust and quality care. Understanding the primary care needs of specific populations is necessary to fulfill the nursing code of ethics. PMID- 28002228 TI - Defining the Location of the Adductor Canal Using Ultrasound. AB - BACKGROUND AND OBJECTIVES: The precise location of the adductor canal remains controversial among anesthesiologists. In numerous studies of the analgesic effect of the so-called adductor canal block for total knee arthroplasty, the needle insertion point has been the midpoint of the thigh, determined as the midpoint between the anterior superior iliac spine and base of patella. "Adductor canal block" may be a misnomer for an approach that is actually an injection into the femoral triangle, a "femoral triangle block." This block probably has a different analgesic effect compared with an injection into the adductor canal. We sought to determine the exact location of the adductor canal using ultrasound and relate it to the midpoint of the thigh. METHODS: Twenty-two volunteers were examined using ultrasound. The proximal end of the adductor canal was identified where the medial border of the sartorius muscle intersects the medial border of the adductor longus muscle. The distal end of the adductor canal is the adductor hiatus, which was also visualized ultrasonographically. RESULTS: The mean distance from the anterior superior iliac spine to the midpoint of the thigh was 22.9 cm (range, 20.3-24.9 cm). The mean distance from the anterior superior iliac spine to the proximal end of the adductor canal was 27.4 cm (range, 24.0-31.4 cm). Consequently, the mean distance from the midpoint of the thigh to the proximal end of the adductor canal was 4.6 cm (range, 2.3-7.0 cm). CONCLUSIONS: In all volunteers, the midpoint of the thigh was proximal to the beginning of the adductor canal, suggesting that an injection performed at this level is in fact a femoral triangle block. PMID- 28002229 TI - Evaluation of Ultrasound-Assisted Thoracic Epidural Placement in Patients Undergoing Upper Abdominal and Thoracic Surgery: A Randomized, Double-Blind Study. AB - BACKGROUND AND OBJECTIVES: The placement of thoracic epidurals can be technically challenging and requires a thorough understanding of neuraxial anatomy. Although ultrasound imaging of the thoracic spine has been described, no outcome studies on the use of this imaging have been performed. We evaluated whether preprocedural ultrasound of the thoracic spine would facilitate the process of epidural catheterization. METHODS: Subjects undergoing thoracic or upper abdominal surgery with planned thoracic epidural placement at T10 or higher were enrolled in this randomized double-blind study. Subjects were allocated into 1 of 2 groups for preoperative epidural placement: ultrasound guidance (group US) or palpation (group Palp). Subjects randomized to group US had a preprocedural ultrasound examination to identify pertinent spinal anatomy and make appropriate marks on the skin identifying midline and interlaminar spaces for targeted Tuohy needle insertion. Subjects in group Palp had a skin marking performed by palpation alone. Using the skin markings, all epidurals were performed using a loss of resistance to saline technique. Block levels were assessed with ice and pain scores obtained by a blinded nurse in the postanesthesia care unit. The primary outcome was procedural time from needle insertion to loss of resistance in the epidural space. RESULTS: Seventy subjects were recruited and completed the study protocol. The median time for epidural needle placement to achieve loss of resistance in group US and group Palp was 188.5 seconds (interquartile range [IQR], 79.0-515.0) and 242.0 seconds (IQR, 87.0-627.0), respectively (P = 0.188). Using ultrasound to mark the skin overlying the targeted epidural space took a median time of 85 seconds (IQR, 69-113) for group US and 35 seconds (IQR, 27-51) for group Palp (P < 0.001). The number of needle passes was not significantly different between the 2 groups (P = 0.31). The use of ultrasound assistance resulted in a decreased number of needle skin punctures to achieve loss of resistance (P = 0.005). Mean pain scores after surgery were lower in group US compared to group Palp: 3.0 versus 4.7, respectively (P = 0.015). CONCLUSIONS: This is the first randomized study to evaluate the efficacy of preprocedural ultrasound marking for placement of thoracic epidural catheters. We observed that preprocedural ultrasound did not significantly reduce the time required to identify the thoracic epidural space via loss of resistance. CLINICAL TRIALS REGISTRATION: NCT02785055 (https://clinicaltrials.gov/). PMID- 28002230 TI - Essential Oils, Part VI: Sandalwood Oil, Ylang-Ylang Oil, and Jasmine Absolute. AB - In this article, some aspects of sandalwood oil, ylang-ylang oil, and jasmine absolute are discussed including their botanical origin, uses of the plants and the oils and absolute, chemical composition, contact allergy to and allergic contact dermatitis from these essential oils and absolute, and their causative allergenic ingredients. PMID- 28002232 TI - Poison Ivy and Related Toxicodendron Extracts in Topical Products. PMID- 28002231 TI - Wet Wipe Allergens: Retrospective Analysis From the North American Contact Dermatitis Group 2011-2014. AB - BACKGROUND: Although there are several case reports of wet wipe-associated contact dermatitis, the prevalence of wipes as a source of allergic contact dermatitis in larger populations and the responsible allergens are largely unknown. OBJECTIVE: The aim of the study was to determine the prevalence of wet wipes as a source of contact allergy and the most commonly associated allergens in a North American tertiary referral patch test population. METHODS: Data collected from 2011 to 2014 by the North American Contact Dermatitis Group was used to conduct a retrospective cross-sectional analysis of patient demographics and patch test results associated with the triple-digit source code for "wet wipe." RESULTS: Of the 9037 patients patch tested during the study period, 79 (0.9%) had a positive patch test reaction to an allergen identified with a wet wipe source. The most commonly associated allergens were preservatives, including the following: methylisothiazolinone (MI) (59.0%), methylchloroisothiazolinone (MCI)/MI (35.6%), bronopol (2-bromo-2-nitropropane-1,3-diol) (27.4%), and iodopropynyl butylcarbamate (12.3%). Fragrance (combined) represented 12.3%. Anal/genital dermatitis was 15 times more likely (P < 0.0001) in those with wet wipe allergy. More than 92% of patients with wipe-associated contact allergy had their contact allergens detected by the North American Contact Dermatitis Group screening series. CONCLUSIONS: Wet wipes are an important source of contact allergy. Preservatives are the main allergens, especially isothiazolinones. PMID- 28002233 TI - Association Between Glove Use While Preparing Patch Tests and Development of Rash. PMID- 28002235 TI - Allergic Contact Dermatitis to 3-o-Ethyl-L-Ascorbic Acid in Skin-lightening Cosmetics. PMID- 28002234 TI - Patch Test Series for Allergic Perineal Dermatitis in the Diapered Infant. AB - BACKGROUND: Allergic perineal dermatitis (PD) due to diaper wipes, topical medicaments, or diapers has been reported. Although patch testing is the criterion standard for detection of allergic contact dermatitis in children, this is limited by body surface area, decreased tolerance of the patch testing procedure, and increased false-positive rates due to irritant reactions. Therefore, a targeted patch testing series is necessary to better screen diapered infants for possible allergic PD. OBJECTIVE: We propose 2 patch test series (PD series 1 and 2) to screen infants with possible allergic PD. METHODS: Allergens are chosen using existing sensitization data of common allergens in children, published case reports, and the collective experience of American Contact Dermatitis Society members through an electronic survey. RESULTS: PD series 1 includes 23 potential allergens found in wet wipes and topical diaper preparations. PD series 2 contains 10 potential allergens most commonly found in diapers. CONCLUSIONS: We believe that these judiciously chosen patch test series will increase the yield of detecting the causes of allergic PD while not exposing children to an unnecessarily large screening patch test panel. PMID- 28002236 TI - Patch Test Reactions to Corticosteroids: Retrospective Analysis From the North American Contact Dermatitis Group 2007-2014. AB - INTRODUCTION: Corticosteroids may cause delayed hypersensitivity. On the basis of structure, the following 4 groups of corticosteroids are recognized: A, B, C, and D (subdivided into D1 and D2). More recently, a newer classification system subdivides corticosteroids into groups 1, 2, and 3. Cross-reactions are unpredictable. The objective of this study was to describe positive patch test and co-reaction patterns to corticosteroids. METHODS AND RESULTS: A retrospective analysis of 17,978 patients patch tested by the North American Contact Dermatitis Group between 2007 and 2014 was performed. Corticosteroids tested during this period included the following: tixocortol-21-pivalate 1.0% petroleum (pet), budesonide 0.1% pet, triamcinolone acetonide 1.0% pet, desoximetasone 1.0% pet, clobetasol-17-propionate 1.0% pet, and hydrocortisone-17-butyrate (HC-17-B) 1.0% (pet and alcohol). Overall, 4.12% (n = 741) of patients had 1 or more positive reactions to corticosteroids. Tixocortol-21-pivalate positivity was the most common (2.26%), followed by budesonide (0.87%), HC-17-B (0.43%), clobetasol-17 proprionate (0.32%), and desoximetasone (0.16%). Reaction strength was strong (++ or +++) in almost twice as many tixocortol and budesonide reactions (>64%) as compared with the other 3 corticosteroids (<34.5%). Of the patients with positive corticosteroid reactions (n = 741), most (70.7%) had sensitivity to only 1 corticosteroid. Co-reactivity was highest between desoximetasone and budesonide. CONCLUSIONS: Sensitivity to corticosteroids is important. Consistent with other studies, the highest frequency of corticosteroid positivity was seen in group A (tixocortol-21-pivalate), followed by group B (budesonide) and D2 (HC-17-B). Co reactivity varied; more studies are needed to fully understand structural cross reactivity. PMID- 28002237 TI - The Latest Occult "Hypoallergenic" Allergen: Ethylhexylglycerin. PMID- 28002238 TI - Microparticles from Patients Undergoing Percutaneous Coronary Intervention Impair Vasodilatation by Uncoupling Endothelial Nitric Oxide Synthase. AB - OBJECTIVES: Percutaneous coronary interventions (PCIs) save countless acute myocardial infarction (AMI) patients. However, endothelial injury is still an inevitable complication. Circulating microparticles (MPs) play important roles in vascular dysfunction. Whether PCI affects function of MPs remains unclear. METHODS: MPs were obtained from AMI patients (n = 38) both preoperatively and 24 h after PCI, and healthy subjects (n = 20). MPs origins were tested by flow cytometry. Rat thoracic aortas were incubated with MPs to determine the effects of MPs on phosphorylation of endothelial nitric oxide synthase (eNOS), caveolin-1 expression, eNOS association with heat shock protein 90 (Hsp90), generation of nitric oxide (NO) and superoxide anion (O2), and endothelial-dependent vasodilatation. RESULTS: Compared with healthy subjects, MP concentrations increased in AMI patients. Undergoing PCI had no further effect on MPs concentration, but it results in increased endothelial-derived MPs proportion and decreased platelet-derived MP ratio. MPs from AMI patients decreased eNOS phosphorylation at Ser1177, increased eNOS phosphorylation at T495 and caveolin-1 expression, decreased eNOS association with Hsp90, decreased NO production but increased (O2) generation, damaged endothelial-dependent vasodilatation. All of these effects of MPs were strengthened by PCI. CONCLUSIONS: PCI further enhances the vascular injury effect of MPs. Circulating MPs may be a potential therapeutic target for patients undergoing PCI. PMID- 28002239 TI - Feasibility of Multiparametric Magnetic Resonance Imaging of the Prostate at 7 T. AB - OBJECTIVES: The aim of this study was to evaluate the technical feasibility of prostate multiparametric magnetic resonance imaging (mpMRI) at a magnetic field strength of 7 T. MATERIALS AND METHODS: In this prospective institutional review board-approved study, 14 patients with biopsy-proven prostate cancer (mean age, 65.2 years; median prostate-specific antigen [PSA], 6.2 ng/mL), all providing signed informed consent, underwent 7 T mpMRI with an external 8-channel body array transmit coil and an endorectal receive coil between September 2013 and October 2014. Image and spectral quality of high-resolution T2-weighted (T2W) imaging (0.3 * 0.3 * 2 mm), diffusion-weighted imaging (DWI; 1.4 * 1.4 * 2 mm or 1.75 * 1.75 * 2 mm), and (H) MR spectroscopic imaging (MRSI; real voxel size, 0.6 mm in 7:16 minutes) were rated on a 5-point scale by 2 radiologists and a spectroscopist. RESULTS: Prostate mpMRI including at least 2 of 3 MR techniques was obtained at 7 T in 13 patients in 65 +/- 12 minutes. Overall T2W and DWI image quality at 7 T was scored as fair (38% and 17%, respectively) to good or very good (55% and 83%, respectively). The main artifacts for T2W imaging were motion and areas of low signal-to-noise ratio, the latter possibly caused by radiofrequency field inhomogeneities. For DWI, the primary artifact was ghosting of the rectal wall in the readout direction. Magnetic resonance spectroscopic imaging quality was rated fair or good in 56% of the acquisitions and was mainly limited by lipid contamination. CONCLUSIONS: Multiparametric MRI of the prostate at 7 T is feasible at unprecedented spatial resolutions for T2W imaging and DWI and within clinically acceptable acquisition times for high-resolution MRSI, using the combination of an external 8-channel body-array transmit coil and an endorectal receive coil. The higher spatial resolutions can yield improved delineation of prostate anatomy, but the robustness of the techniques needs to be improved before clinical adoption of 7 T mpMRI. PMID- 28002240 TI - Longitudinal Computed Tomography Monitoring of Pelvic Bones in Patients With Breast Cancer Using Automated Bone Subtraction Software. AB - OBJECTIVE: The aim of this study was to optimize computed tomography (CT) surveillance of skeletal metastases in patients with breast cancer through the use of osseous subtraction maps between baseline and follow-up examinations created by a novel software algorithm. The new postprocessing algorithm segments the original bone followed by image intensity-based rigid alignment creating gray shaded maps that highlight focal or diffuse loss or increase in bone attenuation. MATERIALS AND METHODS: Institutional review board was obtained for this retrospective data evaluation. A total of 33 consecutive patients (31 female; 2 male; mean age, 59.13 +/- 12.68 years; range, 32-81 years) with breast cancer were included, who underwent 143 standardized baseline and follow-up CT examinations between February 2014 and June 2016. We classified bone metastases into lytic, sclerotic, and mixed osseous lesions. Any new osteolysis inside a known sclerotic lesion and enlargement of pre-existing sclerotic lesions were considered to represent progressive disease (PD), whereas no change was classified as stable disease (SD). Results were compared additionally with the course of the disease considering the entire skeleton and other involved organs. Software-created automated bone subtraction maps were compared with conventional CT interpretations of axial 5-mm and coronal 1-mm reformatted images. Region of interest measurements were used to quantify new lesions. Results were validated by clinical and CT follow-up. Reading time was evaluated. RESULTS: Skeletal metastases were present in 17/33 (51%) patients (9 sclerotic, 2 lytic, 6 mixed) at baseline. The use of bone subtraction maps resulted in an overall change of response classification into PD in 9/33 (8.1%) patients. Compared with conventional CT evaluation, the bone subtraction maps disclosed 123 new or enlarging sclerotic and 32 new lytic metastases in 23/33 (30.9%) examinations. Mean attenuation of new bone lesions (sclerotic or lytic) significantly increased or decreased (P < 0.01) in all patients. Bone attenuation in pelvic areas without evident metastatic disease significantly increased in patients with PD (P = 0.019), whereas there was no change in SD (P = 0.076). Lesion-based sensitivity, specificity, accuracy, positive predictive values, and negative predictive values were 98.7%, 79.5%, 94.5%, 95.1%, and 94.5%, respectively. Interobserver agreement was good (kappa = 0.80; P = 0.077). Reading time was significantly faster for the bone subtraction maps versus 5-mm axial images (P < 0.001). CONCLUSIONS: Longitudinal bone subtraction maps increase the accuracy and efficiency of CT diagnosis of skeletal metastases in patients with breast cancer. PMID- 28002241 TI - Reply: Phenotypic Analysis of Stromal Vascular Fraction after Mechanical Shear Reveals Stress-Induced Progenitor Populations. PMID- 28002243 TI - Smile Reanimation after Unilateral Facial Palsy by Lengthening Temporalis Myoplasty: Objective and Subjective Evaluation on 25 Cases. AB - BACKGROUND: Comparison of functional results of lengthening temporalis myoplasty relies in current practice on subjective scales. The goal of this study was to define a simple, reproducible, objective scale validated through a comparison with a subjective scale for smile symmetrization results after temporal muscle myoplasty. METHODS: A retrospective study was conducted on 25 patients having a unilateral facial palsy and rehabilitated with lengthening temporalis myoplasty. Evaluation consisted of objective measures: smile horizontal symmetry between left and right sides, vertical symmetry, and smile width on healthy and paretic sides on preoperative and postoperative photographs. Subjective scales were also used (i.e., a numeric scale and the Terzis and Noah scale) by a jury (four professionals and four nonprofessionals) and the patient himself or herself. Each evaluation was performed in three conditions: at rest, at intermediary smile, and at maximum smile. RESULTS: Comparison of objective measures on the impaired side showed a postoperative improvement in the three conditions evaluation. Reproducibility of the numeric scale was weak for evaluation at rest and fair for maximum smile evaluation (intraclass correlation coefficient of 0.57). The Terzis and Noah scale was not reproducible from one observer to another. At maximum smile, a correlation between smile symmetry in the vertical plane, smile symmetry in the horizontal plane, and professional evaluation with the numeric scale on the one hand and global patient satisfaction on the other hand was observed. CONCLUSION: Postoperative smile horizontal symmetry between left and right sides, and smile vertical symmetry, are good indicators with which to assess postoperative results of facial palsy rehabilitation. PMID- 28002244 TI - Carpal Tunnel Syndrome after Xiaflex Injection for Dupuytren Disease. PMID- 28002246 TI - Coblation Therapy in the Management of Chronic Wounds. PMID- 28002245 TI - A Temporoparietal Fascia Pocket Method in Elevation of Reconstructed Auricle for Microtia. AB - BACKGROUND: In two-stage procedures for reconstruction of microtia, an axial flap of temporoparietal fascia is widely used to cover the costal cartilage blocks placed behind the framework. Although a temporoparietal fascia flap is undoubtedly reliable, use of the flap is associated with some morbidity and comes at the expense of the option for salvage surgery. METHODS: The authors devised a simplified procedure for covering the cartilage blocks by creating a pocket in the postauricular temporoparietal fascia. In this procedure, the constructed auricle is elevated from the head superficially to the temporoparietal fascia, and a pocket is created under the temporoparietal fascia and the capsule of the auricle framework. Then, cartilage blocks are inserted into the pocket and fixed. A total of 38 reconstructed ears in 38 patients with microtia ranging in age from 9 to 19 years were elevated using the authors' method from 2002 to 2014 and followed for at least 5 months. To evaluate the long-term stability of the method, two-way analysis of variance (p < 0.05) was carried out to analyze the effect on the projection angles of the method (an axial temporoparietal fascia flap method versus a temporoparietal fascia pocket method) over long-term follow up. RESULTS: Good projection of the auricles and creation of well-defined temporoauricular sulci were achieved. Furthermore, the sulci had a tendency to hold their steep profile over a long period. CONCLUSIONS: The temporoparietal fascia pocket method is simple but produces superior results. Moreover, pocket creation is less invasive and has the benefit of sparing temporoparietal fascia flap elevation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28002247 TI - Customizing Extensor Reconstruction in Vascularized Toe Joint Transfers to Finger Proximal Interphalangeal Joints: A Strategic Approach for Correcting Extensor Lag. AB - BACKGROUND: Vascularized toe proximal interphalangeal joint transfer allows the restoration of damaged joints. However, extensor lag and poor arc of motion have been reported. The authors present their outcomes of treatment according to a novel reconstructive algorithm that addresses extensor lag and allows for consistent results postoperatively. METHODS: Vascularized toe joint transfers were performed in a consecutive series of 26 digits in 25 patients. The average age was 30.5 years, with 14 right and 12 left hands. Reconstructed digits included eight index, 10 middle, and eight ring fingers. Simultaneous extensor reconstructions were performed and eight were centralization of lateral bands, five were direct extensor digitorum longus-to-extensor digitorum communis repairs, and 13 were central slip reconstructions. RESULTS: The average length of follow-up was 16.7 months. The average extension lag was 17.9 degrees. The arc of motion was 57.7 degrees (81.7 percent functional use of pretransfer toe proximal interphalangeal joint arc of motion). There was no significant difference in the reconstructed proximal interphalangeal joint arc of motion for the handedness (p = 0.23), recipient digits (p = 0.37), or surgical experience in vascularized toe joint transfer (p = 0.25). The outcomes of different techniques of extensor mechanism reconstruction were similar in terms of extensor lag, arc of motion, and reconstructed finger arc of motion compared with the pretransfer toe proximal interphalangeal joint arc of motion. CONCLUSION: With this treatment algorithm, consistent outcomes can be produced with minimal extensor lag and maximum use of potential toe proximal interphalangeal joint arc of motion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28002248 TI - Redefining the Ideal Buttocks: A Population Analysis. PMID- 28002249 TI - Phenotypic Analysis of Stromal Vascular Fraction after Mechanical Shear Reveals Stress-Induced Progenitor Populations. PMID- 28002250 TI - Adipose Extracellular Matrix/Stromal Vascular Fraction Gel: A Novel Adipose Tissue-Derived Injectable for Stem Cell Therapy. AB - BACKGROUND: Adipose-derived stem cells and other stromal vascular fraction cells were used more often for stem cell therapy, even though limitations such as poor cell retention rate, complicated and expensive isolation processes, and the use of specific laboratory equipment need to be overcome. METHODS: Here, the authors developed a novel but simple method for generating an injectable mixture of stromal vascular fraction cells and native adipose extracellular matrix. It is a purely mechanical process in which lipoaspirate is processed into an extracellular matrix/stromal vascular fraction gel. The standard processing procedure was established using quantized tests. The therapeutic potential of the product for wound healing was then tested. RESULTS: Extracellular matrix/stromal vascular fraction gel derived from lipoaspirate and processed using a standard Coleman technique, followed by 1 minute of mechanical processing by passage back and forth between two 10-ml syringes at a flow rate of 10 ml/second, showed the highest adipose-derived stem cell and endothelial cell density. The stromal vascular fraction cells within the product also showed potential for multipotent differentiation similar to that of normal fat samples. In addition, the product showed better therapeutic results than stromal vascular fraction cell suspension when used to treat a nude mouse model of wound healing. CONCLUSIONS: Extracellular matrix/stromal vascular fraction gel is an autologous injectable derived from native extracellular matrix and is a functional cellular component generated using a simple mechanical process. As such, it may offer a novel mode of tissue repair suitable for clinical application in stem cell therapies. PMID- 28002251 TI - Reply: Redefining the Ideal Buttocks: A Population Analysis. PMID- 28002252 TI - Validating Facial Aesthetic Surgery Results with the FACE-Q. AB - BACKGROUND: In aesthetic clinical practice, surgical outcome is best measured by patient satisfaction and quality of life. For many years, there has been a lack of validated questionnaires. Recently, the FACE-Q was introduced, and the authors present the largest series of face-lift patients evaluated by the FACE-Q with the longest follow-up to date. METHODS: Two hundred consecutive patients were identified who underwent high-superficial musculoaponeurotic system face lifts, with or without additional facial rejuvenation procedures, between January of 2005 and January of 2015. Patients were sent eight FACE-Q scales and were asked to answer questions with regard to their satisfaction. Rank analysis of covariance was used to compare different subgroups. RESULTS: The response rate was 38 percent. Combination of face lift with other procedures resulted in higher satisfaction than face lift alone (p < 0.05). Patients who underwent lipofilling as part of their face lift showed higher satisfaction than patients without lipofilling in three subscales (p < 0.05). CONCLUSIONS: Facial rejuvenation surgery, combining a high-superficial musculoaponeurotic system face lift with lipofilling and/or other facial rejuvenation procedures, resulted in a high level of patient satisfaction. The authors recommend the implementation of the FACE-Q by physicians involved in aesthetic facial surgery, to validate their clinical outcomes from a patient's perspective. PMID- 28002253 TI - Reply: Time to Reconsider a Gold Standard of Lymph Flow Imaging: Importance of Reliability to Detect Abnormal Lymphodynamics in Lymphedema Screening after Cancer Treatments. PMID- 28002256 TI - Risk Factors for Hospital-acquired Clostridium difficile Infection Among Pediatric Patients With Cancer. AB - Hospital-acquired Clostridium difficile infection (CDI) may cause life threatening colitis for children with cancer, making identification of risk factors important. We described characteristics of pediatric cancer patients with primary and recurring CDI, and evaluated potential risk factors. Among 189 cancer patients, 51 cases (27%) of CDI and 94 matched controls of cancer patients without CDI were analyzed. Multivariable logistic regression was used to evaluate the association between CDI and several potential risk factors. Median age of CDI cases was lower (3.3 y; 0.60 to 16.2) than controls (7.7 y; 0.4 to 20.5). Median duration of neutropenia before CDI was longer for CDI cases (10.0 d; 0.0 to 30.0) compared with duration calculated from reference date in controls (6.0 d; 0.0 to 29.0). Multivariable analysis showed that older age was associated with reduced risk (>=7 vs. 0 to 3 y, odds ratio=0.11; 95% confidence interval, 0.02-0.54), and prolonged neutropenia was associated with increased risk (odds ratio=1.11; 95% confidence interval, 1.01-1.22). CDI recurred in 26% of cases. Younger age and prolonged neutropenia were risk factors for CDI in children with cancer. Increasing awareness to these risk factors will help to identify opportunities for CDI prevention in cancer patients. PMID- 28002254 TI - Reconstruction of the Irradiated Breast: A National Claims-Based Assessment of Postoperative Morbidity. AB - BACKGROUND: Implant-based reconstruction rates have risen among irradiation treated breast cancer patients in the United States. This study aims to assess the morbidity associated with various breast reconstruction techniques in irradiated patients. METHODS: From the MarketScan Commercial Claims and Encounters database, the authors selected breast cancer patients who had undergone mastectomy, irradiation, and breast reconstruction from 2009 to 2012. Demographic and clinical treatment data, including data on the timing of irradiation relative to breast reconstruction were recorded. Complications and failures after implant and autologous reconstruction were also recorded. A multivariable logistic regression model was developed with postoperative complications as the dependent variable and patient demographic and clinical variables as independent variables. RESULTS: Four thousand seven hundred eighty one irradiated patients who met the inclusion criteria were selected. A majority of the patients [n = 3846 (80 percent)] underwent reconstruction with implants. Overall complication rates were 45.3 percent and 30.8 percent for patients with implant and autologous reconstruction, respectively. Failure of reconstruction occurred in 29.4 percent of patients with implant reconstruction compared with 4.3 percent of patients with autologous reconstruction. In multivariable logistic regression, irradiated patients with implant reconstruction had two times the odds of having any complication and 11 times the odds of failure relative to patients with autologous reconstruction. CONCLUSIONS: Implant-based breast reconstruction in the irradiated patient, although popular, is associated with significant morbidity. Failures of reconstruction with implants in these patients approach 30 percent in the short term, suggesting a need for careful shared decision-making, with full disclosure of the potential morbidity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28002257 TI - Renal pathophysiology, arterial stiffness, and therapeutic approaches. PMID- 28002258 TI - What systematic reviews bring to the field of hypertension. PMID- 28002259 TI - Heart and kidneys: separate targets of carotid and aortic stiffness? PMID- 28002260 TI - Regulation of sodium balance in the distal nephron: urinary exosomes contribute to knowledge. PMID- 28002261 TI - Arterial pulsatility: the undisclosed driver of microvascular impairment? PMID- 28002262 TI - Managing hypertension in children and adolescents. PMID- 28002263 TI - Reply. PMID- 28002267 TI - Diagnostic and Therapeutic Challenges. PMID- 28002265 TI - Updates on the role of receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand/osteoprotegerin pathway in breast cancer risk and treatment. AB - PURPOSE OF REVIEW: Treatment with bisphosphonates and denosumab is the standard of care in bone metastatic disease. In addition, the adjuvant therapy of denosumab or bisphosphonates is very effective to prevent loss of bone mineral density, for example in osteoporosis. However, it is still unclear if this therapy has an influence on preventing cancer. RECENT FINDINGS: Since the identification of novel genes in the 1980s, it took about 30 years until denosumab, as a fully human mAb against receptor activator of nuclear factor (NF) kappaB ligand (RANKL), could be introduced to clinical practice. The discovery of the receptor activator of NF-kappaB/RANKL/osteoprotegerin pathway in the 1990s is an example of how modern databases of genes were utilized to discover new pathways relevant to a variety of diseases. The essential role of this pathway for the function, differentiation and survival of osteoclasts, and the influence on the bone microenvironment helped to understand the vicious circle of bone resorption and destruction in many skeletal diseases. SUMMARY: In the following review, we discuss the important role of rational targeting concerning receptor activator of NF-kappaB/RANKL/osteoprotegerin and the bisphosphonate therapy and provide an update for the related treatment of patients suffering from breast cancer and further implications for clinical practice and research using denosumab as a potential chemoprevention in BRCA1-related breast cancer. PMID- 28002268 TI - CHOROIDAL THICKNESS AS A PROGNOSTIC FACTOR OF PHOTODYNAMIC THERAPY WITH AFLIBERCEPT OR RANIBIZUMAB FOR POLYPOIDAL CHOROIDAL VASCULOPATHY. AB - PURPOSE: To investigate factors associated with visual improvement and retreatment 12 months after a combination therapy of intravitreal injection of ranibizumab or aflibercept followed by photodynamic therapy for polypoidal choroidal vasculopathy. METHODS: Changes in the best-corrected visual acuity and the subfoveal thickness of the retina and choroid were studied in 56 consecutive eyes with polypoidal choroidal vasculopathy treated initially with a combination therapy of either intravitreal ranibizumab injection (n = 23) or intravitreal aflibercept injection (n = 33) followed by photodynamic therapy. Factors associated with visual improvement and retreatment were investigated. RESULTS: Best-corrected visual acuity significantly improved with significant reduction in central macular thickness and subfoveal choroidal thickness at all points irrespective of treatment modalities (P < 0.001). Better best-corrected visual acuity and improvement of best-corrected visual acuity at 12 months were associated with baseline greater subfoveal choroidal thickness (P = 0.028 and P = 0.028) and baseline smaller greatest linear dimension (P = 0.0077 and P = 0.0077). Retreatment during 12-month follow-up was associated with baseline lesser subfoveal choroidal thickness (P = 0.036). CONCLUSION: Irrespective of treatment modalities, the visual outcome at 12 months is favorable in eyes with polypoidal choroidal vasculopathy treated by photodynamic therapy combined with intravitreal ranibizumab or aflibercept. Baseline greater subfoveal choroidal thickness was associated with a better visual outcome and with reduction in the need for retreatment. PMID- 28002270 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH BEHCET UVEITIS. AB - PURPOSE: To describe optical coherence tomography angiography (OCTA) findings in eyes with Behcet uveitis (BU) and to compare these findings with those of fluorescein angiography (FA). METHODS: Prospective, comparative, cross-sectional study. Patients presenting with clinically active BU involving the posterior segment were evaluated using FA, spectral domain optical coherence tomography (SD OCT), and OCTA. Optical coherence tomography angiograms were reviewed and analyzed. Foveal avascular zone areas and vessel densities were also reported. RESULTS: Twenty-five patients (44 eyes) were included. Perifoveal microvascular changes were more frequently observed on OCTA than on FA (95.5 vs 59.1%; P < 0.001). Disruption of the perifoveal capillary arcade, areas of retinal capillary nonperfusion/hypoperfusion, and perifoveal capillary abnormalities, including rarefied, dilated, or shunting vessels were observed more frequently using OCTA than FA (40.9 vs 25%; P = 0.039, 86.4 vs 34.1%; P < 0.001, and 84.1 vs 36.4%; P < 0.001, respectively). Areas of retinal capillary nonperfusion/hypoperfusion were more frequently observed in the deep than in the superficial capillary plexus (81.8 vs 63.6%; P = 0.039). Capillary abnormalities and disorganization of the normal architecture of the capillary network were more frequent in the deep than in the superficial capillary plexus (P < 0.001). Foveal avascular zone area was not significantly larger in eyes with BU than in control group in both the superficial and the deep capillary plexuses (0.4 vs 0.34 mm; P = 0.23 and 0.72 vs 0.53 mm; P = 0.053, respectively). Capillary vessel density was significantly lower in eyes with BU than in control group in the deep capillary plexus (13.7 vs 17.2 mm 21; P = 0.004). CONCLUSION: OCTA allows better visualization and characterization of perifoveal microvascular changes than FA in eyes with active BU. The deep capillary plexus seemed to be more severely involved than the superficial capillary plexus. PMID- 28002269 TI - EFFICACY OF INTRAVITREAL AFLIBERCEPT IN MACULAR TELANGIECTASIA TYPE 1 IS LINKED TO THE OCULAR ANGIOGENIC PROFILE. AB - PURPOSE: To evaluate intravitreal aflibercept in macular telangiectasia Type 1 (MacTel 1) patients and measure their ocular angiogenic profile. METHODS: Eight subjects with MacTel 1 refractory to bevacizumab, ranibizumab, or laser therapy and switched to aflibercept were included. Best-corrected visual acuity, central macular thickness, and cystic areas quantified on optical coherence tomography B scans were assessed during 12 months. Perifoveal capillary densities were measured on optical coherence tomography angiography. Aqueous humor was sampled from six patients and eight control subjects undergoing cataract extraction. Growth factors were quantified using a multiarray immunoassay. RESULTS: Over 12 months, patients received 6.6 +/- 1.4 (range, 5-8) intravitreal aflibercept injections. Twelve months after switching to aflibercept, best-corrected visual acuity increased by >=5 letters in 5 of 8 patients, compared with preaflibercept levels. Mean best-corrected visual acuity improved from 79.6 (~20/50) to 88.0 (~20/35) Early Treatment Diabetic Retinopathy Study letters (P = 0.042), and central macular thickness decreased from 434 +/- 98 MUm to 293 +/- 59 MUm (P = 0.014). Compared with control subjects, the profile of angiogenic factors in MacTel 1 eyes revealed no difference in vascular endothelial growth factor-A levels but significantly higher levels of placental growth factor (P = 0.029), soluble vascular endothelial growth factor receptor-1 (sFlt-1; P = 0.013), vascular endothelial growth factor-D (P = 0.050), and Tie-2 (P = 0.019). Placental growth factor levels inversely correlated with both superficial and deep capillary plexus densities on optical coherence tomography angiography (P = 0.03). CONCLUSION: The clinical response to aflibercept coupled to the angiogenic profile of MacTel 1 eyes support the implication of the placental growth factor/Flt-1 pathway in MacTel 1. PMID- 28002271 TI - REPRODUCIBILITY AND RELIABILITY OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FOR FOVEAL AVASCULAR ZONE EVALUATION AND MEASUREMENT IN DIFFERENT SETTINGS. AB - PURPOSE: Optical coherence tomography angiography (OCTA) allows delineating the foveal avascular zone (FAZ) easily and noninvasively. The present study aims to test reproducibility and reliability of FAZ evaluation by means of OCTA in different settings. METHODS: Twenty-four eyes of 24 normal subjects were investigated using AngioVue OCTA Imaging System. A series of OCTA acquisitions were taken both in basal and in different experimental settings after vasoactive stimuli. Images were evaluated separately by two operators and FAZ area was measured both manually and using the built-in automated measurement tool. RESULTS: No differences for FAZ area were found in the repetition of basal acquisitions, neither in manual nor in automated measurement (0.215 +/- 0.06 vs. 0.216 +/- 0.07, and 0.268 +/- 0.05 vs. 0.264 +/- 0.09, first vs. second basal measurement in square millimetres for manual and automated evaluation, P = 0.25 and P = 0.35, respectively). Interoperators correlation was optimal (r = 0.978 [95% CI 0.981-0.976]). No differences were found among the other settings, which included first basal and then repeated (second) in the morning, after flickering light stimulus, after a Bruce treadmill stress test, after 30 minutes dark adaptation, and basal in the evening, neither in automated nor in manual measurements. Automated measurements for nonflow areas provided significantly larger diameters than manual ones. CONCLUSION: AngioVue OCTA Imaging System produces highly reproducible FAZ images with a high interoperators concordance level. Optical coherence tomography angiography capability to detect FAZ area seems not to be influenced by any of the vasoactive stimuli considered in the current study. Nonflow areas seem to be larger when measured automatically than manually. PMID- 28002272 TI - BREAST-Q following Breast Reconstruction: Analysis of Breast Perception and Sexuality. PMID- 28002273 TI - Reply: Pretarsal Augmented Lower Blepharoplasty. PMID- 28002275 TI - Reply: Concomitant Liposuction Reduces Complications of Vertical Medial Thigh Lift in Massive Weight Loss Patients. PMID- 28002276 TI - Reply: A Comparison of Superomedial versus Inferior Pedicle Reduction Mammaplasty Using Three-Dimensional Analysis. PMID- 28002277 TI - Use of Acellular Dermal Matrix in Breast Surgery: Our Experience and Analysis of Satisfaction Using BREAST-Q. PMID- 28002278 TI - Concomitant Liposuction Reduces Complications of Vertical Medial Thigh Lift in Massive Weight Loss Patients. PMID- 28002280 TI - Modified Lipoabdominoplasty: Updating Concepts-Our Postbariatric Experience. PMID- 28002281 TI - Cultural Differences in Pretarsal Fullness Acceptance. PMID- 28002282 TI - Microsurgical Reconstruction of Traumatic Lower Extremity Defects in the Pediatric Population. AB - BACKGROUND: Few reports focus exclusively on microsurgical reconstruction of traumatic lower extremity defects in children. Hence, the authors felt it prudent to contribute to this area of clinical research. The authors hypothesized that reconstructive success would be comparable to success rates reported in adults, and that young age or concerns regarding vessel size or behavior do not negatively impact surgical outcome. METHODS: A retrospective review of microsurgical lower extremity reconstruction cases at two academic medical centers was performed. All pediatric patients who underwent microsurgical reconstruction of traumatic lower extremity defects between 1997 and 2012 were included for analysis. RESULTS: Forty flaps transferred in 40 patients with a mean age of 11.4 years (range, 1 to 17 years) were included for analysis. Muscle flaps were predominantly used [n = 23 (57.5 percent)]; however, there was a recent increase in use of fasciocutaneous flaps [n = 16 (40 percent)]. Postoperative complications were seen in 25 percent of patients, with a total flap loss rate of 5 percent. No donor-site complications were observed. The mean postoperative length of hospital stay was 12.9 days (range, 4 to 41 days), with patients returning to full weight-bearing after a mean of 2.6 months (range, 1 to 8 months). CONCLUSIONS: Microsurgical reconstruction of traumatic lower extremity defects in the pediatric population is safe. Concerns related to patient age, vessel size, or vessel behavior (i.e., vasospasm) should not detract from offering free flap reconstruction, as they do not negatively impact outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28002283 TI - A Comparison of Superomedial versus Inferior Pedicle Reduction Mammaplasty Using Three-Dimensional Analysis. PMID- 28002285 TI - OCHROCONIS GALLOPAVA ENDOPHTHALMITIS SUCCESSFULLY TREATED WITH INTRAVITREAL VORICONAZOLE AND AMPHOTERICIN B. AB - PURPOSE: Ochroconis gallopava is a darkly pigmented septated fungus that rarely infects humans, almost universally immunocompromised individuals. Only one previous case has been reported of O. gallopava endophthalmitis, in which the patient progressed to a visual acuity of no light perception. The authors currently describe the first successfully treated case of O. gallopava endophthalmitis. METHODS: A 65-year-old Hispanic woman on chronic immunosuppression after a right lung transplant was admitted to the hospital for O. gallopava respiratory tract infection and was found to have bilateral endogenous endophthalmitis. Examination revealed multiple, cream-colored, chorioretinal lesions in the fundus, including one near the temporal macula in the left eye. There was no diffuse vitritis. Visual acuity was 20/30 in both eyes at presentation but dropped to 20/400 in the right eye and counting fingers at 3 feet in the left eye over the hospital course despite receiving an intravitreal injection of voriconazole in the left eye and concurrent IV amphotericin B, posaconazole, and micafungin. The patient was then treated with multiple simultaneous intravitreal amphotericin B and voriconazole injections bilaterally, as well as IV posaconazole, which was switched to IV voriconazole for improved intraocular penetration. RESULTS: The chorioretinal lesions were noted to regress with treatment. Concomitantly, the patient's respiratory status improved, and she was discharged with a visual acuity of 20/40 in the right eye and 20/60 in the left eye. The patient completed a 1-year course of oral voriconazole as an outpatient without signs of recurrent activity. Seventeen months after the initial presentation, the patient had 20/40 vision bilaterally with a residual, white, fibrotic scar at the temporal macula in the left eye. CONCLUSION: This report describes the first successful treatment regimen against O. gallopava endophthalmitis using a combination of intravitreal amphotericin B and voriconazole injections, as well as IV posaconazole and voriconazole, which resulted in an excellent visual outcome. PMID- 28002284 TI - OUTCOMES OF ANTI-VEGF THERAPY IN CHOROIDAL NEOVASCULARIZATION AFTER MACULAR SURGERY. AB - PURPOSE: To report treatment outcomes of anti-vascular endothelial growth factor (VEGF) therapy in choroidal neovascularization (CNV) presenting after macular surgery. METHODS: Retrospective analysis of 7 eyes of 7 patients, who were diagnosed to have CNV after macular surgery and were treated with anti-vascular endothelial growth factor therapy. Collected data included demographic details; history of present illness; surgical procedure; and clinical examination including visual acuity at presentation and follow-up with imaging and management. Main outcome measures were resolution of CNV activity at the last follow-up. Secondary outcomes included change in visual acuity at final follow-up from baseline, number of injections, treatment free interval, and adverse events. RESULTS: Seven eyes of 7 patients (2 females and 5 males), which underwent macular surgery (4 macular hole repairs and 3 epiretinal membrane (ERM) removal), were included in this study. Two eyes had drusen at the time of surgery; however, five eyes had no preexisting conditions. Mean interval between surgery and CNV development was 21.07 +/- 38.55 months (range, 2 months-9 years). All patients had undergone intravitreal anti-vascular endothelial growth factor injections (range, 2-15; mean number: 5.85) with one eye requiring additional photodynamic therapy (PDT) and focal laser. Visual acuity was unchanged with inactive CNV at the last visit in all eyes after anti-vascular endothelial growth factor therapy. The mean follow-up duration after the development of CNV was 35.5 months (range, 6.5 months-8 years). CONCLUSION: Choroidal neovascularization occurring after otherwise successful macular surgery is uncommon with unknown predisposing factors. This entity appears to have poor visual outcome with currently available anti-vascular endothelial growth factor therapy. PMID- 28002286 TI - MACULAR MICROCYSTS IN SCHWARTZ-MATSUO SYNDROME. AB - PURPOSE: To describe a case of macular microcysts associated with advanced secondary glaucoma from Schwartz-Matsuo syndrome. METHODS: Clinical presentation, color fundus photography, optic disk photography, visual fields, and optical coherence tomography are presented. RESULTS: A 32-year-old woman presented with advanced, unilateral secondary glaucoma associated with a macula-on rhegmatogenous retinal detachment. She was diagnosed with Schwartz-Matsuo syndrome. Spectral domain optical coherence tomography showed macular microcystic changes in the paracentral retina at the level of the inner nuclear layer. CONCLUSION: Macular microcystic changes in the paracentral inner nuclear layer on spectral domain optical coherence tomography have been described in eyes with optic atrophy associated with a variety of diseases. This is the first described case of macular microcysts associated with advanced secondary glaucoma from Schwartz-Matsuo syndrome and may offer insights into the pathogenesis of these microcysts. PMID- 28002287 TI - Salpingo-Oophorectomy at the Time of Benign Hysterectomy: A Systematic Review. PMID- 28002288 TI - Salpingo-oophorectomy at the Time of Benign Hysterectomy: A Systematic Review. PMID- 28002289 TI - In Reply. PMID- 28002290 TI - Group Prenatal Care Compared With Traditional Prenatal Care: A Systematic Review and Meta-analysis. PMID- 28002291 TI - Group Prenatal Care Compared With Traditional Prenatal Care: A Systematic Review and Meta-analysis. PMID- 28002292 TI - In Reply. PMID- 28002293 TI - Simulation Training for Forceps-Assisted Vaginal Delivery and Rates of Maternal Perineal Trauma. PMID- 28002294 TI - In Reply. PMID- 28002295 TI - Recent Increases in the U.S. Maternal Mortality Rate: Disentangling Trends From Measurement Issues. PMID- 28002296 TI - In Reply. PMID- 28002297 TI - Enhanced Recovery Pathways for Improving Outcomes After Minimally Invasive Gynecologic Oncology Surgery. PMID- 28002298 TI - In Reply. PMID- 28002304 TI - Committee Opinion No. 683 Summary: Behavior That Undermines a Culture of Safety. AB - A key element of an organizational safety culture is maintaining an environment of professionalism that encourages communication and promotes high-quality care. Behavior that undermines a culture of safety, including disruptive or intimidating behavior, has a negative effect on the quality and safety of patient care. Intimidating behavior and disruptive behavior are unprofessional and should not be tolerated. Confronting disruptive individuals is difficult. Co-workers often are reluctant to report disruptive behavior because of fear of retaliation and the stigma associated with "blowing the whistle" on a colleague. Additionally, negative behavior of revenue-generating physicians may be overlooked because of concern about the perceived consequences of confronting them. The Joint Commission requires that hospitals establish a code of conduct that "defines acceptable behavior and behavior that undermines a culture of safety." Clear standards of behavior that acknowledge the consequences of disruptive and intimidating behavior must be established and communicated. Institutions and practices should develop a multifaceted approach to address disruptive behavior. Confidential reporting systems and assistance programs for physicians who exhibit disruptive behavior should be established. A concerted effort should be made within each organization to educate staff (ie, medical, nursing, and ancillary staff) about the potential negative effects of disruptive and inappropriate behavior. A clearly delineated hospital-wide policy and procedure relating to disruptive behavior should be developed and enforced by hospital administration. To preserve professional standing, physicians should understand how to respond to and mitigate the effect of complaints or reports. PMID- 28002305 TI - Committee Opinion No. 684 Summary: Delayed Umbilical Cord Clamping After Birth. AB - Delayed umbilical cord clamping appears to be beneficial for term and preterm infants. In term infants, delayed umbilical cord clamping increases hemoglobin levels at birth and improves iron stores in the first several months of life, which may have a favorable effect on developmental outcomes. There is a small increase in jaundice that requires phototherapy in this group of infants. Consequently, health care providers adopting delayed umbilical cord clamping in term infants should ensure that mechanisms are in place to monitor for and treat neonatal jaundice. In preterm infants, delayed umbilical cord clamping is associated with significant neonatal benefits, including improved transitional circulation, better establishment of red blood cell volume, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage. Delayed umbilical cord clamping was not associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor was it associated with a difference in postpartum hemoglobin levels or the need for blood transfusion. Given the benefits to most newborns and concordant with other professional organizations, the American College of Obstetricians and Gynecologists now recommends a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30-60 seconds after birth. The ability to provide delayed umbilical cord clamping may vary among institutions and settings; decisions in those circumstances are best made by the team caring for the mother-infant dyad. PMID- 28002306 TI - Committee Opinion No. 685 Summary: Care for Transgender Adolescents. AB - Gender nonconforming youth are an underserved population who obstetrician gynecologists are seeing increasingly in their practices. Currently, there are large gaps in training, knowledge, and comfort with transgender patients among obstetrician-gynecologists. The purpose of this document is to review current recommendations that apply to an obstetrician-gynecologist. It is important for obstetrician-gynecologists to be aware of the social and mental health risks for the transgender population. Consensus guidelines support initiating medical therapy after an adolescent has an established diagnosis of transgender identity and has reached Tanner stage II development. Medical management involves the suppression of puberty (typically in the form of gonadotropin-releasing hormone agonists) followed by cross-sex hormone therapy to induce puberty at age 16 years. A variety of surgical options are available, including bilateral mastectomy, hysterectomy with bilateral salpingo-oophorectomy or salpingectomy, and possible neophallus creation. Transgender patients are an at-risk population, and preventive medicine is imperative to their health. This includes proper screening for sexually transmitted infections, screening for suicidal thoughts and mental health issues, and appropriate vaccination. Like all patients, transgender adolescents should have a source for ongoing primary care. PMID- 28002307 TI - Committee Opinion No. 686 Summary: Breast and Labial Surgery in Adolescents. AB - The obstetrician-gynecologist may receive requests from adolescents and their families for advice, surgery, or referral for conditions of the breast or vulva to improve appearance and function. Appropriate counseling and guidance of adolescents with these concerns require a comprehensive and thoughtful approach, special knowledge of normal physical and psychosocial growth and development, and assessment of the physical maturity and emotional readiness of the patient. Individuals should be screened for body dysmorphic disorder. If the obstetrician gynecologist suspects an adolescent has body dysmorphic disorder, referral to a mental health professional is appropriate. As with other surgical procedures, credentialing for cosmetic procedures should be based on education, training, experience, and demonstrated competence. PMID- 28002308 TI - Clinical Updates in Women's Health Care Summary: Liver Disease: Reproductive Considerations. AB - All women are at risk of acute and chronic liver diseases. Of particular importance are those diseases that exclusively affect pregnant women and have adverse effects on maternal, fetal, or neonatal outcomes. Acute viral hepatitis is an important cause of liver disease in pregnant women, and hepatitis E infection is associated with substantial mortality. An increasing number of women have chronic liver diseases caused by viral hepatitis, alcoholic liver disease and nonalcoholic fatty liver disease, autoimmune liver diseases, and genetic liver diseases. The presence of chronic liver diseases or cirrhosis in pregnant or nonpregnant women requires alterations in gynecologic care, including contraception, pregnancy planning, cervical cancer screening, human papillomavirus vaccination, and postmenopausal hormone therapy. Women who have had liver and other solid organ transplantation require gynecologic care tailored to their immunosuppressed status. Collaboration between obstetrician gynecologists and hepatologists is essential to provide optimal care to women with acute or chronic liver diseases. Timely referral for evaluation for liver transplantation is mandatory for all women with acute liver failure. PMID- 28002309 TI - Committee Opinion No. 683: Behavior That Undermines a Culture of Safety. AB - A key element of an organizational safety culture is maintaining an environment of professionalism that encourages communication and promotes high-quality care. Behavior that undermines a culture of safety, including disruptive or intimidating behavior, has a negative effect on the quality and safety of patient care. Intimidating behavior and disruptive behavior are unprofessional and should not be tolerated. Confronting disruptive individuals is difficult. Co-workers often are reluctant to report disruptive behavior because of fear of retaliation and the stigma associated with "blowing the whistle" on a colleague. Additionally, negative behavior of revenue-generating physicians may be overlooked because of concern about the perceived consequences of confronting them. The Joint Commission requires that hospitals establish a code of conduct that "defines acceptable behavior and behavior that undermines a culture of safety." Clear standards of behavior that acknowledge the consequences of disruptive and intimidating behavior must be established and communicated. Institutions and practices should develop a multifaceted approach to address disruptive behavior. Confidential reporting systems and assistance programs for physicians who exhibit disruptive behavior should be established. A concerted effort should be made within each organization to educate staff (ie, medical, nursing, and ancillary staff) about the potential negative effects of disruptive and inappropriate behavior. A clearly delineated hospital-wide policy and procedure relating to disruptive behavior should be developed and enforced by hospital administration. To preserve professional standing, physicians should understand how to respond to and mitigate the effect of complaints or reports. PMID- 28002310 TI - Committee Opinion No. 684: Delayed Umbilical Cord Clamping After Birth. AB - Delayed umbilical cord clamping appears to be beneficial for term and preterm infants. In term infants, delayed umbilical cord clamping increases hemoglobin levels at birth and improves iron stores in the first several months of life, which may have a favorable effect on developmental outcomes. There is a small increase in jaundice that requires phototherapy in this group of infants. Consequently, health care providers adopting delayed umbilical cord clamping in term infants should ensure that mechanisms are in place to monitor for and treat neonatal jaundice. In preterm infants, delayed umbilical cord clamping is associated with significant neonatal benefits, including improved transitional circulation, better establishment of red blood cell volume, decreased need for blood transfusion, and lower incidence of necrotizing enterocolitis and intraventricular hemorrhage. Delayed umbilical cord clamping was not associated with an increased risk of postpartum hemorrhage or increased blood loss at delivery, nor was it associated with a difference in postpartum hemoglobin levels or the need for blood transfusion. Given the benefits to most newborns and concordant with other professional organizations, the American College of Obstetricians and Gynecologists now recommends a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30-60 seconds after birth. The ability to provide delayed umbilical cord clamping may vary among institutions and settings; decisions in those circumstances are best made by the team caring for the mother-infant dyad. PMID- 28002311 TI - Committee Opinion No. 685: Care for Transgender Adolescents. AB - Gender nonconforming youth are an underserved population who obstetrician gynecologists are seeing increasingly in their practices. Currently, there are large gaps in training, knowledge, and comfort with transgender patients among obstetrician-gynecologists. The purpose of this document is to review current recommendations that apply to an obstetrician-gynecologist. It is important for obstetrician-gynecologists to be aware of the social and mental health risks for the transgender population. Consensus guidelines support initiating medical therapy after an adolescent has an established diagnosis of transgender identity and has reached Tanner stage II development. Medical management involves the suppression of puberty (typically in the form of gonadotropin-releasing hormone agonists) followed by cross-sex hormone therapy to induce puberty at age 16 years. A variety of surgical options are available, including bilateral mastectomy, hysterectomy with bilateral salpingo-oophorectomy or salpingectomy, and possible neophallus creation. Transgender patients are an at-risk population, and preventive medicine is imperative to their health. This includes proper screening for sexually transmitted infections, screening for suicidal thoughts and mental health issues, and appropriate vaccination. Like all patients, transgender adolescents should have a source for ongoing primary care. PMID- 28002312 TI - Committee Opinion No. 686: Breast and Labial Surgery in Adolescents. AB - The obstetrician-gynecologist may receive requests from adolescents and their families for advice, surgery, or referral for conditions of the breast or vulva to improve appearance and function. Appropriate counseling and guidance of adolescents with these concerns require a comprehensive and thoughtful approach, special knowledge of normal physical and psychosocial growth and development, and assessment of the physical maturity and emotional readiness of the patient. Individuals should be screened for body dysmorphic disorder. If the obstetrician gynecologist suspects an adolescent has body dysmorphic disorder, referral to a mental health professional is appropriate. As with other surgical procedures, credentialing for cosmetic procedures should be based on education, training, experience, and demonstrated competence. PMID- 28002313 TI - Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first-line treatment for patients with metastatic colorectal cancer: Results of a registry based cohort analysis. AB - The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Clinical data were collected from a single-center registry study where mCRC patients received first-line fluoropyrimidine-based chemotherapy combined with either bevacizumab (188 patients with KRAS wild-type or mutated tumors) or cetuximab (101 patients with KRAS wild-type tumors) between January 2009 and December 2013. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics. No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival (PFS) (10.6 vs 8.7 months, P = 0.317), median overall survival (OS) (27.7 vs 28.3 months, P = 0.525), or overall response rate (43.1% vs 53.5%, P = 0.108). For the subset of patients with peritoneal dissemination, bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS (9.6 vs 6.1 months) and OS (26.3 vs 12.7 months), but not for patients without peritoneal dissemination (PFS, 10.6 vs 9.1 months; OS, 27.9 vs 30.7 months) (all unadjusted and adjusted interaction P < 0.05). Our study suggests that bevacizumab- or cetuximab-based regimens have similar effectiveness as first-line treatment of mCRC in Chinese population. Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment. Future prospective studies are required to further confirm these results. PMID- 28002314 TI - Association between polycystic ovary syndrome and the risk of pregnancy complications: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is inconsistently associated with increased risk of adverse pregnancy outcomes. The purpose of this meta-analysis was to summarize the evidence regarding the strength of the association between pregnancy in women with PCOS and pregnancy complications. METHODS: We systematically searched PubMed, EmBase, and the Cochrane Library to identify observational studies up to January 2016. The primary focus was pregnancy outcomes, including gestational diabetes mellitus (GDM), preeclampsia, pregnancy induced hypertension (PIH), preterm delivery, cesarean delivery, oligohydramnios, and polyhydramnios. Effect estimates were pooled using the random-effects model. The analysis was further stratified by factors that could affect these associations. RESULTS: We included 40 observational studies that reported data on a total of 17,816 pregnancies with PCOS and 123,756 pregnancies without PCOS. Overall, PCOS in pregnancy was associated with greater risk of GDM, preeclampsia, PIH, preterm delivery, cesarean delivery, miscarriage, hypoglycemia, and perinatal death. However, PCOS in pregnancy had little or no effect on oligohydramnios, polyhydramnios, large-for-gestational age (LGA), small-for gestational-age (SGA), fetal growth restriction (FGR), preterm premature membrane rupture, fasting blood glucose (FBG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride, total cholesterol, congenital malformation, macrosomia, and respiratory distress syndrome. Subgroup analysis suggested that these associations might be influenced by study design and pre-BMI. CONCLUSION: PCOS in pregnancy is associated with a significantly increased risk of adverse pregnancy, fetal, and neonatal outcomes. PMID- 28002315 TI - A case report and literature review of Churg-Strauss syndrome presenting with myocarditis. AB - BACKGROUND: Churg-Strauss syndrome (CSS) is a multisystem disorder characterized by asthma, prominent peripheral blood eosinophilia, and vasculitis signs. CASE SUMMARY: Here we report a case of CSS presenting with acute myocarditis and heart failure and review the literature on CSS with cardiac involvement. A 59-year-old man with general fatigue, numbness of limbs, and a 2-year history of asthma was admitted to the department of orthopedics. Eosinophilia, history of asthma, lung infiltrates, peripheral neurological damage, and myocarditis suggested the diagnosis of CSS. Transthoracic echocardiography revealed a dilated hypokinetic left ventricle (left ventricular ejection fraction ~40%) with mild segmental abnormalities in the septal and apical segments. CONCLUSION: By reviewing the present case reports, we concluded that (1) the younger age of CSS, the greater occurrence rate of complicating myocarditis and the poorer prognosis; (2) female CSS patients are older than male patients; (3) patients with cardiac involvement usually have a history of severe asthma; (4) markedly increased eosinophil count suggests a potential diagnosis of CSS (when the count increases to 20% of white blood cell counts or 8.1 * 109/L, eosinophils start to infiltrate into myocardium); and (5) negative ANCA status is associated with heart disease in CSS. PMID- 28002316 TI - Comparative study between 2 different doses of pregabalin and lidocaine on pain following propofol injection: A double-blind, randomized clinical consort study. AB - BACKGROUND: Propofol, an intravenous anesthetic, often causes pain on injection, which can be very distressful to patients. We investigated the analgesic effect of pregabalin on pain following propofol injection, compared with lidocaine. METHODS: In a randomized, double-blind, prospective trial, 120 patients were randomized into 3 groups of 40 each; who received oral placebo and intravenous lidocaine 40 mg with venous occlusion for 1 minute (group L, n = 40), oral pregabalin 75 mg and intravenous normal saline with venous occlusion for 1 minute (group LP, n = 40), and oral pregabalin 150 mg and intravenous normal saline with venous occlusion for 1 minute (group HP, n = 40) as pretreatment, followed by administration of 1% propofol 0.5 mg/kg. Pain intensity was measured on a 4-point scale (0 = no, 1 = mild, 2 = moderate, and 3 = severe pain). Any side effects associated with pretreatment substances were recorded during the first 24 hours after surgery. RESULTS: A total of 120 patients completed this trial. Demographic data were similar between groups. The incidence of pain following propofol injection was significantly reduced in group HP (50%) and group L (55%) compared with group LP (92.5%) (P < 0.05, respectively). The incidences of moderate pain in group HP (12.5%) and group L (15%) were significantly decreased compared with group LP (37.5%; both, P < 0.05). There were no significant differences in the incidence of side effects such as headache and dizziness between groups. CONCLUSION: Pretreatment with oral pregabalin 150 mg and intravenous lidocaine 40 mg with venous occlusion equally reduced pain from propofol injection. PMID- 28002317 TI - Factors associated with lower extremity atherosclerotic disease in Chinese patients with type 2 diabetes mellitus: A case-control study. AB - Early detection and treatment of lower extremity atherosclerotic disease (LEAD), and controlling its risk factors are critical in preventing amputation and death in diabetic patients. This study aimed to investigate the factors associated with LEAD in Chinese diabetic patients.In this case-control study, patients with type 2 diabetes mellitus (T2DM) (N = 1289) were divided into 2 groups according to the ultrasonic Doppler examination: with (LEAD+, n = 737) and without (LEAD-, n = 552) LEAD. In subgroup analysis, the LEAD+ group was divided based on the diameter of lower-extremity arteries: LEAD+A (1%-49% reduction) and LEAD+B (>=50% reduction). Clinical and demographic data of patients were analyzed.Compared with the LEAD- group, serum creatinine levels were significantly increased (P < 0.001), whereas glomerular filtration rate (GFR) was significantly decreased (P < 0.001) in the LEAD+ group. Multivariate analysis results showed that GFR (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.986-0.997, P = 0.003), diabetes duration (OR 1.055, 95% CI 1.026-1.084, P < 0.001), age (OR 1.123, 95% CI 1.104 1.142, P < 0.001), and uric acid (OR 1.002, 95% CI 1.000-1.004, P = 0.031) were independently associated with LEAD in patients with T2DM. Furthermore, multivariate analysis showed that age (OR 1.078, 95% CI 1.048-1.109, P < 0.001) and GFR (OR 0.985, 95% CI 0.975-0.994, P = 0.002) were independently associated with the severity of arterial lesions in patients with T2DM and LEAD.The risk factors of LEAD in Chinese patients with T2DM include age, course of disease, uric acid, and GFR. Patients with T2DM, high uric acid levels, and declined GFR could be listed in the high-risk group for LEAD. PMID- 28002318 TI - Brahma-related gene 1 induces apoptosis in a p53-dependent manner in human rheumatoid fibroblast-like synoviocyte MH7A. AB - Blocked apoptosis and aggressive inflammatory responses occur in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA) patients. Although Brahma-related gene 1 (BRG1) is considered as a tumor suppressor, few research covers its role in RA. This study aims to reveal effects and potential mechanisms of BRG1 in human FLS cell line MH7A.BRG1 expression in MH7A cells was altered by transfection of overexpression vectors or short hairpin RNAs (shRNAs). Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometry after transfection. Factors involved in inflammation and apoptosis were quantified by qPCR and Western blot. The interaction between BRG1 and p53 was assessed by immunoprecipitation (IP).Results showed that BRG1 overexpression significantly suppressed MH7A cell viability and induced apoptosis (P < 0.01), and its knockdown had opposite effects. BRG1 reduced mRNA levels of matrix metallopeptidase 3, TIMP metallopeptidase inhibitor 2, cyclooxygenase 2, and interleukin 6, implying its suppressive effects on inflammation. BRG1 interacted with and promoted p53 (P < 0.05). B-cell chronic lymphocytic leukemia/lymphoma 2 was suppressed (P < 0.05), while cytochrome c, caspase 3 (CASP3) and CASP9 were activated (P < 0.01) by BRG1. However, the regulation on these factors was abrogated by p53 knockdown (P < 0.01).These findings suggest that BRG1 may induce apoptosis and suppress inflammation in MH7A cells. Potential functional mechanisms involve the regulation of apoptotic factors by BRG1, which may depend on the recruitment and promotion of p53. This study provides the essential proof for applying BRG1 to the molecular therapy of RA. PMID- 28002319 TI - Response of mouse thymic cells to radiation after transfusion of mesenchymal stem cells. AB - Thymic lymphoma is a highly invasive and even metastatic cancer. This study investigated the effects of mesenchymal stem cells (MSCs) transfusion on cell cycle, cell proliferation, CD3 expression, mutation frequency of T cell receptor using mouse model of thymic lymphoma.C57BL/6J young mouse models of thymoma were injected with MSCs. Six months later, the thymus was taken for pathological examination and flow cytometry studies. The cells were labeled with anti-CD4, CD8, CD3, propidium iodide, or CFDA-SE, cell cycle, proliferation kinetics, and mutation frequency of T cell receptor, respectively.Pathologic results showed that control had clear corticomedular structure with regularly shaped lymphocytes. After radiation, the thymus structure was completely destroyed, with lymphoid tumor cells diffusely distributed and heavily stained, and large nuclei. Transfusion of MSCs resulted in normal thymus structure. Cytometry studies showed that there were more CD4-/CD8- T cells in the thymus of irradiated mice than in control; transfusion of MSCs led to reduced CD4-/CD8- T cells. In irradiated mice, there were less CD4+/CD8+ T cells than in control and MSCs transfusion groups. It was observed that there were more cells arrested in G1 phase in the thymus cells and CD4-/CD8- T cells in irradiated mice than in other 2 groups, whereas there were more cells arrested in S phase in CD4+/CD8+ and CD4+/CD8- T cells in irradiated mice than in the other mice. In the thymus cells, and CD4+/CD8+ and CD4+/CD8- T cells, irradiated mice group had significantly less parent, G2, G3, and G4 cells, and more cells at higher generations, and also higher proliferation index. In CD4-/CD8- T cells, irradiated mice had significantly more parent, G2, and G3 cells, and less G4, G5, G6, and propidium iodide, as compared with the other 2 groups. The expression of CD3 in CD4/CD8 T cells was significantly higher than in control. MSCs transfusion improved CD3 expression, but was still less than the control. Irradiation resulted in very high mutation frequency of T cell receptor, which was barely affected by MSCs transfusion.Mesenchymal stem cell transfusion is able to restore the cell cycle and cell proliferation, but not CD3 expression and mutation frequency of T cell receptor in irradiated mice to control level. PMID- 28002320 TI - CA125 is a potential biomarker to predict surgically incurable gastric and cardia cancer: A retrospective study. AB - Preoperative evaluation of the curability of gastric and cardia cancer is important to avoid risks of unnecessary surgery. Our previous study has reported several clinical parameters associated with incurable gastric surgery. In this study, we aimed to evaluate the correlation between CA125 and the curability of gastric and cardia cancer.A total of 297 cases of gastric and cardia cancer were analyzed retrospectively, including 153 cases with radical surgery and 144 with surgery for incurable gastric or cardia cancer. chi test was performed to analyze the associations between curability or incurable factors and clinicopathological data, including CA125 value. ROC curves were generated, and cutoff points for curability, T status, N status, peritoneal metastasis, and distant metastasis were found, respectively. Binary logistic regression was performed to verify the associations between dependent variables (curability, T status, N status, peritoneal metastasis, and distant metastasis) and covariates (related clinicopathological data from step 1 and cutoff points from step 2).Esophageal involvement, T grade, and CA125 were risk factors of curability. T grade and Borrmann type were risk factors of T status. T grade and CA125 were risk factors of N status. Age, esophageal involvement, T grade, and CA125 were risk factors of peritoneal metastasis. CA125 was risk factor of distant metastasis.CA125 is a potential biological marker for curability prediction of gastric and cardia cancer. PMID- 28002321 TI - Is combined topical with intravenous tranexamic acid superior than topical, intravenous tranexamic acid alone and control groups for blood loss controlling after total knee arthroplasty: A meta-analysis. AB - BACKGROUND: The purpose of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to evaluate the efficacy and safety of combined topical with intravenous tranexamic acid (TXA) versus topical, intravenous TXA alone or control for reducing blood loss after a total knee arthroplasty (TKA). METHODS: In May 2016, a systematic computer-based search was conducted in the PubMed, Embase, Cochrane Library, Web of Science, and Chinese Wanfang database. This systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement criteria. Only patients prepared for primary TKA that administration combined topical with intravenous TXA with topical TXA, intravenous (IV) TXA, or control group for reducing blood loss were included. Eligible criteria were published RCTs about combined topical with intravenous TXA with topical alone or intravenous alone. The primary endpoint was the total blood loss and need for transfusion. The complications of deep venous thrombosis (DVT) were also compiled to assess the safety of combined topical TXA with intravenous TXA. Relative risks (RRs) with 95% CIs were estimated for dichotomous outcomes, and mean differences (MDs) with 95% CIs for continuous outcomes. The Cochrane risk of bias tool was used to appraise a risk of bias. Stata 12.0 software was used for meta-analysis. RESULTS: Fifteen studies involving 1495 patients met the inclusion criteria. The pooled meta-analysis indicated that combined topical TXA with intravenous TXA can reduce the total blood loss compared with placebo with a mean of 458.66 mL and the difference is statistically significant (MD = -458.66, 95% CI: -655.40 to 261.91, P < 0.001). Compared with intravenous TXA, combined administrated TXA can decrease the total blood loss, and the difference is statistically significant (MD = -554.03, 95% CI: -1066.21 to -41.85, P = 0.034). Compared with the topical administration TXA, the pooled meta-analysis indicated that combined TXA can decrease the amount of total blood loss with mean 107.65 mL with statistically significant(MD = -107.65, 95% CI: -525.55 to -239.9141.85, P = 0.001). The pooled results indicated that combined topical with intravenous TXA can decrease the need for transfusion (RR = 0.34, 95% CI: 0.23-0.50, P < 0.001). There is no significant difference between combined topical with intravenous TXA with topical or intravenous TXA (P > 0.05) in terms of need for transfusion and the occurrence of DVT. CONCLUSION: Compared with topical, intravenous TXA alone or control group, combined topical with TXA, can decrease the total blood loss and subsequent need for transfusion without increasing the occurrence of DVT. The dose and timing to administration TXA is different, and more randomized controlled trials are warranted to clarify the optimal dosing and time to administration TXA. PMID- 28002322 TI - The effect of polydeoxyribonucleotide prolotherapy on posterior tibial tendon dysfunction after ankle syndesmotic surgery: A case report. AB - RATIONALE: Ankle syndesmotic injuries occasionally require long-term therapy for recovery and can result in tendon injury. Posterior tibial tendon dysfunction (PTTD) is an acquired deformity that can cause flatfoot deformity. The current nonoperative management of PTTD includes nonsteroidal antiinflammatory drugs (NSAIDs), orthopedic devices. Although various treatment options have been attempted, optimal treatments for each stage of the condition are debated. Polydeoxyribonucleotide (PDRN) is effective in healing of chronic wounds associated with tissue damage by attracting tissue growth factors. PATIENT CONCERNS: A 67-year-old woman who presented at our pain clinic with pain on the inside of ankle. She had a syndesmotic screw fixation 3 years prior. Her ankle pain had persisted after the removal of screws and edema for about 1 month resulting from long-term NSAIDs administration. DIAGNOSES: The origin of the pain was possibly tibialis posterior muscle and posterior tibial tendon and she was diagnosed as PTTD after syndesmosis surgery. INTERVENTIONS: Sono guided prolotherapy with PDRN was carried out. OUTCOMES: Patient showed improvement in the arch of the foot, experienced pain relief, and was able to wear regular shoes without any orthopedic device. LESSONS: This case report highlights that PDRN prolotherapy is a safe and efficient therapeutic option for the treatment of PTTD. PMID- 28002323 TI - Augmentation index (AI) in a dose-response relationship with smoking habits in males: The Tanushimaru study. AB - We investigated the relationship between augmentation index (AI) and smoking habits in community-dwelling Japanese.This cross-sectional study enrolled 1926 subjects (769 males and 1157 females) aged 40 to 95 years who underwent a health check-up in a Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town in Kyushu Island in 2009. The subjects' medical history, alcohol intake, smoking habit, and current medications for hypertension, dyslipidemia, and diabetes were ascertained by questionnaire. Radial arterial pressure wave analysis was used to obtain AI. We analyzed the data stratified by gender.Age-adjusted means of AI in males showed a clear dose-response relationship in 4 categories of smoking habits (P = 0.010). There was no significant relationship between AI and smoking habits in females (P = 0.127). The significant dose-response relationship (P = 0.036) in males between AI and 4 categories of smoking habits still remained even after adjustment for age, body mass index, systolic blood pressure, estimated glomerular filtration rate, glucose, hypertensive medication, and alcohol intake.The present study demonstrated that AI values were significantly associated with smoking habits in a dose-dependent manner in Japanese males. PMID- 28002324 TI - Nonanatomical resection is comparable with anatomical resection in solitary hepatocellular carcinoma <5 cm in the right posterior section. AB - Anatomical resection (AR) is superior to nonanatomical resection (NAR) in theory, but the actual clinical benefit of AR for hepatocellular carcinoma (HCC) is controversial due to the substantial heterogeneity of HCC. Here, we retrospectively compared AR and NAR outcomes for solitary hepatocellular carcinoma (HCC) <5 cm in the right posterior section (RPS) and investigated the risk factors for HCC recurrence and liver-related mortality.The study included 99 consecutive patients who underwent curative surgical resection of an HCC in the RPS (S6 and S7) between January 2003 and December 2009. Each patient had a solitary HCC <5 cm and a noncirrhotic liver.The median estimated blood loss during operation and median operative time were significantly worse in the AR group. In addition, the median tumor size and incidence of microvascular invasion were significantly worse in the AR group. The 1-, 3-, and 5-year disease-free survival rates were 74.1%, 66.3%, and 58.2% in the AR group and 84.7%, 64.4%, and 48.2% in the NAR group, respectively (P = 0.172). The corresponding liver-related overall survival rates were 96.3%, 84.7%, and 77.0% in the AR group and 97.2%, 90.1%, and 88.7% in the NAR group, respectively (P = 0.335). NAR was not associated with HCC recurrence or liver-related mortality in multivariate analysis.The outcomes of NAR for a solitary HCC <5 cm in the RPS are comparable to those achieved with AR with respect to long-term liver-related overall survival and disease-free survival. PMID- 28002325 TI - Flexible transgastric endoscopic liver cyst fenestration: A feasibility study in humans (with video). AB - There is no clinical report on the use of natural orifice transluminal endoscopic surgery (NOTES) for the management of patients with large liver cysts.This study aims to evaluate the feasibility and safety of NOTES for liver cyst fenestration in humans using a currently available technique.From February 2009 to June 2010, 4 cases of transgastric endoscopic liver cyst fenestration were performed; in which 3 cases received NOTES only, while 1 case received additional laparoscopic assistance.Mean time to endoscopically locate the liver cyst was 16 minutes (5-22 minutes). Cysts that were present in the left lobe or on the liver surface were easier to locate endoscopically. Transgastric endoscopic liver cyst fenestration was successful in all patients. The use of an occlusion balloon helped in the endoscopic clipping of the gastrotomy incision. Mean operative time was 101.3 minutes (range, 90-112 minutes), and there were no intra- or postoperative complications including infections. All patients recovered well after the surgery, with only minor postoperative throat pain. There was no recurrence at a mean follow-up of 12 months (range, 6-48 months).Small sample size.It may be technically feasible and safe to perform transgastric endoscopic liver cyst fenestration in humans with no recurrence at follow up. PMID- 28002326 TI - Treatment of a long-acting anticoagulant rodenticide poisoning cohort with vitamin K1 during the maintenance period. AB - Currently, there are few guidelines for the use of vitamin K1 in the maintenance treatment of long-acting anticoagulant rodenticide (LAAR) poisonings. We explored factors in the treatment of LAAR poisoning during the maintenance period in order to suggest feasible treatment models.Data from 24 cases of anticoagulant rodenticide poisoning in our hospital were collected from January 2013 to May 2016. The patients' sex, age, coagulation function, total time from poisoning to treatment with vitamin K1 (prehospital time), vitamin K1 sustained treatment time (VKSTT), anticoagulant rodenticide category, and specific poison dosage were collected. Multivariate analysis was used to evaluate the correlation between vitamin K1 dosage and other factors during the maintenance period.Only VKSTT (partial regression coefficient -1.133, 0.59, P = 0.035) had an obvious influence on the therapeutic dose of vitamin K1 required during the maintenance period.After an initial pulse therapy, the bleeding and coagulation functions were stabilized, and the patients were subsequently treated with vitamin K1 during the maintenance period. Over time, the maintenance dose of vitamin K1 (10 120 mg/d, intravenous drip) was gradually decreased and was not related to toxicant concentration. PMID- 28002327 TI - A Bayesian network meta-analysis of three different surgical procedures for the treatment of humeral shaft fractures. AB - BACKGROUND: The optimal surgical procedure for humeral shaft fractures remains a matter of debate. We aimed to establish the optimum procedure by performing a Bayesian network meta-analysis. METHODS: PubMed, EMBASE, the Cochrane Library, and Medline were searched for both randomized controlled trials and prospective studies of surgical treatment for humeral shaft fractures. The quality of the included studies was assessed according to the Cochrane Collaboration's "Risk of bias". RESULTS: Seventeen RCTs or prospective studies were included in the meta analysis. The pooled results showed that the occurrence rate of radial nerve injury was lowest for minimally invasive plate osteosynthesis (MIPO; SUCRA probability, 95.1%), followed by open reduction and plate osteosynthesis (ORPO; SUCRA probability, 29.5%), and was highest for intramedullary nailing (IMN; SUCRA probability, 25.4%). The aggregated results of pairwise meta-analysis showed no significant difference in radial nerve injury rate when comparing ORPO versus IMN (OR, 1.92; 95% CI, 0.96 to 3.86), ORPO versus MIPO (OR, 3.38; 95% CI, 0.80 to 14.31), or IMN versus MIPO (OR, 3.19; 95% CI, 0.48 to 21.28). Regarding the nonunion, SUCRA probabilities were 90.5%, 40.2%, and 19.3% for MIPO, ORPO, and IMN, respectively. The aggregated results of a pairwise meta-analysis also showed no significant difference for ORPO versus IMN (OR, 0.83; 95% CI, 0.41 to 1.69), ORPO versus MIPO (OR, 2.42; 95% CI, 0.45 to 12.95), or IMN versus MIPO (OR, 2.49; 95% CI, 0.35 to 17.64). CONCLUSION: The current evidence indicates that MIPO is the optimum choice in the treatment of humeral shaft fractures and that ORPO is superior to IMN. PMID- 28002328 TI - Chronic disseminated intravascular coagulation induced by left atrial thrombus in a patient with giant "normal" heart: A case report. AB - INTRODUCTION: We herein describe a patient with chronic disseminated intravascular coagulation (DIC) induced by a giant thrombus in the left atrium.A 63-year-old woman was admitted to our hospital for evaluation of extensive mucocutaneous hemorrhage, especially at the sites of venipuncture, on May 21, 2015. Considering her long history of rheumatic heart disease and atrial fibrillation and her mitral valve replacement performed several years previously, we strongly suspected that the bleeding was closely related to postoperative over anticoagulation of warfarin. After careful investigation, we found that her coagulopathy was induced by the chronic DIC, which was in turn secondary to a left atrial giant thrombus. This is a rarely reported cause of chronic DIC. Cardiac computed tomography and echocardiography showed apparent biatrial enlargement; the morphology and function of the ventricles were unaffected. After anticoagulant therapy, the bleeding tendency and coagulation index were significantly improved. CONCLUSION: A left atrial thrombus should be considered as a differential diagnosis of chronic DIC, especially in patients with predisposing heart conditions. Because treatment of the underlying cause is paramount in the management of chronic DIC, this case is of great clinical value. PMID- 28002329 TI - Incidental pancreatic cystic neoplasms in an asymptomatic healthy population of 21,745 individuals: Large-scale, single-center cohort study. AB - Although incidental pancreatic cystic neoplasms are being diagnosed with increasing frequency, little is known about the accurate prevalence of pancreatic cysts in the general population. The aims of this study were to evaluate the crude prevalence rate of pancreatic cystic neoplasms in asymptomatic healthy adults, and calculate the age- and sex-adjusted nationwide prevalence rate.A total of 21,745 asymptomatic individuals who underwent abdominal computed tomography (CT) as a health screening examination were enrolled between 2003 and 2013 at the Seoul National University Hospital Healthcare System Gangnam Center. Nationwide population data of 2010 were collected from the National Statistical Office, Korea.Incidental pancreatic cystic neoplasms were found in 457 individuals whose mean age was 58.7 years. The types of neoplasms were reviewed by 2 separate designated radiologists and the final diagnosis was made as follows: intraductal papillary mucinous neoplasm: 376 (82%), serous cystic neoplasm: 19 (4%), mucinous cystic neoplasm: 7 (2%), and indeterminate cysts: 55 (12%). Eight cases underwent operation. The crude prevalence rate was 2.1% and the age- and sex-adjusted expected nationwide prevalence was 2.2%. The prevalence increased with age.Here, we reported the first large-scale study among the healthy population to find out the prevalence rate of pancreatic cystic neoplasms; the age- and sex-adjusted prevalence was 2.2%, and increased with age. Further investigations regarding the clinical implications of incidental pancreatic neoplasms are necessary. PMID- 28002330 TI - Isolated metastasis of hepatocellular carcinoma in the right ventricle: A case report. AB - Metastatic hepatocellular carcinoma (HCC) of the right ventricle is very rare and difficult to diagnosis.A 79-year-old man who underwent right hemi-hepatectomy for HCC was admitted to our hospital for chest pain, severe dyspnea, and orthopnea. The echocardiogram showed a tumor located in the right ventricle. A biopsy was obtained, and histopathological findings confirmed metastatic HCC. Palliative resection of the tumor was performed.There is no standard treatment for metastatic HCC into the right ventricle. Thus, treatment should be individualized to the patient, and a multidisciplinary approach should be used. PMID- 28002331 TI - Hepatic perivascular epithelioid cell tumor: Case report and brief literature review. AB - RATIONAL: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm which expresses both myogenic and melanocytic markers. PEComas are found in a variety locations in the body, but up to now only approximately 30 cases about hepatic perivascular epithelioid cell tumor are reported in English language worldwide. PATIENT CONCERNS: A 32-year-old woman was admitted in our hospital with intermittent right upper quadrant pain for 1 month and recent (1 day) progressive deterioration. DIAGNOSES: Based on the results of the laboratory examinations and the findings of the computed tomography, the diagnosis of hepatic hamartoma or the hepatocecullar carcinoma with hemorrhage was made. INTERVENTIONS: The patient underwent a segmentectomy of the liver, and the finally diagnosis of hepatic PEComa was made with immunohistochemical confirmation with HMB-45 and SMA. OUTCOMES: There is no clinical or radiographic evidence of recurrence 9 months after surgery. LESSONS: This kind of tumor is extremely rare and the natural history of PEComa is uncertain, as the treatment protocol for hepatic PEComa has not reached a consensus. But the main treatment of the disease may be surgical resection. Only after long term follow-up can we know whether the tumor is benign or malignant. It appears that longer clinical follow-up is necessary in all patients with hepatic PEComas. PMID- 28002332 TI - The association of the MTHFR C677T polymorphism with inflammatory bowel diseases in the Israeli Jewish population: An example of genetic heterogeneity. AB - MTHFR C677T is a common gene polymorphism that has been shown to be associated with hyperhomocysteinemia. Studies on the role of MTHFR in inflammatory bowel diseases (IBD) have yielded conflicting results, perhaps due in part to genetic heterogeneity. The prevalence of the MTHFR C677T variant allele varies according to Jewish subpopulations: Ashkenazi vs non-Ashkenazi. The aim of this study was to examine the association between MTHFR C677T genotype and IBD in the different Jewish populations.DNA samples were assessed for the presence of the MTHFR C677T variant allele in 445 Jewish Israeli IBD patients: 338 with Crohn's disease [CD] (214 Ashkenazi and 124 non-Ashkenazi Jews) and 107 with ulcerative colitis [UC] (73 Ashkenazi and 34 non-Ashkenazi Jews), and in 347 healthy controls: 173 Ashkenazi and 174 Non-Ashkenazi Jews. Possible genotype-phenotype associations were investigated.We showed a significantly higher frequency of MTHFR 677T variant genotypes in non-Ashkenazi CD patients: Odds ratio of 1.86 for heterozygotes (CT) and 2.89 for homozygotes (TT) compared to non-Ashkenazi healthy controls. No significant association was found for UC in non-Ashkenazi patients or for CD or UC in Ashkenazi patients.Our findings suggest that the MTHFR 677T variant may contribute to the risk of CD in non-Ashkenazi but not Ashkenazi Jews. This may result from genetic heterogeneity and highlights the complexity of the genetic etiology of IBD. PMID- 28002333 TI - Impact of blue-light filtering intraocular lens implantation on the quality of sleep in patients after cataract surgery. AB - BACKGROUND: There are 2 main types of intraocular lens (IOL) currently implanted in patients after cataract surgery. Till now, we do not know exactly what the effect of intraocular lens implantation will be on the quality of sleep after cataract surgery. METHODS: The binocular BF-IOL (BF-IOL Groups) and UVB-IOL (UVB IOL Groups) implantations were performed in 60 and 59 cataract patients, respectively. Pittsburgh Sleep Quality Index (PSQI) questionnaires were administered to evaluate the quality of sleep in patients preoperatively, 1 month (1 m) and 12 months (12 m) postoperatively. Independent sample test and chi test were used to evaluate the difference between the 2 groups; one-way ANOVA was used to evaluate the difference preoperatively and postoperatively in each group. The rank sum test was used for statistical analysis of 7 independent sleep components in PSQI. RESULTS: As compared to preoperatively, the PSQI overall scores in both groups improved significantly postoperatively (P = 0.00 at 1 m and 12 m). Among the 7 components of PSQI, 2 of them (sleep latency and daytime dysfunction) improved greatly postoperatively in both groups (P< 0.05). Although the improvement of PSQI overall score in the UVB-IOL group was greater than that in the BF-IOL Group only at early time (1 m) postoperatively (P = 0.00), but not late time (12 m, P > 0.05) after the cataract surgery. CONCLUSION: The sleep quality of cataract patients improved after IOL implantation, regardless of the type of IOL, suggesting that BF-IOL might serve as an alternative to conventional UVB-IOL without a detrimental effect on quality of sleep after cataract surgery. PMID- 28002334 TI - Gender differences among patients with primary ankylosing spondylitis and spondylitis associated with psoriasis and inflammatory bowel disease in an iberoamerican spondyloarthritis cohort. AB - The aim of the study was to compare clinical manifestations, disease activity, functional capacity, spinal mobility, and radiological findings between men and women from a multicenter, multiethnic Ibero-American cohort of patients with Spondyloarthritis (SpA).This observational cross-section study included 1264 consecutive SpA patients who fulfilled the modified New York criteria for ankylosing spondylitis (AS). Demographic, clinical, and radiologic data were evaluated. Categorical data were compared by X or Fisher's exact tests and continuous variables by ANOVA with post-hoc tests.Primary AS was diagnosed in 1072 patients, psoriatic spondylitis in 147, and spondylitis associated to inflammatory bowel disease (IBD) in 45 patients. Overall, male patients were significantly younger, had longer diagnostic delay, lower disease activity, worse spinal mobility, better quality of life, and more severe radiologic damage. Dactylitis and enthesitis, as well as swollen joint count, were significantly more common among women. In primary AS, there was a marked male predominance (76.2%). Among patients with psoriatic spondylitis, male predominance was lower (57.8%), but was also associated with worse spinal mobility and more severe radiologic damage. In the total population, male patients with primary AS referred higher permanent work disability (13.2% vs 6.9%; P < 0.05), although no difference was observed in psoriatic or IBD spondylitis according to the gender.Among Ibero-American SpA patients, there are some differences in clinical and radiological manifestations, men showing more structural damage, whereas women more active disease. These data suggest that the phenotype of SpA differs between genders. This can influence the subsequent diagnostic approach and therapeutic decisions. PMID- 28002335 TI - Spatial and temporal variations of screening for breast and colorectal cancer in the United States, 2008 to 2012. AB - Cancer screening tests are important tools to combat cancer-related morbidity and mortality. There is limited up-to-date research on spatial and temporal variations of colorectal and breast cancer screening in the United States.County level data of cancer screening adherence rates were generated from 2008 to 2012 Behavioral Risk Factor Surveillance System. We performed the univariate local indicators for spatial analyses (LISA) for the geographic differences of screening adherence rate and the differential LISA for the change of screening adherence rate from 2008 to 2012.In the univariate LISA, low-to-low clusters were consistently identified in counties of New Mexico, Wyoming, and Mississippi (P < 0.05) for both screenings. In the differential LISA, we found low-to-low clusters in Indiana counties (P < 0.05) for mammography screening, which implied that counties with a below-average difference in mammography adherence were surrounded by counties of below-average difference in adherence rates. A high-to-high cluster was also identified in the southern Appalachian counties for mammography screening (P < 0.05). No obvious spatial pattern was found for the colorectal cancer screening adherence rate across the United States.We found low-to-low clusters over time in adherence to screening guidelines for both cancer types in New Mexico, Wyoming, and Mississippi, and clusters of potential decrease in adherence to mammography screening guideline in counties of Indiana. The study also showed improvement on mammography screening clustered in southern Appalachia. The methodology adopted in this study identified areas with clusters of consistent low adherence to screening and a decrease in adherence, which implies that further research and intervention is warranted. PMID- 28002336 TI - The utility of gadoxetic acid-enhanced magnetic resonance imaging in the surveillance for postoperative recurrence of hepatocellular carcinoma. AB - This study aimed to investigate the utility of gadoxetic acid-enhanced magnetic resonance imaging (Gd-MRI) in surveillance for recurrent hepatocellular carcinoma (HCC) after hepatectomy.This retrospective study analyzed 147 patients who underwent surveillance with alternating multidetector computed tomography (MDCT) and Gd-MRI after hepatectomy for HCC. The patients were followed-up every 3 months during the first 2 years, and every 6 months thereafter. At each visit, MDCT was performed but once a year (every 12 months), Gd-MRI was performed instead of MDCT. Each HCC recurrence detection rate of MDCT and Gd-MRI was evaluated, and recurrent HCC characteristics were compared according to the detection test.A total of 63 patients had recurrent HCC. Among them, 9 were detected with Gd-MRI and 29 with MDCT. The baseline characteristics of patients with recurrent HCC showed no significant differences according to the detection test. The HCC recurrence detection rate of Gd-MRI and MDCT was 4.8% (9/180) and 4.3% (29/580), respectively, on the per test basis (P = 0.764). However, in the population with a follow-up period of >=12 months, the detection rate of Gd-MRI and MDCT was 4.3% (7/150) and 1.5% (19/400), respectively (P = 0.035). Recurrent HCCs detected with Gd-MRI were smaller than those detected with MDCT (tumor size < 2 cm, 100% vs 65.5%, P = 0.040).Our data suggest that Gd-MRI has advantages in detecting recurrent HCC after hepatectomy. Surveillance with alternating MDCT and Gd-MRI may identify more recurrent HCC in an early stage than with MDCT alone in patients who received hepatectomy for HCC. PMID- 28002337 TI - Anti-CD19 chimeric antigen receptor T-cell therapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia: Two case reports. AB - RATIONALE: The presence of the Philadelphia chromosome (Ph) in acute lymphoblastic leukemia (ALL) has been associated with a high risk of disease relapse and a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for adults with Ph-positive ALL, but relapse remains the primary cause of treatment failure, and is associated with an extremely poor prognosis. The emergence of resistance to tyrosine kinase inhibitors (TKIs) poses a challenge for patients with disease relapses after initial treatment with TKI-containing regimens. PATIENT CONCERNS: Two patients with TKI-resistant recurrent Ph-positive ALL. DIAGNOSES: Ph-positive ALL. INTERVENTIONS: Anti-CD19 CAR T-cell infusion. OUTCOMES: One patient's bone marrow blasts decreased significantly, and the other reached negative minimal residual disease (MRD). However, we first recorded the development of new-onset acute graft-versus-host disease (aGVHD) after anti-CD19 CAR T-cell infusion in a patient who received allogeneic HSCT. Our 2 case reports also demonstrate the efficacy of anti-CD19 CAR T-cell therapy in the treatment of TKI-resistant Ph positive ALL. LESSONS: Our report suggests that anti-CD19 CAR T-cell therapy may be a promising option for the treatment of relapsed Ph-positive ALL after conventional chemotherapy or allogeneic HSCT. However, caution is due given the possibility of the adverse effects of cytokine release syndrome (CRS)-induced aGVHD for patients receiving allogeneic HSCT. PMID- 28002338 TI - Sputum pentraxin 3 as a candidate to assess airway inflammation and remodeling in childhood asthma. AB - Pentraxin 3 (PTX3) is a soluble pattern recognition receptor and an acute-phase protein. It has gained attention as a new biomarker reflecting tissue inflammation and damage in a variety of diseases. Aim of this study is to investigate the role of PTX3 in childhood asthma.In total, 260 children (140 patients with asthma and 120 controls) were enrolled. PTX3 levels were measured in sputum supernatants using enzyme-linked immunosorbent assay test. We performed spirometry and methacholine challenge tests and measured the total eosinophil count and the serum levels of total IgE and eosinophil cationic protein (ECP) in all subjects.Sputum PTX3 concentration was significantly higher in children with asthma than in control subjects (P < 0.001). Furthermore, sputum PTX3 levels correlated with atopic status and disease severity among patients with asthma. A positive significant correlation was found between sputum PTX3 and the bronchodilator response (r = 0.25, P = 0.013). Sputum PTX3 levels were negatively correlated with forced expiratory volume in 1 second (FEV1) (r = -0.30, P = 0.001), FEV1/forced vital capacity (FVC) (r = -0.27, P = 0.002), and FEF25-75 (r = -0.392, P < 0.001), which are indicators of airway obstruction and inflammation. In addition, the PTX3 concentration in sputum showed negative correlations with post-bronchodilator (BD) FEV1 (r = -0.25, P < 0.001) and post BD FEV1/FVC (r = -0.25, P < 0.001), which are parameters of persistent airflow limitation reflecting airway remodeling.Sputum PTX3 levels increased in children with asthma, suggesting that PTX3 in sputum could be a candidate molecule to evaluate airway inflammation and remodeling in childhood asthma. PMID- 28002339 TI - Delayed treatment of septic arthritis in the neonate: A review of 52 cases. AB - There is still controversy on the management of septic arthritis in neonates. This study aims to investigate the treatment of septic arthritis in neonates.We reviewed 52 neonates (37 males and 15 females) with septic arthritis in our hospital during 2004 to 2015. The mean age at onset of infection was 17.5 +/- 7.6 days, mean age at admission was 32.6 +/- 10.7 days. A total of 56 joints were involved (22 knees, 18 shoulders, 13 hips, and 3 other joints). Thiryt-six patients underwent surgical drainage, 14 patients were treated nonoperatively, 2 families refused treatment. Forty-four patients (48 joints) were followed for 4.5 +/- 1.2 years. Based on treatment, these 48 joints were divided into an operative group and a nonoperative group. Clinical presentations, imaging examination results, treatments, and outcomes were analyzed.Among the patients who were followed-up, the time from onset to treatment in the operatively managed group (12.7 +/- 8.1 days) was significantly shorter than that in the conservatively managed group (20.0 +/- 8.2 days). There were no significant differences between both groups on the age at onset, age at admission, imaging score, length of hospital stay, WBC counts, and intravenous medication time. Thirty-five sites (72.9%) recovered completely. There was no significant difference on recovery rate between operative and nonoperative group. Only 33.3% of the hips recovered, this was significantly lower than that of knee/ankle (85.0%) and shoulder/elbow (78.9%). Sequels were found in 13 joints. Logistic regression indicated that sex, imaging score, and hip joint involvement were predictors of sequel. One point of imaging score increased the risk of sequels by a factor of 2.960, and hip joint involvement increased the risk of sequels by a factor of 12.712. Females were more likely to have sequels than males.Surgical drainage is recommended for early diagnosed neonatal septic arthritis and hip infections. A conservative approach may be more efficient for patients whose diagnosis and treatment had been delayed for more than 2 weeks. Antibiotics should be administered intravenously for 2 weeks and then orally for another 2 weeks. First-generation cephalosporin and clindamycin are recommended empirical antibiotics before causative agent and its resistance pattern are known. PMID- 28002340 TI - PEAR1 gene polymorphism in a Chinese pedigree with pulmonary thromboembolism. AB - To explore the correlation between platelet endothelial aggregation receptor-1 (PEAR1) genetic polymorphism and pulmonary thromboembolism (PTE).Variant loci of the PEAR1 gene were screened in a PTE pedigree, followed by verification using Sanger sequencing. These polymorphic loci were validated in 101 PTE patients and 132 matched normal patients using MassARRAY single nucleotide polymorphism (SNP) genotyping methods. The frequency differences between the allele and genotypes were compared using the Hardy-Weinberg equilibrium test and Chi-square test. The correlation between the PEAR1 gene SNP and PTE was analyzed by comparing the between-group variance differences using the chi test.Three SNPs were identified in the PTE pedigree. There was a heterozygous transition of T>C in rs1952294, and a transition of C>T in rs778026543 in 2 members in the pedigree; however, the rs778026543 was not identified in the 101 PTE patients and 132 healthy controls. The genotype and allele frequencies of rs822442 did not differ significantly between PTE patients and healthy controls (P > 0.05). The variance difference at rs778026543 between pedigree members and healthy controls was significant (P < 0.001), supporting its potential heredity.The PEAR1 polymorphism, rs778026543, but not rs1952294 and rs822442, may be a susceptibility SNP for PTE. PMID- 28002341 TI - Salvianolate injection in the treatment of unstable angina pectoris: A systematic review and meta-analysis. AB - BACKGROUND: To systematically evaluate the clinical efficacy and safety of Salvianolate injection in the treatment of unstable angina pectoris (UAP). METHODS: Using literature databases, we conducted a thorough and systematic retrieval of randomized controlled trials (RCTs) that using Salvianolate injection for treating UAP. The Cochrane Risk of Bias Assessment Tool was used to evaluate the methodological quality of the RCTs, and then the data were extracted and meta-analyzed by RevMan5.2 software. RESULTS: A total of 22 RCTs with 2050 participants were included. The meta-analysis indicated that the combined use of Salvianolate injection and western medicine (WM) in the treatment of UAP can achieve a superior effect in angina pectoris total effective rate (risk ratio [RR] = 1.22, 95% confidence interval [CI] (1.17, 1.27), Z = 10.15, P < 0.00001], and the total effectiveness rate of electrocardiogram [RR = 1.26, 95% CI (1.19,1.34), Z = 7.77, P < 0.00001]. In addition, Salvianolate injection can improve the nitroglycerin withdrawal rate and the serum level of NO, decrease high-sensitivity C-reactive protein. Adverse drug reactions (ADRs) or adverse drug events (ADEs) were reported in 6 RCTs involving 15 cases; however, there were no serious ADRs/ADEs. CONCLUSION: Based on the systematic review, the combined use of Salvianolate injection and WM in the treatment of UAP can achieve a better effect; however, there was no definitive conclusion about its safety. More the large-sample and multicenter RCTs are needed to support its clinical usage. PMID- 28002342 TI - Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE compliant study. AB - We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 (n = 88) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy. Patients in arm 2 (n = 90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P = 0.003]) as well as 5-year OS (34.1% and 18.9% [P = 0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P = 0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer. PMID- 28002343 TI - Florid reactive periostitis in the fifth phalange of a professional boxer: A case report. AB - RATIONALE: Florid reactive periostitis is a rare, benign bone and chondrogenic lesion that develops most frequently in the phalanges of the hands. Although the definitive cause of florid reactive periostitis is unknown, the major inciting factor is generally considered to be trauma, including repetitive minor trauma. PATIENT CONCERNS: We present a case of florid reactive periostitis affecting two contiguous phalangeal bones of the left fifth phalange of a 23-year-old male professional boxer. The patient had experienced chronic pain around the metacarpophalangeal joint of the left fifth phalange when punching with the left hand; this pain was improved but not resolved after conservative treatment. INTERVENTIONS: Plain radiography of the fifth phalange revealed a bulging bone lesion on the volar side of the proximal phalanx and metacarpal of the left fifth phalange. Computed tomography also showed raised bony lesions on the volar side of these bones without bony destruction or intraregional calcification. Surgery was performed and histopathology revealed that the bone specimens comprised a mixture of fibrous connective tissue and relatively immature bone covered by bland osteoblasts. DIAGNOSES: These findings were suggestive of a benign bone formation process, and the lesion was diagnosed as florid reactive periostitis. OUTCOMES: The pain and tenderness in the left fifth phalange experienced during boxing had completely resolved by 6 months postoperatively, and 12 years postoperatively the patient had full range of motion and no recurrence of pain. LESSONS: Traction force, such as those associated with "leading jabs," may induce repetitive minor trauma and subsequent periosteal damage, resulting in the gradual development of bulging bone ridges on the volar surface of the proximal fifth phalange and metacarpus of the hand. PMID- 28002344 TI - The role of ultrasound in the management of undescended testes before and after orchidopexy - an update. AB - The aim of this study was to evaluate the testicular volume and structure using ultrasound (US) before and up to 3 years after orchidopexy in children with different age.A total of 128 patients underwent orchidopexy for undescended testes. Afterwards, patients were invited for annual follow-up and control scrotal US. The total number of analyzed testes after orchidopexy was 184. Patients were divided according to age at the time of surgery: group I (2-4 years old), group II (5-7), and group III (8-10). In all patients, the testicular volume ratio was calculated as the operated testes volume versus the control testes mean volume.There was an increase in the median ratio in all age groups, from 0.86 to 0.95 in group I, 0.82 to 0.92 in group II and 0.78 to 0.90 in group III. In group of the patients 2 to 4 years old the growth of the ratio 3 years after surgery was statistically significant.Abnormalities in the structure of the testes, which may indicate severe damage to the testis, were seen in approximately 20% of patients on initial exams. On follow-up exams, this type of structure remained in 7% of patients. Testes with an initial ratio <0.25 and inhomogeneous structure did not show any significant growth.Scrotal US can be used for an accurate comparative assessment of the structure and growth of the testes before and after orchidopexy.Abnormalities in the structure of the testes may identify testes requiring more advanced methods of evaluation. PMID- 28002345 TI - Comparison of the more than 5-year clinical outcomes of cervical disc arthroplasty versus anterior cervical discectomy and fusion: A protocol for a systematic review and meta-analysis of prospective randomized controlled trials. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) was almost the "golden standard" technique in treatment of symptomatic cervical degenerative disc disease, however, it cause motion loss of the indexed level, increase the intradiscal pressure and motion of the adjacent levels, and may accelerate the degeneration of adjacent level. Cervical disc arthroplasty (CDA) was designed to preserve the motion of index level, avoid the over-activity of adjacent levels and reduce the degeneration of adjacent disc levels, the process of degeneration of adjacent level is very slowly, long term follow up studies should be conducted, this study aim to compare the more than 5 years' long-term clinical outcomes and safety between CDA and ACDF. METHODS: A systematic review and meta analysis that will be performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The electric database of Medline, Embase, and Cochrane library will be systematic search. A standard data form will be used to extract the data of included studies. We will assess the studies according to the Cochrane Handbook for Systematic Reviews of Interventions, and perform analysis in software STATA 12.0. Fixed-effects models will be used for homogeneity data, while random-effects will be used for heterogeneity data. The overall effect sizes will be determined as weighted mean difference (WMD) for continuous outcomes and Relative risk (RR) for dichotomous outcomes. RESULTS: The results of study will be disseminated via both international conference and peer-review journal. CONCLUSION: The conclusion of our study will provide the long-term and updated evidence of clinical outcomes and safety between CDA and ACDF, and help surgeon to change better surgical technique for patients. PMID- 28002346 TI - The preoperative alkaline phosphatase-to-platelet ratio index is an independent prognostic factor for hepatocellular carcinoma after hepatic resection. AB - A simple, inexpensive, and readily available prognostic index is highly needed to accurately predict the prognosis of hepatocellular carcinoma (HCC). This study aimed to develop a simple prognostic index using routine laboratory tests, alkaline phosphatase-to-platelet count ratio index (APPRI), to predict the likelihood of postoperative survival in HCC patients.A total of 246 patients with HCC undergoing curative resection were retrospectively analyzed. Cutoff point for APPRI was calculated using receiver operating characteristic curve analysis, and then the patients were divided into the low-APPRI group (APPRI <= 4.0) and the high-APPRI group (APPRI > 4.0). The influences of APPRI on disease-free survival (DFS) and overall survival (OS) were tested by the Kaplan-Meier method, and multivariate analysis using Cox regression. Elevated APPRI was associated with age, cirrhosis, and aspartate aminotransferase (AST) in HCC. Univariate analysis showed that APPRI > 4.0, tumor size >6 cm, multiple tumors, Barcelona-clinic liver cancer stages B to C, and AST > 40 U/L were significant predictors of worse DFS and OS. A multivariate analysis suggested that APPRI > 4.0 was an independent factor for DFS (hazard ratio [HR] = 1.689; 95% confidence interval [CI], 1.139 2.505; P = 0.009) and OS (HR = 1.664; 95% CI, 1.123-2.466; P = 0.011). Preoperative APPRI > 4.0 was a powerful prognostic predictor of adverse DFS and OS in HCC after surgery. The APPRI may be a promising prognostic marker for HCC after surgical resection. PMID- 28002348 TI - To the Editor. PMID- 28002347 TI - McGrath Series 5 videolaryngoscope vs Airtraq DL videolaryngoscope for double lumen tube intubation: A randomized trial. AB - BACKGROUND: Many studies have shown Airtraq videolaryngoscope provided faster tracheal intubation and a higher success rate than other videolaryngoscopes. Recently, different types of videolaryngoscopes have been reported for use in double-lumen tube (DLT) intubation. However, the advantages and disadvantages between them remain undetermined for DLT intubation. In this study, we compared the Airtraq DL videolaryngoscope with the McGrath Series 5 videolaryngoscope for DLT intubation by experienced anesthesiologists. METHODS: Ninety patients with expected normal airways were randomly allocated to either the Airtraq or McGrath group. The primary outcome was DLT intubation time. The secondary outcomes were glottic view, success rate, subjective ease of intubation (100-mm visual analog scale, 0 = easy; 100 = difficult), incidence of DLT malposition, and postoperative intubation-related complication. RESULTS: The airway characteristics were comparable between the 2 groups. Cormack and Lehane grades significantly improved with the use of the McGrath and Airtraq videolaryngoscopes, compared with the Macintosh laryngoscope. The intubation success rate on the first attempt was 93% in the Airtraq group and 95% in the McGrath group (P > 0.05). The intubation time in the McGrath group is longer than that in the Airtraq group (39.9 [9.1]s vs 28.6 [13.6]s, P < 0.05). But intubation difficulty score, the incidence of DLT malposition and intubation-related complication were comparable between groups (P > 0.05). CONCLUSIONS: When using videolaryngoscopes for DLT intubation, the Airtraq DL is superior to the McGrath Series 5 in intubation time, but it does not decrease intubation difficulty. PMID- 28002349 TI - In Reply. PMID- 28002350 TI - In Reply. PMID- 28002351 TI - Associations Between Supportive Leadership Behavior and the Costs of Absenteeism and Presenteeism: An Epidemiological and Economic Approach. AB - OBJECTIVE: This study investigates associations between supportive leadership behavior (SLB) and presenteeism/absenteeism, and estimates related costs. METHODS: Cross-sectional data from a German industrial sample (n = 17,060) assessing SLB and presenteeism/absenteeism were used. Adjusted interval regressions were performed. The study population was split into tertiles with respect to SLB, and minimum and maximum costs for each tertile were estimated on the basis of national industry averages. RESULTS: Low SLB was associated with higher presenteeism [-0.31, 95% confidence interval (95% CI) -0.33 to -0.28)] and absenteeism (-0.36, 95% CI -0.40 to -0.32). Compared with high SLB, the costs of low SLB for absenteeism are between 534.54 and 1675.16 Euro higher per person and year. For presenteeism, this difference ranges between 63.76 and 433.7 Euro. CONCLUSIONS: SLB has the potential to reduce absenteeism, presenteeism, and associated costs. To contribute to workforce health, productivity, and efficiency, SLB merits being fostered by corporate policy. PMID- 28002352 TI - The Positive Effect of Resilience on Stress and Business Outcomes in Difficult Work Environments. AB - OBJECTIVE: To examine whether resilience has a protective effect in difficult work environments. METHODS: A survey of 2063 individuals measured individual resilience, stress, burnout, sleep problems, likelihood of depression, job satisfaction, intent to quit, absences, and productivity. It also measured work characteristics: job demands, job influence, and social support. Multivariate and logistic regression models examined the main effects and interactions of resilience and job characteristics. RESULTS: High strain work environments (high demand, low influence, and low support) have an unfavorable effect on all outcomes. Resilience has a protective effect on all outcomes. For stress, burnout, and sleep, higher resilience has a more protective effect under low strain conditions. For depression, absence and productivity, resilience has a more protective effect when job strain is high. CONCLUSIONS: Workers with high resilience have better outcomes in difficult work environments. PMID- 28002353 TI - Ambient PM2.5 Aluminum and Elemental Carbon and Placental Abruption Morbidity. AB - PURPOSE: The aim of this study was to assess relationship between exposure to particulate matter (PM) chemicals during pregnancy and the odd of having placental abruption. METHODS: The 2004 to 2007 Florida linked birth certificate records and the Environmental Protection Agency PM speciation data were used. We were interested in placental abruption. We computed adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The odds for placental abruption were increased per interquartile range (IQR) increase in aluminum during the first trimester (OR = 1.10; CI = 1.02 to 1.18) and marginally during the entire pregnancy (OR = 1.06; CI = 0.94 to 1.19). The most substantial association was observed for elemental carbon exposure during the first trimester, resulting in 38% increased odd (OR = 1.09; CI = 1.09 to 1.75) per IQR increase in elemental carbon. CONCLUSION: Women exposure to PM2.5 aluminum and elemental carbon during pregnancy has an increased odd of having placental abruption. PMID- 28002354 TI - Association Between Cardiovascular Disease Risk Factors and Rotator Cuff Tendinopathy: A Cross-Sectional Study. AB - OBJECTIVE: Recent evidence has found potential associations between cardiovascular disease (CVD) risk factors and common musculoskeletal disorders. We evaluated possible associations between risk factors and both glenohumeral joint pain and rotator cuff tendinopathy. METHODS: Data from WISTAH hand study participants (n = 1226) were assessed for associations between Framingham Heart Study CVD risk factors and both health outcomes. RESULTS: A strong association was observed between CVD risk scores and both glenohumeral joint pain and rotator cuff tendinopathy. Peak odds ratios (ORs) of the adjusted models were 4.55 [95% confidence interval (95% CI) 1.97 to 10.31] and 5.97 (95% CI 2.12 to 16.83), respectively. The results show a dose-response trend of increasing risk. CONCLUSIONS: Individual risk factors were associated with both outcomes. Combined, CVD risk factors demonstrated a strong correlation with glenohumeral joint pain and an even stronger correlation with rotator cuff tendinopathy. Results suggest a potentially modifiable disease mechanism. PMID- 28002355 TI - Honest Labor Bears a Lovely Face: Will Late-Life Unemployment Impact Health and Satisfaction in Retirement? AB - OBJECTIVE: Unemployment among older adults during recessionary cycles has been tied to early retirement decisions and negative health outcomes. This study explored episodes of unemployment experienced between age 50 and retirement as predictors of retirement age and health outcomes. METHODS: A total of 1540 participants from the U.S. Health and Retirement Study aged 50 years and older who transitioned from workforce to retirement were analyzed with descriptive statistics and multiple regression controlling for unemployment, demographics, and health status. RESULTS: Late-life unemployment significantly related to earlier retirement age and lowered life satisfaction, independent of income effects. We found no main effect for late-life unemployment on physical health status. CONCLUSIONS: Potential improvements in future life satisfaction might be gained if job search obstacles are removed for older unemployed adults, reducing reliance on involuntary early retirement as an income source. PMID- 28002356 TI - Association of Birthweight With Maternal Trajectories of Effort-Reward Imbalance and Demand-Control Across Pregnancy. AB - OBJECTIVES: We assessed longitudinal patterns of effort-reward imbalance (ERI) and demand-control (DC) scores in pregnancy, and their association with newborn birthweight (BW). METHODS: Sixty-one women were surveyed four times across pregnancy using the ERI and DC questionnaires. Trajectories of change in ERI and DC scores across pregnancy were constructed using growth mixture modeling, and their associations with BW were examined with generalized linear regression. RESULTS: Declining ERI (diminishing effort with stable/increasing reward) was associated with higher BW (408 g; P = 0.015), and was robust to other work factors. DC trajectory was not significantly associated with BW. CONCLUSIONS: Declining ERI may reflect improved work psychosocial climate across pregnancy, or a conscious reduction in effort. The ERI model may represent more flexible work characteristics, whereas job control may be less amenable to short-term alteration. Surveys in more diverse pregnant working populations could be recommended. PMID- 28002357 TI - Pediatric Sacroiliitis: Clinical and Microbiologic Differences Between Infants and Children-Adolescents. AB - BACKGROUND: The aim of this study was to improve knowledge of pediatric pyogenic sacroiliitis (PSI) in the pediatric population based on a consecutive case series. METHOD: We conducted a single-center cross-sectional study on 16 patients admitted to the emergency department of our Hospital between January 1990 and December 2015 with a confirmed diagnosis of PSI. The patients were divided into 2 groups by age: infants (6 months to 4 years) and children-adolescents (4-16 years). The features of PSI, clinical signs and symptoms, laboratory tests, bacteriologic investigations, radiologic examinations and outcome were compared among the 2 groups. RESULTS: Patients in the children-adolescent group usually presented with a history of limping and buttock or lower back pain, and methicillin-susceptible Staphylococcus aureus was the most frequent pathogen. We observed a second peak of incidence of PSI in infants with consistent difference in clinical and microbiologic presentation. Infants were more likely to have an ambiguous onset with the refusal to bear weight as the only consistent clinical manifestations, and biologic investigations demonstrated higher erythrocyte sedimentation rate and platelet counts. However, all blood and joint fluid cultures were sterile in the infant group. CONCLUSION: PSI in infants and adolescents may represent 2 different conditions. Although PSI is mainly caused by S. aureus in the children-adolescent group, clinical manifestations and biologic characteristics of PSI in infants suggest Kingella kingae as the etiology osteoarticular infection. Thus, oropharyngeal swab polymerase chain reaction assay for K. kingae and magnetic resonance imaging should be considered for early diagnosis and treatment of this condition in the younger age group. PMID- 28002358 TI - An Outbreak of Kingella Kingae Infections Complicating a Severe Hand, Foot, And Mouth Disease Outbreak in Nice, France, 2016. AB - We report the investigation methods for the diagnosis of an epidemic and culture negative Kingella kingae endocarditis complicating a severe outbreak of hand, foot and mouth disease in a childcare center. The diagnosis was confirmed by polymerase chain reaction testing performed from cardiac tissue. Our findings argue for the systematic investigation of K. kingae outbreaks by using molecular tools in such context. PMID- 28002359 TI - Safety and Immunogenicity of the Quadrivalent Meningococcal Serogroups A, C, W and Y Tetanus Toxoid Conjugate Vaccine Coadministered With Routine Childhood Vaccines in European Infants: An Open, Randomized Trial. AB - BACKGROUND: This was the first study evaluating the immunogenicity and safety of the quadrivalent meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT) coadministered with routine childhood vaccines in young infants. METHODS: In this open, randomized, controlled, phase III study (NCT01144663), 2095 infants (ages 6 12 weeks) were randomized (1:1:1:1) into 4 groups to receive MenACWY-TT at 2, 3, 4 and 12 months of age, or MenACWY-TT, MenC-cross-reactive material (CRM197) or MenC-TT at 2, 4 and 12 months of age. All participants received PHiD-CV and DTPa HBV-IPV/Hib at 2, 3, 4 and 12 months of age. Immune responses were measured by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement. Solicited and unsolicited symptoms were recorded during 8 and 31 days post-vaccination, respectively, and serious adverse events throughout the study. RESULTS: Noninferiority of immune responses to MenC induced by 2 or 3 doses of MenACWY-TT versus 2 doses of MenC-TT or MenC-CRM197 was demonstrated. Predefined criteria for the immunogenicity of MenACWY-TT to MenA, MenW and MenY were met. One month after 2 or 3 primary MenACWY-TT doses, >=93.1% and >=88.5% of infants had rSBA and hSBA titers >=1:8 for all serogroups. The robust increases in rSBA and hSBA titers observed for all vaccine serogroups postbooster vaccination suggested that MenACWY-TT induced immune memory. MenACWY-TT coadministered with childhood vaccines had a clinically acceptable safety profile. CONCLUSIONS: This study supports the coadministration of MenACWY-TT with routine childhood vaccines as 2 or 3 primary doses during infancy followed by a booster dose in the second year of life. PMID- 28002360 TI - Evidence of Mumps Infection Among Children in the Democratic Republic of Congo. AB - BACKGROUND: Mumps is an acute viral infection and while the infection is usually mild, complications can lead to permanent sequelae including brain damage and deafness. The burden of mumps is currently unknown the Democratic Republic of Congo (DRC), we therefore assessed susceptibility to mumps infection among children 6-59 months of age. METHODS: In collaboration with the 2013-2014 DRC Demographic and Health Survey, we conducted a serosurvey to assess population immunity to vaccine preventable diseases. Dried blood spot samples were collected from children 6 to 59 months of age and processed at the UCLA-DRC laboratory in Kinshasa, DRC using the Dynex Technologies Multiplier FLEX chemiluminescent immunoassay platform (Dynex multiplex assay, Chantilly, VA). Logistic multivariate analyses were used to determine risk factors for mumps seropositivity. RESULTS: Serologic and survey data were matched for 7195, 6-59 month-old children, among whom 22% were positive and 3% indeterminate for mumps antibodies in weighted analyses. In multivariate analyses, the odds of seropositivity increased with increasing age, female gender, number of children in household, increasing socioeconomic status and province (Kinshasa with the highest odds of positive test result compared with all other provinces). CONCLUSION: These data suggest that mumps virus is circulating in DRC and risk of exposure increases with age. At present, the introduction of a combined measles mumps-rubella vaccine remains unlikely, as the capacity to maintain adequate vaccine coverage levels for routine immunization must be improved before additional antigens can be considered for the routine immunization schedule. PMID- 28002362 TI - Point of View. PMID- 28002363 TI - Comparison of Outcomes of Single-Level Anterior Cervical Discectomy With Fusion and Single-Level Artificial Cervical Disc Replacement for Single-Level Cervical Degenerative Disc Disease. AB - STUDY DESIGN: A single-center, prospective comparative study of prospectively collected outcomes, with a minimum 12 months follow-up. OBJECTIVES: The primary purpose of the study is to investigate the clinical, functional, and radiological outcomes of cervical total disc replacement (CTDR) in comparison with anterior cervical discectomy and fusion (ACDF) in the treatment of single-level cervical disc degenerative disease, prospectively. SUMMARY OF BACKGROUND DATA: CTDR has recently been an alternative to ACDF in cervical disc degenerative disease to preserve the motion at the treated level. METHODS: This study included 34 patients, who underwent either single-level ACDF (n = 17) or single-level CTDR (n = 17) at C3 to C7 level for cervical disc degenerative disease between July 2012 to April 2014 with a minimum of 12 months of follow-up. RESULTS: Neck disability index, visual analog scale, and neck-arm pain score showed significant difference between the two groups at final follow-up of 12 months. Modified orthopedic association score and Nurick scale also showed the Japanese significant difference between the two groups at final follow-up of 12 months. Odom criteria were not statistically significant between the two groups at final follow-up. The changes in overall cervical sagittal angle (CSA) were significantly different between the two groups. The segmental angle (SA) was maintained at a significantly higher value in the CTDR group than in the ACDF group during the follow-up period (P < 0.05). The range of motion of the cervical spine and the treated level was well maintained and improved in the CTDR group as compared with ACDF group and showed extremely statistically significant difference between the two groups. CONCLUSION: CTDR was found to be a safe, effective, better, and efficient alternative to the traditional ACDF. CTDR using Prestige LP cervical disc provided a statistically significant clinical, functional, and radiological outcomes between the two groups after 1-year follow-up. LEVEL OF EVIDENCE: 2. PMID- 28002364 TI - Letter. PMID- 28002365 TI - ORCID Registration Required in 2017. PMID- 28002366 TI - Salto Talaris Total Ankle Arthroplasty: Clinical Results at a Mean of 5.2 Years in 78 Patients Treated by a Single Surgeon. AB - BACKGROUND: In recent years, the number of total ankle arthroplasty procedures performed has increased dramatically. We sought to report the clinical results of the largest cohort of patients treated with a modern fixed-bearing total ankle arthroplasty by a single surgeon. METHODS: We retrospectively reviewed the charts of 78 consecutive patients (81 ankles) who underwent total ankle arthroplasty with a minimum clinical follow-up of 2 years. Sixty-three patients completed standardized questionnaires including the Foot and Ankle Disability Index (FADI), the Short Musculoskeletal Function Assessment (SMFA), the Short Form (SF)-36v2, and a visual analog scale (VAS) for pain. In addition, each patient underwent serial range-of-motion examination and radiographic implant evaluation at each follow-up appointment. RESULTS: Implant survival was 97.5% at a mean follow-up time of 5.2 years. There was 1 revision of a tibial component and 1 revision of a talar component. Thirty-six patients underwent a concurrent procedure at the time of the index surgery, with the most common being removal of previous hardware. Seventeen patients underwent additional procedures following the index surgery, with the most common being gutter debridement. Total range of motion averaged 35.5 degrees preoperatively and 39.9 degrees postoperatively (p = 0.02). Fifty seven ankles (70%) had >2 years of radiographic follow-up, and 25 ankles (31%) displayed evidence of lucency around a metallic component at the final radiographic follow-up. Outcome scores at a mean of 5.2 years revealed promising results for the cohort, with a mean VAS pain score of 17.7 and a mean FADI score of 79.1. CONCLUSIONS: Modern fixed-bearing total ankle arthroplasty had excellent implant survival, improved plantar flexion and total range of motion, and had good-to-excellent functional outcome at a mean follow-up of 5.2 years. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002367 TI - Single-Stage Revision Is Effective for Failed Shoulder Arthroplasty with Positive Cultures for Propionibacterium. AB - BACKGROUND: Revision shoulder arthroplasties are often culture-positive for Propionibacterium. This study tests the hypothesis that the functional outcomes of revising Propionibacterium culture-positive failed arthroplasties with a single-stage revision and immediate antibiotic therapy are not inferior to the clinical outcomes of revising failed shoulder arthroplasties that are not culture positive. METHODS: Fifty-five shoulders without obvious clinical evidence of infection had a single-stage revision arthroplasty. The patient self-assessed functional outcomes for shoulders with >=2 positive cultures for Propionibacterium (the culture-positive group) were compared with shoulders with no positive cultures or only 1 positive culture (the control group). RESULTS: The culture-positive group had 89% male patients, with a mean age (and standard deviation) of 63.5 +/- 7.2 years. The mean Simple Shoulder Test (SST) scores for the 27 culture-positive shoulders improved from 3.2 +/- 2.8 points before the surgical procedure to 7.8 +/- 3.3 points at a mean follow-up of 45.8 +/- 11.7 months after the surgical procedure (p < 0.001), a mean improvement of 49% of the maximum possible improvement. The control group had 39% male patients, with a mean age of 67.1 +/- 8.1 years. The mean SST scores for the 28 control shoulders improved from 2.6 +/- 1.9 points preoperatively to 6.1 +/- 3.4 points postoperatively at a mean follow-up of 49.6 +/- 11.8 months (p < 0.001), a mean improvement of 37% of the maximum possible improvement. Subsequent procedures for persistent pain or stiffness were required in 3 patients (11%) in the culture positive group and in 3 patients (11%) in the control group; none of the revisions were culture-positive. Fourteen patients reported side effects to antibiotics. CONCLUSIONS: Clinical outcomes after single-stage revision for Propionibacterium culture-positive shoulders were at least as good as the outcomes in revision procedures for control shoulders. Two-stage revision procedures may not be necessary in the management of these cases. Patients should be educated with regard to potential antibiotic side effects. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002368 TI - Effect of Body Mass Index on Reoperation and Complications After Total Knee Arthroplasty. AB - BACKGROUND: High body mass index (BMI) is associated with increased rates of complications after total knee arthroplasty. To date, to our knowledge, studies have examined risk as a dichotomous variable using specific BMI thresholds. The purpose of this investigation was to quantify implant survival and the risk of common complications after total knee arthroplasty using BMI as a continuous variable. METHODS: Using prospectively collected data from our institutional total joint registry, we analyzed 22,289 consecutive knees, in 16,136 patients, treated with primary total knee arthroplasty from 1985 to 2012. The mean BMI of these patients at the time of the surgical procedure was 31.3 kg/m (range, 11 to 69 kg/m). The Kaplan-Meier survival method was used to estimate survivorship, reoperations, and common complications, with associations of outcomes assessed using a Cox regression model. RESULTS: Utilizing smoothing spline parameterization, we found that reoperation (p < 0.001) and implant revision or removal rates (p < 0.001) increased with increasing BMI after total knee arthroplasty. Increasing BMI also was associated with increased rates of wound infection (hazard ratio [HR], 1.07; p < 0.001) and deep infection (HR, 1.08; p < 0.001) per unit of BMI over 35 kg/m. A BMI of 35 to 40 kg/m was associated with a higher rate of implant revision for aseptic loosening (p < 0.001) and for polyethylene wear (p < 0.001) compared with a BMI of 18 to 24.99 kg/m. There was no correlation between BMI and risk of venous thromboembolism, tibiofemoral instability, or need for knee manipulation. CONCLUSIONS: The rates of reoperation, implant revision or removal, and many common complications after total knee arthroplasty were strongly associated with BMI. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002369 TI - Transient Local Bone Remodeling Effects of rhBMP-2 in an Ovine Interbody Spine Fusion Model. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a powerful osteoinductive morphogen capable of stimulating the migration of mesenchymal stem cells (MSCs) to the site of implantation and inducing the proliferation and differentiation of these MSCs into osteoblasts. Vertebral end plate and vertebral body resorption has been reported after interbody fusion with high doses of rhBMP-2. In this study, we investigated the effects of 2 rhBMP-2 doses on peri-implant bone resorption and bone remodeling at 7 time points in an end-plate-sparing ovine interbody fusion model. METHODS: Twenty-one female sheep underwent an end-plate-sparing discectomy followed by interbody fusion at L2-L3 and L4-L5 using a custom polyetheretherketone (PEEK) interbody fusion device. The PEEK interbody device was filled with 1 of 2 different doses of rhBMP-2 on an absorbable collagen sponge (ACS): 0.13 mg (1*) or 0.90 mg (7*). Bone remodeling and interbody fusion were assessed via high-resolution radiography and histological analyses at 1, 2, 3, 4, 8, 12, and 20 weeks postoperatively. RESULTS: Peri-implant bone resorption peaked between 3 and 8 weeks in both the 1* and the 7* rhBMP-2/ACS-dose group. Osteoclastic activity and corresponding peri implant bone resorption was dose-dependent, with moderate-to-marked resorption at the 7*-dose level and less resorption at the 1*-dose level. Both dose (p < 0.0007) and time (p < 0.0025) affected bone resorption significantly. Transient bone-resorption areas were fully healed by 12 weeks. Osseous bridging was seen at all but 1 spinal level at 12 and at 20 weeks. CONCLUSIONS: In the ovine end-plate sparing interbody fusion model, rhBMP-2 dose-dependent osteoclastic resorption is a transient phenomenon that peaks at 4 weeks postoperatively. CLINICAL RELEVANCE: Using the U.S. Food and Drug Administration (FDA)-approved rhBMP-2 concentration and matching the volume of rhBMP-2/ACS with the volume of desired bone formation within the interbody construct may limit the occurrence of transient bone resorption. PMID- 28002370 TI - Distinct Proximal Humeral Geometry in Chinese Population and Clinical Relevance. AB - BACKGROUND: Replicating humeral anatomy during shoulder arthroplasty is important for good patient outcomes. The proximal humeral geometry of the Chinese population has been rarely reported. We analyzed the geometry of the proximal part of the humerus in Chinese subjects and compared it with that of Western populations and the dimensions of available prostheses. METHODS: Eighty healthy Chinese subjects underwent computed tomography (CT)-arthrography. Three dimensional (3D) digital humeral and glenoid models were reconstructed, and geometric parameters were measured. Humeral measurements included the radius of curvature, articular surface diameter and thickness, anterior-posterior/superior inferior (AP/SI) articular surface diameter ratio, articular surface thickness/radius of curvature ratio, surface arc, inclination angle, retroversion angle, and medial and posterior offsets. Glenoid measurements included SI length, AP length, SI radius, and AP radius. RESULTS: The average radius of curvature (and standard deviation) of the humeral head was 22.1 +/- 1.9 mm, the articular surface diameter averaged 42.9 +/- 3.6 mm, and the articular surface thickness averaged 16.9 +/- 1.5 mm. There was strong linear correlation between the articular surface diameter and thickness (r = 0.696, p = 0.001), with a linear regression relationship of thickness = 0.357 * diameter + 1.615. The AP/SI articular surface diameter ratio averaged 0.93 +/- 0.03; the articular surface thickness/radius of curvature ratio, 0.77 +/- 0.05; the surface arc, 153 degrees +/- 5.6 degrees ; the inclination angle, 133 degrees +/- 3.1 degrees ; and the retroversion angle, 22.6 degrees +/- 10.2 degrees . The medial and posterior offsets averaged 6.3 +/- 0.9 mm and 0.4 +/- 0.78 mm, respectively; the SI and AP lengths, 30.15 +/- 3.70 mm and 20.35 +/- 2.56 mm; and the SI and AP radii, 23.49 +/- 2.48 mm and 25.54 +/- 3.07 mm. Compared with the Western population, the Chinese cohort had a smaller radius of curvature (p < 0.001), smaller articular surface diameter (p = 0.009), larger articular surface thickness/radius of curvature ratio (p < 0.001), larger surface arc (p < 0.001), smaller inclination angle (p < 0.001), and smaller posterior offset (p < 0.001). Unlike the Western population, the Chinese population had higher glenohumeral conformity in the coronal plane than in the axial plane. Many manufacturers' shoulder prostheses do not adequately cover the range of humeral head dimensions in our Chinese cohort. CONCLUSIONS: The geometric parameters of the humeri in the Chinese population differ from those in other populations. These differences have clinical relevance with regard to implant design and arthroplasty technique and likely affect clinical outcomes. PMID- 28002371 TI - Polymicrobial Periprosthetic Joint Infections: Outcome of Treatment and Identification of Risk Factors. AB - BACKGROUND: The treatment outcomes of periprosthetic joint infection are frequently dependent on characteristics of the causative organism. The objective of this comparative study was to investigate the prevalence of and risk factors for development of polymicrobial periprosthetic joint infection, and the outcome of surgical treatment of these patients. METHODS: All patients with polymicrobial, monomicrobial, or culture-negative periprosthetic joint infection treated from 2000 to 2014 were identified at a single institution. Ninety-five patients with a polymicrobial periprosthetic joint infection had a minimum follow up of 12 months. We matched patients with a polymicrobial periprosthetic joint infection with the other cohorts using propensity score matching for several important parameters. Treatment success was defined according to the Delphi criteria; Kaplan-Meier survivorship curves were generated to demonstrate this. A multiple logistic regression analysis was performed to determine risk factors for a polymicrobial periprosthetic joint infection. RESULTS: Overall, 10.3% (108 of 1,045) of the periprosthetic joint infections treated at our institution were polymicrobial in nature. Patients with a polymicrobial periprosthetic joint infection had a higher failure rate at 50.5% (48 of 95) compared with the monomicrobial periprosthetic joint infection cohort at 31.5% (63 of 200) and the culture-negative periprosthetic joint infection cohort at 30.2% (48 of 159) (p = 0.003). The survivorship of the polymicrobial periprosthetic joint infection group was 52.2% at the 2-year follow-up, 49.3% at the 5-year follow-up, and 46.8% at the 10-year follow-up. Patients with polymicrobial periprosthetic joint infection had a higher rate of amputation (odds ratio [OR], 3.80 [95% confidence interval (CI), 1.34 to 10.80]), arthrodesis (OR, 11.06 [95% CI, 1.27 to 96.00]), and periprosthetic joint infection-related mortality (OR, 7.88 [95% CI, 1.60 to 38.67]) compared with patients with monomicrobial periprosthetic joint infection. Isolation of gram-negative organisms (p < 0.01), enterococci (p < 0.01), Escherichia coli (p < 0.01), and atypical organisms (p < 0.01) was associated with polymicrobial periprosthetic joint infection. Only the presence of a sinus tract (OR, 2.20 [95% CI, 1.39 to 3.47]; p = 0.001) was a significant risk factor for polymicrobial periprosthetic joint infection on multivariate analysis. CONCLUSIONS: This study reveals that polymicrobial periprosthetic joint infection, occurring at a relatively low rate, is associated with poor outcomes when compared with monomicrobial and culture-negative periprosthetic joint infection. Patients with polymicrobial infections were more likely to require a salvage procedure or to have periprosthetic joint infection-related mortality. Polymicrobial periprosthetic joint infection was associated with soft-tissue defects such as a sinus tract and certain types of organisms, which should be considered when administering antibiotics to these patients. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002372 TI - Preoperative Prevalence of and Risk Factors for Venous Thromboembolism in Patients with a Hip Fracture: An Indirect Multidetector CT Venography Study. AB - BACKGROUND: This retrospective cohort study investigated the prevalence of and risk factors for preoperative venous thromboembolism (VTE) in patients with a hip fracture and a delay of >24 hours from injury to surgery. METHODS: This observational study included 208 patients with a hip fracture surgically treated at 1 university hospital between December 2010 and August 2014. Patients underwent indirect multidetector computed tomographic (MDCT) venography for preoperative VTE detection after admission. Overall VTE risk and median time from injury to CT scan were calculated. Age, sex, fracture type, time from injury to CT scan, body mass index, preinjury mobility score, previous anticoagulation treatment, previous hospitalization for VTE, varicose veins, and medical comorbidities were considered potential risk factors. RESULTS: The prevalence of preoperative VTE was 11.1% (23 of 208 patients), including 12 patients with deep vein thrombosis alone, 7 patients with pulmonary embolism alone, and 4 patients with both. The mean time from injury to CT scan was 4.9 days. The delay from the time of injury to CT scan averaged 7.6 days for patients who developed preoperative VTE, compared with 4.2 days for patients who had not developed VTE. In the adjusted models, female sex, subtrochanteric fracture, pulmonary disease, cancer, previous hospitalization for VTE, and varicose veins were risk factors for VTE. The final multivariate logistic regression analysis demonstrated that female sex (odds ratio [OR] = 5.86; 95% confidence interval [CI] = 1.21 to 28.21), subtrochanteric fracture (OR = 22.17; 95% CI = 4.02 to 122.06), pulmonary disease (OR = 21.10; 95% CI = 5.35 to 83.21), and previous hospitalization for VTE (OR = 16.36; 95% CI = 3.41 to 78.43) increased the risk of VTE. CONCLUSIONS: Our findings show a high prevalence of preoperative VTE in patients with a hip fracture. Therefore, preoperative investigation for VTE should be routinely considered for patients in whom surgery is delayed for >24 hours. At this time, indirect MDCT venography seems to be effective and useful. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002373 TI - Characteristics and Clinical Relevance of the Osseous Spur in Patients with Congenital Scoliosis and Split Spinal Cord Malformation. AB - BACKGROUND: The natural history of split spinal cord malformation (SCM) is still unclear. Knowledge of the characteristics of the osseous spur and its relationship with the spinal deformity may allow early identification of patients with a higher risk of a neurological deficit and enhance surgical decision making. METHODS: Eighty-five consecutive patients with congenital scoliosis and type-I SCM who had undergone surgical treatment at our hospital from May 2000 to December 2013 were identified retrospectively. There were 22 male and 63 female patients with an average age of 13.9 years at the time of surgery. Preoperative clinical and radiographic data were collected to investigate the characteristics of the scoliosis and the osseous spur. Two groups were identified on the basis of whether the patients had intact neurological function (Group A) or a neurological deficit (Group B). RESULTS: There were 52 patients (61%) in Group A (intact neurological function) and 33 patients (39%) in Group B (neurological deficit). There were no significant differences in the demographic distribution, curve magnitude, or length and thickness of the osseous spur between the 2 groups. In Group A, the location of the osseous spur relative to the apex of the major curve was proximal in 13 patients (25%), distal in 28 (54%), and central in 11 (21%). In Group B, the osseous spur was proximal in 7 (21%), distal in 8 (24%), and central in 18 (55%). The 2 groups differed significantly with respect to the location of the osseous spur (chi square = 10.898, p = 0.004). Group-B patients had a higher proportion of patients with kyphotic deformity (42%) than Group A (10%). The ratio of the diameters of the hemicords (concave side divided by convex side) differed significantly between the 2 groups (0.98 for Group A versus 0.89 for Group B, p = 0.030). CONCLUSIONS: The neurological status in patients with congenital scoliosis and type-I SCM appears to be closely related to the location of the osseous spur relative to the congenital scoliosis. An osseous spur at the apex of the scoliosis may be related to a higher risk of developing a neurological deficit, especially in patients with kyphotic deformity. Asymmetric splitting of the spinal cord may contribute to neurological deficits. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002374 TI - Higher Total Knee Arthroplasty Revision Rates Among United States Blacks Than Whites: A Systematic Literature Review and Meta-Analysis. AB - BACKGROUND: Reportedly 2% to 5.7% of total knee arthroplasties (TKAs) require revision within 5 years. The purpose of this study was to determine whether blacks are at higher risk of TKA revision than whites in the United States. METHODS: We performed a systematic review of English-language articles published from 2000 to 2015. Study inclusion criteria were (1) performance of the study in the United States, (2) TKA as the primary procedure studied, (3) a follow-up period at least 2 years, (4) reporting of revision rates, and (5) analysis of patient race as an independent predictor of revision. We then performed a random effects meta-analysis to calculate a pooled hazard ratio for TKA revision in blacks compared with whites. RESULTS: A total of 4,286 studies were identified and screened by title; 106, by abstract; and 24, by full text. Six studies met the inclusion criteria. Only 4 of the 6 studies could undergo meta-analysis because of overlapping study populations in 3 of them. The meta-analysis represented 451,960 patients who underwent TKA, of whom 28,772 (6.4%) were black. Of the total, 31,568 patients (7.0%) underwent revision surgery. The risk of revision TKA was significantly higher among blacks than whites (pooled hazard ratio, 1.38; 95% confidence interval, 1.20 to 1.58; p < 0.001). Analysis of the 3 studies with overlapping study populations demonstrated discordant results as a result of adjustment compared with non-adjustment for insurance eligibility, a surrogate for socioeconomic status. CONCLUSIONS: Blacks in the United States are at higher risk of revision TKA than whites. Socioeconomic status contributed to revision risk and is an important confounder in analyses of race. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28002375 TI - What's New in Primary Bone Tumors. PMID- 28002377 TI - Own the Bone, a System-Based Intervention, Improves Osteoporosis Care After Fragility Fractures. AB - BACKGROUND: The goal of this study was to evaluate the effectiveness of the American Orthopaedic Association's Own the Bone secondary fracture prevention program in the United States. METHODS: The objective of this quality improvement cohort study was dissemination of Own the Bone and implementation of secondary prevention (osteoporosis pharmacologic and bone mineral density [BMD] test recommendations). The main outcome measures were the number of sites implementing Own the Bone and implementation of secondary prevention, i.e., orders for BMD testing and/or pharmacologic treatment. The 177 sites participating in the program were academic and community hospitals, orthopaedic surgery groups, and a health system; data were obtained from the first 125 sites utilizing its registry, between January 1, 2010, and March 31, 2015. It included all patients, aged 50 years or older, presenting with fragility fractures (n = 23,132) who were enrolled in the Own the Bone web-based registry. The interventions were education, development of program elements, dissemination, implementation, and evaluation of the Own the Bone program at participating sites. RESULTS: A growing number of institutions implemented Own the Bone (14 sites in 2005-2006 to 177 sites in 2015). After consultation, 53% of patients had a BMD test ordered and/or pharmacologic therapy for osteoporosis. CONCLUSIONS: The Own the Bone intervention has succeeded in improving the behaviors of medical professionals in the areas of osteoporosis treatment and counseling, BMD testing, initiation of pharmacotherapy, and coordination of care for patients who have experienced a fragility fracture. PMID- 28002378 TI - Global Forum: Spine Research and Training in Underserved, Low and Middle-Income, Culturally Unique Communities: The World Spine Care Charity Research Program's Challenges and Facilitators. AB - The World Spine Care (WSC), established by volunteers from 5 continents, is dedicated to providing sustainable, evidence-based spine care to individuals and communities in low and middle-income countries consistent with available health care resources and integrated within the local culture. The research committee approves and oversees the WSC's collaborative research and training projects worldwide and serves to create a sustainable research community for underserved populations focused on preventing disability from spinal disorders. The purpose of this article is to describe 4 projects overseen by the WSC research committee and to discuss several challenges and specific facilitators that allowed successful completion of initiatives. These novel projects, which involved establishing spine surgery expertise and data collection in the WSC clinics and surrounding communities, all met their aims. This was achieved by overcoming language and resource challenges, adapting to local customs, and taking time to build mutual respect and to nurture relationships with local investigators and stakeholders. PMID- 28002379 TI - The Ethics of Patient Cost-Sharing for Total Joint Arthroplasty Implants. PMID- 28002380 TI - Propionibacterium: We Found It, Now We Have to Deal with It: Commentary on an article by Jason E. Hsu, MD, et al.: "Single-Stage Revision Is Effective for Failed Shoulder Arthroplasty with Positive Cultures for Propionibacterium". PMID- 28002381 TI - Economic Considerations for Obese Patients Undergoing Total Knee Arthroplasty: Commentary on an article by Eric R. Wagner, MD, et al.: "Effect of Body Mass Index on Reoperation and Complications After Total Knee Arthroplasty". PMID- 28002383 TI - Stress-Induced Parasympathetic Control and Its Association With Inflammatory Reactivity. AB - OBJECTIVE: It has been proposed that the inflammatory cytokine system is regulated through the vagus nerve, where vagal activation inhibits release of inflammatory cytokines and, therefore, inflammation. Thus, loss of vagal activation (i.e., reduced high-frequency heart rate variability [HF-HRV]) should result in greater inflammation. Evidence to date for this relationship has relied on animal models and resting states in humans. The present study used a psychosocial stressor to test whether stress-induced decreases in HF-HRV predict increases in circulating inflammatory markers. METHODS: Thirty healthy young women completed a speech stressor. HF-HRV was assessed before and during the stressor while circulating plasma interleukin 6, tumor necrosis factor alpha, and C-reactive protein were assessed before and 1 hour after the stressor. RESULTS: Consistent with the neural reflex for immunity, greater reductions in HF-HRV during the stressor were associated with greater increases in tumor necrosis factor alpha (beta = -0.29 to -0.47) and interleukin 6 (beta = -0.40 to -0.68) but not C-reactive protein (beta = 0.10 to 0.29) 1 hour after the stressor. CONCLUSIONS: These findings expand on the current literature by showing that changes in HF-HRV predict and precede changes in circulating inflammatory cytokines in humans and may have implications for treatment of inflammatory diseases. PMID- 28002384 TI - A legacy of caring. PMID- 28002382 TI - The Mental Stress Ischemia Prognosis Study: Objectives, Study Design, and Prevalence of Inducible Ischemia. AB - OBJECTIVE: Mental stress-induced myocardial ischemia (MSIMI) is a common phenomenon in patients with coronary artery disease (CAD), but contemporary studies of its prognostic significance and its underlying pathophysiology are limited. METHODS: We prospectively enrolled patients with confirmed CAD in the Mental Stress Ischemia Prognosis Study (MIPS) between 2011 and 2014. All patients underwent mental stress testing using a standardized public speaking task, and ischemia was detected by Tc-sestamibi myocardial perfusion imaging. Patients also underwent conventional stress testing for myocardial ischemia (CSIMI) using exercise or pharmacological stress testing. Furthermore, digital microvascular flow, endothelial function, arterial stiffness, and blood sample collections were performed before, during, and after mental stress. Two-year adverse clinical outcomes are being assessed. RESULTS: Six-hundred ninety-five patients completed baseline enrollment in the MIPS. Their mean (standard deviation) age was 62.9 (9.1) years, 72% were men, 30% were African American, and 32% had a history myocardial infarction. The prevalence of MSIMI and CSIMI is 16.1% and 34.7%, respectively. A total of 151 patients (22.9%) had only CSIMI, 28 (4.2%) had only MSIMI, and 78 (11.8%) had both MSIMI and CSIMI. Patients with ischemia had a lower ejection fraction and higher prevalence of previous coronary artery bypass grafting compared with those without inducible ischemia (p < .050). The prevalence of obstructive CAD was not statistically different between patients with and without MSIMI (p = .426); in contrast, it was higher in patients with CSIMI (p < .001). CONCLUSIONS: The MIPS data will provide useful information to assess the prognostic significance and underlying mechanisms of MSIMI. PMID- 28002385 TI - When peace breaks out: The 42nd American Association for the Surgery of Trauma Fitts Oration. PMID- 28002386 TI - Should grade of solid organ injury determine need for hospitalization in children? AB - BACKGROUND: Management of solid organ injuries (SOI) in children is often predicated on radiologic grade of injury. Hypothesizing that grade may not necessarily determine hospitalization need, we investigated factors associated with hospitalization in cases of isolated SOI in children. METHODS: Retrospective review of all cases admitted to one pediatric trauma centre over 10 yrs revealed 86 cases with SOI established by computed tomography (CT) scan upon admission. Review of all scans by one pediatric radiologist was performed to determine SOI grade. chi and Fisher's tests were used to determine associations with presenting clinical features and SOI grade with early outcomes. RESULTS: Ninety-one cases of SOI were identified. Of these, 56 were isolated to solid organs, whereas the others were multisystem; 12 were grades I and II and 44 grades III to V. Variables associated with length of stay longer than 2 days were admission hematocrit (Hct) less than 33% (p = 0.006) and need for narcotics or anti-emetics upon admission (p = 0.002; p < 0.0001). Significant associations between these features and need for narcotics or anti-emetics the following day were also observed. No features predicted a significant drop in Hct over the first 24 hours or need for transfusion. Nineteen patients did not require narcotics, anti emetics, or transfusions; 11 of these stayed in hospital for 2 days or shorter. The CT grade was not predictive of any short term outcomes. CONCLUSIONS: Clinical status, low admission Hct, and need for medications may be better predictors of admission requirements of patients with isolated SOI than CT grade. Brief emergency department observation and discharge home may be appropriate for stable patients with isolated BAT without concerning clinical features, despite findings of SOI on imaging. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 28002387 TI - Featured Articles for CME Credit January 2017. PMID- 28002389 TI - Transglutaminase 2 Inhibitor KCC009 Induces p53-Independent Radiosensitization in Lung Adenocarcinoma Cells. AB - BACKGROUND The expression of transglutaminase 2 (TG2) is correlated to DNA damage repair and apoptosis through the p53 pathway. The present study aimed to investigate the potential radiosensitization effect and possible mechanisms of the TG2 inhibitor KCC009 in lung cancer in vitro. MATERIAL AND METHODS A single hit multi-target model was used to plot survival curves and to calculate the sensitizing enhancement ratios in lung cancer wild-type or mutant p53 of H1299 cells. We performed analyses for changes of cell cycling and apoptotic responses of cells; Western blot analysis and real-time SYBR Green PCR assay were used to determine the changes of mRNA/protein expressions; ELISA assay was used for examination of cytochrome c release in cytoplasm. RESULTS Our results showed that KCC009 induced radiosensitization in both H1299/WT-p53 and H1299/M175H-p53 cells. KCC009+IR induced G0/G1 arrest in H1299/WT cells and G2/M arrest in H1299/M175H p53 cells. KCC009+IR also induced apoptosis in both cell lines. In addition, KCC009+IR decreased the TG2 expression, and increased the p53 expression in H1299/WT cells but not in H1299/M175H-p53 cells. KCC009+IR also increased the expression of p21, Bax, p-caspase-3, and decreased Bcl-2 and CyclinD expression in H1299/WT cells. While KCC009+IR induced phosphorylation of caspase-3 and increase Cyt-C level in the cytoplasm of, and decreased CyclinB, Bcl-2 expression in H1299/M175H-p53 cells, we noticed that Cyt-C level in the nucleus decreased in the H1299/WT cells. CONCLUSIONS KCC009, a TG2 inhibitor, exhibits potent radiosensitization effects in human lung cancer cells expressing wild-type or mutant p53 with different mechanisms. PMID- 28002390 TI - Therapeutic hypothermia modulates complement factor C3a and C5a levels in a rat model of hypoxic ischemic encephalopathy. AB - BACKGROUND: Therapeutic hypothermia (HT) is the only intervention that improves outcomes in neonatal hypoxic-ischemic encephalopathy (HIE). However, the multifactorial mechanisms by which HT impacts HIE are incompletely understood. The complement system plays a major role in the pathogenesis of ischemia reperfusion injuries such as HIE. We have previously demonstrated that HT modulates complement activity in vitro. METHODS: Term equivalent rat pups were subjected to unilateral carotid ligation followed by hypoxia (8% O2) for 45 min to simulate HIE. A subset of animals was subjected to HT (31-32 degrees C for 6 h). Plasma and brain levels of C3a and C5a were measured. Receptors for C3a (C3aR) and C5a (C5aR) along with C1q, C3, and C9 were characterized in neurons, astrocytes, and microglia. RESULTS: We found that HT increased systemic expression of C3a and decreased expression of C5a after HIE. In the brain, C3aR and C5aR are predominantly expressed on microglia after HIE. HT increased local expression of C3aR and decreased expression on C5aR after HIE. Furthermore, HT decreased local expression of C1q, C3-products, and C9 in the brain. CONCLUSION: HT is associated with significant alteration of complement effectors and their cognate receptors. Complement modulation may improve outcomes in neonatal HIE. PMID- 28002391 TI - Starter formula enriched in prebiotics and probiotics ensures normal growth of infants and promotes gut health: a randomized clinical trial. AB - BACKGROUND: Prebiotics and probiotics exert beneficial effects by modulating gut microbiota and immune system. This study evaluates efficacy and safety of an infant formula containing bovine milk-derived oligosaccharides and Bifidobacterium animalis ssp lactis (B. lactis) (CNCM I-3446) on incidence of diarrhea and febrile infections during the first year of life (primary outcome). METHODS: Full-term infants receiving Test or Control (without bovine milk-derived oligosaccharide and B. lactis) formulae were enrolled in a multicenter, randomized, controlled, and double-blind trial with a reference breastfeeding group. . RESULTS: 413 infants were assigned between Test (n = 206) and Control (n = 207) formula. There was no significant difference for diarrhea and febrile infections incidence between groups at 6 (odds ratio (95% confidence interval) = 0.56 (0.26-1.15), P = 0.096) and 12 mo (odds ratio = 0.66 (0.38-1.14), P = 0.119). Test formula was well tolerated, anthropometrics parameters were not significantly different between groups and aligned with WHO growth standards up to 12 mo. Data from test group showed that gut microbiota pattern, fecal IgA and stool pH were brought to be closer to those of breastfed infants. CONCLUSION: An infant formula enriched with bovine milk-derived oligosaccharide and B. lactis supports normal infant growth, is well tolerated and improves intestinal health markers. No differences in diarrhea and febrile infection incidence were found in the population studied. PMID- 28002392 TI - Microbiota: Reseeding the gut. PMID- 28002394 TI - Q&A: Eva Szigethy. PMID- 28002393 TI - Biology: A slow-motion epidemic. PMID- 28002396 TI - Q&A: Joel Weinstock. PMID- 28002395 TI - Genetics: Clues in the code. PMID- 28002397 TI - Epidemiology: Rising in the East. PMID- 28002398 TI - Inflammatory bowel disease. PMID- 28002399 TI - Cell-based therapy: Cells on trial. PMID- 28002400 TI - Evolution of the global phosphorus cycle. AB - The macronutrient phosphorus is thought to limit primary productivity in the oceans on geological timescales. Although there has been a sustained effort to reconstruct the dynamics of the phosphorus cycle over the past 3.5 billion years, it remains uncertain whether phosphorus limitation persisted throughout Earth's history and therefore whether the phosphorus cycle has consistently modulated biospheric productivity and ocean-atmosphere oxygen levels over time. Here we present a compilation of phosphorus abundances in marine sedimentary rocks spanning the past 3.5 billion years. We find evidence for relatively low authigenic phosphorus burial in shallow marine environments until about 800 to 700 million years ago. Our interpretation of the database leads us to propose that limited marginal phosphorus burial before that time was linked to phosphorus biolimitation, resulting in elemental stoichiometries in primary producers that diverged strongly from the Redfield ratio (the atomic ratio of carbon, nitrogen and phosphorus found in phytoplankton). We place our phosphorus record in a quantitative biogeochemical model framework and find that a combination of enhanced phosphorus scavenging in anoxic, iron-rich oceans and a nutrient-based bistability in atmospheric oxygen levels could have resulted in a stable low oxygen world. The combination of these factors may explain the protracted oxygenation of Earth's surface over the last 3.5 billion years of Earth history. However, our analysis also suggests that a fundamental shift in the phosphorus cycle may have occurred during the late Proterozoic eon (between 800 and 635 million years ago), coincident with a previously inferred shift in marine redox states, severe perturbations to Earth's climate system, and the emergence of animals. PMID- 28002401 TI - Reversible methylation of m6Am in the 5' cap controls mRNA stability. AB - Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5' end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N6,2'-O-dimethyladenosine (m6Am), is a reversible modification that influences cellular mRNA fate. Using a transcriptome wide map of m6Am we find that m6Am-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m6Am-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m6Am is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Am rather than N6-methyladenosine (m6A), and reduces the stability of m6Am mRNAs. Together, these findings show that the methylation status of m6Am in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability. PMID- 28002402 TI - Structural basis of an essential interaction between influenza polymerase and Pol II CTD. AB - The heterotrimeric influenza polymerase (FluPol), comprising subunits PA, PB1 and PB2, binds to the conserved 5' and 3' termini (the 'promoter') of each of the eight single-stranded viral RNA (vRNA) genome segments and performs both transcription and replication of vRNA in the infected cell nucleus. To transcribe viral mRNAs, FluPol associates with cellular RNA polymerase II (Pol II), which enables it to take 5'-capped primers from nascent Pol II transcripts. Here we present a co-crystal structure of bat influenza A polymerase bound to a Pol II C terminal domain (CTD) peptide mimic, which shows two distinct phosphoserine-5 (SeP5)-binding sites in the polymerase PA subunit, accommodating four CTD heptad repeats overall. Mutagenesis of the SeP5-contacting basic residues (PA K289, R454, K635 and R638) weakens CTD repeat binding in vitro without affecting the intrinsic cap-primed (transcription) or unprimed (replication) RNA synthesis activity of recombinant polymerase, whereas in cell-based minigenome assays the same mutations substantially reduce overall polymerase activity. Only recombinant viruses with a single mutation in one of the SeP5-binding sites can be rescued, but these viruses are severely attenuated and genetically unstable. Several previously described mutants that modulate virulence can be rationalized by our results, including a second site mutation (PA(C453R)) that enables the highly attenuated mutant virus (PA(R638A)) to revert to near wild-type infectivity. We conclude that direct binding of FluPol to the SeP5 Pol II CTD is fine-tuned to allow efficient viral transcription and propose that the CTD-binding site on FluPol could be targeted for antiviral drug development. PMID- 28002403 TI - XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. AB - XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair defective disease. PMID- 28002405 TI - Molecular biology: Messenger RNAs marked for longer life. PMID- 28002406 TI - Physiology: Mechanosensor of lung inflation identified. PMID- 28002407 TI - Identification of an atypical monocyte and committed progenitor involved in fibrosis. AB - Monocytes and macrophages comprise a variety of subsets with diverse functions. It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages. However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1+Msr1+Ly6C-F4/80-Mac1+ monocytes, which we term segregated-nucleus containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein beta (C/EBPbeta), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb-/- haematopoietic cells. Adoptive transfer of SatM into Cebpb-/- mice resulted in fibrosis. Notably, SatM are derived from Ly6C-FcepsilonRI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C-FcepsilonRI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBPbeta licenses differentiation of SatM from their committed progenitor. PMID- 28002404 TI - Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. AB - Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 * 10-7, range P = 9.2 * 10-8 to 6.0 * 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 * 10-6, range P = 5.5 * 10-6 to 6.1 * 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 * 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity. PMID- 28002408 TI - Reducing phosphorus accumulation in rice grains with an impaired transporter in the node. AB - Phosphorus is an important nutrient for crop productivity. More than 60% of the total phosphorus in cereal crops is finally allocated into the grains and is therefore removed at harvest. This removal accounts for 85% of the phosphorus fertilizers applied to the field each year. However, because humans and non ruminants such as poultry, swine and fish cannot digest phytate, the major form of phosphorus in the grains, the excreted phosphorus causes eutrophication of waterways. A reduction in phosphorus accumulation in the grain would contribute to sustainable and environmentally friendly agriculture. Here we describe a rice transporter, SULTR-like phosphorus distribution transporter (SPDT), that controls the allocation of phosphorus to the grain. SPDT is expressed in the xylem region of both enlarged- and diffuse-vascular bundles of the nodes, and encodes a plasma membrane-localized transporter for phosphorus. Knockout of this gene in rice (Oryza sativa) altered the distribution of phosphorus, with decreased phosphorus in the grains but increased levels in the leaves. Total phosphorus and phytate in the brown de-husked rice were 20-30% lower in the knockout lines, whereas yield, seed germination and seedling vigour were not affected. These results indicate that SPDT functions in the rice node as a switch to allocate phosphorus preferentially to the grains. This finding provides a potential strategy to reduce the removal of phosphorus from the field and lower the risk of eutrophication of waterways. PMID- 28002409 TI - Spin-orbit-coupled fermions in an optical lattice clock. AB - Engineered spin-orbit coupling (SOC) in cold-atom systems can enable the study of new synthetic materials and complex condensed matter phenomena. However, spontaneous emission in alkali-atom spin-orbit-coupled systems is hindered by heating, limiting the observation of many-body effects and motivating research into potential alternatives. Here we demonstrate that spin-orbit-coupled fermions can be engineered to occur naturally in a one-dimensional optical lattice clock. In contrast to previous SOC experiments, here the SOC is both generated and probed using a direct ultra-narrow optical clock transition between two electronic orbital states in 87Sr atoms. We use clock spectroscopy to prepare lattice band populations, internal electronic states and quasi-momenta, and to produce spin-orbit-coupled dynamics. The exceptionally long lifetime of the excited clock state (160 seconds) eliminates decoherence and atom loss from spontaneous emission at all relevant experimental timescales, allowing subsequent momentum- and spin-resolved in situ probing of the SOC band structure and eigenstates. We use these capabilities to study Bloch oscillations, spin-momentum locking and Van Hove singularities in the transition density of states. Our results lay the groundwork for using fermionic optical lattice clocks to probe new phases of matter. PMID- 28002410 TI - DNA repair: A unifying mechanism in neurodegeneration. PMID- 28002412 TI - Piezo2 senses airway stretch and mediates lung inflation-induced apnoea. AB - Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2+ vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering-Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults. PMID- 28002411 TI - Structure of a CLC chloride ion channel by cryo-electron microscopy. AB - CLC proteins transport chloride (Cl-) ions across cellular membranes to regulate muscle excitability, electrolyte movement across epithelia, and acidification of intracellular organelles. Some CLC proteins are channels that conduct Cl- ions passively, whereas others are secondary active transporters that exchange two Cl- ions for one H+. The structural basis underlying these distinctive transport mechanisms is puzzling because CLC channels and transporters are expected to share the same architecture on the basis of sequence homology. Here we determined the structure of a bovine CLC channel (CLC-K) using cryo-electron microscopy. A conserved loop in the Cl- transport pathway shows a structure markedly different from that of CLC transporters. Consequently, the cytosolic constriction for Cl- passage is widened in CLC-K such that the kinetic barrier previously postulated for Cl-/H+ transporter function would be reduced. Thus, reduction of a kinetic barrier in CLC channels enables fast flow of Cl- down its electrochemical gradient. PMID- 28002413 TI - Trends in ART Initiation among Men and Non-Pregnant/Non-Breastfeeding Women before and after Option B+ in Southern Malawi. AB - BACKGROUND: Option B+ is promoted as a key component to eliminating vertical transmission of HIV; however, little is known about the policy's impact on non targeted populations, such as men and non-pregnant/non-breastfeeding women. We compare ART uptake among non-targeted populations during pre/post Option B+ periods in Zomba District, Malawi. METHODS: Individual-level ART registry data from 27 health facilities were digitized and new ART initiates were disaggregated by sex and type of initiate (Option B+ or not). Data were analyzed over the pre- (January 2009-June 2011) and post- (July 2011- December 2013) Option B+ periods. RESULTS: After the implementation of Option B+, the total number of new female initiates increased significantly (quarterly median: 547 vs. 816; P = 0.001) and their median age decreased from 34 to 31 years (P = <0.001). Both changes were the result of the rapid and sustained uptake of ART among Option B+ clients. Post policy, Option B+ clients represented 48% of all new female initiates while the number of females who initiated through CD4 or WHO staging criteria significantly decreased (quarterly median: 547 vs. 419; P = 0.005). The number and age of male initiates remained stable; however, the proportion of men among new initiates decreased (36% vs. 31%; P = <0.001). CONCLUSIONS: Option B+ shifted the profile of first-time initiates towards younger and fertile women. Declines among non Option B+ women most likely reflect earlier initiation during pregnancies before deteriorations in health. The decreased proportion of men among first-time initiates represents a growing gender disparity in HIV services that deserves immediate attention. PMID- 28002414 TI - Discovery or Extinction of New Scleroderma Species in Amazonia? AB - The Amazon Forest is a hotspot of biodiversity harboring an unknown number of undescribed taxa. Inventory studies are urgent, mainly in the areas most endangered by human activities such as extensive dam construction, where species could be in risk of extinction before being described and named. In 2015, intensive studies performed in a few locations in the Brazilian Amazon rainforest revealed three new species of the genus Scleroderma: S. anomalosporum, S. camassuense and S. duckei. The two first species were located in one of the many areas flooded by construction of hydroelectric dams throughout the Amazon; and the third in the Reserva Florestal Adolpho Ducke, a protected reverse by the INPA. The species were identified through morphology and molecular analyses of barcoding sequences (Internal Transcribed Spacer nrDNA). Scleroderma anomalosporum is characterized mainly by the smooth spores under LM in mature basidiomata (under SEM with small, unevenly distributed granules, a characteristic not observed in other species of the genus), the large size of the basidiomata, up to 120 mm diameter, and the stelliform dehiscence; S. camassuense mainly by the irregular to stellate dehiscence, the subreticulated spores and the bright sulfur-yellow colour, and Scleroderma duckei mainly by the verrucose exoperidium, stelliform dehiscence, and verrucose spores. Description, illustration and affinities with other species of the genus are provided. PMID- 28002415 TI - Menstruation and the Cycle of Poverty: A Cluster Quasi-Randomised Control Trial of Sanitary Pad and Puberty Education Provision in Uganda. AB - BACKGROUND: Poor menstrual knowledge and access to sanitary products have been proposed as barriers to menstrual health and school attendance. In response, interventions targeting these needs have seen increasing implementation in public and private sectors. However, there has been limited assessment of their effectiveness. OBJECTIVES: Assess the impact of providing reusable sanitary pads and puberty education on girls' school attendance and psychosocial wellbeing outcomes. METHODS: A cluster quasi-randomised controlled trial was conducted across 8 schools, including 1124 girls, in rural Uganda. Schools were allocated to one of four conditions: the provision of puberty education alone; reusable sanitary pads alone; puberty education and reusable sanitary pads; and a control (no intervention). The primary outcome was school attendance. Secondary outcomes reflected psychosocial wellbeing. RESULTS: At follow-up, school attendance had worsened for girls across all conditions. Per-protocol analysis revealed that this decline was significantly greater for those in the control condition d = 0.52 (95%CI 0.26-0.77), with those in control schools having a 17.1% (95%CI: 8.7 25.5) greater drop in attendance than those in any intervention school. There were no differences between the intervention conditions. High rates of school drop-out and transfer meant the trial suffered from substantial participant drop out. Intention-to-treat analyses using two different imputation strategies were consistent with the main results, with mean differences of 5.2% attendance in best-case and 24.5% in worst-case imputations. Results were robust to adjustments for clustering. There was no impact of the interventions on girls' self-reported shame or insecurity during menstruation. CONCLUSION: Results of the trial support the hypothesised positive impact of providing sanitary pads or puberty education for girls' school attendance in a developing country context. Findings must be interpreted with caution in light of poor participant retention, intervention fidelity, and the attendance measures used. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201503001044408. PMID- 28002416 TI - Mass Density Measurement of Mineralized Tissue with Grating-Based X-Ray Phase Tomography. AB - Establishing the mineral content distribution in highly mineralized tissues, such as bones and teeth, is fundamental in understanding a variety of structural questions ranging from studies of the mechanical properties to improved pathological investigations. However, non-destructive, volumetric and quantitative density measurements of mineralized samples, some of which may extend several mm in size, remain challenging. Here, we demonstrate the potential of grating-based x-ray phase tomography to gain insight into the three dimensional mass density distribution of tooth tissues in a non-destructive way and with a sensitivity of 85 mg/cm3. Density gradients of 13 - 19% over 1 - 2 mm within typical samples are detected, and local variations in density of 0.4 g/cm3 on a length scale of 0.1 mm are revealed. This method proves to be an excellent quantitative tool for investigations of subtle differences in mineral content of mineralized tissues that can change following treatment or during ageing and healing. PMID- 28002418 TI - Correction: The Causative Gene in Chanarian Dorfman Syndrome Regulates Lipid Droplet Homeostasis in C. elegans. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005284.]. PMID- 28002417 TI - Predicting Rift Valley Fever Inter-epidemic Activities and Outbreak Patterns: Insights from a Stochastic Host-Vector Model. AB - Rift Valley fever (RVF) outbreaks are recurrent, occurring at irregular intervals of up to 15 years at least in East Africa. Between outbreaks disease inter epidemic activities exist and occur at low levels and are maintained by female Aedes mcintoshi mosquitoes which transmit the virus to their eggs leading to disease persistence during unfavourable seasons. Here we formulate and analyse a full stochastic host-vector model with two routes of transmission: vertical and horizontal. By applying branching process theory we establish novel relationships between the basic reproduction number, R0, vertical transmission and the invasion and extinction probabilities. Optimum climatic conditions and presence of mosquitoes have not fully explained the irregular oscillatory behaviour of RVF outbreaks. Using our model without seasonality and applying van Kampen system size expansion techniques, we provide an analytical expression for the spectrum of stochastic fluctuations, revealing how outbreaks multi-year periodicity varies with the vertical transmission. Our theory predicts complex fluctuations with a dominant period of 1 to 10 years which essentially depends on the efficiency of vertical transmission. Our predictions are then compared to temporal patterns of disease outbreaks in Tanzania, Kenya and South Africa. Our analyses show that interaction between nonlinearity, stochasticity and vertical transmission provides a simple but plausible explanation for the irregular oscillatory nature of RVF outbreaks. Therefore, we argue that while rainfall might be the major determinant for the onset and switch-off of an outbreak, the occurrence of a particular outbreak is also a result of a build up phenomena that is correlated to vertical transmission efficiency. PMID- 28002419 TI - Seasonality of Influenza and Respiratory Syncytial Viruses and the Effect of Climate Factors in Subtropical-Tropical Asia Using Influenza-Like Illness Surveillance Data, 2010 -2012. AB - INTRODUCTION: The seasonality of influenza and respiratory syncytial virus (RSV) is well known, and many analyses have been conducted in temperate countries; however, this is still not well understood in tropical countries. Previous studies suggest that climate factors are involved in the seasonality of these viruses. However, the extent of the effect of each climate variable is yet to be defined. MATERIALS AND METHODS: We investigated the pattern of seasonality and the effect of climate variables on influenza and RSV at three sites of different latitudes: the Eastern Visayas region and Baguio City in the Philippines, and Okinawa Prefecture in Japan. Wavelet analysis and the dynamic linear regression model were applied. Climate variables used in the analysis included mean temperature, relative and specific humidity, precipitation, and number of rainy days. The Akaike Information Criterion estimated in each model was used to test the improvement of fit in comparison with the baseline model. RESULTS: At all three study sites, annual seasonal peaks were observed in influenza A and RSV; peaks were unclear for influenza B. Ranges of climate variables at the two Philippine sites were narrower and mean variables were significantly different among the three sites. Whereas all climate variables except the number of rainy days improved model fit to the local trend model, their contributions were modest. Mean temperature and specific humidity were positively associated with influenza and RSV at the Philippine sites and negatively associated with influenza A in Okinawa. Precipitation also improved model fit for influenza and RSV at both Philippine sites, except for the influenza A model in the Eastern Visayas. CONCLUSIONS: Annual seasonal peaks were observed for influenza A and RSV but were less clear for influenza B at all three study sites. Including additional data from subsequent more years would help to ascertain these findings. Annual amplitude and variation in climate variables are more important than their absolute values for determining their effect on the seasonality of influenza and RSV. PMID- 28002420 TI - The Impact of the Newly Licensed Dengue Vaccine in Endemic Countries. AB - BACKGROUND: With approximately 3 billion people at risk of acquiring the infection, dengue fever is now considered the most important mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year, of which 96 million manifest symptoms with any level of disease severity. Treatment of uncomplicated dengue cases is only supportive and severe dengue cases require hospital intensive care. A vaccine now licensed in several countries and developed by Sanofi Pasteur (CYD-TDV, named Dengvaxia), was able to protect, in the first 25 months of the two Phase III, 66% of a subset of 9-16 year old participants. However, a significantly lower efficacy (including negative vaccine efficacy) was noted for children younger than 9 years of age. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of year 3 results of phase III trials of Dengvaxia suggest high rates of protection of vaccinated partial dengue immunes but high rates of hospitalizations during breakthrough dengue infections of persons who were vaccinated when seronegative, with vaccine appearing to induce enhancing antibodies (ADE). An age structured model was developed based on Sanofi's recommendation to vaccinate persons age 945 years in dengue endemic countries. The model was used to explore the clinical burden of two vaccination strategies: 1) Vaccinate 4 or 20% of individuals, ages 9-45 years, seropositives and seronegatives, and 2) vaccinate 4 or 20% of individuals, ages 9-45 years, who are dengue immune only. CONCLUSIONS/SIGNIFICANCE: Our results show that vaccinating dengue monotypic immune individuals prevents dengue hospitalizations, but at the same time dengue infections of vaccine-sensitized persons increases hospitalizations. When the vaccine is given only to partial immune individuals, after immunological screening of the population, disease burden decreases considerably. PMID- 28002421 TI - Baicalin Down-Regulates IL-1beta-Stimulated Extracellular Matrix Production in Nasal Fibroblasts. AB - PURPOSE: Baicalin, a Chinese herbal medicine, has anti-fibrotic and anti inflammatory effects. The aims of present study were to investigate the effects of baicalin on the myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction of interleukin (IL)-1beta stimulated nasal fibroblasts and to determine the molecular mechanism of baicalin in nasal fibroblasts. METHODS: Nasal fibroblasts were isolated from the inferior turbinate of patients. Baicalin was used to treat IL-1beta-stimulated nasal fibroblasts. To evaluate cytotoxicity, a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay was used. The expression levels of alpha-smooth muscle actin (SMA), fibronectin, phospho-mitogen-activated protein kinase (p-MAPK), p Akt, p-p50, p-p65, and p-IkappaBalpha were measured by western blotting, reverse transcription-polymerase chain reaction (RT-PCR),or immunofluorescence staining. Fibroblast migration was analyzed with scratch assays and transwell migration assays. Total collagen was evaluated with the Sircol collagen assay. Contractile activity was measured with a collagen gel contraction assay. RESULTS: Baicalin (0 50 MUM) had no significant cytotoxic effects in nasal fibroblasts. The expression of alpha-SMA and fibronectin were significantly down-regulated in baicalin treated nasal fibroblasts. Migration, collagen production, and contraction of IL 1beta-stimulated nasal fibroblasts were significantly inhibited by baicalin treatment. Baicalin also significantly down-regulated p-MAPK, p-Akt, p-p50, p p65, and p-IkappaBalpha in IL-1beta-stimulated nasal fibroblasts. CONCLUSIONS: We showed that baicalin down-regulated myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction via the MAPK and Akt/ NF kappaB pathways in IL-1beta-stimulated nasal fibroblasts. PMID- 28002422 TI - Developing and Pilot Testing a Spanish Translation of CollaboRATE for Use in the United States. AB - BACKGROUND/AIM: Given the need for access to patient-facing materials in multiple languages, this study aimed to develop and pilot test an accurate and understandable translation of CollaboRATE, a three-item patient-reported measure of shared decision-making, for Spanish-speaking patients in the United States (US). METHOD: We followed the Translate, Review, Adjudicate, Pre-test, Document (TRAPD) survey translation protocol. Cognitive interviews were conducted with Spanish-speaking adults within an urban Massachusetts internal medicine clinic. For the pilot test, all patients with weekday appointments between May 1 and May 29, 2015 were invited to complete CollaboRATE in either English or Spanish upon exit. We calculated the proportion of respondents giving the best score possible on CollaboRATE and compared scores across key patient subgroups. RESULTS: Four rounds of cognitive interviews with 26 people were completed between January and April 2015. Extensive, iterative refinements to survey items between interview rounds led to final items that were generally understood by participants with diverse educational backgrounds. Pilot data collection achieved an overall response rate of 73 percent, with 606 (49%) patients completing Spanish CollaboRATE questionnaires and 624 (51%) patients completing English CollaboRATE questionnaires. The proportion of respondents giving the best score possible on CollaboRATE was the same (86%) for both the English and Spanish versions of the instrument. DISCUSSION: Our translation method, guided by emerging best practices in survey and health measurement translation, encompassed multiple levels of review. By conducting four rounds of cognitive interviews with iterative item refinement between each round, we arrived at a Spanish language version of CollaboRATE that was understandable to a majority of cognitive interview participants and was completed by more than 600 pilot questionnaire respondents. PMID- 28002423 TI - Elevated Serum Levels of Retinol-Binding Protein 4 Are Associated with Breast Cancer Risk: A Case-Control Study. AB - BACKGROUND: Retinol binding protein 4 (RBP4) is a recently identified adipokine that is elevated in patients with obesity or type 2 diabetes. A growing body of research has shown that RBP4 is associated with several types of cancer. However, no studies have investigated the relationship between serum RBP4 levels and breast cancer risk. We performed a case-control study to evaluate the association between serum RBP4 levels and the risk of breast cancer. METHODS: From August 2012 to December 2013, four-hundred subjects including 200 patients diagnosed with primary breast cancer and 200 matched healthy women were consecutively enrolled from Affiliated Hospital of Qingdao University Medical College. Blood samples were collected from healthy controls and breast cancer patients before commencement of treatment. Enzyme-linked immunosorbent assay was used to evaluate the serum RBP4 levels in separated serum samples. Meanwhile, the characteristics of breast cancer cases and controls were collected from medical records and pathological data. RESULTS: The serum levels of RBP4 were significantly higher in patients with breast cancer than that in the healthy control group (33.77+/-9.92 vs. 28.77+/-6.47MUg/ml, P < 0.05). Compared to the subjects in the lowest quartile of serum RBP4 level, the adjusted ORs (95% CIs) is 2.16(1.01-4.61) and 2.07 (1.07-4.00) for women in the second and highest RBP4 tertile, respectively. For breast cancer patients, patients with PR or ER negative displayed significantly higher serum RBP4 levels than those with PR or ER positive. CONCLUSION: Our results for the first time suggested serum RBP4 levels could be associated with the risk of breast cancer. However, further prospective studies are essential to confirm these observed results. PMID- 28002424 TI - Assessment of Accumulation Processes at the Middle Pleistocene Site of Ambrona (Soria, Spain). Density and Orientation Patterns in Spatial Datasets Derived from Excavations Conducted from the 1960s to the Present. AB - The Middle Pleistocene site of Ambrona (Soria, Spain) is a major reference for European Acheulean studies. The origin of the lithic and fauna accumulations at this site was first thought to be anthropogenic, but later studies showed that it was mainly natural. The first person to conduct excavations at the Ambrona site was the Marquis of Cerralbo, in 1914; other research groups followed in more recent times (the Howell & Freeman team and the Santonja & Perez-Gonzalez team). The digs yielded a great amount of information, but until now it had never been unified. In this paper, we compile all the available published and unpublished excavation documentation from the 1960s to the present. We use these maps and sections to present our spatial study of the LSM (Lower Stratigraphic Member) at the Ambrona site, combining stratigraphic criteria with GIS density and orientation analysis. This study enabled us to define the main concentrations of the LSM, providing an initial contribution to an assessment of their accumulation processes. Most of the concentrations preserved in the ancient shore area of the site display marked orientation patterns which coincide with the direction of the main water flows into the Ambrona wetland. However, random orientation patterns were observed in the central part of the site (Alpha concentration); they may be mostly preserved without undergoing transport processes, as previous taphonomic studies also confirm. PMID- 28002425 TI - Genetic Loci and Novel Discrimination Measures Associated with Blood Pressure Variation in African Americans Living in Tallahassee. AB - Sequencing of the human genome and decades of genetic association and linkage studies have dramatically improved our understanding of the etiology of many diseases. However, the multiple causes of complex diseases are still not well understood, in part because genetic and sociocultural risk factors are not typically investigated concurrently. Hypertension is a leading risk factor for cardiovascular disease and afflicts more African Americans than any other racially defined group in the US. Few genetic loci for hypertension have been replicated across populations, which may reflect population-specific differences in genetic variants and/or inattention to relevant sociocultural factors. Discrimination is a salient sociocultural risk factor for poor health and has been associated with hypertension. Here we use a biocultural approach to study blood pressure (BP) variation in African Americans living in Tallahassee, Florida by genotyping over 30,000 single nucleotide polymorphisms (SNPs) and capturing experiences of discrimination using novel measures of unfair treatment of self and others (n = 157). We perform a joint admixture and genetic association analysis for BP that prioritizes regions of the genome with African ancestry. We only report significant SNPs that were confirmed through our simulation analyses, which were performed to determine the false positive rate. We identify eight significant SNPs in five genes that were previously associated with cardiovascular diseases. When we include measures of unfair treatment and test for interactions between SNPs and unfair treatment, we identify a new class of genes involved in multiple phenotypes including psychosocial distress and mood disorders. Our results suggest that inclusion of culturally relevant stress measures, like unfair treatment in African Americans, may reveal new genes and biological pathways relevant to the etiology of hypertension, and may also improve our understanding of the complexity of gene-environment interactions that underlie complex diseases. PMID- 28002426 TI - Assessing Microstructural Substrates of White Matter Abnormalities: A Comparative Study Using DTI and NODDI. AB - Neurite orientation dispersion and density imaging (NODDI) enables more specific characterization of tissue microstructure by estimating neurite density (NDI) and orientation dispersion (ODI), two key contributors to fractional anisotropy (FA). The present work compared NODDI- with diffusion tensor imaging (DTI)-derived indices for investigating white matter abnormalities in a clinical sample. We assessed the added value of NODDI parameters over FA, by contrasting group differences identified by both models. Diffusion-weighted images with multiple shells were acquired in a group of 8 healthy controls and 8 patients with an inherited metabolic disease. Both standard DTI and NODDI analyses were performed. Tract based spatial statistics (TBSS) was used for group inferences, after which overlap and unique contributions across different parameters were evaluated. Results showed that group differences in NDI and ODI were complementary, and together could explain much of the FA results. Further, compared to FA analysis, NDI and ODI gave a pattern of results that was more regionally specific and were able to capture additional discriminative voxels that FA failed to identify. Finally, ODI from single-shell NODDI analysis, but not NDI, was found to reproduce the group differences from the multi-shell analysis. To conclude, by using a clinically feasible acquisition and analysis protocol, we demonstrated that NODDI is of added value to standard DTI, by revealing specific microstructural substrates to white matter changes detected with FA. As the (simpler) DTI model was more sensitive in identifying group differences, NODDI is recommended to be used complementary to DTI, thereby adding greater specificity regarding microstructural underpinnings of the differences. The finding that ODI abnormalities can be identified reliably using single-shell data may allow the retrospective analysis of standard DTI with NODDI. PMID- 28002427 TI - Normal Modes Expose Active Sites in Enzymes. AB - Accurate prediction of active sites is an important tool in bioinformatics. Here we present an improved structure based technique to expose active sites that is based on large changes of solvent accessibility accompanying normal mode dynamics. The technique which detects EXPOsure of active SITes through normal modEs is named EXPOSITE. The technique is trained using a small 133 enzyme dataset and tested using a large 845 enzyme dataset, both with known active site residues. EXPOSITE is also tested in a benchmark protein ligand dataset (PLD) comprising 48 proteins with and without bound ligands. EXPOSITE is shown to successfully locate the active site in most instances, and is found to be more accurate than other structure-based techniques. Interestingly, in several instances, the active site does not correspond to the largest pocket. EXPOSITE is advantageous due to its high precision and paves the way for structure based prediction of active site in enzymes. PMID- 28002428 TI - Integrated Strategy Improves the Prediction Accuracy of miRNA in Large Dataset. AB - MiRNAs are short non-coding RNAs of about 22 nucleotides, which play critical roles in gene expression regulation. The biogenesis of miRNAs is largely determined by the sequence and structural features of their parental RNA molecules. Based on these features, multiple computational tools have been developed to predict if RNA transcripts contain miRNAs or not. Although being very successful, these predictors started to face multiple challenges in recent years. Many predictors were optimized using datasets of hundreds of miRNA samples. The sizes of these datasets are much smaller than the number of known miRNAs. Consequently, the prediction accuracy of these predictors in large dataset becomes unknown and needs to be re-tested. In addition, many predictors were optimized for either high sensitivity or high specificity. These optimization strategies may bring in serious limitations in applications. Moreover, to meet continuously raised expectations on these computational tools, improving the prediction accuracy becomes extremely important. In this study, a meta-predictor mirMeta was developed by integrating a set of non-linear transformations with meta-strategy. More specifically, the outputs of five individual predictors were first preprocessed using non-linear transformations, and then fed into an artificial neural network to make the meta-prediction. The prediction accuracy of meta-predictor was validated using both multi-fold cross validation and independent dataset. The final accuracy of meta-predictor in newly designed large dataset is improved by 7% to 93%. The meta-predictor is also proved to be less dependent on datasets, as well as has refined balance between sensitivity and specificity. This study has two folds of importance: First, it shows that the combination of non-linear transformations and artificial neural networks improves the prediction accuracy of individual predictors. Second, a new miRNA predictor with significantly improved prediction accuracy is developed for the community for identifying novel miRNAs and the complete set of miRNAs. Source code is available at: https://github.com/xueLab/mirMeta. PMID- 28002429 TI - Inter-Gender sEMG Evaluation of Central and Peripheral Fatigue in Biceps Brachii of Young Healthy Subjects. AB - PURPOSE: The purpose of the present study was to evaluate inter-arm and inter gender differences in fractal dimension (FD) and conduction velocity (CV) obtained from multichannel surface electromyographic (sEMG) recordings during sustained fatiguing contractions of the biceps brachii. METHODS: A total of 20 recreationally active males (24+/-6 years) and 18 recreationally active females (22+/-9 years) performed two isometric contractions at 120 degrees elbow joint angle: (1) at 20% maximal voluntary contraction (MVC) for 90 s, and (2) at 60% MVC until exhaustion the time to perform the task has been measured. Signals from sEMG were detected from the biceps brachii using bidimensional arrays of 64 electrodes and initial values and rate of change of CV and FD of the sEMG signal were calculated. RESULTS: No difference between left and right sides and no statistically significant interaction effect of sides with gender were found for all parameters measured. A significant inter-gender difference was found for MVC (p<0.0001). Initial values of CV were higher in females than in males at both force levels (20% MCV: p<0.0001; 60% MCV: p<0.05) whereas a lower initial estimate of FD was observed in females compared to males (20% MCV: p<0.05; 60% MCV: p<0.0001). No difference in CV and FD slopes was found at 20% MVC between genders. At 60% MVC significantly lower CV and FD slopes (CV and FD: p<0.05) and a more protracted time to exhaustion were found in females than in males (p<0.0001). When considering time to exhaustion at both levels of contraction no difference in percentage change (Delta%) of CV and FD slopes was found between genders (p>0.05). During the sustained 60% MVC no statistical correlation was found between MVC and CV or FD initial estimates nor between MVC and CV or FD slopes both in males and females whereas. A significant positive correlation between CV and FD slopes was found in both genders (males: r = 0,61; females: r = 0,55). CONCLUSIONS: Fatigue determines changes in FD and CV values in biceps brachii during sustained contractions at 60% MVC. In particular males show greater increase in the rate of change of CV and FD than females whereas no difference in percentage change of these sEMG descriptors of fatigue was found. A significant correlation between FD and CV slopes found in both genders highlights that central and peripheral myoelectric components of fatigue may interact during submaximal isometric contractions. PMID- 28002431 TI - Reproductive Biology of Albacore Tuna (Thunnus alalunga) in the Western Indian Ocean. AB - The reproductive biology of albacore tuna, Thunnus alalunga, in the western Indian Ocean was examined through analysis of the sex ratio, spawning season, length-at-maturity (L50), spawning frequency and fecundity. From 2013 to 2015, a total of 923 female and 867 male albacore were sampled. A bias in sex ratio was found in favor of females with fork length (LF) < 100 cm. Using histological analyses and gonadosomatic index, spawning was found to occur between 10 degrees S and 30 degrees S, mainly to the east of Madagascar from October to January. Large females contributed more to reproduction through their longer spawning period compared to small individuals. The L50 (mean +/- standard error) of female albacore was estimated at 85.3 +/- 0.7 cm LF. Albacore spawn on average every 2.2 days within the spawning region and spawning months, from November to January. Batch fecundity ranged between 0.26 and 2.09 million oocytes and the relative batch fecundity (mean +/- standard deviation) was estimated at 53.4 +/- 23.2 oocytes g-1 of somatic-gutted weight. The study provides new information on the reproductive development and classification of albacore in the western Indian Ocean. The reproductive parameters will reduce uncertainty in current stock assessment models which will eventually assist the fishery to be sustainable for future generations. PMID- 28002430 TI - A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation. AB - Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives. By exome sequencing, we detected a novel mutation in HRAS gene (NM_005343.2:p.Arg68Trp), present also in the proband's daughter, who showed mild LVH and severe intellectual disability. The cardiac phenotype was indistinguishable between family members carrying either mutation. In silico studies suggested that the mutated HRAS protein is constitutionally activated. Consistently, functional characterization in vitro confirmed elevated HRAS-GTP accumulation and downstream RAS-MAPK pathway activation that are known to drive cell proliferation in LVH. Our study emphasizes the role of RAS signaling in cardiac hypertrophy and highlights the complexity in differential diagnosis of RASopathies. In fact, the mild features of RASopathy and the recurrence of sarcomeric HCM in this family delayed the correct diagnosis until comprehensive genetic testing was performed. PMID- 28002432 TI - Task Differences and Prosociality; Investigating Pet Dogs' Prosocial Preferences in a Token Choice Paradigm. AB - Prosociality has received increasing interest by non-human animal researchers since the initial discoveries that suggested it is not a uniquely human trait. However, thus far studies, even within the same species, have not garnered conclusive results. A prominent suggestion for this disparity is the effect methodology can have on prosocial responses in animals. We recently found evidence of prosociality in domestic dogs towards familiar conspecifics using a bar-pulling paradigm, in which a subject could pull a rope to deliver food to its partner. Therefore, the current study aimed to assess whether dogs would show a similar response in a different paradigm, based on the token exchange task paradigm frequently used with primates. In this task, dogs had the option to touch a token with their nose that delivered a reward to an adjacent receiver enclosure, which contained a familiar conspecific, a stranger or no dog at all. Crucially, we also included a social facilitation control condition, whereby the partner (stranger/familiar) was present but unable to access the food. We found that the familiarity effect remained consistent across tasks, with dogs of both the bar-pulling and token choice experiments providing more food to familiar partners than in a non-social control and providing less food to stranger partners than this same control. However, in contrast to our previous bar-pulling experiment, we could not exclude social facilitation as an underlying motive in the current task. We propose this difference in results between tasks may be related to increased task complexity in the token choice paradigm, making it harder for dogs to discriminate between the test and social facilitation conditions. Overall our findings suggest that subtle methodological changes can have an impact on prosocial behaviours in dogs and highlights the importance of controlling for social facilitation effects in such experiments. PMID- 28002434 TI - Correction: First Demonstration of Antigen Induced Cytokine Expression by CD4-1+ Lymphocytes in a Poikilotherm: Studies in Zebrafish (Danio rerio). AB - [This corrects the article DOI: 10.1371/journal.pone.0126378.]. PMID- 28002433 TI - A Therapeutic Uricase with Reduced Immunogenicity Risk and Improved Development Properties. AB - Humans and higher primates are unique in that they lack uricase, the enzyme capable of oxidizing uric acid. As a consequence of this enzyme deficiency, humans have high serum uric acid levels. In some people, uric acid levels rise above the solubility limit resulting in crystallization in joints, acute inflammation in response to those crystals causes severe pain; a condition known as gout. Treatment for severe gout includes injection of non-human uricase to reduce serum uric acid levels. Krystexxa(r) is a hyper-PEGylated pig-baboon chimeric uricase indicated for chronic refractory gout that induces an immunogenic response in 91% of treated patients, including infusion reactions (26%) and anaphylaxis (6.5%). These properties limit its use and effectiveness. An innovative approach has been used to develop a therapeutic uricase with improved properties such as: soluble expression, neutral pH solubility, high E. coli expression level, thermal stability, and excellent activity. More than 200 diverse uricase sequences were aligned to guide protein engineering and reduce putative sequence liabilities. A single uricase lead candidate was identified, which showed low potential for immunogenicity in >200 human donor samples selected to represent diverse HLA haplotypes. Cysteines were engineered into the lead sequence for site specific PEGylation and studies demonstrated >95% PEGylation efficiency. PEGylated uricase retains enzymatic activity in vitro at neutral pH, in human serum and in vivo (rats and canines) and has an extended half-life. In canines, an 85% reduction in serum uric acid levels was observed with a single subcutaneous injection. This PEGylated, non-immunogenic uricase has the potential to provide meaningful benefits to patients with gout. PMID- 28002435 TI - Transcriptome Profiling of Trypanosoma brucei Development in the Tsetse Fly Vector Glossina morsitans. AB - African trypanosomes, the causative agents of sleeping sickness in humans and nagana in animals, have a complex digenetic life cycle between a mammalian host and an insect vector, the blood-feeding tsetse fly. Although the importance of the insect vector to transmit the disease was first realized over a century ago, many aspects of trypanosome development in tsetse have not progressed beyond a morphological analysis, mainly due to considerable challenges to obtain sufficient material for molecular studies. Here, we used high-throughput RNA Sequencing (RNA-Seq) to profile Trypanosoma brucei transcript levels in three distinct tissues of the tsetse fly, namely the midgut, proventriculus and salivary glands. Consistent with current knowledge and providing a proof of principle, transcripts coding for procyclin isoforms and several components of the cytochrome oxidase complex were highly up-regulated in the midgut transcriptome, whereas transcripts encoding metacyclic VSGs (mVSGs) and the surface coat protein brucei alanine rich protein or BARP were extremely up regulated in the salivary gland transcriptome. Gene ontology analysis also supported the up-regulation of biological processes such as DNA metabolism and DNA replication in the proventriculus transcriptome and major changes in signal transduction and cyclic nucleotide metabolism in the salivary gland transcriptome. Our data highlight a small repertoire of expressed mVSGs and potential signaling pathways involving receptor-type adenylate cyclases and members of a surface carboxylate transporter family, called PADs (Proteins Associated with Differentiation), to cope with the changing environment, as well as RNA-binding proteins as a possible global regulators of gene expression. PMID- 28002436 TI - Biodiversity of Trichoderma Community in the Tidal Flats and Wetland of Southeastern China. AB - To investigate the biodiversity of Trichoderma (Hypocreaceae) and their relation to sediment physical and chemical properties, we collected a total of 491 sediment samples from coastal wetlands (tidal flat and wetland) in Southeast China. Further, we applied two types of molecular approaches such as culture dependent and independent methods for identification of Trichoderma spp. A total of 254 isolates were obtained and identified to 13 species such as T. aureoviride, T. asperellum, T. harzianum, T. atroviride, T. koningiopsis, T. longibrachiatum, T. koningii. T. tawa, T. viridescens, T. virens, T. hamatum, T. viride, and T. velutinum by the culture-dependent (CD) method of these, T. tawa was newly described in China. Subsequently, the culture indepented method of 454 pyrosequencing analysis revealed a total of six species such as T. citrinoviride, T. virens, T. polysporum, T. harzianum/Hypocrea lixii and two unknown species. Notably, T. citrinoviride and T. polysporum were not found by the CD method. Therefore, this work revealed that the combination of these two methods could show the higher biodiversity of Trichoderma spp., than either of this method alone. Among the sampling sites, Hangzhou, Zhejiang Province, exhibited rich biodiversity and low in Fengxian. Correlation and Redundancy discriminant analysis (RDA) revealed that sediment properties of temperature, redox potential (Eh) and pH significantly influenced the biodiversity of Trichoderma spp. PMID- 28002437 TI - Non-Sagittal Knee Joint Kinematics and Kinetics during Gait on Level and Sloped Grounds with Unicompartmental and Total Knee Arthroplasty Patients. AB - After knee arthroplasty (KA) surgery, patients experience abnormal kinematics and kinetics during numerous activities of daily living. Biomechanical investigations have focused primarily on level walking, whereas walking on sloped surfaces, which is stated to affect knee kinematics and kinetics considerably, has been neglected to this day. This study aimed to analyze over-ground walking on level and sloped surfaces with a special focus on transverse and frontal plane knee kinematics and kinetics in patients with KA. A three-dimensional (3D) motion analysis was performed by means of optoelectronic stereophogrammetry 1.8 +/- 0.4 years following total knee arthroplasty (TKA) and unicompartmental arthroplasty surgery (UKA). AnyBodyTM Modeling System was used to conduct inverse dynamics. The TKA group negotiated the decline walking task with reduced peak knee internal rotation angles compared with a healthy control group (CG). First-peak knee adduction moments were diminished by 27% (TKA group) and 22% (UKA group) compared with the CG during decline walking. No significant differences were detected between the TKA and UKA groups, regardless of the locomotion task. Decline walking exposed apparently more abnormal knee frontal and transverse plane adjustments in KA patients than level walking compared with the CG. Hence, walking on sloped surfaces should be included in further motion analysis studies investigating KA patients in order to detect potential deficits that might be not obvious during level walking. PMID- 28002438 TI - Development of a Machine Learning Algorithm for the Surveillance of Autism Spectrum Disorder. AB - The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts population-based surveillance of autism spectrum disorder (ASD) among 8-year old children in multiple US sites. To classify ASD, trained clinicians review developmental evaluations collected from multiple health and education sources to determine whether the child meets the ASD surveillance case criteria. The number of evaluations collected has dramatically increased since the year 2000, challenging the resources and timeliness of the surveillance system. We developed and evaluated a machine learning approach to classify case status in ADDM using words and phrases contained in children's developmental evaluations. We trained a random forest classifier using data from the 2008 Georgia ADDM site which included 1,162 children with 5,396 evaluations (601 children met ADDM ASD criteria using standard ADDM methods). The classifier used the words and phrases from the evaluations to predict ASD case status. We evaluated its performance on the 2010 Georgia ADDM surveillance data (1,450 children with 9,811 evaluations; 754 children met ADDM ASD criteria). We also estimated ASD prevalence using predictions from the classification algorithm. Overall, the machine learning approach predicted ASD case statuses that were 86.5% concordant with the clinician-determined case statuses (84.0% sensitivity, 89.4% predictive value positive). The area under the resulting receiver-operating characteristic curve was 0.932. Algorithm-derived ASD "prevalence" was 1.46% compared to the published (clinician-determined) estimate of 1.55%. Using only the text contained in developmental evaluations, a machine learning algorithm was able to discriminate between children that do and do not meet ASD surveillance criteria at one surveillance site. PMID- 28002439 TI - Dexrazoxane Shows No Protective Effect in the Acute Phase of Reperfusion during Myocardial Infarction in Pigs. AB - Calcium and iron overload participate in the mechanisms of ischemia/reperfusion (I/R) injury during myocardial infarction (MI). Calcium overload induces cardiomyocyte death by hypercontraction, while iron catalyses generation of reactive oxygen species (ROS). We therefore hypothesized that dexrazoxane, an intracellular metal chelator, would attenuate I/R injury. MI was induced in pigs by occlusion of the left anterior descending artery for 1 hour followed by 2 hours reperfusion. Thirty minutes before reperfusion either 5 mg/ml dexrazoxane (n = 5) or saline (n = 5) was infused intravenously. Myocardial necrosis as percentage of the area at ischemic risk was found to be similar in both groups (77.2 +/- 18% for dexrazoxane and 76.4 +/- 14% for saline group) as determined by triphenyl tetrazolium chloride staining of the ischemic myocardium. Also, serum levels of troponin-I were similar in both groups. A conductance catheter was used to measure left ventricular pressure and volume at all times. Markers for tissue damage due to ROS (HNE), endothelial cell activation (CD31) and inflammation (IgG, C3b/c, C5b9, MCP-1) were assessed on tissue and/or in serum. No significant differences were observed between the groups for the parameters analyzed. To conclude, in this clinically relevant model of early reperfusion after acute myocardial ischemia, dexrazoxane lacked attenuating effects on I/R injury as shown by the measured parameters. PMID- 28002440 TI - How Are Gender Equality and Human Rights Interventions Included in Sexual and Reproductive Health Programmes and Policies: A Systematic Review of Existing Research Foci and Gaps. AB - The importance of promoting gender equality and human rights in sexual and reproductive health (SRH) programmes and policies has been affirmed in numerous international and regional agreements, most recently the 2030 Agenda for Sustainable Development. Given the critical role of research to determine what works, we aimed to identify research gaps as part of a broader priority setting exercise on integrating gender equality and human rights approaches in SRH programmes and policies. A systematic literature review of reviews was conducted to examine the question: what do we know about how research in the context of SRH programmes and policies has addressed gender equality and human rights and what are the current gaps in research. We searched three databases for reviews that addressed the research question, were published between 1994-2014, and met methodological standards for systematic reviews, qualitative meta-syntheses and other reviews of relevance to the research question. Additional grey literature was identified based on expert input. Articles were appraised by the primary author and examined by an expert panel. An abstraction and thematic analysis process was used to synthesize findings. Of the 3,073 abstracts identified, 56 articles were reviewed in full and 23 were included along with 10 from the grey literature. The majority focused on interventions addressing gender inequalities; very few reviews explicitly included human rights based interventions. Across both topics, weak study designs and use of intermediate outcome measures limited evidence quality. Further, there was limited evidence on interventions that addressed marginalized groups. Better quality studies, longer-term indicators, and measurement of unintended consequences are needed to better understand the impact of these types of interventions on SRH outcomes. Further efforts are needed to cover research on gender equality and human rights issues as they pertain to a broader set of SRH topics and populations. PMID- 28002441 TI - Galectin-3 and Its Genetic Variation rs4644 Modulate Enterovirus 71 Infection. AB - Galectin-3, a chimeric type beta-galactoside-binding protein, is known to modulate viral infection; however, its role in enterovirus 71 (EV71) infection has not been investigated. We generated galectin-3 null rhabdomyosarcoma (RD) cells and evaluated whether EV71 infection would be affected. In galectin-3 null cells, the released and intracellular EV71 viral loads were suppressed after 24 h of infection, and cell death rates were significantly lower, while cell proliferation remained unaltered. In addition, RD cells expressing a nonsynonymous genetic variant of galectin-3, rs4644 (LGALS3 +191C/A, P64H), produced lower virus titers than those with wild-type galectin-3 (C allele). To clarify whether the in vitro viral load reduction correlates with clinical severity, we enrolled children with laboratory-confirmed EV71 infection. Since hyperglycemia is an indicator of severe EV71 infection in children, 152 of 401 enrolled children had glucose examinations at admission, and 59 subjects had serum glucose levels >= 150 mg/dL. In comparison to the rs4644 AA genotype (2.2 +/- 0.06 log10 mg/dL), serum glucose levels during EV71 infection were higher in patients with CC (2.4 +/- 0.17 log10 mg/dL, p = 0.03) and CA (2.4 +/- 0.15 log10 mg/dL, p = 0.02) genotypes, respectively. These findings suggest that the rs4644 AA genotype of galectin-3 might exert a protective effect. In summary, galectin-3 affects EV71 replication in our cellular model and its variant, rs4644, is associated with hyperglycemia in the clinical setting. The underlying mechanism and its potential therapeutic application warrant further investigation. PMID- 28002442 TI - Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity. AB - Bone development and length relies on the growth plate formation, which is dependent on degradative enzymes such as MMPs. Indeed, deletion of specific members of this enzyme family in mice results in important joint and bone abnormalities, suggesting a role in skeletal development. As such, the control of MMP activity is vital in the complex process of bone formation and growth. We generated a transgenic mouse line to overexpress TIMP3 in mouse chondrocytes using the Col2a1-chondrocyte promoter. This overexpression in cartilage resulted in a transient shortening of growth plate in homozygote mice but bone length was restored at eight weeks of age. However, tibial bone structure and mechanical properties remained compromised. Despite no transgene expression in adult osteoblasts from transgenic mice in vitro, their differentiation capacity was decreased. Neonates, however, did show transgene expression in a subset of bone cells. Our data demonstrate for the first time that transgene function persists in the chondro-osseous lineage continuum and exert influence upon bone quantity and quality. PMID- 28002443 TI - Distributional Variations in the Quantitative Cortical and Trabecular Bone Radiographic Measurements of Mandible, between Male and Female Populations of Korea, and its Utilization. AB - It is important to investigate the irregularities in aging-associated changes in bone, between men and women for bone strength and osteoporosis. The purpose of this study was to characterize the changes and associations of mandibular cortical and trabecular bone measures of men and women based on age and to the evaluation of cortical shape categories, in a large Korean population. Panoramic radiographs of 1047 subjects (603 women and 444 men) aged between 15 to 90 years were used. Mandibular cortical width (MCW), mandibular cortical index (MCI), and fractal dimensions (FD) of the molar, premolar, and anterior regions of the mandibular trabecular bone were measured. Study subjects were grouped into six 10 years age groups. A local linear regression smoothing with bootstrap resampling for robust fitting of data was used to estimate the relationship between radiographic mandibular variables and age groups as well as genders. The mean age of women (49.56 +/- 19.5 years) was significantly higher than that of men (45.57 +/- 19.6 years). The MCW of men and women (3.17mm and 2.91mm, respectively, p < 0.0001) was strongly associated with age and MCI. Indeed, trabecular measures also correlated with age in men (r > -0.140, p = 0.003), though not as strongly as in women (r > -0.210, p < 0.0001). In men aged over 55 years, only MCW was significantly associated (r = -0.412, p < 0.0001). Furthermore, by comparison of mandibular variables from different age groups and MCI categories, the results suggest that MCW was detected to be strongly associated in both men and women for the detection of bone strength and osteoporosis. The FD measures revealed relatively higher association with age among women than men, but not as strong as MCW. PMID- 28002444 TI - Seafood-Processing Sludge Composting: Changes to Microbial Communities and Physico-Chemical Parameters of Static Treatment versus for Turning during the Maturation Stage. AB - In general, in composting facilities the active, or intensive, stage of the process is done separately from the maturation stage, using a specific technology and time. The pre-composted material to be matured can contain enough biodegradable substrates to cause microbial proliferation, which in turn can cause temperatures to increase. Therefore, not controlling the maturation period during waste management at an industrial level can result in undesired outcomes. The main hypothesis of this study is that controlling the maturation stage through turning provides one with an optimized process when compared to the static approach. The waste used was sludge from a seafood-processing plant, mixed with shredded wood (1:2, v/v). The composting system consists of an intensive stage in a 600L static reactor, followed by maturation in triplicate in 200L boxes for 112 days. Two tests were carried out with the same process in reactor and different treatments in boxes: static maturation and turning during maturation when the temperature went above 55 degrees C. PLFAs, organic matter, pH, electrical conductivity, forms of nitrogen and carbon, hydrolytic enzymes and respiratory activity were periodically measured. Turning significantly increased the duration of the thermophilic phase and consequently increased the organic matter degradation. PCA differentiated significantly the two treatments in function of tracking parameters, especially pH, total carbon, forms of nitrogen and C/N ratio. So, stability and maturity optimum values for compost were achieved in less time with turnings. Whereas turning resulted in microbial-group stabilization and a low mono/sat ratio, static treatment produced greater variability in microbial groups and a high mono/sat ratio, the presence of more degradable substrates causes changes in microbial communities and their study during maturation gives an approach of the state of organic-matter degradation. Obtaining quality compost and optimizing the composting process requires using turning as a control mechanism during maturation. PMID- 28002445 TI - Discovering SIFIs in Interbank Communities. AB - This paper proposes a new methodology based on non-negative matrix factorization to detect communities and to identify central nodes in a network as well as within communities. The method is specifically designed for directed weighted networks and, consequently, it has been applied to the interbank network derived from the e-MID interbank market. In an interbank network indeed links are directed, representing flows of funds between lenders and borrowers. Besides distinguishing between Systemically Important Borrowers and Lenders, the technique complements the detection of systemically important banks, revealing the community structure of the network, that proxies the most plausible areas of contagion of institutions' distress. PMID- 28002446 TI - The Agaricus blazei-Based Mushroom Extract, AndosanTM, Protects against Intestinal Tumorigenesis in the A/J Min/+ Mouse. AB - BACKGROUND: The novel A/J Min/+ mouse, which is a model for human Familial Adenomatous Polyposis (FAP), develops spontaneously multiple adenocarcinomas in the colon as well as in the small intestine. Agaricus blazei Murill (AbM) is an edible Basidiomycetes mushroom that has been used in traditional medicine against cancer and other diseases. The mushroom contains immunomodulating beta-glucans and is shown to have antitumor effects in murine cancer models. AndosanTM is a water extract based on AbM (82%), but it also contains the medicinal Basidiomycetes mushrooms Hericeum erinaceus and Grifola frondosa. METHODS AND FINDINGS: Tap water with 10% AndosanTM was provided as the only drinking water for 15 or 22 weeks to A/J Min/+ mice and A/J wild-type mice (one single nucleotide polymorphism (SNP) difference), which then were exsanguinated and their intestines preserved in formaldehyde and the serum frozen. The intestines were examined blindly by microscopy and also stained for the tumor-associated protease, legumain. Serum cytokines (pro- and anti-inflammatory, Th1-, Th2 -and Th17 type) were measured by Luminex multiplex analysis. AndosanTM treated A/J Min/+ mice had a significantly lower number of adenocarcinomas in the intestines, as well as a 60% significantly reduced intestinal tumor load (number of tumors x size) compared to control. There was also reduced legumain expression in intestines from AndosanTM treated animals. Moreover, AndosanTM had a significant cytotoxic effect correlating with apoptosis on the human cancer colon cell line, Caco-2, in vitro. When examining serum from both A/J Min/+ and wild type mice, there was a significant increase in anti-tumor Th1 type and pro-inflammatory cytokines in the AndosanTM treated mice. CONCLUSIONS: The results from this mouse model for colorectal cancer shows significant protection of orally administered AndosanTM against development of intestinal cancer. This is supported by the finding of less legumain in intestines of AndosanTM treated mice and increased systemic Th1 cytokine response. The mechanism is probably both immuno-modulatory and growth inhibition of tumor cells by induction of apoptosis. PMID- 28002447 TI - Influence of Polymorphisms in the HTR3A and HTR3B Genes on Experimental Pain and the Effect of the 5-HT3 Antagonist Granisetron. AB - The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn. PMID- 28002449 TI - Identification of a Differentially Expressed TIR-NBS-LRR Gene in a Major QTL Associated to Leaf Rust Resistance in Salix. AB - An earlier identified major quantitative trait locus for resistance towards the willow leaf rust fungus Melampsora larici-epitea in a Salix viminalis x (S. viminalis * S. schwerinii) population was used to identify potential resistance genes to the rust pathogen. Screening a genomic bacterial artificial chromosome library with markers from the peak position of the QTL region revealed one gene with TIR-NBS-LRR (Toll Interleukin1 Receptor-Nucleotide Binding Site-Leucine-Rich Repeat) domain structure indicative of a resistance gene. The resistance gene analog was denoted RGA1 and further analysis revealed a number of non-synonymous single nucleotide polymorphisms in the LRR domain between the resistant and susceptible Salix genotypes. Gene expression levels under controlled conditions showed a significantly lower constitutive expression of RGA1 in the susceptible genotype. In addition, the susceptible genotype showed a significantly reduced expression level of the RGA1 gene at 24 hours post inoculation with M. larici epitea. This indicates that the pathogen may actively suppress RGA1 gene expression allowing a compatible plant-pathogen interaction and causing infection. PMID- 28002448 TI - Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness. AB - BACKGROUND: Resistance to intravenous immunoglobulin (IVIG) occurs in 10-20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels. METHOD: We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis. RESULTS: Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non responders. CONCLUSIONS: Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics. PMID- 28002450 TI - Seeing It All: Evaluating Supervised Machine Learning Methods for the Classification of Diverse Otariid Behaviours. AB - Constructing activity budgets for marine animals when they are at sea and cannot be directly observed is challenging, but recent advances in bio-logging technology offer solutions to this problem. Accelerometers can potentially identify a wide range of behaviours for animals based on unique patterns of acceleration. However, when analysing data derived from accelerometers, there are many statistical techniques available which when applied to different data sets produce different classification accuracies. We investigated a selection of supervised machine learning methods for interpreting behavioural data from captive otariids (fur seals and sea lions). We conducted controlled experiments with 12 seals, where their behaviours were filmed while they were wearing 3-axis accelerometers. From video we identified 26 behaviours that could be grouped into one of four categories (foraging, resting, travelling and grooming) representing key behaviour states for wild seals. We used data from 10 seals to train four predictive classification models: stochastic gradient boosting (GBM), random forests, support vector machine using four different kernels and a baseline model: penalised logistic regression. We then took the best parameters from each model and cross-validated the results on the two seals unseen so far. We also investigated the influence of feature statistics (describing some characteristic of the seal), testing the models both with and without these. Cross-validation accuracies were lower than training accuracy, but the SVM with a polynomial kernel was still able to classify seal behaviour with high accuracy (>70%). Adding feature statistics improved accuracies across all models tested. Most categories of behaviour -resting, grooming and feeding-were all predicted with reasonable accuracy (52-81%) by the SVM while travelling was poorly categorised (31-41%). These results show that model selection is important when classifying behaviour and that by using animal characteristics we can strengthen the overall accuracy. PMID- 28002451 TI - Investigating the Potential Signaling Pathways That Regulate Activation of the Novel PKC Downstream of Serotonin in Aplysia. AB - Activation of the novel PKC Apl II in sensory neurons by serotonin (5HT) underlies the ability of 5HT to reverse synaptic depression, but the pathway from 5HT to PKC Apl II activation remains unclear. Here we find no evidence for the Aplysia-specific B receptors, or for adenylate cyclase activation, to translocate fluorescently-tagged PKC Apl II. Using an anti-PKC Apl II antibody, we monitor translocation of endogenous PKC Apl II and determine the dose response for PKC Apl II translocation, both in isolated sensory neurons and sensory neurons coupled with motor neurons. Using this assay, we confirm an important role for tyrosine kinase activation in 5HT mediated PKC Apl II translocation, but rule out roles for intracellular tyrosine kinases, epidermal growth factor (EGF) receptors and Trk kinases in this response. A partial inhibition of translocation by a fibroblast growth factor (FGF)-receptor inhibitor led us to clone the Aplysia FGF receptor. Since a number of related receptors have been recently characterized, we use bioinformatics to define the relationship between these receptors and find a single FGF receptor orthologue in Aplysia. However, expression of the FGF receptor did not affect translocation or allow it in motor neurons where 5HT does not normally cause PKC Apl II translocation. These results suggest that additional receptor tyrosine kinases (RTKs) or other molecules must also be involved in translocation of PKC Apl II. PMID- 28002452 TI - The Effector Cig57 Hijacks FCHO-Mediated Vesicular Trafficking to Facilitate Intracellular Replication of Coxiella burnetii. AB - Coxiella burnetii is an intracellular bacterial pathogen that infects alveolar macrophages and replicates within a unique lysosome-derived vacuole. When Coxiella is trafficked to a host cell lysosome the essential Dot/Icm type IV secretion system is activated allowing over 130 bacterial effector proteins to be translocated into the host cytosol. This cohort of effectors is believed to manipulate host cell functions to facilitate Coxiella-containing vacuole (CCV) biogenesis and bacterial replication. Transposon mutagenesis has demonstrated that the Dot/Icm effector Cig57 is required for CCV development and intracellular replication of Coxiella. Here, we demonstrate a role for Cig57 in subverting clathrin-mediated traffic through its interaction with FCHO2, an accessory protein of clathrin coated pits. A yeast two-hybrid screen identified FCHO2 as a binding partner of Cig57 and this interaction was confirmed during infection using immunoprecipitation experiments. The interaction between Cig57 and FCHO2 is dependent on one of three endocytic sorting motif encoded by Cig57. Importantly, complementation analysis demonstrated that this endocytic sorting motif is required for full function of Cig57. Consistent with the intracellular growth defect in cig57-disrupted Coxiella, siRNA gene silencing of FCHO2 or clathrin (CLTC) inhibits Coxiella growth and CCV biogenesis. Clathrin is recruited to the replicative CCV in a manner that is dependent on the interaction between Cig57 and FCHO2. Creation of an FCHO2 knockout cell line confirmed the importance of this protein for CCV expansion, intracellular replication of Coxiella and clathrin recruitment to the CCV. Collectively, these results reveal Cig57 to be a significant virulence factor that co-opts clathrin-mediated trafficking, via interaction with FCHO2, to facilitate the biogenesis of the fusogenic Coxiella replicative vacuole and enable intracellular success of this human pathogen. PMID- 28002453 TI - Comparing Selections of Environmental Variables for Ecological Studies: A Focus on Terrain Attributes. AB - Selecting appropriate environmental variables is a key step in ecology. Terrain attributes (e.g. slope, rugosity) are routinely used as abiotic surrogates of species distribution and to produce habitat maps that can be used in decision making for conservation or management. Selecting appropriate terrain attributes for ecological studies may be a challenging process that can lead users to select a subjective, potentially sub-optimal combination of attributes for their applications. The objective of this paper is to assess the impacts of subjectively selecting terrain attributes for ecological applications by comparing the performance of different combinations of terrain attributes in the production of habitat maps and species distribution models. Seven different selections of terrain attributes, alone or in combination with other environmental variables, were used to map benthic habitats of German Bank (off Nova Scotia, Canada). 29 maps of potential habitats based on unsupervised classifications of biophysical characteristics of German Bank were produced, and 29 species distribution models of sea scallops were generated using MaxEnt. The performances of the 58 maps were quantified and compared to evaluate the effectiveness of the various combinations of environmental variables. One of the combinations of terrain attributes-recommended in a related study and that includes a measure of relative position, slope, two measures of orientation, topographic mean and a measure of rugosity-yielded better results than the other selections for both methodologies, confirming that they together best describe terrain properties. Important differences in performance (up to 47% in accuracy measurement) and spatial outputs (up to 58% in spatial distribution of habitats) highlighted the importance of carefully selecting variables for ecological applications. This paper demonstrates that making a subjective choice of variables may reduce map accuracy and produce maps that do not adequately represent habitats and species distributions, thus having important implications when these maps are used for decision-making. PMID- 28002455 TI - Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study. AB - Bladder inflammation frequently causes cystitis pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency. Although mast cells have been identified to play a critical role in bladder inflammation and pain, the role of mast cells in cystitis-associated LUTD has not been demonstrated. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and LUTD. In this study we investigated the role of mast cells in LUTD using a transgenic autoimmune cystitis model (URO-OVA) that reproduces many clinical correlates of IC/BPS. URO-OVA mice express the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develop bladder inflammation upon introduction of OVA-specific T cells. To investigate the role of mast cells, we crossed URO-OVA mice with mast cell deficient KitW-sh mice to generate URO-OVA/KitW-sh mice that retained urothelial OVA expression but lacked endogenous mast cells. We compared URO-OVA mice with URO-OVA/KitW-sh mice with and without mast cell reconstitution in response to cystitis induction. URO-OVA mice developed profound bladder inflammation with increased mast cell counts and LUTD, including increased total number of voids, decreased mean volume voided per micturition, and decreased maximum volume voided per micturition, after cystitis induction. In contrast, similarly cystitis induced URO-OVA/KitW-sh mice developed reduced bladder inflammation with no mast cells and LUTD detected. However, after mast cell reconstitution URO-OVA/KitW-sh mice restored the ability to develop bladder inflammation and LUTD following cystitis induction. We further treated URO-OVA mice with cromolyn, a mast cell membrane stabilizer, and found that cromolyn treatment reversed bladder inflammation and LUTD in the animal model. Our results provide direct evidence for the role of mast cells in cystitis-associated LUTD, supporting the use of mast cell inhibitors for treatment of certain forms of IC/BPS. PMID- 28002454 TI - Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes. AB - BACKGROUND: The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications. METHODOLOGY: Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses. PRINCIPAL FINDINGS: Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15 fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion. CONCLUSION: These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging. PMID- 28002456 TI - Parental Age of Onset of Cardiovascular Disease as a Predictor for Offspring Age of Onset of Cardiovascular Disease. AB - OBJECTIVE: The risk for cardiovascular disease (CVD) is higher for individuals with a first-degree relative who developed premature CVD (with a threshold at age 55 years for a male or 65 years for a female). However, little is known about the effect that each unit increase or decrease of maternal or paternal age of onset of CVD has on offspring age of onset of CVD. We hypothesized that there is an association between maternal and paternal age of onset of CVD and offspring age of onset of CVD. METHODS: We used the Framingham Heart Study database and performed conditional imputation for CVD-censored parental age (i.e. parents that didn't experience onset of CVD) and Cox proportional regression analysis, with offspring's age of onset of CVD as the dependent variable and parental age of onset of CVD as the primary predictor. Modifiable risk factors in offspring, such as cigarette smoking, body mass index (BMI), diabetes mellitus, systolic blood pressure (SBP), high-density lipoprotein (HDL) level, and low-density lipoprotein (LDL) level, were controlled for. Separate analyses were performed for the association between maternal age of onset of CVD and offspring age of onset of CVD and the association between paternal age of onset of CVD and offspring age of onset of CVD. RESULTS: Parental age of onset of CVD was predictive of offspring age of onset of CVD for maternal age of onset of CVD (P < .0001; N = 1401) and for paternal age of onset of CVD (P = 0.0134; N = 1221). A negative estimate of the coefficient of interest signifies that late onset of cardiovascular events in parents is protective of onset of CVD in offspring. Cigarette smoking and HDL level were important associated confounders. CONCLUSIONS: Offspring age of onset of cardiovascular disease is significantly associated with both maternal and paternal age of onset CVD. The incorporation of the parameters, maternal or paternal age of onset of CVD, into risk estimate calculators may improve accuracy of identification of high-risk patients in clinical settings. PMID- 28002457 TI - Terrorism, Radicalisation, Extremism, Authoritarianism and Fundamentalism: A Systematic Review of the Quality and Psychometric Properties of Assessments. AB - BACKGROUND: Currently, terrorism and suicide bombing are global psychosocial processes that attracts a growing number of psychological and psychiatric contributions to enhance practical counter-terrorism measures. The present study is a systematic review that explores the methodological quality reporting and the psychometric soundness of the instruments developed to identify risk factors of terrorism, extremism, radicalisation, authoritarianism and fundamentalism. METHOD: A systematic search strategy was established to identify instruments and studies developed to screen individuals at risk of committing extremist or terrorist offences using 20 different databases across the fields of law, medicine, psychology, sociology and politics. Information extracted was consolidated into two different tables and a 26-item checklist, reporting respectively background information, the psychometric properties of each tool, and the methodological quality markers of these tools. 37 articles met our criteria, which included a total of 4 instruments to be used operationally by professionals, 17 tools developed as research measures, and 9 inventories that have not been generated from a study. RESULTS: Just over half of the methodological quality markers required for a transparent methodological description of the instruments were reported. The amount of reported psychological properties was even fewer, with only a third of them available across the different studies. The category presenting the least satisfactory results was that containing the 4 instruments to be used operationally by professionals, which can be explained by the fact that half of them refrained from publishing the major part of their findings and relevant guidelines. CONCLUSIONS: A great number of flaws have been identified through this systematic review. The authors encourage future researchers to be more thorough, comprehensive and transparent in their methodology. They also recommend the creation of a multi-disciplinary joint working group in order to best tackle this growing contemporary problem. PMID- 28002458 TI - Validation of EGCRISC for Chronic Hepatitis C Infection Screening and Risk Assessment in the Egyptian Population. AB - Chronic HCV infection, a highly endemic disease in Egypt, is usually asymptomatic for decades after infection. Prediction questionnaire tool was proofed to be a valuable, feasible and efficient instrument for the screening of several diseases. We previously developed an Egyptian HCV risk screening tool (EGCRISC). This study aims to validate/modify EGCRISC. A cross-sectional study testing 4579 individuals by EGCRISC as well as ELISA/PCR was performed. The sample was a stratified cluster sampling from urban and rural areas in Upper and Lower Egypt using a proportional allocation technique. The degree of agreement and positive and negative posttest probabilities were calculated. ROC curve was done and the cutoff points were customized for best performance. The total score was further classified into three levels according to the risk load. The mean age of the participants was 41.1+/-12.2 in whom HCV prevalence was 8.6%. EGCRISC, particularly after modifying the cutoff points, has a good discriminating ability. The degree of agreement was at least 68.1% and the positive posttest probability ranged from 5% to 37.2% whereas the negative posttest probability was in the range 1% to 17%. We conclude that EGCRISC is a valid tool that can potentially screen for HCV infection risk in Egypt and could diminish the demand for mass serologic screening in those apparently at minimal risk. Extensive use of electronic and self- or interviewer-administered risk-based screening strategy may simplify and promote overall screening and detection of HCV dissimilar communities. PMID- 28002459 TI - Targeting Taxanes to Castration-Resistant Prostate Cancer Cells by Nanobubbles and Extracorporeal Shock Waves. AB - To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in urology and orthopedics, with no side effects. Nanobubbles, with an average diameter of 353.3 +/- 15.5 nm, entered two different castration resistant prostate cancer cells (PC3 and DU145) as demonstrated by flow cytometry and immunofluorescence. The shock waves applied increased the amount of intracellular nanobubbles. Loading nanobubbles with paclitaxel and docetaxel and combining them with shock waves generated the highest cytotoxic effects, resulting in a paclitaxel GI50 reduction of about 55% and in a docetaxel GI50 reduction of about 45% respectively. Combined treatment also affected cell migration. Paclitaxel-loaded nanobubbles and shock waves reduced cell migration by more than 85% with respect to paclitaxel alone; whereas docetaxel-loaded nanobubbles and shock waves reduced cell migration by more than 82% with respect to docetaxel alone. The present data suggest that nanobubbles can act as a stable taxane reservoir in castration-resistant prostate cancer cells and shock waves can further increase drug release from nanobubbles leading to higher cytotoxic and anti-migration effect. PMID- 28002461 TI - The Evolution of Facultative Conformity Based on Similarity. AB - Conformist social learning can have a pronounced impact on the cultural evolution of human societies, and it can shape both the genetic and cultural evolution of human social behavior more broadly. Conformist social learning is beneficial when the social learner and the demonstrators from whom she learns are similar in the sense that the same behavior is optimal for both. Otherwise, the social learner's optimum is likely to be rare among demonstrators, and conformity is costly. The trade-off between these two situations has figured prominently in the longstanding debate about the evolution of conformity, but the importance of the trade-off can depend critically on the flexibility of one's social learning strategy. We developed a gene-culture coevolutionary model that allows cognition to encode and process information about the similarity between naive learners and experienced demonstrators. Facultative social learning strategies that condition on perceived similarity evolve under certain circumstances. When this happens, facultative adjustments are often asymmetric. Asymmetric adjustments mean that the tendency to follow the majority when learners perceive demonstrators as similar is stronger than the tendency to follow the minority when learners perceive demonstrators as different. In an associated incentivized experiment, we found that social learners adjusted how they used social information based on perceived similarity, but adjustments were symmetric. The symmetry of adjustments completely eliminated the commonly assumed trade-off between cases in which learners and demonstrators share an optimum versus cases in which they do not. In a second experiment that maximized the potential for social learners to follow their preferred strategies, a few social learners exhibited an inclination to follow the majority. Most, however, did not respond systematically to social information. Additionally, in the complete absence of information about their similarity to demonstrators, social learners were unwilling to make assumptions about whether they shared an optimum with demonstrators. Instead, social learners simply ignored social information even though this was the only information available. Our results suggest that social cognition equips people to use conformity in a discriminating fashion that moderates the evolutionary trade-offs that would occur if conformist social learning was rigidly applied. PMID- 28002460 TI - Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice. AB - BACKGROUND AND AIMS: The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. METHODS: Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro. RESULTS: Compared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1beta, TNF-alpha and IFN-gamma expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-alpha-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation. CONCLUSIONS: Metformin supplementation promotes secretory cell lineage differentiation, suppresses inflammation and improves epithelial barrier function in IL10KO mice likely through activation of AMPK, showing its beneficial effects on gut epithelial. PMID- 28002462 TI - Why Having a (Nonfinancial) Interest Is Not a Conflict of Interest. AB - A current debate about conflicts of interest related to biomedical research is to question whether the focus on financial conflicts of interest overshadows "nonfinancial" interests that could put scientific judgment at equal or greater risk of bias. There is substantial evidence that financial conflicts of interest such as commercial sponsorship of research and investigators lead to systematic biases in scientific research at all stages of the research process. Conflation of "conflicts of interest" with "interests" in general serves to muddy the waters about how to manage conflicts of interest. We call for heightened disclosure of conflicts of interest and policy action beyond disclosure as the sole management strategy. We propose a different strategy to manage interests more broadly to ensure fair representation and accountability. PMID- 28002463 TI - A Modular and Affordable Time-Lapse Imaging and Incubation System Based on 3D Printed Parts, a Smartphone, and Off-The-Shelf Electronics. AB - Time-lapse imaging is a powerful tool for studying cellular dynamics and cell behavior over long periods of time to acquire detailed functional information. However, commercially available time-lapse imaging systems are expensive and this has limited a broader implementation of this technique in low-resource environments. Further, the availability of time-lapse imaging systems often present workflow bottlenecks in well-funded institutions. To address these limitations we have designed a modular and affordable time-lapse imaging and incubation system (ATLIS). The ATLIS enables the transformation of simple inverted microscopes into live cell imaging systems using custom-designed 3D printed parts, a smartphone, and off-the-shelf electronic components. We demonstrate that the ATLIS provides stable environmental conditions to support normal cell behavior during live imaging experiments in both traditional and evaporation-sensitive microfluidic cell culture systems. Thus, the system presented here has the potential to increase the accessibility of time-lapse microscopy of living cells for the wider research community. PMID- 28002464 TI - Contraceptive Use Affects Overall Olfactory Performance: Investigation of Estradiol Dosage and Duration of Intake. AB - The influence of female sex steroids on cognitive performance and sensory perception has been investigated for decades. However, previous research that studied olfaction revealed inconsistent results. The main aim of this study was to investigate the effects of different ethinyl estradiol (EE) concentrations of oral contraceptives and duration of intake on olfactory function. Forty-two healthy women, with regular intake of either high or low EE dosage over at least one year and up to 15 years participated in this study. Results revealed a significant concordance between a priori categorization in the two groups with high and low EE dosage and data-driven hierarchical clustering (p = 0.008). Furthermore, significantly higher olfactory performance was observed in women using low-dose products compared to women using high-dosed products (p = 0.019). These findings indicate different effects of pill use with regard to EE concentration. We therefore strongly recommend the acquisition of information about EE dosage of oral contraceptives to reduce potential confounding factors when investigating sensory systems. PMID- 28002465 TI - Inference of Functionally-Relevant N-acetyltransferase Residues Based on Statistical Correlations. AB - Over evolutionary time, members of a superfamily of homologous proteins sharing a common structural core diverge into subgroups filling various functional niches. At the sequence level, such divergence appears as correlations that arise from residue patterns distinct to each subgroup. Such a superfamily may be viewed as a population of sequences corresponding to a complex, high-dimensional probability distribution. Here we model this distribution as hierarchical interrelated hidden Markov models (hiHMMs), which describe these sequence correlations implicitly. By characterizing such correlations one may hope to obtain information regarding functionally-relevant properties that have thus far evaded detection. To do so, we infer a hiHMM distribution from sequence data using Bayes' theorem and Markov chain Monte Carlo (MCMC) sampling, which is widely recognized as the most effective approach for characterizing a complex, high dimensional distribution. Other routines then map correlated residue patterns to available structures with a view to hypothesis generation. When applied to N-acetyltransferases, this reveals sequence and structural features indicative of functionally important, yet generally unknown biochemical properties. Even for sets of proteins for which nothing is known beyond unannotated sequences and structures, this can lead to helpful insights. We describe, for example, a putative coenzyme-A-induced-fit substrate binding mechanism mediated by arginine residue switching between salt bridge and pi-pi stacking interactions. A suite of programs implementing this approach is available (psed.igs.umaryland.edu). PMID- 28002466 TI - Assessment of the Role of Metabolic Determinants on the Relationship between Insulin Sensitivity and Secretion. AB - BACKGROUND: Insulin secretion correlates inversely with insulin sensitivity, which may suggest the existence of a crosstalk between peripheral organs and pancreas. Such interaction might be mediated through glucose oxidation that may drive the release of circulating factors with action on insulin secretion. AIM: To evaluate the association between whole-body carbohydrate oxidation and circulating factors with insulin secretion to consecutive oral glucose loading in non-diabetic individuals. METHODS: Carbohydrate oxidation was measured after an overnight fast and for 6 hours after two 3-h apart 75-g oral glucose tolerance tests (OGTT) in 53 participants (24/29 males/females; 34+/-9 y; 27+/-4 kg/m2). Insulin secretion was estimated by deconvolution of serum C-peptide concentration, beta cell function by mathematical modelling and insulin sensitivity from an OGTT. Circulating lactate, free-fatty acids (FFA) and candidate chemokines were assessed before and after OGTT. The effect of recombinant RANTES (regulated on activation, normal T cell expressed and secreted) and IL8 (interleukin 8) on insulin secretion from isolated mice islets was also measured. RESULTS: Carbohydrate oxidation assessed over the 6-h period did not relate with insulin secretion (r = -0.11; p = 0.45) or beta cell function indexes. Circulating lactate and FFA showed no association with 6-h insulin secretion. Circulating chemokines concentration increased upon oral glucose stimulation. Insulin secretion associated with plasma IL6 (r = 0.35; p<0.05), RANTES (r = 0.30; p<0.05) and IL8 (r = 0.41; p<0.05) determined at 60 min OGTT. IL8 was independently associated with in vivo insulin secretion; however, it did not affect in vitro insulin secretion. CONCLUSION: Whole-body carbohydrate oxidation appears to have no influence on insulin secretion or putative circulating mediators. IL8 may be a potential factor influencing insulin secretion. PMID- 28002467 TI - Fetal, Infant and Maternal Outcomes among Women with Prolapsed Membranes Admitted before 29 Weeks Gestation. AB - BACKGROUND: Few studies have examined fetal, infant and maternal mortality and morbidity among pregnant women at very early gestation with an open cervix and prolapsed membranes. We carried out a study describing the outcomes of women hospitalized with prolapsed membranes at 22-28 weeks' gestation. METHODS: We prospectively recruited women with singleton pregnancies admitted at 22-28 weeks' gestation to tertiary hospitals of the Canadian Perinatal Network between 2005 and 2009. Time-to-delivery, perinatal death, neonatal intensive care unit (NICU) admission, severe neonatal morbidity and severe maternal morbidity were compared between women admitted at 22-25 vs. 26-28 weeks gestation. Logistic regression was used to estimate adjusted odds ratios (AOR) and 95% confidence intervals. RESULTS: 129 women at 22-25 weeks gestation and 65 women at 26-28 weeks gestation were admitted to hospital and the median time-to-delivery was 4 days in both groups. Stillbirth rates were 12.4% vs 4.6% among women admitted at earlier vs later gestation (AOR 2.8, 95% CI 0.5-14.8), while perinatal death rates were 38.0% vs 6.1% (AOR 14.1, 95% CI 3.5-59.0), respectively. There were no significant differences in NICU admission and severe morbidity among live-born infants; 89.4% and 82.3% died or were admitted to NICU, (P value 0.18), and 53.9% vs 44.0% of NICU infants had severe neonatal morbidity (P value 0.28). Antibiotics, tocolysis and cerclage did not have a significant effect on perinatal death. Maternal death or severe maternal morbidity occurred in 8.5% and 6.2% of women admitted at 22-25 vs 26-28 weeks (AOR 1.2, 95% CI 0.4-4.2). CONCLUSION: Perinatal mortality among women with prolapsed membranes at very early gestation is high, although significantly lower among those admitted at a relatively later gestational age. Rates of adverse maternal outcomes are also high. This information can be used to counsel women with prolapsed membranes at 22 to 28 weeks gestation. PMID- 28002468 TI - Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members. AB - Lysine acetylation has emerged as a dominant post-translational modification (PTM) regulating tau proteins in Alzheimer's disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule-binding region (MTBR), a region that is highly conserved among tau, MAP2, and MAP4 family members, implying that acetylation could represent a conserved regulatory mechanism for MAPs beyond tau. Here, we combined mass spectrometry, biochemical assays, and cell-based approaches to demonstrate that the tau family members MAP2 and MAP4 are also subject to reversible acetylation. We identify a cluster of lysines in the MAP2 and MAP4 MTBR that undergo CBP-catalyzed acetylation, many of which are conserved in tau. Similar to tau, MAP2 acetylation can occur in a cysteine-dependent auto regulatory manner in the presence of acetyl-CoA. Furthermore, tubulin reduced MAP2 acetylation, suggesting tubulin binding dictates MAP acetylation status. Taken together, these results uncover a striking conservation of MAP2/Tau family post-translational modifications that could expand our understanding of the dynamic mechanisms regulating microtubules. PMID- 28002469 TI - Phylodynamic and Phylogeographic Profiles of Subtype B HIV-1 Epidemics in South Spain. AB - BACKGROUND: Since 1982, HIV-1 epidemics have evolved to different scenarios in terms of transmission routes, subtype distribution and characteristics of transmission clusters. We investigated the evolutionary history of HIV-1 subtype B in south Spain. PATIENTS & METHODS: We studied all newly diagnosed HIV-1 subtype B patients in East Andalusia during the 2005-2012 period. For the analysis, we used the reverse transcriptase and protease sequences from baseline resistance, and the Trugene(r) HIV Genotyping kit (Siemens, Barcelona, Spain). Subtyping was done with REGA v3.0. The maximum likelihood trees constructed with RAxML were used to study HIV-1 clustering. Phylogeographic and phylodynamic profiles were studied by Bayesian inference methods with BEAST v1.7.5 and SPREAD v1.0.6. RESULTS: Of the 493 patients infected with HIV-1 subtype B, 234 grouped into 55 clusters, most of which were small (44 clusters <= 5 patients, 31 with 2 patients, 13 with 3). The rest (133/234) were grouped into 11 clusters with >= 5 patients, and most (82%, 109/133) were men who have sex with men (MSM) grouped into 8 clusters. The association with clusters was more frequent in Spanish (p = 0.02) men (p< 0.001), MSM (p<0.001) younger than 35 years (p = 0.001) and with a CD4+ T-cell count above 350 cells/ul (p<0.001). We estimated the date of HIV-1 subtype B regional epidemic diversification around 1970 (95% CI: 1965-1987), with an evolutionary rate of 2.4 (95%CI: 1.7-3.1) x 10-3 substitutions/site/year. Most clusters originated in the 1990s in MSMs. We observed exponential subtype B HIV-1 growth in 1980-1990 and 2005-2008. The most significant migration routes for subtype B went from inland cities to seaside locations. CONCLUSIONS: We provide the first data on the phylodynamic and phylogeographic profiles of HIV-1 subtype B in south Spain. Our findings of transmission clustering among MSMs should alert healthcare managers to enhance preventive measures in this risk group in order to prevent future outbreaks. PMID- 28002470 TI - Sepsis and Hemocyte Loss in Honey Bees (Apis mellifera) Infected with Serratia marcescens Strain Sicaria. AB - Global loss of honey bee colonies is threatening the human food supply. Diverse pathogens reduce honey bee hardiness needed to sustain colonies, especially in winter. We isolated a free-living Gram negative bacillus from hemolymph of worker honey bees (Apis mellifera) found separated from winter clusters. In some hives, greater than 90% of the dying bees detached from the winter cluster were found to contain this bacterium in their hemolymph. Throughout the year, the same organism was rarely found in bees engaged in normal hive activities, but was detected in about half of Varroa destructor mites obtained from colonies that housed the septic bees. Flow cytometry of hemolymph from septic bees showed a significant reduction of plasmatocytes and other types of hemocytes. Interpretation of the16S rRNA sequence of the bacterium indicated that it belongs to the Serratia genus of Gram-negative Gammaproteobacteria, which has not previously been implicated as a pathogen of adult honey bees. Complete genome sequence analysis of the bacterium supported its classification as a novel strain of Serratia marcescens, which was designated as S. marcescens strain sicaria (Ss1). When compared with other strains of S. marcescens, Ss1 demonstrated several phenotypic and genetic differences, including 65 genes not previously found in other Serratia genomes. Some of the unique genes we identified in Ss1 were related to those from bacterial insect pathogens and commensals. Recovery of this organism extends a complex pathosphere of agents which may contribute to failure of honey bee colonies. PMID- 28002471 TI - Dose-Finding Study of Omeprazole on Gastric pH in Neonates with Gastro-Esophageal Acid Reflux Using a Bayesian Sequential Approach. AB - OBJECTIVE: Proton pump inhibitors are frequently administered on clinical symptoms in neonates but benefit remains controversial. Clinical trials validating omeprazole dosage in neonates are limited. The objective of this trial was to determine the minimum effective dose (MED) of omeprazole to treat pathological acid reflux in neonates using reflux index as surrogate marker. DESIGN: Double blind dose-finding trial with continual reassessment method of individual dose administration using a Bayesian approach, aiming to select drug dose as close as possible to the predefined target level of efficacy (with a credibility interval of 95%). SETTING: Neonatal Intensive Care unit of the Robert Debre University Hospital in Paris, France. PATIENTS: Neonates with a postmenstrual age >= 35 weeks and a pathologic 24-hour intra-esophageal pH monitoring defined by a reflux index >= 5% over 24 hours were considered for participation. Recruitment was stratified to 3 groups according to gestational age at birth. INTERVENTION: Five preselected doses of oral omeprazole from 1 to 3 mg/kg/day. MAIN OUTCOME MEASURES: Primary outcome, measured at 35 weeks postmenstrual age or more, was a reflux index <5% during the 24-h pH monitoring registered 72+/-24 hours after omeprazole initiation. RESULTS: Fifty-four neonates with a reflux index ranging from 5.06 to 27.7% were included. Median age was 37.5 days and median postmenstrual age was 36 weeks. In neonates born at less than 32 weeks of GA (n = 30), the MED was 2.5mg/kg/day with an estimated mean posterior probability of success of 97.7% (95% credibility interval: 90.3-99.7%). The MED was 1mg/kg/day for neonates born at more than 32 GA (n = 24). CONCLUSIONS: Omeprazole is extensively prescribed on clinical symptoms but efficacy is not demonstrated while safety concerns do exist. When treatment is required, the daily dose needs to be validated in preterm and term neonates. Optimal doses of omeprazole to increase gastric pH and decrease reflux index below 5% over 24 hours, determined using an adaptive Bayesian design differ among neonates. Both gestational and postnatal ages account for these differences but their differential impact on omeprazole doses remains to be determined. PMID- 28002472 TI - Manual Wheelchair Skills Training for Community-Dwelling Veterans with Spinal Cord Injury: A Randomized Controlled Trial. AB - OBJECTIVES: To test the hypotheses that community-dwelling veterans with spinal cord injury (SCI) who receive the Wheelchair Skills Training Program (WSTP) in their own environments significantly improve their manual wheelchair-skills capacity, retain those improvements at one year and improve participation in comparison with an Educational Control (EC) group. METHODS: We carried out a randomized controlled trial, studying 106 veterans with SCI from three Veterans Affairs rehabilitation centers. Each participant received either five one-on-one WSTP or EC sessions 30-45 minutes in duration. The main outcome measures were the total and subtotal percentage capacity scores from the Wheelchair Skills Test 4.1 (WST) and Craig Handicap Assessment and Reporting Technique (CHART) scores. RESULTS: Participants in the WSTP group improved their total and Advanced-level WST scores by 7.1% and 30.1% relative to baseline (p < 0.001) and retained their scores at one year follow-up. The success rates for individual skills were consistent with the total and subtotal WST scores. The CHART Mobility sub-score improved by 3.2% over baseline (p = 0.021). CONCLUSIONS: Individualized wheelchair skills training in the home environment substantially improves the advanced and total wheelchair skills capacity of experienced community-dwelling veterans with SCI but has only a small impact on participation. PMID- 28002473 TI - Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine. AB - In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Deltanef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Deltanef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Deltanef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity. PMID- 28002474 TI - Characterizing Variability of Modular Brain Connectivity with Constrained Principal Component Analysis. AB - Characterizing the variability of resting-state functional brain connectivity across subjects and/or over time has recently attracted much attention. Principal component analysis (PCA) serves as a fundamental statistical technique for such analyses. However, performing PCA on high-dimensional connectivity matrices yields complicated "eigenconnectivity" patterns, for which systematic interpretation is a challenging issue. Here, we overcome this issue with a novel constrained PCA method for connectivity matrices by extending the idea of the previously proposed orthogonal connectivity factorization method. Our new method, modular connectivity factorization (MCF), explicitly introduces the modularity of brain networks as a parametric constraint on eigenconnectivity matrices. In particular, MCF analyzes the variability in both intra- and inter-module connectivities, simultaneously finding network modules in a principled, data driven manner. The parametric constraint provides a compact module-based visualization scheme with which the result can be intuitively interpreted. We develop an optimization algorithm to solve the constrained PCA problem and validate our method in simulation studies and with a resting-state functional connectivity MRI dataset of 986 subjects. The results show that the proposed MCF method successfully reveals the underlying modular eigenconnectivity patterns in more general situations and is a promising alternative to existing methods. PMID- 28002475 TI - Trans-Boundary Edge Effects in the Western Carpathians: The Influence of Hunting on Large Carnivore Occupancy. AB - The conservation and management of wolves Canis lupus in the periphery of their distribution is challenging. Edges of wolf distribution are characterized by very few and intermittent occurrences of individuals, which are modulated by multiple factors affecting the overall population such as human-caused mortality, management targets and food availability. The knowledge of population dynamics in the edges becomes crucial when hunting takes place nearby the edges, which may preclude population expansion. Here, using as example the occurrence of wolves in the Beskydy Mountains (Czech-Slovak border), which are the edge distribution of the wolf and Eurasian lynx Lynx lynx populations in the West Carpathians, we explored how food availability and hunting in the Slovakian core area affected the dynamics of wolves in the edges of this population. During 2003-2012, we monitored large carnivore occurrence by snow-tracking surveys and tested potential differences in the occurrence of these species in Beskydy Mountains and potential mechanisms behind detected patterns. Despite the proximity to the core area, with several wolf reproductions being confirmed at least in recent years, the wolf was a very rare species in Beskydy and was recorded 14 times less often than the lynx. The expected abundance of wolves in the Beskydy Mountains was inversely related to prey availability in the Slovakian core area. Wolf hunting the year before influenced the expected abundance of wolves in Beskydy area. We discuss how different life histories and legal status of both species probably account for most of the observed difference of occurrence at range margins. PMID- 28002477 TI - Lake Metabolism: Comparison of Lake Metabolic Rates Estimated from a Diel CO2- and the Common Diel O2-Technique. AB - Lake metabolism is a key factor for the understanding of turnover of energy and of organic and inorganic matter in lake ecosystems. Long-term time series on metabolic rates are commonly estimated from diel changes in dissolved oxygen. Here we present long-term data on metabolic rates based on diel changes in total dissolved inorganic carbon (DIC) utilizing an open-water diel CO2-technique. Metabolic rates estimated with this technique and the traditional diel O2 technique agree well in alkaline Lake Illmensee (pH of ~8.5), although the diel changes in molar CO2 concentrations are much smaller than those of the molar O2 concentrations. The open-water diel CO2- and diel O2-techniques provide independent measures of lake metabolic rates that differ in their sensitivity to transport processes. Hence, the combination of both techniques can help to constrain uncertainties arising from assumptions on vertical fluxes due to gas exchange and turbulent diffusion. This is particularly important for estimates of lake respiration rates because these are much more sensitive to assumptions on gradients in vertical fluxes of O2 or DIC than estimates of lake gross primary production. Our data suggest that it can be advantageous to estimate respiration rates assuming negligible gradients in vertical fluxes rather than including gas exchange with the atmosphere but neglecting vertical mixing in the water column. During two months in summer the average lake net production was close to zero suggesting at most slightly autotrophic conditions. However, the lake emitted O2 and CO2 during the entire time period suggesting that O2 and CO2 emissions from lakes can be decoupled from the metabolism in the near surface layer. PMID- 28002476 TI - Bg10: A Novel Metagenomics Alcohol-Tolerant and Glucose-Stimulated GH1 beta Glucosidase Suitable for Lactose-Free Milk Preparation. AB - New beta-glucosidases with product (glucose) or ethanol tolerances are greatly desired to make industrial processes more marketable and efficient. Therefore, this report describes the in silico/vitro characterization of Bg10, a metagenomically derived homodimeric beta-glucosidase that exhibited a Vmax of 10.81 +/- 0.43 MUM min-1, Kcat of 175.1+/- 6.91 min-1, and Km of 0.49 +/- 0.12 mM at a neutral pH and 37 degrees C when pNP-beta-D-glucopyranoside was used as the substrate, and the enzyme retained greater than 80% activity within the respective pH and temperature ranges of 6.5 to 8.0 and 35 to 40 degrees C. The enzyme was stimulated by its product, glucose; consequently, the Bg10 activity against 50 and 100 mM of glucose were increased by 36.8% and 22%, respectively, while half of the activity was retained at 350 mM. Moreover, the Bg10 was able to hydrolyse 55% (milk sample) and 100% (purified sugar) of the lactose at low (6 degrees C) and optimum (37 degrees C) temperatures, respectively, suggesting the possibility of further optimization of the reaction for lactose-free dairy production. In addition, the enzyme was able to fully hydrolyse 40 mM of cellobiose at one hour and was tolerant to ethanol up to concentrations of 500 mM (86% of activity), while a 1 M concentration still resulted in 41% residual activity, which could be interesting for biofuel production. PMID- 28002478 TI - The Effects of Rilmenidine and Perindopril on Arousal Blood Pressure during 24 Hour Recordings in SHR. AB - The surge in arterial pressure during arousal in the waking period is thought to be largely due to activation of the sympathetic nervous system. In this study we compared in SHR the effects of chronic administration of the centrally acting sympatholytic agent rilmenidine with an angiotensin converting enzyme inhibitor perindopril on the rate of rise and power of the surge in mean arterial pressure (MAP) that occurs with arousal associated with the onset of night. Recordings were made using radiotelemetry in 17 adult SHR before and after treatment with rilmenidine (2mg/kg/day), perindopril (1mg/kg/day) or vehicle in the drinking water for 2 weeks. Rilmenidine reduced MAP by 7.2 +/- 1.7mmHg while perindopril reduced MAP by 19 +/- 3mmHg. Double logistic curve fit analysis showed that the rate and power of increase in systolic pressure during the transition from light to dark was reduced by 50% and 65%, respectively, but had no effect on diastolic pressure. Rilmenidine also reduced blood pressure variability in the autonomic frequency in the active period as assessed by spectral analysis which is consistent with reduction in sympathetic nervous system activity. Perindopril had no effect on the rate or power of the arousal surge in either systolic or diastolic pressure. These results suggest that the arousal induced surge in blood pressure can largely be reduced by an antihypertensive agent that inhibits the sympathetic nervous system and that angiotensin converting enzyme inhibition, while effective in reducing blood pressure, does not alter the rate or power of the surge associated with arousal. PMID- 28002480 TI - Optimal Acquisition Number for Hepatic Shear Wave Velocity Measurements in Children. AB - OBJECTIVE: To investigate the minimum optimal acquisition number of hepatic shear wave velocities (SWVs) on ultrasound elastography in children. MATERIALS AND METHODS: We prospectively performed hepatic supersonic shear wave elastography in children of four groups (group A-C, healthy children, group A with 0-5 years old; group B with 6-10 years old; group C with 11-18 years old; and group D, children with previous Kasai operation) with free breathing (FB) and breath holding (BH) status, if possible. SWVs were measured fifteen times for each child at a 4 cm depth for the right lobe using a 1-6 MHz convex transducer. Mean SWVs from three, five, and seven acquisitions were compared to the mean SWV from fifteen measurements, using an intraclass correlation coefficient (ICC) analyzed with the 1,000 times bootstrap method. RESULTS: Total eighty-eight children were included (25 children in group A, 30 children in group B, 21 children in group C, and 12 children in group D). The mean SWVs from fifteen measurements in FB status were 5.5 +/- 1.3 kPa for groups A-C together and 8.0 +/- 2.2 kPa for group D. For all groups together, mean SWVs from the three (ICC 0.944 and 0.937), five (ICC 0.958 and 0.938) and seven (ICC 0.969 and 0.941) acquisitions demonstrated almost perfect agreement with the reference of fifteen acquisitions in both FB and BH status, respectively. A subgroup analysis showed three measurements were in almost perfect agreement during FB for groups B-D and strong agreement (ICC 0.675) for group A. CONCLUSION: Three acquisitions can be enough for hepatic SWVs in children more than 6 years old regardless of breathing status or hepatic pathology. More acquisitions are recommended for children under the age of 5 years during FB. PMID- 28002479 TI - RecoverNow: Feasibility of a Mobile Tablet-Based Rehabilitation Intervention to Treat Post-Stroke Communication Deficits in the Acute Care Setting. AB - BACKGROUND: Approximately 40% of patients diagnosed with stroke experience some degree of aphasia. With limited health care resources, patients' access to speech and language therapies is often delayed. We propose using mobile-platform technology to initiate early speech-language therapy in the acute care setting. For this pilot, our objective was to assess the feasibility of a tablet-based speech-language therapy for patients with communication deficits following acute stroke. METHODS: We enrolled consecutive patients admitted with a stroke and communication deficits with NIHSS score >=1 on the best language and/or dysarthria parameters. We excluded patients with severe comprehension deficits where communication was not possible. Following baseline assessment by a speech language pathologist (SLP), patients were provided with a mobile tablet programmed with individualized therapy applications based on the assessment, and instructed to use it for at least one hour per day. Our objective was to establish feasibility by measuring recruitment rate, adherence rate, retention rate, protocol deviations and acceptability. RESULTS: Over 6 months, 143 patients were admitted with a new diagnosis of stroke: 73 had communication deficits, 44 met inclusion criteria, and 30 were enrolled into RecoverNow (median age 62, 26.6% female) for a recruitment rate of 68% of eligible participants. Participants received mobile tablets at a mean 6.8 days from admission [SEM 1.6], and used them for a mean 149.8 minutes/day [SEM 19.1]. In-hospital retention rate was 97%, and 96% of patients scored the mobile tablet-based communication therapy as at least moderately convenient 3/5 or better with 5/5 being most "convenient". CONCLUSIONS: Individualized speech-language therapy delivered by mobile tablet technology is feasible in acute care. PMID- 28002481 TI - A Rapid Spin Column-Based Method to Enrich Pathogen Transcripts from Eukaryotic Host Cells Prior to Sequencing. AB - When analyzing pathogen transcriptomes during the infection of host cells, the signal-to-background (pathogen-to-host) ratio of nucleic acids (NA) in infected samples is very small. Despite the advancements in next-generation sequencing, the minute amount of pathogen NA makes standard RNA-seq library preps inadequate for effective gene-level analysis of the pathogen in cases with low bacterial loads. In order to provide a more complete picture of the pathogen transcriptome during an infection, we developed a novel pathogen enrichment technique, which can enrich for transcripts from any cultivable bacteria or virus, using common, readily available laboratory equipment and reagents. To evenly enrich for pathogen transcripts, we generate biotinylated pathogen-targeted capture probes in an enzymatic process using the entire genome of the pathogen as a template. The capture probes are hybridized to a strand-specific cDNA library generated from an RNA sample. The biotinylated probes are captured on a monomeric avidin resin in a miniature spin column, and enriched pathogen-specific cDNA is eluted following a series of washes. To test this method, we performed an in vitro time course infection using Klebsiella pneumoniae to infect murine macrophage cells. K. pneumoniae transcript enrichment efficiency was evaluated using RNA-seq. Bacterial transcripts were enriched up to ~400-fold, and allowed the recovery of transcripts from ~2000-3600 genes not observed in untreated control samples. These additional transcripts revealed interesting aspects of K. pneumoniae biology including the expression of putative virulence factors and the expression of several genes responsible for antibiotic resistance even in the absence of drugs. PMID- 28002482 TI - Clinical Characteristics and Treatment Outcomes of Clostridium difficile Infections by PCR Ribotype 017 and 018 Strains. AB - The objective of this study was to identify the clinical characteristics of Clostridium difficile infections (CDIs) caused by toxin A-negative/toxin B positive (A-B+) PCR ribotype 017 (R017) and A+B+ ribotype 018 (R018) strains, prevalent in Asian countries. From February 2010 through January 2013, all CDI patients in our hospital were enrolled; their medical records were retrospectively reviewed, and the isolates were characterized by toxigenic culture and PCR ribotyping. Based on the ribotypes, a total of 510 cases were categorized as R017 (139, 27.3%), R018 (157, 30.8%) and other ribotypes groups (214, 42.0%), and clinical variables were compared between R017 and other ribotypes, R018 and other ribotypes and R018 and R017 groups. The patients with R017 infections had a higher mean Charlson's comorbidity index (OR 1.1, 1-1.21, p = 0.05), lower serum albumin (OR 0.47, 0.31-0.73, p = 0.001) and lower CRP levels (OR 0.96, 0.92-0.99, p = 0.022) than those with other ribotypes. R018 infections caused more azotemia (OR 4.06, 1.28-12.91, p = 0.018) and more frequent severe CDI (OR 1.87, 1.12-3.13, p = 0.016) than the other ribotypes infections. R017 and R018 infections were more often associated with toxin positive stools (OR 2.94, 1.65-4.09, p<0.001; OR 4.55, 2.82-7.33, p<0.001). In terms of treatment outcomes, R017 infections caused a marginally higher 30-day mortality than other ribotypes infection. In a final multiple logistic regression model, 30-day mortality was associated with leukocytosis (OR 2.45, 1.0-6.01, p = 0.05) and hypoalbuminemia (OR 4.57, 1.83-11.39, p = 0.001), but only marginally with R017 infection (OR 2.14, 0.88-5.22, p = 0.094). In conclusion, infections by C. difficile R018 strains tend to cause more severe disease, while there was a trend for higher mortality with R017 infections. PMID- 28002483 TI - Physical Characteristics of a Citrullinated Pro-Filaggrin Epitope Recognized by Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis Sera. AB - Rheumatoid arthritis (RA) is an autoimmune disease of complex etiology. A characteristic feature of a subset of RA is the presence of anti-citrullinated protein antibodies (ACPA), which correlate with a progressive disease course. In this study, we employed streptavidin capture enzyme-linked immunosorbent assay to analyze ACPA reactivity. Using the pro-filaggrin peptide HQCHQEST-Cit GRSRGRCGRSGS, as template, we analyzed the reactivity of RA sera and healthy donor sera to various peptides in order to determine the physical characteristics of the citrullinated pro-filaggrin epitope and to examine whether biotin labelling influence antibody recognition. The full-length cyclic pro-filaggrin peptide and a linear form with a N-terminal biotin, was recognized to the same level, whereas, a notable difference in ACPA reactivity to the linear peptides with a C-terminal biotin was found, probably due to steric hindrance. Screening of linear and cyclic truncated peptides, revealed that small cyclic peptides containing 10-12 amino acids are favored over the linear. Moreover, the charged amino acids C-terminal to citrulline were found to be essential for antibody reactivity, most important was the charged amino acid in position 4 C-terminal to citrulline. Collectively, peptide structure, length, the presence of charged amino acids and biotin labelling markedly influence antibody reactivity. In relation to the clinical diagnostics of ACPA, these findings may reflect the differences in diagnostic assays used for detection of ACPA, which relates to differences in sensitivity and specificity dependent on the assay applied. PMID- 28002484 TI - Renal Fibrosis mRNA Classifier: Validation in Experimental Lithium-Induced Interstitial Fibrosis in the Rat Kidney. AB - Accurate diagnosis of fibrosis is of paramount clinical importance. A human fibrosis classifier based on metzincins and related genes (MARGS) was described previously. In this investigation, expression changes of MARGS genes were explored and evaluated to examine whether the MARGS-based algorithm has any diagnostic value in a rat model of lithium nephropathy. Male Wistar rats (n = 12) were divided into 2 groups (n = 6). One group was given a diet containing lithium (40 mmol/kg food for 7 days, followed by 60mmol/kg food for the rest of the experimental period), while a control group (n = 6) was fed a normal diet. After six months, animals were sacrificed and the renal cortex and medulla of both kidneys removed for analysis. Gene expression changes were analysed using 24 GeneChip(r) Affymetrix Rat Exon 1.0 ST arrays. Statistically relevant genes (p value<0.05, fold change>1.5, t-test) were further examined. Matrix metalloproteinase-2 (MMP2), CD44, and nephroblastoma overexpressed gene (NOV) were overexpressed in the medulla and cortex of lithium-fed rats compared to the control group. TGFbeta2 was overrepresented in the cortex of lithium-fed animals 1.5-fold, and 1.3-fold in the medulla of the same animals. In Gene Set Enrichment Analysis (GSEA), both the medulla and cortex of lithium-fed animals showed an enrichment of the MARGS, TGFbeta network, and extracellular matrix (ECM) gene sets, while the cortex expression signature was enriched in additional fibrosis related-genes and the medulla was also enriched in immune response pathways. Importantly, the MARGS-based fibrosis classifier was able to classify all samples correctly. Immunohistochemistry and qPCR confirmed the up-regulation of NOV, CD44, and TGFbeta2. The MARGS classifier represents a cross-organ and cross species classifier of fibrotic conditions and may help to design a test to diagnose and to monitor fibrosis. The results also provide evidence for a common pathway in the pathogenesis of fibrosis. PMID- 28002485 TI - A Combinatory Antibody-Antigen Microarray Assay for High-Content Screening of Single-Chain Fragment Variable Clones from Recombinant Libraries. AB - We have developed a combinatory antibody-antigen microarray for direct screening of multiple single-chain fragment variable (scFv) clones with no need for pre purification or enrichment before screening. The straightforward workflow allows for early selection of binders to predefined peptide and glycopeptide targets. A capture antibody is contact printed on microarray slides, side by side with the antigens of interest. A large number of scFv clones, in supernatants, are printed on top of the capture antibody and the antigen in a "spot-on-spot" print. The printed scFv clones, which bind to the capture antibody, are detected using biotinylated antigen, while the binding of scFv clones to the printed antigen is detected through a mouse anti-tag antibody. Two different analyses are thus performed on the same slide, generating two kinds of information: one on the ability of an individual scFv clone to bind to the soluble form of the antigen, which may favour selection for higher affinity rather than avidity, while the other allows the identification of large numbers of clones, simultaneously, due to the binding of scFv clones to densely presented antigens, thus providing an overall increased hit rate. The functionality of the new screening approach was illustrated through the generation of antibodies against peptides from the chaperone complex Ku70/Ku80 and the GalNAcalpha-serine/threonine epitope on the IgA1 alpha chain hinge region. In total, 659 scFv clones were screened with a hit rate of approximately 20%. This approach allowed the identification of functional antibodies in both cases, illustrating the usefulness and capacity of this combinatory microarray screening technique for efficient analysis and validation of antibodies at an early stage of antibody generation. PMID- 28002486 TI - Levels of Salivary Enzymes of Apolygus Lucorum (Hemiptera: Miridae), From 1st Instar Nymph to Adult, and Their Potential Relation to Bug Feeding. AB - In recent years, Apolygus lucorum has caused increasing damage to cotton and fruit trees in China. The salivary enzymes secreted by A. lucorum when sucking on host plants induce a series of biochemical reactions in plants, and the pre-oral digestion benefits the bug feeding. In this study, the food intake of A. lucorum from 1st instar nymphs to adults was measured, and the corresponding salivary activity of pectinase, amylase, cellulase, protease, polyphenol oxidase and peroxidase was determined. Daily food intake varied with developmental stage, peaking in 3rd and 4th instar nymphs. Pectinase, amylase, cellulase and protease were detected in both nymphal and adult saliva of A. lucorum, while neither polyphenol oxidase nor peroxidase was detected. Protease activity varied with food intake peaking at the 3rd-4th instar, and then slightly decreasing at the 5th instar. Levels of pectinase, amylase and cellulase increased significantly with the daily feeding level until the 3rd instar, corresponding with increasing damage to host plants. The activity of both cellulase and protease had a significant linear relationship with the average daily food intake. The increasing activity of enzymes in saliva explain stage-specific impacts of A. lucorum on the host plants, and suggest that optimal management of A. lucorum would be confined to its control threshold prior to the peak of daily feeding in the 3rd instar. PMID- 28002487 TI - Long-Term Transcriptomic Effects of Prebiotics and Synbiotics Delivered In Ovo in Broiler Chickens. AB - In ovo delivery of prebiotics and synbiotics in chickens allows for the development of intestinal microflora prior to hatching, which boosts their robustness. The goal of this study was to determine the transcriptomic profile of the spleen (S), cecal tonsils (CT), and large intestine (LI) of adult chickens injected with prebiotics and synbiotics in ovo. On day 12 of embryo development, incubating eggs were injected with prebiotics: inulin alone (P1) or in combination with Lactococcus lactis subsp. lactis IBB2955 (S1), galactooligosaccharides (GOS) alone (P2) or in combination with Lactococcus lactis subsp. cremoris IBB477 (S2); control group (C) was mock injected with physiological saline. Gene expression analysis was conducted using an Affymetrix Chicken Gene 1.1 ST Array Strip. Most of the differentially expressed genes (DEG) were detected in the cecal tonsils of P2 (378 DEG), and were assigned to gene ontology categories: lymphocyte proliferation, activation and differentiation, and cytokine production. Ingenuity pathway analysis of the DEG (CT of P2) indicated the inhibition of humoral and cellular immune responses, e.g., role of NFAT in regulation of immune responses, phagocytosis, production of nitric oxide, NF-kappaB, IL-8, and CXCR4 signaling. The DEG with the highest up-regulation from S1 and P2 were involved in gene expression (PAPOLA, RPL27A, RPLP1, and RPS29) from P1 and P2 in transport (BEST4, SLC9A3, and SLC13A2), metabolism (OGT, ALPP, CA4, and CA7), signaling (FGG, G3BP2, UBB, G3BP2, CACNA1G, and ATP6V0A4), and immune responses (MSMB, LGALS3, CABIN1, CXCR5, PAX5, and TNFRSF14). Two DEG influencing the complement system (SERPING1 and MIR1674) were down-regulated in P2 and S1. In conclusion, GOS injected in ovo provided the most potent stimulation of the host transcriptome. This is likely due to its strong bifidogenic effect, which triggers proliferation of indigenous embryonic microflora in ovo, and indirectly influences gene expression regulation in host tissues, especially cecal tonsils. PMID- 28002489 TI - Correction: CD34 Promotes Pathological Epi-Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy. AB - [This corrects the article DOI: 10.1371/journal.pone.0157902.]. PMID- 28002488 TI - The Accuracy of Diagnostic Tests for Lyme Disease in Humans, A Systematic Review and Meta-Analysis of North American Research. AB - There has been an increasing incidence of Lyme disease (LD) in Canada and the United States corresponding to the expanding range of the Ixodes tick vector and Lyme disease agent (Borrelia burgdorferi sensu stricto). There are many diagnostic tests for LD available in North America, all of which have some performance issues, and physicians are concerned about the appropriate use and interpretation of these tests. The objective of this systematic review is to summarize the North American evidence on the accuracy of diagnostic tests and test regimes at various stages of LD. Included in the review are 48 studies on diagnostic tests used in North America published since 1995. Thirteen studies examined a two-tier serological test protocol vs. clinical diagnosis, 24 studies examined single assays vs. clinical diagnosis, 9 studies examined single immunoblot vs. clinical diagnosis, 7 studies compared culture or PCR direct detection methods vs. clinical diagnosis, 22 studies compared two or more tests with each other and 8 studies compared a two-tiered serological test protocol to another test. Recent studies examining the sensitivity and specificity of various test protocols noted that the Immunetics(r) C6 B. burgdorferi ELISATM and the two tier approach have superior specificity compared to proposed replacements, and the CDC recommended western blot algorithm has equivalent or superior specificity over other proposed test algorithms. There is a dramatic increase in test sensitivity with progression of B. burgdorferi infection from early to late LD. Direct detection methods, culture and PCR of tissue or blood samples were not as sensitive or timely compared to serological testing. It was also noted that there are a large number of both commercial (n = 42) and in-house developed tests used by private laboratories which have not been evaluated in the primary literature. PMID- 28002490 TI - Predicting Suicide Risk in Trauma Exposed Veterans: The Role of Health Promoting Behaviors. AB - INTRODUCTION: Returning veterans of the wars in Iraq and Afghanistan experience high rates of post-traumatic stress disorder (PTSD) and suicidal behavior. Suicidal ideation is among the strongest risk factors for completed suicide. Some research suggests an association between PTSD and suicidal ideation, and that health-promoting behaviors-behaviors that sustain or increase well-being-play a role in this association. The current study examined whether health-promoting behaviors moderate the association between PTSD severity and suicidal ideation. METHODS: Veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF; N = 108) completed measures of PTSD symptoms, trauma exposure, suicidal ideation, and health-promoting behaviors. RESULTS: Moderated regression was used to test the hypothesis. Results indicated that health promoting behaviors, beta = -.06, p = .001, and PTSD symptoms, beta = .36, p < .001, were significantly related to suicidal ideation. Consistent with our main hypothesis, the health promoting behaviors x PTSD interaction term was significantly associated with suicidal ideation, beta = -.09, p = .001. The overall model accounted for 13% of the variance in suicidal ideation. Among individuals with high PTSD symptom severity, those who engaged in more health promoting behaviors reported less suicidal ideation than those who engaged in fewer health promoting behaviors. CONCLUSIONS: Health-promoting behaviors could be important for reducing suicidal ideation among veterans with high levels of PTSD symptoms. It is recommended that future research examine health promotion interventions as a means of reducing suicidal ideation. PMID- 28002491 TI - Perceived Case Management Needs and Service Preferences of Frequent Emergency Department Users: Lessons Learned in a Large Urban Centre. AB - OBJECTIVES: This study aimed to explore the service needs and preferences of frequent emergency department users with mental health and addictions concerns who participated in a brief intensive case management intervention. METHODS: We conducted semi-structured individual interviews with 20 frequent emergency department users with mental health and addictions challenges, 13 service providers involved in the delivery of a brief case management intervention, and a focus group with intervention case managers. Thematic analysis was used to explore perceived service user profiles, service needs and preferences of care. RESULTS: Service users experienced complex health and social needs and social isolation, while exhibiting resilience and the desire to contribute. They described multiple instances of stigmatization in interactions with healthcare professionals. Components of the brief intensive case management intervention perceived to be helpful included system navigation, advocacy, intermediation, and practical needs assistance. Frequent service users valued relational responsiveness, a non-judgmental stance, and a recovery orientation in case managers. CONCLUSION: Interventions for frequent service users in mental health may be enhanced by focusing on the engagement of formal and informal social supports, practical needs assistance, system navigation, advocacy and intermediation, and attention to the recovery goals of service users. PMID- 28002492 TI - Cell-Based Screen Identifies Human Interferon-Stimulated Regulators of Listeria monocytogenes Infection. AB - The type I interferon (IFN) activated transcriptional response is a critical antiviral defense mechanism, yet its role in bacterial pathogenesis remains less well characterized. Using an intracellular pathogen Listeria monocytogenes (Lm) as a model bacterial pathogen, we sought to identify the roles of individual interferon-stimulated genes (ISGs) in context of bacterial infection. Previously, IFN has been implicated in both restricting and promoting Lm growth and immune stimulatory functions in vivo. Here we adapted a gain-of-function flow cytometry based approach to screen a library of more than 350 human ISGs for inhibitors and enhancers of Lm infection. We identify 6 genes, including UNC93B1, MYD88, AQP9, and TRIM14 that potently inhibit Lm infection. These inhibitors act through both transcription-mediated (MYD88) and non-transcriptional mechanisms (TRIM14). Further, we identify and characterize the human high affinity immunoglobulin receptor FcgammaRIa as an enhancer of Lm internalization. Our results reveal that FcgammaRIa promotes Lm uptake in the absence of known host Lm internalization receptors (E-cadherin and c-Met) as well as bacterial surface internalins (InlA and InlB). Additionally, FcgammaRIa-mediated uptake occurs independently of Lm opsonization or canonical FcgammaRIa signaling. Finally, we established the contribution of FcgammaRIa to Lm infection in phagocytic cells, thus potentially linking the IFN response to a novel bacterial uptake pathway. Together, these studies provide an experimental and conceptual basis for deciphering the role of IFN in bacterial defense and virulence at single-gene resolution. PMID- 28002493 TI - About the Sterilization of Chitosan Hydrogel Nanoparticles. AB - In the last years, nanostructured biomaterials have raised a great interest as platforms for delivery of drugs, genes, imaging agents and for tissue engineering applications. In particular, hydrogel nanoparticles (HNP) associate the distinctive features of hydrogels (high water uptake capacity, biocompatibility) with the advantages of being possible to tailor its physicochemical properties at nano-scale to increase solubility, immunocompatibility and cellular uptake. In order to be safe, HNP for biomedical applications, such as injectable or ophthalmic formulations, must be sterile. Literature is very scarce with respect to sterilization effects on nanostructured systems, and even more in what concerns HNP. This work aims to evaluate the effect and effectiveness of different sterilization methods on chitosan (CS) hydrogel nanoparticles. In addition to conventional methods (steam autoclave and gamma irradiation), a recent ozone-based method of sterilization was also tested. A model chitosan tripolyphosphate (TPP) hydrogel nanoparticles (CS-HNP), with a broad spectrum of possible applications was produced and sterilized in the absence and in the presence of protective sugars (glucose and mannitol). Properties like size, zeta potential, absorbance, morphology, chemical structure and cytotoxicity were evaluated. It was found that the CS-HNP degrade by autoclaving and that sugars have no protective effect. Concerning gamma irradiation, the formation of agglomerates was observed, compromising the suspension stability. However, the nanoparticles resistance increases considerably in the presence of the sugars. Ozone sterilization did not lead to significant physical adverse effects, however, slight toxicity signs were observed, contrarily to gamma irradiation where no detectable changes on cells were found. Ozonation in the presence of sugars avoided cytotoxicity. Nevertheless, some chemical alterations were observed in the nanoparticles. PMID- 28002494 TI - Do Student Samples Provide an Accurate Estimate of the General Public? AB - Most psychological studies rely on student samples. Students are usually considered as more homogenous than representative samples both within and across countries. However, little is known about the nature of the differences between student and representative samples. This is an important gap, also because knowledge about the degree of difference between student and representative samples may allow to infer from the former to the latter group. Across 59 countries and 12 personality (Big-5) and attitudinal variables we found that differences between students and general public were partly substantial, incoherent, and contradicted previous findings. Two often used cultural variables, embeddedness and intellectual autonomy, failed to explain the differences between both groups across countries. We further found that students vary as much as the general population both between and within countries. In summary, our results indicate that generalizing from students to the general public can be problematic when personal and attitudinal variables are used, as students vary mostly randomly from the general public. Findings are also discussed in terms of the replication crisis within psychology. PMID- 28002495 TI - Space Use and Habitat Selection by Resident and Transient Red Wolves (Canis rufus). AB - Recovery of large carnivores remains a challenge because complex spatial dynamics that facilitate population persistence are poorly understood. In particular, recovery of the critically endangered red wolf (Canis rufus) has been challenging because of its vulnerability to extinction via human-caused mortality and hybridization with coyotes (Canis latrans). Therefore, understanding red wolf space use and habitat selection is important to assist recovery because key aspects of wolf ecology such as interspecific competition, foraging, and habitat selection are well-known to influence population dynamics and persistence. During 2009-2011, we used global positioning system (GPS) radio-telemetry to quantify space use and 3rd-order habitat selection for resident and transient red wolves on the Albemarle Peninsula of eastern North Carolina. The Albemarle Peninsula was a predominantly agricultural landscape in which red wolves maintained spatially stable home ranges that varied between 25 km2 and 190 km2. Conversely, transient red wolves did not maintain home ranges and traversed areas between 122 km2 and 681 km2. Space use by transient red wolves was not spatially stable and exhibited shifting patterns until residency was achieved by individual wolves. Habitat selection was similar between resident and transient red wolves in which agricultural habitats were selected over forested habitats. However, transients showed stronger selection for edges and roads than resident red wolves. Behaviors of transient wolves are rarely reported in studies of space use and habitat selection because of technological limitations to observed extensive space use and because they do not contribute reproductively to populations. Transients in our study comprised displaced red wolves and younger dispersers that competed for limited space and mating opportunities. Therefore, our results suggest that transiency is likely an important life-history strategy for red wolves that facilitates metapopulation dynamics through short- and long-distance movements and eventual replacement of breeding residents lost to mortality. PMID- 28002496 TI - Exosomal miRs in Lung Cancer: A Mathematical Model. AB - Lung cancer, primarily non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths in the United States and worldwide. While early detection significantly improves five-year survival, there are no reliable diagnostic tools for early detection. Several exosomal microRNAs (miRs) are overexpressed in NSCLC, and have been suggested as potential biomarkers for early detection. The present paper develops a mathematical model for early stage of NSCLC with emphasis on the role of the three highest overexpressed miRs, namely miR-21, miR 205 and miR-155. Simulations of the model provide quantitative relationships between the tumor volume and the total mass of each of the above miRs in the tumor. Because of the positive correlation between these miRs in the tumor tissue and in the blood, the results of the paper may be viewed as a first step toward establishing a combination of miRs 21, 205, 155 and possibly other miRs as serum biomarkers for early detection of NSCLC. PMID- 28002497 TI - A Novel igf3 Gene in Common Carp (Cyprinus carpio): Evidence for Its Role in Regulating Gonadal Development. AB - Since the insulin-like growth factor 3 (igf3) gene was recently discovered in fish ovary, its function in the gonads has received much attention. In this study, we isolated two igf3 subtypes from common carp (Cyprinus carpio), which comprised full-length cDNA of 707 and 1153 nucleotides encoding 205 and 198 amino acids (aa), respectively. The Igf3 aa sequence had the highest gene homology of 72% with the corresponding sequence in zebrafish (Danio rerio). Phylogenetic tree construction revealed that the C. carpio igf3 gene was first clustered with D. rerio and then with other teleost species. Igf3 mRNA was widely expressed, with expression being highest in the gonads and blood. In the gonad development stage, igf3a mRNA expression was highest in the maturity and recession stage of the ovary, and decline phase of the testis, while igf3b was highest in the recession and fully mature periods of the ovaries and testes, respectively. Western blotting of testis protein samples showed two bands of approximately 21 kDa and 34 kDa corresponding to the calculated molecular mass of the two Igf3 subtypes; no signal was detected in the ovary. The Igf3 protein was localized in the ovary granulosa cells and testis spermatogonium and spermatids. 17beta-Ethinylestradiol treatment increased both ovary and testis igf3 mRNA expression. These findings suggest that Igf3 may play an important role in C. carpio gonadal development. PMID- 28002498 TI - A Systematic Literature Review of Self-Reported Smoking Cessation Counseling by Primary Care Physicians. AB - Tobacco consumption is a risk factor for chronic diseases and worldwide around six million people die from long-term exposure to first- or second-hand smoke annually. One effective approach to tobacco control is smoking cessation counseling by primary care physicians. However, research suggests that smoking cessation counseling is not sufficiently implemented in primary care. In order to understand and address the discrepancy between evidence and practice, an overview of counseling practices is needed. Therefore, the aim of this systematic literature review is to assess the frequency of smoking cessation counseling in primary care. Self-reported counseling behavior by physicians is categorized according to the 5A's strategy (ask, advise, assess, assist, arrange). An electronic database search was performed in Embase, Medline, PsycINFO, CINAHL and the Cochrane Library and overall, 3491 records were identified. After duplicates were removed, the title and abstracts of 2468 articles were screened for eligibility according to inclusion/exclusion criteria. The remaining 97 full-text articles reporting smoking cessation counseling by primary care physicians were assessed for eligibility. Eligible studies were those that measured physicians' self-reported smoking cessation counseling activities via questionnaire. Thirty five articles were included in the final review (1 intervention and 34 cross sectional studies). On average, behavior corresponding to the 5A's was reported by 65% of physicians for "Ask", 63% for "Advise", 36% for "Assess", 44% for "Assist", and 22% of physicians for "Arrange", although the measurement and reporting of each of these counseling practices varied across studies. Overall, the results indicate that the first strategies (ask, advise) were more frequently reported than the subsequent strategies (assess, assist, arrange). Moreover, there was considerable variation in the items used to assess counseling behaviour and developing a standardized instrument to assess the counseling strategies implemented in primary care would help to identify and address current gaps in practice. PMID- 28002499 TI - Targeting Abundant Fish Stocks while Avoiding Overfished Species: Video and Fishing Surveys to Inform Management after Long-Term Fishery Closures. AB - Historically, it has been difficult to balance conservation goals and yield objectives when managing multispecies fisheries that include stocks with various vulnerabilities to fishing. As managers try to maximize yield in mixed-stock fisheries, exploitation rates can lead to less productive stocks becoming overfished. In the late 1990s, population declines of several U.S. West Coast groundfish species caused the U.S. Pacific Fishery Management Council to create coast-wide fishery closures, known as Rockfish Conservation Areas, to rebuild overfished species. The fishery closures and other management measures successfully reduced fishing mortality of these species, but constrained fishing opportunities on abundant stocks. Restrictive regulations also caused the unintended consequence of reducing fishery-dependent data available to assess population status of fished species. As stocks rebuild, managers are faced with the challenge of increasing fishing opportunities while minimizing fishing mortality on rebuilding species. We designed a camera system to evaluate fishes in coastal habitats and used experimental gear and fishing techniques paired with video surveys to determine if abundant species could be caught in rocky habitats with minimal catches of co-occurring rebuilding species. We fished a total of 58 days and completed 741 sets with vertical hook-and-line fishing gear. We also conducted 299 video surveys in the same locations where fishing occurred. Comparison of fishing and stereo-video surveys indicated that fishermen could fish with modified hook-and-line gear to catch abundant species while limiting bycatch of rebuilding species. As populations of overfished species continue to recover along the U.S. West Coast, it is important to improve data collection, and video and fishing surveys may be key to assessing species that occur in rocky habitats. PMID- 28002500 TI - New Insights into Tree Height Distribution Based on Mixed Effects Univariate Diffusion Processes. AB - The aim of this paper is twofold: to introduce the mathematics of stochastic differential equations (SDEs) for forest dynamics modeling and to describe how such a model can be applied to aid our understanding of tree height distribution corresponding to a given diameter using the large dataset provided by the Lithuanian National Forest Inventory (LNFI). Tree height-diameter dynamics was examined with Ornstein-Uhlenbeck family mixed effects SDEs. Dynamics of a tree height, volume and their coefficients of variation, quantile regression curves of the tree height, and height-diameter ratio were demonstrated using newly developed tree height distributions for a given diameter. The parameters were estimated by considering a discrete sample of the diameter and height and by using an approximated maximum likelihood procedure. All models were evaluated using a validation dataset. The dataset provided by the LNFI (2006-2010) of Scots pine trees is used in this study to estimate parameters and validate our modeling technique. The verification indicated that the newly developed models are able to accurately capture the behavior of tree height distribution corresponding to a given diameter. All of the results were implemented in a MAPLE symbolic algebra system. PMID- 28002501 TI - Correction: SNP-SNP Interaction Analysis on Soybean Oil Content under Multi Environments. AB - [This corrects the article DOI: 10.1371/journal.pone.0163692.]. PMID- 28002502 TI - EhNPC1 and EhNPC2 Proteins Participate in Trafficking of Exogenous Cholesterol in Entamoeba histolytica Trophozoites: Relevance for Phagocytosis. AB - Entamoeba histolytica, the highly phagocytic protozoan causative of human amoebiasis lacks the machinery to synthesize cholesterol. Here, we investigated the presence of NPC1 and NPC2 proteins in this parasite, which are involved in cholesterol trafficking in mammals. Bioinformatics analysis revealed one Ehnpc1 and two Ehnpc2 genes. EhNPC1 appeared as a transmembrane protein and both EhNPC2 as peripheral membrane proteins. Molecular docking predicted that EhNPC1 and EhNPC2 bind cholesterol and interact with each other. Genes and proteins were identified in trophozoites. Serum pulse-chase and confocal microscopy assays unveiled that after trophozoites sensed the cholesterol source, EhNPC1 and EhNPC2 were organized around the plasma membrane in a punctuated pattern. Vesicles emerged and increased in number and size and some appeared full of cholesterol with EhNPC1 or EhNPC2 facing the extracellular space. Both proteins, but mostly EhNPC2, were found out of the cell associated with cholesterol. EhNPC1 and cholesterol formed networks from the plasma membrane to the nucleus. EhNPC2 appeared in erythrocytes that were being ingested by trophozoites, co-localizing with cholesterol of erythrocytes, whereas EhNPC1 surrounded the phagocytic cup. EhNPC1 and EhNPC2 co-localized with EhSERCA in the endoplasmic reticulum and with lysobisphosphatidic acid and EhADH (an Alix protein) in phagolysosomes. Immunoprecipitation assays confirmed the EhNPC1 and EhNPC2 association with cholesterol, EhRab7A and EhADH. Serum starved and blockage of cholesterol trafficking caused a low rate of phagocytosis and incapability of trophozoites to produce damage in the mouse colon. Ehnpc1 and Ehnpc2 knockdown provoked in trophozoites a lower intracellular cholesterol concentration and a diminished rate of phagocytosis; and Ehnpc1 silencing also produced a decrease of trophozoites movement. Trafficking of EhNPC1 and EhNPC2 during cholesterol uptake and phagocytosis as well as their association with molecules involved in endocytosis strongly suggest that these proteins play a key role in cholesterol uptake. PMID- 28002503 TI - Atmospheric oxidation of halogenated aromatics: comparative analysis of reaction mechanisms and reaction kinetics. AB - Atmospheric transport is the major route for global distribution of semi-volatile compounds such as halogenated aromatics as well as their major exposure route for humans. Their major atmospheric removal process is oxidation by hydroxyl radicals. There is very little information on the reaction mechanism or reaction path dynamics of atmospheric degradation of halogenated benzenes. Furthermore, the measured reaction rate constants are missing for the range of environmentally relevant temperatures, i.e. 230-330 K. A series of recent theoretical studies have provided those valuable missing information for fluorobenzene, chlorobenzene, hexafluorobenzene and hexachlorobenzene. Their comparative analysis has provided additional and more general insight into the mechanism of those important tropospheric degradation processes as well as into the mobility, transport and atmospheric fate of halogenated aromatic systems. It was demonstrated for the first time that the addition of hydroxyl radicals to monohalogenated as well as to perhalogenated benzenes proceeds indirectly, via a prereaction complex and its formation and dynamics have been characterized including the respective transition-state. However, in fluorobenzene and chlorobenzene reactions hydroxyl radical hydrogen is pointing approximately to the center of the aromatic ring while in the case of hexafluorobenzene and hexachlorobenzene, unexpectedly, the oxygen is directed towards the center of the aromatic ring. The reliable rate constants are now available for all environmentally relevant temperatures for the tropospheric oxidation of fluorobenzene, chlorobenzene, hexafluorobenzene and hexachlorobenzene while pentachlorophenol, a well-known organic micropollutant, seems to be a major stable product of tropospheric oxidation of hexachlorobenzene. Their calculated tropospheric lifetimes show that fluorobenzene and chlorobenzene are easily removed from the atmosphere and do not have long-range transport potential while hexafluorobenzene seems to be a potential POP chemical and hexachlorobenzene is clearly a typical persistent organic pollutant. PMID- 28002504 TI - Formation and alteration of airborne particles in the subway environment. AB - Most particles in the rail subway environment are sub-micron sized ferruginous flakes and splinters generated mechanically by frictional wear of brake pads, wheels and rails. To better understand the mechanisms of formation and the alteration processes affecting inhalable particles in subways, PM samples (1-2.5 MUm and 2.5-10 MUm) were collected in the Barcelona Metro and then studied under a scanning electron microscope. Most particles in these samples are hematitic (up to 88%), with relatively minor amounts of mineral matter (up to 9%) and sulphates (up to 5%). Detailed microscopy (using back scattered and TEM-DRX imaging) reveals how many of the metallic particles comprise the metallic Fe nucleus surrounded by hematite (Fe2O3) and a coating of sulphate and chloride salts mixed with mineral matter (including Ca-carbonates, clay minerals and quartz). These observations record the emission of fine to ultrafine FePM by frictional wear at elevated temperatures that promote rapid partial (or complete) oxidation of the native metal. Water condensing on the PM surface during cooling leads to the adsorption of inorganic mineral particles that coat the iron oxide. The distinctively layered polymineralic structure that results from these processes is peculiar to particles generated in the subway environment and very different from PM typically inhaled outdoors. PMID- 28002505 TI - Pointing at Ito cell, from structure to function (? or Cinderella story in liver histology). AB - For more than 130 years, the hepatic stellate cells (also known as Ito cells) have been the object of numerous studies that aimed at their characterization both in normal and postlesional status, where they play a key role in fibrosis progression specific for chronic hepatic pathology. Converged studies on their histophysiology have revealed other functions, namely the involvement in liver embryological development and regeneration, metabolisms regulation, modulation of local inflammatory and immune reactions. Ito cells plasticity is surprising, as they are able to provide the connection between the complex sinusoidal and parenchymal microenvironment, influencing by autocrine and paracrine mechanisms the extracellular matrix content in tight correlation to growth and repair necessities. Last but not least, Ito cells take an active part in systemic homeostasis maintenance by their capacity to store and mobilize vitamin A, respectively. The evolving interest in their research will be undoubtedly followed by a better knowledge of the physiopathological sequences responsible for liver diseases, as new targets for the development of new therapeutic approaches directed toward improvement of prognosis and patients' quality of life. PMID- 28002507 TI - Narrow band imaging endoscopy for detection of precancerous lesions of upper gastrointestinal tract. AB - Gastric cancer (GC) is an important health problem despite the advances in surgery and chemotherapy and although the incidence is decreasing, GC is still considered the second most common cause of deceases produced by cancer. Survival rates in gastric cancer are low, mainly because most patients are often diagnosed in late stages. The current interest in the diagnostic of GC is the detection of early gastric cancer. Advances in high-resolution endoscopic techniques such as narrow band imaging (NBI) allow the detection of early precancerous lesions like polyps or metaplastic mucosa. Performing only white light imaging endoscopy in order to detect gastric cancer can lead to omission or misdiagnose of a considerable number of early gastric cancers. NBI endoscopy associated with other high-resolution examinations is viable in detecting early gastric cancer, though few studies also indicate that the endoscopist's expertise plays an important factor as well. PMID- 28002506 TI - The utility of bone remodeling markers in the diagnosis, evolution and treatment response evaluation in bone metastases. AB - After the lungs and liver, the bone is the third most common site for metastatic disease, appearing frequently in breast and prostate malignancies. These pathological bone events that occur during the evolution of the metastatic disease are usually the onset of osteolysis and they lower the patient's life quality, and are sometimes the cause of death due to the required treatments (surgery, radiotherapy). Due to the nature of the bone remodeling process, the markers that control bone resorption are the main early indicators of bone malignancy. These markers can be found in excess quantities of 50-150% in patients with bone metastases. Analyzing these indicators in conjunction with traditional tumoral markers such as the prostate specific antigen (PSA) and the type I collagen cross-linked telopeptide (ICTP) can often increase the sensibility of the investigation and the chances of diagnosing bone metastases. The studies that were carried out in order to research this area of knowledge have had good and expected results. Most of the efforts are now channeled into developing a better therapeutic strategy that would allow for the early diagnosis and treatment of the pathological bone events. Until these markers can be used as standard investigation methods in all of our patients, some controlled studies must be carried out in order to statistically prove these results, which are purely observational. PMID- 28002508 TI - Histopathological aspects in autoimmune cutaneous manifestations associated with hepatitis C virus infection. AB - Autoimmunity is characterized by activation of the immune system that attacks and destroys wrongly, the body's own structures. All body tissues can be affected (erythrocytes, leukocytes, platelets, blood vessels, muscle tissue, endocrine system, and other), including the skin. Autoimmune diseases have an increased frequency in women, especially in adulthood, and they are associated with hereditary factors. Although the etiology of autoimmune diseases is incompletely elucidated, there is an association between chronic infection with hepatitis C and autoimmunity, association highlighted and well documented in clinical studies. Other viral infections do not have the same connotation in the context of autoimmunity, but it is recognized that they are an important triggering factor in the pathophysiological mechanism. The cases associating chronic hepatitis C treated with interferon and ribavirin, with multiple autoimmune diseases substrate, raising the discussion of a possible pathophysiological correlation between them. PMID- 28002509 TI - Peritumoral inflammatory reaction in non-melanoma skin cancers - histological and immunohistochemical study. AB - Non-melanoma skin cancers (NMSCs) are the most frequent types of cancer in white skin populations, all over the world. In the last 40 years, there was observed a rapid increase of their incidence, because of the UV radiations exposure and weather changes. Although its morbidity is a relatively modest one, the direct social costs of NMSCs are quite substantial due to a high incidence. Due to these reasons, numerous studies try to clarify the etiopathogenic mechanisms of NMSCs, to elaborate treatment and prevention measures. In the last years, a special attention was given to the relation between inflammation and skin cancer. In our study, we performed a histological and immunohistological evaluation of the inflammatory reaction on a number of 73 surgical exeresis pieces coming from the patients diagnosed with NMSCs. Of these, 21 were squamous cell carcinomas (SCCs) and 52 basal cell carcinomas (BCCs). The peritumoral inflammatory reaction in NMSCs was an extremely variable one in intensity and distribution, from one case to another and even from one area to another within the same tumor, thus proving the complexity of the relations between tumor cells and the cells of the immune system. By comparing the intensity of the inflammatory reaction between the two main types of NMSCs, there was observed that in SCCs the inflammatory reaction was more intense in comparison to BCCs. Also, in SCC there was highlighted a more abundant inflammatory infiltrate in poorly differentiated carcinomas, in comparison to the well-differentiated ones. The presence of the immune system cells (T-lymphocytes, macrophages, mast cells) among the tumoral cells, in a direct contact with these, makes us believe that between the two categories of cells there may appear mechanisms of intercellular communication, distinct from the mechanisms of paracrine signaling. PMID- 28002510 TI - Caspase 3 expression and plasma level of Fas ligand as apoptosis biomarkers in inflammatory endotoxemic lung injury. AB - OBJECTIVE: The objective of this study is to evaluate if the immunohistochemical expression of a pulmonary apoptosis marker and plasma level of Fas ligand (FasL) correlates with the dose- and time-dependent severity of lung injury, induced by the administration of lipo-polysaccharide (LPS) in an endotoxemic rat model. MATERIALS AND METHODS: Our study included 30 male Wistar rats, randomly divided into three groups: one control group (n=6) and two experimental groups (n=12/group), in whom we induced endotoxemia by intraperitoneal injection of progressively increasing doses of LPS (5, 10 mg/kg). We measured FasL plasma levels of the rats at different time points and analyzed the relationships with markers of lung injury. To investigate the level of caspase 3-protein expression, the immunohistochemistry of the lung tissue was assessed. RESULTS: The median percentage of caspase 3-stained cells for the 5 mg/kg LPS dose was 0.36%, for the 10 mg/kg LPS dose was 0.4% and for the control group was 0.03% (p<0.0001). The elevated expression levels of caspase 3 were consistent with the altered lung morphologies observed (rs=0.88). LPS administration in rats resulted in a significant dose-dependent increase in the levels of plasma FasL (p<0.0001). These levels correlated with markers of lung injury: degree of hypoxemia (rs= 0.42), histological measured lung injury score (rs=0.72), the density of the caspase 3 staining cells in the immunohistochemistry assessment of apoptosis (rs=0.81) and with the plasma RAGE (receptor for advanced glycated end-products) values (rs=0.70). CONCLUSIONS: Apoptosis is increased in edotoxemia induced lung injury and is likely to contribute to alveolar injury. PMID- 28002511 TI - The prognostic and clinical significance of neuroimagistic and neurobiological vulnerability markers in correlation with the molecular pharmacogenetic testing in psychoses and ultra high-risk categories. AB - We approach an integrated, multidisciplinary, innovative research-action model in children and adolescents with psychosis and ultra high-risk categories. Our main focus was: to investigate the prognostic and clinical significance of neuroimagistic and neurobiological vulnerability markers in correlation with the molecular pharmacogenetic testing in psychoses and ultra high-risk categories; the dynamic evaluation of the clinical evolution for the studied groups in correlation with specific neurobiological and neuroimagistic variables and markers. Our research was conducted in the period 2009-2015 on 87 patients, children and adolescents with psychosis (42 took treatment after pharmacogenetic testing, 45 without) and 65 children with ultra high-risk (UHR) for psychosis - 32 benefited of pharmacotherapy after pharmacogenetic testing and 33 without. Also, the patients were evaluated through magnetic resonance (MR) spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated through the mean change in the Positive and Negative Syndrome Scale (PANSS) total scores, in the Clinical Global Impression of Severity and Improvement (CGI-S/I), Children's Global Assessment Scale (CGAS) and through the change registered for the relevant neurobiological markers and MR spectroscopy metabolites, from baseline until endpoint in different timepoints. Our results, showed statistically significant differences of the clinical scores between the studied groups. Our research was a proof, sustaining the use of the pharmacogenetic testing in clinical practice and the value of investigating relevant neurobiological and neuroimagistic markers for a personalized, tailored therapy for psychotic patients and neuro-psychiatric UHR categories, as a fruitful pathway of intervention and care. PMID- 28002512 TI - Pharmacotoxicological screening on new derivatives of beta-phenylethylamine, potential agonists of beta3-adrenergic receptors. AB - BACKGROUND AND AIMS: Beta3-adrenergic receptors (beta3-ARs) have been initially characterized in 1989. Afterwards, their tissue distribution was established: white and brown adipose tissue, central nervous system, myocardium (atrial and ventricular), blood vessels, smooth gastrointestinal muscles (stomach, small intestine, colon), gallbladder, urinary bladder, prostate, skeletal muscles. Non clinical trials have demonstrated the major implication of beta3-ARs in glucose metabolism, implicitly, in insulin release, and also in obesity. Therefore, new compounds were synthesized starting from beta-phenylethylamine nucleus and substituted in various positions, for possible antidiabetic and/or antiobesity action. MATERIALS AND METHODS: In the present research, the antidiabetic action of newly synthesized compounds was investigated on an experimental model of alloxan-induced diabetes, administered in dose of 130 mg/kg body weight (bw), intraperitoneally (i.p.). After 14 days of treatment, glycemia and enzymes involved in homeostasis of glucose metabolism, glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase (G6Pase) and hexokinase were determined. Animals were then euthanized and histopathology examinations were performed on harvested liver, kidney, spleen and brain in order to document pathological changes induced by alloxan-induced diabetes and/or by tested compounds. RESULTS AND CONCLUSIONS: Glycemia in animals treated with the tested compounds decreased statistically significant for groups C2 and C3 (-42.13% and -37.2%, respectively), compared to diabetic control group. C2 was also the compound to favorably modify the dynamics of determined enzymes, together with the display of very good safety profile supported by minor, non-significant, histopathological changes. PMID- 28002513 TI - A computer-aided diagnostic system for intestinal polyps identified by wireless capsule endoscopy. AB - Small bowel polyps present in images acquired by wireless capsule endoscopy are more difficult to detect using computer-aided diagnostic (CAD) systems. We aimed to identify the optimum morphological characteristics that best describe a polyp and convert them into feature vectors used for automatic detection of polyps present in images acquired by wireless capsule endoscopy (WCE). We prospectively included 54 patients with clinical indications for WCE. Initially, physicians analyzed all images acquired, identifying the frames that contained small bowel polyps. Subsequently, all images were analyzed using an automated computer-aided diagnostic system designed and implemented to convert physical characteristics into vectors of numeric values. The data set was completed with texture and color information, and then analyzed by a feed forward back propagation artificial neural network (ANN) trained to identify the presence of polyps in WCE frames. Overall, the neural network had 93.75% sensitivity, 91.38% specificity, 85.71% positive predictive value (PPV) and 96.36% negative predictive value (NPV). In comparison, physicians' diagnosis indicated 94.79% sensitivity, 93.68% specificity, 89.22% PPV and 97.02% NPV, thus showing that ANN diagnosis was similar to that of human interpretation. Computer-aided diagnostic of small bowel polyps, based on morphological features detection methods, emulation and neural networks classification, seems efficient, fast and reliable for physicians. PMID- 28002514 TI - Lectin purification from carp roe (Cyprinus carpio L.), investigation of its carbohydrate specificity and application in histochemistry. AB - A method of lectin purification from carp roe (CCRA) was elaborated, which includes affinity chromatography on cross-linked ovomucoid and copolymers of polyvinyl alcohol and blood group-specific substances. That allowed obtaining lectin with electrophoretic purity and yielding of ~ 42 mg/kg roe. Electrophoresis in 15% polyacrylamide gel in the presence of beta-mercaptoethanol showed one band with molecular mass ~ 15 kDa, whereas in the absence of beta mercaptoethanol, CCRA exposed band with molecular mass ~ 60 kDa. The resulting lectin was thermostable, withstanding heating to 75 degrees C for 15 minutes, without noticeable loss of hemagglutinating activity. Gel column chromatography on Toyopearl HW-55 determined the lectin molecular weight of 120+/-3 kDa. For the lectin activity, divalent metal ions (Ca2+ and Mg2+) were not necessary. CCRA showed the best agglutination titer with pigeon erythrocytes, weaker - with rabbit and dog erythrocytes, and significantly weaker - with human and rat erythrocytes. CCRA lectin was specific to N-acetyl-D-galactosamine and D galactose group carbohydrates. The best lectin activity inhibition possessed alkaline phosphatase of calf intestine and fetuin. CCRA exposed highest affinity to complex oligosaccharide similar to the receptor of Phaseolus vulgaris erythroagglutinin (PHA-E). A comparative study on the histochemical specificity of CCRA and PHA-E using specimens of normal tissues, and that of colon neoplasia, showed similar, yet not identical binding properties. CCRA lectin rather differentially labeled adenoma and adenocarcinoma of colon, which suggests its prospective applicability in diagnostic histopathology. PMID- 28002515 TI - Morphological, imaging and surgical aspects in endometrial endometrioid adenocarcinoma. AB - Endometrioid endometrial adenocarcinomas (EECs) are frequent genital tumors for which the clinical, imaging and histopathological integrated analysis is the basis of differential diagnosis and therapeutic attitude. This research represents a tertiary multicenter study including 58 cases examined histopathologically and immunohistochemically, surgically treated, on a five years period. The main characteristics of the patients in the study group are represented by the average age of 66 years, associated with obesity, hypertension, diabetes, history of infertility, early menopause, nulliparity or long-time oral contraception. The most important clinical sign was the menopausal or postmenopausal vaginal bleeding. The golden standard in the diagnosis of endometrial carcinoma is the dilation and curettage of the uterine cavity, followed by histopathological assessment. The association between transvaginal ultrasonography (TVUS) and endometrial biopsy increases to 100% the diagnostic sensitivity. The use of an antibodies panel that includes CK, ER, PR, vimentin can guide the diagnosis to EEC and the analysis of Ki67, p16, p53 and CEA immunoreactions can be useful both for EEC differential diagnosis and to assess the tumor aggressiveness. The interrelation between the accurate histopathological diagnosis and the adequate surgical staging is the cornerstone of curative therapy in the EEC. PMID- 28002516 TI - Experimental animal model in a histological study of drug-induced gingival overgrowth. AB - Gingival overgrowth (GO) is a pathology with important aesthetic and functional implications and with a multifactorial pathogenesis. Incriminated etiological factors include antihypertensive, antiepileptic and immunosuppressant medication. We aimed to evaluate the induction of gingival overgrowth on experimental rats, depending on the drug type, dose and duration. In the research conducted by us, the increase in gingival tissue production occurred gradually, depending on the administered medication and the time elapsed after its start. The study conducted shows that experimentally induced gingival overgrowth of the administered drugs is made possible by altering tissue homeostasis through altering the fibrocyte cell populations involved in the tissular turnover as well as those involved in the inflammatory process. A better understanding of the pathogenesis of this undesirable effect may lead to the development of improved management strategies for preventing it, or reducing it through non-surgical methods. PMID- 28002517 TI - Correlations between etiological factors and lesion severity in carotid artery atheromatosis. AB - Occurrence of atheromatous plaques on the internal wall of large and medium sized arteries represents a widely spread disease. It is especially found in the elderly, but also in individuals belonging to the 4th-6th decade of life with an increasing incidence. Correlating the main etiological factors with morphological change severity, in conjunction with settling the importance of each factor on its own in generating and developing arterial plaques, has an important predictive role in the evolution of atherosclerotic pathology. The purpose of this study is to investigate the existence of a correlation between the main factors linked to atheromatosis and the degree of severity of the carotid artery stenosis. This is obtained by ultrasonographic examination of the carotid arteries in correlation with determining serum cholesterol levels, thus ascertaining the risk for atheroma related events and disease progression. PMID- 28002518 TI - Oral toxicity study of certain plant extracts containing pyrrolizidine alkaloids. AB - Pyrrolizidine alkaloids (PAs) are a class of toxic compounds which are found in plants. Poisoning caused by these toxins is associated with acute and chronic liver damage. Tussilago farfara (coltsfoot), Petasites hybridus (common butterbur), Senecio vernalis (eastern groundsel) and Symphytum officinale (comfrey) are traditional phytotherapic species, which beside the therapeutic bioactive compounds contain PAs. The aim of the paper was to assess the safety of some dry extracts obtained from these species. For the determination of acute toxicity, Organization for Economic Cooperation and Development (OECD) Guideline No. 423 was used. For the determination of repeated dose oral toxicity, Senecionis vernalis herba and Symphyti radix extracts (250 mg/kg) were administrated, by gavage, for 28 days, and their effects on animal weight, liver and biliary functions, hepatic tissue and oxidative stress were investigated. After the acute toxicity testing, the dry extracts were placed in the GHS Category V (LD50>5000 mg/kg, p.o.). For the subacute toxicity testing, no death or any signs of toxicity were observed. Also, no significant differences in biochemical parameters were observed between control and treated groups. The observed histopathological lesions were non-specific and were not consistent with the data reported in the literature for PAs exposure. In conclusion, the administration for 28 days, of the tested extracts, in a dose which correspond to a PAs concentration over the limits imposed in some countries, produced no hepatic and biliary toxic effects. Further studies, extended over a longer period of time, are needed in order to determine the safety of plant extracts containing PAs. PMID- 28002519 TI - Correlations between endothelial cell markers CD31, CD34 and CD105 in colorectal carcinoma. AB - PURPOSE: Colorectal carcinoma is an important cause of mortality worldwide. The fact that tumor growth is dependent on angiogenesis has supported researches for new prognostic parameters and the development of novel therapeutic strategies. Accordingly, we sought to evaluate angiogenesis quantitatively by assessing microvessel density in colorectal cancer. MATERIALS AND METHODS: The blood vessels stained with CD31, CD34 and CD105 were counted, and we reported their number per square millimeter in order to obtain microvascular density (MVD). Then, we aimed at comparing the performance of three endothelial cell markers (CD31, CD34, and CD105) on formalin-fixed tissues from 58 patients diagnosed with colorectal cancer. RESULTS: Following the comparison of the average effective vessels marked with the three markers, Student's t-test showed that the mean number of blood vessels marked with CD34 is higher than the blood vessels marked with CD31 and CD105. A significant difference that has been registered between the three levels of the T stage was found in the patients in our study, in terms of value marker CD105, ANOVA p=0.049, which returns to a value <0.05. Quick time decreases the pT stage, the observed differences being close to statistical significance. However, the result of ANOVA test does not allow us to say that differences can be generalized and not just a particular result, valid only for the study group, p=0.061 >0.05. There is a significant difference between patients with stage T, in terms of value: hemoglobin (ANOVA p<0.001), hematocrit (ANOVA p<0.001), mean corpuscular volume (MCV) (ANOVA p<0.001), mean corpuscular hemoglobin (MCH) (ANOVA p=0.002 <0.01 - significant difference with 99% confidence). By calculating the Pearson's correlation coefficient for the relationship CD31-CD105, we obtained a value r=0.440, which corresponds to p=0.0013 <0.05, indicating a statistically noteworthy direct correlation between the two factors. CONCLUSIONS: CD31 marker increases simultaneously with the CD105, in the cases analyzed throughout the present study. The ability of tumors to maintain a high vascular blood density in their inner portions may represent a reliable parameter to evaluate tumor angiogenesis and a finding relevant for future development of therapeutic angiogenesis strategies. PMID- 28002520 TI - Clinical, immunological and pathological profile of infants suffering from cow's milk protein allergy. AB - Cow's milk protein allergy (CMPA) is the most frequently encountered form of food allergy in pediatric patients and occurs secondary to cow's milk proteins (CMP) ingestion. The aim of this study is to define the profile of children suffering from CMPA and to describe the associated pathological findings. The authors performed a retrospective case-control study on 160 infants that presented with CMPA symptoms at "Sf. Maria" Emergency Clinical Hospital for Children, Iassy, Romania, between January 2013 and January 2015. Fifty-five infants were diagnosed with CMPA (Group 1 - cases group) and 105 had no proven allergy (Group 2 - control group). Mean age of patients, gender distribution and prevalence of premature birth registered no statistically significant difference between the two groups. The prevalence of familial history of allergy was higher in case of patients with CMPA (36.36% versus 20% in control group). The delay between the introduction of CMP into alimentation and symptoms' onset was significantly shorter in Group 1 (12 days) compared to Group 2 (42 days) (p=0.0051), thus pleading for an earlier onset of symptoms in case of CMPA. CMPA usually manifested through an association of gastrointestinal (76.36%), cutaneous and mucosal symptoms (70.91%). Specific IgE were positive values in 49 patients with CMPA (89.09%) and 32 patients (30.48%) without CMPA (p<0.001). Endoscopic examinations with tissue sampling were performed in 26 infants with CMPA. Focal erythema, erosions and lymphoid nodular hyperplasia were signaled in 23 cases and eosinophilic infiltration was noticed in 15 cases. In conclusion, specific IgE and pathological changes offer highly reliable methods for CMPA diagnosis. PMID- 28002521 TI - The cadherin switch assessment in the epithelial-mesenchymal transition of urothelial bladder carcinomas. AB - INTRODUCTION: The epithelial-mesenchymal transition (EMT) process is a complex molecular mechanism that is involved in the acquisition of an aggressive, invasive and metastatic phenotype by carcinomas. The cadherin switch consists in the alteration of E-cadherin and N-cadherin expression and is specific for the EMT process. MATERIALS AND METHODS: This study included 35 cases of primitive urothelial carcinomas investigated in relation with clinicopathological prognostic parameters and expression of E- and N-cadherins in the advancing edge and intratumoral compartments. RESULTS: In both compartments, the immunoexpression of E-cadherin decreased, while that of N-cadherin increased in high grade, deeply invasive, or those cases with lymph node metastases and advanced stages carcinomas, with a negative linear correlation observed between their expression percentage values. In this study, it was observed the presence of cadherin switch in urothelial carcinomas, the variation of the two proteins' immunostaining patterns being higher at the advancing edge. The presence of N cadherin in intratumoral compartment designated it as actively involved in EMT process. CONCLUSIONS: The analysis of cadherins switch can be used to identify superficial urothelial carcinoma with invasion and metastasis potential. PMID- 28002522 TI - Primary retroperitoneal seminoma - embryology, histopathology and treatment particularities. AB - INTRODUCTION: Retroperitoneal seminoma is a very rare form of cancer, with embryological origin represented by primordial germ cells from the urogenital ridges left behind during the fetal development. Extragenital germ cell tumors can also occur in the mediastinum or the pineal gland. The aim of this paper is to outline the particularities and draw embryological, histopatological and treatment conclusions regarding extragonadal germ cell tumors. PATIENT AND METHODS: A 43-year-old patient without any additional pathology was admitted for anemia of unknown etiology. The clinical examination revealed through deep abdominal palpation a mass in the left flank, and normal testes. Thoraco-abdomino pelvic computed tomography (CT) scan showed a large retroperitoneal tumor adjacent to the great vessels in the left lumbo-iliac region. The blood work revealed just a low hemoglobin and hematocrit. With the established diagnosis of retroperitoneal tumor, radical surgical removal was decided. During the surgery, we were required to dissect a large solid encapsulated tumor mass from the aorta and the common iliac artery, starting at the renal pedicle all the way to the left iliac bifurcation. The surgical access was obtained through a transperitoneal left subcostal incision prolonged pararectally. Histopathological and immunohistochemical studies revealed a seminoma of the usual type. After the histological findings, the patient's tumor markers were investigated (LDH - lactate dehydrogenase, betaHCG - beta-human chorionic gonadotropin, alphaFP - alpha-fetoprotein), all values being within normal ranges. In addition, the left testicle was thoroughly reexamined, clinically, through ultrasound and magnetic resonance imaging (MRI) scans, and no abnormalities were observed. After the surgery, the patient followed three courses of chemotherapy (BEP - Bleomycin, Etoposide and Cisplatin). RESULTS: The CT scan done 24 months after surgery found no signs of local or distant tumor recurrence. The patient entered a follow-up schedule consisting of periodical clinical, serological and imagistic evaluations. CONCLUSIONS: Primary retroperitoneal seminoma is a rare entity that must be taken into account when treating a retroperitoneal tumor. It develops out of the urogenital ridge, while the testes are normal. Thorough testicular evaluation (clinical, ultrasound and serum markers) is mandatory in all retroperitoneal tumors. The histopathological analysis is crucial for an accurate diagnosis and a proper management strategy. Through radical surgery and chemotherapy, the patients that are diagnosed prior to massive visceral metastatic dissemination can be cured. PMID- 28002523 TI - Histological assessment of fracture healing after reduction of the rat femur using two different osteosynthesis methods. AB - Osteosynthesis using Kirschner (K) wires and plates with screws were compared on the same subject in a previous experimental protocol, but none of them led to fracture healing. We designed a new murine study in order to compare this two methods on different subjects in order to obtain histological proofs of which one is better and to see how limited periosteum removal influence fracture healing. Divided in two equal groups, femoral osteotomies were performed on 30 Brown Norway rats, then reduced using plates and screws in the OPS (osteosynthesis using plates and screws) group and using K-wires in the OIKW (osteosynthesis using Kirschner wire) group. The animals underwent clinical, radiological and histological assessment for eight weeks. The quality of the fracture healing was associated with a higher number of osteocytes/microscopic field at eight weeks. The difference between the groups regarding the number of osteocytes inside lacuna was statistically significant (t-test for equal variances not assumed, p=0.001), which confirms a mean difference of 32 cells/microscopic field (mf) with a 95% confidence interval of 15-50 cells/mf. In conclusion, limited periosteum removal did not influence negatively fracture healing. Therefore, we considered that osteosynthesis using plates and screws led to better results compared to fracture fixation using K-wires. PMID- 28002524 TI - Histopathological consequences of hyperzincemia on rat teeth. Experimental study. AB - The aim of this study was to investigate the histopathological features of dental pulp in acute zinc (Zn) intoxication and to identify possible physiopathological mechanisms of the lesions. Twelve adult male Wistar rats were divided into two groups, the control one and the exposed group. Each animal from the experimental group received a single dose of zinc chloride (ZnCl2) by intraperitoneal injection. Blood samples were collected from exposed animals at 2, 4, and 6 hours after the injection and plasma Zn concentrations were determined by spectrophotometry. After six hours of observation, the animals were sacrificed and two teeth from every rat were removed. Twelve teeth were processed by standard histological technique using Hematoxylin-Eosin (HE) and Szekely trichrome stainings, and the other twelve were subjected to Schliff cutting grinding technique. The experimental group showed increased plasma zinc concentration (0.46+/-0.06 mg/L) after two hours and then slightly decreasing values in the next four hours. Undecalcified teeth did not showed any changing into the dentin or enamel structures, but decalcified teeth revealed numerous deposits into the dental pulp, which consisted of red acellular superposed sediments that could be made up of zinc with some plasma protein, or there could be an unknown compound which precipitated under the influence of zinc cation (Zn2+). We can presume that the dental pulp may be an elective place for zinc accretion and so it must be considered a potential target for this metal. PMID- 28002525 TI - Histopathological findings regarding oncological feasibility of laparoscopic versus open approach for rectal cancer: a retrospective study. AB - Worldwide, colorectal cancer is one of the most prevalent malignancies. Due to oncological safety concerns, data regarding the laparoscopic surgical treatment of rectal cancer is scarce. Our study's main aim was investigate the oncological adequacy of laparoscopic surgery in the treatment of rectal cancer by comparing its oncological reliability with the oncological results obtained after open surgery for rectal cancer. In this retrospective study, 80 patients who underwent surgery for rectal cancer, admitted in our Clinic between January 1, 2014 November 31, 2015 were enrolled. The studied group was stratified according to the way of approach chosen: classic surgery (59 cases) and laparoscopic surgery (21 cases), respectively. Based on the histopathological examination, we analyzed the histological grading of rectal neoplasms, TNM staging, resection margins, lymphovascular and perineural invasion and the number of regional lymph nodes identified in the perirectal adipose tissue. The average number of isolated lymph nodes demonstrated non-significant differences between the two types of approaches: 20 lymph nodes in the classical approach versus 18 lymph nodes in the laparoscopic approach (p=0.109). Lymph nodes affected by metastases were associated in the majority of cases with stage IIIB and stage IIIC rectal cancers (100% and 83.3%, respectively). The laparoscopic approach proved to be efficient in terms of reaching oncological resection limits. On the resection specimens extracted by laparoscopic surgery, the residual tumor (R1) was encountered in 5% of the cases versus in 6.7% of the cases after classic surgery. The laparoscopic approach is oncologically feasible in the rectal cancer surgical treatment. PMID- 28002526 TI - Micro-CT and optical microscopy imagistic investigations of root canal morphology. AB - Protecting the root's internal morphology is the first key toward the success of the endodontic treatment. Due to the vast diversity of endodontic space, it is difficult to visualize and to establish the shape and limits of the root canal, especially the morphology of apical area and lateral root canals. Optical microscopy is a classical imagistic investigation method, widely used along classical methods like radiographs that also offer limited information about root morphology and extension of decay. Micro-computed tomography (micro-CT), a modern imagistic investigation method can provide detailed three-dimensional reconstructions of root canal. Micro-CT is a non-invasive method that has the possibility to offer cross-sectional and axial images of the endodontic space. The success of root canal treatment is based on cleaning and shaping. Beyond these two procedures, sealing the endodontic space by respecting its limits is another prerequisite for long-term success of endodontic therapy. Micro-CT can perform three-dimensional reconstruction of the root canal, root canal filling and can provide accurate images of the endodontic space. The assessment of root morphology can be obtained through imagistic invasive optical microscopy and already mentioned non-invasive methods (micro-CT). The aim of this study is to illustrate and analyze the endodontic space, according to its diversity by using micro-CT, a non-invasive imagistic investigation method an also optical microscopy. The two techniques can also provide the extension of carries or demineralized substance on different levels of the root. PMID- 28002527 TI - Rare thymic malignancy of B-cell origin - T-cell/histiocyte-rich large B-cell lymphoma. AB - AIM: T-cell/histiocyte-rich B-cell lymphoma is a rare type of diffuse large B cell lymphoma reported as involving primarily the thymus only by one paper in the English literature. CASE PRESENTATION: A four and a half years old boy was admitted, after a sudden onset in the middle of the night, with superior vena cava syndrome, resuscitated cardiac and respiratory arrest and severe coma with Glasgow Coma Scale rate of 3. In spite of intensive treatment, the patient repeated twice the cardiac arrest and died sixteen hours after admittance. The autopsy confirmed the existence of a huge mediastinal mass, revealed by the prior to death computed tomography examination, and the thorough histopatological established the diagnosis of T-cell/histiocyte-rich large B-cell lymphoma of the thymus with renal spread. DISCUSSION: The particularities of the presented case are the primary location of the lesion in the thymus, the age of the patient, very young, the lack of lymph nodes involvement and the rapid development of the disease until death without any possibility of therapeutic specific intervention. CONCLUSIONS: The case is the second reported in the literature with primary involvement of the thymus by this rare variant of diffuse large B-cell lymphoma. The histopatological examination is the golden standard for the diagnosis. Any clinical symptom of unexplained fatigue and dyspnea in a child should raise the clinician's suspicion of a mediastinal mass involving the thymus. PMID- 28002528 TI - Redundant plantar skin folds. AB - A 46-year-old female patient presented with photosensitivity, symmetric arthritis, episodic plantar pain and strikingly redundant plantar skin folds, likely due to lipoatrophy after recurrent episodes of plantar panniculitis. In this context, leukopenia with lymphopenia, thrombocytopenia and positive antinuclear antibodies were revelatory for systemic lupus erythematosus. However, a small cerebriform plantar collagenoma, along with discrete dysmorphic features with downslanting palpebral fissures and mild right ptosis, second and third syndactyly and a larger first right toe since childhood, and early-onset bilateral ovarian cystadenoma, suggested a minimal Proteus syndrome. Genetic confirmation could not be performed. As adipose tissue dysregulation may be a feature of Proteus syndrome, the possible mechanisms leading to localized lipoatrophy in this setting are discussed. This case enlights intriguing links between adipogenesis, inflammation and dysmorphology. From a practical point of view, finding and treating an over-imposed inflammation could help limit damage in a hamartomatous syndrome. PMID- 28002529 TI - Delayed interval delivery in twin pregnancy - case reports. AB - The implementation of assisted reproduction has increased the incidence of multiple pregnancies. Prenatal death of one fetus in the second trimester of twin pregnancy confronts the obstetrician with a difficult problem with regard to the management of pregnancy. The scarcity of the condition and the absence of the large-scale studies make it difficult to advise the parents on the prognosis and optimal management. The unavoidable birth or death of one premature neonate has led to the aim of delayed interval delivery for the other twin. We present in this report two cases of twin pregnancies with delayed-interval delivery and favorable outcomes for the surviving twins. The twin pregnancies conceived by in vitro fertilization (IVF) in HitMed Medical Center, Craiova, Romania. In the first case, one fetus dismiss in utero at 20 weeks of gestation. The second fetus was successfully delivered by Caesarean section, at 36 weeks. In the second case, the first fetus was delivered at 22 weeks. To save the surviving fetus, ligation of the umbilical cord at the cervical level was performed. The second fetus was delivered at 31 weeks by Caesarean section, in good conditions. We describe our management of the cases and the deliveries and the neonatal outcomes. In multiple gestation, prolongation of pregnancy after preterm dismiss in utero or even after delivery of one fetus is feasible in a closely monitored environment. PMID- 28002530 TI - Visceral and tissular reactivity in acute heart failure due to supraventricular tachyarrhythmia in a young patient. AB - Observation of major pathological alterations in a young person involves etiological and clinical justifications, in order to properly assess, treat and control these conditions. The aim of this paper is to present severe, acute pathological lesions, installed in a young person, secondary to hypodiastolic heart failure, due to persistent supraventricular tachyarrhythmia, triggered by a post-traumatic external stimulus, with complete remission post-electrical conversion. Pathological and clinical modification are revealed, in a young person, shortly after a minor thoracic trauma, in the absence of traumatic injury but with high-frequency palpitations onset and progressive installation of vascular, visceral and interstitial stasis modifications, as well as of vascular and tissular hypoperfusion with reactive vasoconstriction. These clinical and paraclinical aspects were: stasis hepatomegaly with hepatojugular reflux, pulmonary congestion with stasis rales, peripheral edema, transudative polyserositis - pericarditis, hydrothorax, ascites, dilatation of inferior vena cava and suprahepatic veins, decrease of arterial blood pressure, tissue and cutaneous vasoconstriction. Anatomical and clinical aspects, with major alterations (Vth degree hepatomegaly, polyserositis, peripheral edema, tachyarrhythmic heart contractions, hypotension, pallor accentuated by vasoconstriction) acutely installed in a previously healthy young person, require a rapid lesions diagnosis and emergency treatment due to vital risk, control of acute heart failure manifestations remission and proper monitoring. Differential diagnosis was focused on determining possible aspects like: acute heart failure (of various etiology), internal post-traumatic lesions or hemorrhages, tuberculosis polyserositis, collagenosis, nephrotic syndrome, protein deficiencies, neoplasia with hepatic determinations, hematological diseases (lymphomas, leukemias), considered in young patients. Severe visceral, vascular and tissular pathological alterations were reactively induced in a young person, by stasis and hypoperfusion due to hypodiastolic heart failure caused by persistent supraventricular tachyarrhythmia triggered post-traumatic, on a proarrhythmic structural heart. PMID- 28002531 TI - Parotid sclerosing mucoepidermoid carcinoma: a case report and immunohistochemical study. AB - Here we report the case of a 63-year-old female with a parotid sclerosing mucoepidermoid carcinoma diagnosed and treated at the Department of Oral and Maxillofacial Surgery, Emergency County Hospital of Craiova, Romania. The clinical and imaging investigation revealed a parotid malignant tumor with central fluid-filled cystic formation. Histopathology found an intermediate grade sclerosing mucoepidermoid carcinoma that invaded the adjacent adipose and striated muscle tissues, but without perineural and lymphovascular invasion. The immunohistochemistry investigated mainly biomarkers involved in the induction of a local aggressive behavior. This case report describes a rare parotid sclerosing mucoepidermoid carcinoma with peculiar clinical and morphological characteristic features. The immunohistochemical study sustained its intermediate grade malignancy highlighting the prognostic value of some of the used biomarkers. PMID- 28002532 TI - Stillbirth in dichorionic twins discordant for major and minor anomaly, followed by asynchronous delivery - a rare occurrence. Case presentation. AB - The single stillbirth long-term intrauterine retention in dichorionic twin pregnancy is rarely reported. Also, the birth of a fetus is followed in most cases by immediate expulsion of the second twin. We hereby present an unusual case of asynchronous delivery of dichorionic twins, associating discordance for major and minor anomaly. The intrauterine death of the twin A, presenting a large sacrococcygeal tumor, occurred in the second trimester. The deceased twin A was born at 29 weeks' gestational age (GA). The twin B was extracted by Caesarean section at 31 weeks and had a good outcome. We performed a close follow-up of the high-risk pregnancy and we used tocolytic and antibiotic drugs for prolonging it. Corticoid therapy was administered for the lung maturation of the second twin. The expectant management in the single twin stillbirth dichorionic pregnancy and the asynchronous delivery had a significant impact on the newborn outcome. PMID- 28002533 TI - Smoking-associated nodular glomerulosclerosis, a rare renal pathology resembling diabetic nephropathy: case report. AB - INTRODUCTION: Smoking is an important risk factor not only for cardiovascular and pulmonary diseases, but also for the progression of chronic kidney disease of different etiologies. Nodular glomerulosclerosis is a renal pathology pattern, which was described in different kidney conditions, especially diabetic nephropathy. A very rare association among smoking, hypertension and nodular mesangial glomerulosclerosis has been recently described. CASE PRESENTATION: In this paper, we present the case of a non-diabetic male patient referred to our Department for advanced chronic kidney disease and nephrotic syndrome. After excluding different causes of secondary nephrotic syndrome, a kidney biopsy was performed. The patient was diagnosed with smoking associated nodular glomerulosclerosis, with a histological aspect closely resembling diabetic nephropathy. A low protein and low salt diet was started, accompanied by smoking cessation, the administration of diuretics, of antiproteinuric treatment with angiotensin receptor blocker and antihypertensive therapy. Under this therapy, after six months, the patient evolution was good with a clear improvement of kidney function and important reduction of proteinuria. DISCUSSION: We also present the possible factors that could be involved in the deleterious effects of smoking upon kidney structure endothelial dysfunction, angiogenesis, altered intrarenal hemodynamics, nervous sympathetic system, increased oxidative stress and, very important, the generation of advanced glycation end products, which are also implicated in the development of diabetic nephropathy. CONCLUSIONS: Although a rare condition, smoking associated nodular glomerulosclerosis is a diagnosis not to be missed when dealing with a heavy smoker patient, especially when hypertensive, and sometimes associating nephrotic syndrome and this diagnosis should be considered together with much more frequent causes of nephrotic syndrome. PMID- 28002534 TI - Vaginal epithelioid angiosarcoma: a rare case. AB - Epithelioid angiosarcoma of the vagina is a rare variant, easily misdiagnosed as other epithelial neoplasms. On Hematoxylin-Eosin-stained sections, the pathologist encounters sheets of large, mildly to moderately pleomorphic epithelioid cells, with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. We report the case of a 22-year-old woman initially diagnosed with condiloma-like tumor of the left vaginal wall, which turned out positive at immunostaining for epithelioid angiosarcoma. In her case, after the failure of chemotherapy in controlling the relapse of the disease, the only treatment option was radical hysterectomy with bilateral salpingo-oophorectomy. PMID- 28002535 TI - Acute cellulitis as local reaction to orthopedic implant - case presentation. AB - Due to increasing number of arthroplasties and osteosynthesis, foreign body reaction to implants is a major problem for orthopedic surgeons, since it is considered to be responsible for severe complications impairing the outcome of the treatment and requiring multiple surgery. Different mechanisms have been described as being involved, and research is focused on finding biomaterials with increased biocompatibility in order to minimize these complications. The clinical aspect of this reaction is usually dominated by chronic pain, with mild functional deficits, and the diagnosis results from excluding other causes of chronic pain, such as infection, osteoarthritis, peripheral neuropathies or angiopaties. The authors present a case with unusual clinical aspect, that of acute cellulitis, when early proper treatment, represented by implant removal, allowed healing without the onset of infection or other complications; histological evaluation confirmed the reaction to implant, thus concluding that surgical treatment when intolerance to implant is suspected is the only method to prevent future negative events. PMID- 28002536 TI - A case of Sweet's syndrome associated with uveitis in a young male with ulcerative colitis. AB - Sweet's syndrome is rare acute febrile neutrophilic dermatosis whose onset is either idiopathic or associated with other underlying conditions, such as infections, autoimmune diseases, pregnancy, use of certain medications, or malignancy. We report the case of a young male with known history of ulcerative colitis and abrupt onset of high fever, malaise, blurred vision and eruption of painful erythematous nodules and papules, localized on the head, neck, trunk and upper limbs. Ophthalmological examination established the diagnosis of anterior uveitis. Inflammatory markers were positive. Histological examination of skin lesions revealed a dense neutrophilic infiltrate of the dermis. Clinical, laboratory and histological findings were suggestive for the diagnosis of Sweet's syndrome and uveitis on a background of ulcerative colitis. Systemic and ophthalmic administration of corticotherapy leads to a prompt resolution of symptoms and inflammatory syndrome. The particularity of this case is the occurrence of two simultaneous extraintestinal manifestations in a young male with inflammatory bowel disease and colonic involvement. Although a relatively rare condition, Sweet's syndrome should be considered as a differential diagnosis in patients with acute onset of high fever and skin rash, as it may have notable internal involvement and can be easily treated. PMID- 28002537 TI - Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy in acromegalic patient with severe headache. AB - A 68-year-old female patient was admitted in our clinic with severe frontal bilateral headache, dizziness, depression and cognitive decline in the context of a previously diagnosed acromegaly. She also had high blood pressure, dyslipidemia, secondary diabetes mellitus. Acromegaly was caused by a growth hormone (GH) secreting-pituitary macroadenoma, so a transsphenoidal surgery was performed. The postoperative magnetic resonance imaging (MRI) scan revealed a 20/22/25 mm pituitary mass remnant and medical therapy with somatostatin analogues (SSAs) was started. After nine months of treatment with SSAs, she continued having severe headache, the blood pressure was well controlled, but GH secretion was only partially controlled with insulin-like growth factor-1 (IGF-1) level still above the normal value. The MRI scan showed the same pituitary tumor remnant with supra- and parasellar right extension and also multiple fronto temporo-parietal subcortical lesions that could suggest in the clinical context cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). According to a pregenetic screening tool, the Pescini Scale, the patient had a 19 points score, which is highly suggestive for CADASIL, an inherited cerebrovascular disease due to mutations of the Notch3 gene at the chromosome locus 19p13. In the absence of genetic testing, an alternate way to prove small vessels disease, the skin biopsy, was performed. Electron microscopy showed granular osmiophilic material (GOM) surrounding the vascular smooth muscle cells on that are pathognomonic for the disease. Our report underscores the importance of repeated investigations even in patients with apparently obvious explanations of their condition since they may have multiple diseases with the same presenting clinical signs. PMID- 28002538 TI - Clinical and morphological considerations in one case with cervical cancer and right ureterohydronephrosis. AB - We present the case of a 34-year-old female with cervical cancer and right ureterohydronephrosis. She was admitted to the Urology Clinic of the Emergency County Hospital of Arad, Romania, on November 11, 2015, after previously being diagnosed with stage IIIA cervical cancer in December 2014 and undergoing radio and chemotherapy and laparotomy for staging. At the moment of hospital admission, the patient suffered from fever and right lumbar pain, she was also diagnosed with grade IV right ureterohydronephrosis. The patient was operated at the Urology Clinic of Arad; the intervention involved a total hysterectomy with bilateral adnexectomy and a right obturatory necrectomy of the necrotic lymph nodes. However, the evolution was favorable. The purpose was to increase the patient's survival rate and increase the quality of her life by also applying one palliative method including a urethral stent. As a result, the patient's life was extended. PMID- 28002539 TI - Supernumerary fronto-orbital arteries arising from contralateral anterior cerebral artery associated with partially duplicated anterior communicating artery - case study and literature review. AB - The anatomical variations of the fronto-orbital artery are uncommon and rarely described in literature. During the dissection of a 64-year-old female formalized brain, we discovered a particular congenital abnormality regarding the arterial supply of the right fronto-orbital gyrus. We identified three arterial sources: a low caliber ipsilateral fronto-orbital artery that arises from the A2 segment of the right anterior cerebral artery and ends in the posterior part of the fronto orbital gyrus, a large aberrant contralateral fronto-orbital artery that arises from the A2 segment of the left anterior cerebral artery, supplying most of the right fronto-orbital gyrus and a small accessory branch of the left anterior cerebral artery passing towards the contralateral fronto-orbital gyrus. These abnormalities are associated with a partially duplicated anterior communicating artery. This case shows a unique pattern of congenital brain vascular abnormalities that may have clinical and surgical implications. PMID- 28002540 TI - Gallbladder carcinoma - a rare cause of pyloric-duodenal stenosis. AB - Pyloric duodenal stenosis is usually caused by pyloric, juxtapyloric or duodenal ulcer, or by postbulbar ulcer. Gallbladder cancer (GBC), duodenal diverticula, annular pancreas and superior mesenteric artery syndrome (Wilkie's syndrome) are rare causes of pyloric duodenal stenosis. The case of a 66-year-old female patient is presented. The patient was admitted to hospital presenting anorexia, repeated alimentary vomiting, epigastric pain, and weight loss. Objective clinical examination upon admission: clapotage a jeun is present, triggered by tapping the epigastric region. Laboratory tests reveal moderate anemia, hypokalemic alkalosis, increased levels of cholestatic enzymes and of tumor markers. Gastroendoscopy: Stomach presenting stasis fluid in large quantity. Deformed antropyloric region caused by extrinsic compression. Abdominal native magnetic resonance imaging (MRI) and with contrast medium: cholecyst lumen entirely obstructed with calculi; thickened wall, with heterogeneous gadolinophilia; gadolinophilic mass erasing the bordering limit in relation to the cholecyst wall and the colon hepatic angle, and leaving a print on the pyloric region. During surgery, upon opening the peritoneal cavity, a tumoral pericholecystic block was observed, including the pyloric-duodenal region and the transverse mesocolon. Histopathology tests of tissue samples showed adipose conjunctive tissue with invasive adenocarcinoma. Immunohistochemical tests [cytokeratin (CK) 7, CK17, CK19, CK20, CDX2, mucin (MUC) 1, MUC2, MUC5AC, MUC6, epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA)] were consistent with infiltrating neoplastic carcinoma, originating in the gallbladder epithelium. Gastrointestinal obstruction cases caused by gallbladder carcinoma are rare. The pyloric-duodenal region is more frequently affected, as compared to the small intestine or the colon. PMID- 28002541 TI - Distinction between mesothelioma and lung adenocarcinoma based on immunohistochemistry in a patient with asbestos bodies in bronchoalveolar fluid - case report. AB - Asbestos is a mineral-mined form the rocks, consisting in amosite (brown asbestos), crocidolite (blue asbestos) and/or chrysotile (white asbestos) used in many industries. Researches about the exposure to asbestos dust and asbestosis related diseases started almost a century ago. The first case report of fatal asbestosis disease was published in 1906, in England, by Dr. Hubert Montague Murray. A decade after, asbestos "curious bodies" were firstly described in the lung tissue by Cooke (1926) and McDonald (1927). Occupational exposure to asbestos is now regulated in Romania, but past exposure is still a cause of asbestosis-related diseases (ARDs), including lung cancer. A peculiar association between a lung adenocarcinoma, a previously healed pulmonary tuberculosis (PTB) disease, is reported in a 61-year-old nonsmoker white man, a former factory worker with 29 years of occupational exposure history to cement and asbestos fibers. The positive diagnosis of asbestos exposure was facilitated by asbestos bodies determined in bronchoalveolar lavage fluid. The main purpose of this case report is to describe the development of a right pleural effusion which was not revelatory for a mesothelioma but for an adenocarcinoma of the lung. An accurate morphologic and immunohistochemistry assessment of a pleural biopsy sample excluded mesothelioma and was crucial in the positive diagnosis of adenocarcinoma. In conclusion, unilateral paraneoplastic pleural effusion in a nonsmoker male with occupational exposure to asbestosis fibers was suggestive for adenocarcinoma related asbestosis of the lung. Lung cancer and malignant pleural exudate developed after a long latency cumulative retention time of asbestos fibers. PMID- 28002542 TI - Auditory Training With Multiple Talkers and Passage-Based Semantic Cohesion. AB - Purpose: Current auditory training methods typically result in improvements to speech recognition abilities in quiet, but learner gains may not extend to other domains in speech (e.g., recognition in noise) or self-assessed benefit. This study examined the potential of training involving multiple talkers and training emphasizing discourse-level top-down processing to produce more generalized learning. Method: Normal-hearing participants (N = 64) were randomly assigned to 1 of 4 auditory training protocols using noise-vocoded speech simulating the processing of an 8-channel cochlear implant: sentence-based single-talker training, training with 24 different talkers, passage-based transcription training, and a control (transcribing unvocoded sentence materials). In all cases, participants completed 2 pretests under cochlear implant simulation, 1 hr of training, and 5 posttests to assess perceptual learning and cross-context generalization. Results: Performance above the control was seen in all 3 experimental groups for sentence recognition in quiet. In addition, the multitalker training method generalized to a context word-recognition task, and the passage training method caused gains in sentence recognition in noise. Conclusion: The gains of the multitalker and passage training groups over the control suggest that, with relatively small modifications, improvements to the generalized outcomes of auditory training protocols may be possible. PMID- 28002543 TI - Incidence and Prognosis of Psoriasis and Psoriatic Arthritis in Patients Undergoing Bariatric Surgery. AB - Importance: Psoriasis and obesity are strongly linked, and weight loss appears to improve psoriasis symptoms and severity. Bariatric surgery may induce remission of psoriasis, but data are limited to small studies and case series. Objective: To examine the incidence and prognosis of psoriasis and psoriatic arthritis in patients undergoing bariatric surgery (gastric bypass and gastric banding). Design, Setting, and Participants: This population-based cohort study used individual-level linkage of administrative and public health registers in Denmark. All Danish citizens who received gastric bypass or gastric banding between January 1, 1997, and December 31, 2012, were included in the study. Data analysis was performed from February 4 to April 14, 2016. Main Outcomes and Measures: The outcomes were incident (new-onset) psoriasis or psoriatic arthritis, or progression to severe psoriasis. Incidence rates per 1000 person years were calculated, and crude and adjusted hazard ratios (HRs) were estimated by Cox regression models and presented with 95% CIs. The HRs were obtained by comparing the risk in the cohort of patients presurgery and postsurgery, with the presurgery groups serving as the reference groups. Results: We identified 12 364 and 1071 patients receiving gastric bypass and gastric banding, respectively. The gastric bypass subset was composed of 9480 (76.7%) women and 2884 (23.3%) men at the study start; the mean (SD) age of these patients was 27.8 (10.1) years at the study start and 41.0 (10.0) years at the time of surgery. The gastric banding subset was composed of 800 (74.7%) women and 271 (25.3) men; the mean (SD) age of these patients was 32.3 (10.1) years at the study start and 41.7 (10.0) years at the time of surgery. Adjusted HRs of psoriasis were 0.52 (95% CI, 0.33-0.81) and 1.23 (95% CI, 0.40-3.75) for gastric bypass and gastric banding, respectively. Similarly, adjusted HRs of progression to severe psoriasis were 0.44 (95% CI, 0.23-0.86) and 1.18 (95% CI, 0.12-11.49) for gastric bypass and gastric banding, respectively. Adjusted HRs of psoriatic arthritis were 0.29 (95% CI, 0.12-0.71) and 0.53 (95% CI, 0.08-3.56) for gastric bypass and gastric banding, respectively. Conclusions and Relevance: Gastric bypass was associated with a significantly reduced risk and improved prognosis of psoriasis and psoriatic arthritis, whereas gastric banding was not. This finding may be caused by the postoperative differences in nutrient intake and/or weight loss as well as differences in the secretion of hormones that potentially modulate inflammation. PMID- 28002545 TI - Analysis of Trends in US Melanoma Incidence and Mortality. PMID- 28002544 TI - The Genetic Architecture of Major Depressive Disorder in Han Chinese Women. AB - Importance: Despite the moderate, well-demonstrated heritability of major depressive disorder (MDD), there has been limited success in identifying replicable genetic risk loci, suggesting a complex genetic architecture. Research is needed to quantify the relative contribution of classes of genetic variation across the genome to inform future genetic studies of MDD. Objectives: To apply aggregate genetic risk methods to clarify the genetic architecture of MDD by estimating and partitioning heritability by chromosome, minor allele frequency, and functional annotations and to test for enrichment of rare deleterious variants. Design, Setting, and Participants: The CONVERGE (China, Oxford, and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) study collected data on 5278 patients with recurrent MDD from 58 provincial mental health centers and psychiatric departments of general medical hospitals in 45 cities and 23 provinces of China. Screened controls (n = 5196) were recruited from a range of locations, including general hospitals and local community centers. Data were collected from August 1, 2008, to October 31, 2012. Main Outcomes and Measures: Genetic risk for liability to recurrent MDD was partitioned using sparse whole-genome sequencing. Results: In aggregate, common single-nucleotide polymorphisms (SNPs) explained between 20% and 29% of the variance in MDD risk, and the heritability in MDD explained by each chromosome was proportional to its length (r = 0.680; P = .0003), supporting a common polygenic etiology. Partitioning heritability by minor allele frequency indicated that the variance explained was distributed across the allelic frequency spectrum, although relatively common SNPs accounted for a disproportionate fraction of risk. Partitioning by genic annotation indicated a greater contribution of SNPs in protein-coding regions and within 3'-UTR regions of genes. Enrichment of SNPs associated with DNase I-hypersensitive sites was also found in many tissue types, including brain tissue. Examining burden scores from singleton exonic SNPs predicted to be deleterious indicated that cases had significantly more mutations than controls (odds ratio, 1.009; 95% CI, 1.003 1.014; P = .003), including those occurring in genes expressed in the brain (odds ratio, 1.011; 95% CI, 1.003-1.018; P = .004) and within nuclear-encoded genes with mitochondrial gene products (odds ratio, 1.075; 95% CI, 1.018-1.135; P = .009). Conclusions and Relevance: Results support a complex etiology for MDD and highlight the value of analyzing components of heritability to clarify genetic architecture. PMID- 28002546 TI - Use of Risk Models to Predict Death in the Next Year Among Individual Ambulatory Patients With Heart Failure. AB - Importance: The clinical practice guidelines for heart failure recommend the use of validated risk models to estimate prognosis. Understanding how well models identify individuals who will die in the next year informs decision making for advanced treatments and hospice. Objective: To quantify how risk models calculated in routine practice estimate more than 50% 1-year mortality among ambulatory patients with heart failure who die in the subsequent year. Design, Setting, and Participants: Ambulatory adults with heart failure from 3 integrated health systems were enrolled between 2005 and 2008. The probability of death was estimated using the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk calculator. Baseline covariates were collected from electronic health records. Missing covariates were imputed. Estimated mortality was compared with actual mortality at both population and individual levels. Main Outcomes and Measures: One-year mortality. Results: Among 10 930 patients with heart failure, the median age was 77 years, and 48.0% of these patients were female. In the year after study enrollment, 1661 patients died (15.9% by life-table analysis). At the population level, 1-year predicted mortality among the cohort was 9.7% for the SHFM (C statistic of 0.66) and 17.5% for the MAGGIC risk calculator (C statistic of 0.69). At the individual level, the SHFM predicted a more than 50% probability of dying in the next year for 8 of the 1661 patients who died (sensitivity for 1-year death was 0.5%) and for 5 patients who lived at least a year (positive predictive value, 61.5%). The MAGGIC risk calculator predicted a more than 50% probability of dying in the next year for 52 of the 1661 patients who died (sensitivity, 3.1%) and for 63 patients who lived at least a year (positive predictive value, 45.2%). Conversely, the SHFM estimated that 8496 patients (77.8%) had a less than 15% probability of dying at 1 year, yet this lower-risk end of the score range captured nearly two thirds of deaths (n = 997); similarly, the MAGGIC risk calculator estimated a probability of dying of less than 25% for the majority of patients who died at 1 year (n = 914). Conclusions and Relevance: Although heart failure risk models perform reasonably well at the population level, they do not reliably predict which individual patients will die in the next year. PMID- 28002547 TI - Bullae and Atypical Target Lesions in a Young Woman. PMID- 28002549 TI - Optimizing Outcomes for Cutaneous Head and Neck Melanoma. PMID- 28002548 TI - Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies. AB - Importance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes. Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD. Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012. Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation. Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD. Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively. Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention. PMID- 28002550 TI - Assessing and Refining Myocardial Infarction Risk Estimation Among Patients With Human Immunodeficiency Virus: A Study by the Centers for AIDS Research Network of Integrated Clinical Systems. AB - Importance: Persons with human immunodeficiency virus (HIV) that is treated with antiretroviral therapy have improved longevity but face an elevated risk of myocardial infarction (MI) due to common MI risk factors and HIV-specific factors. Despite these elevated MI rates, optimal methods to predict MI risks for HIV-infected persons remain unclear. Objective: To determine the extent to which existing and de novo estimation tools predict MI in a multicenter HIV cohort with rigorous MI adjudication. Design, Setting, and Participants: We evaluated the performance of standard of care and 2 new data-derived MI risk estimation models in 5 Centers for AIDS Research Network of Integrated Clinical Systems sites across the United States where a multicenter clinical prospective cohort of 19 829 HIV-infected adults received care in inpatient and outpatient settings since 1995. The new risk estimation models were validated in a separate cohort from the derivation cohort. Exposures: Traditional cardiovascular risk factors, HIV viral load, CD4 lymphocyte count, statin use, antihypertensive use, and antiretroviral medication use were used to calculate predicted event rates. Main Outcomes and Measures: We observed MI rates over the course of follow-up that were scaled to 10 years using the Greenwood-Nam-D'Agostino Kaplan-Meier approach to account for dropout and loss to follow-up before 10 years. Results: Of the 11 288 patients with complete baseline data, 6904 were white and 9250 were men. Myocardial infarction rates were higher among black men (6.9 per 1000 person-years) and black women (7.2 per 1000 person-years) than white men (4.4 per 1000 person years) and white women (3.3 per 1000 person-years), older participants (7.5 vs 2.2 MI per 1000 person-years for adults 40 years and older vs < 40 years old at study entry, respectively), and participants who were not virally suppressed (6.3 vs 4.7 per 1000 person-years for participants with and without detectable viral load, respectively). The 2013 Pooled Cohort Equations, which predict composite rates of MI and stroke, adequately discriminated MI risk (Harrell C statistic = 0.75; 95% CI, 0.71-0.78). Two data-derived models incorporating HIV-specific covariates exhibited weak calibration in a validation sample and did not discriminate risk any better (Harrell C statistic = 0.72; 95% CI, 0.67-0.78 and 0.73; 95% CI, 0.68-0.79) than the Pooled Cohort Equations. The Pooled Cohort Equations were moderately calibrated in the Centers for AIDS Research Network of Clinical Systems but predicted consistently lower MI rates. Conclusions and Relevance: The Pooled Cohort Equations discriminated MI risk and were moderately calibrated in this multicenter HIV cohort. Adding HIV-specific factors did not improve model performance. As HIV-infected cohorts capture and assess MI and stroke outcomes, researchers should revisit the performance of risk estimation tools. PMID- 28002551 TI - Bariatric Surgery for Autoimmunity? PMID- 28002552 TI - Black Dermographism. PMID- 28002553 TI - Efficacy of Staged Excision With Permanent Section Margin Control for Cutaneous Head and Neck Melanoma. AB - Importance: Melanoma arising in chronically photodamaged skin, especially on the head and neck, is often characterized by poorly defined clinical margins and unpredictable occult extension. Staged excision techniques have been described to treat these challenging melanomas. Objective: To investigate the local recurrence rates and margin to clearance end points using staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control. Design, Setting, and Participants: In this observational cohort study performed from October 8, 1997, to December 31, 2006, with a median follow-up of 9.3 years, 806 patients with melanoma on the head and neck, where clinical occult extension is common, were studied at an academic medical center. Interventions: Staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control commonly known as the square technique. Main Outcomes and Measures: Local recurrence rates and margin to clearance end points. Results: A total of 806 patients (276 women [34.2%]; 805 white [99.9%]) with a median age at the time of first staged excision procedure of 65 years (range, 20-94 years) participated in the study. The estimated local recurrence rates were 1.4% at 5 years, 1.8% at 7.5 years, and 2.2% at 10 years. For each 50-mm2 increase in the size of the clinical lesion, there was a 9% increase in the rate of local recurrence (hazard ratio, 1.09; 95% CI, 1.02-1.15; P = .02). The mean (SD) margin from lesion to clearance for melanoma in situ was 9.3 (5.1) mm compared with 13.7 (5.9) mm for invasive melanoma. For melanoma in situ, margins were clear after 5 mm or less in 232 excisions (41.1%) and after 10 mm or less in 420 excisions (74.5%). For invasive melanoma, margins were clear after 5 mm or less in 8 excisions (3.0%) and after 10 mm or less in 141 excisions (52.2%). Conclusions and Relevance: Staged excision with comprehensive permanent section margin control of melanomas arising in chronically sun-damaged skin on the head and neck has favorable recurrence rates when melanoma margins are difficult to assess, and recurrence rates are high with traditional techniques. PMID- 28002554 TI - Mobile Intramural Gastroesophageal Junction Mass. PMID- 28002555 TI - Contralateral Prophylactic Mastectomy Decisions in a Population-Based Sample of Patients With Early-Stage Breast Cancer. AB - Importance: Contralateral prophylactic mastectomy (CPM) use is increasing among women with unilateral breast cancer, but little is known about treatment decision making or physician interactions in diverse patient populations. Objective: To evaluate patient motivations, knowledge, and decisions, as well as the impact of surgeon recommendations, in a large, diverse sample of patients who underwent recent treatment for breast cancer. Design, Setting, and Participants: A survey was sent to 3631 women with newly diagnosed, unilateral stage 0, I, or II breast cancer between July 2013 and September 2014. Women were identified through the population-based Surveillance Epidemiology and End Results registries of Los Angeles County and Georgia. Data on surgical decisions, motivations for those decisions, and knowledge were included in the analysis. Logistic and multinomial logistic regression of the data were conducted to identify factors associated with (1) CPM vs all other treatments combined, (2) CPM vs unilateral mastectomy (UM), and (3) CPM vs breast-conserving surgery (BCS). Associations between CPM receipt and surgeon recommendations were also evaluated. All statistical models and summary estimates were weighted to be representative of the target population. Main Outcomes and Measures: Receipt of CPM was the primary dependent variable for analysis and was measured by a woman's self-report of her treatment. Results: Of the 3631 women selected to receive the survey, 2578 (71.0%) responded and 2402 of these respondents who did not have bilateral disease and for whom surgery type was known constituted the final analytic sample. The mean (SD) age was 61.8 (12) years at the time of the survey. Overall, 1301 (43.9%) patients considered CPM (601 [24.8%] considered it very strongly or strongly); only 395 (38.1%) of them knew that CPM does not improve survival for all women with breast cancer. Ultimately, 1466 women (61.6%) received BCS, 508 (21.2%) underwent UM, and 428 (17.3%) received CPM. On multivariable analysis, factors associated with CPM included younger age (per 5-year increase: odds ratio [OR], 0.71; 95% CI, 0.65-0.77), white race (black vs white: OR, 0.50; 95% CI, 0.34-0.74), higher educational level (OR, 1.69; 95% CI, 1.20-2.40), family history (OR, 1.63; 95% CI, 1.22-2.17), and private insurance (Medicaid vs private insurance: OR, 0.47; 95% CI, 0.28-0.79). Among 1569 patients (65.5%) without high genetic risk or an identified mutation, 598 (39.3%) reported a surgeon recommendation against CPM, of whom only 12 (1.9%) underwent CPM, but among the 746 (46.8%) of these women who received no recommendation for or against CPM from a surgeon, 148 (19.0%) underwent CPM. Conclusions and Relevance: Many patients consider CPM, but knowledge about the procedure is low and discussions with surgeons appear to be incomplete. Contralateral prophylactic mastectomy use is substantial among patients without clinical indications but is low when patients report that their surgeon recommended against it. More effective physician-patient communication about CPM is needed to reduce potential overtreatment. PMID- 28002556 TI - Study Suggests Alzheimer and Parkinson Disease Are Not Transmitted Through Blood Transfusion. PMID- 28002557 TI - Reoperation Rates in Ductal Carcinoma In Situ vs Invasive Breast Cancer After Wire-Guided Breast-Conserving Surgery. AB - Importance: New techniques for preoperative localization of nonpalpable breast lesions may decrease the reoperation rate in breast-conserving surgery (BCS) compared with rates after surgery with the standard wire-guided localization. However, a valid reoperation rate for this procedure needs to be established for comparison, as previous studies on this procedure include a variety of malignant and benign breast lesions. Objectives: To determine the reoperation rate after wire-guided BCS in patients with histologically verified nonpalpable invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) and to examine whether the risk of reoperation is associated with DCIS or histologic type of the IBC. Design, Setting, and Participants: This nationwide study including women with histologically verified IBC or DCIS having wire-guided BCS performed between January 1, 2010, and December 31, 2013, used data from the Danish National Patient Registry that were cross-checked with the Danish Breast Cancer Group database and the Danish Pathology Register. Main Outcomes and Measures: Reoperation rate after wire-guided BCS in patients with IBC or DCIS. Results: Wire-guided BCS was performed in 4118 women (mean [SD] age, 60.9 [8.7] years). A total of 725 patients (17.6%) underwent a reoperation: 593 were reexcisions (14.4%) and 132 were mastectomies (3.2%). Significantly more patients with DCIS (271 of 727 [37.3%]) than with IBC (454 of 3391 [13.4%]) underwent a reoperation (adjusted odds ratio, 3.82; 95% CI, 3.19-4.58; P < .001). After the first reexcision, positive margins were still present in 97 patients (16.4%). The risk of repeated positive margins was significantly higher in patients with DCIS vs those with IBC (unadjusted odds ratio, 2.21; 95% CI, 1.42-3.43; P < .001). The risk of reoperation was significantly increased in patients with lobular carcinoma vs those with ductal carcinoma (adjusted odds ratio, 1.44; 95% CI 1.06 1.95; P = .02). A total of 202 patients (4.9%) had a subsequent completion mastectomy, but no difference was found in the type of reoperation between patients with DCIS and those with IBC. Conclusions and Relevance: A lower reoperation rate after wire-guided BCS was found in this study than those shown in previous studies. However, the risk of reoperation in patients with DCIS was 3 times higher than in those with IBC. The widespread use of mammographic screening will increase the number of patients diagnosed with DCIS, making a precise localization of nonpalpable DCIS lesions even more important. PMID- 28002558 TI - Contralateral Prophylactic Mastectomy: Aligning Patient Preferences and Provider Recommendations. PMID- 28002559 TI - Association Between Human Immunodeficiency Virus Infection and Cardiovascular Diseases: Finding a Solution to Double Jeopardy. PMID- 28002561 TI - Compensation of Presbyopia With the Light Sword Lens. AB - Purpose: We present the first physiological evaluation of the use of the light sword lens (LSL) for presbyopia compensation. The LSL is an axially asymmetric optical element designed for imaging with extended depth of focus. Methods: A monocular visual simulator setup is implemented to measure visual acuity (VA). Physiological presbyopia is "mimicked" in human subjects by paralysis of the ciliary muscle, using topical application of a muscarinic antagonist. The effect of a contact lens-configured LSL on the mimicked presbyopia visual system is evaluated by measuring VA as a function of target vergence. The ability of the LSL to compensate presbyopia for 2 photopic luminance values was also analyzed. Results: The average VA values for 11 subjects suggest that the LSL can compensate for presbyopia across a wide range of target vergences for which the LSL was designed (-3 to 0 D). However, the proposed corrector element causes a loss of distance VA. The mean logMAR VA in that target vergence range was 0.07. The VA curves also show that luminance does not affect the expected behavior of the LSL-corrected presbyopic eye. Conclusions: These results indicate that the LSL has significant potential as a visual aid for presbyopia. PMID- 28002560 TI - Clinical Characteristics, Mutation Spectrum, and Prevalence of Aland Eye Disease/Incomplete Congenital Stationary Night Blindness in Denmark. AB - Purpose: To assess clinical characteristics, foveal structure, mutation spectrum, and prevalence rate of Aland eye disease (AED)/incomplete congenital stationary night blindness (iCSNB). Methods: A retrospective survey included individuals diagnosed with AED at a national low-vision center from 1980 to 2014. A subset of affected males underwent ophthalmologic examinations including psychophysical tests, full-field electroretinography, and spectral-domain optical coherence tomography. Results: Over the 34-year period, 74 individuals from 35 families were diagnosed with AED. Sixty individuals from 29 families participated in a follow-up study of whom 59 harbored a CACNA1F mutation and 1 harbored a CABP4 mutation. Among the subjects with a CACNA1F mutation, subnormal visual acuity was present in all, nystagmus was present in 63%, and foveal hypoplasia was observed in 25/43 subjects. Foveal pit volume was significantly reduced as compared to normal (P < 0.0001). Additionally, outer segment length at the fovea was measured in 46 subjects and found to be significantly reduced as compared to normal (P < 0.001). Twenty-nine CACNA1F variations were detected among 34 families in the total cohort, and a novel CABP4 variation was identified in one family. The estimated mean birth prevalence rate was 1 per 22,000 live-born males. Conclusions: Our data support the viewpoint that AED, iCSNB, and X-linked cone rod dystrophy 3 are designations that refer to a broad, continuous spectrum of clinical appearances caused in the majority by a variety of mutations in CACNA1F. We argue that the original designation AED should be used for this entity. PMID- 28002562 TI - Generation of Human Corneal Endothelial Cells via In Vitro Ocular Lineage Restriction of Pluripotent Stem Cells. AB - Purpose: We generate a renewable supply of corneal endothelial cells (CEC) from human pluripotent stem cells (PSCs) under defined culture conditions. Methods: Corneal endothelial cell induction was driven by small molecules in a stepwise fashion of lineage specification. During the initial phase, PSC fate was restricted to the eye field-like state and became eye field stem cells (EFSCs). In the second phase, PSC-derived EFSCs were further directed toward either neural crest lineage or retinal lineage. The CECs were directly induced from ocular neural crest stem cells (NCSCs) by suppressing TGF-beta and ROCK signaling. Results: Under chemically defined conditions, PSCs were massively converted into EFSCs and subsequently NCSCs. Eye field cell identity was characterized by the expression of key fate restriction factors for early eye field cells, such as PAX6, LHX2, and VSX2. The induction of ocular NCSCs was initiated by promoting WNT signaling in EFSCs. Within 2 weeks of induction, the majority of cells expressed the typical neural crest markers p75NTR and HNK-1. Eye field stem cell derived NCSCs can be propagated and cryopreserved. Subsequently, a CEC monolayer was induced from adherent NCSCs in the presence of small molecular inhibitors to suppress TGF-beta and ROCK signaling. The polygon-shaped CEC-like cells became visible after a week in culture. The NCSC-derived CECs expressed typical CEC markers, such as N-Cadherin and Na+/K+-ATPase. Conclusions: A novel small molecule-based approach was developed to derive human CECs from PSCs via ocular lineage specification. Moreover, EFSC-derived NCSCs could serve as an immediate source cell for rapid CEC induction in vitro. PMID- 28002563 TI - Subcellular Localization of a 2-Arachidonoyl Glycerol Signaling Cassette in Retinal Ganglion Cell Axonal Growth In Vitro. AB - Purpose: To investigate whether the subcellular distribution of endocannabinoid (eCB) system (ECS) components in growing RGC axons is consistent with the formation of eCB-enriched "hotspots" and the role of the ECS in RGC axonal growth. Methods: We used immunocytochemistry and image analysis to quantify axonal expression of the ECS components diacylglycerol lipase alpha (DGLalpha), monoacylglycerol lipase (MGL), and cannabinoid receptor type 1 (CB1R) in a mouse retinal explant model. We tested whether pharmacologic antagonists of CB1R and inhibitors of eCB degradation modulate ECS component expression and axonal growth. Results: DGLalpha expression was higher in the distal RGC axon than in the growth cone central domain (GCCD) (95% confidence interval [CI], 106.5% 122.4% at 15 MUm proximal to the GCCD), whereas MGL expression in the same region was not significantly different (95% CI, 88.8%-102.1%). In more proximal axon segments, DGLalpha and MGL expression were both lower than in the GCCD, whereas CB1R expression was 2.5-fold higher in this region (95% CI, 220.3%-278.4% at 50 MUm proximal to the GCCD). The presence of CB1R antagonist O-2050 disrupted profiles of ECS component expression and increased axonal growth (95% CI for the difference of median axon lengths 26.6-55.6 MUM). Conclusions: Our results demonstrate an ECS topology in RGC axons that is consistent with formation of eCB enriched hotspots and suggest that the ECS has a role in CB1R-dependent inhibition of RGC axonal growth in vitro. PMID- 28002564 TI - Subretinal Fluid Levels of Signal-Transduction Proteins and Apoptosis Molecules in Macula-Off Retinal Detachment Undergoing Scleral Buckle Surgery. AB - Purpose: To evaluate signal transduction and early apoptosis protein levels in subretinal fluid collected during scleral buckling surgery for macula-off rhegmatogenous retinal detachment (RRD). Our aim was to assess both their relation with RRD features and their influence on the posttreatment outcome. Methods: Thirty-three eyes of 33 RRD patients scheduled for scleral buckle surgery were enrolled in the study. Undiluted subretinal fluid samples were collected during surgery and analyzed via magnetic bead-based immunoassay. All patients underwent a complete ophthalmologic evaluation at baseline and at each follow-up visit (months 1, 3, and 6). Moreover, both at baseline and at the postsurgery month 6 visit, the patients were tested by means of spectral-domain optical coherence tomography (SD-OCT) in order to evaluate the average ganglion cell-inner plexiform complex thickness, as well as the photoreceptor inner segment/outer segment junction status. Results: Patients' clinical features (retinal detachment size, detachment duration, and occurrence of proliferative vitreoretinopathy) were associated with several early apoptotic factors (caspase 8, caspase-9, and B-cell lymphoma 2 [Bcl-2]-associated death promoter [BAD]). Furthermore, both early apoptosis factors (caspase-8, Bcl-2, and p53) and signal transduction proteins (ERK 1/2) were found to influence the postsurgery month 3 OCT characteristics. Conclusions: Signal-transduction proteins and early apoptosis proteins are associated with different clinical features and postsurgery outcomes. PMID- 28002565 TI - Large Deletions of TSPAN12 Cause Familial Exudative Vitreoretinopathy (FEVR). AB - Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare, hereditary visual disorder. The gene TSPAN12 is associated with autosomal dominant inheritance of FEVR. The prevalence and impact of large deletions/duplications of TSPAN12 on FEVR patients is unknown. To glean better insight of TSPAN12 on FEVR pathology, herein, we describe three FEVR patients with TSPAN12 deletions. Methods: Thirty three Korean FEVR patients, who previously screened negative for TSPAN12 mutations, mutations in other FEVR-associated genes such as NDP, FZD4, LRP5, and large deletions and duplications of NDP, FZD4, and LRP5, were selected for TSPAN12 large deletion and duplication analyses. Semiquantitative multiplex PCR for TSPAN12 gene dosage analyses were performed, followed by droplet digital PCR (ddPCR) for validation. Results: Among the 33 patients, three patients were confirmed to carry large TSPAN12 deletions. Two of them had whole-gene deletions of TSPAN12, and the other patient possessed a deletion of TSPAN12 in exon 4. FEVR severity detected in these patients was not more severe than in a patient with TSPAN12 point mutation. Conclusions: Regarding previously reported proportions of FEVR-associated genes contributing to the disorder's autosomal dominant inheritance pattern in Korea, we determined that patients with TSPAN12 large deletions were more common than patients with single nucleotide variants in TSPAN12. Evaluating TSPAN12 large deletions and duplications should be considered in FEVR screening and diagnosis as well as in routine genetic workups for FEVR patients. PMID- 28002567 TI - Role of miR-146a in the Regulation of Inflammation in an In Vitro Model of Graves' Orbitopathy. PMID- 28002566 TI - cAMP Stimulates Transepithelial Short-Circuit Current and Fluid Transport Across Porcine Ciliary Epithelium. AB - Purpose: To investigate the effects of cAMP on transepithelial electrical parameters and fluid transport across porcine ciliary epithelium. Methods: Transepithelial electrical parameters were determined by mounting freshly isolated porcine ciliary epithelium in a modified Ussing chamber. Similarly, fluid movement across intact ciliary body was measured with a custom-made fluid flow chamber. Results: Addition of 1, 10, and 100 MUM 8-Br-cAMP (cAMP) to the aqueous side (nonpigmented ciliary epithelium, NPE) induced a sustained increase in short-circuit current (Isc). Addition of niflumic acid (NFA) to the aqueous surface effectively blocked the cAMP-induced Isc stimulation. The administration of cAMP to the stromal side (pigmented ciliary epithelium, PE) triggered a significant stimulation of Isc only at 100 MUM. No additive effect was observed with bilateral application of cAMP. Likewise, forskolin caused a significant stimulation of Isc when applied to the aqueous side. Concomitantly, cAMP and forskolin increased fluid transport across porcine ciliary epithelium, and this stimulation was effectively inhibited by aqueous NFA. Depleting Cl- in the bathing solution abolished the baseline Isc and inhibited the subsequent stimulation by cAMP. Pretreatment with protein kinase A (PKA) blockers (H89/KT5720) significantly inhibited the cAMP- and forskolin-induced Isc responses. Conclusions: Our results suggest that cAMP triggers a sustained stimulation of Cl- and fluid transport across porcine ciliary epithelium; Cl- channels in the NPE cells are potentially a cellular site for this PKA-sensitive cAMP-mediated response. PMID- 28002568 TI - Author Response: Role of miR-146a in the Regulation of Inflammation in an In Vitro Model of Graves' Orbitopathy. PMID- 28002569 TI - Protective Role of ICOS and ICOS Ligand in Corneal Transplantation and in Maintenance of Immune Privilege. AB - Purpose: The interaction between the inducible costimulatory molecule (ICOS) and ICOS ligand (ICOSL) has been implicated in the differentiation and functions of T cells. The purpose of the present study was to determine the role of ICOS-ICOSL in the immune privilege of corneal allografts. Methods: Expression of ICOS and ICOSL mRNA from mouse eyes was assessed by RT-PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of ICOS-/- BALB/c recipients and BALB/c wild-type (WT) recipients treated with anti-ICOSL mAb, and graft survival was assessed. A separate set of WT and ICOS-/- BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. In vitro, cornea was incubated with T cells from WT and ICOS-/- BALB/c mice, and destruction of corneal endothelial cells (CECs) and the population of Foxp3+ CD25+ CD4+ T cells was assessed. Results: Inducible costimulatory molecule ligand mRNA was constitutively expressed in the cornea, iris-ciliary body, and retina. Allograft survival in ICOS-/- recipients and WT recipients treated with anti-ICOSL mAb was significantly shorter than in control recipients. Anterior chamber-associated immune deviation was induced less efficiently in ICOS-/- mice. Destruction of CECs by alloreactive ICOS-/- T cells was enhanced compared with WT T cells. After coincubation with allogeneic corneal tissue, the proportion of regulatory T cells was significantly greater among WT T cells than in ICOS-/- T cells. Conclusions: The expression of ICOSL in the cornea and the ICOS-mediated induction of Foxp3+ CD4+ regulatory T cells may contribute to successful corneal allograft survival. PMID- 28002570 TI - Asymmetric Inter-Eye Progression in Stargardt Disease. AB - Purpose: Asymmetry in disease progression between left and right eyes can occur in Stargardt disease (STGD1), and this needs to be considered in novel therapeutic trials with a fellow-eye paired controlled design. This study investigated the inter-eye discordance of best-corrected visual acuity (BCVA) and progression of RPE atrophy in STGD1. Methods: We performed a retrospective cohort study collecting 68 STGD1 patients (136 eyes) with >=1 ABCA4 variants and >=0.5 year follow-up on BCVA and fundus autofluorescence. We compared inter-eye correlations of RPE atrophy progression between early-onset (<=10 years), intermediate-onset (11-44), and late-onset (>=45) STGD1 and ABCA4 variant combinations by chi2 tests. We identified associations of discordant baseline BCVA and RPE atrophy with discordant RPE atrophy progression by odds ratios (OR). We defined discordance by differences >1.5 interquartile ranges +/- first/third interquartiles. Results: Progression of RPE atrophy correlated moderately between eyes (rho = 0.766), which decreased with later onset (P = 9.8 * 10-7) and lower pathogenicity of ABCA4 combinations (P = 0.007). Twelve patients (17.6%) had discordant inter-eye RPE atrophy progression, associated with baseline discordance of RPE atrophy (OR, 6.50 [1.35-31.34]), but not BCVA (OR, 0.33 [0.04 2.85]). Conclusions: Lower inter-eye correlations are more likely found in late onset STGD1 and patients carrying low pathogenic ABCA4 combinations. To achieve the highest power in a therapeutic trial, early-phase studies should minimize inter-eye discordance by selecting early-onset STGD1 patients carrying severe ABCA4 variants without evidence of asymmetry at baseline. PMID- 28002571 TI - Difficulty of Achieving Clear Margins in Nonpalpable Ductal Carcinoma of the Breast. PMID- 28002572 TI - Activation in Bipolar Disorders: A Systematic Review. AB - Importance: Increased activity and energy alongside mood change are identified in the DSM-5 as cardinal symptoms of mania and hypomania. A wide range of existing research suggests that this revision may be valid, but systematic integration of the evidence has not been reported. The term activation is understood as emerging from underlying physiological change and having objective (observable motor activity) and related subjective (energy) levels. Objectives: To systematically review studies of the clinical phenomenon of activation in bipolar disorder, to determine whether activation is statistically abnormal in bipolar disorder and demonstrably distinct from mood, and to identify any significant between- and within-individual differences in the dynamics of activation. Evidence Review: This systematic review of MEDLINE, PsycINFO, EMBASE, CINAHL, and PubMed databases from January 1, 1970, until September 30, 2016, identified 56 of a possible 3284 citations for (1) data-driven analyses of the dimensions and factor structure of mania and bipolar depression and (2) longitudinal studies reporting real-time objective monitoring or momentary assessment of daytime activity in individuals with bipolar disorder compared with other clinical or healthy control samples. Hand search of reference lists, specialty journals, websites, published conference proceedings, and dissertation abstracts and contact with other researchers ensured inclusion of gray literature and additional analyses as well as raw data if appropriate. Quality assessment was perfomed using the National Institutes of Health quality assessment tool. Findings: A total of 56 studies met eligibility criteria for inclusion in the review including 29 analyses of the factor structure of bipolar disorder, 3 of activity data from experimental sampling or ecological momentary assessment, and 20 actigraphy and 4 laboratory based studies. Synthesizing findings across the studies revealed that the most robust finding was that mean levels of activity are lower during euthymia and depression in patients with bipolar disorder compared with healthy controls and other comparison groups (11 studies). The 7 ecological and laboratory studies show less organized or predictable patterns of behavior and a relative lack of habituation among patients with bipolar disorders compared with others. Factor analytic studies provide fairly consistent evidence that mood and activation represent distinct dimensions of bipolar disorder. Ten studies that examined interindividual and intraindividual patterns of activity suggest that mania may be better characterized by differences in robustness, variability, predictability, or complexity of activation rather than mean levels of activity. Conclusions and Relevance: Within the limitations of the data, this synthesis of available evidence broadly supports the elevation of activation as a criterion A symptom for bipolar disorder in DSM-5. Although the importance of activation in bipolar disorders has been acknowledged for more than a century, this review suggests that this critical construct is understudied and should be the topic of more systematic high-quality research. PMID- 28002577 TI - Missing paternal data and adverse birth outcomes in Canada. AB - BACKGROUND: Research on predictors of birth outcomes tends to focus on maternal characteristics. Less is known about the role of paternal factors. Missing paternal data on administrative records may be a marker for risk of adverse birth outcomes. DATA AND METHODS: Analyses were performed on a cohort of births that occurred from May 16, 2004 through May 15, 2006, which was created by linking birth and death registration data with the 2006 Canadian census. Log-binomial and binomial regression were used to estimate relative risks and risk differences for preterm birth, small-for-gestational-age birth, stillbirth and infant mortality associated with the absence of paternal information. Analyses controlled for maternal age, education, household income, parity, marital status, ethnicity and birthplace. RESULTS: The analyses pertained to 135,285 singleton births. Paternal data were missing from the birth registration for 7,461 births (4.6%) and from the census data for 17,713 births (11.4%). The adjusted relative risks associated with missing paternal data on the birth registration were 1.12 (95% CI: 0.99, 1.26) for preterm birth; 1.15 (1.05, 1.26) for small-for-gestational-age birth; 1.86 (1.27, 2.73) for stillbirth; and 1.53 (1.00, 2.34) for infant mortality. Estimates were robust to varying definitions of missing paternal information, based on the birth registration, census data, or both. INTERPRETATION: This study suggests that missing paternal data is a marker for increased risk of adverse birth outcomes, over and above maternal characteristics. PMID- 28002578 TI - Linking the Canadian Community Health Survey and the Canadian Mortality Database: An enhanced data source for the study of mortality. AB - BACKGROUND: This study summarizes the linkage of the Canadian Community Health Survey (CCHS) and the Canadian Mortality Database (CMDB), which was performed to examine relationships between social determinants, health behaviours and mortality in the household population. DATA AND METHODS: The 2000/2001-to-2011 Canadian Community Health Surveys were linked to the 2000-to-2011 CMDB using probabilistic methods based on common identifiers (names, date of birth, postal code and sex) for eligible respondents (85%; n = 614,774). Mortality records from January 1, 2000 through December 31, 2011 for people aged 12 or older were eligible for linkage (n = 2.774 million). The linkage was enhanced with information from the Historical Tax Summary File. Quality assessment consisted of internal and external validation. Cox survival analysis (age-adjusted) was conducted to estimate hazard ratios (HRs) associated with selected health behaviours. RESULTS: Overall, 5.3% of eligible CCHS respondents linked to a mortality record; false positive and false negative rates were 0.04% and 2.43%, respectively. Linkage rates were higher among males (5.8%) and people aged 75 or older (20.2%), reflecting known mortality risks. Survival analyses confirmed elevated mortality risk associated with heavy (HR 2.36, CI 1.84, 2.89) and light smoking (HR 1.91, CI 1.52, 2.33), compared with not smoking; underweight and obesity, compared with normal and overweight; low fruit and vegetable consumption; and lack of physical activity. INTERPRETATION: Linking health behaviour information from the CCHS to mortality data from the CMDB allows for a greater understanding of modifiable determinants of mortality. PMID- 28002579 TI - Acute care hospitalization of refugees to Canada: Linked data for immigrants from Poland, Vietnam and the Middle East. AB - BACKGROUND: Refugees arrive in Canada with settlement challenges different from those faced by other immigrants, including a higher risk of poor health. This study reports hospitalization rates for the three fiscal years from 2006/2007 through 2008/2009 for immigrants who arrived during the 1980-to-2006 period, with a focus on three refugee groups. DATA AND METHODS: Information from two linked databases was used to estimate age-standardized hospitalization rates (ASHRs) per 10,000 population aged 30 or older for all causes (excluding pregnancy) and for leading causes, by immigrant category and by refugee subcategory. The analysis focused on refugees from Poland, Vietnam and the Middle East, whose hospitalization rates were compared with those of the Canadian-born population and/or economic class immigrants from the same areas. RESULTS: Immigrants aged 30 or older, including refugees, had significantly lower all-cause ASHRs than did the Canadian-born population. All-cause ASHRs were 470 per 10,000 for immigrants overall and 494 for refugees, compared with 891 for the Canadian-born. Of the three source areas, immigrants and refugees from Vietnam had lower ASHRs. The circulatory disease-specific ASHR for government-assisted refugees from the Middle East was similar to that of the Canadian-born population (142 and 158, respectively). Except for those from Poland, refugees typically had higher ASHRs than did their economic class counterparts. INTERPRETATION: Refugees, like other immigrants, generally had lower hospitalization rates than did the Canadian-born population, but some subgroups were particularly susceptible to hospitalization for specific chronic diseases. PMID- 28002580 TI - Endothelial progenitor cells derived from the peripheral blood of halfpipe- snowboarding athletes display specific functional properties. AB - In this study, we compared the functional properties of endothelial progenitor cells (EPCs) derived from halfpipe-snowboarding athletes who train under hyperoxic conditions with those derived from normal subjects who lived under normoxic conditions. Peripheral blood-derived EPCs were isolated from both halfpipe-snowboarding athletes and normal humans. Cellular growth dynamics, lipoprotein transport, and gene expression of cultured EPCs were compared between the two groups of cells. Results indicate that cytoactivity of EPCs from athletes was higher than that of EPCs from control subjects. This study suggests that function of EPCs from snowboarding athletes may be better than that of EPCs from normal humans, which demonstrates the benefits of training under hyperoxic conditions. PMID- 28002581 TI - Investigation on the association between IL-10 C819T gene polymorphisms and susceptibility to gastric cancer. AB - We conducted a case-control study to investigate the association between the interleukin-10 (IL-10) C819T polymorphism and susceptibility to gastric cancer in a Chinese population. A total of 157 patients with gastric cancer and 249 controls were consecutively enrolled from the Guizhou Provincial People's Hospital between October 2012 and February 2015. The polymerase chain reaction restriction fragment length polymorphism technique was used to genotype for IL-10 C819T. As determined by chi2-test, there was a significant difference in genotype distributions of IL-10 C819T between gastric cancer patients and controls (chi2 = 7.09; P = 0.03). Based on unconditional logistic regression analysis, the TT genotype of IL-10 C819T was significantly associated with increased risk of gastric cancer when compared with that of the CC genotype [odds ratio (OR) = 2.24; 95% confidence interval (CI) = 1.17-4.26; P = 0.008]. In a dominant model, we found that the CT + TT genotype of IL-10 C819T was associated with susceptibility to gastric cancer compared to that of the CC genotype (OR = 1.63; 95%CI = 1.02-2.64). In a recessive model, the TT genotype of IL-10 C819T was correlated with a higher risk of gastric cancer when compared with that of the CC + CT genotype (OR = 1.75; 95%CI = 1.01-3.02). In conclusion, our study suggests that the IL-10 C819T polymorphism is associated with an increased risk of gastric cancer in co-dominant, dominant, and recessive models. PMID- 28002582 TI - Polymorphism analysis of multi-parent advanced generation inter-cross (MAGIC) populations of upland cotton developed in China. AB - Upland cotton (Gossypium hirsutum L.) is an important cash crop that provides renewable natural fiber worldwide. Currently limited genetic base leads to a decrease in upland cotton genetic diversity. Multi-parent advance generation inter-cross (MAGIC) populations can be used to evaluate complex agronomic traits in crops. In this study, we developed an upland cotton MAGIC population. A total of 258 MAGIC population lines and their twelve founder lines were analyzed, using 432 pairs of simple sequence repeat (SSR) markers. Gene diversity indices and the polymorphism information content were calculated using polymorphism analyses. Our genotype analysis showed that 258 inbred lines could be divided into 158 genotypes. Among these, we identified 17 pairs of specific SSR primers on the A chromosome subgroups and 24 pairs of specific SSR primers on the B chromosome subgroups of upland cotton. These were related to 77 and 128 genotypes, respectively. Our results suggest that the upland cotton MAGIC population contained abundant genetic diversity and may provide enormous resources for future genetic breeding. PMID- 28002583 TI - Association between IL18-607C/A and -137G/C polymorphisms and susceptibility to non-small cell lung cancer in a Chinese population. AB - Lung cancer is one of the main causes of cancer-related mortality in males and females worldwide. A pleiotropic effect has been observed in the interleukin 18 gene (IL18); its effects include the activation of natural killer cell cytotoxicity and the promotion of the Th1 immune response through the alteration of the expression of interferon-gamma and TNF-alpha in humans. IL18 is therefore involved in the elimination of tumor cells in the human body. We recruited 357 patients with non-small cell lung cancer (NSCLC) and 414 controls to evaluate the correlation between two genetic variations (IL18-607C/A and IL18-137G/C) and the pathogenesis of NSCLC. We used polymerase chain reaction-restriction fragment length polymorphism to genotype IL18-607C/A and IL18-137G/C. Statistical analysis revealed that individuals harboring the AA genotype of IL18-607C/A had an increased risk of NSCLC compared to those harboring the CC genotype (OR = 2.20, 95%CI = 1.30-3.74). Individuals expressing the A allele of IL18-607C/A had an elevated risk of developing NSCLC compared to those expressing the C allele (OR = 1.31, 95%CI = 1.06-1.62). In summary, our analysis shows that the IL18-607C/A genetic variation is related to the risk of NSCLC, whereas the IL18-137G/C variation is not. Therefore, the IL18-607C/A variation is related to the pathogenesis of NSCLC in the Chinese population studied. PMID- 28002584 TI - Association between CYP19A1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and the development of endometriosis in a Chinese population. AB - Endometriosis is a common, complicated, and highly heterogeneous endocrine disease. Many genetic factors could affect the development of endometriosis. We performed a case-control study to evaluate the association between polymorphisms in CYP19A1 rs2899470, GSTM1, GSTT1, and GSTP1 rs1695 and the development of endometriosis in a Chinese population. Between March 2014 and October 2015, 262 endometriosis patients and 275 control subjects were recruited from the Inner Mongolia Medical University. Genotyping was conducted using polymerase chain reaction-coupled with restriction fragment length polymorphism. Individuals carrying the TT genotype of CYP19A1 rs2899470 expressed a higher risk of endometriosis than those carrying the GG genotype, and the adjusted ORs (95%CI) was 2.33 (1.27-4.33). Moreover, those with the TG + TT genotype were correlated with an elevated risk of endometriosis, compared to those with the GG genotype (OR = 1.48, 95%CI = 1.03-2.13). However, GSTM1, GSTT1, and GSTP1 rs1695 polymorphisms did not affect the pathogenesis of endometriosis. In conclusion, our results suggested that CYP19A1 rs2899470 polymorphism is associated with risk for endometriosis in the Chinese population. PMID- 28002585 TI - CASE-REPORT Association between an ACAN gene variable number tandem repeat polymorphism and lumbar disc herniation: a case control study. AB - We investigated the association between an aggrecan gene (ACAN) polymorphism and lumbar disc herniation (LDH). This was a case-control study with quinquennial age and gender groups. The study comprised 119 men and women aged between 20 and 60 from Goiania (Brazil). Of these, 39 were allocated to the case group (Ca) and 80 to the control group (Ct). We gathered sociodemographic and clinical data, and peripheral blood samples. DNA was isolated for genotyping the ACAN variable number tandem repeat (VNTR) via conventional polymerase chain reaction (PCR). Data were statistically analyzed using the chi-square test, multiple comparison analysis, the Student t-test, and odds ratios, with a level of significance set at 5% (P <= 0.05). The groups were homogenous in terms of sociodemographic, anthropometric, and life style variables. The allele score for the ACAN VNTR was significantly lower in volunteers with LDH; the A22 allele was significantly more prevalent in this same group; the Ca group presented greater frequency of short alleles A13-A25, whereas the Ct group presented a higher frequency of long alleles. However, this difference was not statistically significant. In both groups, the most common alleles were A28, A27, and A29, and the A26/A26 genotype was significantly more common in the Ca group. The results showed an association between short alleles and LDH among the investigated adults (Ca), corroborating the hypothesis that aggrecan with shorter repeat lengths can lead to a reduction in the physiological proteoglycan function of intervertebral disc hydration and, consequently, increased individual susceptibility to LDH. PMID- 28002586 TI - Correlation between TRAIL and caspase-8 expression and their relationship with cell proliferation and apoptosis in human osteosarcoma. AB - Osteosarcoma is a common malignant bone tumor that mainly affects children and adolescents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily. Caspase-8 appears in the upstream of apoptosis signaling pathway among caspases. We investigated TRAIL and caspase-8 levels in osteosarcoma patients to determine their correlation with cell proliferation and apoptosis. Osteosarcoma and osteochondroma patients receiving surgery in our hospital were selected. TRAIL and caspase-8 expression levels in tissue were determined by immunohistochemistry, and protein levels in cells were evaluated by western blotting. Human osteosarcoma cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The osteosarcoma and osteochondroma cell cycles and apoptosis were investigated by flow cytometry. Correlation analysis was applied to TRAIL and caspase-8 levels during cell apoptosis. Positive TRAIL and caspase-8 expression rates in osteosarcoma tissue were significantly lower than in the controls (P < 0.05). TRAIL (0.114 +/- 0.002) and caspase-8 (0.352 +/- 0.124) levels in experimental cells were obviously lower than in the controls (P < 0.05). Osteosarcoma cells in the experimental group demonstrated higher proliferation and lower apoptosis at 24, 48, and 72 h (P < 0.05). The experimental cell number increased in the G1 stage and decreased in the S stage (P < 0.05). TRAIL and caspase-8 proteins showed positive correlation with apoptosis in osteosarcoma (P < 0.05). Human osteosarcoma presented reduced TRAIL and caspase-8 levels with enhanced cell proliferation and reduced apoptosis. TRAIL and caspase-8 expression levels were positively correlated with apoptosis in osteosarcoma. PMID- 28002587 TI - Blood folic acid, vitamin B12, and homocysteine levels in pregnant women with fetal growth restriction. AB - Deficiencies in nutrients such as folic acid and vitamin B12 may play a role in fetal growth restriction (FGR). However, whether folic acid, vitamin B12, or homocysteine is associated with FGR in Chinese populations remains unclear. This study investigated the relationship between these nutrient deficiencies and FGR in pregnant Chinese women. We selected 116 mother and infant pairs, and categorized the neonates into the FGR, appropriate for gestational age, and large for gestational age groups. Birth weight, body length, head circumference, body mass index (BMI), and Rohrer's body index of the newborns were measured. Serum folic acid, vitamin B12, and homocysteine levels were measured in mothers during the first three days of their hospital stay. Results showed that the FGR group exhibited reduced folic acid and vitamin B12 levels and elevated homocysteine levels than those in the other two groups. Folic acid and vitamin B12 levels were positively correlated with birth weight, head circumference, and BMI, whereas homocysteine level was negatively correlated with these variables. The FGR ratio in the folic acid and vitamin B12 deficiency group was higher than that in the sufficiency group (chi2 = 4.717 and 4.437, P = 0.029 and 0.035, respectively). In addition, elevated homocysteine was associated with FGR (chi2 = 5.366, P = 0.021). In conclusion, we found that folic acid and vitamin B12 deficiency was associated with elevated homocysteine levels, which may increase susceptibility to FGR. PMID- 28002588 TI - Analysis of ADH1B Arg47His, ALDH2 Glu487Lys, and CYP4502E1 polymorphisms in gastric cancer risk and interaction with environmental factors. AB - Gastric cancer is the fourth commonly diagnosed cancer and the second most frequent cause of cancer death worldwide. Genetic variations in ADH1B and ALDH2 may alter the function and activity of the corresponding enzymes, leading to differences in acetaldehyde exposure between drinkers. Cytochrome P4502E1 (CYP4502E1) is a phase I enzyme that plays an important role in metabolizing nitrosamine compounds and the bioactivation of procarcinogens. During the period of July 2013 to July 2015, 246 patients and 274 controls were enrolled from the First Affiliated Hospital of Jinan University. In the codominant model, the AA genotype of ALDH2 Glu487Lys significantly elevated the risk of gastric cancer in comparison with the GG genotype of ALDH2 Glu487Lys. In the recessive model, the AA genotype of ALDH2 Glu487Lys significantly increased the risk of gastric cancer compared to the GG+GA genotype (OR = 2.34 95%CI = 1.02-5.70). We found in the codominant model that individuals harboring the C2/C2 genotype of CYP4502E1 had a higher risk of developing gastric cancer than those with the C1/C1 genotype. In addition, in the recessive model, we found that the C2/C2 genotype correlated with an elevated risk of gastric cancer in comparison with the C1/C1+C1/C2 genotype (OR = 4.90, 95%CI = 2.04-13.51). However, no significant relationship was measured between ADH1B Arg47His and gastric cancer risk. In summary, the results of our study indicate that ALDH2 Glu487Lys and CYP4502E1 polymorphisms could be risk factors for the development of gastric cancer in the Chinese population. PMID- 28002589 TI - Association between COL9A2 Gln326Arg mutations and the development of intervertebral disc disease in a Chinese population. AB - Intervertebral disc disease is a multifactorial condition, yet disease pathogenesis that can be promoted by a single dominant mutation affecting the expression of susceptibility genes. We performed a case-control study to assess the influence of the COL9A2 Gln326Arg polymorphism on risk of intervertebral disc disease in a Chinese population. Between March 2014 and March 2015, a total of 215 patients and 230 healthy controls were recruited from Binzhou Medical University Hospital. Genotyping of COL9A2 Gln326Arg was carried out using polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate logistic regression analyses revealed that the Arg/Arg genotype of COL9A2 Gln326Arg was associated with increased risk of intervertebral disc disease in comparison to the Gln/Gln genotype [crude odds ratio (OR) = 2.25, 95% confidence interval (CI) = 1.12-4.62; adjusted OR = 2.46, 95%CI = 1.20-5.29]. Moreover, the Arg/Arg genotype correlated with an elevated risk of this disease compared to the Gln/Gln + Gln/Arg genotypes (crude OR = 2.21, 95%CI = 1.17-4.30; adjusted OR = 2.42, 95%CI = 1.28-5.51). In conclusion, our results suggest that the COL9A2 Gln326Arg polymorphism contributes to the development of intervertebral disc disease in the Chinese population. PMID- 28002590 TI - Association between -174G/C and -572G/C interleukin 6 gene polymorphisms and severe radiographic damage to the hands of Mexican patients with rheumatoid arthritis: a preliminary report. AB - Several interleukin 6 gene (IL6) polymorphisms are implicated in susceptibility to rheumatoid arthritis (RA). It has not yet been established with certainty if these polymorphisms are associated with the severe radiographic damage observed in some RA patients, particularly those with the development of joint bone ankylosis (JBA). The objective of the present study was to evaluate the association between severe radiographic damage in hands and the -174G/C and 572G/C IL6 polymorphisms in Mexican Mestizo people with RA. Mestizo adults with RA and long disease duration (>5 years) were classified into two groups according to the radiographic damage in their hands: a) severe radiographic damage (JBA and/or joint bone subluxations) and b) mild or moderate radiographic damage. We compared the differences in genotype and allele frequencies of -174G/C and 572G/C IL6 polymorphisms (genotyped using polymerase chain reaction-restriction fragment length polymorphism) between these two groups. Our findings indicated that the -174G/C polymorphism of IL6 is associated with severe joint radiographic damage [maximum likelihood odds ratios (MLE_OR): 8.03; 95%CI 1.22-187.06; P = 0.03], whereas the -572G/C polymorphism of IL6 exhibited no such association (MLE_OR: 1.5; 95%CI 0.52-4.5; P = 0.44). Higher anti-cyclic citrullinated peptide antibody levels were associated with more severe joint radiographic damage (P = 0.04). We conclude that there is a relevant association between the -174G/C IL6 polymorphism and severe radiographic damage. Future studies in other populations are required to confirm our findings. PMID- 28002591 TI - In vivo antimutagenic effects of the Barbados cherry fruit (Malpighia glabra Linnaeus) in a chromosomal aberration assay. AB - Barbados cherry (BC) (Malpighia glabra Linnaeus) is a functional fruit that is consumed to prevent disease. It is used as an adjuvant in the treatment of several diseases, and acts as an antianemic, an appetite stimulant, a wound healer, an anti-inflammatory, a mineralizer, an antifungal, and an antioxidant agent. Several chemotherapeutic agents, such as cyclophosphamide, may result in undesirable side effects, and generate mutations in normal cells. Thus, the present study evaluated the antimutagenic potential of the fresh (BCN) and frozen (BCF) juices of BC pulp, with and without concomitant administration of cyclophosphamide, using a chromosomal aberration test system in the bone marrow cells of Wistar rats treated in vivo for 24 h. The results showed that neither the BC juice (0.4 mg/mL) alone, nor that with concomitant cyclophosphamide (1.5 mg/mL), were cytotoxic. BC has potential as an antimutagenic, and statistically reduced the percentages of chromosomal alterations induced by cyclophosphamide when administered simultaneously (BCN: 80.75%; BCF: 88.26%), pre-treatment (BCN: 86.85%; BCF: 87.32%), or post-treatment (BCN: 90.14%; BCF: 86.85%). This was due to the antioxidant activity of the fruit and the action of its bioactive compounds, which may have inhibited cyclophosphamide metabolism or scavenged the free radicals generated by this compound. Thus, attenuation of cyclophosphamide induced mutagenicity suggests that the consumption of fresh or frozen BC should be encouraged for the prevention of disease, and for the maintenance and promotion of health. PMID- 28002592 TI - Genetic analysis of Apuleia leiocarpa as revealed by random amplified polymorphic DNA markers: prospects for population genetic studies. AB - Apuleia leiocarpa (Vogel) J.F. MacBride is a hardwood species native to South America, which is at serious risk of extinction. Therefore, it is of prime importance to examine the genetic diversity of this species, information required for developing conservation, sustainable management, and breeding strategies. Although scarcely used in recent years, random amplified polymorphic DNA markers are useful resources for the analysis of genetic diversity and structure of tree species. This study represents the first genetic analysis based on DNA markers in A. leiocarpa that aimed to investigate the levels of polymorphism and to select markers for the precise characterization of its genetic structure. We adapted the original DNA extraction protocol based on cetyltrimethyl ammonium bromide, and describe a simple procedure that can be used to obtain high-quality samples from leaf tissues of this tree. Eighteen primers were selected, revealing 92 bands, from which 75 were polymorphic and 61 were sufficient to represent the overall genetic structure of the population without compromising the precision of the analysis. Some fragments were conserved among individuals, which can be sequenced and used to analyze nucleotide diversity parameters through a wider set of A. leiocarpa individuals and populations. The individuals were separated into 11 distinct groups with variable levels of genetic diversity, which is important for selecting desirable genotypes and for the development of a conservation and sustainable management program. Our results are of prime importance for further investigations concerning the genetic characterization of this important, but vulnerable species. PMID- 28002593 TI - Genetic variations of 21 STR markers on chromosomes 13, 18, 21, X, and Y in the south Iranian population. AB - Quantitative fluorescent polymerase chain reaction (QF-PCR), in recent years, has been accepted as a rapid, high throughput, and sensitive method for prenatal diagnosis of common chromosomal aneuploidies. Since short tandem repeats (STRs) are the cornerstone of QF-PCR technique, selection of the most polymorphic STR markers is an essential step for a successful QF-PCR assay. The genetic variation parameters of each STR marker differ among different populations. In this study, we investigated the size, frequency, heterozygosity, polymorphism information content, power of discrimination, and other genetic polymorphism data for 21 STR markers on chromosomes 13, 18, 21, X, and Y in 1000 amniotic fluid samples obtained from south Iranian women. Our results showed that all the 21 STR markers are highly polymorphic and informative in our population. The heterozygosity, polymorphism information content, and power of discrimination of the markers were 62-91.1%, 0.61-0.91, and 0.830-0.976, respectively. The locus D18S386 was the most polymorphic STR, while the locus DXYS218 was the least polymorphic STR among all the studied STRs. The present study has provided extensive data regarding the efficiency of the 21 STR markers for diagnosis of chromosomes 13, 18, 21, X, and Y aneuploidies in the south Iranian population. PMID- 28002594 TI - Effects of miR-27a upregulation on thyroid cancer cells migration, invasion, and angiogenesis. AB - Thyroid cancer is the most common type of endocrine tumor. MicroRNAs (miRNAs) play a critical role in a variety of diseases, especially cancer occurrence and progression. However, the specific mechanism by which miRNAs trigger disease states has not been fully elucidated. This study aims to investigate the role of miR-27a in thyroid cancer cells. A wound healing assay was adopted to examine cell migration. A transwell assay was applied to assess cell invasion. A thyroid cancer xenograft model was established using BALB/c nude mice. Western blot was performed to quantify iNOS expression. Tumor tissue blood vessel density was evaluated via immunohistochemistry assays. The results indicated that miR-27a downregulation inhibited thyroid cancer cell migration, while upregulation of miR 27a promoted thyroid cancer cell migration (P < 0.05). Furthermore, reduction in miR-27a expression suppressed thyroid cancer cell invasion (P < 0.05). In the nude mouse model of thyroid cancer xenograft, upregulation of miR-27 induced iNOS expression in pathological tumor tissues, whereas miR-27a inhibition resulted in the opposite effect (P < 0.05). CD105 level was also significantly increased during miR-27a upregulation, and was declined when miR-27a was inhibited (P < 0.05). In conclusion, miR-27a upregulation in thyroid cancer cells affects tumor cell migration, invasion, and angiogenesis by targeting downstream genes. Therefore, miR27a may act as a biomarker of thyroid cancer. PMID- 28002595 TI - Matrix metalloproteinase gene polymorphisms and susceptibility to systemic sclerosis. AB - The major pathological hallmark of the systemic sclerosis (SSc) is skin and internal organ fibrosis, which results from normal tissue architecture alterations and extracellular matrix (ECM) protein deposition. ECM components are degraded by matrix metalloproteinases (MMP). Promoter region polymorphisms in MMP genes may influence gene expression, resulting in an imbalance between ECM protein production and degradation. Here, we analyzed MMP1 -1607 1G/2G (rs1799750), MMP3 -1171 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms in relation to susceptibility to SSc and its clinical features. The patient group included 98 individuals with longstanding or recently diagnosed disease, meeting the American College of Rheumatology or LeRoy and Medsger criteria for SSc; the control group included 100 healthy blood donors. All participants were of European descent. Genotyping was performed by polymerase chain reaction followed by restriction digestion. Genotype and allele frequencies of MMP polymorphisms were similar between the two groups. In secondary analyses, significantly higher frequency of 1G/2G genotype from MMP1 polymorphism was observed for patients testing positive for antinuclear autoantibodies (P = 0.007), while 1G/1G genotype was associated with interstitial lung disease development (P = 0.018). The 6A/6A genotype from MMP3 polymorphism was absent in patients with calcinosis (P = 0.011), while the MMP3 5A/5A genotype correlated with the presence of anti-topoisomerase I antibodies (P = 0.009) and reduced diffusing capacity for carbon monoxide (P = 0.024). These results suggest that MMP polymorphisms are not associated with SSc susceptibility, although MMP1 and MMP3 variants are associated with specific SSc clinical and laboratory features. PMID- 28002596 TI - Increased relatedness among the neighboring plants from seedling to adult stages in carnauba wax palm. AB - The objective of this study was to assess the spatial genetic structure (SGS) at different life stages (cohorts) in a remnant population (N = 101) of Copernicia prunifera in the semiarid region of northeastern Brazil. Using seven inter-simple sequence repeat molecular markers, we were able to analyze 93 loci with 100% polymorphism. Seedlings had the highest level of genetic diversity (HE = 0.411, HO = 0.599), followed by juveniles (HE = 0.394, HO = 0.579) and adults (HE = 0.267, HO = 0.427). Based on analysis of molecular variance, the majority of genetic variations were observed to occur within the life stages (93.42%) rather than between the life stages (6.58%). We found a recent reduction in the population size (bottleneck) based on the number of loci with heterozygosity excess for the two models used (infinite allele = 92 and stepwise = 91). All the life stages showed significant SGS, with positive and significant kinship values. Sp values were 0.040 for seedlings, 0.093 for juveniles, 0.156 for adults, and 0.053 for the total population. We found an increase in SGS from the seedling to adult stages, indicating that the plants were from related adult progenitors. Data from this study can be used in designing effective management and conservation strategies for the species. PMID- 28002597 TI - Characterization and application of newly developed polymorphic microsatellite markers in the Ezo red fox (Vulpes vulpes schrencki). AB - The Ezo red fox (Vulpes vulpes schrencki), a subspecies endemic to Hokkaido island, Japan, is a known host species for the tapeworm Echinococcus multilocularis. To develop tools for molecular ecological studies, we isolated 28 microsatellite regions from the genome of Ezo red fox, and developed 18 polymorphic microsatellite markers. These markers were characterized using 7 individuals and 22 fecal samples of the Ezo red fox. The number of alleles for these markers ranged from 1 to 7, and the observed heterozygosity, estimated on the basis of the genotypes of 7 individuals, ranged from 0.29 to 1.00. All markers, except DvNok5, were in Hardy-Weinberg equilibrium (P > 0.05), and no linkage disequilibrium was detected among these loci, except between DvNok14 and DvNok28 (P = 0.01). Moreover, six microsatellite loci were successfully genotyped using feces-derived DNA from the Ezo red fox. The markers developed in our study might serve as a useful tool for molecular ecological studies of the Ezo red fox. PMID- 28002598 TI - Molecular characterization and population structure study of cambuci: strategy for conservation and genetic improvement. AB - Cambuci (Campomanesia phaea) belongs to the Myrtaceae family and is native to the Atlantic Forest of Brazil. It has ecological and social appeal but is exposed to problems associated with environmental degradation and expansion of agricultural activities in the region. Comprehensive studies on this species are rare, making its conservation and genetic improvement difficult. Thus, it is important to develop research activities to understand the current situation of the species as well as to make recommendations for its conservation and use. This study was performed to characterize the cambuci accessions found in the germplasm bank of Coordenadoria de Assistencia Tecnica Integral using inter-simple sequence repeat markers, with the goal of understanding the plant's population structure. The results showed the existence of some level of genetic diversity among the cambuci accessions that could be exploited for the genetic improvement of the species. Principal coordinate analysis and discriminant analysis clustered the 80 accessions into three groups, whereas Bayesian model-based clustering analysis clustered them into two groups. The formation of two cluster groups and the high membership coefficients within the groups pointed out the importance of further collection to cover more areas and more genetic variability within the species. The study also showed the lack of conservation activities; therefore, more attention from the appropriate organizations is needed to plan and implement natural and ex situ conservation activities. PMID- 28002599 TI - Factors influencing QTL mapping accuracy under complicated genetic models by computer simulation. AB - The accuracy of quantitative trait loci (QTLs) identified using different sample sizes and marker densities was evaluated in different genetic models. Model I assumed one additive QTL; Model II assumed three additive QTLs plus one pair of epistatic QTLs; and Model III assumed two additive QTLs with opposite genetic effects plus two pairs of epistatic QTLs. Recombinant inbred lines (RILs) (50 1500 samples) were simulated according to the Models to study the influence of different sample sizes under different genetic models on QTL mapping accuracy. RILs with 10-100 target chromosome markers were simulated according to Models I and II to evaluate the influence of marker density on QTL mapping accuracy. Different marker densities did not significantly influence accurate estimation of genetic effects with simple additive models, but influenced QTL mapping accuracy in the additive and epistatic models. The optimum marker density was approximately 20 markers when the recombination fraction between two adjacent markers was 0.056 in the additive and epistatic models. A sample size of 150 was sufficient for detecting simple additive QTLs. Thus, a sample size of approximately 450 is needed to detect QTLs with additive and epistatic models. Sample size must be approximately 750 to detect QTLs with additive, epistatic, and combined effects between QTLs. The sample size should be increased to >750 if the genetic models of the data set become more complicated than Model III. Our results provide a theoretical basis for marker-assisted selection breeding and molecular design breeding. PMID- 28002600 TI - Differential expression of Toll-like receptors in goat dominant and nondominant follicles. AB - The mechanism of dominant follicle selection is unclear because of its physiological complexity. However, some studies have reported that the immune system plays an important role in reproductive physiology. The objective of the current study was to investigate the differential expression of Toll-like receptors (TLRs) in the dominant (DFs) and nondominant follicles (NFs), and to determine the correlation between the expression of TLRs and the related genes, such as WNT4 and FOXL2. In this comparative study, the expression levels of TLRs, WNT4, and FOXL2 genes of DFs and NFs were obtained from three Dazu black goats were estimated using the real-time PCR. Our results showed no significant difference in the expression of seven TLRs (excluding TLR2, TLR5, and TLR8), WNT4, and FOXL2 between the DFs and NFs. In addition, the mRNA expression levels of WNT4 significantly correlated with the relative expression of TLR6 (r = 0.949739, P < 0.01); however, no significant expression of the TLR genes was found to be associated with FOXL2 mRNA expression. Our results support the fact that TLRs are not involved in the process of dominant follicle selection; however, TLR6 might play a role in the development of follicles by interacting with WNT4. PMID- 28002601 TI - Effect of ARMS2 gene polymorphism on intravitreal ranibizumab treatment for neovascular age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. The ARMS2 gene has been found to be associated with AMD. Currently, intravitreal ranibizumab (IVR) treatment is one of the widely used treatments for neovascular AMD. The aim of this study was to investigate the association between the genotype of ARMS2 rs10490924 polymorphism and IVR treatment responsiveness in patients with neovascular AMD. The study included 39 patients with advanced neovascular AMD (patient group) and 250 healthy individuals with exome sequencing data (control group). The patient group was divided into three subgroups: GG (N = 10), TG (N = 14), and TT (N = 15). Before IVR treatment, all patients had intraretinal or subretinal fluid or both. They received three monthly IVR-injection treatments. One month after the third injection, the patients were evaluated as either "responders" or "non-responders" based on the presence or absence of intraretinal or subretinal fluid or both. The patient subgroups TG and TT had an 8.56- and 39-fold higher risk of AMD, respectively, than patient subgroup GG had. The allele frequency was 0.537 and 0.10 in the patient and control groups, respectively. Within the patient subgroup TT, there was a significant difference between the "responders" and "non responders" (P = 0.025). In conclusion, in neovascular AMD patients undergoing IVR treatment, TT genotype tended to be a better predictor of good short-term treatment response, compared to the GG and TG genotypes. Further studies using confirmed genetic biomarkers for individualized optimal treatments are required. PMID- 28002602 TI - Effect of Astragalus polysaccharides on ovariectomy-induced osteoporosis in mice. AB - Postmenopausal osteoporosis, a common type of osteoporosis in women, has become a serious public health issue. Astragalus polysaccharides (APS), possessing various pharmacological activities, are the active ingredients of Radix Astragali. It can be advantageous in the treatment of postmenopausal osteoporosis. In the present study, we evaluated the potential therapeutic effects of APS on postmenopausal osteoporosis by using a mice model induced by ovariectomy (OVX). Forty-eight female 6-week-old outbred ICR mice were randomly divided into six groups (N = 8): Sham group, OVX group, 17 beta-estradiol (E2, 0.1 mg/kg)-treated OVX group, and APS (at three doses: 100, 200, and 400 mg/kg)-treated OVX groups. The effect of APS on the bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry. The serum levels of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), osteocalcin, and tumor necrosis factor (TNF)-alpha were measured using ELISA kits. The results revealed that APS exerted significant anti-osteoporotic activity by increasing the BMD considerably in a dose-dependent manner. APS treatment reduced the serum RANKL levels considerably and increased the serum OPG levels, thereby lowering the ratio of RANKL/OPG. Furthermore, APS also markedly reduced osteocalcin and TNF-alpha concentration in OVX-induced postmenopausal osteoporosis mice model. These results showed that APS exerts a protective effect on bone loss in OVX mice. The molecular mechanism underlying this effect be the reduction of bone resorption and inhibition of osteoclastogenesis. Our findings suggest that APS may be a potential strategy for the prevention and treatment of postmenopausal osteoporosis. PMID- 28002603 TI - Association of growth factor receptor-bound protein 10 gene polymorphism with superovulation traits in Changbaishan black cattle. AB - The application of assisted reproductive technology in animal production benefits the economy and conservation of biological resources. Single nucleotide polymorphism (SNPs) was used as predictive markers for breeding and reproduction. In the present study, we examined the association between a SNP of the grb10 gene and superovulation traits in cattle. Sequencing results indicated a point mutation and statistical analysis showed a significant association of the mutation with superovulation traits. The high number of embryos collected from the heterozygotes suggested that the mutation in the grb10 gene exerted a significant effect on the number of embryos recovered although the quality was not affected. The grb10 gene may serve as a useful biomarker for donor selection. PMID- 28002604 TI - Using the Gene Ontology tool to produce de novo protein-protein interaction networks with IS_A relationship. AB - Since the first assembled genomes, gene sequences alone have not been sufficient to understand complex metabolic processes involving several genes, each playing distinct roles. To identify their roles, a network of interactions, wherein each gene is a node, should be created. Edges connecting nodes are evidence of interaction, for instance, of gene products coexisting in the same cellular component. Such interaction networks are called protein-protein interactions (PPIs). After genome assembling, PPI mapping is used to predict the possibility of proteins interacting with other proteins based on literature evidence and several databases, thus enriching genome annotations. Identifying PPIs involves analyzing each possible protein pair for a set of features, for instance, participation in the same biological process and having the same function and status in a cellular component. Here, we investigated using the three categories of the Gene Ontology (GO) database for efficient PPI prediction, because it provides data about the three features exemplified here. For a broader conclusion, we investigated the genomes of ten different human pathogens, looking for commonality regarding the GO hierarchical relationship-denominated IS_A. The plasmids were examined separately from their main genomes. Protein pairs sharing at least one IS_A value were considered as interacting proteins. STRING results certified the probed interactions as sensitivity (score >0.75) and specificity (score <0.25) analysis. The average areas under the receiver operating characteristic curve for all organisms were 0.66 and 0.53 for their genomes and plasmids, respectively. Thus, GO categories alone could not potentially provide reliable PPI prediction. However, using additional features can improve predictions. PMID- 28002605 TI - Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster. AB - Lifeguard is an integral transmembrane protein that modulates FasL-mediated apoptosis by interfering with the activation of caspase 8. It is evolutionarily conserved, with homologues present in plants, nematodes, zebra fish, frog, chicken, mouse, monkey, and human. The Lifeguard homologue in Drosophila, CG3814, contains the Bax inhibitor-1 family motif of unknown function. Downregulation of Lifeguard disrupts cellular homeostasis and disease by sensitizing neurons to FasL-mediated apoptosis. We used bioinformatic analyses to identify CG3814, a putative homologue of Lifeguard, and knocked down CG3814/LFG expression under the control of the Dopa decarboxylase (Ddc-Gal4) transgene in Drosophila melanogaster neurons to investigate whether it possesses neuroprotective activity. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons resulted in a shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with the degeneration and loss of dopaminergic neurons. Lifeguard interacts with anti apoptotic Bcl-2 proteins and possibly pro-apoptotic proteins to exert its neuroprotective function. The co-expression of Buffy, the sole anti-apoptotic Bcl 2 gene family member in Drosophila, and CG3814/LFG by stable inducible RNA interference, suppresses the shortened lifespan and the premature age-dependent loss in climbing ability. Suppression of CG3814/LFG in the Drosophila eye reduces the number of ommatidia and increases disruption of the ommatidial array. Overexpression of Buffy, along with the knockdown of CG3814/LFG, counteracts the eye phenotypes. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons in Drosophila diminishes its neuroprotective ability and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy. PMID- 28002606 TI - Proposal of a super trait for the optimum selection of popcorn progenies based on path analysis. AB - A challenge faced by popcorn breeding programs is the existence of a negative correlation between the two main traits, popping expansion and yield, which hinders simultaneous gains. The objective of this study was to investigate the use of a new variable or super trait, which favors the reliable selection of superior progenies. The super trait 'expanded popcorn volume per hectare' was introduced in the evaluation of 200 full-sib families of the eighth recurrent intrapopulation selection cycle, which were arranged in randomized blocks with three replicates in two environments. Although the inability to obtain simultaneous gains through selection via popping expansion or yield was confirmed, the super trait was positively associated with both yield and popping expansion, allowing simultaneous gains via indirect selection using 'expanded popcorn volume per hectare' as the main trait. This approach is recommended because this super trait can be used in breeding programs to optimize selective gains for the crop. PMID- 28002607 TI - Targeting of miR-432 to myozenin1 to regulate myoblast proliferation and differentiation. AB - MicroRNAs (miRNAs) play important roles in the development and biochemical functions of skeletal muscles. However, targeting of miRNAs to structural genes involved in Z-discs have not been investigated. Here, we describe a highly expressed miRNA, miR-432, in pig embryonic skeletal muscle, which appeared to target myozenin1 (MYOZ1), a protein involved in the muscular sarcomere microstructure. Our results showed that miR-432 is involved in muscle development in the developing pig. In addition, it promoted differentiation of the C2C12 myoblast cell line into myotubes. We also demonstrated that inhibition of miR-432 reduced proliferation of C2C12 cells, suggesting that miR-432 is involved in regulation of myoblast proliferation. Moreover, molecular markers of muscle differentiation and fiber type (Myh7/ slow and Myh4/ fast IIB) showed that miR 432 reduced the differentiation rate of C2C12 cells. These results provide insights into the potential functions of miR-432 as well as its proposed target, MYOZ1, during muscle development. This may lead to applications for further improvements in porcine muscle growth, and may enhance our understanding of complex inherited human muscle disorders. PMID- 28002608 TI - NtBRC1 suppresses axillary branching in tobacco after decapitation. AB - Axillary branching is controlled by a very complex mechanism involving various endogenous and environmental factors. Previous studies have shown that Tb1/BRC1 is the point of integration in the network of molecular mechanisms regulating axillary branching in plants. In this study, we cloned the Tb1/BRC1 ortholog, NtBRC1, from Nicotiana tabacum and functionally analyzed its role in the control of axillary branching in tobacco. Overexpression of NtBRC1 resulted in significant retardation of axillary branching, and downregulation of this gene resulted in significant acceleration of axillary branching after decapitation. This indicates a negative role for this gene in the regulation of axillary branching. In-line with previous reports, NtBRC1 was found to be expressed predominantly in axillary buds. Additionally, as expected, expression was decreased 8 h following decapitation, which further confirms its role in the suppression of axillary branching. Furthermore, the expression of NtBRC1 was significantly downregulated by cytokinin, but was not affected by GR24, a synthetic strigolactone. Based on the data collected in the present study, we demonstrate that NtBRC1 negatively regulates axillary branching in tobacco after decapitation and functions downstream of the cytokinin signaling pathway inside axillary buds. PMID- 28002609 TI - Bulk segregant analysis (BSA) for improving cold stress resistance in maize using SSR markers. AB - In this study, eight inbred maize lines with high or low tolerance to cold temperature were investigated using bulk segregant analysis (BSA). Genetic diversity and genetic relationships were investigated using 100 simple sequence repeat (SSR) markers linked to cold tolerance in maize. A total of 319 alleles were identified. Among these, 128 were high coldtolerant-specific alleles and 61 were poorly coldtolerant-specific alleles, while the remaining 130 were shared between the two types. The number of alleles per locus ranged from 2 to 5, with an average of 3.19. The major allele frequency varied from 0.39 to 0.53 with an average of 0.47. The average gene diversity and polymorphic information content among all lines were 0.63 and 0.58, respectively. A dendrogram analysis identified three main clusters and most of the high tolerant inbred lines were clearly distinguished from the poorly tolerant inbred lines. In addition to the BSA, a total of 84 SSR markers were identified as high cold tolerance-specific alleles and 52 SSRs were detected as poorly cold tolerance-specific alleles. Of these, bnlg1273, umc1124, dupssr21, mmc0251, mmc0181, and phi041 have great potential for being molecular markers for cold tolerance in maize. Our results were in agreement with results previously reported for SSR markers linked with cold tolerance in maize. The identification and characterization of high and poorly cold tolerant maize lines based on SSR markers will be useful for future maize breeding studies. PMID- 28002610 TI - Is the optimal intervention policy UC superior to the suboptimal policy MFPT over inferred probabilistic Boolean network models? AB - A salient problem in translational genomics is the use of gene regulatory networks to determine therapeutic intervention strategies. Theoretically, in a complete network, the optimal policy performs better than the suboptimal policy. However, this theory may not hold if we intervene in a system based on a control policy derived from imprecise inferred networks, especially in the small-sample scenario. In this paper, we compare the performance of the unconstrained (UC) policy with that of the mean-first-passage-time (MFPT) policy in terms of the quality of the determined control gene and the effectiveness of the policy. Our simulation results reveal that the quality of the control gene determined by the robust MFPT policy is better in the small-sample scenario, whereas the sensitive UC policy performs better in the large-sample scenario. Furthermore, given the same control gene, the MFPT policy is more efficient than the UC policy for the small-sample scenario. Owing to these two features, the MFPT policy performs better in the small-sample scenario and the UC policy performs better only in the large-sample scenario. Additionally, using a relatively complex model (gene number N is more than 1) is beneficial for the intervention process, especially for the sensitive UC policy. PMID- 28002611 TI - Cryopreservation of Schisandra chinensis (Turcz.) Baill callus and subsequent plant regeneration. AB - Cryopreservation has been proven significance as a technique for promising the long-term conservation of plant germplasms. This study aimed to establish a cryopreservation protocol for calli of Schisandra chinensis (Turcz.) Baill, and to explore the effects of different process parameters on callus viability. Effects of desiccation duration, cryoprotectants and cryopreservation methods, thawing temperature, and post-culture conditions on the viability of cryopreserved calli were assessed. Among different cryoprotectants and freezing procedures, the highest survival was recorded when the water content of callus after 30 min desiccation was 57.3%, were loaded into a cryoprotectant containing 10% ethylene glycol, 8% glucose, and 10% DMSO, and frozen slowly (-1 degrees C/min). Rapid thawing at 40 degrees C for 2 min demonstrated the best recovery of cryopreserved S. chinensis calli. Post-culturing in darkness for one week before transfer to light conditions (under 16 h photoperiod at 36 umol.m-2.s-1) was beneficial to callus regeneration. Plants regenerated through somatic embryogenesis from cryopreserved calli remained ploidy stable after cryopreservation. The callus cryopreservation procedure established in this study is a promising tool for the conservation of S. chinensis resources. PMID- 28002612 TI - DeltaF508 mutation screening of healthy individuals from two populations in Espirito Santo State, Brazil. AB - The DeltaF508 mutation is the most common cause of cystic fibrosis and its prevalence varies worldwide. For instance, up to 20-fold variations in its frequency have been recorded across different areas of Brazil. This study aimed to compare the distribution of DeltaF508 among healthy individuals of admixed Portuguese descent from Espirito Santo (ES), a state in Southeastern Brazil, to that in a subpopulation of Pomeranian descent, considered to be an isolated group in which the European gene pool has been preserved, living in Santa Maria do Jetiba (also in ES). We found this mutation to be present at a frequency of 0.81% among the Pomeranian group, and 0% in the general ES population. No genetic differentiation was noted between the two populations examined (FST = 0.004), and these frequencies were found to be similar to those estimated in other states of Southeastern Brazil. Although the population of Santa Maria de Jetiba has retained Pomeranian traits, such as language, fair skin, and eye color, to date, there is no evidence of inbreeding in this group (FIS = -0.004). Screening healthy individuals for the DeltaF508 mutation can facilitate genetic counseling for cystic fibrosis, as well as inform evolutionary and population studies. PMID- 28002613 TI - Different responses of vanillic acid, a phenolic compound, in HTC cells: cytotoxicity, antiproliferative activity, and protection from DNA-induced damage. AB - The consumption of healthy and natural foods has increased over the last few years, primarily because these foods are rich in substances with biological properties of interest, such as exerting anticancer effects and decreasing oxidative stress in living tissues. These foods support adequate nutrition, maintain health, and improve quality of life. Vanillic acid (VA) is a phenolic compound used widely in the food industry as a flavoring, preservative, and food additive. VA can be found in various cereals, whole grains, fruits, herbs, green tea, juices, beers, and wines and possesses antioxidant, hepatoprotective, cardioprotective, and antiapoptotic activities. Studying the cytotoxicity as well as the mutagenic and antimutagenic effects of different concentrations of VA in Rattus norvegicus hepatoma cells (HTC) can identify new cellular activities of this substance. Concentrations up to 100 uM VA are not cytotoxic to HTC cells in a MTT [3-(4,5-dimethilthiazol-2-yl)-2,5-diphenil tetrazolium bromide] assay after 96-h exposure; therefore, VA does not compromise mitochondrial activity. Similarly, concentrations up to 500 uM do not compromise plasma membrane integrity. VA at 10 and 50 uM showed no mutagenic/clastogenic effects, as no significant micronuclei induction was observed. VA 10 uM presented no antiproliferative activity and reduced the cytotoxicity induced by benzo[a]pyrene. The antimutagenic activity of 10 uM VA was observed by the simultaneous, pre-, and post-treatments, as the phenolic compound significantly reduced the frequency of micronuclei induced by the mutagen. These results indicate that VA exerts different responses in HTC cells. Low concentrations present no cytotoxic, mutagenic, or antiproliferative effects and protect cells from DNA damage. PMID- 28002614 TI - Genetic progress in oat associated with fungicide use in Rio Grande do Sul, Brazil. AB - The State of Rio Grande do Sul (RS) is the largest producer of oat in Brazil with the aid of consolidated breeding programs, which are constantly releasing new cultivars. The main objectives of this study were to: 1) evaluate the annual genetic progress in grain yield and hectoliter weight of the oat cultivars in RS, with and without fungicide use on aerial parts of plants; and 2) evaluate the efficiency of oat breeding programs in introducing disease-resistant genes in the released cultivars through network yield trials conducted with and without fungicide use on aerial plant parts. The data on grain yield and hectoliter weight were obtained from 89 competition field trials of oat cultivars carried out from 2007 to 2014 in nine municipalities of RS. Of the total 89 trials, 44 were carried out with fungicide application on aerial plant parts and 45 were carried out without fungicide application. The annual genetic progress in oat cultivars was studied using the methodology proposed by Vencovsky (1988). The annual genetic progress in oat grain yield was 1.02% with fungicide use and 4.02% without fungicide use during the eight-year study period in RS. The annual genetic progress with respect to the hectoliter weight was 0.08% for trials with fungicide use and 0.71% for trials without fungicide use. Performing network yield trials with and without fungicide use on the aerial plants parts is a feasible method to evaluate the efficiency of oat breeding programs in introducing disease-resistant genes in the released cultivars. PMID- 28002615 TI - Genetic variability affecting Exserohilum turcicum resistance in popcorn lines grown under high and low phosphorus conditions. AB - Northern leaf blight (NLB), caused by Exserohilum turcicum, is one of the main foliar diseases that affect popcorn culture. Farmers use many control measures to minimize damage caused by this disease, among which, the use of cultivars with genetic resistance is the most effective and economical. The aim of this study was to investigate genetic variability influencing resistance to NLB in 25 popcorn maize lines grown under high and low phosphorus conditions in relation to foliar fungal disease caused by E. turcicum. We evaluated the disease incidence and severity, by analysis of variance and cluster test (Scott-Knott). There was sufficient genetic variability between strains for resistance traits. Genotypic variance was higher than environmental variance, and had more discriminatory power. We conclude that new progenies could be selected for the establishment of future populations. P-7, P-9, L-59, L-71, and L-76 progenies possess promising characteristics that simultaneously reduce the severity and the incidence of NLB in popcorn plants. PMID- 28002616 TI - Genomic variability of Pantoea ananatis in maize white spot lesions assessed by AFLP markers. AB - Measures to control maize white spot (MWS) caused by Pantoea ananatis are preferentially based on resistant cultivars. A lack of knowledge on the genetic variability of pathogens could interfere with the development and utilization of controlling strategies in this pathosystem. The main goals of this study were to investigate the genetic variability of 90 P. ananatis isolates from three different eco-geographical regions of Brazil by amplified fragment length polymorphism (AFLP), and to determine the presence of a universal P. ananatis plasmid in isolates from tropical Brazil. Analysis of genetic similarity by AFLP allowed us to categorize the 90 isolates into two groups. However, no correlation between the collecting sites and genetic groupings was observed. The polymorphism percentage found in P. ananatis ranged between 24.64 and 92.46%, and genetic diversity was calculated to be 0.07-0.09. The analysis of molecular variance showed that 99.18% of genetic variability was within the populations, providing evidence that evolutionary forces were acting on these populations. All P. ananatis isolates showed the P. ananatis universal plasmid (280 or 352 kb). This is the first report on the presence of a universal P. ananatis plasmid from MWS lesions in the tropical area. PMID- 28002617 TI - AGO4 is specifically required for heterochromatic siRNA accumulation at Pol V dependent loci in Arabidopsis thaliana. AB - In plants, 24 nucleotide long heterochromatic siRNAs (het-siRNAs) transcriptionally regulate gene expression by RNA-directed DNA methylation (RdDM). The biogenesis of most het-siRNAs depends on the plant-specific RNA polymerase IV (Pol IV), and ARGONAUTE4 (AGO4) is a major het-siRNA effector protein. Through genome-wide analysis of sRNA-seq data sets, we found that AGO4 is required for the accumulation of a small subset of het-siRNAs. The accumulation of AGO4-dependent het-siRNAs also requires several factors known to participate in the effector portion of the RdDM pathway, including RNA POLYMERASE V (POL V), DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and SAWADEE HOMEODOMAIN HOMOLOGUE 1 (SHH1). Like many AGO proteins, AGO4 is an endonuclease that can 'slice' RNAs. We found that a slicing-defective AGO4 was unable to fully recover AGO4-dependent het-siRNA accumulation from ago4 mutant plants. Collectively, our data suggest that AGO4-dependent siRNAs are secondary siRNAs dependent on the prior activity of the RdDM pathway at certain loci. PMID- 28002619 TI - Social Anhedonia and Romantic Relationship Processes. AB - OBJECTIVE: Social anhedonia is a deficiency in the capacity to experience pleasure from social interactions. This study examined the implications of social anhedonia for romantic relationship functioning, including the association of social anhedonia with sentiments toward romantic partners that are central to relationship functioning (satisfaction, commitment, regard for the partner, and care for the partner's welfare) and analogous perceptions of the partner's sentiments. METHOD: Data were collected from 281 participants who were involved in romantic relationships. RESULTS: Social anhedonia predicted less satisfaction, regard, and care, and these effects were independent of attachment insecurity and self-esteem. In addition, social anhedonia had an indirect negative effect on commitment via attachment avoidance. Social anhedonia also predicted more negative perceptions of the partner's sentiments. CONCLUSIONS: Results suggest that social anhedonia may undermine the functioning of romantic relationships by reducing positive sentiments toward partners and security in the partner's sentiments toward the self. PMID- 28002618 TI - Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP-TEAD complex. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes-associated protein-1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo-YAP pathway. However, little is known about whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC-1 and SW1990 cells by arresting cells at the G1 phase, and inducing apoptosis in dose- and time-dependent manners. Verteporfin also inhibited the tumor growth on the PDAC xenograft model. Treatment with verteporfin led to downregulation of cyclinD1 and cyclinE1, modulation of Bcl-2 family proteins and activation of PARP. In addition, verteporfin exhibited an inhibitory effect on angiogenesis and vasculogenic mimicry via suppressing Ang2, MMP2, VE-cadherin, and alpha-SMA expression in vitro and in vivo. Mechanism studies demonstrated that verteporfin impaired YAP and TEAD interaction to suppress the expression of targeted genes. Our results provide a foundation for repurposing verteporfin as a promising anti-tumor drug in the treatment of pancreatic cancer by targeting the Hippo pathway. PMID- 28002620 TI - The effect of specific proline residues on the kinetic stability of the triosephosphate isomerases of two trypanosomes. AB - The effect of specific residues on the kinetic stability of two closely related triosephosphate isomerases (from Trypanosoma cruzi, TcTIM and Trypanosoma brucei, TbTIM) has been studied. Based on a comparison of their beta-turn occurrence, we engineered two chimerical enzymes where their super secondary beta-loop-alpha motifs 2 ((betaalpha)2 ) were swapped. Differential scanning calorimetry (DSC) experiments showed that the (betaalpha)2 motif of TcTIM inserted into TbTIM (2Tc) increases the kinetic stability. On the other hand, the presence of the (betaalpha)2 motif of TbTIM inserted into TcTIM (2Tb) gave a chimerical protein difficult to purify in soluble form and with a significantly reduced kinetic stability. The comparison of the contact maps of the (betaalpha)2 of TbTIM and TcTIM showed differences in the contact pattern of residues 43 and 49. In TcTIM these residues are prolines, located at the N-terminal of loop-2 and the C terminal of alpha-helix-2. Twelve mutants were engineered involving residues 43 and 49 to study the effect over the unfolding activation energy barrier (EA ). A systematic analysis of DSC data showed a large decrease on the EA of TcTIM (DeltaEA ranging from 468 to 678 kJ/mol) when the single and double proline mutations are present. The relevance of Pro43 to the kinetic stability is also revealed by mutation S43P, which increased the free energy of the transition state of TbTIM by 17.7 kJ/mol. Overall, the results indicate that protein kinetic stability can be severely affected by punctual mutations, disturbing the complex network of interactions that, in concerted action, determine protein stability. Proteins 2017; 85:571-579. (c) 2016 Wiley Periodicals, Inc. PMID- 28002621 TI - Acupuncture and Acupressure in Labor. AB - Acupuncture and acupressure, 2 modalities of Traditional Chinese Medicine, are based on reducing pain and symptoms of disease through balancing yin and yang. Acupuncture and acupressure have been used in China for reduction of labor pain, labor augmentation, and other intrapartum indications for more than 2 millennia. This article presents a review of the current literature that has addressed the effects of acupuncture and acupressure on intrapartum events. Studies of acupuncture have demonstrated that acupuncture may reduce labor pain, the use of pharmacologic agents, the use of forceps and vacuum-assisted births, and the length of labor. Studies that examined the effect of acupuncture on labor that is induced or augmented for premature rupture of membranes have found that acupuncture may increase the degree of cervical ripening but does not reduce the amount of oxytocin or epidural analgesia administration, nor does it shorten length of induced labor. Acupressure may reduce labor pain and labor duration, but acupressure has not been found to increase cervical ripening or induce labor. There are insufficient studies about acupuncture and acupressure and their effects on labor at this time, and there is need for further research. Areas of uncertainty include efficacy, optimal point selection, best techniques, and length of time for point stimulation. PMID- 28002623 TI - Comprehensive screening for MED12 mutations in gynaecological mesenchymal tumours identified morphologically distinctive mixed epithelial and stromal tumours. AB - AIMS: MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. METHODS AND RESULTS: Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Mullerian adenosarcomas (including three tentatively diagnosed as 'variant adenosarcomas'), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three 'variant adenosarcomas' harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1-SUZ12 or JAZF1-PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated 'variant adenosarcomas' showed distinctive morphological features, including 'fibromyomatous' cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. CONCLUSIONS: These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours. PMID- 28002622 TI - Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation. AB - Epoxyeicosatrienoic acids (EETs) are synthesized in astrocytes, and inhibitors of soluble epoxide hydrolase (sEH), which hydrolyzes EETs, reduce infarct volume in ischemic stroke. Astrocytes can release protective neurotrophic factors, such as vascular endothelial growth factor (VEGF). We found that addition of sEH inhibitors to rat cultured astrocytes immediately after oxygen-glucose deprivation (OGD) markedly increased VEGF concentration in the medium 48 h later and the effect was blocked by an EET antagonist. The sEH inhibitors increased EET concentrations to levels capable of increasing VEGF. When the sEH inhibitors were removed from the medium at 48 h, the increase in VEGF persisted for an additional 48 h. Neurons exposed to OGD and subsequently to astrocyte medium previously conditioned with OGD plus sEH inhibitors showed increased phosphorylation of their VEGF receptor-2, less TUNEL staining, and increased phosphorylation of Akt, which was blocked by a VEGF receptor-2 antagonist. Our findings indicate that sEH inhibitors, applied to cultured astrocytes after an ischemia-like insult, can increase VEGF secretion. The released VEGF then enhances Akt-enabled cell survival signaling in neurons through activation of VEGF receptor-2 leading to less neuronal cell death. These results suggest a new strategy by which astrocytes can be leveraged to support neuroprotection. PMID- 28002624 TI - FlexPepDock lessons from CAPRI peptide-protein rounds and suggested new criteria for assessment of model quality and utility. AB - CAPRI rounds 28 and 29 included, for the first time, peptide-receptor targets of three different systems, reflecting increased appreciation of the importance of peptide-protein interactions. The CAPRI rounds allowed us to objectively assess the performance of Rosetta FlexPepDock, one of the first protocols to explicitly include peptide flexibility in docking, accounting for peptide conformational changes upon binding. We discuss here successes and challenges in modeling these targets: we obtain top-performing, high-resolution models of the peptide motif for cases with known binding sites but there is a need for better modeling of flanking regions, as well as better selection criteria, in particular for unknown binding sites. These rounds have also provided us the opportunity to reassess the success criteria, to better reflect the quality of a peptide-protein complex model. Using all models submitted to CAPRI, we analyze the correlation between current classification criteria and the ability to retrieve critical interface features, such as hydrogen bonds and hotspots. We find that loosening the backbone (and ligand) RMSD threshold, together with a restriction on the side chain RMSD measure, allows us to improve the selection of high-accuracy models. We also suggest a new measure to assess interface hydrogen bond recovery, which is not assessed by the current CAPRI criteria. Finally, we find that surprisingly much can be learned from rather inaccurate models about binding hotspots, suggesting that the current status of peptide-protein docking methods, as reflected by the submitted CAPRI models, can already have a significant impact on our understanding of protein interactions. Proteins 2017; 85:445-462. (c) 2016 Wiley Periodicals, Inc. PMID- 28002625 TI - Is the reproducibility of shear wave elastography of thyroid nodules high enough for clinical use? A methodological study. AB - OBJECTIVE: To systematically assess the reproducibility of thyroid ultrasonographic shear wave elastography (SWE). CONTEXT: SWE has been suggested as a potential tool for thyroid nodule evaluation, but assessment of its reproducibility has been insufficiently addressed. DESIGN: SWE examinations were performed prospectively by two investigators. PATIENTS: Seventy-two patients (male/female: 19/53; mean age: 53 +/- 14 years; malignant/benign 17/55) undergoing thyroid surgery were enrolled in the study. MEASUREMENTS: Repeated and blinded measurements of elasticity index (EI) in predefined regions of interest (ROI) were collected. The inter- and intrarater agreement, along with the day-to day agreement, was evaluated in terms of the 95% limits of agreement (LOA). Results are presented as a ratio, by which 1.0 indicates perfect agreement. RESULTS: The interrater, intrarater and day-to-day LOA showed ratios between repeated measurements of 1.7-3.6, 1.8-3.7 and 2.2-2.9, respectively. These values reflect a low to moderate degree of agreement for all EI outcomes. The interrater LOA was higher for malignant nodules compared with benign nodules for six of seven EI outcomes (P < 0.001-0.03). The proportion of agreement calculated from the optimum cutoff point for differentiating malignant from benign nodules was 63 88% for the investigated EI outcomes. CONCLUSIONS: In this methodological study, EI measured by thyroid SWE seems suboptimal for clinical use, due to a low inter- and intrarater agreement. That EI varies from day to day furthermore jeopardizes the validity of the method. Although the proportion of agreement was acceptable for some EI parameters, it is questionable whether EI assessments can reliably differentiate malignant from benign nodules in the individual patient. PMID- 28002626 TI - Ectoderm-mesoderm crosstalk in the embryonic limb: The role of fibroblast growth factor signaling. AB - In this commentary we focus on the function of FGFs during limb development and morphogenesis. Our goal is to understand, interpret and, when possible, reconcile the interesting findings and conflicting results that remain unexplained. For example, the cell death pattern observed after surgical removal of the AER versus genetic removal of the AER-Fgfs is strikingly different and the field is at an impasse with regard to an explanation. We also discuss the idea that AER function may involve signaling components in addition to the AER-FGFs and that signaling from the non-AER ectoderm may also have a significant contribution. We hope that a re-evaluation of current studies and a discussion of outstanding questions will motivate new experiments, especially considering the availability of new technologies, that will fuel further progress toward understanding the intricate ectoderm-to-mesoderm crosstalk during limb development. Developmental Dynamics 246:208-216, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28002627 TI - High-resolution lipidomics coupled with rapid fixation reveals novel ischemia induced signaling in the rat neurolipidome. AB - The field of lipidomics has evolved vastly since its creation 15 years ago. Advancements in mass spectrometry have allowed for the identification of hundreds of intact lipids and lipid mediators. However, because of the release of fatty acids from the phospholipid membrane in the brain caused by ischemia, identifying the neurolipidome has been challenging. Microwave fixation has been shown to reduce the ischemia-induced release of several lipid mediators. Therefore, this study aimed to develop a method combining high-resolution tandem mass spectrometry (MS/MS), high-energy head-focused microwave fixation and statistical modeling, allowing for the measurement of intact lipids and lipid mediators in order to eliminate the ischemia-induced release of fatty acids and identify the rat neurolipidome. In this study, we demonstrated the ischemia-induced production of bioactive lipid mediators, and the reduction in variability using microwave fixation in combination with liquid chromatography (LC)-MS/MS. We have also illustrated for the first time that microwave fixation eliminates the alterations in intact lipid species following ischemia. While many phospholipid species were unchanged by ischemia, other intact lipid classes, such as diacylglycerol, were lower in concentration following microwave fixation compared to ischemia. PMID- 28002628 TI - Intramolecular anti-Phosphinoauration of Alkynes: An FLP-Motivated Approach to Stable Aurated Phosphindolium Complexes. AB - The synthesis of aurated phosphindolium complexes from easy accessible 1,5 alkynylphosphine derivatives has been studied by using gold(I) complexes featuring carbene and phosphine ligands as initiators. Upon formation of the mixed phosphine NHC/phosphine gold species, elevated temperatures induced the cyclization to give stable aurated phosphindolium salts, which is supported by DFT calculations. The key elementary step that comprises a yet unknown anti phosphinoauration of an unactivated alkyne is favored if bulky NHC ligands are used which was analyzed by kinetic measurements. This concept could furthermore be extended to neutral (phosphindolium)AuCl complexes featuring the yet unknown phosphindole ligand. PMID- 28002629 TI - Possible functions of CD169-positive sinus macrophages in lymph nodes in anti tumor immune responses. AB - The lymph node (LN) is an important immune system in which a number of antigen presenting cells are present that induce rapid immune responses to foreign antigens. While a great number of macrophages exist in lymph nodes, recent studies using animal models have shown that lymph node sinus macrophages are associated with the induction of anti-tumor immunity, playing a significant role in host immune responses against tumor cells. In colorectal tumor, malignant melanoma, and endometrial tumor, it was shown that a high density of CD169 positive macrophages in the LN sinus was a predictive factor for better clinical prognosis. The observations that the density of CD169-positive macrophages in the LN sinus was positively associated with the density of infiltrating T or NK cells in tumor tissues, indicates the significance of CD169-positive macrophages in anti-tumor immune reactions of tumor patients. Moreover, antigen delivery targeting LN macrophages is also considered to be promising approach for vaccination. In this article, we have summarized the significance of CD169 positive LN macrophages in anti-tumor immunity. PMID- 28002631 TI - Estreptococo del Grupo B. PMID- 28002630 TI - Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time dependent Changes in the Absence of Clinical Nephrotoxicity. AB - The success of cisplatin-containing regimens to treat solid tumors is limited, in part, by nephrotoxicity. In rodents, several urinary proteins have emerged that are sensitive indicators of cisplatin-induced kidney injury. We sought to characterize time-dependent changes in the urinary concentrations of 12 proteins, including kidney injury molecule-1 (KIM-1), calbindin, beta 2-microglobulin (beta2M), and trefoil factor 3 (TFF3) after cisplatin therapy. Urine was collected at baseline, 3 days (range, 2-5 days), and 10 days (range, 9-11 days) from 57 patients with solid tumors receiving outpatient cisplatin therapy (>=25 mg/m2 ). Serum creatinine was largely unchanged after cisplatin infusion. However, compared with baseline values, several novel biomarkers were significantly increased in the urine, including beta2M, which was threefold higher by day 3 (P < 0.0001). Urinary KIM-1 and TFF3 were elevated twofold by day 10 (P = 0.002 and P = 0.002, respectively), whereas calbindin levels were increased eightfold (P < 0.0001). We report novel time-dependent changes in the urinary excretion of noninvasive markers of subclinical kidney injury after cisplatin treatment. PMID- 28002632 TI - Hypoxia and hyperoxia differentially control proliferation of rat neural crest stem cells via distinct regulatory pathways of the HIF1alpha-CXCR4 and TP53-TPM1 proteins. AB - BACKGROUND: Neural crest stem cells (NCSCs) are a population of adult multipotent stem cells. We are interested in studying whether oxygen tensions affect the capability of NCSCs to self-renew and repair damaged tissues. NCSCs extracted from the hair follicle bulge region of the rat whisker pad were cultured in vitro under different oxygen tensions. RESULTS: We found significantly increased and decreased rates of cell proliferation in rat NCSCs (rNCSCs) cultured, respectively, at 0.5% and 80% oxygen levels. At 0.5% oxygen, the expression of both hypoxia-inducible factor (HIF) 1alpha and CXCR4 was greatly enhanced in the rNCSC nuclei and was suppressed by incubation with the CXCR4-specific antagonist AMD3100. In addition, the rate of cell apoptosis in the rNCSCs cultured at 80% oxygen was dramatically increased, associated with increased nuclear expression of TP53, decreased cytoplasmic expression of TPM1 (tropomyosin-1), and increased nuclear-to-cytoplasmic translocation of S100A2. Incubation of rNCSCs with the antioxidant N-acetylcysteine (NAC) overcame the inhibitory effect of 80% oxygen on proliferation and survival of rNCSCs. CONCLUSIONS: Our results show for the first time that extreme oxygen tensions directly control NCSC proliferation differentially via distinct regulatory pathways of proteins, with hypoxia via the HIF1alpha-CXCR4 pathway and hyperoxia via the TP53-TPM1 pathway. Developmental Dynamics 246:162-185, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28002633 TI - VTA DA neuron excitatory synapses in Shank3 Deltaex4-9 mouse line. AB - Several mutations within SHANK3 gene have been identified in Autism Spectrum Disorder patients and several studies have now started to show that those mutations could impact different brain circuits leading to the heterogeneity of the disease. Here we show that, compared to a mouse model lacking SHANK3 proline rich containing isoforms, in a mouse model lacking SHANK3 ANK(yrin)-domain containing isoforms, the excitatory synaptic transmission within the Ventral Tegmental Area is not affected. We discuss about the possibility that different domains of SHANK3 are involved in regulating the synapses in a circuit-specific manner resulting in different behavioral and synaptic phenotypes. PMID- 28002635 TI - Heparinase-modified thromboelastography in cats. AB - BACKGROUND: Evaluation of underlying hemostatic function is challenging when feline patients are receiving an anticoagulant medication. Discontinuing the anticoagulant to obtain accurate results for hemostatic testing may lead to thrombotic complications. The addition of heparinase to blood samples may mitigate the effects of exogenous heparin and allow hemostatic testing. METHODS: Tissue factor (TF)-activated thromboelastography (TEG) was performed using citrated whole blood from 19 cats. Assays were performed using citrated whole blood, with and without addition of unfractionated heparin to a concentration of 0.2 U/mL. For each blood sample, TEG assays were performed using a standard cup and a heparinase-coated cup. KEY FINDINGS: For TEG variables R, k, alpha-angle, and MA, mean values were not statistically different when citrated blood was used with standard or heparinase-coated cups. Heparinized blood assayed in standard cups displayed a significantly increased R and k, and significantly decreased alpha-angle and MA when compared to heparinized blood assayed in heparinase coated cups. TEG variables for heparinized blood assayed in heparinase cups was not statistically different from those of the citrated whole blood without added heparin. SIGNIFICANCE: Heparinase modified, TF-activated, TEG reverses heparin effects in feline-citrated blood. PMID- 28002634 TI - FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory. AB - FK506 binding protein 51 (FKBP5) is a co-chaperone of heat shock protein 90 and significantly influences glucocorticoid receptor sensitivity. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene are associated with altered hypothalamus pituitary-adrenal (HPA) axis function, changes in the structure and function of several cognitive brain areas, and increased susceptibility to post-traumatic stress disorder, major depression, bipolar disorder and suicidal events. The mechanisms underlying these associations are largely unknown, but it has been speculated that the influence of these SNPs on emotional memory systems may play a role. In the present study, 112 participants were exposed to the socially evaluated cold pressor test (stress) or control (no stress) conditions immediately prior to learning a list of 42 words. Participant memory was assessed immediately after learning (free recall) and 24 h later (free recall and recognition). Participants provided a saliva sample that enabled the genotyping of three FKBP5 polymorphisms: rs1360780, rs3800373 and rs9296158. Results showed that stress impaired immediate recall in risk allele carriers. More importantly, stress enhanced long-term recall and recognition memory in non-carriers of the risk alleles, effects that were completely absent in risk allele carriers. Follow up analyses revealed that memory performance was correlated with salivary cortisol levels in non-carriers, but not in carriers. These findings suggest that FKBP5 risk allele carriers may possess a sensitized stress response system, perhaps specifically for stress-induced changes in corticosteroid levels, which might aid our understanding of how SNPs in the FKBP5 gene confer increased risk for stress-related psychological disorders and their related phenotypes. PMID- 28002636 TI - Caregiver-mediated exercises for improving outcomes after stroke. AB - BACKGROUND: Stroke is a major cause of long-term disability in adults. Several systematic reviews have shown that a higher intensity of training can lead to better functional outcomes after stroke. Currently, the resources in inpatient settings are not always sufficient and innovative methods are necessary to meet these recommendations without increasing healthcare costs. A resource efficient method to augment intensity of training could be to involve caregivers in exercise training. A caregiver-mediated exercise programme has the potential to improve outcomes in terms of body function, activities, and participation in people with stroke. In addition, caregivers are more actively involved in the rehabilitation process, which may increase feelings of empowerment with reduced levels of caregiver burden and could facilitate the transition from rehabilitation facility (in hospital, rehabilitation centre, or nursing home) to home setting. As a consequence, length of stay might be reduced and early supported discharge could be enhanced. OBJECTIVES: To determine if caregiver mediated exercises (CME) improve functional ability and health-related quality of life in people with stroke, and to determine the effect on caregiver burden. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (October 2015), CENTRAL (the Cochrane Library, 2015, Issue 10), MEDLINE (1946 to October 2015), Embase (1980 to December 2015), CINAHL (1982 to December 2015), SPORTDiscus (1985 to December 2015), three additional databases (two in October 2015, one in December 2015), and six additional trial registers (October 2015). We also screened reference lists of relevant publications and contacted authors in the field. SELECTION CRITERIA: Randomised controlled trials comparing CME to usual care, no intervention, or another intervention as long as it was not caregiver-mediated, aimed at improving motor function in people who have had a stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials. One review author extracted data, and assessed quality and risk of bias, and a second review author cross-checked these data and assessed quality. We determined the quality of the evidence using GRADE. The small number of included studies limited the pre-planned analyses. MAIN RESULTS: We included nine trials about CME, of which six trials with 333 patient-caregiver couples were included in the meta-analysis. The small number of studies, participants, and a variety of outcome measures rendered summarising and combining of data in meta-analysis difficult. In addition, in some studies, CME was the only intervention (CME core), whereas in other studies, caregivers provided another, existing intervention, such as constraint-induced movement therapy. For trials in the latter category, it was difficult to separate the effects of CME from the effects of the other intervention.We found no significant effect of CME on basic ADL when pooling all trial data post intervention (4 studies; standardised mean difference (SMD) 0.21, 95% confidence interval (CI) -0.02 to 0.44; P = 0.07; moderate quality evidence) or at follow-up (2 studies; mean difference (MD) 2.69, 95% CI 8.18 to 13.55; P = 0.63; low-quality evidence). In addition, we found no significant effects of CME on extended ADL at post intervention (two studies; SMD 0.07, 95% CI -0.21 to 0.35; P = 0.64; low-quality evidence) or at follow-up (2 studies; SMD 0.11, 95% CI -0.17 to 0.39; P = 0.45; low-quality evidence).Caregiver burden did not increase at the end of the intervention (2 studies; SMD -0.04, 95% CI -0.45 to 0.37; P = 0.86; moderate-quality evidence) or at follow-up (1 study; MD 0.60, 95% CI -0.71 to 1.91; P = 0.37; very low-quality evidence).At the end of intervention, CME significantly improved the secondary outcomes of standing balance (3 studies; SMD 0.53, 95% CI 0.19 to 0.87; P = 0.002; low-quality evidence) and quality of life (1 study; physical functioning: MD 12.40, 95% CI 1.67 to 23.13; P = 0.02; mobility: MD 18.20, 95% CI 7.54 to 28.86; P = 0.0008; general recovery: MD 15.10, 95% CI 8.44 to 21.76; P < 0.00001; very low-quality evidence). At follow-up, we found a significant effect in favour of CME for Six-Minute Walking Test distance (1 study; MD 109.50 m, 95% CI 17.12 to 201.88; P = 0.02; very low-quality evidence). We also found a significant effect in favour of the control group at the end of intervention, regarding performance time on the Wolf Motor Function test (2 studies; MD -1.72, 95% CI 2.23 to -1.21; P < 0.00001; low-quality evidence). We found no significant effects for the other secondary outcomes (i.e. PATIENT: motor impairment, upper limb function, mood, fatigue, length of stay and adverse events; caregiver: mood and quality of life).In contrast to the primary analysis, sensitivity analysis of CME-core showed a significant effect of CME on basic ADL post intervention (2 studies; MD 9.45, 95% CI 2.11 to 16.78; P = 0.01; moderate-quality evidence).The methodological quality of the included trials and variability in interventions (e.g. content, timing, and duration), affected the validity and generalisability of these observed results. AUTHORS' CONCLUSIONS: There is very low- to moderate quality evidence that CME may be a valuable intervention to augment the pallet of therapeutic options for stroke rehabilitation. Included studies were small, heterogeneous, and some trials had an unclear or high risk of bias. Future high quality research should determine whether CME interventions are (cost-)effective. PMID- 28002637 TI - Interactions Between Therapeutic Proteins and Small Molecules: The Shared Role of Perpetrators and Victims. AB - Therapeutic proteins (TPs) are becoming increasingly important as therapeutic agents. A consequence of expanding their clinical indications is coadministration with well-established small-molecule drugs (sMDs), which could lead to unpredictable effects. According to the existing regulatory guidance, the development of an sMD includes the evaluation of potential drug-drug interactions (DDIs). For TPs, only a few drug interaction studies have been published. Limited clinically relevant models, long half-lives, and complex elimination pathways are among the associated difficulties. PMID- 28002638 TI - Drug-induced ototoxicity: Mechanisms, Pharmacogenetics, and protective strategies. AB - Drug ototoxicity limits the quality of life of patients after treatment, having serious consequences, especially for psychosocial development of children. Although the ototoxicity of many drugs resolves after treatment discontinuation, the use of platinum derivatives and aminoglycosides is associated with permanent hearing loss. In this review, we have listed ototoxic drugs and the mechanisms by which they damage the ears. Moreover, possible protective strategies and important methods for early detection of ototoxic effects are discussed. PMID- 28002639 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron. PMID- 28002640 TI - Activation of galanin and cholecystokinin receptors in the lumbosacral spinal cord is required for ejaculation in male rats. AB - The spinal ejaculation generator is comprised of lumbar spinothalamic (LSt) cells and their axonal projections to autonomic and motor neurons in the lumbosacral spinal cord. LSt cells regulate ejaculatory reflexes by release of neuropeptides that are co-expressed in their axons, as previously demonstrated for gastrin releasing peptide and enkephalin. Here, the role of two other neuropeptides co expressed in LSt cells for ejaculatory reflexes is demonstrated: galanin and cholecystokinin (CCK). Adult male rats were anesthetized, spinalized, and received intrathecal infusions of galanin receptor antagonist Galantide (1 or 10 nmol) or CCK receptor antagonist proglumide (71 or 714 nmol). The dorsal penile nerve (DPN) was electrically stimulated to trigger ejaculatory reflexes and seminal vesicle pressure (SVP) and rhythmic contractions of the bulbocavernosus muscle (BCM) were analyzed as parameters of emission and expulsion respectively. Treatment with galanin or CCK antagonists significantly reduced SVP increases and BCM bursting, demonstrating that galanin and CCK are required for ejaculation. Next, anesthetized, spinalized males received intrathecal infusions of galanin (0.15 or 0.3 nmol) or CCK(26-33) (4.35 nmol) and effects on subthreshold DPN stimulations were determined. Intrathecal infusions of galanin or CCK facilitated ejaculatory reflexes induced by subthreshold DPN stimulation in all animals, but did not trigger ejaculatory reflexes in the absence of DPN stimulation. Together, these results demonstrate that galanin and CCK both act in the spinal ejaculation generator to regulate ejaculation. However, effects of galanin and CCK were dependent on DPN stimulation, suggesting that these neuropeptides may act in concert with other LSt co-expressed neuropeptides. PMID- 28002641 TI - Nestin phosphorylation at threonines 315 and 1299 correlates with proliferation and metastasis of human pancreatic cancer. AB - The neuroepithelial stem cell marker nestin is a cytoskeletal protein that regulates cell proliferation, invasion, and stemness in various tumors, including pancreatic tumors. In the present study, we examined the expression and roles of phosphorylated nestin in pancreatic cancer cells. Nestin phosphorylation at threonines 315 (Thr315) and 1299 (Thr1299) was observed during mitosis in human pancreatic cancer cells. Nestin phosphorylation was positively correlated with a cell proliferation marker, MIB-1 expression in human pancreatic cancer samples. Transfection of MIA PaCa-2 cells with nestin mutated at Thr315 and/or Thr1299 (to suppress phosphorylation) resulted in lower proliferation rates than those in control groups. Transfecting MIA PaCa-2 cells with wild-type nestin or with nestin mutated at Thr315 increased migration and invasion. In contrast, transfection with nestin mutated at both phosphorylation sites (Thr315 and Thr1299) did not enhance cell migration or invasion. In an intra-splenic xenograft experiment using MIA PaCa-2 cells, tumors expressing the nestin double mutant formed fewer liver metastases than tumors expressing wild-type nestin. Nestin phosphorylation at these two sites was decreased upon treatment with inhibitors for cyclin dependent kinases, AKT, and Aurora in PANC-1 cells, which express a high baseline level of phosphorylated nestin. These findings suggest that phosphorylation of nestin at Thr315 and/or Thr1299 affects cell proliferation, and inhibition of both phosphorylation sites suppresses invasion and metastasis of human pancreatic cancer. Inhibiting nestin phosphorylation at these two sites may represent a novel therapeutic strategy for pancreatic cancer. PMID- 28002642 TI - Modification of Obstetric Emergency Simulation Scenarios for Realism in a Home Birth Setting. AB - INTRODUCTION: Clinical competency and clear communication are essential for intrapartum care providers who encounter high-stakes, low-frequency emergencies. The challenge for these providers is to maintain infrequently used skills. The challenge is even more significant for midwives who manage births at home and who, due to low practice volume and low-risk clientele, may rarely encounter an emergency. In addition, access to team simulation may be limited for home-birth midwives. This project modified existing validated obstetric simulation scenarios for a home-birth setting. METHODS: Twelve certified professional midwives (CPMs) in active home-birth practice participated in shoulder dystocia and postpartum hemorrhage simulations. The simulations were staged to resemble home-birth settings, supplies, and personnel. Fidelity (realism) of the simulations was assessed with the Simulation Design Scale, and satisfaction and self-confidence were assessed with the Student Satisfaction and Self-Confidence in Learning Scale. Both utilized a 5-point Likert scale, with higher scores suggesting greater levels of fidelity, participant satisfaction, and self-confidence. RESULTS: Simulation Design Scale scores indicated participants agreed fidelity was achieved for the home-birth setting, while scores on the Student Satisfaction and Self-Confidence in Learning indicated high levels of participant satisfaction and self-confidence. DISCUSSION: If offered without modification, simulation scenarios designed for use in hospitals may lose fidelity for home-birth midwives, particularly in the environmental and psychological components. Simulation is standard of care in most settings, an excellent vehicle for maintaining skills, and some evidence suggests it results in improved perinatal outcomes. Additional study is needed in this area to support home-birth providers in maintaining skills. This pilot study suggests that simulation scenarios intended for hospital use can be successfully adapted to the home-birth setting. PMID- 28002643 TI - Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma. AB - Heterogeneity of BRAF mutation in melanoma has been a controversial subject. Quantitative data on BRAF allele frequency (AF) are sparse, and the potential relationship with response to BRAF inhibitors (BRAFi) in patients with metastatic melanoma is unknown. We quantitatively measured BRAF AF in a cohort of treatment naive metastatic melanoma samples by pyrosequencing and correlated with survival data in patients treated with BRAFi as part of their clinical care. Fifty-two samples from 50 patients were analysed. BRAF V600E mutations were detected in 71.1% of samples followed by V600K (25%) and V600R (3.9%). There was a wide range of AF from 3.9% to 80.3% (median 41.3%). In 33 patients treated with BRAFi, there was no difference in overall or progression-free survival when the patients were categorized into high or low AF groups. There was no correlation between AF and degree of response, and no difference in survival based on genotype. PMID- 28002644 TI - A novel phased-concept course for the delivery of anatomy and orthopedics training in medical education. AB - Integration of anatomy and clinical teaching is a theoretical ideal, yet there is a worldwide paucity of such amalgamation. These teaching models provide support for medical trainees, an important element in Germany where orthopedic intern numbers have declined and anecdotal evidence suggests disinterest in orthopedics. The aim of the study was to develop an integrated anatomy-surgical course for undergraduate medical training, assess the model developed, and explore how medical students perceive orthopedics as a career. The course was to deliver medical anatomy and clinical orthopedic training, focusing on interdisciplinary teaching and learning, vertical integration of clinical knowledge and skills, and professional interaction. Survey evaluation of the course and students' perceptions of orthopedic careers was performed, including Likert-type responses rating variables of interest. A phased-concept program of five courses, each optional and under one-week in duration, was developed parallel to the undergraduate medical program. Delivered by anatomists and surgeons, courses included biomechanics, advanced dissection, surgical approaches, casts and implants, and sports medicine. Course data indicate positive support for course format, stimulation of interest, and high clinical relevance. Students are generally interested in surgery, and identify hierarchy, lawsuits, bureaucracy and physical stress as barriers to orthopedic careers. This novel phased-concept successfully delivers combined anatomy and surgery training in a vertically integrated format while addressing students' clinical and professional skills. The format facilitates an appreciation of potential career options in orthopedics, while fostering professional skills during medical training. Barriers to careers in orthopedics can now be addressed in future courses. Anat Sci Educ 10: 372-382. (c) 2016 American Association of Anatomists. PMID- 28002645 TI - Biologically Active Heterocyclic Hybrids Based on Quinazolinone, Benzofuran and Imidazolium Moieties: Synthesis, Characterization, Cytotoxic and Antibacterial Evaluation. AB - Cytotoxic and antimicrobial agents structurally based on quinazolinone, benzofuran and imidazole pharmacophores, have been designed and synthesized. Spectral (IR, 1 H-NMR) and elemental analysis data established the structures of these novel 3-[1-(1-benzofuran-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)ethyl]-1-methyl 1H-imidazol-3-ium chloride hybrid derivatives. All the synthesized compounds were evaluated for in vitro cytotoxicity and antimicrobial activities. Cytotoxic evaluation using MTT assay revealed that compounds 12c, 12g and 12i exhibited significant cytotoxicity with IC50 values 1, 1, and 0.57 MUm on this cell line, respectively. Biological activity of the synthesized compounds as antibacterial agent were also evaluated against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungi (Candida albicans) strains. All compounds 12a - 12i showed slightly higher activity against Gram-positive bacteria than the Gram-negative one. Among the nine new compounds screened, 3-[1-(5-bromo-1-benzofuran-2-yl)-2-(6-chloro-4 oxoquinazolin-3(4H)-yl)ethyl]-1-methyl-1H-imidazol-3-ium chloride (12e) has pronounced higher antimicrobial activity against all tested strains. These results demonstrated potential importance of molecular hybridization in the development of new lead molecules with major cytotoxicity and antimicrobial activity. PMID- 28002646 TI - Elevated bile amylase level without pancreaticobiliary maljunction is a risk factor for gallbladder carcinoma. AB - BACKGROUND: Elevated bile amylase level in patients with pancreaticobiliary maljunction (PBM) or high confluence of pancreaticobiliary ducts (HCPBD) is well known as a risk factor for gallbladder carcinoma (GBC) development. However, the effects of occult pancreaticobiliary reflux (OPR), a condition characterized by high bile amylase level in the presence of an anatomically normal pancreaticobiliary junction, on GBC development remain unclear. The aim of this study was to assess the relationship between OPR and GBC. METHODS: Clinicopathological data of 52 patients who were preoperatively diagnosed with gallbladder (GB) tumor (22 malignant, 30 benign) were retrospectively reviewed. All of the patients underwent preoperative endoscopic retrograde cholangiopancreatography to evaluate pancreaticobiliary junction morphology and bile amylase level. The relationship between the histological diagnosis of GB lesions, and pancreaticobiliary junction morphology and bile amylase level were investigated. RESULTS: Pancreaticobiliary maljunction, HCPBD, and normal pancreaticobiliary junction (NPJ) were identified in 12, nine, and 31 patients, respectively. The rates of GBC in patients with PBM, HCPBD, and NPJ were 58% (7/12), 67% (6/9), and 29% (9/31), respectively. Of the 31 patients with NPJ, 22 had OPR and nine of these had GBC. None of the patients with NPJ and normal bile amylase level had GBC. Additionally, among patients with NPJ, bile amylase level was significantly higher in patients with GBC than in patients with benign tumors. CONCLUSIONS: Occult pancreaticobiliary reflux, like PBM and HCPBD, is a risk factor for GBC development. PMID- 28002647 TI - IL-7 and procalcitonin are useful biomarkers in the comprehensive evaluation of the severity of acute cholangitis. AB - BACKGROUND: The incidence of biliary tract infection (BTI), especially healthcare associated cholangitis, is increasing. However, there are few reports concerning biomarkers of acute cholangitis. We therefore performed an exhaustive investigation of several biomarkers. METHODS: We retrospectively measured 11 cytokines, six chemokines and procalcitonin (PCT), and endotoxin activity assay (EAA) values (IRB: 110512019) of 61 samples with acute cholangitis. RESULT: The 28-day mortality rate was 9.8%. The levels of most cytokines and chemokines were significantly correlated with each other. A low IL-7 level was found to predict blood culture positivity. Low IL-7 level was also found to predict disseminated intravascular coagulation. Low IL-7 levels and a high PCT level were found to be predictors of severe cholangitis. The 28-day mortality in the group of patients with an IL-7 level of <=6.0 and a PCT level of >0.5 was 18.2%. It was significantly higher than in the other group. CONCLUSION: The combined use of IL 7 and PCT may be useful for evaluating severe acute cholangitis; these results may suggest that severe acute cholangitis is affected by immunosuppressive changes. PMID- 28002648 TI - Association between TCF7L2 polymorphisms and gestational diabetes mellitus: A meta-analysis. AB - AIMS/INTRODUCTION: Studies have been carried out to evaluate the correlation between TCF7L2 genetic polymorphisms and gestational diabetes mellitus (GDM) risk. However, the conclusions from these studies are incomplete, because partial single nucleotide polymorphisms (SNPs) were analyzed. We carried out a meta analysis aimed to systematically evaluate TCF7L2 gene polymorphisms and GDM susceptibility in all population and racial/ethnic subgroups to afford a foundation for future research. MATERIALS AND METHODS: Published studies censoring TCF7L2 variants and GDM risk were captured from the EMBASE, PubMed, CNKI and Wanfang databases. The meta-analysis was processed using software of RevMan 5.2 and Stata13. The relationship between TCF7L2 polymorphism and GDM occurrence was evaluated by pooled odds ratios. Stratified analysis based on race/ethnicity was also carried out. The allele-specific odds ratios and 95% confidence intervals were counted, and based on homogeneity evaluated using the I2 -test, fixed- or random-effects pooled measures were selected. RESULTS: A total of 22 studies were covered, capturing eight TCF7L2 SNPs and involving 5,573 cases and 13,266 controls. Six of eight SNPs showed significant relationships with GDM occurrence, of which the SNPs rs7903146, rs12255372 and rs7901695 were the most powerful. Stratified analysis by race/ethnicity showed discrepant results in these three SNPs. In Caucasians and other races, all these SNPs were found to have a significant association with GDM risk, but in Asians, only SNP rs7903146 showed a significant association. CONCLUSIONS: Six of eight SNPs were found to have significant associations between TCF7L2 variants and GDM risk in the overall population, with the most powerful in SNPs being rs7903146, rs12255372 and rs7901695, but the contribution of these SNPs to GDM risk were variable among different racial/ethnic groups. PMID- 28002649 TI - Toward modeling locomotion using electromyography-informed 3D models: application to cerebral palsy. AB - This position paper proposes a modeling pipeline to develop clinically relevant neuromusculoskeletal models to understand and treat complex neurological disorders. Although applicable to a variety of neurological conditions, we provide direct pipeline applicative examples in the context of cerebral palsy (CP). This paper highlights technologies in: (1) patient-specific segmental rigid body models developed from magnetic resonance imaging for use in inverse kinematics and inverse dynamics pipelines; (2) efficient population-based approaches to derive skeletal models and muscle origins/insertions that are useful for population statistics and consistent creation of continuum models; (3) continuum muscle descriptions to account for complex muscle architecture including spatially varying material properties with muscle wrapping; (4) muscle and tendon properties specific to CP; and (5) neural-based electromyography informed methods for muscle force prediction. This represents a novel modeling pipeline that couples for the first time electromyography extracted features of disrupted neuromuscular behavior with advanced numerical methods for modeling CP specific musculoskeletal morphology and function. The translation of such pipeline to the clinical level will provide a new class of biomarkers that objectively describe the neuromusculoskeletal determinants of pathological locomotion and complement current clinical assessment techniques, which often rely on subjective judgment. WIREs Syst Biol Med 2017, 9:e1368. doi: 10.1002/wsbm.1368 For further resources related to this article, please visit the WIREs website. PMID- 28002650 TI - Discovery of short linear motif-mediated interactions through phage display of intrinsically disordered regions of the human proteome. AB - The intrinsically disordered regions of eukaryotic proteomes are enriched in short linear motifs (SLiMs), which are of crucial relevance for cellular signaling and protein regulation; many mediate interactions by providing binding sites for peptide-binding domains. The vast majority of SLiMs remain to be discovered highlighting the need for experimental methods for their large-scale identification. We present a novel proteomic peptide phage display (ProP-PD) library that displays peptides representing the disordered regions of the human proteome, allowing direct large-scale interrogation of most potential binding SLiMs in the proteome. The performance of the ProP-PD library was validated through selections against SLiM-binding bait domains with distinct folds and binding preferences. The vast majority of identified binding peptides contained sequences that matched the known SLiM-binding specificities of the bait proteins. For SHANK1 PDZ, we establish a novel consensus TxF motif for its non-C-terminal ligands. The binding peptides mostly represented novel target proteins, however, several previously validated protein-protein interactions (PPIs) were also discovered. We determined the affinities between the VHS domain of GGA1 and three identified ligands to 40-130 MUm through isothermal titration calorimetry, and confirmed interactions through coimmunoprecipitation using full-length proteins. Taken together, we outline a general pipeline for the design and construction of ProP-PD libraries and the analysis of ProP-PD-derived, SLiM-based PPIs. We demonstrated the methods potential to identify low affinity motif-mediated interactions for modular domains with distinct binding preferences. The approach is a highly useful complement to the current toolbox of methods for PPI discovery. PMID- 28002651 TI - A Test of the ARCC(c) Model Improves Implementation of Evidence-Based Practice, Healthcare Culture, and Patient Outcomes. AB - BACKGROUND: Although several models of evidence-based practice (EBP) exist, there is a paucity of studies that have been conducted to evaluate their implementation in healthcare settings. AIM: The purpose of this study was to examine the impact of the Advancing Research and Clinical practice through close Collaboration (ARCC) Model on organizational culture, clinicians' EBP beliefs and EBP implementation, and patient outcomes at one healthcare system in the western United States. DESIGN: A pre-test, post-test longitudinal pre-experimental study was conducted with follow-up immediately following full implementation of the ARCC Model. SETTING AND SAMPLE: The study was conducted at a 341-bed acute care hospital in the western region of the United States. The sample consisted of 58 interprofessional healthcare professionals. METHODS: The ARCC Model was implemented in a sequential format over 12 months with the key strategy of preparing a critical mass of EBP mentors for the healthcare system. Healthcare professionals' EBP beliefs, EBP implementation, and organizational culture were measured with valid and reliable instruments. Patient outcomes were collected in aggregate from the hospital's medical records. RESULTS: Findings indicated significant increases in clinicians' EBP beliefs and EBP implementation along with positive movement toward an organizational EBP culture. Study findings also indicated substantial improvements in several patient outcomes. LINKING EVIDENCE TO ACTION: Implementation of the ARCC Model in healthcare systems can enhance clinicians' beliefs and implementation of evidence-based care, improve patient outcomes, and move organizational culture toward EBP. PMID- 28002653 TI - Differences in the expression of cell cycle genes in osteoblasts and endothelial cells cultured on the surfaces of Ti6Al4V and Ti6Al7Nb alloys. AB - Three medically used alloys (Ti6Al4V, Ti6Al7Nb, and AISI 316 L) are compared due to proliferative potential and metabolic response of human cells (osteoblasts line Saos-2 and endothelial cells line EA.hy-926) seeded on the surfaces of these alloys. Although no statistically significant difference in the proliferative potential of the cells cultured on the surfaces of examined biomaterials was observed, it does not exclude relevant differences in metabolic response of these cells assessed as changes in genes' expression. As a result of our studies it was demonstrated that the changes in the expression of examined genes were very common. Our observation suggests the presence of the process of selective recognition of the contacted biomaterials by the cells seeded on their surfaces. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1607-1617, 2017. PMID- 28002654 TI - Nurses' Evidence-Based Practice Beliefs and the Role of Evidence-Based Practice Mentors at University Hospitals in Finland. AB - BACKGROUND: Although systematic implementation of evidence-based practice (EBP) is essential to effectively improve patient outcomes, quality, and value of care, nurses do not consistently use evidence in practice. Uptake is hampered by lack of nurses' readiness for EBP, including nurses' EBP beliefs and lack of EBP mentors. Favorable EBP beliefs are foundational to Registered Nurses' (RNs) use and integration of best evidence into clinical decision making, whereas EBP mentors are in a key role for strengthening RNs' beliefs in the value of EBP and confidence in their ability to implement EBP. Although nurses' EBP beliefs and role of BP mentors have been widely studied in countries leading the EBP movement, less is known about them in the non-English-speaking world. AIMS: To determine RNs EBP beliefs and the role of EBP mentors at Finnish university hospitals and to explore the associations between RNs' EBP beliefs and sociodemographic factors. METHODS: A cross-sectional descriptive survey was conducted in November-December 2014 at every university hospital in Finland with a convenience sample (n = 943) of practicing RNs. The data were collected via an electronic survey, and analyzed using descriptive and inferential statistics. RESULTS: RNs reported low levels of EBP beliefs in the degree to which they believed that clinical nursing practice and their own practice were based on evidence. EBP mentors worked in many professional nursing roles. Several significant differences were found between RN's EBP beliefs and sociodemographic variables. LINKING EVIDENCE TO ACTION: Although RNs were familiar with and believed in the value of EBP in improving care quality and patient outcomes, their ratings were low about the degree to which they believed that clinical nursing practice and their own practice were based on evidence, indicating a modest level of individual EBP readiness among Finnish RNs required for integrating best evidence into clinical care delivery. PMID- 28002652 TI - Biomimetic calcium phosphate/polyelectrolyte multilayer coatings for sequential delivery of multiple biological factors. AB - Combinations of growth factors synergistically enhance tissue regeneration, but typically require sequential, rather than co-delivery from biomaterials for maximum efficacy. Polyelectrolyte multilayer (PEM) coatings can deliver multiple factors without loss of activity; however, sequential delivery from PEM has been limited due to interlayer diffusion that results in co-delivery of the factors. This study shows that addition of a biomimetic calcium phosphate (bCaP) barrier layer to a PEM coating effectively prevents interlayer diffusion and enables sequential delivery of two different biomolecules via direct cell access. A simulated body fluid method was used to deposit a layer of bCaP followed by 30 bilayers of PEM made with poly-l-Lysine (+) and poly l-Glutamic acid (-) (bCaP PEM). Measurements of MC3T3-E1 proliferation and viability over time on bCaP-PEM were used to demonstrate the sequential delivery kinetics of a proliferative factor [fibroblast growth factor-2 (FGF-2)] followed by a cytotoxic factor (antimycin A, AntiA). FGF-2 and AntiA both retained their bioactivity within bCaP PEM, yet no release of FGF-2 or AntiA from bCaP-PEM was observed when cells were absent indicating a cell-mediated, local delivery process. This coating technique is useful for a variety of applications that would benefit from highly localized, sequential delivery of multiple biomolecules governed by cell initiated degradation that avoids off-target effects associated with diffusion-based release. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1500 1509, 2017. PMID- 28002656 TI - Cytometry Advancement: A Perspective from China:. PMID- 28002655 TI - Optimal dosage regimen for rituximab in ABO-incompatible living donor liver transplantation. AB - BACKGROUND: Rituximab has greatly improved the outcomes of ABO-incompatible living donor liver transplantation (ABO-I LDLT). To clarify the optimal regimen for rituximab in adult ABO-I LDLT, a multicenter study was conducted in Japan. METHODS: Clinical data of 33 adult patients undergoing ABO-I LDLT at 15 centers in 2013 were retrospectively corrected. RESULTS: The targeted blood type was A1 in 18, B in 14, and AB in one patient. Rituximab was administered at 7 to 48 days before LT, at a dose of 375 mg/m2 in 12 patients, 500 mg in 15 patients, 300 mg in five patients, and 100 mg in one patient. Adverse effects of rituximab were tolerable. Overall 1-year patient survival was 81%; antibody-mediated rejection (AMR) occurred in three patients (9%), two of whom died. Rituximab dose was significantly lower in patients with AMR (P < 0.001, 137 +/- 61 vs. 307 +/- 66 mg/m2 ). Among rituximab dose (n = 28), local infusion (n = 11), splenectomy (n = 23), prophylactic intravenous immunoglobulins (n = 12), preoperative tacrolimus (n = 9), preoperative antimetabolites (n = 21), and plasmapheresis (n = 23), only rituximab dose was a significantly favorable factor for AMR (P < 0.001). CONCLUSION: The use of rituximab at sufficient doses is recommended in adult ABO I LDLT. PMID- 28002657 TI - Sometimes simpler is better: VLog, a general but easy-to-implement log-like transform for cytometry. AB - The fundamental purpose of log and log-like transforms for cytometry is to make measured population variabilities as uniform as possible. The long-standing success of the log transform was its ability to stabilize linearly increasing gain-dependent uncertainties and the success of the log-like transforms is that they extend this notion to include zero and negative measurement values. This study derives and examines a transform called VLog that stabilizes the three general sources of variability: (1) gain-dependent variability, (2) photo electron counting error, and (3) signal-independent sources of error. Somewhat surprisingly, this transform has a closed-form solution and therefore is relatively simple to implement. By including some quantitation elements in its formulation, the shape-dependent arguments, alpha and beta, usually do not require optimization for different datasets. The simplicity and generality of the transform may make it a useful tool for cytometry and possibly other technologies. (c) 2016 International Society for Advancement of Cytometry. PMID- 28002658 TI - Tramadol-Induced Hypomania and Serotonin Syndrome. PMID- 28002659 TI - Trait-Related Cortical-Subcortical Dissociation in Bipolar Disorder: Analysis of Network Degree Centrality. AB - BACKGROUND: Bipolar disorder is a systemic brain disorder. Accumulated evidence suggested that cortical-subcortical imbalance could be a trait-related pathogenic factor of bipolar disorder. Degree centrality, a robust index of focal connectivity in which the number of direct connections from one node to all nodes is counted, has not previously been studied in bipolar disorder as a whole. METHODS: Resting state functional magnetic resonance imaging was performed on 52 patients with DSM-IV bipolar I disorder and 70 healthy controls recruited between September 2009 and July 2014. Degree centrality was calculated within cerebral gray matter for each subject and compared between patients with bipolar disorder and healthy controls. Hub distributions of both groups were explored. Effects of medication exposure and mood state on degree centrality, as well as cortical subcortical degree centrality correlations, were explored. RESULTS: Compared to healthy controls, patients with bipolar disorder exhibited significant decrease in degree centrality in cortical regions, including the middle temporal pole, inferior temporal gyrus, and ventral prefrontal cortex, but showed significant increase in degree centrality mainly in subcortical regions, including caudate, thalamus, parahippocampal gyrus, hippocampi, anterior cingulate, insula, and amygdala, and a small portion of cortical regions, such as superior and middle frontal gyrus (P < .05, corrected). Spatial distributions of the 2 groups were very similar. No significant effects of medication exposure or mood state on degree centrality were found. Patients with bipolar disorder also showed significant decrease in cortical-subcortical degree centrality correlation (P = .003). CONCLUSIONS: These findings further contribute to the mounting evidence of cortical-subcortical dissociation in bipolar disorder pathophysiology. In addition, this study supports the continued development and implementation of graph-based techniques to enhance our understanding of the underlying neural mechanisms in mental disorders such as bipolar disorder, which are increasingly viewed as systemic brain disorders rather than disorders arising from disruption within a single structure or a limited number of structures. Due to the heterogeneity of our sample, as well as the small sample size of each medication and mood state subgroups, further investigation is needed to support our findings. PMID- 28002660 TI - Recovery From Anorexia Nervosa and Bulimia Nervosa at 22-Year Follow-Up. AB - OBJECTIVE: The course of eating disorders is often protracted, with fewer than half of adults achieving recovery from anorexia nervosa or bulimia nervosa. Some argue for palliative management when duration exceeds a decade, yet outcomes beyond 20 years are rarely described. This study investigates early and long-term recovery in the Massachusetts General Hospital Longitudinal Study of Anorexia and Bulimia Nervosa. METHODS: Females with DSM-III-R/DSM-IV anorexia nervosa or bulimia nervosa were assessed at 9 and at 20 to 25 years of follow-up (mean [SD] = 22.10 [1.10] years; study initiated in 1987, last follow-up conducted in 2013) via structured clinical interview (Longitudinal Interval Follow-Up Evaluation of Eating Disorders [LIFE-EAT-II]). Seventy-seven percent of the original cohort was re-interviewed, and multiple imputation was used to include all surviving participants from the original cohort (N = 228). Kaplan-Meier curves estimated recovery by 9-year follow-up, and McNemar test examined concordance between recovery at 9-year and 22-year follow-up. RESULTS: At 22-year follow-up, 62.8% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa recovered, compared to 31.4% of participants with anorexia nervosa and 68.2% of participants with bulimia nervosa by 9-year follow-up. Approximately half of those with anorexia nervosa who had not recovered by 9 years progressed to recovery at 22 years. Early recovery was associated with increased likelihood of long-term recovery in anorexia nervosa (odds ratio [OR] = 10.5; 95% CI, 3.77 29.28; McNemar chi21 = 31.39; P < .01) but not in bulimia nervosa (OR = 1.0; 95% CI, 0.49-2.05; McNemar chi21 = 0; P = 1.0). CONCLUSION: At 22 years, approximately two-thirds of females with anorexia nervosa and bulimia nervosa were recovered. Recovery from bulimia nervosa happened earlier, but recovery from anorexia nervosa continued over the long term, arguing against the implementation of palliative care for most individuals with eating disorders. PMID- 28002661 TI - Potential Applications of the National Institute of Mental Health's Research Domain Criteria (RDoC) to Clinical Psychiatric Practice: How RDoC Might Be Used in Assessment, Diagnostic Processes, Case Formulation, Treatment Planning, and Clinical Notes. AB - Offering a new framework for understanding and studying basic dimensions of normal and abnormal human functioning and mental disorders, the National Institute of Mental Health (NIMH) has initiated the Research Domain Criteria (RDoC) project in which a series of higher order domains, representing major systems of emotion, cognition, motivation, and social behavior, and their constituent operationally defined constructs serve as organizing templates for further research and inquiry, eg, to discover validated biomarkers and endophenotypes. Cutting across traditional DSM diagnoses, the domains are defined as Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Systems for Social Processes, and Arousal/Regulatory Systems. To inform educators, trainees, and practitioners about RDoC, alert them to potential practical applications, and encourage their broad exploration in clinical settings, this article reviews the RDoC domains and their subsystem constructs with regard to potential current clinical considerations and applications. We describe ways in which the RDoC domains and constructs offer transdiagnostic frameworks for complementing traditional practice; suggest clinical questions to help elucidate salient information; and, translating RDoC domains and constructs headings into clinically friendly language, offer a template for the psychiatric review of systems that can serve in clinical notes. PMID- 28002662 TI - Association Between Lithium Use and Risk of Alzheimer's Disease. AB - OBJECTIVE: Current evidence for the association between use of lithium and risk of dementia is mixed. The objective of this study was to assess the risk of Alzheimer's disease associated with use of lithium. METHODS: A population-based, nested case-control study was conducted using data from the National Health Insurance Research Database in 2002 covering 24.5 million beneficiaries of the Taiwan National Health Insurance Program from January 1, 1997, to December 31, 2009. A total of 2,548,625 older people were included in the study cohort. We analyzed 63,347 cases of Alzheimer's disease (ICD-9-CM codes 290.0-290.3, and 331.0) and 2 controls per case matched by age, sex, and index date (the date of the first AD claim). Conditional logistic regression was performed, adjusting for health care utilization, use of other common mood stabilizers (valproic acid and carbamazepine), hypothyroidism, type 2 diabetes, hypertension, hyperlipidemia, chronic kidney disease, epilepsy, schizophrenia, and bipolar disorder. RESULTS: We identified 63,347 cases with Alzheimer's disease and 126,694 controls. The adjusted odds ratio (aOR) of Alzheimer's disease risk with lithium use was 1.79 (95% confidence interval [CI], 1.34-2.38) in the general population. However, when we restricted the analyses to patients with bipolar disorder to minimize potential confounding by indication, lithium was not associated with Alzheimer's disease risk (aOR = 1.36; 95% CI, 0.89-2.09), and there were no apparent trends of greater risk with increasing duration or dose. CONCLUSIONS: These findings do not support an increased or decreased risk of lithium use with Alzheimer's disease when taking into account potential confounding by indication. Further investigations of the effect of lithium with dementia need to consider the influence of confounding by indication. PMID- 28002663 TI - Psychiatric Disease Preceding Intracranial Tumor Diagnosis: Investigating the Association. AB - Objective: Here, we examine rates of intracranial tumor diagnoses in patients with and without comorbid psychiatric diagnoses to better understand how psychiatric disease may alter risk profiles for brain tumor diagnosis. Methods: We used a longitudinal version of the California Office of Statewide Health Planning and Development (OSHPD) database, which includes all inpatient admissions in California from 1995 to 2010. We examined patients with confirmed hospital admissions from 1997 to 2004. Patients with an intracranial tumor or psychiatric diagnosis on their first hospital admission were excluded. The primary outcome of interest was the diagnosis of intracranial tumor on any subsequent hospitalization within 5 years. Risk of tumor diagnosis was determined via Cox proportional hazard models adjusted for age, gender, race/ethnicity, and comorbidity burden. Subset analyses were performed for various tumor types. Results: The risk for diagnosis of an intracranial tumor within 5 years, as determined by the hazard ratio, was 1.61 (95% CI, 1.28-2.04) for bipolar, 1.59 (95% CI, 1.41-1.72) for anxious, and 1.34 (95% CI, 1.25-1.43) for depressed cohorts relative to controls. More specifically, the risk for diagnosis of a primary benign neoplasm was elevated in depressed patients, while the risk for diagnosis of a meningioma was elevated in depressed, anxious, and bipolar disorder patients. Conclusions: Patients admitted with certain psychiatric diagnoses appear more likely to be readmitted within 5 years with specific types of intracranial tumor diagnoses. The association between certain psychiatric diagnoses and subsequent brain tumor diagnosis most likely reflects the long-held belief that slow-growing tumors may first present as psychiatric symptoms before being diagnosed. Primary care physicians should consider the possibility of an underlying intracranial tumor in patients with new psychiatric diagnoses. PMID- 28002664 TI - Evaluating the Life Cycle Environmental Benefits and Trade-Offs of Water Reuse Systems for Net-Zero Buildings. AB - Aging water infrastructure and increased water scarcity have resulted in higher interest in water reuse and decentralization. Rating systems for high-performance buildings implicitly promote the use of building-scale, decentralized water supply and treatment technologies. It is important to recognize the potential benefits and trade-offs of decentralized and centralized water systems in the context of high-performance buildings. For this reason and to fill a gap in the current literature, we completed a life cycle assessment (LCA) of the decentralized water system of a high-performance, net-zero energy, net-zero water building (NZB) that received multiple green building certifications and compared the results with two modeled buildings (conventional and water efficient) using centralized water systems. We investigated the NZB's impacts over varying lifetimes, conducted a break-even analysis, and included Monte Carlo uncertainty analysis. The results show that, although the NZB performs better in most categories than the conventional building, the water efficient building generally outperforms the NZB. The lifetime of the NZB, septic tank aeration, and use of solar energy have been found to be important factors in the NZB's impacts. While these findings are specific to the case study building, location, and treatment technologies, the framework for comparison of water and wastewater impacts of various buildings can be applied during building design to aid decision making. As we design and operate high-performance buildings, the potential trade-offs of advanced decentralized water treatment systems should be considered. PMID- 28002665 TI - Chemistry-Driven Approaches for Ultrasensitive Nucleic Acid Detection. AB - Methods that can rapidly and specifically analyze nucleic acid sequences will revolutionize the diagnosis and treatment of disease by allowing molecular-level information to be used during routine medicine. In this Perspective, we discuss chemistry-driven approaches that will make the detection of DNA and RNA sequences more routine in clinical settings. In addition, we discuss unmet needs and areas where future effort is necessary to enable nucleic acids analysis to become a mainstream tool in routine clinical medicine. Methods for next-generation sequencing of DNA are producing a wealth of information by allowing the study of how specific genetic mutations or single nucleotide polymorphisms influence the onset of disease, prognosis, or response to treatment. To give this information clinical utility, new methods of detecting nucleic acid sequences are being developed in order to rapidly obtain genetic information in more streamlined formats, and with the ability to obtain information outside of a laboratory setting. Challenges remain in this area, however, and new chemistries that will facilitate fast, simple nucleic acids analysis in a clinical setting are needed. PMID- 28002666 TI - Transient Supersaturation Supports Drug Absorption from Lipid-Based Formulations for Short Periods of Time, but Ongoing Solubilization Is Required for Longer Absorption Periods. AB - The current studies sought to explore the impact of drug supersaturation and precipitation during the dispersion and digestion of lipid-based formulations (LBFs), on in vivo absorption using a coupled in vitro digestion-in vivo perfusion absorption model. Fenofibrate absorption was evaluated from a number of LBFs with different solubilization and supersaturation capacities, and conditions at the absorptive membrane manipulated by changing perfusion conditions, intestine segment lengths, and by the conduct of experiments in the presence or absence of suspended/precipitated drug. LBF dispersion and digestion resulted in varying periods of supersaturation across the different formulations. Even fleeting (5-10 min) periods of supersaturation were able to drive flux across a perfused 10 cm intestinal segment for up to 60 min, although over longer infusion periods (60-80 min) flux dropped in the absence of ongoing drug solubilization and supersaturation. In contrast, the presence or absence of precipitated/suspended drug, had little impact on drug flux. When perfused intestinal segment lengths were extended, the role of initial supersaturation was attenuated and ongoing solubilization conditions became the primary driver of absorptive flux. The data suggest that for highly permeable drugs such as fenofibrate, a short period of supersaturation at the absorptive membrane may be sufficient to drive absorptive drug flux in spite of significant drug precipitation on formulation dispersion or digestion in vitro. In contrast, where longer periods of absorption are required, for example, at higher doses, the requirement for ongoing solubilization and supersaturation becomes more apparent. PMID- 28002667 TI - Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe. AB - p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and >=18000-fold selectivity over the BET family, together with >=70-fold selectivity over the wider bromodomain families. PMID- 28002668 TI - A Ligand-Dissociation-Involved Mechanism in Amide Formation of Monofluoroacylboronates with Hydroxylamines. AB - Acylborons, as a growing class of boron reagents, were successfully applied to amide ligation and showed potential in chemoselective bioconjugation reactions in recent years. In this manuscript, a density functional theory (DFT) study was performed to investigate the mechanism of the amide formation between monofluoroacylboronates and hydroxylamines. An updated pathway was clarified herein, including water-assisted hemiaminal formation, pyridine ligand dissociation, elimination via a six-membered-ring transition state, and water assisted tautomerization. The proposed mechanism was further examined by applying it to investigate the activation barriers of other monofluoroacylboronates, and the related calculations well reproduced the experimentally reported relative reactivities. On the basis of these results, we found that the ortho substitution of the pyridine ligand destabilizes the acylboron substrates and the hemiaminal intermediates by steric effects and thus lowers the energy demand of the ligand dissociation and elimination steps. By contrast, the para substitution of the pyridine ligand with an electron-donating group enhances the coordination of the ligand by electronic effects, which is a disadvantage to the ligand dissociation and elimination steps. The ligand bearing a rigid linkage blocks the rotation of the pyridine ligand and makes ligand dissociation difficult. PMID- 28002669 TI - Intermolecular Aminocarbonylation of Alkenes using Concerted Cycloadditions of Iminoisocyanates. AB - The aminocarbonylation of alkenes is a powerful method for accessing the beta amino carbonyl motif that remains underdeveloped. Herein, the development of intermolecular aminocarbonylation reactivity of iminoisocyanates with alkenes is presented. This includes the discovery of a fluorenone-derived reagent, which was effective for many alkene classes and facilitated derivatization. Electron-rich substrates were most reactive, and this indicated that the LUMO of the iminoisocyanate is reacting with the HOMO of the alkene. Computational and experimental results support a concerted asynchronous [3 + 2] cycloaddition involving an iminoisocyanate, which was observed for the first time by FTIR under the reaction conditions. The products of this reaction are complex azomethine imines, which are precursors to valuable beta-amino carbonyl compounds such as beta-amino amides and esters, pyrazolones, and bicyclic pyrazolidinones. A kinetic resolution of the azomethine imines by enantioselective reduction (s = 13 43) allows access to enantioenriched products. Overall, this work provides a new tool to convert alkenes into beta-amino carbonyl compounds. PMID- 28002670 TI - Chemoenzymatic Approach for the Preparation of Asymmetric Bi-, Tri-, and Tetra Antennary N-Glycans from a Common Precursor. AB - Progress in glycoscience is hampered by a lack of well-defined complex oligosaccharide standards that are needed to fabricate the next generation of microarrays, to develop analytical protocols to determine exact structures of isolated glycans, and to elucidate pathways of glycan biosynthesis. We describe here a chemoenzymatic methodology that makes it possible, for the first time, to prepare any bi-, tri-, and tetra-antennary asymmetric N-glycan from a single precursor. It is based on the chemical synthesis of a tetra-antennary glycan that has N-acetylglucosamine (GlcNAc), N-acetyllactosamine (LacNAc), and unnatural Galalpha(1,4)-GlcNAc and Manbeta(1,4)-GlcNAc appendages. Mammalian glycosyltransferases recognize only the terminal LacNAc moiety as a substrate, and thus this structure can be uniquely extended. Next, the beta-GlcNAc terminating antenna can be converted into LacNAc by galactosylation and can then be enzymatically modified into a complex structure. The unnatural alpha-Gal and beta-Man terminating antennae can sequentially be decaged by an appropriate glycosidase to liberate a terminal beta-GlcNAc moiety, which can be converted into LacNAc and then elaborated by a panel of glycosyltransferases. Asymmetric bi and triantennary glycans could be obtained by removal of a terminal beta-GlcNAc moiety by treatment with beta-N-acetylglucosaminidase and selective extension of the other arms. The power of the methodology is demonstrated by the preparation of an asymmetric tetra-antennary N-glycan found in human breast carcinoma tissue, which represents the most complex N-glycan ever synthesized. Multistage mass spectrometry of the two isomeric triantennary glycans uncovered unique fragment ions that will facilitate identification of exact structures of glycans in biological samples. PMID- 28002671 TI - Vapor-Phase Epitaxial Growth of Aligned Nanowire Networks of Cesium Lead Halide Perovskites (CsPbX3, X = Cl, Br, I). AB - With the intense interest in inorganic cesium lead halide perovskites and their nanostructures for optoelectronic applications, high-quality crystalline nanomaterials with controllable morphologies and growth directions are desirable. Here, we report a vapor-phase epitaxial growth of horizontal single-crystal CsPbX3 (X = Cl, Br, I) nanowires (NWs) and microwires (MWs) with controlled crystallographic orientations on the (001) plane of phlogopite and muscovite mica. Moreover, single NWs, Y-shaped branches, interconnected NW or MW networks with 6-fold symmetry, and, eventually, highly dense epitaxial network of CsPbBr3 with nearly continuous coverage were controllably obtained by varying the growth time. Detailed structural study revealed that the CsPbBr3 wires grow along the [001] directions and have the (100) facets exposed. The incommensurate heteroepitaxial lattice match between the CsPbBr3 and mica crystal structures and the growth mechanism of these horizontal wires due to asymmetric lattice mismatch were proposed. Furthermore, the photoluminescence waveguiding and good performance from the photodetector device fabricated with these CsPbBr3 networks demonstrated that these well-connected CsPbBr3 NWs could serve as straightforward platforms for fundamental studies and optoelectronic applications. PMID- 28002672 TI - Hybrid Nanowire Ion-to-Electron Transducers for Integrated Bioelectronic Circuitry. AB - A key task in the emerging field of bioelectronics is the transduction between ionic/protonic and electronic signals at high fidelity. This is a considerable challenge since the two carrier types exhibit intrinsically different physics and are best supported by very different materials types-electronic signals in inorganic semiconductors and ionic/protonic signals in organic or bio-organic polymers, gels, or electrolytes. Here we demonstrate a new class of organic inorganic transducing interface featuring semiconducting nanowires electrostatically gated using a solid proton-transporting hygroscopic polymer. This model platform allows us to study the basic transducing mechanisms as well as deliver high fidelity signal conversion by tapping into and drawing together the best candidates from traditionally disparate realms of electronic materials research. By combining complementary n- and p-type transducers we demonstrate functional logic with significant potential for scaling toward high-density integrated bioelectronic circuitry. PMID- 28002673 TI - Conduction Band Offset and Polarization Effects in InAs Nanowire Polytype Junctions. AB - Although zinc-blende (ZB) and wurtzite (WZ) structures differ only in the atomic stacking sequence, mixing of crystal phases can strongly affect the electronic properties, a problem particularly common to bottom up-grown nanostructures. A lack of understanding of the nature of electronic transport at crystal phase junctions thus severely limits our ability to develop functional nanowire devices. In this work we investigated electron transport in InAs nanowires with designed mixing of crystal structures, ZB/WZ/ZB, by temperature-dependent electrical measurements. The WZ inclusion gives rise to an energy barrier in the conduction band. Interpreting the experimental result in terms of thermionic emission and using a drift-diffusion model, we extracted values for the WZ/ZB band offset, 135 +/- 10 meV, and interface sheet polarization charge density on the order of 10-3 C/m2. The extracted polarization charge density is 1-2 orders of magnitude smaller than previous experimental results, but in good agreement with first principle calculation of spontaneous polarization in WZ InAs. When the WZ length is reduced below 20 nm, an effective barrier lowering is observed, indicating the increasing importance of tunneling transport. Finally, we found that band-bending at ZB/WZ junctions can lead to bound electron states within an enclosed WZ segment of sufficient length, evidenced by our observation of Coulomb blockade at low temperature. These findings provide critical input for modeling and designing the electronic properties of novel functional devices, such as nanowire transistors, where crystal polytypes are commonly found. PMID- 28002674 TI - Parametric Resonance of Magnetization Excited by Electric Field. AB - Manipulation of magnetization by electric field is a central goal of spintronics because it enables energy-efficient operation of spin-based devices. Spin wave devices are promising candidates for low-power information processing, but a method for energy-efficient excitation of short-wavelength spin waves has been lacking. Here we show that spin waves in nanoscale magnetic tunnel junctions can be generated via parametric resonance induced by electric field. Parametric excitation of magnetization is a versatile method of short-wavelength spin wave generation, and thus, our results pave the way toward energy-efficient nanomagnonic devices. PMID- 28002675 TI - Flexible, All-Inorganic Actuators Based on Vanadium Dioxide and Carbon Nanotube Bimorphs. AB - Flexible actuators responsive to multiple stimuli are much desired in wearable electronics. However, general designs containing organic materials are usually subject to slow response and limited lifetime, or high triggering threshold. In this study, we develop flexible, all-inorganic actuators based on bimorph structures composed of vanadium dioxide (VO2) and carbon nanotube (CNT) thin films. The drastic, reversible phase transition of VO2 drives the actuators to deliver giant amplitude, fast response up to ~100 Hz, and long lifetime more than 1 000 000 actuation cycles. The excellent electrical conductivity and light absorption of CNT thin films enable the actuators to be highly responsive to multiple stimuli including light, electric, and heat. The power consumption of the actuators can be much reduced by doping VO2 to lower its phase transition temperature. These flexible bimorph actuators find applications in biomimetic inspect wings, millimeter-scale fingers, and physiological-temperature driven switches. PMID- 28002676 TI - Wurtzite/Zinc-Blende 'K'-shape InAs Nanowires with Embedded Two-Dimensional Wurtzite Plates. AB - The prediction that Majorana Fermions obey nonabelian exchange statistics can only be tested by interchanging such carriers in "Y'- or 'X'- (or 'K'-) shaped nanowire networks. Here we report the molecular beam epitaxy (MBE) growth of 'K' shaped InAs nanowires consisting of two interconnected wurtzite wires with an additional zinc-blende wire in between. Moreover, occasionally, the growth results in formation of a purely wurtzite two-dimensional plate between the zinc blende nanowire and one (sometimes both) intersecting wurtzite arm. By modeling the crystal structure we explain the transformation from wurtzite to zinc-blende and the coexistence of both crystallographic phases in such nanowire structures. To the best of our knowledge neither the MBE growth of an InAs nano-object showing combination of wurtzite and zinc-blende crystal structures nor the growth of pure wurtzite InAs nanoplates in this geometry has been reported before. PMID- 28002677 TI - Atom-by-Atom Analysis of Semiconductor Nanowires with Parts Per Million Sensitivity. AB - The functionality of semiconductor devices is determined by the incorporation of dopants at concentrations down to the parts per million (ppm) level and below. Optimization of intentional and unintentional impurity doping relies on methods to detect and map the level of impurities. Detecting such low concentrations of impurities in nanostructures is however challenging to date as on the one hand methods used for macroscopic samples cannot be applied due to the inherent small volumes or faceted surfaces and on the other hand conventional microscopic analysis techniques are not sufficiently sensitive. Here, we show that we can detect and map impurities at the ppm level in semiconductor nanowires using atom probe tomography. We develop a method applicable to a wide variety of nanowires relevant for electronic and optical devices. We expect that it will contribute significantly to the further optimization of the synthesis of nanowires, nanostructures and devices based on these structures. PMID- 28002678 TI - Transfer of Montelukast into Human Milk During Lactation. AB - AIM: The aim of this study was to determine levels of montelukast in human milk and to develop a simple, sensitive analytical method using mass spectrometry. METHODS: Milk samples were collected from seven breastfeeding mothers, age 26-35 years, at 0, 1, 2, 4, 8, and 12 hours after oral ingestion of 10 mg montelukast. The samples were analyzed using a new Liquid Chromatography-Tandem Mass Spectrometry method. Area under the milk concentration time curve from zero to the time of the last sample (12 hours) was estimated by the linear trapezoidal rule. RESULTS: Average montelukast levels (Cavg) in milk were 5.3 ng/mL, and the relative infant dose was 0.68% of the maternal dose. The maximum concentration (Cmax) observed at 4 hours (Tmax) was 9.7 ng/mL. CONCLUSION: The exposure to the infant seems to be very low, far below therapeutic ranges in an infant. Our data suggest that montelukast is probably safe to use in a breastfeeding mother. PMID- 28002681 TI - A Mindfulness-Based Intervention for Adolescents and Young Adults After Cancer Treatment: Effects on Quality of Life, Emotional Distress, and Cognitive Vulnerability. AB - PURPOSE: Adolescent and young adult cancer (AYAC) survivors show an elevated risk of distress. Targeted psychosocial interventions for this distinct population are needed. This study examined the potential efficacy of a mindfulness-based intervention (MBI) to alleviate emotional distress and improve quality of life (QoL) in AYAC survivors. METHODS: Participants were 16 AYAC survivors, aged 14 24, who had completed acute medical treatment. A two-baseline (8 and 1 week before the intervention), post- (1 week after the intervention) and 3 months follow-up within-subjects design was used. Each participant completed two baseline assessments, followed by an 8-week MBI. The primary outcome variables were emotional distress and QoL. Secondary outcomes were cognitive vulnerability factors and mindfulness skills. RESULTS: Multilevel modeling showed (1) a significant reduction in emotional distress and improvement in QoL at 3 months of follow-up, (2) a significant reduction in negative attitudes toward self (i.e., a cognitive vulnerability factor), and (3) a significant improvement in mindfulness skills. CONCLUSION: MBI is a promising approach that is used to treat emotional distress and to improve QoL in AYAC survivors. Further research using randomized controlled trials is needed to generalize these findings. Trial registration information: www.trialregister.nl ; NTR4358. PMID- 28002680 TI - Diagnosis and Treatment of Fibrotic Hypersensitivity Pneumonia. Where We Stand and Where We Need to Go. PMID- 28002682 TI - Human Milk and Matched Serum Demonstrate Concentration of Select miRNAs. AB - BACKGROUND: Pregnancy-associated breast cancers (PABCs), especially those diagnosed after childbirth, are often aggressive, with a poor prognosis. Factors influencing PABC are largely unknown. Micro(mi)RNAs are present in many human body fluids and shown to influence cancer development and/or growth. SUBJECTS AND METHODS: In six nursing mothers, we determined if breast cancer-associated miRNAs were (1) detectable in human breast milk and (2) if detectable, their relative expression in milk fractions compared to matched serum. We evaluated by quantitative PCR the expression of 11 cancer-associated miRNAs (10a-5p, 16, 21, 100, 140, 145, 155, 181, 199, 205, 212) in breast milk cells, fat and supernatant (skim milk), and matched serum. RESULTS: miRNA expression was detectable in all samples. For 10/11 miRNAs, mean relative expression compared to control (DeltaCt) values was lowest in milk cells, the exception being miR205. Relative concentration was highest in the skim fraction of milk for all miRNAs. Expression was higher in skim milk than matched serum for 7/11 miRNAs and in serum for 4/11 miRNAs. miR205 expression was higher in all milk fractions than in matched serum. CONCLUSION: In conclusion, the expression of breast cancer-associated miRNAs is detectable in human breast milk and serum samples. The concentration is highest in skim milk, but is also detectable in milk fat and milk cells. PMID- 28002683 TI - A Prediction Model to Help with the Assessment of Adenopathy in Lung Cancer: HAL. AB - RATIONALE: Estimating the probability of finding N2 or N3 (prN2/3) malignant nodal disease on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with non-small cell lung cancer (NSCLC) can facilitate the selection of subsequent management strategies. OBJECTIVES: To develop a clinical prediction model for estimating the prN2/3. METHODS: We used the AQuIRE (American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education) registry to identify patients with NSCLC with clinical radiographic stage T1-3, N0-3, M0 disease that had EBUS-TBNA for staging. The dependent variable was the presence of N2 or N3 disease (vs. N0 or N1) as assessed by EBUS-TBNA. Univariate followed by multivariable logistic regression analysis was used to develop a parsimonious clinical prediction model to estimate prN2/3. External validation was performed using data from three other hospitals. MEASUREMENTS AND MAIN RESULTS: The model derivation cohort (n = 633) had a 25% prevalence of malignant N2 or N3 disease. Younger age, central location, adenocarcinoma histology, and higher positron emission tomography-computed tomography N stage were associated with a higher prN2/3. Area under the receiver operating characteristic curve was 0.85 (95% confidence interval, 0.82-0.89), model fit was acceptable (Hosmer-Lemeshow, P = 0.62; Brier score, 0.125). We externally validated the model in 722 patients. Area under the receiver operating characteristic curve was 0.88 (95% confidence interval, 0.85-0.90). Calibration using the general calibration model method resulted in acceptable goodness of fit (Hosmer-Lemeshow test, P = 0.54; Brier score, 0.132). CONCLUSIONS: Our prediction rule can be used to estimate prN2/3 in patients with NSCLC. The model has the potential to facilitate clinical decision making in the staging of NSCLC. PMID- 28002684 TI - Effects of caffeine on endurance capacity and psychological state in young females and males exercising in the heat. AB - Acute caffeine ingestion is considered effective in improving endurance capacity and psychological state. However, current knowledge is based on the findings of studies that have been conducted on male subjects mainly in temperate environmental conditions, but some physiological and psychological effects of caffeine differ between the sexes. The purpose of this study was to compare the physical performance and psychological effects of caffeine in young women and men exercising in the heat. Thirteen male and 10 female students completed 2 constant load walks (60% of thermoneutral peak oxygen consumption on a treadmill until volitional exhaustion) in a hot-dry environment (air temperature, 42 degrees C; relative humidity, 20%) after caffeine (6 mg.kg-1) and placebo (wheat flour) ingestion in a double-blind, randomly assigned, crossover manner. Caffeine, compared with placebo, induced greater increases (p < 0.05) in heart rate (HR) and blood lactate concentrations in both males and females but had no impact on rectal or skin temperatures or on walking time to exhaustion in subjects of either gender. Caffeine decreased (p < 0.05) ratings of perceived exertion and fatigue in males, but not in females. In females, but not in males, a stronger belief that they had been administered caffeine was associated with a shorter time to exhaustion. In conclusion, acute caffeine ingestion increases HR and blood lactate levels during exercise in the heat, but it has no impact on thermoregulation or endurance capacity in either gender. Under exercise-heat stress, caffeine reduces ratings of perceived exertion and fatigue in males but not in females. PMID- 28002686 TI - Research on Social Networking Sites and Social Support from 2004 to 2015: A Narrative Review and Directions for Future Research. AB - The article presents a narrative review of scholarship on social support through social networking sites (SNSs) published from 2004 to 2015. By searching keywords related to social support and SNSs in major databases for social sciences, we identified and content analyzed directly relevant articles (N = 88). The article summarizes the prevalence of theory usage; the function of theory usage (e.g., testing a theory, developing a theory); major theories referenced; and methodologies, including research designs, measurement, and the roles of social support and SNS examined in this literature. It also reports four themes identified across the studies, indicating the trends in the current research. Based on the review, the article presents a discussion about study sites, conceptualization of social support, theoretical coherence, the role of social networks, and the dynamic relationships between SNS use and social support, which points out potential avenues for shaping a future research agenda. PMID- 28002679 TI - Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. AB - BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 MUg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.). PMID- 28002685 TI - Effects of blood-flow restriction on biomarkers of myogenesis in response to resistance exercise. AB - We investigated the acute myogenic response to resistance exercise with and without blood-flow restriction (BFR). Six men and women (age, 22 +/- 1 years) performed unilateral knee extensions at 40% of 1-repetition maximum with or without (CNTRL) BFR applied via pressure cuff inflated to 220 mm Hg. Muscle biopsies were collected at 4 h and 24 h postexercise. Addition of BFR increased myoD and c-Met messenger RNA expression relative to CNTRL. Expression of hepatocyte growth factor protein was significantly higher following CNTRL. PMID- 28002687 TI - Surviving Without Oxygen: How Low Can the Human Brain Go? AB - Bailey, Damian M., Christopher K. Willie, Ryan L. Hoiland, Anthony R. Bain, David B. MacLeod, Maria A. Santoro, Daniel K. DeMasi, Andrea Andrijanic, Tanja Mijacika, Otto F. Barak, Zeljko Dujic, and Philip N. Ainslie. Surviving without oxygen: how low can the human brain go? High Alt Med Biol 18:73-79, 2017.-Hypoxic cerebral vasodilation is a highly conserved physiological response coupling cerebral O2 delivery (CDO2) to metabolic demand with increasingly important roles identified for the red blood cell (sensor) and nitric oxide (effector). In the current article, we reexamine previously published cerebral blood flow (CBF) and arterial blood gas data obtained in freedivers and mountaineers, extreme athletes in whom the lowest arterial partial pressures of O2 (19-23 mmHg) and greatest extremes of carbon dioxide (16-61 mmHg) were recorded during (acute) maximal static dry apnea or (chronic) exposure to terrestrial high altitude. Data highlight compensatory increases in CBF (+96% in freedivers to +209% in mountaineers relative to normoxic baseline controls) that were sufficient to sustain CDO2 (+24% in freedivers to +183% in mountaineers) even in the face of the most severe reductions in arterial O2 content (-61% in freedivers to -9% in mountaineers) reported in the literature, consistent with the conservation of mass principle. These unique findings highlight to what extent cerebral vasodilation likely contributes toward these athletes' extraordinary abilities to survive in such harsh environments characterized by physiological extremes of hypoxemia, alkalosis, and acidosis helping define the human brain's remarkable limits of tolerance. PMID- 28002689 TI - Design and Implementation of a Telepediatric Primary-Level and Low-Cost System to Reduce Unnecessary Patient Transfers. AB - BACKGROUND: Most inhabitants in Latin America are concentrated in large urban foci with different access to facilities. Although the main hospitals offer specialized services, economically vulnerable populations cannot easily afford these services, the pediatric population being most affected. This article presents the design and implementation of a low cost telepediatric system, applied to primary care hospitals through a study in Bogota, Colombia, mainly aimed to reduce the number of unnecessary transfers commonly sent to specialized medical services. MATERIALS AND METHODS: The system was carried out over 6 months with a higher incidence of acute respiratory illness in children between 0 and 5 years in nine primary care hospitals in Bogota. Nineteen (n = 19) pediatricians were trained by a group of engineers that supports the system permanently. The reduction of patient transfers was compared with previous reports of the National Statistical Department in Colombia. RESULTS: The system reduced both the number of patient transfers to higher level hospitals by 83% and the waiting times for patient transfer, improving healthcare in pediatric patients at a reasonable cost, affecting more than 700 patients. At the same time, a decrease of about 17% in the use of antibiotics was observed, which is an important current public health issue. CONCLUSIONS: The use of telemedicine improves the efficiency of public health resources, even in big cities such as Bogota, reducing the number of unnecessary patient transfers and the optimization and appropriate use of medicines. PMID- 28002690 TI - DIABSAT Telemedicine Itinerant Screening of Chronic Complications of Diabetes Using a Satellite. AB - BACKGROUND: Health authorities recommend regular screening for the chronic complications of diabetes. The ENTRED * survey results show that insufficient screening is undertaken. The DIABSAT ? program aims to improve care for diabetes patients in rural areas of the Midi-Pyrenees region, telemonitoring complications of diabetes through an itinerant screening service. METHODS: A vehicle was equipped with a satellite dish and medical equipment for screening ophthalmological, renal, vascular, and neuropathic damage and assessing the level of risk of diabetic foot ulceration. Onboard, a nurse performs some or all of the tests on patients who have had no diabetes review for over a year. The data are entered into a computer and transmitted by satellite for interpretation by designated specialists. The results are sent to patients, general practitioners (GPs), and diabetologists. RESULTS: Two hundred twenty-eight screening days were held in six departments of the Midi-Pyrenees between 2010 and 2013. 1,545 patients were screened: mean age 70.7 years, 55.8% men. 93.4% diagnosed with type 2 diabetes, mean duration 11.7 years. Recruitment was chiefly by health professionals (55%). 17-32% of tests detected pathologies: 18.7% diabetic retinopathy, 31.9% microalbuminuria, 17.2% lower limb arteriopathy, 28.3% peripheral neuropathy, and 28.2% high risk of foot ulceration (grade 2: 20.6% and grade 3: 7.6%). CONCLUSION: The large number of patients screened and the high rate of pathological results found, confirm telemonitoring viability and relevance. DIABSAT, a primary resource for healthcare professionals, improves healthcare access through its innovative organization and use of satellite technology. PMID- 28002691 TI - The Silorane-based Resin Composites: A Review. AB - This article aims to review the research done on the silorane-based resin composites (SBRC) regarding polymerization shrinkage and contraction stresses and their ability to improve the shortcomings of the methacrylate-based resin composites (MRBC). Special attention is given to their physical and mechanical properties, bond strength, marginal adaptation, and cusp deflection. The clinical significance of this material is critically appraised with a focus on the ability of SBRC to strengthen the tooth structure as a direct restorative material. A search of English peer-reviewed dental literature (2003-2015) from PubMed and MEDLINE databases was conducted with the terms "low shrinkage" and "silorane composites." The list was screened, and 70 articles that were relevant to the objectives of this work were included. PMID- 28002692 TI - Faculty Postings. PMID- 28002693 TI - Degree of Conversion and Polymerization Shrinkage of Bulk-Fill Resin-Based Composites. AB - This study evaluated the degree of conversion (DC) and polymerization shrinkage (PS) of contemporary bulk-fill resin-based composites (RBCs) including giomer materials. Two giomer bulk-fill (Beautifil Bulk Restorative [BBR], Beautifil Bulk Flowable [BBF]), two nongiomer bulk-fill (Tetric N-Ceram Bulk-fill [TNB], Smart Dentin Replacement [SDR]), and three conventional non-bulk-fill (Beautifil II [BT], Beautifil Flow Plus [BF], Tetric N-Ceram [TN]) RBCs were selected for the study. To evaluate the DC, disc-shaped specimens of 5-mm diameter and 2-mm, 4-mm, and 6-mm thickness were fabricated using customized Teflon molds. The molds were bulk filled with the various RBCs and cured for 20 seconds using a light-emitting diode curing light with an irradiance of 950 mW/cm2. The DC (n=3) was determined by attenuated total reflectance Fourier transform infrared spectroscopy by computing the spectra of cured and uncured specimens. PS (n=3) was measured with the Acuvol volumetric shrinkage analyzer by calculating specimen volumes before and after light curing. The mean DC for the various materials ranged from 46.03% to 69.86%, 45.94% to 69.38%, and 30.65% to 67.85% for 2 mm, 4 mm, and 6 mm, respectively. For all depths, SDR had the highest DC. While no significant difference in DC was observed between depths of 2 mm and 4 mm for the bulk-fill RBCs, DC at 2 mm was significantly greater than 6 mm. For the conventional RBCs, DC at 2 mm was significantly higher than at 4 mm and 6 mm. Mean PS ranged from 1.48% to 4.26% for BBR and BF, respectively. The DC at 2 mm and PS of bulk-fill RBCs were lower than their conventional counterparts. At 4 mm, the DC of giomer bulk-fill RBCs was lower than that of nongiomer bulk-fill materials. PMID- 28002688 TI - Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. AB - BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .). PMID- 28002694 TI - How to Bridge Research Results to Everyday Clinical Care? AB - Laboratory and clinical studies are essential to the advancement of sciences. However, a significant gap exists between the research findings and clinical practice. Therefore, research findings can be of little importance if their outcome cannot be directly or indirectly applied to everyday clinical care or readily translated. This paper focuses on how we can shorten the gap between the generation of new knowledge and their implementation into everyday clinical care. A new model is discussed where clinicians are the ones generating the research idea are paired with researchers. They collaborate on studies whose results are readily applicable to everyday practice. Partnering with health providers on studies that address everyday clinical research questions is a potential solution to speed up the translation of the research findings. Generating clinically applicable results can better improve the health of the public. Quoting Dr. Lawrence W. Green: "If we want more evidence-based practice, we need more practice-based evidence." This paper presents the practice-based research model as a solution to address this knowledge gap. PMID- 28002695 TI - Clinical Effectiveness of Different Polishing Systems and Self-Etch Adhesives in Class V Composite Resin Restorations: Two-Year Randomized Controlled Clinical Trial. AB - The aim of this randomized controlled clinical trial was to compare the clinical effectiveness of different polishing systems and self-etch adhesives in class V composite resin restorations. A total of 164 noncarious cervical lesions (NCCLs) from 35 patients were randomly allocated to one of four experimental groups, each of which used a combination of polishing systems and adhesives. The two polishing systems used were Sof-Lex XT (Sof), a multistep abrasive disc, and Enhance/Pogo (EP), a simplified abrasive-impregnated rubber instrument. The adhesive systems were Clearfil SE bond (CS), a two-step self-etch adhesive, and Xeno V (XE), a one step self-etch adhesive. All NCCLs were restored with light-cured microhybrid resin composites (Z250). Restorations were evaluated at baseline and at 6, 12, 18, and 24 months by two blinded independent examiners using modified FDI criteria. The Fisher exact test and generalized estimating equation analysis considering repeated measurements were performed to compare the outcomes between the polishing systems and adhesives. Three restorations were dislodged: two in CS/Sof and one in CS/EP. None of the restorations required any repair or retreatment except those showing retention loss. Sof was superior to EP with regard to surface luster, staining, and marginal adaptation (p<0.05). CS and XE did not show differences in any criteria (p>0.05). Sof is clinically superior to EP for polishing performance in class V composite resin restoration. XE demonstrates clinically equivalent bonding performance to CS. PMID- 28002697 TI - Sequenom v. Ariosa - The Death of a Genetic Testing Patent. PMID- 28002698 TI - Severe Malaria in African Children - The Need for Continuing Investment. PMID- 28002699 TI - Daratumumab and Blood-Compatibility Testing. PMID- 28002700 TI - All in a Day's Work - Equity vs. Equality at a Public ICU in Brazil. PMID- 28002701 TI - A Police-Led Addiction Treatment Referral Program in Massachusetts. PMID- 28002702 TI - Acute Rheumatic Fever with Erythema Marginatum. PMID- 28002703 TI - Uterine Rupture with Protruded Legs in a Large Amniocele. PMID- 28002704 TI - Interim Buprenorphine vs. Waiting List for Opioid Dependence. PMID- 28002705 TI - Case 39-2016. A 74-Year-Old Man with Rectal Bleeding and a History of Prostate Cancer. PMID- 28002706 TI - Atrial Fibrillation and PCI - Do We Still Need Aspirin? PMID- 28002707 TI - Primary Sclerosing Cholangitis. PMID- 28002708 TI - Primary Sclerosing Cholangitis. PMID- 28002709 TI - Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children. AB - BACKGROUND: Limiting the duration of antimicrobial treatment constitutes a potential strategy to reduce the risk of antimicrobial resistance among children with acute otitis media. METHODS: We assigned 520 children, 6 to 23 months of age, with acute otitis media to receive amoxicillin-clavulanate either for a standard duration of 10 days or for a reduced duration of 5 days followed by placebo for 5 days. We measured rates of clinical response (in a systematic fashion, on the basis of signs and symptomatic response), recurrence, and nasopharyngeal colonization, and we analyzed episode outcomes using a noninferiority approach. Symptom scores ranged from 0 to 14, with higher numbers indicating more severe symptoms. RESULTS: Children who were treated with amoxicillin-clavulanate for 5 days were more likely than those who were treated for 10 days to have clinical failure (77 of 229 children [34%] vs. 39 of 238 [16%]; difference, 17 percentage points [based on unrounded data]; 95% confidence interval, 9 to 25). The mean symptom scores over the period from day 6 to day 14 were 1.61 in the 5-day group and 1.34 in the 10-day group (P=0.07); the mean scores at the day-12-to-14 assessment were 1.89 versus 1.20 (P=0.001). The percentage of children whose symptom scores decreased more than 50% (indicating less severe symptoms) from baseline to the end of treatment was lower in the 5 day group than in the 10-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P=0.003). We found no significant between-group differences in rates of recurrence, adverse events, or nasopharyngeal colonization with penicillin nonsusceptible pathogens. Clinical-failure rates were greater among children who had been exposed to three or more children for 10 or more hours per week than among those with less exposure (P=0.02) and were also greater among children with infection in both ears than among those with infection in one ear (P<0.001). CONCLUSIONS: Among children 6 to 23 months of age with acute otitis media, reduced-duration antimicrobial treatment resulted in less favorable outcomes than standard-duration treatment; in addition, neither the rate of adverse events nor the rate of emergence of antimicrobial resistance was lower with the shorter regimen. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources; ClinicalTrials.gov number, NCT01511107 .). PMID- 28002710 TI - Acute Otitis Media - The Long and the Short of It. PMID- 28002711 TI - Andexanet Alfa for Factor Xa Inhibitor Reversal. PMID- 28002712 TI - Andexanet Alfa for Factor Xa Inhibitor Reversal. PMID- 28002713 TI - Tracking the Fate of Cells in Health and Disease. PMID- 28002715 TI - Neonatal Abstinence Syndrome. PMID- 28002716 TI - Clinical Judgment and Evidence Based Knowledge: A Prescription for Clinical Confidence. PMID- 28002714 TI - Hypothermia for Neuroprotection in Convulsive Status Epilepticus. AB - BACKGROUND: Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus. METHODS: In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34 degrees C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, "super-refractory" status epilepticus (resistant to general anesthesia), and functional sequelae on day 90. RESULTS: A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group. CONCLUSIONS: In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .). PMID- 28002717 TI - Vertical Alveolar Ridge Augmentation in Implant Dentistry: A Surgical Manual and Horizontal Alveolar Ridge Augmentation in Implant Dentistry: A Surgical Manual. Tolstunov L, ed. Hoboken, NJ: John Wiley & Sons, Inc. Hoboken, New Jersey. PMID- 28002718 TI - Nurse provision of support to help inpatients quit smoking. AB - Issue addressed Identification of the factors that facilitate nurses to provide smoking cessation advice to hospitalised patients. Method Six semistructured focus groups with 26 nurses were conducted in June 2015. Participants completed a structured survey to collect patient demographic data and assess attitudes towards their role in addressing smoking cessation among inpatients. Results Important themes that emerged from the qualitative data were: nurses' negative perceptions of smokers, nurses' confidence in their knowledge of smoking cessation care and nurses' uncertainty around whose role it is to provide smoking cessation care. Conclusion Nurses require training in order to confidently and competently address smoking among inpatients as part of routine care. Formal ways to document the smoking status of inpatients and the offer of smoking cessation support from a nurse to an inpatient would enhance the communication between nurses around which inpatients had been asked about their smoking status and which had not. For patients who are resistant to conventional cessation strategies, innovative ways are needed to reduce the harm caused to them by tobacco use. So what? Nurses need to be provided with education and training around smoking cessation to increase their confidence and skills to provide smoking cessation care to inpatients. PMID- 28002719 TI - Establishing a sustainable childhood obesity monitoring system in regional Victoria. AB - Issue addressed Childhood obesity poses a significant immediate and long-term burden to individuals, societies and health systems. Infrequent and inadequate monitoring has led to uncertainty about trends in childhood obesity prevalence in many countries. High-quality data, collected at regular intervals, over extended timeframes, with high response rates and timely feedback are essential to support prevention efforts. Our aim was to establish a sustainable childhood obesity monitoring system in regional Australia to collect accurate anthropometric and behavioural data, provide timely feedback to communities and build community engagement and capacity. Methods All schools from six government regions of South West Victoria were invited to participate. Passive (opt-out) consent was used to collect measured anthropometric and self-reported behavioural data from children in years 2, 4, and 6, aged 7-12 years. Results We achieved a 70% school participation rate (n=46) and a 93% student response rate (n=2198) among government and independent schools. Results were reported within 10 weeks post data collection. Harnessing high levels of community engagement throughout the planning, data collection and reporting phases increased community capacity and data utility. Conclusions The monitoring system achieved high response rates, community engagement and community capacity building, and delivered results back to the community in a timely manner. So what? This system has the potential to provide sustainable monitoring of childhood obesity that is not dependent on external funding. The results of this monitoring will likely inform health promotion efforts in communities across the region. PMID- 28002720 TI - Optimization of fipronil degradation by heterogeneous photocatalysis: Identification of transformation products and toxicity assessment. AB - In this work it was studied the degradation of the insecticide fipronil (FIP) by heterogeneous photocatalysis induced by TiO2 P25. Using chemometric methods (Factorial Design and Response Surface Methodology), it was possible to evaluate the role of interaction between pH of the reaction medium, the reaction time and concentration of TiO2, optimizing the conditions for degradation using artificial radiation. Under the optimized conditions (79.4 mg L-1 TiO2 and 66.3 min of reaction time for 1.1 mg L-1 of FIP, at pH 5.6-5.8 (natural pH of the irradiated suspension)), 90.9% of FIP degradation was achieved at a degradation rate of 1.54 * 10-2 m2 kJ-1 in terms of accumulated UVA radiation, corresponding to a pseudo first order rate constant of 1.34 * 10-2 min-1 and a half-life of 51.7 min. Under the same conditions, these assays were extended to the use of solar radiation, when the degradation rate was 14% higher, with half-life of 45 min, suggesting that in both cases FIP degradation was successful. Four by-products of FIP photocatalytic degradation could be separated, identified, and their formation and consumption followed by UHPLC-Q-TOF. Although the same intermediates have been obtained using both irradiation sources, a faster degradation of the transformation products (TPs) was observed under solar irradiation due to its expressive photonic flux covering the UVA and UVB. It is noteworthy that both the untreated effluent and the identified compounds have low toxicity with respect to V. fischeri, suggesting that the heterogeneous photocatalysis may be a good alternative for treatment of wastewaters containing FIP and its TPs, mainly when solar radiation is the source of radiation, since under this condition the power consumption during the treatment can be significantly reduced. PMID- 28002721 TI - Perceptual similarity in visual search for multiple targets. AB - Visual search for multiple targets can cause errors called subsequent search misses (SSM) - a decrease in accuracy at detecting a second target after a first target has been found. One of the possible explanations of SSM errors is perceptual set. After the first target has been found, the subjects become biased to find perceptually similar targets, therefore they are more likely to find perceptually similar targets and less likely to find the targets that are perceptually dissimilar. This study investigated the role of perceptual similarity in SSM errors. The search array in each trial consisted of 20 stimuli (ellipses and crosses, black and white, small and big, oriented horizontally and vertically), which could contain one, two or no targets. In case of two targets, the targets could have two, three or four shared features (in the last case the targets were identical). The error rate decreased with increasing the similarity between the targets. These results state the role of perceptual similarity and have implications for the perceptual set theory. PMID- 28002722 TI - One Niche to Rule Both Maintenance and Loss of Stemness in HSCs. AB - Hemato-lymphopoiesis initiated by hematopoietic stem cells (HSCs) is tightly regulated by factors present in the bone marrow (BM) niche. Using genetically modified mice, Gomes et al. (2016) show that IL-7 is produced by HSC niche forming cells and find that the same niche that controls HSC self-renewal can also support differentiation. PMID- 28002723 TI - Precision Targeting: Mast Cells Wipe Out Infected Bladder Epithelia. AB - Exfoliating infected bladder epithelium is a powerful host defense mechanism that reduces bacterial burden. In this issue of Immunity, Choi et al. (2016) present a function of mast cells that orchestrates the infected epithelial cell exfoliation via cytolytic granules. PMID- 28002724 TI - Too Much of a Good Thing? Chronic IFN Fuels Resistance to Cancer Immunotherapy. AB - Immune checkpoint blockade (ICB) is revolutionizing cancer medicine, yet the molecular basis of resistance remains unclear. In a recent issue of Cell, Benci et al. (2016) demonstrate that sustained interferon signaling is central to the development of PD-L1-dependent and -independent resistance to ICB. PMID- 28002725 TI - Sifting through CD8+ T Cell Memory. AB - In this issue of Immunity, Gerlach et al. (2016) describe three distinct memory CD8+ T cell subsets based upon expression of the fractalkine receptor CX3CR1. Their findings revise the paradigm of effector and central memory T cells by revealing a subset of CD8+ memory T cells defined by intermediate levels of expression of CX3CR1 that conducts tissue surveillance. PMID- 28002726 TI - Immune Cell Intolerance for Excess Cholesterol. AB - Chronic metabolic challenges have severe consequences on physiological systems. In this issue of Immunity, Ito et al. (2016) show that defects in cholesterol metabolism in CD11c+ immune cells result in impaired antigen presentation and ultimately in autoimmune disease. PMID- 28002727 TI - Allergen Exposure: When Timing Is Everything. AB - It is known that young children exposed to allergens are prone to develop asthma later in life. In this issue of Immunity, de Kleer et al. (2016) identify IL-33 as a key player in the developing lung for sensitization to environmental allergens and airway hyperreactivity. PMID- 28002728 TI - Expanding the Immunology Toolbox: Embracing Public-Data Reuse and Crowdsourcing. AB - New technologies have been propelling dramatic increases in the volume and diversity of large-scale public data, which can potentially be reused to answer questions beyond those originally envisioned. However, this often requires computational and statistical skills beyond the reach of most bench scientists. The development of educational and accessible computational tools is thus critical, as are crowdsourcing efforts that utilize the community's expertise to curate public data for hypothesis generation and testing. Here we review the history of public-data reuse and argue for greater incorporation of computational and statistical sciences into the biomedical education curriculum and the development of biologist-friendly crowdsourcing tools. Finally, we provide a resource list for the reuse of public data and highlight an illustrative crowdsourcing exercise to explore public gene-expression data of human autoimmune diseases and corresponding mouse models. Through education, tool development, and community engagement, immunologists will be poised to transform public data into biological insights. PMID- 28002729 TI - The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells. AB - Inflammation triggers the differentiation of Ly6Chi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2 dependent, Flt3+CD11c-MHCII+PU.1hi subset. This subset acted as a precursor for FcgammaRIII+PD-L2+CD209a+, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3 CD11c-MHCII-PU.1lo monocytes differentiated into FcgammaRIII+PD-L2-CD209a-iNOS+ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the precursor activities of monocytes toward moDCs or microbicidal macrophages. Indeed, Sfpi1+/- mice had reduced Flt3+CD11c-MHCII+ monocytes and GM-CSF-dependent FcgammaRIII+PD-L2+CD209a+ moDCs but generated iNOS+ macrophages more efficiently. Therefore, intercellular disparities of PU.1 expression within naive monocytes segregate progenitor activity for inflammatory iNOS+ macrophages or moDCs. PMID- 28002730 TI - Inhaled Fine Particles Induce Alveolar Macrophage Death and Interleukin-1alpha Release to Promote Inducible Bronchus-Associated Lymphoid Tissue Formation. AB - Particulate pollution is thought to function as an adjuvant that can induce allergic responses. However, the exact cell types and immunological factors that initiate the lung-specific immune responses are unclear. We found that upon intratracheal instillation, particulates such as aluminum salts and silica killed alveolar macrophages (AMs), which then released interleukin-1alpha (IL-1alpha) and caused inducible bronchus-associated lymphoid tissue (iBALT) formation in the lung. IL-1alpha release continued for up to 2 weeks after particulate exposure, and type-2 allergic immune responses were induced by the inhalation of antigen during IL-1alpha release and iBALT formation, even long after particulate instillation. Recombinant IL-1alpha was sufficient to induce iBALTs, which coincided with subsequent immunoglobulin E responses, and IL-1-receptor-deficient mice failed to induce iBALT formation. Therefore, the AM-IL-1alpha-iBALT axis might be a therapeutic target for particulate-induced allergic inflammation. PMID- 28002731 TI - Cholesterol Accumulation in CD11c+ Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease. AB - Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR alpha and beta in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c+ cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRbeta-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies. Cholesterol accumulation in lymphoid organs promoted T cell priming and stimulated the production of the B cell growth factors Baff and April. Conversely, B cell expansion and the development of autoantibodies in ApoE/LXR-beta-deficient mice was reversed by ApoA-I expression. These findings implicate cholesterol imbalance as a contributor to immune dysfunction and suggest that stimulating HDL-dependent reverse cholesterol transport could be beneficial in the setting of autoimmune disease. PMID- 28002732 TI - Methyl-CpG/MBD2 Interaction Requires Minimum Separation and Exhibits Minimal Sequence Specificity. AB - Determining the pattern of methylation at CpG dinucleotides in a cell remains an essential component of epigenetic profiling. The correlations among methylation, gene expression, and accompanying disease have just begun to be explored. Many experiments for sensing methylation use a relatively inexpensive, high-throughput approach with a methyl-binding domain (MBD) protein that preferentially binds to methylated CpGs. Here, we characterize the cooperativity and sequence specificity of MBD2-DNA binding in a pulldown experiment revealing three potential biases in such experiments. The first is caused by steric clashes between two MBD2 proteins at mCpGs separated by 2 bp or less, which suggests that simultaneous binding at these sites is inhibited. This is confirmed by comparing input versus pulldown high-throughput sequencing data on M.SssI-treated samples, from which we also find that pulldown efficiency sharply increases for DNA fragments with four or more mCpGs. Analysis of these two data sets was again employed to investigate MBD2's sequence preferences surrounding a methylated CpG (mCpG). In comparing the distributions of bases at positions with respect to an mCpG, statistically significant preferences for certain bases were found, although the corresponding biases in pulldown efficiency were all <5%. While this suggests that mCpG sequence context can mostly be ignored in MBD2 binding, the statistical certainty exhibited by our high-throughput approach bodes well for future applications. PMID- 28002733 TI - Single-Molecule DNA Polymerase Dynamics at a Bacterial Replisome in Live Cells. AB - PolC is one of two essential replicative DNA polymerases found in the Gram positive bacterium Bacillus subtilis. The B. subtilis replisome is eukaryotic like in that it relies on a two DNA polymerase system for chromosomal replication. To quantitatively image how the replicative DNA polymerase PolC functions in B. subtilis, we applied photobleaching-assisted microscopy, three dimensional superresolution imaging, and single-particle tracking to examine the in vivo behavior of PolC at single-molecule resolution. We report the stoichiometry of PolC proteins within each cell and within each replisome, we elucidate the diffusion characteristics of individual PolC molecules, and we quantify the exchange dynamics for PolC engaged in lagging strand synthesis. We show that PolC is highly dynamic: this DNA polymerase is constantly recruited to and released from a centrally located replisome, providing, to our knowledge, new insight into the organization and dynamics of the replisome in bacterial cells. PMID- 28002734 TI - SF1 Phosphorylation Enhances Specific Binding to U2AF65 and Reduces Binding to 3' Splice-Site RNA. AB - Splicing factor 1 (SF1) recognizes 3' splice sites of the major class of introns as a ternary complex with U2AF65 and U2AF35 splicing factors. A conserved SPSP motif in a coiled-coil domain of SF1 is highly phosphorylated in proliferating human cells and is required for cell proliferation. The UHM kinase 1 (UHMK1), also called KIS, double-phosphorylates both serines of this SF1 motif. Here, we use isothermal titration calorimetry to demonstrate that UHMK1 phosphorylation of the SF1 SPSP motif slightly enhances specific binding of phospho-SF1 to its cognate U2AF65 protein partner. Conversely, quantitative fluorescence anisotropy RNA binding assays and isothermal titration calorimetry experiments establish that double-SPSP phosphorylation reduces phospho-SF1 and phospho-SF1-U2AF65 binding affinities for either optimal or suboptimal splice-site RNAs. Domain substitution and mutagenesis experiments further demonstrate that arginines surrounding the phosphorylated SF1 loop are required for cooperative 3' splice site recognition by the SF1-U2AF65 complex (where cooperativity is defined as a nonadditive increase in RNA binding by the protein complex relative to the individual proteins). In the context of local, intracellular concentrations, the subtle effects of SF1 phosphorylation on its associations with U2AF65 and splice site RNAs are likely to influence pre-mRNA splicing. However, considering roles for SF1 in pre-mRNA retention and transcriptional repression, as well as in splicing, future comprehensive investigations are needed to fully explain the requirement for SF1 SPSP phosphorylation in proliferating human cells. PMID- 28002735 TI - Characterization of the Folding of a 52-Knotted Protein Using Engineered Single Tryptophan Variants. AB - An increasing number of proteins that contain topological knots have been identified over the past two decades; however, their folding mechanisms are still not well understood. UCH-L1 has a 52-knotted topology. Here, we constructed a series of variants that contain a single tryptophan at different locations along the polypeptide chain. A study of the thermodynamic properties of the variants shows that the structure of UCH-L1 is remarkably tolerant to incorporation of bulky tryptophan side chains. Comprehensive kinetic studies of the variants reveal that they fold via parallel pathways on which there are two intermediate states very similar to wild-type UCH-L1. The structures of the intermediate states do not change significantly with mutation and therefore occupy local minima on the energy landscape that have relatively narrow basins. The kinetic studies also establish that there are considerably more tertiary interactions in the intermediate states than results from previous NMR studies suggested. The two intermediates differ from each other in the extent to which tertiary interactions between the highly stable central beta-sheet and flanking alpha-helices and loop regions are formed. There is strong evidence that these states are aggregation prone. The transition states from both I1 and I2 to the native state are plastic and change with mutation and denaturant concentration. Previous studies indicated that the threading event that creates the 52 knot occurs during these steps, suggesting that there is a broad energy barrier consistent with the chain undergoing some searching of conformational space as the threading takes place. PMID- 28002736 TI - A Unique Light-Driven Proton Transportation Signal in Halorhodopsin from Natronomonas pharaonis. AB - Halorhodopsin (HR) is a seven-transmembrane retinylidene protein from haloarchaea that is commonly known to function as a light-driven inward chloride pump. However, previous studies have indicated that despite the general characteristics that most HRs share, HRs from distinct species differ in many aspects. We present indium-tin-oxide-based photocurrent measurements that reveal a light-induced signal generated by proton release that is observed solely in NpHR via purified protein-based assays, demonstrating that indeed HRs are not all identical. We conducted mutagenesis studies on several conserved residues that are considered critical for chloride stability among HRs. Intriguingly, the photocurrent signals were eliminated after specific point mutations. We propose an NpHR light-driven, cytoplasmic-side proton circulation model to explain the unique light-induced photocurrent recorded in NpHR. Notably, the photocurrent and various photocycle intermediates were recorded simultaneously. This approach provides a high resolution method for further investigations of the proton-assisted chloride translocation mechanism. PMID- 28002737 TI - Heterotypic Coiled-Coil Formation is Essential for the Correct Assembly of the Septin Heterofilament. AB - Protein-protein interactions play a critical role in promoting the stability of protein quaternary structure and in the assembly of large macromolecular complexes. What drives the stabilization of such assemblies is a central question in biology. A limiting factor in fully understanding such systems is the transient nature of many complexes, making structural studies difficult. Septins comprise a conserved family of guanine nucleotide binding proteins that polymerize in the form of heterofilaments. In structural terms, they have a common organization: a central GTPase domain, an N-terminal domain, and a C terminal domain; the latter is predicted to form a coiled coil. Currently, even for the best characterized human septin heterocomplex (SEPT2/SEPT6/SEPT7), the role of C-terminal domain is not fully established, and this is partly due to the absence of electron density for the C-terminal domains in the x-ray structure. Here we present results on the homo/heterotypical affinity for the C-terminal domains of human septins belonging to the SEPT6 and SEPT7 groups (SEPT6C/8C/10C/11C and SEPT7C, respectively) and provide clear evidence that this domain determines the preference for heterotypic interactions at one specific interface during the assembly of the heterofilament. This observation has wider implications where macromolecular assemblies are defined by coiled-coil protein interactions. PMID- 28002738 TI - Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain. AB - The signaling of a G protein-coupled receptor (GPCR) is dictated by the complementary responsiveness of interacting intracellular effectors such as G proteins. Many GPCRs are known to couple to more than one G protein subtype and induce a multitude of signaling pathways, although the in vivo relevance of particular pathways is mostly unrecognized. Dissecting GPCR signaling in terms of the pathways that are activated will boost our understanding of the molecular fundamentals of hormone action. The structural determinants governing the selectivity of GPCR/G protein coupling, however, remain obscure. Here, we describe the design of soluble GPCR mimetics to study the details of the interplay between G-proteins and activators. We constructed functional mimetics of the intracellular domain of a model GPCR, the thyrotropin receptor. We based the construction on a unique scaffold, 6-Helix, an artificial protein that was derived from the elements of the trimer-of-hairpins structure of HIV gp41 and represents a bundle of six alpha-helices. The 6-Helix scaffold, which endowed the substituted thyrotropin receptor intracellular domain elements with spatial constraints analogous to those found in native receptors, enabled the reconstitution of a microdomain that consists of intracellular loops 2 and 3, and is capable of binding and activating Galpha-(s). The 6-Helix-based mimetics could be used as a platform to study the molecular basis of GPCR/G protein recognition. Such knowledge could help investigators develop novel therapeutic strategies for GPCR-related disorders by targeting the GPCR/G protein interfaces and counteracting cellular dysfunctions via focused tuning of GPCR signaling. PMID- 28002739 TI - Hydrogen Bond Network of Water around Protein Investigated with Terahertz and Infrared Spectroscopy. AB - The dynamical and structural properties of water at protein interfaces were characterized on the basis of the broadband complex dielectric constant (0.25 to 400 THz) of albumin aqueous solutions. Our analysis of the dielectric responses between 0.25 and 12 THz first revealed hydration water with retarded reorientational dynamics extending ~8.5 A (corresponding to three to four layers) out from the albumin surface. Second, the number of nonhydrogen-bonded water was decreased in the presence of the albumin solute, indicating protein inhibits the fragmentation of the water hydrogen-bond network. Finally, water molecules at the albumin interface were found to form a distorted hydrogen-bond structure due to topological and energetic disorder of the protein surface. In addition, the intramolecular O-H stretching vibration of water (~100 THz), which is sensitive to hydrogen-bond environment, pointed to a trend that hydration water has a larger population of strongly hydrogen-bonded water molecules compared with that of bulk water. From these experimental results, we concluded that the "strengthened" water hydrogen bonds at the protein interface dynamically slow down the reorientational motion of water and form the less-defective hydrogen bond network by inhibiting the fragmentation of water-water hydrogen bonds. Nevertheless, such a strengthened water hydrogen-bond network is composed of heterogeneous hydrogen-bond distances and angles, and thus characterized as structurally "distorted." PMID- 28002740 TI - The Dynamic Behavior of the P2X4 Ion Channel in the Closed Conformation. AB - We present the results of a detailed molecular dynamics study of the closed form of the P2X4 receptor. The fluctuations observed in the simulations were compared with the changes that occur in the transition from the closed to the open structure. To get further insight on the opening mechanism, the actual displacements were decomposed into interchain motions and intrachain deformations. This analysis revealed that the iris-like expansion of the transmembrane helices mainly results from interchain motions that already take place in the closed conformation. However, these movements cannot reach the amplitude required for the opening of the channel because they are impeded by interactions occurring around the ATP binding pocket. This suggests that the union of ATP produces distortions in the chains that eliminate the restrictions on the interchain displacements, leading to the opening of the pore. PMID- 28002741 TI - Shape Transformations of Lipid Bilayers Following Rapid Cholesterol Uptake. AB - High cholesterol levels in the blood increase the risk of atherosclerosis. A common explanation is that the cholesterol increase in the plasma membrane perturbs the shape and functions of cells by disrupting the cell signaling pathways and the formation of membrane rafts. In this work, we show that after enhanced transient uptake of cholesterol, mono-component lipid bilayers change their shape similarly to cell membranes in vivo. The bilayers either expel lipid protrusions or spread laterally as a result of the ensuing changes in their lipid density, the mechanical constraints imposed on them, and the properties of cyclodextrin used as a cholesterol donor. In light of the increasingly recognized link between membrane tension and cell behavior, we propose that the physical adaptation of the plasma membrane to cholesterol uptake may play a substantial role in the biological response. PMID- 28002742 TI - Cadherin Diffusion in Supported Lipid Bilayers Exhibits Calcium-Dependent Dynamic Heterogeneity. AB - Ca2+ ions are critical to cadherin ectodomain rigidity, which is required for the activation of adhesive functions. Therefore, changes in Ca2+ concentration, both in vivo and in vitro, can affect cadherin conformation and function. We employed single-molecule tracking to measure the diffusion of cadherin ectodomains tethered to supported lipid bilayers at varying Ca2+ concentrations. At a relatively high Ca2+ concentration of 2 mM, cadherin molecules exhibited a fast diffusion coefficient that was identical to that of individual lipid molecules in the bilayer (Dfast ~ 3 MUm2/s). At lower Ca2+ concentrations, where cadherin molecules were less rigid, the ensemble-average cadherin diffusion coefficient was systematically smaller. Individual cadherin trajectories were temporally heterogeneous, exhibiting alternating periods of fast and slow diffusion; the periods of slow diffusion (Dslow ~ 0.1 MUm2/s) were more prevalent at lower Ca2+ concentration. These observations suggested that more flexible cadherin ectodomains at lower Ca2+ concentration alternated between upright and lying-down conformations, where the latter interacted with more lipid molecules and experienced greater viscous drag. PMID- 28002743 TI - Ordered Membrane Domain-Forming Properties of the Lipids of Borrelia burgdorferi. AB - Co-existing disordered and ordered (raft) membrane domains exist in Borrelia burgdorferi, the causative agent of Lyme disease. However, although B. burgdorferi contains cholesterol lipids, it lacks sphingolipids-a crucial component of rafts in eukaryotes. To define the principles of ordered lipid domain formation in Borrelia, the domain forming properties of vesicles composed of its three major lipids, acylated cholesteryl galactoside (ACGal), monogalactosyl diacyglycerol (MGalD), and phosphatidylcholine (PC) and/or their mixtures were studied. Anisotropy and fluorescence resonance energy transfer measurements were used to assay membrane order and ordered-domain formation. ACGal had the highest potential to form ordered domains. Interestingly, mixtures of ACGal with B. burgdorferi PC formed ordered domains more readily than mixtures of ACGal with MGalD. This appears to reflect the relatively high level of saturation observed for B. burgdorferi PC, as vesicles containing ACGal and PC, but in which the unsaturated lipid dioleoyl PC was substituted for Borrelia PC, failed to form ordered domains. In addition, the properties of ACGal were compared to those of cholesterol. Depending on what other lipids were present, ordered-domain formation in the presence of ACGal was greater than or equal to that in the presence of cholesterol. Giant unilamellar vesicles formed from ACGal containing mixtures showed rounded domain shapes similar to those in analogous vesicles containing cholesterol, indicative of liquid-ordered state rather than solid-like gel-state domain formation. Over all, principles of ordered-domain formation in B. burgdorferi appear to be very similar to those in eukaryotes, with saturated PC taking the place of sphingolipids, but with ACGal being the main lipid component inducing ordered-domain formation. PMID- 28002745 TI - Toward Hydrodynamics with Solvent Free Lipid Models: STRD Martini. AB - Solvent hydrodynamics are incorporated into simulations of the solvent-free Dry Martini model. The solvent hydrodynamics are modeled with the stochastic rotation dynamics (SRD) algorithm, a particle-based method for resolving fluid hydrodynamics. SRD does not require calculation of particle-particle distances in the solvent, and so is scalable to arbitrary volumes of solvent with minimal additional computational overhead. The viscosity of the solvent is easily tuned via parameters of the algorithm to span an order of magnitude in viscosity around the viscosity of water at room temperature. The combination "Stochastic Thermostatted Rotation Dynamics (STRD) with Martini" was implemented in Gromacs v.5.01. Simulations of an SRD/palmitoyloleoylphosphatidylcholine membrane demonstrate that the solvent may be included without reparametrizing the lipid model, with minimal perturbation to the thermodynamics. A recent generalization of Saffman-Delbruck theory to periodic geometries by Camley and Brown indicates that lipid dynamics are contaminated by a finite-size effect in typical molecular dynamics (MD) simulations, and that very large systems are required for quantitative simulation of dynamics. Analysis of lipid translational diffusion in this work shows good agreement with the theory, and with explicitly solvated simulations. This indicates that STRD Martini is a viable approach for quantitative simulation of membrane dynamics and does not require massive computational overhead to model the solvent. PMID- 28002744 TI - Structural and Dynamic Insights of the Interaction between Tritrpticin and Micelles: An NMR Study. AB - A large number of antimicrobial peptides (AMPs) acts with high selectivity and specificity through interactions with membrane lipid components. These peptides undergo complex conformational changes in solution; upon binding to an interface, one major conformation is stabilized. Here we describe a study of the interaction between tritrpticin (TRP3), a cathelicidin AMP, and micelles of different chemical composition. The peptide's structure and dynamics were examined using one-dimensional and two-dimensional NMR. Our data showed that the interaction occurred by conformational selection and the peptide acquired similar structures in all systems studied, despite differences in detergent headgroup charge or dipole orientation. Fluorescence and paramagnetic relaxation enhancement experiments showed that the peptide is located in the interface region and is slightly more deeply inserted in 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-1' rac-glycerol (LMPG, anionic) than in 1-lauroyl-2-hydroxy-sn-glycero-3 phosphocholine (LLPC, zwitterionic) micelles. Moreover, the tilt angle of an assumed helical portion of the peptide is similar in both systems. In previous work we proposed that TRP3 acts by a toroidal pore mechanism. In view of the high hydrophobic core exposure, hydration, and curvature presented by micelles, the conformation of TRP3 in these systems could be related to the peptide's conformation in the toroidal pore. PMID- 28002746 TI - Frustrated Phagocytic Spreading of J774A-1 Macrophages Ends in Myosin II Dependent Contraction. AB - Conventional studies of dynamic phagocytic behavior have been limited in terms of spatial and temporal resolution due to the inherent three-dimensionality and small features of phagocytosis. To overcome these issues, we use a series of frustrated phagocytosis assays to quantitatively characterize phagocytic spreading dynamics. Our investigation reveals that frustrated phagocytic spreading occurs in phases and is punctuated by a distinct period of contraction. The spreading duration and peak contact areas are independent of the surface opsonin density, although the opsonin density does affect the likelihood that a cell will spread. This reinforces the idea that phagocytosis dynamics are primarily dictated by cytoskeletal activity. Structured illumination microscopy reveals that F-actin is reorganized during the course of frustrated phagocytosis. F-actin in early stages is consistent with that observed in lamellipodial protrusions. During the contraction phase, it is bundled into fibers that surround the cell and is reminiscent of a contractile belt. Using traction force microscopy, we show that cells exert significant strain on the underlying substrate during the contraction phase but little strain during the spreading phase, demonstrating that phagocytes actively constrict during late-stage phagocytosis. We also find that late-stage contraction initiates after the cell surface area increases by 225%, which is consistent with the point at which cortical tension begins to rise. Moreover, reducing tension by exposing cells to hypertonic buffer shifts the onset of contraction to occur in larger contact areas. Together, these findings provide further evidence that tension plays a significant role in signaling late-stage phagocytic activity. PMID- 28002747 TI - Mechanical Criterion for the Rupture of a Cell Membrane under Compression. AB - We investigate the mechanical conditions leading to the rupture of the plasma membrane of an endothelial cell subjected to a local, compressive force. Membrane rupture is induced by tilted microindentation, a technique used to perform mechanical measurements on adherent cells. In this technique, the applied force can be deduced from the measured horizontal displacement of a microindenter's tip, as imaged with an inverted microscope and without the need for optical sensors to measure the microindenter's deflection. We show that plasma membrane rupture of endothelial cells occurs at a well-defined value of the applied compressive stress. As a point of reference, we use numerical simulations to estimate the magnitude of the compressive stresses exerted on endothelial cells during the deployment of a stent. PMID- 28002748 TI - A Mathematical Model of Venous Thrombosis Initiation. AB - We present a mathematical model for the initiation of venous thrombosis (VT) due to slow flow and the consequent activation of the endothelial cells (ECs) lining the vein, in the absence of overt mechanical disruption of the EC layer. It includes all reactions of the tissue factor (TF) pathway of coagulation through fibrin formation, incorporates the accumulation of blood cells on activated ECs, accounts for the flow-mediated delivery and removal of coagulation proteins and blood cells from the locus of the reactions, and accounts for the activity of major inhibitors including heparan-sulfate-accelerated antithrombin and activated protein C. The model reveals that the occurrence of robust thrombin generation (a thrombin burst) depends in a threshold manner on the density of TF on the activated ECs and on the concentration of thrombomodulin and the degree of heparan-sulfate accelerated antithrombin activity on those cells. Small changes in any of these in appropriate narrow ranges switches the response between "no burst" and "burst." The model predicts synergies among the inhibitors, both in terms of each inhibitor's multiple targets, and in terms of interactions between the different inhibitors. The model strongly suggests that the rate and extent of accumulation of activated monocytes, platelets, and MPs that can support the coagulation reactions has a powerful influence on whether a thrombin burst occurs and the thrombin response when it does. The slow rate of accumulation of cells supporting coagulation is one reason that the progress of VT is so much slower than that of arterial thrombosis initiated by subendothelial exposure. PMID- 28002749 TI - Hexagonal Patterning of the Insect Compound Eye: Facet Area Variation, Defects, and Disorder. AB - The regular hexagonal array morphology of facets (ommatidia) in the Drosophila compound eye is accomplished by regulation of cell differentiation and planar cell polarity during development. Mutations in certain genes disrupt regulation, causing a breakdown of this perfect symmetry, so that the ommatidial pattern shows onset of disorder in the form of packing defects. We analyze a variety of such mutants and compare them to normal (wild-type), finding that mutants show increased local variation in ommatidial area, which is sufficient to induce a significant number of defects. A model formalism based on Voronoi construction is developed to predict the observed correlation between ommatidium size variation and the number of defects, and to study the onset of disorder in this system with statistical tools. The model uncovers a previously unknown large-scale systematic size variation of the ommatidia across the eye of both wild-type and mutant animals. Such systematic variation of area, as well as its statistical fluctuations, are found to have distinct effects on eye disorder that can both be quantitatively modeled. Furthermore, the topological order is also influenced by the internal structure of the ommatidia, with cells of greater relative mechanical stiffness providing constraints to ommatidial deformation and thus to defect generation. Without free parameters, the simulation predicts the size topology correlation for both wild-type and mutant eyes. This work develops formalisms of size-topology correlation that are very general and can be potentially applied to other cellular structures near the onset of disorder. PMID- 28002750 TI - Local Turgor Pressure Reduction via Channel Clustering. AB - The primary drivers of yeast endocytosis are actin polymerization and curvature generating proteins, such as clathrin and BAR domain proteins. Previous work has indicated that these factors may not be capable of generating the forces necessary to overcome turgor pressure. Thus local reduction of the turgor pressure, via localized accumulation or activation of solute channels, might facilitate endocytosis. The possible reduction in turgor pressure was calculated numerically, by solving the diffusion equation through a Legendre polynomial expansion. It was found that for a region of increased permeability having radius 45 nm, as few as 60 channels with a spacing of 10 nm could locally decrease the turgor pressure by 50%. We identified a key dimensionless parameter, p = P1a/D, where P1 is the increased permeability, a is the radius of the permeable region, and D is the solute diffusion coefficient. When p > 0.44, the turgor pressure is locally reduced by >50%. An approximate analytic theory was used to generate explicit formulas for the turgor pressure reduction in terms of key parameters. These findings may also be relevant to plants, where the mechanisms that allow endocytosis to proceed despite high turgor pressure are largely unknown. PMID- 28002752 TI - Coronary atherosclerosis burden by coronary computed tomography in type II diabetes with preclinical non-obstructive carotid atherosclerosis and without inducible myocardial ischemia. AB - AIMS: To quantify cardiovascular risk in persons with type-2 diabetes (DM) and established carotid atherosclerosis, without inducible myocardial ischemia by stress imaging. METHODS: We selected clinically healthy DM and subjects without DM (nonDM, controls) with non-obstructive carotid atherosclerosis and without significant coronary artery disease (CAD) by stress echocardiography. Coronary flow velocity reserve (CFR) was assessed during stress echocardiography. In those with negative stress imaging, coronary artery calcium (CAC) assessment by computed tomography (CT) was proposed. Outcome at 180-day follow-up was performed by visits or telephone interview. RESULTS: Total CAC was greater in DM (n=19) than in nonDM (n=19, CAC: 225+/-158 vs 78+/-65Agatston units, 156+/-161 vs 53+/ 51 in the left anterior descendent artery, both p<0.05). Coronary stenosis burden was greater in DM than in nonDM, albeit <75% in all cases; CFR was lower in DM than nonDM (p<0.05). Mean age was slightly higher (69+/-6 vs 64+/-12, p>0.2), and male gender tended to be less frequent (63 vs 79%) with DM than with nonDM; all subjects showed dyslipidemia, and almost all had arterial hypertension. Based on CAC, a 10-year cardiovascular risk was 10-20% in 78% of the DM and in 28% of the non-DM, and was >20% in 11% of the DM but in none of the nonDM. A single non fatal myocardial infarction was recorded within 180days from test, among DM. CONCLUSIONS: Based on CAC, in the presence of non-obstructive carotid atherosclerosis, asymptomatic DM may show significantly higher CAD burden than nonDM even in the absence of inducible myocardial ischemia. PMID- 28002751 TI - Validity of hospital discharge records to identify pregestational diabetes in an Italian population. AB - AIMS: In recent years, the prevalence of pregestational diabetes (PGDM) and the concern about the possibility of adverse pregnancy outcomes in affected women have been increasing. Routinely collected health data represent a timely and cost efficient approach in PGDM epidemiological research. This study aims to evaluate the reliability of hospital discharge (HD) coding to identify a population-based cohort of pregnant women with PGDM and to assess trends in prevalence in two provinces of Northern Italy. METHODS: We selected all deliveries occurred in the period 1997-2010 with ICD-9-CM codes for PGDM in HD record and we matched up to 5 controls from mothers without diabetes. We used Diabetes Registers (DRs) as the gold standard for validation analysis. RESULTS: We selected 3800 women, 653 with diabetes and 3147 without diabetes. The agreement between HD records and DRs was 90.7%, with K=0.58. We detected 350 false positives and only 1 false negative. Sensitivity was 99.3%, specificity 90.0%, positive predictive value 46.4% and negative predictive value 99.9%. Of the false positives, 48.6% had gestational diabetes and 2.3% impaired glucose tolerance. After the validation process, PGDM prevalence decreased from 4.4 to 2.0 per 1000 deliveries. CONCLUSIONS: Our results show that HD facilitate detection of almost all PGDM cases, but they also include a large number of false positives, mainly due to gestational diabetes. This misclassification causes a large overestimation of PGMD prevalence. Our findings require accuracy evaluation of ICD-9-CM codes, before they can be widely applied to epidemiological research and public health surveillance related to PGDM. PMID- 28002753 TI - Fatigue in type 1 diabetes: A systematic review of Observational studies. AB - AIM: To systematically review the literature on fatigue in people with type 1 diabetes. METHODS: In the period from April to June 2015 and with an updated search in May 2016, eight electronic databases as well as the grey literature were searched. Studies of all types of design were included if they reported data on fatigue in adult people with type 1 diabetes. All studies were assessed for quality. RESULTS: Out of 4259 references (including grey literature), 10 papers were reviewed in full. Three of these papers investigated fatigue as the primary endpoint, and one was assessed to be high quality. Two papers provided a definition of fatigue. Prevalence estimates ranged from 23 to 40%, dependent on the cut-off used. Six different questionnaires were used to measure fatigue/vitality and these were only validated to a limited extent in a diabetes population. Several demographic, personal and clinical factors were associated with fatigue, but the results were conflicting. CONCLUSIONS: Few studies have been published that investigate fatigue in type 1 diabetes and there is a large variability in findings due to different measurement methods and factors investigated. There is still an unmet need to understand what contributes to fatigue in these patients through rigorous research. PMID- 28002754 TI - Iron nanomedicines induce Toll-like receptor activation, cytokine production and complement activation. AB - Approximately a dozen of intravenous iron nanomedicines gained marketing authorization in the last two decades. These products are generally considered as safe, but have been associated with an increased risk for hypersensitivity-like reactions of which the underlying mechanisms are unknown. We hypothesized that iron nanomedicines can trigger the innate immune system. We hereto investigated the physico-chemical properties of ferric gluconate, iron sucrose, ferric carboxymaltose and iron isomaltoside 1000 and comparatively studied their interaction with Toll-like receptors, the complement system and peripheral blood mononuclear cells. Two out of four formulations appeared as aggregates by Scanning Transmission Electron Microscopy analysis and were actively taken up by HEK293T- and peripheral blood mononuclear cells in a cholesterol-dependent manner. These formulations triggered in vitro activation of intracellular Toll like receptors 3, -7 and -9 in a dose- and serum-dependent manner. In parallel experiments, we determined that these compounds activated the complement system. Finally, we found that uptake of aggregation-prone iron nanomedicines by peripheral blood mononuclear cells in whole blood induced production of the proinflammatory cytokine IL-1beta, but not IL-6. PMID- 28002755 TI - Meta-analysis of social cognition in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is associated with executive dysfunction and behavioural impairment. Recent studies suggested that social cognitive deficits might also be a prominent feature of ALS. Current meta-analysis aimed to summarize available evidence for deficits in social cognition including theory of mind (ToM) and emotion recognition in ALS. In this meta-analysis of 15 studies, facial emotion recognition and ToM performances of 389 patients with ALS and 471 healthy controls were compared. ALS was associated with significant impairments with medium effect sizes in ToM (d = .65) and facial emotion recognition (d = .69). Among individual emotions recognition of disgust and surprise were particularly impaired. Deficits in perspective taking (d = .73) aspects of ToM (ToM-PT) was more pronounced in comparison to decoding (d = .28) aspects of ToM (ToM-decoding). The severity of social cognitive impairment was similar to level of executive dysfunction and there was a significant relationship between social cognition and executive dysfunction. Deficits in social cognition are part of the cognitive phenotype of ALS. PMID- 28002756 TI - Co-creation of a pedagogical space to support qualitative inquiry: An advanced qualitative collective. AB - BACKGROUND: Situated in a research-intensive School of Nursing, the Advanced Qualitative Collective (AQC) provides an innovative educational forum for the study of qualitative research by doctoral and postdoctoral scholars. This long standing collective is guided by a faculty facilitator using a collaborative co learning approach to address individual and group needs, from the conception of research projects through dissemination of completed qualitative research. This article describes the dynamics of the AQC and the ways a co-created pedagogical entity supports professional development among its diverse members. The informal, participatory style, and dynamic content used by the AQC resists a course structure typical of doctoral education in health sciences, and promotes engagement and self-direction. The AQC provides opportunities for members to examine theoretical frameworks and methodologies rarely addressed within a positivism-dominant learning environment while simultaneously serving as an alternative exemplar for the pedagogy of research. PMID- 28002757 TI - The Khorana score for the prediction of venous thromboembolism in patients with pancreatic cancer. AB - BACKGROUND: The Khorana score is a clinical prediction score developed to identify ambulatory cancer patients at high risk of venous thromboembolism (VTE), who may be eligible for thromboprophylaxis. This score has been validated in various populations with cancer, but its performance in patients with pancreatic cancer is less clear. PATIENTS AND METHODS: This is a single center, retrospective cohort study in which consecutive, ambulatory patients with pancreatic adenocarcinoma, who started neoadjuvant or palliative chemotherapy at our center between 2003 and 2014 were included. At baseline, the Khorana score classified patients as 'intermediate risk' (2 points) or 'high risk' (>=3 points) for VTE. The primary outcome was the composite of objectively confirmed symptomatic or incidental lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE) during 2-year follow-up. RESULTS: The study group comprised 178 patients. The mean age was 62years and 62% had distant metastasis. Overall, 22 of 178 patients (12.4%) developed lower extremity DVT or PE. The estimated cumulative incidence at 6months was 8.2% in 'intermediate risk' patients and 9.5% in the 'high risk' patients (subhazard ratio for first 6months: 1.23; 95% CI: 0.41-3.65). At 2years, the cumulative incidence was higher in 'intermediate risk' patients (15.3%) than in 'high risk' patients (10.1%). CONCLUSIONS: In the present study, the Khorana score was not able to discriminate between pancreatic cancer patients at intermediate risk and high risk of VTE. Physicians should have a low threshold of considering thromboprophylaxis in patients with pancreatic cancer given the high absolute VTE risk. PMID- 28002758 TI - Association between schizophrenia and urinary incontinence: A population-based study. AB - BACKGROUND: Urinary incontinence (UI) is defined as the involuntary loss of urine and can constitute a hygiene or social problem for affected patients. Whether the UI incidence is higher in patients with schizophrenia than in the general population remains undetermined. METHODS: The patients were selected from the Taiwan National Health Insurance Research Database, using claims data from 2005 to 2011. We compared the risk of UI between schizophrenia and nonschizophrenia groups. Logistic regression models were employed for analyzing the risk of UI after adjustment for sex, age, and comorbidities. RESULTS: The adjusted odds ratio for UI in the schizophrenia group was 1.78-fold higher than that in the nonschizophrenia group. Furthermore, male patients with schizophrenia were more susceptible to UI than their female counterparts, and a higher risk of UI was observed among younger patients with schizophrenia. CONCLUSION: Compared with the general population, the risk of UI was higher among the patients with schizophrenia. Early diagnosis and intervention can increase the quality of life among patients with schizophrenia. PMID- 28002759 TI - On-line prediction of sodium content in vacuum packed dry-cured ham slices by non invasive near infrared spectroscopy. AB - In the present study, non-invasive near infrared spectroscopy (NIRS) was evaluated as a potential on-line analytical technique to predict the sodium content in dry-cured ham slices. Samples of 310 packages were scanned by applying a remote fibre-optic probe to the surface of the slices, at different temperatures, with no previous manipulation. The sodium content of the meat samples was determined by a reference method based on Inductively Coupled Plasma Atomic Emission Spectrophotometry (ICP-AES) after chemical digestion. Partial least squares (PLS) regression was used as a chemometrics method to perform the calibrations. The models yielded acceptable results with cross validation correlation coefficients (R2CV) determined 86.2-90.2%. The prediction capacity reached in the external validation was 3.63, with a standard prediction error of 0.12% Na. These results show that NIR measurements could be implemented on the packaging line of dry-cured ham slices to provide accurate and relevant information about the sodium content of each packaged products. PMID- 28002760 TI - Evaluating filterability of different types of sludge by statistical analysis: The role of key organic compounds in extracellular polymeric substances. AB - An investigation was conducted for 20 different types of sludge in order to identify the key organic compounds in extracellular polymeric substances (EPS) that are important in assessing variations of sludge filterability. The different types of sludge varied in initial total solids (TS) content, organic composition and pre-treatment methods. For instance, some of the sludges were pre-treated by acid, ultrasonic, thermal, alkaline, or advanced oxidation technique. The Pearson's correlation results showed significant correlations between sludge filterability and zeta potential, pH, dissolved organic carbon, protein and polysaccharide in soluble EPS (SB EPS), loosely bound EPS (LB EPS) and tightly bound EPS (TB EPS). The principal component analysis (PCA) method was used to further explore correlations between variables and similarities among EPS fractions of different types of sludge. Two principal components were extracted: principal component 1 accounted for 59.24% of total EPS variations, while principal component 2 accounted for 25.46% of total EPS variations. Dissolved organic carbon, protein and polysaccharide in LB EPS showed higher eigenvector projection values than the corresponding compounds in SB EPS and TB EPS in principal component 1. Further characterization of fractionized key organic compounds in LB EPS was conducted with size-exclusion chromatography-organic carbon detection-organic nitrogen detection (LC-OCD-OND). A numerical multiple linear regression model was established to describe relationship between organic compounds in LB EPS and sludge filterability. PMID- 28002761 TI - An intraovarian mechanism that enhances the effect of an FSH surge on recovery of subordinate follicles in heifers. AB - The effect of the future dominant follicle (DF), corpus luteum (CL), and side (left ovary [LO] and right ovary [RO]) on FSH-induced recovery (increase in diameter) of regressing subordinate follicles was studied in heifers. The DF of wave 2 and the largest subordinate follicle remained intact (controls, n = 14 heifers) or were ablated (n = 14 heifers) on a mean of 13 d postovulation when the DF was ~10 mm (hour 0). Concentration of FSH (P < 0.0004) and diameter of subordinate follicles (P < 0.0002) decreased between hours -48 to 0 combined for the control and ablation groups. Thereafter, follicle diameter continued to decrease in the controls. Concentration of FSH increased (P < 0.05) and diameter of subordinates began to increase at hour 12 in the ablation group. Follicle stimulating hormone increased to hour 24 and then returned to the hour 0 concentration by hour 72, completing the induced FSH surge. Concentration of LH began to increase at hour 0 in each group and at a similar rate between groups. Follicle recovery in the ablation group was compared among 8 subgroups as defined by the 2 sides and 4 intraovarian patterns (DF-CL pattern, both structures in same ovary; DF pattern, DF alone; CL pattern, CL alone; and devoid pattern, both structures absent). Follicle diameter increased (P < 0.05) between hours 24 and 48, and diameter at hours 24, 48, 72, and 96 involved a 3-way interaction (P < 0.0001) of pattern, side, and hour. The interaction was similar when diameter of the DF that originated from a recovered subordinate was either included or excluded in the analysis. Diameter of subordinate follicles in the ablation group at hour 96 was greater (P < 0.05) in the DF-CL/RO and DF/RO subgroups than that in the devoid/LO, devoid/RO, and CL/LO subgroups. The DF-CL/LO and CL/RO subgroups were intermediate. For follicles that decreased in diameter before hour 0, a greater (P < 0.05) percentage increased after hour 0 when the ovary contained a DF and was in the RO (DF-CL/RO and DF/RO subgroups) than for the remaining subgroups even after excluding the DF that originated from a subordinate. Results supported the hypotheses that (1) an induced FSH surge can stimulate the recovery of regressing subordinate follicles and (2) recovery of regressing subordinate follicles by FSH involves an intraovarian mechanism. Our interpretation is that the intraovarian mechanism that enhances the stimulatory effect of FSH on recovery of subordinate follicles was effective only in RO and only when it contained a DF. PMID- 28002762 TI - Long-circulating polyhydroxybutyrate-co-hydroxyvalerate nanoparticles for tumor targeted docetaxel delivery: Formulation, optimization and in vitro characterization. AB - In the present research an attempt was made to develop and optimize docetaxel loaded polyhydroxybutyrate-co-hydroxyvalerate (PHBV) nanoparticles, using modified emulsification solvent evaporation technique and design of experiment (DOE) methodology. Formulation of docetaxel-loaded PHBV nanoparticles was conducted by factor screening studies with Plackett-Burman design (PBD) followed by Box-Behnken experimental design (BBD) to evaluate the effect of independent variables on responses. Five most important independent variables were screened out, which were obtained from failure mode effect analysis (FMEA) and factor screening studies. The effect of formulation parameters on selected responses was depicted by 2-D and 3-D response surface methodology (RSM). The final optimized batch was evaluated by various in vitro characterizations. The observed particle size, zeta potential and entrapment efficiency of optimized formulation was found to be 283+/-2.79nm, -17+/-2.64mV and 44+/-0.59% respectively. Morphological studies demonstrated the smooth and spherical shape of nanoparticles. In vitro drug release follows the Peppas-Korsmeyer model of drug release kinetics. Cytotoxicity study was assessed using MCF-7 for percentage inhibition of human breast cancer cell line. These results indicate that the PHBV Nanoparticles could be a promising drug delivery system for efficient prolong drug release. PMID- 28002764 TI - Identify biosorption effects of Thiobacillus towards perfluorooctanoic acid (PFOA): Pilot study from field to laboratory. AB - The concentration of Perfluoroalkyl acids (PFAAs) and the bacterial community composition along the Xiaoqing River were explored with HPLC-MS/MS and Illumina high-throughput sequencing in present study. The results showed that perfluorooctanoic acid (PFOA) was the predominant PFAAs in all sediment samples, and high level of PFOA could lead to an evident increase in the abundance of Thiobacillus. Thiobacillus was identified with the survival ability in high concentrations of PFOA accordingly. Therefore, Thiobacillus thioparus and Thiobacillus denitrificans were selected as receptors to design indoor biosorption experiment. The growth curves under different PFOA concentrations and residual rates of PFOA in the processes of cultivation were analyzed. The results showed that upwards concentrations of PFOA below 5000 ng/L led to an obvious increase in the growth rate of T. thioparus. Whereas PFOA promoted the growth of T. denitrificans in a relatively limited range of concentration, and the effect was not obvious. The addition of different concentrations of PFOA had no apparent effects on pH values in the media of both T. thioparus and T. denitrificans. The concentrations of PFOA in liquid media reduced after the process of bacteria culturing. The removal rates of T. thioparus and T. denitrificans to PFOA were 21.1-26.8% and 13.5-18.4%, respectively. The current findings indicated that T. thioparus could play a significant role as potential biosorbent with the ability to eliminate PFOA effectively in aquatic environment, which would provide novel information for PFOA ecological decontamination and remediation. PMID- 28002763 TI - High removal efficacy of Hg(II) and MeHg(II) ions from aqueous solution by organoalkoxysilane-grafted lignocellulosic waste biomass. AB - An effective organoalkoxysilanes-grafted lignocellulosic waste biomass (OS-LWB) adsorbent aiming for high removal towards inorganic and organic mercury (Hg(II) and MeHg(II)) ions was prepared. Organoalkoxysilanes (OS) namely mercaptoproyltriethoxylsilane (MPTES), aminopropyltriethoxylsilane (APTES), aminoethylaminopropyltriethoxylsilane (AEPTES), bis(triethoxysilylpropyl) tetrasulfide (BTESPT), methacrylopropyltrimethoxylsilane (MPS) and ureidopropyltriethoxylsilane (URS) were grafted onto the LWB using the same conditions. The MPTES grafted lignocellulosic waste biomass (MPTES-LWB) showed the highest adsorption capacity towards both mercury ions. The adsorption behavior of inorganic and organic mercury ions (Hg(II) and MeHg(II)) in batch adsorption studies shows that it was independent with pH of the solutions and dependent on initial concentration, temperature and contact time. The maximum adsorption capacity of Hg(II) was greater than MeHg(II) which respectively followed the Temkin and Langmuir models. The kinetic data analysis showed that the adsorptions of Hg(II) and MeHg(II) onto MPTES-LWB were respectively controlled by the physical process of film diffusion and the chemical process of physisorption interactions. The overall mechanism of Hg(II) and MeHg(II) adsorption was a combination of diffusion and chemical interaction mechanisms. Regeneration results were very encouraging especially for the Hg(II); this therefore further demonstrated the potential application of organosilane-grafted lignocellulosic waste biomass as low-cost adsorbents for mercury removal process. PMID- 28002765 TI - Developmental toxicity of 2,4-dichlorophenoxyacetic acid in zebrafish embryos. AB - 2,4-Dichlorophenoxyacetic acid (2,4-D) is widely used in agriculture as herbicide/pesticide, plant growth regulator and fruit preservative agent. It progressively accumulates in the environment including surface water, air and soil. It could be detected in human food and urine, which poses great risk to the living organisms. In the present study, we investigated the developmental toxicity of 2,4-D on zebrafish (Danio rerio) embryo. 2,4-D exposure significantly decreased both the survival rate (LC50 = 46.71 mg/L) and hatching rate (IC50 = 46.26 mg/L) of zebrafish embryos. The most common developmental defect in 2,4-D treated embryos was pericardial edema. 2,4-D (25 mg/L) upregulated marker genes of cardiac development (vmhc, amhc, hand2, vegf, and gata1) and downregulated marker genes of oxidative stress (cat and gpx1a). Whole mount in situ hybridization confirmed the vmhc and amhc upregulation by 2,4-D treatment. LC/MS/MS showed that the bioaccumulation of 2,4-D in zebrafish embryos were increased in a time-dependent manner after 25 mg/L of 2,4-D treatment. Taken together, our study investigated the toxic effects of 2,4-D on zebrafish embryonic development and its potential molecular mechanisms, gave evidence for the full understanding of 2,4-D toxicity on living organisms and shed light on its environmental impact. PMID- 28002766 TI - Understanding the insight into the mechanisms and dynamics of the Cl-initiated oxidation of (CH3)3CC(O)X and the subsequent reactions in the presence of NO and O2 (X = F, Cl, and Br). AB - In this work, the density functional and high-level ab initio theories are adopted to investigate the mechanisms and kinetics of reaction of (CH3)3CC(O)X (X = F, Cl, and Br) with atomic chlorine. Rate coefficients for the reactions of chlorine atom with (CH3)3CC(O)F (k1), (CH3)3CC(O)Cl (k2), and (CH3)3CC(O)Br (k3) are calculated using canonical variational transition state theory coupled with small curvature tunneling method over a wide range of temperatures from 250 to 1000 K. The dynamic calculations are performed by the variational transition state theory with the interpolated single-point energies method at the CCSD(T)/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of theory. Computed rate constant is in good line with the available experimental value. The rate constants for the title reactions are in this order: k11 CFU/100 mL) and treatment is required to meet human consumption standards. Motorized traffic mostly affects the presence of metals such as zinc (31.7 MUg/L). In the future, sustainable mobility patterns might result in improved rainwater quality standards. PMID- 28002778 TI - The modified swirl sedimentation tanks for water purification. AB - This paper discusses design, evaluation, and application for the use of swirl/vortex technologies as liquid purification system. A study was performed using modified swirl sedimentation tanks. The vortex separators (OW, OWK, OWR and OWKR) have been studied under laboratory conditions at liquid flow rate from 2.8?10-5 to 5.1?10-4 [m3/s]. The pressure drop and the efficiency of purification of liquid stream were analyzed. The suspended particles of different diameters were successfully removed from liquid with the application of swirl chambers of proposed constructions. It was found that damming of liquid in the tank increases alongside liquid stream at the inlet and depends on the tank construction. The efficiency of the sedimentation tanks increases alongside the diameters of solid particles and decrease in the liquid flow rate. The best construction proved to be the OWR sedimentation tank due to smallest liquid damming, even at high flow rates, and the highest efficiency of the purification liquid stream for solid particles of the smallest diameter. The proposed solution is an alternative to the classical constructions of sedimentation tanks. PMID- 28002779 TI - Degradation of chlorinated paraben by integrated irradiation and biological treatment process. AB - Chlorinated paraben, namely, methyl 3, 5-dichloro-4-hydroxybenzoate (MDHB) is the by-product of chlorination disinfection of paraben and frequently detected in the aquatic environments, which exhibited higher persistence and toxicity than paraben itself. In this paper, the combined irradiation and biological treatment process was employed to investigate the removal of MDHB from aqueous solution. The results showed that the removal efficiency of MDHB and total organic carbon (TOC) by irradiation process increased with radiation dose no matter what the initial concentration of MDHB was. The maximum removal efficiency of MDHB was 100%, 91.1%, 93%, respectively, for the initial concentration of MDHB of 1 mg/L, 5 mg/L and 10 mg/L with the radiation dose of 800 Gy. However, the maximum removal efficiency of TOC among all the experimental groups was only 15.3% obtained with the initial concentration of 1 mg/L at dose of 800 Gy. The subsequent biological treatment enhanced the mineralization of MDHB. The suitable radiation dose for the subsequent biological treatment was determined to be 600 Gy. In this case the removal efficiency of TOC increased to about 70%. Compared to the single biological treatment, the integrated irradiation and biological treatment significantly increase the degradation and mineralization of MDHB. Moreover, the dechlorination efficiency reached 77.4% during the integrated irradiation and biological treatment process. In addition, eight intermediates were identified during the combined process and the possible degradation pathway was proposed. PMID- 28002780 TI - Study on optimization of process parameters for enhancing the multi-hydrolytic enzyme activity in garbage enzyme produced from preconsumer organic waste. AB - The garbage enzymes produced from preconsumer organic waste containing multi hydrolytic enzyme activity which helps to solubilize the waste activated sludge. The continuous production of garbage enzyme and its scaling up process need a globe optimized condition. In present study the effect of fruit peel composition and sonication time on enzyme activity were investigated. Garbage enzyme produced from 6g pineapple peels: 4g citrus peels pre-treated with ultrasound for 20min shows higher hydrolytic enzymes activity. Simultaneously statistical optimization tools were used to model garbage enzyme production with higher activity of amylase, lipase and protease. The maximum activity of amylase, lipase and protease were predicted to be 56.409, 44.039, 74.990U/ml respectively at optimal conditions (pH (6), temperature (37 degrees C), agitation (218 RPM) and fermentation duration (3days)). These optimized conditions can be successfully used for large scale production of garbage enzyme with higher hydrolytic enzyme activity. PMID- 28002781 TI - Performance of aerobic nitrite granules treating an anaerobic pre-treated wastewater originating from the potato industry. AB - In this study nitrogen removal via nitrite >80% was achieved after approximately 80days in a sequencing batch reactor (SBR) treating pre-treated industrial wastewater originating from the potato industry. Thereafter, SBR performance was investigated during the formation of aerobic nitrite granules (ANG). The first granules appeared after 26days leading to full granulation after 64days. ANG showed excellent settling properties, as the Sludge Volume Index (SVI) went down to 16mL/g and a SVI10/SVI30=1 was obtained. qPCR analysis showed that slow growing organisms, especially polyphosphate accumulating organisms (PAO) were stimulated by an anaerobic feeding strategy. The average nitrogen removal was 95.3% over the entire operational period, and it mainly followed the "nitrite route". Moreover, with ANG also phosphorus removal efficiencies up to 65.7% could be achieved. However, it has to be mentioned that nitrous oxide was an important denitrification product, which implies some environmental concerns. PMID- 28002782 TI - Realization of quantifying interfacial interactions between a randomly rough membrane surface and a foulant particle. AB - Quantification of interfacial interaction with randomly rough surface is the prerequisite to quantitatively understand and control the interface behaviors such as adhesion, flocculation and membrane fouling. In this study, it was found that membrane surface was randomly rough with obvious fractal characteristics. The randomly rough surface of membrane could be well reconstructed by the fractal geometry represented by a modified Weierstrass-Mandelbrot function. A novel method, which combined composite Simpson's approach, surface element integration method and approximation by computer programming, was developed. By using this method, this study provided the first realization of quantifying interfacial energy between randomly rough surface of membrane and a foulant particle. The calculated interactions with randomly rough surface of membrane were significantly different from those with smooth surface of membrane, indicating the significant effect of surface topography on interactions. This proposed method could be also potentially used to investigate various natural interface environmental phenomena. PMID- 28002783 TI - Supply chain carbon footprinting and responsibility allocation under emission regulations. AB - Reduction of greenhouse gas emissions has become an enormous challenge for any single enterprise and its supply chain because of the increasing concern on global warming. This paper investigates carbon footprinting and responsibility allocation for supply chains involved in joint production. Our study is conducted from the perspective of a social planner who aims to achieve social value optimization. The carbon footprinting model is based on operational activities rather than on firms because joint production blurs the organizational boundaries of footprints. A general model is proposed for responsibility allocation among firms who seek to maximize individual profits. This study looks into ways for the decentralized supply chain to achieve centralized optimality of social value under two emission regulations. Given a balanced allocation for the entire supply chain, we examine the necessity of over-allocation to certain firms under specific situations and find opportunities for the firms to avoid over allocation. The comparison of the two regulations reveals that setting an emission standard per unit of product will motivate firms to follow the standard and improve their emission efficiencies. Hence, a more efficient and promising policy is needed in contrast to existing regulations on total production. PMID- 28002784 TI - Integrative analysis of the Lake Simcoe watershed (Ontario, Canada) as a socio ecological system. AB - Striving for long-term sustainability in catchments dominated by human activities requires development of interdisciplinary research methods to account for the interplay between environmental concerns and socio-economic pressures. In this study, we present an integrative analysis of the Lake Simcoe watershed, Ontario, Canada, as viewed from the perspective of a socio-ecological system. Key features of our analysis are (i) the equally weighted consideration of environmental attributes with socioeconomic priorities and (ii) the identification of the minimal number of key socio-hydrological variables that should be included in a parsimonious watershed management framework, aiming to establish linkages between urbanization trends and nutrient export. Drawing parallels with the concept of Hydrological Response Units, we used Self-Organizing Mapping to delineate spatial organizations with similar socio-economic and environmental attributes, also referred to as Socio-Environmental Management Units (SEMUs). Our analysis provides evidence of two SEMUs with contrasting features, the "undisturbed" and "anthropogenically-influenced", within the Lake Simcoe watershed. The "undisturbed" cluster occupies approximately half of the Lake Simcoe catchment (45%) and is characterized by low landscape diversity and low average population density <0.4 humans ha-1. By contrast, the socio-environmental functional properties of the "anthropogenically-influenced" cluster highlight the likelihood of a stability loss in the long-run, as inferred from the distinct signature of urbanization activities on the tributary nutrient export, and the loss of subwatershed sensitivity to natural mechanisms that may ameliorate the degradation patterns. Our study also examines how the SEMU concept can augment the contemporary integrated watershed management practices and provides directions in order to promote environmental programs for lake conservation and to increase public awareness and engagement in stewardship initiatives. PMID- 28002785 TI - Usage of Riot Control Agents and other methods resulting in physical and psychological injuries sustained during civil unrest in Turkey in 2013. AB - Turkey has experienced a wave of demonstrations in the summer of 2013, called Gezi Park Demonstrations. Between 31 May and 30 August, 297 people who had been subjected to trauma by several methods of demonstration control and Riot Control Agents applied to the Human Rights Foundation of Turkey Rehabilitation Centers to receive treatment/rehabilitation and/or documentation. 296 patients except one 5 year-old child were included in the study. Of the 296 patients; 175 were male, 120 were female, and one was a transgender individual. The highest number of applications was received by the Istanbul center with 216 patients. The mean age of applicants was 33.85, and the age range was 15-71 years. While 268 of applicants (91%) stated that they had been exposed to Riot Control Agents, 62 patients suffered only chemical exposure who had no other traumatic injuries whereas 234 patients suffered at least one blunt trauma injury. Blunt trauma injuries are due to being shot by gas canisters in 127 patients (43%), by plastic bullets in 31 patients (10%). 59 patients (20%) were severely beaten, and 30 patients (10%) were injured by pressurized cold water ejected by water cannons. Thirteen patients (4.4%) suffered injuries that caused loss of vision or eye. Psychiatric evaluations were carried out for 117 patients while 43% of them were diagnosed with Acute Stress Disorder. Post Traumatic Stress Disorder and Major Depressive Disorder followed this diagnosis. This study includes the medical evaluation of injuries allegedly sustained during Gezi Park demonstrations in 2013 as a result of several methods of demonstration control and/or by being exposed to Riot Control Agents. The aim is to discuss different types of injuries due to those methods and health consequences of Riot Control Agents. PMID- 28002786 TI - Plasma concentrations of CCL3 and CCL4 in the cardiac and digestive clinical forms of chronic Chagas disease. AB - The aim of this study was to investigate the plasma levels of the CCL3 and CCL4 chemokines in patients with the cardiac and digestive clinical forms of chronic Chagas disease and in cardiac patients with and without left ventricular systolic dysfunction (LVSD). Plasma samples from 75 patients were evaluated by enzyme linked immunosorbent assay (ELISA) to confirm infection by T. cruzi. Plasma levels of the CCL3 and CCL4 chemokines were measured using Milliplex(r) MAP assay (Millipore). There were no significant differences in the levels of CCL3 and CCL4 between patients with the digestive and cardiac clinical forms of Chagas disease. Moreover, no significant differences were found between patients without LVSD and those with LVSD. Higher CCL3 and CCL4 plasma levels were found in patients with LVSD compared to those with the digestive form of the disease. The CCL3 and CCL4 chemokines might not be involved in differential susceptibility to the digestive and cardiac clinical forms of chronic Chagas disease, and it seems they do not influence the development of LVSD. PMID- 28002787 TI - Diterpenes biochemical profile and transcriptional analysis of cytochrome P450s genes in leaves, roots, flowers, and during Coffea arabica L. fruit development. AB - Lipids are among the major chemical compounds present in coffee beans, and they affect the flavor and aroma of the coffee beverage. Coffee oil is rich in kaurene diterpene compounds, mainly cafestol (CAF) and kahweol (KAH), which are related to plant defense mechanisms and to nutraceutical and sensorial beverage characteristics. Despite their importance, the final steps of coffee diterpenes biosynthesis remain unknown. To understand the molecular basis of coffee diterpenes biosynthesis, we report the content dynamics of CAF and KAH in several Coffea arabica tissues and the transcriptional analysis of cytochrome P450 genes (P450). We measured CAF and KAH concentrations in leaves, roots, flower buds, flowers and fruit tissues at seven developmental stages (30-240 days after flowering - DAF) using HPLC. Higher CAF levels were detected in flower buds and flowers when compared to fruits. In contrast, KAH concentration increased along fruit development, peaking at 120 DAF. We did not detect CAF or KAH in leaves, and higher amounts of KAH than CAF were detected in roots. Using P450 candidate genes from a coffee EST database, we performed RT-qPCR transcriptional analysis of leaves, flowers and fruits at three developmental stages (90, 120 and 150 DAF). Three P450 genes (CaCYP76C4, CaCYP82C2 and CaCYP74A1) had transcriptional patterns similar to CAF concentration and two P450 genes (CaCYP71A25 and CaCYP701A3) have transcript accumulation similar to KAH concentration. These data warrant further investigation of these P450s as potential candidate genes involved in the final stages of the CAF and KAH biosynthetic pathways. PMID- 28002788 TI - Tianshengyuan-1 (TSY-1) regulates cellular Telomerase activity by methylation of TERT promoter. AB - Telomere and Telomerase have recently been explored as anti-aging and anti-cancer drug targets with only limited success. Previously we showed that the Chinese herbal medicine Tianshengyuan-1 (TSY-1), an agent used to treat bone marrow deficiency, has a profound effect on stimulating Telomerase activity in hematopoietic cells. Here, the mechanism of TSY-1 on cellular Telomerase activity was further investigated using HL60, a promyelocytic leukemia cell line, normal peripheral blood mononuclear cells, and CD34+ hematopoietic stem cells derived from umbilical cord blood. TSY-1 increases Telomerase activity in normal peripheral blood mononuclear cells and CD34+ hematopoietic stem cells with innately low Telomerase activity but decreases Telomerase activity in HL60 cells with high intrinsic Telomerase activity, both in a dose-response manner. Gene profiling analysis identified Telomerase reverse transcriptase (TERT) as the potential target gene associated with the TSY-1 effect, which was verified by both RT-PCR and western blot analysis. The beta-galactosidase reporter staining assay showed that the effect of TSY-1 on Telomerase activity correlates with cell senescence. TSY-1 induced hypomethylation within TERT core promoter in HL60 cells but induced hypermethylation within TERT core promoter in normal peripheral blood mononuclear cells and CD34+ hematopoietic stem cells. TSY-1 appears to affect the Telomerase activity in different cell lines differently and the effect is associated with TERT expression, possibly via the methylation of TERT promoter. PMID- 28002789 TI - MicroRNA-17 is downregulated in esophageal adenocarcinoma cancer stem-like cells and promotes a radioresistant phenotype. AB - Resistance to neoadjuvant chemoradiation therapy (CRT) remains a critical barrier to the effective treatment of esophageal adenocarcinoma (EAC). Cancer stem-like cells (CSCs) are a distinct subpopulation of cells implicated in the resistance of tumors to anti-cancer therapy. However, their role in the resistance of EAC to CRT is largely unknown. In this study, using a novel in vitro isogenic model of radioresistant EAC, we demonstrate that radioresistant EAC cells have enhanced tumorigenicity in vivo, increased expression of CSC-associated markers and enhanced holoclone forming ability. Further investigation identified a subpopulation of cells that are characterised by high aldehyde dehydrogenase (ALDH) activity, enhanced radioresistance and decreased expression of miR-17-5p. In vitro, miR-17-5p was demonstrated to significantly sensitise radioresistant cells to X-ray radiation and promoted the repression of genes with miR-17-5p binding sites, such as C6orf120. In vivo, miR-17-5p was significantly decreased, whilst C6orf120 was significantly increased, in pre-treatment EAC tumour samples from patients who demonstrated a poor response to neoadjuvant CRT. This study sheds novel insights into the role of CSCs in the resistance of EAC to CRT and highlights miR-17-5p as a potential biomarker of CRT sensitivity and novel therapeutic target in treatment resistant EAC. PMID- 28002790 TI - Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. AB - Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40 TAg inhibits TP53/CDKN1A and CDKN2A/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549:BRAF fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, CDKN2A (p16), CDKN1A (p21), and TP53 (p53) protein, and gene-expression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by TERT expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while BRAF V600E- and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient derived long term expandable PA cell line expressing the KIAA1549:BRAF-fusion suitable for preclinical drug testing. PMID- 28002791 TI - Chinese herb cinobufagin-reduced cancer pain is associated with increased peripheral opioids by invaded CD3/4/8 lymphocytes. AB - OBJECTIVES: To investigate the mechanism of cinobufagin-reduced cancer pain in mouse cancer pain model and in vitro cell co-culture system. METHODS: Female Kunming mice were randomly divided into 4 groups. One group of animals was set as normal control without any treatment. Other three groups of animals received H22 hepatoma cell inoculation in right hind paw. At day 9 after inoculation, mice in other three groups were injected intraperitoneally once a day for 8 days with the solvent, morphine or cinobufagin, respectively. The pain behavior was recorded daily. On the last day, all mice were sacrificed and xenograft tissues homogenate and plasma levels of beta-endorphin (beta-END), corticotropin-releasing factor (CRF) and interleukin-1beta (IL-1beta) were assessed by ELISA assay. Immunohistochemistry was performed to determine the expression of beta-END, pro opiomelanocortin (POMC) and the MU-opioid receptor (MU-OR) in the xenograft tissues. Immunofluorescence was used to localize lymphocytes with expression of CD3+, CD4+ and CD8+ in xenograft tumors and adjacent tissues. Mice splenic lymphocytes and H22 hepatoma carcinoma ascites cells were prepared for co culture. beta-END and CRF were detected in co-culture supernatants. The MTT assay and cytometry were used to assess cell proliferation. RT-PCR was conducted to determine the gene expression of POMC and Cathepsin L (CTSL). Chemotaxis was examined using a transwell-based migration assay. RESULTS: Compared to the model group, the thermal and mechanical pain thresholds were increased in mice after cinobufagin treatment. The expression of beta-END and CRF in the plasma and tumor tissues of cinobufagin group were much higher than that of the model group mice, but the expression of IL-1beta in the plasma and tumor tissues was much lower than that in the model group mice. Meanwhile, the expression of beta-END, POMC and MU-OR proteins was significantly increased in the xenograft tissues from cinobufagin group. Lymphocyte population of CD3+, CD4+, CD8+ were also elevated in xenograft tumors and adjacent tissues. In the cell co-culture assays, the content of beta-END in the supernatant was significantly increased by cinobufagin in a dose-dependent manner. Cinobufagin also largely increased the proliferation of immune cells and inhibited H22 hepatoma carcinoma cell proliferation in single or co-culture cell assays. Gene expression of POMC and CTSL in cinobufagin group was significantly up-regulated comparing to the control group. Finally, cinobufagin addition enhanced the migration of immune cells in transwell assay. CONCLUSIONS: Cinobufagin-induced local analgesic effect might be associated with increased activity of POMC/beta-END/MU-OR pathway released from invaded CD3/4/8 lymphocytes in cancer tissues. PMID- 28002792 TI - Radiotherapy improves survival in early stage extranodal natural killer/T cell lymphoma patients receiving asparaginase-based chemotherapy. AB - This study retrospectively investigated asparaginase-based chemotherapy treatment outcomes with or without radiotherapy in 143 patients with stage IE-IIE extranodal natural killer/T cell lymphoma (ENKTCL). All patients received a median of three cycles of asparaginase-based chemotherapy, while 121 patients received radiotherapy following the chemotherapy. The complete remission (CR) rate for all patients post-chemotherapy was 58.7%, and rose to 73.4% by the end of treatment. Patients who received radiotherapy achieved better survival outcomes than those who did not (89.7% vs. 49.0% for 2-year overall survival (OS), P<0.001; 86.8% vs. 37.4% for 2-year progression-free survival (PFS), P<0.001). Additionally, even patients who achieved CR post-chemotherapy exhibited differential survival rates with or without radiotherapy (90.8% vs. 60% for 2 year OS, P=0.006; 86.1% vs. 60% for 2-year PFS, P=0.044). Multivariate analysis revealed that radiotherapy was an independent factor favoring OS (HR=0.098, 95%CI=0.031-0.314, P=0.001) and PFS (HR=0.156, 95%CI=0.062-0.396, P=0.001). Thus, radiotherapy is recommended for stage IE-IIE ENKTCL patients treated with asparaginase-based chemotherapy, even in cases of CR following chemotherapy. PMID- 28002794 TI - Oxygen sensors and neuronal adaptation to ischemia. PMID- 28002793 TI - Next generation sequencing of vitreoretinal lymphomas from small-volume intraocular liquid biopsies: new routes to targeted therapies. AB - BACKGROUND: Vitreoretinal lymphoma (VRL), the most common lymphoma of the eye, is a rare form of primary CNS lymphoma (PCNSL). Most frequently a high-grade diffuse large B cell lymphoma, VRL can cause vision loss and its prognosis remains dismal: the overall survival time is 3 years after diagnosis. Radiotherapy and chemotherapy are used but remain frequently ineffective, and no standardized treatment regimen exists. Furthermore, no biologically targeted treatments, based on the genetic profile of the tumor, are available, as VRL has hitherto not comprehensively been profiled. To address these unmet needs, we hypothesized that a next generation sequencing (NGS)-based, National Cancer Institute (NCI) MATCH Trial-modified panel would be able to identify actionable genomic alterations from small-volume, intraocular liquid biopsies. METHODS AND FINDINGS: In this retrospective study, we collected diluted vitreous biopsies from 4 patients with a high suspicion for VRL. Following cytological confirmation of lymphoma (all were diffuse large B cell lymphomas), we subjected genomic DNA from the biopsies to NGS, using a panel containing 126 genes (3,435 amplicons across several hotspots per gene), which was modified from that of the NCI MATCH Trial, a new trial that has matched patients with cancers that have not responded (or never responded), to investigational therapeutics based on their prioritized mutation profile rather than site of tumor origin. Using a validated bioinformatics pipeline, we assessed for the presence of actionable mutations and copy number alterations. In all four small-volume, intraocular liquid biopsies, we obtained sufficient genomic DNA for analysis, even in diluted samples in which the undiluted vitreous was used for cytology and flow cytometry. Using NGS, we found targetable heterozygous gain-of-function mutations in the MYD88 oncogene, and confirmed in our cohort the presence the L265 mutations, previously described using PCR-based assays. For the first time in VRL, we also identified the MYD88 S243N mutation. We also identified two-copy copy number losses in the tumor suppressor CDKN2A in all four cases, and one copy loss of the tumor suppressor PTEN in one sample. In one case, in which vitreous biopsies were originally read as cytologically negative, but which was confirmed as lymphoma when a lesion appeared in the brain two years later, our NGS-based approach detected tumoral DNA in the banked, original liquid biopsy. CONCLUSIONS: We performed the first systematic exploration of the actionable cancer genome in VRL. Our NGS-based approach identified exploitable genomic alterations such as gain-of-function MYD88 oncogene mutations and loss of the tumor suppressor CDKN2A, and thus illuminates new routes to biologically targeted therapies for VRL, a cancer with a dismal prognosis. This precision medicine strategy could be used to nominate novel, targeted therapies in lymphomas and other blinding and deadly ocular, orbital, and ocular adnexal diseases for which few treatments exist. PMID- 28002795 TI - Sodium fluoride (NaF) causes toxic effects on splenic development in mice. AB - At present, very limited studies focus on the toxic effect of sodium fluoride (NaF) on splenic development of human and animals in vivo. This study was firstly designed to evaluate the toxic effects of NaF on the splenic development of mice in vivo by observing histopathological lesions, changes of splenic growth index (GI), T and B cells, immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM) contents, cytokine protein expression levels, and cell cycle and cyclins/cdks protein expression levels using the methods of pathology, flow cytometry (FCM), western blot (WB), and enzyme-linked immunosorbent assay (ELISA). A total of 240 ICR mice were equally allocated into four groups with intragastric administration of distilled water in the control group and 12, 24, 48 mg/kg NaF solution in the experimental groups for 42 days. The results showed that NaF in 12 mg/kg and over caused the toxic effects on splenic development, which was characterized by reducing growth index and lymphocytes in the white and red pulp histopathologically, increasing cell percentages of the G0/G1 phase and decreasing cell percentages of the S phase, and reducing T cells and B cells as well as IgA, IgG, and IgM contents when compared with those in the control group. Concurrently, cytokines including interleukin-2 (IL-2), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma) and cyclin (E/D and CDK2/4) protein expression levels were markedly decreased (P < 0.05 or P < 0.01), and interleukin-10 (IL-10) protein expression levels were significantly increased (P < 0.05 and P < 0.01) in the three NaF treated groups. Toxic effects finally impaired the splenic cellular immunity and humoral immunity due to the reduction of T and B cell population and activity. Cell cycle arrest is the molecular basis of NaF-caused toxic effects on the splenic development. PMID- 28002796 TI - Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model. AB - Interleukin (IL)-12 is a potent antitumor cytokine. However, immunosuppressive tumor microenvironments containing transforming growth factor-beta (TGF-beta) attenuate cytokine-mediated antitumor immune responses. To enhance the efficacy of IL-12-mediated cancer immunotherapy, decorin (DCN) was explored as an adjuvant for overcoming TGF-beta-mediated immunosuppression. We designed and generated a novel oncolytic adenovirus (Ad) coexpressing IL-12 and DCN (RdB/IL12/DCN). RdB/IL12/DCN-treated tumors showed significantly greater levels of interferon (IFN)-gamma, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and IFN-gamma-secreting immune cells than tumors treated with cognate control oncolytic Ad expressing a single therapeutic gene (RdB/DCN or RdB/IL12). Moreover, RdB/IL12/DCN attenuated intratumoral TGF-beta expression, which positively correlated with reduction of Treg cells in draining lymph nodes and tumor tissues. Furthermore, tumor tissue treated with RdB/IL12/DCN showed increases infiltration of CD8+ T cells and proficient viral spreading within tumor tissues. These results demonstrated that an oncolytic Ad co-expressing IL 12 and DCN induces a potent antitumor immune response via restoration of antitumor immune function in a weakly immunogenic murine 4T1 orthotopic breast cancer model. These findings provide new insights into the therapeutic mechanisms of IL-12 plus DCN, making it a promising cancer immunotherapeutic agent for overcoming tumor-induced immunosuppression. PMID- 28002797 TI - Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer. AB - PURPOSE: Next Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations. AIM: To identify variants in 15 CRC-associated genes in patients of Iranian descent. RESULTS: There were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFbetaR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%). MATERIALS AND METHODS: CRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established. CONCLUSION: These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies. PMID- 28002798 TI - IL-17A weakens the antitumor immuity by inhibiting apoptosis of MDSCs in Lewis lung carcinoma bearing mice. AB - Myeloid-derived suppressor cells (MDSCs) weaken the antitumor immune response through the inhibition of effector T cell activity and the production of immunosuppressive factors in pathological sites. It is well established that interleukin-17A (IL-17A) has a remarkable role on the promotion of inflammation and tumor formation, and IL-17 has been implicated in the enhancement of immunosuppression of MDSCs, which consequently promotes tumor progression. A detailed study of this relationship remains elusive. In our study, we not only confirmed the promotion of IL-17 on Lewis lung carcinoma (LLC) development but also surprisingly showed that IL-17 could extend the fate and enhance the immunosuppressive effect of MDSCs through activating ERK1/2. Additionally, the effect of IL-17 on MDSCs was reversed, even in tumors by blocking ERK1/2. Interdicting the signaling molecule ERK1/2 could increase the apoptosis of MDSCs and weaken the suppressive activity of MDSCs, so that thereafter, the antitumor immunity could be restored partly. Therefore, these findings offer new insights into the importance of IL-17 and the downstream signaling factor ERK1/2 for MDSCs. PMID- 28002799 TI - Induction of specific T helper-9 cells to inhibit glioma cell growth. AB - The effects of Staphylococcal enterotoxin B (SEB) on regulation of immune response have been recognized; whether SEB can enhance the effects of immunotherapy on glioma remains to be investigated. This study tests a hypothesis that administration with SEB enhances the effects of specific immunotherapy on glioma growth in mice. In this study, a glioma-bearing mouse model was developed by adoptive transfer with GL261 cells (a mouse glioma cell line). The mice were treated with the GL261 cell extracts (used as an Ag) with or without administration of SEB. We observed that treating glioma-bearing mice with the glioma Ag and SEB induced glioma-specific Th9 cells in both glioma tissue and the spleen. Treating CD4+ CD25- T cells with SEB increased p300 phosphorylation, histone H3K4 acetylation at the interleukin (IL)-9 promoter locus, and increased the IL-9 transcriptional factor binding to the IL-9 promoter. Treating CD4+ CD25- T cells with both SEB and glioma Ag induced glioma-specific Th9 cells. The glioma specific Th9 cells induced glioma cell apoptosis in the culture. Treating the glioma-bearing mice with SEB and glioma Ag significantly inhibited the glioma growth. In conclusion, SEB plus glioma Ag immunotherapy inhibits the experimental glioma growth, which may be a novel therapeutic remedy for the treatment of glioma. PMID- 28002800 TI - Sprouty2 correlates with favorable prognosis of gastric adenocarcinoma via suppressing FGFR2-induced ERK phosphorylation and cancer progression. AB - Fibroblast growth factor receptor 2 (FGFR2) has been identified as a predictive biomarker for unfavorable prognosis of gastric adenocarcinoma. As a well-defined antagonist in FGFR2-induced RAS/ERK activation, ectopic expression of sprouty (SPRY) family was reported in several kinds of cancers except gastric cancer. To explore the clinical significance of SPRY family and its correlation with FGFR2, we detected the expression of FGFR2 and SPRY family in 104 cases of gastric adenocarcinoma and subsequently analyzed their correlations with clinicopathological factors and overall survival rates by univariate and multivariate analysis. As the result, we demonstrated that both FGFR2 high expression and SPRY2 low-expression indicated poorer prognosis of gastric adenocarcinoma. SPRY2 low-expression was significantly associated with FGFR2 high expression, positive lymphatic invasion and metastasis. We further proved that SPRY2 could suppress FGFR2-induced ERK phosphorylation, cell proliferation and invasion with experiments in vitro and in vivo. In conclusion, we demonstrated that SPRY2 low-expression is a biomarker for unfavorable prognosis in gastric adenocarcinoma. SPRY2 can antagonize FGFR2-induced proliferation and invasion via suppressing ERK phosphorylation in gastric cancer cells, indicating SPRY2 as a potential therapeutic target for gastric adenocarcinoma treatment. PMID- 28002801 TI - Effect of 3q oncogenes SEC62 and SOX2 on lymphatic metastasis and clinical outcome of head and neck squamous cell carcinomas. AB - Chromosome 3q26 amplification represents a frequent alteration in head and neck squamous cell carcinomas (HNSCCs). Overexpression of 3q26 encoded genes SEC62 and SOX2 was detected in various cancers, including HNSCCs, indicating their potential function as oncogenes. In our study, we elucidated the function of SEC62 and SOX2 in HNSCC patients, with a main focus on their effect on lymphatic metastasis and patient survival. We analyzed SEC62 and SOX2 expression in tissue specimens from 65 HNSCC patients and 29 patients with cervical cancer of unknown primary (CUP); a higher SEC62 and lower SOX2 expression was observed in the lymph node metastases from HNSCC patients compared with the respective primary tumor. Lymph node metastases from CUP patients showed higher SEC62 and lower SOX2 expression compared with lymph node metastases from HNSCC patients. When proceeding from the N1 to the N3 stage, SEC62 expression in the lymph node metastases showed an increase and SOX2 expression showed a decrease. Moreover, both genes showed a highly significant relevance as prognostic biomarkers, with the worst prognosis for patients with high SEC62 and low SOX2 expression levels. In functional analyses, knockdown of SEC62 resulted in an inhibition of HNSCC cell migration while, conversely, SEC62 and SOX2 overexpression stimulated cell migration. Taken together, our study showed that the expression of the 3q oncogenes SEC62 and SOX2 affects lymphatic metastasis and cell migration in HNSCC and CUP patients and has a high prognostic relevance in these diseases. PMID- 28002802 TI - Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications. AB - The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling. Strikingly, BEZ235 but neither BKM120 nor everolimus markedly enhanced the ERK pathway. This effect was reproduced by the combination of BKM120 and everolimus, suggesting the involvement of mTORC2 via a PI3K-independent mechanism. Silencing of RICTOR in LMS cells confirmed the role of mTORC2 in the regulation of ERK activity. Combined treatment with BEZ235 and GSK1120212, a potent MEK inhibitor, resulted in synergistic growth inhibition and apoptosis induction in vitro and in vivo. These findings document for the first time that dual PI3K/mTOR inhibition in leiomyosarcomas suppress a negative feedback loop mediated by mTORC2, leading to enhanced ERK pathway activity. Thus, combining a dual PI3K/mTOR inhibitor with MEK inhibitors may be a relevant approach to increase anti-tumor activity and prevent drug resistance in patients with LMS. PMID- 28002803 TI - Increased body mass index is associated with improved overall survival in extranodal natural killer/T-cell lymphoma, nasal type. AB - OBJECTIVES: The role of body mass index (BMI) in lymphoma survival outcomes is controversial. The prognostic significance of BMI in extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is unclear. We evaluated the prognostic role of BMI in patients with ENKTL. METHODS: We retrospectively analyzed 742 patients with newly diagnosed ENKTL. The prognostic value of BMI was compared between patients with low BMIs (< 20.0 kg/m2) and patients with high BMIs (>= 20.0 kg/m2). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) was also evaluated and compared with that of the BMI classification. RESULTS: Patients with low BMIs tended to exhibit higher Eastern Cooperative Oncology Group performance status (ECOG PS) scores (>= 2) (P = 0.001), more frequent B symptoms (P < 0.001), lower albumin levels (P < 0.001), higher KPI scores (P = 0.03), and lower rates of complete remission (P < 0.001) than patients with high BMIs, as well as inferior progression-free survival (PFS, P = 0.003), and inferior overall survival (OS, P = 0.001). Multivariate analysis demonstrated that age > 60 years, mass > 5 cm, stage III/IV, elevated LDH levels, albumin levels < 35 g/L and low BMIs were independent adverse predictors of OS. The BMI classification was found to be superior to the IPI with respect to predicting patient outcomes among low-risk patients and the KPI with respect to distinguishing between intermediate-low- and high-intermediate-risk patients. CONCLUSIONS: Higher BMI at the time of diagnosis is associated with improved overall survival in ENKTL. Using the BMI classification may improve the IPI and KPI prognostic models. PMID- 28002805 TI - Expression of PSMA in tumor neovasculature of high grade sarcomas including synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma and MPNST. AB - AIMS: PSMA (prostate specific membrane antigen) is physiologically expressed in normal prostate tissue. It is overexpressed in prostate cancer cells and has been suggested as a target for antibody-based radioligand therapy. As PSMA expression so far has not been systematically analyzed in soft tissue tumors, the current study aims at investigating a large cohort of different subtypes. METHODS AND RESULTS: Immunohistochemistry was used to detect PSMA expression in 779 samples of soft tissue tumors and Ewing sarcoma as a primary bone malignancy. CD34 coexpression was employed to study PSMA expression in the neovasculature. PSMA expression was found in the tumor-associated neovasculature of 151/779 soft tissue/bone tumors (19.38%) and was more frequent in malignant tumors compared to tumors with intermediate or benign biological potential (p=0.078). Strong neovascular PSMA expression was predominantly observed in subsets of different sarcomas including 3/20 rhabdomyosarcomas (15%), 4/21 malignant peripheral nerve sheath tumors (19.05%), 6/16 synovial sarcomas (35.29%) and 6/33 undifferentiated pleomorphic sarcomas (18.18%). CONCLUSION: We conclude that PSMA is expressed in the neovasculature of a subset of soft tissue tumors to a variable extent. Our observation of strong PSMA expression predominantly occurring in sarcomas might provide a rationale to evaluate PSMA-targeted radioligand therapy in these entities. PMID- 28002804 TI - Endometrial cancer cells exhibit high expression of p110beta and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation. AB - PTEN loss and constitutive activation of the class I phosphoinositide 3-kinase (PI3K) pathway are key drivers of endometrial tumorigenesis. In some cancer types, PTEN-deficient tumors are reliant on class I PI3K p110beta (encoded by PIK3CB) activity but little is known about this contribution in endometrial tumorigenesis. In this study, we find that p110beta is overexpressed in a panel of 7 endometrial cancer cell lines compared to non-transformed cells. Furthermore, in 234 clinically annotated patient samples, PIK3CB mRNA levels increase significantly in the early phase of tumorigenesis from precursors to low grade primary malignant lesions whereas PIK3CA levels are higher in non endometrioid compared to endometrioid primary tumors. While high levels of either PIK3CA or PIK3CB associate with poor prognosis, only elevated PIK3CB mRNA levels correlate with a high cell cycle signature score in clinical samples. In cancer cell lines, p110alpha inhibition reduces cell viability by inducing cell death in PIK3CA mutant cells while p110beta inhibition delayed proliferation in PTEN deficient cells, but not in WT cells. Taken together, our findings suggest that PIK3CB/p110beta contributes to some of the pleiotropic functions of PI3K in endometrial cancer, particularly in the early steps by contributing to cell proliferation. PMID- 28002806 TI - Quality measurement on shear wave speed imaging: diagnostic value in differentiation of thyroid malignancy and the associated factors. AB - To evaluate the associated factors for quality measurement (QM) on shear wave speed (SWS) imaging and the additional value of QM for differentiation of thyroid nodules. A consecutive series of 238 patients with 254 thyroid nodules were enrolled. They were all evaluated by conventional ultrasound and SWS imaging and were finally proven pathologically. QM was used to assess whether SWS propagation was authentic and was classified as high QM and Low QM. Twelve variables were analyzed to evaluate the associated factors for QM using binary logistic regression. Receiver operating characteristic (ROC) curve was plotted on SWS and SWS+QM. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and area under ROC curve (AUC) were calculated. The study included 170 benign thyroid nodules (160 high QM and 10 low QM) and 84 malignant thyroid nodules (56 high QM and 28 low QM) (P < 0.001). The mean SWS of benign and malignant nodules were 2.51 +/- 0.47 m/s and 3.43 +/- 1.21 m/s respectively (P < 0.001). The sensitivities, specificities, PPVs, NPVs, accuracies and AUCs were 77.4%, 80.0%, 65.7%, 87.7%, 79.1%, 0.82 for SWS alone with SWS >= 2.78 m/s; 33.3-34.5%, 91.2-94.1%, 65.9-73.7%, 73.8-74.1%, 72.4-74.0%, 0.63-0.64 for QM alone and 84.5-85.7%, 72.4-75.9%, 60.5-63.4%, 90.8-91.0%, 76.8 78.7%, 0.79-0.80 for SWS+QM. Nodule depth was identified to be the strongest associated factor for QM of SWS, followed by malignancy and SWS. In conclusion, QM for thyroid nodule is associated with nodule depth, malignancy, and SWS. QM improves the specificity in comparison with SWS alone, whereas SWS+QM does not improve the overall diagnostic performance. PMID- 28002807 TI - Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells. AB - Receptor tyrosine kinase (RTK) signaling pathways are frequently activated in cancer cells due to mutations of RTKs and/or their downstream signaling proteins such as KRAS and BRAF. About 40% colorectal cancers (CRCs) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs, AKT, MEK, or BRAF. Therefore, an understanding of the molecular mechanisms of the drug resistance is necessary for developing effective strategies to treat the diseases. Here we report the discovery of an AKT/ERK reactivation mechanism that account for the cancer cell resistance to the AKT and MEK inhibitors treatments. The reactivations of AKT and ERK after the AKT or MEK inhibitor treatment were caused by a relief of an AKT or ERK-mediated feedback inhibition of the RTKs and/or their downstream pathways. A combination of RTK inhibitors, based on the RTK activation/phosphorylation profile, synergized with the AKT inhibitor, but not the MEK inhibitor, to completely inhibit the AKT phosphorylation and to block the growth of KRAS/BRAF mutant CRC cells. These results underscored the importance of AKT and the AKT feedback signaling to cancer cell growth and offered a novel therapeutic approach for the treatment of KRAS/BRAF mutant CRC cells. PMID- 28002808 TI - Sublobar resection is associated with improved outcomes over radiotherapy in the management of high-risk elderly patients with Stage I non-small cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND AND AIM: A matched-pair comparison was performed to compare the efficacy and safety of sublobar resection versus radiotherapy for high-risk elderly patients with Stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We searched the Cochrane Library, MEDLINE, CENTRAL, EMBASE and manual searches. The meta-analysis was performed to compare overall survival, pattern of failure, and toxicity among the homogeneous studies. Subdivided analyses were also performed. RESULTS: Sixteen studies containing 11540 patients were included in the meta-analysis. Among these studies, 9 were propensity-score matched (PSM) cohort studies, and 7 were cohort studies. Sublobar resection, compared with radiotherapy (either conventional fraction radiation therapy or stereotactic body radiation therapy), significantly improved the overall survival regardless in both PSM and non-PSM analyses (all p < 0.05). However, the difference in the pattern of failure and toxicity were not significant (all p > 0.05). CONCLUSIONS: Sublobar resection was associated with improved outcomes in high-risk elderly patients with Stage I NSCLC, which supports the need to compare both treatments in large prospective, randomized, controlled clinical trials. PMID- 28002809 TI - Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer. AB - PURPOSE: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. EXPERIMENTAL DESIGN: The HR status of 12 OCCC cell lines was determined using RAD51/gammaH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry. RESULTS: A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 9.4 (SD +/- 0.29) vs -8.1 (SD +/- 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases. CONCLUSIONS: A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by gammaH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs. PMID- 28002810 TI - Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. AB - Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms. In fact, several novel pathways leading to escape from anti-EGFR therapy have been reported in recent years. In this review, we provide an overview of known and novel mechanisms that contribute to both primary and acquired anti-EGFR therapy resistance, and enlist possible treatment strategies to overcome or reverse this resistance. PMID- 28002811 TI - Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer. AB - Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts. PMID- 28002812 TI - Toll-like receptor 4 rs11536889 is associated with angiographic extent and severity of coronary artery disease in a Chinese population. AB - Toll-like receptor 4 (TLR4) is a key modulator in many inflammation-related diseases. Polymorphisms in the TLR4 gene may alter TLR4 expression and affect the extent and severity of coronary artery disease (CAD). We analyzed 3 polymorphisms of TLR4 in 607 Chinese subjects who underwent coronary arteriography. Blood samples were collected to identify the polymorphisms. We evaluated the relationships between the polymorphisms and the number of vessels involved in coronary stenosis, Gensini scores, and Duke prognostic scores. We found that rs11536889 was associated with an increased risk of 3-vessel disease. When subjects with 3-vessel disease were compared to subjects with nonsignificant CAD, rs11536889 variant genotypes were associated with an increased risk of 3-vessel disease (GC/CC vs. GG: OR=2.06, 95%CI=1.21-3.51). When subjects with 3-vessel disease were compared to subjects with 1-vessel disease, rs11536889 variant genotypes were associated with an increased risk of 3-vessel disease (GC vs. GG: OR=2.14, 95%CI=1.20-3.79; GC/CC vs. GG: OR=2.06, 95%CI=1.20-3.54). When subjects with 3-vessel disease were compared to subjects with non-3-vessel disease, rs11536889 variant genotypes were associated with an increased risk of 3-vessel disease (GC vs. GG: OR=1.76, 95%CI=1.12-2.75; GC/CC vs. GG: OR=1.83, 95%CI=1.19 2.82). The TLR4 rs11536889 polymorphism was also related to Gensini score (P=0.02). The Gensini score was higher in subjects with the variant CC and GC/CC genotype than in subjects with the wild GG genotype (61.28+/- 1.84 and 57.64+/ 34.82 vs. 51.27+/-34.57). Our results demonstrate that TLR4 rs11536889 polymorphism is a novel genetic factor in the development of CAD, influencing the extent and severity of CAD. PMID- 28002814 TI - The Global Rise of Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization in Pediatric Hydrocephalus. AB - In the quest to identify the optimal means of cerebrospinal fluid diversion free of shunt dependency, endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) has been proposed as a promising procedure in select children. Supplementing traditional ETV with obliteration of the choroid plexus has been shown to decrease the likelihood of ultimate shunt dependency by roughly 20%. Originally devised to treat hydrocephalus in infants in sub-Saharan Africa, ETV/CPC has gained eager attention and cautious support in the developed world. Herein, we offer a comprehensive review of ETV/CPC beginning with the history and theory behind the operation. Next, we delve into the data supporting its use across heterogeneous pediatric populations, and finally we discuss clinical outcomes and future directions. PMID- 28002813 TI - Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway. AB - Here we provide evidence to link sub-lethal oxidative stress to lysosome biogenesis. Exposure of cells to sub-lethal concentrations of exogenously added hydrogen peroxide resulted in cytosol to nuclear translocation of the Transcription Factor EB (TFEB), the master controller of lysosome biogenesis and function. Nuclear translocation of TFEB was dependent upon the activation of a cathepsin-caspase 3 signaling pathway, downstream of lysosomal membrane permeabilization and accompanied by a significant increase in lysosome numbers as well as induction of TFEB-dependent lysosome-associated genes expression such as Ctsl, Lamp2 and its spliced variant Lamp2a, Neu1and Ctsb and Sqstm1 and Atg9b. The effects of sub-lethal oxidative stress on lysosomal gene expression and biogenesis were rescued upon gene silencing of caspase 3 and TFEB. Notably, caspase 3 activation was not associated with phenotypic hallmarks of apoptosis, evidenced by the absence of caspase 3 substrate cleavage, such as PARP, Lamin A/C or gelsolin. Taken together, these data demonstrate for the first time an unexpected and non-canonical role of a cathepsin-caspase 3 axis in the nuclear translocation of TFEB leading to lysosome biogenesis under conditions of sub lethal oxidative stress. PMID- 28002815 TI - Cortical Actin Alteration at the Matrix-Side Cytoplasm in Lung Adenocarcinoma Cells and Its Significance in Invasion. AB - OBJECTIVES: Cortical actin is a thin layer of filamentous (F-)actin that lies beneath the plasma membrane, and its role in pathophysiology remains unclear. We investigated the subcellular localization of cortical actin by the histopathological and experimental studies of lung adenocarcinomas. MATERIALS AND METHODS: The subcellular localization of cortical actin was studied in surgically resected lung adenocarcinomas tissues and in 3-dimensionally cultured lung adenocarcinoma A549 cells. RESULTS: In normal type II alveolar cells and the bronchiolar epithelium, cortical actin was localized to the apical-side cytoplasm. In invasive adenocarcinoma cells, cortical actin was frequently localized to the matrix side. The degree of cortical actin localized to the matrix side was associated with the loss of basement membrane and a poor prognosis. In A549 cell spheroids cultured in a type I collagen and basement membrane extract MatrigelTM mixed gel, cortical F-actin was localized to the matrix side with phosphorylated myosin light chain. Super-resolution and electron microscopy results suggest that compact wrinkling of the plasma membrane by myosin-mediated F-actin contraction is an explanation for cortical actin accumulation at the matrix side. The myosin II inhibitor blebbistatin suppressed the 3-dimensional collective migration of A549 cells induced by constitutively active Cdc42 and MT1-MMP. CONCLUSION: Cortical actin accumulation at the matrix side cytoplasm of cancer cells occurs in invasive lung adenocarcinomas and it possibly participates in the migration of cancer cells through myosin-mediated contraction. PMID- 28002817 TI - Meta-Analysis for Penalized Regression Methods with Multi-Cohort Genome-Wide Association Studies. AB - OBJECTIVE: Penalized regression has been successfully applied in genome-wide association studies. While meta-analysis is often conducted to increase power and protect patients' confidentiality, methods for meta-analyzing results of penalized regression in multi-cohort setting are still under development. METHODS: We propose to use a data-splitting method to obtain valid p values (or equivalently, coefficient estimates and standard errors) for meta-analysis across multiple cohorts. We examine two ways of splitting data in multi-cohort setting and propose three methods to conduct meta-analysis based on p values. We compare the three meta-analysis methods to mega-analysis, which consists of pooling individual level data. We also apply our proposed meta-analysis approaches to the Framingham Heart Study data, where we divide the original dataset into four parts to create a multi-cohort scenario. RESULTS: The simulations suggest that splitting cohorts has better performance than splitting data within each cohort. The real data application also shows that this method provides results that are similar to the mega-analysis. CONCLUSION: After comparing the three methods that we proposed to conduct meta-analysis, we recommend splitting cohorts rather than datasets to obtain valid p values for meta-analysis of results from penalized regression in multi-cohort setting. PMID- 28002816 TI - Associations of Serum Osteocalcin and Polymorphisms of the Osteocalcin Gene with Bone Mineral Density in Postmenopausal and Elderly Chinese Women. AB - BACKGROUND: The aims of this study were: (1) to evaluate the association of serum osteocalcin with bone mineral density (BMD) and markers of bone metabolism in postmenopausal and elderly Chinese women, and (2) to observe the relationships of single-nucleotide polymorphisms (SNPs) in and around the osteocalcin gene with osteocalcin and BMD. METHODS: A cross-sectional study was conducted with 725 postmenopausal Chinese women. Five SNPs (rs1543294, rs1800247, rs759330, rs2842880, and rs933489) of the osteocalcin gene were genotyped. Serum osteocalcin and intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], and type I collagen containing cross-linked C-telopeptide (beta-CTX) were measured. The BMD of the lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry. RESULTS: Osteocalcin was positively correlated with serum phosphorus (p = 0.001), alkaline phosphatase (ALP; p < 0.001), PTH (p = 0.002) and beta-CTX (p < 0.001), and negatively correlated with BMD at the lumbar spine (p < 0.001) and total hip (p = 0.002). No significant association was obtained between the SNPs, haplotypes of the osteocalcin gene, and BMD or osteocalcin. CONCLUSION: Our results suggest that osteocalcin was positively correlated with serum phosphorus, ALP, PTH, and beta-CTX, but negatively correlated with BMD at the lumbar spine and total hip. Common genetic variants of the osteocalcin gene may not be a major contributor to variations in serum osteocalcin or BMD in postmenopausal and elderly Chinese women. PMID- 28002818 TI - Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial. AB - BACKGROUND/AIMS: To assess auxological and safety data for growth hormone (GH) treated children with SHOX deficiency. METHODS: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. RESULTS: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92 1.58). No new GH-related safety concerns were identified. CONCLUSION: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns. PMID- 28002819 TI - Divergence between C. melo and African Cucumis Species Identified by Chromosome Painting and rDNA Distribution Pattern. AB - The 5S and 45S rDNA sites are useful chromosome landmarks and can provide valuable information about karyotype evolution and species interrelationships. In this study, we employed fluorescence in situ hybridization (FISH) to determine the number and chromosomal location of 5S and 45S rDNA loci in 8 diploid Cucumis species. Two oligonucleotide painting probes specific for the rDNA-bearing chromosomes in C. melo were hybridized to other Cucumis species in order to investigate the homeologies among the rDNA-carrying chromosomes in Cucumis species. The analyzed diploid species showed 3 types of rDNA distribution patterns, which provided clear cytogenetic evidence on the divergence between C. melo and wild diploid African Cucumis species. The present results not only show species interrelationships in the genus Cucumis, but the rDNA FISH patterns can also be used as cytological markers for the discrimination of closely related species. The data will be helpful for breeders to choose the most suitable species from various wild species for improvement of cultivated melon. PMID- 28002820 TI - Zika Virus Infection in the Elderly: Possible Relationship with Guillain-Barre Syndrome. AB - The Zika virus (ZIKV) outbreak in French Polynesia, in 2013, and in Brazil, in 2015, was correlated with neurological complications, which comprised, among others, congenital microcephaly and Guillain-Barre syndrome (GBS), which includes a group of acute autoimmune neuropathies generally reported after respiratory or gastrointestinal infectious diseases. Despite being relatively rare, the incidence rate of GBS rises with age, which makes GBS more frequent in the elderly, in whom it is also a more severe disease with slower recovery than in younger patients. Different forms of GBS have been described having diagnostic confirmation of a previous infection with the ZIKV virus. Although we do not have enough evidence that elderly people are a particularly susceptible population to developing GBS following ZIKV infection, this is plausible. We should consider this possibility, particularly taking into account that aging subjects are more susceptible to infections. In this context, a deeper understanding of how the immune system in the elderly functions in relation to ZIKV infection is necessary, as well as an understanding of what kind of alterations of the nervous system such an infection triggers in the elderly, beyond GBS. This will be relevant for better therapeutic interventions and for designing vaccine candidates that can be applied in an aging population, particularly those prone to develop ZIKV-induced autoimmunity. PMID- 28002821 TI - Cutaneous Metastasis: A Study of 138 Cases Diagnosed by Fine-Needle Aspiration Cytology. AB - BACKGROUND: Cutaneous metastases can occur in a wide variety of internal malignancies and may be the first sign of a clinically silent visceral cancer. STUDY DESIGN: A retrospective analysis was made of 138 cases diagnosed with cutaneous and subcutaneous metastasis on fine-needle aspiration cytology (FNAC). Primary tumors of the skin/subcutis were excluded. RESULTS: Of 138 cases, the primary was known in 101 cases and unknown in 37 cases. The age of the patients ranged from 5 to 86 years, and 76 (55.1%) were male and 62 (44.9%) were female. Clinically, the most common lesion was a single nodule (n = 77, 55.8%). The chest wall was the predominant site (n = 53, 38.4%). In males and females, the most common primary sites were the lung (n = 16) and breast (n = 24), respectively. On cytology, the most common diagnosis was metastatic adenocarcinoma (n = 41, 29.7%). Of 37 cases with an unknown primary, FNAC helped to locate the primary site in 17 (45.9%) cases, while in 20 cases it remained undiagnosed. CONCLUSIONS: FNAC is a rapid and safe technique that can be used as a first line of investigation for confirmation of metastatic lesions of the skin. Critical evaluation of cytomorphological features along with relevant clinical details could help in the localization of an unknown primary site in some cases. PMID- 28002822 TI - The VEGFR Inhibitor Cediranib Improves the Efficacy of Fractionated Radiotherapy in a Colorectal Cancer Xenograft Model. AB - BACKGROUND/PURPOSE: Radiotherapy (RT) increases local tumor control in locally advanced rectal cancer, but complete histological response is seen in only a minority of cases. Antiangiogenic therapy has been proposed to improve RT efficacy by "normalizing" the tumor microvasculature. Here, we examined whether cediranib, a pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, improves microvascular function and tumor control in combination with RT in a mouse colorectal cancer (CRC) model. METHODS: CRC xenografts (HT29) were grown subcutaneously in mice. Animals were treated for 5 consecutive days with vehicle, RT (1.8 Gy daily), cediranib (6 mg/kg po), or combined therapy (cediranib 2 h prior to radiation). Tumor volume was measured with calipers. Vascular changes were analyzed by dynamic contrast-enhanced MRI, oxygenation and interstitial fluid pressure probes and histology. To investigate vascular changes more in detail, a second set of mice were fitted with titanium dorsal skinfold window chambers, wherein a HT29 tumor cell suspension was injected. In vivo fluorescence microscopy was performed before and after treatment (same treatment protocol). RESULTS: In vivo microscopy analyses showed that VEGFR inhibition with cediranib led to a "normalization" of the vessel wall, with decreased microvessel permeability (p < 0.0001) and tortuosity (p < 0.01), and a trend to decreased vessel diameters. This seemed to lead to lower tumor hypoxia rates in the cediranib and combination groups compared to the control and RT groups. This led to an increased tumor control in the combination group compared to controls or monotherapy (p < 0.0001). CONCLUSIONS: The combination of RT with cediranib enhances tumor control in a CRC xenograft mouse model. Microvascular analyses suggest that cediranib leads to vascular normalization and improved oxygenation. PMID- 28002823 TI - The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care. AB - Genomic alterations are important biological markers for cancer diagnosis and prognosis, disease classification, risk stratification, and treatment selection. Chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are superb new tools for evaluating cancer genomes. These state-of the-art technologies offer high-throughput, highly accurate, targeted and whole genome evaluation of genomic alterations in tumor tissues. The application of CMA and NGS technologies in cancer research has generated a wealth of useful information about the landscape of genomic alterations in cancer and their implications in cancer care. As the knowledge base in cancer genomics and genome biology grows, the focus of research is now shifting toward the clinical applications of these technologies to improve patient care. Although not yet standard of care in cancer, there is an increasing interest among the cancer genomics communities in applying these new technologies to cancer diagnosis in the Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. Many clinical laboratories have already started adopting these technologies for cancer genomic analysis. We anticipate that CMA and NGS will soon become the major diagnostic means for cancer genomic analysis to meet the increasing demands of precision cancer care. PMID- 28002824 TI - A General Framework for the Evaluation of Genetic Association Studies Using Multiple Marginal Models. AB - OBJECTIVE: In this study, we present a simultaneous inference procedure as a unified analysis framework for genetic association studies. METHODS: The method is based on the formulation of multiple marginal models that reflect different modes of inheritance. The basic advantage of this methodology is that no explicit formulation of the correlation between the test statistics is required. Moreover, the genotype scores are considered as a quantitative explanatory variable, i.e., regression models are used. RESULTS: The proposed approach covers a wide variety of endpoints (binary, count, quantitative, and time-to-event data). In addition, multiple endpoints of different types can be assessed simultaneously. This allows the detection of pleiotropic effects while taking the mode of inheritance into account. Moreover, multiple loci can be assessed simultaneously. CONCLUSION: The flexibility of the proposed approach is demonstrated while analyzing a variety of data examples. PMID- 28002825 TI - From Common to Rare Variants: The Genetic Component of Alzheimer Disease. AB - Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Abeta peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Abeta peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Abeta production/secretion, aggregation, clearance, or toxicity. Among them, the APOE epsilon4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants. PMID- 28002826 TI - The CAPN2/CAPN8 Locus on Chromosome 1q Is Associated with Variation in Serum Alpha-Carotene Concentrations. AB - BACKGROUND/AIMS: Alpha-carotene is a provitamin A carotenoid present in fruits and vegetables. Higher serum concentrations of alpha-carotene have been associated with lower risk of cancer and all-cause mortality. Previous studies have suggested that genetic variants influence serum concentrations of provitamin A carotenoids, but to date no variants have been robustly associated with serum alpha-carotene concentrations. The aim of this study was to identify genetic associations with serum alpha-carotene concentrations using the genome-wide association study (GWAS) approach. METHODS: A GWAS of serum alpha-carotene concentrations was conducted in 433 Old Order Amish adults who had consumed a 6 day controlled diet. Linear regression models adjusting for age, gender, and family structure were utilized to evaluate associations between genetic variants and serum alpha-carotene concentrations. RESULTS: Genome-wide significant associations with alpha-carotene concentrations were observed for loci on chromosome 1q41 between the genes CAPN2 and CAPN8 (rs12137025, p = 3.55 * 10-8), chromosome 2p21 in PRKCE (rs2594495, p = 1.01 * 10-8), and chromosome 4q34 (rs17830069, p = 2.89 * 10-8). CONCLUSIONS: We identified 3 novel loci associated with serum alpha-carotene concentrations among a population that consumed a controlled diet. While replication is necessary, the CAPN2/CAPN8 locus provides compelling evidence for an association with serum alpha-carotene concentrations and may suggest a relationship with the development and progression of cancers. PMID- 28002827 TI - The in vivo Inhibition of Oral Biofilm Accumulation and Streptococcus mutans by Ceramic Water. AB - Combustion-synthesized titanium carbide ceramics uniformly disperse silver, producing silver ions and hydroxyl radicals in water. This generates antimicrobial activity against various bacteria. One such bacterium is Streptococcus mutans, a gram-positive anaerobic bacterium known as a major pathogen of dental caries. In this study, we analyzed the inhibition of oral biofilms and S. mutans by ceramic water in in vitro and human studies. S. mutans strains showed significantly lower antimicrobial and sucrose-dependent adhesion activity in the presence of ceramic powder compared with untreated culture medium. Confocal microscopy revealed that S. mutans biofilm structures with ceramic powder were thin and coarse. Twenty-seven volunteers (13 males, 14 females; 18-37 years old, mean 25.2 years) were enrolled for subsequent studies. After each meal, one group was asked to rinse with ceramic water while the other rinsed with untreated water for 1 week. After 1 week, the rinsing contents were switched between the groups and the same protocol was followed for an additional week. After rinsing with ceramic water, the average plaque score was 43.0 +/- 3.7, which was significantly lower than the baseline value (74.1 +/- 5.7, p < 0.001). However, no significant difference was observed when rinsing with untreated water. In addition, the total number of S. mutans in saliva was significantly reduced after rinsing with ceramic water compared with untreated water (p < 0.05). These results suggest that ceramic water possesses antimicrobial activity against S. mutans and inhibits biofilm formation. Rinsing with ceramic water can also inhibit dental plaque formation and S. mutans colonization in humans. PMID- 28002828 TI - Piper betle Induced Cytoprotective Genes and Proteins via the Nrf2/ARE Pathway in Aging Mice. AB - BACKGROUND/AIMS: The objective of this study was to elucidate the underlying antioxidant mechanism of aqueous extract of Piper betle (PB) in aging rats. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway involving phase II detoxifying and antioxidant enzymes plays an important role in the antioxidant system by reducing electrophiles and reactive oxygen species through induction of phase II enzymes and proteins. METHODS: Genes and proteins of phase II detoxifying antioxidant enzymes were analyzed by QuantiGenePlex 2.0 Assay and Western blot analysis. RESULTS: PB significantly induced genes and proteins of phase II and antioxidant enzymes, NAD(P)H quinone oxidoreductase 1, and catalase in aging mice (p < 0.05). The expression of these enzymes were stimulated via translocation of Nrf2 into the nucleus, indicating the involvement of ARE, a cis acting motif located in the promoter region of nearly all phase II genes. CONCLUSIONS: PB was testified for the first time to induce cytoprotective genes through the Nrf2/ARE signaling pathway, thus unraveling the antioxidant mechanism of PB during the aging process. PMID- 28002829 TI - Reduced Serum Levels of Zinc and Superoxide Dismutase in Obese Individuals. AB - The oxidant-stress (OS) has an essential role to play in the pathogenesis and progression of many diseases. OS is the outcome when the level of free-radical formation is increased or protective-antioxidant-mechanisms are compromised. Its value is expected to increase, although its emerging roles have not been conclusive in different studies. The objective of this study was to explore the level of zinc, copper, and antioxidant in response to obesity-related-stress by measuring superoxide-dismutase (SOD) levels as a key antioxidant-enzyme in 706 individuals with/without obesity. Anthropometric/biochemical parameters including total-cholesterol (TC), fasting-blood-glucose, high-density-lipoprotein (HDL), low-density-lipoprotein, and triglycerides were determined. The activity of SOD was measured followed by the measurement of Cu and Zn levels. Obese subjects had a significantly higher level of body mass index (BMI) and TC, while the level of HDL was lower in the obese group, as compared to the related values in control subjects. The level of Zn was significantly decreased in the obese group, while the level of Cu and Cu/Zn ratio increased. Additionally, we observed that the SOD level was less in obese subjects when compared to that in the non-obese subjects. In addition to the complications of high BMI, low level of Zn and SOD in obesity can be considered a risk factor, resulting in a reduced antioxidant response, supporting the need for identifying a suitable treatment option for this group. PMID- 28002830 TI - Erratum. PMID- 28002831 TI - Erratum. PMID- 28002832 TI - Acute and Chronic Posttraumatic Stress Symptoms in the Emergence of Posttraumatic Stress Disorder: A Network Analysis. AB - Importance: Little is understood about how the symptoms of posttraumatic stress develop over time into the syndrome of posttraumatic stress disorder (PTSD). Objective: To use a network analysis approach to identify the nature of the association between PTSD symptoms in the acute phase after trauma and the chronic phase. Design, Setting, and Participants: A prospective cohort study enrolled 1138 patients recently admitted with traumatic injury to 1 of 4 major trauma hospitals across Australia from March 13, 2004, to February 26, 2006. Participants underwent assessment during hospital admission (n = 1388) and at 12 months after injury (n = 852). Networks of symptom associations were analyzed in the acute and chronic phases using partial correlations, relative importance estimates, and centrality measures of each symptom in terms of its association strengths, closeness to other symptoms, and importance in connecting other symptoms to each other. Data were analyzed from March 3 to September 5, 2016. Main Outcomes and Measures: Severity of PTSD was assessed at each assessment with the Clinician-Administered PTSD Scale. Results: Of the 1138 patients undergoing assessment at admission (837 men [73.6%] and 301 women [26.4%]; mean [SD] age, 37.90 [13.62] years), strong connections were found in the acute phase. Reexperiencing symptoms were central to other symptoms in the acute phase, with intrusions and physiological reactivity among the most central symptoms in the networks in terms of the extent to which they occur between other symptoms (mean [SD], 1.2 [0.7] and 1.0 [0.9], respectively), closeness to other symptoms (mean [SD], 0.9 [0.3] and 1.1 [0.9], respectively), and strength of the associations (mean [SD], 1.6 [0.3] and 1.5 [0.3] respectively) among flashbacks, intrusions, and avoidance of thoughts, with moderately strong connections between intrusions and nightmares, being upset by reminders, and physiological reactivity. Intrusions and physiological reactivity were central in the acute phase. Among the 852 patients (73.6%) who completed the 12-month assessment, overall network connectivity was significantly stronger at 12 months than in the acute phase (global strength values, 6.57 vs 7.60; paired difference, 1.03; P < .001). The network associations among the reexperiencing symptoms were strengthened at 12 months, and physiological reactivity was strongly associated with the startle response, which was also associated with hypervigilance. Strong connectivity among emotional numbing, detachment from others, and disinterest in activities as well as moderately strong links among irritability (anger), concentration deficits, and sleep disturbance were found. Conclusions and Relevance: As time elapses after trauma, fear circuitry and dysphoric PTSD symptoms appear to emerge as connected networks. Intrusive memories and reactivity are centrally associated with other symptoms in the acute phase, potentially pointing to the utility of addressing these symptoms in early intervention strategies. PMID- 28002833 TI - Quality of Evidence Underlying the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines on the Management of Atrial Fibrillation. AB - Importance: The joint American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) guidelines on the management of atrial fibrillation (AF) are used extensively to guide patient care. Objective: To describe the evidence base and changes over time in the AHA/ACC/HRS guidelines on AF with respect to the distribution of recommendations across classes of recommendations and levels of evidence. Data Sources: Data from the AHA/ACC/HRS guidelines on AF from 2001, 2006, 2011, and 2014 were abstracted. A total of 437 recommendations were included. Data Extraction and Synthesis: The number of recommendations and distribution of classes of recommendation (I, II, and III) and levels of evidence (A, B, and C) were determined for each guideline edition. Changes in recommendation class and level of evidence were analyzed using the 2001 and 2014 guidelines. Results: From 2001 to 2014, the total number of AF recommendations increased from 95 to 113. Numerically, there was a nonsignificant increase in the use of level of evidence B (30.5% to 39.8%; P = .17) and a nonsignificant decrease in the use of level of evidence C (60.0% to 51.3%; P = .21), with limited changes in the use of level A evidence (8.4% to 8.8%; P = .92). In the 2014 guideline document, 10 of 113 (8.8%) recommendations were supported by level of evidence A, whereas 58 of 113 (51.3%) were supported by level of evidence C. Most recommendations were equally split among class I (49/113; 43.4%) and class IIa/IIb (49/113; 43.4%), with the minority (15/113; 13.3%) assigned as class III. Most class I recommendations were supported by level of evidence C (29/49; 59.2%), whereas only 6 of 49 (12.2%) were supported by level of evidence A. No rate control category recommendations were supported by level of evidence A. Conclusions and Relevance: Some aspects of the quality of evidence underlying AHA/ACC/HRS AF guidelines have improved over time. However, the use of level of evidence A remains low and has not increased since 2001. These findings highlight the need for focused and pragmatic randomized studies on the clinical management of AF. PMID- 28002834 TI - Cost-effectiveness and Budget Effect Analysis of a Population-Based Skin Cancer Screening. AB - Importance: Several epidemiological studies show an alarming global increase in incidence of melanoma and nonmelanoma skin cancer. Objectives: To examine the cost-effectiveness of 2 population-based skin cancer screening methods and to assess their budget effect and the influence on skin cancer epidemiological findings. Design, Setting, and Participants: A Markov model with a latent period of 20 years and a time horizon of 50 years was used to analyze the cost effectiveness (societal perspective) and budget effect (public health care payer perspective) of 2 population-based skin cancer screening programs in Belgium compared with the absence of a screening program. A health economic analysis was based on a clinical trial performed in 2014 in Belgium. In the economic model, the total Belgian population 18 years or older was assumed to have been invited for the screening program. Main Outcomes and Measures: The influence of the screening program on skin cancer epidemiological findings and the cost per quality-adjusted life-year (QALY) gained, as well as the budget effect, expressed as the net costs for the health care payer over 50 years. Results: All participants (1668 total-body skin examination [TBSE] and 248 lesion-directed screening [LDS]) were screened by a team of 6 dermatologists from March 14 to 18, 2014, for TSBE and April 22 and 25 to 27, 2014, for LDS. Both screening strategies produced a gain in QALYs, resulting in incremental cost-effectiveness ratios of ?33 072 (US $35 475) per QALY in men and ?18 687 (US $20 044) per QALY in women for TBSE and ?34 836 (US $37 365) per QALY in men and ?19 470 (US $20 884) per QALY in women for LDS. With a 1-time screening, a 4.0% decrease in the incidence rates of stage III and IV melanoma was predicted at the population level relative to the comparator. The budget effect analysis demonstrated that during 20 years, a 1-time screening would incur a net cost for the health care payer of almost ?36 million (US $38.6 million) for TBSE or just over ?6 million (US $6.4 million) for LDS (?4.1 [US $4.40] or ?0.7 [US $0.80], respectively, per adult). Conclusions and Relevance: These results can be interpreted as cost effective at a willingness-to-pay threshold in Belgium of ?35 000 (US $37 541) per QALY gained. Based on these findings, a 1-time TBSE in the general adult population 18 years or older is the most cost-effective strategy and is predicted to result in a reduction of skin cancer mortality over 20 years and 50 years. The cost-effectiveness for skin cancer screening is higher in women than in men. PMID- 28002835 TI - Seeing Speech Production Through the Window of Complex Interactions: Introduction to the Supplement of Select Papers From the 10th International Seminar on Speech Production (ISSP) in Cologne. AB - Purpose: As the famous linguist and anthropologist C. Hockett noted about 30 years ago, "What one sees of language, as of anything, depends on the angle of view, and different explorers approach from different directions. Unfortunately, sometimes they become so enamored of their particular approach that they incline to scoff at any other, so that instead of everybody being the richer for the variety, everybody loses. ... It is obviously impossible to see all of anything from a single vantage point. So it is never inappropriate to seek new perspectives" (Hockett, 1987, p. 1). This supplement takes such a broad perspective and contains a selection of peer-reviewed papers seeing speech production through the window of complex interactions between physical, linguistic, social, and communicative factors. Papers were presented at the 10th International Seminar on Speech Production in Cologne. We hope to encourage the reader to continue working in this exciting direction. PMID- 28002836 TI - Lip Movements for an Unfamiliar Vowel: Mandarin Front Rounded Vowel Produced by Japanese Speakers. AB - Purpose: The study was aimed at investigating what kind of lip positions are selected by Japanese adult participants for an unfamiliar Mandarin rounded vowel /y/ and if their lip positions are related to and/or differentiated from those for their native vowels. Method: Videotaping and post hoc tracking measurements for lip positions, namely protrusion and vertical aperture, and acoustic analysis of vowel formants were conducted on participants' production in a repetition task. Results: First, 31.2% of all productions of /y/ were produced with either protruded or compressed rounding. Second, the lip positions for /y/ were differentiated from those for the perceived nearest native vowel; although they correlated with them in terms of vertical aperture, they did not in terms of protrusion/retraction. Conclusions: Lip positions for a novel rounded vowel seemed to be produced as a modification of existing lip positions from the native repertoire. Moreover, the degree of vertical aperture might be easily transferred, and the degree of protrusion is less likely to be retained in the new lip positions. PMID- 28002837 TI - Influences of Tone on Vowel Articulation in Mandarin Chinese. AB - Purpose: Models of speech production often abstract away from shared physiology in pitch control and lingual articulation, positing independent control of tone and vowel units. We assess the validity of this assumption in Mandarin Chinese by evaluating the stability of lingual articulation for vowels across variation in tone. Method: Electromagnetic articulography was used to track flesh points on the tongue (tip, body, dorsum), lips, and jaw while native Mandarin speakers (n = 6) produced 3 vowels, /pa/, /pi/, /pu/, combined with 4 Mandarin tones: T1 "high," T2 "rising," T3 "low," and T4 "falling." Results: Consistent with physiological expectations, tones that begin low, T2 and T3, conditioned a lower position of the tongue body for the vowel /a/. For the vowel /i/, we found the opposite effect, whereby tones that begin low, T2 and T3, conditioned a higher tongue body position. Conclusions: The physiology of pitch control exerts systematic variation on the lingual articulation of /a/ across tones. The effects of tone on /i/ articulation are in the opposite direction predicted by physiological considerations. Physiologically arbitrary variation of the type observed for /i/ challenges the assumption that phonetic patterns can be determined by independent control of tone (source) and vowel (filter) production units. PMID- 28002838 TI - Effect of Domain Initial Strengthening on Vowel Height and Backness Contrasts in French: Acoustic and Ultrasound Data. AB - Purpose: Phonetic variation due to domain initial strengthening was investigated with respect to the acoustic and articulatory distinctiveness of vowels within a subset of the French oral vowel system /i, e, E, a, o, u/, organized along 4 degrees of height for the front vowels and 2 degrees of backness at the close and midclose height levels. Method: Acoustic and lingual ultrasound data were examined to characterize the production of vowels in intonational phrase initial position, compared with intonational phrase medial position, for 4 speakers. Results: Formant values and estimates of lingual constriction location and degree differed according to the prosodic position independent of vowel duration, with a higher F1 for /a/, a higher F2 for /E/, a backer constriction for /o/ and /a/ but a fronter constriction for /E/, and a narrower constriction for /e, E, u, o/ but a wider constriction for /a/. For most speakers, these variations enlarge the acoustic and/or articulatory distance between members of the pairs /e-E/, /E-a/, /u-o/, /i-u/, and /e-o/ but reduce the distinction within the pair /i-e/. Conclusions: These changes in intonational phrase initial position are vowel dependent and frequently contribute to augmenting the phonetic distinctiveness between vowels contrasting along the height and backness dimensions. PMID- 28002839 TI - Mumbling: Macho or Morphology? AB - Purpose: Mumbling as opposed to clear speech is a typical male characteristic in speech and can be the consequence of a small jaw opening. Whereas behavioral reasons have often been offered to explain sex-specific differences with respect to clear speech, the purpose of this study is to investigate a potential anatomical reason for smaller jaw openings in male than in female speakers. Method: Articulatory data from 2 data sets (American English and German) were analyzed with respect to jaw opening in low vowels during speech. Particular focus was placed on sex-specific differences, also incorporating potential interactions with different accent conditions in 1 of the data sets. In addition, a modeling study compared the articulatory consequences of similar jaw-opening settings in a typical male and a typical female articulatory model. Results: Greater jaw openings were found for the female speakers, in particular in the accented condition, where jaw opening was found to be larger. In line with this finding, the modeling study showed that similar jaw-opening settings in male and female speakers led to differences in pharyngeal constriction, resulting in complete radico-pharyngeal closure in the male model. Conclusion: The empirical and modeling findings suggest a possible physiological component in sex-specific differences in speech clarity for low vowels. PMID- 28002840 TI - Suprasegmental Characteristics of Spontaneous Speech Produced in Good and Challenging Communicative Conditions by Talkers Aged 9-14 Years. AB - Purpose: This study investigated the acoustic characteristics of spontaneous speech by talkers aged 9-14 years and their ability to adapt these characteristics to maintain effective communication when intelligibility was artificially degraded for their interlocutor. Method: Recordings were made for 96 children (50 female participants, 46 male participants) engaged in a problem solving task with a same-sex friend; recordings for 20 adults were used as reference. The task was carried out in good listening conditions (normal transmission) and in degraded transmission conditions. Articulation rate, median fundamental frequency (f0), f0 range, and relative energy in the 1- to 3-kHz range were analyzed. Results: With increasing age, children significantly reduced their median f0 and f0 range, became faster talkers, and reduced their mid frequency energy in spontaneous speech. Children produced similar clear speech adaptations (in degraded transmission conditions) as adults, but only children aged 11-14 years increased their f0 range, an unhelpful strategy not transmitted via the vocoder. Changes made by children were consistent with a general increase in vocal effort. Conclusion: Further developments in speech production take place during later childhood. Children use clear speech strategies to benefit an interlocutor facing intelligibility problems but may not be able to attune these strategies to the same degree as adults. PMID- 28002841 TI - Voice Quality and Gender Stereotypes: A Study of Lebanese Women With Reinke's Edema. AB - Purpose: Women with Reinke's edema (RW) report being mistaken for men during telephone conversations. For this reason, their masculine-sounding voices are interesting for the study of gender stereotypes. The study's objective is to verify their complaint and to understand the cues used in gender identification. Method: Using a self-evaluation study, we verified RW's perception of their own voices. We compared the acoustic parameters of vowels produced by 10 RW to those produced by 10 men and 10 women with healthy voices (hereafter referred to as NW) in Lebanese Arabic. We conducted a perception study for the evaluation of RW, healthy men's, and NW voices by naive listeners. Results: RW self-evaluated their voices as masculine and their gender identities as feminine. The acoustic parameters that distinguish RW from NW voices concern fundamental frequency, spectral slope, harmonicity of the voicing signal, and complexity of the spectral envelope. Naive listeners very often rate RW as surely masculine. Conclusions: Listeners may rate RW's gender incorrectly. These incorrect gender ratings are correlated with acoustic measures of fundamental frequency and voice quality. Further investigations will reveal the contribution of each of these parameters to gender perception and guide the treatment plan of patients complaining of a gender ambiguous voice. PMID- 28002842 TI - Efficacy of Antibody to PNAG Against Keratitis Caused by Fungal Pathogens. AB - Purpose: Developing immunotherapies for fungal eye infections is a high priority. We analyzed fungal pathogens for expression of the surface polysaccharide, poly-N acetyl glucosamine (PNAG), and used a mouse model of ocular keratitis caused by Aspergillus flavus, A. fumigatus, or Fusarium solani to determine if PNAG was an immunotherapy target and requirements for ancillary cellular and molecular immune effectors. Methods: Enzyme-linked immunosorbent assay (ELISA) or immunofluorescence was used to detect PNAG on fungal cells. Keratitis was induced by scratching corneas of C57BL/6, IL-17R KO, RAG-1 KO, or IL-22 KO mice followed by inoculation with fungal pathogens. Goat antibodies to PNAG, a PNAG-specific human IgG1 monoclonal antibody, or control antibodies were injected either prophylactically plus therapeutically or therapeutically only, and corneal pathology and fungal levels determined in infected eyes at 24 or 48 hours after infection. Results: All tested fungal species produced PNAG. Prophylactic or therapeutic treatment by intraperitoneal (IP) injection of antibody to PNAG combined with post-infection topical application of antibody, the latter also used for A. fumigatus, led to reduced fungal levels, corneal pathology, and cytokine expression. Topical administration only of the PNAG monoclonal antibodies (MAb) reduced fungal loads and corneal pathology. There was no antibody protection in IL-17R KO, RAG-1 KO, or IL-22 KO mice. Conclusions: Poly-N acetyl glucosamine is produced by clinically important fungal ocular pathogens. Antibody to PNAG demonstrated protection against Aspergillus and Fusarium keratitis, requiring T cells producing IL-17 and IL-22. These findings indicate the potential to prevent or treat fungal infections by vaccines and immunotherapeutics to PNAG. PMID- 28002844 TI - Activation of the Rho/Rho Kinase Signaling Pathway Is Involved in Cell Death of Corneal Endothelium. AB - Purpose: Rho kinase (ROCK) pathways control fundamental cell functions, making ROCK an important therapeutic target in several pathophysiologic conditions. The purpose of this study was to investigate whether inhibition of ROCK can suppress apoptosis of the corneal endothelium and to determine the role of ROCK signaling in regulating apoptosis. Methods: The effects of inhibitors of ROCK or myosin light chain (MLC) were evaluated in cultured monkey corneal endothelial cells (MCECs) irradiated with ultraviolet (UV) (100 J/m2) to induce apoptosis. Annexin V and TUNEL staining and Western blot for apoptosis-related proteins and focal adhesion complexes were then performed. RhoA activation was further evaluated by pull-down assays. ROCK inhibitor and caspase inhibitor effects on apoptosis were also evaluated in MCECs treated with ethylene glycol tetraacetic acid (EGTA) to induce MLC phosphorylation. Results: ROCK or MLC inhibition suppressed the caspase-3 cleavage and Annexin V and TUNEL expression typically seen during UV mediated apoptosis of MCECs. The apoptotic stimulus activated RhoA and then induced phosphorylation of MLC via ROCK activation. EGTA-mediated phosphorylation of MLC was sufficient to induce the loss of cell contact with the substrate and subsequent apoptosis. Western blot showed that ROCK inhibition upregulated the expression of the focal adhesion complex in adhered cells, following UV stress. Conclusions: Apoptotic stimuli activated Rho/ROCK/MLC phosphorylation in the corneal endothelium, and subsequent actomyosin contraction induced apoptosis by loss of cell adhesion. ROCK inhibition suppressed MLC phosphorylation and subsequent cell death, and it counteracted the loss of cell adhesion by activating the focal adhesion complex. PMID- 28002843 TI - Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages. AB - Purpose: Mutations in membrane frizzled-related protein (MFRP) are associated with nanophthalmia, hyperopia, foveoschisis, irregular patches of RPE atrophy, and optic disc drusen in humans. Mouse mfrp mutants show retinal degeneration but no change in eye size or refractive state. The goal of this work was to generate zebrafish mutants to investigate the loss of Mfrp on eye size and refractive state, and to characterize other phenotypes observed. Methods: Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 methods were used to generate multiple frameshift mutations in zebrafish mfrp causing premature translational stops in Mfrp. Spectral-domain optical coherence tomography (SD OCT) was used to measure eye metrics and refractive state, and immunohistochemistry was used to study adult eyes. Gene expression levels were measured using quantitative PCR. Results: Zebrafish Mfrp was shown to localize to apical and basal regions of RPE cells, as well as the ciliary marginal zone. Loss of Mfrp in mutant zebrafish was verified histologically. Zebrafish eyes that were mfrp mutant showed reduced axial length causing hyperopia, RPE folding, and macrophages were observed subretinally. Visual acuity was reduced in mfrp mutant animals. Conclusions: Mutation of zebrafish mfrp results in hyperopia with subretinal macrophage infiltration, phenocopying aspects of human and mouse Mfrp deficiency. These mutant zebrafish will be useful in studying the onset and progression of Mfrp-related nanophthalmia, the cues that initiate the recruitment of macrophages, and the mechanisms of Mfrp function. PMID- 28002845 TI - Myopia Development Among Young Schoolchildren: The Myopia Investigation Study in Taipei. AB - Purpose: To investigate the annual incidence of myopia and associated factors among young schoolchildren in Taipei City. Methods: The Myopia Investigation Study in Taipei was a citywide, population-based cohort study. During the fall 2013 semester (baseline), a total of 11,590 grade 2 schoolchildren completed ocular examination and were included for further analysis. A parent-completed questionnaire was administered to collect data on risk factors for myopia development. Follow-up visits were arranged biannually over 3 years. The first year results are reported here. Schoolchildren who were emmetropic/hyperopic at baseline and had myopia (spherical equivalent <= -0.5 diopters) in either eye at follow-up were identified as having incident myopia. Results: Among 7376 baseline nonmyopic participants, 6794 (92.1%) were examined during the first-year follow up, and 1856 (25.2%) with incident myopia were identified. The incidence density of myopia was 31.7 (95% confidence interval [CI]: 30.6-32.8) per 100 person years. Cox hazard proportional regression analysis revealed that participants who were emmetropic at baseline (hazards ratio [HR]: 19.37; 95% CI: 4.84-77.57), who had two myopic parents (HR: 1.21; 95% CI: 1.04-1.42), and who spent >=5 hours every week on after-school tutoring programs (HR: 1.12; 95% CI: 1.02-1.22) had greater risk for incident myopia. By contrast, protective factors included suburban area of residence (HR: 0.91; 95% CI: 0.83-1.00) and spending >=30 minutes outdoors after school every weekday (HR: 0.90; 95% CI: 0.82-0.99). Conclusions: This study provides population-based data on the annual incidence of myopia among Taiwanese schoolchildren, and found that baseline refractive status, parental myopia, area of residence, time outdoors after school on weekdays, and time spent on after-school tutoring programs are associated with risk of new onset myopia. PMID- 28002846 TI - Unchanged Neurotrophic Factors and Their Receptors Correlate With Sparing in Extraocular Muscles in Amyotrophic Lateral Sclerosis. AB - Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice. Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRalpha 1). Results: There was an intrinsic difference in NTF expression between EOMs and limb muscles in control mice: EOMs presented significantly lower number of neuromuscular junctions (NMJs) labeled for BDNF and NT-4 at 50 days, and for BDNF and GDNF at 150 days, compared with the control limb muscles of corresponding age. In ALS transgenic mice at 150 days, NTF expression in limb muscles was significantly changed but not in EOMs: the limb muscles presented a significant decline in the number of NMJs labeled for BDNF, NT-4, GDNF, p75NTR, TrkB, and TrkC, which was not observed in EOMs. Conclusions: The significant differences in expression of NTFs on NMJs between EOMs and limb muscles in both control and ALS transgenic mice suggest that NTF may be involved in the pathogenesis of ALS and the resistance of EOMs to the disease. PMID- 28002847 TI - Pyometra and Pregnancy with Herlyn-Werner-Wunderlich Syndrome. AB - We describe a Herlyn-Werner-Wunderlich syndrome (HWWS) patient with previous history of infertility who got pregnant without treatment and presented a pyometra in the contralateral uterus throughout the gestational period, despite multiple antibiotic treatments. Due to the uterus' congenital anomaly and the possibility of ascending infection with subsequent abortion, this pregnancy was classified as high-risk. We believe that the partial horizontal septum in the vagina may have contributed to the closure of the gravid uterus cervix, thus ensuring that the pregnancy came to term, with an uneventful vaginal delivery. PMID- 28002848 TI - Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review. AB - Breast cancer is the most common type of cancer and the leading cause of cancer related death among women worldwide. Hormone receptor-positive (HR+) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemotherapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2+) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HR+ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field. PMID- 28002849 TI - Penile Replantation: A Retrospective Analysis of Outcomes and Complications. AB - Purpose Penile replantation is an uncommonly performed procedure, which can alleviate physical and psychosocial sequelae of penile amputation. This study critically appraises the current literature on penile replantation. Methods A comprehensive literature search of the Medline, PubMed, and Google Scholar databases was conducted with multiple search terms related to penile replantation. Data on outcomes, complications, and patient satisfaction were collected. Results A total of 74 articles met inclusion criteria. One hundred and six patients underwent penile replantation, but outcome, complication, and satisfaction data were not standardized across all patients. Penile amputation most often resulted from self-mutilation or trauma. The majority were complete amputations (74.8%). Full sensation was maintained in 68.4% of patients. Most reported adequate urinary function (97.4%) and normal erection (77.5%). Skin necrosis (54.8%) and venous congestion (20.2%) were the most common complications. Urethral stricture (11.0%) and fistula (6.6%) were common urethral complications. Most (91.6%) patients reported overall satisfaction although there was a lack of patient-reported outcomes. Multivariate analysis suggested that complete amputation (beta = 3.15, 95% CI 0.41-5.89, p = 0.024), anastomosis of the superficial dorsal artery (beta = 9.88, 95% CI 0.74-19.02, p = 0.034), and increasing number of nerves coapted (beta = 1.75, 95% CI 0.11-3.38, p = 0.036) were associated with favorable sexual, urinary, and sensation outcomes. Increasing number of vessels anastomosed (beta = -3.74, 95% CI -7.15 to -0.32, p = 0.032) was associated with unfavorable outcomes. Conclusion Although penile replantation is associated with complications, it has a high rate of satisfaction and efficacy. Coaptation of multiple nerves and anastomosis of the superficial dorsal artery should be completed. PMID- 28002850 TI - Medical Management of Endometriosis in Patients with Chronic Pelvic Pain. AB - Endometriosis is a common cause of pelvic pain in women of reproductive age. Traditional medical therapies are hormonal in nature, including estrogen progestin contraceptives, progestins, and gonadotropin-releasing hormone (GnRH) agonists. Other hormonal options are androgens and aromatase inhibitors, with research also suggesting a possible role for GnRH antagonists and selective progesterone receptor modulators. Other than nonsteroidal anti-inflammatories, further work is required for nonhormonal therapies such as antiangiogenic and immune-modulating drugs. Medical treatment of endometriosis can be complex, and requires consideration of side effects, the anatomic type of endometriosis, role of surgery, current infertility or future fertility desires, and other contributors to pain (e.g., central sensitization). These factors should be discussed for each patient, to ensure personalized treatment and optimal outcomes. PMID- 28002851 TI - Prenatal Ultrasonographic Diagnosis of Cataract: In Utero Manifestations of Cryptic Disease. AB - PURPOSE: To report and review our experience with antenatal evaluation for fetuses diagnosed with congenital cataract. MATERIALS AND METHODS: We retrospectively identified pregnancies diagnosed with fetal cataract during antenatal ultrasound. Evaluation of fetal eyes included intraocular anatomy and biometry. Data on fetal malformations, serology and fetal karyotype were collected. RESULTS: 8 cases, identified over the course of 10 years, were reviewed. Week 15 was the mean time for diagnosis (range 11 - 34). Extraocular anomalies were demonstrated in 6 cases (central nervous system, cardiac and renal systems). Additional intraocular abnormalities were detected in two cases: one fetus had persistent hyperplastic primary vitreous and another had bilateral retinal detachment. All cases but one involved cataracts in both eyes. The unilateral case was associated with microphthalmic aphakia. All cases had negative serology for TORCHs. 7 out of the 8 fetuses were terminated. The only one who survived developed in utero cataracts secondary to maternal steroid therapy. He underwent bilateral cataract extraction during the first weeks of life and ophthalmologic evaluation at 2 years of age was unremarkable, without any visual impairment. CONCLUSION: In most cases, fetal cataract was associated with additional abnormalities, both intra- and extra-ocular. In instances when cataracts are isolated, we suggest conducting a detailed and thorough in utero ophthalmic examination in order to improve antenatal parental counselling. PMID- 28002852 TI - Q Fever Pneumonia in Southwest Germany: Radiographic and Clinical Findings. AB - Purpose Q fever is a worldwide zoonosis that causes clinical symptoms ranging from mild flu-like symptoms to severe pneumonia and/or hepatitis. This retrospective study was conducted to describe the radiographic and clinical signs in patients with acute Q fever pneumonia in Southwest Germany. Patients and Methods 40 patients with IgM-positive Q fever-related pneumonia who were treated in the years 2006 to 2016 in our hospital were retrospectively identified. Clinical and laboratory data were analyzed. Chest radiographs were reviewed by two radiologists and interpreted using a standardized protocol. Results Females and males were equally affected. The mean age was 44.9 +/- 15.7 years. About half of the patients (45 %) acquired their infection in the second quarter of the year. The main complaints were fever, cough and dyspnea. While the white cell blood count was in the normal range in most of the patients, the CRP value was markedly elevated. Q fever-related hepatitis was found in 63 % of the patients. Air space opacification was the predominant radiographic sign and was found in 27 of the patients (82 %). The typical chest radiographic pattern was a single segmental opacity. However, multiple segmental opacities and patchy opacities were also found. Lobar opacities were found in only 2 (6 %) of the patients. Conclusion Unilobar, unilateral, segmental opacities are the key feature of Q fever pneumonia chest radiographs. Definitive radiographic differentiation from other community-acquired pneumonias is not possible, but Q fever pneumonia should be considered in middle-aged patients with segmental opacities living in an endemic area. Key points . Unilobar, unilateral, segmental opacities are the key feature of Q fever pneumonia.. . Lobar and patchy as well as multisegmental opacities are also found.. . Chest radiography does not allow the differentiation of Q fever from other pneumonias.. Citation Format . Biecker A, Bitzer M, Biecker E. Q Fever Pneumonia in Southwest Germany: Radiographic and Clinical Findings. Fortschr Rontgenstr 2017; 189: 146 - 151. PMID- 28002853 TI - Comparison of Lumbar Lordosis in Lateral Radiographs in Standing Position with supine MR Imaging in consideration of the Sacral Slope. AB - Purpose To investigate the influence of sacral slope on the correlation between measurements of lumbar lordosis obtained by standing radiographs and magnetic resonance images in supine position (MRI). Little information is available on the correlation between measurements of lumbar lordosis obtained by radiographic and MR images. Most relevant studies have shown correlations for the thoracic spine, but detailed analyses on the lumbar spine are lacking. Methods MR images and standing lateral radiographs of 63 patients without actual low back pain or radiographic pathologies of the lumbar spine were analyzed. Standing radiographic measurements included the sagittal parameters pelvic incidence (PI) pelvic tilt (PT), and sacral slope (SS); MR images were used to additionally measure lumbar L1-S1 lordosis and single level lordosis. Differences between radiographic and MRI measurements were analyzed and divided into 4 subgroups of different sacral slope according to Roussouly's classification. Results Global lumbar lordosis (L1 S1) was 44.99 degrees (+/- 10 754) on radiographs and 47.91 degrees (+/- 9.170) on MRI, yielding a clinically relevant correlation (r = 0.61, p < 0.01). Measurements of single level lordosis only showed minor differences. At all levels except for L5 / S1, lordosis measured by means of standing radiographs was higher than that measured by MRI. The difference in global lumbar L1-S1 lordosis was -2.9 degrees . Analysis of the Roussouly groups showed the largest difference for L1-S1 (-8.3 degrees ) in group 2. In group 4, when measured on MRI, L5 / S1 lordosis (25.71 degrees ) was lower than L4 / L5 lordosis (27.63 degrees ) compared to the other groups. Conclusions Although measurements of global lumbar lordosis significantly differed between the two scanning technologies, the mean difference was just 2.9 degrees . MRI in supine position may be used for estimating global lumbar lordosis, but single level lordosis should be determined by means of standing radiographs. Key Points . Large difference between radiographic and MRI measurements of level L5 / S1.. . MRI can be used for estimating global lumbar lordosis.. . Analysis of single level lordosis necessitates measurement in standing radiographs.. Citation Format . Benditz A, Boluki D, Weber M et al. Comparison of Lumbar Lordosis in Lateral Radiographs in Standing Position with supine MR Imaging in consideration of the Sacral Slope. Fortschr Rontgenstr 2017; 189: 233 - 239. PMID- 28002854 TI - Improved Image Quality and Detectability of Hypovascular Liver Metastases on DECT with Different Adjusted Window Settings. AB - Objective To investigate dual-energy CT of hypovascular liver metastases (LMs) with special focus on window settings (WSs). The aim of the study is to investigate the extent to which adapted WSs and the low-energy images of DECT improve the visibility especially of smaller LMs. Materials and Methods 30 patients with LMs of colorectal cancer were investigated with DECT of the liver. In each patient contrast-enhanced DECT imaging with portal-venous delay was performed. The total number, mean number and conspicuity (1 = excellent - 5 = poor) of LMs were documented on 80-kVp images and virtual 120-kVp images with different WSs (25/200 HU, 50/200, 75/200 HU, 25/350 HU, 50/350 HU, 75/350 HU, 25/500 HU, 50/500 HU, 75/500 HU). The attenuation (HU) of LMs and several anatomic regions and the background noise on 80 kVp images and virtual 120 kVp images were documented. Signal (liver)/noise and liver/LM ratio (SNR/LLMR) were calculated. The total number of LMs depending on size (< 1 cm, 1 - 2 cm, > 2 cm) on 80 kVp images and virtual 120 kVp images with previously investigated best and regular WSs were documented. Results The highest total number, mean number per patient and total number of LMs < 1 cm were detected with the WS 25/350 HU on 80kVp images (7.0; p = 0.02/218; p = 0.01/64;p < 0.001) compared to the WS 75/200 HU on virtual 120 kVp images and the regular WS 50/350 HU on 80 kVp images and virtual 120 kVp images. The best conspicuity of LMs on 80 kVp images was documented with the WS 25/350 HU compared to the best WS on virtual 120 kVp images with 75/200 HU (1.2 vs. 2.5; p = 0.01). HU of normal liver, aorta, SNR and LLMR differed significantly between 80 kVp images and virtual 120 kVp images (128.1 vs. 93.6; < 0.05/192.8 vs. 131.4; < 0.05/10.3 vs. 8.1; p < 0.05/2.8 vs. 2.1; p < 0.05). Conclusion Low kVp images of DECT datasets are more precise in detecting hypovascular liver metastases than virtual 120 kVp images. Dedicated window settings have a relevant influence on conspicuity. Key points: . DECT is a promising tool for detecting hypovascular liver metastases.. . The diagnostic value of low kVp image data can be significantly increased by using special window settings.. . Use of only the low kVp images would lead to reduced radiation exposure.. Citation Format . Altenbernd Jens, Forsting Michael, Lauenstein Thomas et al. Improved Image Quality and Detectability of Hypovascular Liver Metastases on DECT with Different Adjusted Window Settings. Fortschr Rontgenstr 2017; 189: 228 - 232. PMID- 28002855 TI - ? PMID- 28002856 TI - [The Changing Value of Mother's Milk. Feeding Premature and Sick Newborns Since the Late 19th Century]. AB - In the 1960s/early 70s there was a widespread conviction in West Germany that mother's milk was no longer essential even for premature infants given the availability of improved industrial milk products. But today the superiority of human milk is again undisputed, and progress in neonatology has created a growing target group of extremely premature infants who show clear benefits from being fed with human milk, particularly regarding improved outcomes. Currently there is a revival of donor milk banks (FMB). Globally there are around 500, 15 in Germany. Until the 1960s, mother's milk was the preferred means of German pediatricians to counter infant mortality. During the German Empire and the Weimar Republic doctors widely recommended nursing and engaged wet nurses to meet the demand for human milk and the first donor milk banks were set up; during the Nazi regime there were dozens. The GDR continued using donor milk, while FRG milk banks were shut down in the 70s. The history of milk banks has been shaped not only by science, but also by culture, politics and economics. In the German Empire and the Weimar Republic, social, national and eugenic considerations became intertwined in the struggle against infant mortality. In Nazi Germany human milk was used to strengthen the "German Volksgemeinschaft" ("community of the German people"), particularly individuals who were considered as "erbgesund" ("hereditarily healthy"). Massive advertising of the baby food industry in the West and public debate about pollutants and HIV/AIDS increased doubts about the advantages of natural feeding. In East Germany the planned economy, state health system and censored media significantly contributed to the survival of milk banks. PMID- 28002858 TI - Is Individualizing Breast Compression during Mammography useful? - Investigations of pain indications during mammography relating to compression force and surface area of the compressed breast. AB - Purpose The aim of this paper is to determine how the presence of pain during mammographic compression could be reduced. To this end, we examine its relationship with compression force, surface-area of the compressed breast, breast density (ACR) and former operations. Materials and Methods In 199 women 765 mammograms were performed. Women were asked to rate the level of pain on a scale of 0 - 10 (0: no, 10: highest pain). The surface-area of the breast under compression captured by the mammograms was measured using planimetry. 52 of the 199 women were asked to identify the area of the upper body with the highest level of pain. Results The thickness of the compressed breast was 65.2 % of the uncompressed breast at a force of 10 daN (57.8 % at 15 daN). When the force was increased from 10 daN to 15 daN, the average glandular dose (AGD) declined by 17 %. Tolerance of compression was associated with the size of the breast. More than 50 % of the mammograms with a small compression less than 9 daN were associated with higher level of pain. In the oblique projection, 60 % of the women specified the axilla as the area of maximum pain. Conclusion Women with larger breasts tolerated a greater force of compression. This implies a need for individualised examination depending on the size of the breast. Women with increased pain susceptibility terminated the compression early regardless of a small compression less than 9 daN. More than 50 % of the women identified areas outside breast as especially painful. Therefore, during examination, the areas around the breast should also be taken into consideration in order to minimize unnecessary discomfort. Key Points . With increased mammographic compression force, the effectiveness of breast thickness reduction declined.. . A compression force of 15 daN enabled an additional reduction by 17 % in average glandular dose (AGD) compared to 10 daN.. . Tolerance of increased compression force was related to breast surface area.. . Women with increased susceptibility of pain terminated the compression at a low force of less than 9 daN. . Pain relating to the mammographic procedure was identified outside the breast by more than 50 % of the women.. Citation Format . Feder K, Grunert JH. Is Individualizing Breast Compression during Mammography useful? - Investigations of pain indications during mammography relating to compression force and surface area of the compressed breast. Fortschr Rontgenstr 2017; 189: 39 - 48. PMID- 28002857 TI - MRI of the Prostate: Recommendations on Patient Preparation and Scanning Protocol. AB - The Working Group Uroradiology and Urogenital Diagnosis of the German Roentgen Society has developed uniform recommendations for the preparation and implementation of prostate MRI. In the first part detailed recommendations are given in tabular form regarding 1. anamnestic data before prostate MRI, 2. termination of examinations and preparation of examinations, 3. examination protocol and 4. MRI-guided in-bore biopsy. In the second part, the recommendations are discussed in detail and relevant background information is provided. Key Points: . Uniform recommendations for prostate MRI has been developed from the Working Group Uroradiology and Urogenital Diagnosis of the German Roentgen Society.. . Necessary anamnestic data, recommendations for termination of examinations and prepararion of examinations, examination protocol and MRI guided in-bore biopsy are detailed expressed and documented.. Citation Format . Franiel T., Quentin M., Mueller-Lisse U. G. et al. MRI of the Prostate: Recommendations on Patient Preparation and Scanning Protocol. Fortschr Rontgenstr 2017; 189: 21 - 28. PMID- 28002860 TI - Non-Spine MSK Interventions. PMID- 28002859 TI - Increase in FLAIR Signal of the Fluid Within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases? AB - Purpose Increase in FLAIR signal of the fluid within the resection cavity is described as a highly specific and early sign for tumor recurrence in gliomas. The aim of this study was to assess the prognostic value of FLAIR signal increase in partially or completely resected brain metastases. Materials and Methods 209 cases of surgery for brain metastases were assessed. 41 cases with at least two follow-up MRIs were retrospectively included in this study. Quantitative and qualitative assessment of the FLAIR signal intensity of the fluid within the resection cavity was performed in the MRI examination at recurrent disease/last contact and in the previous MRI examination. Results 3 of 6 cases with local tumor recurrence showed a FLAIR signal increase (sensitivity 50.0 %, specificity 100.0 %). In one case, this sign was observed even about 3 months before tumor recurrence. The specificity of FLAIR signal increase for overall tumor recurrence (local and distant) was also 100.0 %, but with a lower sensitivity of 13.0 %. Quantitative analysis showed significant differences for signal intensity of the resection cavity as well as for the change of signal intensity of the resection cavity in cases with or without local tumor recurrence. Conclusion An increase in FLAIR signal of the fluid within the resection cavity might be a highly specific and early sign of local tumor recurrence/tumor progression also for brain metastases. Key points: . An increase in FLAIR signal intensity of the fluid within the resection cavity is also observed in previously resected brain metastases.. . The pathophysiology of this sign might be due to a cell proliferative process.. Citation Format . Bette S, Gempt J, Wiestler B et al. Increase of the FLAIR Signal of the Fluid within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases?. Fortschr Rontgenstr 2017; 189: 63 - 70. PMID- 28002861 TI - Injectable Corticosteroids: Take Precautions and Use Caution. AB - Corticosteroids are routinely injected into soft tissues, tendon sheaths, bursae, and joints. These anti-inflammatory agents have different potency and solubility, and solubility is inversely correlated with the duration of action. Corticosteroids carry a low risk of complications but commonly cause systemic and local adverse effects. The use of intra-articular corticosteroid injections in the treatment of inflammatory arthritis and osteoarthritis is well established. Evidence also supports the use of injectable corticosteroids in the treatment of inflammatory tenosynovitis and bursitis associated with rheumatic diseases, trigger finger and de Quervain disease, and carpal tunnel syndrome. The role of corticosteroid injections in the management of rotator cuff disease remains unclear. Strong scientific evidence indicates that corticosteroid injections for lateral epicondylosis worsen the long-term outcomes of patients. This review article discusses the considerations related to the use of corticosteroid injections in the management of nonspinal musculoskeletal conditions. PMID- 28002862 TI - Ultrasound-Guided Percutaneous Irrigation of Calcific Tendinopathy. AB - Rotator cuff calcific tendinopathy (RCCT) is a common disease that may cause highly disabling shoulder pain. No treatment is required for asymptomatic calcifications; mild symptoms may be treated conservatively. Among several therapeutic options, ultrasound-guided percutaneous irrigation of calcific tendinopathy (US-PICT) is currently accepted as the first-line safe and effective treatment for RCCT, with significant pain improvement and a very low rate of minor complications. Different approaches have been reported to dissolve calcified deposits, all including the use of a fluid (local anesthetic or saline solution) and the use of one or two needles to inject and retrieve the fluid/dissolved calcium. This review describes both one-needle and two-needle US PICT techniques, providing technical and practical information that can improve daily clinical practice. PMID- 28002863 TI - Ultrasound-Guided Percutaneous Tenotomy. AB - Of the many treatment options for tendinopathy, percutaneous tenotomy has been used throughout the body with success. With this procedure, a needle is repeatedly passed into the abnormal tendon with the goal of converting a chronic degenerative process to an acute inflammatory condition that will progress to tendon healing. Ultrasound guidance for this procedure is essential to ensure that the abnormal region of the tendon is accurately targeted. The treatment has few contraindications, and negligible complications have been described. This article reviews the rationale behind tenotomy for the treatment of tendinopathy and the ultrasound-guided technique. The current literature comparing the results of tenotomy to other percutaneous tendon treatments is also reviewed, although many of the other tendon injection treatments incorporate tenotomy as part of the procedure. PMID- 28002864 TI - Ultrasound-Guided Platelet-Rich Plasma Treatment: Application and Technique. AB - Platelet-rich plasma injection is a minimally invasive treatment method for common overuse tendon injuries. This article discusses the biology of platelet rich plasma (PRP), the healing cascade that PRP promotes, and how PRP composition may differ depending on centrifuge method. It also highlights the common uses of PRP tendon injection and offers an update on the most current clinical evidence based literature. PMID- 28002865 TI - Percutaneous Release Procedures: Trigger Finger and Carpal Tunnel. AB - Trigger digit and carpal tunnel syndrome are both conditions traditionally treated with open surgery but are potentially amenable to curative treatment using percutaneous techniques. The advantages of minimally invasive techniques are lower risk of wound breakdown and infection, quicker healing, reduced postprocedural pain, reduced complications, and a quicker return to normal activity. The advent of high-resolution ultrasound has allowed percutaneous release procedures for these conditions to be developed and performed with a potential for a reduced risk of complications and an increased likelihood of success. This article reviews the literature as well as our institutional experience in performing ultrasound-guided percutaneous release for trigger digit and carpal tunnel syndrome. PMID- 28002866 TI - Botulinum Toxin Injections in Musculoskeletal Disorders. AB - Botulinum toxin (BTX) is used for multiple clinical indications due to its ability to induce temporary chemodenervation and muscle paralysis. This property has supported its application in treating a variety of musculoskeletal conditions, especially those involving muscular hyperactivity and contractures such as cerebral palsy and dystonia. However, off-label use of BTX injection in other musculoskeletal disorders is gaining increased acceptance, such as in neurogenic thoracic outlet syndrome, epicondylitis, and shoulder pain after stroke. This review discusses the mechanism of action, best practices, and current indications of BTX injections in the musculoskeletal system. We also discuss the state of the science regarding BTX injections for musculoskeletal disorders and the available evidence supporting its use. PMID- 28002867 TI - Update on Ultrasound-Guided Interventional Procedures on Peripheral Nerves. AB - This article is a practical review update on ultrasound (US)-guided interventional procedures on peripheral nerves. Technical considerations, biopsy techniques, and some examples of injections are described. US is considered a safe imaging guidance for interventional procedures, due to its high spatial resolution and the possibility to image the needle and inject drugs in real time. US-guided injections could be considered a diagnostic and therapeutic option in the most common neuropathy, before or as an alternative to surgery. US-guided injection techniques in patients with carpal tunnel syndrome, cubital tunnel syndrome, meralgia paresthetica, and Morton neuroma are reviewed. US-guided injections of the iliohypogastric, ilioinguinal, genitofemoral, and pudendal nerve are also illustrated. Knowledge of anatomy is crucial; therefore a brief description of the courses of anatomical nerves and clinical notes are also reported. Treatment of stump neuromas treatment was excluded. PMID- 28002868 TI - Ultrasound-Guided Cryoanalgesia of Peripheral Nerve Lesions. AB - The real-time nature of ultrasound makes it ideally suited to provide guidance for a variety of musculoskeletal interventional procedures involving peripheral nerves. Continuous observation of the needle ensures proper placement and allows continuous monitoring when performing localized ablative therapy and therefore more accurate positioning of a cryoprobe, use of smaller needles, as well as access to small structures. We describe our experience performing cryoablative procedures. Patients undergoing cryoneurolysis have largely reported varying degrees of long-term pain relief and improvement in function; no serious complications have yet been identified. Ultrasound-guided cryoneurolysis can provide a useful, safe alternative to other ablative techniques to achieve long term analgesia from painful peripheral nerve lesions. PMID- 28002869 TI - Percutaneous Ablation in Painful Bone Tumors. AB - Percutaneous image-guided ablation has been shown to be safe and effective for the treatment of benign osseous lesions and has evolved into the treatment of metastatic lesions for both pain palliation and local tumor control. Ablation is increasingly becoming part of the treatment algorithm of painful bone lesions, requiring multidisciplinary input from radiation, surgical, and medical oncologists. Substantial pain reduction is often possible in those who have failed to benefit from conventional therapies such as systemic and radiation therapy. This review details the basics of bone ablation including indications, treatment algorithms, ablation modalities, role of imaging, thermo-protective techniques, and the emerging use for local tumor control in patients with oligometastatic disease. PMID- 28002870 TI - Radiofrequency Ablation of Osteoid Osteoma: Difficult-to-Reach Places. AB - Osteoid osteomas are small painful benign bone tumors that can be effectively treated by radiofrequency ablation (RFA) in most situations. This article briefly reviews the typical imaging findings of osteoid osteomas and the RFA technique used to treat them at our institution. It concludes with several examples of osteoid osteomas in difficult-to-reach places and the approaches used to access and treat them. PMID- 28002871 TI - Recommendations of the ESSR Arthritis Subcommittee on Ultrasonography in Inflammatory Joint Disease. AB - This article presents the recommendations of the European Society of Musculoskeletal Radiology Arthritis Subcommittee on the use of ultrasonography (US) in rheumatic disease, focused on the examination of joints in the adult population. The recommended examination technique and protocols used in a radiologic work-up are discussed. The main US features that can lead to a final diagnosis in the most common rheumatic diseases are addressed. The differential diagnosis that should be considered at image interpretation is presented. The role of US in interventional procedures and clinically important recent developments is also discussed. PMID- 28002872 TI - Lutein facilitates physiological revascularization in a mouse model of retinopathy of prematurity. AB - BACKGROUND: Retinopathy of prematurity is one of the leading causes of childhood blindness worldwide, with vessel growth cessation and vessel loss in phase I followed by neovascularization in phase II. Ischaemia contributes to its pathogenesis, and lutein protects against ischaemia-induced retinal damages. We aimed to investigate the effects of lutein on a murine model of oxygen-induced retinopathy. METHODS: Mouse pups were exposed to 75% oxygen for 5 days and returned to room air for another 5 days. Vascular obliteration, neovascularization and blood vessel leakage were examined. Immunohistochemistry for glial cells and microglia were performed. RESULTS: Compared with vehicle controls, mouse pups receiving lutein treatment displayed smaller central vaso obliterated area and reduced blood vessel leakage. No significant difference in neovascular area was found between lutein and vehicle controls. Lutein promoted endothelial tip cell formation and maintained the astrocytic template in the avascular area in oxygen-induced retinopathy. No significant changes in Muller cell gliosis and microglial activation in the central avascular area were found in lutein-treated pups. CONCLUSIONS: Our observations indicated that lutein significantly promoted normal retinal vascular regrowth in the central avascular area, possibly through promoting endothelial tip cell formation and preserving astrocytic template. Our results indicated that lutein might be considered as a supplement for the treatment of proliferative retinopathy of prematurity because of its role in facilitating the revascularization of normal vasculature. PMID- 28002873 TI - Effects of pupil dilation on MAIA microperimetry. AB - BACKGROUND: Macular Integrity Assessment microperimetry assesses macular sensitivity to projected point light sources and maps eye movements to assess fixation stability. Although microperimetry is gaining prominence as an assessment tool in clinical and research settings, there is no consensus on whether it should be performed before or after pupil dilation. No studies to date have examined the effect of pupil dilation on results. The aim of this project was to elucidate the effect of pupil dilation on microperimetry outcomes. DESIGN: Prospective audit. PARTICIPANTS: Twenty healthy patients from postoperative cataract clinic and 10 patients with choroideremia to simulate a disease with peripheral visual field loss. METHODS: Subjects underwent 10-2 68-point field testing using the Macular Integrity Assessment microperimeter on each eye. Subjects then underwent randomized dilation of one eye, and the test was repeated in both eyes. MAIN OUTCOME MEASURES: We compared changes in threshold sensitivity and fixation stability pre-pupil and post-pupil dilation. The undilated eye was analysed for any learning or fatigue effect caused by test repetition. RESULTS: Dilation produced no significant effect on threshold sensitivity (dilation effect: -0.29 decibels, P = 0.23) or fixation stability in healthy controls or in choroideremia patients (dilation effect: +0.08log bivariate contour ellipse area, P = 0.14). There was also no significant learning effect seen in the undilated eye, with no improvement in threshold sensitivity (order of eye testing: +0.03log bivariate contour ellipse area, P = 0.71). CONCLUSIONS: In the clinical setting, patients may be tested for 10 degree microperimetry with or without pupil dilation, as both scenarios yield consistent and interchangeable results. PMID- 28002874 TI - High serum alanine aminotransferase is associated with the risk of colorectal adenoma in Korean men. AB - BACKGROUND AND AIM: An elevated alanine aminotransferase (ALT) is frequently observed in subjects with metabolic syndrome, which is associated with the risk of colorectal adenoma (CRA). However, the relationship between ALT and CRA remains unclear. Therefore, we aimed to investigate whether high serum ALT is associated with the risk of CRA in a metabolically healthy population. METHODS: We conducted this cross-sectional study in 27,717 asymptomatic Korean adults who underwent a health checkup. Subjects were categorized as adenoma-free, hyperplastic polyp, low-risk adenoma, or high-risk adenoma. High-risk adenoma was defined as three or more adenomas, any adenoma >= 10 mm, or adenoma with high grade dysplasia or villous features. RESULTS: Among all participants, 10.3% and 1.5% of cases were categorized as low-risk and high-risk adenoma, respectively. In multivariate analyses adjusting for age, sex, body mass index, smoking habits, alcohol intake, regular exercise, aspirin and analgesics use, family history of colon cancer, education level, fatty liver, high-sensitivity C reactive protein, homeostasis model assessment of insulin resistance, total cholesterol, and triglyceride, an increase in ALT was positively associated with the prevalence of low-risk and high-risk adenoma (P for trend = 0.029 and 0.027, respectively). The highest quartile group of ALT level showed a significantly increased prevalence in low-risk (odds ratio, 1.17) and high-risk adenoma (odds ratio, 1.48) groups compared with the lowest quartile group. This phenomenon persisted in the subgroup analysis in men, but not in women. CONCLUSIONS: In the asymptomatic healthy population, high serum ALT is significantly associated with the risk of CRA. PMID- 28002876 TI - Outcomes of treatment with daclatasvir and asunaprevir for recurrent hepatitis C after liver transplantation. AB - AIM: The development of direct-acting oral agents has dramatically changed the treatment strategy of hepatitis C virus (HCV) infection. Here we aimed to reveal the efficacy and safety of daclatasvir (DCV) and asunaprevir (ASV) for recurrent HCV genotype 1 infection after liver transplantation (LT). METHODS: A retrospective study was undertaken on nine patients who underwent a 24-week DCV/ASV treatment regimen for recurrent HCV genotype 1 infection. Five of the patients were men; four had failed treatment with pegylated interferon (Peg IFN)/ribavirin, two had failed simeprevir/Peg-IFN/ribavirin, one had the resistance-associated variant Y93H in the NS5A region, and one underwent maintenance dialysis. RESULTS: Median time to treatment initiation following LT was 70 months. Of the nine patients treated with DCV/ASV, eight (88.9%) achieved a sustained viral response 12 weeks after completion of therapy (SVR12). The patient with virologic failure had failed simeprevir/Peg-interferon/ribavirin therapy 4 months before undergoing the DCV/ASV treatment regimen. In addition, a resistance-associated variant D168E in the NS3 region was detected in the patient after discontinuation of the DCV/ASV regimen. The trough level of tacrolimus tended to decrease, and renal function showed no significant changes during treatment. Adverse events occurred in two patients (22.2%), but no severe adverse events occurred during treatment. CONCLUSIONS: The DCV/ASV regimen was well tolerated, resulting in high rates of sustained viral response 12 weeks after completion of therapy for LT patients with recurrent HCV genotype 1 infection. PMID- 28002875 TI - Outcomes from massive paracetamol overdose: a retrospective observational study. AB - LINKED ARTICLE: This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163-5. https://doi.org/10.1111/bcp.13279 AIMS: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardized, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAPpl ) and treatment nomogram thresholds at those time points (APAPt ) provides a useful assessment tool. METHODS: This is a retrospective observational study of all patients (n = 545) between 2005 and 2013 admitted to a tertiary care toxicology service with acute non-staggered paracetamol overdose. Massive overdoses were defined as extrapolated 4-h plasma paracetamol concentrations >250 mg l-1 , or reported ingestions >=30 g. Outcomes (liver injury, coagulopathy and kidney injury) were assessed in relation to reported dose and APAPpl :APAPt ratio (based on a treatment line through 100 mg l-1 at 4 h), and time to acetylcysteine. RESULTS: Ingestions of >=30 g paracetamol correlated with higher peak serum aminotransferase (r = 0.212, P < 0.0001) and creatinine (r = 0.138, P = 0.002) concentrations. Acute liver injury, hepatotoxicity and coagulopathy were more frequent with APAPpl :APAPt >= 3 with odds ratios (OR) and 95% confidence intervals (CI) of 9.19 (5.04-16.68), 35.95 (8.80-158.1) and 8.34 (4.43-15.84), respectively (P < 0.0001). Heightened risk persisted in patients receiving acetylcysteine within 8 h of overdose. CONCLUSION: Patients presenting following massive paracetamol overdose are at higher risk of organ injury, even when acetylcysteine is administered early. Enhanced therapeutic strategies should be considered in those who have an APAPpl :APAPt >= 3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort. PMID- 28002877 TI - The drugs that mostly frequently induce acute kidney injury: a case - noncase study of a pharmacovigilance database. AB - AIMS: Acute kidney injury (AKI) is associated with a high hospitalization rate, accelerated long-term decline in kidney function and a high mortality rate. Adverse drug reactions (ADRs) constitute one of the most important modifiable factors in the context of AKI. Most studies of drug-induced AKI have focused on a sole drug class. The objective of the present study was to establish a comprehensive overview of drug-induced AKI on the basis of spontaneously reported ADRs in the French national pharmacovigilance database (FPVD). METHODS: We performed a case-noncase study of drug-induced AKI. Cases corresponded to the reports of AKI recorded in the FPVD between 1 January 2015 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs (excluding AKI) recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and the 95% confidence interval. RESULTS: Of the 38 782 ADRs recorded in the FPVD during the study period, 3.2% were classified as cases of AKI. A total of 1254 patients experienced AKI (males: 55%; mean age +/- standard deviation: 68.7 +/- 15.0 years). Overall, 15.2% of the patients required renal replacement therapy. Two or more concomitantly administered drugs were involved in 66% of the cases of AKI. The most frequently implicated drug classes were antibacterial agents for systemic use (29.5%), diuretics (18.5%), agents acting on the renin-angiotensin system (16.3%), antineoplastic agents (10.2%) and anti-inflammatory agents (5.4%). Gentamicin, eplerenone, spironolactone, candesartan, cisplatin and acyclovir had the highest RORs (>10). CONCLUSION: A comprehensive study of a national pharmacovigilance database enabled us to identify the drug classes that most frequently induced AKI. Even though most of the identified drugs were already known to induce AKI, the present work should raise physicians' awareness of the compounds responsible for triggering this potentially life-threatening condition. PMID- 28002878 TI - Fluid dipping technology of chimpanzees in Comoe National Park, Ivory Coast. AB - Over a 6 month period during the dry season, from the end of October 2014 to the beginning of May 2015, we studied tool use behavior of previously unstudied and non-habituated savanna chimpanzees (Pan troglodytes verus) living in the Comoe National Park, Ivory Coast (CI). We analyzed all the stick tools and leaf-sponges found that the chimpanzees used to forage for ants, termites, honey, and water. We found a particular behavior to be widespread across different chimpanzee communities in the park, namely, dipping for water from tree holes using sticks with especially long brush-tip modifications, using camera traps, we recorded adults, juveniles, and infants of three communities displaying this behavior. We compared water dipping and honey dipping tools used by Comoe chimpanzees and found significant differences in the total length, diameter, and brush length of the different types of fluid-dipping tools used. We found that water dipping tools had consistently longer and thicker brush-tips than honey dipping tools. Although this behavior was observed only during the late dry season, the chimpanzees always had alternative water sources available, like pools and rivers, in which they drank without the use of a tool. It remains unclear whether the use of a tool increases efficient access to water. This is the first time that water dipping behavior with sticks has been found as a widespread and well established behavior across different age and sex classes and communities, suggesting the possibility of cultural transmission. It is crucial that we conserve this population of chimpanzees, not only because they may represent the second largest population in the country, but also because of their unique behavioral repertoire. PMID- 28002879 TI - 195 Pt NMR parameters as strong descriptors in one-parameter QSAR models for platinum-based antitumor compounds. AB - Highly predictive one-parameter quantitative structure-activity relationship models have been developed for platinum-based anticancer drugs using the 195 Pt NMR parameters as strong descriptors. The developed quantitative structure activity relationship models were applied in diverse homogeneous sets of antiproliferative Pt(II) and Pt(IV) compounds. These observations form the basis for making predictions of cytotoxicity for a broad range of platinum-based antitumor compounds just from inspection of calculated or experimentally determined 195 Pt NMR parameters. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28002880 TI - Beware the TIGER-X's stripes: rapid cataract formation in patients taking Rociletinib. PMID- 28002881 TI - Assessing the clinical and economic impact of increasing treatment uptake in chronic hepatitis B infection using a Markov model. AB - : Treatment uptake in chronic hepatitis B virus (HBV) infection is low in South Australia, and the cost-effectiveness of increasing treatment uptake rates in this population has not been assessed. AIMS AND METHODS: Using a cohort Markov model, cost-effectiveness was assessed for three different treatment uptake scenarios: 2.9% (current level-scenario 1), 10% (scenario 2), and 15% (scenario 3). The initial HBV population included 2550 treatment eligible patients who transitioned between six different health states over a 10-year period. Treatment transition probabilities were based on tenofovir therapy, while those not assigned to treatment followed the natural history transition probabilities. We estimated the incremental cost per quality adjusted life year gained using the prevented number of deaths, hepatocellular carcinoma, and liver transplants. RESULTS: Scenario 3 was associated with the lowest mean cost/person over 10 years (AU$60 133), compared with scenario 2 (AU$61 964) and scenario 1 (AU$64 597). Scenario 3 was also associated with the highest quality adjusted life year gained (8.196) compared with scenario 2 (7.985) and scenario 1 (7.684). Scenario 3 would result in 50% reduction in hepatocellular carcinoma and 30% reduction in HBV related mortality compared with scenario 1, over a 10-year period. Higher treatment uptake was found to be cost-effective with at least 2 years of treatment at either 10% or 15% of the target population. CONCLUSION: Maximizing the treatment uptake in the existing HBV population from 2.9% to 15% was cost effective for periods of 2 years or more. This was due to a reduction in the number of expected clinical events. PMID- 28002882 TI - Pharmacokinetics and safety of a single dose of the novel necrosis inhibitor LC28 0126 in healthy male subjects. AB - AIMS: A novel necrosis inhibitor, LC28-0126, is expected to have a cellular protective effect from ischaemic reperfusion injury in acute myocardial infarction. The objective of this study was to investigate the safety, tolerability and pharmacokinetics of LC28-0126 after a single intravenous administration in healthy male subjects. METHODS: The study was a dose-block randomized, double-blind, placebo-controlled, single ascending dose, first-in human trial. Subjects were randomly assigned to receive 0.3, 1, 3, 10, 25, 50, 100 or 200 mg of LC28-0126. LC28-0126 was infused for 30 min and 5 min in cohorts 1 and 2, respectively. An interim analysis to assess the tolerability and pharmacokinetics was conducted in each dose group. Blood samples were taken to determine plasma LC28-0126 concentrations from predose to 48 or 144 h postdose, and urine samples were taken from predose to 48 or 72 h postdose. RESULTS: Overall, 89 subjects were randomly assigned to the dose groups of the two cohorts. LC28-0126 was well tolerated, and no serious adverse events were reported. LC28-0126 showed rapid disposition in the distribution phase. Overall, the fraction of unchanged LC28-0126 excreted during the 48 or 72 h after administration was below 5%. The systemic exposure of LC28-0126 tends to be increased in a dose-proportional manner in the dose range of 0.3-200 mg. CONCLUSIONS: A single intravenous dose of LC28-0126 was safe and well tolerated up to 200 mg. Furthermore, LC28-0126 demonstrated a predictable pharmacokinetic profile after a single intravenous infusion of doses ranging from 0.3 to 200 mg. PMID- 28002884 TI - Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma. AB - AIM: Forkhead Box M1 (FoxM1) is a proliferation-specific transcription factor. In this study, we aimed to elucidate the clinicopathological and prognostic values of FoxM1 expression in human hepatocellular carcinoma (HCC) and correlate FoxM1 expression with various etiologies of liver diseases. We also investigated its therapeutic value in HCC. METHODS: We investigated the expression of FoxM1 in tumor tissues and adjacent non-tumor tissues of 79 Japanese HCC patients by quantitative real-time reverse transcription-polymerase chain reaction analysis. Depletion by siRNA or specific inhibition by siomycin A were also used to investigate the effect of FoxM1 inhibition on stem-like features of human HCC cells. RESULTS: Quantitative real-time reverse transcription-polymerase chain reaction analysis showed that tumor tissues displayed an approximately 14-fold increase in FoxM1 expression compared with adjacent non-tumor tissues. Interestingly, the expression levels of FoxM1in tumor tissues did not depend on the etiology of liver disease. The expression of FoxM1 in tumor tissues was associated with serum alpha-fetoprotein level, maximum tumor size, histological grade, TNM staging, and portal involvement. Kaplan-Meier analysis indicated that the high FoxM1 expression (>=median) group had a poor prognosis compared with the low FoxM1 expression (77 million TCRbeta clonotype sequences. First, we assessed whether any of 50 previously published sequences were enriched in B27-positive AS patients. We then used training and test cohorts to identify discovered motifs that were enriched in B27-positive AS patients versus controls. RESULTS: Six previously published and 11 discovered motifs were enriched in the B27-positive AS samples as compared to controls. After combining motifs related by sequence, we identified a total of 15 independent motifs. Both the full set of 15 motifs and a set of 6 published motifs were enriched in the B27-positive AS patients as compared to B27-positive healthy individuals (P = 0.049 and P = 0.001, respectively). Using an independent cohort, we validated that at least some of these motifs were associated with AS, and not simply with B27-positive status. CONCLUSION: We identified TCRbeta motifs that are enriched in B27-positive AS patients as compared to B27-positive healthy controls. This suggests that a common antigen, presented by HLA-B27 and detected by CD8+ T cells, may be associated with AS disease pathogenesis. PMID- 28002890 TI - Editorial: Do Not Let Gout Apathy Lead to Gouty Arthropathy. PMID- 28002889 TI - Variability in response to albuminuria-lowering drugs: true or random? AB - AIMS: Albuminuria-lowering drugs have shown different effect size in different individuals. Since urine albumin levels are known to vary considerably from day to-day, we questioned whether the between-individual variability in albuminuria response after therapy initiation reflects a random variability or a true response variation to treatment. In addition, we questioned whether the response variability is drug dependent. METHODS: To determine whether the response to treatment is random or a true drug response, we correlated in six clinical trials the change in albuminuria during placebo or active treatment (on-treatment) with the change in albuminuria during wash-out (off-treatment). If these responses correlate during active treatment, it suggests that at least part of the response variability can be attributed to drug response variability. We tested this for enalapril, losartan, aliskiren, atrasentan and paricalcitol. RESULTS: No correlation between the on- and off-treatment albuminuria change was observed in the placebo arm of all clinical trials (R2 < 0.01). However, we observed significant associations between the on- and off-treatment response (R2 0.14 to 0.57; all P < 0.015) for different albuminuria lowering drugs. Additionally, the albuminuria responses strongly correlated when the same individual was re-exposed to the same drug at the same dose: lisinopril 10 mg day-1 (R2 = 53%; P < 0.01), losartan 50 mg day-1 (R2 = 63%; P < 0.01). CONCLUSION: The degree of albuminuria lowering with antialbuminuric drugs varies between patients. This variability in response appears drug-class independent. Identifying which factors determine this initial short-term variation in drug response appears important since the degree of albuminuria lowering is related to subsequent long-term renoprotection. PMID- 28002891 TI - Reply. PMID- 28002892 TI - Weight loss and waist reduction is associated with improvement in gastroesophageal disease reflux symptoms: A longitudinal study of 15 295 subjects undergoing health checkups. AB - BACKGROUND: General obesity and abdominal obesity is an established risk factor of gastroesophageal reflux disease (GERD). However, the influence of weight or waist change on improvement of GERD is unclear. Our aim was to investigate if weight loss or waist reduction improves GERD symptoms and esophagitis. METHODS: A retrospective longitudinal study of 15 295 subjects who underwent gastroscopy for a health checkup and reported GERD symptoms between 2011 and 2013, and repeated a checkup until 2014 was conducted. The improvement of GERD symptoms and esophagitis according to weight loss (>=-2, -0.5 to -2 kg/m2 in body mass index [BMI]), waist reduction (>=-5, -0.1 to -0.5 cm) and baseline BMI/waist circumference (WC) categories was assessed using logistic regression. KEY RESULTS: Weight loss or waist reduction was associated with improvement in GERD symptoms only in subjects with general or abdominal obesity. Among subjects with general obesity (BMI >=25 kg/m2 ) and decreased >=2 kg/m2 in BMI, the adjusted odds ratio (OR) of improvement in GERD symptoms was 2.34 (95% confidence interval [CI] 1.70-2.83). Among subjects with abdominal obesity (WC >=90 cm) and decreased >=5 cm in WC, the corresponding OR was 2.16 (95% CI 1.56-2.90). There was no association between weight loss or waist reduction and improvement in esophagitis. CONCLUSIONS & INFERENCES: Weight loss or waist reduction was associated with improvement in GERD symptoms only in subjects with general or abdominal obesity. Weight loss or waist reduction will be an important treatment option in obese patients. PMID- 28002893 TI - Intraindividual variability in reaction time before and after neoadjuvant chemotherapy in women diagnosed with breast cancer. AB - OBJECTIVE: Women treated with chemotherapy for breast cancer experience subtle cognitive deficits. Research has focused on mean performance level, yet recent work suggests that within-person variability in reaction time performance may underlie cognitive symptoms. We examined intraindividual variability (IIV) in women diagnosed with breast cancer and treated with neoadjuvant chemotherapy. METHODS: Patients (n = 28) were assessed at baseline before chemotherapy (T1), approximately 1 month after chemotherapy but prior to surgery (T2), and after surgery about 9 months post chemotherapy (T3). Healthy women of similar age and education (n = 20) were assessed at comparable time intervals. Using a standardized regression-based approach, we examined changes in mean performance level and IIV (eg, intraindividual standard deviation) on a Stroop task and self report measures of cognitive function from T1 to T2 and T1 to T3. RESULTS: At T1, women with breast cancer were more variable than controls as task complexity increased. Change scores from T1 to T2 were similar between groups on all Stroop performance measures. From T1 to T3, controls improved more than women with breast cancer. IIV was more sensitive than mean reaction time in capturing group differences. Additional analyses showed increased cognitive symptoms reported by women with breast cancer from T1 to T3. Specifically, change in language symptoms was positively correlated with change in variability. CONCLUSIONS: Women with breast cancer declined in attention and inhibitory control relative to pretreatment performance. Future studies should include measures of variability, because they are an important sensitive indicator of change in cognitive function. PMID- 28002894 TI - Effect of nerve growth factor on cultured human chondrocytes. AB - Nerve growth factor (NGF) is involved in several joint diseases. It participates in nociception and neurogenic inflammation and its concentrations increase in synovial fluid and tissue from arthritis. However, data about its role in articular cartilage are scant and conflicting. This study analysed effects of different NGF concentrations on cultured human chondrocytes by evaluating cell proliferation, cell phenotype, and gene expression. The MTT test excluded an influence on cell viability. Alcian blue and S100 staining demonstrated that NGF may induce de-differentiation of the chondrocyte phenotype. Real-time PCR showed that NGF did not influence gene expression of type I, II and XI collagen, TGF beta, IGF-1 and metalloproteinase (MMP)-13, while it reduced the expression of MMP-3. These findings show that NGF may have uncertain effects in human chondrocytes. Further investigations by wider gene expression and protein synthesis analyses are required to determine how chondrocytes may be influenced by NGF. PMID- 28002895 TI - Hybrid complexes of high and low molecular weight: evaluation using an in vitro model of osteoarthritis. AB - Hyaluronan (HA) is central in joint and cartilage functions and to restore synovial fluid viscosity. In patients with osteoarthritis (OA), molecular weight (MW) and concentration of hyaluronic acid (HA) are reduced, diminishing joint lubrication. IL-1beta treatment was used to mimic osteoarthritis in a chondrocytes based in vitro model. The aim of our research, using this model and human chondrocytes was to assess the anti-inflammatory effect of H/L-HA hybrid complexes (SINOVIAL-HL(r)) in comparison with HA at high (H-HA) and low molecular weight (L-HA) separately used, through the evaluation of specific biomarkers involved in cartilage degradation and correlated to osteoarthritis. Specifically, TNF-alpha and IL-6 mRNA were evaluated by qRT-PCR. Cytokines levels were measured using Bio-plex assays and COMP-2 through immunofluorescence staining and western blot. H/L-HA significantly reduced inflammation biomarkers respect to both L-HA or H-HA separately considered at transcriptional and protein level. PMID- 28002896 TI - Comparing hybrid hyaluronic acid with PRP in end career athletes with degenerative cartilage lesions of the knee. AB - Cartilage lesions are very common causes of chronic knee pain in athletes. Current treatment options consist in conservative strategies, such as viscosupplementation and platelet-rich plasma injections. This randomized controlled trial aims to investigate the effect of intra-articular Hybrid Hyaluronic Acid injections compared to PRP for the treatment of cartilage lesions among athletes at the end of their career. Since March 2015, 48 professional soccer players were randomized into two groups: 24 patients received 3 injections of HHA and 23 patients received 3 intra-articular injections of PRP. All patients achieved a statistically significant clinical improvement from preoperative to postoperative time in both groups. Patients in the HHA group showed a significant superiority compared to PRP group at 3 and 6 months. Intergroup differences decrease gradually until loss of significance at 12 months follow-up. Athletes with chronic degenerative cartilage lesions of the knee responded positively both to HHA and PRP until last follow up. PMID- 28002897 TI - Comparison of three novel biphasic scaffolds for one-stage treatment of osteochondral defects in a sheep model. AB - In the last years, several tissue engineering techniques have been applied to develop different kinds of osteochondral substitutes to overcome the scarce reparative properties of this tissue. The aim of this study was to generate and compare three biphasic scaffolds in an osteochondral lesion in a large-animal model. A critical osteochondral defect was generated in the medial femoral condyle of 18 skeletally mature sheep. Three defects were left untreated, the remaining lesions were divided into three groups: 5 lesions were treated with a biphasic scaffold made of collagen type I and small cylinders of Magnesium Hydroxyapatite; 5 lesions were treated with a biphasic substituted formed by collagen type I and Wollastonite, 5 lesions were treated with a scaffold made of collagen type I and small cylinders of Wollastonite/Hydroxyapatite. Animals were sacrificed after 3 months and samples were analyzed by CT and MRI, macroscopic evaluation and histology. Our study demonstrated that one of these novel biphasic scaffolds possesses the potential for being applied for one-stage procedures for osteochondral defects. PMID- 28002898 TI - Tranexamic acid effects on cartilage and synovial tissue: an in vitro study for a possible safe intra-articular use. AB - The possible toxic effects of intra-articular tranexamic acid (TA) are still debated. The aim of this study was to evaluate TA effects on human cartilage fragments and synovial biopsies. Explant culture of minced articular cartilage underwent prolonged TA exposure. Histological analysis, immunofluorescence and colorimetric assay for quantification of s-GAG and DNA were performed at the end term. Synoviocytes were cultured for 48h in presence of TA. Light microscopy and flow cytometry analysis were performed at the end of the exposure to TA and one week after the treatment. TA exposure did not influence i) the chondrocyte outgrowth and migration, ii) the expression of chondrogenic and proliferative markers and iii) the s-GAG/DNA ratio. TA treatment did not affect synoviocytes' morphology and treated cells were phenotypically similar to control cells. This study demonstrated that TA does not negatively affect chondrocytes and synoviocytes cultured in vitro. Thus, our findings may be clinically relevant in order to validate the intra-articular TA administration during orthopedic procedures. PMID- 28002899 TI - Intraoperative application Platelet rich fibrin, postoperative injections OF PRP or microfracture only for osteochondral lesions of the knee: a five-year retrospective evaluation. AB - Cartilage lesions are the most common cause of chronic knee pain. Micro fracturing is reliable, effective, easy to perform and inexpensive. We propose a novel approach to cartilage lesions where microfractures are performed contextually to intra-operative or post-operative administration of platelet concentrates. We retrospectively evaluate 48 patients divided in 3 groups. Group 1: 15 patients underwent microfractures and intraoperative administration of PRF (PRF group); group 2: 16 microfractures and postoperative injections of PRP (PRP group); group 3: 17 patients with isolated microfractures (Microfractures group). Clinical scores (IKDC, VAS pain) were administered at 2 and 5 years postoperative and MRI was performed to evaluate the lesions of patients according to the MOCART criteria (2006). Patients treated with platelet concentrates achieved better clinical results compared to patients treated with microfracture only. The PRF group showed better results than the PRP group at 2 years, with loss of significance at 5 years. At MOCART score, PRF group obtained better results earlier than the other two groups. PMID- 28002901 TI - Homologous platelet-rich plasma for the treatment of knee involvement in primary Sjogren?s syndrome. AB - Primary Sjogren?s syndrome (pSS) is a chronic autoimmune disease characterized by dry eyes, dry mouth, and other clinical manifestations. The most common extraglandular manifestation of pSS is articular involvement and to date their management is unclear. The aims of the current pilot study were to assess the safety and the outcomes of homologous platelet-rich plasma (HPRP) injections in pSS cohort affected by knee arthralgia/arthritis at short-term follow up. This pilot study provides the first evidence that HPRP injections are a safe treatment and induce a short-term clinical improvement. Although the lack of a control group, randomization and long-term follow up prevents the assessment of the real effectiveness of this treatment, further studies are needed to confirm these findings and to determine the mechanism of action, biological changes and disease modifying properties of PRP. PMID- 28002900 TI - Pain reduction and improvement of function following ultrasound-guided intra articular injections of triamcinolone hexacetonide and hyaluronic acid in hip osteoarthritis. AB - The scientific literature has shown positive results regarding intra-articular injections of hyaluronic acid in osteoarthritic joints. When injecting in the hip joint, the guidance of ultrasound can provide higher injection accuracy and repeatability. However, due to the methodological limitations in the current available literature, its recommendation in the current practice is still controversial. This study shows that ultrasound-guided intra-articular injections of triamcinolone hexacetonide and hyaluronic acid can improve pain, function and quality of life in patients with symptomatic and radiographic hip osteoarthritis. In addition, the administration of triamcinolone hexacetonide and hyaluronic acid to the hip joint in these patients can delay the need for interventional surgery. PMID- 28002902 TI - Bone marrow concentrated cells and stromal vascular fraction cells injections for osteoarthritis treatment: a systematic review. AB - The aim of this systematic review is to examine current clinical evidences supporting the intraarticular injection of bone marrow concentrate cells (BMC) and adipose-derived stromal vascular fraction cells (SVF) for the treatment of osteoarthritis (OA). The research was performed on PubMed (Medline), EMBASE and Cochrane Library considering the English literature. Only clinical trials have been included. The systematic research identified twelve clinical trials. Articles included in the study, were one of level II, four of level III, six of level IV and one level V. Among clinical trials, none were randomized, four were comparative, seven were case series, and one was a case report. Seven studies were focused on the use of SVF (1332 patients) and five on the use of BMC (963 patients), with preliminary interesting findings in the OA treatment. Despite the growing interest in this biological approach for OA, knowledge on this topic is still preliminary. Randomized controlled trials are needed to support the potential of BMC and SVF injections and to evaluate advantages and disadvantages with respect to the available treatments. PMID- 28002903 TI - The cytokinome in osteoarthritis, a new paradigm in diagnosis and prognosis of cartilage disease. AB - At present, diagnosis and progression monitoring of osteoarthritis (OA) is made through radiological and clinical assessment. Several studies investigated the role of synovial fluid analysis, to find out whether joint disease could be characterized by the pattern of cytokines, which acts during the pathogenic process or in specific stages of it. Online PubMed-Medline search was performed in order to retrieve evidence concerning synovial fluid analysis of cytokines involved in OA degenerative process. Concerning pro-inflammatory cytokines, it has been shown that interleukin (IL)-6, TNF-alpha and IL-17 are mainly over expressed in the synovial fluid of OA joints, as well as anti-inflammatory cytokine IL-10. Variations of cytokines levels occur with radiological and clinical progression. It was also reported that metalloproteinases are involved. Synovial fluid analysis may be helpful in defining stage and type of OA, but more research is needed, especially focusing on the variation of sets of cytokines during OA stages and correlating these patterns with clinical features. PMID- 28002904 TI - The meniscus vascularization: the direct correlation with tissue composition for tissue engineering purposes. AB - Meniscal lesions still represent an unsolved problem in clinical practice. Like the articular cartilage, meniscus has a scarce healing potential. Thus, when this tissue is damaged, the joint biomechanics is completely altered, leading to the development and progression of premature osteoarthritis. Therefore, in the last years, several tissue-engineering strategies have been developed to regenerate the meniscus with debated results. The comprehension of complex processes underlying meniscus maturation and structure is essential for a correct approach for the generation of a biomimetic meniscal substitute. In this chapter, we will first review the morphology of the meniscus during growth, focusing on the unique pattern of vascularization, and then we will discuss the most common tissue engineering strategies for meniscus repair. PMID- 28002905 TI - Arthroscopic all-inside treatment of popliteomeniscal fascicles tears: surgical technique and results from the first 6 consecutive patients. AB - Athletes whose knees are subjected to sudden changes of direction and high jumps such as martial arts athletes, dancers, wrestlers and football players are at higher risk of injuring popliteomeniscal fascicles. Painful squatting and mechanical symptoms such as locking sensation are common. Current available treatments includes open or arthroscopic in repair. Arthroscopic repair with all inside device can relieve symptoms and restore knee function. Six patients from two surgical centers with isolated popliteomeniscal fascicles tears were treated with arthroscopic all-inside repair. The surgical technique is thoroughly described. All patients showed consistent symptoms and MRI findings, as well as meniscal hypermobility during arthroscopic probing. Moreover, four out of six showed a chondral lesion of the lateral femoral condyle. All of them had their lateral meniscus sutured with one or more sutures. Symptoms were relieved and all but one were able to return to play at the pre-injury level. No postoperative complications were encountered. The diagnosis of the disruption of popliteomeniscal fascicles is challenging and often seen in athletes that play sports which involve repetitive twisting. However, patients? complaints are consistent. Arthroscopic repair with an all-inside device showed to be a reliable and easy technique for addressing the condition, although some issues still need to be investigated, such as how much constraint the repair should provide. Arthroscopic all-inside repair of popliteomeniscal tears prove to be safe and effective in the short-term follow-up, allowing for sport activity resumption. PMID- 28002906 TI - Tears of popliteomeniscal fascicles, diagnostic and clinical implications. A review of the evidence. AB - Postero-lateral corner of the knee is composed of several structures including the popliteo-meniscal fascicles (PMFs). These fibrous structures form a stable ligamentous complex around the popliteus tendon, which stabilize the lateral meniscus, increasing the strength of postero-lateral corner. Studies were retrieved through an electronic search of CINAHL, EMBASE, and Pub-Med, until May 2016. Studies in English, Italian, French, and Spanish were considered for inclusion. Randomized controlled trials, prospective and retrospective comparative studies, case series, and case reports were included. Studies eligible for inclusion concerned PMFs anatomy, biomechanics, diagnostic assessment of PMFs tears and clinical options for tears management. Thirteen studies were included in this review. There were: 7 case series, 4 case reports and 3 anatomical studies. Through anatomic dissection, two or three PMFs (antero inferior fascicle, aiPMF; postero-superior fascicle, psPMF; postero-inferior fascicle, piPMF) can be indentified and isolated. Evaluation through MRI can be a useful diagnostic tool in detecting PMFs tears, especially using proton density (PD) sequences. The biomechanical analysis assessed that lateral meniscus (LM) motion is directly related with PMFs integrity and increased with section of one or both the fascicles. The clinical studies clearly state that a snapping syndrome, associated with lateral knee pain, can develop when one or both PMFs are torn. The three PMFs described are considered as relevant components of the popliteal hiatus, in the posterolateral aspect of the knee. MRI evaluation can detect these fibrous fascicles with good sensitivity. More studies with larger samples would be needed for a clear comprehension of PMFs function and clinical management of PMFs tears, especially with large case series and modern biomechanical testing. PMID- 28002907 TI - TGF-beta1 differentially modulates the collagen VI alpha5 and alpha6 chains in human tendon cultures. AB - Collagen VI is a microfibrillar collagen with a potential regulatory role in tendon repair mechanism. We studied the expression of collagen VI alpha5 and alpha6 chains in normal human tendon fibroblast cultures, both under basal condition and in response to TGF-beta1, a potent regulator of tendon healing. Under basal condition, we found that the alpha5 chain was expressed, although to a lesser extent with respect to the alpha3 chain; in contrast, the alpha6 chain was absent. The treatment with TGFbeta1 induced an opposite effect on the expression of the alpha5 and alpha6 chains; in fact, while the alpha5 chain was dramatically reduced, the alpha6 chain was induced and released in the culture medium. These data indicate that collagen VI alpha5 and alpha6 chains are differentially involved in tendon matrix homeostasis. The alpha6 chain may represent a new potential biomarker for monitoring TGFbeta1-related events in tendon, as healing and fibrotic scar formation. PMID- 28002908 TI - Heat shock induces the expression of pro-inflammatory cytokines in human Achilles tendon tenocytes. AB - The aim of our study is to investigate the behaviour of healthy and tendinopathic human tenocytes after a heat shock. After we harvested tendinopathic and healthy human tendon samples, we split tenocytes into 4 groups: 3 groups were submitted to heat shock, followed by different periods of post-heating (2, 4 and 20 h). The other group represents our negative control. The target genes were analysed using Real Time PCR. IL-1beta and IL-6 expression were significantly increased in tendinopathic samples after heat shock. COL1 and COL3 expression were increased in non-stimulated tendinopathic tenocytes, but their levels significantly decreased after heat shock (p less than 0.01). COL3 levels increase in healthy samples after 20 h post-heating (p less than 0.01). COL1 and COL3 decreased after heat shock as a sign of the failure of repair mechanisms in tendinopathic tendons. Heat shock in in vitro models was insufficient to trigger pro inflammatory cytokines in healthy human tenocytes. PMID- 28002909 TI - Risk factors for post-operative shoulder stiffness: are there new candidates? AB - The aim of this study was to document the incidence of postoperative shoulder stiffness (SS) after arthroscopic rotator cuff repair and evaluate the role of risk factors for its development. Seventy-five consecutive patients that underwent arthroscopic rotator cuff repair were included. The incidence of postoperative SS was prospectively investigated and the presence of 20 potential risk factors was documented retrospectively. The incidence of post-operative SS was 10.4%. All patients were women, and sex was significantly associated to pathology development (p=0.0067). The presence of gastroesophageal diseases was found to be significantly associated with post-operative SS development (p=0.0046). A significant association between the occurrence of post-operative SS and the presence of gastroesophageal diseases was identified. This finding, not yet reported in literature, deserves further investigation. The incidence of postoperative SS fell among previously reported ranges, with females significantly more affected than men. PMID- 28002910 TI - Surgical treatment of insertional Achilles tendinopathy: a systematic review. AB - Insertional Achilles tendinopathy is a frequent cause of pain and performance impairment of the ankle. It is more common in runners, but may also affect general population. Conservative treatment is the gold standard in the early phases but 10% to 30% of patients require surgery. The aim of this study is to review the current literature in order to evaluate current surgical strategies for Insertional Achilles tendinopathy and to analyze the effectiveness of the available techniques. We performed a systematic review of the literature, to identify studies reporting clinical outcome after surgical treatment for Insertional Achilles tendinopathy in any population group with at least 6 months follow-up. The quality of the articles included was evaluated by the Coleman Methodology Score and correlated with the reported outcome and year of publication. We identified 16 studies reporting on 465 surgically treated Insertional Achilles tendinopathy with a mean follow-up of 29.8 months. Average age at the time of surgery was 53 years. Two different categories of surgical treatment were distinct: debridement alone or debridement with augmentation in case of excessive tendon loss. Results were excellent or good in 89.6% of cases and fair or poor in 10.4%. Average complications rate was 18.3%, with 15.7% of minor and 2.6% of major complications with no difference in the two groups. Negative correlation was found between Coleman Methodology Score and the reported outcome and positive correlation was found between Coleman Methodology Score and year of publication. Good or excellent outcome can be expected after surgical treatment for Insertional Achilles tendinopathy whatever the adopted procedure, but there is no specific evidence regarding which surgical technique provides a better outcome or a lower rate of complications. Research with higher levels of evidence and methodology that is more rigorous are needed in order to evaluate the optimal surgical strategy for patients with IAT. PMID- 28002911 TI - Extracorporeal shock waves induce osteogenic differentiation of human bone-marrow stromal cells. AB - The effects of treatment with shock waves (SW) on osteoblastic cells have already been described. Furthermore, the effects of treatment with SW are also determined by the contextual stimulation of other cell lines, in particular of mesenchymal cells. This is the first experimental study of stimulation of a human mesenchymal stem cell line, taken from bone marrow, using SW (electromagnetic device), with two energy levels. The results showed a significant increase in expression of the main osteoblastic differentiation genes: BMP2, alkaline phosphatase, osteocalcin, COL1A1, RUNX2. The monitoring within 96 hours demonstrated a progressive increase of cell adhesion and an intense cell proliferation at 48 h. The differentiation response and proliferation of stem cells after treatment with SW shows that this therapy is an effective method of regenerative medicine. PMID- 28002912 TI - Association between markers of bone loss and urinary lithogenic risk factors in osteopenic postmenopausal women. AB - In this study, we explored if urinary lithogenic risk parameters could have some application for monitoring bone health status. We recruited 20 women with postmenopausal osteopenia and a negative medical history for nephrolithiasis. Markers of lithogenic risk were evaluated on 24-h urine and fastingmorning urine. Serum levels of bone turnover markers (BTM) were measured in fasting-blood samples. We found that cross-linked telopeptide of type I collagen (CTX) was significantly correlated with 24-h calcium excretion. N-terminal propeptide of type I procollagen (PINP) correlated with 24-h excretion of potassium, calcium and citrate. CTX had considerably increased in patients with pH less than 5.5. Low citrate levels (less than 3.3 mmol/24 h) were associated with lower levels of CTX and PINP. Our findings suggest that a low-grade acidosis and some lithogenic risk factors are detectable in a proportion of patients with postmenopausal osteopenia. Further studies are necessary to confirm that this evaluation could be clinically relevant. PMID- 28002913 TI - Pregnancy-associated osteoporosis (PAO) with multiple vertebral fragility fractures: diagnosis and treatment in a young primigravid woman. AB - PAO is an uncommon condition affecting pregnant women during last trimester or early post-delivery period; it is often asymptomatic or presents with pain related to some acute fragility fractures. The diagnosis is often delayed or missed, the etiology remains unknown and no guidelines about treatment have been published. We present one case of PAO in a 33-year-old primigravid woman presenting acute worsening back pain. Our patient was treated with a TLSO brace, oral 25 (OH)-vitamin D supplementation and Teriparatide for 6 months. A short review of the literature has been included and useful advice about how to suspect and diagnose this uncommon disease were given in order to recognize and treat such a debilitating and severe condition for young mothers as best as possible, based on the available scientific evidences. PMID- 28002914 TI - Treatment options of simple bone cysts: the role of bone substitutes, growth factors and literature review. AB - The solitary bone cyst is a typical tumor-like lesion of the immature skeleton, whose etio-pathogenesis is still unclear. The purpose of this work is to perform a review of the literature about the different surgical approaches focusing on the role of bone substitutes and growth factors. Literature analysis shows injection techniques of substances such as methylprednisolone, autologous bone marrow, demineralized bone matrix, calcium sulphate and surgical techniques that involve the resection and curettage associated with bone graft and/or intramedullary nailing. Although there are good results currently associated to these techniques and the different ways of treatment, the only evidence-based treatment is given by injections of steroids. However, given the high rate of failure, autologous bone marrow and platelet gel represent a viable therapeutic option. PMID- 28002915 TI - Autologous bone marrow concentrate combined with platelet-rich plasma enhance bone allograft potential to induce spinal fusion. AB - Bone marrow cells concentrate (BMCs) is a source of osteoprogenitor cells and platelet-rich plasma (PRP) is a source of growth factors. The objective of the study was to determine whether BMC and PRP could increase the potential of bone allograft to induce posterolateral-lumbar spinal fusion compared to the bone allograft alone. A prospective nonrandomized radiographic study has been conduced on 10 patients with posterolateral instrumented fusion for degenerative lumbar disease with 1-year follow-up using CT scan. A fresh frozen bone allograft alone and bone allograft with a mixture of autologous BMC and PRP blended with thrombin were apposed in the right and left posterolateral side, respectively. CT showed good right fusion masses (allograft alone) in 4 patients and poor in 6; good left masses (BMC and PRP plus allograft) in 9 patients and poor in 1. The differences detected between right-side and left-side masses show an advantage in adding BMC and PRP to the bone allograft to increase spinal fusion rate. PMID- 28002916 TI - Mesenchymal stem cells for intervertebral disc regeneration. AB - Low back pain (LBP) is one of the most common disabling symptoms affecting the adult population throughout the industrialized world. The main cause underlying this condition is intervertebral disc degeneration (IDD), which is characterized by progressive decrease of the proteoglycan content within the nucleus pulposus (NP), leading to disc dehydration and loss of its morpho-functional and biomechanical properties. To date, LBP treatment is based upon conservative and invasive procedures which are not capable of restoring the degenerative alterations of the disc, as they only help relieve the symptoms and/or slow down disc degeneration and are, nonetheless, characterized by significant comorbidities, costs and secondary risks. The potential use of different mesenchymal stem/stromal cells (MSCs) for treating IDD has been promisingly tested in vitro and in vivo. The combination of different cell types, preconditioning culture conditions, engineered scaffolds and delivery systems have yielded proof of disc matrix reconstitution, increased cell viability and tissue regeneration in several experimental settings. This article reviews the current literature on stem cell-based therapy for IDD and the outcomes that diverse approaches have achieved. PMID- 28002917 TI - Simultaneous double rod and en-bloc direct vertebral rotation technique for correction of main thoracic adolescent idiopathic scoliosis: retrospective analysis of 14 cases. AB - Adolescent idiopathic scoliosis (AIS) is a triplanar deformity associated with rib hump, especially when a principle thoracic curve is present. The aim of this study is to evaluate the results of AIS correction retrospectively, using simultaneous double rod derotation manoeuvre technique followed by en-bloc direct vertebral rotation (DVR). Fourteen patients were included in this study. Coronal and sagittal thoracic Cobb angle, global coronal balance, sagittal balance, rib hump prominence, Scoliosis Research Society outcome instrument score (SRS-22) and Walter Reed visual assessment scale (WR-VAS) values were recorded pre- and postoperatively and evaluated. Results were evaluated at a mean follow-up of 2 years. Good to excellent radiographic and clinical results were obtained in all patients. No major perioperative complications occurred. This technique has proved to be effective for surgical correction of the deformity in Lenke type 1 AIS with good clinical and radiological results and low rate of complications. PMID- 28002918 TI - The correlation between preoperative levels of albumin and tlc and mortality in patients with femoral neck fracture. AB - A femoral neck fracture in an elderly patient often represents a major challenge for the orthopaedic surgeon who has to face not only the fracture, but also all the multiple issues related to age. Among others, malnutrition has been recognised as an important factor associated with severe aggravation in these patients. One-hundred-and-forty-seven patients were enrolled to investigate the use of two markers of patient nutritional status, i.e. serum albumin level and total leukocyte count (TLC), as predictors of mortality in the elderly patient suffering from proximal femur fracture. We found that low preoperative values of serum albumin and TLC proved to be directly related to worse outcomes. Therefore, these exams can be useful to identify patients with a femoral neck fracture that have higher risk of malnutrition and consequent higher mortality and that can benefit from some measures, such as albumin or protein nutritional supplement. PMID- 28002919 TI - Is a minimally invasive anterior approach effective in old patients? A pilot study. AB - Minimally invasive approach to the hip is a blood preserving surgery, with rapid rehabilitation, and low dislocation rate. Intuitively, these characteristics render this approach extremely suitable in the elderly patient. The aim of this study was to analyze the early clinical and radiographic results in the first 30 consecutive patients above 70 years of age undergoing THR through a minimally invasive anterior approach. Clinical evaluations showed an improvement of the Harris Hip Score and WOMAC score after surgery. Radiographic assessment showed cup orientation averaging 47 degrees (range 40 degrees ?59 degrees ) and no valgus stem aligned. Allogeneic blood transfusion was required in only 6 patients (19.8%). One patient experienced an intraoperative fracture of the greater trochanter. No early implant dislocation was observed in the study population. In conclusion we advise a minimally invasive anterior approach for THR in older patients when a careful patient selection has been done. PMID- 28002920 TI - Isolate acetabular cup revision through the direct anterior hip approach: surgical technique, early experience and review of the literature. AB - Direct anterior approach to the hip allows perfect exposure of the acetabulum and an easy proximal and medial extension that makes it eligible for isolate acetabular cup revision although it is seldom used and there are only few published studies. On 23 consecutive acetabular revision (16 cases Paprosky grade 1 or 2, 5 cases 3A, 1 case 3B and 1 case 4) at an average 28-month follow up, we did not record failures or major complications. Early complications included prolonged wound healing in 4 cases and transient femoral cutaneous nerve palsy in 2 cases, the mean postoperative Harris Hip Score was 82.2 with 82.5% of excellent and good results. Our results are consistent with those reported in the literature with similar techniques. The direct anterior approach has shown excellent results for isolated cup revision, though is probably better suited for surgeons that have some experience with the same approach for primary cases. PMID- 28002921 TI - Restoring the femoral offset prevent early migration of the stem in total hip arthroplasty: an EBRA-FCA study. AB - The use of modular stems is still debated and controversial. Some authors have highlighted a number of disadvantages of modular prostheses including high costs, the tendency to fracture, the fretting and corrosion and the increased production of debris. Other authors have emphasized several advantages to adapt the prosthesis to the morphometric differences of patients, to allow better accuracy in restoring the anatomy and biomechanics of hip joint. The advantages of the modular devices appear to be more evident in patients with developmental dysplasia of the hip (DDH). In our study we compared 96 patients, operated for arthritis of the hip with 55 modular neck prostheses (PROFEMUR(r), Wright(r) Arlington, Tennesse, USA) and 41 standard femoral stems (SYMAX(r), Striker(r) Kalamazoo, Michigan, USA). The precision of restoring the natural offset during surgery was correlated with the clinical outcome and the radiological early migration of each stem measured using the computer-assisted EBRA-FCA method. The average preoperative HHS (Harris Hip Score) was 44 (23-66); the postoperative 86.56 in the 55 patients operated with modular prostheses and 81.70 in the 41 patients with monoblock stem. The worst HH Scores were seen in patients in whom the offset was not restored properly. On the contrary, the best scores have been reached in patients in which that value is closer to the ?target? value (offset value of the contralateral hip). Restoring the proper offset seems to determine an appropriate tension of the abductor muscles of the hip and implies a better functioning of the joint and a better primary stability of the implant, with less early migration. This has to be a primary objective of THA surgery. PMID- 28002922 TI - The adult zebrafish as polyhedric model for skeletal studies. AB - In the last decade, several examples have been produced by scientific literature about zebrafish as a model to study human bone diseases. In fish, bone turnover, reparation and remodeling of the adult bone tissue cannot be studied in embryonic or juvenile stages. In addition, fins and scales represent unique anatomical features useful to study adult bone metabolism and diseases. For these reasons, the adult zebrafish represents an innovative and readily available resource for studying the bone metabolism at cellular and molecular level. Although the adult fish is less used than the embryo, several applications have been found in the last years with the production of innovative pathological models in adult zebrafish, helpful to understand the mechanisms of bone physiopathology. The use of mutants, regenerating organs, transgenic fish and scales have increased the power of this model in the last years. PMID- 28002923 TI - Tendinopathic supraspinatus tenocytes may have a neuroendocrine-like function, secreting CGRP, SP and VEGF: a pilot immunohistochemistry study. AB - We wanted to observe and compare the appearance of neurovascular tissue from tendon ex vivo, in patients with and without painful rotator cuff tendinopathy. Supraspinatus tendons were biopsied from 5 participants with painful tendinopathy and normal tendon from a young male. Slides were stained with haematoxylin and eosin and toluidine blue for histological assessment. Immunohistochemical markers for general nerves (protein gene-product 9.5 and synaptophysin), sensory nerves (calcitonin gene-related peptide; substance-P) and vascularisation (vascular endothelial growth factor) were used. PGP9.5 and CGRP-immunoreactive fibres were associated with vessels in cases and control. Synaptophysinlabelled fibres were observed in close relation to vessels in tendinopathy. PGP9.5, CGRP, SP and VEGF immunoreaction also labelled tenocyte-like cells in degenerative areas and fibres in regions of fat and collagen. Sensory innervation and vascularity are increased in tendinopathy. The evidence for innervation and vascularity of symptomatic rotator cuff tendon may aid the development of novel investigations and therapies in the management of patients with this ailment. PMID- 28002924 TI - Quantitative study on Vancomycin release from cement in 3 different formulations: preliminary results and antimicrobial activity. AB - The purpose of this study is to investigate the best preparation method of the cement powder mixture, solvent and antibiotic in order to obtain the greatest amount of antibiotic in the joint for the longest time as possible. At time T0 the three samples, packed in a sterile environment in different formulations, were placed in sterile tubes, adding to each one 5 ml of saline phosphate buffer solution (PBS) and put in a stove at 37 degrees C for 24 h. A sample of PBS without cement (T control) was also created. Qualitative and quantitative assessment of the incubated liquid with cement was performed along with biochemical analysis with High Performance Liquid Chromatography (HPLC). The analysis of the raw data demonstrated that at T1 there was a prevalence of antibiotic release from sample , compared to sample 2 and 3. This difference was maintained until the T20; from T21 the antibiotic release gradually leveled in 3 samples. The elution of the antibiotic remained detectable up to T60. Our work shows that the sample preparation is decisive on the quantity of released antibiotic. These results are confirmed by microbiological tests. It is useful to know the actual kinetics of antibiotics in articulation. Further studies are necessary to determine the effectiveness of antibiotic against micro-organisms and how long it acts. PMID- 28002925 TI - Association Between Hearing Impairment and Albuminuria With or Without Diabetes Mellitus. AB - OBJECTIVES: Few studies have evaluated the accurate association between hearing loss (HL) and albuminuria in patients with or without diabetes mellitus (DM). The aim of our study was to identify the clinical effects of albuminuria on HL with or without DM. METHODS: This study included 9,762 patients from the Korean National Health and Nutrition Examination Survey between 2011 and 2013. Participants were divided into 4 groups based on DM and urine albumin/creatinine ratio levels: group 1 included participants with neither DM nor albuminuria, group 2 included participants without DM and with albuminuria, group 3 included patients with DM and without albuminuria, and group 4 included patients with both DM and albuminuria. The low- or mid-frequency and high-frequency, and average hearing threshold values were obtained. RESULTS: There were 7,508, 545, 1,325, and 384 participants in groups 1, 2, 3, and 4, respectively. Univariate and multivariate analyses showed that the 3 hearing thresholds in group 1 were the lowest and those in group 4 were the highest among the 4 groups. No significant differences were observed in those thresholds between groups 2 and 3. Group 4 was associated with HL compared with the other groups, but moderate to severe HL was not associated with DM or albuminuria. CONCLUSION: The presence of albuminuria was associated with a modest effect on hearing thresholds regardless of presence of DM. PMID- 28002926 TI - Age-Related Changes in Nuclear Factor Erythroid 2-Related Factor 2 and Reactive Oxygen Species and Mitochondrial Structure in the Tongues of Fischer 344 Rats. AB - OBJECTIVES: Previously the authors reported age-related changes in the activities of anti-oxidative enzyme activities and protein expressions in the tongues of rats. Because more information is required about relations between aging and oxidative stress and anti-oxidative enzyme efficiency, the authors investigated differences between the expression of master regulator of anti-oxidative enzymes (nuclear factor erythroid 2-related factor 2 [Nrf2]), levels of reactive oxygen species (ROS), and mitochondrial structures in the tongues of young and aged Fischer 344 rats. METHODS: Age-dependent changes in Nrf2 protein and ROS were determined by Western blotting and using chemical kits, respectively. Tongue specimens were examined by electron microscopy. The study was conducted using rats aged 7 months (young, n=8) or 22 months (old, n=8). RESULTS: Nrf2 protein levels in the tongues of aged rats were lower than in young rats. ROS levels were higher in older rats and mitochondrial structural deficits were observed their tongues. Three young rats showed moderate mitochondrial degeneration, whereas profound degeneration with mitochondrial cristae disruption, swelling, rupture, or intramitochondrial vacuole formation was observed in all 8 old rats. Notably, mitochondrial rupture was observed in 5 old rats. CONCLUSION: Antioxidant defense systems of old rats were compromised by Nrf2 deficiency, which could lead to the deleterious accumulation and release of ROS and probably mitochondrial structural deficits in aged tongue tissues. PMID- 28002928 TI - Volatile compounds and some physico-chemical properties of pastirma produced with different nitrate levels. AB - OBJECTIVE: The aim of the study was to evaluate the effects of different nitrate levels (150, 300, 450, and 600 ppm KNO3) on the volatile compounds and some other properties of pastirma. METHODS: Pastirma samples were produced under the controlled condition and analyses of volatile compounds, and thiobarbituric acid reactive substances (TBARS) as an indicator of lipid oxidation, non-protein nitrogenous matter content as an indicator of proteolysis, color and residual nitrite were carried out on the final product. The profile of volatile compounds of pastirma samples was analyzed by gas chromatography/mass spectrometry using a solid phase microextraction. RESULTS: Nitrate level had a significant effect on pH value (p<0.05) and a very significant effect on TBARS value (p<0.01). No significant differences were determined in terms of aw value, non-protein nitrogenous substance content, color and residual nitrite between pastirma groups produced by using different nitrate levels. Nitrate level had a significant (p<0.05) or a very significant (p<0.01) effect on some volatile compounds. It was determined that the amounts and counts of volatile compounds were lower in the 450 and especially 600 ppm nitrate levels than 150 and 300 ppm nitrate levels (p<0.05). While the use of 600 ppm nitrate did not cause an increase in residual nitrite levels, the use of 150 ppm nitrate did not negatively affect the color of pastirma. However, the levels of volatile compounds decreased with an increasing level of nitrate. CONCLUSION: The use of 600 ppm nitrate is not a risk in terms of residual nitrite in pastirma produced under controlled condition, however, this level is not suitable due to decrease in the amount of volatile compounds. PMID- 28002927 TI - Human lactoferrin efficiently targeted into caprine beta-lactoglobulin locus with transcription activator-like effector nucleases. AB - OBJECTIVE: To create genetically modified goat as a biopharming source of recombinant human lacotoferrin (hLF) with transcription activator-like effector nucleases. METHODS: TALENs and targeting vector were transferred into cultured fibroblasts to insert hLF cDNA in the goat beta-lactoglobulin (BLG) locus with homology-directed repair. The gene targeted efficiency was checked using sequencing and TE7I assay. The bi-allelic gene targeted colonies were isolated and confirmed with polymerase chain reaction, and used as donor cells for somatic cell nuclear transfer (SCNT). RESULTS: The targeted efficiency for BLG gene was approximately 10%. Among 12 Bi-allelic gene targeted colonies, five were used in first round SCNT and 4 recipients (23%) were confirmed pregnant at 30 d. In second round SCNT, 7 (53%), 4 (31%), and 3 (23%) recipients were confirmed to be pregnant by ultrasound on 30 d, 60 d, and 90 d. CONCLUSION: This finding signifies the combined use of TALENs and SCNT can generate bi-allelic knock-in fibroblasts that can be cloned in a fetus. Therefore, it might lay the foundation for transgenic hLF goat generation and possible use of their mammary gland as a bioreactor for large-scale production of recombinant hLF. PMID- 28002929 TI - Coat colour phenotype of Qingyu pig is associated with polymorphisms of melanocortin receptor 1 gene. AB - OBJECTIVE: Qingyu pig, a Chinese indigenous pig breed, exhibits two types of coat colour phenotypes, including pure black and white with black spotting respectively. Melanocortin receptor 1 (MC1R) and agouti signaling protein (ASIP) are two widely reported pivotal genes that significantly affect the regulation of coat colour. The objectives of this study were to investigate whether the polymorphisms of these two genes are associated with coat colour and analyze the molecular mechanism of the coat colour separation in Qingyu pig. METHODS: We studied the phenotype segregation and used polymerase chain reaction amplification and Sanger sequencing to investigate the polymorphism of MC1R and ASIP in 121 Qingyu pigs, consisting of 115 black and 6 white with black spotted pigs. RESULTS: Coat colour of Qingyu pig is associated with the polymorphisms of MC1R but not ASIP. We only found 2 haplotypes, EQY and Eqy , based on the 13 observed mutations from MC1R gene. Among which, Eqy presented a recessive inheritance mode in black spotted Qingyu pigs. Further analysis revealed a g.462 463CC insertion that caused a frameshift mutation and a premature stop codon, thus changed the first transmembrane domain completely and lost the remaining six transmembrane domains. Altogether, our results strongly support that the variety of Qingyu pig's coat colour is related to MC1R. CONCLUSION: Our findings indicated that black coat colour in Qingyu pig was dominant to white with black spotted phenotype and MC1R gene polymorphism was associated with coat colour separation in Qingyu pig. PMID- 28002930 TI - Grazing system and floor type effects on blood biochemistry, growth and carcass characteristics of Nguni goats. AB - OBJECTIVE: Purpose was to determine the effects of grazing system and floor type on concentrations of blood metabolites, activity of creatine kinase, body weight and carcass characteristics of castrated Nguni goats. METHODS: Forty eight, 7 month old goats were randomly allocated to herding and tethering treatments from 0800 to 1300 hours and accommodated on slatted and earth floors daily. Blood samples were collected by jugular venipuncture every fifteenth day for metabolite analysis. Slaughter was done at a commercial abattoir following 5 months of monitoring. RESULTS: Tethered goats had significantly higher concentrations of urea (5.19 mmol/L) (p< 0.001), creatinine (55.87 MUmol/L) (p<0.05), total protein (64.60 g/L) (p<0.01), and globulin (49.79 g/L) (p<0.001), whereas herded goats had higher glucose (3.38 mmol/L) (p<0.001), albumin (15.33 g/L) (p<0.05), albumin/globulin ratio (0.34) (p<0.01), and body weight (24.87 kg) (p< 0.001). Slatted floors caused higher (p<0.01) albumin at 15.37 g/L. The interaction of grazing system and floor type affected creatinine, total protein, globulin at (p<0.01) and albumen/globulin ratio at (p<0.01). The least creatinine concentration and albumin/globulin ratio was in herded and tethered goats that were accommodated on earth floors, respectively. The highest total protein and globulin concentrations were in serum of tethered goats that were accommodated on earth floors. The highest (p<0.05) dressing percentage (45.26%) was in herded goats accommodated on slatted floors. CONCLUSION: Herding of goats lowered globulin concentration, improved estimated feed intake, blood glucose and albumin concentrations, albumin globulin ratio, increased body weights and weight related carcass characteristics. Floor type had very little effects on metabolites where earth floors only reduced albumin concentration. Tethering and housing goats on earth floors resulted in double stress that increased chronic infections. PMID- 28002931 TI - Cacao bean husk: an applicable bedding material in dairy free-stall barns. AB - OBJECTIVE: The objectives of the study were to assess the effect of cacao bean husk as bedding material in free-stall barn on the behavior, productivity, and udder health of dairy cattle, and on the ammonia concentrations in the barn. METHODS: Four different stall surfaces (no bedding, cacao bean husk, sawdust, and chopped wheat straw) were each continuously tested for a period of 1 week to determine their effects on nine lactating Holstein cows housed in the free-stall barn with rubber matting. The lying time and the milk yield were measured between d 4 and d 7. Blood samples for plasma cortisol concentration and teat swabs for bacterial counts were obtained prior to morning milking on d 7. The time-averaged gas-phase ammonia concentrations in the barn were measured between d 2 and d 7. RESULTS: The cows spent approximately 2 h more per day lying in the stalls when bedding was available than without bedding. The milk yield increased in the experimental periods when cows had access to bedding materials as compared to the period without bedding. The lying time was positively correlated with the milk yield. Bacterial counts on the teat ends recorded for cows housed on cacao bean husk were significantly lower than those recorded for cows housed without bedding. Ammonia concentration under cacao bean husk bedding decreased by 6%, 15%, and 21% as compared to no bedding, sawdust, and chopped wheat straw, respectively. The cortisol concentration was lowest in the period when cacao bean husk bedding was used. We observed a positive correlation between the ammonia concentrations in the barn and the plasma cortisol concentrations. CONCLUSION: Cacao bean husk is a potential alternative of conventional bedding material, such as sawdust or chopped wheat straw, with beneficial effects on udder health and ammonia concentrations in the barns. PMID- 28002932 TI - Expression of Egr3 in mouse gonads and its localization and function in oocytes. AB - OBJECTIVE: The early growth response (Egr) family consists of four members (Egr1, Egr2, Egr3, and Egr4) that are zinc finger transcription factors. Among them, Egr3 is involved in transcriptional regulation of target genes during muscle spindle formation and neurite outgrowth. We previously showed that the immunoreactive Egr3 is localized on oocyte spindle and accumulate near the microtubule organizing center during meiosis I in mice. Egr3 was also shown to be localized on spermatocytes. We herein investigated if Egr3 is expressed in mouse gonads and if Egr3 blockade results in any defect in oocyte maturation. METHODS: Expression of Egr3 in mouse gonads was examined by reverse transcription polymerase chain reaction. Full-length Egr3 and truncated Egr3 (DeltaEgr3) complementary RNAs (cRNAs) with Xpress tag at N-terminus and DsRed2 at C terminus, and small interfering RNA (siRNA) targeting Egr3 were microinjected into mouse oocytes at germinal vesicle stage. Localization of microinjected Egr3 was examined by confocal live imaging and immunofluorescence staining. RESULTS: Egr3 mRNA was detected in mouse ovaries and testes from 1 to 4 week-old mice. An uncharacterized longer transcript containing 5'untranslated region was also detected in 3 and 4 week-old gonads. Microinjected Xpress-Egr3-DsRed2 or Xpress DeltaEgr3-DsRed2 localized to nuclei and chromosomes during meiotic progression. Microinjection of these cRNAs or Egr3 siRNA in oocytes did not affect meiotic maturation. Immunofluorescence staining of Egr3 in Xpress-DeltaEgr3-DsRed2 injected oocytes showed a positive signal only on meiotic spindle, suggesting that this antibody does not detect endogenous or exogenous Egr3 in mouse oocytes. CONCLUSION: The results show that Egr3 localizes to chromosomes during meiotic progression and that certain antibodies may not faithfully represent localization of target proteins in oocytes. Egr3 seems to be dispensable during oocyte maturation in mice. PMID- 28002933 TI - Effects of different methionine sources on production and reproduction performance, egg quality and serum biochemical indices of broiler breeders. AB - OBJECTIVE: The study was conducted to evaluate the effects of different methionine (Met) sources on production performance, reproduction performance, egg quality and serum biochemical indices in broiler breeders. METHODS: After receiving a basal diet (containing 0.25% Met) for a 2-wk pretreatment period, a total of 360 39-wk-old Lingnan yellow broiler breeders were randomly allocated to four treatments with six replicates each (15 birds per replicate). Breeders were fed with basal diets (control) or diets supplemented with DL-methionine (DLM), DL 2-hydroxy-4-methylthio butytric calcium (MHA-Ca) and coated DL-Met (CME) respectively. RESULTS: The results showed that CME supplementation promoted laying rate and decreased feed-to-egg ratio (F/E) (p<0.05), DLM and MHA-Ca supplementation decreased F/E (p<0.05) when compared with control group. The rate of fertility, hatchability and birthrate were higher (p<0.05) in DLM, MHA-Ca, and CME groups than control group. Compared with control group, CME increased the eggshell thickness (p<0.05); MHA-Ca improved the eggshell thickness, shell ratio and eggshell strength (p<0.05). Results also showed that CME elevated the concentration of total protein in serum (p<0.05); MHA-Ca improved the concentration of calcium in serum (p<0.05). The concentration of serum uric acid in DLM, MHA-Ca, and CME groups was lower than that in control group (p<0.05). Besides, CME had higher concentrations of serum taurine, cysteine and cystanthionine (p<0.05) while MHA-Ca and DLM promoted the serum taurine concentration (p<0.05) compared with control group. CONCLUSION: Based on the results, it was concluded that Met supplementation could enhance the production and reproduction performance as well as the antioxidant status and egg quality of broiler breeders. In terms of improving the production performance, reproduction performance and antioxidant performance, CME was superior to DLM and MHA-Ca; but in regard to the enhancement of eggshell quality and serum Ca concentration, MHA Ca was superior to DLM and CME. PMID- 28002934 TI - Determination of the quality of stripe-marked and cracked eggs during storage. AB - OBJECTIVE: Stripe marks, which occasionally occur on the shell, do not cause breakage to the shell and shell membranes of eggs. This study investigated the quality of intact eggs (IEs), minor stripe-marked eggs (MEs), severe stripe marked eggs (SEs), and cracked eggs (CEs) during 3-week storage at 25 degrees C. METHODS: Shell eggs were collected the day after being laid and were washed. Among them, eggs without any visual cracks or stripe marks on the shells were evaluated as IEs by the plant employees using candling in a darkened egg storage room; the remaining eggs exhibited some eggshell defects. At day 3, the eggs were further categorized into IEs, MEs, SEs, CEs, and broken eggs (BEs) on the basis of the description given. Except BEs, which were discarded, the remaining eggs were stored at 25 degrees C (approximate relative humidity 50%) and then analyzed. RESULTS: Stripe marks were observed primarily within the first 3 days after washing. At day 3, CEs had significantly (p<0.05) lower Haugh unit values, but all eggs had grades AA or A, according to the United States Department of Agriculture standard. As storage time increased, differences in egg quality between groups were more obvious. IEs had the highest eggshell breaking strength. During storage, the total plate counts and pathogens, namely Escherichia coli, Campylobacter spp., Staphylococcus aureus, and Salmonella spp., were not detectable in the internal content of IEs and SEs. CONCLUSION: In conclusion, cracks degraded egg quality severely and minor stripe marks only slightly influenced the egg quality. PMID- 28002935 TI - Growth performance, nutrients digestibility, and blood metabolites of lambs fed diets supplemented with probiotics during pre- and post-weaning period. AB - OBJECTIVE: Two experiments were conducted to evaluate the effects on growth performance, digestibility, and blood metabolites of lambs during pre- and post weaning period of inclusion of a commercial probiotic (PRO) containing a mixture of two strains of Pediococcus, Pediococcus acidilactici (1*106 colony-forming unit [cfu]/g) and Pediococcus pentosaceus (1.3*106 cfu/g), with dextrose as the carrier compound compared to a diet based on concentrate mixture and wheat straw. METHODS: In exp. 1, 24 male lambs of about 15+/-2.6 d age and initial body weight (BW) of 5.52+/-0.6 kg were randomly allocated into three groups. One group received control diet without additives, and remainders received control diet supplemented with 0.5 or 1 g PRO/lamb/d. Daily feed intake and biweekly BW were recorded. In exp. 2, five lambs, (initial BW = 29.72+/-1.15 kg, age = 6.54+/-0.32 mo) were used as experimental animals in a digestion trial. They were fed the same diets as in Exp. 1. RESULTS: The supplementation of PRO did not result in any significant differences in milk intake, average daily gain (ADG), or total gain between treatments during the pre-weaning period. Total dry matter intake tended to be greater (p = 0.07) with addition of PRO in the post-weaning diets. During post-weaning phase, the final BW, ADG, total gain, and feed conversion ratio of the lambs receiving PRO treatments tended to be greater (p<=0.10) than the control group. Addition of PRO in post-weaning diet decreased (p<=0.01) blood urea and cholesterol concentrations. With the exception of ether extract digestibility, all nutrients digestibility were improved with inclusion PRO in the post-weaning diets. CONCLUSION: Lambs that received PRO in post-weaning diet appeared to show a better performance than lambs in pre-weaning period. Addition of the probiotic in the post-weaning diet trended towards improved dry matter intake, growth performance, feed conversion ratio, and nutrients digestibility. PMID- 28002936 TI - Evaluation of the nutritional value of locally produced forage in Korea using chemical analysis and in vitro ruminal fermentation. AB - OBJECTIVE: The use of locally produced forage (LPF) in cattle production has economic and environmental advantages over imported forage. The objective of this study was to characterize the nutritional value of LPF commonly used in Korea. Differences in ruminal fermentation characteristics were also examined for the LPF species commonly produced from two major production regions: Chungcheong and Jeolla. METHODS: Ten LPF (five from each of the two regions) and six of the most widely used imported forages originating from North America were obtained at least three times throughout a year. Each forage species was pooled and analyzed for nutrient content using detailed chemical analysis. Ruminal fermentation characteristics were also determined by in vitro anaerobic incubations using strained rumen fluid for 0, 3, 6, 12, 24, and 48 h. At each incubation time, total gas, pH, ammonia, volatile fatty acid (VFA) concentrations, and neutral detergent fiber digestibility were measured. By fitting an exponential model, gas production kinetics were obtained. RESULTS: Significant differences were found in the non-fiber carbohydrate (NFC) content among the forage species and the regions (p<0.01). No nutrient, other than NFC, showed significant differences among the regions. Crude protein, NFC, and acid detergent lignin significantly differed by forage species. The amount of acid detergent insoluble protein tended to differ among the forages. The forages produced in Chungcheong had a higher amount of NFC than that in Jeolla (p<0.05). There were differences in ruminal fermentation of LPF between the two regions and interactions between regions and forage species were also significant (p<0.05). The pH following a 48-h ruminal fermentation was lower in the forages from Chungcheong than from Jeolla (p<0.01), and total VFA concentration was higher in Chungcheong than in Jeolla (p = 0.05). This implies that fermentation was more active with the forages from Chungcheong than from Jeolla. Analysis of gas production profiles showed the rate of fermentation differed among forage species (p<0.05). CONCLUSION: The results of the present study showed that the nutritional values of some LPF (i.e., corn silage and Italian ryegrass) are comparable to those of imported forages widely used in Korea. This study also indicated that the nutritional value of LPF differs by origin, as well as by forage species. Detailed analyses of nutrient composition and digestion kinetics of LPF should be routinely employed to evaluate the correct nutritional value of LPF and to increase their use in the field. PMID- 28002937 TI - Effect of increasing dietary metabolizable protein on nitrogen efficiency in Holstein dairy cows. AB - OBJECTIVE: The objective of the study was to determine the effects of increasing levels of metabolizable protein (MP) on lactation performance and nitrogen (N) efficiencies in lactating dairy cows. METHODS: Nine multiparous cows in mid lactation [113+/-25 days in milk] received three treatments in a 3*3 Latin square design with a period length of 21 days. The treatments were three diets, designed to provide similar energy and increasing supply of MP (g/d) (2,371 [low], 2,561 [medium], and 2,711 [high] with corresponding crude protein levels [%]) 15.2, 18.4, and 20.9, respectively. RESULTS: Increasing MP supplies did not modify dry matter intake, however, it increased milk protein, fat, and lactose yield linearly. Similarly, fat corrected milk increased linearly (9.3%) due to an increase in both milk yield (5.2%) and milk fat content (7.8%). No effects were observed on milk protein and lactose contents across the treatments. Milk nitrogen efficiency (MNE) decreased from 0.26 to 0.20; whereas, the metabolic efficiency of MP decreased from 0.70 to 0.60 in low to high MP supplies, respectively. The concentration of blood urea nitrogen (BUN) increased linearly in response to increasing MP supplies. CONCLUSION: Increasing MP supplies resulted in increased milk protein yield; however, a higher BUN and low MNE indicated an efficient utilization of dietary protein at low MP supplies. PMID- 28002938 TI - Behaviors and body weight of suckling piglets in different social environments. AB - OBJECTIVE: This study was conducted to characterize the behaviors and the body weight of suckling piglets in different social environments. METHODS: Two groups of sows and suckling piglets housed either in individual farrowing crates in separate pens (1.8*2.4 m, the control group) or in groups of three sows with their piglets in farrowing crates in a large common enclosure (5.4*2.2 m, the treatment group) were observed with the aid of video technology for 9 consecutive hours on days 1, 2, and 3, after mixing. RESULTS: Suckling, agonistic, and elimination behaviors of suckling piglets were significantly higher in the control group than in the treatment group. Inactive behavior was higher in the treatment group than in the control group. Most of the effects of the social environment on the suckling piglets seem to be the result of large reductions in behaviors and body weight for piglets switching from high activity to low activity. Moreover, suckling behavior and birth body weight were highly correlated with body weight at the end of the test. CONCLUSION: The social environment that resulted from mixing, thus, had significant effects on the behavior and body weight of suckling piglets, and behavioral characteristics, therefore, should be considered when making improvements to the husbandry and care methods used in swine production. PMID- 28002939 TI - Chicoric Acid Ameliorates Lipopolysaccharide-Induced Oxidative Stress via Promoting the Keap1/Nrf2 Transcriptional Signaling Pathway in BV-2 Microglial Cells and Mouse Brain. AB - As a major nutraceutical component of a typical Mediterranean vegetable chicory, chicoric acid (CA) has been well-documented due to its excellent antioxidant and antiobesity bioactivities. In the current study, the effects of CA on lipopolysaccharide (LPS)-stimulated oxidative stress in BV-2 microglia and C57BL/6J mice and the underlying molecular mechanisms were investigated. Results demonstrated that CA significantly reversed LPS-elicited cell viability decrease, mitochondrial dysfunction, activation of NFkappaB and MAPK stress pathways, and inflammation responses via balancing cellular redox status. Furthermore, molecular modeling study demonstrated that CA could insert into the pocket of Keap1 and up-regulated Nrf2 signaling and, thus, transcriptionally regulate downstream expressions of antioxidant enzymes including HO-1 and NQO-1 in both microglial cells and ip injection of LPS-treated mouse brain. These results suggested that CA attenuated LPS-induced oxidative stress via mediating Keap1/Nrf2 transcriptional pathways and downstream enzyme expressions, which indicated that CA has great potential as a nutritional preventive strategy in oxidative stress-related neuroinflammation. PMID- 28002940 TI - Development and Validation of a Qualitative Method for Target Screening of 448 Pesticide Residues in Fruits and Vegetables Using UHPLC/ESI Q-Orbitrap Based on Data-Independent Acquisition and Compound Database. AB - A semiautomated qualitative method for target screening of 448 pesticide residues in fruits and vegetables was developed and validated using ultrahigh-performance liquid chromatography coupled with electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC/ESI Q-Orbitrap). The Q-Orbitrap Full MS/dd-MS2 (data dependent acquisition) was used to acquire product-ion spectra of individual pesticides to build a compound database or an MS library, while its Full MS/DIA (data independent acquisition) was utilized for sample data acquisition from fruit and vegetable matrices fortified with pesticides at 10 and 100 MUg/kg for target screening purpose. Accurate mass, retention time and response threshold were three key parameters in a compound database that were used to detect incurred pesticide residues in samples. The concepts and practical aspects of in-spectrum mass correction or solvent background lock-mass correction, retention time alignment and response threshold adjustment are discussed while building a functional and working compound database for target screening. The validated target screening method is capable of screening at least 94% and 99% of 448 pesticides at 10 and 100 MUg/kg, respectively, in fruits and vegetables without having to evaluate every compound manually during data processing, which significantly reduced the workload in routine practice. PMID- 28002941 TI - Fine-tuning Nanocarriers Specifically toward Cargo: A Competitive Study on Solubilizing Related Photosensitizers for Photodynamic Therapy. AB - Tailor-made drug solubilizers are studied based on peptide-poly(ethylene glycol) conjugates, which exhibit peptide segments constituting binding motifs for the small-molecule drugs of interest to render them water-soluble. Suitable 7mer peptides are selected via combinatorial means by screening large one-bead-one compound (OBOC) peptide libraries. The capability of the screening method to read out structural detail of the drugs is investigated by comparing three related photosensitizers (Chlorin E6 (Ce6), Pheophorbide A (Pba) and meta tetra(hydroxyphenyl)chlorin (m-THPC), which are applicable for photodynamic cancer therapy. The screening procedure delivers de novo solubilizers that show the best solubilization efficiency for the drug the screening is performed with. While molecular recognition events between peptide and drug are not expected to be found, significant binding capacity differences of, e.g., the Ce6-solubilizer for Pba are suggesting selectivity in drug binding, even among structurally closely related drugs. Cyro-Electron microscopy revealed the formation of colloidal aggregates between drug moieties and peptide conjugates. Insights into relevant amino acids in the identified peptide sequences are gained by studying capacities of systematic point mutations (alanine scans), enabling understanding of drug-binding motifs. These reveal the importance of sequence positioning of appropriate H-bonding between polar functional groups of the peptide and the drugs, which agrees well with computational binding studies performed on drug/peptide model complexes. PMID- 28002942 TI - Atomic Scale Study on Growth and Heteroepitaxy of ZnO Monolayer on Graphene. AB - Atomically thin semiconducting oxide on graphene carries a unique combination of wide band gap, high charge carrier mobility, and optical transparency, which can be widely applied for optoelectronics. However, study on the epitaxial formation and properties of oxide monolayer on graphene remains unexplored due to hydrophobic graphene surface and limits of conventional bulk deposition technique. Here, we report atomic scale study of heteroepitaxial growth and relationship of a single-atom-thick ZnO layer on graphene using atomic layer deposition. We demonstrate atom-by-atom growth of zinc and oxygen at the preferential zigzag edge of a ZnO monolayer on graphene through in situ observation. We experimentally determine that the thinnest ZnO monolayer has a wide band gap (up to 4.0 eV), due to quantum confinement and graphene-like structure, and high optical transparency. This study can lead to a new class of atomically thin two-dimensional heterostructures of semiconducting oxides formed by highly controlled epitaxial growth. PMID- 28002943 TI - A Divergent Route to Eravacycline. AB - A convergent route to eravacycline (1) has been developed by employing Michael Dieckmann cyclization between enone 3 and a fully built and protected left-hand piece (LHP, 2). After construction of the core eravacycline structure, a deprotection reaction was developed, allowing for the isoxazole ring opening and global deprotection to be achieved in one pot. The LHP is synthesized from readily available 4-fluoro-3-methylphenol in six steps featuring a palladium catalyzed phenyl carboxylation in the last step. PMID- 28002944 TI - Ag-Assisted Fluorination of Unprotected 4,6-Disubstituted 2-Aminopyrimidines with Selectfluor. AB - A direct fluorination of 4,6-disubstituted 2-aminopyrimidines with Selectfluor in the presence of Ag(I) is presented, affording the corresponding 4,6-disubstituted 5-fluoro-2-aminopyrimidines with acceptable to high yield. Ag(I) is crucial for this chemoselective fluorination process. The transformation of 4,6-diphenyl 5 fluoro-2-aminopyrimidine into N-(5-fluoro-4,6-diphenylpyrimidin-2-yl)-4 methylbenzenesulfonamide is discussed, and the reaction mechanism is investigated, as well. PMID- 28002945 TI - Mesoporous Silica Nanoparticles Capped with Graphene Quantum Dots for Potential Chemo-Photothermal Synergistic Cancer Therapy. AB - In this study, mesoporous silica nanoparticles (MSNs) have been successfully capped with graphene quantum dots (GQDs) to form multifunctional GQD-MSNs with the potential for synergistic chemo-photothermal therapy. The structure, drug release behavior, photothermal effect, and synergistic therapeutic efficiency of GQD-MSNs to 4T1 breast cancer cells were investigated. The results showed that GQD-MSNs were monodisperse and had a particle size of 50-60 nm. Using doxorubicin hydrochloride (DOX) as a model drug, the DOX-loaded GQD-MSNs (DOX-GQD-MSNs) not only exhibited pH- and temperature-responsive drug-release behavior, but using near-infrared irradiation, they efficiently generated heat to kill cancer cells. Furthermore, GQD-MSNs were biocompatible and were internalized by 4T1 cells. Compared with chemotherapy and photothermal therapy alone, DOX-GQD-MSNs were much more effective in killing the 4T1 cells owing to a synergistic chemo-photothermal effect. Therefore, GQD-MSNs may have promising applications in cancer therapy. PMID- 28002946 TI - Influence of Monovalent Cation Size on Nanodomain Formation in Anionic Zwitterionic Mixed Bilayers. AB - Phosphatidylserine (PS) and phosphatidylcholine (PC) are two of the major anionic and zwitterionic phospholipids in mammalian cell membranes. Ion-PS interaction is hypothesized to play a crucial role in a range of biological events including membrane fusion, lipid phase modulation, membrane protein insertion and translocation. In this study, we characterize lipid nanodomain formation in PC/PS mixed bilayers using coarse-grained simulations. We investigate the role of monovalent cation sizes in modulating lipid-ion binding modes and lipid demixing. Our simulations suggest that certain lipid-ion binding modes lead to growth of ion-mediated PS lipid clusters. The existing literature reveals the polymorphism in binding and partitioning patterns in monovalent cations (Na+, K+, and Li+) with anionic lipids. Our work provides a microscopic view on the ion-size dependent PS lipid packing pattern observed experimentally. A coupled relationship between lipid curvature and asymmetry is observed in highly demixed PC/PS mixed bilayers. PMID- 28002948 TI - Survival of Vinyl Chloride Respiring Dehalococcoides mccartyi under Long-Term Electron Donor Limitation. AB - In anoxic groundwater aquifers, the long-term survival of Dehalococcoides mccartyi populations expressing the gene vcrA (or bvcA) encoding reductive vinyl chloride dehalogenases are important to achieve complete dechlorination of tetrachloroethene (PCE) and trichloroethene (TCE) to nonchlorinated ethene. The absence or inactivity of vcrA-containing Dehalococcoides results in the accumulation of the harmful chlorinated intermediates dichloroethene (DCE) and vinyl chloride (VC). Although vcrA-containing Dehalococcoides subpopulations depend on synergistic interaction with other organohalide-respiring populations generating their metabolic electron acceptors (DCE and VC), their survival requires successful competition for electron donor within the entire organohalide respiring microbial community. To understand this dualism of synergy and competition under growth conditions relevant in contaminated aquifers, we investigated Dehalococcoides-level population structure when subjected to a change in the ratio of electron donor to chlorinated electron acceptor in continuously stirred tank reactors (CSTRs) operated over 7 years. When the electron donor formate was supplied in stoichiometric excess to TCE, both tceA containing and vcrA-containing Dehalococcoides populations persisted, and near complete dechlorination to ethene was stably maintained. When the electron donor formate was supplied at substoichiometric concentrations, the interactions between tceA-containing and vcrA-containing populations shifted toward direct competition for the same limiting catabolic electron donor substrate with subsequent niche exclusion of the vcrA-containing population. After more than 2000 days of operation under electron donor limitation, increasing the electron donor to TCE ratio facilitated a recovery of the vcrA-containing Dehalococoides population to its original frequency. We demonstrate that electron donor scarcity alone, in the absence of competing metabolic processes or inhibitory dechlorination intermediate products, is sufficient to alter the Dehalococcoides population structure. These results underscore the importance of electron donor and chloroethene stoichiometry in maintaining balanced functional performance within consortia composed of multiple D. mccartyi subpopulations, even when other competing electron acceptor processes are absent. PMID- 28002947 TI - A Carbocyclic Curcumin Inhibits Proliferation of Gram-Positive Bacteria by Targeting FtsZ. AB - Inhibition of FtsZ assembly has been found to stall bacterial cell division. Here, we report the identification of a potent carbocyclic curcumin analogue (2d) that inhibits Bacillus subtilis 168 cell proliferation by targeting the assembly of FtsZ. 2d also showed potent inhibitory activity (minimum inhibitory concentrations of 2-4 mg/L) against several clinically important species of Gram positive bacteria, including methicillin-resistant Staphylococcus aureus. In addition, 2d displayed a significantly reduced inhibitory effect on human cervical cancer cells in comparison to its effect on bacterial cells. Using live cell imaging of GFP-FtsZ by confocal microscopy, 2d was found to rapidly perturb the cytokinetic FtsZ rings in Bacillus subtilis cells. The immunofluorescence imaging of FtsZ also showed that 2d destroyed the Z-ring in bacteria within 5 min. Prolonged treatment with 2d produced filamentous bacteria, but 2d had no detectable effect either on the nucleoids or on the membrane potential of bacteria. 2d inhibited FtsZ assembly in vitro, whereas it had minimal effects on tubulin assembly. Interestingly, 2d strongly enhanced the GTPase activity of FtsZ and reduced the GTPase activity of tubulin. Furthermore, 2d bound to purified FtsZ with a dissociation constant of 4.0 +/- 1.1 MUM, and the binding of 2d altered the secondary structures of FtsZ. The results together suggested that the non-natural curcumin analogue 2d possesses powerful antibacterial activity against important pathogenic bacteria, and the evidence indicates that 2d inhibits bacterial proliferation by targeting FtsZ. PMID- 28002949 TI - Comprehensive Study of the Effects of Nanopore Structures on Enzyme Activity for the Enzyme Based Electrochemical Biosensors Based on Molecular Simulation. AB - Assembly of biocompatible nanostructures to retain the enzyme activity and improve the biocatalytic ability is a decisive factor for enhancing the performance of enzyme biosensors. However, there is still a lack of molecular level understandings of the physicochemical interaction mechanism at the interface of biosensor electrodes and enzymes. Here, for the first time at molecular level, the effects of two classic biosensor electrode materials with different electrical properties and morphologies and glucose oxidase (GOD) on retaining the enzyme conformation were analyzed by molecular dynamics simulation. First, for the immobilization of GOD, the interfaces of zinc oxide (ZnO) with different electrical properties and 10 nm diameter ZnO nanopore were studied. Then, to simulate the sensing process when electric voltages are applied, positively charged gold planes and 10 nm diameter gold nanopore were investigated as well. The results showed that the nanopore structure was confirmed to be well adapted for the enzyme conformation retaining compared to the plane structure for both ZnO and gold materials, and they almost fit well with the sensitivity measurement results from many previously reported experimental studies. This study also indicates that molecular modeling of the interactions between biomolecules and functional nanostructures is helpful for developing high performance enzyme nanobiosensors. PMID- 28002950 TI - Energetics of Radical Formation in Eumelanin Building Blocks: Implications for Understanding Photoprotection Mechanisms in Eumelanin. AB - The supramolecular structure of melanin pigments is characterized by a high concentration of radical species. Therefore, the energetics of the radical formation in melanin building blocks is key for understanding the structure and the electronic properties of the pigments at the molecular level. Nevertheless, the radical energetics of even the simplest melanin building blocks are largely unknown. In order to address this fundamental issue, the bond dissociation enthalpies (BDEs) for the melanin monomers 5,6-dihydroxy-1H-indole-2-carboxylic acid (DHICA), 1H-indole-5,6-diol (DHI), and 1H-indole-5,6-dione (IQ) were determined through high-accuracy ab initio quantum chemistry methods. Our results provide strong evidence of the importance on BDEs for explaining the experimentally observed dependence of the antioxidant properties of eumelanin pigments on the DHICA/DHI ratio, and the role that these two species play on the photoprotection mechanism. PMID- 28002951 TI - Experimentally Determined Site-Specific Reactivity of the Gas-Phase OH and Cl + i Butanol Reactions Between 251 and 340 K. AB - Product branching ratios for the gas-phase reactions of i-butanol, (CH3)2CHCH2OH, with OH radicals (251, 294, and 340 K) and Cl atoms (294 K) were quantified in an environmental chamber study and used to interpret i-butanol site-specific reactivity. i-Butyraldehyde, acetone, acetaldehyde, and formaldehyde were observed as major stable end products in both reaction systems with carbon mass balance indistinguishable from unity. Product branching ratios for OH oxidation were found to be temperature-dependent with the alpha, beta, and gamma channels changing from 34 +/- 6 to 47 +/- 1%, from 58 +/- 6 to 37 +/- 9%, and from 8 +/- 1 to 16 +/- 4%, respectively, between 251 and 340 K. Recommended temperature dependent site-specific modified Arrhenius expressions for the OH reaction rate coefficient are (cm3 molecule-1 s-1): kalpha(T) = 8.64 * 10-18 * T1.91exp(666/T); kbeta(T) = 5.15 * 10-19 * T2.04exp(1304/T); kgamma(T) = 3.20 * 10-17 * T1.78exp(107/T); kOH(T) = 2.10 * 10-18 * T2exp(-23/T), where kTotal(T) = kalpha(T) + kbeta(T) + kgamma(T) + kOH(T). The expressions were constrained using the product branching ratios measured in this study and previous total phenomenological rate coefficient measurements. The site-specific expressions compare reasonably well with recent theoretical work. It is shown that use of i butanol would result in acetone as the dominant degradation product under most atmospheric conditions. PMID- 28002952 TI - Thermal Isomerization Mechanism in Dronpa and Its Mutants. AB - The photoswitching speed of the reversibly switchable fluorescent proteins (RSFPs) from the family of green fluorescent proteins (GFPs) changes upon mutation which is of direct importance for various high-resolution techniques. Dronpa is one of the most used RSFPs. Its point mutants rsFastLime (Dronpa V157G) and rsKame (Dronpa V157L) exhibit a striking difference in their photoswitching speed. Here the QM/MM on-the-fly string method is used in order to explore the details of the thermal isomerization mechanism. The four principal ways in which isomerization may occur have been scrutinized for each of the three proteins. It has been shown that thermal isomerization occurs via a one-bond-flip mechanism in all three proteins, although, in rsKame, where the chromophore is constrained more, the activation free energy difference between hula-twist and one-bond-flip is significantly smaller. Functional mode analysis has been applied to examine the motions of the amino acids during the isomerization. It clearly identifies the importance of Val/Leu 157 as well as the amino acids in the alpha-helix during the isomerization. PMID- 28002953 TI - Correction to "Isonitrile as an Ultrasensitive Infrared Reporter of Hydrogen Bonding Structure and Dynamics". PMID- 28002954 TI - Engineering the Excited-State Dynamics of 3-Aminoquinoline by Chemical Modification and Temperature Variation. AB - The role of the amino group in the excited-state dynamics of 3-aminoquinoline (3AQ) has been investigated by comparison with its synthetic derivative 3 (piperidin-1-yl)quinoline (3PQ). The absence of amino hydrogen atoms in 3PQ eliminates, to a large extent, the complexity of the excited-state processes observed in 3AQ. The polarity of the medium is found to be the most important determinant in the nonradiative rate constants of 3PQ, unlike in 3AQ where hydrogen bonding plays the most significant role. The nonradiative rate constants decrease with increase in micropolarity. This trend is opposite to what is usually observed with dipolar states. Temperature dependence of the fluorescence spectra and lifetime has been studied to understand this unexpected observation. An unusual redshift in the emission of 3AQ and 3PQ is observed in nonpolar media at low temperatures. This is surprising, as a process involving a barrier is expected to be hindered at low temperatures and be manifested in a blueshift of the spectra, due to the predominance of the locally excited (LE) state. Moreover, the variation of emission maxima of 3AQ with temperature is sigmoidal in nature, indicating the involvement of two distinct states. The counterintuitive observation of the predominance of the state with comparatively lower emission energy, at low temperatures, establishes the following: the photophysics in 3AQ is dominated by a LE state at room temperature in nonpolar media. This state is associated with rapid flip-flop of the amino group, which provides an efficient nonradiative channel of deactivation. At low temperatures, this flip-flop is hindered and the molecule can undergo intramolecular charge transfer (ICT), whereby the lower energy state is populated. In the case of 3PQ, the ICT state is the only one present, owing to the tertiary amino group. PMID- 28002955 TI - Aqueous Hydricity from Calculations of Reduction Potential and Acidity in Water. AB - Hydricity, or hydride donating ability, is a thermodynamic value that helps define the reactivity of transition metal hydrides. To avoid some of the challenges of experimental hydricity measurements in water, a computational method for the determination of aqueous hydricity values has been developed. With a thermochemical cycle involving deprotonation of the metal hydride (pKa), 2e- oxidation of the metal (E degrees ), and 2e- reduction of the proton, hydricity values are provided along with other valuable thermodynamic information. The impact of empirical corrections (for example, calibrating reduction potentials with 2e- organic versus 1e- inorganic potentials) was assessed in the calculation of the reduction potentials, acidities, and hydricities of a series of iridium hydride complexes. Calculated hydricities are consistent with electronic trends and agree well with experimental values. PMID- 28002956 TI - Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells. AB - A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro. PMID- 28002957 TI - Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain. AB - Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a-c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [124/125I]4d and [11C]4e (i.e., [124/125I]11d and [11C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET. PMID- 28002958 TI - Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3 yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia. AB - The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia. PMID- 28002959 TI - Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion. AB - Polymerization of the cytosolic protein actin is critical to cell movement and host cell invasion by the malaria parasite, Plasmodium falciparum. Any disruption to actin polymerization dynamics will render the parasite incapable of invading a host cell and thereby unable to cause infection. Here, we explore the potential of using truncated latrunculins as potential chemotherapeutics for the treatment of malaria. Exploration of the binding interactions of the natural actin inhibitor latrunculins with actin revealed how a truncated core of the inhibitor could retain its key interaction features with actin. This truncated core was synthesized and subjected to preliminary structure-activity relationship studies to generate a focused set of analogues. Biochemical analyses of these analogues demonstrate their 6-fold increased activity compared with that of latrunculin B against P. falciparum and a 16-fold improved selectivity ex vivo. These data establish the latrunculin core as a potential focus for future structure-based drug design of chemotherapeutics against malaria. PMID- 28002960 TI - Characterization of New Cationic N,N-Dimethyl[70]fulleropyrrolidinium Iodide Derivatives as Potent HIV-1 Maturation Inhibitors. AB - HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% of HIV-1 infectivity at low micromolar concentrations. Analysis of the HIV-1 life cycle indicated that these compounds inhibit viral maturation by impairing Gag and Gag-Pol processing. Importantly, fullerene derivatives 2a-c did not inhibit in vitro PR activity and strongly interacted with HIV immature capsid protein in pull-down experiments. Furthermore, these compounds potently blocked infectivity of viruses harboring mutant PR that are resistant to multiple PR inhibitors or mutant Gag proteins that confer resistance to the maturation inhibitor Bevirimat. Collectively, our studies indicate fullerene derivatives 2a c as potent and novel HIV-1 maturation inhibitors. PMID- 28002961 TI - Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors. AB - Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes. PMID- 28002962 TI - Correction to 2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists. PMID- 28002963 TI - Structure-Activity Relationship for Sulfonamide Inhibition of Helicobacter pylori alpha-Carbonic Anhydrase. AB - alpha-Carbonic anhydrase of Helicobacter pylori (HpalphaCA) plays an important role in the acclimation of this oncobacterium to the acidic pH of the stomach. Sulfonamide inhibitors of HpalphaCA possess anti-H. pylori activity. The crystal structures of complexes of HpalphaCA with a family of acetazolamide-related sulfonamides have been determined. Analysis of the structures revealed that the mode of sulfonamide binding correlates well with their inhibitory activities. In addition, comparisons with the corresponding inhibitor complexes of human carbonic anhydrase II (HCAII) indicated that HpalphaCA possesses an additional, alternative binding site for sulfonamides that is not present in HCAII. Furthermore, the hydrophobic pocket in HCAII that stabilizes the apolar moiety of sulfonamide inhibitors is replaced with a more open, hydrophilic pocket in HpalphaCA. Thus, our analysis identified major structural features can be exploited in the design of selective and more potent inhibitors of HpalphaCA that may lead to novel antimicrobials. PMID- 28002964 TI - Asymmetric Hydroboration Approach to the Scalable Synthesis of ((1R,3S)-1-Amino-3 ((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986104) as a Potent S1P1 Receptor Modulator. AB - We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 -> 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay. PMID- 28002965 TI - In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives. AB - Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7, and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high antiparasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent. PMID- 28002966 TI - Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA. AB - Small molecules that bind to RNA potently and specifically are relatively rare. The study of molecules that bind to the HIV-1 transactivation response (TAR) hairpin, a cis-acting HIV genomic element, has long been an important model system for the chemistry of targeting RNA. Here we report the synthesis, biochemical, and structural evaluation of a series of molecules that bind to HIV 1 TAR RNA. A promising analogue, 15, retained the TAR binding affinity of the initial hit and displaced a Tat-derived peptide with an IC50 of 40 MUM. NMR characterization of a soluble analogue, 2, revealed a noncanonical binding mode for this class of compounds. Finally, evaluation of 2 and 15 by selective 2' hydroxyl acylation analyzed by primer extension (SHAPE) indicates specificity in binding to TAR within the context of an in vitro-synthesized 365-nt HIV-1 5' untranslated region (UTR). Thus, these compounds exhibit a novel and specific mode of interaction with TAR, providing important suggestions for RNA ligand design. PMID- 28002967 TI - Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4 hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371.HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity. AB - As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6 dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371.HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value. PMID- 28002968 TI - Insights into the Antimicrobial Activity and Cytotoxicity of Engineered alpha Helical Peptide Amphiphiles. AB - Antimicrobial peptides (AMPs) have gained increasing attention, as they can overcome recurring microbial invasions. However, their poor antimicrobial activity and potential cytotoxicity remain impediments to their clinical applications as novel therapeutic agents. To enhance the antimicrobial activity and cell selectivity of AMPs, a series of amphiphilic peptides based on leucocin A were designed by substituting noncharged hydrophilic residues with arginine and leucine. Of the engineered peptides, peptide 7 (WRL3) (WLRAFRRLVRRLARGLRR-NH2) exhibited the highest cell selectivity toward bacterial cells over erythrocytes and macrophages. Fluorescent measurements and microscopic observations demonstrated that 7 increased cell membrane permeability and disrupted membrane envelope integrity, and eventually led to whole cell lysis. Additionally, flow cytometry analysis and subcellular localization studies revealed that 7 showed potent cytotoxicity against human hepatoma cells HepG2. In summary, the data indicate that these engineered peptides, in particular 7, have enormous promise for antibacterial and/or antitumor therapeutics. PMID- 28002969 TI - Consolidation of molecular testing in clinical virology. AB - INTRODUCTION: The development of quantitative methods for the detection of viral nucleic acids have significantly improved our ability to manage disease progression and to assess the efficacy of antiviral treatment. Moreover, major advances in molecular technologies during the last decade have allowed the identification of new host genetic markers associated with antiviral drug response but have also strongly revolutionized the way we see and perform virus diagnostics in the coming years. Areas covered: In this review, we describe the history and development of virology diagnostic methods, dedicating particular emphasis on the gradual evolution and recent advances toward the introduction of multiparametric platforms for the syndromic diagnosis. In parallel, we outline the consolidation of viral genome quantification practice in different clinical settings. Expert commentary: More rapid, accurate and affordable molecular technology can be predictable with particular emphasis on emerging techniques (next generation sequencing, digital PCR, point of care testing and syndromic diagnosis) to simplify viral diagnosis in the next future. PMID- 28002970 TI - Comparison of medication adherence in diabetes mellitus patients on human versus analogue insulins. AB - : Objetive: This study evaluated the results of treatment adherence scales in two cohorts of patients with diabetes mellitus treated either with human or analogue insulins. METHODS: A cohort study was conducted in diabetes mellitus patients older than 18 that were being treated with human or analogue insulins. Two instruments were applied to each patient [medication possession ratio, Morisky Green test] to evaluate treatment adherence. RESULTS: A total of 238 patients, were included. The majority (69.4%) of the subjects had human insulin and 30.6% had insulin analogue prescriptions. Out of the total, 163 (68.5%) cases were classified as adherent to therapy, according to the type of insulin, as follows: 69.9% for conventional and 65.3% for analogues; without differences between the groups (CI95%:0.450-1.458). The adherence to treatment was more probable in patients with elementary-secondary education (OR:2.341; CI95%:1.199-4.568) and less probable for those in the age range of 31-45 years (OR:0.427; CI95%:0.187 0.971). CONCLUSIONS: The results of this study show that there are no significant statistical differences in adherence when comparing human with analogue insulin therapy. Strategies to improve treatment adherence are particularly important since they improve the clinical results. PMID- 28002971 TI - New and developing therapies for AL amyloidosis. AB - INTRODUCTION: Systemic light-chain (AL) amyloidosis is an infiltrative disorder associated with an underlying plasma cells dyscrasia, in which monoclonal immunoglobulin light chains accumulate in an abnormal misfolded form as amyloid fibrils in the extracellular space. Symptoms and prognosis are governed by which organs are affected, and cardiac involvement is the major determinant of survival. Diagnosis requires demonstration of amyloid deposition and confirmation of the fibril protein type. Areas covered: This review will focus on the available treatments for systemic AL amyloidosis and on new drug targets and therapeutic approaches. Expert opinion: At present, the choice of upfront treatment lies between autologous stem cell transplantation (ASCT) and combination chemotherapy. Chemotherapy agents include dexamethasone, melphalan, cyclophosphamide, thalidomide, bortezomib, lenalidomide, bendamustine in various combinations. Few randomized controlled trials have been performed in AL amyloidosis and treatment has been substantially influenced by clinical practice in myeloma. It has become clear that the best prospects of survival and preservation or improvement in amyloid related organ function require as near complete suppression as possible of the underlying hematological disorder. Future directions include therapies designed to target amyloid deposits directly, in particular anti-amyloid antibodies which are now well advanced in development and are showing great potential. PMID- 28002972 TI - Response to: Drug therapy for ectopic fat: myth or reality? PMID- 28002973 TI - Pomalidomide in multiple myeloma. PMID- 28002974 TI - Proteomics for early prenatal screening of pregnancy complications: a 2017 perspective. PMID- 28002975 TI - Short-term effects of air pollution on hospitalization for acute myocardial infarction: age effect on lag pattern. AB - The aim of the present study is to analyse the age effect on the lag patterns of relative risk of hospitalization for acute myocardial infarction and NO2, PM10 and O3. Daily hospitalizations for AMI during the period 2008-2011 were extracted from administrative data. Analyses were performed using the quasi-Poisson regression model adjusted for seasonality, long-term trend, day of the week and temperature. We observed very different patterns depending on age. For NO2 and PM10, the younger group (25-54 years) shows a more delayed effect in comparison with the two older age groups (55-64 and >= 65 years). Overall, the associations between NO2 and AMI are higher compared to PM10. There are no associations between O3 and AMI. This study indicates that age plays a major role in the lag pattern. Younger people have delayed effects, but they are nevertheless sensitive to air pollution. PMID- 28002976 TI - Exposure to organophosphate (OP) pesticides and health conditions in agricultural and non-agricultural workers from Maule, Chile. AB - The objective was to evaluate the characteristics of exposure to OP pesticides and health status in Chilean farm workers from the Maule Region. An occupational health questionnaire was administered in 207 agricultural and non-agricultural workers. For the group of agricultural workers, we asked about specific occupational exposure history and symptoms of OP pesticide poisoning. The main health problem of the exposed group was previous OP pesticide poisoning (p < 0.001). Fifty-six percent of agricultural workers reported symptoms consistent with acute OP pesticide poisoning. The use of respiratory personal protective equipment and younger age were protective against these symptoms, and number of years of OP pesticide exposure was positively associated with reporting symptoms of poisoning. Of the pesticide applicators 47 % reported using chlorpyrifos. The regulations regarding use and application of pesticides should be strengthened, as should training and intervention with workers to improve the use of personal protective equipment. PMID- 28002977 TI - Prenatal exposure to tobacco smoke leads to increased mitochondrial DNA content in umbilical cord serum associated to reduced gestational age. AB - We investigated if prenatal exposures to tobacco smoke lead to changes in mitochondrial DNA content (mtDNA) in cord serum and adversely affect newborns' health. Umbilical cord serum cotinine levels were used to determine in utero exposure to smoking. Cord serum mtDNA was measured by quantitative polymerase chain reaction analysis of the genes coding for cytochrome c oxidase1 (MT-CO1) and cytochrome c oxidase2 (MT-CO2). Log transformed levels of mtDNA coding for MT CO1 and MT-CO2 were significantly higher among infants of active smokers with higher serum level of cotinine (p < 0.05) and inversely associated with gestational age (p = 0.08; p = 0.02). Structural equation modeling results confirmed a positive association between cotinine and MT-CO1 and2 (p < 0.01) and inverse associations with gestational age (p = 0.02) and IGF-1 (p < 0.01). We identified a dose-dependent increase in the level of MT-CO1 and MT-CO2 associated to increased cord serum cotinine and decreased gestational age. PMID- 28002978 TI - Electromyographic analysis of relevant muscle groups during completion of computer tasks using different computer mouse positions. AB - BACKGROUND: We analyzed muscular activity for different computer mouse positions during the completion of a timed computer task and determined whether the different mouse positions could affect muscular activity, productivity and perceived fatigue. METHODS: The subjects were nine healthy young men. Two mouse positions were studied: the distal position (DP), with the forearm rested on the desk; the proximal position (PP), with only the wrist rested on the desk. The subjects performed a 16-min task in each position. Surface electromyography data were recorded for the upper back and shoulder muscles. Work productivity and muscular activity were measured for each mouse position. A visual analog scale was used to assess subjective fatigue. RESULTS: Muscular activity was higher in muscle (m.) deltoideus (posterior) for the DP, while it was significantly higher in m. inferior infraspinatus for the PP. The visual analog scale score was significantly higher and work productivity was lower in the PP. CONCLUSIONS: We found that using a mouse in the DP rather than the PP leads to less activity of the external rotators, less perceived fatigue and more productivity. This suggests that the DP is preferable to the PP for computer work involving a mouse. PMID- 28002979 TI - Antibiotic stewardship in community-acquired pneumonia. AB - INTRODUCTION: Community-acquired pneumonia (CAP) continues to be associated with significant mortality and morbidity. As with other infectious diseases, in recent years there has been a marked increase in resistance to the antibiotics commonly used against the pathogens that cause CAP. Antimicrobial stewardship denotes coordinated interventions to improve and measure the appropriate use of antibiotics by encouraging the selection of optimal drug regimens. Areas covered: Several elements can be applied to antibiotic stewardship strategies for CAP in order to maintain or improve patient outcomes. In this regard, antibiotic de escalation, duration of antibiotic treatment, adherence to CAP guidelines recommendations about empirical treatment, and switching from intravenous to oral antibiotic therapy may each be relevant in this context. Antimicrobial stewardship strategies, such as prospective audit with intervention and feedback, clinical pathways, and dedicated multidisciplinary teams, that have included some of these elements have demonstrated improvements in antimicrobial use for CAP without negatively affecting clinical outcomes. Expert commentary: Although there are a limited number of randomized clinical studies addressing antimicrobial stewardship strategies in CAP, there is evidence that antibiotic stewardship initiatives can be securely applied, providing benefits to both healthcare systems and patients. PMID- 28002980 TI - Targeting the EGFR T790M mutation in non-small-cell lung cancer. AB - INTRODUCTION: The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation. Areas covered: This review is focused on the implications of tumor heterogeneity for targeting the T790M in patients with NSCLC. Expert opinion: Pre-clinical and clinical data suggest that the T790M is heterogeneously expressed in tumors that become resistant to first- and second-generation EGFR TKIs. These findings have important implications for the molecular diagnostic of the T790M mutation. Indeed, the analysis of both the circulating free tumor DNA (ctDNA) isolated from plasma and the tumor tissue might provide complimentary information to identify patients carrying the T790M mutation. However, further studies are needed to better understand the influence of tumor heterogeneity on the activity of drugs targeting the T790M. PMID- 28002981 TI - Resting-state fMRI data reflects default network activity rather than null data: A defense of commonly employed methods to correct for multiple comparisons. AB - Analysis of functional magnetic resonance imaging (fMRI) data typically involves over one hundred thousand independent statistical tests; therefore, it is necessary to correct for multiple comparisons to control familywise error. In a recent paper, Eklund, Nichols, and Knutsson used resting-state fMRI data to evaluate commonly employed methods to correct for multiple comparisons and reported unacceptable rates of familywise error. Eklund et al.'s analysis was based on the assumption that resting-state fMRI data reflect null data; however, their 'null data' actually reflected default network activity that inflated familywise error. As such, Eklund et al.'s results provide no basis to question the validity of the thousands of published fMRI studies that have corrected for multiple comparisons or the commonly employed methods to correct for multiple comparisons. PMID- 28002982 TI - Dangerous girls and cheating boys: Zulu-speaking disabled young peoples' constructs of heterosexual relationships in Kwazulu-Natal, South Africa. AB - Across South Africa there is a growing body of work that explores gender dynamics in heterosexual relationships between young people aged 15-24 years. This is mainly influenced by the high prevalence of HIV and the incidence of intimate partner violence in this age group. Most studies to date have been based upon non disabled young people, with limited focus on young disabled people. In an attempt to address this gap, this paper describes findings from a study conducted with 22 Zulu-speaking young people with visual and physical disabilities in KwaZulu Natal. Throughout the findings, young disabled participants appeared to downplay their disability with respect to intimate relationships and accentuated the interweaving of complementary and contentious discourses of gender and cultural identity. Taking cognisance of the intersectionality of gender and cultural discourses, the paper extend constructs of disabled sexualities beyond an exclusive gaze on disability in the South African context. PMID- 28002984 TI - Corrigendum. PMID- 28002983 TI - The more you lose the more you miss: accuracy of postpartum blood loss visual estimation. A systematic review of the literature. AB - Midwives and nurses have a key role in monitoring postpartum period. They represent the first line professional figure in quantifying blood loss, initiating early diagnosis of obstetric hemorrhage, and mobilizing a team response, if needed. These actions are crucial in determining maternal outcome in postpartum hemorrhage (PPH). In our review we aimed to: (1) Provide a picture of PPH including its pathophysiology, epidemiology, and associated complications; (2) Discuss diagnosis of this dangerous postpartum event; and, (3) Especially evaluate the efficiency of the employment of visual blood loss estimation as a rapid way to suspect PPH and activate the patient assessment. PMID- 28002985 TI - On the malleability of the meaning of contexts: the influence of another person's emotion expressions on situation perception. AB - Research on the relationship between context and facial expressions generally assumes a unidirectional effect of context on expressions. However, according to the model of the meaning of emotion expressions in context (MEEC) the effect should be bidirectional. The present research tested the effect of emotion expression on the interpretation of scenes. A total of 380 participants either (a) rated facial expressions with regard to the likely appraisal of the eliciting situation by the emoter, (b) appraised the scenes alone or (c) appraised scenes shown together with the expressions they supposedly elicited. The findings strongly supported the MEEC. When a scene was combined with an expression signalling a situation that is undesirable, or high in locus of control or sudden, the participants appraised the scene correspondingly. Thus, the meaning of scenes is malleable and affected by the way that people are seen to react to them. PMID- 28002986 TI - Evaluating the effects of copper supplement during pregnancy on premature rupture of membranes and pregnancy outcome. AB - OBJECTIVE: To evaluate the effects of copper (Cu) supplementation during pregnancy on the rupture of membranes and pregnancy outcomes. METHODS: Study was conducted as a triple-blind randomized clinical trial. In one group, Cu in a dose of 1000 mg per day, and in the other group, placebo was prescribed orally from 16th week of pregnancy. RESULTS: The women of the two groups did not have significant difference according to age, gestational age at recruitment, BMI, and socioeconomic conditions. There was no statistically significant difference between case and control group regarding the incidence of PPROM, PROM, preterm labor, vaginal bleeding during pregnancy, preeclampsia, and the incidence of placenta abruption. There was a 75% and 90% decrease in depressive symptoms in 2nd trimester and 3rd trimester in supplemented group, respectively. Also, there was a 45% and 80% decrease in anxiety symptoms in 2nd trimester and 3rd trimester in the supplemented group, respectively The rate of infection during pregnancy was significantly higher in control group (p = 0.046). There was no difference between the two groups according to neonatal outcomes. CONCLUSIONS: Cu supplementation during pregnancy could not influence positively on ROM; however, it could improve some mood status of the women. PMID- 28002987 TI - Decision making under uncertainty in a spiking neural network model of the basal ganglia. AB - The mechanisms of decision-making and action selection are generally thought to be under the control of parallel cortico-subcortical loops connecting back to distinct areas of cortex through the basal ganglia and processing motor, cognitive and limbic modalities of decision-making. We have used these properties to develop and extend a connectionist model at a spiking neuron level based on a previous rate model approach. This model is demonstrated on decision-making tasks that have been studied in primates and the electrophysiology interpreted to show that the decision is made in two steps. To model this, we have used two parallel loops, each of which performs decision-making based on interactions between positive and negative feedback pathways. This model is able to perform two-level decision-making as in primates. We show here that, before learning, synaptic noise is sufficient to drive the decision-making process and that, after learning, the decision is based on the choice that has proven most likely to be rewarded. The model is then submitted to lesion tests, reversal learning and extinction protocols. We show that, under these conditions, it behaves in a consistent manner and provides predictions in accordance with observed experimental data. PMID- 28002988 TI - The Suicide Narrative Interview: adolescents' attachment expectancies and symptom severity in a clinical sample. AB - Insecure attachment styles have consistently been identified as risk factors for adolescent psychopathology and, more specifically, suicidal ideation. However, much less is known about the mechanisms that account for the relationship between attachment styles and severity of suicidal ideation within clinical samples. In the current study, adolescents' expectancies for caregiver availability and responsiveness were coded from transcripts of the Suicide Narrative Interview in a clinical sample of 129 depressed and suicidal adolescents. Results indicated that negative expectancies for caregiver availability in the Suicide Narrative Interview were associated both with attachment insecurity and with the intensity of adolescents' suicidal ideation. The implications of adolescents' expectancies for caregiver availability as targets for clinical intervention are discussed. PMID- 28002989 TI - Fine-needle aspiration cytology (FNAC): is it useful in preoperative diagnosis of parotid gland lesions? AB - BACKGROUND: Salivary gland tumors are an uncommon entity and its histopathology is highly varied due to heterogeneous cellular composition. The role of the preoperative fine-needle aspiration cytology (FNAC) remains controversial. The purpose of this study is to compare the cytologic findings of salivary gland lesions with the histologic diagnoses, in order to assess the usefulness and accuracy of fine-needle aspiration cytology in the diagnosis of parotid gland tumors. METHODS: A retrospective study was performed, regarding patients (n = 65) submitted to surgery for the treatment of parotid gland disease, who had performed preoperative FNAC, in our department between 2002 and 2012. A histologic diagnosis was considered as the gold standard for the assessment of sensitivity and specificity of FNAC. A cytohistologic correlation was done and appropriate statistical tests were applied. RESULTS: Concordance between FNAC and histological specimen analysis was 78%. FNAC specificity was 82% and sensitivity was 71%. Positive and negative predictive values were 65% and 86% and positive likelihood ratio and negative likelihood ratio were 3.92 and 0.35, respectively. The diagnostic accuracy for this test was 78%. CONCLUSION: Preoperative FNAC of parotid lesions is reasonably accurate and useful in diagnosing benign from malignant lesions and in planning appropriate approach for treatment. PMID- 28002990 TI - Translation and validation of the Perinatal Grief Scale in a sample of Greek women with perinatal loss during the 1st and 2nd trimester of pregnancy. AB - OBJECTIVE: To translate and validate the Perinatal Grief Scale (PGS) (short version) in a sample of Greek women with perinatal loss during the first and second trimester of pregnancy. METHODS: One hundred seventy-six women were approached a few hours after the loss. Along with the PGS, three more questionnaires were completed: the Edinburgh Postnatal Depression Scale (EPDS), the Hospital Anxiety and Depression Scale (HADS) and the State-Trait Anxiety Inventory (STAI), in order to assess the convergent validity of the PGS. RESULTS: Total sample mean age was 34.1 years (SD = 5.2). Mean values and Cronbach's alpha coefficients for PGS subscales exceeded the minimum reliability standard of 0.70. Mean score for "Active grief" was 31.47 (SD = 9.31), for "Difficulty Coping" was 23.13 (SD = 7.54) and for "Despair" was 21.07 (SD = 7.07). By applying Pearson's correlation coefficients, PGS subscales positively correlated with scores on EPDS, STAI and HADS. CONCLUSIONS: The PGS Greek version is a reliable instrument in terms of internal consistency and the Cronbach's alpha coefficients are high. The Greek version of PGS can be a useful instrument for the detection of the psychological impact after a perinatal loss and it has implications for both scientific research and clinical routine. PMID- 28002991 TI - Intraindividual reaction time variability predicts prospective memory failures in older adults. AB - This study investigated the relationship between intraindividual variability (IIV) in reaction time and prospective memory errors in older adults using data from the Zurich Longitudinal Study of Cognitive Aging (n = 336 individuals aged 66-81 years). The results indicated that increased IIV measured from independent tasks was associated with a greater proportion of prospective memory errors. These significant findings were not influenced by age and did not vary according to prospective memory cue type. Variability is thought to reflect fluctuations in attentional and executive control and these attentional processes may also impact on prospective memory through failure to detect the target cue. The findings suggest, therefore, that measures of variability may have some potential in the identification of older persons who are more vulnerable to everyday errors such as prospective memory failures. PMID- 28002993 TI - Epigenetics, Bone Remodeling and Osteoporosis. AB - Epigenetic regulation, including modifications of DNA, histone proteins and non coding RNAs, play an important role in the regulation of gene expression and keep the heritable traits of progeny cells without changing DNA sequence. Recent years, epigenetic regulation of bone homeostasis are widely investigated and considered as a vital factor during the differentiation and function of osteoblasts, osteoclasts and osteocytes. Osteoporosis is a common degenerative bone disease which is characterized with decreased bone strength and increased risk of fracture. It has been testified that the abnormal bone metabolism homeostasis, especially in osteoclast function, take a fundamental role in osteoporosis pathogenesis. The reports between osteoporosis and epigenetic regulations are also increased gradually in recent years. In this review, we summarize the current developments of epigenetic regulation mechanism in bone development and remodeling, and emphasize the epigenetic features of osteoporosis and the potent therapy application of epigenetic drugs for osteoporosis. PMID- 28002994 TI - Implementation of the Prevention of Mother-to-Child Transmission (PMTCT) Program in the Northern Cape, South Africa. AB - BACKGROUND: South Africa's Prevention of Mother-to-Child Transmission (PMTCT) of Human Immunodeficiency Virus (HIV) program has been implemented for over ten years. This has led to a considerable reduction in mother-to-child transmissions. In 2010, the Northern Cape Province had a 1.4% transmission rate, being the lowest in the country. OBJECTIVE: To describe the implementation of the PMTCT program in the Frances Baard district, Northern Cape Province; South Africa and identify factors that may influence the effectiveness of this program. METHOD: 100 Mother-child pairs from four clinics participated in this cross-sectional study. Information was collected on socio demographics, antenatal clinic attendance, feeding counseling, knowledge and practices, CD4 cell count and HIV stage, antiretroviral treatment (ART) initiation/adherence and partner involvement. RESULTS: Almost 25% of mothers first attended an antenatal clinic during their third trimester, out of them, 52.2% were tested for HIV infection for the first time. Most of the mothers received counseling on feeding practices during antenatal visits (97%), after labor (64%) and during post natal visits (84%). Most mothers knew the definition (77%) and recommended duration (76%) of exclusive breastfeeding and the dangers of defaulting ART when breastfeeding (75%), but only two mothers knew the risk of mixed feeding. Fifteen mothers were pressured to stop breastfeeding by healthcare professionals before 12 months. More than half (52%) of the mothers started ART during their last pregnancy, among them, 50% only started treatment after 14 weeks of gestation. The children who received ART, 13.7% defaulted their treatment for one day or more. All three HIV infected children's mothers defaulted their own ART while breastfeeding. CONCLUSION: The PMTCT program is implemented according to the national policy in this district. Earlier ART initiation and improved compliance, education of healthcare workers, more focused counseling sessions and improving community awareness of early antenatal visits may improve effectiveness of this program. PMID- 28002999 TI - Targeting Leptin as a Therapeutic Strategy against Ovarian Cancer Peritoneal Metastasis. AB - BACKGROUND/AIMS: Epithelial ovarian cancer (OC) is the leading cause of death in patients with gynecologic malignancy. Malignant ascites, a shared symptom of advanced OC patients, plays an important role in the peritoneal metastasis cascade of OC. Since leptin existed in great amount in malignant ascites, we speculated that it might be involved in the modulation of tumor cells malignant behavior. METHOD: Here, we demonstrated that blocking of leptin could significantly suppress ovarian malignant ascitesinduced metastatic aggravation of OC cells. Furthermore, our results suggested that leptin was highly expressed in OC and correlated with poor outcome of OC patients. Recombinant leptin notably promoted the migration, invasion and proliferation of OC cells. RESULT: Mechanistically, we found that leptin induced epithelial-mesenchymal transition (EMT) program in OC cells through the activation of the PI3K/Akt/mTOR pathway. Pharmacological inhibition of the PI3K/Akt/mTOR pathway partly impaired leptin induced malignant transformation of OC cells. More importantly, our in vivo xenograft experiment showed that blocking of leptin could dramatically inhibit OC cells peritoneal dissemination. CONCLUSION: Collectively, this study emphasized the importance of leptin in OC progression and illustrated a novel mechanism that the PI3K/Akt/mTOR pathway was involved in leptin-induced EMT. Our findings provide new insights into leptin exertion on OC metastasis and identify the potential of leptin neutralizing as a novel strategy against OC peritoneal dissemination. PMID- 28003000 TI - Double Edge Sword Behavior of Carbendazim: A Potent Fungicide With Anticancer Therapeutic Properties. AB - BACKGROUND: A number of benzimidazole derivatives such as benomyl and carbendazim have been known for their potential role as agricultural fungicides. Simultaneously carbendazim has also been found to inhibit proliferation of mammalian tumor cells specifically drug and multidrug resistant cell lines. OBJECTIVE: To understand the dual role of Carbendazim as a fungicide and an anticancer agent, the study has been planned referring to the earlier studies in literature. RESULTS: Studies carried out with fungal and mammalian cells have highlighted the potential role of carbendazim in inhibiting proliferation of cells, thereby exhibiting therapeutic implications against cancer. Because of its promising preclinical antitumor activity, Carbendazim had undergone phase I clinical trials and is under further clinical investigations for the treatment of cancer. A number of theoretical interactions have been pinpointed. There are many anticancer drugs in the market, but their usefulness is limited because of drug resistance in a significant proportion of patients. The hunger for newer drugs drives anticancer drug discovery research on a global platform and requires innovations to ensure a sustainable pipeline of lead compounds. CONCLUSION: Current review highlights the dual role of carbendazim as a fungicide and an anticancer agent. Further, the harmful effects of carbendazim and emphasis upon the need for more pharmacokinetic studies and pharmacovigilance data to ascertain its clinical significance, have also been discussed. PMID- 28003001 TI - Molecular, Cellular and Pharmaceutical Aspects of Bone Grafting Materials and Membranes During Maxillary Sinus-lift Procedures. Part 1: A General Overview. AB - Sinus augmentation procedure has been demonstrated to be a highly predictable treatment in posterior maxilla atrophy. All the surgical interventions in the maxillary region require deep knowledge of anatomy and possible anatomical variations. In this article, pre-operative and post- operative assessments of sinus cavity as well as novel approaches to deepen our knowledge of the behavior of bone substitute materials are described. The awareness of the patient's morphologic conditions enables exact planning of invasive surgery and aids to avoid complications. Pre- operative radiologic evaluation of the region before sinus lift is advisable both for a planning of the sinus augmentation and for selection and alignment of the optimum placement of implants. On the orthopantomography it is possible to measure the vertical dimension of graft, but not the volume and 3D changes. Cone-beam computed tomography (CBCT) has become the "gold standard" to plan a comprehensive implant treatment and to achieve a post-operative assessment. A computer-aided design/computer-aided manufacturing (CAD/CAM) technique is proposed to produce custom-made block grafts for sinus lift procedure, and a customized cutting guide to accurately place the lateral wall and ease membrane elevation. This procedure allows to reduce intervention time, to precisely adapt the scaffold, to reduce risk of complications and to improve operation quality. Recently, a novel approach has been used to deepen our knowledge of the behavior of BSBs: by means of synchrotron micro-tomography (SCT). It is a 3-D analyzing method, suitable to examine the dynamic and spatial arrangement of regenerative phenomena in complex anatomical structures such as bone, where tissues with several morphologies (alveolar process, unmineralized extracellular matrix, regenerated vessels, etc.) compete to achieve the final goal of bone regeneration. PMID- 28003002 TI - Impact of Different Implant Surfaces Topographies on Peri-Implant Tissues: An Update of Current Available Data on Dental Implants Retrieved from Human Jaws. AB - The high success range obtained with the implant-supported restorations has improved its applicability on routine of the daily clinical practice. This elevated percentage of success is related to the previous pre-clinical data obtained from animal and in vitro studies that evaluated the impact of implant surface topographies on bone tissue. However, the histological evaluation of human bone tissue is scarce. Therefore, the aim of this review is to depict an actual panorama of the data available on boneto- implant contact (BIC) of retrieved implants from human jaws. Some aspects of implant surface topography as well as systemic conditions as osteoporosis and smoking habit were demonstrated to have a strong impact, suggesting that the data obtained from human bone tissue is still valuable for the better understanding of the osseointegration process. This article also highlighted that most data in humans are difficult to interpret, due to the lack of detailed information about the surfaces found in retrieved implants. Without the definition of the surface characteristics, it is difficult to link exactly the surface patterns to specific clinical observations, and all observations remain de facto incomplete. As a conclusion, data from implants retrieved from human jaws are very important for our understanding, however the studies remain scarce and data is fragmented. This important approach should be improved, completed and developed in the future. PMID- 28003004 TI - Defense Against Pathogens: Structural Insights into the Mechanism of Chitin Induced Activation of Innate Immunity. AB - Pattern recognition receptors on the plant cell surface mediate the recognition of microbe-associated molecular patterns, in a process which activates downstream immune signaling. These receptors are plasma membrane-localized kinases which need to be autophosphorylated to activate downstream responses. Perception of attacks from fungi occurs through recognition of chitin, a polymer of an N acetylglucosamine which is a characteristic component of the cell walls of fungi. This process is regulated in Arabidopsis by chitin elicitor receptor kinase CERK1. A more complex process characterizes rice, in which regulation of chitin perception is operated by a complex composed of OsCERK1, a homolog of CERK1, and the chitin elicitor binding protein OsCEBiP. Recent literature has provided a mechanistic description of the complex regulation of activation of innate immunity in rice and an advance in the structural description of molecular players involved in this process. This review describes the current status of the understanding of molecular events involved in innate immunity activation in rice. PMID- 28003005 TI - Targeting Cysteine Proteases from Plasmodium falciparum: A General Overview, Rational Drug Design and Computational Approaches for Drug Discovery. AB - BACKGROUND: The Plasmodium falciparum cysteine proteases, also known as falcipains, are involved in different erythrocytic cycle processes of the malaria parasite, e.g. hydrolysis of host haemoglobin, erythrocyte invasion, and erythrocyte rupture. With the biochemical characterization of four falcipains so far, FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases. They could therefore be referred to as potential anti-malarial drug targets in the search for novel therapies, which could ease the burden caused by the increasing resistance to current antimalarial drugs. OBJECTIVES: This review provides a summary of the most important results, highlighting the drug design approaches essential for the understanding of the mechanism of inhibition and discovery of inhibitors against cysteine proteases from P. falciparum. RESULTS: Rational and computer-aided drug discovery approaches for the design of promising falcipain inhibitors are described herein, with a focus on a variety of structure-based and ligand-based modeling approaches. Moreover, the key features of ligand recognition against these targets are emphasized. CONCLUSION: This review would be of interest to scientists engaged in the development of drug design strategies to target the cysteine proteases, FP-2 and FP-3. PMID- 28003007 TI - ICP-MS: Analytical Method for Identification and Detection of Elemental Impurities. AB - Aim of this article is to review and discuss the currently used quantitative analytical method ICP-MS, which is used for quality control of pharmaceutical products. ICP-MS technique has several applications such as determination of single elements, multi element analysis in synthetic drugs, heavy metals in environmental water, trace element content of selected fertilizers and dairy manures. ICP-MS is also used for determination of toxic and essential elements in different varieties of food samples and metal pollutant present in the environment. The pharmaceuticals may generate impurities at various stages of development, transportation and storage which make them risky to be administered. Thus, it is essential that these impurities must be detected and quantified. ICP MS plays an important function in the recognition and revealing of elemental impurities. PMID- 28003008 TI - Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP 1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues. PMID- 28003009 TI - Hot Topics in Dry AMD. AB - BACKGROUND: The global prevalence of AMD is projected to be 196 million by the year 2020. Despite substantial progress in the development of new therapies for wet AMD using inhibition of vascular endothelial growth factor (VEGF), the severe visual impairment associated with geographic atrophy in dry AMD remains untreatable. A number of therapeutic options for dry AMD are being developed and are in various stages of clinical trials. METHODS: Review of literature. RESULTS: Enhancers of choroidal blood flow, neuroprotectants and anti-complement factors are the key targets in the research for the treatment of dry AMD. These molecules aim to promote the function of the retinal pigment epithelium and preserve the photoreceptors. CONCLUSION: New molecules are being developed for the treatment of dry AMD, and anti-complement therapy appears to be the most promising among them. PMID- 28003010 TI - Endothelial Progenitor Cells as a Therapeutic Approach for Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, a leading cause of death and disability in developed countries. Therapeutic options are notably limited. There is no specific pharmacological treatment, and early surgery has few indications that represent only a small clinically relevant survival advantage. It is therefore mandatory to investigate repairing processes after ICH in order to develop related therapeutic strategies. METHODS: The goal of this review is to discuss the current status of knowledge about the potential therapeutic role of endothelial progenitor cells (EPCs) in ICH, as well as the possible molecular mechanisms and future perspectives. RESULTS: ICH is characterized by a primary vascular rupture, followed by a secondary vascular tearing due to the peripheral pressure exerted by the hematoma. Hypoperfusion may also play a role, although not as markedly as in ischemic stroke. In this context, the repairing of damaged vessels and the development of new ones seem logical therapeutic targets. Circulating EPCs have been suggested to play a major role in re-endothelization, angiogenesis and vasculogenesis. Congruently, EPC levels have been associated with good neurological and functional outcome as well as with reduced residual volume in patients with acute ICH. CONCLUSION: An EPC based therapy, acting primarily through angiogenic mechanisms, may be a valid therapeutic option in ICH. PMID- 28003011 TI - Targeting the Brain with Nanomedicine. AB - Herein, we review innovative nanomedicine-based approaches for treating, preventing and diagnosing neurodegenerative diseases. We focus on nanoscale systems such as polymeric nanoparticles (NPs), liposomes, micelles and other vehicles (e.g. dendrimers, nanogels, nanoemulsions and nanosuspensions) for targeted delivery of bioactive molecules to the brain. To ensure maximum selectivity for optimal therapeutic or diagnostic results, researchers must employ delivery systems that are non-toxic, biodegradable and biocompatible. This entails: (i) use of "safe" materials, such as polymers or lipids; (ii) targeting to the brain and, specifically, to the desired active site within the brain; (iii) controlled release of the loaded agent; and (iv) use of agents that, once released into the brain, will exhibit the desired pharmacologic activity. Here, we explore the design and preclinical use of representative delivery systems that have been proposed to date. We then analyze the principal challenges that have delayed clinical application of these and other approaches. Lastly, we look at future developments in this area, addressing the needs for increased penetration of the blood brain barrier (BBB), enhanced targeting of specific brain sites, improved therapeutic efficacy and lower neurotoxicity. PMID- 28003012 TI - The Potential of Nano-Vehicle Mediated Therapy in Vasculitis and Multiple Sclerosis. AB - The induction of immune tolerance towards self-antigens presents as a viable future strategy in the treatment of auto-immune diseases, including vasculitis and multiple sclerosis (MS). As specific targets are currently lacking for vasculitis due to incomplete understanding of the pathologies underlying this disease, current treatment options are based on modalities that induce general immune suppression. However, many immune suppressants used in the clinic are known to display wide biodistribution and are thus often accompanied by several adverse effects. Nano-vehicles (NVs) possess the ability to overcome such limitations by enabling more specific delivery of their content through modifications with targeting moieties. In this review, we describe the latest insights in the pathology of vasculitis that may function as potential targets for NV carrier systems, allowing more specific delivery of currently used immune suppressants. In addition, we describe the existing strategies to induce artificial immune tolerance and explore the feasibility of inducing regulatory T cell (Treg) mediated tolerance for MS, possibly mediated by NVs. PMID- 28003013 TI - Oral Antiplatelet and Anticoagulant Agents in the Prevention and Management of Ischemic Stroke. AB - Despite numerous advances over the last 50 years, stroke continues to be a leading cause of death and disability worldwide. The treatment and prevention of stroke has undergone extensive study, and significant advances in medical management have occurred within the past decade principally with the development of new classes of orally active anticoagulant drugs. Here we review these recent breakthroughs and the varying roles of anticoagulants and antiplatelet agents in the prevention and management of different ischemic stroke subtypes, as well as describe the benefits and ongoing challenges to incorporating the novel oral anticoagulants (NOACs) into clinical management guidelines. Current guidelines recommend (a) administration of the antiplatelet agent aspirin in the acute management of ischemic stroke, (b) antiplatelet therapy - aspirin, clopidogrel, dypiridamole - in the secondary prevention of noncardioembolic (large artery atherosclerosis) ischemic stroke, and (c) anticoagulants - warfarin and the NOACs - in the secondary prevention of cardioembolic (atrial fibrillation related) ischemic stroke. In phase III clinical trials of the NOACs, dabigatran 150mg BID and apixaban 5mg BID were superior to warfarin in the prevention of stroke/systemic embolism while rivaroxaban 20mg QD demonstrated noninferiority. Both dabigatran and rivaroxaban had similar rates of major bleeding as warfarin but apixaban showed significantly reduced incidence of this complication. As application of novel anticoagulant agents increases, with concomitant study in a variety of clinical settings; their promise in reducing the incidence of stroke, as well as that of therapeutic complications related to warfarin, should be further elaborated. PMID- 28003014 TI - Antiplatelet and Anticoagulation Therapy in Structural Heart Disease Interventions Beyond TAVI. AB - Transcatheter interventions for structural heart disease represent an emerging field in interventional cardiology. Undoubtedly, there is an absolute necessity for antiplatelet and/or anticoagulation treatment prior, during and post such interventions. However, currently administered regimens are mainly based in expert consensus recommendations. In the present review we aim to summarize data regarding anti platelet and/or anticoagulation treatment in the following transcatheter structural heart interventions: left atrial appendage closure, atrial septal defect closure, patent foramen oval closure, paravalvular leak closure. PMID- 28003015 TI - Do physical activity interventions in Indigenous people in Australia and New Zealand improve activity levels and health outcomes? A systematic review. AB - BACKGROUND: Indigenous Australians and New Zealanders have a significantly shorter life expectancy than non-Indigenous people, mainly due to differences in prevalence of chronic diseases. Physical activity helps in the prevention and management of chronic diseases, however, activity levels are lower in Indigenous than in non-Indigenous people. OBJECTIVE: To synthesise the literature on the effects of physical activity interventions for Indigenous people in Australia and New Zealand on activity levels and health outcomes. METHODS: The Cochrane Library, MEDLINE, SPORTSDiscus and PsycINFO were searched for peer-reviewed articles and grey literature was searched. Interventions targeted Indigenous people in Australia or New Zealand aged 18+ years and their primary or secondary aim was to increase activity levels. Data were extracted by one author and verified by another. Risk of bias was assessed independently by two authors. Data were synthesised narratively. RESULTS: 407 records were screened and 13 studies included. Interventions included individual and group based exercise programs and community lifestyle interventions of four weeks to two years. Six studies assessed physical activity via subjective (n = 4) or objective (n = 2) measures, with significant improvements in one study. Weight and BMI were assessed in all but one study, with significant reductions reported in seven of 12 studies. All five studies that used fitness tests reported improvements, as did four out of eight measuring blood pressure and seven out of nine in clinical markers. CONCLUSIONS: There was no clear evidence for an effect of physical activity interventions on activity levels, however, there were positive effects on activity related fitness and health outcomes. TRIAL REGISTRATION: The review protocol was registered with PROSPERO (registration number: CRD42015016915 ). PMID- 28003016 TI - Stochastic modelling of infectious diseases for heterogeneous populations. AB - BACKGROUND: Infectious diseases such as SARS and H1N1 can significantly impact people's lives and cause severe social and economic damages. Recent outbreaks have stressed the urgency of effective research on the dynamics of infectious disease spread. However, it is difficult to predict when and where outbreaks may emerge and how infectious diseases spread because many factors affect their transmission, and some of them may be unknown. METHODS: One feasible means to promptly detect an outbreak and track the progress of disease spread is to implement surveillance systems in regional or national health and medical centres. The accumulated surveillance data, including temporal, spatial, clinical, and demographic information can provide valuable information that can be exploited to better understand and model the dynamics of infectious disease spread. The aim of this work is to develop and empirically evaluate a stochastic model that allows the investigation of transmission patterns of infectious diseases in heterogeneous populations. RESULTS: We test the proposed model on simulation data and apply it to the surveillance data from the 2009 H1N1 pandemic in Hong Kong. In the simulation experiment, our model achieves high accuracy in parameter estimation (less than 10.0 % mean absolute percentage error). In terms of the forward prediction of case incidence, the mean absolute percentage errors are 17.3 % for the simulation experiment and 20.0 % for the experiment on the real surveillance data. CONCLUSION: We propose a stochastic model to study the dynamics of infectious disease spread in heterogeneous populations from temporal spatial surveillance data. The proposed model is evaluated using both simulated data and the real data from the 2009 H1N1 epidemic in Hong Kong and achieves acceptable prediction accuracy. We believe that our model can provide valuable insights for public health authorities to predict the effect of disease spread and analyse its underlying factors and to guide new control efforts. PMID- 28003018 TI - Prostatic urethra malformation associated with retrograde ejaculation: a case report. AB - BACKGROUND: Retrograde ejaculation can have anatomical, neurogenic, or pharmacological causes. Among these factors, malformation of the prostatic urethra is an uncommon cause. CASE PRESENTATION: We describe a 29-year-old Han Chinese man with absence of his verumontanum combined with ejaculatory duct cysts, and no other cause for ejaculatory dysfunction. His verumontanum was replaced by a deep groove adjacent to his bladder neck, which could significantly influence bladder neck contraction. In addition, the large cysts in the ejaculatory duct could obstruct the anterior outlet of his prostatic urethra and prevent seminal fluid flow in an anterograde direction. There are few reports of retrograde ejaculation associated with congenital malformations of the posterior urethra. Malformations associated with bladder neck laxity and increased tone of the prostatic urethral outlet can contribute to retrograde ejaculation. CONCLUSIONS: Malformation of the prostatic urethra is an uncommon cause of retrograde ejaculation, and can be difficult to treat. PMID- 28003017 TI - Potential immunosuppressive effects of Escherichia coli O157:H7 experimental infection on the bovine host. AB - BACKGROUND: Enterohaemorrhagic Escherichia coli (EHEC), like E. coli O157:H7 are frequently detected in bovine faecal samples at slaughter. Cattle do not show clinical symptoms upon infection, but for humans the consequences after consuming contaminated beef can be severe. The immune response against EHEC in cattle cannot always clear the infection as persistent colonization and shedding in infected animals over a period of months often occurs. In previous infection trials, we observed a primary immune response after infection which was unable to protect cattle from re-infection. These results may reflect a suppression of certain immune pathways, making cattle more prone to persistent colonization after re-infection. To test this, RNA-Seq was used for transcriptome analysis of recto-anal junction tissue and ileal Peyer's patches in nine Holstein-Friesian calves in response to a primary and secondary Escherichia coli O157:H7 infection with the Shiga toxin (Stx) negative NCTC12900 strain. Non-infected calves served as controls. RESULTS: In tissue of the recto-anal junction, only 15 genes were found to be significantly affected by a first infection compared to 1159 genes in the ileal Peyer's patches. Whereas, re-infection significantly changed the expression of 10 and 17 genes in the recto-anal junction tissue and the Peyer's patches, respectively. A significant downregulation of 69 immunostimulatory genes and a significant upregulation of seven immune suppressing genes was observed. CONCLUSIONS: Although the recto-anal junction is a major site of colonization, this area does not seem to be modulated upon infection to the same extent as ileal Peyer's patches as the changes in gene expression were remarkably higher in the ileal Peyer's patches than in the recto-anal junction during a primary but not a secondary infection. We can conclude that the main effect on the transcriptome was immunosuppression by E. coli O157:H7 (Stx-) due to an upregulation of immune suppressive effects (7/12 genes) or a downregulation of immunostimulatory effects (69/94 genes) in the ileal Peyer's patches. These data might indicate that a primary infection promotes a re-infection with EHEC by suppressing the immune function. PMID- 28003019 TI - Agonists and knockdown of estrogen receptor beta differentially affect invasion of triple-negative breast cancer cells in vitro. AB - BACKGROUND: Estrogen receptor beta (ERbeta) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple negative breast cancer (TNBC). Thus, ERbeta might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ERbeta in invasion of two triple-negative breast cancer cell lines. METHODS: MDA-MB-231 and HS578T breast cancer cells were treated with the specific ERbeta agonists ERB-041, WAY200070, Liquiritigenin and 3beta-Adiol. Knockdown of ERbeta expression was performed by means of siRNA transfection. Effects on cellular invasion were assessed in vitro by means of a modified Boyden chamber assay. Transcriptome analyses were performed using Affymetrix Human Gene 1.0 ST microarrays. Pathway and gene network analyses were performed by means of Genomatix and Ingenuity Pathway Analysis software. RESULTS: Invasiveness of MBA MB-231 and HS578T breast cancer cells decreased after treatment with ERbeta agonists ERB-041 and WAY200070. Agonists Liquiritigenin and 3beta-Adiol only reduced invasion of MDA-MB-231 cells. Knockdown of ERbeta expression increased invasiveness of MDA-MB-231 cells about 3-fold. Transcriptome and pathway analyses revealed that ERbeta knockdown led to activation of TGFbeta signalling and induced expression of a network of genes with functions in extracellular matrix, tumor cell invasion and vitamin D3 metabolism. CONCLUSIONS: Our data suggest that ERbeta suppresses invasiveness of triple-negative breast cancer cells in vitro. Whether ERbeta agonists might be useful drugs in the treatment of triple-negative breast cancer, has to be evaluated in further animal and clinical studies. PMID- 28003020 TI - Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer Rokitansky-Kuster-Hauser syndrome in co-occurrence: two case reports and a review of the literature. AB - BACKGROUND: The vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer Rokitansky-Kuster-Hauser syndrome are rare conditions. We aimed to present two cases with the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer Rokitansky-Kuster-Hauser co-occurrence from our local surgical center and through a systematic literature search detect published cases. Furthermore, we aimed to collect existing knowledge in the embryopathogenesis and genetics in order to discuss a possible link between the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Kuster-Hauser syndrome. CASE PRESENTATION: Our first case was a white girl delivered by caesarean section at 37 weeks of gestation; our second case was a white girl born at a gestational age of 40 weeks. A co-occurrence of vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Kuster-Hauser syndrome was diagnosed in both cases. We performed a systematic literature search in PubMed ((VACTERL) OR (VATER)) AND ((MRKH) OR (Mayer-Rokitansky-Kuster-Hauser) OR (mullerian agenesis) OR (mullerian aplasia) OR (MURCS)) without limitations. A similar search was performed in Embase and the Cochrane library. We added two cases from our local center. All cases (n = 9) presented with anal atresia and renal defect. Vertebral defects were present in eight patients. Rectovestibular fistula was confirmed in seven patients. Along with the uterovaginal agenesis, fallopian tube aplasia appeared in five of nine cases and in two cases ovarian involvement also existed. CONCLUSIONS: The co-occurrence of the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Kuster-Hauser syndrome is extremely rare. This group of patients has unusual phenotypic characteristics. The long-term outcome after treatment of defects is not well reported. A single unifying cause is not known and the etiology probably includes both genetic and non-genetic causes. We stress the importance of future studies to optimized treatment, follow up, and etiology. PMID- 28003021 TI - Smoking influences the need for surgery in patients with the inflammatory bowel diseases: a systematic review and meta-analysis incorporating disease duration. AB - BACKGROUND: Studies examining the association between smoking and the need for surgery in patients with Crohn's disease and ulcerative colitis have reached inconsistent conclusions. These studies often do not differentiate between patients undergoing early surgery and patients having surgery later in their disease course. Our study examined the association between smoking status and time to first bowel resection in patients with Crohn's disease and ulcerative colitis. METHODS: We searched MEDLINE and EMBASE for studies (n = 12) reporting on the association between smoking status (current, former, and never) and surgery in IBD, and incorporated disease duration in the analysis. Hazard ratios (HR) with 95% confidence intervals (CI) were pooled across studies using random effects models. RESULTS: Current smokers with Crohn's disease were at increased risk of intestinal resection compared to never smokers (HR 1.27, 95% CI 1.08 to 1.49); however, there was no difference in the need for surgery when comparing former and never smokers (HR 1.11, 95% CI 0.95 to 1.30). In patients with ulcerative colitis, there was no difference in the need for colectomy when comparing current smokers to never smokers (HR 0.98, 95% CI 0.67 to 1.44). Former smokers with ulcerative colitis were at increased risk of colectomy (HR 1.38, 95% CI 1.04 to 1.83) compared to never smokers. CONCLUSIONS: Current smokers with Crohn's disease are at increased risk of surgery, while former smokers with ulcerative colitis have increased risk of colectomy. PMID- 28003022 TI - The variability and reproducibility of whole genome sequencing technology for detecting resistance to anti-tuberculous drugs. AB - BACKGROUND: The emergence of resistance to anti-tuberculosis drugs is a serious and growing threat to public health. Next-generation sequencing is rapidly gaining traction as a diagnostic tool for investigating drug resistance in Mycobacterium tuberculosis to aid treatment decisions. However, there are few little data regarding the precision of such sequencing for assigning resistance profiles. METHODS: We investigated two sequencing platforms (Illumina MiSeq, Ion Torrent PGMTM) and two rapid analytic pipelines (TBProfiler, Mykrobe predictor) using a well characterised reference strain (H37Rv) and clinical isolates from patients with tuberculosis resistant to up to 13 drugs. Results were compared to phenotypic drug susceptibility testing. To assess analytical robustness individual DNA samples were subjected to repeated sequencing. RESULTS: The MiSeq and Ion PGM systems accurately predicted drug-resistance profiles and there was high reproducibility between biological and technical sample replicates. Estimated variant error rates were low (MiSeq 1 per 77 kbp, Ion PGM 1 per 41 kbp) and genomic coverage high (MiSeq 51-fold, Ion PGM 53-fold). MiSeq provided superior coverage in GC-rich regions, which translated into incremental detection of putative genotypic drug-specific resistance, including for resistance to para aminosalicylic acid and pyrazinamide. The TBProfiler bioinformatics pipeline was concordant with reported phenotypic susceptibility for all drugs tested except pyrazinamide and para-aminosalicylic acid, with an overall concordance of 95.3%. When using the Mykrobe predictor concordance with phenotypic testing was 73.6%. CONCLUSIONS: We have demonstrated high comparative reproducibility of two sequencing platforms, and high predictive ability of the TBProfiler mutation library and analytical pipeline, when profiling resistance to first- and second line anti-tuberculosis drugs. However, platform-specific variability in coverage of some genome regions may have implications for predicting resistance to specific drugs. These findings may have implications for future clinical practice and thus deserve further scrutiny, set within larger studies and using updated mutation libraries. PMID- 28003023 TI - The prognostic influence of body mass index, resting energy expenditure and fasting blood glucose on postoperative patients with esophageal cancer. AB - BACKGROUND: Body mass index (BMI), resting energy expenditure (REE) and fasting blood glucose (FBG) are major preoperative assessments of patients' nutrition and metabolic state. The relations and effects of these indices on esophageal cancer patients' postoperative short-term and long-term outcomes remain controversial and unclear. We aimed to study the impact of BMI, REE and FBG in esophageal cancer patients undergoing esophagectomy. METHODS: Three hundred and six esophageal cancer patients who underwent esophagectomy were observed retrospectively. Clinical characteristics, postoperative complications and survival analysis were compared among different BMI, REE and FBG groups. RESULTS: There were significant linear relationships between REE, BMI and FBG indices, patients with low BMI tended to have low REE (p < 0.001) and low FBG (p = 0.003). No significant difference was found in case of mortality and postoperative complications among different groups. Low BMI (X 2 = 6.141, p = 0.046), REE (X 2 = 6.630, p = 0.010) and FBG (X 2 = 5.379, p = 0.020) were related to poor survival. FBG <=90 mg/dL was independently associated with poor survival (HR = 0.695; 95 % CI 0.489-0.987, p = 0.042). BMI and REE came to be stronger prognostic factors on lymph node-negative patients and proved to be independent prognostic indicators (HR = 0.540; 95 % CI 0.304-0.959, p = 0.035 and HR = 0.457; 95 % CI 0.216-0.967, p = 0.041, respectively). CONCLUSIONS: BMI, REE and FBG are important prognostic factors in patients with esophageal cancer undergoing esophagectomy and preoperative evaluation of these indices help to determine the prognosis in these patients. PMID- 28003024 TI - Perceived stress and bruxism in university students. AB - BACKGROUND: Many studies have shown the correlation between bruxism and stress that affects the quality of life of university students. The present study highlights this correlation-for the first time-in a group of university students in Italy. METHODS: We have investigated the prevalence of awake and asleep bruxism and its correlation with perceived stress in a group of 278 Italian undergraduate students (117 M). A self report questionnaire was constructed using a socio-demographic test, the Perceived Stress Scale (PSS) and the item n. 8 of the Fonseca Questionnaire for presence of bruxism. RESULTS: The perceived stress score using PSS-10 scale was 32.2 (SD 4.6, 95% CL 31.6-32.7) for all the subjects, with significant gender difference: M = 31.2 and F = 32.9 (P = 0.0019). The prevalence for awake bruxism was 37.9% (F = 40.8%; M = 34.2%,), while for sleep bruxism was 31.8% (F = 33.3%; M = 29.1%), both without significant gender difference. A positive correlation, with significant concordance and dependence, between stress score and awake bruxism was present for male students only. CONCLUSIONS: University students showed higher bruxism and stress levels compared to the general population, with higher stress for females, but, even if female students show higher stress, a correlation between stress and bruxism exists only for male gender. Further studies should be performed. PMID- 28003025 TI - Challenges and strategies for sustaining youth-friendly health services - a qualitative study from the perspective of professionals at youth clinics in northern Sweden. AB - BACKGROUND: Youth-friendly health-care services - those that are accessible, acceptable, equitable, appropriate and effective for different youth subpopulations - are beneficial for youth health, but not easy to implement and sustain. Sweden is among the few countries where youth-friendly health-care services have been integrated within the public health system and sustained for a long time. This study explores the challenges and strategies in providing sustainable youth-friendly health-care services, from the perspective of professionals working in youth clinics in northern Sweden. METHODS: Eleven semi structured interviews with various health-care professionals working in youth clinics in northern Sweden were conducted. The interviews were transcribed verbatim, and analysed using thematic analysis in relation to the World Health Organization domains of youth friendliness. RESULTS: Four themes emerged from the analysis of the data: 1) 'Meeting youths on their own terms - the key to ensuring a holistic and youth-centred care' was related to the acceptability and appropriateness of the services; 2) 'Organizational challenges and strategies in keeping professionals' expertise on youth updated' referred to the domain of effectiveness; 3) 'Youth clinics are accessible for those who know and can reach them' was related to the domains of accessibility and equity, and 4) 'The challenge of combining strong directions and flexibility in diverse local realities' focused on the struggle to sustain the youth clinics organization and their goals within the broader health system. CONCLUSIONS: Professionals working in youth clinics are perceived as motivated, interested and knowledgeable about youth, and the clinics ensure confidentiality and a youth-centred and holistic approach. Challenges remain, especially in terms of ensuring equitable access to different youth subpopulations, improving monitoring routines and ensuring training and competence for all professionals, independently of the location and characteristics of the clinic. Youth clinics are perceived as an indisputable part of the Swedish health system, but organizational challenges are also pointed out in terms of weak clear directives and leadership, heavy workload, local/regional diversity and unequitable distribution of resources. PMID- 28003026 TI - A nurse-led clinic for patients consulting with osteoarthritis in general practice: development and impact of training in a cluster randomised controlled trial. AB - BACKGROUND: Despite a lack of service provision for people with osteoarthritis (OA), each year 1 in 5 of the general population consults a GP about a musculoskeletal condition such as OA. Consequently this may provide an opportunity for practice nurses to take an active role in helping patients manage their condition. A nurse led clinic for supporting patients with OA was developed for the MOSAICS study investigating how to implement the NICE 2014 OA Guideline core recommendations. This paper has two main objectives, firstly to provide an overview of the nurse-led OA clinic, and secondly to describe the development, key learning objectives, content and impact of the training to support its delivery. METHODS: A training programme was developed and delivered to provide practice nurses with the knowledge and skill set needed to run the nurse-led OA clinic. The impact of the training programme on knowledge, confidence and OA management was evaluated using case report forms and pre and post training questionnaires. RESULTS: The pre-training questionnaire identified a gap between what practice nurses feel they can do and what they should be doing in line with NICE OA guidelines. Evaluation of the training suggests that it enabled practice nurses to feel more knowledgeable and confident in supporting patients to manage their OA and this was reflected in the clinical management patients received in the nurse-led OA clinics. CONCLUSIONS: A significant gap between what is recommended and what practice nurses feel they can currently provide in terms of OA management was evident. The development of a nurse training programme goes some way to develop a system in primary care for delivering the core recommendations by NICE. TRIAL REGISTRATION: The cluster trial linked to this training was conducted from May 2012 through February 2014 by the Arthritis Research UK Primary Care Centre, Keele University, UK (Trial registration number ISRCTN06984617 ). PMID- 28003027 TI - Lifetime body size and estrogen-receptor-positive breast cancer risk in the California Teachers Study cohort. AB - BACKGROUND: Obesity is a public health epidemic and an important breast cancer risk factor. The relationship between interrelated body measurements is complex and most studies fail to account for this complexity. We identified key aspects of body size which jointly, over the life-course (since adolescence), are associated with estrogen-receptor-positive (ER+) breast cancer risk. METHODS: Among 109,862 women participating in the California Teachers Study cohort, 3844 were diagnosed with invasive ER+ breast cancer between 1997-1998 and December 2011. Based on validated self-reported height and weight at age 18, baseline, and 10-year follow up and waist circumference at 2-year and 10-year follow up, we identified 16 a priori body-size phenotypes. Multivariable Cox proportional hazards models provided estimates of hazard rate ratios (HR) and 95% confidence intervals (CI). RESULTS: Premenopausal breast cancer was influenced by adolescent, but not adult, body size (HR = 0.51, 95% CI 0.31-0.86 for body mass index (BMI; kg/m2) >=25 vs <20 at age 18). Among postmenopausal women currently using hormone therapy, only those with the greatest body size had increased breast cancer risk (HR = 1.36, 95% CI 1.13-1.64 for height >=67 inches and adult BMI >=25 vs height <67). Among postmenopausal women not currently using hormone therapy, the relationship between body size and risk was complex, with the largest effects of adiposity among short women. Among short women, those with gluteal adiposity (HR = 2.70, 95% CI 1.77-4.10) and those who continued to gain weight throughout adulthood (HR = 2.57, 95% CI 1.60-4.12) were at greatest risk, whereas those who had been overweight/obese since adolescence were not at increased risk (HR = 1.33, 95% CI 0.84-2.10). Height was associated with a small increased risk, with borderline statistical significance. CONCLUSIONS: Considering absolute body mass in adolescence and at two points in adulthood, dynamic changes in adiposity over time, and body fat distribution, we identified obesity phenotypes associated with ER+ breast cancer risk. Our approach more clearly identifies specific risk groups than do analyses that evaluate similar measures separately. These findings may aid in improving risk prediction models and developing targeted interventions, and may clarify inconsistent findings across studies. PMID- 28003028 TI - Worsening cholestasis and possible cefuroxime-induced liver injury following "successful" therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone: a case report. AB - BACKGROUND: Cefuroxime very rarely causes drug-induced liver injury. We present a case of a patient with paradoxical worsening of jaundice caused by cefuroxime induced cholestasis following therapeutic endoscopic retrograde cholangiopancreatography for a distal common bile duct stone. CASE PRESENTATION: A 51-year-old, previously healthy Sri Lankan man presented to our hospital with obstructive jaundice caused by a distal common bile duct stone. Endoscopic retrograde cholangiopancreatography with stone extraction, common bile duct clearance, and stenting failed to improve the cholestasis, with paradoxical worsening of his jaundice. A liver biopsy revealed features of drug-induced intrahepatic cholestasis. Although his case was complicated by an episode of cholangitis, the patient made a complete recovery in 4 months with supportive treatment and withdrawal of the offending drug. CONCLUSIONS: This case highlights a very rare drug-induced liver injury caused by cefuroxime as well as our approach to treating a patient with paradoxical worsening of jaundice after therapeutic endoscopic retrograde cholangiopancreatography. PMID- 28003029 TI - ABO and Rhesus (D) blood group distribution among blood donors in rural south western Uganda: a retrospective study. AB - BACKGROUND: In Uganda, geographical distribution of blood groups and Rhesus (D) factor varies across the country. The aim of this study was to examine the distribution of these groups among voluntary blood donors in rural southwestern Uganda. RESULTS: Twenty-three thousand five hundred four (23,504) blood donors were included in the study. The donors had a mean age of 21 years (SD +/- 5.7) and were mainly male (73%). The distribution of ABO blood group was; blood group O (50.3%); blood group A (24.6%); blood group B (20.7%) and blood group AB (4.5%). The proportions of Rhesus (D) positive and Rhesus (D) negative were 98 and 2% respectively. The proportion of non-adult donors (<18 years) was significantly higher among the female than the male donors (p value <0.001). A significantly higher proportion of males than females were Rhesus (D) negative (p value <0.001). No significant relationship was found between age and blood group distribution. CONCLUSION: The sequence of ABO distribution among the rural population in southwestern Uganda is; O > A > B > AB, with males as the predominant donors. The frequency of Rhesus (D) negative is very low in rural southwestern Ugandan and is mainly among males. The blood bank services in southwestern Uganda need to develop innovative strategies targeting female donors who are more likely to boost blood stocks in the region. PMID- 28003030 TI - Prognostic value of p53 for colorectal cancer after surgical resection of pulmonary metastases. AB - BACKGROUND: Pulmonary metastases occur in up to 25% of colorectal cancer (CRC) patients. Many studies have reported that pulmonary metastasectomy might increase 5-year survival of these patients. The aim of this study was to describe our experience with pulmonary metastasectomy for metastatic colorectal cancer and to explore the prognostic value of p53 overexpression and other factors. METHODS: Between July 2002 and December 2013, the clinicopathological data of 88 patients with colorectal carcinoma who underwent pulmonary metastases resection were retrospectively reviewed and analyzed. Clinical, biochemical and imaging, and operative data, and expression of p53 were retrospectively collected. Immunohistochemical staining for p53 was performed on paraffin-embedded 5-MUm sections using mouse anti-human tumor protein p53 monoclonal antibody (DO-7, Dako, Denmark). Overall survival (OS) was calculated from resection of pulmonary metastases to death. The prognostic effect of each variable on survival was evaluated using the Kaplan-Meier method and log-rank test. For the multivariate analysis of prognostic factors, the Cox regression model was used. RESULTS: There were 58 men and 30 women in this study, and their median age was 55 (range 31 to 85). Video-assisted thoracoscopic surgery (VATS) was performed in 59 cases (78%), and 29 patients (19%) underwent thoracotomy. Lung wedge resection and pulmonary lobectomy were performed in 52 (59.1%) and 36 (40.9%) patients, respectively. After a median follow-up duration of 44 months, the cumulative 5-year survival was 45.4%, and the median overall survival was 57.8 months. The expression of p53 significantly influenced survival. In patients with p53 protein overexpression, we observed a median OS of 46.1 months, whereas the median OS of patients with negative protein expression of p53 was 62.6 months (p = 0.047). However, in multivariate analysis, p53 overexpression was failed to be an independently significant prognostic factor for survival. CONCLUSIONS: Pulmonary resection of metastatic colorectal cancer might offer a chance to prolong survival including those patients with extrapulmonary metastases. p53 protein expression was identified as a prognosis-related factor for surgery. PMID- 28003031 TI - Pyomyositis is not only a tropical pathology: a case series. AB - BACKGROUND: Pyomyositis is an acute bacterial infection of skeletal muscle that results in localized abscess formation. This infection was thought to be endemic to tropical countries, and is also known as "tropical pyomyositis". However, pyomyositis is increasingly recognized in temperate climates and is frequently associated with an immunosuppressive condition, such as human immunodeficiency virus, malignancy, and diabetes mellitus. It is also found in healthy and athletic people after strenuous or vigorous exercise or following localized and possibly unnoticed trauma. It can be primary or secondary to neighboring or remote infection. Primary pyomyositis is a rare condition that can affect children and adolescents. Diagnosis can be delayed because the affected muscle is deeply situated and local signs are not apparent. This delay in diagnosis can result in increased morbidity and a significant mortality rate. The pediatric population, which comprises 35% of the reported pyomyositis cases, is an especially difficult subset of patients to diagnose. CASE PRESENTATION: In our series, we describe the cases of four previously healthy Caucasian children who were admitted to our Pediatric Department with different clinical presentations. Pyomyositis in our patients was related to factors affecting the muscle itself, including strenuous exercise and direct muscle trauma. Therapy was started with a cephalosporin antibiotic and teicoplanin was subsequently added. The minimum length of therapy was 3 weeks. CONCLUSIONS: The diagnosis of pyomyositis in our patients, none of whom were immune-compromised, is confirmation that this disease is not an exclusive pathology of tropical countries and demonstrates that there is an increasing prevalence of pyomyositis in temperate climates. PMID- 28003032 TI - Commercial sex and risk of HIV, syphilis, and herpes simplex virus-2 among men who have sex with men in six Chinese cities. AB - BACKGROUND: Men who have sex with men (MSM) are at high risk of HIV and sexually transmitted infections (STIs) in China and globally. Engaging in commercial sex put them at even greater risk. This study estimated the prevalence of HIV/STIs among three subgroups of MSM: MSM who sold sex (MSM-selling), MSM who bought sex (MSM-buying), and non-commercial MSM (NC-MSM) and evaluated the relationship between commercial sex and HIV/STIs. METHODS: We conducted a cross-sectional survey among MSM in six Chinese cities (Shenyang, Ji'nan, Changsha, Zhengzhou, Nanjing, and Kunming) from 2012 to 2013. Data on socio-demographics and sexual behaviors were collected. Serological tests were conducted to detect HIV, syphilis, and human simplex virus type 2 (HSV-2). RESULTS: Of 3717 MSM, 6.8% were engaged in commercial sex. The overall prevalence of HIV, syphilis and HSV-2 infections was 11.1, 8.8 and 12.1%, respectively. MSM-selling had higher prevalence of HIV (13.4%), syphilis (12.1%) and HSV-2 (17.9%) than NC-MSM (10.9, 8.7 and 11.9% for HIV, syphilis and HSV-2, respectively), though the differences are not statistically significant. Among MSM-selling, HIV prevalence was significantly higher for those who found sex partners via Internet than those did not (19.4% vs. 8.1%, P = 0.04). Compared to NC-MSM, MSM-selling were more likely to use recreation drugs (59.3% vs. 26.3%), have unprotected anal intercourse (77.9% vs. 61.7%), and have >=10 male sex partners (46.2% vs. 6.2%) in the past 6 months (each P < 0.05). CONCLUSIONS: All three subgroups of MSM in six large Chinese cities have high prevalence of HIV/STIs. Those who sell sex only have a particularly high risk of acquiring and transmitting disease, and therefore, they should be considered as a priority group in HIV/STIs surveillance and intervention programs. PMID- 28003034 TI - Resistance training program for fatigue management in the workplace: exercise protocol in a cluster randomized controlled trial. AB - BACKGROUND: Fatigue is a multifactorial condition that leads to disease and loss in production, and it affects a large number of workers worldwide. This study aims to demonstrate a resistance exercise protocol that individuals will perform during the work schedule, and to evaluate the effectiveness of this exercises program for fatigue control. METHODS/DESIGN: This is a cluster randomized controlled trial with two arms and is assessor blinded. A total of 352 workers of both sexes, aged 18-65 years, from a medium-sized dairy plant were enrolled in this study. Participants will be recruited from 13 production sectors according to the eligibility criteria and will be randomized by clusters to either the Progressive Resistance Exercise (PRE) intervention group or the Compensatory Workplace Exercise (CWE) comparative group. A resistance exercise program will be implemented for both groups. The groups will receive instructions on self management, breaks, adjustments to workstations, and the benefits of physical exercise. The PRE group will perform resistance exercises with gradual loads in an exercise room, and the CWE group will perform exercise at their workstations using elastic bands. The exercise sessions will be held 3 times a week for 20 min. The primary outcome measures will be symptoms of physical and mental fatigue, and muscular fatigue based on a one-repetition maximum (1RM). The secondary outcome measures will be level of physical activity, musculoskeletal symptoms, physical condition, perceived exposure, and productivity. The workers will be assessed at baseline and after a 4-month program. A linear mixed model will be applied on an intention-to-treat basis. DISCUSSION: This intervention is expected to reduce symptoms of fatigue in the workers. The exercise program is indicating in the workplace, although there are few studies describing the effects of exercise on the control of fatigue in the workplace. Emphasis will be placed on adherence to the program, which may result in significant and clinically important reductions in fatigue. It is also expected that the findings of this study will contribute significantly to the decision-making capacity of professionals working in the field of occupational health. TRIAL REGISTRATION: U.S. National Institutes of Health, ClinicalTrials.gov Identifier: NCT02172053 . Date registered 19 June 2014. PMID- 28003033 TI - Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis. AB - BACKGROUND: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all cause mortality. METHODS: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; >50 participants; stratification of population according to SPPB value; data on all cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index. RESULTS: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 +/- 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95%CI 2.86-3.79), 4-6 (OR 2.14, 95%CI 1.92-2.39), and 7-9 (OR 1.50, 95%CI 1.32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men. CONCLUSIONS: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs. The study protocol was published on PROSPERO (CRD42015024916). PMID- 28003035 TI - The Ontario Neurodegenerative Disease Research Initiative (ONDRI). AB - Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource. PMID- 28003036 TI - Improving Pediatric Education for Emergency Medical Services Providers: A Qualitative Study. AB - OBJECTIVES: Previous studies have illustrated pediatric knowledge deficits among Emergency Medical Services (EMS) providers. The purpose of this study was to identify perspectives of a diverse group of EMS providers regarding pediatric prehospital care educational deficits and proposed methods of training improvements. METHODS: Purposive sampling was used to recruit EMS providers in diverse settings for study participation. Two separate focus groups of EMS providers (administrative and non-administrative personnel) were held in three locations (urban, suburban, and rural). A professional moderator facilitated focus group discussion using a guide developed by the study team. A grounded theory approach was used to analyze data. RESULTS: Forty-two participants provided data. Four major themes were identified: (1) suboptimal previous pediatric training and training gaps in continuing pediatric education; (2) opportunities for improved interactions with emergency department (ED) staff, including case-based feedback on patient care; (3) barriers to optimal pediatric prehospital care; and (4) proposed pediatric training improvements. CONCLUSION: Focus groups identified four themes surrounding preparation of EMS personnel for providing care to pediatric patients. These themes can guide future educational interventions for EMS to improve pediatric prehospital care. Brown SA , Hayden TC , Randell KA , Rappaport L , Stevenson MD , Kim IK . Improving pediatric education for Emergency Medical Services providers: a qualitative study. Prehosp Disaster Med. 2017;32(1):20-26. PMID- 28003037 TI - Med Diet 4.0: the Mediterranean diet with four sustainable benefits. AB - OBJECTIVE: To characterize the multiple dimensions and benefits of the Mediterranean diet as a sustainable diet, in order to revitalize this intangible food heritage at the country level; and to develop a multidimensional framework - the Med Diet 4.0 - in which four sustainability benefits of the Mediterranean diet are presented in parallel: major health and nutrition benefits, low environmental impacts and richness in biodiversity, high sociocultural food values, and positive local economic returns. DESIGN: A narrative review was applied at the country level to highlight the multiple sustainable benefits of the Mediterranean diet into a single multidimensional framework: the Med Diet 4.0. Setting/subjects We included studies published in English in peer-reviewed journals that contained data on the characterization of sustainable diets and of the Mediterranean diet. The methodological framework approach was finalized through a series of meetings, workshops and conferences where the framework was presented, discussed and ultimately refined. RESULTS: The Med Diet 4.0 provides a conceptual multidimensional framework to characterize the Mediterranean diet as a sustainable diet model, by applying principles of sustainability to the Mediterranean diet. CONCLUSIONS: By providing a broader understanding of the many sustainable benefits of the Mediterranean diet, the Med Diet 4.0 can contribute to the revitalization of the Mediterranean diet by improving its current perception not only as a healthy diet but also a sustainable lifestyle model, with country-specific and culturally appropriate variations. It also takes into account the identity and diversity of food cultures and systems, expressed within the notion of the Mediterranean diet, across the Mediterranean region and in other parts of the world. Further multidisciplinary studies are needed for the assessment of the sustainability of the Mediterranean diet to include these new dimensions. PMID- 28003038 TI - Variation matters and should be included in health care research for comparison of outcomes. AB - BACKGROUND: Health care is provided under the conditions in which people live and under the rules and regulations of a prevailing health system. As a consequence, 'local' circumstances are an important determinant of the actual care that can be provided and its effects on the health of individuals and populations. This plays in particular, but not exclusively, a role in community-based primary health care. Although this is generally accepted, there is little insight in the impact of the setting and context in which health care is provided on the outcome of care. Aim This paper argues the case to use this natural variation within and between countries as an opportunity to be used as a form of natural experiment in health research. Arguments We argue that analysing and comparing outcomes across settings, that is comparative outcomes of interventions that have been performed under different health care conditions will improve the understanding of how the real-life setting in which health care is provided - including the health system, the socio-economic circumstances and prevailing cultural values - do determine outcome of care. Recommendations To facilitate comparison of research findings across health systems and different socio-economic and cultural contexts, we recommend a more detailed reporting of the conditions and circumstances under which health research has been performed. A set of core variables is proposed for studies in primary health care. PMID- 28003039 TI - Toward the Atomic-Level Mass Analysis of Biomolecules by the Scanning Atom Probe. AB - In 1994, a new type of atom probe instrument, named the scanning atom probe (SAP), was proposed. The unique feature of the SAP is the introduction of a small extraction electrode, which scans over a specimen surface and confines the high field, required for field evaporation of surface atoms in a small space, between the specimen and the electrode. Thus, the SAP does not require a sharp specimen tip. This indicates that the SAP can mass analyze the specimens which are difficult to form in a sharp tip, such as organic materials and biomolecules. Clean single wall carbon nanotubes (CNT), made by high-pressure carbon monoxide process are found to be the best substrates for biomolecules. Various amino acids and dipeptide biomolecules were successfully mass analyzed, revealing characteristic clusters formed by strongly bound atoms in the specimens. The mass analysis indicates that SAP analysis of biomolecules is not only qualitative, but also quantitative. PMID- 28003040 TI - Nutritional and microbiological quality of commercial and homemade blenderized whole food enteral diets for home-based enteral nutritional therapy in adults. AB - BACKGROUND & AIMS: Serious nutritional and contamination risks may be involved in the preparation of blenderized tube-feeding diets and in the handling of commercial diets. Their nutritional and microbiological quality in home settings is unknown. The objective of this study was to assess the nutritional and microbiological quality of commercial enteral and homemade blenderized whole foods diets intended to adult patients in home nutritional therapy. METHODS: In a cross sectional study, 66 samples of commercial (CD) and noncommercial (NCD) enteral diets were collected at the homes of patients in home enteral nutritional therapy, 33 of each type. Commercial diets were either powder (PCD; n = 13) or liquid (LCD; n = 20). The samples were analyzed in laboratory to assess their nutritional and microbiological quality. Anthropometric data of mid upper arm circumference (MUAC) and triceps skinfold (TST) thickness were obtained from the patients' medical records. RESULTS: NCD presented significantly lower values for protein, fat, fiber, carbohydrate and energy while water content was significantly higher. PCD and LCD did not show any statistically significant differences between them. In the NCD, the values measured for macronutrients and energy corresponded to less than 50% of the prescribed values (except for fat). In CD, protein value was about 20% more than the prescribed value; fat and energy values corresponded to approximately 100% of the prescription, while carbohydrate corresponded to 92%. Regardless the type of the diet, prevalence of undernutrition was high in both groups though patients of the NCD presented a higher percentage. Samples of NCD complied significantly less with the microbiological standards; only 6.0% complied with the standard for coliform bacteria. Escherichia coli was detected in 10, 2, and 2 samples of NCD, PCD and LCD, respectively. CONCLUSIONS: Homemade blenderized enteral diets showed low values of energy and macronutrients, delivered less than 50% of the prescribed values and had high levels of bacterial contamination. PMID- 28003041 TI - The impact of oat (Avena sativa) consumption on biomarkers of renal function in patients with chronic kidney disease: A parallel randomized clinical trial. AB - BACKGROUND & OBJECTIVE: Animal studies report that oat (Avena sativa L) intake has favorable effects on kidney function. However, the effects of oat consumption have not been assessed in humans. The aim of this study was to examine the impact of oat intake on biomarkers of renal function in patients with chronic kidney disease (CKD). METHODS: Fifty-two patients with CKD were randomly assigned to a control group (recommended to reduce intake of dietary protein, phosphorus, sodium and potassium) or an oat consumption group (given nutritional recommendations for controls +50 g/day oats). Blood urea nitrogen (BUN), serum creatinine (SCr), urine creatinine, serum albumin, serum potassium, parathyroid hormone (PTH), serum klotho and urine protein concentration were measured at baseline and after an eight-week intervention. Creatinine clearance was calculated using urine creatinine concentration. RESULTS: Within group analysis showed a significant increase in BUN (P = 0.02) and serum potassium (P = 0.01) and a marginally significant increment in SCr (P = 0.08) among controls. However, changes in the oat group were not significant. In a multivariate adjusted model, we observed a significant difference in change of serum potassium (-0.03 mEq/L for oat group and 0.13 mEq/L for control group; P = 0.01) and a marginally significant difference in change of serum albumin (0.01 g/dl for oat group and 0.08 for control group; P = 0.08) between the two groups. There was no change in PTH concentration. CONCLUSION: Intake of oats may have a beneficial effect on serum albumin and serum potassium in patients with CKD. REGISTRATION CODE: Present study registered under IRCT.ir identifier no. IRCT2015050414551N2. PMID- 28003042 TI - Epidemiology of hepatitis B infection in Finland: Implications for immunisation policy. AB - OBJECTIVES: We describe the current epidemiology of acute and chronic hepatitis B infections in Finland. We estimate the total incidence of chronic hepatitis B following from the current incidence of acute infections and the influx of chronic carriers of hepatitis B associated with net immigration. We evaluate the incidence of hepatitis B infections preventable by a universal vaccination programme among infants. METHODS: We analysed hepatitis B cases reported to the National Infectious Disease Register during 2004-2012 and used pre-developed methods to adjust for acute asymptomatic infections. We estimated the projected incidence of chronic infection by applying age-specific risks of chronic infection to the estimated incidence of acute infection. We estimated the influx of chronic carriers associated with immigration by utilising data on immigration during 2004-2012 and the WHO regional estimates of carriage prevalence. RESULTS: The estimated incidence of acute hepatitis B infection in Finland, adjusted for asymptomatic infections, was 1.67 per 100,000 per year (95% Crl 1.43-1.94) which is 4.2-fold to the register-based incidence. The estimated lifetime risks of acute and chronic hepatitis B infections were 0.13% and 0.01%, respectively. We estimated that annually seven new chronic infections would result from infections acquired in Finland. These new chronic infections accounted for 1.2% of the total incidence of chronic infections. We estimated that eventually three chronic infections per year would be potentially preventable by a universal infant vaccination programme. CONCLUSIONS: Partly due to the fact that hepatitis B infections in neonates and in children are rare, a very limited number of chronic hepatitis B infections resulted from infection acquired within the country. A vast majority of chronic hepatitis B infections occurred among foreign-born persons and were therefore not preventable by a universal infant immunisation programme in Finland. Even with a targeted immunisation programme, the incidence of hepatitis B infection has remained low. PMID- 28003043 TI - Genetic impact on the treatment & management of Hirschsprung disease. AB - BACKGROUND: The identification of Hirschsprung's disease (HD) as a genetic condition has been a major step forward in understanding the development of the enteric nervous system and conditions arising from ganglion cell maldevelopment. METHOD: A study of the role of genetics in HD was carried out based on previously published findings from more than 400 cases of HD. RESULTS: There are at least 7 pertinent clinical questions related to HD which were further investigated. These included: diagnosis, familial recurrence, long segment and total colonic aganglionosis, syndromic associations, the question of HD-associated enterocolitis, potential causes of postoperative obstructive symptoms after successful surgery, and the apparent low prevalence in premature infants. This review aimed at evaluating the most important concepts of where we have got to in our understanding of where genetic solutions/directions to these clinical problems might lie. Possible genetic reasons for the low prevalence in premature infants was also considered and the possible plasticity of the ENS at that stage as a potential "door of hope" in the future management of HD. CONCLUSION: The study of genetics has made a massive contribution to the understanding and management of HD. It opens a "door of hope" to the future management of the condition. LEVEL OF EVIDENCE: Level V. PMID- 28003044 TI - REPLY: Treatment with oxLDL antibody reduces cathepsin S expression in atherosclerosis via down-regulating ADAR1-mediated RNA editing. PMID- 28003045 TI - Stains: A novel therapy thought in myocardial ischemia reperfusion injury other than lipid lowering. PMID- 28003046 TI - Corrigendum to "Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs" [Biomaterials 76C (2015) 399-407]. PMID- 28003047 TI - Bioactive isopimarane diterpenoids from the stems of Euonymus oblongifolius. AB - Seven isopimarane diterpenes and one abietane diterpene, together with six known sesquiterpene derivatives, were isolated from the stems of Euonymus oblongifolius. Their structures were elucidated on the basis of spectroscopic analyses, and the absolute configuration of euonymusisopimaric acid A was confirmed by single-crystal X-ray crystallographic analysis using anomalous scattering of Cu Kalpha radiation. All of the isolated compounds were evaluated for their ability to inhibit LPS-induced nitric oxide production in the murine microglia BV2 cell line, and for their cytotoxic activity against five human cancer cell lines. Euonymusisopimaric acids A, E and F inhibited LPS-induced nitric oxide production in the murine microglia BV2 cell line, with IC50 values of 2.4, 4.8, and 1.6 MUM, respectively. Euonymusisopimaric acid B exhibited moderate cytotoxicity against A549 cell line growth, with an IC50 value of 2.6 MUM. PMID- 28003048 TI - Response to the letter by Tomoyuki Kawada regarding the article entitled "Association between hypoglycemia and dementia in patients with type 2 diabetes". PMID- 28003049 TI - Toxicity and transformation of graphene oxide and reduced graphene oxide in bacteria biofilm. AB - Impact of graphene based material (GNMs) on bacteria biofilm has not been well understood yet. In this study, we compared the impact of graphene oxide (GO) and reduced graphene oxide (rGO) on biofilm formation and development in Luria Bertani (LB) medium using Escherichia coli and Staphylococcus aureus as models. GO significantly enhanced the cell growth, biofilm formation, and biofilm development even up to a concentration of 500mg/L. In contrast, rGO (>=50mg/L) strongly inhibited cell growth and biofilm formation. However, the inhibitory effects of rGO (50mg/L and 100mg/L) were attenuated in the mature phase (>24h) and eliminated at 48h. GO at 250mg/L decreased the reactive oxygen species (ROS) levels in biofilm and extracellular region at mature phase. ROS levels were significantly increased by rGO at early phase, while they returned to the same levels as control at mature phase. These results suggest that oxidative stress contributed to the inhibitory effect of rGO on bacterial biofilm. We further found that supplement of extracellular polymeric substances (EPS) in the growth medium attenuated the inhibitory effect of rGO on the growth of developed biofilm. XPS results showed that rGO were oxidized to GO which can enhance the bacterial growth. We deduced that the elimination of the toxicity of rGO at mature phase was contributed by EPS protection and the oxidation of rGO. This study provides new insights into the interaction of GNMs with bacteria biofilm. PMID- 28003050 TI - Microbial community structures in high rate algae ponds for bioconversion of agricultural wastes from livestock industry for feed production. AB - Dynamics of seasonal microbial community compositions in algae cultivation ponds are complex. However, there is very limited knowledge on bacterial communities that may play significant roles with algae in the bioconversion of manure nutrients to animal feed. In this study, water samples were collected during winter, spring, summer, and fall from the dairy lagoon effluent (DLE), high rate algae ponds (HRAP) that were fed with diluted DLE, and municipal waste water treatment plant (WWTP) effluent which was included as a comparison system for the analysis of total bacteria, Cyanobacteria, and microalgae communities using MiSeq Illumina sequencing targeting the 16S V4 rDNA region. The main objective was to examine dynamics in microbial community composition in the HRAP used for the production of algal biomass. DNA was extracted from the different sample types using three commercially available DNA extraction kits; MoBio Power water extraction kit, Zymo fungi/bacterial extraction kit, and MP Biomedicals FastDNA SPIN Kit. Permutational analysis of variance (PERMANOVA) using distance matrices on each variable showed significant differences (P=0.001) in beta-diversity based on sample source. Environmental variables such as hydraulic retention time (HRT; P<0.031), total N (P<0.002), total inorganic N (P<0.002), total P (P<0.002), alkalinity (P<0.002), pH (P<0.022), total suspended solid (TSS; P<0.003), and volatile suspended solids (VSS; P<0.002) significantly affected microbial communities in DLE, HRAP, and WWTP. Of the operational taxonomic units (OTUs) identified to phyla level, the dominant classes of bacteria identified were: Cyanobacteria, Alpha-, Beta-, Gamma-, Epsilon-, and Delta-proteobacteria, Bacteroidetes, Firmicutes, and Planctomycetes. Our data suggest that microbial communities were significantly affected in HRAP by different environmental variables, and care must be taken in extraction procedures when evaluating specific groups of microbial communities for specific functions. PMID- 28003051 TI - Interaction of chiral herbicides with soil microorganisms, algae and vascular plants. AB - Chiral herbicides are often used in agriculture as racemic mixtures, although studies have shown that the fate and toxicity of herbicide enantiomers to target and non-target plants can be enantioselective and that herbicide toxicity can be mediated by only one enantiomer. If one enantiomer is active against the target plant, the use of enantiomer-rich herbicide mixtures instead of racemic herbicides could decrease the amount of herbicide applied to a crop and the cost of herbicide application, as well as unintended toxic herbicide effects in the environment. Such a change in the management of herbicide applications requires in-depth knowledge and a critical analysis of the fate and effects of herbicide enantiomers in the environment. This review article first synthesizes the current state of knowledge on soil and plant biodegradation of herbicide enantiomers. Second, we discuss our understanding of the biochemical toxicity mechanisms associated with both enantiomers in target and non-target plants gained from state-of-the-art genomic, proteomic and metabolomic tools. Third, we present the emerging view on the "side effects" of herbicides in the root microbiome and their repercussions on target or non-target plant metabolism. Although our review of the literature indicates that the toxicity of herbicide enantiomers is highly variable depending on plant species and herbicides, we found general trends in the enantioselective toxic effects of different herbicides in vascular plants and algae. The present study will be helpful for pesticide risk assessments as well as for the management of applying enriched-enantiomer herbicides. PMID- 28003052 TI - Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects. AB - PURPOSE: The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. METHODS: This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. FINDINGS: A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax?C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic pharmacodynamic link model. IMPLICATIONS: The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316. PMID- 28003053 TI - SGLT2 Inhibitor-associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis. AB - PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents available on the market. Regulator warnings and concerns regarding the risk of developing diabetic ketoacidosis (DKA), however, have dampened enthusiasm for the class despite the combined glycemic, blood pressure, and occasional weight benefits of SGLT2 inhibitors. With the goal of improving patient safety, a cross-Canada expert panel and writing group were convened to review the evidence to-date on reported SGLT2 inhibitor-related DKA incidents and to offer recommendations for preventing and recognizing patients with SGLT2 inhibitor-associated DKA. METHODS: Reports covering DKA events in subjects taking SGLT2 inhibitors that were published in PubMed, presented at professional conferences, or in the public domain from January 2013 to mid-August 2016 were reviewed by the group independently and collectively. Practical recommendations for diagnosis and prevention were established by the panel. FINDINGS: DKA is rarely associated with SGLT2 inhibitor therapy. Patients with SGLT2 inhibitor-associated DKA may be euglycemic (plasma glucose level <14 mmol/L). DKA is more likely in patients with insulin-deficient diabetes, including those with type 2 diabetes, and is typically precipitated by insulin omission or dose reduction, severe acute illness, dehydration, extensive exercise, surgery, low-carbohydrate diets, or excessive alcohol intake. SGLT2 inhibitor-associated DKA may be prevented by withholding SGLT2 inhibitors when precipitants develop, avoiding insulin omission or inappropriate insulin dose reduction, and by following sick day protocols as recommended. IMPLICATIONS: Preventive strategies should help avoid SGLT2 inhibitor-associated DKA. All SGLT2 inhibitor-treated patients presenting with signs or symptoms of DKA should be suspected to have DKA and be investigated for DKA, especially euglycemic patients. If DKA is diagnosed, SGLT2 inhibitor treatment should be stopped, and the DKA should be treated with a traditional treatment protocol. PMID- 28003054 TI - Assessment of sediment pollution by metals. A case study from Cienfuegos Bay, Cuba. AB - Sediments were grouped in three zones of the bay: two in the northern basin with higher metal contamination; and another in the southern basin, where lithogenic metals were predominant. Sediment pollution classification made using Index of geoaccumulation and Enrichment factor was consistent, indicating higher accumulation of Cd and Pb in the northern basin. The negative influence of activities linked to petrol was predicted by V/Ni and V/(Ni+V) ratios. Cd and Pb did not represent a potential risk; while Cu and Ni could be risky for biota in most sediment, according to Screening Quick Reference Tables (SQuiRTs). Comparison of bioavailable fraction of metals with references in SQuiRTs corroborated the low potential damage on the biota due to As, Cd, Pb, Cr, Zn; and a higher potential damage due to Cu; while an attenuation of the risk due to Ni predicted by SQuiRTs could be expected. PMID- 28003055 TI - Determination and speciation of cadmium in microcosms with Bunodosoma caissarum and Perna perna using isotopically enriched 116Cd. AB - The study of the uptake and distribution of elements in marine environments is of great interest for understanding their pathways and accumulation. Here, we investigated in laboratory experiments the accumulation behavior of Cd in the sea anemone Bunodosoma caissarum and the mussel Perna perna. Specimens were incubated with isotopically enriched 116Cd in aquariums. Cd concentrations in the seawater and in the tissues of B. caissarum and P. perna were followed by inductively coupled plasma-mass spectrometry (ICP-MS) by means of isotope dilution analysis. Bioconcentration factors for B. caissarum and P. perna exposed to 0.9MUg.L-1 of 116Cd were determined to be 80.5 and 850, respectively. P. perna specimens exposed to 4.5MUg.L-1 of 116Cd reached 530. Cytosolic proteins associated with Cd from the tissues were extracted and further analyzed by size-exclusion chromatography coupled to ICP-MS. Cd accumulation could be detected in both organisms ranging from high-molecular to low-molecular species. PMID- 28003056 TI - Effectiveness of a chemical herder in association with in-situ burning of oil spills in ice-infested water. AB - The average herded slick thickness, surface distribution and burning efficiency of a light crude oil were studied in ice-infested water to determine the effectiveness of a chemical herder in facilitating the in-situ burning of oil. Experiments were performed in a small scale (1.0m2) and an intermediate scale (19m2) setup with open water and 3/10, 5/10 and 7/10 brash ice coverages. The herded slick thicknesses (3-8mm) were ignitable in each experiment. The presence of ice caused fracturing of the oil during the herding process, which reduced the size of the herded slicks and, as a consequence, their ignitability, which in turn decreased the burning efficiency. Burning efficiencies relative to the ignited fraction of the oil were in the expected range (42-86%). This shows that the herder will be an effective tool for in-situ burning of oil when the ignitability issues due to fracturing of the oil are resolved. PMID- 28003057 TI - Allelopathic effect of Chattonella marina var. marina (Raphidophyceae) on Gymnodinium catenatum (Dinophycea). AB - The allelopathic effect of the raphidophyte Chattonella marina var. marina on the dinoflagellate Gymnodinium catenatum was determined. Both species are harmful algal bloom forming algae, produce toxic metabolites, and can co-exist in the environment. In general, raphidophytes tend to dominate over dinoflagellates, which may indicate an allelopathic effect of the former algae. Strains of C. marina var. marina and G. catenatum isolated from Bahia de La Paz were cultured in bi-algal cultures with and without cell contact. Additionally, cultures of G. catenatum were exposed to cell-free culture filtrates of the raphidophyte to test whether soluble allelopathic molecules are active. During late stationary phase, both species were cultivated in mixed cultures for 72h using the following cell abundance proportions: 20*103cellsL-1: 20*103cellsL-1 (1:1; G. catenatum: C. marina); 10*103cellsL-1: 20*103cellsL-1 (1:2), and 20*103cellsL-1: 10*103cellsL-1 (2:1). Cells of G. catenatum were also exposed to different volumes of cell filtrates of C. marina (10, 20, and 50mL) using the same cell abundance proportions for 24h. Samples were taken daily for cell counts and microscopic observations. Growth inhibition was higher when there was cell contact between both species, however mortality of G. catenatum was also observed without direct cell contact, indicating that toxic metabolites are liberated to the culture medium. Changes in cell morphology of G. catenatum occurred in the presence of cells and filtrates of C. marina, such as loss of flagella and motility, swelling, loss of girdle and sulci, prominent nucleus, rupture of cell membrane, and cell lysis. Induction of temporary cysts was also observed. These results suggest that toxic metabolites are liberated to the medium by C. marina, affecting G. catenatum by inhibiting its growth and causing changes in its life history, providing new insights of interactions between raphidophytes and dinoflagellates that could happen in the natural environment when both species are present. PMID- 28003058 TI - Effect of the endoparasite Amoebophrya sp. on toxin content and composition in the paralytic shellfish poisoning dinoflagellate Alexandrium fundyense (Dinophyceae). AB - Members of the Amoebophrya ceratii complex are endoparasitic dinoflagellates that parasitize a number of their dinoflagellate relatives, including toxic and/or harmful algal bloom-forming species. Despite many studies on the occurrence, prevalence, biology and molecular phylogeny of Amoebophrya spp., little attention has been given to toxin dynamics of host population following parasitism. Using Amoebophrya sp. infecting the paralytic shellfish toxin (PSP)-producing dinoflagellate Alexandrium fundyense, we addressed the following questions: (1) does parasitism by Amoebophrya sp. alter toxin content and toxin profiles of the dinoflagellate A. fundyense over the infection cycle? and (2) do parasite dinospores produced at the end of the infection cycle retain host toxins and thus potentially act as a vector to convey PSP toxin through the marine microbial food web? Toxin time-course experiments showed that the PSP toxin contents did not vary significantly over the infection cycle, but mean toxin content for infected cultures was significantly higher than that for uninfected cultures. Host toxins were not detected in the free-living, dinospore stage of the parasite. Therefore, our results indicate that Amoebophrya sp. does not function as a vector for transferring PSP toxins to higher trophic levels. Rather, Amoebophrya infections appear to play an important role in maintaining healthy ecosystems by transforming potent toxins-producing dinoflagellates into non-toxic dinospores, representing "edible food" for consumers of the marine microbial food-web during toxic algal bloom event. PMID- 28003059 TI - Nutrient quotas and carbon content variability of Prorocentrum minimum (Pavillard) Schiller, 1933. AB - Frequency, severity, and geographic range of harmful blooms caused by a dinoflagellate Prorocentrum minimum have been increasing significantly over the past few decades. The ability to adapt nutrient quotas and carbon content to a wide range of environmental conditions is one of the key factors for the proliferation of P. minimum. Understanding the limits of stoichiometric variability in terms of nutrient quotas and carbon content would help explain the observed trends and assist in P. minimum growth model creation. This manuscript aggregates information from 15 studies to investigate variability in nutrient quotas and carbon content for a broad range of P. minimum isolates and clonal lines. Nitrogen quota, phosphorus quota, and carbon content in the studies varied between 11-107.5pgNcell-1, 1.45-17.58pgPcell-1, and 70-656.36pgCcell-1, respectively. Regression analysis was used to estimate average nitrogen and phosphorus quotas as functions of carbon, and to show that carbon content variability explains 55% of nitrogen and 23% of phosphorus quota variability. Confidence intervals for data (CID) found during the analysis were used to define maximal and minimal nutrient quotas as functions of carbon content. The ratios of the upper and lower CID ranges can, therefore, be used to estimate nutrient storage capacity as a function of carbon content. The new results and comparison with other species show that, at least for P. minimum, carbon-based quotas are more suitable for modelling than cell-based quotas. Finally, results indicate that environmental nutrient availability affects quotas more than light does: while quota variability due to light remains within 80% CID, nutrient variability covers the 95% CID. PMID- 28003060 TI - Two decades of Pseudo-nitzschia spp. blooms and king scallop (Pecten maximus) contamination by domoic acid along the French Atlantic and English Channel coasts: Seasonal dynamics, spatial heterogeneity and interannual variability. AB - King scallop contamination (Pecten maximus) by domoic acid, a neurotoxin produced by some species of the diatom Pseudo-nitzschia, is highly problematic because of its lengthy retention in the bivalve tissue, leading to prolonged fishery closures. Data collected within the French Phytoplankton and Phycotoxin monitoring network (REPHY) over the 1995-2012 period were used to characterize the seasonal dynamics and the interannual variability of P.-nitzschia spp. blooms as well as the contamination of king scallop fishing grounds, in six contrasted bays distributed along the French Atlantic coast and English Channel. Monitoring revealed that these toxic events have become more frequent since the year 2000, but with varying magnitudes, frequencies and timing depending on the bay. Two bays, located in southern Brittany, exhibited both recurrent contaminations and high P.-nitzschia abundances. The Brest bay and the Seine bay were intermittently affected. The Pertuis Breton exhibited only one major toxic event related to an exceptionally intense bloom of P.-nitzschia in 2010, and the Saint Brieuc bay neither showed significant contamination nor high P.-nitzschia abundance. While high P.-nitzschia abundance appeared to be correlated to scallop toxicity, this study highlights the difficulty in linking P.-nitzschia spp. blooms to king scallop contamination through monitoring. Indeed, P.-nitzschia was determined at the genus level and data regarding species abundances and their toxicity levels are an absolute prerequisite to further assess the environmental control of ASP events. As results describe distinct P.-nitzschia bloom dynamics along the French coast, this may suggest distinct controlling factors. They also revealed that major climatic events, such as the winter storm Xynthia in 2010, can trigger toxicity in P.-nitzschia over a large spatial scale and impact king scallop fisheries all along the coast. PMID- 28003061 TI - Azadinium poporum from the Argentine Continental Shelf, Southwestern Atlantic, produces azaspiracid-2 and azaspiracid-2 phosphate. AB - The marine dinophycean genus Azadinium has been identified as the primary source of azaspiracids (AZA), a group of lipophilic phycotoxins known to accumulate in shellfish. Blooms of Azadinium in the southern Atlantic off Argentina have been described from the 1990s, but due to a lack of cultures, the diversity of South Atlantic Azadinium has not yet been fully explored and their toxin production potential is completely unknown. During a spring 2010 research cruise covering the El Rincon (ER) estuarine system (North Patagonian coast, Argentina, Southwestern Atlantic) a search was conducted for the presence of Azadinium. Although neither Azadinium cells nor AZA in field plankton samples were detected, 10 clonal strains of Azadinium poporum were successfuly established by incubation of sediment samples. Argentinean A. poporum were more variable in size and shape than the type description but conformed to it by the presence of multiple pyrenoids with starch sheath, in plate pattern and arrangement, and in the position of the ventral pore located on the left side of the pore plate. In contrast to all previous description of A. poporum, isolates of the Argentinean A. poporum possessed a distinct field of pores on the second antapical plate. Conspecificity of the Argentinean isolates with A. poporum was confirmed by molecular phylogeny of concatenated ITS and LSU rDNA sequences, where all Argentinean isolates together with some Chinese A. poporum strains formed a well supported ribotype clade within A. poporum. All isolates produced AZA with the same profile, consisting of AZA-2 as the major compound and, to a lesser extent, its phosphated form. This is the first report of a phosphated marine algal toxin. This first confirmation of the presence of AZA producing Azadinium in the Argentinean coastal area underlines the risk of AZA shellfish contamination episodes in the Southwestern Atlantic region. PMID- 28003062 TI - Bioactive compounds of marine dinoflagellate isolates from western Greenland and their phylogenetic association within the genus Alexandrium. AB - The diversity and biogeography of populations of the toxigenic marine dinoflagellate genus Alexandrium, a major global cause of paralytic shellfish poisoning (PSP), are represented by only a few studies based upon a low number of cultured isolates and remain poorly described in Arctic and sub-Arctic waters. Multiple clonal isolates (n=22) of the Alexandrium tamarense species complex, and a single isolate of A. tamutum, were collected from the water column while on board an oceanographic expedition to the west coast of Greenland. After culturing of these isolates under controlled conditions, their phylogenetic affinities within the genus Alexandrium were characterized by sequence analysis of nuclear large sub-unit (LSU) rDNA. Based upon morphological and molecular genetic criteria, all isolates of the A. tamarense species complex were consistent with membership in the Group I ribotype (previously known as the North American ribotype). Phenotypic signatures were also analyzed based upon their respective profiles of paralytic shellfish toxins (PST) and allelochemical interactions against a target cryptophyte Rhodomonas, as determined by lytic potency. All isolates conforming to the A. tamarense Group I produced PST, but no toxins were detected in A. tamutum P2E2. Unusually, only carbamoyl toxins were produced among the A. tamarense Group I isolates from Greenland; sulfocarbamoyl derivatives, generally present in A. tamarense population from other locations, including the Arctic, North Pacific and North Atlantic, were absent from all isolates. Allelochemical activity, causing cell lysis of Rhodomonas, but generally being unrelated to cellular PST, was expressed by all A. tamarense isolates and also by A. tamutum, but varied widely in potency. Comparison of the genotypic (rDNA) and phenotypic (PST profile, allelochemical activity) characteristics of Greenland isolates with those of other Arctic populations reveals a complex pattern of intra-specific diversity. Estimation of diversity relationships is problematic because of the distinct patterns of divergence and lack of evidence of linkage among the alternative biomarkers and morphology. Nevertheless, such studies are necessary as the basis for constructing hindcasting scenarios and predicting changes in Alexandrium species distribution in the Arctic from the regional to the global scale. PMID- 28003063 TI - Increased potential for wound activated production of Prostaglandin E2 and related toxic compounds in non-native populations of Gracilaria vermiculophylla. AB - The capacity of the East Asian seaweed Gracilaria vermiculophylla ("Ogonori") for production of prostaglandin E2 from arachidonic acid occasionally causes food poisoning after ingestion. During the last two decades the alga has been introduced to Europe and North America. Non-native populations have been shown to be generally less palatable to marine herbivores than native populations. We hypothesized that the difference in palatability among populations could be due to differences in the algal content of prostaglandins. We therefore compared the capacity for wound-activated production of prostaglandins and other eicosatetraenoid oxylipins among five native populations in East Asia and seven non-native populations in Europe and NW Mexico, using a targeted metabolomics approach. In two independent experiments non-native populations exhibited a significant tendency to produce more eicosatetraenoids than native populations after acclimation to identical conditions and subsequent artificial wounding. Fourteen out of 15 eicosatetraenoids that were detected in experiment I and all 19 eicosatetraenoids that were detected in experiment II reached higher mean concentrations in non-native than in native specimens. Wounding of non-native specimens resulted on average in 390% more 15-keto-PGE2, in 90% more PGE2, in 37% more PGA2 and in 96% more 7,8-di-hydroxy-eicosatetraenoic acid than wounding of native specimens. Not only PGE2, but also PGA2 and dihydroxylated eicosatetraenoic acid are known to deter various biological enemies of G. vermiculophylla that cause tissue or cell wounding, and in the present study the latter two compounds also repelled the mesograzer Littorina brevicula. Non-native populations of G. vermiculophylla are thus more defended against herbivory than native populations. This increased capacity for activated chemical defense may have contributed to their invasion success and at the same time it poses an elevated risk for human food safety. PMID- 28003064 TI - Saxitoxin increases phocine distemper virus replication upon in-vitro infection in harbor seal immune cells. AB - Several marine mammal epizootics have been closely linked to infectious diseases, as well as to the biotoxins produced by harmful algal blooms (HABs). In two of three saxitoxin (STX) associated mortality events, dolphin morbillivirus (DMV) or phocine distemper virus (PDV) was isolated in affected individuals. While STX is notorious for its neurotoxicity, immunotoxic effects have also been described. This study investigated the role of STX in altering immune function, specifically T lymphocyte proliferation, in harbor seals (Phoca vitulina concolor) upon in vitro exposure. In addition, the study also examined whether exposure to STX could alter the susceptibility of harbor seal immune cells to PDV infection upon in-vitro exposure. STX caused an increase in harbor seal lymphocyte proliferation at 10ppb and exposure to STX significantly increased the amount of virus present in lymphocytes. These results suggest that low levels of STX within the range of those reported in northeast U.S. seals may affect the likelihood of systemic PDV infection upon in-vivo exposure in susceptible seals. Given the concurrent increase in morbillivirus epizootics and HAB events in the last 25 years, the relationship between low level toxin exposure and host susceptibility to morbillivirus needs to be further explored. PMID- 28003065 TI - Easy detection of multiple Alexandrium species using DNA chromatography chip. AB - In this study, the Kaneka DNA chromatography chip (KDCC) for the Alexandrium species was successfully developed for simultaneous detection of five Alexandrium species. This method utilizes a DNA-DNA hybridization technology. In the PCR process, specifically designed tagged-primers are used, i.e. a forward primer consisting of a tag domain, which can conjugate with gold nanocolloids on the chip, and a primer domain, which can anneal/amplify the target sequence. However, the reverse primer consists of a tag domain, which can hybridize to the solid phased capture probe on the chip, and a primer domain, which can anneal/amplify the target sequence. As a result, a red line that originates from gold nanocolloids appears as a positive signal on the chip, and the amplicon is detected visually by the naked eye. This technique is simple, because it is possible to visually detect the target species soon after (<5min) the application of 2MUL of PCR amplicon and 65MUL of development buffer to the sample pad of the chip. Further, this technique is relatively inexpensive and does not require expensive laboratory equipment, such as real-time Q-PCR machines or DNA microarray detectors, but a thermal cycler. Regarding the detection limit of KDCC for the five Alexandrium species, it varied among species and it was <0.1-10pg and equivalent to 5-500 copies of rRNA genes, indicating that the technique is sensitive enough for practical use to detect several cells of the target species from 1L of seawater. The detection sensitivity of KDCC was also evaluated with two different techniques, i.e. a multiplex-PCR and a digital DNA hybridization by digital DNA chip analyzer (DDCA), using natural plankton assemblages. There was no significant difference in the detection sensitivity among the three techniques, suggesting KDCC can be readily used to monitor the HAB species. PMID- 28003066 TI - Auld Lang Syne: A New Year Brings Awards and a New Cover. AB - "Auld Lang Syne," a traditional poem used to welcome the New Year, asks rhetorically, "Should old acquaintance be forgot, and never brought to mind?" At Arthroscopy, the answer is a resounding no. We view January as an opportunity to celebrate the abundance and excellence of research published in Arthroscopy. This year, we have decided to spread our applause, approval, and appreciation to recognize both award winners and runners-up, whose distinction in research epitomizes the bounty that is Arthroscopy. In addition, we proudly introduce a new cover. PMID- 28003067 TI - Editorial Commentary: Hip Capsule: To Repair or Not? AB - Arthroscopic hip capsular repair is an area of intense interest. Basic science studies suggest that adverse changes in capsular stability/restraint may occur with capsulotomy and capsulectomy, that repair may ameliorate these changes, and, most recently, that the repaired capsule usually heals. Clinical studies suggest that in some conditions, most notably mild dysplasia, capsular repair or plication may improve short-term outcomes, but in general, the role of capsular closure is less clear. At present, perhaps a selective approach is merited, with capsular closure performed in patients with dysplasia, focal or generalized hyperlaxity, and/or increased femoral anteversion. The comparative outcomes from smaller, more vertically oriented capsulotomies with less violation of the iliofemoral ligament deserve investigation. PMID- 28003068 TI - A Prospective Randomized Controlled Trial Comparing the Efficacy of Fascia Iliaca Compartment Block Versus Local Anesthetic Infiltration After Hip Arthroscopic Surgery. AB - PURPOSE: To compare the efficacy of fascia iliaca compartment block (FICB) with local anesthetic infiltration (LAI) of the arthroscopy portals for pain control after hip arthroscopy. METHODS: A prospective single-blinded randomized controlled trial that involved patients who underwent hip arthroscopy was performed. Participants were randomized to receiving either FICB or LAI of the portal tracts with local anesthetic. Supplemental analgesia was also used in both groups on an on-demand basis. The primary outcome measure was the postoperative level of pain as assessed by numeric pain score at 1, 3, 6, and 24 hours after the procedure in both groups. Secondary outcome measures were the frequency and the dose of morphine and other medications consumed at 1 and 24 hours after surgery as well as any other adverse events relating to pain or medications used for pain relief in both the groups. RESULTS: The study had to be terminated early because there was a significant statistical difference in the primary outcome measure after the recruitment of 46 patients: 20 in the LAI group and 26 in the FICB group. Severity of pain in the FICB group was higher especially during the first hour postoperatively (P = .02). This was associated with a higher consumption of opioids and other analgesics, which resulted in more side effects such as nausea and vomiting. CONCLUSIONS: LAI provided a better analgesia after arthroscopic surgery of the hip in comparison with FICB and was also associated with reduced consumption of opioids and a lower rate of side effects. LEVEL OF EVIDENCE: Level I, single-blinded randomized controlled study. PMID- 28003069 TI - Editorial Commentary: The Anterolateral Ligament of the Knee Seems More Fact Than Fiction. AB - It seems like the anterolateral ligament of the knee both exists and, furthermore, is beneficial to repair during anterior cruciate ligament surgery. PMID- 28003070 TI - Editorial Commentary: Should I Order Prophylactic Antibiotics for My Next Knee Scope? AB - Postoperative infections are going to happen. The question of whether prophylactic antibiotics can lower the infection rate in routine knee arthroscopy is investigated. Although a large number of cases were included in the study, the results did not reach statistical significance. Nevertheless, a significant trend toward a lower incidence of deep infection was seen when antibiotics were given. PMID- 28003071 TI - Editorial Commentary: Bulk Osteochondral Talar Grafts Compromise Future Arthrodesis or Prosthesis. AB - In general, osteochondral allograft should include minimal "osteo" or bone. In cases that require a bulk allograft, even after creeping substitution and healing, most of the graft remains dead bone. Bulk dead bone is a particular problem in the talus, should a patient need revision to a prosthesis or arthrodesis. As an alternative, drilling, bone grafting, and fixation of existing cartilage, when possible, is preferred. PMID- 28003072 TI - Editorial Commentary: Rising Interest in "Big Data" in Arthroscopy: Is the Juice Worth the Squeeze? AB - The use of "big data" in orthopaedic sports medicine research is on the rise. Greater access to data sources that allow for analysis of outpatient procedures has contributed to this surge. Important advantages and disadvantages to each database exist and should be understood to properly interpret these studies. In the era of value-based medicine, this macro data will drive policy and payment. PMID- 28003073 TI - Editorial Commentary: A No-Difference Study That May Make a Difference in the Treatment of Disorders of the Shoulder Biceps Brachii Tendon. AB - Biceps tenodesis for disorders of the biceps brachii is frequently performed; nevertheless the optimum procedure, and particularly the level of tenodesis either above the pectoralis major tendon or inferior to the tendon, is yet to be determined. Both have purported advantages. Studies that do not find a difference in outcomes between the 2 groups in the publishing vernacular are sometimes referred to as no-difference investigations and are slightly less likely to be published, known as publication bias. This may be the rare "no-difference" investigation that makes a difference in the treatment of the biceps brachii. PMID- 28003074 TI - Shoulder Arthroscopy Complication and Readmission Rates: Impact on Value. AB - In medicine, value is defined as outcome divided by cost. Adverse events after medical treatment result in diminished outcomes and increased costs. As we evolve toward value-driven care, we must quantify the incidence of and risk factors for adverse events in order to minimize this dual-and multiplicative-effect. PMID- 28003075 TI - Editorial Commentary: Arthroscopically Assisted Acromioclavicular Joint Reconstruction-Not Seeing Does Not Mean Do Not Worry. AB - To minimize risks during arthroscopic-assisted reduction and internal fixation of acromioclavicular dislocation, drilling should only be performed with an anatomically reduced clavicle. This re-creates the important distances to the neurovascular structures because a posteriorly displaced clavicle reduces the distance to the suprascapular nerve. In addition, visualization is of high importance for the arthroscopic coracoid preparation, as are mini-open incisions, to create an accurate and well-placed tunnel for drilling. Last, because the highest potential risk of neurovascular injuries occurs with the drilling itself instead of the final construct, all possible assistance and supports guiding the surgeon should be used to avoid any pitfalls. Hence, radiography and arthroscopy are helpful tools to create and check precise tunnel placement. Still, there are risks, and surgeons must be aware of and mitigate against neurovascular complications. PMID- 28003076 TI - Editorial Commentary: Is Posterior Distal Clavicle Beveling for Chronic Nonincarcerated Type IV Acromioclavicular Separation a Sufficient Treatment? AB - While low-grade acromioclavicular injuries can be managed nonoperatively, high grade separations may result in persistent pain or functional decline and require surgical intervention. The authors of "Posterior Distal Clavicle Beveling for Chronic Nonincarcerated Type IV Acromioclavicular Separations: Surgical Technique and Early Clinical Outcomes" present a case series reporting convincing results concerning functional outcomes and early return-to-sport rates for this rather rare condition. While this technique seemed to work well in this small series of patients, in our opinion, this procedure should be reserved for use in exceptional cases only. PMID- 28003078 TI - Ligand trap for the activin type IIA receptor. The long-sought drug to overcome the calcification paradox in CKD? AB - The chronic kidney disease-mineral and bone disorder syndrome illustrates the association between a disturbed physiological bone turnover/mineralization and pathologic vascular mineralization; the so-called calcification paradox. This implies that treatments aimed at curing bone disorders might have serious implications for cardiovascular health and vice versa. Hence, there is an urgent need for treatments that are able to break through this cross-talk. Hereto, compounds such as those interfering with activin type IIA receptor signaling and acting upstream of the Wnt-beta-catenin pathway are of particular interest. PMID- 28003079 TI - Leukocyte-derived microvesicles dock on glomerular endothelial cells: stardust in the kidney. AB - Microvesicles are released from the plasma membrane of various cell types, can be taken up by other cells, and can transport membrane proteins and cytosolic contents between cells. Kahn et al. demonstrate that leukocyte-derived microvesicles bearing B1-kinin receptors are enriched in the plasma of vasculitis patients and dock on endothelial cells in the glomerulus. Cell culture experiments suggest that B1-receptors transferred by these microvesicles are functionally active on acceptor cells. PMID- 28003080 TI - Hemoglobin target in children with chronic kidney disease: valuable new information. AB - The international guideline from Kidney Disease: Improving Global Outcomes suggests a hemoglobin target of 11 to 12 g/dl for children with chronic kidney disease. However, information to support this proposal is very limited in the pediatric population. Because of controversy, the unmet need is the establishment of an appropriate target hemoglobin level in children with chronic kidney disease. Here, Rheault and colleagues provide valuable new information, reporting the association of hemoglobin levels with cardiovascular morbidity in pediatric hemodialysis patients. PMID- 28003081 TI - Transitional B cell subsets-a convincing predictive biomarker for allograft loss? AB - In this issue, Cherukuri and colleagues describe a convincing association between the proportion of transitional B lymphocyte subsets in kidney transplant recipients and long-term outcomes, and present a biologically plausible mechanism, based on differential ability of T1 and T2 cells to regulate in vitro T cell responses to explain the link. Further work is clearly needed to validate their claim that measurement of T1/T2 ratios may represent a reliable and reproducible predictive biomarker of transplant outcomes. PMID- 28003082 TI - Urinary biomarkers of tubular injury in chronic kidney disease. AB - It has been suggested that urinary biomarkers of tubular injury might help predict progression to end-stage renal disease. In this issue, Hsu et al. report that in those with established chronic kidney disease, this information does not add to what we know by quantifying creatinine and albuminuria. Here we discuss the evidence for urinary tubular injury markers in predicting renal outcomes in chronic kidney disease and the areas where measurement of these molecules might be useful in the future. PMID- 28003084 TI - Counterfeit and substandard drugs in Sub-Saharan Africa may pose a major hurdle to H3Africa's initiative to study genetics of kidney disease progression. PMID- 28003083 TI - Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. AB - Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care. PMID- 28003085 TI - The Authors Reply. PMID- 28003086 TI - Calibration of noninvasive central blood pressure devices and negative aortic-to brachial systolic pressure amplification. PMID- 28003087 TI - The Authors Reply. PMID- 28003088 TI - Right ventricular perforation by tunneled hemodialysis catheter. PMID- 28003089 TI - An unusual case of tubulointerstitial renal mastocytosis. PMID- 28003091 TI - Recycling to discover something new: the role of autophagy in kidney disease. AB - This year, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for his groundbreaking work in dissecting the mechanisms of autophagy, a cellular process resulting in the organized degradation of cytoplasmic components. Ohsumi's work paved the way for subsequent studies that demonstrated critical roles for autophagy in modulating both acute and chronic kidney injury. This work may lead to future therapeutic approaches that target the autophagy system to prevent or treat kidney diseases. PMID- 28003092 TI - A rose by any other name: is stage 3a chronic kidney disease really a disease? AB - Experts have questioned the clinical relevance of early stage 3 chronic kidney disease, particularly in elderly individuals and in those without albuminuria. A recent study published in PLoS Medicine provides further evidence that many older adults with stage 3a chronic kidney disease will never worsen, whereas some may even improve. Despite limited generalizability, the results support the current, more nuanced classification of chronic kidney disease for use in clinical practice and in future epidemiologic research. PMID- 28003093 TI - Peritubular capillaries: an important piece of the puzzle. AB - The thorough investigation of peritubular capillary changes during renal fibrosis presented in this issue provides novel insights, not only into the value of elaborate methodological approaches, but also the necessity to carefully dissect pathophysiology using current techniques. This study strengthens the existing view of a uniform progression of renal fibrosis and is consistent with other recent studies pointing toward the relevance of early alterations of peritubular capillaries as initiators of renal fibrosis. PMID- 28003094 TI - Ecological correlations of dietary food intake and mental health disorders. AB - This paper examines the ecological association of dietary food intake with mental health outcomes on the group level across countries. Published data from the World Mental Health Survey were used to compare lifetime prevalence of four categories of mental health disorders (anxiety disorders, mood disorders, impulse control disorders, and substance use disorders) with a country's fish/seafood and sugar/sweetener supply quantity using the Spearman rank correlation. Data were compared for 17 countries across the world. Sugar and sweetener supply quantity was significantly and positively associated with anxiety disorders (rho=0.75, p=0.001), mood disorders (rho=0.75, p=0.001), impulse control disorders (rho=0.78, p=0.001), and substance use disorders (rho=0.68, p=0.007). Fish and seafood supply quantity had no significant association with any mental health disorders. Mental health disorders represent a significant health problem around the world. Public health measures aimed at improving the quality and availability of a nation's food supply could have a significant positive impact on mental health. Further randomized studies are needed to further validate the study findings. PMID- 28003095 TI - Weight Control in Adolescents: Focus Groups With Korean Adolescents and Their Teachers. AB - PURPOSE: This qualitative descriptive study sought to identify perceptions about and status of weight control in adolescents from the perspective of adolescents and their teachers. METHODS: Focus groups were used with six separate groups, 20 adolescents divided into four groups and 14 teachers divided into two groups. The qualitative data were analyzed using a thematic analysis in NVivo 11.0. Consolidated criteria for reporting qualitative studies (COREQ) were followed. RESULTS: We extracted three themes and 12 sub-themes with 52 meaningful codes. Both adolescents and teachers stated that perceptions about weight control in adolescents were overly weighted toward management of one's appearance. The adolescents reported an increase in weight gained during adolescence, especially after entering high school, and they noted a lack of participation in physical activities and the presence of unhealthy dietary behaviors. However, adolescents perceived excessive weight gain during adolescence as natural, as long as they studied hard. Their teachers and parents were also permissive about weight gain resulted from study. The participants suggested that a weight control program for adolescents should be conducted in schools and should include every student in order to avoid discrimination. In addition, teacher involvement was emphasized to promote participation of adolescents in a school program. CONCLUSION: Our findings indicate that adolescents, especially those in a society emphasizing academics, need to practice healthy weight control behaviors. A school-based weight control program involving teachers and peers would be suitable and should be provided to all students regardless of weight classification. PMID- 28003096 TI - Conformational status of cytochrome c upon N-homocysteinylation: Implications to cytochrome c release. AB - One of the proposed mechanisms of homocysteine (Hcy) toxicity is the post translational modification of proteins by its metabolite, homocysteine thiolactone (HTL). Incubation of proteins with HTL has been shown to form covalent adducts with epsilon-amino group of lysine residues of protein (called N homocysteinylation) which ultimately results in structural and functional alterations of the modified proteins. In the present study, the effects of HTL on the conformational and heme status of cytochrome c (cyt c) were investigated. Spectroscopic analyses revealed that HTL-modified cyt c undergoes certain conformational alterations leading to disturbed heme-Trp distance and packing of the apolar groups. These alterations were accompanied with the reduction of the heme moiety and activation of peroxidase-like function of cyt c, which is known to be a crucial event for initiation of the intrinsic apoptotic pathway. Further structural characterization revealed that disruption of the heme-Met80 interaction, thereby converting the hexa-coordinate cyt c to a penta-coordinate species (with a free heme ligand), was responsible for the activation of the peroxidase activity. The study provides insights for the possible role of cyt c N homocysteinylation in eliciting its toxicity and cell death. PMID- 28003099 TI - Long-term Results of 18 Fat Injections in Unilateral Vocal Fold Paralysis. AB - OBJECTIVE: The purposes of this study were to assess the long-term efficacy of medialization laryngoplasty via injection of autologous fat in patients with unilateral laryngeal paralysis, and to discuss the results based on the volume of fat injected and the size of the initial glottic gap. STUDY DESIGN: This was a retrospective study with clinical reevaluation of 18 patients treated for unilateral laryngeal paralysis at Liege University Hospital between April 1, 2011, and December 1, 2014. METHOD: The voice examination included subjective scales (GRBAS and the Voice Handicap Index), a report on acoustic and aerodynamic voice parameters, and laryngostroboscopic assessment of glottic closure and mucosal wave (T0: preoperative; T1: immediate postoperative; T2: >1 year). RESULTS: The median follow-up duration was 19 months. We observed a significant improvement in maximum phonation time; mean flow rate; jitter; the Voice Handicap Index; the G, R, B, and A subscales of the GRBAS-I; and glottic closure at T1. These parameters remained stable over time, without any significant difference except for shimmer and glottic closure between T1 and T2. Regardless of the volume of fat injected and the magnitude of the initial glottic gap, we did not see any significant difference from one assessment time to another. CONCLUSION: Medialization laryngoplasty by means of the injection of autologous fat is a safe, effective surgical technique for patients with unilateral laryngeal paralysis regardless of the size of the initial glottic gap. The results are maintained longer than 1 year, and no evidence of significant resorption of the fat was found in our study over a period of 12-58 months. The volume of fat injected does not seem to affect the functional results. PMID- 28003098 TI - Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease. AB - In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms. PMID- 28003097 TI - Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis. AB - The Hippo signaling pathway, also known as the Salvador-Warts-Hippo pathway, is a regulator of organ size. The pathway takes its name from the Drosophila protein kinase, Hippo (STK4/MST1 and STK3/MST2 in mammals), which, when inactivated, leads to considerable tissue overgrowth. In mammals, MST1 and MST2 negatively regulate the transcriptional co-activators yes-associated protein 1 and WW domain containing transcription regulator 1 (WWTR1/TAZ), which together regulate expression of genes that control proliferation, survival, and differentiation. Yes-associated protein 1 and TAZ activation have been associated with liver development, regeneration, and tumorigenesis. How their activity is dynamically regulated in these contexts is just beginning to be elucidated. We review the mechanisms of Hippo signaling in the liver and explore outstanding questions for future research. PMID- 28003100 TI - How 'social' is recreational running? Findings from a qualitative study in London and implications for public health promotion. AB - Recreational running is increasingly widespread and could therefore be seen as the obvious target for those hoping to encourage greater public health through exercise. Existing qualitative research on this topic has, however, tended to focus on groups of highly committed runners. It is accordingly unclear whether their findings can be extrapolated to the much larger population of comparatively casual runners. This existing work has also tended to emphasise the social nature of the activity in particular ways. Whilst much recreational running happens alone, most commonly these studies have centred on the establishment of shared identities and group subcultures. Drawing on a study involving accompanied runs and interviews with recreational runners who do not belong to running clubs in London, this paper presents an alternative account. These respondents were relatively uninterested in the idea of proper running technique, ambivalent about the presence of others when running, and reticent about being pulled into a more committed collective practice. In view of how these more casual runners may be of particular interest to public health promoters, this finding suggests future campaigns might do well not to focus too greatly on the potential enjoyments of running community membership and start instead with a different set of social dynamics. PMID- 28003101 TI - Formative HIV Research With Youth in Kenya: Findings From a Psychosocial Needs Assessment. PMID- 28003102 TI - Contextualizing Psychosocial Determinants of Alcohol Use by Age Cohorts of Adults Living With HIV, Ages 50 and Older. AB - We examined the influence of age on associations between affective states, social support, and alcohol use by age cohorts. We recruited 96 older Black adults living with HIV from the southeastern United States in 2013 and 2014. Participants completed questionnaires assessing demographics, psychological function, and substance use. Hierarchical regression analyses assessed the relationship between psychosocial factors and alcohol use in a 50- to 59-year-old group, and a 60-years-and-older age group. After controlling for covariates, trait anger, state anger, and life stress were positively associated with alcohol consumption in the younger group, while social support was negatively associated with alcohol consumption in the older group. Interventions should target negative affective states in 50- to 59-year-old adults with HIV, and preserve social support for adults with HIV as they age, as such interventions will likely have an impact on these individuals' alcohol consumption and longstanding quality of life. PMID- 28003104 TI - Role of Simulation in Endovascular Aneurysm Repair (EVAR) Training: A Preliminary Study. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) requires a high-level of technical-competency to avoid device-related complications. Virtual reality simulation-based training (SBT) may offer an alternative method of psychomotor skill acquisition; however, its role in EVAR training is undefined. This study aimed to: a) benchmark competency levels using EVAR SBT, and b) investigate the impact of supervised SBT on trainee performance. METHODS: EVAR procedure-related metrics were benchmarked by six experienced consultants using a Simbionix Angiomentor EVAR simulator. Sixteen vascular surgical trainees performing a comparable EVAR before and after structured SBT (>4 teaching sessions) were assessed utilising a modified Likert-scale score. These were benchmarked for comparison against the standard set by the consultant body. RESULTS: Median procedural-time for consultants was 43.5 min (IQR 7.5). A significant improvement in trainee procedural-time following SBT was observed (median procedural time 77 min [IQR 20.75] vs. 56 min [IQR: 7.00], p < .0001). The mean (SD) trainee Likert score pre- and post-SBT improved (16.6 [SD 1.455] vs. 28.63 [SD 2.986], p < .0001). Fewer endoleaks were observed (p = .0063) and trainees chose an appropriately sized device more often after SBT. CONCLUSION: This study suggests that EVAR-SBT should be considered as an adjunct to standard psychomotor skill teaching techniques for EVAR within the vascular surgery training curricula. PMID- 28003103 TI - Retinopathy predicts progression of fasting plasma glucose: An Early Diabetes Intervention Program (EDIP) analysis. AB - BACKGROUND: Retinopathy is increasingly recognized in prediabetic populations, and may herald increased risk of metabolic worsening. The Early Diabetes Intervention Program (EDIP) evaluated worsening of glycemia in screen-detected Type 2 diabetes, following participants for up to 5years. Here we have evaluated whether the presence of retinopathy at the time of detection of diabetes was associated with accelerated progression of glycemia. METHODS: We prospectively studied 194 participants from EDIP with available baseline retinal photographs. Retinopathy was determined at baseline using 7-field fundus photography and defined as an Early Treatment of Diabetic Retinopathy Study Scale grading score of >=20. RESULTS: At baseline, 12% of participants had classical retinal lesions indicating retinopathy. In univariate Cox proportional hazard analysis, the presence of retinopathy at baseline was associated with a doubled risk of progression of fasting plasma glucose (HR 2.02; 95% CI 1.05-3.89). The retinopathy effect was robust to individual adjustment for age and glucose, the most potent determinants of progression in EDIP. CONCLUSION: Retinopathy was associated with increased risk of progression of fasting plasma glucose among adults with screen-detected, early diabetes. Early detection of retinopathy may help individualize more aggressive therapy to prevent progressive metabolic worsening in early diabetes. PMID- 28003105 TI - Motor cortex plasticity can indicate vulnerability to motor fluctuation and high L-DOPA need in drug-naive Parkinson's disease. AB - INTRODUCTION: Motor cortex plasticity is reported to be decreased in Parkinson's disease in studies which pooled patients in various stages of the disease. Whether the early decrease in plasticity is related to the motor signs or is linked to the future development of motor complications of treatment is unclear. The aim of the study was to test if motor cortex plasticity and its cerebellar modulation are impaired in treatment-naive Parkinson's disease, are related to the motor signs of the disease and predict occurrence of motor complications of treatment. METHODS: Twenty-nine denovo patients with Parkinson's disease were longitudinally assessed for motor complications for four years. Using transcranial magnetic stimulation, the plasticity of the motor cortex and its cerebellar modulation were measured (response to paired-associative stimulation alone or preceded by 2 active cerebellar stimulation protocols), both in the untreated state and after a single dose of L-DOPA. Twenty-six matched, healthy volunteers were tested, only without L-DOPA. RESULTS: Patients and healthy controls had similar proportions of responders and non-responders to plasticity induction. In the untreated state, the more efficient was the cerebellar modulation of motor cortex plasticity, the lower were the bradykinesia and rigidity scores. The extent of the individual plastic response to paired associative stimulation could indicate a vulnerability to develop early motor fluctuation but not dyskinesia. CONCLUSIONS: Measuring motor cortex plasticity in denovo Parkinson's disease could be a neurophysiological parameter that may help identify patients with greater propensity for early motor fluctuations. PMID- 28003106 TI - ST segment elevations in a patient with neutropenic fever. PMID- 28003107 TI - Metabolic Syndrome and the Risk of Ischemic Stroke: Methodological Issues. PMID- 28003108 TI - The evolution of a microsurgical reconstruction service at a central England Major Trauma Centre. PMID- 28003109 TI - Bilateral hand transplantation: Supporting the patient's choice. AB - Bilateral hand transplantation, as a fairly new reconstructive option for amputees, raises major ethical questions. This article, which is based on the reflections arising from the rich experience of Lyon's team in this field, addresses the topic of supporting the patient in his choice for or against this procedure. How should autonomy be understood in this particular setting? The developing field of composite tissue allotransplantation needs to establish a common thinking on this subject. The article emphasises that, even if it is their right to decide, patients have to be carefully supported to help them make the most consolidated choice possible in this challenging procedure. We deal with the question of the choice between the uncertainty in this innovative procedure and a life-threatening treatment to alleviate a handicap. We outline that the entire process of hand allograft is a unique opportunity for the patients to strengthen and exercise their autonomy in interaction with the medical team. PMID- 28003110 TI - Eosinophilic pneumonia caused by daptomycin: Six cases from two institutions and a review of the literature. AB - Here we report six cases of daptomycin (DAP)-induced eosinophilic pneumonia (DIEP) encountered at two medical centers and present a review of 43 DIEP patients from 26 studies to compare the clinical characteristics and radiographic findings of acute and chronic eosinophilic pneumonia (AEP; CEP). Four of the six patients did not exhibit respiratory symptoms, and one patient with only fever was misdiagnosed with DAP-induced fever. According to our literature review and the present findings, male sex and old age were dominant risk factors for DIEP. Fever and fine crackles were the most common clinical manifestations. The DAP dose and duration of administration were not significant risk factors for DIEP, and we also could not find any association between allergic predisposition and DIEP. Among the reviewed patients, 51.8% did not show more than 25% eosinophils in bronchoalveolar lavage, which is a criterion for the diagnosis of drug-induced eosinophilic pneumonia. Chest images of all patients showed CEP patterns such as multiple reticulonodular infiltrates in the subpleural region and diffuse bilateral pulmonary infiltrates with ground-glass opacities. However, 66.7% of patients also exhibited pleural effusion, a feature specific to AEP. All patients showed prompt recovery after DAP withdrawal. Our results suggest that clinicians should consider DIEP as a differential diagnosis when patients receiving DAP therapy, particularly men and elderly patients, present with fever, even in the absence of respiratory symptoms. Furthermore, they should be aware that the occurrence of DIEP is independent of the DAP dose and administration duration, and allergic reaction. PMID- 28003111 TI - Influence of the degree of adherence to the Mediterranean diet on the cardiometabolic risk in peri and menopausal women. The Flamenco project. AB - BACKGROUND AND AIMS: The Mediterranean diet (MD) has been associated with reduced morbidity from cardiovascular diseases in the general population. The aim of this study was to assess whether different degrees of adherence to the MD were associated with the cardiometabolic risk in peri and menopausal women. METHODS AND RESULTS: This cross-sectional study included 198 peri and menopausal women participating in the Flamenco project. Validated questionnaires were used to assess menopause health-related quality of life and degree of adherence to the MD (low, medium and high). The following cardiometabolic risk factors were assessed: fat mass percentage, waist circumference, blood pressure and resting heart rate, plasma markers (total cholesterol, high and low-density lipoprotein cholesterol [HDL-C and LDL-C, respectively], total cholesterol/HDL ratio, triglycerides, C reactive protein and fasting glucose), Physical activity levels and smoking status. The degree of adherence to the MD among the study sample was 27%, 40% and 30% for low, medium and high adherence, respectively. After controlling for potential confounders, women with a high adherence to the MD showed lower plasma total cholesterol (p = 0.025), resting heart rate (p = 0.005), LDL-C (p = 0.019), triglycerides (p = 0.046) and C-reactive protein (p = 0.009) compared to those with a low adherence. Likewise women with high adherence to the MD showed lower total cholesterol/HDL-C ratio (p = 0.020) compared to those with a medium adherence. The high MD adherence group also showed lower clustered cardiometabolic risk (p = 0.004). Moreover, when analysing specific MD components, whole grain cereals, pulses (both p < 0.05) and red wine (p < 0.01) consumption were inversely associated with the clustered cardiometabolic risk. CONCLUSION: The present findings suggest that a high but not medium adherence to the MD is associated with a cardioprotective effect in peri and menopausal women. As a low percentage of the sample showed a high adherence to the MD, future research aimed at increasing the adherence to this dietary pattern for a better cardiometabolic status during peri and menopause is warranted. PMID- 28003112 TI - Study of Duchenne muscular dystrophy long-term survivors aged 40 years and older living in specialized institutions in Japan. AB - The national muscular dystrophy wards database of Japan lists 118 long-term Duchenne muscular dystrophy (DMD) patients who were at least 40 years old as of October 1, 2013. To elucidate the clinical features of DMD patients aged 40 years and older, we obtained gene analysis and muscle biopsy findings, as well as medical condition information. Ninety-four of the registered patients consented to participate, of whom 55 meeting genetic or biochemical criteria confirming DMD were analyzed. The mean age at the time of the study was 43.6 +/- 3.0 years, while at the time of independent ambulation loss it was 10.6 +/- 1.5 years and at mechanical ventilation introduction it was 24.1 +/- 5.5 years. All were receiving continuous ventilation support, 27 with non-invasive positive pressure ventilation and 28 with tracheal intermittent positive pressure ventilation. Thirty-eight were receiving beta-blockers or a renin-angiotensin system inhibitor, while 9 were free from those agents. Forty had maintained oral nutrition. The 55 analyzed patients had survived into their 40s by receiving multidisciplinary intervention. Our findings emphasize the need of future studies to investigate disease modifiers and the mechanism of long-term survival. In addition, establishment of a worldwide care standard with focus on quality of life for adult males with DMD is important. PMID- 28003113 TI - Lymphoma in Taiwan: Review of 1347 neoplasms from a single institution according to the 2016 Revision of the World Health Organization Classification. AB - BACKGROUND/PURPOSE: Lymphoid neoplasms are heterogeneous and types of lymphoma vary in different geographic regions. In this study, we aimed at classifying the lymphoid neoplasms at our institution in Taiwan and to compare the relative frequency of various types of lymphoma in different countries. METHODS: We retrospectively searched the files of patients diagnosed with lymphoma at our institution from 2000 to 2015 based on the 2016 Revision of the World Health Organization classification. RESULTS: We identified 1339 patients with lymphoid neoplasms; among them, eight had two distinct types of lymphoid neoplasms. Of the 1347 neoplasms, 6.09% were Hodgkin lymphomas (HLs) and 93.31%, non-HL (NHLs). Among the 1257 NHLs, 82.66% were of B-cell lineage and 17.34% of T-cell lineage. The most common B-cell lymphoma types were diffuse large B-cell lymphoma, follicular lymphoma, and mucosa-associated lymphoid tissue lymphoma. Among T-cell neoplasms, 37% cases were of nodal origin and 63% cases arose in extranodal sites. The most common nodal and extranodal T-cell neoplasms were angioimmunoblastic T-cell lymphoma and extranodal natural killer/T-cell lymphoma, nasal type, respectively. CONCLUSION: We analyzed the largest series of lymphomas to date from Taiwan and concluded that HL was rare and T-cell neoplasms comprised around 17% of all NHLs in Taiwan. The relative frequency of the major lymphoma types is similar in East Asian countries, with only a minor difference, but the overall pattern in the East is quite different from that in the West, with the latter showing a higher frequency of HL and a lower rate of T-cell neoplasms. PMID- 28003114 TI - Does tracheal intubation really matter? Discrepant survival between laryngeal mask and endotracheal intubation during out-of-hospital cardiac arrest. PMID- 28003115 TI - Clinical outcomes of operative repair of complete rupture of the proximal interphalangeal joint collateral ligament: Comparison with non-operative treatment. AB - OBJECTIVES: The purpose of this study was to compare the outcomes of non operative treatment and operative repair of grade III injuries with complete rupture of the collateral ligament of the proximal interphalangeal (PIP) joint. PATIENTS AND METHODS: Seventeen patients with grade III injuries with at least 6 months of follow-up were included. Seven patients underwent non-operative treatment and 10 patients underwent operative treatment. We evaluated the following clinical outcomes after treatment: 1) range of motion of the PIP and distal interphalangeal (DIP) joints, 2) joint stability, 3) pain score, and 4) amount of fusiform deformity of the PIP joint. RESULTS: There was no instability in the lateral stress test in either group. The ranges of motion of the PIP and DIP joints were not statistically different between the two groups at final follow-up. However, the ranges of motion recovered more quickly in the operative group than the non-operative group within the first 3 months after treatment. Patients in the operative group had less pain and better cosmetic appearance of the PIP joint. CONCLUSION: Our results suggest that operative repair of the PIP collateral ligament can provide good joint stability, rapid functional recovery, and minimize fusiform deformity of the PIP joint. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 28003116 TI - Development of a low-maintenance measurement approach to continuously estimate methane emissions: A case study. AB - The chemical breakdown of organic matter in landfills represents a significant source of methane gas (CH4). Current estimates suggest that landfills are responsible for between 3% and 19% of global anthropogenic emissions. The net CH4 emissions resulting from biogeochemical processes and their modulation by microbes in landfills are poorly constrained by imprecise knowledge of environmental constraints. The uncertainty in absolute CH4 emissions from landfills is therefore considerable. This study investigates a new method to estimate the temporal variability of CH4 emissions using meteorological and CH4 concentration measurements downwind of a landfill site in Suffolk, UK from July to September 2014, taking advantage of the statistics that such a measurement approach offers versus shorter-term, but more complex and instantaneously accurate, flux snapshots. Methane emissions were calculated from CH4 concentrations measured 700m from the perimeter of the landfill with observed concentrations ranging from background to 46.4ppm. Using an atmospheric dispersion model, we estimate a mean emission flux of 709MUgm-2s-1 over this period, with a maximum value of 6.21mgm-2s-1, reflecting the wide natural variability in biogeochemical and other environmental controls on net site emission. The emissions calculated suggest that meteorological conditions have an influence on the magnitude of CH4 emissions. We also investigate the factors responsible for the large variability observed in the estimated CH4 emissions, and suggest that the largest component arises from uncertainty in the spatial distribution of CH4 emissions within the landfill area. The results determined using the low-maintenance approach discussed in this paper suggest that a network of cheaper, less precise CH4 sensors could be used to measure a continuous CH4 emission time series from a landfill site, something that is not practical using far-field approaches such as tracer release methods. Even though there are limitations to the approach described here, this easy, low-maintenance, low-cost method could be used by landfill operators to estimate time-averaged CH4 emissions and their impact downwind by simultaneously monitoring plume advection and CH4 concentrations. PMID- 28003117 TI - Facebook network structure and awareness of preexposure prophylaxis among young men who have sex with men. AB - BACKGROUND: Young Black men who have sex with men (YBMSM) are the only population in the United States who have experienced rising human immunodeficiency virus incidence over the past decade. Consistent pre-exposure prophylaxis (PrEP) use can substantially reduce the risk of human immunodeficiency virus acquisition. What differentiates those who become aware of PrEP, and those who do not, remains largely unknown. METHODS: The social networks of YBMSM can impact their awareness of PrEP; to examine this impact, we used two waves of Facebook data from "uConnect"-a longitudinal cohort study of YBMSM in Chicago (n = 266). RESULTS: While PrEP awareness increased from 45% at baseline to 75% at follow-up, its use remained low (4% and 6%). There were 88 PrEP-unaware individuals at baseline who became aware (BA) by follow-up, and 56 who remained persistently unaware. While the persistently unawares had a higher median number of total Facebook friends, the BAs had a higher median numbers of friends who participated in uConnect, who were PrEP-aware, and who practiced behaviors previously found to be associated with individual-level awareness of PrEP at baseline. The BAs also had substantially more "influential" friends. CONCLUSION: These findings demonstrate the potential of social networks in raising PrEP awareness and use among YBMSM. PMID- 28003118 TI - Accuracy of biopsy for the preoperative diagnosis of superficial nonampullary duodenal adenocarcinoma. AB - BACKGROUND AND AIMS: Endoscopic biopsy sampling for the diagnosis of duodenal adenocarcinoma is not perfect. We investigated the accuracy of biopsy specimen diagnoses of superficial nonampullary duodenal epithelial tumors (NADETs). METHODS: Clinicopathologic data were retrospectively reviewed for 95 superficial NADETs from 95 patients who underwent endoscopic resection. Preoperative diagnoses based on biopsy specimens were compared with histologic diagnoses of resected specimens. RESULTS: Among the 21 lesions with biopsy specimen diagnoses of carcinoma, 12 (57.1%) were histologically diagnosed as adenomas after resection. Among the 74 lesions with biopsy specimen diagnoses of adenoma, 15 (20.3%) were histologically diagnosed as carcinomas after resection. The duodenal biopsy specimen predicted final histologic diagnoses of carcinoma with a sensitivity of 37.5% (95% CI, 18.8-59.4), specificity of 83.1% (95% CI, 72.3 91.0), accuracy of 71.6% (95% CI, 61.4-80.4), positive predictive value of 42.9% (95% CI, 21.8-66.0), and negative predictive value of 79.7% (95% CI, 68.8-88.2). Among 61 cases considered suitable for EMR, treatment modality was converted from EMR to endoscopic submucosal dissection because of the nonlifting sign in 15 cases (24.6%). CONCLUSIONS: The accuracy of duodenal biopsy sampling was relatively low. Duodenal biopsy sampling may induce unexpected fibrosis. New endoscopic modalities that can improve preoperative diagnosis yield of NADETs are eagerly awaited. PMID- 28003119 TI - Secretomes of Mycoplasma hyopneumoniae and Mycoplasma flocculare reveal differences associated to pathogenesis. AB - : Mycoplasma hyopneumoniae and Mycoplasma flocculare cohabit the porcine respiratory tract. However, M. hyopneumoniae causes the porcine enzootic pneumonia, while M. flocculare is a commensal bacterium. Comparative analyses demonstrated high similarity between these species, which includes the sharing of all predicted virulence factors. Nevertheless, studies related to soluble secretomes of mycoplasmas were little known, although they are important for bacterial-host interactions. The aim of this study was to perform a comparative analysis between the soluble secreted proteins repertoires of the pathogenic Mycoplasma hyopneumoniae and its closely related commensal Mycoplasma flocculare. For that, bacteria were cultured in medium with reduced serum concentration and secreted proteins were identified by a LC-MS/MS proteomics approach. Altogether, 62 and 26 proteins were identified as secreted by M. hyopneumoniae and M. flocculare, respectively, being just seven proteins shared between these bacteria. In M. hyopneumoniae secretome, 15 proteins described as virulence factors were found; while four putative virulence factors were identified in M. flocculare secretome. For the first time, clear differences related to virulence were found between these species, helping to elucidate the pathogenic nature of M. hyopneumoniae to swine hosts. BIOLOGICAL SIGNIFICANCE: For the first time, the secretomes of two porcine respiratory mycoplasmas, namely the pathogenic M. hyopneumoniae and the commensal M. flocculare were compared. The presented results revealed previously unknown differences between these two genetically related species, some of which are associated to the M. hyopneumoniae ability to cause porcine enzootic pneumonia. PMID- 28003120 TI - Nanodiamond-Manganese dual mode MRI contrast agents for enhanced liver tumor detection. AB - Contrast agent-enhanced magnetic resonance (MR) imaging is critical for the diagnosis and monitoring of a number of diseases, including cancer. Certain clinical applications, including the detection of liver tumors, rely on both T1 and T2-weighted images even though contrast agent-enhanced MR imaging is not always reliable. Thus, there is a need for improved dual mode contrast agents with enhanced sensitivity. We report the development of a nanodiamond-manganese dual mode contrast agent that enhanced both T1 and T2-weighted MR imaging. Conjugation of manganese to nanodiamonds resulted in improved longitudinal and transverse relaxivity efficacy over unmodified MnCl2 as well as clinical contrast agents. Following intravenous administration, nanodiamond-manganese complexes outperformed current clinical contrast agents in an orthotopic liver cancer mouse model while also reducing blood serum concentration of toxic free Mn2+ ions. Thus, nanodiamond-manganese complexes may serve as more effective dual mode MRI contrast agent, particularly in cancer. PMID- 28003121 TI - Silencing peroxiredoxin-2 sensitizes human colorectal cancer cells to ionizing radiation and oxaliplatin. AB - Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. Antioxidant enzymes decrease the generation of ionizing radiation (IR) induced free radicals and therefore are associate to radioresistance. The main goal of this work is to study the involvement of peroxiredoxin-2 (Prx2) in the radio and chemoradiotherapy response in CRC cells in vitro and in vivo. We found that Prx2 oxidation state is associated to differential response to ionizing radiation in CRC cell lines. HCT116 radioresistant CRC cell line have lower ROS levels and a higher monomer/dimer Prx2 ratio, compared to halfway resistant Caco 2 and T84, and radiosensitive LoVo cell line. Constitutive and transient Prx2 silencing in CRC cells increase ROS levels, and most importantly, enhance in vitro radiation sensitivity. In addition, we showed that administration of IR plus oxaliplatin in down regulated Prx2 HCT116 cells has higher citotoxic effect than in control cells. Finally, radiosensitizing effect of Prx2 depletion was confirmed in vivo. These results suggest that Prx2 is an important component in tumoral radiation response, and their inhibition could improve radio and chemoradiotherapy protocols in patients with CRC. PMID- 28003122 TI - Metronomic chemotherapy: A relook at its basis and rationale. AB - Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema. PMID- 28003123 TI - Chronic norovirus infection among solid organ recipients in a tertiary care hospital, the Netherlands, 2006-2014. AB - OBJECTIVES: Immunocompromised patients can suffer prolonged norovirus symptoms and virus shedding for many years. Little is known about the prevalence of chronic norovirus infection among solid organ transplant (SOT) recipients. In this study, 2182 SOT recipients were retrospectively tested for chronic norovirus infection. METHODS: The first and last norovirus positive faecal samples of SOT recipients were sequenced to distinguish between persisting infection and re infection. Patient charts were reviewed to obtain data on health status and treatments. RESULTS: In all, 101 of 2182 (4.6%) recipients were norovirus infected and 23 (22.8%) of these developed chronic norovirus infection. Chronic norovirus infection was found among allogeneic heart, kidney and lung transplant recipients. The median shedding period at the end of the study period was 218 days (range 32-1164 days). CONCLUSIONS: This study shows that chronic norovirus infection is not a rare phenomenon among SOT recipients in a tertiary-care hospital. Further research is needed to study the risk of norovirus transmission to other immunocompromised patients in the hospital and to the general population. PMID- 28003124 TI - CMI Theme Issues: Invitation to submit papers. PMID- 28003125 TI - Identification of a novel starch synthase III from the picoalgae Ostreococcus tauri. AB - Hydrosoluble glycogen is the major energy storage compound in bacteria, archaea, fungi, and animal cells. In contrast, photosynthetic eukaryotes have evolved to build a highly organized semicrystalline granule of starch. Several enzymes are involved in polysaccharide synthesis, among which glycogen or starch synthase catalyze the elongation of the alpha-1,4-glucan chain. Ostreococcus tauri, accumulates a single starch granule and contains three starch synthase III (SSIII) isoforms, known as OsttaSSIII-A, OsttaSSIII-B and OsttaSSIII-C. After amino acids sequence analysis we found that OsttaSSIII-C lacks starch-binding domains, being 49% identical to the catalytic region of the SSIII from Arabidopsis thaliana and 32% identical to the entire Escherichia coli glycogen synthase. The recombinant, highly purified OsttaSSIII-C exhibited preference to use as a primer branched glycans (such as rabbit muscle glycogen and amylopectin), rather than amylose. Also, the enzyme displayed a high affinity toward ADP-glucose. We found a marked conservation of the amino acids located in the catalytic site, and specifically determined the role of residues R270, K275 and E352 by site-directed mutagenesis. Results show that these residues are important for OsttaSSIII-C activity, suggesting a strong similarity between the active site of the O. tauri SSIII-C isoform and other bacterial glycogen synthases. PMID- 28003126 TI - Emerging role of Hippo signalling in pancreatic biology: YAP re-expression and plausible link to islet cell apoptosis and replication. AB - Diabetes mellitus is an ailment that develops when the functional capacity of the pancreas does not meet the metabolic requirements of the whole body, either due to insulin insufficiency or resistance to insulin action. Current therapies that control glycaemia are limited by their unwanted effects or their inability to prevent the development of long-term complications. Regeneration and replacement of beta cell therapies are shaping the goals of future management of diabetes. The Hippo pathway, first discovered in Drosophila melanogaster, plays a vital role in controlling the organ size. Nuclear recruitment of YAP/TAZ (Yes associated protein/transcriptional co-activator with PDZ-binding motif), a mammalian analogue of Yorkie protein found in Drosophila, activates cell proliferation and inhibits apoptosis. YAP was found to regulate early pancreatic development followed by downregulation during Ngn3-specific endocrine lineage maturation corresponding to their mitotic quiescence. Recent evidences have shown that optimum modulation of upstream kinases in the Hippo signalling pathway may lead to apoptosis inhibition and renewal of progenitor as well as stem cells in case of tissue or cell injury. This article reviews the evidences linking the role of various components of the Hippo pathway to pancreatic regeneration. In particular, the focus is on the beneficial role of induced YAP expression and its nuclear distribution on apoptosis and replication of adult pancreatic beta islets. This approach may be of immense significance towards our fight against diabetes; thus, more insightful research is warranted in the area of Hippo signalling pathway and its involvement in pancreatic regeneration. PMID- 28003127 TI - Consolidation and reconsolidation are impaired by oral propranolol administered before but not after memory (re)activation in humans. AB - Propranolol administered immediately after learning or after recall has been found to impair memory consolidation or reconsolidation (respectively) in animals, but less reliably so in humans. Since reconsolidation impairment has been proposed as a treatment for mental disorders that have at their core an emotional memory, it is desirable to understand how to reliably reduce the strength of pathogenic memories in humans. We postulated that since humans (unlike experimental animals) typically receive propranolol orally, this introduces a delay before this drug can exert its memory impairment effects, which may render it less effective. As a means to test this, in two double-blind placebo-controlled experiments, we examined the capacity of propranolol to impair consolidation and reconsolidation as a function of timing of ingestion in healthy subjects. In Experiment 1, (n=36), propranolol administered immediately after learning or recall failed to impair the consolidation or reconsolidation of the memory of a standardized slideshow with an accompanying emotional story. In Experiment 2 (n=50), propranolol given 60-75min before learning or recall successfully impaired memory consolidation and reconsolidation. These results suggest that it is possible to achieve reliable memory impairment in humans if propranolol is given before learning or before recall, but not after. PMID- 28003128 TI - Structural and binding studies of a C-type galactose-binding lectin from Bothrops jararacussu snake venom. AB - BJcuL is a snake venom galactoside-binding lectin (SVgalL) isolated from Bothrops jararacussu and is involved in a wide variety of biological activities including triggering of pro-inflammatory response, disruption of microbial biofilm structure and induction of apoptosis. In the present work, we determined the crystallographic structure of BJcuL, the first holo structure of a SVgalL, and introduced the fluorescence-based thermal stability assay (Thermofluor) as a tool for screening and characterization of the binding mechanism of SVgalL ligands. BJcuL structure revealed the existence of a porous and flexible decameric arrangement composed of disulfide-linked dimers related by a five-fold symmetry. Each monomer contains the canonical carbohydrate recognition domain, a calcium ion required for BJcuL lectinic activity and a sodium ion required for protein stabilization. BJcuL thermostability was found to be induced by calcium ion and galactoside sugars which exhibit hyperbolic saturation profiles dependent on ligand concentration. Serendipitously, the gentamicin group of aminoglycoside antibiotics (gAGAs) was also identified as BJcuL ligands. On contrast, gAGAs exhibited a sigmoidal saturation profile compatible with a cooperative mechanism of binding. Thermofluor, hemagglutination inhibition assay and molecular docking strategies were used to identify a distinct binding site in BJcuL localized at the dimeric interface near the fully conserved intermolecular Cys86-Cys86 disulfide bond. The hybrid approach used in the present work provided novel insights into structural behavior and functional diversification of SVgaLs. PMID- 28003129 TI - Comparison and standardization of soil enzyme assay for meaningful data interpretation. AB - Data interpretation and comparison in enzyme assays can be challenging because of the complex nature of the environment and variations in methods employed. This letter provides an overview of common enzyme assays, the need for methods standardization, and solutions addressing some of the concerns in microplate fluorimetric assay approaches. PMID- 28003130 TI - Ethnopharmacological survey of medicinal plants used in Daraa-Tafilalet region (Province of Errachidia), Morocco. AB - ETHNOPHARMACOLOGICAL RELEVANCE: We carried out an ethnobotanical survey in Tafilalet region. This region is classified by the UNESCO as a reserve of biosphere and represents an important area with important knowledge of traditional medicine, especially the use of medicinal plants for human healthcare. Furthermore, the geographic location of this region makes this site a diverse and interesting resource of herbal biodiversity. THE AIM OF THE STUDY: The study aimed to collect information about medicinal plants used in Tafilalet region as well as the indigenous knowledge related to the use of this natural resource in healthcare by the local population in order to preserve and protect this invaluable inheritance from loss and overlook. We aimed also to compare taxa used by the indigenous people of Tafilalet for health-care purposes in comparison with other regions of Morocco as well as neighboring countries. MATERIAL AND METHODS: The total of informants interviewed in this study was 1616 (1500 were local inhabitants and 116 were herbalists). This enquiry was carried out through semi-structured and unstructured interviews and the sampling technique used was the stratified sample (9 stratums). Data obtained were analyzed calculating 6 indices: Use Value (UV), Family Use Value (FUV), Fidelity Level (FL), Rank Order Priority (ROP), Informant Consensus Factor (Fic) and Jaccard similarity Index (JI). RESULTS: 194 species belonging to 69 families were inventoried in this survey and 17 species were cited for the first time in an ethnobotanical survey in Morocco. The highest value of UV was obtained for Rosmarinus officinalis L. (UV=0.24) and Liliaceae was the family frequently used by inhabitants of Tafilalet (FUV=0.106). In addition, the highest value of FL was recorded for Cistus salviifolius L. and Daphne gnidium L. with FL value of 100% for both species and Origanium vulgare L. had the highest ROP with a value of 53% while the highest value of FIC was mentioned for digestive system disorders (FIC=0.29). Concerning the level of similarity between our study and other regions of Morocco, the province of Tata seems to be the most similar to Tafilalet (JI=42.97), while M'sila (Algeria) was the most similar to Tafilalet among areas in neighboring countries (JI=13.00). CONCLUSION: Despite the richness which characterizes Tafilalet regarding diversity and effectiveness of medicinal plants as well as the largest culture and knowledge related to the popular phytotherapy among local people in this region, several procedures must be realized to protect and to valorize this interesting inheritance. PMID- 28003131 TI - CRISPR/Cas9-mediated integration enables TAG-eCLIP of endogenously tagged RNA binding proteins. AB - Identification of in vivo direct RNA targets for RNA binding proteins (RBPs) provides critical insight into their regulatory activities and mechanisms. Recently, we described a methodology for enhanced crosslinking and immunoprecipitation followed by high-throughput sequencing (eCLIP) using antibodies against endogenous RNA binding proteins. However, in many cases it is desirable to profile targets of an RNA binding protein for which an immunoprecipitation-grade antibody is lacking. Here we describe a scalable method for using CRISPR/Cas9-mediated homologous recombination to insert a peptide tag into the endogenous RNA binding protein locus. Further, we show that TAG-eCLIP performed using tag-specific antibodies can yield the same robust binding profiles after proper control normalization as eCLIP with antibodies against endogenous proteins. Finally, we note that antibodies against commonly used tags can immunoprecipitate significant amounts of antibody-specific RNA, emphasizing the need for paired controls alongside each experiment for normalization. TAG eCLIP enables eCLIP profiling of new native proteins where no suitable antibody exists, expanding the RBP-RNA interaction landscape. PMID- 28003132 TI - Frequency and Morbidity of Temporomandibular Joint Involvement in Adult Patients With a History of Juvenile Idiopathic Arthritis. AB - PURPOSE: Most patients with juvenile idiopathic arthritis (JIA) have temporomandibular joint (TMJ) involvement, but little is known about the natural history of TMJ disease as these children enter adulthood. The purpose of this study was to evaluate adults with a history of JIA to document the frequency and severity of TMJ abnormalities and morbidity. The authors hypothesized that most would have persistent TMJ disease as adults. MATERIALS AND METHODS: This cross sectional study included adults (>19 years of age) with JIA who were managed at Boston Children's Hospital (BCH) as children and at Brigham and Women's Hospital (BWH) as adults. History of a TMJ problem was not considered for enrollment. Patients completed a questionnaire and underwent physical examination and maxillofacial cone-beam computed tomography (CBCT). Additional data were obtained from medical records. Associations between TMJ abnormalities at CBCT and arthritis history, TMJ pain and function, facial asymmetry, malocclusion, and cephalometric analysis were examined. RESULTS: Of 129 eligible patients contacted, 21 (42 TMJs) were enrolled. Mean age was 26.0 +/- 6.1 years and mean duration of care for JIA at the BCH and BWH was 13.7 +/- 6.5 years. TMJ pain was present in 62% of patients (n = 13); 43% (n = 9) had a TMJ functional limitation and 76% (n = 16) had lower facial asymmetry. Abnormalities were found in the TMJs on 55% of CBCT scans, with 79% showing bilateral deformities. There was at least 1 cephalometric measurement of mandibular size or position that was more than 1 standard deviation beyond normal in 81% of patients (n = 17). Only 4 patients (19%) had previously been evaluated for a TMJ problem. CONCLUSION: TMJ abnormalities and related morbidity are common in adult patients with a history of JIA. Therefore, an early screening protocol for TMJ involvement in children with a new diagnosis of JIA would be beneficial and long-term follow-up into adulthood should be routine. PMID- 28003133 TI - Myofascial Induction Effects on Neck-Shoulder Pain in Breast Cancer Survivors: Randomized, Single-Blind, Placebo-Controlled Crossover Design. AB - OBJECTIVES: To (1) investigate the immediate effects of myofascial induction (MI), with placebo electrotherapy as a control, on perceived pain, cervical/shoulder range of motion (ROM), and mood state in breast cancer survivors (BCSs) with shoulder/arm morbidity; and (2) examine the relationships between pain modifications and cervical/shoulder ROM on the side affected by breast cancer. DESIGN: Randomized, single-blind, placebo-controlled crossover study. SETTING: Physical therapy laboratory. PARTICIPANTS: BCSs (N=21) who had a diagnosis of stage I-IIIA breast cancer and had completed adjuvant therapy (except hormonal treatment). INTERVENTION: During each session, the BCSs received either an MI (fascial unwinding) intervention focused on the upper limb area following the Pilat approach or placebo pulsed shortwave therapy (control group). Each session lasted 30 minutes, and an adequate washout period of 4 weeks between sessions was established. MAIN OUTCOME MEASURES: The visual analog scale (VAS) for pain and anxiety, shoulder-cervical goniometry for ROM, the Profile of Mood States for psychological distress, and the Attitudes Towards Massage Scale were used. RESULTS: An analysis of covariance (ANCOVA) revealed significant time * group interactions for VAS affected arm (P=.031) but not for VAS cervical (P=.332), VAS nonaffected arm (P=.698), or VAS anxiety (P=.266). The ANCOVA also revealed significant interactions for affected shoulder flexion (P<.001), abduction (P<.001), external rotation (P=.004), and internal rotation (P=.001). Significant interactions for affected cervical rotation (P=.022) and affected cervical lateral flexion (P=.038) were also found. A significant negative correlation was found between changes in VAS affected arm and shoulder/arm internal rotation ROM (r=-.46; P=.03). CONCLUSIONS: A single MI session decreases pain intensity and improves neck-shoulder ROM to a greater degree than placebo electrotherapy for BCSs experiencing pain. PMID- 28003134 TI - Benefits of Centralized Scheduling in a Postacute Residential Rehabilitation Program for People With Acquired Brain Lesions: A Pilot Study. AB - OBJECTIVE: To determine whether the use of a designated staff person to coordinate and schedule therapy services in a postacute residential rehabilitation program for people with acquired brain lesions results in (1) a higher-intensity treatment and a reduced length of stay; (2) reduced rehabilitation costs; and (3) increased patient and staff satisfaction. DESIGN: This nonrandomized retrospective study from 2009 through 2012 uses data collected relative to 2 different methods of scheduling: (1) self-planning, in which each single team member makes appointments that are then displayed on a shared board; and (2) managed planning, in which appointments are made by a designated staff person. SETTING: A residential center for people with postacute acquired brain lesions. PARTICIPANTS: Patients (N=20) with acquired brain lesions who had similar clinical and demographic characteristics comprised the managed planning group (n=10) and the self-planning group (n=10). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Organizational measures (length of stay in rehabilitation, number of treatment hours, total cost of rehabilitation), clinical outcome scales (Disability Rating Scale, FIM, and Barthel Index), perceived quality of treatment by patients (questionnaire), and perceived satisfaction of team members (Job Descriptive Index). RESULTS: All patients improved on all clinical rating scales at the time of discharge (all effect sizes are large). In the managed planning group, the number of treatment hours increased (Cohen's d=2.15), resulting in reduced length of stay (Cohen's d=.95) and cost of rehabilitation (Cohen's d=1.22). In addition, the quality of treatment perceived by the patients and their families increased, while team member satisfaction did not change. CONCLUSIONS: The use of a designated staff person to manage therapy services improves efficiency and efficacy of a patient-centered health care system. The proposed scheduling system results in a remarkable cost saving for the National Health System. PMID- 28003135 TI - Effect of patient positioning on carbon-ion therapy planned dose distribution to pancreatic tumors and organs at risk. AB - PURPOSE: Pancreatic tumor treatment dose distribution variations associated with supine and prone patient positioning were evaluated. METHODS: A total of 33 patients with pancreatic tumors who underwent CT in the supine and prone positions were analyzed retrospectively. Gross tumor volume (GTV), planning target volume (PTV), and organs at risk (OARs) (duodenum and stomach) were contoured. The prescribed dose of 55.2Gy (RBE) was planned from four beam angles (0 degrees , 90 degrees , 180 degrees , and 270 degrees ). Patient collimator and compensating boli were designed for each field. Dose distributions were calculated for each field in the supine and prone positions. To improve dose distribution, patient positioning was selected from supine or prone for each beam field. RESULTS: Compared with conventional beam angle and patient positioning, D2cc of 1st-2nd portion of duodenum (D1-D2), 3rd-4th portion of duodenum (D3-D4), and stomach could be reduced to a maximum of 6.4Gy (RBE), 3.5Gy (RBE), and 4.5Gy (RBE) by selection of patient positioning. V10 of D1-D2, D3-D4, and stomach could be reduced to a maximum of 7.2cc, 11.3cc, and 11.5cc, respectively. D95 of GTV and PTV were improved to a maximum of 6.9% and 3.7% of the prescribed dose, respectively. CONCLUSIONS: Optimization of patient positioning for each beam angle in treatment planning has the potential to reduce OARs dose maintaining tumor dose in pancreatic treatment. PMID- 28003136 TI - Practical approaches to approximating MTF and NPS in CT with an example application to task-based observer studies. AB - PURPOSE: To investigate two methods of approximating the Modulation Transfer Function (MTF) and Noise Power Spectrum (NPS) in computed tomography (CT) for a range of scan parameters, from limited image acquisitions. METHODS: The two methods consist of 1) using a linear systems approach to approximate the NPS for different filtered backprojection (FBP) kernels with a filter function derived from the kernel ratio of determined MTFs and 2) using an empirical fitted model to approximate the MTF and NPS. In both cases a scaling function accounts for variations in mAs and kV. The two methods of approximating the MTF/NPS are further investigated by comparing image quality figure of merits (FOM) d' and AUC calculated using approximations of the MTF/NPS and MTF/NPS that have been determined for different mAs/kV levels and reconstruction kernels. RESULTS: The greatest RMSE for NPS approximated for a range of mAs/kVp/convolution kernels using both methods and compared to determined NPS was 0.05 of the peak value. The RMSE for FOM with the kernel ratio method were at most 0.1 for d' and 0.01 for the AUC. Using the empirical model method, the RMSE for FOM were at most 0.02 for d' and 0.001 for the AUC. CONCLUSIONS: The two methods proposed in this paper can provide a convenient way of approximating the MTF and NPS for use in, among other things, mathematical observer studies. Both methods require a relatively small number of direct determinations of NPS from scan acquisitions to model the NPS/MTF for arbitrary mAs and kV. PMID- 28003137 TI - A feasible and automatic free tool for T1 and ECV mapping. AB - PURPOSE: Cardiac magnetic resonance (CMR) is a useful non-invasive tool for characterizing tissues and detecting myocardial fibrosis and edema. Estimation of extracellular volume fraction (ECV) using T1 sequences is emerging as an accurate biomarker in cardiac diseases associated with diffuse fibrosis. In this study, automatic software for T1 and ECV map generation consisting of an executable file was developed and validated using phantom and human data. METHODS: T1 mapping was performed in phantoms and 30 subjects (22 patients and 8 healthy subjects) on a 1.5T MR scanner using the modified Look-Locker inversion-recovery (MOLLI) sequence prototype before and 15 min after contrast agent administration. T1 maps were generated using a Fast Nonlinear Least Squares algorithm. Myocardial ECV maps were generated using both pre- and post-contrast T1 image registration and automatic extraction of blood relaxation rates. RESULTS: Using our software, pre- and post-contrast T1 maps were obtained in phantoms and healthy subjects resulting in a robust and reliable quantification as compared to reference software. Coregistration of pre- and post-contrast images improved the quality of ECV maps. Mean ECV value in healthy subjects was 24.5%+/-2.5%. CONCLUSIONS: This study demonstrated that it is possible to obtain accurate T1 maps and informative ECV maps using our software. Pixel-wise ECV maps obtained with this automatic software made it possible to visualize and evaluate the extent and severity of ECV alterations. PMID- 28003138 TI - Rational design, synthesis and in vitro evaluation of novel exo-methylene butyrolactone salicyloylamide as NF-kappaB inhibitor. AB - (-)-Dehydroxymethylepoxyquinomicin ((-)-DHMEQ, 1) is a specific inhibitor of NF kappaB. It binds to SH group in the specific cysteine residue of NF-kappaB components with its epoxide moiety to inhibit DNA binding. In the present research, we have designed and synthesized an epoxide-free analog called (S)-beta salicyloylamino-alpha-exo-methylene-y-butyrolactone (SEMBL, 3). SEMBL inhibited DNA binding of NF-kappaB component p65 in vitro. It inhibited LPS-induced NF kappaB activation, iNOS expression, and inflammatory cytokine secretions. It also inhibited NF-kappaB and cellular invasion in ovarian carcinoma ES-2 cells. Moreover, its stability in aqueous solution was greatly enhanced compared with ( )-DHMEQ. Thus, SEMBL has a potential to be a candidate for a new anti inflammatory and anticancer agent. PMID- 28003139 TI - Antileishmanial evaluation of clubbed bis(indolyl)-pyridine derivatives: One-pot synthesis, in vitro biological evaluations and in silico ADME prediction. AB - A new series of bis(indolyl)-pyridine derivatives 6(a-m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure-activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC50=102.47MUM) and 6f (IC50=99.49MUM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC50=490.00MUM). All the synthesized compounds (MIC range=41.35-228.69MUg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range=100.00-250.00MUg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives. PMID- 28003140 TI - Slow generation of hydrogen sulfide from sulfane sulfurs and NADH models. AB - Here we report the model studies of the reactions between NADH models (using HEH and BNAH) and sulfane sulfurs (using polysulfides). Such reactions could lead to the oxidation of NADH models and the production of hydrogen sulfide (H2S). Kinetics of the reaction between BNAH and elemental sulfur S8 were determined in ethanol and the second-order rate constant was found to be 0.074M-1min-1 (at 37 degrees C) suggesting this is a slow process. PMID- 28003141 TI - Identification and optimization of a novel series of indoleamine 2,3-dioxygenase inhibitors. AB - The discovery of a series of structurally-novel biaryl urea IDO inhibitors is described. Optimization of a micromolar hit through iterative cycles of synthesis and screening in an assay measuring IDO-mediated intracellular conversion of tryptophan to kynurenine led to potent inhibitors with favorable selectivity and metabolic stability profiles. PMID- 28003142 TI - Design, synthesis and biological activity of novel molecules designed to target PARP and DNA. AB - In order to enhance the cytotoxic potential of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1 or 2 deficient tumours, we designed a series of molecules containing a 1,2,3-triazene moiety tethered to a PARP targeting scaffold. A cell based selectivity assay involving a BRCA2-deficient Chinese hamster cell line and its corresponding BRCA2 wild type transfectant, was used to predict the PARP targeting potential of the latter agents. The results showed that adding a DNA damaging function to the PARP inhibitors decreased but did not abrogate the selective targeting of the BRCA2-deficient cells. The DNA damaging moiety augmented the potency in BRCA2 deficient cells by 2-20 fold. The most selective dual PARP-DNA targeting agent 14b was found to possess dual DNA and PARP targeting properties. PMID- 28003143 TI - Adverse Childhood Experiences and ADHD Diagnosis at Age 9 Years in a National Urban Sample. AB - OBJECTIVE: To examine associations between adverse childhood experiences (ACEs) and attention-deficit/hyperactivity disorder (ADHD) at age 9 years using longitudinal data and assess the extent to which ACEs during middle childhood are independently associated with ADHD at age 9 years. METHODS: We conducted a secondary analysis of data from the Fragile Families urban birth cohort 5- and 9 year interviews. The sample was limited to children for whom mothers were the primary caregiver and mother-reported information on 8 ACEs and ADHD were available at age 5 and 9 years. We examined associations between ACEs and parent reported ADHD at age 9 years using logistic regression and controlling for potential confounders. RESULTS: We included 1572 children; 48% were African American, 11% had parent-reported ADHD at age 9 years, 41% and 42% experienced >=1 ACE by age 5 years and between the ages of 5 and 9 years, respectively. ACEs before age 5 years were associated with ADHD at age 9 years. One, 2, and >=3 ACEs between age 5 and 9 years were associated with ADHD at age 9 years even after controlling for ACEs before age 5 years and ADHD at age 5 years (adjusted odds ratio [AOR], 1.9; 95% confidence interval [CI], 1.2-3; AOR, 2.1; 95% CI, 1.2-3.8; and AOR, 2.2; 95% CI, 1.1-4.3). CONCLUSIONS: In this study of urban children, ACEs occurring before age 5 years as well as between the ages of 5 and 9 years were associated with ADHD at age 9 years. Even after controlling for early childhood ACEs and ADHD at age 5 years, the association between ADHD and ACEs in middle childhood remained significant, highlighting the importance of screening and intervention throughout childhood. PMID- 28003144 TI - Self-assembled supramolecular polymers with tailorable properties that enhance cell attachment and proliferation. AB - : Self-assembled supramolecular scaffolds, a combination of noncovalent interactions within a biocompatible polymer substrate, can be used for efficient construction of highly-controlled self-organizing hierarchical structures; these newly-developed biomaterials exhibit excellent mechanical properties, tunable surface hydrophilicity, low cytotoxicity and high biodegradability, making them highly attractive for tissue engineering and regenerative medicine applications. Herein, we demonstrate a novel supramolecular poly(epsilon-caprolactone) (PCL) containing self-complementary sextuple hydrogen-bonded uracil-diamidopyridine (U DPy) moieties, which undergoes spontaneous self-assembly to form supramolecular polymer networks. Inclusion of various U-DPy contents enhanced the mechanical strength and viscosities of the resulting materials by up to two orders of magnitude compared to control PCL. Surface wettability and morphological studies confirmed physically-crosslinked films can be readily tailored to provide the desired surface properties. Cell viability assays indicated the excellent in vitro biocompatibility of U-DPy-functionalized substrates and indicate the potential of these materials for various biomedical applications. More importantly, mouse fibroblast NIH/3T3 cells cultured on these substrates displayed a more elongated cell morphology and had substantially higher cell densities than cells seeded on control PCL substrate, which indicates that introduction of U-DPy moieties into polymer matrixes could be used to create tissue culture surfaces that enhance cell attachment and proliferation. This new system is suggested as a potential route towards the practical realization of next-generation tissue-engineering scaffolds. STATEMENT OF SIGNIFICANCE: In this study, we report a significant breakthrough in development of self-assembled supramolecular polymers to form well-defined scaffolds through self-complementary hydrogen-bonding interactions. These newly developed materials exhibited extremely good mechanical properties, fine-tunable hydrophilic characteristics and excellent biocompatibility due to hydrogen-bond-induced physical cross linking. Importantly, cell adhesion and proliferation assays indicated that these substrates efficiently promoted the growth of mouse embryonic fibroblasts NIH/3T3 cells in vitro. Thus, this finding provides a simple and effective route for the development of next-generation tissue-engineering scaffolds that have improved mechanical properties, increased surface hydrophilicity and can enhance the growth and biological activity of adherent cells. PMID- 28003145 TI - A simple basis for determination of the modulus and hydraulic conductivity of human ocular surface using nano-indentation. AB - : This paper presents a simple analysis based upon Darcy's Law and indentation contact mechanics to determine the effective hydraulic conductivity and elastic modulus of fluid filled tissues. The approach is illustrated with the mechanical response of the human ocular surface using a 500MUm radius spherical tipped indenter. Indentations of various regions of the ocular surface including the corneal stroma, limbal region and sclera have been conducted. Force-control indentations were made to a maximum force, which was maintained before unloading. Measurements of the indentation response of cornea at three different loading rates were also made. Elastic like response was observed during loading, which was followed by extensive creep prior to unloading. STATEMENT OF SIGNIFICANCE: This manuscript attempts to provide a relatively simply model for the contact loading of fluid containing tissues and materials. It shows that the response of such materials provides a basis for determining the effective modulus and effective hydraulic conductivity (permeability) in much the same manner that hardness and modulus do for the indentation of elastic-plastic materials. Eye tissue with its anisotropic elastic and permeability properties is used to illustrate the approach. PMID- 28003146 TI - Injectable hyaluronic acid down-regulates interferon signaling molecules, IGFBP3 and IFIT3 in the bovine intervertebral disc. AB - : Low back pain which is a major cause of disability for people aged between 20 and 50years imposes a serious socio-economic burden. The current focus of regenerative medicine is on identifying molecular markers to facilitate the design of targeted therapeutics. Previously, we have demonstrated that expression of the anti-proliferative interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and pro-apoptotic insulin-like growth factor-binding protein-3 (IGFBP3), are up-regulated as downstream targets of the inflammatory cytokine interferon alpha (IFNalpha) signaling pathway in the human annulus fibrosus (AF). Here, we hypothesised that injection of hyaluronic acid (HA) would have an anti inflammatory and matrix modulatory effect on injured and IFNalpha2beta inflamed bovine intervertebral discs (IVD). Discs with an AF defect and challenged with IFNalpha2beta were used in a bovine IVD organ culture model to test the effect of HA on the IFNalpha2beta pathway, as well as the matrix proteins aggrecan and collagen I. qRT-PCR was used to assess the gene expression of IFNalpha2beta signaling molecules. Additionally, immunostaining was used to measure protein expression. Our results show that HA treatment significantly down-regulates IFNAR1, IFNAR2, STAT1/2, JAK1, IFIT3 and IGFBP3 mRNA expression in the inflamed groups. Protein analysis confirmed the PCR results. In the extracellular matrix, aggrecan and collagen I were up-regulated while ADAMTS4 was down-regulated upon treatment of the injured and inflamed discs with HA. Hence, HA demonstrates both an anti-inflammatory role, resulting in the down-regulation of IFIT3 and IGFBP3 in the AF, and a matrix modulatory effect by up-regulating aggrecan and collagen I expression. STATEMENT OF SIGNIFICANCE: The pro-inflammatory environment of the degenerated IVD represents a challenge for regenerative therapies. The study demonstrates that hyaluronan acts as an anti-inflammatory molecule by down regulating IFNAR1 and IFNAR2, the signaling molecules STAT1, STAT2, JAK1 and the downstream apoptotic targets IGFBP3 and IFIT3. We also demonstrated that hyaluronan modulates the disc matrix environment by increasing aggrecan and collagen I synthesis and down-regulating ADAMTS4 that degrades the matrix under inflammatory conditions. The significance of this work lies in the fact that hyaluronan acts as an anti-inflammatory molecule by shifting the disc environment towards a more anabolic state and by promoting native IVD matrix production. PMID- 28003147 TI - Developing the Quantitative Histopathology Image Ontology (QHIO): A case study using the hot spot detection problem. AB - Interoperability across data sets is a key challenge for quantitative histopathological imaging. There is a need for an ontology that can support effective merging of pathological image data with associated clinical and demographic data. To foster organized, cross-disciplinary, information-driven collaborations in the pathological imaging field, we propose to develop an ontology to represent imaging data and methods used in pathological imaging and analysis, and call it Quantitative Histopathological Imaging Ontology - QHIO. We apply QHIO to breast cancer hot-spot detection with the goal of enhancing reliability of detection by promoting the sharing of data between image analysts. PMID- 28003148 TI - Evidence of "hidden hearing loss" following noise exposures that produce robust TTS and ABR wave-I amplitude reductions. AB - In animals, noise exposures that produce robust temporary threshold shifts (TTS) can produce immediate damage to afferent synapses and long-term degeneration of low spontaneous rate auditory nerve fibers. This synaptopathic damage has been shown to correlate with reduced auditory brainstem response (ABR) wave-I amplitudes at suprathreshold levels. The perceptual consequences of this "synaptopathy" remain unknown but have been suggested to include compromised hearing performance in competing background noise. Here, we used a modified startle inhibition paradigm to evaluate whether noise exposures that produce robust TTS and ABR wave-I reduction but not permanent threshold shift (PTS) reduced hearing-in-noise performance. Animals exposed to 109 dB SPL octave band noise showed TTS >30 dB 24-h post noise and modest but persistent ABR wave-I reduction 2 weeks post noise despite full recovery of ABR thresholds. Hearing-in noise performance was negatively affected by the noise exposure. However, the effect was observed only at the poorest signal to noise ratio and was frequency specific. Although TTS >30 dB 24-h post noise was a predictor of functional deficits, there was no relationship between the degree of ABR wave-I reduction and degree of functional impairment. PMID- 28003149 TI - Elucidation of the first definitively identified life cycle for a marine turtle blood fluke (Trematoda: Spirorchiidae) enables informed control. AB - Blood flukes of the family Spirorchiidae are significant pathogens of both free ranging and captive marine turtles. Despite a significant proportion of marine turtle mortality being attributable to spirorchiid infections, details of their life cycles remain almost entirely unknown. Here we report on the molecular elucidation of the complete life cycle of a marine spirorchiid, identified as Amphiorchis sp., infecting vermetid gastropods and captive hatched neonate Caretta caretta in the Oceanografic Aquarium, in Valencia, Spain. Specimens of a vermetid gastropod, Thylaeodus cf. rugulosus (Monterosato, 1878), collected from the aquarium filtration system housing diseased C. caretta, were infected with sporocysts and cercariae consistent with the family Spirorchiidae. We generated rDNA sequence data [internal transcribed spacer 2 (ITS2) and partial 28S rDNA] from infections from the vermetid which were identical to sequences generated from eggs from the serosa of the intestine of neonate C. caretta, and an adult spirorchiid from the liver of a C. caretta from Florida, USA. Given the reliability of these markers in the delineation of trematode species, we consider all three stages to represent the same species and tentatively identify it as a species of Amphiorchis Price, 1934. The source of infection at the Oceanografic Foundation Rehabilitation Centre, Valencia, Spain, is inferred to be an adult C. caretta from the western Mediterranean being rehabilitated in the same facility. Phylogenetic analysis suggests that this Amphiorchis sp. is closely related to other spirorchiids of marine turtles (species of Carettacola Manter & Larson, 1950, Hapalotrema Looss, 1899 and Learedius Price, 1934). We discuss implications of the present findings for the control of spirorchiidiasis in captivity, for the better understanding of epidemiology in wild individuals, and the elucidation of further life cycles. PMID- 28003150 TI - Concomitant helminth infection downmodulates the Vaccinia virus-specific immune response and potentiates virus-associated pathology. AB - The aim of this work was to elucidate the immunopathological mechanisms of how helminths may influence the course of a viral infection, using a murine model. Severe virulence, a relevant increase in the virus titres in the lung and a higher mortality rate were observed in Ascaris and Vaccinia virus (VACV) co infected mice, compared with VACV mono-infected mice. Immunopathological analysis suggested that the ablation of CD8+ T cells, the marked reduction of circulating CD4+ T cells producing IFN-gamma, and the robust pulmonary inflammation were associated with the increase of morbidity/mortality in co-infection and subsequently with the negative impact of concomitant pulmonary ascariasis and respiratory VACV infection for the host. On the other hand, when evaluating the impact of the co-infection on the parasitic burden, co-infected mice presented a marked decrease in the total number of migrating Ascaris lung-stage larvae in comparison with Ascaris mono-infection. Taken together, our major findings suggest that Ascaris and VACV co-infection may potentiate the virus-associated pathology by the downmodulation of the VACV-specific immune response. Moreover, this study provides new evidence of how helminth parasites may influence the course of a coincident viral infection. PMID- 28003151 TI - Urogenital schistosomiasis during pregnancy is associated with low birth weight delivery: analysis of a prospective cohort of pregnant women and their offspring in Gabon. AB - An estimated 40 million women of childbearing age suffer from schistosomiasis. Animal models indicate a deleterious effect of maternal schistosomiasis on pregnancy outcomes. To date there is a lack of epidemiological evidence evaluating schistosomiasis-related morbidity in pregnancy. This study was designed to describe the impact of urogenital schistosomiasis on pregnancy outcomes in a highly endemic region of central Africa. Pregnant women attending antenatal clinics in Fougamou and Lambarene, Gabon, were consecutively screened for the presence of Schistosoma haematobium eggs in diurnal urine samples. Maternal and newborn characteristics assessed at delivery were compared between infected and uninfected mothers. The impact of maternal schistosomiasis on low birth weight and preterm delivery was assessed using logistic regression analysis. Urogenital schistosomiasis was diagnosed in 103 (9%) of 1115 pregnant women. Maternal age was inversely associated with the prevalence of urogenital schistosomiasis, with a higher burden amongst nulliparous women. Low birth weight was more common amongst infants of S. haematobium-infected mothers. This association was unaffected by controlling for demographic characteristics, gestational age and Plasmodium infection status (adjusted Odds Ratio 1.93; 95% confidence interval: 1.08-3.42). Other risk factors associated with low birth weight delivery were underweight mothers (adjusted Odds Ratio 2.34; 95% confidence interval: 1.12-4.92), peripheral or placental Plasmodium falciparum infection (adjusted Odds Ratio 2.04; 95% confidence interval: 1.18-3.53) and preterm birth (adjusted Odds Ratio 3.12; 95% confidence interval: 1.97-4.96). Preterm delivery was not associated with S. haematobium infection (adjusted Odds Ratio 1.07 95% confidence interval: 0.57-1.98). In conclusion, this study indicates that pregnant women with urogenital schistosomiasis are at an increased risk for low birth weight deliveries. Further studies evaluating targeted treatment and prevention programmes for urogenital schistosomiasis in pregnant women and their impact on delivery outcomes are warranted. PMID- 28003152 TI - The microbiome, immunity, and schizophrenia and bipolar disorder. AB - Schizophrenia and bipolar disorder are serious neuropsychiatric disorders of uncertain etiology. Recent studies indicate that immune activation may contribute to the etiopathogenesis of these disorders. Numerous studies in animal models indicate that the mucosal microbiome may influence cognition and behavior by altering the functioning of the immune system. It is thus likely that the microbiome plays a role in human psychiatric disorders. The study of immune alterations and the microbiome in schizophrenia and bipolar disorder is in its infancy. Two recent investigations of the oro-pharyngeal microbiota in schizophrenia found differences between cases and controls. Other studies have found increased gastrointestinal inflammation in schizophrenia and bipolar disorder based on measures of microbial translocation. Several studies have also found an association between the receipt of antibiotics and an increased incidence of psychiatric disorders, perhaps due to alterations in the microbiome. Studies to characterize the intestinal microbiome of individuals with these disorders are in progress. The ultimate test of the role of the microbiome and immune-mediated pathology in schizophrenia and bipolar disorder will come from clinical trials of therapeutic agents which alter gut microbiota or gastrointestinal inflammation. The successful development of such modalities would represent a novel strategy to prevent and treat serious psychiatric disorders. PMID- 28003153 TI - Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. AB - Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Abeta-induced caspase 1 activation in microglia and this was accompanied by IL-1beta release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Abeta phagocytosis in vitro, and it reduced Abeta accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function. PMID- 28003154 TI - Antipsychotics influence Toll-like receptor (TLR) expression and its relationship with cognitive functions in schizophrenia. AB - Increasing evidence suggests that altered immune functions are related to the pathophysiology of schizophrenia. Relatively little information is available on Toll-like receptors (TLRs), which are implicated in the recognition of molecular patterns associated with pathogens and internal cellular damage signals. By using immunophenotyping and flow cytometry, we investigated TLRs in CD14+ monocytes, CD4+CD25+Foxp3+ regulatory T cells (Treg), and CD3+CD4+CD25+ activated T cells (Tact) in 35 drug-naive patients with schizophrenia before and after an 8-week period of antipsychotic treatment with risperidone or olanzapine. As compared with 30 healthy control individuals, drug-naive patients with schizophrenia exhibited an increased percentage of TLR4+ and TLR5+ monocytes and TLR5+ Treg/Tact cells. At the end of the treatment period, we observed normalized TLR4+ monocytes and an up-regulation of TLR2+ monocytes and Treg/Tact cells. Mean fluorescent intensity values, indicating receptor density, were consistent with these findings. In the drug-naive state, but not after treatment, higher percentages of TLR4+ and TLR5+ monocytes were correlated with more severe cognitive deficits. Positive, negative, and general clinical symptoms were not associated with TLRs. There were no significant differences between patients receiving olanzapine and risperidone. These results indicate that abnormal expression of TLRs can be detected in the earliest stage of schizophrenia, which is modulated by antipsychotics. Immunological alterations in unmedicated schizophrenia patients may be linked to cognitive deficits. PMID- 28003155 TI - Different proactive and reactive action control in fencers' and boxers' brain. AB - Practicing sport at top level requires excellent physical and cognitive skills. The goal of the present study was to investigate whether specific sport practice may affect the preparation-perception-action stages of processing during a visuo motor task requiring perceptual discrimination and fast response. We recruited 39 participants (two groups of professional fencers and boxers, and a control group; N=13 for each group) and measured behavioral performance and event-related potentials (ERPs) while performing a go/no-go task. Results revealed that athletes were faster than controls, while fencers were more accurate than boxers. ERP analysis revealed that motor preparation, indexed by the Bereitschaftspotential (BP), was increased in athletes than controls, whereas the top-down attentional control, reflected by the prefrontal negativity (pN) component, was enhanced only in fencers when compared to controls. Most of the post-stimulus ERPs i.e. the N1, the N2, the P3, and the pP2, were enhanced in fencers. Combat sports require fast action execution, but the preparatory brain activity might differ according to the specific practice required by each discipline. Boxers might afford to commit more errors (as reflected by high commission error (CE) rate and by a small pN amplitude), while fencers have to be as much fast and accurate as possible (thanks to an enhanced pN amplitude). Although the possible influence of repetitive head blows on cerebral activity cannot be excluded in boxers, our results suggest that cognitive benefits of high level sport practice might also be transferred to the daily (i.e., no sport related) activities. PMID- 28003156 TI - Direct comparison of microglial dynamics and inflammatory profile in photothrombotic and arterial occlusion evoked stroke. AB - Many focal cerebral ischemia models utilize the middle cerebral artery occlusion (MCAO) evoked by coagulation to induce ischemic damage in the cortex and mimic the pathology observed in human patients. A second, increasingly popular model, the photothrombotic stroke, uses a laser beam to irradiate the MCA after administration of a photosensitizing dye. This widely used procedure is slowly replacing the MCAO model because of the easiness of the surgical protocol and the reproducibility of the damage. However, the photochemical reaction also results in wider microvascular injury. In this study, we have evaluated the impact of these two types of stroke in the cell survival and evolution of stroke, focusing on microglial cells, the first responders to cell injury. Two groups of heterozygote Cx3CR1-GFP reporter mice (to follow microglia) were subject to stroke injury either with coagulator-mediated occlusion or photothrombotic MCA damage. Microglial cells' dynamics of activation and phagocytosis together with astrocytic response and leukocyte infiltration were characterized at 1, 3 and 7days after damage. Photothrombotic stroke delayed microglial and astrocytic invasion of the ischemic core and accumulation of phagocytic microglia. It also elicited higher levels of inflammatory cytokines/chemokines and increased infiltration from the periphery. In addition, only the neurons in the MCAO stroke showed phenotype plasticity by downregulating the transcription factor NeuN. These data provide a better understanding of the exact temporal and spatial dynamics of the inflammatory response in these two animal models of stroke and identify more relevant targets for human therapy. PMID- 28003157 TI - ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury. AB - In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. The present goal was to enquire if ASIC channels modulated KA damage in relation to locomotor network function and cell death. Mouse spinal cord slices were treated with KA (0.01 or 0.1mM) for 1h, and then washed out for 24h prior to analysis. RT-PCR results showed that KA (at 0.01mM concentration that is near-threshold for damage) increased mRNA expression of ASIC1a, ASIC1b, ASIC2 and ASIC3, an effect reversed by the ASIC inhibitor 4',6 diamidino-2-phenylindole (DAPI). A KA neurotoxic dose (0.1mM) reduced ASIC1a and ASIC2 expression. Cell viability assays demonstrated KA-induced large damage in spinal slices from mice with ASIC1a gene ablation. Likewise, immunohistochemistry indicated significant neuronal loss when KA was followed by the ASIC inhibitors DAPI or amiloride. Electrophysiological recording from ventral roots of isolated spinal cords showed that alternating oscillatory cycles were slowed down by 0.01mMKA, and intensely inhibited by subsequently applied DAPI or amiloride. Our data suggest that early rise in ASIC expression and function counteracted deleterious effects on spinal networks by raising the excitotoxicity threshold, a result with potential implications for improving neuroprotection. PMID- 28003158 TI - Central sensitization-related changes of effective and functional connectivity in the rat inflammatory trigeminal pain model. AB - Central sensitization is a key mechanism in the pathology of several neuropathic pain disorders. We aimed to investigate the underlying brain connectivity changes in a rat model of chronic pain. Non-noxious whisker stimulation was used to evoke blood-oxygen-level-dependent (BOLD) responses in a block-design functional Magnetic Resonance Imaging (fMRI) experiment on 9.4T. Measurements were repeated two days and one week after injecting complete Freund's adjuvant into the rats' whisker pad. We found that acute pain reduced activation in the barrel cortex, most probably due to a plateau effect. After one week, increased activation of the anterior cingulate cortex was found. Analyses of effective connectivity driven by stimulus-related activation revealed that chronic pain-related central sensitization manifested as a widespread alteration in the activity of the somatosensory network. Changes were mainly mediated by the anterior cingulate cortex and the striatum and affected the somatosensory and motor cortices and the superior colliculus. Functional connectivity analysis of nested BOLD oscillations justified that the anterior cingular-somatosensory interplay is a key element of network changes. Additionally, a decreased cingulo-motor functional connectivity implies that alterations also involve the output tract of the network. Our results extend the knowledge about the role of the cingulate cortex in the chronification of pain and indicate that integration of multiple connectivity analysis could be fruitful in studying the central sensitization in the pain matrix. PMID- 28003159 TI - Both anodal and cathodal transcranial direct current stimulation improves semantic processing. AB - Transcranial direct current stimulation (tDCS) is a common method to modulate cortical activity. Anodal tDCS is usually associated with an enhancement of the stimulated brain area, whereas cathodal tDCS is often described as inhibitory brain stimulation method. Our aim was to investigate whether this canonical assumption derived from the motor system could be transferred to the semantic system. Three groups with 20 healthy subjects each were stimulated at Wernicke's area with either anodal, cathodal or sham tDCS. Subsequently, they performed a simple lexical decision task for a duration of about 25min. Subjects receiving anodal tDCS revealed faster reaction times (RTs) compared to the sham group, although not reaching statistical significance. Surprisingly, in the cathodal group RTs were decreased significantly. All subjects were faster in the second half of the task, but the tDCS-induced improvement lasted for the entire duration of the task. Error rates were not influenced by tDCS, neither were RTs in a choice reaction time task. Thus, both anodal and cathodal tDCS applied to Wernicke's area improved semantic processing. Recently, a meta-analysis revealed that the canonical anodal excitation and cathodal inhibition assumption is observed rarely in cognitive studies. In particular, an inhibitory effect of cathodal tDCS on cognition is rare. Our findings thus support the speculation, that especially language functions could be somewhat 'immune' to cathodal inhibition. PMID- 28003160 TI - Regulatory factor X1 depresses ApoE-dependent Abeta uptake by miRNA-124 in microglial response to oxidative stress. AB - Decreased proteolytic clearance of soluble amyloid beta (Abeta) in microglia affects Abeta accumulation on Alzheimer's disease progression. However, the potential molecular mechanism by which microglial Abeta uptake is regulated remains unclear. In this study, we identified a microRNA, miR-124, that was down regulated in aging with a function in regulating apolipoprotein E (ApoE) dependent Abeta uptake by targeting regulatory factor X1 (RFX1) transcripts on BV2 microglia cell. Decreased expression of miRNA-124 in BV2 cells exposed to mild hydrogen peroxide increased RFX1 protein level and decreased the expression of ApoE, a gene which has been suggested to enhance cellular Abeta uptake in microglia. We also identified a miR-124 binding site in the 3'-UTR of RFX1 mRNA and a RFX1 binding site in the first intron of ApoE gene. Furthermore, interfering this signaling pathway by knocking down RFX1 significantly improved Abeta uptake in BV2 cells. These data demonstrate the mechanism through which decreased miR-124 expression under oxidative stress slowed Abeta uptake and suggest that RFX1 might be a target for improving Abeta clearance during aging. PMID- 28003162 TI - Amygdalar and hippocampal connections with brainstem and spinal cord: A diffusion MRI study in human brain. AB - The limbic system has a central role for the integration of several cognitive and visceral functions through an extended network of connections involving the hippocampus and the amygdala. A number of studies performed in humans have been dedicated to the investigation of supratentorial limbic pathways by means of non invasive MRI approaches, such as DTI. However, detection of possible limbic connections involving the brainstem and the spinal cord is still missing. Subtentorial limbic pathways have been previously studied in animals by means of invasive approaches, including viral tracing. The detection of limbic connections with the brainstem and the spinal cord has raised several new hypotheses regarding the interaction between the central nervous system and the periphery of the body. We investigated subtentorial limbic connections in twenty-one healthy humans by means of probabilistic constrained spherical deconvolution tractography. Our connectivity analysis showed, for both the hippocampus and the amygdala, a high probability of connections with the midbrain, pons, and bulb. Moreover, hippocampal and amygdalar pathways reaching the cervical spinal cord were also detected. Quantitative evaluation of diffusion parameters was also performed. Findings of the present study are in agreement with the literature and provide the first report of possible limbic connections between the brainstem and the spinal cord in human brain. Since these pathways might also have important implications both in physiological and pathological contexts, further studies should be conducted in order to confirm our data as well as to define functional features of these brain connections. PMID- 28003161 TI - Apolipoprotein E4 causes early olfactory network abnormalities and short-term olfactory memory impairments. AB - While apolipoprotein (Apo) E4 is linked to increased incidence of Alzheimer's disease (AD), there is growing evidence that it plays a role in functional brain irregularities that are independent of AD pathology. However, ApoE4-driven functional differences within olfactory processing regions have yet to be examined. Utilizing knock-in mice humanized to ApoE4 versus the more common ApoE3, we examined a simple olfactory perceptual memory that relies on the transfer of information from the olfactory bulb (OB) to the piriform cortex (PCX), the primary cortical region involved in higher order olfaction. In addition, we have recorded in vivo resting and odor-evoked local field potentials (LPF) from both brain regions and measured corresponding odor response magnitudes in anesthetized young (6-month-old) and middle-aged (12-month-old) ApoE mice. Young ApoE4 compared to ApoE3 mice exhibited a behavioral olfactory deficit coinciding with hyperactive odor-evoked response magnitudes within the OB that were not observed in older ApoE4 mice. Meanwhile, middle-aged ApoE4 compared to ApoE3 mice exhibited heightened response magnitudes in the PCX without a corresponding olfactory deficit, suggesting a shift with aging in ApoE4-driven effects from OB to PCX. Interestingly, the increased ApoE4-specific response in the PCX at middle-age was primarily due to a dampening of baseline spontaneous activity rather than an increase in evoked response power. Our findings indicate that early ApoE4-driven olfactory memory impairments and OB network abnormalities may be a precursor to later network dysfunction in the PCX, a region that not only is targeted early in AD, but may be selectively vulnerable to ApoE4 genotype. PMID- 28003164 TI - Comparison of Transarticular Screw Fixation and C1 Lateral Mass-C2 Pedicle Screw Fixation in Patients with Rheumatoid Arthritis with Atlantoaxial Instability. AB - BACKGROUND: Many surgical procedures have been introduced to manage atlantoaxial instability caused by rheumatoid arthritis (RA) to prevent complications and improve fusion rate. We report the surgical outcome between transarticular screw fixation (TAF) and C1 lateral mass-C2 pedicle screw fixation (C1LM-C2P) in patients with atlantoaxial instability from RA. METHODS: Between 2002 and 2012, 58 patients were enrolled in the study. According to surgical procedures, patients were divided into 2 groups: group I who received TAF (n = 33) and group II who received C1LM-C2P (n = 25). Bony fusion was assessed by radiologic comparison immediately after the operation and 1 year postoperatively. In addition, complications and clinical and functional outcomes were evaluated. RESULTS: Overall, bone fusion was achieved in 32 patients in group I (97%). In group II, the fusion rate was evaluated in 100% of patients. Complications (regardless of neurologic deterioration) were cable loosening and screw malposition in group I and violation into the vertebral canal and spinal canal in group II. There was no statistical significance in fusion rate, clinical outcomes, or complications. The 12-month atlantodental interval after operation for the C1LM-C2P group was significantly lower than that for the TAF group after adjusting for all variables. CONCLUSIONS: Two surgical techniques showed a good fusion rate by rigid fixation in the immediate postoperative period and fewer surgery-related complications in patients with RA. Because surgical complications are more likely during the learning curve (as with other surgical techniques), surgeons should carefully evaluate patients before surgery by radiologic and neurologic examinations. PMID- 28003163 TI - Stereotactic Electroencephalography Is a Safe Procedure, Including for Insular Implantations. AB - BACKGROUND: In some cases of drug-resistant focal epilepsy, noninvasive presurgical investigation may be insufficient to identify the ictal onset zone and the eloquent cortical areas. In such situations, invasive investigations are proposed using either stereotactic electroencephalography (SEEG) or subdural grid electrodes. Meta-analysis suggests that SEEG is safer than subdural grid electrodes, but insular implantation of SEEG electrodes has been thought to carry an additional risk of intraparenchymal hemorrhagic complications. Our objectives were to determine whether an insular SEEG trajectory is a risk factor for intracranial hematoma and to report the global safety of the procedure and provide some guidelines to prevent and detect complications. METHODS: In a retrospective analysis of a surgical series of 525 consecutive procedures between 1995 and 2015, all electrodes were classified according to their insular or extrainsular trajectory. All complications were classified as major or minor according to their potential consequences regarding patient neurologic status. RESULTS: Four intraparenchymal hematomas, all related to extrainsular electrodes (4/4974; 0.08%) were reported; no hematoma was found along insular electrodes (0/1042; 0%). There were 8 major complications (1.52%): 7 intracranial hematomas (1.33%) and 1 case of meningitis. Two patients had long-term neurologic impairment (0.38%), and 1 death (not directly related to the procedure) occurred (0.19%). Eleven minor complications (2.09%) were encountered, including broken electrode (1.52%), acute pneumocephalus (0.38%), and local cutaneous infection (0.19%). CONCLUSIONS: SEEG is a safe procedure. Insular trajectories cannot be considered an additional risk of intracranial bleeding. PMID- 28003165 TI - Exceptional Rare Giant Craniofacial Chondroid Tumor in Adult. AB - We present a rare case of giant soap bubble-shaped cystic lesion in the craniofacial region in an adult female. Histopathologic examination revealed the tumor consisted of 3 components including chondroblastoma, chondromyxoid fibroma, and hemorrhagic aneurysmal bone cyst. The present case is rare in terms of size, location, and histopathologic diagnosis, which is probably the result of underdeveloped health care in the remote place. PMID- 28003166 TI - Analysis of the Fusion and Graft Resorption Rates, as Measured by Computed Tomography, 1 Year After Posterior Cervical Fusion Using a Cervical Pedicle Screw. AB - BACKGROUND: We previously showed that cervical pedicle screw (CPS) placement is safe even with the freehand technique. The posterolateral fusion rate 1 year after CPS placement, as measured by computed tomography (CT), is reported here. The graft resorption rates when different graft materials were used were also analyzed. METHODS: Between 2012 and 2015, 93 patients underwent posterior cervical fusion surgery with the CPS from C2 to C7. Of these patients, 56 consented to CT scans immediately and 1 year after surgery. These patients formed the present study group. The patients were categorized according to whether the graft material was local bone, allograft, or a mixture. Graft volume was measured at both CT scans. Graft resorption rate was determined by comparing the 2 scans. Radiologic fusion was assessed on the 1 year postoperative CT scan and radiography. RESULTS: The reason for surgery was trauma (n = 19), degenerative disease (n = 35), tumor (n = 1), and spondylitis (n = 1). Surgery was performed with CPS fixation and decompression. Even although iliac bone grafting was not performed, the overall fusion rate was 98.2% (55/56). The single fusion failure case received a mixture of local bone and allograft. Although the allograft group showed the greatest graft resorption rate (91.5%), all patients in this group had a bony bridge that crossed the facet joint on the 1 year CT scan. CONCLUSIONS: CPS placement yielded a posterolateral cervical fusion rate of 98.2%. Despite the high resorption rate of allograft only, this material yielded fusion rates that were similar to those of the other materials. Thus, the strong fixation power of CPS might compensate for the delayed fusion and high resorption rates of allograft bone chips. PMID- 28003167 TI - Surgery for Malignant Spinal Tumors: Beyond the Lure of the "Technically Sweet". PMID- 28003168 TI - Endoscopic Endonasal Surgery for Remission of Cushing Disease Caused by Ectopic Intracavernous Macroadenoma: Case Report and Literature Review. AB - BACKGROUND: Complete surgical resection of an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma is the gold standard of treatment of Cushing disease. Ectopic location of these adenomas is an extremely rare condition that may compromise the diagnosis and surgical success. We present the first case of an ectopic intracavernous ACTH-secreting macroadenoma totally resected with endoscopic endonasal surgery (EES). CASE DESCRIPTION: A 36-year-old woman presented with Cushing syndrome. Increased ACTH, serum cortisol, and free urine cortisol levels were identified; however, pituitary magnetic resonance imaging failed to show a pituitary tumor; instead, a parasellar lesion in the left cavernous sinus (CS) was noticed. Inferior petrosal sinus sampling showed a significant central to peripheral and lateralized left-sided ACTH gradient. The patient underwent EES. No tumor was found in the sella; however, the left CS was widely explored and a tumor was found lateral to the paraclival segment of the carotid artery. There were no complications after EES. Pathology confirmed the diagnosis of an ACTH-secreting adenoma. During the immediate postoperative course, serum cortisol levels decreased lower than 5 MUg/dL. Postoperative magnetic resonance imaging showed complete tumor resection. At 20 months follow up, the patient remained in clinical and biochemical remission of Cushing disease. CONCLUSIONS: Only 12 cases of ectopic intracavernous ACTH-secreting adenomas have been reported and all were microadenomas. The presence of an ectopic ACTH-secreting macroadenoma in the CS represents a surgical challenge. EES is the ideal approach for complete resection of ectopic intracavernous adenomas, allowing for a wide exploration of the CS with no surgical complications. PMID- 28003169 TI - Association of Prior Falls with Adverse Outcomes After Neurosurgical Operations in the Elderly. AB - BACKGROUND: Despite the increasing number of elderly patients undergoing neurosurgical interventions, there are limited resources for preoperative assessment of frailty in this population. We investigated the association between recent history of falls and surgical outcomes for these patients. METHODS: We performed a prospective cohort study of all patients, 65 years and older, undergoing elective neurosurgical procedures from 2014-2015 in a tertiary referral medical center. We examined the association of sustaining a fall in the 6 months before the operation with discharge to a facility, readmissions, and complications in the first 30 days after discharge. In order to control for confounding, we used multivariable regression models and propensity score conditioning. Mixed-effects models were used to control for clustering at the surgeon level. RESULTS: During the study period, 143 elderly patients underwent a neurosurgical procedure and met the inclusion criteria. Of these, 53.1% had a history of falls preoperatively. Mixed-effects multivariable logistic regression analysis demonstrated an association between preoperative falls and discharge to a facility (odds ratio [OR], 1.35; 95% confidence interval [CI], 1.23-1.47), 30 day readmissions (OR, 1.57; 95% CI, 1.36-1.78), and 30-day complications (OR, 1.13; 95% CI, 1.03-1.23). Similar associations were present in propensity score adjusted models and models stratified by cranial and spinal procedures. CONCLUSIONS: History of at least 1 fall in the 6 months before a neurosurgical operation was associated with increased risk of discharge to a facility, readmissions, and complications in the first 30 days after discharge. History of prior falls should be taken into account during the preoperative risk assessment of neurosurgical patients. PMID- 28003170 TI - Impact of Race on 30-Day Complication Rates After Elective Complex Spinal Fusion (>=5 Levels): A Single Institutional Study of 446 Patients. AB - OBJECTIVE: Racial disparities have been shown to affect surgical outcomes. However, the effect of race on complex spinal fusion outcomes remains understudied. The aim of this study is to determine if patient race affects 30 day complication rates after elective complex spinal fusion (>=5 levels). METHODS: The medical records of 490 adult patients with spinal deformity undergoing elective complex spinal fusion (>=5 levels) at a major academic institution from 2005 to 2015 were reviewed. We identified 52 black patients (11.7%) and 438 white patients (88.3%). Patient demographics, comorbidities, and intraoperative and 30-day postoperative complication and readmission rates were collected. The primary outcome investigated in this study was the rate of 30-day postoperative complications. RESULTS: Patient demographics and comorbidities were similar between both groups, including age, gender, and body mass index. Median (interquartile range) number of fusion levels and operative time were similar between the cohorts (black, 6.5 [5-9] vs. white, 7 [5-9]; P = 0.55; and black, 307.3 +/- 120.2 minutes vs. white, 321.3 +/- 135.3 minutes; P = 0.45, respectively). Both cohorts had similar postoperative complications and lengths of hospital stay (black, 7.2 +/- 5.4 days vs. white: 6.5 +/- 4.9; P = 0.37). There was no significant difference in 30-day readmission between the cohorts (black, 9.6% vs. white, 12.8%; P = 0.66). There were no observed differences in 30-day complication rates, including: pain (P = 0.74), urinary tract infection (P = 0.68), hardware failure (P = 0.36), wound dehiscence (P = 0.29), and drainage (P = 0.86). CONCLUSIONS: Our study suggests that there is no difference between races in 30-day complication and readmission rates after complex spinal surgery requiring >=5 levels of fusion. PMID- 28003171 TI - A Contralateral Transcondylar Fossa Approach with Bilateral V3 Segment Exposure for Repairing Complex Vertebral Artery Aneurysms. AB - BACKGROUND AND IMPORTANCE: Microsurgical treatment for vertebral artery aneurysms can be approached through the lateral aspect of the brainstem and cerebellum. A contralateral approach may be selected in complex aneurysms with tortuous running and the intracranial vertebral artery distal to the aneurysm located in the contralateral cerebellopontine angle. When repairing the aneurysm, exposing the V3 segment before craniotomy is advantageous. We describe the detailed surgical procedures of the contralateral transcondylar fossa approach with bilateral V3 segment exposure for the repair of a complex vertebral artery aneurysm. CLINICAL PRESENTATION: A 48-year-old woman presented with a 23-mm unruptured thrombosed fusiform aneurysm in the right vertebral artery. The aneurysm and the V4 segment distal to it deviated to the left, and the aneurysm was compressing the left anterior aspect of the medulla oblongata. We treated the patient with trapping and thrombectomy, using a contralateral transcondylar fossa approach with bilateral V3 exposure. During the procedure, proximal vascular control was achieved by occluding the contralateral V3 segment and distal control was achieved by occluding the V4 segment. The aneurysm was successfully trapped and decompressed. The patient's postoperative course was good and she was discharged with a modified Rankin Scale score of 0. CONCLUSIONS: The contralateral transcondylar fossa approach with bilateral V3 exposure is feasible for the repair of complex vertebral artery aneurysms showing a deviated and difficult to access V4 segment proximal to the aneurysm. Bilateral V3 exposure may also facilitate aneurysm bypass procedures such as those using a V3-V4 anastomosis. PMID- 28003172 TI - Suprasellar Epidermoid Cyst with Atypical Imaging Findings. AB - A 65-year-old female presented with progressive unilateral vision loss leading to blindness and features of central diabetes insipidus (DI) for 3 months' duration. Imaging showed a well-circumscribed, lobulated, rim-enhancing suprasellar lesion with inhomogeneous diffusion restriction. Through a pterional trans-sylvian approach, subtotal resection was performed and histopathology revealed features of an epidermoid cyst. At 5 months' follow-up, she had improvement of her diabetes insipidus but no visual improvement. This paper presents a case of suprasellar epidermoid with atypical imaging findings. PMID- 28003173 TI - Increasing Consumer Engagement by Tailoring a Public Reporting Website on the Quality of Diabetes Care: A Qualitative Study. AB - BACKGROUND: The majority of health care utilization decisions in the United States are made by persons with multiple chronic conditions. Existing public reports of health system quality do not distinguish care for these persons and are often not used by the consumers they aim to reach. OBJECTIVE: Our goal was to determine if tailoring quality reports to persons with diabetes mellitus and co occurring chronic conditions would increase user engagement with a website that publicly reports the quality of diabetes care. METHODS: We adapted an existing consumer-focused public reporting website using adult learning theory to display diabetes quality reports tailored to the user's chronic condition profile. We conducted in-depth cognitive interviews with 20 individuals who either had diabetes and/or cared for someone with diabetes to assess the website. Interviews were audiotaped and transcribed, then analyzed using thematic content analysis. RESULTS: Three themes emerged that suggested increased engagement from tailoring the site to a user's chronic conditions: ability to interact, relevance, and feeling empowered to act. CONCLUSIONS: We conclude that tailoring can be used to improve public reporting sites for individuals with chronic conditions, ultimately allowing consumers to make more informed health care decisions. PMID- 28003174 TI - Recruiting Pregnant Patients for Survey Research: A Head to Head Comparison of Social Media-Based Versus Clinic-Based Approaches. AB - BACKGROUND: Recruiting a diverse sample of pregnant women for clinical research is a challenging but crucial task for improving obstetric services and maternal and child health outcomes. OBJECTIVE: To compare the feasibility and cost of recruiting pregnant women for survey research using social media-based and clinic based approaches. METHODS: Advertisements were used to recruit pregnant women from the social media website Facebook. In-person methods were used to recruit pregnant women from the outpatient clinic of a large, tertiary care center. In both approaches, potential respondents were invited to participate in a 15-minute Web-based survey. Each recruitment method was monitored for 1 month. Using bivariate statistics, we compared the number, demographic characteristics, and health characteristics of women recruited and the cost per completed survey for each recruitment method. RESULTS: The social media-based approach recruited 1178 women and the clinic-based approach recruited 219 women. A higher proportion of subjects recruited through social media identified as African American (29.4%, 207/705 vs 11.2%, 20/179), reported household incomes =91st or >=98th centile body mass index (BMI)) children aged 6-11 years and their parents/carers, recruited March 2012 February 2014. INTERVENTIONS: FFH; a 10-week community-based family programme addressing parenting, lifestyle change and social and emotional development. UC; usual support for childhood obesity at each site. MAIN OUTCOME MEASURES: Primary outcomes were 12-months change in children's BMI z-score and incremental cost per quality-adjusted life-year gained (QALY). Secondary outcomes included changes in children's physical activity, fruit and vegetable consumption and quality of life, parents' BMI and mental well-being, family eating/activity, parent-child relationships and parenting style. RESULTS: 115 families (128 children) were randomised to FFH (n=56) or UC (n=59). There was no significant difference in BMI z-score 12-months change (0.114, 95% CI -0.001 to 0.229, p=0.053; p=0.026 in favour of UC with missing value multiple imputation). One secondary outcome, change in children's waist z-score, was significantly different between groups in favour of UC (0.15, 95% CI 0.00 to 0.29). Economic evaluation showed that mean costs were significantly higher for FFH than UC (L998 vs L548, p<0.001). Mean incremental cost-effectiveness of FFH was estimated at L552 175 per QALY. CONCLUSIONS: FFH was neither effective nor cost-effective for the management of obesity compared with UC. TRIAL REGISTRATION NUMBER: ISRCTN45032201. PMID- 28003179 TI - Proteomic Profiling of Serial Prediagnostic Serum Samples for Early Detection of Colon Cancer in the U.S. Military. AB - Background: Serum proteomic biomarkers offer a promising approach for early detection of cancer. In this study, we aimed to identify proteomic profiles that could distinguish colon cancer cases from controls using serial prediagnostic serum samples.Methods: This was a nested case-control study of active duty military members. Cases consisted of 264 patients diagnosed with colon cancer between 2001 and 2009. Controls were matched to cases on age, gender, race, serum sample count, and collection date. We identified peaks that discriminated cases from controls using random forest data analysis with a 2/3 training and 1/3 validation dataset. We then included epidemiologic data to see whether further improvement of model performance was obtainable. Proteins that corresponded to discriminatory peaks were identified.Results: Peaks with m/z values of 3,119.32, 2,886.67, 2,939.23, and 5,078.81 were found to discriminate cases from controls with a sensitivity of 69% and a specificity of 67% in the year before diagnosis. When smoking status was included, sensitivity increased to 76% while histories of other cancer and tonsillectomy raised specificity to 76%. Peaks at 2,886.67 and 3,119.32 m/z were identified as histone acetyltransferases while 2,939.24 m/z was a transporting ATPase subunit.Conclusions: Proteomic profiles in the year before cancer diagnosis have the potential to discriminate colon cancer patients from controls, and the addition of epidemiologic information may increase the sensitivity and specificity of discrimination.Impact: Our findings indicate the potential value of using serum prediagnostic proteomic biomarkers in combination with epidemiologic data for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 26(5); 711-8. (c)2016 AACR. PMID- 28003180 TI - Years of Life and Productivity Loss from Potentially Avoidable Colorectal Cancer Deaths in U.S. Counties with Lower Educational Attainment (2008-2012). AB - Background: Educational attainment (EA) is inversely associated with colorectal cancer risk. Colorectal cancer screening can save lives if precancerous polyps or early cancers are found and successfully treated. This study aims to estimate the potential productivity loss (PPL) and associated avoidable colorectal cancer related deaths among screen-eligible adults residing in lower EA counties in the United States.Methods: Mortality and population data were used to examine colorectal cancer deaths (2008-2012) among adults aged 50 to 74 years in lower EA counties, and to estimate the expected number of deaths using the mortality experience from high EA counties. Excess deaths (observed-expected) were used to estimate potential years life lost, and the human capital method was used to estimate PPL in 2012 U.S. dollars.Results: County-level colorectal cancer death rates were inversely associated with county-level EA. Of the 100,857 colorectal cancer deaths in lower EA counties, we estimated that more than 21,000 (1 in 5) was potentially avoidable and resulted in nearly $2 billion annual productivity loss.Conclusions: County-level EA disparities contribute to a large number of potentially avoidable colorectal cancer-related deaths. Increased prevention and improved screening potentially could decrease deaths and help reduce the associated economic burden in lower EA communities. Increased screening could further reduce deaths in all EA groups.Impact: These results estimate the large economic impact of potentially avoidable colorectal cancer-related deaths in economically disadvantaged communities, as measured by lower EA. Cancer Epidemiol Biomarkers Prev; 26(5); 736-42. (c)2016 AACR. PMID- 28003184 TI - Synthetic Biology in Cell and Organ Transplantation. AB - The transplantation of cells and organs has an extensive history, with blood transfusion and skin grafts described as some of the earliest medical interventions. The speed and efficiency of the human immune system evolved to rapidly recognize and remove pathogens; the human immune system also serves as a barrier against the transplant of cells and organs from even highly related donors. Although this shows the remarkable effectiveness of the immune system, the engineering of cells and organs that will survive in a host patient over the long term remains a steep challenge. Progress in the understanding of host immune responses to donor cells and organs, combined with the rapid advancement in synthetic biology applications, allows the rational engineering of more effective solutions for transplantation. PMID- 28003185 TI - TIA-1 Is a Functional Prion-Like Protein. AB - Prions are self-propagating protein conformations that are traditionally regarded as agents of neurodegenerative disease in animals. However, it has become evident that prion-like aggregation of endogenous proteins can also occur under normal physiological conditions (e.g., during memory storage or activation of the immune response). In this review, we focus on the functional prion-related protein TIA 1, an RNA-binding protein that is involved in multiple aspects of RNA metabolism but is best understood in terms of its role in stress granule assembly during the cellular stress response. We propose that stress granule formation provides a useful conceptual framework with which to address the positive role of TIA-1 prion-like aggregation. Elucidating the function of TIA-1 prion-like aggregation will advance our understanding of how prion-based molecular switches are used in normal physiological settings. PMID- 28003186 TI - Posttranslational Modifications of Tubulin and Cilia. AB - Tubulin undergoes several highly conserved posttranslational modifications (PTMs) including acetylation, detyrosination, glutamylation, and glycylation. These PTMs accumulate on a subset of microtubules that are long-lived, including those in the basal bodies and axonemes. Tubulin PTMs are distributed nonuniformly. In the outer doublet microtubules of the axoneme, the B-tubules are highly enriched in the detyrosinated, polyglutamylated, and polyglycylated tubulin, whereas the A tubules contain mostly unmodified tubulin. The nonuniform patterns of tubulin PTMs may functionalize microtubules in a position-dependent manner. Recent studies indicate that tubulin PTMs contribute to the assembly, disassembly, maintenance, and motility of cilia. In particular, tubulin glutamylation has emerged as a key PTM that affects ciliary motility through regulation of axonemal dynein arms and controls the stability and length of the axoneme. PMID- 28003183 TI - Directional Fluid Transport across Organ-Blood Barriers: Physiology and Cell Biology. AB - Directional fluid flow is an essential process for embryo development as well as for organ and organism homeostasis. Here, we review the diverse structure of various organ-blood barriers, the driving forces, transporters, and polarity mechanisms that regulate fluid transport across them, focusing on kidney-, eye-, and brain-blood barriers. We end by discussing how cross talk between barrier epithelial and endothelial cells, perivascular cells, and basement membrane signaling contribute to generate and maintain organ-blood barriers. PMID- 28003187 TI - Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy. AB - Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17-28. (c)2016 AACR. PMID- 28003188 TI - Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells. AB - We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury. PMID- 28003189 TI - Involvement of ENaC in the development of salt-sensitive hypertension. AB - Salt-sensitive hypertension is associated with renal and vascular dysfunctions, which lead to impaired fluid excretion, increased cardiac output, and total peripheral resistance. It is commonly accepted that increased renal sodium handling and plasma volume expansion are necessary factors for the development of salt-induced hypertension. The epithelial sodium channel (ENaC) is a trimeric ion channel expressed in the distal nephron that plays a critical role in the regulation of sodium reabsorption in both normal and pathological conditions. In this mini-review, we summarize recent studies investigating the role of ENaC in the development of salt-sensitive hypertension. On the basis of experimental data obtained from the Dahl salt-sensitive rats, we and others have demonstrated that abnormal ENaC activation in response to a dietary NaCl load contributes to the development of high blood pressure in this model. The role of different humoral factors, such as the components of the renin-angiotensin-aldosterone system, members of the epidermal growth factors family, arginine vasopressin, and oxidative stress mediating the effects of dietary salt on ENaC are discussed in this review to highlight future research directions and to determine potential molecular targets for drug development. PMID- 28003190 TI - Effects of exogenous desmopressin on a model of heat stress nephropathy in mice. AB - Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway. PMID- 28003191 TI - Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms. AB - Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP. PMID- 28003192 TI - Mineral Types and Tree Species Determine the Functional and Taxonomic Structures of Forest Soil Bacterial Communities. AB - Although minerals represent important soil constituents, their impact on the diversity and structure of soil microbial communities remains poorly documented. In this study, pure mineral particles with various chemistries (i.e., obsidian, apatite, and calcite) were considered. Each mineral type was conditioned in mesh bags and incubated in soil below different tree stands (beech, coppice with standards, and Corsican pine) for 2.5 years to determine the relative impacts of mineralogy and mineral weatherability on the taxonomic and functional diversities of mineral-associated bacterial communities. After this incubation period, the minerals and the surrounding bulk soil were collected to determine mass loss and to perform soil analyses, enzymatic assays, and cultivation-dependent and independent analyses. Notably, our 16S rRNA gene pyrosequencing analyses revealed that after the 2.5-year incubation period, the mineral-associated bacterial communities strongly differed from those of the surrounding bulk soil for all tree stands considered. When focusing only on minerals, our analyses showed that the bacterial communities associated with calcite, the less recalcitrant mineral type, significantly differed from those that colonized obsidian and apatite minerals. The cultivation-dependent analysis revealed significantly higher abundances of effective mineral-weathering bacteria on the most recalcitrant minerals (i.e., apatite and obsidian). Together, our data showed an enrichment of Betaproteobacteria and effective mineral-weathering bacteria related to the Burkholderia and Collimonas genera on the minerals, suggesting a key role for these taxa in mineral weathering and nutrient cycling in nutrient-poor forest ecosystems.IMPORTANCE Forests are usually developed on nutrient-poor and rocky soils, while nutrient-rich soils have been dedicated to agriculture. In this context, nutrient recycling and nutrient access are key processes in such environments. Deciphering how soil mineralogy influences the diversity, structure, and function of soil bacterial communities in relation to the soil conditions is crucial to better understanding the relative role of the soil bacterial communities in nutrient cycling and plant nutrition in nutrient-poor environments. The present study determined in detail the diversity and structure of bacterial communities associated with different mineral types incubated for 2.5 years in the soil under different tree species using cultivation-dependent and -independent analyses. Our data showed an enrichment of specific bacterial taxa on the minerals, specifically on the most weathered minerals, suggesting that they play key roles in mineral weathering and nutrient cycling in nutrient poor forest ecosystems. PMID- 28003193 TI - Fermentative Production of Cysteine by Pantoea ananatis. AB - Cysteine is a commercially important amino acid; however, it lacks an efficient fermentative production method. Due to its cytotoxicity, intracellular cysteine levels are stringently controlled via several regulatory modes. Managing its toxic effects as well as understanding and deregulating the complexities of regulation are crucial for establishing the fermentative production of cysteine. The regulatory modes include feedback inhibition of key metabolic enzymes, degradation, efflux pumps, and the transcriptional regulation of biosynthetic genes by a master cysteine regulator, CysB. These processes have been extensively studied using Escherichia coli for overproducing cysteine by fermentation. In this study, we genetically engineered Pantoea ananatis, an emerging host for the fermentative production of bio-based materials, to identify key factors required for cysteine production. According to this and our previous studies, we identified a major cysteine desulfhydrase gene, ccdA (formerly PAJ_0331), involved in cysteine degradation, and the cysteine efflux pump genes cefA and cefB (formerly PAJ_3026 and PAJ_p0018, respectively), which may be responsible for downregulating the intracellular cysteine level. Our findings revealed that ccdA deletion and cefA and cefB overexpression are crucial factors for establishing fermentative cysteine production in P. ananatis and for obtaining a higher cysteine yield when combined with genes in the cysteine biosynthetic pathway. To our knowledge, this is the first demonstration of cysteine production in P. ananatis, which has fundamental implications for establishing overproduction in this microbe.IMPORTANCE The efficient production of cysteine is a major challenge in the amino acid fermentation industry. In this study, we identified cysteine efflux pumps and degradation pathways as essential elements and genetically engineered Pantoea ananatis, an emerging host for the fermentative production of bio-based materials, to establish the fermentative production of cysteine. This study provides crucial insights into the design and construction of cysteine-producing strains, which may play central roles in realizing commercial basis production. PMID- 28003194 TI - LacI Transcriptional Regulatory Networks in Clostridium thermocellum DSM1313. AB - Organisms regulate gene expression in response to the environment to coordinate metabolic reactions. Clostridium thermocellum expresses enzymes for both lignocellulose solubilization and its fermentation to produce ethanol. One LacI regulator termed GlyR3 in C. thermocellum ATCC 27405 was previously identified as a repressor of neighboring genes with repression relieved by laminaribiose (a beta-1,3 disaccharide). To better understand the three C. thermocellum LacI regulons, deletion mutants were constructed using the genetically tractable DSM1313 strain. DSM1313 lacI genes Clo1313_2023, Clo1313_0089, and Clo1313_0396 encode homologs of GlyR1, GlyR2, and GlyR3 from strain ATCC 27405, respectively. Growth on cellobiose or pretreated switchgrass was unaffected by any of the gene deletions under controlled-pH fermentations. Global gene expression patterns from time course analyses identified glycoside hydrolase genes encoding hemicellulases, including cellulosomal enzymes, that were highly upregulated (5- to 100-fold) in the absence of each LacI regulator, suggesting that these were repressed under wild-type conditions and that relatively few genes were controlled by each regulator under the conditions tested. Clo1313_2022, encoding lichenase enzyme LicB, was derepressed in a DeltaglyR1 strain. Higher expression of Clo1313_1398, which encodes the Man5A mannanase, was observed in a DeltaglyR2 strain, and alpha-mannobiose was identified as a probable inducer for GlyR2 regulated genes. For the DeltaglyR3 strain, upregulation of the two genes adjacent to glyR3 in the celC-glyR3-licA operon was consistent with earlier studies. Electrophoretic mobility shift assays have confirmed LacI transcription factor binding to specific regions of gene promoters.IMPORTANCE Understanding C. thermocellum gene regulation is of importance for improved fundamental knowledge of this industrially relevant bacterium. Most LacI transcription factors regulate local genomic regions; however, a small number of those genes encode global regulatory proteins with extensive regulons. This study indicates that there are small specific C. thermocellum LacI regulons. The identification of LacI repressor activity for hemicellulase gene expression is a key result of this work and will add to the small body of existing literature on the area of gene regulation in C. thermocellum. PMID- 28003195 TI - New Multilocus Variable-Number Tandem-Repeat Analysis (MLVA) Scheme for Fine Scale Monitoring and Microevolution-Related Study of Ralstonia pseudosolanacearum Phylotype I Populations. AB - Bacterial wilt caused by the Ralstonia solanacearum species complex (RSSC) is considered one of the most harmful plant diseases in the world. Special attention should be paid to R. pseudosolanacearum phylotype I due to its large host range, its worldwide distribution, and its high evolutionary potential. So far, the molecular epidemiology and population genetics of this bacterium are poorly understood. Until now, the genetic structure of the RSSC has been analyzed on the worldwide and regional scales. Emerging questions regarding evolutionary forces in RSSC adaptation to hosts now require genetic markers that are able to monitor RSSC field populations. In this study, we aimed to evaluate the multilocus variable-number tandem-repeat analysis (MLVA) approach for its ability to discriminate genetically close phylotype I strains and for population genetics studies. We developed a new MLVA scheme (MLVA-7) allowing us to genotype 580 R. pseudosolanacearum phylotype I strains extracted from susceptible and resistant hosts and from different habitats (stem, soil, and rhizosphere). Based on specificity, polymorphism, and the amplification success rate, we selected seven fast-evolving variable-number tandem-repeat (VNTR) markers. The newly developed MLVA-7 scheme showed higher discriminatory power than the previously published MLVA-13 scheme when applied to collections sampled from the same location on different dates and to collections from different locations on very small scales. Our study provides a valuable tool for fine-scale monitoring and microevolution related study of R. pseudosolanacearum phylotype I populations.IMPORTANCE Understanding the evolutionary dynamics of adaptation of plant pathogens to new hosts or ecological niches has become a key point for the development of innovative disease management strategies, including durable resistance. Whereas the molecular mechanisms underlying virulence or pathogenicity changes have been studied thoroughly, the population genetics of plant pathogen adaptation remains an open, unexplored field, especially for plant-pathogenic bacteria. MLVA has become increasingly popular for epidemiosurveillance and molecular epidemiology studies of plant pathogens. However, this method has been used mostly for genotyping and identification on a regional or global scale. In this study, we developed a new MLVA scheme, targeting phylotype I of the soilborne Ralstonia solanacearum species complex (RSSC), specifically to address the bacterial population genetics on the field scale. Such a MLVA scheme, based on fast evolving loci, may be a tool of choice for field experimental evolution and spatial genetics studies. PMID- 28003196 TI - An Expanded Transposon Mutant Library Reveals that Vibrio fischeri delta Aminolevulinate Auxotrophs Can Colonize Euprymna scolopes. AB - Libraries of defined mutants are valuable research tools but necessarily lack gene knockouts that are lethal under the conditions used in library construction. In this study, we augmented a Vibrio fischeri mutant library generated on a rich medium (LBS, which contains [per liter] 10 g of tryptone, 5 g of yeast extract, 20 g of NaCl, and 50 mM Tris [pH 7.5]) by selecting transposon insertion mutants on supplemented LBS and screening for those unable to grow on LBS. We isolated strains with insertions in alr, glr (murI), glmS, several heme biosynthesis genes, and ftsA, as well as a mutant disrupted 14 bp upstream of ftsQ Mutants with insertions in ftsA or upstream of ftsQ were recovered by addition of Mg2+ to LBS, but their cell morphology and motility were affected. The ftsA mutant was more strongly affected and formed cells or chains of cells that appeared to wind back on themselves helically. Growth of mutants with insertions in glmS, alr, or glr was recovered with N-acetylglucosamine (NAG), d-alanine, or d-glutamate, respectively. We hypothesized that NAG, d-alanine, or d-glutamate might be available to V. fischeri in the Euprymna scolopes light organ; however, none of these mutants colonized the host effectively. In contrast, hemA and hemL mutants, which are auxotrophic for delta-aminolevulinate (ALA), colonized at wild-type levels, although mutants later in the heme biosynthetic pathway were severely impaired or unable to colonize. Our findings parallel observations that legume hosts provide Bradyrhizobium symbionts with ALA, but they contrast with virulence phenotypes of hemA mutants in some pathogens. The results further inform our understanding of the symbiotic light organ environment.IMPORTANCE By supplementing a rich yeast-based medium, we were able to recover V. fischeri mutants with insertions in conditionally essential genes, and further characterization of these mutants provided new insights into this bacterium's symbiotic environment. Most notably, we show evidence that the squid host can provide V. fischeri with enough ALA to support its growth in the light organ, paralleling the finding that legumes provide Bradyrhizobium ALA in symbiotic nodules. Taken together, our results show how a simple method of augmenting already rich media can expand the reach and utility of defined mutant libraries. PMID- 28003197 TI - Antibacterial Mechanism of 405-Nanometer Light-Emitting Diode against Salmonella at Refrigeration Temperature. AB - The aim of this study was to elucidate the antibacterial mechanism of 405 +/- 5 nm light-emitting diode (LED) illumination against Salmonella at 4 degrees C in phosphate-buffered saline (PBS) by determining endogenous coproporphyrin content, DNA oxidation, damage to membrane function, and morphological change. Gene expression levels, including of oxyR, recA, rpoS, sodA, and soxR, were also examined to understand the response of Salmonella to LED illumination. The results showed that Salmonella strains responded differently to LED illumination, revealing that S. enterica serovar Enteritidis (ATCC 13076) and S. enterica subsp. enterica serovar Saintpaul (ATCC 9712) were more susceptible and resistant, respectively, than the 16 other strains tested. There was no difference in the amounts of endogenous coproporphyrin in the two strains. Compared with that in nonilluminated cells, the DNA oxidation levels in illuminated cells increased. In illuminated cells, we observed a loss of efflux pump activity, damage to the glucose uptake system, and changes in membrane potential and integrity. Transmission electron microscopy revealed a disorganization of chromosomes and ribosomes due to LED illumination. The levels of the five genes measured in the nonilluminated and illuminated S Saintpaul cells were upregulated in PBS at a set temperature of 4 degrees C, indicating that increased gene expression levels might be due to a temperature shift and nutrient deficiency rather than to LED illumination. In contrast, only oxyR in S Enteritidis cells was upregulated. Thus, different sensitivities of the two strains to LED illumination were attributed to differences in gene regulation.IMPORTANCE Bacterial inactivation using visible light has recently received attention as a safe and environmentally friendly technology, in contrast with UV light, which has detrimental effects on human health and the environment. This study was designed to understand how 405 +/- 5-nm light-emitting diode (LED) illumination kills Salmonella strains at refrigeration temperature. The data clearly demonstrated that the effectiveness of LED illumination on Salmonella strains depended highly on the serotype and strain. Our findings also revealed that its antibacterial mechanism was mainly attributed to DNA oxidation and a loss of membrane functions rather than membrane lipid peroxidation, which has been proposed by other researchers who studied the antibacterial effect of LED illumination by adding exogenous photosensitizers, such as chlorophyllin and hypericin. Therefore, this study suggests that the detailed antibacterial mechanisms of 405-nm LED illumination without additional photosensitizers may differ from that by exogenous photosensitizers. Furthermore, a change in stress related gene regulation may alter the susceptibility of Salmonella cells to LED illumination at refrigeration temperature. Thus, our study provides new insights into the antibacterial mechanism of 405 +/- 5-nm LED illumination on Salmonella cells. PMID- 28003198 TI - Transcriptomic Responses in the Bloom-Forming Cyanobacterium Microcystis Induced during Exposure to Zooplankton. AB - The bloom-forming, toxic cyanobacterium Microcystis synthesizes multiple secondary metabolites and has been shown to deter zooplankton grazing. However, the biochemical and/or molecular basis by which Microcystis deters zooplankton remains unclear. This global transcriptomic study explored the response of Microcystis to direct and indirect exposures to multiple densities of two cladoceran grazers, Daphnia pulex and D. magna Higher densities of both daphnids significantly reduced Microcystis cell densities and elicited a stronger transcriptional response in Microcystis While many putative grazer deterrence genes (encoding microcystin, aeruginosin, cyanopeptolin, and microviridin) were largely unaffected by zooplankton, transcripts for heat shock proteins (hsp) increased in abundance. Beyond metabolites and hsp, large increases in the abundances of transcripts from photosynthetic processes were observed, evidencing energy acquisition pathways were stimulated by grazing. In addition, transcripts of genes associated with the production of extracellular polysaccharides and gas vesicles significantly increased in abundance. These genes have been associated with colony formation and may have been invoked to deter grazers. Collectively, this study demonstrates that daphnid grazers induce a significant transcriptomic response in Microcystis, suggesting this cyanobacterium upregulates specific biochemical pathways to adapt to predation.IMPORTANCE This work explores the transcriptomic responses of Microcystis aeruginosa following exposure to grazing by two cladocerans, Daphnia magna and D. pulex Contrary to previous hypotheses, Microcystis did not employ putative grazing deterrent secondary metabolites in response to the cladocerans, suggesting they may have other roles within the cell, such as oxidative stress protection. The transcriptional metabolic signature during intense grazing was largely reflective of a growth and stress response, although increasing abundances of transcripts encoding extracellular polysaccharides and gas vesicles were potentially related to predator avoidance. PMID- 28003199 TI - Four Inserts within the Catalytic Domain Confer Extra Stability and Activity to Hyperthermostable Pyrolysin from Pyrococcus furiosus. AB - Pyrolysin from the hyperthermophilic archaeon Pyrococcus furiosus is the prototype of the pyrolysin family of the subtilisin-like serine protease superfamily (subtilases). It contains four inserts (IS147, IS29, IS27, and IS8) of unknown function in the catalytic domain. We performed domain deletions and showed that three inserts are either essential (IS147 and IS27) or important (IS8) for efficient maturation of pyrolysin at high temperatures, whereas IS29 is dispensable. The large insert IS147 contains Ca3 and Ca4, two calcium-binding Dx[DN]xDG motifs that are conserved in many pyrolysin-like proteases. Mutagenesis revealed that the Ca3 site contributes to enzyme thermostability and the Ca4 site is necessary for pyrolysin to fold into a maturation-competent conformation. Mature insert-deletion variants were characterized and showed that IS29 and IS8 contribute to enzyme activity and stability, respectively. In the presence of NaCl, pyrolysin undergoes autocleavage at two sites: one within IS29 and the other in IS27 Disrupting the ion pairs in IS27 and IS8 induces autocleavage in the absence of salts. Interestingly, autocleavage products combine noncovalently to form an active, nicked enzyme that is resistant to SDS and urea denaturation. Additionally, a single mutation in IS29 increases resistance to salt-induced autocleavage and further increases enzyme thermostability. Our results suggest that these extra structural elements play a crucial role in adapting pyrolysin to hyperthermal environments.IMPORTANCE Pyrolysin-like proteases belong to the subtilase superfamily and are characterized by large inserts and long C-terminal extensions; however, the role of the inserts in enzyme function is unclear. Our results demonstrate that four inserts in the catalytic domain of hyperthermostable pyrolysin contribute to the folding, maturation, stability, and activity of the enzyme at high temperatures. The modification of extra structural elements in pyrolysin-like proteases is a promising strategy for modulating global structure stability and enzymatic activity of this class of protease. PMID- 28003201 TI - Effects of free sugars on blood pressure and lipids: a systematic review and meta analysis of nutritional isoenergetic intervention trials. AB - BACKGROUND: Sugar has been suggested as a central risk factor in the development of noncommunicable diseases. OBJECTIVE: We assessed the evidence of the effects of free sugars compared with complex carbohydrates on selected cardiovascular disease risk factors. DESIGN: We conducted a systematic review and meta-analysis of intervention trials to compare diets that provide a given amount of energy from free sugars with a control diet that provides the same amount of energy from complex carbohydrates. The primary outcomes were: blood pressure, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triacylglycerols, apolipoproteins A-I and B, or very low density lipoprotein cholesterol. Body weight was also recorded but was not a primary outcome of the studies. RESULTS: In all, 28 studies involving 510 volunteers were included. When free sugars were substituted for complex carbohydrates, no significant increases were detected in systolic or diastolic blood pressure, and no heterogeneity was observed. There were significant increases in HDL cholesterol, LDL cholesterol, and triacylglycerols, although for LDL cholesterol and triacylglycerols there was significant heterogeneity between studies and evidence of publication bias. After adjustment for missing studies, these increases lost significance. Subgroup analyses showed that diets providing the largest total energy intake and energy exchange enhanced the effect of free sugars on total and LDL cholesterol and triacylglycerols. The increase of triacylglycerols was no longer significant when studies with the highest risk of bias were excluded or when only randomized trials were considered. Free sugars had no effect on body weight. CONCLUSIONS: In short- or moderate-term isoenergetic intervention trials, the substitution of free sugars for complex carbohydrates had no effect on blood pressure or body weight and an unclear effect on blood lipid profile. Further independent trials are required to assess whether the reduction of free sugars improves cardiovascular disease risk factors. This review was registered at http://www.crd.york.ac.uk/prospero as CRD42016042930. PMID- 28003200 TI - Genome Integration and Excision by a New Streptomyces Bacteriophage, phiJoe. AB - Bacteriophages are the source of many valuable tools for molecular biology and genetic manipulation. In Streptomyces, most DNA cloning vectors are based on serine integrase site-specific DNA recombination systems derived from phage. Because of their efficiency and simplicity, serine integrases are also used for diverse synthetic biology applications. Here, we present the genome of a new Streptomyces phage, phiJoe, and investigate the conditions for integration and excision of the phiJoe genome. phiJoe belongs to the largest Streptomyces phage cluster (R4-like) and encodes a serine integrase. The attB site from Streptomyces venezuelae was used efficiently by an integrating plasmid, pCMF92, constructed using the phiJoe int-attP locus. The attB site for phiJoe integrase was occupied in several Streptomyces genomes, including that of S. coelicolor, by a mobile element that varies in gene content and size between host species. Serine integrases require a phage-encoded recombination directionality factor (RDF) to activate the excision reaction. The phiJoe RDF was identified, and its function was confirmed in vivo Both the integrase and RDF were active in in vitro recombination assays. The phiJoe site-specific recombination system is likely to be an important addition to the synthetic biology and genome engineering toolbox.IMPORTANCEStreptomyces spp. are prolific producers of secondary metabolites, including many clinically useful antibiotics. Bacteriophage-derived integrases are important tools for genetic engineering, as they enable integration of heterologous DNA into the Streptomyces chromosome with ease and high efficiency. Recently, researchers have been applying phage integrases for a variety of applications in synthetic biology, including rapid assembly of novel combinations of genes, biosensors, and biocomputing. An important requirement for optimal experimental design and predictability when using integrases, however, is the need for multiple enzymes with different specificities for their integration sites. In order to provide a broad platform of integrases, we identified and validated the integrase from a newly isolated Streptomyces phage, phiJoe. phiJoe integrase is active in vitro and in vivo The specific recognition site for integration is present in a wide range of different actinobacteria, including Streptomyces venezuelae, an emerging model bacterium in Streptomyces research. PMID- 28003202 TI - Anthropometry: continued refinements and new developments of an ancient method. PMID- 28003204 TI - Nonviolent civil insecurity is negatively associated with subsequent height-for age in children aged <5 y born between 1998 and 2014 in rural areas of Africa. AB - BACKGROUND: Civil wars and wars between states have occurred less frequently since the start of the 21st century, but civil insecurity outside the contexts of official wars continues to plague many parts of the world. The nutritional consequences of civil insecurity may disproportionately affect children, especially if experienced during sensitive developmental periods. OBJECTIVES: This study estimated the associations between localized nonviolent and violent civil insecurity during key child nutritional periods and subsequent height-for age z scores (HAZs) in 145,948 children born between 1998 and 2014 in Africa and examined the type of place of residence as a mediating factor. DESIGN: A collection of 61 geo-referenced Demographic and Health Surveys implemented between 1998 and 2014 were merged with data from the high-resolution Armed Conflict Location and Event Data Project to construct a repeat cross-sectional database, which was analyzed by using a difference-in-differences model with maternal fixed-effects. RESULTS: Exposure to 1 nonviolent localized civil insecurity event (mean +/- SD: 0.42 +/- 1.87 events) during pregnancy for children living in rural areas was associated with a reduction of 0.01 SD in HAZ (P = 0.024). Exposure to 5 localized civil conflict fatalities (mean +/- SD: 1.41 +/- 10.21 fatalities) for children living in rural areas during the complementary feeding stage was associated with a 0.002-SD decrease in HAZ (P = 0.030). There were no measurable associations between civil insecurity and child heights in urban areas, even though children in urban areas experience more civil insecurity. CONCLUSIONS: Exposure to both violent and nonviolent civil insecurity had negative associations with subsequent HAZ, but only in rural areas. The associations found were small in magnitude but still meaningful from a child development perspective, because these events do not necessarily occur in the context of official wars, they are often nonviolent, and they are endemic to the region. PMID- 28003203 TI - Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies. AB - BACKGROUND: Cocoa flavanol intake, especially that of (-)-epicatechin, has been linked to beneficial effects on human cardiovascular function. However, cocoa also contains the methylxanthines theobromine and caffeine, which may also affect vascular function. OBJECTIVE: We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol dependent vascular effects. DESIGN: Test drinks that contained various amounts of cocoa flavanols (0-820 mg) and methylxanthines (0-220 mg), either together or individually, were consumed by healthy volunteers (n = 47) in 4 different clinical studies-3 with a randomized, double-masked crossover design and 1 with 4 parallel crossover studies. Vascular status was assessed by measuring flow mediated vasodilation (FMD), brachial pulse wave velocity (bPWV), circulating angiogenic cells (CACs), and blood pressure before and 2 h after the ingestion of test drinks. RESULTS: Although cocoa flavanol intake increased FMD 2 h after intake, the consumption of cocoa flavanols with methylxanthines resulted in a greater enhancement of FMD. Methylxanthine intake alone did not result in statistically significant changes in FMD. Cocoa flavanol ingestion alone decreased bPWV and diastolic blood pressure and increased CACs. Each of these changes was more pronounced when cocoa flavanols and methylxanthines were ingested together. It is important to note that the area under the curve of the plasma concentration of (-)-epicatechin metabolites over time was higher after the co-ingestion of cocoa flavanols and methylxanthines than after the intake of cocoa flavanols alone. Similar results were obtained when pure (-)-epicatechin and the methylxanthines theobromine and caffeine were consumed together. CONCLUSION: A substantial interaction between cocoa flavanols and methylxanthines exists at the level of absorption, in which the methylxanthines mediate an increased plasma concentration of (-)-epicatechin metabolites that coincides with enhanced vascular effects commonly ascribed to cocoa flavanol intake. This trial was registered at clinicaltrials.gov as NCT02149238. PMID- 28003205 TI - Incorporating freeze-dried strawberry powder into a high-fat meal does not alter postprandial vascular function or blood markers of cardiovascular disease risk: a randomized controlled trial. AB - BACKGROUND: Postprandial dysmetabolism-an exaggerated spike in triglycerides, glucose, and insulin-increases cardiovascular disease risk by inducing oxidative stress, inflammation, and endothelial dysfunction. Polyphenol-rich foods may blunt these effects when they are incorporated into a high-fat, calorie-dense meal. Strawberries are a rich source of polyphenols, but there is little research on their postprandial effects. OBJECTIVE: This study was designed to investigate the effect of adding 40 g freeze-dried strawberry powder (~1 lb. or 0.45 kg fresh strawberries) to a high-fat (50 g total fat) meal on postprandial vascular function, as well as triglyceride, glucose, and insulin responses. DESIGN: Healthy, overweight or obese [mean +/- SEM body mass index (in kg/m2): 31 +/- 0.5] adults (mean +/- SEM age: 28 +/- 2 y; 17 men and 13 women) consumed a control meal and a strawberry meal in a randomized crossover design. Testing sessions were separated by >=1 wk for men and ~1 mo for women to control for hormonal variations. Blood samples were obtained before the meal and 0.5, 1, 2, and 4 h after the meal. Central blood pressure and arterial stiffness indexes were measured at baseline and 2 and 4 h postmeal with the use of pulse waveform analysis. RESULTS: There were no significant differences between the strawberry and control meals for any outcomes. Consumption of either meal significantly decreased the augmentation index at 2 and 4 h (P < 0.002) and significantly increased triglycerides, insulin, and glucose at all time points (P < 0.001) relative to baseline. CONCLUSIONS: The strawberry intervention did not alter vascular function or attenuate postprandial metabolic derangements in triglycerides, glucose, or insulin relative to the control meal. Additional research is needed to clarify whether strawberries or other polyphenol-rich interventions improve postprandial responses, and future studies should take into account the acute meal-induced improvements in measures of vascular function. This trial was registered at clinicaltrials.gov as NCT01989637. PMID- 28003207 TI - Breaking down, starting up: can a vitamin C-enriched gelatin supplement before exercise increase collagen synthesis? PMID- 28003208 TI - Gut permeability, obesity, and metabolic disorders: who is the chicken and who is the egg? PMID- 28003206 TI - A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations. AB - BACKGROUND: Food fortification has been recommended to improve a population's micronutrient status. Biofortification techniques modestly elevate the zinc content of cereals, but few studies have reported a positive impact on functional indicators of zinc status. OBJECTIVE: We determined the impact of a modest increase in dietary zinc that was similar to that provided by biofortification programs on whole-body and cellular indicators of zinc status. DESIGN: Eighteen men participated in a 6-wk controlled consumption study of a low-zinc, rice-based diet. The diet contained 6 mg Zn/d for 2 wk and was followed by 10 mg Zn/d for 4 wk. To reduce zinc absorption, phytate was added to the diet during the initial period. Indicators of zinc homeostasis, including total absorbed zinc (TAZ), the exchangeable zinc pool (EZP), plasma and cellular zinc concentrations, zinc transporter gene expression, and other metabolic indicators (i.e., DNA damage, inflammation, and oxidative stress), were measured before and after each dietary zinc period. RESULTS: TAZ increased with increased dietary zinc, but plasma zinc concentrations and EZP size were unchanged. Erythrocyte and leukocyte zinc concentrations and zinc transporter expressions were not altered. However, leukocyte DNA strand breaks decreased with increased dietary zinc, and the level of proteins involved in DNA repair and antioxidant and immune functions were restored after the dietary-zinc increase. CONCLUSIONS: A moderate 4-mg/d increase in dietary zinc, similar to that which would be expected from zinc-biofortified crops, improves zinc absorption but does not alter plasma zinc. The repair of DNA strand breaks improves, as do serum protein concentrations that are associated with the DNA repair process. This trial was registered at clinicaltrials.gov as NCT02861352. PMID- 28003209 TI - Relying on biomarkers for intake assessment in nutrition. PMID- 28003210 TI - Plasma hyperosmolality improves tolerance to combined heat stress and central hypovolemia in humans. AB - : Heat stress profoundly impairs tolerance to central hypovolemia in humans via a number of mechanisms including heat-induced hypovolemia. However, heat stress also elevates plasma osmolality; the effects of which on tolerance to central hypovolemia remain unknown. This study examined the effect of plasma hyperosmolality on tolerance to central hypovolemia in heat-stressed humans. With the use of a counterbalanced and crossover design, 12 subjects (1 female) received intravenous infusion of either 0.9% iso-osmotic (ISO) or 3.0% hyperosmotic (HYPER) saline. Subjects were subsequently heated until core temperature increased ~1.4 degrees C, after which all subjects underwent progressive lower-body negative pressure (LBNP) to presyncope. Plasma hyperosmolality improved LBNP tolerance (ISO: 288 +/- 193 vs. HYPER: 382 +/- 145 mmHg * min, P = 0.04). However, no differences in mean arterial pressure (P = 0.10), heart rate (P = 0.09), or muscle sympathetic nerve activity (P = 0.60, n = 6) were observed between conditions. When individual data were assessed, LBNP tolerance improved >=25% in eight subjects but remained unchanged in the remaining four subjects. In subjects who exhibited improved LBNP tolerance, plasma hyperosmolality resulted in elevated mean arterial pressure (ISO: 62 +/- 10 vs. HYPER: 72 +/- 9 mmHg, P < 0.01) and a greater increase in heart rate (ISO: +12 +/- 24 vs. HYPER: +23 +/- 17 beats/min, P = 0.05) before presyncope. No differences in these variables were observed between conditions in subjects that did not improve LBNP tolerance (all P >= 0.55). These results suggest that plasma hyperosmolality improves tolerance to central hypovolemia during heat stress in most, but not all, individuals. PMID- 28003211 TI - Lower-limb hot-water immersion acutely induces beneficial hemodynamic and cardiovascular responses in peripheral arterial disease and healthy, elderly controls. AB - Passive heat induces beneficial perfusion profiles, provides substantive cardiovascular strain, and reduces blood pressure, thereby holding potential for healthy and cardiovascular disease populations. The aim of this study was to assess acute responses to passive heat via lower-limb, hot-water immersion in patients with peripheral arterial disease (PAD) and healthy, elderly controls. Eleven patients with PAD (age 71 +/- 6 yr, 7 male, 4 female) and 10 controls (age 72 +/- 7 yr, 8 male, 2 female) underwent hot-water immersion (30-min waist-level immersion in 42.1 +/- 0.6 degrees C water). Before, during, and following immersion, brachial and popliteal artery diameter, blood flow, and shear stress were assessed using duplex ultrasound. Lower-limb perfusion was measured also using venous occlusion plethysmography and near-infrared spectroscopy. During immersion, shear rate increased (P < 0.0001) comparably between groups in the popliteal artery (controls: +183 +/- 26%; PAD: +258 +/- 54%) and brachial artery (controls: +117 +/- 24%; PAD: +107 +/- 32%). Lower-limb blood flow increased significantly in both groups, as measured from duplex ultrasound (>200%), plethysmography (>100%), and spectroscopy, while central and peripheral pulse wave velocity decreased in both groups. Mean arterial blood pressure was reduced by 22 +/- 9 mmHg (main effect P < 0.0001, interaction P = 0.60) during immersion, and remained 7 +/- 7 mmHg lower 3 h afterward. In PAD, popliteal shear profiles and claudication both compared favorably with those measured immediately following symptom-limited walking. A 30-min hot-water immersion is a practical means of delivering heat therapy to PAD patients and healthy, elderly individuals to induce appreciable systemic (chronotropic and blood pressure lowering) and hemodynamic (upper and lower-limb perfusion and shear rate increases) responses. PMID- 28003212 TI - Subfornical organ neurons integrate cardiovascular and metabolic signals. AB - The subfornical organ (SFO) is a critical circumventricular organ involved in the control of cardiovascular and metabolic homeostasis. Despite the plethora of circulating signals continuously sensed by the SFO, studies investigating how these signals are integrated are lacking. In this study, we use patch-clamp techniques to investigate how the traditionally classified "cardiovascular" hormone ANG II, "metabolic" hormone CCK and "metabolic" signal glucose interact and are integrated in the SFO. Sequential bath application of CCK (10 nM) and ANG (10 nM) onto dissociated SFO neurons revealed that 63% of responsive SFO neurons depolarized to both CCK and ANG; 25% depolarized to ANG only; and 12% hyperpolarized to CCK only. We next investigated the effects of glucose by incubating and recording neurons in either hypoglycemic, normoglycemic, or hyperglycemic conditions and comparing the proportions of responses to ANG (n = 55) or CCK (n = 83) application in each condition. A hyperglycemic environment was associated with a larger proportion of depolarizing responses to ANG (chi2, P < 0.05), and a smaller proportion of depolarizing responses along with a larger proportion of hyperpolarizing responses to CCK (chi2, P < 0.01). Our data demonstrate that SFO neurons excited by CCK are also excited by ANG and that glucose environment affects the responsiveness of neurons to both of these hormones, highlighting the ability of SFO neurons to integrate multiple metabolic and cardiovascular signals. These findings have important implications for this structure's role in the control of various autonomic functions during hyperglycemia. PMID- 28003213 TI - Molecular mechanisms underlying active desalination and low water permeability in the esophagus of eels acclimated to seawater. AB - Marine teleosts can absorb imbibed seawater (SW) to maintain water balance, with esophageal desalination playing an essential role. NaCl absorption from luminal SW was enhanced 10-fold in the esophagus of SW-acclimated eels, and removal of Na+ or Cl- from luminal SW abolished the facilitated absorption, indicating coupled transport. Mucosal/serosal application of various blockers for Na+/Cl- transporters profoundly decreased the absorption. Among the transporter genes expressed in eel esophagus detected by RNA-seq, dimethyl amiloride-sensitive Na+/H+ exchanger (NHE3) and 4,4'-diisothiocyano-2,2'-disulfonic acid-sensitive Cl /[Formula: see text] exchanger (AE) coupled by the scaffolding protein on the apical membrane of epithelial cells, and ouabain-sensitive Na+-K+-ATPases (NKA1alpha1c and NKA3alpha) and diphenylamine-2-carboxylic acid-sensitive Cl- channel (CLCN2) on the basolateral membrane, may be responsible for enhanced transcellular NaCl transport because of their profound upregulation after SW acclimation. Upregulated carbonic anhydrase 2a (CA2a) supplies H+ and [Formula: see text] for activation of the coupled NHE and AE. Apical hydrochlorothiazide sensitive Na+-Cl- cotransporters and basolateral Na+-[Formula: see text] cotransporter (NBCe1) and AE1 are other possible candidates. Concerning the low water permeability that is typically seen in marine teleost esophagus, downregulated aquaporin genes (aqp1a and aqp3) and upregulated claudin gene (cldn15a) are candidates for transcellular/paracellular route. In situ hybridization showed that these upregulated transporters and tight-junction protein genes were expressed in the absorptive columnar epithelial cells of eel esophagus. These results allow us to provide a full picture of the molecular mechanism of active desalination and low water permeability that are characteristic to marine teleost esophagus and gain deeper insights into the role of gastrointestinal tracts in SW acclimation. PMID- 28003214 TI - Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia. AB - Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of DeltaFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/DeltaFosB with a RAS component, angiotensin converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/DeltaFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/DeltaFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/DeltaFosB association with the ACE1 gene within the MnPO following CIH. FosB/DeltaFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure. PMID- 28003215 TI - Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice. AB - Sirt1 is a member of the sirtuin family of proteins and has important roles in numerous biological processes. Sirt1-/- mice display an increased frequency of abnormal spermatozoa, but the mechanism of Sirt1 in spermiogenesis remains largely unknown. Here, we report that Sirt1 might be directly involved in spermiogenesis in germ cells but not in steroidogenic cells. Germ cell-specific Sirt1 knockout mice were almost completely infertile; the early mitotic and meiotic progression of germ cells in spermatogenesis were not obviously affected after Sirt1 depletion, but subsequent spermiogenesis was disrupted by a defect in acrosome biogenesis, which resulted in a phenotype similar to that observed in human globozoospermia. In addition, LC3 and Atg7 deacetylation was disrupted in spermatids after knocking out Sirt1, which affected the redistribution of LC3 from the nucleus to the cytoplasm and the activation of autophagy. Furthermore, Sirt1 depletion resulted in the failure of LC3 to be recruited to Golgi apparatus derived vesicles and in the failure of GOPC and PICK1 to be recruited to nucleus associated acrosomal vesicles. Taken together, these findings reveal that Sirt1 has a novel physiological function in acrosome biogenesis. PMID- 28003217 TI - The Early Clinical Response Endpoint: Great Timing by the Food and Drug Administration? PMID- 28003216 TI - Challenges in Interpretation of Diagnostic Test Results in a Mumps Outbreak in a Highly Vaccinated Population. AB - In spite of a greatly reduced incidence rate due to vaccination, mumps outbreaks continue to occur in several areas of the world, sometimes in vaccinated populations. This article describes an outbreak in a highly vaccinated population in southwestern Ontario, Canada, and the challenges encountered in interpreting the results of diagnostic tests used in the outbreak. During the outbreak, patients were interviewed and classified according to the outbreak case definition, and specimens were collected for diagnostic testing according to Ontario guidelines. Twenty-seven individuals were classified as confirmed cases (n = 19) or suspect cases (n = 8) according to the case definition, only 9 of which were laboratory-confirmed cases: 7 confirmed by reverse transcriptase PCR (RT-PCR) and 2 by IgM serology. All 19 confirmed cases represented patients who were associated with secondary schools in the local area and had been vaccinated against mumps with one (n = 2) or two (n = 17) doses of the measles-mumps-rubella (MMR) vaccine. This is the first published report of an outbreak of mumps in Ontario in which all confirmed cases had been vaccinated against the disease. It highlights the limitations of and difficulties in interpreting current mumps diagnostic tests when used in vaccinated individuals. PMID- 28003218 TI - Early Clinical Response as a Predictor of Late Treatment Success in Patients With Acute Bacterial Skin and Skin Structure Infections: Retrospective Analysis of 2 Randomized Controlled Trials. AB - : In the treatment of acute bacterial skin and skin structure infections, pooled data from 2 clinical trials (N = 1333 patients) showed that programmatic and investigator-assessed early treatment success both had a high positive predictive value (94.3%-100.0%) for late clinical cure, including among hospitalized patients. The negative predictive value of programmatic early success was <20%. These exploratory findings require prospective real-world evaluation. CLINICAL TRIALS REGISTRATION: NCT01170221; NCT01421511. PMID- 28003220 TI - Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis of Lipoprotein(a). AB - RATIONALE: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like lipoprotein and important cardiovascular risk factor whose cognate receptor and intracellular fate remains unknown. OBJECTIVE: Our study aimed to determine the intracellular trafficking pathway for Lp(a) and the receptor responsible for its uptake in liver cells. METHODS AND RESULTS: Human hepatoma cells were treated with Lp(a) purified from human plasma and Lp(a) uptake studied using Western blot analysis and intracellular localization of Lp(a) by confocal microscopy. Lp(a) was maximally internalized by 2 hours and was detected by an antiapo(a) antibody to be localized to Rab5-positive early endosomes, the trans-Golgi network, and subsequently Rab11-positive recycling endosomes. In human hepatoma cells, the apo(a) component from the internalized Lp(a) was resecreted back into the cellular media, whereas the low-density lipoprotein component was localized to the lysosomal compartment. Lp(a) internalization was reduced 0.35-fold in HAP1 and 0.33-fold in human hepatoma cells in which the plasminogen receptor (KT) was knocked out. Conversely, Lp(a) internalization was enhanced 2-fold in HAP1 and 1.6-fold in human hepatoma cells in which plasminogen receptor (KT) was overexpressed, showing for the first time the role of a specific plasminogen receptor in Lp(a) uptake. CONCLUSIONS: The novel findings that Lp(a) is internalized by the plasminogen receptor, plasminogen receptor (KT), and the apo(a) component is recycled may have important implications for the catabolism and function of Lp(a). PMID- 28003219 TI - Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. AB - RATIONALE: Direct conversion or reprogramming of human postnatal cells into endothelial cells (ECs), bypassing stem or progenitor cell status, is crucial for regenerative medicine, cell therapy, and pathophysiological investigation but has remained largely unexplored. OBJECTIVE: We sought to directly reprogram human postnatal dermal fibroblasts to ECs with vasculogenic and endothelial transcription factors and determine their vascularizing and therapeutic potential. METHODS AND RESULTS: We utilized various combinations of 7 EC transcription factors to transduce human postnatal dermal fibroblasts and found that ER71/ETV2 (ETS variant 2) alone best induced endothelial features. KDR+ (kinase insert domain receptor) cells sorted at day 7 from ER71/ETV2-transduced human postnatal dermal fibroblasts showed less mature but enriched endothelial characteristics and thus were referred to as early reprogrammed ECs (rECs), and did not undergo maturation by further culture. After a period of several weeks' transgene-free culture followed by transient reinduction of ER71/ETV2, early rECs matured during 3 months of culture and showed reduced ETV2 expression, reaching a mature phenotype similar to postnatal human ECs. These were termed late rECs. While early rECs exhibited an immature phenotype, their implantation into ischemic hindlimbs induced enhanced recovery from ischemia. These 2 rECs showed clear capacity for contributing to new vessel formation through direct vascular incorporation in vivo. Paracrine or proangiogenic effects of implanted early rECs played a significant role in repairing hindlimb ischemia. CONCLUSIONS: This study for the first time demonstrates that ER71/ETV2 alone can directly reprogram human postnatal cells to functional, mature ECs after an intervening transgene-free period. These rECs could be valuable for cell therapy, personalized disease investigation, and exploration of the reprogramming process. PMID- 28003221 TI - Regional Longitudinal Deformation Improves Prediction of Ventricular Tachyarrhythmias in Patients With Heart Failure With Reduced Ejection Fraction: A MADIT-CRT Substudy (Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy). AB - BACKGROUND: Left ventricular dysfunction is a known predictor of ventricular arrhythmias. We hypothesized that measures of regional longitudinal deformation by speckle-tracking echocardiography predict ventricular tachyarrhythmias and provide incremental prognostic information over clinical and conventional echocardiographic characteristics. METHODS AND RESULTS: We studied 1064 patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) with speckle-tracking data available. Peak longitudinal strain was obtained for the septal, lateral, anterior, and inferior myocardial walls at baseline. The end point was the first event of ventricular tachycardia (VT) or fibrillation (VF). During the median follow-up of 2.9 years, 254 (24%) patients developed VT/VF. Patients with VT/VF had significantly lower left ventricular ejection fraction (28.3% versus 29.5%; P<0.001) and longitudinal strain in all myocardial walls compared with patients without VT/VF (anterior-strain, -7.7% versus -8.8%; P<0.001; lateral-strain, 7.3% versus -7.9%; P=0.022; inferior-strain, -8.3% versus -9.9%; P<0.001; septal strain, -9.1% versus -10.0%; P<0.001). After multivariate adjustment, only anterior and inferior longitudinal strain remained independent predictors of VT/VF (anterior: hazard ratio, 1.08 [1.03-1.13]; P=0.001; inferior: hazard ratio, 1.08 [1.04-1.12]; P<0.001; per 1% absolute decrease for both). When including B type natriuretic peptide in the model, only a decreasing myocardial function in the inferior myocardial wall predicted VT/VF (hazard ratio, 1.05 [1.00-1.11]; P=0.039). Only strain obtained from the inferior myocardial wall provided incremental prognostic information for VT/VF over clinical and echocardiographic parameters (C statistic 0.71 versus 0.69; P=0.005). CONCLUSIONS: Assessment of regional longitudinal myocardial deformation in the inferior region provided incremental prognostic information over clinical and echocardiographic risk factors in predicting ventricular tachyarrhythmias. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. PMID- 28003222 TI - Normal Reference Values and z Scores of the Pulmonary Artery Acceleration Time in Children and Its Importance for the Assessment of Pulmonary Hypertension. AB - BACKGROUND: Pulsed-wave Doppler determination of the pulmonary artery acceleration time (PAAT) as a surrogate for pulmonary artery pressure was found to be of clinical value for assessment of pulmonary hypertension (PH) with studies to date exclusively performed in adults. This study aims to provide representative, normal reference values for PAAT in children of all ages. Moreover, we validated abnormal PAAT values in 54 children with PH. METHODS AND RESULTS: We conducted a prospective echocardiographic study in 756 healthy children (aged 1 day to 18 years) and in 54 children with PH. Possible associations of age, body length, body weight, body surface area, and heart rate on PAAT were investigated. The PAAT correlated positively with age (r=0.848), body length (r=0.871), body surface area (r=0.856), and body weight (r=0.825) and negatively with heart rate (r=-0.906). PAAT increased with age (neonates: median: 81 ms, range: 53-104; 18th year of life: median: 151 ms, range: 107-187). Receiver operating characteristic analysis for detecting PH patients using age specific z scores showed an excellent performance of PAAT (P<0.001; area under the curve, 0.98; 95% confidence interval, 0.97-0.99) with a best cutoff score according to Youden index of -1.565 (sensitivity: 92%, specificity: 96%). PAAT values of PH patients negatively correlated (rho=-0.497) with pulmonary vascular resistance. CONCLUSIONS: The PAAT normal reference values and z scores we provide here will be useful to identify children with a shortened PAAT. Abnormal PAAT values with scores <-2 were predictive of PH. PMID- 28003223 TI - Ventricular Arrhythmias and Reduced Echocardiographic Inferior Wall Strain: Is Regional Function an Important Risk Marker? PMID- 28003224 TI - C-reactive protein isoforms differentially affect outer blood-retinal barrier integrity and function. AB - The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier (oBRB) and is the prime target of early age-related macular degeneration (AMD). C reactive protein (CRP), a serum biomarker for chronic inflammation and AMD, presents two different isoforms, monomeric (mCRP) and pentameric (pCRP), that may have a different effect on inflammation and barrier function in the RPE. The results reported in this study suggest that mCRP but not pCRP impairs RPE functionality by increasing paracellular permeability and disrupting the tight junction proteins ZO-1 and occludin in RPE cells. Additionally, we evaluated the effect of drugs commonly used in clinical settings on mCRP-induced barrier dysfunction. We found that a corticosteroid (methylprednisolone) and an anti-VEGF agent (bevacizumab) prevented mCRP-induced ARPE-19 barrier disruption and IL-8 production. Furthermore, bevacizumab was also able to revert mCRP-induced IL-8 increase after mCRP stimulation. In conclusion, the presence of mCRP within retinal tissue may lead to disruption of the oBRB, an effect that may be modified in the presence of corticosteroids or anti-VEGF drugs. PMID- 28003225 TI - Muscle-specific microRNA-206 targets multiple components in dystrophic skeletal muscle representing beneficial adaptations. AB - Over the last several years, converging lines of evidence have indicated that miR 206 plays a pivotal role in promoting muscle differentiation and regeneration, thereby potentially impacting positively on the progression of neuromuscular disorders, including Duchenne muscular dystrophy (DMD). Despite several studies showing the regulatory function of miR-206 on target mRNAs in skeletal muscle cells, the effects of overexpression of miR-206 in dystrophic muscles remain to be established. Here, we found that miR-206 overexpression in mdx mouse muscles simultaneously targets multiple mRNAs and proteins implicated in satellite cell differentiation, muscle regeneration, and at the neuromuscular junction. Overexpression of miR-206 also increased the levels of several muscle-specific mRNAs/proteins, while enhancing utrophin A expression at the sarcolemma. Finally, we also observed that the increased expression of miR-206 in dystrophin-deficient mouse muscle decreased the production of proinflammatory cytokines and infiltration of macrophages. Taken together, our results show that miR-206 acts as a pleiotropic regulator that targets multiple key mRNAs and proteins expected to provide beneficial adaptations in dystrophic muscle, thus highlighting its therapeutic potential for DMD. PMID- 28003226 TI - Canstatin stimulates migration of rat cardiac fibroblasts via secretion of matrix metalloproteinase-2. AB - Type IV collagen, a nonfibrillar type, is ubiquitously expressed in the basement membrane around cardiomyocytes. Canstatin, a cleaved product of alpha2 chain of type IV collagen, is an antiangiogenic factor. Because it has not been clarified whether canstatin exerts other biological activities in heart, we investigated the effects of canstatin on adult rat cardiac fibroblasts. Cell migration was determined by Boyden chamber assay. Western blotting was performed to detect secretion of matrix metalloproteinase-2 (MMP-2) and MMP-9 and phosphorylation of extracellular signal-regulated kinase (ERK). Localization of MMP-2 was detected by immunofluorescence staining. Canstatin (250 ng/ml) significantly increased migration, secretion, and activity of MMP-2 but not MMP-9. CTTHWGFTLC peptide, an MMP inhibitor and small interfering RNA (siRNA) against MMP-2 suppressed the canstatin-induced (250 ng/ml, 24 h) migration. Canstatin (250 ng/ml, 30 min) significantly increased phosphorylation of ERK. PD98059, a MEK inhibitor, significantly suppressed the canstatin-induced (250 ng/ml, 24 h) migration but not secretion of MMP-2. An increase in MMP-2 expression was observed in cytoplasm of the canstatin-treated (250 ng/ml) cardiac fibroblasts (within 30 min). Canstatin induced actin stress fiber formation, which was inhibited by Y-27632, a Rho-associated kinase inhibitor. Y-27632 also suppressed the canstatin-induced (250 ng/ml, 24 h) MMP-2 secretion. Canstatin (250 ng/ml, 30 min) failed to induce ERK phosphorylation in MMP-2 siRNA-treated cardiac fibroblasts. In conclusion, this study revealed a novel function of canstatin for inducing cell migration of adult rat cardiac fibroblasts at least in part by ERK phosphorylation through MMP 2 secretion, possibly via actin cytoskeletal change. PMID- 28003227 TI - Peripheral osteoma in an unusual location on the mandible. AB - Osteoma is a benign, slow-growing, painless, discrete lesion which is characterised with the proliferation of a compact or cancellous bone. Osteomas are rare on the jaws. Lesions of the mandible developed most often in the condyle, angle and margin. Osteoma developed on the genial tubercle area had only been reported in one case. A 50-year-old female patient has been admitted to our department with the symptom of a hard mass under the chin area. In extra-oral and radiographic examinations, a 1*1 cm size, round, palpable, immobile, radiopaque mass has been determined on the genial tubercle area. The lesion has been completely removed under local anaesthesia by extra-oral approach. Her recovery period was uneventful. Osteoma diagnosis was confirmed with histopathological examination. There is no recurrence at 3-year follow-up. The purpose of this case report is to present a peripheral osteoma case that occurred in the genial tubercle area which is an unusual place. PMID- 28003228 TI - Missing the point: self-inflicted traumatic brain injury in psychosis. AB - A 36-year-old man was brought to the emergency department by emergency medical services after being found acting unusually at a gas station with blood on his head and clothing. He presented acutely psychotic and reported that he had a pen in his head. Medical evaluation was notable for a superficial puncture wound to the right temple, and he was medically cleared for psychiatric evaluation. After he developed nausea and headache later that evening, the CT scan revealed a temporal bone fracture, pneumocephalus, intraparenchymal haemorrhage and the presence of a metal pen tip lodged in the brain parenchyma. The full nature of the injury went undiscovered in the emergency department for 16 hours due to the superficial appearance of the injury and his acute psychosis with prominent delusional thought content and disorganisation. He underwent craniotomy with removal of the pen and subsequent hospitalisation for intravenous antibiotics, followed by a prolonged psychiatric hospitalisation for psychosis. PMID- 28003229 TI - Case of coeliac disease presenting in the psychiatry ward. AB - We describe a case of coeliac disease that was diagnosed in the psychiatry inpatient unit of a general hospital. The patient was admitted due to suicidal behaviours and developed an agitated catatonic state while in the inpatient psychiatry unit. An extensive diagnostic study allowed for the diagnosis of coeliac disease and while her state was unresponsive to antidepressants, anxiolytics, antipsychotics and electroconvulsive therapy, the patient improved significantly when a gluten-free diet was started. While it is well known that, occasionally, gluten sensitivity and coeliac disease can present as brain gluten sensitivity, such cases are typically characterised by motor and/or cognitive symptoms and by white matter abnormalities. Psychiatric presentations of these conditions have only rarely been reported. PMID- 28003230 TI - Prenatal intestinal volvulus: look for cystic fibrosis. AB - Intestinal volvulus is a life-threatening emergency requiring prompt surgical management. Prenatal intestinal volvulus is rare, and most are secondary to intestinal atresia, mesenteric defect or without any underlying cause. Cystic fibrosis (CF) is known to cause digestive tract disorders. After birth, 10-15% of newborns with CF may develop intestinal obstruction within a few days of birth because of meconial ileus.1 This obstruction is a result of dehydrated thickened meconium obstructing the intestinal lumen. We report two cases of fetuses with prenatal diagnosis of segmental volvulus in whom CF was diagnosed. PMID- 28003231 TI - Large bowel perforation secondary to CMV colitis: an unusual primary presentation of HIV infection. AB - We report a case of HIV-associated Cytomegalovirus colitis complicated by large bowel perforation. A 62-year-old man of same-sex relationship was not known to have HIV, but a diagnosis of inflammatory bowel disease was made early in his admission, with steroid treatment initiated. He was later confirmed to be HIV positive, and found to have multiple microperforations of the bowel necessitating ileocecectomy and Hartmann's procedures. PMID- 28003232 TI - Anaplastic large cell lymphoma masquerading as osteomyelitis of the shoulder: an uncommon presentation. AB - The presentation of anaplastic lymphoma kinase protein (ALK)-negative anaplastic large cell lymphoma (ALCL) in bone is rare. We describe a patient with ALK negative ALCL presenting with clinical and radiographic findings suggesting osteomyelitis 6 months after left rotator cuff repair surgery. A review of the characteristics of ALK-negative ALCL with primary bone involvement is presented. ALCL should be considered in patients not responding to therapies for osteomyelitis. PMID- 28003233 TI - Primary omental pregnancy. AB - We present a case of primary omental ectopic pregnancy in a 31-year-old woman which was discovered intraoperatively during a diagnostic laparoscopy and subsequently removed via mini-laparotomy. We emphasise the rarity of this diagnosis, and the importance of careful inspection of the abdominal cavity including the omentum should an ectopic pregnancy be suspected when bilateral fallopian tubes and ovaries appear normal during surgical exploration. PMID- 28003234 TI - Fingolimod (Gilenya) and melanoma. AB - The Food and Drug Administration (FDA) had approved fingolimod usage for multiple sclerosis in 2010. Melanoma after the usage of fingolimod immunomodulation was reported rarely in clinical trials, and only two case reports exist in the published literature, both occurring in Europe. Most of the incidences reported in clinical trials were in-situ, whereas both case reports were of malignant melanoma. Fingolimod has been found to inhibit metastatic melanoma growth in a mouse model that depends on vascular endothelial growth factor (VEGF)-induced angiogenesis for metastasis. However, there are numerous pathways of angiogenesis and tumour growth found in vivo by which melanoma can expand that do not mandate VEGF. We report a case of superficial spreading malignant melanoma occurring after fingolimod therapy in the USA. PMID- 28003235 TI - Patients' perception of DED and its relation with time to diagnosis and quality of life: an international and multilingual survey. AB - BACKGROUND/AIMS: To improve understanding of patients' experience and perception of dry eye disease (DED) and its impact on quality of life (QoL). METHODS: This survey was observational, non-interventional and cross-sectional. The survey was conducted online on 706 patients with DED from five European countries (France, Germany, Italy, Spain and the UK). All patients met the following inclusion criteria: 40 years or older with DED diagnosed by a healthcare professional (HCP), not wearing contact lenses and using tear substitutes daily for at least 6 months. The survey (performed in the five native languages) included 9 screening questions (inclusion criteria) and 26 complementary questions about patients' demography, disease history, DED diagnosis, use of relief treatments, perceptions of DED condition and its impact on QoL. RESULTS: Overall, 218 of 706 (31%) patients perceived DED as a 'disease' or even a 'handicap', and 468 of 706 (66%) as a 'discomfort'. High impact of DED on patients' QoL was associated with negative perception, delay in diagnosis, visits to more than one HCP before diagnosis and high frequency of treatment use. This survey also provided us with a list of language-specific keywords that patients used most frequently to spontaneously describe their condition. CONCLUSIONS: Findings showed that negative perception of DED, delayed diagnosis and high frequency of treatment use were inter-related, and that all have a negative impact on patients' QoL. The generated language-specific keywords used to describe DED could serve as the basis for a comprehensive QoL questionnaire to be used in clinical settings. PMID- 28003237 TI - Towards the reduction of injury and illness in athletes: defining our research priorities. PMID- 28003236 TI - Targeting DNA Repair in Cancer: Beyond PARP Inhibitors. AB - : Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations. SIGNIFICANCE: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. (c)2016 AACR. PMID- 28003238 TI - Calculating acute:chronic workload ratios using exponentially weighted moving averages provides a more sensitive indicator of injury likelihood than rolling averages. AB - OBJECTIVE: To determine if any differences exist between the rolling averages and exponentially weighted moving averages (EWMA) models of acute:chronic workload ratio (ACWR) calculation and subsequent injury risk. METHODS: A cohort of 59 elite Australian football players from 1 club participated in this 2-year study. Global positioning system (GPS) technology was used to quantify external workloads of players, and non-contact 'time-loss' injuries were recorded. The ACWR were calculated for a range of variables using 2 models: (1) rolling averages, and (2) EWMA. Logistic regression models were used to assess both the likelihood of sustaining an injury and the difference in injury likelihood between models. RESULTS: There were significant differences in the ACWR values between models for moderate (ACWR 1.0-1.49; p=0.021), high (ACWR 1.50-1.99; p=0.012) and very high (ACWR >2.0; p=0.001) ACWR ranges. Although both models demonstrated significant (p<0.05) associations between a very high ACWR (ie, >2.0) and an increase in injury risk for total distance ((relative risk, RR)=6.52 21.28) and high-speed distance (RR=5.87-13.43), the EWMA model was more sensitive for detecting this increased risk. The variance (R2) in injury explained by each ACWR model was significantly (p<0.05) greater using the EWMA model. CONCLUSIONS: These findings demonstrate that large spikes in workload are associated with an increased injury risk using both models, although the EWMA model is more sensitive to detect increases in injury risk with higher ACWR. PMID- 28003239 TI - Systematic review and meta-analysis of the effects of football heading. AB - AIM/OBJECTIVE: The objective of this study was to provide a meta-analysis examining the effects of football heading. DESIGN: Meta-analytical review on football heading effects on neurocognitive performance, cognition and symptom reports. DATA SOURCES: Combinations of the key terms were entered into the following electronic database search engines: Cochrane Libraries, PyscARTICLE, PyscINFO, PubMed, ProQuest, SPORTDiscus and Web of Science on 7 July 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: The following inclusion criteria were used to determine eligibility for studies: (1) the study examined and reported on soccer athletes; (2) the population's age, sex and sport position was described; (3) cognitive function, symptoms, balance or other outcomes were quantitatively measured; (4) football heading exposure was quantitatively measured between at least two groups and (5) the study was written in the English language after December 1979. RESULTS: The literature search process identified 467 unique studies. After applying exclusion criteria, 28 studies remained. Included studies had a total of 2288 participants (female participants =933, male participants =1355), aged 13-70 years. The overall results of random effects modelling of football heading were found to be inconclusive across all outcomes, groups and time points. No moderating variables related to methodological, sample or study characteristics were supported in the analysis; age was a potential moderating variable. SUMMARY/CONCLUSIONS: We provide the first meta-analytical review of football heading effects aggregated from multiple studies and extended findings from a recent systematic review of the effects of football heading. Our analysis indicates no overall effect for heading a football on adverse outcomes. PMID- 28003240 TI - Optimising bone health in the young male athlete. PMID- 28003241 TI - Physical activity promotion in physiotherapy practice: a systematic scoping review of a decade of literature. AB - BACKGROUND: The health benefits of physical activity (PA) have been extensively documented. Globally PA levels are low with only a small proportion of the population reaching recommended levels. Insufficient PA is seen as a major public health problem with high cost to society. Physiotherapists work with people to manage long-term conditions and are well placed to deliver individual interventions to increase PA. Despite this, little is known about the evidence that exists in this field. METHODS: This scoping review comprises a comprehensive search of key databases using predetermined search terms. This is supplemented with a parallel search that incorporated novel social media strands. In line with current guidance, a robust screening process took place using agreed inclusion and exclusion criteria. RESULTS: 31 studies met the inclusion criteria. The number of studies published annually increased over the decade. Ireland and USA yielded the largest number of publications with only 1 study from the UK. The target populations included physiotherapists and service users from a range of clinical populations. The studies were mainly quantitative and observational in design with a predominance of studies that scoped attitudes, perceptions, barriers and current practice. CONCLUSIONS: This reconnaissance has shown the state of the evidence to be sparse and disparate. However, the sharp rise in published work in recent years is encouraging. The predominance of scoping studies and the clear social, economic and political drivers for change in this area highlights a need for more pragmatic, interventional studies that can inform clinical practice. PMID- 28003243 TI - Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice. AB - Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimer's disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimer's disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease relative to age matched control individuals. We then treated APP/PS1DeltaE9 mice having established Alzheimer's disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-beta42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer's disease hallmarks in APP/PS1DeltaE9 mice with established pathology. Therefore, this should prompt the investigation of low dose IL-2 in Alzheimer's disease and other neuroinflammatory/neurodegenerative disorders. PMID- 28003242 TI - Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers. AB - See Coulthard and Knight (doi:10.1093/aww335) for a scientific commentary on this article.Individuals with mild cognitive impairment and Alzheimer's disease clinical diagnoses can display significant phenotypic heterogeneity. This variability likely reflects underlying genetic, environmental and neuropathological differences. Characterizing this heterogeneity is important for precision diagnostics, personalized predictions, and recruitment of relatively homogeneous sets of patients into clinical trials. In this study, we apply state of-the-art semi-supervised machine learning methods to the Alzheimer's disease Neuroimaging cohort (ADNI) to elucidate the heterogeneity of neuroanatomical differences between subjects with mild cognitive impairment (n = 530) and Alzheimer's disease (n = 314) and cognitively normal individuals (n = 399), thereby adding to an increasing literature aiming to establish neuroanatomical and neuropathological (e.g. amyloid and tau deposition) dimensions in Alzheimer's disease and its prodromal stages. These dimensional approaches aim to provide surrogate measures of heterogeneous underlying pathologic processes leading to cognitive impairment. We relate these neuroimaging patterns to cerebrospinal fluid biomarkers, white matter hyperintensities, cognitive and clinical measures, and longitudinal trajectories. We identified four such atrophy patterns: (i) individuals with largely normal neuroanatomical profiles, who also turned out to have the least abnormal cognitive and cerebrospinal fluid biomarker profiles and the slowest clinical progression during follow-up; (ii) individuals with classical Alzheimer's disease neuroanatomical, cognitive, cerebrospinal fluid biomarkers and clinical profile, who presented the fastest clinical progression; (iii) individuals with a diffuse pattern of atrophy with relatively less pronounced involvement of the medial temporal lobe, abnormal cerebrospinal fluid amyloid-beta1-42 values, and proportionally greater executive impairment; and (iv) individuals with notably focal involvement of the medial temporal lobe and a slow steady progression, likely representing in early Alzheimer's disease stages. These four atrophy patterns effectively define a 4-dimensional categorization of neuroanatomical alterations in mild cognitive impairment and Alzheimer's disease that can complement existing dimensional approaches for staging Alzheimer's disease using a variety of biomarkers, which offer the potential for enabling precision diagnostics and prognostics, as well as targeted patient recruitment of relatively homogeneous subgroups of subjects for clinical trials. PMID- 28003244 TI - The Alcohol Use Disorders Identification Test (AUDIT): Exploring the Factor Structure and Cutoff Thresholds in a Representative Post-Conflict Population in Northern Uganda. AB - Aims: Despite increased use of the Alcohol Use Disorders Identification Test (AUDIT) in sub-Saharan Africa, few studies have assessed its underlying conceptual framework, and none have done so in post-conflict settings. Further, significant inconsistencies exist between definitions used for problematic consumption. Such is the case in Uganda, facing one of the highest per-capita alcohol consumption levels regionally, which is thought to be hindering rebuilding in the North after two decades of civil war. This study explores the impact of varying designation cutoff thresholds in the AUDIT as well as its conceptual factor structure in a representative sample of the population. Methods: In all, 1720 Cango Lyec Project participants completed socio-economic and mental health questionnaires, provided blood samples and took the AUDIT. Participant characteristics and consumption designations were compared at AUDIT summary score thresholds of >=3, >=5 and >=8. Confirmatory factor analyses (CFA) explored one-, two- and three-factor level models overall and by sex with relative and absolute fit indicators. Results: There were no significant differences in participant demographic characteristics between thresholds. At higher cutoffs, the test increased in specificity to identify those with hazardous drinking, disordered drinking and suffering from alcohol-related harms. All conceptual models indicated good fit, with three-factor models superior overall and within both sexes. Conclusion: In Northern Uganda, a three-factor AUDIT model best explores alcohol use in the population and is appropriate for use in both sexes. Lower cutoff thresholds are recommended to identify those with potentially disordered drinking to best plan effective interventions and treatments. Short summary: A CFA of the AUDIT showed good fit for one-, two, and three-factor models overall and by sex in a representative sample in post conflict Northern Uganda. A three-plus total AUDIT cutoff score is suggested to screen for hazardous drinking in this or similar populations. PMID- 28003245 TI - Impulsivity Moderates Subjective Responses to Alcohol in Alcohol-Dependent Individuals. AB - Aims: Studies of social drinkers indicate that subjective response (SR) to alcohol and impulsivity are risk factors for the development of alcohol use disorder which may be related. It is unclear, however, whether there are significant relationships between SR and impulsivity among individuals with alcohol dependence. Using data from an intravenous (IV) alcohol challenge study, the present study is the first to explore the relationship between impulsivity and SR during alcohol administration among alcohol-dependent individuals. Methods: Non-treatment-seeking, alcohol-dependent individuals (N = 42) completed the Delay Discounting Task to measure impulsivity and then completed two counterbalanced, placebo-controlled IV alcohol administration sessions, which included assessments of SR at breath alcohol concentration (BrAC) levels of 0.00, 0.02, 0.04 and 0.06 g/dl. Results: Analyses revealed that more impulsive participants experienced higher subjective stimulation and positive mood in response to rising BrACs as compared to less impulsive individuals. More impulsive participants also experienced increased sedation over time regardless of condition (i.e. alcohol vs. saline). Conclusion: These findings suggest that among alcohol-dependent individuals, impulsivity is positively associated with the hedonic effects of alcohol as compared to placebo. High impulsivity may characterize a subset of alcohol-dependent individuals who drink to experience the rewarding effects of alcohol. PMID- 28003247 TI - Impaired High-Density Lipoprotein Anti-Oxidative Function Is Associated With Outcome in Patients With Chronic Heart Failure. AB - BACKGROUND: Oxidative stress is mechanistically linked to the pathogenesis of chronic heart failure (CHF). Antioxidative functions of high-density lipoprotein (HDL) particles have been found impaired in patients with ischemic cardiomyopathy; however, the impact of antioxidative HDL capacities on clinical outcome in CHF patients is unknown. We therefore investigated the predictive value of antioxidative HDL function on mortality in a representative cohort of patients with CHF. METHODS AND RESULTS: We prospectively enrolled 320 consecutive patients admitted to our outpatient department for heart failure and determined antioxidative HDL function using the HDL oxidative index (HOI). During a median follow-up time of 2.8 (IQR: 1.8-4.9) years, 88 (27.5%) patients reached the combined cardiovascular endpoint defined as the combination of death due to cardiovascular events and heart transplantation. An HOI >=1 was significantly associated with survival free of cardiovascular events in Cox regression analysis with a hazard ratio (HR) of 2.28 (95% CI 1.48-3.51, P<0.001). This association remained significant after comprehensive multivariable adjustment for potential confounders with an adjusted HR of 1.83 (95% CI 1.1-2.92, P=0.012). Determination of HOI significantly enhanced risk prediction beyond that achievable with N terminal pro-B-type natriuretic peptide indicated by improvements in net reclassification index (32.4%, P=0.009) and integrated discrimination improvement (1.4%, P=0.04). CONCLUSIONS: Impaired antioxidative HDL function represents a strong and independent predictor of mortality in patients with CHF. Implementation of HOI leads to a substantial improvement of risk prediction in patients with CHF. PMID- 28003248 TI - Development of a Smartphone-Enabled Hypertension and Diabetes Mellitus Management Package to Facilitate Evidence-Based Care Delivery in Primary Healthcare Facilities in India: The mPower Heart Project. AB - BACKGROUND: The high burden of undetected and undertreated hypertension and diabetes mellitus is a major health challenge worldwide. The mPower Heart Project aimed to develop and test a feasible and scalable intervention for hypertension and diabetes mellitus by task-sharing with the use of a mobile phone-based clinical decision support system at Community Health Centers in Himachal Pradesh, India. METHODS AND RESULTS: The development of the intervention and mobile phone based clinical decision support system was carried out using mixed methods in five Community Health Centers. The intervention was subsequently evaluated using pre-post evaluation design. During intervention, a nurse care coordinator screened, examined, and entered patient parameters into mobile phone-based clinical decision support system to generate a prescription, which was vetted by a physician. The change in systolic blood pressure, diastolic blood pressure, and fasting plasma glucose (FPG) over 18 months of intervention was quantified using generalized estimating equations models. During intervention, 6797 participants were enrolled. Six thousand sixteen participants had hypertension (mean systolic blood pressure: 146.1 mm Hg, 95% CI: 145.7, 146.5; diastolic blood pressure: 89.52 mm Hg, 95% CI: 89.33, 89.72), of which 3152 (52%) subjects were newly detected. Similarly, 1516 participants had diabetes mellitus (mean FPG: 177.9 mg/dL, 95% CI: 175.8, 180.0), of which 450 (30%) subjects were newly detected. The changes in systolic blood pressure, diastolic blood pressure, and FPG observed at 18 months of follow-up were -14.6 mm Hg (95% CI: -15.3, -13.8), -7.6 mm Hg (CI: -8.0, -7.2), and -50.0 mg/dL (95% CI: -54.6, -45.5), respectively, and were statistically significant even after adjusting for age, sex, and Community Health Center. CONCLUSIONS: A nurse-facilitated, mobile phone-based clinical decision support system-enabled intervention in primary care was associated with improvements in blood pressure and blood glucose control and has the potential to scale-up in resource poor settings. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01794052. Clinical Trial Registry-India: CTRI/2013/02/003412. PMID- 28003249 TI - Endothelial Function Assessed by Automatic Measurement of Enclosed Zone Flow Mediated Vasodilation Using an Oscillometric Method Is an Independent Predictor of Cardiovascular Events. AB - BACKGROUND: A new device for automatic measurement of flow-mediated vasodilation (FMD) using an oscillometric method has been developed to solve technical problems of conventional FMD measurement. This device measures enclosed zone FMD (ezFMD). The purpose of this study was to evaluate the prognostic value of endothelial function assessed by ezFMD for future cardiovascular events. METHODS AND RESULTS: We measured ezFMD in 272 participants who underwent health-screening examinations. First, we investigated cross-sectional associations between ezFMD and cardiovascular risk factors, and then we assessed the associations between ezFMD and first major cardiovascular events (death from cardiovascular causes, stroke, and coronary revascularization). Univariate regression analysis revealed that ezFMD was significantly correlated with age, triglycerides, glucose, smoking pack-years, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and Framingham risk score. During a median follow-up period of 36.1 months (interquartile range 18.8-40.1 months), 12 participants died (6 from cardiovascular causes), 3 had stroke, 8 had coronary revascularization, and 10 were hospitalized for heart failure. There was no episode of acute coronary syndrome during the study period. Participants were divided into tertiles (low, intermediate, and high) based on ezFMD. Kaplan-Meier curves for first major cardiovascular events among the 3 groups were significantly different (P=0.004). After adjustment for cardiovascular risk factors, the low group was significantly associated with an increased risk of first major cardiovascular events compared with the high group (hazard ratio 6.47; 95% CI 1.09-125.55; P=0.038). CONCLUSIONS: These findings suggest that endothelial function assessed by ezFMD may be useful as a surrogate marker of future cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: https://upload.umin.ac.jp. Unique identifier: UMIN000004902. PMID- 28003252 TI - Association of Family History With Cardiovascular Disease in Hypertensive Individuals in a Multiethnic Population. AB - BACKGROUND: Hypertension alone is a poor predictor of the individual risk of cardiovascular disease. Hereditary factors of which hypertension is merely a marker may explain why some hypertensive individuals appear more susceptible to cardiovascular disease, and why some ethnicities have more often seemingly hypertension-related cardiovascular disease than others. We hypothesize that, in hypertensive individuals, a positive family history of cardiovascular disease identifies a high-risk subpopulation. METHODS AND RESULTS: Healthy Life in Urban Settings (HELIUS) is a cohort study among participants of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan origin aged 70 years and younger. In participants with hypertension (n=6467), we used logistic regression to assess the association of family history of cardiovascular disease with prevalent stroke and nonstroke cardiovascular disease, adjusting for sex, age, education, and smoking. To detect ethnic differences, we tested for interaction between family history and ethnicity and stratified the analysis by ethnicity. A positive family history was associated with a higher prevalence of nonstroke cardiovascular disease (odds ratio [OR], 2.05; 95% CI, 1.65-2.54) and stroke (OR, 1.62; 95% CI, 1.19-2.20). The strongest association of family history with nonstroke cardiovascular disease was found among the Dutch (OR, 2.47; 95% CI, 1.37-4.44) and with stroke among the African Surinamese (OR, 2.17; 95% CI, 1.32-3.57). The interaction between family history and African Surinamese origin for stroke was statistically significant. CONCLUSIONS: In multiethnic populations of hypertensive patients, a positive family history of cardiovascular disease may be used clinically to identify individuals at high risk for nonstroke cardiovascular disease regardless of ethnic origin and African Surinamese individuals at high risk for stroke. PMID- 28003251 TI - Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension. AB - BACKGROUND: Options for interventional therapy to lower blood pressure (BP) in patients with treatment-resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH. METHODS AND RESULTS: The randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment-resistant hypertension (office systolic BP >=140 mm Hg, average daytime ambulatory BP >=135/85 mm Hg, and treatment with >=3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177+/-18 mm Hg versus 169+/-17 mm Hg, P=0.163) and 24-hour ambulatory systolic BP (159+/-16 mm Hg versus 154+/-11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: -29+/-21 mm Hg versus ISH: -22+/-31 mm Hg, P=0.445) and 24-hour ambulatory systolic BP (CH: -14+/-20 mm Hg versus ISH: -13+/-15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction >=10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932). CONCLUSIONS: Our data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24-hour ambulatory systolic BP in patients with combined and isolated systolic hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498. PMID- 28003250 TI - Association of Major Depression With Risk of Ischemic Heart Disease in a Mega Cohort of Chinese Adults: The China Kadoorie Biobank Study. AB - BACKGROUND: Increasing evidence has suggested that major depression (MD) is associated with an increased risk of ischemic heart disease (IHD). We examined this association in Chinese adults using data from the China Kadoorie Biobank study. METHODS AND RESULTS: Over 0.5 million adults aged 30 to 79 years were followed from baseline interview (2004-2008) until December 31, 2013. Past year MD was measured with the modified Chinese version of Composite International Diagnostic Interview-Short Form at baseline. Incident IHD cases were identified through linkage to related medical databases, and defined as having International Statistical Classification of Diseases and Related Health Problems 10th Revision codes of I20 to I25. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs for the MD-IHD association with adjustment for sociodemographic variables and established cardiovascular risk factors. During 3 423 542 person-years of follow-up, 24 705 incident IHD cases were documented. Higher IHD incidence was observed in participants with MD compared with those without (8.76 versus 7.21 per 1000 person-years), and the multivariable-adjusted hazard ratio was 1.32 (95% CI 1.15-1.53). Geographic location modified the association (P for interaction=0.005), and a positive association was observed in urban residents (hazard ratio 1.72; 95% CI 1.39-2.14) but not rural residents (1.13; 0.93-1.37). Compared with participants without depressive symptoms, the hazard ratio (95% CI) of IHD was 1.13 (1.04-1.23) for those with depressive symptoms only and 1.33 (1.15-1.53) for those with MD. CONCLUSIONS: Past year major depression was associated with an increased risk of IHD in Chinese adults, independent of other major cardiovascular risk factors. PMID- 28003253 TI - Insurance Status Among Adults With Hypertension-The Impact of Underinsurance. AB - BACKGROUND: Hypertension is a major risk factor for heart disease and stroke. Health insurance coverage affects hypertension treatment and control, but limited information is available for US adults with hypertension who are classified as underinsured. METHODS AND RESULTS: Using Behavioral Risk Factor Surveillance System 2013 data, we identified adults with self-reported hypertension. On the basis of self-reported health insurance status and health care-related financial burdens, participants were categorized as uninsured, underinsured, or adequately insured. Proxies for health care received included whether they reported taking antihypertensive medications and whether they visited a doctor for a routine checkup in the past year. We assessed the association between health insurance status and health care received, adjusting for selected sociodemographic characteristics. Among 123 257 participants from 38 states and District of Columbia with self-reported hypertension, 12% were uninsured, 26% were underinsured, and 62% were adequately insured. In adjusted models using adequately insured participants as referent, both uninsured (adjusted odds ratio, 0.39; 95% CI, 0.35-0.43) and underinsured (0.83, 0.76-0.89) participants were less likely to report using antihypertensive medication than those of adequately insured participants. Similarly, adjusted odds ratio of visiting a doctor for routine checkup in the past year were 0.25 (0.23-0.28) for those who were uninsured and 0.78 (0.72-0.84) for those who were underinsured compared to those with adequate insurance. CONCLUSIONS: Uninsured and underinsured participants with hypertension were less likely to report receiving care compared to those with adequate insurance coverage. Disparities in health care coverage may necessitate targeted interventions, even among people with health insurance. PMID- 28003254 TI - Health Insurance and Blood Pressure Control. PMID- 28003256 TI - Recycler: an algorithm for detecting plasmids from de novo assembly graphs. AB - Motivation: Plasmids and other mobile elements are central contributors to microbial evolution and genome innovation. Recently, they have been found to have important roles in antibiotic resistance and in affecting production of metabolites used in industrial and agricultural applications. However, their characterization through deep sequencing remains challenging, in spite of rapid drops in cost and throughput increases for sequencing. Here, we attempt to ameliorate this situation by introducing a new circular element assembly algorithm, leveraging assembly graphs provided by a conventional de novo assembler and alignments of paired-end reads to assemble cyclic sequences likely to be plasmids, phages and other circular elements. Results: We introduce Recycler, the first tool that can extract complete circular contigs from sequence data of isolate microbial genomes, plasmidome and metagenome sequence data. We show that Recycler greatly increases the number of true plasmids recovered relative to other approaches while remaining highly accurate. We demonstrate this trend via simulations of plasmidomes, comparisons of predictions with reference data for isolate samples, and assessments of annotation accuracy on metagenome data. In addition, we provide validation by DNA amplification of 77 plasmids predicted by Recycler from the different sequenced samples in which Recycler showed mean accuracy of 89% across all data types-isolate, microbiome and plasmidome. Availability and Implementation: Recycler is available at http://github.com/Shamir-Lab/Recycler. Contact: imizrahi@bgu.ac.il. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003255 TI - Pain Tolerance in Persons With Recognized and Unrecognized Myocardial Infarction: A Population-Based, Cross-Sectional Study. AB - BACKGROUND: Unrecognized myocardial infarction (MI) is a prevalent condition associated with a similar risk of death as recognized MI. It is unknown why some persons experience MI with few or no symptoms; however, one possible explanation is attenuated pain sensitivity. To our knowledge, no previous study has examined the association between pain sensitivity and recognition of MI. METHODS AND RESULTS: We conducted a population-based cross-sectional study with 4849 included participants who underwent the cold pressor test (a common experimental pain assay) and ECG. Unrecognized MI was present in 387 (8%) and recognized MI in 227 (4.7%) participants. Participants with unrecognized MI endured the cold pressor test significantly longer than participants with recognized MI (hazard ratio for aborting the cold pressor test, 0.64; CI, 0.47-0.88), adjusted for age and sex. The association was attenuated and borderline significant after multivariable adjustment. The association between unrecognized MI and lower pain sensitivity was stronger in women than in men, and statistically significant in women only, but interaction testing was not statistically significant (P for interaction=0.14). CONCLUSIONS: Our findings suggest that persons who experience unrecognized MI have reduced pain sensitivity compared with persons who experience recognized MI. This may partially explain the lack of symptoms associated with unrecognized MI. PMID- 28003257 TI - HYSYS: have you swapped your samples? AB - Motivation: The application of a genomics assay to samples from a cohort is a frequently applied experimental design in cancer genomics studies. The collection and analysis of cancer sequencing data in the clinical setting is an elaborate process that may involve consenting patients, obtaining possibly-multiple DNA samples, sequencing and analysis. Many of these steps are manual. At any stage mistakes can occur that cause a DNA sample to be labelled incorrectly. However, there is a paucity of methods in the literature to identify such swaps specifically in cancer studies. Results: Here, we introduce a simple method, HYSYS, to estimate the relatedness of samples and test for sample swaps and contamination. The test uses the concordance of homozygous SNPs between samples. The method is motivated by the observation that homozygous germline population variants rarely change in the disease and are not affected by loss of heterozygosity. Our tools include visualization and a testing framework to flag possible sample swaps. We demonstrate the utility of this approach on a small cohort. Availability and Implementation: http://github.com/PapenfussLab/HaveYouSwappedYourSamples. Contact: papenfuss@wehi.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003259 TI - MEGA-V: detection of variant gene sets in patient cohorts. AB - Summary: : Detecting significant associations between genetic variants and disease may prove particularly challenging when the variants are rare in the population and/or act together with other variants to cause the disease. We have developed a statistical framework named Mutation Enrichment Gene set Analysis of Variants (MEGA-V) that specifically detects the enrichments of genetic alterations within a process in a cohort of interest. By focusing on the mutations of several genes contributing to the same function rather than on those affecting a single gene, MEGA-V increases the power to detect statistically significant associations. Availability and Implementation: MEGA-V is available at https://github.com/ciccalab/MEGA. Contact: francesca.ciccarelli@kcl.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003258 TI - The Ark: a customizable web-based data management tool for health and medical research. AB - Summary: The Ark is an open-source web-based tool that allows researchers to manage health and medical research data for humans and animals without specialized database skills or programming expertise. The system provides data management for core research information including demographic, phenotype, biospecimen and pedigree data, in addition to supporting typical investigator requirements such as tracking participant consent and correspondence, whilst also being able to generate custom data exports and reports. The Ark is 'study generic' by design and highly configurable via its web interface, allowing researchers to tailor the system to the specific data management requirements of their study. Availability and Implementation: Source code for The Ark can be obtained freely from the website https://github.com/The-Ark-Informatics/ark/ . The source code can be modified and redistributed under the terms of the GNU GPL v3 license. Documentation and a pre-configured virtual appliance can be found at the website http://sphinx.org.au/the-ark/ . Contact: adrianb@unimelb.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003260 TI - T-BAS: Tree-Based Alignment Selector toolkit for phylogenetic-based placement, alignment downloads and metadata visualization: an example with the Pezizomycotina tree of life. AB - Motivation: High-quality phylogenetic placement of sequence data has the potential to greatly accelerate studies of the diversity, systematics, ecology and functional biology of diverse groups. We developed the Tree-Based Alignment Selector (T-BAS) toolkit to allow evolutionary placement and visualization of diverse DNA sequences representing unknown taxa within a robust phylogenetic context, and to permit the downloading of highly curated, single- and multi-locus alignments for specific clades. Results: In its initial form, T-BAS v1.0 uses a core phylogeny of 979 taxa (including 23 outgroup taxa, as well as 61 orders, 175 families and 496 genera) representing all 13 classes of largest subphylum of Fungi-Pezizomycotina (Ascomycota)-based on sequence alignments for six loci (nr5.8S, nrLSU, nrSSU, mtSSU, RPB1, RPB2 ). T-BAS v1.0 has three main uses: (i) Users may download alignments and voucher tables for members of the Pezizomycotina directly from the reference tree, facilitating systematics studies of focal clades. (ii) Users may upload sequence files with reads representing unknown taxa and place these on the phylogeny using either BLAST or phylogeny based approaches, and then use the displayed tree to select reference taxa to include when downloading alignments. The placement of unknowns can be performed for large numbers of Sanger sequences obtained from fungal cultures and for alignable, short reads of environmental amplicons. (iii) User-customizable metadata can be visualized on the tree. Availability and Implementation: T-BAS Version 1.0 is available online at http://tbas.hpc.ncsu.edu . Registration is required to access the CIPRES Science Gateway and NSF XSEDE's large computational resources. Contact: icarbon@ncsu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003261 TI - Innovations and challenges in detecting long read overlaps: an evaluation of the state-of-the-art. AB - : Identifying overlaps between error-prone long reads, specifically those from Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PB), is essential for certain downstream applications, including error correction and de novo assembly. Though akin to the read-to-reference alignment problem, read-to-read overlap detection is a distinct problem that can benefit from specialized algorithms that perform efficiently and robustly on high error rate long reads. Here, we review the current state-of-the-art read-to-read overlap tools for error-prone long reads, including BLASR, DALIGNER, MHAP, GraphMap and Minimap. These specialized bioinformatics tools differ not just in their algorithmic designs and methodology, but also in their robustness of performance on a variety of datasets, time and memory efficiency and scalability. We highlight the algorithmic features of these tools, as well as their potential issues and biases when utilizing any particular method. To supplement our review of the algorithms, we benchmarked these tools, tracking their resource needs and computational performance, and assessed the specificity and precision of each. In the versions of the tools tested, we observed that Minimap is the most computationally efficient, specific and sensitive method on the ONT datasets tested; whereas GraphMap and DALIGNER are the most specific and sensitive methods on the tested PB datasets. The concepts surveyed may apply to future sequencing technologies, as scalability is becoming more relevant with increased sequencing throughput. Contact: cjustin@bcgsc.ca , ibirol@bcgsc.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003263 TI - bnstruct: an R package for Bayesian Network structure learning in the presence of missing data. AB - Motivation: A Bayesian Network is a probabilistic graphical model that encodes probabilistic dependencies between a set of random variables. We introduce bnstruct, an open source R package to (i) learn the structure and the parameters of a Bayesian Network from data in the presence of missing values and (ii) perform reasoning and inference on the learned Bayesian Networks. To the best of our knowledge, there is no other open source software that provides methods for all of these tasks, particularly the manipulation of missing data, which is a common situation in practice. Availability and Implementation: The software is implemented in R and C and is available on CRAN under a GPL licence. Contact: francesco.sambo@unipd.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003262 TI - Defining the clonality of peripheral T cell lymphomas using RNA-seq. AB - Motivation: In T-cell lymphoma, malignant T cells arising from a founding clone share an identical T cell receptor (TCR) and can be identified by the over representation of this TCR relative to TCRs from the patient's repertoire of normal T cells. Here, we demonstrate that TCR information extracted from RNA-seq data can provide a higher resolution view of peripheral T cell lymphomas (PTCLs) than that provided by conventional methods. Results: For 60 subjects with PTCL, flow cytometry/FACS was used to identify and sort aberrant T cell populations from diagnostic lymph node cell suspensions. For samples that did not appear to contain aberrant T cell populations, T helper (T H ), T follicular helper (T FH ) and cytotoxic T lymphocyte (CTL) subsets were sorted. RNA-seq was performed on sorted T cell populations, and TCR alpha and beta chain sequences were extracted and quantified directly from the RNA-seq data. 96% of the immunophenotypically aberrant samples had a dominant T cell clone readily identifiable by RNA-seq. Of the samples where no aberrant population was found by flow cytometry, 80% had a dominant clone by RNA-seq. This demonstrates the increased sensitivity and diagnostic ability of RNA-seq over flow cytometry and shows that the presence of a normal immunophenotype does not exclude clonality. Availability and Implementation: R scripts used in the processing of the data are available online at https://www.github.com/scottdbrown/RNAseq-TcellClonality. Contacts: rholt@bcgsc.ca or ksavage@bccancer.bc.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003264 TI - A general framework for association analysis of microbial communities on a taxonomic tree. AB - Motivation: : Association analysis of microbiome composition with disease-related outcomes provides invaluable knowledge towards understanding the roles of microbes in the underlying disease mechanisms. Proper analysis of sparse compositional microbiome data is challenging. Existing methods rely on strong assumptions on the data structure and fail to pinpoint the associated microbial communities. Results: : We develop a general framework to: (i) perform robust association tests for the microbial community that exhibits arbitrary inter-taxa dependencies; (ii) localize lineages on the taxonomic tree that are associated with covariates (e.g. disease status); and (iii) assess the overall association of the whole microbial community with the covariates. Unlike existing methods for microbiome association analysis, our framework does not make any distributional assumptions on the microbiome data; it allows for the adjustment of confounding variables and accommodates excessive zero observations; and it incorporates taxonomic information. We perform extensive simulation studies under a wide-range of scenarios to evaluate the new methods and demonstrate substantial power gain over existing methods. The advantages of the proposed framework are further demonstrated with real datasets from two microbiome studies. The relevant R package miLineage is publicly available. Availability and Implementation: : miLineage package, manual and tutorial are available at https://medschool.vanderbilt.edu/tang-lab/software/miLineage . Contact: z.tang@vanderbilt.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003266 TI - GWAlpha: genome-wide estimation of additive effects (alpha) based on trait quantile distribution from pool-sequencing experiments. AB - Motivation: Sequencing pools of individuals (Pool-Seq) is a cost-effective way to gain insight into the genetics of complex traits, but as yet no parametric method has been developed to both test for genetic effects and estimate their magnitude. Here, we propose GWAlpha, a flexible method to obtain parametric estimates of genetic effects genome-wide from Pool-Seq experiments. Results: We showed that GWAlpha powerfully replicates the results of Genome-Wide Association Studies (GWAS) from model organisms. We perform simulation studies that illustrate the effect on power of sample size and number of pools and test the method on different experimental data. Availability and Implementation: GWAlpha is implemented in python, designed to run on Linux operating system and tested on Mac OS. It is freely available at https://github.com/aflevel/GWAlpha . Contact: afournier@unimelb.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28003267 TI - Public health budgets "must be protected" to guarantee NHS's long term future. PMID- 28003269 TI - SRF/myocardin: a novel molecular axis regulating vascular smooth muscle cell stiffening in hypertension. PMID- 28003268 TI - Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension. AB - AIMS: Increased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway. METHODS AND RESULTS: Four month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame. CONCLUSIONS: SRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness. PMID- 28003270 TI - Akap-mediated signalling: the importance of being in the right place at the right time. PMID- 28003271 TI - A new side to an old coin: dynamin related protein-1 with benefits in the heart. PMID- 28003272 TI - Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia. AB - Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. We analyzed 57 AML patients with normal karyotype by using Illumina's 450k array and showed that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, chromatin immunoprecipitation sequencing analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is therefore not sufficient for enhancer activation. Some sites of hypomethylation occur at weak/poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML-specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes, including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation and cause perturbed enhancer activity in cytogenetically normal AML that contributes to a leukemic transcriptome. PMID- 28003273 TI - EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia-like B-cell malignancies. AB - Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5+ B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein Barr virus-induced gene 2 (EBI2 or GPR183) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (IgM) and IgG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5+ B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies. PMID- 28003275 TI - TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) is an aggressive neoplasm of B- or T-lymphoid progenitors and is the commonest childhood tumor. ALL comprises multiple subtypes characterized by distinct genetic alterations, with stereotyped patterns of aneuploidy present in many cases. Although alterations of TP53 are common in many tumors, they are infrequent in ALL, with the exception of two ALL subtypes associated with poor outcome: relapsed disease and ALL with hypodiploidy. TP53 alterations are present in almost all cases of ALL with low hypodiploidy and are associated with alterations of the lymphoid transcription factor IKZF2 and the tumor-suppressor gene loci CDKN2A and CDKN2B. Remarkably, more than half of TP53 mutations in low-hypodiploid ALL in children are present in nontumor cells, indicating that low-hypodiploid ALL is a manifestation of Li-Fraumeni syndrome. These findings have profound implications for our understanding of the genetic pathogenesis of hypodiploid ALL, suggesting that alteration of TP53 function may promote the distinctive aneuploidy characteristic of hypodiploid ALL. Moreover, the identification of hypodiploidy mandates offering testing for TP53 mutational status to patients and their relatives, with appropriate counseling and disease surveillance. PMID- 28003276 TI - Lesion-Directed Therapies and Monitoring Tumor Evolution Using Liquid Biopsies. AB - Precision oncology relies on targeted drugs, such as kinase inhibitors, that are presently administered based on molecular profiles obtained from surgical or bioptic tissue samples. The inherent ability of human tumors to molecularly evolve in response to drug pressures represents a daunting diagnostic challenge. Circulating free DNA (cfDNA) released from primary and metastatic lesions can be used to draw molecular maps that can be continuously updated to match each tumor's evolution. We will present evidence that liquid biopsies can effectively interrogate how targeted therapies drive lesion-specific drug-resistance mechanisms. The impact of drug-induced molecular heterogeneity on subsequent lines of treatment will also be discussed. PMID- 28003277 TI - Genetics of beta-Amyloid Precursor Protein in Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of beta-amyloid (Abeta), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Abeta is generated by proteolytic processing of the beta-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of APP, leading to elevated APP expression, increased Abeta deposition, and characteristic AD neuropathology. Sequencing of APP in familial early-onset AD identified missense mutations that cause AD, while a recently discovered coding variant, APP A673T, reduces the risk for AD. Cellular and animal studies show that risk-associated mutations increase total Abeta levels, Abeta42 levels, or Abeta fibrillogenesis, while protective alleles reduce Abeta levels. Together, these studies provide compelling evidence for the Abeta hypothesis and suggest that therapeutics that reduces Abeta levels or Abeta fibrillogenesis should lower the risk for or prevent AD. PMID- 28003274 TI - Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. AB - The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 * 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen. PMID- 28003278 TI - Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS). AB - Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology. Because the same phenotypes can have multiple causes, including different gene mutations, there may be multiple molecular mechanisms causing ALS, implying that the disease is a syndrome. Conversely, multiple phenotypes can be caused by a single gene mutation; thus, a single molecular mechanism could be compatible with clinical heterogeneity. The pathogenic mechanism(s) in ALS remain unknown, but active propagation of the pathology neuroanatomically is likely a primary component. PMID- 28003279 TI - Structural Biology of PrP Prions. AB - Prion diseases are characterized by the deposition of amyloids, misfolded conformers of the prion protein. The misfolded conformation is self-replicating, by a mechanism solely enciphered in the conformation of the protein. Because of low solubility and heterogeneous aggregate sizes, the detailed atomic structure of the infectious isoform is still unknown. Progress has, however, been made, and has allowed insights into the structural and disease-related mechanisms of prions. Many structural models have been proposed, and a number of them support a consensus trimeric beta-helical model, significantly more complex than simple amyloid models. There is evidence that such complexity may be a necessary property of prion structure. Knowledge of the structure of prions will provide a greater understanding of the protein isoform conversion mechanism, and could eventually lead to rationally designed intervention strategies. PMID- 28003280 TI - Malaria Modeling in the Era of Eradication. AB - Mathematical models provide the essential basis of rational research and development strategies in malaria, informing the choice of which technologies to target, which deployment strategies to consider, and which populations to focus on. The Internet and remote sensing technologies also enable assembly of ever more relevant field data. Together with supercomputing technology, this has made available timely descriptions of the geography of malaria transmission and disease across the world and made it possible for policy and planning to be informed by detailed simulations of the potential impact of intervention programs. These information technology advances do not replace the basic understanding of the dynamics of malaria transmission that should be embedded in the thinking of anyone planning malaria interventions. The appropriate use of modeling may determine whether we are living in an era of hubris or indeed in an age of eradication. PMID- 28003281 TI - DNMT3A in Leukemia. AB - DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) patients making this gene an attractive target for new therapies. Here, we discuss the biology of DNMT3A and its role in controlling hematopoietic stem cell fate decisions. In addition, we review how mutant DNMT3A may contribute to leukemogenesis and the clinical relevance of DNMT3A mutations in hematologic cancers. PMID- 28003282 TI - A systematic review on the effect of the organisation of hospital discharge on patient health outcomes. AB - OBJECTIVE: The transition from hospital to home represents a key step in the management of patients and several problems related to this transition may arise, with potential adverse effects on patient health after discharge. The purpose of our study was to explore the association between components of the hospital discharge process including subsequent continuity of care and patient outcomes in the post-discharge period. DESIGN: Systematic review of observational and interventional studies. SETTING: We conducted a combined search in the Medline and Web of Science databases. Additional studies were identified by screening the bibliographies of the included studies. The data collection process was conducted using a standardised predefined grid that included quality criteria. PARTICIPANTS: A standard patient population returning home after hospitalisation. PRIMARY AND SECONDARY OUTCOMES: Adverse health outcomes occurring after hospital discharge. RESULTS: In the 20 studies fulfilling our eligibility criteria, the main discharge-process components explored were: discharge summary (n=2), discharge instructions (n=2), drug-related problems at discharge (n=4), transition from hospital to home (n=5) and continuity of care after hospital discharge (n=7). The major subsequent patient health outcomes measured were: rehospitalisations (n=18), emergency department visits (n=8) and mortality (n=5). Eight of the 18 studies exploring rehospitalisations and two of the eight studies examining emergency department visits reported at least one significant association between the discharge process and these outcomes. None of the studies investigating patient mortality reported any significant such associations between the discharge process and these outcomes. CONCLUSIONS: Irrespective of the component of the discharge process explored, the outcome considered (composite or not), the sample size and the study design, no consistent statistical association between hospital discharge and patient health outcome was identified. This systematic review highlights a wide heterogeneity between studies, especially in terms of the component(s) of the hospital discharge process investigated, study designs, outcomes and follow-up durations. PMID- 28003283 TI - Clinical practitioners' views on the management of patients with medically unexplained physical symptoms (MUPS): a qualitative study. AB - OBJECTIVES: By identifying strategies that practicing physicians use in managing patients with medically unexplained physical symptoms (MUPS), we present an interim practical management guide (IPMG) that clinical practitioners may find useful in their clinical practices and that may help guide future research. DESIGN: A qualitative research study based on interview data from practicing physicians with experience in dealing with MUPS and known to the physician members of the research team. A parallel exploration of patient experiences was carried out simultaneously and is reported elsewhere. SETTING: 2 urban centres in 2 different Canadian provinces in a healthcare system where family physicians provide the majority of primary care and self-referral to specialists rarely occurs. PARTICIPANTS: The physician members of the research team invited practicing family and specialty physicians to participate in the study. RESULTS: We characterise the care of patients with MUPS in terms of a 4-part framework: (1) the challenge of diagnosis; (2) the challenge of management/treatment; (3) the importance of communication and (4) the importance of the therapeutic relationship. CONCLUSIONS: On the basis of the details in the different parts of the framework, we propose an IPMG that practitioners may find useful to facilitate the clinical care of patients with MUPS. The guide can be readily implemented into the practice of any physician who cares for patients with MUPS. PMID- 28003284 TI - Association between reported sleep need and sleepiness at the wheel: comparative study on French highways between 1996 and 2011. AB - OBJECTIVE: To investigate the evolution over 15 years of sleep schedules, sleepiness at the wheel and driving risk among highway drivers. METHODS: Comparative survey including questions on usual sleep schedules and before the trip, sleepiness at the wheel, the Epworth sleepiness scale, Basic Nordic Sleep Questionnaire (BNSQ) and a travel questionnaire. RESULTS: 80% of drivers stopped by the highway patrol agreed to participate in both studies with a total of 3545 drivers in 2011 and 2196 drivers in 1996 interviewed. After standardisation based on sex, age and mean annual driving distance, drivers in 2011 reported shorter sleep time on week days (p<0.0001), and week-ends (p<0.0001) and shorter optimal sleep time (p<0.0001) compared to 1996 drivers. There were more drivers sleepy at the wheel in 2011 than in 1996 (p<0.0001) and 2.5 times more drivers in 2011 than in 1996 had an Epworth sleepiness score >15 indicating severe sleepiness. CONCLUSIONS: Even if drivers in 2011 reported good sleep hygiene prior to a highway journey, drivers have reduced their mean weekly sleep duration over 15 years and have a higher risk of sleepiness at the wheel. Sleep hygiene for automobile drivers remains an important concept to address. PMID- 28003285 TI - Nairobi Newborn Study: a protocol for an observational study to estimate the gaps in provision and quality of inpatient newborn care in Nairobi City County, Kenya. AB - INTRODUCTION: Progress has been made in Kenya towards reducing child mortality as part of efforts aligned with the fourth Millennium Development Goal. However, little advancement has been made in reducing mortality among newborns, which now accounts for 45% of all child deaths. The frequently unanticipated nature of neonatal illness, its severity and the high dependency of sick newborns on skilled care make the provision of inpatient hospital services one key component of strategies to improve newborn survival. METHODS AND ANALYSES: This project aims to assess the availability and quality of inpatient newborn care in hospitals in Nairobi City County across the public, private and not-for-profit sectors and align this to the estimated need for such services, providing a description of the quantity and quality gaps between capacity and demand. The population level burden of disease will be estimated using morbidity incidence estimates from a literature review applied to subcounty estimates of population adjusted births, providing a spatially disaggregated estimate of need within the county. This will be followed by a survey of neonatal services across all health facilities providing 24/7 inpatient newborn care in the county. The survey will include: a retrospective audit of admission registers to estimate the usage of facilities and case-mix of patients; a structural assessment of facilities to gain insight into capacity; a questionnaire to nursing staff focusing on the process of delivering key obstetric and neonatal interventions; and a retrospective case audit to assess adherence to guidelines by clinicians. ETHICS AND DISSEMINATION: This study has been approved by the Kenya Medical Research Institute Scientific and Ethics Review Unit (SSC protocol No.2999). Results will be disseminated: to participating facilities through individualised reports and a joint workshop; to local and national stakeholders through meetings and a summary report; and to the international community through peer-review publication and international meetings. PMID- 28003286 TI - Prescription of renin-angiotensin system blockers and risk of acute kidney injury: a population-based cohort study. AB - OBJECTIVE: To investigate whether there is an association between use of ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) and risk of acute kidney injury (AKI). STUDY DESIGN: We conducted a new-user cohort study of the rate of AKI among users of common antihypertensives. SETTING: UK primary care practices contributing to the Clinical Practice Research Datalink (CPRD) eligible for linkage to hospital records data from the Hospital Episode Statistics (HES) database between April 1997 and March 2014. PARTICIPANTS: New users of antihypertensives: ACEI/ARB, beta-blockers, calcium channel blockers and thiazide diuretics. OUTCOMES: The outcome was first episode of AKI. We estimated incidence rate ratio (RR) for AKI during time exposed to ACEI/ARB compared to time unexposed, adjusting for age, sex, comorbidities, use of other antihypertensive drugs and calendar period using Poisson regression. Covariates were time updated. RESULTS: Among 570 445 participants, 303 761 were prescribed ACEI/ARB with a mean follow-up of 4.1 years. The adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 1.12 (95% CI 1.07 to 1.17). This relative risk varied depending on absolute risk of AKI, with lower or no increased relative risk from the drugs among those at greatest absolute risk. For example, among people with stage 4 chronic kidney disease (who had 6.69 (95% CI 5.57 to 8.03) times higher rate of AKI compared to those without chronic kidney disease), the adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 0.66 (95% CI 0.44 to 0.97) in contrast to 1.17 (95% CI 1.09 to 1.25) among people without chronic kidney disease. CONCLUSIONS: Treatment with ACEI/ARB is associated with only a small increase in AKI risk while individual patient characteristics are much more strongly associated with the rate of AKI. The degree of increased risk varies between patient groups. PMID- 28003288 TI - Protocol for a multicentre study to assess feasibility, acceptability, effectiveness and direct costs of TRIumPH (Treatment and Recovery In PsycHosis): integrated care pathway for psychosis. AB - INTRODUCTION: Duration of untreated psychosis (time between the onset of symptoms and start of treatment) is considered the strongest predictor of symptom severity and outcome. Integrated care pathways that prescribe timeframes around access and interventions can potentially improve quality of care. METHODS AND ANALYSIS: A multicentre mixed methods study to assess feasibility, acceptability, effectiveness and analysis of direct costs of an integrated care pathway for psychosis. A pragmatic, non-randomised, controlled trial design is used to compare the impact of Treatment and Recovery In PsycHosis (TRIumPH; Intervention) by comparison between NHS organisations that adopt TRIumPH and those that continue with care as usual (Control). Quantitative and qualitative methods will be used. We will use routinely collected quantitative data and study-specific questionnaires and focus groups to compare service user outcomes, satisfaction and adherence to intervention between sites that adopt TRIumPH versus sites that continue with usual care pathways. SETTING: 4 UK Mental health organisations. Two will implement TRIumPH whereas two will continue care as usual. PARTICIPANTS: Staff, carers, individuals accepted to early intervention in psychosis teams in participating organisations for the study period. INTERVENTION: TRIumPH Integrated Care Pathway for psychosis that has a holistic approach and prescribes time frames against interventions; developed using intelligence from data; co produced with patients, carers, clinicians and other stakeholders. OUTCOMES: Feasibility will be assessed through adherence to the process measures. Satisfaction and acceptability will be assessed using questionnaires and focus groups. Effectiveness will be assessed through data collection and evaluation of patient outcomes, including clinical, functional and recovery outcomes, physical health, acute care use. Outcome measures will be assessed at baseline, 12 and 24 months to measure whether there is an effect and if so, whether this is sustained over time. Outcomes measures at the adopter sites will be compared to their own baseline and against comparator sites. ETHICS AND DISSEMINATION: Ethics approval was obtained from East of Scotland Research Ethics Service (REC Ref no: LR/15/ES/0091). The results will be disseminated through publications, conference presentations, reports to the organisation. STUDY REGISTRATION: UK Clinical Research Network Portfolio: 19187. PMID- 28003287 TI - Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific. AB - PURPOSE: The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria-nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists. PARTICIPANTS: Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015. FINDINGS TO DATE: Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort. FUTURE PLANS: This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria-nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective. PMID- 28003289 TI - Burden of multimorbidity in relation to age, gender and immigrant status: a cross sectional study based on administrative data. AB - OBJECTIVES: Many studies have investigated multimorbidity, whose prevalence varies according to settings and data sources. However, few studies on this topic have been conducted in Italy, a country with universal healthcare and one of the most aged populations in the world. The aim of this study was to estimate the prevalence of multimorbidity in a Northern Italian region, to investigate its distribution by age, gender and citizenship and to analyse the correlations of diseases. DESIGN: Cross-sectional study based on administrative data. SETTING: Emilia-Romagna, an Italian region with ~4.4 million inhabitants, of which almost one-fourth are aged >=65 years. PARTICIPANTS: All adults residing in Emilia Romagna on 31 December 2012. Hospitalisations, drug prescriptions and contacts with community mental health services from 2003 to 2012 were traced to identify the presence of 17 physical and 9 mental health disorders. PRIMARY AND SECONDARY OUTCOME MEASURES: Descriptive analysis of differences in the prevalence of multimorbidity in relation to age, gender and citizenship. The correlations of diseases were analysed using exploratory factor analysis. RESULTS: The study population included 622 026 men and 751 011women, with a mean age of 66.4 years. Patients with multimorbidity were 33.5% in 75 years and >60% among patients aged >=90 years; among patients aged >=65 years, the proportion of multimorbidity was 39.9%. After standardisation by age and gender, multimorbidity was significantly more frequent among Italian citizens than among immigrants. Factor analysis identified 5 multimorbidity patterns: (1) psychiatric disorders, (2) cardiovascular, renal, pulmonary and cerebrovascular diseases, (3) neurological diseases, (4) liver diseases, AIDS/HIV and substance abuse and (5) tumours. CONCLUSIONS: Multimorbidity was highly prevalent in Emilia-Romagna and strongly associated with age. This finding highlights the need for healthcare providers to adopt individualised care plans and ensure continuity of care. PMID- 28003291 TI - PubMed search filters for the study of putative outdoor air pollution determinants of disease. AB - OBJECTIVES: Several PubMed search filters have been developed in contexts other than environmental. We aimed at identifying efficient PubMed search filters for the study of environmental determinants of diseases related to outdoor air pollution. METHODS: We compiled a list of Medical Subject Headings (MeSH) and non MeSH terms seeming pertinent to outdoor air pollutants exposure as determinants of diseases in the general population. We estimated proportions of potentially pertinent articles to formulate two filters (one 'more specific', one 'more sensitive'). Their overall performance was evaluated as compared with our gold standard derived from systematic reviews on diseases potentially related to outdoor air pollution. We tested these filters in the study of three diseases potentially associated with outdoor air pollution and calculated the number of needed to read (NNR) abstracts to identify one potentially pertinent article in the context of these diseases. Last searches were run in January 2016. RESULTS: The 'more specific' filter was based on the combination of terms that yielded a threshold of potentially pertinent articles >=40%. The 'more sensitive' filter was based on the combination of all search terms under study. When compared with the gold standard, the 'more specific' filter reported the highest specificity (67.4%; with a sensitivity of 82.5%), while the 'more sensitive' one reported the highest sensitivity (98.5%; with a specificity of 47.9%). The NNR to find one potentially pertinent article was 1.9 for the 'more specific' filter and 3.3 for the 'more sensitive' one. CONCLUSIONS: The proposed search filters could help healthcare professionals investigate environmental determinants of medical conditions that could be potentially related to outdoor air pollution. PMID- 28003290 TI - Surgical versus conservative treatment for lumbar disc herniation: a prospective cohort study. AB - OBJECTIVES: Evidence comparing the effectiveness of surgical and conservative treatment of symptomatic lumbar disc herniation is controversial. We sought to compare short-term and long-term effectiveness of surgical and conservative treatment in sciatica symptom severity and quality of life in patients with lumbar disc herniation in a routine clinical setting. METHODS: A prospective cohort study of a routine clinical practice registry consisting of 370 patients. Outcome measures were the North American Spine Society questionnaire and the 36 Item Short-Form Health Survey to assess patient-reported back pain, physical function, neurogenic symptoms and quality of life. Primary outcomes were back pain at 6 and 12 weeks. Standard open discectomy was assessed versus conservative interventions at 6, 12, 52 and 104 weeks. We filled in missing outcome variable values with multiple imputation, accounted for repeated measures within patients with mixed-effects models and adjusted baseline group differences in relevant prognostic indicators by inverse probability of treatment weighting. RESULTS: Surgical treatment patients reported less back pain at 6 weeks than those receiving conservative therapy (-0.97; 95% CI -1.89 to -0.09), were more likely to report >=50% decrease in back pain symptoms from baseline to 6 weeks (48% vs 17%, risk difference: 0.34; 95% CI 0.16 to 0.47) and reported less physical function disability at 52 weeks (-3.7; 95% CI -7.4 to -0.1). The other assessments showed minimal between-group differences with CIs, including the null effect. CONCLUSIONS: Compared with conservative therapy, surgical treatment provided faster relief from back pain symptoms in patients with lumbar disc herniation, but did not show a benefit over conservative treatment in midterm and long-term follow-up. PMID- 28003292 TI - Eatwell Guide: modelling the dietary and cost implications of incorporating new sugar and fibre guidelines. AB - OBJECTIVES: To model food group consumption and price of diet associated with achieving UK dietary recommendations while deviating as little as possible from the current UK diet, in order to support the redevelopment of the UK food-based dietary guidelines (now called the Eatwell Guide). DESIGN: Optimisation modelling, minimising an objective function of the difference between population mean modelled and current consumption of 125 food groups, and constraints of nutrient and food-based recommendations. SETTING: The UK. POPULATION: Adults aged 19 years and above from the National Diet and Nutrition Survey 2008-2011. MAIN OUTCOME MEASURES: Proportion of diet consisting of major foods groups and price of the optimised diet. RESULTS: The optimised diet has an increase in consumption of 'potatoes, bread, rice, pasta and other starchy carbohydrates' (+69%) and 'fruit and vegetables' (+54%) and reductions in consumption of 'beans, pulses, fish, eggs, meat and other proteins' (-24%), 'dairy and alternatives' (-21%) and 'foods high in fat and sugar' (-53%). Results within food groups show considerable variety (eg, +90% for beans and pulses, -78% for red meat). The modelled diet would cost L5.99 (L5.93 to L6.05) per adult per day, very similar to the cost of the current diet: L6.02 (L5.96 to L6.08). The optimised diet would result in increased consumption of n-3 fatty acids and most micronutrients (including iron and folate), but decreased consumption of zinc and small decreases in consumption of calcium and riboflavin. CONCLUSIONS: To achieve the UK dietary recommendations would require large changes in the average diet of UK adults, including in food groups where current average consumption is well within the recommended range (eg, processed meat) or where there are no current recommendations (eg, dairy). These large changes in the diet will not lead to significant changes in the price of the diet. PMID- 28003293 TI - Estimating change in cardiovascular disease and diabetes burdens due to dietary and metabolic factors in Korea 1998-2011: a comparative risk assessment analysis. AB - OBJECTIVES: Over the past 10 years, the burden of chronic diseases in Korea has increased. However, there are currently no quantitative estimates of how changes in diet and metabolic factors have contributed to these shifting burdens. This study aims to evaluate the contributions of dietary and metabolic risk factors to death from cardiometabolic diseases (CMDs) such as cardiovascular conditions, strokes and diabetes in Korea, and to estimate how these contributions have changed over the past 10 years (1998-2011). DESIGN AND METHODS: We used data on 6 dietary and 4 metabolic risk factors by sex, age and year from the Korea National Health and Nutrition Examination Survey. The relative risks for the effects of the risk factors on CMD mortality were obtained from meta-analyses. The population-attributable fraction attributable to the risk factors was calculated by using a comparative risk assessment approach across sex and age strata (males and females, age groups 25-34, 35-44, 45-54, 55-64, 65-74 and 75+ years) from 1998 to 2011. RESULTS: The results showed that a suboptimal diet and high blood pressure were the main risk factors for CMD mortality in Korea. High blood pressure accounted for 127 096 (95% uncertainty interval (UI): 121 907 to 132 218) deaths from CMD. Among the individual dietary risk factors, a high intake of sodium (42 387 deaths; 95% UI: 42 387 to 65 094) and a low intake of fruit (50 244 deaths; 95% UI: 40 981 to 59 178) and whole grains (54 248 deaths; 95% UI: 47 020 to 61 343) were responsible for the highest number of CMD deaths in Korea. CONCLUSIONS: Indicating the relative importance of risk factors in Korea, the results suggest that metabolic and dietary risk factors were major contributors to CMD mortality. PMID- 28003294 TI - Acute uncomplicated appendicitis study: rationale and protocol for a multicentre, prospective randomised controlled non-inferiority study to evaluate the safety and effectiveness of non-operative management in children with acute uncomplicated appendicitis. AB - INTRODUCTION: This article presents an overview of a prospective randomised controlled non-inferiority study designed to evaluate the safety and effectiveness of non-operative management (NOM) with operative management in children with acute uncomplicated appendicitis (AUA). Here, we present the study protocol for this APRES study, a multicentre Australian study. The rationale and details of future analysis, in particular, non-inferiority calculations, cost effectiveness, feasibility and acceptability of each intervention. DESIGN: A multicentre, prospective randomised controlled clinical trial, conducted in 2 Australian tertiary paediatric hospitals. PARTICIPANTS: Children who meet the inclusion criteria of an age between 5 and 15 years and a clinical diagnosis of AUA will be invited to participate, and after consent will be randomised via a computer-based program into treatment groups. The study started in June 2016, and the target recruitment is 220 patients. INTERVENTIONS: Children in the control group will be treated with prophylactic antibiotics and appendicectomy, and those in the intervention group will be treated with antibiotic therapy alone. Primary outcome measures include unplanned or unnecessary operation and complications at 30 days. Secondary outcomes include longer term complications within 1 year, length of stay, time off work and school analgesic requirements and cost. ANALYSIS: Data analyses will be on the intention-to-treat principle using non inferiority analysis. Analysis will include the Pearson chi2 test for categorical variables and independent sample t-test or Mann-Whitney test for continuous variables. Non-inferiority for NOM will be tested using 1-sided Wald tests with an alpha level of 0.05. ETHICS AND DISSEMINATION: The research has been approved by the Human Research Ethics Committee of the Sydney Children's Hospital Network. In addition, results will be reported through academic journals, seminars and conference presentations. TRIAL REGISTRATION NUMBERS: NCT02795793; ACTRN12616000788471. PMID- 28003295 TI - 'It promoted a positive culture around falls prevention': staff response to a patient education programme-a qualitative evaluation. AB - OBJECTIVES: The purpose of this study was to understand how staff responded to individualised patient falls prevention education delivered as part of a cluster randomised trial, including how they perceived the education contributed to falls prevention on their wards. DESIGN: A qualitative explanatory study. METHODS: 5 focus groups were conducted at participatory hospital sites. The purposive sample of clinical staff (including nurses, physiotherapists and quality improvement staff) worked on aged care rehabilitation wards when a cluster randomised trial evaluating a patient education programme was conducted. During the intervention period, an educator, who was a trained health professional and not a member of staff, provided individualised falls prevention education to patients with good levels of cognition (Mini-Mental State Examination >23/30). Clinical staff were provided with training to support the programme and their feedback was sought after the trial concluded, to understand how they perceived the programme impacted on falls prevention. Data were thematically analysed using NVivo qualitative data analysis software. RESULTS: 5 focus groups were conducted at different hospitals (n=30 participants). Staff perceived that the education created a positive culture around falls prevention and further, facilitated teamwork, whereby patients and staff worked together to address falls prevention. The educator was perceived to be a valuable member of the team. Staff reported that they developed increased knowledge and awareness about creating a safe ward environment. Patients being proactive and empowered to engage in falls prevention strategies, such as ringing the bell for assistance, was viewed as supporting staff falls prevention efforts and motivating staff to change practice. CONCLUSIONS: Staff responded positively to patient falls prevention education being delivered on their wards. Providing individualised patient education to older patients with good levels of cognition can empower staff and patients to work as a team to address falls prevention on hospital rehabilitation wards. PMID- 28003296 TI - Feasibility of a web-based suicide awareness programme for Asian American college students. AB - OBJECTIVE: The Truth about Suicide video has been widely used but has never been empirically tested regarding its cultural appropriateness for Asian Americans. The purpose of the study was to determine the feasibility of using the video in a web-based suicide awareness programme for Asian American and non-Hispanic white college students. METHODS: A cross-sectional, comparative, web-based study was conducted with 227 Asian Americans and 204 non-Hispanic whites at a university in the Midwest region of the USA. Study participants completed a questionnaire measuring their cultural orientation and attitudes towards suicide, watched the 27 min video, completed a debriefing session and evaluated the video's overall suitability. RESULTS: Asian Americans rated the suicide awareness video significantly lower for cultural relevance than did non-Hispanic whites (F=5.479, p=0.02). Collectivist cultural orientation was a significant predictor for cultural relevance, credibility and appeal; however, evaluation of the video's cultural relevance was negatively affected by Asian ethnicity. CONCLUSIONS: Cultural orientation and race/ethnicity should be strongly considered when web based suicide awareness programmes are developed for college students. PMID- 28003297 TI - Commissioning care for people with dementia at the end of life: a mixed-methods study. AB - OBJECTIVES: To understand how end-of-life (EoL) care for people with dementia is currently commissioned (ie, contracted) and organised, with a view to informing the development of commissioning guidance for good-quality community-based EoL care in dementia. DESIGN: Mixed-methods study; narrative review and qualitative interviews. SETTING: 8 National Health Service (NHS) clinical commissioning groups (CCGs) and five adult services across England. METHODS: Narrative review of evidence; 20 semistructured interviews (telephone and face-to-face) with professionals involved in commissioning EoL care for people with dementia. MAIN OUTCOME MEASURES: Summary of the existing evidence base for commissioning, commissioners' approaches to the commissioning process for EoL care for people with dementia in England. RESULTS: In the context of commissioning EoL for people with dementia, the literature review generated three key themes: (1) importance of joint commissioning; (2) lack of clarity for the process and (3) factors influencing commissioning. In exploring health professionals' perceptions of the commissioning process, 'uncertainty' was elicited as an overarching theme across the CCGs interviewed. Organisation of the process, lack of expertise, issues surrounding integration and the art of specification were considered important factors that contribute to the uncertainty surrounding the commissioning process. CONCLUSIONS: The current evidence base for commissioning EoL care is limited with considerable uncertainty as how clinical commissioners in England undertake the process to ensure future services are evidence-based. PMID- 28003298 TI - Interventions for the prevention of cardiovascular diseases: a protocol for a systematic review of economic evaluations in low-income and middle-income countries. AB - INTRODUCTION: Low-income and middle-income countries (LMICs) are experiencing a growing disease burden due to cardiovascular and other chronic non-communicable diseases. Interventions for the control of these diseases are paramount; however, these countries are faced with competing health and financial needs. There is an urgent need for quality evidence on cost-effective strategies to address these chronic diseases. We aim to synthesise the current literature on economic evaluations of interventions for primary and secondary cardiovascular disease prevention in LMICs. METHODS AND ANALYSIS: A systematic review of studies (published and unpublished) in LMICs up to 30 October 2016 will be conducted. The following databases will be searched: PubMed/MEDLINE, EMBASE, SCOPUS, CINAHL, Web of Science, EconLit, NHS Economic Evaluations Database (NHS EED). Data sources specific to African literature, such as the WHO AFROLIB, Africa Index Medicus and African Journals online (AJOL) as well as grey literature, will also be searched. 2 reviewers shall independently screen potential articles for inclusion and disagreements shall be resolved by consensus. Quality appraisal of studies shall be done using Drummond's checklist for economic evaluation of studies. A descriptive synthesis of the evidence obtained is planned. The primary outcomes will be costs per life years gained or unit of clinical outcome, cost per quality adjusted life years or disability-adjusted life years. This systematic review protocol has been prepared according to the Preferred Reporting Items for Systematic reviews and Meta-analyses for Protocols (PRISMA-P) 2015 statement. ETHICS AND DISSEMINATION: Ethics approval is not required considering that this is a protocol for a systematic review of published studies. Results from this review will be disseminated via conference presentations and peer-reviewed journal publications. TRIAL REGISTRATION NUMBER: CRD42016043510. PMID- 28003299 TI - Clinical impact of lifestyle interventions for the prevention of diabetes: an overview of systematic reviews. AB - OBJECTIVES: To review the clinical outcomes of combined diet and physical activity interventions for populations at high risk of type 2 diabetes. DESIGN: Overview of systematic reviews (search dates April-December 2015). SETTING: Any level of care; no geographical restriction. PARTICIPANTS: Adults at high risk of diabetes (as per measures of glycaemia, risk assessment or presence of risk factors). INTERVENTIONS: Combined diet and physical activity interventions including >=2 interactions with a healthcare professional, and >=12 months follow up. OUTCOME MEASURES: Primary: glycaemia, diabetes incidence. Secondary: behaviour change, measures of adiposity, vascular disease and mortality. RESULTS: 19 recent reviews were identified for inclusion; 5 with AMSTAR scores <8. Most considered only randomised controlled trials (RCTs), and RCTs were the major data source in the remainder. Five trials were included in most reviews. Almost all analyses reported that interventions were associated with net reductions in diabetes incidence, measures of glycaemia and adiposity, at follow-up durations of up to 23 years (typically <6). Small effect sizes and potentially transient effect were reported in some studies, and some reviewers noted that durability of intervention impact was potentially sensitive to duration of intervention and adherence to behaviour change. Behaviour change, vascular disease and mortality outcome data were infrequently reported, and evidence of the impact of intervention on these outcomes was minimal. Evidence for age effect was mixed, and sex and ethnicity effect were little considered. CONCLUSIONS: Relatively long duration lifestyle interventions can limit or delay progression to diabetes under trial conditions. However, outcomes from more time-limited interventions, and those applied in routine clinical settings, appear more variable, in keeping with the findings of recent pragmatic trials. There is little evidence of intervention impact on vascular outcomes or mortality end points in any context. 'Real-world' implementation of lifestyle interventions for diabetes prevention may be expected to lead to modest outcomes. PMID- 28003300 TI - Protocol for developing, disseminating and implementing a core outcome set for endometriosis. AB - INTRODUCTION: Endometriosis is a common gynaecological disease characterised by pain and subfertility. Randomised controlled trials evaluating treatments for endometriosis have reported many different outcomes and outcome measures. This variation restricts effective data synthesis limiting the usefulness of research to inform clinical practice. To address these methodological concerns, we aim to develop, disseminate and implement a core outcome set for endometriosis engaging with key stakeholders, including healthcare professionals, researchers and women with endometriosis. METHODS AND ANALYSIS: An international steering group has been established, including healthcare professionals, researchers and patient representatives. Potential outcomes identified from a systematic review of the literature will be entered into a modified Delphi method. Key stakeholders will be invited to participate including healthcare professionals, researchers and women with endometriosis. Participants will be invited to score individual outcomes on a nine-point Likert scale anchored between 1 (not important) and 9 (critical). Repeated reflection and rescoring should promote whole and individual stakeholder group converge towards consensus, 'core', outcomes. High-quality outcome measures will be associated with core outcomes. ETHICS AND DISSEMINATION: The implementation of a core outcome set for endometriosis within future clinical trials, systematic reviews and clinical guidelines will enhance the availability of comparable data to facilitate evidence-based patient care. This study was prospectively registered with Core Outcome Measures in Effectiveness Trials Initiative; number: 691. PMID- 28003301 TI - Safety and feasibility of sublingual microcirculation assessment in the emergency department for civilian and military patients with traumatic haemorrhagic shock: a prospective cohort study. AB - OBJECTIVES: Sublingual microcirculatory monitoring for traumatic haemorrhagic shock (THS) may predict clinical outcomes better than traditional blood pressure and cardiac output, but is not usually performed until the patient reaches the intensive care unit (ICU), missing earlier data of potential importance. This pilot study assessed for the first time the feasibility and safety of sublingual video-microscopy for THS in the emergency department (ED), and whether it yields useable data for analysis. SETTING: A safety and feasibility assessment was undertaken as part of the prospective observational MICROSHOCK study; sublingual video-microscopy was performed at the UK-led Role 3 medical facility at Camp Bastion, Afghanistan, and in the ED in 3 UK Major Trauma Centres. PARTICIPANTS: There were 15 casualties (2 military, 13 civilian) who presented with traumatic haemorrhagic shock with a median injury severity score of 26. The median age was 41; the majority (n=12) were male. The most common injury mechanism was road traffic accident. PRIMARY AND SECONDARY OUTCOME MEASURES: Safety and feasibility were the primary outcomes, as measured by lack of adverse events or clinical interruptions, and successful acquisition and storage of data. The secondary outcome was the quality of acquired video clips according to validated criteria, in order to determine whether useful data could be obtained in this emergency context. RESULTS: Video-microscopy was successfully performed and stored for analysis for all patients, yielding 161 video clips. There were no adverse events or episodes where clinical management was affected or interrupted. There were 104 (64.6%) video clips from 14 patients of sufficient quality for analysis. CONCLUSIONS: Early sublingual microcirculatory monitoring in the ED for patients with THS is safe and feasible, even in a deployed military setting, and yields videos of satisfactory quality in a high proportion of cases. Further investigations of early microcirculatory behaviour in this context are warranted. TRIAL REGISTRATION NUMBER: NCT02111109. PMID- 28003303 TI - Correction. PMID- 28003302 TI - Cost-effectiveness of Early Surgery versus Conservative Treatment with Optional Delayed Meniscectomy for Patients over 45 years with non-obstructive meniscal tears (ESCAPE study): protocol of a randomised controlled trial. AB - INTRODUCTION: Recent studies show similar outcome between surgery and conservative treatment in patients with non-obstructive meniscal tears. However, surgery is still often preferred over conservative treatment. When conservative treatment is non-inferior to surgery, shifting the current standard treatment choice to conservative treatment alone could save over ?30 millions of direct medical costs on an annual basis. Economic evaluation studies comparing surgery to conservative treatment are lacking. METHODS AND ANALYSIS: A multicentre randomised controlled trial (RCT) with an economic evaluation alongside was performed to assess the (cost)-effectiveness of surgery and conservative treatment for meniscal tears. We will include 402 participants between 45 and 70 years with an MRI-confirmed symptomatic, non-obstructive meniscal tears to prove non-inferiority of conservative treatment. Block randomisation will be web-based. The primary outcome measure is a physical function, measured by the International Knee Documentation Committee 'Subjective Knee Form'. Furthermore, we will perform a cost-effectiveness and cost-utility analysis from societal perspective and a budget impact analysis from a societal, government and insurer perspective. Secondary outcomes include general health, quality of life, activity level, knee pain, physical examination, progression of osteoarthritis and the occurrence of adverse events. ETHICS AND DISSEMINATION: This RCT will be performed in accordance with the Declaration of Helsinki and has been approved by the Ethics Committee (number NL44188.100.13). The results of this study will be reported in peer-reviewed journals and at international conferences. We further aim to disseminate our results to guideline committees. TRIAL REGISTRATION NUMBER: NCT01850719. PMID- 28003305 TI - Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2, in Malignant Pleural Mesothelioma. AB - Purpose: To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene LATS2, a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis.Experimental Design: Sixty-one MPM primary cultures established in our laboratory were screened for mutations in LATS2 Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, Western blot analysis, and reverse phase protein array. Cell proliferation, viability, apoptosis, mobility, and invasion were determined after siRNA knockdown or YAP (verteporfin), mTOR (rapamycin), and mTOR/PI3K/AKT (PF-04691502) inhibitor treatment.Results: The LATS2 gene was altered in 11% of MPM by point mutations and large exon deletions. Genetic data coupled with transcriptomic data allowed the identification of a new MPM molecular subgroup, C2LN, characterized by a co-occurring mutation in the LATS2 and NF2 genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of LATS2 and NF2 leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2LN MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The MOK gene was identified as a potential biomarker of the C2LN MPM subgroup and PF-04691502 sensitivity.Conclusions: We identified a new MPM molecular subgroup that shares common genetic and transcriptomic characteristics. Our results made it possible to highlight a greater sensitivity to an anticancer compound for this MPM subgroup and to identify a specific potential biomarker. Clin Cancer Res; 23(12); 3191-202. (c)2016 AACR. PMID- 28003306 TI - microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma. AB - Purpose:MYCN is one of the most well-characterized genetic markers of neuroblastoma. However, the mechanisms as to how MYCN mediate neuroblastoma tumorigenesis are not fully clear. Increasing evidence has confirmed that the dysregulation of miRNAs is involved in MYCN-mediated neuroblastoma tumorigenesis, supporting their potential as therapeutic targets for neuroblastoma. Although miR 221 has been reported as one of the upregulated miRNAs, the interplay between miR 221 and MYCN-mediated neuroblastoma progression remains largely elusive.Experimental Design: The expression of miR-221 in the formalin-fixed, paraffin-embedded tissues from 31 confirmed patients with neuroblastoma was detected by locked nucleic acid-in situ hybridization and qRT-PCR. The correlation between miR-221 expression and clinical features in patients with neuroblastoma was assessed. The mechanisms as to how miR-221 regulate MYCN in neuroblastoma were addressed. The effect of miR-221 on cellular proliferation in neuroblastoma was determined both in vitro and in vivoResults: miR-221 was significantly upregulated in neuroblastoma tumor cells and tissues that overexpress MYCN, and high expression of miR-221 was positively associated with poor survival in patients with neuroblastoma. Nemo-like kinase (NLK) as a direct target of miR-221 in neuroblastoma was verified. In addition, overexpression of miR-221 decreased LEF1 phosphorylation but increased the expression of MYCN via targeting of NLK and further regulated cell cycle, particularly in S-phase, promoting the growth of neuroblastoma cells.Conclusions: This study provides a novel insight for miR-221 in the control of neuroblastoma cell proliferation and tumorigenesis, suggesting potentials of miR-221 as a prognosis marker and therapeutic target for patients with MYCN overexpressing neuroblastoma. Clin Cancer Res; 23(11); 2905-18. (c)2016 AACR. PMID- 28003308 TI - Corrigendum. PMID- 28003307 TI - PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses. AB - Purpose: Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kalpha,beta in tumor growth and PI3Kgamma,delta in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity.Experimental Design: The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kgamma-null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice and PI3Kgammanull versus PI3KgammaWT mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 MUg, twice weekly) was evaluated in PyMT tumor-bearing mice.Results: Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of PI3Kgamma in the host. The antitumor effect of PI3Kgamma loss in host, but not tumor, was partially reversed by CD8+ T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone.Conclusions: PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer. Clin Cancer Res; 23(13); 3371-84. (c)2016 AACR. PMID- 28003311 TI - Unlocking the potential of orphan legumes. AB - Orphan, or underutilized, legumes are domesticated legumes with useful properties, but with less importance than major world crops due to use and supply constraints. However, they play a significant role in many developing countries, providing food security and nutrition to consumers, as well as income to resource poor farmers. They have been largely neglected by both researchers and industry due to their limited economic importance in the global market. Orphan legumes are better adapted than the major legume crops to extreme soil and climatic conditions, with high tolerance to abiotic environmental stresses such as drought. As a stress response they can also produce compounds with pharmaceutical value. Orphan legumes are therefore a likely source of important traits for introduction into major crops to aid in combating the stresses associated with global climate change. Modern large-scale genomics techniques are now being applied to many of these previously understudied crops, with the first successes reported in the genomics area. However, greater investment of resources and manpower are necessary if the potential of orphan legumes is to be unlocked and applied in the future. PMID- 28003310 TI - Molecular phylogeny and forms of photosynthesis in tribe Salsoleae (Chenopodiaceae). AB - While many C4 lineages have Kranz anatomy around individual veins, Salsoleae have evolved the Salsoloid Kranz anatomy where a continuous dual layer of chlorenchyma cells encloses the vascular and water-storage tissue. With the aim of elucidating the evolution of C4 photosynthesis in Salsoleae, a broadly sampled molecular phylogeny and anatomical survey was conducted, together with biochemical, microscopic, and physiological analyses of selected photosynthetic types. From analyses of photosynthetic phenotypes, a model for evolution of this form of C4 was compared with models for evolution of Kranz anatomy around individual veins. A functionally C3 proto-Kranz phenotype (Proto-Kranz Sympegmoid) and intermediates with a photorespiratory pump (Kranz-like Sympegmoid and Kranz-like Salsoloid types) are considered crucial transitional steps towards C4 development. The molecular phylogeny provides evidence for C3 being the ancestral photosynthetic pathway but there is no phylogenetic evidence for the ancestry of C3-C4 intermediacy with respect to C4 in Salsoleae. Traits considered advantageous in arid conditions, such as annual life form, central sclerenchyma in leaves, and reduction of surface area, evolved repeatedly in Salsoleae. The recurrent evolution of a green stem cortex taking over photosynthesis in C4 clades of Salsoleae concurrent with leaf reduction was probably favoured by the higher productivity of the C4 cycle. PMID- 28003309 TI - Progress toward active or passive HIV-1 vaccination. AB - AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly desirable. Most vaccines in clinical use today prevent infection because they elicit antibodies that block pathogen entry. Consistent with this general rule, studies in experimental animals have shown that broadly neutralizing antibodies to HIV-1 can prevent infection, suggesting that a vaccine that elicits such antibodies would be protective. However, despite significant efforts over the last 30 years, attempts to elicit broadly HIV-1 neutralizing antibodies by vaccination failed until recent experiments in genetically engineered mice were finally successful. Here, we review the key breakthroughs and remaining obstacles to the development of active and passive HIV-1 vaccines. PMID- 28003312 TI - Energetics and the immune system: Trade-offs associated with non-acute levels of CRP in adolescent Gambian girls. AB - BACKGROUND AND OBJECTIVES: The human immune system is an ever-changing composition of innumerable cells and proteins, continually ready to respond to pathogens or insults. The cost of maintaining this state of immunological readiness is rarely considered. In this paper we aim to discern a cost to non acute immune function by investigating how low levels of C-reactive protein (CRP) relate to other energetic demands and resources in adolescent Gambian girls. METHODOLOGY: Data from a longitudinal study of 66 adolescent girls was used to test hypotheses around investment in immune function. Non-acute (under 2 mg/L) CRP was used as an index of immune function. Predictor variables include linear height velocity, adiposity, leptin, and measures of energy balance. RESULTS: Non acute log CRP was positively associated with adiposity (beta = 0.16, p < 0.001, R2 = 0.17) and levels of the adipokine leptin (beta = 1.17, p = 0.006, R2 = 0.09). CRP was also negatively associated with increased investment in growth, as measured by height velocity (beta = -0.58, p < 0.001, R2 = 0.13) and lean mass deposition beta = -0.42, p = 0.005, R2 = 0.08). Relationships between adiposity and growth explained some, but not all, of this association. We do not find that CRP was related to energy balance. CONCLUSIONS AND IMPLICATIONS: These data support a hypothesis that investment in non-acute immune function is facultative, and sensitive to energetic resources and demands. We also find support for an adaptive association between the immune system and adipose tissue. PMID- 28003314 TI - Maintaining hair follicle stem cell identity in a dish. PMID- 28003313 TI - Suicidal Risks in Reports of Long-Term Controlled Trials of Antidepressants for Major Depressive Disorder II. PMID- 28003315 TI - COPI-TRAPPII activates Rab18 and regulates its lipid droplet association. AB - The transport protein particle (TRAPP) was initially identified as a vesicle tethering factor in yeast and as a guanine nucleotide exchange factor (GEF) for Ypt1/Rab1. In mammals, structures and functions of various TRAPP complexes are beginning to be understood. We found that mammalian TRAPPII was a GEF for both Rab18 and Rab1. Inactivation of TRAPPII-specific subunits by various methods including siRNA depletion and CRISPR-Cas9-mediated deletion reduced lipolysis and resulted in aberrantly large lipid droplets. Recruitment of Rab18 onto lipid droplet (LD) surface was defective in TRAPPII-deleted cells, but the localization of Rab1 on Golgi was not affected. COPI regulates LD homeostasis. We found that the previously documented interaction between TRAPPII and COPI was also required for the recruitment of Rab18 to the LD We hypothesize that the interaction between COPI and TRAPPII helps bring TRAPPII onto LD surface, and TRAPPII, in turn, activates Rab18 and recruits it on the LD surface to facilitate its functions in LD homeostasis. PMID- 28003317 TI - Rare small intestinal volvulus from entrapment in hepato-diaphragmatic adhesions in a 45-year-old lady. AB - Small intestinal volvulus is rare in adults and rarely caused by string adhesions between the liver and the diaphragm. Similar adhesions were described in Fitz Hugh-Curtis syndrome. We report a 45-year-old lady with small intestinal volvulus from entrapment of a loop in string adhesions between the liver and the diaphragm. Her plain radiographs showed a significant shadow of the trapped loop. PMID- 28003316 TI - Projecting Individualized Absolute Invasive Breast Cancer Risk in US Hispanic Women. AB - Background: There is no model to estimate absolute invasive breast cancer risk for Hispanic women. Methods: The San Francisco Bay Area Breast Cancer Study (SFBCS) provided data on Hispanic breast cancer case patients (533 US-born, 553 foreign-born) and control participants (464 US-born, 947 foreign-born). These data yielded estimates of relative risk (RR) and attributable risk (AR) separately for US-born and foreign-born women. Nativity-specific absolute risks were estimated by combining RR and AR information with nativity-specific invasive breast cancer incidence and competing mortality rates from the California Cancer Registry and Surveillance, Epidemiology, and End Results program to develop the Hispanic risk model (HRM). In independent data, we assessed model calibration through observed/expected (O/E) ratios, and we estimated discriminatory accuracy with the area under the receiver operating characteristic curve (AUC) statistic. Results: The US-born HRM included age at first full-term pregnancy, biopsy for benign breast disease, and family history of breast cancer; the foreign-born HRM also included age at menarche. The HRM estimated lower risks than the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) for US-born Hispanic women, but higher risks in foreign-born women. In independent data from the Women's Health Initiative, the HRM was well calibrated for US-born women (observed/expected [O/E] ratio = 1.07, 95% confidence interval [CI] = 0.81 to 1.40), but seemed to overestimate risk in foreign-born women (O/E ratio = 0.66, 95% CI = 0.41 to 1.07). The AUC was 0.564 (95% CI = 0.485 to 0.644) for US-born and 0.625 (95% CI = 0.487 to 0.764) for foreign-born women. Conclusions: The HRM is the first absolute risk model that is based entirely on data specific to Hispanic women by nativity. Further studies in Hispanic women are warranted to evaluate its validity. PMID- 28003318 TI - Splenic injury following elective colonoscopy: a rare complication. AB - Splenic injury is an extremely rare, yet serious, complication related to colonoscopy. So far, less than 80 cases have been reported worldwide since 1970. With the increasing use of colonoscopy, endoscopists, surgeons and radiologists are more likely to encounter this unusual complication. Increased splenocolic adhesions, splenomegaly or underlying splenic disease might, inter alia, constitute a predisposing factor. However, it might also occur in patients without significant adhesions or underlying splenic pathology. Patients with abdominal pain, hypotension and a fall in hematocrit without rectal bleeding after colonoscopy, should be suspected of having splenic injury. Most patients present with symptoms within 24 hours after colonoscopy, nevertheless, delayed presentations have been described as well. We report such a case of splenic injury secondary to colonoscopy. The patient was presented with hemorrhagic shock and abdominal pain following a colonoscopy which had taken place before 36 hours, an urgent splenectomy was required with successful outcome. PMID- 28003319 TI - Hypothyroid-induced acute compartment syndrome in all extremities. AB - Acute compartment syndrome (ACS) is an uncommon complication of uncontrolled hypothyroidism. If unrecognized, this can lead to ischemia, necrosis and potential limb loss. A 49-year-old female presented with the sudden onset of bilateral lower and upper extremity swelling and pain. The lower extremity anterior compartments were painful and tense. The extensor surface of the upper extremities exhibited swelling and pain. Motor function was intact, however, limited due to pain. Bilateral lower extremity fasciotomies were performed. Postoperative Day 1, upper extremity motor function decreased significantly and paresthesias occurred. She therefore underwent bilateral forearm fasciotomies. The pathogenesis of hypothyroidism-induced compartment syndrome is unclear. Thyroid-stimulating hormone-induced fibroblast activation results in increased glycosaminoglycan deposition. The primary glycosaminoglycan in hypothyroid myxedematous changes is hyaluronic acid, which binds water causing edema. This increases vascular permeability, extravasation of proteins and impaired lymphatic drainage. These contribute to increased intra-compartmental pressure and subsequent ACS. PMID- 28003320 TI - Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration resistant prostate cancer-updated results. AB - A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28-1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18 0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. PMID- 28003321 TI - Collaborative care intervention for the perceived care needs of women with breast cancer undergoing adjuvant therapy after surgery: a feasibility study. AB - Objective: This study aimed to investigate the feasibility of an intervention program for women with breast cancer undergoing adjuvant anticancer therapy, and determine its preliminary effectiveness in reducing their unmet needs and psychological distress. Methods: The intervention was based on the collaborative care model, and compromised four domains: identification of unmet needs, problem solving therapy and behavioral activation supervised by a psychiatrist, psychoeducation and referral to relevant departments. Eligible women with breast cancer were provided the collaborative care intervention over four sessions. The feasibility of the program was evaluated by the percentage of women who entered the intervention and by the percentage of adherence to the program. Self-reported outcomes were measured by the Supportive Care Needs Survey-Short Form 34 (SCNS SF34), the Profile of Mood States (POMS), the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Concern about Recurrence Scale, and pre- and post-intervention satisfaction with medical care. Results: In total, 40 patients participated in this study. The rate of participation in the intervention was 68%, and the rate of adherence was 93%. Participants had significantly improved scores on total perceived needs, physical needs and psychological needs on the SCNS-SF34; vigor and confusion on the POMS and function (physical, emotional and cognitive), nausea and vomiting, dyspnea, appetite loss and financial difficulties on the EORTC QLQ-C30 compared with the baseline assessment. Conclusions: Our findings indicated the intervention program was feasible. Further study is needed to demonstrate the program's effectiveness in reducing unmet needs. PMID- 28003322 TI - High impact of methylation accumulation on metachronous gastric cancer: 5-year follow-up of a multicentre prospective cohort study. PMID- 28003323 TI - Precise long non-coding RNA modulation in visual maintenance and impairment. AB - Long non-coding RNAs (lncRNAs) are remarkably powerful, flexible and pervasive cellular regulators. With the help of cheaper RNA-seq, high-throughput screening of lncRNAs has become widely applied and has identified large numbers of specific lncRNAs in various physiological or pathological processes. Vision is known to be a complex and vital perception that comprises 80% of the sensory information we receive. A consensus has been reached that normal visual maintenance and impairment are primarily driven by gene regulation. Recently, it has become understood that lncRNAs are key regulators in most biological processes, including cell proliferation, apoptosis, differentiation, immune responses, oxidative stress and inflammation. Our review is intended to provide insight towards a comprehensive view of the precise modulation of lncRNAs in visual maintenance and impairment. We also highlight the challenges and future directions in conducting lncRNA studies, particularly in patients whose lncRNAs may hold expanded promise for diagnostic, prognostic and therapeutic applications. PMID- 28003324 TI - E-cigarettes and equity: a systematic review of differences in awareness and use between sociodemographic groups. AB - OBJECTIVE: To assess whether electronic cigarette (e-cigarette) awareness, 'ever use' and current use vary significantly between different sociodemographic groups. DESIGN: Systematic review. DATA SOURCES: Published and unpublished reports identified by searching seven electronic databases (PubMed, MEDLINE, Web of Science, EMBASE, Global Health, PsycINFO, CINAHL Plus) and grey literature sources. STUDY SELECTION: Systematic search for and appraisal of cross-sectional or longitudinal studies that assessed e-cigarette awareness, 'ever use' or current use, and included subgroup analysis of 1 or more PROGRESS Plus sociodemographic groups. No geographical or time restrictions imposed. Assessment by multiple reviewers, with 17% of full articles screened meeting the selection criteria. DATA EXTRACTION: Data extracted and checked by multiple reviewers, with quality assessed using an adapted tool developed by the Joanna Briggs Institute. DATA SYNTHESIS: Results of narrative synthesis suggest broadly that awareness, 'ever use' and current use of e-cigarettes may be particularly prevalent among older adolescents and younger adults, males, people of white ethnicity and particularly in the case of awareness and 'ever use'-those of intermediate or high levels of education. In some cases, results also varied within and between countries. CONCLUSIONS: E-cigarette awareness, 'ever use' and current use appear to be patterned by a number of sociodemographic factors which vary between different countries and subnational localities. Care will therefore be required to ensure neither the potential benefits nor the potential risks of e-cigarettes exacerbate existing health inequalities. PMID- 28003325 TI - Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma. AB - Using multiple drugs to kill cancer cells can decrease drug resistance development. However, this approach is frequently limited by the bioavailability and toxicity of the combined agents and delivery at ratios to specific locations that synergistically kill cancer cells. Loading the individual agents into a nanoparticle that releases the drugs at synergizing ratios at a single location is one approach to resolve this concern. Celecoxib and plumbagin are two drugs that were identified from a screen to synergistically kill melanoma cells compared with normal cells. Combined use of these agents by traditional approaches was not possible due to poor bioavailability and toxicologic concerns. This study details the development of a nanoliposomal-based agent containing celecoxib and plumbagin, called CelePlum-777, which is stable and releases these drugs at an optimal ratio for maximal synergistic killing efficacy. CelePlum-777 was more effective at killing melanoma than normal cells and inhibited xenograft melanoma tumor growth by up to 72% without apparent toxicity. Mechanistically, the drug combination in CelePlum-777 led to enhanced inhibition of melanoma cell proliferation mediated by decreasing levels of key cyclins important for cancer cell proliferation and survival, which was not observed with the individual agents. Thus, a novel nanoparticle-based drug has been developed containing celecoxib and plumbagin that lacks toxicity and delivers the agents at a synergistically killing drug ratio to kill cancer cells. Mol Cancer Ther; 16(3); 440-52. (c)2016 AACR. PMID- 28003326 TI - Forever Young: The Role of Ubiquitin Receptor DA1 and E3 Ligase BIG BROTHER in Controlling Leaf Growth and Development. AB - The final size of plant organs is determined by a combination of cell proliferation and cell expansion. Leaves account for a large part of above-ground biomass and provide energy to complete the plant's life cycle. Although the final size of leaves is remarkably constant under fixed environmental conditions, several genes have been described to enhance leaf growth when their expression is modulated. In Arabidopsis (Arabidopsis thaliana), mutations in DA1 and BB increase leaf size, an effect that is synergistically enhanced in the double mutant. Here, we show that overexpression of a dominant-negative version of DA1 enhances leaf size in a broad range of natural accessions of this species, indicating a highly conserved role of this protein in controlling organ size. We also found that during early stages of development, leaves of da1-1 and bb/eod1-2 mutants were already larger than the isogenic Col-0 wild type, but this phenotype was triggered by different cellular mechanisms. Later during development, da1-1 and bb/eod1-2 leaves showed a prolonged longevity, which was enhanced in the double mutant. Conversely, ectopic expression of DA1 or BB restricted growth and promoted leaf senescence. In concert, shortly upon induction of DA1 and BB expression, several marker genes for the transition from proliferation to expansion were highly up-regulated. Additionally, multiple genes involved in maintaining the mitotic cell cycle were rapidly down-regulated and senescence genes were strongly up-regulated, particularly upon BB induction. With these results, we demonstrate that DA1 and BB restrict leaf size and promote senescence through converging and different mechanisms. PMID- 28003327 TI - Identification and Characterization of Arabidopsis Seed Coat Mucilage Proteins. AB - Plant cell wall proteins are important regulators of cell wall architecture and function. However, because cell wall proteins are difficult to extract and analyze, they are generally poorly understood. Here, we describe the identification and characterization of proteins integral to the Arabidopsis (Arabidopsis thaliana) seed coat mucilage, a specialized layer of the extracellular matrix composed of plant cell wall carbohydrates that is used as a model for cell wall research. The proteins identified in mucilage include those previously identified by genetic analysis, and several mucilage proteins are reduced in mucilage-deficient mutant seeds, suggesting that these proteins are genuinely associated with the mucilage. Arabidopsis mucilage has both nonadherent and adherent layers. Both layers have similar protein profiles except for proteins involved in lipid metabolism, which are present exclusively in the adherent mucilage. The most abundant mucilage proteins include a family of proteins named TESTA ABUNDANT1 (TBA1) to TBA3; a less abundant fourth homolog was named TBA-LIKE (TBAL). TBA and TBAL transcripts and promoter activities were detected in developing seed coats, and their expression requires seed coat differentiation regulators. TBA proteins are secreted to the mucilage pocket during differentiation. Although reverse genetics failed to identify a function for TBAs/TBAL, the TBA promoters are highly expressed and cell type specific and so should be very useful tools for targeting proteins to the seed coat epidermis. Altogether, these results highlight the mucilage proteome as a model for cell walls in general, as it shares similarities with other cell wall proteomes while also containing mucilage-specific features. PMID- 28003329 TI - Early-Onset Juvenile SLE Associated With a Novel Mutation in Protein Kinase C delta. AB - Juvenile systemic lupus erythematosus (jSLE) is rare before 5 years of age. Monogenic causes are suspected in cases of very early onset jSLE particularly in the context of a family history and/or consanguinity. We performed whole-exome sequencing and homozygosity mapping in the siblings presented with early-onset jSLE. A novel homozygous missense mutation in protein kinase C delta (c.1294G>T; p.Gly432Trp) was identified in both patients. One patient showed a marked clinical response and resolution inflammation with rituximab therapy. This report demonstrates the clinical importance of identifying monogenic causes of rare disease to provide a definitive diagnosis, help rationalize treatment, and facilitate genetic counseling. PMID- 28003331 TI - Andrew Ewald: Understanding cellular cooperation. PMID- 28003330 TI - Interrogating cellular perception and decision making with optogenetic tools. AB - Optogenetics promises to deepen our understanding of how cells perceive and respond to complex and dynamic signals and how this perception regulates normal and abnormal function. In this study, we present our vision for how these nascent tools may transform our view of fundamental cell biological processes. PMID- 28003332 TI - From static to animated: Measuring mechanical forces in tissues. AB - Cells are physical objects that exert mechanical forces on their surroundings as they migrate and take their places within tissues. New techniques are now poised to enable the measurement of cell-generated mechanical forces in intact tissues in vivo, which will illuminate the secret dynamic lives of cells and change our current perception of cell biology. PMID- 28003333 TI - Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2. AB - The critical initiation phase of clathrin-mediated endocytosis (CME) determines where and when endocytosis occurs. Heterotetrameric adaptor protein 2 (AP2) complexes, which initiate clathrin-coated pit (CCP) assembly, are activated by conformational changes in response to phosphatidylinositol-4,5-bisphosphate (PIP2) and cargo binding at multiple sites. However, the functional hierarchy of interactions and how these conformational changes relate to distinct steps in CCP formation in living cells remains unknown. We used quantitative live-cell analyses to measure discrete early stages of CME and show how sequential, allosterically regulated conformational changes activate AP2 to drive both nucleation and subsequent stabilization of nascent CCPs. Our data establish that cargoes containing Yxxphi motif, but not dileucine motif, play a critical role in the earliest stages of AP2 activation and CCP nucleation. Interestingly, these cargo and PIP2 interactions are not conserved in yeast. Thus, we speculate that AP2 has evolved as a key regulatory node to coordinate CCP formation and cargo sorting and ensure high spatial and temporal regulation of CME. PMID- 28003334 TI - HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. AB - Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc The increased levels of DNA damage sensitised Huwe1 deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a potential vulnerability of HUWE1-mutated tumours to DNA-damaging agents and inhibitors of anti-apoptotic proteins. PMID- 28003335 TI - The RAS-related GTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism. AB - Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15.3 versus 5.6 months of progression-free survival). Moreover, a better response to EGFR-TKI was associated with low RHOB levels in a panel of lung tumor cell lines and in a lung specific tetracycline-inducible EGFRL858R transgenic mouse model. High RHOB expression was also found to prevent erlotinib-induced AKT inhibition in vitro and in vivo Furthermore, a combination of the new-generation AKT inhibitor G594 with erlotinib induced tumor cell death in vitro and tumor regression in vivo in RHOB-positive cells. Our results support a role for RHOB/AKT signaling in the resistance to EGFR-TKI and propose RHOB as a potential predictor of patient response to EGFR-TKI treatment. PMID- 28003336 TI - Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina. AB - Age-related macular degeneration (AMD) is a major cause of blindness in the elderly population. Its pathophysiology is linked to reactive oxygen species (ROS) and activation of the complement system. Sialic acid polymers prevent ROS production of human mononuclear phagocytes via the inhibitory sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC11) receptor. Here, we show that low-dose intravitreal injection of low molecular weight polysialic acid with average degree of polymerization 20 (polySia avDP20) in humanized transgenic mice expressing SIGLEC11 on mononuclear phagocytes reduced their reactivity and vascular leakage induced by laser coagulation. Furthermore, polySia avDP20 prevented deposition of the membrane attack complex in both SIGLEC11 transgenic and wild-type animals. In vitro, polySia avDP20 showed two independent, but synergistic effects on the innate immune system. First, polySia avDP20 prevented tumor necrosis factor-alpha, vascular endothelial growth factor A, and superoxide production by SIGLEC11-positive phagocytes. Second, polySia avDP20 directly interfered with complement activation. Our data provide evidence that polySia avDP20 ameliorates laser-induced damage in the retina and thus is a promising candidate to prevent AMD-related inflammation and angiogenesis. PMID- 28003338 TI - A predicted cation transporter protein, BPSS1228, is involved in intracellular behaviour of Burkholderia pseudomallei in a human lung epithelial cell line (A549). AB - Burkholderia pseudomallei causes melioidosis, a potentially fatal infectious disease in tropical and subtropical countries worldwide. The intracellular behaviour of this pathogen in host cells has been reported to impact the severity of melioidosis, including the development of septicaemia, a consequence of pneumonia melioidosis. We previously identified a predicted cation transporter protein, BPSS1228, that participates in the transitional stage of this intracellular pathogen. For further analysis, in this study B. pseudomallei bpss1228 mutant and complemented strains were constructed and bacterial infectivity on human lung epithelial cells, A549, investigated in vitro Burkholderia pseudomallei bpss1228 mutant showed impaired bacterial adhesion and invasion into A549 cells compared with wild-type strain, while the deficient phenotypes were restored to wild-type levels by the complemented strain. Additionally, the inactivation of bpss1228 in the mutant strain affected flagella based swimming on a semi-solid surface and resistance to acid stresses simulating intracellular environments. These observations of BPSS1228 relating to B. pseudomallei infection strategies shed a new light on its association with intracellular B. pseudomallei during the interaction with host cells. PMID- 28003337 TI - Bacterial biodegradation of neonicotinoid pesticides in soil and water systems. AB - Neonicotinoids are neurotoxic systemic insecticides used in plant protection worldwide. Unfortunately, application of neonicotinoids affects both beneficial and target insects indiscriminately. Being water soluble and persistent, these pesticides are capable of disrupting both food chains and biogeochemical cycles. This review focuses on the biodegradation of neonicotinoids in soil and water systems by the bacterial community. Several bacterial strains have been isolated and identified as capable of transforming neonicotinoids in the presence of an additional carbon source. Environmental parameters have been established for accelerated transformation in some of these strains. Studies have also indicated that enhanced biotransformation of these pesticides can be accomplished by mixed microbial populations under optimised environmental conditions. Substantial research into the identification of neonicotinoid-mineralising bacterial strains and identification of the genes and enzymes responsible for neonicotinoid degradation is still required to complete the understanding of microbial biodegradation pathways, and advance bioremediation efforts. PMID- 28003339 TI - LRGUK1 is part of a multiprotein complex required for manchette function and male fertility. AB - Infertility occurs in 1 in 20 young men and is idiopathic in origin in most. We have reported that the leucine-rich repeat (LRR) and guanylate kinase-like domain containing, isoform (LRGUK)-1 is essential for sperm head shaping, via the manchette, and the initiation of sperm tail growth from the centriole/basal body, and thus, male fertility. Within this study we have used a yeast 2-hybrid screen of an adult testis library to identify LRGUK1-binding partners, which were then validated with a range of techniques. The data indicate that LRGUK1 likely achieves its function in partnership with members of the HOOK family of proteins (HOOK-1-3), Rab3-interacting molecule binding protein (RIMBP)-3 and kinesin light chain (KLC)-3, all of which are associated with intracellular protein transport as cargo adaptor proteins and are localized to the manchette. LRGUK1 consists of 3 domains; an LRR, a guanylate kinase (GUK)-like and an unnamed domain. In the present study, we showed that the GUK-like domain is essential for binding to HOOK2 and RIMBP3, and the LRR domain is essential for binding to KLC3. These findings establish LRGUK1 as a key component of a multiprotein complex with an essential role in microtubule dynamics within haploid male germ cells.-Okuda, H., DeBoer, K., O'Connor, A. E., Merriner, D. J., Jamsai, D., O'Bryan, M. K. LRGUK1 is part of a multiprotein complex required for manchette function and male fertility. PMID- 28003340 TI - Histone deacetylase inhibitor apicidin increases expression of the alpha secretase ADAM10 through transcription factor USF1-mediated mechanisms. AB - ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) is the alpha-secretase that is involved in APP (beta-amyloid precursor protein) processing. Enhancement of the nonamyloidogenic APP pathway by ADAM10 provides therapeutic potential for Alzheimer's disease (AD). By using high-throughput screening that targeted ADAM10, we determined that apicidin-an inhibitor of HDACs (histone deacetylases)-significantly increased mRNA and protein levels of ADAM10 in SH-SY5Y cells. A luciferase assay revealed that the nucleotides -444 to -300 in the ADAM10 promoter were sufficient to mediate this effect. In addition, knockdown of USF1 (upstream transcription factor 1) and HDAC2/3 prevented apicidin regulation of ADAM10. Moreover, USF1 acetylation was increased by apicidin, which enhanced the association of USF1 with HDAC2/3 and with the ADAM10 promoter. We further found that apicidin did not affect the phosphorylation of ERK or USF1; however, ERK inhibitor U0126 blocked the effect of apicidin on ADAM10. Finally, apicidin increased the level of alpha-site C-terminal fragment from APP and reduced the production of beta-amyloid peptide 1-42. Collectively, our study provides evidence that ADAM10 expression can be regulated by HDAC2/3 inhibitor apicidin via USF1-dependent mechanisms in which ERK signaling plays an important role. Thus, HDAC regulation of ADAM10 might shed new light on the understanding of AD pathology.-Hu, X.-T., Zhu, B.-L., Zhao, L.-G., Wang, J.-W., Liu, L., Lai, Y.-J., He, L., Deng, X.-J., Chen, G.-J. Histone deacetylase inhibitor apicidin increases expression of the alpha-secretase ADAM10 through transcription factor USF1-mediated mechanisms. PMID- 28003341 TI - Chicoric acid supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of NF-kappaB. AB - Chicoric acid (CA), a natural phenolic acid extracted from chicory and the echinacea (purple coneflower) plant (Echinacea purpurea), has been regarded as a nutraceutical that has powerful antioxidant and antiobesity activities. We investigated the inhibitory effects of CA on systemic inflammation-induced neuroinflammation, amyloidogenesis, and cognitive impairment. C57BL/6J mice were treated with 0.05% CA in the drinking water for 45 d. The mice were then treated by intraperitoneal injection of lipopolysaccharide (LPS). It was found that CA prevented LPS-induced memory impairment and neuronal loss through behavioral tests and histological examination. Furthermore, amyloidogenesis in the CNS was detected. The results showed that CA prevented LPS-induced increases in amyloid beta (1-42 specific) (Abeta1-42) accumulation, levels of amyloid precursor protein, and neuronal beta-secretase 1 (BACE1), as well as the equilibrium cholinergic system in mouse brain. Moreover, CA down-regulated LPS-induced glial overactivation by inhibiting the MAPK and NF-kappaB pathway. Consequently, CA reduced the levels of NF-kappaB transcriptionally regulated inflammatory mediators and cytokines such as iNOS, cyclooxygenase-2 (COX-2), IL-1beta, and TNF alpha in both mouse brain and BV2 microglial cells. These results demonstrated that CA alleviated memory impairment and amyloidogenesis triggered by LPS through suppressing NF-kappaB transcriptional pathway, suggesting that CA might be a plausible therapeutic intervention for neuroinflammation-related diseases such as Alzheimer disease.-Liu, Q., Chen, Y., Shen, C., Xiao, Y., Wang, Y., Liu, Z., Liu, X. Chicoric acid supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of NF-kappaB. PMID- 28003342 TI - Ceramides and mitochondrial fatty acid oxidation in obesity. AB - Obesity is an epidemic, complex disease that is characterized by increased glucose, lipids, and low-grade inflammation in the circulation, among other factors. It creates the perfect scenario for the production of ceramide, the building block of the sphingolipid family of lipids, which is involved in metabolic disorders such as obesity, diabetes, and cardiovascular disease. In addition, obesity causes a decrease in fatty acid oxidation (FAO), which contributes to lipid accumulation within the cells, conferring more susceptibility to cell dysfunction. C16:0 ceramide, a specific ceramide species, has been identified recently as the principal mediator of obesity-derived insulin resistance, impaired fatty acid oxidation, and hepatic steatosis. In this review, we have sought to cover the importance of the ceramide species and their metabolism, the main ceramide signaling pathways in obesity, and the link between C16:0 ceramide, FAO, and obesity.-Fucho, R., Casals, N., Serra, D., Herrero, L. Ceramides and mitochondrial fatty acid oxidation in obesity. PMID- 28003343 TI - Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin beta and promotes transendothelial cell migration. AB - The adhesion molecule CD99 is essential for the transendothelial migration of leukocytes. In this study, we used biochemical and cellular assays to show that CD99 undergoes ectodomain shedding by the metalloprotease meprin beta and subsequent intramembrane proteolysis by gamma-secretase. The cleavage site in CD99 was identified by mass spectrometry within an acidic region highly conserved through different vertebrate species. This finding fits perfectly to the unique cleavage specificity of meprin beta with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin beta would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin beta induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin beta in Mep1b-/- mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin beta could serve as a therapeutic target, given that in a proof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin beta inhibitor treated mice.-Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Kollmann, S., Wichert, R., Otte, A., Ohler, A., Stirnberg, M., Lucius, R., Koudelka, T., Tholey, A., Biasin, V., Pietrzik, C. U., Kwapiszewska, G., Becker-Pauly, C. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin beta and promotes transendothelial cell migration. PMID- 28003345 TI - KCTD Hetero-oligomers Confer Unique Kinetic Properties on Hippocampal GABAB Receptor-Induced K+ Currents. AB - : GABAB receptors are the G-protein coupled receptors for the main inhibitory neurotransmitter in the brain, GABA. GABAB receptors were shown to associate with homo-oligomers of auxiliary KCTD8, KCTD12, KCTD12b, and KCTD16 subunits (named after their T1 K+-channel tetramerization domain) that regulate G-protein signaling of the receptor. Here we provide evidence that GABAB receptors also associate with hetero-oligomers of KCTD subunits. Coimmunoprecipitation experiments indicate that two-thirds of the KCTD16 proteins in the hippocampus of adult mice associate with KCTD12. We show that the KCTD proteins hetero oligomerize through self-interacting T1 and H1 homology domains. Bioluminescence resonance energy transfer measurements in live cells reveal that KCTD12/KCTD16 hetero-oligomers associate with both the receptor and the G-protein. Electrophysiological experiments demonstrate that KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties on G-protein-activated Kir3 currents. During prolonged receptor activation (one min) KCTD12/KCTD16 hetero-oligomers produce moderately desensitizing fast deactivating K+ currents, whereas KCTD12 and KCTD16 homo-oligomers produce strongly desensitizing fast deactivating currents and nondesensitizing slowly deactivating currents, respectively. During short activation (2 s) KCTD12/KCTD16 hetero-oligomers produce nondesensitizing slowly deactivating currents. Electrophysiological recordings from hippocampal neurons of KCTD knock-out mice are consistent with these findings and indicate that KCTD12/KCTD16 hetero-oligomers increase the duration of slow IPSCs. In summary, our data demonstrate that simultaneous assembly of distinct KCTDs at the receptor increases the molecular and functional repertoire of native GABAB receptors and modulates physiologically induced K+ current responses in the hippocampus. SIGNIFICANCE STATEMENT: The KCTD proteins 8, 12, and 16 are auxiliary subunits of GABAB receptors that differentially regulate G-protein signaling of the receptor. The KCTD proteins are generally assumed to function as homo-oligomers. Here we show that the KCTD proteins also assemble hetero-oligomers in all possible dual combinations. Experiments in live cells demonstrate that KCTD hetero-oligomers form at least tetramers and that these tetramers directly interact with the receptor and the G-protein. KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties to GABAB receptor-induced Kir3 currents in heterologous cells. KCTD12/KCTD16 hetero-oligomers are abundant in the hippocampus, where they prolong the duration of slow IPSCs in pyramidal cells. Our data therefore support that KCTD hetero-oligomers modulate physiologically induced K+ current responses in the brain. PMID- 28003344 TI - Differentiating lower motor neuron syndromes. AB - Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features. PMID- 28003346 TI - Edge-Related Activity Is Not Necessary to Explain Orientation Decoding in Human Visual Cortex. AB - : Multivariate pattern analysis is a powerful technique; however, a significant theoretical limitation in neuroscience is the ambiguity in interpreting the source of decodable information used by classifiers. This is exemplified by the continued controversy over the source of orientation decoding from fMRI responses in human V1. Recently Carlson (2014) identified a potential source of decodable information by modeling voxel responses based on the Hubel and Wiesel (1972) ice cube model of visual cortex. The model revealed that activity associated with the edges of gratings covaries with orientation and could potentially be used to discriminate orientation. Here we empirically evaluate whether "edge-related activity" underlies orientation decoding from patterns of BOLD response in human V1. First, we systematically mapped classifier performance as a function of stimulus location using population receptive field modeling to isolate each voxel's overlap with a large annular grating stimulus. Orientation was decodable across the stimulus; however, peak decoding performance occurred for voxels with receptive fields closer to the fovea and overlapping with the inner edge. Critically, we did not observe the expected second peak in decoding performance at the outer stimulus edge as predicted by the edge account. Second, we evaluated whether voxels that contribute most to classifier performance have receptive fields that cluster in cortical regions corresponding to the retinotopic location of the stimulus edge. Instead, we find the distribution of highly weighted voxels to be approximately random, with a modest bias toward more foveal voxels. Our results demonstrate that edge-related activity is likely not necessary for orientation decoding. SIGNIFICANCE STATEMENT: A significant theoretical limitation of multivariate pattern analysis in neuroscience is the ambiguity in interpreting the source of decodable information used by classifiers. For example, orientation can be decoded from BOLD activation patterns in human V1, even though orientation columns are at a finer spatial scale than 3T fMRI. Consequently, the source of decodable information remains controversial. Here we test the proposal that information related to the stimulus edges underlies orientation decoding. We map voxel population receptive fields in V1 and evaluate orientation decoding performance as a function of stimulus location in retinotopic cortex. We find orientation is decodable from voxels whose receptive fields do not overlap with the stimulus edges, suggesting edge-related activity does not substantially drive orientation decoding. PMID- 28003328 TI - Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB. AB - The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials. PMID- 28003347 TI - Olfactory Bulb Deep Short-Axon Cells Mediate Widespread Inhibition of Tufted Cell Apical Dendrites. AB - : In the main olfactory bulb (MOB), the first station of sensory processing in the olfactory system, GABAergic interneuron signaling shapes principal neuron activity to regulate olfaction. However, a lack of known selective markers for MOB interneurons has strongly impeded cell-type-selective investigation of interneuron function. Here, we identify the first selective marker of glomerular layer-projecting deep short-axon cells (GL-dSACs) and investigate systematically the structure, abundance, intrinsic physiology, feedforward sensory input, neuromodulation, synaptic output, and functional role of GL-dSACs in the mouse MOB circuit. GL-dSACs are located in the internal plexiform layer, where they integrate centrifugal cholinergic input with highly convergent feedforward sensory input. GL-dSAC axons arborize extensively across the glomerular layer to provide highly divergent yet selective output onto interneurons and principal tufted cells. GL-dSACs are thus capable of shifting the balance of principal tufted versus mitral cell activity across large expanses of the MOB in response to diverse sensory and top-down neuromodulatory input. SIGNIFICANCE STATEMENT: The identification of cell-type-selective molecular markers has fostered tremendous insight into how distinct interneurons shape sensory processing and behavior. In the main olfactory bulb (MOB), inhibitory circuits regulate the activity of principal cells precisely to drive olfactory-guided behavior. However, selective markers for MOB interneurons remain largely unknown, limiting mechanistic understanding of olfaction. Here, we identify the first selective marker of a novel population of deep short-axon cell interneurons with superficial axonal projections to the sensory input layer of the MOB. Using this marker, together with immunohistochemistry, acute slice electrophysiology, and optogenetic circuit mapping, we reveal that this novel interneuron population integrates centrifugal cholinergic input with broadly tuned feedforward sensory input to modulate principal cell activity selectively. PMID- 28003348 TI - Spatiotemporal Filter for Visual Motion Integration from Pursuit Eye Movements in Humans and Monkeys. AB - Despite the enduring interest in motion integration, a direct measure of the space-time filter that the brain imposes on a visual scene has been elusive. This is perhaps because of the challenge of estimating a 3D function from perceptual reports in psychophysical tasks. We take a different approach. We exploit the close connection between visual motion estimates and smooth pursuit eye movements to measure stimulus-response correlations across space and time, computing the linear space-time filter for global motion direction in humans and monkeys. Although derived from eye movements, we find that the filter predicts perceptual motion estimates quite well. To distinguish visual from motor contributions to the temporal duration of the pursuit motion filter, we recorded single-unit responses in the monkey middle temporal cortical area (MT). We find that pursuit response delays are consistent with the distribution of cortical neuron latencies and that temporal motion integration for pursuit is consistent with a short integration MT subpopulation. Remarkably, the visual system appears to preferentially weight motion signals across a narrow range of foveal eccentricities rather than uniformly over the whole visual field, with a transiently enhanced contribution from locations along the direction of motion. We find that the visual system is most sensitive to motion falling at approximately one-third the radius of the stimulus aperture. Hypothesizing that the visual drive for pursuit is related to the filtered motion energy in a motion stimulus, we compare measured and predicted eye acceleration across several other target forms.SIGNIFICANCE STATEMENT A compact model of the spatial and temporal processing underlying global motion perception has been elusive. We used visually driven smooth eye movements to find the 3D space-time function that best predicts both eye movements and perception of translating dot patterns. We found that the visual system does not appear to use all available motion signals uniformly, but rather weights motion preferentially in a narrow band at approximately one-third the radius of the stimulus. Although not universal, the filter predicts responses to other types of stimuli, demonstrating a remarkable degree of generalization that may lead to a deeper understanding of visual motion processing. PMID- 28003349 TI - Assessment and Optimization of the GeneXpert Diagnostic Platform for Detection of Ebola Virus RNA in Seminal Fluid. AB - Recent studies have suggested that Ebola virus (EBOV) ribonucleic acid (RNA) potentially present in the semen of a large number of survivors of Ebola virus disease (EVD) in Western Africa may contribute to sexual transmission of EVD and generate new clusters of cases in regions previously declared EVD-free. These findings drive the immediate need for a reliable, rapid, user-friendly assay for detection of EBOV RNA in semen that is deployable to multiple sites across Western Africa. In this study, we optimized the Xpert EBOV assay for semen samples by adding dithiothreitol. Compared to the assays currently in use in Liberia (including Ebola Zaire Target 1, major groove binder real-time-polymerase chain reaction assays, and original Xpert EBOV assay), the modified Xpert EBOV assay demonstrated greater sensitivity than the comparator assays. Thus, the modified Xpert EBOV assay is optimal for large-scale monitoring of EBOV RNA persistence in male survivors. PMID- 28003350 TI - Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction. AB - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8+ T-cell cytotoxicity, separated the 2 groups. NK/CD8+ T cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression. PMID- 28003351 TI - Human MicroRNA Responses Predict Cytomegalovirus Replication Following Solid Organ Transplantation. AB - Background: Homo sapiens mature micro-ribonucleic acid (miRNA)-200b-3p and 200c 3p are predicted to bind to 3' untranslated region of mRNA encoding human cytomegalovirus (HCMV) immediate early protein 2 (IE2). We hypothesized that expression of these miRNAs pretransplant could predict HCMV replication after solid organ transplantation (SOT). Methods: A total of 272 SOT recipients were HCMV-seropositive pretransplant and were managed using preemptive therapy. Pretransplant peripheral blood mononuclear cells were stimulated with HCMV followed by collection of RNA 1 day poststimulation. The miRNAs were quantified using real-time reverse transcription-polymerase chain reaction. Human foreskin fibroblasts were transfected with 200b-3p and 200c-3p and infected with HCMV 1 hour post-transfection. Protein was collected at 3 days postinfection (dpi) and 7 dpi underwent immunoblotting for IE2. Results: Medians of 200b-3p and 200c-3p were significantly lower in recipients with HCMV replication (n = 144) (361.6 vs 552.6, P = .035; 3586.8 vs 12986.8 copies/MUL, P = .03, respectively). Multivariate regression revealed that 200b-3p >=100 copies/MUL (odds ratio [OR]: 0.53; P = .02), was associated with less HCMV replication. Transfection with 200b 3p resulted in 2.7- and 2.5-fold decreased IE2 at 3 dpi and 7 dpi, respectively, compared to mock cells. Conclusions: MicroRNAs may play a biologically relevant role in controlling HCMV replication post-transplant. PMID- 28003352 TI - The Duration of Intestinal Immunity After an Inactivated Poliovirus Vaccine Booster Dose in Children Immunized With Oral Vaccine: A Randomized Controlled Trial. AB - Background: In 2014, 2 studies showed that inactivated poliovirus vaccine (IPV) boosts intestinal immunity in children previously immunized with oral poliovirus vaccine (OPV). As a result, IPV was introduced in mass campaigns to help achieve polio eradication. Methods: We conducted an open-label, randomized, controlled trial to assess the duration of the boost in intestinal immunity following a dose of IPV given to OPV-immunized children. Nine hundred healthy children in Vellore, India, aged 1-4 years were randomized (1:1:1) to receive IPV at 5 months (arm A), at enrollment (arm B), or no vaccine (arm C). The primary outcome was poliovirus shedding in stool 7 days after bivalent OPV challenge at 11 months. Results: For children in arms A, B, and C, 284 (94.7%), 297 (99.0%), and 296 (98.7%), respectively, were eligible for primary per-protocol analysis. Poliovirus shedding 7 days after challenge was less prevalent in arms A and B compared with C (24.6%, 25.6%, and 36.4%, respectively; risk ratio 0.68 [95% confidence interval: 0.53-0.87] for A versus C, and 0.70 [0.55-0.90] for B versus C). Conclusions: Protection against poliovirus remained elevated 6 and 11 months after an IPV boost, although at a lower level than reported at 1 month. Clinical Trials Registration: CTRI/2014/09/004979. PMID- 28003354 TI - Codon 91 Gyrase A Testing Is Necessary and Sufficient to Predict Ciprofloxacin Susceptibility in Neisseria gonorrhoeae. PMID- 28003353 TI - Staphylococcus aureus in the Intensive Care Unit: Are These Golden Grapes Ripe for a New Approach? AB - Staphylococcus aureus is the leading cause of infection in the setting of critical illness and injury. This pathogen causes life-threatening infection in otherwise healthy individuals and also complicates the clinical course of patients requiring intensive care as a result of their primary medical or surgical disease processes. S. aureus infection in the intensive care unit (ICU) most commonly manifests as sepsis, ventilator-associated pneumonia, and infection of surgical sites and indwelling medical devices. With the epidemic spread of methicillin-resistant S. aureus, many cases of staphylococcal infection in the ICU are now classified as drug resistant, prompting hospital-based screening for methicillin-resistant S. aureus and implementation of both isolation practices and decolonization strategies in ICU patients. The genetic adaptability of S. aureus, heterogeneity of disease presentation, clinical course, and outcome between individual S. aureus-infected ICU patients remains enigmatic, suggesting a need to define disease classification subtypes that inform disease progression and therapy. We propose that S. aureus infection in the ICU now presents a unique opportunity for individualized risk stratification coupled with the investigation of novel approaches to mitigate disease. Given our increasing knowledge of the molecular pathogenesis of S. aureus disease, we suggest that the application of molecular pathological epidemiology to S. aureus infection can usher in a new era of highly focused personalized therapy that may be particularly beneficial in the setting of critical illness and injury. PMID- 28003355 TI - Reply to Allan-Blitz and Klausner. PMID- 28003356 TI - Antiviral Activity of the Combination of Interferon and Ribavirin Against Chikungunya Virus: Are the Results Conclusive? PMID- 28003357 TI - Reply to Scagnolari et al. PMID- 28003358 TI - Heat Shock Protein 90 Modulates Lipid Homeostasis by Regulating the Stability and Function of Sterol Regulatory Element-binding Protein (SREBP) and SREBP Cleavage activating Protein. AB - Sterol regulatory element-binding proteins (SREBPs) are the key transcription factors that modulate lipid biosynthesis. SREBPs are synthesized as endoplasmic reticulum-bound precursors that require proteolytic activation in the Golgi apparatus. The stability and maturation of precursor SREBPs depend on their binding to SREBP cleavage-activating protein (SCAP), which escorts the SCAP-SREBP complex to the Golgi apparatus. In this study, we identified heat shock protein (HSP) 90 as a novel SREBP regulator that binds to and stabilizes SCAP-SREBP. In HepG2 cells, HSP90 inhibition led to proteasome-dependent degradation of SCAP SREBP, which resulted in the down-regulation of SREBP target genes and the reduction in intracellular triglyceride and cholesterol levels. We also demonstrated in vivo that HSP90 inhibition decreased SCAP-SREBP protein, down regulated SREBP target genes, and reduced lipids levels in mouse livers. We propose that HSP90 plays an indispensable role in SREBP regulation by stabilizing the SCAP-SREBP complex, facilitating the activation of SREBP to maintain lipids homeostasis. PMID- 28003359 TI - A Single Amino Acid Mutation Converts (R)-5-Diphosphomevalonate Decarboxylase into a Kinase. AB - The biosynthesis of isopentenyl diphosphate, a fundamental precursor for isoprenoids, via the mevalonate pathway is completed by diphosphomevalonate decarboxylase. This enzyme catalyzes the formation of isopentenyl diphosphate through the ATP-dependent phosphorylation of the 3-hydroxyl group of (R)-5 diphosphomevalonate followed by decarboxylation coupled with the elimination of the 3-phosphate group. In this reaction, a conserved aspartate residue has been proposed to be involved in the phosphorylation step as the general base catalyst that abstracts a proton from the 3-hydroxyl group. In this study, the catalytic mechanism of this rare type of decarboxylase is re-investigated by structural and mutagenic studies on the enzyme from a thermoacidophilic archaeon Sulfolobus solfataricus The crystal structures of the archaeal enzyme in complex with (R)-5 diphosphomevalonate and adenosine 5'-O-(3-thio)triphosphate or with (R)-5 diphosphomevalonate and ADP are newly solved, and theoretical analysis based on the structure suggests the inability of proton abstraction by the conserved aspartate residue, Asp-281. Site-directed mutagenesis on Asp-281 creates mutants that only show diphosphomevalonate 3-kinase activity, demonstrating that the residue is required in the process of phosphate elimination/decarboxylation, rather than in the preceding phosphorylation step. These results enable discussion of the catalytic roles of the aspartate residue and provide clear proof of the involvement of a long predicted intermediate, (R)-3-phospho-5 diphosphomevalonate, in the reaction of the enzyme. PMID- 28003360 TI - Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation. AB - Diabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulin-like growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is down regulated, and cells become resistant to insulin. Under these conditions, the IGF I receptor signals through an alternate scaffold protein, SHPS-1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS-1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS-1 expression in VSMCs in non-diabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF-I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up regulated in IRS-1-/- mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild-type mice during hyperglycemia. These findings illuminate a new function of IRS-1: that of maintaining cells in their normal, differentiated state. Because IRS-1 is down regulated in states of insulin resistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications. PMID- 28003361 TI - Thioredoxin-1 Selectively Activates Transglutaminase 2 in the Extracellular Matrix of the Small Intestine: IMPLICATIONS FOR CELIAC DISEASE. AB - Transglutaminase 2 (TG2) catalyzes transamidation or deamidation of its substrates and is ordinarily maintained in a catalytically inactive state in the intestine and other organs. Aberrant TG2 activity is thought to play a role in celiac disease, suggesting that a better understanding of TG2 regulation could help to elucidate the mechanistic basis of this malady. Structural and biochemical analysis has led to the hypothesis that extracellular TG2 activation involves reduction of an allosteric disulfide bond by thioredoxin-1 (TRX), but cellular and in vivo evidence for this proposal is lacking. To test the physiological relevance of this hypothesis, we first showed that macrophages exposed to pro-inflammatory stimuli released TRX in sufficient quantities to activate their extracellular pools of TG2. By using the C35S mutant of TRX, which formed a metastable mixed disulfide bond with TG2, we demonstrated that these proteins specifically recognized each other in the extracellular matrix of fibroblasts. When injected into mice and visualized with antibodies, we observed the C35S TRX mutant bound to endogenous TG2 as its principal protein partner in the small intestine. Control experiments showed no labeling of TG2 knock-out mice. Intravenous administration of recombinant TRX in wild-type mice, but not TG2 knock-out mice, led to a rapid rise in intestinal transglutaminase activity in a manner that could be inhibited by small molecules targeting TG2 or TRX. Our findings support the potential pathophysiological relevance of TRX in celiac disease and establish the Cys370-Cys371 disulfide bond of TG2 as one of clearest examples of an allosteric disulfide bond in mammals. PMID- 28003362 TI - Phosphorylation of Rap1 by cAMP-dependent Protein Kinase (PKA) Creates a Binding Site for KSR to Sustain ERK Activation by cAMP. AB - Cyclic adenosine monophosphate (cAMP) is an important mediator of hormonal stimulation of cell growth and differentiation through its activation of the extracellular signal-regulated kinase (ERK) cascade. Two small G proteins, Ras and Rap1 have been proposed to mediate this activation. Using HEK293 cells as a model system, we have recently shown that both Ras and Rap1 are required for cAMP signaling to ERKs. However, cAMP-dependent Ras signaling to ERKs is transient and rapidly terminated by PKA phosphorylation of the Raf isoforms C-Raf and B-Raf. In contrast, cAMP-dependent Rap1 signaling to ERKs and Rap1 is potentiated by PKA. We show that this is due to sustained binding of B-Raf to Rap1. One of the targets of PKA is Rap1 itself, directly phosphorylating Rap1a on serine 180 and Rap1b on serine 179. We show that these phosphorylations create potential binding sites for the adaptor protein 14-3-3 that links Rap1 to the scaffold protein KSR. These results suggest that Rap1 activation of ERKs requires PKA phosphorylation and KSR binding. Because KSR and B-Raf exist as heterodimers within the cell, this binding also brings B-Raf to Rap1, allowing Rap1 to couple to ERKs through B Raf binding to Rap1 independently of its Ras-binding domain. PMID- 28003363 TI - Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences beta1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus. AB - Binding of ICAP1 (integrin cytoplasmic domain-associated protein-1) to the cytoplasmic tails of beta1 integrins inhibits integrin activation. ICAP1 also binds to KRIT1 (Krev interaction trapped-1), a protein whose loss of function leads to cerebral cavernous malformation, a cerebrovascular dysplasia occurring in up to 0.5% of the population. We previously showed that KRIT1 functions as a switch for beta1 integrin activation by antagonizing ICAP1-mediated inhibition of integrin activation. Here we use overexpression studies, mutagenesis, and flow cytometry to show that ICAP1 contains a functional nuclear localization signal and that nuclear localization impairs the ability of ICAP1 to suppress integrin activation. Moreover, we find that ICAP1 drives the nuclear localization of KRIT1 in a manner dependent upon a direct ICAP1/KRIT1 interaction. Thus, nuclear cytoplasmic shuttling of ICAP1 influences both integrin activation and KRIT1 localization, presumably impacting nuclear functions of KRIT1. PMID- 28003364 TI - Stromal Interaction Molecule 1 (STIM1) Regulates ATP-sensitive Potassium (KATP) and Store-operated Ca2+ Channels in MIN6 beta-Cells. AB - Stromal interaction molecule 1 (STIM1) regulates store-operated Ca2+ entry (SOCE) and other ion channels either as an endoplasmic reticulum Ca2+-sensing protein or when present in the plasma membrane. However, the role of STIM1 in insulin secreting beta-cells is unresolved. We report that lowering expression of STIM1, the gene that encodes STIM1, in insulin-secreting MIN6 beta-cells with RNA interference inhibits SOCE and ATP-sensitive K+ (KATP) channel activation. The effects of STIM1 knockdown were reversed by transduction of MIN6 cells with an adenovirus gene shuttle vector that expressed human STIM1 Immunoprecipitation studies revealed that STIM1 binds to nucleotide binding fold-1 (NBF1) of the sulfonylurea receptor 1 (SUR1) subunit of the KATP channel. Binding of STIM1 to SUR1 was enhanced by poly-lysine. Our data indicate that SOCE and KATP channel activity are regulated by STIM1. This suggests that STIM1 is a multifunctional signaling effector that participates in the control of membrane excitability and Ca2+ signaling events in beta-cells. PMID- 28003365 TI - Impairment of Cargo Transportation Caused by gbf1 Mutation Disrupts Vascular Integrity and Causes Hemorrhage in Zebrafish Embryos. AB - ADP-ribosylation factor GTPases are activated by guanine nucleotide exchange factors including Gbf1 (Golgi brefeldin A-resistant factor 1) and play important roles in regulating organelle structure and cargo-selective vesicle trafficking. However, the developmental role of Gbf1 in vertebrates remains elusive. In this study, we report the zebrafish mutant line tsu3994 that arises from N-ethyl-N nitrosourea (ENU)-mediated mutagenesis and is characterized by prominent intracerebral and trunk hemorrhage. The mutant embryos develop hemorrhage accompanied by fewer pigments and shorter caudal fin at day 2 of development. The hemorrhage phenotype is caused by vascular breakage in a cell autonomous fashion. Positional cloning identifies a T -> G nucleotide substitution in the 23rd exon of the gbf1 locus, resulting in a leucine -> arginine substitution (L1246R) in the HDS2 domain. The mutant phenotype is mimicked by gbf1 knockouts and morphants, suggesting a nature of loss of function. Experimental results in mammalian cells show that the mutant form Gbf1(L1246R) is unable to be recruited to the Golgi apparatus and fails to activate Arf1 for recruiting COPI complex. The hemorrhage in tsu3994 mutants can be prevented partially and temporally by treating with the endoplasmic reticulum stress/apoptosis inhibitor tauroursodeoxycholic acid or by knocking down the proapoptotic gene baxb Therefore, endothelial endoplasmic reticulum stress and subsequent apoptosis induced by gbf1 deficiency may account for the vascular collapse and hemorrhage. PMID- 28003366 TI - Neuroendocrine Cells of the Prostate Derive from the Neural Crest. AB - The histogenesis of prostatic neuroendocrine cells is controversial: a stem cell hypothesis with a urogenital sinus-derived progeny of all prostatic epithelial cells is opposed by a dual origin hypothesis, favoring the derivation of neuroendocrine cells from the neural crest, with the secretory and basal cells being of urogenital sinus origin. A computer-assisted 3D reconstruction was used to analyze the distribution of chromogranin A immunoreactive cells in serial sections of human fetal prostate specimens (gestation weeks 18 and 25). Immunohistochemical double labeling studies with YFP and serotonin antisera combined with electron microscopy were carried out on double-transgenic Wnt1 Cre/ROSA26-YFP mice showing stable YFP expression in all neural crest-derived cell populations despite loss of Wnt1 expression. 3D reconstruction of the distribution pattern of neuroendocrine cells in the human fetal prostate indicates a migration of paraganglionic cells passing the stroma and reaching the prostate ducts. Double-transgenic mice showed 55% double labeling of periurethral neuroendocrine cells expressing both serotonin and YFP, whereas single serotonin labeling was observed in 36% and exclusive YFP labeling in 9%. The results favor the assumption of a major fraction of neural crest-derived neuroendocrine cells in both the human and murine prostates. PMID- 28003367 TI - Attenuation of Phosphorylation-dependent Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Disease-causing Mutations at the Transmission Interface. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is a multidomain membrane protein that functions as a phosphorylation-regulated anion channel. The interface between its two cytosolic nucleotide binding domains and coupling helices conferred by intracellular loops extending from the channel pore domains has been referred to as a transmission interface and is thought to be critical for the regulated channel activity of CFTR. Phosphorylation of the regulatory domain of CFTR by protein kinase A (PKA) is required for its channel activity. However, it was unclear if phosphorylation modifies the transmission interface. Here, we studied purified full-length CFTR protein using spectroscopic techniques to determine the consequences of PKA-mediated phosphorylation. Synchrotron radiation circular dichroism spectroscopy confirmed that purified full-length wild-type CFTR is folded and structurally responsive to phosphorylation. Intrinsic tryptophan fluorescence studies of CFTR showed that phosphorylation reduced iodide-mediated quenching, consistent with an effect of phosphorylation in burying tryptophans at the transmission interface. Importantly, the rate of phosphorylation-dependent channel activation was compromised by the introduction of disease-causing mutations in either of the two coupling helices predicted to interact with nucleotide binding domain 1 at the interface. Together, these results suggest that phosphorylation modifies the interface between the catalytic and pore domains of CFTR and that this modification facilitates CFTR channel activation. PMID- 28003369 TI - Sharing sensitive health information through social media in the Arab world. AB - Background: Sharing daily activities on social media has become a part of our lifestyle, but little is known about sharing sensitive health information in the Arab world. Objective: The objective of this study is to explore how social media users in the Arab world share sensitive health information through Facebook. Design: A retrospective qualitative analysis was used in the study. Settings and participants: A total of 110 Facebook groups, related to HIV, sickle cell and depression were screened between 5 June and 1 December 2014. Results: Forty four Facebook groups met the inclusion criteria. 28 471 posts were extracted, of which 649 met inclusion criteria. Forty two percent of health information exchanged were related to HIV, 34% to depression and 24% to sickle cell diseases. The majority of postings were from Egypt 21.1%, Saudi Arabia 20%, Algeria 10% and Libya 9.2%. Male posts were 54.2% while 45.8% were posted by females. Individuals utilized Facebook groups to share personal experiences of their disease 31%, in addition to being used for seeking queries 13.6%, offering explicit advice 8.3%, reporting signs and symptoms of the disease 7.3% and posting their communication with the health-care provider 6.6%. Conclusions: Users in the Arab world use social media to exchange sensitive health information, which could have serious implications regarding the privacy of the information shared with other members of the group. On the other hand, sharing health information could have positive effects for patients, such as sharing disease experiences and peer support. However, more work is needed to ensure that Facebook users in the Arab world are aware of the potential consequences of sharing sensitive health information through social media. PMID- 28003368 TI - UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase. AB - Recent genome-wide studies found that patients with hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels suffer from Kaufman oculocerebrofacial syndrome (KOS, also reported as blepharophimosis-ptosis intellectual disability syndrome). The primary cause of KOS is autosomal recessive mutations in the gene UBE3B However, to date, there are no studies that have determined the cellular or enzymatic function of UBE3B. Here, we report that UBE3B is a mitochondrion-associated protein with homologous to the E6-AP Cterminus (HECT) E3 ubiquitin ligase activity. Mutating the catalytic cysteine (C1036A) or deleting the entire HECT domain (amino acids 758-1068) results in loss of UBE3B's ubiquitylation activity. Knockdown of UBE3B in human cells induces changes in mitochondrial morphology and physiology, a decrease in mitochondrial volume, and a severe suppression of cellular proliferation. We also discovered that UBE3B interacts with calmodulin via its N-terminal isoleucine glutamine (IQ) motif. Deletion of the IQ motif (amino acids 29-58) results in loss of calmodulin binding and a significant increase in the in vitro ubiquitylation activity of UBE3B. In addition, we found that changes in calcium levels in vitro disrupt the calmodulin-UBE3B interaction. These studies demonstrate that UBE3B is an E3 ubiquitin ligase and reveal that the enzyme is regulated by calmodulin. Furthermore, the modulation of UBE3B via calmodulin and calcium implicates a role for calcium signaling in mitochondrial protein ubiquitylation, protein turnover, and disease. PMID- 28003370 TI - A literature-based economic evaluation of healthcare preventable adverse events in Europe. AB - Purpose: To establish from the literature, cost of preventable adverse events (PAEs) to member states of the Joint Action European Union Network for Patient Safety and Quality of Care. Data sources: We searched MEDLINE, EMBASE and CINAHL for studies in Europe estimating cost of adverse events (AEs) and PAEs (2000 March 2016). Using data from the literature, we estimated PAE costs based on national 2013 total health expenditure (THE) data reported by World Health Organization and converted to 2015 Euros. Study selection/Data extraction: Information on type, frequency and incremental cost per episode or estimated cost of AEs was extracted. Total annual disability-adjusted life years (DALYs) resulting from PAEs in 30 EU nations were calculated using an estimate from a published study and adjusted for the percentage of AEs considered preventable. Result of data synthesis: Published estimates of costs of AEs and PAEs vary based on the care setting, methodology, population and year conducted. Only one study was from primary care, the majority were conducted in acute care. Nine studies estimated percentage of THE caused by AEs, 13 studies calculated attributable length of stay. We estimated the annual cost of PAEs to the 30 nations in 2015 to be in the range of 17-38 billion Euros, total DALYs lost from AEs as 3.5 million, of which 1.5 million DALYs were likely due to PAEs. Conclusion: The economic burden of AEs and PAEs is substantial. However, whether patient safety interventions will be 'cost saving' depends on the effectiveness and costs of the interventions. PMID- 28003371 TI - Combining Genotype, Phenotype, and Environment to Infer Potential Candidate Genes. AB - Population genomic analysis can be an important tool in understanding local adaptation. Identification of potential adaptive loci in such analyses is usually based on the survey of a large genomic dataset in combination with environmental variables. Phenotypic data are less commonly incorporated into such studies, although combining a genome scan analysis with a phenotypic trait analysis can greatly improve the insights obtained from each analysis individually. Here, we aimed to identify loci potentially involved in adaptation to climate in 283 Loblolly pine (Pinus taeda) samples from throughout the species' range in the southeastern United States. We analyzed associations between phenotypic, molecular, and environmental variables from datasets of 3082 single nucleotide polymorphism (SNP) loci and 3 categories of phenotypic traits (gene expression, metabolites, and whole-plant traits). We found only 6 SNP loci that displayed potential signals of local adaptation. Five of the 6 identified SNPs are linked to gene expression traits for lignin development, and 1 is linked with whole plant traits. We subsequently compared the 6 candidate genes with environmental variables and found a high correlation in only 3 of them (R2 > 0.2). Our study highlights the need for a combination of genotypes, phenotypes, and environmental variables, and for an appropriate sampling scheme and study design, to improve confidence in the identification of potential candidate genes. PMID- 28003372 TI - Population Genetics of Overwintering Monarch Butterflies, Danaus plexippus (Linnaeus), from Central Mexico Inferred from Mitochondrial DNA and Microsatellite Markers. AB - Population genetic variation and demographic history in Danaus plexippus (L.), from Mexico were assessed based on analyses of mitochondrial cytochrome c oxidase subunit I (COI; 658 bp) and subunit II (COII; 503 bp) gene segments and 7 microsatellite loci. The sample of 133 individuals included both migratory monarchs, mainly from 4 overwintering sites within the Monarch Butterfly Biosphere Reserve (MBBR) in central Mexico (states of Michoacan and Mexico), and a nonmigratory population from Irapuato, Guanajuato. Haplotype (h) and nucleotide (pi) diversities were relatively low, averaging 0.466 and 0.00073, respectively, for COI, and 0.629 and 0.00245 for COII. Analysis of molecular variance of the COI data set, which included additional GenBank sequences from a nonmigratory Costa Rican population, showed significant population structure between Mexican migratory monarchs and nonmigratory monarchs from both Mexico and Costa Rica, suggesting limited gene flow between the 2 behaviorally distinct groups. Interestingly, while the COI haplotype frequencies of the nonmigratory populations differed from the migratory, they were similar to each other, despite the great physical distance between them. Microsatellite analyses, however, suggested a lack of structure between the 2 groups, possibly owing to the number of significant deviations from Hardy-Weinberg equilibrium resulting from heterzoygote deficiencies found for most of the loci. Estimates of demographic history of the combined migratory MBBR monarch population, based on the mismatch distribution and Bayesian skyline analyses of the concatenated COI and COII data set (n = 89) suggested a population expansion dating to the late Pleistocene (~35000-40000 years before present) followed by a stable effective female population size (Nef) of about 6 million over the last 10000 years. PMID- 28003373 TI - Chronic Inflammation: Accelerator of Biological Aging. AB - Biological aging is characterized by a chronic low-grade inflammation level. This chronic phenomenon has been named "inflamm-aging" and is a highly significant risk factor for morbidity and mortality in the older persons. The most common theories of inflamm-aging include redox stress, mitochondrial dysfunction, glycation, deregulation of the immune system, hormonal changes, epigenetic modifications, and dysfunction telomere attrition. Inflamm-aging plays a role in the initiation and progression of age-related diseases such as type II diabetes, Alzheimer's disease, cardiovascular disease, frailty, sarcopenia, osteoporosis, and cancer. This review will cover the identification of pathways that control age-related inflammation across multiple systems and its potential causal role in contributing to adverse health outcomes. PMID- 28003374 TI - Effects of Calorie Restriction in Obese Older Adults: The CROSSROADS Randomized Controlled Trial. AB - Background: We lack a comprehensive assessment of the risks and benefits of calorie restriction in older adults at high risk for cardiometabolic disease. Calorie restriction may reduce visceral adipose tissue (VAT) but also have negative effects on lean mass and quality of life. Methods: We conducted a 52 week, randomized controlled trial involving 164 older adults with obesity taking at least one medication for hyperlipidemia, hypertension, or diabetes. Interventions included an exercise intervention alone (Exercise), or with diet modification and body weight maintenance (Maintenance), or with diet modification and energy restriction (Weight Loss). The primary outcome was change in VAT at 12 months. Secondary outcomes included cardiometabolic risk factors, functional status, and quality of life. Results: A total of 148 participants had measured weight at 12 months. Despite loss of -1.6% +/- 0.3% body fat and 4.1% +/- 0.7% initial body weight, Weight Loss did not have statistically greater loss of VAT ( 192.6 +/- 185.2 cm3) or lean mass (-0.4 +/- 0.3 kg) compared with Exercise (VAT = -21.9 +/- 173.7 cm3; lean mass = 0.3 +/- 0.3 kg). Quality of life improved in all groups with no differences between groups. No significant changes in physical function were observed. Weight Loss had significantly greater improvements in blood glucose (-8.3 +/- 3.6 mg/dL, p < .05) and HDL-cholesterol (5.3 +/- 1.9, p < .01) compared with Exercise. There were no group differences in the frequency of adverse events. Conclusions: While moderate calorie restriction did not significantly decrease VAT in older adults at high risk for cardiometabolic disease, it did reduce total body fat and cardiometabolic risk factors without significantly more adverse events and lean mass loss. PMID- 28003375 TI - Assessing and Measuring Chronic Multimorbidity in the Older Population: A Proposal for Its Operationalization. AB - Background: Although the definition of multimorbidity as "the simultaneous presence of two or more chronic diseases" is well established, its operationalization is not yet agreed. This study aims to provide a clinically driven comprehensive list of chronic conditions to be included when measuring multimorbidity. Methods: Based on a consensus definition of chronic disease, all four-digit level codes from the International Classification of Diseases, 10th revision (ICD-10) were classified as chronic or not by an international and multidisciplinary team. Chronic ICD-10 codes were subsequently grouped into broader categories according to clinical criteria. Last, we showed proof of concept by applying the classification to older adults from the Swedish National study of Aging and Care in Kungsholmen (SNAC-K) using also inpatient data from the Swedish National Patient Register. Results: A disease or condition was considered to be chronic if it had a prolonged duration and either (a) left residual disability or worsening quality of life or (b) required a long period of care, treatment, or rehabilitation. After applying this definition in relation to populations of older adults, 918 chronic ICD-10 codes were identified and grouped into 60 chronic disease categories. In SNAC-K, 88.6% had >=2 of these 60 disease categories, 73.2% had >=3, and 55.8% had >=4. Conclusions: This operational measure of multimorbidity, which can be implemented using either or both clinical and administrative data, may facilitate its monitoring and international comparison. Once validated, it may enable the advancement and evolution of conceptual and theoretical aspects of multimorbidity that will eventually lead to better care. PMID- 28003376 TI - Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity. AB - The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus. PMID- 28003378 TI - Chronic Type I IFN Is Sufficient To Promote Immunosuppression through Accumulation of Myeloid-Derived Suppressor Cells. AB - Failure of the immune system to eradicate viruses results in chronic viral infections, which are associated with increased susceptibility to secondary infections. Pathogenic HIV or lymphocytic choriomeningitis virus chronic infections display a persistent type I IFN signature. In chronic lymphocytic choriomeningitis virus infection, blockade of type I IFN signaling partially restores antiviral responses. In a mouse model, we tested whether chronic administration of type I IFN, at doses mimicking chronic viral infection, induced immunosuppression. Chronic exposure of mice to IFN-alpha alone was sufficient to strongly suppress specific CD8+ T cells responses to subsequent vaccinia virus infection. It resulted in the accumulation of Ly6Chi monocytes. These monocytes were similar, phenotypically and functionally, to the myeloid-derived suppressor cells found in cancer because they exerted a potent suppression on CD8+ T cell responses in vitro. They acted at least partly through the l-arginine pathway. In vivo, their elimination restored antiviral CD8+ T cell responses. Our work provides a specific mechanism accounting for the role of IFN-alpha in immunosuppression and predicts that type I IFN modulation will be pivotal to cure human chronic infections, cancer, or autoimmune diseases. PMID- 28003377 TI - IL-10 Receptor Signaling Is Essential for TR1 Cell Function In Vivo. AB - IL-10 is essential to maintain intestinal homeostasis. CD4+ T regulatory type 1 (TR1) cells produce large amounts of this cytokine and are therefore currently being examined in clinical trials as T cell therapy in patients with inflammatory bowel disease. However, factors and molecular signals sustaining TR1 cell regulatory activity still need to be identified to optimize the efficiency and ensure the safety of these trials. We investigated the role of IL-10 signaling in mature TR1 cells in vivo. Double IL-10eGFP Foxp3mRFP reporter mice and transgenic mice with impairment in IL-10 receptor signaling were used to test the activity of TR1 cells in a murine inflammatory bowel disease model, a model that resembles the trials performed in humans. The molecular signaling was elucidated in vitro. Finally, we used human TR1 cells, currently employed for cell therapy, to confirm our results. We found that murine TR1 cells expressed functional IL-10Ralpha. TR1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. TR1 cells required IL-10 receptor signaling to activate p38 MAPK, thereby sustaining IL-10 production, which ultimately mediated their suppressive activity. Finally, we confirmed these data using human TR1 cells. In conclusion, TR1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that to optimize TR1 cell-based therapy, IL-10 receptor expression has to be taken into consideration. PMID- 28003379 TI - Key Residues at Third CDR3beta Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs. AB - The human invariant NK (iNK) TCR is largely composed of the invariant TCR Valpha24-Jalpha18 chain and semivariant TCR Vbeta11 chains with variable CDR3beta sequences. The direct role of CDR3beta in Ag recognition has been studied extensively. Although it was noted that CDR3beta can interact with CDR3alpha, how this interaction might indirectly influence Ag recognition is not fully elucidated. We observed that the third position of Vbeta11 CDR3 can encode an Arg or Ser residue as a result of somatic rearrangement. Clonotypic analysis of the two iNK TCR types with a single amino acid substitution revealed that the staining intensity by anti-Valpha24 Abs depends on whether Ser or Arg is encoded. When stained with an anti-Valpha24-Jalpha18 Ab, human primary invariant NKT cells could be divided into Valpha24 low- and high-intensity subsets, and Arg-encoding TCR Vbeta11 chains were more frequently isolated from the Valpha24 low-intensity subpopulation compared with the Valpha24 high-intensity subpopulation. The Arg/Ser substitution also influenced Ag recognition as determined by CD1d multimer staining and CD1d-restricted functional responses. Importantly, in silico modeling validated that this Ser-to-Arg mutation could alter the structure of the CDR3beta loop, as well as the CDR3alpha loop. Collectively, these results indicate that the Arg/Ser encoded at the third CDR3beta residue can effectively modulate the overall structure of, and Ag recognition by, human iNK TCRs. PMID- 28003380 TI - Control of Circulating IgE by the Vitamin D Receptor In Vivo Involves B Cell Intrinsic and Extrinsic Mechanisms. AB - Vitamin D deficiency is associated with the development of asthma and allergy. The active form of vitamin D [1,25(OH)2D] regulates B cells in vitro and mice without the vitamin D receptor (VDR knockout [KO]) have high serum IgE. Whole body VDR KO, T cell-specific VDR (T-VDR) KO, B cell-specific VDR (B-VDR) KO, and vitamin D deficient mice were used to determine the targets of vitamin D in the regulation of IgE in vivo. Vitamin D deficient, VDR KO, and B-VDR KO mice developed hyper-IgE, whereas T-VDR KO mice did not. The data show that IL-10 secretion by B cells and CD1d expression on IL-10 secreting B cells was lower in VDR KO mice. Mesenteric lymph node cultures from VDR KO and B-VDR KO mice secreted higher IgE ex vivo than wild-type (WT) cultures, and the addition of IL 10 eliminated the difference in IgE production between VDR KO and WT cultures. The increase in IgE in VDR KO mice was 2-fold greater than in the B-VDR KO mice, suggesting that VDR deficiency in non-B cells contributes to hyper-IgE in vivo. Antibiotic depletion of the microbiota raised serum IgE 4-fold in both WT and VDR KO mice. The VDR directly and indirectly regulates IgE production in B cells. Through the VDR, vitamin D is an environmental factor that helps to maintain low serum IgE responses. PMID- 28003381 TI - IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations. AB - In animal models, IL-12 and IL-23 participate in the development of malignant neoplasms of keratinocytes. However, the role of these cytokines in pigmented lesion development and their progression to melanoma has received little attention. IL-12p35, IL-23p19, and IL-12/IL-23p40 knockout mice on a C3H/HeN background, subjected to a melanomagenesis protocol, demonstrated profound differences in susceptibility to nevus initiation, transformation, tumorigenicity, and metastatic potential. IL-23 was found to be essential for melanocyte homeostasis, whereas IL-12 supported nevus development. A direct action of IL-23 on primary melanocytes, shown to be IL-23R+, demonstrated that DNA repair of damaged melanocytes requires IL-23. Furthermore, IL-23 modulated the cutaneous microenvironment by limiting regulatory T cells and IFN-gamma and inhibiting IL-10 production. Neutralizing Ab to IFN-gamma, but not IL-17, inhibited nevus development (p < 0.01). PMID- 28003383 TI - Come See the Bias Inherent in the System! PMID- 28003382 TI - MEK1/2 Inhibition Promotes Macrophage Reparative Properties. AB - Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. Although many of the intracellular signaling pathways involved in the proinflammatory responses of macrophages are well characterized, the components that regulate macrophage reparative properties are less well understood. We identified the MEK1/2 pathway as a key regulator of macrophage reparative properties. Pharmacological inhibition of the MEK1/2 pathway by a MEK1/2 inhibitor (MEKi) significantly increased expression of IL 4/IL-13 (M2)-responsive genes in murine bone marrow-derived and alveolar macrophages. Deletion of the MEK1 gene using LysMCre+/+Mek1fl/fl macrophages as an alternate approach yielded similar results. MEKi enhanced STAT6 phosphorylation, and MEKi-induced changes in M2 polarization were dependent on STAT6. In addition, MEKi treatment significantly increased murine and human macrophage efferocytosis of apoptotic cells, independent of macrophage polarization and STAT6. These phenotypes were associated with increased gene and protein expression of Mertk, Tyro3, and Abca1, three proteins that promote macrophage efferocytosis. We also studied the effects of MEKi on in vivo macrophage efferocytosis and polarization. MEKi-treated mice had increased efferocytosis of apoptotic polymorphonuclear leukocytes instilled into the peritoneum. Furthermore, administration of MEKi after LPS-induced lung injury led to improved recovery of weight, fewer neutrophils in the alveolar compartment, and greater macrophage M2 polarization. Collectively, these results show that MEK1/2 inhibition is capable of promoting the reparative properties of murine and human macrophages. These studies suggest that the MEK1/2 pathway may be a therapeutic target to promote the resolution of inflammation via modulation of macrophage functions. PMID- 28003384 TI - Shaping Attitudes of Psychiatry Residents Toward Forensic Patients. AB - With increasing criminalization of the mentally ill, individuals with mental disorders more frequently come into contact with the legal system. Psychiatrists may find themselves evaluating these individuals in a forensic context or treating them. Unfortunately, resident trainees and psychiatrists may be uncomfortable with forensic matters and treating patients with medicolegal problems. To clarify the attitudes and experience of Canadian psychiatry trainees, attendees at a national psychiatry review course were polled. The results show significant discomfort and a lack of didactic and clinical education concerning these patients and their problems. However, didactic and clinical education were shown to be associated with both increased comfort with and willingness to treat these patients. PMID- 28003385 TI - Evidence for Greater Forensic Education of all Psychiatry Residents. AB - Booth and his colleagues have made an important contribution to the emerging evidence base that shows education in forensic psychiatry topics can improve attitudes toward the field. Given the desinstitutionalization of those with severe mental illness from state psychiatric facilities and the incarceration of many individuals with severe mental illness in correctional facilities, the need to train many more psychiatrists with competence in correctional settings is clear. Simply training more forensic psychiatrists will not both meet the psychiatric needs of incarcerated patients and fulfill the essential roles forensic psychiatrists play in the justice system. Therefore, it is essential that all psychiatry residency programs include time allotted to forensic psychiatry just as time is allotted to the other major subspecialties, including child and adolescent psychiatry, addiction psychiatry, geriatric psychiatry, and psychosomatic medicine. It is likely that the only way to achieve this necessary outcome is through advocacy for the Accreditation Council for Graduate Medical Education (ACGME) to mandate a rotation in forensic psychiatry, for psychiatry residency programs to be accredited. PMID- 28003386 TI - A Proposed Model for Assessing Defendant Competence to Self-Represent. AB - The increasing number of criminal defendants who are choosing to self-represent poses special challenges for legal systems with regard to the types of limits that should be placed on a defendant's basic human right to defend himself without the assistance of counsel. While courts strive to respect the dignity and autonomy of the defendant that are encompassed in this right, they also want to ensure that justice is delivered and the dignity of the courtroom is maintained. The Supreme Court of the United States, in its opinion in Indiana v. Edwards (2008), held that while the right to self-represent recognized in Faretta v. California (1975) remains, states and trial judges can place limits on a defendant's right to self-representation when a defendant lacks the mental capacities needed to prepare and conduct an adequate defense. Following the court's lead, we first examine the types and range of tasks that a defendant who chooses to self-represent must perform. Based on this analysis, we propose a five part model that forensic practitioners can use as a conceptual framework for assessing whether a defendant has deficits that would affect his competence to perform critical self-representation tasks. The five areas that the model recommends practitioners assess are whether a defendant can engage in goal directed behaviors, has sufficient communication skills, can engage in constructive social intercourse, can control his emotions in an adversarial arena, and has the cognitive abilities needed to argue his case adequately. It is recommended that practitioners use the model in their testimony to provide the trier of fact with a comprehensive report of the areas in which a defendant has deficits that will prevent him from protecting his interests in receiving a fair and equitable trial. PMID- 28003387 TI - Enhancing the Value of Expert Assistance in Pro Se Competence Determinations. AB - Forensic mental health practitioners are comfortable assessing criminal defendants' competence to stand trial. They have a long history of making such assessments and a large body of research and scholarship to guide them. In recent years, however, the courts have drawn a distinction between general trial competence (i.e., competence while represented by counsel) and competence to proceed pro se (i.e., competence without counsel). The seminal case on point is Indiana v. Edwards (554 U.S. 164 (2008)). In Edwards, the Court found that general trial competence may provide an inadequate measure of pro se competence. Recognizing the profession's need for direction in making the more particularized assessment called for in pro se cases, White and Gutheil offer a new "Model for Assessing Defendant Competence to Self-Represent." Neatly tied to the elements of pro se competence, discussed in Edwards, and envisioning a fresh new role for experts, consistent with the Court's reasoning, the model provides a valuable resource for forensic practitioners. PMID- 28003388 TI - Characteristics of Misdemeanants Treated for Competency Restoration. AB - There are an estimated 60,000 evaluations annually for competence to stand trial for felony indictments and likely more for misdemeanor indictments. Thus, there is an increasing interest in determining factors associated with a defendant's likelihood of being restored to competence to stand trial. Although previous studies have found that a misdemeanor charge predicts significantly less likelihood of restoration of competence when compared with felony charges, states typically allow treatment facilities less time to restore misdemeanor defendants than felony defendants. As there are no studies examining factors associated with restoration of competence to stand trial for misdemeanor defendants, separately from felony defendants, we conducted a retrospective study to examine demographic, clinical, and forensic characteristics associated with restoration of competence to stand trial of misdemeanor defendants. Almost 70 percent of defendants regained competence to stand trial during the study period. When restorable, defendants regained competence in less than three weeks, on average, which addresses a current question in the field regarding time limits for restoration of competence to stand trial. Single marital status and length of stay in the treatment facility during restoration of competence to stand trial were significantly associated with restorability. States may consider such factors when developing and reviewing time limit policies in consideration of the Jackson v. Indiana ruling and when designing interventions aimed at restoring competence to stand trial to misdemeanor defendants in a cost-efficient manner. PMID- 28003389 TI - Predictors of Competency to Stand Trial in Connecticut's Inpatient Juvenile Competency Restoration Program. AB - There are substantial differences between adults and juveniles in the context of competency restoration. Among juveniles, factors such as maturity level, age, intellectual functioning, and psychiatric diagnoses may affect competency to stand trial. In this study, subjects included all juveniles who were admitted to the Albert J. Solnit Children's Center for inpatient competency restoration in the period spanning January 1, 2005, through December 31, 2012. Sixty-one juveniles were referred during this period, and 58 were included in the final analyses. Several demographic and clinical variables were tested to identify which factors were associated with successful competency restoration. There was a high rate of psychiatric comorbidity in the sample, with 54 of 58 juveniles (93%), having more than one Axis I disorder. IQ was the only significant predictor of successful competency restoration. These findings suggest that cognitive limitations may be a robust predictor of competency restoration among juveniles who are deemed incompetent to stand trial. Furthermore, policy makers may want to consider more specialized services for youths whose intellectual deficits are severe enough to impact their ability to regain competency. Limitations of this study, policy recommendations, and suggestions for future research are discussed. PMID- 28003390 TI - Diagnostic Changes to DSM-5: The Potential Impact on Juvenile Justice. AB - Legal decision-makers have discretion at every stage of processing in the juvenile justice system, and individual youth characteristics (e.g., a particular psychiatric diagnosis) influence how a youth progresses through the system. As a result, changes in diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) may affect the rates of diagnoses among justice-involved youths and subsequently influence youths' experiences within the justice system. In this article, we identify the diagnoses most likely to exert such influences and review the prevalence of diagnosis and psychiatric disorder symptomatology in justice-involved youths. We highlight the DSM-5 changes in diagnostic criteria for internalizing and externalizing disorders that commonly occur among justice-involved youths and the potential impact of these changes on the rates of diagnoses within this population. Finally, we address the limitations of using psychiatric diagnoses in juvenile justice decision making, including the potential for biasing legal decision-makers and the importance of considering context as part of diagnosis. PMID- 28003391 TI - Unsolicited E-mails to Forensic Psychiatrists. AB - E-mail communication is pervasive. Since many forensic psychiatrists have their e mail addresses available online (either on personal websites, university websites, or articles they have authored), they are likely to receive unsolicited e-mails. Although there is an emerging body of literature about exchanging e-mail with patients, there is little guidance about how to respond to e-mails from nonpatients. Therefore, we used a Delphi technique to develop a consensus about salient points for the forensic psychiatrist to consider regarding responding to e-mails from nonpatients and the risks entailed. Four scenarios are described, including e-mails from nonpatients and unknown others requesting advice or help. The potential ethics-related, legal, moral, and practical concerns for forensic psychiatrists are discussed. Finally, potential pitfalls for forensic psychiatrists are described. PMID- 28003392 TI - My Life in Prison. PMID- 28003393 TI - Revisiting the Decision of Death in Hurst v. Florida. AB - The United States Supreme Court has considered the question of whether a judge or a jury must make the findings necessary to support imposition of the death penalty in several notable cases, including Spaziano v. Florida (1984), Hildwin v. Florida (1989), and Ring v. Arizona (2002). In 2016, the U.S. Supreme Court revisited the subject in Hurst v. Florida Florida Statute S 921.141 allows the judge, after weighing aggravating and mitigating circumstances, to enter a sentence of life imprisonment or death. Before Hurst, Florida's bifurcated sentencing proceedings included an advisory sentence from jurors and a separate judicial hearing without juror involvement. In Hurst, the Court revisited the question of whether Florida's capital sentencing scheme violates the Sixth Amendment, which requires a jury, not a judge, to find each fact necessary to impose a sentence of death in light of Ring In an eight-to-one decision, the Court reversed the judgment of the Florida Supreme Court, holding that the Sixth Amendment requires a jury to find the aggravating factors necessary for imposing the death penalty. The role of Florida juries in capital sentencing proceedings was thereby elevated from advisory to determinative. We examine the Court's decision and offer commentary regarding this shift from judge to jury in the final imposition of the death penalty and the overall effect of this landmark case. PMID- 28003394 TI - Retrospective Postconviction Competency to Stand Trial Assessments. PMID- 28003395 TI - The Best-Interest Model of Termination of Parental Rights. PMID- 28003396 TI - Mental Health Staff at Prison Not Liable for Failure to Warn Unidentifiable Victim Upon Release of Inmate. PMID- 28003397 TI - GPS Monitoring for Life. PMID- 28003398 TI - Distinguishing Physician Misconduct from Physician Disability. PMID- 28003399 TI - Criteria for Increasing Involuntary Medication Dosage for a Committed Insanity Acquittee. PMID- 28003400 TI - Defendant's Competence to Participate in a Sexually Violent Offender Commitment Hearing. PMID- 28003401 TI - Habeas Corpus Petitions and the Antiterrorism and Effective Death Penalty Act of 1996. PMID- 28003402 TI - Ability to Waive the Right to Counsel When Competency is Questioned. PMID- 28003405 TI - Challenges and Limitations to Treating ADHD in Incarcerated Populations. PMID- 28003407 TI - Muscarinic acetylcholine receptors control baseline activity and Hebbian stimulus timing-dependent plasticity in fusiform cells of the dorsal cochlear nucleus. AB - Cholinergic modulation contributes to adaptive sensory processing by controlling spontaneous and stimulus-evoked neural activity and long-term synaptic plasticity. In the dorsal cochlear nucleus (DCN), in vitro activation of muscarinic acetylcholine receptors (mAChRs) alters the spontaneous activity of DCN neurons and interacts with N-methyl-d-aspartate (NMDA) and endocannabinoid receptors to modulate the plasticity of parallel fiber synapses onto fusiform cells by converting Hebbian long-term potentiation to anti-Hebbian long-term depression. Because noise exposure and tinnitus are known to increase spontaneous activity in fusiform cells as well as alter stimulus timing-dependent plasticity (StTDP), it is important to understand the contribution of mAChRs to in vivo spontaneous activity and plasticity in fusiform cells. In the present study, we blocked mAChRs actions by infusing atropine, a mAChR antagonist, into the DCN fusiform cell layer in normal hearing guinea pigs. Atropine delivery leads to decreased spontaneous firing rates and increased synchronization of fusiform cell spiking activity. Consistent with StTDP alterations observed in tinnitus animals, atropine infusion induced a dominant pattern of inversion of StTDP mean population learning rule from a Hebbian to an anti-Hebbian profile. Units preserving their initial Hebbian learning rules shifted toward more excitatory changes in StTDP, whereas units with initial suppressive learning rules transitioned toward a Hebbian profile. Together, these results implicate muscarinic cholinergic modulation as a factor in controlling in vivo fusiform cell baseline activity and plasticity, suggesting a central role in the maladaptive plasticity associated with tinnitus pathology.NEW & NOTEWORTHY This study is the first to use a novel method of atropine infusion directly into the fusiform cell layer of the dorsal cochlear nucleus coupled with simultaneous recordings of neural activity to clarify the contribution of muscarinic acetylcholine receptors (mAChRs) to in vivo fusiform cell baseline activity and auditory-somatosensory plasticity. We have determined that blocking the mAChRs increases the synchronization of spiking activity across the fusiform cell population and induces a dominant pattern of inversion in their stimulus timing dependent plasticity. These modifications are consistent with similar changes established in previous tinnitus studies, suggesting that mAChRs might have a critical contribution in mediating the maladaptive alterations associated with tinnitus pathology. Blocking mAChRs also resulted in decreased fusiform cell spontaneous firing rates, which is in contrast with their tinnitus hyperactivity, suggesting that changes in the interactions between the cholinergic and GABAergic systems might also be an underlying factor in tinnitus pathology. PMID- 28003406 TI - Interfacing to the brain's motor decisions. AB - It has been long known that neural activity, recorded with electrophysiological methods, contains rich information about a subject's motor intentions, sensory experiences, allocation of attention, action planning, and even abstract thoughts. All these functions have been the subject of neurophysiological investigations, with the goal of understanding how neuronal activity represents behavioral parameters, sensory inputs, and cognitive functions. The field of brain-machine interfaces (BMIs) strives for a somewhat different goal: it endeavors to extract information from neural modulations to create a communication link between the brain and external devices. Although many remarkable successes have been already achieved in the BMI field, questions remain regarding the possibility of decoding high-order neural representations, such as decision making. Could BMIs be employed to decode the neural representations of decisions underlying goal-directed actions? In this review we lay out a framework that describes the computations underlying goal-directed actions as a multistep process performed by multiple cortical and subcortical areas. We then discuss how BMIs could connect to different decision-making steps and decode the neural processing ongoing before movements are initiated. Such decision-making BMIs could operate as a system with prediction that offers many advantages, such as shorter reaction time, better error processing, and improved unsupervised learning. To present the current state of the art, we review several recent BMIs incorporating decision-making components. PMID- 28003408 TI - Intrinsic functional architecture of the macaque dorsal and ventral lateral frontal cortex. AB - Investigations of the cellular and connectional organization of the lateral frontal cortex (LFC) of the macaque monkey provide indispensable knowledge for generating hypotheses about the human LFC. However, despite numerous investigations, there are still debates on the organization of this brain region. In vivo neuroimaging techniques such as resting-state functional magnetic resonance imaging (fMRI) can be used to define the functional circuitry of brain areas, producing results largely consistent with gold-standard invasive tract tracing techniques and offering the opportunity for cross-species comparisons within the same modality. Our results using resting-state fMRI from macaque monkeys to uncover the intrinsic functional architecture of the LFC corroborate previous findings and inform current debates. Specifically, within the dorsal LFC, we show that 1) the region along the midline and anterior to the superior arcuate sulcus is divided in two areas separated by the posterior supraprincipal dimple, 2) the cytoarchitectonically defined area 6DC/F2 contains two connectional divisions, and 3) a distinct area occupies the cortex around the spur of the arcuate sulcus, updating what was previously proposed to be the border between dorsal and ventral motor/premotor areas. Within the ventral LFC, the derived parcellation clearly suggests the presence of distinct areas: 1) an area with a somatomotor/orofacial connectional signature (putative area 44), 2) an area with an oculomotor connectional signature (putative frontal eye fields), and 3) premotor areas possibly hosting laryngeal and arm representations. Our results illustrate in detail the intrinsic functional architecture of the macaque LFC, thus providing valuable evidence for debates on its organization.NEW & NOTEWORTHY Resting-state functional MRI is used as a complementary method to invasive techniques to inform current debates on the organization of the macaque lateral frontal cortex. Given that the macaque cortex serves as a model for the human cortex, our results help generate more fine-tuned hypothesis for the organization of the human lateral frontal cortex. PMID- 28003409 TI - A circuit for saccadic suppression in the primate brain. AB - Saccades should cause us to see a blur as the eyes sweep across a visual scene. Specific brain mechanisms prevent this by producing suppression during saccades. Neuronal correlates of such suppression were first established in the visual superficial layers of the superior colliculus (SC) and subsequently have been observed in cortical visual areas, including the middle temporal visual area (MT). In this study, we investigated suppression in a recently identified circuit linking visual SC (SCs) to MT through the inferior pulvinar (PI). We examined responses to visual stimuli presented just before saccades to reveal a neuronal correlate of suppression driven by a copy of the saccade command, referred to as a corollary discharge. We found that visual responses were similarly suppressed in SCs, PI, and MT. Within each region, suppression of visual responses occurred with saccades into both visual hemifields, but only in the contralateral hemifield did this suppression consistently begin before the saccade (~100 ms). The consistency of the signal along the circuit led us to hypothesize that the suppression in MT was influenced by input from the SC. We tested this hypothesis in one monkey by inactivating neurons within the SC and found evidence that suppression in MT depends on corollary discharge signals from motor SC (SCi). Combining these results with recent findings in rodents, we propose a complete circuit originating with corollary discharge signals in SCi that produces suppression in visual SCs, PI, and ultimately, MT cortex.NEW & NOTEWORTHY A fundamental puzzle in visual neuroscience is that we frequently make rapid eye movements (saccades) but seldom perceive the visual blur accompanying each movement. We investigated neuronal correlates of this saccadic suppression by recording from and perturbing a recently identified circuit from brainstem to cortex. We found suppression at each stage, with evidence that it was driven by an internally generated signal. We conclude that this circuit contributes to neuronal suppression of visual signals during eye movements. PMID- 28003411 TI - Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat. AB - Cortical slow oscillations (0.1-1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC. In rodents the medial prefrontal cortex (mPFC) consists of several subregions: anterior cingulate cortex (ACC), prelimbic (PrL), infralimbic (IL), and dorsal peduncular cortices (DP). Although each region has a distinct anatomy and function, it is not known whether slow or fast network oscillations differ between subregions in vivo. We have simultaneously recorded slow and fast network oscillations in all four subregions of the rodent mPFC under urethane anesthesia. Slow oscillations were synchronous between the mPFC subregions, and across the hemispheres, with no consistent amplitude difference between subregions. Delta (2-4 Hz) activity showed only small differences between subregions. However, oscillations in the spindle (6-15 Hz)-, beta (20-30 Hz), gamma (30-80 Hz)-, and high-gamma (80-150 Hz)-frequency bands were consistently larger in the dorsal regions (ACC and PrL) compared with ventral regions (IL and DP). In dorsal regions the peak power of spindle, beta, and gamma activity occurred early after onset of the Up-state. In the ventral regions, especially the DP, the oscillatory power in the spindle-, beta-, and gamma-frequency ranges peaked later in the Up-state. These results suggest variations in fast network oscillations within the mPFC that may reflect the different functions and connectivity of these subregions.NEW & NOTEWORTHY We demonstrate, in the urethane anesthetized rat, that within the medial prefrontal cortex (mPFC) there are clear subregional differences in the fast network oscillations associated with the slow oscillation Up-state. These differences, particularly between the dorsal and ventral subregions of the mPFC, may reflect the different functions and connectivity of these subregions. PMID- 28003410 TI - Proximal-distal differences in movement smoothness reflect differences in biomechanics. AB - Smoothness is a hallmark of healthy movement. Past research indicates that smoothness may be a side product of a control strategy that minimizes error. However, this is not the only reason for smooth movements. Our musculoskeletal system itself contributes to movement smoothness: the mechanical impedance (inertia, damping, and stiffness) of our limbs and joints resists sudden change, resulting in a natural smoothing effect. How the biomechanics and neural control interact to result in an observed level of smoothness is not clear. The purpose of this study is to 1) characterize the smoothness of wrist rotations, 2) compare it with the smoothness of planar shoulder-elbow (reaching) movements, and 3) determine the cause of observed differences in smoothness. Ten healthy subjects performed wrist and reaching movements involving different targets, directions, and speeds. We found wrist movements to be significantly less smooth than reaching movements and to vary in smoothness with movement direction. To identify the causes underlying these observations, we tested a number of hypotheses involving differences in bandwidth, signal-dependent noise, speed, impedance anisotropy, and movement duration. Our simulations revealed that proximal-distal differences in smoothness reflect proximal-distal differences in biomechanics: the greater impedance of the shoulder-elbow filters neural noise more than the wrist. In contrast, differences in signal-dependent noise and speed were not sufficiently large to recreate the observed differences in smoothness. We also found that the variation in wrist movement smoothness with direction appear to be caused by, or at least correlated with, differences in movement duration, not impedance anisotropy.NEW & NOTEWORTHY This article presents the first thorough characterization of the smoothness of wrist rotations (flexion-extension and radial-ulnar deviation) and comparison with the smoothness of reaching (shoulder elbow) movements. We found wrist rotations to be significantly less smooth than reaching movements and determined that this difference reflects proximal-distal differences in biomechanics: the greater impedance (inertia, damping, stiffness) of the shoulder-elbow filters noise in the command signal more than the impedance of the wrist. PMID- 28003412 TI - Dicer maintains the identity and function of proprioceptive sensory neurons. AB - Neuronal cell identity is established during development and must be maintained throughout an animal's life (Fishell G, Heintz N. Neuron 80: 602-612, 2013). Transcription factors critical for establishing neuronal identity can be required for maintaining it (Deneris ES, Hobert O. Nat Neurosci 17: 899-907, 2014). Posttranscriptional regulation also plays an important role in neuronal differentiation (Bian S, Sun T. Mol Neurobiol 44: 359-373, 2011), but its role in maintaining cell identity is less established. To better understand how posttranscriptional regulation might contribute to cell identity, we examined the proprioceptive neurons in the dorsal root ganglion (DRG), a highly specialized sensory neuron class, with well-established properties that distinguish them from other neurons in the ganglion. By conditionally ablating Dicer in mice, using parvalbumin (Pvalb)-driven Cre recombinase, we impaired posttranscriptional regulation in the proprioceptive sensory neuron population. Knockout (KO) animals display a progressive form of ataxia at the beginning of the fourth postnatal week that is accompanied by a cell death within the DRG. Before cell loss, expression profiling shows a reduction of proprioceptor specific genes and an increased expression of nonproprioceptive genes normally enriched in other ganglion neurons. Furthermore, although central connections of these neurons are intact, the peripheral connections to the muscle are functionally impaired. Posttranscriptional regulation is therefore necessary to retain the transcriptional identity and support functional specialization of the proprioceptive sensory neurons.NEW & NOTEWORTHY We have demonstrated that selectively impairing Dicer in parvalbumin-positive neurons, which include the proprioceptors, triggers behavioral changes, a lack of muscle connectivity, and a loss of transcriptional identity as observed through RNA sequencing. These results suggest that Dicer and, most likely by extension, microRNAs are crucially important for maintaining proprioception. Additionally, this study hints at the larger question of how neurons maintain their functional and molecular specificity. PMID- 28003413 TI - Single-neuron responses to intraoral delivery of odor solutions in primary olfactory and gustatory cortex. AB - Smell plays a major role in our perception of food. Odorants released inside the mouth during consumption are combined with taste and texture qualities of a food to guide flavor preference learning and food choice behavior. Here, we built on recent physiological findings that implicated primary sensory cortex in multisensory flavor processing. Specifically, we used extracellular recordings in awake rats to characterize responses of single neurons in primary olfactory (OC) and gustatory cortex (GC) to intraoral delivery of odor solutions and compare odor responses to taste and plain water responses. The data reveal responses to olfactory, oral somatosensory, and gustatory qualities of intraoral stimuli in both OC and GC. Moreover, modality-specific responses overlap in time, indicating temporal convergence of multisensory, flavor-related inputs. The results extend previous work suggesting a role for primary OC in mediating influences of taste on smell that characterize flavor perception and point to an integral role for GC in olfactory processing.NEW & NOTEWORTHY Food perception is inherently multisensory, taking into account taste, smell, and texture qualities. However, the neural mechanisms underlying flavor perception remain unknown. Recording neural activity directly from the rat brain while animals consume multisensory flavor stimuli, we demonstrate that information about odor, taste, and mouthfeel of food converges on primary taste and smell cortex. The results suggest that processing of naturalistic, multisensory information involves an interacting network of primary sensory areas. PMID- 28003414 TI - High-velocity stimulation evokes "dense" population response in layer 2/3 vibrissal cortex. AB - Supragranular layers of sensory cortex are known to exhibit sparse firing. In rodent vibrissal cortex, a small fraction of neurons in layer 2 and 3 (L2/3) respond to whisker stimulation. In this study, we combined whole cell recording and two-photon imaging in anesthetized mice and quantified the synaptic response and spiking profile of L2/3 neurons. Previous literature has shown that neurons across layers of vibrissal cortex are tuned to the velocity of whisker movement. We therefore used a broad range of stimuli that included the standard range of velocities (0-1.2 deg/ms) and extended to a "sharp" high-velocity deflection (3.8 deg/ms). Consistent with previous literature, whole cell recording revealed a sparse response to the standard range of velocities: although all recorded cells showed tuning to velocity in their postsynaptic potentials, only a small fraction produced stimulus-evoked spikes. In contrast, the sharp stimulus evoked reliable spiking in the majority of neurons. The action potential threshold of spikes evoked by the sharp stimulus was significantly lower than that of the spontaneous spikes. Juxtacellular recordings confirmed that application of sharp stimulus to single or multiple whiskers produced temporally precise spiking with minimal trial-to-trial spike count variability (Fano factors equal or close to the theoretical minimum). Two-photon imaging further confirmed that most neurons that were not responsive to the standard deflections responded to the sharp stimulus. Altogether, our results indicate that sparseness in L2/3 cortex depends on the choice of stimulus: strong single- or multiwhisker stimulation can induce the transition from sparse to "dense" population response.NEW & NOTEWORTHY In superficial layers of sensory cortex, only a small fraction of neurons fire most of the spontaneous and sensory evoked spikes. However, the functional relevance of such "sparse" activity remains unknown. We found that a "dense" population response is evoked by high-velocity micromotions applied to whiskers. Our results suggest that flashes of precisely timed population response on an almost silent background can provide a high capacity for coding of ecologically salient stimuli. PMID- 28003415 TI - Rapid and flexible whole body postural responses are evoked from perturbations to the upper limb during goal-directed reaching. AB - An important aspect of motor control is the ability to perform tasks with the upper limbs while maintaining whole body balance. However, little is known about the coordination of upper limb voluntary and whole body postural control after mechanical disturbances that require both upper limb motor corrections to attain a behavioral goal and lower limb motor responses to maintain whole body balance. The present study identified the temporal organization of muscle responses and center of pressure (COP) changes following mechanical perturbations during reaching. Our results demonstrate that muscle responses in the upper limb are evoked first (~50 ms), with lower limb muscle activity occurring immediately after, in as little as ~60 ms after perturbation. Hand motion was immediately altered by the load, while COP changes occurred after ~100 ms, when lower limb muscle activity was already present. Our secondary findings showed that both muscle activity and COP changes were influenced by behavioral context (by altering target shape, circle vs. rectangle). Voluntary and postural actions initially directed the hand toward the center of both target types, but after the perturbation upper limb and postural responses redirected the hand toward different spatial locations along the rectangle. Muscle activity was increased for both upper and lower limbs when correcting to the circle vs. the rectangle, and these differences emerged as early as the long-latency epoch (~75-120 ms). Our results demonstrate that postural responses are rapidly and flexibly altered to consider the behavioral goal of the upper limb.NEW & NOTEWORTHY The present work establishes that, when reaching to a target while standing, perturbations applied to the upper limb elicit a rapid response in lower limb muscles. Unlike voluntary movements, postural responses do not occur before corrections of the upper limb. We show the first evidence that corrective postural adjustments are modulated by upper limb behavioral context (target shape). Importantly, this indicates that postural responses take into account upper limb feedback for online control. PMID- 28003417 TI - Development of the atrial septum in relation to postnatal anatomy and interatrial communications. AB - The atrial septum is probe patent in some 30% of the population, and is prone to have overt defects. Atrial septation is the coming together of several myocardial structures and mesenchymal tissues of intracardiac and extracardiac origin that must change identity to myocardium. We propose that the propensity for malformation of the atrial septum reflects this complicated morphogenesis. The morphogenesis of the atrial septum initiates from a ridge of mesenchyme, only a few hundred micrometres long, in the roof of the undivided atrial cavity. By growth of the myocardial primary septum, the mesenchymal ridge will be approximated to, and ultimately fuse, with the mesenchyme of the atrioventricular cushions. This fusion also takes in the so-called vestibular spine, and serves to close the primary atrial foramen. Interatrial communication is maintained by the development of perforations in the myocardial septum that will coalesce to produce the secondary foramen. Late in gestation, an infolding of the right atrial roof, previously identified as the secondary septum, will come to form the roof of the secondary foramen. Muscularisation of the mesenchymal ridge and vestibular spine serves to reinforce the attachment of the primary muscular septum to the atrioventricular insulating plane, with the muscularised components, and the cranial infolding, then producing the rims of the oval fossa as seen in the postnatal heart. We show that other lesions that produce the potential for interatrial shunting are outside the confines of the atrial septum, and hence are best considered as interatrial communications, rather than 'atrial septal defects'. PMID- 28003416 TI - Fractionation of muscle activity in rapid responses to startling cues. AB - Movements in response to acoustically startling cues have shorter reaction times than those following less intense sounds; this is known as the StartReact effect. The neural underpinnings for StartReact are unclear. One possibility is that startling cues preferentially invoke the reticulospinal tract to convey motor commands to spinal motoneurons. Reticulospinal outputs are highly divergent, controlling large groups of muscles in synergistic patterns. By contrast the dominant pathway in primate voluntary movement is the corticospinal tract, which can access small groups of muscles selectively. We therefore hypothesized that StartReact responses would be less fractionated than standard voluntary reactions. Electromyogram recordings were made from 15 muscles in 10 healthy human subjects as they carried out 32 varied movements with the right forelimb in response to startling and nonstartling auditory cues. Movements were chosen to elicit a wide range of muscle activations. Multidimensional muscle activity patterns were calculated at delays from 0 to 100 ms after the onset of muscle activity and subjected to principal component analysis to assess fractionation. In all cases, a similar proportion of the total variance could be explained by a reduced number of principal components for the startling and the nonstartling cue. Muscle activity patterns for a given task were very similar in response to startling and nonstartling cues. This suggests that movements produced in the StartReact paradigm rely on similar contributions from different descending pathways as those following voluntary responses to nonstartling cues.NEW & NOTEWORTHY We demonstrate that the ability to activate muscles selectively is preserved during the very rapid reactions produced following a startling cue. This suggests that the contributions from different descending pathways are comparable between these rapid reactions and more typical voluntary movements. PMID- 28003418 TI - A 72-year-old male with recurrent syncope. AB - CLINICAL INTRODUCTION: A 72-year-old patient presented with recurrent syncope 1 year after a myocardial infarction. Two recent falls resulted in fractures to the femur. Serial troponins were negative and ECG demonstrated fixed inferior ST segment elevation and pathological Q waves. A Holter monitor recorded non sustained ventricular tachycardia. A subsequent echocardiogram was abnormal, and further investigation with a three-dimensional (3D) cardiac CT coronary angiogram was performed (figure 1). QUESTION: What is the most likely diagnosis? Cardiac tumourHypertrophic obstructive cardiomyopathyVentricular aneurysmVentricular diverticulum heartjnl;103/10/800/HEARTJNL2016309670F1F1HEARTJNL2016309670F1Figure 1Cardiac CT coronary angiogram-three-dimensional reconstruction. PMID- 28003419 TI - 47-year-old female with an apical mass. AB - CLINICAL INTRODUCTION: A 47-year-old female with no medical history presented with a sudden collapse. Physical examination, chest X-ray and high-sensitivity cardiac troponin I were normal, however ECG demonstrated anterior T-wave inversion. CT pulmonary angiography was performed which ruled out pulmonary embolism but revealed a non-calcified, homogenous mass at the left ventricular (LV) apex. It was not clear whether this mass was intramyocardial or pericardial. Transthoracic echocardiography confirmed the apical mass but was unable to establish its aetiology. Subsequent cardiac MR (CMR) demonstrated a highly vascular intramyocardial mass on perfusion imaging (Figure 1A, online supplementary video A), with striking, homogenous late gadolinium enhancement (Figure 1B) consistent with a diagnosis of cardiac fibroma.1 The patient underwent successful surgical excision of the mass (see online supplementary image A) and made a good symptomatic recovery, quickly mobilising around the ward. On examination, the patient was afebrile but had a blood pressure of 90/40 mm Hg and raised venous pressure. Postoperative imaging with echocardiography (see online supplementary video B) and CMR (Figure 1C, D and online supplementary video C) revealed some unexpected findings. Study the provided images. QUESTION: What is the next most appropriate management step? Antibiotic therapy for pericardial abscessAnticoagulation for LV thrombusIntravenous fluids with close clinical and imaging follow-up of the intramyocardial haemorrhage and pericardial haematomaReturn to theatre for excision of residual tumourUrgent pericardiocentesis to drain pericardial collection. PMID- 28003421 TI - Progress towards Rapid Detection of Measles Vaccine Strains: a Tool To Inform Public Health Interventions. AB - Rapid differentiation of vaccine from wild-type strains in suspect measles cases is a valuable epidemiological tool that informs the public health response to this highly infectious disease. Few public health laboratories sequence measles virus-positive specimens to determine genotype, and the vaccine-specific real time reverse transcriptase PCR (rRT-PCR) assay described by F. Roy et al. (J. Clin. Microbiol. 55:735-743, 2017, https://doi.org/10.1128/JCM.01879-16) offers a rapid, easily adoptable method to identify measles vaccine strains in suspect cases. PMID- 28003420 TI - Characterization of Metarhizium viride Mycosis in Veiled Chameleons (Chamaeleo calyptratus), Panther Chameleons (Furcifer pardalis), and Inland Bearded Dragons (Pogona vitticeps). AB - Metarhizium viride has been associated with fatal systemic mycoses in chameleons, but subsequent data on mycoses caused by this fungus in reptiles are lacking. The aim of this investigation was therefore to obtain information on the presence of M. viride in reptiles kept as pets in captivity and its association with clinical signs and pathological findings as well as improvement of diagnostic procedures. Beside 18S ribosomal DNA (rDNA) (small subunit [SSU]) and internal transcribed spacer region 1 (ITS-1), a fragment of the large subunit (LSU) of 28S rDNA, including domain 1 (D1) and D2, was sequenced for the identification of the fungus and phylogenetic analysis. Cultural isolation and histopathological examinations as well as the pattern of antifungal drug resistance, determined by using agar diffusion testing, were additionally used for comparison of the isolates. In total, 20 isolates from eight inland bearded dragons (Pogona vitticeps), six veiled chameleons (Chamaeleo calyptratus), and six panther chameleons (Furcifer pardalis) were examined. Most of the lizards suffered from fungal glossitis, stomatitis, and pharyngitis or died due to visceral mycosis. Treatment with different antifungal drugs according to resistance patterns in all three different lizard species was unsuccessful. Sequence analysis resulted in four different genotypes of M. viride based on differences in the LSU fragment, whereas the SSU and ITS-1 were identical in all isolates. Sequence analysis of the SSU fragment revealed the first presentation of a valid large fragment of the SSU of M. viride According to statistical analysis, genotypes did not correlate with differences in pathogenicity, antifungal susceptibility, or species specificity. PMID- 28003422 TI - Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Combined Species Identification and Drug Sensitivity Testing in Mycobacteria. AB - Species identification and drug susceptibility testing (DST) of mycobacteria are important yet complex processes traditionally reserved for reference laboratories. Recent technical improvements in matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has started to facilitate routine mycobacterial identifications in clinical laboratories. In this paper, we investigate the possibility of performing phenotypic MALDI-based DST in mycobacteriology using the recently described MALDI Biotyper antibiotic susceptibility test rapid assay (MBT-ASTRA). We randomly selected 72 clinical Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) strains, subjected them to MBT-ASTRA methodology, and compared its results to current gold standard methods. Drug susceptibility was tested for rifampin, isoniazid, linezolid, and ethambutol (M. tuberculosis, n = 39), and clarithromycin and rifabutin (NTM, n = 33). Combined species identification was performed using the Biotyper Mycobacteria Library 4.0. Mycobacterium-specific MBT-ASTRA parameters were derived (calculation window, m/z 5,000 to 13,000, area under the curve [AUC] of >0.015, relative growth [RG] of <0.5; see the text for details). Using these settings, MBT-ASTRA analyses returned 175/177 M. tuberculosis and 65/66 NTM drug resistance profiles which corresponded to standard testing results. Turnaround times were not significantly different in M. tuberculosis testing, but the MBT ASTRA method delivered on average a week faster than routine DST in NTM. Databases searches returned 90.4% correct species-level identifications, which increased to 98.6% when score thresholds were lowered to 1.65. In conclusion, the MBT-ASTRA technology holds promise to facilitate and fasten mycobacterial DST and to combine it directly with high-confidence species-level identifications. Given the ease of interpretation, its application in NTM typing might be the first in finding its way to current diagnostic workflows. However, further validations and automation are required before routine implementation can be envisioned. PMID- 28003423 TI - Biographical Feature: Thomas F. Smith, Ph.D. PMID- 28003424 TI - Genomic Variation in IbA10G2 and Other Patient-Derived Cryptosporidium hominis Subtypes. AB - In order to improve genotyping and epidemiological analysis of Cryptosporidium spp., genomic data need to be generated directly from a broad range of clinical specimens. Utilizing a robust method that we developed for the purification and generation of amplified target DNA, we present its application for the successful isolation and whole-genome sequencing of 14 different Cryptosporidium hominis patient specimens. Six isolates of subtype IbA10G2 were analyzed together with a single representative each of 8 other subtypes: IaA20R3, IaA23R3, IbA9G3, IbA13G3, IdA14, IeA11G3T3, IfA12G1, and IkA18G1. Parasite burden was measured over a range of more than 2 orders of magnitude for all samples, while the genomes were sequenced to mean depths of between 17* and 490* coverage. Sequence homology-based functional annotation identified several genes of interest, including the gene encoding Cryptosporidium oocyst wall protein 9 (COWP9), which presented a predicted loss-of-function mutation in all the sequence subtypes, except for that seen with IbA10G2, which has a sequence identical to the Cryptosporidium parvum reference Iowa II sequence. Furthermore, phylogenetic analysis showed that all the IbA10G2 genomes form a monophyletic clade in the C. hominis tree as expected and yet display some heterogeneity within the IbA10G2 subtype. The current report validates the aforementioned method for isolating and sequencing Cryptosporidium directly from clinical stool samples. In addition, the analysis demonstrates the potential in mining data generated from sequencing multiple whole genomes of Cryptosporidium from human fecal samples, while alluding to the potential for a higher degree of genotyping within Cryptosporidium epidemiology. PMID- 28003425 TI - Evaluation of Pyrrolidonyl Arylamidase Activity in Staphylococcus delphini. AB - Clinical reference textbooks lack data for pyrrolidonyl arylamidase (PYR) activity in Staphylococcus delphini This study evaluated PYR activities of 21 S. delphini strains by reference broth, rapid disc, and rapid slide methods. Species and subgroup identifications were confirmed by nucleic acid-based methods and included nine group A and 12 group B strains. Testing by rapid PYR methods with products from four manufacturers was performed at two testing locations, and, with the exception of one strain tested at one location using reagents from one manufacturer, each S. delphini strain tested positive for PYR activity. Therefore, PYR may be a useful single-test adjunct for distinguishing Staphylococcus aureus from S. delphini and other members of the Staphylococcus intermedius group. PMID- 28003426 TI - Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins. AB - Hepatocellular carcinoma (HCC) is a common form of cancer with prevalence worldwide. There are many factors that lead to the development and progression of HCC. This study aimed to identify potential new tumor suppressors, examine their function as cell cycle modulators, and investigate their impact on the cyclin family of proteins and cyclin-dependent kinases (CDKs). In this study, the pyruvate dehydrogenase kinase (PDK)4 gene was shown to have potential tumor suppressor characteristics. PDK4 expression was significantly downregulated in human HCC. Pdk4-/- mouse liver exhibited a consistent increase in cell cycle regulator proteins, including cyclin D1, cyclin E1, cyclin A2, some associated CDKs, and transcription factor E2F1. PDK4-knockdown HCC cells also progressed faster through the cell cycle, which concurrently expressed high levels of cyclins and E2F1 as seen in the Pdk4-/- mice. Interestingly, the induced cyclin E1 and cyclin A2 caused by Pdk4 deficiency was repressed by arsenic treatment in mouse liver and in HCC cells. E2f1 deficiency in E2f1-/- mouse liver or knockdown E2F1 using small hairpin RNAs in HCC cells significantly decreased cyclin E1, cyclin A2, and E2F1 proteins. In contrast, inhibition of PDK4 activity in HCC cells increased cyclin E1, cyclin A2, and E2F1 proteins. These findings demonstrate that PDK4 is a critical regulator of hepatocyte proliferation via E2F1-mediated regulation of cyclins. PMID- 28003427 TI - Characterization of C-S lyase from Lactobacillus delbrueckii subsp. bulgaricus ATCC BAA-365 and its potential role in food flavour applications. AB - Volatile thiols have substantial impact on the aroma of many beverages and foods. Thus, the control of their formation, which has been linked to C-S lyase enzymatic activities, is of great significance in industrial applications involving food flavours. Herein, we have carried out a spectroscopic and functional characterization of a putative pyridoxal 5'-phosphate (PLP)-dependent C-S lyase from the lactic acid bacterium Lactobacillus delbrueckii subsp. bulgaricus ATCC BAA-365 (LDB C-S lyase). Recombinant LDB C-S lyase exists as a tetramer in solution and shows spectral properties of enzymes containing PLP as cofactor. The enzyme has a broad substrate specificity toward sulphur-containing amino acids with aminoethyl-L-cysteine and L-cystine being the most effective substrates over L-cysteine and L-cystathionine. Notably, the protein also reveals cysteine-S-conjugate beta-lyase activity in vitro, and is able to cleave a cysteinylated substrate precursor into the corresponding flavour-contributing thiol, with a catalytic efficiency higher than L-cystathionine. Contrary to similar enzymes of other lactic acid bacteria however, LDB C-S lyase is not capable of alpha,gamma-elimination activity towards L-methionine to produce methanethiol, which is a significant compound in flavour development. Based on our results, future developments can be expected regarding the flavour-forming potential of Lactobacillus C-S lyase and its use in enhancing food flavours. PMID- 28003428 TI - Evaluation of compound selectivity of aldo-keto reductases using differential scanning fluorimetry. AB - Inhibitors of AKR1B10 belonging to the aldo-keto reductase (AKR) superfamily are considered promising candidates for anti-cancer drugs. AKR1B1, a structurally similar isoform of AKR1B10, is involved in glucose metabolism. Thus, selective inhibition of AKR1B10 is required for the development of anti-cancer drugs. In this study, we first compared correlations between melting temperature and the 50% inhibition concentration obtained from differential scanning fluorimetry (DSF) and an enzyme inhibitory experiment, respectively, and a good correlation was found, except for compounds with low solubility. This result indicates that the DSF method is useful for drug screening for the AKR superfamily. We then evaluated their selectivity as inhibitors against all seven major human AKR1 family proteins and found that C18 is most specific for AKR1B10. PMID- 28003429 TI - Molecular cloning of rat acss3 and characterization of mammalian propionyl-CoA synthetase in the liver mitochondrial matrix. AB - Among the three acyl-CoA synthetase short-chain family members (ACSS), ACSS3 is poorly characterized. To characterize ACSS3, we performed molecular cloning and protein expression of rat acss3 and determined its intracellular localization, tissue distribution, and substrate specificity. Transient expression of rat ACSS3 in HeLa cells resulted in a 10-fold increase of acetyl-CoA synthetase activity compared with that in control cells. The acss3 transcripts are expressed in a wide range of tissues, with the highest levels observed in liver tissue followed by kidney tissue. Subcellular fractionation using liver tissue showed that ACSS3 is localized into the mitochondrial matrix. Among the short-chain fatty acids examined, recombinant ACSS3, purified from Escherichia coli cells transformed with the plasmid containing rat acss3, preferentially utilized propionate with a KM value of 0.19 mM. Knockdown of acss3 in HepG2 cells resulted in a significant decrease of ACSS3 expression level and propionyl-CoA synthetase activity in cell lysates. Levels of ACSS3 in the liver and the activity of propionyl-CoA synthetase in the mitochondria were significantly increased by fasting. These results suggested that ACSS3 is a liver mitochondrial matrix enzyme with high affinity to propionic acid, and its expression level is upregulated under ketogenic conditions. PMID- 28003430 TI - Conformational changes in inhibitory PAS domain protein associated with binding of HIF-1alpha and Bcl-xL in living cells. AB - Inhibitory PAS domain protein (IPAS) is a dual function protein acting as a transcriptional repressor and as a pro-apoptotic protein. Simultaneous dual-color single-molecule imaging of EGFP-IPAS coexpressed with Mit-TagRFP-T in living HeLa cells revealed that fraction of EGFP-IPAS was arrested in the nucleus and on mitochondria. Transiently expressed Cerulean-IPAS in HEK293T cells was present in nuclear speckles when coexpressed with Citrine-HIF-1alpha or Citrine-HLF. Fluorescence lifetime imaging microscopy (FLIM) analysis of Citrine-IPAS-Cerulean in living CHO-K1 cells clarified the presence of intramolecular FRET. Reduced lifetimes of the donor were partially restored by coexpression of HIF-1alpha or Bcl-xL, binding proteins of IPAS in the nucleus and mitochondria, respectively. This alteration in lifetimes demonstrates that conformational changes occurred in IPAS by their binding. PMID- 28003431 TI - Targeting the Hippo signalling pathway for cancer treatment. AB - The Hippo signalling pathway monitors cell-cell contact and external factors that shape tissue structure. In mice, tumourigenesis and developmental abnormalities are common consequences of dysregulated Hippo signalling. Expression of Hippo pathway components is also frequently altered in human tumours and correlates with poor prognosis and reduced patient survival. Thus, the Hippo pathway is an attractive anti-cancer target. Here, we provide an overview of the function and regulation of Hippo signalling components and summarize progress to date on the development of agents able to regulate Hippo signalling for cancer therapy. PMID- 28003432 TI - Autophagy-independent function of Atg8 in lipid droplet dynamics in yeast. AB - Dynamic features of lipid droplets include growth and degradation of the organelle. Autophagy, a system for the transport of cytoplasmic components to be degraded into the lysosome/vacuole, is regarded to be responsible for the degradation of lipid droplets. Atg8 protein in the yeast Saccharomyces cerevisiae is recruited to membrane structures synthesized during autophagy via a lipidation process. In this study, we report a novel function of Atg8 in lipid droplet dynamics. We found that loss of Atg8 specifically resulted in a decrease in the quantity of lipid droplets in cells at stationary phase. This protein was detected in a lipid droplet fraction independent of its lipidation. Loss of Atg8 hemifusion activity also caused a decrease in the quantity of lipid droplets. Consistent with these results, isolated lipid droplets underwent assembly into large clusters when incubated with Atg8 possessing hemifusion activity. The loss of Atg8 did not reduce the quantity of lipid droplets in a mutant defective in lipolysis, another system for lipid droplet degradation, which strongly suggests the function of Atg8 in antagonizing lipolysis. Together these results indicate a specific function of Atg8 in maintaining the quantity of lipid droplets that is independent of its autophagic function. PMID- 28003433 TI - Angiodysplasia in embryo lacking protein arginine methyltransferase 1 in vascular endothelial cells. AB - Protein arginine methyltransferase 1 (PRMT1) is involved in multiple cellular functions including proliferation and differentiation. Although PRMT1 is expressed in vascular endothelial cells (ECs), which are responsible for angiogenesis during embryonic development, its role has remained elusive. In this study, we generated endothelial-specific prmt1-knockout (Prmt1-ECKO) mice, and found that they died before embryonic day 15. The superficial temporal arteries in these embryos were poorly perfused with blood, and whole-mount 3D imaging revealed dilated and segmentalized luminal structures in Prmt1-ECKO fetuses in comparison with those of controls. Our findings provide evidence that PRMT1 is important for embryonic vascular formation. PMID- 28003434 TI - Gene cloning, recombinant expression, purification and characterization of l methionine decarboxylase from Streptomyces sp. 590. AB - l-Methionine decarboxylase (MetDC) from Streptomyces sp. 590 depends on pyridoxal 5'-phosphate and catalyzes the non-oxidative decarboxylation of l-methionine to produce 3-methylthiopropylamine and carbon dioxide. MetDC gene (mdc) was determined to consist of 1,674 bp encoding 557 amino acids, and the amino acid sequence is similar to that of l-histidine decarboxylases and l-valine decarboxylases from Streptomyces sp. strains. The mdc gene was cloned and recombinant MetDC was heterologously expressed by Escherichia coli. The purification of recombinant MetDC was carried out by DEAE-Toyopearl and Ni-NTA agarose column chromatography. The recombinant enzyme was homodimeric with a molecular mass of 61,000 Da and showed optimal activity between 45 to 55 degrees C and at pH 6.6, and the stability below 30 degrees C and between pH 4.6 to 7.0. l-Methionine and l-norleucine were good substrates for MetDC. The Michaelis constants for l-methionine and l-norleucine were 30 and 73 mM, respectively. The recombinant MetDC (0.50 U/ml) severely inhibited growth of human tumour cells A431 (epidermoid ovarian carcinoma cell line) and MDA-MB-231 (breast cancer cell line), however showed relatively low cytotoxicity for human normal cell NHDF-Neo (dermal fibroblast cell line from neonatal foreskin). This study revealed the properties of the gene and the protein sequence of MetDC for the first time. PMID- 28003435 TI - Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource. AB - Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies. PMID- 28003437 TI - Editor's Highlight: Prospective Analyses of Volatile Organic Compounds in Obstructive Sleep Apnea Patients. AB - Various volatile organic compounds (VOCs) are known to be toxic. Although exhaled VOC patterns change in obstructive sleep apnea (OSA) patients, individual VOC profiles are not fully determined. The primary outcome was VOC characterizations; secondary outcomes included their relationships with sleep and clinical parameters in OSA patients. We prospectively examined 32 OSA patients with an apnea-hypopnea index (AHI) >= 15 by full polysomnography, and 33 age- and sex matched controls without obvious OSA symptoms. Nine severe OSA patients were examined before and after continuous positive airway pressure (CPAP) treatment. By applying a method which eliminates environmental VOC influences, exhaled VOCs were identified by gas chromatography (GC)-mass spectrometry, and their concentrations were determined by GC. Exhaled aromatic hydrocarbon concentrations (toluene, ethylbenzene, p-xylene, and phenylacetic acid) in the severe OSA groups (AHI >= 30) and exhaled saturated hydrocarbon concentrations (hexane, heptane, octane, nonane, and decane) in the most severe OSA group (AHI >= 60) were higher than those in the control group. Exhaled isoprene concentrations were increased in all OSA groups (AHI >= 15); acetone concentration was increased in the most severe OSA group. Ethylbenzene, p-xylene, phenylacetic acid, and nonane concentrations were increased according to OSA severity, and correlated with AHI, arousal index, and duration of percutaneous oxygen saturation (SpO2) <= 90%. Multiple regression analyses revealed these 4 VOC levels were associated with the duration of SpO2 <= 90%. Isoprene and acetone decreased after CPAP treatment. OSA increased some toxic VOCs, and some correlated with OSA severity. CPAP treatment possibly ameliorates these productions. PMID- 28003436 TI - Integrating transcriptomic and proteomic data for accurate assembly and annotation of genomes. AB - Complementing genome sequence with deep transcriptome and proteome data could enable more accurate assembly and annotation of newly sequenced genomes. Here, we provide a proof-of-concept of an integrated approach for analysis of the genome and proteome of Anopheles stephensi, which is one of the most important vectors of the malaria parasite. To achieve broad coverage of genes, we carried out transcriptome sequencing and deep proteome profiling of multiple anatomically distinct sites. Based on transcriptomic data alone, we identified and corrected 535 events of incomplete genome assembly involving 1196 scaffolds and 868 protein coding gene models. This proteogenomic approach enabled us to add 365 genes that were missed during genome annotation and identify 917 gene correction events through discovery of 151 novel exons, 297 protein extensions, 231 exon extensions, 192 novel protein start sites, 19 novel translational frames, 28 events of joining of exons, and 76 events of joining of adjacent genes as a single gene. Incorporation of proteomic evidence allowed us to change the designation of more than 87 predicted "noncoding RNAs" to conventional mRNAs coded by protein-coding genes. Importantly, extension of the newly corrected genome assemblies and gene models to 15 other newly assembled Anopheline genomes led to the discovery of a large number of apparent discrepancies in assembly and annotation of these genomes. Our data provide a framework for how future genome sequencing efforts should incorporate transcriptomic and proteomic analysis in combination with simultaneous manual curation to achieve near complete assembly and accurate annotation of genomes. PMID- 28003438 TI - From the Cover: BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms. AB - Polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with adverse neurodevelopmental outcomes in children and preclinical models; however, the mechanisms by which PBDEs cause developmental neurotoxicity remain speculative. The structural similarity between PBDEs and nondioxin-like (NDL) polychlorinated biphenyls (PCBs) suggests shared toxicological properties. Consistent with this, both NDL PCBs and PBDEs have been shown to stabilize ryanodine receptors (RyRs) in the open configuration. NDL PCB effects on RyR activity are causally linked to increased dendritic arborization, but whether PBDEs similarly enhance dendritic growth is not known. In this study, we quantified the effects of individual PBDE congeners on not only dendritic but also axonal growth since both are regulated by RyR-dependent mechanisms, and both are critical determinants of neuronal connectivity. Neuronal-glial co-cultures dissociated from the neonatal rat hippocampus were exposed to BDE-47 or BDE-49 in the culture medium. At concentrations ranging from 20 pM to 2 uM, neither PBDE congener altered dendritic arborization. In contrast, at concentrations >= 200 pM, both congeners delayed neuronal polarization resulting in significant inhibition of axonal outgrowth during the first few days in vitro. The axon inhibitory effects of these PBDE congeners occurred independent of cytotoxicity, and were blocked by pharmacological antagonism of RyR or siRNA knockdown of RyR2. These results demonstrate that the molecular and cellular mechanisms by which PBDEs interfere with neurodevelopment overlap with but are distinct from those of NDL PCBs, and suggest that altered patterns of neuronal connectivity may contribute to the developmental neurotoxicity of PBDEs. PMID- 28003439 TI - From the Cover: Prolonged Exposure to Volatile Anesthetic Isoflurane Worsens the Outcome of Polymicrobial Abdominal Sepsis. AB - Sepsis continues to result in high morbidity and mortality. General anesthesia is often administered to septic patients, but the impacts of general anesthesia on host defense are not well understood. General anesthesia can be given by volatile and intravenous anesthetics. Our previous in vitro study showed that volatile anesthetic isoflurane directly inhibits leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), critical adhesion molecules on leukocytes. Thus, the role of isoflurane exposure on in vivo LFA-1 and Mac-1 function was examined using polymicrobial abdominal sepsis model in mice. As a comparison, intravenous anesthetic propofol was given to a group of mice. Wild type, LFA-1, Mac-1, and adhesion molecule-1 knockout mice were used. Following the induction of polymicrobial abdominal sepsis by cecal ligation and puncture, groups of mice were exposed to isoflurane for either 2 or 6 h, or to propofol for 6 h, and their outcomes were examined. Bacterial loads in tissues and blood, neutrophil recruitment to the peritoneal cavity and phagocytosis were studied. Six hours of isoflurane exposure worsened the outcome of abdominal sepsis (P < .0001) with higher bacterial loads in tissues, but 2 h of isoflurane or 6 h of propofol exposure did not. Isoflurane impaired neutrophil recruitment to the abdominal cavity by inhibiting LFA-1 function. Isoflurane also impaired bacterial phagocytosis via complement receptors including Mac-1. In conclusion, prolonged isoflurane exposure worsened the outcome of experimental polymicrobial abdominal sepsis and was associated with impaired neutrophil recruitment and bacterial phagocytosis via reduced LFA-1 and Mac-1 function. PMID- 28003440 TI - From the Cover: ZnO Nanoparticles Enhanced Germ Cell Apoptosis in Caenorhabditis elegans, in Comparison with ZnCl2. AB - Effects of ZnO NPs and ionic Zn on germline apoptosis and the regulation of genes in the apoptosis pathway were investigated in vivo using the model organism Caenorhabditis elegans.Age synchronized Bristol N2 worms were exposed to ZnO NPs and ZnCl2 at concentrations of 6.14 * 10-1, 61.4, and 614 MUM form larval stage 1 (L1) to early adulthood. Possible ZnO nanoparticles were observed under the worm cuticle and also in the gonadal region by transmission electron microscopy (TEM). ZnO NPs and ZnCl2 both significantly increased the number of apoptotic cells as compared with controls in the 61.4 and 614 MUM treatment groups (P < .05). However, ZnO NPs induced more apoptotic cells in the 61.4 MUM treatment than ZnCl2 (P < .05), suggesting ZnO NP is more potent in inducing apoptosis at specific exposure concentration. Findings using the MD701 (bcIs39 [(lim-7)ced 1p::GFP + lin-15(+)]) strain further confirmed the observations in N2 strain. Genes involved in the apoptosis pathway (ced-13, ced-3, ced-4, ced-9, cep-1, dpl 1, efl-1, efl-2, egl-1, egl-38, lin-35, pax-2, and sir-2.1) were in general upregulated in response to ZnO NP exposure. The cep-1/p53 gene was up-regulated in gene expression assay. In the cep-1 loss of function mutant, no significant increase in apoptosis was observed. Therefore, the increased apoptosis resulting from ZnO NPs exposure is likely cep-1/p53 dependent. This study provides evidence that ZnO nanoparticles affect germ cell apoptotic machinery as a potential mechanism of reproductive toxicity. PMID- 28003441 TI - Home ranges, habitat and body mass: simple correlates of home range size in ungulates. AB - The spatial scale of animal space use, e.g. measured as individual home range size, is a key trait with important implications for ecological and evolutionary processes as well as management and conservation of populations and ecosystems. Explaining variation in home range size has therefore received great attention in ecological research. However, few studies have examined multiple hypotheses simultaneously, which is important provided the complex interactions between life history, social system and behaviour. Here, we review previous studies on home range size in ungulates, supplementing with a meta-analysis, to assess how differences in habitat use and species characteristics affect the relationship between body mass and home range size. Habitat type was the main factor explaining interspecific differences in home range size after accounting for species body mass and group size. Species using open habitats had larger home ranges for a given body mass than species using closed habitats, whereas species in open habitats showed a much weaker allometric relationship compared with species living in closed habitats. We found no support for relationships between home range size and species diet or mating system, or any sexual differences. These patterns suggest that the spatial scale of animal movement mainly is a combined effect of body mass, group size and the landscape structure. Accordingly, landscape management must acknowledge the influence of spatial distribution of habitat types on animal behaviour to ensure natural processes affecting demography and viability of ungulate populations. PMID- 28003442 TI - The heritability of chimpanzee and human brain asymmetry. AB - Human brains are markedly asymmetric in structure and lateralized in function, which suggests a relationship between these two properties. The brains of other closely related primates, such as chimpanzees, show similar patterns of asymmetry, but to a lesser degree, indicating an increase in anatomical and functional asymmetry during hominin evolution. We analysed the heritability of cerebral asymmetry in chimpanzees and humans using classic morphometrics, geometric morphometrics, and quantitative genetic techniques. In our analyses, we separated directional asymmetry and fluctuating asymmetry (FA), which is indicative of environmental influences during development. We show that directional patterns of asymmetry, those that are consistently present in most individuals in a population, do not have significant heritability when measured through simple linear metrics, but they have marginally significant heritability in humans when assessed through three-dimensional configurations of landmarks that reflect variation in the size, position, and orientation of different cortical regions with respect to each other. Furthermore, genetic correlations between left and right hemispheres are substantially lower in humans than in chimpanzees, which points to a relatively stronger environmental influence on left-right differences in humans. We also show that the level of FA has significant heritability in both species in some regions of the cerebral cortex. This suggests that brain responsiveness to environmental influences, which may reflect neural plasticity, has genetic bases in both species. These results have implications for the evolvability of brain asymmetry and plasticity among humans and our close relatives. PMID- 28003443 TI - The emergence of core eudicots: new floral evidence from the earliest Late Cretaceous. AB - Eudicots, the most diverse of the three major clades of living angiosperms, are first recognized in the latest Barremian-earliest Aptian. All Early Cretaceous forms appear to be related to species-poor lineages that diverged before the rise of core eudicots, which today comprise more than 70% of angiosperm species. Here, we report the discovery of a well-preserved flower, Caliciflora mauldinensis, from the earliest Late Cretaceous, with unequivocal core eudicot features, including five sepals, five petals and two whorls of stamens borne on the rim of a floral cup containing three free carpels. Pollen is tricolporate. Carpels mature into follicular fruitlets. This character combination suggests a phylogenetic position among rosids, but more specific assignment is precluded by complex patterns of character evolution among the very large number of potentially relevant extant taxa. The whorled floral organization is consistent with ideas that this stable pattern evolved early and was a prerequisite for more integrated patterns of floral architecture that evolved later. However, limited floral synorganization in Caliciflora and all earlier eudicot flowers recognized so far, calls into question hypotheses that substantial diversification of core eudicots had already occurred by the end of the Early Cretaceous. PMID- 28003444 TI - Specialized proteinine rove beetles shed light on insect-fungal associations in the Cretaceous. AB - Insects and fungi have a long history of association in shared habitats. Fungus feeding, or mycophagy, is remarkably widespread in beetles (Coleoptera) and appears to be a primitive feeding habit that preceded feeding on plant tissues. Numerous Mesozoic beetles belonging to extant fungus-associated families are known, but direct fossil evidence elucidating mycophagy in insects has remained elusive. Here, we report a remarkable genus and species, Vetuproteinus cretaceus gen. et sp. nov., belonging to a new tribe (Vetuproteinini trib. nov.) of the extant rove beetle subfamily Proteininae (Staphylinidae) in Mid-Cretaceous Burmese amber. The mouthparts of this beetle have a markedly enlarged protruding galea bearing an apparent spore brush, a specialized structure we infer was used to scrape spores off surfaces and direct them into the mouth, as in multiple modern spore-feeding beetles. Considering the long evolutionary history of Fungi, the Mid-Cretaceous beetles likely fed on ancient Basidiomycota and/or Ascomycota fungi or spore-producing organisms such as slime moulds (Myxomycetes). The discovery of the first Mesozoic proteinine illustrates the antiquity of the subfamily, and suggests that ancestral Proteininae were already diverse and widespread in Pangaea before the supercontinent broke up. PMID- 28003445 TI - Distance-decay effect in stone tool transport by wild chimpanzees. AB - Stone tool transport leaves long-lasting behavioural evidence in the landscape. However, it remains unknown how large-scale patterns of stone distribution emerge through undirected, short-term transport behaviours. One of the longest studied groups of stone-tool-using primates are the chimpanzees of the Tai National Park in Ivory Coast, West Africa. Using hammerstones left behind at chimpanzee Panda nut-cracking sites, we tested for a distance-decay effect, in which the weight of material decreases with increasing distance from raw material sources. We found that this effect exists over a range of more than 2 km, despite the fact that observed, short-term tool transport does not appear to involve deliberate movements away from raw material sources. Tools from the millennia-old Noulo site in the Tai forest fit the same pattern. The fact that chimpanzees show both complex short-term behavioural planning, and yet produce a landscape-wide pattern over the long term, raises the question of whether similar processes operate within other stone-tool-using primates, including hominins. Where hominin landscapes have discrete material sources, a distance-decay effect, and increasing use of stone materials away from sources, the Tai chimpanzees provide a relevant analogy for understanding the formation of those landscapes. PMID- 28003446 TI - Transcriptional regulation of a horizontally transferred gene from bacterium to chordate. AB - The horizontal transfer of genes between distantly related organisms is undoubtedly a major factor in the evolution of novel traits. Because genes are functionless without expression, horizontally transferred genes must acquire appropriate transcriptional regulations in their recipient organisms, although the evolutionary mechanism is not known well. The defining characteristic of tunicates is the presence of a cellulose containing tunic covering the adult and larval body surface. Cellulose synthase was acquired by horizontal gene transfer from Actinobacteria. We found that acquisition of the binding site of AP-2 transcription factor was essential for tunicate cellulose synthase to gain epidermal-specific expression. Actinobacteria have very GC-rich genomes, regions of which are capable of inducing specific expression in the tunicate epidermis as the AP-2 binds to a GC-rich region. Therefore, the actinobacterial cellulose synthase could have been potentiated to evolve its new function in the ancestor of tunicates with a higher probability than the evolution depending solely on a spontaneous event. PMID- 28003447 TI - Sensory specificity and speciation: a potential neuronal pathway for host fruit odour discrimination in Rhagoletis pomonella. AB - Behavioural changes in habitat or mate choice can trigger population divergence, leading to speciation. However, little is known about the neurological bases for such changes. Rhagoletis pomonella (Diptera: Tephritidae) is a model for ecological speciation via host plant shifts. Within the past 180 years, Rhagoletis flies infesting hawthorn (Crataegus spp.) shifted to attack domesticated apple (Malus pumila). The two populations differ in their olfactory preferences for apple versus hawthorn fruit. Here, we looked for patterns of sensory organization that may have contributed to this shift by characterizing the morphology, specificity and distribution of olfactory sensory neurons (OSNs) on the antennae of Rhagoletis responding to host fruit and non-host volatiles. Of 28 OSN classes identified, two colocalized OSN pairs were found that specifically responded to the major behavioural attractant and antagonist volatiles for each fly population. A reversal in the response of these OSNs to fruit volatiles, either through a switch in receptor expression between these paired neurons or changes in neuronal projections in the brain, could therefore account for the behavioural difference between apple and hawthorn flies. The finding supports the hypothesis that relatively minor changes in olfactory sensory pathways may contribute to rapid host shifting and divergence in Rhagoletis. PMID- 28003448 TI - The costs of a big brain: extreme encephalization results in higher energetic demand and reduced hypoxia tolerance in weakly electric African fishes. AB - A large brain can offer several cognitive advantages. However, brain tissue has an especially high metabolic rate. Thus, evolving an enlarged brain requires either a decrease in other energetic requirements, or an increase in overall energy consumption. Previous studies have found conflicting evidence for these hypotheses, leaving the metabolic costs and constraints in the evolution of increased encephalization unclear. Mormyrid electric fishes have extreme encephalization comparable to that of primates. Here, we show that brain size varies widely among mormyrid species, and that there is little evidence for a trade-off with organ size, but instead a correlation between brain size and resting oxygen consumption rate. Additionally, we show that increased brain size correlates with decreased hypoxia tolerance. Our data thus provide a non mammalian example of extreme encephalization that is accommodated by an increase in overall energy consumption. Previous studies have found energetic trade-offs with variation in brain size in taxa that have not experienced extreme encephalization comparable with that of primates and mormyrids. Therefore, we suggest that energetic trade-offs can only explain the evolution of moderate increases in brain size, and that the energetic requirements of extreme encephalization may necessitate increased overall energy investment. PMID- 28003449 TI - Antibody responses to avian influenza viruses in wild birds broaden with age. AB - For viruses such as avian influenza, immunity within a host population can drive the emergence of new strains by selecting for viruses with novel antigens that avoid immune recognition. The accumulation of acquired immunity with age is hypothesized to affect how influenza viruses emerge and spread in species of different lifespans. Despite its importance for understanding the behaviour of avian influenza viruses, little is known about age-related accumulation of immunity in the virus's primary reservoir, wild birds. To address this, we studied the age structure of immune responses to avian influenza virus in a wild swan population (Cygnus olor), before and after the population experienced an outbreak of highly pathogenic H5N1 avian influenza in 2008. We performed haemagglutination inhibition assays on sampled sera for five avian influenza strains and show that breadth of response accumulates with age. The observed age related distribution of antibody responses to avian influenza strains may explain the age-dependent mortality observed during the highly pathogenic H5N1 outbreak. Age structures and species lifespan are probably important determinants of viral epidemiology and virulence in birds. PMID- 28003450 TI - Comparative tests of the role of dewlap size in Anolis lizard speciation. AB - Phenotypic traits may be linked to speciation in two distinct ways: character values may influence the rate of speciation or diversification in the trait may be associated with speciation events. Traits involved in signal transmission, such as the dewlap of Anolis lizards, are often involved in the speciation process. The dewlap is an important visual signal with roles in species recognition and sexual selection, and dewlaps vary among species in relative size as well as colour and pattern. We compile a dataset of relative dewlap size digitized from photographs of 184 anole species from across the genus' geographical range. We use phylogenetic comparative methods to test two hypotheses: that larger dewlaps are associated with higher speciation rates, and that relative dewlap area diversifies according to a speciational model of evolution. We find no evidence of trait-dependent speciation, indicating that larger signals do not enhance any role the dewlap has in promoting speciation. Instead, we find a signal of mixed speciational and gradual trait evolution, with a particularly strong signal of speciational change in the dewlaps of mainland lineages. This indicates that dewlap size diversifies in association with the speciation process, suggesting that divergent selection may play a role in the macroevolution of this signalling trait. PMID- 28003451 TI - Urbanization drives the evolution of parallel clines in plant populations. AB - Urban ecosystems are an increasingly dominant feature of terrestrial landscapes. While evidence that species can adapt to urban environments is accumulating, the mechanisms through which urbanization imposes natural selection on populations are poorly understood. The identification of adaptive phenotypic changes (i.e. clines) along urbanization gradients would facilitate our understanding of the selective factors driving adaptation in cities. Here, we test for phenotypic clines in urban ecosystems by sampling the frequency of a Mendelian-inherited trait-cyanogenesis-in white clover (Trifolium repens L.) populations along urbanization gradients in four cities. Cyanogenesis protects plants from herbivores, but reduces tolerance to freezing temperatures. We found that the frequency of cyanogenic plants within populations decreased towards the urban centre in three of four cities. A field experiment indicated that spatial variation in herbivory is unlikely to explain these clines. Rather, colder minimum winter ground temperatures in urban areas compared with non-urban areas, caused by reduced snow cover in cities, may select against cyanogenesis. In the city with no cline, high snow cover might protect plants from freezing damage in the city centre. Our study suggests that populations are adapting to urbanization gradients, but regional climatic patterns may ultimately determine whether adaptation occurs. PMID- 28003452 TI - Faithful or not: direct and indirect effects of climate on extra-pair paternities in a population of Alpine marmots. AB - Despite being identified an area that is poorly understood regarding the effects of climate change, behavioural responses to climatic variability are seldom explored. Climatic variability is likely to cause large inter-annual variation in the frequency of extra-pair litters produced, a widespread alternative mating tactic to help prevent, correct or minimize the negative consequences of sub optimal mate choice. In this study, we investigated how climatic variability affects the inter-annual variation in the proportion of extra-pair litters in a wild population of Alpine marmots. During 22 years of monitoring, the annual proportion of extra-pair litters directly increased with the onset of earlier springs and indirectly with increased snow in winters. Snowier winters resulted in a higher proportion of families with sexually mature male subordinates and thus, created a social context within which extra-pair paternity was favoured. Earlier spring snowmelt could create this pattern by relaxing energetic, movement and time constraints. Further, deeper snow in winter could also contribute by increasing litter size and juvenile survival. Optimal mate choice is particularly relevant to generate adaptive genetic diversity. Understanding the influence of environmental conditions and the capacity of the individuals to cope with them is crucial within the context of rapid climate change. PMID- 28003453 TI - Size evolution in microorganisms masks trade-offs predicted by the growth rate hypothesis. AB - Adaptation to local resource availability depends on responses in growth rate and nutrient acquisition. The growth rate hypothesis (GRH) suggests that growing fast should impair competitive abilities for phosphorus and nitrogen due to high demand for biosynthesis. However, in microorganisms, size influences both growth and uptake rates, which may mask trade-offs and instead generate a positive relationship between these traits (size hypothesis, SH). Here, we evolved a gradient of maximum growth rate (MUmax) from a single bacterium ancestor to test the relationship among MUmax, competitive ability for nutrients and cell size, while controlling for evolutionary history. We found a strong positive correlation between MUmax and competitive ability for phosphorus, associated with a trade-off between MUmax and cell size: strains selected for high MUmax were smaller and better competitors for phosphorus. Our results strongly support the SH, while the trade-offs expected under GRH were not apparent. Beyond plasticity, unicellular populations can respond rapidly to selection pressure through joint evolution of their size and maximum growth rate. Our study stresses that physiological links between these traits tightly shape the evolution of competitive strategies. PMID- 28003455 TI - Sex as a strategy against rapidly evolving parasites. AB - Why is sex ubiquitous when asexual reproduction is much less costly? Sex disrupts coadapted gene complexes; it also causes costs associated with mate finding and the production of males who do not themselves bear offspring. Theory predicts parasites select for host sex, because genetically variable offspring can escape infection from parasites adapted to infect the previous generations. We examine this using a facultative sexual crustacean, Daphnia magna, and its sterilizing bacterial parasite, Pasteuria ramosa We obtained sexually and asexually produced offspring from wild-caught hosts and exposed them to contemporary parasites or parasites isolated from the same population one year later. We found rapid parasite adaptation to replicate within asexual but not sexual offspring. Moreover, sexually produced offspring were twice as resistant to infection as asexuals when exposed to parasites that had coevolved alongside their parents (i.e. the year two parasite). This fulfils the requirement that the benefits of sex must be both large and rapid for sex to be favoured by selection. PMID- 28003454 TI - Modulation of recognition memory performance by light requires both melanopsin and classical photoreceptors. AB - Acute light exposure exerts various effects on physiology and behaviour. Although the effects of light on brain network activity in humans are well demonstrated, the effects of light on cognitive performance are inconclusive, with the size, as well as direction, of the effect depending on the nature of the task. Similarly, in nocturnal rodents, bright light can either facilitate or disrupt performance depending on the type of task employed. Crucially, it is unclear whether the effects of light on behavioural performance are mediated via the classical image forming rods and cones or the melanopsin-expressing photosensitive retinal ganglion cells. Here, we investigate the modulatory effects of light on memory performance in mice using the spontaneous object recognition task. Importantly, we examine which photoreceptors are required to mediate the effects of light on memory performance. By using a cross-over design, we show that object recognition memory is disrupted when the test phase is conducted under a bright light (350 lux), regardless of the light level in the sample phase (10 or 350 lux), demonstrating that exposure to a bright light at the time of test, rather than at the time of encoding, impairs performance. Strikingly, the modulatory effect of light on memory performance is completely abolished in both melanopsin-deficient and rodless-coneless mice. Our findings provide direct evidence that melanopsin driven and rod/cone-driven photoresponses are integrated in order to mediate the effect of light on memory performance. PMID- 28003456 TI - Partitioning prediction uncertainty in climate-dependent population models. AB - The science of complex systems is increasingly asked to forecast the consequences of climate change. As a result, scientists are now engaged in making predictions about an uncertain future, which entails the efficient communication of this uncertainty. Here we show the benefits of hierarchically decomposing the uncertainty in predicted changes in animal population size into its components due to structural uncertainty in climate scenarios (greenhouse gas emissions and global circulation models), structural uncertainty in the demographic model, climatic stochasticity, environmental stochasticity unexplained by climate demographic trait relationships, and sampling variance in demographic parameter estimates. We quantify components of uncertainty surrounding the future abundance of a migratory bird, the greater snow goose (Chen caeruslescens atlantica), using a process-based demographic model covering their full annual cycle. Our model predicts a slow population increase but with a large prediction uncertainty. As expected from theoretical variance decomposition rules, the contribution of sampling variance to prediction uncertainty rapidly overcomes that of process variance and dominates. Among the sources of process variance, uncertainty in the climate scenarios contributed less than 3% of the total prediction variance over a 40-year period, much less than environmental stochasticity. Our study exemplifies opportunities to improve the forecasting of complex systems using long-term studies and the challenges inherent to predicting the future of stochastic systems. PMID- 28003457 TI - Direct transfer of learned behaviour via cell fusion in non-neural organisms. AB - Cell fusion is a fundamental phenomenon observed in all eukaryotes. Cells can exchange resources such as molecules or organelles during fusion. In this paper, we ask whether a cell can also transfer an adaptive response to a fusion partner. We addressed this question in the unicellular slime mould Physarum polycephalum, in which cell-cell fusion is extremely common. Slime moulds are capable of habituation, a simple form of learning, when repeatedly exposed to an innocuous repellent, despite lacking neurons and comprising only a single cell. In this paper, we present a set of experiments demonstrating that slime moulds habituated to a repellent can transfer this adaptive response by cell fusion to individuals that have never encountered the repellent. In addition, we show that a slime mould resulting from the fusion of a minority of habituated slime moulds and a majority of unhabituated ones still shows an adaptive response to the repellent. Finally, we further reveal that fusion must last a certain time to ensure an effective transfer of the behavioural adaptation between slime moulds. Our results provide strong experimental evidence that slime moulds exhibit transfer of learned behaviour during cell fusion and raise the possibility that similar phenomena may occur in other cell-cell fusion systems. PMID- 28003458 TI - Correction to 'Blood does not buy goodwill: allowing culling increases poaching of a large carnivore'. PMID- 28003459 TI - Correction to 'Proto-cooperation: group hunting sailfish improve hunting success by alternating attacks on grouping prey'. PMID- 28003460 TI - Controlled fluorescence in a beetle's photonic structure and its sensitivity to environmentally induced changes. AB - The scales covering the elytra of the male Hoplia coerulea beetle contain fluorophores embedded within a porous photonic structure. The photonic structure controls both insect colour (reflected light) and fluorescence emission. Herein, the effects of water-induced changes on the fluorescence emission from the beetle were investigated. The fluorescence emission peak wavelength was observed to blue shift on water immersion of the elytra whereas its reflectance peak wavelength was observed to red-shift. Time-resolved fluorescence measurements, together with optical simulations, confirmed that the radiative emission is controlled by a naturally engineered photonic bandgap while the elytra are in the dry state, whereas non-radiative relaxation pathways dominate the emission response of wet elytra. PMID- 28003461 TI - Restriction to gene flow is associated with changes in the molecular basis of pyrethroid resistance in the malaria vector Anopheles funestus. AB - Resistance to pyrethroids, the sole insecticide class recommended for treating bed nets, threatens the control of major malaria vectors, including Anopheles funestus Effective management of resistance requires an understanding of the dynamics and mechanisms driving resistance. Here, using genome-wide transcription and genetic diversity analyses, we show that a shift in the molecular basis of pyrethroid resistance in southern African populations of this species is associated with a restricted gene flow. Across the most highly endemic and densely populated regions in Malawi, An. funestus is resistant to pyrethroids, carbamates, and organochlorides. Genome-wide microarray-based transcription analysis identified overexpression of cytochrome P450 genes as the main mechanism driving this resistance. The most up-regulated genes include cytochrome P450s (CYP) CYP6P9a, CYP6P9b and CYP6M7. However, a significant shift in the overexpression profile of these genes was detected across a south/north transect, with CYP6P9a and CYP6P9b more highly overexpressed in the southern resistance front and CYP6M7 predominant in the northern front. A genome-wide genetic structure analysis of southern African populations of An. funestus from Zambia, Malawi, and Mozambique revealed a restriction of gene flow between populations, in line with the geographical variation observed in the transcriptomic analysis. Genetic polymorphism analysis of the three key resistance genes, CYP6P9a, CYP6P9b, and CYP6M7, support barriers to gene flow that are shaping the underlying molecular basis of pyrethroid resistance across southern Africa. This barrier to gene flow is likely to impact the design and implementation of resistance management strategies in the region. PMID- 28003462 TI - Whole-GUV patch-clamping. AB - Studying how the membrane modulates ion channel and transporter activity is challenging because cells actively regulate membrane properties, whereas existing in vitro systems have limitations, such as residual solvent and unphysiologically high membrane tension. Cell-sized giant unilamellar vesicles (GUVs) would be ideal for in vitro electrophysiology, but efforts to measure the membrane current of intact GUVs have been unsuccessful. In this work, two challenges for obtaining the "whole-GUV" patch-clamp configuration were identified and resolved. First, unless the patch pipette and GUV pressures are precisely matched in the GUV attached configuration, breaking the patch membrane also ruptures the GUV. Second, GUVs shrink irreversibly because the membrane/glass adhesion creating the high-resistance seal (>1 GOmega) continuously pulls membrane into the pipette. In contrast, for cell-derived giant plasma membrane vesicles (GPMVs), breaking the patch membrane allows the GPMV contents to passivate the pipette surface, thereby dynamically blocking membrane spreading in the whole-GMPV mode. To mimic this dynamic passivation mechanism, beta-casein was encapsulated into GUVs, yielding a stable, high-resistance, whole-GUV configuration for a range of membrane compositions. Specific membrane capacitance measurements confirmed that the membranes were truly solvent-free and that membrane tension could be controlled over a physiological range. Finally, the potential for ion transport studies was tested using the model ion channel, gramicidin, and voltage-clamp fluorometry measurements were performed with a voltage-dependent fluorophore/quencher pair. Whole-GUV patch-clamping allows ion transport and other voltage-dependent processes to be studied while controlling membrane composition, tension, and shape. PMID- 28003463 TI - Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. AB - Skeletal muscle contractions are initiated by an increase in Ca2+ released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+ These findings define critical roles for Stac3 in EC coupling and human disease. PMID- 28003464 TI - Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells. AB - Novel APOBEC1 target 1 (Nat1) (also known as "p97," "Dap5," and "Eif4g2") is a ubiquitously expressed cytoplasmic protein that is homologous to the C-terminal two thirds of eukaryotic translation initiation factor 4G (Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mES cells) are resistant to differentiation. In the current study, we found that NAT1 and eIF4G1 share many binding proteins, such as the eukaryotic translation initiation factors eIF3 and eIF4A and ribosomal proteins. However, NAT1 did not bind to eIF4E or poly(A) binding proteins, which are critical for cap-dependent translation initiation. In contrast, compared with eIF4G1, NAT1 preferentially interacted with eIF2, fragile X mental retardation proteins (FMR), and related proteins and especially with members of the proline-rich and coiled-coil-containing protein 2 (PRRC2) family. We also found that Nat1-null mES cells possess a transcriptional profile similar, although not identical, to the ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and glycogen synthase kinase 3 (GSK3) signaling pathways. In Nat1-null mES cells, the ERK pathway is suppressed even without inhibitors. Ribosome profiling revealed that translation of mitogen activated protein kinase kinase kinase 3 (Map3k3) and son of sevenless homolog 1 (Sos1) is suppressed in the absence of Nat1 Forced expression of Map3k3 induced differentiation of Nat1-null mES cells. These data collectively show that Nat1 is involved in the translation of proteins that are required for cell differentiation. PMID- 28003465 TI - Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. AB - The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ~16 A from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus. PMID- 28003466 TI - Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy. AB - We used stimulated emission depletion (STED) superresolution microscopy to analyze the nanoscale organization of 12 glial and axonal proteins at the nodes of Ranvier of teased sciatic nerve fibers. Cytoskeletal proteins of the axon (betaIV spectrin, ankyrin G) exhibit a high degree of one-dimensional longitudinal order at nodal gaps. In contrast, axonal and glial nodal adhesion molecules [neurofascin-186, neuron glial-related cell adhesion molecule (NrCAM)] can arrange in a more complex, 2D hexagonal-like lattice but still feature a ~190 nm periodicity. Such a lattice-like organization is also found for glial actin. Sodium and potassium channels exhibit a one-dimensional periodicity, with the Nav channels appearing to have a lower degree of organization. At paranodes, both axonal proteins (betaII spectrin, Caspr) and glial proteins (neurofascin-155, ankyrin B) form periodic quasi-one-dimensional arrangements, with a high degree of interdependence between the position of the axonal and the glial proteins. The results indicate the presence of mechanisms that finely align the cytoskeleton of the axon with the one of the Schwann cells, both at paranodal junctions (with myelin loops) and at nodal gaps (with microvilli). Taken together, our observations reveal the importance of the lateral organization of proteins at the nodes of Ranvier and pave the way for deeper investigations of the molecular ultrastructural mechanisms involved in action potential propagation, the formation of the nodes, axon-glia interactions, and demyelination diseases. PMID- 28003468 TI - The Clinical Features of Paranoia in the 20th Century and Their Representation in Diagnostic Criteria From DSM-III Through DSM-5. AB - This review traces, through psychiatric textbooks, the history of the Kraepelinian concept of paranoia in the 20th century and then relates the common reported symptoms and signs to the diagnostic criteria for paranoia/delusional disorder in DSM-III through DSM-5. Clinical descriptions of paranoia appearing in 10 textbooks, published 1899 to 1970, revealed 11 prominent symptoms and signs reported by 5 or more authors. Three symptoms (systematized delusions, minimal hallucinations, and prominent ideas of reference) and 2 signs (chronic course and minimal affective deterioration) were reported by 8 or 9 of the authors. Four textbook authors rejected the Kraepelinian concept of paranoia. A weak relationship was seen between the frequency with which the clinical features were reported and the likelihood of their inclusion in modern DSM manuals. Indeed, the diagnostic criteria for paranoia/delusional disorder shifted substantially from DSM-III to DSM-5. The modern operationalized criteria for paranoia/delusional disorder do not well reflect the symptoms and signs frequently reported by historical experts. In contrast to results of similar reviews for depression, schizophrenia and mania, the clinical construct of paranoia/delusional disorder has been somewhat unstable in Western Psychiatry since the turn of the 20th century as reflected in both textbooks and the DSM editions. PMID- 28003467 TI - Prefrontal Cortex Dysfunction Increases Susceptibility to Schizophrenia-Like Changes Induced by Adolescent Stress Exposure. AB - Stress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different stressful events during adolescence (restraint stress [RS], footshock [FS], or the combination of FS and RS) on behaviors correlated with schizophrenia in rats as adults. At adulthood, animals were tested for anxiety responses (elevated plus-maze), cognitive function (novel-object recognition test) and dopamine (DA) system responsivity (locomotor response to amphetamine and DA neuron activity in the ventral tegmental area (VTA) using in vivo electrophysiology). All adolescent stressors impaired weight gain and induced anxiety-like responses in adults. FS and FS + RS also disrupted cognitive function. Interestingly, only the combination of FS and RS induced a DA hyper responsivity as indicated by augmented locomotor response to amphetamine and increased number of spontaneously active DA neurons which was confined to the lateral VTA. Additionally, prelimbic (pl) mPFC lesions triggered a DA hyper responsivity in animals exposed to FS alone during adolescence. Our results are consistent with previous studies showing long-lasting changes induced by stressful events during adolescence. The impact on DA system activity, however, seems to depend on intense multiple stressors. Our data also suggest that plPFC dysfunction increases the vulnerability to stress in terms of changes in the DA system. Hence, stress during adolescence could be a precipitating factor for the transition to schizophrenia, and stress control at this vulnerable period may circumvent these changes to prevent the emergence of psychosis. PMID- 28003469 TI - Mistakes I Have Made in My Research Career. PMID- 28003470 TI - Primate-specific oestrogen-responsive long non-coding RNAs regulate proliferation and viability of human breast cancer cells. AB - Long non-coding RNAs (lncRNAs) are transcripts of a recently discovered class of genes which do not code for proteins. LncRNA genes are approximately as numerous as protein-coding genes in the human genome. However, comparatively little remains known about lncRNA functions. We globally interrogated changes in the lncRNA transcriptome of oestrogen receptor positive human breast cancer cells following treatment with oestrogen, and identified 127 oestrogen-responsive lncRNAs. Consistent with the emerging evidence that most human lncRNA genes lack homologues outside of primates, our evolutionary analysis revealed primate specific lncRNAs downstream of oestrogen signalling. We demonstrate, using multiple functional assays to probe gain- and loss-of-function phenotypes in two oestrogen receptor positive human breast cancer cell lines, that two primate specific oestrogen-responsive lncRNAs identified in this study (the oestrogen repressed lncRNA BC041455, which reduces cell viability, and the oestrogen induced lncRNA CR593775, which increases cell viability) exert previously unrecognized functions in cell proliferation and growth factor signalling pathways. The results suggest that oestrogen-responsive lncRNAs are capable of altering the proliferation and viability of human breast cancer cells. No effects on cellular phenotypes were associated with control transfections. As heretofore unappreciated components of key signalling pathways in cancers, including the MAP kinase pathway, lncRNAs hence represent a novel mechanism of action for oestrogen effects on cellular proliferation and viability phenotypes. This finding warrants further investigation in basic and translational studies of breast and potentially other types of cancers, has broad relevance to lncRNAs in other nuclear hormone receptor pathways, and should facilitate exploiting and targeting these cell viability modulating lncRNAs in post-genomic therapeutics. PMID- 28003471 TI - piRNA-associated proteins and retrotransposons are differentially expressed in murine testis and ovary of aryl hydrocarbon receptor deficient mice. AB - Previous studies suggested that the aryl hydrocarbon receptor (AhR) contributes to mice reproduction and fertility. However, the mechanisms involved remain mostly unknown. Retrotransposon silencing by Piwi-interacting RNAs (piRNAs) is essential for germ cell maturation and, remarkably, AhR has been identified as a regulator of murine B1-SINE retrotransposons. Here, using littermate AhR+/+ and AhR-/- mice, we report that AhR regulates the general course of spermatogenesis and oogenesis by a mechanism likely to be associated with piRNA-associated proteins, piRNAs and retrotransposons. piRNA-associated proteins MVH and Miwi are upregulated in leptotene to pachytene spermatocytes with a more precocious timing in AhR-/- than in AhR+/+ testes. piRNAs and transcripts from B1-SINE, LINE-1 and IAP retrotransposons increased at these meiotic stages in AhR-null testes. Moreover, B1-SINE transcripts colocalize with MVH and Miwi in leptonema and pachynema spermatocytes. Unexpectedly, AhR-/- males have increased sperm counts, higher sperm functionality and enhanced fertility than AhR+/+ mice. In contrast, piRNA-associated proteins and B1-SINE and IAP-derived transcripts are reduced in adult AhR-/- ovaries. Accordingly, AhR-null female mice have lower numbers of follicles when compared with AhR+/+ mice. Thus, AhR deficiency differentially affects testis and ovary development possibly by a process involving piRNA associated proteins, piRNAs and transposable elements. PMID- 28003472 TI - A decision underlies phototaxis in an insect. AB - Like a moth into the flame-phototaxis is an iconic example for innate preferences. Such preferences probably reflect evolutionary adaptations to predictable situations and have traditionally been conceptualized as hard-wired stimulus-response links. Perhaps for that reason, the century-old discovery of flexibility in Drosophila phototaxis has received little attention. Here, we report that across several different behavioural tests, light/dark preference tested in walking is dependent on various aspects of flight. If we temporarily compromise flying ability, walking photopreference reverses concomitantly. Neuronal activity in circuits expressing dopamine and octopamine, respectively, plays a differential role in photopreference, suggesting a potential involvement of these biogenic amines in this case of behavioural flexibility. We conclude that flies monitor their ability to fly, and that flying ability exerts a fundamental effect on action selection in Drosophila This work suggests that even behaviours which appear simple and hard-wired comprise a value-driven decision making stage, negotiating the external situation with the animal's internal state, before an action is selected. PMID- 28003473 TI - Primase is required for helicase activity and helicase alters the specificity of primase in the enteropathogen Clostridium difficile. AB - DNA replication is an essential and conserved process in all domains of life and may serve as a target for the development of new antimicrobials. However, such developments are hindered by subtle mechanistic differences and limited understanding of DNA replication in pathogenic microorganisms. Clostridium difficile is the main cause of healthcare-associated diarrhoea and its DNA replication machinery is virtually uncharacterized. We identify and characterize the mechanistic details of the putative replicative helicase (CD3657), helicase loader ATPase (CD3654) and primase (CD1454) of C. difficile, and reconstitute helicase and primase activities in vitro We demonstrate a direct and ATP dependent interaction between the helicase loader and the helicase. Furthermore, we find that helicase activity is dependent on the presence of primase in vitro The inherent trinucleotide specificity of primase is determined by a single lysine residue and is similar to the primase of the extreme thermophile Aquifex aeolicus. However, the presence of helicase allows more efficient de novo synthesis of RNA primers from non-preferred trinucleotides. Thus, loader-helicase primase interactions, which crucially mediate helicase loading and activation during DNA replication in all organisms, differ critically in C. difficile from that of the well-studied Gram-positive Bacillus subtilis model. PMID- 28003474 TI - Phylogenomics-guided discovery of a novel conserved cassette of short linear motifs in BubR1 essential for the spindle checkpoint. AB - The spindle assembly checkpoint (SAC) maintains genomic integrity by preventing progression of mitotic cell division until all chromosomes are stably attached to spindle microtubules. The SAC critically relies on the paralogues Bub1 and BubR1/Mad3, which integrate kinetochore-spindle attachment status with generation of the anaphase inhibitory complex MCC. We previously reported on the widespread occurrences of independent gene duplications of an ancestral 'MadBub' gene in eukaryotic evolution and the striking parallel subfunctionalization that lead to loss of kinase function in BubR1/Mad3-like paralogues. Here, we present an elaborate subfunctionalization analysis of the Bub1/BubR1 gene family and perform de novo sequence discovery in a comparative phylogenomics framework to trace the distribution of ancestral sequence features to extant paralogues throughout the eukaryotic tree of life. We show that known ancestral sequence features are consistently retained in the same functional paralogue: GLEBS/CMI/CDII/kinase in the Bub1-like and KEN1/KEN2/D-Box in the BubR1/Mad3-like. The recently described ABBA motif can be found in either or both paralogues. We however discovered two additional ABBA motifs that flank KEN2. This cassette of ABBA1-KEN2-ABBA2 forms a strictly conserved module in all ancestral and BubR1/Mad3-like proteins, suggestive of a specific and crucial SAC function. Indeed, deletion of the ABBA motifs in human BUBR1 abrogates the SAC and affects APC/C-Cdc20 interactions. Our detailed comparative genomics analyses thus enabled discovery of a conserved cassette of motifs essential for the SAC and shows how this approach can be used to uncover hitherto unrecognized functional protein features. PMID- 28003476 TI - Efficient DNA binding of NF-kappaB requires the chaperone-like function of NPM1. AB - NPM1/nucleophosmin is frequently overexpressed in various tumors, although the oncogenic role of NPM1 remains unclear. Here we revealed the link between NPM1 and nuclear factor-kappaB (NF-kappaB), a master regulator of inflammation. We found that NPM1 knockdown decreased NF-kappaB-mediated transcription of selected target genes by decreasing the recruitment of NF-kappaB p65 to the gene promoters. NPM1 is directly associated with the DNA binding domain of p65 to enhance its DNA binding activity without being a part of the DNA-NF-kappaB complex. This result suggests that NF-kappaB requires the chaperone-like function of NPM1 for DNA binding. Furthermore, we demonstrated that NPM1 was required for efficient inflammatory gene expression induced by tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide in fibroblasts and macrophages. The NF-kappaB mediated invasion of breast cancer cells was significantly decreased by NPM1 knockdown. Our study suggests a novel mechanistic insight into the NF-kappaB mediated transcription and an oncogenic role of NPM1 in both tumor cells and the tumor micro-environment through the regulation of NF-kappaB. PMID- 28003475 TI - Single cell transcriptomics reveals unanticipated features of early hematopoietic precursors. AB - Molecular changes underlying stem cell differentiation are of fundamental interest. scRNA-seq on murine hematopoietic stem cells (HSC) and their progeny MPP1 separated the cells into 3 main clusters with distinct features: active, quiescent, and an un-characterized cluster. Induction of anemia resulted in mobilization of the quiescent to the active cluster and of the early to later stage of cell cycle, with marked increase in expression of certain transcription factors (TFs) while maintaining expression of interferon response genes. Cells with surface markers of long term HSC increased the expression of a group of TFs expressed highly in normal cycling MPP1 cells. However, at least Id1 and Hes1 were significantly activated in both HSC and MPP1 cells in anemic mice. Lineage specific genes were differently expressed between cells, and correlated with the cell cycle stages with a specific augmentation of erythroid related genes in the G2/M phase. Most lineage specific TFs were stochastically expressed in the early precursor cells, but a few, such as Klf1, were detected only at very low levels in few precursor cells. The activation of these factors may correlate with stages of differentiation. This study reveals effects of cell cycle progression on the expression of lineage specific genes in precursor cells, and suggests that hematopoietic stress changes the balance of renewal and differentiation in these homeostatic cells. PMID- 28003478 TI - Injury at work and migrant workers: a priority for a global agenda in occupational health. PMID- 28003477 TI - Argonaute proteins regulate HIV-1 multiply spliced RNA and viral production in a Dicer independent manner. AB - Argonaute (Ago) proteins associate with microRNAs (miRNAs) to form the core of the RNA-induced silencing complex (RISC) that mediates post-transcriptional gene silencing of target mRNAs. As key players in anti-viral defense, Ago proteins are thought to have the ability to interact with human immunodeficiency virus type 1 (HIV-1) RNA. However, the role of this interaction in regulating HIV-1 replication has been debated. Here, we used high throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) to explore the interaction between Ago2 and HIV-1 RNA in infected cells. By only considering reads of 50 nucleotides length in our analysis, we identified more than 30 distinct binding sites for Ago2 along the viral RNA genome. Using reporter assays, we found four binding sites, located near splice donor sites, capable of repressing Luciferase gene expression in an Ago-dependent manner. Furthermore, inhibition of Ago1 and Ago2 levels in cells expressing HIV-1 led to an increase of viral multiply spliced transcripts and to a strong reduction in the extracellular CAp24 level. Depletion of Dicer did not affect these activities. Our results highlight a new role of Ago proteins in the control of multiply spliced HIV-1 transcript levels and viral production, independently of the miRNA pathway. PMID- 28003479 TI - Recognising the value of infection prevention and its role in addressing the antimicrobial resistance crisis. PMID- 28003480 TI - Nonstructural Protein 4 of Porcine Reproductive and Respiratory Syndrome Virus Modulates Cell Surface Swine Leukocyte Antigen Class I Expression by Downregulating beta2-Microglobulin Transcription. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of PRRS, which has important impacts on the pig industry. PRRSV infection results in disruption of the swine leukocyte antigen class I (SLA-I) antigen presentation pathway. In this study, highly pathogenic PRRSV (HP-PRRSV) infection inhibited transcription of the beta2-microglobulin (beta2M) gene (B2M) and reduced cellular levels of beta2M, which forms a heterotrimeric complex with the SLA-I heavy chain and a variable peptide and plays a critical role in SLA-I antigen presentation. HP-PRRSV nonstructural protein 4 (Nsp4) was involved in the downregulation of beta2M expression. Exogenous expression of Nsp4 downregulated beta2M expression at both the mRNA and the protein level and reduced SLA-I expression on the cell surface. Nsp4 bound to the porcine B2M promoter and inhibited its transcriptional activity. Domain III of Nsp4 and the enhancer PAM element of the porcine B2M promoter were identified as essential for the interaction between Nsp4 and B2M These findings demonstrate a novel mechanism whereby HP-PRRSV may modulate the SLA-I antigen presentation pathway and provide new insights into the functions of HP-PRRSV Nsp4. IMPORTANCE PRRSV modulates the host response by disrupting the SLA-I antigen presentation pathway. We show that HP-PRRSV downregulates SLA-I expression on the cell surface via transcriptional inhibition of B2M expression by viral Nsp4. The interaction between domain III of Nsp4 and the enhancer PAM element of the porcine B2M promoter is essential for inhibiting B2M transcription. These observations reveal a novel mechanism whereby HP-PRRSV may modulate SLA-I antigen presentation and provide new insights into the functions of viral Nsp4. PMID- 28003481 TI - Shifting Clade Distribution, Reassortment, and Emergence of New Subtypes of Highly Pathogenic Avian Influenza A(H5) Viruses Collected from Vietnamese Poultry from 2012 to 2015. AB - Whole-genome sequences of representative highly pathogenic avian influenza A(H5) viruses from Vietnam were generated, comprising samples from poultry outbreaks and active market surveillance collected from January 2012 to August 2015. Six hemagglutinin gene clades were characterized. Clade 1.1.2 was predominant in southern Mekong provinces throughout 2012 and 2013 but gradually disappeared and was not detected after April 2014. Clade 2.3.2.1c viruses spread rapidly during 2012 and were detected in the south and center of the country. A number of clade 1.1.2 and 2.3.2.1c interclade reassortant viruses were detected with different combinations of internal genes derived from 2.3.2.1a and 2.3.2.1b viruses, indicating extensive cocirculation. Although reassortment generated genetic diversity at the genotype level, there was relatively little genetic drift within the individual gene segments, suggesting genetic stasis over recent years. Antigenically, clade 1.1.2, 2.3.2.1a, 2.3.2.1b, and 2.3.2.1c viruses remained related to earlier viruses and WHO-recommended prepandemic vaccine strains representing these clades. Clade 7.2 viruses, although detected in only low numbers, were the exception, as indicated by introduction of a genetically and antigenically diverse strain in 2013. Clade 2.3.4.4 viruses (H5N1 and H5N6) were likely introduced in April 2014 and appeared to gain dominance across northern and central regions. Antigenic analyses of clade 2.3.4.4 viruses compared to existing clade 2.3.4 candidate vaccine viruses (CVV) indicated the need for an updated vaccine virus. A/Sichuan/26221/2014 (H5N6) virus was developed, and ferret antisera generated against this virus were demonstrated to inhibit some but not all clade 2.3.4.4 viruses, suggesting consideration of alternative clade 2.3.4.4 CVVs.IMPORTANCE Highly pathogenic avian influenza (HPAI) A(H5) viruses have circulated continuously in Vietnam since 2003, resulting in hundreds of poultry outbreaks and sporadic human infections. Despite a significant reduction in the number of human infections in recent years, poultry outbreaks continue to occur and the virus continues to diversify. Vaccination of poultry has been used as a means to control the spread and impact of the virus, but due to the diversity and changing distribution of antigenically distinct viruses, the utility of vaccines in the face of mismatched circulating strains remains questionable. This study assessed the putative amino acid changes in viruses leading to antigenic variability, underscoring the complexity of vaccine selection for both veterinary and public health purposes. Given the overlapping geographic distributions of multiple, antigenically distinct clades of HPAI A(H5) viruses in Vietnam, the vaccine efficacy of bivalent poultry vaccine formulations should be tested in the future. PMID- 28003482 TI - NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses. AB - Influenza virus NS1 protein is a nonstructural, multifunctional protein that counteracts host innate immune responses, modulating virus pathogenesis. NS1 protein variability in subjects infected with H3N2 influenza A viruses (IAVs) during the 2010/2011 season was analyzed, and amino acid changes in residues 86, 189, and 194 were found. The consequences of these mutations for the NS1-mediated inhibition of IFN responses and the pathogenesis of the virus were evaluated, showing that NS1 mutations D189N and V194I impaired the ability of the NS1 protein to inhibit general gene expression, most probably because these mutations decreased the binding of NS1 to the cleavage and polyadenylation specificity factor 30 (CPSF30). A recombinant A/Puerto Rico/8/34 (PR8) H1N1 virus encoding the H3N2 NS1-D189N protein was slightly attenuated, whereas the virus encoding the H3N2 NS1-V194I protein was further attenuated in mice. The higher attenuation of this virus could not be explained by differences in the ability of the two NS1 proteins to counteract host innate immune responses, indicating that another factor must be responsible. In fact, we showed that the virus encoding the H3N2 NS1-V194I protein demonstrated a temperature-sensitive (ts) phenotype, providing a most likely explanation for the stronger attenuation observed. As far as we know, this is the first description of a mutation in NS1 residue 194 conferring a ts phenotype. These studies are relevant in order to identify new residues important for NS1 functions and in human influenza virus surveillance to assess mutations affecting the pathogenicity of circulating viruses.IMPORTANCE Influenza viral infections represent a serious public health problem, with influenza virus causing a contagious respiratory disease that is most effectively prevented through vaccination. The multifunctional nonstructural protein 1 (NS1) is the main viral factor counteracting the host antiviral response. Therefore, influenza virus surveillance to identify new mutations in the NS1 protein affecting the pathogenicity of the circulating viruses is highly important. In this work, we evaluated amino acid variability in the NS1 proteins from H3N2 human seasonal viruses and the effect of the mutations on innate immune responses and virus pathogenesis. NS1 mutations D189N and V194I impaired the ability of the NS1 protein to inhibit general gene expression, and recombinant viruses harboring these mutations were attenuated in a mouse model of influenza infection. Interestingly, a virus encoding the H3N2 NS1-V194I protein demonstrated a temperature-sensitive phenotype, further attenuating the virus in vivo. PMID- 28003483 TI - Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice. AB - Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization. PMID- 28003484 TI - Potential Role for a beta-Catenin Coactivator (High-Mobility Group AT-Hook 1 Protein) during the Latency-Reactivation Cycle of Bovine Herpesvirus 1. AB - The latency-related (LR) RNA encoded by bovine herpesvirus 1 (BoHV-1) is abundantly expressed in latently infected sensory neurons. Although the LR gene encodes several products, ORF2 appears to mediate important steps during the latency-reactivation cycle because a mutant virus containing stop codons at the amino terminus of ORF2 does not reactivate from latency in calves. We recently found that the Wnt/beta-catenin signaling pathway is regulated during the BoHV-1 latency-reactivation cycle (Y. Liu, M. Hancock, A. Workman, A. Doster, and C. Jones, J Virol 90:3148-3159, 2016). In the present study, a beta-catenin coactivator, high-mobility group AT-hook 1 protein (HMGA1), was detected in significantly more neurons in the trigeminal ganglia of latently infected calves than in those of uninfected calves. Consequently, we hypothesized that HMGA1 cooperates with ORF2 and beta-catenin to maintain latency. In support of this hypothesis, coimmunoprecipitation studies demonstrated that ORF2 stably interacts with a complex containing beta-catenin and/or HMGA1 in transfected mouse neuroblastoma (Neuro-2A) cells. Confocal microscopy provided evidence that ORF2 was relocalized by HMGA1 and beta-catenin in Neuro-2A cells. ORF2 consistently enhanced the ability of HMGA1 to stimulate beta-catenin-dependent transcription, suggesting that interactions between ORF2 and a complex containing beta-catenin and HMGA1 have functional significance. An ORF2 stop codon mutant, an ORF2 nuclear localization mutant, or a mutant lacking the 5 protein kinase A or C phosphorylation sites interfered with its ability to stimulate beta-catenin dependent transcription. Since the canonical Wnt/beta-catenin signaling pathway promotes neurogenesis (synapse formation and remodeling) and inhibits neurodegeneration, interactions between ORF2, HMGA1, and beta-catenin may be important for certain aspects of the latency-reactivation cycle.IMPORTANCE The lifelong latency of bovine herpesvirus 1 (BoHV-1) requires that significant numbers of infected sensory neurons survive infection and maintain normal functions. Consequently, we hypothesize that viral products expressed during latency cooperate with neuronal factors to maintain latency. Our studies revealed that a beta-catenin coactivator, high-mobility group AT-hook 1 protein (HMGA1), was readily detected in a subset of trigeminal ganglion neurons in latently infected calves but not in uninfected calves. A viral protein (ORF2) expressed in latently infected neurons interacted with beta-catenin and HMGA1 in transfected cells, which resulted in the nuclear localization of beta-catenin. This interaction correlated with the ability of ORF2 to stimulate the coactivator functions of HMGA1. These findings are significant because the canonical Wnt/beta catenin signaling pathway promotes neurogenesis and inhibits neurodegeneration. PMID- 28003485 TI - Genesis and Dissemination of Highly Pathogenic H5N6 Avian Influenza Viruses. AB - Clade 2.3.4.4 highly pathogenic avian influenza viruses (H5Nx) have spread from Asia to other parts of the world. Since 2014, human infections with clade 2.3.4.4 highly pathogenic avian influenza H5N6 viruses have been continuously reported in China. To investigate the genesis of the virus, we analyzed 123 H5 or N6 environmental viruses sampled from live-poultry markets or farms from 2012 to 2015 in Mainland China. Our results indicated that clade 2.3.4.4 H5N2/N6/N8 viruses shared the same hemagglutinin gene as originated in early 2009. From 2012 to 2015, the genesis of highly pathogenic avian influenza H5N6 viruses occurred via two independent pathways. Three major reassortant H5N6 viruses (reassortants A, B, and C) were generated. Internal genes of reassortant A and B viruses and reassortant C viruses derived from clade 2.3.2.1c H5N1 and H9N2 viruses, respectively. Many mammalian adaption mutations and antigenic variations were detected among the three reassortant viruses. Considering their wide circulation and dynamic reassortment in poultry, we highly recommend close monitoring of the viruses in poultry and humans. IMPORTANCE Since 2014, clade 2.3.4.4 highly pathogenic avian influenza (H5Nx) viruses have caused many outbreaks in both wild and domestic birds globally. Severe human cases with novel H5N6 viruses in this group were also reported in China in 2014 and 2015. To investigate the genesis of the genetic diversity of these H5N6 viruses, we sequenced 123 H5 or N6 environmental viruses sampled from 2012 to 2015 in China. Sequence analysis indicated that three major reassortants of these H5N6 viruses had been generated by two independent evolutionary pathways. The H5N6 reassortant viruses had been detected in most provinces of southern China and neighboring countries. Considering the mammalian adaption mutations and antigenic variation detected, the spread of these viruses should be monitored carefully due to their pandemic potential. PMID- 28003486 TI - Feline Immunodeficiency Virus Cross-Species Transmission: Implications for Emergence of New Lentiviral Infections. AB - Owing to a complex history of host-parasite coevolution, lentiviruses exhibit a high degree of species specificity. Given the well-documented viral archeology of human immunodeficiency virus (HIV) emergence following human exposures to simian immunodeficiency virus (SIV), an understanding of processes that promote successful cross-species lentiviral transmissions is highly relevant. We previously reported natural cross-species transmission of a subtype of feline immunodeficiency virus, puma lentivirus A (PLVA), between bobcats (Lynx rufus) and mountain lions (Puma concolor) for a small number of animals in California and Florida. In this study, we investigate host-specific selection pressures, within-host viral fitness, and inter- versus intraspecies transmission patterns among a larger collection of PLV isolates from free-ranging bobcats and mountain lions. Analyses of proviral and viral RNA levels demonstrate that PLVA fitness is severely restricted in mountain lions compared to that in bobcats. We document evidence of diversifying selection in three of six PLVA genomes from mountain lions, but we did not detect selection among 20 PLVA isolates from bobcats. These findings support the hypothesis that PLVA is a bobcat-adapted virus which is less fit in mountain lions and under intense selection pressure in the novel host. Ancestral reconstruction of transmission events reveals that intraspecific PLVA transmission has occurred among panthers (Puma concolor coryi) in Florida following the initial cross-species infection from bobcats. In contrast, interspecific transmission from bobcats to mountain lions predominates in California. These findings document outcomes of cross-species lentiviral transmission events among felids that compare to the emergence of HIV from nonhuman primates.IMPORTANCE Cross-species transmission episodes can be singular, dead-end events or can result in viral replication and spread in the new species. The factors that determine which outcome will occur are complex, and the risk of new virus emergence is therefore difficult to predict. We used molecular techniques to evaluate the transmission, fitness, and adaptation of puma lentivirus A (PLVA) between bobcats and mountain lions in two geographic regions. Our findings illustrate that mountain lion exposure to PLVA is relatively common but does not routinely result in communicable infections in the new host. This is attributed to efficient species barriers that largely prevent lentiviral adaptation. However, the evolutionary capacity for lentiviruses to adapt to novel environments may ultimately overcome host restriction mechanisms over time and under certain ecological circumstances. This phenomenon provides a unique opportunity to examine cross-species transmission events leading to new lentiviral emergence. PMID- 28003487 TI - Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry. AB - Herpes simplex virus (HSV) entry into a subset of cells requires endocytosis and endosomal low pH. Preexposure of isolated virions to mildly acidic pH of 5 to 6 partially inactivates HSV infectivity in an irreversible manner. Acid inactivation is a hallmark of viruses that enter via low-pH pathways; this occurs by pretriggering conformational changes essential for fusion. The target and mechanism(s) of low-pH inactivation of HSV are unclear. Here, low-pH-treated HSV 1 was defective in fusion activity and yet retained normal levels of attachment to cell surface heparan sulfate and binding to nectin-1 receptor. Low-pH triggered conformational changes in gB reported to date are reversible, despite irreversible low-pH inactivation. gB conformational changes and their reversibility were measured by antigenic analysis with a panel of monoclonal antibodies and by detecting changes in oligomeric conformation. Three-hour treatment of HSV-1 virions with pH 5 or multiple sequential treatments at pH 5 followed by neutral pH caused an irreversible >2.5 log infectivity reduction. While changes in several gB antigenic sites were reversible, alteration of the H126 epitope was irreversible. gB oligomeric conformational change remained reversible under all conditions tested. Altogether, our results reveal that oligomeric alterations and fusion domain changes represent distinct conformational changes in gB, and the latter correlates with irreversible low-pH inactivation of HSV. We propose that conformational change in the gB fusion domain is important for activation of membrane fusion during viral entry and that in the absence of a host target membrane, this change results in irreversible inactivation of virions.IMPORTANCE HSV-1 is an important pathogen with a high seroprevalence throughout the human population. HSV infects cells via multiple pathways, including a low-pH route into epithelial cells, the primary portal into the host. HSV is inactivated by low-pH preexposure, and gB, a class III fusion protein, undergoes reversible conformational changes in response to low-pH exposure. Here, we show that low-pH inactivation of HSV is irreversible and due to a defect in virion fusion activity. We identified an irreversible change in the fusion domain of gB following multiple sequential low-pH exposures or following prolonged low-pH treatment. This change appears to be separable from the alteration in gB quaternary structure. Together, the results are consistent with a model by which low pH can have an activating or inactivating effect on HSV depending on the presence of a target membrane. PMID- 28003488 TI - Ribosome Profiling Reveals Translational Upregulation of Cellular Oxidative Phosphorylation mRNAs during Vaccinia Virus-Induced Host Shutoff. AB - Vaccinia virus infection causes a host shutoff that is marked by global inhibition of host protein synthesis. Though the host shutoff may facilitate reallocation of cellular resources for viral replication and evasion of host antiviral immune responses, it poses a challenge for continuous synthesis of cellular proteins that are important for viral replication. It is, however, unclear whether and how certain cellular proteins may be selectively synthesized during the vaccinia virus-induced host shutoff. Using simultaneous RNA sequencing and ribosome profiling, two techniques quantifying genome-wide levels of mRNA and active protein translation, respectively, we analyzed the responses of host cells to vaccinia virus infection at both the transcriptional and translational levels. The analyses showed that cellular mRNA depletion played a dominant role in the shutoff of host protein synthesis. Though the cellular mRNAs were significantly reduced, the relative translation efficiency of a subset of cellular mRNAs increased, particularly those involved in oxidative phosphorylation that are responsible for cellular energy production. Further experiments demonstrated that the protein levels and activities of oxidative phosphorylation increased during vaccinia virus infection, while inhibition of the cellular oxidative phosphorylation function significantly suppressed vaccinia virus replication. Moreover, the short 5' untranslated region of the oxidative phosphorylation mRNAs contributed to the translational upregulation. These results provide evidence of a mechanism that couples translational control and energy metabolism, two processes that all viruses depend on host cells to provide, to support vaccinia virus replication during a host shutoff.IMPORTANCE Many viral infections cause global host protein synthesis shutoff. While host protein synthesis shutoff benefits the virus by relocating cellular resources to viral replication, it also poses a challenge to the maintenance of cellular functions necessary for viral replication if continuous protein synthesis is required. Here we measured the host mRNA translation rate during a vaccinia virus-induced host shutoff by analyzing total and actively translating mRNAs in a genome-wide manner. This study revealed that oxidative phosphorylation mRNAs were translationally upregulated during vaccinia virus-induced host protein synthesis shutoff. Oxidative phosphorylation is the major cellular energy-producing pathway, and we further showed that maintenance of its function is important for vaccinia virus replication. This study highlights the fact that vaccinia virus infection can enhance cellular energy production through translational upregulation in the context of an overall host protein synthesis shutoff to meet energy expenditure. PMID- 28003489 TI - Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency. AB - Epstein-Barr virus (EBV) latently infects normal B cells and contributes to the development of certain human lymphomas. Newly infected B cells support a highly transforming form (type III) of viral latency; however, long-term EBV infection in immunocompetent hosts is limited to B cells with a more restricted form of latency (type I) in which most viral gene expression is silenced by promoter DNA methylation. How EBV converts latency type is unclear, although it is known that type I latency is associated with a germinal center (GC) B cell phenotype, and type III latency with an activated B cell (ABC) phenotype. In this study, we have examined whether expression of TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells. We found that TET2 expression is inhibited in normal GC cells and GC type lymphomas. In contrast, TET2 is expressed in normal naive B cells and ABC type lymphomas. We also demonstrate that GC type cell lines have increased 5mC levels and reduced 5hmC levels in comparison to those of ABC type lines. Finally, we show that TET2 promotes the ability of the EBV transcription factor EBNA2 to convert EBV-infected cells from type I to type III latency. These findings demonstrate that TET2 expression is repressed in GC cells independent of EBV infection and suggest that TET2 promotes type III EBV latency in B cells with an ABC or naive phenotype by enhancing EBNA2 activation of methylated EBV promoters.IMPORTANCE EBV establishes several different types of viral latency in B cells. However, cellular factors that determine whether EBV enters the highly transforming type III latency, versus the more restricted type I latency, have not been well characterized. Here we show that TET2, a cellular enzyme that initiates DNA demethylation by converting 5 methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells by enhancing the ability of the viral transcription factor EBNA2 to activate methylated viral promoters that are expressed in type III (but not type I) latency. Furthermore, we demonstrate that (independent of EBV) TET2 is turned off in normal and malignant germinal center (GC) B cells but expressed in other B cell types. Thus, restricted TET2 expression in GC cells may promote type I EBV latency. PMID- 28003490 TI - Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase L. AB - Viruses in the family Coronaviridae, within the order Nidovirales, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3' ends of their genomes, that often act as host cell antagonists. We previously showed that 2',5'-phosphodiesterases (2',5'-PDEs) encoded by the prototypical Betacoronavirus, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2',5'-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHVMut) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2',5'-PDEs encoded by the human coronavirus HCoV OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHVMut in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHVMut replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it.IMPORTANCE Viruses in the family Coronaviridae include important human and animal pathogens, including the recently emerged viruses severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV). We showed previously that two viruses within the genus Betacoronavirus, mouse hepatitis virus (MHV) and MERS-CoV, encode 2',5'-phosphodiesterases (2',5'-PDEs) that antagonize the OAS-RNase L pathway, and we report here that these proteins are furthermore conserved among additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses, suggesting that they may play critical roles in pathogenesis. As there are no licensed vaccines or effective antivirals against human coronaviruses and few against those infecting animals, identifying viral proteins contributing to virulence can inform therapeutic development. Thus, this work demonstrates that a potent antagonist of host antiviral defenses is encoded by multiple and diverse viruses within the family Coronaviridae, presenting a possible broad-spectrum therapeutic target. PMID- 28003493 TI - What drives osteoarthritis?-synovial versus subchondral bone pathology. AB - Subchondral bone and the synovium play an important role in the initiation and progression of OA. MRI often permits an early detection of synovial hypertrophy and bone marrow lesions, both of which can precede cartilage damage. Newer imaging modalities including CT osteoabsorptiometry and hybrid SPECT-CT have underlined the importance of bone in OA pathogenesis. The subchondral bone in OA undergoes an uncoupled remodelling process, which is notably characterized by macrophage infiltration and osteoclast formation. Concomitant increased osteoblast activity leads to spatial remineralization and osteosclerosis in end stage disease. A plethora of metabolic and mechanical factors can lead to synovitis in OA. Synovial tissue is highly vascularized and thus exposed to systemic influences such as hypercholesterolaemia or low grade inflammation. This review aims to describe the current understanding of synovitis and subchondral bone pathology and their connection in OA. PMID- 28003491 TI - Disruption of Stress Granule Formation by the Multifunctional Cricket Paralysis Virus 1A Protein. AB - Stress granules (SGs) are cytosolic ribonucleoprotein aggregates that are induced during cellular stress. Several viruses modulate SG formation, suggesting that SGs have an impact on virus infection. However, the mechanisms and impact of modulating SG assembly in infected cells are not completely understood. In this study, we identify the dicistrovirus cricket paralysis virus 1A (CrPV-1A) protein that functions to inhibit SG assembly during infection. Moreover, besides inhibiting RNA interference, CrPV-1A also inhibits host transcription, which indirectly modulates SG assembly. Thus, CrPV-1A is a multifunctional protein. We identify a key R146A residue that is responsible for these effects, and mutant CrPV(R146A) virus infection is attenuated in Drosophila melanogaster S2 cells and adult fruit flies and results in increased SG formation. Treatment of CrPV(R146A) infected cells with actinomycin D, which represses transcription, restores SG assembly suppression and viral yield. In summary, CrPV-1A modulates several cellular processes to generate a cellular environment that promotes viral translation and replication.IMPORTANCE RNA viruses encode a limited set of viral proteins to modulate an array of cellular processes in order to facilitate viral replication and inhibit antiviral defenses. In this study, we identified a viral protein, called CrPV-1A, within the dicistrovirus cricket paralysis virus that can inhibit host transcription, modulate viral translation, and block a cellular process called stress granule assembly. We also identified a specific amino acid within CrPV-1A that is important for these cellular processes and that mutant viruses containing mutations of CrPV-1A attenuate virus infection. We also demonstrate that the CrPV-1A protein can also modulate cellular processes in human cells, suggesting that the mode of action of CrPV-1A is conserved. We propose that CrPV-1A is a multifunctional, versatile protein that creates a cellular environment in virus-infected cells that permits productive virus infection. PMID- 28003494 TI - Thalamic stroke resulting in rheumatoid appearances in the hand. PMID- 28003492 TI - Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors. AB - Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations.IMPORTANCE The development of an efficient vaccine able to prevent HIV infection is a worldwide priority. Knowledge of the envelope glycoprotein structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission. Here we identify residues in the HIV-1 transmembrane envelope glycoprotein that stabilize the unliganded state by modulating the transitions from the unliganded state to the CD4-bound state. PMID- 28003496 TI - PPARGC1B: insight into the expression of the gouty inflammation phenotype: PPARGC1B and gouty inflammation. PMID- 28003495 TI - Efficacy and safety of anti-TNF therapies in psoriatic arthritis: an observational study from the British Society for Rheumatology Biologics Register. PMID- 28003498 TI - A good sleep for a fresh mind in patients with acute traumatic brain injury. PMID- 28003497 TI - Expanding the spectrum of congenital myopathy linked to recessive mutations in SCN4A. PMID- 28003499 TI - New-onset seizure in HIV-infected adult Zambians: A search for causes and consequences. AB - OBJECTIVE: To identify the etiology of new-onset seizure in HIV-infected Zambian adults and identify risk factors for seizure recurrence. METHODS: A prospective cohort study enrolling HIV-infected adults with new-onset seizure within 2 weeks of index seizure obtained clinical, laboratory, and neuroimaging data to determine seizure etiology. Participants were followed to identify risk factors for seizure recurrence. Risk factors for mortality were examined as mortality rates were unexpectedly high. RESULTS: Eighty-one patients with CSF for analysis were enrolled and followed for a median of 306 days (interquartile range 61-636). Most (91%) were at WHO stage III/IV and 66 (81%) had a pre-seizure Karnofsky score >=50. Prolonged or multiple seizures occurred in 46 (57%), including 12 (15%) with status epilepticus. Seizure etiologies included CNS opportunistic infections (OI) in 21 (26%), hyponatremia in 23 (28%), and other infections in 8 (10%). OIs included Cryptococcus (17%), JC virus (7%) and 5% each for tuberculosis, cytomegalovirus, and varicella-zoster virus. No etiology could be identified in 16 (20%). Thirty (37%) patients died during follow-up and 20 (25%) had recurrent seizures with survival being the only identifiable risk factor. CONCLUSIONS: HIV-infected adults with new-onset seizure in Zambia often have advanced HIV disease with OI being the most frequent seizure etiology. Seizure recurrence is common but no risk factors for recurrence other than survival were identified. These findings suggest an urgent need for immune reconstitution in this population. Initiating treatment for seizure prophylaxis where only enzyme inducing antiepileptic medications are available could threaten antiretroviral efficacy. PMID- 28003501 TI - Exercise for stroke prevention: The neglected prescription. PMID- 28003500 TI - Relationship between risk factor control and vascular events in the SAMMPRIS trial. AB - OBJECTIVE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study is the first stroke prevention trial to include protocol-driven intensive management of multiple risk factors. In this prespecified analysis, we aimed to investigate the relationship between risk factor control during follow-up and outcome of patients in the medical arm of SAMMPRIS. METHODS: Data from SAMMPRIS participants in the medical arm (n = 227) were analyzed. Risk factors were recorded at baseline, 30 days, 4 months, and then every 4 months for a mean follow-up of 32 months. For each patient, values for all risk factor measures were averaged and dichotomized as in or out of target. RESULTS: Participants who were out of target for systolic blood pressure and physical activity, as well as those with higher mean low-density lipoprotein cholesterol and non-high-density lipoprotein, were more likely to have a recurrent vascular event (stroke, myocardial infarction, or vascular death) at 3 years compared to those who had good risk factor control. In the multivariable analysis, greater physical activity decreased the likelihood of a recurrent stroke, myocardial infarction, or vascular death (odds ratio 0.6, confidence interval 0.4-0.8). CONCLUSIONS: Raised blood pressure, cholesterol, and physical inactivity should be aggressively treated in patients with intracranial atherosclerosis to prevent future vascular events. Physical activity, which has not received attention in stroke prevention trials, was the strongest predictor of a good outcome in the medical arm in SAMMPRIS. CLINICALTRIALSGOV IDENTIFIER: NCT00576693. PMID- 28003502 TI - Effect of interferon-free therapy on cognition in HCV and HCV/HIV infection: A pilot study. PMID- 28003503 TI - Parallel recovery of consciousness and sleep in acute traumatic brain injury. AB - OBJECTIVE: To investigate whether the progressive recuperation of consciousness was associated with the reconsolidation of sleep and wake states in hospitalized patients with acute traumatic brain injury (TBI). METHODS: This study comprised 30 hospitalized patients (age 29.1 +/- 13.5 years) in the acute phase of moderate or severe TBI. Testing started 21.0 +/- 13.7 days postinjury. Consciousness level and cognitive functioning were assessed daily with the Rancho Los Amigos scale of cognitive functioning (RLA). Sleep and wake cycle characteristics were estimated with continuous wrist actigraphy. Mixed model analyses were performed on 233 days with the RLA (fixed effect) and sleep-wake variables (random effects). Linear contrast analyses were performed in order to verify if consolidation of the sleep and wake states improved linearly with increasing RLA score. RESULTS: Associations were found between scores on the consciousness/cognitive functioning scale and measures of sleep-wake cycle consolidation (p < 0.001), nighttime sleep duration (p = 0.018), and nighttime fragmentation index (p < 0.001). These associations showed strong linear relationships (p < 0.01 for all), revealing that consciousness and cognition improved in parallel with sleep-wake quality. Consolidated 24-hour sleep-wake cycle occurred when patients were able to give context-appropriate, goal-directed responses. CONCLUSIONS: Our results showed that when the brain has not sufficiently recovered a certain level of consciousness, it is also unable to generate a 24-hour sleep-wake cycle and consolidated nighttime sleep. This study contributes to elucidating the pathophysiology of severe sleep-wake cycle alterations in the acute phase of moderate to severe TBI. PMID- 28003504 TI - The trouble with plasma cells: Getting to the root cause. PMID- 28003505 TI - Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. AB - OBJECTIVE: We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti NMDA receptor (anti-NMDAR) encephalitis. METHODS: Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1-6 cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events was closely monitored. RESULTS: Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile. CONCLUSIONS: Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory anti-NMDAR encephalitis. CLASSIFICATION OF EVIDENCE: This retrospective case series provides Class IV evidence that bortezomib reduces antibody titers and improves the clinical course of patients with severe anti-NMDAR encephalitis. PMID- 28003506 TI - Developing a Biomarker Feedback Intervention to Motivate Smoking Cessation During Pregnancy: Phase II MAW Study. AB - Introduction: The prevalence of smoking during pregnancy for Alaska Native (AN) women is more than triple that of non-Native Alaska women. In this qualitative study, we solicited input from AN women and others to determine how best to present findings from an earlier study demonstrating a strong correlation between biomarkers for maternal smoking (cotinine) and neonatal exposure to a tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) to motivate cessation. Methods: We developed a brochure incorporating generalized biomarker information. Using in-depth individual interviews with pregnant and postpartum AN women and partners/family members, we explored applicability and acceptability of the information. Postpartum women, who had participated in the earlier correlation study, additionally received their individual biomarker results. We assessed whether being presented general or individual biomarker information would motivate cessation using content analysis. Results: We conducted 39 interviews: 16 pregnant women, 12 postpartum women, and 11 partners/family members. Overall, participants agreed the biomarker information was new, but understandable as presented. Postpartum women shared that learning their personal results inspired them to want to quit or cut back smoking while pregnant women indicated the generalized correlation information was less helpful in motivating cessation. Conclusion: Generalized information about fetal exposure to carcinogens may be more effective in motivating pregnant women to quit smoking when combined with individual cotinine testing. Implications: Using feedback from this study, we refined and are currently evaluating an intervention incorporating generalized correlation information from Phase I and cotinine testing to determine its effectiveness in motivating smoking cessation among pregnant AN women. PMID- 28003507 TI - Low Nicotine Content Descriptors Reduce Perceived Health Risks and Positive Cigarette Ratings in Participants Using Very Low Nicotine Content Cigarettes. AB - Introduction: Understanding how smokers perceive reduced nicotine content cigarettes will be important if the FDA and global regulatory agencies implement reduced nicotine product standards for cigarettes. Prior research has shown that some smokers incorrectly believe "light" cigarettes are less harmful than regular cigarettes. Similar misunderstandings of health risk could also apply to reduced nicotine cigarettes. To date, most studies of reduced nicotine cigarettes have blinded subjects to the nicotine content. Therefore, little is known about how smokers experience reduced nicotine content cigarettes when they are aware of the reduced content, and how use may be impacted. Methods: The present study was a within-subjects experiment with 68 adult daily smokers who smoked two identical very low nicotine content Quest 3 (0.05 mg nicotine yield) cigarettes. Subjects were told that one cigarette contained "average" nicotine content, and the other contained "very low" nicotine content. After smoking each cigarette, subjects completed subjective measures about their smoking experience. Results: Subjects rated the "very low" nicotine cigarette as less harmful to their health overall compared to the "average" nicotine cigarette; this effect held true for specific smoking-related diseases. Additionally, they rated the "very low" nicotine cigarette as having less desirable subjective effects than the "average" nicotine cigarette and predicted having greater interest in quitting smoking in the future if only the "very low" nicotine cigarette was available. Conclusions: Explicit knowledge of very low nicotine content changes smokers' perceptions of very low nicotine content cigarettes, resulting in reduced predicted harm, subjective ratings and predicted future use. Implications: Before a reduced nicotine product standard for cigarettes can be implemented, it is important to understand how product information impacts how smokers think about and experience very low nicotine content cigarettes. Prior research has shown that smokers incorrectly believed light cigarettes were less harmful products. As such, smokers may also misunderstand the health risks associated with smoking very low nicotine content cigarettes. This study highlights the importance of smokers' perceptions of nicotine content in cigarettes on the perceived health risks and the subjective effects of smoking very low nicotine content cigarettes. PMID- 28003508 TI - Cigar Product Modification Among High School Youth. AB - Introduction: Prevalence of cigar use has been increasing among youth. Research indicates that youth are modifying cigar products either by "freaking" (ie, removing the filter paper) or "blunting" (removing the tobacco and supplementing or replacing with marijuana), yet little is known about youth who engage in this behavior. Thus, this study examines demographic and concurrent substance use behaviors of youth who modify cigars. Methods: Data from the 2013 Cuyahoga County Youth Risk Behavior survey were examined (n = 16 855). The survey collected data on demographics, cigar product use, cigar modification behaviors, and current cigarette, hookah and marijuana use. Responses to cigar product use items were used to create a composite to classify youth in one of eight unique user categories. Univariate and bivariate statistics were calculated using SPSS complex samples procedures. Results: Overall, 15.2% reported current cigar product use, 11.0% reported current freaking, and 18.5% reported current blunt use; taken together, 25.3% of respondents reported any current use of a cigar product. When examined by user category, of those who endorsed any cigar product use, cigars, cigarillos, and little cigars use only was most endorsed (26.3%), followed by Blunt only (25.2%) and all three (ie, cigars, cigarillos, and little cigars, freaking, and blunting; 17.4%). Conclusion: A substantial proportion of high school youth who report using cigar products are modifying them in some way, with nearly half freaking and nearly two-thirds blunting. Given the FDA Center for Tobacco products recent extension of its regulatory authority to include cigar products, it is imperative to understand more about the prevalence of and reasons for cigar modification behaviors. Implications: Although the FDA has recently enacted regulatory authority over cigar products, little is known about cigar product modification. This is the first study to concurrently examine two unique cigar modification behaviors, "freaking" (ie, removing the filter paper) and "blunting" (removing the tobacco and supplementing or replacing with marijuana). A significant proportion of high school youth are modifying cigar products to be used as a tobacco product and as a mechanism to smoke marijuana. More research is needed to understand these behaviors to prevent and reduce the use of cigar products among youth. PMID- 28003509 TI - The Importance of Relevant Emotional Arousal in the Efficacy of Pictorial Health Warnings for Cigarettes. AB - Introduction: Warning labels for cigarettes proposed by Food and Drug Administration (FDA) were rejected by the courts partly because they were thought to be emotionally evocative but have no educational value. To address this issue, we compared three types of smoking warnings: (1) FDA-proposed warnings with pictures illustrating the smoking hazards; (2) warnings with the same text information paired with equally aversive but smoking-irrelevant images; and (3) text-only warnings. Methods: Smokers recruited through Amazon's Mechanical Turk were randomly assigned to one of the three conditions. They reported how many cigarettes they smoked per day (CPD) during the past week and then viewed eight different warnings. After viewing each warning, they rated its believability and perceived ability to motivate quitting. One week later, 62.3% of participants again reported CPD during the past week, rated how the warnings they viewed the week before changed their feeling about smoking, rated their intention to quit in the next 30 days, and recalled as much as they could about each of the warnings they viewed. Results: Compared to the irrelevant image and text-only warnings, FDA warnings were seen as more believable and able to motivate quitting and at the follow-up, produced lower CPD, worse feeling about smoking, and more memory for warning information, controlling for age and baseline CPD. Conclusions: Emotionally evocative warning images are not effective in communicating the risks of smoking, unless they pertain to smoking-related hazards. In future versions of warning labels, pictorial contents should be pretested for the ability to enhance the health-hazard message. Implications: Our study shows that contrary to court opinions, FDA-proposed pictorial warnings for cigarettes are more effective in communicating smoking-related hazards than warnings that merely contain emotionally aversive but smoking-irrelevant images. The suggestion that FDA's proposed warnings employed emotionally arousing pictures with no information value was not supported. Pictures that illustrate the risk carry information that enhances the persuasiveness of the warning. The congruence between pictures and text should be a criterion for selecting warning images in the future. PMID- 28003510 TI - Racial/Ethnic Differences in Duration of Smoking Among Former Smokers in the National Health and Nutrition Examination Surveys. AB - Introduction: The burden of tobacco-related disease is not uniformly distributed across racial/ethnic groups. Differences in smoking duration by race/ethnicity may contribute to this disparity. Previous studies have examined racial/ethnic differences in smoking duration among ever smokers (former and current smokers combined). It is unknown if racial/ethnic differences in smoking duration are evident among quitters. This study examined racial/ethnic differences in duration of smoking among former smokers in the United States. Methods: We studied 6030 white, black, and Mexican-American former smokers (3647 men and 2383 women) aged 20-79 years who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 through 2012. Mean differences in smoking duration by race/ethnicity were estimated using linear regression models. Results: After adjustment for demographics, age at smoking initiation and smoking intensity, compared to white men, black men smoked for 2.3 (95% confidence interval [CI]: 1.3, 3.3) years longer before quitting and Mexican-American men for 0.2 (95% CI: 1.6, 1.2) years less before quitting. Compared to white women, black women smoked for 1.9 (95% CI: 0.7, 3.0) years longer before quitting and Mexican-American women for 0.9 (95% CI: -2.4, 0.5) years less before quitting. Conclusions: In a representative sample of US adults, black former smokers continued smoking for longer periods before quitting compared to white former smokers. These findings support the need for smoking cessation efforts that address racial/ethnic differences in smoking behaviors. The longer time to quit among black former smokers should be investigated as an explanation for racial/ethnic disparities in smoking-associated diseases. Implications: In a representative sample of US adults that successfully quit smoking, the timing of smoking cessation differed by race/ethnicity with blacks smoking for longer periods before quitting compared to whites. Racial/ethnic differences in duration of smoking among former smokers differed by participant age and age at smoking initiation. These findings support the need for smoking cessation efforts that address racial/ethnic differences in smoking behaviors. PMID- 28003511 TI - Tobacco Consumption and Toxicant Exposure of Cigarette Smokers Using Electronic Cigarettes. AB - Background: There is considerable debate about the benefits and risks of electronic cigarettes (ECs). To better understand the risk-benefit ratio of ECs, more information is needed about net nicotine consumption and toxicant exposure of cigarette smokers switching to ECs. Methods: Forty cigarette smokers (>=1 year of smoking) interested in switching to ECs but not necessarily quitting smoking were enrolled in a 4-week observational study and provided an e-Go C non-variable battery and refillable atomizers and choice of eight flavors in 12 or 24 mg nicotine dosage. Measurement of urinary cotinine (metabolite of nicotine), 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; a pulmonary carcinogen), and eight volatile organic compounds (VOCs) that are toxic tobacco smoke constituents was conducted at baseline and week 4. Results: All participants with follow-up data (92.5%) reported using the study EC. Of the 40 smokers, 16 reported no cigarettes at week 2 (40%) and six continued to report no cigarettes at week 4 (15%). Change in nicotine intake over the 4 weeks was non-significant (p = .90). Carbon monoxide (p < .001), NNAL (p < .01) and metabolites of benzene (p < .01) and acrylonitrile (p = .001) were significantly decreased in the study sample. Smokers switching exclusively to ECs for at least half of the study period demonstrated significant reductions in metabolites of ethylene oxide (p = .03) and acrylamide (p < .01). Conclusion: Smokers using ECs over 4 weeks maintained cotinine levels and experienced significant reductions in carbon monoxide, NNAL, and two out of eight measured VOC metabolites. Those who switched exclusively to ECs for at least half of the study period significantly reduced two additional VOCs. Implications: This study extends current literature by measuring change in smoking dependence and disease-associated biomarkers, NNAL and a panel of eight common VOCs that are toxic tobacco smoke constituents in smokers who switch to ECs. The findings support the idea of harm reduction, however some levels of toxicant exposure are still of clinical concern, particularly for dual users. Extrapolation of these results must be careful to separate the different toxic exposure results for exclusive switchers versus dual cigarette + EC users, and not to equate harm reduction with the idea that using ECs is harmless. PMID- 28003512 TI - Characteristics of "American Snus" and Swedish Snus Products for Sale in Massachusetts, USA. AB - Introduction: Snus may present lower health risks than cigarettes, but its harm reduction potential may be undermined if used dually with cigarettes. The likelihood of exclusive snus use compared with dual use may depend in part on the capacity of snus to deliver nicotine in doses that are satisfactory to smokers. We examined characteristics of "American snus" products, including nicotine levels, and compared to snus products that are more typical of Sweden. Methods: Tobacco industry reports for snus products submitted to the Massachusetts Department of Public Health for the year 2014 were used to assess moisture (%), pH, total nicotine, and unionized (free) nicotine (both mg/g and percent of total). A total of 14 ("American") snus products made by American manufacturers Philip Morris USA (n = 6), R.J. Reynolds Tobacco Company (n = 6), and US Smokeless Tobacco Company (n = 2), were compared with Swedish-style ("Swedish") snus products (n = 10) made by Swedish Match North America. Results: Compared with Swedish snus, American snus brands contained significantly lower concentrations of unionized nicotine (median: 0.52 mg/g vs. 6.52 mg/g; p < .001) and proportion of unionized nicotine (median: 3.17% vs. 81.8%; p < .001). American snus brands also had significantly lower pH (median: 6.54 vs. 8.68; p < .001) and moisture (median: 30.3% vs. 53.4%; p < .001). Conclusions: Swedish-made snus has higher unionized nicotine, measured by concentration and proportion of total nicotine, compared with snus products made by American manufacturers. These findings suggest that American snus products have lower addiction potential than Swedish snus, and may be more likely to be used dually with cigarettes than as a sole source of nicotine. Implications: American snus products contain significantly lower unionized nicotine, lower pH, and lower moisture, compared with Swedish snus products. Snus addiction potential and patterns of usage, including co-use with cigarettes, may differ between American and Swedish snus products due to differences in snus product characteristics. PMID- 28003513 TI - Maternal Smoking During Pregnancy Is Associated With Offspring's Musculoskeletal Pain in Adolescence: Structural Equation Modeling. AB - Introduction: Smoking and behavioral problems are related to musculoskeletal (MS) pain in adolescence. Maternal smoking during pregnancy (MSDP) is associated with offspring's behavioral problems but its relation to MS pain in adolescence is unknown. Our purpose was to investigate whether there is an association between MSDP, the number of pain sites in adolescence, and the factors that potentially mediate this relationship. Methods: We evaluated the association of MSDP with offspring's MS pain at 16 years among participants of the Northern Finland Birth Cohort 1986 (n = 6436, 3360 girls, 68% of all births) using Chi-square test and independent samples t test. We used structural equation modeling to assess the mediating factors stratified by gender. Results: MSDP was frequent (22%) associating with paternal smoking (p < .001), externalization problems at 8 years (p = .009 boys, p = .002 girls), offspring's smoking at 16 years (p < .001), externalizing problems at 16 years (p < .001), family's social class (p < .001) and intactness of the family status (p < .001). The mean number of offspring's MS pain sites was higher among adolescents whose mothers had smoked during pregnancy than among those whose mothers were nonsmokers (p = .002 boys, p = .012 girls). The association between MSDP and MS pain at 16 years was mediated by externalizing problems at 8 years (p < .001) and 16 years (p < 0.001). Conclusions: MSDP increased the risk of offspring's MS pain in adolescence, and the association was mediated by offspring's externalizing problems during childhood and early adolescence. Implications: This study indicates that MSDP increases the risk of MS pain in adolescence and the effect is mediated by externalizing problems. Our results add to the evidence on harmfulness of MSDP for offspring, and can be used as additional information in interventions aiming to influence MSDP. PMID- 28003514 TI - S. cerevisiae Trm140 has two recognition modes for 3-methylcytidine modification of the anticodon loop of tRNA substrates. AB - The 3-methylcytidine (m3C) modification is ubiquitous in eukaryotic tRNA, widely found at C32 in the anticodon loop of tRNAThr, tRNASer, and some tRNAArg species, as well as in the variable loop (V-loop) of certain tRNASer species. In the yeast Saccharomyces cerevisiae, formation of m3C32 requires Trm140 for six tRNA substrates, including three tRNAThr species and three tRNASer species, whereas in Schizosaccharomyces pombe, two Trm140 homologs are used, one for tRNAThr and one for tRNASer The occurrence of a single Trm140 homolog is conserved broadly among Ascomycota, whereas multiple Trm140-related homologs are found in metazoans and other fungi. We investigate here how S. cerevisiae Trm140 protein recognizes its six tRNA substrates. We show that Trm140 has two modes of tRNA substrate recognition. Trm140 recognizes G35-U36-t6A37 of the anticodon loop of tRNAThr substrates, and this sequence is an identity element because it can be used to direct m3C modification of tRNAPhe However, Trm140 recognition of tRNASer substrates is different, since their anticodons do not share G35-U36 and do not have any nucleotides in common. Rather, specificity of Trm140 for tRNASer is achieved by seryl-tRNA synthetase and the distinctive tRNASer V-loop, as well as by t6A37 and i6A37 We provide evidence that all of these components are important in vivo and that seryl-tRNA synthetase greatly stimulates m3C modification of tRNASer(CGA) and tRNASer(UGA) in vitro. In addition, our results show that Trm140 binding is a significant driving force for tRNA modification and suggest separate contributions from each recognition element for the modification. PMID- 28003515 TI - Conserved binding of GCAC motifs by MEC-8, couch potato, and the RBPMS protein family. AB - Precise regulation of mRNA processing, translation, localization, and stability relies on specific interactions with RNA-binding proteins whose biological function and target preference are dictated by their preferred RNA motifs. The RBPMS family of RNA-binding proteins is defined by a conserved RNA recognition motif (RRM) domain found in metazoan RBPMS/Hermes and RBPMS2, Drosophila couch potato, and MEC-8 from Caenorhabditis elegans In order to determine the parameters of RNA sequence recognition by the RBPMS family, we have first used the N-terminal domain from MEC-8 in binding assays and have demonstrated a preference for two GCAC motifs optimally separated by >6 nucleotides (nt). We have also determined the crystal structure of the dimeric N-terminal RRM domain from MEC-8 in the unbound form, and in complex with an oligonucleotide harboring two copies of the optimal GCAC motif. The atomic details reveal the molecular network that provides specificity to all four bases in the motif, including multiple hydrogen bonds to the initial guanine. Further studies with human RBPMS, as well as Drosophila couch potato, confirm a general preference for this double GCAC motif by other members of the protein family and the presence of this motif in known targets. PMID- 28003516 TI - Linking maternal and somatic 5S rRNA types with different sequence-specific non LTR retrotransposons. AB - 5S rRNA is a ribosomal core component, transcribed from many gene copies organized in genomic repeats. Some eukaryotic species have two 5S rRNA types defined by their predominant expression in oogenesis or adult tissue. Our next generation sequencing study on zebrafish egg, embryo, and adult tissue identified maternal-type 5S rRNA that is exclusively accumulated during oogenesis, replaced throughout the embryogenesis by a somatic-type, and thus virtually absent in adult somatic tissue. The maternal-type 5S rDNA contains several thousands of gene copies on chromosome 4 in tandem repeats with small intergenic regions, whereas the somatic-type is present in only 12 gene copies on chromosome 18 with large intergenic regions. The nine-nucleotide variation between the two 5S rRNA types likely affects TFIII binding and riboprotein L5 binding, probably leading to storage of maternal-type rRNA. Remarkably, these sequence differences are located exactly at the sequence-specific target site for genome integration by the 5S rRNA-specific Mutsu retrotransposon family. Thus, we could define maternal and somatic-type MutsuDr subfamilies. Furthermore, we identified four additional maternal-type and two new somatic-type MutsuDr subfamilies, each with their own target sequence. This target-site specificity, frequently intact maternal-type retrotransposon elements, plus specific presence of Mutsu retrotransposon RNA and piRNA in egg and adult tissue, suggest an involvement of retrotransposons in achieving the differential copy number of the two types of 5S rDNA loci. PMID- 28003517 TI - Predator diversity reduces habitat colonization by mosquitoes and midges. AB - Changes in predator diversity via extinction and invasion are increasingly widespread and can have important ecological and socio-economic consequences. Anticipating and managing these consequences requires understanding how predators shape ecological communities. Previous predator biodiversity research has focused on post-colonization processes. However, predators can also shape communities by altering patterns of prey habitat selection during colonization. The sensitivity of this non-consumptive top down mechanism to changes in predator diversity is largely unexamined. To address this gap, we examined patterns of dipteran oviposition habitat selection in experimental aquatic habitats in response to varied predator species richness while holding predator abundance constant. Caged predators were used in order to disentangle behavioural oviposition responses to predator cues from potential post-oviposition consumption of eggs and larvae. We hypothesized that because increases in predator richness often result in greater prey mortality than would be predicted from independent effects of predators, prey should avoid predator-rich habitats during colonization. Consistent with this hypothesis, predator-rich habitats received 48% fewer dipteran eggs than predicted, including 60% fewer mosquito eggs and 38% fewer midge eggs. Our findings highlight the potentially important links between predator biodiversity, prey habitat selection and the ecosystem service of pest regulation. PMID- 28003518 TI - Independent natural genetic variation of punishment- versus relief-memory. AB - A painful event establishes two opponent memories: cues that are associated with pain onset are remembered negatively, whereas cues that coincide with the relief at pain offset acquire positive valence. Such punishment- versus relief-memories are conserved across species, including humans, and the balance between them is critical for adaptive behaviour with respect to pain and trauma. In the fruit fly, Drosophila melanogaster as a study case, we found that both punishment- and relief-memories display natural variation across wild-derived inbred strains, but they do not covary, suggesting a considerable level of dissociation in their genetic effectors. This provokes the question whether there may be heritable inter-individual differences in the balance between these opponent memories in man, with potential psycho-clinical implications. PMID- 28003519 TI - A trade-off between reproductive investment and maternal cerebellum size in a precocial bird. AB - Natural selection favours increased investment in reproduction, yet considerable variation in parental investment is observed in natural populations. Life-history theory predicts that this variation is maintained by a trade-off between the benefits of increased reproductive investment and its associated costs for the parents. The nature of these costs of reproduction, however, remains poorly understood. The brain is an energetically highly expensive organ and increased reproductive investment may, therefore, negatively affect brain maintenance. Using artificial selection lines for high and low prenatal maternal investment in a precocial bird, the Japanese quail (Coturnix japonica), we provide experimental evidence for this hypothesis by showing that increased prenatal provisioning negatively affects the size of a particular brain region of the mother, the cerebellum. Our finding suggests that cognitive demands may constrain the evolution of parental investment, and vice versa, contributing to the maintenance of variation in reproductive behaviour in animal populations. PMID- 28003520 TI - Higher temperature exacerbates the impact of sediments on embryo performances in a salmonid. AB - In a warming climate, higher temperatures are likely to modulate positively or negatively the effect of other environmental factors on biota, although such interactions are poorly documented. Here, we explore under controlled conditions the combined effects of two common stressors in freshwater ecosystems, higher temperature and sediment load, on the embryonic development of arctic charr (Salvelinus alpinus L.). In the warm treatment, embryos had a lower survival, a longer incubation period and a smaller body size with a bigger yolk sac volume. Our data show a significant interaction between temperature and sediment load with temperature increasing dramatically the negative effects of sediment load on fitness-related traits. In the climate change context, these findings highlight the importance of taking into account different thermal scenarios when examining the effect of environmental or anthropogenic stressors. PMID- 28003521 TI - Micropyle number is associated with elevated female promiscuity in Lepidoptera. AB - In the majority of insects, sperm fertilize the egg via a narrow canal through the outer chorion called the micropyle. Despite having this one primary function, there is considerable unexplained variation in the location, arrangement and number of micropyles within and between species. Here, we examined the relationship between micropyle number and female mating pattern through a comparative analysis across Lepidoptera. Three functional hypotheses could explain profound micropylar variation: (i) increasing micropyle number reduces the risk of infertility through sperm limitation in species that mate infrequently; (ii) decreasing micropyle number reduces the risk of pathological polyspermy in species that mate more frequently; and (iii) increasing micropyle number allows females to exert greater control over fertilization within the context of post-copulatory sexual selection, which will be more intense in promiscuous species. Micropyle number was positively related to the degree of female promiscuity as measured by spermatophore count, regardless of phylogenetic signal, supporting the hypothesis that micropyle number is shaped by post copulatory sexual selection. We discuss this finding in the context of cryptic female choice, sperm limitation and physiological polyspermy. PMID- 28003522 TI - Patterns of migrating soaring migrants indicate attraction to marine wind farms. AB - Monitoring of bird migration at marine wind farms has a short history, and unsurprisingly most studies have focused on the potential for collisions. Risk for population impacts may exist to soaring migrants such as raptors with K strategic life-history characteristics. Soaring migrants display strong dependence on thermals and updrafts and an affinity to land areas and islands during their migration, a behaviour that creates corridors where raptors move across narrow straits and sounds and are attracted to islands. Several migration corridors for soaring birds overlap with the development regions for marine wind farms in NW Europe. However, no empirical data have yet been available on avoidance or attraction rates and behavioural reactions of soaring migrants to marine wind farms. Based on a post-construction monitoring study, we show that all raptor species displayed a significant attraction behaviour towards a wind farm. The modified migratory behaviour was also significantly different from the behaviour at nearby reference sites. The attraction was inversely related to distance to the wind farm and was primarily recorded during periods of adverse wind conditions. The attraction behaviour suggests that migrating raptor species are far more at risk of colliding with wind turbines at sea than hitherto assessed. PMID- 28003523 TI - An experimental evolution study confirms that discontinuous gas exchange does not contribute to body water conservation in locusts. AB - The adaptive nature of discontinuous gas exchange (DGE) in insects is contentious. The classic 'hygric hypothesis', which posits that DGE serves to reduce respiratory water loss (RWL), is still the best supported. We thus focused on the hygric hypothesis in this first-ever experimental evolution study of any of the competing adaptive hypotheses. We compared populations of the migratory locust (Locusta migratoria) that underwent 10 consecutive generations of selection for desiccation resistance with control populations. Selected locusts survived 36% longer under desiccation stress but DGE prevalence did not differ between these and control populations (approx. 75%). Evolved changes in DGE properties in the selected locusts included longer cycle and interburst durations. However, in contrast with predictions of the hygric hypothesis, these changes were not associated with reduced RWL rates. Other responses observed in the selected locusts were higher body water content when hydrated and lower total evaporative water loss rates. Hence, our data suggest that DGE cycle properties in selected locusts are a consequence of an evolved increased ability to store water, and thus an improved capacity to buffer accumulated CO2, rather than an adaptive response to desiccation. We conclude that DGE is unlikely to be an evolutionary response to dehydration challenge in locusts. PMID- 28003524 TI - Genetic colour polymorphism is associated with avian malarial infections. AB - Individual genetic diversity is predicted to influence host-parasite interactions. Together with the genes directly associated with immune responses, variation in genes regulating vertebrate melanin-based pigmentation may play an important role in these interactions, mainly through the pleiotropic effects that affect colour-specific physiology, behaviour and immunity. Here, we test the hypothesis that the prevalence of avian malarial parasites differs between phenotypes in a raptor species in which the genetic basis of colour polymorphism and its pleiotropic effects over immune functions are known. We found that dark morphs had a higher prevalence of Plasmodium parasites than pale ones but detected no such association for Haemoproteus This pattern may be associated with unequal exposure to vectors or, as suggested by our circumstantial evidence, to a differential ability to mount an immune response against blood parasites. PMID- 28003525 TI - Correction to 'Through the eyes of a bird: modelling visually guided obstacle flight'. PMID- 28003527 TI - Niepce-Bell or Turing: how to test odour reproduction. AB - Decades before the existence of anything resembling an artificial intelligence system, Alan Turing raised the question of how to test whether machines can think, or, in modern terminology, whether a computer claimed to exhibit intelligence indeed does so. This paper raises the analogous issue for olfaction: how to test the validity of a system claimed to reproduce arbitrary odours artificially, in a way recognizable to humans. Although odour reproduction systems are still far from being viable, the question of how to test candidates thereof is claimed to be interesting and non-trivial, and a novel method is proposed. Despite the similarity between the two questions and their surfacing long before the tested systems exist, the present question cannot be answered adequately by a Turing-like method. Instead, our test is very different: it is conditional, requiring from the artificial no more than is required from the original, and it employs a novel method of immersion that takes advantage of the availability of easily recognizable reproduction methods for sight and sound, a la Nicephore Niepce and Alexander Graham Bell. PMID- 28003526 TI - Differential cell-matrix responses in hypoxia-stimulated aortic versus mitral valves. AB - Tissue oxygenation often plays a significant role in disease and is an essential design consideration for tissue engineering. Here, oxygen diffusion profiles of porcine aortic and mitral valve leaflets were determined using an oxygen diffusion chamber in conjunction with computational models. Results from these studies revealed the differences between aortic and mitral valve leaflet diffusion profiles and suggested that diffusion alone was insufficient for normal oxygen delivery in mitral valves. During fibrotic valve disease, leaflet thickening due to abnormal extracellular matrix is likely to reduce regional oxygen availability. To assess the impact of low oxygen levels on valve behaviour, whole leaflet organ cultures were created to induce leaflet hypoxia. These studies revealed a loss of layer stratification and elevated levels of hypoxia inducible factor 1-alpha in both aortic and mitral valve hypoxic groups. Mitral valves also exhibited altered expression of angiogenic factors in response to low oxygen environments when compared with normoxic groups. Hypoxia affected aortic and mitral valves differently, and mitral valves appeared to show a stenotic, rheumatic phenotype accompanied by significant cell death. These results indicate that hypoxia could be a factor in mid to late valve disease progression, especially with the reduction in chondromodulin-1 expression shown by hypoxic mitral valves. PMID- 28003529 TI - Managing aquatic parasites for reduced drug resistance: lessons from the land. AB - Atlantic salmon farming is one of the largest aquaculture industries in the world. A major problem in salmon farms is the sea louse ectoparasite Lepeophtheirus salmonis, which can cause stress, secondary infection and sometimes mortality in the salmon host. Sea lice have substantial impacts on farm economics and potentially nearby wild salmonid populations. The most common method of controlling sea louse infestations is application of chemicals. However, most farming regions worldwide have observed resistance to the small set of treatment chemicals that are available. Despite this, there has been little investigation of treatment strategies for managing resistance in aquaculture. In this article, we compare four archetypical treatment strategies inspired by agriculture, where the topic has a rich history of study, and add a fifth strategy common in aquaculture. We use an agent-based model (ABM) to simulate these strategies and their varying applications of chemicals over time and space. We analyse the ABM output to compare how the strategies perform in controlling louse abundance, number of treatments required and levels of resistance in the sea louse population. Our results indicated that among the approaches considered applying chemicals in combination was the most effective over the long term. PMID- 28003528 TI - Behavioural change models for infectious disease transmission: a systematic review (2010-2015). AB - We review behavioural change models (BCMs) for infectious disease transmission in humans. Following the Cochrane collaboration guidelines and the PRISMA statement, our systematic search and selection yielded 178 papers covering the period 2010 2015. We observe an increasing trend in published BCMs, frequently coupled to (re)emergence events, and propose a categorization by distinguishing how information translates into preventive actions. Behaviour is usually captured by introducing information as a dynamic parameter (76/178) or by introducing an economic objective function, either with (26/178) or without (37/178) imitation. Approaches using information thresholds (29/178) and exogenous behaviour formation (16/178) are also popular. We further classify according to disease, prevention measure, transmission model (with 81/178 population, 6/178 metapopulation and 91/178 individual-level models) and the way prevention impacts transmission. We highlight the minority (15%) of studies that use any real-life data for parametrization or validation and note that BCMs increasingly use social media data and generally incorporate multiple sources of information (16/178), multiple types of information (17/178) or both (9/178). We conclude that individual-level models are increasingly used and useful to model behaviour changes. Despite recent advancements, we remain concerned that most models are purely theoretical and lack representative data and a validation process. PMID- 28003531 TI - Bayes Factors Unmask Highly Variable Information Content, Bias, and Extreme Influence in Phylogenomic Analyses. AB - As the application of genomic data in phylogenetics has become routine, a number of cases have arisen where alternative data sets strongly support conflicting conclusions. This sensitivity to analytical decisions has prevented firm resolution of some of the most recalcitrant nodes in the tree of life. To better understand the causes and nature of this sensitivity, we analyzed several phylogenomic data sets using an alternative measure of topological support (the Bayes factor) that both demonstrates and averts several limitations of more frequently employed support measures (such as Markov chain Monte Carlo estimates of posterior probabilities). Bayes factors reveal important, previously hidden, differences across six "phylogenomic" data sets collected to resolve the phylogenetic placement of turtles within Amniota. These data sets vary substantially in their support for well-established amniote relationships, particularly in the proportion of genes that contain extreme amounts of information as well as the proportion that strongly reject these uncontroversial relationships. All six data sets contain little information to resolve the phylogenetic placement of turtles relative to other amniotes. Bayes factors also reveal that a very small number of extremely influential genes (less than 1% of genes in a data set) can fundamentally change significant phylogenetic conclusions. In one example, these genes are shown to contain previously unrecognized paralogs. This study demonstrates both that the resolution of difficult phylogenomic problems remains sensitive to seemingly minor analysis details and that Bayes factors are a valuable tool for identifying and solving these challenges. PMID- 28003530 TI - The stentable in vitro artery: an instrumented platform for endovascular device development and optimization. AB - Although vascular disease is a leading cause of mortality, in vitro tools for controlled, quantitative studies of vascular biological processes in an environment that reflects physiological complexity remain limited. We developed a novel in vitro artery that exhibits a number of unique features distinguishing it from tissue-engineered or organ-on-a-chip constructs, most notably that it allows deployment of endovascular devices including stents, quantitative real-time tracking of cellular responses and detailed measurement of flow velocity and lumenal shear stress using particle image velocimetry. The wall of the stentable in vitro artery consists of an annular collagen hydrogel containing smooth muscle cells (SMCs) and whose lumenal surface is lined with a monolayer of endothelial cells (ECs). The system has in vivo dimensions and physiological flow conditions and allows automated high-resolution live imaging of both SMCs and ECs. To demonstrate proof-of-concept, we imaged and quantified EC wound healing, SMC motility and altered shear stresses on the endothelium after deployment of a coronary stent. The stentable in vitro artery provides a unique platform suited for a broad array of research applications. Wide-scale adoption of this system promises to enhance our understanding of important biological events affecting endovascular device performance and to reduce dependence on animal studies. PMID- 28003532 TI - Uncovering Higher-Taxon Diversification Dynamics from Clade Age and Species Richness Data. AB - The relationship between clade age and species richness has been increasingly used in macroevolutionary studies as evidence for ecologically versus time dependent diversification processes. However, theory suggests that phylogenetic structure, age type (crown or stem age), and taxonomic delimitation can affect estimates of the age-richness correlation (ARC) considerably. We currently lack an integrative understanding of how these different factors affect ARCs, which in turn, obscures further interpretations. To assess its informative breadth, we characterize ARC behavior with simulated and empirical phylogenies, considering phylogenetic structure and both crown and stem ages. First, we develop a two state birth-death model to simulate phylogenies including the origin of higher taxa and a hierarchical taxonomy to determine ARC expectations under ecologically and time-dependent diversification processes. Then, we estimate ARCs across various taxonomic ranks of extant amphibians, squamate reptiles, mammals, birds, and flowering plants. We find that our model reproduces the general ARC trends of a wide range of biological systems despite the particularities of taxonomic practice within each, suggesting that the model is adequate to establish a framework of ARC null expectations for different diversification processes when taxa are defined with a hierarchical taxonomy. ARCs estimated with crown ages were positive in all the scenarios we studied, including ecologically dependent processes. Negative ARCs were only found at less inclusive taxonomic ranks, when considering stem age, and when rates varied among clades. This was the case both in ecologically and time-dependent processes. Together, our results warn against direct interpretations of single ARC estimates and advocate for a more integrative use of ARCs across age types and taxonomic ranks in diversification studies. [Birth-Death models; crown age; diversity dependence; extinction; phylogenetic structure; speciation; stem age; taxonomy; time dependence; tree simulations.]. PMID- 28003533 TI - A Unifying Comparative Phylogenetic Framework Including Traits Coevolving Across Interacting Lineages. AB - Models of phenotypic evolution fit to phylogenetic comparative data are widely used to make inferences regarding the tempo and mode of trait evolution. A wide range of models is already available for this type of analysis, and the field is still under active development. One of the most needed development concerns models that better account for the effect of within- and between-clade interspecific interactions on trait evolution, which can result from processes as diverse as competition, predation, parasitism, or mutualism. Here, we begin by developing a very general comparative phylogenetic framework for (multi)-trait evolution that can be applied to both ultrametric and nonultrametric trees. This framework not only encapsulates many previous models of continuous univariate and multivariate phenotypic evolution, but also paves the way for the consideration of a much broader series of models in which lineages coevolve, meaning that trait changes in one lineage are influenced by the value of traits in other, interacting lineages. Next, we provide a standard way for deriving the probabilistic distribution of traits at tip branches under our framework. We show that a multivariate normal distribution remains the expected distribution for a broad class of models accounting for interspecific interactions. Our derivations allow us to fit various models efficiently, and in particular greatly reduce the computation time needed to fit the recently proposed phenotype matching model. Finally, we illustrate the utility of our framework by developing a toy model for mutualistic coevolution. Our framework should foster a new era in the study of coevolution from comparative data. PMID- 28003535 TI - Species Delimitation with Gene Flow. AB - Species are commonly thought to be evolutionarily independent in a way that populations within a species are not. In recent years, studies that seek to identify evolutionarily independent lineages (i.e., to delimit species) using genetic data have typically adopted multispecies coalescent approaches that assume that evolutionary independence is formed by the differential sorting of ancestral alleles due to genetic drift. However, gene flow appears to be common among populations and nascent species, and while this process may inhibit lineage divergence (and thus independence), it is usually not explicitly considered when delimiting species. In this article, we apply Phylogeographic Inference using Approximate Likelihoods (PHRAPL), a recently described method for phylogeographic model selection, to species delimitation. We describe an approach to delimiting species using PHRAPL that attempts to account for both genetic drift and gene flow, and we compare the method's performance to that of a popular delimitation approach (BPP) using both simulated and empirical datasets. PHRAPL generally infers the correct demographic-delimitation model when the generating model includes gene flow between taxa, given a sufficient amount of data. When the generating model includes only isolation in the recent past, PHRAPL will in some cases fail to differentiate between gene flow and divergence, leading to model misspecification. Nevertheless, the explicit consideration of gene flow by PHRAPL is an important complement to existing delimitation approaches, particularly in systems where gene flow is likely important. [approximate likelihoods; coalescent simulations; genealogical divergence index; Homo sapiens; isolation-with migration; multispecies coalescent; Sarracenia; Scincella.]. PMID- 28003534 TI - Dental Data Perform Relatively Poorly in Reconstructing Mammal Phylogenies: Morphological Partitions Evaluated with Molecular Benchmarks. AB - Phylogenetic trees underpin reconstructions of evolutionary history and tests of evolutionary hypotheses. They are inferred from both molecular and morphological data, yet the relative value of morphology has been questioned in this context due to perceived homoplasy, developmental linkage, and nonindependence of characters. Nevertheless, fossil data are limited to incomplete subsets of preserved morphology, and different regions are treated as equivalent. Through meta-analysis of 40 data sets, we show here that the dental and osteological characters of mammals convey significantly different phylogenetic signals, and that osteological characters are significantly more compatible with molecular trees. Furthermore, the application of simplified paleontological filters (retaining only dental data) results in significantly greater loss of phylogenetic signal than random character ablation. Although the mammal fossil record is largely comprised of teeth, dental data alone are generally found to be less reliable for phylogenetic reconstruction given their incongruence with osteological and molecular data. These findings highlight the need for rigorous meta-analyses of distributions of homoplasy in morphological data. These tests, and consequent refinements to phylogenetic analyses that they permit, promise to improve the quality of all macroevolutionary studies that hinge on accurate trees. [Homoplasy; Mammalia; morphology; osteology; phylogeny; teeth. PMID- 28003536 TI - Deficient melanocortin-4 receptor causes abnormal reproductive neuroendocrine profile in female mice. AB - Deletion of the melanocortin-4-receptor (Mc4r) gene in mice causes hyperphagia, followed by hyperinsulinemia, obesity and progressive infertility. Evidence shows that the number of developed corpora lutea is reduced in obese MC4R-knockout (MC4R KO) female mice, but the mechanism is unclear. The effect of hyperphagia and obesity by MC4R KO on pulsatile luteinizing hormone (LH) secretion and ovulation remains unknown. In MC4R KO mice and wild-type littermates (WT LM) during the diestrus period throughout different ages, we examined and monitored their metabolic status, pulsatile LH profiles, follicular morphology and the number of corpora lutea. MC4R KO mice were hyperphagic, obese, hyperglycemic, hyperinsulinemic and demonstrated insulin resistance and hepatic steatosis. Irregular estrous cycles and significant changes in the LH secretion profiles were observed in sexually matured 16- to 28-week MC4R KO mice, without any difference in testosterone levels. In addition, MC4R KO mice at 16 weeks of age had significantly fewer corpora lutea than same age WT LM mice. The ovary examinations of MC4R KO mice at 28 weeks of age showed predominantly antral and preovulatory follicles with no corpora lutea. These findings were consistent with the decrease in total, pulsatile, mass and basal LH releases in MC4R KO mice. The characteristics of hormone profiles in obese MC4R KO mice indicate that MC4R plays an important role in regulating LH release, ovulation and reproductive ability probably via hyperphagia-induced obesity. Further study of correlation between metabolic and reproductive regulatory hormones is warranted to dissect the pathological mechanism underlying obesity-induced infertility.Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction-online.org/content/153/3/267/suppl/DC1. PMID- 28003537 TI - Ileal Digesta Nondietary Substrates from Cannulated Pigs Are Major Contributors to In Vitro Human Hindgut Short-Chain Fatty Acid Production. AB - BACKGROUND: It has been assumed that short-chain fatty acids (SCFAs) in the colon originate mainly from dietary fiber fermentation. However, SCFAs in the colon are also produced from the fermentation of nondietary material. OBJECTIVES: We aimed to predict the relative contributions of dietary and nondietary substrates in the production of SCFAs with the use of a human fecal inoculum for diets containing kiwifruit as a model fiber. METHODS: Terminal ileal digesta were collected from ileal-cannulated male pigs [n = 7; mean +/- SD: 41.4 +/- 2.98 kg body weight] adapted (44-d feeding) to diets containing either 25 g/kg dry matter (DM) of kiwifruit fiber (KFf) (25 KFf) or 50 g/kg DM of KFf (50 KFf) and then again after receiving a fiber-free diet (n = 14) for a further 7 d. Pigs were used as a model for adult humans for digestion in the upper digestive tract (mouth to the terminal ileum). The ileal digesta (either unfractionated or fractionated into crude mucin and microbial fractions) were fermented in vitro for 24 h with the use of a fresh human fecal inoculum to predict SCFA production in the human hindgut. RESULTS: SCFAs of nondietary origin were the main source (65%) of total SCFAs predicted to be produced in the human hindgut. The contribution of SCFAs from KFf was only 26% of the total SCFAs, and that from total dietary material was 35%. The higher contribution of nondietary material to total predicted SCFA production was observed at both dietary fiber concentrations. Predicted SCFA intake from dietary fiber was 76 and 105 mmol/kg diet DM intake for the diets containing 25 KFf and 50 KFf, respectively, and from the nondietary substrates it was 178 and 280 mmol/kg diet DM intake, respectively. CONCLUSION: A considerable proportion of the SCFAs produced in the human hindgut seems to be derived from the fermentation of nondietary substrates. PMID- 28003539 TI - Prenatal Docosahexaenoic Acid Supplementation Does Not Affect Nonfasting Serum Lipid and Glucose Concentrations of Offspring at 4 Years of Age in a Follow-Up of a Randomized Controlled Clinical Trial in Mexico. AB - BACKGROUND: Docosahexaenoic acid (DHA) has regulatory effects on lipid and glucose metabolism. Differences in DHA availability during specific developmental windows may program metabolic changes. OBJECTIVE: We investigated the effects of maternal DHA supplementation during pregnancy on the nonfasting serum lipid and glucose concentrations of offspring at 4 y of age. METHODS: We used data from the Prenatal Omega-3 Fatty Acid Supplementation, Growth, and Development trial, a double-blind randomized controlled trial conducted in Mexico. Pregnant women were supplemented daily with 400 mg DHA or placebo from 18-22 wk of gestation to delivery. The primary outcomes of the trial were offspring growth and neurological development. Nonfasting blood samples were obtained from the offspring at 4 y of age. We analyzed serum total, HDL, non-HDL, and LDL cholesterol; the total-to-HDL cholesterol ratio; apolipoprotein B (apoB); triglycerides; glucose; and insulin as secondary outcomes and compared their concentrations between treatment groups. RESULTS: Data from 524 offspring were available. The women were compliant with the intervention based on pill counts and changes in cord blood and breast milk DHA concentrations. None of the between group differences (DHA compared with placebo), adjusted for maternal height and time since last food intake, were significant (P range 0.27-0.83). Means (95% CIs) were as follows: total cholesterol (TC), 1.73 mg/dL (-2.63, 6.09 mg/dL); HDL cholesterol, 0.66 mg/dL (-1.07, 2.39 mg/dL); non-HDL cholesterol, 1.77 mg/dL ( 1.83, 5.37 mg/dL); LDL cholesterol, 1.62 mg/dL (-2.21, 5.45 mg/dL); TC:HDL ratio, 0.01 (-0.09, 0.11); apoB, -0.15 mg/dL (-2.78, 2.48 mg/dL); triglycerides, 0.21 mg/dL (-10.93, 10.52 mg/dL); glucose, -0.67 mg/dL (-2.46, 1.11 mg/dL); and insulin, 0.62 MUU/mL (-0.88, 2.11 MUU/mL). CONCLUSION: Prenatal DHA supplementation does not affect nonfasting serum lipid and glucose concentrations of offspring at 4 y of age. This trial was registered at clinicaltrials.gov as NCT00646360. PMID- 28003538 TI - Whey Protein Supplementation and Higher Total Protein Intake Do Not Influence Bone Quantity in Overweight and Obese Adults Following a 36-Week Exercise and Diet Intervention. AB - BACKGROUND: Controversy exists concerning the effects of higher total protein intake (TPro) on bone health, which may be associated with reduced bone mineral density (BMD). However, whey protein (WP) may induce bone formation because of its basic component, milk basic protein. OBJECTIVE: This study assessed the effects of WP supplementation, TPro, and change in TPro (postsupplementation - presupplementation) on BMD and bone mineral content (BMC; total body, lumbar spine, total femur, and femoral neck) in overweight and class I obese middle-aged adults following an exercise intervention. METHODS: This analysis used data from a double-blind, randomized, placebo-controlled 36-wk WP supplementation trial, wherein participants consumed a 1.7-MJ (400-kcal) supplement (0, 20, 40, or 60 g WP/d) along with their otherwise unrestricted diet while participating in a resistance and aerobic exercise intervention (3 d/wk). TPro was the summation of WP and habitual dietary intakes (4-d food record). Statistical analyses for WP were based on group and bone data [n = 186, 108 women; mean +/- SD age: 49 +/- 8 y; body mass index (BMI; in kg/m2): 30.1 +/- 2.8], whereas TPro was based on dietary and bone data (n = 113, 70 women; age 50 +/- 8 y; BMI 30.1 +/- 2.9). RESULTS: WP supplementation, regardless of dose, did not influence BMD or BMC following the intervention. By using a multiple linear regression model, TPro (expressed as g/d or g . kg-1 . d-1) and change in TPro (expressed as g/d) were not associated with responses over time in total or regional BMD or BMC. By using a cluster analysis approach [<1.0 (n = 41), 1.0-1.2 (n = 28), and >=1.2 g . kg-1 . d-1 (n = 44)], TPro was also not associated with responses in total or regional BMD or BMC over time. CONCLUSION: WP supplementation and total dietary protein intake did not negatively or beneficially influence bone quantity in overweight and obese adults during a 9-mo exercise intervention. This trial was registered at clinicaltrials.gov as NCT00812409. PMID- 28003541 TI - Mesenchymal metamorphosis. PMID- 28003542 TI - Cheap-seq. PMID- 28003540 TI - Following the World Health Organization's Recommendation of Exclusive Breastfeeding to 6 Months of Age Does Not Impact the Growth of Rural Gambian Infants. AB - BACKGROUND: The WHO recommends exclusive breastfeeding (EBF) for the first 6 mo of life. OBJECTIVE: The objective of this study was to assess the benefit of EBF to age 6 mo on growth in a large sample of rural Gambian infants at high risk of undernutrition. METHODS: Infants with growth monitoring from birth to 2 y of age (n = 756) from the ENID (Early Nutrition and Immune Development) trial were categorized as exclusively breastfed if only breast milk and no other liquids or foods were given. EBF status was entered into confounder-adjusted multilevel models to test associations with growth trajectories by using >11,000 weight-for age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z score observations. RESULTS: Thirty-two percent of infants were exclusively breastfed to age 6 mo. The mean age of discontinuation of EBF was 5.2 mo, and growth faltering started at ~3.5 mo of age. Some evidence for a difference in WAZ and WHZ was found between infants who were exclusively breastfed to age 6 mo (EBF-6) and those who were not (nEBF-6), at 6 and 12 mo of age, with EBF-6 children having a higher mean z score. The differences in z scores between the 2 groups were small in magnitude (at 6 mo of age: 0.147 WAZ; 95% CI: -0.001, 0.293 WAZ; 0.189 WHZ; 95% CI: 0.038, 0.341 WHZ). No evidence for a difference between EBF-6 and nEBF-6 infants was observed for LAZ at any time point (6, 12, and 24 mo of age). Furthermore, a higher mean WLZ at 3 mo of age was associated with a subsequent higher mean age at discontinuation of EBF, which implied reverse causality in this setting (coefficient: 0.060; 95% CI: 0.008, 0.120). CONCLUSION: This study suggests that EBF to age 6 mo has limited benefit to the growth of rural Gambian infants. This trial was registered at http://www.isrctn.com as ISRCTN49285450. PMID- 28003543 TI - Stress: A deadly weapon. PMID- 28003544 TI - Committing CAR T cells to memory. PMID- 28003545 TI - Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. AB - The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti-PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti-PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types. PMID- 28003546 TI - Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy. AB - Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease specific treatments. We sought to identify signaling pathways that modulate polyQ AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser96 Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser96 phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA. PMID- 28003547 TI - Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease. AB - Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from the consumption of meat products contaminated by the agent causing bovine spongiform encephalopathy. Evidence supporting the presence of a population of silent carriers that can potentially transmit the disease through blood transfusion is increasing. The development of a blood-screening assay for both symptomatic vCJD patients and asymptomatic carriers is urgently required. We show that a diagnostic assay combining plasminogen-bead capture and protein misfolding cyclic amplification (PMCA) technologies consistently detected minute amounts of abnormal prion protein from French and British vCJD cases in the required femtomolar range. This assay allowed the blinded identification of 18 patients with clinical vCJD among 256 plasma samples from the two most affected countries, with 100% sensitivity [95% confidence interval (CI), 81.5 to 100%], 99.2% analytical specificity (95% CI, 95.9 to 100%), and 100% diagnostic specificity (95% CI, 96.5 to 100%). This assay also allowed the detection of silent carriage of prions 1.3 and 2.6 years before the clinical onset in two blood donors who later developed vCJD. These data provide a key step toward the validation of this PMCA technology as a blood-based diagnostic test for vCJD and support its potential for detecting presymptomatic patients, a prerequisite for limiting the risk of vCJD transmission through blood transfusion. PMID- 28003548 TI - Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease. AB - Human prion diseases are infectious and invariably fatal neurodegenerative diseases. They include sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, and variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrPSc) in the blood of patients affected by prion disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrPSc could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrPSc concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology. PMID- 28003550 TI - Comment on "A small-molecule antivirulence agent for treating Clostridium difficile infection". AB - New insights into the mechanism of action of ebselen, a small-molecule antivirulence agent that reduces disease pathology in a mouse model of Clostridium difficile infection, suggest a different molecular target may be responsible for its efficacy. PMID- 28003549 TI - First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases. AB - Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR's CD3epsilon subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low-molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell-mediated autoimmune and inflammatory diseases. PMID- 28003551 TI - Response to Comment on "A small-molecule antivirulence agent for treating Clostridium difficile infection". AB - Ebselen's antivirulence activity in Clostridium difficile infection is likely due to multiple modes of action, but the contribution of each to its efficacy remains unclear. PMID- 28003552 TI - Performance of the New Turbine Mid-Level Critical Care Ventilators. AB - BACKGROUND: During recent years, ventilators using turbines as flow-generating systems have become increasingly more relevant. This bench study was designed to compare triggering and pressurization of 7 turbine mid-level ICU ventilators. METHODS: We used a dual-chamber lung model to test 7 mid-level ICU ventilators in pressure support mode with levels of 10, 15, and 20 cm H2O with 2 PEEP levels of 5 cm H2O and the minimum level allowed by the ventilator. A ventilator was connected to the master chamber to simulate 2 different effort levels. Pressure drop, trigger delay time, time to minimum pressure, and pressure time products (PTP) during trigger and the first 300 and 500 ms were analyzed. RESULTS: In the trigger evaluation, the Savina had the highest delay time, whereas the C2, the V60, and the Trilogy had the lowest pressure drops and PTP values in both effort levels. In pressurization capacity assessment using ideal PTP300 and PTP500 percentages, the C2 and the V680 had the best results, and the Carina and the Savina had lower values, with no differences between both effort levels. Differences between PEEP levels did not seem to be relevant. CONCLUSIONS: Pressure support mode for tested ventilators worked properly, but pressurization capacity and trigger function performance were clearly superior in the newest machines. The use of PEEP did not modify the results. PMID- 28003553 TI - Economics of Home Monitoring for Apnea in Late Preterm Infants. AB - BACKGROUND: Apnea of prematurity affects a small proportion but large absolute number of late preterm infants, with out-patient management variably utilized despite relative clinical equipoise and potential for improved cost effectiveness. METHODS: Over a 5-y period, from 2009 to 2013, infants born at >=34 weeks gestational age at a level IIIB academic center in Boston, Massachusetts, with discharge-delaying apnea, bradycardia, and desaturation (ABD) events were identified. In-patient costs for discharge-delaying ABD events were compared with hypothetical out-patient management. Out-patient costs took into account 4-10 d of in-patient observation for ABD events before caffeine initiation, 3-5 d of additional in-patient observation before discharge, daily caffeine until 43 weeks corrected gestational age, home pulse oximetry monitoring until 44 weeks corrected gestational age, and consideration of variable readmission rates ranging from 0 to 10%. RESULTS: A total of 425 late preterm and term infants were included in our analysis. Utilization of hypothetical out patient management resulted in cost savings per eligible patient ranging from $2,422 to $62, dependent upon variable periods of in-patient observation. Sensitivity analysis demonstrated few instances of decreased relative cost effectiveness. CONCLUSIONS: Out-patient management of discharge-delaying ABD events in a late preterm and term population was a cost-effective alternative to prolonged in-patient observation. PMID- 28003554 TI - Reliability of Vibrating Mesh Technology. AB - BACKGROUND: For delivery of inhaled aerosols, vibrating mesh systems are more efficient than jet nebulizers are and do not require added gas flow. We assessed the reliability of a vibrating mesh nebulizer (Aerogen Solo, Aerogen Ltd, Galway Ireland) suitable for use in mechanical ventilation. METHODS: An initial observational study was performed with 6 nebulizers to determine run time and efficiency using normal saline and distilled water. Nebulizers were run until cessation of aerosol production was noted, with residual volume and run time recorded. Three controllers were used to assess the impact of the controller on nebulizer function. Following the observational study, a more detailed experimental protocol was performed using 20 nebulizers. For this analysis, 2 controllers were used, and time to cessation of aerosol production was noted. Gravimetric techniques were used to measure residual volume. Total nebulization time and residual volume were recorded. Failure was defined as premature cessation of aerosol production represented by residual volume of > 10% of the nebulizer charge. RESULTS: In the initial observational protocol, an unexpected sporadic failure rate was noted of 25% in 55 experimental runs. In the experimental protocol, a failure rate was noted of 30% in 40 experimental runs. Failed runs in the experimental protocol exhibited a wide range of retained volume averaging +/- SD 36 +/- 21.3% compared with 3.2 +/- 1.5% (P = .001) in successful runs. Small but significant differences existed in nebulization time between controllers. CONCLUSIONS: Aerogen Solo nebulization was often randomly interrupted with a wide range of retained volumes. PMID- 28003555 TI - Redesign of an Open-System Oxygen Face Mask With Mainstream Capnometer for Children. AB - BACKGROUND: Partial pressure of end-tidal carbon dioxide (PETCO2 ) monitoring in children is important to detect apnea or hypopnea early to intervene before hypoxemia develops. Monitoring PETCO2 in children without a tracheal tube is challenging. To improve PETCO2 measurement accuracy in a commercially available mask with a mainstream CO2 detector, we implemented design changes with deform and-hold shaping technology and anterior-posterior adjustment of the expiratory gas flow cup. METHODS: Two sizes of redesigned face masks (small for 7-20 kg, medium for 10-40 kg) were evaluated. Initial bench testing used a simulator modeling a spontaneously breathing infant and child with a natural airway. An infant/child manikin head was connected to the breathing lung simulator. A mass flow controller provided expiratory CO2. Mask fit was then evaluated on healthy human subjects to identify anatomical features associated with good fit, defined as square shape capnography waveform during expiration. A 3-dimensional digital scan was used to quantify anatomical features. The gaps between face mask rims and facial surface were manually measured. RESULTS: Bench testing revealed a PETCO2 difference of 3.4 +/- 1.5 mm Hg between a measured PETCO2 by the redesigned mask and CO2 concentration at trachea, as compared with 6.7 +/- 6.2 mm Hg between PETCO2 measured by nasal cannula and trachea (P < .001). In the human mask fit study, 35 children (13 +/- 4 kg) with the small mask and 38 (24 +/- 8 kg) with the medium mask were evaluated. Capnography tracing was successfully obtained in 86% of the small and 100% of the medium masks. In children with small size masks, the gap between the face mask rim and the child's face was not statistically different among those with good mask fit and without (1.0 +/- 1.5 mm vs 1.4 +/- 1.9 mm, P = .73). CONCLUSIONS: PETCO2 measurement by a redesigned open-system face mask with a mainstream CO2 detector was accurate in the bench setting. The redesigned face mask can attain good mask fit and accurate capnography tracings in the majority of infants and children. PMID- 28003556 TI - A Comparison of Different Techniques for Interfacing Capnography With Adult and Pediatric Supplemental Oxygen Masks. AB - BACKGROUND: Accurately measuring the partial pressure of end-tidal CO2 (PETCO2 ) in non-intubated patients is problematic due to dilution of expired CO2 at high O2 flows and mask designs that may either cause CO2 rebreathing or inadequately capture expired CO2. We evaluated the performance of 2 capnographic O2 masks (Cap ONE and OxyMask) against a clinically expedient method using a standard O2 mask with a flow-directed nasal cannula used for capnography (CapnoLine) in a spontaneous breathing model of an adult and child under conditions of normal ventilation, hypoventilation, and hyperventilation. METHODS: An ASL-5000 simulator was attached to a manikin face with a catheter port, through which various CO2/air mixtures were bled into the ASL-5000 to achieve a PETCO2 of 40, 65, and 30 mm Hg. Both PETCO2 and inspired PCO2 were measured at O2 flows of 5, 10, 15, and 20 L/min (adult model) and 2, 4, 6, 8, and 10 L/min (pediatric model). RESULTS: PETCO2 decreased to varying degrees as O2 flow increased, depending upon the breathing pattern. Although all devices appeared to perform reasonably well under normal and hyperventilation conditions, the clinically expedient method was associated with substantially more CO2 rebreathing. PETCO2 usually deteriorated more under simulated hypoventilation, regardless of the measurement method. CONCLUSIONS: Both of the specially designed O2 capnography masks provided reasonably stable PETCO2 without significant CO2 rebreathing at the commonly used O2 flows. Because of their open design, PETCO2 measured at high O2 flows may produce artificially lower readings that may not reflect arterial CO2 levels compared with lower O2 flows. PMID- 28003558 TI - Prevention of COPD Readmissions: A Work in Progress. PMID- 28003557 TI - Comparing the Effects of Two Different Levels of Hyperoxygenation on Gas Exchange During Open Endotracheal Suctioning: A Randomized Crossover Study. AB - BACKGROUND: Endotracheal suctioning is required for mechanically ventilated patients to maintain a patent airway. Studies show that open endotracheal suctioning affects respiratory mechanics and gas exchange. The aim of this study was to compare the effectiveness of hyperoxygenation with FIO2 + 0.20 above baseline and hyperoxygenation with FIO2 1.0 in preventing hypoxemia, and to determine the impact of open endotracheal suctioning on the pulmonary ventilation of critical subjects receiving mechanical ventilatory support. METHODS: This prospective randomized crossover study was conducted in the ICU. Sixty-eight mechanically ventilated subjects with FIO2 <= 0.6 and requiring endotracheal suctioning were included in this study. Open endotracheal suctioning was performed using 2 different intervention sequences: hyperoxygenation of 0.20 above baseline FIO2 (FIO2 + 0.20) and 1.0 hyperoxygenation (FIO2 1.0). Oxygenation was assessed via oxygen saturation as measured by pulse oximetry (SpO2 ), and changes in lung ventilation were measured via alveolar gas volume (VA), alveolar minute volume (VA min), carbon dioxide (CO2) production (VCO2 ), mixed exhaled partial pressure of CO2 (PECO2 ), exhaled tidal CO2 volume (VTCO2), end-tidal CO2 (PETCO2 ), anatomical dead space to tidal volume ratio (VD/VT), and anatomical dead space volume of each breath (VD) using volumetric capnography, and breathing frequency (f), heart rate, and mean arterial pressure using a multiparameter monitor. RESULTS: SpO2 levels were significantly higher within interventions (FIO2 + 0.20 and 1.0) 1 min before and after suction. Also, there was a significant increase in PETCO2 , PECO2 , heart rate, and mean arterial pressure immediately after the procedure compared with baseline, and in VTCO2, only for FIO2 + 0.20. Baseline values were not found to be significantly different between the groups in case of any dependent variable. CONCLUSIONS: In mechanically ventilated adult subjects, hyperoxygenation with FIO2 + 0.20 above baseline prevents hypoxemia. Also, transient changes in pulmonary ventilation with open circuit suctioning were confirmed by volumetric capnography analysis. (Trial registration: ClinicalTrials.gov NCT02440919). PMID- 28003559 TI - Leak Compensation Algorithms: The Key Remedy to Noninvasive Ventilation Failure? PMID- 28003562 TI - A novel diffusion-tensor MRI approach for skeletal muscle fascicle length measurements. AB - Musculoskeletal (dys-)function relies for a large part on muscle architecture which can be obtained using Diffusion-Tensor MRI (DT-MRI) and fiber tractography. However, reconstructed tracts often continue along the tendon or aponeurosis when using conventional methods, thus overestimating fascicle lengths. In this study, we propose a new method for semiautomatic segmentation of tendinous tissue using tract density (TD). We investigated the feasibility and repeatability of this method to quantify the mean fascicle length per muscle. Additionally, we examined whether the method facilitates measuring changes in fascicle length of lower leg muscles with different foot positions. Five healthy subjects underwent two DT-MRI scans of the right lower leg, with the foot in 15 degrees dorsiflexion, neutral, and 30 degrees plantarflexion positions. Repeatability of fascicle length measurements was assessed using Bland-Altman analysis. Changes in fascicle lengths between the foot positions were tested using a repeated multivariate analysis of variance (MANOVA). Bland-Altman analysis showed good agreement between repeated measurements. The coefficients of variation in neutral position were 8.3, 16.7, 11.2, and 10.4% for soleus (SOL), fibularis longus (FL), extensor digitorum longus (EDL), and tibialis anterior (TA), respectively. The plantarflexors (SOL and FL) showed significant increase in fascicle length from plantarflexion to dorsiflexion, whereas the dorsiflexors (EDL and TA) exhibited a significant decrease. The use of a tract density for semiautomatic segmentation of tendinous structures provides more accurate estimates of the mean fascicle length than traditional fiber tractography methods. The method shows moderate to good repeatability and allows for quantification of changes in fascicle lengths due to passive stretch. PMID- 28003563 TI - The portal-drained viscera release fibroblast growth factor 19 in humans. AB - Fibroblast growth factor 19 (FGF19) is an ileum-derived endrocrine factor that is produced in response to transepithelial bile salt flux. FGF19 represses bile salt synthesis in the liver. Despite the general assumption that FGF19 signals to the liver via portal blood, no human data are available to support this notion. The aim was to study portal FGF19 levels, and determined bile salt and FGF19 fluxes across visceral organs in humans. Bile salt and FGF19 levels were assessed in arterial, portal, and hepatic venous blood collected from fasted patients who underwent partial liver resection for colorectal liver metastases (n = 30). Fluxes across the portal-drained viscera (PDV), liver, and splanchnic area were calculated. Portal bile salt levels (7.8 [5.0-12.4] MUmol/L) were higher than levels in arterial (2.7 [1.7-5.5] MUmol/L, P < 0.0001) and hepatic venous blood (3.4 [2.5-6.5] MUmol/L, P < 0.0001). Bile salts released by the PDV (+1.2 [+0.7 +2.0] mmol kg-1 h-1, P < 0.0001) were largely taken up by the liver (-1.0 [-1.8 to -0.4] mmol kg-1 h-1, P < 0.0001). Portal levels of FGF19 (161 +/- 78 pg/mL) were higher than arterial levels (135 +/- 65 pg/mL, P = 0.046). A net release of FGF19 by the PDV (+4.0 [+2.1 to +9.9] ng kg-1 h-1, P < 0.0001) was calculated. There was no significant flux of FGF19 across the liver (-0.2 [-3.7 to +7.4] ng kg-1 h-1, P = 0.93). In conclusion, FGF19 levels in human portal blood are higher than in arterial blood. FGF19 is released by the portal-drained viscera under fasted steady state conditions. PMID- 28003564 TI - Anticoagulation increases alveolar hemorrhage in mice infected with influenza A. AB - Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild-type mice. Wild-type mice were anticoagulated with either warfarin or the direct thrombin inhibitor dabigatran etexilate and then infected with a mouse adapted influenza virus (A/Puerto Rico/8/34 H1N1). Alveolar hemorrhage was assessed by measuring hemoglobin levels in the bronchoalveolar lavage fluid (BALF). We also measured vascular permeability and viral genomes in the lung, as well as white blood cells, inflammatory mediators, and protein in BALF Survival and body weight were monitored for 14 days after influenza A infection. In infected mice receiving either warfarin or dabigatran etexilate we observed decreased activation of coagulation in the BALF and increased alveolar hemorrhage. Warfarin but not dabigatran etexilate increased vascular permeability and mortality of influenza A-infected mice. Anticoagulation did not affect levels of influenza A genomes, white blood cells, inflammatory mediators, or protein in the BALF Our study indicates that systemic anticoagulation increases alveolar hemorrhage in influenza A-infected mice. PMID- 28003565 TI - Histological evidence for reversible cardiomyocyte changes and serum cardiac troponin T elevation after exercise in rats. AB - This study characterized cardiac troponin T (cTnT) appearance and associated histological evidence of reversible or irreversible changes in myocardial ultrastructure, determined via electron microscopy, in rats undertaking isoproterenol (ISO) infusion or an endurance exercise challenge. Male rats were randomized into ISO and exercise groups. In ISO trials rats were killed 5 h (ISO 5H) and 24 h (ISO-REC19H) after a single ISO or saline injection (SAL-5H; SAL REC19H). In the exercise trials rats were killed before, as a control (EXE-CON), immediately after (EXE-END5H) and 19 h after (EXE-REC19H) a 5-h bout of swimming with 5% body weight attached to their tail. Serum cTnT was quantified by electrochemiluminescence, and myocardial samples in ISO-REC19H, EXE-REC19H and SAL-REC19H were harvested for assessment of specific mitochondrial injury scores using electron-microscopy. cTnT was undetectable in all control animals (SAL 5H/SAL-REC19H and EXE-CON). cTnT increased in all animals after ISO and exercise but the response was significantly higher (P < 0.05) at ISO-5H (median [range]: 2.60 [1.76-6.18] MUg . L-1) than at EXE-END5H (median [range]: 0.05 [0.02-0.14] MUg . L-1). cTnT returned to baseline at EXE-REC19H, but had not completely recovered at ISO-REC19H (median [range]: 0.17 [0.09-1.22] MUg . L-1). Mitochondrial "injury scores" were significantly higher (P < 0.05) in ISO-REC19H compared to EXE-REC19H and SAL-REC19H, with no difference between EXE-REC19H and SAL-REC19H. Mitochondria from EXE-REC19H appeared aggregated in nonlinear clusters in a small number of scans. These findings suggest that acute exercise induced appearance of cTnT in this animal model is only associated with reversible changes in cardiomyocyte structure. PMID- 28003567 TI - A new species of Spirorchis MacCallum, 1918 (Digenea: Schistosomatoidea) and Spirorchis cf. scripta from chicken turtle, Deirochelys reticularia (Emydidae), with an emendation and molecular phylogeny of Spirorchis. AB - Chicken turtles, Deirochelys reticularia (Latreille in Sonnini et Latreille) (Testudines: Emydidae) from Alabama, USA were infected by Spirorchis collinsi Roberts et Bullard sp. n. and Spirorchis cf. scripta. The new species is most easily differentiated from its congeners by the combination of having caeca that extend far beyond the genitalia, intercaecal genitalia positioned in the middle portion of the body, a testicular column that nearly abuts the caecal bifurcation, a cirrus sac positioned between the testes and ovary, a massive Mehlis' gland, an elongate, longitudinal metraterm that extends anteriad beyond the level of the ovary, a pre-ovarian genital pore, and a prominent, intercaecal Manter's organ. The specimens of S. cf. scripta differed from the holotype and published descriptions of Spirorchis scripta Stunkard, 1923 by several subtle morphological features, perhaps comprising intraspecific variation, but collectively warranted a detailed description herein. Based on examinations of the aforementioned specimens plus the holotype, paratypes and vouchers of morphologically-similar congeners, Spirorchis MacCallum, 1918 is emended to include the presence of oral sucker spines, a pharynx, lateral oesophageal diverticula ('plicate organ') and a median oesophageal diverticulum ('oeseophageal pouch'). Phylogenetic analysis of the nuclear large subunit rDNA (28S) recovered S. collinsi sister to Spirorchis picta Stunkard, 1923, > 99% similarity between S. cf. scripta and S. scripta, and a monophyletic Spirorchis MacCallum, 1918. No blood fluke infection has been reported previously from these drainages, Alabama, or this turtle species. This is the first new species of Spirorchis to be described from North America in 26 years. PMID- 28003566 TI - Plasma from exercised rats administered to sedentary rats induces systemic and tissue inflammation. AB - Recent studies have consistently supported the active role of blood in mediating biochemical and physiological tissue adaptations. However, no study has investigated the possible contribution of circulating factors in an exercise setting. The aim of the study was to investigate the role of circulating factors in exercise adaptations by chronically administering to sedentary animals blood plasma collected from acutely exercised animals. Phase 1: Blood plasma was collected from rats that swam to exhaustion and from sedentary rats. Phase 2: Other rats were divided into two groups (n = 20 per group): the first group involved rats that were injected intravenously with blood plasma originating from rats that previously swam to exhaustion, the second group consisted of rats that were injected intravenously with blood plasma originating from sedentary rats. Tail-vein injections (2 mL/kg) were performed daily for 21 consecutive days. Inflammatory markers (C-reactive protein, interleukins-1alpha, 2, 6, 8, 10 and tumor necrosis factor-a) were measured in blood plasma, muscle, and adipose tissue. Sedentary rats administered with plasma from exercised rats had significantly higher levels in all inflammatory markers measured in blood, skeletal muscle and adipose tissue, compared to the sedentary rats administered with resting plasma. Our data demonstrate that administration of "exercised" blood to sedentary rats induced inflammation in plasma, muscle and adipose tissue. Exercise adaptations are not solely due to intrinsic processes in muscle or adipose tissue. Blood factors also play a crucial role in mediating signals for tissue adaptations. PMID- 28003568 TI - Hemoperitoneum due to breaking uterine adenosarcoma located in the omentum. Report of a case. AB - AIM: We report an unusual case of broken adenosarcoma located in the omentum that has procured a clinical situation of acute abdomen in a patient. CASE REPORT: A 79 year-old woman went to the emergency room for growing abdominal pain and then transferred to our department. In previous years the patient had removed endo cervical and endometrial fibro-glandular polyps and subsequently to a total laparoscopic hysterectomy with bilateral oophorectomy was performed for another endometrial fibroglandular polyp; other vaginal recurrences were then removed. We performed a computed tomography thanks to which we made a diagnosis of moderate hemoperitoneum. RESULTS: The patient underwent to a laparotomy. After abdominal blood removal was evidenced the presence of a damaged big cystic formation starting from the epiploon, containing blood and necrotic debris treated with omentectomy. The subsequent histopathological examination revealed that this tumor was an adenosarcoma. DISCUSSION: Rarely adenosarcoma can grow in extrauterine locations. The simptoms are related to the localization. Even during an emergency surgery it is important to respect the criteria of oncological radicality. You must avoid the tumor dissemination in order to reduce late recurrences, and to achieve a better final histologic diagnosis should avoid intraoperative extemporaneous histological examination. CONCLUSIONS: This case is an example of how many diagnostic pitfalls you can hide in emergency surgery, but in conclusion it remains a doubt about our experience: it is not possible to know if this tumor was a primary extra-uterine neoplasm or a recurrence of fibro glandular polyps removed years before already in malignant transformation? KEY WORDS: Acute Abdomen, Adenosarcoma, Hemoperitoneum, Omentum. PMID- 28003569 TI - Assessment criteria for vitamin D deficiency/insufficiency in Japan - proposal by an expert panel supported by Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society [Opinion]. AB - Vitamin D is indispensable for the maintenance of bone and mineral health. Inadequate vitamin D action increases the risk for various musculoskeletal/mineral events including fracture, fall, secondary hyperparathyroidism, diminished response to antiresorptives, rickets/osteomalacia, and hypocalcemia. Its most common cause in recent years is vitamin D deficiency/insufficiency, clinically defined by low serum 25 hydroxyvitamin D [25(OH)D] level. Guidelines for vitamin D insufficiency/deficiency defined by serum 25(OH)D concentrations have been published all over the world. In Japan, however, the information on the associations between serum 25(OH)D and bone and mineral disorders has not been widely shared among healthcare providers, partly because its measurement had not been reimbursed with national medical insurance policy until August 2016. We have set out to collect and analyze Japanese data on the relationship between serum 25(OH)D concentration and bone and mineral events. Integrating these domestic data and published guidelines worldwide, here we present the following assessment criteria for vitamin D sufficiency/insufficiency/deficiency using serum 25(OH)D level in Japan. 1) Serum 25(OH)D level equal to or above 30 ng/mL is considered to be vitamin D sufficient. 2) Serum 25(OH)D level less than 30 ng/mL but not less than 20 ng/mL is considered to be vitamin D insufficient. 3) Serum 25(OH)D level less than 20 ng/mL is considered to be vitamin D deficient. We believe that these criteria will be clinically helpful in the assessment of serum 25(OH)D concentrations and further expect that they will form a basis for the future development of guidelines for the management of vitamin D deficiency/insufficiency. PMID- 28003570 TI - Correlations between Cognitive Impairments and Employment Status in Patients with Diffuse Axonal Injury. AB - Patients with diffuse axonal injury (DAI) may initially present with prominent physical impairments, but their cognitive dysfunctions are more persistent and are attributable to later unemployment. In this study, we analyzed how the findings of early and delayed neuropsychological assessments correlated with employment outcome of patients with DAI. A total of 56 patients with DAI without motor or visual dysfunction were included in this study. The neuropsychological battery consisted of the Wechsler Adult Intelligent Scale - Revised (WAIS-R), Wechsler Memory Scale - Revised (WMS-R), Trail Making Test (TMT), Wisconsin Card Sorting Test (WCST), and Word Fluency Test (WFT). This battery of tests was administered twice in early stage after injury and in later stage. The results of all of the neuropsychological tests improved significantly (P <0.001) between the early and later assessments. All scores other than TMT part A and B improved to the normal range (Z-score >= 2). The patient characteristics (age, gender, initial Glasgow Coma Scale, and duration of posttraumatic amnesia) had no relationship to the outcome. The results of TMT part B, however, were significantly correlated with employment outcome in both the early and later assessments (P = 0.01, 0.04). Given that TMT evaluates visual attention, we surmise that a lack of attention may be the core symptom of the cognitive deficit and cause the re-employment failure in patients with DAI. TMT part B in both early and later assessments has the potential to accurately predict chronic functional outcome. PMID- 28003571 TI - Identification of beta-globin haplotypes linked to sickle hemoglobin (Hb S) alleles in Mazandaran province, Iran. AB - Carrier frequency of the betaS allele has been reported to be 0.19% in Mazandaran province, northern Iran. Haplotype analysis of the betaS allele helps trace the origin of its encoded hemoglobin (Hb) variant, Hb S, in a region. The aim of this study was to investigate the haplotypes associated with betaS alleles in Mazandaran province. Capillary electrophoresis was carried out to detect individuals suspected to have a betaS allele(s). DNA analysis (PCR-RFLP) was used for final confirmation. To identify 5' to 3' beta-globin gene cluster haplotypes associated with betaS alleles, family linkage analysis was applied. Six polymorphic sites (HincII 5' to epsilon, XmnI 5' to Ggamma, HindIII in Ggamma, HindIII in Agamma, HincII 3' to psibeta and AvaII in beta) were investigated using the PCR-RFLP method. Five different haplotypes were linked to betaS alleles, while betaA alleles were associated with nine haplotypes. Among the betaS alleles, 53.9% were associated with the Benin (----++) haplotype, and the Arab-Indian (+++-++) haplotype had the second-highest frequency (23%). Unlike southern provinces, where the Arab-Indian haplotype is prominent, the Benin haplotype is the most frequent haplotype in northern Iran, and this may represent a founder effect. Since the Benin haplotype does not carry the XmnI polymorphism 5' to the Ggamma gene, which is responsible for high expression of Hb F, a severe form of sickle cell disease can be anticipated in patients that are homozygous for the betaS allele in the northern region. PMID- 28003572 TI - Geographical variation in soil bacterial community structure in tropical forests in Southeast Asia and temperate forests in Japan based on pyrosequencing analysis of 16S rRNA. AB - Geographical variation in soil bacterial community structure in 26 tropical forests in Southeast Asia (Malaysia, Indonesia and Singapore) and two temperate forests in Japan was investigated to elucidate the environmental factors and mechanisms that influence biogeography of soil bacterial diversity and composition. Despite substantial environmental differences, bacterial phyla were represented in similar proportions, with Acidobacteria and Proteobacteria the dominant phyla in all forests except one mangrove forest in Sarawak, although highly significant heterogeneity in frequency of individual phyla was detected among forests. In contrast, species diversity (alpha-diversity) differed to a much greater extent, being nearly six-fold higher in the mangrove forest (Chao1 index = 6,862) than in forests in Singapore and Sarawak (~1,250). In addition, natural mixed dipterocarp forests had lower species diversity than acacia and oil palm plantations, indicating that aboveground tree composition does not influence soil bacterial diversity. Shannon and Chao1 indices were correlated positively, implying that skewed operational taxonomic unit (OTU) distribution was associated with the abundance of overall and rare (singleton) OTUs. No OTUs were represented in all 28 forests, and forest-specific OTUs accounted for over 70% of all detected OTUs. Forests that were geographically adjacent and/or of the same forest type had similar bacterial species composition, and a positive correlation was detected between species divergence (beta-diversity) and direct distance between forests. Both alpha- and beta-diversities were correlated with soil pH. These results suggest that soil bacterial communities in different forests evolve largely independently of each other and that soil bacterial communities adapt to their local environment, modulated by bacterial dispersal (distance effect) and forest type. Therefore, we conclude that the biogeography of soil bacteria communities described here is non-random, reflecting the influences of contemporary environmental factors and evolutionary history. PMID- 28003573 TI - A novel missense variant in the DIAPH1 gene in a Korean family with autosomal dominant nonsyndromic hearing loss. AB - Hair cells in the cochlea display highly regulated actin polymerization, which is mediated by the human diaphanous-related formin 1 gene (DIAPH1; also called DFNA1, DIA1). DFNA1, the first type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is known to be associated with mutations in DIAPH1. However, no genetic study of DFNA1 in Koreans with hearing loss has yet been reported. A 51 year-old patient in a Korean family with ADNSHL was examined by pure-tone audiometry, and genetic analysis of DIAPH1 was performed. A novel variant, p.I530S (c.1589T > G), was identified in the DIAPH1 gene, and the mutation was located in the highly conserved coiled-coil domain of the DIA1 protein, where an amino acid substitution was predicted to change the domain structure. Further functional investigations will provide more information to help us understand the role of DIAPH1 in maintenance of hair cell function in the auditory pathway. PMID- 28003574 TI - Sodium Bicarbonate-Ascorbic Acid Combination for Prevention of Contrast-Induced Nephropathy in Chronic Kidney Disease Patients Undergoing Catheterization. AB - BACKGROUND: Sodium bicarbonate and ascorbic acid have been proposed to prevent contrast-induced nephropathy (CIN). The present study evaluated the effect of their combined use on CIN incidence.Methods and Results:We prospectively enrolled 429 patients with chronic kidney disease (CKD: baseline estimated glomerular filtration rate <60 mL/min/1.73 m2) prior to elective coronary catheterization. CIN was defined as absolute (>=0.5 mg/dL) or relative (>=25%) increase in serum creatinine within 72 h. In the saline hydration (n=218) and combined sodium bicarbonate+ascorbic acid (n=211) groups, a total of 1,500-2,500 mL 0.9% saline was given before and after the procedure. In addition, the combination group received 20 mEq sodium bicarbonate and 3 g ascorbic acid i.v. before the procedure, followed by 2 g ascorbic acid after the procedure and a further 2 g after 12 h. There were no significant differences between the basic characteristics and contrast volume in the 2 groups. CIN occurred in 19 patients (8.7%) in the saline group, and in 6 patients (2.8%) in the combined treatment group (P=0.008). CONCLUSIONS: Combined sodium bicarbonate and ascorbic acid could prevent CIN following catheterization in CKD patients. PMID- 28003575 TI - Higher Body Mass Index Increases Risk of HeartMate II Pump Thrombosis But Does Not Adversely Affect Long-Term Survival. AB - BACKGROUND: Obesity has been correlated with various adverse events in patients who receive left ventricular assist devices (LVAD). In this study, we sought to further characterize the role of obesity in this patient population.Methods and Results:We performed a retrospective analysis of 164 patients implanted with a HeartMate II from August 2008 to December 2014. Patients were categorized into 2 BMI groups based on WHO guidelines: BMI 18.5-30 kg/m2(n=99) and BMI >30 kg/m2(n=65). Patient demographics, adverse outcome and long-term survival were compared between the 2 groups. For any outcome associated with BMI groups, we performed a Cox regression to identify confounding comorbidities. Preoperative demographics and comorbidities were similar. Patients with BMI >30 were younger (P=0.01) and had a higher incidence of type 2 diabetes (P=0.01). While rate of pump thrombosis was higher among patients with BMI >30 (P=0.02), overall survival at 2 years did not differ. The most common cause of death was hemorrhagic stroke in the obese group. On multivariable cox regression analysis, BMI was an independent risk factor of pump thrombosis. CONCLUSIONS: Higher BMI does not reduce survival after VAD implantation but it does appear to increase the risk of pump thrombosis. Further studies to characterize the role of BMI in survival and thrombosis rates are warranted. PMID- 28003576 TI - Ventricular Fibrillation Triggered by Earthquake During the Accumoli-Amatrice Disaster in Italy. PMID- 28003579 TI - Effect of 1,25-dihydroxyvitamin D3 on spontaneous calcium responses in rat dental epithelial SF2 cells revealed by long-term imaging. AB - Genetically encoded calcium indicators (GECIs) are suitable for long-term imaging studies. In this study, we employed a highly sensitive GECI, G-GECO, and achieved efficient gene delivery with an adenoviral vector. The adenoviral vector allowed us to express G-GECO in more than 80% of cells. More than 80% of G-GECO expressing cells showed an ATP-induced increase in fluorescence intensity due to Ca2+ release from intracellular stores and subsequent Ca2+ entry. The fluorescence intensity of these cells was increased more than 2-fold by stimulation with 10 MUM ATP. We applied long-term imaging (for ~10 h) to monitor Ca2+ responses in SF2, a rat dental epithelial cell line, in culture conditions. SF2 cells showed intermittent rises in the intracellular Ca2+ concentration in the presence of 100 nM 1,25-dihydroxyvitamin D3. Many of these Ca2+ responses began at a specific location in the cytoplasm and spread throughout the entire cytoplasm. The combination of efficient gene delivery with an adenoviral vector and long-term imaging with a highly sensitive GECI enabled detection of intermittent Ca2+ responses that occur only 3-10 times/h/100 cells. This method could be useful to study the effects of Ca2+ responses for regulating longterm processes, such as gene expression, cell migration, and cell division, in many cell types. PMID- 28003580 TI - Identification of the odor-active volatile compound (Z,Z)-4,7-tridecadienal as a potential ligand for the transmembrane receptor CD36. AB - Cluster of differentiation 36 (CD36) is a broadly expressed transmembrane protein that has multiple ligands, including oxidized low-density lipoproteins. We found recently that CD36 is expressed in olfactory sensory neurons and postulated that it plays a role in the detection of distinct odorants in the nasal cavity. To date, however, there have been few examples of attempts to identify CD36 recognizable odorants. In this study, by an in vitro assay using a peptide mimic of the receptor, we provided evidence that CD36 recognizes (Z,Z)-4,7 tridecadienal, an odor-active volatile compound that is known to occur in Katsuobushi (dried, fermented, and smoked skipjack tuna commonly used in Japanese cuisine as a seasoning) and in the preorbital secretion of male oribi. In addition, by comparing the data with those of its related compounds, we provided information on the structural requirements of (Z,Z)-4,7-tridecadienal for recognition by CD36. For instance, we showed that flexible rotation around the C2 C3 bond of the volatile may be of importance in gaining access to CD36. Identification of (Z,Z)-4,7-tridecadienal as the ligand prompts us to hypothesize that CD36 could participate in the control of distinct mammalian behaviors (e.g., food selection) through its ability to recognize specific odorants in the environment. PMID- 28003581 TI - Triterpenes suppress octanoylated ghrelin production in ghrelin-expressing human gastric carcinoma cells. AB - Ghrelin is an appetite-stimulating peptide hormone with an octanoyl modification at serine 3 that is essential for its orexigenic effect. Ghrelin O acyltransferase (GOAT) is the enzyme that catalyzes ghrelin acylation using fatty acyl-coenzyme A as a substrate. We previously developed an assay system based on the AGS-GHRL8 cell line that produces octanoylated ghrelin in the presence of octanoic acid, and demonstrated that some fatty acids suppressed octanoylated ghrelin production. Recent studies have reported that triterpenes have anti obesity effect. Since such triterpenes, like fatty acids, have a carboxyl group, we speculated that they can suppress octanoylated ghrelin production. To test this hypothesis, we investigated the effect of triterpenes on octanoylated ghrelin production. Asiatic acid, corosolic acid, glycyrrhetinic acid, oleanolic acid and ursolic acid suppressed octanoylated ghrelin levels in AGS-GHRL8 cells without decreasing transcript expression of GOAT or furin, a protease required for ghrelin maturation. beta-amyrin had no effect on octanoylated ghrelin level, which was only slightly inhibited by uvaol; the fact that both these triterpenes lack a carboxyl group indicates that this group is important for suppressing octanoylated ghrelin production. These results suggest that triterpenes may have the potential as obesity-preventing agents with suppressive effect on octanoylated ghrelin production. PMID- 28003582 TI - The broad distribution of GP2 in mucous glands and secretory products. AB - GP2, a GPI-anchored glycoprotein that is a useful marker for M cells of Peyer's patches, is functionally related to the uptake of pathogenic bacteria in the gut lumen. Our immunostaining throughout the whole body of mice detected a broader localization than previously found of GP2 in various mucous glands and secretory cells. In the oral cavity, the palatine gland and lingual gland intensely expressed GP2 with immunolabeling along the basolateral membrane of acini and in luminal secretions of ducts. Secretory portions of the duodenal gland as well as the pancreas were immunoreactive for GP2 in the digestive tract. Luminal contents in the small intestine contained aggregations of GP2-immunoreactive substances which mixed with bacteria. The bulbourethral gland of Cowper displayed the GP2 immunoreactivity among the male reproductive organs. The vaginal epithelium contained many GP2-immunoreactive goblet-like cells, the occurrence of which dramatically changed according to the estrous cycle. These findings show that GP2 is a popular secretory product released from mucous glands and secretory cells and may support defense mechanisms against pathogenic bacteria in the tubular organs open to the external milieu. PMID- 28003583 TI - Optimizing an ion semiconductor sequencing data analysis method to identify somatic mutations in the genomes of cancer cells in clinical tissue samples. AB - Identification of causal genomic alterations is an indispensable step in the implementation of personalized cancer medicine. Analytical methods play a central role in identifying such changes because of the vast amount of data produced by next generation sequencer. Most analytical techniques are designed for the Illumina platform and are therefore suboptimal for analyzing datasets generated by whole exome sequencing (WES) using the Ion Proton System. Accurate identification of somatic mutations requires the characterization of platform dependent error profiles and genomic properties that affect the accuracy of sequence data as well as platform-oriented optimization of the pipeline. Therefore, we used the Ion Proton System to perform WES of DNAs isolated from tumor and matched control tissues of 1,058 patients with cancer who were treated at the Shizuoka Cancer Center Hospital. Among the initially identified candidate somatic single-nucleotide variants (SNVs), 10,279 were validated by manual inspection of the WES data followed by Sanger sequencing. These validated SNVs were used as an objective standard to determine an optimum cutoff value to improve the pipeline. Using this optimized pipeline analysis, 189,381 SNVs were identified in 1,101 samples. The analytical technique presented here is a useful resource for conducting clinical WES, particularly using semiconductor-based sequencing technology. PMID- 28003584 TI - Integrated next-generation sequencing analysis of whole exome and 409 cancer related genes. AB - The use of next-generation sequencing (NGS) techniques to analyze the genomes of cancer cells has identified numerous genomic alterations, including single-base substitutions, small insertions and deletions, amplification, recombination, and epigenetic modifications. NGS contributes to the clinical management of patients as well as new discoveries that identify the mechanisms of tumorigenesis. Moreover, analysis of gene panels targeting actionable mutations enhances efforts to optimize the selection of chemotherapeutic regimens. However, whole genome sequencing takes several days and costs at least $10,000, depending on sequence coverage. Therefore, laboratories with relatively limited resources must employ a more economical approach. For this purpose, we conducted an integrated nucleotide sequence analysis of a panel of 409-cancer related genes (409-CRG) combined with whole exome sequencing (WES). Analysis of the 409-CRG panel detected low frequency variants with high sensitivity, and WES identified moderate and high frequency somatic variants as well as germline variants. PMID- 28003585 TI - Cold stimulation evokes exocytotic vesicle release from PC12 cells. AB - The mechanism of peripheral blood circulation failure by low temperatures, known as Raynaud's phenomenon, is not well understood at present. We examined the possibility that the efferent fibers of peripheral sympathetic neurons may release transmitters directly by cold sensation. PC12 cells, a culture model of sympathetic neurons, were placed at 25 degrees C for 30 min, fixed with the tannic acid-glutaraldehyde-osmium method and observed by electron microscopy. The number of omega-shaped exocytotic vesicle figures increased significantly compared with that in the control (37 degrees C), although it was lower than that of the positive control (high potassium stimulation at 25 degrees C and 37 degrees C). As it is known that PC12 cells and sympathetic neurons do not express the typical cold sensing channels (TRPA1 and TRPM8), our results suggest that the peripheral sympathetic neurons may have an unknown cold monitoring system which reacts to low temperatures, release transmitters by exocytosis and directly regulate local blood circulation. PMID- 28003587 TI - Free T3 to free T4 ratio less than 2.0 suggests low T3 syndrome rather than central hypothyroidism from the age of two to eighteen years. AB - No serological cut-off exists to separate low T3 syndrome (LT) and central hypothyroidism (CH). The objective of this retrospective study was to propose such a cut-off. The first participant group comprised 52 patients from the age of six to twenty years. This group consisted of patients of 36 anorexia nervosa with LT and 16 CH. The second participant groups comprised 229 patients of all the same range of ages at the same hospital and included LT (n = 58) and CH (n = 4) patients, respectively. The third group of participants comprised 125 LT and 27 CH patients at the same hospital at all ages less than eighteen years. The last group of participants comprised 10 CH patients from the other two hospitals. The main outcome measure was fT3/fT4 ratio (pg/mL, ng/dL respectively). This ratio in the first group was significantly different (p < 0.05) between LT and CH. When the cut off value of fT3/fT4 was set as 2.0, the sensitivity of the LT and CH patients in the second group was 62% and 100%, respectively. This cut-off value of 2.0 was useful for distinguishing LT from CH only above the age of two years, as shown in the third group. The fT3/fT4 in 10 subjects with CH in the last group, aged 2 to 7 years, ranged from 2.55 to 7.71. In conclusion, fT3/fT4 less than 2.0 suggests LT rather than CH for patients from the age of two to eighteen years. PMID- 28003586 TI - Current Status and Future Prospects for Esophageal Cancer Treatment. AB - The local control effect of esophagectomy with three-field lymph node dissection (3FLD) is reaching its limit pending technical advancement. Minimally invasive esophagectomy (MIE) by thoracotomy is slowly gaining acceptance due to advantages in short-term outcomes. Although the evidence is slowly increasing, MIE is still controversial. Also, the results of treatment by surgery alone are limiting, and multimodality therapy, which includes surgical and non-surgical treatment options including chemotherapy, radiotherapy, and endoscopic treatment, has become the mainstream therapy. Esophagectomy after neoadjuvant chemotherapy (NAC) is the standard treatment for clinical stages II/III (except for T4) esophageal cancer, whereas chemoradiotherapy (CRT) is regarded as the standard treatment for patients who wish to preserve their esophagus, those who refuse surgery, and those with inoperable disease. CRT is also usually selected for clinical stage IV esophageal cancer. On the other hand, with the spread of CRT, salvage esophagectomy has traditionally been recognized as a feasible option; however, many clinicians oppose the use of surgery due to the associated unfavorable morbidity and mortality profile. In the future, the improvement of each treatment result and the establishment of individual strategies are important although esophageal cancer has many treatment options. PMID- 28003588 TI - Effectiveness of Medium-Chain Triglyceride Oil Therapy in Two Japanese Citrin Deficient Siblings: Evaluation Using Oral Glucose Tolerance Tests. AB - Citrin deficiency, an inherited defect of the liver-type mitochondrial aspartate/glutamate carrier isoform (citrin), may cause impairment of glycolysis because of an increase in the cytosolic NADH/NAD+ ratio. We report a Japanese boy whose main complaint was recurrent hypoglycemic episodes. He was suspected as having citrin deficiency because of his peculiar preference for protein- and fat rich food. His young sister also had a similar food preference. Both siblings were diagnosed with citrin deficiency by genetic analysis. The brother and sister underwent an oral glucose tolerance test (OGTT) at 10 and 7 yr of age, respectively. Blood glucose, ammonia, lactic acid, pyruvic acid, and insulin levels were monitored before starting the test, and then every 30 min. During this test, they maintained blood glucose levels until 180 min. At 210 min, they experienced vomiting, feeling ill, and decreased blood glucose levels (2.9 and 2.8 mmol/l in the brother and sister, respectively). The sister and brother recovered uneventfully by intravenous glucose injection. In a second OGTT, 4 months after medium-chain triglyceride (MCT) oil supplementation, they had no major symptoms and normal glucose levels were maintained, even after 240 min. Additionally, after MCT oil therapy, their food preference slightly changed as they started eating more carbohydrates. Our OGTT data suggest excess carbohydrate intake has adverse consequences in patients with citrin deficiency, including hypoglycemia after a few hours. MCT oil therapy may be effective in preventing such hypoglycemia and improving metabolic derangement, even during the so-called apparently healthy period. PMID- 28003589 TI - Acute Encephalitis Syndrome in Adults and Its Correlation with Cytokine Levels in the Serum and Cerebrospinal Fluid. AB - Acute encephalitis syndrome (AES) is a major health problem in developing countries including India. Neuronal injury in encephalitis is attributed to direct toxicity from pathogens and proinflammatory cytokines. In this study, we assessed cytokine levels in serum and cerebrospinal fluid (CSF), and their correlation with clinical symptoms. In our study, patients with AES for a duration of less than 2 weeks underwent brain imaging followed by CSF analysis for routine parameters and viral studies. We assessed interleukin (IL)-6, IL-10, and regulated on activation, normal T cell expressed and secreted (RANTES) levels in the serum samples of all patients and in 50 CSF samples and compared them with serum cytokine levels of 64 age- and sex-matched controls. Of the 87 AES patients, 13 had Japanese encephalitis (JE). Serum IL-6, IL-10, and RANTES levels were significantly elevated in patients with AES compared with that in controls. Serum IL-10 levels were significantly reduced while RANTES levels were significantly elevated in patients who died. CSF IL-6 and IL-10 levels were significantly elevated in the non-JE group compared with that in JE patients. RANTES levels in the CSF were high in patients who had no seizures. IL-10 exerts its anti-inflammatory effect by modulating the innate and adaptive immune response, thus limiting the production of pro-inflammatory cytokines. Higher IL 10 levels were found to be protective in patients with acute encephalitis. PMID- 28003590 TI - Multicenter Study of the Clinical Presentation of Staphylococcus lugdunensis Bacteremia in Japan. AB - Staphylococcus lugdunensis (SL) is a bacterium with a highly pathogenicity than most other coagulase-negative Staphylococcus spp. (CoNS). In Japan, data on this pathogen are sparse, and the current prevalence of SL bacteremia is unknown. Therefore, we investigated the prevalence of SL in blood culture specimens in a prospective multicenter study across 5 facilities. A total of 3,284 patients had positive blood cultures, and 2,478 patients had bacteremia. Among the patients with bacteremia, 7 patients (0.28%) had SL bacteremia. A total of 281 patients had CoNS bacteremia, with SL accounting for 2.49% of these cases. Of the 7 patients with SL bacteremia, 1 patient (14.3%) had infective endocarditis, and 1 patient (14.3%) died within 30 days. In this study, SL resulted in the development of bacteremia in select patients. Clinicians in Japan should be aware of the prevalence of SL and the complications of SL bacteremia. PMID- 28003591 TI - Comparison of Enterohemorrhagic Escherichia coli (EHEC) O157 and EHEC Non-O157 Isolates from Patients with Diarrhea in Korea. AB - We compared 47 enterohemorrhagic Escherichia coli (EHEC) O157 isolates with 184 EHEC non-O157 isolates from Korean patients with diarrhea. In the O157 group, the strains harboring both Shiga toxin genes (stx1 and stx2) were detected with highest frequency, whereas the strains harboring only stx1 gene were most frequently detected in the non-O157 group. Eight virulence genes (eaeA, hlyA, ehx, iha, efa1, tir, toxB, and espA) were found to show a higher frequency of occurrence in the O157 group than in the non-O157 group. In addition, the symptom of bloody diarrhea was exhibited at a higher rate in the O157 group (51.1%) than in the non-O157 group (16.8%). Our findings demonstrate that EHEC O157 strains are more frequently implicated in cases of bloody diarrhea in the Korean population than EHEC non-O157 strains. PMID- 28003592 TI - Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia. AB - The purpose of this study was to investigate extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilities, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC) typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin (p < 0.0001) and the quinolones nalidixic acid (p=0.004) and ciprofloxacin (p < 0.0001) than non-producers. In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL producing E. coli ST617 appear to have spread to Indonesia. PMID- 28003593 TI - Dengue Virus-Induced Reactive Oxygen Species Production in Rat Microglial Cells. AB - Encephalitis has been described worldwide as a severe complication in patients infected by dengue virus. Reactive oxygen species (ROS) production is a key mechanism involved in the neuronal damage caused by viral encephalitis. In the present study, the capability of dengue virus serotypes 2 (DENV2) and DENV4 to induce ROS production was investigated in a rat microglial cell line, HAPI cells. The cells were infected with DENV2 and DENV4 at a multiplicity of infection of 0.1 for a 2-h adsorption period. Japanese encephalitis virus (JEV) was used as the reference. DENV2- and DENV4-induced microglial activation and significantly increased ROS production corresponded to decreased cell viability. The activity of DENV4 was significantly higher than the activities of DENV2 and JEV at 48 and 72 h post infection. DENV4 partly induced ROS production via an iron-induced Fenton reaction, as demonstrated by the treatment with an iron chelator, deferiprone. Despite the induction of increased inducible nitric oxide synthase expression and nitric oxide (NO) production by JEV, DENV2, and DENV4 did not induce NO production, suggesting the activation of different pathways in response to infections by different viruses. In conclusion, DENV2 and DENV4 have the capability to induce ROS production and activate microglia, which have been reported as the key components of neuronal damage. PMID- 28003594 TI - First Isolation of a Hybrid Shigatoxigenic and Enterotoxigenic Escherichia coli Strain Harboring the stx2 and elt Genes in Korea. PMID- 28003595 TI - Detection of Measles Virus Genotypes B3, D4, D5, D8, and H1 in the Surveillance System in Hokkaido, Japan, 2006-2015, the Last Decade toward the Elimination. AB - Measles is an acute and highly contagious disease caused by measles virus (MeV). The government of Japan, following the last epidemic in 2007 and 2008, which was caused by genotype D5 strains, introduced a catch-up-vaccination program for teenagers during Japan fiscal years 2008-2012 and a mandatory case-based reporting system for the nationwide elimination. Furthermore, laboratory confirmation of measles cases by genotyping of isolates has been performed to clarify the source of infection and support the interruption of measles cases. Owing to these preventive measures, the number of measles cases has been steadily decreasing after the last epidemic. In March 2015, Japan was internationally verified as having achieved measles elimination by the World Health Organization Regional Office for the Western Pacific. The continuous elimination of measles and high levels of vaccination coverage for MeV have been maintained nationally. However, imported or import-associated cases of measles have sporadically occurred during this time. After the last nationwide epidemic, 17 imported or import-associated measles cases (MeV strains identified as genotypes H1, D4, D8, and B3) were reported in Hokkaido, the northern islands of Japan. In this study, we present the occurrence of measles and surveillance activities in Hokkaido during 2006-2015. PMID- 28003596 TI - A Case Study of Rat Bite Fever Caused by Streptobacillus moniliformis. AB - We report a case of rat bite fever, diagnosed based on positive cultures of Streptobacillus moniliformis from blood and synovial fluid. The patient was a 45 year-old man who presented with history of a rat bite and alcoholic liver cirrhosis. He had been bitten on his third finger by a rat, which was caught in a mousetrap installed in his house. Over the course of approximately 2 weeks after the bite, the patient developed fever, rash, and arthralgia. The patient was admitted to our hospital and treated with a combination of ampicillin-sulbactam, vancomycin (VAN), and minocycline (MIN) antibiotics. Initial culture findings from the Anaerobic/F resin blood culture were positive for gram-negative bacillus after overnight incubation. Thus, S. moniliformis infection was suspected, and administration of VAN and MIN was ceased. On hospital day 8, the treatment was switched to oral amoxicillin-clavulanic acid, and the patient was discharged from the hospital. Subsequently, the pathogen was also detected in synovial fluid and identified as S. moniliformis using 16S rRNA sequencing analysis. PMID- 28003597 TI - Safety and Immunogenicity of a 9-Valent Human Papillomavirus Vaccine Administered to 9- to 15-Year-Old Japanese Girls. AB - A 9-valent human papillomavirus (HPV 6/11/16/18/31/33/45/52/58) virus-like particle vaccine (9vHPV) has been proven highly efficacious in preventing anogenital diseases related to HPV, in a pivotal phase III study for women aged 16-26 years. Here, we report the results of an open-label phase III study conducted to bridge the gap between the findings in women aged 16-26 years and Japanese girls aged 9-15 years. All subjects (n = 100) received a 3-dose regimen of 9vHPV vaccine on day 1 and at months 2 and 6. Anti-HPV serological assays were performed on day 1 and at months 7, 12, 24, and 30. At month 7 (4 weeks after the third dose), 100% of the subjects exhibited seroconversion for each type of HPV. Increases in geometric mean of the titers for anti-HPV 6/11/16/18/31/33/45/52/58 in the subjects were similar to those in Japanese women aged 16-26 years in a previous phase III study. Persistence of the anti-HPV response was observed for 2 years after administration of the third dose. In addition, administration of the 9vHPV vaccine was generally well-tolerated in Japanese girls. PMID- 28003598 TI - iTRAQ-based Quantitative Proteomics Study in Patients with Refractory Mycoplasma pneumoniae Pneumonia. AB - Mycoplasma pneumoniae (MP) is a leading cause of community-acquired pneumonia in children and young adults. Although MP pneumonia is usually benign and self limited, in some cases it can develop into life-threating refractory MP pneumonia (RMPP). However, the pathogenesis of RMPP is poorly understood. The identification and characterization of proteins related to RMPP could provide a proof of principle to facilitate appropriate diagnostic and therapeutic strategies for treating paients with MP. In this study, we used a quantitative proteomic technique (iTRAQ) to analyze MP-related proteins in serum samples from 5 patients with RMPP, 5 patients with non-refractory MP pneumonia (NRMPP), and 5 healthy children. Functional classification, sub-cellular localization, and protein interaction network analysis were carried out based on protein annotation through evolutionary relationship (PANTHER) and Cytoscape analysis. A total of 260 differentially expressed proteins were identified in the RMPP and NRMPP groups. Compared to the control group, the NRMPP and RMPP groups showed 134 (70 up-regulated and 64 down-regulated) and 126 (63 up-regulated and 63 down regulated) differentially expressed proteins, respectively. The complex functional classification and protein interaction network of the identified proteins reflected the complex pathogenesis of RMPP. Our study provides the first comprehensive proteome map of RMPP-related proteins from MP pneumonia. These profiles may be useful as part of a diagnostic panel, and the identified proteins provide new insights into the pathological mechanisms underlying RMPP. PMID- 28003599 TI - Establishment of Subclones of the Severe Fever with Thrombocytopenia Syndrome Virus YG1 Strain Selected Using Low pH-Dependent Cell Fusion Activity. AB - The first clinical case of the YG1 strain of the severe fever with thrombocytopenia syndrome virus (SFTSV) has been isolated in Japan. We found that only some of the cells underwent low pH-dependent cell fusion, although all of the cells were confirmed to have been infected with the virus. This suggested that the YG1 strain consists of a heterogeneous mixture of related viruses. Here, we established 3 subclones (termed E3, A4, and B7) from the YG1 strain, using the limiting dilution method with the pH-dependent cell fusion activity. Subclone E3 showed weak fusion activity and cytopathic effects (CPE) in Vero E6 cells. The amino acid sequence of E3 was identical to the published sequence for the YG1 strain, and it likely comprises a subpopulation of the YG1 strain. Subclone A4 displayed strong fusion activity under acidic conditions. In contrast, subclone B7 showed strong fusion activity and CPE under neutral and acidic conditions. Two amino acid differences shared between B7 and A4 were found in the envelope glycoproteins. In addition, an amino acid variant of the RNA-dependent RNA polymerase was found only in B7. These subclones will be valuable tools to elucidate cell fusion mechanisms of SFTSV and the relationship between viral proteins and their functions. PMID- 28003600 TI - Identification of Group G Streptococcal Isolates from Companion Animals in Japan and Their Antimicrobial Resistance Patterns. AB - In this study, we conducted a species-level identification of group G streptococcal (GGS) isolates from companion animals in Japan and analyzed antimicrobial resistance (AMR) patterns. Strains were isolated from sterile and non-sterile specimens collected from 72 animals with clinical signs or symptoms in April-May, 2015. We identified the strain by 16S rRNA sequencing, mass spectrometry (MS), and an automated method based on their biochemical properties. Antimicrobial susceptibility was determined using the broth microdilution method and E-test. AMR determinants (erm(A), erm(B), mef(A), tet(M), tet(O), tet(K), tet(L), and tet(S)) in corresponding resistant isolates were amplified by PCR. The 16S rRNA sequencing identified the GGS species as Streptococcus canis (n = 68), Streptococcus dysgalactiae subsp. equisimilis (n = 3), and S. dysgalactiae subsp. dysgalactiae (n = 1). However, there were discrepancies between the sequencing data and both the MS and automated identification data. MS and the automated biochemical technique identified 18 and 37 of the 68 sequencing identified S. canis strains, respectively. The AMR rates were 20.8% for tetracycline and 5.6% for clarithromycin, with minimum inhibitory concentrations (MIC)50 -MIC90 of 2-64 and <= 0.12-0.25MUg/mL, respectively. AMR genotyping showed single or combined genotypes: erm(B) or tet(M)-tet(O)-tet(S). Our findings show the unique characteristics of GGS isolates from companion animals in Japan in terms of species-level identification and AMR patterns. PMID- 28003601 TI - Molecular Epidemiological Study of Mumps Epidemics of 2015 in Okinawa, Japan. AB - Although major mumps epidemics occurred every 4-5 years in Okinawa Prefecture in Japan, no laboratory diagnoses were conducted. A mumps epidemic started in Okinawa in October 2014, and we collected clinical samples from 31 patients in 4 areas (Hokubu, Nanbu, Miyako, and Yaeyama) from July to December 2015, for virus isolation and RT-PCR, whose positive ratios were 52% and 87%, respectively. Phylogenetic analyses showed that all isolates were classified into genotype G, and with one exception, consisted of 2 subgenotypes, Ge (55.6%) and Gw (40.7%), which have been prominent in Japan recently. One isolate was classified in another lineage, which was detected in Japan for the first time, and was similar to a Hong Kong isolate from 2014. Remarkably, the geographic distributions of the 2 major lineages were separated. The Ge viruses were isolated from the main island of Okinawa and the Yaeyama Islands, whereas the Gw isolates were mainly detected from the Miyako Islands. These results suggest that the Ge and Gw mumps viruses mainly caused the mumps epidemics of 2015 in Okinawa, and that they spread independently in separate regions. This is the first report describing the molecular epidemiology of mumps epidemics in Okinawa Prefecture. PMID- 28003602 TI - Evaluation of Immunochromatographic Tests and a New Enzyme Immunoassay for Detection of a Novel GII.17 Norovirus in Stool Samples. AB - A novel GII.17 norovirus (NoV), Kawasaki 2014, has spread to several regions of the world. Rapid and reliable diagnostic tests are needed for the detection of this new NoV variant. In this study,analytical sensitivity of 7 different immunochromatographic (IC) test kits (6 are on the market in Japan and one in Europe) was evaluated by means of confirmed GII.17 NoV-positive stool samples. The stool samples were also tested by a bioluminescent enzyme immunoassay (BLEIA). Real-time RT-PCR served as a reference (gold standard) method. Among the 7 IC kits, RIDA QUICK was the most sensitive, with the limit of detection of 107 copies/ml, whereas the limits of detection of the other IC kits ranged from 108 to 109 copies/ml. It should be pointed out that the limit of detection of BLEIA was approximately 100- to 1,000-fold better (104-105 copies/ml) than that of RIDA QUICK. Nevertheless, the procedure of BLEIA took more time and required sophisticated equipment. PMID- 28003604 TI - Genetic Characterization of Rare Genotype GII.5 Sapovirus Strain Detected from a Suspected Food-Borne Gastroenteritis Outbreak among Adults in Japan in 2010. PMID- 28003603 TI - A Single Vaccination of Nonhuman Primates with Highly Attenuated Smallpox Vaccine, LC16m8, Provides Long-term Protection against Monkeypox. AB - Monkeypox virus (MPXV) causes human monkeypox (human MPX), which is a similar disease to smallpox in humans. A previous study showed that a single vaccination of monkeys with LC16m8, a highly attenuated smallpox vaccine, protected them from MPX from 4-5 weeks post-vaccination. In this study, we evaluated the long-term efficacy of a single vaccination with LC16m8 in a nonhuman primate model of MPXV infection. The monkeys were inoculated with either LC16m8, Lister (parental strain of LC16m8), or a mock-up vaccine, and then challenged with MPXV via a subcutaneous route, at 6 and 12 months after vaccination, which we compared with either Lister or the mock-up vaccination. The LC16m8 monkeys exhibited almost no MPX-associated symptoms, whereas most of the naive monkeys died. LC16m8 generated the protective memory immune response against MPXV, as suggested by the immediate viremia reduction and the response of the IgG antibody. The results demonstrated that the vaccination of monkeys with a single dose of LC16m8 provided durable protection against MPXV for longer than one year after immunization. The results suggest that the vaccination of humans with LC16m8 could induce long-term protection against MPXV infection. PMID- 28003605 TI - Contribution of Streptococcus gordonii Hsa Adhesin to Biofilm Formation. AB - Adhesion of oral mitis group streptococci, such as Streptococcus gordonii, to acquired pellicle on the tooth surface is the first step in oral biofilm formation. S. gordonii strain DL1 possesses an Hsa adhesin, which recognizes the terminal sialic acid of host sialoglycoconjugates. The aim of the present study was to investigate the role of the Hsa adhesin in biofilm formation. The biofilm forming ability of a S. gordonii hsa mutant on microtiter plates pre-coated with saliva, fetuin, or mucin was significantly lower than that of wild-type strain DL1. In contrast, no significant difference in biofilm-forming ability was observed in plates pre-coated with bovine serum albumin, which does not contain sialic acid. The biofilm-forming ability of strain DL1 in saliva-coated microtiter plates was also significantly reduced when the plate was pre-treated with neuraminidase. The sialic acid-dependent biofilm-forming ability of different wild-type S. gordonii strains varied. However, Southern and western blot analyses showed that all the tested wild-type strains possessed and expressed hsa homologs, respectively. These results indicate that the binding of Hsa adhesin to sialoglycoconjugates is associated with biofilm formation of S. gordonii DL1, and imply variation in the contribution of Hsa and its homologs to S. gordonii biofilm formation. PMID- 28003606 TI - Solubility Testing of Sucrose Esters of Fatty Acids in International Food Additive Specifications. AB - We investigated the solubility of 10 samples of sucrose esters of fatty acids (SEFA) products that are commercially available worldwide as food additives (emulsifiers). Although one sample dissolved transparently in both water and ethanol, other samples produced white turbidity and/or precipitates and did not meet the solubility criterion established by the Joint Food and Agriculture Organization of the United Nations (FAO)/WHO Expert Committee on Food Additives (JECFA). When the sample solutions were heated, the solubility in both water and ethanol increased. All of the samples dissolved transparently in ethanol, and dispersed and became white without producing precipitates in water. The present study suggests that the current solubility criterion of the JECFA SEFA specifications needs to be revised. PMID- 28003607 TI - Examination for Effectiveness of Scatter Correction in Portable Chest Radiography. AB - OBJECTIVES: The aim of this study was to evaluate the effectiveness of scatter correction in the portable chest radiography. METHODS: Digital radiographies were performed without anti-scatter grid (grid), with the scatter correction and with the grid ratio of 3 : 1 in this study. The scatter fraction and the detectability of low contrast signals were measured using the four acrylic phantoms of different thicknesses. The chest phantom radiographs were assessed subjectively, in random order, by six radiologic technologists. RESULTS: The scatter fraction was higher in the no-grid technique, and was lower for the grid technique. The detectability of low contrast signals did not significantly differ between the scatter correction and the grid technique (p>0.05). The area under the receiver operating characteristic curve for the grid technique was higher than that for the scatter correction technique (0.888 vs. 0.855), although no significant difference was found between the grid and the scatter correction technique (p> 0.05). The ability to detect the nasogastric tube was significantly better in the grid technique (p<0.001). DISCUSSION: In the scatter correction technique, the ability of scatter removal increased as the scatter fraction increased. The scatter correction technique was unnecessary to extremely accurate alignment. In addition, patient dose can be reduced by the scatter correction technique. CONCLUSIONS: It seemed to be effective for the scatter correction in the portable chest radiography. PMID- 28003608 TI - The Effects of Misalignment between PET and CT Scans on Brain PET Study Using CT based Attenuation Correction: A Phantom Study. AB - PURPOSE: The aim of this study was to evaluate the effects of inaccurate attenuation correction due to the misalignment between the computed tomography (CT)-based MU-map and the positron emission tomography (PET) data on a brain PET. METHODS: CT and PET scans were performed on a 3-dimension (3D) brain phantom, in which the grey matter region was filled with 18F-fluorodeoxyglucose (18F-FDG), and the skull region was filled with/without the bone-equivalent solution. The shifted PET images relative to the CT image were generated by the software-based translation of PET data in the cephalad/caudal and right directions, with a magnitude of the shift up to 30 mm and a step size of 5 mm. The regions of interest (ROIs) were drawn on the areas of the temporal lobes, parietal lobes, thalami, and cerebellums in the no-shifted image (reference). For each ROI, the radioactivity concentrations in the shifted images were compared with those of the reference. RESULTS: The errors in the radioactivity concentrations were increased with the increasing magnitude of the shift in all brain regions except for thalamus. For a 5 mm shift in the right direction, +/- 10% errors were observed in the left/right temporal lobes. The accuracy of the radioactivity concentration in the temporal lobe was very sensitive to misalignment in the right directions. CONCLUSION: The misalignment between CT-based MU-map and PET data had larger effects on the surface regions of the brain rather than on deep brain structures. PMID- 28003609 TI - The Development of Vibration System for Applying Magnetic Resonance Elastography (MRE) to the Supraspinatus Muscle. AB - Palpation is a standard clinical tool to diagnose abnormal stiffness changes in soft tissues. However, it is difficult to palpate the supraspinatus muscle because it locates under the trapezius muscle. The magnetic resonance elastography (MRE) uses harmonic mechanical excitation to quantitatively measure the stiffness (shear modulus) of both the superficial and deep tissues. The purpose of this study was to build a vibration system for applying the MRE to the supraspinatus muscle. In this study, a power amplifier and a pneumatic pressure generator were used to supply vibrations to a vibration pad. Six healthy volunteers underwent MRE. We investigated the effects of position (the head of the humerus and the trapezius muscle) of the vibration pad on the patterns of wave propagation (wave image). When the vibration pad was placed in the trapezius muscle, the wave images represented clear wave propagation. On the other hand, when the vibration pad was placed in the head of the humerus, the wave images represented unclear wave propagation. This result might be caused by wave interferences resulting from the vibrations from bones and an intramuscular tendon of the supraspinatus muscle. The mean shear modulus also was 8.12 +/- 1.83 (mean +/- SD) kPa, when the vibration pad was placed in the trapezius muscle. Our results demonstrated that the vibration pad should be placed in the trapezius muscle in the MRE of the supraspinatus muscle. PMID- 28003610 TI - The Impact of Gadolinium-based Contrast Agent for Carbon Ion Radiotherapy. AB - PURPOSE: The contrast agent used in the diagnostic department has high atomic numbers and might influence dose deposition in the particle therapy. In particular, the influence of gadolinium-based (Gd) contrast agent on range in carbon ion radiotherapy has not yet been evaluated. For this reason, we avoid carbon treatment and planning computed tomography (CT) acquisition on days when the contrast-enhanced magnetic resonance image (MRI) is performed. In this study, we evaluated the time required for this beam range effect to vanish by evaluating the temporal changes in the CT values after an enhanced MRI as well as the stopping power of Gd solution. MATERIALS AND METHODS: Two types of diluted solutions with Gd contrast agent were used for comparing their transferred stopping power (TSP) and measured stopping power (MSP). The TSP was calculated with a CT value to stopping power ratio table that was created previously. Additionally, to evaluate in vivo attenuation, we measured the CT values in the renal pelvis from the CT images with and without contrast agent for 73 patients. RESULTS: The maximum difference between the TSP and MSP was 85%. The difference between the TSP after 4 hours and the TSP with non-enhanced cases was less than 1%. Moreover, the difference between the MSP after 1 hour and the MSP with non enhanced cases was less than 0.1%. CONCLUSION: It was found that the impact of Gd contrast agent can be neglected 1 hour after administration for carbon beam irradiation and 4 hours after for planning the CT image acquisition. PMID- 28003611 TI - The Effect of Metal Artifact Reduction at Different Calibrated and Display Field of Views in Computed Tomography. AB - PURPOSE: The purpose of this study was to investigate the effects of the metal artifact reduction using single energy metal artifact reduction (SEMAR) with a prosthetic hip joint in different field of view (FOV). METHODS: A prosthetic hip joint was arranged at the center of the phantom. The phantom images were scanned by changing calibrated-FOV (C-FOV) of 240, 320, 400, and 500 mm. Those images were reconstructed by changing the display-FOV (D-FOV) of 120, 180, 240, and 320 mm. The metal artifact reduction with the SEMAR was evaluated by calculating the artifact index (AI) and its decrease ratio. RESULTS: The AI of C-FOV (500 mm) and D-FOV (120, 180, 240, or 320 mm) were 15.8, 15.8, 15.7, and 14.4 with SEMAR. For changed C-FOV, the AI of C-FOV (240 mm) was significantly higher than any other C FOVs. The AI of C-FOV (240 mm) was 29.8-30.0 and that of the other C-FOV were 12.4-15.8 with SEMAR. In addition, the decrease ratio of AI was 52.2-54.1% for C FOV (240 mm) and 58.9-73.2% for the other C-FOVs. CONCLUSION: Although the SEMAR decreased the metal artifact, the effect of reducing the metal artifact was affected by C-FOV. PMID- 28003612 TI - The Advantage of 80-row Non-helical Scan Method for Head Computed Tomography: In Basal Ganglia and Parietal. AB - PURPOSE: The purpose of this study was to evaluate the advantage of 80-row non helical scan methods (NH) for the head computed tomography (CT). METHODS: We calculated the noise power spectrum (NPS), contrast-to-noise ratio (CNR), CT values and standard deviation (SD) at slice position, and coefficient of variation (CV) value in head phantom. This study compared the NH method with the helical scan method (HE). RESULTS: The NPS and CNR of NH were improved compared to the HE in equivalent volume-CT dose index (CTDIvol). However, the NH was inferior to the HE in CT values and the SD at slice position. The CV values of NH were increased than the HE in the skull base. On the other hand, the CV values of NH were decreased than the HE in basal ganglia and parietal. CONCLUSIONS: The non helical scan method in head CT have advantage for the detection of lesion in basal ganglia and parietal. PMID- 28003613 TI - Development of the Diagnostic Reference Levels in the IVR. PMID- 28003615 TI - Participation/Dispatch Reports on International Conferences in 2016. PMID- 28003614 TI - 6. Ethics in Clinical Research (1). PMID- 28003616 TI - Standards for Dose Management on Radiation Systems. PMID- 28003617 TI - Erratum. PMID- 28003618 TI - I Think about "Discovery of New Things by Studying the Past". PMID- 28003619 TI - Mass-forming Retroperitoneal Endometriosis Including a Fat Component: A Diagnostic Dilemma. PMID- 28003620 TI - Synthetic MR Imaging in the Diagnosis of Bacterial Meningitis. PMID- 28003621 TI - The Mechanism Causing High-signal Intensity on Diffusion-weighted Imaging in Adnexal Torsion: Two Case Reports. AB - We report two cases with adnexal torsion to assess the mechanism of very strong signal intensity in ovarian lesions on DW imaging using MR imaging such as T2* weighted imaging. MR imaging findings of the cases suggest that the very strong signal intensity on DW imaging is contributed to cytotoxic edema with or without vasogenic edema, as well as oxyhemoglobin or extracellular methemoglobin. PMID- 28003622 TI - Cranial Pachymeningeal Involvement in POEMS Syndrome: Evaluation by Pre- and Post contrast FLAIR and T1-weighted Imaging. AB - PURPOSE: To evaluate the cranial pachymeningeal involvement of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome using pre- and post-contrast fluid-attenuated inversion recovery (FLAIR) and T1-weighted imaging (T1WI). METHODS: The appearance of pachymeningeal involvement in nine cases of POEMS syndrome was evaluated using pre- and post contrast FLAIR and T1WI. The degree of pachymeningeal thickening was graded as normal or abnormal using pre-contrast FLAIR. The degrees of contrast enhancement effect were evaluated based on pre- and post-contrast images, and recorded in each of three separate anatomical areas, i.e., the falx cerebri, cerebral convexity, and tentorium cerebelli. The degrees of contrast enhancement of pachymeninges were graded as not detected (ND), positive, or prominent on post contrast FLAIR, and normal range (NR), positive, and prominent on post-contrast T1WI. RESULTS: Pre-contrast FLAIR demonstrated 41% of pachymeningeal anatomical regions as areas of thickening. Post-contrast FLAIR did not detect any contrast enhancement on 26% of the regions but showed positive enhancement on 30% and prominent enhancement on 44%. Post-contrast T1WI showed normal range enhancement on 48%, positive enhancement on 11%, and prominent enhancement on 41% of the regions. Post-contrast FLAIR showed the highest percentage for detection of pachymeningeal abnormalities (74%). CONCLUSION: Post-contrast FLAIR may contribute to objective judgment in the evaluation of pachymeningeal involvement in POEMS syndrome. PMID- 28003623 TI - Internal Structures of the Globus Pallidus in Patients with Parkinson's Disease: Evaluation with Phase Difference-enhanced Imaging. AB - PURPOSE: The medial medullary lamina (MML) separates the medial globus pallidus (GPm) from the lateral. The aim of this study was to assess the changes in appearance of MML related to age using the phase difference-enhanced (PADRE) imaging and to determine whether PADRE can depict the MML in the patients with Parkinson's disease (PD). MATERIALS AND METHODS: We enrolled 20 patients with PD and 50 normal control subjects (NC). First, for the visualization of the MML in the NC, we compared the PADRE, susceptibility-weighted imaging (SWI)-like images and T2 weighted imaging (WI) by using multiple comparison. The grading methods are as follows: grade 1; MML was not delineated, grade 2; less than half of MML was delineated, grade 3; more than half of MML was delineated and grade 4; whole MML was clearly delineated. We determined grade 3 and 4 as good depiction, delineating the GPm. Then, we evaluated patients with PD using the same method. RESULTS: In NC, the delineation of MML was good in 84% of cases on PADRE, but only 34% of cases showed a good depiction on SWI-like images (average grading score 3.31 vs 2.11, P < 0.05). No MML was delineated in all cases on T2 WI. Although younger subjects tended to show whole MML clearly, a part of MML tends to be obscured with age on PADRE. In patients with PD the depiction of MML on PADRE was also good in 90% of cases. CONCLUSION: The PADRE technique facilitates the depiction of the MML within globus pallidus (GP) on a broad range of age NC and patients with PD and it is superior to SWI-like images and T2 WI. PMID- 28003624 TI - Viability of Oxygen-enhanced Ventilation Imaging of the Lungs Using Ultra-short Echo Time MRI. AB - PURPOSE: To assess the viability of oxygen-enhanced ventilation images using ultra-short echo time magnetic resonance imaging (UTE-MRI). METHODS: We evaluated the oxygen enhancement of the pulmonary T2*, and pulmonary signals in each TE (0.2, 0.8, 1.4, 2.0 ms) in 21 nonsmokers. RESULTS: The oxygen enhancement of pulmonary signals was the most significant (32%) at the 0.2 ms TE, the second in the pulmonary T2* (-18%). CONCLUSIONS: Pulmonary images using UTE-MRI are useful for ventilation imaging. PMID- 28003625 TI - Gene-Targeted Analysis of Clinically Diagnosed Long QT Russian Families. AB - Long QT syndrome (LQTS) has great genetic heterogeneity: more than 500 mutations have been described in several genes. Despite many advances, a genetic diagnosis still cannot be established in 25-30% of patients. The aim of the present study was to perform genetic evaluation in 9 Russian families with LQTS; here we report the results of 4 positive probands and their relatives (a total of 16 individuals). All subjects underwent clinical examination, 12-lead ECG, and Holter monitoring. Genetic analysis of the 14 genes mainly involved in LQTS was performed using a next-generation sequencing approach. We identified two new mutations (KCNQ1 gene) and 6 known mutations (AKAP9, ANK2, KCNE1 and KCNJ2 genes) in 4 out of 9 probands, some of which have already been described in association with LQTS. Segregation studies suggest a possible causative role for KCNQ1 p.(Leu342Pro), AKAP9 p.(Arg1609Lys), KCNE1 p.(Asp85Asn), and KCNJ2 p.(Arg82Gln) variations. Our study confirmed the high genetic heterogeneity of this disease and highlights the difficulties to reveal clear pathogenic genotypes also in large pedigrees. To the best of our knowledge, this is the first genetic study of LQTS patients from Russian families. PMID- 28003626 TI - Methods of Rapid Microbiological Assay and Their Application to Pharmaceutical and Medical Device Fabrication. AB - There are several rapid microbiological methods becoming available that have useful applications in pharmaceutical and medical devices. They are ATP bioluminescence, fluorescent labeling, electrical resistance, and nucleic acid probes. In choosing to employ rapid methods, the microbiologist should examine their prospective performances against the specific requirements for that sector. Some methods may require expensive equipment and offer full automation, and others represent only a small investment. The regulatory view of these methods is changing and they still officially have not been approved in medical and pharmaceutical area, but it will still be up to the microbiologist to demonstrate that the method chosen is fit for the purpose intended. PMID- 28003627 TI - Validation Study and Quality Assurance of Pharmaceutical Water, Waterborne Microorganisms and Endotoxins. AB - Water for injection (WFI) and purified water are the most widely used and stringently regulated raw material in pharmaceutical manufacturing. WFI is utilized for a parenteral drug product. Water system is monitored at frequent and routine frequency for demonstrating the overall system control and stability of performance. The critical ports demonstrating systemic control should be monitored more frequently. For reducing the overall risk of microbial contamination or microbial build-up, it is important to develop appropriate alert and action levels. The assignment of alert and action levels should be performance-based, derived from the historic data and well below water specifications. These levels and overall excursion rates should be assessed annually. An action level should not be established at a level equivalent to the specification. Consecutive or multiple alert level excursions and each action level excursion should be comprehensively investigated with appropriate corrective and preventive action. It is important to analyze the efficacy of the corrective and preventive action to reduce the overall excursion rates. PMID- 28003628 TI - Prediction of Competitive Microbial Growth. AB - Prediction of competitive microbial growth is becoming important for microbial food safety. There would be two approaches to predict competitive microbial growth with mathematical models. The first approach is the development of a growth model for competitive microbes. Among several candidates for the competition model considered, the combination of the primary growth model of the new logistic (NL) model and the competition model of the Lotka-Vorttera (LV) model showed the best performance in predicting microbial competitive growth in the mixed culture of two species. This system further successfully predicted the growth of three competitive species in mixed culture. The second approach is the application of the secondary model especially for the parameter of the maximum cell population in the primary growth model. The combination of the NL model and a polynomial model for the maximum population successfully predicted Salmonella growth in raw ground beef. This system further successfully predicted Salmonella growth in beef at various initial concentrations and temperatures. The first approach requires microbial growth data in monoculture for analysis. The second approach to the prediction of competitive growth from the viewpoint of microbial food safety would be more suitable for practical application. PMID- 28003629 TI - Bacterial Contamination into Ready-to-Eat Foods Sold in Middle Thailand. AB - Bacterial contamination in ready-to-eat (RTE) foods prepared and sold by small businesses in middle Thailand was surveyed. The 135 samples were randomly purchased from open markets and supermarkets in Bangkok and Pathum Thani provinces during May 2013 to February 2015. The results indicated that the rate of contamination in cooked pork, chicken meat and cooked aquatic items were 13/39 (33%), 18/45 (40%) and 14/57 (25%), respectively and the rate of bacterial contamination of collected samples from open market and supermarket were 26/67 (39%) and 19/68 (27%), respectively. Therefore, no statistically significant difference of contamination rate between two kinds of market or among three categories of food. The most contaminated pathogenic bacteria was Staphylococcus aureus 27/135 (20%) while that of Salmonella spp. was the lowest 5/135 (4%) in each categories of collected food samples. Implementation of suitable hygienic practices in the small food businesses are thought to be required to reduce the risk of foodborne illnesses caused by the consumption of RTE foods sold in middle Thailand. PMID- 28003630 TI - In Vitro Evaluation of the Biocompatibility of Newly Synthesized Bis-Quaternary Ammonium Compounds with Spacer Structures Derived from Pentaerythritol or Hydroquinone. AB - With the object of developing new biocides milder for human use than the current antiseptics, we synthesized a series of bis-quaternary ammonium compounds (bis QACs). The antimicrobial activity of the newly synthesized bis-QACs and common biocides used as antiseptics was compared by examining minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs). Moreover, the cytotoxicity of these compounds against human cells was determined to calculate the biocompatibility index (BI) of these compounds. BI was the ratio of the concentration of a biocide giving a 50% lethal effect on normal human epidermal keratinocytes to its MBC against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The commonly used antiseptics tested were benzalkonium chloride (BAC), octenidine dihydrochloride (OCT), chlorhexidine digluconate (CHG) and polyhexamethylene biguanide (PHMB). In comparison with these antiseptics, it was shown that some of new bis-QACs exhibited a wider and more potent antimicrobial spectrum than OCT. The cytotoxicity of these bis-QACs was equal or lower compared to that of the quaternary ammonium compounds (BAC and OCT), although these bis-QACs showed higher toxicity than the biguanide-based compounds (CHG and PHMB). Finally, the comparison of BIs revealed that new bis-QACs such as N-dodecyl {4,4'-(2,4,8,10-tetraoxaspiro[5.5]undecan-3,9-diyl) }dipyridinium dibromide (4TOSU-12), 3,3'-[1,4-Phenylenebis (oxy)]bis (1-dodecylpyridinium) dibromide (3PHBO-12) and 3-(3-Hydroxy-2-(hydroxymethyl)-2-{[(1-dodecylpyridinium 3-yl) oxy]methyl}propoxy)-1-dodecylpyridinium dibromide (3HHDMP-12) had equal or greater biocompatibility than the commonly used biocides tested. Thus, these results strongly suggested that 4TOSU-12, 3PHBO-12 and 3HHDMP-12 could be useful as antiseptics for topical application to the skin. PMID- 28003631 TI - Bacterial and Fungal Counts of Dried and Semi-Dried Foods Collected from Dhaka, Bangladesh, and Their Reduction Methods. AB - Food is a basic necessity for human survival, but it is still the vehicle for the transmission of food borne disease. Various studies have examined the roles of spices, herbs, nuts, and semi-dried fruits, making the need for safe and convenient methods of decontamination a necessity. The current study determined the bacterial and fungal loads of 26 spices and herbs, 5 nuts, 10 semi-dried fruits and 5 other foods. Spices, herbs and semi-dried foods demonstrated the highest bacterial and fungal loads with the majority showing over 104 CFU/mL. Nuts and other foods showed growths ranging from 102 to 106 CFU/mL. The current study also attempted to determine the effects of heat and plasma treatment. The log reduction of bacterial growth after heat treatment (maximum: 120 min for 60C) was between 0.08 to 4.47, and the log reduction after plasma treatment (maximum: 40 min) ranged from 2.37 to 5.75. Spices showed the lowest rates of reduction, whereas the semi-dried and other foods showed moderate to high levels of decrease after heat treatment. The log reduction of fungal growth after heat treatment ranged from 0.27 to 4.40, and log reduction after plasma treatment ranged from 2.15 to 5.91.Furthermore, we validated the sterilization effect of plasma treatment against Bacillus spp. and Staphylococcus spp. by using scanning electron microscopy. Both treatment methods could prove to be advantageous in the agriculture related fields, enhancing the quality of the foods. PMID- 28003632 TI - Isolation and Characterization of a Variant Manganese Resistant Strain of Saccharomyces cerevisiae. AB - Manganese contamination in water is one of the most serious problems in Southeast Asian countries, including Vietnam. Bioremediation using microorganisms, especially from the brewing yeast Saccharomyces cerevisiae, is expected to be a useful technique to remove manganese from contaminated water. Yeast strain S. cerevisiae BY4741 as the wild-type strain and some manganese accumulating mutants bred from BY4741 were examined for cell growth and manganese accumulation in YPD liquid medium containing various concentrations of Mn2+. Variants accumulating larger concentrations of manganese were isolated by the repeated screening of survivors in YPD media containing10mM Mn2+. Manganese was accumulated by the yeast cells during growth, but the growth of BY4741 was retarded with increasing Mn2+ concentrations and almost inhibited at 15mM Mn2+. One variant isolate, named IM3, showed no retardation of growth up to 15 mM Mn2+ and could absorb over 4-fold more manganese than the BY4741 strain. Effects of culture temperature and pH on the growth and manganese accumulation were analyzed for IM3. Maximum accumulation was shown at 30C, pH 6.0 while the optimal growth was shown at 37C, pH 5.0 - 7.0. Interestingly, IM3 could grow a little at pH 9.0 when manganese was added to the culture media, while it could not grow without the addition of manganese. PMID- 28003633 TI - Influence of Detection Methods in Characterizing Escherichia coli O157:H7 in Raw Goat Meat Using Conventional and Molecular Methods. AB - Presence of Escherichia coli O157:H7 on fresh goat meat samples (n= 40) of Dhaka city was analyzed using conventional and molecular methods. A total of 86 presumptive E. coli O157:H7 colonies were isolated from 60% of the samples using selective agar plating method. After conventional biochemical assay followed by API 20E assay, only 11 isolates were found to be E. coli O157:H7. Further serological test identified only four isolates that has strong agglutination reaction against anti-H7 sensitized latex. The biochemically and serologically confirmed isolates were then screened for major virulence factors include eaeA, rfbE, fliC, stx1 and stx2 genes by PCR. PCR analysis of positive isolates showed, 10 isolates were eaeA and rfbE genes positive but fliC gene was only in six, indicating that these isolates were H7 positive with flagellum antigens which might not expressed or detected in serotyping tests. Multiplex PCR against eaeA, stx1 and stx2 genes of the isolates showed similar results as when done individually. These results revealed that only 7% of the primary presumptive E. coli O157:H7 was found to be stx producing E. coli O157:H7 and thus greatly influenced the detection of the pathogen in meat samples. PMID- 28003634 TI - Inactivation of Vibrio parahaemolyticus Unattached and Attached to a Solid Surface in pH-Controlled Sodium Hypochlorite Solutions. AB - The inactivation of Vibrio parahaemolyticus cells that were unattached or attached to a polyethylene terephthalate (PET) disc in pH-controlled sodium hypochlorite (NaOCl) solutions was studied under turbulent conditions. No significant desorption of attached cells occurred at the free available chlorine (FAC) concentrations from 0.1 to 1.0 mg/l. The number of viable cells was estimated by microbial calorimetry. The logarithmic relative reduction of viable cells was proportional to the product of the FAC concentration and time. In the pH range of 5.6 to 9.3, the first-order inactivation rate constants for unattached and attached cells increased with decreasing solution pH. It was found that the rate constants for unattached cells were approximately 6 to 7 times higher than those for attached cells at all pH values examined. It was confirmed that attached cells were more resistant to NaOCl solutions than unattached cells even when accessibility of attached cells to HOCl/OCl- was enhanced under turbulent conditions. PMID- 28003635 TI - Effects of STAT3 inhibitors on neural functional recovery after spinal cord injury in rats. AB - Spinal cord injuries (SCIs) can induce primary and secondary injury, resulting in severe neurological damage and dysfunction in patients. Studies have reported that signal transducer and activator of transcription 3 (STAT3) plays an important role in the inflammatory immune response and neural stem cell differentiation. In order to examine whether a STAT3 inhibitor can prevent worsening of an SCI and promote neural stem cell differentiation, a rat model of surgically induced SCI was created and rats were treated with the STAT3 inhibitor S31-201. Tissue from the injured region was harvested and fixed in formalin and paraffin. H&E staining was used to look for morphological changes. The Basso, Beattie, and Bresnahan locomotor scale (BBB score), somatosensory evoked potentials (SEP), and motor evoked potentials (MEP) were examined. Western blotting was used to detect the expression of beta-tubulin sh, vimentin, GFAP, NF 200, and OX-42 protein. Results indicated that the STAT3 inhibitor S31-201 reduces the extent of SCI and it promotes neural stem cell differentiation. PMID- 28003636 TI - Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology. AB - Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach. PMID- 28003637 TI - Differential toxicity between perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). AB - Perfluoroalkyl substances (PFASs) are persistent environmental contaminants. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are representatives of PFASs. Recently, the U.S. Environmental Protection Agency (US EPA) set the health advisory level as 70 parts per trillion for lifetime exposure to PFOS and PFOA from drinking water, based on the EPA's 2016 Health Effects Support Documents. Then, a monograph on PFOA was made available online by the International Agency for Research on Cancer, where the agency classified PFOA as "possibly carcinogenic to humans" (Group 2B). The distinction between PFOS and PFOA, however, may not be easily understood from the above documents. This paper discussed differential toxicity between PFOS and PFOA focusing on neurotoxicity, developmental toxicity and carcinogenicity, mainly based on these documents. The conclusions are as follows: Further mechanistic studies may be necessary for ultrasonic-induced PFOS-specific neurotoxicity. To support the hypothesis for PFOS-specific neonatal death that PFOS interacts directly with components of natural lung surfactant, in vivo studies to relate the physicochemical effects to lung collapse may be required. PFOA-induced DNA damage secondary to oxidative stress may develop to mutagenicity under the condition where PFOA-induced apoptosis is not sufficient to remove the damaged cells. A study to find whether PFOA induces apoptosis in normal human cells may contribute to assessment of human carcinogenicity. Studies for new targets such as hepatocyte nuclear factor 4alpha (HNF4alpha) may help clarify the underlying mechanism for PFOA-induced carcinogenicity. PMID- 28003638 TI - Chemical toxicology of reactive species in the atmosphere: two decades of progress in an electron acceptor and an electrophile. AB - Air pollutants such as diesel exhaust particles (DEP) are thought to cause pulmonary diseases such as asthma as a result of oxidative stress. While DEP contain a large number of polycyclic aromatic hydrocarbons, we have focused on 9,10-phenanthrenequinone (9,10-PQ) and 1,2-naphthoquinone (1,2-NQ) because of their chemical properties based on their oxidative and chemical modification capabilities. We have found that 9,10-PQ interacts with electron donors such as NADPH (in the presence of enzymes) and dithiols, resulting in generation of excess reactive oxygen species (ROS) through redox cycling. We have also shown that 1,2-NQ is able to modify protein thiols, leading to protein adducts associated with activation of redox signal transduction pathways at lower concentrations and toxicity at higher concentrations. In this review, we briefly introduce our findings from the last two decades. PMID- 28003639 TI - Simultaneous Periprosthetic Fractures of the Femur and the Acetabulum After Bipolar Hip Arthroplasty. AB - BACKGROUND Although periprosthetic fractures of the femur are a recognized complication of total hip arthroplasty, periprosthetic fractures of the acetabulum are rare. Simultaneous periprosthetic fractures of both the acetabulum and the femur have not been reported, to our knowledge. CASE REPORT We report a simultaneous fracture of the acetabulum and the femur in a 68-year-old female patient who had previously sustained a subcapital fracture of the femur, treated with a bipolar uncemented prosthesis. We discuss the possible mechanism of this combination of fractures. CONCLUSIONS Simultaneous periprosthetic fractures of the femur and the acetabulum can occur if, in the presence of osteoporotic bone, the metallic femoral head has migrated medially in the acetabulum while the femoral stem is not loose. PMID- 28003641 TI - Systemic lupus erythematosus: iNKT cells guard the heart against disease. PMID- 28003640 TI - Induction of Apoptosis in U937 Cells by Using a Combination of Bortezomib and Low Intensity Ultrasound. AB - BACKGROUND We scrutinized the feasibility of apoptosis induction in blood cancer cells by means of low-intensity ultrasound and the proteasome inhibitor bortezomib (Velcade). MATERIAL AND METHODS Human leukemic monocyte lymphoma U937 cells were subjected to ultrasound in the presence of bortezomib and the echo contrast agent Sonazoid. Two types of acoustic intensity (0.18 W/cm2 and 0.05 W/cm2) were used for the experiments. Treated U937 cells were analyzed for viability and levels of early and late apoptosis. In addition, scanning electron microscopy analysis of treated cells was performed. RESULTS The percentage of cells that underwent early apoptosis in the group treated with ultrasound and Sonazoid was 8.0+/-1.31% (intensity 0.18 W/cm2) and 7.0+/-1.69% (0.05 W/cm2). However, coupling of bortezomib and Sonazoid resulted in an increase in the percentage of cells in the early apoptosis phase, up to 32.50+/-3.59% (intensity 0.18 W/cm2) and 33.0+/-4.90% (0.05 W/cm2). The percentage of U937 cells in the late apoptosis stage was not significantly different from that in the group treated with bortezomib only. CONCLUSIONS Our findings indicate the feasibility of apoptosis induction in blood cancer cells by using a combination of bortezomib, ultrasound contrast agents, and low-intensity ultrasound. PMID- 28003642 TI - CAR T-cell therapy of solid tumors. AB - The potential for immunotherapy as a treatment option for cancer is clear from remarkable responses of some leukemia patients to adoptive cell transfer using autologous T cells genetically modified to express chimeric antigen receptors (CARs). However, the vast majority of cancers, in particular the more common solid cancers, such as those of the breast, colon and lung, fail to respond significantly to infusions of CAR T cells. Solid cancers present some formidable barriers to adoptive cell transfer, including suppression of T-cell function and inhibition of T-cell localization. In this review, we discuss the current state of CAR T-cell therapy in solid cancers, the variety of concepts being investigated to overcome these barriers as well as approaches aimed at increasing the specificity and safety of adoptive cell transfer. PMID- 28003644 TI - Norrbottnian clinical variant of Gaucher disease in Southern Italy. AB - The Norrbottnian type of Gaucher disease (GD), as described many years ago, is due to a unique neuronopathic variant (c.1448T>G; L444P) that may have appeared during or before the sixteenth century in northern Sweden. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular, Norrbottnian patients described in Sweden and Poland seem to share identical clinical histories characterized by the early onset of significant hepatosplenomegaly, often requiring splenectomy at an early age. Neurological involvement generally appears during the first or second decade of life, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment. Osteopenia occurs primarily in the spine, causing a severe and progressive thoracic kyphosis, although the involvement of other skeletal sites cannot be excluded. Here, we report on four Gaucher type 3 patients with Southern Italian ancestry presenting with clinical features and disease progression comparable to those of the 'Norrbottnian' Swedish phenotype, particularly regarding skeletal involvement with poor responsiveness to any therapeutical approach. Although a common ancestry among Southern Italian and Swedish Norrbottnian GD patients could not be investigated, the genotype [L444P]+[L444P] is the most frequently encountered in Southern Italy. PMID- 28003643 TI - Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails. AB - Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys. PMID- 28003646 TI - Relationships between blood pressure variability and indices of large artery stiffness: does the microvasculature play a role? PMID- 28003645 TI - HMSN Lom in 12 Czech patients, with one unusual case due to uniparental isodisomy of chromosome 8. AB - Hereditary motor and sensory neuropathy-type Lom (HMSNL), also known as CMT4D, a demyelinating neuropathy with late-onset deafness is an autosomal recessive disorder threatening Roma population worldwide. The clinical phenotype was reported in several case reports before the gene discovery. HMSNL is caused by a homozygous founder mutation p.Arg148* in the N-Myc downstream-regulated gene 1. Here, we report findings from the Czech Republic, where HMSNL was found in 12 Czech patients from eight families. In these 12 patients, 11 of the causes were due to p.Arg148* mutation inherited from both parents by the autosomal recessive mechanism. But in one case, the recessive mutation was inherited only from one parent (father) and unmasked owing to an uniparental isodisomy of the entire chromosome eight. The inherited peripheral neuropathy owing to an isodisomy of the whole chromosome pointed to an interesting, less frequent possibility of recessive disease and complications with genetic counseling. PMID- 28003648 TI - Cardiac structural remodeling in hypertensive cardiomyopathy. AB - Heart failure with preserved ejection fraction (HFpEF), which is a primary driver of morbidity and mortality, accounts for approximately half of all heart failure cases. Therefore, it is essential to develop preclinical animal models for HFpEF pharmacological treatment strategies. We created a porcine model of severe hypertension and hyperlipidemia by using a combination of deoxycorticosterone acetate (DOCA, 100 mg kg-1), Western diet (WD) and angiotensin II infusion. Systolic blood pressure, echocardiography and invasive pressure-volume loop were assessed at baseline, 12 weeks and 18 weeks. A detailed histological assessment was also performed to determine the cardiac structural remodeling. Compared with controls (n=10), hypertensive animals (n=10) showed markedly higher systolic blood pressure (181 vs. 86 mm Hg) at 18 weeks. Concentric remodeling, characterized by a normal chamber size with a thicker wall, was observed in hypertensive animals. Left ventricle diastolic function showed a tendency toward decline, according to the echocardiographic data. Hemodynamic data showed that the end-diastolic pressure-volume relationship was elevated without changes in the end-systolic pressure-volume relationship. Histological results revealed that the fibrotic area in hypertensive animals (P<0.05 vs. controls) and the fibrotic area in the posterior wall of hypertensive animals' left atria were larger than other sites of the left atria (P<0.05 vs. other sites). This model can mimic clinical HFpEF to some degree. We found that the posterior wall of the left atrium is more susceptible to atrial remodeling associated with hypertension compared with other regions of the left atrium. PMID- 28003647 TI - Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview. AB - The etiopathogenesis of cardiovascular diseases (CVDs) is multifactorial. Adverse blood pressure (BP) is a major independent risk factor for epidemic CVD affecting ~40% of the adult population worldwide and resulting in significant morbidity and mortality. Metabolic phenotyping of biological fluids has proven its application in characterizing low-molecular-weight metabolites providing novel insights into gene-environmental-gut microbiome interaction in relation to a disease state. In this review, we synthesize key results from the INTERnational study of MAcro/micronutrients and blood Pressure (INTERMAP) Study, a cross-sectional epidemiologic study of 4680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom and the United States. We describe the advancements we have made regarding the following: (1) analytical techniques for high-throughput metabolic phenotyping; (2) statistical analyses for biomarker identification; (3) discovery of unique food-specific biomarkers; and (4) application of metabolome-wide association studies to gain a better understanding into the molecular mechanisms of cross-cultural and regional BP differences. PMID- 28003649 TI - Between-visit reproducibility of inter-arm systolic blood pressure differences in treated hypertensive patients: the coconet study. AB - Inter-arm systolic blood pressure (BP) differences (sIADs) have recently been recognized as a risk factor for cardiovascular mortality. However, sIAD reproducibility remains unresolved from a controlled trial perspective. We evaluated the between-visit reproducibility of sIADs in hypertensive patients. We examined 1875 hypertensive participants aged 20 years and older (mean age: 62.3 years, 45.4% female) from nine primary clinics and 27 secondary and tertiary hospitals. The BPs in both arms were automatically and simultaneously measured in triplicate with a cuff-oscillometric BP device. BP measurements were obtained at baseline and at 3-month follow-up time points. Increased sIAD was defined as an absolute difference of ?10 mm Hg in the average systolic BPs between the left and right arms. The overall mean sIAD was 4.33+/-4.17 mm Hg. The prevalences of increased sIAD at baseline and at the 3-month measurements were 7.6% and 7.1%, respectively. The intraclass correlation coefficient for the between-visit sIADs was 0.304 (95% confidence interval (CI) 0.262-0.344). The kappa-value between the baseline and follow-up increased sIADs was 0.165 (95% CI 0.096-0.234). The percentage of patients who exhibited an increased sIAD at 3 months compared with the initially increased sIAD at baseline was 21.8%. The reproducibility of sIAD determination between baseline and the 3-month follow-up measurements lacked agreement in the hypertensive patients. Further studies should identify the relevant variables and characteristics of this poor reproducibility (CRIS number; KCT0001235). PMID- 28003653 TI - Learning and memory: Working out working memory. PMID- 28003654 TI - Neurodevelopmental disorders: A painful role for SHANK3. PMID- 28003650 TI - The time is ripe to reevaluate the second derivative of the digital photoplethysmogram (SDPTG), originating in Japan, as an important tool for cardiovascular risk and central hemodynamic assessment. PMID- 28003655 TI - Sensory systems: Smelling trouble. PMID- 28003657 TI - The Light Intermediate Chain 2 Subpopulation of Dynein Regulates Mitotic Spindle Orientation. AB - Cytoplasmic dynein 1 is a multi-protein intracellular motor essential for mediating several mitotic functions, including the establishment of proper spindle orientation. The functional relevance and mechanistic distinctions between two discrete dynein subpopulations distinguished only by Light Intermediate Chain (LIC) homologues, LIC1 and LIC2 is unknown during mitosis. Here, we identify LIC2-dynein as the major mediator of proper spindle orientation and uncover its underlying molecular mechanism. Cortically localized dynein, essential for maintaining correct spindle orientation, consists majorly of LIC2 dynein, which interacts with cortical 14-3-3 epsilon- zeta and Par3, conserved proteins required for orienting the spindle. LIC2-dynein is also responsible for the majority of dynein-mediated asymmetric poleward transport of NuMA, helping focus microtubule minus ends. In addition, LIC2-dynein dominates in equatorially aligning chromosomes at metaphase and in regulating mitotic spindle length. Key mitotic functions of LIC2 were remarkably conserved in and essential for early embryonic divisions and development in zebrafish. Thus LIC2-dynein exclusively engages with two major cortical pathways to govern spindle orientation. Overall, we identify a novel selectivity of molecular interactions between the two LICs in mitosis as the underlying basis for their uneven distribution of labour in ensuring proper spindle orientation. PMID- 28003658 TI - The emergence of waves in random discrete systems. AB - Essential criteria for the emergence of wave-like manifestations occurring in an entirely discrete system are identified using a simple model for the movement of particles through a network. The dynamics are entirely stochastic and memoryless involving a birth-death-migration process. The requirements are that the network should have at least three nodes, that migration should have a directional bias, and that the particle dynamics have a non-local dependence. Well defined bifurcations mark transitions between amorphous, wave-like and collapsed states with an intermittent regime between the latter two. PMID- 28003659 TI - Interferometric analysis of laser-driven cylindrically focusing shock waves in a thin liquid layer. AB - Shock waves in condensed matter are of great importance for many areas of science and technology ranging from inertially confined fusion to planetary science and medicine. In laboratory studies of shock waves, there is a need in developing diagnostic techniques capable of measuring parameters of materials under shock with high spatial resolution. Here, time-resolved interferometric imaging is used to study laser-driven focusing shock waves in a thin liquid layer in an all optical experiment. Shock waves are generated in a 10 um-thick layer of water by focusing intense picosecond laser pulses into a ring of 95 um radius. Using a Mach-Zehnder interferometer and time-delayed femtosecond laser pulses, we obtain a series of images tracing the shock wave as it converges at the center of the ring before reemerging as a diverging shock, resulting in the formation of a cavitation bubble. Through quantitative analysis of the interferograms, density profiles of shocked samples are extracted. The experimental geometry used in our study opens prospects for spatially resolved spectroscopic studies of materials under shock compression. PMID- 28003656 TI - Closed-loop brain training: the science of neurofeedback. AB - Neurofeedback is a psychophysiological procedure in which online feedback of neural activation is provided to the participant for the purpose of self regulation. Learning control over specific neural substrates has been shown to change specific behaviours. As a progenitor of brain-machine interfaces, neurofeedback has provided a novel way to investigate brain function and neuroplasticity. In this Review, we examine the mechanisms underlying neurofeedback, which have started to be uncovered. We also discuss how neurofeedback is being used in novel experimental and clinical paradigms from a multidisciplinary perspective, encompassing neuroscientific, neuroengineering and learning-science viewpoints. PMID- 28003665 TI - Covering gastroenterology and hepatology. PMID- 28003666 TI - Pancreatic cancer: Pancreatic carcinogenesis - several small steps or one giant leap? PMID- 28003660 TI - Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers. AB - DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1-3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets. PMID- 28003667 TI - Urinary Cross-linked N-terminal Telopeptide of Type I Collagen Levels of Infants with Osteogenesis Imperfecta and Healthy Infants. AB - The urinary cross-linked N-terminal telopeptide of type I collagen (uNTx) levels in infantile osteogenesis imperfecta (OI) have not been well studied. Here we investigated the levels of uNTx in infants with OI and healthy infants. We collected spot urine samples from 30 infants with OI (male/female, 14/16; Sillence classification, I/II/III/IV: 15/3/6/6; age, 5.2+/-4.4 months) and 120 healthy infants (male/female, 75/45; age, 5.1+/-4.1 months) for the measurement of uNTx levels. The uNTx levels of the OI infants were significantly lower than those of the healthy infants (mean+/-SD, 1,363.7+/-530.1 vs. 2,622.2+/-1,202.6 nmol BCE/mmol Cr; p<0.001). The uNTx levels of the infants with type I OI were significantly lower than those of the age-matched healthy infants, although an overlap was observed between the 2 groups. Among the 1-month-old infants, the uNTx levels of the infants with types I, III or IV OI were significantly lower than those of the healthy infants, without overlap (1,622.5+/-235.8 vs. 3,781.0+/ 1,027.1 nmol BCE/mmol Cr; p<0.001). These results indicate that uNTx levels are significantly lower in infants with OI than in healthy infants, and they suggest that uNTx might be useful as a reference for diagnosing OI. PMID- 28003661 TI - Lower and upper bounds for entanglement of Renyi-alpha entropy. AB - Entanglement Renyi-alpha entropy is an entanglement measure. It reduces to the standard entanglement of formation when alpha tends to 1. We derive analytical lower and upper bounds for the entanglement Renyi-alpha entropy of arbitrary dimensional bipartite quantum systems. We also demonstrate the application our bound for some concrete examples. Moreover, we establish the relation between entanglement Renyi-alpha entropy and some other entanglement measures. PMID- 28003668 TI - Concurrent Lateral Meniscal Repair with Anterior Cruciate Ligament Reconstruction Induces the Extrusion of the Lateral Meniscus: Assessments of Magnetic Resonance Images. AB - Concurrent meniscal repair with anterior cruciate ligament (ACL) reconstruction has shown good clinical outcomes, but it has a considerable risk of progressing to post-traumatic osteoarthritis of the knee. Here we investigated postoperative changes in the position of the lateral meniscus (LM) and assessed the short-term clinical results after concurrent LM repair with ACL reconstruction. Twentyseven patients underwent LM repair of a peripheral longitudinal tear concomitant with ACL reconstruction. We evaluated the preoperative and postoperative values of the Lysholm score and anteroposterior instability. The length and width of the lateral tibial plateau were determined by radiographic images. The length, width, body width, extrusion, and height of the LM were measured in magnetic resonance images and compared between the preoperative and postoperative measurements. Our analysis revealed that concurrent LM repair with ACL reconstruction improved the shortterm clinical outcomes. Although the body width and height of the LM did not change, the postoperative LM extrusion and LM width were significantly increased after the surgery. The post-traumatic transposition of the LM may not be completely prevented by LM repair concomitant with ACL reconstruction. PMID- 28003669 TI - Neurological Recovery after Posterior Spinal Surgery in Patients with Metastatic Epidural Spinal Cord Compression. AB - Metastatic epidural spinal cord compression (MESCC) is a common complication in patients with a malignant tumor, but it is difficult to decide the proper time to perform the necessary surgery. Here we analyzed the prognostic factors for postoperative walking ability. We retrospectively reviewed the cases of 112 MESCC patients treated surgically at our institute and divided them into ambulatory (n= 88) and non-ambulatory (n=24) groups based on their American Spinal Injury Association (ASIA) Impairment Scale grades at the final follow-up. We also classified the patients preoperatively using the revised Tokuhashi score. We assessed the correlation between preoperative or intraoperative factors and postoperative walking ability in both groups. Of the 10 patients classified preoperatively as grade A or B, 2 (20% ) were ambulatory at the final follow-up. Of the 102 patients classified preoperatively as grade C, D or E, 86 (84% ) were ambulatory at the final follow-up (p<0.001). There were no significant differences between the groups in the average total Tokuhashi score. Our analysis revealed that the severity of paralysis significantly affects neurological recovery in patients with MESCC. Patients with MESCC should receive surgery before the preoperative ASIA Impairment Scale grade falls below grade C. PMID- 28003670 TI - Isoflurane Induces Transient Impairment of Retention of Spatial Working Memory in Rats. AB - Postoperative cognitive dysfunction (POCD) occurs in nearly one-third of patients after non-cardiac surgery. Many animal behavior studies have investigated the effect of general anesthesia on cognitive function. However, there have been no studies examining the effects on working memory specifically, with a focus on the retention of working memory. We demonstrate here that isoflurane anesthesia induces deficits in the retention of spatial working memory in rats, as revealed by an increase in isoflurane- induced across-phase errors in the delayed spatial win-shift (SWSh) task with a 30-min delay in an 8-arm radial arm maze on post anesthesia days (PADs) 1,2,4, and 10. A post-hoc analysis revealed a significant increase in across-phase errors on PAD 1 and recovery on PAD 10 in the isoflurane group. In contrast, within-phase errors independent of the retention of working memory were unaffected by isoflurane. These results demonstrate that isoflurane anesthesia transiently impairs the retention of spatial working memory in rats. PMID- 28003671 TI - Observational Study to Assess and Predict Serious Adverse Events after Major Surgery. AB - Many patients suffer from postoperative serious adverse events (SAEs). Here we sought to determine the incidence of SAEs, assess the accuracy of currently used scoring systems in predicting postoperative SAEs, and determine whether a combination of scoring systems would better predict postoperative SAEs. We prospectively evaluated patients who underwent major surgery. We calculated 4 scores: American Society of Anesthesiologists physical status (ASA-PS) score, the Charlson Score, the POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) score, and the Surgical Apgar Score (SAS). We assessed the occurrence of SAEs. We assessed the association between each score and SAEs. We combined these scoring systems to find the best combination to predict the occurrence of SAEs. Among 284 patients, 43 suffered SAEs. All scoring systems could predict SAEs. However, their predictive power was not high (the area under the receiver operating characteristic curves [AUROC] 0.6 0.7). A combination of the ASA-PS score and the SAS was the most predictive of postoperative SAEs (AUROC 0.714). The incidence of postoperative SAEs was 15.1 . The combination of the ASA-PS score and the SAS may be a useful tool for predicting postoperative serious adverse events after major surgery. PMID- 28003672 TI - Clinical Outcomes of Endoscopic Hemostasis in Marginal Ulcer Bleeding. AB - The usefulness of endoscopy in marginal ulcer bleeding has rarely been studied, and the optimal method for preventing rebleeding is unclear. Here we assessed the efficacy of endoscopy in marginal ulcer bleeding and examined the efficacy of proton pump inhibitors (PPIs) in the prevention of rebleeding. A total of 28 patients with marginal ulcer bleeding (21 men, 7 women; median age 58.5 years) were treated by endoscopy. We analyzed the clinical characteristics, results of endoscopic therapy, characteristics of rebleeding patients, and relation between the use of PPIs and the duration of rebleeding. Sixteen patients had active bleeding. Initial hemostasis was achieved in all patients. There were no procedure-related adverse events. Rebleeding occurred in one patient within the first month and in 7 patients thereafter. There was a significant difference in the rebleeding rate between the patients who received a PPI and those who did not. In a multivariate analysis, the non-use of PPIs was a risk factor for rebleeding (hazard ratio, 6.22). Therapeutic endoscopy is effective in achieving hemostasis from marginal ulcer bleeding. PPIs may prevent rebleeding from marginal ulcers. PMID- 28003673 TI - Shortening Oblique Osteotomy with Screw Fixation for Correction of the Lesser Metatarsophalangeal Joints of Rheumatoid Forefoot. AB - The metatarsophalangeal (MTP) joints are often and predominantly affected in rheumatoid arthritis. The aim of the current study was to describe surgical techniques of shortening oblique osteotomy for lesser metatarsal bone with screw fixation at the osteotomy site, and to investigate the short-term clinical outcomes of our procedure. Twenty-seven feet (78 toes) of 24 RA patients underwent the shortening oblique osteotomy for the correction of deformity at the lesser MTP joints. The average Japanese Society of Surgery of the Foot (JSSF) standard rating system for the RA foot and ankle scale improved significantly from 59.6 points preoperatively to 88.3 points postoperatively (p<0.001). Twenty four feet (89% ) were free from metatarsalgia and symptomatic callosities at the lesser MTP joint after surgery. Our present findings showed satisfactory early clinical outcomes of the shortening oblique osteotomy of the metatarsal bone with screw fixation for RA forefoot. PMID- 28003674 TI - Prenatal Diagnosis of Interrupted Aortic Arch: Usefulness of Three-Vessel and Four-Chamber Views. AB - Interrupted aortic arch (IAA) is fatal if not diagnosed. Prenatal diagnosis is helpful, but it is difficult to detect IAA and even more so to differentiate types A and B prenatally. Our objectives were to find a way to detect IAA using 2 views-three-vessel view (3VV) and four-chamber view (4CV)-and to differentiate between types A and B. We retrospectively analyzed fetal echocardiographic images and medical records of eight IAA patients. All eight patients had a ventricular septal defect (VSD) on 4CV. The aorta/main pulmonary artery (Ao/MPA) diameter ratio on 3VV was significantly low, which is characteristic of type B IAA. The left/right ventricular diameter (LV/RV) ratio on 4CV was 0.61+/- 0.17 for type A and almost 1.0 for type B. The thymus was not observed on 3VV in some type B IAA patients. These findings suggest that we could increase the number of prenatal diagnoses of IAA using the Ao/MPA ratio on 3VV and the presence of VSD on 4CV. Additionally, we could differentiate types A and B with the LV/RV ratio on 4CV, the Ao/MPA ratio, and the presence of a thymus on 3VV, which results in better management of IAA after birth. PMID- 28003675 TI - Surgery in the Standing Position by a Surgeon with Achilles Tendon Rupture. AB - Unexpected injuries can have a profound effect on a surgeon's performance and thus on patients and surgical departments. Here we describe a technique for performing surgery in the standing position, as done by a surgeon with an Achilles tendon rupture. During his prescribed 45-day non-weight-bearing period for the left ankle after surgery for an Achilles tendon rupture, the surgeon was able to participate in 15 surgeries as an operator or assistant, due to his use of a combination of injured-leg genuflection on a stool and a 'Surgical Body Support' device. Similarly injured surgeons may benefit from such support. PMID- 28003676 TI - A Case of Refractory Systemic Capillary Leak Syndrome (Clarkson's Disease) during Pregnancy. AB - A 32-year-old woman, pregnant with twins, presented with a chief complaint of general fatigue. Her general condition had rapidly deteriorated since her last visit to the primary obstetrician; the patient was then referred to our hospital because of suspected fetal death. She underwent emergency cesarean section because fetal death had indeed occurred, and she was then admitted to the intensive care unit (ICU). On ICU admission, she was found to be in shock. Laboratory analysis revealed extreme hemoconcentration and a low albumin level, and initially, septic shock with obstetric complications was suspected. However, because she did not respond to conventional therapy but instead, rapidly developed severe generalized edema, systemic capillary leak syndrome (SCLS) was diagnosed. The patient remained in shock for several days until undergoing plasma exchange (PE), despite some earlier empirical treatments. She eventually recovered from profound shock status and was discharged from the ICU without sequelae. Among potentially effective treatments, PE seemed to be the most reasonable choice for the treatment of her SCLS. PMID- 28003677 TI - Two Relapsed Stage III Childhood Anaplastic Large Cell Lymphoma Patients with NPM ALK Fusion in Bone Marrow from Initial Diagnosis. AB - Childhood anaplastic large cell lymphoma (ALCL) accounts for approx. 10-30% of cases of non-Hodgkin lymphoma, and the ALCL99 study reported 60-75 disease-free survival; however, a relatively high relapse rate was observed (25-30% ). We report 2 patients with Stage III ALCL who relapsed 6-18 months after the end of ALCL99 chemotherapy. A retrospective molecular analysis identified the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion gene in the first diagnostic bone marrow samples taken from both patients. However, antibodies against the ALK protein appeared to be relatively low in the serum of both patients (*100 and *750). An increase in chemotherapy intensity may be beneficial if Stage III ALCL patients are shown to be NPM-ALK chimera-positive in the first diagnostic bone marrow sample. PMID- 28003679 TI - Acute Bowel Injury due to Cryoablation for Renal Cell Carcinoma: Correlated Radiologic and Pathologic Findings. AB - An 87-year-old Japanese man underwent percutaneous cryoablation (PCA) therapy for his renal cell tumor. We displaced the colon from the tumor using hydrodissection. Computed tomography (CT) immediately after PCA was indicative of iceball extension to the colon wall, and a discontinuous enhancement of the colon wall was observed. We therefore performed an emergency surgery. On laparotomy, we observed a dark-purple area on the affected area of the colon, and the resected specimen showed focal, deep ulceration on the mucosal surface. Photomicrography revealed mucosal necrosis, submucosal hemorrhage, and necrotic foci in the muscularis propria, corresponding to the discontinuous colon wall enhancement on CT and the deep ulceration and dark-purple area on laparotomy. He recovered from surgery and was discharged without any complications. PMID- 28003678 TI - Usefulness of Thoracoscopic Debridement for Chronic Empyema after an Extrapleural Pneumonectomy. AB - We present the case of a 65-year-old Japanese man diagnosed with chronic empyema (without a bronchopleural fistula) that occurred 7 months after he underwent an extrapleural pneumonectomy for right malignant pleural mesothelioma (MPM). Following thoracic drainage and irrigation for 1 month, we performed surgery by a thoracoscopic approach, in light of his general condition. We performed debridement and removal of the Gore-Tex polytetrafluoroethylene (PTFE) patch that had been used for the reconstruction of the diaphragm and the pericardium. The empyema had not relapsed when he died from recurrence of the MPM at 4 months after the thoracoscopic surgery. This patient's case suggests that thoracoscopic debridement and patch removal can be a therapeutic option for not only early stage (exudative or fibrinopurulent) empyema but also late-stage (organized and chronic) empyema without a bronchopleural fistula, particularly for patients in poor general condition. PMID- 28003680 TI - Pseudoaneurysm of the Perforating Branch of the Deep Femoral Artery Following Anterior Cruciate Ligament Reconstruction. AB - The present report describes the first known, case of a pseudoaneurysm of the perforating branch of the deep femoral artery following anterior cruciate ligament (ACL) reconstruction. A 19-year-old man underwent ACL reconstruction using the outside-in femoral tunnel-creation method. Seven days after the surgery, he complained of abnormal thigh pain and had swelling with local heat on the distal lateral thigh. Magnetic resonance imaging, computed tomography, and color Doppler ultrasonography showed the pseudoaneurysm in the thigh. Resection surgery was successfully performed by a vascular surgeon 12 days after ACL reconstruction. Careful examination and awareness of postoperative symptoms such as thigh pain and swelling after ACL reconstruction were critical for the early diagnosis of pseudoaneurysm. PMID- 28003681 TI - Poverty and Economic Decision-Making: Evidence from Changes in Financial Resources at Payday. AB - We study the effect of financial resources on decision-making. Low-income U.S. households are randomly assigned to receive an online survey before or after payday. The survey collects measures of cognitive function and administers risk and intertemporal choice tasks. The study design generates variation in cash, checking and savings balances, and expenditures. Before-payday participants behave as if they are more present-biased when making intertemporal choices about monetary rewards but not when making intertemporal choices about non-monetary real-effort tasks. Nor do we find before-after differences in risk-taking, the quality of decision-making, the performance in cognitive function tasks, or in heuristic judgments. PMID- 28003682 TI - Clarification? Yes! Standarization? No. Or: What Kind of Cooperation for the Sociology of Culture? AB - Christian Smith's paper "The Incoherence of 'Culture' in American Sociology" is a valuable provocation that can prompt us to reflect on the role of concepts and on the role of agreement on the definition of concepts in scientific research. In this comment paper, I raise questions about Smith's empirical expectation that sociologists should agree on a concept of culture based on debates in the sociology of science. I also suggest that in terms of the future agenda for the sociology of culture, we should distinguish between dialogue and clarification on the one hand, which I agree is needed, and standardization on the other hand, which seems incompatible with open-minded empirical research. Rather than work on agreement on what culture is, we might work on clarifying relevant distinctions among dimensions of culture. PMID- 28003683 TI - Recent ASA Presidents and 'Top' Journals: Observed Publication Patterns, Alleged Cartels and Varying Careers. AB - It has been common for studies presented as about American sociology as a whole to rely on data compiled from leading journals (American Sociological Review [ASR] and American Journal of Sociology [AJS]), or about presidents of the American Sociological Association [ASA], to represent it. Clearly those are important, but neither can be regarded as providing a representative sample of American sociology. Recently, Stephen Turner has suggested that dominance in the ASA rests with a 'cartel' initially formed in graduate school, and that it favors work in a style associated with the leading journals. The adequacy of these ideas is examined in the light of available data on the last 20 years, which show that very few of the presidents were in the same graduate schools at the same time. All presidents have had distinguished academic records, but it is shown that their publication strategies have varied considerably. Some have had no ASR publications except their presidential addresses, while books and large numbers of other journals not normally mentioned in this context have figured in their contributions, as well as being more prominent in citations. It seems clear that articles in the leading journals have not been as closely tied to prestigious careers as has sometimes been suggested, and that if there is a cartel it has not included all the presidents. PMID- 28003684 TI - Weighing Evidence "Steampunk" Style via the Meta-Analyser. AB - The funnel plot is a graphical visualization of summary data estimates from a meta-analysis, and is a useful tool for detecting departures from the standard modeling assumptions. Although perhaps not widely appreciated, a simple extension of the funnel plot can help to facilitate an intuitive interpretation of the mathematics underlying a meta-analysis at a more fundamental level, by equating it to determining the center of mass of a physical system. We used this analogy to explain the concepts of weighing evidence and of biased evidence to a young audience at the Cambridge Science Festival, without recourse to precise definitions or statistical formulas and with a little help from Sherlock Holmes! Following on from the science fair, we have developed an interactive web application (named the Meta-Analyser) to bring these ideas to a wider audience. We envisage that our application will be a useful tool for researchers when interpreting their data. First, to facilitate a simple understanding of fixed and random effects modeling approaches; second, to assess the importance of outliers; and third, to show the impact of adjusting for small study bias. This final aim is realized by introducing a novel graphical interpretation of the well-known method of Egger regression. PMID- 28003685 TI - Further ALMA observations and detailed modeling of the Red Rectangle. AB - AIMS: We aim to study the rotating and expanding gas in the Red Rectangle, which is a well known object that recently left the asymptotic giant branch (AGB) phase. We analyze the properties of both components and the relation between them. Rotating disks have been very elusive in post-AGB nebulae, in which gas is almost always found to be in expansion. METHODS: We present new high-quality ALMA observations of C17O J=6-5 and H13CN J=4-3 line emission and results from a new reduction of already published 13CO J=3-2 data. A detailed model fitting of all the molecular line data, including previous maps and single-dish observations of lines of CO, CII, and CI, was performed using a sophisticated code that includes an accurate nonlocal treatment of radiative transfer in 2D. These observations (of low- and high-opacity lines requiring various degrees of excitation) and the corresponding modeling allowed us to deepen the analysis of the nebular properties. We also stress the uncertainties, particularly in the determination of the boundaries of the CO-rich gas and some properties of the outflow. RESULTS: We confirm the presence of a rotating equatorial disk and an outflow, which is mainly formed of gas leaving the disk. The mass of the disk is ~ 0.01 M?, and that of the CO-rich outflow is around ten times smaller. High temperatures of ? 100 K are derived for most components. From comparison of the mass values, we roughly estimate the lifetime of the rotating disk, which is found to be of about 10000 yr. Taking data of a few other post-AGB composite nebulae into account, we find that the lifetimes of disks around post-AGB stars typically range between 5000 and more than 20000 yr. The angular momentum of the disk is found to be high, ~ 9 M? AU km s-1, which is comparable to that of the stellar system at present. Our observations of H13CN show a particularly wide velocity dispersion and indicate that this molecule is only abundant in the inner Keplerian disk, at ? 60 AU from the stellar system. We suggest that HCN is formed in a dense photodissociation region (PDR) due to the UV excess known to be produced by the stellar system, following chemical mechanisms that are well established for interstellar medium PDRs and disks orbiting young stars. We further suggest that this UV excess could lead to an efficient formation and excitation of PAHs and other C-bearing macromolecules, whose emission is very intense in the optical counterpart. PMID- 28003686 TI - Trans-cis molecular photoswitching in interstellar Space. AB - As many organic molecules, formic acid (HCOOH) has two conformers (trans and cis). The energy barrier to internal conversion from trans to cis is much higher than the thermal energy available in molecular clouds. Thus, only the most stable conformer (trans) is expected to exist in detectable amounts. We report the first interstellar detection of cis-HCOOH. Its presence in ultraviolet (UV) irradiated gas exclusively (the Orion Bar photodissociation region), with a low trans-to-cis abundance ratio of 2.8 +/- 1.0, supports a photoswitching mechanism: a given conformer absorbs a stellar photon that radiatively excites the molecule to electronic states above the interconversion barrier. Subsequent fluorescent decay leaves the molecule in a different conformer form. This mechanism, which we specifically study with ab initio quantum calculations, was not considered in Space before but likely induces structural changes of a variety of interstellar molecules submitted to UV radiation. PMID- 28003687 TI - Entropy-as-a-Service: Unlocking the Full Potential of Cryptography. AB - Securing the Internet requires strong cryptography, which depends on the availability of good entropy for generating unpredictable keys and accurate clocks. Attacks abusing weak keys or old inputs portend challenges for the Internet. EaaS is a novel architecture providing entropy and timestamps from a decentralized root of trust, scaling gracefully across diverse geopolitical locales and remaining trustworthy unless much of the collective is compromised. PMID- 28003688 TI - The Indian Journal of Anaesthesia: The timeline never ceases. PMID- 28003689 TI - Airway management guidelines: A safe passage to India. PMID- 28003690 TI - All India Difficult Airway Association 2016 guidelines for the management of unanticipated difficult tracheal intubation in adults. AB - The All India Difficult Airway Association (AIDAA) guidelines for management of the unanticipated difficult airway in adults provide a structured, stepwise approach to manage unanticipated difficulty during tracheal intubation in adults. They have been developed based on the available evidence; wherever robust evidence was lacking, or to suit the needs and situation in India, recommendations were arrived at by consensus opinion of airway experts, incorporating the responses to a questionnaire sent to members of the AIDAA and the Indian Society of Anaesthesiologists. We recommend optimum pre-oxygenation and nasal insufflation of 15 L/min oxygen during apnoea in all patients, and calling for help if the initial attempt at intubation is unsuccessful. Transnasal humidified rapid insufflations of oxygen at 70 L/min (transnasal humidified rapid insufflation ventilatory exchange) should be used when available. We recommend no more than three attempts at tracheal intubation and two attempts at supraglottic airway device (SAD) insertion if intubation fails, provided oxygen saturation remains >= 95%. Intubation should be confirmed by capnography. Blind tracheal intubation through the SAD is not recommended. If SAD insertion fails, one final attempt at mask ventilation should be tried after ensuring neuromuscular blockade using the optimal technique for mask ventilation. Failure to intubate the trachea as well as an inability to ventilate the lungs by face mask and SAD constitutes 'complete ventilation failure', and emergency cricothyroidotomy should be performed. Patient counselling, documentation and standard reporting of the airway difficulty using a 'difficult airway alert form' must be done. In addition, the AIDAA provides suggestions for the contents of a difficult airway cart. PMID- 28003691 TI - All India Difficult Airway Association 2016 guidelines for the management of unanticipated difficult tracheal intubation in obstetrics. AB - The various physiological changes in pregnancy make the parturient vulnerable for early and rapid desaturation. Severe hypoxaemia during intubation can potentially compromise two lives (mother and foetus). Thus tracheal intubation in the pregnant patient poses unique challenges, and necessitates meticulous planning, ready availability of equipment and expertise to ensure maternal and foetal safety. The All India Difficult Airway Association (AIDAA) proposes a stepwise plan for the safe management of the airway in obstetric patients. These guidelines have been developed based on available evidence; wherever robust evidence was lacking, recommendations were arrived at by consensus opinion of airway experts, incorporating the responses to a questionnaire sent to members of the AIDAA and the Indian Society of Anaesthesiologists (ISA). Modified rapid sequence induction using gentle intermittent positive pressure ventilation with pressure limited to <=20 cm H2O is acceptable. Partial or complete release of cricoid pressure is recommended when face mask ventilation, placement of supraglottic airway device (SAD) or tracheal intubation prove difficult. One should call for early expert assistance. Maternal SpO2 should be maintained >=95%. Apnoeic oxygenation with nasal insufflation of 15 L/min oxygen during apnoea should be performed in all patients. If tracheal intubation fails, a second- generation SAD should be inserted. The decision to continue anaesthesia and surgery via the SAD, or perform fibreoptic-guided intubation via the SAD or wake up the patient depends on the urgency of surgery, foeto-maternal status and availability of resources and expertise. Emergency cricothyroidotomy must be performed if complete ventilation failure occurs. PMID- 28003692 TI - All India Difficult Airway Association 2016 guidelines for the management of unanticipated difficult tracheal intubation in Paediatrics. AB - The All India Difficult Airway Association guidelines for the management of the unanticipated difficult tracheal intubation in paediatrics are developed to provide a structured, stepwise approach to manage unanticipated difficulty during tracheal intubation in children between 1 and 12 years of age. The incidence of unanticipated difficult airway in normal children is relatively rare. The recommendations for the management of difficult airway in children are mostly derived from extrapolation of adult data because of non-availability of proven evidence on the management of difficult airway in children. Children have a narrow margin of safety and mismanagement of the difficult airway can lead to disastrous consequences. In our country, a systematic approach to airway management in children is lacking, thus having a guideline would be beneficial. This is a sincere effort to protocolise airway management in children, using the best available evidence and consensus opinion put together to make airway management for children as safe as possible in our country. PMID- 28003693 TI - All India Difficult Airway Association 2016 guidelines for the management of anticipated difficult extubation. AB - Extubation has an important role in optimal patient recovery in the perioperative period. The All India Difficult Airway Association (AIDAA) reiterates that extubation is as important as intubation and requires proper planning. AIDAA has formulated an algorithm based on the current evidence, member survey and expert opinion to incorporate all patients of difficult extubation for a successful extubation. The algorithm is not designed for a routine extubation in a normal airway without any associated comorbidity. Extubation remains an elective procedure, and hence, patient assessment including concerns related to airway needs to be done and an extubation strategy must be planned before extubation. Extubation planning would broadly be dependent on preventing reflex responses (haemodynamic and cardiovascular), presence of difficult airway at initial airway management, delayed recovery after the surgical intervention or airway difficulty due to pre-existing diseases. At times, maintaining a patent airway may become difficult either due to direct handling during initial airway management or due to surgical intervention. This also mandates a careful planning before extubation to avoid extubation failure. Certain long-standing diseases such as goitre or presence of obesity and obstructive sleep apnoea may have increased chances of airway collapse. These patients require planned extubation strategies for extubation. This would avoid airway collapse leading to airway obstruction and its sequelae. AIDAA suggests that the extubation plan would be based on assessment of the airway. Patients requiring suppression of haemodynamic responses would require awake extubation with pharmacological attenuation or extubation under deep anaesthesia using supraglottic devices as bridge. Patients with difficult airway (before surgery or after surgical intervention) or delayed recovery or difficulty due to pre-existing diseases would require step-wise approach. Oxygen supplementation should continue throughout the extubation procedure. A systematic approach as briefed in the algorithm needs to be complemented with good clinical judgement for an uneventful extubation. PMID- 28003694 TI - The All India Difficult Airway Association 2016 guidelines for tracheal intubation in the Intensive Care Unit. AB - Tracheal intubation (TI) is a routine procedure in the Intensive Care Unit (ICU) and is often life-saving. In contrast to the controlled conditions in the operating room, critically ill patients with respiratory failure and shock are physiologically unstable. These factors, along with a suboptimal evaluation of the airway and limited oxygen reserves despite adequate pre-oxygenation, are responsible for a high incidence of life-threatening complications such as severe hypoxaemia and cardiovascular collapse during TI in the ICU. The All India Difficult Airway Association (AIDAA) proposes a stepwise plan for safe management of the airway in critically ill patients. These guidelines have been developed based on available evidence; wherever robust evidence was lacking, recommendations were arrived at by consensus opinion of airway experts, incorporating the responses to a questionnaire sent to members of the AIDAA and the Indian Society of Anaesthesiologists. Non-invasive positive pressure ventilation during pre-oxygenation improves oxygen stores in patients with respiratory pathology. Nasal insufflation of oxygen at 15 L/min can increase the duration of apnoea before the occurrence of hypoxaemia. High-flow nasal cannula oxygenation at 60-70 L/min may also increase safety during TI in critically ill patients. Stable haemodynamics and gas exchange must be maintained during rapid sequence induction. It is necessary to implement an intubation protocol during routine airway management in the ICU. Adherence to a plan for difficult airway management incorporating the use of intubation aids and airway rescue devices and strategies is useful. PMID- 28003695 TI - Anaesthesia for foetoscopic Laser ablation- a retrospective study. AB - BACKGROUND AND AIMS: Twin pregnancy with monochorionic placenta may be associated with arteriovenous vascular anastomosis of the placental vessels resulting in twin-to-twin transfusion syndrome (TTTS) and twin reversed arterial perfusion syndrome (TRAP). Foetoscopic LASER ablation (FLA) is the treatment of choice in reducing foetal mortality related to this. METHODS: A retrospective review of medical records of 41 FLA procedures for TTTS and TRAP were analysed for anaesthetic management. Thirty-four patients received subarachnoid block, three combined spinal-epidural block, three general anaesthesia and one local anaesthesia with sedation. Nitroglycerine 5 mg patch was used for tocolysis 1 h before the procedure and continued for 24-48 h postoperatively. RESULTS: Bupivacaine was used in 34 patients, and ropivacaine in three patients. Mean dose of bupivacaine 0.5% was 2.43 +/- 0.32 ml and ropivacaine 0.75% was 2.85 +/- 0.19 ml. The mean duration of surgery was 117.07 +/- 28 min. Mild hypotension occurred in all patients under spinal anaesthesia and was treated with vasopressors. The foetal outcome among all 41 patients were 13 delivered live twins, 15 had a single live baby with intrauterine death of other twin baby. In 12 patients, both babies were intrauterine death. One patient was lost for follow-up. CONCLUSION: Foetoscopic procedures can be done under central neuraxial block, however occasionally general anaesthesia may be required. PMID- 28003696 TI - Comparative randomised study of GlideScope(r) video laryngoscope versus flexible fibre-optic bronchoscope for awake nasal intubation of oropharyngeal cancer patients with anticipated difficult intubation. AB - BACKGROUND AND AIMS: Awake flexible fibre-optic bronchoscope (FFS) is the standard method of intubation in difficult airway in oral cancer patients. We decided to evaluate GlideScope(r) video laryngoscope (GL) for intubation as compared to the standard FFS for nasal intubation in such patients. METHODS: After the ethical committee approval, we included 54 oropharyngeal cancer patients divided randomly into two equal groups: Group G and Group F. After pre medication and pre-oxygenation, awake nasal intubation was performed using GL in Group G and FFS in Group F. In both groups, we compared intubation time in seconds (mean +/- standard deviation) (primary outcome), success rate of the first intubation attempt, percentage of Cormack and Lehane glottic score and incidence of complications. We assumed that GL could be a suitable alternative for the standard FFS in nasal intubation of patients with oropharyngeal cancer. Success rate of the first attempt and Cormack and Lehane glottic score were compared using Chi-square test. RESULTS: Intubation time in seconds was significantly shorter in Group G (70.85 +/- 8.88 S) than in Group F (90.26 +/- 9.41 S) with (P < 0.001). The success rate of the first attempt intubation was slightly higher in Group G (81.5%) than Group F (78.8%). Cormack and Lehane glottic Score I and II showed insignificant difference between both Group G (92.6%) and Group F (96.3%). We detected three cases of sore throat in each group. CONCLUSION: GlideScope(r) could be a suitable alternative to FFS in nasal intubation of oropharyngeal cancer patients. PMID- 28003697 TI - Isoflurane versus sevoflurane with interscalene block for shoulder arthroscopic procedures: Value of process capability indices as an additional tool for data analysis. AB - BACKGROUND AND AIMS: Hypotensive anaesthesia reduces intra-articular bleed and promotes visualisation during arthroscopy. The haemodynamic effects of inhalational agents isoflurane and sevoflurane were studied extensively, and both were found to reduce mean arterial pressures (MBP) to an equivalent magnitude. We investigated the relative ability of isoflurane vis-a-vis sevoflurane to maintain the target systolic blood pressure (SBP) in patients undergoing shoulder arthroscopic procedures. METHODS: In a prospective randomised study, 59 patients in two groups of 30 and 29 patients each received concomitant general anaesthesia (1.2-1.5 MAC of isoflurane and sevoflurane) and interscalene brachial plexus block. Nitrous oxide was used in both groups. Intraoperatively, serial blood pressure recordings of SBP, diastolic blood pressure (DBP), MBP and heart rates were done at every 3rd min intervals. The manipulations needed to achieve target SBP (T = 90 mmHg) for optimal arthroscopic visualisation and treat unacceptable hypotensive episodes were noted. Conventional statistical tests and process capability index (PCI) evaluation were both deployed for data analysis. RESULTS: Lower mean SBP and DBPs were recorded for isoflurane patients as compared to sevoflurane (P < 0.05, for mean, maximum and minimum recordings). Higher mean heart rates were recorded for isoflurane (P < 0.05). PCIs indicated that isoflurane was superior to sevoflurane in the ease of achieving target SBP of 90 mmHg as well as maintaining blood pressures in the range of 80-100 mmHg. CONCLUSION: Isoflurane provides better intraoperative haemodynamic status vis-a vis sevoflurane in patients undergoing shoulder arthroscopic surgery with preliminary interscalene blockade. The PCI can be a useful additional medical data analysis tool. PMID- 28003698 TI - Comparison of caudal and intravenous dexamethasone as adjuvants for caudal epidural block: A double blinded randomised controlled trial. AB - BACKGROUND AND AIMS: Dexamethasone has a powerful anti-inflammatory action with significant analgesic benefits. The aim of this study was to compare the efficacy of dexamethasone administered through intravenous (IV) and caudal route on post operative analgesia in paediatric inguinal herniotomy patients. METHODS: One hundred and five paediatric patients undergoing inguinal herniotomy were included and divided into three groups. Each patient received a single caudal dose of ropivacaine 0.15%, 1.5 mL/kg combined with either corresponding volume of normal saline (Group 1) or caudal dexamethasone 0.1 mg/kg (Group 2) or IV dexamethasone 0.5 mg/kg (Group 3). Baseline, intra- and post-operative haemodynamic parameters, pain scores, time to rescue analgesia, total analgesic consumption and adverse effects were evaluated for 24 h after surgery. Unpaired Student's t-test and analysis of variance were applied for quantitative data and Chi-square test for qualitative data. Time to first analgesic administration was analysed by Kaplan Meier survival analysis and log-rank test. RESULTS: Duration of analgesia was significantly longer (P < 0.001), and total consumption of analgesics was significantly lower (P < 0.001) in Group II and III compared to Group I. The incidence of nausea and vomiting was higher in Group I (31.4%) compared to Group II and III (8.6%). CONCLUSIONS: Addition of dexamethasone both caudally or intravenously as an adjuvant to caudal 0.15% ropivacaine significantly reduced the intensity of post-operative pain and prolonged the duration of post-operative analgesia with the significant advantage of caudal over IV route. PMID- 28003699 TI - An unusual presentation of autonomic dysreflexia in a patient with cold abscess of cervical spine for anterolateral decompression. AB - A young female having complaints of quadriparesis along with bladder and bowel involvement, diagnosed to have osseous destruction of C4, C6, C7, T2 vertebral bodies with pre- and para-vertebral abscess, was taken up for anterolateral decompression and fusion of cervical spine. She presented with anxiety, agitation, sweating and headache and was in hypertensive crisis which was refractory to antihypertensives, anxiolytics and analgesics but showed a reasonable response to intravenous dexmedetomidine and finally responded dramatically to rectal evacuation. Autonomic dysreflexia was suspected with stimulus arising from distended rectum as all other causes of hypertension were ruled out. PMID- 28003700 TI - 'Can't ventilate' during surgery: Nightmare for anaesthesiologist. PMID- 28003701 TI - Evaluation of paranasal sinuses on available computed tomography in head and neck cancer patients: An assessment tool for nasotracheal intubation. PMID- 28003702 TI - Airway management in a child with partial mandibulo-maxillary fusion. PMID- 28003703 TI - Difficulty in diagnosing physical damage to the airway tube of the ProSeal laryngeal mask airway. PMID- 28003704 TI - Halothane: I am still there. PMID- 28003705 TI - Erratum: Overcoming airway challenges with the C MAC(r) video laryngoscope in a child with Goldenhar syndrome. AB - [This corrects the article on p. 868 in vol. 60, PMID: 27942068.]. PMID- 28003706 TI - CAUSAL EFFECTS OF HEALTH SHOCKS ON CONSUMPTION AND DEBT: QUASI-EXPERIMENTAL EVIDENCE FROM BUS ACCIDENT INJURIES. AB - Endogeneity between health and wealth presents a challenge for estimating causal effects of health shocks. Using a quasi-experimental design, comprising exogenous shocks sustained as bus accident injuries in India, with controls drawn from travelers on the same bus routes one year later, I present new evidence of causal effects on consumption and debt. Using primary household survey data, I find that households faced with shock-related expenditures are able to smooth consumption on food, housing, and festivals, with small reductions in educational spending. Debt was the principal mitigating mechanism households used, leading to significantly larger levels of indebtedness. PMID- 28003707 TI - Trust and Fertility Dynamics. AB - We argue that the divergence in fertility trends in advanced societies is influenced by the interaction of long-standing differences in generalized trust with the increase in women's educational attainment. Our argument builds on the idea that trust enhances individuals' and couples' willingness to outsource childcare to outside their extended family. This becomes critically important as women's increased education enhances the demand for combining work and family life. We test our hypothesis using data from the World Values Survey and European Values Study on 36 industrialized countries between the years 1981 and 2009. Multilevel statistical analyses reveal that the interaction between national level generalized trust and cohort-level women's education is positively associated with completed fertility. As education among women expands, high levels of generalized trust moderate fertility decline. PMID- 28003708 TI - Dance/Movement Therapy and the Arts in Healthcare: The First 50 Years. PMID- 28003709 TI - Comment. PMID- 28003710 TI - Comment. AB - Xu, Muller, Wahed, and Thall proposed a Bayesian model to analyze an acute leukemia study involving multi-stage chemotherapy regimes. We discuss two alternative methods, Q-learning and O-learning, to solve the same problem from the machine learning point of view. The numerical studies show that these methods can be flexible and have advantages in some situations to handle treatment heterogeneity while being robust to model misspecification. PMID- 28003711 TI - Compact NMR relaxometry of human blood and blood components. AB - Nuclear magnetic resonance relaxometry is a uniquely practical and versatile implementation of NMR technology. Because it does not depend on chemical shift resolution, it can be performed using low-field compact instruments deployed in atypical settings. Early relaxometry studies of human blood were focused on developing a diagnostic test for cancer. Those efforts were misplaced, as the measurements were not specific to cancer. However, important lessons were learned about the factors that drive the water longitudinal (T1) and transverse (T2) relaxation times. One key factor is the overall distribution of proteins and lipoproteins. Plasma water T2 can detect shifts in the blood proteome resulting from inflammation, insulin resistance and dyslipidemia. In whole blood, T2 is sensitive to hemoglobin content and oxygenation, although the latter can be suppressed by manipulating the static and applied magnetic fields. Current applications of compact NMR relaxometry include blood tests for candidiasis, hemostasis, malaria and insulin resistance. PMID- 28003712 TI - PRELIMINARY RESULTS OF BTDF CALIBRATION OF TRANSMISSIVE SOLAR DIFFUSERS FOR REMOTE SENSING. AB - Satellite instruments operating in the reflected solar wavelength region require accurate and precise determination of the optical properties of their diffusers used in pre-flight and post-flight calibrations. The majority of recent and current space instruments use reflective diffusers. As a result, numerous Bidirectional Reflectance Distribution Function (BRDF) calibration comparisons have been conducted between the National Institute of Standards and Technology (NIST) and other industry and university-based metrology laboratories. However, based on literature searches and communications with NIST and other laboratories, no Bidirectional Transmittance Distribution Function (BTDF) measurement comparisons have been conducted between National Measurement Laboratories (NMLs) and other metrology laboratories. On the other hand, there is a growing interest in the use of transmissive diffusers in the calibration of satellite, air-borne, and ground-based remote sensing instruments. Current remote sensing instruments employing transmissive diffusers include the Ozone Mapping and Profiler Suite instrument (OMPS) Limb instrument on the Suomi-National Polar-orbiting Partnership (S-NPP) platform,, the Geostationary Ocean Color Imager (GOCI) on the Korea Aerospace Research Institute's (KARI) Communication, Ocean, and Meteorological Satellite (COMS), the Ozone Monitoring Instrument (OMI) on NASA's Earth Observing System (EOS) Aura platform, the Tropospheric Emissions: Monitoring of Pollution (TEMPO) instrument and the Geostationary Environmental Monitoring Spectrometer (GEMS).. This ensemble of instruments requires validated BTDF measurements of their on-board transmissive diffusers from the ultraviolet through the near infrared. This paper presents the preliminary results of a BTDF comparison between the NASA Diffuser Calibration Laboratory (DCL) and NIST on quartz and thin Spectralon samples. PMID- 28003713 TI - N-Acetyl-L-cysteine Protects the Enterocyte against Oxidative Damage by Modulation of Mitochondrial Function. AB - The neonatal small intestine is susceptible to damage caused by oxidative stress. This study aimed to evaluate the protective role of antioxidant N-acetylcysteine (NAC) in intestinal epithelial cells against oxidative damage induced by H2O2. IPEC-J2 cells were cultured in DMEM-H with NAC and H2O2. After 2-day incubation, IPEC-J2 cells were collected for analysis of DNA synthesis, antioxidation capacity, mitochondrial respiration, and cell apoptosis. The results showed that H2O2 significantly decreased (P < 0.05) proliferation rate, mitochondrial respiration, and antioxidation capacity and increased cell apoptosis and the abundance of associated proteins, including cytochrome C, Bcl-XL, cleaved caspase 3, and total caspase-3. NAC supplementation remarkably increased (P < 0.05) proliferation rate, antioxidation capacity, and mitochondrial bioenergetics but decreased cell apoptosis. These findings indicate that NAC might rescue the intestinal injury induced by H2O2. PMID- 28003714 TI - Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. AB - In previous studies, abdominal obesity has been related to total low-grade inflammation and in some cases has resulted in insulin resistance and other metabolism related disorders such as diabetes. Quercetin is a polyphenol, which is a derivative of plants, and has been shown in vitro as well as in a few animal models to have several potential anti-inflammatory as well as anticarcinogenic applications. The substance has also been shown to aid in the attenuation of lipid peroxidation, platelet aggregation, and capillary permeability. However, further research is called for to gain a better understanding of how quercetin is able to provide these beneficial effects. This manuscript reviewed quercetin's anti-inflammatory properties in relation to obesity and type 2 diabetes. PMID- 28003715 TI - High-Fructose Intake Impairs the Hepatic Hypolipidemic Effects of a High-Fat Fish Oil Diet in C57BL/6 Mice. AB - BACKGROUND: Overnutrition of saturated fats and fructose is one of the major factors for the development of nonalcoholic fatty liver disease. Because omega-3 polyunsaturated fatty acids (n-3fa) have established lipid lowering properties, we tested the hypothesis that n-3fa prevents high-fat and fructose-induced fatty liver disease in mice. METHODS: Male C57BL/6J mice were randomly assigned to one of the following diet groups for 14 weeks: normal diet (ND), high-fat lard-based diet (HFD), HFD with fructose (HFD + Fru), high-fat fish-oil diet (FOD), or FOD + Fru. RESULTS: Despite for the development of obesity and insulin resistance, FOD had 65.3% lower (P < 0.001) hepatic triglyceride levels than HFD + Fru, which was blunted to a 38.5% difference (P = 0.173) in FOD + Fru. The lower hepatic triglyceride levels were associated with a lower expression of lipogenic genes LXRalpha and FASN, as well as the expression of genes associated with fatty acid uptake and triglyceride synthesis, CD36 and SCD1, respectively. Conversely, the blunted hypotriglyceride effect of FOD + Fru was associated with a higher expression of CD36 and SCD1. CONCLUSIONS: During overnutrition, a diet rich in n 3fa may prevent the severity of hepatic steatosis; however, when juxtaposed with a diet high in fructose, the deleterious effects of overnutrition blunted the hypolipidemic effects of n-3fa. PMID- 28003716 TI - Pharmacologic Treatment of Alcoholic Hepatitis: Examining Outcomes Based on Disease Severity Stratification. AB - OBJECTIVES: Maddrey discriminant function (MDF) score is a measure of disease prognosis in alcoholic hepatitis (AH) used to identify patients at highest risk of mortality and determine the need for initiation of pharmacologic treatment. The purpose of this study was to evaluate the effects of pharmacologic therapy for hospitalized AH patients as stratified by MDF score. METHODS: A retrospective review of patients with an AH diagnosis admitted to a Methodist LeBonheur Healthcare adult hospital between 06/2009 and 06/2014 was conducted. Patients >=18 years of age with an ICD-9 code for AH were evaluated. RESULTS: Of the 493 patients screened, 234 met the inclusion criteria, comprised of 62 patients with an MDF >= 32 (treatment, n = 42 vs. no treatment, n = 20) and 172 patients with an MDF < 32 (treatment, n = 15 vs. no treatment, n = 157). For the patients with an MDF >= 32, there was no statistically significant difference between the treatment group vs. non-treatment group regarding 28-day mortality (31% vs. 11%, respectively; P = 0.18) and 6-month mortality (45% treatment vs. 38% non treatment; P = 0.75). For the patients with an MDF <32, there was no statistically significant difference between the treatment group vs. non treatment group regarding 28-day mortality (0% vs. 7%, respectively; P > 0.99) and 6-month mortality (11% treatment vs. 13% non-treatment; P > 0.99). There was no difference in incidence of acute kidney injury, hepatorenal syndrome, development of infection or hepatic encephalopathy between the treatment vs. non treatment groups. CONCLUSIONS: Pharmacologic treatment showed no survival benefit, regardless of disease severity. Given the mortality risk seen in mild moderate AH patients not receiving treatment and concern for a possible treatment ceiling effect in severe AH patients, more data are needed to adequately assess the utility of MDF in selecting appropriate candidates for AH treatment. PMID- 28003717 TI - Noninvasive Assessment of Liver Fibrosis By Transient Elastography and FIB4/APRI for Prediction of Treatment Response in Chronic Hepatitis C-An Experience from a Tertiary Care Hospital. AB - BACKGROUND: Liver fibrosis and its sequel cirrhosis represent a major health care burden, and assessment of fibrosis by biopsy is gradually being replaced by noninvasive methods. In clinical practice, the determination of fibrosis stage is important, since patients with advanced fibrosis have faster progression to cirrhosis and antiviral therapy is indicated in these patients. AIMS: To assess the role of transient elastography (TE) and compare it with APRI and FIB4 for predicting liver fibrosis and assessing the effect of host and viral factors on fibrosis and treatment outcome in CHC patients. METHODS: In a retrospective analysis, 330 CHC patients underwent liver stiffness measurement (LSM) by TE and tests needed for calculating APRI and FIB4 scores at baseline. 228 patients received a combination of Pegylated IFN-based antiviral therapy and were analyzed for therapeutic response. RESULTS: The study included 330 patients (median age 39 years [range 18-67]), predominantly males (n = 227, 68.8%) with baseline LSMs. The median liver stiffness was 7.8 kPa (range 3.2-69.1 kPa). LSMs and its thresholds for severe fibrosis progression (>=9.5 kPa) and cirrhosis (>=12.5 kPa) were significantly higher in patients with age >=40 years, diabetes mellitus, and patients with significant alcohol intake (P = 0.003 to P < 0.001). By taking TE as a reference, the diagnostic accuracy of FIB4 scores for predicting cirrhosis (AUROC 0.896) was good (+LR 13.4) compared to APRI (AUROC 0.823) with moderate likelihood ratio (+LR 6.9). Among 228 treated patients the SVR rate in genotype 3 was 70% versus 57.8% in genotype 1. Fibrosis score F4 (P = 0.023) and HCV genotype (P = 0.008) were independent predictors of SVR. CONCLUSION: The study shows that LSM by TE and fibrosis assessment by FIB4/APRI scores can be used with fair reliability to predict fibrosis and treatment response in patients with CHC infection. PMID- 28003718 TI - Histological Evaluation of Non-alcoholic Fatty Liver Disease and Its Correlation with Different Noninvasive Scoring Systems with Special Reference to Fibrosis: A Single Center Experience. AB - BACKGROUND: Although liver biopsy remains the gold standard for the diagnosis of non-alcoholic fatty liver disease [NAFLD], many non-invasive markers of liver fibrosis have recently been proposed and assessed as surrogates of liver biopsy. AIMS AND OBJECTIVE: To evaluate the degree of liver fibrosis by different non invasive fibrosis scoring systems and to compare each non-invasive fibrosis scoring system with histological fibrosis stage. MATERIALS AND METHODS: The study population consists of consecutive patients with biopsy proven NAFLD. Complete medical history was taken and physical examination was done in all patients along with appropriate biochemical evaluations. NAFLD fibrosis score, BARD score, BAAT score and APRI score were calculated and each score was compared with histological fibrosis staging. RESULTS: The study population consisted of 60 patients having mean age 39.73 years (SD 9.62, range 17-63 years) including 51 (85%) males and 9 (15%) females. On histology fibrosis was present in 68.3% (41/60) patients. Out of 60 patients 41 had fibrosis and among them 17, 22, 2 patients had grade 1, 2, 3 fibrosis respectively and no one had grade 4 fibrosis. 61.67% (37/60) had definite NASH. Comparing the fibrosis of histology with the noninvasive scoring systems, the sensitivity and specificity of NAFLD fibrosis score were 5.56% and 100% respectively. BARD score had 45.83% sensitivity and 80.55% specificity. The sensitivities of BAAT score and APRI score were 0% and 29.16% respectively and the specificities were 100% and 97.22% respectively. CONCLUSION: The noninvasive scoring systems like NFS, BARD, BAAT, and APRI are not sensitive enough to detect fibrosis but highly specific to include fibrosis if scores are more than cut-off values in our cohort, however they cannot replace liver biopsy. Newer more efficient non-invasive scoring systems have to be devised for the Indian NAFLD population. PMID- 28003719 TI - Cirrhotic Patients Have Worse Bowel Preparation at Screening Colonoscopy than Chronic Liver Disease Patients without Cirrhosis. AB - BACKGROUND: Cirrhosis has been shown in small studies to be a predictor of suboptimal bowel preparation at screening colonoscopy. It has yet to be established whether patients with chronic liver disease in the absence of cirrhosis experience equally poor colon cleansing. Intestinal dysmotility related to cirrhosis might impair bowel preparation in this population more than those with chronic liver disease without cirrhosis. OBJECTIVE: This study compared the quality of bowel preparation in cirrhotic and non-cirrhotic patients with chronic liver disease and determined whether this influenced polyp detection rate. METHODS: A retrospective study of patients with chronic liver disease, both cirrhotic and non-cirrhotic, who underwent screening colonoscopy was performed. Patient characteristics, concomitant medication use, adequacy of bowel preparation, and the total number and types of polyps found were compared between cirrhotic and non-cirrhotic groups. RESULTS: 330 patients fulfilled inclusion criteria; 36% (n = 120) were cirrhotic. Cirrhotic patients had significantly worse bowel preparation scores compared with non-cirrhotics (mean 3.4 +/- 1.1 vs. 3.7 +/- 0.9, P = 0.003). Worse bowel preparation scores in cirrhotics vs. non cirrhotics persisted despite controlling for age, sex, and concomitant diabetes mellitus (DM) (P = 0.0027). Among the cirrhotics, 48% had the lowest preparation scores compared with 30% of non-cirrhotics. No difference in polyp detection rate was found between cirrhotics and non-cirrhotics. Severity of cirrhosis as assessed by the MELD score did not predict worse bowel preparation. CONCLUSIONS: Cirrhotics have significantly worse bowel preparation scores compared to non cirrhotics with chronic liver disease. No correlation between MELD score and bowel preparation score was observed in the cirrhotic cohort. PMID- 28003722 TI - Hepatocellular Carcinoma Presenting as Dyspnea at Rest due to Innumerable Lung Metastasis. AB - Hepatocellular carcinoma (HCC) the most common primary tumor of the liver usually develops in the setting of chronic liver disease. The presentation is usually due to worsening of chronic liver disease or being detected incidentally on imaging. Rarely metastasis to distant organ becomes the presentation. The authors describe a case of a 70-year-old woman who presented with dyspnea of 2 weeks duration. She was diagnosed as having HCC and extensive multiple pulmonary metastases. She was symptomatic only for the pulmonary metastasis with only 2 lesions in the liver. Because of advanced nature of disease, no specific therapy for the tumor was possible. PMID- 28003720 TI - Role of Diffusion Weighted Imaging (DWI) for Hepatocellular Carcinoma (HCC) Detection and its Grading on 3T MRI: A Prospective Study. AB - BACKGROUND: Limited studies have evaluated the role of diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) for histologically grading the hepatocellular carcinoma (HCC). OBJECTIVE: To compare the efficacy of DWI with dynamic contrast enhanced magnetic resonance (DCEMR) in detection of HCC in cirrhosis, and to evaluate whether DWI can be used instead of DCEMR. METHODS: 20 patients of either sex with cirrhosis and suspected of having HCC on screening USG were included in this prospective study approved by the Institutional Ethics Committee. All patients underwent DCEMR of the abdomen on 3T scanner and fine needle aspiration of the lesions. MR protocol included T1WI, T2WI, DWI, and dynamic CEMR. The results of diffusion weighted imaging were compared with DCEMR to find the efficacy of DWI vis-a-vis CEMR. RESULTS: DWI had a sensitivity and specificity of 100%, for diagnosis of lesions in cases having single lesion on CEMR, and sensitivity of 75% and specificity of 100% for diagnosis of lesions in cases having multiple lesions. There was a decreasing trend of ADC values with increasing grade of the tumor; however, the decreasing trend was not statistically significant. A cut-off ADC value of 0.8705 resulted in a sensitivity of 75% and specificity of 50% for differentiating between well differentiated and other grades of HCC. CONCLUSION: DWI can be used as an alternative for the detection and characterization of HCC, especially in patients with impaired renal function or contrast allergies precluding the use of contrast. In addition, DWI with ADC measurement may be helpful for non-invasive and preoperative prediction of the degree of differentiation of HCC. PMID- 28003721 TI - Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics. AB - Primary Biliary Cholangitis is a progressive, autoimmune cholestatic liver disorder. Cholestasis with disease progression may lead to dyslipidemia, osteodystrophy and fat-soluble vitamin deficiency. Portal hypertension may develop prior to advanced stages of fibrosis. Untreated disease may lead to cirrhosis, hepatocellular cancer and need for orthotopic liver transplantation. Classically, diagnosis is made with elevation of alkaline phosphatase, demonstration of circulating antimitochondrial antibody, and if performed: asymmetric destruction/nonsupperative cholangitis of intralobular bile ducts on biopsy. Disease pathogenesis is complex and results from innate and adaptive (cell-mediated and humoral) responses that lead to inflammation of biliary duct epithelium. Ongoing damage is amplified and sustained through bile acid toxicity. Use of weight based (13-15mg/kg) ursodeoxycholic acid is well established in retarding disease progression and improving survival; however, is ineffective in achieving complete biochemical remission in many. Recently, a Farnesoid X Receptor agonist, obeticholic acid, has been approved for use. A number of ongoing clinical studies are underway to evaluate utility of fibric acid derivatives, biologics, antifibrotics, and stem cells as monotherapy or in combination with ursodeoxycholic acid for primary biliary cholangitis. The aim of this review is to discuss disease pathogenesis and highlight rationale/implications for both established and novel therapeutics. PMID- 28003723 TI - Multifocal Intrahepatic Artery Aneurysm with FDG-avid Thrombosis Simulating Metastasis: Report of a Rare Case. AB - Hepatic artery aneurysm (HAA), although rare, represents a serious diagnostic and therapeutic challenge due to high rupture rate and associated mortality. Early detection and accurate diagnosis are essential for successful management. Here, we present an extremely rare case of multi-focal intrahepatic HAA with confined intrahepatic rupture and hypermetabolic activity at PET imaging, simulating metastasis of melanoma. A retrospective review found only two other HAA at our institution between 2000 and 2015, both of which involved the extrahepatic artery. This report highlights the importance of clinical, radiological, and pathological correlation in the management of this rare condition. PMID- 28003724 TI - Balloon-Occluded Retrograde Transvenous Obliteration (BRTO): A Novel Method of Control of Bleeding from Post-Glue Ulcer over Gastric Varices. Report of Two Cases and Review of Literature. AB - Bleeding gastric varices (GV) are managed by cyanoacrylate glue injection with transjugular intrahepatic portosystemic shunt (TIPSS) as modality for treatment failure. Ulcer can form at the site of glue injection over GV and it can cause bleeding. Treatment approach for such bleed is not well described. Balloon occluded retrograde transvenous obliteration (BRTO), TIPSS, and devascularization remain the treatment options in this scenario. BRTO is an endovascular procedure where a balloon catheter is inserted into a draining vein of GV, and the sclerosant can be injected into the varices through the catheter during balloon occlusion. BRTO has the benefit of increasing portal hepatic blood flow and can also be useful in patients who may not tolerate TIPSS. We report two cases where BRTO was done for control of bleeding from ulcers formed over previously injected GV. PMID- 28003725 TI - Neonatal Cholestasis as Initial Presentation of Portosystemic Shunt: A Case Report. AB - Congenital intrahepatic portosystemic shunts are rare in children. Portosystemic venous malformations are characterized by extreme clinical variability. We report a full-term 33-day-old male infant presenting with neonatal jaundice. On physical examination, he had generalized icterus and the liver was palpable 3.5 cm below the right costal margin. He had no other symptoms. Laboratory tests showed AST 632 U/L, ALT 198 U/L, total bilirubin 12.1 mg/dL, conjugated bilirubin 10.2 mg/dL, alkaline phosphatase 753 U/L, GGT 47 U/L and glucose 67 U/L. Colour Doppler ultrasonography showed the left portal vein was more dilated than the right portal branch and communication with dilated left hepatic vein. There was no evidence of portal hypertension, heart failure, hepatopulmonary syndrome and encephalopathy during his hospital stay, so he was discharged from the pediatric department and his parents advised to attend monthly follow-up. Congenital portosystemic shunts are rarely observed in the childhood period.1 Depending on anatomic characteristics they may be intrahepatic or extrahepatic.2 Intrahepatic portosystemic shunts (PSS) are observed between the portal vein and hepatic vein or vena cava inferior.3, 4 Small shunts may close themselves before the age of 2 years.5 With the increase in use of imaging methods, diagnosing PSS has become easier, with an increase in the number of cases reported.6 Neonatal cholestatis is a frequent complication of PSS.1 We present a case presenting with neonatal cholestasis diagnosed with congenital intrahepatic PSS. PMID- 28003726 TI - Enucleation Sign: A Computed Tomographic Appearance of Ruptured Hepatocellular Carcinoma. AB - Rupture of hepatocellular carcinoma (HCC) is a catastrophic complication, which carries high mortality. We report a case of spontaneous rupture of HCC, diagnosis of which was considered on clinical presentation and confirmed on computed tomographic (CT) scan. On CT scan, characteristic 'enucleation sign' was observed on arterial phase imaging, where a hypervascular peripheral mass showing central necrosis was seen protruding from liver surface with discontinuity of hepatic parenchyma associated with high attenuation ascites. PMID- 28003727 TI - An Unusual Complication of Pyogenic Liver Abscess. PMID- 28003728 TI - Looking Beyond Sorafenib to Treat Advanced Hepatocellular Carcinoma. PMID- 28003729 TI - "There is soccer but we have to watch": the embodied consequences of rhetorics of inclusion for South African children with cerebral palsy. AB - Twenty years after the advent of democracy in South Africa (SA), there have been some successes in the achievement of greater equality, access and inclusion for many persons with disabilities. The move towards inclusive education may, however, have had unanticipated embodied consequences for people positioned discursively as included, but who in fact may in some respects be further marginalised than they had been under apartheid. We describe ethnographic research conducted in a special needs school in SA to explore the lived experiences of children with cerebral palsy and their involvement in physical activity. Our study shows how inclusive educational practices in SA have impeded involvement in sport for some children with motor impairments because of resource limitations and other historic reasons. This paper raises important questions about the role of community psychology in recognising, naming and contributing to action around injustices, which may be hard to see but which can have profound effects on the lives and bodies of those who experience exclusion. PMID- 28003730 TI - Accumulation of cholesterol and increased demand for zinc in serum-deprived RPE cells. AB - PURPOSE: Having observed that confluent ARPE-19 cells (derived from human RPE) survive well in high-glucose serum-free medium (SFM) without further feeding for several days, we investigated the expression profile of RPE cells under the same conditions. METHODS: Expression profiles were examined with microarray and quantitative PCR (qPCR) analyses, followed by western blot analysis of key regulated proteins. The effects of low-density lipoprotein (LDL) and zinc supplementation were examined with qPCR. Immunofluorescence was used to localize the LDL receptor and to examine LDL uptake. Cellular cholesterol levels were measured with filipin binding. Expression patterns in primary fetal RPE cells were compared using qPCR. RESULTS: Microarray analyses of gene expression in ARPE 19, confirmed with qPCR, showed upregulation of lipid and cholesterol biosynthesis pathways in SFM. At the protein level, the cholesterol synthesis control factor SRBEF2 was activated, and other key lipid synthesis proteins increased. Supplementation of SFM with LDL reversed the upregulation of lipid and cholesterol synthesis genes, but not of cholesterol transport genes. The LDL receptor relocated to the plasma membrane, and LDL uptake was activated by day 5 7 in SFM, suggesting increased demand for cholesterol. Confluent ARPE-19 cells in SFM accumulated intracellular cholesterol, compared with cells supplemented with serum, over 7 days. Over the same time course in SFM, the expression of metallothioneins decreased while the major zinc transporter was upregulated, consistent with a parallel increase in demand for zinc. Supplementation with zinc reversed expression changes for metallothionein genes, but not for other zinc related genes. Similar patterns of regulation were also seen in primary fetal human RPE cells in SFM. CONCLUSIONS: ARPE-19 cells respond to serum deprivation and starvation with upregulation of the lipid and cholesterol pathways, accumulation of intracellular cholesterol, and increased demand for zinc. Similar trends are seen in primary fetal RPE cells. Cholesterol accumulation basal to RPE is a prominent feature of age-related macular degeneration (AMD), while dietary zinc is protective. It is conceivable that accumulating defects in Bruch's membrane and dysfunction of the choriocapillaris could impede transport between RPE and vasculature in AMD. Thus, this pattern of response to serum deprivation in RPE-derived cells may have relevance for some aspects of the progression of AMD. PMID- 28003731 TI - A regulatory sequence from the retinoid X receptor gamma gene directs expression to horizontal cells and photoreceptors in the embryonic chicken retina. AB - PURPOSE: Combining techniques of episomal vector gene-specific Cre expression and genomic integration using the piggyBac transposon system enables studies of gene expression-specific cell lineage tracing in the chicken retina. In this work, we aimed to target the retinal horizontal cell progenitors. METHODS: A 208 bp gene regulatory sequence from the chicken retinoid X receptor gammagene (RXRgamma208) was used to drive Cre expression. RXRgamma is expressed in progenitors and photoreceptors during development. The vector was combined with a piggyBac "donor" vector containing a floxed STOP sequence followed by enhanced green fluorescent protein (EGFP), as well as a piggyBac helper vector for efficient integration into the host cell genome. The vectors were introduced into the embryonic chicken retina with in ovo electroporation. Tissue electroporation targets specific developmental time points and in specific structures. RESULTS: Cells that drove Cre expression from the regulatory RXRgamma208 sequence excised the floxed STOP-sequence and expressed GFP. The approach generated a stable lineage with robust expression of GFP in retinal cells that have activated transcription from the RXRgamma208 sequence. Furthermore, GFP was expressed in cells that express horizontal or photoreceptor markers when electroporation was performed between developmental stages 22 and 28. Electroporation of a stage 12 optic cup gave multiple cell types in accordance with RXRgamma gene expression in the early retina. CONCLUSIONS: In this study, we describe an easy, cost effective, and time-efficient method for testing regulatory sequences in general. More specifically, our results open up the possibility for further studies of the RXRgamma-gene regulatory network governing the formation of photoreceptor and horizontal cells. In addition, the method presents approaches to target the expression of effector genes, such as regulators of cell fate or cell cycle progression, to these cells and their progenitor. PMID- 28003732 TI - Regulation of photoreceptor gene transcription via a highly conserved transcriptional regulatory element by vsx gene products. AB - PURPOSE: The photoreceptor conserved element-1 (PCE-1) sequence is found in the transcriptional regulatory regions of many genes expressed in photoreceptors. The retinal homeobox (Rx or Rax) gene product functions by binding to PCE-1 sites. However, other transcriptional regulators have also been reported to bind to PCE 1. One of these, vsx2, is expressed in retinal progenitor and bipolar cells. The purpose of this study is to identify Xenopus laevis vsx gene products and characterize vsx gene product expression and function with respect to the PCE-1 site. METHODS: X. laevis vsx gene products were amplified with PCR. Expression patterns were determined with in situ hybridization using whole or sectioned X. laevis embryos and digoxigenin- or fluorescein-labeled antisense riboprobes. DNA binding characteristics of the vsx gene products were analyzed with electrophoretic mobility shift assays (EMSAs) using in vitro translated proteins and radiolabeled oligonucleotide probes. Gene transactivation assays were performed using luciferase-based reporters and in vitro transcribed effector gene products, injected into X. laevis embryos. RESULTS: We identified one vsx1 and two vsx2 gene products. The two vsx2 gene products are generated by alternate mRNA splicing. We verified that these gene products are expressed in the developing retina and that expression resolves into distinct cell types in the mature retina. Finally, we found that vsx gene products can bind the PCE-1 site in vitro and that the two vsx2 isoforms have different gene transactivation activities. CONCLUSIONS: vsx gene products are expressed in the developing and mature neural retina. vsx gene products can bind the PCE-1 site in vitro and influence the expression of a rhodopsin promoter-luciferase reporter gene. The two isoforms of vsx have different gene transactivation activities in this reporter gene system. PMID- 28003733 TI - MMP19 expression in the human optic nerve. AB - PURPOSE: The defining feature of glaucoma is excavation of the optic nerve head; however, the mechanism of this loss of tissue is not well understood. We recently discovered a copy number variation upstream of matrix metalloproteinase 19 (MMP19) in a large, autosomal dominant pedigree with a congenital malformation of the optic disc called cavitary optic disc anomaly (CODA). Patients with CODA have abnormal optic discs that exhibit an excavated shape similar to cupping seen in glaucoma. The goal of this study is to characterize the localization of MMP19 within the human optic nerve. METHODS: The MMP19 protein in the optic nerve was evaluated with western blot analysis and with immunohistochemistry in sagittal and en face/cross sections of optic nerves obtained from healthy human donor eyes. RESULTS: The MMP19 protein was detected in the human optic nerve, retina, and RPE/choroid with western blot analysis, with highest expression in the retina and the optic nerve. Using immunohistochemistry, MMP19 was localized within the optic nerve to the extracellular space within the septa that separate bundles of optic nerve axons into fascicles. The presence of MMP19 within the optic nerve septa was further confirmed by the colocalization of MMP19 to this structure with type IV collagen. Strong labeling of MMP19 was also detected in the arachnoid layer of the optic nerve sheath. Finally, immunohistochemistry of the optic nerve cross sections demonstrated that MMP19 shows a peripheral to central gradient, with more abundant labeling along the edges of the optic nerve and in the arachnoid layer than in the center of the nerve. CONCLUSIONS: Abundant MMP19 was detected in the optic nerve head, the primary site of pathology in patients with CODA. The localization of MMP19 to the optic nerve septa is consistent with its predicted secretion and accumulation within the extracellular spaces of this tissue. Moreover, the lateral localization of MMP19 observed in the optic nerve cross sections suggests that it might have a role in regulating adhesion to the optic nerve to the scleral canal and remodeling the extracellular matrix that provides the structural integrity of the optic disc. Dysregulation of MMP19 production might, therefore, undermine the connections between the optic nerve and the scleral canal and cause a collapse of the optic disc and the development of CODA. Similar processes might also be at work in the formation of optic disc cupping in glaucoma. PMID- 28003734 TI - DEBS - a unification theory for dry eye and blepharitis. AB - For many years, blepharitis and dry eye disease have been thought to be two distinct diseases, and evaporative dry eye distinct from aqueous insufficiency. In this treatise, we propose a new way of looking at dry eye, both evaporative and insufficiency, as the natural sequelae of decades of chronic blepharitis. Dry eye is simply the late form and late manifestation of one disease, blepharitis. We suggest the use of a new term in describing this one chronic disease, namely dry eye blepharitis syndrome (DEBS). Bacteria colonize the lid margin within a structure known as a biofilm. The biofilm allows for population densities that initiate quorum-sensing gene activation. These newly activated gene products consist of inflammatory virulence factors, such as exotoxins, cytolytic toxins, and super-antigens, which are then present for the rest of the patient's life. The biofilm never goes away; it only thickens with age, producing increasing quantities of bacterial virulence factors, and thus, increasing inflammation. These virulence factors are likely the culprits that first cause follicular inflammation, then meibomian gland dysfunction, aqueous insufficiency, and finally, after many decades, lid destruction. We suggest that there are four stages of DEBS which correlate with the clinical manifestations of folliculitis, meibomitis, lacrimalitis, and finally lid structure damage evidenced by entropion, ectropion, and floppy eyelid syndrome. When one fully understands the structure and location of the glands within the lid, it becomes easy to understand this staged disease process. The longer a gland can resist the relentless encroachment of the invading biofilm, the longer it can maintain normal function. The stages depend purely on anatomy and years of biofilm presence. Dry eye now becomes a very easy disease to understand. We feel that dry eye should be treated and prevented by early and routine biofilm removal through electromechanical lid margin debridement. PMID- 28003736 TI - Erratum: Outcomes of combined trabecular micro-bypass and phacoemulsification in a predominantly Hispanic patient population [Corrigendum]. AB - [This corrects the article on p. 1931 in vol. 10, PMID: 27784981.]. PMID- 28003735 TI - Oxygen permeability of the pigmented material used in cosmetic daily disposable contact lenses. AB - PURPOSE: To evaluate the individual contributions of pigment colorant and packing solution containing polyvinyl pyrrolidone (PVP) on the oxygen permeability (Dk) of a cosmetic printed etafilcon A daily disposable contact lens packaged with PVP. METHOD: The oxygen transport of a contact lens is evaluated through the central optical zone of the lens. Cosmetic printed contact lenses contain pigment colorant in the periphery or mid-periphery of the lens. Therefore, to assess the impact of cosmetic print on oxygen permeability, special lenses need to be produced that contain the colorant within the central optical zone. This technique was used to obtain multiple measurements of nonedge-corrected Dk/t of both the center pigmented lens and its nonpigmented equivalent, using a polarographic measurement described in International Organization for Standardization (ISO) 18369-4:2006(E), and the Dk derived for each measurement is corrected for edge effect. In addition, the edge-corrected Dk values of lenses made from the same monomer batch were measured. The lenses were packaged and autoclaved with and without proprietary technology which embeds PVP in the contact lens during autoclaving. The resulting Dk value of the printed lens material was then used with thickness data to generate true Dk/t profiles for a given lens power. RESULTS: The edge-corrected Dk of the printed etafilcon A lens with offset pigment colorant was measured to be 19.7*10-11 (cm2/s) (mL O2/mL.mmHg) at 35 degrees C. This was within +/-20% tolerance range as specified in ISO 18369-2:2012(E) for the edge-corrected Dk of the nonpigmented etafilcon A control lens evaluated during the same session, 19.5*10-11 (cm2/s) (mL O2/mL.mmHg). The edge-corrected Dk values of the lenses packaged with PVP (mean 20.1, standard deviation [SD] 0.3) were also within the +/-20% tolerance range compared to those packaged without PVP (mean 20.0, SD 0.3). CONCLUSION: The pigment colorant and PVP embedded in the contact lens during autoclaving were not found to influence the oxygen permeability of the etafilcon A material. PMID- 28003737 TI - Comparison of Goldmann applanation tonometry and Pascal dynamic contour tonometry in relation to central corneal thickness and corneal curvature. AB - PURPOSE: The aim of the study was to assess the influence of central corneal thickness (CCT) and corneal curvature in tonometry measurements taken by Goldmann applanation tonometry (GAT) and Pascal dynamic contour tonometry (DCT). METHODS: This was a prospective study of 185 eyes from 97 subjects, attending outpatient ophthalmology appointments, who underwent intraocular pressure measurements by GAT and Pascal DCT. CCT and corneal curvature were obtained using ultrasound pachymetry and Orbscan topography, respectively. All measurements were carried out among males and females during the period 2009-2012. Apart from the usual descriptive and exploratory data analysis, one-way analysis of variance and agreement analysis were performed, linear as well as intraclass correlation coefficients were estimated, and multiple scatter and Bland-Altman plots were produced. RESULTS: Mean IOP measurements obtained were 17.21+/-4.10 mmHg by DCT and 13.23+/-4.07 mmHg by GAT. Mean difference between the GAT and DCT measurements was 3.88+/-2.8 mmHg. Mean CCT and corneal curvature were 522.78+/-52 MUm and 43.83+/-2.9823 D, respectively. CONCLUSION: Intraocular pressure measured by GAT was consistently lower when compared with DCT, and this difference was greatest with thinner CCT. Flat corneas seem to influence GAT measurements compared to DCT. PMID- 28003738 TI - Practice patterns of ophthalmologists administering intravitreal injections in Europe: a longitudinal survey. AB - PURPOSE: This study was performed to understand the practice patterns of ophthalmologists administering intravitreal (IVT) injections in Europe after the procedure became routine. METHODS: As part of a prospective, multinational, non interventional cohort study in 13 countries in Europe between 2006 and 2012, ophthalmologists completed the Baseline Questionnaire and the Follow-up Questionnaire 1 year after baseline. RESULTS AND DISCUSSION: Of the 125 ophthalmologists who participated in the study, 113 (90.4%) completed the Baseline Questionnaire. Most of these ophthalmologists were medical retina specialists (43.0%). The median number of IVT injections that the ophthalmologists performed per month during the year prior to completing the Baseline Questionnaire was 20.0. The majority of the ophthalmologists had performed their last IVT injection prior to completing the questionnaire in an operating room or theater (68.4%). When performing IVT injections, a majority of the ophthalmologists reported applying povidone-iodine (90.4%) before IVT injections and topical antibiotics right after IVT injections (89.5%). In addition, 81.6% of the ophthalmologists reported using a sterile adhesive eye drape and 80.7% reported using an eyelid speculum. In all, 95 ophthalmologists (76%) completed the Follow-up Questionnaire. The median number of IVT injections performed per month during the year prior to completing the Follow-up Questionnaire by these ophthalmologists was increased to 35. The results of the Follow-up Questionnaire on administering IVT injections were similar to those of the Baseline Questionnaire. A majority of the ophthalmologists reported applying povidone-iodine (87.4%) before IVT injections, topical antibiotics right after IVT injections (89.5%), and an eyelid speculum (85.3%). CONCLUSION: The results of this study indicated a good adherence to all aspects of the guidelines on IVT injections. It seemed that ophthalmologists were more experienced in IVT injections after they became a routine treatment procedure. PMID- 28003739 TI - Visual, aberrometric, photic phenomena, and patient satisfaction after myopic wavefront-guided LASIK using a high-resolution aberrometer. AB - PURPOSE: The purpose of this study was to evaluate the visual, refractive, and aberrometric outcomes as well as the level of patient satisfaction and photic phenomena after myopic laser in situ keratomileusis (LASIK) surgery using wavefront-guided (WFG) ablations based on measurements obtained with a high resolution aberrometer. PATIENTS AND METHODS: This study was a prospective analysis including 253 eyes of 127 patients (aged between 19 years and 54 years) undergoing WFG LASIK using the STAR S4 IR Excimer Laser System combined with the iDesign System and iFS Femtosecond Laser. Visual, refractive, and aberrometric outcomes during a 2-month follow-up as well as patient satisfaction and photic phenomena were evaluated by means of a questionnaire. RESULTS: A total of 85% (215/253) and 99% (251/253) of eyes achieved a postoperative (Postop) uncorrected distance visual acuity of 20/16 and 20/20, respectively, and all eyes achieved an uncorrected distance visual acuity of 20/25. Postop spherical equivalent values were within +/-0.25 D and +/-0.50 D in 97% and 100% of eyes, respectively. Likewise, manifest cylinder was <0.25 D in 97% (245/253) of eyes. A statistically significant reduction was found in the total root mean square (P<0.001) and in the level of primary spherical aberration (P=0.001). Postop difficulties related to vision were graded as minimal, with low levels of photic phenomena and high levels of patient satisfaction. The level of difficulty to perform daily activities and the level of glare perceived by patients while driving car were significantly decreased (P<0.001). CONCLUSION: WFG LASIK surgery using the technology evaluated is predictable and effective for the correction of myopia and leads to high levels of patient satisfaction. PMID- 28003740 TI - Dose-dependent effects of cisplatin on the severity of testicular injury in Sprague Dawley rats: reactive oxygen species and endoplasmic reticulum stress. AB - Cisplatin (CIS) is used in the treatment of cancer, but its nonspecific systemic actions lead to toxic effects on other parts of the body. This study investigated the severity of CIS toxicity by increasing its dose over a constant time period. Sprague Dawley rats were divided into five treatment groups and control group with CIS (2, 4, 6, 8, and 10 mg/kg) administered intraperitoneally for 5 days. The body and organs were weighed, epididymal sperm was counted, and sperm motility and sperm apoptosis were evaluated. Blood samples were evaluated for complete blood count, reactive oxygen and nitrogen species, malondialdehyde levels, and total testosterone. The testicular tissue was examined for steroidogenic acute regulatory protein and endoplasmic reticulum stress protein. Epididymal sperm was collected for CatSper Western blot. The toxic effects of different doses of CIS on the testis and kidney were compared histologically. The weights of body, testis, epididymis, prostate, seminal vesicle, and kidney; sperm count; sperm motility; steroidogenic acute regulatory protein level; and epididymal sperm count were significantly lower in the CIS-treated groups than in the control group. In contrast, sperm apoptosis, plasma reactive oxygen and nitrogen species, and malondialdehyde, testosterone, red blood cell, hematocrit, hemoglobin, and endoplasmic reticulum stress protein levels all increased. Though CIS effectively treats cancer, at an increased dose it is toxic and life threatening to the genitourinary system and other parts of the body. PMID- 28003741 TI - Factors influencing the quality of life perception in patients with type 2 diabetes mellitus. AB - PURPOSE: To evaluate the impact of several factors on the patient's perception on quality of life in a group of patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: In this cross-sectional study, 198 patients with T2DM were enrolled according to a consecutive-case population-based study design. In all participants, the perception on the quality of life was measured using the quality of life index - diabetes version III proposed by Ferrans and Powers. We evaluated the impact of several anthropometric and diabetes-related (ie, diabetes history and quality of glycemic control) factors on the patient's perception on the quality of life. RESULTS: The presence of diabetes complications was associated with a decreased quality of life: retinopathy (1 vs 5 points; P<0.001), chronic kidney disease (-1 vs 5 points; P<0.001), and neuropathy (-1 vs 5 points; P<0.001). A significant reverse correlation was found between the patient's quality of life and depression's severity (Spearman's r=-0.345; P<0.001) and body mass index (Spearman's r=-0.158; P=0.026). A positive association between the quality of life and the quality of diabetes-related self care activities was found (Spearman's r=0.338; P<0.001). No significant association was found between the patient's quality of life and the quality of glycemic control, diabetes duration, age, gender, or smoking status. CONCLUSION: To improve the patient's quality of life, special care should be given to the modifiable diabetes-related factors: the prevention and treatment of diabetes complications, treatment of depression, and weight loss in obese and overweight patients. PMID- 28003742 TI - Major air pollutants and risk of COPD exacerbations: a systematic review and meta analysis. AB - BACKGROUND: Short-term exposure to major air pollutants (O3, CO, NO2, SO2, PM10, and PM2.5) has been associated with respiratory risk. However, evidence on the risk of chronic obstructive pulmonary disease (COPD) exacerbations is still limited. The present study aimed at evaluating the associations between short term exposure to major air pollutants and the risk of COPD exacerbations. METHODS: After a systematic search up until March 30, 2016, in both English and Chinese electronic databases such as PubMed, EMBASE, and CNKI, the pooled relative risks and 95% confidence intervals were estimated by using the random effects model. In addition, the population-attributable fractions (PAFs) were also calculated, and a subgroup analysis was conducted. Heterogeneity was assessed by I2. RESULTS: In total, 59 studies were included. In the single pollutant model, the risks of COPD were calculated by each 10 MUg/m3 increase in pollutant concentrations, with the exception of CO (100 MUg/m3). There was a significant association between short-term exposure and COPD exacerbation risk for all the gaseous and particulate pollutants. The associations were strongest at lag0 and lag3 for gaseous and particulate air pollutants, respectively. The subgroup analysis not only further confirmed the overall adverse effects but also reduced the heterogeneities obviously. When 100% exposure was assumed, PAFs ranged from 0.60% to 4.31%, depending on the pollutants. The adverse health effects of SO2 and NO2 exposure were more significant in low-/middle-income countries than in high-income countries: SO2, relative risk: 1.012 (95% confidence interval: 1.001, 1.023); and NO2, relative risk: 1.019 (95% confidence interval: 1.014, 1.024). CONCLUSION: Short-term exposure to air pollutants increases the burden of risk of COPD acute exacerbations significantly. Controlling ambient air pollution would provide benefits to COPD patients. PMID- 28003743 TI - Prognostic utility of admission cell-free DNA levels in patients with chronic obstructive pulmonary disease exacerbations. AB - BACKGROUND: Chronic obstructive pulmonary disease exacerbations (COPDEs) are associated with increased morbidity and mortality. Cell-free DNA (cfDNA) is a novel biomarker associated with clinical outcomes in several disease states but has not been studied in COPD. The objectives of this study were to assess cfDNA levels during a COPDE, to evaluate the association of cfDNA with clinical parameters and to explore the prognostic implications of cfDNA levels on long term survival. METHODS: This was an observational study that assessed cfDNA levels in patients admitted to hospital for a COPDE. Plasma cfDNA levels of COPDE patients were compared to those of matched stable COPD patients and healthy controls. Multivariable and Cox regression analyses were used to assess the association of cfDNA levels with blood gas parameters and long-term survival. RESULTS: A total of 62 patients (46 males, forced expiratory volume in 1 second [FEV1] 38%+/-13%) were included. The median cfDNA levels on admission for COPDE patients was 1,634 ng/mL (interquartile range [IQR] 1,016-2,319) compared to 781 ng/mL (IQR 523-855) for stable COPD patients, matched for age and disease severity, and 352 ng/mL (IQR 209-636) for healthy controls (P<0.0001, for both comparisons). cfDNA was correlated with partial arterial pressure of carbon dioxide (PaCO2, r=0.35) and pH (r=-0.35), P=0.01 for both comparisons. In a multivariable analysis, PaCO2 was the only independent predictor of cfDNA. Using a cfDNA level of 1,924 ng/mL (threshold for abnormal PaCO2), those with high levels had a trend for increased 5-year mortality risk adjusted for age, sex and FEV1% (hazard ratio 1.92, 95% confidence interval 0.93-3.95, P=0.08). CONCLUSION: Plasma cfDNA might offer a novel technique to identify COPD patients at increased risk of poor outcomes, but the prognostic utility of this measurement requires further study. PMID- 28003744 TI - Endocan and the respiratory system: a review. AB - Endocan, formerly called endothelial cell-specific molecule 1, is an endothelial cell-associated proteoglycan that is preferentially expressed by renal and pulmonary endothelium. It is upregulated by proangiogenic molecules as well as by pro-inflammatory cytokines, and since it reflects endothelial activation and dysfunction, it is regarded as a novel tissue and blood-based relevant biomarker. As such, it is increasingly being researched and evaluated in a wide spectrum of healthy and disease pathophysiological processes. Here, we review the present scientific knowledge on endocan, with emphasis on the evidence that underlines its possible clinical value as a prognostic marker in several malignant, inflammatory and obstructive disorders of the respiratory system. PMID- 28003745 TI - Biophysical evaluation of aminoclay as an effective protectant for protein stabilization during freeze-drying and storage. AB - This study aimed to evaluate aminoclay (3-aminopropyl-functionalized magnesium phyllosilicate) as an effective protectant for the stabilization of protein formulation in freeze-drying. Bovine serum albumin (BSA), as a model protein, was freeze-dried with aminoclay at various concentrations, and the effects of aminoclay on the structural stability of proteins were compared with those of the conventional stabilizers. The structural characteristics of the protein were determined by size exclusion chromatography (SEC), circular dichroism (CD), and Fourier transform infrared (FTIR) spectroscopy. Furthermore, physicochemical and morphological characteristics were examined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). XRPD and DSC patterns indicated that the glass transition temperature (Tg) of the amorphous formulation of aminoclay mixed with proteins was gradually elevated as the concentration of aminoclay increased. FTIR and CD spectral analysis suggested that the protein structure was well maintained with aminoclay during the freeze drying process and 3 months of storage at 4 degrees C and 40 degrees C. Furthermore, aminoclay conferred the greatest protection against aggregation and retained the monomer content of BSA even at a high temperature. The morphological characteristics of lyophilized proteins were also well conserved during the storage with aminoclay. These results suggested that aminoclay may be useful as an alternative stabilizer for maintaining the structural stability of protein formulations. PMID- 28003746 TI - Evaluation of beta-cyclodextrin-modified gemini surfactant-based delivery systems in melanoma models. AB - Novel drug delivery systems are developed to improve the biological behavior of poorly soluble drugs and to improve therapeutic outcomes. In melanoma therapy, the goal is efficient drug delivery and mitigation of drug resistance. Melphalan (Mel), a currently used therapeutic agent for melanoma, requires solvent system for solubilization, leading to poor chemical stability. Moreover, drug resistance often renders the drug inefficient in clinical setting. A novel beta-cyclodextrin modified gemini surfactant (CDgemini) delivery system was developed to incorporate Mel in order to improve its physicochemical and biological behavior. Melphalan nanoparticles (Mel-NP) showed optimal particle size in the 200-250 nm range for endocytosis and induced significantly higher cell death compared with Mel (50% of inhibitory concentration [IC50] of 36 uM for the complexes vs 82 uM for Mel). The CDgemini delivery system did not alter the pathway of the cellular death triggered by Mel and caused no intrinsic toxicity to the cells. The Mel-NP complexes induced significant cell death in melanoma cells that were rendered resistant to Mel. These findings demonstrate in principle the applicability of the CDgemini delivery system as safe and efficient alternative to the current melanoma therapy, especially in chemoresistant cases. PMID- 28003748 TI - Manipulation of Schwann cell migration across the astrocyte boundary by polysialyltransferase-loaded superparamagnetic nanoparticles under magnetic field. AB - Schwann cell (SC) transplantation is an attractive strategy for spinal cord injury (SCI). However, the efficacy of SC transplantation has been limited by the poor migratory ability of SCs in the astrocyte-rich central nervous system (CNS) environment and the inability to intermingle with the host astrocyte. In this study, we first magnetofected SCs by polysialyltransferase-functionalized superparamagnetic iron oxide nanoparticles (PST/SPIONs) to induce overexpression of polysialylation of neural cell adhesion molecule (PSA-NCAM) to enhance SC migration ability, before manipulating the direction of SC migration with the assistance of an applied magnetic field (MF). It was found that magnetofection with PST/SPIONs significantly upregulated the expression of PSA-NCAM in SCs, which significantly enhanced the migration ability of SCs, but without preferential direction in the absence of MF. The number and averaged maximum distance of SCs with PST/SPIONs migrating into the astrocyte domain were significantly enhanced by an applied MF. In a 300 MUm row along the astrocyte boundary, the number of SCs with PST/SPIONs migrating into the astrocyte domain under an MF was 2.95 and 6.71 times higher than that in the absence of MF and the intact control SCs, respectively. More interestingly, a confrontation assay demonstrated that SCs with PST/SPIONs were in close contact with astrocytes and no longer formed boundaries in the presence of MF. In conclusion, SCs with PST/SPIONs showed enhanced preferential migration along the axis of a magnetic force, which might be beneficial for the formation of Bungner bands in the CNS. These findings raise the possibilities of enhancing the migration of transplanted SCs in astrocyte-rich CNS regions in a specific direction and creating an SC bridge in the CNS environment to guide regenerated axons to their distal destination in the treatment of SCI. PMID- 28003747 TI - MicroRNA-200c delivered by solid lipid nanoparticles enhances the effect of paclitaxel on breast cancer stem cell. AB - BACKGROUND: One of the major obstacles in the treatment of breast cancer is breast cancer stem cells (BCSC) which are resistant to standard chemotherapeutic drugs. It has been proven that microRNA-200c (miR-200c) can restore sensitivity to microtubule-targeting chemotherapeutic drugs by reducing the expression of class III beta-tubulin. In this study, combination therapy with miR-200c and paclitaxel (PTX) mediated by lipid nanoparticles was investigated as an alternative strategy against BCSC. MATERIALS AND METHODS: A cationic lipid 1,2 dioleoyl-3-trimethylammonium-propane was strategically selected to formulate solid lipid nanoparticles (SLN) for miR-200c delivery. Nanostructured lipid carriers (NLC) with 20 wt% oleic acid were prepared for PTX delivery. Mammospheres, which gained the characteristics of BCSC, were used as a cell model to evaluate the efficiency of combination therapy. RESULTS: The cationic SLN could condense anionic miRNA to form SLN/miRNA complexes via charge interactions and could protect miRNA from degradation by ribonuclease. SLN/miR-200c complexes achieved 11.6-fold expression of miR-200c after incubation for 24 hours, compared with that of LipofectamineTM 2000/miR-200c complexes (*P<0.05). Intracellular drug release assay proved that miRNA can be released from SLN/miRNA complexes efficiently in 12 hours after cellular uptake. After BCSC were transfected with SLN/miR-200c, the expression of class III beta-tubulin was effectively downregulated and the cellular cytotoxicity of PTX-loaded NLC (NLC/PTX) against BCSC was enhanced significantly (**P<0.01). CONCLUSION: The results indicated that the cationic SLN could serve as a promising carrier for miRNA delivery. In addition, the combination therapy of miR-200c and PTX revealed a novel therapeutic strategy for the treatment of BCSC. PMID- 28003749 TI - Associations between dopamine D2 receptor gene polymorphisms and schizophrenia risk: a PRISMA compliant meta-analysis. AB - OBJECTIVE: To determine the relationships between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia using meta-analysis. METHOD: The PubMed, Embase, and China National Knowledge Infrastructure databases were searched to identify relevant literature published up to February 2016. The allele contrast model was used. Stata software was used for statistical analysis, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated to evaluate the associations between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia. Meta-regression and publication bias, trim-and-fill, subgroup, sensitivity, cumulative, and fail-safe number analyses were also performed. RESULTS: This meta-analysis included 81 studies. The rs1801028 and rs1799732 were associated with schizophrenia risk among Asians (P=0.04, OR =1.25, 95% CI =1.01 1.55; P<0.01, OR =0.76, 95% CI =0.63-0.92, respectively), while the rs6277 was associated with schizophrenia risk in Caucasians (P<0.01, OR=0.72, 95% CI =0.66 0.79). The rs1800497 was also associated with schizophrenia risk in population based controls (P<0.01, OR =0.84, 95% CI =0.72-0.97). The rs6275, rs1079597, and rs1800498 were not associated with schizophrenia risk. In addition, meta regression indicated that the controls may be sources of heterogeneity for the rs1801028 single-nucleotide polymorphism (SNP), while ethnicity may be sources of heterogeneity for the rs6277 SNP. Publication bias was significant for the rs1801028 SNP, and this result changed after the publication bias was adjusted using the trim-and-fill method. CONCLUSION: This meta-analysis demonstrated that the rs1801028 may be a risk factor for susceptibility to schizophrenia among Asians, while the rs1799732 may be a protective factor for that population. Large sample studies are necessary to verify the results of this meta-analysis. PMID- 28003750 TI - Baicalein improves behavioral dysfunction induced by Alzheimer's disease in rats. AB - BACKGROUND: Alzheimer's disease (AD) is considered to be a neurodegenerative disorder that is characterized by increased oxidative stress. Medicinal plants, with their antioxidant properties, have been used to cure several human diseases. The aim of the current study was to explore the protective and therapeutic effect of baicalein on AD-induced rats. MATERIALS AND METHODS: Swiss Wistar rats were used in the study. The rats were divided into five groups. Group I: normal control group treated with water; Group II: disease control treated with AlCl3 to induce the mimicking AD for 4 successive weeks (SW); Group III: normal control group treated with baicalein (5 mg/kg) for 2 SW followed by combination of baicalein and AlCl3 for 4 SW; Group IV: normal control group treated with baicalein (10 mg/kg) for 2 SW followed by combination of baicalein and AlCl3 for 4 SW; Group V: normal control group treated with rivastigmine (0.3 mg/kg) for 2 SW followed by combination of rivastigmine and AlCl3 for 4 SW. Moreover, the therapeutic groups are as follows: Group VI: AD disease control treated with AlCl3 for 4 SW and serving as the therapeutic positive group; Group VII: AD disease control + baicalein (5 mg/kg) for 12 SW; Group VIII: AD disease control + baicalein (10 mg/kg) for 12 SW; Group IX: AD disease control + rivastigmine (0.3 mg/kg) for 12 SW. Behavioral test, T-maze, and rotarod test were also performed before and after the treatment. At the end of the experimental study, all the rats were sacrificed and their brains were removed and divided into two portions. The first portion was homogenated for estimating the level of acetylcholinesterase (AchE) and acetylcholine (Ach). Another portion was used for histopathological evaluation. RESULTS: The current investigation showed that baicalein significantly reduced the duration of revolving on the rotarod, cage activity, and T-maze activity in a dose-dependent manner compared with the AD control group rats. It also altered the AchE and Ach levels in the brain homogenates. The histopathology study also provides strength to the protective effect of baicalein. CONCLUSION: The current study showed that baicalein significantly (P<0.05) improved the biochemical and histopathological condition of AD in rats. PMID- 28003751 TI - Effect of dexmedetomidine on hippocampal neuron development and BDNF-TrkB signal expression in neonatal rats. AB - The study aimed to explore the effect of dexmedetomidine (DEX) on hippocampal neuron development process and on molecular expression of brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway in neonatal rats. The hippocampal neuron cells were isolated from newborn neonatal rats and cultured in vitro. One control group and three treated groups with 1, 10, and 100 MUmol/L DEX were used for the study. Cell activity and apoptosis were detected by the MTT and terminal deoxynucleotidyl transferase-mediated biotinylated uridine triphosphate (UTP) nick end labeling assays. The synaptophysin (SYN) and postsynaptic density 95 (PSD95) were detected by quantitative polymerase chain reaction. There was no difference in the viability of neuron cells among the different dose groups of DEX and the control group during days 2-10 (P>0.05). Compared to the control group, there was no significant difference (P>0.05) in the expressions of SYN and PSD95 in the groups treated with 1 and 10 MUmol/L DEX, whereas significant difference in the expression was observed in the group treated with 100 MUmol/L DEX (P<0.01). Compared with the control group, the expression of BDNF was significantly upregulated (P<0.05) in the group treated with 100 MUmol/L DEX. There were no significant differences in TrkB expression among the four groups. The expression of p-N-methyl-D-aspartate receptor increased with an increase in the concentration of DEX; however, only the high dose revealed a significant upregulation compared with the control group. The neuroprotective effect of DEX may be achieved by upregulating the expression of BDNF and phosphorylation level of N-methyl-D-aspartate receptor. PMID- 28003752 TI - Treadmill exercise promotes neuroprotection against cerebral ischemia-reperfusion injury via downregulation of pro-inflammatory mediators. AB - BACKGROUND: Stroke is one of the major causes of morbidity and mortality worldwide, which is associated with serious physical deficits that affect daily living and quality of life and produces immense public health and economic burdens. Both clinical and experimental data suggest that early physical training after ischemic brain injury may reduce the extent of motor dysfunction. However, the exact mechanisms have not been fully elucidated. The aim of this study was to investigate the effects of aerobic exercise on neuroprotection and understand the underlying mechanisms. MATERIALS AND METHODS: Middle cerebral artery occlusion (MCAO) was conducted to establish a rat model of cerebral ischemia-reperfusion injury to mimic ischemic stroke. Experimental animals were divided into the following three groups: sham (n=34), MCAO (n=39), and MCAO plus treadmill exercise (n=28). The effects of aerobic exercise intervention on ischemic brain injury were evaluated using functional scoring, histological analysis, and Bio Plex Protein Assays. RESULTS: Early aerobic exercise intervention was found to improve motor function, prevent death of neuronal cells, and suppress the activation of microglial cells and astrocytes. Furthermore, it was observed that aerobic exercise downregulated the expression of the cytokine interleukin-1beta and the chemokine monocyte chemotactic protein-1 after transient MCAO in experimental rats. CONCLUSION: This study demonstrates that treadmill exercise rehabilitation promotes neuroprotection against cerebral ischemia-reperfusion injury via the downregulation of proinflammatory mediators. PMID- 28003753 TI - The impact of residual symptoms on relapse and quality of life among Thai depressive patients. AB - PURPOSE: Residual symptoms of depressive disorder are major predictors of relapse of depression and lower quality of life. This study aims to investigate the prevalence of residual symptoms, relapse rates, and quality of life among patients with depressive disorder. PATIENTS AND METHODS: Data were collected during the Thai Study of Affective Disorder (THAISAD) project. The Hamilton Rating Scale for Depression (HAMD) was used to measure the severity and residual symptoms of depression, and EQ-5D instrument was used to measure the quality of life. Demographic and clinical data at the baseline were described by mean +/- standard deviation (SD). Prevalence of residual symptoms of depression was determined and presented as percentage. Regression analysis was utilized to predict relapse and patients' quality of life at 6 months postbaseline. RESULTS: A total of 224 depressive disorder patients were recruited. Most of the patients (93.3%) had at least one residual symptom, and the most common was anxiety symptoms (76.3%; 95% confidence interval [CI], 0.71-0.82). After 3 months postbaseline, 114 patients (50.9%) were in remission and within 6 months, 44 of them (38.6%) relapsed. Regression analysis showed that residual insomnia symptoms were significantly associated with these relapse cases (odds ratio [OR] =5.290, 95% CI, 1.42-19.76). Regarding quality of life, residual core mood and insomnia significantly predicted the EQ-5D scores at 6 months postbaseline (B =-2.670, 95% CI, -0.181 to -0.027 and B =-3.109, 95% CI, -0.172 to -0.038, respectively). CONCLUSION: Residual symptoms are common in patients receiving treatment for depressive disorder and were found to be associated with relapses and quality of life. Clinicians need to be aware of these residual symptoms when carrying out follow-up treatment in patients with depressive disorder, so that prompt action can be taken to mitigate the risk of relapse. PMID- 28003754 TI - Associations between the mismatch-negativity component and symptom severity in children and adolescents with attention deficit/hyperactivity disorder. AB - AIM: Cognitive impairment is an important predictor of functional outcome in patients with attention deficit/hyperactivity disorder (ADHD). However, the neurophysiology of ADHD-related cognitive impairments remains unclear. Event related potentials (ERPs) represent the noninvasive measurement of neural correlates of cognitive function. Mismatch negativity (MMN) is an ERP component that is presumed to index the preattentive monitoring of changes in the auditory environment. MATERIALS AND METHODS: Previous studies have shown altered MMN amplitude and latency in patients with ADHD. However, little is known about the relationship between MMN and ADHD-symptom severity. To address this, we measured the amplitude and latency of MMN in ERPs and assessed correlations with the clinical severity of ADHD, as measured by the ADHD Rating Scale IV - Japanese version. Participants were 51 treatment-naive children and adolescents with ADHD (mean age 10.42+/-3.35 years) and 15 normally developing age- and sex-matched children (mean age 11.8+/-3.36 years). RESULTS: In the ADHD group, MMN amplitudes were attenuated at the central electrode and MMN latencies prolonged at the parietal electrode (Pz) relative to those in the control group. Furthermore, MMN amplitudes at Pz were negatively correlated with ADHD full-scale and hyperactivity-impulsivity and inattention subscale scores, and MMN latency at Pz was positively correlated with ADHD hyperactivity-impulsivity subscale scores. CONCLUSION: Our data suggest that MMN reflects the severity of ADHD symptoms in children and adolescents, and provides support for the use of ERPs in evaluating ADHD symptoms in patients. PMID- 28003755 TI - Neuroprotection and acidosis induced by cortical spreading depression. PMID- 28003756 TI - Omega-3 carboxylic acids monotherapy and combination with statins in the management of dyslipidemia. AB - The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management placed greater emphasis on statin therapy given the well established benefits in primary and secondary prevention of cardiovascular disease. Residual risk may remain after statin initiation, in part because of triglyceride-rich lipoprotein cholesterol. Several large trials have failed to show benefit with non-statin cholesterol-lowering medications in the reduction of cardiovascular events. Yet, subgroup analyses showed a benefit in those with hypertriglyceridemia and lower high-density lipoprotein cholesterol level, a high risk pattern of dyslipidemia. This review discusses the benefits of omega-3 carboxylic acids, a recently approved formulation of omega-3 fatty acid with enhanced bioavailability, in the treatment of dyslipidemia both as monotherapy and combination therapy with a statin. PMID- 28003757 TI - Results of a venous thromboembolism prophylaxis program for hospitalized patients. AB - INTRODUCTION: Venous thromboembolism (VTE) is the leading cause of preventable death in hospitalized patients. However, existing prophylaxis guidelines are rarely followed. OBJECTIVE: The aim of the study was to present and discuss implementation strategies and the results of a VTE prophylaxis program for medical and surgical patients admitted to a large general hospital. PATIENTS AND METHODS: This prospective observational study was conducted to describe the strategy used to implement a VTE prophylaxis program in hospitalized medical and surgical patients and to analyze the results in terms of the risk assessment rate within the first 24 hours after admission, adequacy of the prophylaxis prescription, and prevalence of VTE in the discharge records before and after program implementation. We used the Mantel-Haenszel chi-square test for the linear trend of the data analysis and set the significance level to P<0.05. RESULTS: With the support of an institutional VTE prophylaxis committee, a multiple-strategy approach was used in the implementation of the protocol, which included continuing education, complete data recording using computerized systems, and continuous auditing of and feedback to the medical staff and multidisciplinary teams. Approximately 90% of patients were evaluated within the first 24 hours after admission, and no significant difference in this percentage was observed among the years analyzed. A progressive increase in adherence to protocol recommendations, from 63.8% in 2010 to 75.0% in 2014 (P<0.001), was noted. The prevalence of symptomatic VTE in the discharge records of patients decreased from 2.03% in 2009 to 1.69% in 2014 (P=0.033). CONCLUSION: The implementation of a VTE prophylaxis program targeting adult patients admitted to a large hospital employing a multiple-strategy approach achieved high rates of risk assessment within 24 hours of admission, improved the adherence to prophylaxis recommendations in high-risk patients, and reduced the rate of VTE events in the discharge records. PMID- 28003758 TI - BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy. AB - Melanoma is an aggressive malignancy that frequently spreads to the brain, resulting in rapid deterioration in both quality and quantity of life. Historically, treatment options for melanoma brain metastases (MBM) have predominantly consisted of surgery and radiotherapy. While these options can help provide local control, the majority of patients still develop intracranial progression. Indeed, novel therapeutic options, including molecularly targeted agents and immunotherapy, have improved outcomes and are now changing the role of radiotherapy. Up to 50% of melanomas contain an activating BRAF mutation, resulting in hyperactive cellular proliferation and survival. Drugs that target BRAF have been introduced for the treatment of metastatic melanoma and offer hope in improving disease outcomes; however, many of these trials either excluded or had a limited amount of patients with MBM. Recent studies have revealed that melanoma cell lines become more radiosensitive following BRAF inhibition, thus providing a potential synergistic mechanism when combining BRAF inhibitor (BRAFi) and radiotherapy. However, neurotoxicity concerns also exist with this combination. This article reviews the efficacy and limitations of BRAFi therapy for MBM, describes current evidence for combining BRAFis with radiation, discusses the rationale and evidence for combination modalities, and highlights emerging clinical trials specifically investigating this combination in MBM. PMID- 28003759 TI - Omega-3 polyunsaturated fatty acids in the prevention of postoperative complications in colorectal cancer: a meta-analysis. AB - OBJECTIVE: To evaluate systematically the clinical efficacy of omega-3 polyunsaturated fatty acids (PUFAs) in the prevention of postoperative complications in colorectal cancer (CRC) patients. MATERIALS AND METHODS: Published articles were identified by using search terms in online databases - PubMed, Embase, and the Cochrane Library - up to March 2016. Only randomized controlled trials investigating the efficacy of omega-3 PUFAs in CRC were selected and analyzed through a meta-analysis. Subgroup, sensitivity, and inverted funnel-plot analyses were also conducted. RESULTS: Eleven articles with 694 CRC patients were finally included. Compared with control, omega-3 PUFA enriched enteral or parenteral nutrition during the perioperative period reduced infectious complications (risk ratio [RR] 0.63, 95% confidence interval [CI] 0.47 0.86; P=0.004), tumor necrosis factor alpha (standard mean difference [SMD] 0.37, 95% CI -0.66 to -0.07; P=0.01), interleukin-6 (SMD -0.36, 95% CI -0.66 to 0.07; P=0.02), and hospital stay (MD -2.09, 95% CI -3.71 to -0.48; P=0.01). No significant difference was found in total complications, surgical site infection, or CD4+:CD8+ cell ratio. CONCLUSION: Short-term omega-3 PUFA administration was associated with reduced postoperative infectious complications, inflammatory cytokines, and hospital stay after CRC surgery. Due to heterogeneity and relatively small sample size, the optimal timing and route of administration deserve further study. PMID- 28003760 TI - Comparison of the clinical features and hematopoietic stem cell transplantation outcomes of mediastinal malignant germ cell tumors with nonmediastinal extragonadal placements. AB - OBJECTIVE: Even though the primary mediastinal extragonadal germ cell tumors (EGCTs) are rare, they are noteworthy in the differential diagnosis of mediastinal masses. In this study, we aimed to identify the clinical features of mediastinal malignant GCTs and compare the results of hematopoietic stem cell transplantation between mediastinal and nonmediastinal malignant EGCTs. METHOD: Data of the patients with EGCT who were treated and underwent hematopoietic stem cell transplantation at our hospital between 1988 and 2015 were retrieved retrospectively. Results were compared between mediastinal and nonmediastinal EGCTs. RESULTS: Data of 65 patients diagnosed with EGCT (37 [56.92%] cases with mediastinal EGCT and 28 [43.07%] cases with nonmediastinal EGCT) were assessed. The clinical stages, frequency of pretransplant status, mean pretransplant time, and mean number of chemotherapy lines before hematopoietic stem cell transplantation were not significantly different between groups. Although the overall survival did not significantly differ between groups, the 5-year survival was significantly higher in mediastinal EGCTs (P=0.02). Yolk sac tumor was significantly more common in mediastinal EGCTs (P=0.05). Mortality rates were higher in seminomas and yolk sac tumors in all cases, higher in embryonal carcinomas in mediastinal EGCT group and higher in yolk sac tumors in nonmediastinal EGCT group. While choriocarcinomas had more aggressive courses in mediastinal EGCTs, seminomas and yolk sac tumors had poorer prognosis in nonmediastinal EGCTs. Short pretransplant time and persistence of elevated posttransplant betahCG and AFP levels were the significant mortality risk factors both in mediastinal and nonmediastinal EGCTs. CONCLUSION: Mediastinal placement of EGCT was not a poor prognostic factor; furthermore, the 5-year survival was significantly higher in mediastinal EGCTs. According to our knowledge, this is the first study that compares the clinical outcomes of hematopoietic stem cell transplantation of mediastinal and nonmediastinal malignant EGCTs. PMID- 28003761 TI - Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer. AB - BACKGROUND: Nowadays, despite great progress in cancer research, the detailed mechanisms of colorectal cancer (CRC) are still poorly understood. Circular RNAs (circRNAs), a new star of the non-coding RNA network, have been identified as critical regulators in various cancers, including CRC. METHODS AND RESULTS: In this study, by using unsupervised hierarchical clustering analysis, a novel dysregulated circRNA, hsa_circ_0000069, was found. The expression of hsa_circ_0000069 was measured in 30 paired CRC tissues and adjacent noncancerous tissues using quantitative polymerase chain reaction. A high expression of hsa_circ_0000069 was observed in CRC tissues and correlated with patients' age and tumor, node, metastasis (TNM) stage (P<0.05). Furthermore, by using specifically designed siRNAs in CRC cells, a functional analysis was performed which revealed that hsa_circ_0000069 knockdown could notably inhibit cell proliferation, migration, and invasion, and induce G0/G1 phase arrest of cell cycle in vitro. CONCLUSION: This study's findings are the first to demonstrate that hsa_circ_0000069, an important regulator in cancer progression, could be a promising target in the diagnosis and therapy in colorectal cancer. PMID- 28003762 TI - Biomarkers in pancreatic adenocarcinoma: current perspectives. AB - Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19 9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC. PMID- 28003763 TI - Isoorientin induces apoptosis, decreases invasiveness, and downregulates VEGF secretion by activating AMPK signaling in pancreatic cancer cells. AB - Isoorientin (or homoorientin) is a flavone, which is a chemical flavonoid-like compound, and a 6-C-glucoside of luteolin. Isoorientin has been demonstrated to have anti-cancer activities against various tumors, but its effects on pancreatic cancer (PC) have not been studied in detail. In this study, we aim to investigate whether isoorientin has potential anti-PC effects and its underlying mechanism. In PC, isoorientin strongly inhibited the survival of the cells, induced cell apoptosis, and decreased its malignancy by reversing the expression of epithelial mesenchymal transition and matrix metalloproteinase and decreased vascular endothelial growth factor expression. Meanwhile, we investigated the activity of the AMP-activated protein kinase (AMPK) signaling pathway after isoorientin treatment, which was forcefully activated by isoorientin, as expected. In addition, in the PC cells that were transfected with lentivirus to interfere with the expression of the gene PRKAA1, there were no differences in the apoptosis rate and the expression of malignancy biomarkers in the tumors of the isoorientin treated and untreated groups. Thus, we demonstrated that isoorientin has potential antitumor effects via the AMPK signaling pathway, and isoorientin merits further investigation. PMID- 28003764 TI - Correlation between epidermal growth factor receptor tyrosine kinase inhibitor efficacy and circulating tumor cell levels in patients with advanced non-small cell lung cancer. AB - OBJECTIVE: The aim of this study was to investigate the correlation between the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and circulating tumor cell (CTC) levels in patients with advanced non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs in reducing CTC counts in patients with advanced NSCLC was studied. PATIENTS AND METHODS: A total of 66 patients with advanced NSCLC were enrolled and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients' median CTC counts. All the patients were treated with an EGFR-TKI, and the treatment efficacy and prognoses were compared. RESULTS: The treatment efficacies were 53.3% (16/30) and 27.8% (10/36) for the low CTC group and high CTC group, respectively, and this difference was statistically significant (P<0.05). The median overall survival was 22.8 months (95% confidence interval [CI]: 18.9-26.8 months) for the low CTC group and 18.3 months (95% CI: 2.9-8.2 months) for the high CTC group. The median progression-free survival was 11.5 months (95% CI: 8.1 15 months) and 5.6 months (95% CI: 2.9-8.2 months) for the low and high CTC groups, respectively, and the difference was statistically significant (P<0.05). CONCLUSION: The CTC count can be used as an index for predicting the EGFR-TKI effect on patients with advanced NSCLC. Efficacy and prognosis of EGFR-TKI treatment and CTC count were considered important, and the CTC count could be used to predict the efficacy of EGFR-TKI treatment and prognosis of advanced NSCLC. The change in CTC expression levels can be used as an index for evaluating the prognosis of patients with advanced NSCLC. PMID- 28003765 TI - beta-Elemene treatment of glioblastoma: a single-center retrospective study. AB - Glioblastoma (GBM) is the most common primary malignancy in the central nervous system. In this study, we investigated the therapeutic effects of beta-elemene (ELE) treatment in patients with newly diagnosed GBM who received concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide. Our results indicated that compared with control, patients who received ELE showed significantly longer median progression-free survival (PFS) (8 months vs 11 months; P<0.001) and overall survival (OS) (18 months vs 21 months; P<0.001). Despite the O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, ELE treatment could significantly prolong the PFS (P=0.038) and OS (P=0.016). In multivariate analysis, ELE was a significant prognostic factor for PFS (hazard ratio [HR], 0.34; 95% confidence interval [95% CI]: 0.15-0.62; P=0.011) and OS (HR, 0.31; 95% CI: 0.14-0.69; P=0.006). Furthermore, ELE could significantly reduce the hematologic toxicities induced by chemoradiotherapy. In conclusion, ELE might provide a survival benefit in patients with GBM. Further study for verification might be needed. PMID- 28003766 TI - A pilot study employing hepatic intra-arterial irinotecan injection of drug eluting beads as salvage therapy in liver metastatic colorectal cancer patients without extrahepatic involvement: the first southern Italy experience. AB - BACKGROUND: The main aim of this prospective study was to evaluate the efficacy of drug-eluting beads with irinotecan (DEBIRI) for liver metastases from colorectal cancer. Secondary aims were to evaluate survival and toxicity. METHODS: Twenty-five patients with metastases in <50% of the liver and without extrahepatic involvement were enrolled. Treatment response assessment was performed by multidetector contrast enhancement computed tomography (MDCT) with evaluation of the enhancement pattern of the target lesion and tumor response rates according to modified Response Evaluation Criteria in Solid Tumors (mRECIST, Version 1.1). All adverse events were recorded by the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events, Version 3.0. Associations of tumor response and variables were calculated using the chi squared test. Overall survival (OS) was calculated using the Kaplan-Meier method. Comparisons were made using the log-rank test. RESULTS: According to mRECIST, complete response (CR) was observed in 21.8% of patients, partial response (PR) in 13%, stable disease (SD) in 52.2% and progressive disease (PD) in 13% of patients. Response rate (RR = CR + PR) was 34.8%. No associations between treatment response and variables such as Dukes' classification, grading and Kras status were found (P>0.05). The median OS was 37 months (95% CI: 13.881 to 60.119). Cox regression model showed that neither site, Dukes' classification, grading, Kras status nor number of chemotherapy treatments pre-DEBIRI influenced the OS. The log-rank test showed no statistically significant difference in OS among patients who underwent 1, 2 or 3 DEBIRI treatments (chi2=2.831, P=0.09). In our study, the main toxicities included postembolization syndrome (PES), hypertransaminasemia and fever. CONCLUSION: The favorable tumor response and the favorable toxicity profile make DEBIRI treatment a potential third-line therapy. Although further larger studies are needed to confirm these data, we can state that DEBIRI is an attractive emerging treatment in these patients. PMID- 28003767 TI - The benefit of using bladder sub-volume equivalent uniform dose constraints in prostate intensity-modulated radiotherapy planning. AB - BACKGROUND: To assess the benefits of bladder wall sub-volume equivalent uniform dose (EUD) constraints in prostate cancer intensity-modulated radiotherapy (IMRT) planning. METHODS: Two IMRT plans, with and without EUD constraints on the bladder wall, were generated using beams that deliver 80 Gy to the prostate and 46 Gy to the seminal vesicles and were compared in 53 prostate cancer patients. The bladder wall was defined as the volume between the external manually delineated wall and a contraction of 7 mm apart from it. The bladder wall was then separated into two parts: the internal-bladder wall (bla-in) represented by the portion of the bladder wall that intersected with the planning target volume (PTV) plus 5 mm extension; the external-bladder wall (bla-ex) represented by the remaining part of the bladder wall. In the IMRT plan with EUD constraints, the values of "a" parameter for the EUD models were 10.0 for bla-in and 2.3 for bla ex. The plans with and without EUD constraints were compared in terms of dose volume histograms, 5-year bladder and rectum normal tissue complication probability values, as well as tumor control probability (TCP) values. RESULTS: The use of bladder sub-volume EUD constraints decreased both the doses to the bladder wall (V70: 22.76% vs 19.65%, Dmean: 39.82 Gy vs 35.45 Gy) and the 5-year bladder complication probabilities (>=LENT/SOMA Grade 2: 20.35% vs 17.96%; bladder bleeding: 10.63% vs 8.64%). The doses to the rectum wall and the rectum complication probabilities were also slightly decreased by the EUD constraints compared to physical constraints only. The minimal dose and the V76Gy of PTVprostate were, however, slightly decreased by EUD optimization, nevertheless without significant difference in TCP values between the two plans, and the PTV parameters finally respected the Groupe d'Etude des Tumeurs Uro-Genitales recommendations. CONCLUSION: Separating the bladder wall into two parts with appropriate EUD optimization may reduce bladder toxicity in prostate IMRT. Combining biological constraints with physical constraints in the organs at risk at the inverse planning step of IMRT may improve the dose distribution. PMID- 28003768 TI - Symptom profiles of subsyndromal depression in disease clusters of diabetes, excess weight, and progressive cerebrovascular conditions: a promising new type of finding from a reliable innovation to estimate exhaustively specified multiple indicators-multiple causes (MIMIC) models. AB - Addressing subsyndromal depression in cerebrovascular conditions, diabetes, and obesity reduces morbidity and risk of major depression. However, depression may be masked because self-reported symptoms may not reveal dysphoric (sad) mood. In this study, the first wave (2,812 elders) from the New Haven Epidemiological Study of the Elderly (EPESE) was used. These population-weighted data combined a stratified, systematic, clustered random sample from independent residences and a census of senior housing. Physical conditions included progressive cerebrovascular disease (CVD; hypertension, silent CVD, stroke, and vascular cognitive impairment [VCI]) and co-occurring excess weight and/or diabetes. These conditions and interactions (clusters) simultaneously predicted 20 depression items and a latent trait of depression in participants with subsyndromal (including subthreshold) depression (11<= Center for Epidemiologic Studies Depression Scale [CES-D] score <=27). The option for maximum likelihood estimation with standard errors that are robust to non-normality and non independence in complex random samples (MLR) in Mplus and an innovation created by the author were used for estimating unbiased effects from latent trait models with exhaustive specification. Symptom profiles reveal masked depression in 1) older males, related to the metabolic syndrome (hypertension-overweight-diabetes; silent CVD-overweight; and silent CVD-diabetes) and 2) older females or the full sample, related to several diabetes and/or overweight clusters that involve stroke or VCI. Several other disease clusters are equivocal regarding masked depression; a couple do emphasize dysphoric mood. Replicating findings could identify subgroups for cost-effective screening of subsyndromal depression. PMID- 28003769 TI - Chronic radiation-induced dermatitis: challenges and solutions. AB - Chronic radiation dermatitis is a late side effect of skin irradiation, which may deteriorate patients' quality of life. There is a lack of precise data about its incidence; however, several risk factors may predispose to the development of this condition. It includes radiotherapy dose, fractionation, technique, concurrent systemic therapy, comorbidities, and personal and genetic factors. Chronic radiation dermatitis is mostly caused by the imbalance of proinflammatory and profibrotic cytokines. Clinical manifestation includes changes in skin appearance, wounds, ulcerations, necrosis, fibrosis, and secondary cancers. The most severe complication of irradiation is extensive radiation-induced fibrosis (RIF). RIF can manifest in many ways, such as skin induration and retraction, lymphedema or restriction of joint motion. Diagnosis of chronic radiation dermatitis is usually made by clinical examination. In case of unclear clinical manifestation, a biopsy and histopathological examination are recommended to exclude secondary malignancy. The most effective prophylaxis of chronic radiation dermatitis is the use of proper radiation therapy techniques to avoid unnecessary irradiation of healthy skin. Treatment of chronic radiation dermatitis is demanding. The majority of the interventions are based only on clinical practice. Telangiectasia may be treated with pulse dye laser therapy. Chronic postirradiation wounds need special dressings. In case of necrosis or severe ulceration, surgical intervention may be considered. Management of RIF should be complex. Available methods are rehabilitative care, pharmacotherapy, hyperbaric oxygen therapy, and laser therapy. Future challenges include the assessment of late skin toxicity in modern irradiation techniques. Special attention should be paid on genomics and radiomics that allow scientists and clinicians to select patients who are at risk of the development of chronic radiation dermatitis. Novel treatment methods and clinical trials are strongly needed to provide more efficacious therapies. PMID- 28003770 TI - Advances in the management of erythropoietic protoporphyria - role of afamelanotide. AB - Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced quality of life. They are due to marked overproduction of protoporphyrin (PP) chiefly by erythroblasts and reticulocytes. In EPP, the underlying genetic defect is in the ferrochelatase gene, which encodes the final enzyme in the heme synthetic pathway. In XLPP, the genetic defect is a gain-of function mutation, usually a four-base deletion, in the gene that encodes the enzyme 5-aminolevulinic acid synthase-2, the first and rate-controlling enzyme of heme synthesis in developing red blood cells. The excess PP causes acute and painful photosensitivity, being activated by light in the long ultraviolet to blue spectrum (380-420 nm, the Soret band). Although several treatments have been proposed, presently no very effective treatment exists for EPP or XLPP. Afamelanotide (Scenesse(r)) is a first-in-class synthetic analog of alpha melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. This paper provides a review of the clinical characteristics and current therapies for EPP/XLPP. We discuss the pharmacology, clinical efficacy, safety, and tolerability of afamelanotide and summarize the results of several key Phase II and III clinical trials. These data indicate that afamelanotide is a promising therapy for those with these debilitating diseases. PMID- 28003771 TI - Heart rate variability during treatment of breakthrough pain in patients with advanced cancer: a pilot study. AB - BACKGROUND: Decisions on the intensity of analgesic therapy and judgments regarding its efficacy are difficult at the end of life, when many patients are not fully conscious and pain is a very common symptom. In healthy individuals and in postoperative settings, nociception and subsequent pain relief have been shown to induce changes in the autonomic nervous system (ANS), which can be detected by measuring heart rate variability (HRV). OBJECTIVES: The changes in the ANS were studied by measuring HRV during opioid therapy for cancer breakthrough pain (CBTP) in palliative-care patients with cancer and compared these changes with patient-reported pain levels on a numeric rating scale (NRS). PATIENTS AND METHODS: The study included ten patients with advanced cancer and baseline opioid therapy. In each patient, a 24-hour peak-to-peak HRV measurement with a sampling rate of 4,000 Hz was performed. High frequency (HF), low frequency (LF), total power, pNN50 (indicating parasympathetic activity), and log LF/HF were obtained in two intervals prior to therapy and in four intervals thereafter. Intensity of CBTP was recorded using a patient-reported NRS prior to therapy and 30 minutes afterward. RESULTS: CBTP occurred in seven patients (three males and four females; mean age: 62 +/- 5.2 years) and was treated with opioids. A highly significant positive correlation was found between opioid-induced reduction in patient-reported pain intensity based on NRS and changes in log LF/HF (r > 0.700; p < 0.05). Log LF/HF decreased in patients who had a reduction in pain of >2 points on the NRS but remained unchanged in the other patients. CONCLUSION: Our data suggest that log LF/HF may be a useful surrogate marker for alleviation of CBTP in patients with advanced cancer and might allow detection of pain without active contribution from patients. PMID- 28003772 TI - Determinants of institutional delivery service utilization among pastorals of Liben Zone, Somali Regional State, Ethiopia, 2015. AB - Maternal health service utilizations are poorly equipped, inaccessible, negligible, and not well documented in the pastoral society. This research describes a quantitative and qualitative study on the determinants of institutional delivery among pastoralists of Liben Zone with special emphasis on Filtu and Deka Suftu woredas of Somali Region, Ethiopia. The study was funded by the project "Fostering health care for refugees and pastoral communities in Somali Region, Ethiopia". This community-based cross-sectional study was conducted during November 2015. Interviews through a questionnaire and focus group discussions were used to collect the data. Proportional to size allocation followed by systematic sampling technique was used to identify the study units. The major determinants of institutional delivery in the study area were as follows: being apparently healthy, lack of knowledge, long waiting time, poor quality services, cultural beliefs, religious misconception, partner decision, and long travel. Around one-third (133, 34.5%) of the women had visited at least once for their pregnancy. More than half (78, 58.6%) of the women had visited health facilities due to health problems and only 27 (19.9%) women had attended the recommended four antenatal care visits. Majority (268, 69.6%) of the pregnant women preferred to give birth at home. Women who attended antenatal care were two times more likely to deliver at health facilities (AOR, 95% confidence interval [CI] =2.38, 1.065-4.96). Women whose family members preferred health facilities had 14 times more probability to give birth in health institutions (AOR, 95% CI =13.79, 5.28-35.8). Women living in proximity to a health facility were 13 times more likely to give birth at health facilities than women living far away (AOR, 95% CI =13.37, 5.9-29.85). Nomadic way of life, service inaccessibility, and sociodemographic and cultural obstacles have an effect on the utilization of delivery services. Increasing access, information, education, and communication need to reach pastoral women in need. PMID- 28003773 TI - Determinants of pelvic organ prolapse among gynecologic patients in Bahir Dar, North West Ethiopia: a case-control study. AB - INTRODUCTION: Pelvic organ prolapse (POP) is a significant public health problem in developing countries including Ethiopia. However, less has been documented on risk factors of POP. Therefore, the aim of this study was to identify the determinants factors of POP. METHODS: An unmatched case-control study was conducted among gynecologic patients in Bahir Dar city, North West Ethiopia, from July to October 2014. A total of 370 women (selected from outpatient departments) were included in the study. Cases (clients with stage III or IV POP) and controls (who declared free of any stages of POP) were identified by physicians using the Pelvic Organ Prolapse Quantitative Examination tool. Data analysis was carried out by SPSS version 20.0. Descriptive, bivariate, and multivariable logistic regression analyses were performed. Statistical differences were considered at P<0.05, and the strength of association was assessed by odds ratio (OR) and respective confidence intervals (CIs). RESULTS: This study revealed that determinants such as age of women (>40 years) (adjusted OR [AOR] =3.0 [95% CI: 1.59-5.89]), sphincter damage (AOR =8.1 [95% CI: 1.67-39.7]), family history of POP (AOR =4.9 [95% CI: 1.94-12.63]), parity (>=4) (AOR =4.5 [95% CI: 2.26-9.10]), nonattendance of formal education (AOR =4.3 [95% CI: 1.25-14.8]), carrying heavy objects (AOR =3.1 [95% CI: 1.56-6.30]), body mass index (BMI) <18.5 kg/m2 (AOR =3.1 [95% CI: 1.22-7.82]), and delivery assisted by nonhealth professionals (AOR =2.6 [95% CI: 1.24-5.56]) were significantly associated with POP. CONCLUSION: In our study, sphincter damage, family history of POP, being uneducated, having >=4 vaginal deliveries, carrying heavy objects, BMI <18.5 kg/m2, age >=40 years, and having delivery assisted by nonhealth professional were the independent determinants of POP. Therefore, skilled delivery, further promoting family planning and girls' education, early pelvic floor assessment, and counseling on avoidance of carrying heavy objects are recommended. PMID- 28003774 TI - Effectiveness of the multidimensional ergonomic intervention model to reduce musculoskeletal discomfort among street sweepers in Chiang Rai Province, Thailand. AB - The aim of this study was to evaluate the effectiveness of multidimensional ergonomic intervention (MEI) model to reduce musculoskeletal discomfort (MSD) among street sweepers. A quasi-experimental study was conducted in Chiang Rai Province. The MEI model was designed on the basis of four core components: cognitive behavior therapy, ergonomic education training, stretching exercise, and the foam sleeve broom handle grip. Seventy-five street sweepers volunteered for the screening process on MSD of having level score >=4 by physiotherapist. Face to face interviews were used mainly in order to diagnose MSD. Physical examination was performed by physiotherapist and physical performance by sports scientist. The findings showed that the MEI model among the intervention group significantly reduced MSD compared with that among control group at exit model and follow-up (P<0.01). This research suggests that the MEI model was appropriate to reduce MSD associated with repetitive movement and awkward postures on task. PMID- 28003775 TI - The essential role of mentors in medical institutions. PMID- 28003777 TI - Correlation between practice location as a surrogate for UV exposure and practice patterns to prevent corneal haze after photorefractive keratectomy (PRK). AB - BACKGROUND: PRK is a refractive surgery that reshapes the corneal surface by excimer laser photoablation to correct refractive errors. The effect of increased ultraviolet (UV) exposure on promoting post-PRK corneal haze has been reported in the literature; however, information is lacking regarding the effect of ambient UV exposure on physician practice patterns. The aim of this study was to evaluate the effect of ophthalmologists' practice location on their reported practice patterns to prevent post-PRK corneal haze. METHODS: A cross-sectional observational study was conducted through an online survey sent to ophthalmologists performing PRK. The survey recorded the primary city of practice from which the two independent variables, latitude and average annual sunshine days, were determined. It also measured the frequency of use of postoperative preventive interventions (dependent variables) which are as follows: intraoperative Mitomycin-C, oral vitamin C, sunglasses, topical corticosteroids, topical cyclosporine, oral tetracyclines and amniotic membrane graft. RESULTS: Fifty-one ophthalmologists completed the survey. Practice locations' mean latitude was 36.4 degrees north, and average sunshine days annually accounted for 60% of year days. There was no significant relation between latitude/average annual sunshine days and usual post-PRK prophylactic treatments (P > 0.05). The commonest protective maneuvers were sunglasses (78%), prolonged topical corticosteroids (57%), Mitomycin-C (39%) and oral vitamin C (37%). CONCLUSION: We found no significant difference in ophthalmologists' practice patterns to prevent post-PRK corneal haze in relation to practice location latitude and average sunshine days. Moreover, the results demonstrated that the most widely used postoperative measures to prevent post-PRK haze are sunglasses, Mitomycin-C, topical corticosteroids, and oral Vitamin C. PMID- 28003776 TI - Chronic Abdominal Pain in Children and Adolescents: Parental Threat Perception Plays a Major Role in Seeking Medical Consultations. AB - Background. Pain symptoms, associated impairment, and parental perception of threat are reported to be predictors of health care utilization (HCU) in childhood chronic abdominal pain (CAP). However, mediating variables and their interrelations have not yet been systematically studied. Objectives. This study aims to identify mediating pathways of influence between child's abdominal pain and the number of pain-related medical visits. Methods. In a multicenter study, we recruited N = 151 parent-child dyads with children aged 6-17 years suffering from CAP. A composite measure of pain symptoms was defined as predictor and the number of pain-related medical visits as outcome variable. This relation was analyzed by serial mediation, including child- and parent-reported impairment and parental threat perception as mediators. Results. Only parental threat perception significantly linked child's pain symptoms to the number of medical visits. Measures of impairment did not have a significant effect. Conclusions. Parental pain-related threat perception is strongly related to health care seeking in childhood CAP. Addressing threat perception might be a fruitful parent-centered approach in clinical practice. PMID- 28003778 TI - The adjunctive use of pre-operative intravitreal bevacizumab in the setting of proliferative diabetic retinopathy. AB - PURPOSE: To evaluate the efficacy of pre-operative intravitreal bevacizumab injection on the rate of postoperative vitreous hemorrhage in patients undergoing vitrectomy for complications of proliferative diabetic retinopathy. METHODS: Consecutive retrospective comparative cohort study. Forty eyes of 37 patients who received pre-operative intravitreal bevacizumab 1.25 mg were compared to a similar group of 44 eyes of 44 patients who had undergone vitrectomy surgery prior to the availability and widespread use of pre-operative intravitreal bevacizumab. The primary outcome measure was the incidence of post-vitrectomy hemorrhage at one week after surgery. Secondary outcome measures included are postoperative vitreous hemorrhage at one month and changes in the best-corrected visual acuity (BCVA). For statistical analysis, the paired Student's t-test and Fisher's exact test were used. RESULTS: Four out of 40 eyes (10%) pretreated with intravitreal bevacizumab vs. 12 of 44 eyes (27%) not pretreated with intravitreal bevacizumab had a clinically significant postoperative vitreous hemorrhage at one week. The mean best-corrected visual acuity (BCVA) in bevacizumab group improved from a mean of hand motions to a mean of 20/300 at 1 month (range: 20/25-light perception; p < .001) and mean BCVA in the non-injected group improved from preoperative mean of hand motion to 20/200 at one month follow-up (range: 20/25 no light perception; p < .001). In both groups, 4 patients (12%) needed repeat vitrectomy. CONCLUSION: There is a trend to reduced incidence of early post vitrectomy hemorrhage in patients undergoing vitrectomy for complications of proliferative diabetic retinopathy that have been pre-treated with intravitreal bevacizumab 1 week prior to surgery. PMID- 28003779 TI - Pneumatic displacement of submacular haemorrhage. AB - PURPOSE: To evaluate the outcomes of pneumatic displacement of submacular hemorrhage secondary to choroidal neovascular membrane (CNV) (n = 9) and retinal arterial macroaneurysm (RAM) (n = 3). METHODS: This is a retrospective case series study of 12 eyes from 12 patients in Aberdeen Royal Infirmary, Aberdeen, UK. The mean duration of visual loss was 10.8 +/- 4.11 days. All cases received intravitreal injection of expansile gas within 24 h of presentation (C3F8 in 11 cases and SF6 in one case) and postured face down for five days. Anterior chamber paracentesis was done right after gas injection. Intravitreal anti-VEGF was injected at the same time in cases with CNV. Further anti-VEGF injections were done in CNV cases as needed afterwards. Cases were followed up for 6 months. RESULTS: The submacular hemorrhage was successfully displaced from underneath the fovea in all but one case. The bleeding disappeared totally in 44% of cases and was inferiorly displaced in 56%. VA improvement at 6 months was statistically significantly higher than baseline VA. All cases but 2 (one because of subfoveal fibrosis and one because of late presentation) experienced improved VA. The mean VA improved from 1.37 +/- 0.18 logMAR at baseline to 0.83 +/- 0.26 logMAR at 6 months. No complication related to the procedure was reported. CONCLUSION: Pneumatic displacement of submacular hemorrhage appears to be a safe and effective technique to treat the condition. It is an easy procedure that can be done in outpatient setting. Further studies are needed to validate our results. PMID- 28003780 TI - Aflibercept in refractory wet AMD treated with ranibizumab: Anatomical and visual outcome. AB - PURPOSE: To assess the anatomical outcome of patients with exudative age-related macular degeneration resistant to ranibizumab treated with aflibercept. METHOD: Prospective, interventional, case series, where we treated a group of patients deemed resistant to Ranibizumab after 6 months of persistence of intra- or subretinal fluid despite continuous treatment. RESULTS: The study included 17 patients, 3 males and 14 females. The average males age was 85 (range 83-87), and that of females was 79.64 (range 68-88). At the start of the study, the central foveal thickness CFT average was 534.76 MUm (range 252-999). At 1 month and after 1 injection of Aflibercept, the CFT average was 324.82 MUm (range 222-585). At 4 months and after 3 consecutive injections of Aflibercept the CFT average was 294.76 MUm (range 184-640). At 6 months the CFT average was 356 MUm (range 206 609). At the 5th visit only 8 out 17 (47%) patients required repeated injection either for persistent fluids or for recurrence. At the 6th and final visit only 4 out of 17 (23.5%) needed repeated injections, of them only one was treated on the visit before and treatment was given as very little response was observed from last injection, and all other 3 were not treated on the visit before. CONCLUSION: Our results showed that aflibercept was able to dry the macula even in advanced case of wet AMD resistant to Ranibizumab. PMID- 28003781 TI - Evaluation of the acute effect of haemodialysis on retina and optic nerve with optical coherence tomography. AB - PURPOSE: The primary objective of haemodialysis (HD) was to correct the composition and volume of body fluids. The aim of this study was to evaluate the acute effect of HD on mean arterial pressure changes and on retina and optic nerve with optical coherence tomography (OCT). METHODS: Fifty-three eyes of 28 patients were enrolled in this study. The patients' retinal and RNFL thicknesses were measured by OCT and mean arterial pressure alterations were recorded before and immediately after HD session. RESULTS: The results show that while there was a reduction at central foveal thickness and ganglion cell layer thickness, central subfield and RNFL thickness were increased with HD session. But none of them were statistically significant (p = 0.320, p = 0.792, p = 0.744, p = 0.390). The mean arterial pressure of the patients decreased significantly (p < 0.05) but it was not correlated with retinal and RNFL values. CONCLUSION: The changes in retinal and RNFL findings were not significant. But these alterations may effect the long term follow-up of the patients with retinal and optic nerve disease. Therefore it is important to pay attention HD session time for these patients' measurements. PMID- 28003782 TI - Corneal endothelial cell density in healthy Caucasian population. AB - AIM: To reveal the changes of corneal endothelial characteristics with aging among Caucasian population. METHODS: Non-contact specular microscopy was performed in 564 eyes of 282 healthy Caucasian Turkish patients. Endothelial cell density (MCD), mean cell area (MCA), coefficient of variation (CV) in cell size, percentage of hexagonal cells, and central corneal thickness (CCT) were measured. RESULTS: The mean age was 42 +/- 17.1 (6-85) years. The MCD of the population was 2732 +/- 305 cell/mm2 (range, 1904-3802 cell/mm2). The MCA was 368 +/- 41 m2 (range, 263-522 m2). The mean CV in cell size was 34 +/- 7 (range, 25-68), the mean percentage of hexagonal cells was 46 +/- 8% (range, 25-76%), and CCT was 513 +/- 39 (range, 407-623). There was statistically significantly negative correlation (p < 0.05) between age and cell density, hexagonality, and pachymetry. There was statistically significant correlation (p < 0.05) between age and MCA. CONCLUSION: We report the normal values of corneal endothelial characteristics in Caucasian Turkish eyes. Over the age of 20, the MCD of Caucasian eyes is more than the Indian and Iranian eyes and less than the Chinese eyes. Caucasian population's cell density in under the age of 20 is 3101 +/- 268 cell/mm2. PMID- 28003783 TI - Does occlusion therapy improve control in intermittent exotropia? AB - PURPOSE: The aim of this study was to evaluate the effectiveness of occlusion therapy in the control of intermittent exotropia (IXT) in children between 4 and 10 years in Saudi Arabia. This study will highlight the importance of patching IXT patients and assist to approach the proper use of occlusion therapy. METHODS: A clinical, prospective cohort pilot study was performed on 21 untreated IXT patients. Evaluation of the deviation angle, amplitudes, stereopsis and control before, during and after occlusion therapy was performed. RESULTS: Eleven percent of the subjects demonstrated a decrease in the deviation angle by 50% while 55.5% attained normal ranges for base-out fusional amplitudes and 77% attained success for the control. CONCLUSION: We suggest that alternate occlusion therapy can improve the sensory status and strengthen the fusional amplitudes but does not improve the deviation angle and therefore is useful to postpone surgery in young children and may improve surgical outcome. PMID- 28003784 TI - Pros and cons of immediately sequential bilateral cataract surgery (ISBCS). AB - Immediately sequential bilateral cataract surgery (ISBCS) is currently a "hot topic" in ophthalmology. There are well-documented advantages in terms of quicker visual rehabilitation and reduced costs. The risk of bilateral simultaneous endophthalmitis and bilateral blindness is now recognized to be minuscule with the advent of intracameral antibiotics and modern management of endophthalmitis. Refractive surprises are rare for normal eyes and with the use of optical biometry. Where a general anesthetic is indicated for cataract surgery, the risk of death from a second anesthetic is much higher than the risk of blindness. A widely recognized protocol from the International Society of Bilateral Cataract Surgeons needs to be adhered to if surgeons wish to start practicing ISBCS. PMID- 28003785 TI - Central retinal vein occlusion associated with high blood levels of lipoprotein (a).: Is lipoprotein (a) a reliable marker for identification of predisposed individuals? AB - To report a case of central retinal vein occlusion (CRVO) associated with abnormal elevation of Lipoprotein (a) [Lp(a)] plasma levels, without local or systemic risk factors. A 74-year-old man was referred to our department for cataract surgery in his left eye, and his anamnesis was negative for systemic diseases. Two months later, the patient presented with sudden visual loss in his operated eye, and comprehensive ophthalmic examination was performed, including Fluorescein Angiography (FA) and Optical Coherent Tomography (OCT). Serum concentrations of anticardiolipin and antiphospholipids antibodies, homocysteine and Lp(a) were measured. Ophthalmoscopy showed the classic features of acute CRVO, FA and OCT confirmed the initial diagnosis. Blood tests were negative for hyperhomocysteinemia, anticardiolipin and antiphospholipids antibodies, and an abnormal Lp(a) plasma concentration of 1.7 g/L was found. The patient was sent to the internist for further investigation and treatment. Lp(a) can be an useful marker for early identification of predisposed individuals to CRVO and may be involved in its pathogenesis, presumably through its pro-atherogenic and antifibrinolytic action. PMID- 28003786 TI - Accidental macular injury with class IVb laser outside the medical settings. AB - In the medical settings, safety precautions are used to mitigate inadvertent ocular damage due to laser beams. High power lasers are illegal in many countries; however, they are sometimes used on social occasions. Use by an untrained member of the public can result in severe accidental ocular damage. We report a case of macular damage and central visual loss due to the illegal use of a class IVb 2000 mW power laser in a 20-year-old male. To our knowledge, this is the first case of macular injury due to this particular type of laser. The case history and management over a 6-month period is described. Pubic education initiatives are required to increase the awareness of the dangerous nature of laser beam exposure outside a medical setting. PMID- 28003787 TI - Pseudoduplication of the optic disc in moderate myopia. AB - We report a case of optic disc pseudoduplication without pathological myopia. A 79-year-old woman presented with gradually decreased vision. Fundus examination showed macular drusen in both eyes and subretinal haemorrhage in the left eye. Both optic discs appeared to be tilted and the left optic disc was seen to be inferiorly duplicated. Pseudodoubling of the optic discs can be caused by optic disc and peripapillary chorioretinal colobomas and pathological myopia. Considering that our patient did not have enough axial length to merit a diagnosis of pathological myopia and no pathological fundus lesions typical of elongated sclera, we suggest that acquired pseudoduplication is not a condition unique to pathological myopia, but can occur in all myopic patients. The clinical materials, including ophthalmological examination, fundus fluorescent angiography and MRI scan of the orbit, were reported, and its pertinent literatures were reviewed. PMID- 28003788 TI - Multimodal imaging of membranoproliferative glomerulonephritis type II. AB - To report the fundus findings on multimodal imaging of a membranoproliferative glomerulonephritis type II (MPGNII) patient. A 41-year-old woman had a medical history of renal transplantation for MPGNII 5 years prior to presentation to our clinic for ophthalmic examination. Fundus examination showed macular retinal pigment epithelial changes and large peripapillary atrophy in the right eye, and yellowish bilateral drusen-like deposits peripherally. Fundus fluorescein angiography and indocyanine green angiography revealed multifocal hyperfluorescence in the peripheral retina with accompanying deposits. A hyperautofluorescence pattern was seen in the fundus autofluorescence (FAF) images of the deposits. Spectral domain optical coherence tomography (SD-OCT) scans of the drusen-like material showed retinal pigment epithelium (RPE) elevations with moderate hyperreflectivity underneath. Multiple imaging modalities of the posterior segment can provide detailed information about the ocular involvement of MPGNII and help us to confirm the diagnosis and to follow the lesions. PMID- 28003789 TI - An after after-cataract: A curious case of visual axis re-opacification. AB - Posterior capsular opacification (PCO) is common after cataract surgery. Recurrence is very rare after a successful Yttrium aluminium-garnet (YAG) capsulotomy in adults. We report a case of visual axis re-opacification after a successful YAG capsulotomy for PCO in an adult. A 60-year male underwent phacoemulsification with +20.0 D acrylic hydrophobic intraocular lens implantation and silicon oil removal (SOR) five months after a successful retinal detachment repair. He underwent a capsulotomy after two months of surgery; however, the visual axis re-opacified after three more months. A YAG anterior hyaloidotomy resulted into improved vision which was maintained over further follow-up. In a post-vitrectomy pseudophakic eye, compression by silicon oil on the posterior capsule is lost after SOR, causing easier and faster migration of lens epithelial cells from the equator to the centre forming an early PCO. Recurrence is possible due to the proliferation of lens epithelial cells along anterior hyaloid also. This case highlights the infrequent scenario of visual axis re-opacification and therefore has teaching value for residents and trainee doctors, who should be made aware of this occurrence. Patients should be explained about this possibility when undergoing YAG capsulotomy in complicated cases such as this one. PMID- 28003790 TI - Bilateral cataract surgery in a 56-year-old man following presbyopia laser in situ keratomileusis: A case report. AB - We describe a case of bilateral cataract surgery in a 56-year-old man following presbyopia laser in situ keratomileusis. The preoperative refraction was -2.00 in the right eye and -0.75 * 105 in the left eye. On the last examination, the uncorrected distance visual acuity was 20/80 that can be corrected to 20/20 in the right eye with a refraction of -2.25 and 20/20 in the left eye, whereas the visual acuity for reading was 20/40 in the right eye and 20/80 in the left eye with a refraction of +2.25. His monovision surgery design of previous cornea surgery was also taken into consideration for the phacoemulsification and posterior chamber intraocular lens (IOL) implantation. Two-step surgery is helpful for predicting an accurate IOL degree. PMID- 28003791 TI - Accidental detection of an intra-nasal foreign body during probing for congenital nasolacrimal duct obstruction. PMID- 28003792 TI - Earliest datable records of aurora-like phenomena in the astronomical diaries from Babylonia. AB - The astronomical diaries from Babylonia (ADB) are excellent sources of information of natural phenomena, including astronomical ones, in pre-Christ era because it contains the record of highly continuous and systematic observations. In this article, we present results of a survey of aurora-like phenomena in ADB, spanning from BCE 652 to BCE 61. We have found nine records of aurora-like phenomena. Philological and scientific examinations suggest that five of them can be considered as likely candidate for aurora observations. They provide unique information about the solar and aurora activities in the first millennium BCE. Graphical abstract. PMID- 28003793 TI - Visual Semantic Based 3D Video Retrieval System Using HDFS. AB - This paper brings out a neoteric frame of reference for visual semantic based 3d video search and retrieval applications. Newfangled 3D retrieval application spotlight on shape analysis like object matching, classification and retrieval not only sticking up entirely with video retrieval. In this ambit, we delve into 3D-CBVR (Content Based Video Retrieval) concept for the first time. For this purpose, we intent to hitch on BOVW and Mapreduce in 3D framework. Instead of conventional shape based local descriptors, we tried to coalesce shape, color and texture for feature extraction. For this purpose, we have used combination of geometric & topological features for shape and 3D co-occurrence matrix for color and texture. After thriving extraction of local descriptors, TB-PCT (Threshold Based- Predictive Clustering Tree) algorithm is used to generate visual codebook and histogram is produced. Further, matching is performed using soft weighting scheme with L2 distance function. As a final step, retrieved results are ranked according to the Index value and acknowledged to the user as a feedback .In order to handle prodigious amount of data and Efficacious retrieval, we have incorporated HDFS in our Intellection. Using 3D video dataset, we future the performance of our proposed system which can pan out that the proposed work gives meticulous result and also reduce the time intricacy. PMID- 28003794 TI - Synthesis of indium nanoparticles at ambient temperature; simultaneous phase transfer and ripening. AB - The synthesis of size-monodispersed indium nanoparticles via an innovative simultaneous phase transfer and ripening method is reported. The formation of nanoparticles occurs in a one-step process instead of well-known two-step phase transfer approaches. The synthesis involves the reduction of InCl3 with LiBH4 at ambient temperature and although the reduction occurs at room temperature, fine indium nanoparticles, with a mean diameter of 6.4 +/- 0.4 nm, were obtained directly in non-polar n-dodecane. The direct synthesis of indium nanoparticles in n-dodecane facilitates their fast formation and enhances their size monodispersity. In addition, the nanoparticles were highly stable for more than 2 months. The nanoparticles were characterised by dynamic light scattering (DLS), small angle X-ray scattering (SAXS), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS) and Fourier transform infrared (FT-IR) spectroscopy to determine their morphology, structure and phase purity. PMID- 28003795 TI - The effect of size on the strength of FCC metals at elevated temperatures: annealed copper. AB - As the length scale of sample dimensions is reduced to the micron and sub-micron scales, the strength of various materials has been observed to increase with decreasing size, a fact commonly referred to as the 'sample size effect'. In this work, the influence of temperature on the sample size effect in copper is investigated using in situ microcompression testing at 25, 200 and 400 degrees C in the SEM on vacuum-annealed copper structures, and the resulting deformed structures were analysed using X-ray MULaue diffraction and scanning electron microscopy. For pillars with sizes between 0.4 and 4 MUm, the size effect was measured to be constant with temperature, within the measurement precision, up to half of the melting point of copper. It is expected that the size effect will remain constant with temperature until diffusion-controlled dislocation motion becomes significant at higher temperatures and/or lower strain rates. Furthermore, the annealing treatment of the copper micropillars produced structures which yielded at stresses three times greater than their un-annealed, FIB-machined counterparts. PMID- 28003796 TI - A novel targeted/untargeted GC-Orbitrap metabolomics methodology applied to Candida albicans and Staphylococcus aureus biofilms. AB - INTRODUCTION: Combined infections from Candida albicans and Staphylococcus aureus are a leading cause of death in the developed world. Evidence suggests that Candida enhances the virulence of Staphylococcus-hyphae penetrate through tissue barriers, while S. aureus tightly associates with the hyphae to obtain entry to the host organism. Indeed, in a biofilm state, C. albicans enhances the antimicrobial resistance characteristics of S. aureus. The association of these microorganisms is also associated with significantly increased morbidity and mortality. Due to this tight association we hypothesised that metabolic effects were also in evidence. OBJECTIVES: To explore the interaction, we used a novel GC Orbitrap-based mass spectrometer, the Q Exactive GC, which combines the high peak capacity and chromatographic resolution of gas chromatography with the sub-ppm mass accuracy of an Orbitrap system. This allows the capability to leverage the widely available electron ionisation libraries for untargeted applications, along with expanding accurate mass libraries and targeted matches based around authentic standards. METHODS: Optimised C. albicans and S. aureus mono- and co cultured biofilms were analysed using the new instrument in addition to the fresh and spent bacterial growth media. RESULTS: The targeted analysis experiment was based around 36 sugars and sugar phosphates, 22 amino acids and five organic acids. Untargeted analysis resulted in the detection of 465 features from fresh and spent medium and 405 from biofilm samples. Three significantly changing compounds that matched to high scoring library fragment patterns were chosen for validation. CONCLUSION: Evaluation of the results demonstrates that the Q Exactive GC is suitable for metabolomics analysis using a targeted/untargeted methodology. Many of the results were as expected: e.g. rapid consumption of glucose and fructose from the medium regardless of the cell type. Modulation of sugar-phosphate levels also suggest that the pentose phosphate pathway could be enhanced in the cells from co-cultured biofilms. Untargeted metabolomics results suggested significant production of cell-wall biosynthesis components and the consumption of non-proteinaceous amino-acids. PMID- 28003797 TI - BSGE/ESGE guideline on management of fluid distension media in operative hysteroscopy. PMID- 28003798 TI - A patient-preference cohort study of office versus inpatient uterine polyp treatment for abnormal uterine bleeding. AB - Uterine polyps can cause abnormal bleeding in women. Conventional practise is to remove them under general anaesthesia but advances in technology have made it possible to perform polypectomy in the office setting. We conducted a patient preference study to explore women's preferences for treatment setting and to evaluate the effectiveness and treatment experience of women undergoing uterine polypectomy. Three hundred ninety-nine women with abnormal uterine bleeding who were found to have uterine polyps at diagnostic hysteroscopy were recruited. Office polypectomies were performed in office hysteroscopy clinics, and inpatient procedures were undertaken in operating theatres. Three hundred twenty-four of 399 (81 %) expressed a preference for office treatment. There was no difference found between office treatment and inpatient treatment in terms of alleviating abnormal uterine bleeding as assessed by patients and in improving disease specific quality of life. Acceptability was lower and patient pain scores were significantly higher in the office group. When offered a choice of treatment setting for uterine polypectomy, patients have a preference for office over inpatient treatment. Ambulatory gynaecology services should be available within healthcare systems to meet patient demand. PMID- 28003799 TI - Ergonomics of laparoscopic graspers and the importance of haptic feedback: the surgeons' perspective. AB - Haptic feedback is drastically reduced in laparoscopic surgery compared to open surgery. Introducing enhanced haptic feedback in laparoscopic instruments might well improve surgical safety and efficiency. In the design process of a laparoscopic grasper with enhanced haptic feedback, handle design should be addressed to strive for optimal usability and comfort. Additionally, the surgeons' perspective on the potential benefits of haptic feedback should be assessed to ascertain the clinical interest of enhanced haptic feedback. A questionnaire was designed to determine surgeons' use and preferences for laparoscopic instruments and expectations about enhanced haptic feedback. Surgeons were also asked whether they experience physical complaints related to laparoscopic instruments. The questionnaire was distributed to a group of laparoscopic surgeons based in Europe. From the 279 contacted subjects, 98 completed the questionnaire (response rate 35 %). Of all respondents, 77 % reported physical complaints directly attributable to the use of laparoscopic instruments. No evident similarity in the main preference for graspers was found, either with or without haptic feedback. According to respondents, the added value of haptic feedback could be of particular use in feeling differences in tissue consistencies, feeling the applied pressure, locating a tumor or enlarged lymph node, feeling arterial pulse, and limiting strain in the surgeon's hand. This study stresses that the high prevalence of physical complaints directly related to laparoscopic instruments among laparoscopic surgeons is still relevant. Furthermore, the potential benefits of enhanced haptic feedback in laparoscopic surgery are recognized by laparoscopic specialists. Therefore, haptic feedback is considered an unmet need in laparoscopy. PMID- 28003800 TI - Retention of laparoscopic psychomotor skills after a structured training program depends on the quality of the training and on the complexity of the task. AB - This follow-up RCT was conducted to evaluate laparoscopic psychomotor skills retention after finishing a structured training program. In a first study, 80 gynecologists were randomly allocated to four groups to follow different training programs for hand-eye coordination (task 1) with the dominant hand (task 1-a) and the non-dominant hand (task 1-b) and laparoscopic intra-corporeal knot tying (task 2) in the Laparoscopic Skills Testing and Training (LASTT) model. First, baseline skills were tested (T1). Then, participants trained task 1 (G1: 1-a and 1-b, G2: 1-a only, G3 and G4: none) and then task 2 (all groups but G4). After training all groups were tested again to evaluate skills acquisition (T2). For this study, 2 years after a resting period, 73 participants were recruited and tested again to evaluate skills retention (T3). All groups had comparable skills at T1 for all tasks. At T2, G1, G2, and G3 improved their skills, but the level of improvement was different (G1 = G2 > G3 > G4 for task 1; G1 = G2 = G3 > G4 for task 2). At T3, all groups retained their task 1 skills at the same level than at T2. For task 2, however, a skill decay was already noticed for G2 and G3, being G1 the only group that retained their skills at the post-training level. Training improves laparoscopic skills, which can be retained over time depending on the comprehensiveness of the training program and on the complexity of the task. For high complexity tasks, full training is advisable for both skills acquisition and retention. PMID- 28003801 TI - Deep infiltrating endometriosis affecting the urinary tract-surgical treatment and fertility outcomes in 2004-2013. AB - Urinary tract endometriosis (UTE) is a rare form of deep infiltrating endometriosis. We studied the operative treatment of UTE and evaluated postoperative recurrences and fertility outcomes. This is a retrospective cohort study of 53 women who underwent operative treatment for UTE in 2004-2013 at Helsinki University Hospital, and were followed-up until the end of 2014. The data were gathered from the hospital's electronic database. The main outcome measures were complications, reoperations, postoperative pregnancies, and deliveries. Preoperative diagnosis was accurate in 72 % with bladder endometriosis and in 93 % with ureteral disease. Thirty-one (58 %) of the 53 operations were performed via laparoscopy. Postoperative complications requiring re-intervention occurred in five cases (9 %). Five reoperations were performed in four cases due to endometriosis recurrence, only two due to recurrence of UTE (4 %). Twenty-eight women wished for pregnancy; 18 (64 %) of them conceived. Infertility treatment was needed in 20 (71 %) cases. Twelve (75 %) women delivered via cesarean section; intraoperative difficulties occurred in ten (83 %). The complication rate with UTE operations is acceptable and recurrences are rare. Infertility is common, but 57 % of those who wished for a child succeeded. A majority of the deliveries involved unplanned and complicated cesarean section. PMID- 28003802 TI - Restricted Feeding Schedules Modulate in a Different Manner the Expression of Clock Genes in Rat Hypothalamic Nuclei. AB - Food access restriction is associated to changes in gene expression of the circadian clock system. However, there are only a few studies investigating the effects of non-photic synchronizers, such as food entrainment, on the expression of clock genes in the central oscillators. We hypothesized that different feeding restriction patterns could modulate the expression of clock genes in the suprachiasmatic nucleus (SCN) "master" clock and in extra-SCN oscillators such as the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei. Wistar rats were divided into four groups: Control group (CG; food available ad libitum), Restricted night-fed (RF-n; food access during 2 h at night), Restricted day-fed (RF-d; food access during 2 h at daytime), Day-fed (DF; food access during 12 h at daytime). After 21 days, rats were decapitated between ZT2-ZT3 (0800-0900 h); ZT11-ZT12 (1700-1800 h), or ZT17-18 (2300-2400 h). Plasma corticosterone was measured by radioimmunoassay (RIA). The expression of Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, Rev-erbalpha, and Roralpha were assessed in SCN, PVN, and ARC hypothalamic nuclei by RT-PCR and calculated by the 2[ DeltaDeltaCT(Cyclethreshold)](2-DeltaDeltaCT) method. Restricted food availability during few h led to decreased body weight in RF-n and RF-d groups compared to controls and DF group. We also observed an anticipatory corticosterone peak before food availability in RF-n and RF-d groups. Furthermore, the pattern of clock gene expression in response to RF-n, RF-d, and DF schedules was affected differently in the SCN, PVN, and ARC hypothalamic nuclei. In conclusion, the master oscillator in SCN as well as the oscillator in PVN and ARC, all brain areas involved in food intake, responds in a tissue specific manner to feeding restriction. PMID- 28003803 TI - Affective Priming by Eye Gaze Stimuli: Behavioral and Electrophysiological Evidence. AB - The present study employed the affective priming paradigm and measurements of event-related potentials (ERPs) to investigate implicit affective reactions elicited by gaze stimuli. Participants categorized positive and negative words primed by direct gaze, averted gaze and closed eyes. The behavioral response time (RT) results indicated that direct gaze implicitly elicited more positive affective reactions than did closed eyes. Analyses of the ERP responses to the target words revealed a priming effect on the N170 and an interaction on late positive potential (LPP) responses, and congruently with the behavioral results, suggested that, compared to closed eyes, direct gaze was affectively more congruent with positive words and more incongruent with negative words. The priming effect on the N170 response indicated that gaze stimuli influenced the subsequent affective word processing at an early stage of information processing. In conclusion, the present behavioral and electrophysiological evidence suggests that direct gaze automatically activates more positive affective reactions than closed eyes. PMID- 28003804 TI - Golden Needle Mushroom: A Culinary Medicine with Evidenced-Based Biological Activities and Health Promoting Properties. AB - Flammulina velutipes (enoki, velvet shank, golden needle mushroom or winter mushroom), one of the main edible mushrooms on the market, has long been recognized for its nutritional value and delicious taste. In recent decades, research has expanded beyond detailing its nutritional composition and delved into the biological activities and potential health benefits of its constituents. Many bioactive constituents from a range of families have been isolated from different parts of the mushroom, including carbohydrates, protein, lipids, glycoproteins, phenols, and sesquiterpenes. These compounds have been demonstrated to exhibit various biological activities, such as antitumour and anticancer activities, anti-atherosclerotic and thrombosis inhibition activity, antihypertensive and cholesterol lowering effects, anti-aging and antioxidant properties, ability to aid with restoring memory and overcoming learning deficits, anti-inflammatory, immunomodulatory, anti-bacterial, ribosome inactivation and melanosis inhibition. This review aims to consolidate the information concerning the phytochemistry and biological activities of various compounds isolated from F. velutipes to demonstrate that this mushroom is not only a great source of nutrients but also possesses tremendous potential in pharmaceutical drug development. PMID- 28003805 TI - Glioblastoma Stem-Like Cells: Characteristics, Microenvironment, and Therapy. AB - Glioblastoma multiforme (GBM), grade IV astrocytoma, is the most fatal malignant primary brain tumor. GBM contains functional subsets of cells called glioblastoma stem-like cells (GSCs), which are radioresistant and chemoresistant and eventually lead to tumor recurrence. Recent studies showed that GSCs reside in particular tumor niches that are necessary to support their behavior. To successfully eradicate GBM growth and recurrence, new strategies selectively targeting GSCs and/or their microenvironmental niche should be designed. In this regard, here we focus on elucidating the molecular mechanisms that govern these GSC properties and on understanding the mechanism of the microenvironmental signals within the tumor mass. Moreover, to overcome the blood-brain barrier, which represents a critical limitation of GBM treatments, a new drug delivery system should be developed. Nanoparticles can be easily modified by different methods to facilitate delivery efficiency of chemotherapeutics, to enhance the accumulation within the tumors, and to promote the capacity for targeting the GSCs. Therefore, nanotechnology has become the most promising approach to GSC targeting therapy. Additionally, we discussed the future of nanotechnology-based targeted therapy and point out the disadvantages that should be overcome. PMID- 28003806 TI - Psychological Disorders and Ecological Factors Affect the Development of Executive Functions: Some Perspectives. AB - The links between deficits in executive functions (EFs) (e.g., mental flexibility, inhibition capacities, etc.) and some psychological disorders (e.g., anxiety and depressive disorders) have been investigated in the past decades or so. Observations evidenced that some deficits in working memory, planning, and mental flexibility were highly correlated with anxiety and depressive disorders. The majority of studies focused on adults' population, whereas it seems important to adopt a developmental perspective to fully understand the dynamic relation of these EF/psychological disorders. We suggest to focus on the following two axes in future research: (i) relations between EF and anxiety traits through development and (ii) the possible role of external factors such as parent-child relationships on the development of EF. PMID- 28003807 TI - Corrigendum: Unmet Needs in the Management of Cervical Dystonia. AB - [This corrects the article on p. 165 in vol. 7, PMID: 27733842.]. PMID- 28003808 TI - Microbiome Selection Could Spur Next-Generation Plant Breeding Strategies. AB - "No plant is an island too..." Plants, though sessile, have developed a unique strategy to counter biotic and abiotic stresses by symbiotically co-evolving with microorganisms and tapping into their genome for this purpose. Soil is the bank of microbial diversity from which a plant selectively sources its microbiome to suit its needs. Besides soil, seeds, which carry the genetic blueprint of plants during trans-generational propagation, are home to diverse microbiota that acts as the principal source of microbial inoculum in crop cultivation. Overall, a plant is ensconced both on the outside and inside with a diverse assemblage of microbiota. Together, the plant genome and the genes of the microbiota that the plant harbors in different plant tissues, i.e., the 'plant microbiome,' form the holobiome which is now considered as unit of selection: 'the holobiont.' The 'plant microbiome' not only helps plants to remain fit but also offers critical genetic variability, hitherto, not employed in the breeding strategy by plant breeders, who traditionally have exploited the genetic variability of the host for developing high yielding or disease tolerant or drought resistant varieties. This fresh knowledge of the microbiome, particularly of the rhizosphere, offering genetic variability to plants, opens up new horizons for breeding that could usher in cultivation of next-generation crops depending less on inorganic inputs, resistant to insect pest and diseases and resilient to climatic perturbations. We surmise, from ever increasing evidences, that plants and their microbial symbionts need to be co-propagated as life-long partners in future strategies for plant breeding. In this perspective, we propose bottom-up approach to co propagate the co-evolved, the plant along with the target microbiome, through - (i) reciprocal soil transplantation method, or (ii) artificial ecosystem selection method of synthetic microbiome inocula, or (iii) by exploration of microRNA transfer method - for realizing this next-generation plant breeding approach. Our aim, thus, is to bring closer the information accrued through the advanced nucleotide sequencing and bioinformatics in conjunction with conventional culture-dependent isolation method for practical application in plant breeding and overall agriculture. PMID- 28003810 TI - Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis. AB - Clematichinenoside AR (C-AR) is a triterpene saponin isolated from the root of Clematis manshurica Rupr., which is a herbal medicine used in traditional Chinese medicine for the treatment of arthritis. C-AR exerts anti-inflammatory and immunosuppressive properties, but little is known about its action in the suppression of fibroblast activation. Low oxygen tension and transforming growth factor-beta (TGF-beta1) induction in the synovium contribute to fibrosis in arthritis. This study was designed to investigate the effect of C-AR on synovial fibrosis from the aspects of hypoxic TGF-beta1 and hypoxia-inducible transcription factor-1alpha (HIF-1alpha) induction. In the synovium of rheumatoid arthritis (RA) rats, hypoxic TGF-beta1 induction increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1alpha induction. In response to NLRP3 inflammasome activation, the released IL-1beta further increased TGF-beta1 induction, suggesting the forward cycle between inflammation and fibrosis in myofibroblast activation. In the synovium of RA rats, C-AR inhibited hypoxic TGF-beta1 induction and suppressed succinate-associated NLRP3 inflammasome activation by inhibiting SDH activity, and thereby prevented myofibroblast activation by blocking the cross-talk between inflammation and fibrosis. Taken together, these results showed that succinate worked as a metabolic signaling, linking inflammation with fibrosis through NLRP3 inflammasome activation. These findings suggested that synovial succinate accumulation and HIF-1alpha induction might be therapeutical targets for the prevention of fibrosis in arthritis. PMID- 28003809 TI - Cytotoxic CD4 T Cells: Differentiation, Function, and Application to Dengue Virus Infection. AB - Dengue virus (DENV) has spread through most tropical and subtropical areas of the world and represents a serious public health problem. The control of DENV infection has not yet been fully successful due to lack of effective therapeutics or vaccines. Nevertheless, a better understanding of the immune responses against DENV infection may reveal new strategies for eliciting and improving antiviral immunity. T cells provide protective immunity against various viral infections by generating effector cells that cooperate to eliminate antigens and memory cells that can survive for long periods with enhanced abilities to control recurring pathogens. Following activation, CD8 T cells can migrate to sites of infection and kill infected cells, whereas CD4 T cells contribute to the elimination of pathogens by trafficking to infected tissues and providing help to innate immune responses, B cells, as well as CD8 T cells. However, it is now evident that CD4 T cells can also perform cytotoxic functions and induce the apoptosis of target cells. Importantly, accumulating studies demonstrate that cytotoxic CD4 T cells develop following DENV infections and may play a crucial role in protecting the host from severe dengue disease. We review our current understanding of the differentiation and function of cytotoxic CD4 T cells, with a focus on DENV infection, and discuss the potential of harnessing these cells for the prevention and treatment of DENV infection and disease. PMID- 28003811 TI - Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn's Disease and Ulcerative Colitis. AB - BACKGROUND: Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: We conducted a prospective study of U.S. women enrolled in the Nurses' Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case-control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naive and memory T cells, differentiated with TGFbeta1 or TH17 conditions. RESULTS: Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naive and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells. CONCLUSION: Dietary potassium is inversely associated with risk of CD with both in vitro and gene-environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway. PMID- 28003814 TI - The Selective Estrogen Receptor Modulator Raloxifene Inhibits Neutrophil Extracellular Trap Formation. AB - Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effects on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs). Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ERalpha and ERbeta, known targets of raloxifene. Similar to raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA-induced ERK phosphorylation, but not reactive oxygen species production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistant Staphylococcus aureus. Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production. PMID- 28003813 TI - Context-Specific and Immune Cell-Dependent Antitumor Activities of alpha1 Antitrypsin. AB - alpha1-antitrypsin (AAT), a circulating glycoprotein that rises during acute phase responses and healthy pregnancies, exhibits immunomodulatory properties in several T-cell-dependent immune pathologies. However, AAT does not directly interfere with T-cell responses; instead, it facilitates polarization of macrophages and dendritic cells towards M2-like and tolerogenic cells, respectively. AAT also allows NK cell responses against tumor cells, while attenuating DC-dependent induction of autoimmune NK cell activities. Since AAT treated macrophages bear resemblance to cancer-promoting tumor-associated macrophages (TAMs), it became imperative to examine the possible induction of tumor permissive conditions by AAT. Here, AAT treatment is examined for its effect on tumor development, metastatic spread, and tumor immunology. Systemic AAT treatment of mice inoculated with B16-F10 melanoma cells resulted in significant inhibition of tumor growth and metastatic spread. Using NK cell resistant RMA cells, we show that AAT interferes with tumor development in a CD8+ T-cell-dependent manner. Unexpectedly, upon analysis of tumor cellular composition, we identified functional tumor-infiltrating CD8+ T-cells alongside M1-like TAMs in AAT-treated mice. Based on the ability of AAT to undergo chemical modifications, we emulated conditions of elevated reactive nitrogen and oxygen species. Indeed, macrophages were stimulated by treatment with nitrosylated AAT, and IFNgamma transcripts were significantly elevated in tumors extracted soon after ischemia-reperfusion challenge. These context-specific changes may explain the differential effects of AAT on immune responses towards tumor cells versus benign antigenic targets. These data suggest that systemically elevated levels of AAT may accommodate its physiological function in inflammatory resolution, without compromising tumor-targeting immune responses. PMID- 28003812 TI - Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses. AB - BACKGROUND: Semaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development. METHODS: Human tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C-/- mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation were analyzed by confocal microscopy. RESULTS: Gene array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24 h, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C-/- mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ human B-cells. Within 72 h of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F actin, B-cell receptor, and Plexin-B2. Cell polarization was impaired in Sema4C-/ mice. CONCLUSION: We have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles. PMID- 28003815 TI - Degranulation Response in Cytotoxic Rat Lymphocytes Measured with a Novel CD107a Antibody. AB - Measuring degranulation through CD107a expression has become an advantageous tool for testing the functional capacity of cytotoxic cells. Such functional studies have been hampered in the rat by the lack of a suitable anti-rat CD107a antibody. In this study, we report a novel hybridoma generated by immunizing Armenian inbred hamsters with transfected Chinese hamster ovary cells expressing CD107a. The SIM1 clone exhibited specific reactivity with CD107a and measured degranulation from natural killer (NK) cells stimulated with target cells or mAb crosslinking of their activating receptors. Degranulation in IL-2-activated NK cells could also be measured, when using low effector to target ratios. SIM1 also stained activated CD8, but not CD4 T cells. This report characterizes the degranulation response in cytotoxic rat cells with a new antibody against rat CD107a. PMID- 28003817 TI - Corrigendum: Increased Permeability of the Aquaporin SoPIP2;1 by Mercury and Mutations in Loop A. AB - [This corrects the article on p. 1249 in vol. 7, PMID: 27625657.]. PMID- 28003818 TI - Nanoparticle-aided Radiotherapy for Retinoblastoma and Choroidal Melanoma. AB - This work investigates the dosimetric feasibility of employing gold nanoparticles (AuNPs) or carboplatin nano-particles (CNPs) to enhance radiotherapy (RT) treatment efficacy for ocular cancers: retinoblastoma (Rb) and choroidal melanoma (CM), during kV-energy internal and external beam radiotherapy. The results predict that substantial dose enhancement may be achieved by employing AuNPs or CNPs in conjunction with radiotherapy for ocular cancer using kV-energy photon beams. Brachytherapy sources yield higher dose enhancement than the external beam in kV energy range. However, the external beam has the advantage of being non invasive. PMID- 28003816 TI - HLA Mismatching Strategies for Solid Organ Transplantation - A Balancing Act. AB - HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant. However, other factors such as donor age, donor type, and immunosuppression protocol, can affect the benefit derived from matching. Furthermore, finding a well-matched donor may not be possible for all patients and usually prolongs waiting time. Strategies to optimize transplantation for patients without a well-matched donor should take into account the immunologic barrier represented by different mismatches: what are the least immunogenic mismatches considering the patient's HLA phenotype; should repeated mismatches be avoided; is the patient sensitized to HLA and, if so, what are the strengths of the patient's antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor population through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor. PMID- 28003819 TI - Clinicomycological Characterization of Superficial Mycoses from a Tertiary Care Hospital in Nepal. AB - Background. Superficial mycosis is a common fungal infection worldwide, mainly caused by dermatophytes. However, the prevalence of species varies geographically. In addition, fungal treatment is best guided according to species isolated. This study was carried out to determine the clinical as well as mycological profile of superficial mycoses in a tertiary care hospital, Nepal. Methods. This was a prospective case-control laboratory based study conducted over a period of six months from January to June 2014 at Tribhuvan University Teaching Hospital, Nepal. A total of 200 specimens were collected from the patients suspected of superficial mycoses. The specimens were macroscopically as well as microscopically examined. The growth was observed up to 4 weeks. Results. Out of total 200 specimens from the patients suspected of superficial mycoses, tinea corporis 50 (25%) was most common clinical types. KOH mount was positive in 89 (44.5%) and culture was positive in 111 (55.5%). Trichophyton mentagrophytes 44 (39.6%) was the most common isolate. Conclusions. The diagnostic yields of KOH mount and culture were found to be complementary to each other. Thus both the methods added with clinical findings are equally important to establish superficial mycosis. PMID- 28003821 TI - The Use of Complementary and Alternative Medicine among Patients with Inflammatory Bowel Disease Is Associated with Reduced Health-Related Quality of Life. AB - Background and Aims. Complementary and alternative medicine (CAM) use among patients with inflammatory bowel disease (IBD) is common. The aim of this study was to explore associations between CAM use and health-related quality of life (HRQoL) as well as identifying whether sociodemographic factors, disease activity, and personal resources (self-efficacy) influence HRQoL scores in users and nonusers of CAM. Methods. Measures included sociodemographic and disease related data, the International-CAM Questionnaire, and General Self-Efficacy Scale. A univariate analysis of variance was used to assess the association between CAM use and HRQoL. The associations between clinical, demographic, and personal factors and HRQoL were examined through linear regression analyses. Results. CAM users had statistically significant lower SF-36 scores compared to nonusers and the background population. Nonusers scored significantly lower compared to the background population in two out of the eight SF-36 dimensions. Independent of CAM use, disease activity had a negative impact and self-efficacy had a positive impact on HRQoL. Conclusions. HRQoL in CAM users with IBD was significantly lower compared to nonusers and the background population. Independent of CAM use, disease activity was negatively associated with HRQoL. Self-efficacy had a positive impact on the mental health dimensions in both CAM users and nonusers. PMID- 28003820 TI - Feasibility and Efficacy of S-Adenosyl-L-methionine in Patients with HBV-Related HCC with Different BCLC Stages. AB - Aims. To understand the feasibility and efficacy of treatment with SAMe in patients with hepatitis B-related HCC with different Barcelona Clinic Liver Cancer (BCLC) stages. Methods. We retrospectively enrolled 697 patients with BCLC early-stage (stages 0-A) and advanced-stage (stages B-C) HCC who underwent SAMe therapy (354 cases) or no SAMe therapy (343 cases). The baseline characteristics, postoperative recoveries, and 24-month overall survival rates of the patients in the 2 groups were compared. Cox regression model analysis was performed to confirm the independent variables influencing the survival rate. Results. For patients in the early-stage (BCLC stages A1-A4) group, little benefit of SAMe therapy was observed. For advanced-stage (BCLC B-C) patients, SAMe therapy reduced alanine aminotransferase (ALT) and aspartate transaminase (AST) levels and effectively delayed the recurrence time and enhanced the 24-month survival rate. Cox regression model analysis in the advanced-stage group revealed that treatment with SAMe, preoperative viral load, and Child-Pugh grade were independent variables influencing survival time. Conclusion. SAMe therapy exhibited protective and therapeutic efficacy for BCLC advanced-stage HBV-related HCC patients. And the efficacy of SAMe therapy should be further explored in randomized prospective clinical trials. PMID- 28003822 TI - Guy's Stone Score (GSS) Based on Intravenous Pyelogram (IVP) Findings Predicting Upper Pole Access Percutaneous Nephrolithotomy (PCNL) Outcomes. AB - Objective. To predict the success rate and complications following percutaneous nephrolithotomy via the upper pole using the Guy's Stone Score (GSS) based on the findings of a preoperative intravenous pyelogram (IVP). Patients and Methods. Two hundred and twenty-seven renal operations, which were carried out using PCNL via the upper pole, were classified according to the GSS assigned. Any complications were classified according to the Clavien classification. The success rates and incidence of any complications were compared between each GSS. Results. The immediate success rates were 87.50% of GSS1, 71.43% of GSS2, 53.62% of GSS3, and 38.46% of GSS4, P < 0.01. There were statistically significant differences between the groups in stone size, overall immediate success rate, operative time, number of access tracts, and frequency of tubeless PCNL. Major complications (a Clavien score of 3-5) were significantly higher in the cases with a higher GSS. Conclusion. A GSS based on an IVP is a simple and reliable tool in predicting the success rate and possible complications following upper pole access PCNL. PMID- 28003824 TI - Accuracy of the One-Stage and Two-Stage Impression Techniques: A Comparative Analysis. AB - Introduction. One of the main steps of impression is the selection and preparation of an appropriate tray. Hence, the present study aimed to analyze and compare the accuracy of one- and two-stage impression techniques. Materials and Methods. A resin laboratory-made model, as the first molar, was prepared by standard method for full crowns with processed preparation finish line of 1 mm depth and convergence angle of 3-4 degrees . Impression was made 20 times with one-stage technique and 20 times with two-stage technique using an appropriate tray. To measure the marginal gap, the distance between the restoration margin and preparation finish line of plaster dies was vertically determined in mid mesial, distal, buccal, and lingual (MDBL) regions by a stereomicroscope using a standard method. Results. The results of independent test showed that the mean value of the marginal gap obtained by one-stage impression technique was higher than that of two-stage impression technique. Further, there was no significant difference between one- and two-stage impression techniques in mid buccal region, but a significant difference was reported between the two impression techniques in MDL regions and in general. Conclusion. The findings of the present study indicated higher accuracy for two-stage impression technique than for the one stage impression technique. PMID- 28003823 TI - Larger Thyroid Volume and Adequate Iodine Nutrition in Chinese Schoolchildren: Local Normative Reference Values Compared with WHO/IGN. AB - Objective. Thyroid volume measured by ultrasound to define goiter needs reliable local thyroid volume reference from iodine-sufficient populations. The aim of this study is to explore the reference interval for normal thyroid volume in schoolchildren aged 8-10 years from Zhejiang Province, China. Methods. A probability-proportionate-to-size sampling method was applied to select a representative sample of 1213 children aged 8-10 years in Zhejiang Province to detect the thyroid volume, salt iodine, and urine iodine. Results. Median urinary iodine concentration in involved schoolchildren was 178.30 (125.00) MUg l-1, with the percentage of samples less than 100 MUg l-1 as 12.69% and more than 300 MUg l 1 as 15.25%. Thyroid volume was significantly correlated with age and anthropometric measurements independently of each other. The 97th percentile of thyroid volume in our study was larger generally than the new international reference. Conclusions. The iodine nutritional status in Zhejiang Province was at an adequate level. Despite some limitations in this study, we initially established the reference values for thyroid volume in 8-10-year-old schoolchildren in Zhejiang Province, China, as a local reference to be used for monitoring iodine deficiency disorders. PMID- 28003826 TI - Pericardial Effusion due to Primary Malignant Pericardial Mesothelioma: A Common Finding but an Uncommon Cause. AB - This case report describes a 37-year-old female who was admitted to our Emergency Department because of shortness of breath. On physical examination, she had dyspnea and tachycardia and blood pressure was 80/50 mmHg with a pulsus paradoxus of 22 mmHg. Neck veins were distended, heart sounds were distant, and dullness was found on both lung bases. Her chest X-ray revealed bilateral pleural effusion and cardiomegaly. On both computed tomography and echocardiography the heart was of normal size and a large pericardial effusion was noted. The echocardiogram showed signs of impending tamponade, so the patient underwent an emergent pericardiocentesis. No infectious etiology was found and she was assumed to have viral pericarditis and was treated accordingly. However, when the pericardial effusion recurred and empirical therapy for tuberculosis failed, a pericardial window was performed. A typical staining pattern for mesothelioma was found on her pericardial biopsy specimen. Since no other mesodermal tissue was affected, a diagnosis of primary malignant pericardial mesothelioma was made. Chemotherapy was not effective and she passed away a year after the diagnosis was made. This case highlights the difficulties in diagnosing this uncommon disease in patients that present with the common finding of pericardial effusion. PMID- 28003825 TI - Endometrial Volume Measured by VOCAL Compared to Office Hysteroscopy for Diagnosis of Endometrial Polyps in Premenopausal Women with Abnormal Uterine Bleeding. AB - The aim is to compare hysteroscopy, two-dimensional transvaginal ultrasound (2D TVUS), and three-dimensional (3D) Virtual Organ Computer-aided AnaLysisTM (VOCAL) to detect endometrial polyps (EPs) in premenopausal women with abnormal uterine bleeding (AUB). This prospective study was done at Ain Shams Maternity Hospital, Egypt, from March 5, 2015, to December 30, 2015, enrolling 118 premenopausal women with AUB. 2D TVUS, 3D VOCAL, and hysteroscopy were done. 109 patients reached final analysis. 36 women (33%) were diagnosed with EP by 2D TVUS. 50 (45.9%) had EP by hysteroscopy. Endometrial thickness was 10.1 mm by 2D TVUS and endometrial volume was 4.92 mL by VOCAL in women with EP by hysteroscopy compared to 9.9 mm and 3.50 mL in women with no EP, respectively (P = 0.223; P = 0.06). 2D TVUS has sensitivity, specificity, and positive and negative predictive values of 54%, 84.7%, 75%, and 68.5%, respectively. Endometrial thickness of >7.5 mm has sensitivity, specificity, positive and negative predictive values, and overall accuracy of 82%, 37.3%, 52.6%, 71%, and 57.8%, respectively. Endometrial volume of >1.2 mL has sensitivity, specificity, positive and negative predictive values, and overall accuracy of 90%, 42.4%, 57%, 83.3%, and 64.2%, respectively. 3D VOCAL may be used as a noninvasive method for the diagnosis of EP in premenopausal women with AUB. PMID- 28003827 TI - When the Patient Believes That the Organs Are Destroyed: Manifestation of Cotard's Syndrome. AB - Cotard's Syndrome (CS) is a rare clinical event described for the first time in 1880 by the neurologist and psychiatrist Jules Cotard and characterized by negation delusions (or nihilists). Immortality and hypochondriac delusions are also typical. Nowadays, it is known that CS can be associated with many neuropsychiatric conditions. In this article, we describe the case of a patient that believed not having more organs and having the body deformed and whose CS was associated with a bigger depressive disorder. Although the electroconvulsive therapy is the most described treatment modality in the literature, the reported case had therapeutic success with association of imipramine and risperidone. PMID- 28003828 TI - Volar Locking Plate Breakage after Nonunion of a Distal Radius Osteotomy. AB - We report a 38-year-old male with a nonunion followed by plate breakage after volar plating of a distal radius osteotomy. Volar locking plates have added a new approach to the treatment of distal radius malunions, due to a lower morbidity of the surgical approach and the strength of the final construction, allowing early mobilization and return to function. Conclusion. Plate breakage is an uncommon complication of volar locking plate fixation. To our knowledge, few cases have been described after a distal radius fracture and no case has been described after a distal radius corrective osteotomy. In the present case, plate breakage appears to have occurred as a result of a combination of multiple factors as the large corrective lengthening osteotomy, the use of demineralized bone matrix instead of bone graft, and the inappropriate fixation technique as an unfilled screw on the osteotomy site, rather than the choice of plate. PMID- 28003829 TI - Cardiac Arrest as a Consequence of Air Embolism: A Case Report and Literature Review. AB - Air embolism is an infrequent but potentially catastrophic complication. It could be a complication of invasive procedures including surgery, central line placement, positive pressure ventilation, trauma, hemodialysis, pacemaker placement, cardiac ablation, and decompression sickness. Usually, it does not cause any hemodynamic complication. In rare cases, it could lodge in the heart and cause cardiac arrest. We present a case of an 82-year-old white female who underwent computed tomography (CT) guided biopsy of right lung pulmonary nodule. When she was turned over after the lung biopsy, she became unresponsive and developed cardiopulmonary arrest. She underwent successful resuscitation and ultimately was intubated. CT chest was performed immediately after resuscitation which showed frothy air dense material in the left atrium and one of the right pulmonary veins suggesting a Broncho venous fistula with air embolism. Although very rare, air embolism could be catastrophic resulting in cardiac arrest. Supportive care including mechanical ventilation, vasopressors, volume resuscitation, and supplemental oxygen is the initial management. Patients with cardiac, neurological, or respiratory complications benefit from hyperbaric oxygen therapy. PMID- 28003830 TI - Epididymal Adenomatoid Tumor: A Very Rare Paratesticular Tumor of Childhood. AB - Adenomatoid tumor is an uncommon benign mesothelial neoplasm, usually localized in the epididymis. It is the most common paratesticular tumor of middle-aged patients (average age of clinical presentation: 36 years). However, these tumors in pediatric and pubertal patients are extremely rare. Due to their rarity, we present a case of adenomatoid tumor of the tail of the epididymis in a 16-year old patient. After systematic research of the current literature, we did not find another case report of epididymal adenomatoid tumor in a male patient aged 16 years old or less. This notice and our concern, as well, about the patient's surveillance protocol during the postoperative period were the motive for this case study. PMID- 28003831 TI - In Vitro Osteogenic Potential of Green Fluorescent Protein Labelled Human Embryonic Stem Cell-Derived Osteoprogenitors. AB - Cellular therapy using stem cells in bone regeneration has gained increasing interest. Various studies suggest the clinical utility of osteoprogenitors-like mesenchymal stem cells in bone regeneration. However, limited availability of mesenchymal stem cells and conflicting evidence on their therapeutic efficacy limit their clinical application. Human embryonic stem cells (hESCs) are potentially an unlimited source of healthy and functional osteoprogenitors (OPs) that could be utilized for bone regenerative applications. However, limited ability to track hESC-derived progenies in vivo greatly hinders translational studies. Hence, in this study, we aimed to establish hESC-derived OPs (hESC-OPs) expressing green fluorescent protein (GFP) and to investigate their osteogenic differentiation potential in vitro. We fluorescently labelled H9-hESCs using a plasmid vector encoding GFP. The GFP-expressing hESCs were differentiated into hESC-OPs. The hESC-OPsGFP+ stably expressed high levels of GFP, CD73, CD90, and CD105. They possessed osteogenic differentiation potential in vitro as demonstrated by increased expression of COL1A1, RUNX2, OSTERIX, and OPG transcripts and mineralized nodules positive for Alizarin Red and immunocytochemical expression of osteocalcin, alkaline phosphatase, and collagen I. In conclusion, we have demonstrated that fluorescently labelled hESC-OPs can maintain their GFP expression for the long term and their potential for osteogenic differentiation in vitro. In future, these fluorescently labelled hESC OPs could be used for noninvasive assessment of bone regeneration, safety, and therapeutic efficacy. PMID- 28003832 TI - Identification of CHD1L as an Important Regulator for Spermatogonial Stem Cell Survival and Self-Renewal. AB - Chromodomain helicase/ATPase DNA binding protein 1-like gene (Chd1l) participates in chromatin-dependent processes, including transcriptional activation and DNA repair. In this study, we have found for the first time that Chd1l is mainly expressed in the testicular tissues of prepubertal and adult mice and colocalized with PLZF, OCT4, and GFRalpha1 in the neonatal mouse testis and THY1+ undifferentiated spermatogonia or spermatogonial stem cells (SSCs). Knockdown of endogenous Chd1l in cultured mouse undifferentiated SSCs inhibited the expression levels of Oct4, Plzf, Gfralpha1, and Pcna genes, suppressed SSC colony formation, and reduced BrdU incorporation, while increasing SSC apoptosis. Moreover, the Chd1l gene expression is activated by GDNF in the cultured mouse SSCs, and the GDNF signaling pathway was modulated by endogenous levels of Chd1l; as demonstrated by the gene expression levels of GDNF, inducible transcripts Etv5, Bcl6b, Pou3f, and Lhx1, but not that of GDNF-independent gene, Taf4b, were significantly downregulated by Chd1l knockdown in mouse SSCs. Taken together, this study provides the first evidence to support the notion that Chd1l is an intrinsic and novel regulator for SSC survival and self-renewal, and it exerts such regulation at least partially through a GDNF signaling pathway. PMID- 28003833 TI - Combined MSC and GLP-1 Therapy Modulates Collagen Remodeling and Apoptosis following Myocardial Infarction. AB - Background. Mesenchymal stem cells (MSCs) and glucagon-like peptide-1 (GLP-1) are being tested as treatment strategies for myocardial infarction (MI); however, their mechanisms in the heart are not fully understood. Methods. We examined the effects of MSCs, either native, or engineered to secrete a GLP-1 fusion protein (MSCs +/- GLP-1), on human cardiomyocyte apoptosis in vitro. The effect on cardiac remodeling when encapsulated in alginate beads (CellBeads-MSC and CellBeads-MSC + GLP-1) was also evaluated in a pig MI model, whereby pigs were treated with Empty Beads, CellBeads-MSC, or CellBeads-MSC + GLP-1 and sacrificed at one or four weeks following MI. Results. MSC + GLP-1 conditioned media demonstrated antiapoptotic effects on ischaemic human cardiomyocytes in vitro. In vivo, qRT-PCR revealed large changes in the expression of several genes involved in extracellular matrix remodeling, which were altered following MSC +/- GLP treatment. After four weeks, infarcted areas were imaged using atomic force microscopy, demonstrating significant alterations between groups in the structure of collagen fibrils and resulting scar. Conclusions. These data demonstrate that MSCs +/- GLP-1 exhibit modulatory effects on healing post-MI, affecting both apoptosis and collagen scar formation. These data support the premise that both MSCs and GLP-1 could be beneficial in MI treatment. PMID- 28003834 TI - Discharge against Medical Advice at Neonatal Intensive Care Unit in Gujarat, India. AB - Objective. We explored reasons for discharged against medical advice (DAMA) of neonates from a neonatal intensive care unit (NICU) through in-depth interviews of the parents/guardians. Methods. Of 456 babies admitted to NICU during April 2014 to March 2015, 116 babies were DAMA. Parents of randomly selected 50 babies of these 116, residing within 50 kilometers, were approached for in-depth interviews at their homes. Audio recordings were done and manually transcribed, analyzed in detail to explore common threads leading to DAMA. Basic demographic information of the newborns was retrieved from hospital records. Results. The prevalence of DAMA was 25.4%. Of 50 parents approached, 41 in-depth interviews were completed. Nonaffordability (38.6%), no improvement (14.6%), poor prognosis (12%), and inappropriate behavior of the patient relation office personnel (10.6%) were major factors contributing to DAMA. Parents of 6.6% neonates wanted guarantee of survival and 5.3% parents reported poor behavior of nurses. No gender bias was observed related to DAMA. One-third of neonates (34.1%) were DAMA on first day of admission. Conclusions. The issue of DAMA needs attention. Besides nonaffordability and clinical characteristics of the baby, communication (breaking bad news, counseling, etc.) and lack of adequate infrastructure for relatives emerged as modifiable factors leading to DAMA. PMID- 28003835 TI - A Citizen-Science Study Documents Environmental Exposures and Asthma Prevalence in Two Communities. AB - A citizen-science study was conducted in two low-income, flood-prone communities in Atlanta, Georgia, in order to document environmental exposures and the prevalence of occupant asthma. Teams consisting of a public-health graduate student and a resident from one of the two communities administered a questionnaire, inspected residences for mold growth, and collected a dust sample for quantifying mold contamination. The dust samples were analyzed for the 36 molds that make up the Environmental Relative Moldiness Index (ERMI). Most residents (76%) were renters. The median duration of residence was 2.5 years. Although only 12% of occupants reported a history of flooding, 46% reported at least one water leak. Homes with visible mold (35%) had significantly (P < 0.05) higher mean ERMI values compared to homes without (14.0 versus 9.6). The prevalence of self-reported, current asthma among participants was 14%. In logistic regression models controlling for indoor smoking, among participants residing at their current residence for two years or less, a positive association was observed between asthma and the homes' ERMI values (adjusted odds ratio per unit increase in ERMI = 1.12, 95% confidence intervals (CI): 1.01-1.25; two tailed P = 0.04). Documentation of the exposures and asthma prevalence has been presented to the communities and public officials. Community-based organizations have taken responsibility for planning and implementing activities in response to the study findings. PMID- 28003836 TI - Dramatic improvement in dissolution rate of albendazole by a simple, one-step, industrially scalable technique. AB - Low solubility and dissolution rate are the primary challenges in the drug development which substantially impact the oral absorption and bioavailability of drugs. Due to the poor water solubility, Albendazole (ABZ) is poorly absorbed from the gastrointestinal tract and shows low oral bioavailability (5%) which is a major disadvantage for the systemic use of ABZ. To improve the solubility and dissolution rate of ABZ, different classes of hydrophilic excipients such as sugars (lactose, sucrose, and glucose), polyols (mannitol and sorbitol), ionic surfactant (sodium lauryl sulfate) and non-ionic surfactant (Cremophor A25) were co-spray dried with ABZ. The crystallinity changes in the processed drug were characterized by differential scanning calorimetry and X-Ray diffraction methods were used to interpret the enhanced solubility and dissolution rate of the drug. Results showed that the solubility and dissolution rate of ABZ were increased 1.8 2.6 folds and 3-25 folds, respectively. Unexpectedly, SLS decreased the solubility index of drug powder even lower than the unprocessed drug which was attributed to drug-SLS ionic interaction as depicted from Fourier transform infrared spectroscopy. It was concluded that by applying the facile, one-step, industrially scalable technique and the use of small amounts of excipient (only 4% of the formulation), a great improvement (21 folds) in dissolution rate of ABZ was achieved. This finding may be used in the pharmaceutical industries for the formulation of therapeutically efficient dosage forms of class II and IV drugs classified in biopharmaceutical classification system. PMID- 28003837 TI - A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors. AB - In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600EB-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site. PMID- 28003838 TI - Anxiolytic-like effect of hydroalcoholic extract of ripe pistachio hulls in adult female Wistar rats and its possible mechanisms. AB - The present study was designed to study the preventive effect of hydroalcoholic extract of ripe pistachio hulls (RPH) in the elevated plus maze model of anxiety. One hundred twenty female wistar rats in their estrous cycle were divided into 15 groups of 8 each and received various concentrations of hydroalcoholic extract of RPH except the control groups. Elevated plus maze was used to measure the level of anxiety. Percentage of time spent in the open arms (%OAT), percentage of the number of entries into the open arms (%OAE), locomotor activity, and time spent in the closed arms (CAT), and the number of entries in to the closed arms (CAE) were measured and compared. Dose-response experiments showed that only 10 mg/kg dose of RPH extract significantly increased %OAT (P < 0.001) and %OAE (P < 0.05) compared to the control group, indicating anti-anxiety effects of the extract. Also, pentylenetetrazol and an estrogen receptor antagonist (ERA) tamoxifen could block anti-anxiety effects of the extract (P < 0.001). It was also noticed that tamoxifen was able to significantly reduce locomotor activity. As the RPH extract showed a preventive effect in experimental model of anxiety, it might be concomitantly administered with other anxiolytic medications. PMID- 28003839 TI - Twin arginine translocation system in secretory expression of recombinant human growth hormone. AB - Recombinant protein production in E. coli has several advantages over other expression systems. Misfolding, inclusion body formation, and lack of eukaryotic post translational modification are the most disadvantages of this system. Exporting of correctly folded proteins to the outside of reductive cytoplasmic environment through twin-arginine system could help to pass these limiting steps. Two signal sequences, TorA and SufI are used at N-terminal of human growth hormone (hGH) bearing DsbA gene sequence at C-terminal to enhance folding. The synthetic cassettes including the signal sequence, hGH and DsbA were transformed into E. coli BL21 (DE3) to study the effect of signal sequence and DsbA chaperone on translocation and folding of the protein. The results confirmed using signal sequence at N-terminal of targeted protein and coexpression with DsbA could transport proteins to the periplasmic space and culture media compared to control groups. Although there is no protein band of somatropin in SDS-Page of culture media samples when using SufI as signaling sequence, the study demonstrated TorA signal sequence could transport the target protein to the culture media. However, there was a considerable amount of hGH in periplasmic space when using SufI compared to control. PMID- 28003840 TI - Lovastatin prevents bleomycin-induced DNA damage to HepG2 cells. AB - Lovastatin as a member of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors is used as a lipid-lowering agent. It can also inhibit the formation of hydrogen peroxide and superoxide anion and finally leads to decline in oxidative stress processes. Here, we evaluated whether lovastatin can increase DNA damage resistance of HepG2 cells against genotoxicity of the anticancer drug bleomycin (BLM). HepG2 cells were incubated with different concentrations of lovastatin (0.1, 0.5, 1, 5 uM) before exposure to BLM (0.5 ug/mL for one h). The genotoxic dose of BLM and lovastatin was separately determined and comet assay was used to evaluate the genotoxicity. After trapping cells in agarose coated lames, they were lysed and the electrophoresis was done in alkaline pH, then colored and monitored by florescent microscope. The results of this study indicated that lovastatin in doses lower than 5 uM has genoprotective effect and in doses higher than 50 uM is genotoxic. In conclusion, lovastatin is able to protect genotoxic effects of BLM in HepG2 cells. Further studies are needed to elucidate the mechanism(s) involved in this process. PMID- 28003841 TI - Cytotoxic effects of Pinus eldarica essential oil and extracts on HeLa and MCF-7 cell lines. AB - Several attempts have so far been made in the search of new anticancer agents of plant origin. Some studies have reported that different species of Pine genus possess cytotoxic activities against various cancer cell lines. In the present study, we evaluated the cytotoxic effects of Pinus eldarica bark and leaf extracts or leaf essential oil on HeLa and MCF-7 tumor cell lines. Hydroalcoholic and phenolic extracts and the essential oil of plant were prepared. Total phenolic contents of the extracts were measured using Folin-Ciocalteu reagent. Essential oil components were determined by gas chromatography-mass spectroscopy (GC-MS). Cytotoxic activity of the extracts and essential oil against HeLa and MCF-7 tumor cell lines were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The polyphenolic content of hydroalcoholic and phenolic extracts of the bark and hydroalcoholic extract of the leaf were 48.31%, 47.2%, and 8.47%, respectively. According to the GC-MS analysis, the major components of the leaf oil of P. eldarica were: beta -caryophyllene (14.8%), germacrene D (12.9%), alpha-terpinenyl acetate (8.15%), alpha -pinene (5.7%), and -alpha humulene (5.9%). Bark extracts and leaf essential oil of P. eldarica significantly reduced the viability of both HeLa and MCF-7 cells in a concentration dependent manner. However, leaf extract showed less inhibitory effects against both cell lines. The essential oil of P. eldarica was more cytotoxic than its hydroalcoholic and phenolic extracts. The terpenes and phenolic compounds were probably responsible for cytotoxicity of P. eldarica. Therefore, P. eldarica might have a good potential for active anticancer agents. PMID- 28003843 TI - Spasmodic versus spasmolytic activities of Euphorbia spinidens extract on rat isolated uterus. AB - Preterm contraction of uterus is a main cause of miscarriages and preterm labour. Euphorbia known as Ferphion in Iranian traditional medicine texts like Al-Hawi, is reported for prevention of preterm labour. Therefore, the objective of this research was to investigate the effect of Euphorbia spinidens Bornm. Ex Prokh. on motility of rat uterus. Uterine horns were isolated form non-pregnant female rats pretreated with estrogen. E. spinidens hydroalcoholic extract was examined on KCl (80 mM) induced and spontaneous periodic contraction in isolate uterine strips suspended in an organ bath and compared with nifedipine and ritodrine. In isolated rat uterine strips, E. spinidens extract (1-500 ug/mL) showed mixed effects. At lower concentrations, firstly potentiated the spontaneous periodic contraction, while in concentrations above 256 ug/mL the spontaneous periodic contractions were completely attenuated. These findings demonstrated that although lower concentrations of hydroalcoholic extract potentiated the spontaneous periodic contraction of rat uterine smooth muscle, but at higher concentrations it had inhibitory effect on rat uterus contraction. PMID- 28003842 TI - Biomimetic proopiomelanocortin suppresses capsaicin-induced sensory irritation in humans. AB - Sensitive skin is a frequently mentioned cosmetic complaint. Addition of a biomimetic of neuromediator has recently appeared as a promising new way to cure skin care product problems. This study was aimed to assess the inhibitory effect of a biomimetic lipopeptide derived from proopiomelanocortin (bPOMC) on capsaicin induced sensory irritation in human volunteers and also to compare its protective effect with that of the well-known anti irritant strontium chloride. The effect of each test compound was studied on 28 selected healthy volunteers with sensitive skin in accordance with a double-blind vehicle-controlled protocol. From day 1 to day 13 each group was applied the test compound (bPOMC or strontium chloride) to one wing of the nose and the corresponding placebo (vehicle) to the other side twice daily. On days 0 and 14, acute skin irritation was induced by capsaicin solution and quantified using clinical stinging test assessments. Following the application of capsaicin solution, sensory irritation was evaluated using a 4-point numeric scale. The sensations perceived before and after treatment (on days 0 and 14) was calculated for the two zones (test materials and vehicle). Ultimately the percentage of variation between each sample and the placebo and also the inhibitory effect of bPOMC compared to that of strontium chloride were reported. Clinical results showed that after two weeks treatment, the levels of skin comfort reported in the group treated with bPOMC were significantly higher than those obtained in the placebo group and the inhibitory effect of bPOMC was about 47% higher than that of strontium chloride. The results of the present study support the hypothesis that biomimetic peptides may be effective on sensitive skin. PMID- 28003844 TI - Antihypertensive effects of new dihydropyridine derivatives on phenylephrine raised blood pressure in rats. AB - Changes in the substitutions at C-3 and C-5 positions of 4-(1-methyl-5-nitro-2 imidazolyl) dihydropyridine analogs of nifedipine have led to changes in potency of the compounds. The objective of the present study was to examine the hypotensive effects of 5 newly synthesized dihydropyridine derivatives of nifedipine in rats with phenylephrine-raised blood pressure. Anesthetized Sprague Dawley rats were randomly assigned to 19 groups of 7 animals each. Control group received the vehicle dimethylsulfoxide (0.05 mL), 3 groups were given nifedipine at 100, 300, or 1000 MUg/kg, and 5 other groups each composed of 3 subgroups administered one of the 5 new dihydropyridine compound at 100, 300, or 1000 MUg/kg. All animals were initially infused with 20 ug/kg/min phenylephrine for 45 min, and were then given a bolus of either dimethylsulfoxide, nifedipine, or new dihydropyridine compounds 20 min after the commencement of phenylephrine infusion. Blood pressure and heart rate (HR) of the animals were measured before and at the end of phenylephrine infusion, or 25 min after injection of vehicle or compounds. Compared to dimethylsulfoxide, nifedipine, and new 1, 4 dihydropyridine derivatives caused significant reductions in MBP. Moreover, cyclohexyl propyl, phenyl butyl, and cyclohexyl methyl analogs of 1, 4-dihydro 2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazoyl)-3,5-pyridinedicarboxylase at 100 MUg/kg, phenyl butyl, and cyclohexyl methyl analogs at 300 MUg/kg, and cyclohexyl methyl analogs at 1000 MUg/kg reduced MBP similar to nifedipine. There was no significant difference between HR of all groups before and after administration of the compounds. The findings indicated that changes in substitution at C-3 and C-5 positions of 2-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine were associated with changes in hypotensive activity of the compounds. PMID- 28003845 TI - All-trans retinoic acid and genistein induce cell apoptosis in OVCAR-3 cells by increasing the P14 tumor suppressor gene. AB - In this study, we evaluated the effects of all-trans retinoic acid (ATRA) alone or in combination with genistein (GEN) in p14 tumor suppressor gene and subsequent apoptosis of human ovarian carcinoma cells (OVCAR-3). The cells were treated with ATRA or GEN at concentrations of 50 and 25 MUM respectively, either alone or in combination for 24 and 48 h. The cell viability was evaluated using 3 (4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The percentage of cell apoptosis was determined using flow cytometry and p14 gene expression was measured using real time PCR. The MTT results showed that in both ATRA and GEN treated groups, the cell viabilityviability in group treated for 48 h was significantly lower than group treated for 24 h. The flow cytometry results showed that the percentage of apoptotic cells in groups that treated with ATRA and GEN in combination for 24 h and 48 h was significantly more than all other tested groups. The real time results showed that the mRNA level of p14 in cells treated with both drugs for 48 h was significantly higher than all other groups. In conclusion, we confirm that GEN in combination with ATRA is an effective strategy to up regulate the p14 tumor suppressor gene and induce cell apoptosis in OVCAR-3 cell line. PMID- 28003846 TI - Paeoniflorin Attenuated Oxidative Stress in Rat COPD Model Induced by Cigarette Smoke. AB - Paeoniflorin (PF), a monoterpene glucoside, might have an effect on the oxidative stress. However, the mechanism is still unknown. In this study, we made the COPD model in Sprague-Dawley (SD) rats by exposing them to the smoke of 20 cigarettes for 1 hour/day and 6 days/week, for 12 weeks, 24 weeks, or 36 weeks. Our findings suggested that smoke inhalation can trigger the oxidative stress from the very beginning. A 24-week treatment of PF especially in the dosage of 40 mg/kg.d can attenuate oxygen stress by partially quenching reactive oxygen species (ROS) and upregulating antioxidant enzymes via an Nrf2-dependent mechanism. PMID- 28003847 TI - In Vitro Protective Effect of Phikud Navakot Extraction on Erythrocyte. AB - Phikud Navakot (PN), Thai herbal remedy in National List of Essential Medicines, has been claimed to reduce many cardiovascular symptoms especially dizziness and fainting. Apart from blood supply, erythrocyte morphology, in both shape and size, is one of the main consideration factors in cardiovascular diseases and may be affected by vascular oxidative stress. However, little is known about antioxidative property of PN on erythrocyte to preserve red blood cell integrity. In this study, 1,000 MUM hydrogen peroxide-induced oxidative stress was conducted on sheep erythrocyte. Three doses of PN (1, 0.5, and 0.25 mg/mL) and 10 MUM of ascorbic acid were compared. The released hemoglobin absorbance was measured to demonstrate hemolysis. Electron microscopic and immunohistochemical studies were also performed to characterize dysmorphic erythrocyte and osmotic ability in relation to aquaporin- (AQP-) 1 expression, respectively. The results revealed that all doses of PN and ascorbic acid decreased the severity of dysmorphic erythrocyte, particularly echinocyte, acanthocyte, knizocyte, codocyte, clumping, and other malformations. However, the most effective was 0.5 mg/mL PN dosage. In addition, hydrostatic pressure may be increased in dysmorphic erythrocyte in association with AQP-1 upregulation. Our results demonstrated that PN composes antioxidative effect to maintain the integrity and osmotic ability on sheep erythrocyte. PMID- 28003848 TI - Acupuncture for Smoking Cessation in Hong Kong: A Prospective Multicenter Observational Study. AB - This was a prospective multicenter observational study, aiming to explore the effects of acupuncture on smoking cessation in Hong Kong. From March of 2010 to August of 2015, a total of 5202 smokers were recruited based on inclusion criteria and treated with acupuncture for 8 weeks. As a result, 2940 subjects finished the study with a drop-out rate of 43.48%. The self-reported 7-day point abstinence rate was 34.00% in Week 8 and 18.40% in Week 52. The exhaled carbon monoxide level and the number of cigarettes smoked per day were reduced significantly after treatment. The time to relapse was calculated to be 38.71 days. In addition, "cigarettes smoked per day," "Fagerstrom Test for Nicotine Dependence," "total sessions of acupuncture," "whether finished 8 acupuncture treatments in the first month," and "total sessions of acupuncture" were believed to be essential factors for abstinence success. It was concluded that acupuncture was a safe method for smoking cessation and was effective in helping smokers to quit; therefore, acupuncture could be considered as one of the methods to help smokers quit. Further studies regarding the effect differences between acupuncture and medications were needed to clarify the overall benefits of acupuncture. PMID- 28003849 TI - Conifer Green Needle Complex in Patients with Precancerous Gastric Lesions: An Observational Pilot Study. AB - Objectives. Helicobacter pylori infection is common and can lead to precancerous gastric lesions. Standard antibiotic therapy has a failure rate of more than 25% from antibiotic resistance. The primary aim of this observational pilot study was to test the feasibility of a large-scale clinical trial of Conifer Green Needle Complex (CGNC) to treat precancerous gastric lesions. Secondary aims were to investigate H. pylori infection, stomach function, and histopathology of the gastric mucosa. Methods. A tablet form of CGNC (extracted from Pinus sylvestris and Picea abies (L) Karst) was prescribed to 26 patients with precancerous gastric lesions (two tablets, 100 mg CGNC/tablet, three times per day for six months). Another 24 patients received no treatment. Results. Compared with control patients, CGNC-treated patients showed total or partial regression (using the quantitative Rome III diagnostic criteria) of dyspeptic symptoms (92.3%, p < 0.0001), eradication of H. pylori infection (57.1%, p < 0.03), a reduction in endoscopic signs of gastritis (92.3%, p < 0.001), an increase of pepsinogen pepsin in the gastric juice (57.7%, p < 0.05), and total regression or reduction in the degree of intestinal metaplasia (46.2%, p < 0.05) and lymphoplasmacytic infiltration (53.8%, p < 0.05). Conclusions. This study justifies a randomised controlled trial with CGNC in patients with atrophic gastritis. PMID- 28003850 TI - Cerebral Targeting of Acupuncture at Combined Acupoints in Treating Essential Hypertension: An Rs-fMRI Study and Curative Effect Evidence. AB - The study attempted to explore that the synergistic effect of acupoints combination is not a simple superposition of single acupoint's effect by comparing and analyzing the changes of blood pressure (BP), SF-36, and brain regions after acupuncture treatment. 47 patients were randomly divided into LR3+KI3 group, LR3 group, and KI3 group. Subjects received Rs-fMRI scan, BP measurement, and SF-36 questionnaires before and after treatment and short-term acupuncture treatment. After treatment, there were no significant differences in BP and SF-36 among 3 groups, compared to the case before treatment, SBP of 3 groups decreased, and DBP significantly decreased while vitality and mental health significantly increased in LR3+KI3 group. Both number and scopes of changes of brain regions in LR3+KI3 group were the largest, which mainly included BAs 3, 4, 8, 19, 21, 24, 32, 44, and 45. In conclusion, acupuncture at LR3+KI3 may auxiliarily reduce BP and improve the vitality and mental health of patients, and the changes of brain regions were related to somatesthesia, movement, vision, audition, emotion and mood, language, memory, etc. BAs 4, 9, 10, 24, 31, 32, and 46 may be the targeting brain areas of acupuncture in assisting hypotension. It is suggested that acupoints combination of LR3+KI3 maybe generates a synergistic effect, and it is not simple sum of single acupoint effect. PMID- 28003851 TI - Perception Study of Traditional Korean Medical Students on the Medical Education Using the Dundee Ready Educational Environment Measure. AB - Background. In Korea, a few studies regarding traditional Korean medicine (TKM) education have been conducted. The aim of this study is to evaluate students' perceptions regarding TKM education in Korea and compare them with those of other countries using a quantitative scale, Dundee Ready Educational Environment Measure (DREEM). Materials and Methods. We conducted a survey using DREEM in a TKM college. Totally, 325 students responded to this survey and we performed the descriptive statistics of scores in all items, subscales, and total. Additionally, subgroup comparisons according to gender, school year, and academic achievement were analyzed. Results. Mean overall DREEM score was 94.65 out of 200, which is relatively low compared to previous studies. Particularly, perceptions regarding subscales of learning, atmosphere, and self-perceptions were interpreted as problematic. There was no statistically significant difference between genders in spite of some differences among groups based on school year or academic achievement. Conclusions. We could examine students' perceptions regarding TKM education at a TKM college using DREEM for which validity and reliability were verified. TKM education was perceived relatively poor, but these quantitative indicators suggested which parts of education need improvement. We expect DREEM to be used widely in TKM or traditional medical education field. PMID- 28003852 TI - Shugan Xiaozhi Decoction Attenuates Nonalcoholic Steatohepatitis by Enhancing PPARalpha and L-FABP Expressions in High-Fat-Fed Rats. AB - This study aimed to investigate the effects of Shugan Xiaozhi decoction (SX) on nonalcoholic steatohepatitis (NASH) induced by high-fat diet in rats. The rats were randomly divided into 6 groups, namely, control, model, fenofibrate, and three different dosage of SX (10, 20, and 40 g/kg/day, p.o.). After establishing the NASH model, at 8 weeks of the experiment, treatments were administrated intragastrically to the fenofibrate and SX groups. All rats were killed after 4 weeks of treatment. Compared with the model group, alanine aminotransferase (ALT), aspartate aminotransferase (AST), free fatty acid (FFA), total cholesterol (TC), triacylglycerol (TG), and low-density lipoprotein cholesterol (LDL) serum in the serum were significantly reduced in all SX treatment groups in a dose dependent manner. Evidence showed that SX could protect the liver by upregulating the gene and protein expressions of peroxisome proliferator-activated receptor alpha (PPARalpha) and liver fatty acid binding protein (L-FABP) in a dose dependent manner. Chemical constituents of SX were further analyzed by ultraperformance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC-ESI-MS) and 30 chemicals in the ethanolic extract were tentatively identified. To conclude, our results clearly indicated that SX could protect liver functions and relieve hepatic steatosis and inflammation. PMID- 28003853 TI - Computational Methods and Models in Circulatory and Reproductive Systems. PMID- 28003854 TI - One-step grafting of polymers to graphene oxide. AB - The direct grafting of poly(N-isopropylacrylamide) to the basal plane of graphene oxide has been achieved in a single step: cleavage of the terminal thiocarbonylthio group on RAFT grown poly(N-isopropylacrylamide) reveals a reactive thiol that attacks the epoxides present across the surface of graphene oxide. The new composite material was characterised by a combination of SSNMR, FTIR, Raman, EDX, XPS, TGA and contact angle measurement; it shows enhanced thermal stability and solubility in water. PMID- 28003855 TI - Activation of Ice Recrystallization Inhibition Activity of Poly(vinyl alcohol) using a Supramolecular Trigger. AB - Antifreeze (glyco)proteins (AF(G)Ps) have potent ice recrystallisation inhibition (IRI) activity - a desirable phenomenon in applications such as cryopreservation, frozen food and more. In Nature AF(G)P activity is regulated by protein expression levels in response to an environmental stimulus; temperature. However, this level of regulation is not possible in synthetic systems. Here, a synthetic macromolecular mimic is introduced, using supramolecular assembly to regulate activity. Catechol-terminated poly(vinyl alcohol) was synthesised by RAFT polymerization. Upon addition of Fe3+, larger supramolecular star polymers form by assembly with two or three catechols. This increase in molecular weight effectively 'switches on' the IRI activity and is the first example of external control over the function of AFP mimetics. This provides a simple but elegant solution to the challenge of external control of AFP-mimetic function. PMID- 28003856 TI - Exact p-values for Simon's two-stage designs in clinical trials. AB - In a one-sided hypothesis testing problem in clinical trials, the monotonic condition of a tail probability function is fundamentally important to guarantee that the actual type I and II error rates occur at the boundary of their associated parameter spaces. Otherwise, one has to search for the actual rates over the complete parameter space, which could be very computationally intensive. This important property has been extensively studied in traditional one-stage study settings (e.g., non-inferiority or superiority between two binomial proportions), but there is very limited research for this property in a two-stage design setting, e.g., Simon's two-stage design. In this note, we theoretically prove that the tail probability is an increasing function of the parameter in Simon's two-stage design. This proof not only provides theoretical justification that p-value occurs at the boundary of the parameter space, but also helps to reduce the computational intensity for study design search. PMID- 28003857 TI - Assessing sedimentation equilibrium profiles in analytical ultracentrifugation experiments on macromolecules: from simple average molecular weight analysis to molecular weight distribution and interaction analysis. AB - Molecular weights (molar masses), molecular weight distributions, dissociation constants and other interaction parameters are fundamental characteristics of proteins, nucleic acids, polysaccharides and glycoconjugates in solution. Sedimentation equilibrium analytical ultracentrifugation provides a powerful method with no supplementary immobilization, columns or membranes required. It is a particularly powerful tool when used in conjunction with its sister technique, namely sedimentation velocity. Here, we describe key approaches now available and their application to the characterization of antibodies, polysaccharides and glycoconjugates. We indicate how major complications, such as thermodynamic non ideality, can now be routinely dealt with, thanks to a great extent to the extensive contribution of Professor Don Winzor over several decades of research. PMID- 28003858 TI - Analytical methods for structural ensembles and dynamics of intrinsically disordered proteins. AB - Intrinsically disordered proteins, proteins that do not have a well-defined three dimensional structure, make up a significant proportion of our proteome and are particularly prevalent in signaling and regulation. Although their importance has been realized for two decades, there is a lack of high-resolution experimental data. Molecular dynamics simulations have been crucial in reaching our current understanding of the dynamical structural ensemble sampled by intrinsically disordered proteins. In this review, we discuss enhanced sampling simulation methods that are particularly suitable to characterize the structural ensemble, along with examples of applications and limitations. The dynamics within the ensemble can be rigorously analyzed using Markov state models. We discuss recent developments that make Markov state modeling a viable approach for studying intrinsically disordered proteins. Finally, we briefly discuss challenges and future directions when applying molecular dynamics simulations to study intrinsically disordered proteins. PMID- 28003860 TI - Model diagnostics in reduced-rank estimation. AB - Reduced-rank methods are very popular in high-dimensional multivariate analysis for conducting simultaneous dimension reduction and model estimation. However, the commonly-used reduced-rank methods are not robust, as the underlying reduced rank structure can be easily distorted by only a few data outliers. Anomalies are bound to exist in big data problems, and in some applications they themselves could be of the primary interest. While naive residual analysis is often inadequate for outlier detection due to potential masking and swamping, robust reduced-rank estimation approaches could be computationally demanding. Under Stein's unbiased risk estimation framework, we propose a set of tools, including leverage score and generalized information score, to perform model diagnostics and outlier detection in large-scale reduced-rank estimation. The leverage scores give an exact decomposition of the so-called model degrees of freedom to the observation level, which lead to exact decomposition of many commonly-used information criteria; the resulting quantities are thus named information scores of the observations. The proposed information score approach provides a principled way of combining the residuals and leverage scores for anomaly detection. Simulation studies confirm that the proposed diagnostic tools work well. A pattern recognition example with hand-writing digital images and a time series analysis example with monthly U.S. macroeconomic data further demonstrate the efficacy of the proposed approaches. PMID- 28003861 TI - REI-1, a Novel Rab11 GEF with a SH3BP5 domain. AB - The small GTPase Rab proteins are key regulators of membrane trafficking. Rab11 is one of the best-characterized molecules among the Rab family proteins and it plays multiple roles in endocytic recycling, exocytosis, and cytokinesis. However, it remains unclear how Rab11 is activated at a precise timing and location and regulates its diverse functions. Specifically, our knowledge of the upstream regulatory factors that activate Rab11 is limited. In this regard, we have identified the RAB-11-interacting protein-1 (REI-1) as a novel guanine nucleotide exchange factor (GEF) for RAB-11 in Caenorhabditis elegans (C. elegans). REI-1 family proteins are conserved among metazoans, and its human homolog, SH3BP5, also exhibits strong GEF activity toward human Rab11. In C. elegans, REI-1 is expressed in the germline and co-localizes with RAB-11 on late Golgi membranes. The loss of REI-1 impaired the targeting of RAB-11 to the late Golgi compartment, as well as the recycling endosomes in embryos and further reduced the recruitment of RAB-11 to the cleavage furrow, resulting in the delay of cytokinesis. We suggest that REI-1 is the GEF responsible for regulating RAB 11 localization and function in early embryos. PMID- 28003859 TI - Measurement of amyloid formation by turbidity assay-seeing through the cloud. AB - Detection of amyloid growth is commonly carried out by measurement of solution turbidity, a low-cost assay procedure based on the intrinsic light scattering properties of the protein aggregate. Here, we review the biophysical chemistry associated with the turbidimetric assay methodology, exploring the reviewed literature using a series of pedagogical kinetic simulations. In turn, these simulations are used to interrogate the literature concerned with in vitro drug screening and the assessment of amyloid aggregation mechanisms. PMID- 28003862 TI - Watching a memory form-VSD imaging reveals a novel memory mechanism. AB - Studies of the mechanisms underlying memory formation have largely focused on the synapse. However, recent evidence suggests that additional, non-synaptic, mechanisms also play important roles in this process. We recently described a novel memory mechanism whereby a particular class of neurons was recruited into the Tritonia escape swim network with sensitization, a non-associative form of learning. Neurons that in the naive state were loosely-affiliated with the network were rapidly recruited in, transitioning from variably bursting (VB) to reliably bursting (RB). Even after the memory had faded some new neurons remained, and some original members had left, leaving the network in an altered state. Further, we identified a candidate cellular mechanism underlying these network changes. Our study supports the view that brain networks may have surprisingly fluid functional structures and adds to the growing body of evidence that non-synaptic mechanisms often operate synergistically with changes at the synapse to mediate memory formation. PMID- 28003863 TI - Resolving Contributions of Oxygen-Consuming and ROS-Generating Enzymes at the Synapse. AB - Disruption of cellular redox homeostasis is implicated in a wide variety of pathologic conditions and aging. A fundamental factor that dictates such balance is the ratio between mitochondria-mediated complete oxygen reduction into water and incomplete reduction into superoxide radical by mitochondria and NADPH oxidase (NOX) enzymatic activity. Here we determined mitochondrial as well as NOX dependent rates of oxygen consumption in parallel with H2O2 generation in freshly isolated synaptosomes using high resolution respirometry combined with fluorescence or electrochemical sensory. Our results indicate that although synaptic mitochondria exhibit substantially higher respiratory activities (8-82 fold greater than NOX oxygen consumption depending on mitochondrial respiratory state), NADPH-dependent oxygen consumption is associated with greater H2O2 production (6-7-fold higher NOX-H2O2). We also show that, in terms of the consumed oxygen, while synaptic mitochondria "leaked" 0.71% +/- 0.12 H2O2 during NAD+-linked resting, 0.21% +/- 0.04 during NAD+-linked active respiration, and 0.07% +/- 0.02 during FAD+-linked active respiration, NOX converted 38% +/- 13 of O2 into H2O2. Our results indicate that NOX rather than mitochondria is the major source of synaptic H2O2. The present approach may assist in the identification of redox-modulating synaptic factors that underlie a variety of physiological and pathological processes in neurons. PMID- 28003864 TI - Virus Infections on Prion Diseased Mice Exacerbate Inflammatory Microglial Response. AB - We investigated possible interaction between an arbovirus infection and the ME7 induced mice prion disease. C57BL/6, females, 6-week-old, were submitted to a bilateral intrahippocampal injection of ME7 prion strain (ME7) or normal brain homogenate (NBH). After injections, animals were organized into two groups: NBH (n = 26) and ME7 (n = 29). At 15th week after injections (wpi), animals were challenged intranasally with a suspension of Piry arbovirus 0.001% or with NBH. Behavioral changes in ME7 animals appeared in burrowing activity at 14 wpi. Hyperactivity on open field test, errors on rod bridge, and time reduction in inverted screen were detected at 15th, 19th, and 20th wpi respectively. Burrowing was more sensitive to earlier hippocampus dysfunction. However, Piry-infection did not significantly affect the already ongoing burrowing decline in the ME7 treated mice. After behavioral tests, brains were processed for IBA1, protease resistant form of PrP, and Piry virus antigens. Although virus infection in isolation did not change the number of microglia in CA1, virus infection in prion diseased mice (at 17th wpi) induced changes in number and morphology of microglia in a laminar-dependent way. We suggest that virus infection exacerbates microglial inflammatory response to a greater degree in prion-infected mice, and this is not necessarily correlated with hippocampal-dependent behavioral deficits. PMID- 28003865 TI - Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts. AB - Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC) or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts. PMID- 28003867 TI - What makes a compliant Phase III and pre-launch patient advocacy strategy? AB - BACKGROUND: A key task for the pharmaceutical industry is to understand the compliance implications of engaging with a patient advocacy group (PAG). This presents challenges for the industry to negotiate the ethical and reputational issues that can arise when working with a PAG. OBJECTIVE: To gain the views of pharmaceutical industry executives on future compliance challenges when working with PAGs. STUDY DESIGN: We conducted two surveys among two sets of industry executives: one group focussed on market access roles and the other focussed on non-market access roles. RESULTS: Transparency was identified as the biggest challenge, followed by project rationale and then by project ownership. CONCLUSION: We explore how this can be overcome and make recommendations on how best to work compliantly with PAGs. PMID- 28003866 TI - SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model. AB - Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI. PMID- 28003868 TI - Outcome of one hundred consecutive ICSI attempts using patient operated home sonography for monitoring follicular growth. AB - OBJECTIVE: cohort study describing clinical and laboratory outcomes in ICSI patients using self-operated endovaginal tele-monitoring (SOET). SETTING: University department of reproductive medicine. PATIENTS: 78 patients undergoing 100 consecutive ICSI attempts. INTERVENTIONS: patients' recorded vaginal sonograms and sent recordings using the cloud based Sonaura device to the care provider who procured responses, avoiding hospital visits. MAIN OUTCOME MEASURES: Number of cycles without hospital visit, laboratory and clinical variables, transportation avoided. RESULTS: In 100 attempts, only one patient missed her follicles, 9 hospital visits occurred for circumstantial reasons and 90 attempts were completed without any hospital visit between initiation and puncture. Mean number +/- 2SD was for oocytes 11.7+/-6.6, metaphase-II oocytes 8.5+/-5.4, 2PN zygotes 5.5+/-3.7, good day-5 blastocysts 2.4+/-2.4, embryos transferred 1.0+/ 0.7 and embryos frozen 1.3+/-2.2. Percentages of total (+HCG), clinical (cardiac activity) and on-going pregnancies (>20 weeks) were 40%, 35% and 29% per started cycle and 48.8%, 42.7% and 35.4% per embryo transfer. CONCLUSIONS: Using SOET, 90% of ICSI (and IVF) patients can avoid visits to care providers for making sonograms. Results were similar as in patients with a similar profile using traditional monitoring. In appropriate patients, SOET is an efficient, safe and patient-friendly alternative for ovarian stimulation monitoring in IVF/ICSI programmes. PMID- 28003869 TI - Attitudes toward Regulations of Reproductive Care in the European Union: A Comparison between Travellers for Cross-Border Reproductive Care and Citizens of the Local Country. AB - This paper compares two populations with respect to attitudes toward the regulation of reproductive care by the European Union. The two populations are 252 individuals who crossed a national border to receive treatment at an independent clinic in Spain and 45 Spanish citizens who received treatment in their home country. Online surveys were sent to former patients (from many different countries) of a private Spanish clinic. By comparing those who engaged in cross-border reproductive care (CBRC) with those who did not, we examined attitudes toward whether or not the EU should extend to all clients in all countries the type of services the clinic provided. These services included access to anonymous donors and conception via egg or embryo donation. We found that those who travelled abroad were less in favor of EU expanding regulation for the type of services they received than were those in Spain. This study is unusual in focusing on political attitudes rather than the nature of the experience and consequences of cross-border reproductive care. We suggest that individuals who engage in CBRC might be reluctant to see the EU extend reproductive care broadly because debates within both the EU and their home countries could result in the elimination of options that are now available through travel. We suggest that individuals from countries that are popular destinations for CBRC like Spain might want to extend EU reproductive care more broadly so as to reduce the pressure on the medical services in their own country. We suggest directions for further research. PMID- 28003870 TI - New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes. AB - Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi). Loss-of-function mutations in genes in the homologous recombination pathway, especially BRCA1 and BRCA2, predict higher rates of platinum sensitivity, better overall survival (OS), and better response to PARPi in women with OC. Among patients with platinum-sensitive recurrent OC, a BRCA mutation is the first genetically defined predictive marker for targeted therapy, since these patients are most likely to benefit from treatment with a PARPi, such as olaparib. In patients with platinum-sensitive recurrent OC without a BRCA mutation, bevacizumab currently seems to be the best maintenance option. Women with OC are progressively more routinely screened for germline BRCA mutations, and the implication of somatic BRCA mutations is increasingly being recognized in OC. Therefore, the recommendations should be updated to reflect the importance of both types of mutations. Together, these data highlight the fact that treatment of recurrent OC can be optimized using genomic contributions to individualize therapy and to improve treatment response. PMID- 28003871 TI - Laparoscopic posterior Colpotomy for a Cervico-vaginal Leiomyoma: hymen conservative technique. AB - BACKGROUND: Leiomyomas are the most common benign tumours of the uterus. The diagnosis, evaluation and treatment of prolapsed pedunculated submucous myoma may need vaginal access compromising sometimes the hymenal integrity. Laparoscopic management of a pedunculated submucous myoma in a Middle Eastern virgin patient is described as a safe alternative. CASE: A 20-year-old, nulliparous virgin woman presented to the outpatient clinic for irregular menstrual bleeding of 2 months duration. Imaging revealed a 5*5 cm solid mass in the cervico-vaginal location filling the vagina suggestive of a prolapsed pedunculated submucous leiomyoma. Due to the patient's desire of preserving her intact hymen, a laparoscopic posterior colpotomy was performed and the mass was removed successfully. CONCLUSION: Laparoscopic posterior colpotomy, preserving the hymenal integrity in a virgin patient, provides excellent access and visualization and it is a safe tool for the management of a cervico-vaginal pedunculated submucous myoma by a skilled laparoscopic gynaecologic surgeon. PMID- 28003872 TI - A reversible posterior leucoencephalopathy syndrome including blindness caused by preeclampsia. AB - Complications of (pre)eclampsia may involve multiple systems and organs. Neurological symptoms may occur. Visual symptoms concern up to 25% the of patients with severe preeclampsia and 50% of the patients with eclampsia. An uncommon effect of severe preeclampsia is sudden blindness. Blindness may be part of a clinical and radiological presentation named Posterior Reversible Encephalopathy Syndrome (PRES). PRES may lead to permanent neurological deficit, recurrences or death. We report the case of a 24-year-old Caucasian patient, gravida 5 para 2 who developed preeclampsia and PRES complicated with blindness at 32 weeks of gestation. Optimal care allowed visual symptoms to resolve within 24 hours and a favourable maternal outcome and no long- term sequelae. We describe different causes and manifestations of PRES and highlight the need for immediate care in order to optimize the chance of symptoms reversibility. PMID- 28003873 TI - Is anti-hormonal treatment in DCIS of the breast a need? AB - Ductal carcinomas in situ (DCIS) represent one fifth of all detected breast cancers. The detection of DCIS can be regarded as collateral damage of breast cancer screening. The treatment of DCIS is based on surgery with or without radiotherapy. Women treated for DCIS have a 10 years survival of 98 %. Could there be a role for systemic therapy in case of a DCIS? Recent published studies suggest there is. However, anti-hormonal therapy (tamoxifen, anastrozole) in DCIS causes an increased morbidity without a reduced mortality. There is an urgent need for evidence-based guidelines in the management of DCIS in order to make appropriate shared decisions. PMID- 28003874 TI - Helen B. Taussig (1898-1986). PMID- 28003875 TI - Optimal threshold estimation for binary classifiers using game theory. AB - Many bioinformatics algorithms can be understood as binary classifiers. They are usually trained by maximizing the area under the receiver operating characteristic ( ROC) curve. On the other hand, choosing the best threshold for practical use is a complex task, due to uncertain and context-dependent skews in the abundance of positives in nature and in the yields/costs for correct/incorrect classification. We argue that considering a classifier as a player in a zero-sum game allows us to use the minimax principle from game theory to determine the optimal operating point. The proposed classifier threshold corresponds to the intersection between the ROC curve and the descending diagonal in ROC space and yields a minimax accuracy of 1-FPR. Our proposal can be readily implemented in practice, and reveals that the empirical condition for threshold estimation of "specificity equals sensitivity" maximizes robustness against uncertainties in the abundance of positives in nature and classification costs. PMID- 28003876 TI - Highlights from the ISCB Student Council Symposia in 2016. AB - This editorial provides a brief overview of the 12th International Society for Computational Biology (ISCB) Student Council Symposium and the 4th European Student Council Symposium held in Florida, USA and The Hague, Netherlands, respectively. Further, the role of the ISCB Student Council in promoting education and networking in the field of computational biology is also highlighted. PMID- 28003877 TI - Hemodynamic monitoring in the critically ill: an overview of current cardiac output monitoring methods. AB - Critically ill patients are often hemodynamically unstable (or at risk of becoming unstable) owing to hypovolemia, cardiac dysfunction, or alterations of vasomotor function, leading to organ dysfunction, deterioration into multi-organ failure, and eventually death. With hemodynamic monitoring, we aim to guide our medical management so as to prevent or treat organ failure and improve the outcomes of our patients. Therapeutic measures may include fluid resuscitation, vasopressors, or inotropic agents. Both resuscitation and de-resuscitation phases can be guided using hemodynamic monitoring. This monitoring itself includes several different techniques, each with its own advantages and disadvantages, and may range from invasive to less- and even non-invasive techniques, calibrated or non-calibrated. This article will discuss the indications and basics of monitoring, further elaborating on the different techniques of monitoring. PMID- 28003879 TI - Should hydrogen therapy be included in a musculoskeletal medicine routine? AB - Molecular hydrogen (H 2) has recently been recognized as a potential novel therapeutic agent in biomedicine. Initially proposed to be a possible treatment for certain types of neuromuscular disorders, cardio-metabolic diseases and cancer, H 2 improved clinical end-points and surrogate markers in several clinical trials, mainly acting as an anti-inflammatory agent and powerful antioxidant. In this paper, the medicinal properties of H 2 in musculoskeletal medicine are discussed with the aim to provide an updated and practical overview for health professionals working in this field. PMID- 28003878 TI - Estimating limits for natural human embryo mortality. AB - Natural human embryonic mortality is generally considered to be high. Values of 70% and higher are widely cited. However, it is difficult to determine accurately owing to an absence of direct data quantifying embryo loss between fertilisation and implantation. The best available data for quantifying pregnancy loss come from three published prospective studies (Wilcox, Zinaman and Wang) with daily cycle by cycle monitoring of human chorionic gonadotrophin (hCG) in women attempting to conceive. Declining conception rates cycle by cycle in these studies indicate that a proportion of the study participants were sub-fertile. Hence, estimates of fecundability and pre-implantation embryo mortality obtained from the whole study cohort will inevitably be biased. This new re-analysis of aggregate data from these studies confirms the impression that discrete fertile and sub-fertile sub-cohorts were present. The proportion of sub-fertile women in the three studies was estimated as 28.1% (Wilcox), 22.8% (Zinaman) and 6.0% (Wang). The probability of conceiving an hCG pregnancy (indicating embryo implantation) was, respectively, 43.2%, 38.1% and 46.2% among normally fertile women, and 7.6%, 2.5% and 4.7% among sub-fertile women. Pre-implantation loss is impossible to calculate directly from available data although plausible limits can be estimated. Based on this new analysis and a model for evaluating reproductive success and failure it is proposed that a plausible range for normal human embryo and fetal mortality from fertilisation to birth is 40-60%. PMID- 28003880 TI - Surgical proficiency decreases the rate of healing abnormalities using anterior transobturator mesh in cystocele women. AB - Aims: The objective of this study is to report the outcomes of cystocele repair with anterior transobutrator mesh kits. Methods: 119 consecutive women with cystoceles were treated between January 2006 and November 2010 by a single surgeon at a university hospital using the anterior transobturator mesh kit procedure. Postoperative follow-up visits were scheduled at 1, 6, and 12 months after surgery. Results: A total of 114 women who were operated on with the anterior transobturator mesh kit completed 12 months of follow-up. The population had a mean age of 65.8 +/- 7.0, a body mass index of 25.1 +/- 3.0, and a parity average of 4.0 +/- 1.7. An overall anatomic cure was reported for 108 patients (94.7%). The Ba point of the POP-Q exam used for grading cystoceles decreased significantly from 2.5 +/- 1.6 cm to -2.8 +/- 0.8 cm after 12 months (P < 0.01). One patient (0.9%) presented with bladder perforation, and five patients (4.4%) showed with healing abnormalities. Surgical case volume was negatively correlated with healing abnormalities after adjusting for age, body mass index, operation time, and parity (P = 0.15). Conclusion: The surgeon's experience decreases the incidence of healing abnormalities using anterior transobturator mesh in cystocele women. The anatomical cure rate of anterior transobturator mesh is quite good. PMID- 28003881 TI - Approaches to R education in Canadian universities. AB - Introduction: R language is a powerful tool used in a wide array of research disciplines and owes a large amount of its success to its open source and adaptable nature. The popularity of R has grown rapidly over the past two decades and the number of users and packages is increasing at a near exponential rate. This rapid growth has prompted a number of formal and informal online and text resources, the volume of which is beginning to present challenges to novices learning R. Students are often first exposed to R in upper division undergraduate classes or during their graduate studies. The way R is presented likely has consequences for the fundamental understanding of the program and language itself; user comprehension of R may be better if learning the language itself followed by conducting analyses, compared to someone who is learning another subject (e.g. statistics) using R for the first time. Consequently, an understanding of the approaches to R education is critical. Methods: To establish how students are exposed to R, we used a survey to evaluate the current use in Canadian university courses, including the context in which R is presented and the types of uses of R in the classroom. Additionally, we looked at the reasons professors either do or don't use/teach R. Results: We found that R is used in a broad range of course disciplines beyond statistics (e.g. ecology) and just over one half of Canadian universities have at least one course that uses R. Discussion and Conclusions: Developing programming-literate students is of utmost importance and our hope is that this benchmark study will influence how post secondary educators, as well as other programmers, approach R, specifically when developing educational and supplemental content in online, text, and package specific formats aiding in student's comprehension of the R language. PMID- 28003882 TI - Evolutionary relations and population differentiation of Acipenser gueldenstaedtii Brandt, Acipenser persicus Borodin, and Acipenser baerii Brandt. AB - Russian ( Acipenser gueldenstaedtii), Persian ( A. persicus) and Siberian ( A. baerii) sturgeons are closely related 'Ponto-Caspian' species. Investigation of their population structure is an important problem, the solution of which determines measures for conservation of these species. According to previous studies, 'baerii-like' mitotypes were found in the Caspian Sea among 35% of Russian sturgeon specimens, but were not found in Persian sturgeons. This confirms genetic isolation of the Persian sturgeon from the Russian sturgeon in the Caspian Sea. However, in order to clarify the relationships of these species it is necessary to analyze nuclear DNA markers. The amplified fragment length polymorphism (method) allows estimating interpopulation and interspecific genetic distances using nuclear DNA markers. In the present study, four samples were compared: Persian sturgeons from the South Caspian Sea, Russian sturgeons from the Caspian Sea and the Sea of Azov, and Siberian sturgeons from the Ob' River, which are close to these two species, but are also clearly morphologically and genetically distinct from them. For the AFLP method, eight pairs of selective primers were used. The analysis revealed that the Siberian sturgeon has formed a separate branch from the overall Persian-Russian sturgeons cluster, which was an expected result. In addition, the results showed that the Caspian Russian sturgeon is closer to the Persian sturgeon from the Caspian Sea than to the Russian Sturgeon from the Sea of Azov. The present DNA marker data confirm that despite the genetic isolation of the Persian sturgeon from the Russian sturgeon in the Caspian Sea, the Persian sturgeon is a young species. PMID- 28003883 TI - The interplay between plasticity and evolution in response to human-induced environmental change. AB - Some populations will cope with human-induced environmental change, and others will undergo extirpation; understanding the mechanisms that underlie these responses is key to forecasting responses to environmental change. In cases where organisms cannot disperse to track suitable habitats, plastic and evolved responses to environmental change will determine whether populations persist or perish. However, the majority of studies consider plasticity and evolution in isolation when in fact plasticity can shape evolution and plasticity itself can evolve. In particular, whether cryptic genetic variation exposed by environmental novelty can facilitate adaptive evolution has been a source of controversy and debate in the literature and has received even less attention in the context of human-induced environmental change. However, given that many studies indicate organisms will be unable to keep pace with environmental change, we need to understand how often and the degree to which plasticity can facilitate adaptive evolutionary change under novel environmental conditions. PMID- 28003884 TI - The Need for Psychological Interventional Supportive Services for Omani Women Diagnosed with Breast Cancer. PMID- 28003885 TI - Statin-Associated Muscle Adverse Events: Update for clinicians. AB - Statins are potent medications which reduce low-density lipoprotein cholesterol (LDL-C) levels. Their efficacy in cardiovascular risk reduction is well established and indications for their use are expanding. While statins are generally well tolerated and safe, adverse events are relatively common, particularly statin-associated muscle adverse events (SaMAEs), which are the most frequently encountered type of adverse event. Recent guidelines and guideline updates on SaMAEs and statin intolerance have included revised definitions of SaMAEs, incorporating new evidence on their pathogenesis and management. As SaMAEs emerge as a therapeutic challenge, it is important for physicians to be aware of updates on management strategies to ensure better patient outcomes. The majority of patients who are considered statin-intolerant can nevertheless tolerate some forms of statin therapy and successfully achieve optimal LDL-C levels. This review article discusses the recent classification of SaMAEs with emphasis on pathogenesis and management strategies. PMID- 28003886 TI - Porcelain Gallbladder: Decoding the malignant truth. AB - Gallbladder calcification, also referred to as porcelain gallbladder, has received significant attention in the medical literature due to its perceived role in increasing the risk of developing a gallbladder carcinoma. However, recent reports raise questions challenging this purported high risk. While previous studies reported a concomitant incidence of gallbladder cancer in porcelain gallbladder ranging from 7-60%, more recent analyses indicate the incidence to be much lower (6%). Based on evidence in the current literature, a prophylactic cholecystectomy is not routinely recommended for all patients with porcelain gallbladder and should be restricted to those with conventional indications, such as young patients. However, it is important to note that a nonoperative approach may require prolonged follow-up. A laparoscopic cholecystectomy is a feasible therapeutic option for patients with porcelain gallbladder, although some researchers have indicated a higher incidence of complications and conversion due to technical difficulties. PMID- 28003887 TI - Histological Evaluation of Hydroxyapatite Granules with and without Platelet-Rich Plasma versus an Autologous Bone Graft: Comparative study of biomaterials used for spinal fusion in a New Zealand white rabbit model. AB - OBJECTIVES: Hydroxyapatite (HA) has osteoconductive properties and is widely used as a bone graft substitute. Platelet-rich plasma (PRP) is an autologous product with osteoinductive effects. Hypothetically, a combination of both would augment the bone formation effect of HA and widen its application in spinal fusion surgeries. This study aimed to compare new bone formation with HA granules alone and in combination with PRP versus an autologous bone graft during a lumbar intertransverse process spinal fusion. METHODS: A total of 16 adult New Zealand white rabbits underwent single-level bilateral intertransverse process fusion at the L5-L6 vertebrae. One side of the spine received either HA granules alone or a combination of HA granules and PRP, while the contralateral side received an autologous bone graft. Four animals each from the HA group and the HA plus PRP group versus the autograft group were assessed either at six or 16 weeks by undecalcified histology and histomorphometry. The mean percentage of new bone areas over the corresponding fusion masses were compared between groups. RESULTS: No significant difference in new bone formation was observed between the HA and HA plus PRP groups at six or 16 weeks. The autograft group had significantly more new bone formation at six and 16 weeks (P = 0.004 and <0.001, respectively). CONCLUSION: An autologous bone graft remains superior to HA granules, with or without PRP. HA granules demonstrated an excellent osteoconductive scaffold but had poor biodegradability. While PRP enhances the properties of HA granules, these biomaterials do not have a synergistic effect. PMID- 28003888 TI - Lumbar Kinematics, Functional Disability and Fear Avoidance Beliefs Among Adults with Nonspecific Chronic Low Back Pain. AB - OBJECTIVES: This study aimed to examine correlations between lumbar kinematics, functional disability and fear avoidance beliefs among adults with nonspecific chronic low back pain (LBP). METHODS: This cross-sectional study was conducted between March and December 2014. A total of 32 adults diagnosed with nonspecific chronic LBP were recruited from outpatients attending either an orthopaedic clinic at a university hospital or a private physiotherapy clinic in Malaysia. Lumbar kinematics were measured using sensors attached at the first lumbar (L1) and second sacral (S2) vertebrae levels. The Oswestry Disability Index (ODI) and Fear-Avoidance Beliefs Questionnaire (FABQ) were used to assess degree of functional disability and fear avoidance beliefs, respectively. RESULTS: For maximum range of motion, positive correlations were observed between ODI scores and right lateral flexion and right rotation (P = 0.01 each), although there was a negative correlation with left rotation (P = 0.03). With maximum angular velocity, ODI scores were positively correlated with right and left lateral flexion L1 (P = 0.01 and <0.01, respectively) but negatively correlated with left lateral flexion L2 (P = 0.04). Regarding minimum angular velocity, ODI scores were positively correlated with left lateral flexion S2 (P <0.01) but negatively correlated with right and left lateral flexion L1 (P = 0.02 each), right rotation L1 (P = 0.02) and left rotation S2 (P = 0.01). No significant correlations were found between lumbar kinematics and FABQ scores. CONCLUSION: These findings suggest that certain lumbar kinematic parameters are correlated with functional disability, but not with fear avoidance beliefs. PMID- 28003889 TI - Knowledge and Health Beliefs Regarding Sickle Cell Disease Among Omanis in a Primary Healthcare Setting: Cross-sectional study. AB - OBJECTIVES: Sickle cell disease (SCD) is a global health concern associated with high childhood morbidity and mortality; in Oman, the prevalence of SCD is 0.2%. Public awareness of SCD and the need for premarital screening (PMS) are essential to reduce the incidence of this disease. This study aimed to assess awareness of and beliefs regarding SCD and PMS among Omanis in a primary healthcare setting. METHODS: This cross-sectional study took place in five health centres located in Al-Seeb Province, Muscat, Oman, between June and August 2015. A total of 500 Omanis aged >=18 years old attending the clinics were invited to participate in the study. A previously described questionnaire by Gustafson et al. was used to measure awareness of and beliefs regarding SCD and PMS. RESULTS: A total of 450 Omani adults completed the questionnaire (response rate: 90.0%). The majority (67.8%) were aware that SCD is genetically inherited and 85.1% believed in the value of PMS; however, only 24.4% reported having undergone PMS previously. Few participants were aware that SCD can be very painful (20.2%) and can cause strokes, infections and organ damage (20.0%). More than half (56.7%) reported that the availability of educational material on SCD or PMS in Oman was inadequate. Participants' education levels were positively associated with accurate SCD knowledge (P <0.05). CONCLUSION: Despite the free availability of PMS services in local health centres, few Omanis reported having undergone PMS previously. Health promotion and education programmes are therefore needed in Oman in order to increase public awareness of SCD and the value of PMS. PMID- 28003890 TI - Use of Intracervical Foley Catheter for Induction of Labour in Cases of Previous Caesarean Section: Experience of a single tertiary centre in Oman. AB - OBJECTIVES: This study aimed to evaluate rates of success and perinatal complications of labour induction using an intracervical Foley catheter among women with a previous Caesarean delivery at a tertiary centre in Oman. METHODS: This retrospective cohort study included 68 pregnant women with a history of a previous Caesarean section who were admitted for induction via Foley catheter between January 2011 and December 2013 to the Sultan Qaboos University Hospital, Muscat, Oman. Patient data were collected from electronic and delivery ward records. RESULTS: Most women were 25-35 years old (76.5%) and 20 women had had one previous vaginal delivery (29.4%). The most common indication for induction of labour was intrauterine growth restriction with oligohydramnios (27.9%). Most women delivered after 40 gestational weeks (48.5%) and there were no neonatal admissions or complications. The majority experienced no complications during the induction period (85.3%), although a few had vaginal bleeding (5.9%), intrapartum fever (4.4%), rupture of the membranes (2.9%) and cord prolapse shortly after insertion of the Foley catheter (1.5%). However, no cases of uterine rupture or scar dehiscence were noted. Overall, the success rate of vaginal birth after a previous Caesarean delivery was 69.1%, with the remaining patients undergoing an emergency Caesarean section (30.9%). CONCLUSION: The use of a Foley catheter in the induction of labour in women with a previous Caesarean delivery appears a safe option with a good success rate and few maternal and fetal complications. PMID- 28003891 TI - Arterial Resistance in Late First Trimester as a Predictor of Subsequent Pregnancy-Related Hypertension. AB - OBJECTIVES: This study aimed to examine the association between indicators of arterial resistance occurring late in the first trimester and the subsequent development of pregnancy-related hypertension. METHODS: This study took place between May 2014 and August 2015 and included 329 consecutive women with singleton pregnancies attending the antenatal clinics of a medical college in Karnataka, India, during this period. Pulse pressure (PP) and uterine artery Doppler parameters were recorded between 11-14 gestational weeks. Consequently, women were followed-up until after delivery for subsequent hypertension. RESULTS: Hypertension occurred more frequently if PP was high (17.6% versus 14.4% of pregnancies without high PP; P = 0.713), if a diastolic notch (DN) was present (15.1% versus 12.8% of pregnancies with an absent DN; P = 0.612) and if the resistive index (RI) was raised (22.2% versus 14.3% of pregnancies without raised RI; P = 0.366). A raised pulsatility index (PI) was significantly associated with hypertension (P = 0.013). The risk of hypertension was approximately seven-fold higher if two or more arterial resistance indicators were used, except with a present DN plus a raised RI or a present DN plus high PP. All arterial resistance indicators showed negative predictability (>85.6%) and good specificity (>=95.0%), except for the presence of a DN. A population-specific cut-off PI value of 1.72 had high negative predictability (92.8%) and good sensitivity (70.8%) and specificity (65.1%). CONCLUSION: Raised PI in the late first trimester was a significant predictor of hypertension later in pregnancy. A combination of arterial resistance indicators may enhance prediction of subsequent hypertension. PMID- 28003892 TI - Early Versus Late Tracheostomy for Patients with High and Low Cervical Spinal Cord Injuries. AB - OBJECTIVES: This study aimed to evaluate the effects of early versus late tracheostomies among patients with cervical spinal cord injuries (CSCIs). METHODS: This retrospective study included 69 adult CSCI patients who underwent bedside percutaneous tracheostomies at the Intensive Care Unit of Khoula Hospital, Muscat, Oman, between January 2011 and October 2015. The tracheostomy was considered early if the procedure took place within one week of the CSCI. The impact of an early tracheostomy on patient outcomes was analysed in terms of duration of mechanical ventilation and intensive care unit (ICU) stay among patients with high (C1-C2 vertebrae) and low (C3-C7 vertebrae) CSCIs. Ventilator dependence, bradycardia episodes and surgical intervention outcomes were also examined. RESULTS: Patients with a high CSCI who underwent an early tracheostomy spent significantly fewer days on mechanical ventilation compared to those who underwent a late tracheostomy (9.3 +/- 7.2 days versus 13.7 +/- 3.2 days; P = 0.041). Low CSCI patients who received an early tracheostomy also experienced significantly fewer days on mechanical ventilation compared to those undergoing a late tracheostomy (12.1 +/- 10.4 days versus 25.2 +/- 17.7 days; P = 0.035). Moreover, ICU mortality was significantly lower for high CSCI patients who underwent an early tracheostomy (P = 0.015). However, there was no association between length of ICU stay and either type of CSCI or timing of the tracheostomy procedure. CONCLUSION: An early tracheostomy is beneficial in reducing the duration of mechanical ventilation among patients with CSCIs, irrespective of the level of injury. PMID- 28003893 TI - Comparison of Postoperative Drain Insertion versus No Drain Insertion in Thyroidectomies: Retrospective case-control study from the Sultan Qaboos University Hospital, Muscat, Oman. AB - OBJECTIVES: A thyroidectomy is a frequently performed surgical procedure which can result in life-threatening complications. The insertion of a drain after a thyroidectomy has been suggested to prevent such complications. This study aimed to evaluate the use of surgical drains following thyroidectomies in relation to postoperative complications and mass sizes. METHODS: This retrospective case control study included all thyroidectomies conducted at the Sultan Qaboos University Hospital, Muscat, Oman, from January 2011 to December 2013. Length of hospital stay, readmission, postoperative complications and mass size were evaluated. RESULTS: During the study period, 250 surgeries were carried out on 241 patients. The majority of patients were female (87.2%). Drains were inserted postoperatively after 202 surgeries (80.8%) compared to 48 surgeries (19.2%) without drains. A total of 32 surgeries (12.8%) were conducted on patients with thyroid masses <1 cm, 138 (55.2%) on those with masses between 1-4 cm and 80 (32.0%) on those with masses >4 cm. The association between drain use and mass size was not significant (P = 0.439). Although postoperative complications were more prevalent in patients with drains, the relationship between these factors was not significant (P >0.050). Length of hospital stay was significantly longer among patients with postoperative drains (P <0.010). CONCLUSION: The routine insertion of drains after thyroid surgeries was found to result in longer hospital stays and did not reduce rates of post-thyroidectomy complications. Thyroid mass size should not be used as an indicator for the insertion of a drain after thyroidectomy. PMID- 28003894 TI - A Hypothetical Model to Predict Nursing Students' Perceptions of the Usefulness of Pre-Service Integrated Management of Childhood Illness Training. AB - OBJECTIVES: This study aimed to test a hypothetical model to predict nursing students' perceptions of the usefulness of pre-service Integrated Management of Childhood Illness (IMCI) training and their intention to apply this training in clinical practice. METHODS: This study was carried out at the Sur Nursing Institute, Sur, Oman, in May 2015. Using six predefined constructs, a hypothetical structural model was created. The constructs were used as latent variables to highlight their probable impact on intention to apply IMCI-related knowledge and skills in practice. A structured validated questionnaire was subsequently developed to assess the perceptions of nursing students. Factor loadings and calculated variances were examined to ensure convergent validity. Cronbach's alpha was used to calculate internal consistency reliability. RESULTS: Factor loadings for each item in the model were above 0.70. All of the constructs had Cronbach's alpha values over 0.700, except for enhanced assessment skills (Cronbach's alpha: 0.694). The variance extracted value was 0.815 for perceived usefulness, 0.800 for enhanced assessment skills, 0.687 for enhanced knowledge, attitudes and skills, 0.697 for enhanced confidence, 0.674 for enhanced counselling skills and 0.805 for future intention to use IMCI in a clinical setting. CONCLUSION: Overall, the results support the hypothetical model and indicate that nursing students perceive IMCI training to be beneficial and intend to apply IMCI-related knowledge and skills in clinical practice. PMID- 28003895 TI - Perceptions of the Use of Blueprinting in a Formative Theory Assessment in Pharmacology Education. AB - OBJECTIVES: This study aimed to assess perceptions of the use of a blueprint in a pharmacology formative theory assessment. METHODS: This study took place from October 2015 to February 2016 at a medical college in Gujurat, India. Faculty from the Department of Pharmacology used an internal syllabus to prepare an assessment blueprint. A total of 12 faculty members prepared learning objectives and categorised cognitive domain levels by consensus. Learning objectives were scored according to clinical importance and marks were distributed according to proportional weighting. A three-dimensional test specification table of syllabus content, assessment tools and cognitive domains was prepared. Based on this table, a theory paper was created and administered to 126 pharmacology students. Feedback was then collected from the faculty members and students using a 5-point Likert scale. RESULTS: The majority of faculty members agreed that using a blueprint ensured proper weighting of marks for important topics (90.00%), aligned questions with learning objectives (80.00%), distributed questions according to clinical importance (100.00%) and minimised inter-examiner variations in selecting questions (90.00%). Few faculty members believed that use of the blueprint created too many easy questions (10.00%) or too many difficult questions (10.00%). Most students felt that the paper had a uniform distribution of questions from the syllabus (90.24%), that important topics were appropriately weighted (77.23%), was well organised (79.67%) and tested indepth subject knowledge (74.80%). CONCLUSION: These findings indicate that blueprinting should be an integral part of written assessments in pharmacology education. PMID- 28003896 TI - Laparoscopic Splenectomy Alone for Sickle Cell Disease: Account of 50 paediatric cases. AB - OBJECTIVES: In Oman, the most frequent indication for a splenectomy in children is sickle cell disease (SCD), which is one of the most common haematological disorders in the Gulf region. This study aimed to describe paediatric laparoscopic splenectomies alone for SCD at a tertiary hospital in Oman. METHODS: This study was conducted between February 2010 and October 2015 at the Sultan Qaboos University Hospital, Muscat, Oman. The medical records of all children aged <=15 years old undergoing splenectomies during the study period were reviewed. RESULTS: A total of 71 children underwent laparoscopic splenectomies during the study period; of these, 50 children (28 male and 22 female) underwent laparoscopic splenectomies alone for SCD. The children's weight ranged between 11 43 kg. The most common indication for a splenectomy was a recurrent splenic sequestration crisis (92%). Surgically removed spleens weighed between 155-1,200 g and measured between 9-22 cm. Operative times ranged between 66-204 minutes and intraoperative blood loss ranged between 10-800 mL. One patient required conversion to an open splenectomy. Postoperative complications were noted in only four patients. The median hospital stay duration was three days. CONCLUSION: Among this cohort, the mean operating time was comparable to that reported in the international literature. In addition, rates of conversion and postoperative complications were very low. These findings indicate that a laparoscopic splenectomy alone in paediatric patients with SCD is a feasible option. PMID- 28003897 TI - Use of Prescription Drugs and Investigations by Doctors in Primary Care Settings in Oman and the UK. AB - OBJECTIVES: This audit aimed to investigate the use of prescription drugs and investigations by trainee doctors in primary care settings in Oman and the UK. METHODS: This audit took place between February and April 2015. The medical records of consecutive patients seen by five family medicine trainee doctors at a primary care setting in Oman were retrospectively reviewed. These data were compared to those gathered from two trainees at a general practice clinic in the UK as well as an experienced general practitioner (GP) who had practiced in both countries. RESULTS: The average number of items prescribed per patient was 1.19, 0.43 and 0.24 and the rate of investigations was 20%, 21% and 11% for Omani trainees, UK trainees and the GP, respectively. CONCLUSION: This audit suggests that family medicine trainees in Oman prescribe almost three times as many drugs as trainees in the UK. The findings also point towards an over-investigation of the relatively young Omani patient population. PMID- 28003898 TI - Clinical Significance of an Unusual Variation: Anomalous additional belly of the sternothyroid muscle. AB - The infrahyoid muscles are involved in vocalisation and swallowing; among these, the sternothyroid muscle is derived from the common primitive sheet. The improper differentiation of this muscle may therefore result in morphological variations. We report an unusual variation found during the dissection of a 65-year-old male cadaver at the Sri Manakula Vinayagar Medical College, Madagadipet, Pondicherry, India, in 2015. An anomalous belly of the right sternothyroid muscle was observed between the internal jugular (IJ) vein and the internal carotid artery with an additional insertion into the tympanic plate and petrous part of the temporal bone and the presence of a levator glandulae thyroideae muscle. The anomalous muscle may compress the IJ vein if it is related to the neurovascular structures of neck; hence, knowledge of variations of the infrahyoid muscles can aid in the evaluation of IJ vein compression among patients with idiopathic symptoms resulting from venous congestion. PMID- 28003899 TI - Dental and Anaesthetic Challenges in a Patient with Dystrophic Epidermolysis Bullosa. AB - Epidermolysis bullosa is a group of rare genetic disorders characterised by skin and mucous membrane fragility and systemic manifestations of variable severity. We report a case of dystrophic epidermolysis bullosa in an 18-year-old male patient who presented to the Department of Oral Health at Sultan Qaboos University Hospital, Muscat, Oman, in 2015 with recurrent dental pain and infections. Due to the poor dental status of the patient and anticipated operative difficulties due to microstomia and limited mouth opening, the patient underwent full dental clearance under general anaesthesia. This article discusses the dental and anaesthetic challenges encountered during the management of this patient and provides a brief literature review. PMID- 28003900 TI - Relapse of Multiple Myeloma Presenting as Lower Lip Numbness. AB - Multiple myeloma (MM) is an uncommon malignancy characterised by the proliferation of clonal plasma cells. There are few published reports describing the extramedullary presentation of MM manifesting primarily in the head and neck region. In addition, the occurrence of an isolated relapse of MM in these sites is exceedingly rare. We report a 56-year-old female who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2010 with sudden-onset numbness of the lower lip. She had a history of MM in remission following chemotherapy and a bone marrow transplant. Clinical and radiographic examinations were indicative of a possible relapse of MM, which was subsequently confirmed by bone marrow aspiration and histopathological evaluation. This unique case highlights the unusual site of relapse of a haematolymphoid malignancy. PMID- 28003901 TI - Bilateral Anterior Ischaemic Optic Neuropathy in a Child on Continuous Peritoneal Dialysis: Case report and literature review. AB - Non-arteritic anterior ischaemic optic neuropathy (NAION) is a serious complication of continuous peritoneal dialysis (CPD) which can lead to poor vision and blindness. We report a five-year-old girl who had undergone a bilateral nephrectomy at the age of one year and was on home CPD. She was referred to the Paediatric Ophthalmology Unit of Sultan Qaboos University Hospital, Muscat, Oman, in 2013 with acute bilateral vision loss, preceded by a three-day history of poor oral intake. At presentation, the patient had severe systemic hypotension. An ophthalmological examination revealed severe bilateral visual impairment and NAION. She was treated with intravenous methylprednisolone and normal saline boluses. At a five-month follow-up, the visual acuity of the right eye had improved but vision in the left eye remained the same. Acute bilateral blindness due to NAION while on CPD is a rare condition in childhood. Paediatricians should be aware of this complication in order to ensure prompt management. PMID- 28003902 TI - Missed Gastric Injuries in Blunt Abdominal Trauma: Case report with review of literature. AB - Hollow viscus injuries of the digestive tract are an uncommon occurrence in blunt abdominal trauma. We report a 39-year-old male who was hit by a vehicle as a pedestrian and admitted to the Sultan Qaboos University Hospital, Muscat, Oman, in 2015. He underwent an exploratory laparotomy which revealed injuries to the distal stomach, liver and descending colon. Postoperatively, the patient was febrile, tachycardic and hypotensive. Abdominal examination revealed distention and tenderness. The next day, a repeat laparotomy identified a gastric injury which had not been diagnosed during the initial laparotomy. Although the defect was repaired, the patient subsequently died as a result of multiorgan failure. Missed gastric injuries are rare and are associated with a grave prognosis, particularly for trauma patients. Delays in diagnosis, in addition to associated injuries, contribute to a high mortality rate. PMID- 28003903 TI - Transcatheter Closure of Ruptured Sinus of Valsalva Aneurysm: Report of two cases. AB - A ruptured sinus of Valsalva aneurysm (RSVA) is a rare cardiac anomaly. Traditionally, RSVAs were repaired surgically; however, percutaneous transcatheter closure is the current treatment of choice. We report two cases of RSVA which were closed using this approach. The first case was a 45-year-old female who presented to the Royal Hospital, Muscat, Oman, in 2014 with a RSVA in the right ventricle. The second case was a 39-year-old male who was admitted to the Sultan Qaboos University Hospital, Muscat, in 2015 with a large multifenestrated RSVA extending into the right ventricle outflow tract. Each patient underwent transcutaneous cardiac catheterisation using three-dimensional echocardiography. Both interventions were technically successful; however, the second patient required a subsequent surgery due to the continuing presence of a significant shunt. Transcatheter closure of RSVAs is an effective alternative to surgical repair, although large multifenestrated RSVAs should be repaired surgically to ensure complete closure. PMID- 28003904 TI - A Case of Deep Vein Thrombosis and Intracranial Sinus Thrombosis: Possible rare complications of childhood abdominal tuberculosis. AB - Severe pulmonary tuberculosis (TB) complicated by deep vein thrombosis (DVT) in adults has been reported previously in the medical literature; however, childhood extrapulmonary TB complicated by DVT is rare. We report a 13-year-old girl who presented to the Department of Pediatrics at the Postgraduate Institute of Medical Sciences in Rohtak, India, in 2012 with abdominal TB complicated by DVT and intracranial sinus thrombosis. She was treated with a course of four antitubercular drugs and short-term anticoagulation therapy with a positive outcome over the next six months. To the best of the authors' knowledge, no previous reports have yet suggested a possible association between childhood TB and intracranial sinus thrombosis. PMID- 28003905 TI - Coexistence of Autism Spectrum Disorders Among Three Children with Tuberous Sclerosis Complex: Case reports and review of literature. AB - Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous disorder inherited in an autosomal dominant manner and characterised by benign tumours in the brain and other vital organs such as the heart, eyes, kidneys, skin and lungs. Links between autism spectrum disorder (ASD) and TSC have been postulated for many decades, with TSC considered to be one of the main syndromic causes of ASD; however, precise confirmation of a relationship between these two disorders required validated diagnostic tools. Fortunately, accurate evaluation of this relationship is now possible with standardised criteria for ASD diagnosis. We report three children who presented to the Sultan Qaboos University Hospital, Muscat, Oman, between 2014 and 2015 with ASD and TSC. These cases demonstrate the spectrum of neuropsychiatric involvement in TSC and highlight the importance of screening children with TSC for ASD features in order to encourage the early enrolment of these children in educational and rehabilitation programmes. PMID- 28003906 TI - Large Bilateral Symptomatic Pelvic Lymphoceles Following a Radical Prostatectomy. PMID- 28003907 TI - Multiple Pyoderma Gangrenosum Ulcers Associated with Cocaine Abuse. PMID- 28003908 TI - Rickettsial Infection Diagnosed in a Clinical Context in Oman. PMID- 28003909 TI - Erratum Notice of Author Name Correction: Currently Available Tools and Teaching Strategies for the Interprofessional Education of Students in Health Professions: Literature review. AB - [This corrects the article on p. e277 in vol. 16, PMID: 27606105.]. PMID- 28003910 TI - Assessment of Tear Film Quality among Smokers Using Tear Ferning Patterns. AB - Purpose. To investigate the effect of cigarette smoking on the ocular tear film. Methods. Thirty healthy young male cigarette smokers (20-38 years old) and 30 healthy age matched nonsmokers were enrolled in the study. McMonnies questionnaire, slit lamp, and PRT test were used to screen the subjects. Tear samples were collected from the right eyes and tear ferning patterns were observed and graded. Results. The mean MacMonnies scores and TF grades were significantly higher in the smoker subjects (mean +/- SD = 9.83 +/- 5.22 and 0.96 +/- 0.54, resp.) compared to nonsmokers (mean +/- SD = 5.96 +/- 3.06 and 0.41 +/- 0.38, resp.). The mean values obtained from PRT and TBUT tests were 22.23 +/- 6.35 mm and 12.17 +/- 3.81 s for smokers and 22.16 +/- 5.63 mm and 14.13 +/- 2.62 s for nonsmokers, respectively. Strong correlations were found between MacMonnies scores and both PRT (r = 0.596) and TF (r = 0.516). There was statistically significant difference in TF grades (p = 0.00), TBUT (p = 0.036) and McMonnies (p = 0.02) between smokers and nonsmokers. Conclusion. Cigarette smoking could have a significant effect on the tear film quality of the eye. PMID- 28003911 TI - Automated Fluid Management for Treatment of Rhabdomyolysis. AB - Purpose. Fluid therapy aimed at increasing urine output is a commonly employed strategy to prevent acute kidney injury (AKI) in critically ill patients with rhabdomyolysis. Automated fluid management has the potential to optimise urine output while avoiding fluid accumulation in rhabdomyolysis patients. Methods. In a single centre clinical service evaluation we compared a convenience sample of critically ill adults with rhabdomyolysis treated with automated fluid management using the RenalGuard(r) device to patients managed with manual fluid adjustment following our standard rhabdomyolysis protocol. Primary outcome was number of hours with urine output >2 mL/kg during first 48 h of therapy. Results. Eight patients treated with RenalGuard were compared to 28 patients treated with manual fluid management. Number of hours of target urine output was greater in the RenalGuard versus the Standard group (176/312 (56.4%) versus 534/1305 (40.9%); p < 0.01). Urine output was significantly higher in the first 24 h in the RenalGuard group (median (IQR) 4033 mL (3682-7363) versus 2913 mL (2263-4188 mL); p < 0.01). Fluid balance, electrolyte, diuretics, and bicarbonate use were comparable between groups. Conclusions. Automated fluid management resulted in a higher urine output more quickly in the treatment of rhabdomyolysis. Further research is needed to analyse the effect of diuresis-matched hydration for the prevention of AKI in rhabdomyolysis. PMID- 28003913 TI - A Rare Case of Primary Meningococcal Myopericarditis in a 71-Year-Old Male. AB - We describe a case of primary meningococcal C pericarditis with myocardial involvement in a 71-year-old male that is thus far the oldest patient with isolated meningococcal pericardial disease and only the third patient with primary meningococcal myopericarditis described in English literature. Our patient was successfully treated by full sternotomy and surgical drainage combined with intravenous ceftriaxone. Mild symptoms unresponsive to anti inflammatory treatment and leukocytosis may guide clinicians towards the correct diagnosis. It is important to recognize this cause of pericarditis as the relatively mild clinical presentation may rapidly progress into tamponade and right-sided heart failure. PMID- 28003914 TI - Addison's Disease and Dilated Cardiomyopathy: A Case Report and Review of the Literature. AB - Addison's disease is often accompanied by a number of cardiovascular manifestations. We report the case of a 30-year-old man who presented with a new onset dilated cardiomyopathy due to Addison's disease. The clinical presentation, treatment, and outcomes of this rare hormone mediated cardiac disorder are reviewed. PMID- 28003912 TI - Reduced gamma-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naive Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk. AB - Altered gamma-aminobutyric acid (GABA), glutamate (Glu) levels, and an imbalance between GABAergic and glutamatergic neurotransmissions have been involved in the pathophysiology of schizophrenia. However, it remains unclear how these abnormalities impact the onset and course of psychosis. In the present study, 21 drug-naive subjects at ultrahigh risk for psychosis (UHR), 16 drug-naive patients with first-episode schizophrenia (FES), and 23 healthy controls (HC) were enrolled. In vivo GABA and glutamate+glutamine (Glx) levels in the medial prefrontal cortex were measured using proton magnetic resonance spectroscopy. Medial prefrontal GABA and Glx levels in FES patients were significantly lower than those in HC and UHR, respectively. GABA and Glx levels in UHR were comparable with those in HC. In each group, there was a positive correlation between GABA and Glx levels. Reduced medial prefrontal GABA and Glx levels thus may play an important role in the early stages of schizophrenia. PMID- 28003915 TI - Inflammatory Pseudotumor Originating from the Right Ventricular Outflow Tract. AB - Introduction. Inflammatory pseudotumor is an uncommon entity, and its cardiac origin is exceedingly rare. Case History. A previously healthy 27-year-old man was found to have a systolic murmur during preemployment screening evaluation. A transthoracic echocardiogram revealed a 4 * 2.5 cm mass originating from the right ventricle (RV) outflow tract extending into the aortic root. A computed tomography guided biopsy confirmed an IgG4-related inflammatory pseudotumor. Patient was started on oral prednisone with subsequent reduction in mass size. Conclusion. Cardiac inflammatory pseudotumors are markedly rare tumors that should be considered in the differential of intracardiac tumors which otherwise includes cardiac fibromas, myxomas, and sarcomas. PMID- 28003916 TI - Oral Rehabilitation and Management for Secondary Sjogren's Syndrome in a Child. AB - The aim of this paper is to describe a rare case report of a pediatric patient with secondary Sjogren's syndrome (SSS). A 12-year-old female child was referred to the Pediatric Dentistry Clinic with the chief complaint of tooth pain, dry mouth, and tooth sensibility. The patient was submitted to orthodontic treatment prior to syndrome diagnosis. The clinical treatment consisted of the interruption of orthodontic treatment and restoring the oral condition with dental treatment and the use of artificial saliva in an innovative apparatus. Dental therapy involved the control of dental caries, periodontal disease, and opportunistic fungal infections and the use of fluoride-rich solutions. The present clinical case describes clinical and laboratory aspects of SSS in pediatric patients. The management of the oral findings promoted an improvement in the oral health status and quality of life of the child. PMID- 28003917 TI - Frontal Mucocele following Previous Facial Trauma with Hardware Reconstruction. AB - Mucoceles are cysts that can develop after facial bone fractures, especially those involving the frontal sinuses. Despite being rare, mucoceles can result in serious delayed sequelae. We present a case of a frontal mucocele that developed two years after extensive facial trauma following a motor vehicle crash (MVC) and review the emergency department (ED) evaluation and treatment of mucocele. Early recognition, appropriate imaging, and an interdisciplinary approach are essential for managing these rare sequelae of facial trauma. PMID- 28003918 TI - Superior Mesenteric Artery Syndrome with Abdominal Compartment Syndrome. AB - Superior Mesenteric Artery (SMA) syndrome is a condition in which the duodenum becomes compressed between the SMA and the aorta, resulting in bowel obstruction which subsequently compresses surrounding structures. Pressure on the inferior vena cava (IVC) and aorta decreases cardiac output which compromises distal blood flow, resulting in abdominal compartment syndrome with ischemia and renal failure. A 15-year-old male with SMA syndrome presented with 12 hours of pain, a distended, rigid abdomen, mottled skin below the waist, and decreased motor and sensory function in the lower extremities. Exploratory laparotomy revealed ischemic small bowel and stomach with abdominal compartment syndrome. Despite decompression, the patient arrested from hyperkalemia following reperfusion. PMID- 28003919 TI - Successful Pregnancy Outcome in Women with Recurrent IVF Failure and Anti-hCG Autoimmunity: A Report of Three Cases. AB - We report three cases of effective management of infertility in women with a history of repeated unsuccessful IVF attempts, who have developed antibodies to hCG. A novel approach to conservative treatment of immunologic reproductive failure, suggested for selected patients, included membrane plasmapheresis, combined prednisolone, and intravenous immunoglobulin therapy. No adverse side effects were observed; all cases resulted in pregnancy and subsequent life births. In order to be given an adequate efficient treatment, women with recurrent implantation failure should be suspected for autoimmune factor of infertility and its possible association with anti-hCG autoimmunity. PMID- 28003920 TI - A Rare Case of Coexistence of Borderline Lepromatous Leprosy with Tuberculosis Verrucosa Cutis. AB - Occurrence of pulmonary tuberculosis with leprosy is known but association of cutaneous tuberculosis with leprosy is rare. We report a case of borderline lepromatous leprosy coexistent with tuberculosis verrucosa cutis in a 29-year-old male, who presented with multiple skin coloured nodules and hyperkeratotic scaly lesions of 3-month duration. Dual infections are associated with high mortality and morbidity. Therefore early diagnosis and management helps to reduce mortality and to mitigate the effects of morbidity. PMID- 28003921 TI - Bullous Dermatosis in an End-Stage Renal Disease Patient: A Case Report and Literature Review. AB - Patients with advanced chronic kidney disease including ESRD patients may present with a wide spectrum of cutaneous abnormalities, ranging from xerosis to hyperpigmentation to severe deforming necrotizing lesions. Skin problems are not uncommon in this population of patients, with a clinical presentation that can be quite bizarre, mandating a long list of differential diagnostic possibilities, and subsequent rise of a puzzling diagnostic challenge. We describe an ESRD patient who presented with blistering, nonhealing ulcerative lesions with a diagnostic skin biopsy revealing a mixed pattern of linear IgA bullous dermatosis and dermatitis herpetiformis. A clinical remission could be achieved with pulse intravenous steroids followed by oral maintenance in combination with dapsone, with no evidence of recurrence. PMID- 28003922 TI - Motor Speech Apraxia in a 70-Year-Old Man with Left Dorsolateral Frontal Arachnoid Cyst: A [18F]FDG PET-CT Study. AB - Motor speech apraxia is a speech disorder of impaired syllable sequencing which, when seen with advancing age, is suggestive of a neurodegenerative process affecting cortical structures in the left frontal lobe. Arachnoid cysts can be associated with neurologic symptoms due to compression of underlying brain structures though indications for surgical intervention are unclear. We present the case of a 70-year-old man who presented with a two-year history of speech changes along with decreased initiation and talkativeness, shorter utterances, and dysnomia. [18F]Fluorodeoxyglucose (FDG) Positron Emission and Computed Tomography (PET-CT) and magnetic resonance imaging (MRI) showed very focal left frontal cortical hypometabolism immediately adjacent to an arachnoid cyst but no specific evidence of a neurodegenerative process. PMID- 28003923 TI - Interdigital Neuroma in the Second Intermetatarsal Space Associated with Metatarsophalangeal Joint Instability. AB - The entrapment theory is the most commonly accepted theory concerning the development of interdigital neuroma; it incriminates the deep transverse metatarsal ligament as the major causative factor of the condition. This report presents a patient with interdigital neuroma in the second intermetatarsal space, which was strongly suspected to be caused by the metatarsophalangeal joint instability due to plantar plate injury. Surgical intervention revealed that the neuroma was located more distally and dorsally than the deep transverse metatarsal ligament and was pinched between the adjacent metatarsal heads, suggesting the involvement of the metatarsophalangeal joint instability and chronic trauma as etiologies in this case. PMID- 28003924 TI - Intrathyroidal Clear Cell Tumor of Parathyroid Origin with Review of Literature. AB - Water-clear cell adenoma (WCCA) of the parathyroid gland is an exceedingly rare neoplasm. To date, 17 cases have been reported in the literature, with only one of them being intrathyroidal. Here we report a case of a 34-year-old woman who presented for evaluation of a goiter and was found to have a thyroid nodule and abnormal thyroid function tests (TFT). Fine needle aspiration biopsy of the nodule revealed thyroid follicular cells without atypia and subsequent Afirma(r) Gene Expression Classifier (GEC) testing results were suspicious for malignancy. As a result, the patient underwent a right thyroid lobectomy and isthmusectomy. Histological sections revealed an intrathyroidal nodule consistent with a clear cell neoplasm of parathyroid origin. The histologic appearance together with the immune profile was diagnostic of WCCA, with diffuse positivity for GATA3, focal weak positivity for parathyroid hormone, and negativity for PAX8, thyroglobulin, TTF1, synaptophysin, chromogranin, and S100p. Our study focuses on the clinical presentation, current management strategies, and review of the available literature surrounding this rare diagnosis. The ultimate goal is to help endocrinologists and surgeons establish a foundational treatment plan for intrathyroidal clear cell tumor cases. PMID- 28003925 TI - Fetal Valproate Syndrome with Limb Defects: An Indian Case Report. AB - Epilepsy is a common disorder and exposure to antiepileptic drugs during pregnancy increases the risk of teratogenicity. Older AEDs such as valproate and phenobarbital are associated with a higher risk of major malformations in the fetus than newer AEDs like lamotrigine and levetiracetam. Exposure to valproic acid during first trimester can result in fetal valproate syndrome (FVS), comprising typical facial features, developmental delay, and a variety of malformations such as neural tube defects, cardiac and genitourinary malformations, and limb defects. We are presenting an Indian case of FVS with major limb defects. PMID- 28003926 TI - Torsion of a Communicating Hydrocele Presented as Acute Scrotum: A Case Report and Literature Review. AB - Torsion of a communicating hydrocele is extremely rare, and the cause is unclear. We report the case of a 3-year-old boy referred to us with acute scrotum. Operative findings revealed torsion of a communicating hydrocele with a 360 degree rotation of the distal end. We performed surgical excision of the necrotic cystic mass and high ligation of the peritoneal communication. A high index of suspicion is required for the correct diagnosis and treatment of this condition, which should be included among the causes of acute scrotum in childhood. PMID- 28003927 TI - Thymic Epidermoid Cyst: Clinical and Imaging Manifestations of This Rare Anterior Mediastinal Mass. AB - Thymic epidermoid cysts are an extremely rare entity. These arise from epidermal cells that migrate to the thymus. The radiologic diagnosis of this rare lesion is challenging. We describe a case of an otherwise healthy 35-year-old woman who presented with an acute onset of chest pain and shortness of breath. She was found to have an anterior mediastinal mass. The imaging findings were, however, not characteristic for any single diagnostic entity. Since the imaging was inconclusive, surgical resection was performed for definitive diagnosis. The mass was found to be a thymic epidermoid cyst. This case underlines the significance for radiologists to be aware that epidermoid cysts can occur in the thymus and should be considered in the differential diagnosis for a heterogeneous anterior mediastinal mass. PMID- 28003928 TI - Ectopic Pregnancy in a Cesarean Section Scar: Successful Management Using Vacuum Aspiration under Laparoscopic Supervision-Mini Review of Current Literature. AB - A cesarean scar ectopic pregnancy (CSEP) is a fairly uncommon presentation wherein the conceptus is implanted deep in the myometrium and at the exact scar site of the previous cesarean section. There are various CSEP management options that range from medical treatment to surgical interventions such as dilatation and curettage, laparoscopic excision, resection by laparotomy, or, sometimes, a combination of these modalities. Establishing a diagnosis of CSEP can be challenging. Given the relatively rare incidence of CSEP, its management is controversial and current standards of therapy have been derived from data obtained from a limited number of patients. Herein, we present transvaginal ultrasonography (TVUS) imaging findings and management strategies used in a case of CSEP along with the short review of current literature. PMID- 28003929 TI - Rapid Quantitative Analysis of Forest Biomass Using Fourier Transform Infrared Spectroscopy and Partial Least Squares Regression. AB - Fourier transform infrared reflectance (FTIR) spectroscopy has been used to predict properties of forest logging residue, a very heterogeneous feedstock material. Properties studied included the chemical composition, thermal reactivity, and energy content. The ability to rapidly determine these properties is vital in the optimization of conversion technologies for the successful commercialization of biobased products. Partial least squares regression of first derivative treated FTIR spectra had good correlations with the conventionally measured properties. For the chemical composition, constructed models generally did a better job of predicting the extractives and lignin content than the carbohydrates. In predicting the thermochemical properties, models for volatile matter and fixed carbon performed very well (i.e., R2 > 0.80, RPD > 2.0). The effect of reducing the wavenumber range to the fingerprint region for PLS modeling and the relationship between the chemical composition and higher heating value of logging residue were also explored. This study is new and different in that it is the first to use FTIR spectroscopy to quantitatively analyze forest logging residue, an abundant resource that can be used as a feedstock in the emerging low carbon economy. Furthermore, it provides a complete and systematic characterization of this heterogeneous raw material. PMID- 28003930 TI - The Development of Criteria for the Selection of Chinese Peer Educators in HIV Management: A Delphi Study. AB - To develop an expert consensus opinion of the criteria for selection of peer educator for HIV/AIDS care program, twenty experts were invited to complete a two round Delphi consultation. Response rates of the panelists for the first and second rounds were both 100%, and the authority coefficient of the experts was 0.75. Experts achieved consensus on a total of nine items (75%) on completion of the study. The Precedence Chart Method was used to calculate the weight of each indicator, and then a priority list was generated accordingly. This study provides the initial selection criteria for HIV/AIDS peer educators in Shanghai as well as in China. PMID- 28003931 TI - Stability of Thawed Apheresis Fresh-Frozen Plasma Stored for up to 120 Hours at 1 degrees C to 6 degrees C. AB - Regulations concerning the storage of transfusable plasma differ internationally. In Canada, plasma obtained from whole blood donations and frozen within 24 hours of phlebotomy (frozen plasma, FP) may be thawed and transfused within 120 hours of refrigerated storage. However, plasma frozen within 8 hours of phlebotomy following apheresis donation (FFPA) must be transfused within 24 hours of thawing and refrigeration. Our objectives were to measure coagulation factors (F) V, VII, and VIII, fibrinogen activities, and the prothrombin time (PT) in thawed refrigerated FFPA at 0, 24, and 120 hours of storage and to compare these values to those in thawed refrigerated FP. Fibrinogen activity remained unchanged over time, while mean factor levels in 28 FFPA units declined by 17% (FV), 19.7% (FVII), and 54.6% (FVIII) over 120 hours, while PT values rose to 7.6%. Factor activities were significantly higher in FFPA than FP after 120 hours of refrigerated storage. Residual FVIII activities in thawed FFPA met predefined noninferiority criteria compared to thawed FP after 120 hours. These results support a change in Canadian regulations to permit transfusion of thawed FFPA made in a closed system and refrigerated for up to 120 hours, one that could reduce wastage of transfusable plasma. PMID- 28003933 TI - alphaSMA Expression in Large Colonies of Colony-Forming Units-Fibroblast as an Early Predictor of Bone Marrow MSC Expandability. AB - Clinical applications of mesenchymal stromal cells (MSCs) require the manufacture of large cell lots, which involves multiple passages for cell expansion and sometimes genetic modification. MSCs from various sources, including bone marrow (BM), exhibit high donor-to-donor variability in their growth characteristics. This can lead to unpredictable manufacturing outcomes with respect to success or failure of individual lots. Early determination of lot success has the potential to reduce the cost and improve the efficiency of the MSC manufacturing process. However, methods that effectively predict lot growth potential early in the manufacturing process are currently lacking. Here we report that the growth potential of an MSC lot can be predicted a few days after BM plating based on alpha-smooth muscle actin (alphaSMA) protein expression in large colony-forming unit-fibroblast (CFU-f) colonies. The proposed prediction method could be a useful tool to prospectively determine MSC lot success or failure. PMID- 28003932 TI - Allogeneic Mesenchymal Stem Cell Transplantation in Dogs With Keratoconjunctivitis Sicca. AB - Keratoconjunctivitis sicca (KCS) is a dysfunction in tear production associated with clinical signs, which include conjunctival hyperemia, ocular discharge, discomfort, pain, and, eventually, corneal vascularization and pigmentation. Immunosuppressive drugs are routinely administrated for long periods to treat KCS but with side effects and limited results. Evaluation of the clinical benefits of intralacrimal transplantation of allogeneic mesenchymal stem cells (MSCs) in dogs with mild-moderate and severe KCS was done. A total of 24 eyes with KCS from 15 dogs of different breeds were enrolled in the present study. A single transplantation of MSCs (1 * 106) directly into lacrimal glands (dorsal and third eyelid) was performed. The Schirmer tear tests (STTs) and ocular surface improvements were used to assess short- and long-term effects of these cells. The STTs were carried out on day 0 (before MSCs transplantation) and on days 7, 14, 21, and 28, as well as 6 and 12 months after MSC transplantation. Our data demonstrate that allogeneic MSC transplantation in KCS dogs is safe since no adverse effects were observed immediately after transplantation and in short- and long-term follow-ups. A statistically significant increase in the STT and ocular surface improvements was found in all eyes studied. In all the eyes with mild moderate KCS, STT values reverted to those of healthy eyes, while in eyes with severe KCS, although complete reversion was not found, there was improvement in tear production and in other clinical signs. Our study shows that a single dose of a low number of MSCs can be used to treat KCS in dogs. In contrast to immunosuppressive drug use, MSC transplantation has an effect over a long period (up to 12 months), even after a single administration, and does not require daily drug administration. PMID- 28003934 TI - Stability Enhancement Using Hyaluronic Acid Gels for Delivery of Human Fetal Progenitor Tenocytes. AB - Tendon afflictions are very common, and their negative impact is high both at the workplace and in leisure activities. Tendinopathies are increasing in prevalence and can lead to tendon ruptures, where healing is a long process with outcomes that are often disappointing. Human fetal progenitor tenocytes (hFPTs) have been recently tested in vitro as a potential cell source to stimulate tendon regeneration. The aim of the present study was to compare different commercial hyaluronic acid (HA) gels, which could be used to resuspend hFPTs in a formulation that would allow for good delivery of the cells. No medium or growth supplement was used in the formulation in order to make it therapeutically dispensable. These conditions are stringent for cells, but surprisingly, we found that different formulations could allow a good survival for up to 3 days when stored at 4 degrees C (refrigerator stable). The gels must allow a good survival of the cells in parallel with a good stability of the preparation over time and sufficient viscosity to remain in place if deposited on a wounded location. Moreover, the cells must conserve their ability to attach and to proliferate. hFPTs were able to survive and to recover from all of the tested gels, but some products showed some advantages over others in terms of survival and viscosity. Finally, the Ostenil Tendon HA gel fulfilled all of the requirements and presented the best compromise between a good survival and sufficient rheological characteristics to create an interesting cell delivery system. PMID- 28003935 TI - Aggregation of Engineered Human beta-Cells Into Pseudoislets: Insulin Secretion and Gene Expression Profile in Normoxic and Hypoxic Milieu. AB - Innovative treatments to cure type 1 diabetes are being actively researched. Among the different strategies, the replacement of beta-cells has given promising results. Classically, islets from cadaveric donors are transplanted into diabetic patients, but recently phase I clinical trials that use stem cell-derived beta cells have been started. Such protocols require either an immunosuppressive treatment or the macroencapsulation of the beta-cells. They involve cell aggregation and the exposure of the cells to hypoxia. Using an engineered human beta-cell, we have addressed these two problems: a novel human beta-cell line called EndoC-betaH3 was cultured as single cells or aggregated clusters. EndoC betaH3 cells were also cultured at normal atmospheric oxygen tension (pO2 = 21%) or hypoxia (pO2 = 3%) in the presence or absence of modulators of the hypoxia inducible factor 1alpha (HIF1alpha) pathway. Cell aggregation improved glucose stimulated insulin secretion, demonstrating the benefit of cell-cell contacts. Low oxygen tension decreased beta-cell viability and their sensitivity to glucose, but did not alter insulin production nor the insulin secretion capacity of the remaining cells. To investigate the role of HIF1alpha, we first used a HIF stabilizer at pO2 = 21%. This led to a mild decrease in cell viability, impaired glucose sensitivity, and altered insulin secretion. Finally, we used a HIF inhibitor on EndoC-betaH3 pseudoislets exposed to hypoxia. Such treatment considerably decreased cell viability. In conclusion, aggregation of the EndoC betaH3 cells seems to be important to improve their function. A fraction of the EndoC-betaH3 cells are resistant to hypoxia, depending on the level of activity of HIF1alpha. Thus, these cells represent a good human cell model for future investigations on islet cell transplantation analysis. PMID- 28003936 TI - Towards quantitative viromics for both double-stranded and single-stranded DNA viruses. AB - BACKGROUND: Viruses strongly influence microbial population dynamics and ecosystem functions. However, our ability to quantitatively evaluate those viral impacts is limited to the few cultivated viruses and double-stranded DNA (dsDNA) viral genomes captured in quantitative viral metagenomes (viromes). This leaves the ecology of non-dsDNA viruses nearly unknown, including single-stranded DNA (ssDNA) viruses that have been frequently observed in viromes, but not quantified due to amplification biases in sequencing library preparations (Multiple Displacement Amplification, Linker Amplification or Tagmentation). METHODS: Here we designed mock viral communities including both ssDNA and dsDNA viruses to evaluate the capability of a sequencing library preparation approach including an Adaptase step prior to Linker Amplification for quantitative amplification of both dsDNA and ssDNA templates. We then surveyed aquatic samples to provide first estimates of the abundance of ssDNA viruses. RESULTS: Mock community experiments confirmed the biased nature of existing library preparation methods for ssDNA templates (either largely enriched or selected against) and showed that the protocol using Adaptase plus Linker Amplification yielded viromes that were +/ 1.8-fold quantitative for ssDNA and dsDNA viruses. Application of this protocol to community virus DNA from three freshwater and three marine samples revealed that ssDNA viruses as a whole represent only a minor fraction (<5%) of DNA virus communities, though individual ssDNA genomes, both eukaryote-infecting Circular Rep-Encoding Single-Stranded DNA (CRESS-DNA) viruses and bacteriophages from the Microviridae family, can be among the most abundant viral genomes in a sample. DISCUSSION: Together these findings provide empirical data for a new virome library preparation protocol, and a first estimate of ssDNA virus abundance in aquatic systems. PMID- 28003937 TI - Accuracy of Breath-hold CT in Treatment Planning for Lung Stereotactic Ablative Radiotherapy. AB - PURPOSE: The objectives of this study are (1) to measure concordance of tumor position on breath-hold (BH) computed tomography (CT) scans relative to the natural tumor path during free breathing (FB) and (2) to evaluate the benefits of the breathing monitoring device Abches (Apex Medical, Tokyo) for stereotactic ablative radiotherapy (SABR) treatment planning. METHODS: In 53 lung cancer patients treated with CyberKnifeTM robotic radiosurgery system, FB four dimensional computerized tomography (4DCT) and end-expiration (EE) BH CT images were obtained. Extent of natural tumor motion was assessed with rigid registration derived from end-inspiration (EI) and EE phases of the 4DCT. Tumor displacement in BH scans relative to the natural tumor path was measured relative to the EE 4DCT phase. RESULTS: Mean tumor motion (+/- 1 SD) during natural FB was 1 +/- 1 mm, 2 +/- 2 mm, and 6 +/- 6 mm in medio-lateral, anterior-posterior, and cranio-caudal directions, respectively. Tumor position on BH CT scan was closer to EE than EI 4DCT phase for 35/53 patients (66%). Difference of BH tumor position vs. EE state was 4 +/- 3 mm. Gross tumor displacements perpendicular to natural tumor path were as great as 11 mm (anterior-posterior) and were seen with or without the breathing monitoring device. CONCLUSION: Tumor position during BH CT may not accurately correspond to positions observed on FB 4DCT. Hence, accurate and custom 4D analysis for each individual patient is recommended for treatment planning, especially those involving BH acquisitions. PMID- 28003938 TI - An Interventional Study on the Clinical Usefulness and Outcomes of Electroconvulsive Therapy in Medication-Resistant Mental Disorders. AB - BACKGROUND: Resistance to recommended medications has been an issue in dealing with a number of psychiatric ailments, and it is showing up as an ongoing challenge for contemporary mental health experts. Resistant psychiatric disorders not only increase the morbidity of patients suffering from such severe conditions but also intensify the problems of their caretakers. This has vigorously started to cause the costs to increase for healthcare services. Thanks to electroconvulsive therapy (ECT), we now have an effective method that is proving to be a fruitful final course of action in this micro-epidemic of resistant psychiatric diseases. However, the medical literature of case reports or studies in this niche is scarce. Also, no such comprehensive study has been carried out in the Southeast Asian region to date for the assessment of the effectiveness of electroconvulsive therapy in patients with medication-resistant psychiatric disorders. AIM: To assess the effectiveness of ECT in medication-resistant psychiatric patients at the post-ECT course, three-month follow-up, and six-month follow-up. MATERIALS AND METHODS: The study was a prospective and interventional study (without controls) conducted in the Institute of Mental Health and Neurosciences (IMHANS), Srinagar, India. Fifty-six patients with pharmacotherapy resistant psychiatric disorders were included in the study. The patients were assessed at the end of the ECT course, at the three-month follow-up, and at the six-month follow-up by the Clinical Global Impression (CGI), Montgomery Asberg Depression Rating Scale (MADRS), Young Manic Rating Scale (YMRS) and the Yale Brown Obsessive Compulsive Scale (YBOCS). Improvement was defined with the help of the CGI subscale by comparing the position of the patient at admission to the projected condition with ECT. STATISTICAL ANALYSIS: Analysis of Variance (ANOVA) was used for analysis of the quantitative data. For the pair-wise comparison of the groups, the post hoc tests were used. Pearson's chi-square test was used for analysis of qualitative data. A p-value of < 0.05 was considered to be statistically significant, and all the data analysis was done using SPSS Version 20.0. RESULTS: The CGI scale revealed that statistically significant improvement occurred in patients at the end of ECT course, at the three-month follow-up as well as at the six-month follow-up. CONCLUSION: ECT should be used for the treatment of pharmacotherapy-resistant psychiatric patients and the benefits can be seen even six months after an ECT course completion. Further work in this field should focus on educating the general public about the usefulness of ECT in the treatment of resistant mental illnesses. The myths related to the so-called psychiatric assault from ECT should be removed. PMID- 28003939 TI - A Rare Combination of Complex Elbow Dislocation and Distal Radial Fracture in Adults. AB - Although it is common for separate elbow joint dislocation and fracture of forearm bones to occur, it is a rare sighting for both elbow dislocation and ipsilateral fracture of the distal radius. We report a case of an anterior dislocation of the elbow with ipsilateral fracture of the distal radius. The case was treated operatively. We describe two possible mechanisms of injury for these rare injury types. The case underlines the importance of assessing the wrist in the case of an elbow fracture and vice versa. PMID- 28003940 TI - Intraventricular Undifferentiated Pleomorphic Sarcoma: A Case Report. AB - Undifferentiated pleomorphic sarcoma is a histologic diagnosis based on cell morphology. These tumors are found throughout the body. They are rarely found in the central nervous system and almost never occur as a primary intraventricular tumor. We present the unusual case of a 68-year-old woman with an intraventricular undifferentiated pleomorphic sarcoma. We go on to discuss the clinical presentation, radiographic characteristics, and management paradigm for these rare lesions. Our patient presented with acute confusion, inability to balance a checkbook, and gait imbalance. CT and MRI demonstrated a 4 x 3.6 x 3.6 cm enhancing lesion in the left lateral ventricle abutting the foramen of Monro. Pathology revealed an undifferentiated pleomorphic sarcoma. PMID- 28003941 TI - Negative Pressure Wound Therapy with Instillation in a Chronic Non-Healing Right Hip Trochanteric Pressure Ulcer. AB - Complex pressure ulcer wound sites often present with a wide scope of barriers to healing ranging from high colonization of multi-drug-resistant pathogens to tortuous internal anatomy which make the wound recalcitrant to traditional wound care including standard negative pressure wound therapy (NPWT). Negative pressure wound therapy with instillation (NPWTi-d) provides an opportunity to manage and heal wounds with indications not met by standard NPWT such as cavitating wounds with complex undermining and tunneling. In this clinical case report, a patient who presented with a chronic, non-healing Stage IV pressure ulcer underwent a tensor fascia lata flap reconstruction that was complicated by a partial flap-tip nonadherence with associated partial dehiscence of the flap incision that proved unresolvable until application of adjunctive NPWTi-d which allowed the wound to experience a robust rate of granulation, contraction, and closure. PMID- 28003942 TI - Clinical Usage and Economic Effectiveness of a Recently Developed Epidermal Autograft Harvesting System in 13 Chronic Wound Patients in a University-Based Wound Center. AB - INTRODUCTION: Chronic wounds are a significant healthcare problem in the United States. Their costs approach 25 billion dollars in the United States. Current wound-care treatments of local wound care, moist dressings, and source control, while necessary for wound healing, are frequently not enough to ensure complete wound closure. The current surgical technique of split-thickness skin grafting is an operative procedure, painful, time-consuming, and leaves significant donor site wounds. A recently developed and marketed epidermal autograft harvester was tested at our university hospital wound center on 13 patients with wounds of various etiologies. Their clinical outcomes were evaluated, as were the costs associated with its usage compared with the potential costs of continued wound care without autograft placement. METHODS: Thirteen patients whose wounds appeared to have "stalled" or reached a plateau in healing by measurement data and visual evidence were chosen to receive an epidermal autograft to accelerate wound closure. Wound-types included diabetic ulcers, venous or lymphedema-related ulcers, surgical site wounds, and traumatic wounds. Time-to-healing in days, when applicable, was captured. Wound center billing and charges were available and evaluated for nine of the 13 patients. Costs of standard care continuation compared with the cost of epidermal autograft technology usage were compared. RESULTS: Healing rates were 62%; eight of the 13 patients had healed within four months, two were lost to follow-up, and three have wounds that remain open. Four of the patients healed in less than one month. The comparatively rapid closure of the open wound(s) post-epidermal autograft placement potentially reduced healthcare costs based on charges at an average of $1,153 per patient and yielded an average of $650 to the wound center, not applying the routine costs of dressings applied in the center. Conclusion: The epidermal autograft harvester accelerated healing in eight of the 13 of the patients (62%) we treated at the time of the writing of this article. By accelerating wound healing in our patient population, costs associated with subsequent wound care seem to have decreased to a dramatic degree and wound center finances have improved. No wound recurrence has been noted once the wounds had healed in our year-long experience with the technology. In addition, the procedure has been well-tolerated and easy to perform. Given the improved outcomes, cost-savings, and a better financial outlook for the wound center, utilization of the novel epidermal autograft harvester is proving itself to be in the "win-win" category of wound care treatments. PMID- 28003943 TI - Envisioning and Leading Organizational Transformation: One Organ Procurement Organization's Journey. AB - BACKGROUND: In 2012, one organ procurement organization (OPO) welcomed a new President and Chief Executive Officer (CEO). This OPO, LifeShare Transplant Donor Services of Oklahoma (LifeShare), had just celebrated its 25th anniversary in 2011. While LifeShare was well-established chronologically, growth in organ donors and organs transplanted from these donors had occurred at a much slower rate during the collaborative era and afterward (2003-2011) than the donor/transplant growth the United States (US), as a whole, had experienced. While this performance had been stable, it was in the lower quartile of US OPOs on a per capita basis (organs transplanted per donor), and conversion rates were unremarkable. It was the sense of the OPO and donation service area (DSA) constituents that there was an opportunity for growth. It was under this premise that the new CEO was recruited in late 2011 and assumed leadership in February 2012. METHOD: It important to note that the new CEO (the author) found LifeShare possessed numerous significant assets upon which to build. These included a strong core of committed and dedicated staff, a supportive Board, supportive transplant centers, and a strong state donor registry. Therefore, it was apparent that, while achieving the DSA's potential would require a transformation of the organization, the transformation did not necessarily require replacing core staff, often a common step undertaken by new chief executives. Beginning in 2012, the CEO sought to transform both the culture and the operation of the organization by focusing on a short list of key strategies. Culturally, three primary initiatives were undertaken: leadership development, staff development, and establishing "organizational clarity". Operationally, the primary focus was identifying organ donor potential and then, based upon the opportunities for improvement, focusing on operational policies and practices. As LifeShare's team began to identify pockets of unrealized potential donors, recognized best practices were deployed to areas of opportunity, including responding to all vented referrals, implementation of dedicated family requestors, broadening of already-existing in-house coordinator programs, and aggressive expansion of the donors after cardiac death (DCD) program. RESULTS: From 2008 through 2011, the four years prior to the organization beginning its change journey, LifeShare recovered 344 organ donors from which 1,007 organs were transplanted in 48 months. During the first 48 months of the change journey (2012 through 2015), 498 organ donors (+44.8%) provided 1,536 organs transplanted (+52.5%). DCD donors increased from 22 to 91 (+413.4%) and brain death (BD) donors from 322 to 407 (+26.4%). While the rate of growth is slowing somewhat, the first eight months of 2016 continue to show a percentage growth over 2015 in double digits for both organ donors and organs transplanted. DISCUSSION: Clearly, our results have been transformed and continue to be transformed. A cultural foundation for both leadership and staff, combined with a single-minded focus on maximizing recovery of potential organ donors and maximizing transplantation of every potential organ, has allowed us to achieve exceptional growth rates on a scale that has resulted in more than 500 additional organs transplanted and lives saved over the last four years when compared to pre-change results. PMID- 28003944 TI - Role of Intraoperative Nerve Monitoring During Parathyroidectomy to Prevent Recurrent Laryngeal Nerve Injury. AB - Injury to the recurrent laryngeal nerve (RLN) is a well known, though less frequent, complication of parathyroid surgery. In recent years, the use of intraoperative nerve monitoring (IONM) has gained popularity amongst surgeons when operating on thyroid gland; however, its utilization in parathyroid surgery is not established. This trend continues to rise, despite multiple studies documenting no statistically significant difference that IONM decreases the incidence of RLN injury. Most surgeons use this technology as an adjunct to visualization alone for identification of RLN. The purpose of this review is to discuss the possible role of IONM in parathyroid surgery with regards to the accuracy, efficacy, and recent trends in the utilization of this technology. There is insufficient evidence that IONM reduces the risk of RLN injury in parathyroidectomy. Although IONM may decrease the likelihood of nerve injury by helping to identify and map the RLN during thyroidectomy, we did not find studies exclusive to parathyroid surgery to see if its use can be supported for parathyroidectomy. Despite this lack of evidence, we believe that IONM is a promising adjunct to visualization alone in detecting nerve structures during neck dissection, but more clinical trials are warranted to establish its role in preventing nerve injury in parathyroid surgery. PMID- 28003945 TI - Autologous Epidermal Grafting Using a Novel Negative Pressure Epidermal Harvesting System in a Case of Stable Vitiligo. AB - Vitiligo is a common pigmentary disorder of the skin with a great amount of social stigma attached to it. Though various medical modalities are available for the treatment of stable vitiligo, surgical modality remains the treatment of choice for stable and localized vitiligo. The surgical options range from simple punch grafting to the recent epidermal harvesting methods using a negative pressure unit. Although successful use of multiple methods of epidermal grafting has been reported, most of them are cumbersome and time-consuming. The new automated epidermal harvesting system now commercially available involves a tool that applies both heat and suction concurrently to normal skin to induce epidermal micrografts. Hence it serves as a safe, quick and cost-effective method without anesthesia, with a very minimal downtime for healing and requires an optimal expertise. The duration of repigmentation seems to be faster and more uniform compared to other procedures. We would like to share our experience with the negative pressure epidermal harvesting method in a patient with stable vitiligo. PMID- 28003946 TI - Dosimetric Study of Automatic Brain Metastases Planning in Comparison with Conventional Multi-Isocenter Dynamic Conformal Arc Therapy and Gamma Knife Radiosurgery for Multiple Brain Metastases. AB - OBJECTIVE: The efficacy of stereotactic radiosurgery (SRS) using Gamma Knife (GK) (Elekta, Tokyo) is well known. Recently, Automatic Brain Metastases Planning (ABMP) Element (BrainLAB, Tokyo) for a LINAC-based radiation system was commercially released. It covers multiple off-isocenter targets simultaneously inside a multi-leaf collimator field and enables SRS / stereotactic radiotherapy (SRT) with a single group of LINAC-based dynamic conformal multi-arcs (DCA) for multiple brain metastases. In this study, dose planning of ABMP (ABMP-single isocenter DCA (ABMP-SIDCA)) for SRS of small multiple brain metastases was evaluated in comparison with those of conventional multi-isocenter DCA (MIDCA SRS) (iPlan, BrainLAB, Tokyo) and GK-SRS (GKRS). METHODS: Simulation planning was performed with ABMP-SIDCA and GKRS in the two cases of multiple small brain metastases (nine tumors in both), which had been originally treated with iPlan MIDCA. First, a dosimetric comparison was done between ABMP-SIDCA and iPlan-MIDCA in the same setting of planning target volume (PTV) margin and D95 (dose covering 95% of PTV volume). Second, dosimetry of GKRS with a margin dose of 20 Gy was compared with that of ABMP-SIDCA in the setting of PTV margin of 0, 1 mm, and 2 mm, and D95=100% dose (20 Gy). RESULTS: First, the maximum dose of PTV and minimum dose of gross tumor volume (GTV) were significantly greater in ABMP-SIDCA than in iPlan-MIDCA. Conformity index (CI, 1/Paddick's CI) and gradient index (GI, V (half of prescription dose) / V (prescription dose)) in ABMP-SIDCA were comparable with those of iPlan-MIDCA. Second, PIV (prescription isodose volume) of GKRS was consistent with that of 1 mm margin - ABMP-SIDCA plan in Case 1 and that of no-margin ABMP-SIDCA plan in Case 2. Considering the dose gradient, the mean of V (half of prescription dose) of ABMP-SIDCA was not broad, comparable to GKRS, in either Case 1 or 2. CONCLUSIONS: The conformity and dose gradient with ABMP-SIDCA were as good as those of conventional MIDCA for each lesion. If the conditions of the LINAC system permit a minimal PTV margin (1 mm or less), ABMP SIDCA might provide excellent dose fall-off comparable with that of GKRS thereby enabling a short treatment time. PMID- 28003947 TI - The Use of the Target Cancellation Task to Identify Eloquent Visuospatial Regions in Awake Craniotomies: Technical Note. AB - The success of awake craniotomies relies on the patient's performance of function specific tasks that are simple, quick, and reproducible. Intraoperative identification of visuospatial function through cortical and subcortical mapping has utilized a variety of intraoperative tests, each with its own benefits and drawbacks. In light of this, we developed a simple software program that aids in preventing neglect by simulating a target-cancellation task on a portable electronic device. In this report, we describe the interactive target cancellation task and have reviewed seven consecutive patients who underwent awake craniotomy for parietal and/or posterior temporal infiltrating brain tumors of the non-dominant hemisphere. Each of these patients performed target cancellation and line bisection tasks intraoperatively. The outcomes of each patient and testing scenario are described. Positive intraoperative cortical and subcortical sites involved with visuospatial processing were identified in three of the seven patients using the target cancellation and confirmed utilizing the line-bisection task. No identification of visuospatial function was accomplished utilizing the line-bisection task alone. Complete visuospatial function mapping was completed in less than 10 minutes in all patients. No patients had preoperative or postoperative hemineglect. Our findings highlight the feasibility of the target cancellation technique for use during awake craniotomy to aid in avoiding postoperative hemineglect. Target cancellation may offer an alternative method of cortical and subcortical visuospatial mapping in patients unable to perform other commonly used modalities. PMID- 28003948 TI - Salvage Plasmapheresis for Post-hepatectomy Liver Failure. AB - In the latest decades, an important change has been registered in liver surgery related to the progress of surgical techniques, critical care, and postoperative treatment, allowing a sharp decrease in mortality and morbidity. However, management of post-hepatectomy liver failure (PHLF) still remains a challenge and no supportive treatment has been found to be generally effective. The present study is a reappraisal of plasmapheresis as a potential supportive measure in patients with PHLF following major liver resection. PMID- 28003949 TI - Radiosurgery to the Postoperative Tumor Bed for Metastatic Carcinoma Versus Whole Brain Radiation After Surgery. AB - BACKGROUND: The treatment paradigm from postoperative whole brain radiation therapy (WBRT) to post-operative stereotactic radiosurgery (SRS) to the tumor bed has shifted with little data to evaluate whether each treatment modality confers equivalent tumor control and survival outcomes. METHODS: Patients with surgical resection of single brain metastases from January 2010 to December 2014 were treated postoperatively with either WBRT or SRS. Retrospective patient data was compared for local control, distant brain recurrence, overall survival, and radiation complications. RESULTS: Forty-six received WBRT, and 37 received tumor bed SRS. Twelve of 35 (34%) SRS patients experienced local recurrence compared to 17 of 31 (55%) WBRT patients (p = 0.09). The median survival was 440 days (14.7 months) for SRS and 202 days (6.7 months) for WBRT (p = 0.062, log-rank). SRS demonstrated improved survival benefit in the first six months (p = 0.0034; Wilcoxon). Radiation-related adverse changes after SRS (22%) were not statistically different from WBRT (8.7%) (p = 0.152). Age (p = 0.08), systemic cancer status (p = 0.30), Graded Prognostic Assessment (p = 0.28), number of brain metastases at diagnosis (p = 0.65), tumor volume at diagnosis (p = 0.13), new brain lesions (p = 0.74) and neurologic versus systemic cause of death (p = 0.11) did not differ between the groups. CONCLUSIONS: Following surgical resection, tumor bed SRS can be used effectively in lieu of WBRT to treat brain metastases with comparable local control and distant control and without significantly more adverse events. PMID- 28003951 TI - A soft stretchable bending sensor and data glove applications. AB - Soft sensors are required to accommodate the flexible and deformable natures of the human body in wearable device applications. They are also suitable for integration with soft robotic devices to monitor the performance status and provide references for feedback control. However, the choices for bending sensors are still highly limited. In this paper, a soft bending sensor is presented. By careful design with a blend of sensitive and insensitive regions, the sensor could be stretchable while being insensitive to stretching. An analytical study was presented on how to design the sensor with the named bending/stretching feature. This feature enables the sensor to be implemented in measuring human motions where a large amount of skin stretch is involved. Two sensor gloves were designed and fabricated based on the proposed soft bending sensor, aiming for different application scenarios. Both the sensor and the gloves were evaluated using a dedicated evaluation platform with experimental results compared against each other. PMID- 28003950 TI - Toward understanding the impacts of sediment contamination on a native fish species: transcriptional effects, EROD activity, and biliary PAH metabolites. AB - BACKGROUND: Both frequency and intensity of flood events are expected to increase as a result of global climate change in the upcoming decades, potentially resulting in increased re-suspension of sediments in fluvial systems. Contamination of these re-suspended sediments with legacy contaminants, including dioxins and dioxin-like compounds (DLCs), as well as polycyclic aromatic hydrocarbons (PAHs) is of great ecotoxicological concern. DLCs, and to some extent also PAHs, exhibit their toxicity through activation of the aryl hydrocarbon receptor (AhR). However, interactions of DLCs with pathways other than those known to be mediated through the AhR are not fully understood to date. METHODS: This study aimed to investigate molecular and biochemical effects in roach (Rutilus rutilus) during a 10 days exposure to suspensions of three natural sediments that differed in the level of DLC contamination. Concentrations of biliary PAH metabolites and hepatic 7-ethoxyresorufin-O-deethylase activity were quantified in exposed fish. Furthermore, the abundance of transcripts of several genes related to energy metabolism, response to oxidative stress, and apoptosis, as well as cytochrome P450 1A (cyp1a) was quantified. RESULTS: Biliary PAH metabolites and activation of the AhR were confirmed as suitable early warning biomarkers of exposure to suspended sediments containing DLCs and PAHs that corresponded well with analytically determined concentrations of those contaminants. Although the abundances of transcripts of superoxide dismutase (sod), protein kinase c delta (pkcd), and ATP-binding cassette transporter c9 (abcc9) were altered by the treatment compared with unexposed control fish, none of these showed a time- or concentration-dependent response. The abundance of transcripts of pyruvate carboxylase (pc) and transferrin variant d (tfd) remained unaltered by the treatments. CONCLUSIONS: We have shown that contaminated sediments can become a risk for fish during re-suspension events (e.g., flooding and dredging). We have also demonstrated that roach, which are native to most European freshwater systems, are suitable sentinel species due to their great sensitivity and ecological relevance. Roach may be particularly suitable in future field studies to assess the toxicological concerns associated with the release of DLCs and PAHs during sediment re-suspension. PMID- 28003952 TI - Automatic software correction of residual aberrations in reconstructed HRTEM exit waves of crystalline samples. AB - We develop an automatic and objective method to measure and correct residual aberrations in atomic-resolution HRTEM complex exit waves for crystalline samples aligned along a low-index zone axis. Our method uses the approximate rotational point symmetry of a column of atoms or single atom to iteratively calculate a best-fit numerical phase plate for this symmetry condition, and does not require information about the sample thickness or precise structure. We apply our method to two experimental focal series reconstructions, imaging a beta-Si3N4 wedge with O and N doping, and a single-layer graphene grain boundary. We use peak and lattice fitting to evaluate the precision of the corrected exit waves. We also apply our method to the exit wave of a Si wedge retrieved by off-axis electron holography. In all cases, the software correction of the residual aberration function improves the accuracy of the measured exit waves. PMID- 28003953 TI - The MAX IV imaging concept. AB - The MAX IV Laboratory is currently the synchrotron X-ray source with the beam of highest brilliance. Four imaging beamlines are in construction or in the project phase. Their common characteristic will be the high acquisition rates of phase enhanced images. This high data flow will be managed at the local computing cluster jointly with the Swedish National Computing Infrastructure. A common image reconstruction and analysis platform is being designed to offer reliable quantification of the multidimensional images acquired at all the imaging beamlines at MAX IV. PMID- 28003954 TI - Improved tomographic reconstruction of large-scale real-world data by filter optimization. AB - In advanced tomographic experiments, large detector sizes and large numbers of acquired datasets can make it difficult to process the data in a reasonable time. At the same time, the acquired projections are often limited in some way, for example having a low number of projections or a low signal-to-noise ratio. Direct analytical reconstruction methods are able to produce reconstructions in very little time, even for large-scale data, but the quality of these reconstructions can be insufficient for further analysis in cases with limited data. Iterative reconstruction methods typically produce more accurate reconstructions, but take significantly more time to compute, which limits their usefulness in practice. In this paper, we present the application of the SIRT-FBP method to large-scale real world tomographic data. The SIRT-FBP method is able to accurately approximate the simultaneous iterative reconstruction technique (SIRT) method by the computationally efficient filtered backprojection (FBP) method, using precomputed experiment-specific filters. We specifically focus on the many implementation details that are important for application on large-scale real-world data, and give solutions to common problems that occur with experimental data. We show that SIRT-FBP filters can be computed in reasonable time, even for large problem sizes, and that precomputed filters can be reused for future experiments. Reconstruction results are given for three different experiments, and are compared with results of popular existing methods. The results show that the SIRT FBP method is able to accurately approximate iterative reconstructions of experimental data. Furthermore, they show that, in practice, the SIRT-FBP method can produce more accurate reconstructions than standard direct analytical reconstructions with popular filters, without increasing the required computation time. PMID- 28003955 TI - Cognitive Behavioural Therapy for Insomnia in Psychiatric Disorders. AB - Insomnia means difficulties in initiating or maintaining sleep and is commonly comorbid with psychiatric disorders. From being considered secondary to primary psychiatric disorders, comorbid insomnia is now considered an independent health issue that warrants treatment in its own right. Cognitive behavioural therapy for insomnia (CBT-I) is an evidence-based treatment for insomnia. The effects from CBT-I on comorbid psychiatric conditions have received increasing interest as insomnia comorbid with psychiatric disorders has been associated with more severe psychiatric symptomologies, and there are studies that indicate effects from CBT I on both insomnia and psychiatric symptomology. During recent years, the literature on CBT-I for comorbid psychiatric groups has expanded and has advanced methodologically. This article reviews recent studies on the effects from CBT-I on sleep, daytime symptoms and function and psychiatric comorbidities for people with anxiety, depression, bipolar disorder, psychotic disorders and post traumatic stress disorder. Future strategies for research are suggested. PMID- 28003956 TI - Global Burden of Childhood Tuberculosis. AB - In 2015, the World Health Organization (WHO) declared tuberculosis (TB) to be responsible for more deaths than any other single infectious disease. The burden of TB among children has frequently been dismissed as relatively low with resulting deaths contributing very little to global under-five all-cause mortality, although without rigorous estimates of these statistics, the burden of childhood TB was, in reality, unknown. Recent work in the area has resulted in a WHO estimate of 1 million new cases of childhood TB in 2014 resulting in 136,000 deaths. Around 3% of these cases likely have multidrug-resistant TB and at least 40,000 are in HIV-infected children. TB is now thought to be a major or contributory cause of many deaths in children under five years old, despite not being recorded as such, and is likely in the top ten causes of global mortality in this age group. In particular, recent work has shown that TB is an under-lying cause of a substantial proportion of pneumonia deaths in TB-endemic countries. Childhood TB should be given higher priority: we need to identify children at greatest risk of TB disease and death and make more use of tools such as active case-finding and preventive therapy. TB is a preventable and treatable disease from which no child should die. PMID- 28003957 TI - Making music for mental health: how group drumming mediates recovery. AB - BACKGROUND: While music-making interventions are increasingly recognised as enhancing mental health, little is known of why music may engender such benefit. The objective of this article is to elucidate the features of a programme of group drumming known to enable mental health recovery. METHODS: Qualitative research was conducted with 39 mental health patients and carers who had demonstrated recovery following engagement with a programme of group djembe drumming in the UK. Data were collected through semi-structured individual interviews and focus group interviews designed to understand the connection between drumming and recovery and analysed using Interpretative Phenomenological Analysis (IPA). RESULTS: Results revealed three overarching features of the drumming intervention: (1) the specific features of drumming, including drumming as a form of non-verbal communication, as a connection with life through rhythm, and as a grounding experience that both generates and liberates energy; (2) the specific features of the group, including the group as a space of connection in and through the rhythmic features of the drumming, as well as facilitating feelings of belonging, acceptance, safety and care, and new social interactions; (3) the specific features of the learning, including learning as an inclusive activity in which the concept of mistakes is dissolved and in which there is musical freedom, supported by an embodied learning process expedited by the musical facilitator. CONCLUSION: The findings provide support for the conceptual notion of 'creative practice as mutual recovery', demonstrating that group drumming provides a creative and mutual learning space in which mental health recovery can take place. PMID- 28003958 TI - Metrics of brain network architecture capture the impact of disease in children with epilepsy. AB - BACKGROUND AND OBJECTIVE: Epilepsy is associated with alterations in the structural framework of the cerebral network. The aim of this study was to measure the potential of global metrics of network architecture derived from resting state functional MRI to capture the impact of epilepsy on the developing brain. METHODS: Pediatric patients were retrospectively identified with: 1. Focal epilepsy; 2. Brain MRI at 3 Tesla, including resting state functional MRI; 3. Full scale IQ measured by a pediatric neuropsychologist. The cerebral cortex was parcellated into approximately 700 gray matter network nodes. The strength of a connection between two nodes was defined as the correlation between their resting BOLD signal time series. The following global network metrics were then calculated: clustering coefficient, transitivity, modularity, path length, and global efficiency. Epilepsy duration was used as an index for the cumulative impact of epilepsy on the brain. RESULTS: 45 patients met criteria (age: 4-19 years). After accounting for age of epilepsy onset, epilepsy duration was inversely related to IQ (p: 0.01). Epilepsy duration predicted by a machine learning algorithm on the basis of the five global network metrics was highly correlated with actual epilepsy duration (r: 0.95; p: 0.0001). Specifically, modularity and to a lesser extent path length and global efficiency were independently associated with epilepsy duration. CONCLUSIONS: We observed that a machine learning algorithm accurately predicted epilepsy duration based on global metrics of network architecture derived from resting state fMRI. These findings suggest that network metrics have the potential to form the basis for statistical models that translate quantitative imaging data into patient-level markers of cognitive deterioration. PMID- 28003959 TI - Use of T1-weighted/T2-weighted magnetic resonance ratio to elucidate changes due to amyloid beta accumulation in cognitively normal subjects. AB - The ratio of signal intensity in T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) was recently proposed to enhance the sensitivity of detecting changes in disease-related signal intensity. The objective of this study was to test the effectiveness of T1w/T2w image ratios as an easily accessible biomarker for amyloid beta (Abeta) accumulation. We performed the T1w/T2w analysis in cognitively normal elderly individuals. We applied [11C] Pittsburgh Compound B (PiB)-PET to the same individuals, and Abeta deposition was quantified by its binding potential (PiB-BPND). The subjects were divided into low and high PiB-BPND groups, and group differences in regional T1w/T2w values were evaluated. In the regions where we found a significant group difference, we conducted a correlation analysis between regional T1w/T2w values and PiB-BPND. Subjects with high global cortical PiB-BPND showed a significantly higher regional T1w/T2w ratio in the frontal cortex and anterior cingulate cortex. We found a significant positive relationship between the regional T1w/T2w ratio and Abeta accumulation. Moreover, with a T1w/T2w ratio of 0.55 in the medial frontal regions, we correctly discriminated subjects with high PiB-BPND from the entire subject population with a sensitivity of 84.6% and specificity of 80.0%. Our results indicate that early Abeta-induced pathological changes can be detected using the T1w/T2w ratio on MRI. We believe that the T1w/T2w ratio is a prospective stable biological marker of early Abeta accumulation in cognitively normal individuals. The availability of such an accessible marker would improve the efficiency of clinical trials focusing on the initial disease stages by reducing the number of subjects who require screening by Abeta-PET scan or lumbar puncture. PMID- 28003960 TI - Development of cortical thickness and surface area in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder often associated with changes in cortical volume. The constituents of cortical volume - cortical thickness and surface area - have separable developmental trajectories and are related to different neurobiological processes. However, little is known about the developmental trajectories of cortical thickness and surface area in ASD. In this magnetic resonance imaging (MRI) study, we used an accelerated longitudinal design to investigate the cortical development in 90 individuals with ASD and 90 typically developing controls, aged 9 to 20 years. We quantified cortical measures using the FreeSurfer software package, and then used linear mixed model analyses to estimate the developmental trajectories for each cortical measure. Our primary finding was that the development of surface area follows a linear trajectory in ASD that differs from typically developing controls. In typical development, we found a decline in cortical surface area between the ages of 9 and 20 that was absent in ASD. We found this pattern in all regions where developmental trajectories for surface area differed between groups. When we applied a more stringent correction that takes the interdependency of measures into account, this effect on cortical surface area retained significance for left banks of superior temporal sulcus, postcentral area, and right supramarginal area. These areas have previously been implicated in ASD and are involved in the interpretation and processing of audiovisual social stimuli and distinction between self and others. Although some differences in cortical volume and thickness were found, none survived the more stringent correction for multiple testing. This study underscores the importance of distinguishing between cortical surface area and thickness in investigating cortical development, and suggests the development of cortical surface area is of importance to ASD. PMID- 28003961 TI - Structural alterations of the brainstem in migraine. AB - Atypical brainstem modulation of pain might contribute to changes in sensory processing typical of migraine. The study objective was to investigate whether migraine is associated with brainstem structural alterations that correlate with this altered pain processing. MRI T1-weighted images of 55 migraine patients and 58 healthy controls were used to: (1) create deformable mesh models of the brainstem that allow for shape analyses; (2) calculate volumes of the midbrain, pons, medulla and the superior cerebellar peduncles; (3) interrogate correlations between regional brainstem volumes, cutaneous heat pain thresholds, and allodynia symptoms. Migraineurs had smaller midbrain volumes (healthy controls = 61.28 mm3, SD = 5.89; migraineurs = 58.80 mm3, SD = 6.64; p = 0.038), and significant (p < 0.05) inward deformations in the ventral midbrain and pons, and outward deformations in the lateral medulla and dorsolateral pons relative to healthy controls. Migraineurs had a negative correlation between ASC-12 allodynia symptom severity with midbrain volume (r = - 0.32; p = 0.019) and a positive correlation between cutaneous heat pain thresholds with medulla (r = 0.337; p = 0.012) and cerebellar peduncle volumes (r = 0.435; p = 0.001). Migraineurs with greater symptoms of allodynia have smaller midbrain volumes and migraineurs with lower heat pain thresholds have smaller medulla and cerebellar peduncles. The brainstem likely plays a role in altered sensory processing in migraine and brainstem structure might reflect severity of allodynia and hypersensitivity to pain in migraine. PMID- 28003962 TI - Cortical arousal in children and adolescents with functional neurological symptoms during the auditory oddball task. AB - OBJECTIVE: Stress, pain, injury, and psychological trauma all induce arousal mediated changes in brain network organization. The associated, high level of arousal may disrupt motor-sensory processing and result in aberrant patterns of motor function, including functional neurological symptoms. We used the auditory oddball paradigm to assess cortical arousal in children and adolescents with functional neurological symptom disorder. METHOD: Electroencephalogram (EEG) data was collected in fifty-seven children and adolescents (41 girls; 16 boys, aged 8.5-18 years) with acute functional neurological symptoms and age- sex- matched controls during a conventional auditory oddball task. The high-resolution fragmentary decomposition technique was used to analyse the amplitude of event related potentials (ERPs) to target tones at midline sites (Fz, Cz, and Pz). RESULTS: Compared to age- and sex-matched controls, and across all three midline sites, children and adolescents with functional neurological symptoms showed increased amplitude of all ERP components (P50, N100, P200, N200, and P300) (t value range 2.28-8.20; p value-range 0.023 to < 0.001) to the emotionally-neutral auditory stimulus. CONCLUSIONS: Our findings add to a growing literature indicating that a baseline state of high arousal may be a precondition for generating functional neurological symptoms, a finding that helps explain why a range of psychological and physiological stressors can trigger functional neurological symptoms in some patients. Interventions that target cortical arousal may be central to the treatment of paediatric patients with functional neurological symptom disorder. PMID- 28003964 TI - Low dose clozapine controls adult-onset psychosis associated with the neurogenic ataxia-retinitis pigmentosa (NARP) mutation. PMID- 28003963 TI - Transcriptome analysis reveals common differential and global gene expression profiles in bluetongue virus serotype 16 (BTV-16) infected peripheral blood mononuclear cells (PBMCs) in sheep and goats. AB - Bluetongue is an economically important infectious, arthropod borne viral disease of domestic and wild ruminants, caused by Bluetongue virus (BTV). Sheep are considered the most susceptible hosts, while cattle, buffalo and goats serve as reservoirs. The viral pathogenesis of BTV resulting in presence or absence of clinical disease among different hosts is not clearly understood. In the present study, transcriptome of sheep and goats peripheral blood mononuclear cells infected with BTV-16 was explored. The differentially expressed genes (DEGs) identified were found to be significantly enriched for immune system processes - NFkappaB signaling, MAPK signaling, Ras signaling, NOD signaling, RIG signaling, TNF signaling, TLR signaling, JAK-STAT signaling and VEGF signaling pathways. Greater numbers of DEGs were found to be involved in immune system processes in goats than in sheep. Interestingly, the DEHC (differentially expressed highly connected) gene network was found to be dense in goats than in sheep. Majority of the DEHC genes in the network were upregulated in goats but down-regulated in sheep. The network of differentially expressed immune genes with the other genes further confirmed these findings. Interferon stimulated genes - IFIT1 (ISG56), IFIT2 (ISG54) and IFIT3 (ISG60) responsible for antiviral state in the host were found to be upregulated in both the species. STAT2 was the TF commonly identified to co-regulate the DEGs, with its network showing genes that are downregulated in sheep but upregulated in goats. The genes dysregulated and the networks perturbed in the present study indicate host variability with a positive shift in immune response to BTV in goats than in sheep. PMID- 28003965 TI - A method to implement the reservoir-wave hypothesis using phase-contrast magnetic resonance imaging. AB - The reservoir-wave hypothesis states that the blood pressure waveform can be usefully divided into a "reservoir pressure" related to the global compliance and resistance of the arterial system, and an "excess pressure" that depends on local conditions. The formulation of the reservoir-wave hypothesis applied to the area waveform is shown, and the analysis is applied to area and velocity data from high-resolution phase-contrast cardiovascular magnetic resonance (CMR) imaging. A validation study shows the success of the principle, with the method producing largely robust and physically reasonable parameters, and the linear relationship between flow and wave pressure seen in the traditional pressure formulation is retained. The method was successfully tested on a cohort of 20 subjects (age range: 20-74 years; 17 males). This paper: *Demonstrates the feasibility of deriving reservoir data non-invasively from CMR.*Includes a validation cohort (CMR data).*Suggests clinical applications of the method. PMID- 28003966 TI - Performance of Kalon herpes simplex virus 2 assay using dried blood spots among young women in Uganda. AB - The study evaluated the performance of the Kalon HSV-2 assay on dried blood spots (DBS) of various dilutions compared with plasma from young women aged 18-24 years in Uganda. We estimated the sensitivity and specificity of three DBS dilutions using plasma as the reference. All three evaluated DBS dilutions yielded low sensitivities and specificities with DBS 1:2 yielding the highest concurrence. Other HSV-2 assays should be examined with regard to their utility for testing DBS. PMID- 28003967 TI - Immune oppression array elucidating immune escape and survival mechanisms in uveal melanoma. AB - AIM: To examine the genetic profile of primary uveal melanoma (UM) as compared to UM in immune escape. METHODS: Dendritic cells (DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate CTLs(CTLs). When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction (qRT PCR), and analyzed the correlation of these expressions and patients' survival. RESULTS: Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2. The expression of these genes in the relapsed UM was significantly greater than those in primary UM. UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression. CONCLUSION: Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells. PMID- 28003968 TI - Effects of retinoic acid receptor-gamma on the Aspergillus fumigatus induced innate immunity response in human corneal epithelial cells. AB - AIM: To explore the effects of retinoic acid receptor-gamma (RARgamma) on innate immune responses against Aspergillus fumigatus (A. fumigatus) in cultured human corneal epithelial cells (HCECs). METHODS: The HCECs were stimulated with A. fumigatus hyphae for 0, 2, 4, 8, 12 and 16h. RARgamma mRNA and protein levels were tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Then HCECs were pretreated with or without BMS961 (RARgamma agonist, 1 ug/mL). The mRNA and protein expression of Dectin-1 and the downstream cytokines (TNF-alpha and IL-6) were determined by qRT-PCR, Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: The expression of RARgamma was upregulated after stimulation with A. fumigatus. RARgamma mRNA began to rise at 4h and peaked at 8h (P<0.001). The protein of RARgamma reached to the peak at 16h (P<0.001). Pretreated with BMS961 before A. fumigatus hyphae stimulation, expression of Dectin-1, TNF-alpha and IL-6 decreased dramatically at mRNA and protein levels. CONCLUSION: HCECs can express RARgamma and A. fumigatus hyphae infection can increase RARgamma expression. BMS961 can inhibit the expression of Dectin-1 and pro-inflammatory cytokines, and play an anti-inflammatory role in innate immune responses against A. fumigatus. PMID- 28003969 TI - Expression and regulation of microRNA-29a and microRNA-29c in early diabetic rat cataract formation. AB - AIM: To determine the role of microRNA (miRNA)-29a and miRNA-29c in the regulation of apoptosis in early rat diabetic cataract formation. METHODS: Streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were used in the study. The expression level of miRNA-29a, miRNA-29c, and BCL2-modifying factor (BMF) in lens epithelial cells (LECs) samples were measured using quantitative real-time polymerase chain reaction. Prediction algorithms of miRanda, TargetScan 6.2, and mirRDB to perform a miRNA gene network analysis were used for the potential miRNA-29a and miRNA-29c targets. RESULTS: The miRNA-29a and miRNA-29c expression levels were all significantly lower in the control group compared to the 2 and 4wk diabetic samples (P<0.01). The network analysis indicated that one miRNA-29a and miRNA-29c targets was BMF. There was significantly higher expression of BMF mRNA compared to the normal controls (P<0.01). CONCLUSION: Apoptosis occurs in rat LECs following high blood glucose exposure. It is likely that apoptosis during diabetic cataract formation involves the decreased expression of miRNA-29a and miRNA-29c and the increased expression of BMF. PMID- 28003970 TI - Effects of resveratrol on ARPE-19 cell proliferation and migration via regulating the expression of proliferating cell nuclear antigen, P21, P27 and p38MAPK/MMP-9. AB - AIM: To explore whether resveratrol (Res) can inhibit human retinal pigment epithelial cell (ARPE-19 cell) proliferation and migration, and to research the molecular mechanisms. METHODS: ARPE-19 cells were pretreated with various concentrations at 0, 50, 100, 150, 200 and 300 umol/L of Res, and with 0 umol/L Res as the control for 24, 48 and 72h. The cell proliferation, apoptosis and migration were measured with cell counting kit-8 (CCK-8), flow cytometry, and wound-healing and Transwell assays, respectively. The expression of proliferating cell nuclear antigen (PCNA), P21 and P27, as well as matrix metalloproteinase-9 (MMP-9) and p38 mitogen-activated protein kinases (p38MAPK) was identified by Western blot. RESULTS: Cell proliferation was effectively inhibited by Res (P<0.05). When pretreated with Res, cells arrested in S-phase increased remarkably (P<0.05), but the apoptosis ratios showed no significant difference between the treatment and control groups (P>0.05). Cell migration was suppressed by Res both in wound-healing assay and Transwell migration assay (P<0.05). Decreases of PCNA, MMP-9 and p38MAPK, as well as increases of P21 and P27 were detected by Western blot (P<0.05). CONCLUSION: Res can inhibit APRE-19 cell proliferation and migration in a concentration-dependent manner with up regulation of the expression of P21 and P27, and down-regulation of PCNA, MMP-9 and p38MAPK. PMID- 28003971 TI - Optic neuropathy and increased retinal glial fibrillary acidic protein due to microbead-induced ocular hypertension in the rabbit. AB - AIM: To characterize whether a glaucoma model with chronic elevation of the intraocular pressure (IOP) was able to be induced by anterior chamber injection of microbeads in rabbits. METHODS: In order to screen the optimal dose of microbead injection, IOP was measured every 3d for 4wk using handheld applanation tonometer after a single intracameral injection of 10 uL, 25 uL, 50 uL or 100 uL microbeads (5*106 beads/mL; n=6/group) in New Zealand White rabbits. To prolong IOP elevation, two intracameral injections of 50 uL microbeads or phosphate buffer saline (PBS) were made respectively at days 0 and 21 (n=24/group). The fellow eye was not treated. At 5wk after the second injection of microbeads or PBS, bright-field microscopy and transmission electron microscopy (TEM) were used to assess the changes in the retina. The expression of glial fibrillary acidic protein (GFAP) in the retina was evaluated by immunofluorescence, quantitative real-time polymerase chain reaction and Western blot at 5wk after the second injection of microbeads. RESULTS: Following a single intracameral injection of 10 uL, 25 uL, 50 uL or 100 uL microbead, IOP levels showed a gradual increase and a later decrease over a 4wk period after a single injection of microbead into the anterior chamber of rabbits. A peak IOP was observed at day 15 after injection. No significant difference in peak value of IOP was found between 10 uL and 25 uL groups (17.13+/-1.25 mm Hg vs 17.63+/-0.74 mm Hg; P=0.346). The peak value of IOP from 50 uL group (23.25+/-1.16 mm Hg) was significantly higher than 10 uL and 25 uL groups (all P<0.05). Administration of 100 uL microbead solution (23.00+/-0.93 mm Hg) did not lead to a significant increase in IOP compared to the 50 uL group (P=0.64). A prolonged elevated IOP duration up to 8wk was achieved by administering two injections of 50 uL microbeads (20.48+/-1.21 mm Hg vs 13.60+/ 0.90 mm Hg in PBS-injected group; P<0.05). The bright-field and TEM were used to assess the changes of retinal ganglion cells (RGCs). Compared with PBS-injected group, the extended IOP elevation was associated with the degeneration of optic nerve, the reduction of RGC axons (47.16%, P<0.05) and the increased GFAP expression in the retina (4.74+/-1.10 vs 1.00+/-0.46, P<0.05). CONCLUSION: Two injections of microbeads into the ocular anterior chamber of rabbits lead to a prolonged IOP elevation which results in structural abnormality as well as loss in RGCs and their axons without observable ocular structural damage or inflammatory response. We have therefore established a novel and practical model of experimental glaucoma in rabbits. PMID- 28003972 TI - Changes of meibomian glands in patients with type 2 diabetes mellitus. AB - AIM: To investigate the morphological changes of meibomian glands in patients with type 2 diabetes mellitus (DM). METHODS: Of 118 eyes (118 patients) with type 2 DM (DM group) and 100 eyes of 100 control subjects (control group) were enrolled. After completing an ocular surface disease index (OSDI) questionnaire, the non-invasive tear film break-up time (NI-BUT) and the structure of the meibomian glands (MGs, meibography) were assessed by the Keratograph 5M system. Partial or complete loss of MG was scored for each eyelid from grade 0 (no loss) to grade 3 (lost area was >2/3 of the total MG area), which were also examined by laser scanning confocal microscopy (LSCM). The primary outcomes were meibomian gland acinar unit density (MGAUD), meibomian gland acinar longest diameter (MGALD) and meibomian gland acinar shortest diameter (MGASD). RESULTS: Compared with control group, the OSDI was significantly higher in DM group (Z=-5.916; P<0.001), while the NI-BUT was significantly lower (Z=-7.765; P<0.001). Keratograph showed that there were more MGs dropout in DM group than that in control group. The meiboscore was significantly higher in DM group compared with control group (Z=-3.937; P<0.001). LSCM revealed that there were cytological alterations of MGs in DM group compared with control group, which included enlargement of MG acinar units and decreased in density of MG acinar units. Specifically, there were lower MGAUD, larger MGALD and MGASD in DM group than control group (Z=-10.120, -9.4442, -7.771; P<0.001). CONCLUSION: Compared with the normal control participants, the patients with type 2 DM had more unstable tear films and severe symptoms of dry eye. Using Keratograph 5M system and LSCM, we found that the patients with type 2 DM had more significant morphological and cytological changes and dysfunction in MGs. PMID- 28003973 TI - Cosmetic evaluation of surgical scars after external dacryocystorhinostomy. AB - AIM: To evaluate the surgical scars of external dacryocystorhinostomy (DCR) cosmetically. METHODS: Totally 50 consecutive cases of primary acquired nasolacrimal duct obstruction (PANDO) were included in the study. Surgical scars were assessed by the patients and two independent observers at 2, 6 and 12wk postoperatively on the basis of visibility of the scars and still photographs respectively and were graded from 0-3. Kappa test was utilised to check the agreement of scar grading between the two observers. Wilcoxan signed ranks test was used to analyse the improvement of scar grading. RESULTS: Thirty-four (68%) patients graded their incision site as very visible (grade 3) at 2wk. At 6 and 12wk, incision site was observed as grade 3 by 7 (14%) and 1 (2%) patients respectively. Photographic evaluation of patients by 2 observers showed an average score of 2.75, 1.94 and 0.94 at 2, 6 and 12wk respectively. Change in scar grading from grade 3 to grade 0 in consecutive follow-up (2, 6 and 12wk) was found to be highly significant both for the patient as well for the observers (P<0.0001). CONCLUSION: The external DCR is a highly effective and safe procedure and in view of low percentage of cases who complained of marked scarring in the present study, thus scarring should not be the main ground for deciding the approach to DCR surgery, even in young cosmetically conscious patients. PMID- 28003974 TI - Etiology, diagnosis, management and outcomes of epiphora referrals to an oculoplastic practice. AB - AIM: To investigate the etiology, diagnosis, management and outcome of epiphora referrals to an oculoplastic practice. METHODS: Retrospective chart review of patients referred for epiphora to an oculoplastic clinic between 2005 and 2009. Patient demographics, past history, ophthalmic examination, treatment and outcome were analyzed. RESULTS: There were 237 subjects with a primary complaint of epiphora. They included 130 (55%) females and 107 (45%) males with an average age of 55.9+/-25.9y. The most common cause of epiphora was lacrimal obstruction (46%); followed by multifactorial epiphora (22%), reflex tearing (22%) and eyelid malposition (11%). Differences in prevalence of etiology were noted in terms of age and gender distribution. Of the 182 (77%) patients who returned for follow up, 41 (23%) reported a complete resolution and 102 (56%) reported a significant improvement in their symptoms. CONCLUSION: Epiphora is a common condition with many causes. A thorough history and examination are required to provide the appropriate treatment tailored to the underlying cause. PMID- 28003975 TI - Preoperative evaluation and outcome of corneal transplantation for limbal dermoids: a ten-year follow-up study. AB - AIM: To summarize preoperative evaluation and outcome of corneal transplantation for limbal dermoids for ten years. METHODS: Eighty-five patients diagnosed with limbal dermoids and treated with corneal transplantation were analyzed retrospectively. All patients were further divided into two groups according to absence or presence of neovascularization surrounding the dermoids in the corneal stroma. Eighty-two eyes were treated with tumor excision combined with partial lamellar sclerokeratoplasty, and the other three eyes were performed by penetrating keratoplasty. The size and location of the tumor, the associated ocular and systemic anomalies, the depth of the corneal penetration of tumor tissues, the preoperative and postoperative best-corrected visual acuity (BCVA), graft survival and cosmetic outcome, and surgical complications were recorded respectively. RESULTS: The average age at surgery was 5.3y (range, 3mo-36y). The mean size of dermoids was 6.1+/-1.6 mm. The 43.5% of eyes (37/85) were present with hair at the surface of the dermoid and 72.9% of dermoids were located inferotemporal of the eye. Amplyopia was present in 34.1% of patients (29/85) and 9.4% of patients (8/85) had lipodermoids. Eighteen patients suffered from Goldenhar's syndrome with an accessory ear. The 75% of patients in group 1 had involvement of the corneal deep stroma down to Descemet's membrane without involving it, but 71.4% of patients had Descemet's membrane involvement in group 2. Preoperative BCVA ranged from counting fingers to 20/20. Postoperatively 81.1% had a BCVA of 20/800 or better. There was no significant difference between the post-surgical BCVA of the two groups (t=1.584, P>0.05). The grafts of 70.5% patients were present as 1+ opacity, 21.1% as 2+ opacity, 8.2% as 3+ opacity and none as 4+ opacity. Surgical complications included graft rejection, microperforation, prolonged reepithelialization, steroid glaucoma, interface neovascularization, and interface hemorrhage. CONCLUSION: The dermoids with neovascularization surrounding them in the corneal stroma invaded deeper tissues in the cornea than those with no neovascularization surrounding them in the corneal stroma. Therefore, surgeons should take care to avoid corneal perforation during the corneal transplantation operation. The majority of patients markedly improved their cosmetic appearance after surgery. PMID- 28003977 TI - Combination of Toric and multifocal intraocular lens implantation in bilateral cataract patients with unilateral astigmatism. AB - AIM: To assess the binocular visual function in bilateral cataract patients with unilateral astigmatism after combined implantations of Toric with multifocal intraocular lens (IOL), and to compare with that of Toric and monofocal IOL implantation. METHODS: All the 30 patients with unilateral astigmatism suffered bilateral cataract were randomly divided into two groups: Toric plus multifocal IOL group and Toric plus monofocal IOL group. Uncorrected and corrected visual acuity at distance (5.0 m), intermediate distance (0.6 m), and near (0.33 m), contrast sensitivity, and stereopsis were assessed 6mo after surgery. Patients were also surveyed for visual disturbances and spectacle dependence. RESULTS: Binocular uncorrected visual acuity (LogMAR) of Toric/multifocal IOL eyes at distance, intermediate, near were 0.05+/-0.05, 0.24+/-0.10, and 0.14+/-0.06 respectively. The values of Toric plus monofocal IOL eyes were 0.06+/-0.07, 0.26+/-0.08, and 0.37+/-0.10 respectively. These values did not indicate significant differences between two groups with exception of near visual acuity. In the photopic condition (with or without glare), the contrast sensitivity of multifocal IOL eyes was significant lower than the monofocal IOL eyes in 18 cpd. In the mesopic condition, the contrast sensitivity of multifocal group was significant lower than monofocal group in 12 cpd, and in mesopic glare condition, this significant difference was found both in 6 cpd and 12 cpd. The stereopsis of Toric/multifocal IOL eyes decreased slightly (100+/-80 seconds of arc, t=2.222, P=0.136). Mean near vision for patient satisfaction was statistically significantly higher in Toric/multifocal IOL group patients versus than that in Toric/monofocal IOL group (80% vs 25.5%, P=0.000). Visual disturbance was not noticed in either group. CONCLUSION: Although the combination of Toric and multifocal IOL implantation results in compromising stereoacuity, it can still provide patients with high levels of spectacle freedom and good overall binocular visual acuity. PMID- 28003976 TI - Application of optical coherence tomography angiography in assessment of posterior scleral reinforcement for pathologic myopia. AB - AIM: To investigate the effect of posterior scleral reinforcement (PSR) on circulation of pathologic myopia eyes with posterior staphyloma by optical coherence tomography angiography (OCTA). METHODS: The study included 30 pathologic myopia eyes with posterior staphyloma which underwent PSR (PSR group) for 6 to 18mo ago, and 30 age and myopia matched eyes without PSR surgery as control group. Macular, choriocapillaris and radial peripapillary capillary (RPC) flow density were measured by OCTA, and the measurements were compared between groups. RESULTS: OCTA found no significant differences in macular flow density between PSR and control groups. For the superficial flow, whole enface flow density (WED), fovea density (FD), and parafoveal density (PD) were 46.55%+/ 5.19% vs 47.29%+/-4.12% (P=0.542), 31.45%+/-6.35% vs 31.17%+/-4.48% (P=0.841), and 48.82%+/-5.66% vs 49.21%+/-4.15% (P=0.756) in PSR and control groups, respectively. For the deep flow, WED, FD, and PD were 52.07%+/-5.78% vs 53.95%+/ 4.62% (P=0.168), 29.62%+/-6.55% vs 29.50%+/-6.38% (P=0.940), and 56.93%+/-6.17% vs 58.15%+/-5.13% (P=0.407) in PSR and control groups, respectively. The choriocapillary flow density was 61.18+/-3.25% in PSR group vs 60.88%+/-2.56% in control group (P=0.692). Also, OCTA found no significant differences in RPCs flow density between PSR and control groups. The optic disc WED, inside disc flow density and peripapillary flow density were 48.47%+/-4.77% vs 48.11%+/-4.57% (P=0.813), 45.47%+/-11.44% vs 46.68%+/-9.02% (P=0.709), 54.32%+/-5.29% vs 52.47%+/-6.62% (P=0.349) in PSR and control groups, respectively. CONCLUSION: OCTA provides a non-invasive and quantitative approach for monitoring macular and papillary blood flow in pathologic myopia. PSR can not improve but may maintain the circulation of pathologic myopia eyes with posterior staphyloma. PMID- 28003978 TI - Panretinal photocoagulation versus panretinal photocoagulation plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy. AB - AIM: To evaluate the effects of panretinal photocoagulation (PRP) compared with PRP plus intravitreal bevacizumab (IVB) in patients with high-risk proliferative diabetic retinopathy (PDR) according to the Early Treatment Diabetic Retinopathy Study criteria. METHODS: The data were collected retrospectively from the eyes of high-risk PDR patients, which were divided into two groups. After treated with standard PRP, the eyes were randomly assigned to receive only PRP (PRP group) or PRP plus intravitreal injection of 1.25 mg of bevacizumab (PRP-Plus group). Patients underwent complete ophthalmic evaluation, including best corrected visual acuity (BCVA), intraocular pressure (IOP), and new vessel size in fluorescein angiography (FA) and optical coherence tomography for the assessment of central subfield macular thickness (CSMT) at baseline and at weeks 12 (+/-2), 16 (+/-2), 24 (+/-2) and 48 (+/-2). Main outcome measures also included vitreous clear-up time and neovascularization on the disc (NVD) regression time. Adverse events associated with intravitreal injection were investigated. RESULTS: Thirty consecutive patients (n=36 eyes) completed the 48-week follow-up. There was no significant difference between the PRP and PRP-Plus groups with respect to age, gender, type or duration of diabetes, area of fluorescein leakage from active neovascularizations (NVs), BCVA or CSMT at baseline. The mean vitreous clear-up time was 12.1+/-3.4wk after PRP and 8.4+/-3.5wk after PRP combined with IVB. The mean time interval from treatment to complete NVD regression on FA examination was 15.2+/-3.5wk in PRP group and 12.5+/-3.1wk in PRP-Plus group. No significant difference in CSMT was observed between the groups throughout the study period. However, the total area of actively leaking NVs was significantly reduced in the PRP-Plus group compared with the PRP group (P<0.05). Patients received an average of 1.3 injections (range: 1-2). Ten eyes (27.8%) underwent 2 injections. Two eyes had ocular complication of PDR progression to dense vitreous hemorrhage (VH). No major adverse events were identified. CONCLUSION: The adjunctive use of IVB with PRP is associated with a greater reduction in the area of active leaking NVs than PRP alone in patients with high-risk PDR. Short-term results suggest combined IVB and PRP achieved rapid clearance of VH and regression of retinal NV in the treatment of high-risk PDR. Further studies are needed to determine the effect of repeated intravitreal bevacizumab injections and the proper number of bevacizumab injections as an adjuvant. PMID- 28003979 TI - Evaluation of fundus autofluorescence patterns in age-related macular degeneration. AB - AIM: To study the various morphological patterns of fundus autofluorescence (FAF) images in patients with age-related macular degeneration (AMD) in Indian population. METHODS: Totally 179 eyes of 104 patients with clinical diagnosis of AMD were recruited into the study. Autofluorescence images were captured using confocal scanning laser ophthalmoscope and the patterns of FAF were classified. RESULTS: Of 179 eyes, 27 (15.08%) were early AMD, 58 (32.41%) were intermediate AMD, 94 eyes (52.51%) were late AMD. Of 94 eyes with late AMD, 79 (84.04%) were neovascular AMD and 15 (15.96%) were central geographic atrophy. In eyes with early and intermediate AMD, 9 patterns of FAF were noted. Six patterns (normal, minimal change, focal increased, patchy increased, linear, reticular) were similar to that in the published classification. Two patterns (lacelike and speckled) described in the published classification were not found. Three new patterns (focal hypo-fluorescence, patchy hypo-fluorescence, mixed focal hypo fluorescence and hyper-fluorescence) were detected. In eyes with neovascular AMD, 6 morphological patterns of FAF were noted. Two patterns (mixed hypo-fluorescence and hyper-fluorescence, central hypo-fluorescence with hyper-fluorescent rim) were similar to that in published classification. Two patterns (normal, near normal or normal background fluorescence in the centre of hypo-fluorescent area) described in the published classification were not found. Four new patterns (minimal change, hypo-fluorescent patch, central hypo-fluorescence with surrounding reticular, bull's eye) were recognized. In eye with central geographic atrophy 5 morphological patterns were noted and these were similar to that in published classification. CONCLUSION: Phenotypic differences in the pattern of FAF exist in the study population compared to existing classification systems. PMID- 28003980 TI - Effect of incision types for Artisan phakic intraocular lens implantation on ocular higher order aberrations. AB - AIM: To evaluate the effect of incision types for Artisan phakic intraocular lens (PIOL) implantation on ocular higher-order aberrations (HOAs). METHODS: A retrospective review was conducted of the patients who had undergone Artisan PIOL implantation for the correction of myopia and followed up for at least 6mo. Patients are classified into 2 groups considering the incision type: cornea group with patients undergone clear corneal incision; sclera group with patients undergone sclera tunnel incision. All patients with postoperative astigmatism of under 1 diopter (D) were included to minimize the effect of residual astigmatism on postoperative HOAs. Visual acuity, special equivalents, astigmatism, predictability (+/-1 D from target refraction), HOAs (coma, trefoil, spherical aberration), and corneal endothelial counts were analyzed preoperatively and 6mo postoperatively. RESULTS: At the postoperative 6mo, all patients of both groups achieved uncorrected visual acuity of 16/20 or better, and significantly decreased the spherical equivalents compared with preoperative values. The predictability of refractive correction was 96% in the former, and 94% in the latter. Unlike the sclera group, preoperative astigmatism decreased significantly in cornea group at postoperative 6mo. The HOAs increased significantly at postoperative 6mo compared to the preoperative values in both groups, and the root mean square (RMS) total and trefoil wavefront aberration of cornea group were significantly higher than those of sclera group. CONCLUSION: Although corneal incision significantly reduces preexisting astigmatism, the postoperative 6mo of total RMS and trefoil aberration change may deteriorate the visual quality after Artisan PIOL implantation. PMID- 28003981 TI - Phakic posterior chamber intraocular lens for unilateral high myopic amblyopia in Chinese pediatric patients. AB - AIM: To assess the outcomes of posterior chamber implantable collamer lens (ICL) implantation in Chinese pediatric patients with unilateral high myopic amblyopia. METHODS: Eleven eyes of 11 amblyopic patients aged 11.02+/-3.34y underwent ICL (model V4, Staar Surgical Inc.) implantation to treat unilateral anisometropia were studied. Visual acuity, cycloplegic refraction, contrast sensitivity, stereopsis, intraocular pressure (IOP), vaulting, corneal endothelial cell count and complications were evaluated. Patients completed follow-up at 3d, 1, 3mo and the last follow-up time (mean 8.18+/-2.82mo) after surgery. RESULTS: The mean myopic anisometropia was -13.70+/-3.25 D preoperatively and +0.69+/-2.63 D at 8mo postoperatively. The logMAR corrected distance visual acuity (CDVA) of the amblyopic eye was 1.51+/-0.72 preoperatively and 0.75+/-0.40 at 8mo postoperatively. The logMAR CDVA at 3d, 1, 3 and 8mo postoperatively improved by a mean of 0.64, 1.55, 1.82 and 2.64 lines and gained more than 2 lines accounted for 18%, 45%, 45%, 64%, respectively. The contrast sensitivity of 0.5, 1 and 2 cpd in amblyopic eyes was significantly increased after surgery. No patient had near stereopsis recovery. The vaulting at 3 and 8mo was significantly lower than that at 1mo postoperatively. No other intraoperative or postoperative complications were observed, except an acute pupillary block glaucoma happened in a patient at two weeks postoperatively. CONCLUSION: This short-term results indicate that ICL implantation can be a promising alternative therapy for high myopic anisometropic amblyopia in pediatric patients who have failed with conventional treatments and not suitable to corneal refraction surgery. PMID- 28003982 TI - Assessment of contrast sensitivity loss after intrastromal femtosecond laser and LASIK procedure. AB - AIM: To assess the loss of contrast sensitivity (CS) function for INTRACOR or intrastromal femtosecond laser presbyopia procedure to conventional LASIK procedures. METHODS: Patients were recruited from a refractive surgery center for either INTRACOR or conventional LASIK. INTRACOR was performed on 8 eyes and LASIK was performed for 40 eyes in an overlapping period. Pre-operative evaluation and post-operative follow up for up to three months was done. Drops of CS in 4 spatial frequency (3 cpd, 6 cpd, 12 cpd and 18 cpd) right before and 3mo after the surgery were compared by Wilcoxon signed ranks test. RESULTS: For INTRACOR, CS threshold showed significant drop at both glare and non-glare condition, the drop was seen in all 4 spatial frequency. The averaged loss over the 4 spatial frequencies 3mo after surgery was 1.18 for non-glare and 0.71 for glare. For LASIK the CS threshold drop was most significant in 12 cpd for glare. CONCLUSION: INTRACOR procedure produces a gain of near vision for presbyopia patients but also introduces a high lost of contrast sensitivity plus worsen of vision quality. Pre-surgical patient selection and advise should be given with specific regards to night driving and glare conditions. PMID- 28003983 TI - Essential infantile esotropia with inferior oblique hyperfunction: long term follow-up of 6 muscles approach. AB - AIM: To evaluate long term follow-up (10y) of 6 muscle surgical approach in essential infantile esotropia (EIE). METHODS: A 6 muscle approach to EIE was retrospectively evaluated in patients with inferior oblique (IO) hyperfunction and lateral rectus (LR) pseudoparalysis, who underwent surgery at different ages. Different clinical characters were analyzed pre- and postoperatively, in patients who underwent a 6 muscles approach <=4 years of age. All patients underwent a multiple muscles approach: bilateral medial recti (MR) recession (4-5 mm), bilateral LR resection (lower than 7 mm) and bilateral IO recession and anteroposition. Of 108 children with preoperative angle >=+30 prism diopters (PD) and IO hyperfunction were selected from larger cohort of patients (n=213, 103 females and 110 males) after excluding patients with: angle variability, who underwent reoperation and with incomplete follow up. Preoperative assessment and complete orthoptic examination were performed. Follow-up was performed 3mo, 2, 5 and 10y after surgery. Statistical analysis was performes using SAS statistical software package (version 9.1, SAS Institute Inc., Cary, NC, USA). RESULTS: Ten years follow up data analysis showed the following percentage of orthotropic patients: (0 PD): 3mo, 22.2%; 2y, 16.7%; 5y, 25.0% and 10y, 27.8%. A slight, significant (P<0.01), increase of 2y follow up residual deviation was found when compared to 3mo one. Stationary surgical results is reported during time, with a trend of mean residual deviation reduction (P=0.04). CONCLUSION: Our results confirm the reliability of multiple muscles surgical approach in the treatment of patients affected by EIE with OI hyperfunction. PMID- 28003984 TI - Incidence of orbital, conjunctival and lacrimal gland malignant tumors in USA from Surveillance, Epidemiology and End Results, 1973-2009. AB - AIM: To determine the types and incidence of tumors affecting the orbit, conjunctiva and lacrimal glands and to study the trend line of these tumors in the United States from 1973 to 2009. METHODS: We used the publicly available Surveillance, Epidemiology and End Results (SEER) database registries to determine the incidence rates. Age was adjusted to the 2000 US Standard Population. Patients were stratified according to age group, gender, race and histological grouping of tumor lesions. Three age groups were defined: 0-19, 20 49 and >=50y. Annual percentage changes were calculated to examine trends. RESULTS: The overall age adjusted incidence rate was 3.39 (95%CI: 3.27-3.52) per million person-years. The tumors were more prevalent in age group >=50 counting 9.51 (95%CI: 9.11-9.92) per million person-years. Most of the soft tissue sarcomas occurred in the young age with incidence rate of 0.35 (95%CI: 0.28-0.42) per million person-years. Lymphomas were the dominant subtype in the adult population with incidence rate of 5.74 (95%CI: 5.43-6.06) per million person years. Incidence rates were higher in males than females with an overall rate ratio of 1.31 (95%CI: 1.21-1.41) mainly caused by the increase in carcinoma subtypes. White race had a higher tumor incidence with a rate ratio of 1.47(95%CI: 1.25-1.73) driven by the higher incidence of most histological subtypes. Orbital tumors showed a higher incidence rate followed by conjunctival and lacrimal gland tumors with incidence rates of 1.59, 1.37 and 0.43 per million person-years respectively. The trend line of overall incidence of tumors showed a significant increase (APC=3.11, 95%CI: 2.61-3.61) mainly due to increase of lymphomas. This increase was higher than the increase of lymphomas at other sites. CONCLUSION: Orbital, conjunctival and lacrimal gland malignant tumors differ among children and adults. Over the years there has been a noticeable increase in incidence rates of orbital and lacrimal gland tumors mainly caused by an increase in lymphomas and an apparent increase due to advances in diagnostic techniques. ICD-O-3 topographical coding should be improved to consider the different orbital bones and ocular structures. PMID- 28003985 TI - Comparison of canaloplasty and trabeculectomy for open angle glaucoma: a Meta analysis. AB - AIM: To evaluate the advantage of canaloplasty compared to trabeculectomy for patients with open angle glaucoma. METHODS: Potentially relevant studies were systematically searched using various databases from inception until December 2015. The outcome analyses performed automatically using Revman 5.3 included intraocular pressure reduction (IOPR), postoperative success rate, anti-glaucoma medications reduction and the incidence of adverse events. RESULTS: We included four qualified studies incorporating a total of 215 eyes for quantitative synthesis. The weighted mean difference (WMD) of IOPR between canaloplasty and trabeculectomy from baseline to 12mo was -2.33 (95%CI: -4.00, -0.66). There was not significant improvement in the complete or qualified success rate (OR: 0.58, 95%CI: 0.26, 1.31; OR: 0.50, 95%CI: 0.10, 2.44, respectively). Similarly, no statistically significance was observed in anti-glaucoma mediations reduction (WMD: -0.54, 95%CI: -1.18, 0.09). Sensitivity analysis of the primary outcome estimate confirmed the stability of the Meta-analysis result. CONCLUSION: Trabeculectomy seems to be more effective in lowering IOP up to 12mo when comparing with canaloplasty. Canaloplasty does not seem to be inferior to trabeculectomy considering the postoperative success rate or the number of postoperative anti-glaucoma medications. Meanwhile, it has an advantage of less bleb related complications. PMID- 28003986 TI - Therapeutic and inducing effect of corneal crosslinking on infectious keratitis. AB - The corneal crosslinking (CXL) with riboflavin and ultraviolet-A (UVA) is a new therapy method to successfully treat infectious keratitis in clinical practice. However, there are rare reports on the complications of CXL such as the secondary keratitis. The diverse clinical outcomes on keratitis have highlighted the necessity to further evaluate the efficacy and complications of CXL. We reviewed the positive and negative reports on UVA/riboflavin related with keratitis and provided our opinion on the therapeutic and side effect of UVA/riboflavin crosslinking on keratitis. PMID- 28003987 TI - Biomechanics of the sclera and effects on intraocular pressure. AB - Accumulating evidence indicates that glaucoma is a multifactorial neurodegenerative disease characterized by the loss of retinal ganglion cells (RGC), resulting in gradual and progressive permanent loss of vision. Reducing intraocular pressure (IOP) remains the only proven method for preventing and delaying the progression of glaucomatous visual impairment. However, the specific role of IOP in optic nerve injury remains controversial, and little is known about the biomechanical mechanism by which elevated IOP leads to the loss of RGC. Published studies suggest that the biomechanical properties of the sclera and scleral lamina cribrosa determine the biomechanical changes of optic nerve head, and play an important role in the pathologic process of loss of RGC and optic nerve damage. This review focuses on the current understanding of biomechanics of sclera in glaucoma and provides an overview of the possible interactions between the sclera and IOP. Treatments and interventions aimed at the sclera are also discussed. PMID- 28003989 TI - Descemet's membrane detachments post cataract surgery: a management paradigm. AB - Descemet's membrane detachments (DMD) are relatively common after cataract surgery and most do not require any treatment. However, if large DMD are not treated appropriately, significant visual morbidity can ensue. We aim to develop a guideline for the management of DMD post cataract surgery based on a retrospective review of all cases encountered at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia over a 4-year period from 2010 to 2014. We suggest conservative management if the visual axis is not involved; however, after 3mo surgical intervention may be warranted to prevent corneal sequelae. In cases where the visual axis is involved we suggest early intervention with air tamponade. The main risk factor for irreversible corneal oedema and subsequent endothelial transplant appears to be direct endothelial trauma rather than the DMD itself. PMID- 28003988 TI - Eye pathologies in neonates. AB - In the United Kingdom, newborn assessment incorporates a screening eye examination for any structural abnormalities, observation of neonate's visual behaviour and direct ophthalmoscopy examination looking for red reflex. Early identification and immediate management of eye related pathologies should commence soon after birth as early diagnosis and prompt intervention may have significant impact on the prognosis for many potentially blinding but treatable disorders such as congenital cataracts and retinoblastoma. If left undetected and untreated, such problems may potentially lead to irreversible damage to the vision which persists into adulthood resulting in lack of self-confidence together with difficulties in educational attainment and job opportunities. PMID- 28003990 TI - Glaucoma domiciliary service by optometrist. PMID- 28003991 TI - The pathogenic spectrum of fungal keratitis in northwestern China. PMID- 28003992 TI - Giant non-pulsatile polypoidal choroidal vasculopathy. PMID- 28003993 TI - Abnormal medial rectus insertion presenting exotropia: a case report and review of the literature. PMID- 28003995 TI - Gait Training in Chronic Stroke Using Walk-Even Feedback Device: A Pilot Study. AB - Asymmetrical gait and a reduction in weight bearing on the affected side are a common finding in chronic stroke survivors. The purpose of this pilot study was to determine the effectiveness of a shoe insole device that we developed, called Walk-Even, in correcting asymmetric gait in chronic stroke survivors. Six individuals with chronic (>6 months) stroke underwent 8 weeks of intervention with 2 sessions/week, each consisting of 20 minutes of gait training and 20 minutes of lower-extremity strength training. The 2 control participants underwent conventional gait training, while 4 participants underwent gait training using the Walk-Even. Following intervention, all the participants improved on most of the gait measures: peak pressure of the foot, time of transfer of weight from heel-to-forefoot, center of pressure (COP) trajectory, COP velocity, asymmetry ratio of stance, mean-force-heel, mean-force-metatarsals, Timed "Up and Go," and Activities-specific Balance Scale. The improvement was more pronounced in the 4 participants that underwent training with Walk-Even compared to the control participants. This pilot study suggests that a combination of strength and gait training with real-time feedback may reduce temporal asymmetry and enhance weight-bearing on the affected side in chronic stroke survivors. A large randomized controlled study is needed to confirm its efficacy. PMID- 28003994 TI - Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites? AB - Immunotherapy is now advancing at remarkable pace for tumors located in various tissues, including the brain. Strategies launched decades ago, such as tumor antigen-specific therapeutic vaccines and adoptive transfer of tumor-infiltrating lymphocytes are being complemented by molecular engineering approaches allowing the development of tumor-specific TCR transgenic and chimeric antigen receptor T cells. In addition, the spectacular results obtained in the last years with immune checkpoint inhibitors are transfiguring immunotherapy, these agents being used both as single molecules, but also in combination with other immunotherapeutic modalities. Implementation of these various strategies is ongoing for more and more malignancies, including tumors located in the brain, raising the question of the immunological particularities of this site. This may necessitate cautious selection of tumor antigens, minimizing the immunosuppressive environment and promoting efficient T cell trafficking to the tumor. Once these aspects are taken into account, we might efficiently design immunotherapy for patients suffering from tumors located in the brain, with beneficial clinical outcome. PMID- 28003996 TI - Scavenger Receptor Class B, Type I, a CD36 Related Protein in Macrobrachium nipponense: Characterization, RNA Interference, and Expression Analysis with Different Dietary Lipid Sources. AB - The scavenger receptor class B, type I (SR-BI), is a member of the CD36 superfamily comprising transmembrane proteins involved in mammalian and fish lipid homeostasis regulation. We hypothesize that this receptor plays an important role in Macrobrachium nipponense lipid metabolism. However, little attention has been paid to SR-BI in commercial crustaceans. In the present study, we report a cDNA encoding M. nipponense scavenger receptor class B, type I (designated as MnSR-BI), obtained from a hepatopancreas cDNA library. The complete MnSR-BI coding sequence was 1545 bp, encoding 514 amino acid peptides. The MnSR-BI primary structure consisted of a CD36 domain that contained two transmembrane regions at the N- and C-terminals of the protein. SR-BI mRNA expression was specifically detected in muscle, gill, ovum, intestine, hepatopancreas, stomach, and ovary tissues. Furthermore, its expression in the hepatopancreas was regulated by dietary lipid sources, with prawns fed soybean and linseed oils exhibiting higher expression levels. RNAi-based SR-BI silencing resulted in the suppression of its expression in the hepatopancreas and variation in the expression of lipid metabolism-related genes. This is the first report of SR-BI in freshwater prawns and provides the basis for further studies on SR-BI in crustaceans. PMID- 28003997 TI - Genetic Diversity of Cowpea (Vigna unguiculata (L.) Walp.) Accession in Kenya Gene Bank Based on Simple Sequence Repeat Markers. AB - Increased agricultural production is an urgent issue. Projected global population is 9 million people by mid of this century. Estimation projects death of 1 million people for lack of food quality (micronutrient deficit) and quantity (protein deficit). Majority of these people will be living in developing countries. Other global challenges include shrinking cultivable lands, salinity, and flooding due to climate changes, new emerging pathogens, and pests. These affect crop production. Furthermore, they are major threats to crop genetic resources and food security. Genetic diversity in cultivated crops indicates gene pool richness. It is the greatest resource for plant breeders to select lines that enhance food security. This study was conducted by Masinde Muliro University to evaluate genetic diversity in 19 cowpea accessions from Kenya national gene bank. Accessions clustered into two major groups. High divergence was observed between accessions from Ethiopia and Australia and those from Western Kenya. Upper Volta accessions were closely related to those from Western Kenya. Low variation was observed between accessions from Eastern and Rift Valley than those from Western and Coastal regions of Kenya. Diversity obtained in this study can further be exploited for the improvement of cowpea in Kenya as a measure of food security. PMID- 28003998 TI - Association between the Achievement of Target Range CKD-MBD Markers and Mortality in Prevalent Hemodialysis Patients in Taiwan by Using the Kidney Disease: Improving Global Outcomes Clinical Guidelines. AB - Background. This study evaluated the association between achieving target chronic kidney disease-mineral and bone disorder (CKD-MBD) marker levels and mortality in Taiwanese hemodialysis (HD) patients. Target levels were based on the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Methods. We performed a retrospective medical record review of 1126 HD patients between 2009 and 2013. A logistic regression model was used to evaluate the relationship between achieving target marker levels and the risk for all-cause and cardiovascular (CV) mortality. Reference target ranges were 7.9 <= calcium (Ca) <= 9.9 mg/dL, 2.4 <= phosphate (P) <= 4.7 mg/dL, and 144 <= intact parathyroid hormone (iPTH) <= 648 pg/mL. Results. Achievement of target P levels was associated with a lower risk for all-cause mortality compared to achievement of either target Ca or iPTH levels. Achieving target P + iPTH levels (OR 1.32) was associated with a lower odds ratio for all-cause mortality compared to achieving target Ca + P (OR 1.66) and Ca + iPTH (OR 1.43) levels. Similar trends were observed for CV mortality risk. Conclusions. The present study demonstrated that achieving serum P levels within the KDIGO target range is the most important factor for lowering mortality in HD patients. PMID- 28004000 TI - Utility of Ultrasonography in Assessing the Effectiveness of Extracorporeal Shock Wave Therapy in Insertional Achilles Tendinopathy. AB - Introduction. The aim of this study was to investigate the utility of ultrasonography (US) for predicting and assessing the effectiveness of extracorporeal shock wave therapy (ESWT) in insertional Achilles tendinopathy (IAT). Methods. A total of 42 patients with an established diagnosis of chronic IAT were examined by US before ESWT and at 4 weeks and 12 weeks after ESWT. The thickness and cross-sectional area (CSA) of the Achilles tendon, size of calcific plaques, tendon structure score, and neovascularization score were measured at each time point. Results. After therapy, Victorian Institute of Sport Assessment Achilles (VISA-A) scores increased significantly, and the size of calcific plaques decreased (P < 0.05). Neovascularization scores increased at the 4th week and then decreased at the 12th week (P < 0.05). The thickness, CSA, and structure of the Achilles tendon did not change. Variables observed by US at baseline were not associated with changes in VISA-A scores at follow-up. However, the changes in calcific plaque size and neovascularization scores were related to the improvement of VISA-A scores between pre- and posttherapy (P < 0.01). Conclusion. Ultrasonography can reveal some changes in the insertion of the Achilles tendon after ESWT, but the outcome of ESWT in IAT cannot be predicted by the variables observed by US. PMID- 28003999 TI - Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature. AB - T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression. PMID- 28004001 TI - Mechanical Properties of Calcium Fluoride-Based Composite Materials. AB - Aim of the study was to evaluate mechanical properties of light-curing composite materials modified with the addition of calcium fluoride. The study used one experimental light-curing composite material (ECM) and one commercially available flowable light-curing composite material (FA) that were modified with 0.5-5.0 wt% anhydrous calcium fluoride. Morphology of the samples and uniformity of CaF2 distribution were analyzed using Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS). Mechanical properties were tested after 24-hour storage of specimens in dry or wet conditions. Stored dry ECM enriched with 0.5 1.0 wt% CaF2 showed higher tensile strength values, while water storage of all modified ECM specimens decreased their tensile strength. The highest Vickers hardness tested after dry storage was observed for 2.5 wt% CaF2 content in ECM. The addition of 2.0-5.0 wt% CaF2 to FA caused significant decrease in tensile strength after dry storage and overall tensile strength decrease of modified FA specimens after water storage. The content of 2.0 wt% CaF2 in FA resulted in the highest Vickers hardness tested after wet storage. Commercially available composite material (FA), unmodified with fluoride addition, demonstrated overall significantly higher mechanical properties. PMID- 28004002 TI - Depth Attenuation Degree Based Visualization for Cardiac Ischemic Electrophysiological Feature Exploration. AB - Although heart researches and acquirement of clinical and experimental data are progressively open to public use, cardiac biophysical functions are still not well understood. Due to the complex and fine structures of the heart, cardiac electrophysiological features of interest may be occluded when there is a necessity to demonstrate cardiac electrophysiological behaviors. To investigate cardiac abnormal electrophysiological features under the pathological condition, in this paper, we implement a human cardiac ischemic model and acquire the electrophysiological data of excitation propagation. A visualization framework is then proposed which integrates a novel depth weighted optic attenuation model into the pathological electrophysiological model. The hidden feature of interest in pathological tissue can be revealed from sophisticated overlapping biophysical information. Experiment results verify the effectiveness of the proposed method for intuitively exploring and inspecting cardiac electrophysiological activities, which is fundamental in analyzing and explaining biophysical mechanisms of cardiac functions for doctors and medical staff. PMID- 28004003 TI - Early Sexual Debut and HIV Infection among Men Who Have Sex with Men in Shenzhen, China. AB - Studies investigating the association between early sexual debut and human immunodeficiency virus (HIV) infection have mainly focused on Africans or females but rarely on men who have sex with men (MSM) in China. This study, therefore, mainly aimed at exploring the association between early sexual debut and HIV infection among MSM in Shenzhen, China. A total of 533 MSM were enrolled in this study using a convenience sampling method. Information about sociodemographic characteristics and risky sexual behaviors was collected. It was found that the prevalence of HIV infection was 24.2% among this study population and 66.4% of the MSM reported having had vaginal sexual intercourse with females. The mean ages at first vaginal sexual intercourse, first anal sexual intercourse, and first sexual intercourse were 21.38, 22.43, and 19.87 years, respectively. Multivariable logistic regression analyses showed that the MSM who experienced early anal sexual debut were more likely to be infected with HIV than those who did not. The results indicate that HIV infection is quite prevalent among MSM in Shenzhen. Early and efficient intervention strategies should be taken, and the MSM experiencing early anal sexual debut should be given special attention. PMID- 28004004 TI - Accuracy Assessment of Using Rapid Prototyping Drill Templates for Atlantoaxial Screw Placement: A Cadaver Study. AB - Purpose. To preliminarily evaluate the feasibility and accuracy of using rapid prototyping drill templates (RPDTs) for C1 lateral mass screw (C1-LMS) and C2 pedicle screw (C2-PS) placement. Methods. 23 formalin-fixed craniocervical cadaver specimens were randomly divided into two groups. In the conventional method group, intraoperative fluoroscopy was used to assist the screw placement. In the RPDT navigation group, specific RPDTs were constructed for each specimen and were used intraoperatively for screw placement navigation. The screw position, the operating time, and the fluoroscopy time for each screw placement were compared between the 2 groups. Results. Compared with the conventional method, the RPDT technique significantly increased the placement accuracy of the C2-PS (p < 0.05). In the axial plane, using RPDTs also significantly increased C1 LMS placement accuracy (p < 0.05). In the sagittal plane, although using RPDTs had a very high accuracy rate (100%) in C1-LMS placement, it was not statistically significant compared with the conventional method (p > 0.05). Moreover, the RPDT technique significantly decreased the operating and fluoroscopy times. Conclusion. Using RPDTs significantly increases the accuracy of C1-LMS and C2-PS placement while decreasing the screw placement time and the radiation exposure. Due to these advantages, this approach is worth promoting for use in the Harms technique. PMID- 28004005 TI - Clinical Comparison of Outcomes of Early versus Delayed Carotid Artery Stenting for Symptomatic Cerebral Watershed Infarction due to Stenosis of the Proximal Internal Carotid Artery. AB - The aim of this study was to compare the clinical outcomes of early versus delayed carotid artery stenting (CAS) for symptomatic cerebral watershed infarction (sCWI) patients due to stenosis of the proximal internal carotid artery. We retrospectively collected clinical data of those who underwent early or delayed CAS from March 2011 to April 2014. The time of early CAS and delayed CAS was within a week of symptom onset and after four weeks from symptom onset. Clinical data such as second stroke, the National Institutes of Health Stroke Scale (NHISS) score, and modified Rankin Scale (mRS) score and periprocedural complications were collected. The rate of second stroke in early CAS group is lower when compared to that of delayed CAS group. There was no significant difference regarding periprocedural complications in both groups. There was a significant difference regarding mean NHISS score 90 days after CAS in two groups. Early CAS group had a significant better good outcome (mRS score <= 2) than delayed CAS group. We suggest early CAS for sCWI due to severe proximal internal carotid artery stenosis as it provides lower rate of second stroke, comparable periprocedural complications, and better functional outcomes compared to that of delayed CAS. PMID- 28004006 TI - The Different Effects of Atorvastatin and Pravastatin on Cell Death and PARP Activity in Pancreatic NIT-1 Cells. AB - Statins have been widely used drugs for lowering low-density lipoprotein and for preventing heart attack and stroke. However, the increased risk for developing diabetes during extended stain use and the molecular mechanisms remain unclear. The objective of this study was to elucidate the signaling pathway and biological function between necrosis and autophagy induced by atorvastatin (AS) and pravastatin (PS). Here we observed that atorvastatin (AS) can increase intracellular reactive oxygen species (ROS) and induce necrotic cell death and autophagy in NIT-1 cells, whereas pravastatin (PS) does not cause ROS and cell death but also induces autophagy. PARP1 exhibited a dual role in modulating necrosis and autophagy in AS- and PS-treated NIT-1 cells through RIP1-RIP3-MLKL pathway and PARP1-AMPK-mTOR pathway. Lastly, AS treatment induced mitochondrial morphology injury significantly more than PS treatment did. Thus, the PARP1 activation should be considered in the development of effective statin therapies for diabetes. Future studies may examine specific mechanisms and pathways in mitochondria, autophagy, and oxidative stress in vivo. PMID- 28004008 TI - Incidence of Prediabetes and Type 2 Diabetes among People Aged over 20 Years in Ahvaz: A 5-Year Perspective Study (2009-2014). AB - Background. The present study is the fourth cohort study conducted in the Middle East on the evaluation of prediabetes and type 2 diabetes, implemented in Ahvaz, Iran. Methodology. The individuals aged over twenty years who had participated in a study on the prevalence of metabolic syndrome in 2009 (Phase 1) in Ahvaz were invited again in 2014. The questionnaires were completed via interview, and anthropometric parameters were measured by standard method. The logistic regression and chi-square test were used for data analysis. Results. In the median of five-year follow-up, a number of 593 people participated in reexamination from which 396 individuals were nondiabetic in Phase 1. The incidence of diabetes and prediabetes was 21.9 and 40.6 per 1000 person-years, respectively. Among Phase 1 prediabetics, 16.8% were diagnosed with diabetes in a five-year period. The factors affecting the incidence of prediabetes among the people younger than 65 years include age, family history of diabetes, and gender. The age factor plays an important role in the transformation of prediabetes to diabetes. Conclusion. The city of Ahvaz with type 2 diabetes incidence of 13.64 per 1000 person-years is one of the areas with high incidence of diabetes in Iran. PMID- 28004007 TI - Clinical Efficacy of Two Different Methods to Initiate Sensor-Augmented Insulin Pumps: A Randomized Controlled Trial. AB - Aim. To analyze clinical effect of a novel approach to initiate sensor-augmented insulin pumps in type 1 diabetes mellitus (T1DM) patients through early real-time continuous glucose monitoring (RT-CGM) initiation. Methods. A 26-week pilot study with T1DM subjects randomized (1 : 1) to start RT-CGM three weeks before continuous subcutaneous insulin infusion (CGM pre-CSII) or adding RT-CGM three weeks after continuous subcutaneous insulin infusion (CGM post-CSII). Results. Twenty-two patients were enrolled with a mean age of 36.6 yr. (range 19-59 yr.) and T1DM duration of 16.8 +/- 10.6 yr. Higher adherence in CGM pre-CSII patients was confirmed at study end (84.6 +/- 11.1% versus 64.0 +/- 25.4%; P = 0.01). The two intervention groups had similar HbA1c reduction at study end of -0.6% (P = 0.9). Hypoglycemic event frequency reduction was observed from baseline to study end only in CGM pre-CSII group (mean difference in change, -6.3%; 95% confidence interval, -12.0 to -0.5; P = 0.04). Moreover, no severe hypoglycemia was detected among CGM pre-CSII subjects during the study follow-up (0.0 +/- 0.0 events versus 0.63 +/- 1.0 events; P = 0.03). CGM pre-CSII patients showed better satisfaction than CGM post-CSII patients at the end of the study (27.3 +/- 9.3 versus 32.9 +/- 7.2; P = 0.04). Conclusions. CGM pre-CSII is a novel approach to improve glycemic control and satisfaction in type 1 diabetes sensor-augmented pump treated patients. PMID- 28004009 TI - Powered Lower-Limb Exoskeletons to Restore Gait for Individuals with Paraplegia - a Review. AB - Individuals with paraplegia due to spinal cord injury rank restoration of walking high on the list of priorities to improving their quality of life. Powered lower limb exoskeleton technology provides the ability to restore standing up, sitting down, and walking movements for individuals with paraplegia. The robotic exoskeletons generally have electrical motors located at the hip and knee joint centers, which move the wearers' lower limbs through the appropriate range of motion for gait according to control systems using either trajectory control or impedance control. Users of exoskeletons are able to walk at average gait speeds of 0.26 m/s and distances ranging between 121-171 m. However, the achieved gait speeds and distances fall short of those required for full community ambulation (0.8 m/s and at least 230 m), restricting use of the devices to limited community use with stand-by assist or supervised rehabilitation settings. Improvement in the gait speed and distance may be achievable by combining a specially designed powered exoskeleton with neuromuscular stimulation technologies resulting in a hybrid system that fully engages the user and achieves the necessary requirements to ambulate in the community environment with benefits of muscle contraction. PMID- 28004010 TI - Electron and lattice dynamics of transition metal thin films observed by ultrafast electron diffraction and transient optical measurements. AB - We report the ultrafast dynamics of electrons and lattice in transition metal thin films (Au, Cu, and Mo) investigated by a combination of ultrafast electron diffraction (UED) and pump-probe optical methods. For a single-crystalline Au thin film, we observe the suppression of the diffraction intensity occuring in 10 ps, which direcly reflects the lattice thermalization via the electron-phonon interaction. By using the two-temperature model, the electron-phonon coupling constant (g) and the electron and lattice temperatures (Te, Tl) are evaluated from UED, with which we simulate the transient optical transmittance. The simulation well agrees with the experimentally obtained transmittance data, except for the slight deviations at the initial photoexcitation and the relaxed quasi-equilibrium state. We also present the results similarly obtained for polycrystalline Au, Cu, and Mo thin films and demonstrate the electron and lattice dynamics occurring in metals with different electron-phonon coupling strengths. PMID- 28004011 TI - METHODS TO ENHANCE THE REPRODUCIBILITY OF PRECISION MEDICINE. PMID- 28004012 TI - Newcastle disease in Nigeria: epizootiology and current knowledge of circulating genotypes. AB - Over the years, Newcastle disease (ND) has defied all available control measures. The disease has remained at the forefront of infectious diseases afflicting poultry production after avian influenza. Despite the continuous global use of million doses of ND vaccine annually, the causative pathogen, avian paramyxovirus type 1 also known as Newcastle disease virus (NDV) has continued to evolve causing, even more, a threat not only to the unvaccinated but the vaccinated flocks inclusive. The disease has been well studied in the developed countries where the virus is found in circulation. However, limited information exists on the epizootiology and circulating genotypes of the virus in developing countries where the majority of the flocks are raised on the extensive management system. Identification of virulent NDV in apparently healthy free-range ducks in this system calls for concern and pragmatic approach to investigate factor(s) that favour the virus inhabiting the ducks without clinical manifestation of the disease. Recently, novel genotypes (XIV, XVII, and XVIII) with peculiarity to West and Central African countries have been discovered and due to lack or poor surveillance system possibility of hitherto unreported genotypes are likely. This review elucidates and discusses available literature on the diversity of the circulating NDV genotypes across the West Africa countries and the epizootiology (molecular) of the disease in Nigeria with the view of identifying gaps in knowledge that can assist in the development of effective vaccines and control strategies to combat the peril of the disease. PMID- 28004013 TI - Aberrant expression of interleukin-6 and its receptor in Fallopian tubes bearing an ectopic pregnancy with and without tubal cytomegalovirus infection. AB - Cytomegalovirus (CMV) has recently been suggested as a potential risk factor for the development of ectopic pregnancy (EP) following upper genital tract infection in women. However, little is known about its associated underlying pathogenic mechanisms. This was a prospective case-control study that measured the prevalence of CMV infection in Fallopian tubes (FT) bearing an EP and its effects on the tubal expression of interleukin (IL)-6 and its signaling molecules, which are known to play significant roles in the immune response against CMV infection as well as embryo implantation. Fresh FTs from 96 EPs during salpingectomy and another 61 women at the midluteal phase during total abdominal hysterectomy (TAH) were collected to measure the rate of CMV by an IVD CE PCR kit. The participants were then classified to measure the expression of IL-6, its receptor (IL6R) and intracellular mediators (gp-130, STAT3) by immunohistochemistry and quantitative RT-PCR. The results showed significantly higher (P = 0.01) rates of CMV in FTs obtained from EP (22.9 %) compared with controls (8.2 %). IL-6 (P = 0.003), IL6Ralpha (P = 0.02), gp 130 (P = 0.008) and STAT3 (P = 0.03) were significantly higher in TAH-positive (n = 5) compared with TAH-negative FTs by immunohistochemistry. Furthermore, the expression in the non-infected EP samples was significantly higher for IL-6 (P = 0.004), IL6R (P = 0.007), gp130 (P = 0.006) and STAT3 (P = 0.007) compared with negative TAH. Similar results were observed by quantitative PCR. CMV-positive EP samples showed the highest significant increase of the studied molecules by all techniques. In conclusion, Fallopian tubal infection with CMV is higher in EP and could predispose to embryo implantation by up-regulating the expression of IL-6 and its related molecules as part of tubal innate immune response. Further in vitro and in vivo studies are compulsory to illustrate the roles of IL-6 and CMV in the pathogenesis of EP. PMID- 28004014 TI - Risky exposures and national estimate of HCV seroprevalence among school children in urban Egypt. AB - Hepatitis C virus (HCV) is a significant cause of morbidity and mortality all over the world, particularly in Egypt. Limited data are available concerning the national seroprevalence and the possible modes of transmission of HCV in the pediatric age group. The aim of this study was to obtain a better estimate of the national hepatitis C seroprevalence and the possible risky exposures among healthy school children in Alexandria; the second biggest city in Egypt. HCV knowledge and counseling for school children were also investigated. A total of 500 school children, age between 6 and 15 years were evaluated for HCV seropositivity and interviewed for potential disease risk factors. The seropositivity for Anti-HCV Ab was 2.8 %. About 71.4 % of seropositive children were 10-15 years old. Urban residence, chronic disease, male circumcision and invasive procedures were detected as significant risk factors for acquiring HCV infection among the studied children. The level of awareness of hepatitis C among school children was very low (3.6 %) and was correlated with the age and educational level. HCV infection continues to occur in children and is frequently unrecognized. This mandates immediate intervention and robust control strategies in the settings of exposure combined with health education programs to limit further HCV spread. PMID- 28004016 TI - Peginterferon Alfa-2a/Ribavirin treatment efficacy in chronic hepatitis C patients is related to natural killer group 2D gene rs1049174 GC polymorphism. AB - Natural killer group 2D (NKG2D), as an activating receptor, plays pivotal role in viral infectious diseases. Several single nucleotide polymorphisms (SNPs) in the NKG2D gene have characterized that the rs1049174G/C SNP of NKG2D is in the spotlight of notice because of its role in activating of human T cells. This study aimed to investigate rs1049174G/C genetic polymorphism in Chronic Hepatitis C (CHC) patients. The study compromised 107 CHC patients with genotype 1a and 1b. All recruited patients were under treatment with Peginterferon Alfa-2a/Ribavirin according to standard protocol. After completing treatment, 67 patients showed sustained virologic response (SVR) and the rest of patients did not respond to the treatment and considered as non-responder (NR). Genotyping of NKG2D rs1049174G/C SNP was performed using PCR-RFLP method in SVR and NR patients. The NKG2D rs1049174 genotypes frequency for GG, GC and CC were 45, 41 and 14 % respectively. Genotypes distribution were significantly different between SVR and NR groups (p = 0.005). So that the patients with the homozygous GG genotype demonstrated a higher response to Peginterferon Alfa-2a/Ribavirin therapy against HCV infection (OR = 6.0, 95 %CI 1.71-21.08, p = 0.005). In conclusion, the rs1049174 GG genotype of NKG2D receptor is an effective factor in successfully treatment of CHC patients by Peginterferon Alfa-2a/Ribavirin. PMID- 28004015 TI - Influenza infection modulates vesicular trafficking and induces Golgi complex disruption. AB - Influenza A virus (IFV) replicates its genome in the nucleus of infected cells and uses the cellular protein transport system for genome trafficking from the nucleus to the plasma membrane. However, many details of the mechanism of this process, and its relationship to subsequent cytoplasmic virus trafficking, have not been elucidated. We examined the effect of nuclear transport inhibitors Leptomycin B (LB), 5,6 dichloro-1-beta-d-ribofuranosyl-benzimidazole (DRB), the vesicular transport inhibitor Brefeldin A (BFA), the caspase inhibitor ZWEHD, and microtubule inhibitor Nocodazole (NOC) on virus replication and intracellular trafficking of viral nucleoprotein (NP) from the nucleus to the ER and Golgi. Also, we carried out complementary studies to determine the effect of IFV on intracellular membranes. Inhibition of the CRM1 and TAP-P15 nuclear transport pathways by DRB and LB blocked completely the export of virus. Inhibition of vesicular trafficking by BFA, NOC, and ZWEHD also affected influenza infection. Interestingly, IFV infection induced fragmentation of the Golgi complex resulting in diffuse distribution of large and small vesicles throughout the cytoplasm. Live-cell microscopy revealed expansion of Golgi localization signals indicating progressive dispersion of Golgi positive structures, resulting in the disassembly of the Golgi ribbon structure. Other vesicular components (Rab1b, ARF1 and GBF1) were also found to be required for IFV infection. Furthermore, the exact step at which IFV infection disrupts vesicle trafficking was identified as the ER-Golgi intermediate compartment. These findings suggest that IFV NP is trafficked from the nucleus via the CRM1 and TAP pathways. IFV modulates vesicular trafficking inducing disruption of the Golgi complex. These studies provide insight on the ways in which IFV affects intracellular trafficking of different host proteins and will facilitate identification of useful pharmaceutical targets to abrogate virus replication. PMID- 28004017 TI - Development of a multiplex RT-PCR for simultaneous diagnosis of human metapneumovirus (HMPV) and human respiratory syncytial virus (HRSV) from clinical specimens. AB - Human metapneumovirus (HMPV) and human respiratory syncytial virus (HRSV) are ubiquitous respiratory viral pathogens. They belong to the family Paramyxoviridae (subfamily Pneumovirinae) and is responsible for acute respiratory tract infections in children, elderly and immunocompromised patients. We designed and tested a multiplex reverse transcriptase polymerase chain reaction (mRT-PCR) as a cost-effective alternative to real-time PCR and cell culture based detection for HMPV and HRSV. The newly developed PCR was used to screen nasal/throat swab samples from 356 patients with suspected acute respiratory infection attending the Government Medical College, Thiruvananthapuram, Kerala, India. The method was compared with a commercially available kit employing real time PCR, for its sensitivity and specificity. 53 (14.9 %) samples were positive for at least one tested pathogen by mRT-PCR. All except one among the positive samples showed similar pathogen profile when tested using real time PCR. 8 (15.1 %) among these 53 were positive for HRSVA, 33 (62.3 %) positive for HRSVB and 12 (22.6 %) were positive for HMPV. 17 (32.7 %) samples showed co-infections in them. Sensitivity and specificity of the mRT-PCR was comparable to that of the commercial kit. Our findings indicate that this newly developed mRT-PCR can be used as a cost effective alternative for laboratory diagnosis of HMPV/HRSV infection and will significantly reduce diagnostic costs for these viruses in clinical settings. PMID- 28004018 TI - Isolation and phylogenetic characterization of haemagglutinin and neuraminidase genes of H9N2 low pathogenicity avian influenza virus isolated from commercial layers in India. AB - Avian influenza is a highly infectious and dynamically evolving disease of birds causing high morbidity and mortality. It is caused by avian influenza virus (AIV) that belongs to the family Orthomyxoviridae. Two types of AIV have been described based on their pathogenicity viz. highly pathogenic avian influenza virus that causes severe disease with high mortality and low pathogenic avian influenza virus (LPAI) that generally causes asymptomatic infection or a mild disease. The H9N2 subtype is the widely circulated LPAI type in the world. The H9N2 subtype of was first reported from northern India in March 2003. However, systematical surveillance information for the evolution of H9N2 viruses in poultry flocks of Southern India is lacking. The present study reports the isolation and characterization of H9N2 isolates from the southern parts of the country during the period between May 2010 and September 2011. Out of the 30 poultry flocks investigated, six were found to be positive for HA activity. Further, all the six samples conformed as AIV. Partial nucleotide sequencing of the HA and NA genes revealed that all were belonging to the H9N2 subtype. Phylogenetically, the HA and NA genes of the H9N2 viruses from India clustered with those isolated from Bangladesh, Pakistan and the Middle East, although we were not able to conclude on their exact geographic origin. PMID- 28004019 TI - Role of nitric oxide in the regulation of immune responses during rabies virus infection in mice. AB - Rabies virus (RABV) stimulates nitric oxide (NO) production, which either triggers T cell differentiation or suppresses T cell function depending on its concentration. Herein, we assessed the potential role of NO in regulation of immune responses during RABV infection in mice model. The experimental animals were divided into four groups and 100LD50 of challenge virus standard (CVS) strain of RABV was inoculated intracerebrally on day 0 and subsequently aminoguanidine (AG; inducible nitric oxide synthase inhibitor) was injected intraperitoneally twice a day, up to 6 days. The samples were collected at 2, 4, 6, 8, 9, 10 and 12 days post infection (DPI). The immune cells including CD4+, CD8+ T lymphocytes and natural killer (NK) cells were estimated from peripheral blood mononuclear cells (PBMCs) and splenocytes. Serum total NO concentration, histopathology, immunohistochemistry, direct fluorescent antibody technique and TUNEL assay was performed. Infection with CVS resulted in significant early increase in CD4+, CD8+ and NK cells in blood and spleen until 2 DPI. From 4 DPI onwards significant reduction was noticed in these parameters which coincided with increased NO on 4 DPI, rising to maximum on 8 DPI, until their death on 10 DPI. Conversely, the CVS-AG treated group showed lower levels of NO and increased number of CD4+, CD8+ and NK cells. Increased number of cells in blood and spleen coincided with increased survival time, delayed development of clinical signs, reduced viral load and less apoptotic cells. NO played important role in regulation of immune responses during RABV infection. The findings of present study confirmed the role of NO and/or iNOS using iNOS inhibitor (aminoguanidine) in immune response during RABV infection, which would further help in understanding the virus immunopathogenesis with adoption of newer antiviral strategies to counter the progression of disease. PMID- 28004020 TI - Molecular epidemiology and evolutionary analysis of dengue virus type 2, circulating in Delhi, India. AB - Dengue virus type 2 (DENV-2) has been associated with severe dengue outbreaks in many countries including India. Its predominance was recorded nearly after a decade in the capital city, Delhi in 2013. The present study characterizes DENV-2 circulated during 2013-2014. Analysis based on envelope (E) gene showed the presence of two clades (I and II) of DENV-2, within the Cosmopolitan genotype. Analysis of time of most recent common ancestor revealed the existence of clade I for more than a decade (95 % HPD 13-16 years) however, clade II showed comparatively recent emergence (95 % HPD 5-13 years). Presence of different clades is of high significance as this may result in increased virus transmission and major outbreaks. Further, the presence of a unique amino acid substitution, Q325H was also observed in an isolate; 14/D2/Del/2013 (KT717981). This substitution falls in immune epitope (epitope id: 150268) and may have important role in host immune response. PMID- 28004022 TI - Dataset for corporate valuation and analyses of peer effects in corporate practices and local factors favoring innovation. AB - This data article provides cross-sectionals on the local values of the coefficients of ROE, R&D-TO-SALES, and TOTAL ASSET as regressors of the MARKET-TO BOOK ratio and is related to the research article entitled "Do Local Causations Matter? The Effect of Firm Location on the Relations of ROE, R&D, and Firm Size with Market-to-Book" (A. Carosi, 2016) [1]. The data are aggregated at the regional level (NUTS2). The reported data are the regional average values of the coefficients of ROE, R&D-TO-SALES, and LN(TOTAL ASSET) on LN(MARKET-TO-BOOK), estimated upon the Italian non-financial listed firms in 1999-2007. Local coefficient estimates for family firms and utilities are also provided. PMID- 28004021 TI - Data on evolution of intrinsically disordered regions of the human kinome and contribution of FAK1 IDRs to cytoskeletal remodeling. AB - We present data on the evolution of intrinsically disordered regions (IDRs) taking into account the entire human protein kinome. The evolutionary data of the IDRs with respect to the kinase domains (KDs) and kinases as a whole protein (WP) are reported. Further, we have reported its post translational modifications of FAK1 IDRs and their contribution to the cytoskeletal remodeling. We also report the data to build a protein-protein interaction (PPI) network of primary and secondary FAK1-interacting hybrid proteins. Detailed analysis of the data and its effect on FAK1-related functions have been described in "Structural pliability adjacent to the kinase domain highlights contribution of FAK1 IDRs to cytoskeletal remodeling" (Kathiriya et. al., 2016) [1]. PMID- 28004023 TI - Dataset concerning the analytical approximation of the Ae3 temperature. AB - In this paper we present a new polynomial function for calculating the local phase transformation temperature (Ae3 ) between the austenite+ferrite and the fully austenitic phase fields during heating and cooling of steel:[Formula: see text] The dataset includes the terms of the function and the values for the polynomial coefficients for major alloying elements in steel. A short description of the approximation method used to derive and validate the coefficients has also been included. For discussion and application of this model, please refer to the full length article entitled "The role of aluminium in chemical and phase segregation in a TRIP-assisted dual phase steel" 10.1016/j.actamat.2016.05.046 (Ennis et al., 2016) [1]. PMID- 28004024 TI - Transcriptomes of bovine ovarian follicular and luteal cells. AB - Affymetrix Bovine GeneChip(r) Gene 1.0 ST Array RNA expression analysis was performed on four somatic ovarian cell types: the granulosa cells (GCs) and theca cells (TCs) of the dominant follicle and the large luteal cells (LLCs) and small luteal cells (SLCs) of the corpus luteum. The normalized linear microarray data was deposited to the NCBI GEO repository (GSE83524). Subsequent ANOVA determined genes that were enriched (>=2 fold more) or decreased (<=-2 fold less) in one cell type compared to all three other cell types, and these analyzed and filtered datasets are presented as tables. Genes that were shared in enriched expression in both follicular cell types (GCs and TCs) or in both luteal cells types (LLCs and SLCs) are also reported in tables. The standard deviation of the analyzed array data in relation to the log of the expression values is shown as a figure. These data have been further analyzed and interpreted in the companion article "Gene expression profiling of ovarian follicular and luteal cells provides insight into cellular identities and functions" (Romereim et al., 2017) [1]. PMID- 28004025 TI - Callus cell, shoot and stem proliferation data from pineapple crown and banana inflorescence in vitro: Biochemical and antioxidant properties. AB - The data article contains the experimental data and images on the callus cell, shoot and stem proliferation from pineapple crown slice and banana inflorescence in vitro. Investigated data are related to the research article "Effects of benzylaminopurine and naphthalene acetic acid on proliferation and shoot growth of pineapple (Ananas comosus L. Merr) in vitro" Alsaif et al. (2011) [1] and "Plantlet Production through Development of Competent Multiple Meristem Cultures from Male Inflorescence of Banana, Musa acuminta cv. 'Pisang Mas'(AA)" Wirakarnain et al. (2008) [2]. In the experimental data 1, physiological, (shoot weight, number length and stem proliferation) biochemical (total sugar and chlorophyll) and nutritional ((K+ and NO3-) data using BAP, MS medium and NAA growth regulators in pineapple have been explored. In the experimental data 2, physiological, (callus weight, shoot number and length) biochemical (total sugar, chlorophyll, total phenol, DPPH) and nutritional (K+ and NO3-) data employing BAP +IAA, MS medium and NAA growth regulators in banana have been exhibited. Overall quantitative measurement was observed by Spectrophotometer. In the experimental data, BAP was shown the best effective hormone for the both pineapple and banana explants regeneration. PMID- 28004026 TI - Flow cytometric data analysis of circulating progenitor cell stability. AB - A recent publication by Mekonnen et al. demonstrated that among women with non obstructive coronary artery disease, higher levels of circulating progenitor cells in the blood (CPC), were associated with impaired coronary flow reserve [1]. We performed a quality control assessment of the stability of circulating blood progenitor cells in blood samples stored at 4 degrees C, to determine the time period during which blood samples can be analyzed and yield consistent data for progenitor cell content. Healthy volunteers (n=6) were recruited and underwent phlebotomy, and blood was stored in EDTA tubes at 4 degrees C. Flow cytometry was performed to quantitate progenitor cell subsets at 0-4 h, 24 h, and 48 h post phlebotomy. All processed samples were fixed with 1% Paraformaldehyde and 1,000,000 total data events were collected. We found no significant differences in PC data for both CD34+ (P=0.68 for one-way ANOVA) and CD34+/CD133+ (P=0.74 for one-way ANOVA). PMID- 28004027 TI - Visceral metastatic angiosarcoma treated effectively with oral cyclophosphamide combined with propranolol. PMID- 28004028 TI - Nevoid hyperkeratosis of the nipple mimicking a pigmented basal cell carcinoma. PMID- 28004029 TI - Idiopathic erythema multiforme: Evidence of underlying Janus kinase-signal transducer and activator of transcription activation and successful treatment with tofacitinib. PMID- 28004030 TI - Clinical trials in low and middle-income countries - Successes and challenges. AB - Gynecologic malignancies affect women in low and middle-income countries (LMICs) at equal or higher rates compared to high income countries (HICs), yet practice guidelines based on clinical trials performed in HICs do not routinely account for resource disparities between these regions. There is a need and growing interest for executing clinical trials in LMICs. This has led to the creation of multinational cooperative groups and the initiation of several ongoing clinical trials in Mexico, China, and Korea. In this article we describe the challenges involved in initiating clinical trials in LMICs, review current efforts within surgical, medical, and radiation oncology, and introduce high priority topics for future research. PMID- 28004031 TI - Caregiving and mental health among workers: Longitudinal evidence from a large cohort of adults in Thailand. AB - BACKGROUND: As people in middle and lower income countries live longer, more people become sick, disabled, and frail and the demand for family caregiving grows. Thailand faces such challenges. This study investigates the relationship between caregiving and mental health among workers drawn from a large longitudinal cohort of Thai adults. METHODS: Participants were drawn from the Thai Health-Risk Transition Study, a cohort study since 2005 of distance-learning adult Open University students residing nationwide. Caregiving status and binary psychological distress outcome (score 19-30 on Kessler 6) were recorded in 2009 and 2013 among cohort members who were paid workers at both years (n=33,972). Multivariate logistic regression was used to estimate the relationship between four-year longitudinal caregiving status and psychological distress in 2013, adjusting for potential covariates. RESULTS: Longitudinal analyses revealed the transitional nature of care with 25% exiting and 10% entering the caring role during the four-year follow-up. Based on multivariate logistic regression, 2009 2013 caregiving status was significantly associated with psychological distress. Cohort members transitioning into caregiving and those who were caregivers in both 2009 and 2013 had a higher risk for psychological distress than non caregivers (Adjusted Odds Ratios 1.40 [1.02-1.96] and 1.64 [1.16-2.33], respectively). CONCLUSION: Our findings provide evidence on caregiving and associated risk for psychological distress among working Thais. This adds to the limited existing literature in middle-income countries and highlights the potential pressure among caregivers in balancing work and care while preserving their own mental health. PMID- 28004032 TI - Histological and Metabolic State of Dams Suckling Small Litter or MSG-Treated Pups. AB - Lactation is an important function that is dependent on changes in the maternal homeostasis and sustained by histological maternal adjustments. We evaluated how offspring manipulations during the lactational phase can modulate maternal morphologic aspects in the mammary gland, adipose tissue, and pancreatic islets of lactating dams. Two different models of litter-manipulation-during-lactation were used: litter sizes, small litters (SL) or normal litters (NL) and subcutaneous injections in the puppies of monosodium glutamate (MSG), or saline (CON). SL Dams and MSG Dams presented an increase in WAT content and higher plasma levels of glucose, triglycerides, and insulin, in relation to NL Dams and CON Dams, respectively. The MG of SL Dams and MSG Dams presented a high adipocyte content and reduced alveoli development and the milk of the SL Dams presented a higher calorie and triglyceride content, compared to that of the NL Dams. SL Dams presented a reduction in islet size and greater lipid droplet accumulation in BAT, in relation to NL Dams. SL Dams and MSG Dams present similar responses to offspring manipulation during lactation, resulting in changes in metabolic parameters. These alterations were associated with higher fat accumulation in BAT and changes in milk composition only in SL Dams. PMID- 28004033 TI - Psychomotor Development in Cri du Chat Syndrome: Comparison in Two Italian Cohorts with Different Rehabilitation Methods. AB - The Cri du Chat syndrome (CdC) is a rare genetic disorder caused by variable size deletions of the short arm of chromosome 5 (5p-). It is well known that home reared patients show better performances as compared to institutionalised cases, and it was reported that continuous educational intervention can ameliorate their performances. To assess the efficacy of educational intervention and to develop new CdC oriented programs of rehabilitation, we compare the results obtained for many developmental skills in two groups of CdC patients undergoing two different rehabilitation programs. Using data on the development of a group of CdC patients obtained by validated Italian translation for the Denver Developmental Screening Test II, we compared a group of 13 patients undergoing an educational program developed for CdC patients, the Mayer Project (MP), with a second group of 15 cases in whom caring was not specifically oriented. A positive impact of the MP was reported by parents, observing an improvement in social skills obtained, even if no significant differences were observed when the items of the Denver Test are studied. The need for personalized care in CdC patients and the choice of different methods to compare the results are also discussed. PMID- 28004034 TI - Klebsiella pneumoniae Planktonic and Biofilm Reduction by Different Plant Extracts: In Vitro Study. AB - This study evaluated the action of Pfaffia paniculata K., Juglans regia L., and Rosmarius officinalis L. extracts against planktonic form and biofilm of Klebsiella pneumoniae (ATCC 4352). Minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) values were determined for each extract by microdilution broth method, according to Clinical and Laboratory Standards Institute. Next, antimicrobial activity of the extracts on biofilm was analyzed. For this, standardized suspension at 107 UFC/mL of K. pneumoniae was distributed into 96-well microplates (n = 10) and after 48 h at 37 degrees C and biofilm was subjected to treatment for 5 min with the extracts at a concentration of 200 mg/mL. ANOVA and Tukey tests (5%) were used to verify statistical significant reduction (p < 0.05) of planktonic form and biofilm. P paniculata K., R. officinalis L., and J. regia L. showed reductions in biomass of 55.6, 58.1, and 18.65% and cell viability reduction of 72.4, 65.1, and 31.5%, respectively. The reduction obtained with P. paniculata and R. officinalis extracts was similar to the reduction obtained with chlorhexidine digluconate 2%. In conclusion, all extracts have microbicidal action on the planktonic form but only P. paniculata K. and R. officinalis L. were effective against biofilm. PMID- 28004035 TI - Reliability and Factorial Structure of the Farsi Version of the Arabic Scale of Death Anxiety in an Iranian Middle-Aged Sample. AB - The present study aimed to explore the psychometric properties of the Arabic Scale of Death Anxiety (ASDA) in an Iranian middle-aged sample. A sample of 55 volunteer Iranian persons took part in the study. Cronbach's alpha of the ASDA was found to be high (0.91) and Spearman-Brown and Guttman Split-Half coefficients were 0.86. The factor analysis of the ASDA items yielded five factors accounting for 72.49% of the total variance and labeled (F1) fear of death and fear of dead people; (F2) fear of postmortem events and fear of tombs; (F3) fear of lethal disease; (F4) preoccupation with after death, and death fear in sleep; and (F5) fear of deprivation of own ones. The ASDA has a good validity and reliability, and it can be used in clinical, educational, and research settings. PMID- 28004037 TI - Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC. AB - OBJECTIVE: Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating genomic alterations in PIK3CA (the gene encoding the catalytic subunit of PI3K, targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We hypothesized that co-dependent pathways, including the Ras-MEK-ERK pathway, may still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance. METHODS: We assessed the hypothesis using resazurin cell viability and trypan blue exclusion assays. We also used Western blot to characterize Ras-MEK-ERK pathway activity. STUDY DESIGN: We evaluated this hypothesis in six PIK3CA-amplified, PI3K inhibitor resistant HNSCC cell lines following treatment with pan and alpha-isoform selective PI3K inhibitors (BKM120 and HS-173 respectively). We also tested the effect of combination treatment with PI3K inhibitor HS-173 and MEK inhibitor trametinib or EGFR inhibitor gefitinib. RESULTS: Our results displayed maintenance of Ras-MEK-ERK pathway activity in 4 of 6 HNSCC cell lines after PI3K inhibitor treatment. We also found that UM-SCC-69 and UM-SCC-108 cells display synergistic responses to dual therapy. CONCLUSION: This study suggests that inhibition of the PI3K and Ras-MEK-ERK pathways might be effective in some HNSCC patients; however, it also prompts the study of additional resistance mechanisms to identify synergistic combination therapies for tumors resistant to these di therapies. PMID- 28004036 TI - The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity. AB - The global obesity epidemic, dubbed "globesity" by the World Health Organisation, is a pressing public health issue. The aetiology of obesity is multifactorial incorporating both genetic and environmental factors. Recently, epidemiological studies have observed an association between microbes and obesity. Obesity promoting microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxaemia. This is an influx of bacterial endotoxins into the systemic circulation, believed to underpin obesity pathogenesis. Adipocyte dysfunction and subsequent adipokine secretion characterised by low grade inflammation, were conventionally attributed to persistent hyperlipidaemia. They were thought of as pivotal in perpetuating obesity. It is now debated whether infection and endotoxaemia are also implicated in initiating and perpetuating low grade inflammation. The fact that obesity has a prevalence of over 600 million and serves as a risk factor for chronic diseases including cardiovascular disease and type 2 diabetes mellitus is testament to the importance of exploring the role of microbes in obesity pathobiology. It is on this basis that Massachusetts General Hospital is sponsoring the Faecal Microbiota Transplant for Obesity and Metabolism clinical trial, to study the impact of microbiome composition on weight. The association of microbes with obesity, namely, adenovirus infection and metabolic endotoxaemia, is reviewed. PMID- 28004039 TI - Building an Evaluation Scale using Item Response Theory. AB - Evaluation of NLP methods requires testing against a previously vetted gold standard test set and reporting standard metrics (accuracy/precision/recall/F1). The current assumption is that all items in a given test set are equal with regards to difficulty and discriminating power. We propose Item Response Theory (IRT) from psychometrics as an alternative means for gold-standard test-set generation and NLP system evaluation. IRT is able to describe characteristics of individual items - their difficulty and discriminating power - and can account for these characteristics in its estimation of human intelligence or ability for an NLP task. In this paper, we demonstrate IRT by generating a gold-standard test set for Recognizing Textual Entailment. By collecting a large number of human responses and fitting our IRT model, we show that our IRT model compares NLP systems with the performance in a human population and is able to provide more insight into system performance than standard evaluation metrics. We show that a high accuracy score does not always imply a high IRT score, which depends on the item characteristics and the response pattern. PMID- 28004038 TI - Increasing Rates of Fluoroquinolone Resistance in Escherichia coli Isolated From the Blood and Urine of Patients with Hematologic Malignancies and Stem Cell Transplant Recipients. AB - Fluoroquinolone (FQ) antibiotics have been shown to reduce mortality and the number of febrile episodes when used as prophylaxis during neutropenia. Prior studies suggest that prophylaxis may result in increasing rates of FQ resistance. Fluoroquinolone non-susceptibility trends in Escherichia coli isolated from blood and urine cultures were evaluated over a 16-year period during which prophylaxis was initiated in patients with hematologic malignancies and stem cell transplants. Non-susceptibility rates increased after the introduction of prophylaxis, with yearly non-susceptibility rates rising from 30%-33% to 40%-88% in blood isolates. The high rates of non-susceptibility now observed raise concerns about the continued efficacy of FQ prophylaxis. This concern exists particularly in those patients undergoing stem cell transplants where the total FQ non-susceptibility rates over the study period were 82.3%. Further evaluation of the effect of FQ prophylaxis on antibiotic resistance and its efficacy in the setting of increased rates of resistance is warranted. PMID- 28004040 TI - Structured prediction models for RNN based sequence labeling in clinical text. AB - Sequence labeling is a widely used method for named entity recognition and information extraction from unstructured natural language data. In clinical domain one major application of sequence labeling involves extraction of medical entities such as medication, indication, and side-effects from Electronic Health Record narratives. Sequence labeling in this domain, presents its own set of challenges and objectives. In this work we experimented with various CRF based structured learning models with Recurrent Neural Networks. We extend the previously studied LSTM-CRF models with explicit modeling of pairwise potentials. We also propose an approximate version of skip-chain CRF inference with RNN potentials. We use these methodologies for structured prediction in order to improve the exact phrase detection of various medical entities. PMID- 28004041 TI - Physician-Driven Management of Patient Progress Notes in an Intensive Care Unit. AB - We describe fieldwork in which we studied hospital ICU physicians and their strategies and documentation aids for composing patient progress notes. We then present a clinical documentation prototype, activeNotes, that supports the creation of these notes, using techniques designed based on our fieldwork. ActiveNotes integrates automated, context-sensitive patient data retrieval, and user control of automated data updates and alerts via tagging, into the documentation process. We performed a qualitative study of activeNotes with 15 physicians at the hospital to explore the utility of our information retrieval and tagging techniques. The physicians indicated their desire to use tags for a number of purposes, some of them extensions to what we intended, and others new to us and unexplored in other systems of which we are aware. We discuss the physicians' responses to our prototype and distill several of their proposed uses of tags: to assist in note content management, communication with other clinicians, and care delivery. PMID- 28004042 TI - Highly porous N-doped graphene nanosheets for rapid removal of heavy metals from water by capacitive deionization. AB - This work reports on a highly porous N-doped graphene-based capacitive deionization device, which exhibits a high removal efficiency (90-100%), fast removal (<30 min), and good regeneration performance (10 cycles, 99% retention) for multiple heavy metals (Pb2+, Cd2+, Cu2+, Fe2+, etc.) in water with a wide range of concentrations (0.05-200 ppm). PMID- 28004043 TI - Single plasmonic nanoparticles as ultrasensitive sensors. AB - Plasmonic nanoparticles, especially Au and Ag, exhibit unique and tuneable optical properties due to their localized surface plasmon resonance, which have been widely applied in cell imaging, biocatalysis and biosensing. Notably, dark field microscopy enables the observation of the scattering spectra of single nanoparticles and therefore has been intensively used in the construction of various nanosensors. In this mini review, we will briefly introduce the recent applications of plasmonic nanoparticles based on dark-field microscopy. Ultrasensitive sensors at the single-nanoparticle level are mainly focused by Rayleigh scattering spectroscopy, which is sensitive to their geometry, plasmon coupling, plasmon resonance energy transfer and assembly. Fabrication methods for the nanomaterials and new analysis techniques will also be discussed in detail. PMID- 28004044 TI - Photoluminescence quenching of inorganic cesium lead halides perovskite quantum dots (CsPbX3) by electron/hole acceptor. AB - Recently, all-inorganic cesium lead halide perovskites (CsPbX3) quantum dots (QDs) have attracted great attention due to their halogen composition and size tunable band gap engineering, the same physical mechanism that is responsible for excellent performance in light-emitting devices. However, little is known about the time-resolved fluorescence quenching dynamics process of these CsPbX3 QDs. In this article, we present comprehensive contrastive spectral studies on the electron and hole extraction dynamics of CsPbX3 colloidal QDs with and without quencher by time-resolved femtosecond transient absorption (TA) and time correlated single-photon counting (TCSPC) spectroscopy methods. We have identified that the partial electrons of the conduction band and holes of the valence band of CsPbX3 QDs can be directly extracted by tetracyanoethylene (TCNE) and phenothiazine (PTZ), respectively. Moreover, compared with the CsPbBr3 QDs, the CsPbI3 QDs showed relatively slower charge extraction rates. We also found that the CsPbBr3 QDs with smaller size showed faster carrier recombination rates and photoluminescence (PL) decay lifetime due to the relatively stronger quantum confinement effects. We believe that this study may be useful for realising optimal applications in photovoltaic and light emission devices. PMID- 28004045 TI - New phosphorescent platinum(ii) complexes with tetradentate C*N^N*C ligands: liquid crystallinity and polarized emission. AB - New phosphorescent, liquid crystalline cyclometalated tetradentate platinum complexes (Pt-L16, Pt-L12 and Pt-L6) based on the tetradentate C*N^N*C ligands (C*N^N*C = 6,6'-bis(4-(alkoxy)-phenoxy)-2,2'-bipyridine) are designed and synthesized. Their crystal structure, and photophysical, electrochemical and liquid crystal characteristics were investigated. The X-ray structure of Pt-L12 shows a severe distortion of this complex towards a tetrahedral geometry. All complexes are emissive both in degassed solution and in the solid state at room temperature with emission maxima in the red region of the spectrum. Pt-L16 and Pt L12 show monotropic smectic liquid crystal characteristics. Moreover, these liquid crystal complexes can be aligned on a rubbed nylon-6 glass substrate and produce polarized emission with a dichroic ratio of 5.1. PMID- 28004046 TI - Effects of Ru(ii/iii) redox on the Co(ii) coordination number and magnetic properties of 1D cyanide-bridged Co-Ru compounds. AB - A new 1D cyanide-bridged Co-Ru compound, {[trans RuIII(dmap)4(CN)2Co(dipic)(MeOH)](PF6)}n (1a) (dmap = 4-dimethylaminopyridine, dipic = pyridine-2,6-dicarboxylate), and its reduced state, [trans RuII(dmap)4(CN)2Co(dipic)]n (1b) have been synthesized. Upon the Ru center reduction from iii to ii, the MeOH solvent molecule bound to Co(ii) in 1a is expelled. 1a displays ferrimagnetic properties but 1b is only a paramagnetic compound. PMID- 28004047 TI - Synthesis of organosilicon derivatives of [1]benzothieno[3,2-b][1]-benzothiophene for efficient monolayer Langmuir-Blodgett organic field effect transistors. AB - For the first time, the synthesis of organosilicon derivatives of dialkyl[1]benzothieno[3,2-b][1]-benzothiophene (BTBT) capable of forming a semiconducting monolayer at the water-air interface is reported. Self-assembled monolayer organic field-effect transistors prepared from these materials using the Langmuir-Blodgett technique showed high hole mobilities and excellent air stability. PMID- 28004049 TI - Dioxygen bound cobalt corroles. AB - Two cobalt-dioxygen adducts, [CoH8]-O2 and [CoCl8]-O2, chelated by electron-rich and electron-poor corroles, respectively, were isolated in solution. Characterization by resonance Raman (rR) and EPR spectroscopy, together with DFT analyses, point towards (corrole) cobalt(iii)-O2- structures in both cases. The most significant insight was obtained from the Co-O and O-O stretching frequencies, which revealed that the Co-O bond in [CoH8]-O2 is somewhat stronger than in [CoCl8]-O2 and its O-O is weaker, but also that the differences are truly minute (8-10 cm-1 for the O-O stretch). These conclusions are vital regarding the various applications that rely on efficient reduction of molecular oxygen. In particular, these kinds of cobalt complexes are perfectly suited for serving as electrocatalysts that may be tuned to operate at minimal overpotential without losing almost anything in terms of activity. PMID- 28004048 TI - Computational studies on the interactions of glycine amino acid with graphene, h BN and h-SiC monolayers. AB - In the present work, the adsorption of glycine amino acid and its zwitterionic form onto three different hexagonal sheets, namely graphene, boron-nitride (h-BN) and silicon carbide (h-SiC), has been investigated within the framework of Density Functional Theory (DFT) calculations. The energetics and geometrical parameters of the considered systems have been explored at the GGA-PBE level in combination with Grimme's empirical dispersion corrections with Becke-Johnson damping, the DFT-D3(BJ) method. Based on the obtained results, we found that both the glycine molecule and its zwitterionic conformation tend to be chemisorbed onto the surface of h-SiC (Eads ranges from -1.01 to -1.319 eV) while the types of interactions are recognized to be of non-covalent nature for the case of graphene (Eads ranges from -0.121 to -0.345 eV) and h-BN (Eads ranges from -0.103 eV to -0.325 eV) systems. Moreover, the empirical dispersion corrections applied in these calculations significantly improved the results and confirmed the crucial role of dispersion corrections in obtaining reliable geometries and adsorption energies. Our findings revealed that the electronic properties of the considered systems did not change during the adsorption process and these monolayers preserve their inherent electronic properties as they interact with the glycine molecule. Using the SMD implicit solvation model, the effect of solvation has also been evaluated by re-optimizing the structures within a medium with a dielectric constant of 78.39 (liquid water) and it has been shown that the strength of the interaction between the glycine conformers and hexagonal sheets has decreased. The accuracy of the obtained values has been evaluated by some benchmark calculations at the hybrid PW6B95 level of theory and reasonable consistency is found between the results of the PBE-D3 method and our benchmark system. In summary, h-SiC exhibited the highest affinity toward glycine conformers and gained an important edge over other monolayers. Our findings would actively encourage experimentalists to explore the potential applications of these materials in drug delivery, biofunctionalization of nanostructured monolayers as well as electronic and nanosensor devices. PMID- 28004050 TI - Hexamethylenetetramine carboxyborane: synthesis, structural characterization and CO releasing properties. AB - Carbon monoxide, although widely known as a toxic gas, has received great attention in the past few decades due to its promising role as a medical gas. Several classes of carbon monoxide releasing molecules (CORMs) have been synthesised with many of them having pharmacological activities under physiological conditions. Herein, we report the synthesis and structural characterization of the first example of amine carboxyborane that releases CO under physiological conditions without the aid of inducers. A representative compound hexamethylenetetramine carboxyborane (HMTA-CB) described here has a half life of 2.7 days and gradually releases CO with the rate constant of 3.0 * 10-6 s 1. Its ability to promote cell growth shows the beneficial effect of slow CO release to supplement CO in small amounts over time. PMID- 28004052 TI - An Au/AgBr-Ag heterostructure plasmonic photocatalyst with enhanced catalytic activity under visible light. AB - This study reports an easy synthesis protocol of a novel bimetallic silver halide (Au/AgBr-Ag) plasmonic heterostructure as a visible light induced photocatalyst. In this process, first CTAB capped Au NPs were coated with AgBr, and then Ag nanoparticles were formed on the surface of AgBr by photoreduction, while exposing to daylight at room temperature. The presence of Au and Ag improves the visible absorption ability of NPs and avoids charge recombination of the semiconductor AgBr during photoexcitation, which in turn enhances 16 and 8.9 fold the photocatalytic efficiency of Rhodamine B dye degradation under visible light irradiation compared to that of pure AgBr and AgBr/Ag, respectively. The recycling tests of the photocatalyst show only ~8.7% decrease in efficiency after the 5th cycle of reuse without changing the morphology. During the photocatalytic process, active superoxide radicals (O2-) play a major role, proved through scavenger trapping and photoluminescence experiments. The presence of two plasmonic metals (Au and Ag) in the heterostructure helps to improve visible light absorption as well as avoid charge recombination of the semiconductor AgBr to act as a better photocatalyst. Since this heteronanostructure can be easily synthesized by a one-step method, this study could provide a new approach for the development of efficient bimetallic/semiconductor halide plasmonic photocatalysts with enhanced visible absorption and better charge separation. PMID- 28004051 TI - Replica exchange molecular dynamics study of the truncated amyloid beta (11-40) trimer in solution. AB - Amyloid beta (Abeta) oligomers are neurotoxic compounds that destroy the brain of Alzheimer's disease patients. Recent studies indicated that the trimer is one of the most cytotoxic forms of low molecular weight Abeta oligomers. As there was limited information about the structure of the Abeta trimer, either by experiment or by computation, we determined in this work the structure of the 3Abeta11-40 oligomer for the first time using the temperature replica exchange molecular dynamics simulations in the presence of an explicit solvent. More than 20.0 MUs of MD simulations were performed. The probability of the beta-content and random coil structure of the solvated trimer amounts to 42 +/- 6 and 49 +/- 7% which is in good agreement with experiments. Intermolecular interactions in central hydrophobic cores play a key role in stabilizing the oligomer. Intermolecular polar contacts between D23 and residues 24-29 replace the salt bridge D23-K28 to secure the loop region. The hydrophilic region of the N-terminus is maintained by the intermolecular polar crossing contacts H13A-Q15B and H13B-Q15C. The difference in the free energy of binding between the constituting monomers and the others amounts to -36 +/- 8 kcal mol-1. The collision cross section of the representative structures of the trimer was computed to be 1330 +/- 47 A2, which is in good agreement with previous experiments. PMID- 28004053 TI - Atmospheric implication of the hydrogen bonding interaction in hydrated clusters of HONO and dimethylamine in the nighttime. AB - In this study, the stability of clusters formed by the trans- and cis-isomers of nitrous acid (HONO) with dimethylamine (DMA) and water has been characterized by density functional theory. The large red shifts of the OH-stretching transitions of both HONO isomers in the clusters indicate the formation of strong hydrogen bonds. At standard temperature and pressure, H2O (acceptor) binds to HONO (donor) with binding energies of -25.0 to -24.6 kJ mol-1, less stable than those of DMA (acceptor) with HONO (donor) (-50.5 to -45.3 kJ mol-1). Our findings indicate that hydration enhances proton transfer from HONO to DMA, and consequently increases the interaction strength (binding energies = -67.8 to -78.6 kJ mol-1). The topological and generalized Kohn-Sham energy decomposition confirms strong hydrogen bond interactions. The clustering of HONO with DMA in the atmosphere is negligible as compared to the important H2SO4-DMA clusters. PMID- 28004054 TI - A reliable amplified fluorescence-enhanced chemosensor (Eu-MIL-61) for the directional detection of Ag+ in an aqueous solution. AB - A robust gallium carboxylate Ga(OH)(btec).0.5H2O (MIL-61) was synthesized under mild hydrothermal conditions and selected as the parent MOF to prepare Eu-MIL-61 by post-synthetic modification due to the uncoordinated carbonyl group of the ligand (pyromellitic acid (H4btec)). The firm framework, permanent porosity, and non-coordinated sites make MIL-61 a good scaffold for immobilizing and sensitizing Eu3+. The products showed excellent luminescence and, more significantly, Eu-MIL-61 showed excellent selectivity with photoluminescence enhancement, fast response time, and low detection limit for Ag+ ions in the aqueous solutions. In addition, the frameworks were not susceptible to the acid base property of solutions, which can be further applied to monitor the concentration of Ag+ in several daily water samples. PMID- 28004055 TI - Thrombocytopathy leading to impaired in vivo haemostasis and thrombosis in platelet type von Willebrand disease. AB - Platelet defects due to hyper-responsive GPIbalpha causing enhanced VWF interaction, counter-intuitively result in bleeding rather than thrombosis. The historical explanation of platelet/VWF clearance fails to explain mechanisms of impaired haemostasis particularly in light of reported poor platelet binding to fibrinogen. This study aimed to evaluate the defects of platelets with hyper responsive GPIbalpha and their contribution to impaired in vivo thrombosis. Using the PT-VWD mouse model, platelets from the hTgG233V were compared to control hTgWT mice. Platelets' pro-coagulant capacity was evaluated using flowcytometry assessment of P-selectin and annexin V. Whole blood platelet aggregation in response to ADP, collagen and thrombin was tested. Clot kinetics using laser injury thrombosis model and the effect of GPIbalpha inhibition in vivo using 6B4; a monoclonal antibody, were evaluated. Thrombin-induced platelet P-selectin and PS exposure were significantly reduced in hTgG233V compared to hTgWT and not significantly different when compared to unstimulated platelets. The hTgG233V platelets aggregated normally in response to collagen, and had a delayed response to ADP and thrombin, when compared to hTgWT platelets. Laser injury showed significant impairment of in vivo thrombus formation in hTgG233V compared to hTgWT mice. There was a significant lag in in vitro clot formation in turbidity assay but no impairment in thrombin generation was observed using thromboelastography. The in vivo inhibition of GPIbalpha facilitated new - unstable - clot formation but did not improve the lag. We conclude platelets with hyper-responsive GPIbalpha have complex intrinsic defects beyond the previously described mechanisms. Abnormal signalling through GPIbalpha and potential therapy using inhibitors require further investigations. PMID- 28004056 TI - Fc-saxatilin suppresses hypoxia-induced vascular leakage by regulating endothelial occludin expression. AB - Vascular leakage due to compromised integrity of the endothelial barrier is closely associated with brain damage in several neurological disorders, including ischaemic stroke. Saxatilin, a snake venom disintegrin containing the Arg-Gly-Asp (RGD) motif, exerts thrombolytic and antiplatelet effects by interacting with multiple integrins on platelets. Integrin signalling is indispensable for regulation of endothelial permeability. Saxatilin may play a role in vascular leakage after ischaemia because it has high affinity for endothelial integrins. Here, we determined whether Fc-saxatilin, an Fc-fusion protein of saxatilin, could prevent vascular leakage under hypoxic or ischaemic conditions. In mouse brain microvascular endothelial cells, hypoxia increased the permeability to FITC dextran, and this effect was attenuated by Fc-saxatilin treatment. Fc-saxatilin also blocked vascular leakage of Evans Blue in the ischaemic brain induced by middle cerebral artery occlusion in mice. Furthermore, the expression of occludin, a tight junction protein, was reduced by hypoxia in endothelial cells. This downregulation of occludin was attenuated by Fc-saxatilin treatment. We also determined the activity of matrix metalloproteinases (MMPs) 2 and 9 because they are implicated in the degradation of occludin and of the microvascular basal lamina. Hypoxia increased MMP-9 activity, and this increase was attenuated by Fc saxatilin treatment. Fc-saxatilin specifically bound to integrin alphavbeta3 of the endothelial cells and inhibited hypoxia-induced activation of FAK, a downstream signalling molecule in integrin-dependent signal transduction. Taken together, these results provide new insights into the mechanism via which Fc saxatilin, as an integrin antagonist, prevents vascular leakage under ischemic conditions by regulating occludin expression in endothelial tight junctions. PMID- 28004057 TI - Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B. AB - The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents >=12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (<=2 IU/dl). Here, we report interim, long-term safety and efficacy data from B YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20-100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8-16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (on-demand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had >=100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (>=12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (>=12 years: 2.3; 6 to <12 years: 2.4), and modified (>=12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the long-term safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks. PMID- 28004058 TI - Contrasting effects of myeloid and endothelial ADAM17 on atherosclerosis development. PMID- 28004059 TI - Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention. AB - Antithrombotic medications reduce thrombosis but increase bleeding. Identification of ST-elevation myocardial infarction (STEMI) patients at risk of recurrent thrombosis could allow targeted treatment with potent antithrombotic medications, with less potent agents in others, to reduce bleeding. Conventional platelet function tests assess platelet reactivity only, yet there is increasing evidence that endogenous thrombolytic potential determines outcome following thrombus initiation. We investigated whether assessing both platelet reactivity and endogenous thrombolysis, could identify STEMI patients at high-risk of recurrent thrombotic events. Thrombotic status was assessed in STEMI patients, before and after primary percutaneous coronary intervention (PPCI), at discharge and at 30 days; with 12 months' follow-up. The time to form an occlusive thrombus under high shear (occlusion time, OT), and time to restore flow by endogenous thrombolysis (lysis time, LT) was measured using the point-of-care Global Thrombosis Test (GTT) in the cardiac catheterisation laboratory. Impaired endogenous thrombolysis (prolonged LT >= 3000 s), seen in 13 % patients pre-PPCI, was related to major adverse cardiac events, MACE (HR: 3.31, 95 %CI: 1.02-10.78, p = 0.045), driven by cardiovascular death (HR: 4.17, 95 %CI: 0.99-17.51, p = 0.05). Enhanced (rapid) endogenous thrombolysis (LT < 1000 s) was associated with spontaneous reperfusion, ST-segment resolution and Thrombolysis In Myocardial Infarction 3 flow pre-PPCI. Baseline OT was shorter in those with MACE (especially recurrent myocardial infarction and stroke) than those without (253 +/- 150 s vs 354 +/- 134 s, p=0.017). Endogenous thrombolysis, when impaired, is associated with increased cardiovascular risk, and when enhanced, with spontaneous reperfusion. Endogenous thrombolysis may be a novel target for pharmacological intervention, and allow targeting of potent antithrombotic medications to high-risk patients. PMID- 28004060 TI - Switching from ticagrelor to clopidogrel: New answers and further questions. PMID- 28004061 TI - The role of microRNAs in prethrombotic status associated with coronary artery disease. AB - The acute cardiovascular events following thrombus formation is a primary cause of morbidity and mortality of patients with coronary artery disease (CAD). Numerous studies have shown that a prethrombotic status, which can be defined as an imbalance between the procoagulant and anticoagulant conditions, would exist for a period of time before thrombogenesis. Therefore, early diagnosis and intervention of prethrombotic status are important for reducing acute cardiovascular events. However, none of prethrombotic indicators have been identified as golden standard for diagnosis of prethrombotic status to date. MicroRNAs (miRNAs), a class of short non-coding RNAs, have been shown to be involved in pathophysiologic processes related to prethrombotic status, such as endothelial dysfunction, platelet activation, impaired fibrinolysis and elevated procoagulant factors, etc. Owing to their multiple and fine-tuning impacts on gene expression, miRNAs raise a novel understanding in the underlying mechanism of prethrombotic status. This review aims to discuss the role of miRNAs in prethrombotic status, especially the differently expressed miRNAs in CAD, which may be meaningful for developing promising diagnostic biomarkers and therapeutic strategies for CAD patients in future. PMID- 28004062 TI - Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding. A risk modelling analysis. AB - The optimal timing of vitamin K antagonists (VKAs) resumption after an upper gastrointestinal (GI) bleeding, in patients with continued indication for oral anticoagulation, is uncertain. We included consecutive cases of VKA-associated upper GI bleeding from three hospitals retrospectively. Data on the bleeding location, timing of VKA resumption, recurrent GI bleeding and thromboembolic events were collected. A model was constructed to evaluate the 'total risk', based on the sum of the cumulative rates of recurrent GI bleeding and thromboembolic events, depending on the timing of VKA resumption. A total of 121 (58 %) of 207 patients with VKA-associated upper GI bleeding were restarted on anticoagulation after a median (interquartile range) of one (0.2-3.4) week after the index bleeding. Restarting VKAs was associated with a reduced risk of thromboembolism (HR 0.19; 95 % CI, 0.07-0.55) and death (HR 0.61; 95 % CI, 0.39 0.94), but with an increased risk of recurrent GI bleeding (HR 2.5; 95 % CI, 1.4 4.5). The composite risk obtained from the combined statistical model of recurrent GI bleeding, and thromboembolism decreased if VKAs were resumed after three weeks and reached a nadir at six weeks after the index GI bleeding. On this background we will discuss how the disutility of the outcomes may influence the decision regarding timing of resumption. In conclusion, the optimal timing of VKA resumption after VKA-associated upper GI bleeding appears to be between 3-6 weeks after the index bleeding event but has to take into account the degree of thromboembolic risk, patient values and preferences. PMID- 28004063 TI - D-dimer and the Risk of Stroke and Coronary Heart Disease. The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. AB - D-dimer, a biomarker of coagulation, is higher in blacks than in whites and has been associated with stroke and coronary heart disease (CHD). It was our objective to assess the association of higher D-dimer with stroke and CHD in blacks and whites. REGARDS recruited 30,239 black and white participants across the contiguous US and measured baseline D-dimer in stroke (n=646) and CHD (n=654) cases and a cohort random sample (n=1,104). Cox models adjusting for cardiovascular risk factors determined the hazard ratio (HR) for increasing D dimer for cardiovascular disease with bootstrapping to assess the difference in HR for CHD versus stroke by race. D-dimer was higher with increasing age, female sex, diabetes, hypertension, pre-baseline cardiovascular disease and higher C reactive protein (CRP). Accounting for cardiovascular risk factors, each doubling of D-dimer was associated with increased stroke (hazard ratio [HR] 1.15; 95 % confidence interval [CI] 1.01, 1.31) and CHD (HR 1.27; 95 % CI 1.11, 1.45) risk. The difference in the HR between CHD and stroke was 0.20 (95 % CI >0.00, 0.58) for blacks and 0.02 (95 % CI -0.30, 0.27) for whites. CRP mediated 22 % (95 % CI 5 %, 41 %) of the association between D-dimer and CHD and none of the association with stroke. Higher D-dimer increased the risk of stroke and CHD independent of cardiovascular risk factors and CRP, with perhaps a stronger association for CHD versus stroke in blacks than whites. These findings highlight potential different pathophysiology of vascular disease by disease site and race suggesting potential further studies targeting haemostasis in primary prevention of vascular disease. PMID- 28004064 TI - [Secondary hyperuricemia in chronic renal failure promotes vascular calcification in rats]. AB - The present study was aimed to explore the effects of hyperuricemia on vascular calcification in chronic renal failure (CRF) and the mechanisms. Adenine diet induced CRF rat model was used. Twenty-three male 8-week-old Wistar rats were randomly divided into control group (Ctr, n = 5), CRF group (n = 8) and CRF plus allopurinol group (CRF + ALL, n = 10), and the rats were given standard diet plus standard drinking water, adenine diet plus standard drinking water and adenine diet plus allopurinol drinking for 6 weeks, respectively. Vascular calcification of abdominal aorta was identified by o-cresolphthalein complexone copper assay and Von Kossa staining. The mRNA expression levels of osteogenic/chondrogenic regulatory factors (Cbfalpha1, Msx2, Osx, and Sox9), vascular smooth muscle cell (VSMC) lineage markers (SM22a and Acta2) and calcification inhibitors (Mgp and Opn) were detected by real-time PCR. The results showed that the levels of serum phosphorus (Pi), urea nitrogen, creatinine and uric acid were significantly increased in the CRF rats, whereas allopurinol reversed the levels of serum urea nitrogen, creatinine and uric acid, except for serum Pi. The calcium content of rat abdominal aorta in the CRF group was significantly higher than that of the Ctr group (P < 0.05), but it was partially rescued in the CRF + ALL group (P < 0.05); Compared with the Ctr group, Cbfalpha1, Msx2, Osx and Sox9 mRNA levels of abdominal aorta in the CRF group were significantly up-regulated, while SM22a, Acta2, Mgp and Opn mRNA levels were down-regulated. In the CRF + ALL group, the changes of Msx2, Osx, SM22a and Opn mRNA levels were reversed (P < 0.05). Allopurinol had no effect on high Pi-induced VSMC calcification, and uric acid (6 and 7 mg/dL) significantly increased high Pi-induced VSMC calcification in vitro (P < 0.05). These results suggest that hyperuricemia in CRF may promote the osteoblast/chondrocyte-like cells differentiation of VSMC and further exacerbate vascular calcification. PMID- 28004065 TI - [Progesterone-induced microRNA-1a inhibits the proliferation of endometrial epithelial cells]. AB - The aim of the present study was to investigate the effects of progesterone (P4) induced microRNA-1a (miR-1a) on the proliferation of endometrial epithelial cells (EECs) and the underlying mechanism. In vivo, following subcutaneous injection of estradiol (E2) alone (E2 group) or combined injections of E2 and P4 (E2P4 group) in ovariectomized mice, quantitative real-time PCR (qPCR) was used to check the expression of miR-1a-3p in the directly isolated mouse EECs. The agomir or antagomir specific for miR-1a-3p was injected into one side of the uterine horns of ovariectomized mice pretreated with E2 alone or in combination with P4, and the non-specific control agomir or antagomir was injected into their contralateral horns. Flow cytometry was used to analyze the cell cycle of EECs. Immunohistochemistry (IHC) was used to examine the location and expression of cyclin D2, cyclin E1, and cyclin E2 in the uterine tissue sections. In vitro, primary cultured mouse EECs were pretreated with E2 alone (E2 group) or in combination with P4 (E2P4 group). qPCR was used to detect the expression of miR 1a-3p. Exogenous mimic of miR-1a-3p was transfected into E2-pretreated EECs, and EdU incorporation analysis was used to test the proliferation activity of the EECs. The result of in vivo experiment showed that the expression of miR-1a-3p in E2P4 group was significantly higher than that in E2 group (P < 0.05). The miR-1a 3p agomir arrested cell cycle at G1 to S transition in the mice injected subcutaneously with E2 alone (P < 0.05). Conversely, silencing of miR-1a-3p with transfection of miR-1a-3p antagomir promoted the entry of cells into S phase in the mice injected subcutaneously with both E2 and P4 (P < 0.05). The expressions of cyclin E1 and cyclin E2, except for cyclin D2, in uterine sections were also dramatically reduced by miR-1a-3p overexpression in the uterine epithelium (P < 0.05). In vitro, miR-1a-3p was not expressed in the cells of both E2 and E2P4 groups. The mimic of miR-1a-3p decreased EECs proliferation activity (P < 0.05). These results indicate that P4-induced miR-1a can inhibit the expression of cyclin E1 and cyclin E2, consequently suppressing the proliferation of mouse EECs by arresting cells at G1/S phase. PMID- 28004066 TI - [Effect of secretin on the expression of cPLA2 and mPGEs-1 in mouse endometrial stromal cell during early pregnancy]. AB - Secretin, a gastrointestinal peptide, has been found to be expressed in mouse endometrial stromal cells (mESCs) during early pregnancy. In order to further investigate the function of secretin during embryo implantation, the expression levels of secretin, secretin receptor, cytosolic phospholipase A2 (cPLA2) and membrane prostaglandin E synthase 1 (mPGEs-1) were detected in the mice uterus from day 4 to 8 of pregnancy by real-time PCR, ELISA and in situ hybridization. mESCs isolated and cultured from day 4 of pregnancy were transfected with secretin expression vectors or treated with H89, a PKA inhibitor. Then the expression levels of cPLA2, mPGEs-1 and cAMP responsive element-binding protein (CREB) were detected by real-time PCR and Western blot. The concentration of prostaglandin E2 (PGE2) in the supernatant was determined by ELISA. The result showed that secretin, cPLA2 and mPGEs-1 mRNA expression increased gradually in implantation sites from day 5 to day 7 of pregnancy with the same tendency. The secretin levels in serum were significantly higher on days 6, 7 and 8 of pregnancy than that on day 5 of pregnancy. The concentration of secretin was significantly higher in implantation sites on days 6, 7 than that in non implantation site on day 5. Transfection of secretin expression vector promoted cPLA2, p-cPLA2 and mPGEs-1 expressions in mESCs, but not PGE2 level in the supernatant. H89 could effectively inhibit the expression of CREB, p-CREB, p cPLA2 and cPLA2 induced by secretin. The results showed that the increased secretin expression in mESCs during embryo implantation may promote p-cPLA2, cPLA2 and mPGEs-1 expression, and the promotion may be through PKA signaling pathway. PMID- 28004067 TI - [Advanced glycated albumin induces macrophage apoptosis via activating caspase-12 pathway]. AB - The purpose of the present study was to investigate the effect of advanced glycated albumin (AGE-alb) on the activation of caspase-12, a key molecule in endoplasmic reticulum stress (ERS)-associated apoptotic pathway, and to elucidate the underlying molecular mechanisms of macrophage apoptosis. RAW264.7 macrophages were treated with AGE-alb (2, 4 and 6 g/L), control albumin (C-alb, 4 g/L), tunicamycin (TM, 4 mg/L), or pretreated with 4-phenylbutyric acid (PBA, 5 mmol/L) for 1 h and then treated with AGE-alb (4 g/L). After incubation for 24 h, the cell viability and apoptosis were determined by using MTT assay and TUNEL detection kit, respectively. Lactate dehydrogenase (LDH) activity in media was determined by using an assay kit. The protein levels of caspase-12 were examined by Western blot analysis. The results showed that like TM (an ERS inducer), incubation with AGE-alb led to significant decrease in viability and increase in LDH activity in media and apoptotic rate in a dose-dependent manner. In addition, AGE-alb induced activation of caspase-12 especially at the concentration of 4 and 6 g/L (P < 0.01), which was similar to TM. However, PBA (an ERS inhibitor) protected RAW264.7 macrophages from AGE-alb-induced decrease in viability and increases in LDH activity and apoptosis. Moreover, PBA also inhibited the caspase 12 activation induced by AGE-alb (P < 0.05). These results suggest that AGE-alb may induce apoptosis in RAW 264.7 macrophages, and the mechanism may be related to the activation of ERS-associated apoptotic pathway mediated by caspase-12. PMID- 28004068 TI - [Up-regulation of ErbB3-binding protein 1 inhibits the growth of esophageal carcinoma cells]. AB - The objective of this study was to investigate the role of ErbB3-binding protein 1 (Ebp1) in the growth of esophageal squamous cell carcinoma (ESCC) cells and the underlying mechanism. Eca109 and KYSE150 cells were transfected with lentiviral vector carrying Ebp1 gene. The mRNA levels of Ebp1 in esophageal cancer tissues and paired adjacent normal tissues were examined by real-time PCR. The growth and viability of esophageal carcinoma cells were assessed using MTT and crystal violet assays, respectively. Clone-forming abilities of Eca109 and KYSE150 cells were analyzed by soft agar assay. Apoptotic rates of esophageal carcinoma cells were detected by flow cytometry, and expression levels of the proteins involved in apoptosis were assessed by Western blot. Tumorigenicity of Eca109 cells were detected by nude mouse transplantation tumor experiment. The results indicated that the mRNA levels of Ebp1 in esophageal cancer tissues was down-regulated compared with paired adjacent normal tissues. The growth and viability of Eca109 and KYSE150 cells were all suppressed by Ebp1 overexpression. Besides, Ebp1 overexpression induced apoptosis, increased Rb and P53 expressions, and decreased CyclinD1 expression in Eca109 and KYSE150 cells. In addition, Ebp1 overexpression inhibited the tumorigenesis of Eca109 cells in vivo. These results suggest that Ebp1 may suppress the growth of esophageal carcinoma cells in vitro and in vivo by inducing apoptosis. PMID- 28004069 TI - [Emodin ameliorates the peritoneal dialysis-related peritoneal fibrosis via inhibiting the activation of Notch pathway]. AB - Long term peritoneal dialysis (PD) is often associated with peritoneal fibrosis. The aim of this study was to explore the effect of emodin on PD-related peritoneal fibrosis and its related cellular and molecular mechanism. PD-related peritoneal fibrosis rats and cultured rat peritoneal mesothelial cells were recruited in the experiment. PD-related peritoneal fibrosis was induced by intraperitoneal injection of lactate-buffered solution containing 4.25% glucose. The peritoneal equilibrium test (PET) was performed at the end of 2 weeks, 4 weeks, and 6 weeks, respectively. HE staining and Masson staining were used for histopathological evaluation. Enzyme linked immunosorbent assay (ELISA) was used to measure the plasma N-terminal procollagen III propeptide (PIIINP) level. Real time PCR technique was used to detect the mRNA levels of Notch1, Jagged-1, and Hes-1 in peritoneal tissue. Western blot was applied to identify the protein levels of Notch1, Jagged-1, Hes-1, and Notch intracellular domain (NICD). In vitro, Notch1 overexpressing or knockdown rat peritoneal mesothelial cells were established and Western blot was used to examine the effect of emodin on the expressions of Hes-1 and Hey. Compared with the control group, HE staining revealed that PD rats suffered from decreasing in mesothelial cells, or detaching from surface of parietal peritoneum, accompanied by infiltration of inflammatory cells; Masson staining result showed thickened peritonea (P < 0.01), and the collagen deposition in the parietal peritoneum was increased; also, PIIINP level in plasma was elevated (P < 0.01). Treatment of the PD rats with emodin increased mesothelial cells in peritoneal tissue, and decreased the peritoneal thickness (P < 0.01), collagen depositions, as well as the plasma PIIINP level (P < 0.05). The expressions of Notch1, Jagged-1, Hes-1 and NICD in peritoneal tissue were also attenuated (P < 0.05 or P < 0.01). In cultured rat peritoneal mesothelial cells, compared with emodin group, emodin further inhibited the expressions of Hes-1 and Hey induced by Notch1-overexpression (P < 0.05), but not the expressions of Hes-1 and Hey induced by Notch1-knockdown (P > 0.05). Therefore, the activation of Notch pathway may be involved in the pathological process of PD-induced peritoneal fibrosis. Emodin may ameliorate the PD-related peritoneal fibrosis through inhibiting the activation of Notch pathway. PMID- 28004070 TI - [Effect of opioid receptors on acute stress-induced changes in recognition memory]. AB - Although ample evidence has shown that acute stress impairs memory, the influences of acute stress on different phases of memory, such as acquisition, consolidation and retrieval, are different. Experimental data from both human and animals support that endogenous opioid system plays a role in stress, as endogenous opioid release is increased and opioid receptors are activated during stress experience. On the other hand, endogenous opioid system mediates learning and memory. The aim of the present study was to investigate the effect of acute forced swimming stress on recognition memory of C57 mice and the role of opioid receptors in this process by using a three-day pattern of new object recognition task. The results showed that 15-min acute forced swimming damaged the retrieval of recognition memory, but had no effect on acquisition and consolidation of recognition memory. No significant change of object recognition memory was found in mice that were given naloxone, an opioid receptor antagonist, by intraperitoneal injection. But intraperitoneal injection of naloxone before forced swimming stress could inhibit the impairment of recognition memory retrieval caused by forced swimming stress. The results of real-time PCR showed that acute forced swimming decreased the MU opioid receptor mRNA levels in whole brain and hippocampus, while the injection of naloxone before stress could reverse this change. These results suggest that acute stress may impair recognition memory retrieval via opioid receptors. PMID- 28004071 TI - [N-acetyl-L-cysteine reduces the ozone-induced lung inflammation response in mice]. AB - In this study, we investigated the protective effect of the antioxidant N-acetyl L-cysteine (NAC) on the lung inflammation caused by ozone (O3) exposure in mice. Thirty-two C57BL/6 mice were randomly divided into control group, O3 group, O3+NAC group and NAC group. Mice were exposed to O3 (1.0 ppm) or fresh air for 3 h on the day 1, day 3 and day 5, respectively. NAC (100 mg/kg) was intraperitoneally applied to the mice 1 h before each exposure. At 24 h after the 3-time exposure, the alveolar wall structure was severely damaged and the infiltrated inflammatory cells were apparent perivascularly and peribronchiolarly. Significant increases in the total white blood cell count, macrophage, lymphocyte and neutrophil counts, as well as total protein concentration were observed in the bronchoalveolar lavage fluid (BALF) (P < 0.05). The IL-6, IL-8 (P < 0.01) and MDA levels (P < 0.05) in the lung homogenates were elevated coherently. Administration of NAC could attenuate the alveolar wall structure damage induced by O3 exposure and reduce the amount of infiltrated inflammatory cells, total and differential leukocyte counts (P < 0.05), as well as the IL-6, IL-8 (P < 0.01) and MDA release (P < 0.05). Western blotting results showed that the O3 exposure up-regulated the p38 MAPK and NF kappaB p65 protein expression in the lung tissue of mice (P < 0.05), which could be alleviated by NAC (P < 0.05). These results indicated that NAC could protect against O3-induced pulmonary inflammation in mice. The beneficial effect of NAC might be related with the p38 MAPK and NF-kappaB p65 signal pathway. PMID- 28004072 TI - [Temporal and spatial changes of alpha7nAChR and nNOS in cerebral cortex and hippocampus of Abeta-induced cognitive dysfunction rats]. AB - The present study was to explore the temporal and spatial distributions and variations of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) and neuronal nitric oxide synthetase (nNOS) in cerebral cortex and hippocampus of Abeta induced cognitive dysfunction rats. Sixty Sprague-Dawley (SD) rats were randomly divided into six groups. Three experimental groups were intracerebroventricularly (i.c.v.) injected with condensed-amyloid beta peptides 1-42 (Abeta1-42, 2.5 ug/uL, 4 uL) and were observed on day 7 (7 d Abeta group), day 14 (14 d Abeta group) and day 21 (21 d Abeta group), respectively. Three control groups were i.c.v. injected with equivalent volume of normal saline and observed at the same time points as the experimental groups. The learning and memory abilities of rats were tested with Y-maze; the locations and protein expression levels of alpha7nAChR and nNOS in cerebral cortex and hippocampal CA1, CA3, DG regions were measured by immunohistochemistry and Western blot, respectively. The result showed that, compared with the control groups, the three experimental groups exhibited decreased learning and memory behavioral abilities, and down-regulated expressions of nNOS and alpha7nAChR in prefrontal cortex and hippocampal regions, especially in superficial layer of prefrontal cortex and hippocampal CA3 region. Comparisons among the three experimental groups showed that the inhibitory effects of Abeta on the abilities of learning and memory and the expressions of alpha7nAChR and nNOS in prefrontal cortex and hippocampus were time dependent. The results suggest that the coincident declines of alpha7nAChR and nNOS in prefrontal cortex and hippocampus may be the foundations of the cognitive dysfunction. PMID- 28004073 TI - [HIF-2alpha/Notch3 pathway mediates CoCl2-induced migration and invasion in human breast cancer MCF-7 cells]. AB - The aim of this study is to investigate the effects of hypoxia inducible factor 2alpha (HIF-2alpha) and Notch3 on CoCl2-induced migration and invasion of human breast cancer cell line MCF-7. MCF-7 cells were exposed to normoxia (21% O2) or chemical hypoxia (21% O2 plus CoCl2). Short hairpin RNA (shRNA) was used to knock down HIF-2alpha and Notch3 in MCF-7 cells. The mRNA expression levels of HIF 2alpha, Notch3 and Hey1 were measured by RT-PCR. Western blot was performed to determine the protein expression levels of HIF-2alpha, Notch3, Hey1, Snail and E cadherin. CoCl2 treatment resulted in higher protein expression levels of HIF 2alpha, Notch3, Hey1, Snail (P < 0.05) and lower levels of E-cadherin (P < 0.05), and promoted migration and invasion of MCF-7 cells (P < 0.05). shRNA-HIF-2alpha suppressed CoCl2-induced mRNA expression of Notch3 and Hey1. Notch3 knockdown down-regulated Snail and up-regulated E-cadherin at protein level under simulated hypoxia (P < 0.05), and inhibited CoCl2-induced migration and invasion of MCF-7 cells (P < 0.05). In conclusion, our data provide evidence that HIF-2alpha may promote the migration and invasion of MCF-7 cells under chemical hypoxic conditions by potentiating Notch3 pathway. PMID- 28004074 TI - [Research progress in signal bias of G protein-coupled receptor and its mechanism]. AB - G protein-coupled receptors (GPCRs) mediate signal transduction via G protein or beta-arrestin. Several biased ligands and receptors that preferentially signal through either G protein- or beta-arrestin-mediated pathways have been identified. These discoveries have redefined the classical GPCR signaling paradigm. Distinct ligand-receptor binding sites might be one of the main reasons for biased signal transduction. It is posited that multiple active conformations of receptors lead to distinct kinase phosphorylation patterns on C terminus of receptors. Phosphorylation patterns decide which signal pathway will be transduced. The biased signal pathway transduction has been found in more than 40 GPCRs till now. A few of them have been found involved in fine-regulation of physiological processes. However, most others still need further investigation. The biased ligands may be developed as tools for understanding the basic physiology of GPCR, and, potentially and most importantly, as fine-tuned therapeutics that maximize beneficial effects and minimize adverse or unwanted effects. These studies will provide new insights into new drug discovery. PMID- 28004075 TI - Regulation of reproduction by the circadian rhythms. AB - Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. Circadian rhythm is controlled by the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and the peripheral clocks in various tissues. More importantly, the central clock can integrate photic/nonphotic signals to generate rhythmic outputs, and then drive the slave oscillators in peripheral tissues through neuroendocrine and behavioral signals. Human reproductive activities, as some other physiological functions, are controlled by the biological clocks. Accumulating lines of epidemiological and genetic evidence indicate that disruption of circadian clock can be directly involved in multiple pathological processes, including infertility. In this review, we mainly discuss the presence of a circadian clock in reproductive tissues and its roles in follicles development, ovulation, spermatogenesis, fertilization and embryo implantation, etc. As the increased shift work and assisted reproductive technologies possibly disrupt circadian rhythmicity to impact reproduction, the importance of circadian rhythms should be highlighted in the regulation of reproductive process. PMID- 28004076 TI - [Research progress of Kruppel-like factor 7]. AB - Kruppel-like factor 7 (KLF7), a member of Kruppel-like transcription factors (KLFs), also known as ubiquitous Kruppel- like factor (UKLF), is ubiquitously expressed in various tissues of adult human beings. Genetics reports showed that the genetic polymorphism of KLF7 is associated with obesity, type 2 diabetes, mental development in human beings; and KLF7 methylation is associated with the development of diffuse gastric cancer (gastric adenocarcinoma). In addition, some genomics reports suggested that KLF7 is one of the key transcription factors in the regulatory networks of serum markers change during the cardiovascular disease. The function studies showed that KLF7 is involved in the regulation of the development and function of the nervous system and adipose tissue, type 2 diabetes, blood diseases, as well as pluripotent cells maintenance. This review summarizes the research progress of KLF7 in genetic characteristics, protein structure and gene function. PMID- 28004077 TI - The Interaction of Acrolein with Pristine and N-doped TiO2 Anatase Nanoparticles: A DFT Study. AB - Density functional theory calculations were carried out in order to study the effects of the adsorption of acrolein molecule on the structural and electronic properties of TiO2 anatase nanoparticles. The ability of pristine and N-doped TiO2 anatase nanoparticles to recognize toxic acrolein (C3H4O) molecule was surveyed in detail. It was concluded that acrolein molecule chemisorbs on the N doped anatase nanoparticles with large adsorption energy and small distance with respect to the nanoparticle. The results indicate that the adsorption of acrolein on the N-doped TiO2 is energetically more favorable than the adsorption on the pristine one, suggesting that the N doping can energetically facilitate the adsorption of acrolein on the N-doped nanoparticle. It means that the N-doped TiO2 nanoparticle can react with acrolein molecule more efficiently. The interaction between acrolein molecule and N-doped TiO2 can induce substantial variations in the HOMO/LUMO molecular orbitals of the nanoparticle, changing its electrical conductivity which is helpful for developing novel sensor devices for the removal of harmful acrolein molecule. The large overlaps in the projected density of states spectra reveal the formation of chemical bond between two interacting atoms. Charge analysis based on Mulliken charges indicates that charge is transferred from the acrolein molecule to the TiO2 nanoparticle. PMID- 28004078 TI - Synthesis and Biological Evaluation of Triazole linked Thiazolidenone Glycosides. AB - In a one pot procedure a series of novel triazole linked thiazolidinone derivatives 8a-g and 9a-g was prepared by condensation of (3aR,5S,6R,6aR)-6-((1 (4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydro[2,3-d] [1,3]dioxole-5-carbaldehyde 7 with mercapto acids and primary amines in the presence of ZnCl2 under both microwave irradiation and conventional heating conditions. Compound 7 was prepared from diacetone D-glucose with oxidation followed by reduction, click reaction, primary acetonide deprotection and with oxidative cleavage. Characterization of new compounds has been done by means of IR, NMR, MS and elemental analysis. The nematicidal and antibacterial activity of the compounds has also been evaluated. PMID- 28004079 TI - The Enhancement of H2O2/UV AOPs for the Removal of Selected Organic Pollutants from Drinking Water with Hydrodynamic Cavitation. AB - Drinking water contains organic matter that occasionally needs to be treated to assure its sufficient quality and safety for the consumers. H2O2 and UV advanced oxidation processes (H2O2/UV AOPs) were combined with hydrodynamic cavitation (HC) to assess the effects on the removal of selected organic pollutants. Water samples containing humic acid, methylene blue dye and micropollutants (metaldehyde, diatrizoic acid, iohexol) were treated first by H2O2 (dosages from 1 to 12 mg L-1) and UV (dosages from 300 to 2800 mJ cm-2) AOPs alone and later in combination with HC, generated by nozzles and orifice plates (4, 8, 18 orifices). Using HC, the removal of humic acid was enhanced by 5-15%, methylene blue by 5 20% and metaldehyde by approx. 10%. Under favouring conditions, i.e. high UV absorbance of the matrix (more than 0.050 cm-1 at a wavelength of 254 nm) and a high pollutant to oxidants ratio, HC was found to improve the hydrodynamic conditions in the photolytic reactor, to improve the subjection of the H2O2 to the UV fluence rate distribution and to enhance the removal of the tested organic pollutants, thus showing promising potential of further research in this field. PMID- 28004080 TI - In Situ Preparation, Structure, Photoluminescence and Theoretical Study of an Unusual Bismuth Complex. AB - A novel bismuth photoluminescent material, (N,N'-dimethyl-2,2'-bipy)2(Bi2Cl10) . 2H2O (1) (bipy = bipyridine), with the N,N'-dimethyl-2,2'-bipy2+ moiety obtained in situ, has been synthesized under solvothermal conditions and characterized by single-crystal X-ray diffraction. Compound 1 is characterized by an isolated structure, consisting of N,N'-dimethyl- 2,2'-bipy2+ cations, Bi2Cl10 4- anions and lattice water molecules. Photoluminescence experiments with solidstate samples discover that compound 1 exhibits a strong emission in the green region. Time-dependent density functional theory (TDDFT) calculation reveals that the essence of the photoluminescence of 1 can be assigned to the combination of the metal-to-ligand charge transfer (MLCT) (from the HOMO of the bismuth ion to the LUMO of the N,N'-dimethyl-2,2'-bipy2+ moiety) and the ligand-to-ligand charge transfer (LLCT) (from the HOMO of the chloride ions to the LUMO of the N,N' dimethyl-2,2'-bipy2+ moiety). PMID- 28004081 TI - Determination of the Activity Signature of Key Carbohydrate Metabolism Enzymes in Phenolic-rich Grapevine Tissues. AB - Physiological studies in plants often require enzyme extraction from tissues containing high concentrations of phenols and polyphenols. Unless removed or neutralized, such compounds may hinder extraction, inactivate enzymes, and interfere with enzyme detection. The following protocol for activity assays for enzymes of primary carbohydrate metabolism, while based on our recently published one for quantitative measurement of activities using coupled spectrophotometric assays in a 96-well format, is tailored to the complexities of phenolic- and anthocyanin-rich extracts from grapevine leaf. As a case study we applied the protocol to grapevine leaf samples infected with plant pathogenic bacteria 'Candidatus Phytoplasma solani', known to alter carbohydrate metabolism in grapevine. The described adaptations may be useful for determination of metabolic fingerprints for physiological phenotyping of other plant species with inherently high levels of phenolic compounds. PMID- 28004082 TI - New Algorithm for Microstructural Information Determination from the Overlapping X-ray Diffraction Profiles. AB - Knowledge about the microstructure is crucial in targeted synthesis of novel nanomaterials. The microstructural parameters, crystallite size and crystallite strain play a major role in physical and chemical properties of the material. X ray diffraction (XRD) is a very suitable method for this task, since it is non destructive and it enables a very quick and precise determination of these parameters. The main problem lies in the case where the two neighboring diffraction profiles overlap each other. Here we present a new method for the separation of the overlapping profiles based on the differentiation of the profiles. Further, this method is appropriate for non-crystallographers working in the field of material science since it does not require any crystallographic experience and the full knowledge about the structure of the sample investigated. The microstructural results obtained by the proposed method are very accurate. PMID- 28004083 TI - Synthesis of a Series of Novel Tetra-tert-butylcalix[4]arene Linked to 1,2,4 Triazole and 1,3,4-Oxadiazole Derivatives. AB - A series of tetra-tert-butylcalix[4]arene linked to 1,2,4-triazole-5-thiones and 1,3,4-oxadiazole-5-thiones derivatives at lower rim were synthesized by the reaction of 1,2,4-triazole-5-thione and 1,3,4-oxadiazole-5-thione with 5,11,17,23 tetra-tert-butyl-25,27-bis(3-bromopropoxy)-26,28-dihydroxycalix[4]arene (2). The synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR spectral data, elemental analysis and ESI-MS. PMID- 28004084 TI - A Novel Synthesis of Zinc Borates from a Zinc Oxide Precursor via Ultrasonic Irradiation. AB - In this study, zinc borate hydrate (Zn3B6O12 . 3.5H2O) was synthesized from zinc oxide (ZnO) and boric acid (H3BO3) via a novel method of ultrasonic irradiation. X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR) and Raman spectroscopy were used to characterize the synthesized products. Scanning electron microscopy (SEM) was used to determine the effects of reaction time and reaction temperature on the morphology of the products. Thermal dehydration kinetics were studied using thermal gravimetry and differential thermal gravimetry analysis (TG/DTA). The Doyle and Kissinger non-isothermal kinetic methods were used to analyse the TG/DTA data. The XRD results confirmed the successful synthesis of Zn3B6O12 . 3.5H2O at a range of reaction temperatures and times. Additionally, FT-IR and Raman analysis of the products identified peaks specific to zinc borate. Using the methods of Doyle and Kissinger, the activation energies of thermal dehydration of zinc borate were found to be 341.61 kJ/mol and 390.17 kJ/mol, respectively. PMID- 28004085 TI - Preparation of Cu Nanocomposites from EDA, DETA, and Jeffamine Cored PAMAM Dendrimers with TRIS and Carboxyl Surface Functional Groups. AB - This study presents the synthesis and UV-Vis characterization of Cu nanocomposites from ethylenediamine (EDA) (E), diethylenetriamine (DETA) (D), and Jeffamine(r) T-403 (P) cored PAMAM dendrimers (PAMAMs) with TRIS and carboxyl surface functional groups. Cu-PAMAM dendrimer encapsulated nanoparticles (Cu DENs) were characterized by UV-Vis spectroscopy. Disappearance of the 680 nm d-d transition and 270-300 nm ligand to metal charge transfer (LMCT) peaks and the formation of monotically increasing exponential band were used as the evidence of the successful synthesis of Cu-DENs in addition to immediate color change of dendrimer-metal mixture solutions from blue to golden brown by reduction. Synthesized Cu-DENs could be facilitated as novel alternatives to the existing nanomaterials used in a wide range of applications involving bio and chemical sensors, catalysis, hydrogenations, oxidations, semiconductors, noble metals, magnetic dendrimer nanocomposites, environmental cleanup and many others. PMID- 28004086 TI - Beyond the use of an Explanatory Key Accompanying Submicroscopic Representations. AB - When learning chemistry, students encounter various visualizations introducing scientific concepts and processes unobservable to the naked eye. It is often assumed that these visualizations support students' understanding and enable them to solve problems more efficiently. The research presented here investigates students' use of an explanatory key while solving tasks based on submicroscopic representations. The following features of the explanatory key were examined: 1) colored versus black-and-white, and 2) pictorial versus textual. Eye-fixation patterns and students' verbal explanations indicated that the presence of color in the key does not influence students' task solving. However, significant differences were observed with regard to a textual versus pictorial key used in the tasks: students spent more time and fixated more frequently on the key while solving tasks using a textual key in comparison to a pictorial key. The results indicate that the type of explanatory key might play an important role in revealing students' representational competence with regard to submicroscopic representations. PMID- 28004087 TI - Design, Synthesis, in vitro Antiproliferative Activity, Binding Modeling of 1,2,4,-Triazoles as New Anti-Breast Cancer Agents. AB - This article demonstrates the synthesis of 1,2,4-triazole derivatives and their applications in medicine particularly as anti-breast cancer agents which is a major issue of the present. The synthesized compounds were characterized by elemental analysis, FT-IR and NMR. DFT was used to study the quantum chemical calculations of geometries and vibrational wave numbers of 3-hydroxynaphthyl and p-tolyl substituted 1,2,4-triazoles in the ground state. The scaled harmonic vibrational frequencies obtained from the DFT method were compared with those of the FT-IR spectra and found good agreement. The synthesized 1,2,4-triazole naphthyl hybrids were screened for the anticancer activity against MCF-7 breast cancer lines. Among them compounds 3 and 7 showed broad spectrum anticancer activity with IC50 values 9.7 MUM and 7.10 MUM, respectively and their activity is comparable to that of the standard drugs. The molecular model for binding between the compounds (1-8) and the active site of BRCA2 was obtained on the basis of the computational docking results and the structure-activity relationship. PMID- 28004088 TI - Determination of Trace Cr(VI) with Diphenylcarbazide by MUFIA-Thermal Lens Microscopy. AB - The optimum reaction parameters for the interaction of hexavalent chromium [Cr(VI)] with diphenylcarbazide in microfluidic chips (MUFIA) with thermal-lens microscopic detection were selected. The characteristic feature of the applied flow scheme is the injection of the reagent into the stream containing the test metal, which enables in-field and real-time monitoring of Cr(VI) simply by flowing the sample continuously through the microchip. The limit of detection of Cr(VI) under the selected conditions (signal generating wavelength, 514.5 nm; excitation power, 100 mW; detection position, 10 cm downstream from the mixing zone of the microchip; flow rate 10 MUL min-1; injection volume, 1.4 MUL) is 15 ng mL-1 (2.9 * 10-7 mol L-1). The linear range is 40 ng mL-1 - 10 MUg mL-1 with a relative standard deviation no higher than 10% in the concentration range 0.1-1 MUg mL-1. The online monitoring by this scheme provides the possibility of up to 360 analyses per hour. PMID- 28004089 TI - Divisible Atoms or None at All? Facing the European Contributions to Developments of Chemistry and Physics in China. AB - One of the most important Mid-European professor with more than six thousand academic descendants was the leading Slovenian erudite Jurij Vega. In broader sense, Vega's and other applied sciences of the south of Holy Roman Empire of German Nationality were connected with the mercury mine of Idrija during the last half of millennia. The Idrija Mine used to be one of the two top European producers of mercury, the basic substance of atomistic alchemists. Idrija Mine contributions to the history of techniques, their examinations and approbations is comparable to the other Mid-European achievements. The peculiarities of Idrija mining environment where people valued mostly the applicative knowhow is put into the limelight. The applicative abilities of Idrija employers affected the broader surroundings including Vega's Jesuit teachers in nearby Ljubljana and the phenomena of comparatively many China-Based Jesuits connected with the area of modern Slovenia. The Jesuits' Mid-European education and networks are put into the limelight, as well as their adopted Chinese networks used for their bridging between Eastern and Western Sciences. The Western origin of the scientific technologic-industrial revolution(s) with causes for their apparent nonexistence in Chinese frames is discussed as another Eurocentric rhetorical racist question which presumes the scientific-technologic-industrial revolution(s) as something good, positive, and therefore predominantly European. The Chinese ways into progress without those troublemaking revolutions is focused for the first time in historiography from combined scientific, moral, religious, and economic viewpoints. The Chinese contributions to particular areas of research in chemistry and physics is focused to find out the preferences and most frequent stages of (European) paradigms involved in the Chinese networks. Some predictions of future interests of Chinese chemistry and physics are provided. The Chinese Holistic Confucian distrust in atoms is discussed as possible new paradigm which could rename the destructible divisible entities of future physics, and with more difficulties also of chemistry. The word atom meaning indivisible not compound entity is basically in contradiction with the characteristics of item it is supposed to describe. The suffix "a" provides a negation in Ancient Greek language. The suffix should be omitted to use tom (tauomicronMUomicronsigma) to manage the actual situation of a-toms (=Toms) as compound of elementary particles. In late 19th century after the European Spring of Nations actually two basically different concepts of atoms of chemists and physicists accomplished a kind of symbioses. The suggestion is put forward that while indivisible atoms soon became contradictions in physics, they still retain some value in chemistry which should be taken into account in the attempt to hange the name of atom. The research of human genome as the atom of genetics is similar in broader sense, while there is no basic problem with the nomenclature of genome. The genome manipulations are far less obstructed with Chinese traditions compared to Christian beliefs. PMID- 28004090 TI - DNA Minor Groove Binders-Inspired by Nature. AB - The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of authors. These compounds were subject to a large array of assays. Some of these compounds showed high activity against a range of Gram-positive, Gram-negative bacteria as well as fungi. To explore the anti-parasitic activity of this class of compounds, specific modifications had to be made. A number of these compounds proved to be active against Trypanosoma brucei. The binding of a number of these compounds to short sequences of DNA were also examined using footprinting assays as well as NMR spectroscopy. Computer modelling was employed on selected compounds to understand the way these compounds bind to specific DNA sequences. A large number of variations were made to the standard structure of Distamycin. These changes involved the replacement of the pyrrole moieties as well as the head and tail groups with a number of heterocyclic compounds. Some of these minor groove binders (MGBs) were also investigated for their capability for the treatment of cancer and in particular lung cancer. PMID- 28004091 TI - Comparison of ELISA, HPLC-FLD and HPLC-MS/MS Methods for Determination of Aflatoxin M1 in Natural Contaminated Milk Samples. AB - Presence of aflatoxin M1 (AFM1) in milk should be continuously controlled in order to protect the population from risks associated with its proven toxicity and carcinogenicity. During recent years, there has been an increase in demand for development of sensitive, accurate, simple and fast method which is reliable for detection of AFM1 at low concentrations found in milk samples. For that purpose, enzyme linked immunosorbent asssay (ELISA), high performance liquid chromatography with fluorescence detector (HPLC-FLD) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) were optimized and validated in order to apply them for AFM1 analysis in naturally contaminated milk samples, and to assess the closeness of agreement between results of three different methods. The obtained validation parameters indicate that all three methods are suitable for determination of AFM1 in milk samples. The statistical analysis of variance between the methods and the obtained correlation coefficients indicate that there is a strong correlation between methods. All three methods are satisfactory in meeting the requirements for official control purposes. To the best of author's knowledge, this study represents the first report of an investigation and comparison of ELISA, HPLC-FLD and HPLC-MS/MS methods for determination of AFM1 in naturally contaminated milk samples. PMID- 28004092 TI - Synthesis and Structural Evaluation of 5-Methyl-6-acetyl Substituted Indole and Gramine. AB - The synthesis and crystal structures of 1-(5-methyl-1H-indol-6-yl)ethan-1-one (7), C11H11NO, and 1-3-[(dimethylamino) methyl]-5-methyl-1H-indol-6-ylethan-1-one (8), C14H18N2O, are reported. The synthesis is based on the Diels-Alder cycloaddition of a substituted 2H-pyran-2-one derivative, followed by an acid catalyzed cyclization and concomitant deprotection (the last two steps were carried out as a one-pot domino process) yielding substituted indole 7, which was further derivatized via Mannich reaction to the gramine derivative 8. Both structures 7 and 8 were determined on the basis of IR, 1H NMR and mass spectroscopy, as well as by the elemental analysis and melting point determination. According to the single-crystal X-Ray diffraction analysis, the structure 7 has a single unique molecule in the asymmetric unit whereas the structure 8 contains four unique molecules in the asymmetric unit. Molecules 7 are linked via N-H...O hydrogen bonds between the secondary amine group and carbonyl moiety of the acetyl group of adjacent molecules, whereas molecules 8 are linked via N-H...N hydrogen bonds between the secondary and tertiary amine groups of adjacent molecules. Both structures are further stabilized by weak C H...O, C-H...pi and pi...pi interactions. PMID- 28004093 TI - Direct Laser Synthesis of Ag Nanoparticles from Ammonia-alcoholic Solutions of AgNO3. AB - Ag nanoparticles were synthesized as a result of irradiation of ammonia-alcoholic solution of AgNO3 with focused beam of Nd:YAG laser. The synthesized nanoparticles were characterized with SEM and EDX analysis, dynamic light scattering technique, absorption and luminescence spectroscopies. The average size of synthesized nanoparticles which is from 25 to 100 nm demonstrates a linear dependence on molar concentration of the used solution. Optical and luminescence properties of obtained Ag nanoparticles were demonstrated. PMID- 28004094 TI - Chemiluminescence Determination of Local Anaesthetic Mepivacaine in Human Plasma and Pharmaceuticals. AB - In this study, a new method has been developed for the simple determination of mepivacaine (carbocaine). The method is based on the enhancement effect of mepivacaine in the chemiluminescence (CL) reaction of tris(1,10 phenanthroline) ruthenium(II) with cerium(IV). A mechanism for the CL reaction has been proposed on the basis of UV-Vis, fluorescent and CL spectra. Under optimum conditions, the CL intensity was proportional to the concentration of the drug in solution over the range 0.45-226.25 MUg mL-1 (R2 = 0.9996). The LOD was 0.34 MUg mL-1 (S/N = 3). LOD was about 10 times lower than the therapeutic concentration of mepivacaine. The percent of relative standard deviation for determination of 11 replicates at level of 9.05 MUg mL-1 and 90.50 MUg mL-1 of mepivacaine were 1.8 and 3.7%, respectively. The proposed method was applied successfully for the determination of mepivacaine in human plasma and injectable solutions. PMID- 28004095 TI - Epitope Mapping of Mono- and Polyclonal Antibodies by Screening Phage-displayed Random Peptide Libraries. AB - Detailed knowledge of antigenic determinants is crucial when characterizing therapeutic and diagnostic antibodies, assessing vaccine effectiveness and developing epitope-based vaccines. Most epitope mapping approaches are labor intensive and costly. In this study, we evaluated panning of phage-displayed random peptide libraries against antibodies as a tool for cognate epitope identification. We used six antibodies directed to three model protein antigens as targets to show that the approach is applicable to both mono- and polyclonal antibodies. The technique is well-suited especially for identification of linear epitopes. Mapping of conformational epitopes is more challenging, tends to be more subjective and requires use of computational tools. Nevertheless, when combined with functional data such as structure-activity relationship of antigen muteins, one can make reliable conformational epitope predictions based on phage display experiment data. As the described approach is fast and relatively inexpensive, we suggest it is employed early in antibody characterization and later validated by complementary methods. PMID- 28004096 TI - Nano-Rb2HPW12O40 as an Efficient and Novel Catalyst for One-Pot Synthesis of beta Amino Ketones. AB - The aim of the research described was to study Rb2HPW12O40 as a green and heterogeneous catalyst for the Mannich reaction. One-pot multi-component condensation of an aldehyde, an amine and a ketone at ambient temperature affords the corresponding beta-amino ketones using novel nano-sized Rb2HPW12O40. Simple purification, short reaction time and high yield are some of the advantages of this reaction. Also, the catalyst can be readily isolated. The nano catalyst Rb2HPW12O40 has been characterized by Fourier transform infrared spectroscopy, X ray powder diffraction and scanning electron microscopy. PMID- 28004097 TI - Electro-catalytic Oxidation of Catechol at Poly(1-amino-9,10-anthraquinone)-SDS Composite Film. AB - An electro-chemically active composite film containing the environmentally friendly surfactant sodium dodecyl sulfate (SDS) and poly(1-amino-9,10 anthraquinone) (PAAQ) is used as an electron transfer mediator in the electro chemical oxidation of catechol. Compared with the bare platinum (Pt) electrode, the Pt/PAAQ-SDS modified electrode remarkably lowers the anodic peak potential of catechol, and increases the peak currents. The results obtained indicate that the activation energy for the electro-chemical oxidation of catechol at the polymer film is low (7.05 kJ mol-1). The influence of the operational conditions on the response current of the catechol sensor is also investigated. Studying the surface morphology of the modified electrode reveals a more porous structure for it due to the incorporation of the anionic surfactant on the PAAQ film. The modified electrode displays a linear response in the concentration range of 0.01 8.0 mM for catechol. A lower detection limit was obtained to be 2.60 MUM. The ability of the modified electrode is also examined for the electro-chemical detection of hydroquinone (HQ) with simplicity. PMID- 28004098 TI - The Formation of Passive Layers on Zinc Based Platings. AB - Zinc-iron (ZnFe) and zinc-iron-cobalt (ZnFeCo) platings were achieved on carbon steel applying 3 mA current values. Then, oxalate (OX) and tartrate (Tart) passive layers obtained in sodium oxalate and sodium tartrate medium were formed on carbon steel, ZnFe and ZnFeCo plated carbon steel. SEM images showed that the passive layers on CS, CS/ZnFe and CS/ZnFeCo electrodes exhibited different crystal structures. Corrosion tests revealed that the ZnFeCo particles provided a significant barrier efficiency on CS layer when compared with ZnFe alloy plating. Furthermore, OX layers on ZnFe and ZnFeCo plated carbon steel electrodes exhibited better physical barrier behavior on than those of Tart layers in longer periods. PMID- 28004099 TI - Synthesis, Crystal Structures and Antibacterial Activities of Trifluoromethylsulfonate Salts of 2-[(3-Chloropyridinium-2-yl)hydrazonomethyl]-6 methoxyphenol and its Copper(II) and Cobalt(III) Complexes. AB - A new trifluoromethylsulfonate salt of 2-[(3-chloropyridinium-2 yl)hydrazonomethyl]-6-methoxyphenol, (HL)CF3SO3, and its copper(II) and cobalt(III) complexes, [CuL(OH2)]CF3SO3 . 0.5H2O (1) and [CoL2]CF3SO3 . CH3OH (2), were prepared and characterized by physico-chemical methods and single crystal X-ray analysis. A trifluoromethylsulfonate anion is present in each of the compounds. The Cu atom in complex 1 is coordinated by the phenolate O, imino N and pyridine N atoms of L ligand, giving square planar geometry. The Co atom in complex 2 is coordinated by two phenolate O, two imino N and two pyridine N atoms from two L ligands, giving octahedral geometry. The three compounds were tested in vitro for their antibacterial activities. PMID- 28004100 TI - Synthesis, Crystal Structure, and Catalytic Property of Dioxomolybdenum(VI) Complex Derived from 4-Bromo-N'-(4-diethylamino-2-hydroxybenzylidene) benzohydrazide. AB - A novel dioxomolybdenum(VI) complex, [MoO2L(MeOH)], where L is the anion of 4 bromo-N'-(4-diethylamino-2-hydroxybenzylidene)benzohydrazide, has been synthesized and characterized by physico-chemical methods and single crystal X ray determination. In the complex the Mo atom is in octahedral coordination, with three donor atoms of the hydrazone ligand, two oxo groups, and one methanol O atom. The complex exhibits catalytic property for the sulfoxidation reactions. In the presence of the complex a 93% conversion of the sulfide to the corresponding sulfoxide was observed within 60 min and the 100% conversion was achieved after 2 h. PMID- 28004101 TI - Salicylic Acid and Calcium Treatments Improves Wheat Vigor, Lipids and Phenolics Under High Salinity. AB - Seed vigor is a complex physiological trait required to ensure the rapid and uniform emergence of plants in the field under different environmental conditions. Therefore, salicylic acid (SA, 0.5 mM) and calcium (Ca2+, 50 mM) priming were used as exogenous growth enhancers to stimulate wheat (Triticum durum Desf. cv. Yelken) seed vigor under high salinity. The main aim was to address whether priming of wheat with SA, Ca2+ and SA+Ca (SA, 0.5 mM + Ca2+, 50 mM; their combination) could bring about supplementary agronomic benefits particularly under stressful environments such as salinity. Exogenous application of SA or Ca2+ alone improved plant behavior in the presence of salinity stress. Nevertheless, the best results in terms of growth, seed vigor and total phenolic flavonoids, chlorophyll - carotenoids contents and phenylalanine ammonia-lyase (PAL), ascorbic acide oxidase (AAO) activities and lipid peroxidation levels (LPO) were obtained in response to the combined SA+Ca treatment. PMID- 28004102 TI - Toluene, Methanol and Benzaldehyde Removal from Gas Streams by Adsorption onto Natural Clay and Faujasite-Y type Zeolite. AB - A great number of pollution problems come as a result of the emission of Volatile Organic Compounds (VOCs) into the environment and their control becomes a serious challenge for the global chemical industry. Adsorption is a widely used technique for the removal of VOCs due to its high efficiency, low cost, and convenient operation. In this study, the feasibility to use a locally available clay, as adsorbent material to control VOCs emissions is evaluated. Natural clay is characterised by different physical-chemical methods and adsorptive interaction features between VOCs and natural clay are identified. Toluene (T), methanol (M) and benzaldehyde (B) are used here as representatives of three different kinds of VOCs. Adsorption isotherms onto natural clay and faujasite-Y type zeolite (Fau Y) are obtained at room temperature. According to Langmuir model data, maximum adsorption capacities (qm) of Fez natural clay and zeolite toward methanol (M), toluene (T) and benzaldehyde (B) at 300 K are 8, 0.89 and 3.1 mmol g-1, and 15, 1.91 and 13.9 mmol g-1 respectively. In addition, the effect of temperature on the adsorption of toluene onto natural clay is evaluated in the range from 300 to 323K. An increase on temperature reduces the adsorption capacity of natural clay toward toluene, indicating that an exothermic physical adsorption process takes place. The enthalpy of adsorption of toluene onto Fez natural clay was found to be -54 kJ mol-1. A preliminary cost analysis shows that natural clay could be used as an alternative low cost adsorbent in the control of VOCs from contaminated gas streams with a cost of US$ 0.02 kg-1 compared to Fau Y zeolite with US$ 10 kg-1. PMID- 28004103 TI - Synthesis, Structure Evaluation, Spectroscopic and Antibacterial Investigation of Metal Complexes with 2-(Pyridin-4-yl)quinoline-4-carboxylic Acid. AB - Four metal complexes based on quinoline carboxylate ligand from 2-(pyridin-4 yl)quinoline-4-carboxylic acid (HL), [ML2(H2O)2] . 2H2On (M = MnII, 1; M = CoII, 2; M = CdII, 3) and [Ag2L2(H2O)2] . 3H2On (4) have been synthesized under hydrothermal conditions. Their structures were determined by elemental analyses, IR spectra, and further characterized by single-crystal X-ray diffraction analysis. Complexes 1-3 feature a 1D chain structure which is further linked together to construct the 3D supramolecular network through hydrogen bonds. Complex 4 exhibits a 3D configuration. The fluorescent behavior and antibacterial activities of these compounds have been investigated. PMID- 28004104 TI - Synthesis and Crystal Structure of a 4,4'-bipyridine Linked Dinuclear Copper(II) Complex Derived from 2-{[2-(2-hydroxyethylamino)ethylimino]methyl}-6 methylphenol. AB - A novel 4,4'-bipyridine linked dinuclear copper(II) complex, [Cu2L2(bipy)](NO3)2.bipy (L = 2-[2-(2-hydroxyethylamino) ethylimino]methyl-6 methylphenol; bipy = 4,4'-bipyridine), was prepared and characterized by elemental analyses, IR spectroscopy, and single-crystal X-ray diffraction. The Cu...Cu distance is 11.129(2) A. The CuII atom is coordinated by one phenolate O, one imine N, and one amine N atoms of a Schiff base ligand, and one N atom of the bridging 4,4'-bipyridine ligand, forming a square planar geometry. In the crystal structure of the complex, the dinuclear copper complex cations are linked by 4,4' bipyridine molecules through intermolecular O-H...N hydrogen bonds, to form 1D chains running in the [2 0 -1] direction. PMID- 28004105 TI - UHRF2 decreases H3K9ac expression by interacting with it through the PHD and SRA/YDG domain in HepG2 hepatocellular carcinoma cells. AB - Ubiquitin-like with PHD and ring finger domains 2 (UHRF2) is a multi-domain E3 ubiquitin ligase which is involved in epigenetic regulation and plays an essential role in tumorigenesis. However, the role of UHRF2 in histone H3 acetylation has not yet been fully elucidated and few studies have reported its role in hepatocellular carcinoma (HCC). In this study, we examined the correlation between UHRF2 and acetylated H3 in HCC. Immunohistochemistry and western blot analysis demonstrated that the levels of histone H3 lysine 9 acetylation (H3K9ac) and histone H3 lysine 14 acetylation (H3K14ac) were higher in the HCC tissues and HepG2 HCC cells compared with the adjacent non-tumor tissues and L02 normal cells. The level of UHRF2 was higher in the HCC tissues compared with the adjacent non-tumor tissues, but its expression did not exhibit a significant difference between the HepG2 HCC cells and the L02 normal cells. In addition, when comparing the HCC tissues, a higher expression of UHRF2 correlated with a lower expression of H3K9ac in the HCC tissues. The overexpression of UHRF2 increased the expression of H3K9ac in L02 normal cells (P<0.01), but decreased the expression of H3K9ac in HepG2 cancer cells (P<0.05). Moreover, immunofluorescence staining and co-immunoprecipitation assay indicated that UHRF2 co-localized and interacted with H3K9ac in L02 and HepG2 cells and the plant homeodomain (PHD) finger domain was the key domain for UHRF2 directly binding to H3K9ac. Taken together, these results suggest that UHRF2 decreases the expression of H3K9ac in HepG2 HCC cells and interacts with it through the PHD domain. PMID- 28004106 TI - Resveratrol upregulates SOCS1 production by lipopolysaccharide-stimulated RAW264.7 macrophages by inhibiting miR-155. AB - Resveratrol is a polyphenolic compound extracted from grapes and the Chinese herb, Polygonum cuspidatum. In the present study, in order to elucidate the molecular mechanisms of action of resveratrol in host immune cells, we examined the effects of resveratrol on the inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. The cells were treated with resveratrol prior to stimulation with LPS (1 ug/ml). Resveratrol downregulated the expression of inflammatory markers, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, induced by LPS, and inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT)1/STAT3. Resveratrol also upregulated the production of suppressor of cytokine signaling 1 (SOCS1; a STAT inhibitor) and suppressed the expression of miR-155, which plays an essential role in the innate and adaptive immune response. Given the elevated levels of SOCS1 in LPS-induced inflammation, our results suggest that resveratrol exerts anti-inflammatory effects due to the upregulation of SOCS1, which is a potential target of miR-155, as well as of miR 155 mimics and inhibitors. These findings suggest the benefits of resveratrol, which are derived from its regulation of SOCS1 expression via the inhibition of miR-155, and indicate that resveratrol may be developed as a useful agent for the treatment of inflammatory diseases. PMID- 28004107 TI - Humulus japonicus inhibits the progression of Alzheimer's disease in a APP/PS1 transgenic mouse model. AB - Humulus japonicus Siebold & Zucc. (HJ) has traditionally been administered to patients with pulmonary disease, skin disease and hypertension in Korea, and it is considered to exert anti-inflammatory, antioxidant, antimicrobial and antimycobacterial effects. However, its effects against Alzheimer's disease (AD) have yet to be explored. Thus, this study was carried out to investigate whether HJ has a beneficial effect on the progression of AD in an animal model. A methanolic extract of HJ (500 mg/kg/day) was intragastrically administered to 5 month-old APP/PS1 transgenic (Tg-APP/PS1) mice for 2.5 months. Novel object recognition and Y-maze alteration tests were used to assess cognitive function, and an immunohistochemical assay was performed to assess amyloid beta (Abeta)deposition, tau phosphorylation and gliosis. An in vitro assay using a microglial cell line was also performed to investigate the anti-inflammatory effects of HJ. Our results revealed that HJ significantly decreased the mRNA and protein expression levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide in the microglial cell line. The administration of HJ for 2 months improved the cognitive function of Tg-APP/PS1 mice. HJ notably reduced the area occupied by Abeta and neurofibrillary tangles, and the number of activated astrocytes and microglia in the cortex of Tg-APP/PS1 mice. The findings of our study suggest that HJ has the therapeutic potential to inhibit the progression of AD and to improve cognitive deterioration in Tg-APP/PS1 mice. PMID- 28004108 TI - Potential role of BCL2 in the recurrence of uterine smooth muscle tumors of uncertain malignant potential. AB - Uterine smooth muscle tumors are the most common female genital tract neoplasms. While leiomyosarcoma has been studied at length, smooth muscle tumors of uncertain malignant potential (STUMPs) still have ambiguous and unresolved issues, with a risk of relapse and evolution largely undefined. We performed an array comparative genomic hybridization analysis on a primitive STUMP and its local recurrence, histologically diagnosed as undifferentiated sarcoma. To the best of our knowledge, our report is the first genomic study on primitive STUMPs and the different relapsed tumors. The results showed few copy number alterations shared between both samples and the high heterogeneity in the STUMP was apparently lost in the sarcoma. Surprisingly the STUMP presented an amplification of the BCL2 gene, not observed in the relapsed tumor. Additionally, fluorescence in situ hybridization and immunohistochemical staining were performed to confirm BCL2 amplification and expression in these samples and in two other cases of primitive STUMPs and their corresponding relapsed tumors. The presence of BCL2 in multiple copies and expression in the two primitive STUMPs and two relapsed tumors was confirmed. The marked amplification of the BCL2 gene present in the primitive STUMP and the multiple copies also observed in other cases, suggest its potential role as a marker of STUMP malignant potential and recurrence. PMID- 28004109 TI - Identification of TMPRSS2-ERG mechanisms in prostate cancer invasiveness: Involvement of MMP-9 and plexin B1. AB - The relationship of TMPRSS2-ERG fusion gene with matrix metalloproteinase-9 (MMP 9) and PLXNB1 (plexin B1) in regulation of prostate cancer (PCa) aggressiveness was investigated. Fluorescence in situ hybridization (FISH) assays, qRT-PCR and western blot analysis were employed to detect the expression of TMPRSS2-ERG fusion gene, ERG, MMP-9 and PLXNB1 of 135 human tissues, which included 55 metastatic PCa cases, 50 localized PCa cases and 30 BPH cases. Then using siRNA (anti-ERG, MMP-9 and PLXNB1, respectively) downregulation of the target gene of VCaP and PC-3 cells, MTT and Transwell were performed. The results showed that the positive rate of TMPRSS2-ERG fusion was 38.1% (40/105) in total PCa samples, 47.3% (26/55) of metastatic PCa, 28.0% (14/50) of localized PCa, while 0.0% (0/30) in BPH samples. The mRNA and protein expression of ERG, MMP-9 and PLXNB1 were higher in metastatic PCa (P<0.0001), and the mRNA expression of the three genes were positively correlated with TMPRSS2-ERG fusionin PCa group (P<0.0001). siRNA transfected PCa cells can effectively downregulate the target gene expression, and we identified that MMP-9 and PLXNB1 expression were all regulated by TMPRSS2-ERG fusion gene. While only PLXNB1 contributed to TMPRSS2-ERG mediated enhancements of VCaP cell migration and invasion. The results demonstrated that PLXNB1, but not MMP-9, was the target gene directly related to TMPRSS2-ERG in PCa cell migration and invasion. PMID- 28004110 TI - Effects of the regulation of polysialyltransferase ST8SiaII on the invasiveness and metastasis of small cell lung cancer cells. AB - Invasiveness and metastasis may seriously affect the prognosis of small cell lung cancer (SCLC). In the present study, we analyzed the effects and inherent mechanisms of action of polysialic acid-modified neural cell adhesion molecule (NCAM) on the invasive and metastatic potential of SCLC. Gene transfection and short hairpin RNA (shRNA) interference were used to enhance or inhibit, respectively, the expression of polysialyltransferase ST8SiaII in the SCLC cell line H446. We studied in vitro positive or negative changes in the invasive and metastatic potential of the SCLC cells as well as the changes in expression of genes related to signaling molecules and metastasis. When ST8SiaII expression was enhanced, the in vitro transmembrane invasion (P<0.01) and migration (P<0.01) abilities of the SCLC cells markedly increased. Phosphorylation levels of fibroblast growth factor receptor 1 (FGFR1), extracellular signal-related kinase 1/2 (ERK1/2), and matrix metalloproteinase-9 (MMP-9) in the SCLC cells were also significantly increased. In contrast, when ST8SiaII expression was inhibited, the transmembrane invasion (P<0.01) and migration (P<0.01) of the SCLC cells as well as expression of the above signaling molecules were suppressed. Polysialic acid modified NCAM on the surface of SCLC cells is closely related to the metastatic potential of these cells; regulation of ST8SiaII may thus affect the invasiveness and metastasis of SCLC, and these processes may be associated with phosphorylation of FGFR1, ERK1/2 or MMP-9. PMID- 28004111 TI - COL11A1 is overexpressed in gastric cancer tissues and regulates proliferation, migration and invasion of HGC-27 gastric cancer cells in vitro. AB - The role of COL11A1 in carcinogenesis is increasingly recognized. However, the biological role and potential mechanisms of COL11A1 in gastric cancer have not been elucidated. In the present study, the COL11A1 mRNA expression in 57 patients with gastric cancer was measured by reverse transcription quantitative PCR (RT qPCR), and the biological effects of COL11A1 suppression were determined using MTS, monolayer colony formation, flow cytometry and Transwell assays. In addition, the potential molecular mechanisms of COL11A1 in gastric cancer were analyzed by western blotting and cDNA microarray analysis. Compared with matched adjacent non-tumor tissue, COL11A1 mRNA was significantly overexpressed in tumor tissue and was positively related to age, tumor invasion depth, tumor size and lymph node positivity. Moreover, in vitro experiments demonstrated that COL11A1 suppression by short hairpin RNA (shRNA) significantly inhibited the proliferation, migration and invasion of HGC-27 cells and that COL11A1 suppression promoted cell apoptosis, induced G1-phase cell cycle arrest and led to a significant downregulation of cyclin D1 and upregulation of p21 and cleaved caspase-3. In addition, the cDNA microarray analysis of HGC-27 cells with and without COL11A1 suppression indicated that COL11A1 may regulate multiple genes responsible for cell growth and/or invasion, including downregulation of CDK6, TIAM1, ITGB8 and WNT5A and upregulation of RGS2 and NEFL following suppression of COL11A1 expression in HGC-27 cells, validated with RT-qPCR assays. Taken together, our findings demonstrate that COL11A1 might be an oncogene in GC and is a promising therapeutic target in cancer treatment. PMID- 28004112 TI - Evaluation of antitumor activity of Artemisia capillaris extract against hepatocellular carcinoma through the inhibition of IL-6/STAT3 signaling axis. AB - Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays critical roles in the development and progression of hepatocellular carcinoma (HCC). Artemisia capillaris (AC) has been widely used to treat various liver diseases including HCC as a herbal medicine. The effects of AC on IL-6/STAT3 signaling axis in HCC cells and subsequent anticancer activity of AC against HCC were analyzed using HCC cell lines and HBV W4P-LHB-expressing NIH3T3 cell line, which has been shown to gain tumorigenicity by activating IL 6/STAT3 signaling in our previous study. AC extract significantly suppressed the growth and colony formation of HCC cells. In addition, it inhibited the activation of STAT3 by IL-6 and subsequent synthesis of downstream molecules in HCC and W4P-NIH3T3 cells. Consequently, migration of cells was significantly suppressed by the AC extract. Collectively, the findings suggest that AC extract is capable of conferring various antitumor effects against HCC through the modulation of the IL-6/STAT3 pathway. The results provide a basis for the therapeutic use of AC in the treatment of HCC. Identification of the compound responsible for the effect may lead to the development of a novel anticancer agent against HCC. PMID- 28004113 TI - Suberoyl bis-hydroxamic acid activates Notch1 signaling and induces apoptosis in anaplastic thyroid carcinoma through p53. AB - Anaplastic thyroid cancer (ATC), usually derived from well-differentiated thyroid cancers is one of the most lethal human endocrine malignancies. In the present study, we report that in human ATC tumor tissue samples exist undetectable Notch1 and the active Notch1 intracellular domain could not be detected in ATC-CAL-62 cells. Interesting, suberoyl bis-hydroxamic acid (SBHA) administration could induce Notch1 intracellular domain levels in a dose-dependent manner, coupled with the increase of p53 and p21. Furthermore, ectopic expression of Notch1 or deletion of p53 with small-interfering RNA was able to abolish the effects of SBHA to elevation of Notch1 and p53 in ATC cells. As a result, SBHA treatment efficiently induced ATC cell apoptosis. These results indicate that SBHA may play antitumor functions via regulating Notch1/p53 signals, and highlight that SBHA could have clinical potential to benefit the therapy of ATC patients. PMID- 28004114 TI - miR-20a-directed regulation of BID is associated with the TRAIL sensitivity in colorectal cancer. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that play important roles in cancer processes. Although miR-20a has been reported to be altered in a range of cancers, the role of miR-20a in colorectal cancer is not fully characterized, and the relationship between miR-20a dysregulation and the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) sensitivity is not defined. In the present study, we demonstrated significant upregulation of miR-20a in the serum of colorectal cancer patients, tumor tissues and cell lines by quantitative RT PCR analysis. Furthermore, we found that the TRAIL-induced apoptosis was associated with the expression level of miR-20a in colorectal cancer. The knockdown of miR-20a by inhibitors increased the antitumor effect of TRAIL via caspase-8 dependent pathway. BID, which is a pro-apoptotic member of the Bcl-2 family, was found to be directly regulated by miR-20a in SW480 cells. The knockdown of miR-20a inhibited the translocation of tBID to the mitochondria, which induced the mitochondrial pathway of apoptosis. Notably, we found that the knockdown of miR-20a also reversed the resistance of TRAIL in established TRAIL resistant SW480 cells by tBID-mitochondria pathway. Therefore, our results suggest that miR-20a acts as a tumor promoter in colorectal cancer, and the understanding of the miR-20a might be a potential therapeutic target for colorectal cancer. PMID- 28004115 TI - Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma. AB - The overexpression of histone deacetylases (HDACs) has been observed in many cancers and inhibition of specific HDAC has emerged as a new target for cancer therapy. The present study examined the expression of HDAC8 and the inhibitory effect of HDAC8 in oral squamous cell carcinoma (OSCC). The expression of HDAC8 was measured in human OSCC tissues and OSCC cell lines using immunohistochemistry and immunoblotting. HDAC8 was knocked down in OSCC cells by transfection with HDAC8 siRNAs and cell proliferation was quantified. Apoptosis and autophagy were measured using flow cytometry and immunoblotting. HDAC8 were overexpressed in OSCC tissues and OSCC cells, mainly localized in the cytoplasm. HDAC8 siRNAs effectively reduced the level of HDAC8 expression and HDAC8 silencing significantly inhibited the proliferation of OSCC cells. HDAC8 knockdown induced apoptotic cell death through caspases activation and pro-survival autophagy in OSCC cells. Combination with HDAC silencing and autophagy inhibition enhanced cell death by increasing apoptosis in OSCC cells. This study suggests that inhibition of HDAC8 might become a novel therapeutic strategy for OSCC. PMID- 28004116 TI - miR-592 functions as a tumor suppressor in human non-small cell lung cancer by targeting SOX9. AB - A growing body of evidence suggests that microRNA-592 (miR-592) may be involved in the initiation and progression of cancer by targeting various molecules in several human cancers. However, the function and underlying molecular mechanism of miR-592 in non-small cell lung cancer (NSCLC) remains unclear. In the present study, we found that miR-592 was significantly downregulated in NSCLC cell lines and tissues by real-time quantitative RT-PCR (qRT-PCR), and that lower miR-592 expression was negatively associated with advanced tumor/nodes/metastasis (TNM) classification stages (P<0.01) and lymph node metastasis (P<0.01). Function assay demonstrated that the miR-592 mimic reduced in vitro cell proliferation, colony formation, migration and invasion in A549 cells (a NSCLC-derived cell line), and inhibited in vivo tumor cell growth in xenografted nude mice. Furthermore, the gender determining region Y (SRY)-related high mobility group box 9 (SOX9) was confirmed as a direct target of miR-592, using luciferase reporter, qRT-PCR and western blot assays. Enforced overexpression of SOX9 effectively reversed the tumor suppressive functions of miR-592 on NSCLC proliferation, colony formation, migration and invasion. These findings suggested that miR-592 functions as tumor suppressor in NSCLC by suppressing the activity of SOX9, and that miR-592 might serve as a promising therapeutic target for NSCLC treatment. PMID- 28004117 TI - A blood-based gene expression and signaling pathway analysis to differentiate between high and low grade gliomas. AB - The aims of the present study were to undertake gene expression profiling of the blood of glioma patients to determine key genetic components of signaling pathways and to develop a panel of genes that could be used as a potential blood based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples. In this study, blood samples were obtained from glioma patients, non-glioma and control subjects. Ten samples each were obtained from patients with high and low grade tumours, respectively, ten samples from non glioma patients and twenty samples from control subjects. Total RNA was isolated from each sample after which first and second strand synthesis was performed. The resulting cRNA was then hybridized with the Agilent Whole Human Genome (4x44K) microarray chip according to the manufacturer's instructions. Universal Human Reference RNA and samples were labeled with Cy3 CTP and Cy5 CTP, respectively. Microarray data were analyzed by the Agilent Gene Spring 12.1V software using stringent criteria which included at least a 2-fold difference in gene expression between samples. Statistical analysis was performed using the unpaired Student's t-test with a p<0.01. Pathway enrichment was also performed, with key genes selected for validation using droplet digital polymerase chain reaction (ddPCR). The gene expression profiling indicated that were a substantial number of genes that were differentially expressed with more than a 2-fold change (p<0.01) between each of the four different conditions. We selected key genes within significant pathways that were analyzed through pathway enrichment. These key genes included regulators of cell proliferation, transcription factors, cytokines and tumour suppressor genes. In the present study, we showed that key genes involved in significant and well established pathways, could possibly be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples. PMID- 28004118 TI - PEG10 is imperative for TGF-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Substantial evidence indicates that transforming growth factor-beta 1 (TGF-beta1) plays a vital role in epithelial-mesenchymal transition (EMT). PEG10 has been shown involved in invasion and metastasis of tumors. The present study investigated the role of PEG10 in TGF-beta1-triggered EMT in hepatocellular carcinoma (HCC) progression. Immunohistochemistry and real-time PCR were used to measure the expression level of PEG10 in clinical HCC tissues with or without lymph node metastasis, and normal tissues. The results showed that PEG10 expression is higher in HCC tissues and associated with overall survival (OS) and lymph node metastasis. Moreover, PEG10 expression level was remarkably higher in hepatic cancer cells than the normal hepatic cell line L02. In the present study, we constructed an adenovirus vector containing the coding area of PEG10 (Ad PEG10) and infected HepG2 cells and found that overexpression of PEG10 promoted the cell migration, invasion ability and EMT of HepG2 cells. TGF-beta1 acted on HepG2 cells by enhancing cell migration, invasion, EMT and upregulating PEG10 expression level. However, cells pretreated with adenovirus vector of PEG10 shRNAs (Ad-shRNA1 and Ad-shRNA2) did not occur EMT prior to TGF-beta1 stimulation. Moreover, TGF-beta1 did not increase the migration and invasion of cells with PEG10 knockdown and overexpression of PEG10 confers chemoresistance to HepG2 cells. Accordingly, sufficient PEG10 expression level is essential for TGF beta1 induced EMT and associated with the chemoresistance in HepG2 cells. PMID- 28004119 TI - Yttrium-90 radioembolization for colorectal cancer liver metastases in KRAS wild type and mutant patients: Clinical and ccfDNA studies. AB - Patients with unresectable, chemo-refractory colorectal cancer liver metastases (CRCLM) have limited local treatment options. We report our institutional experience on the efficacy of resin-based yttrium-90 (90Y) radioembolization for the treatment of CRCLM and our findings on associated circulating cell-free DNA (ccfDNA) studies. A total of 58 patients treated with 90Y for CRCLM at the Medstar Georgetown University Hospital had a median survival of 6 months [95% confidence interval (CI), 4.55-7.45 months] after treatment, with a 12-month survival rate of 33%. The median survival from treatment stratified by mutational status was longer in the wild-type (WT) as compared to the KRAS mutant patients at 7 vs. 5 months, but did not achieve statistical significance (p=0.059). Median tumor local control duration after 90Y treatment was 2 months (95% CI, 0.34-3.66 months) for the entire cohort and was longer in the WT vs. the mutant patients (2 vs. 1 month, respectively, p=0.088). Plasma was prospectively collected from a subset of 9 patients both before and after single lobe treatment, and ccfDNA concentration and fragmentation index (FI) were measured using quantitative PCR and atomic-force microscopy (AFM). In the WT and KRAS mutant patients, DNA FI was reduced from a median of 0.73-0.65 after treatment. A reduction in DNA FI after single lobe treatment was associated with an improved overall survival (p=0.046). Analysis by AFM of paired pre- and post-treatment samples from KRAS mutant and WT patients revealed a larger average decrease in fragment size in the WT patients (p=0.013). 90Y radioembolization extends local control for CRCLM, however, KRAS mutant tumors may be more radio-resistant to treatment. Changes in the FI of patients following treatment were noted and may be evaluated in a larger study for relevance as a biomarker of response. PMID- 28004120 TI - Genetic differences in osteogenic differentiation potency in the thoracic ossification of the ligamentum flavum under cyclic mechanical stress. AB - Mechanical stress and genetic factors play important roles in the occurrence of thoracic ossification of ligament flavum (TOLF), which can occur at one, two, or multiple levels of the spine. It is unclear whether single- and multiple-level TOLF differ in terms of osteogenic differentiation potency and osteogenesis related gene expression under cyclic mechanical stress. This was addressed in the present study using patients with non-TOLF and single- and multiple-level TOLF (n=8 per group). Primary ligament cells were cultured and osteogenesis was induced by application of cyclic mechanical stress. Osteogenic differentiation was assessed by evaluating alkaline phosphatase (ALP) activity and the mRNA and protein expression of osteogenesis-related genes, including ALP, bone morphogenetic protein 2 (BMP2), Runt-related transcription factor-2 (Runx-2), osterix, osteopontin (OPN) and osteocalcin. The application of cyclic mechanical stress resulted in higher ALP activity in the multiple-level than in the single level TOLF group, whereas no changes were observed in the non-TOLF group. The ALP, BMP2, OPN and osterix mRNA levels were higher in the multiple-level as compared to the single-level TOLF group, and the levels of all osteogenesis related genes, apart from Runx2, were higher in the multiple-level as compared to the non-TOLF group. The osterix and ALP protein levels were higher in the multiple-level TOLF group than in the other 2 groups, and were increased with the longer duration of stress. These results highlight the differences in osteogenic differentiation potency between single- and multiple-level TOLF that may be related to the different pathogenesis and genetic background. PMID- 28004121 TI - Pifithrin-MU is efficacious against non-small cell lung cancer via inhibition of heat shock protein 70. AB - Heat-shock protein (Hsp) 70, known as a pro-survival protein, is aberrantly expressed in several malignancies. The small molecule 2-phenylethyenesulfonamide (PES), also referred to as pifithrin-MU, is known as an HSP70 inhibitor, which exhibits antitumor activities in a variety of cancer cell lines. However, little is known about its effect on non-small cell lung cancer (NSCLC) cell lines. This study aimed to investigate the effect of PES on human NSCLC cell lines A549 and H460, and explore the possible underlying mechanism of action. Cell viability assay by using CCK-8 kits was performed to demonstrate that PES dose- and time dependently inhibited proliferation of A549 and H460 cells. Wound healing assay and Transwell migration assay results indicated that PES inhibited cell migration of A549 and H460 cells. Flow cytometry results demonstrated that PES resulted in G0/G1 phase cell cycle arrest, and induced apoptosis via a caspase-dependent manner in A549 and H460 cells. Western blotting results suggested that phosphorylation of AKT and ERK was inhibited by PES treatment. In addition, death receptor 4 (DR4) and DR5 were increased by PES treatment. Overexpression of Hsp70 in A549 cells attenuated the growth inhibitory efficiency of PES. Knockdown of Hsp70 in A549 cells enhanced sensitivity of PES to cell growth inhibition, suggesting that the inhibitory effect of PES on cell proliferation is specifically through Hsp70-dependent mechanism. PES and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) exerts a potent synergistic effect on cell proliferation inhibition and induction of apoptosis in A549 and H460 cells. In a mouse xenograft model of lung cancer by A549 cells, PES treatment displayed significant inhibitory effects on tumor growth. All these findings suggest that PES shows antitumor activity against human NSCLC in vitro and in vivo, and therefore may be a promising agent for use to the treatment of NSCLC. PMID- 28004122 TI - ? PMID- 28004123 TI - [Ureteral stricture as a late complication of radiotherapy : Possible treatment options]. AB - Ureteral strictures are uncommon complications of radiotherapy which are often recognized late. Their consequences range from harmless dilatation of the ureter to loss of renal function and potential life-threatening urosepsis.Therapy of radiogenic ureteral stricture is a challenging task for every urologist. Several surgical strategies including minimally invasive procedures, reconstruction and partial or complete replacement of the ureter are available.This article provides an overview of the various options in the treatment of radiogenic stricture of the ureter, focusing on the use of ileum and colon segments for ureteral substitution. PMID- 28004125 TI - Mesenchymal stem cells provide novel insights into ankylosing spondylitis. PMID- 28004124 TI - Attenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells. AB - : Restenosis after angioplasty is a serious clinical problem that can result in re-occlusion of the coronary artery. Although current drug-eluting stents have proved to be more effective in reducing restenosis, they have drawbacks of inhibiting reendothelialization to promote thrombosis. New treatment options are in urgent need. We have shown that netrin-1, an axon-guiding protein, promotes angiogenesis and cardioprotection via production of nitric oxide (NO). The present study examined whether and how netrin-1 attenuates neointimal formation in a femoral wire injury model. Infusion of netrin-1 into C57BL/6 mice markedly attenuated neointimal formation following wire injury of femoral arteries, measured by intimal to media ratio (from 1.94 +/- 0.55 to 0.45 +/- 0.86 at 4 weeks). Proliferation of VSMC in situ was largely reduced. This protective effect was absent in DCC+/- animals. NO production was increased by netrin-1 in both intact and injured femoral arteries, indicating netrin-1 stimulation of endogenous NO production from intact endothelium and remaining endothelial cells post-injury. VSMC migration was abrogated by netrin-1 via a NO/cGMP/p38 MAPK pathway, while timely EPC homing was induced. Injection of netrin-1 preconditioned wild-type EPCs, but not EPCs of DCC+/- animals, substantially attenuated neointimal formation. EPC proliferation, NO production, and resistance to oxidative stress induced apoptosis were augmented by netrin-1 treatment. In conclusion, our data for the first time demonstrate that netrin-1 is highly effective in reducing neointimal formation following vascular endothelial injury, which is dependent on DCC, and attributed to inhibition of VSMC proliferation and migration, as well as improved EPC function. These data may support usage of netrin-1 and netrin-1 preconditioned EPCs as novel therapies for post angioplasty restenosis. KEY MESSAGE: Netrin-1 attenuates neointimal formation following post endothelial injury via DCC and NO. Netrin-1 inhibits VSMC proliferation in situ following endothelial injury. Netrin-1 inhibits VSMC migration via a NO/cGMP/p38 MAPK pathway. Netrin-1 augments proliferation of endothelial progenitor cells (EPCs) and EPC eNOS/NO activation. Netrin-1 enhances resistance of EPCs to oxidative stress, improving re-endothelialization following injury. PMID- 28004127 TI - [Surgical access routes to the hip joint in the elderly]. AB - There are a large number of different approaches to the hip joint. Several conventional and minimally invasive portals exist and numerous technical variations with different instrument sets are available. All approaches can be regarded as standard and can be utilized lege artis. The main differences between approaches are their potential to preserve muscles and avoid damage which would slow down rehabilitation and mobilization. In the elderly the preservation of abductor function is, in the authors' opinion, of utmost importance. A well functioning gluteal system provides a limp-free gait, supports joint stability and reduces the probability of dislocations. The direct anterior approach has some advantages; however, minimally invasive approaches should be used with care. Surgical experience, experience with a specific approach and the availability of specialized instruments as well as sufficient training are mandatory for a successful performance. A surgeon should always choose the approach with which he has most experience. PMID- 28004126 TI - The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization. AB - : Acriflavine, a fluorescent drug previously used for bacterial and trypanosomal infections, reduces hypoxia-inducible factor-1 (HIF-1) and HIF-2 transcriptional activity. In mice with oxygen-induced ischemic retinopathy, intraocular or intraperitoneal injections of acriflavine caused dose-dependent suppression of retinal neovascularization (NV) and significantly reduced expression of HIF-1 responsive genes. Intraocular injection of 100 ng caused inner retina fluorescence within 1 h that was seen throughout the entire retina between 1 and 5 days, and at 7 days after injection, strongly suppressed choroidal NV at Bruch's membrane rupture sites. After suprachoroidal injection of 300 ng in rats, there was retinal fluorescence in the quadrant of the injection at 1 h that spread throughout the entire retina and choroid by 1 day, was detectable for 5 days, and dramatically reduced choroidal NV 14 days after rupture of Bruch's membrane. After topical administration of acriflavine in mice, fluorescence was seen in the retina and retinal pigmented epithelium within 5 min and was detectable for 6-12 h. Administration of 0.5% drops to the cornea twice a day significantly reduced choroidal NV in mice. Electroretinographic b-wave amplitudes were normal 7 days after intravitreous injection of 100 ng of acriflavine in mice, showed mild threshold reductions at highest stimulus intensities after injection of 250 ng, and more extensive changes after injection of 500 ng. These data provide additional evidence for an important role for HIF-1 in retinal and choroidal NV and suggest that acriflavine can target HIF-1 through a variety of modes of administration and has good potential to provide a novel therapy for retinal and choroidal vascular diseases. KEY MESSAGE: Acriflavine, an inhibitor of HIF-1, suppresses retinal and choroidal neovascularization. HIF-1 plays a critical role in ocular neovascularization. Acriflavine's fluorescence provides a mean to track its entry and exit from the retina. Acriflavine has therapeutic potential for the treatment of ocular neovascularization. PMID- 28004128 TI - [Endoprosthesis failure in the ankle joint : Histopathological diagnostics and classification]. AB - INTRODUCTION: Endoprostheses of the ankle joint show higher revision rates of 3.29 revisions per 100 component years. The aims of this study were the application and modification of the consensus classification of the synovia-like interface membrane (SLIM) for periprosthetic failure of the ankle joint, the etiological clarification of periprosthetic pseudocysts and a detailed measurement of proliferative activity (Ki67) in the region of osteolysis. MATERIAL AND METHOD: Tissue samples from 159 patients were examined according to the criteria of the standardized consensus classification. Of these, 117 cases were derived from periprosthetic membranes of the ankle. The control group included 42 tissue specimens from the hip and knee joints. Particle identification and characterization were carried out using the particle algorithm. An immunohistochemical examination with Ki67 proliferation was performed in all cases of ankle pseudocysts and 19 control cases. RESULTS: The consensus classification of SLIM is transferrable to endoprosthetic failure of the ankle joint. Periprosthetic pseudocysts with the histopathological characteristics of the appropriate SLIM subtype were detectable in 39 cases of ankle joint endoprostheses (33.3%). The mean value of the Ki67 index was 14% and showed an increased proliferation rate in periprosthetic pseudocysts of the ankle (p-value 0.02037). CONCLUSION: In periprosthetic pseudocysts an above average higher detection rate of type 1 SLIM induced by abrasion (51.3%) with an increased Ki67 proliferation fraction (p-value 0.02037) was found, which can be interpreted as local destructive intraosseus synovialitis. This can be the reason for formation of pseudocystic osteolysis caused by high mechanical stress in ankle endoprostheses. A simplified diagnostic classification scoring system of dysfunctional endoprostheses of the ankle is proposed for collation of periprosthetic pseudocysts, ossifications and the Ki67 proliferation fraction. PMID- 28004129 TI - Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials. AB - PURPOSE: We performed an individual patient data meta-analysis to assess the possible benefits and harms of statin therapy in adults with acute respiratory distress syndrome (ARDS) and to investigate effects in specific ARDS subgroups. METHODS: We identified randomised clinical trials up to 31 October 2016 that had investigated statin therapy versus placebo in patients with ARDS. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed for primary and secondary outcomes, and one-stage regression models with single treatment-covariate interactions for subgroup analyses. Risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: Six trials with a total of 1755 patients were included. For the primary outcomes, there was no significant effect of statin therapy on 28-day mortality [relative risk (RR) 1.03, 95% CI 0.86-1.23], ventilator-free days (mean difference 0.34 days, 95% CI 0.68 to 1.36) or serious adverse events (RR 1.14, 95% CI 0.84-1.53). There was a significantly increased incidence of raised serum creatine kinase or transaminase levels with statin therapy (106/879; 12.1%) versus control (78/876; 8.9%) (RR 1.40, 95% CI 1.07-1.83, p = 0.015). There were no significant treatment-covariate interactions in the predefined subgroups investigated. CONCLUSIONS: We found no clinical benefit from initiation of statin therapy in adult patients with ARDS, either overall or in predefined subgroups. While there was an increased incidence of raised serum creatine kinase and transaminase levels, there was no difference in serious adverse events among groups. Therefore, we do not recommend initiation of statin therapy for the treatment of ARDS. PMID- 28004130 TI - Multifocal bone and bone marrow lesions in children - MRI findings. AB - Polyostotic bone and bone marrow lesions in children may be due to various disorders. Radiographically, lytic lesions may become apparent after loss of more than 50% of the bone mineral content. Scintigraphy requires osteoblastic activity and is not specific. MRI may significantly contribute to the correct diagnosis and management. Accurate interpretation of MRI examinations requires understanding of the normal conversion pattern of bone marrow in childhood and of the appearances of red marrow rests and hyperplasia. Differential diagnosis is wide: Malignancies include metastases, multifocal primary sarcomas and hematological diseases. Benign entities include benign tumors and tumor-like lesions, histiocytosis, infectious and inflammatory diseases, multiple stress fractures/reactions and bone infarcts/ischemia. PMID- 28004131 TI - Ancient and Recent Duplications Support Functional Diversity of Daphnia Opsins. AB - Daphnia pulex has the largest known family of opsins, genes critical for photoreception and vision in animals. This diversity may be functionally redundant, arising from recent processes, or ancient duplications may have been preserved due to distinct functions and independent contributions to fitness. We analyzed opsins in D. pulex and its distant congener Daphnia magna. We identified 48 opsins in the D. pulex genome and 32 in D. magna. We inferred the complement of opsins in the last common ancestor of all Daphnia and evaluated the history of opsin duplication and loss. We further analyzed sequence variation to assess possible functional diversification among Daphnia opsins. Much of the opsin expansion occurred before the D. pulex-D. magna split more than 145 Mya, and both Daphnia lineages preserved most ancient opsins. More recent expansion occurred in pteropsins and long-wavelength visual opsins in both species, particularly D. pulex. Recent duplications were not random: the same ancestral genes duplicated independently in each modern species. Most ancient and some recent duplications involved differentiation at residues known to influence spectral tuning of visual opsins. Arthropsins show evidence of gene conversion between tandemly arrayed paralogs in functionally important domains. Intron-exon gene structure was generally conserved within clades inferred from sequences, although pteropsins showed substantial intron size variation. Overall, our analyses support the hypotheses that diverse opsins are maintained due to diverse functional roles in photoreception and vision, that functional diversification is both ancient and recent, and that multiple evolutionary processes have influenced different types of opsins. PMID- 28004132 TI - [Image-guided intensity-modulated radiation therapy decreases late gastrointestinal side effects after radiation therapy for prostate cancer]. PMID- 28004133 TI - Tail autotomy affects bipedalism but not sprint performance in a cursorial Mediterranean lizard. AB - Running is essential in all terrestrial animals mainly for finding food and mates and escaping from predators. Lizards employ running in all their everyday functions, among which defense stands out. Besides flight, tail autotomy is another very common antipredatory strategy within most lizard families. The impact of tail loss to sprint performance seems to be species dependent. In some lizard species, tail shedding reduces sprint speed, in other species, increases it, and, in a few species, speed is not affected at all. Here, we aimed to clarify the effect of tail autotomy on the sprint performance of a cursorial lizard with particular adaptations for running, such as bipedalism and spike-like protruding scales (fringes) on the toepads that allow high speed on sandy substrates. We hypothesized that individuals that performed bipedalism, and have more and larger fringes, would achieve higher sprint performance. We also anticipated that tail shedding would affect sprint speed (though we were not able to define in what way because of the unpredictable effects that tail loss has on different species). According to our results, individuals that ran bipedally were faster; limb length and fringe size had limited effects on sprint performance whereas tail autotomy affected quadrupedal running only in females. Nonetheless, tail loss significantly affected bipedalism: the ability for running on hindlimbs was completely lost in all adult individuals and in 72.3% of juveniles. PMID- 28004134 TI - Genetic analysis and mapping of adult plant resistance loci to leaf rust in durum wheat cultivar Bairds. AB - KEY MESSAGE: New leaf rust adult plant resistance (APR) QTL QLr.cim - 6BL was mapped and confirmed the known pleotropic APR gene Lr46 effect on leaf rust in durum wheat line Bairds. CIMMYT-derived durum wheat line Bairds displays an adequate level of adult plant resistance (APR) to leaf rust in Mexican field environments. A recombinant inbred line (RIL) population developed from a cross of Bairds with susceptible parent Atred#1 was phenotyped for leaf rust response at Ciudad Obregon, Mexico, during 2013, 2014, 2015 and 2016 under artificially created epidemics of Puccinia triticina (Pt) race BBG/BP. The RIL population and its parents were genotyped with the 50 K diversity arrays technology (DArT) sequence system and simple sequence repeat (SSR) markers. A genetic map comprising 1150 markers was used to map the resistance loci. Four significant quantitative trait loci (QTLs) were detected on chromosomes 1BL, 2BC (centromere region), 5BL and 6BL. These QTLs, named Lr46, QLr.cim-2BC, QLr.cim-5BL and QLr.cim-6BL, respectively, explained 13.5-60.8%, 9.0-14.3%, 2.8-13.9%, and 11.6 29.4%, respectively, of leaf rust severity variation by the inclusive composite interval mapping method. All of these resistance loci were contributed by the resistant parent Bairds, except for QLr.cim-2BC, which came from susceptible parent Atred#1. Among these, the QTL on chromosome 1BL was the known pleiotropic APR gene Lr46, whereas QLr.cim-6BL, a consistently detected locus, should be a new leaf rust resistance locus in durum wheat. The mean leaf rust severity of RILs carrying all four QTLs ranged from 8.0 to 17.5%, whereas it ranged from 10.9 to 38.5% for three QTLs (Lr46 + 5BL + 6BL) derived from the resistant parent Bairds. Two RILs with four QTLs combinations can be used as sources of complex APR in durum wheat breeding. PMID- 28004136 TI - Accumulation of Mercury in The Tissues of the Great Cormorant (Phalacrocorax carbo) From Common Carp. AB - The aim of this work is to assess mercury content in the great cormorant in the Trebon region pond systems (Czech Republic) in terms of its potential to accumulate mercury from common carp. Selected tissues samples were taken from 51 cormorants and 30 common carp. In the food chain the cormorant was found to have the potential to accumulate mercury, where the muscle total mercury was roughly 35 times higher compared to the total mercury content in the carp muscle as its food. A statistically significantly higher overall mercury content (p < 0.01) has been found in the kidney and liver (2.23 +/- 0.30, 2.12 +/- 0.22 mg/kg) compared to other tissues examined in cormorants. The proportion of muscle methylmercury in the total mercury content of the cormorant was within the range 64.3%-87.3%. The results can help us to gain a better understanding of how mercury is distributed and accumulated in the aquatic food chain. PMID- 28004135 TI - Nodal parameters of FDG PET/CT performed during radiotherapy for locally advanced mucosal primary head and neck squamous cell carcinoma can predict treatment outcomes: SUVmean and response rate are useful imaging biomarkers. AB - PURPOSE: To evaluate the prognostic utility of nodal metabolic parameters derived from FDG PET/CT performed before radiotherapy (prePET) and during the third week of radiotherapy (iPET) in patients with mucosal primary head and neck squamous cell carcinoma (MPHNSCC). METHODS: This analysis included 75 patients with newly diagnosed locally advanced node-positive MPHNSCC treated with radical radiotherapy and concurrent systemic therapy who underwent prePET and iPET: N1 11 patients, N2a 38, N2b 12, N2c 9, N3 5. The median follow-up was 28 months (9 - 70 months). The maximum and mean standardized uptake values (SUVmax and SUVmean), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of the index lymph node (node with the highest TLG) and the combined total lymph nodes, and their percentage reductions on iPET were determined, and the results were correlated with 3-year Kaplan-Meier locoregional, regional and distant metastatic failure-free survival (FFS), disease-free survival (DFS) and overall survival (OS). Optimal cut-off values were derived from receiver operating characteristic curves. Cox regression univariate and multivariate analyses with clinical covariates were performed. RESULTS: Based on assessment of residual nodal metabolic burden during treatment, the iPET index node SUVmean (optimal cut-off value 2.95 g/ml) and the total node SUVmean (optimal cut-off value 3.25) were the best independent predictors of outcome in the multivariate analysis: index node SUVmean for DFS and OS p = 0.033 and 0.003, respectively, and the total node SUVmean for locoregional FFS, DFS and OS p = 0.028, 0.025 and 0.014, respectively. Based on the assessment of response rates during treatment, a reduction of more than 50 % in the total node TLG was the best biomarker for locoregional and regional FFS, DFS and OS in the multivariate analysis (p = 0.001, 0.016, 0.001 and 0.004, respectively), and reduction in the total node MTV for locoregional FFS, DFS and OS (p = 0.026, 0.003 and 0.014, respectively). There were no significant correlations between oncological outcomes and prePET nodal parameters. CONCLUSION: We demonstrated that the index node and total node SUVmean on iPET and a reduction of more than 50 % in MTV and TLG are useful imaging biomarkers, and can potentially identify those patients with MPHNSCC who have a high risk of locoregional metastatic failure and death. PMID- 28004137 TI - Abdominal wall endometriosis: differentiation from other masses using CT features. AB - PURPOSE: To assess the utility of morphologic and quantitative CT features in differentiating abdominal wall endometriosis (AWE) from other masses of the abdominal wall. METHODS: Retrospective IRB-approved study of 105 consecutive women from two institutions who underwent CT and biopsy/resection of abdominal wall masses. CTs were independently reviewed by two radiologists blinded to final histopathologic diagnoses. Associations between CT features and pathology were tested using Fisher's Exact Test. Sensitivity, specificity, positive, and negative predictive values were calculated. P values were adjusted for multiple variable testing. RESULTS: 24.8% (26/105) of patients had histologically proven abdominal wall endometriosis. The other most common diagnoses included adenocarcinoma NOS (21%; 22/105), desmoid (14.3%; 15/105), and leiomyosarcoma (8.6%; 9/105). CT features significantly associated with endometriosis for both readers were location below the umbilicus (P = 0.0188), homogeneous density (P = 0.0188), and presence of linear infiltration irradiating peripherally from a central soft tissue nodule (i.e., "gorgon" sign) (P < 0.0001). The highest combined sensitivity (0.69, 95% CI: 0.48-0.86) and specificity (0.97, 95% CI: 0.91-1.00) for both readers occurred for patients having all three of these features present. Border type (P = 0.0199) was only significant for R2, peritoneal extension (P = 0.0188) was only significantly for R1, and the remainder of features were insignificant (P = 0.06-60). There was overlap in Hounsfield units on non-contrast CT (N = 26) between AWE (median: 45HU, range: 39 54) and other abdominal wall masses (median: 38.5HU, range: 15-58). CONCLUSION: CT features are helpful in differentiating AWE from other abdominal wall soft tissue masses. Such differentiation may assist decisions regarding possible biopsy and treatment planning. PMID- 28004138 TI - Investigation of volumetric apparent diffusion coefficient histogram analysis for assessing complete response and clinical outcomes following pre-operative chemoradiation treatment for rectal carcinoma. AB - PURPOSE: To investigate the relationship of pre-treatment volumetric apparent diffusion coefficient (ADC) histogram parameters with post-operative histopathologic treatment response and clinical outcomes following pre-operative chemoradiation treatment (CRT) in rectal cancer. MATERIALS AND METHODS: In a Health Insurance Portability and Accountability Act compliant retrospective study, 78 rectal cancer patients treated with pre-operative CRT and rectal MRI were included. MR imaging analysis was performed using OncoTREAT (software tool). Multiple volumetric ADC histogram parameters (voxel distribution across ADC ranges, kurtosis, and skewness) were assessed. Correlation was made to post operative pathological complete response, clinical, or radiological evidence of disease progression using the Mann-Whitney test. RESULTS: Post CRT, 8 patients showed pathologic complete response and 13 patients showed distant disease progression. Pre-treatment mean ADC was 1.2 * 10-3 mm2/s (range 0.3-1.99 * 10-3 mm2/s). Mean kurtosis measured was 0.56 (range -1 to 6; SD 1.36). Mean skewness was 0.3 (range -1 to 2; SD 0.69). Skewness had significant correlation (p value = 0.006) with disease progression. The mean rectal tumor volume was 24cc (range 1cc 134cc). Pre-treatment MRI tumor volume showed significant correlation (p value = 0.013) with pathologic complete response. Mean ADC and percentage voxels distribution against ADC ranges had no significant correlation with treatment response or disease outcomes. CONCLUSION: Volumetric ADC histogram analysis of pre-CRT rectal cancer MRI appears promising for prediction of post-CRT complete response and disease progression. PMID- 28004139 TI - Genome Shuffling of Stenotrophomonas maltophilia OK-5 for Improving the Degradation of Explosive RDX (Hexahydro-1,3,5-trinitro-1,3,5-triazine). AB - A genome-shuffled Stenotrophomonas maltophilia strain showing the enhanced ability of RDX degradation was constructed, and its characteristics were compared with those of the wild-type one. The shuffled strain was able to completely degrade 25, 50, and 75 uM RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) within 10, 30, and 50 days, respectively. However, it took 30 and 70 days for the wild type strain to degrade 25 and 50 uM RDX, respectively, and at day 70, the strain degraded only 67% of 75 uM RDX. The shuffled strain reached its maximum growth at 50-60 days and exhibited approximately 1.5-fold increased cell numbers. SEM revealed more severe damage on the surface of the wild-type cells compared to the genome-shuffled cells. The mRNA levels of dnaK and groEL encoding the heat shock proteins were increased by 2.5-fold and fourfold, and DnaK and GroEL proteins were more highly produced in the shuffled cells. In addition, the mRNA levels of pnrB encoding a TNT nitroreductase, and algA involved in exopolymer biosynthesis, were slightly higher in the shuffled strain, but not as high as those of dnaK and groEL. These results indicate that the genome shuffling rendered the shuffled cells more resistant to RDX stress. A proteomic comparison revealed changes in the production levels of certain proteins including nitrate and cell protection, particularly those involved in metabolism. These proteomic analyses provide clues for understanding the improved RDX degradation by the genome-shuffled S. maltophilia strain. PMID- 28004140 TI - Understanding Land System Change Through Scenario-Based Simulations: A Case Study from the Drylands in Northern China. AB - The drylands in northern China are expected to face dramatic land system change in the context of socioeconomic development and environmental conservation. Recent studies have addressed changes of land cover with socioeconomic development in the drylands in northern China. However, the changes in land use intensity and the potential role of environmental conservation measures have yet to be adequately examined. Given the importance of land management intensity to the ecological conditions and regional sustainability, our study projected land system change in Hohhot city in the drylands in northern China from 2013 to 2030. Here, land systems are defined as combinations of land cover and land use intensity. Using the CLUMondo model, we simulated land system change in Hohhot under three scenarios: a scenario following historical trends, a scenario with strong socioeconomic and land use planning, and a scenario focused on achieving environmental conservation targets. Our results showed that Hohhot is likely to experience agricultural intensification and urban growth under all three scenarios. The agricultural intensity and the urban growth rate were much higher under the historical trend scenario compared to those with more planning interventions. The dynamics of grasslands depend strongly on projections of livestock and other claims on land resources. In the historical trend scenario, intensively grazed grasslands increase whereas a large amount of the current area of grasslands with livestock converts to forest under the scenario with strong planning. Strong conversion from grasslands with livestock and extensive cropland to semi-natural grasslands was estimated under the conservation scenario. The findings provide an input into discussions about environmental management, planning and sustainable land system design for Hohhot. PMID- 28004141 TI - Social Perception of Public Water Supply Network and Groundwater Quality in an Urban Setting Facing Saltwater Intrusion and Water Shortages. AB - Perceptions developed by consumers regarding the quality of water reaching their household can affect the ultimate use of the water. This study identified key factors influencing consumers' perception of water quality in a highly urbanized coastal city, experiencing chronic water shortages, overexploitation of groundwater, and accelerated saltwater intrusion. Household surveys were administered to residents to capture views and perceptions of consumed water. Concomitantly, groundwater and tap water samples were collected and analyzed at each residence for comparison with perceptions. People's rating of groundwater quality was found to correlate to the measured water quality both in the dry and wet seasons. In contrast, perceptions regarding the water quality of the public water supply network did not show any correlation with the measured tap water quality indicators. Logistic regression models developed to predict perception based on salient variables indicated that age, apartment ownership, and levels of total dissolved solids play a significant role in shaping perceptions regarding groundwater quality. Perceptions concerning the water quality of the public water supply network appeared to be independent of the measured total dissolved solids levels at the tap but correlated to those measured in the wells. The study highlights misconceptions that can arise as a result of uncontrolled cross connections of groundwater to the public supply network water and the development of misaligned perceptions based on prior consumption patterns, water shortages, and a rapidly salinizing groundwater aquifer. PMID- 28004143 TI - Elementary proof of convergence to the mean-field model for the SIR process. AB - The susceptible-infected-recovered (SIR) model has been used extensively to model disease spread and other processes. Despite the widespread usage of this ordinary differential equation (ODE) based model which represents the mean-field approximation of the underlying stochastic SIR process on contact networks, only few rigorous approaches exist and these use complex semigroup and martingale techniques to prove that the expected fraction of the susceptible and infected nodes of the stochastic SIR process on a complete graph converges as the number of nodes increases to the solution of the mean-field ODE model. Extending the elementary proof of convergence for the SIS process introduced by Armbruster and Beck (IMA J Appl Math, doi: 10.1093/imamat/hxw010 , 2016) to the SIR process, we show convergence using only a system of three ODEs, simple probabilistic inequalities, and basic ODE theory. Our approach can also be generalized to many other types of compartmental models (e.g., susceptible-infected-recovered susceptible (SIRS)) which are linear ODEs with the addition of quadratic terms for the number of new infections similar to the SI term in the SIR model. PMID- 28004144 TI - [Regional differences in the prevalence of cardiovascular risk factors in men and women in Germany]. AB - BACKGROUND: More than half of all cardiovascular diseases are caused by eight, mostly preventable risk factors. OBJECTIVES: In view of the considerable differences in the prevalence and mortality of cardiovascular diseases between the 16 German federal states, the regional distribution of cardiovascular risk factors was analyzed stratified for men and women, using population-based data. METHODS: Pooled data (n = 62,606) from the national, telephone health surveys "German Health Update" from 2009, 2010 and 2012 were used to estimate the prevalence of physical inactivity, risky alcohol consumption, smoking, low fruit and vegetable consumption, obesity and diagnosed hypertension, diabetes and dyslipidemia and the accumulated number of risk factors stratified for men and women in the federal states. Furthermore, we analyzed the influence of age and social status on prevalence differences. RESULTS: At the national level, 36.0% of men and 26.6% of women had three or more risk factors. Large differences between men and women were found for risky alcohol consumption (32.8% versus 21.7%), low fruit and vegetable consumption (20.6% versus 10.4%) and current smoking (32.6% versus 24.9%). The prevalence of all eight risk factors differed considerably between federal states. The highest prevalence of physical inactivity, obesity, hypertension and diabetes in both sexes as well as risky alcohol consumption in men were observed in the Eastern federal states (except for Berlin). Sachsen Anhalt was the only federal state with the highest prevalence for two risk factors. Current smoking was most prevalent in the three federal city states Berlin, Hamburg and Bremen. Saarland had the highest prevalence of low fruit and vegetable consumption in both sexes. Regional differences remained after adjustment for age and social status. CONCLUSIONS: There is evidence for regional differences in cardiovascular risk factor levels in Germany that resemble variations in the prevalence and mortality of cardiovascular diseases between federal states with a more unfavorable situation in the East (except for Berlin). Overall, this study shows a considerable need for the prevention of mostly modifiable risk factors for cardiovascular diseases in men and women in Germany. PMID- 28004142 TI - The evolution of outcomes and indications for the dual-mobility cup: a systematic review. AB - PURPOSE: Instability following total hip arthroplasty remains a common and disabling complication. The dual mobility cup (DMC) allows a reduction in the dislocation rate. An increasing number of studies have been undertaken to better understand DMC long term outcomes and complications. The goal of this systematic review was to clarify its different uses and outcomes according to the indications. METHODS: A comprehensive literature review was performed using the keywords 'dual mobility' and 'tripolar cup' with no limit regarding the year of publication. One hundred seventy six publications were identified. RESULTS: Current literature shows that "contemporary" dual mobility cup are a significant indication to manage instability following primary and revision hip arthroplasty. Survivorship at midterm is comparable to other articulations for primary THA, but is more difficult to evaluate in revision. Intra-prosthetic dislocation, wear, and loosening are now uncommon with new generations of DMC. CONCLUSIONS: Compared to previous generations of DMC, the current "contemporary" DMC presents a significant improvement. Current literature reveals a tendency to increase the indications but further studies with long term follow up remain important to consolidate these findings. PMID- 28004145 TI - Nobel Prize nominees and the rise of urology in Europe around 1900. AB - PURPOSE: Recent historical research has reconstructed the roads leading to the Nobel Prize for the trained urologists Werner Forssmann (1904-1979) in 1956 and Charles Huggins (1901-1997) in 1966. However, the story of urology and the Nobel Prize does not start and end with the laureates. Taking James Israel (1848-1926), Felix Guyon (1831-1920), and Peter J Freyer (1852-1921) as examples, this paper shows that pioneers in urology were in fact runners-up for the award much earlier. METHODS: The study is based on an analysis of original files in the Nobel Prize archive in Stockholm, scientific publications of the early twentieth century, and secondary literature. RESULT AND CONCLUSION: We argue that Israel's, Guyon's, and Freyer's candidacies reflect not only scientific trends and controversies in urology at the turn of twentieth century, but that the development of the specialty itself was reflected in nominations of physicians working on problems of the genito-urinary system. PMID- 28004146 TI - Residual tumor resection (RTR). AB - Residual tumor resection in patients with advanced testicular tumor plays a vital role in the multimodal treatment. Treatment indications for residual tumor resection have changed over the last two decades. While patients with advanced seminoma after chemotherapy or radiotherapy rarely need surgery, it is mandatory for most non-seminomatous tumor patients to undergo post-chemotherapy tumor resection. Due to adjunctive surgical procedures, the operation is surgically demanding and should be performed only in specialized high-volume referral centers. Additional surgical procedures such as nephrectomy, partial colectomy or vascular interventions including caval and aortic resection with grafting might be required. Consequently, several complications can be seen in the peri- and postoperative course. We aim to describe indications for residual tumor resection, operative technique, including adjunctive surgeries and the most common peri- and postoperative complications. PMID- 28004147 TI - Developing anti-neoplastic biotherapeutics against eIF4F. AB - Biotherapeutics have revolutionized modern medicine by providing medicines that would not have been possible with small molecules. With respect to cancer therapies, this represents the current sector of the pharmaceutical industry having the largest therapeutic impact, as exemplified by the development of recombinant antibodies and cell-based therapies. In cancer, one of the most common regulatory alterations is the perturbation of translational control. Among these, changes in eukaryotic initiation factor 4F (eIF4F) are associated with tumor initiation, progression, and drug resistance in a number of settings. This, coupled with the fact that systemic suppression of eIF4F appears well tolerated, indicates that therapeutic agents targeting eIF4F hold much therapeutic potential. Here, we discuss opportunities offered by biologicals for this purpose. PMID- 28004148 TI - An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice. AB - AIMS/HYPOTHESIS: Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla2)GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla2)GIP and xenin-8-Gln. METHODS: Following confirmation of enzymatic stability, insulin secretory activity of (DAla2)GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla2)GIP/xenin-8-Gln was determined in high-fat-fed mice. RESULTS: All peptides significantly (p < 0.05 to p < 0.001) enhanced in vitro insulin secretion from pancreatic clonal BRIN-BD11 cells, with xenin (and particularly GIP)-related signalling pathways, being important for this action. Administration of (DAla2)GIP or (DAla2)GIP/xenin-8-Gln in combination with glucose significantly (p < 0.05) lowered blood glucose and increased plasma insulin in mice, with a protracted response of up to 4 h. All treatments elicited appetite-suppressive effects (p < 0.05), particularly (DAla2)GIP/xenin-8-Gln and xenin-8-Gln at elevated doses of 250 nmol/kg. Twice-daily administration of (DAla2)GIP/xenin-8-Gln or (DAla2)GIP for 21 days to high-fat-fed mice returned circulating blood glucose to lean control levels. In addition, (DAla2)GIP/xenin-8 Gln treatment significantly (p < 0.05) reduced glycaemic levels during a 24 h glucose profile assessment. Neither of the treatment regimens had an effect on body weight, energy intake or circulating insulin concentrations. However, insulin sensitivity was significantly (p < 0.001) improved by both treatments. Interestingly, GIP-mediated glucose-lowering (p < 0.05) and insulin-releasing (p < 0.05 to p < 0.01) effects were substantially improved by (DAla2)GIP and (DAla2)GIP/xenin-8-Gln treatment. Pancreatic islet and beta cell area (p < 0.001), as well as pancreatic insulin content (p < 0.05), were augmented in (DAla2)GIP/xenin-8-Gln-treated mice, related to enhanced proliferation and decreased apoptosis of beta cells, whereas (DAla2)GIP evoked increases (p < 0.05 to p < 0.01) in islet number. CONCLUSIONS/INTERPRETATION: These studies highlight the clear potential of GIP/xenin hybrids for the treatment of type 2 diabetes. PMID- 28004149 TI - The heritable basis of gene-environment interactions in cardiometabolic traits. AB - AIMS/HYPOTHESIS: Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions. METHODS: Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software. RESULTS: All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h 2) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction. CONCLUSIONS/INTERPRETATION: Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease. PMID- 28004150 TI - Assessment of urinary microparticles in normotensive patients with type 1 diabetes. AB - AIMS/HYPOTHESIS: Assessment of urinary extracellular vesicles including exosomes and microparticles (MPs) is an emerging approach for non-invasive detection of renal injury. We have previously reported that podocyte-derived MPs are increased in diabetic mice in advance of albuminuria. Here, we hypothesised that type 1 diabetes and acute hyperglycaemia would increase urinary podocyte MP levels in uncomplicated diabetes. METHODS: In this post hoc exploratory analysis, we examined archived urine samples from normoalbuminuric patients with uncomplicated type 1 diabetes studied under clamped euglycaemia and hyperglycaemia and compared with healthy controls. Urinary vesicles were assessed by electron microscopy and nanoparticle tracking while podocyte MPs were assessed by flow cytometry. RESULTS: Neither vesicle size nor total number were significantly altered in type 1 diabetes or acute hyperglycaemia. By contrast, urinary podocyte MP levels were higher in type 1 diabetes (0.47 [0.00-3.42] MPs/MUmol creatinine [Cr]) compared with healthy controls (0.00 [0.00-0.00] MPs/MUmol Cr, p < 0.05) and increased under hyperglycaemic clamp (0.36 [0.00-4.15] MPs/MUmol Cr during euglycaemia vs 2.70 [0.00-15.91] MPs/MUmol Cr during hyperglycaemia, p < 0.05). Levels of urinary albumin to creatinine ratio and nephrin (surrogates of podocyte injury) were unchanged by type 1 diabetes or acute hyperglycaemia. CONCLUSION/INTERPRETATION: Taken together, our data show that urinary podocyte MP levels are higher in patients with type 1 diabetes in advance of changes in other biomarkers (albuminuria, nephrin). Examination of podocyte MPs may serve as an early biomarker of glomerular injury in uncomplicated type 1 diabetes. PMID- 28004152 TI - Comparative transcriptomes reveal novel evolutionary strategies adopted by Saccharomyces cerevisiae with improved xylose utilization capability. AB - Production of ethanol from xylose by recombinant Saccharomyces cerevisiae is suboptimal with slow fermentation rate, compared with that from glucose. In this study, a strain-expressing Scheffersomyces stipitis xylose reductase-xylitol dehydrogenase (XR-XDH) pathway was subjected to adaptive evolution on xylose; this approach generated populations with the significantly improved cell growth and ethanol production rate. Mutants were isolated, and the best one was used for sporulation to generate eight stable mutant strains with improved xylose fermentation ability. They were used in a microarray assay to study the molecular basis of the enhanced phenotype. The enriched transcriptional differences among the eight mutant strains and the native strain revealed novel responses to xylose, which likely contributes to the improved xylose utilization. The upregulated vitamin B1 and B6 biosynthesis indicated that thiamine served as an important cofactor in xylose metabolism and may alleviate the redox stress. The increased expression of genes involved in sulfur amino acid biosynthesis and the decreased expression of genes related to Fe(II) transport may alleviate redox stress as well. Meanwhile, it was remarkable that several glucose-repressible genes, including genes of the galactose metabolism, gluconeogenesis, and ethanol catabolism, had a lower expression level after adaptive evolution. Concomitantly, the expression levels of two regulators of the glucose signaling pathway, Rgs2 and Sip4, decreased, indicating a reshaped signaling pathway to xylose after adaptive evolution. Our findings provide new targets for construction of a superior bioethanol producing strain through inverse metabolic engineering. PMID- 28004153 TI - Studies on the removal of Cd ions by gastrointestinal lactobacilli. AB - Accumulation of toxic metal ions in food and water is nowadays a growing health related problem. One detoxification method involves the use of microorganisms naturally inhabiting the gastrointestinal tract (GIT). The purpose of this study was to prove that lactic acid bacteria derived from the GIT are able to effectively remove Cd2+ from water solution. Seven strains of lactobacilli, out of 11 examined, showed tolerance to high concentrations of cadmium ions. The metal-removal efficiencies of these seven lactobacilli ranged from 6 to 138.4 MUg/h mg. Among these bacteria, Lactobacillus gallinarum and Lactobacillus crispatus belonged to the highest (85%) Cd-removal efficiency class. An analysis of the zeta potential (zeta) indicated that the bacterial cell surface had a negative charge at the pH ranging from 3 to 10. The presence of carboxyl, amide, and phosphate groups was favorable for Cd2+ binding to the cell surface, which found confirmation in FTIR-ATR spectra. Elemental SEM/EDS analysis and TEM imaging not only confirmed the adsorption of Cd2+ on the cell envelope but also gave us a reason to suppose that Lb. crispatus accumulates metal ions inside the cell. Our findings open perspectives for further research on the new biological function of GIT lactobacilli as natural biosorbents. PMID- 28004154 TI - Optimization of conditions for cadmium selenide quantum dot biosynthesis in Saccharomyces cerevisiae. AB - The biosynthesis of quantum dots has been explored as an alternative to traditional physicochemical methods; however, relatively few studies have determined optimal synthesis parameters. Saccharomyces cerevisiae sequentially treated with sodium selenite and cadmium chloride synthesized CdSe quantum dots in the cytoplasm. These nanoparticles displayed a prominent yellow fluorescence, with an emission maximum of approximately 540 nm. The requirement for glutathione in the biosynthetic mechanism was explored by depleting its intracellular content through cellular treatments with 1-chloro-2,4-dinitrobenzene and buthionine sulfoximine. Synthesis was significantly inhibited by both of these reagents when they were applied after selenite treatment prior to the addition of cadmium, thereby indicating that glutathione contributes to the biosynthetic process. Determining the optimum conditions for biosynthesis revealed that quantum dots were produced most efficiently at entry into stationary phase followed by direct addition of 1 mM selenite for only 6 h and then immediately incubating these cells in fresh growth medium containing 3 mM Cd (II). Synthesis of quantum dots reached a maximum at 84 h of reaction time. Biosynthesis of 800-MUg g-1 fresh weight cells was achieved. For the first time, significant efforts have been undertaken to optimize each aspect of the CdSe biosynthetic procedure in S. cerevisiae, resulting in a 70% increased production. PMID- 28004151 TI - Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes. AB - AIMS/HYPOTHESIS: Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of nutritional status at the cellular and organismic level. While mTORC1 mediates beta cell growth and expansion, its hyperactivation has been observed in pancreatic islets from animal models of type 2 diabetes and leads to beta cell loss. We sought to determine whether such mTORC1 activation occurs in humans with type 2 diabetes or in metabolically stressed human islets and whether mTORC1 blockade can restore beta cell function of diabetic islets. METHODS: Human islets isolated from non-diabetic controls and individuals with type 2 diabetes, as well as human islets and INS-1E cells exposed to increased glucose (22.2 mmol/l), were examined for mTORC1/2 activity by western blotting analysis of phosphorylation of mTORC1 downstream targets ribosomal protein S6 kinase 1 (S6K1), S6 and eukaryotic translation initiation factor 4E binding protein 1 (4E BP1) and mTORC2 downstream targets Akt and N-myc downstream regulated 1 (NDRG1). mTORC1/2 complexes' integrity was assessed by immunoprecipitation and subsequent western blot analysis. Cell-type specific expression of activated mTORC1 in human islets was examined by immunostaining of pS6 (Ser 235/236) in human islet sections. Beta cell function was measured by glucose-stimulated insulin secretion (GSIS). RESULTS: While mTORC2 signalling was diminished, mTORC1 activity was markedly increased in islets from patients with type 2 diabetes and in islets and beta cells exposed to increased glucose concentrations. Under high-glucose conditions in metabolically stressed human islets, we identified a reciprocal regulation of different mTOR complexes, with functional upregulation of mTORC1 and downregulation of mTORC2. pS6 immunostaining showed beta cell-specific upregulation of mTORC1 in islets isolated from patients with type 2 diabetes. Inhibition of mTORC1-S6K1 signalling improved GSIS and restored mTORC2 activity in islets from patients with type 2 diabetes as well as in islets isolated from diabetic db/db mice and mice fed a high-fat/high-sucrose diet. CONCLUSIONS/INTERPRETATION: Our data show the aberrant mTORC1 activity in islets from patients with type 2 diabetes, in human islets cultured under diabetes associated increased glucose conditions and in diabetic mouse islets. This suggests that elevated mTORC1 activation is a striking pathogenic hallmark of islets in type 2 diabetes, contributing to impaired beta cell function and survival in the presence of metabolic stress. PMID- 28004155 TI - [Retinal imaging of the macula and optic disc in neurodegenerative diseases]. AB - BACKGROUND: Due to current demographic trends, the prevalence of mild cognitive impairment and dementia is expected to increase considerably. For potential new therapies it is important to identify patients at risk as early as possible. Currently, there is no population-based screening. Therefore, identification of biomarkers that will help screen the population at risk is urgently needed. Thus, a literature review on retinal pathology in neurodegenerative diseases was performed. METHODS: PubMed was searched for studies published up to August 2016 using the following keywords: "mild cognitive impairment", "dementia", "eye", "ocular biomarkers", "OCT" and "OCT angiography". Relevant publications were selected and summarized qualitatively. RESULTS: Multiple studies using noninvasive in vivo optical coherence tomography (OCT) imaging showed nonspecific retinal pathological changes in patients with neurodegenerative diseases such as mild cognitive impairment, Alzheimer's and Parkinson's disease. Pathological changes in macular volume, optic nerve fiber layer thickness and the ganglion cell complex were observed. However, based on available evidence, no ocular biomarkers for neurodegeneration which could be integrated in routine clinical diagnostics have been identified. CONCLUSION: The potential use of OCT in the early diagnostic workup and monitoring of progression of neurodegenerative diseases needs to be further explored in longitudinal studies with large cohorts. PMID- 28004156 TI - [Intramuscular depot steroids : Possible treatment of postsurgical cystoid macula edema with steroid response?] AB - We report on a patient with postsurgical cystoid macular edema (CME) after phacoemulsification and multifocal intraocular lens (MIOL) implantation. At first, there was a very good reaction to intravitreal triamcinolone, inducing complete regression of the edema without increasing intraocular pressure (IOP). One year later the patient suffered from retinal detachment and was treated with vitrectomy, laser, and gas tamponade. Afterward, he developed macular pucker with edema. After surgical treatment with pucker peeling and intravitreal triamcinolone, the patient showed a steroid response and an increase IOP. Postoperatively, there was a recurrence of CME. A coincidental administration of a steroid injection intramuscularly by the general practitioner achieved a prompt reduction of the CME without increasing IOP. This case shows that an initially good reaction to triamcinolone without increasing IOP does not rule out a future steroid response, and that a potential treatment option for CME in patients with a known steroid response could consist of intramuscularly injected steroids. PMID- 28004157 TI - [Deep Anterior Lamellar Keratoplasty : Experiences and results of the first 100 consecutive DALK from the University Eye Hospital of Cologne]. AB - BACKGROUND: Deep anterior lamellar keratoplasty (DALK) is a treatment option for patients with diseases of the corneal stroma without endothelial involvement and has been used at the Department of Ophthalmology of the University of Cologne since July 2011. Experiences and results of the first 100 consecutive cases from Cologne with a minimum follow-up of 1 year are summarized. MATERIALS AND METHODS: We included the first 100 consecutive DALKs. Indications for anterior lamellar keratoplasty, the feasibility of the surgery, the postoperative course, in addition to the complications and clinical outcome 3 months after complete suture removal, were examined. The rate of conversion to penetrating keratoplasty in all planned DALKs during the observation period was also recorded. Mean follow-up was 25.6 +/- 13 months. RESULTS: In 99 eyes of 97 patients (72 men, 25 women; aged 43.5 +/- 16.9 years), the first 100 DALKs were performed in the period between 26 July 2011 and 27 January 2015 (87 cases electively, 13 cases as DALK a chaud, 1 of which was a second DALK). The most common indications were keratoconus (68%), corneal ulcers (13%), and corneal scarring (13%). On average, visual acuity increased from 0.83 +/- 0.4 to 0.09 +/- 0.1 logMAR. In 6 eyes (6%) grafts could not be preserved because of a corneal ulcer (n = 5, n = 3 of which were recurrent episodes), and in 1 case because of postoperative bulbus trauma. Rate of conversion to penetrating keratoplasty during the observation period was 11.5%. In eyes with keratoconus, visual acuity increased from 0.89 +/- 0.4 before DALK to 0.06 +/- 0.1 logMAR (best-corrected with contact lens) and the conversion rate was 17.6%. CONCLUSION: DALK represents a reliable technique for corneal transplantation in different pathological conditions of the cornea and the risk of endothelial immune responses can be avoided completely. In keratoconus and corneal scarring in particular, DALK can be used as a safe treatment option with very good results. PMID- 28004158 TI - Location-Related Differences in Weathering Behaviors and Populations of Culturable Rock-Weathering Bacteria Along a Hillside of a Rock Mountain. AB - Bacteria play important roles in rock weathering, elemental cycling, and soil formation. However, little is known about the weathering potential and population of bacteria inhabiting surfaces of rocks. In this study, we isolated bacteria from the top, middle, and bottom rock samples along a hillside of a rock (trachyte) mountain as well as adjacent soils and characterized rock-weathering behaviors and populations of the bacteria. Per gram of rock or surface soil, 106 107 colony forming units were obtained and total 192 bacteria were isolated. Laboratory rock dissolution experiments indicated that the proportions of the highly effective Fe (ranging from 67 to 92 %), Al (ranging from 40 to 48 %), and Cu (ranging from 54 to 81 %) solubilizers were significantly higher in the top rock and soil samples, while the proportion of the highly effective Si (56 %) solubilizers was significantly higher in the middle rock samples. Furthermore, 78, 96, and 6 % of bacteria from the top rocks, soils, and middle rocks, respectively, significantly acidified the culture medium (pH < 4.0) in the rock dissolution process. Most rock-weathering bacteria (79 %) from the rocks were different to those from the soils and most of them (species level) have not been previously reported. Furthermore, location-specific rock-weathering bacterial populations were found and Bacillus species were the most (66 %) frequently isolated rock-weathering bacteria in the rocks based on cultivation methods. Notably, the top rocks and soils had the highest and lowest diversity of rock weathering bacterial populations, respectively. The results suggested location related differences in element (Si, Al, Fe, and Cu) releasing effectiveness and communities of rock-weathering bacteria along the hillside of the rock mountain. PMID- 28004159 TI - Assessment of tibial and common peroneal nerves in diabetic peripheral neuropathy by diffusion tensor imaging: a case control study. AB - OBJECTIVES: To determine the diagnostic accuracy and interobserver performance of diffusion tensor imaging (DTI) in diabetic peripheral neuropathy (DPN) and detect correlations with electrophysiology. METHODS: Twelve healthy volunteers (controls) and ten DPN patients were enrolled to undergo MR examinations. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of tibial nerve (TN) and common peroneal nerve (CPN) were measured. Unpaired t test and Levene tests were performed to assess differences between the two groups. Receiver operating characteristic (ROC) analysis was performed for FA and ADC values. Pearson correlation coefficient was used to assess the correlation between DTI and electrophysiology parameters in the patient group. RESULTS: The FA values of TN and CPN in the DPN group were significantly lower and ADC were higher than the control group (p < 0.05). Interobserver agreement was excellent. FA positively correlated and ADC negatively correlated with motor nerve conduction velocity (MCV) (p < 0.05). There were no significant differences between motor nerve conduction amplitude and DTI parameters (p > 0.05). Moderate diagnostic accuracy of DTI was seen in the diagnosis of DPN. CONCLUSIONS: DTI demonstrates moderate diagnostic accuracy and excellent interobserver performance in the detection of DPN involving the TN and CPN. There is moderate correlation with MCV. KEY POINTS: * FA values of TN and CPN are significantly lower in DPN. * ADC values of TN and CPN are significantly higher in DPN. * DTI demonstrates moderate diagnostic accuracy in detection of DPN. * There is excellent interobserver performance in DTI measurements. * Moderate correlation is seen between DTI parameters and MCV. PMID- 28004160 TI - Noninvasive IDH1 mutation estimation based on a quantitative radiomics approach for grade II glioma. AB - OBJECTIVE: The status of isocitrate dehydrogenase 1 (IDH1) is highly correlated with the development, treatment and prognosis of glioma. We explored a noninvasive method to reveal IDH1 status by using a quantitative radiomics approach for grade II glioma. METHODS: A primary cohort consisting of 110 patients pathologically diagnosed with grade II glioma was retrospectively studied. The radiomics method developed in this paper includes image segmentation, high-throughput feature extraction, radiomics sequencing, feature selection and classification. Using the leave-one-out cross-validation (LOOCV) method, the classification result was compared with the real IDH1 situation from Sanger sequencing. Another independent validation cohort containing 30 patients was utilised to further test the method. RESULTS: A total of 671 high-throughput features were extracted and quantized. 110 features were selected by improved genetic algorithm. In LOOCV, the noninvasive IDH1 status estimation based on the proposed approach presented an estimation accuracy of 0.80, sensitivity of 0.83 and specificity of 0.74. Area under the receiver operating characteristic curve reached 0.86. Further validation on the independent cohort of 30 patients produced similar results. CONCLUSIONS: Radiomics is a potentially useful approach for estimating IDH1 mutation status noninvasively using conventional T2-FLAIR MRI images. The estimation accuracy could potentially be improved by using multiple imaging modalities. KEY POINTS: * Noninvasive IDH1 status estimation can be obtained with a radiomics approach. * Automatic and quantitative processes were established for noninvasive biomarker estimation. * High-throughput MRI features are highly correlated to IDH1 states. * Area under the ROC curve of the proposed estimation method reached 0.86. PMID- 28004161 TI - MRI fused with prone FDG PET/CT improves the primary tumour staging of patients with breast cancer. AB - OBJECTIVE: Our aim was to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in primary tumour staging of patients with breast cancer. METHODS: This retrospective study evaluated 45 women with 49 pathologically proven breast carcinomas. MRI and prone PET-CT scans with time-of flight and point-spread-function reconstruction were performed with the same dedicated breast coil. The studies were assessed by a radiologist and a nuclear medicine physician, and evaluation of fused images was made by consensus. The final diagnosis was based on pathology (90 lesions) or follow-up >= 24 months (17 lesions). RESULTS: The study assessed 72 malignant and 35 benign lesions with a median size of 1.8 cm (range 0.3-8.4 cm): 31 focal, nine multifocal and nine multicentric cases. In lesion-by-lesion analysis, sensitivity, specificity, positive and negative predictive values were 97%, 80%, 91% and 93% for MRI, 96%, 71%, 87%, and 89% for prone PET, and 97%. 94%, 97% and 94% for MRI fused with PET. Areas under the curve (AUC) were 0.953, 0.850, and 0.983, respectively (p < 0.01). CONCLUSIONS: MRI fused with FDG-PET is more accurate than FDG-PET in primary tumour staging of breast cancer patients and increases the specificity of MRI. KEY POINTS: * FDG PET-CT may improve the specificity of MRI in breast cancer staging. * MRI fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose PET-CT has better overall diagnostic performance than MRI. * The clinical role of fused PET-MRI has not yet been established. PMID- 28004162 TI - Multiparametric dynamic contrast-enhanced ultrasound imaging of prostate cancer. AB - OBJECTIVES: The aim of this study is to improve the accuracy of dynamic contrast enhanced ultrasound (DCE-US) for prostate cancer (PCa) localization by means of a multiparametric approach. MATERIALS AND METHODS: Thirteen different parameters related to either perfusion or dispersion were extracted pixel-by-pixel from 45 DCE-US recordings in 19 patients referred for radical prostatectomy. Multiparametric maps were retrospectively produced using a Gaussian mixture model algorithm. These were subsequently evaluated on their pixel-wise performance in classifying 43 benign and 42 malignant histopathologically confirmed regions of interest, using a prostate-based leave-one-out procedure. RESULTS: The combination of the spatiotemporal correlation (r), mean transit time (MU), curve skewness (kappa), and peak time (PT) yielded an accuracy of 81% +/- 11%, which was higher than the best performing single parameters: r (73%), MU (72%), and wash-in time (72%). The negative predictive value increased to 83% +/- 16% from 70%, 69% and 67%, respectively. Pixel inclusion based on the confidence level boosted these measures to 90% with half of the pixels excluded, but without disregarding any prostate or region. CONCLUSIONS: Our results suggest multiparametric DCE-US analysis might be a useful diagnostic tool for PCa, possibly supporting future targeting of biopsies or therapy. Application in other types of cancer can also be foreseen. KEY POINTS: * DCE-US can be used to extract both perfusion and dispersion-related parameters. * Multiparametric DCE-US performs better in detecting PCa than single-parametric DCE-US. * Multiparametric DCE-US might become a useful tool for PCa localization. PMID- 28004163 TI - Treatment of cerebral vasospasm following aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. AB - OBJECTIVES: To examine the clinical outcome of aneurysmal subarachnoid haemorrhage (aSAH) patients exposed to cerebral vasospasm (CVS)-targeted treatments in a meta-analysis and to evaluate the efficacy of intra-arterial (IA) approaches in patients with severe/refractory vasospasm. METHODS: Randomised controlled trials, prospective and retrospective observational studies reporting clinical outcomes of aSAH patients exposed to CVS targeted treatments, published between 2006-2016 were searched using PubMed, EMBASE and the Cochrane Library. The main endpoint was the proportion of unfavourable outcomes, defined as a modified Rankin score of 3-6 at last follow-up. RESULTS: Sixty-two studies, including 26 randomised controlled trials, were included (8,976 patients). At last follow-up 2,490 of the 8,976 patients had an unfavourable outcome, including death (random-effect weighted-average, 33.7%; 99% confidence interval [CI], 28.1 39.7%; Q value, 806.0; I 2 = 92.7%). The RR of unfavourable outcome was lower in patients treated with Cilostazol (RR = 0.46; 95% CI, 0.25-0.85; P = 0.001; Q value, 1.5; I 2 = 0); and in refractory CVS patients treated by IA intervention (RR = 0.68; 95% CI, 0.57-0.80; P < 0.0001; number needed to treat with IA intervention, 6.2; 95% CI, 4.3-11.2) when compared with the best available medical treatment. CONCLUSIONS: Endovascular treatment may improve the outcome of patients with severe-refractory vasospasm. Further studies are needed to confirm this result. KEY POINTS: * 33.7% of patients with cerebral Vasospasm following aneurysmal subarachnoid-hemorrhage have an unfavorable outcome. * Refractory vasospasm patients treated using endovascular interventions have lower relative risk of unfavourable outcome. * Subarachnoid haemorrhage patients with severe vasospasm may benefit from endovascular interventions. * The relative risk of unfavourable outcome is lower in patients treated with Cilostazol. PMID- 28004165 TI - Erratum to: Does the initiation of urate-lowering treatment during an acute gout attack prolong the current episode and precipitate recurrent attacks: a systematic literature review. PMID- 28004164 TI - Longitudinal transition trajectory of gouty arthritis and its comorbidities: a population-based study. AB - The aim of the study was to investigate the longitudinal transition trajectory of gout and its comorbidities in male patients with gout in different age groups. A total of 3973 male patients who received a new diagnosis of gouty arthritis were identified from the Taiwan Longitudinal Health Insurance Database and divided into two age cohorts (<50 and >=50 years). Each patient was individually followed from 2000 to 2009 to identify associated comorbidities, namely hypertension, hypercholesterolemia, diabetes mellitus, cardiovascular diseases, and chronic kidney disease. Two outcome measurements of stroke and all-cause cancer were further identified until 2010. The transition trajectory was divided into the following five phenotype groups: persistent hypertension combined with a high prevalence of various gout-related comorbidities, persistent hypercholesterolemia combined with a moderate prevalence of various gout-related comorbidities, persistent low prevalence of various gout-related comorbidities, moderate to high prevalence of various gout-related comorbidities, and low to high prevalence of various gout-related comorbidities. Although the younger and older patients had a similar longitudinal transition trajectory of gout-related comorbidities, the older patients had a higher 10-year likelihood of transition from a low or moderate to a high prevalence of various gout-related comorbidities. In addition, the incidences of stroke and all-cause cancer were higher in the groups with high and moderate to high prevalences of various gout-related comorbidities than in the other groups. The occurrence of gouty arthritis in different life stages can cause cluster effects involving varying degrees of comorbidities over time. The findings of the current study can provide additional knowledge and increase clinical awareness regarding the early assessment and management of gout-related comorbidities in clinical practice. PMID- 28004166 TI - Anti-angiotensin II type 1 receptor autoantibodies (AT1R-AAs) in patients with systemic sclerosis: lack of association with disease manifestations. AB - Angiotensin II type 1 receptor autoantibodies (AT1R-AAs) are known to be associated with malignant hypertension, preeclampsia, and vascular rejection in kidney transplantation. They were also suspected to have pathogenetic role in vasculopathic changes in systemic sclerosis (SSc). Clinical data regarding AT1R AAs in SSc are scarce. In this work, we will examine the relationship between serum levels of AT1R-AAs and disease manifestations. Serum samples from SSc patients and healthy controls were analyzed for AT1R-AAs by using a commercial ELISA kit. We examined the association of serum levels of AT1R-AA with disease duration, systolic pulmonary artery pressure (sPAP) measurements, and disease manifestations like cutaneous, lung and esophageal involvements, and the presence of digital ulcers in a cross-sectional manner. There was no statistically significant difference in levels of AT1R-AAs between SSc (n = 93) patients and healthy controls (n = 66) (p = 0.23). Serum levels of AT1R-AAs were not correlated with disease duration, sPAP measurements, and showed no association with disease manifestations like lung involvement, esophageal involvement, digital ulcers, and cutaneous fibrosis. In our SSc cohort, AT1R-AA serum levels were not different from healthy subjects and higher levels were not associated with any disease manifestation neither. PMID- 28004167 TI - Ultrasound-Guided Angioplasty of Dysfunctional Vascular Access for Haemodialysis. The Pros and Cons. AB - PURPOSE: To describe the benefits and the disadvantages of angioplasty in dialysis fistulas using only ultrasound guidance. MATERIALS AND METHODS: This is a prospective study in 132 failing or non-maturing arteriovenous accesses that underwent 189 ultrasound-guided balloon angioplasties. The technical success was defined as non-use of X-ray fluoroscopy during the procedure. RESULTS: 127 procedures (67%) were successfully completed without fluoroscopy. Most failures were due to difficulty to traverse aneurismal segments, as well as anastomotic stenoses. Including initial failures, the primary patency rates at 6, 12 months and 2 years were 75 +/- 3, 41 +/- 3 and 14 +/- 2%, respectively. CONCLUSION: Endovascular repair of the dysfunctional vascular access for haemodialysis under ultrasound guidance is feasible and safe in roughly two-thirds of cases. PMID- 28004168 TI - Review of the Clinical Evidence for the Use of DEBIRI in the Treatment of Colorectal Metastatic Disease. AB - Colorectal cancer is a common malignancy that most commonly metastasizes to the liver. There has been considerable effort in developing new treatment options for these patients. One method that has been developed for the treatment of colorectal metastases to the liver is irinotecan-loaded drug-eluting bead (DEBIRI) embolization. This article reviews the current literature on DEBIRI and discusses the state of current knowledge and possible areas of future investigation. PMID- 28004169 TI - Comparison of Inversion ("flipping") Rates Among Different Port Designs: A Single Center Experience. AB - PURPOSE: To compare incidence of port inversion among different types of implantable venous access devices. MATERIALS AND METHODS: Records of patients who underwent imaging-guided subcutaneous port placement without port fixation between July 2001 and April 2015 were reviewed with use of a quality assurance database. 1930 patients with complete follow-up (death or explant) were included in the study. Collected data included date and indication for port placement, port type, venous access site, immediate and long-term complications, indication for removal, and total number of catheter days. BMI of patients with inverted ports was also calculated. RESULTS: Port inversion within the pocket was observed in 18 patients (0.9%) including 7/82 (9%) of Dignity ports, 4/126 (3%) of Vaxcel plastic arm ports, 3/142 (2%) of Smartports, 2/100 (2%) of Powerports, 1/14 (7%) of Vaccess ports, and 1/1421 (0.07%) of Vortex LP ports. Among these designs, the inversion rate was significantly lower in Vortex LP ports (0.1%) (P < 0.05). There was a trend toward higher inversion rate of Dignity ports, which have a rectangular design with a relatively narrow base. Mean dwell in inverted ports was 114 days (7-580). CONCLUSION: The incidence of port inversion without suture fixation of the port base to the pocket is extremely low. The present study shows differences in inversion incidence based on port design. LEVEL OF EVIDENCE: Case Series, Level IV. PMID- 28004170 TI - Uterine Artery Embolization for Retained Products of Conception with Marked Vascularity: A Safe and Efficient First-Line Treatment. AB - OBJECTIVE: To report our clinical practice regarding a case series of retained products of conception (RPOC) with marked vascularity (MV) managed with selective uterine artery embolization (UAE) as first-line treatment. METHODS: This was a monocentric, retrospective study of 31 consecutive cases of RPOC with MV diagnosed by Doppler ultrasound in the context of postpartum/postabortal bleeding. The primary outcome was the absence of rebleeding following embolization. RESULTS: RPOC with MV occurred after abortion in 27 out of 31 patients (87%). The time elapsed between delivery/abortion and UAE ranged from 1 to 210 days (mean 55.7 +/- 45 days). Primary clinical success was achieved in 23 women (74.2%) following a single embolization. In total, 27 out of 31 women (87%) had been exclusively managed by UAE with conservative success. Although procedural success was achieved in this number, six women had a further procedure to evacuate RPOC despite procedural success. Large uterine arteriovenous (AV) shunts associated with RPOC were observed in five cases (16.1%), among which two were successfully treated after a single UAE and one after two UAEs, while hysterectomy was performed in the last two cases despite two and three UAE procedures respectively. RPOC was histologically proven in ten cases (32.2%) including four out of five cases of uterine AV shunt. CONCLUSION: RPOC with MV can present with large uterine AV shunt, particularly in case of late management. Uterine artery embolization is an effective and safe first-line treatment, and should be evaluated for this indication in larger prospective trials. PMID- 28004171 TI - Surface-enhanced Raman spectroscopy introduced into the International Standard Organization (ISO) regulations as an alternative method for detection and identification of pathogens in the food industry. AB - We show that surface-enhanced Raman spectroscopy (SERS) coupled with principal component analysis (PCA) can serve as a fast, reliable, and easy method for detection and identification of food-borne bacteria, namely Salmonella spp., Listeria monocytogenes, and Cronobacter spp., in different types of food matrices (salmon, eggs, powdered infant formula milk, mixed herbs, respectively). The main aim of this work was to introduce the SERS technique into three ISO (6579:2002; 11290-1:1996/A1:2004; 22964:2006) standard procedures required for detection of these bacteria in food. Our study demonstrates that the SERS technique is effective in distinguishing very closely related bacteria within a genus grown on solid and liquid media. The advantages of the proposed ISO-SERS method for bacteria identification include simplicity and reduced time of analysis, from almost 144 h required by standard methods to 48 h for the SERS-based approach. Additionally, PCA allows one to perform statistical classification of studied bacteria and to identify the spectrum of an unknown sample. Calculated first and second principal components (PC-1, PC-2) account for 96, 98, and 90% of total variance in the spectra and enable one to identify the Salmonella spp., L. monocytogenes, and Cronobacter spp., respectively. Moreover, the presented study demonstrates the excellent possibility for simultaneous detection of analyzed food-borne bacteria in one sample test (98% of PC-1 and PC-2) with a goal of splitting the data set into three separated clusters corresponding to the three studied bacteria species. The studies described in this paper suggest that SERS represents an alternative to standard microorganism diagnostic procedures. Graphical Abstract New approach of the SERS strategy for detection and identification of food-borne bacteria, namely S. enterica, L. monocytogenes, and C. sakazakii in selected food matrices. PMID- 28004172 TI - Hydrophobic ionic liquids for quantitative bacterial cell lysis with subsequent DNA quantification. AB - DNA is one of the most frequently analyzed molecules in the life sciences. In this article we describe a simple and fast protocol for quantitative DNA isolation from bacteria based on hydrophobic ionic liquid supported cell lysis at elevated temperatures (120-150 degrees C) for subsequent PCR-based analysis. From a set of five hydrophobic ionic liquids, 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide was identified as the most suitable for quantitative cell lysis and DNA extraction because of limited quantitative PCR inhibition by the aqueous eluate as well as no detectable DNA uptake. The newly developed method was able to efficiently lyse Gram-negative bacterial cells, whereas Gram-positive cells were protected by their thick cell wall. The performance of the final protocol resulted in quantitative DNA extraction efficiencies for Gram-negative bacteria similar to those obtained with a commercial kit, whereas the number of handling steps, and especially the time required, was dramatically reduced. Graphical Abstract After careful evaluation of five hydrophobic ionic liquids, 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([BMPyr + ][Ntf 2- ]) was identified as the most suitable ionic liquid for quantitative cell lysis and DNA extraction. When used for Gram-negative bacteria, the protocol presented is simple and very fast and achieves DNA extraction efficiencies similar to those obtained with a commercial kit. ddH 2 O double-distilled water, qPCR quantitative PCR. PMID- 28004173 TI - No difference in prevalence of radiographic subspinal impingement of the hip between symptomatic and asymptomatic subjects. AB - PURPOSE: The study determined the prevalence of subspinal impingement (SSI) in symptomatic and asymptomatic individuals, morphologic characteristics in symptomatic patients, and risk factors for SSI. METHODS: The study cohort consisted of 427 patients (427 hips; median age 33.4 years; range 19-50 years) with mechanical symptoms who underwent multi-detector computed tomography arthrography (symptomatic patients) and 259 control (asymptomatic) patients who underwent abdominopelvic three-dimensional CT because of a ureter stone or minor trauma. Two orthopaedic surgeons reviewed the images to evaluate the prevalence of SSI and the relationship with morphologic abnormalities. Radiologic parameters were further compared between the SSI and non-SSI groups in symptomatic patients using the Chi-squared test or two-sample t test. Variables with p values <0.10 (sex and age) were included in the multi-variate analysis. Logistic regression analysis was carried out to identify independent risk factors for SSI. RESULTS: The prevalence of SSI in symptomatic and asymptomatic patients was 65/427 (15.2%) and 40/259 (15.4%), respectively (n.s.). Structural bony abnormalities in symptomatic patients were not associated with the presence of SSI (n.s.). Binary logistic regression analysis revealed that youth (odds ratio 0.952, 95% CI 0.922 0.984) was the only significant factor for SSI. CONCLUSIONS: SSI had a similar prevalence in symptomatic and asymptomatic patients and was not rare in either group. Therefore, clinical implication of SSI in symptomatic patient should be re evaluated through further study. LEVEL OF EVIDENCE: Level IV. PMID- 28004174 TI - Altered patterns of displacement within the Achilles tendon following surgical repair. AB - PURPOSE: Ultrasound speckle tracking was used to compare tendon deformation patterns between uninjured and surgically repaired Achilles tendons at 14-27 month follow-up. The hypothesis was that the non-homogenous displacement pattern previously described in uninjured tendons, where displacement within deep layers of the tendons exceeds that of superficial layers, is altered following tendon rupture and subsequent surgical repair. METHODS: In the first part of this study, an in-house-developed block-matching speckle tracking algorithm was evaluated for assessment of displacement on porcine flexor digitorum tendons. Displacement data from speckle tracking were compared to displacement data from manual tracking. In the second part of the study, eleven patients with previous unilateral surgically treated Achilles tendon rupture were investigated using ultrasound speckle tracking. The difference in superficial and deep tendon displacement was assessed. Displacement patterns in the surgically repaired and uninjured tendons were compared during passive motion (Thompson's squeeze test) and during active ankle dorsiflexion. RESULTS: The difference in peak displacement between superficial and deep layers was significantly (p < 0.01) larger in the uninjured tendons as compared to the surgically repaired tendons both during Thompson's test (-0.7 +/- 0.2 mm compared to -0.1 +/- 0.1 mm) and active dorsiflexion (3.3 +/- 1.1 mm compared to 0.3 +/- 0.2 mm). The evaluation of the speckle tracking algorithm showed correlations of r >= 0.89 between displacement data acquired from speckle tracking and the reference displacement acquired from manual tracking. Speckle tracking systematically underestimated the magnitude of displacement with coefficients of variation of less than 11.7%. CONCLUSIONS: Uninjured Achilles tendons display a non-uniform displacement pattern thought to reflect gliding between fascicles. This pattern was altered after a mean duration of 19 +/- 4 months following surgical repair of the tendon indicating that fascicle sliding is impaired. This may affect modulation of the action between different components of the triceps surae, which in turn may affect force transmission and tendon elasticity resulting in impaired function and risk of re rupture. PMID- 28004175 TI - Left ventricular reverse remodeling is not related to biopsy-detected extracellular matrix fibrosis and serum markers of fibrosis in dilated cardiomyopathy, regardless of the definition used for LVRR. AB - Left ventricular reverse remodeling (LVRR) is reported in dilated cardiomyopathy (DCM) patients (pts). However, numerous definitions of LVRR exist. Measurements of serum markers of fibrosis provide insight into myocardial fibrosis. The relationship between LVRR and fibrosis is poorly understood. From July 2014 until October 2015, we included 63 consecutive DCM pts (48 +/- 12.1 years, EF 24.4 +/- 7.4%) with completed baseline and 3-month follow-up echocardiograms. LVRR was assessed on the basis of four differing definitions. Procollagens type I and III carboxy- and amino-terminal peptides (PICP, PINP, PIIICP, and PIIINP), collagen 1, ostepontin, tumor growth factor beta-1, connective tissue growth factor, and matrix metalloproteinases (MMP-2, MMP-9), and their tissue inhibitor (TIMP-1) were measured in serum. In addition, all pts underwent right ventricular endomyocardial biopsy. Depending on the definition chosen, LVRR could be diagnosed in between 14.3 and 50.8% pts. Regardless of the LVRR definition used, the frequency of LVRR was similar in fibrosis negative and positive DCM. Minor differences of markers of fibrosis were detected between pts with and without LVRR. For every LVRR definition, adjusted and unadjusted models were constructed to evaluate the predictive value of serum fibrosis parameters. Only an increase of TIMP-1 by 1 ng/ml was found to independently increase the probability of LVRR by 0.016%. The choice of a particular definition of LVRR determines the final diagnosis, and this has a profound impact on subsequent management. LVRR is unrelated to biopsy-detected ECM fibrosis. Serum markers of fibrosis are only weakly related to LVRR, and are not of use in the prediction of LVRR. PMID- 28004176 TI - Overlapping implantation of bioresorbable novolimus-eluting scaffolds: an observational optical coherence tomography study. AB - Overlapping implantation of bioresorbable vascular scaffolds is frequently necessary, but its influence on vessel and scaffold structure has not been thoroughly analyzed previously. The aim of this study was to analyze the acute effects of overlapping implantation on BRS as determined by optical coherence tomography (OCT). A total of 38 patients with de novo coronary artery stenoses who underwent OCT in the context of implantation of novolimus-eluting BRS (DESolve, Elixir Medical Corporation, Sunnyvale, California, USA) were investigated. In 15 patients, overlapping implantation of two BRS was performed, while 23 patients with implantation of one single BRS served as the control group. OCT data were retrospectively analyzed regarding acute scaffold implantation results. There were no significant differences between the overlap and control group in terms of residual in-scaffold area stenosis, scaffold area, mean or minimal lumen area, eccentricity index, incomplete scaffold apposition area or malapposition. While strut fracture was slightly more frequent in BRS with overlap its incidence was low overall. In patients with overlapping BRS, overlap segments did not display smaller lumen areas than segments without overlap (mean lumen area overlap: 8.16 +/- 2.97 mm2 vs. no overlap: 7.70 +/- 2.55 mm2; p = 0.71; minimal lumen area overlap: 6.83 +/- 2.71 mm2 vs. no overlap: 6.17 +/- 2.58 mm2; p = 0.37). Acute mechanical performance of novolimus-eluting BRS is not impaired by overlapping implantation. It can be assumed that vessel expansion compensates for the double scaffold layer in the overlap area resulting in a similar lumen area in overlap areas and in those with a single strut layer. PMID- 28004177 TI - Torsional osteotomies of the tibia in patellofemoral dysbalance. AB - BACKGROUND AND PURPOSE: Anterior knee pain or patellofemoral instability is common symptom of patellofemoral dysbalance or maltracking. Tibial torsional deformities can be the reason of this pathology. After appropriate diagnostic investigation, the treatment of choice is a torsional osteotomy. This study addresses the diagnostic investigation, treatment, and the outcome of torsional osteotomies of the tibia. Does this treatment result in patellofemoral stability and provide pain relief? METHODS: Forty-nine tibial torsional osteotomies were included. The major symptoms were patellofemoral instability in 19 cases and anterior knee pain in 42 cases. In addition to clinical and radiographic analysis, a torsional angle CT scan was performed pre-operatively. A visual analog scale (VAS), the Japanese Knee Society score, the Tegner activity score, and the Lysholm score were assessed pre-operatively and at the 42-month follow up. RESULTS: Mean tibial external torsion was 47.4 degrees (SD 5.41; range 37 degrees -66 degrees ; standard value 34 degrees ). Surgical treatment consisted of an acute supratuberositary tibial internal torsional osteotomy (mean 10.8 degrees ; SD 3.01 degrees ; range 5 degrees -18 degrees ). At the follow-up investigation, the Tegner activity score was increased 0.4 points (p value 0.014) from 3.9 (SD 1.33; range 2-7) to 4.3 (SD 1.25; range 0-7). The Lysholm score increased 26 points (SD 16.32; p value 0.001) from 66 (SD 14.94; range 32-94) to 92 (SD 9.29; range 70-100) and the Japanese Knee Society score increased 18 points (SD 14.70; p value 0.001) from 72 (SD 13.72, range 49-100) to 90 (SD 9.85, range 60-100). VAS was reduced 3.4 points (SD 2.89; p value 0.001) from 5.7 (SD 2.78; range 0-10) to 2.3 (SD 1.83; range 0-7). As regards patellofemoral instability, no redislocation occurred in the follow-up period. INTERPRETATION: The results of this study show that in cases of tibial maltorsion, a torsional osteotomy can lead to patellofemoral stability and pain relief, and should be considered as a treatment option. The improved clinical scores in the present investigation show the value of the procedure. Level of evidence Level IV. PMID- 28004178 TI - Dysphagia After Eating Raw Fish. PMID- 28004179 TI - The Prevalence of Oropharyngeal Dysphagia in Danish Patients Hospitalised with Community-Acquired Pneumonia. AB - Community-acquired pneumonia (CAP) and oropharyngeal dysphagia (OD) are prevalent conditions in the elderly. The aim of this study was to explore the relationship between CAP, OD, and frailty in patients admitted to a department of respiratory medicine at a regional hospital. The outcome was mortality during hospitalization and within 30 days of discharge and rehospitalization within 30 days of discharge. A total of 154 consecutive patients (54.5% male, mean age 77.4 years (SD 11.51)) hospitalized because of CAP from September 1, 2013 to March 31, 2014 at North Denmark Regional Hospital were included in this study. The volume viscosity swallow test was conducted for each patient. A total of 34.42% patients presented with OD. Patients with OD and CAP presented significant differences in age, CURB-65, and dementia compared with those of patients with CAP alone. The majority lived in nursing homes, had a lower body mass index, Barthel 20 score, and handgrip strength, and had poor oral health compared with patients with CAP only. Patients with OD presented an increased length of stay in hospital (P < 0.001), intra-hospital mortality (P < 0.001), and 30-day mortality rate (P < 0.001) compared with those of patients with CAP only. Their rate of rehospitalization 0-30 days after discharge was also increased (P < 0.001) compared with that of patients with CAP only. Thus, OD is related to frailty and poor outcome. PMID- 28004180 TI - Functional analysis of oxidative burst in sugarcane smut-resistant and susceptible genotypes. AB - MAIN CONCLUSION: Smut pathogen induced an early modulation of the production and scavenging of reactive oxygen species during defence responses in resistant sugarcane that coincided with the developmental stages of fungal growth. Sporisorium scitamineum is the causal agent of sugarcane smut disease. In this study, we characterized sugarcane reactive oxygen species (ROS) metabolism in response to the pathogen in smut-resistant and -susceptible genotypes. Sporisorium scitamineum teliospore germination and appressorium formation coincided with H2O2 accumulation in resistant plants. The superoxide dismutase (SOD) activity was not responsive in any of the genotypes; however, a higher number of isoenzymes were detected in resistant plants. In addition, related to resistance were lipid peroxidation, a decrease in catalase (CAT), and an increase in glutathione S-transferase (GST) activities and an earlier transcript accumulation of ROS marker genes (CAT3, CATA, CATB, GST31, GSTt3, and peroxidase 5-like). Furthermore, based on proteomic data, we suggested that the source of the increased hydrogen peroxide (H2O2) may be due to a protein of the class III peroxidase, which was inhibited in the susceptible genotype. H2O2 is sensed and probably transduced through overlapping systems related to ascorbate-glutathione and thioredoxin to influence signalling pathways, as revealed by the presence of thioredoxin h-type, ascorbate peroxidase, and guanine nucleotide-binding proteins in the infected resistant plants. Altogether, our data depicted the balance of the oxidative burst and antioxidant enzyme activity in the outcome of this interaction. PMID- 28004181 TI - The Effect of Aerosol Saline on Laboratory-Induced Dyspnea. AB - PURPOSE: In the 'placebo arm' of a recent study, we found that aerosol saline (sham treatment) produced substantial relief of laboratory-induced dyspnea (Breathing discomfort-BD) in nearly half the subjects. The sham intervention included a physiological change, and instructions to subjects could have produced expectation of dyspnea relief. In the present study, we attempted to discover whether the response to sham aerosol was driven by behavioral or physiological aspects of the intervention. METHODS: Dyspnea (air hunger) was evoked by constraining tidal volume during graded hypercapnia. We measured [Formula: see text] versus BD relationship before and after aerosol saline. To minimize subjects' expectations of dyspnea relief, participants were clearly instructed that we would only deliver saline aerosol. In Protocol 1, we delivered aerosol saline with a ventilator (mimicking our prior study); in Protocol 2, we delivered aerosol without a ventilator. RESULTS: Administration of aerosol saline had little effect on BD in this group of subjects with one exception: one subject experienced appreciable reduction in BD in Protocol 1. This treatment effect was less in Protocol 2. The two most likely explanations are (a) that procedures surrounding ventilator administration of aerosol produced a psychological placebo treatment effect even though the subject knew a drug was not given; (b) there were behavioral changes in breathing undetected by our measurements of respiratory flow and volume that altered the subjects comfort. CONCLUSION: When the expectation of treatment effect is minimized, a significant reduction in dyspnea in response to saline placebo is uncommon but not impossible. PMID- 28004183 TI - Hydroxychloroquine-induced cardiomyopathy in a patient with limited cutaneous systemic sclerosis. PMID- 28004182 TI - CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly. AB - Autosomal recessive primary microcephaly (MCPH) is characterized by a substantial reduction in brain size but with normal architecture. It is often linked to mutations in genes coding for centrosomal proteins; however, their role in brain size regulation is not completely understood. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a novel mutation (XM_011518861.1; c.4114C > T) in CDK5RAP2, the gene associated with primary microcephaly-3 (MCPH3), leading to a premature stop codon (p.Arg1372*). CDK5RAP2 is a component of the pericentriolar material important for the microtubule-organizing function of the centrosome. Patient-derived primary fibroblasts had strongly decreased CDK5RAP2 amounts, showed centrosomal and nuclear abnormalities and exhibited changes in cell size and migration. We further identified an interaction of CDK5RAP2 with the Hippo pathway components MST1 kinase and the transcriptional regulator TAZ. This finding potentially provides a mechanism through which the Hippo pathway with its roles in the regulation of centrosome number is linked to the centrosome. In the patient fibroblasts, we observed higher levels of TAZ and YAP. However, common target genes of the Hippo pathway were downregulated as compared to the control with the exception of BIRC5 (Survivin), which was significantly upregulated. We propose that the centrosomal deficiencies and the altered cellular properties in the patient fibroblasts can also result from the observed changes in the Hippo pathway components which could thus be relevant for MCPH and play a role in brain size regulation and development. PMID- 28004184 TI - Midregional proadrenomedullin and growth differentiation factor-15 are not influenced by obesity in heart failure patients. AB - BACKGROUND: Obesity is a risk factor for heart failure (HF) and identification of symptomatic, and obese HF patients are challenging, because obesity can mimic HF symptoms. We aimed to evaluate novel biomarkers for HF in obese subjects of the general population. METHODS: Midregional proadrenomedullin (MR-proADM), growth differentiation factor-15 (GDF-15), midregional pro-atrial natriuretic peptide (MR-proANP), and NT-proBNP were measured in 5000 individuals of the population based Gutenberg Health Study (GHS), including 1204 obese individuals (BMI >= 30 kg/m2) and 107 individuals with HF. RESULTS: NT-proBNP and MR-proANP were lower in obese vs. non-obese HF individuals (p = 0.013 and p = 0.01, respectively), whereas GDF-15 was similar and MR-proADM was higher in obese vs. non-obese HF individuals. All biomarkers increased the odds ratio (OR) for prevalent HF. For NT-proBNP and MR-proANP, this increase was lower in obese vs. non-obese individuals, whereas it was comparable for MR-proADM and GDF-15. All biomarkers were associated with increased all-cause mortality (median follow-up 7.3 years, 211 events). Results were validated in 8373 individuals (n = 1734 with BMI >= 30 kg/m2) of the FINRISK study with a median follow-up of 13.8 years (1030 events). Using a dichotomized biomarker cutoff for HF, the best predictor for all-cause mortality in obese subjects was GDF-15 (p < 0.001). CONCLUSION: All biomarkers were associated with HF and higher risk for all-cause mortality in the general population. In contrast to the natriuretic peptides NT-proBNP and MR-proANP, the novel biomarkers MR-proADM and GDF-15 were not lower in obese HF individuals, indicating their potential to facilitate HF diagnosis and prognosis in an increasingly obese HF population. PMID- 28004187 TI - Erratum to: Abstracts : XXXI International Congress of the IAP and 28th Congress of the ESP. PMID- 28004186 TI - Non-thiolate ligation of nickel by nucleotide-free UreG of Klebsiella aerogenes. AB - Nickel-dependent ureases are activated by a multiprotein complex that includes the GTPase UreG. Prior studies showed that nucleotide-free UreG from Klebsiella aerogenes is monomeric and binds one nickel or zinc ion with near-equivalent affinity using an undefined binding site, whereas nucleotide-free UreG from Helicobacter pylori selectively binds one zinc ion per dimer via a universally conserved Cys-Pro-His motif in each protomer. Iodoacetamide-treated K. aerogenes UreG was nearly unaffected in nickel binding compared to non-treated sample, suggesting the absence of thiolate ligands to the metal. X-ray absorption spectroscopy of nickel-bound UreG showed the metal possessed four-coordinate geometry with all O/N donor ligands including one imidazole, thus confirming the absence of thiolate ligation. The nickel site in Strep-tag II-modified protein possessed six-coordinate geometry, again with all O/N donor ligands, but now including two or three imidazoles. An identical site was noted for the Strep-tag II-modified H74A variant, substituted in the Cys-Pro-His motif, ruling out coordination by this His residue. These results are consistent with metal binding to both His6 and a His residue of the fusion peptide in Strep-tagged K. aerogenes UreG. We conclude that the nickel- and zinc-binding site in nucleotide-free K. aerogenes UreG is distinct from that of nucleotide-free H. pylori UreG and does not involve the Cys-Pro-His motif. Further, we show the Strep-tag II can perturb metal coordination of this protein. PMID- 28004185 TI - Divergent mechanisms of iron-containing enzymes for hydrocarbon biosynthesis. AB - Increasing levels of energy consumption, dwindling resources, and environmental considerations have served as compelling motivations to explore renewable alternatives to petroleum-based fuels, including enzymatic routes for hydrocarbon synthesis. Phylogenetically diverse species have long been recognized to produce hydrocarbons, but many of the enzymes responsible have been identified within the past decade. The enzymatic conversion of Cn chain length fatty aldehydes (or acids) to Cn-1 hydrocarbons, alkanes or alkenes, involves a C-C scission reaction. Surprisingly, the enzymes involved in hydrocarbon synthesis utilize non heme mononuclear iron, dinuclear iron, and thiolate-ligated heme cofactors that are most often associated with monooxygenation reactions. In this review, we examine the mechanisms of several enzymes involved in hydrocarbon biosynthesis, with specific emphasis on the structural and electronic changes that enable this functional switch. PMID- 28004189 TI - Therapeutic clowns in pediatrics: a systematic review and meta-analysis of randomized controlled trials-corrigendum. PMID- 28004188 TI - Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. AB - : In this prospective study, we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA (hs-PDA) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses. Laboratory investigations such as renal function test, liver function test, complete blood count, and blood gases were conducted in addition to echocardiographic examinations. All investigations were done before and 3 days after treatment. There was no significant difference between all groups regarding efficacy of PDA closure (P = 0.868). There was a significant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups (P < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups (P < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group (P = 0.003). No significant difference of hemoglobin (HB) level or liver enzymes in all groups (P > 0.05). Ventilatory settings improved significantly in patients with successful closure of PDA than those with failed PDA closure (P < 0.001). CONCLUSION: Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding. What is Known: * Hemodynamically significant patent ductus arteriosus has many complications for preterm and low birth weight neonates and better to be closed. Many drugs were used for medical closure of PDA e.g. indomethacin, ibuprofen and recently paracetamol. Many studies compare safety and efficacy of paracetamol with either indomethacin or ibuprofen. What is New: * It is the first large study that compares the efficacy and side effects of the three drugs in one study. PMID- 28004190 TI - Systematic review of the implementation of simulation training in surgical residency curriculum. AB - PURPOSE: We reviewed the literature regarding the specific methods and strategies for implementing simulation-based training into the modern surgical residency curriculum. Residency programs are still struggling with how best to implement it into their curricula from a practical viewpoint. METHODS: A systematic review was performed using Ovid MEDLINE, EMBASE, PubMed, PsycINFO, Web of Science, and other resources for studies involving the use of simulation for technical skills training in the surgical residency curriculum. Studies were selected based on the integration of simulation into the curriculum and/or a description of the details of implementation and the resources required. RESULTS: In total, 2533 unique citations were retrieved based on this search, and 31 articles met the inclusion criteria. Most simulators were focused on laparoscopic procedures, and training occurred most often in a skills lab. The assessment of skills consisted mostly of speed of task completion. Only 4 studies addressed issues of cost, and 6 programs mentioned human resources without any mention of skills center personnel or administrative support. CONCLUSIONS: All of the studies described the nature of the simulation training, but very few commented on how it was actually implemented and what was needed from organizational, administrative and logistical perspectives. PMID- 28004192 TI - The association between interleukin-10 (IL-10) -592C/A, -819T/C, -1082G/A promoter polymorphisms and endometriosis. AB - PURPOSE: Endometriosis has an incidence reaching up to 50% in infertile women. Cytokine-mediated immune responses seem to play an important role in endometriosis pathogenesis, but still the etiology and pathophysiology remain unclear. In the current study we tried to investigate whether there is a relationship between IL-10 genetic polymorphism, serum levels of IL-10 and the presence of advanced endometriosis. METHODS: The presence of IL-10 592C/A, 819T/C, 1082G/A promoter polymorphisms and IL-10 serum levels were investigated in advanced endometriosis patients compared to healthy controls. Genomic DNA was extracted from peripheral blood leukocytes and further analyzed by PCR. RESULTS: IL-10 serum levels were higher in endometriosis group compared to controls (1.48, 0.68, p < 0.001). We have observed an association between IL-10 592C/C and 819C/C genotypes, presence of C alleles and an increased risk of endometriosis. No difference was observed in IL-10 serum levels corresponding to different alleles or genotypes. CONCLUSION: Our results suggest that IL-10 592A/C and 819T/C promoter polymorphisms confer susceptibility to advanced endometriosis. No associations were found between the IL-10 1082A/G polymorphism and susceptibility to advanced endometriosis. PMID- 28004193 TI - Lymphocyte immunotherapy in the treatment of recurrent miscarriage: systematic review and meta-analysis. AB - PURPOSE: Recurrent miscarriage (RM) affects up to 2-3% of couples of reproductive age. There are several causes for this condition, including immunologic. The embryo is considered an allograft, subject to the rejection mechanisms of the maternal immune system. Immunotherapy involving immunization with lymphocytes is considered in cases of idiopathic RM. However, there is still no consensus regarding the efficacy and safety of this therapy. METHODS: This systematic review and meta-analysis evaluated the data available in the literature regarding the efficacy and safety of the use of immunotherapy with lymphocytes in couples with history of RM. Searches in PubMed/Medline, SCOPUS, and Cochrane Library databases were conducted, using the following keywords: "recurrent miscarriage," "lymphocyte immunotherapy," and "meta-analysis." Statistical analyses were performed using Review Manager 5.3 (RevMan), version 5.3. RESULTS: Six published meta-analysis were retrieved; two found no improvements in the rate of live births after the use of immunization with lymphocytes in the treatment of RM, and four found a beneficial effect of the use of immunotherapy with lymphocytes in cases of RM, with significant improvements in the rate of live births. CONCLUSION: Data available in the literature supports the efficacy and safety of immunotherapy with lymphocytes in cases of RM without an identified cause. PMID- 28004194 TI - Did I see your hand moving? The effect of movement-related information on the Corsi block tapping task. AB - The Corsi Block Tapping Task is a widespread test used to assess spatial working memory. Previous research hypothesized that the discrepancy found in some cases between the traditional and the digital (touchscreen) version of the Corsi block tapping task may be due to a direct motor resonance between the experimenter's and the participant's hand movements. However, we hypothesize that this discrepancy might be due to extra movement-related information included in the traditional version, lacking in the digital one. We investigated the effects of such task-irrelevant information using eCorsi, a touchscreen version of the task. In Experiment 1, we manipulate timing in sequence presentation, creating three conditions. In the Congruent condition, the inter-stimulus intervals reflected the physical distance in which the stimuli were spatially placed: The longer the spatial distance, the longer the temporal interval. In the Incongruent condition the timing changed randomly. Finally, in the Isochronous condition every stimulus appeared after a fixed interval, independently from its spatial position. The results showed a performance enhancement in the Congruent condition, suggesting an incidental spatio-temporal binding. In Experiment 2, we added straight lines between each location in the sequences: In the Trajectories condition participants saw trajectories from one spatial position to the other during sequence presentation, while a condition without such trajectories served as control. Results showed better performances in the Trajectories condition. We suggest that the timing and trajectories information play a significant role in the discrepancies found between the traditional and the touchscreen version of the Corsi Block Tapping Task, without the necessity of explanations involving direct motor resonance (e.g. seeing an actual hand moving) as a causal factor. PMID- 28004195 TI - The periprostatic venous plexus: an unusual source of fatal pulmonary embolism during corporoplasty. AB - When a sudden death occurs during a minor surgical intervention, it may require a careful and extensive postmortem investigation. One such case concerns a 61-year old male patient affected by Peyronie's disease, who died suddenly during a corporoplasty procedure. Autopsy and histologic examinations showed a massive bilateral pulmonary micro-embolism brought on by periprostatic venous plexus thrombosis. The cause of death was attributed to intraoperative fatal pulmonary micro-embolism. Pulmonary thromboembolism is a major cause of death and is known to be a possible complication of surgery. Nevertheless, the periprostatic venous plexus is an unusual site of thrombosis, as it has been demonstrated that the majority of emboli originate in the legs. In this case, the embolism was massive and fatal and occurred during a minor surgical procedure, even though the patient was not at risk for venous thromboembolism, nor did he have a significant past medical history. PMID- 28004196 TI - A method for identifying color vision deficiency malingering. AB - PURPOSE: To propose a new test to identify color vision deficiency malingering. METHODS: An online survey was distributed to 130 truly color vision deficient participants and 160 participants willing to simulate color vision deficiency. The survey contained three sets of six color-adjusted versions of the standard Ishihara color plates each, as well as one set of six control plates. The plates that best discriminated both participant groups were selected for a "balanced" test emphasizing both sensitivity and specificity. A "specific" test that prioritized high specificity was also created by selecting from these plates. Statistical measures of the test (sensitivity, specificity, and Youden index) were assessed at each possible cut-off threshold, and a receiver operating characteristic (ROC) function with its area under the curve (AUC) charted. RESULTS: The redshift plate set was identified as having the highest difference of means between groups (-58%, CI: -64 to -52%), as well as the widest gap between group modes. Statistical measures of the "balanced" test show an optimal cut-off of at least two incorrectly identified plates to suggest malingering (Youden index: 0.773, sensitivity: 83.3%, specificity: 94.0%, AUC of ROC 0.918). The "specific" test was able to identify color vision deficiency simulators with a specificity of 100% when using a cut-off of at least two incorrectly identified plates (Youden index 0.599, sensitivity 59.9%, specificity 100%, AUC of ROC 0.881). CONCLUSIONS: Our proposed test for identifying color vision deficiency malingering demonstrates a high degree of reliability with AUCs of 0.918 and 0.881 for the "balanced" and "specific" tests, respectively. A cut-off threshold of at least two missed plates on the "specific" test was able to identify color vision deficiency simulators with 100% specificity. PMID- 28004197 TI - Poor outcomes despite aspirin or statin use in high-risk patients with retinal vein occlusion. AB - PURPOSE: Since atherosclerosis contributes to the pathophysiology of retinal vein occlusion (RVO), we aimed to assess the effects of aspirin and statins on the visual outcomes of RVO in high-risk patients, whom we define to have hypertension and open-angle glaucoma prior to RVO. METHODS: We conducted a retrospective case control study of adults diagnosed with RVO between 2006 and 2014. To evaluate for a preventive effect of these medications, we compared the prevalence of aspirin or statin use (either separately or concomitantly) among high-risk patients who developed RVO and among those who did not during at least 2 years of follow-up. To evaluate for a therapeutic effect, we then compared the final follow-up visual acuity (VA) of high-risk RVO patients who had and who had not been taking a statin prior to the RVO. RESULTS: We analyzed 43 eyes [23 central RVOs (CRVOs), 16 branch RVOs (BRVOs), and 4 hemi-RVOs (HRVOs)] from 42 high-risk patients, along with 129 high-risk controls. There was no significant difference (p = 0.47) in aspirin exposure between the control (60%) and RVO (67%) groups, and the increased statin exposure among controls (72% vs. 53% for the cases; p = 0.03) paralleled their higher prevalence of hyperlipidemia. The non-statin and statin RVO groups each had a mean VA of 20/800 at a mean 30 and 43 months of follow-up, respectively. CONCLUSIONS: No preventive benefit of aspirin or statins, and no therapeutic benefit of statins, was found for RVO in high-risk patients. High risk RVO patients suffer substantially worse outcomes than those reported in other studies not limited to such patients. PMID- 28004198 TI - Leukoaraiosis is a predictor of futile recanalization in acute ischemic stroke. AB - Futile recanalization occurs when successful recanalization fails to improve clinical outcome in acute ischemic stroke patients. Predictors of futile recanalization are still debated and may help in selecting patients for reperfusion strategies. We aim to determine whether leukoaraiosis may be useful in predicting futile recanalization in acute ischemic stroke patients treated by endovascular mechanical thrombectomy. We included in the analysis patients with acute ischemic stroke due to anterior circulation large vessel occlusion undergoing endovascular mechanical thrombectomy obtaining complete vessel recanalization. Demographics, vascular risk factors, baseline National Institutes of Health Stroke Scale score, time from symptoms onset to recanalization, Alberta Stroke Program Early CT Score, and leukoaraiosis graded on a 4-point van Swieten scale were collected. We dichotomized patients into those with moderate-severe leukoaraiosis (2-4) versus those with absent-slight leukoaraiosis (0, 1). Outcome measures were symptomatic intracranial hemorrhage, and modified Rankin scale score at 90 days. The relationships among radiological parameters and clinical data with outcome measures were studied with univariate and multivariable analyses. Sixty-eight patients were identified. Recanalization was futile in 32.4% of cases. On multivariable logistic regression analysis, the presence of moderate-severe LA was independent predictors of FR (P = 0.01). Furthermore, higher NIHSS score at baseline (P < 0.01) end endovascular mechanical thrombectomy alone treatment (P < 0.01) resulted associated with futile recanalization. Our results showed that the presence of moderate-severe leukoaraiosis is associated with poor outcome in recanalized patients. PMID- 28004199 TI - The effect of esophagogastroduodenoscopy probe insertion on the intracuff pressure of airway devices in children during general anesthesia. AB - Given the size of the esophagogastroduodenoscopy (EGD) probe and the compressibility of the pediatric airway, the EGD probe may increase the intracuff pressure (IP) of an airway device. The current study evaluated IP changes during EGD examination under general anesthesia in pediatric patients. Following the induction of anesthesia, a laryngeal mask airway (LMA) or endotracheal tube (ETT) was placed without neuromuscular blockade. The IP was measured at baseline, during EGD probe insertion, while the EGD probe was in place, and after probe removal. The study cohort included 101 patients (mean age 11.3 years). The airway was secured with an LMA and an ETT in 88 and 13 patients, respectively. The IP increased from 27 +/- 15 cmH2O at baseline to 34 +/- 17 cmH2O during probe insertion (p < 0.001), remained at 33 +/- 16 cmH2O while the probe was in place, and decreased to 26 +/- 14 cmH2O after probe removal. The IP of the LMA or ETT increased during EGD probe insertion and remained elevated while the probe was in place. High IP may compromise mucosal perfusion resulting in a sore throat when using an LMA or the potential for airway damage if an ETT is used. Removal of air from the cuff and titration of the IP should be considered after EGD insertion. PMID- 28004200 TI - Hyperinsulinemic normoglycemia decreases glucose variability during cardiac surgery. AB - PURPOSE: Increased glucose variability may be associated with worse outcomes in critically ill patients. Hyperinsulinemic normoglycemia provides intensive glucose control during surgery and may reduce glucose variability. Our objective was to compare glycemic variability between two methods of glucose control in cardiac surgical patients: hyperinsulinemic normoglycemia vs standard insulin infusion. We also assessed whether the effect differed between patients with and without diabetes mellitus. METHODS: We compared measures of glycemic variability, including the primary outcome, average real variability (ARV), and secondary outcomes, within-patient standard deviation (SD) and glucose lability index (GLI), in 252 patients who received hyperinsulinemic normoglycemia and 266 patients who received standard therapy. Data was randomly sampled from each patient treated with hyperinsulinemic normoglycemia, so patients in each group had a similar number of glucose measurements. The significance level for each hypothesis was 0.05, and 0.025 within diabetic status. RESULTS: For nondiabetic patients, hyperinsulinemic normoglycemia reduced mean glucose measure-to-measure variability for ARV by an estimated -0.23 (97.5% CI -0.30, -0.16) mg/dl/min (P < 0.001) versus standard care. There was no difference in glycemic variability between groups for diabetic patients, with difference in means (97.5% CI) of 0.10 (-0.20, 0.02) mg/dl/min, P = 0.07. Mean SD was lower for hyperinsulinemic normoglycemia patients overall, with difference in means (95% CI) of -19 (-22, 16), P < 0.001, with a stronger effect in nondiabetics (interaction P = 0.042). GLI was also lower with hyperinsulinemic normoglycemia. CONCLUSION: Hyperinsulinemic normoglycemia decreases glucose variability for cardiac surgical patients with a stronger effect in nondiabetic patients. PMID- 28004201 TI - Autonomic disturbances including impaired hand thermoregulation in multiple system atrophy and Parkinson's disease. AB - Autonomic dysfunction in multiple system atrophy (MSA) comprises cardinal symptoms of orthostatic hypotension (OH) and urinary incontinence. Additionally, cardiovagal and sudomotor abnormalities can be present. Previous studies compared hand skin temperature and its response to cooling in subjects with probable MSA and Parkinson's disease (PD). Significant differences were found indicating that disturbed thermoregulation belongs to MSA autonomic features and could be helpful in differentiation of MSA from PD. The objective of this study was to improve our knowledge about impaired thermoregulation of distal extremities in MSA with parkinsonian features (MSA-P) and PD and to assess the possible interrelations for the different subtypes of autonomic dysfunction in a large cohort of MSA-P, PD and control patients. The patients underwent a standard cooling-rewarming procedure, termed ice test (IT). Electroneurography, heart rate variability, sympathetic skin response and orthostatic tests were performed for the subdivision of the patients. The prevalence of pathological IT was slightly increased in MSA compared with PD and control groups. The presence of pathological IT was related with older patient's age in PD and control groups significantly (p < 0.05). This relation was absent for the MSA patients, who themselves were significantly younger (p = 0.001). Significant association between the presence of pathological IT and OH was determined (p < 0.001). Defective thermoregulation of distal extremities seems to be more severe in the MSA patients. The dysfunction of preganglionic sympathetic neurons might be involved in impaired response to cooling for MSA. The results suggest pathophysiological affinity of impaired sympathetic neurovascular regulation between pathological IT and OH. PMID- 28004202 TI - The impact of early versus late levodopa administration. AB - Long-term levodopa therapy in patients with Parkinson's disease (PD) is associated with motor complications including motor fluctuations (MF) and levodopa-induced dyskinesias (LID). The time to appearance of MF and LID is apparently related to both the timing and the duration of levodopa therapy, but is highly variable. We performed a retrospective analysis of all levodopa-treated PD patients to explore the effect of time from PD onset to levodopa initiation on time to MF or LID. We used a Cox multivariate regression model after stratifying patients into four quartiles, according to the time to levodopa initiation. Data from 170 PD patients (117 males, age at onset: 65.1 +/- 11.6 years, time to levodopa treatment: 23.8 +/- 28.4 months) was included in the analysis. Early levodopa administration was associated with a shorter time from diagnosis to both MF (p < 0.001) and LID (p = 0.001). The hazard ratio to develop MF and LID from the time of PD diagnosis was 2.48 (p < 0.001) and 2.71 (p = 0.002), respectively. In our population, we found that delaying levodopa administration was associated with a longer time to the appearance of motor complications after diagnosis. While disease duration is the most important determinant of the onset of motor complications, delaying levodopa could prolong the 'complication-free' period. PMID- 28004203 TI - Aging effect on muscle synergies in stepping forth during a forward perturbation. AB - PURPOSE: We explored changes in muscle interactions during healthy aging as a window into neural control strategies of postural preparation to action/perturbation. In particular, we quantified the strength of multi-muscle synergies stabilizing the center of pressure (COP) displacement during the preparation for making a step associated with support surface translations. METHODS: Young and elderly subjects were required to make a step in response to support surface perturbations. Surface muscle activity of 11 leg and trunk muscles was analyzed to identify sets of 4 muscle modes (M-modes). Linear combinations of M-modes and their relationship to changes in the COP displacement in the anterior-posterior direction were then determined. Uncontrolled manifold analysis was performed to determine variance components in the M-mode space and indices of M-mode synergy stabilizing COP displacement. RESULTS: Prior to the step initiation, the older subjects showed strong synergies that stabilized COP displacement to forward perturbation of the support surface. However, the synergy indices were significantly lower than those of the young subjects during preparation for making a step. The timings of early postural adjustment (EPA) and anticipatory postural adjustment (APA) were consistently earlier in the young subjects as compared to the older subjects. For both groups, the timing of EPA did not change across tasks, while APA showed delayed timing in response to the support surface translations. CONCLUSIONS: We infer that changes in the indices of synergies with age may present challenges for the control of postural preparation to external perturbation in older adults. They may lead to excessive muscle co-contractions and low stability of COP displacement. The results reported here could have clinical relevance when identifying the risk of making a step, which has been linked to an increased risk of falls among the elderly. PMID- 28004204 TI - Treatment of lupus erythematosus of the eyelids with pulsed dye laser. PMID- 28004205 TI - Vascular alterations after photodynamic therapy mediated by 5-aminolevulinic acid in oral leukoplakia. AB - Impairment of vascular functions after photodynamic therapy (PDT) is frequently associated with tumor remission and is considered one of the main antineoplastic PDT effects. Vascular alterations in oral leukoplakia (OL) treated with PDT have not yet been described. The aim of this study was to evaluate the effect of topical 5-ALA-mediated PDT on the vascular network of 4NQO-induced OL in rats. After applying 4NQO topically on the tongue during 16 weeks, there was induction of dysplastic lesions, which were treated with two PDT sessions (with an interval of 72 h between them), using topical application of 5-ALA and posterior irradiation with a laser (90 J/cm2 fluency). Histological sections of the tongues were obtained and analyzed concerning plasmatic exudation and microvessel density after immunolabeling with CD31 and CD34 vessel markers. There was intense plasmatic exudation after 6 h of the first PDT session; at 6 h of the second PDT session, there was a significant reduction in the density of CD31- and CD34 positive microvessels in comparison to controls (p < 0.05). In the PDT intervals, there was an increase in the density of CD31 and CD34 microvessels, suggesting angiogenesis. Topical application of 5-ALA-mediated PDT caused an immediate deleterious effect on the vascular network, increasing vessel permeability and reducing vessel density, mainly after two sessions of the treatment. However, secondary angiogenesis emerged in these lesions during intervals of the PDT session. This fact may be considered during the adoption of a PDT protocol, to avoid OL resistance and recurrence after the treatment. PMID- 28004206 TI - Drug innovation, price controls, and parallel trade. AB - We study the long-run welfare effects of parallel trade (PT) in pharmaceuticals. We develop a two-country model of PT with endogenous quality, where the pharmaceutical firm negotiates the price of the drug with the government in the foreign country. We show that, even though the foreign government does not consider global R&D costs, (the threat of) PT improves the quality of the drug as long as the foreign consumers' valuation of quality is high enough. We find that the firm's short-run profit may be higher when PT is allowed. Nonetheless, this is neither necessary nor sufficient for improving drug quality in the long run. We also show that improving drug quality is a sufficient condition for PT to increase global welfare. Finally, we show that, when PT is allowed, drug quality may be higher with than without price controls. PMID- 28004207 TI - Rationing in health care provision: a welfare approach. AB - We study the welfare properties of direct restrictions based on cost effectiveness and indirect methods represented by waiting lists in a public health care system. Health care is supplied for free by the public health sector, but patients can choose to address their demand elsewhere by stipulating a private health care insurance policy to avoid restrictions. Our model shows that if the individual response to treatment is independent of income and cannot be observed by the patient, the choice of opting out simply depends on income, and the redistributive effects of both instruments are quite similar. In general, restrictions may only improve welfare of relatively rich individuals, usually those that opt out of the public health care system. From a policy point of view, our model casts serious doubts upon the use of these instruments for redistributive purposes. PMID- 28004208 TI - Biotransformation of beta-keto nitriles to chiral (S)-beta-amino acids using nitrilase and omega-transaminase. AB - OBJECTIVE: To enzymatically synthesize enantiomerically pure beta-amino acids from beta-keto nitriles using nitrilase and omega-transaminase. RESULTS: An enzyme cascade system was designed where in beta-keto nitriles are initially hydrolyzed to beta-keto acids using nitrilase from Bradyrhizobium japonicum and subsequently beta-keto acids were converted to beta-amino acids using omega transaminases. Five different omega-transaminases were tested for this cascade reaction, To enhance the yields of beta-amino acids, the concentrations of nitrilase and amino donor were optimized. Using this enzymatic reaction, enantiomerically pure (S)-beta-amino acids (ee > 99%) were generated. As nitrilase is the bottleneck in this reaction, molecular docking analysis was carried out to depict the poor affinity of nitrilase towards beta-keto acids. CONCLUSIONS: A novel enzymatic route to generate enantiomerically pure aromatic (S)-beta-amino acids from beta-keto nitriles is demonstrated for the first time. PMID- 28004209 TI - Sealing of calcified plaques after bioresorbable scaffold implantations: a five year follow up. PMID- 28004210 TI - Exuberant mitral annular calcification. AB - Mitral annular calcification (MAC) is a chronic, progressive process characterized by calcium deposition on the mitral valve annulus. There is no current grading system to relay the severity of MAC. The primary purpose of this study was to investigate the extreme end of the severity spectrum in order to describe "exuberant mitral annular calcification", and a retrospective chart review of all patients with exuberant mitral annulus calcification evaluated at Mayo Clinic Rochester between January 1996 and December 2014 was performed. This is the first study to define criteria of "exuberant mitral annular calcification", emphasizing the importance of identifying the extreme degree of mitral annular calcification. PMID- 28004211 TI - From paediatrics to geriatrics: a life course perspective on the MRC National Survey of Health and Development. PMID- 28004212 TI - Application of actuator-driven pulsed water jet in aneurysmal subarachnoid hemorrhage surgery: its effectiveness for dissection around ruptured aneurysmal walls and subarachnoid clot removal. AB - In clipping surgery for aneurysmal subarachnoid hemorrhage (aSAH), critical steps include clot removal and dissection of aneurysms without premature rupture or brain injuries. To pursue this goal, a piezo actuator-driven pulsed water jet (ADPJ) system was introduced in this study. This study included 42 patients, who suffered aSAH and underwent clipping surgery. Eleven patients underwent surgery with the assistance of the ADPJ system (ADPJ group). In the other 31 patients, surgery was performed without the ADPJ system (Control group). The ADPJ system was used for clot removal and aneurysmal dissection. The clinical impact of the ADPJ system was judged by comparing the rate of premature rupture, degree of clot removal, and clinical outcomes. Intraoperatively, a premature rupture was encountered in 18.2 and 25.8% of cases in the ADPJ and control groups, respectively. Although the differences were not statistically significant, intraoperative observation suggested that the ADPJ system was effective in clot removal and dissection of aneurysms in a safe manner. Computed tomography scans indicated the achievement of higher degrees of clot removal, especially when the ADPJ system was used for cases with preoperative clot volumes of more than 25 ml (p = 0.047, Mann-Whitney U test). Clinical outcomes, including incidence of postoperative brain injury or symptomatic vasospasm, were similar in both groups. We described our preliminary surgical results using the ADPJ system for aSAH. Although further study is needed, the ADPJ system was considered a safe and effective tool for clot removal and dissection of aneurysms. PMID- 28004213 TI - The Impact of Postgraduate Health Technology Innovation Training: Outcomes of the Stanford Biodesign Fellowship. AB - Stanford Biodesign launched its Innovation Fellowship in 2001 as a first-of-its kind postgraduate training experience for teaching biomedical technology innovators a need-driven process for developing medical technologies and delivering them to patients. Since then, many design-oriented educational programs have been initiated, yet the impact of this type of training remains poorly understood. This study measures the career focus, leadership trajectory, and productivity of 114 Biodesign Innovation Fellowship alumni based on survey data and public career information. It also compares alumni on certain publicly available metrics to finalists interviewed but not selected. Overall, 60% of alumni are employed in health technology in contrast to 35% of finalists interviewed but not selected. On leadership, 72% of alumni hold managerial or higher positions compared to 48% of the finalist group. A total of 67% of alumni reported that the fellowship had been "extremely beneficial" on their careers. As a measure of technology translation, more than 440,000 patients have been reached with technologies developed directly out of the Biodesign Innovation Fellowship, with another 1,000,000+ aided by solutions initiated by alumni after their training. This study suggests a positive impact of the fellowship program on the career focus, leadership, and productivity of its alumni. PMID- 28004214 TI - Biomaterial Scaffolds for Reproductive Tissue Engineering. AB - The reproductive system usually involves gamete producing gonads, a series of specialized ducts, accessory glands and the external genitalia. Despite there are many traditional methods such as hormonal and surgical approaches, at present no effective treatments exist to help patients suffering from serious diseases of reproductive system, including congenital and acquired abnormalities, malignant tumor, traumatic, infectious etiologies, inflammation and iatrogenic injuries. Tissue engineering holds promise for reproductive medicine through the development of biological alternative. Till now, a diverse range of biomaterials have been utilized as suitable substrates to match both the mechanical and biological context of reproductive tissues. The current review will focus mainly on the applications of biomaterial scaffolds and their major achievements in each region of reproductive systems. PMID- 28004215 TI - Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorder in Japan: A Randomized, Double-blind, Placebo-controlled Study. AB - We evaluated the efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents (6-17 years) with autism spectrum disorder (ASD) in a randomized, double-blind, placebo-controlled 8-week study in Japan. Patients received flexibly dosed aripiprazole (1-15 mg/day) or placebo. Ninety-two patients were randomized to placebo (n = 45) or aripiprazole (n = 47). Aripiprazole produced a significant improvement in the mean parent/caregiver rated Aberrant Behavior Checklist Japanese Version irritability subscale score relative to placebo from week 3 through week 8. Administration of aripiprazole provided significantly greater improvement in the mean clinician-rated Clinical Global Impression-Improvement scores than placebo from week 2 through week 8. All patients randomized to aripiprazole completed the study, and no serious adverse events were reported. Three patients in placebo group discontinued. Aripiprazole was effective and generally safe and well-tolerated in the treatment of irritability associated with ASD in Japanese children and adolescents. PMID- 28004217 TI - Lactobacillus kefiri shows inter-strain variations in the amino acid sequence of the S-layer proteins. AB - The S-layer is a proteinaceous envelope constituted by subunits that self assemble to form a two-dimensional lattice that covers the surface of different species of Bacteria and Archaea, and it could be involved in cell recognition of microbes among other several distinct functions. In this work, both proteomic and genomic approaches were used to gain knowledge about the sequences of the S-layer protein (SLPs) encoding genes expressed by six aggregative and sixteen non aggregative strains of potentially probiotic Lactobacillus kefiri. Peptide mass fingerprint (PMF) analysis confirmed the identity of SLPs extracted from L. kefiri, and based on the homology with phylogenetically related species, primers located outside and inside the SLP-genes were employed to amplify genomic DNA. The O-glycosylation site SASSAS was found in all L. kefiri SLPs. Ten strains were selected for sequencing of the complete genes. The total length of the mature proteins varies from 492 to 576 amino acids, and all SLPs have a calculated pI between 9.37 and 9.60. The N-terminal region is relatively conserved and shows a high percentage of positively charged amino acids. Major differences among strains are found in the C-terminal region. Different groups could be distinguished regarding the mature SLPs and the similarities observed in the PMF spectra. Interestingly, SLPs of the aggregative strains are 100% homologous, although these strains were isolated from different kefir grains. This knowledge provides relevant data for better understanding of the mechanisms involved in SLPs functionality and could contribute to the development of products of biotechnological interest from potentially probiotic bacteria. PMID- 28004218 TI - Religion, Spirituality, and HIV Clinical Outcomes: A Systematic Review of the Literature. AB - This systematic review evaluates the association between religion, spirituality and clinical outcomes in HIV-infected individuals. A systematic literature review was conducted for all English language articles published between 1980 and 2016 in relevant databases. Six hundred fourteen studies were evaluated. 15 met inclusion criteria. Ten (67%) studies reported a positive association between religion or spirituality and a clinical HIV outcome. Two (13%) studies failed to detect such an association; and two (13%) demonstrated a negative association. One study (7%) identified features of religiosity and spirituality that had both negative and positive associations with HIV clinical outcomes. Recognizing the religious or spiritual commitments of patients may serve as an important component of patient care. Further longitudinal studies and interventions might be required to further clarify the potential impact of religion and spirituality on HIV clinical outcomes. PMID- 28004216 TI - Pectinolytic yeasts from cold environments: novel findings of Guehomyces pullulans, Cystofilobasidium infirmominiatum and Cryptococcus adeliensis producing pectinases. AB - One hundred and three yeasts isolated from soil samples from King George Island and Tierra del Fuego province were screened in relation with their capability to produce pectinolytic enzymes. Although all the yeasts showed well-developed colonies at 20 degrees C, only eight showed a clear halo around the colony, indicative of pectin degradation. A secondary screening demonstrated that only four yeasts were capable to produce pectinases at low temperatures (8 degrees C). It could be seen that the selected yeasts were able to grow and produce high levels of polygalacturonase activity when submerged fermentations were performed using pectin-containing fruit wastes as substrates. None of the strains produced neither lyase nor rhamnogalacturonan hydrolase activities. Regarding pectin esterase activity, it was only produced in lower amounts by G. pullulans 8E (0.022 U ml-1). A TLC analysis of the substrate cleavage pattern of the pectinolytic systems was consistent with an endo-type activity. The clarification of apple juice was only accomplished by G. pullulans pectinolytic system, with a clarification of 80% (%T650) using 4 U/ml of enzyme at 20 degrees C. As far as we concern this work describes for the first time the production of pectinases by the cold-adapted yeasts species Cystofilobasidium infirmominiatum, Cryptococcus adeliensis and G. pullulans. PMID- 28004219 TI - Progress and Challenges in Ending HIV and AIDS in Australia. AB - This review considers Australia's progress towards the elimination of HIV and AIDS, as specified in international targets. In particular, it considers the reaction to recent media reports that Australia has 'ended AIDS' and evaluates progress towards reducing HIV transmission. Recent surveillance data and research show significant improvements in HIV testing and treatment, but countervailing trends such as increased condomless sex between gay and other men who have sex with men. Pre-exposure prophylaxis (PrEP) is being implemented at scale in some jurisdictions, with the hope that this will significantly alter the trajectory of Australia's HIV epidemic, which has been stable for the last five years (at around 1000-1100 infections per year). The ongoing challenge in maintaining investment, while also considering how to respond to the diversification of the local epidemic, means that Australia has entered a critical period in which evidence of PrEP's impact is eagerly awaited. PMID- 28004220 TI - Recurrence risk perception and quality of life following treatment of breast cancer. AB - PURPOSE: Little is known about different ways of assessing risk of distant recurrence following cancer treatment (e.g., numeric or descriptive). We sought to evaluate the association between overestimation of risk of distant recurrence of breast cancer and key patient-reported outcomes, including quality of life and worry. METHODS: We surveyed a weighted random sample of newly diagnosed patients with early-stage breast cancer identified through SEER registries of Los Angeles County & Georgia (2013-14) ~2 months after surgery (N = 2578, RR = 71%). Actual 10-year risk of distant recurrence after treatment was based on clinical factors for women with DCIS & low-risk invasive cancer (Stg 1A, ER+, HER2-, Gr 1-2). Women reported perceptions of their risk numerically (0-100%), with values >=10% for DCIS & >=20% for invasive considered overestimates. Perceptions of "moderate, high or very high" risk were considered descriptive overestimates. In our analytic sample (N = 927), we assessed factors correlated with both types of overestimation and report multivariable associations between overestimation and QoL (PROMIS physical & mental health) and frequent worry. RESULTS: 30.4% of women substantially overestimated their risk of distant recurrence numerically and 14.7% descriptively. Few factors other than family history were significantly associated with either type of overestimation. Both types of overestimation were significantly associated with frequent worry, and lower QoL. CONCLUSIONS: Ensuring understanding of systemic recurrence risk, particularly among patients with favorable prognosis, is important. Better risk communication by clinicians may translate to better risk comprehension among patients and to improvements in QoL. PMID- 28004221 TI - Overexpression of teneurin transmembrane protein 1 is a potential marker of disease progression in papillary thyroid carcinoma. AB - Although papillary thyroid cancer is a relatively indolent malignancy, its progression may be associated with dedifferentiation and resistance to radioactive iodine treatment. In this study, patterns of differentially expressed genes in association with disease progression were systemically evaluated. We firstly performed transcriptome analyses for four matched cancerous and noncancerous tissue pairs of the classical subtype of papillary thyroid cancer. Among the upregulated and downregulated genes, the expression of 164 and 183 genes increased and decreased, respectively, from stage I to stage IV. Functional enrichment and pathway analysis showed that angiogenesis pathway was upregulated, whereas oxidation-reduction and metabolism of reactive oxygen species were downregulated. Teneurin transmembrane protein 1 (TENM1) expression was highly upregulated in cancerous tissues and negative in benign thyroid tissues. By immunohistochemistry, TENM1 expression in papillary thyroid cancer was associated with the classical subtype (p = 0.018), extrathyroidal invasion (p = 0.001), BRAF V600E mutation (p < 0.001), and an advanced stage (p = 0.019). Taken together, our results indicate that distinct pathways are involved in papillary thyroid cancer progression, and TENM1 is a potential marker of cancer progression. PMID- 28004222 TI - Auditory preference of children with autism spectrum disorders. AB - Research on children with autism spectrum disorders suggests differences from neurotypical children in the preference for 'social' versus 'nonsocial' sounds. Conclusions have been based largely on the use of head-turn methodology which has various limitations as a means of establishing auditory preference. In the present study, preference was assessed by measuring the frequency with which children pressed a button to hear different sounds using an interactive toy. Contrary to prior results, both groups displayed a strong preference for the highly social sounds. These findings have implications for approaches to language intervention and for theoretical debates regarding social motivation. PMID- 28004223 TI - Identification of MSH2 inversion of exons 1-7 in clinical evaluation of families with suspected Lynch syndrome. AB - Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining. PMID- 28004224 TI - Antioxidant and antiproliferative effects of different solvent fractions from Terminalia belerica Roxb. fruit on various cancer cells. AB - Terminalia belerica Roxb. fruits have been previously reported against diabetes, ulcer, microbial problems and hepatotoxicity. The present study was aimed to investigate antioxidant and anticancer potential of sequentially fractionated hexane (TBHE), chloroform (TBCE), ethyl acetate (TBEE), butanol (TBBE) and water (TBWE) extracts from the 70% methanolic extract of T. belerica fruits. TBCE, TBEE, TBBE and TBWE showed excellent ROS (reactive oxygen species) and RNS (reactive nitrogen species) scavenging activities which was investigated using 11 different assays for various free radicals. Among 5 fractions, TBHE and TBCE remained nontoxic to any of the malignant cell lines including normal cells (WI 38). TBBE and TBWE inhibited the proliferation of breast (MCF-7), cervical (HeLa) and brain (U87) cancer cells by inducing G2/M arrest while TBEE caused apoptosis. However, these fractions did not inhibit the proliferation of lung (A549) and liver (HepG2) cancer cells. BrdU incorporation study also suggested the efficient anticancer potential of TBEE, TBBE and TBWE. Moreover, TBBE and TBWE treated MCF 7, HeLa and U87 cells showed upregulation of p53 and p21 proteins. Phytochemical analysis reflected the presence of adequate quantities of different phytochemicals. Moreover, HPLC analysis show peaks of purpurin, catechin, tannic acid, reserpine, ellagic acid, methyl gallate, aconitine and rutin in TBBE, TBWE and TBEE. Hence these polar extracts of T. belerica can be used to develop drug against different types of cancer. PMID- 28004225 TI - Modeling viscous dissipation during vocal fold contact: the influence of tissue viscosity and thickness with implications for hydration. AB - The mechanics of vocal fold contact during phonation is known to play a crucial role in both normal and pathological speech production, though the underlying physics is not well understood. Herein, a viscoelastic model of the stresses during vocal fold contact is developed. This model assumes the cover to be a poroelastic structure wherein interstitial fluid translocates in response to mechanical squeezing. The maximum interstitial fluid pressure is found to generally increase with decreasing viscous dissipation and/or decreasing tissue elasticity. A global minimum in the total contact stress, comprising interstitial fluid pressure and elastic stress in the tissue, is observed over the studied dimensionless parameter range. Interestingly, physiologically reasonable estimates for the governing parameters fall within this global minimum region. The model is validated against prior experimental and computational work, wherein the predicted contact stress magnitude and impact duration agree well with published results. Lastly, observations of the potential relationship between vocal fold hydration and increased risk of tissue damage are discussed based upon model predictions of stress as functions of cover layer thickness and viscosity. PMID- 28004227 TI - Trichophyton rubrum Infection Characterized by Majocchi's Granuloma and Deeper Dermatophytosis: Case Report and Review of Published Literature. AB - Infections caused by Trichophyton rubrum are very common in dermatological disease. It most often appears as superficial cutaneous mycosis, such as tinea manuum, tinea pedis, and tinea corporis. However, deep infection caused by T. rubrum was rarely reported. We describe a case of mixed type of deep infection caused by T. rubrum in a 45-year-old man with no significant immunodeficiency. This patient had a history of onychomycosis on the toenails without regular treatment for nearly 6 years. And, he had erythema, papule, and nodules on the submandibular area, neck, and chest for almost 1 year. After treated with intravenous infusion of cefotiam for 2 weeks, the lesion aggravated. The fungal direct microscopic examination of pyogenic fluid was positive, and the fungal cultures that produced reddish-brown and yellow pigment showed cottony, wooly, and white colony. After the DNA sequencing, it was identified as T. rubrum. We gave the patient oral terbinafine 250 mg per day and bifonazole cream for external use. Six months later, the patient's skin lesion was disappeared, and healthy nail growth was seen in two-thirds of nail bed. The terbinafine is effective against deep infection caused by T. rubrum. PMID- 28004226 TI - Prediction of femoral strength using 3D finite element models reconstructed from DXA images: validation against experiments. AB - Computed tomography (CT)-based finite element (FE) models may improve the current osteoporosis diagnostics and prediction of fracture risk by providing an estimate for femoral strength. However, the need for a CT scan, as opposed to the conventional use of dual-energy X-ray absorptiometry (DXA) for osteoporosis diagnostics, is considered a major obstacle. The 3D shape and bone mineral density (BMD) distribution of a femur can be reconstructed using a statistical shape and appearance model (SSAM) and the DXA image of the femur. Then, the reconstructed shape and BMD could be used to build FE models to predict bone strength. Since high accuracy is needed in all steps of the analysis, this study aimed at evaluating the ability of a 3D FE model built from one 2D DXA image to predict the strains and fracture load of human femora. Three cadaver femora were retrieved, for which experimental measurements from ex vivo mechanical tests were available. FE models were built using the SSAM-based reconstructions: using only the SSAM-reconstructed shape, only the SSAM-reconstructed BMD distribution, and the full SSAM-based reconstruction (including both shape and BMD distribution). When compared with experimental data, the SSAM-based models predicted accurately principal strains (coefficient of determination >0.83, normalized root-mean square error <16%) and femoral strength (standard error of the estimate 1215 N). These results were only slightly inferior to those obtained with CT-based FE models, but with the considerable advantage of the models being built from DXA images. In summary, the results support the feasibility of SSAM-based models as a practical tool to introduce FE-based bone strength estimation in the current fracture risk diagnostics. PMID- 28004228 TI - Erratum to: Thoracic and cardiovascular surgery in Japan during 2013 : Annual report by The Japanese Association for Thoracic Surgery. PMID- 28004229 TI - Patient-specific 3D hemodynamics modelling of left coronary artery under hyperemic conditions. AB - The purpose of this study is to investigate the effect of various degrees of percentage stenosis on hemodynamic parameters during the hyperemic flow condition. 3D patient-specific coronary artery models were generated based on the CT scan data using MIMICS-18. Numerical simulation was performed for normal and stenosed coronary artery models of 70, 80 and 90% AS (area stenosis). Pressure, velocity, wall shear stress and fractional flow reserve (FFR) were measured and compared with the normal coronary artery model during the cardiac cycle. The results show that, as the percentage AS increase, the pressure drop increases as compared with the normal coronary artery model. Considerable elevation of velocity was observed as the percentage AS increases. The results also demonstrate a recirculation zone immediate after the stenosis which could lead to further progression of stenosis in the flow-disturbed area. Highest wall shear stress was observed for 90% AS as compared to other models that could result in the rupture of coronary artery. The FFR of 90% AS is found to be considerably low. PMID- 28004230 TI - In Silico Mining of Conserved miRNAs of Indian Catfish Clarias batrachus (Linnaeus, 1758) from the Contigs, ESTs, and BAC End Sequences. AB - MicroRNAs are small non-coding RNAs which play significant role in RNA interference. The present work deals with mining of the conserved miRNA and their target genes from the contigs, ESTs, and BAC end sequences of commercially important catfish, Clarias batrachus, from India. A total of 138, 1 and 1 conserved pre-miRNA sequences, were mined from the contigs, ESTs, and BAC end sequences, respectively. The analysis of families of the conserved pre-miRNA revealed conservation of the fish-specific family mir-430 and other important families, such as mir-455, let-7, mir-133, and mir-137. The mir-455 is involved in hypoxia signaling, let-7 family represents potential anti-tumor molecules involved in human cancer therapy, whereas mir-133 and mir-137 have high therapeutic potentials. Using an alternate computational in silico approach, mining of mature miRNAs resulted in identification of 210 mature miRNAs from contigs, 1 from EST, and 2 each from forward as well as reverse BAC end sequences. Target prediction of these putative miRNAs resulted in the identification of 66,758 and 18,747 target genes in C. batrachus and Danio rerio, respectively. Functional annotation of these miRNAs indicated their involvement in diverse biological functions. The findings of the present study can serve as a valuable resource for further functional genomics studies in C. batrachus. PMID- 28004231 TI - Bipolar 1 As Graphic Memoir. PMID- 28004232 TI - Splicing features in the expression of the complementary-sense genes of Beet curly top Iran virus. AB - Beet curly top Iran virus (BCTIV) is a distinct geminivirus which has been reported from sugar-beet-growing farms in Iran. In this study, the role of the splicing in expression of complementary-sense genes of BCTIV was studied. Total RNA was extracted from BCTIV-infected tissue, and the predicted intron position of complementary-sense mRNA transcripts was amplified by RT-PCR followed by cloning of the amplicons. Sequence confirmed that both spliced and unspliced mRNAs are synthesized by the same transcription unit. Sequence comparison showed that a 155-nt segment (intron) corresponding to nucleotides 1890-2044 of the viral genome has been removed from the latter transcript and therefore fusion of the C1:C2 genes resulted creation of a continuous reading frame for potential production of intact replication initiator protein (Rep). BCTIV intron comprises of most consensus splicing signals required for splicing in eukaryotes and several plant viruses including mastre- and capulaviruses. PMID- 28004233 TI - Investing in Relationships and Teams to Support Managing Complexity. PMID- 28004234 TI - Predictors of Treatment Effectiveness for Youth with ASD and Comorbid Anxiety Disorders: It all Depends on the Family? AB - The study aimed to explore predictors of treatment effectiveness in a sample of 79 children with ASD who received cognitive behavioral therapy (CBT) for their anxiety disorders. Severity of anxiety disorders and anxiety symptoms were used to measure treatment effectiveness and was assessed pre-treatment, post treatment, 3 months-, 1 and 2 years after CBT. Child characteristics and maternal anxiety did not predict treatment effect. Children with anxious fathers and children in 'un-involved' families had less anxiety symptoms at pre-treatment and displayed a less steep decline. Children from 'authoritarian' families showed higher pre-treatment anxiety levels but responded quite well to treatment. Findings stress the importance of parent (father) and family factors in the treatment of anxiety disorders in youth with ASD. PMID- 28004235 TI - Hypopituitarism-needs modern individualized treatment. PMID- 28004236 TI - Ghrelin is independently associated with anti-mullerian hormone levels in obese but not non-obese women with polycystic ovary syndrome. AB - Ghrelin is an endogenous appetite stimulant that may have a role in ovarian function. Women with polycystic ovary syndrome have anovulation and frequently weight management issues; however the associations between ghrelin and hormonal markers in polycystic ovary syndrome have not been well studied. In order to characterize the association between total ghrelin levels and ovarian function and the possible modification of this relationship by obesity, we examined total ghrelin levels and anti-mullerian hormone, total testosterone, and insulin in obese and non-obese women with and without polycystic ovary syndrome. Total ghrelin levels were lower in obese women with polycystic ovary syndrome (n = 45) compared to obese controls (n = 33) (p = 0.005), but similar in non-obese women with polycystic ovary syndrome (n = 20) compared to non-obese controls (n = 21) (p = NS). In the obese polycystic ovary syndrome group, anti-mullerian hormone was associated with ghrelin levels independent of age, insulin, and total testosterone (p = 0.008). There was no association between total ghrelin and anti mullerian hormone levels in non-obese women with polycystic ovary syndrome, non obese controls, or obese controls (p = NS). Our results provide evidence for a potential relationship between ghrelin and ovarian function in obese women with polycystic ovary syndrome that was not observed in non-obese women with polycystic ovary syndrome or controls. PMID- 28004237 TI - Sanggenol F exerts anti-diabetic effects via promoting adipocyte differentiation and modifying adipokines expression. AB - Adipose tissue is not only a lipid storage site, but also a well-known endocrine organ. Dysfunction of adipose tissue is associated with irregular lipid metabolism, ectopic lipid accumulation and insulin resistance. It is proposed that modulating on adipose tissue is a reasonable way to ameliorate glucose and lipid metabolism. (+/-)-sanggenol F (SGF, purity >98.5%) was synthesized as a racemic mixture of natural (+)-sanggenol F. In this study, SGF was found to promote adipocyte differentiation, enhance insulin sensitivity, and upregulate beneficial adipokines expression in 3T3-L1 cells. Furthermore, in vivo study showed that treatment with SGF for 4 weeks improved glucose metabolism, by decreasing fasting blood glucose and enhancing insulin sensitivity. It also improved lipid metabolism, with reduced serum lipid level and ameliorated hepatic steatosis in db/db mice. During the process of target finding, we found that SGF had multiple activities of protein tyrosine phosphatase 1B inhibition, peroxisome proliferator-activated receptor gamma and peroxisome proliferator-activated receptor alpha agonism. These results showed the potential of SGF as a candidate for the therapy of type 2 diabetes. PMID- 28004238 TI - Development and validation of a questionnaire to measure moral distress in community pharmacists. AB - Background Pharmacists work within a highly-regulated occupational sphere, and are bound by strict legal frameworks and codes of professional conduct. This regulatory environment creates the potential for moral distress to occur due to the limitations it places on acting in congruence with moral judgements. Very little research regarding this phenomenon has been undertaken in pharmacy: thus, prominent research gaps have arisen for the development of a robust tool to measure and quantify moral distress experienced in the profession. Objective The aim of this study was to develop an instrument to measure moral distress in community pharmacists. Setting Community pharmacies in the United Kingdom. Method This study adopted a three-phase exploratory sequential mixed-method design. Three semi-structured focus groups were then conducted to allow pharmacists to identify and explore scenarios that cause moral distress. Each of the identified scenarios were developed into a statement, which was paired with twin seven-point Likert scales to measure the frequency and intensity of the distress, respectively. Content validity, reliability, and construct validity were all tested, and the questionnaire was refined. Main outcome measure The successful development of the valid instrument for use in the United Kingdom. Results This research has led to the development of a valid and reliable instrument to measure moral distress in community pharmacists in the UK. The questionnaire has already been distributed to a large sample of community pharmacists. Conclusion Results from this distribution will be used to inform the formulation of coping strategies for dealing with moral distress. PMID- 28004239 TI - Impact of team-versus ward-aligned clinical pharmacy on unintentional medication discrepancies at admission. AB - Background Medication reconciliation at admission to hospital reduces the prevalence of medication errors. Strategies are needed to ensure timely and efficient delivery of this service. Objective To investigate the effect of aligning clinical pharmacy services with consultant teams, by pharmacists attending post-admission ward rounds, in comparison to a ward-based service, on prevalence of unintentional unresolved discrepancies 48 h into admission. Setting A 243-bed public university teaching hospital in Ireland. Method A prospective, uncontrolled before-after observational study. A gold standard preadmission medication list was completed for each patient and compared with the patient's admission medication prescription and discrepancies were noted. Unresolved discrepancies were examined at 48 h after admission to determine if they were intentional or unintentional. Main outcome measured Number of patients with one or more unintentional, unresolved discrepancy 48 h into admission. Results Data were collected for 140 patients, of whom 73.5% were over 65 years of age. There were no differences between before (ward-aligned) and after (team-aligned) groups regarding age, number of medications or comorbidities. There was a statistically significant reduction in the prevalence of unintentional, unresolved discrepancy(s) per patient (67.3 vs. 27.3%, p < 0.001) and per medication (13.7 vs. 4.1%, p < 0.001) between the groups, favouring the team-based service. The effect remained statistically significant having adjusted for patient age, number of medications and comorbidities (adjusted odds ratio 4.9, 95% confidence interval 2.3-10.6). Conclusion A consultant team-based clinical pharmacy service contributed positively to medication reconciliation at admission, reducing the prevalence of unintentional, unresolved discrepancy(s) present 48 h after admission. PMID- 28004240 TI - Silencing of an alpha-dioxygenase gene, Ca-DOX, retards growth and suppresses basal disease resistance responses in Capsicum annum. AB - Alpha-dioxygenases (alpha-DOX) catalyzing the primary oxygenation of fatty acids to oxylipins were recently found in plants. Here, the biological roles of the pepper alpha-DOX (Ca-DOX) gene, which is strongly induced during non-host pathogen infection in chili pepper, were examined. Virus-induced gene silencing demonstrated that down-regulation of Ca-DOX enhanced susceptibility to bacterial pathogens and suppressed the hypersensitive response via the suppression of pathogenesis-related genes such as PR4, proteinase inhibitor II and lipid transfer protein (PR14). Ca-DOX-silenced pepper plants also exhibited more retarded growth with lower epidermal cell numbers and reduced cell wall thickness than control plants. To better understand regulation of Ca-DOX, transgenic Arabidopsis plants harboring the beta-glucuronidase (GUS) reporter gene driven from a putative Ca-DOX promoter were generated. GUS expression was significantly induced upon avirulent pathogen infection in transgenic Arabidopsis leaves, whereas GUS induction was relatively weak upon virulent pathogen treatment. After treatment with plant hormones, early and strong GUS expression was seen after treatment of salicylic acid, whereas ethylene and methyl jasmonate treatments produced relatively weak and late GUS signals. These results will enable us to further understand the role of alpha-DOX, which is important in lipid metabolism, defense responses, and growth development in plants. PMID- 28004241 TI - The Arabidopsis THO/TREX component TEX1 functionally interacts with MOS11 and modulates mRNA export and alternative splicing events. AB - KEY MESSAGE: We identify proteins that associate with the THO core complex, and show that the TEX1 and MOS11 components functionally interact, affecting mRNA export and splicing as well as plant development. TREX (TRanscription-EXport) is a multiprotein complex that plays a central role in the coordination of synthesis, processing and nuclear export of mRNAs. Using targeted proteomics, we identified proteins that associate with the THO core complex of Arabidopsis TREX. In addition to the RNA helicase UAP56 and the mRNA export factors ALY2-4 and MOS11 we detected interactions with the mRNA export complex TREX-2 and multiple spliceosomal components. Plants defective in the THO component TEX1 or in the mRNA export factor MOS11 (orthologue of human CIP29) are mildly affected. However, tex1 mos11 double-mutant plants show marked defects in vegetative and reproductive development. In tex1 plants, the levels of tasiRNAs are reduced, while miR173 levels are decreased in mos11 mutants. In nuclei of mos11 cells increased mRNA accumulation was observed, while no mRNA export defect was detected with tex1 cells. Nevertheless, in tex1 mos11 double-mutants, the mRNA export defect was clearly enhanced relative to mos11. The subnuclear distribution of TEX1 substantially overlaps with that of splicing-related SR proteins and in tex1 plants the ratio of certain alternative splicing events is altered. Our results demonstrate that Arabidopsis TEX1 and MOS11 are involved in distinct steps of the biogenesis of mRNAs and small RNAs, and that they interact regarding some aspects, but act independently in others. PMID- 28004242 TI - Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia-reperfusion injury. AB - Ischemic cardiac injury is the main contributor to heart failure, and the regenerative capacity of intrinsic stem cells plays an important role in tissue repair after injury. However, stem cells in aged individuals have reduced regenerative potential and aged tissues lack the capacity to renew. Growth differentiation factor 11 (GDF11), from the activin-transforming growth factor beta superfamily, has been shown to promote stem cell activity and rejuvenation. We carried out non-invasive targeted delivery of the GDF11 gene to the heart using ultrasound-targeted microbubble destruction (UTMD) and cationic microbubble (CMB) to investigate the ability of GDF11 to rejuvenate the aged heart and improve tissue regeneration after injury. Young (3 months) and old (21 months) mice were used to evaluate the expression of GDF11 mRNA in the myocardium at baseline and after ischemia/reperfusion (I/R) and myocardial infarction. GDF11 expression decreased with age and following myocardial injury. UTMD-mediated delivery of the GDF11 plasmid to the aged heart after I/R injury effectively and selectively increased GDF11 expression in the heart, and improved cardiac function and reduced infarct size. Over-expression of GDF11 decreased senescence markers, p16 and p53, as well as the number of p16+ cells in old mouse hearts. Furthermore, increased proliferation of cardiac stem cell antigen 1 (Sca-1+) cells and increased homing of endothelial progenitor cells and angiogenesis in old ischemic hearts occurred after GDF11 over-expression. Repetitive targeted delivery of the GDF11 gene via UTMD can rejuvenate the aged mouse heart and protect it from I/R injury. PMID- 28004243 TI - Zero-profile anchored cage reduces risk of postoperative dysphagia compared with cage with plate fixation after anterior cervical discectomy and fusion. AB - PURPOSE: To compare the rate of postoperative dysphagia between zero-profile anchored cage fixation (ZPC group) and cage with plate fixation (CP group) after anterior cervical discectomy and fusion (ACDF). METHODS: A meta-analysis of cohort studies between zero-profile anchored cage and conventional cage with plate fixation after ACDF for the treatment of cervical diseases from 2008 to May 2016. An extensive search of studies was performed in PubMed, Medline, Embase, Cochrane library and Google Scholar. Dysphagia rate was extracted. Data analysis was conducted with RevMan 5.2. RESULTS: Sixteen trials involving 1066 patients were included in this meta-analysis. The results suggested that the ZPC group were associated with lower incidences of dysphagia than the CP group at postoperative immediately, 2 weeks, 2, 3, 6 and 12 months. In subgroup analysis, although significant differences were only found in the mild dysphagia at 3 and 6 months postoperatively and in the moderate dysphagia at 2 weeks after surgery; the ZPC group had a lower rate of postoperative dysphagia than the CCP group in short, medium and long term follow-up periods. CONCLUSIONS: Zero-profile anchored cage had a lower risk of postoperative dysphagia than cage with plate. PMID- 28004244 TI - Gender differences after lumbar sequestrectomy: a prospective clinical trial using quantitative sensory testing. AB - BACKGROUND: Quantitative sensory testing (QST) gained popularity to evaluate the time course of recovery in sensory dysfunction and the results of different treatment options. Concerning sex differences in lumbar spine surgery, female gender seems to play a major role as a negative prognostic factor in different spinal disorders. For this purpose, we hypothesised that there are also comparable differences in pain patterns in men and women after lumbar sequestrectomy using QST. METHODS: We applied the QST protocol of the German Research Network on Neuropathic Pain in 53 patients (21 women and 32 men) with a single lumbar disc herniation confirmed on MRI treated by a lumbar sequestrectomy. Further evaluation included a detailed medical history, a physical examination, and various questionnaires: Beck-Depression-Inventory, Oswestry Disability Index, Core Outcome Measure Index, painDETECT-Questionnaire and EQ-5D thermometer. RESULTS: Our analyses showed lower heat thresholds in females preoperatively, that adjusted to that of males 1 week postoperatively. Pressure pain thresholds were lower in women as well, but differed between genders throughout the study. Vibration perception deficits resolve earlier in female than in male patients. Both, women and men, had an excellent overall improvement, postoperatively. CONCLUSION: Our results clearly revealed pre- and postoperative differences in pain perception between genders. These differences have to be taken into account in the evaluation of outcome between genders. Therefore, QST seems to be a good method to evaluate the time course of recovery after surgery. PMID- 28004245 TI - Repairing the ruptured annular fibrosus by using type I collagen combined with citric acid, EDC and NHS: an in vivo study. AB - OBJECTIVES: To explore the effect of citric acid (CA)-1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC)/N-hydroxysuccinimide (NHS) collagen gel on repairing annular defects. METHODS: Type I collagen was extracted from the rat tail tendon and crosslinked with CA at different mass ratio using EDC and NHS as crosslinking reagents to prepare four kinds of collagen gels. Forty-eight adult SD rats were divided into first sham group (n = 8), second group (n = 10) which was punctured and injected with CA-EDC/NHS collagen gel, third group (n = 10) which was punctured and injected with CA-EDC/NHS collagen gel, fourth group (n = 10) which was punctured and injected with EDC/NHS collagen gel, and fifth group (n = 10) which was punctured and untreated. X-ray images and magnetic resonance imaging images were obtained before puncture and at the 1st, 2nd, and 4th week after puncture. At each time point, disc height index (%DHI), voxel count and modified MRI Pfirrmann grading were collected and analyzed. All animals were killed at the 4th week to study the morphology. RESULTS: The discs in the second group showed only slight degeneration compared with the healthy discs, and the results of %DHI (average 79%), voxel count (average 126.9), Pfirrmann grading (average grade 1.3) and morphology in the second group indicated less degeneration tendency compared with the other three puncture groups at the 4th week (P < 0.05). The annular fibrosus was partially repaired by the collagen gels that bridged the defects. CONCLUSIONS: CA-EDC/NHS collagen gel is capable of repairing annular defects induced by needle puncture, which may be closely related to the dose of CA. PMID- 28004246 TI - Reproducibility of three-dimensional posterior cranial base angles using low-dose computed tomography. AB - OBJECTIVES: One of the key aspects of three-dimensional (3D) craniofacial cephalometry is the measurement of posterior cranial base angle as this area is deeply involved in craniofacial development. The purpose of our retrospective study was to define the best reproducible 3D posterior cranial base angles among five 3D angles transposed from 2D cephalometry (Cousin, BL1 of Ross and Ravosa, Bjork, Delaire, CBA4 of Liberman) and seven 3D angles based on physical anthropology studies and on new concepts (R1 to R7). The null hypothesis was that all 3D posterior cranial base angles were equally reproducible. MATERIAL AND METHODS: We used a preoperative low-dose computed tomography (CT) data from 20 adult patients undergoing orthognathic surgery after approval by local ethical committee. Two independent observers performed two series of 23 3D landmark identifications on 3D CT surface rendering of each patient using Maxilim software. Then, the same observers performed twice 3D cephalometric analyses (23 landmarks, 4 midpoints, 19 planes) that provided the automatic measurement of 12 posterior cranial base angles. RESULTS: Inter-observer correlation coefficient varied from 0.545 (Cousin) to 0.695 (CBA4 of Liberman) and from -0.177 (R2) to 0.827 (R4). CONCLUSIONS: The null hypothesis was rejected. The most reproducible angle was 3D angle R4 based on "basion," "superior optic" (right, left), and "crista galli inferior" landmarks. CLINICAL RELEVANCE: R4 angle might be used as reference 3D posterior cranial base angle in further clinical studies involving 3D cephalometry as a diagnostic tool for orthodontics and for orthognathic surgery. PMID- 28004247 TI - Efficacy of desensitizing products containing 8% arginine and calcium carbonate for hypersensitivity relief in MIH-affected molars: an 8-week clinical study. AB - OBJECTIVES: The objective of this study was to compare the efficacy in reducing hypersensitivity in molar incisor hypomineralization (MIH)-affected molars immediately and over 8 weeks combining a single in-office application and a homed based program with desensitizing products containing 8% arginine and calcium carbonate. MATERIALS AND METHODS: Nineteen children with at least one MIH affected molar with hypersensitivity were included. Hypersensitivity was assessed with an evaporative (air) stimulus and a tactile stimulus. Each child received a single in-office treatment with a desensitizing paste containing 8% arginine and calcium carbonate (elmex Sensitive Professional desensitizing paste), followed by 8 weeks of brushing twice daily with a desensitizing toothpaste containing 8% arginine, calcium carbonate with 1450 ppm fluoride (elmex Sensitive Professional toothpaste), using the elmex Sensitive Professional toothbrush. Additionally, the corresponding mouthwash (elmex Sensitive Professional mouthwash) was used. Clinical assessments were made at baseline, immediately after the in-office treatment and after 1, 2, 4 and 8 weeks of brushing twice daily. RESULTS: Fifty six molars with an air blast hypersensitivity score of 2 or 3 (Schiff Cold Air Sensitivity Scale) were included. Application of the desensitizing paste decreased hypersensitivity significantly immediately and throughout the 8 weeks recalls (p < 0.001). CONCLUSIONS: In conclusion, 8% arginine and calcium carbonate were able to reduce hypersensitivity successfully during this 8-week trial. CLINICAL RELEVANCE: Hypersensitivity is a major complaint in patients with MIH. This is the first study evaluating the desensitizing effect of a desensitizing paste containing 8% arginine and calcium carbonate in patients with MIH. PMID- 28004248 TI - Message from the Editor-in-Chief regarding ethical violations. PMID- 28004249 TI - Delayed perforation occurring on the 24th day after endoscopic submucosal dissection for early gastric cancer. AB - Delayed perforation occurs after 0.5% of endoscopic submucosal dissection (ESD) procedures for early gastric cancer (EGC). This complication can occur within a few hours or days after ESD. There are few reports in the English literature concerning patients who developed delayed perforation after ESD for EGC. An 81 year-old woman was referred to the emergency department of our hospital on the 24th day after ESD because of abdominal pain. We diagnosed her with delayed perforation with peritonitis after ESD for EGC using computed tomography (CT) and esophagogastroduodenoscopy (EGD). We performed primary closure with interrupted sutures covered via pedicled omentoplasty. The patient was discharged 13 days after surgery without any postoperative complications. Delayed perforation is generally treated with conservative, surgical, or endoscopic methods. Several benefits of endoscopic clipping have been reported. However, in the present case, we performed emergency surgery while considering possible fatal complications, such as severe peritonitis. It is important to recognize delayed perforation in the differential diagnosis. The decision to perform surgery should be made after carefully considering the degree of perforation based on EGD, CT findings, and patient conditions. PMID- 28004251 TI - Identification and sequence determination of a new chrysovirus infecting the entomopathogenic fungus Isaria javanica. AB - A new double-stranded RNA (dsRNA) mycovirus has been identified in the isolate NB IFR-19 of the entomopathogenic fungus Isaria javanica. Isaria javanica chrysovirus-1 (IjCV-1) constitutes a new member of the Chrysoviridae family, and its genome is made up of four dsRNA elements designated dsRNA1, 2, 3 and 4 from largest to smallest. dsRNA1 and dsRNA2 encode an RNA-dependent RNA polymerase (RdRp) and a coat protein (CP), respectively. dsRNA3 and 4 encode hypothetical proteins of unknown function. IjCV-1 constitutes the first report of a chrysovirus infecting the entomopathogenic fungus Isaria javanica. PMID- 28004250 TI - The genome sequence of Brassica campestris chrysovirus 1, a novel putative plant infecting tripartite chrysovirus. AB - A putative chrysovirus recovered from Brassica campestris var. purpurea and provisionally named "Brassica campestris chrysovirus 1" (BrcCV1) was sequenced. The genome of the putative BrcCV1 consists of three double-stranded RNAs (dsRNAs) comprising 3,639 (dsRNA 1), 3,567 (dsRNA 2) and 3,337 (dsRNA 3) base pairs, respectively, each containing a single open reading frame (ORF 1-3). The putative proteins encoded by ORF 1-3 show homologies to RdRp, CP and chryso-P3 of approved or tentative chrysoviruses. In addition, the three dsRNAs of BrcCV1 contain highly conserved 5' and 3' untranslated regions (UTRs) in a way similar to known chrysoviruses. In a phylogenetic tree based on the conserved amino acid sequences of the RdRps of chrysoviruses, totiviruses and partitiviruses, the putative BrcCV1 formed a separate clade with Raphanus sativus chrysovirus 1 (RasCV1), a putative trisegmented, plant-infecting chrysovirus, in the family Chrysoviridae. PMID- 28004252 TI - Genomic characterization of a bovine viral diarrhea virus subtype 1i in Brazil. AB - Bovine viral diarrhea virus 1 (BVDV-1) belongs to the genus Pestivirus within the family Flaviviridae. Based on the 5' untranslated region (UTR) sequence, BVDV-1 can be divided into at least 17 subtypes (1a though 1q). BVDV-1i is an uncommon subtype that has been reported in the United Kingdom and Uruguay. Here, we report the complete genome sequence of the first subtype 1i BVDV-1 (strain ACM/BR/2016) isolated from cattle in southern Brazil. The genome is 12,231 nt in length and contains a single ORF that encodes a polyprotein of 3,896 amino acids, flanked by 5' and 3'UTRs of 325 and 220 nt, respectively. Phylogenetic inferences based on the whole genome, the 5'UTR, and the Npro region showed that strain ACM/BR/2016 is closely related to previously characterized BVDV-1i members. Its 5'UTR shares the highest nucleotide identity (90.5%) with BVDV-1i strains from United Kingdom, and its Npro is most closely related to that of a Uruguayan strain (90.6%). To the best of our knowledge, this is the first BVDV-1i strain from which the whole genome has been completely sequenced and characterized. The complete genome of a BVDV-1i will help future studies on pestivirus evolution and heterogeneity. PMID- 28004253 TI - A novel single-stranded RNA virus in Nesidiocoris tenuis. AB - The complete genome sequence of a novel single-stranded RNA virus in Nesidiocoris tenuis was determined by RNA-seq and rapid amplification of cDNA ends (RACE) methodologies and was named N. tenuis virus 1. The genomic RNA was 3970 nucleotides (nt) in length and contained two putative open reading frames (ORFs). ORF1 encoded a polypeptide with 283 amino acids containing a viral (superfamily 1) RNA helicase (Hel) domain, and ORF2 encoded a polypeptide with 294 amino acids containing an RNA-dependent RNA polymerase (RdRP) domain. Phylogenetic analysis using the deduced amino acid sequences indicated that the N. tenuis virus 1 clustered with Blackford virus; however, the low bootstrap values and unique genomic structure suggested that the virus is a prototype of a new type of unclassified viruses. The prevalence of N. tenuis virus 1 infection in field populations of N. tenuis differed between three locations, with 28.32% of the 113 sampled individuals testing positive for the virus. PMID- 28004254 TI - Identification of novel Newcastle disease virus sub-genotype VII-(j) based on the fusion protein. AB - Newcastle disease virus (NDV) is believed to be the cause of fatal poultry disease worldwide. The fusion (F) protein plays a key role in virus pathogenesis, and it is also used for Newcastle disease virus classification. In this study, we determined the complete coding sequence of the F gene in new velogenic NDV isolates with an intravenous pathogenicity index (IVPI) of 1.8 and a mean death time (MDT) of 72 or 48 h. Complete sequences of the F genes of new Iranian isolates were amplified and sequenced in both directions. These isolates were compared to 195 nucleotide sequences from GenBank (available as of 07/17/2016). A phylogenetic tree was constructed for the F gene, using MEGA6 software with statistical analysis based on 500 bootstrap replicates. Evolutionary distances revealed that the new virulent isolates from Iran belonged to genotype VII in a new distinct sub-genotype named VII-(j). This new sub-genotype showed 3% divergence from genotype VIId. Recombination analysis showed that these new isolates were not recombinant NDVs. PMID- 28004255 TI - Robustness, flexibility, and sensitivity in a multifunctional motor control model. AB - Motor systems must adapt to perturbations and changing conditions both within and outside the body. We refer to the ability of a system to maintain performance despite perturbations as "robustness," and the ability of a system to deploy alternative strategies that improve fitness as "flexibility." Different classes of pattern-generating circuits yield dynamics with differential sensitivities to perturbations and parameter variation. Depending on the task and the type of perturbation, high sensitivity can either facilitate or hinder robustness and flexibility. Here we explore the role of multiple coexisting oscillatory modes and sensory feedback in allowing multiphasic motor pattern generation to be both robust and flexible. As a concrete example, we focus on a nominal neuromechanical model of triphasic motor patterns in the feeding apparatus of the marine mollusk Aplysia californica. We find that the model can operate within two distinct oscillatory modes and that the system exhibits bistability between the two. In the "heteroclinic mode," higher sensitivity makes the system more robust to changing mechanical loads, but less robust to internal parameter variations. In the "limit cycle mode," lower sensitivity makes the system more robust to changes in internal parameter values, but less robust to changes in mechanical load. Finally, we show that overall performance on a variable feeding task is improved when the system can flexibly transition between oscillatory modes in response to the changing demands of the task. Thus, our results suggest that the interplay of sensory feedback and multiple oscillatory modes can allow motor systems to be both robust and flexible in a variable environment. PMID- 28004256 TI - Typical predictive eye movements during action observation without effector specific motor simulation. AB - When watching someone reaching to grasp an object, we typically gaze at the object before the agent's hand reaches it-that is, we make a "predictive eye movement" to the object. The received explanation is that predictive eye movements rely on a direct matching process, by which the observed action is mapped onto the motor representation of the same body movements in the observer's brain. In this article, we report evidence that calls for a reexamination of this account. We recorded the eye movements of an individual born without arms (D.C.) while he watched an actor reaching for one of two different-sized objects with a power grasp, a precision grasp, or a closed fist. D.C. showed typical predictive eye movements modulated by the actor's hand shape. This finding constitutes proof of concept that predictive eye movements during action observation can rely on visual and inferential processes, unaided by effector-specific motor simulation. PMID- 28004257 TI - Literature Review of Cosmetic Procedures in Men: Approaches and Techniques are Gender Specific. AB - The proportion of men receiving non-surgical cosmetic procedures has risen substantially in recent years. Various physiologic, anatomic, and motivational considerations differentiate the treatments for male and female patients. Nevertheless, research regarding approaches to the male cosmetic patient is scarce. We sought to provide an overview and sex-specific discussion of the most popular cosmetic dermatologic procedures pursued by men by conducting a comprehensive literature review pertaining to non-surgical cosmetic procedures in male patients. The most common and rapidly expanding non-surgical interventions in men include botulinum toxin, filler injection, chemical peels, microdermabrasion, laser resurfacing, laser hair removal, hair transplantation, and minimally invasive techniques for adipose tissue reduction. Important sex specific factors associated with each of these procedures should be considered to best serve the male cosmetic patient. PMID- 28004258 TI - Hints for control of infection in unique extrahepatic vertebral alveolar echinococcosis. AB - The prognosis of vertebral alveolar echinococcosis (AE) is poor. We report on the unique outcome of a patient with preexisting liver cirrhosis, in whom a diagnosis of vertebral AE was established on vertebral histopathology (D4 corporectomy in 2010 for paraplegia). Therapeutic drug monitoring of albendazole (ABZ) showed that a low dosage was appropriate. The patient recovered and ABZ withdrawal was decided in 2014, with no relapse 18 months later. In this patient, infection was purely or mainly localized in the dorsal spine, and this may have been favored by liver cirrhosis. A longer follow-up is, however, needed to confirm cure. PMID- 28004259 TI - Can a Multifaceted Intervention Including Motivational Interviewing Improve Medication Adherence, Quality of Life, and Mortality Rates in Older Patients Undergoing Coronary Artery Bypass Surgery? A Multicenter, Randomized Controlled Trial with 18-Month Follow-Up. AB - BACKGROUND: Patients undergoing coronary artery bypass graft (CABG) surgery are required to take a complex regimen of medications for extended periods, and they may have negative outcomes because they struggle to adhere to this regimen. Designing effective interventions to promote medication adherence in this patient group is therefore important. OBJECTIVE: The present study aimed to evaluate the long-term effects of a multifaceted intervention (psycho-education, motivational interviewing, and short message services) on medication adherence, quality of life (QoL), and mortality rates in older patients undergoing CABG surgery. METHODS: Patients aged over 65 years from 12 centers were assigned to the intervention (EXP; n = 144) or treatment-as-usual (TAU; n = 144) groups using cluster randomization at center level. Medication adherence was evaluated using the Medication Adherence Rating Scale (MARS), pharmacy refill rate, and lipid profile; QoL was evaluated using Short Form-36. Data were collected at baseline; 3, 6, and 18 months after intervention. Survival status was followed up at 18 months. Multi-level regressions and survival analyses for hazard ratio (HR) were used for analyses. RESULTS: Compared with patients who received TAU, the MARS, pharmacy refill rate, and lipid profile of patients in the EXP group improved 6 months after surgery (p < 0.01) and remained so 18 months after surgery (p < 0.01). QoL also increased among patients in the EXP group as compared with those who received TAU at 18 months post-surgery (physical component summary score p = 0.02; mental component summary score p = 0.04). HR in the EXP group compared with the TAU group was 0.38 (p = 0.04). CONCLUSION: The findings suggest that a multifaceted intervention can improve medication adherence in older patients undergoing CABG surgery, with these improvements being maintained after 18 months. QoL and survival rates increased as a function of better medication adherence. ClinicalTrials.gov NCT02109523. PMID- 28004260 TI - The influence of closure technique in total laryngectomy on the development of a pseudo-diverticulum and dysphagia. AB - OBJECTIVE: In total laryngectomy, the neopharynx can be closed in several ways. It is suggested that a pseudo-diverticulum is seen more frequently in patients closed with vertical closure than with "T"-shaped closure, causing postoperative dysphagia. We report the results of patients treated with vertical closure and "T"-shaped closure with regard to the formation of a pseudo-diverticulum and postoperative dysphagia. METHODS: In our retrospective cohort study, we identified 117 consecutive laryngectomized patients treated in the VU University Medical Center of Amsterdam between March 2009 and December 2013. Evaluations with statistical analysis of postoperative outcome measures (the formation of a pseudo-diverticulum and dysphagia), qualitative and quantitative variables were conducted. RESULTS: Patient demographics were similar between the vertical-shaped closure and the "T"-shaped closure groups. In 84.6% of patients with vertical closure, a pseudo-diverticulum was seen compared to 18.5% with "T"-shaped closure (p < 0.001). Dysphagia was increasingly seen in patients with a pseudo diverticulum (60.5%) compared to patients without a pseudo-diverticulum (39.5%) (p = 0.090). CONCLUSION: Formation of a pseudo-diverticulum is more frequently seen in laryngectomy patients closed with vertical closure than in patients closed with "T"-shaped closure of the neopharynx. It is favorable to implement "T"-shaped closure in laryngectomy. PMID- 28004261 TI - The therapy with ethosomes containing 5-fluorouracil for laryngotracheal stenosis in rabbit models. AB - The aim of this study is to evaluate the efficacy of ethosomes encapsulated with 5-fluorouracil (5-FU) in treatment of laryngotracheal stenosis in rabbit models. The 5-FU ethosome was prepared by the thin film hydration method, and the amorphous, size distribution and the encapsulation efficiency was investigated. The tracheal mucosa were scraped about 0.5 cm with a nylon brush to induce the scar in airway grow, then models were divided into three groups: 5-FU ethosome group, 5-FU group and saline group, drug were injected into scar of every group by paracentesis guided under endoscope, respectively. The stenosis states were observed under laryngo fiberscope immediate, 7, 14 and 21 days after administrated. Airway stenosis of 5-FU ethosome group has no significant difference when compared with 5-FU group at 7 days after administration, but 5-FU ethosome significantly reduced the airway stenosis after 21-day administration when compared with 5-FU group again and has no restenosis during the period under observation. The fact that ethosomes encapsulated with 5-FU were effective for laryngotracheal stenosis suggests that it has potential as a new method for ameliorating airway stenosis originating from granulation tissue. PMID- 28004263 TI - Transoral robotic surgery for the pediatric head and neck surgeries. AB - Pediatric robotic surgery is a relatively new technology that has been shown to be safe and feasible for a number of pediatric procedures. Our literature analysis was performed using Pubmed database between January 2005 and December 2015, using key words: "robotic," "robotic surgery," "TORS," "pediatric," "children," "head and neck," and "da Vinci". We selected only publications in English. Eight published reports met the selection criteria. We totally found 41 patients, and the age range was between 2 months and 19 years. The cases are 16 only lingual tonsillectomy, nine base of tongue and lingual tonsillectomy, two malignant disease in the oropharynx (high-grade undifferentiated sarcoma and biphasic synovial sarcoma), one tongue base thyroglossal duct cyst, 11 laryngeal cleft cyst, one posterior glottic stenosis, and one congenital true vocal cord paralysis surgeries. One intraoperative complication was reported. No patient needed postoperative tracheotomy. Hospital duration time had a range of 1-16 days. TORS is new for pediatric patients in head and neck areas, and there were few reports. It is becoming increasingly used in head and neck surgeries and those reports above are encouraging for pediatric robotic airway surgeries in otolaryngology in the future. PMID- 28004262 TI - Diagnostic accuracy of tubomanometry R value in detecting the Eustachian tube pressure equalizing function. AB - Tubomanometry is a relatively novel Eustachian tube (ET) function testing method. A number of recent studies have utilized the R value of Tubomanometry as the main objective measure in reporting their outcome in balloon dilation of ET. There is, however, a lack of evidence concerning the reliability or validity of Tubomanometry measurements. The objectives of this study are to determine the accuracy of Tubomanometry for detecting ET opening as compared to tympanometry and determine its usefulness as a measure of ET function. Healthy subjects between ages 8 and 76 years with an intact tympanic membrane and no middle ear (ME) effusion were prospectively tested. Primary outcomes were the ET opening as determined by the Tubomanometry R value and the increase in ME pressure with tympanometry-measured in relation to a swallow at a nasopharyngeal pressure of 300 daPa. The accuracy of the tubomanometry R value for identifying a successful ET opening was made in reference to the change of ME pressure. A total of 280 measurements were available from 258 ears in 137 subjects. The presence of tubomanometry R value showed high sensitivity of detecting ET opening for the criteria of >5 daPa ME pressure increase (187/202) but low specificity for detecting ET non-opening (34/78). The R value criterion described in the original manuscripts on Tubomanometry is sensitive but not specific for ET opening. The need for validation of the tubomanometry test obviates its use as the main objective outcome measure for the balloon dilation of ET procedure. PMID- 28004264 TI - Current status of medical science in Turkey : Why this special issue? PMID- 28004265 TI - Active surveillance for low-risk prostate cancer in Austria: the online registry of the Qualitatspartnerschaft Urologie (QuapU). AB - BACKGROUND: Active surveillance (AS) is a well-recognized strategy to reduce the risk of overtreatment in men with low-risk prostate cancer. No data on this approach are available from Austria. METHODS: The Qualitatspartnerschaft Urologie (QuapU) developed an online database for patients managed with AS in Austria. Principal inclusion/exclusion criteria corresponded to those of the S3 prostate cancer guideline of German urologists: prostate-specific antigen (PSA) <10 ng/ml, Gleason score <7 (maximum 20% of biopsies being positive). Control visits were scheduled at 3-month intervals, control biopsies were scheduled at 12 and 36 months. RESULTS: To date 131 patients have been entered into this data base. Mean patient age is 64 years, 6% were younger than 50 years, two thirds of patients were aged 50-70 years and 25% were older than 70 years. Mean PSA value was 5.9 ng/ml (PSA 0-4 ng/ml: 15%; PSA >4-10 ng/ml: 85%). The prostate volume averaged 39 ml. The mean time under AS was 17.5 months (<12 months: 60%; >12 months: 40%). The AS adherence at 12 months was 85% and at 24 months 76%. To date, a total of 23 patients (17.6%) stopped AS. The most frequent reasons for discontinuing AS were patient wish for active treatment (43.5%) and PSA progression (30.4%). A histological progression was rarely seen (6.1%) and the control biopsy rate was low (19.8%). CONCLUSION: This study is the first description of AS in Austria and documents the feasibility of an online registry for AS. The data confirm the international experience with this approach with acceptable adherence rates. PMID- 28004266 TI - Long-term major adverse cardiac and cerebrovascular events (MACCE) rate : Comparison of retrograde and antegrade recanalization of chronic total coronary occlusions. AB - BACKGROUND: The recanalization success rate of chronic total occlusion (CTO) percutaneous coronary interventions (PCI) can be increased by the retrograde approach; however, the long-term outcome of patients undergoing retrograde procedures is unknown. AIM: We aimed to evaluate the long-term major adverse cardiac and cerebrovascular event (MACCE) rate (e.g. death, myocardial infarction, coronary artery bypass surgery and stroke) in patients after retrograde versus antegrade CTO-PCI. METHODS AND RESULTS: In a prospective single center study from January 2008 to June 2012, 396 consecutive patients with CTO (>=3 months old) were enrolled. The mean age was 63.4 +/- 10.3 years and 86.4% were male. The success rate of the total patient cohort was 88.6%. The retrograde PCI, only attempted after a failed antegrade intervention, was performed in 18% (n = 71) of patients. Long-term MACCE rate (mean follow up 2.3 +/- 1.6 years) was significantly higher in the unsuccessful compared to the successful CTO-PCI group (23.1% versus 9.4%, p = 0.01) and this was also the case in the subgroup of antegrade CTO-PCI. In the retrograde subgroup, however, procedural success had no impact on outcome. Patients with unsuccessful retrograde CTO-PCI had a significantly better collateral connection compared to patients with an unsuccessful antegrade approach. Independent predictors for MACCE were peripheral artery disease and an ejection fraction <=30%. CONCLUSION: The long-term MACCE rate after unsuccessful recanalization was significantly higher, which was driven by a higher MACCE rate after unsuccessful versus successful antegrade approaches. In contrast, procedural success in the retrograde group had no impact on outcome. PMID- 28004267 TI - Effect of delivery mode on neonatal outcome among preterm infants: an observational study. AB - BACKGROUND: The optimal mode of delivery as a predictor for outcomes in preterm infants is under debate. The purpose of this study was to evaluate the effect of the delivery mode on neonatal outcome among preterm infants in different birthweight categories. METHODS: A retrospective analysis of singleton preterm deliveries from 23 + 0 to 33 + 6 gestational weeks was performed. Infants were categorized based on birthweight as large for gestational age (LGA), appropriate for gestational age (AGA) and small for gestational age (SGA). The Apgar score at 5 min served as the main outcome parameter. A sensitivity analysis was performed to adjust for maternal age, parity and fetal malformations as potential confounders. RESULTS: Out of 1320 singleton preterm infants, 970 (73.5%) were delivered by cesarean section and 350 (26.5%) were delivered vaginally. The AGA infants between 23 + 0 and 27 + 6 weeks showed better outcomes after cesarean section (p < 0.01 from 23 + 0-24 + 6; p = 0.03 from 25 + 0-27 + 6), whereas AGA infants between 31 + 0 and 33 + 6 gestational weeks showed better outcomes after vaginal delivery (p = 0.02). Cesarean section was beneficial in extremely and very preterm SGA infants (p = 0.01 from 25 + 0-27 + 6; p = 0.02 from 28 + 0-30 + 6). The sensitivity analysis showed no confounding effect of other variables. CONCLUSION: There is a benefit from cesarean section in AGA preterm infants until 28 weeks of gestation and in SGA preterm infants until 31 weeks of gestation. Vaginal delivery should be chosen for moderately preterm AGA infants. PMID- 28004270 TI - Determinants of folate and vitamin B12 plasma levels in the French E3N-EPIC cohort. AB - PURPOSE: Impaired B vitamin status has been identified as a risk factor for major chronic diseases. This study aims at examining the determinants of plasma folate and vitamin B12 concentrations, considering lifestyle factors and MTHFR polymorphisms. METHODS: A total of 988 women aged 40-65 years from the French E3N cohort were investigated. Intakes of folate and vitamin B12 were assessed using food frequency questionnaires, and plasma concentrations were measured by microbiological assay. Dietary scores were computed to summarize folate and vitamin B12 dietary sources. MTHFR-C677T and MTHFR-A1298C were determined by Kaspar assay. Pearson's partial correlation coefficients and multivariable linear regression models were used to assess correlations between main determinants and plasma folate and vitamin B12 levels. RESULTS: The partial correlation coefficient between dietary intakes and plasma folate was 0.19 (p value <0.001) and 0.08 (p value = 0.008) for vitamin B12. Dietary scores were the main determinant of B vitamin plasma concentrations with a percent change per unit increase of 12.64% (p value <0.001) for folate and 7.6% (p value <0.001) for vitamin B12. Homozygous (T/T) or heterozygous (C/T) women for MTHFR-C677T had lower plasma folate concentrations [C/T: -6.48% (p value = 0.038) and T/T: 15.89% (p value <0.001)] compared to women carrying the C/C genotype. Other determinants of B vitamin plasma concentration include: smoking status for folate, and age and hormone replacement therapy for vitamin B12. CONCLUSIONS: We confirmed previous findings on the role of diet as main determinant of folate and vitamin B12 plasma concentrations. However, the impact of genetic polymorphisms and lifestyle factors on plasma B vitamin concentrations should not be neglected. PMID- 28004269 TI - Erratum to: Foods contributing to vitamin B6, folate, and vitamin B12 intakes and biomarkers status in European adolescents: The HELENA study. PMID- 28004268 TI - Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study. AB - PURPOSE: Proper evaluation of polyphenols intake at the population level is a necessary step in order to establish possible associations with health outcomes. Available data are limited, and so far no study has been performed in people with diabetes. The aim of this work was to document the intake of polyphenols and their major food sources in a cohort of people with type 2 diabetes and in socio demographic subgroups. METHODS: We studied 2573 men and women aged 50-75 years. Among others, anthropometry was measured by standard protocol and dietary habits were investigated by food frequency questionnaire (EPIC). The intake of polyphenols was evaluated using US Department of Agriculture and Phenol-Explorer databases. RESULTS: The mean total polyphenol intake was 683.3 +/- 5.8 mg/day. Non-alcoholic beverages represented the main food source of dietary polyphenols and provided 35.5% of total polyphenol intake, followed by fruits (23.0%), alcoholic beverages (14.0%), vegetables (12.4%), cereal products and tubers (4.6%), legumes (3.7%) and oils (2.1%); chocolate, cakes and nuts are negligible sources of polyphenols in this cohort. The two most important polyphenol classes contributing to the total intake were flavonoids (47.5%) and phenolic acids (47.4%). Polyphenol intake increased with age and education level and decreased with BMI; furthermore, in the northern regions of Italy, the polyphenol intake was slightly, but significantly higher than in the central or southern regions. CONCLUSIONS: The study documents for the first time the intake of polyphenols and their main food sources in people with diabetes using validated and complete databases of the polyphenol content of food. Compared with published data, collected in people without diabetes, these results suggest a lower intake and a different pattern of intake in people with diabetes. PMID- 28004271 TI - Maternal vitamin D deficiency during pregnancy affects expression of adipogenic regulating genes peroxisome proliferator-activated receptor gamma (PPARgamma) and vitamin D receptor (VDR) in lean male mice offspring. AB - PURPOSE: Maternal vitamin D deficiency during pregnancy is a widespread issue that may have long-lasting consequences on offspring adiposity. We sought to determine how maternal vitamin D deficiency during the perinatal period would affect offspring adipose tissue development and gene expression. METHODS: Female C57BL/6 J mice were fed either a vitamin D deficient (VDD) or control diet from 4 weeks before pregnancy (periconception) until 7 days postparturition. Male offspring were weighed and euthanized at 75 days of age (early adult period), at which point serum was collected for biochemical analyses, and perigonadal and subcutaneous white adipose tissue (PGAT and SQAT, respectively) were excised, weighed, then flash-frozen for later histology and analyses of adipogenic gene expression. RESULTS: All adult male offspring were nonobese; there were no significant differences in body weight, adipose pad weight, or adipocyte size. However, VDD-exposed offspring had greater expression of the adipogenic regulating genes peroxisome proliferator-activated receptor gamma (Pparg) and vitamin D receptor (Vdr). CONCLUSIONS: This study suggests that exposure to vitamin D deficiency during the perinatal period can directly affect genes involved in the development of adipose tissue in nonobese offspring. These novel findings invite further investigation into the mechanisms by which maternal vitamin D status during pregnancy affects adipose development and metabolic health of offspring. PMID- 28004272 TI - Rice bran protein hydrolysates attenuate diabetic nephropathy in diabetic animal model. AB - INTRODUCTION: Diabetic nephropathy (DN) is an important microvascular complication of uncontrolled diabetes. The features of DN include albuminuria, extracellular matrix alterations, and progressive renal insufficiency. Rice bran protein hydrolysates (RBPs) have been reported to have antihyperglycemic, lipid lowering, and anti-inflammatory effects in diabetic rats. Our study was to investigate the renoprotective effects of RBP in diabetic animals and mesangial cultured cells. METHODS: Eight-week-old male db/m and db/db mice were orally treated with tap water or RBP (100 or 500 mg/kg/day) for 8 weeks. At the end of the experiment, diabetic nephropathy in kidney tissues was investigated for histological, ultrastructural, and clinical chemistry changes, and biomarkers of angiogenesis, fibrosis, inflammation, and antioxidant in kidney were analyzed by Western blotting. Protection against proangiogenic proteins and induction of cytoprotection by RBP in cultured mesangial cells was evaluated. RESULTS: RBP treatment improved insulin sensitivity, decreased elevated fasting serum glucose levels, and improved serum lipid levels and urinary albumin/creatinine ratios in diabetic mice. RBP ameliorated the decreases in podocyte slit pore numbers, thickening of glomerular basement membranes, and mesangial matrix expansion and suppressed elevation of MCP-1, ICAM-1, HIF-1alpha, VEGF, TGF-beta, p-Smad2/3, and type IV collagen expression. Moreover, RBP restored suppressed antioxidant Nrf2 and HO-1 expression. In cultured mesangial cells, RBP inhibited high glucose induced angiogenic protein expression and induced the expression of Nrf2 and HO 1. CONCLUSION: RBP attenuates the progression of diabetic nephropathy and restored renal function by suppressing the expression of proangiogenic and profibrotic proteins, inhibiting proinflammatory mediators, and restoring the antioxidant and cytoprotective system. PMID- 28004274 TI - Imaging biomarkers of dementia: recommended visual rating scales with teaching cases. AB - : The diagnostic work up of dementia may benefit from structured reporting of CT and/or MRI and the use of standardised visual rating scales. We advocate a more widespread use of standardised scales as part of the workflow in clinical and research evaluation of dementia. We propose routine clinical use of rating scales for medial temporal atrophy (MTA), global cortical atrophy (GCA) and white matter hyperintensities (WMH). These scales can be used for evaluation of both CT and MRI and are efficient in routine imaging assessment in dementia, and may improve the accuracy of diagnosis. Our review provides detailed imaging examples of rating increments in each of these scales and a separate teaching file. The radiologist should relate visual ratings to the clinical assessment and other biomarkers to assist the clinician in the diagnostic decision. TEACHING POINTS: * Clinical dementia diagnostics would benefit from structured radiological reporting. * Standardised rating scales should be used in dementia assessment. * It is important to relate imaging findings to the clinically suspected diagnosis. PMID- 28004273 TI - Occipital Nerve Field Transcranial Direct Current Stimulation Normalizes Imbalance Between Pain Detecting and Pain Inhibitory Pathways in Fibromyalgia. AB - Occipital nerve field (OCF) stimulation with subcutaneously implanted electrodes is used to treat headaches, more generalized pain, and even failed back surgery syndrome via unknown mechanisms. Transcranial direct current stimulation (tDCS) can predict the efficacy of implanted electrodes. The purpose of this study is to unravel the neural mechanisms involved in global pain suppression, mediated by occipital nerve field stimulation, within the realm of fibromyalgia. Nineteen patients with fibromyalgia underwent a placebo-controlled OCF tDCS. Electroencephalograms were recorded at baseline after active and sham stimulation. In comparison with healthy controls, patients with fibromyalgia demonstrate increased dorsal anterior cingulate cortex, increased premotor/dorsolateral prefrontal cortex activity, and an imbalance between pain detecting dorsal anterior cingulate cortex and pain-suppressing pregenual anterior cingulate cortex activity, which is normalized after active tDCS but not sham stimulation associated with increased pregenual anterior cingulate cortex activation. The imbalance improvement between the pregenual anterior cingulate cortex and the dorsal anterior cingulate cortex is related to clinical changes. An imbalance assumes these areas communicate and, indeed, abnormal functional connectivity between the dorsal anterior cingulate cortex and pregenual anterior cingulate cortex is noted to be caused by a dysfunctional effective connectivity from the pregenual anterior cingulate cortex to the dorsal anterior cingulate cortex, which improves and normalizes after real tDCS but not sham tDCS. In conclusion, OCF tDCS exerts its effect via activation of the descending pain inhibitory pathway and de-activation of the salience network, both of which are abnormal in fibromyalgia. PMID- 28004275 TI - Perceived Benefits and Factors that Influence the Ability to Establish and Maintain Patient Support Groups in Rare Diseases: A Scoping Review. AB - BACKGROUND: Support groups are an important resource for many people living with rare diseases. The perceived benefits of participating in support groups for people with rare diseases and factors that may influence the ability to successfully establish and maintain these groups are not well understood. Thus, the objective of this scoping review was to provide a mapping of the available evidence on the (1) benefits or perceived benefits of participating in rare disease support groups and (2) barriers and facilitators of establishing and maintaining these groups. METHODS: CINAHL and PubMed were searched from January 2000 to August 2015, with no language restrictions. Publications that described the benefits or perceived benefits of participating in rare disease support groups or the barriers and facilitators of establishing and maintaining them were eligible for inclusion. Two investigators independently evaluated titles/abstracts and full-text publications for eligibility, and extracted data from each included publication. RESULTS: Ten publications were included in the scoping review. There was no trial evidence on support group benefits. All ten publications reported on the perceived benefits of participating in rare disease support groups. Three reported on barriers and facilitators of establishing and maintaining them. Overall, seven different perceived benefits of participating in rare disease support groups were identified: (1) meeting and befriending other people with the same rare disease and similar experiences; (2) learning about the disease and related treatments; (3) giving and receiving emotional support; (4) having a place to speak openly about the disease and one's feelings; (5) learning coping skills; (6) feeling empowered and hopeful; and (7) advocating to improve healthcare for other rare disease patients. Several facilitators (e.g., meeting via teleconference) and barriers (e.g., getting patients and/or family members to lead the group) of establishing and maintaining these groups were identified. CONCLUSIONS: Rare disease support groups are an important source of emotional and practical support for many patients. There is no trial evidence on the benefits of these groups and limited evidence on the perceived benefits and barriers and facilitators to establishing and maintaining them. PMID- 28004276 TI - Stationary and transient Soret separation in a binary mixture with a consolute critical point. AB - The stationary and transient Soret separation in a binary mixture with a consolute critical point is studied theoretically. The mixture is placed between two parallel plates kept at different temperatures. A polymer blend is used as a model system. Analytical solutions are constructed to describe the stationary separation in a binary mixture with variable Soret coefficient. The latter strongly depends on temperature and concentration and enhances near a consolute critical point due to reduced diffusion. As a result, a large concentration gradient is observed locally, while much smaller concentration variations are found in the rest of the layer. It is shown that complete separation can be obtained by applying a small temperature difference first, waiting for the establishment of stationary state, and then increasing this difference again. In this case, the critical temperature lies between hot and cold wall temperatures, while the mixture still remains in the one-phase region. When the initial (mean) temperature or concentration are shifted away from the near-critical values, the separation decreases. The analysis of transient behavior shows that the Soret separation occurs much faster than diffusion to the homogeneous state when the initial concentration is close to the critical one. It happens due to the decrease (increase) of the local relaxation time during the Soret (Diffusion) steps. The transient times of these steps become comparable for small temperature differences or off-critical initial concentrations. An unusual (non-exponential) separation dynamics is observed when the separation starts in the off-critical domain, and then enhances greatly when the system enters into the near-critical region. It is also found that the transient time decreases with increasing the applied temperature difference. PMID- 28004279 TI - In vitro cultured fetal fibroblasts have myofibroblast-associated characteristics and produce a fibrotic-like environment upon stimulation with TGF-beta1: Is there a thin line between fetal scarless healing and fibrosis? AB - Transforming growth factor-beta (TGF-beta) is a cytokine occurring in three isoforms with an important function in development and wound healing. In wound healing, prolonged TGF-beta signaling results in myofibroblast differentiation and fibrosis. In contrast, the developing second-trimester fetal skin contains high levels of all three TGF-beta isoforms but still has the intrinsic capacity to heal without scarring. Insight into TGF-beta signal transduction during fetal wound healing might lead to methods to control the signaling pathway during adult wound healing. In this study, we imitated wound healing in vitro by stimulating fibroblasts with TGF-beta1 and examining myofibroblast differentiation. The aim was to gain insight into TGF-beta signaling in human fibroblasts from fetal and adult dermis. First, TGF-beta1 stimulation resulted in similar or even more severe upregulation of myofibroblast-associated genes in fetal fibroblasts compared to adult fibroblasts. Second, fetal fibroblasts also had higher protein levels of myofibroblast-marker alpha-smooth muscle actin (alpha-SMA). Third, stimulated fetal fibroblasts in collagen matrices had higher protein levels of alpha-SMA, produced more of the fibrotic protein fibronectin splice-variant extra domain A (FnEDA), and showed enhanced contraction. Finally, fetal fibroblasts also produced significant higher levels of TGF-beta1. Altogether, these data show that in vitro cultured fetal fibroblasts have myofibroblast-associated characteristics and do produce a fibrotic environment. As healthy fetal skin has high levels of TGF-beta1, FnEDA, and collagen-III as well, these findings correlate with the in vivo situation. Therefore, our study demonstrates that there are similarities between fetal skin development and fibrosis and shows the necessity to discriminate between these processes. PMID- 28004278 TI - Histones facilitate alpha-synuclein aggregation during neuronal apoptosis. AB - Ample in vitro and in vivo experimental evidence supports the hypothesis that intercellular transmission of alpha-synuclein (alphaS) is a mechanism underlying the spread of alphaS pathology in Parkinson's disease and related disorders. What remains unexplained is where and how initial transmissible alphaS aggregates form. In a previous study, we demonstrated that alphaS aggregates rapidly form in neurons with impaired nuclear membrane integrity due to the interaction between nuclear proaggregant factor(s) and alphaS and that such aggregates may serve as a source for alphaS seeding. In the present study, we identify histones as a potential nuclear proaggregant factor for alphaS aggregation in both apoptotic neurons and brains with alphaS pathology. We further demonstrate that histone induced aggregates contain a range of alphaS oligomers, including protofibrils and mature fibrils, and that these alphaS aggregates can seed additional aggregation. Importantly, we demonstrate transmissibility in mouse brains from stereotaxic injection. This study provides new clues to the mechanism underlying initial pathological aggregation of alphaS in PD and related disorders, and could lead to novel diagnostic and therapeutic approaches. PMID- 28004277 TI - Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy. AB - The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 - and Abcd1 - /Abcd2 -/- mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 - /Abcd2 -/- mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated. PMID- 28004280 TI - Genetic structure of Hepatica nobilis var. japonica, focusing on within population flower color polymorphism. AB - How phenotypic or genetic diversity is maintained in a natural habitat is a fundamental question in evolutionary biology. Flower color polymorphism in plants is a common polymorphism. Hepatica nobilis var. japonica on the Sea of Japan (SJ) side of the Japanese mainland exhibits within population flower color polymorphism (e.g., white, pink, and purple), while only white flowers are observed on the Pacific Ocean (PO) side. To determine the relationships between flower color polymorphism, within and among populations, and the genetic structure of H. nobilis var. japonica, we estimated the genetic variation using simple sequence repeat (SSR) markers. First, we examined whether cryptic lineages corresponding to distinct flower colors contribute to the flower color polymorphisms in H. nobilis var. japonica. In our field observations, no bias in color frequency was observed among populations on Sado Island, a region with high variation in flower color. Simple sequence repeat (SSR) analyses revealed that 18% of the genetic variance was explained by differences among populations, whereas no genetic variation was explained by flower color hue or intensity (0% for both components). These results indicate that the flower color polymorphism is likely not explained by cryptic lineages that have different flower colors. In contrast, populations in the SJ and PO regions were genetically distinguishable. As with the other plant species in these regions, refugial isolation and subsequent migration history may have caused the genetic structure as well as the spatially heterogeneous patterns of flower color polymorphisms in H. nobilis var. japonica. PMID- 28004281 TI - Molecular and karyological data confirm that the enigmatic genus Platypholis from Bonin-Islands (SE Japan) is phylogenetically nested within Orobanche (Orobanchaceae). AB - Molecular phylogenetic studies have greatly improved our understanding of phylogenetic relationships of non-photosynthetic parasitic broomrapes (Orobanche and related genera, Orobanchaceae), but a few genera have remained unstudied. One of those is Platypholis, whose sole species, Platypholis boninsimae, is restricted to the Bonin-Islands (Ogasawara Islands) about 1000 km southeast of Japan. Based on overall morphological similarity, Platypholis has been merged with Orobanche, but this hypothesis has never been tested with molecular data. Employing maximum likelihood and Bayesian analyses on a family-wide data set (two plastid markers, matK and rps2, and three nuclear markers, ITS, phyA and phyB) as well as on an ITS data set focusing on Orobanche s. str., it is shown that P. boninsimae Maxim. is phylogenetically closely linked to or even nested within Orobanche s. str. This position is supported both by morphological evidence and by the newly obtained chromosome number of 2n = 38, which is characteristic for the genus Orobanche s. str. PMID- 28004282 TI - A subclass of HSP70s regulate development and abiotic stress responses in Arabidopsis thaliana. AB - Members of the HSP70 family function as molecular chaperones to maintain cellular homeostasis and help plants cope with environmental stimuli. However, due to functional redundancy and lack of effective chemical inhibitors, our knowledge of functions of individual HSP70s has remained limited. Here, we confirmed a subclass of HSP70s, including HSP70-1, -2, -3, -4, and -5, localized to the cytosol and nucleus in Arabidopsis thaliana. Histochemical analyses of promoter:GUS reporter lines showed that HSP70-1, -2, -3, and -4 genes were widely expressed, but HSP70-5 was not. In addition, individual HSP70 showed not only similar but also distinct transcriptions when treated by different abiotic stresses and phytohormones. No apparent phenotype was observed when individual HSP70 genes were overexpressed or knocked-out/down, but the double mutant hsp70-1 hsp70-4 and triple mutant hsp70-2 hsp70-4 hsp70-5 plants exhibited developmental phenotypes with shortened specific growth periods, curly and round leaves, twisted petioles, thin stems, and short siliques. Moreover, both mutants were hypersensitive to heat, cold, high glucose, salt and osmotic stress, but hyposensitive to abscisic acid. Genes related to flowering, and the cytokinin, brassinosteroid, and abscisic acid signaling pathways were differentially expressed in both mutants. Our studies suggest that, the individual HSP70 possibly performs both redundant and specific functions with the other members in the cytosolic/nuclear HSP70 subclass, and apart from enabling plants to cope with abiotic stresses, this subclass of cytosolic/nuclear HSP70 proteins also participates in diverse developmental processes and signaling pathways. PMID- 28004283 TI - The Achilles' heel of Sugarbaker. PMID- 28004284 TI - A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors. AB - Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade >= 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity. PMID- 28004285 TI - Is the Positive Illusory Bias Common in Young Adolescents with ADHD? A Fresh Look at Prevalence and Stability Using Latent Profile and Transition Analyses. AB - The goal of this study was to use novel approaches that do not require the use of arbitrary cut-points (i.e., latent profile/transition analysis) to evaluate the prevalence and stability of the positive illusory bias (PIB) in young adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants were 326 middle-school students diagnosed with ADHD (Mage = 12.26 years, 71% male, 77% Caucasian). The Self-Perception Profile for Children (SPPC) was completed by participants and their parents at baseline and again 12 and 18 months later. Cross-sectional results revealed four subgroups based on SPPC responses. Only a small subset (18.4%) of youth with ADHD exhibited a global PIB, across the behavioral, scholastic, and social domains, with an additional 29% displaying a PIB in the scholastic domain only. Additionally, average parent/adolescent-rated competence within each subgroup was in line with an objective measure of scholastic competence (i.e., grades). When examined longitudinally, only a PIB in the social domain was stable across the 18-month study period and only for half of the sample. These findings suggest that the PIB is not ubiquitous in youth with ADHD, with many young adolescents rating themselves accurately relative to their parents and their grades. Further, when stability across time is considered, the PIB may be specific to social functioning, as opposed to a global, cross-domain phenomenon. Implications for the future measurement of the PIB are discussed. PMID- 28004286 TI - The 2016 Tamio Yamakawa award. PMID- 28004287 TI - An Efficient Remote Authentication Scheme for Wireless Body Area Network. AB - Wireless body area network (WBAN) provide a mechanism of transmitting a persons physiological data to application providers e.g. hospital. Given the limited range of connectivity associated with WBAN, an intermediate portable device e.g. smartphone, placed within WBAN's connectivity, forwards the data to a remote server. This data, if not protected from an unauthorized access and modification may be lead to poor diagnosis. In order to ensure security and privacy between WBAN and a server at the application provider, several authentication schemes have been proposed. Recently, Wang and Zhang proposed an authentication scheme for WBAN using bilinear pairing. However, in their scheme, an application provider could easily impersonate a client. In order to overcome this weakness, we propose an efficient remote authentication scheme for WBAN. In terms of performance, our scheme can not only provide a malicious insider security, but also reduce running time of WBAN (client) by 51 % as compared to Wang and Zhang scheme. PMID- 28004288 TI - In-vivo quantification of the revascularization of a human acellular dermis seeded with EPCs and MSCs in co-culture with fibroblasts and pericytes in the dorsal chamber model in pre-irradiated tissue. AB - INTRODUCTION: Transplantation of a cell-seeded graft may improve wound healing after radiotherapy. However, the survival of the seeded cells depends on a rapid vascularization of the graft. Co-culturing of adult stem cells may be a promising strategy to accelerate the vessel formation inside the graft. Thus, we compared the in vivo angiogenic potency of mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) using dorsal skinfold chambers and intravital microscopy. MATERIALS AND METHODS: Cells were isolated from rat bone marrow and adipose tissue and characterized by immunostaining and flow cytometry. Forty-eight rats received a dorsal skinfold chamber and were divided into 2 main groups, irradiated and non-irradiated. Each of these 2 groups were further subdivided into 4 groups: unseeded matrices, matrices + fibroblasts + pericytes, matrices + fibroblasts + pericytes + MSCs and matrices + fibroblasts + pericytes + EPCs. Vessel densities were quantified semi-automatically using FIJI. RESULTS: Fibroblasts + pericytes - seeded matrices showed a significantly higher vascular density in all groups with an exception of non-irradiated rats at day 12 compared to unseeded matrices. Co-seeding of MSCs increased vessel densities in both, irradiated and non-irradiated groups. Co-seeding with EPCs did not result in an increase of vascularization in none of the groups. DISCUSSION: We demonstrated that the pre-radiation treatment led to a significant decreased vascularization of the implanted grafts. The augmentation of the matrices with fibroblasts and pericytes in co-culture increased the vascularization compared to the non-seeded matrices. A further significant enhancement of vessel ingrowth into the matrices could be achieved by the co-seeding with MSCs in both, irradiated and non irradiated groups. PMID- 28004289 TI - Mechanisms for nickel(0)/N-heterocyclic carbene-catalyzed intramolecular alkene hydroacylation: insights from a DFT study. AB - Density functional calculations have been applied to study and elucidate nickel(0)/N-heterocyclic carbene-catalyzed intramolecular alkene hydroacylation. The calculations showed that nickel(0)-catalyzed intramolecular alkene hydroacylation involved four potential reaction channels (I, II, III, and IV), and pathway IV was predicted to be more favorable than the other three. Two pathways, I and II, had three steps (oxidative addition, hydrogen migration, reductive elimination), and the rate-determining step was hydrogen migration. Pathway III proceeded through oxidative cyclization, beta-hydride elimination, and hydrogen migration, and the rate-determining step was beta-hydride elimination. Pathway IV included four steps (oxidative cyclization, dimerization, beta-hydride elimination, hydrogen migration), and the rate-determining step was again beta-hydride elimination. Oxidative cyclization was easy and led to rapid dimerization, greatly reducing the free energy of beta-hydride elimination. The binuclear nickelacycle intermediate was observed in Ogoshi's experiments, and it was identified by nuclear magnetic resonance (NMR). The dominant product was the five-membered benzocyclic ketone p1. All results agreed with Ogoshi's experiments. Graphical Abstract Nickel(0)-catalyzed intramolecular alkene hydroacylation involved four potential reaction channels. The binuclear nickelacycle intermediate was important, and the dimerization greatly reduced the free energy of the beta-hydride elimination. PMID- 28004290 TI - Quantitative Analysis of Aquaporin Expression Levels during the Development and Maturation of the Inner Ear. AB - Aquaporins (AQPs) are a family of small membrane proteins that transport water molecules across the plasma membrane along the osmotic gradient. Mammals express 13 subtypes of AQPs, including the recently reported "subcellular AQPs", AQP11 and 12. Each organ expresses specific subsets of AQP subtypes, and in the inner ear, AQPs are essential for the establishment and maintenance of two distinct fluids, endolymph and perilymph. To evaluate the contribution of AQPs during the establishment of inner ear function, we used quantitative reverse transcription polymerase chain reaction to quantify the expression levels of all known AQPs during the entire development and maturation of the inner ear. Using systematic and longitudinal quantification, we found that AQP11 was majorly and constantly expressed in the inner ear, and that the expression levels of several AQPs follow characteristic longitudinal patterns: increasing (Aqp0, 1, and 9), decreasing (Aqp6, 8, and 12), and peak of expression on E18 (Aqp2, 5, and 7). In particular, the expression level of Aqp9 increased by 70-fold during P3-P21. We also performed in situ hybridization of Aqp11, and determined the unique localization of Aqp11 in the outer hair cells. Immunohistochemistry of AQP9 revealed its localization in the supporting cells inside the organ of Corti, and in the root cells. The emergence of AQP9 expression in these cells was during P3-P21, which was coincident with the marked increase of its expression level. Combining these quantification and localization data, we discuss the possible contributions of these AQPs to inner ear function. PMID- 28004291 TI - Sacubitril/Valsartan (LCZ696) in Heart Failure. AB - It has been known since the 1990s that long-term morbidity and mortality is improved in patients with heart failure with reduced ejection fraction (HFrEF) by treatments that target the renin-angiotensin-aldosterone system (RAAS). It has also long been thought that enhancement of the activity of natriuretic peptides (NPs) could potentially benefit patients with HFrEF, but multiple attempts to realize this benefit had failed over the years - until 2014, when a large, phase III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing sacubitril/valsartan with enalapril, a well-established treatment for HFrEF. Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS activation through blockade of angiotensin II type 1 receptors and enhances vasoactive peptides including NPs through inhibition of neprilysin, the enzyme responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated with sacubitril/valsartan had 20% less risk for cardiovascular death or hospitalization for heart failure (the primary endpoint), 20% less risk for cardiovascular death, 21% less risk for first hospitalization for heart failure, and 16% less risk for death from any cause, compared with enalapril (all p < 0.001). Concerning tolerability, the sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough, compared with the enalapril group. The use of sacubitril/valsartan has been endorsed by the latest heart failure treatment guidelines in Europe and the USA. This chapter reviews the discoveries, scientific reasoning, and clinical evidence that led to the development of sacubitril/valsartan, the first novel therapy in a new drug class to improve survival in HFrEF in the last 15 years. PMID- 28004292 TI - CORR Insights(r): Periprosthetic Occult Fractures of the Acetabulum Occur Frequently During Primary THA. PMID- 28004293 TI - Fucoidan reduced the invasion of oral squamous cell carcinoma cells and modified their effects to macrophages. AB - Fucoidan is a complex of polysaccharides showing antitumor and immunomodulation properties. Our previous studies found its regulation to myeloid immune cells, including macrophages. Aberrant infiltration and functions of macrophages are commonly found in oral squamous cell carcinoma (OSCC). In this study, we analyzed the effects of fucoidan on invasion of OSCC cells, and their regulation to macrophages, trying to evaluate its role as a potential therapy for OSCC. CAL27 and THP-1-derived macrophages were used as models for OSCC cells and tumor infiltrated macrophages in the in vitro study, respectively. The effects of fucoidan on invasion of OSCC cells and their recruitment to macrophages were analyzed by transwell assay. KIF4A siRNA transfection was performed to investigate its role in fucoidan-modulated OSCC cells invasion. CCL3-neutralizing antibody was added into the conditioned medium of OSCC cells to evaluate its role in fucoidan-mediated macrophages recruitment and re-education. Fucoidan reduced the invasive potential of CAL27 cells with a decrease of MMP-2 and KIF4A transcription. KIF4A knockdown in CAL27 cells led to decreased invasion and MMP-2 expression. The conditioned medium of fucoidan-treated CAL27 cells promoted recruitment and inflammatory cytokines secretion on THP-1-derived macrophages. Further analysis found that fucoidan increased CCL3 production in CAL27 cells. Blocking CCL3 expression reversed the effects of fucoidan on macrophage recruitment and re-education. Our study found that fucoidan regulated the invasion of OSCC cells and also their recruiting and re-educating effects on macrophages, suggesting it could be a complementary approach in the treatment of OSCC. PMID- 28004294 TI - Identification, Synthesis, and Field Tests of the Sex Pheromone of Margarodes prieskaensis (Jakubski). AB - Here, we report the identification and synthesis of the sex pheromone of female Margarodes prieskaensis (Jakubski), and the attractiveness of the synthetic pheromone to males in field trapping tests. Volatile organic compounds were collected from virgin females using a sample enrichment probe (SEP). Analyses by gas chromatography coupled to mass spectrometry revealed the presence of only two constituents. By scaling up the SEP, sufficient of the major constituent was collected for 1H and 13C nuclear magnetic resonance (NMR) analyses and ancillary NMR techniques. The sex attractant was identified as (2R,4R,6R,8R)-2,4,6,8 tetramethylundecan-1-ol. The enantiomerically pure compound was synthesized from octadecyl (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoate, a minor component of the uropygial (preen) gland secretion of the domestic goose, Anser domesticus. Field trapping experiments, carried out in vineyards in the Northern Cape Province of South Africa, showed that the synthetic compound was as attractive to winged males of M. prieskaensis as virgin females. The second compound detected was identified as the corresponding acetate, but addition of this did not affect the attractiveness of the major component. We believe this to be the first identification of a sex attractant of the Margarodidae. PMID- 28004296 TI - Orthopedic surgeons' attitudes to osteoporosis investigation and management after minimal trauma fracture (MTF). AB - : A study of orthopedic surgeons in rural and regional Southeast Australia to determine attitudes to investigation and management of osteoporosis found they believe follow-up in regard to osteoporosis after MTF is important; responsibility for follow-up diagnosis and management lies with primary health care and current communication systems are poor. PURPOSE/INTRODUCTION: The investigation and treatment of osteoporosis after minimal trauma fracture (MTF) is regarded as sub-optimal. There is strong evidence of the benefit of identifying and treating osteoporosis after MTF, and there has been discussion of the possible role that orthopedic surgeons might play in the management of osteoporosis after MTF. The study surveyed orthopedic surgeons in rural and regional Southeast Australia to determine their attitudes to investigation and management of osteoporosis, the role health professionals should play, and the communication and co-ordination of follow-up care. METHODS: A survey was developed and piloted prior to being posted to 69 orthopedic surgeons asking for their opinions about the general management of osteoporosis, and the roles and responsibilities of health professionals in dealing with osteoporosis following an MTF. RESULTS: Responses were received from 42 participants (60.8%) with the majority of respondents agreeing that it is important to treat osteoporosis following MTF. Less than 15% of respondents felt that it was their responsibility to initiate discussion or treatment or investigation after MTF. No respondent felt that the coordination of osteoporosis care was good and 45% stated it was poor. Communication after discharge is mostly left to the hospital (30%), while 20% stated they did not follow up at all. CONCLUSIONS: This study shows that many rural orthopedic surgeons believe that follow-up in regard to osteoporosis after MTF is important, that responsibility for follow-up diagnosis and management of osteoporosis lies with primary health care and the current communication systems are poor. PMID- 28004297 TI - Evaluation of the first fracture liaison service in the Greek healthcare setting. AB - : We evaluated the first implementation of FLS in the Greek healthcare setting, at the 251 Hellenic Air Force and VA General Hospital of Athens. Participation rate was moderate (54.5%) and needs improvement; osteoporosis medication was either suggested or reviewed in 74 out of the 116 patients recruited. PURPOSE: The purpose of this study was to evaluate the first implementation of a fracture liaison service (FLS) in Greece, at the 251 Hellenic Air Force and VA General Hospital, Athens. METHODS: Single-center, prospective study from May 1, 2013 to April 30, 2015 (first year-second year follow-up) was conducted. Patients of both genders aged 40-90 years old, with a history of a low trauma fracture and willing to participate, were included after identification by an FLS nurse. Following recruitment, osteoporosis risk factors were assessed, FRAX score was calculated for treatment-naive patients, bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA), and osteoporosis treatment was suggested where applicable. The rate of participation, the indication of osteoporosis treatment, and the difficulties met were evaluated. RESULTS: Of the eligible 213 patients, 97 (45.5%) were reluctant to participate for personal reasons. From the 116 initially recruited patients (mean age 74.8 +/- 12 years), 77 (66.4%) discontinued their participation at some point for various reasons and 39 patients concluded the study. All 116 patients were assessed for osteoporosis risk factors and given a tailor-made exercise and education program, while FRAX score was assessed in all treatment-naive patients (74 patients, 63.8%). Osteoporosis medication was suggested or reviewed in 74 patients; however, an adherence rate of 100% is only available for the 24 who concluded the study. CONCLUSIONS: We report the first implementation of FLS in the Greek healthcare setting. The participation rate is moderate and definitely needs improvement. PMID- 28004298 TI - Comparing self-perceived and estimated fracture risk by FRAX(r) of women with osteoporosis. AB - : In this study, we compared subjective fracture risks of Hungarian women with osteoporosis to FRAX(r)-based estimates. Patients with a previous fracture, parental hip fracture, low femoral T-score, higher age, and higher BMI were more likely to underestimate their risks. Patients also failed to associate risk factors with an increased risk of fractures. PURPOSE: The main objectives were to explore associations between self-perceived 10-year fracture risks of women with osteoporosis (OP) and their risks calculated by the FRAX(r) algorithm and to identify determinants of the underestimation of risk. METHODS: We carried out a cross-sectional study in 11 OP centers in Hungary and collected data on the risk factors considered by the FRAX(r) calculator. Patients estimated their subjective 10-year probability of any major osteoporotic and hip fracture numerically, in percentages and also on a visual analog scale (VAS). We compared subjective and FRAX(r) estimates and applied logistic regression to analyze the determinants of the underestimation of risk. Associations between risk factors and subjective risk were explored using linear probability models. RESULTS: Nine hundred seventy two OP patients were included in the analysis. Major OP and hip fracture risk by FRAX(r) were on average 20.1 and 10.5%, while subjective estimates were significantly higher, 30.0 and 24.7%, respectively. Correlations between FRAX(r) and subjective measures were very weak (r = 0.12-0.16). Underestimation of major OP fracture risk was associated with having had a single previous fracture (OR = 2.0), parental hip fracture (OR = 3.4), femoral T-score <=-2.5 (OR = 4.2), higher age, body mass index, and better general health state. We did not find significant associations between subjective risk estimates and most of the risk factors except for previous fractures. CONCLUSIONS: Hungarian OP patients fail to recognize most of the risk factors of fractures. Thus, education of patients about these risk factors would be beneficial especially for the elderly with a low femoral T-score and parental hip fracture history. PMID- 28004295 TI - Vitamin D status correction in Saudi Arabia: an experts' consensus under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases (ESCEO). AB - BACKGROUND: Vitamin D deficiency is common in the Middle East and in Saudi Arabia, in particular. While several international recommendations on the management of vitamin D deficiency have been documented and practiced globally, these recommendations should be adapted to the conditions of the Middle Eastern region. To address this challenge, the Prince Mutaib Chair for Biomarkers of Osteoporosis (PMCO) in King Saud University (KSU), Riyadh, KSA, together with local experts and in cooperation with the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), organized a panel that formulated unified recommendations in the diagnosis and treatment of vitamin D deficiency in the region. METHODS: The selection of local and international experts commenced during the 2nd International Vitamin D Symposium conducted in Riyadh, Saudi Arabia, last January 20--21, 2016. Reviews of the most recent literature were done, and face-to-face meetings were conducted for revisions and final recommendations. RESULTS: Vitamin D sufficiency is defined as circulating serum 25(OH)D >=50 nmol (>=20 ng/ml) for the general population and vitamin D adequacy as serum 25(OH)D >75 nmol/L l (>30 ng/ml) for the frail and osteoporotic elderly. Despite overwhelming prevalence of vitamin D deficiency, universal screening is not recommended. Recommendations for the general population, children, pregnant/lactating women, post-menopausal women, the elderly, and those with subsequent metabolic diseases were provided. RESULTS: Vitamin D sufficiency is defined as circulating serum 25(OH)D >=50 nmol (>=20 ng/ml) for the general population and vitamin D adequacy as serum 25(OH)D >75 nmol/L l (>30 ng/ml) for the frail and osteoporotic elderly. Despite overwhelming prevalence of vitamin D deficiency, universal screening is not recommended. Recommendations for the general population, children, pregnant/lactating women, post-menopausal women, the elderly, and those with subsequent metabolic diseases were provided. CONCLUSION: Vitamin D supplementation/correction is advised in all persons whose serum 25(OH)D falls below 50 nmol/l (20 ng/ml), and achieving a target of 75 nmol/l (30 ng/ml) is particularly suited for frail, osteoporotic, and older patients. Conducting well-designed clinical trials in the region that will address economic implications and investigations on the treatment persistence and compliance to vitamin D treatment in the region are encouraged. PMID- 28004299 TI - Evaluation of sarcopenia in patients with distal radius fractures. AB - : Sarcopenia is more prevalent in patients with distal radius fracture (DRF) than in age- and sex-matched controls. Lower appendicular mass index in men and weaker grip strength in both men and women increase the likelihood of DRF. INTRODUCTION: Sarcopenia is a core component of physical frailty that predisposes older people to falls and negatively impacts the activities of daily living. The objectives of this study were to compare the prevalence of sarcopenia in patients with DRF with that in age- and sex-matched controls without DRF; and evaluate the association between sarcopenia and the occurrence of DRF. METHODS: We prospectively recruited 132 patients over 50 years of age who sustained DRF due to fall and 132 age- and sex-matched controls without DRF. A definition of sarcopenia was based on the consensus of the Asian Working Group for Sarcopenia. Sarcopenic components including appendicular lean body mass, grip strength, and gait speed were compared between the two groups. Other factors assessed for the occurrence of DRF were age, gender, body mass index (BMI), lumbar, and hip bone mineral density (BMD) values. A conditional logistic regression analysis was conducted to evaluate the associations between sarcopenia and the occurrence of DRF. RESULTS: A total of 39 (30%) of 132 DRF patients were sarcopenic, whereas 23 (17%) of the 132 controls were within the sarcopenic criteria (p = 0.048). The patient group had significantly lower lean body mass and weaker grip strength than those of the control group. However, there was no significant difference in gait speed between the two groups. According to regression analysis, lower appendicular mass index in men was associated with an increased incidence of DRF (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.72, 0.95) while weaker grip strength and lower total hip BMD values were associated with the occurrence of DRF in both men (OR = 0.77, 95% CI = 0.63, 0.92; and OR = 0.79, 95% CI = 0.64, 0.94, respectively) and women (OR = 0.78, 95% CI = 0.64, 0.93, and OR = 0.73, 95% CI = 0.52, 0.92, respectively). CONCLUSIONS: Sarcopenia is more prevalent in patients with DRF than in age- and sex-matched controls. Lower appendicular mass in men, weaker grip strength, and lower hip BMD in both men and women increase the likelihood of DRF. PMID- 28004300 TI - Effect of Wenhua Juanbi Recipe () on expression of receptor activator of nuclear factor kappa B ligand, osteoprotegerin, and tumor necrosis factor receptor superfamily member 14 in rats with collagen-induced arthritis. AB - OBJECTIVES: To study the effect of Wenhua Juanbi Recipe (, WJR) on expression of receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor receptor superfamily member 14 (TNFRSF14, also known as LIGHT) in rats with collagen-induced arthritis (CIA). METHODS: CIA rats were generated by subcutaneous injection of bovine collagen type-II at the tail base. Sixty CIA rats were randomly assigned (10 animals/group) to: model, methotrexate (MTX)-treated (0.78 mg/kg body weight), and WJR-treated (22.9 g/kg) groups. Healthy normal rats (n=10) were used as the normal control. Treatments or saline were administered once daily by oral gavage. Rats were sacrifificed at day 28 post-treatment and knee synovium and peripheral blood serum were collected. Toe swelling degree and expression of RANKL, OPG, and LIGHT were determined by Western blot and immunohistochemistry. RESULTS: Compared with the normal group, toe swelling degree was signifificantly increased in the model group (P<0.01). After treatment, toe swelling degree decreased signifificantly in the WJR and MTX groups compared with the model group (P<0.01). Compared with the normal group, expression of RANKL and LIGHT were signifificantly increased and OPG signifificantly decreased in peripheral blood and synovium of the model group (P<0.01). Conversely, RANKL and LIGHT expression were signifificantly reduced and OPG increased in the WJR and MTX groups compared with the model group (P<0.01). No statistically significant difference existed between WJR and MTX groups. CONCLUSION: WJR likely acts by reducing RANKL expression and increasing OPG expression, thus inhibiting RANKL/RANK interaction and reducing LIGHT expression, thereby inhibiting osteoclast formation/activation to block bone erosion. PMID- 28004301 TI - Evidence and expert opinions: Dry needling versus acupuncture (I) : The American Alliance for Professional Acupuncture Safety (AAPAS) White Paper 2016. AB - In the last twenty years, in the United States and other Western countries, dry needling (DN) became a hot and debatable topic, not only in academic but also in legal fields. This White Paper is to provide the authoritative information of DN versus acupuncture to academic scholars, healthcare professional administrators, lawmakers, and the general public through providing the authoritative evidence and experts' opinions regarding critical issues of DN versus acupuncture, and then reach consensus. DN is the use of dry needles alone, either solid filiform acupuncture needles or hollow-core hypodermic needles, to insert into the body for the treatment of muscle pain and related myofascial pain syndrome. DN is sometimes also known as intramuscular stimulati on, trigger points (TrP) acupuncture, TrP DN, myofascial TrP DN, or biomedical acupuncture. In Western countries, DN is a form of simplified acupuncture using biomedical language in treating myofascial pain, a contemporary development of a portion of Ashi point acupuncture from Chinese acupuncture. It seeks to redefine acupuncture by reframing its theoretical principles in a Western manner. DN-like needling with filiform needles have been widely used in Chinese acupuncture practice over the past 2,000 years, and with hypodermic needles has been used in China in acupuncture practice for at least 72 years. In Eastern countries, such as China, since late of 1800s or earlier, DN is a common name of acupuncture among acupuncturists and the general public, which has a broader scope of indications, not limited to treating the myofascial pain. PMID- 28004302 TI - An ethical evaluation index system for clinical approval of medical technology in China: A structural equation model study. AB - OBJECTIVE: To construct a quantitative ethical evaluation index system for the clinical approval of medical technology in China. METHODS: Exploratory factor analysis (EFA) and first-order confirmatory factor analysis (CFA) based on a structure equation model (SEM), higher-order CFA and normalisation were used to establish an ethical evaluation index system for the clinical approval of medical technology. Data were processed in SPSS 13.0 and Lisre l5.3. RESULTS: There were 52 third class indices, 15 second class indices, and 3 first class indices in this ethical evaluation index system. The weight of each index was calculated by normalisation. CONCLUSION: This study developed a three-level ethical evaluation index system, comprising 70 indices, for the clinical approval of medical technology. PMID- 28004303 TI - Silibinin ameliorates Abeta25-35-induced memory deficits in rats by modulating autophagy and attenuating neuroinflammation as well as oxidative stress. AB - Alzheimer's disease (AD) is a progressive, neurodegenerative disease. Accumulating evidence suggests that inflammatory response, oxidative stress and autophagy are involved in amyloid beta (Abeta)-induced memory deficits. Silibinin (silybin), a flavonoid derived from the herb milk thistle, is well known for its hepatoprotective activities. In this study, we investigated the neuroprotective effect of silibinin on Abeta25-35-injected rats. Results demonstrated that silibinin significantly attenuated Abeta25-35-induced memory deficits in Morris water maze and novel object-recognition tests. Silibinin exerted anxiolytic effect in Abeta25-35-injected rats as determined in elevated plus maze test. Silibinin attenuated the inflammatory responses, increased glutathione (GSH) levels and decreased malondialdehyde (MDA) levels, and upregulated autophagy levels in the Abeta25-35-injected rats. In conclusion, silibinin is a potential candidate for AD treatment because of its anti-inflammatory, antioxidant and autophagy regulating activities. PMID- 28004304 TI - Changes in Fasting and Prandial Gut and Adiposity Hormones Following Vertical Sleeve Gastrectomy or Roux-en-Y-Gastric Bypass: an 18-Month Prospective Study. AB - BACKGROUND: Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) produce substantial weight loss, both primarily through gastric restriction but with potentially different hormonal signaling. This prospective, observational study compared changes in gut-derived hormones in VSG, RYGB, and weight-stable participants at 6 and 18 months post-surgery. METHODS: Sixty-four obese, non diabetic women, including 18 VSG, 23 RYGB, and 23 weight-stable controls completed assessments at baseline and 6 months, before and after consuming a mixed-nutrient meal; blood sampling occurred for 180 min post-meal. Fifty-one participants completed the 18-month outcome. Change from baseline in post prandial area under the curve (over 180 min) for GLP-1, PYY3-36, ghrelin, and leptin was measured at 6 and 18 months post-surgery. RESULTS: At 18 months, VSG and RYGB participants lost a mean (+/-SEM) of 25.5 +/- 2.3% and 34.2 +/- 4.2% of initial weight, respectively (p < 0.156), which both differed (p < 0.001) from the +1.7 +/- 1.0% gain in the control group. Fasting ghrelin declined significantly more in VSG than RYGB participants at both months 6 (p = 0.0199) and 18 (p = 0.0003). In response to the mixed-nutrient meal, GLP-1 and PYY3-36 demonstrated an exaggerated post-prandial response that was significantly greater in RYGB than VSG at 6 months (p < 0.0001 and p = 0.0062, respectively) but not 18 months (p = 0.0296 and p = 0.1210). CONCLUSIONS: VSG and RYGB both produced substantial weight losses at 18 months. The data suggest a role of gastrointestinal hormones as mediators of weight loss. PMID- 28004305 TI - Topiramate in the Treatment of Generalized Convulsive Status Epilepticus in Adults: A Systematic Review with Individual Patient Data Analysis. AB - BACKGROUND: Generalized convulsive status epilepticus (GCSE) is a medical emergency associated with high morbidity and mortality that requires prompt medical intervention. Topiramate (TPM) is an antiepileptic drug effective against a broad spectrum of seizure types, and has been proposed as a possible therapeutic option for super-refractory status epilepticus (SRSE), the most severe form of GCSE. AIM: This review aimed to evaluate the role of TPM in GCSE, including SRSE. METHODS: MEDLINE, CENTRAL, ClinicalTrials.gov, LILACS, Google Scholar, and Opengrey.eu were systematically searched. We compared: (1) patients who did and who did not receive TPM as their last drug; (2) patients receiving TPM as the last drug and achieving SE control and patients receiving TPM as the last drug but without termination of SE. RESULTS: The literature search yielded 1164 results, with individual data available for 35 patients (six with SRSE) from four studies. SE was controlled in 68.6% of patients receiving TPM either as the last drug (20) or not (15), and in 14 of the 20 patients receiving TPM as the last drug (70%). Only six patients received TPM for SRSE; in five of them, TPM was administered as the last drug with resolution of SE in four. When comparing patients who did and did not receive TPM as the last drug, no statistically significant difference was found for any of the variables considered; similarly, no difference was found comparing patients receiving TPM as the last drug and achieving SE control with those receiving TPM as the last drug but without termination of SE. CONCLUSIONS: The lack of a statistically significant difference is likely to be due to the small sample size. In only a few patients was TPM used for SRSE. There is an unmet need for high-quality studies to evaluate the role of TPM in GCSE. PMID- 28004306 TI - Arthroscopic Bankart repair associated with subscapularis augmentation (ASA) versus open Latarjet to treat recurrent anterior shoulder instability with moderate glenoid bone loss: clinical comparison of two series. AB - PURPOSE: The treatment of chronic anterior shoulder instability with glenoid bone loss is still debated. The purpose of this study is to compare short-term results of two techniques treating chronic shoulder instability with moderate glenoid bone loss: bone block according to open Latarjet-Patte procedure and arthroscopic Bankart repair in association with subscapularis augmentation. METHODS: Ninety one patients with moderate anterior glenoid bone loss underwent from 2011 to 2015. From these patients, two groups of 20 individuals each have been selected. The groups were homogeneous in terms of age, gender, dominance and glenoid bone loss. In group A, an open Latarjet procedure has been performed, and in group B, an arthroscopic Bankart repair associated with subscapularis augmentation has been performed. The mean follow-up in group A was 21 months (20-39 months), while in group B was 20 months (15-36 months). QuickDash score, Constant and Rowe shoulder scores, were used for evaluations of results. RESULTS: The mean preoperative rate of QuickDash score was 3.6 for group A and 4.0 for group B; Rowe Score was 50.0 for group A and 50.0 for group B. Preoperative mean Constant score was 56.2 for Latarjet-Patte and 55.2 for Bankart plus ASA. Postoperative mean QuickDash score was in group A 1.8 and 1.7 in group B; Rowe Score was 89.8 and 91.6; Constant Score was 93.3 and 93.8. No complications related to surgery have been observed for both procedures. Not statistically significant difference was reported between the two groups (p > .05). Postoperatively, the mean deficit of external rotation in ER1 was -9 degrees in group A and -8 in group B; In ER2, the mean deficit was -5 degrees in both groups (p = .0942). CONCLUSIONS: Arthroscopic subscapularis augmentation of Bankart repair is an effective procedure for the treatment of recurrent anterior shoulder instability with glenoid bone loss without any significant difference in comparison with the well known open Latarjet procedure. PMID- 28004307 TI - The Potential of Social Media and Internet-Based Data in Preventing and Fighting Infectious Diseases: From Internet to Twitter. AB - Health threats due to infectious diseases used to be a major public health concerns around the globe till mid of twentieth century when effective public health interventions helped in eradicating a number of infectious diseases around the world. Over the past 15 years, there has been a rise in the number of emerging and reemerging infectious diseases being reported such as the Acute Respiratory Syndrome (SARS) in 2002, HINI in 2009, Middle East Respiratory Syndrome (MERS) in 2012, Ebola in 2014, and Zika in 2016. These emerging viral infectious diseases have led to serious public health concerns leading to death and causing fear and anxiety among the public. More importantly, at the moment, the prevention and control of viral infectious diseases is difficult due to a lack of effective vaccines. Thus having real-time reporting tools are paramount to alert relevant public health surveillance systems and authorities about taking the right and necessary actions to control and minimize the potential harmful effects of viral infectious diseases. Social media and Internet-based data can play a major role in real-time reporting to empower active public health surveillance systems for controlling and fighting infectious diseases. PMID- 28004308 TI - Cutaneous Side Effects and Transepidermal Water Loss To Gefitinib: A Study of 11 Patients. AB - INTRODUCTION: Cutaneous side effects caused by epidermal growth factor receptor (EGFR) inhibitors occurred in 45-100% of patients which may lead to therapy modification or interruption. This study aimed to evaluate cutaneous side effects and transepidermal water loss (TEWL) values in non-small cell lung carcinoma (NSCLC) patients who received gefitinib EGFR inhibitor. METHODS: A descriptive observational study with cross-sectional design and a consecutive sampling method was conducted from 1 February to 4 March 2016. Eleven NSCLC patients with EGFR mutation who visited the Hemato-Oncology Clinic/Internal Medicine Department, Dr. Hasan Sadikin General Hospital, Bandung, Indonesia, were assessed through history taking, physical examination, and TEWL examination using Tewameter. RESULTS: Ten of the eleven patients experienced cutaneous side effects. The most frequently observed was xerosis cutis (8/10 patients), followed by acneiform eruptions (7/10 patients), and paronychia (3/10 patients). None of these patients experienced hair changes, mucositis, or drug hypersensitivity. Mean TEWL value of these patients was higher than normal (11.205 +/- 1.881 g/m2/h). CONCLUSIONS: Patients who received gefitinib EGFR inhibitor experienced cutaneous side effects including xerosis cutis, acneiform eruptions, and paronychia, and have mean TEWL values higher than normal. Therefore, it might affect the skin barrier function. PMID- 28004309 TI - A Theoretical Study on the Role of Astrocytic Activity in Neuronal Hyperexcitability by a Novel Neuron-Glia Mass Model. AB - Recent experimental evidence on the clustering of glutamate and GABA transporters on astrocytic processes surrounding synaptic terminals pose the question of the functional relevance of the astrocytes in the regulation of neural activity. In this perspective, we introduce a new computational model that embeds recent findings on neuron-astrocyte coupling at the mesoscopic scale intra- and inter layer local neural circuits. The model consists of a mass model for the neural compartment and an astrocyte compartment which controls dynamics of extracellular glutamate and GABA concentrations. By arguments based on bifurcation theory, we use the model to study the impact of deficiency of astrocytic glutamate and GABA uptakes on neural activity. While deficient astrocytic GABA uptake naturally results in increased neuronal inhibition, which in turn results in a decreased neuronal firing, deficient glutamate uptake by astrocytes may either decrease or increase neuronal firing either transiently or permanently. Given the relevance of neuronal hyperexcitability (or lack thereof) in the brain pathophysiology, we provide biophysical conditions for the onset identifying different physiologically relevant regimes of operation for astrocytic uptake transporters. PMID- 28004310 TI - High Body Mass Index and Use of Fentanyl Iontophoretic Transdermal System in Postoperative Pain Management: Results of a Pooled Analysis of Six Phase 3/3B Trials. AB - INTRODUCTION: Postoperative pain management can be challenging in patients with a high body mass index (BMI) especially as a result of poor venous access and delayed ambulation that can result in serious complications. Fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient-controlled analgesic method available for use in acute postoperative pain. The primary objective of these analyses was to determine if there were any differences between patients with high BMI (>40 kg/m2) and lower BMIs (<30 kg/m2 and 35-40 kg/m2) in terms of efficacy or safety. METHODS: Data from three registration, placebo-controlled trials and three active-comparator trials using fentanyl ITS (IONSYS(r), The Medicines Company, Parsippany, NJ) for the management of postoperative pain were analyzed using BMI categories of <35 kg/m2, 35-40 kg/m2, and >40 kg/m2. The majority of patients had lower abdominal or orthopedic surgery. For these analyses, the primary efficacy variables were assessed via patient global assessment of pain control (PGA) at 24 h and investigator global assessment (IGA) at study discharge. PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment "success" defined as either excellent or good. Safety was evaluated via treatment emergent adverse events (TEAEs). RESULTS: There were 1403 patients randomly assigned and treated with fentanyl ITS for at least 3 h (BMI <35 kg/m2: 1180; 35-40 kg/m2: 136, BMI >40 kg/m2: 85; and 2 missing). PGA treatment success, which evaluates the method of pain control, at 24 h was consistent in the high and low BMI groups in patients treated with fentanyl ITS (<35 kg/m2: 946/1180 [80.2%]; 35-40 kg/m2: 103/136 [75.7%]; and >40 kg/m2: 65/85 [76.5%]). The IGA results at study discharge were similar to the PGA. Safety appeared similar with fentanyl ITS across the BMI groups. CONCLUSION: In these analyses, fentanyl ITS was as efficacious, as assessed by the PGA ratings of treatment "success", in patients with high BMI (>40 kg/m2) as it was for those with lower BMIs (<35 kg/m2 or 35-40 kg/m2) and was generally well tolerated across all BMI categories. PMID- 28004311 TI - Does inflammation get on nerves in patients with heart failure? PMID- 28004312 TI - Quantitative measurements of myocardial perfusion and function from SPECT (and PET) studies depend on the method used to perform those measurements. PMID- 28004313 TI - Gated SPECT myocardial perfusion imaging quality assurance in current and future practice. PMID- 28004314 TI - Pharmacological Treatment in gamma-Hydroxybutyrate (GHB) and gamma-Butyrolactone (GBL) Dependence: Detoxification and Relapse Prevention. AB - The misuse of gamma-hydroxybutyrate (GHB) for recreational purposes has resulted in an increase in GHB-related problems such as intoxications, dependence and withdrawal in several countries in Europe, Australia and the US over the last decade. However, prevalence rates of misuse of GHB and its precursor, gamma butyrolactone (GBL), are still relatively low. In this qualitative review paper, after a short introduction on the pharmacology of GHB/GBL, followed by a summary of the epidemiology of GHB abuse, an overview of GHB dependence syndrome and GHB/GBL withdrawal syndrome is provided. Finally, the existing literature on management of GHB detoxification, both planned and unplanned, as well as the available management of GHB withdrawal syndrome, is summarized. Although no systematic studies on detoxification and management of withdrawal have been performed to date, general recommendations are given on pharmacological treatment and preferred treatment setting. PMID- 28004315 TI - Bioflavonoid Fisetin Loaded alpha-Tocopherol-Poly(lactic acid)-Based Polymeric Micelles for Enhanced Anticancer Efficacy in Breast Cancers. AB - PURPOSE: In this study, tocopherol based polymeric micelles were successfully prepared to enhance the anticancer effect of fisetin (FIS) in breast cancer cells. METHODS: The drug-loaded carrier was characterized in terms of physicochemical and in vivo parameters. RESULTS: Compared to FIS, FIS-TPN showed higher cellular uptake in MCF-7 breast cancer cells as revealed by CLSM and flow cytometry. The cytotoxicity assay results clearly showed that the free FIS and FIS-TPN exhibited a typical dose-dependent toxic effect in MCF-7 breast cancer cells. Especially, enhanced cytotoxic effect of FIS was observed when loaded in a nanocarrier. Free FIS induced a ~11% apoptosis whereas FIS-TPN induced a significantly greater apoptosis of ~20% by the end of 24 h. At 48 h, similar trend continued and free FIS showed ~30% of apoptosis whereas ~42% cell apoptosis was observed in FIS-TPN treated group. Notably, migration of cancer cell was significantly inhibited when treated with FIS-TPN formulations. The FIS-TPN significantly reduced to tumor burden and H&E staining showed the lowest tumor volume and higher cell apoptosis. CONCLUSIONS: All the findings suggest that the fisetin-loaded TPGS-PLA polymeric micelles serve as a potential candidate and promising alternative for the effective treatment of breast cancers. PMID- 28004316 TI - Denatured Whey Protein Powder as a New Matrix Excipient: Design and Evaluation of Mucoadhesive Tablets for Sustained Drug Release Applications. AB - PURPOSE: In earlier study, we proposed denatured whey protein (DWP) powder obtained by atomization as a new excipient to promote oral drug delivery. In this work, we evaluate the possibility to formulate tablets based on DWP powders and to characterize their role as a matrix mucoadhesive excipient. METHODS: Tablets containing increased amount of DWP (10 to 30%) were produced by direct compression after mixing with theophylline, microcrystalline cellulose, Aerosil(r) and magnesium stearate. Dissolution behaviors of obtained tablets were evaluated in different USP buffers (pH 1.2, 4.5 and 6.8) and in simulated gastric and intestinal fluids and mechanisms analyzed by multiple mathematical models. Swelling, erosion and mucoadhesion were also evaluated. Finally, release and absorption were studied in the artificial digestive system (TIM 1). RESULTS: Tablets based on DWP and containing 300 mg of theophylline were obtained by direct compression. These tablets exhibited controlled release driven by diffusion starting from 15% DWP content whatever the pH studied. They also showed a great extent of swelling and water uptake while matrix weight loss was limited. Addition of enzymes accelerated drug release which became governed by erosion according to Peppas model. CONCLUSIONS: The present study shows that DWP powders can be successfully used as a pharmaceutical excipient, and in particular as a matrix mucoadhesive controlled release tablets. PMID- 28004317 TI - Biodegradable Polymersomes as Nanocarriers for Doxorubicin Hydrochloride: Enhanced Cytotoxicity in MCF-7/ADR Cells and Prolonged Blood Circulation. AB - PURPOSE: DOX is one of the most potent anticancer drugs. But its short half-life and the occurrence of multi-drug resistance (MDR) markedly limit its clinical application. To solve these problems, we develop DOX loaded polymersomes (DOX polymersomes). METHODS: An methoxy poly(ethylene glycol)-b-poly(epsilon caprolactone) (mPEG-b-PCL) copolymer was synthesized and used to prepare DOX polymersomes. The pharmaceutical properties of DOX polymersomes were characterized. The in vitro release profile of DOX from polymersomes was investigated. The in vitro cytotoxicity and cell uptake studies were performed on MCF-7 and MCF-7/ADR cells. The in vivo pharmacokinetic profiles were investigated on Sprague-Dawley rats. RESULTS: DOX polymersomes had a nano-scale particle size of about 60 nm with a hydrophobic membrane about 10 nm in thickness. Release of DOX from the polymersomes took place in a sustained manner. Cell experiments showed DOX polymersomes enhanced the cytotoxicity and the intracellular accumulation of DOX in MCF-7/ADR cells, compared with free DOX. In vivo pharmacokinetic study showed the DOX polymersomes increased the bioavailability and prolonged the circulation time in rats. CONCLUSIONS: The entrapment of DOX in biodegradable polymersomes could enhance cytotoxicity in MCF-7/ADR cells and improve its in vivo pharmacokinetic profile. PMID- 28004318 TI - Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging. AB - PURPOSE: A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XMUCT) and terahertz pulsed imaging (TPI). METHODS: Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XMUCT and TPI. Liquid self nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined. RESULTS: A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XMUCT data. The print resolution and accuracy was characterised by XMUCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5 +/- 0.75% larger than designed; n = 3). CONCLUSIONS: The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XMUCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms. PMID- 28004319 TI - Testing a model of health-related quality of life in women living with HIV infection. AB - PURPOSE: The purpose of this secondary analysis was to test Ferrans et al.'s (J Nurs Scholarsh 37(4):336-342, 2005) revised model of health-related quality of life (HRQoL) (2005) modified from the Wilson and Cleary (J Am Med Assoc 273(1):59 65, 1995) model on women living with HIV. The primary aim was to test this model, examining the relations among the five central components (biological function, symptoms, functional status, general health perceptions, and HRQoL). The secondary aim was to explore the individual (age, children, race, marital status, education) and environmental (HIV-related stigma, social support) characteristics that may impact the main components of the model. METHODS: This study employed a cross-sectional correlational design using baseline data from 178 women living with HIV/AIDS who participated in one of the two independent randomized controlled trials designed to enhance HIV medication adherence. Path analysis using structural equation modeling was used to examine the hypothesized multivariate relations proposed in the revised Wilson and Cleary (J Am Med Assoc 273(1):59-65, 1995) model of HRQoL. RESULTS: While the revised model did not fit, exploratory post hoc modified models with a path from depressive symptoms to overall general health had an adequate model fit. Women with lower depressive symptoms (r = -.457, p < .01), lower HIV-related stigma (r = -.462, p < .01), higher social support (r = .413, p < .01), higher physical functioning (r = .350, p < .01), and higher general health perceptions (r = .537, p < .01) had higher overall HRQoL. CONCLUSIONS: The results of this study have the potential to assist healthcare professionals in improving HRQoL for women living with HIV/AIDS. PMID- 28004320 TI - Sensitivity and responsiveness of the EQ-5D-3L in patients with uncontrolled focal seizures: an analysis of Phase III trials of adjunctive brivaracetam. AB - PURPOSE: Preference-based measures are required to measure the impact of interventions for cost-effectiveness analysis. This study assessed the psychometric performance of the EQ-5D-3L in adults with uncontrolled focal (partial-onset) seizures. METHODS: Data from three Phase III studies of an antiepileptic drug (adjunctive brivaracetam; n = 1095) were used. Analysis included correlations between EQ-5D-3L and Quality of Life in Epilepsy Inventory (QOLIE-31P) and seizure frequency. Known group validity was based on ability of the EQ-5D-3L to discriminate between baseline QOLIE-31P total scores, seizure type and number of antiepileptic drugs using effect sizes (ES). Responsiveness assessed proportions reporting highest or lowest scores, overall change using standardized response means (SRM) and change by responder and clinician/patient evaluation groups using ES. RESULTS: Correlations were weak to moderate (rho = 0.2-0.4) between EQ-5D-3L dimensions and QOLIE-31P subscales, apart from medication effects (rho < 0.1); seizure frequency was not associated with either measure. Known group analysis had small ES. A quarter (24.9%) of patients had a baseline EQ-5D-3L utility score of 1 (full health) but lower average QOLIE-31P scores. SRMs were small (<0.1) in EQ-5D-3L compared with 0.1-0.4 for QOLIE-31P subscales. Results across the studies were mixed for responder status and clinician/patient evaluation of improvement for EQ-5D-3L. CONCLUSIONS: EQ-5D-3L had weak-to-moderate correlations with QOLIE-31P and varied with QOLIE-31P severity groups, but showed less responsiveness than QOLIE-31P. Given this lack of sensitivity, EQ-5D-3L may not be appropriate for measuring the impact of interventions in cost-effectiveness analysis in this population and disease specific preference-based measures may be more appropriate. PMID- 28004321 TI - Improvement in the quality of life following cholecystectomy: a randomized multicenter study of health status (RAND-36) in patients with laparoscopic cholecystectomy versus minilaparotomy cholecystectomy. AB - PURPOSE: The assessment of the quality of life (QoL) in minilaparotomy cholecystectomy (MC) versus laparoscopic cholecystectomy (LC) with the ultrasonic dissection in both groups has not been addressed earlier. METHODS: Initially, 109 patients with non-complicated symptomatic gallstone disease were randomized to undergo either MC (n = 59) or LC (n = 50). RAND-36 survey was conducted preoperatively and at 4 weeks and 6 months postoperatively. The end point of our study was to determine differences in health status in MC versus LC groups. RESULTS: QoL improved significantly in both groups, and the recovery was similar in the two groups, except from the higher score in 'health change' subscale at 4 weeks in MC group [MC score 75.0 (25.0) vs. LC score 56.5 (23.2), p = 0.008]. The MC and LC groups combined, RAND-36 scores increased significantly in 'physical functioning' [combined mean (SD) preoperative score 80.5 (23.9) vs. 6-month postoperative score 86.5 (21.7), p = 0.015], 'vitality' [64.5 (19.2) vs. 73.5 (18.3), p = 0.001], 'health change' [43.0 (21.6) vs. 74.6 (25.4), p = 0.0001] and 'bodily pain' scores [57.7 (26.3) vs. 75.5 (25.5), p = 0.001], respectively. Four RAND-36 domains indicated statistically significant health status differences in comparing the preoperative and postoperative RAND-36 scores in LC and MC groups combined. CONCLUSIONS: Four RAND-36 domains indicated a significant positive change in QoL after cholecystectomy. PMID- 28004322 TI - Liver stiffness predicts the response to direct-acting antiviral-based therapy against chronic hepatitis C in cirrhotic patients. AB - The purpose of this investigation was to evaluate the impact of liver stiffness (LS) on the response to direct-acting antiviral (DAA)-based therapy against hepatitis C virus (HCV) infection in cirrhotic patients. Those patients included in two Spanish prospective cohorts of patients receiving therapy based on at least one DAA, who showed a baseline LS >= 12.5 kPa and who had reached the scheduled time point for sustained virological response evaluation 12 weeks after completing therapy (SVR12) were analysed. Pegylated interferon/ribavirin-based therapy plus an HCV NS3/4A protease inhibitor (PR-PI group) was administered to 198 subjects, while 146 received interferon-free regimens (IFN-free group). The numbers of patients with SVR12 according to an LS < 21 kPa versus >=21 kPa were 59/99 (59.6%) versus 46/99 (46.5%) in the PR-PI group (p = 0.064) and 41/43 (95.3%) versus 90/103 (87.4%) in the IFN-free group (p = 0.232). Corresponding figures for the relapse rates in those who presented end-of-treatment response (ETR) were 3/62 (4.8%) versus 10/56 (17.9%, p = 0.024) and 1/42 (2.4%) versus 8/98 (8.2%, p = 0.278), respectively. In a multivariate analysis adjusted for age, sex and use of interferon, a baseline LS >= 21 kPa was identified as an independent predictor of relapse [adjusted odds ratio, AOR (95% confidence interval, CI): 4.228 (1.344-13.306); p = 0.014] in those patients with ETR. LS above 21 kPa is associated with higher rates of relapse to DAA-based therapy in HCV-infected patients with cirrhosis in clinical practice. LS could help us to tailor the duration and composition of DAA-based combinations in cirrhotic subjects, in order to minimise the likelihood of relapse. PMID- 28004323 TI - Rapid MRSA PCR on respiratory specimens from ventilated patients with suspected pneumonia: a tool to facilitate antimicrobial stewardship. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of pneumonia in ventilated patients. Our objective was to evaluate the GeneXpert MRSA/SA SSTI Assay (Xpert MRSA/SA) (Cepheid, Sunnyvale, CA) for use in lower respiratory tract (LRT) specimens for rapid MRSA detection and to determine the potentially saved antibiotic-days if a culture-based identification method was replaced by this assay. Remnant LRT samples from ventilated patients submitted to the microbiology laboratory for routine culture were tested using conventional culture and Xpert MRSA/SA. One hundred of 310 LRT specimens met the inclusion criteria. Ten samples were positive for MRSA by Xpert MRSA/SA, while six were positive by routine culture methods. Xpert MRSA/SA correctly identified 5/6 positive and 89/94 negative MRSA specimens, for a sensitivity of 83.3%, specificity of 94.7%, positive predictive value of 45.6%, and negative predictive value of 98.9%. The assay also correctly detected 3/3 positive and 90/97 negative methicillin-susceptible S. aureus (MSSA) specimens, for a sensitivity of 100%, specificity of 92.8%, positive predictive value of 30%, and negative predictive value of 100%. A total of 748 vancomycin and 305 linezolid antibiotic-days were associated with the enrolled specimens. Vancomycin and linezolid utilization could decrease by 68.4% and 83%, respectively, if discontinued 1 day after negative polymerase chain reaction (PCR) results. The Xpert MRSA/SA SSTI rapid MRSA PCR assay performed well in respiratory samples from ventilated patients with suspected pneumonia and has the potential to facilitate stewardship efforts such as reducing empiric vancomycin and linezolid therapy. PMID- 28004324 TI - CT characteristics of traumatic sacral fractures in association with pelvic ring injuries: correlation using the Young-Burgess classification system. AB - PURPOSE: The purpose of the study is to determine the incidence of sacral fracture patterns on CT imaging of pelvic trauma patients with correlation with mechanism of injury and pelvic ring injury pattern using the Young-Burgess classification system. MATERIALS AND METHODS: This is a retrospective review of all pelvic CTs with pelvic fractures performed at our level 1 trauma center during a 4-year period from July 2010 to June 2014. RESULTS: Sacral fractures were very common in pelvic trauma patients, being present in 60% of patients presenting to our institution with pelvic fractures. Longitudinal fractures were almost always associated with additional pelvic ring injuries. Denis zone 1 fractures had the highest association with lateral compression pelvic ring injuries. Denis zone 2 and 3 fractures were seen with increased frequency in AP compression and vertical shear injuries. A third of transverse sacral fractures occurred in isolation, with isolated transverse sacral fractures typically occurring in the low (S3-S5) sacrum. Almost half of combined transverse and longitudinal sacral fractures occurred without an additional pelvic fracture present. Sacral avulsions almost always occurred as part of a pelvic ring fracture pattern, most commonly in AP compression injuries. Coccyx fractures frequently occurred in isolation, but were commonly seen in vertical shear injuries when associated with a pelvic ring injury pattern. CONCLUSION: Avulsion fractures and longitudinal fractures of the sacrum are almost always associated with anterior pelvic ring injury. Conversely, transverse fractures of the lower sacrum and combined longitudinal and transverse sacral fractures are prone to occur in isolation. PMID- 28004325 TI - Remarkable CT features of shock thyroid in traumatic and non-traumatic patients. AB - Shock thyroid is a part of the hypovolemic shock complex, which is a constellation of secondary computed tomographic (CT) findings that are observed in patients with hypovolemic shock. However, to the best of our knowledge, there has only been a single report on this condition, which described three cases associated with significant thoracoabdominal trauma. Here, we report four patients with profound hypotension who exhibited similar CT findings as those described in the initial report on shock thyroid, but with a more diverse clinical spectrum. PMID- 28004326 TI - Utility of MDCT findings in predicting patient management outcomes in renal trauma. AB - PURPOSE: The purpose of this study is to assess the utility of computed tomography (CT) in predicting clinical outcomes in renal trauma. MATERIALS/METHODS: This retrospective study was IRB approved and HIPAA compliant; informed consent was waived. One-hundred-sixty-two, trauma-related renal injuries (157 adults) from January 01, 2006 to December 31, 2013 were included in this retrospective study. CT findings of vascular and collecting system (CS) injuries were recorded, and American Association for the Surgery of Trauma (AAST) renal injury grades were assigned. Fisher's exact test evaluated correlations between AAST grade and active hemorrhage, AAST grade and surgical/endovascular therapy, active hemorrhage and surgical/endovascular therapy, and size of perinephric hematomas and CS injuries. The unpaired t test correlated to the size of perinephric hematomas in CS injuries diagnosed on initial versus repeat imaging. RESULTS: AAST grades were as follows: 120 grades I-III and 42 grade IV/V. Active hemorrhage was diagnosed in 25 (15%) patients and CS injury in 22 (14%) patients. Seven (8%) patients received surgical/endovascular therapy. There were statistically significant correlations between AAST grade and active hemorrhage (p = 0.003), active hemorrhage and surgical/endovascular therapy (p < 0.0001), and large perinephric hematomas (>2 cm) and CS injuries (p < 0.0001). There was no significant correlation between AAST grade and surgical/endovascular therapy (p = 0.08). Of the CS injuries (50%), 11/22 had no evidence of CS injury on initial imaging, being detected on follow-up CT. These "masked cases" demonstrated significant differences in perinephric hematoma size when compared to CS injuries diagnosed on initial imaging (p = 0.01). CONCLUSION: Active hemorrhage in renal trauma is a significant predictor of surgical/endovascular therapy, in contradistinction to the AAST grade. In collecting system injuries, a large fraction was not detectable on initial CT, supporting the need for repeat imaging in cases with large perinephric hematomas. PMID- 28004327 TI - Nutritional and Bioenergetic Considerations in Critically Ill Patients with Acute Neurological Injury. AB - The brain, due to intensive cellular processes and maintenance of electrochemical gradients, is heavily dependent on a constant supply of energy. Brain injury, and critical illness in general, induces a state of increased metabolism and catabolism, which has been proven to lead to poor outcomes. Of all the biochemical interventions undertaken in the ICU, providing nutritional support is perhaps one of the most undervalued, but potentially among the safest, and most effective interventions. Adequate provisions of calories and protein have been shown to improve patient outcomes, and guidelines for the nutritional support of the critically ill patient are reviewed. However, there are no such specific guidelines for the critically ill patient with neurological injury. Patients with primary or secondary neurological disorders are frequently undernourished, while data suggest this population would benefit from early and adequate nutritional support, although comprehensive clinical evidence is lacking. We review the joint recommendations from the Society for Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition, as they pertain to neurocritical care, and assess the recommendations for addressing nutrition in this patient population. PMID- 28004328 TI - Management of Acute Hypertensive Response in Intracerebral Hemorrhage Patients After ATACH-2 Trial. AB - Acute hypertensive response is elevation of systolic blood pressure (SBP) in the first 24 h after symptom onset which is highly prevalent in patients with intracerebral hemorrhage (ICH). Observational studies suggested association between acute hypertensive response and hematoma expansion, peri-hematoma edema and death and disability, and possible reduction in these adverse outcomes with treatment of acute hypertensive response. Recent clinical trials have focused on determining the clinical efficacy of early intensive SBP reduction in ICH patients. The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-2) trial was the latest phase 3 randomized controlled multicenter clinical trial aimed to study the efficacy of early intensive reduction of SBP in ICH patients. In this review article, we summarize the results of recent clinical trials, treatment principles based on the latest guidelines, and the anticipated interpretation and incorporation of ATACH-2 trial results in clinical practice. PMID- 28004329 TI - Validation of the Glycemic Stress Index in Pediatric Neurosurgical Intensive Care. AB - BACKGROUND: Studies have suggested that both the degree and the duration of hyperglycemia are independent risk factors for adverse outcome both in pediatric anesthesia and in critically ill children. In a recent paper, we combined intraoperative glycemic variations and length of surgery creating a metabolic glucose-related stress index called "Glycemic Stress Index" (GSI). AIM: To validate GSI for predicting PICU stay in a population of children undergoing different major neurosurgical procedures. METHODS: A total of 352 patients with craniotomy were enrolled. Basic clinical data and PICU length of stay were recorded real time. Intraoperative blood loss has been determined considering the estimated red cell volume loss ratio. GSI was calculated and subjected to ROC analysis having as targets PICU length of stay >100 or >200 h. RESULTS: The overall mean PICU stay was 35 h. Correlation analysis confirmed a low but highly significant direct correlation between GSI and PICU length of stay. ROC analysis showed an area under the ROC curve (AUC) of 0.74 (p = 0.03) for GSI to predict PICU stay >200 h and an AUC of 0.67 (p = 0.01) to predict PICU stay >100 h. Best predictive cutoff values were 4.5 and 3.9, for PICU stay >200 and >100 h, respectively. Overall accuracy for the test is higher in predicting PICU stay >200 h. CONCLUSIONS: GSI significantly predicts prolonged PICU stay after major neurosurgery in a mixed population of children affected by different neurosurgical conditions. PMID- 28004330 TI - Lymphopenia, Infectious Complications, and Outcome in Spontaneous Intracerebral Hemorrhage. AB - BACKGROUND: Lymphopenia is increasingly recognized as a consequence of acute illness and may predispose to infections. We investigated whether admission lymphopenia (AL) is associated with increased risk of infectious complications and poor outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: We retrospectively analyzed a prospectively collected cohort of ICH patients ascertained between 1994 and 2015. We identified subjects with lymphocyte count obtained within 24 h from onset, and AL was defined as lymphocyte count <1000/MUL. Infectious complications were assessed through retrospective chart review. Association between AL, infections, and mortality was investigated using multivariable logistic regression. RESULTS: Of the 2014 patients meeting inclusion criteria, 548 (27.2%) had AL and 605 (30.0%) developed an infectious complication. Case-fatality at 90 days was 36.9%. Patients with AL had larger hematoma volumes, higher frequency of intraventricular hemorrhage, and lower Glasgow Coma Scale score on presentation (all p < 0.001). AL was independently associated with increased risk of pneumonia [odds ratio (OR) 1.97, 95% confidence interval (CI) 1.50-2.58, p < 0.001] and multiple infections (OR 1.84, 95% CI 1.24-2.71, p = 0.003). AL was also an independent predictor of 90 day mortality (OR 1.55, 95% CI 1.18-2.04, p = 0.002) after adjusting for confounders. CONCLUSIONS: AL is common in ICH patients and independently associated with increased risk of infectious complications and poor outcome. Further studies will be needed to determine whether prophylactic antibiotics in ICH patients with AL can improve outcome. PMID- 28004331 TI - Delayed Deterioration of EEG Background Rhythm Post-cardiac Arrest. AB - BACKGROUND: Electroencephalogram (EEG) background continuity is associated with a favorable prognosis in cardiac arrest patients post-therapeutic hypothermia. However, the continuous EEG in a subset of patients will undergo 'delayed EEG deterioration'; they will invariably have poor outcome. The aim of this study was to characterize this phenomenon. METHODS: We studied a prospectively collected cohort of consecutive cardiac arrest patients who underwent therapeutic hypothermia between July 2012 and May 2015. We identified patients with an initially favorable EEG rhythm post-cooling and characterized a subset of patients with delayed EEG deterioration. RESULTS: A total of 133 patients were included in the analysis. Of these, 69/133 (51.9%) had an initially favorable EEG. Of those patients with initially favorable EEG, 7/69 (10.1%) had a subsequent deterioration. Delayed EEG deterioration was associated with poor outcome. The median time to deterioration was 55 h. CONCLUSIONS: Delayed EEG deterioration is associated with poor clinical outcomes. We hypothesize that this is the result of delayed neuronal degeneration, the exact mechanism requiring further exploration. Identifying patients with delayed EEG deterioration post therapeutic hypothermia is paramount as further interventions may yet salvage their outcomes, though further study is needed. PMID- 28004332 TI - Clinical and Laboratory Characteristics for the Diagnosis of Bacterial Ventriculitis After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: The diagnosis of nosocomial bacterial ventriculitis in patients with subarachnoid hemorrhage (SAH) can be challenging. METHODS: We performed a retrospective study on the diagnostic accuracy of clinical and laboratory characteristics for the diagnosis of bacterial ventriculitis in 209 consecutive patients with an aneurysmal SAH admitted in a tertiary referral center from 2008 to 2010. Diagnostic value of clinical characteristics and inflammatory indexes in CSF and blood were determined for three diagnostic categories: (1) no suspicion for bacterial ventriculitis; (2) clinical suspicion for bacterial ventriculitis, defined as initiation of empirical antibiotic treatment for ventriculitis, but negative CSF cultures; and (3) CSF culture-positive bacterial ventriculitis. RESULTS: Empirical antibiotics for suspected ventriculitis was initiated in 48 of 209 (23 %) patients. CSF cultures were positive in 11 (5 %) patients. Within the group of suspected ventriculitis, only longer duration of CSF drainage and lower CSF red blood cell counts predicted for culture positivity. None of the other clinical features or inflammatory indexes in CSF and blood were associated with culture-proven bacterial ventriculitis. CONCLUSIONS: Nosocomial bacterial ventriculitis in patients with aneurysmal SAH is often suspected but confirmed by culture in a minority of cases. Improvement of diagnostics for nosocomial bacterial ventriculitis in patients with aneurysmal SAH is needed. PMID- 28004333 TI - The Relationship Between the Decreased Rate of Initial Blood Glucose and Neurologic Outcomes in Survivors of Out-of-Hospital Cardiac Arrest Receiving Therapeutic Hypothermia. AB - BACKGROUND: Hyperglycemia in out-of-hospital cardiac arrest (OHCA) survivors is associated with poor outcomes. However, in the control of initial hyperglycemia, an adequate strategy to improve patients' neurologic outcomes remains undetermined. Prior to the establishment of such strategy, we need to determine whether a decreased rate of initial blood glucose (BG) affects patient outcomes. METHODS: One hundred and forty-five adult non-traumatic OHCA survivors treated with therapeutic hypothermia between April 2007 and December 2011 were enrolled in this single-center retrospective cohort study. Based on the cerebral performance category (CPC) at 6 months after OHCA, study populations were categorized as "Good CPC group" (favorable outcome, CPC1 and CPC2) and "Poor CPC group" (unfavorable outcome, CPC3-CPC5). Variables related to BG were obtained, and the rate of BG change was calculated. RESULTS: In the Good CPC group, the time required to attain target BG levels was shorter [7.4 (2.97-18.13) vs. 13.17 (7.55-27.0) h, p < 0.001], and the average rate of glucose decrease until the attainment of target BG levels was faster [17.06 (6.67-34.49) vs. 8.33 (4.26 18.55) mg/dl/h, p = 0.005] than in the Poor CPC group. Using multivariate analysis, the faster rate (odds ratio 1.074; 95% confidence interval 1.029-1.12; p = 0.001) and the shorter time (odds ratio 13.888; 95% confidence interval 2.271 84.906; p = 0.004) required to attain target BG levels were independently related to favorable neurologic outcomes. CONCLUSIONS: Faster rates of initial BG decrease and the shorter time required to attain target BG levels were associated with favorable neurologic outcome in survivors of OHCA receiving therapeutic hypothermia. PMID- 28004335 TI - Self-determination theory and weight loss in a Diabetes Prevention Program translation trial. AB - We examined self-determination theory (SDT) and weight loss, and hypothesized that the Diabetes Prevention Program's (DPP) intervention would result in an increase in autonomous regulation of motivation (AR) in participants. Further, that those with higher AR, and those who perceived educators as supporting SDT defined needs, would lose more weight. Support, Health Information, Nutrition and Exercise (SHINE) Study data (N = 257) were analyzed. SHINE was a randomized, controlled DPP translation trial (2-years, telephonic, primary care staff). Autonomous motivation in males increased significantly, while females showed no change. Males with high AR, but not females, lost more weight. However, the significance of these relationships varied over time. Participants who perceived educators as more supportive of psychological needs lost more weight (especially males). However, effect of support on weight loss was not mediated by AR change. Autonomous motivation and educator support are relevant to male weight loss. Future research might develop interventions to enhance autonomous motivation and educator support, and understand change pathways. PMID- 28004336 TI - Quantification of the IgG2/4 kappa Monoclonal Therapeutic Eculizumab from Serum Using Isotype Specific Affinity Purification and Microflow LC-ESI-Q-TOF Mass Spectrometry. AB - As therapeutic monoclonal antibodies (mAbs) become more humanized, traditional tryptic peptide approaches used to measure biologics in serum become more challenging since unique clonotypic peptides used for quantifying the mAb may also be found in the normal serum polyclonal background. An alternative approach is to monitor the unique molecular mass of the intact light chain portion of the mAbs using liquid chromatography-mass spectrometry (LC-MS). Distinguishing a therapeutic mAb from a patient's normal polyclonal immunoglobulin (Ig) repertoire is the primary limiting factor when determining the limit of quantitation (LOQ) in serum. The ability to selectively extract subclass specific Igs from serum reduces the polyclonal background in a sample. We present here the development of an LC-MS method to quantify eculizumab in serum. Eculizumab is a complement component 5 (C5) binding mAb that is fully humanized and contains portions of both IgG2 and IgG4 subclasses. Our group developed a method that uses Life Technologies CaptureSelect IgG4 (Hu) affinity matrix. We show here the ability to quantitate eculizumab with a LOQ of 5 mcg/mL by removing the higher abundance IgG1, IgG2, and IgG3 from the polyclonal background, making this approach a simple and efficient procedure. Graphical Abstract ?. PMID- 28004334 TI - Noninvasive Neuromonitoring: Current Utility in Subarachnoid Hemorrhage, Traumatic Brain Injury, and Stroke. AB - Noninvasive neuromonitoring is increasingly being used to monitor the course of primary brain injury and limit secondary brain damage of patients in the neurocritical care unit. Proposed advantages over invasive neuromonitoring methods include a lower risk of infection and bleeding, no need for surgical installation, mobility and portability of some devices, and safety. The question, however, is whether noninvasive neuromonitoring is practical and trustworthy enough already. We searched the recent literature and reviewed English-language studies on noninvasive neuromonitoring in subarachnoid hemorrhage, traumatic brain injury, and ischemic and hemorrhagic stroke between the years 2010 and 2015. We found 88 studies that were eligible for review including the methods transcranial ultrasound, electroencephalography, evoked potentials, near-infrared spectroscopy, bispectral index, and pupillometry. Noninvasive neuromonitoring cannot yet completely replace invasive methods in most situations, but has great potential being complementarily integrated into multimodality monitoring, for guiding management, and for limiting the use of invasive devices and in-hospital transports for imaging. PMID- 28004337 TI - Erratum to: The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model. PMID- 28004338 TI - Network Analysis Identifies Disease-Specific Pathways for Parkinson's Disease. AB - Neurodegenerative diseases are characterized by the progressive loss of specific neurons in selected regions of the central nervous system. The main clinical manifestation (movement disorders, cognitive impairment, and/or psychiatric disturbances) depends on the neuron population being primarily affected. Parkinson's disease is a common movement disorder, whose etiology remains mostly unknown. Progressive loss of dopaminergic neurons in the substantia nigra causes an impairment of the motor control. Some of the pathogenetic mechanisms causing the progressive deterioration of these neurons are not specific for Parkinson's disease but are shared by other neurodegenerative diseases, like Alzheimer's disease and amyotrophic lateral sclerosis. Here, we performed a meta-analysis of the literature of all the quantitative proteomic investigations of neuronal alterations in different models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis to distinguish between general and Parkinson's disease-specific pattern of neurodegeneration. Then, we merged proteomics data with genetics information from the DisGeNET database. The comparison of gene and protein information allowed us to identify 25 proteins involved uniquely in Parkinson's disease and we verified the alteration of one of them, i.e., transaldolase 1 (TALDO1), in the substantia nigra of 5 patients. By using open source bioinformatics tools, we identified the biological processes specifically affected in Parkinson's disease, i.e., proteolysis, mitochondrion organization, and mitophagy. Eventually, we highlighted four cellular component complexes mostly involved in the pathogenesis: the proteasome complex, the protein phosphatase 2A, the chaperonins CCT complex, and the complex III of the respiratory chain. PMID- 28004339 TI - BACE1-Deficient Mice Exhibit Alterations in Immune System Pathways. AB - BACE1 encodes for the beta-site amyloid precursor protein cleaving enzyme 1 or beta-secretase. Genetic deletion of Bace1 leads to behavioral alterations and affects midbrain dopaminergic signaling and memory processes. In order to further understand the role of BACE1 in brain function and behavior, we performed microarray transcriptome profiling and gene pathway analysis in the hippocampus of BACE1-deficient mice compared to wild type. We identified a total of 91 differentially expressed genes (DEGs), mostly enriched in pathways related to the immune and inflammation systems, particularly IL-9 and NF-kappaB activation pathways. Serum levels of IL-9 were elevated in BACE1-deficient mice. Our network analysis supports an intimate connection between immune response via NF-kappaB and BACE1 signaling through the NRG1/Akt1 pathway. Our findings warrant future mechanistic studies to determine if BACE1 signaling and the IL-9 pathway interact to alter behavior and brain function. This study opens new avenues in the investigation of hippocampus-related neuroimmunological and neuroinflammation associated disorders. PMID- 28004340 TI - Lipoprotein (a) as a Predictor of Early Stroke Recurrence in Acute Ischemic Stroke. AB - Inflammation plays a crucial role in the pathogenesis of stroke. This study aims to determine lipoprotein (a) [Lp(a)] levels in serum and to investigate their associations with stroke recurrence events in a 3-month follow-up study in patients with acute ischemic stroke (AIS). Serum Lp(a) levels were determined in 203 ischemic stroke patients and 120 normal controls at admission. The severity and clinical outcome of ischemic stroke patients were evaluated by the National Institutes of Health Stroke Scale (NIHSS). We followed the participants for a median of 3 months using a standard questionnaire to determine the stroke recurrence events. The correlation analysis and multiple linear regression analysis were performed. Compared with controls, serum Lp(a) levels were significantly increased in ischemic stroke patients than in controls. NIHSS scores and infarct volume were positively correlated with Lp(a) (P < 0.001). Finally, 34 patients (16.7%; 95% CI, 11.6-21.9%) had a stroke recurrence. Serum Lp(a) levels in patients with recurrent stroke were significantly higher as compared with those in patients without recurrent stroke (P < 0.001). In multivariate analysis, there was an increased risk of stroke recurrence associated with Lp(a) levels >=300 mg/l (OR, 2.87; 95% CI, 1.98-4.32; P = 0.009) after adjusting for possible confounders. With an AUC of 0.872 (95% CI, 0.816 0.927), Lp(a) showed a significantly greater discriminatory ability to predict stroke recurrence as compared with NIHSS score (AUC, 0.782; 95% CI, 0.704-0.859; P < 0.01). Our findings suggest that elevated serum Lp(a) levels can predict the risk of early stroke recurrence in patients with first-ever ischemic stroke. Further research is needed to replicate these findings. PMID- 28004341 TI - 2017 in-training initiative of the Journal of Assisted Reproduction and Genetics: the JARG Young Investigator Forum. AB - The Journal of Assisted Reproduction and Genetics introduces the JARG Young Investigator Forum, an in-training initiative aimed to expand opportunities for young investigators. The JARG Young Investigator Forum has three primary goals: first, to increase opportunities for trainees and young investigators to contribute as researchers and writers. Trainees will be invited to publish mini reviews based on their area of research interest/expertise and will have the opportunity to indicate "in-training" when submitting manuscripts as first author Educational research pertaining to reproductive medicine training will be added to the purview of the journal. Second, the Young Investigator Forum will increase opportunities for trainees to serve as journal reviewers and will provide mentorship throughout the peer review process. Third, trainees will have the unique opportunity to gain editorial experience by serving as a "guest editor" of the Young Investigator Forum, overseeing all editorial aspects of their assigned particular issue. Through authorship, peer review, and editorial experience, we seek to nurture the academic skills that are critical to a well-rounded career. The JARG Young Investigator Forum aims to foster career development for a generation of trainees who represent the future of reproductive medicine, and here, we outline the primary goals and objectives of the initiative. PMID- 28004342 TI - Acyclovir-Polyethylene Glycol 6000 Binary Dispersions: Mechanistic Insights. AB - The dissolution and subsequent oral bioavailability of acyclovir (ACY) is limited by its poor aqueous solubility. An attempt has been made in this work to provide mechanistic insights into the solubility enhancement and dissolution of ACY by using the water-soluble carrier polyethylene glycol 6000 (PEG6000). Solid dispersions with varying ratios of the drug (ACY) and carrier (PEG6000) were prepared and evaluated by phase solubility, in vitro release studies, kinetic analysis, in situ perfusion, and in vitro permeation studies. Solid state characterization was done by powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) analysis, and surface morphology was assessed by polarizing microscopic image analysis, scanning electron microscopy, atomic force microscopy, and nuclear magnetic resonance analysis. Thermodynamic parameters indicated the solubilization effect of the carrier. The aqueous solubility and dissolution of ACY was found to be higher in all samples. The findings of XRD, DSC, FTIR and NMR analysis confirmed the formation of solid solution, crystallinity reduction, and the absence of interaction between the drug and carrier. SEM and AFM analysis reports ratified the particle size reduction and change in the surface morphology in samples. The permeation coefficient and amount of ACY diffused were higher in samples in comparison to pure ACY. Stability was found to be higher in dispersions. The results suggest that the study findings provided clear mechanical insights into the solubility and dissolution enhancement of ACY in PEG6000, and such findings could lay the platform for resolving the poor aqueous solubility issues in formulation development. PMID- 28004343 TI - Naproxen Microparticulate Systems Prepared Using In Situ Crystallisation and Freeze-Drying Techniques. AB - Poor drug solubility and dissolution rate remain to be one of the major problems facing pharmaceutical scientists, with approximately 40% of drugs in the industry categorised as practically insoluble or poorly water soluble. This in turn can lead to serious delivery challenges and poor bioavailability. The aim of this research was to investigate the effects of the surfactants, poloxamer 407 (P407) and caprol(r) PGE 860 (CAP), at various concentrations (0.1, 0.5, 1 and 3% w/v) on the enhancement of the dissolution properties of poorly water-soluble drug, naproxen, using in situ micronisation by solvent change method and freeze-drying. The extent at which freeze-drying influences the dissolution rate of naproxen microcrystals is investigated in this study by comparison with desiccant-drying. All formulations were evaluated and characterised using particle size analysis and morphology, in vitro dissolution studies, differential scanning calorimetry (DSC), and Fourier transform infra-red (FT-IR) spectroscopy. An increase in poloxamer 407 concentration in freeze-dried formulations led to enhancement of drug dissolution compared to desiccator-dried formulations, naproxen/caprol(r) PGE 860 formulations and untreated drug. DSC and FT-IR results show no significant chemical interactions between drug and poloxamer 407, with only very small changes to drug crystallinity. On the other hand, caprol(r) PGE 860 showed some interactions with drug components, alterations to the crystal lattice of naproxen, and poor dissolution profiles using both drying methods, making it a poor choice of excipient. PMID- 28004344 TI - Preparation and Characterization of Copolymer Micelles for the Solubilization and In Vitro Release of Luteolin and Luteoloside. AB - Luteolin (LUT) and luteoloside (LUS) belong to flavonoids with high anticancer potential and were loaded into biodegradable diblock copolymer micelles of methoxy polyethylene glycol-polycaprolactone (mPEG5K-PCL10K), methoxy polyethylene glycol-polylactide-co-glycolide (mPEG5K-PLGA10K), and methoxy polyethylene glycol-polylactide (mPEG5K-PDLLA10K) by a self-assembly method, creating water-soluble LUT and LUS copolymer micelles, respectively. The solubilization formulations of the copolymer micelles were optimized with response surface methodology (RSM). The obtained drug micelles are torispherical under transmission electron microscope (TEM) with an average diameter of about 70 nm. The mPEG5K-PLGA10K exhibited higher loading capacity for LUS which was 4.33%, and LUT- (or LUS)-loaded mPEG5K-PCL10K exhibited a better stability and encapsulation efficiency which was 65.1 and 55.8%, respectively. The in vitro drug release study showed above 47% of LUT was released from micelles at pH 7.4 PBS; however, no more than 35% of LUT was released at pH 6.4 PBS within 24 h. Meanwhile, no more than 30% of LUS was released from micelles whether at pH 6.4 or 7.4 PBS solution within 24 h. PMID- 28004345 TI - A Ratiomeric Fluorescent Sensor for Zn2+ Based on N,N'-Di(quinolin-8 yl)oxalamide. AB - A new ratiometric fluorescent sensor (DQO) based on N,N'-Di(quinolin-8-yl) oxalamide has been designed and synthesized for selective detection of Zn2+. The fluorescence ratio (I 536 nm/I 450 nm) of DQO was enhanced 10-fold when Zn2+ was present in a buffer aqueous solution at pH 8.66. The sensor showed linear response toward Zn2+ in the concentration range 0-15 MUM, and the detection limit was calculated to be 2.4 MUM. A Job's plot implied the formation of a DQO/Zn2+ complex with 1:1 stoichiometry, and the apparent association constant of DQO/Zn2+ complex was computed to be 1.5 * 104 M-1. PMID- 28004346 TI - Bioavailability and Bioequivalence Aspects of Oral Modified-Release Drug Products. AB - Oral modified-release (MR) products are dosage forms administered through the mouth and designed to release drug in a controlled manner to achieve maximum efficacy, minimal side effects, and better patient compliance. With significant progress in pharmaceutical technologies and favored therapeutic benefit, more and more oral MR products including the generic versions of these products are being developed, marketed, and used in the USA. Because different types of MR products may exhibit unique drug release modes and specific pharmacokinetic profiles, a better understanding of the regulation and evaluation of these generic MR products can help development and marketing of generic MR products that are therapeutically equivalent to the corresponding reference product. This review summarizes the general regulatory requirements for establishing bioequivalence between generic and reference oral MR products. In addition, some special regulatory considerations for bioequivalence evaluation are highlighted with examples of specific oral MR drug products. PMID- 28004347 TI - Optimal Affinity of a Monoclonal Antibody: Guiding Principles Using Mechanistic Modeling. AB - Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant ([Formula: see text]) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general [Formula: see text] to achieve 90% coverage for a soluble target is one tenth of its baseline concentration ([Formula: see text]), and is independent of the dosing interval, target turnover rate or the presence of competing ligands. For membrane-bound internalizing targets, it is equal to the ratio of internalization rate of mAb-target complex and association rate constant ([Formula: see text]). In cases where soluble and membrane-bound forms of the target co-exist, [Formula: see text] lies within a range determined by the internalization rate ([Formula: see text]) of the mAb membrane target complex and the ratio of baseline concentrations of soluble and membrane-bound forms ([Formula: see text]). Finally, to demonstrate practical application of these general rules, we collected target expression and turnover data to project [Formula: see text] for a number of marketed mAbs against soluble (TNFalpha, RANKL, and VEGF) and membrane-bound targets (CD20, EGFR, and HER2). PMID- 28004348 TI - Compositing climate change vulnerability of a Mediterranean region using spatiotemporally dynamic proxies for ecological and socioeconomic impacts and stabilities. AB - The study presents a new methodology to quantify spatiotemporal dynamics of climate change vulnerability at a regional scale adopting a new conceptual model of vulnerability as a function of climate change impacts, ecological stability, and socioeconomic stability. Spatiotemporal trends of equally weighted proxy variables for the three vulnerability components were generated to develop a composite climate change vulnerability index (CCVI) for a Mediterranean region of Turkey combining Landsat time series data, digital elevation model (DEM)-derived data, ordinary kriging, and geographical information system. Climate change impact was based on spatiotemporal trends of August land surface temperature (LST) between 1987 and 2016. Ecological stability was based on DEM, slope, aspect, and spatiotemporal trends of normalized difference vegetation index (NDVI), while socioeconomic stability was quantified as a function of spatiotemporal trends of land cover, population density, per capita gross domestic product, and illiteracy. The zones ranked on the five classes of no-to extreme vulnerability were identified where highly and moderately vulnerable lands covered 0.02% (12 km2) and 11.8% (6374 km2) of the study region, respectively, mostly occurring in the interior central part. The adoption of this composite CCVI approach is expected to lead to spatiotemporally dynamic policy recommendations towards sustainability and tailor preventive and mitigative measures to locally specific characteristics of coupled ecological-socioeconomic systems. PMID- 28004349 TI - Geotechnical assessment of road failure and slope monitoring along Nsukka-Adoru Idah highway, Southeastern Nigeria. AB - The quality of highway pavement is greatly influenced by the subgrade materials, the general geology of the area, and the materials used for construction. Investigation into the 75-km Nsukka-Adoru-Idah highway revealed that the pavement was underlain by three lithological units-Imo, Nsukka, and Ajali formations. The geotechnical evaluation carried out in the study includes the particle size distribution, Atterberg limit, specific gravity, compaction tests, and California bearing ratio (CBR). The base course has clay/silt (7-14%), fine sand (1-4%), medium sand (6-13%), and coarse sand (65-86%), while the subgrade presented clay/silt (74-82%), fine sand (6-9%), medium sand (10-17%), and coarse sand (1 3%). The average specific gravity results for the studied base course and subgrades are 2.58 and 2.52. Liquid limit (LL) result ranges from 27 to 60%, while plastic limit (PL) ranges between 17 and 24%, and plasticity index (PI) ranges from 5 to 39%. The maximum dry density (MDD) result ranges from 1.70 to 2.10 mg/m3, while the optimum moisture content (OMC) for the samples ranges between 14.1 and 18.0%. The CBR result for soaked and unsoaked samples ranges from 37 to 74 and 48 to 83%, respectively. The low unsoaked CBR (<80%) and high Atterberg limits (LL > 30% and PI > 12%) failed the stipulated Nigerian standard, signifying the need for stabilization. A geotechnical model of a highway road cut generated a factor of safety of 1.45, indicating possibility of slope failure. PMID- 28004350 TI - Identification of an RNA aptamer binding hTERT-derived peptide and inhibiting telomerase activity in MCF7 cells. AB - Human telomerase reverse transcriptase is an essential rate-limiting component of telomerase complex. hTERT protein in association with other proteins and the human telomerase RNA (hTR) shows telomerase activity, essential for maintaining genomic integrity in proliferating cells. hTERT binds hTR through a decapeptide located in the RID2 (RNA interactive domain 2) domain of N-terminal region. Since hTERT is essential for telomerase activity, inhibitors of hTERT are of great interest as potential anti-cancer agent. We have selected RNA aptamers against a synthetic peptide from the RID2 domain of hTERT by employing in vitro selection protocol (SELEX). The selected RNAs could bind the free peptide, as CD spectra suggested conformational change in aptamer upon RID2 binding. Extracts of cultured breast cancer cells (MCF7) expressing this aptamer showed lower telomerase activity as estimated by TRAP assay. hTERT-binding RNA aptamers hold promise as probable anti-cancer therapeutic agent. PMID- 28004351 TI - Withania somnifera as a potential anxiolytic and immunomodulatory agent in acute sleep deprived female Wistar rats. AB - Sleep is a profound regulator of cellular immunity, and the curtailment of sleep in present day lifestyle leads to disruption of neuro-immune-endocrine interactions. No therapeutic remedy is yet known for the amelioration of detrimental effects caused by sleep deprivation (SD). The current study was aimed to elucidate the effects of acute SD on immune function and its modulation by water extract from leaves of Withania somnifera (ASH-WEX). Three groups of animals, i.e. Vehicle-Undisturbed sleep (VUD), Vehicle-Sleep deprived (VSD) and ASH-WEX fed sleep deprived (WSD) rats were tested for their anxiety-like behaviour and further used for the study of inflammatory and apoptotic markers expression in piriform cortex and hippocampus regions of the brain. VSD animals showed high level of anxiety in elevated plus maze test, which was ameliorated in WSD group. The stress induced expression of inflammatory and immune response markers GFAP, TNFalpha, IL-6, OX-18 and OX-42 in VSD animals was found to be modulated by ASH-WEX. Further, the stress induced apoptosis was suppressed in WSD group as indicated by expression of NF-kappaB, AP-1, Bcl-xL and Cytochrome c. This study provides scientific validation to the anxiolytic, anti-inflammatory and anti-apoptotic properties of ASH-WEX, which may serve as an effective dietary supplement for management of SD induced stress and associated functional impairments. PMID- 28004352 TI - Central Nervous System Involvement at the Time of Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with a Poor Outcome in Patients with Acute Myeloid Leukemia. AB - Recent reports suggested that central nervous system (CNS) involvement (CNS+) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not an independent predictor of survival after allo-HSCT. However, these studies did not analyze minimal residual disease in the CNS at the time of allo-HSCT. We evaluated the effect of residual CNS+ on the transplant outcomes of 214 AML patients in a single institution. Twenty-one (10%) patients were diagnosed with CNS+ prior to allo-HSCT. Of these, 13 patients had CNS disease at the time of allo-HSCT. The patients in CNS+ AML remission at the time of allo-HSCT had better overall survival (OS) than the patients who were not in remission (2-year OS: 55% vs. 7.7%, p = 0.0001). In multivariate analyses, CNS+ at the time of allo-HSCT (hazard ratio (HR), 1.9; 95% confidence interval (CI), 1.05-3.59; p = 0.04), age over 50 years at the time of allo-HSCT, and non complete remission disease status in bone marrow at the time of allo-HSCT were independent adverse factors for OS. However, a prior history of CNS+ before allo HSCT did not independently affect OS (HR, 1.27; 95% CI 0.53-2.07; p = 0.6). Early diagnosis and eradication of CNS+ at the time of allo-HSCT may be necessary to improve the outcome for patients with CNS+ AML. PMID- 28004353 TI - Association of CCND1 Gene c.870G>A Polymorphism with Breast Cancer Risk: A Case ControlStudy and a Meta-Analysis. AB - Cyclin D1 (CCND1) plays an essential role in regulating the progress of the cell cycle from G1 to S phase. There is a common c.870G>A polymorphism in the CCND1 gene. The aim of this study was to investigate the association of CCND1 gene c.870G>A polymorphism with breast cancer risk in a case-control study, which followed by a meta-analysis and an in silico analysis. Three hundred and thirty five subjects composed of 174 women with breast cancer and 161 healthy controls were included in the case-control study. CCND1 gene c.870G>A genotyping was performed by PCR-RFLP. Meta-analysis was done for 14 studies composed of 7281 cases and 6820 controls. Some bioinformatics tools were applied to investigate the effects of c.870G>A on the mRNA splicing and structure. Our data obtained from case-control study revealed that GA genotype (OR: 1.89, 95%CI: 1.12-3.17, p = 0.017), AA genotype (OR: 1.95, 95%CI: 1.08-3.53, p = 0.027), and A allele (OR: 1.44, 95%CI: 1.06-1.95, p = 0.019) were significantly associated with breast cancer risk. The results of meta-analysis showed a significant association between CCND1 c.870G>A polymorphism and breast cancer risk, especially in Caucasian population. In silico analysis revealed that c.870G>A transition affect CCND1 mRNA splicing and secondary structure. PMID- 28004354 TI - Systematic Investigation of Expression of G2/M Transition Genes Reveals CDC25 Alteration in Nonfunctioning Pituitary Adenomas. AB - Dysregulation of G1/S checkpoint of cell cycle has been reported in pituitary adenomas. In addition, our previous finding showing that deregulation of Wee1 kinase by microRNAs together with other studies demonstrating alteration of G2/M transition in nonfunctioning pituitary adenomas (NFPAs) suggest that G2/M transition may also be important in pituitary tumorigenesis. To systematically study the expression of members of the G2/M transition in NFPAs and to investigate potential microRNA (miRNA) involvement. Totally, 80 NFPA and 14 normal pituitary (NP) tissues were examined. Expression of 46 genes encoding members of the G2/M transition was profiled on 34 NFPA and 10 NP samples on TaqMan Low Density Array. Expression of CDC25A and two miRNAs targeting CDC25A were validated by individual quantitative real time PCR using TaqMan assays. Protein expression of CDC25A, CDC25C, CDK1 and phospho-CDK1 (Tyr-15) was investigated on tissue microarray and immunohistochemistry. Several genes' expression alteration were observed in NFPA compared to normal tissues by transcription profiling. On protein level CDC25A and both the total and the phospho-CDK1 were overexpressed in adenoma tissues. CDC25A correlated with nuclear localized CDK1 (nCDK1) and with tumor size and nCDK1 with Ki-67 index. Comparing primary vs. recurrent adenomas we found that Ki-67 proliferation index was higher and phospho-CDK1 (inactive form) was downregulated in recurrent tumors compared to primary adenomas. Investigating the potential causes behind CDC25A overexpression we could not find copy number variation at the coding region nor expression alteration of CDC25A regulating transcription factors however CDC25A targeting miRNAs were downregulated in NFPA and negatively correlated with CDC25A expression. Our results suggest that among alterations of G2/M transition of the cell cycle, overexpression of the CDK1 and CDC25A may have a role in the pathogenesis of the NFPA and that CDC25A is potentially regulated by miRNAs. PMID- 28004355 TI - Research Professionals' Perspectives, Barriers, and Recommendations Regarding Minority Participation in Clinical Trials. AB - OBJECTIVE: This study aims to investigate research professionals' perspectives regarding minority participation in clinical trials. METHODS: A web-based survey of research professionals at US institutions receiving NIH and/or AHRQ funding to conduct clinical research in 2013. Descriptive statistics, mean, standard deviation (SD), and the Wilcoxon rank-sum test were utilized for analysis. RESULTS: Distributed were 13,041 surveys with 967 (7.4%) responses. Overall and race-stratified analyses included 633 and 521 surveys, respectively. A majority agreed that patients' race (mean, 3.4; SD = 1.0) and primary language (mean, 4.0; SD = 0.9) have an effect on enrollment. They had more success in enrolling those whose primary language was the same as their own (mean, 3.8; SD = 1.0), and that a language barrier and time spent arranging for interpreters had prevented them from offering a study to potential candidates (mean, 3.2; SD = 1.2). Non Caucasian respondents were more likely to agree that "fear of unknown side effects" was a deterrent for minorities (p < 0.01), "minorities are more likely to be unavailable for follow-up phone calls" (p = 0.07), and "the unavailability of translated material discourages non-English speakers from participation" (p = 0.08). They also were more likely to be neutral or agree with being discouraged from enrolling minorities because of the possibility of their withdrawal or being less likely to be available for phone follow-ups and follow-up visits (all p < 0.01). CONCLUSION: Despite a few subtle racial differences in research professionals' perspectives, a majority expressed no hesitation in enrolling minorities. Patients' race and primary language appeared to influence enrollment. A language barrier appeared to be the strongest barrier for research professionals. PMID- 28004356 TI - Risk of Recurrence and Mortality in a Multi-Ethnic Breast Cancer Population. AB - BACKGROUND: Compared to non-Hispanic whites, African-American women tend to be diagnosed with breast cancer at an earlier age, to have less favorable tumor characteristics, and to have poorer outcomes from breast cancer. The extent to which differences in clinical characteristics account for the black/white disparity in breast cancer mortality is unclear. The purpose of this investigation was to examine the association of clinical, demographic, and treatment variables with total mortality and breast cancer recurrence by race/ethnicity in a cohort of women diagnosed with invasive breast cancer. METHODS: To this end, we used data on 3890 invasive breast cancer cases diagnosed at a single medical center. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of tumor characteristics and treatment variables with mortality and recurrence. RESULTS: Compared to white women, black women with breast cancer presented with tumors that had worse prognostic factors, particularly higher stage, lower frequency of hormone-receptor positive tumors, and higher frequency of comorbidities. Hispanics also generally had less favorable prognostic factors compared to non-Hispanic whites. Among estrogen receptor-positive cases, blacks had roughly a two-fold increased risk of recurrence compared to non-Hispanic whites. However, ethnicity/race was not associated with total mortality. Tumor stage, tumor size, and Charlson comorbidity index were positively associated with mortality, and mammography and chemotherapy and hormone therapy were inversely associated with mortality. CONCLUSION: In spite of poorer prognostic factors among blacks compared whites, race/ethnicity was not associated with total mortality in our study. PMID- 28004357 TI - Yttrium-90 radioembolization for colorectal cancer liver metastases: a prospective cohort study on circulating angiogenic factors and treatment response. AB - BACKGROUND: Yttrium-90 radioembolization (90Y-RE) as a treatment for liver tumours induces radiation damage and hypoxia in liver tissue, which is also a trigger for systemic release of angiogenic factors, potentially stimulating tumour growth. We examined changes in circulating angiogenic factors following 90Y-RE and investigated the association between response and angiogenic factors. In this prospective study, 42 patients with unresectable, chemorefractory metastatic colorectal cancer (CRCLM) were treated with 90Y-RE. Blood samples were collected pre-treatment and at 0, 1, 3, 7 and 30 days of follow-up. Response was measured with MRI according to RECIST 1.1 at 1 month and subsequently 3-month interval until progressive disease (PD) occurred. Associations between circulating angiogenic factors and response were examined with linear mixed model analysis. RESULTS: Following 90Y-RE, three angiogenic factors demonstrated an increase in plasma levels, i.e., vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and angiopoietin-2 (Ang-2). Non-responders (= PD at 1-month follow-up, n = 10) had a significant increase of Ang-2 and HGF at 3 and 7 days post treatment compared to responders (= stable disease or better, n = 32), who showed little to no changes in plasma levels (respectively p = 0.01 and p = 0.007). Median overall survival was 9.2 months (95% confidence interval 6.1 12.4). CONCLUSIONS: Significant increases in plasma levels of Ang-2 and HGF in the first week after treatment were associated with rapid progressive disease of liver lesions at 1 month after 90Y-RE. Combination of 90Y-RE with anti-angiogenic therapy may reduce these effects and result in better response. PMID- 28004358 TI - 13C and 15N chemical shift assignments of mammalian Y145Stop prion protein amyloid fibrils. AB - The Y145Stop prion protein (PrP23-144), which has been linked to the development of a heritable prionopathy in humans, is a valuable in vitro model for elucidating the structural and molecular basis of amyloid seeding specificities. Here we report the sequential backbone and side-chain 13C and 15N assignments of mouse and Syrian hamster PrP23-144 amyloid fibrils determined by using 2D and 3D magic-angle spinning solid-state NMR. The assigned chemical shifts were used to predict the secondary structures for the core regions of the mouse and Syrian hamster PrP23-144 amyloids, and the results compared to those for human PrP23-144 amyloid, which has previously been analyzed by solid-state NMR techniques. PMID- 28004359 TI - Human biological and nonbiological point-light movements: Creation and validation of the dataset. AB - Human action perception is so powerful that people can identify movement efficiently in the absence of pictorial information, such as in point-light displays. Interest is growing in this type of stimulus for research in neuroscience. This interest stems from the advantage of separating the component of pure human action kinematics from other pictorial information, such as facial expression and muscle contraction. Although several groups have previously developed datasets of human point-light actions, due to the lack of datasets composed of daily actions with short durations, we developed 20 biological and 40 control (scrambled) point-light movements by using the technique of recording people wearing reflector patches. The videos are about 1 s long. Subsequently, we performed a judgment task in which 100 participants (50 male and 50 female) evaluated each video according to three categories: human action resemblance, performed action, and gender of actor. We present the mean scores of each evaluation for each video, and further propose a selection of the most suitable videos to be used as human point-light action displays and scrambled point-light displays for control. Finally, we discuss our findings on the gender attributions of the point-light displays. PMID- 28004360 TI - Minimally Invasive Adipose Graft Transposition Procedure. AB - Recently, a new surgical technique to rescue infarcted myocardium (AGTP) has already tested (NCT01473433, AdiFLAP Trial). Here, we present the new minimally invasive AGTP (mi-AGTP) by thoracoscopy. PMID- 28004362 TI - Contribution of target alteration, protection and efflux pump in achieving high ciprofloxacin resistance in Enterobacteriaceae. AB - The study aims at revealing the comprehensive contribution of target alteration, target protection and efflux pump to the development of high level of ciprofloxacin (CIP) resistance in Enterobacteriaceae bacteria of environmental, clinical and poultry origins. Antibiotic susceptibility test was used to detect CIP resistant (CIPR) isolates and MICCIP was determined by broth microdilution method. The presence of qnrS gene was identified by PCR and Southern blot hybridization (SBH) confirmed their location. Checkerboard titration demonstrated the effect of NMP on CIP action. PCR followed by sequencing and in silico analysis revealed the contribution of mutations in acrR, marR and gyrA to CIPR development. Out of 152 isolates, 101 were detected as CIPR. Randomly selected 53 isolates (MICCIP 4-512 ug/mL) were identified as Escherichia spp. (26), Enterobacter spp. (7), Klebsiella spp. (5) and Salmonella spp. (15) and of them 31 isolates carried qnrS. qnrS harboring 18 highly CIPR isolates (MICCIP: 256-512 ug/mL) were selected for further study. SBH confirmed 7 isolates harbored qnrS gene in plasmids. The acrA, acrB and tolC were present in all 18 isolates and NMP had an additive (12-isolates) or synergistic (6-isolates) effect on CIP action. Most isolates contained double amino acid (aa) substitutions (S83L and D87N) in QRDR of GyrA resulting in an altered conformation of putative CIP binding pocket. However, some isolates contained single (S83L or S83Y) or no aa substitution but showed high CIPR implicating that the concerted action of three mechanisms is responsible for high CIPR with the most significant role of efflux pump. PMID- 28004363 TI - Effect of chlorine dosage in prechlorination on trihalomethanes and haloacetic acids during water treatment process. AB - To identify the effect of chlorine dosage in prechlorination on the formation of disinfection by-products during drinking water treatment process, the relationship between chlorine dosage and concentrations of THMs and HAAs was analyzed. Furthermore, the variation about the ratio of THMs/HAAs was also analyzed. The results indicated that concentrations of THMs and HAAs would rise with the increase of chlorine dosage, and TCM was the main product of four THMs, while DCAA and TCAA were the primary products of five HAAs. Moreover, the ratio of THMs to HAAs rose with the chlorine dosage increase. Thus, chlorine dosage in prechlorination had a significant impact on THMs and HAAs and should be controlled effectively. PMID- 28004361 TI - A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. AB - Obinutuzumab (GA101) is a novel, type II, glycoengineered, humanized anti-CD20 monoclonal antibody that has been developed to address the need for new therapeutics with improved efficacy in patients with lymphocytic leukemia and lymphoma of B-cell origin. Obinutuzumab has a distinct mode of action relative to type I anti-CD20 antibodies, such as rituximab, working primarily by inducing direct cell death and antibody-dependent cell-mediated cytotoxicity. Obinutuzumab is under investigation in a wide-ranging program of clinical trials in patients with B-cell malignancies. Efficacy as monotherapy has been reported in patients with relapsed/refractory indolent and aggressive non-Hodgkin lymphoma (NHL) and in chronic lymphocytic leukemia (CLL) of B-cell origin. Improved outcomes have also been noted when obinutuzumab is added to chemotherapy in patients with B cell NHL, and superiority over rituximab has been reported with combination therapy in patients with CLL. Ongoing research is focusing on developing options for chemotherapy-free treatment and on new combinations of obinutuzumab with novel targeted agents. PMID- 28004364 TI - Cytotoxic effects of moderate static magnetic field exposure on human periphery blood mononuclear cells are influenced by Val16Ala-MnSOD gene polymorphism. AB - Technological advancement has increasingly exposed humans to magnetic fields (MFs). However, more insights are necessary into the potential toxicity of MF exposure as a result of genetic variations related to oxidative metabolism. Therefore, the following study has assessed an in vitro cytotoxic effect of static magnetic field (SMF) (5 mT) on cells with Val16Ala polymorphism (AA, VA, and VV) in the manganese superoxide dismutase gene. Homozygous Val16Ala superoxide dismutase 2 (SOD2) genotypes present oxidative imbalance that is associated with risk to several chronic degenerative diseases (VV produces less efficient and AA more efficient SOD2 enzyme). Blood samples from healthy adult subject carriers with different Val16Ala-SOD2 genotypes were obtained and exposed to MF at different times (0, 1, 3, 6 h). The cytotoxic effect as well as oxidative stress was evaluated after incubation of 24 h at 37 degrees C. In addition, apoptosis induction has been analyzed by flow cytometry as well as Bcl 2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and caspases 8 and 3 gene expression. SMF cytotoxic effect has been observed in AA cells at all times of exposure, whereas AV cells presented higher mortality only after 6 h of exposure at SMF. Higher apoptosis induction has been observed in AA cells when compared to VV and AV cells. These results suggest a toxicogenetic SMF effect related to an imbalance in SOD2 activity. PMID- 28004365 TI - Co-modified MCM-41 as an effective adsorbent for levofloxacin removal from aqueous solution: optimization of process parameters, isotherm, and thermodynamic studies. AB - Antibiotics are emerging contaminants due to their potential risks to human health and ecosystems. Poor biodegradability makes it necessary to develop effective physical-chemical methods to eliminate these contaminants from water. The cobalt-modified MCM-41 was prepared by a one-pot hydrothermal method and characterized by SAXRD, N2 adsorption-desorption, SEM, UV-Vis DR, and FTIR spectroscopy. The results revealed that the prepared 3% Co-MCM-41 possessed mesoporous structure with BET surface areas at around 898.5 m2g-1. The adsorption performance of 3% Co-MCM-41 toward levofloxacin (LVF) was investigated by batch experiments. The adsorption of LVF on 3% Co-MCM-41 was very fast and reached equilibrium within 2 h. The adsorption kinetics followed the pseudo-second-order kinetic model with the second-order rate constants in the range of 0.00198 0.00391 g mg-1 min-1. The adsorption isotherms could be well represented by the Langmuir, Freundlich, and Dubinin-Radushkevich (D-R) isotherm equations. Nevertheless, D-R isotherm provided the best fit based on the coefficient of determination and average relative error values. The mean free energy of adsorption (E) calculated from D-R model was about 11 kJ mol-1, indicating that the adsorption was mainly governed by a chemisorption process. Moreover, the adsorption capacity was investigated as a function of pH, adsorbent dosage, LVF concentration, and temperature with help of respond surface methodology (RSM). A quadratic model was established, and an optimal condition was obtained as follows: pH 8.5, adsorbent dosage of 1 g L-1, initial LVF concentration of 119.8 mg L-1, and temperature of 31.6 degrees C. Under the optimal condition, the adsorption capacity of 3% Co-MCM-41 to LVF could reach about 108.1 mg g-1. The solution pH, adsorbent dosage, LVF concentration, and a combination of adsorbent dose and LVF concentration were significant factors affecting the adsorption process. The adsorption thermodynamic functions were also determined. The negative DeltaH 0 (-33.50 kJ mol-1) and DeltaS 0 (-43.57 J mol-1 K-1) suggested that the adsorption was an exothermic process accompanied by decreasing disorder. This study may indicate that 3% Co-MCM-41 is a promising adsorbent for removing emerging pollutants of LVF from water. PMID- 28004366 TI - Microbial synthesis of bimetallic PdPt nanoparticles for catalytic reduction of 4 nitrophenol. AB - Bimetallic nanoparticles are generally believed to have improved catalytic activity and stability due to geometric and electronic changes. In this work, biogenic-Pd (bio-Pd), biogenic-Pt (bio-Pt), and biogenic-PdPt (bio-PdPt) nanoparticles were synthesized by Shewanella oneidensis MR-1 in the absence or presence of quinone. Compared with direct microbial reduction process, the addition of anthraquinone-2,6-disulfonate (AQDS) could promote the reduction efficiency of Pd(II) or/and Pt(IV) and result in decrease of particles size. All kinds of nanoparticles could catalyze 4-nitrophenol reduction by NaBH4 and their catalytic activities took the following order: bio-PdPt (AQDS) ~ bio-PdPt > bio Pd (AQDS) > bio-Pd > bio-Pt (AQDS) ~ bio-Pt. Moreover, the bio-PdPt (AQDS) nanoparticles could be reused for 6 cycles. We believe that this simple and efficient biosynthesis approach for synthesizing bimetallic bio-PdPt nanocatalysts is important for preparing active and stable catalysts. PMID- 28004367 TI - Acute and chronic toxicity of diuron and carbofuran to the neotropical cladoceran Ceriodaphnia silvestrii. AB - In order to contribute to the increase of the body of knowledge on the sensitivity of tropical indigenous species to pesticides, acute and chronic toxicity tests were conducted with the neotropical cladoceran Ceriodaphnia silvestrii. Tests were carried out with the active ingredients diuron and carbofuran and one of their commercial formulations, the Diuron Nortox(r) 500 SC and the Furadan(r) 350 SC, respectively. For carbofuran, the active ingredient was more toxic than the commercial product, whereas for diuron, the commercial product appeared more toxic. In addition, hormetic effects on fertility were recorded for intermediate diuron concentrations. Acute and chronic toxicity data indicated that C. silvestrii was among the most sensitive invertebrate species for both test compounds. Based on concentrations measured in Brazilian water bodies, these compounds represent ecological risks for causing direct and indirect toxic effects on C. silvestrii and other aquatic organisms. Our results support previous claims on the advantages of using native species to better tune ecological risk assessment of chemicals in tropical ecosystems. PMID- 28004368 TI - Control of the pollution of antibiotic resistance genes in soils by quorum sensing inhibition. AB - To investigate whether pollution from antibiotic resistance genes (ARGs) could be affected by bacterial quorum sensing, the oxytetracycline (OTC)-containing manure was fertilized to establish the ARG-polluted soil environment. Under long-term OTC stress, substantial ARGs in the range from 10-4 to 10-3 RG/16S rRNA (resistance genes/16S rRNA) were detected in the antibiotics control (AC) group, in which OTC-containing manure was fertilized. Meanwhile, 10-6 RG/16S rRNA was detected in biological control (BC) group, in which non-OTC-containing manure was fertilized. Subsequently, two typical quorum sensing inhibitors, 4-nitropyridine N-oxide (4-NPO) and 3,4-dibromo-2H-furan-5-one (DBF), were used to treat the ARG polluted soils. These two groups called 4-NPO treatments (NT) and DBF treatments (FT), respectively. There were no significant differences in bacterial growth and OTC degradation in NT and FT groups, compared to AC group. However, acyl homoserine lactones such as C4-HSL, C6-HSL, and C8-HSL decreased significantly in both NT and FT groups, compared to AC group. Meanwhile, the abundance of most ARGs decreased dramatically. In FT group, the concentrations of tet(L) and tet(Q) were below the detection limits. It was demonstrated that quorum sensing inhibition could be an effective way to prevent and control the pollution of ARGs in soil. PMID- 28004369 TI - Mycorrhizal colonization status of lowland rice (Oryza sativa L.) in the southeastern region of China. AB - The accumulation, distribution, and speciation of contaminants, such as arsenic, in rice can be affected by soil microorganisms such as arbuscular mycorrhizal fungi (AMF). As a potential measure to control contaminant acquisition in rice, the status and performance of AMF in the field need to be investigated. Root samples of rice plants were collected in seven different cities in Guangdong, Jiangxi, Hubei, and Jiangsu Provinces in China in order to investigate the colonization rate of AMF. The total DNA of the roots was extracted, followed by PCR and sequencing, and further confirmed the existence of AMF. The highest colonization rates (19.5 +/- 7.2%) were observed in samples from Huizhou City, Guangdong Province. Sequences of ribosomal DNA derived from Pingtan (PT) and Shuikou (SK) in Huizhou shared a similarity of 73 and 86% to Glomus cf. clarum Att894-7 (FM865542) and "uncultured fungus" (EF434122.1), respectively. The moisture tolerance of the AMF from different sources was tested by subjecting to different levels of water content in the soil. Only AMF from PT, SK, and LJ colonized rice under a condition of 100% of the soil water holding capacity (WHC), but not those isolated from upland plants. The AM colonization rate could be governed by the lighting conditions and temperature. AMF isolated in paddy fields has been shown to have more tolerance to moisture than other upland species. Radial oxygen loss (species and stress dependent) could be an essential factor influencing the colonization rate and requires more investigation. PMID- 28004370 TI - Equilibrium modeling of cadmium biosorption from aqueous solution by compost. AB - One of the most serious environmental issues of the present century is metal contamination of the aqueous environment due to the release of metal-containing effluents into the water bodies. Cadmium (Cd) is one of the toxic heavy metals which is not biodegradable thereby causing high risks to animals, plants, and humans. In the present study, potential and feasibility of compost derived from fruits and vegetables for Cd biosorption from aqueous solution were investigated. The batch biosorption experiments were performed to evaluate the effects of Cd concentrations (5, 15, 30, and 60 mg/L), compost biomass (0.5, 1.0, and 1.5 g/100 mL), pH (4, 6, and 8), contact time (1, 4, and 19 h), and temperature (28 and 35 degrees C) on Cd sorption and removal by compost. The biosorption of Cd was found to be highly dependent on initial Cd concentration, sorbent biomass, pH, contact time, and temperature of aqueous solution. It was observed that Cd sorption by compost was rapid up to 4 h, and then it became slow and stable as the contact time shifted towards equilibrium state (19 h). At equilibrium, the Cd sorption (q = 0.33-5.43 mg/g compost) and removal (45-99%) were observed at pH 6 and temperature 28 degrees C depending upon Cd concentrations and sorbent biomass in aqueous solution. The equilibrium experimental data were fitted well with Langmuir adsorption isotherm model (q max = 6.35-7.14 mg/g compost, R 2 = 0.77 0.98). FTIR spectrum of the compost indicated the presence of hydroxyl and carboxyl groups, which might be involved in the biosorption of Cd through ion exchange and complexation mechanisms. The optimal environmental conditions (pH 6, sorbent biomass 0.5 g/100 mL, and temperature 28 degrees C) induced more Cd sorption on compost at equilibrium. Results show compost as a cost-effective adsorbent material having high potential for heavy metal remediation from aqueous solution. PMID- 28004371 TI - Modulation of erythromycin-induced biochemical responses in crucian carp by ketoconazole. AB - The individual and combined biochemical responses of erythromycin and ketoconazole have been examined in an organism representative of the aquatic environment, crucian carp (Carassius auratus). The possible interactions between erythromycin and ketoconazole were investigated on the bioaccumulation and the expression of biotransformation enzymes 7-ethoxyresorufin-O-deethylase (EROD) and glutathione S-transferase (GST), and an antioxidant defense enzyme superoxide dismutase (SOD) in fish tissues. After 14 days of combined exposure (erythromycin + ketoconazole), the addition of ketoconazole at nominal concentrations of 0.2, 2, and 20 MUg/L significantly increased the accumulation of erythromycin in fish bile; however, elevated erythromycin accumulation levels were not observed in the other test tissues. The inductions of EROD and SOD activity to erythromycin were inhibited by the combined exposure of ketoconazole in most cases; however, the GST activity returned to normal with exposure time and concentration of combined administration. From the tested pharmaceutical mixtures, it indicated that certain specific combinations may pose some perturbations in biochemical responses in fish and also provide a better understanding of the effects of toxic mixtures. PMID- 28004372 TI - Greenhouse gas emissions during plantation stage of palm oil-based biofuel production addressing different land conversion scenarios in Malaysia. AB - The environmental impacts with regard to agro-based biofuel production have been associated with the impact of greenhouse gas (GHG) emissions. In this study, field GHG emissions during plantation stage of palm oil-based biofuel production associated with land use changes for oil palm plantation development have been evaluated. Three different sites of different land use changes prior to oil palm plantation were chosen; converted land-use (large and small-scales) and logged over forest. Field sampling for determination of soil N-mineralisation and soil organic carbon (SOC) was undertaken at the sites according to the age of palm, i.e. <5 years (immature), 5-20 and >21 years (mature oil palms). The field data were incorporated into the estimation of nitrous oxide (N2O) and the resulting CO2-eq emissions as well as for estimation of carbon stock changes. Irrespective of the land conversion scenarios, the nitrous oxide emissions were found in the range of 6.47-7.78 kg N2O-N/ha resulting in 498-590 kg CO2-eq/ha. On the other hand, the conversion of tropical forest into oil palm plantation has resulted in relatively higher GHG emissions (i.e. four times higher and carbon stock reduction by >50%) compared to converted land use (converted rubber plantation) for oil palm development. The conversion from previously rubber plantation into oil palm plantation would increase the carbon savings (20% in increase) thus sustaining the environmental benefits from the palm oil-based biofuel production. PMID- 28004373 TI - Erratum to: Achromobacter xylosoxidans as a new microorganism strain colonizing high-density polyethylene as a key step to its biodegradation. PMID- 28004374 TI - Individual differences in media multitasking and performance on the n-back. AB - A number of studies have recently examined the link between individual differences in media multitasking (using the MMI) and performance on working memory paradigms. However, these studies have yielded mixed results. Here we examine the relation between media multitasking and one particular working memory paradigm-the n-back (2- and 3-back)-improving upon previous research by (a) treating media multitasking as a continuous variable and adopting a correlational approach as well as (b) using a large sample of participants. First, we found that higher scores on the MMI were associated with a greater proportion of omitted trials on both the 2-back and 3-back, indicating that heavier media multitaskers were more disengaged during the n-back. In line with such a claim, heavier media multitaskers were also more likely to confess to responding randomly during various portions of the experiment, and to report media multitasking during the experiment itself. Importantly, when controlling for the relation between MMI scores and omissions, higher scores on the MMI were associated with an increase in false alarms, but not with a change in hits. These findings refine the extant literature on media multitasking and working memory performance (specifically, performance on the n-back), and suggest that media multitasking may be related to the propensity to disengage from ongoing tasks. PMID- 28004375 TI - Gorham-Stout Disease: a Clinical Case Report and Immunological Mechanisms in Bone Erosion. AB - Gorham-Stout disease (GSD) is a rare condition of osteolysis with excessive lymphangiogenesis within bone tissue. The etiology of this condition remains unknown but seems to affect mainly children and young adults of both genders all over the world. Unfortunately, there is no standardized method for diagnosis; however, histopathology remains as the gold standard. This condition is often misdiagnosed due to its varying clinical presentations from case-to-case. Here, we report the case of an 8-year-old girl who presented with chronic mandibular pain during mastication and received multiple antibiotic treatment due to infectious origin suspicion. After integrating information from clinical manifestations, radiographic, laboratory, and histopathology information, she was diagnosed with GSD. Additionally, due to the lack of literature with respect to insights into biological mechanisms and standardized treatment for this condition, we underwent a literature revision to provide information related to activation of cells from the immune system, such as macrophages, T-cells, and dendritic cells, and their contribution to the lymphangiogenesis, angiogenesis, and osteoclastogenic process in GSD. It is important to consider these mechanisms in patients with GSD, especially since new studies performed in earlier stages are required to confirm their use as novel diagnostic tools and find new possibilities for treatment. PMID- 28004376 TI - Population Pharmacokinetics and Pharmacodynamics Modelling of Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. AB - INTRODUCTION: Dilmapimod is a potent p38 mitogen-activated protein kinase (MAPK) inhibitor and was investigated in a study (NCT00996840) for its anti-inflammatory effect in non-head injury trauma patients at risk for developing acute respiratory distress syndrome (ARDS). The purpose of this paper is to present the details of the development of a population pharmacokinetic (PK) model, an empirical population placebo response model, and the exploration of a PK/pharmacodynamic (PD) model of dilmapimod. METHODS: A population PK model was developed to characterise the PK profile of dilmapimod in this patient population; the potential effect of available covariates on the PK of dilmapimod was evaluated. An empirical population placebo response model was conducted, and a population PK/PD model was explored to evaluate the relationship between dilmapimod concentration and C-reactive protein (CRP) (a systemic biomarker of p38 inhibition). All analyses were performed using NONMEM software. RESULTS: Following intravenous dosing, dilmapimod was quickly distributed to peripheral compartments and then slowly eliminated. The plasma concentration of dilmapimod was adequately described by a three-compartment model. It increased approximately proportionally to the increase in dose. The population clearance (CL) parameter value was 35.87 L/h, and the steady-state volume of distribution (Vss) [sum of the volume of distribution of the central compartment (Vc) and of the peripheral compartments V2 and V3] was 160 L. The effect of body mass index (BMI) on CL and inter-compartment clearance (Q2) was found statistically significant, with an increase in BMI of 1 kg/m2 resulting in a 1.79 L/h and 0.52 L/h increase in CL and Q2, respectively. The CRP profile post injury was adequately described by an indirect response model, with a sharp increase in the CRP levels following injury, followed by them slowly diminishing. Data exploration indicated potential drug effects of dilmapimod on inhibiting the production of CRP levels; however, the current small dataset did not show a statistically significant improvement in the PK/PD modelling. CONCLUSION: The population PK modelling adequately evaluated the dilmapimod plasma concentration-time profiles in severe trauma subjects at risk for ARDS, and BMI was found to be a significant covariate in the PK model. An indirect response model was adequate to describe the production and degradation of CRP levels in these subjects. PMID- 28004377 TI - ? AB - Extractions of mandibular third molars are a common procedure in dental practice. In cases where a close anatomical relationship of the root and the inferior alveolar nerve exists, the risk of transient or even permanent nerve injury increases. Nerve injury is difficult to manage and symptoms may cause severe patient discomfort, i.e. lifelong dysesthesia, i.e. painful sensation of the lower lip and chin area on the affected side. An alternative surgical procedure is coronectomy, which has first been described 25 year ago. Instead of complete tooth removal only the crown is extracted and the root is intentionally left in situ. A lower incidence of inferior alveolar nerve injury has been found with coronectomy in case of high-risk mandibular third molars, as was shown in randomized controlled trials. Coronectomy is presented in detail with indications as well as contraindications. A patient case is shown and recent literature is discussed. PMID- 28004378 TI - Evaluation of the dental curriculum at the University of Basel. Does the Master of Dental Medicine adequately prepare for the professional practice? AB - The present study reports the results of a structured survey of graduates intending to evaluate the education at the Dental School of the University of Basel in the years from 2006 to 2014. In addition, dentists and practice owners supervising graduates from Basel in daily clinical routine or hiring them as assistant dentists were questioned. The aims of the current survey were (1) to analyze own subjective experiences, (2) to assess potential differences between the cohorts prior to and after the implementation of the Bologna reform, (3) to compare the rating regarding theoretical knowledge and practical skills, and (4) to disclose potential for improvement. It was found that according to both their own assessment and the rating of the practice owners, graduates possess the basic dental expertise. The alumni rated their theoretical knowledge higher than their clinical practical skills and indicated a potential for intensification in the fields of dental surgery and implantology. When comparing the cohorts who had completed their studies according to the old (until 2010) and new study regulations, there were only minor differences; the own skills related to patient information about treatments were better rated by alumni who had been trained according to the new study regulations. The curriculum leading to the Master of Dental Medicine at the University of Basel fundamentally prepares graduates for the professional activity, but the additional acquisition of clinical experience in daily practice is indispensable. PMID- 28004379 TI - ? AB - Reliable analgesia can nowadays be achieved with several techniques and different anesthetic solutions, but side effects may be encountered. Severe and potentially fatal cardiovascular reactions can be the result of an intravascular injection. An easy to use, effective and safe alternative is the periodontal ligament injection. Nerve damage or cardiovascular side effects are not to be expected. This type of anesthesia can be of advantage for many dental procedures. With new devices like the computer-controlled local anesthetic delivery system, the periodontal ligament injection is a convenient way of local anesthesia for both patient and dentist. PMID- 28004380 TI - Impact of Health System Affiliation on Hospital Resource Use Intensity and Quality of Care. AB - OBJECTIVE: To assess the impact of hospital affiliation, centralization, and managed care plan ownership on inpatient cost and quality. DATA SOURCES: Inpatient discharges from 3,957 community hospitals in 44 states and American Hospital Association Annual Survey data from 2010 to 2012. STUDY DESIGN: We conducted a retrospective longitudinal regression analysis using hierarchical modeling of discharges clustered within hospitals. DATA COLLECTION: Detailed discharge data including costs, length of stay, and patient characteristics from the Healthcare Cost and Utilization Project State Inpatient Databases were merged with hospital survey data from the American Hospital Association. PRINCIPAL FINDINGS: Hospitals affiliated with health systems had a higher cost per discharge and better quality of care compared with independent hospitals. Centralized systems in particular had the highest cost per discharge and longest stays. Independent hospitals with managed care plans had a higher cost per discharge and better quality of care compared with other independent hospitals. CONCLUSIONS: Increasing prevalence of health systems and hospital managed care ownership may lead to higher quality but are unlikely to reduce hospital discharge costs. Encouraging participation in innovative payment and delivery reform models, such as accountable care organizations, may be more powerful options. PMID- 28004381 TI - Deregulated ALG-2/HEBP2 axis alters microtubule dynamics and mitotic spindle behavior to stimulate cancer development. AB - Cancer cells are characterized by genomic instability, resulting in the accumulation of mutations that promote cancer progression. One way that genomic instability can arise is through improper regulation of the microtubule cytoskeleton that impacts the function of the mitotic spindle. In this study, we have identified a critical role for the interaction between apoptosis-linked gene 2 (ALG-2) and heme-binding protein 2 (HEBP2) in the above processes. Our data show that the gene copy numbers and mRNA levels for both ALG-2 and HEBP2 are significantly upregulated in breast and lung cancer. Coexpression of ALG-2 and HEBP2 markedly increases the cytoplasmic pool of ALG-2 and alters the subcellular distribution of HEBP2. Our data further reveal that abnormality in the ALG 2/HEBP2 interaction impairs spindle orientation and positioning during mitosis. In addition, this complex appears to modulate the dynamic properties of microtubules in cancer cells. These finding thus uncover an important function for deregulated ALG-2/HEBP2 axis in cancer development by influencing microtubule dynamics and spindle behavior, providing novel insight into the etiology and pathogenesis of cancer. PMID- 28004382 TI - Help to go: T cells transfer CD40L to antigen-presenting B cells. AB - Most immune cell communication takes place by intercellular transfer of cytokines or the contact-dependent interaction of surface receptors in immunological synapses. In this issue of the European Journal of Immunology, Gardell and Parker (Eur. J. Immunol. 2017, 47, 41-50) point to a new, hybrid mechanism for Th1-cell delivery of help to B cells, based on contact-dependent CD40L transfer. The transfer process and its specificity are both cell contact dependent and antigen dependent. CD40 expression is also required on the B-cell surface to capture the CD40L presented by the Th1 cell. While further studies are needed to confirm the phenomenon in vivo and to test the role of transferred CD40L in other aspects of T-cell help, this study provides an exceptional take-off point and makes excellent use of mouse genetics to work out some possible rules for B cells being able to order help 'to go'. PMID- 28004383 TI - A real-time digital bio-imaging system to quantify cellular cytotoxicity as an alternative to the standard chromium-51 release assay. AB - Reliable measurement of cellular cytotoxicity is essential for the characterization of immune responses and for the monitoring of antibody treatment efficacy. Until now, the standard 51 Cr-release assay has remained the sole sensitive assay that measures cellular cytotoxicity. Alternative non-radioactive assays have been developed but they do not provide accurate measurement of target cell cytotoxicity. The cost and hazard of handling radioactivity are strong incentives to find alternative solutions to 51 Cr. We took advantage of the recent development of cell-imaging multimode readers to develop a novel non radioactive and real-time cytotoxic assay that demonstrates good reproducibility and sensitivity. The extent of target-cell cytotoxicity is monitored over time by imaging and quantifying live fluorescent target cells in 96-well plates. We have developed classical natural killer cell assays in the presence or absence of blocking antibodies and antibody-dependent cell-mediated cytotoxicity. We show that in these assays, cell killing occurs within the first 2 hr with half maximum killing reached after 30 min. This technology has numerous applications such as natural killer and T-cell cytotoxicity assays and can be extended to cell survival and apoptosis measurement assays. PMID- 28004384 TI - Genetic heterogeneity in Pakistani microcephaly families revisited. AB - Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity. PMID- 28004385 TI - Space-Time Cluster Analysis to Detect Innovative Clinical Practices: A Case Study of Aripiprazole in the Department of Veterans Affairs. AB - OBJECTIVE: To identify space-time clusters of changes in prescribing aripiprazole for bipolar disorder among providers in the VA. DATA SOURCES: VA administrative data from 2002 to 2010 were used to identify prescriptions of aripiprazole for bipolar disorder. Prescriber characteristics were obtained using the Personnel and Accounting Integrated Database. STUDY DESIGN: We conducted a retrospective space-time cluster analysis using the space-time permutation statistic. DATA EXTRACTION METHODS: All VA service users with a diagnosis of bipolar disorder were included in the patient population. Individuals with any schizophrenia spectrum diagnoses were excluded. We also identified all clinicians who wrote a prescription for any bipolar disorder medication. PRINCIPAL FINDINGS: The study population included 32,630 prescribers. Of these, 8,643 wrote qualifying prescriptions. We identified three clusters of aripiprazole prescribing centered in Massachusetts, Ohio, and the Pacific Northwest. Clusters were associated with prescribing by VA-employed (vs. contracted) prescribers. Nurses with prescribing privileges were more likely to make a prescription for aripiprazole in cluster locations compared with psychiatrists. Primary care physicians were less likely. CONCLUSIONS: Early prescribing of aripiprazole for bipolar disorder clustered geographically and was associated with prescriber subgroups. These methods support prospective surveillance of practice changes and identification of associated health system characteristics. PMID- 28004386 TI - Proinflammatory signaling functions of thrombin in cancer. AB - Thrombin-induced activation of protease-activated receptors (PARs) represents a link between inflammation and cancer. Proinflammatory signaling functions of thrombin are associated with several inflammatory diseases including neurodegenerative, cardiovascular, and of special interest in this review cancer. Thrombin-induced inflammatory responses up-regulates expression of cytokines, adhesion molecules, angiogenic factors, and matrix-degrading proteases that facilitate tumor cells proliferation, angiogenesis, invasion, and metastasis. This review summarizes the current knowledge about the mechanisms of thrombin mediated proinflammatory responses in cancer pathology for a better understanding and hence a better management of this disease. PMID- 28004387 TI - The reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) among dermatologists, rheumatologists and neurologists. AB - BACKGROUND: Previous studies have shown that skin disease in dermatomyositis (DM) is best assessed using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). Although the CDASI has been validated for use by dermatologists, it has not been validated for use by other physicians such as rheumatologists and neurologists, who also manage patients with DM and assess skin activity in clinical trials. OBJECTIVES: To assess the reliability of the CDASI among dermatologists, rheumatologists and neurologists. METHODS: Fifteen patients with cutaneous DM were assessed using the CDASI and the Physician Global Assessment (PGA) by five dermatologists, five rheumatologists and five neurologists. RESULTS: The mean CDASI activity scores for dermatologists, rheumatologists and neurologists were 21.0, 21.8 and 20.8, respectively. These mean scores were not different among the specialists. The CDASI damage score means for dermatologists, rheumatologists and neurologists were 5.3, 7.0 and 4.8, respectively. The mean scores between dermatologists and rheumatologists were significantly different, but the means between dermatologists and neurologists were not. The intraclass correlation coefficients (ICCs) for interrater reliability for CDASI activity and damage were good to excellent for dermatologists and rheumatologists, and moderate to excellent for neurologists. The ICCs for intrarater reliability for CDASI activity and damage were excellent for dermatologists and rheumatologists and moderate to excellent for neurologists. The PGA displayed lower interrater and intrarater reliability relative to the CDASI. CONCLUSIONS: Our results confirm the reliability of the CDASI when used by dermatologists and rheumatologists. The data for its use by neurologists were not as robust. PMID- 28004388 TI - LCN2 overexpression in bone enhances the hematopoietic compartment via modulation of the bone marrow microenvironment. AB - Lipocalin-2 (LCN2) is a member of the lipocalin family whose expression is modulated in several conditions, including cell differentiation, innate immunity, stress, and cancer. Although it is known that it is expressed in bone, its function in this tissue remains poorly studied. To this end, we took advantage of transgenic mice lines that expressed LCN2 driven by a bone specific type I collagen (LCN2-Tg). In the bone marrow (BM) of LCN2-Tg mice we observed an increased number of phenotypically long-term hematopoietic stem cells (LT-HSC) that also displayed a higher proliferation rate compared to wild-type controls (Wt). Furthermore, hematopoietic progenitor cells, obtained from LCN2-Tg BM showed an increased clonogenic capacity compared to those obtained from LCN2-Tg spleen, a higher concentration of serum erythropoietin and a higher number of mature erythrocytes in the peripheral blood of old LCN2-Tg animals compared to aged-matched wt. The findings of a combined increase in the BM of the LCN2-Tg mice of SDF-1, SCF, and TIMP-1 levels along with the reduction of both MMP-9 activity and cathepsin K concentration may explain the observed effects on the HSC compartment. This study shows that LCN2 overexpression in bones modifies the BM microenvironment via modulation of the expression of key secreted factors and cytokines, which in turn regulate the HSC niche behavior enhancing both HSC homing in young mice and erythrocytes production in older mice. PMID- 28004389 TI - WITHDRAWN: Community-based population-level interventions for promoting child oral health. AB - BACKGROUND: Dental caries and gingival and periodontal disease are commonly occurring, preventable chronic conditions. Even though much is known about how to treat oral disease, currently we do not know which community-based population level interventions are most effective and equitable in preventing poor oral health. OBJECTIVES: Primary * To determine the effectiveness of community-based population-level oral health promotion interventions in preventing dental caries and gingival and periodontal disease among children from birth to 18 years of age. Secondary * To determine the most effective types of interventions (environmental, social, community and multi-component) and guiding theoretical frameworks.* To identify interventions that reduce inequality in oral health outcomes.* To examine the influence of context in the design, delivery and outcomes of interventions. SEARCH METHODS: We searched the following databases from January 1996 to April 2014: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Education Resource Information Center (ERIC), BIOSIS Previews, Web of Science, the Database of Abstracts of Reviews of Effects (DARE), ScienceDirect, Sociological Abstracts, Social Science Citation Index, PsycINFO, SCOPUS, ProQuest Dissertations & Theses and Conference Proceedings Citation Index - Science. SELECTION CRITERIA: Included studies were individual- and cluster randomised controlled trials (RCTs), controlled before-and-after studies and quasi-experimental and interrupted time series. To be included, interventions had to target the primary outcomes: dental caries (measured as decayed, missing and filled deciduous teeth/surfaces, dmft/s; Decayed, Missing and Filled permanent teeth/surfaces, DMFT/S) and gingival or periodontal disease among children from birth to 18 years of age. Studies had to report on one or more of the primary outcomes at baseline and post intervention, or had to provide change scores for both intervention and control groups. Interventions were excluded if they were solely of a chemical nature (e.g. chlorhexidine, fluoride varnish), were delivered primarily in a dental clinical setting or comprised solely fluoridation. DATA COLLECTION AND ANALYSIS: Two review authors independently performed screening, data extraction and assessment of risk of bias of included studies (a team of six review authors - four review authors and two research assistants - assessed all studies). We calculated mean differences with 95% confidence intervals for continuous data. When data permitted, we undertook meta analysis of primary outcome measures using a fixed-effect model to summarise results across studies. We used the I2 statistic as a measure of statistical heterogeneity. MAIN RESULTS: This review includes findings from 38 studies (total n = 119,789 children, including one national study of 99,071 children, which contributed 80% of total participants) on community-based oral health promotion interventions delivered in a variety of settings and incorporating a range of health promotion strategies (e.g. policy, educational activities, professional oral health care, supervised toothbrushing programmes, motivational interviewing). We categorised interventions as dietary interventions (n = 3), oral health education (OHE) alone (n = 17), OHE in combination with supervised toothbrushing with fluoridated toothpaste (n = 8) and OHE in combination with a variety of other interventions (including professional preventive oral health care, n = 10). Interventions generally were implemented for less than one year (n = 26), and only 11 studies were RCTs. We graded the evidence as having moderate to very low quality.We conducted meta-analyses examining impact on dental caries of each intervention type, although not all studies provided sufficient data to allow pooling of effects across similar interventions. Meta-analyses of the effects of OHE alone on caries may show little or no effect on DMFT (two studies, mean difference (MD) 0.12, 95% confidence interval (CI) -0.11 to 0.36, low quality evidence), dmft (three studies, MD -0.3, 95% CI -1.11 to 0.52, low quality evidence) and DMFS (one study, MD -0.01, 95% CI -0.24 to 0.22, very low quality evidence). Analysis of studies testing OHE in combination with supervised toothbrushing with fluoridated toothpaste may show a beneficial effect on dmfs (three studies, MD -1.59, 95% CI -2.67 to -0.52, low-quality evidence) and dmft (two studies, MD -0.97, 95% CI -1.06 to -0.89, low-quality evidence) but may show little effect on DMFS (two studies, MD -0.02, 95% CI -0.13 to 0.10, low-quality evidence) and DMFT (three studies, MD -0.02, 95% CI -0.11 to 0.07, moderate quality evidence). Meta-analyses of two studies of OHE in an educational setting combined with professional preventive oral care in a dental clinic setting probably show a very small effect on DMFT (-0.09 weighted mean difference (WMD), 95% CI -0.1 to -0.08, moderate-quality evidence). Data were inadequate for meta analyses on gingival health, although positive impact was reported. AUTHORS' CONCLUSIONS: This review provides evidence of low certainty suggesting that community-based oral health promotion interventions that combine oral health education with supervised toothbrushing or professional preventive oral care can reduce dental caries in children. Other interventions, such as those that aim to promote access to fluoride, improve children's diets or provide oral health education alone, show only limited impact. We found no clear indication of when is the most effective time to intervene during childhood. Cost-effectiveness, long-term sustainability and equity of impacts and adverse outcomes were not widely reported by study authors, limiting our ability to make inferences on these aspects. More rigorous measurement and reporting of study results would improve the quality of the evidence. PMID- 28004390 TI - Skin-mimetic chromatography for prediction of human percutaneous absorption of biologically active compounds occurring in medicinal plant extracts. AB - The main aim of this study was to predict quantitatively human percutaneous absorption of chosen compounds commonly occurring in plants which can be used as medicinal extracts in the drug and beauty industries. The most important human percutaneous descriptors, i.e. logKp (logarithm of the water/skin partition coefficient) and logJmax (logarithm of the maximum flux of solutes penetrating the skin), of fatty acids and polyphenols were determined using both in vitro and in silico methods. For in vitro determination of human percutaneous absorption, micellar liquid chromatography based on hexadecyltrimethylammonium bromide, sodium dodecyl sulfate and polyoxyethylene (23) lauryl ether (Brij35) was used. Human percutaneous absorption was characterized by entirely new QSAR/QRAR models based on retention, lipophilic, steric and electronic data as well as on the linear free energy relationship parameters. Many different correlations between human skin absorption and different physicochemical parameters were performed, e.g. the in silico estimated logKp value was correlated with the retention parameter logkw (logarithm of the retention factor extrapolated to pure water) from the systems imitating a cutaneous environment (R2 = 0.92). Moreover, the influence of lipophilicity on percutaneous absorption was examined. The obtained correlation was excellent (R2 = 0.95). PMID- 28004391 TI - Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling. PMID- 28004393 TI - Chorionic villus sampling fails to confirm mosaic trisomy 21 fetus after positive cell-free DNA. PMID- 28004392 TI - A critical period of corticomuscular and EMG-EMG coherence detection in healthy infants aged 9-25 weeks. AB - KEY POINTS: The early postnatal development of functional corticospinal connections in human infants is not fully clarified. Corticospinal drive to upper and lower limb muscle shows developmental changes with an increased functional coupling in infants between 9 and 25 weeks in the beta frequency band. The changes in functional coupling coincide with the developmental period where fidgety movements are present in healthy infants. Data support a possible sensitive period where functional connections between corticospinal tract fibres and spinal motoneurones undergo activity-dependent reorganization. ABSTRACT: The early postnatal development of functional corticospinal connections in human infants is not fully clarified. We used EEG and EMG to investigate the development of corticomuscular and intramuscular coherence as indicators of functional corticospinal connectivity in healthy infants aged 1-66 weeks. EEG was recorded over leg and hand area of motor cortex. EMG recordings were made from right ankle dorsiflexor and right wrist extensor muscles. Quantification of the amount of corticomuscular coherence in the 20-40 Hz frequency band showed a significantly larger coherence for infants aged 9-25 weeks compared to younger and older infants. Coherence between paired EMG recordings from tibialis anterior muscle in the 20-40 Hz frequency band was also significantly larger for the 9-25 week age group. A low-amplitude, broad-duration (40-50 ms) central peak of EMG EMG synchronization was observed for infants younger than 9 weeks, whereas a short-lasting (10-20 ms) central peak was observed for EMG-EMG synchronization in older infants. This peak was largest for infants aged 9-25 weeks. These data suggest that the corticospinal drive to lower and upper limb muscles shows significant developmental changes with an increase in functional coupling in infants aged 9-25 weeks, a period which coincides partly with the developmental period of normal fidgety movements. We propose that these neurophysiological findings may reflect the existence of a sensitive period where the functional connections between corticospinal tract fibres and spinal motoneurones undergo activity-dependent reorganization. This may be relevant for the timing of early therapy interventions in infants with pre- and perinatal brain injury. PMID- 28004394 TI - Fetal therapy for Down syndrome: an ethical exploration. AB - BACKGROUND: Parallel to recent advances in prenatal screening for Down syndrome (DS), therapies for different aspects of the condition have become available. As intellectual disability is a key aspect, this is an active area for research. Several groups have hypothesized that prenatal interventions will give better chances at improving cognitive functioning in persons with DS than postnatal treatment. Clinical trials are being developed. METHOD: We first discuss the ethical pros and cons of trying to improve cognitive functioning in persons with DS to see if there are categorical objections to the general idea, and then move on to explore ethically relevant aspects of the prospect of developing fetal therapy for DS (FTDS). RESULTS: Only on the basis of a one-dimensional emphasis on the social model of disability would (fetal) therapy aimed at cognitive improvement be inherently problematic. CONCLUSIONS: Inviting pregnant women to participate in FTDS-research should be based on adequate pre-clinical trials, as well as information aimed at avoiding the so-called 'therapeutic misconception'. Should FTDS be proven to be effective and safe, women carrying a fetus with trisomy 21 who have decided to continue the pregnancy may have a moral obligation to make use of this option. (c) 2016 John Wiley & Sons, Ltd. PMID- 28004397 TI - General health influences episodes of xerostomia: a prospective population-based study. AB - OBJECTIVES: The aim of this study was to investigate the associated factors of changes in symptoms of xerostomia (SOX) in adults aged 20-59. METHODS: A prospective population-based study was conducted in 2009 (n = 1720) and 2012 (n = 1222) in the urban area of Florianopolis, SC, Brazil. Information on SOX was collected in both years together with age, family income, years of schooling, smoking habit, alcohol consumption, changes in the body mass index (BMI; kg/m2), medicine use, self-reported diagnosis of chronic diseases, change in hypertension status and in the use and need for dentures, and number of remaining teeth. Associated factors with changes in SOX were investigated using multinomial logistic regression, considering those who had never reported this symptom as the reference. RESULTS: Prevalence of regular SOX was equal to 3.8% (95% CI: 2.9-5.1) and irregular (one period only) equal to 12.2% (95% CI: 10.2-14.5). Age, smoking habit, medicine use, self-reported diagnosis of depression, and weight gain increased the probability of regular SOX, whereas highest schooling level was associated with lower probability of this symptom. CONCLUSIONS: General and psychosocial health influenced the number of episodes of xerostomia symptoms, calling for multidisciplinary actions to prevent common risk behaviors for oral and general diseases. PMID- 28004396 TI - The absorption kinetics of ketoconazole plays a major role in explaining the reported variability in the level of interaction with midazolam: Interplay between formulation and inhibition of gut wall and liver metabolism. AB - The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400 mg) and of staggering its dosage (400 mg at -12, -2, 0, 2 and 4 h), with respect to the administration of a single 5 mg oral dose of midazolam (MDZ) on the extent of inhibition of the metabolism of the latter, was evaluated in healthy subjects in two separate studies. Escalation of the ketoconazole dosage resulted in 2.3 (1.9), 2.7 (1.7) and 4.2 (2.5) -fold increases in the mean AUC(0,12h) (and Cmax ) values of midazolam. Dose-staggering was associated with 3.9 (2.5), 4.9 (2.9), 5.4 (2.8), 2.0 (1.3) and 1.2 (0.9) -fold increases in the mean AUC(0,12h) (and Cmax ) of midazolam. These findings could be predicted by physiologically based pharmacokinetic (PBPK) modelling using the ADAM (advanced dissolution absorption and metabolism) model within the Simcyp Simulator (Version 12 Release 2) to characterize the absorption kinetics of ketoconazole with respect to disintegration time, supersaturation ratio and precipitation rate. This study also emphasizes a need to account for inter-individual variability in the gut wall and systemic exposure of inhibitors with physicochemical properties similar to ketoconazole, in particular in their rate of oral absorption and when using different pharmaceutical formulations, in designing and evaluating the extent of drug-drug interactions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28004398 TI - Detection of D151G/N mutations in the neuraminidase gene of influenza A (H3N2) viruses by real-time RT-PCR allelic discrimination assay. AB - Single nucleotide polymorphisms (SNPs) at D151 position of neuraminidase (NA) gene of influenza A (H3N2) virus has been associated with drug resistance and increased binding affinity. NA-D151G/N-substitutions of influenza A (H3N2) viruses are frequently induced and selected by culturing in Madin-Darby canine kidney (MDCK) cell lines. It is important to consider and exclude D151G/N mutants after isolation of influenza virus in MDCK cell line; since, the substitutions can highly influence the results of experimental research. The study aims to develop an allelic discrimination real-time reverse transcriptase polymerase chain reaction (RT-PCR) for the screening of D151G/N mutants. Thirty-six influenza A (H3N2) virus isolates were included and screened for D151G/N mutants using allelic discrimination assay. Out of the 36 isolates, 11 isolates (30.5%) were detected as heterozygous for D and G/N substitutions. Twenty-one (58.3%) isolates were identified as homozygous wild type and four isolates (11.1%) were undetermined. Isolates with substitutions at D151 position were sequenced by Sanger sequencing method. The present study demonstrates a rapid and convenient method for primary screening of the mutation after culturing of the influenza virus in MDCK cell lines in order to avoid potential misinterpretations of results and improve the quality of experimental research. PMID- 28004395 TI - Myocardial tissue deformation is reduced in subjects with coronary microvascular dysfunction but not rescued by treatment with ranolazine. AB - BACKGROUND: Patients with coronary microvascular dysfunction (CMD) often have diastolic dysfunction, representing an important therapeutic target. Ranolazine-a late sodium current inhibitor-improves diastolic function in animal models and subjects with obstructive coronary artery disease (CAD). HYPOTHESIS: We hypothesized that ranolazine would beneficially alter diastolic function in CMD. METHODS: To test this hypothesis, we performed retrospective tissue tracking analysis to evaluate systolic/diastolic strain, using cardiac magnetic resonance imaging cine images acquired in a recently completed, randomized, double-blind, placebo-controlled, crossover trial of short-term ranolazine in subjects with CMD and from 43 healthy reference controls. RESULTS: Diastolic strain rate was impaired in CMD vs controls (circumferential diastolic strain rate: 99.9% +/- 2.5%/s vs 120.1% +/- 4.0%/s, P = 0.0003; radial diastolic strain rate: -199.5% +/ 5.5%/s vs -243.1% +/- 9.6%/s, P = 0.0008, case vs control). Moreover, peak systolic circumferential strain (CS) and radial strain (RS) were also impaired in cases vs controls (CS: -18.8% +/- 0.3% vs -20.7% +/- 0.3%; RS: 35.8% +/- 0.7% vs 41.4% +/- 0.9%; respectively; both P < 0.0001), despite similar and preserved ejection fraction. In contrast to our hypothesis, however, we observed no significant changes in left ventricular diastolic function in CMD cases after 2 weeks of ranolazine vs placebo. CONCLUSIONS: The case-control comparison both confirms and extends our prior observations of diastolic dysfunction in CMD. That CMD cases were also found to have subclinical systolic dysfunction is a novel finding, highlighting the utility of this retrospective approach. In contrast to previous studies in obstructive CAD, ranolazine did not improve diastolic function in CMD. PMID- 28004399 TI - Polymorphisms in IRG1 gene associated with immune responses to hepatitis B vaccination in a Chinese Han population and function to restrain the HBV life cycle. AB - Vaccination against the hepatitis B virus (HBV) is extensively used as an effective method to prevent HBV infection. However, nearly 10% of healthy adults fail to produce a protective level of antibodies against the hepatitis B vaccine, and multiple genetic variants are known to affect the immune response to the hepatitis B vaccine. The aim of the present study was to investigate the association between polymorphisms in immunoresponsive gene 1 (IRG1) gene and the immune response to hepatitis B vaccination in a Chinese Han population. Four single nucleotide polymorphisms (SNPs) located in the IRG1 gene were genotyped in 1230 high-responders and 451 non-responders to hepatitis B vaccination. The SNPs rs17470171 and rs17385627 were associated with the immune response to hepatitis B vaccination (P = 0.014 and 0.029, respectively). In addition, the haplotypes G-A A-A (rs614171-rs17470171-rs9530614-rs17385627, P = 0.0042, OR = 0.68) and A-A (rs17470171-rs17385627, P = 0.0065, OR = 0.72) exerted a protective role in the immune response to hepatitis B vaccination. Allele 'A' of rs17470171 and allele 'A' of rs17385627 show higher levels of expression for the IRG1 gene compared with allele 'C' of rs17470171 and allele 'T' of rs17385627 as demonstrated by luciferase reporter and overexpression assays. In addition, we observed that IRG1 inhibited the HBV life cycle and that IRG1 rs17385627 allele 'A' was more effective than rs17385627 allele 'T' at eliminating HBV in HepG2.2.15 cells. These findings suggest that polymorphisms in the IRG1 gene are associated with the immune response to hepatitis B vaccination. The antiviral effect of IRG1 was confirmed using HBV infection cell models. PMID- 28004400 TI - Role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography in evaluating breast mucosa-associated lymphoid tissue lymphoma: A case series. AB - Mucosa-associated lymphatic tissue (MALT) lymphoma of the breast is an extremely rare disease; its pathogenesis is not clear because of the rarity of disease, and the best diagnostic method has yet to be established. The metabolic behavior of this lymphoma is not still clear because only a few case reports are present in literature describing the possible role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in this field. This report presents 4 cases of women with histologically proven breast MALT lymphoma who underwent 7 18F-FDG PET/CT throughout the course of disease. All patients underwent staging PET/CT showing in all cases an FDG avid lesion corresponding to breast lymphoma; 3 patients underwent 18F-FDG PET/CT also after chemotherapy. Our results suggest that breast MALT lymphomas are 18F-FDG-avid lymphomas. Positron emission tomography/computed tomography showed heterogeneous but high FDG uptake (mean maximum standardized uptake value 7.9), suggesting that it could be part of diagnostic workup and restaging process. PMID- 28004401 TI - Hypoxia-inducible factors as neuroprotective agent in Alzheimer's disease. AB - Beta amyloid (Abeta)-42 peptide and phosphorylated tau protein have been demonstrated as the pathological hallmarks of Alzheimer's disease (AD). A gradual decline of oxygen and glucose supply to the brain during aging or hypoxia was manifested as a contributing factor to hypometabolism. The brain regions susceptible to hypometabolism are the hippocampus, entorhinal cortex and cognition-associated neocortical regions like parietal, temporal and frontal cortex. In AD patients, the brain regions with hypometabolism can trigger overexpression of amyloid precursor protein and decrease the clearance of Abeta. Abeta and hypoxia can evoke inflammation, oxidative stress and finally neuronal cell death. Among the transcription factors involved in the compensatory mechanism, hypoxia-inducible factor-1 alpha (HIF-1alpha) has a major role in the cellular adaptation by inducing the expression of several proteins, including vascular endothelial growth factor, erythropoietin and inducible nitric oxide synthase. Therefore, maintaining the HIF-1alpha level by inhibiting the prolyl 4 hydroxylase was effective to attenuate the nerve damage during hypoxia and postpone the incidence of AD. Agents such as iron chelators, and heavy metals like cobalt and nickel were demonstrated to be effective in maintaining the HIF 1alpha level in the nerve. This review article discusses the possible role of HIF 1alpha as a neuroprotector in AD and the future perspectives. PMID- 28004402 TI - Impact of influenza in the post-pandemic phase: Clinical features in hospitalized patients with influenza A (H1N1) pdm09 and H3N2 viruses, during 2013 in Santa Fe, Argentina. AB - It is important to characterize the clinical and epidemiological pattern of the influenza A (H1N1) pdm09 virus and compare it with influenza A (H3N2) virus, as surveyed in just a few studies, in order to contribute to the implementation and strengthening of influenza control and prevention strategies. The aims in this study were to describe influenza clinical and epidemiological characteristics in hospitalized patients, caused by influenza A (H1N1)pdm09 and influenza A (H3N2) viruses during 2013, in Santa Fe, Argentina. A retrospective study was conducted over 2013 among hospitalized patients with laboratory-confirmed influenza diagnosis. In contrast to patients with influenza A (H3N2) (20.5%), a higher proportion of hospitalizations associated with influenza H1N1pdm were reported among adults aged 35-65 years (42.8%). Of all patients, 73.6% had an underlying medical condition. Hospitalized patients with H1N1pdm were subject to 2.6 (95%CI, 1.0-6.8) times higher risk of severity, than those hospitalized with influenza A (H3N2). This results demonstrate the impact in the post-pandemic era of H1N1pdm virus, with increased risk of severe disease, in relation to H3N2 virus, both viruses co-circulating during 2013. PMID- 28004403 TI - Size matters, proportion too: coupling of experiments and theory reveals relative roles of K+ channels in action potential stability. PMID- 28004404 TI - Hyponatremia in a multiple myeloma patient treated with bortezomib. PMID- 28004406 TI - DEVELOPMENT AND SOCIALIZATION OF PHYSICAL AGGRESSION IN VERY YOUNG BOYS. AB - The expression of physical aggression is normative in early child development; it peaks in the second year of life, with steep declines for most children by the third and fourth years as children learn alternatives to aggression. Some children, however, fail to demonstrate declines in aggressive acts, and many of these are boys. The current review uses a dynamic systems (DS) approach to identify early individual and contextual factors that may dynamically influence trajectories of aggression as a characteristic way of engaging within communities and relationships. Within the DS framework, we focus on the parent-infant relationship as central to the development of adaptive emotion-regulation capacities of the infant and young child. Biological sex differences that may influence this early relationship are highlighted, as is the influence of contextual processes such as family violence. Clinical implications suggested by both the empirical and theoretical literatures are then described. PMID- 28004405 TI - Expert clinical management of autoimmune hepatitis in the real world. AB - BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis. PMID- 28004407 TI - REFLECTING ON THE PRACTICE OF INFANT MENTAL HEALTH AND THE REDUCTION OF RISK IN INFANCY AND EARLY PARENTHOOD: AN ESSAY. AB - This essay discusses infant mental health (IMH) as well as its origins and relational framework. The author then reflects, professionally and personally, on the meaning of psychological vulnerability of boys under 5 years of age, the importance of early caregiving relationships to the reduction of risk, and implications for education and training in the IMH field. PMID- 28004408 TI - Ten-Year Clinical Experience with the Lumenless, Catheter-Delivered, 4.1-Fr Diameter Pacing Lead in Patients with and without Congenital Heart. AB - BACKGROUND: Patients with congenital heart defects (CHD) often present more challenges to pacing therapy due to anatomy than those without CHD. The lumenless, 4.1Fr diameter M3830 pacing lead (Medtronic, Inc., Minneapolis, MN, USA), approved for use in 2005, has, to date, reported to have excellent short term (<6 years) lead performance. Unfortunately, very long-term performance is unknown, especially among CHD patients and with implants at alternate pacing (AP) sites. This study reports a 10-year clinical experience with the M3830 lead. METHODS: Records of patients who received the M3830 lead were reviewed: patient demographics, implant techniques and locations, sensing and pacing characteristics, impedances (Imp), and any complications at implant and follow up. RESULTS: From 2005 to 2015, 141 patients (ages 2-50, mean 20.1 years, 57% males) received 212 leads: atrial 115; ventricle 97. CHD was present in 62% of patients. Leads were inserted at AP sites in 96% of patients. Postimplant follow up was from 3 months to 10 years (mean 56.3 months). Comparative implant versus follow-up values (mean +/- standard deviation) were available on 196 leads (92.5%), showing persistently low (<1 v @ 0.4-0.5 ms) pacing thresholds (P = 0.57). Sensing was also comparable (atrial leads, P = 0.41; ventricular leads, P = 0.9). Impedances differed (P < 0.05) but remained within the normal range. Two A leads became dislodged and one was repositioned while two other leads (1 A, 1 V) were extracted. There are no differences observed in the pacing characteristics between the CHD and non-CHD groups on follow-up. CONCLUSIONS: The 4.1Fr lumenless pacing lead shows ease of implant regardless of CHD or AP site, excellent very long-term (10 years) stability, and performance indices with a very low rate of complications. PMID- 28004409 TI - Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins. AB - Tannins, polyphenols in medicinal plants, have been divided into two groups of hydrolysable and condensed tannins, including gallotannins, ellagitannins, and ( )-epigallocatechin-3-gallate (EGCG). Potent anticancer activities have been observed in tannins (especially EGCG) with multiple mechanisms, such as apoptosis, cell cycle arrest, and inhibition of invasion and metastases. Furthermore, the combinational effects of tannins and anticancer drugs have been demonstrated in this review, including chemoprotective, chemosensitive, and antagonizing effects accompanying with anticancer effect. However, the applications of tannins have been hindered due to their poor liposolubility, low bioavailability, off-taste, and shorter half-life time in human body, such as EGCG, gallic acid, and ellagic acid. To tackle these obstacles, novel drug delivery systems have been employed to deliver tannins with the aim of improving their applications, such as gelatin nanoparticles, micelles, nanogold, liposomes, and so on. In this review, the chemical characteristics, anticancer properties, and drug delivery systems of tannins were discussed with an attempt to provide a systemic reference to promote the development of tannins as anticancer agents. PMID- 28004410 TI - Informed choice and decision making in women offered cell-free DNA prenatal genetic screening. PMID- 28004411 TI - Non-chemosensitive parafacial neurons simultaneously regulate active expiration and airway patency under hypercapnia in rats. AB - KEY POINTS: Hypercapnia or parafacial respiratory group (pFRG) disinhibition at normocapnia evokes active expiration in rats by recruitment of pFRG late expiratory (late-E) neurons. We show that hypercapnia simultaneously evoked active expiration and exaggerated glottal dilatation by late-E synaptic excitation of abdominal, hypoglossal and laryngeal motoneurons. Simultaneous rhythmic expiratory activity in previously silent pFRG late-E neurons, which did not express the marker of ventral medullary CO2 -sensitive neurons (transcription factor Phox2b), was also evoked by hypercapnia. Hypercapnia-evoked active expiration, neural and neuronal late-E activities were eliminated by pFRG inhibition, but not after blockade of synaptic excitation. Hypercapnia produces disinhibition of non-chemosensitive pFRG late-E neurons to evoke active expiration and concomitant cranial motor respiratory responses controlling the oropharyngeal and upper airway patency. ABSTRACT: Hypercapnia produces active expiration in rats and the recruitment of late-expiratory (late-E) neurons located in the parafacial respiratory group (pFRG) of the ventral medullary brainstem. We tested the hypothesis that hypercapnia produces active expiration and concomitant cranial respiratory motor responses controlling the oropharyngeal and upper airway patency by disinhibition of pFRG late-E neurons, but not via synaptic excitation. Phrenic nerve, abdominal nerve (AbN), cranial respiratory motor nerves, subglottal pressure, and medullary and spinal neurons/motoneurons were recorded in in situ preparations of juvenile rats. Hypercapnia evoked AbN active expiration, exaggerated late-E discharges in cranial respiratory motor outflows, and glottal dilatation via late-E synaptic excitation of abdominal, hypoglossal and laryngeal motoneurons. Simultaneous rhythmic late-E activity in previously silent pFRG neurons, which did not express the marker of ventral medullary CO2 -sensitive neurons (transcription factor Phox2b), was also evoked by hypercapnia. In addition, hypercapnia-evoked AbN active expiration, neural and neuronal late-E activities were eliminated by pFRG inhibition, but not after blockade of synaptic excitation. On the other hand, pFRG inhibition did not affect either hypercapnia-induced inspiratory increases in respiratory motor outflows or CO2 sensitivity of the more medial Phox2b-positive neurons in the retrotrapezoid nucleus (RTN). Our data suggest that neither RTN Phox2b-positive nor other CO2 -sensitive brainstem neurons activate Phox2b-negative pFRG late-E neurons under hypercapnia to produce AbN active expiration and concomitant cranial motor respiratory responses controlling the oropharyngeal and upper airway patency. Hypercapnia produces disinhibition of non-chemosensitive pFRG late-E neurons in in situ preparations of juvenile rats to activate abdominal, hypoglossal and laryngeal motoneurons. PMID- 28004412 TI - Conceptualization of physical exercise and keeping fit by child wheelchair users and their parents. AB - AIM: To gain a better understanding of how children aged 6-18 years who use wheelchairs and their families conceptualized physical exercise and keeping fit. BACKGROUND: Disabled children with reduced mobility are commonly overweight and unfit. Nurse-led health screening programmes in schools commonly exclude disabled children if they cannot use standard weighing scales or stand against height measuring sticks. DESIGN: Qualitative interview study at two time points over 6 months with children who use wheelchairs and their families. METHODS: Framework analysis using the theory of planned behaviour. FINDINGS: Mainly physically active participants were recruited (24 children and 23 parents) 2013-2014. Despite engaging in high levels of physical exercise, children were assessed as fit but had elevated body fat and did not realize how fit they were or that they were slightly overweight and nor did their parents. Children enjoyed the social benefits of exercise. Unlike their parents, children confused the purpose and outcomes of physical exercise with therapy (e.g. physiotherapy) and incorrectly understood the effects of physical exercise on body function and strength, preventing stiffness, increasing stamina and reducing fatigue. A new model was developed to show children's misconceptions. CONCLUSIONS: Proactive parents can overcome barriers to enable their children to benefit from physical exercise. Professionals need to increase communication clarity to improve children's understanding of therapy compared with physical exercise outcomes. Inclusion of children who use wheelchairs in health education policy; routine health screening; physical education classes and teacher training requires improvement. Body composition measurement is recommended, for which nurses will need training. PMID- 28004413 TI - Direct oral anticoagulant use in nonvalvular atrial fibrillation with valvular heart disease: a systematic review. AB - Direct oral anticoagulants (DOACs) are indicated for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), which, according to the American College of Cardiology/American Heart Association/Heart Rhythm Society atrial fibrillation (AF) guidelines, excludes patients with rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair. However, the data regarding use of DOACs in AF patients with other types of valvular heart disease (VHD) are unclear. We aimed to summarize and evaluate the literature regarding the safety and efficacy of DOAC use in NVAF patients with other types of VHD. After an extensive literature search, a total of 1 prospective controlled trial, 4 subanalyses, and 1 abstract were identified. Efficacy of the DOAC agents in NVAF patients with VHD mirrored the overall trial results. Bleeding risk was significantly increased in VHD patients treated with rivaroxaban, but not for dabigatran or apixaban. Of the bioprosthetic valve patients enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, no safety or efficacy concerns were identified. In conclusion, subanalyses of DOAC landmark AF trials revealed that dabigatran, rivaroxaban, and apixaban may be safely used in AF patients with certain types of VHD: aortic stenosis, aortic regurgitation, and mitral regurgitation. More evidence is needed before routinely recommending these agents for patients with bioprosthetic valves or mild mitral stenosis. Patients with moderate to severe mitral stenosis or mechanical valves should continue to receive warfarin, as these patients were excluded from all landmark AF trials. PMID- 28004414 TI - An Expectation Maximization algorithm for fitting the generalized odds-rate model to interval censored data. AB - The generalized odds-rate model is a class of semiparametric regression models, which includes the proportional hazards and proportional odds models as special cases. There are few works on estimation of the generalized odds-rate model with interval censored data because of the challenges in maximizing the complex likelihood function. In this paper, we propose a gamma-Poisson data augmentation approach to develop an Expectation Maximization algorithm, which can be used to fit the generalized odds-rate model to interval censored data. The proposed Expectation Maximization algorithm is easy to implement and is computationally efficient. The performance of the proposed method is evaluated by comprehensive simulation studies and illustrated through applications to datasets from breast cancer and hemophilia studies. In order to make the proposed method easy to use in practice, an R package 'ICGOR' was developed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28004415 TI - Serum cholesterol and risk of lower urinary tract symptoms progression: Results from the Reduction by Dutasteride of Prostate Cancer Events study. AB - OBJECTIVE: To determine if cholesterol is a risk factor for the development of lower urinary tract symptoms in asymptomatic men. METHODS: A post-hoc analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study was carried out in 2323 men with baseline International Prostate Symptom Score <8 and not taking benign prostatic hyperplasia or cholesterol medications. Cox proportion models were used to test the association between cholesterol, high-density lipoprotein, low-density lipoprotein and the cholesterol : high-density lipoprotein ratio with incident lower urinary tract symptoms, defined as first report of medical treatment, surgery or two reports of an International Prostate Symptom Score >14. RESULTS: A total of 253 men (10.9%) developed incident lower urinary tract symptoms. On crude analysis, higher high-density lipoprotein was associated with a decreased lower urinary tract symptoms risk (hazard ratio 0.89, P = 0.024), whereas total cholesterol and low-density lipoprotein showed no association. After multivariable adjustment, the association between high-density lipoprotein and incident lower urinary tract symptoms remained significant (hazard ratio 0.89, P = 0.044), whereas no association was observed for low density lipoprotein (P = 0.611). There was a trend for higher cholesterol to be linked with higher lower urinary tract symptoms risk, though this was not statistically significant (hazard ratio 1.04, P = 0.054). A higher cholesterol : high-density lipoprotein ratio was associated with increased lower urinary tract symptoms risk on crude (hazard ratio 1.11, P = 0.016) and adjusted models (hazard ratio 1.12, P = 0.012). CONCLUSIONS: Among asymptomatic men participating in the REDUCE study, higher cholesterol was associated with increased incident lower urinary tract symptoms risk, though the association was not significant. A higher cholesterol : high-density lipoprotein ratio was associated with increased incident lower urinary tract symptoms, whereas higher high-density lipoprotein was protective. These findings suggest dyslipidemia might play a role in lower urinary tract symptoms progression. PMID- 28004416 TI - Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome. AB - Prader-Will syndrome (PWS) is characterized by hyperphagia, growth hormone deficiency and central hypogonadism caused by the dysfunction of the hypothalamus. Patients with PWS present with methylation abnormalities of the PWS imprinting control region in chromosome 15q11.2, subject to parent-of-origin specific methylation and controlling the parent-of-origin-specific expression of other paternally expressed genes flanking the region. In theory, the reversal of hypermethylation in the hypothalamic cells could be a promising strategy for the treatment of PWS patients, since cardinal symptoms of PWS patients are correlated with dysfunction of the hypothalamus. The genome-wide methylation status dramatically changes during the reprograming of somatic cells into induced pluripotent stem cells (iPSCs) and during the in vitro culture of iPSCs. Here, we tested the methylation status of the chromosome 15q11.2 region in iPSCs from a PWS patient using pyrosequencing and a more detailed method of genome-wide DNA methylation profiling to reveal whether iPSCs with a partially unmethylated status for the chromosome 15q11.2 region exhibit global methylation aberrations. As a result, we were able to show that a fully methylated status for chromosome 15q11.2 in a PWS patient could be reversed to a partially unmethylated status in at least some of the PWS-iPSC lines. Genome-wide DNA methylation profiling revealed that the partial unmethylation occurred at differentially methylated regions located in chromosome 15q11.2, but not at other differentially methylated regions associated with genome imprinting. The present data potentially opens a door to cell-based therapy for PWS patients and, possibly, patients with other disorders associated with genomic imprinting. PMID- 28004417 TI - Differences in attentional functioning between preterm and full-term children underline the importance of new neuropsychological detection techniques. AB - AIM: The aim of this study was to investigate specific attentional components in preterm born children who had not yet started school. METHODS: Between January and December 2011, we assessed 52 preterm and 52 full-term children aged between five years five months and six years two months, of comparable age and gender, at the Medical University of Vienna. Different attentional components were evaluated through selected subtests of the Test of Attentional Performance and the German version of the Wechsler Intelligence Scale for Children. Each child's behaviour was also evaluated using parental ratings and descriptive item-based evaluation during neuropsychological assessment. RESULTS: Children born preterm showed poor attentional performance in sustained attention, focused attention and distractibility, as well as reductions in processing speed in divided attention and flexibility tasks. Children born preterm also showed decreased volitional attention compared with automatic attention. No problems were detected in alertness or inhibition. In addition, a higher rate of aborted tests, decreased motivation and poorer parental ratings were detected among the preterm population compared with full-term born children. CONCLUSION: Our results highlighted differences in attentional functioning between preterm and full-term children, indicating the importance of new neuropsychological techniques for the detection of specific attentional disorders. PMID- 28004418 TI - Sublingual immunization with Japanese encephalitis virus vaccine effectively induces immunity through both cellular and humoral immune responses in mice. AB - The Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis. Although there are four classes of vaccines against JEV, all of them are administered by s.c or i.m injection. Here, the effectiveness of sublingual (s.l.) administration of a JEV live-attenuated vaccine or recombinant modified vaccinia virus Ankara (MVA) vaccine, including JEV prM/E, was investigated. The mice were immunized three times i.m. or s.c. One week after the final immunization by both s.l. and i.m. routes, the titers of IgG1 induced by the recombinant MVA vaccine were higher than those induced by the live-attenuated vaccine, whereas the titers of IgG2a induced by the live-attenuated vaccine were higher than those induced by the recombinant MVA vaccine. However, both vaccines induced neutralizing antibodies when given by either s.l. or i.m. routes, indicating that both vaccines induce appropriate Th1 and Th2 cell responses through the s.l. and i.m. routes. Moreover, both vaccines protected against induction of proinflammatory cytokines and focal spleen white pulp hyperplasia after viral challenge. Virus-specific IFN-gamma+ CD4+ and CD8+ T cells appeared to increase in mice immunized via both s.l. and i.m. routes. Interestingly, virus specific IL-17+ CD4+ T cells increased significantly only in the mice immunized via the s.l. route; however, the increased IL-17 did not affect pathogenicity after viral challenge. These results suggest that s.l. immunization may be as useful as i.m. injection for induction of protective immune responses against JEV by both live-attenuated and recombinant MVA vaccines. PMID- 28004419 TI - Ordered CaSi2 Microwall Arrays on Si Substrates Induced by the Kirkendall Effect. AB - We have specified the synthetic conditions to obtain one-directionally ordered CaSi2 microwall arrays vertically grown on a Si substrate. Our basic concept is based on the utilization of the Kirkendall effect for reactive deposition epitaxy (RDE). We found for the first time that: 1) a much larger Ca vapor supply on the Si substrate than the conventional RDE, 2) the adoption of a two-step heating process, and 3) the selection of the crystal axis of the Si surface are the keys to control the microstructures of CaSi2 on the Si substrate. The CaSi phase was first formed on Si, then the CaSi2 phase was formed at the CaSi/Si interface. Based on the Kirkendall effect, the interdiffusion of Ca and Si was enhanced in the vertical direction rather than in the parallel direction to the Si surface. CaSi2 tends to grow along four equivalent Si{111} planes, however, the specific orientation of the Si surface resulted in CaSi2 microwalls grown along its Si(111? ) plane, the only plane directing nearly vertical to the surface among the Si{111} planes. These results suggest that the Kirkendall effect under asymmetric growth of target materials would be a rational strategy to obtain their ordered microstructures. PMID- 28004420 TI - The Lipid A from Rhodopseudomonas palustris Strain BisA53 LPS Possesses a Unique Structure and Low Immunostimulant Properties. AB - The search for novel lipid A analogues from any biological source that can act as antagonists, displaying inhibitory activity towards the production of pro inflammatory cytokines, or as immunomodulators in mammals, is a very topical issue. To this aim, the structure and immunological properties of the lipopolysaccharide lipid A from the purple nonsulfur bacterium Rhodopseudomonas palustris strain BisA53 have been determined. This lipid A displays a unique structural feature, with a non-phosphorylated skeleton made up of the tetrasaccharide Manp-alpha-(1->4)-GlcpN3N-beta-1->6-GlcpN3N-alpha-(1->1)-alpha GalpA, and four primary amide-linked 14:0(3-OH) and, as secondary O-acyl substituents, a 16:0 and the very long-chain fatty acid 26:0(25-OAc), appended on the GlcpN3N units. This lipid A architecture is definitely rare, so far identified only in the genus Bradyrhizobium. Immunological tests on both murine bone-marrow-derived and human monocyte-derived macrophages revealed an extremely low immunostimulant capability of this LPS lipid A. PMID- 28004421 TI - Comparison of neutrophil functions between two strains of inbred mice. AB - In this study, differences between two strains of inbred mice in aspects of neutrophil function, namely Rac1 expression, chemotaxis, nicotinamide adenine dinucleotide phosphate oxidase activity and formation of neutrophil extracellular traps (NETs), were determined. Neutrophils from CBA/CaH mice exhibited weaker Rac1 expression and a slower chemotactic gradient than BALB/c mice. Furthermore, PMA- or fMLP-stimulated neutrophils from CBA/CaH mice generated much less superoxide and NETs than similarly stimulated neutrophils from BALB/c mice. These findings suggest that neutrophils from BALB/c mice are functionally more efficient than those from CBA/CaH mice. PMID- 28004422 TI - Microtubule-associated proteins, Bik1 and Bim1, are required for faithful partitioning of the endogenous 2 micron plasmids in budding yeast. AB - The 2 MU plasmid of budding yeast shows high mitotic stability similar to that of chromosomes by using its self-encoded systems, namely partitioning and amplification. The partitioning system consists of the plasmid-borne proteins Rep1, Rep2 and a cis-acting locus STB that, along with several host factors, ensures efficient segregation of the plasmid. The plasmids show high stability as they presumably co-segregate with chromosomes through utilization of various host factors. To acquire these host factors, the plasmids are thought to localize to a certain sub-nuclear locale probably assisted by the motor protein, Kip1 and microtubules. Here, we show that the microtubule-associated proteins Bik1 and Bim1 are also important host factors in this process, perhaps by acting as an adapter between the plasmid and the motor and thus helping to anchor the plasmid to microtubules. Abrogation of Kip1 recruitment at STB in the absence of Bik1 argues for its function at STB upstream of Kip1. Consistent with this, both Bik1 and Bim1 associate with plasmids without any assistance from the Rep proteins. As observed earlier with other host factors, lack of Bik1 or Bim1 also causes a cohesion defect between sister plasmids leading to plasmid missegregation. PMID- 28004423 TI - Sulfamide-Lattice Restructuring To Form Dimensionally Controlled Molecular Arrays and Gel-Forming Systems. AB - A design approach that incorporates structural requirements for the formation of a 1D assembly, fibril stability, and fibril-fibril interactions for gelation was attempted by using amino acid-based sulfamides with the general structure Aa-NH SO2 -NH-Aa (Aa=amino acid). A preference for 1D assembly alone was not a sufficient condition for gelation, which became evident from studies involving sulfamide esters 1-5. Reducing the crystallization tendency without hindering unidirectional growth was executed through diacids of the sulfamide precursors with various amines that form an envelope around the sulfamide core through salt bridges. This strategy was fruitful, and gels of a wide variety of solvents could be formed by varying the acid and amine components. The use of dodecylamine or benzylamine, which could stabilize the molecular layers through alkyl-chain segregation or pi-pi interactions improved the gelation tendency, whereas the nature of the amino acid side chain, especially the rotational freedom and hydrophobicity, had a direct role in dictating the solvent preference. Crystallographic studies of these two-component systems gave molecular-level insight into the assembly and showed the importance of anisotropy in the distribution of secondary interactions in gelation. PMID- 28004424 TI - Access to Enantiopure Triarylmethanes and 1,1-Diarylalkanes by NHC-Catalyzed Acylative Desymmetrization. AB - We present herein an unprecedented, efficient and enantioselective synthesis of triarylmethanes and 1,1-diarylalkanes through N-heterocyclic carbene-catalyzed acylative desymmetrization of bisphenols. This method utilizes readily available substrates, reagents and a simple procedure to deliver the valuable products in excellent enantiopurity. DFT calculations reveal that the selectivity is governed by the C-C bond cleavage step of the tetrahedral intermediate leading to the ester product. A transition state model featuring a combination of intramolecular hydrogen bond and steric effect is developed to explain the enantioselectivity. PMID- 28004425 TI - Angiopoietin-like 4: A molecular link between insulin resistance and rheumatoid arthritis. AB - Recent evidence suggests that common factor(s) or molecule(s) might regulate lipid and glucose metabolism, inflammation, and bone and cartilage degeneration. These findings may be particularly relevant for cases of rheumatoid arthritis, in which chronic inflammation occurs in an autoimmune context and causes the degradation of articular joints as well as insulin resistance and cardiovascular complications. Candidates for this common regulatory system include signals mediated by peroxisome proliferator-activated regulator and its response factor, angiopoietin-like 4. The expression and bioactivity of angiopoietin-like 4, an adipocytokine that was originally reported to have an angiogenic function, have been detected not only in the vascular system and adipose tissue but also in rheumatoid joints. An essential role for angiopoietin-like 4 has been established in dyslipidemia, and recent reports indicate that it may modulate bone and cartilage catabolism in rheumatoid arthritis. The enhanced expression of angiopoietin-like 4 in rheumatoid arthritis may explain the occurrence of insulin resistance, cardiovascular risk, and joint destruction, thereby suggesting that this molecule could be a potential target for anti-rheumatoid arthritis strategies. This review describes recent research on the role of angiopoietin like 4 in chronic inflammatory conditions and rheumatoid arthritis, as well as potential therapeutic candidates. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:939-943, 2017. PMID- 28004426 TI - Inhibition of Anaphase-Promoting Complex by Silence APC/CCdh1 to Enhance Radiosensitivity of Nasopharyngeal Carcinoma Cells. AB - The aim of this study was to investigate the possibility of APC/CCdh1 as a potential therapeutic target in the radiosensitivity of nasopharyngeal carcinoma (NPC) cell CNE-1, and explain the role of APC subunits after silence of Cdh1 combined with radiotherapy. Transfection with Cdh1 shRNA significantly increased the radiosensitivity of CNE-1 cells and the radiation enhancement ratio (RER) of sh-Cdh1 cells was 1.76. Knockdown of Cdh1 in CNE-1 cells increased irradiation induced apoptosis and G2/M phase cell cycle arrest. The levels of CDC20 and CylinB1 increased and the levels of Ku70 and APC3 decreased after irradiation. APC/CCdh1 is involved in regulation of radiosensitivity in human NPC CNE-1 cells. Our study may provide a promising therapeutic strategy for NPC by targeting Cdh1. J. Cell. Biochem. 118: 3150-3157, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28004427 TI - Single-Site Osmium Catalysts on MgO: Reactivity and Catalysis of CO Oxidation. AB - MgO-supported osmium dioxo species, described as Os(=O)2 {-Osupport }1 or 2 (the brackets denote O atoms of the MgO surface), formed from Os3 (CO)12 via supported Os(CO)2 , and characterized by spectroscopy, microscopy, and theory, react with ethylene at 298 K to form osmium glycol species or with CO to give osmium mono- and di-carbonyls. Os(=O)2 {-Osupport }1 or 2 is the precursor of a CO oxidation catalyst characterized by a turnover frequency of 4.0*10-3 (molecules of CO)/(Os atom*s) at 473 K; the active species are inferred to be osmium monocarbonyls. The structures and frequencies calculated at the level of density functional theory with the B3LYP functional bolster the experimental results and facilitate structural assignments. The lowest-energy structures have various osmium oxidation and spin states. The results demonstrate not only new chemistry of the supported single-site catalysts but also their complexity and the value of complementary techniques used in concert to unravel the chemistry. PMID- 28004428 TI - Residential Mobility and Social Behaviors of Adolescents: A Systematic Review of the Literature. AB - PROBLEM: The association between residential mobility and negative behaviors in adolescence has attracted multidisciplinary attention. METHODS: The purpose of this article is to conduct a systematic literature review in order to synthesize research that measured mobility and at least one social behavior among participants 11 thru 18 years of age. The systematic search yielded 22 studies. FINDINGS: Residential mobility is associated with negative behaviors among adolescents, including social problems, delinquency, substance and nicotine use, and adolescent pregnancy. However, these effects are explained by neighborhood disadvantage and inherent differences between movers and nonmovers. CONCLUSION: For youth from disadvantaged backgrounds, moving may be one indicator of problem behaviors. Attending to when and why youth move-and to where-contributes to an understanding of the etiology of risky behaviors. PMID- 28004429 TI - The cost of diagnosis and early support in patients with cognitive decline. AB - OBJECTIVE: Recent research indicates considerable heterogeneity in the provision of memory assessment services (MAS). However, little is known on the extent of variation in the costs of the services MAS provide. We investigated the costs of supporting patients with suspected dementia, including assessment and support over the following 6 months. METHODS: Clinic costs were estimated on the basis of an organisational survey reporting staff roll, grade and activities. Costs of primary health and social care were estimated from questionnaire data reported by carers of patients at baseline, 3 and 6 months after referral. RESULTS: Mean monthly staff costs at MAS were L73 000. Imaging at assessment costs an additional L3500 per month. Monthly clinic cost per new patient assessed varied from L320 to L5400 across clinics. Additional primary health and social care costs of L130-220 a month between baseline and 6 months were reported by carers. Costs of pharmacological and non-pharmacological treatments reported by carers were small. Informal care costs dwarfed health and social care costs when valued at a modest unit cost. The overall mean cost of supporting a patient for 6 months varied from L1600 to L2500 dependent on assumptions regarding the proportion of MAS intervention and review costs accrued at 6 months. CONCLUSIONS: There is considerable variation in the intensity and associated costs of services provided by MAS. Further research should ascertain to what extent such variation is associated with differences in patient outcomes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28004430 TI - Evaluation of [18 F]BR420 and [18 F]BR351 as radiotracers for MMP-9 imaging in colorectal cancer. AB - MMP-9 is a zinc-dependent endopeptidase that is involved in the proteolytic degradation of the extracellular matrix and plays an important role in cancer migration, invasion, and metastasis. The aim of this study was to evaluate the potential of MMP-tracers [18 F]BR420 and [18 F]BR351 for MMP-9 imaging in a colorectal cancer xenograft model. [18 F]BR420 and [18 F]BR351 were synthesized using an automated synthesis module. For [18 F]BR420, a novel and improved radiosynthesis was developed. Plasma stability and MMP-9-targeting capacity of both radiotracers was compared in the Colo205 colorectal cancer model. MMP-9 and MMP-2 expression levels in the tumors were evaluated by immunohistochemistry and in situ zymography. MUPET imaging as well as ex vivo biodistribution revealed a higher tumor uptake for [18 F]BR420 (3.15% +/- 0.03% ID/g vs 0.94% +/- 0.18% ID/g for [18 F]BR351 at 2 hours pi) but slower blood clearance compared with [18 F]BR351. [18 F]BR351 was quickly metabolized in plasma with 20.28% +/- 5.41% of intact tracer remaining at 15 minutes postinjection (PI). By contrast, [18 F]BR420 displayed a higher metabolic stability with >86% intact tracer remaining at 2 hours PI. Immunohistochemistry revealed the presence of MMP-9 and MMP-2 in the tumor tissue, which was confirmed by in situ zymography. However, an autoradiography analysis of tracer distribution in the tumors did not correlate with MMP-9 expression. [18 F]BR420 displayed a higher tumor uptake and higher stability compared with [18 F]BR351 but a low tumor-to-blood ratio and discrepancy between tracer distribution and MMP-9 immunohistochemistry. Therefore, both tracers will not be usefulness for MMP-9 imaging in colorectal cancer. PMID- 28004431 TI - Changing paradigms and challenges: evidence on the epidemiological and economic burden of diabetes in Latin America. PMID- 28004432 TI - Role of coagulation factors in urological malignancy: A prospective, controlled study on prostate, renal and bladder cancer. AB - OBJECTIVES: To study the behavior of specific coagulation factors in different types of non-metastatic urological cancers, and to identify their possible role as diagnostic and prognostic markers. METHODS: This was a prospective controlled study, which included three cancer patient groups and a control group of healthy individuals. The cancer subgroups consisted of renal (n = 44), prostate (n = 56) and bladder cancer (n = 47). We excluded patients receiving anticoagulant therapy, or with significant comorbidity. In all patients, certain coagulation parameters were measured (prothrombin time, international normalized ratio, partial thromboplastin time, D-dimers, fibrinogen, F1 + 2, thrombin-antithrombin complex). Statistical analysis was carried out to explore the association of hemostasis markers with tumor-nodes-metastasis stage, Gleason score, transitional cell carcinoma grade, Fuhrman grade and prostate-specific antigen. RESULTS: Our final sample consisted in 58 control patients and 147 patients with urological cancer. We found specific patterns of increased coagulation factors in the different cancers that were statistically significant. Renal cancer showed increased levels of D-dimers, partial thromboplastin time and fibrinogen. D dimers and fibrinogen were increased in prostate cancer; whereas in bladder cancer, only fibrinogen was elevated. Correlations were found between certain factors and tumor stage and grading, with D-dimers being independently associated with higher tumor grade. Thrombin-antithrombin complex was associated with Gleason score. Furthermore, D-dimers, fibrinogen and F1 + 2 were associated with higher tumor stages (II-IV). CONCLUSIONS: The coagulation pathway seems to be activated in urological malignancies. Specific panels of coagulation factors might play a role as screening or prognostic tools in earlier stages of renal, prostate and bladder cancer. Further research should also focus on their role in the association of cancer with thromboembolic events. PMID- 28004433 TI - Effects of early and delayed initiation of exercise training on cardiac and haemodynamic function after spinal cord injury. AB - NEW FINDINGS: What is the central question of this study? How does early versus delayed initiation of passive hindlimb cycling, as well as detraining, affect cardiac function and blood pressure control in a rodent model of spinal cord injury? What is the main finding and its importance? Early or delayed initiation of hindlimb cycling improves cardiac and haemodynamic function in spinal cord injury, although the benefits of early administration are more pronounced. We also demonstrate the need for exercise to be maintained, because detraining rapidly reverses the cardiac and haemodynamic benefits. Spinal cord injury (SCI) reduces physical activity and alters descending supraspinal cardiovascular control, predisposing this population to early onset of cardiovascular disease. We used a T3 SCI rodent model to investigate the effect of early versus delayed passive hindlimb cycling (PHLC), as well as the effect of detraining on cardiac dysfunction and blood pressure control, including autonomic dysreflexia (AD). Twenty male Wistar rats were divided into an early PHLC initiation group followed by a period of detraining (PHLC starting day 6 post-SCI, for 4 weeks, followed by 4 weeks of detraining; 'early PHLC/detraining' group) and a delayed PHLC intervention group (no PHLC for first 5 weeks post-SCI, followed by PHLC for 4 weeks; 'no PHLC/delayed PHLC' group). At 5 weeks post-SCI, the no PHLC/delayed PHLC group exhibited a decline in almost all cardiac indices (all P < 0.029), which was maintained in the early PHLC/detraining group. Also, the severity of induced AD was reduced in the early PHLC/detraining versus no PHLC/delayed PHLC group (all P < 0.0279). At 9 weeks post-SCI, no PHLC/delayed PHLC animals exhibited a reversal of cardiac dysfunction such that all indices were not different from pre-SCI, whereas early PHLC/detraining rats exhibited a reduction in all cardiac indices relative to pre-SCI (all P < 0.049), except ejection fraction. Between weeks 7 and 9 post-SCI, the no PHLC/delayed PHLC rats exhibited fewer spontaneous AD events than the early PHLC/detraining rats (P < 0.01). We show, for the first time, that delayed exercise promotes similar improvements in cardiac and haemodynamic function to those observed with early initiation. Furthermore, exercise needs to be maintained, because detraining reduces these cardiohaemodynamic benefits. PMID- 28004434 TI - Mortality and morbidity in offspring of mothers with diabetes compared with a population group: a Danish cohort study with 8-35 years of follow-up. AB - AIMS: To assess mortality and morbidity in the offspring of mothers with diabetes compared with a control cohort of offspring of mothers without diabetes. METHODS: The mortality rate, percentage of days admitted to hospital, diagnostic categories and incidence of diabetes mellitus among 691 offspring of mothers with diabetes were compared with a control group of 168 831 offspring not exposed to maternal diabetes. Offspring of mothers with diabetes were identified from the North Jutland Pregnancy database (521 Type 1; 34 Type 2; 136 gestational diabetes) born between 1976 and 2003. Outcome data were retrieved from the National Registry of Patients with follow-up until 31 December 2011. In a subgroup with the longest hospital stay we reviewed hospital records for clinical details until 2016. RESULTS: Mortality was 1.45% in the diabetes group compared with 1.36% in the control group. In the first 2 years, offspring exposed to diabetes spent significantly more time in hospital than the control offspring, but this difference faded to an insignificant difference of 0.04% of time spent in hospital between age 2 and 8 years. The offspring of mothers with diabetes had a sixfold increased risk of developing diabetes mellitus. CONCLUSIONS: The offspring of mothers with and without diabetes had almost identical mortality. The increased morbidity was restricted to the first 2 years of life, and was primarily attributable to a few individuals with very severe but probably non diabetes-related disease burden. The large majority of offspring of mothers with diabetes experienced health conditions similar to those not exposed to diabetes. PMID- 28004435 TI - Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. AB - A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2 weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis. PMID- 28004437 TI - Desolvation Induced Origami of Photocurable Polymers by Digit Light Processing. AB - Self-folding origami is of great interest in current research on functional materials and structures, but there is still a challenge to develop a simple method to create freestanding, reversible, and complex origami structures. This communication provides a feasible solution to this challenge by developing a method based on the digit light processing technique and desolvation-induced self folding. In this new method, flat polymer sheets can be cured by a light field from a commercial projector with varying intensity, and the self-folding process is triggered by desolvation in water. Folded origami structures can be recovered once immersed in the swelling medium. The self-folding process is investigated both experimentally and theoretically. Diverse 3D origami shapes are demonstrated. This method can be used for responsive actuators and the fabrication of 3D electronic devices. PMID- 28004436 TI - Vein graft disease in a knockout mouse model of hyperhomocysteinaemia. AB - A major reason for vein graft failure after coronary artery bypass grafting is neointimal hyperplasia and thrombosis. Elevated serum levels of homocysteine (Hcy) are associated with higher incidence of cardiovascular disease, but homocysteine levels also tend to increase during the first weeks or months after cardiac surgery. To investigate this further, C57BL/6J mice (WT) and cystathionine-beta-synthase heterozygous knockout mice (CBS+/-), a mouse model for hyperhomocysteinaemia, underwent interposition of the vena cava of donor mice into the carotid artery of recipient mice. Two experimental groups were examined: 20 mice of each group underwent bypass surgery (group 1: WT donor and WT recipient; group 2: CBS+/- donor and CBS+/- recipient). After 4 weeks, the veins were harvested, dehydrated, paraffin-embedded, stained and analysed by histomorphology and immunohistochemistry. Additionally, serum Hcy levels in CBS knockout animals and in WT animals before and after bypass surgery were measured. At 4 weeks postoperatively, group 2 mice showed a higher percentage of thrombosis compared to controls, a threefold increase in neointima formation, higher general vascularization, a lower percentage of elastic fibres with shortage and fragmentation in the neointima, a lower percentage of acid mucopolysaccharides in the neointima and a more intense fibrosis in the neointima and media. In conclusion, hyperhomocysteinaemic cystathionine-beta-synthase knockout mice can play an important role in the study of mechanisms of vein graft failure. But further in vitro and in vivo studies are necessary to answer the question whether or not homocysteine itself or a related metabolic factor is the key aetiologic agent for accelerated vein graft disease. PMID- 28004438 TI - Polycyclopentene-Crystal-Decorated Carbon Nanotubes by Convenient Large-Scale In Situ Polymerization and their Lotus-Leaf-Like Superhydrophobic Films. AB - In situ Pd-catalyzed cyclopentene polymerization in the presence of multi-walled carbon nanotubes (MWCNTs) is demonstrated to effectively render, on a large scale, polycyclopentene-crystal-decorated MWCNTs. Controlling the catalyst loading and/or time in the polymerization offers a convenient tuning of the polymer content and the morphology of the decorated MWCNTs. Appealingly, films made of the decorated carbon nanotubes through simple vacuum filtration show the characteristic lotus-leaf-like superhydrophobicity with high water contact angle (>150 degrees ), low contact angle hysteresis (<10 degrees ), and low water adhesion, while being electrically conductive. This is the first demonstration of the direct fabrication of lotus-leaf-like superhydrophobic films with solution grown polymer-crystal-decorated carbon nanotubes. PMID- 28004439 TI - Prediction of fetal growth restriction using estimated fetal weight vs a combined screening model in the third trimester. AB - OBJECTIVES: To compare the performance of third-trimester screening, based on estimated fetal weight centile (EFWc) vs a combined model including maternal baseline characteristics, fetoplacental ultrasound and maternal biochemical markers, for the prediction of small-for-gestational-age (SGA) neonates and late onset fetal growth restriction (FGR). METHODS: This was a nested case-control study within a prospective cohort of 1590 singleton gestations undergoing third trimester (32 + 0 to 36 + 6 weeks' gestation) evaluation. Maternal baseline characteristics, mean arterial pressure, fetoplacental ultrasound and circulating biochemical markers (placental growth factor (PlGF), lipocalin-2, unconjugated estriol and inhibin A) were assessed in all women who subsequently delivered a SGA neonate (n = 175), defined as birth weight < 10th centile according to customized standards, and in a control group (n = 875). Among SGA cases, those with birth weight < 3rd centile and/or abnormal uterine artery pulsatility index (UtA-PI) and/or abnormal cerebroplacental ratio (CPR) were classified as FGR. Logistic regression predictive models were developed for SGA and FGR, and their performance was compared with that obtained using EFWc alone. RESULTS: In SGA cases, EFWc, CPR Z-score and maternal serum concentrations of unconjugated estriol and PlGF were significantly lower, while mean UtA-PI Z-score and lipocalin-2 and inhibin A concentrations were significantly higher, compared with controls. Using EFWc alone, 52% (area under receiver-operating characteristics curve (AUC), 0.82 (95% CI, 0.77-0.85)) of SGA and 64% (AUC, 0.86 (95% CI, 0.81 0.91)) of FGR cases were predicted at a 10% false-positive rate. A combined screening model including a-priori risk (maternal characteristics), EFWc, UtA-PI, PlGF and estriol (with lipocalin-2 for SGA) achieved a detection rate of 61% (AUC, 0.86 (95% CI, 0.83-0.89)) for SGA cases and 77% (AUC, 0.92 (95% CI, 0.88 0.95)) for FGR. The combined model for the prediction of SGA and FGR performed significantly better than did using EFWc alone (P < 0.001 and P = 0.002, respectively). CONCLUSIONS: A multivariable integrative model of maternal characteristics, fetoplacental ultrasound and maternal biochemical markers modestly improved the detection of SGA and FGR cases at 32-36 weeks' gestation when compared with screening based on EFWc alone. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28004440 TI - Patients' perception of chemotherapy side effects: Expectations, doctor-patient communication and impact on quality of life - An Italian survey. AB - Chemotherapy side effects (CSE) have a strong impact on patients' quality of life (QOL). To assess patient perceptions of CSE, their impact on QOL and doctor patient communication regarding these aspects, a survey was conducted among Italian cancer patients. Patients at least 18 years of age, who received chemotherapy, were administered a dedicated questionnaire to assess their point of view on five domains: expectations about CSE and impact on QOL; doctor-patient communication about CSE; treatments to reduce the impact of CSE; sexual life; family relationships/activities and employment. A total of 761 patients participated. CSE had a considerable impact on patient QOL. Nausea/vomiting was the most feared adverse effect before initiating chemotherapy and the one most commonly experienced during treatment. Patients generally reported good doctor patient communication regarding information about CSE. In almost all cases, the oncologists prescribed an antiemetic treatment, but the incidence of nausea/vomiting was high. Cancer and CSE severely affected sexual life, daily activities and employment. CSE had a strong negative impact on QOL. Good doctor patient communication is essential. Improving antiemetic strategies may improve QOL. Doctors' ability to inform patients about delicate issues, such as the impact of CSE on sexual life, needs to be improved. PMID- 28004441 TI - Referred symptom from myofascial pain syndrome: One of the most important causes of sensory disturbance in breast cancer patients using taxanes. AB - The aim of this retrospective study was to evaluate common causes of upper extremity sensory disturbance in breast cancer patients. Breast cancer patients who received surgery and taxane chemotherapy (CTx) with upper extremity sensory disturbance that began after CTx were included. With comprehensive clinical history, physical examination and electrodiagnostic results, diagnosis for each patient was made. Fifty-two patients were included: 23 (44.2%) were diagnosed with chemotherapy-induced peripheral neuropathy (CIPN), 7 (13.5%) with myofascial pain syndrome (MPS), six (11.5%) with carpal tunnel syndrome (CTS), four (7.7%) with CIPN and MPS, and three (5.8%) with CIPN and CTS. CIPN was more correlated with sensory symptoms at upper and lower extremities, a shorter time from CTx start, and adriamycin and cytoxan (AC) plus paclitaxel, than with AC plus docetaxel and fluorouracil, epirubicin and cyclophosphamide plus taxanes. MPS was correlated with longer duration of CTx and use of hormone therapy. CTS was correlated with wrist trauma history. Patients with CIPN showed similar degrees of pain even after 3 months of treatment, in comparison to the patients with MPS and CTS. When breast cancer patients complain of upper extremity sensory disturbance, various causes, especially referred symptom from MPS, should be considered for effective treatment. PMID- 28004442 TI - Psychopathological Differences Between Suicide Ideators and Suicide Attempters in Patients with Mental Disorders. AB - BACKGROUND: Although suicide is one of the leading causes of death worldwide, there is a need for studies to identify variables that can differentiate patients with suicide ideation at risk of transitioning to an attempt. METHOD: In this study, we assessed suicide ideation and attempts, non-suicidal self-injury (NSSI), hopelessness, borderline symptoms and meaning in life in a sample of 348 patients with different diagnoses of mental disorders. We divided the sample into four subgroups: patients without suicide ideation or suicide attempts; patients with current suicide ideation; patients with lifetime suicide attempts and patients with a suicide attempt in the previous year. RESULTS: The group with suicide attempts in the previous year showed higher levels of hopelessness, borderline symptoms and NSSI, and lower levels of meaning in life than the other groups. LIMITATIONS: Groups were composed of unequal numbers of patients, and in some of them, the sample size was small. The sample was composed mainly of women with eating disorders. The study design was retrospective, and so the results must be considered in terms of correlates. CONCLUSIONS: Our results suggest that hopelessness, borderline symptoms-including NSSI-and meaning in life play a key role in suicide attempts. Thus, psychotherapeutic interventions should focus on managing NSSI, searching for meaning and managing emptiness, loss of control and feelings such as self-contempt in patients with suicide ideation. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Recent suicide attempters show higher levels of hopelessness, borderline symptoms and NSSI than lifetime attempters and suicide ideators. Clinicians should focus attention on assessing hopelessness, borderline symptoms and NSSI in those with suicide ideation. Lower levels of meaning in life are related to recent suicide attempts. Levels of hopelessness differentiate between recent and lifetime suicide attempters. PMID- 28004443 TI - Amyloid beta induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase- and mitochondria-dependent ROS production. AB - Amyloid beta (Abeta)-induced chronic inflammation is believed to be a key pathogenic process in early-stage age-related macular degeneration (AMD). Nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation triggered by Abeta is responsible for retinal pigment epithelium (RPE) dysfunction in the onset of AMD; however, the detailed molecular mechanism remains unclear. In this study, we investigated the involvement of NADPH oxidase- and mitochondria-derived reactive oxygen species (ROS) in the process of Abeta1-40 -induced NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. The results showed that Abeta1-40 could induce excessive ROS generation, MAPK/NF-kappaB signaling activation and subsequently NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. Furthermore, the inductive effect of Abeta1-40 on NLRP3 inflammasome activation was mediated in a manner dependent on NADPH oxidase- and mitochondria-derived ROS. Our findings may provide a novel insight into the molecular mechanism by which Abeta contributes to the early-stage AMD. PMID- 28004444 TI - Changing survival of people with myeloma and end stage kidney disease: A cohort study using Australian and New Zealand dialysis and transplant registry 1963 2013. AB - BACKGROUND: It is unclear whether recent advances in myeloma therapy have improved survival for all those with myeloma and end stage kidney disease (ESKD). METHODS: Population-based registry cohort study using Australia and New Zealand Dialysis and Transplant Registry data 1963-2013. We measured survival of people with myeloma and other plasma cell dyscrasias and ESKD over time, and investigated prognostic factors for improved survival using survival analysis (results expressed as hazard ratios (HR) with 95% confidence intervals). RESULTS: We included 65 940 people (207 595 person-years); 1067 people (1.6%) with myeloma and 572 (0.9%) with other plasma cell dyscrasia. Myeloma ESKD rose from 0.8% before 1994 to 2.2% in 2004 and remained stable. People with myeloma were older, and age increased over time, from 62.5 before 1994 to 70.1 years from 2010, but the non-myeloma group age increased more steeply (52.0 before 1994; 62.2 from 2010). In myeloma patients, survival improved (P < 0.001) with recent predicted 5 year survival of 27.5% aged <55, 32.2% aged 55-64, 16.3% for 65-74 and 12.7% aged >=75 years. Survival did not improve for plasma cell dyscrasia patients (P = 0.70). Myeloma patients on peritoneal dialysis had improved survival compared with those on haemodialysis (HR 0.7, CI 0.6-0.9), but those aged >=65 had poorer survival (65-74 years HR 1.5, CI1.2-1.9; >=75 HR 1.7, CI1.3-2.1), as did diabetics (HR 1.3, CI1.1-1.6). CONCLUSIONS: The proportion of people with myeloma and ESKD remains stable, but their survival has progressively improved in Australia and New Zealand. On starting ESKD treatment with myeloma, a 59 year old without diabetes on peritoneal dialysis can expect a 45% 5 year survival, where a 75-year-old diabetic on haemodialysis has 9% 5 year survival. PMID- 28004445 TI - Helping r-proteins on their way to maturity: Chaperones for the royals of the protein world.... PMID- 28004446 TI - Is H3K4me3 instructive for transcription activation? AB - Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a near-universal chromatin modification at the transcription start site of active genes in eukaryotes from yeast to man and its levels reflect the amount of transcription. Because of this association, H3K4me3 is often described as an 'activating' histone modification and assumed to have an instructive role in the transcription of genes, but the field is lacking a conserved mechanism to support this view. The overwhelming finding from genome-wide studies is that actually very little transcription changes upon removal of most H3K4me3 under steady-state or dynamically changing conditions, including at mammalian CpG island promoters. Instead, rather than a major role in instructing transcription, time-resolved experiments provide more evidence supporting the deposition of H3K4me3 into chromatin as a result of transcription, influencing processes such as memory of previous states, transcriptional consistency between cells in a population and transcription termination. PMID- 28004448 TI - Social networks, social support and social negativity: A qualitative study of head and neck cancer caregivers' experiences. AB - Head and neck cancer is a serious form of cancer that can generate substantial physical and psychosocial morbidity. Informal caregivers can help patients to manage head and neck cancer and its emotional impacts, both during and after treatment. Caregivers, however, can experience considerable stress as a result of their caring activities. Supportive relationships can protect caregivers from psychosocial strain. Thirty-one head and neck cancer caregivers were interviewed about their experiences of accessing social support from their social networks; difficulties that they experienced accessing this support; and strategies that they used to address these difficulties. Results suggest that head and neck cancer caregivers strongly value social support, but can find it difficult to obtain, and a number of them experience socially negative responses from their networks. Some carers attempt to answer or supplement support deficiencies by turning to non-human coping supports, such as pets, spiritual figures or medication. Implications for theory and practice are discussed. PMID- 28004449 TI - Genomic pathobiology of gastric carcinoma. AB - With the recent advances in genome sequencing technologies, comprehensive cancer genomic profiling has revealed the in-depth molecular mechanisms of gastric malignancies. New insights into the carcinogenesis pathways of gastric cancers have been acquired, not only by DNA sequencing, but also by the expression profiling of the transcriptome, the identification of chimeric genes, and epi genetic profiling (such as DNA hypermethylation). Global genomic profiling of gastric cancers, in combination with histopathology, etiology, and cancer biology, has clarified that gastric cancers can be categorized into four subtypes with specific genomic characteristics. Here, we summarize recent knowledge concerning the clinically relevant genomic classifications of gastric cancers and discuss the therapeutic implications for such genomic subtypes, including future perspectives for immune-checkpoint blockade therapies against gastric malignancies. PMID- 28004447 TI - Beyond force generation: Why is a dynamic ring of FtsZ polymers essential for bacterial cytokinesis? AB - We propose that the essential function of the most highly conserved protein in bacterial cytokinesis, FtsZ, is not to generate a mechanical force to drive cell division. Rather, we suggest that FtsZ acts as a signal-processing hub to coordinate cell wall synthesis at the division septum with a diverse array of cellular processes, ensuring that the cell divides smoothly at the correct time and place, and with the correct septum morphology. Here, we explore how the polymerization properties of FtsZ, which have been widely attributed to force generation, can also be advantageous in this signal processing role. We suggest mechanisms by which FtsZ senses and integrates both mechanical and biochemical signals, and conclude by proposing experiments to investigate how FtsZ contributes to the remarkable spatial and temporal precision of bacterial cytokinesis. PMID- 28004450 TI - Cross-sectional study to assess the need to commence opportunistic screening of women for cervical cancer presenting with sexually transmitted disease in Western India. AB - This study examines the prevalence of suspected cervical cancer (established through the use of visual inspection with Lugol's Iodine - VILI) among outpatients attending Surat Municipal Institute of Medical Education & Research Hospital, India. A cross-sectional study was conducted on 356 patients; 178 with an established sexually transmitted disease (STD) and 178 patients without. Patients with positive results were investigated with cervical biopsy; out of 356 patients, 21.91% patients with STD and 12.35% patients without STD tested positive for VILI respectively (p = .017). The factors found to be significantly associated with a positive VILI test were STD, marital status, oral contraceptive pill use, a complaint of PV bleeding, white discharge on speculum examination (PS) and cervical erosion on PS. On applying multiple logistic regression, STD, age of patient in years, parity, OC pill use, a complaint of PV bleeding and cervical erosion on PS were found to be significant predictors of VILI positivity among the patients. STD patients are 2.5 times more likely to test positive for VILI than patients without STD. In Indian populations comparable to ours, opportunistic screening should be considered in gynaecology outpatient clinics for women presenting with complaints related to STDs. PMID- 28004451 TI - Total depression and subtypes in prostate cancer survivors 10 years after treatment. AB - To describe the prevalence, severity and nature of depression in a sample of prostate cancer (PCa) survivors 10 years after diagnosis and treatment, 146 Australian patients from the RADAR trial who received their diagnosis 10 years previously completed the Zung Self-rating Depression Scale and a background questionnaire. Prevalence rates for clinically significant depression and severe depression were higher than those reported for the non-PCa men of the same age in Australia. The most common subtype of depression was Anhedonia, followed by Cognitive depression. Change in eating habits was the most powerful depression symptom predicting Anhedonia. By providing the first detailed documentation of major depression prevalence in PCa survivors, plus describing the nature of that depression, these data suggest that there is an ongoing need to provide treatments for these men and that those treatments should be focussed upon loss of previously available sources of enjoyment. PMID- 28004452 TI - Inhibitory mechanism of l-glutamic acid on spawning of the starfish Patiria (Asterina) pectinifera. AB - l-Glutamic acid was previously identified as an inhibitor of spawning in the starfish Patiria (Asterina) pectinifera; this study examined how l-glutamic acid works. Oocyte release from ovaries of P. pectinifera occurred after germinal vesicle breakdown (GVBD) and follicular envelope breakdown (FEBD) when gonads were incubated ex vivo with either relaxin-like gonad-stimulating peptide (RGP) or 1-methyladenine (1-MeAde). l-Glutamic acid blocked this spawning phenotype, causing the mature oocytes to remain within the ovaries. Neither RGP-induced 1 MeAde production in ovarian follicle cells nor 1-MeAde-induced GVBD and FEBD was affected by l-glutamic acid. l-Glutamic acid may act through metabotropic receptors in the ovaries to inhibit spawning, as l-(+)-2-amino-4-phosphonobutyric acid, an agonist for metabotropic glutamate receptors, also inhibited spawning induced by 1-MeAde. Application of acetylcholine (ACH) to ovaries under inhibitory conditions with l-glutamic acid, however, brought about spawning, possibly by inducing contraction of the ovarian wall to discharge mature oocytes from the ovaries concurrently with GVBD and FEBD. Thus, l-glutamic acid may inhibit ACH secretion from gonadal nerve cells in the ovary. Mol. Reprod. Dev. 84: 246-256, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28004453 TI - A Leaf-Inspired Luminescent Solar Concentrator for Energy-Efficient Continuous Flow Photochemistry. AB - The use of solar light to promote chemical reactions holds significant potential with regard to sustainable energy solutions. While the number of visible light induced transformations has increased significantly, the use of abundant solar light has been extremely limited. We report a leaf-inspired photomicroreactor that constitutes a merger between luminescent solar concentrators (LSCs) and flow photochemistry to enable green and efficient reactions powered by solar irradiation. This device based on fluorescent dye-doped polydimethylsiloxane collects sunlight, focuses the energy to a narrow wavelength region, and then transports that energy to embedded microchannels where the flowing reactants are converted. PMID- 28004454 TI - Controlled Synthesis of Uniform, Micrometer-Sized Ruthenium-Functionalized Poly(N Isopropylacrylamide) Gel Particles and their Application to the Catalysis of the Belousov-Zhabotinsky Reaction. AB - Ruthenium-functionalized poly(N-isopropyl acrylamide)-based chemically oscillating microgels with diameters between 1 and 6 um are synthesized by a modified precipitation polymerization approach. It is found that the initial amount of N-isopropyl acrylamide (NIPAAm) can significantly affect the final sizes of the microgels. 2.5 g of initial NIPAAm results in microgels with maximum average diameter of ~6 +/- 0.5 um. Making use of their fluorescence due to their ruthenium contents and their larger sizes compared to microgels prepared using other traditional methods, the impact of changes in the NaBrO3 concentrations on their microscopic behavior is studied using a combination of fluorescence microscopy and dynamic light scattering techniques. When increasing the concentration of NaBrO3 in a solution, the microgels first experience a decrease in size followed by aggregation that leads to the loss of colloidal stability. Finally, the redox potential behavior and optical performance of the Belousov Zhabotinsky reaction catalyzed by these microgels are studied by electrochemical and spectroscopic means. PMID- 28004455 TI - Engineering central metabolism - a grand challenge for plant biologists. AB - The goal of increasing crop productivity and nutrient-use efficiency is being addressed by a number of ambitious research projects seeking to re-engineer photosynthetic biochemistry. Many of these projects will require the engineering of substantial changes in fluxes of central metabolism. However, as has been amply demonstrated in simpler systems such as microbes, central metabolism is extremely difficult to rationally engineer. This is because of multiple layers of regulation that operate to maintain metabolic steady state and because of the highly connected nature of central metabolism. In this review we discuss new approaches for metabolic engineering that have the potential to address these problems and dramatically improve the success with which we can rationally engineer central metabolism in plants. In particular, we advocate the adoption of an iterative 'design-build-test-learn' cycle using fast-to-transform model plants as test beds. This approach can be realised by coupling new molecular tools to incorporate multiple transgenes in nuclear and plastid genomes with computational modelling to design the engineering strategy and to understand the metabolic phenotype of the engineered organism. We also envisage that mutagenesis could be used to fine-tune the balance between the endogenous metabolic network and the introduced enzymes. Finally, we emphasise the importance of considering the plant as a whole system and not isolated organs: the greatest increase in crop productivity will be achieved if both source and sink metabolism are engineered. PMID- 28004456 TI - Maternal endothelial function and vascular stiffness after HELLP syndrome: a case control study. AB - OBJECTIVES: To assess endothelial function and arterial stiffness in women with a previous pregnancy complicated by pre-eclampsia (PE) with hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, and to compare these findings to those in women with previous PE but no HELLP and to those in controls with previous uncomplicated pregnancy, in order to investigate the influence of HELLP syndrome on subsequent cardiovascular impairment. METHODS: In this prospective single-center case-control study, we performed peripheral arterial tonometry (PAT) (using the EndoPAT method) and pulse-wave velocity (PWV) assessment in 109 women who had had a singleton pregnancy complicated by PE with (n = 49) or without (n = 60) HELLP syndrome, as well as in 60 controls with previous uncomplicated pregnancy, between 6 months and 4 years after delivery. The following EndoPAT and PWV indices were compared between groups: reactive hyperemia index (RHI), as an indication of endothelial function, and peripheral and aortic heart-rate-corrected augmentation indices (AIx) standardized for a heart rate of 75 bpm (AIx@75) and carotid-femoral pulse-wave velocity (cfPWV), as indications of arterial stiffness. RESULTS: PAT and arterial stiffness indices were significantly different between PE cases, with or without previous HELLP, and controls, except for carotid-femoral PWV. There were no significant differences among PE groups: women who had experienced HELLP and those with a history of PE without HELLP showed similar rates of RHI <= 1.67 (28.6% vs 18.3%, P = 0.254) and RHI <= 2.00 (61.2% vs 41.7%, P = 0.055), peripheral AIx@75 >= 17% (38.8% vs 30.0%, P = 0.417), aortic AIx@75 >= 35% (29.2% vs 20.0%, P = 0.461) and cfPWV * 0.8 > 9.6 m/s, which occurred in only three women, all in the group without previous HELLP (0% vs 5.0%, P = 0.251). On multivariate regression analysis, HELLP syndrome, intrauterine growth restriction (IUGR) and early-onset PE independently predicted endothelial dysfunction at 6 months to 4 years postpartum, after correcting for uterine artery pulsatility index, birth-weight percentile, and maternal blood pressure, age and body mass index. Women with both previous HELLP and early-onset IUGR had a significantly higher prevalence of endothelial dysfunction (P = 0.001). CONCLUSION: Similar vascular abnormalities were found in women previously affected by HELLP syndrome and those with previous PE without HELLP. However, a history of HELLP syndrome, IUGR and early-onset PE seems to identify a subgroup of women with a higher risk for future development of endothelial dysfunction. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28004457 TI - Clinical and ultrasound characteristics of surgically removed adnexal lesions with largest diameter <= 2.5 cm: a pictorial essay. AB - OBJECTIVES: To describe the ultrasound characteristics, indications for surgery and histological diagnoses of surgically removed adnexal masses with a largest diameter of <= 2.5 cm (very small tumors), to estimate the sensitivity and specificity of diagnosis of malignancy by subjective assessment of ultrasound images of very small tumors and to present a collection of ultrasound images of surgically removed very small tumors, with emphasis on those causing diagnostic difficulty. METHODS: Information on surgically removed adnexal tumors with a largest diameter of <= 2.5 cm was retrieved from the ultrasound databases of seven participating centers. The ultrasound images were described using the International Ovarian Tumor Analysis terminology. The original diagnosis, based on subjective assessment of the ultrasound images by the ultrasound examiner, was used to calculate the sensitivity and specificity of diagnosis of malignancy. RESULTS: Of the 129 identified adnexal masses with largest diameter <= 2.5 cm, 104 (81%) were benign, 15 (12%) borderline malignant and 10 (8%) invasive tumors. The main indication for performing surgery was suspicion of malignancy in 22% (23/104) of the benign tumors and in all 25 malignant tumors. None of the malignant tumors was a unilocular cyst (vs 50% of the benign tumors), all malignancies contained solid components (vs 43% of the benign tumors), 80% of the borderline tumors had papillary projections (vs 21% of the benign tumors and 20% of the invasive malignancies) and all invasive tumors and 80% of the borderline tumors were vascularized on color/power Doppler examination (vs 44% of the benign tumors). The ovarian crescent sign was present in 85% of the benign tumors, 80% of the borderline tumors and 50% of the invasive malignancies. The sensitivity of diagnosis of malignancy by subjective assessment of ultrasound images was 100% (25/25) and the specificity was 86% (89/104). Excluding unilocular cysts, the specificity was 71% (37/52). Analysis of images illustrated the difficulty in distinguishing benign from borderline very small cysts with papillations and benign from malignant very small well vascularized (color score 3 or 4) solid adnexal tumors. CONCLUSIONS: Very small malignant tumors manifest generally accepted ultrasound signs of malignancy. Small unilocular cysts are usually benign, while small non-unilocular masses, particularly ones with solid components, incur a risk of malignancy and pose a clinical dilemma. (c) 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 28004459 TI - External validation of ADNEX model for diagnosing ovarian cancer: evaluating performance of differentiation between tumor subgroups. PMID- 28004458 TI - Zwitterionic Iron Oxide (gamma-Fe2 O3 ) Nanoparticles Based on P(2VP-grad-AA) Copolymers. AB - This study presents the synthesis and characterization of zwitterionic core-shell hybrid nanoparticles consisting of a core of iron oxide multicore nanoparticles (MCNPs, gamma-Fe2 O3 ) and a shell of sultonated poly(2-vinylpyridine-grad acrylic acid) copolymers. The gradient copolymers are prepared by reversible addition fragmentation chain transfer polymerization of 2-vinylpyridine (2VP), followed by the addition of tert-butyl acrylate and subsequent hydrolysis. Grafting of P(2VP-grad-AA) onto MCNP results in P(2VP-grad-AA)@MCNP, followed by quaternization using 1,3-propanesultone-leading to P(2VPS -grad-AA)@MCNP with a zwitterionic shell. The resulting particles are characterized by transmission electron microscopy, dynamic light scattering, and thermogravimetric analysis measurements, showing particle diameters of ~70-90 nm and an overall content of the copolymer shell of ~10%. Turbidity measurements indicate increased stability toward secondary aggregation after coating if compared to the pristine MCNP and additional cytotoxicity tests do not reveal any significant influence on cell viability. PMID- 28004460 TI - A Surfactant-Free and Shape-Controlled Synthesis of Nonspherical Janus Particles with Thermally Tunable Amphiphilicity. AB - A surfactant-free approach is proposed to synthesize nonspherical Janus particles with temperature-dependent wettability on hydrophobic surfaces. Sub-micrometer sized particles comprising poly(styrene-co-divinylbenzene) core and a thermally responsive poly(N-isopropylacrylamide-co-methacrylic acid) shell are first synthesized to stabilize styrene droplets in water, producing a Pickering emulsion. Upon heating to 80 degrees C and subsequent addition of initiators to the aqueous phase, styrene droplets are polymerized and combine with the core shell particles to construct dumbbell-shaped nonspherical particles. The shape of the nonspherical particles is controllable by adjusting the equilibrium time of the Pickering emulsion at 80 degrees C, which is conducted prior to polymerization. The mechanism of formation is discussed in more detail. Since molecular surfactants or stabilizers are not used during the synthesis, the present nonspherical particles well exhibit their own temperature-dependent amphiphilic characteristics. The aqueous dispersion containing the dumbbell shaped particles alters its wettability on hydrophobic polymer surfaces according to temperature changes, demonstrating its temperature-dependent amphiphilicity change. PMID- 28004461 TI - En route towards the peptide gamma-helix: X-ray diffraction analyses and conformational energy calculations of Adm-rich short peptides. AB - We performed the solution-phase synthesis of a set of model peptides, including homo-oligomers, based on the 2-aminoadamantane-2-carboxylic acid (Adm) residue, an extremely bulky, highly lipophilic, tricyclic, achiral, Calpha tetrasubstituted alpha-amino acid. In particular, for the difficult peptide coupling reaction between two Adm residues, we took advantage of the Meldal's alpha-azidoacyl chloride approach. Most of the synthesized Adm peptides were characterized by single-crystal X-ray diffraction analyses. The results indicate a significant propensity for the Adm residue to adopt gamma-turn and gamma-turn like conformations. Interestingly, we found that a -CO-(Adm)2 -NH- sequence is folded in the crystal state into a regular, incipient gamma-helix, at variance with the behavior of all of the homo-dipeptides from Calpha -tetrasubstituted alpha-amino acids already investigated, which tend to adopt either the beta-turn or the fully extended conformation. Our density functional theory conformational energy calculations on the terminally blocked homo-peptides (n = 2-8) fully confirmed the crystal-state data, strongly supporting the view that this rigid Calpha -tetrasubstituted alpha-amino acid residue is largely the most effective building block for gamma-helix induction, although to a limited length (anti cooperative effect). Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28004462 TI - Care-givers' reflections on an ethics education immersive simulation care experience: A series of epiphanous events. AB - There has been little previous scholarship regarding the aims, options and impact of ethics education on residential care-givers. This manuscript details findings from a pragmatic cluster trial evaluating the impact of three different approaches to ethics education. The focus of the article is on one of the interventions, an immersive simulation experience. The simulation experience required residential care-givers to assume the profile of elderly care-recipients for a 24-hr period. The care-givers were student nurses. The project was reviewed favourably by a university ethics committee, and participants provided informed consent. Data from six postsimulation experience focus groups were analysed thematically and three themes were identified: the experience of vulnerability, dignity in care and the organisation of care. Findings suggest that the immersive simulation experience had a powerful immediate impact as participants described epiphanous insights relating to their care experiences. It is suggested that reflecting on and recording epiphanous events has the potential to sustain ethical care practices. Further research is required to evaluate the impact of different ethics education interventions in different cultural contexts. Exploration is also required regarding the meaning and significance of care epiphanies, those "most delicate and evanescent of moments," for the sustainability of ethical care. PMID- 28004463 TI - Duty and dilemma: Perioperative nurses hiding an objection to participate in organ procurement surgery. AB - Perioperative nurses assist in organ procurement surgery; however, there is a dearth of information of how they encounter making conscientious objection requests or refusals to participate in organ procurement surgery. Organ procurement surgical procedures can present to the operating room ad hoc and can catch a nurse who may not desire to participate by surprise with little opportunity to refuse as a result of staffing, skill mix or organizational work demands. This paper that stems from a larger doctoral research study exploring the experiences of perioperative nurses participating in multi-organ procurement surgery used a grounded theory method to develop a substantive theory of the nurses' experiences. This current paper aimed to highlight the experiences of perioperative nurses when confronted with expressing a conscientious objection towards their participation in these procedures. A number of organizational and cultural barriers within the healthcare organization were seen to hamper their ability in expressing a conscience-based refusal, which lead to their reluctant participation. Perioperative nurses must feel safe to express a conscientious objection towards these types of surgical procedures and feel supported in doing so by their respective hospital organizations and not be forced to participate unwillingly. PMID- 28004464 TI - Chemical Bonding Analysis as a Guide for the Preparation of New Compounds: The Case of VIrGe and HfPtGe. AB - The chemical bonding of transition metal compounds with a MgAgAs-type of crystal structure is analyzed with quantum chemical position-space techniques. The observed trends in QTAIM Madelung energy and nearest neighbor electron sharing explain the occurrence of recently synthesized MgAgAs-type compounds, TiPtGe and TaIrGe, at the boundary to the TiNiSi-type crystal structure. These bonding indicators are used to identify favorable element combinations for new MgAgAs type compounds. The new phases-the high-temperature VIrGe and the low-temperature HfPtGe-showing this type of crystal structure are prepared and characterized by powder X-ray diffraction and differential thermal analysis. PMID- 28004465 TI - Beryllium Phosphine Complexes: Synthesis, Properties, and Reactivity of (PMe3 )2 BeCl2 and (Ph2 PC3 H6 PPh2 )BeCl2. AB - The directed synthesis, spectroscopic properties, and reactivity of bis(trimethylphosphine) beryllium dichloride (1) and bis(diphenylphosphino)propane beryllium dichloride (2) are reported, including the crystal structure of (PMe3 )2 BeCl2 (1). These four-coordinate beryllium compounds can be alkylated with n-butyllithium (n BuLi) to give three-coordinate (Ph2 PC3 H6 PPh2 )Ben Bu2 (3) and (PMe3 )Ben Bu2 (4). PMe3 can be removed from (PMe3 )Ben Bu2 (4) in vacuo to yield [n Bu2 Be]2 (5). For the first time, the presence of [n Bu2 Be]2 as a dimer in solution, which has been postulated for decades, could be observed spectroscopically. This novel, ether-free pathway provides access to beryllium dialkyl compounds that have never been in contact with oxygen-atom-containing reagents or solvents. This "freeness from oxygen" is crucial for semiconductor applications where oxygen is often unwanted and must be avoided at all costs. PMID- 28004466 TI - Interband Absorption Enhanced Optical Activity in Discrete Au@Ag Core-Shell Nanocuboids: Probing Extended Helical Conformation of Chemisorbed Cysteine Molecules. AB - Detailed understanding of the interaction between a chiral molecule and a noble metal surface is essential to rationalize and advance interfacial self-assembly of amino acids and metal-mediated anchoring of proteins. Here we demonstrate that individual Au@Ag core-shell nanocuboids can serve as a plasmonic reporter of an extended helical network formed among chemisorbed cysteine molecules, through generating an interband absorption enhanced, Ag-surface-exclusive circular dichroism (CD) band in the UV region. The observed unusual, strong CD response in the hybrid Au@Ag-cysteine system can be used to probe in real time conformational evolution and structural rearrangement of biomolecules in general and also monitor the interfacial interaction between a metal surface and an adsorbed molecule, opening up the possibility of using Ag nanostructures as promising stereochemically attuned nanosensors. PMID- 28004467 TI - Podocalyxin influences malignant potential by controlling epithelial-mesenchymal transition in lung adenocarcinoma. AB - Epithelial-mesenchymal transition (EMT) plays an important role in the progression of lung carcinoma. Podocalyxin (PODXL), which belongs to the CD34 family and regulates cell morphology, has been linked to EMT in lung cancer, and PODXL overexpression is associated with poor prognosis in several different classes of cancers. The aim of this study was to clarify the role of PODXL overexpression in EMT in lung cancer, and to determine the prognostic value of PODXL overexpression in tumors from lung cancer patients. The morphology, EMT marker expression, and migration and invasion abilities of engineered A549 PODXL knockdown (KD) or PODXL-overexpression (OE) lung adenocarcinoma cells were examined. PODXL expression levels were assessed by immunohistochemistry in 114 human clinical lung adenocarcinoma specimens and correlated with clinical outcomes. PODXL-KD cells were epithelial in shape, whereas PODXL-OE cells displayed mesenchymal morphology. Epithelial markers were upregulated in PODXL-KD cells and downregulated in PODXL-OE cells, whereas mesenchymal markers were downregulated in the former and upregulated in the latter. A highly selective inhibitor of phosphatidylinositol 3-kinase-Akt signaling attenuated EMT of PODXL OE cells, while a transforming growth factor inhibitor did not, suggesting that PODXL induces EMT of lung adenocarcinoma cells via the phosphatidylinositol 3 kinase pathway. In lung adenocarcinoma clinical specimens, PODXL expression was detected in minimally invasive and invasive adenocarcinoma, but not in non invasive adenocarcinoma. Disease free survival and cancer-specific survival were significantly worse for patients whose tumors overexpressed PODXL. PODXL overexpression induces EMT in lung adenocarcinoma and contributes to tumor progression. PMID- 28004468 TI - First 2 cases with thiamine-responsive megaloblastic anemia in the Czech Republic, a rare form of monogenic diabetes mellitus: a novel mutation in the thiamine transporter SLC19A2 gene-intron 1 mutation c.204+2T>G. AB - Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive disorder caused by mutations in the SLC19A2 gene. To date at least 43 mutations have been reported for the gene encoding a plasma membrane thiamine transporter protein (THTR-1). TRMA has been reported in less than 80 cases worldwide. Here, we illustrate 2 female patients with TRMA first diagnosed in the Czech Republic and in central Europe being confirmed by sequencing of the THTR-1 gene SLC19A2. Both subjects are compound heterozygotes with 3 different mutations in the SLC19A2 gene. In case 2, the SLC19A2 intron 1 mutation c.204+2T>G has never been reported before. TRMA subjects are at risk of diabetic ketoacidosis during intercurrent disease and arrythmias. Thiamine supplementation has prevented hematological disorders over a few years in both pediatric subjects, and improved glycaemic control of diabetes mellitus. Patient 1 was suffering from hearing loss and rod-cone dystrophy at the time of diagnosis, however, she was unresponsive to thiamine substitution. Our patient 2 developed the hearing loss despite the early thiamine substitution, however no visual disorder had developed. The novel mutation described here extends the list of SLC19A2 mutations causing TRMA. PMID- 28004469 TI - Long-term follow-up after proton beam therapy for pediatric tumors: a Japanese national survey. AB - Proton beam therapy (PBT) is a potential new alternative to treatment with photon radiotherapy that may reduce the risk of late toxicity and secondary cancer, especially for pediatric tumors. The goal of this study was to evaluate the long term benefits of PBT in cancer survivors. A retrospective observational study of pediatric patients who received PBT was performed at four institutions in Japan. Of 343 patients, 62 were followed up for 5 or more years. These patients included 40 males and 22 females, and had a median age of 10 years (range: 0-19 years) at the time of treatment. The irradiation dose ranged from 10.8 to 81.2 GyE (median: 50.4 GyE). The median follow-up period was 8.1 years (5.0-31.2 years). The 5-, 10 and 20-year rates for grade 2 or higher late toxicities were 18%, 35% and 45%, respectively, and those for grade 3 or higher late toxicities were 6%, 17% and 17% respectively. Univariate analysis showed that the irradiated site (head and neck, brain) was significantly associated with late toxicities. No malignant secondary tumors occurred within the irradiated field. The 10- and 20-year cumulative rates for all secondary tumors, malignant secondary tumors, and malignant nonhematologic secondary tumors were 8% and 16%, 5% and 13%, and 3% and 11%, respectively. Our data indicate that PBT has the potential to reduce the risk of late mortality and secondary malignancy. Longer follow-up is needed to confirm the benefits of PBT for pediatric tumors. PMID- 28004470 TI - Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers. AB - Rat bladder cancer is nearly always papillary non-invasive urothelial carcinoma (UC). To establish an animal model mimicking invasive UC that arises from papillary non-invasive UC in the bladder, male human c-Ha-ras proto-oncogene transgenic rats (Hras128) were treated with 0.05% N-butyl-N (hydroxybutyl)nitrosameine (BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in their diet as follows: BBN (8 weeks)->PEITC (8 weeks); PEITC (8 weeks)->BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN->PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non-invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non-invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 (CA2), an overexpressed protein, showed that the relative number of CA2-positive UC was significantly higher for invasive UC compared to non-invasive UC in rats. Moreover, the incidence of CA2-positive cancers was also significantly higher for human muscle-invasive bladder cancer (MIBC) compared to non-MIBC (NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion-associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers. PMID- 28004471 TI - Chiral Self-Sorting of [2+3] Salicylimine Cage Compounds. AB - An inherently chiral C3 -symmetric triaminotribenzotriquinacene was condensed in racemic and enantiomerically pure form with a bis(salicylaldehyde) to form [2+3] salicylimine cage compounds. Investigations on the chiral self-sorting revealed that while entropy favors narcissistic self-sorting in solution, selective social self-sorting can be achieved by exploiting the difference in solubility between the homochiral and heterochiral cages. Gas sorption measurements further showed that seemingly small structural differences can have a significant impact on the surface area of microporous covalent cage compounds. PMID- 28004472 TI - Postural care for people with intellectual disabilities and severely impaired motor function: A scoping review. AB - BACKGROUND: Poor postural care can have severe and life-threatening complications. This scoping review aims to map and summarize existing evidence regarding postural care for people with intellectual disabilities and severely impaired motor function. METHOD: Studies were identified via electronic database searches (MEDLINE, CINAHL, PsycINFO and Web of Science) covering January 1990 to March 2016, and email requests to researcher networks. Results were collated via descriptive numerical summary of studies and thematic analysis. RESULTS: Twenty three studies were identified and summarized narratively in relation to three themes: characteristics and prevalence, interventions and service related issues. The evidence base is small with significant gaps. Lack of evidence for night-time positioning equipment and 24-hr postural care needs to be addressed urgently. CONCLUSION: Future research should be clearly directed towards ascertaining how best postural care interventions can be employed to help improve the health and quality of life of people with intellectual disabilities. PMID- 28004473 TI - A qualitative exploration of participants' experiences of taking part in a walking programme: Perceived benefits, barriers, choices and use of intervention resources. AB - BACKGROUND: Adults with intellectual disabilities (ID) experience significant inequalities and tend to be more sedentary and less physically active than the wider population. Walking programmes are an effective way to increase physical activity (PA) but have not been used in studies involving adults with intellectual disabilities. METHOD: Nineteen adults with intellectual disabilities participated in semistructured interviews or focus groups exploring their experiences of taking part in a walking programme (Walk Well). Data were coded using thematic analysis. RESULTS: Four overarching themes emerged: perceived benefits of taking part in the programme, perceived drawbacks/ barriers, walking choices and using the Walk Well resources. While there was not a significant increase in walking for all, the participants reported positive experiences of taking part in the programme. Self-monitoring proved difficult for some, particularly reading the daily step count recorded on the pedometer and writing it in the diary. Carers also played an important role in facilitating and preventing behaviour change in adults with intellectual disabilities. CONCLUSION: Additional barriers prevent many adults with intellectual disabilities from participating in PA. Capturing participant experiences provides important information for designing effective and equitable health improvement programmes. PMID- 28004474 TI - Gastrointestinal dysmotility and pancreatic insufficiency in 2 siblings with Donohue syndrome. AB - Donohue syndrome is a rare congenital syndrome of insulin-resistance and abnormal glucose homeostasis, caused by mutations in the insulin receptor (INSR) gene. It is characterized by specific phenotypic and clinical features and the diagnosis is based on clinical, biochemical and genetic criteria. We report 2 siblings with Donohue syndrome (cases 1, 2) with multiple clinical and biochemical characteristics. Both patients shared the same mutation and presented with intra uterine growth restriction, failure to thrive, fasting hyperinsulinaemic hypoglycaemia and episodic post-prandial hyperglycaemia. Less common clinical features were also present, such as atrial septal defect and biventricular hypertrophy, clotting disorders, abnormal liver function tests and nephrocalcinosis. Interestingly, 2 previously unrecognized manifestations of the syndrome were also identified: severe gastrointestinal dysmotility (case 1) and exocrine pancreatic insufficiency (case 2). The co-existence of all the above clinical features makes these cases extremely rare. Gastrointestinal dysmotility should always be considered as a potentially fatal feature in patients with the syndrome, due to the complexity of the possible co-morbidities. In addition, our clinical experience for the first time suggests that pancreatic exocrine insufficiency may offer a possible explanation for the growth retardation observed in some patients with this syndrome. Our finding that replacement treatment with pancreatic enzymes improved weight gain (case 2) implies that all patients with Donohue syndrome should be investigated for exocrine pancreatic insufficiency. PMID- 28004475 TI - Structure-based approaches for the design of benzimidazole-2-carbamate derivatives as tubulin polymerization inhibitors. AB - Microtubules are highly dynamic assemblies of alpha/beta-tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (betaI) and class III (betaIII) beta-tubulin isotypes in breast and lung cancers and the highly expressed class VI (betaVI) beta-tubulin isotype in normal blood cells have increased the interest for designing specific tubulin-binding anticancer therapies. To this end, we employed our previously proposed model of the beta tubulin-nocodazole complex, supported by the recently determined X-ray structure, to identify the fundamental structural differences between beta-tubulin isotypes. Moreover, we employed docking and molecular dynamics (MD) simulations to determine the binding mode of a series of benzimidazole-2-carbamete (BzC) derivatives in the betaI-, betaIII-, and betaVI-tubulin isotypes. Our results demonstrate that Ala198 in the betaVI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between betaI- and betaIII-BzC complexes were observed; however, Ser239 in the betaIII isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the beta-tubulin-BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics. PMID- 28004476 TI - Epidemiology characteristics, reporting characteristics, and methodological quality of systematic reviews and meta-analyses on traditional Chinese medicine nursing interventions published in Chinese journals. AB - To evaluate the epidemiological characteristics, reporting characteristics, and methodological quality of systematic reviews in the traditional Chinese medicine nursing field published in Chinese journals. The number of systematic reviews in the traditional Chinese medicine nursing field has increased, but their epidemiology, quality, and reporting characteristics have not been assessed completely. We generated an overview of reviews using a narrative approach. Four Chinese databases were searched for systematic reviews from inception to December 2015. The Preferred Reporting Items of Systematic Reviews and Meta-analyses and the Assessment of Multiple Systematic Reviews checklists were adopted to evaluate reporting and methodological quality, respectively. A total of 73 eligible systematic reviews, published from 2005 to 2015, were included. The deficiencies in reporting characteristics mainly lay in the lack of structured abstract or protocol, incomplete reporting of search strategies, study selection, and risk of bias. The deficiencies in methodological quality were reflected in the lack of a priori design and conflict of interest, incomplete literature searches, and assessment of publication bias. The quality of the evaluated reviews was unsatisfactory; attention should be paid to the improvement of reporting and methodological quality in the conduct of systematic reviews. PMID- 28004477 TI - Revisiting autoimmune gastritis in children and adolescents with type 1 diabetes. AB - OBJECTIVE: Assess the frequency of anti-H+ /K+ adenosine triphosphatase (ATPase) autoantibodies (AAB) and symptoms of autoimmune gastritis in children and adolescents with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Anti-H+ /K+ ATPase AAB were measured in 402 children and adolescents (210 boys and 192 girls, 11.1 +/- 4.5 years) treated for T1D (screened positive for beta-cell AAB), along with search of symptoms of anemia (hemoglobin, serum iron, and ferritin levels) and gastric pain. The AAB specific for thyroperoxydase, thyroglobulin, and transglutaminase were also measured. RESULTS: Anti-H+ /K+ ATPase AAB were present in 6.5% of children. Their frequency increased with age: 4% at 10 years, 10% at 15 years, and 20% at 20 years. Iron deficiency (45% vs 3.8%), iron deficiency anemia (36% vs 3.8%), antithyroid AAB (24% vs 9.7%), and family history of Graves' disease (25% vs 5.6%) were more frequent in patients with anti-H+ /K+ ATPase AAB. Two patients, a 13-year-old girl and a 11-year-old boy, experienced symptoms (iron deficiency anemia and epigastric pain) which led to diagnosis of autoimmune gastritis confirmed upon fibroscopy. Both showed high levels of anti H+ /K+ ATPase AAB and atrophic gastritis. CONCLUSIONS: Autoimmune gastritis presents an age-dependent frequency in children and adolescents with T1D but is rarely symptomatic. Screening for anti-H+ /K+ ATPase AAB should thus target patients with iron deficiency, anemia, epigastralgia, autoimmune thyroiditis, or age over 15 years. PMID- 28004478 TI - CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency. AB - Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRalpha and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. PMID- 28004479 TI - Female suicides: Psychosocial and psychiatric characteristics identified by a psychological autopsy study in Japan. AB - AIM: Although the female suicide rate in Japan is one of the highest among OECD countries, little has been done to assess the psychosocial and psychiatric characteristics of Japanese female suicide completers. This study aimed to examine sex differences in psychosocial and psychiatric characteristics of suicide completers using a psychological autopsy study method, and to identify female suicide factors and intervention points to prevent female suicides. METHODS: A semi-structured interview was conducted with close family members of adult suicide completers. The interview included questions regarding sociodemographic factors, suicide characteristics, previous suicidal behaviors and a family history of suicidal behaviors, financial problems, and physical/psychiatric problems. Fisher's exact test and the Student's t-test were used to explore sex differences in these survey items, and individual descriptive information of female suicide cases was also examined. RESULTS: Of the 92 suicide completers, 28 were female and 64 were male. Females had a significantly higher prevalence of a history of self-harm/suicide attempts (P < 0.001). The prevalence of eating disorders was significantly higher among females than males (P < 0.01). CONCLUSION: The findings of this study highlight the importance of providing psychological and social support to caregivers of those who repeatedly attempt suicide and express suicidal thoughts, and to suggest the need to improve community care systems to be aware of suicide risk factors among female suicide attempters. PMID- 28004480 TI - A metagenomic study of the preventive effect of Lactobacillus rhamnosus GG on intestinal polyp formation in ApcMin/+ mice. AB - AIMS: To investigate the in vivo effects of Lactobacillus rhamnosus GG (LGG) on intestinal polyp development and the interaction between this single-organism probiotic and the gut microbiota therein. METHODS AND RESULTS: The ApcMin/+ mouse model was used to study the potential preventive effect of LGG on intestinal polyposis, while shotgun metagenomic sequencing was employed to characterize both taxonomic and functional changes within the gut microbial community. We found that the progression of intestinal polyps in the control group altered the community functional profile remarkably despite small variation in the taxonomic diversity. In comparison, the consumption of LGG helped maintain the overall functional potential and taxonomic profile in the resident microbes, thereby leading to a 25% decrease of total polyp counts. Furthermore, we found that LGG enriched those microbes or microbial activities related to short-chain fatty acid production (e.g. Roseburia and Coprococcus), as well as suppressed the ones that can lead to inflammation (e.g. Bilophila wadsworthia). CONCLUSIONS: Our study using shotgun metagenomics highlights how single probiotic LGG may exert its beneficial effects and decrease polyp formation in mice by maintaining gut microbial functionality. SIGNIFICANCE AND IMPACT OF THE STUDY: This probiotic intervention targeting microbiota may be used in conjugation with other dietary supplements or drugs as part of prevention strategies for early-stage colon cancer, after further clinical validations in human. PMID- 28004481 TI - Multidimensional cognitive impairment in unipolar and bipolar depression and the moderator effect of adverse childhood experiences. AB - AIM: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. These deficits are observable both in major depressive disorder (MDD) and in bipolar disorder (BD) and are present in each phase of the illness, including euthymia. Adverse childhood experiences (ACE) have been associated with an increased risk of developing psychiatric disorders and cognitive deficits. The aim of this study was to assess neuropsychological performances in a sample of MDD and BD patients during a depressive episode compared to healthy controls (HC) and, to investigate if ACE affect the cognitive profiles in the three groups. METHODS: Seventy-six BD patients, 57 MDD patients, and 57 HC underwent neuropsychological assessment for cognitive performances through the Brief Assessment of Cognition in Schizophrenia and Wisconsin Card Sorting Test. RESULTS: Both BD and MDD patients obtained significantly lower domain scores across the entire battery compared to HC. Splitting the sample according to exposure to ACE (high and low), the differences observed in the whole sample persisted only in the subsample of those patients exposed to high ACE. CONCLUSION: This study confirms that cognitive impairment is present both in MDD and BD, albeit in different degrees of severity, and highlights the importance of early stress as a moderator factor when investigating cognitive functions in mood disorders. PMID- 28004482 TI - 1,1,3,3-Tetratriflylpropene (TTP): A Strong, Allylic C-H Acid for Bronsted and Lewis Acid Catalysis. AB - Tetratrifylpropene (TTP) has been developed as a highly acidic, allylic C-H acid for Bronsted and Lewis acid catalysis. It can readily be obtained in two steps and consistently shows exceptional catalytic activities for Mukaiyama aldol, Hosomi-Sakurai, and Friedel-Crafts acylation reactions. X-ray analyses of TTP and its salts confirm its designed, allylic structure, in which the negative charge is delocalized over four triflyl groups. NMR experiments, acidity measurements, and theoretical investigations provide further insights to rationalize the remarkable reactivity of TTP. PMID- 28004485 TI - Association of membranoproliferative glomerulonephritis with renal cell carcinoma. PMID- 28004484 TI - Adolescent life with diabetes-Gender matters for level of distress. Experiences from the national TODS study. AB - OBJECTIVE: To examine the relationship between diabetes distress and gender, and the association with glycemic control, social support, health behaviors, and socio-economic status. METHODS: All adolescents, aged 15 to 18 years, in the national, pediatric diabetes registry SWEDIABKIDS with type 1 diabetes were invited to complete an online questionnaire. A total of 2112 teenagers were identified. RESULTS: 453 complete responses were valid for analyses. Young women scored significantly higher on the distress-screening instrument DDS-2. Almost half of the female respondents exhibited moderate to severe diabetes distress more than twice the proportion than among male respondents (44% vs 19%). Females reported twice as high scores on the fear of hypoglycemia scale (P < 0.0001) and had a higher HbA1c value than males (P < 0.0001). Gender was highly correlated with distress level even when controlling for multiple factors that may affect distress (parameterfemale = 0.4, P = 0.0003). Particular social problems were highly significant, that is, those who trust that their parents can handle their diabetes when necessary were significantly less distressed than others (P = 0.018). Higher HbA1c levels were associated with higher distress scores (P = 0.0005 [female], P = 0.0487 [male]). CONCLUSIONS: Diabetes-related distress is a great burden for adolescents living with diabetes. Actively involved family and friends may reduce diabetes distress, but female adolescents appear to be particularly vulnerable and may need extra focus and support. Our findings indicate that pediatric diabetes teams working with teenagers must intensify the care during this vulnerable period of life in order to reduce the risk of both psychological and vascular complications in young adults. PMID- 28004486 TI - Pharmacological interventions for the management of acute hyperkalaemia in adults. PMID- 28004483 TI - Concomitant elevations of MMP-9, NGAL, proMMP-9/NGAL and neutrophil elastase in serum of smokers with chronic obstructive pulmonary disease. AB - A growing body of evidence points towards smoking-related phenotypic differences in chronic obstructive pulmonary disease (COPD). As COPD is associated with systemic inflammation, we determined whether smoking status is related to serum levels of matrix metalloproteinase-9 (pro- and active MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and the proMMP-9/NGAL complex in patients with COPD. Serum samples were collected in 100 stable-phase COPD patients (82 smokers, 18 never-smokers) and 28 healthy adults (21 smokers, 7 never-smokers). Serum levels of studied factors were measured in ELISA. Our data provide the first evidence of simultaneously elevated serum levels of MMP-9, NGAL and proMMP 9/NGAL in COPD smokers. While the triad discriminated between smokers and non smokers in the COPD group, MMP-9 and proMMP-9/NGAL (but not NGAL) discriminated between smokers with and without COPD. Adjustment for age and smoking pack-years did not alter the findings. Serum MMP-9, NGAL and proMMP-9/NGAL levels were not correlated with the GOLD stage or FEV1 decline. Furthermore, serum levels of neutrophil elastase (NE) and MMP-3 (but not of IL-6 and MMP-12) were also higher in COPD smokers than in healthy smokers before and after adjustment for age and pack-years. Among COPD smokers, levels of MMP-9, NGAL and proMMP-9/NGAL were positively correlated with NE (P < 0.0001) but not with the remaining factors. Gelatin zymography detected proMMP-9 in serum samples of healthy and COPD smoking groups. Our results suggest that associated serum levels of proMMP-9, NGAL, proMMP-9/NGAL and NE may reflect the state of systemic inflammation in COPD related to cigarette smoking. PMID- 28004487 TI - Simple equation for calculation of plasma clearance for evaluation of renal function without urine collection in rats. AB - To develop an equation for the evaluation of renal function in rats using three dilutions of plasma samples and to validate this method by comparison with a reference method. The investigation was conducted in Sprague-Dawley (SD) rats after delivery of three doses of iohexol, with blood samples collected before and after dosage using a quantitative blood collection method. Plasma iohexol concentrations were detected by high performance liquid chromatography (HPLC). The extraction recovery of iohexol from plasma was >97.30% and the calibration curve was linear (r2 = 0.9997) over iohexol concentrations ranging from 10 to 1000 ug/mL. The method had an RE of <9.310 and intra- and inter-day RSD of <5.137% and <3.693%, respectively. The plasma clearance values obtained from the equation correlated closely (r = 0.763) with those obtained using the reference method. The relatively correlation in the results obtained using the method under investigation and the reference method indicate that this new equation can be used for preliminary assessment of renal function in rats. PMID- 28004488 TI - Mesorhizobium peritonitis: The first reported case. PMID- 28004490 TI - N,P-Heterocyclic Germylene/B(C6 F5 )3 Adducts: A Lewis Pair with Multi-reactive Sites. AB - An N,P-heterocyclic germylene/B(C6 F5 )3 Lewis adduct 2 presenting multi-reactive sites (P/B Lewis pair, germylene, Ge=P pi-bond) is reported. In contrast to classical frustrated Lewis pairs or divalent Group 14 element species, 2 is able to activate two small molecules simultaneously. Of particular interest, 2 reacts with silanes leading to the formation of original cationic germylenes 3, and can be used as a metal-free catalyst for selective CO2 -hydrosilylation to H2 C(OSiEt3 )2 . PMID- 28004489 TI - Asymmetric Strecker Reaction Arising from the Molecular Orientation of an Achiral Imine at the Single-Crystal Face: Enantioenriched l- and d-Amino Acids. AB - Strecker synthesis has long been considered one of the prebiotic reactions for the synthesis of alpha-amino acids. However, the correlation between the origin of chirality and highly enantioenriched alpha-amino acids through this method remains a puzzle. In the reaction, it may be conceivable that the handedness of amino acids has been determined at the formation stage of the chiral intermediate alpha-aminonitrile, that is, the enantioselective addition of hydrogen cyanide to an imine. Herein, an enantiotopic crystal surface of an achiral imine acted as an origin of chirality for the enantioselective formation of alpha-aminonitriles by the addition of HCN. In conjunction with the amplification of the enantiomeric excess and multiplication of enantioenriched aminonitrile, a large amount of near enantiopure alpha-amino acids, with the l- and d-handedness corresponding to the molecular orientation of the imine, is reported. PMID- 28004491 TI - Emerging biopharmaceuticals from bioactive peptides derived from marine organisms. AB - Biologically active natural products are spontaneous medicinal entrants, which encourage synthetic access for enhancing and supporting drug discovery and development. Marine bioactive peptides are considered as a rich source of natural products that may provide long-term health, in addition to many prophylactic and curative medicinal drug treatments. The large literature concerning marine peptides has been collected, which shows high potential of nutraceutical and therapeutic efficacy encompassing wide spectra of bioactivities against a number of infection-causing agents. Their antimicrobial, antimalarial, antitumor, antiviral, and cardioprotective actions have achieved the attention of the pharmaceutical industry toward new design of drug formulations, for treatment and prevention of several infections. However, the mechanism of action of many peptide molecules has been still untapped. So in this regard, this paper reviews several peptide compounds by which they interfere with human pathogenesis. This knowledge is one of the key tools to be understood especially for the biotransformation of biomolecules into targeted medicines. The fact that different diseases have the capability to fight at different sites inside the body can lead to a new wave of increasing the chances to produce targeted medicines. PMID- 28004492 TI - Relationship between maternal mindfulness and anxiety 1 month after childbirth. AB - AIM: To investigate the relationship between maternal mindfulness and maternal anxiety 1 month after childbirth. METHODS: A cross-sectional design was used, featuring anonymous questionnaires that were completed between July and December 2014 at two Japanese hospitals. The participants (n = 151) completed the Mindful Attention Awareness Scale (Japanese version) and the State-Trait Anxiety Inventory Form X (Japanese version). The data analysis was carried out by using a hierarchical multiple regression. RESULTS: The state and trait anxiety scores showed significant relationships with mindfulness, the mother's age, and the perceived difference between the expectations of motherhood before childbirth and the reality of post-partum daily life. Furthermore, the amount of average sleep time in the past week (including naps) showed a negative association with the state anxiety score, whereas the marital relationship showed a positive association with trait anxiety. Finally, at 1 month post-partum, the mothers with greater mindfulness scores showed lower anxiety. CONCLUSIONS: Improvements in mindfulness could help mothers to reduce their post-partum anxiety. PMID- 28004493 TI - Economic evaluation of nasogastric versus intravenous hydration in infants with bronchiolitis. AB - OBJECTIVE: Bronchiolitis is the most common lower respiratory tract infection in infants and the leading cause of hospitalisation. We aimed to assess whether intravenous hydration (IVH) was more cost-effective than nasogastric hydration (NGH) as a planned secondary economic analysis of a randomised trial involving 759 infants (aged 2-12 months) admitted to hospital with a clinical diagnosis of bronchiolitis and requiring non-oral hydration. No Australian cost data exist to aid clinicians in decision-making around interventions in bronchiolitis. METHODS: Cost data collections included hospital and intervention-specific costs. The economic analysis was reduced to a cost-minimisation study, focusing on intervention-specific costs of IVH versus NGH, as length of stay was equal between groups. All analyses are reported as intention to treat. RESULTS: Intervention costs were greater for IVH than NGH ($113 vs $74; cost difference of $39 per child). The intervention-specific cost advantage to NGH was robust to inter-site variation in unit prices and treatment activity. CONCLUSION: Intervention-specific costs account for <10% of total costs of bronchiolitis admissions, with NGH having a small cost saving across all sites. PMID- 28004494 TI - Photochemically Induced ATRP of (Meth)Acrylates in the Presence of Air: The Effect of Light Intensity, Ligand, and Oxygen Concentration. AB - Well-defined poly(methyl methacrylate) (PMMA) and poly(methyl acrylate) (PMA) are prepared via photochemically induced atom transfer radical polymerization (photoATRP) using ppm amounts of CuBr2 /tris(2-pyridylmethyl)amine and CuBr2 /tris[2-(dimethylamino)ethyl]amine catalyst complexes, respectively, without degassing of polymerization mixture and with no need to introduce an external reducing agent to the system. The effect of ligand to CuBr2 ratio on kinetic and induction period during the polymerization of MMA and MA is investigated. The induction period is influenced also by the amount of oxygen in the polymerization system. Both the kinetics of MA polymerization and the induction period are affected by light intensity. Finally, the high livingness and initiation efficiency of the photoATRP system in the presence of air are proved by chain extension polymerizations. The presented system is valuable from an industrial point of view, since after optimization, well-defined and high-molar-mass poly(meth)acrylates can be prepared without the necessity of degassing the system, while the polymerization can be proceeded quickly and without an induction period. PMID- 28004495 TI - Molecular dynamics simulation on the inhibition mechanism of peptide-based inhibitor of islet amyloid polypeptide (IAPP) to islet amyloid polypeptide (IAPP22-28 ) oligomers. AB - Aggregation of islet amyloid polypeptide (IAPP) is implicated in the development of type 2 diabetes. The modified NFGAIL with double N-methylated at Gly24 and Ile26 has the property of soluble, non-amyloidogenic, non-cytotoxic, and the ability of inhibiting amyloid formation and cytotoxicity of IAPP. To discover the inhibition mechanism of this peptide inhibitor and provide useful information to design more potential peptide inhibitors, molecular dynamics simulations in explicit solvent were performed. The simulation results reveal that Gly24 and Ile26 are of importance in IAPP aggregation, and N-methylation at these two key residues will disrupt the stability of formed oligomer and prevent the conformation transition of free monomer near the oligomer template. The origin of the N-methylated peptide inhibitor inhibiting IAPP aggregation is that it can keep good binding with IAPP template by stable hydrogen bonding interaction. Furthermore, it cannot induce the conformational transition of free monomer by preventing the hydrogen bond interaction between free monomer and boundary peptide. The structural environment can largely affect the stacking of free monomers to the template. Our study sheds light on the inhibition mechanism of peptide inhibitor at molecular level and may provide guidance for the future design and discovery of new peptide inhibitors. PMID- 28004497 TI - Prevent the need for front of neck access. PMID- 28004498 TI - Reply to Engelhardt, Thomas; Schmidt, Alexander; Machotta, Andreas, regarding their comment 'Prevent the Need for Front of Neck Access'. PMID- 28004496 TI - Maxillary sinus volume: new physiopathological data in fungal ball genesis? A retrospective study. AB - OBJECTIVES: The goal of this study was to compare maxillary sinus (MS) volume in patients with, or without, maxillary fungal ball. DESIGN: Monocentric retrospective study performed on 115 patient CT scans. SETTINGS: We defined two groups of patients according to the absence (control group) or the presence (fungal ball group) of unilateral fungal ball in the MS. Sinus 3D reconstruction was created from CT scan. PARTICIPANTS: Control group: 71 patients (36 women - 50.7%); mean age was 51 years. Fungal ball group: 44 patients (29 women - 65.9%); mean age was 54.5 years. MAIN OUTCOME MEASURE: The univariate association between MS volume and sinus covariates was tested by anova. Multivariate analysis was made including all variables statistically significant in univariate analysis. RESULTS: In the control group, mean MS volume was 14 766 mm3 . The volumes of the two MSs were not statistically different in the control group (P = 0.145). In the fungal ball group, mean MS volume was 15 982 mm3 . Fungal ball was found in the smallest MS in 41 of 44 cases. Univariate analysis showed a statistical difference between the pathological and the non-pathological MS volumes (P < 10-4 ). Multivariate analysis confirmed the correlation between MS volume and the presence of a fungal ball (P < 10-4 ). CONCLUSIONS: This study suggests that maxillary fungal ball is associated with a smaller size of the affected MS. PMID- 28004499 TI - Codeine: an old drug with new precautions. PMID- 28004501 TI - In this issue: January 2017. PMID- 28004500 TI - Comment on 'Optimized preoperative fasting times decrease ketone body concentration and stabilize mean arterial blood pressure during induction of anesthesia in children younger than 36 months: a prospective observational cohort study'. PMID- 28004502 TI - A false comfort with codeine. PMID- 28004503 TI - Perioperative fluid administration in children: is there consensus? PMID- 28004505 TI - Editorial: Getting care of older people right: the need for appropriate frailty assessment? PMID- 28004504 TI - Association between 24-hour combined multichannel intraluminal impedance-pH monitoring and symptoms or quality of life in patients with laryngopharyngeal reflux. AB - OBJECTIVE: To evaluate the association between the parameters of 24-hour multichannel intraluminal impedance (MII)-pH monitoring and the symptoms or quality of life (QoL) in laryngopharyngeal reflux (LPR) patients. DESIGN: Prospective cohort study without controls. SETTING: University teaching hospital. METHODS: Forty-five LPR patients were selected from subjects who underwent 24 hour MII-pH monitoring and were diagnosed with LPR from September 2014 to May 2015. Reflux Symptom Index (RSI), Health-related Quality of Life (HRQoL), Short Form 12 (SF-12) Survey questionnaires were surveyed. Spearman's correlation was used to analyse the association between the symptoms or QoL and 24-hour MII-pH monitoring. RESULTS: Most parameters in 24-hour MII-pH monitoring showed weak or no correlation with RSI, HRQoL and SF-12. Only number of non-acid reflux events that reached the larynx and pharynx (LPR-non-acid) and number of total reflux events that reached the larynx and pharynx (LPR-total) parameters showed strong correlation with heartburn in RSI (R = 0.520, P < 0.001, R = 0.478, P = 0.001, respectively). Multiple regression analysis showed that there was only one significant regression coefficient between LPR-non-acid and voice/hoarseness portion of HRQoL (b = 1.719, P = 0.022). CONCLUSION: Most parameters of 24-hour MII-pH monitoring did not reflect subjective symptoms or QoL in patients with LPR. PMID- 28004506 TI - Impact of an education session on clinical handover between medical shifts in an emergency department: A pilot study. AB - OBJECTIVE: To evaluate the impact of a medical education session on the implementation of a new change of shift medical clinical handover format in an urban hospital ED. METHODS: This pilot study used a pre- and post-intervention design. The intervention consisted of a 1 h education session to teach a new handover format, SBARM (Situation, Background, Assessment, Recommendation, Medication). Data were collected through observations of doctors performing clinical handover and individual interviews with participants. RESULTS: The educational intervention led to an increased focus on checking medication charts, but had minimal effect on changing other aspects of clinical handover at doctors' change of shift times. Perceived increased time spent on handover using the new system was seen as a major barrier to the implementation of SBARM. The addition of 'M' to 'SBAR' heightened awareness of checking medication and fluid charts. CONCLUSION: Time pressures need to be taken into consideration when introducing changes to current processes. Also, it is recommended that, in addition to ongoing education, senior clinicians are engaged during the planning and execution stages of changes to practice. PMID- 28004507 TI - Abdominal surface i.v. access as a temporising measure in resuscitation. PMID- 28004508 TI - The molecular basis of jaundice: An old symptom revisited. AB - Increased serum bilirubin level is a widely used diagnostic marker for hepatic illnesses. Nevertheless, mild elevation of unconjugated serum bilirubin (such as in Gilbert syndrome) has been recently demonstrated to correlate with low risk of chronic inflammatory and/or oxidative stress-mediated diseases. In accord, a low serum bilirubin level has emerged as an important predisposing factor or a biomarker of these pathologic conditions including cardiovascular, tumour, and possibly neurodegenerative diseases. Bilirubin possesses multiple biological actions with interaction in a complex network of enzymatic and signalling pathways. The fact that the liver is the main organ controlling the bioavailability of bilirubin emphasizes the central role of this organ in human health. PMID- 28004509 TI - Serial changes of computed tomographic peritoneogram in patients with symptomatic ultrafiltration failure complicating continuous ambulatory peritoneal dialysis. AB - INTRODUCTION: It is well-known that continuous ambulatory peritoneal dialysis (CAPD) is associated with complications. And some of these complications are well demonstrated as abnormalities on computed tomographic peritoneogram (CTP). The objective of our study is to document the serial changes of these complications. METHODS: We retrospectively reviewed 125 patients treated with CAPD for end staged renal failure (ESRF) who had CTP conducted in our hospital between December 2006 and August 2015. A total of 164 (n = 164) CTPs were performed. Patients with only one CTP performed were excluded from our study. A retrospective review of 68 serial CTPs studies on 28 patients during the 9-year period was undertaken. We looked into the serial changes on CTP. RESULTS: Among the 28 patients who had serial imaging, 46.43% of patients were found to have retroperitoneal leakage; 92.31% of them showed resolution in subsequent serial CTP. 21.43% of patients had anterior abdominal wall leakage; none of them resolved in subsequent CTP. 14.29% of patients were found to have inguinal hernias; 75% of them showed interval progression in subsequent serial CTPs. CONCLUSION: Retroperitoneal leakage is a common complication in patients on CAPD and tends to resolve whereas other complications including anterior abdominal wall leakage and hernias are unlikely to resolve and may progress further. PMID- 28004510 TI - Mothers' intentions to vaccinate their teenaged children against human papillomavirus, as predicted by sex in South Korea: An application of the theory of planned behavior. AB - AIM: This study was conducted in order to examine the intention of mothers to vaccinate their teenaged children against human papillomavirus (HPV) infection, according to the children's sex. Based on the theory of planned behavior, the study identified the sex-specific predictors of mothers' intention to vaccinate their teenaged children against HPV. METHODS: This was a descriptive survey study that included, as participants, 200 mothers whose teenaged children were not vaccinated against HPV. RESULTS: The mothers' experience with HPV vaccination was a significant predictor of their childrens' HPV vaccination status. For the mothers of sons, subjective norms, attitudes, and perceived behavioral control were found to be significant predictors of intention of HPV vaccination, with an explanatory power of 69.5%. For those with daughters, only attitudes and subjective norms were significant predictors, with an explanatory power of 79.6%. CONCLUSION: The application of the theory of planned behavior is an effective method to determine the predictors of children's HPV vaccination status. In order to improve the HPV vaccination rate of teenaged children, strategies for education and effective promotion that involve mothers should be developed. PMID- 28004511 TI - Integrin-Targeting Fluorescent Proteins: Exploration of RGD Insertion Sites. AB - The potential of the fluorescent protein scaffold to control peptide sequence functionality is illustrated by an exploration of fluorescent proteins as novel probes for targeting integrins. A library of fluorescent mCitrine proteins with RGD motifs incorporated at several positions in loops within the protein main chain was generated and characterized. Amino acid mutations to RGD as well as RGD insertions were evaluated: both led to constructs with typical mCitrine fluorescent properties. Screening experiments against four human integrin receptors revealed two strong-binding constructs and two selective integrin binders. The effect of the site of RGD incorporation illustrates the importance of the protein scaffold on RGD sequence functionality, leading to fluorescent protein constructs with the potential for selective integrin targeting. PMID- 28004512 TI - A Rapid Access Clinic to improve delivery of ambulatory care to cancer patients. AB - BACKGROUND: Cancer patients may find it challenging to access timely advice and care. We evaluated the improvement in delivering ambulatory care in establishing a Rapid Assessment Clinic (RAC) in a cancer center. METHODS: Patients receiving chemotherapy who presented for assessment at the RAC from September 2013 to June 2014 were included for review. Patient demographics, tumor characteristics, presenting complaints, time to assessment, total time spent at the RAC and assessment outcome were extracted. Similar data for cancer patients presented to the emergency department (ED) but were appropriate for RAC assessment from February 2012 to August 2012 were reviewed for comparison. For patients with febrile neutropenia, time to empirical antibiotic therapy was also reviewed and analyzed. RESULTS: Comparing to ED presentation (n = 152), patients reviewed at the RAC (n = 217) had a shorter waiting time to medical review (28.5 vs 40 min, P = 0.12), shorter total time spent for review (3.1 vs 9.7 hrs, P < 0.001), lesser rate of hospital admission (14.3% vs 69.1%, P < 0.001) and shorter inpatient length of stay (4 vs 7 days, P = 0.013). Presentations of febrile neutropenia were reviewed more promptly in ED (6 vs 9.5 min, P = 0.37), but this did not result in earlier empirical antibiotic administration (79 vs 74 min, P = 0.84). CONCLUSION: Comparing to ED, RAC had improved timeliness of care, resulting in a lower rate of hospital admission and inpatient length of stay for cancer patients. There was, however, no difference in the management of febrile neutropenia. PMID- 28004513 TI - Simplified, serine-rich theta-defensin analogues as antitumour peptides. AB - theta-defensins belong to the family of host defence peptides. They are the only known example of cyclic polypeptides in animal proteomes. This study presents the synthesis of simplified theta-defensin analogues with pairs of cysteine replaced either by alanine, leucine or serine residues. Cytotoxicity tests were performed on human mammary epithelial (HB2) and breast cancer (SKBR3, MDA-MB-231) cell lines to determine whether peptides are selectively targeting cancer cells. The effect of these peptides was also evaluated in 3D Matrigel cultures, which are based on extracellular matrix components and therefore closely represent in vivo conditions. Finally, to determine whether analogues are able to sensitize MDA-MB 231 triple-negative breast cancer cells to chemotherapeutics, we co-administrated peptides with cisplatin or doxorubicin hydrochloride also in 3D Matrigel cultures. Additionally, cytotoxicity towards peripheral blood mononuclear cells and haemolytic effect were examined for a chosen representative of synthesized compounds. The results showed that positively charged serine-containing theta defensin derivatives were more cytotoxic towards breast cancer cells (SKBR3, MDA MB-231) than towards mammary epithelial cells (HB2). Analogues enhanced the effect of cisplatin and doxorubicin hydrochloride on triple-negative breast cancer cell line (MDA-MB-231). PMID- 28004514 TI - The Taipan snake venom time can be used to detect lupus anticoagulant in patients treated by rivaroxaban. PMID- 28004515 TI - Cardiac risk index as a simple geometric indicator to select patients for the heart-sparing radiotherapy of left-sided breast cancer. AB - INTRODUCTION: This is a dosimetric study to identify a simple geometric indicator to discriminate patients who meet the selection criterion for heart-sparing radiotherapy (RT). The authors proposed a cardiac risk index (CRI), directly measurable from the CT images at the time of scanning. METHODS: Treatment plans were regenerated using the CT data of 312 consecutive patients with left-sided breast cancer. Dosimetric analysis was performed to estimate the risk of cardiac mortality using cardiac dosimetric parameters, such as the relative heart volumes receiving >=25 Gy (heart V25 ). For each CT data set, in-field heart depth (HD) and in-field heart width (HW) were measured to generate the geometric parameters, including maximum HW (HWmax ) and maximum HD (HDmax ). Seven geometric parameters were evaluated as candidates for CRI. Receiver operating characteristic (ROC) curve analyses were used to examine the overall discriminatory power of the geometric parameters to select high-risk patients (heart V25 >= 10%). RESULTS: Seventy-one high-risk (22.8%) and 241 low-risk patients (77.2%) were identified by dosimetric analysis. The geometric and dosimetric parameters were significantly higher in the high-risk group. Heart V25 showed the strong positive correlations with all geometric parameters examined (r > 0.8, p < 0.001). The product of HDmax and HWmax (CRI) revealed the largest area under the curve (AUC) value (0.969) and maintained 100% sensitivity and 88% specificity at the optimal cut-off value of 14.58 cm2 . CONCLUSIONS: Cardiac risk index proposed as a simple geometric indicator to select high-risk patients provides useful guidance for clinicians considering optimal implementation of heart-sparing RT. PMID- 28004516 TI - Interaction Mechanism and Clustering among RGD Peptides and Integrins. AB - Peptides with an exposed arginine-glycine-aspartate (Arg-Gly-Asp, RGD) sequence targeting the integrin alphaV beta3 play an important role in targeted anticancer drug delivery. The interaction of multiple RGD-containing peptides and two alphaV beta3 molecules was studied via MD simulation. Results revealed that not all six RGD-containing peptides interact with alphaV beta3 and interaction strengths differed among the peptides. The specific identification sites included the guanidine group of the ARG residue in the RGD peptide and the carboxyl group of the ASP residue in integrin alphaV beta3 . Therefore, formation of a salt bridge between ARGRGD and the ASP residue was the main mechanism of interaction. H-bonds also played an important role in the observed interaction. The interaction between RGD-containing peptides and alphaV beta3 was influenced by two factors: the relative orientation and distance between these groups. The RGD cluster, which could markedly increase the number of absorbed RGD monomers and enhance the cellular uptake of nano-medicines, was observed in this system. PMID- 28004517 TI - Selective Metal-free HB(C6 F5 )2 Catalyzed Allene Cyclotrimerization: Formation of 1,3,5-Trimethylenecyclohexane and Its Tris-hydroboration Product. AB - Allene is cyclotrimerized under metal-free conditions with the borane HB(C6 F5 )2 catalyst to selectively give 1,3,5-trimethylenecyclohexane (3 a). Three-fold hydroboration of the 1,3,5-cyclotrimer with Piers' borane gives the all-cis 1,3,5 CH2 B(C6 F5 )2 substituted cyclohexane product 14. PMID- 28004518 TI - Reinventing Design Principles for Developing Low-Viscosity Carbon Dioxide-Binding Organic Liquids for Flue Gas Clean Up. AB - Anthropogenic CO2 emissions from point sources (e.g., coal fired-power plants) account for the majority of the greenhouse gases in the atmosphere. Water-lean solvent systems such as CO2 -binding organic liquids (CO2 BOLs) are being developed to reduce the energy requirement for CO2 capture. Many water-lean solvents such as CO2 BOLs are currently limited by the high viscosities of concentrated electrolyte solvents, thus many of these solvents have yet to move toward commercialization. Conventional standard trial-and-error approaches for viscosity reduction, while effective, are time consuming and economically expensive. We rethink the metrics and design principles of low-viscosity CO2 capture solvents using a combined synthesis and computational modeling approach. We critically study the effects of viscosity reducing factors such as orientation of hydrogen bonding, introduction of higher degrees of freedom, and cation or anion charge solvation, and assess whether or how each factor affects viscosity of CO2 BOL CO2 capture solvents. Ultimately, we found that hydrogen bond orientation and strength is the predominant factor influencing the viscosity in CO2 BOL solvents. With this knowledge, a new CO2 BOL variant, 1-MEIPADM-2-BOL, was synthesized and tested, resulting in a solvent that is approximately 60 % less viscous at 25 mol % CO2 loading than our base compound 1-IPADM-2-BOL. The insights gained from the current study redefine the fundamental concepts and understanding of what influences viscosity in concentrated organic CO2 -capture solvents. PMID- 28004519 TI - Antimicrobial assay and genetic screening of selected freshwater Cyanobacteria and identification of a biomolecule dihydro-2H-pyran-2-one derivative. AB - AIMS: Explorations of freshwater Cyanobacteria as antimicrobial (bacteria, fungi and methicillin-resistant Staphylococcus aureus (MRSA) strains) drug resource using bioassay, NRPS (non-ribosomal polypeptide synthetase) and PKS (polyketide synthase) genes, as well as in silico approach. METHODS AND RESULTS: We have bioassayed the extracts of Phormidium CCC727, Geitlerinema CCC728, Arthrospira CCC729, Leptolyngbya CCC732, Phormidium CCC730, Phormidium CCC731 against six pathogenic bacteria comprising Gram (+ve): S. aureus including seven clinical MRSA and Enterococcus faecalis, Gram (-ve): Escherichia coli, Salmonella Typhimurium, Klebsiella pneumoniae and Shigella boydii along with non-pathogenic Enterobacter aerogenes as well as fungal strains (Cryptococcus neoformans and Candida albicans, C. krusei, C. tropicalis and Aspergillus niger) exhibiting antimicrobial potential. The NRPS and PKS genes of the target strains were also amplified and sequenced. The putative protein structures were predicted using bioinformatics approach. CONCLUSION: PKS gene expression indicated beta keto-acyl synthase as one of the important active domains in the biomolecules related to antitumour and antifungal group. The simultaneous identification of the biomolecule (dihydro-2H-pyran-2-one derivative) was also inferred spectroscopically. SIGNIFICANCE AND IMPACT OF THE STUDY: Freshwater Cyanobacteria are prolific producers of secondary metabolite(s) that may act as the antimicrobial drug resource in addition to their much explored marine counterpart. PMID- 28004520 TI - Detection of Bovine Viral Diarrhoea Virus 2 as the Cause of Abortion Outbreaks on Commercial Sheep Flocks. AB - Outbreaks of abortions and lambs born with nervous clinical signs and/or congenital malformations affected different sheep farms in Spain. Initial diagnosis of 'border disease-like' was established, based on clinical signs, serology and/or RNA detection by a pan-pestivirus RT-PCR. However, further investigation using immunohistochemical and molecular techniques identified BVDV 2b as the aetiological agent. PMID- 28004521 TI - Spur cell anemia in Wilson's disease: a rare presentation. PMID- 28004522 TI - Dual Infection with Bluetongue Virus Serotypes and First-Time Isolation of Serotype 5 in India. AB - Bluetongue is endemic in India and has been reported from most Indian states. Of late, the clinical disease is most frequently seen in the states of Andhra Pradesh, Telangana (erstwhile Andhra Pradesh state), Tamil Nadu and Karnataka. Our analysis of diagnostic samples from bluetongue outbreaks during 2010-2011 from the state of Karnataka identified bluetongue virus (BTV) serotype 5 (BTV-5) for the first time in India. One of the diagnostic samples (CH1) and subsequent virus isolate (IND2010/02) contained both BTV-2 and BTV-5. Segment 2 (seg-2) sequence data (400 bp: nucleotides 2538-2921) for IND2010/02-BTV5, showed 94.3% nucleotide identity to BTV-5 from South Africa (Accession no. AJ585126), confirming the virus serotype and also indicating that Seg-2 was derived from a Western topotype, which is in contrast to serotype 2, that belongs to an Eastern topotype. BTV-5 has been recently reported from Africa, China, French islands and the Americas. Although the exact source of the Indian BTV-5 isolate is still to be confirmed, recent identification of additional exotic serotypes in India is of real concern and might add to the severity of the disease seen in these outbreaks. PMID- 28004524 TI - A Cell-Based Self-Assembly Approach for the Production of Human Osseous Tissues from Adipose-Derived Stromal/Stem Cells. AB - Achieving optimal bone defect repair is a clinical challenge driving intensive research in the field of bone tissue engineering. Many strategies focus on seeding graft materials with progenitor cells prior to in vivo implantation. Given the benefits of closely mimicking tissue structure and function with natural materials, the authors hypothesize that under specific culture conditions, human adipose-derived stem/stromal cells (hASCs) can solely be used to engineer human reconstructed osseous tissues (hROTs) by undergoing osteoblastic differentiation with concomitant extracellular matrix production and mineralization. Therefore, the authors are developing a self-assembly methodology allowing the production of such osseous tissues. Three-dimensional (3D) tissues reconstructed from osteogenically-induced cell sheets contain abundant collagen type I and are 2.7-fold less contractile compared to non-osteogenically induced tissues. In particular, hROT differentiation and mineralization is reflected by a greater amount of homogenously distributed alkaline phosphatase, as well as higher calcium-containing hydroxyapatite (P < 0.0001) and osteocalcin (P < 0.0001) levels compared to non-induced tissues. Taken together, these findings show that hASC-driven tissue engineering leads to hROTs that demonstrate structural and functional characteristics similar to native osseous tissue. These highly biomimetic human osseous tissues will advantageously serve as a platform for molecular studies as well as for future therapeutic in vivo translation. PMID- 28004525 TI - UK tertiary centre experience of outcomes from osseointegrated transcutaneous magnetic bone conduction hearing system implanted in twenty-five patients using a linear incision technique. PMID- 28004523 TI - Accuracy of self-report of HIV viral load among people with HIV on antiretroviral treatment. AB - OBJECTIVES: The aim of the study was to assess, among people living with HIV, knowledge of their latest HIV viral load (VL) and CD4 count. METHODS: Agreement between self-report and clinic record was assessed among 2771 HIV-diagnosed individuals on antiretroviral treatment (ART) in the UK Antiretrovirals, Sexual Transmission Risk and Attitudes Study (2011-2012). A confidential self-completed questionnaire collected information on demographic, socioeconomic, HIV-related and health-related factors. Participants were asked to self-report their latest VL [undetectable (<= 50 copies/mL), detectable (> 50 copies/mL) or "don't know"] and CD4 count (< 200, 200-350, 351-500 or > 500 cells/MUL, or "don't know"). Latest clinic-recorded VL and CD4 count were documented. RESULTS: Of 2678 participants on ART, 434 (16.2%) did not accurately report whether their VL was undetectable. Of 2334 participants with clinic-recorded VL <= 50 copies/mL, 2061 (88.3%) correctly reported undetectable VL; 49 (2.1%) reported detectable VL; 224 (9.6%) did not know their VL. Of 344 participants with clinic-recorded VL > 50 copies/mL, 183 (53.2%) correctly reported detectable VL; 76 (22.1%) reported undetectable VL; 85 (24.7%) did not know their VL. Of 2137 participants who reported undetectable VL, clinic-recorded VL was <= 50 copies/mL for 2061 (96.4%) and <1000 copies/mL for 2122 (99.3%). In analyses adjusted for gender/sexual orientation, ethnicity, age and time since starting ART, factors strongly associated with inaccurate self-report of VL (including "don't know") included socioeconomic disadvantage [prevalence ratio (95% CI) for "not" vs. "always" having enough money for basic needs: 2.4 (1.9, 3.1)], poor English fluency [3.5 (2.4, 5.1) vs. UK born], nondisclosure of HIV status [1.7 (1.3, 2.1)], ART nonadherence [2.1 (1.7, 2.7) for three or more missed doses vs. none in the past 2 weeks] and depressive symptoms (PHQ-9 score >= 10) [1.9 (1.6, 2.2)]. Overall, 612 (22.9%) of 2667 participants on ART did not accurately self-report whether or not their CD4 count was <= 350 cells/MUL. CONCLUSIONS: There is a high level of accuracy of a self-report of undetectable VL in people on ART in the UK. Overall, accurate knowledge of personal VL level varied according to demographic, socioeconomic, HIV-related and health-related factors. Active identification of people who may benefit from increased levels of support and engagement in care is important. PMID- 28004526 TI - Exercise therapy in oncology rehabilitation in Australia: A mixed-methods study. AB - AIM: Oncology rehabilitation improves outcomes for cancer survivors but little is known about program availability in Australia. The aims of this study were: to describe oncology rehabilitation programs in Australia: determine whether the exercise component of programs is consistent with guidelines: and to explore barriers and facilitators to program implementation. METHODS: A sequential, explanatory mixed-methods study was completed in two phases: (1) a survey of Australian oncology rehabilitation programs; and (2) purposively sampled follow up semistructured interviews with senior clinicians working in oncology rehabilitation who were involved with exercise prescription. RESULTS: Hospitals and/or cancer centers from 42 public hospital health networks (representing 163 hospitals) and 39 private hospitals were contacted to identify 31 oncology rehabilitation programs. All 31 surveys were returned (100% response rate). Programs were typically multidisciplinary, ran twice weekly, provided education and exercise and included self-management strategies. Exercise prescription and progression was patient centered and included a combination of resistance and aerobic training supplemented by balance, pelvic floor, and core stability exercises. Challenges to implementation included a lack of awareness of programs in the community and organizational barriers such as funding. Strong links with oncologists facilitated program referrals. CONCLUSION: Despite evidence to support oncology rehabilitation, there are few programs in Australia and there are challenges that limit it becoming part of standard practice. Programs that exist are multidisciplinary with a focus on exercise with the majority of programs following a cardiac rehabilitation model of care. PMID- 28004527 TI - Efficacy of balloon sinuplasty in treatment of frontal rhinosinusitis: a prospective study in sixty patients. PMID- 28004529 TI - Web Alert: Drugs from Marine Microbes: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 28004528 TI - Minimal residual disease monitoring in childhood B lymphoblastic leukemia with t(12;21)(p13;q22); ETV6-RUNX1: concordant results using quantitation of fusion transcript and flow cytometry. AB - INTRODUCTION: The translocation t(12;21)(p13;q22) resulting in the fusion gene ETV6-RUNX1, is the most frequent gene fusion in childhood B lymphoblastic leukemia. In the Nordic Society of Paediatric Haematology and Oncology ALL-2008 treatment protocol, treatment stratification in B-lineage ALL is based on results of minimal residual disease (MRD) analysis with fluorescence-activated cell sorting (FACS). In this study, we determined whether RT-qPCR of the ETV6-RUNX1 fusion transcript can be a reliable alternative for MRD analysis. METHODS: Seventy-eight bone marrow samples from 29 children at diagnosis and day 15, 29, and 78 during treatment were analyzed for MRD with FACS and with quantitative reverse transcription polymerase chain reaction (RT-qPCR). Fusion transcript MRD was defined as the ETV6-RUNX1/GUSB ratio at the follow-up time point (day 15/29/78) divided with the ETV6-RUNX1/GUSB ratio at diagnosis (%). RESULTS: MRD analysis with FACS and with RT-qPCR of ETV6-RUNX1 fusion transcript showed strong correlation. All cases showed concordant results at the treatment stratifying time points day 29 and day 78, when comparing the two methods with a cutoff set to 0.1%. CONCLUSION: RT-qPCR is a valuable addition and could also be an alternative to FACS in cases where FACS is not achievable for MRD analysis. PMID- 28004530 TI - Intracellular Microreactors as Artificial Organelles to Conduct Multiple Enzymatic Reactions Simultaneously. AB - The creation of artificial organelles is a new paradigm in medical therapy that aims to substitute for missing cellular function by replenishing a specific cellular task. Artificial organelles tackle the challenge of mimicking metabolism, which is the set of chemical reactions that occur within a cell, mainly catalyzed by enzymes. So far, the few reported carriers able to conduct enzymatic reactions intracellularly are based on single-compartment carriers. However, cell organelles outperform by conducting multiple reactions simultaneously within confined sub-compartments. Here, the field of artificial organelles is advanced by reporting the assembly of a microreactor consisting of polymer capsules entrapping gold nanoclusters (AuNCs) and liposomes as sub compartments. The fluorescence properties of AuNCs are employed to monitor the microreactors uptake by macrophages. Encapsulation is demonstrated and functionality of microreactors with trypsin (TRP) and horseradish peroxidase (HRP)-loaded liposomes is preserved. Multiple enzymatic reactions taking place simultaneously is demonstrated by exposing macrophages with the internalized microreactors to bis-(benzyloxycarbonyl-Ile-Pro-Arg)-Rho-110 and Amplex Red substrates, which are specific for TRP and HRP, respectively. Conversion of the substrates into the respective fluorescent products is observed. This report on the first microreactor conducting multiple enzymatic reactions simultaneously inside a cell is a considerable step in the field of artificial organelles. PMID- 28004531 TI - Radioembolization for hepatocellular carcinoma: gaining insight on a personalized approach. PMID- 28004532 TI - A Model Study to Unravel the Complexity of Bio-Oil from Organic Wastes. AB - Binary and ternary mixtures of cellulose, bovine serum albumin (BSA) and tripalmitin, as biomass reference compounds for carbohydrates, proteins and triglycerides, respectively, were treated under hydrothermal liquefaction (HTL) conditions to describe the main reaction pathways involved in the process of bio oil production from municipal organic wastes. Several analytical techniques (elemental analysis, GC-MS, atmospheric-pressure photo-ionisation high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and 13 C cross polarisation magic-angle spinning NMR spectroscopy) were used for the molecular level characterisation of the resulting aqueous phase, solid residue and bio-oil, in particular. The main reaction pathways led to free fatty acids, fatty acid amides, 2,5-diketopiperazines and Maillard-type compounds as the main components of the bio-oil. The relationship of such compounds to the original components of the biomass was thus determined, which highlights the fate of the heteroatom containing molecules in particular. Finally, the molecular composition of the bio oils from our reference compounds was matched with that of the bio-oil from municipal organic waste biomass by comparing their high-resolution Fourier transform ion cyclotron resonance mass spectra, and we obtained a surprisingly high similarity. Hence, the ternary mixture acts as a reliable biomass model and is a powerful tool to clarify the degradation mechanisms that occur in the biomass under HTL treatment, with the ultimate goal to improve the HTL process itself by modulating the input of the organic starting matter and then the upgrading steps to bio-fuels. PMID- 28004533 TI - New olfactometric findings in Parkinson's disease. AB - OBJECTIVES: To investigate in Parkinson's disease-affected patients a correlation between hyposmia and gastrointestinal dysfunction and their possible identical etiopathogenesis. DESIGN: Retrospective cohort study. SETTING: ENT and neurology departments (Gemelli Hospital, Rome, Italy). PARTICIPANTS: A total of 78 patients with diagnosis of PD according to the UK Brain Bank criteria. INCLUSION CRITERIA: informed consent and olfactory testing executed; exclusion criteria: signs of dementia according to the DSM-IV criteria; Mini Mental State Examination score <=26; head trauma; central neurological disorders, nasal or systemic diseases potentially affecting olfactory function. Motor condition was assessed by means of Hoehn and Yahr staging and by section III of the Unified PD Rating Scale, performed off and on medications. MAIN OUTCOME MEASURES: The patients underwent olfactory evaluation (TDI score), after rhinomanometry with nasal decongestion. A total of 25 non-motor symptoms were evaluated through an interview. RESULTS: Olfactory dysfunction was objectively found in 91.0% of patients, a percentage higher than the subjective hyposmia reported (55.1%) P = 0.0001. Seven patients (9.0%) were normosmic, 49 (62.8%) hyposmic and 22 (28.2%) anosmic. Subjective hyposmia, constipation, bloating and dyspepsia differed across groups, being higher in anosmic and hyposmic ones than in the normosmic group. P value was <=0.05 for each symptom. Despite the original results, this study has the limitation of being based on subjective ratings by a relatively limited group of patients. CONCLUSIONS: Hyposmia and gastrointestinal symptoms are correlated, and this would support a possible common origin; the CNS could be reached through two different pathways, both starting in the peripheral nervous system. PMID- 28004535 TI - Do you drink more than your doctor? PMID- 28004534 TI - Differential expression levels and methylation status of ROBO1 in mantle cell lymphoma and chronic lymphocytic leukaemia. PMID- 28004536 TI - What can we learn when the government pays for our errors? PMID- 28004537 TI - ? PMID- 28004538 TI - ? PMID- 28004539 TI - ? PMID- 28004540 TI - ? PMID- 28004541 TI - [With lives at stake]. PMID- 28004542 TI - Prehospital thoracotomy for traumatic cardiac arrest. PMID- 28004543 TI - Investigating near-death experiences. PMID- 28004544 TI - [How many injuries are treated in specialist health services annually?]. PMID- 28004545 TI - ? PMID- 28004546 TI - Pathology-related cases in the Norwegian System of Patient Injury Compensation in the period 2010-2015. AB - BACKGROUND: The Norwegian System of Patient Injury Compensation (NPE) processes compensation claims from patients who complain about malpractice in the health services. A wrong diagnosis in pathology may cause serious injury to the patient, but the incidence of compensation claims is unknown, because pathology is not specified as a separate category in NPE's statistics. Knowledge about errors is required to assess quality-enhancing measures. We have therefore searched through the NPE records to identify cases whose background stems from errors committed in pathology departments and laboratories. MATERIAL AND METHOD: We have searched through the NPE records for cases related to pathology for the years 2010 - 2015. RESULTS: During this period the NPE processed a total of 26 600 cases, of which 93 were related to pathology. The compensation claim was upheld in 66 cases, resulting in total compensation payments amounting to NOK 63 million. False negative results in the form of undetected diagnoses were the most frequent grounds for compensation claims (63 cases), with an undetected malignant melanoma (n = 23) or atypia in cell samples from the cervix uteri (n = 16) as the major groups. Sixteen cases involved non-diagnostic issues such as mix-up of samples (n = 8), contamination of samples (n = 4) or delayed responses (n = 4). INTERPRETATION: The number of compensation claims caused by errors in pathology diagnostics is low in relative terms. The errors may, however, be of a serious nature, especially if malignant conditions are overlooked or samples mixed up. PMID- 28004547 TI - Complaints to the Norwegian System of Patient Injury Compensation 2001-14 following nerve blockade. AB - BACKGROUND: There has been a steady increase in cases reported to the Norwegian System of Patient Injury Compensation (NPE). We wished to look into what might characterise those cases of central and peripheral nerve blockade for anaesthesia that led to compensation claims. MATERIAL AND METHOD: Cases with codes for central and peripheral blockade within the field of anaesthesiology were retrieved from the NPE database for the period 2001 - 14. The cases were evaluated on the basis of variables including sex, age, type of anaesthesia, diagnosis, type of injury, site of injury, damages received, and written descriptions of treatment and injury. The expert reports were anonymised and reviewed in detail. RESULTS: A total of 339 patient compensation claims relating to nerve blockade were identified, of which 149 concerned spinal anaesthesia, 142 epidural anaesthesia, 21 combined spinal and epidural anaesthesia and 27 peripheral nerve blockade. The group consisted of 236 women and 103 men, and the average age was 46 years. The 339 cases comprised 0.8 % of all cases reported to the NPE in this period. A total of 107 claims resulted in compensation. Eighty two million Norwegian kroner were paid out in total. INTERPRETATION: Peripheral and central nerve blockade accounts for only a small proportion of cases handled by the NPE. Only one in three applicants had their claim upheld, but when claims were upheld, the injuries were often severe and led to substantial pay-outs. PMID- 28004548 TI - [Psychogenic non-epileptic seizures in children]. PMID- 28004549 TI - [Hummingbird on MRI]. PMID- 28004550 TI - A man with fever and joint pain. PMID- 28004551 TI - [Santa Claus - a global health threat]. PMID- 28004552 TI - [Robert Schumanns right hand]. PMID- 28004553 TI - [Untreated syphilis - from Oslo to Tuskegee]. AB - In the period from 1891 - 1910, around 2000 patients with syphilis were admitted to the Department of Dermatology, Oslo University Hospital, Rikshospitalet. The head of the department, Caesar Boeck (1845 - 1917), believed in allowing the disease to take its natural course and withheld treatment. He made detailed notes of the diagnosis and the clinical course of the disease for all his patients. Boeck's material is unique, and forms the basis for our current knowledge about the prognosis and course of syphilis infections. In 1928, the patients were scrutinised by Boeck's successor in the Department of Dermatology, Edvin Bruusgaard (1869 - 1934), and later by Trygve Gjestland (1911 - 1993). Gjestland's doctoral thesis from 1955 has remained as "The Oslo study of untreated syphilis." This article presents a medical historical background for the study. Bruusgaard's and Gjestland's research was important for the Tuskegee Study in the USA, and the Oslo study gave implicit support to this research project, which posterity has emphatically condemned as ethically unacceptable. PMID- 28004555 TI - [Read!]. PMID- 28004554 TI - Hereditary haemochromatosis through 150 years. PMID- 28004556 TI - ? PMID- 28004557 TI - ? PMID- 28004558 TI - ? PMID- 28004559 TI - ? PMID- 28004560 TI - ? PMID- 28004561 TI - [The art of medicine at out-of-hours services]. PMID- 28004562 TI - ? PMID- 28004563 TI - ? PMID- 28004564 TI - ? PMID- 28004565 TI - ? PMID- 28004566 TI - Antifouling Manganese Oxide Nanoparticles: Synthesis, Characterization, and Applications for Enhanced MR Imaging of Tumors. AB - Antifouling manganese oxide (Mn3O4) nanoparticles (NPs) were synthesized by solvothermal decomposition of tris(2,4-pentanedionato) manganese(III) in the presence of trisodium citrate, followed by surface modification with polyethylene glycol and l-cysteine. The as-prepared nanoparticles have a uniform size distribution, good colloidal stability and good cytocompatibility. The modification of l-cysteine rendered the particles with much longer blood circulation time (half-decay time of 28.4 h) than those without l-cysteine modification (18.5 h), and decreased macrophage cellular uptake. Thanks to desirable antifouling property and relatively high r1 relaxivity (3.66 mM-1 s-1), the l-cysteine-modified Mn3O4 NPs can be used for enhanced tumor magnetic resonance imaging applications. PMID- 28004567 TI - DNA Origami-Graphene Hybrid Nanopore for DNA Detection. AB - DNA origami nanostructures can be used to functionalize solid-state nanopores for single molecule studies. In this study, we characterized a nanopore in a DNA origami-graphene heterostructure for DNA detection. The DNA origami nanopore is functionalized with a specific nucleotide type at the edge of the pore. Using extensive molecular dynamics (MD) simulations, we computed and analyzed the ionic conductivity of nanopores in heterostructures carpeted with one or two layers of DNA origami on graphene. We demonstrate that a nanopore in DNA origami-graphene gives rise to distinguishable dwell times for the four DNA base types, whereas for a nanopore in bare graphene, the dwell time is almost the same for all types of bases. The specific interactions (hydrogen bonds) between DNA origami and the translocating DNA strand yield different residence times and ionic currents. We also conclude that the speed of DNA translocation decreases due to the friction between the dangling bases at the pore mouth and the sequencing DNA strands. PMID- 28004568 TI - Multicopper Laccase Mimicking Nanozymes with Nucleotides as Ligands. AB - Using nanomaterials to achieve functional enzyme mimics (nanozymes) is attractive for both applied and fundamental research. Laccases are multicopper oxidases highly important for biotechnology and environmental remediation. In this work, we report an exceptionally simple yet functional laccase mimic based on guanosine monophosphate (GMP) coordinated copper. It forms an amorphous metal-organic framework (MOF) material. The ratio of copper and GMP is 3:4 as determined by isothermal titration calorimetry. It has excellent laccase-like activity and converts a diverse range of phenol containing substrates such as hydroquinone, naphthol, catechol and epinephrine. Comparative work shows that the activity is originated from guanosine coordination instead of phosphate binding in GMP. Cu2+ is required and cannot be substituted by other metal ions. At the same mass concentration, the Cu/GMP nanozyme has a higher Vmax and similar Km compared to the protein laccase. To achieve the same catalytic efficiency, the cost of the Gu/GMP is ~2400-fold lower than that of laccase. The Cu/GMP is much more stable at extreme pH, high salt, high temperature and for long-term storage. This is one of the first laccase-mimicking nanozymes, which will find important applications in analytical chemistry, environmental protection, and biotechnology. PMID- 28004569 TI - Strategies for the Activation and Release of the Membranolytic Peptide Melittin from Liposomes Using Endosomal pH as a Trigger. AB - Endosomolytic peptides are often coupled to drug delivery systems to enhance endosomal escape, which is crucial for the delivery of macromolecular drugs that are vulnerable to degradation in the endolysosomal pathway. Melittin is a 26 amino acid peptide derived from bee venom that has a very high membranolytic activity. However, such lytic peptides also impose a significant safety risk when applied in vivo as they often have similar activity against red blood cells and other nontarget cell membranes. Our aim is to control the membrane-disrupting capacity of these peptides in time and space by physically constraining them to a nanocarrier surface in such a way that they only become activated when delivered inside acidic endosomes. To this end, a variety of chemical approaches for the coupling of lytic peptides to liposomes via functionalized PEG-lipids were explored, including maleimide-thiol chemistry, click-chemistry, and aldehyde hydrazide chemistry. The latter enables reversible conjugation via a hydrazone bond, allowing for release of the peptide under endosomal conditions. By carefully choosing the conjugation site and by using a pH activated analog of the melittin peptide, lytic activity toward a model membrane is completely inhibited at physiological pH. At endosomal pH the activity is restored by hydrolysis of the acid-labile hydrazone bond, releasing the peptide in its most active, free form. Furthermore, using an analogue containing a nonhydrolyzable bond as a control, it was shown that the activity observed can be completely attributed to release of the peptide, validating dynamic covalent conjugation as a suitable strategy to maintain safety during circulation. PMID- 28004570 TI - Hollow Mesoporous Silica Nanoparticles with Tunable Structures for Controlled Drug Delivery. AB - A size-controllable and facile synthetic strategy has been developed to fabricate a series of hollow mesoporous silica nanoparticles (HMSNs) with tunable hollow cores or shell thicknesses by employing gold nanoparticles (Au NPs) and cetyltrimethylammonium bromide (CTAB) as dual templates. Various sizes of Au NPs and different amounts of tetraethyl orthosilicate contributed to structure tailored mesoporous silica-coated Au NPs. After calcination, CTAB molecules were completely removed, and Au NPs could still support the silica shell due to the high melting point. HMSNs were ultimately obtained by etching Au NPs. Applications of HMSNs as nanocarriers for delivering drugs were investigated. Significantly, it was flexible and convenient to control drug-loading/releasing behavior of HMSNs just by tuning the hollow cores or shell thicknesses. Intracellular experiments have proven that HMSNs are suitable for delivering drugs. We anticipate that this study could provide an important avenue for the synthesis of HMSNs and further contribute to advancing practical applications of HMSNs in drug delivery systems. PMID- 28004571 TI - Optimized, Fast-Throughput UHPLC-DAD Based Method for Carotenoid Quantification in Spinach, Serum, Chylomicrons, and Feces. AB - An improved UHPLC-DAD-based method was developed and validated for quantification of major carotenoids present in spinach, serum, chylomicrons, and feces. Separation was achieved with gradient elution within 12.5 min for six dietary carotenoids and the internal standard, echinenone. The proposed method provides, for all standard components, resolution > 1.1, linearity covering the target range (R > 0.99), LOQ < 0.035 mg/L, and intraday and interday RSDs < 2 and 10%, respectively. Suitability of the method was tested on biological matrices. Method precision (RSD%) for carotenoid quantification in serum, chylomicrons, and feces was below 10% for intra- and interday analysis, except for lycopene. Method accuracy was consistent with mean recoveries ranging from 78.8 to 96.9% and from 57.2 to 96.9% for all carotenoids, except for lycopene, in serum and feces, respectively. Additionally, an interlaboratory validation study on spinach at two institutions showed no significant differences in lutein or beta-carotene content, when evaluated on four occasions. PMID- 28004572 TI - Infusing Lubricant onto Erasable Microstructured Surfaces toward Guided Sliding of Liquid Droplets. AB - Introducing a lubricant layer onto surfaces has emerged as a novel strategy to address a wide range of interface-related challenges. Recent studies of lubricant infused surfaces have extended beyond repelling liquids to manipulating the mobility of fluids. In this study, we report a design of slippery surfaces based on infusing lubricant onto a polyelectrolyte multilayer film whose surface microstructures can be erased rapidly under mild condition. Unlike other lubricant-infused surfaces, the liquid movements (e.g., moving resistance and direction) on such surfaces can be manipulated via programming the surface microstructures beforehand. The work reported here offers a versatile design concept of lubricant-infused surfaces and may turn on new applications of this emerging class of bioinspired materials. PMID- 28004574 TI - Wrinkled Surface-Mediated Antibacterial Activity of Graphene Oxide Nanosheets. AB - Surface wrinkles are commonly observed in large-scale of graphene films. As a new feature, the wrinkled surface of graphene films may directly affect bacterial viability by means of various interactions of bacterial cells with graphene sheets. In the present study, we introduce a wrinkled surface geometry of graphene oxide (GO) thin films for antibacterial application. Highly wrinkled GO films were formed by vacuum filtration of a GO suspension through a prestrained filter. Several types of wrinkled GO surfaces were obtained with different roughness grades determined by root-mean-square values. Antibacterial activity of the fabricated GO films toward three different bacterial species, Escherichia coli, Mycobacterium smegmatis, and Staphylococcus aureus, was evaluated in relation to surface roughness. Because of their nanoscopically corrugated nature, the wrinkled GO films exhibited excellent antibacterial properties. On the basis of our detailed observations, we propose a novel concept of the surrounded contact-based mechanism for antimicrobial activity of wrinkled GO films. It postulates formation of a mechanically robust GO surface "trap" that prompts interaction of bacteria with the diameter-matched GO sink, which results in substantial damages to the bacterial cell membrane. We believe that our approach uncovered a novel use of a promising two-dimensional material for highly effective antibacterial treatment. PMID- 28004575 TI - Whole Milk Increases Intestinal ANGPTL4 Expression and Excretion of Fatty Acids through Feces and Urine. AB - The angiopoietin-like 4 (ANGPLT4) protein is involved in lipid metabolism and is known to inhibit lipoprotein lipase in the bloodstream. We investigated the effect of milk on intestinal ANGPTL4 and the metabolic profile of growing pigs and the effect of free fatty acids (FFAs) on ANGPTL4 in ex vivo and in vitro assays. Feeding pigs whole milk increased intestinal ANGPTL4 mRNA and increased fecal excretion of long-chain FFA compared to the control group fed soybean oil (n = 9). Furthermore, FFAs (C4-C8) induced ANGPTL4 gene expression in porcine intestinal tissue mounted in Ussing chambers and ANGPTL4 protein secretion to both the apical and basolateral sides of intestinal Caco-2 cells on permeable membranes. Altogether, these results support an ANGPTL4-induced secretion of fecal FFAs. Urinary levels of FFAs (C4-C12), 3-hydroxyadipic acid, and suberic acid were also increased by milk consumption, indicating higher energy expenditure compared to the control group. PMID- 28004573 TI - Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen. AB - Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography. PMID- 28004577 TI - Property Self-Optimization During Wear of MoS2. AB - Knowledge of their bulk physical properties often guides selection of appropriate tribological coating materials. However, these properties as well as the microstructure evolve dramatically under the extreme conditions imposed during mechanical wear. The dynamic response ultimately governs the material's wear performance; thus, understanding the dynamic evolution of the system is critical. This work characterizes the change in mechanical properties and microstructure as a function of wear cycles in model MoS2 films using a combination of nanowear testing, transmission electron microscopy, and site-specific nanopillar compression. Notably, mechanical wear enhances the mechanical properties of the MoS2 while simultaneously evolving a microstructure that reduces the coefficient of friction and wear rate. We hypothesize that this self-optimizing behavior underpins the exceptional lubricity and antiwear performance of MoS2. PMID- 28004576 TI - Identification of Novel Brominated Compounds in Flame Retarded Plastics Containing TBBPA by Combining Isotope Pattern and Mass Defect Cluster Analysis. AB - The study of not only main flame retardants but also of related degradation products or impurities has gained attention in the last years and is relevant to assess the safety of our consumer products and the emission of potential contaminants into the environment. In this study, we show that plastics casings of electric/electronic devices containing TBBPA contain also a complex mixture of related brominated chemicals. These compounds were most probably coming from impurities, byproducts, or degradation products of TBBPA and TBBPA derivatives. A total of 14 brominated compounds were identified based on accurate mass measurements (formulas and tentative structures proposed). The formulas (or number of bromine elements) for 19 other brominated compounds of minor intensity are also provided. A new script for the recognition of halogenated compounds based on combining a simplified isotope pattern and mass defect cluster analysis was developed in R for the screening. The identified compounds could be relevant from an environmental and industrial point of view. PMID- 28004578 TI - Prebiotic Carbohydrates: Effect on Reconstitution, Storage, Release, and Antioxidant Properties of Lime Essential Oil Microparticles. AB - The aim of this study was to include prebiotic biopolymers as wall material in microparticles of lime essential oil. Whey protein isolate (WPI), inulin (IN), and oligofructose (OL) biopolymers were used in the following combinations: WPI, WPI/IN (4:1), and WPI/OL (4:1). The emulsion droplets in the presence of inulin and oligofructose showed larger sizes on reconstitution. There was no significant difference in solubility of the particles, but the wettability was improved on addition of the polysaccharides. The size of the oligofructose chains favored the adsorption of water. Prebiotic biopolymers reduced thermal and chemical stability of the encapsulated oil. Microparticles produced with WPI showed a higher bioactive compound release rate, mainly due to its structural properties, that enabled rapid diffusion of oil through the pores. The use of prebiotic biopolymers can be a good option to add value to encapsulated products, thus promoting health benefits. PMID- 28004579 TI - Eco-Friendly Composite of Fe3O4-Reduced Graphene Oxide Particles for Efficient Enzyme Immobilization. AB - A novel type of spherical and porous composites were synthesized to dually benefit from reduced graphene oxide (rGO) and magnetic materials as supports for enzyme immobilization. Three magnetic composite particles of Fe3O4 and rGO containing 71% (rGO-Fe3O4-M1), 36% (rGO-Fe3O4-M2), and 18% (rGO-Fe3O4-M3) Fe were prepared using a one-pot spray pyrolysis method and were used for the immobilization of the model enzymes, laccase and horseradish peroxidase (HRP). The rGO-Fe3O4 composite particles prepared by spray pyrolysis process had a regular shape, finite size, and uniform composition. The immobilization of laccase and HRP on rGO-Fe3O4-M1 resulted in 112 and 89.8% immobilization efficiency higher than that of synthesized pure Fe3O4 and rGO particles, respectively. The stability of laccase was improved by approximately 15-fold at 25 degrees C. Furthermore, rGO-Fe3O4-M1-immobilized laccase exhibited 92.6% of residual activity after 10 cycles of reuse and was 192% more efficient in oxidizing different phenolic compounds than the free enzyme. Therefore, these unique composite particles containing rGO and Fe3O4 may be promising supports for the efficient immobilization of industrially important enzymes with lower acute toxicity toward Vibrio fischeri than commercial pure Fe3O4 particles. PMID- 28004580 TI - CuCl-Catalyzed Ullmann-Type C-N Cross-Coupling Reaction of Carbazoles and 2 Bromopyridine Derivatives. AB - A CuCl-catalyzed Ullmann-type C-N cross-coupling reaction of carbazoles and 2 bromopyridine derivatives has been developed for the synthesis of N heteroarylcarbazole derivatives employing 1-methyl-imidazole and t-BuOLi as ligand and base, respectively, both of which are found to significantly promote the reaction. Low cost and low loading of both catalyst and ligand, together with high reaction yields, render this practical reaction to be suitable for large scale preparations and could be useful in material science. PMID- 28004581 TI - Precise Side-Chain Engineering of Thienylenevinylene-Benzotriazole-Based Conjugated Polymers with Coplanar Backbone for Organic Field Effect Transistors and CMOS-like Inverters. AB - Two donor-acceptor (D-A) alternating conjugated polymers based on thienylenevinylene-benzotriazole (TV-BTz), PTV6B with a linear side chain and PTVEhB with a branched side chain, were synthesized and characterized for organic field effect transistors (OFETs) and complementary metal-oxide-semiconductor (CMOS)-like inverters. According to density functional theory (DFT), polymers based on TV-BTz exhibit a coplanar and rigid structure with no significant twists, which could cause to an increase in charge-carrier mobility in OFETs. Alternating alkyl side chains of the polymers impacted neither the band gap nor the energy level. However, it significantly affected the morphology and crystallinity when the polymer films were thermally annealed. To investigate the effect of thermal annealing on the morphology and crystallinity, we characterized the polymer films using atomic force microscopy (AFM) and 2D-grazing incidence X ray diffraction (2D-GIWAXD). Fibrillary morphologies with larger domains and increased crystallinity were observed in the polymer films after thermal annealing. These polymers exhibited improved charge-carrier mobilities in annealed films at 200 degrees C and demonstrated optimal OFET device performance with p-type transport characteristics with charge-carrier mobilities of 1.51 cm2/(V s) (PTV6B) and 2.58 cm2/(V s) (PTVEhB). Furthermore, CMOS-like inorganic (ZnO)-organic (PTVEhB) hybrid bilayer inverter showed that the inverting voltage (Vinv) was positioned near the ideal switching point at half (1/2) of supplied voltage (VDD) due to fairly balanced p- and n-channels. PMID- 28004583 TI - Mesoporous Silica Coated Polydopamine Functionalized Reduced Graphene Oxide for Synergistic Targeted Chemo-Photothermal Therapy. AB - The integration of different therapies into a single nanoplatform has shown great promise for synergistic tumor treatment. Herein, mesoporous silica (MS) coated polydopamine functionalized reduced graphene oxide (pRGO) further modified with hyaluronic acid (HA) (pRGO@MS-HA) has been utilized as a versatile nanoplatform for synergistic targeted chemo-photothermal therapy against cancer. A facile and green chemical method is adopted for the simultaneous reduction and noncovalent functionalization of graphene oxide (GO) by using mussel inspired dopamine (DA) to enhance biocompatibility and the photothermal effect. Then, it was coated with mesoporous silica (MS) (pRGO@MS) to enhance doxorubicin (DOX) loading and be further modified with the targeting moieties hyaluronic acid (HA). The pH dependent and near-infrared (NIR) laser irradiation-triggered DOX release from pRGO@MS(DOX)-HA is observed, which could enhance the chemo-photothermal therapy effect. In vitro experimental results confirm that pRGO@MS(DOX)-HA exhibits good dispersibility, excellent photothermal property, remarkable tumor cell killing efficiency, and specificity to target tumor cells. In vivo antitumor experiments further demonstrated that pRGO@MS(DOX)-HA could exhibit an excellent synergistic antitumor efficacy, which is much more distinct than any monotherapy. This work presents a novel nanoplatform which could load chemotherapy drugs with high efficiency and be used as light-mediated photothermal cancer therapy agent. PMID- 28004582 TI - Weighted Protein Interaction Network Analysis of Frontotemporal Dementia. AB - The genetic analysis of complex disorders has undoubtedly led to the identification of a wealth of associations between genes and specific traits. However, moving from genetics to biochemistry one gene at a time has, to date, rather proved inefficient and under-powered to comprehensively explain the molecular basis of phenotypes. Here we present a novel approach, weighted protein protein interaction network analysis (W-PPI-NA), to highlight key functional players within relevant biological processes associated with a given trait. This is exemplified in the current study by applying W-PPI-NA to frontotemporal dementia (FTD): We first built the state of the art FTD protein network (FTD-PN) and then analyzed both its topological and functional features. The FTD-PN resulted from the sum of the individual interactomes built around FTD-spectrum genes, leading to a total of 4198 nodes. Twenty nine of 4198 nodes, called inter interactome hubs (IIHs), represented those interactors able to bridge over 60% of the individual interactomes. Functional annotation analysis not only reiterated and reinforced previous findings from single genes and gene-coexpression analyses but also indicated a number of novel potential disease related mechanisms, including DNA damage response, gene expression regulation, and cell waste disposal and potential biomarkers or therapeutic targets including EP300. These processes and targets likely represent the functional core impacted in FTD, reflecting the underlying genetic architecture contributing to disease. The approach presented in this study can be applied to other complex traits for which risk-causative genes are known as it provides a promising tool for setting the foundations for collating genomics and wet laboratory data in a bidirectional manner. This is and will be critical to accelerate molecular target prioritization and drug discovery. PMID- 28004584 TI - Isolation of insecticidal components in Inula salsoloides Ostenf. and characterisation of their activities. AB - The ethanol extract from Inula salsoloides (Turcz.) Ostenf was found to cause high mortality against Plutella xylostella L. (Lepidoptera: Plutellidae). The active components were isolated and identified. Two compounds were obtained and identified to be inulasalsolin and taraxasterol. Both compounds showed anti feedant effects against third instar larvae of P. xylostella with AFC50 of 0.030 and 0.053 mg/mL and insecticidal activities with LC50 of 0.19 and 0.49 mg/mL, respectively. The two compounds also exhibited high toxicity to cabbage aphid, Brevicoryne brassicae L. (Hemiptera: Aphididae) with LC50 values of 0.021 and 0.098 mg/mL. This is the first report on the study of insecticidal components of I. salsoloides and their activity against insects. PMID- 28004585 TI - Chemical constituents and antileukemic activity of Eugenia dysenterica. AB - The study about Eugenia dysenterica led to the isolation of 3-acetyl-urs-12-en-28 oic (1), 3-acetyl-olean-12-en-28-oic acid (2) and isoquercetin (3) from the stem barks, and of 3-O-beta-glucopyranosyl-beta-sitosterol (4), methyl 3-hydroxy-4 methoxybenzoate (5), methyl 4-hydroxyphenyl propionate (6), E-methyl-4 hydroxycinnamate (7), quercetin-3-O-(6??-O-galloyl)-beta-d-glucopyranoside (8) and quercetin-3-O-beta-d-galactopyranoside (9) from the leaves. The structures 1 9 were set through the analysis of their NMR spectroscopic data. Compounds 2, 3 and 5-8 were reported for the first time in the Eugenia genus. Compound 8 reduced cell viability and presented IC50 values 40.3 and 36.7 MUM, for the CCRF-CEM and the Kasumi-1 cells, respectively. PMID- 28004586 TI - Psycho-ophthalmology: Contributions of Health psychology to the assessment and treatment of glaucoma. AB - BACKGROUND: Asymptomatic in its early stages, glaucoma is the second leading cause of blindness worldwide. While psychosocial factors are taken into consideration for a host of diseases such as cancer, heart disease and autoimmune conditions, to date, psychological issues have been ignored in the clinical management of glaucoma. OBJECTIVE: This work reviews the most relevant contributions from a health psychology perspective for the assessment and treatment of glaucoma, which is emerging in the field of psycho-ophthalmology. METHOD: To provide scientific evidence regarding contributions of psychology to the comprehension of glaucoma, a bibliographic review of three databases (Psicodoc, PsycInfo and Medline) was conducted, spanning the period between 1940 and 2016. RESULTS: This review yielded a total of 66 studies published in the period analysed and identified three areas where health psychology has made substantive contributions to glaucoma screening, monitoring and treatment: the emotional impact on patients suffering from glaucoma, the adherence to treatment and the effects of stress on intraocular pressure. CONCLUSIONS: A health psychology approach for research and therapy of glaucoma must focus on the management of the negative affect associated with the diagnosis, the optimisation of treatment adherence and the stress management of the intraocular pressure measurements. PMID- 28004587 TI - Biotransformation of 20(R)-panaxatriol by Mucor racemosus and the anti-hepatic fibrosis activity of some products. AB - Biocatalysis of 20(R)-panaxatriol (PT) was performed by the fungus Mucor racemosus. Six metabolites (1-6) including five new compounds were obtained, and their structures were elucidated as 20(R),25-epoxy-12beta,24beta dihydroxydammaran-3,6-dione (2), 20(R),25-epoxy-12beta,22beta-dihydroxydammaran 3,6-dione (3), 20(R),25-epoxy-23beta-hydroxydammaran-3,6,12-trione (4), 20(R),25 epoxy-12beta,23alpha- dihydroxydammaran-3,6-dione (5), and 20(R),25-epoxy-12beta hydroxydammaran-3,6,23-trione (6) by spectroscopic analysis. Pharmacological studies revealed that compounds 2, 3 and 5 exhibited significant antihepatic fibrosis activity, while 4 and 6 showed cytotoxicity against HSC-T6 cells. PMID- 28004588 TI - 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. AB - INTRODUCTION: This is the 33rd Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2015, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 9.52 [7.40, 13.6] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system. METHODS: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure. RESULTS: In 2015, 2,792,130 closed encounters were logged by NPDS: 2,168,371 human exposures, 55,516 animal exposures, 560,467 information calls, 7657 human confirmed nonexposures, and 119 animal confirmed nonexposures. US PCs also made 2,695,699 follow-up calls in 2015. Total encounters showed a 3.42% decline from 2014, while health care facility (HCF) human exposure cases increased by 5.09% from 2014. All information calls decreased by 15.5% but HCF information calls increased 2.67%, and while medication identification requests (Drug ID) decreased 31.7%, human exposures reported to US PCs were essentially flat, increasing by 0.149%. Human exposures with less serious outcomes have decreased 2.95% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.34% per year since 2000. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.1%), household cleaning substances (7.54%), cosmetics/personal care products (7.41%), sedatives/hypnotics/antipsychotics (5.83%), and antidepressants (4.58%). Sedative/Hypnotics/Antipsychotics exposures as a class increased the most rapidly (2597 calls (11.4%)/year) over the last 14 years for cases showing more serious outcomes. The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (13.6%), household cleaning substances (11.2%), analgesics (9.12%), foreign bodies/toys/miscellaneous (6.45%), and topical preparations (5.33%). Drug identification requests comprised 35.0% of all information calls. NPDS documented 1831 human exposures resulting in death with 1371 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2 Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in calls involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, viral, bacterial, venomous, chemical agent, or commercial product), the identification of events of public health significance, resilience, response and situational awareness tracking. NPDS is a model system for the real-time surveillance of national and global public health. PMID- 28004589 TI - An update on the safety and interactions of antifungal drugs in stem cell transplant recipients. AB - INTRODUCTION: Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Improvement in the management of IFDs have been achieved with the availability of new effective and safe antifungal drugs, however, many of these newer treatments have some limitations in their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article is an update of a previous review published in this journal evaluating the safety profile of the antifungal drugs. Interesting new features include the availability of the new drug isavuconazole and the new tablet and intravenous formulations of posaconazole. Different dosages and new ways of administration of liposomal Amphotericin B (L-AmB) and echinocandins may be considered in the HSCT practice. Expert opinion: Nephrotoxicity continues to be a clinically relevant and frequent side effect of L-AmB which may cause a reduced clearance of other renally eliminated drugs frequently used in HSCT patients. Echinocandins are favorable therapeutic options in view of their low toxicity and uncommon drug drug interactions. Important limitations of triazoles are represented by hepatic toxicity and certain side effects particularly after prolonged treatments. The new triazole isavuconazole and the new tablet formulation of posaconazole will be probably increasingly used in the HSCT setting not only due to their efficacy but in particular for their interesting toxicity profile and pharmacokinetic characteristics. The knowledge of these pharmacological findings is crucial in the daily care of allogeneic HSCT patients. PMID- 28004590 TI - Optimization of treatment leachates from young, middle-aged and elderly landfills with bipolar membrane electrodialysis. AB - In this study, a bipolar membrane electrodialysis (BMED) process, which is thought to be an effective treatment method for leachate, was evaluated for leachates of three different ages ('young', 'middle-aged' and 'elderly'). The leachates were pretreated to eliminate membrane fouling problems prior to the BMED process. Experimental studies were carried out to determine optimal operating conditions for the three differently aged leachates in the BMED process. According to the experiment results, there was a high removal efficiency of conductivity determined at 4 membrane - 25 V for young and elderly leachate and at 1 membrane - 25 V for middle-aged leachate. It was found that the operating times required to reach the optimal endpoints (at conductivity of about 2 mS/cm) of BMED process were 90, 180 and 300 min for the middle-aged, young and elderly leachates, respectively. Under the optimum operating conditions for the BMED process, removal efficiencies of conductivity and chemical oxygen demand were determined to be 89.5% and 60% for young, 82.5% and 30% for middle-aged and 91.8% and 26% for elderly leachate, respectively. PMID- 28004591 TI - Long acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs. AB - INTRODUCTION: Long acting muscarinic receptor antagonists (LAMA) reverse airflow obstruction by antagonizing para-sympathetic bronchoconstricting effects within the airways. For years, tiotropium, has been the cornerstone LAMA for chronic obstructive pulmonary disease (COPD) management. Recently, new agents, aclidinium bromide, glycopyrronium bromide, and umeclidinium bromide, have been developed and introduced into clinical practice. Areas covered: This article reviews the clinical efficacy and adverse effects of currently available LAMAs in COPD treatment as well as developing LAMAs in early clinical trials and preclinical studies (V0162, TD-4208, CHF 5407, AZD9164, AZD8683, bencycloquidium). In addition, a new class of molecule that combines muscarinic antagonist and beta2 adrenergic properties (MABA) is described and current developmental progress discussed (GSK-961081, THRX-200495). Expert opinion: Future key areas for developing drugs for the management of COPD include prolonged duration of action, optimal delivery systems, synergistic combinations with other drugs, maximization of benefits and minimization of adverse effects. The development of new LAMA and MABA molecules provides exciting progress towards simpler and more effective COPD management. PMID- 28004592 TI - Non-culture based diagnostics for intravascular catheter related bloodstream infections. AB - INTRODUCTION: intravascular catheter related bloodstream infection (IVC-BSI) is a leading cause of nosocomial infections and associated with significant morbidity and mortality. Early detection and adequate treatment of causative pathogens is critical for a favourable outcome. However, it takes significant time to receive microbiological results due to the current reference diagnostic method's reliance on microbial growth. Areas covered: This review discusses culture and non-culture based techniques for the diagnosis of non IVC-BSI and IVC-BSI, including molecular methods and biomarkers. Different diagnostic strategies are evaluated and the potential of new generation of diagnostic assays highlighted. Expert commentary: The development of additional diagnostic methods has potential to beneficially supplement conventional culture diagnosis, and molecular techniques have particular potential to fulfil this need. They would also contribute significant new knowledge on the bacterial species present on catheters that are generally missed by diagnosis using traditionally culture-dependent methods. Advances in molecular strategies, together with new biomarkers, might lead to the development of faster, more sensitive and cheaper technologies and instruments. This review aims to provide a platform for the further development of IVCBSI diagnostic techniques. PMID- 28004593 TI - Identification of a new tadalafil analogue in commercial dietary supplements: isopropylnortadalafil. AB - A new tadalafil analogue was found in a commercial dietary supplement for enhancing sexual performance. The compound was detected by a high-performance liquid chromatography-diode array detector (HPLC-DAD). The analogue was isolated using semi-preparative HPLC, and its accurate mass was established by two LC-high resolution-mass spectrometers (LC-HRMS). The structure was determined by nuclear magnetic resonance (NMR) spectroscopy. The accurate mass of the compound corresponded to a molecular formula of C24H23N3O4. The compound was identified as a structural analogue of tadalafil in which the N-methyl group of tadalafil was replaced with an N-isopropyl group. We have named the new analogue isopropylnortadalafil and it is first reported herein. PMID- 28004595 TI - Subsurface nitrate reduction under wetlands takes place in narrow superficial zones. AB - This study aims to investigate the depth distribution of the Nitrate Reduction Potential (NRP) on a natural and a re-established wetland. The obtained NRP provides a valuable data of the driving factors affecting denitrification, the Dissimilatory Nitrate Reduction to Ammonium (DNRA) process and the performance of a re-established wetland. Intact soil cores were collected and divided in slices for the determination of Organic Matter (OM) through Loss of Ignition (LOI) as well as Dissolved Organic Carbon (DOC) and NRP spiking nitrate in batch tests. The Nitrate Reduction (NR) was fitted as a pseudo-first order rate constant (k) from where NRPs were obtained. NR took place in a narrow superficial zone showing a dropping natural logarithmic trend along depth. The main driving factor of denitrification, besides depth, was OM. Although, DOC and LOI could not express by themselves and absolute correlation with NRP, high amounts of DOC ensured enough quantity and quality of labile OM for NR. Besides, high concentration of LOI but a scarce abundance of DOC failed to drive NR. DNRA was only important in superficial samples with high contents of OM. Lastly, the high NRP of the re established wetland confirms that wetlands can be restored satisfactorily. PMID- 28004596 TI - Combination of photocatalytic and membrane distillation hybrid processes for reactive dyes treatment. AB - In this study, the degradation of azo dye solutions (Reactive Red 180 and Reactive Orange 16) of textile industry wastewater was investigated for using innovative hybrid process of photocatalytic and membrane distillation (MD) processes. Photocatalytic oxidation was conducted with semiconductor catalysts (ZnO and TiO2) and their mixture under UVA and UVC irradiation. More effective results were obtained under UVA at the initial stages of the reactions for both dye solutions. ZnO and TiO2 catalysts have given similar efficient results, but results with ZnO were better at initial stages. For the next stage, hybrid design of MD and photocatalytic processes was performed sequentially. Initially, the photocatalytic process was conducted for at least 1 h at initial values of 100 mg/L RR-180 dye solutions and 1 g/L ZnO catalyst loading under UVA irradiation and then treated solution was run through the distillation module at different temperatures (30 degrees C and 40 degrees C) and flow rates (210, 425, and 665 mL/min). Three types of membranes (polypropylene, polytetrafluoroethylene, and polyvinylidene fluoride) with different pore sizes (0.45 and 0.22 MUm) were used in the module. Increasing temperature on the side of treated solution and decreasing the temperature on the other side has increased the distillate efficiency. PMID- 28004597 TI - Functional proteomic insights in B-cell chronic lymphocytic leukemia. AB - INTRODUCTION: B cell chronic lymphocytic leukemia (B-CLL) is a hematological malignancy considered as the most common leukemia in the Western world. The understanding of B cell differentiation is crucial for the diagnosis, prognosis, and treatment of the disease. Areas covered: In this review, B-cell ontogeny and its relation with the CLL development, in combination with the proteomic approaches which could provide a deep characterization of the disease through the characterization of the cellular signaling pathways involved in the pathological cells is described. Expert commentary: Although conventional strategies (genome sequencing, morphology assays, and immunophenotyping by flow cytometry and/or immunochemistry) have allowed the establishment of the disease stage based on different parameters, it is still necessary to utilize novel approaches (e.g., proteomics) that have the potential to simultaneously analyze thousands of molecules to improve understanding of CLL. PMID- 28004598 TI - Natalizumab treatment of multiple sclerosis: new insights. AB - Natalizumab is a monoclonal antibody directed against the alpha4 chain of the very late activating antigen 4 and alpha4beta7 integrins, present on the leukocytes surface, used as monotherapy for the treatment of relapsing-remitting multiple sclerosis. It substantially reduces relapse rate and the accumulation of disability, but its use is associated with a very adverse event, that is the development of progressive multifocal leukoencephalopathy, a fatal demyelinating disease of the CNS, due to the lytic replication of the human polyomavirus JC. The main focus of the review is to describe the newest insights on natalizumab, its current use in the clinical practice, the natalizumab-treated patients' management and the risk stratification related to the progressive multifocal leukoencephalopathy development. PMID- 28004599 TI - Drug therapy for ectopic fat: myth or reality? PMID- 28004600 TI - Thoughts on investigational hedgehog pathway inhibitors for the treatment of cancer. PMID- 28004601 TI - Does the evidence support a survival benefit of albumin infusion in patients with cirrhosis undergoing large-volume paracentesis? PMID- 28004602 TI - Posterior hippocampal stroke presenting with transient global amnesia. AB - The acute onset of isolated amnesia is an intriguing challenge for neurologist, because the lack of associated signs can be misleading for diagnosis. The most common cause is transient global amnesia (TGA), a benign condition, but rarely it results from abuse of substance/alcohol or cerebrovascular diseases. In the latter, the brain region involved is the hippocampus. We describe a patient with presenting symptoms of TGA, but affected by an ischemic hippocampal stroke. The computed tomography angiography helped the etiologic diagnosis showing an hemodynamic stenosis of the posterior P2P segment. Interestingly, neuropsychological features were consistent with those found in patients suffering TGA. PMID- 28004603 TI - Asiatic acid attenuates pre-neoplastic lesions, oxidative stress, biotransforming enzymes and histopathological alterations in 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis. AB - Asiatic acid (AA), a pentacyclic triterpenoid, derived from the tropical medicinal plant Centella asiatica is known to exhibit numerous pharmacological properties. We hypothesized that AA will have chemopreventive potential against 1,2-dimethylhydrazine (DMH)-induced experimental colon carcinogenesis in male Wistar rats. Rats were arbitrarily divided into six groups. Group I rats were processed as control. Group II rats received AA (8 mg/kg b.w., p.o.) and groups III-VI rats received subcutaneous injections of DMH (20 mg/kg b.w.) once a week, for the first four weeks. In addition, groups IV-VI rats received AA at the doses of 2, 4 and 8 mg/kg b.w., respectively, for 16 weeks. Our results discovered that supplementation with AA to the DMH-exposed rats significantly decreased the incidence of polyps and Aberrant crypt foci (ACF) as compared to the DMH-alone exposed rats. Moreover, in the AA-supplemented DMH-exposed rats, we ascertained increased activities of the antioxidants and decreased levels of lipid peroxidation (LPO) in the liver and circulation and enhanced levels of both LPO and antioxidants in the colon, which were altered in the DMH-alone-exposed rats. Furthermore, we also observed altered activities of vitamins C and E and biotransforming enzymes in DMH-alone-exposed rats, which were reversed on AA supplementation. All the observations were supported by our histological findings. Thus, we can conclude that, AA could be used as an effective chemopreventive agent against DMH-induced colon carcinogenesis. PMID- 28004604 TI - Issues in contemporary and potential future molecular diagnostics for dengue. AB - INTRODUCTION: Dengue has been the most common arbovirus infection worldwide with 2.5 billion people living in over 100 endemic tropical and subtropical regions. Due to the high number of asymptomatic cases and the signs and symptoms being rather unspecific, dengue cases are often under-reported and might influence dengue surveillance programs. Therefore, a rapid, easy to use, inexpensive, and highly sensitive and specific diagnostic tool is essential for early and accurate diagnosis to ease the clinical management of patients as well as for the development of new interventions. Areas covered: This report discusses the contemporary dengue diagnostic tool, mainly from the aspect of molecular diagnosis where an overview of several nuclei acid amplification tests has been included. Potential molecular diagnostic tools such as biosensor and microarray are also discussed in this report. Expert commentary: Rapidness and accuracy in terms of sensitivity and specificity is imperative in dengue diagnosis for both clinical management and surveillance of dengue to ensure early treatment and corrective control measures can be carried out. In the next five years it is expected that there will be newer tests developed using not only the lateral flow techniques but more specifically biosensors and nanotechnology. These new technologies will have to be validated with the appropriate number and category of samples and to address the issue of cross-reactivity. PMID- 28004605 TI - Abstracts for Acta Clinica Belgica "25th meeting of the Belgian Endocrine Society". PMID- 28004606 TI - Abstracts for Acta Clinica Belgica "26th meeting of the Belgian Endocrine Society". PMID- 28004607 TI - Comparison of food colour regulations in the EU and the US: a review of current provisions. AB - This review describes the European Union and the US regulations applicable to food colours. Despite the different regulatory frameworks, the overall approach is similar, based on well-established risk-assessment procedures and risk management measures. However, differences impacting free movement of goods can be found in the details and implementation of regulations. Using additives approved only in the US or in the EU implies that producers aiming to export need to adjust their product composition to the export market. Failure to comply may give rise to claims of adulteration, misbranding or non-compliance and rejection at the border or recall from the market. A careful comparison of the level of protection provided by the two sets of regulations, the criteria of good manufacturing practice (GMP) inspections and the certification requirements could be key to aligning the rules and to negotiating mutual recognition agreements. This review provides an extensive overview of the similarities and differences in regulating food colours in the EU and the US. PMID- 28004608 TI - Modeling the within-host dynamics of cholera: bacterial-viral interaction. AB - Novel deterministic and stochastic models are proposed in this paper for the within-host dynamics of cholera, with a focus on the bacterial-viral interaction. The deterministic model is a system of differential equations describing the interaction among the two types of vibrios and the viruses. The stochastic model is a system of Markov jump processes that is derived based on the dynamics of the deterministic model. The multitype branching process approximation is applied to estimate the extinction probability of bacteria and viruses within a human host during the early stage of the bacterial-viral infection. Accordingly, a closed form expression is derived for the disease extinction probability, and analytic estimates are validated with numerical simulations. The local and global dynamics of the bacterial-viral interaction are analysed using the deterministic model, and the result indicates that there is a sharp disease threshold characterized by the basic reproduction number [Formula: see text]: if [Formula: see text], vibrios ingested from the environment into human body will not cause cholera infection; if [Formula: see text], vibrios will grow with increased toxicity and persist within the host, leading to human cholera. In contrast, the stochastic model indicates, more realistically, that there is always a positive probability of disease extinction within the human host. PMID- 28004609 TI - Occurrence of 3-monochloropropanediol esters and glycidyl esters in commercial infant formulas in the United States. AB - This work presents occurrence data for fatty acid esters of 3-chloro-1,2 propanediol (3-MCPD) and glycidol in 98 infant formula samples purchased in the United States. These contaminants are considered potentially carcinogenic and/or genotoxic, making their presence in refined oils and foods a potential health risk. Recently, attention has focused on methodology to quantify MCPD and glycidyl esters in infant formula for risk-assessment purposes. Occurrence data for 3-MCPD and glycidyl esters were produced using a procedure for extracting fat from infant formula and an LC-MS/MS method for analysing fat extracts for intact esters. Infant formulas were produced by seven manufacturers, five of which use palm oil and/or palm olein in their formulations. In formulas containing palm/palm olein, concentrations for bound 3-MCPD and glycidol ranged from 0.021 to 0.92 mg kg-1 (ppm) and from < LOQ to 0.40 mg kg-1 (ppm), respectively. Formulas not containing palm/palm olein, bound 3-MCPD and glycidol concentrations ranged from 0.072 to 0.16 mg kg-1 (ppm) and from 0.005 to 0.15 mg kg-1 (ppm), respectively. Although formulas from manufacturers A and G did not contain palm/palm olein, formulas from manufacturer E (containing palm olein) had the lowest concentrations of bound 3-MCPD and glycidol, demonstrating the effectiveness of industrial mitigation strategies. PMID- 28004610 TI - Endogenous level of acetic acid in yellowfin tuna (Thunnus albacares): a pilot study about a possible controversy on its residue nature. AB - A method based on headspace solid-phase microextraction (HS-SPME) followed by GC MS analysis was developed for the determination of underivatised acetic acid in fresh tuna fish muscle. Parameters such as the fibre selected and the extraction time and temperature were optimised and the linearity, detection limits and precision of the whole analytical procedure were assessed. The method was then applied to determine the acetic acid concentration in fresh yellowfin tuna muscles (Thunnus albacares) in order to evaluate the endogenous level and its variations during the shelf life under different storage conditions. A qualitative comparison was also made with variations in histamine levels to evaluate the possibility of the joint monitoring of acetic acid and histamine to identify fish stored in poor conditions. The caudal area always had a lower content of acetic acid than the ventral area, independent of the storage time and temperature. A difference was found between the 6- and 3-day time points and day 0 at a storage temperature of 8 degrees C and between the 6-day time point and day 0 at a storage temperature of 0 degrees C, independent of the anatomical area of the sampled tissue. The evaluation of acetic acid could represent an important approach in the field of food safety to detect the illicit use of acetic acid as an antibacterial preservative treatment or to eliminate the unpleasant smell of trimethylamine. PMID- 28004611 TI - Exploring the experiences of teenagers with cochlear implants. AB - OBJECTIVES: Teenage cochlear implant users' perceptions of deafness, surgery, fitting of the device and life as a cochlear implant wearer were explored in order to gain a more comprehensive understanding of teenagers' experiences of living with the device. METHODS: Semi-structured in-depth interviews were undertaken and analysed using thematic analysis. Ten teenagers aged 14-16 years with at least one cochlear implant were interviewed. RESULTS: Seven teenagers experienced great pre-operative anxiety and two reported significant post operative pain. Four of the teenagers described a mismatch between their expectations and the disappointing reality of adjusting to the device. However, all the teenagers reported an enhanced sense of well-being as a result of being able to interact more easily with their world around them. The teenagers differed in the extent to which they identified with the hearing and deaf world. DISCUSSION: Despite the early challenges, over time the teenagers experienced many functional and psychosocial benefits. Most felt their lives were now easier as a result of the cochlear implant(s). They described complex, flexible identities. CONCLUSIONS: By giving prominence to the teenagers' voices this study has added new knowledge concerning their experience of surgery. The findings also more fully revealed the challenges of adjusting to the device and the impact of having a cochlear implant on the teenagers' identities. Clinical recommendations are made to address the gaps in service highlighted by these findings. PMID- 28004612 TI - Erratum. PMID- 28004613 TI - The Role of EGFR-Met Interactions in the Pathogenesis of Glioblastoma and Resistance to Treatment. AB - Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is a devastating and intractable disease with a poor outcome. Aberrant receptor tyrosine kinase signaling is a key driver in gliomagenesis and resistance to treatment. EGFR gene amplification and mutations are an important genetic alteration in GBM resulting in increased expression of EGFR wild type (EGFRwt) as well as mutant oncogenic forms of the EGFR. EGFRvIII is the most common oncogenic mutant in GBM and is usually co-expressed with EGFRwt. EGFRvIII does not bind ligand and is constitutively active. Recent studies have also highlighted a key role for Met in gliomagenesis and the EGFR and Met may act in concert to promote the malignant phenotype. Met is transactivated by EGFRvIII and plays a key role in EGFRvIII-mediated resistance to targeted treatment. HGF, a Met ligand, is highly expressed in GBM. HGF and Met create an important autocrine signaling loop that promotes GBM invasion. In addition, HGF/Met is able to induce EGFR activation, leading to enhanced activation of oncogenic signaling in GBM. In this review, we discuss the evidence for EGFR and Met interaction in GBM and discuss the mechanisms and biological consequences of transactivation between the two kinases. Additionally, we discuss the therapeutic potential of targeting both EGFR and Met signaling for the treatment of GBM. PMID- 28004614 TI - Disrupting intergenerational continuity in harsh parenting: Self-control and a supportive partner. AB - Harsh, abusive, and rejecting behavior by parents toward their children is associated with increased risk for many developmental problems for youth. Children raised by harsh parents are also more likely to treat their own children harshly. The present study addresses conditions that would break this intergenerational cycle of harsh parenting. Data come from a three-generation study of a cohort of 290 adolescents (Generation 2 [G2], 52% female) grown to adulthood and their parents (Generation 1 [G1]). During adolescence, observers rated G1 harsh parenting to G2. Several years later observers rated G2 harsh parenting toward their oldest child (Generation 3 [G3]). Several adaptive systems fundamental to human resilience attenuate intergenerational continuity in harshness. G2 parents were relatively less harsh to G3 children (notwithstanding a history of harshness from G1) when G2's romantic partner (a) communicated positively with G2 and (b) had a good relationship with G3, and (c) when G2 was high on self-control. Interventions that target all of these protective factors may not only break but also reverse the intergenerational cycle of child maltreatment. PMID- 28004615 TI - Healthy eating patterns associated with acculturation, sex and BMI among Mexican Americans. AB - OBJECTIVE: Examine relationships of healthy and unhealthy dietary patterns with BMI, sex, age and acculturation among Mexican Americans. DESIGN: Cross-sectional. Participants completed culturally tailored Healthy and Unhealthy Eating Indices. Multivariable mixed-effect Poisson regression models compared food pattern index scores and dietary intake of specific foods by BMI, sex, age and acculturation defined by language preference and generational status. SETTING: Participants recruited from the Cameron County Hispanic Cohort study, Texas-Mexico border region, between 2008 and 2011. SUBJECTS: Mexican-American males and females aged 18-97 years (n 1250). RESULTS: Participants were primarily female (55.3 %), overweight or obese (85.7 %), preferred Spanish language (68.0 %) and first generation status (60.3 %). Among first-generation participants, bilingual participants were less likely to have a healthy eating pattern than preferred Spanish-speaking participants (rate ratio (RR)=0.79, P=0.0218). This association was also found in males (RR=0.81, P=0.0098). Preferred English-speaking females were less likely to consume healthy foods than preferred Spanish-speaking females (RR=0.84, P=0.0293). Among second-generation participants, preferred English speaking participants were more likely to report a higher unhealthy eating pattern than preferred Spanish-speaking participants (RR=1.23, P=0.0114). Higher unhealthy eating patterns were also found in females who preferred English v. females who preferred Spanish (RR=1.23, P=0.0107) or were bilingual (RR=1.26, P=0.0159). Younger, male participants were more likely to have a higher unhealthy eating pattern. BMI and diabetes status were not significantly associated with healthy or unhealthy eating patterns. CONCLUSIONS: Acculturation, age, sex and education are associated with healthy and unhealthy dietary patterns. Nutrition interventions for Mexican Americans should tailor approaches by these characteristics. PMID- 28004616 TI - Age- and time-dependent prevalence and incidence of hepatitis C virus infection in drug users in France, 2004-2011: model-based estimation from two national cross-sectional serosurveys. AB - Hepatitis C virus (HCV) infection is a public health issue worldwide. Injecting drug use remains the major mode of transmission in developed countries. Monitoring the HCV transmission dynamic over time is crucial, especially to assess the effect of harm reduction measures in drug users (DU). Our objective was to estimate the prevalence and incidence of HCV infection in DU in France using data from a repeated cross-sectional survey conducted in 2004 and 2011. Age and time-dependent HCV prevalence was estimated through logistic regression models adjusted for HIV serostatus or injecting practices. HCV incidence was estimated from a mathematical model linking prevalence and incidence. HCV prevalence decreased from 58.2% [95% confidence interval (CI) 49.7-66.8] in 2004 to 43.2% (95% CI 38.8-47.7) in 2011. HCV incidence decreased from 7.9/100 person years (95% CI 6.4-9.4) in 2004 to 4.4/100 person-years (95% CI 3.3-5.9) in 2011. HCV prevalence and incidence were significantly associated with age, calendar time, HIV serostatus and injecting practices. In 2011, the highest estimated incidence was in active injecting DU (11.2/100 person-years). Given the forthcoming objective of generalizing access to new direct antiviral agents for HCV infection, our results contribute to decision-making and policy development regarding treatment scale-up and disease prevention in the DU population. PMID- 28004617 TI - Hydrolysable tannin-based diet rich in gallotannins has a minimal impact on pig performance but significantly reduces salivary and bulbourethral gland size. AB - Tannins have long been considered 'anti-nutritional' factors in monogastric nutrition, shown to reduce feed intake and palatability. However, recent studies revealed that compared with condensed tannins, hydrolysable tannins (HT) appear to have far less impact on growth performance, but may be inhibitory to the total activity of caecal bacteria. This in turn could reduce microbial synthesis of skatole and indole in the hindgut of entire male pigs (EM). Thus, the objective of this study was to determine the impact of a group of dietary HT on growth performance, carcass traits and boar taint compounds of group housed EM. For the study, 36 Swiss Large White boars were assigned within litter to three treatment groups. Boars were offered ad libitum one of three finisher diets supplemented with 0 (C), 15 (T15) or 30 g/kg (T30) of HT from day 105 to 165 of age. Growth performance, carcass characteristics, boar taint compounds in the adipose tissue and cytochrome P450 (CYP) isoenzymes CYP2E1, CYP1A2 and CYP2A19 gene expression in the liver was assessed. Compared with C, feed efficiency but not daily gain and daily feed intake was lower (P<0.05) in T15 and T30 boars. Except for the percentage carcass weight loss during cooling, which tended (P<0.10) to be greater in T30 than C and T15, carcass characteristics were not affected by the diets. In line with the numerically lower androstenone level, bulbourethral and salivary glands of T30 boars were lighter (P<0.05) than of T15 with intermediate values for C. Indole level was lower (P<0.05) in the adipose tissue of T30 than C pigs with intermediate levels in T15. Skatole levels tended (P<0.10) to be lower in T30 and C than T15 pigs. Hepatic gene expression of CYP isoenzymes did not differ between-treatment groups, but was negatively correlated (P<0.05) with androstenone (CYP2E1 and CYP1A2), skatole (CYP2E1, CYP2A) and indole (CYP2A) level. In line with the numerically highest androstenone and skatole concentrations, boar taint odour but not flavour was detected by the panellists in loins from T15 compared with loins from C and T30 boars. These results provide evidence that HT affected metabolism of indolic compounds and androstenone and that they affected the development of accessory sex glands. However, the effects were too small to be detected by sensory evaluation. PMID- 28004618 TI - Organisation of services for managing ADHD. AB - There is considerable variation in practice, both between and with different countries in the management of attention deficit hyperactivity disorder (ADHD). Whilst there is no one optimal model of service organisation there are general principles of care that can be introduced to reduce this variability. There are frequent debates and discussions about which professional group is best placed to manage ADHD at different points in the life cycle. Who delivers care is however less important than ensuring that training schemes provide adequate exposure, training and experience to both the core and non-core skills required to provide a comprehensive package of care. Most evidence-based guidelines recommend a multi modal, multi-professional and multi-agency approach. Many also promote the use of both stepped care and shared care approaches for the management of ADHD. As most of those with ADHD continue to have ADHD-related problems into adulthood, it is important to consider how best to transition care into adulthood and think about who should deliver care to adults with ADHD. Young people with ADHD should generally be transferred to adult mental health services if they continue to have significant symptoms of ADHD or other coexisting conditions that require treatment. Unfortunately services for adults with ADHD remain relatively scarce across much of the world and some adult psychiatrists remain unsure of the diagnosis and uncertain about the appropriate use of ADHD medications in adults, but there is a strong case for increased services for adults. ADHD is on the one hand easy to treat; it is much more difficult to treat well. Although optimised care for ADHD requires routine measurement of outcomes, this often does not happen in routine clinical practice. Focusing on optimising symptoms and minimising adverse effects can significantly improve both short- and long-term outcomes. PMID- 28004619 TI - High occurrence and unusual serotype diversity of non-typhoidal Salmonella in non clinical niches, Angola. AB - Non-typhoidal Salmonella is an important burden, particularly in developing countries of the African region. We report for the first time in Angola, a sub Saharan African country with commercial/travel relationships with Europe, an unexpectedly high occurrence of Salmonella (n = 12/63, 19%) from a high diversity of sources, particularly farm and wild animals. The detection of diverse serotypes (n = 12), involving putative new S. enterica subsp. salamae serotypes, is also of note, reinforcing the need for a comprehensive surveillance in Angola critical to identify animal/food/environmental sources of salmonellosis with impact on animal health, local people, tourists and exported products. PMID- 28004620 TI - Policy for the complex burden of malnutrition in Africa: a research agenda to bring consumers and supply chains together. PMID- 28004621 TI - Augmentation of phenelzine with aripiprazole and quetiapine in a treatment resistant patient with psychotic unipolar depression: case report and literature review. AB - Irreversible monoamine oxidase inhibitor (MAOI) antidepressants have significant efficacy in treatment-resistant unipolar depression, but in some instances patients may not achieve remission. Among the adjunctive and augmentation strategies, certain second-generation antipsychotics (SGAs) have approval for inadequate responders to antidepressant therapy, including aripiprazole, brexpiprazole, and quetiapine, with lurasidone and the olanzapine/fluoxetine combination indicated for bipolar depression. Clinicians may eschew SGA options in part due to the limited literature on SGA-MAOI combinations, with only one published case involving aripiprazole, and none for olanzapine, lurasidone, or brexpiprazole. In addition to the limited publication history on SGA-MAOI treatment, clinicians may also be deterred by uncertainty regarding SGA mechanisms and the risk of serotonin syndrome or other adverse outcomes. This paper describes the case of a 54-year-old male with a history of psychotic unipolar depression treated with a combination of phenelzine, aripiprazole, and quetiapine, and reviews the 12 published cases of SGA-MAOI combination therapy with a focus on the pharmacological basis for serotonin syndrome, and the SGA mechanisms that should not be associated with a risk for this syndrome. PMID- 28004623 TI - New EMA report on paliperidone 3-month injections: taking clinical and policy decisions without an adequate evidence base. AB - Three-month long-acting paliperidone is a new, recently marketed, formulation of paliperidone, characterised by the longest available dosing interval among long acting antipsychotics. The clinical profile of 3-month long-acting paliperidone was recently summarised by the European Medicines Agency (EMA) in a public assessment report, released in April 2016. In this commentary, the main strengths and limitations of the EMA assessment report were appraised and discussed, in order to highlight possible implications for clinical practice, future research and regulatory practices for drug approval. PMID- 28004622 TI - Moving towards a reliable HIV incidence test - current status, resources available, future directions and challenges ahead. AB - In 2011 the Incidence Assay Critical Path Working Group reviewed the current state of HIV incidence assays and helped to determine a critical path to the introduction of an HIV incidence assay. At that time the Consortium for Evaluation and Performance of HIV Incidence Assays (CEPHIA) was formed to spur progress and raise standards among assay developers, scientists and laboratories involved in HIV incidence measurement and to structure and conduct a direct independent comparative evaluation of the performance of 10 existing HIV incidence assays, to be considered singly and in combinations as recent infection test algorithms. In this paper we report on a new framework for HIV incidence assay evaluation that has emerged from this effort over the past 5 years, which includes a preliminary target product profile for an incidence assay, a consensus around key performance metrics along with analytical tools and deployment of a standardized approach for incidence assay evaluation. The specimen panels for this evaluation have been collected in large volumes, characterized using a novel approach for infection dating rules and assembled into panels designed to assess the impact of important sources of measurement error with incidence assays such as viral subtype, elite host control of viraemia and antiretroviral treatment. We present the specific rationale for several of these innovations, and discuss important resources for assay developers and researchers that have recently become available. Finally, we summarize the key remaining steps on the path to development and implementation of reliable assays for monitoring HIV incidence at a population level. PMID- 28004624 TI - Intrauterine growth restriction increases circulating mitochondrial DNA and Toll like receptor 9 expression in adult offspring: could aerobic training counteract these adaptations? AB - It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-alpha expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-alpha levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-alpha levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF alpha among restricted rats. The cardiac TNF-alpha content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-alpha. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring. PMID- 28004625 TI - Pregnancy, perinatal and postpartum complications as determinants of postpartum depression: the Rhea mother-child cohort in Crete, Greece. AB - AIMS: Few epidemiological studies evaluated associations between perinatal complications and maternal mood at the early postpartum period and the findings are inconsistent. We aimed at investigating a wide range of complications during pregnancy, at delivery, and at the early postpartum period as determinants of postpartum depression (PPD) at 8 weeks postpartum. METHODS: A total of 1037 women who enrolled in the Rhea mother-child cohort in Crete, Greece participated in the present study. Information on pregnancy, perinatal and postpartum complications was obtained from clinical records or by questionnaires. Postpartum depressive symptoms were assessed at 8 weeks postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multivariable linear and logistic regression models were fit to estimate the association between pregnancy, perinatal and postpartum complications and maternal depressive symptoms, adjusting also for potential confounders. RESULTS: The prevalence of women with probable depression (EPDS score >= 13) was 13.6% at 8 weeks postpartum. Gestational hypertension and/or preeclampsia (beta coefficient 1.86, 95% CI: 0.32, 3.41) and breastfeeding difficulties (beta coefficient 0.77, 95% CI: 0.02, 1.53) were significantly associated with higher PPD symptoms. Sleep patterns during pregnancy, such as sleep deprivation (OR = 3.57, 95% CI: 1.91, 6.67) and snoring (OR = 1.81, 95% CI: 1.11, 2.93), and breastfeeding duration less than 2 months (OR = 1.77, 95% CI: 1.19, 2.64) were significantly associated with increase in the odds for PPD. Some other complications, such as unplanned pregnancy and hospitalisation during pregnancy were also associated with EPDS score, but these associations were explained by socio-demographic characteristics of the mother. CONCLUSIONS: We found that several pregnancy, perinatal and postpartum complications may have an adverse effect on maternal mood at the early postpartum period. These findings have considerable implications for developing effective prevention and early psychoeducational intervention strategies for women at risk of developing PPD. PMID- 28004627 TI - Making Universal Health Coverage a reality: bridging the gap between Global Mental Health and practical integration into local health systems. PMID- 28004626 TI - Treating mixed mania/hypomania: a review and synthesis of the evidence. AB - The DSM-5 incorporates a broad concept of mixed states and captured >=3 nonoverlapping symptoms of the opposite polarity using a "with mixed features" specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed. PMID- 28004628 TI - A Rare Infectious Cause of Transverse Myelitis. PMID- 28004629 TI - Manifestations of Tuberous Sclerosis Complex: The Experience of a Provincial Clinic. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a neurocutaneous disorder with a wide spectrum of manifestations. Recent consensus recommendations stress the importance of multidisciplinary management of children with TSC. The objective of this study was to examine the manifestations of TSC at a large referral centre to determine the care needs of this population. METHODS: A retrospective, systematic chart review was performed of children with TSC managed at British Columbia Children's Hospital. Patients were identified through epilepsy and clinical neurophysiology databases. RESULTS: The study population comprised 81 patients, born between 1987 and 2014, who were a median of 10 years (range, 0.2-23.2) at most recent follow-up. Epilepsy occurred in 91% of patients, including 32% with a history of infantile spasms. Nineteen patients underwent epilepsy surgery, nine (47%) of whom were seizure-free at most recent follow-up. Overall, 61% of epilepsy patients had been seizure-free for at least 1 year at the time of last follow-up. Neuropsychiatric disorders were diagnosed in 49% of children, with autism (25%), attention deficit hyperactivity order (19%) and anxiety (16%) being the most common. Cardiac rhabdomyomata occurred in 35% of children and renal angiomyolipomas were seen in 43%. A total of 91% had skin manifestations. CONCLUSION: This study outlines the multisystem manifestations of TSC, observed through a large pediatric referral center. Epilepsy and neuropsychiatric disorders are the major source of morbidity in this age group and provide many challenges to the treating clinician. Because a subset of the study population is still quite young, the prevalence of neuropsychiatric disorders is likely underestimated. PMID- 28004630 TI - Functional Magnetic Resonance Imaging for Preoperative Planning in Brain Tumour Surgery. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) is being increasingly used for the preoperative evaluation of patients with brain tumours. METHODS: The study is a retrospective chart review investigating the use of clinical fMRI from 2002 through 2013 in the preoperative evaluation of brain tumour patients. Baseline demographic and clinical data were collected. The specific fMRI protocols used for each patient were recorded. RESULTS: Sixty patients were identified over the 12-year period. The tumour types most commonly investigated were high-grade glioma (World Health Organization grade III or IV), low-grade glioma (World Health Organization grade II), and meningioma. Most common presenting symptoms were seizures (69.6%), language deficits (23.2%), and headache (19.6%). There was a predominance of left hemispheric lesions investigated with fMRI (76.8% vs 23.2% for right). The most commonly involved lobes were frontal (64.3%), temporal (33.9%), parietal (21.4%), and insular (7.1%). The most common fMRI paradigms were language (83.9%), motor (75.0%), sensory (16.1%), and memory (10.7%). The majority of patients ultimately underwent a craniotomy (75.0%), whereas smaller groups underwent stereotactic biopsy (8.9%) and nonsurgical management (16.1%). Time from request for fMRI to actual fMRI acquisition was 3.1+/-2.3 weeks. Time from fMRI acquisition to intervention was 4.9+/-5.5 weeks. CONCLUSIONS: We have characterized patient demographics in a retrospective single-surgeon cohort undergoing preoperative clinical fMRI at a Canadian centre. Our experience suggests an acceptable wait time from scan request to scan completion/analysis and from scan to intervention. PMID- 28004631 TI - National Perspectives on the Training of Neurosurgery Residents in Stereotactic Radiosurgery. AB - BACKGROUND: Despite the critical role played by neurosurgeons in performing radiosurgery, neurosurgery residents in Canada have limited exposure to radiosurgery during their training. A survey of neurosurgery residents and faculty along with radiation oncology faculty was conducted to analyze perspectives regarding incorporating formal radiosurgery training into the neurosurgery residency curriculum Methods: An online survey platform was employed. Descriptive statistics were used to summarize center and respondent characteristics. Categorical variables were compared using odds ratios and corresponding 95% confidence intervals. The chi-squared test was utilized to assess statistical significance. A value of p<0.05 was considered significant Results: The response rate was 31% (119/381); 87% (102/119) of respondents were from the neurosurgical specialty and 13% (17/119) from radiation oncology. Some 46% of residents (18/40) were "very uncomfortable" with radiosurgery techniques, and 57% of faculty (42/73) believed that dedicated radiosurgery training would be beneficial though impractical. No respondents felt that "no training" would be beneficial. A total of 46% of residents (19/41) felt that this training would be beneficial and that time should be taken away from other rotations, if needed, while 58% of faculty (42/73) and 75% (28/41) of residents believed that either 1 or 1-3 months of time dedicated to training in radiosurgery would suffice Conclusions: Canadian neurosurgeons are actively involved in radiosurgery. Despite residents anticipating a greater role for radiosurgery in their future, they are uncomfortable with the practice. With the indications for radiosurgery expanding, this training gap can have serious adverse consequences for patients. Considerations regarding the incorporation and optimal duration of dedicated radiosurgery training into the Canadian neurosurgery residency curriculum are necessary. PMID- 28004632 TI - Adjacent Segment Pathology: Progressive Disease Course or a Product of Iatrogenic Fusion? AB - OBJECTIVE: Cervical spine clinical adjacent segment pathology (CASP) has a reported 3% annual incidence and 26% ten-year prevalence. Its pathophysiology remains controversial, whether due to mechanical stress of a fusion segment on adjacent levels or due to patient propensity to develop progressive degenerative change. We investigate this relationship by comparing prevalence of CASP in traumatic and spondylotic patient cohorts. METHOD: A retrospective review of traumatic cervical spine fusion cases performed by the local group of neurosurgeons from 2004-2008 was completed. Surgery for CASP and presence of radiological adjacent segment pathology (RASP) were identified by telephone and electronic medical record (EMR) review, and compared to those in patients having elective cervical fusion for degenerative disease. RESULTS: There was a higher proportion of males (50/100 vs. 37/46, p0.05). Mean follow-up times were different (6.4 years in the trauma group, 7.1 years in the degenerative group; p<0.01), although this was not thought to be clinically significant. The degenerative group was found to have a significantly higher reoperation rate for CASP (10/100 vs. 0/46, p=0.031, Fisher's Exact Test), and rate of RASP (20/100 vs. 1/32, p=0.025) Conclusion: This is the only cohort study to our knowledge comparing surgery for CASP in trauma patients to those with degenerative disease. A higher rate of repeat surgery in degenerative disease patients was found. This suggests that CASP is more related to patient factors predisposing to progressive degenerative disease and not increased mechanical stress. PMID- 28004633 TI - Endovascular Revascularization of a Symptomatic Common Carotid Artery Occlusion. AB - Although the common carotid artery is the second most common site for extracranial carotid artery stenosis, complete symptomatic occlusion in the absence of devastating stroke is rare. We present a case of complete common carotid artery occlusion failing medical management and requiring endovascular intervention. The clinical presentation, diagnostic investigations, and management of complete carotid artery occlusions are discussed. PMID- 28004634 TI - Polymorphisms in K13, pfcrt, pfmdr1, pfdhfr, and pfdhps in parasites isolated from symptomatic malaria patients in Burkina Faso. AB - BACKGROUND: The emergence of resistance to artemisinin derivatives in western Cambodia is threatening to revert the recent advances made toward global malaria control and elimination. Known resistance-mediating polymorphisms in the K13, pfcrt, pfmdr1, pfdhfr, and pfdhps genes are of greatest importance for monitoring the spread of antimalarial drug resistance. METHODS: Samples for the present study were collected from 244 patients with uncomplicated malaria in health centers of Bobo-Dioulasso, Burkina Faso. Blood sample was collected on filter paper before the subject received any treatment. The parasite DNA was then extracted and amplified by Polymerase Chain Reaction (PCR) to evaluate the prevalence of polymorphism of pfcrtK76T, pfmdr1 (N86Y, Y184F), and pfdhps (A437G, K540E). The K13 gene polymorphism was analyzed by nested PCR followed by sequencing. RESULTS: The overall results showed 2.26% (5/221) of K13 synonymous mutant alleles (two C469C, one Y493Y, one G496G, and one V589V), 24.78%, 19.58%, 68.75%, 60.9%, 53.7%, 63.8%, and 64.28%, respectively, for mutant pfcrt 76T, pfmdr1-86Y, pfmdr1-184F, pfdhfr51I, pfdhfr59R, pfdhfr108N, and pfdhps 437G. We did not report any mutation at codon 540 of pfdhps. CONCLUSION: These results provide baseline prevalence of known drug resistance polymorphisms and suggest that artemisinin combination therapies may retain good efficacy in the treatment of uncomplicated malaria in Burkina Faso. PMID- 28004636 TI - LIGHTing tumor up for checkpoint blockade. PMID- 28004635 TI - Host specificity and the structure of helminth parasite communities of fishes in a Neotropical river in Mexico. AB - In a tropical locality of Rio La Antigua, Veracruz, Mexico, 11 fish species, represented by 244 individual fish from six freshwater fish families living sympatrically and synchronically, were examined for helminth parasites. A total of 36 taxa of helminths were recorded, 24 autogenic and 12 allogenic forms, including 6 monogeneans, 14 trematodes, 1 cestode, and 15 nematodes. Most helminth taxa were recovered for 10/11 of the component communities we analyzed. The results contribute empirical evidence that host specificity is an important force in the development of helminth communities of freshwater fishes. Each fish family has their own set of parasites, host species belonging to the same taxon share parasite species. High component community similarity among related host species was recorded, demonstrated by high prevalence and abundance, as well as dominance, of autogenic specialist species in each component community. Most autogenic helminth species are numerically and reproductively successful in relatively few host species. Autogenic helminths common in one host species are not common in others. Our findings give empirical support to the idea that low levels of sharing of parasites favor animal coexistence and high species richness, because large phylogenetic differences allow potentially competing animals to consume the same resources without being sensitive of another's parasites. PMID- 28004637 TI - Task-space separation principle: a force-field approach to motion planning for redundant manipulators. AB - In this work, we address human-like motor planning in redundant manipulators. Specifically, we want to capture postural synergies such as Donders' law, experimentally observed in humans during kinematically redundant tasks, and infer a minimal set of parameters to implement similar postural synergies in a kinematic model. For the model itself, although the focus of this paper is to solve redundancy by implementing postural strategies derived from experimental data, we also want to ensure that such postural control strategies do not interfere with other possible forms of motion control (in the task-space), i.e. solving the posture/movement problem. The redundancy problem is framed as a constrained optimization problem, traditionally solved via the method of Lagrange multipliers. The posture/movement problem can be tackled via the separation principle which, derived from experimental evidence, posits that the brain processes static torques (i.e. posture-dependent, such as gravitational torques) separately from dynamic torques (i.e. velocity-dependent). The separation principle has traditionally been applied at a joint torque level. Our main contribution is to apply the separation principle to Lagrange multipliers, which act as task-space force fields, leading to a task-space separation principle. In this way, we can separate postural control (implementing Donders' law) from various types of tasks-space movement planners. As an example, the proposed framework is applied to the (redundant) task of pointing with the human wrist. Nonlinear inverse optimization (NIO) is used to fit the model parameters and to capture motor strategies displayed by six human subjects during pointing tasks. The novelty of our NIO approach is that (i) the fitted motor strategy, rather than raw data, is used to filter and down-sample human behaviours; (ii) our framework is used to efficiently simulate model behaviour iteratively, until it converges towards the experimental human strategies. PMID- 28004638 TI - Infrared phonons as a probe of spin-liquid states in herbertsmithite ZnCu3(OH)6Cl2. AB - We report on temperature dependence of the infrared reflectivity spectra of a single crystalline herbertsmithite in two polarizations-parallel and perpendicular to the kagome plane of Cu atoms. We observe anomalous broadening of the low frequency phonons possibly caused by fluctuations in the exotic dynamical magnetic order of the spin liquid. PMID- 28004639 TI - Human breath metabolomics using an optimized non-invasive exhaled breath condensate sampler. AB - Exhaled breath condensate (EBC) analysis is a developing field with tremendous promise to advance personalized, non-invasive health diagnostics as new analytical instrumentation platforms and detection methods are developed. Multiple commercially-available and researcher-built experimental samplers are reported in the literature. However, there is very limited information available to determine an effective breath sampling approach, especially regarding the dependence of breath sample metabolomic content on the collection device design and sampling methodology. This lack of an optimal standard procedure results in a range of reported results that are sometimes contradictory. Here, we present a design of a portable human EBC sampler optimized for collection and preservation of the rich metabolomic content of breath. The performance of the engineered device is compared to two commercially available breath collection devices: the RTubeTM and TurboDECCS. A number of design and performance parameters are considered, including: condenser temperature stability during sampling, collection efficiency, condenser material choice, and saliva contamination in the collected breath samples. The significance of the biological content of breath samples, collected with each device, is evaluated with a set of mass spectrometry methods and was the primary factor for evaluating device performance. The design includes an adjustable mass-size threshold for aerodynamic filtering of saliva droplets from the breath flow. Engineering an inexpensive device that allows efficient collection of metalomic-rich breath samples is intended to aid further advancement in the field of breath analysis for non-invasive health diagnostic. EBC sampling from human volunteers was performed under UC Davis IRB protocol 63701-3 (09/30/2014-07/07/2017). PMID- 28004640 TI - Designing synthetic RNA for delivery by nanoparticles. AB - The rapid development of synthetic biology and nanobiotechnology has led to the construction of various synthetic RNA nanoparticles of different functionalities and potential applications. As they occur naturally, nucleic acids are an attractive construction material for biocompatible nanoscaffold and nanomachine design. In this review, we provide an overview of the types of RNA and nucleic acid's nanoparticle design, with the focus on relevant nanostructures utilized for gene-expression regulation in cellular models. Structural analysis and modeling is addressed along with the tools available for RNA structural prediction. The functionalization of RNA-based nanoparticles leading to prospective applications of such constructs in potential therapies is shown. The route from the nanoparticle design and modeling through synthesis and functionalization to cellular application is also described. For a better understanding of the fate of targeted RNA after delivery, an overview of RNA processing inside the cell is also provided. PMID- 28004641 TI - Understanding spatial and temporal patterning of astrocyte calcium transients via interactions between network transport and extracellular diffusion. AB - Astrocytes form interconnected networks in the brain and communicate via calcium signaling. We investigate how modes of coupling between astrocytes influence the spatio-temporal patterns of calcium signaling within astrocyte networks and specifically how these network interactions promote coordination within this group of cells. To investigate these complex phenomena, we study reduced cultured networks of astrocytes and neurons. We image the spatial temporal patterns of astrocyte calcium activity and quantify how perturbing the coupling between astrocytes influences astrocyte activity patterns. To gain insight into the pattern formation observed in these cultured networks, we compare the experimentally observed calcium activity patterns to the patterns produced by a reduced computational model, where we represent astrocytes as simple units that integrate input through two mechanisms: gap junction coupling (network transport) and chemical release (extracellular diffusion). We examine the activity patterns in the simulated astrocyte network and their dependence upon these two coupling mechanisms. We find that gap junctions and extracellular chemical release interact in astrocyte networks to modulate the spatiotemporal patterns of their calcium dynamics. We show agreement between the computational and experimental findings, which suggests that the complex global patterns can be understood as a result of simple local coupling mechanisms. PMID- 28004642 TI - Linearity of electrical impedance tomography during maximum effort breathing and forced expiration maneuvers. AB - Electrical impedance tomography (EIT) provides global and regional information about ventilation by means of relative changes in electrical impedance measured with electrodes placed around the thorax. In combination with lung function tests, e.g. spirometry and body plethysmography, regional information about lung ventilation can be achieved. Impedance changes strictly correlate with lung volume during tidal breathing and mechanical ventilation. Initial studies presumed a correlation also during forced expiration maneuvers. To quantify the validity of this correlation in extreme lung volume changes during forced breathing, a measurement system was set up and applied on seven lung-healthy volunteers. Simultaneous measurements of changes in lung volume using EIT imaging and pneumotachography were obtained with different breathing patterns. Data was divided into a synchronizing phase (spontaneous breathing) and a test phase (maximum effort breathing and forced maneuvers). The EIT impedance changes correlate strictly with spirometric data during slow breathing with increasing and maximum effort ([Formula: see text]) and during forced expiration maneuvers ([Formula: see text]). Strong correlations in spirometric volume parameters [Formula: see text] ([Formula: see text]), [Formula: see text]/FVC ([Formula: see text]), and flow parameters PEF, [Formula: see text], [Formula: see text], [Formula: see text] ([Formula: see text]) were observed. According to the linearity during forced expiration maneuvers, EIT can be used during pulmonary function testing in combination with spirometry for visualisation of regional lung ventilation. PMID- 28004643 TI - Electrically driven magnetic antenna based on multiferroic composites. AB - We suggest and demonstrate via large scale numerical simulations an electrically operated spin-wave inducer based on composite multiferroic junctions. Specifically, we consider an interfacially coupled ferromagnetic/ferroelectric structure that emits controllably spin waves in the ferromagnets if the ferroelectric polarization is poled by an external electric field. The roles of geometry and material properties are discussed. PMID- 28004644 TI - Enhancing performance of a motor imagery based brain-computer interface by incorporating electrical stimulation-induced SSSEP. AB - OBJECTIVE: We proposed a novel simultaneous hybrid brain-computer interface (BCI) by incorporating electrical stimulation into a motor imagery (MI) based BCI system. The goal of this study was to enhance the overall performance of an MI based BCI. In addition, the brain oscillatory pattern in the hybrid task was also investigated. APPROACH: 64-channel electroencephalographic (EEG) data were recorded during MI, selective attention (SA) and hybrid tasks in fourteen healthy subjects. In the hybrid task, subjects performed MI with electrical stimulation which was applied to bilateral median nerve on wrists simultaneously. MAIN RESULTS: The hybrid task clearly presented additional steady-state somatosensory evoked potential (SSSEP) induced by electrical stimulation with MI-induced event related desynchronization (ERD). By combining ERD and SSSEP features, the performance in the hybrid task was significantly better than in both MI and SA tasks, achieving a ~14% improvement in total relative to the MI task alone and reaching ~89% in mean classification accuracy. On the contrary, there was no significant enhancement obtained in performance while separate ERD feature was utilized in the hybrid task. In terms of the hybrid task, the performance using combined feature was significantly better than using separate ERD or SSSEP feature. SIGNIFICANCE: The results in this work validate the feasibility of our proposed approach to form a novel MI-SSSEP hybrid BCI outperforming a conventional MI-based BCI through combing MI with electrical stimulation. PMID- 28004645 TI - Pressure-induced superconductivity in the giant Rashba system BiTeI. AB - At ambient pressure, BiTeI exhibits a giant Rashba splitting of the bulk electronic bands. At low pressures, BiTeI undergoes a transition from trivial insulator to topological insulator. At still higher pressures, two structural transitions are known to occur. We have carried out a series of electrical resistivity and AC magnetic susceptibility measurements on BiTeI at pressure up to ~40 GPa in an effort to characterize the properties of the high-pressure phases. A previous calculation found that the high-pressure orthorhombic P4/nmm structure BiTeI is a metal. We find that this structure is superconducting with T c values as high as 6 K. AC magnetic susceptibility measurements support the bulk nature of the superconductivity. Using electronic structure and phonon calculations, we compute T c and find that our data is consistent with phonon mediated superconductivity. PMID- 28004646 TI - Exhaled breath condensate pH and cysteinyl leukotriens in patients with chronic cough secondary to acid gastroesophageal reflux. AB - Chronic cough is one of the most common clinical problems and it may be secondary to different stimuli and diseases, including low-level physical and chemical stimulation of the esophageal-bronchial reflex, suggestive of cough-reflex hyperresponsiveness, in patients with gastroesophageal reflux; however, it is still debated whether gastroesophageal reflux could induce airway inflammation and acidification. The aim of this study was to investigate airway pH and cysteynil-leukotrienes (Cys-LTs) concentration (a marker of airway inflammation) in exhaled breath condensate (EBC). Patients with chronic cough and for which all known causes, excluding gastroesophageal reflux, had been investigated and ruled out, were enrolled in the study. All patients underwent 24 h pH monitoring, and EBC was collected to assess pH and Cys-LTs concentration. Forty-five patients were included in the study and those with gastroesophageal reflux had significantly lower EBC-pH and higher concentration of EBC-Cys-LTs. There was a linear inverse correlation between EBC-pH values and EBC-Cys-LTs logarithmically transformed, and a multivariate analysis confirmed that the only significant determinat variable of EBC-Cys-LTs was the presence of gastroesophageal reflux. This study adds knowledge on possible mechanisms related to chronic cough associated with gastroesophageal reflux, which seems to be strictly dependent on airway acidification and the production of Cys-LTs, therefore suggesting an underlying neurogenic inflammation with tachykinins involvement. PMID- 28004647 TI - Lichen nitidus presenting with trachyonychia. PMID- 28004648 TI - Superficial granulomatous pyoderma: A great mimicker. PMID- 28004649 TI - Dermoscopy of Biett's sign and differential diagnosis with annular maculo-papular rashes with scaling. PMID- 28004651 TI - Autophagy: A brief overview in perspective of dermatology. AB - Autophagy, literally meaning "self-eating," is an intracellular catabolic process of delivering cytosol and/or its specific content to the lysosomes for degradation.The resulting macromolecular constituents are recycled and utilized again by the cells. Basal level autophagy plays an important role in cellular homeostasis through the elimination of the old or damaged organelles, as well as aggregated intracellular proteins. Autophagy refers to sequestration of intact organelles along with a portion of cytosol, into a double-or multi-membrane structure known as phagophore, which elongates, and after closure, forms a vesicular structure known as the autophagosome. Subsequently, the mature autophagosome fuses with a lysosome, thereby forming a single membrane structure, an autolysosome. Autophagy plays a critical role in inflammation, autoimmunity and cellular differentiation. Skin serves as the first line of defense against a variety of environmental insults and autophagy is thought to be a form of an endogenous defense mechanism against such environmental derangements. Autophagy has been linked with keratinocyte differentiation and melanocyte survival, as well as with the pathogenesis of diverse skin disorders including systemic lupus erythematosus, systemic sclerosis, psoriasis, vitiligo, infectious skin diseases and cancer. Autophagy has been one of the most studied phenomena in cell biology and pathophysiology, and given its broad clinical implications, has become a major target for drug discovery. The last decade has seen a substantial upsurge in autophagy-related research and publications; still, the dermatology literature appears to be less initiated. Autophagy will probably change our understanding of dermatological disorders/medicines. Hence, a basic knowledge of autophagy is a prerequisite to understand the developments in the field of autophagy-related research. PMID- 28004652 TI - Cutaneous changes in internal malignancy: Study from a tertiary care center. AB - BACKGROUND: A wide variety of systemic diseases and internal malignancies have cutaneous manifestations. In the context of internal malignancy, many cutaneous changes are highly specific to the underlying malignancy, while other changes are nonspecific. Some changes are also due to the modalities employed in the treatment of malignancies. METHODS: Two hundred and fifty patients who were diagnosed with internal malignancy and who were attending the department of radiation oncology, were evaluated at the Department of Dermatology, Sexually Transmitted Diseases and Leprosy of Government Medical College, Srinagar. The study was conducted over a period of 5 months. Relevant investigations, wherever needed, were carried out. RESULTS: Among the 250 cases examined, nonspecific cutaneous changes were seen in 39 (15.6%) cases, whereas specific skin lesions in the form of cutaneous metastases were seen in two (0.8%) patients. Nail changes and hair changes were also seen in some patients. LIMITATIONS: As this was a cross-sectional study and most of the patients were lost to follow up, we could not assess the outcome of the dermatological changes seen in the affected patients. CONCLUSION: Many dermatological changes are noticed early in the course of malignancy, reflecting a strong association of the cutaneous change with malignancy. Few manifestations occur late in the course of the disease, indicating dissemination or immunosuppression. Some changes reflect radiation induced or chemotherapy-induced toxicity, indicating the need for treatment modifications. PMID- 28004653 TI - Evidence for ion migration in hybrid perovskite solar cells with minimal hysteresis. AB - Ion migration has been proposed as a possible cause of photovoltaic current voltage hysteresis in hybrid perovskite solar cells. A major objection to this hypothesis is that hysteresis can be reduced by changing the interfacial contact materials; however, this is unlikely to significantly influence the behaviour of mobile ionic charge within the perovskite phase. Here, we show that the primary effects of ion migration can be observed regardless of whether the contacts were changed to give devices with or without significant hysteresis. Transient optoelectronic measurements combined with device simulations indicate that electric-field screening, consistent with ion migration, is similar in both high and low hysteresis CH3NH3PbI3 cells. Simulation of the photovoltage and photocurrent transients shows that hysteresis requires the combination of both mobile ionic charge and recombination near the perovskite-contact interfaces. Passivating contact recombination results in higher photogenerated charge concentrations at forward bias which screen the ionic charge, reducing hysteresis. PMID- 28004655 TI - The role of space-based observation in understanding and responding to active tectonics and earthquakes. PMID- 28004654 TI - Hepcidin inhibits Smad3 phosphorylation in hepatic stellate cells by impeding ferroportin-mediated regulation of Akt. AB - Hepatic stellate cell (HSC) activation on liver injury facilitates fibrosis. Hepatokines affecting HSCs are largely unknown. Here we show that hepcidin inhibits HSC activation and ameliorates liver fibrosis. We observe that hepcidin levels are inversely correlated with exacerbation of fibrosis in patients, and also confirm the relationship in animal models. Adenoviral delivery of hepcidin to mice attenuates liver fibrosis induced by CCl4 treatment or bile duct ligation. In cell-based assays, either hepcidin from hepatocytes or exogenous hepcidin suppresses HSC activation by inhibiting TGFbeta1-mediated Smad3 phosphorylation via Akt. In activated HSCs, ferroportin is upregulated, which can be prevented by hepcidin treatment. Similarly, ferroportin knockdown in HSCs prohibits TGFbeta1-inducible Smad3 phosphorylation and increases Akt phosphorylation, whereas ferroportin over-expression has the opposite effect. HSC specific ferroportin deletion also ameliorates liver fibrosis. In summary, hepcidin suppresses liver fibrosis by impeding TGFbeta1-induced Smad3 phosphorylation in HSCs, which depends on Akt activated by a deficiency of ferroportin. PMID- 28004656 TI - Co-delivery of indoleamine 2,3-dioxygenase prevents loss of expression of an antigenic transgene in dystrophic mouse muscles. AB - A significant problem affecting gene therapy approaches aiming at achieving long term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial beta-galactosidase, with an immunosuppressive factor, indoleamine 2,3 dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy. This treatment prevented loss of expression of the transgene concomitant with significantly elevated expression of T-regulatory (Treg) markers in the IDO1-expressing muscles. Moreover, co-expression of IDO1 resulted in reduced serum levels of anti-beta-gal antibodies. These data indicate that co expression of genes encoding immunomodulatory enzymes controlling kynurenine pathways provide a viable strategy for preventing loss of transgenes targeted into dystrophic muscles with pre-existing inflammation. PMID- 28004658 TI - Sheehan syndrome. PMID- 28004657 TI - Predictors of elevational biodiversity gradients change from single taxa to the multi-taxa community level. AB - The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities. PMID- 28004659 TI - Erratum: Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells. PMID- 28004660 TI - Corrigendum: CryoEM structure of the Methanospirillum hungatei archaellum reveals structural features distinct from the bacterial flagellum and type IV pilus. PMID- 28004662 TI - 3. Quantum Satellites. PMID- 28004663 TI - The Brainy Big Cats. PMID- 28004661 TI - Atomic-level insights in optimizing reaction paths for hydroformylation reaction over Rh/CoO single-atom catalyst. AB - Rh-based heterogeneous catalysts generally have limited selectivity relative to their homogeneous counterparts in hydroformylation reactions despite of the convenience of catalyst separation in heterogeneous catalysis. Here, we develop CoO-supported Rh single-atom catalysts (Rh/CoO) with remarkable activity and selectivity towards propene hydroformylation. By increasing Rh mass loading, isolated Rh atoms switch to aggregated clusters of different atomicity. During the hydroformylation, Rh/CoO achieves the optimal selectivity of 94.4% for butyraldehyde and the highest turnover frequency number of 2,065 h-1 among the obtained atomic-scale Rh-based catalysts. Mechanistic studies reveal that a structural reconstruction of Rh single atoms in Rh/CoO occurs during the catalytic process, facilitating the adsorption and activation of reactants. In kinetic view, linear products are determined as the dominating products by analysing reaction paths deriving from the two most stable co-adsorbed configurations. As a bridge of homogeneous and heterogeneous catalysis, single atom catalysts can be potentially applied in other industrial reactions. PMID- 28004664 TI - Teen Takes on Drought. PMID- 28004665 TI - When Medical Tests Mislead. PMID- 28004666 TI - 2016 World Changing Ideas. PMID- 28004667 TI - Is the Rise in Twin Births Cresting? PMID- 28004668 TI - Science Has a Gender Problem. PMID- 28004669 TI - The Evolution of Myths. PMID- 28004671 TI - Your Pun-Divided Attention. PMID- 28004672 TI - 4. Ingestible Micro Robots. PMID- 28004673 TI - Born This Way. PMID- 28004675 TI - 50, 100 &150 Years Ago. PMID- 28004676 TI - 6. Cool Clothes. PMID- 28004678 TI - 5. Poverty-Predicting Software. PMID- 28004677 TI - 8. Sight-Reading Software. PMID- 28004679 TI - 10. Super-Molecules from Superatoms. PMID- 28004680 TI - Solar System Smashup. PMID- 28004681 TI - Bringing Up Baby, Helping the Economy. PMID- 28004683 TI - The Milky Way, Transformed. PMID- 28004682 TI - 9. Paper Diagnostics That Cost Pennies. PMID- 28004684 TI - Surge Protector. PMID- 28004685 TI - HIV's Achilles' Heel. PMID- 28004686 TI - Quick Hits. PMID- 28004687 TI - P.U. to Cu. PMID- 28004688 TI - The Looming Threat of Factory Superbugs. PMID- 28004689 TI - Organelle Overhaul. PMID- 28004690 TI - The Permafrost Prediction. PMID- 28004691 TI - The Plight of the Celebrity Scientist. PMID- 28004692 TI - Obama's Conservation Legacy. PMID- 28004693 TI - One's True Nature. PMID- 28004694 TI - Hope Springs Eternal for Easy Access to Water on Europa. PMID- 28004695 TI - 2. New Antibiotics from Scratch. PMID- 28004697 TI - 7. The Ultimate virus fighter. PMID- 28004698 TI - 1. Carbon-Breathing Batteries. PMID- 28004699 TI - Recommended. PMID- 28004700 TI - Resistance Is Futile. PMID- 28004701 TI - Top-down modulation of olfactory-guided behaviours by the anterior olfactory nucleus pars medialis and ventral hippocampus. AB - Olfactory processing is thought to be actively modulated by the top-down input from cortical regions, but the behavioural function of these signals remains unclear. Here we find that cortical feedback from the anterior olfactory nucleus pars medialis (mAON) bidirectionally modulates olfactory sensitivity and olfaction-dependent behaviours. To identify a limbic input that tunes this mAON switch, we further demonstrate that optogenetic stimulation of ventral hippocampal inputs to the mAON is sufficient to alter olfaction-dependent behaviours. PMID- 28004702 TI - High-throughput SRCD using multi-well plates and its applications. AB - The sample compartment for high-throughput synchrotron radiation circular dichroism (HT-SRCD) has been developed to satisfy an increased demand of protein characterisation in terms of folding and binding interaction properties not only in the traditional field of structural biology but also in the growing research area of material science with the potential to save time by 80%. As the understanding of protein behaviour in different solvent environments has increased dramatically the development of novel functions such as recombinant proteins modified to have different functions from harvesting solar energy to metabolonics for cleaning heavy and metal and organic molecule pollutions, there is a need to characterise speedily these system. PMID- 28004703 TI - Hidden Side Effects. PMID- 28004704 TI - Keep Hospitals Weapons-Free. PMID- 28004705 TI - Tangled Up in Spacetime. PMID- 28004706 TI - Heart Therapy. PMID- 28004709 TI - When Facts Backfire. PMID- 28004708 TI - 50, 100 &150 Years Ago. PMID- 28004710 TI - Lab-Built Brains. PMID- 28004712 TI - STDs on the Up. PMID- 28004711 TI - Your E-mail Password Will Never Be Safe. PMID- 28004713 TI - Data Deliver in the Clutch. PMID- 28004715 TI - Letters. PMID- 28004714 TI - Let NASA Take Flight. PMID- 28004716 TI - Bats in the Bronx. PMID- 28004717 TI - Telescopic Tag Team. PMID- 28004718 TI - What's Next for Science? PMID- 28004720 TI - Taking Wing. PMID- 28004721 TI - Whose Tools Are These? PMID- 28004722 TI - The Remarkable Timing of Seals. PMID- 28004723 TI - The Case for Robot Disobedience. PMID- 28004724 TI - Wildlife Warrior. PMID- 28004725 TI - Veggies with Vision. PMID- 28004726 TI - Top Air Polluters. PMID- 28004727 TI - Cold Comfort. PMID- 28004728 TI - Animal CSI. PMID- 28004729 TI - Could a Special Diet Replace Chemotherapy? PMID- 28004730 TI - Arterial waveform parameters in a large, population-based sample of adults: relationships with ethnicity and lifestyle factors. AB - Little is known about how aortic waveform parameters vary with ethnicity and lifestyle factors. We investigated these issues in a large, population-based sample. We carried out a cross-sectional analysis of 4798 men and women, aged 50 84 years from Auckland, New Zealand. Participants were 3961 European, 321 Pacific, 266 Maori and 250 South Asian people. We assessed modifiable lifestyle factors via questionnaires, and measured body mass index (BMI) and brachial blood pressure (BP). Suprasystolic oscillometry was used to derive aortic pressure, from which several haemodynamic parameters were calculated. Heavy alcohol consumption and BMI were positively related to most waveform parameters. Current smokers had higher levels of aortic augmentation index than non-smokers (difference=3.7%, P<0.0001). Aortic waveform parameters, controlling for demographics, antihypertensives, diabetes and cardiovascular disease (CVD), were higher in non-Europeans than in Europeans. Further adjustment for brachial BP or lifestyle factors (particularly BMI) reduced many differences but several remained. Despite even further adjustment for mean arterial pressure, pulse rate, height and total:high-density lipoprotein cholesterol, compared with Europeans, South Asians had higher levels of all measured aortic waveform parameters (for example, for backward pressure amplitude: beta=1.5 mm Hg; P<0.0001), whereas Pacific people had 9% higher loge (excess pressure integral) (P<0.0001). In conclusion, aortic waveform parameters varied with ethnicity in line with the greater prevalence of CVD among non-white populations. Generally, this was true even after accounting for brachial BP, suggesting that waveform parameters may have increased usefulness in capturing ethnic variations in cardiovascular risk. Heavy alcohol consumption, smoking and especially BMI may partially contribute to elevated levels of these parameters. PMID- 28004731 TI - Differential Association of Metabolic Risk Factors with Open Angle Glaucoma according to Obesity in a Korean Population. AB - The associations of the metabolic syndrome (MetS) with intraocular pressure and primary open angle glaucoma (OAG) have been reported. This study aimed to determine whether a difference in association exists between OAG and metabolic risk factors according to obesity status among Korean adults. A total of 8,816 participants (>=40 years) in the Korea National Health and Nutrition Examination Survey were classified into obese, body mass index (BMI) >= 25 kg/m2 and non obese, BMI < 25 kg/m2. The prevalence of MetS was 40.1% in non-obese OAG and 66.0% in obese OAG. The prevalence of OAG increased with increasing number components for MetS in total population and in non-obese subjects (P < 0.001, respectively), while the prevalence of OAG was not associated with number of components for MetS in obese subjects (P = 0.14). In non-obese individuals, subjects with high triglycerides, high blood pressure (BP), and MetS were more likely to have OAG compared with those without high triglycerides, high BP, and MetS after adjusting for potential confounders. However, MetS or its components exhibited no significant association with glaucoma status in obese individuals. Our study provides understanding on the differences in association of OAG with MetS and its components according to obesity status. PMID- 28004732 TI - Molecular typing and virulence analysis of multidrug resistant Klebsiella pneumoniae clinical isolates recovered from Egyptian hospitals. AB - Klebsiella pneumonia infection rates have increased dramatically. Molecular typing and virulence analysis are powerful tools that can shed light on Klebsiella pneumonia infections. Whereas 77.7% (28/36) of clinical isolates indicated multidrug resistant (MDR) patterns, 50% (18/36) indicated carpabenem resistance. Gene prevalence for the AcrAB efflux pump (82.14%) was more than that of the mdtK efflux pump (32.14%) in the MDR isolates. FimH-1 and mrkD genes were prevalent in wound and blood isolates. FimH-1 gene was prevalent in sputum while mrkD gene was prevalent in urine. Serum resistance associated with outer membrane protein coding gene (traT) was found in all blood isolates. IucC, entB, and Irp-1 were detected in 32.14%, 78.5% and 10.7% of MDR isolates, respectively. We used two Polymerase Chain Reaction (PCR) analyses: Enterobacterial Repetitive Intergenic Consensus (ERIC) and Random Amplified Polymorphic DNA (RAPD). ERIC-PCR revealed 21 and RAPD-PCR revealed 18 distinct patterns of isolates with similarity >=80%. ERIC genotyping significantly correlated with resistance patterns and virulence determinants. RAPD genotyping significantly correlated with resistance patterns but not with virulence determinants. Both RAPD and ERIC genotyping methods had no correlation with the capsule types. These findings can help up better predict MDR Klebsiella pneumoniae outbreaks associated with specific genotyping patterns. PMID- 28004733 TI - Environmental variation and the evolution of large brains in birds. AB - Environmental variability has long been postulated as a major selective force in the evolution of large brains. However, assembling evidence for this hypothesis has proved difficult. Here, by combining brain size information for over 1,200 bird species with remote-sensing analyses to estimate temporal variation in ecosystem productivity, we show that larger brains (relative to body size) are more likely to occur in species exposed to larger environmental variation throughout their geographic range. Our reconstructions of evolutionary trajectories are consistent with the hypothesis that larger brains (relative to body size) evolved when the species invaded more seasonal regions. However, the alternative-that the species already possessed larger brains when they invaded more seasonal regions-cannot be completely ruled out. Regardless of the exact mechanism, our findings provide strong empirical support for the association between large brains and environmental variability. PMID- 28004734 TI - Corrigendum: Quantitative Proteomics Reveals the Defense Response of Wheat against Puccinia striiformis f. sp. tritici. PMID- 28004736 TI - Quantum phase transition induced by real-space topology. AB - A quantum phase transition (QPT), including both topological and symmetry breaking types, is usually induced by the change of global parameters, such as external fields or global coupling constants. In this work, we demonstrate the existence of QPT induced by the real-space topology of the system. We investigate the groundstate properties of the tight-binding model on a honeycomb lattice with the torus geometry based on exact results. It is shown that the ground state experiences a second-order QPT, exhibiting the scaling behavior, when the torus switches to a tube, which reveals the connection between quantum phase and the real-space topology of the system. PMID- 28004735 TI - Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord. AB - Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with MU opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic. PMID- 28004738 TI - Corrigendum: Changes in Central Asia's Water Tower: Past, Present and Future. PMID- 28004737 TI - Investigating the Neuroprotective Effects of Turmeric Extract: Structural Interactions of beta-Amyloid Peptide with Single Curcuminoids. AB - A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action of Curcuma longa extracts in Alzheimer's disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components of Curcuma longa extracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Abeta-peptide. When the CYC and curcumin metabolite tetrahydrocurcumin (5, THC) were inserted into an anionic lipid solution, a significant modification of the Abeta CD curves was detected. These data were implemented by EPR experiments, demonstrating that CYC reaches the inner part of the bilayer, while the other curcuminoids are localized close to the membrane interface. Computational studies provided a model for the curcuminoid-Abeta interaction, highlighting the importance of a constrained "semi folded" conformation to interact with Abeta analogously to the pattern observed in alpha-helical coiled-coil peptide structures. This combined approach led to a better understanding of the intriguing in vitro and in vivo activity of curcuminoids as anti-Alzheimer agents, paving a new path for the rational design of optimized druggable analogues. PMID- 28004739 TI - Molecular characterization of firefly nuptial gifts: a multi-omics approach sheds light on postcopulatory sexual selection. AB - Postcopulatory sexual selection is recognized as a key driver of reproductive trait evolution, including the machinery required to produce endogenous nuptial gifts. Despite the importance of such gifts, the molecular composition of the non gametic components of male ejaculates and their interactions with female reproductive tracts remain poorly understood. During mating, male Photinus fireflies transfer to females a spermatophore gift manufactured by multiple reproductive glands. Here we combined transcriptomics of both male and female reproductive glands with proteomics and metabolomics to better understand the synthesis, composition and fate of the spermatophore in the common Eastern firefly, Photinus pyralis. Our transcriptome of male glands revealed up regulation of proteases that may enhance male fertilization success and activate female immune response. Using bottom-up proteomics we identified 208 functionally annotated proteins that males transfer to the female in their spermatophore. Targeted metabolomic analysis also provided the first evidence that Photinus nuptial gifts contain lucibufagin, a firefly defensive toxin. The reproductive tracts of female fireflies showed increased gene expression for several proteases that may be involved in egg production. This study offers new insights into the molecular composition of male spermatophores, and extends our understanding of how nuptial gifts may mediate postcopulatory interactions between the sexes. PMID- 28004740 TI - Simultaneous Analysis of Secondary Structure and Light Scattering from Circular Dichroism Titrations: Application to Vectofusin-1. AB - Circular Dichroism data are often decomposed into their constituent spectra to quantify the secondary structure of peptides or proteins but the estimation of the secondary structure content fails when light scattering leads to spectral distortion. If peptide-induced liposome self-association occurs, subtracting control curves cannot correct for this. We show that if the cause of the light scattering is independent from the peptide structural changes, the CD spectra can be corrected using principal component analysis (PCA). The light scattering itself is analysed and found to be in good agreement with backscattering experiments. This method therefore allows to simultaneously follow structural changes related to peptide-liposome binding as well as peptide induced liposome self-association. We apply this method to study the structural changes and liposome binding of vectofusin-1, a transduction enhancing peptide used in lentivirus based gene therapy. Vectofusin-1 binds to POPC/POPS liposomes, causing a reversal of the negative liposome charge at high peptide concentrations. When the peptide charges exactly neutralise the lipid charges on both leaflets reversible liposome self-association occurs. These results are in good agreement with biological observations and provide further insight into the conditions required for efficent transduction enhancement. PMID- 28004741 TI - Deep sequencing of wheat sRNA transcriptome reveals distinct temporal expression pattern of miRNAs in response to heat, light and UV. AB - Understanding of plant adaptation to abiotic stresses has implications in plant breeding, especially in the context of climate change. MicroRNAs (miRNAs) and short interfering RNAs play a crucial role in gene regulation. Here, wheat plants were exposed to one of the following stresses: continuous light, heat or ultraviolet radiations over five consecutive days and leaf tissues from three biological replicates were harvested at 0, 1, 2, 3, 7 and 10 days after treatment (DAT). A total of 72 small RNA libraries were sequenced on the Illumina platform generating ~524 million reads corresponding to ~129 million distinct tags from which 232 conserved miRNAs were identified. The expression levels of 1, 2 and 79 miRNAs were affected by ultraviolet radiation, continuous light and heat, respectively. Approximately 55% of the differentially expressed miRNAs were downregulated at 0 and 1 DAT including miR398, miR528 and miR156 that control mRNAs involved in activation of signal transduction pathways and flowering. Other putative targets included histone variants and methyltransferases. These results suggest a temporal miRNA-guided post-transcriptional regulation that enables wheat to respond to abiotic stresses, particularly heat. Designing novel wheat breeding strategies such as regulatory gene-based marker assisted selection depends on accurate identification of stress induced miRNAs. PMID- 28004742 TI - First molecular and isotopic evidence of millet processing in prehistoric pottery vessels. AB - Analysis of organic residues in pottery vessels has been successful in detecting a range of animal and plant products as indicators of food preparation and consumption in the past. However, the identification of plant remains, especially grain crops in pottery, has proved elusive. Extending the spectrum is highly desirable, not only to strengthen our understanding of the dispersal of crops from centres of domestication but also to determine modes of food processing, artefact function and the culinary significance of the crop. Here, we propose a new approach to identify millet in pottery vessels, a crop that spread throughout much of Eurasia during prehistory following its domestication, most likely in northern China. We report the successful identification of miliacin (olean-18-en 3beta-ol methyl ether), a pentacyclic triterpene methyl ether that is enriched in grains of common/broomcorn millet (Panicum miliaceum), in Bronze Age pottery vessels from the Korean Peninsula and northern Europe. The presence of millet is supported by enriched carbon stable isotope values of bulk charred organic matter sampled from pottery vessel surfaces and extracted n-alkanoic acids, consistent with a C4 plant origin. These data represent the first identification of millet in archaeological ceramic vessels, providing a means to track the introduction, spread and consumption of this important crop. PMID- 28004743 TI - A new formulation of Bacillus thuringiensis: UV protection and sustained release mosquito larvae studies. AB - Persistence of Bacillus thuringiensis is an important factor in determining the success of this product as a pest control agent. In this report we present the development of a highly active mosquitocidal formulation with high resistance to UV. LLP29-M19 strain of Bt, selected by repeated exposure to UV was found to be highly resistant to UV. The product was optimized and the methods used were statistically analyzed. Using single-factor experiments it was determined that the optimal concentration of sodium alginate, CaCl2 and hollow glass beads in the formulation were 1.0%, 2.0% and 3.5%, respectively. Plackett-Burman design was used to screen the interaction of the three factors, CaCl2, sodium alginate and hollow glass beads in the sustained-release formulation. The best combined concentration and mutual effects of the three factors were optimized by response surface methodology. The results showed that the most favorable composition was sodium alginate 0.78%, CaCl2 4.52%, hollow glass bead 3.12%, bacterial powder 3.0%, melanin 0.015%, sodium benzoate 0.2%, and mouse feed 0.5%, resulting in the immobilization time of 4.5 h, at which time the corrected sustained-release virulence rose 2391.67 fold, which was 6.07-fold higher than the basic formulation and deviated only 5.0% from the value predicted by RSM. PMID- 28004744 TI - Mitoxantrone and Analogues Bind and Stabilize i-Motif Forming DNA Sequences. AB - There are hundreds of ligands which can interact with G-quadruplex DNA, yet very few which target i-motif. To appreciate an understanding between the dynamics between these structures and how they can be affected by intervention with small molecule ligands, more i-motif binding compounds are required. Herein we describe how the drug mitoxantrone can bind, induce folding of and stabilise i-motif forming DNA sequences, even at physiological pH. Additionally, mitoxantrone was found to bind i-motif forming sequences preferentially over double helical DNA. We also describe the stabilisation properties of analogues of mitoxantrone. This offers a new family of ligands with potential for use in experiments into the structure and function of i-motif forming DNA sequences. PMID- 28004745 TI - PKCE switches Aurora B specificity to exit the abscission checkpoint. AB - The 'NoCut', or Aurora B abscission checkpoint can be activated if DNA is retained in the cleavage furrow after completion of anaphase. Checkpoint failure leads to incomplete abscission and a binucleate outcome. These phenotypes are also observed after loss of PKCE in transformed cell models. Here we show that PKCE directly modulates the Aurora B-dependent abscission checkpoint by phosphorylating Aurora B at S227. This phosphorylation invokes a switch in Aurora B specificity, with increased phosphorylation of a subset of target substrates, including the CPC subunit Borealin. This switch is essential for abscission checkpoint exit. Preventing the phosphorylation of Borealin leads to abscission failure, as does expression of a non-phosphorylatable Aurora B S227A mutant. Further, depletion of the ESCRT-III component and Aurora B substrate CHMP4C enables abscission, bypassing the PKCE-Aurora B exit pathway. Thus, we demonstrate that PKCE signals through Aurora B to exit the abscission checkpoint and complete cell division. PMID- 28004747 TI - Corrigendum: A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition. PMID- 28004746 TI - Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings. AB - Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8-11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations. PMID- 28004748 TI - Multimodal Sensing Strategy Using pH Dependent Fluorescence Switchable System. AB - Biomolecules assisted preparation of fluorescent gold nanoparticles (FL-Au NPs) has been reported in this work using glucose oxidase enzyme as both reducing and stabilizing agent and demonstrated their application through multimodal sensing strategy for selective detection of cysteine (Cys). Three different methods namely fluorescence turn OFF-ON strategy, naked eye detection and electrochemical methods are used for Cys detection by employing FL-Au NPs as a common probe. In case of fluorescence turn-OFF method a strong interaction between Au NPs and thiol results in quenching of fluorescence due to replacement of glucose oxidase by Cys at neutral pH. Second mode is based on fluorescence switch-ON strategy where initial fluorescence is significantly quenched by either excess acid or base and further addition of Cys results in appearance of rosy-red and green fluorescence respectively. Visual colour change and fluorescence emission arises due to etching of Au atoms on the surface by thiol leading to formation of Au nanoclusters. Finally, electrochemical sensing of Cys is also carried out using cyclic voltammetry in 0.1 M PBS solution. These findings provide a suitable platform for Cys detection over a wide range of pH and concentration levels and hence the sensitivity can also be tuned accordingly. PMID- 28004749 TI - Colours' Impact on Morality: Evidence from Event-related Potentials. AB - Black and white have been shown to be representations of moral concepts. The purpose of this study was to investigate whether colours other than black and white have similar effects on words related to morality and to determine the time course of these effects. We presented moral and immoral words in three colours (red, green and blue) in a Moral Stroop task and used the event-related potential (ERP) technique to identify the temporal dynamics of the impact of colours on moral judgement. The behavioural results showed that it took longer for people to judge immoral words than moral words when the words were coloured green than when they were red or blue. The ERP results revealed the time course of these effects. Three stages were identified in the significant effects of P200, N300 and LPC. These findings suggest a metaphorical association between the colour green and moral information. PMID- 28004750 TI - SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. AB - We currently have limited knowledge of the involvement of long non-coding RNAs (lncRNAs) in normal cellular processes and pathologies. Here, we identify and characterize SNHG5 as a stable cytoplasmic lncRNA with up-regulated expression in colorectal cancer. Depletion of SNHG5 induces cell cycle arrest and apoptosis in vitro and limits tumour outgrowth in vivo, whereas SNHG5 overexpression counteracts oxaliplatin-induced apoptosis. Using an unbiased approach, we identify 121 transcript sites interacting with SNHG5 in the cytoplasm. Importantly, knockdown of key SNHG5 target transcripts, including SPATS2, induces apoptosis and thus mimics the effect seen following SNHG5 depletion. Mechanistically, we suggest that SNHG5 stabilizes the target transcripts by blocking their degradation by STAU1. Accordingly, depletion of STAU1 rescues the apoptosis induced after SNHG5 knockdown. Hence, we characterize SNHG5 as a lncRNA promoting tumour cell survival in colorectal cancer and delineate a novel mechanism in which a cytoplasmic lncRNA functions through blocking the action of STAU1. PMID- 28004752 TI - Rapid stability of ferroelectric polarization in the Ca, Ce hybrid doped BaTiO3 ceramics. AB - In this work, we report a rapid stability phenomenon of ferroelectric polarization in the Ca, Ce hybrid doped BaTiO3 ceramics (BCaxT+BTCe8) (x = 10, 20, 24, 30 mol%) prepared by separate doping Ca2+ and Ce4+ ions. Double hysteresis loops are identified in the aged BCaxT+BTCe8 samples; meanwhile, the polarization of these loops present a rapid decrease within very short aging time (about 1 h), and then the polarization remains almost unchanged over the followed ~1000 h. This phenomenon is not reported in previous researches. Raman scattering spectrum indicates that oxygen vacancies are generated because of Ca2+ ions entering into Ti sites partly in the BCaxT+BTCe8 samples, and then the oxygen vacancies are quantitatively characterized by half of the Ce3+ content through the XPS test. The emergence of the aging phenomenon is explained through the defect dipole reorientation mechanism. The larger radius of Ca2+ ions is further discussed as a possible reason for the rapid stability phenomenon of ferroelectric polarization. It may provide an effective design method from the viewpoint of the ionic radius to accelerate polarization stability, and thus to facilitate the possible practical applications of the aging effect. PMID- 28004751 TI - Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF 1alpha/HDAC1/Slug axis. AB - Hypoxia is a major driving force of cancer invasion and metastasis. Here we show that death domain-associated protein (Daxx) acts to negatively regulate hypoxia induced cell dissemination and invasion by inhibiting the HIF-1alpha/HDAC1/Slug pathway. Daxx directly binds to the DNA-binding domain of Slug, impeding histone deacetylase 1 (HDAC1) recruitment and antagonizing Slug E-box binding. This, in turn, stimulates E-cadherin and occludin expression and suppresses Slug-mediated epithelial-mesenchymal transition (EMT) and cell invasiveness. Under hypoxic conditions, stabilized hypoxia-inducible factor (HIF)-1alpha downregulates Daxx expression and promotes cancer invasion, whereas re-expression of Daxx represses hypoxia-induced cancer invasion. Daxx also suppresses Slug-mediated lung cancer metastasis in an orthotopic lung metastasis mouse model. Using clinical tumour samples, we confirmed that the HIF-1alpha/Daxx/Slug pathway is an outcome predictor. Our results support that Daxx can act as a repressor in controlling HIF-1alpha/HDAC1/Slug-mediated cancer cell invasion and is a potential therapeutic target for inhibition of cancer metastasis. PMID- 28004753 TI - Proximity does not contribute to activity enhancement in the glucose oxidase horseradish peroxidase cascade. AB - A proximity effect has been invoked to explain the enhanced activity of enzyme cascades on DNA scaffolds. Using the cascade reaction carried out by glucose oxidase and horseradish peroxidase as a model system, here we study the kinetics of the cascade reaction when the enzymes are free in solution, when they are conjugated to each other and when a competing enzyme is present. No proximity effect is found, which is in agreement with models predicting that the rapidly diffusing hydrogen peroxide intermediate is well mixed. We suggest that the reason for the activity enhancement of enzymes localized by DNA scaffolds is that the pH near the surface of the negatively charged DNA nanostructures is lower than that in the bulk solution, creating a more optimal pH environment for the anchored enzymes. Our findings challenge the notion of a proximity effect and provide new insights into the role of DNA scaffolds. PMID- 28004754 TI - An exactly solvable, spatial model of mutation accumulation in cancer. AB - One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours, even if different fragments of the tumour grow sub exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model. PMID- 28004755 TI - STAT3 Undergoes Acetylation-dependent Mitochondrial Translocation to Regulate Pyruvate Metabolism. AB - Cytoplasmic STAT3, after activation by growth factors, translocates to different subcellular compartments, including nuclei and mitochondria, where it carries out different biological functions. However, the precise mechanism by which STAT3 undergoes mitochondrial translocation and subsequently regulates the tricarboxylic acid (TCA) cycle-electron transport chain (ETC) remains poorly understood. Here, we clarify this process by visualizing STAT3 acetylation in starved cells after serum reintroduction or insulin stimulation. CBP-acetylated STAT3 undergoes mitochondrial translocation in response to serum introduction or insulin stimulation. In mitochondria, STAT3 associates with the pyruvate dehydrogenase complex E1 (PDC-E1) and subsequently accelerates the conversion of pyruvate to acetyl-CoA, elevates the mitochondrial membrane potential, and promotes ATP synthesis. SIRT5 deacetylates STAT3, thereby inhibiting its function in mitochondrial pyruvate metabolism. In the A549 lung cancer cell line, constitutively acetylated STAT3 localizes to mitochondria, where it maintains the mitochondrial membrane potential and ATP synthesis in an active state. PMID- 28004756 TI - Alteration of platelet GPVI signaling in ST-elevation myocardial infarction patients demonstrated by a combination of proteomic, biochemical, and functional approaches. AB - The platelet-specific collagen receptor glycoprotein VI (GPVI) is critical for the formation of arterial thrombosis in vivo. We analyzed GPVI-activated platelets from ST-elevation myocardial infarction (STEMI) patients and matched stable coronary artery disease (SCAD) controls in order to provide novel clues on the degree of involvement of GPVI signaling in the acute event. Firstly, platelets were isolated from systemic venous blood and activated with the GPVI specific agonist CRP (collagen-related peptide). STEMI and SCAD samples were compared by a phosphoproteomics approach. Validations were by immunoblotting in systemic and intracoronary blood from independent cohorts of patients. Twenty-six differentially regulated proteins were identified when comparing CRP-activated systemic platelets from STEMI and SCAD patients, 4 of which were selected for validation studies: PLCgamma2, G6f, SLP-76, and Dok-2. Immunoblot analyses showed these four proteins had higher tyrosine phosphorylation levels in response to CRP in platelets from STEMI patients, being these levels more pronounced at the culprit site of coronary artery occlusion. Moreover, platelet aggregation studies showed a higher response to GPVI agonists in STEMI patients compared to SCAD controls. In conclusion, we show an altered activation state of GPVI signaling in STEMI patients, confirming this receptor as a promising anti-thrombotic target for myocardial infarction. PMID- 28004758 TI - The identity of belowground herbivores, not herbivore diversity, mediates impacts on plant productivity. AB - Across many ecosystems, increases in species biodiversity generally results in greater resource acquisition by consumers. Few studies examining the impacts of consumer diversity on resource capture have focused on terrestrial herbivores, however, especially taxa that feed belowground. Here we conducted field mesocosm experiments to examine the effects of variation in species richness and composition within a community of wireworm herbivores on wheat plant productivity. Our experiments involved wireworm communities consisting of between one and three species, with all possible combinations of species represented. We found that the presence of wireworms reduced plant biomass and seed viability, but wireworm species richness did not impact these plant metrics. Species identity effects were strong, as two species, Limonius californicus and Selatosomus pruininus, had significantly stronger impacts on plants compared to L. infuscatus. Communities with either of the two most impactful species consistently had the greatest impact on wheat plants. The effects of wireworms were thus strongly dependent on the particular species present rather than the overall diversity of the wireworm community. More broadly, our study supports the general finding that the identity of particular consumer species within communities often has greater impacts on ecosystem functioning than species richness. PMID- 28004757 TI - Direct measurements of multi-photon induced nonlinear lattice dynamics in semiconductors via time-resolved x-ray scattering. AB - Nonlinear optical phenomena in semiconductors present several fundamental problems in modern optics that are of great importance for the development of optoelectronic devices. In particular, the details of photo-induced lattice dynamics at early time-scales prior to carrier recombination remain poorly understood. We demonstrate the first integrated measurements of both optical and structural, material-dependent quantities while also inferring the bulk impulsive strain profile by using high spatial-resolution time-resolved x-ray scattering (TRXS) on bulk crystalline gallium arsenide. Our findings reveal distinctive laser-fluence dependent crystal lattice responses, which are not described by previous TRXS experiments or models. The initial linear expansion of the crystal upon laser excitation stagnates at a laser fluence corresponding to the saturation of the free carrier density before resuming expansion in a third regime at higher fluences where two-photon absorption becomes dominant. Our interpretations of the lattice dynamics as nonlinear optical effects are confirmed by numerical simulations and by additional measurements in an n-type semiconductor that allows higher-order nonlinear optical processes to be directly observed as modulations of x-ray diffraction lineshapes. PMID- 28004759 TI - Blocking triggering receptor expressed on myeloid cells-1 attenuates lipopolysaccharide-induced acute lung injury via inhibiting NLRP3 inflammasome activation. AB - Acute lung injury (ALI) is associated with high mortality and uncontrolled inflammation plays a critical role in ALI. TREM-1 is an amplifier of inflammatory response, and is involved in the pathogenesis of many infectious diseases. NLRP3 inflammasome is a member of NLRs family that contributes to ALI. However, the effect of TREM-1 on NLRP3 inflammasome and ALI is still unknown. This study aimed to determine the effect of TREM-1 modulation on LPS-induced ALI and activation of the NLRP3 inflammasome. We showed that LR12, a TREM-1 antagonist peptide, significantly improved survival of mice after lethal doses of LPS. LR12 also attenuated inflammation and lung tissue damage by reducing histopathologic changes, infiltration of the macrophage and neutrophil into the lung, and production of the pro-inflammatory cytokine, and oxidative stress. LR12 decreased expression of the NLRP3, pro-caspase-1 and pro-IL-1beta, and inhibited priming of the NLRP3 inflammasome by inhibiting NF-kappaB. LR12 also reduced the expression of NLRP3 and caspase-1 p10 protein, and secretion of the IL-1beta, inhibited activation of the NLRP3 inflammasome by decreasing ROS. For the first time, these data show that TREM-1 aggravates inflammation in ALI by activating NLRP3 inflammasome, and blocking TREM-1 may be a potential therapeutic approach for ALI. PMID- 28004760 TI - Angiotensin II increases glomerular permeability by beta-arrestin mediated nephrin endocytosis. AB - Glomerular permeability and subsequent albuminuria are early clinical markers for glomerular injury in hypertensive nephropathy. Albuminuria predicts mortality and cardiovascular morbidity. AT1 receptor blockers protect from albuminuria, cardiovascular morbidity and mortality. A blood pressure independent, molecular mechanism for angiotensin II (Ang II) dependent albuminuria has long been postulated. Albuminuria results from a defective glomerular filter. Nephrin is a major structural component of the glomerular slit diaphragm and its endocytosis is mediated by beta-arrestin2. Ang II stimulation increases nephrin-beta arrestin2 binding, nephrin endocytosis and glomerular permeability in mice. This Ang II effect is mediated by AT1-receptors. AT1-receptor mutants identified G protein signaling to be essential for this Ang II effect. Galphaq knockdown and phospholipase C inhibition block Ang II mediated enhanced nephrin endocytosis. Nephrin Y1217 is the critical residue controlling nephrin binding to beta arrestin under Ang II stimulation. Nephrin Y1217 also mediates cytoskeletal anchoring to actin via nck2. Ang II stimulation decreases nephrin nck2 binding. We conclude that Ang II weakens the structural integrity of the slit diaphragm by increased nephrin endocytosis and decreased nephrin binding to nck2, which leads to increased glomerular permeability. This novel molecular mechanism of Ang II supports the use of AT1-receptor blockers to prevent albuminuria even in normotensives. PMID- 28004761 TI - NF-kappaB signalling and cell fate decisions in response to a short pulse of tumour necrosis factor. AB - In tissues and tumours, cell behaviours are regulated by multiple time-varying signals. While in the laboratory cells are often exposed to a stimulus for the duration of the experiment, in vivo exposures may be much shorter. In this study, we monitored NF-kappaB and caspase signalling in human cancer cells treated with a short pulse of Tumour Necrosis Factor (TNF). TNF is an inflammatory cytokine that can induce both the pro-survival NF-kappaB-driven gene transcription pathway and the pro-apoptotic caspase pathway. We find that a few seconds of exposure to TNF is sufficient to activate the NF-kappaB pathway in HeLa cells and induce apoptotic cell death in both HeLa and Kym-1 cells. Strikingly, a 1-min pulse of TNF can be more effective at killing than a 1-hour pulse, indicating that in addition to TNF concentration, duration of exposure also coordinates cell fate decisions. PMID- 28004762 TI - A simple and rapid method for optical visualization and quantification of bacteria on textiles. AB - To prevent bacterial contamination on textiles and the associated undesired effects different biocidal coatings have been investigated and applied. However, due to health and environmental concerns anti-adhesive coatings preventing the binding of bacteria would be favored. To develop such anti-adhesive coatings simple assays for reliable and fast screening are beneficial. Here an easy-to handle, robust and rapid assay to assess bacteria on textiles utilizing a tetrazolium salt was reported. The assay allowed direct eye visualization of the color change of the textiles containing bacteria, facilitating fast screening. Quantification of the adhered bacteria could be done by generating standard curves which correlate the staining intensity to cell numbers. An additional advantage of the described assay is that with the same detection method anti adhesive and biocidal effects can be investigated. The method was applied to different coatings, using Pseudomonas aeruginosa and Staphylococcus aureus as model organisms. The detection limit was found to be between 2.5 * 106 and 9.4 * 108 for P. aeruginosa and between 1 * 106 and 3.3 * 108 for S. aureus. The anti adhesive coating PLUMA was demonstrated to reduce bacterial adhesion without killing them, whereas the biocidal coating TH22-27 caused a clear reduction in the number of viable cells. PMID- 28004764 TI - Sheehan syndrome. AB - Sheehan syndrome or postpartum hypopituitarism is a condition characterized by hypopituitarism due to necrosis of the pituitary gland. The initial insult is caused by massive postpartum haemorrhage (PPH), leading to impaired blood supply to the pituitary gland, which has become enlarged during pregnancy. Small sella turcica size, vasospasms (caused by PPH) and/or thrombosis (associated with pregnancy or coagulation disorders) are predisposing factors; autoimmunity might be involved in the progressive worsening of pituitary functions. Symptoms are caused by a decrease or absence of one or more of the pituitary hormones, and vary, among others, from failure to lactate and nonspecific symptoms (such as fatigue) to severe adrenal crisis. In accordance with the location of hormone secreting cells relative to the vasculature, the secretion of growth hormone and prolactin is most commonly affected, followed by follicle-stimulating hormone and luteinizing hormone; severe necrosis of the pituitary gland also affects the secretion of thyroid-stimulating hormone and adrenocorticotropic hormone. Symptoms usually become evident years after delivery, but can, in rare cases, develop acutely. The incidence of Sheehan syndrome depends, to a large extent, on the occurrence and management of PPH. Sheehan syndrome is an important cause of hypopituitarism in developing countries, but has become rare in developed countries. Diagnosis is based on clinical manifestations combined with a history of severe PPH; hormone levels and/or stimulation tests can confirm clinical suspicion. Hormone replacement therapy is the only available management option so far. PMID- 28004763 TI - Tyrosine Hydroxylase Binding to Phospholipid Membranes Prompts Its Amyloid Aggregation and Compromises Bilayer Integrity. AB - Tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine neurotransmitters and hormones, binds to negatively charged phospholipid membranes. Binding to both large and giant unilamellar vesicles causes membrane permeabilization, as observed by efflux and influx of fluorescence dyes. Whereas the initial protein-membrane interaction involves the N-terminal tail that constitutes an extension of the regulatory ACT-domain, prolonged membrane binding induces misfolding and self-oligomerization of TH over time as shown by circular dichroism and Thioflavin T fluorescence. The gradual amyloid-like aggregation likely occurs through cross-beta interactions involving aggregation-prone motives in the catalytic domains, consistent with the formation of chain and ring-like protofilaments observed by atomic force microscopy in monolayer-bound TH. PC12 cells treated with the neurotoxin 6-hydroxydopamine displayed increased TH levels in the mitochondrial fraction, while incubation of isolated mitochondria with TH led to a decrease in the mitochondrial membrane potential. Furthermore, cell-substrate impedance and viability assays showed that supplementing the culture media with TH compromises cell viability over time. Our results revealed that the disruptive effect of TH on cell membranes may be a cytotoxic and pathogenic factor if the regulation and intracellular stability of TH is compromised. PMID- 28004765 TI - Fasting plasma glucose variability and all-cause mortality among type 2 diabetes patients: a dynamic cohort study in Shanghai, China. AB - The study aims to examine whether the variation of fasting plasma glucose (FPG), represented by coefficient of variation (CV), independently predicts all-cause mortality among Chinese type 2 diabetes patients. This retrospective cohort study was designed based on a standardized electronic management system of diabetes patients in Shanghai, China. 8871 type 2 diabetes patients were enrolled between 1 January 2007 and 31 December 2007 and were followed-up for all-cause mortality until 31 December 2014. All patients were grouped by the quartiles of CV of FPG. 1136 patients deceased during following-up. After adjusting for other risk factors, CV of FPG was not independently associated with all-cause mortality. Stratified analysis by mean FPG levels (<7 mmol/L and >=7 mmol/L) observed a significant modifying effect of CV of FPG (P for interact test <0.01). CV of FPG was independently associated with all-cause mortality in patients whose glucose control was poor, with the HRs (95% CI) for the second, third, fourth vs first quartiles of CV of FPG being 1.23(0.94-1.61), 1.23(0.94-1.61), and 1.63(1.25 2.13), respectively. Our results suggest that variability of FPG may be an important predictor of mortality among type 2 diabetes in China, particularly for those with their glycemic status uncontrolled. PMID- 28004767 TI - Formation of amorphous calcium carbonate in caves and its implications for speleothem research. AB - Speleothem deposits are among the most valuable continental formations in paleoclimate research, as they can be dated using absolute dating methods, and they also provide valuable climate proxies. However, alteration processes such as post-depositional mineralogical transformations can significantly influence the paleoclimatic application of their geochemical data. An innovative sampling and measurement protocol combined with scanning and transmission electron microscopy, X-ray diffraction and Fourier transform infrared spectroscopy is presented, demonstrating that carbonate precipitating from drip water in caves at ~10 degrees C contains amorphous calcium carbonate (ACC) that later transforms to nanocrystalline calcite. Stable oxygen isotope fractionations among calcite, ACC and water were also determined, proving that ACC is 18O-depleted (by >2.4 +/- 0.80/00) relative to calcite. This, in turn, has serious consequences for speleothem-based fluid inclusion research as closed system transformation of ACC to calcite may induce a negative oxygen isotope shift in fluid inclusion water, resulting in deterioration of the original compositions. ACC formation increases the speleothems' sensitivity to alteration as its interaction with external solutions may result in the partial loss of original proxy signals. Mineralogical analysis of freshly precipitating carbonate at the studied speleothem site is suggested in order to determine the potential influence of ACC formation. PMID- 28004766 TI - Reduced host-specificity in a parasite infecting non-littoral Lake Tanganyika cichlids evidenced by intraspecific morphological and genetic diversity. AB - Lake Tanganyika is well-known for its high species-richness and rapid radiation processes. Its assemblage of cichlid fishes recently gained momentum as a framework to study parasite ecology and evolution. It offers a rare chance to investigate the influence of a deepwater lifestyle in a freshwater fish-parasite system. Our study represents the first investigation of parasite intraspecific genetic structure related to host specificity in the lake. It focused on the monogenean flatworm Cichlidogyrus casuarinus infecting deepwater cichlids belonging to Bathybates and Hemibates. Morphological examination of C. casuarinus had previously suggested a broad host range, while the lake's other Cichlidogyrus species are usually host specific. However, ongoing speciation or cryptic diversity could not be excluded. To distinguish between these hypotheses, we analysed intraspecific diversity of C. casuarinus. Monogeneans from nearly all representatives of the host genera were examined using morphometrics, geomorphometrics and genetics. We confirmed the low host-specificity of C. casuarinus based on morphology and nuclear DNA. Yet, intraspecific variation of sclerotized structures was observed. Nevertheless, the highly variable mitochondrial DNA indicated recent population expansion, but no ongoing parasite speciation, confirming, for the first time in freshwater, reduced parasite host specificity in the deepwater realm, probably an adaptation to low host availability. PMID- 28004768 TI - Pressure effect on iron-based superconductor LaFeAsO1-xHx: Peculiar response of 1111-type structure. AB - A systematic study of the crystal structure of a layered iron oxypnictide LaFeAsO1-xHx as a function of pressure was performed using synchrotron X-ray diffraction. This compound exhibits a unique phase diagram of two superconducting phases and two parent phases. We established that the As-Fe-As angle of the FeAs4 tetrahedron widens on the application of pressure due to the interspace between the layers being nearly infilled by the large La and As atoms. Such rarely observed behaviour in iron pnictides implies that the FeAs4 coordination deviates from the regular tetrahedron in the present systems. This breaks a widely accepted structural guide that the superconductivity favours the regular tetrahedron, albeit the superconducting transition temperature (Tc) increases from 18 K at ambient pressure to 52 K at 6 GPa for x = 0.2. In the phase diagram, the second parent phase at x ~ 0.5 is suppressed by pressure as low as ~1.5 GPa in contrast to the first parent phase at x ~ 0, which is robust against pressure. We suggest that certain spin-fluctuation from the second parent phase is strongly related to high-Tc under pressure. PMID- 28004769 TI - Single-cell analysis of differences in transcriptomic profiles of oocytes and cumulus cells at GV, MI, MII stages from PCOS patients. AB - Polycystic ovary syndrome (PCOS) is a common frequent endocrine disorder among women of reproductive age. Although assisted reproductive techniques (ARTs) are used to address subfertility in PCOS women, their effectiveness is not clear. Our aim was to compare transcriptomic profiles of oocytes and cumulus cells (CCs) between women with and without PCOS, and assess the effectiveness of ARTs in treating PCOS patients. We collected oocytes and CCs from 16 patients with and without PCOS patients to categorize them into 6 groups according to oocyte nuclear maturation. Transcriptional gene expression of oocyte and CCs was determined via single-cell RNA sequencing. The ratio of fertilization and cleavage was higher in PCOS patients than in non-PCOS patients undergoing ARTs, and there was no difference in the number of high-quality embryos between the groups. Differentially expressed genes including PPP2R1A, PDGFRA, EGFR, GJA1, PTGS2, TNFAIP6, TGF-beta1, CAV1, INHBB et al. were investigated as potential causes of PCOS oocytes and CCs disorder at early stages, but their expression returned to the normal level at the metaphase II (MII) stage via ARTs. In conclusion, ARTs can improve the quality of cumulus-oocyte complex (COC) and increase the ratio of fertilization and cleavage in PCOS women. PMID- 28004770 TI - Multimodal Magnetic Resonance and Near-Infrared-Fluorescent Imaging of Intraperitoneal Ovarian Cancer Using a Dual-Mode-Dual-Gadolinium Liposomal Contrast Agent. AB - The degree of tumor removal at surgery is a major factor in predicting outcome for ovarian cancer. A single multimodality agent that can be used with magnetic resonance (MR) for staging and pre-surgical planning, and with optical imaging to aid surgical removal of tumors, would present a new paradigm for ovarian cancer. We assessed whether a dual-mode, dual-Gadolinium (DM-Dual-Gd-ICG) contrast agent can be used to visualize ovarian tumors in the peritoneal cavity by multimodal MR and near infra-red imaging (NIR). Intraperitoneal ovarian tumors (Hey-A8 or OVCAR3) in mice enhanced on MR two days after intravenous DM-Dual Gd-ICG injection compared to controls (SNR, CNR, p < 0.05, n = 6). As seen on open abdomen and excised tumors views and confirmed by optical radiant efficiency measurement, Hey-A8 or OVCAR3 tumors from animals injected with DM-Dual Gd-ICG had increased fluorescence (p < 0.05, n = 6). This suggests clinical potential to localize ovarian tumors by MR for staging and surgical planning, and, by NIR at surgery for resection. PMID- 28004771 TI - Spatially-Resolved Proteomics: Rapid Quantitative Analysis of Laser Capture Microdissected Alveolar Tissue Samples. AB - Laser capture microdissection (LCM)-enabled region-specific tissue analyses are critical to better understand complex multicellular processes. However, current proteomics workflows entail several manual sample preparation steps and are challenged by the microscopic mass-limited samples generated by LCM, impacting measurement robustness, quantification and throughput. Here, we coupled LCM with a proteomics workflow that provides fully automated analysis of proteomes from microdissected tissues. Benchmarking against the current state-of-the-art in ultrasensitive global proteomics (FASP workflow), our approach demonstrated significant improvements in quantification (~2-fold lower variance) and throughput (>5 times faster). Using our approach we for the first time characterized, to a depth of >3,400 proteins, the ontogeny of protein changes during normal lung development in microdissected alveolar tissue containing only 4,000 cells. Our analysis revealed seven defined modules of coordinated transcription factor-signaling molecule expression patterns, suggesting a complex network of temporal regulatory control directs normal lung development with epigenetic regulation fine-tuning pre-natal developmental processes. PMID- 28004772 TI - Composition of the Hemagglutinin Polybasic Proteolytic Cleavage Motif Mediates Variable Virulence of H7N7 Avian Influenza Viruses. AB - Acquisition of a polybasic cleavage site (pCS) in the hemagglutinin (HA) is a prerequisite for the shift of low pathogenic (LP) avian influenza virus (AIV) to the highly pathogenic (HP) form in chickens. Whereas presence of a pCS is required for high pathogenicity, less is known about the effect of composition of pCS on virulence of AIV particularly H7N7. Here, we investigated the virulence of four avian H7N7 viruses after insertion of different naturally occurring pCS from two HPAIV H7N7 (designated pCSGE and pCSUK) or from H7N1 (pCSIT). In vitro, the different pCS motifs modulated viral replication and the HA cleavability independent on the HA background. However, in vivo, the level of virulence conferred by the different pCS varied significantly. Within the respective viral backgrounds viruses with pCSIT and pCSGE were more virulent than those coding for pCSUK. The latter showed also the most restricted spread in inoculated birds. Besides the pCS, other gene segments modulated virulence of these H7N7 viruses. Together, the specific composition of the pCS significantly influences virulence of H7N7 viruses. Eurasian LPAIV H7N7 may shift to high pathogenicity after acquisition of "specific" pCS motifs and/or other gene segments from HPAIV. PMID- 28004773 TI - Single-photon multi-ports router based on the coupled cavity optomechanical system. AB - A scheme of single-photon multi-port router is put forward by coupling two optomechanical cavities with waveguides. It is shown that the coupled two optomechanical cavities can exhibit photon blockade effect, which is generated from interference of three mode interaction. A single-photon travel along the system is calculated. The results show that the single photon can be controlled in the multi-port system because of the radiation pressure, which should be useful for constructing quantum network. PMID- 28004774 TI - Non-native three-dimensional block copolymer morphologies. AB - Self-assembly is a powerful paradigm, wherein molecules spontaneously form ordered phases exhibiting well-defined nanoscale periodicity and shapes. However, the inherent energy-minimization aspect of self-assembly yields a very limited set of morphologies, such as lamellae or hexagonally packed cylinders. Here, we show how soft self-assembling materials-block copolymer thin films-can be manipulated to form a diverse library of previously unreported morphologies. In this iterative assembly process, each polymer layer acts as both a structural component of the final morphology and a template for directing the order of subsequent layers. Specifically, block copolymer films are immobilized on surfaces, and template successive layers through subtle surface topography. This strategy generates an enormous variety of three-dimensional morphologies that are absent in the native block copolymer phase diagram. PMID- 28004775 TI - Effects of elevated mean and extremely high temperatures on the physio-ecological characteristics of geographically distinctive populations of Cunninghamia lanceolata. AB - Conventional models for predicting species distribution under global warming scenarios often treat one species as a homogeneous whole. In the present study, we selected Cunninghamia lanceolata (C. lanceolata), a widely distributed species in China, to investigate the physio-ecological responses of five populations under different temperature regimes. The results demonstrate that increased mean temperatures induce increased growth performance among northern populations, which exhibited the greatest germination capacity and largest increase in the overlap between the growth curve and the monthly average temperature. However,tolerance of the southern population to extremely high temperatures was stronger than among the population from the northern region,shown by the best growth and the most stable photosynthetic system of the southern population under extremely high temperature. This result indicates that the growth advantage among northern populations due to increased mean temperatures may be weakened by lower tolerance to extremely high temperatures. This finding is antithetical to the predicted results. The theoretical coupling model constructed here illustrates that the difference in growth between populations at high and low latitudes and altitudes under global warming will decrease because of the frequent occurrence of extremely high temperatures. PMID- 28004776 TI - A20 Curtails Primary but Augments Secondary CD8+ T Cell Responses in Intracellular Bacterial Infection. AB - The ubiquitin-modifying enzyme A20, an important negative feedback regulator of NF-kappaB, impairs the expansion of tumor-specific CD8+ T cells but augments the proliferation of autoimmune CD4+ T cells. To study the T cell-specific function of A20 in bacterial infection, we infected T cell-specific A20 knockout (CD4-Cre A20fl/fl) and control mice with Listeria monocytogenes. A20-deficient pathogen specific CD8+ T cells expanded stronger resulting in improved pathogen control at day 7 p.i. Imaging flow cytometry revealed that A20-deficient Listeria-specific CD8+ T cells underwent increased apoptosis and necroptosis resulting in reduced numbers of memory CD8+ T cells. In contrast, the primary CD4+ T cell response was A20-independent. Upon secondary infection, the increase and function of pathogen specific CD8+ T cells, as well as pathogen control were significantly impaired in CD4-Cre A20fl/fl mice. In vitro, apoptosis and necroptosis of Listeria-specific A20-deficient CD8+ T cells were strongly induced as demonstrated by increased caspase-3/7 activity, RIPK1/RIPK3 complex formation and more morphologically apoptotic and necroptotic CD8+ T cells. In vitro, A20 limited CD95L and TNF induced caspase3/7 activation. In conclusion, T cell-specific A20 limited the expansion but reduced apoptosis and necroptosis of Listeria-specific CD8+ T cells, resulting in an impaired pathogen control in primary but improved clearance in secondary infection. PMID- 28004777 TI - Gene expression differences in Longissimus muscle of Nelore steers genetically divergent for residual feed intake. AB - Residual feed intake (RFI), a measure of feed efficiency (FE), is defined as the difference between the observed and the predictable feed intake considering size and growth of the animal. It is extremely important to beef production systems due to its impact on the allocation of land areas to alternative agricultural production, animal methane emissions, food demand and cost of production. Global differential gene expression analysis between high and low RFI groups (HRFI and LRFI: less and more efficient, respectively) revealed 73 differentially expressed (DE) annotated genes in Longissimus thoracis (LT) muscle of Nelore steers. These genes are involved in the overrepresented pathways Metabolism of Xenobiotics by Cytochrome P450 and Butanoate and Tryptophan Metabolism. Among the DE transcripts were several proteins related to mitochondrial function and the metabolism of lipids. Our findings indicate that observed gene expression differences are primarily related to metabolic processes underlying oxidative stress. Genes involved in the metabolism of xenobiotics and antioxidant mechanisms were primarily down-regulated, while genes responsible for lipid oxidation and ketogenesis were up-regulated in HRFI group. By using LT muscle, this study reinforces our previous findings using liver tissue and reveals new genes and likely tissue-specific regulators playing key-roles in these processes. PMID- 28004778 TI - Glycosides from edible sea cucumbers stimulate macrophages via purinergic receptors. AB - Since ancient times, edible sea cucumbers have been considered a jewel of the seabed and used in Asian folk medicine for stimulation of resistance against different diseases. However, the power of this sea food has not been established on a molecular level. A particular group of triterpene glycosides was found to be characteristic metabolites of the animals, responsible for this biological action. Using one of them, cucumarioside A2-2 (CA2-2) from the edible Cucumaria japonica species as an example as well as inhibitory analysis, patch-clamp on single macrophages, small interfering RNA technique, immunoblotting, SPR analysis, computer modeling and other methods, we demonstrate low doses of CA2-2 specifically to interact with P2X receptors (predominantly P2X4) on membranes of mature macrophages, enhancing the reversible ATP-dependent Ca2+ intake and recovering Ca2+ transport at inactivation of these receptors. As result, interaction of glycosides of this type with P2X receptors leads to activation of cellular immunity. PMID- 28004779 TI - Estimation of the toxicity of sulfadiazine to Daphnia magna using negligible depletion hollow-fiber liquid-phase microextraction independent of ambient pH. AB - The toxicity of ionizable organic compounds to organisms depends on the pH, which therefore affects risk assessments of these compounds. However, there is not a direct chemical method to predict the toxicity of ionizable organic compounds. To determine whether hollow-fiber liquid-phase microextraction (HF-LPME) is applicable for this purpose, a three-phase HF-LPME was used to measure sulfadiazine and estimate its toxicity to Daphnia magna in solutions of different pH. The result indicated that the sulfadiazine concentrations measured by HF-LPME decreased with increasing pH, which is consistent with the decreased toxicity. The concentration immobilize 50% of the daphnids (EC50) in 48 h calculated from nominal concentrations increased from 11.93 to 273.5 mg L-1 as the pH increased from 6.0 to 8.5, and the coefficient of variation (CV) of the EC50 values reached 104.6%. When calculated from the concentrations measured by HF-LPME (pH 12 acceptor phase), the EC50 ranged from 223.4 to 394.6 mg L-1, and the CV decreased to 27.60%, suggesting that the concentrations measured by HF-LPME can be used to estimate the toxicity of sulfadiazine irrespective of the solution pH. PMID- 28004780 TI - ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C gamma1 and protein kinase C pathways. AB - The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression. Restored TG1 expression of EGF-stimulated differentiated Adam17-/- keratinocytes was strongly repressed by inhibitors for PLCgamma1 or protein kinase C (PKC) pathways, while treatment with the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate restored TG activity in the epidermis of keratinocyte-specific Adam17-/- (AD17DeltaKC) mice. Further investigations emphasized the expression of PKCeta, a mediator of TGM1 transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKCeta, significantly improved TG activity in epidermis of AD17DeltaKC mice. Our results suggest ADAM17/EGFR-driven PLCgamma1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation. These findings may help to identify new therapeutic targets for inflammatory skin diseases related to epidermal barrier defects. PMID- 28004781 TI - Functional insights into the late embryogenesis abundant (LEA) protein family from Dendrobium officinale (Orchidaceae) using an Escherichia coli system. AB - Late embryogenesis abundant (LEA) proteins, a diverse family, accumulate during seed desiccation in the later stages of embryogenesis. LEA proteins are associated with tolerance to abiotic stresses, such as drought, salinity and high or cold temperature. Here, we report the first comprehensive survey of the LEA gene family in Dendrobium officinale, an important and widely grown medicinal orchid in China. Based on phylogenetic relationships with the complete set of Arabidopsis and Oryza LEA proteins, 17 genes encoding D. officinale LEAs (DofLEAs) were identified and their deduced proteins were classified into seven groups. The motif composition of these deduced proteins was correlated with the gene structure found in each LEA group. Our results reveal the DofLEA genes are widely distributed and expressed in tissues. Additionally, 11 genes from different groups were introduced into Escherichia coli to assess the functions of DofLEAs. Expression of 6 and 7 DofLEAs in E. coli improved growth performance compared with the control under salt and heat stress, respectively. Based on qPCR data, all of these genes were up-regulated in various tissues following exposure to salt and heat stresses. Our results suggest that DofLEAs play an important role in responses to abiotic stress. PMID- 28004782 TI - Hydrogen sulfide - cysteine cycle system enhances cadmium tolerance through alleviating cadmium-induced oxidative stress and ion toxicity in Arabidopsis roots. AB - Cadmium (Cd2+) is a common toxic heavy metal ion. We investigated the roles of hydrogen sulfide (H2S) and cysteine (Cys) in plant responses to Cd2+ stress. The expression of H2S synthetic genes LCD and DES1 were induced by Cd2+ within 3 h, and endogenous H2S was then rapidly released. H2S promoted the expression of Cys synthesis-related genes SAT1 and OASA1, which led to endogenous Cys accumulation. The H2S and Cys cycle system was stimulated by Cd2+ stress, and it maintained high levels in plant cells. H2S inhibited the ROS burst by inducing alternative respiration capacity (AP) and antioxidase activity. H2S weakened Cd2+ toxicity by inducing the metallothionein (MTs) genes expression. Cys promoted GSH accumulation and inhibited the ROS burst, and GSH induced the expression of phytochelatin (PCs) genes, counteracting Cd2+ toxicity. In summary, the H2S and Cys cycle system played a key role in plant responses to Cd2+ stress. The Cd2+ tolerance was weakened when the cycle system was blocked in lcddes1-1 and oasa1 mutants. This paper is the first to describe the role of the H2S and Cys cycle system in Cd2+ stress and to explore the relevant and specificity mechanisms of H2S and Cys in mediating Cd2+ stress. PMID- 28004783 TI - Temperature and microwave near field imaging by thermo-elastic optical indicator microscopy. AB - A high resolution imaging of the temperature and microwave near field can be a powerful tool for the non-destructive testing of materials and devices. However, it is presently a very challenging issue due to the lack of a practical measurement pathway. In this work, we propose and demonstrate experimentally a practical method resolving the issue by using a conventional CCD-based optical indicator microscope system. The present method utilizes the heat caused by an interaction between the material and an electromagnetic wave, and visualizes the heat source distribution from the measured photoelastic images. By using a slide glass coated by a metal thin film as the indicator, we obtain optically resolved temperature, electric, and magnetic microwave near field images selectively with a comparable sensitivity, response time, and bandwidth of existing methods. The present method provides a practical way to characterize the thermal and electromagnetic properties of materials and devices under various environments. PMID- 28004784 TI - The isolation and characterization of resident yeasts from the phylloplane of Arabidopsis thaliana. AB - The genetic model plant Arabidopsis thaliana (arabidopsis) has been instrumental to recent advances in our understanding of the molecular function of the plant immune system. However, this work has not yet included plant associated and phytopathogenic yeasts largely due to a lack of yeast species known to interact with arabidopsis. The plant phylloplane is a significant habitat for neutral residents, plant-growth and health-promoting species, and latent-pathogenic species. However, yeast phylloplane residents of arabidopsis remain underexplored. To address this, resident yeasts from the phyllosphere of wild arabidopsis collected in field conditions have been isolated and characterized. A total of 95 yeast strains representing 23 species in 9 genera were discovered, including potentially psychrophilic and pathogenic strains. Physiological characterization revealed thermotolerance profiles, sensitivity to the arabidopsis phytoalexin camalexin, the production of indolic compounds, and the ability to activate auxin responses in planta. These results indicate a rich diversity of yeasts present in the arabidopsis phylloplane and have created culture resources and information useful in the development of model systems for arabidopsis-yeast interactions. PMID- 28004785 TI - Quasi mode-locking of coherent feedback random fiber laser. AB - Mode-locking is a milestone in the history of lasers that allows the generation of short light pulses and stabilization of lasers. This phenomenon is known to occur only in standard ordered lasers for long time and until recently it is found that it also occurs in disordered random lasers formed by nanoscale particles. Here, we report the realization of a so-called quasi mode-locking of coherent feedback random fiber laser which consists of a partially disordered linear cavity formed between a point reflector and a random distributed fiber Bragg grating array with an inserted graphene saturable absorber. We show that multi-groups of regular light pulses/sub-pulses with different repetition frequencies are generated within the quasi mode-locking regime through the so called collective resonances phenomenon in such a random fiber laser. This work may provide a platform to study mode locking as well as pulse dynamic regulation of random lasing emission of coherent feedback disordered structures and pave the way to the development of novel multi-frequency pulse fiber lasers with potentially wide frequency tuning range. PMID- 28004786 TI - GPS-PAIL: prediction of lysine acetyltransferase-specific modification sites from protein sequences. AB - Protein acetylation catalyzed by specific histone acetyltransferases (HATs) is an essential post-translational modification (PTM) and involved in the regulation a broad spectrum of biological processes in eukaryotes. Although several ten thousands of acetylation sites have been experimentally identified, the upstream HATs for most of the sites are unclear. Thus, the identification of HAT-specific acetylation sites is fundamental for understanding the regulatory mechanisms of protein acetylation. In this work, we first collected 702 known HAT-specific acetylation sites of 205 proteins from the literature and public data resources, and a motif-based analysis demonstrated that different types of HATs exhibit similar but considerably distinct sequence preferences for substrate recognition. Using 544 human HAT-specific sites for training, we constructed a highly useful tool of GPS-PAIL for the prediction of HAT-specific sites for up to seven HATs, including CREBBP, EP300, HAT1, KAT2A, KAT2B, KAT5 and KAT8. The prediction accuracy of GPS-PAIL was critically evaluated, with a satisfying performance. Using GPS-PAIL, we also performed a large-scale prediction of potential HATs for known acetylation sites identified from high-throughput experiments in nine eukaryotes. Both online service and local packages were implemented, and GPS-PAIL is freely available at: http://pail.biocuckoo.org. PMID- 28004787 TI - Cross-protective efficacy of dendritic cells targeting conserved influenza virus antigen expressed by Lactobacillus plantarum. AB - Avian influenza virus (AIV) can infect birds and mammals, including humans, and are thus a serious threat to public health. Vaccination is vital for controlling AIV circulation. In this study, we generated a recombinant lactobacillus expressing the NP-M1-DCpep of H9N2 avian influenza virus and evaluated the activation effect of NC8-pSIP409-NP-M1-DCpep on dendritic cells (DCs) in a mouse model. The specific mucosal antibody responses and B and T cell responses in lymphoid tissues were also characterized. Importantly, we confirmed that specific CD8 T cells presented in vitro and antigen-specific cytotoxicity (activated the expression of CD107a) and in vivo antigen-specific cytotoxicity after vaccination. The adoptive transfer of NC8-pSIP409-NP-M1-DCpep-primed CD8+ T cells into NOD-SCID mice resulted in effective protection against mouse-adapted AIV infection. In addition, we observed protection in immunized mice challenged with mouse-adapted H9N2 AIV and H1N1 influenza virus, as evidenced by reductions in the lung virus titers, improvements in lung pathology, and weight loss and complete survival. Our data are promising for the generation of effective, non traditional influenza vaccines against AIVs. PMID- 28004788 TI - Multi-InDel Analysis for Ancestry Inference of Sub-Populations in China. AB - Ancestry inference is of great interest in diverse areas of scientific researches, including the forensic biology, medical genetics and anthropology. Various methods have been published for distinguishing populations. However, few reports refer to sub-populations (like ethnic groups) within Asian populations for the limitation of markers. Several InDel loci located very tightly in physical positions were treated as one marker by us, which is multi-InDel. The multi-InDel shows potential as Ancestry Inference Marker (AIM). In this study, we performed a genome-wide scan for multi-InDels as AIM. After examining the FST distributions in the 1000 Genomes Database, 12 candidates were selected and validated for eastern Asian populations. A multiplexed assay was developed as a panel to genotype 12 multi-InDel markers simultaneously. Ancestry component analysis with STRUCTURE and principal component analysis (PCA) were employed to estimate its capability for ancestry inference. Furthermore, ancestry assignments of trial individuals were conducted. It proved to be very effective when 210 samples from Han and Tibetan individuals in China were tested. The panel consisting of multi-InDel markers exhibited considerable potency in ancestry inference, and was suggested to be applied in forensic practices and genetic population studies. PMID- 28004789 TI - Assessment of turbulent viscous stress using ICOSA 4D Flow MRI for prediction of hemodynamic blood damage. AB - Flow-induced blood damage plays an important role in determining the hemodynamic impact of abnormal blood flow, but quantifying of these effects, which are dominated by shear stresses in highly fluctuating turbulent flow, has not been feasible. This study evaluated the novel application of turbulence tensor measurements using simulated 4D Flow MRI data with six-directional velocity encoding for assessing hemodynamic stresses and corresponding blood damage index (BDI) in stenotic turbulent blood flow. The results showed that 4D Flow MRI underestimates the maximum principal shear stress of laminar viscous stress (PLVS), and overestimates the maximum principal shear stress of Reynolds stress (PRSS) with increasing voxel size. PLVS and PRSS were also overestimated by about 1.2 and 4.6 times at medium signal to noise ratio (SNR) = 20. In contrast, the square sum of the turbulent viscous shear stress (TVSS), which is used for blood damage index (BDI) estimation, was not severely affected by SNR and voxel size. The square sum of TVSS and the BDI at SNR >20 were underestimated by less than 1% and 10%, respectively. In conclusion, this study demonstrated the feasibility of 4D Flow MRI based quantification of TVSS and BDI which are closely linked to blood damage. PMID- 28004790 TI - New Formyl Phloroglucinol Meroterpenoids from the Leaves of Eucalyptus robusta. AB - Seven new formyl phloroglucinol meroterpenoids (FPMs), namely eucalrobusones J-P (1-7), as well as three known ones (8-10) were isolated from the leaves of Eucalyptus robusta. Their structures were elucidated by spectroscopic data analysis, and their absolute configurations were determined by applications of the Snatzke's helicity rule and the electron circular dichroism (ECD) calculation. These FPMs are diverse in coupling patterns between phloroglucinol and sesquiterpenoid units, forming novel polycyclic ring systems. Compound 1 possesses a new carbon skeleton that a 1-oxaspiro[5.6]dodecane core is formed through C-14 rather than C-4 of the aromadendrane moiety. Compound 2 features a novel 6/7/5 ring-fused 6-oxabicyclo[3.2.2]nonane skeleton. Compounds 3-5 are rare aristolane-based FPMs. By forming different oxo bridges, compound 3 is the first sample of FPM with benzo-dihydrofuran structure, and compound 4 possesses a novel 6/6/6/6/3-fused pentacyclic skeleton. Compounds 1, 6, and 8 exhibited significant antifungal activities against Candida glabrata with MIC50 values of 2.57, 1.95, and 2.49 MUg/mL, respectively. PMID- 28004791 TI - Free Triiodothyronine Level Correlates with Myocardial Injury and Prognosis in Idiopathic Dilated Cardiomyopathy: Evidence from Cardiac MRI and SPECT/PET Imaging. AB - Thyroid dysfunction is associated with poor prognosis in heart failure, but theories of mechanisms are mainly based on animal experiments, not on human level. We aimed to explore the relation between thyroid function and myocardial injuries in idiopathic dilated cardiomyopathy (IDCM) using cardiac magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Myocardial fibrosis was detected by late gadolinium enhancement (LGE) MRI, and myocardial perfusion/metabolism was evaluated by 99mTc-MIBI SPECT /18F-FDG PET imaging. Across the quartiles of FT3, decreased percentage of segments with LGE and perfusion/metabolism abnormalities were found. As for FT4 and TSH levels, no significant distribution trend of myocardial injuries could be detected. In logistic analysis, FT3 was independently associated with the presence of LGE (OR: 0.140, 95% CI: 0.035 0.567), perfusion abnormalities (OR: 0.172, 95% CI: 0.040-0.738) and metabolism abnormalities (OR: 0.281, 95% CI: 0.081-0.971). After a median follow-up of 46 months, LGE-positive and FT3 < 2.77 pg/mL was identified as the strongest predictor of cardiac events (HR: 8.623, 95% CI: 3.626-16.438). Low FT3 level is associated with myocardial fibrosis and perfusion/metabolism abnormalities in patients with IDCM. The combination of FT3 level and LGE provides useful information for assessing the prognosis of IDCM. PMID- 28004793 TI - Aromatic molecules on low-index coinage metal surfaces: Many-body dispersion effects. AB - Understanding the binding mechanism for aromatic molecules on transition-metal surfaces in atomic scale is a major challenge in designing functional interfaces for to (opto)electronic devices. Here, we employ the state-of-the-art many-body dispersion (MBD) approach, coupled with density functional theory methods, to study the interactions of benzene with low-index coinage metal surfaces. The many body effects contribute mostly to the (111) surface, and leastly to the (110) surface. This corresponds to the same sequence of planar atomic density of face centered-cubic lattices, i.e., (111) > (100) > (110). The binding energy for benzene/Au(110) is even stronger than that for benzene/Ag(110), due to a larger broadening of molecular orbitals in the former case. On the other hand, our calculations show almost identical binding energies for benzene on Ag(111) and Au(111), which contradicts the classic d-band center theory that could well predict the trend in chemisorption energies for various small molecules on a number of metal surfaces. Our results provide important insight into the benchmark adsorption systems with opener surfaces, which could help in designing more complex functional interfaces. PMID- 28004792 TI - NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae. AB - Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) recognizes muramyl dipeptide (MDP) of bacterial cell walls, triggering NFkappaB-induced pro inflammation. As most human pathogenic filariae contain Wolbachia endobacteria that synthesize the MDP-containing cell wall precursor lipid II, NOD2's role during infection with the rodent filaria Litomosoides sigmodontis was investigated. In NFkappaB reporter-cells, worm-extract containing Wolbachia induced NOD2 and NOD1. NOD2-deficient mice infected with L. sigmodontis had significantly more worms than wildtype controls early in infection. Increased worm burden was not observed after subcutaneous infection, suggesting that protective NOD2-dependent immune responses occur within the skin. Flow cytometry demonstrated that neutrophil recruitment to the skin was impaired in NOD2-/- mice after intradermal injection of third stage larvae (L3), and blood neutrophil numbers were reduced after L. sigmodontis infection. PCR array supported the requirement of NOD2 for recruitment of neutrophils to the skin, as genes associated with neutrophil recruitment and activation were downregulated in NOD2 /- mice after intradermal L3 injection. Neutrophil depletion before L. sigmodontis infection increased worm recovery in wildtype mice, confirming that neutrophils are essential against invading L3 larvae. This study indicates that NOD-like receptors are implemented in first-line protective immune responses against filarial nematodes. PMID- 28004794 TI - Imaging molecular geometry with electron momentum spectroscopy. AB - Electron momentum spectroscopy is a unique tool for imaging orbital-specific electron density of molecule in momentum space. However, the molecular geometry information is usually veiled due to the single-centered character of momentum space wavefunction of molecular orbital (MO). Here we demonstrate the retrieval of interatomic distances from the multicenter interference effect revealed in the ratios of electron momentum profiles between two MOs with symmetric and anti symmetric characters. A very sensitive dependence of the oscillation period on interatomic distance is observed, which is used to determine F-F distance in CF4 and O-O distance in CO2 with sub-Angstrom precision. Thus, using one spectrometer, and in one measurement, the electron density distributions of MOs and the molecular geometry information can be obtained simultaneously. Our approach provides a new robust tool for imaging molecules with high precision and has potential to apply to ultrafast imaging of molecular dynamics if combined with ultrashort electron pulses in the future. PMID- 28004795 TI - Coupled ATPase-adenylate kinase activity in ABC transporters. AB - ATP-binding cassette (ABC) transporters, a superfamily of integral membrane proteins, catalyse the translocation of substrates across the cellular membrane by ATP hydrolysis. Here we demonstrate by nucleotide turnover and binding studies based on 31P solid-state NMR spectroscopy that the ABC exporter and lipid A flippase MsbA can couple ATP hydrolysis to an adenylate kinase activity, where ADP is converted into AMP and ATP. Single-point mutations reveal that both ATPase and adenylate kinase mechanisms are associated with the same conserved motifs of the nucleotide-binding domain. Based on these results, we propose a model for the coupled ATPase-adenylate kinase mechanism, involving the canonical and an additional nucleotide-binding site. We extend these findings to other prokaryotic ABC exporters, namely LmrA and TmrAB, suggesting that the coupled activities are a general feature of ABC exporters. PMID- 28004796 TI - Osteoarthritis and the risk of cardiovascular disease: a meta-analysis of observational studies. AB - Previous observational studies have suggested a potential relationship between osteoarthritis (OA) and the risk of cardiovascular disease (CVD), with conflicting results. We aimed to provide a systematic and quantitative summary of the association between OA and the risk of CVD. We searched Medline and EMBASE to retrieve prospective and retrospective studies that reported risk estimates of the association between OA status and CVD risk. Pooled estimates were calculated by a random effects model. The search yielded 15 articles including a total of 358,944 participants, including 80,911 OA patients and 29,213 CVD patients. Overall, the risk of CVD was significantly increased by 24% (RR: 1.24, 95% CI: 1.12 to 1.37, P < 0.001) in patients with OA compared with the general population, with no significant publication bias. Furthermore, sensitivity analysis indicated that our results were robust and were not influenced by any one study. In conclusion, this meta-analysis provides strong evidence that OA is a significant risk factor for CVD. PMID- 28004798 TI - The dynamic monitoring of aeolian desertification land distribution and its response to climate change in northern China. AB - Aeolian desertification is poorly understood despite its importance for indicating environment change. Here we exploit Gaofen-1(GF-1) and Moderate Resolution Imaging Spectroradiometer (MODIS) data to develop a quick and efficient method for large scale aeolian desertification dynamic monitoring in northern China. This method, which is based on Normalized Difference Desertification Index (NDDI) calculated by band1 &band2 of MODIS reflectance data (MODIS09A1). Then we analyze spatial-temporal change of aeolian desertification area and detect its possible influencing factors, such as precipitation, temperature, wind speed and population by Convergent Cross Mapping (CCM) model. It suggests that aeolian desertification area with population indicates feedback (bi-directional causality) between the two variables (P < 0.05), but forcing of aeolian desertification area by population is weak. Meanwhile, we find aeolian desertification area is significantly affected by temperature, as expected. However, there is no obvious forcing for the aeolian desertification area and precipitation. Aeolian desertification area with wind speed indicates feedback (bi-directional causality) between the two variables with significant signal (P < 0.01). We infer that aeolian desertification is greatly affected by natural factors compared with anthropogenic factors. For the desertification in China, we are greatly convinced that desertification prevention is better than control. PMID- 28004797 TI - Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity. AB - Bone loss is a serious problem in spaceflight; however, the initial action of microgravity has not been identified. To examine this action, we performed live imaging of animals during a space mission followed by transcriptome analysis using medaka transgenic lines expressing osteoblast and osteoclast-specific promoter-driven GFP and DsRed. In live-imaging for osteoblasts, the intensity of osterix- or osteocalcin-DsRed fluorescence in pharyngeal bones was significantly enhanced 1 day after launch; and this enhancement continued for 8 or 5 days. In osteoclasts, the signals of TRAP-GFP and MMP9-DsRed were highly increased at days 4 and 6 after launch in flight. HiSeq from pharyngeal bones of juvenile fish at day 2 after launch showed up-regulation of 2 osteoblast- and 3 osteoclast- related genes. Gene ontology analysis for the whole-body showed that transcription of genes in the category "nucleus" was significantly enhanced; particularly, transcription-regulators were more up-regulated at day 2 than at day 6. Lastly, we identified 5 genes, c-fos, jun-B-like, pai-1, ddit4 and tsc22d3, which were up-regulated commonly in the whole-body at days 2 and 6, and in the pharyngeal bone at day 2. Our results suggested that exposure to microgravity immediately induced dynamic alteration of gene expression levels in osteoblasts and osteoclasts. PMID- 28004799 TI - Controlled Orientation of Active Sites in a Nanostructured Multienzyme Complex. AB - Multistep cascade reactions in nature maximize reaction efficiency by co assembling related enzymes. Such organization facilitates the processing of intermediates by downstream enzymes. Previously, the studies on multienzyme nanocomplexes assembled on DNA scaffolds demonstrated that closer interenzyme distance enhances the overall reaction efficiency. However, it remains unknown how the active site orientation controlled at nanoscale can have an effect on multienzyme reaction. Here, we show that controlled alignment of active sites promotes the multienzyme reaction efficiency. By genetic incorporation of a non natural amino acid and two compatible bioorthogonal chemistries, we conjugated mannitol dehydrogenase to formate dehydrogenase with the defined active site arrangement with the residue-level accuracy. The study revealed that the multienzyme complex with the active sites directed towards each other exhibits four-fold higher relative efficiency enhancement in the cascade reaction and produces 60% more D-mannitol than the other complex with active sites directed away from each other. PMID- 28004800 TI - Passive immunization with anti-ActA and anti-listeriolysin O antibodies protects against Listeria monocytogenes infection in mice. AB - Listeria monocytogenes is an intracellular pathogen that causes listeriosis. Due to its intracellular niche, L. monocytogenes has evolved to limit immune recognition and response to infection. Antibodies that are slightly induced by listerial infection are completely unable to protect re-infection of L. monocytogenes. Thus, a role of antibody on the protective effect against L. monocytogenes infection has been neglected for a long time. In the present study, we reported that passive immunization with an excessive amount of antibodies against ActA and listeriolysin O (LLO) attenuates severity of L. monocytogenes infection. Combination of these antibodies improved survival of L. monocytogenes infected mice. Bacterial load in spleen and liver of listerial infected mice and infected RAW264.7 cells were significantly reduced by administration of anti-ActA and anti-LLO antibodies. In addition, anti-LLO antibody neutralized LLO activity and inhibited the bacterial escape from the lysosomal compartments. Moreover, anti-ActA antibody neutralized ActA activity and suppressed actin tail formation and cell-to-cell spread. Thus, our studies reveal that passive immunization with the excessive amount of anti-ActA and -LLO antibodies has potential to provide the protective effect against listerial infection. PMID- 28004801 TI - The differentiated airway epithelium infected by influenza viruses maintains the barrier function despite a dramatic loss of ciliated cells. AB - Virus-host interactions in the respiratory epithelium during long term influenza virus infection are not well characterized. Therefore, we developed an air-liquid interface culture system for differentiated porcine respiratory epithelial cells to study the effect of virus-induced cellular damage. In our well-differentiated cells, alpha2,6-linked sialic acid is predominantly expressed on the apical surface and the basal cells mainly express alpha2,3-linked sialic acid. During the whole infection period, release of infectious virus was maintained at a high titre for more than seven days. The infected epithelial cells were subject to apoptosis resulting in the loss of ciliated cells together with a thinner thickness. Nevertheless, the airway epithelium maintained trans-epithelial electrical resistance and retained its barrier function. The loss of ciliated cells was compensated by the cells which contained the KRT5 basal cell marker but were not yet differentiated into ciliated cells. These specialized cells showed an increase of alpha2,3-linked sialic acid on the apical surface. In sum, our results help to explain the localized infection of the airway epithelium by influenza viruses. The impairment of mucociliary clearance in the epithelial cells provides an explanation why prior viral infection renders the host more susceptible to secondary co-infection by another pathogen. PMID- 28004802 TI - Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy. AB - The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+ T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+ T-cell responses. In addition, activating endogenous host CD103+ DCs and the CD40-CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+ T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy. PMID- 28004803 TI - Convergent evidence for the molecular basis of musical traits. AB - To obtain aggregate evidence for the molecular basis of musical abilities and the effects of music, we integrated gene-level data from 105 published studies across multiple species including humans, songbirds and several other animals and used a convergent evidence method to prioritize the top candidate genes. Several of the identified top candidate genes like EGR1, FOS, ARC, BDNF and DUSP1 are known to be activity-dependent immediate early genes that respond to sensory and motor stimuli in the brain. Several other top candidate genes like MAPK10, SNCA, ARHGAP24, TET2, UBE2D3, FAM13A and NUDT9 are located on chromosome 4q21-q24, on the candidate genomic region for music abilities in humans. Functional annotation analyses showed the enrichment of genes involved in functions like cognition, learning, memory, neuronal excitation and apoptosis, long-term potentiation and CDK5 signaling pathway. Interestingly, all these biological functions are known to be essential processes underlying learning and memory that are also fundamental for musical abilities including recognition and production of sound. In summary, our study prioritized top candidate genes related to musical traits. PMID- 28004804 TI - Distribution of Herbivorous Fish Is Frozen by Low Temperature. AB - The number of herbivores in populations of ectothermic vertebrates decreases with increasing latitude. At higher latitudes, fish consuming plant matter are exclusively omnivorous. We assess whether omnivorous fish readily shift to herbivory or whether animal prey is typically preferred. We address temperature as the key factor causing their absence at higher latitudes and discuss the potential poleward dispersion caused by climate changes. A controlled experiment illustrates that rudd (Scardinius erythrophthalmus) readily utilize plant matter at water temperatures above 20 degrees C and avoid its consumption below 20 degrees C. Field data support these results, showing that plant matter dominates rudd diets during the summer and is absent during the spring. Utilizing cellulose requires the enzyme cellulase, which is produced by microorganisms growing at temperatures of 15-42 degrees C. Water temperatures at higher latitudes do not reach 15 degrees C year-round; at our latitude of 50 degrees N~150 days/year. Hence, the species richness of omnivorous fish decreases dramatically above 55 degrees latitude. Our results provide support for the hypothesis that strict herbivorous specialists have developed only in the tropics. Temperatures below 15 degrees C, even for a short time period, inactivate cellulase and cause diet limitations for omnivorous fish. However, we may expect increases in herbivory at higher latitudes caused by climate change. PMID- 28004805 TI - Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein. AB - Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2alpha, ATF4, IRE1alpha, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway. PMID- 28004806 TI - Fixation Probabilities for Any Configuration of Two Strategies on Regular Graphs. AB - Population structure and spatial heterogeneity are integral components of evolutionary dynamics, in general, and of evolution of cooperation, in particular. Structure can promote the emergence of cooperation in some populations and suppress it in others. Here, we provide results for weak selection to favor cooperation on regular graphs for any configuration, meaning any arrangement of cooperators and defectors. Our results extend previous work on fixation probabilities of rare mutants. We find that for any configuration cooperation is never favored for birth-death (BD) updating. In contrast, for death-birth (DB) updating, we derive a simple, computationally tractable formula for weak selection to favor cooperation when starting from any configuration containing any number of cooperators. This formula elucidates two important features: (i) the takeover of cooperation can be enhanced by the strategic placement of cooperators and (ii) adding more cooperators to a configuration can sometimes suppress the evolution of cooperation. These findings give a formal account for how selection acts on all transient states that appear in evolutionary trajectories. They also inform the strategic design of initial states in social networks to maximally promote cooperation. We also derive general results that characterize the interaction of any two strategies, not only cooperation and defection. PMID- 28004808 TI - IL-13 is a therapeutic target in radiation lung injury. AB - Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-beta1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Ralpha2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Ralpha2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL 13 may be useful in screening for timely delivery of anti-IL-13 therapeutics. PMID- 28004809 TI - Characterization of the relationship between polar and lateral flagellar structural genes in the deep-sea bacterium Shewanella piezotolerans WP3. AB - Bacteria with a dual flagellar system, which consists of a polar flagellum (PF) and several lateral flagella (LF), have been identified in diverse environments. Nevertheless, whether and how these two flagellar systems interact with each other is largely unknown. In the present study, the relationship between the structural genes for the PF and LF of the deep-sea bacterium Shewanella piezotolerans WP3 was investigated by genetic, phenotypic and phylogenetic analyses. The mutation of PF genes induced the expression of LF genes and the production of LF in liquid medium, while the defective LF genes led to a decrease in PF gene transcription. However, the level of PF flagellin remained unchanged in LF gene mutants. Further investigation showed that the flgH2 gene (encoding LF L-ring protein) can compensate for mutations of the flgH1 gene (encoding PF L ring protein), but this compensation does not occur between the flagellar hook filament junction proteins (FlgL1, FlgL2). Swarming motility was shown to specifically require LF genes, and PF genes cannot substitute for the LF genes in the lateral flagella synthesis. Considering the importance of flagella-dependent motility for bacterial survival in the abyssal sediment, our study thus provided a better understanding of the adaptation strategy of benthic bacteria. PMID- 28004810 TI - A plant tendril mimic soft actuator with phototunable bending and chiral twisting motion modes. AB - In nature, plant tendrils can produce two fundamental motion modes, bending and chiral twisting (helical curling) distortions, under the stimuli of sunlight, humidity, wetting or other atmospheric conditions. To date, many artificial plant like mechanical machines have been developed. Although some previously reported materials could realize bending or chiral twisting through tailoring the samples into various ribbons along different orientations, each single ribbon could execute only one deformation mode. The challenging task is how to endow one individual plant tendril mimic material with two different, fully tunable and reversible motion modes (bending and chiral twisting). Here we show a dual-layer, dual-composition polysiloxane-based liquid crystal soft actuator strategy to synthesize a plant tendril mimic material capable of performing two different three-dimensional reversible transformations (bending versus chiral twisting) through modulation of the wavelength band of light stimuli (ultraviolet versus near-infrared). This material has broad application prospects in biomimetic control devices. PMID- 28004807 TI - Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. AB - Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria. PMID- 28004811 TI - Nitrite addition to acidified sludge significantly improves digestibility, toxic metal removal, dewaterability and pathogen reduction. AB - Sludge management is a major issue for water utilities globally. Poor digestibility and dewaterability are the main factors determining the cost for sludge management, whereas pathogen and toxic metal concentrations limit beneficial reuse. In this study, the effects of low level nitrite addition to acidified sludge to simultaneously enhance digestibility, toxic metal removal, dewaterability and pathogen reduction were investigated. Waste activated sludge (WAS) from a full-scale waste water treatment plant was treated at pH 2 with 10 mg NO2--N/L for 5 h. Biochemical methane potential tests showed an increase in the methane production of 28%, corresponding to an improvement from 247 +/- 8 L CH4/kg VS to 317 +/- 1 L CH4/kg VS. The enhanced removal of toxic metals further increased the methane production by another 18% to 360 +/- 6 L CH4/kg VS (a total increase of 46%). The solids content of dewatered sludge increased from 14.6 +/- 1.4% in the control to 18.2 +/- 0.8%. A 4-log reduction for both total coliforms and E. coli was achieved. Overall, this study highlights the potential of acidification with low level nitrite addition as an effective and simple method achieving multiple improvements in terms of sludge management. PMID- 28004812 TI - p120-catenin prevents multinucleation through control of MKLP1-dependent RhoA activity during cytokinesis. AB - Spatiotemporal activation of RhoA and actomyosin contraction underpins cellular adhesion and division. Loss of cell-cell adhesion and chromosomal instability are cardinal events that drive tumour progression. Here, we show that p120-catenin (p120) not only controls cell-cell adhesion, but also acts as a critical regulator of cytokinesis. We find that p120 regulates actomyosin contractility through concomitant binding to RhoA and the centralspindlin component MKLP1, independent of cadherin association. In anaphase, p120 is enriched at the cleavage furrow where it binds MKLP1 to spatially control RhoA GTPase cycling. Binding of p120 to MKLP1 during cytokinesis depends on the N-terminal coiled-coil domain of p120 isoform 1A. Importantly, clinical data show that loss of p120 expression is a common event in breast cancer that strongly correlates with multinucleation and adverse patient survival. In summary, our study identifies p120 loss as a driver event of chromosomal instability in cancer. PMID- 28004813 TI - Electrical stimulation drives chondrogenesis of mesenchymal stem cells in the absence of exogenous growth factors. AB - Electrical stimulation (ES) is known to guide the development and regeneration of many tissues. However, although preclinical and clinical studies have demonstrated superior effects of ES on cartilage repair, the effects of ES on chondrogenesis remain elusive. Since mesenchyme stem cells (MSCs) have high therapeutic potential for cartilage regeneration, we investigated the actions of ES during chondrogenesis of MSCs. Herein, we demonstrate for the first time that ES enhances expression levels of chondrogenic markers, such as type II collagen, aggrecan, and Sox9, and decreases type I collagen levels, thereby inducing differentiation of MSCs into hyaline chondrogenic cells without the addition of exogenous growth factors. ES also induced MSC condensation and subsequent chondrogenesis by driving Ca2+/ATP oscillations, which are known to be essential for prechondrogenic condensation. In subsequent experiments, the effects of ES on ATP oscillations and chondrogenesis were dependent on extracellular ATP signaling via P2X4 receptors, and ES induced significant increases in TGF-beta1 and BMP2 expression. However, the inhibition of TGF-beta signaling blocked ES-driven condensation, whereas the inhibition of BMP signaling did not, indicating that TGF-beta signaling but not BMP signaling mediates ES-driven condensation. These findings may contribute to the development of electrotherapeutic strategies for cartilage repair using MSCs. PMID- 28004814 TI - Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration. AB - The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment. PMID- 28004815 TI - Bmi1-positive cells in the lingual epithelium could serve as cancer stem cells in tongue cancer. AB - We recently reported that the polycomb complex protein Bmi1 is a marker for lingual epithelial stem cells (LESCs), which are involved in the long-term maintenance of lingual epithelial tissue in the physiological state. However, the precise role of LESCs in generating tongue tumors and Bmi1-positive cell lineage dynamics in tongue cancers are unclear. Here, using a mouse model of chemically (4-nitroquinoline-1-oxide: 4-NQO) induced tongue cancer and the multicolor lineage tracing method, we found that each unit of the tumor was generated by a single cell and that the assembly of such cells formed a polyclonal tumor. Although many Bmi1-positive cells within the tongue cancer specimens failed to proliferate, some proliferated continuously and supplied tumor cells to the surrounding area. This process eventually led to the formation of areas derived from single cells after 1-3 months, as determined using the multicolor lineage tracing method, indicating that such cells could serve as cancer stem cells. These results indicate that LESCs could serve as the origin for tongue cancer and that cancer stem cells are present in tongue tumors. PMID- 28004817 TI - Assessment of myocardial function in elite athlete's heart at rest - 2D speckle tracking echocardiography in Korean elite soccer players. AB - The purpose of this study was to investigate Korean elite soccer players' myocardial function using the conventional and advanced speckle tracking imaging to compare the difference with the normal controls. We used 2D echocardiography speckle tracking echocardiography (STE) to evaluate LV regional strain in 29 elite soccer players compared to 29 age-matched healthy controls. Conventional, tissue Doppler, and STI echocardiography was performed, for strain at base and apex, rotation and torsion. There is no difference in longitudinal strain (-17.6 +/- 1.8 vs -17.3 +/- 2.9, p = ns), and basal radial strain. However, the significant increases were noticed in basal circumferential strain (-17.5 +/- 2.6 vs -15.5 +/- 8.9, p = 0.05), apical radial strain (33.1 +/- 20.5 vs 22.5 +/- 19.4, p = 0.02), and apical circumferential strain in soccer players (-21.4 +/- 4.8 vs -16.8 +/- 7.6, p = 0.005). Soccer players showed the higher rotation at base (-3.9 +/- 1.9 vs -2.6 +/- 3.2, p = 0.03), and apex (6.98 +/- 2.62 vs 6.21 +/ 3.81, p = 0.05), higher torsion (10.9 +/- 3.7 vs 8.8 +/- 6.3, p = 0.05). In conclusion, the elite soccer players' heart demonstrated the unique ventricular adaptation. These alterations could benefit the cardiovascular adjustment to exercise without much loss of myocardial energy expenditure. PMID- 28004816 TI - A combined reference panel from the 1000 Genomes and UK10K projects improved rare variant imputation in European and Chinese samples. AB - Imputation using the 1000 Genomes haplotype reference panel has been widely adapted to estimate genotypes in genome wide association studies. To evaluate imputation quality with a relatively larger reference panel and a reference panel composed of different ethnic populations, we conducted imputations in the Framingham Heart Study and the North Chinese Study using a combined reference panel from the 1000 Genomes (N = 1,092) and UK10K (N = 3,781) projects. For rare variants with 0.01% < MAF <= 0.5%, imputation in the Framingham Heart Study with the combined reference panel increased well-imputed genotypes (with imputation quality score >=0.4) from 62.9% to 76.1% when compared to imputation with the 1000 Genomes. For the North Chinese samples, imputation of rare variants with 0.01% < MAF <= 0.5% with the combined reference panel increased well-imputed genotypes by from 49.8% to 61.8%. The predominant European ancestry of the UK10K and the combined reference panels may explain why there was less of an increase in imputation success in the North Chinese samples. Our results underscore the importance and potential of larger reference panels to impute rare variants, while recognizing that increasing ethnic specific variants in reference panels may result in better imputation for genotypes in some ethnic groups. PMID- 28004819 TI - Long-Term Stable Organic Photodetectors with Ultra Low Dark Currents for High Detectivity Applications. AB - Printed organic photodetectors can transform plastic, paper or glass into smart surfaces. This innovative technology is now growing exponentially due to the strong demand in human-machine interfaces. To date, only niche markets are targeted since organic sensors still present reduced performances in comparison with their inorganic counterparts. Here we demonstrate that it is possible to engineer a state-of-the-art organic photodetector approaching the performances of Si-based photodiodes in terms of dark current, responsivity and detectivity. Only three solution-processed layers and two low-temperature annealing steps are needed to achieve the performance that is significantly better than most of the organic photodetectors reported so far. We also perform a long-term ageing study. Lifetimes of over 14,000 hours under continuous operation are more than promising and demonstrate that organic photodetectors can reach a competitive level of stability for successful commercialization of this new and promising technology. PMID- 28004818 TI - 3-D Microwell Array System for Culturing Virus Infected Tumor Cells. AB - Cancer cells have been increasingly grown in pharmaceutical research to understand tumorigenesis and develop new therapeutic drugs. Currently, cells are typically grown using two-dimensional (2-D) cell culture approaches, where the native tumor microenvironment is difficult to recapitulate. Thus, one of the main obstacles in oncology is the lack of proper infection models that recount main features present in tumors. In recent years, microtechnology-based platforms have been employed to generate three-dimensional (3-D) models that better mimic the native microenvironment in cell culture. Here, we present an innovative approach to culture Kaposi's sarcoma-associated herpesvirus (KSHV) infected human B cells in 3-D using a microwell array system. The results demonstrate that the KSHV infected B cells can be grown up to 15 days in a 3-D culture. Compared with 2-D, cells grown in 3-D had increased numbers of KSHV latency-associated nuclear antigen (LANA) dots, as detected by immunofluorescence microscopy, indicating a higher viral genome copy number. Cells in 3-D also demonstrated a higher rate of lytic reactivation. The 3-D microwell array system has the potential to improve 3 D cell oncology models and allow for better-controlled studies for drug discovery. PMID- 28004820 TI - Detection of timescales in evolving complex systems. AB - Most complex systems are intrinsically dynamic in nature. The evolution of a dynamic complex system is typically represented as a sequence of snapshots, where each snapshot describes the configuration of the system at a particular instant of time. This is often done by using constant intervals but a better approach would be to define dynamic intervals that match the evolution of the system's configuration. To this end, we propose a method that aims at detecting evolutionary changes in the configuration of a complex system, and generates intervals accordingly. We show that evolutionary timescales can be identified by looking for peaks in the similarity between the sets of events on consecutive time intervals of data. Tests on simple toy models reveal that the technique is able to detect evolutionary timescales of time-varying data both when the evolution is smooth as well as when it changes sharply. This is further corroborated by analyses of several real datasets. Our method is scalable to extremely large datasets and is computationally efficient. This allows a quick, parameter-free detection of multiple timescales in the evolution of a complex system. PMID- 28004821 TI - Two-dimensional distributed-phase-reference protocol for quantum key distribution. AB - Quantum key distribution (QKD) and quantum communication enable the secure exchange of information between remote parties. Currently, the distributed-phase reference (DPR) protocols, which are based on weak coherent pulses, are among the most practical solutions for long-range QKD. During the last 10 years, long distance fiber-based DPR systems have been successfully demonstrated, although fundamental obstacles such as intrinsic channel losses limit their performance. Here, we introduce the first two-dimensional DPR-QKD protocol in which information is encoded in the time and phase of weak coherent pulses. The ability of extracting two bits of information per detection event, enables a higher secret key rate in specific realistic network scenarios. Moreover, despite the use of more dimensions, the proposed protocol remains simple, practical, and fully integrable. PMID- 28004822 TI - Mass spectrometry imaging of biomarker lipids for phagocytosis and signalling during focal cerebral ischaemia. AB - Focal cerebral ischaemia has an initial phase of inflammation and tissue injury followed by a later phase of resolution and repair. Mass spectrometry imaging (desorption electrospray ionization and matrix assisted laser desorption ionization) was applied on brain sections from mice 2 h, 24 h, 5d, 7d, and 20d after permanent focal cerebral ischaemia. Within 24 h, N-acyl phosphatidylethanolamines, lysophosphatidylcholine, and ceramide accumulated, while sphingomyelin disappeared. At the later resolution stages, bis(monoacylglycero)phosphate (BMP(22:6/22:6)), 2-arachidonoyl-glycerol, ceramide phosphate, sphingosine-1-phosphate, lysophosphatidylserine, and cholesteryl ester appeared. At day 5 to 7, dihydroxy derivates of docosahexaenoic and docosapentaenoic acid, some of which may be pro-resolving mediators, e.g. resolvins, were found in the injured area, and BMP(22:6/22:6) co-localized with the macrophage biomarker CD11b, and probably with cholesteryl ester. Mass spectrometry imaging can visualize spatiotemporal changes in the lipidome during the progression and resolution of focal cerebral inflammation and suggests that BMP(22:6/22:6) and N-acyl-phosphatidylethanolamines can be used as biomarkers for phagocytizing macrophages/microglia cells and dead neurones, respectively. PMID- 28004823 TI - Paclobutrazol induces tolerance in tomato to deficit irrigation through diversified effects on plant morphology, physiology and metabolism. AB - Dwindling water resources combined with meeting the demands for food security require maximizing water use efficiency (WUE) both in rainfed and irrigated agriculture. In this regard, deficit irrigation (DI), defined as the administration of water below full crop-water requirements (evapotranspiration), is a valuable practice to contain irrigation water use. In this study, the mechanism of paclobutrazol (Pbz)-mediated improvement in tolerance to water deficit in tomato was thoroughly investigated. Tomato plants were subjected to normal irrigated and deficit irrigated conditions plus Pbz application (0.8 and 1.6 ppm). A comprehensive morpho-physiological, metabolomics and molecular analysis was undertaken. Findings revealed that Pbz application reduced plant height, improved stem diameter and leaf number, altered root architecture, enhanced photosynthetic rates and WUE of tomato plants under deficit irrigation. Pbz differentially induced expression of genes and accumulation of metabolites of the tricarboxylic acid (TCA) cycle, gamma-aminobutyric acid (GABA-shunt pathway), glutathione ascorbate (GSH-ASC)-cycle, cell wall and sugar metabolism, abscisic acid (ABA), spermidine (Spd) content and expression of an aquaporin (AP) protein under deficit irrigation. Our results suggest that Pbz application could significantly improve tolerance in tomato plants under limited water availability through selective changes in morpho-physiology and induction of stress-related molecular processes. PMID- 28004825 TI - Tunable Spin dependent beam shift by simultaneously tailoring geometric and dynamical phases of light in inhomogeneous anisotropic medium. AB - Spin orbit interaction and the resulting Spin Hall effect of light are under recent intensive investigations because of their fundamental nature and potential applications. Here, we report an interesting manifestation of spin Hall effect of light and demonstrate its tunability in an inhomogeneous anisotropic medium exhibiting spatially varying retardance level. In our system, the beam shift occurs only for one circular polarization mode keeping the other orthogonal mode unaffected, which is shown to arise due to the combined spatial gradients of the geometric phase and the dynamical phase of light. The constituent two orthogonal circular polarization modes of an input linearly polarized light evolve in different trajectories, eventually manifesting as a large and tunable spin separation. The spin dependent beam shift and the demonstrated principle of simultaneously tailoring space-varying geometric and dynamical phase of light for achieving its tunability (of both magnitude and direction), may provide an attractive route towards development of spin-optical devices. PMID- 28004824 TI - High performing solution-coated electrolyte-gated organic field-effect transistors for aqueous media operation. AB - Since the first demonstration, the electrolyte-gated organic field-effect transistors (EGOFETs) have immediately gained much attention for the development of cutting-edge technology and they are expected to have a strong impact in the field of (bio-)sensors. However EGOFETs directly expose their active material towards the aqueous media, hence a limited library of organic semiconductors is actually suitable. By using two mostly unexplored strategies in EGOFETs such as blended materials together with a printing technique, we have successfully widened this library. Our benchmarks were 6,13 bis(triisopropylsilylethynyl)pentacene and 2,8-difluoro-5,11 bis(triethylsilylethynyl)anthradithiophene (diF-TES-ADT), which have been firstly blended with polystyrene and secondly deposited by means of the bar-assisted meniscus shearing (BAMS) technique. Our approach yielded thin films (i.e. no thicker than 30 nm) suitable for organic electronics and stable in liquid environment. Up to date, these EGOFETs show unprecedented performances. Furthermore, an extremely harsh environment, like NaCl 1M, has been used in order to test the limit of operability of these electronic devices. Albeit an electrical worsening is observed, our devices can operate under different electrical stresses within the time frame of hours up to a week. In conclusion, our approach turns out to be a powerful tool for the EGOFET manufacturing. PMID- 28004826 TI - A general nonaqueous sol-gel route to g-C3N4-coupling photocatalysts: the case of Z-scheme g-C3N4/TiO2 with enhanced photodegradation toward RhB under visible light. AB - The g-C3N4-coupling TiO2 photocatalysts with controllable particle size as well as the interface contact were prepared by a general nonaqueous sol-gel method. The structural and morphological features of g-C3N4/TiO2 were investigated through the X-ray diffraction, Fourier transformed infrared spectra, scanning electron microscopy and transmission electron microscopy, respectively. It is found the TiO2 nanoparticles with a size of 7.3 +/- 1.6 nm are uniformly anchored on the surface of the g-C3N4 nanosheets in isolation. The photocatalytic properties of as-prepared g-C3N4/TiO2 were tested by degradation of Rhodamine B (RhB) under visible light, and an enhanced activity is observed. The mechanism of the enhanced activity was further investigated through N2 adsorption-desorption isotherms, UV-vis spectra, photoluminescence spectra, photoelectrochemical measurements, radical trapping experiments and X-ray photoelectron spectroscopy. Furthermore, the photocatalytic performances of obtained g-C3N4/TiO2 under sunlight were also evaluated in aspects of degradation efficiency and stability. The results indicate that the obtained g-C3N4/TiO2 is one promising photocatalyst for practical applications. The study of as-prepared g-C3N4/TiO2 also implies that the present method could be a general route of g-C3N4-coupling photocatalysts. PMID- 28004827 TI - HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels. AB - A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1- and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative feedback mechanism on membrane lipids. PMID- 28004828 TI - Analysis of CXCR5+Th17 cells in relation to disease activity and TNF inhibitor therapy in Rheumatoid Arthritis. AB - Th17 and TfH cells are thought to promote tissue inflammation and autoantibody production, respectively, in autoimmune diseases including rheumatoid arthritis (RA). TfH cells that co-express Th17 markers (CXCR5+Th17) encompass both of these pathogenic functions, and are increased in some human autoimmune settings including juvenile dermatomyositis. We investigated CXCR5+Th17 cells in RA subjects with stable or active disease and before and after TNF inhibitor therapy. CXCR5+Th17 cell frequency was increased in RA compared to healthy controls, but other helper T cell subsets were not different. CXCR5+Th17 cells correlated with disease activity in subjects with active RA prior to initiation of TNF inhibitor therapy. Baseline CXCR5+Th17 cells also correlated with numbers of swollen joints as late as one year post-therapy. CXCR5+Th17 cell frequencies were unaltered by TNF blockade and in fact remained remarkably stable within individuals. We conclude that CXCR5+Th17 cells are not a direct target of TNF blockade and therefore cannot serve as a biomarker of current disease activity. However, basal CXCR5+Th17 cell frequency may indicate underlying differences in disease phenotype between patients and predict ultimate success of TNF inhibitor therapy. PMID- 28004829 TI - Synergistic Effect of Atmospheric-pressure Plasma and TiO2 Photocatalysis on Inactivation of Escherichia coli Cells in Aqueous Media. AB - Atmospheric-pressure plasma and TiO2 photocatalysis have been widely investigated separately for the management and reduction of microorganisms in aqueous solutions. In this paper, the two methods were combined in order to achieve a more profound understanding of their interactions in disinfection of water contaminated by Escherichia coli. Under water discharges carried out by microplasma jet arrays can result in a rapid inactivation of E. coli cells. The inactivation efficiency is largely dependent on the feed gases used, the plasma treatment time, and the discharge power. Compared to atmospheric-pressure N2, He and air microplasma arrays, O2 microplasma had the highest activity against E. coli cells in aqueous solution, and showed >99.9% bacterial inactivation efficiency within 4 min. Addition of TiO2 photocatalytic film to the plasma discharge reactor significantly enhanced the inactivation efficiency of the O2 microplasma system, decreasing the time required to achieve 99.9% killing of E. coli cells to 1 min. This may be attributed to the enhancement of ROS generation due to high catalytic activity and stability of the TiO2 photocatalyst in the combined plasma-TiO2 systems. Present work demonstrated the synergistic effect of the two agents, which can be correlated in order to maximize treatment efficiency. PMID- 28004830 TI - Fluid flow facilitates inward rectifier K+ current by convectively restoring [K+] at the cell membrane surface. AB - The inward rectifier Kir2.1 current (IKir2.1) was reported to be facilitated by fluid flow. However, the mechanism underlying this facilitation remains uncertain. We hypothesized that during K+ influx or efflux, [K+] adjacent to the outer mouth of the Kir2.1 channel might decrease or increase, respectively, compared with the average [K+] of the bulk extracellular solution, and that fluid flow could restore the original [K+] and result in the apparent facilitation of IKir2.1. We recorded the IKir2.1 in RBL-2H3 cells and HEK293T cells that were ectopically over-expressed with Kir2.1 channels by using the whole-cell patch clamp technique. Fluid-flow application immediately increased the IKir2.1, which was not prevented by either the pretreatment with inhibitors of various protein kinases or the modulation of the cytoskeleton and caveolae. The magnitudes of the increases of IKir2.1 by fluid flow were driving force-dependent. Simulations performed using the Nernst-Planck mass equation indicated that [K+] near the membrane surface fell markedly below the average [K+] of the bulk extracellular solution during K+ influx, and, notably, that fluid flow restored the decreased [K+] at the cell surface in a flow rate-dependent manner. These results support the "convection-regulation hypothesis" and define a novel interpretation of fluid flow-induced modulation of ion channels. PMID- 28004831 TI - An Adaptation To Life In Acid Through A Novel Mevalonate Pathway. AB - Extreme acidophiles are capable of growth at pH values near zero. Sustaining life in acidic environments requires extensive adaptations of membranes, proton pumps, and DNA repair mechanisms. Here we describe an adaptation of a core biochemical pathway, the mevalonate pathway, in extreme acidophiles. Two previously known mevalonate pathways involve ATP dependent decarboxylation of either mevalonate 5 phosphate or mevalonate 5-pyrophosphate, in which a single enzyme carries out two essential steps: (1) phosphorylation of the mevalonate moiety at the 3-OH position and (2) subsequent decarboxylation. We now demonstrate that in extreme acidophiles, decarboxylation is carried out by two separate steps: previously identified enzymes generate mevalonate 3,5-bisphosphate and a new decarboxylase we describe here, mevalonate 3,5-bisphosphate decarboxylase, produces isopentenyl phosphate. Why use two enzymes in acidophiles when one enzyme provides both functionalities in all other organisms examined to date? We find that at low pH, the dual function enzyme, mevalonate 5-phosphate decarboxylase is unable to carry out the first phosphorylation step, yet retains its ability to perform decarboxylation. We therefore propose that extreme acidophiles had to replace the dual-purpose enzyme with two specialized enzymes to efficiently produce isoprenoids in extremely acidic environments. PMID- 28004833 TI - First-principles study of the electronic and optical properties of a new metallic MoAlB. AB - The structural, elastic, electronic and optical properties of MoAlB were investigated by first-principles calculations. The hardness of MoAlB is 12.71 GPa, which is relatively softer and easily machinable compared to the other borides. The analysis of the band structure and density (DOS) of states indicates that MoAlB has a metallic nature. The analysis of the electron localization function (ELF) shows that the Mo-B bond is a polar covalent bond with a short distance, which may increase the stability of the compound. The calculation of the phonon frequencies confirms the dynamical stability of MoAlB. Optical properties of MoAlB are investigated. In the energy range up to ~19 eV, MoAlB possesses high reflectivity and has the strongest absorption in the energy range of 0-23.0 eV. In addition, the plasma frequency of MoAlB is 20.4 eV and MoAlB can change from a metallic to a dielectric response if the incident light has a frequency greater than 20.4 eV. PMID- 28004832 TI - Theoretic Study on Dispersion Mechanism of Boron Nitride Nanotubes by Polynucleotides. AB - Due to the unique electrical and mechanical properties of boron nitride nanotubes (BNNT), BNNT has been a promising material for many potential applications, especially in biomedical field. Understanding the dispersion of BNNT in aqueous solution by biomolecules is essential for its use in biomedical applications. In this study, BNNT wrapped by polynucleotides in aqueous solution was investigated by molecular dynamics (MD) simulations. Our results demonstrated that the BNNT wrapped by polynucleotides could greatly hinder the aggregation of BNNTs and improve the dispersion of BNNTs in aqueous solution. Dispersion of BNNTs with the assistance of polynucleotides is greatly affected by the wrapping manner of polynucleotides on BNNT, which mainly depends on two factors: the type of polynucleotides and the radius of BNNT. The interaction between polynucleotides and BNNT(9, 9) is larger than that between polynucleotides and BNNT(5, 5), which leads to the fact that dispersion of BNNT(9, 9) is better than that of BNNT(5, 5) with the assistance of polynucleotides in aqueous solution. Our study revealed the molecular-level dispersion mechanism of BNNT with the assistance of polynucleotides in aqueous solution. It shades a light on the understanding of dispersion of single wall nanotubes by biomolecules. PMID- 28004834 TI - Kink pair production and dislocation motion. AB - The motion of extended defects called dislocations controls the mechanical properties of crystalline materials such as strength and ductility. Under moderate applied loads, this motion proceeds via the thermal nucleation of kink pairs. The nucleation rate is known to be a highly nonlinear function of the applied load, and its calculation has long been a theoretical challenge. In this article, a stochastic path integral approach is used to derive a simple, general, and exact formula for the rate. The predictions are in excellent agreement with experimental and computational investigations, and unambiguously explain the origin of the observed extreme nonlinearity. The results can also be applied to other systems modelled by an elastic string interacting with a periodic potential, such as Josephson junctions in superconductors. PMID- 28004835 TI - Genomes of coral dinoflagellate symbionts highlight evolutionary adaptations conducive to a symbiotic lifestyle. AB - Despite half a century of research, the biology of dinoflagellates remains enigmatic: they defy many functional and genetic traits attributed to typical eukaryotic cells. Genomic approaches to study dinoflagellates are often stymied due to their large, multi-gigabase genomes. Members of the genus Symbiodinium are photosynthetic endosymbionts of stony corals that provide the foundation of coral reef ecosystems. Their smaller genome sizes provide an opportunity to interrogate evolution and functionality of dinoflagellate genomes and endosymbiosis. We sequenced the genome of the ancestral Symbiodinium microadriaticum and compared it to the genomes of the more derived Symbiodinium minutum and Symbiodinium kawagutii and eukaryote model systems as well as transcriptomes from other dinoflagellates. Comparative analyses of genome and transcriptome protein sets show that all dinoflagellates, not only Symbiodinium, possess significantly more transmembrane transporters involved in the exchange of amino acids, lipids, and glycerol than other eukaryotes. Importantly, we find that only Symbiodinium harbor an extensive transporter repertoire associated with the provisioning of carbon and nitrogen. Analyses of these transporters show species-specific expansions, which provides a genomic basis to explain differential compatibilities to an array of hosts and environments, and highlights the putative importance of gene duplications as an evolutionary mechanism in dinoflagellates and Symbiodinium. PMID- 28004836 TI - An expressed, endogenous Nodavirus-like element captured by a retrotransposon in the genome of the plant parasitic nematode Bursaphelenchus xylophilus. AB - Recently, nematode viruses infecting Caenorhabditis elegans have been reported from the family Nodaviridae, the first nematode viruses described. Here, we report the observation of a novel endogenous viral element (EVE) in the genome of Bursaphelenchus xylophilus, a plant parasitic nematode unrelated to other nematodes from which viruses have been characterised. This element derives from a different clade of nodaviruses to the previously reported nematode viruses. This represents the first endogenous nodavirus sequence, the first nematode endogenous viral element, and significantly extends our knowledge of the potential diversity of the Nodaviridae. A search for endogenous elements related to the Nodaviridae did not reveal any elements in other available nematode genomes. Further surveillance for endogenous viral elements is warranted as our knowledge of nematode genome diversity, and in particular of free-living nematodes, expands. PMID- 28004837 TI - The DE and FG loops of the HPV major capsid protein contribute to the epitopes of vaccine-induced cross-neutralising antibodies. AB - The human papillomavirus (HPV) vaccines consist of major capsid protein (L1) virus-like particles (VLP) and are highly efficacious against the development of cervical cancer precursors attributable to oncogenic genotypes, HPV16 and HPV18. A degree of vaccine-induced cross-protection has also been demonstrated against genetically-related genotypes in the Alpha-7 (HPV18-like) and Alpha-9 (HPV16 like) species groups which is coincident with the detection of L1 cross neutralising antibodies. In this study the L1 domains recognised by inter genotype cross-neutralising antibodies were delineated. L1 crystallographic homology models predicted a degree of structural diversity between the L1 loops of HPV16 and the non-vaccine Alpha-9 genotypes. These structural predictions informed the design of chimeric pseudovirions with inter-genotype loop swaps which demonstrated that the L1 domains recognised by inter-genotype cross neutralising antibodies comprise residues within the DE loop and the late region of the FG loop. These data contribute to our understanding of the L1 domains recognised by vaccine-induced cross-neutralising antibodies. Such specificities may play a critical role in vaccine-induced cross-protection. PMID- 28004839 TI - Ultrahigh Oxidation Resistance and High Electrical Conductivity in Copper-Silver Powder. AB - The electrical conductivity of pure Cu powder is typically deteriorated at elevated temperatures due to the oxidation by forming non-conducting oxides on surface, while enhancing oxidation resistance via alloying is often accompanied by a drastic decline of electrical conductivity. Obtaining Cu powder with both a high electrical conductivity and a high oxidation resistance represents one of the key challenges in developing next-generation electrical transferring powder. Here, we fabricate a Cu-Ag powder with a continuous Ag network along grain boundaries of Cu particles and demonstrate that this new structure can inhibit the preferential oxidation in grain boundaries at elevated temperatures. As a result, the Cu-Ag powder displays considerably high electrical conductivity and high oxidation resistance up to approximately 300 degrees C, which are markedly higher than that of pure Cu powder. This study paves a new pathway for developing novel Cu powders with much enhanced electrical conductivity and oxidation resistance in service. PMID- 28004838 TI - Genome-wide analysis of long-term evolutionary domestication in Drosophila melanogaster. AB - Experimental evolutionary genomics now allows biologists to test fundamental theories concerning the genetic basis of adaptation. We have conducted one of the longest laboratory evolution experiments with any sexually-reproducing metazoan, Drosophila melanogaster. We used next-generation resequencing data from this experiment to examine genome-wide patterns of genetic variation over an evolutionary time-scale that approaches 1,000 generations. We also compared measures of variation within and differentiation between our populations to simulations based on a variety of evolutionary scenarios. Our analysis yielded no clear evidence of hard selective sweeps, whereby natural selection acts to increase the frequency of a newly-arising mutation in a population until it becomes fixed. We do find evidence for selection acting on standing genetic variation, as independent replicate populations exhibit similar population genetic dynamics, without obvious fixation of candidate alleles under selection. A hidden-Markov model test for selection also found widespread evidence for selection. We found more genetic variation genome-wide, and less differentiation between replicate populations genome-wide, than arose in any of our simulated evolutionary scenarios. PMID- 28004840 TI - Dual observation of the ATP-evoked small GTPase activation and Ca2+ transient in astrocytes using a dark red fluorescent protein. AB - Intracellular signal transduction involves a number of biochemical reactions, which largely consist of protein-protein interactions and protein conformational changes. Monitoring Forster resonance energy transfer (FRET) by fluorescence lifetime imaging microscopy (FLIM), called FLIM-FRET, is one of the best ways to visualize such protein dynamics. Here, we attempted to apply dark red fluorescent proteins with significantly smaller quantum yields. Application of the dark mCherry mutants to single-molecule FRET sensors revealed that these dark mCherry mutants are a good acceptor in a pair with mRuby2. Because the FRET measurement between mRuby2 and dark mCherry requires only the red region of wavelengths, it facilitates dual observation with other signaling sensors such as genetically encoded Ca2+ sensors. Taking advantage of this approach, we attempted dual observation of Ca2+ and Rho GTPase (RhoA and Cdc42) activities in astrocytes and found that ATP triggers both RhoA and Cdc42 activation. In early phase, while Cdc42 activity is independent of Ca2+ transient evoked by ATP, RhoA activity is Ca2+ dependent. Moreover, the transient Ca2+ upregulation triggers long-lasting Cdc42 and RhoA activities, thereby converting short-term Ca2+ signaling to long term signaling. Thus, the new FRET pair should be useful for dual observation of intracellular biochemical reactions. PMID- 28004842 TI - Puzzles in modern biology. I. Male sterility, failure reveals design. AB - Many human males produce dysfunctional sperm. Various plants frequently abort pollen. Hybrid matings often produce sterile males. Widespread male sterility is puzzling. Natural selection prunes reproductive failure. Puzzling failure implies something that we do not understand about how organisms are designed. Solving the puzzle reveals the hidden processes of design. PMID- 28004841 TI - The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway. AB - Excessive activation of the TLR4 signalling pathway is critical for inflammation associated disorders, while negative regulators play key roles in restraining TLR4 from over-activation. Naringenin is a citrus flavonoid with remarkable anti inflammatory activity, but the mechanisms underlying its inhibition of LPS/TLR4 signalling are less clear. This study investigated the molecular targets and therapeutic effects of naringenin in vitro and in vivo. In LPS-stimulated murine macrophages, naringenin suppressed the expression of TNF-alpha, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2). Naringenin also inhibited NF-kappaB and mitogen-activated protein kinase (MAPK) activation. However, it did not affect the IRF3 signalling pathway or interferon production, which upregulate activating transcription factor 3 (ATF3), an inducible negative regulator of TLR4 signalling. Naringenin was demonstrated to directly increase ATF3 expression. Inhibition of AMPK and its upstream calcium dependent signalling reduced ATF3 expression and dampened the anti-inflammatory activity of naringenin. In murine endotoxaemia models, naringenin ameliorated pro inflammatory reactions and improved survival. Furthermore, it induced AMPK activation in lung tissues, which was required for ATF3 upregulation and the enhanced anti-inflammatory activity. Overall, this study reveals a novel mechanism of naringenin through AMPK-ATF3-dependent negative regulation of the LPS/TLR4 signalling pathway, which thereby confers protection against murine endotoxaemia. PMID- 28004843 TI - Correction: Highlights from Faraday Discussion 194: Ultrafast Imaging of Photochemical Dynamics, Edinburgh, 2016. AB - Correction for 'Highlights from Faraday Discussion 193: Ultrafast Imaging of Photochemical Dynamics, Edinburgh, 2016' by Adam Kirrander and Russell S. Minns, Chem. Commun., 2016, 52, 13631-13636. PMID- 28004844 TI - Lifecycle of Weibel-Palade bodies. AB - Weibel-Palade bodies (WPBs) are rod or cigar-shaped secretory organelles that are formed by the vascular endothelium. They contain a diverse set of proteins that either function in haemostasis, inflammation, or angiogenesis. Biogenesis of the WPB occurs at the Golgi apparatus in a process that is dependent on the main component of the WPB, the haemostatic protein von Willebrand Factor (VWF). During this process the organelle is directed towards the regulated secretion pathway by recruiting the machinery that responds to exocytosis stimulating agonists. Upon maturation in the periphery of the cell the WPB recruits Rab27A which regulates WPB secretion. To date several signaling pathways have been found to stimulate WPB release. These signaling pathways can trigger several secretion modes including single WPB release and multigranular exocytosis. In this review we will give an overview of the WPB lifecycle from biogenesis to secretion and we will discuss several deficiencies that affect the WPB lifecycle. PMID- 28004845 TI - Polymyalgia rheumatica detected by SPECT/CT using 99mTc-labeled monoclonal antibody Fab'-fragments. PMID- 28004847 TI - Developmental Trends in Flexibility and Automaticity of Social Cognition. AB - Age-related changes in flexibility and automaticity of reasoning about social situations were investigated. Children (N = 101; age range = 7;8-17;7) were presented with the flexibility and automaticity of social cognition (FASC), a new measure of social cognition in which cartoon vignettes of social situations are presented and participants explain what is happening and why. Scenarios vary on whether the scenario is socially ambiguous and whether or not language is used. Flexibility is determined by the number of unique, plausible explanations, and automaticity is indicated by speed of response. Overall, both flexibility and automaticity increased significantly with age. Language and social ambiguity influenced performance. Future work should investigate differences in FASC in older populations and clinical groups. PMID- 28004846 TI - Short-term economic impact of the Zika virus outbreak. AB - Zika virus (ZIKV) is mainly transmitted by mosquitoes bites. However, transmission by sexual contacts has been reported in 11 non endemic countries. The rapid spread of ZIKV in Latin American and Caribbean Countries (LCR), person to-person transmission and perceived risk on people's well being can affect the emerging economies of LCR which historically dependent on truism. Here we present an analysis on economic outputs for assessing the current impact of ZIKV on markets. Our analysis show an unexpected resilience of LCR markets to international alerts. This positive response represents an opportunity to scale up interventions for preventing the further spreading of the ZIKV epidemic. PMID- 28004848 TI - Analysing animal social network dynamics: the potential of stochastic actor oriented models. AB - Animals are embedded in dynamically changing networks of relationships with conspecifics. These dynamic networks are fundamental aspects of their environment, creating selection on behaviours and other traits. However, most social network-based approaches in ecology are constrained to considering networks as static, despite several calls for such analyses to become more dynamic. There are a number of statistical analyses developed in the social sciences that are increasingly being applied to animal networks, of which stochastic actor-oriented models (SAOMs) are a principal example. SAOMs are a class of individual-based models designed to model transitions in networks between discrete time points, as influenced by network structure and covariates. It is not clear, however, how useful such techniques are to ecologists, and whether they are suited to animal social networks. We review the recent applications of SAOMs to animal networks, outlining findings and assessing the strengths and weaknesses of SAOMs when applied to animal rather than human networks. We go on to highlight the types of ecological and evolutionary processes that SAOMs can be used to study. SAOMs can include effects and covariates for individuals, dyads and populations, which can be constant or variable. This allows for the examination of a wide range of questions of interest to ecologists. However, high-resolution data are required, meaning SAOMs will not be useable in all study systems. It remains unclear how robust SAOMs are to missing data and uncertainty around social relationships. Ultimately, we encourage the careful application of SAOMs in appropriate systems, with dynamic network analyses likely to prove highly informative. Researchers can then extend the basic method to tackle a range of existing questions in ecology and explore novel lines of questioning. PMID- 28004849 TI - Isotopic niches support the resource breadth hypothesis. AB - Because a broad spectrum of resource use allows species to persist in a wide range of habitat types, and thus permits them to occupy large geographical areas, and because broadly distributed species have access to more diverse resource bases, the resource breadth hypothesis posits that the diversity of resources used by organisms should be positively related with the extent of their geographic ranges. We investigated isotopic niche width in a small radiation of South American birds in the genus Cinclodes. We analysed feathers of 12 species of Cinclodes to test the isotopic version of the resource breadth hypothesis and to examine the correlation between isotopic niche breadth and morphology. We found a positive correlation between the widths of hydrogen and oxygen isotopic niches (which estimate breadth of elevational range) and widths of the carbon and nitrogen isotopic niches (which estimates the diversity of resources consumed, and hence of habitats used). We also found a positive correlation between broad isotopic niches and wing morphology. Our study not only supports the resource breadth hypothesis but it also highlights the usefulness of stable isotope analyses as tools in the exploration of ecological niches. It is an example of a macroecological application of stable isotopes. It also illustrates the importance of scientific collections in ecological studies. PMID- 28004850 TI - Meta-analysis of prophylactic mesh to prevent parastomal hernia. AB - BACKGROUND: Rates of parastomal hernia following stoma formation remain high. Previous systematic reviews suggested that prophylactic mesh reduces the rate of parastomal hernia; however, a larger trial has recently called this into question. The aim was to determine whether mesh placed at the time of primary stoma creation prevents parastomal hernia. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase and CINAHL were searched using medical subject headings for parastomal hernia, mesh and prevention. Reference lists of identified studies, clinicaltrials.gov and the WHO International Clinical Trials Registry were also searched. All randomized clinical trials were included. Two authors extracted data from each study independently using a purpose-designed sheet. Risk of bias was assessed by a tool based on that developed by Cochrane. RESULTS: Ten randomized trials were identified among 150 studies screened. In total 649 patients were included in the analysis (324 received mesh). Overall the rates of parastomal hernia were 53 of 324 (16.4 per cent) in the mesh group and 119 of 325 (36.6 per cent) in the non-mesh group (odds ratio 0.24, 95 per cent c.i. 0.12 to 0.50; P < 0.001). Mesh reduced the rate of parastomal hernia repair by 65 (95 per cent c.i. 28 to 85) per cent (P = 0.02). There were no differences in rates of parastomal infection, stomal stenosis or necrosis. Mesh type and position, and study quality did not have an independent effect on this relationship. CONCLUSION: Mesh placed prophylactically at the time of stoma creation reduced the rate of parastomal hernia, without an increase in mesh related complications. PMID- 28004851 TI - Relationship Quality with Parents: Implications for Own and Partner Well-Being in Middle-Aged Couples. AB - Relationships with parents have significant implications for well-being throughout the lifespan. At midlife, these ties are situated within both developmental and family contexts that often involve the adult offspring's spouse. Yet, it is not known how ties with aging parents are related to psychological well-being within middle-aged couples. This study examined how middle-aged wives' and husbands' views of the current quality of relationships with their own parents (positive and negative) are linked to their own and their partner's psychological well-being. Using a sample of 132 middle-aged couples from Wave 1 of the Family Exchanges Study, we estimated actor-partner interdependence models to evaluate these dyadic associations while controlling for each spouse's marital satisfaction. Both actor and partner effects were observed. With respect to actor effects, wives who reported more negative relationship quality with their own parents had elevated depressive symptoms and lower life satisfaction. Husbands who reported more negative relationship quality with their own parents had lower life satisfaction. In terms of partner effects, husbands had lower depressive symptoms and greater life satisfaction when wives reported more positive relationship quality with their own parents. Finally, the link between wives' positive ties with parents and husbands' lower depressive symptoms was intensified when husbands had less positive relationships with their own parents. Findings suggest that relationship quality with wives' aging parents has implications for both spouses' well-being and may serve as a critical social resource for husbands. PMID- 28004852 TI - Splenic preservation in laparoscopic distal pancreatectomy. AB - BACKGROUND: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) is designed principally for the removal of benign and low-grade malignant lesions in the left pancreas. The aims of this study were to compare LSPDP with laparoscopic distal pancreatectomy with splenectomy (LDPS), compare two splenic preservation techniques (splenic vessel preservation and Warshaw technique) and investigate factors that influence splenic preservation. METHODS: Information from patients who underwent laparoscopic distal pancreatectomy between December 2004 and January 2016 at a single institution was reviewed. Data were extracted from a prospectively developed database. Intention-to-treat and propensity score matching analyses were employed. Univariable and multivariable analyses were used to investigate factors affecting splenic preservation. RESULTS: There were 206 patients in total (126 planned LSPDP and 80 planned LDPS procedures), of whom 108 underwent LSPDP and 98 LDPS. In intention-to-treat analysis, the duration of surgery was significantly shorter in the LSPDP group than in the LDPS group (mean 191.0 versus 220.5 min respectively; P < 0.001). Tumour size was an independent risk factor for splenic vessel resection in planned splenic vessel preservation operations, and a cut-off value of 3 cm provided optimal diagnostic accuracy. After a median follow-up of 35.9 months, there were no clinically significant splenic infarctions and no patient developed gastrointestinal bleeding after LSPDP. CONCLUSION: Planned LSPDP had a high splenic preservation rate and was associated with significantly shorter operating time than LDPS. Splenic vessel preservation could be predicted using a tumour cut-off size of 3 cm. PMID- 28004853 TI - Ustekinumab therapy for Crohn's disease during pregnancy: a case report and review of the literature. AB - WHAT IS KNOWN AND OBJECTIVES: The safety of continued ustekinumab (UST) therapy during pregnancy remains unclear in patients with Crohn's disease (CD). There are no meta-analysis reports of exposure to UST during pregnancy. The objective was to describe a case of a pregnant patient with CD who was successfully treated with UST maintenance therapy throughout the pregnancy and delivered a baby boy without any congenital malformations, neurological abnormalities or birth defects. CASE SUMMARY: A 37-year-old patient with CD treated with UST became pregnant. She had been receiving UST for 8 months at the time. After discussion with the patient and the obstetric team, the UST therapy was continued. The result of treatment was an uneventful pregnancy with delivery, at term, of a healthy boy and the maintenance of clinical, biological and endoscopic remission of CD during and after pregnancy. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first reported use of continued UST therapy for CD throughout a pregnancy. The result of treatment was an uncomplicated pregnancy with the mother giving birth to a healthy boy at term and the maintenance of clinical biological and endoscopic remission of CD during and after pregnancy. PMID- 28004854 TI - Progress in Understanding Degradation Mechanisms and Improving Stability in Organic Photovoltaics. AB - Understanding the degradation mechanisms of organic photovoltaics is particularly important, as they tend to degrade faster than their inorganic counterparts, such as silicon and cadmium telluride. An overview is provided here of the main degradation mechanisms that researchers have identified so far that cause extrinsic degradation from oxygen and water, intrinsic degradation in the dark, and photo-induced burn-in. In addition, it provides methods for researchers to identify these mechanisms in new materials and device structures to screen them more quickly for promising long-term performance. These general strategies will likely be helpful in other photovoltaic technologies that suffer from insufficient stability, such as perovskite solar cells. Finally, the most promising lifetime results are highlighted and recommendations to improve long term performance are made. To prevent degradation from oxygen and water for sufficiently long time periods, OPVs will likely need to be encapsulated by barrier materials with lower permeation rates of oxygen and water than typical flexible substrate materials. To improve stability at operating temperatures, materials will likely require glass transition temperatures above 100 degrees C. Methods to prevent photo-induced burn-in are least understood, but recent research indicates that using pure materials with dense and ordered film morphologies can reduce the burn-in effect. PMID- 28004855 TI - Mineral Nano-Interconnectivity Stiffens and Toughens Nacre-like Composite Materials. AB - Bulk nacre-like composites with mineral nano-interconnectivity at the same length scale as in the biological material are produced using magnetic alignment and selective sintering techniques. These materials display stiffness and strength levels comparable to that of continuous fiber composites with the advantage of easier processability inherent of discontinuous composites. This opens new possibilities to produce parts with more complex designs. PMID- 28004856 TI - Effect of early allograft dysfunction on outcomes following liver transplantation. AB - Early allograft dysfunction (EAD) following liver transplantation (LT) remains a challenge for patients and clinicians. We retrospectively analyzed the effect of pre-defined EAD on outcomes in a 10-year cohort of deceased-donor LT recipients with clearly defined exclusion criteria. EAD was defined by at least one of the following: AST or ALT >2000 IU/L within first-week post-LT, total bilirubin >=10 mg/dL, and/or INR >=1.6 on post-operative day 7. Ten patients developed primary graft failure and were analyzed separately. EAD occurred in 86 (36%) recipients in a final cohort of 239 patients. In univariate and multivariate analyses, EAD was significantly associated with mechanical ventilation >=2 days or death on days 0, 1, PACU/SICU stay >2 days or death on days 0-2 and renal failure (RF) at time of hospital discharge (all P<.05). EAD was also significantly associated with higher one-year graft loss in both uni- and multivariate Cox hazard analyses (P=.0203 and .0248, respectively). There was no difference in patient mortality between groups in either of the Cox proportional hazard models. In conclusion, we observed significant effects of EAD on short-term post-LT outcomes and lower graft survival. PMID- 28004858 TI - New evidence comes to light: How is alpha-synuclein aggregation related to mitochondrial protein import in Parkinson's disease? PMID- 28004857 TI - PolyWhips: Directional Particle Transport by Gradient-Directed Growth and Stiffening of Supramolecular Assemblies. AB - Growth of rigid rods occurs via supramolecular assembly of a nonconjugated pi donor pi-acceptor monomer and is triggered by a NaCl gradient. The mechanical stiffness of this material is controlled by the local salt concentration and is ion specific. The continuous and well-controlled growth process is exploited to power the directional transport of sub-millimeter polymer particles. PMID- 28004859 TI - Parkinson's disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta. AB - BACKGROUND: In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with associated neuroinflammation and microglial activation continue, as does local iron accumulation. Previous studies investigating nigral iron accumulation used T2 / T2*-weighted contrasts to define the regions of interest in the SN. Given that T2 / T2*-weighted contrasts lack sensitivity to neuromelanin and thereby SNpc, neuromelanin-sensitive MRI provides better delineation of SNpc and allows the examination of increased iron deposition in SNpc more specifically and accurately. OBJECTIVES: To examine regions of the SNpc, defined by neuromelanin-sensitive MRI, exhibiting iron deposition in PD. METHODS: T1 -weighted and susceptibility weighted imaging data were obtained in a cohort of 82 subjects (54 controls and 28 PD patients). The PD patients were clinically diagnosed with an average UPDRS-III score of 37.9 +/- 12.5 in the off medication state. Susceptibility weighted imaging data were analyzed using SNpc regions of interest defined by neuromelanin-sensitive MRI. RESULTS: Compared to control subjects, significantly more hypointense signal was observed in the SNpc defined by neuromelanin-sensitive MRI in the PD patients. In the PD group, the lateral ventral region of SNpc exhibited the greatest increase of hypointensity. This increase in the lateral ventral region of SNpc robustly differentiated PD patients from controls. CONCLUSION: T2*-weighted hypointense signal in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. It is most likely a measure sensitive to PD-related iron deposition and may serve as a robust biomarker of PD. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 28004860 TI - A Vertical Organic Transistor Architecture for Fast Nonvolatile Memory. AB - A new device architecture for fast organic transistor memory is developed, based on a vertical organic transistor configuration incorporating high-performance ambipolar conjugated polymers and unipolar small molecules as the transport layers, to achieve reliable and fast programming and erasing of the threshold voltage shift in less than 200 ns. PMID- 28004861 TI - 3D Chemical Patterning of Micromaterials for Encoded Functionality. AB - Programming local chemical properties of microscale soft materials with 3D complex shapes is indispensable for creating sophisticated functionalities, which has not yet been possible with existing methods. Precise spatiotemporal control of two-photon crosslinking is employed as an enabling tool for 3D patterning of microprinted structures for encoding versatile chemical moieties. PMID- 28004862 TI - Active Electrochemical Plasmonic Switching on Polyaniline-Coated Gold Nanocrystals. AB - High-performance electrochemical plasmonic switching is realized on both single particle and ensemble levels by coating polyaniline on colloidal gold nanocrystals through surfactant-assisted oxidative polymerization. Under small applied potentials, the core@shell nanostructures exhibit reversible plasmon shifts as large as 150 nm, a switching time of less than 10 ms, and a high switching stability. PMID- 28004864 TI - Bandgap Control via Structural and Chemical Tuning of Transition Metal Perovskite Chalcogenides. AB - Transition metal perovskite chalcogenides are a new class of versatile semiconductors with high absorption coefficient and luminescence efficiency. Polycrystalline materials synthesized by an iodine-catalyzed solid-state reaction show distinctive optical colors and tunable bandgaps across the visible range in photoluminescence, with one of the materials' external efficiency approaching the level of single-crystal InP and CdSe. PMID- 28004863 TI - In-Plane Deformation Mechanics for Highly Stretchable Electronics. AB - Scissoring in thick bars suppresses buckling behavior in serpentine traces that have thicknesses greater than their widths, as detailed in a systematic set of analytical and experimental studies. Scissoring in thick copper traces enables elastic stretchability as large as ~350%, corresponding to a sixfold improvement over previously reported values for thin geometries (~60%). PMID- 28004865 TI - The putative kinase substrate MUSE7 negatively impacts the accumulation of NLR proteins. AB - Stringent modulation of immune signaling in plants is necessary to enable a rapid response to pathogen attack without spurious defense activation. To identify genes involved in plant immunity, a forward genetic screen for enhancers of the autoimmune snc1 (suppressor of npr1, constitutive 1) mutant was conducted. The snc1 mutant contains a gain-of-function mutation in a gene encoding a NOD-like receptor (NLR) protein. The isolated muse7 (mutant, snc1-enhancing, 7) mutant was shown to confer a reversion to autoimmune phenotypes in the wild-type-like mos4 (modifier of snc1, 4) snc1 background. Positional cloning revealed that MUSE7 encodes an evolutionarily conserved putative kinase substrate of unknown function. The muse7 single mutants display enhanced resistance to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. While transcription of SNC1 is not enhanced, elevated SNC1 protein accumulation is associated with mutations in muse7. Accumulation of two additional NLR proteins, RPS2 (RESISTANCE TO PSEUDOMONAS SYRINGAE 2) and RPM1 (RESISTANCE TO PSEUDOMONAS SYRINGAE pv. MACULICOLA 1), was also observed in muse7 plants. Although proteasome-mediated degradation of NLR proteins is a well studied event in plant immunity, no interactions were detected between MUSE7 and selected components of this pathway. This study has demonstrated a role for MUSE7 in modulating plant immune responses through negatively affecting NLR accumulation, and will benefit future studies of MUSE7 homologs in other species. PMID- 28004866 TI - Motivational changes of cannabis use prior to and during the course of schizophrenia. AB - BACKGROUND AND OBJECTIVES: We investigated subjective reasons/motivation for cannabis use in patients with schizophrenia (n = 51) compared to otherwise healthy cannabis users (n = 109). Moreover, we explored possible changes in the motivational patterns of both groups over time. METHODS: A questionnaire was developed with six dimensions of motivations to use cannabis: affect regulation, relaxation, habit, structuring everyday life, creativity, and sociability. Participants filled out the instrument regarding their present and initial use of cannabis. RESULTS: At the time of onset of consumption, groups only differed significantly in habit with higher ratings for patients with schizophrenia and cannabis use (SCH+CAN group) and in sociability with higher ratings for otherwise healthy users (CAN group). In respect of present use, the motivation to consume cannabis was significantly higher for affect regulation and structuring everyday life in the SCH+CAN group and for relaxation and sociability in the CAN group. With reference to time-based variations, the SCH+CAN group reported increased relevance of structuring everyday life over time. Furthermore, the CAN group reported increased importance of habit over time, whereas the SCH+CAN patients showed decreased ratings of habit over time. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our findings must be considered preliminary because of the retrospective nature of the assessment. Nevertheless, the present study provides an indication of the time-dependent variation of cannabis-use motivation in schizophrenia, which may provide a better understanding of the functions of cannabis use within the population. Results argue for specific motivational based interventions for the group of schizophrenia patients with regular cannabis use. (Am J Addict 2017;26:122-128). PMID- 28004867 TI - Doublet asymmetry for estimating polarization in hyperpolarized 13 C-pyruvate studies. AB - Hyperpolarized 13 C MRS allows in vivo interrogation of key metabolic pathways, with pyruvate (Pyr) the substrate of choice for current clinical studies. Knowledge of the liquid-state polarization is needed for full quantitation, and asymmetry of the C2 doublet, arising from 1% naturally abundant [1,2-13 C]Pyr in any hyperpolarized [1-13 C]Pyr sample, has been suggested as a direct measure of in vivo C1 polarization via the use of an in vitro calibration curve. Here we show that different polarization levels can yield the same C2 -doublet asymmetry, thus limiting the utility of this metric for quantitation. Furthermore, although the time evolution of doublet asymmetry is poorly modeled using the expected dominant relaxation mechanisms of carbon-proton dipolar coupling and chemical shift anisotropy, the inclusion of a C-C dipolar coupling term can explain the observed initial evolution of the C2 doublet asymmetry beyond its expected thermal equilibrium value. PMID- 28004868 TI - Physiological redox signalling and regulation of ion channels: implications for pulmonary hypertension. AB - NEW FINDINGS: What is the topic of this review? The review concerns the role of reactive oxygen species as physiological second messengers in potentiating G protein-coupled receptor-mediated vasoconstriction and its potential dysregulation by oxidant stress in pulmonary hypertension. What advances does it highlight? The review highlights the concept that physiological signalling by reactive oxygen species must normally be highly compartmentalized to prevent self regenerating oxidant stress and promiscuous and uncontrolled signalling, which contribute to the aetiology. Pulmonary hypertension is associated with oxidant stress and increased generation of reactive oxygen species (ROS) by NADPH oxidases (NOX), mitochondria and other sources. There is considerable evidence that these contribute to the aetiology via promotion of pulmonary vascular remodelling, endothelial dysfunction and enhanced vasoreactivity. However, it is now recognized that ROS act as important signalling mediators and second messengers in normal physiological conditions. Many ion channels and protein kinases crucial to pulmonary vascular function are directly or indirectly affected by redox/ROS, including K+ , Ca2+ and non-selective cation channels and Rho kinase. However, the inherent difficulties in quantifying ROS, particularly in subcellular compartments, make it uncertain whether these reported effects are of relevance in physiological rather than pathological conditions. In an attempt to address such issues, we have focused on the role of physiologically generated ROS in the regulation of G-protein-coupled receptor (GPCR)-activated vasoconstrictor pathways. We have recently reported a novel mechanism whereby low concentrations of GPCR-linked vasoconstrictors greatly potentiate Ca2+ entry via a NOX1- and ROS-mediated pathway parallel to the classical vasoconstrictor pathways of Ca2+ mobilization and activation of Rho kinase. Our findings imply that ROS signalling is highly compartmentalized in physiological conditions, but that this may be compromised by pathological increases in oxidant production, for example in pulmonary hypertension, leading to promiscuous actions that contribute to the aetiology. This model is consistent with the proposal that targeted antioxidants could prove to be an effective therapy for pulmonary hypertension. PMID- 28004869 TI - Activation tagging of Arabidopsis POLYGALACTURONASE INVOLVED IN EXPANSION2 promotes hypocotyl elongation, leaf expansion, stem lignification, mechanical stiffening, and lodging. AB - Pectin is the most abundant component of primary cell walls in eudicot plants. The modification and degradation of pectin affects multiple processes during plant development, including cell expansion, organ initiation, and cell separation. However, the extent to which pectin degradation by polygalacturonases affects stem development and secondary wall formation remains unclear. Using an activation tag screen, we identified a transgenic Arabidopsis thaliana line with longer etiolated hypocotyls, which overexpresses a gene encoding a polygalacturonase. We designated this gene as POLYGALACTURONASE INVOLVED IN EXPANSION2 (PGX2), and the corresponding activation tagged line as PGX2AT . PGX2 is widely expressed in young seedlings and in roots, stems, leaves, flowers, and siliques of adult plants. PGX2-GFP localizes to the cell wall, and PGX2AT plants show higher total polygalacturonase activity and smaller pectin molecular masses than wild-type controls, supporting a function for this protein in apoplastic pectin degradation. A heterologously expressed, truncated version of PGX2 also displays polygalacturonase activity in vitro. Like previously identified PGX1AT plants, PGX2AT plants have longer hypocotyls and larger rosette leaves, but they also uniquely display early flowering, earlier stem lignification, and lodging stems with enhanced mechanical stiffness that is possibly due to decreased stem thickness. Together, these results indicate that PGX2 both functions in cell expansion and influences secondary wall formation, providing a possible link between these two developmental processes. PMID- 28004870 TI - Carbones as Ligands in Novel Main-Group Compounds E[C(NHC)2 ]2 (E=Be, B+ , C2+ , N3+ , Mg, Al+ , Si2+ , P3+ ): A Theoretical Study. AB - Quantum chemical calculations of the main-group compounds E[C(NHCMe )2 ]2 (E=Be, B+ , C2+ , N3+ , Mg, Al+ , Si2+ , P3+ ) have been carried out using density functional theory at the BP86/def2-TZVPP and BP86-D3(BJ)/def2-TZVPP levels of theory. The geometry optimization at BP86/def2-TZVPP gives equilibrium structures with two-coordinated species E and bending angles C-E-C between 152.5 degrees (E=Be) and 110.5 degrees (E=Al). Inclusion of dispersion forces at BP86 D3(BJ)/def2-TZVPP yields a three-coordinated beryllium compound Be[C(NHCMe )2 ]2 as the only energy minimum form. Three-coordinated isomers are found besides the two-coordinated energy minima for the boron and carbon cations B[C(NHCMe )2 ]2+ and C[C(NHCMe )2 ]22+ . The three-coordinated form of the boron compound is energetically lower lying than the two-coordinated form, while the opposite trend is calculated for the carbon species. The theoretically predicted bond dissociation energies suggest that all compounds are viable species for experimental studies. The X-ray structure of the benzoannelated homologue of P[C(NHCMe )2 ]23+ that was recently reported by Dordevic et al. agrees quite well with the calculated geometry of the molecule. A detailed bonding analysis using charge and energy decomposition methods shows that the two-coordinated neutral compounds Be[C(NHCMe )2 ]2 and Mg[C(NHCMe )2 ]2 possess strongly positively charged atoms Be and Mg. The carbodicarbene groups C(NHCMe )2 serve as acceptor ligands in the compounds and may be sketched with dative bonds (NHCMe )2 C<-E >C(NHCMe )2 (E=Be, Mg). Dative bonds in which the carbones C(NHCMe )2 are donor ligands are suggested for the cations (NHCMe )2 C->E<-C(NHCMe )2 (E=B+ , Al+ ). The dications and trications possess electron-sharing bonds in which the bonding situation is best described with the formula [(NHCMe )2 C]+ -E-[C(NHCMe )2 ]+ (E=C, Si, N+ , P+ ). PMID- 28004871 TI - The iron-sulfur cluster biosynthesis protein SUFB is required for chlorophyll synthesis, but not phytochrome signaling. AB - Proteins that contain iron-sulfur (Fe-S) clusters play pivotal roles in various metabolic processes such as photosynthesis and redox metabolism. Among the proteins involved in the biosynthesis of Fe-S clusters in plants, the SUFB subunit of the SUFBCD complex appears to be unique because SUFB has been reported to be involved in chlorophyll metabolism and phytochrome-mediated signaling. To gain insights into the function of the SUFB protein, we analyzed the phenotypes of two SUFB mutants, laf6 and hmc1, and RNA interference (RNAi) lines with reduced SUFB expression. When grown in the light, the laf6 and hmc1 mutants and the SUFB RNAi lines accumulated higher levels of the chlorophyll biosynthesis intermediate Mg-protoporphyrin IX monomethylester (Mg-proto MME), consistent with the impairment of Mg-proto MME cyclase activity. Both SUFC- and SUFD-deficient RNAi lines accumulated the same intermediate, suggesting that inhibition of Fe-S cluster synthesis is the primary cause of this impairment. Dark-grown laf6 seedlings also showed an increase in protoporphyrin IX (Proto IX), Mg-proto, Mg proto MME and 3,8-divinyl protochlorophyllide a (DV-Pchlide) levels, but this was not observed in hmc1 or the SUFB RNAi lines, nor was it complemented by SUFB overexpression. In addition, the long hypocotyl in far-red light phenotype of the laf6 mutant could not be rescued by SUFB overexpression and segregated from the pale-green SUFB-deficient phenotype, indicating it is not caused by mutation at the SUFB locus. These results demonstrate that biosynthesis of Fe-S clusters is important for chlorophyll biosynthesis, but that the laf6 phenotype is not due to a SUFB mutation. PMID- 28004872 TI - Random regression models to estimate genetic parameters for weights in Murrah buffaloes. AB - This article reports genetic analysis of the weight at different ages of Murrah water buffaloes, using random regression models (RRM). Models ranging from third to sixth order polynomial were used to describe direct genetic and animal permanent environmental effects. Contemporary group was included as a fixed effect, and a cubic polynomial was used to model the mean curve of the population. The residual was modeled considering a log-linear function. Two models were selected for study of genetic parameters. The first model included third and sixth order polynomials for direct genetic and animal permanent environmental effects (M36). The second model included sixth order polynomials for all random effects (M66). The estimates of heritability varied from 0.16 + 0.04 (44 days) to 0.38 + 0.04 (568 days) for model M36 and from 0.16 + 0.05 (33 days) to 0.42 + 0.05 (600 days) for model M66. Regarding estimates of the correlation for all effects, the magnitude tended to decline with the increase of the time span between measurements. These results indicate that the species has potential for genetic selection based on weight at different ages, since we found favorable genetic variability within the herd, with selection likely to be more efficient at ages near 600 days. PMID- 28004873 TI - Plant defence induced by PGPR against Spodoptera litura in tomato (Solanum lycopersicum L.). AB - : The research conducted including its rationale: Spodoptera litura is the major pest of tomato causing significant reduction in tomato yield. Application of Plant growth promoting rhizobacteria(PGPR) prevent use of chemical fertilizer and synthetic pesticides through enhancement of plant growth and yield and induction of systemic resistance. Present investigation is an attempt to evaluate the role of PGPR, Pseudomonas putida and Rothia sp. on the physiology and yield of tomato fruit infested with the S. litura. Central methods applied: The surface sterilized seeds of tomato were inoculated with 48 h culture of P. putida and Rothia sp. At 6-7 branching stage of the plant, the larvae of S. litura at 2nd in star was used to infect the tomato plant leaves. KEY RESULTS: The S. litura infestation decreased dry weight of shoots and roots by 46% and 22%, and significant reduction was recorded in tomato fruit yield. The P. putida and Rothia sp. inoculations alleviated the adverse effects of insect infestation and resulted in 60% increase in plant biomass and 40% increase in yield over infested plants. Main conclusions including key points of discussion: PGPR: Defense appears to be mediated via increase in proline production, enhanced activities of antioxidant enzymes, stimulation in the activities of protease and polyphenol oxidases, increased contents of phenolics, protein and chlorophyll. The formulation of biopesticide involving PGPR comprise an environment friendly and sustainable approach to overcome insect infestation. PMID- 28004874 TI - Ultrafast Spin Crossover in [FeII (bpy)3 ]2+ : Revealing Two Competing Mechanisms by Extreme Ultraviolet Photoemission Spectroscopy. AB - Photoinduced spin-flip in FeII complexes is an ultrafast phenomenon that has the potential to become an alternative to conventional processing and magnetic storage of information. Following the initial excitation by visible light into the singlet metal-to-ligand charge-transfer state, the electronic transition to the high-spin quintet state may undergo different pathways. Here we apply ultrafast XUV (extreme ultraviolet) photoemission spectroscopy to track the low to-high spin dynamics in the aqueous iron tris-bipyridine complex, [Fe(bpy)3 ]2+ , by monitoring the transient electron density distribution among excited states with femtosecond time resolution. Aided by first-principles calculations, this approach enables us to reveal unambiguously both the sequential and direct de excitation pathways from singlet to quintet state, with a branching ratio of 4.5:1. PMID- 28004875 TI - Development and Cycloaddition Reactivity of a New Class of Pyridine-Based Mesoionic 1,3-Dipole. AB - We describe here the development and structural characterization of a new type of mesoionic 1,3-dipole, which can be generated in the one-step reaction of imines with pyridine- or quinoline-based acid chlorides. Coupling the formation of these dipoles with alkyne cycloaddition can open a general and modular route to synthesize indolizines from combinations of available and diversifiable building blocks. PMID- 28004876 TI - Towards the Development of Small-Molecule MO25 Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors. AB - The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes increases of up to 100-fold in their catalytic activity. Various animal models have shown that the inhibition of SPAK and OSR1 lowers blood pressure, and so here we present a new indirect approach to inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed a fluorescent polarisation assay and used it in screening of a small in-house library of ~4000 compounds. This led to the identification of one compound-HK01-as the first small-molecule inhibitor of the MO25-dependent activation of SPAK and OSR1 in vitro. Our data confirm the feasibility of targeting this protein-protein interaction by small-molecule compounds and highlights their potential to modulate ion co-transporters and thus cellular electrolyte balance. PMID- 28004877 TI - Oxygen Activation at the Active Site of a Fungal Lytic Polysaccharide Monooxygenase. AB - Lytic polysaccharide monooxygenases have attracted vast attention owing to their abilities to disrupt glycosidic bonds via oxidation instead of hydrolysis and to enhance enzymatic digestion of recalcitrant substrates including chitin and cellulose. We have determined high-resolution X-ray crystal structures of an enzyme from Neurospora crassa in the resting state and of a copper(II) dioxo intermediate complex formed in the absence of substrate. X-ray crystal structures also revealed "pre-bound" molecular oxygen adjacent to the active site. An examination of protonation states enabled by neutron crystallography and density functional theory calculations identified a role for a conserved histidine in promoting oxygen activation. These results provide a new structural description of oxygen activation by substrate free lytic polysaccharide monooxygenases and provide insights that can be extended to reactivity in the enzyme-substrate complex. PMID- 28004878 TI - The First Isolation and Characterisation of the Protist Labyrinthula sp. in Southeastern Australia. AB - As a result of anthropogenic influences and global climate change, emerging infectious marine diseases are thought to be increasingly more common and more severe than in the past. The aim of our investigation was to confirm the presence of Labyrinthula, the aetiological agent of the seagrass wasting disease, in Southeastern Australia and provide the first isolation and characterisation of this protist, in Australia. Colonies and individual cells were positively identified as Labyrinthula using published descriptions, diagrams, and photographs. Their identity was then confirmed using DNA barcoding of a region of the 18S rRNA gene. Species level identification of isolates was not possible as the taxonomy of the Labyrinthula is still poorly resolved. Still, a diversity of Labyrinthula was isolated from small sections of the southeast coast of Australia. The isolates were grouped into three haplotypes that are biogeographically restricted. These haplotypes are closely related to previously identified saprotrophic clades. The study highlights the need for further investigation into the global distribution of Labyrinthula, including phylogenetic pathogenicity and analysis of host-parasite interactions in response to stressors. Given the results of our analyses, it is prudent to continue research into disease and epidemic agents to better prepare researchers for potential future outbreaks. PMID- 28004879 TI - Comprehension and Generation of Metaphoric Language in Children, Adolescents, and Adults with Dyslexia. AB - Difficulties with figurative language comprehension were documented in adult dyslexia (DYS). In the present research, we investigated the comprehension and generation of metaphors in 37 children, 35 adolescents, and 34 adults with and without DYS. We also tested the contribution of executive function to metaphor processing. A multiple-choice questionnaire with conventional and novel metaphors was used to assess comprehension; a concept-explanation task was used to test conventional and novel metaphor generation (verbal creativity). The findings indicated differences between the dyslexic children and the control group in conventional metaphor comprehension. However, both groups performed similarly in the novel metaphor comprehension test. Furthermore, although children and adolescents with DYS showed similar performance in metaphor generation as their typically developing peers, adults with DYS generated more metaphors than controls. While scores on tests of verbal knowledge and mental flexibility contributed to the prediction of conventional metaphor comprehension, scores on non-verbal tests and mental flexibility contributed to the prediction of novel metaphor generation. Our findings suggest that individuals with DYS are not impaired in novel metaphor comprehension and metaphor generation and that metaphor comprehension and generation utilize different cognitive resources. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28004880 TI - Electrohydrodynamic-Induced SERS Immunoassay for Extensive Multiplexed Biomarker Sensing. AB - Cancer diagnosis and patient monitoring require sensitive and simultaneous measurement of multiple cancer biomarkers considering that single biomarker analysis present inadequate information on the underlying biological transformations. Thus, development of sensitive and selective assays for multiple biomarker detection might improve clinical diagnosis and expedite the treatment process. Herein, a microfluidic platform for the rapid, sensitive, and parallel detection of multiple cancer-specific protein biomarkers from complex biological samples is presented. This approach utilizes alternating current electrohydrodynamic-induced surface shear forces that provide exquisite control over fluid flow thereby enhancing target-sensor interactions and minimizing non specific binding. Further, the use of surface-enhanced Raman scattering-based spectral encoding with individual barcodes for different targets enables specific and simultaneous detection of captured protein biomarkers. Using this approach, the specific and sensitive detection of clinically relevant biomarkers including human epidermal growth factor receptor 2 (HER2); Mucin 1, cell surface associated (MUC1); epidermal growth factor receptor; and Mucin 16, cell surface associated (MUC16) at concentrations as low as 10 fg mL-1 in patient serum is demonstrated. Successful target detection from patient samples further demonstrates the potential of this current approach for the clinical diagnosis, which envisages a clinical translation for a rapid and sensitive appraisal of clinical samples in cancer diagnostics. PMID- 28004881 TI - Efficacy and toxicity of PACEBOM chemotherapy in relapsed/refractory aggressive lymphoma in the rituximab era. AB - AIM: Relapsed/refractory (R/R) aggressive lymphoma outcomes are poor. There is no standard treatment. PACEBOM (prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine and methotrexate) has shown efficacy for several lymphoma subtypes in published reports. We evaluate PACEBOM+/-rituximab for R/R aggressive lymphomas in this millennium. METHODS: In this retrospective, single-center study, R/R aggressive lymphoma patients who received PACEBOM or its derivatives were identified from the pharmacy database. Demographic, treatment, toxicity and survival data were collected. RESULTS: A total of 37 eligible patients were identified. Histological subtypes included 20 Diffuse Large B-Cell Lymphoma (DLBCL), 10 T-Cell Lymphoma (TCL) and 7 Hodgkin lymphoma. All DLBCL patients had received prior rituximab. Thirty-one (84%) received second-line PACEBOM. Median number of cycles was six (1-6). Eighteen out of 20 B-cell lymphoma patients received R-PACEBOM. Overall response rate was 65%, 70% and 71% in patients with DLBCL, TCL and Hodgkin lymphoma respectively. Thirteen patients underwent autologous stem cell transplant post-PACEBOM. Median follow-up was 49 months (3-201). Most common grade 3-4 toxicities were neutropenia (46%), anemia (24%) and thrombocytopenia (16%). No additional toxicity was seen in patients who received rituximab. CONCLUSION: In this cohort, PACEBOM is active in R/R aggressive lymphoma with manageable toxicity and can be safely combined with rituximab. Outcomes were similar to reports of other salvage regimens. PACEBOM remains a suitable option for R/R aggressive lymphoma, in patients exposed to prior rituximab and those planned for autologous stem cell transplant. PMID- 28004882 TI - The current practice, preparedness and educational preparation of oncology professionals to provide spiritual care. AB - AIM: Limited data are available on how spiritual needs of patients with cancer care are addressed by Australian oncologists. The objectives of this study were to explore the current practice, preparedness and education of Australian oncologists and oncology trainees on the provision of spiritual care for their patients with cancer. METHODS: Participants were recruited through oncology professional organizations and data collected through an anonymous online survey using a validated questionnaire. RESULTS: Responses from a total of 69 medical professionals were suitable for data analysis. The majority of the respondents had encountered patients with spiritual care needs during clinical consultations. Only 45% of the respondents perceived that they were able to meet the spiritual needs of their patients. Barriers to providing spiritual care identified a lack of time, education and understanding of spirituality and spiritual care in the context of health. Only 25% stated they had received some form of education on spiritual care with 7% of these stated that the education was adequate. Participants believed that they learnt how to provide spiritual care on the job or because of their self-interest, and not as formal training. CONCLUSION: The results of this study indicate that Australian oncology professionals often encounter patients with spiritual care needs in their clinical practice. Despite this finding, only a small proportion of the medical professionals had education on spiritual care during their professional training. Forty-five percent of the medical practitioners believed that they were able to partly or completely meet their patients' spiritual care needs. PMID- 28004883 TI - Afatinib successfully treated leptomeningeal metastasis during erlotinib treatment in a patient with EGFR-mutant (Exon18:G719S) lung adenocarcinoma as a second-line chemotherapy. AB - Exon18 mutations are detected in 3.6% of epidermal growth factor receptor mutations. Exon 18 mutations as driver mutations have higher sensitivities in vitro to second-generation (G)-tyrosine kinase inhibitors (TKIs) than to first G- and third G-TKIs at clinically relevant doses. In clinical trial, first G-TKIs have moderate but insufficient efficacy, and afatinib was more active in uncommon epidermal growth factor receptor mutations. Here, we present a case of a woman who was initially prescribed erlotinib for lung adenocarcinoma with an exon18 mutation. She developed a leptomeningeal metastasis during treatment and was switched to afatinib. Subsequently, her symptoms improved and she is currently treated with maintenance afatinib therapy. This report suggests improved efficacy of afatinib compared to erlotinib for refractory leptomeningeal metastasis in exon18 mutation. PMID- 28004884 TI - Fermentation of glycerol by Anaerobium acetethylicum and its potential use in biofuel production. AB - Growth of biodiesel industries resulted in increased coproduction of crude glycerol which is therefore becoming a waste product instead of a valuable 'coproduct'. Glycerol can be used for the production of valuable chemicals, e.g. biofuels, to reduce glycerol waste disposal. In this study, a novel bacterial strain is described which converts glycerol mainly to ethanol and hydrogen with very little amounts of acetate, formate and 1,2-propanediol as coproducts. The bacterium offers certain advantages over previously studied glycerol-fermenting microorganisms. Anaerobium acetethylicum during growth with glycerol produces very little side products and grows in the presence of maximum glycerol concentrations up to 1500 mM and in the complete absence of complex organic supplements such as yeast extract or tryptone. The highest observed growth rate of 0.116 h-1 is similar to that of other glycerol degraders, and the maximum concentration of ethanol that can be tolerated was found to be about 60 mM (2.8 g l-1 ) and further growth was likely inhibited due to ethanol toxicity. Proteome analysis as well as enzyme assays performed in cell-free extracts demonstrated that glycerol is degraded via glyceraldehyde-3-phosphate, which is further metabolized through the lower part of glycolysis leading to formation of mainly ethanol and hydrogen. In conclusion, fermentation of glycerol to ethanol and hydrogen by this bacterium represents a remarkable option to add value to the biodiesel industries by utilization of surplus glycerol. PMID- 28004885 TI - Novel thermostable antibiotic resistance enzymes from the Atlantis II Deep Red Sea brine pool. AB - The advent of metagenomics has greatly facilitated the discovery of enzymes with useful biochemical characteristics for industrial and biomedical applications, from environmental niches. In this study, we used sequence-based metagenomics to identify two antibiotic resistance enzymes from the secluded, lower convective layer of Atlantis II Deep Red Sea brine pool (68 degrees C, ~2200 m depth and 2500/00 salinity). We assembled > 4 000 000 metagenomic reads, producing 43 555 contigs. Open reading frames (ORFs) called from these contigs were aligned to polypeptides from the Comprehensive Antibiotic Resistance Database using BLASTX. Two ORFs were selected for further analysis. The ORFs putatively coded for 3' aminoglycoside phosphotransferase [APH(3')] and a class A beta-lactamase (ABL). Both genes were cloned, expressed and characterized for activity and thermal stability. Both enzymes were active in vitro, while only APH(3') was active in vivo. Interestingly, APH(3') proved to be thermostable (Tm = 61.7 degrees C and ~40% residual activity after 30 min of incubation at 65 degrees C). On the other hand, ABL was not as thermostable, with a Tm = 43.3 degrees C. In conclusion, we have discovered two novel AR enzymes with potential application as thermophilic selection markers. PMID- 28004886 TI - Fine-Tuning of the Carbon Dioxide Capture Capability of Diamine-Grafted Metal Organic Framework Adsorbents Through Amine Functionalization. AB - A combined sonication and microwave irradiation procedure provides the most effective functionalization of ethylenediamine (en) and branched primary diamines of 1-methylethylenediamine (men) and 1,1-dimethylethylenediamine (den) onto the open metal sites of Mg2 (dobpdc) (1). The CO2 capacities of the advanced adsorbents 1-en and 1-men under simulated flue gas conditions are 19 wt % and 17.4 wt %, respectively, which are the highest values reported among amine functionalized metal-organic frameworks (MOFs) to date. Moreover, 1-den exhibits both a significant working capacity (12.2 wt %) and superb CO2 uptake (11 wt %) at 3 % CO2 . Additionally, this framework showcases the superior recyclability; ultrahigh stability after exposure to O2 , moisture, and SO2 ; and exceptional CO2 adsorption capacity under humid conditions, which are unprecedented among MOFs. We also elucidate that the performance of CO2 adsorption can be controlled by the structure of the diamine ligands grafted such as the number of amine end groups or the presence of side groups, which provides the first systematic and comprehensive demonstration of fine-tuning of CO2 uptake capability using different amines. PMID- 28004887 TI - Green Synthesis of Sub-10 nm Gadolinium-Based Nanoparticles for Sparkling Kidneys, Tumor, and Angiogenesis of Tumor-Bearing Mice in Magnetic Resonance Imaging. AB - Gadolinium (Gd)-based nanoparticles are known for their high potential in magnetic resonance imaging (MRI). However, further MRI applications of these nanoparticles are hampered by their relatively large sizes resulting in poor organ/tumor targeting. In this study, ultrafine sub-10 nm and biocompatible Gd based nanoparticles are synthesized in a bioinspired, environmentally benign, and straightforward fashion. This novel green synthetic strategy is developed for growing dextran-coated Gd-based nanoparticles (GdNPs@Dex). The as-prepared GdNPs@Dex is not only biocompatible but also stable with a sub-10 nm size. It exhibits higher longitudinal and transverse relaxivities in water (r1 and r2 values of 5.43 and 7.502 s-1 * 10-3 m-1 of Gd3+ , respectively) than those measured for Gd-DTPA solution (r1 and r2 values of 3.42 and 3.86 s-1 * 10-3 m-1 of Gd3+ , respectively). In vivo dynamic T1 -weighted MRI in tumor-bearing mice shows GdNPs@Dex can selectively target kidneys and tumor, in addition to liver and spleen. GdNPs@Dex is found particularly capable for determining the tumor boundary with clearly enhanced tumor angiogenesis. GdNPs@Dex is also found cleared from body gradually mainly via hepatobiliary and renal processing with no obvious systemic toxicity. With this green synthesis strategy, the sub-10 nm GdNPs@Dex presents promising potentials for translational biomedical imaging applications. PMID- 28004888 TI - Thinking big: towards ideal strains and processes for large-scale aerobic biofuels production. PMID- 28004889 TI - Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease. AB - To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-beta (Abeta), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal Abeta investigation. Variations include: (i) location and number of an Abeta interacting moiety; (ii) metal binding site; and (iii) denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure-mechanism-based strategy of tool invention for such a complicated brain disease. PMID- 28004890 TI - Uncovering the behavior and cognition of the earliest stone tool makers. PMID- 28004891 TI - Gang Warfare: What are the criteria for deriving assertions from facts in science? PMID- 28004892 TI - Tropical forests and the genus Homo. AB - Tropical forests constitute some of the most diverse and complex terrestrial ecosystems on the planet. From the Miocene onward, they have acted as a backdrop to the ongoing evolution of our closest living relatives, the great apes, and provided the cradle for the emergence of early hominins, who retained arboreal physiological adaptations at least into the Late Pliocene. There also now exists growing evidence, from the Late Pleistocene onward, for tool-assisted intensification of tropical forest occupation and resource extraction by our own species, Homo sapiens. However, between the Late Pliocene and Late Pleistocene there is an apparent gap in clear and convincing evidence for the use of tropical forests by hominins, including early members of our own genus. In discussions of Late Pliocene and Early Pleistocene hominin evolution, including the emergence and later expansion of Homo species across the globe, tropical forest adaptations tend to be eclipsed by open, savanna environments. Thus far, it is not clear whether this Early-Middle Pleistocene lacuna in Homo-rainforest interaction is real and representative of an adaptive shift with the emergence of our species or if it is simply reflective of preservation bias. PMID- 28004893 TI - The psychology of cooperation: Insights from chimpanzees and children. AB - Across all cultures, humans engage in cooperative activities that can be as simple as preparing a meal or sharing food with others and as complex as playing in an orchestra or donating to charity. Although intraspecific cooperation exists among many other animal species, only humans engage in such a wide array of cooperative interaction and participate in large-scale cooperation that extends beyond kin and even includes strangers. PMID- 28004894 TI - Explanations for adaptations, just-so stories, and limitations on evidence in evolutionary biology. AB - Explanations of the historical origin of specific individual traits are a key part of the research program in paleontology and evolutionary biology. Why did bipedalism evolve in the human lineage? Why did some dinosaurs and related species have head crests? Why did viviparity evolve in some reptiles? Why did the common ancestor of primates evolve stereoscopic vision, grasping hands and feet, nails instead of claws, and large brains? These are difficult questions. To varying degrees, an explanation must grapple with (1) judgments about changes in fitness that might follow from a change in morphology - without actually observing behavior or measuring reproductive success, (2) the relationship between genes and traits, (3) limitations on doing relevant experiments, (4) the interpretation of causes that are almost certainly contingent, multifactorial, interactive, hierarchical, nonlinear, emergent, and probabilistic rather than deterministic, (5) limited information about variation and ontogeny, (6) a dataset based on the random fortunes of the historical record, including only partial hard-tissue morphology and no soft-tissue morphology, (7) an equally partial and problematic (for example, time-averaged) record of the environment, (8) the compression of all data into a geological time scale that is likely to miss biologically important events or fluctuations, (9) dependence on a process that can only be inferred ("form and even behavior may leave fossil traces, but forces like natural selection do not", 1:130 ) and finally, (10) the assumption of the "adaptationist programme"2 that the trait in question is in fact an adaptation rather than a consequence of genetic drift, correlated evolution, pleiotropy, exaptation, or other mechanisms. PMID- 28004895 TI - Cooperation, collective action, and the archeology of large-scale societies. AB - Archeologists investigating the emergence of large-scale societies in the past have renewed interest in examining the dynamics of cooperation as a means of understanding societal change and organizational variability within human groups over time. Unlike earlier approaches to these issues, which used models designated voluntaristic or managerial, contemporary research articulates more explicitly with frameworks for cooperation and collective action used in other fields, thereby facilitating empirical testing through better definition of the costs, benefits, and social mechanisms associated with success or failure in coordinated group action. Current scholarship is nevertheless bifurcated along lines of epistemology and scale, which is understandable but problematic for forging a broader, more transdisciplinary field of cooperation studies. Here, we point to some areas of potential overlap by reviewing archeological research that places the dynamics of social cooperation and competition in the foreground of the emergence of large-scale societies, which we define as those having larger populations, greater concentrations of political power, and higher degrees of social inequality. We focus on key issues involving the communal-resource management of subsistence and other economic goods, as well as the revenue flows that undergird political institutions. Drawing on archeological cases from across the globe, with greater detail from our area of expertise in Mesoamerica, we offer suggestions for strengthening analytical methods and generating more transdisciplinary research programs that address human societies across scalar and temporal spectra. PMID- 28004896 TI - Treatment of acute thoracoabdominal aortic aneurysms. AB - INTRODUCTION: Acute thoracoabdominal aortic aneurysms (aTAAA) are an uncommon and lethal condition associated with an extremely high mortality and morbidity rates. Both endovascular and open repair may be offered in emergency. aim of this study is to report our results and present a literature review regarding endovascular and open surgical repair of aTAAA. EVIDENCE ACQUISITION: MEDLINE, EMBASE, and the Cochrane Library CENTRAL databases were searched from 1991 to 2016. Also, a retrospective analysis of all consecutive patients who underwent aTAAA open and endovascular treatment at our Institution between 1993 and 2016 was performed. EVIDENCE SYNTHESIS: From the literature search 671 patients who underwent open repair and 26 patients treated with endovascular techniques were found. Contained rupture (56.98%) was the most common clinical presentation of aTAAA and operative mortality ranged from 11.7% to 27.4%. The overall 30-days survival rate ranged from 73.5% to 87.5%. At 5-year and 10-years, survival rate was 48% and 35%, respectively. At our Institution, 12 patients were operated for an aTAAA; mortality rate was 58.3% (7/12 cases). Since 2014, 7 additional patients have been treated by means of endovascular techniques. The 30-day survival was 100%. CONCLUSIONS: aTAAA is a threatening condition, however, the overall literature results do not reflect this scenario because stable patients and cases limited to the descending thoracic aorta are usually considered together with TAAA ruptures. The endovascular treatment may be a very valuable alternative although it is still limited by anatomic and logistic issues and only case reports and short series are reported in literature. PMID- 28004897 TI - Management of acute aortic thrombosis. AB - Acute aortic thrombosis (AAT) is a rare life threatening event that leads to a sudden occlusion of the aorta. The mortality and morbidity of AAT is still high despite modern surgical techniques. Usually it is the result of a large saddle embolus to the aortic bifurcation, in situ thrombosis of an atherosclerotic aorta or acute occlusion of an abdominal aortic aneurysm. Clinical symptoms depend on the level of the aortic occlusion and can be mistaken for a stroke or similar neurological disease. The combination of age and advanced cardiac disease seems to be significant risks factors for AAT. In patients who have no cardiac or vascular disease this catastrophic event is very rare and is mostly due to hypercoagulable disorders. Revascularization of the ischemic organ/limb as soon as possible is the major aim in the therapy of AAT to avoid further ischemic damage. Surgical reperfusion is the first line approach. If the accepting clinic has no facilities for an immediate surgical intervention it is of primary importance that these patients should be referred to an appropriate center for further management. Paradox seems the fact that most of the patients die as a consequence of reperfusion injury/postperfusion syndrome that occurs after revascularization of acute ischemic limbs. PMID- 28004899 TI - Evidence overview: benefit of cerebral protection devices during carotid artery stenting. AB - Embolic protection devices (EPDs) are often used during carotid angioplasty and stenting (CAS) to reduce procedural cerebral emboli. This manuscript seeks to present an overview of evidence on EPDs during CAS. There are three categories of EPDs: distal occlusion (DO-EPD), filter (F-EPD) and proximal occlusion (PO-EPD). DO and F-EPDs have the disadvantage that the device has to be advanced through the stenosis, without protection and that the device may damage the distal internal carotid artery (ICA). F-EPDs have the advantage of maintaining antegrade flow throughout the procedure. PO-EPDs occlude the ICA and external carotid artery (ECA) (blocking antegrade flow), but do not require manipulation of the stenosis before protection is established. All devices add to procedural time and costs. Many single-center series and meta-analyses have shown lower incidence of procedural complications and surrogate endpoints when EPDs are used. However, these series are hampered by a serious confounder: protected cases were generally performed later, when institutions had more experience and when newer stents, techniques etc. had become available. Two small randomized trials showed no difference between filter-protected and unprotected procedures in clinical outcome, but found significantly more surrogate endpoints (diffusion-weighted MRI lesions and transcranial Doppler detected micro-emboli) in the protected groups. Comparing between groups of EPDs, some studies slightly favored PO to F-EPDs, while others found no difference. All devices were associated with low numbers of clinical cerebral complications, but frequent surrogate signs of cerebral embolization. In conclusion, all currently available EPDs still result in some degree of cerebral embolization. No solid recommendation for a particular type of EPDs, if any, can be derived from literature. PMID- 28004898 TI - Tips and tricks in vascular access for (T)EVAR. AB - Endovascular repair has become the treatment of choice for thoracic and abdominal aortic pathologies in the last decades, and is associated with excellent results in terms of perioperative, mid- and long-term morbidity and mortality. Access vessels play a central role in these procedures since access-related issues can increase the rates of technical failures and determine clinical complications for the patient. Therefore, accurate preoperative clinical evaluation and review of the preoperative images are mandatory. In this review, we report on the access related issues that can be encountered during EVAR and TEVAR, and present solutions and strategies to minimize access-related adverse outcomes. PMID- 28004900 TI - Current management of inguinal false aneurysms. AB - False aneurysms are formed as a result of bleeding causing a hematoma to compress the surrounding tissue. The majority of false aneurysms presenting to the vascular surgeon are caused by iatrogenic injury to an artery. Although anastomotic failure occurs, a much higher number is caused by bleeding from puncture sites after percutaneous intervention. Anticoagulative medication, low patelet counts and severely calcified vessels increase the risk of forming a false aneurysm. Experienced specialists may make the diagnosis from physical examination, but ultrasound imaging is almost always needed in order to decide for a treatment strategy. Small aneurysms with a diameter of less than 3 cm tend to thrombose spontaneously except in patients in anticoagulative treatment. Treatment options include ultrasound guided compression, which may be effective in a high proportion of patients who are not in anti-coagulative treatment, but may require prolonged compression and cause pain and discomfort. Duplex guided injection of thrombin or glue requires less time of compression and can be effective in patient s on antiocoagulative treatment, but may cause spillage of adhesive material into the crural vessels. Endovascular treatment with coils or covered stent grafts have proven useful in infected ilio-femoral false aneurysms. Open surgical repair may be the best treatment in the setting of imminent rupture, massive hematoma and skin necrosis. We present three patient cases treated with open surgery, endovascular coiling, and thrombin injection. PMID- 28004901 TI - A study on level of physical activity, depression, anxiety and stress symptoms among adolescents. AB - BACKGROUND: Inadequate physical activity has adverse health consequences among adolescents. Mental health problem can be developed by lack of physical activity however it is controversial. The current study aimed to examine the association between level of physical activity with depression, anxiety and stress symptoms among adolescents. METHODS: A representative sample of 1747 adolescents (13-14 years) was randomly selected from 6 schools in a south part of Malaysia. Respondents were asked to fill consent form, and questionnaires including Depression Anxiety and Stress Scale-21 and Physical Activity Questionnaire for Adolescents. RESULTS: Majority of respondents (71.9%) was Malay and more than half of the adolescents had low physical activity. About 40% had depression symptoms, followed by anxiety symptoms (65.9%) and stress symptoms (38.5%). Level of physical activity was significantly associated with gender, anxiety and stress (P<0.001). There were no associations with race, religion and depression symptom. CONCLUSIONS: This study provides some evidence among school-going adolescents related to anxiety and stress symptoms and low physical activities. Further studies are needed to show the protection effects of higher physical activity for depression, anxiety and stress symptoms in adolescents. PMID- 28004902 TI - Effectiveness of "Step into Health" program in Qatar: a pedometer-based longitudinal study. AB - BACKGROUND: This study examines the impact of a one-year pedometer-based intervention on increasing the physical activity level among adult population in Qatar. METHODS: This longitudinal study was conducted over a one-year period and included a total of 268 adults aged between 18-64 years old. Data were extracted and used from the "Step into Health" (SIH) program, a community-based program launched in 2012, as an approach to improve physical activity in Qatar. Walking intervention encouraged members of SIH to accumulate 10,000 steps or more per day and monitor their progress through a pedometer supported by a self-monitoring online account and a reinforcement system. RESULTS: This study shows a significant increase in average daily steps from 3933+/-3240 steps/day at baseline into 7507+/-5416 steps/week at the 12th month (P<0.001). It was found that 18.6% of participants met the daily target of 10,000 steps or more; however, there was a considerable increase of 39.2% by the 12th month. Females showed an increase in their physical activity; still, they remain less active than males. It was found that non-Arabs subgroup were more active than Arabs. Interestingly, older members (>=50 years old) were more active throughout the study period. CONCLUSIONS: Pedometer program was found to be effective in increasing the level of physical activity among participants. A decline in physical activity has been observed during hot weather, while re-enforcement campaign had a positive impact on the number of steps/day. PMID- 28004903 TI - Fluid intake behavior in athletes during typical training bouts. AB - BACKGROUND: Hydration habits during training may differ depending on sports mode and individual characteristics. The aim of this study was to assess fluid intake behavior in a wide sample of Italian athletes during their regular training. METHODS: Data on hydration habits during training were collected from a random sample of competitive athletes. Hydration strategies and personal characteristics were queried via questionnaire, including athletes' quantity and type of fluid ingested during a typical training bout, sport characteristics (e.g. mode and training duration), and whether their coach encouraged them to drink during trainings. RESULTS: Three hundred and fifty-two competitive athletes participated to the study; two hundred eighty-nine athletes correctly completed all survey items (age: 8-63 years, median: 21+/-13 years). Athletes were involved in international (3.1%), national (34.1%) and regional (44.9%) competitions. Median fluid intakes during training were 0.25 L/h; 150 athletes reported fluid intake below the median, whilst 23 athletes (6.5% of total sample) reported fluid intake at or above currently published exercise hydration guidelines (NATA and ACSM). Binary logistic regression indicated that the number of pauses to drink (B=0.771, P=0.000), duration of a typical training bout (B=-2.237, P=0.000), and a coach's encouragement to drink (B=0.601, P=0.030) were each associated with fluid consumption above or below the median value. CONCLUSIONS: Athletes across all disciplines reported drinking less fluid during training than currently espoused in hydration guidelines. A coach's encouragement to drink, the number of pauses during training, and bout duration each influence total fluid volume consumed, regardless of competition level, sex or the age of an athlete. PMID- 28004904 TI - Children and adolescent physical activity participation and enjoyment during active play. AB - BACKGROUND: Girls' (9-19 years) participation in physical activity (PA) is known to decrease at a faster rate than boys. A reduction in PA attractiveness (enjoyment) and lower psychosocial profile of girls approaching biological maturity may underlie the decreasing rate of PA participation. Since engaging children in active play programs improves health related quality of life indictors and enjoyment levels; the purposes of this study were to: 1) assess psychosocial status and PA attractiveness/enjoyment of boys and girls to an eight week active play program; and 2) investigate the relationships among PA participation, psychosocial status and PA attractiveness with both age and maturity status for boys and girls following an active play PA program. METHODS: Thirty-three children (age 9.8+/-1.3 years; weight 43.1+/-13.4 kg; BMI 20.8+/-3.2 kg/m2) were recruited to participate in an active play program for 8 weeks (4x/week; 1hr/d). M-S estimates ranged from -6.7 to -2.5 years away from biological maturity Daily program PA was assessed and compared to pre-post measures of psychosocial functioning and PA attractiveness. Statistical procedures were performed using ANOVA and/or Pearson's correlation r (SPSS v. 22.0) with P=0.05. RESULTS: PA participation in the active play program showed a group average of 39+/-11% time spent in moderate-vigorous PA (%MVPA) with boys averaging 45% MVPA and girls averaging 30% MVPA (P<0.05). PA attractiveness scores for boys did not change following the program; whereas girls improved from 67+/-13% to 76+/-9% (P<0.05). Minimal changes were noted for the health-related quality of life measures as a result of the PA program. Comparing PA attractiveness to %MVPA, 80% of girls reporting positive changes or no change; in contrast 56% of boys responded with negative/less PA attractiveness. PA attractiveness for all children was negatively associated with age (r=-0.19) and/or M-S (r=-0.29). The relationships, however, were gender specific with boys exhibiting a coefficient of -0.28 (age) and -0.61 (M-S) (P<0.05). For girls, increased PA attractiveness promoted less decline in %MVPA for M-S (r=0.18) compared to age (r=-0.17). CONCLUSIONS: For girls, approaching biological maturity, PA enjoyment/attractiveness can be positively influenced with an active play program, which is a major consideration promoting PA participation in girls but not boys. PMID- 28004905 TI - Subjective cognitive dysfunction in rehabilitation outpatients with musculoskeletal disorders or chronic pain. AB - BACKGROUND: Rehabilitation patients, without brain damage, sometimes complain about poor concentration and problems with their memory. The magnitude and associations, of this cognitive dysfunction, with different factors is unclear. AIM: To determine the magnitude of cognitive dysfunction in rehabilitation outpatient and to explore its associations with patient characteristics, diagnosis, surgery, pain, stress, anxiety and depression. DESIGN: Cross sectional. SETTING: Rehabilitation outpatients. POPULATION: Between July 2009 and January 2012, 274 rehabilitation outpatients were included and divided in 8 different groups through diagnosis. METHODS: Cognitive functioning was assessed using the cognitive failure questionnaire and compared with the general Dutch population. Associations of gender, age, diagnosis, recent surgery, pain and stress coping ability with cognitive function was explored. Mediation of depression and anxiety was explored. RESULTS: The rehabilitation patients had a significantly higher score on the CFQ (mean 35.9+/-13.4) when compared to the general Dutch population (mean 31.8+/-11.1). Mean difference is 4.1, 95% confidence interval 2.60 to 5.60. In the stepwise linear regression analysis only gender, diagnosis and stress coping ability were significantly associated. A significant mediation effect was found of anxiety (P<=0.001) and depression (P<=0.005) between stress coping ability and cognitive function. CONCLUSIONS: Rehabilitation outpatients experience more cognitive problems in comparison to the general Dutch population. Reported dysfunction of cognition in rehabilitation outpatients are associated with stress coping ability and for a small amount to gender and diagnosis. The association of stress coping ability and cognitive dysfunction is mediated by depression and anxiety. Women tend to report more dysfunctional cognition compared to men. Patient characteristics, surgery and experienced pain have no significant influence on the experienced cognitive dysfunction. CLINICAL REHABILITATION IMPACT: Cognitive problems reported by patients should be addressed by adapting the rehabilitation program, for instance write down instructions, repeat explanations and take more time for instructions. Cognitive problems in rehabilitation patients without brain damage is probably a stress coping problem and can be addressed by boosting resilience. Targeting depression or anxiety is another option of treatment cognition if those are mediating between stress coping and cognitive problems. PMID- 28004906 TI - Transcranial and spinal cord magnetic stimulation in treatment of spasticity: a literature review and meta-analysis. AB - INTRODUCTION: Spasticity is associated with various diseases of the nervous system. Current treatments such as drug therapy, botulinum toxin injections, kinesitherapy, and physiotherapy are not sufficiently effective in a large number of patients. Transcranial magnetic stimulation (TMS) can be considered as an alternative method of treatment. The purpose of this article was to conduct a systematic review and meta-analysis of all available publications assessing the efficacy of repetitive TMS in treatment of spasticity. EVIDENCE ACQUISITION: Search for articles was conducted in databases PubMed, Willey, and Google. Keywords included "TMS", "spasticity", "TMS and spasticity", "non-invasive brain stimulation", and "non-invasive spinal cord stimulation". The difference in scores according to the Modified Ashworth Scale (MAS) for one joint before and after treatment was taken as the effect size. EVIDENCE SYNTHESIS: We found 26 articles that examined the TMS efficacy in treatment of spasticity. Meta-analysis included 6 trials comprising 149 patients who underwent real stimulation or simulation. No statistically significant difference in the effect of real and simulated stimulation was found in stroke patients. In patients with spinal cord injury and spasticity, the mean effect size value and the 95% confidence interval were -0.80 and (-1.12, -0.49), respectively, in a group of real stimulation; in the case of simulated stimulation, these parameters were 0.15 and (-0.30, -0.00), respectively. Statistically significant differences between groups of real stimulation and simulation were demonstrated for using high-frequency repetitive TMS or iTBS mode for the M1 area of the spastic leg (P=0.0002). CONCLUSIONS: According to the meta-analysis, the statistically significant effect of TMS in the form of reduced spasticity was demonstrated only for the developed due to lesions at the brain stem and spinal cord level. To clarify the amount of the antispasmodic effect of repetitive TMS at other lesion levels, in particular in patients with hemispheric stroke, further research is required. PMID- 28004907 TI - Gallium-Doped Li7La3Zr2O12 Garnet-Type Electrolytes with High Lithium-Ion Conductivity. AB - Owing to their high conductivity, crystalline Li7-3xGaxLa3Zr2O12 garnets are promising electrolytes for all-solid-state lithium-ion batteries. Herein, the influence of Ga doping on the phase, lithium-ion distribution, and conductivity of Li7-3xGaxLa3Zr2O12 garnets is investigated, with the determined concentration and mobility of lithium ions shedding light on the origin of the high conductivity of Li7-3xGaxLa3Zr2O12. When the Ga concentration exceeds 0.20 Ga per formula unit, the garnet-type material is found to assume a cubic structure, but lower Ga concentrations result in the coexistence of cubic and tetragonal phases. Most lithium within Li7-3xGaxLa3Zr2O12 is found to reside at the octahedral 96h site, away from the central octahedral 48g site, while the remaining lithium resides at the tetrahedral 24d site. Such kind of lithium distribution leads to high lithium-ion mobility, which is the origin of the high conductivity; the highest lithium-ion conductivity of 1.46 mS/cm at 25 degrees C is found to be achieved for Li7-3xGaxLa3Zr2O12 at x = 0.25. Additionally, there are two lithium ion migration pathways in the Li7-3xGaxLa3Zr2O12 garnets: 96h-96h and 24d-96h 24d, but the lithium ions transporting through the 96h-96h pathway determine the overall conductivity. PMID- 28004908 TI - Triumphing over Charge Transfer Limitations of PEDOT Nanofiber Reduction Catalyst by 1,2-Ethanedithiol Doping for Quantum Dot Solar Cells. AB - Charge transfer between a conducting polymer-based counter electrode (CE) and a polysulfide (S2-/Sn2-) electrolyte mediator is a key limitation to improvements of solar energy conversion efficiency (ECE) in quantum-dot-sensitized solar cells (QDSCs). In this paper, 1,2-ethanedithiol (EDT) was doped into nanofibrous poly(3,4-ethylenedioxythiophene) (PEDOT NF) to overcome the charge transfer limitation between PEDOT NF and S2-/Sn2-. EDT not only helps to reduce the aggregation and thus enhance the linearization of the PEDOT chains but also changes the molecular conformation of the PEDOT chains from a benzoid to a quinoid structure. EDT-doped PEDOT NF-based CEs showed almost 3.7 times higher conductivity, better electrocatalytic activity, and improved compatibility with S2-/Sn2- in an aqueous electrolyte. As a result, the charge transfer resistance between the polymer-based CE and the S2-/Sn2- electrolyte was significantly reduced, resulting in over 3% ECE in QDSCs, more than double that of a bare PEDOT NF-based CE. PMID- 28004909 TI - A Rationally Designed, General Strategy for Membrane Orientation of Photoinduced Electron Transfer-Based Voltage-Sensitive Dyes. AB - Voltage imaging with fluorescent dyes offers promise for interrogating the complex roles of membrane potential in coordinating the activity of neurons in the brain. Yet, low sensitivity often limits the broad applicability of optical voltage indicators. In this paper, we use molecular dynamics (MD) simulations to guide the design of new, ultrasensitive fluorescent voltage indicators that use photoinduced electron transfer (PeT) as a voltage-sensing switch. MD simulations predict an approximately 16% increase in voltage sensitivity resulting purely from improved alignment of dye with the membrane. We confirm this theoretical finding by synthesizing 9 new voltage-sensitive (VoltageFluor, or VF) dyes and establishing that all of them display the expected improvement of approximately 19%. This synergistic outworking of theory and experiment enabled computational and theoretical estimation of VF dye orientation in lipid bilayers and has yielded the most sensitive PeT-based VF dye to date. We use this new voltage indicator to monitor voltage spikes in neurons from rat hippocampus and human pluripotent-stem-cell-derived dopaminergic neurons. PMID- 28004910 TI - Multifunctional Dextran Sulfate-Coated Reconstituted High Density Lipoproteins Target Macrophages and Promote Beneficial Antiatherosclerotic Mechanisms. AB - An atorvastatin calcium (AT)-loaded dextran sulfate (DXS)-coated core-shell reconstituted high density lipoprotein (rHDL), termed AT-DXS-LP-rHDL, was developed for targeted drug delivery to macrophages and suppression of inflammation via the high affinity of DXS with scavenge receptor class AI (SR-AI) as well as depletion of intracellular cholesterol by apolipoprotein A-I (apoA-I) mediated cholesterol efflux. These core-shell nanoparticles comprising an AT loaded negatively charged poly(lactide-co-glycolide) (PLGA) core and a cationic lipid bilayer shell were prepared by nanoprecipitation method followed by thin film hydration and extrusion. The nanoparticles were further functionalized with apoA-I and DXS via sodium cholate mediation and electrostatic interaction, respectively. The core-shell structure and the surface coating of apoA-I and DXS were verified by the increased particle size, inverted zeta potential, and reduced in vitro drug release rate. The TEM image further confirmed the entrapment of the PLGA nanoparticles in the aqueous interior of the liposomes. In vitro cell viability assay showed the biocompatibility of the AT-loaded nanocarriers. The cellular uptake study illustrated that the targeting efficacy to macrophages increased in the following order: PLGA nanoparticles (P-NP), core shell nanoparticles (LP-NP), core-shell rHDL (LP-rHDL), and DXS-LP-rHDL. Moreover, cellular drug efficacy of AT-loaded nanoparticles in preventing macrophage-derived foam cell formation and inflammation such as intracellular lipid deposition, cholesterol esters content, DiI-oxLDL uptake, cholesterol efflux, and secretion of TNF-alpha, IL-6, and IL-10 was much better than that of the drug-free nanoparticles, consistent with the results of cellular uptake study. Collectively, AT-DXS-LP-rHDL, as multifunctional carriers, could not only deliver more drug to macrophages, but also present antiatherogenic actions of the biofunctional nanocarriers through damping oxidized low density lipoproteins (oxLDL) uptake and promoting cholesterol efflux. PMID- 28004911 TI - Plasmon-Enhanced Photocatalytic CO(2) Conversion within Metal-Organic Frameworks under Visible Light. AB - Materials development for artificial photosynthesis, in particular, CO2 reduction, has been under extensive efforts, ranging from inorganic semiconductors to molecular complexes. In this report, we demonstrate a metal organic framework (MOF)-coated nanoparticle photocatalyst with enhanced CO2 reduction activity and stability, which stems from having two different functional units for activity enhancement and catalytic stability combined together as a single construct. Covalently attaching a CO2-to-CO conversion photocatalyst ReI(CO)3(BPYDC)Cl, BPYDC = 2,2'-bipyridine-5,5'-dicarboxylate, to a zirconium MOF, UiO-67 (Ren-MOF), prevents dimerization leading to deactivation. By systematically controlling its density in the framework (n = 0, 1, 2, 3, 5, 11, 16, and 24 complexes per unit cell), the highest photocatalytic activity was found for Re3-MOF. Structural analysis of Ren-MOFs suggests that a fine balance of proximity between photoactive centers is needed for cooperatively enhanced photocatalytic activity, where an optimum number of Re complexes per unit cell should reach the highest activity. Based on the structure-activity correlation of Ren-MOFs, Re3-MOF was coated onto Ag nanocubes (Ag?Re3-MOF), which spatially confined photoactive Re centers to the intensified near-surface electric fields at the surface of Ag nanocubes, resulting in a 7-fold enhancement of CO2-to-CO conversion under visible light with long-term stability maintained up to 48 h. PMID- 28004912 TI - First-Principles Investigation of the Epitaxial Stabilization of Oxide Polymorphs: TiO2 on (Sr,Ba)TiO3. AB - Metastable polymorphs, many of which have never been fabricated, have been predicted to exhibit interesting and technologically relevant properties. Epitaxial synthesis is a powerful structure-directing method that can produce metastable polymorphs but is typically done in a trial and error fashion. Unfortunately, the relevant thermodynamic terms governing epitaxial synthesis of new materials are unknown. Accurate calculation of the relevant thermodynamic terms and their incorporation into predictive models would accelerate the synthesis of metastable polymorphs by identifying thermodynamically favorable paths. Using density functional theory with three different functionals, we computed several relevant terms for TiO2 anatase (A) and rutile (R) film growth on low-index surfaces of SrTiO3 (STO) and BaTiO3 (BTO) cubic perovskites. After identifying potential coherent epitaxial interfaces based on experimental observations, the volumetric formation, volumetric strain, and areal substrate film interface energies were calculated for (001)A?(001)(S/B)TO, (102)A?(011)(S/B)TO, (100)R?(111)(S/B)TO, and (112)A?(111)(S/B)TO coherent interfaces. These terms were integrated into a standard model of epitaxial nucleation, and the results yielded reasonable agreement between experimental observations and DFT predictions of the preferred epitaxial polymorph. Predicted trends in epitaxial stability were essentially independent of the three functionals used in the calculations. These results are discussed in light of their promise that DFT-informed epitaxial film growth can accelerate fabrication of new polymorphs. These results also validate the recently proposed 20 kJ/mol stability window for predicting which polymorphs could be epitaxially stabilized. PMID- 28004913 TI - Geochemical Parameters and Reductive Dechlorination Determine Aerobic Cometabolic vs Aerobic Metabolic Vinyl Chloride Biodegradation at Oxic/Anoxic Interface of Hyporheic Zones. AB - Hyporheic zones mediate vinyl chloride (VC) biodegradation in groundwater discharging into surface waters. At the oxic/anoxic interface (OAI) of hyporheic zones subjected to redox oscillations, VC is degraded via coexisting aerobic ethenotrophic and anaerobic reductive dechlorination pathways. However, the identity of aerobic VC degradation pathways (cometabolic vs metabolic) and their interactions with reductive dechlorination in relation to riverbed sediment geochemistry remain ill-defined. We addressed this using microcosms containing OAI sediments incubated under fluctuating oxic/anoxic atmosphere. Under oxic atmosphere, aerobic metabolic VC oxidation was absent in sediments with high total organic carbon (TOC) and VC was reductively dechlorinated to ethene. Ethene was oxidized by ethenotrophs that can degrade VC cometabolically. Contrastingly, VC was metabolically oxidized by ethenotrophs in low-TOC sediments with low reductive dechlorination potential. Accordingly, enrichment and isolation of metabolic VC-oxidizing ethenotrophs was successful only from the low-TOC sediment. Sequence analysis of etnE genes from the microcosms as well phylogenetic typing of the isolates showed that ethenotrophs in the sediments were facultative anaerobic Proteobacteria capable of coping with OAI-associated redox fluctuations. Our results suggest that local sediment heterogeneity supports/selects divergent VC degradation processes at the OAI and that high reductive dechlorination potential suppresses development of aerobic metabolic VC oxidation potential. PMID- 28004914 TI - First-Principles Investigations of the Working Mechanism of 2D h-BN as an Interfacial Layer for the Anode of Lithium Metal Batteries. AB - An issue with the use of metallic lithium as an anode material for lithium-based batteries is dendrite growth, causing a periodic breaking and repair of the solid electrolyte interphase (SEI) layer. Adding 2D atomic crystals, such as h-BN, as an interfacial layer between the lithium metal anode and liquid electrolyte has been demonstrated to be effective to mitigate dendrite growth, thereby enhancing the Columbic efficiency of lithium metal batteries. But the underlying mechanism leading to the reduced dendrite growth remains unknown. In this work, with the aid of first-principle calculations, we find that the interaction between the h BN and lithium metal layers is a weak van der Waals force, and two atomic layers of h-BN are thick enough to block the electron tunneling from lithium metal to electrolyte, thus prohibiting the decomposition of electrolyte. The interlayer spacing between the h-BN and lithium metal layers can provide larger adsorption energies toward lithium atoms than that provided by bare lithium or h-BN, making lithium atoms prefer to intercalate under the cover of h-BN during the plating process. The combined high stiffness of h-BN and the low diffusion energy barriers of lithium at the Li/h-BN interfaces induce a uniform distribution of lithium under h-BN, therefore effectively suppressing dendrite growth. PMID- 28004916 TI - Liquid Organic Hydrogen Carriers (LOHCs): Toward a Hydrogen-free Hydrogen Economy. AB - The need to drastically reduce CO2 emissions will lead to the transformation of our current, carbon-based energy system to a more sustainable, renewable-based one. In this process, hydrogen will gain increasing importance as secondary energy vector. Energy storage requirements on the TWh scale (to bridge extended times of low wind and sun harvest) and global logistics of renewable energy equivalents will create additional driving forces toward a future hydrogen economy. However, the nature of hydrogen requires dedicated infrastructures, and this has prevented so far the introduction of elemental hydrogen into the energy sector to a large extent. Recent scientific and technological progress in handling hydrogen in chemically bound form as liquid organic hydrogen carrier (LOHC) supports the technological vision that a future hydrogen economy may work without handling large amounts of elemental hydrogen. LOHC systems are composed of pairs of hydrogen-lean and hydrogen-rich organic compounds that store hydrogen by repeated catalytic hydrogenation and dehydrogenation cycles. While hydrogen handling in the form of LOHCs allows for using the existing infrastructure for fuels, it also builds on the existing public confidence in dealing with liquid energy carriers. In contrast to hydrogen storage by hydrogenation of gases, such as CO2 or N2, hydrogen release from LOHC systems produces pure hydrogen after condensation of the high-boiling carrier compounds. This Account highlights the current state-of-the-art in hydrogen storage using LOHC systems. It first introduces fundamental aspects of a future hydrogen economy and derives therefrom requirements for suitable LOHC compounds. Molecular structures that have been successfully applied in the literature are presented, and their property profiles are discussed. Fundamental and applied aspects of the involved hydrogenation and dehydrogenation catalysis are discussed, characteristic differences for the catalytic conversion of pure hydrocarbon and nitrogen-containing LOHC compounds are derived from the literature, and attractive future research directions are highlighted. Finally, applications of the LOHC technology are presented. This part covers stationary energy storage (on-grid and off-grid), hydrogen logistics, and on-board hydrogen production for mobile applications. Technology readiness of these fields is very different. For stationary energy storage systems, the feasibility of the LOHC technology has been recently proven in commercial demonstrators, and cost aspects will decide on their further commercial success. For other highly attractive options, such as, hydrogen delivery to hydrogen filling stations or direct-LOHC-fuel cell applications, significant efforts in fundamental and applied research are still needed and, hopefully, encouraged by this Account. PMID- 28004915 TI - High-Energy Dissipation Performance in Epoxy Coatings by the Synergistic Effect of Carbon Nanotube/Block Copolymer Conjugates. AB - Hierarchical assembly of hard/soft nanoparticles holds great potential as reinforcements for polymer nanocomposites with tailored properties. Here, we present a facile strategy to integrate polystyrene-grafted carbon nanotubes (PSgCNT) (0.05-0.3 wt %) and poly(styrene-b-[isoprene-ran-epoxyisoprene]-b styrene) block copolymer (10 wt %) into epoxy coatings using an ultrasound assisted noncovalent functionalization process. The method leads to cured nanocomposites with core-shell block copolymer (BCP) nanodomains which are associated with carbon nanotubes (CNT) giving rise to CNT-BCP hybrid structures. Nanocomposite energy dissipation and reduced Young's Modulus (E*) is determined from force-distance curves by atomic force microscopy operating in the PeakForce QNM imaging mode and compared to thermosets modified with BCP and purified carbon nanotubes (pCNT). Remarkably, nanocomposites bearing PSgCNT-BCP conjugates display an increase in energy dissipation of up to 7.1-fold with respect to neat epoxy and 53% more than materials prepared with pCNT and BCP at the same CNT load (0.3 wt %), while reduced Young's Modulus shows no significant change with CNT type and increases up to 25% compared to neat epoxy E* at a CNT load of 0.3 wt %. The energy dissipation performance of nanocomposites is also reflected by the lower wear coefficients of materials with PSgCNT and BCP compared to those with pCNT and BCP, as determined by abrasion tests. Furthermore, scanning electron microscopy (SEM) images taken on wear surfaces show that materials incorporating PSgCNT and BCP exhibit much more surface deformation under shear forces in agreement with their higher ability to dissipate more energy before particle release. We propose that the synergistic effect observed in energy dissipation arises from hierarchical assembly of PSgCNT and BCP within the epoxy matrix and provides clues that the CNT-BCP interface has a significant role in the mechanisms of energy dissipation of epoxy coating modified by CNT-BCP conjugates. These findings provide a means to design epoxy-based coatings with high-energy dissipation performance. PMID- 28004917 TI - Non-Deprotonative Primary and Secondary Amination of (Hetero)Arylmetals. AB - Herein we disclose a novel method for the facile transfer of primary (-NH2) and secondary amino groups (-NHR) to heteroaryl- as well as arylcuprates at low temperature without the need for precious metal catalysts, ligands, excess reagents, protecting and/or directing groups. This one-pot transformation allows unprecedented functional group tolerance and it is well-suited for the amination of electron-rich, electron-deficient as well as structurally complex (hetero)arylmetals. In some of the cases, only catalytic amounts of a copper(I) salt is required. PMID- 28004919 TI - Correction to "Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via Palladium-Catalyzed Intramolecular Amination of C(sp3)-H and C(sp2) H Bonds at gamma and delta Positions". PMID- 28004918 TI - Unusual Cage Rearrangements in 10-Vertex nido-5,6-Dicarbaborane Derivatives: An Interplay between Theory and Experiment. AB - The reaction between selected X-nido-5,6-C2B8H11 compounds (where X = Cl, Br, I) and "Proton Sponge" [PS; 1,8-bis(dimethylamino)naphthalene], followed by acidification, results in extensive rearrangement of all cage vertices. Specifically, deprotonation of 7-X-5,6-C2B8H11 compounds with one equivalent of PS in hexane or CH2Cl2 at ambient temperature led to a 7 -> 10 halogen rearrangement, forming a series of PSH+[10-X-5,6-C2B8H10]- salts. Reprotonation using concentrated H2SO4 in CH2Cl2 generates a series of neutral carbaboranes 10 X-5,6-C2B8H11, with the overall 7 -> 10 conversion being 75%, 95%, and 100% for X = Cl, Br, and I, respectively. Under similar conditions, 4-Cl-5,6-C2B8H11 gave ~66% conversion to 3-Cl-5,6-C2B8H11. Since these rearrangements could not be rationalized using the B-vertex swing mechanism, new cage rearrangement mechanisms, which are substantiated using DFT calculations, have been proposed. Experimental 11B NMR chemical shifts are well reproduced by the computations; as expected delta(11B) for B(10) atoms in derivatives with X = Br and I are heavily affected by spin-orbit coupling. PMID- 28004920 TI - Estimating the Donor-Acceptor Distance To Tune the Emission Efficiency of Luminescent Lanthanide Compounds. AB - The influence of the donor-acceptor distance RL on the photophysical properties, including the emission quantum yield, of two europium complexes with the same coordination number, and thus similar microsymmetries, was investigated by spectroscopic and computational methods. K3[Eu(dipicCbz)3] was synthesized using the new ligand dipicCbz and its photophysical properties compared to Cs3[Eu(dipic)3]. We found that a 50% increase in RL from 4.1 to 6.5 A results in a substantial decrease in the emission efficiency from 24 to 1.8%. PMID- 28004921 TI - Streamlining the Design-to-Build Transition with Build-Optimization Software Tools. AB - Scaling-up capabilities for the design, build, and test of synthetic biology constructs holds great promise for the development of new applications in fuels, chemical production, or cellular-behavior engineering. Construct design is an essential component in this process; however, not every designed DNA sequence can be readily manufactured, even using state-of-the-art DNA synthesis methods. Current biological computer-aided design and manufacture tools (bioCAD/CAM) do not adequately consider the limitations of DNA synthesis technologies when generating their outputs. Designed sequences that violate DNA synthesis constraints may require substantial sequence redesign or lead to price-premiums and temporal delays, which adversely impact the efficiency of the DNA manufacturing process. We have developed a suite of build-optimization software tools (BOOST) to streamline the design-build transition in synthetic biology engineering workflows. BOOST incorporates knowledge of DNA synthesis success determinants into the design process to output ready-to-build sequences, preempting the need for sequence redesign. The BOOST web application is available at https://boost.jgi.doe.gov and its Application Program Interfaces (API) enable integration into automated, customized DNA design processes. The herein presented results highlight the effectiveness of BOOST in reducing DNA synthesis costs and timelines. PMID- 28004922 TI - Fluorene Conjugated Polymer/Nickel Oxide Nanocomposite Hole Transport Layer Enhances the Efficiency of Organic Photovoltaic Devices. AB - A nanocomposite layer comprising the conjugated polymer poly[(9,9-bis(3'-(N,N dimethylamino)propyl)-2,7-fluorene)-alt-2,7-(9,9-dioctyl)fluorene] (PFN) and nickel oxide (NiOx) has been employed as the hole transport layer (HTL) in organic photovoltaics (OPVs) featuring PBDTTBO-C8 and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as the active layer. The optimal device incorporating the PFN:NiOx nanocomposite as the HTLs displayed a power conversion efficiency (PCE) to 6.2%, up from 4.5% for the corresponding device incorporating pristine NiOx as the HTL layer: a nearly 40% improvement in PCE. X-ray photoelectron spectroscopy (XPS) was used to determine the types of chemical bonding, ultraviolet photoelectron spectroscopy (UPS) to measure the change in work function, and atomic force microscopy (AFM) to examine the morphology of the composite layers. The growth of nickel trioxide, Ni2O3, in the PFN:NiOx layer played a key role in producing the p-doping effect and in tuning the work function, thereby improving the overall device performance. PMID- 28004923 TI - Synthesis, Crystal Structure, and Properties of La4Zn7P10 and La4Mg1.5Zn8.5P12. AB - Two new zinc phosphides, La4Zn7P10 and La4Mg1.5Zn8.5P12, were synthesized via transport reactions, and their crystal structures were determined by single crystal X-ray diffraction. La4Zn7P10 and La4Mg1.5Zn8.5P12 are built from three dimensional Zn-P and Zn-Mg-P anionic frameworks that encapsulate lanthanum atoms. The anionic framework of La4Zn7P10 is constructed from one-dimensional Zn4P6, Zn2P4, and ZnP4 chains. The Zn4P6 chains are also the main building units in La4Mg1.5Zn8.5P12. In La4Zn7P10, the displacement of a zinc atom from the origin of the unit cell causes the Zn4 position to split into two equivalent atomic sites, each with 50% occupancy. The splitting of the atomic position substantially modifies the electronic properties, as suggested by theoretical calculations. The necessity of splitting can be overcome by replacement of zinc with magnesium in La4Mg1.5Zn8.5P12. Investigation of the transport properties of a densified polycrystalline sample of La4Zn7P10 demonstrates that it is an n-type semiconductor with a small bandgap of ~0.04 eV at 300 K. La4Zn7P10 also exhibits low thermal conductivity, 1.3 Wm-1 K-1 at 300 K, which mainly originates from the lattice thermal conductivity. La4Zn7P10 is stable in a sealed evacuated ampule up to 1123 K as revealed by differential scanning calorimetry. PMID- 28004924 TI - Aldehyde Deformylation and Catalytic C-H Activation Resulting from a Shared Cobalt(II) Precursor. AB - The tetradentate ligand N,N'-dibenzyl-N,N'-bis(2-pyridylmethyl)-1,2 cyclohexanediamine (bbpc) was used to prepare cobalt(II) diacetonitrilo and cobalt(III) peroxo complexes, the latter of which was structurally characterized. The cobalt(III) peroxo compound forms from reactions between the cobalt(II) complex, hydrogen peroxide, and a base, and it stoichiometrically reacts with aldehydes to yield mixtures of alkenes and ketones. The cobalt(II) precursor is capable of catalyzing the activation of weak C-H bonds by either iodosobenzene or m-chloroperbenzoic acid. This chemistry differs from most previously characterized cobalt-mediated C-H activation in that (1) it is catalytic, rather than stoichiometric, with respect to the cobalt and (2) it does not need a second Lewis acid metal ion in order to proceed. PMID- 28004926 TI - Slow Magnetic Relaxation in Weak Easy-Plane Anisotropy: the Case of a Combined Magnetic and HFEPR Study. AB - Two pseudotetrahedral cobalt(II) complexes exhibiting slow magnetic relaxation under an applied direct-current field are investigated. The weak easy-plane anisotropy is accurately determined by high-field/high-frequency electron paramagnetic resonance spectroscopy as D = 2.57 cm-1 and E = 0.82 cm-1 for 1 and D = 5.56 cm-1 and E = 1.05 cm-1 for 2. In addition, hysteresis loops are observed for the two compounds at very low temperatures. PMID- 28004925 TI - Small Molecule-Based Pattern Recognition To Classify RNA Structure. AB - Three-dimensional RNA structures are notoriously difficult to determine, and the link between secondary structure and RNA conformation is only beginning to be understood. These challenges have hindered the identification of guiding principles for small molecule:RNA recognition. We herein demonstrate that the strong and differential binding ability of aminoglycosides to RNA structures can be used to classify five canonical RNA secondary structure motifs through principal component analysis (PCA). In these analyses, the aminoglycosides act as receptors, while RNA structures labeled with a benzofuranyluridine fluorophore act as analytes. Complete (100%) predictive ability for this RNA training set was achieved by incorporating two exhaustively guanidinylated aminoglycosides into the receptor library. The PCA was then externally validated using biologically relevant RNA constructs. In bulge-stem-loop constructs of HIV-1 transactivation response element (TAR) RNA, we achieved nucleotide-specific classification of two independent secondary structure motifs. Furthermore, examination of cheminformatic parameters and PCA loading factors revealed trends in aminoglycoside:RNA recognition, including the importance of shape-based discrimination, and suggested the potential for size and sequence discrimination within RNA structural motifs. These studies present a new approach to classifying RNA structure and provide direct evidence that RNA topology, in addition to sequence, is critical for the molecular recognition of RNA. PMID- 28004927 TI - Model of the Interaction between the NF-kappaB Inhibitory Protein p100 and the E3 Ubiquitin Ligase beta-TrCP based on NMR and Docking Experiments. AB - NF-kappaB is a major transcription factor whose activation is triggered through two main activation pathways: the canonical pathway involving disruption of IkappaB-alpha/NF-kappaB complexes and the alternative pathway whose activation relies on the inducible proteolysis of the inhibitory protein p100. One central step controlling p100 processing consists in the interaction of the E3 ubiquitin ligase beta-TrCP with p100, thereby leading to its ubiquitinylation and subsequent either complete degradation or partial proteolysis by the proteasome. However, the interaction mechanism between p100 and beta-TrCP is still poorly defined. In this work, a diphosphorylated 21-mer p100 peptide model containing the phosphodegron motif was used to characterize the interaction with beta-TrCP by NMR. In parallel, docking simulations were performed in order to obtain a model of the 21P-p100/beta-TrCP complex. Saturation transfer difference (STD) experiments were performed in order to highlight the residues of p100 involved in the interaction with the beta-TrCP protein. These results highlighted the importance of pSer865 and pSer869 residues in the interaction with beta-TrCP and particularly the Tyr867 that fits inside the hydrophobe beta-TrCP cavity with the Arg474 guanidinium group. Four other arginines, Arg285, Arg410, Arg431, and Arg521, were found essential in the stabilization of p100 on the beta-TrCP surface. Importantly, the requirement for these five arginine residues of beta TrCP for the interaction with p100 was further confirmed in vivo, thereby validating the docking model through a biological approach. PMID- 28004928 TI - Iterative Design and in Vivo Evaluation of an Oncolytic Antilymphoma Peptide. AB - Oncolytic peptides represent a promising new strategy within the field of cancer immunotherapy. Here we describe the systematic design and evaluation of short antilymphoma peptides within this paradigm. The peptides were tested in vitro and in vivo to identify a lead compound for further evaluation as novel oncolytic immunotherapeutic. In vitro tests revealed peptides with high activity against several lymphoma types and low cytotoxicity toward normal cells. Treated lymphoma cells exhibited a reduced mitochondrial membrane potential that resulted in an irreversible disintegration of their plasma membranes. No caspase activation or ultrastructural features of apoptotic cell death were observed. One of these peptides, 11, was shown to induce complete tumor regression and protective immunity following intralesional treatment of murine A20 B-lymphomas. Due to its selectivity for lymphoma cells and its ability to induce tumor-specific immune responses, 11 has the potential to be used in intralesional treatment of accessible lymphoma tumors. PMID- 28004929 TI - Detection of Electrochemical Reaction Products from the Sodium-Oxygen Cell with Solid-State 23Na NMR Spectroscopy. AB - 23Na MAS NMR spectra of sodium-oxygen (Na-O2) cathodes reveals a combination of degradation species: newly observed sodium fluoride (NaF) and the expected sodium carbonate (Na2CO3), as well as the desired reaction product sodium peroxide (Na2O2). The initial reaction product, sodium superoxide (NaO2), is not present in a measurable quantity in the 23Na NMR spectra of the cycled electrodes. The reactivity of solid NaO2 is probed further, and NaF is found to be formed through a reaction between the electrochemically generated NaO2 and the electrode binder, polyvinylidene fluoride (PVDF). The instability of cell components in the presence of desired electrochemical reaction products is clearly problematic and bears further investigation. PMID- 28004930 TI - On Atomistic Models for Molecular Oxygen. AB - Molecular oxygen (O2) is key to all life on earth, as it is constantly cycled via photosynthesis and cellular respiration. Substantial scientific effort has been devoted to understanding every part of this cycle. Classical molecular dynamics (MD) simulations have been used to study some of the key processes involved in cellular respiration: O2 permeation through alveolar monolayers and cellular membranes, its binding to hemoglobin during transport in the bloodstream, as well as its transport along optimal pathways toward its reduction sites in proteins. Moreover, MD simulations can help interpret the results of several imaging techniques in which O2 is used because of its paramagnetic nature. However, despite the widespread use of computational models for the O2 molecule, their performances have never been systematically evaluated. In this paper, we assess the performances of 14 different models of O2 available in the literature by calculating four thermodynamic properties: density, heat of vaporization, free energy of hydration, and free energy of solvation in hexadecane. For each property, reliable experimental data are available. Most models perform reasonably well in predicting the correct trends, but they fail to reproduce the experimental data quantitatively. We then develop new models for O2, with and without a quadrupole moment, and compare their behavior with the behavior of previously published models. The new models show significant improvement in terms of density, heat of vaporization, and free energy of hydration. However, quantitative agreement with water-oil partitioning is not reached due to discrepancies between the calculated and measured free energies of solvation in hexadecane. We suggest that classical pairwise-additive models may be inadequate to properly describe the thermodynamics of solvation of apolar species, such as O2, in apolar solvents. PMID- 28004931 TI - Properties of Augmented Kohn-Sham Potential for Energy as Simple Sum of Orbital Energies. AB - A recent modification to the traditional Kohn-Sham method ( Levy , M. ; Zahariev , F. Phys. Rev. Lett. 2014 , 113 , 113002 ; Levy , M. ; Zahariev , F. Mol. Phys. 2016 , 114 , 1162 - 1164 ), which gives the ground-state energy as a direct sum of the occupied orbital energies, is discussed and its properties are numerically illustrated on representative atoms and ions. It is observed that current approximate density functionals tend to give surprisingly small errors for the highest occupied orbital energies that are obtained with the augmented potential. The appropriately shifted Kohn-Sham potential is the basic object within this direct-energy Kohn-Sham method and needs to be approximated. To facilitate approximations, several constraints to the augmented Kohn-Sham potential are presented. PMID- 28004932 TI - Efficient Implementation of Energy Decomposition Analysis for Second-Order Moller Plesset Perturbation Theory and Application to Anion-pi Interactions. AB - Energy decomposition analysis (EDA) is a widely used tool for extracting physical and chemical insights from electronic structure calculations of intermolecular interactions, as well as for the development of advanced force fields for describing those interactions. Recently, the absolutely localized molecular orbital (ALMO) EDA has been extended from the self-consistent field level to the second-order Moller-Plesset (MP2) theory level. This paper reports an efficient implementation of the MP2 ALMO-EDA that scales optimally, employs the resolution of the identity (RI) approximation for post-SCF matrix elements, and is shared memory parallel. The algorithms necessary to achieve this implementation are described in detail. Performance tests using the aug-cc-pVTZ basis set for water clusters of up to 10 molecules are reported. The timings suggest that the MP2 ALMO-EDA is computationally feasible whenever MP2 energy calculations themselves are feasible, and the cost is dominated by the SCF itself in this size regime. The MP2 ALMO-EDA is applied to study the origin of substituent effects in anion pi interactions between chloride and benzene and mono- through hexafluorobenzene. The effect of fluoro substituents was primarily to change the frozen interaction. Detailed analysis supports the interpretation that anion-pi interactions are favorable because of electrostatic interaction with the substituents. PMID- 28004933 TI - Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd Catalyzed Tandem Oxidative Cyclization-Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding. AB - Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl2/1,4 benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-exo Markovnikov regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization. PMID- 28004934 TI - Synthesis of Functionalized 3-Spiro[cyclopropa[a]pyrrolizine]- and 3-Spiro[3 azabicyclo[3.1.0]hexane]oxindoles from Cyclopropenes and Azomethine Ylides via [3 + 2]-Cycloaddition. AB - 3-Spiro[cyclopropa[a]pyrrolizine]- and 3-spiro[3 azabicyclo[3.1.0]hexane]oxindoles were prepared in moderate to high yields via one-pot three-component reactions using substituted isatins, alpha-amino acids, and cyclopropenes. The key step is an intramolecular [3 + 2]-cycloaddition reaction of an in situ generated azomethine ylide onto a cyclopropene. Both N substituted and N-unsubstituted alpha-amino acids, dipeptide Gly-Gly, and also benzylamine were used as the amine component for the azomethine ylide generation. The anticancer activity of some of the obtained compounds against human leukemia K562 cell line was evaluated by flow cytometry in vitro. PMID- 28004935 TI - Asymmetric Synthesis of Rauhut-Currier type Products by a Regioselective Mukaiyama Reaction under Bifunctional Catalysis. AB - The reactivity and the regioselective functionalization of silyl-diene enol ethers under a bifunctional organocatalyst provokes a dramatic change in the regioselectivity, from the 1,5- to the 1,3-functionalization. This variation makes possible the 1,3-addition of silyl-dienol ethers to nitroalkenes, giving access to the synthesis of tri- and tetrasubstituted double bonds in Rauhut Currier type products. The process takes place under smooth conditions, nonanionic conditions, and with a high enantiomeric excess. A rational mechanistic pathway is presented based on DFT and mechanistic experiments. PMID- 28004936 TI - Computational Study of the Degradation of S-Adenosyl Methionine in Water. AB - The degradation of S-adenosyl methionine (SAM) to homoserine-gamma-lactone (HSL) and methyltioadenine (MTA) in water is studied with MD simulations. The AM1 Hamiltonian is used for the quantum part and the flexible AMBER force field for the H2O molecules. The MD simulations predict the free energy barrier for the degradation reaction to be between 109 and 112 kJ mol-1 and an overall gain in free energy of -26 kJ mol-1. The high barrier and the low energy gain of this reaction can be linked to interactions among the carboxylate group of the SAM molecule and solvent H2O molecules, which are not observed on the product side. Hence, the H2O molecules effectively slow down the reaction that otherwise would be much faster. PMID- 28004937 TI - One Substrate, Two Modes of C-H Functionalization: A Metal-Controlled Site Selectivity Switch in C-H Arylation Reactions. AB - A unique site-selectivity switch has been achieved in the ruthenium-catalyzed C-H arylation reaction of N-acetyl-1,2-dihydroisoquinolines. This metal-mediated switch is antipodal to the previous report on the palladium-mediated C-4 C-H arylation on the same substrate. Mechanistic details reveal interesting aspects of the reaction pathway, and kinetic studies bring out the difference in the modes of C-H activation adopted by the two catalytic systems. PMID- 28004938 TI - Using Force Matching To Determine Reactive Force Fields for Water under Extreme Thermodynamic Conditions. AB - We present a method for the creation of classical force fields for water under dissociative thermodynamic conditions by force matching to molecular dynamics trajectories from Kohn-Sham density functional theory (DFT). We apply our method to liquid water under dissociative conditions, where molecular lifetimes are less than 1 ps, and superionic water, where hydrogen ions diffuse at liquid-like rates through an oxygen lattice. We find that, in general, our new models are capable of accurately reproducing the structural and dynamic properties computed from DFT, as well as the molecular concentrations and lifetimes. Overall, our force matching approach presents a relatively simple way to create classical reactive force fields for a single thermodynamic state point that largely retains the accuracy of DFT while having the potential to access experimental time and length scales. PMID- 28004939 TI - Fabrication of Photocatalytic Paper Using TiO2 Nanoparticles Confined in Hollow Silica Capsules. AB - TiO2 nanoparticles (NPs) encapsulated in hollow silica spheres (TiO2@HSSs) show a shielding-effect that can insulate photocatalytically active TiO2 NPs from the surrounding environment and thus prohibit the self-degradation of organic support materials under ultraviolet (UV)-light irradiation. In this study, photocatalytically active papers were fabricated by combining TiO2@HSS and cellulose fibers, and their photocatalytic activities and durability under UV light irradiation were examined. The yolk-shell nanostructured TiO2@HSS, which has an ample void space between inner TiO2 NPs and an outer silica shell, was synthesized using a facile single-step method utilizing an oil-in-water microemulsion as an organic template. The thus-prepared TiO2@HSS particles were deposited onto a cellulose paper either by the chemical adhesion process via ionic bonding or by the physical adhesion process using a dual polymer system. The obtained paper containing TiO2@HSS particles with high air permeability exhibited a higher photocatalytic activity in the photocatalytic decomposition of volatile organic compounds than unsupported powdery TiO2@HSS particles because of the uniform dispersion on the paper with a reticular fiber network. In addition, the paper was hardly damaged under UV-light irradiation, whereas the paper containing naked TiO2 NPs showed a marked deterioration with a considerably decreased strength, owing to the ability of the silica shell to prevent direct contact between TiO2 and organic fibers. This study can offer a promising method to fabricate photocatalytically active papers with a photoresistance property available for real air cleaning. PMID- 28004940 TI - Binderless, Free-Standing Porous Interconnects of Ni-Fe Alloy Decorated Reduced Graphene Oxide for Oxygen Evolution Reaction. AB - We report the synthesis of lightweight, free-standing Ni-Fe@rGO porous interconnects by carbothermal reduction of Ni-FeOx using graphene oxide (GO) as the reducing agent. Here, we take advantage of the oxygen functionalities present in GO to aid in anchoring the metal ions followed by epoxide-assisted Ni-FeOx@GO network formation. When pyrolyzed under inert conditions, Ni-FeOx@GO networks were converted to Ni-Fe@rGO by simple carbothermal metal reduction at 800 degrees C. The Ni-Fe@rGO monoliths were found to be macroporous, electrically conducting, and electrocatalytic toward oxygen evolution reaction (OER). The monoliths exhibited excellent OER activity yielding a current density of 10 mA cm 2 at an overpotential of 350 mV versus RHE, Tafel slope of 38 mV decade-1, and a TOF value of 50 s-1 on par with the established Ni-Fe based electrocatalysts. PMID- 28004941 TI - Cooperative Bronsted Acid-Type Organocatalysis for the Stereoselective Synthesis of Deoxyglycosides. AB - A practical approach for the alpha-stereoselective synthesis of deoxyglycosides using cooperative Bronsted acid-type organocatalysis has been developed. The method is tolerant of a wide range of glycoside donors and acceptors, and its versatility is exemplified in the one-pot synthesis of a trisaccharide. Mechanistic studies suggest that thiourea-induced acid amplification of the chiral acid via H-bonding is key for the enhancement in reaction rate and yield, while stereocontrol is dependent on the chirality of the acid. PMID- 28004942 TI - Flexible Tetrahydropyran Synthesis from Homopropargylic Alcohols Using Sequential Pd-Au Catalysis. AB - A flexible synthetic method toward highly substituted tetrahydropyran is reported. The key transformation involves atom-efficient sequential metal catalysis consisting of Pd-catalyzed addition of homopropargylic alcohols to alkoxyallene and the subsequent gold(I)-catalyzed cycloisomerization. Notably, this method gives access to both 2,6-cis- and 2,6-trans-tetrahydropyrans possessing diverse substitution patterns. PMID- 28004943 TI - Visible-Light-Induced Acetalization of Aldehydes with Alcohols. AB - In this work, we have achieved a simple and general method for acetalization of aldehydes by means of a photochemical reaction under low-energy visible light irradiation. A broad range of aromatic, heteroaromatic, and aliphatic aldehydes have been protected under neutral conditions in good to excellent yields using a catalytic amount of Eosin Y as the photocatalyst. Our visible light mediated acetalization strategies are successful for more challenging acid-sensitive aldehydes and sterically hindered aldehydes. Notably, this protocol is chemoselective to aldehydes, while ketones remain intact. PMID- 28004944 TI - Phomopsterones A and B, Two Functionalized Ergostane-Type Steroids from the Endophytic Fungus Phomopsis sp. TJ507A. AB - Two new functionalized ergostane-type steroids, phomopsterones A (1) and B (2), were isolated from the plant-derived Phomopsis sp. TJ507A. Their structures were determined on the basis of spectroscopic data, a modified Mosher's method, X-ray crystallographic analysis, and quantum chemical calculations. Compound 1 is an unprecedented ergosteroid featuring a rearranged bicyclo[3.3.1]nonane motif resulting from B-ring scission and a subsequent 180 degrees rotation of the ring A during biosynthesis. Compound 2 exhibited anti-inflammatory activity. PMID- 28004945 TI - Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4 Kinase IIIbeta (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology. AB - Phosphatidylinositol 4-kinase IIIbeta (PI4KB) is indispensable for the replication of various positive-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, we report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These "hybrids" not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compounds exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. Our crystallographic analysis unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity. PMID- 28004946 TI - Fluorescent Inhibitors as Tools To Characterize Enzymes: Case Study of the Lipid Kinase Phosphatidylinositol 4-Kinase IIIbeta (PI4KB). AB - The lipid kinase phosphatidylinositol 4-kinase IIIbeta (PI4KB) is an essential host factor for many positive-sense single-stranded RNA (+RNA) viruses including human pathogens hepatitis C virus (HCV), Severe acute respiratory syndrome (SARS), coxsackie viruses, and rhinoviruses. Inhibitors of PI4KB are considered to be potential broad-spectrum virostatics, and it is therefore critical to develop a biochemical understanding of the kinase. Here, we present highly potent and selective fluorescent inhibitors that we show to be useful chemical biology tools especially in determination of dissociation constants. Moreover, we show that the coumarin-labeled inhibitor can be used to image PI4KB in cells using fluorescence-lifetime imaging microscopy (FLIM) microscopy. PMID- 28004949 TI - Effects of endothelin-induced prefrontal cortical lesions on delay discounting in the rat. AB - Stroke is one of the most prominent causes of neurological disability, and the number of stroke cases worldwide is expected to grow due to increases in both average life span and population. As such, new methods for both acute treatment and poststroke rehabilitation will be increasingly necessary. Although a number of approaches to restoring motor function poststroke are in development, there are few methods to alleviate the cognitive deficits caused by this disease. As well, there are very few preclinical models of stroke with a specific focus on higher-order cognitive functions. The goal of the current experiments was to examine the effects of bilateral ischemic lesions, produced by targeted microinjections of endothelin-1 (ET-1) in the medial (mPFC) and orbital (oPFC) prefrontal cortices of adult male Sprague-Dawley rats (n = 39) on inhibitory control as measured through a delay discounting paradigm. The ET-1 injections to the mPFC and oPFC resulted in average lesion volumes of 17.98 mm3 +/- 2.841 mm3 (Mean +/- SE) and 26.05 mm3 +/- 4.052 mm3 (Mean +/- SE), respectively. During delay discounting testing, wherein animals were offered a small, immediately available food reward versus a large, but delayed reward, it was found that animals with lesions to the oPFC were more likely to choose the immediately available reward as compared to their mPFC or control counterparts. We conclude that using ET-1 in the oPFC may be a new and viable method to study the effects of ischemic lesions on higher-order cognitive dysfunction poststroke. (PsycINFO Database Record PMID- 28004948 TI - Smoking-induced affect modulation in nonwithdrawn smokers with posttraumatic stress disorder, depression, and in those with no psychiatric disorder. AB - This research sought to determine whether smoking influences affect by means other than withdrawal reduction. Little previous evidence suggests such an effect. We surmised that such an effect would be especially apparent in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), 2 disorders that are frequently comorbid with smoking and that involve dysregulated affect. Participants were U.S. veterans who were regular smokers (N = 159): 52 with PTSD (58% with comorbid MDD), 51 with MDD, and 56 controls with no psychiatric disorder. During 3 positive and 3 negative mood induction trials (scheduled over 2 sessions), nonwithdrawn participants smoked either a nicotine containing cigarette (NIC+), a nicotine-free cigarette (NIC-), or held a pen. Positive and negative affect were each measured before and after mood induction. Results showed a significant 2-way interaction of Smoking Condition * Time on negative affect during the negative mood induction (F(6, 576) = 2.41, p = .03) in those with PTSD and controls. In these groups, both NIC+ and NIC-, relative to pen, produced lower negative affect ratings after the negative mood induction. There was also a 2-way interaction of Smoking Condition * Time on positive affect response to the positive mood induction among those with PTSD and controls (F(6, 564) = 3.17, p = .005) and among MDD and controls (F(6, 564) = 2.27, p = .036). Among all smokers, NIC+ enhanced the magnitude and duration of positive affect more than did NIC-. Results revealed affect modulation outside the context of withdrawal relief; such effects may motivate smoking among those with psychiatric diagnoses, and among smokers in general. (PsycINFO Database Record PMID- 28004950 TI - Stimulation of 5-HT2A receptors recovers sensory responsiveness in acute spinal neonatal rats. AB - Quipazine is a 5-HT2A-receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents. Sensory stimulation also activates sensory and motor circuits and promotes recovery after spinal cord injury. In rats, tail pinching is an effective and robust method of sacrocaudal sensory afferent stimulation that induces motor activity, including alternating stepping. In this study, responsiveness to a tail pinch following treatment with quipazine (or saline vehicle control) was examined in spinal cord transected (at midthoracic level) and intact neonatal rats. Rat pups were secured in the supine posture with limbs unrestricted. Quipazine or saline was administered intraperitoneally and after a 10-min period, a tail pinch was administered. A 1-min baseline period prior to tail-pinch administration and a 1-min response period postpinch was observed and hind-limb motor activity, including locomotor-like stepping behavior, was recorded and analyzed. Neonatal rats showed an immediate and robust response to sensory stimulation induced by the tail pinch. Quipazine recovered hind-limb movement and step frequency in spinal rats back to intact levels, suggesting a synergistic, additive effect of 5-HT-receptor and sensory stimulation in spinal rats. Although levels of activity in spinal rats were restored with quipazine, movement quality (high vs. low amplitude) was only partially restored. (PsycINFO Database Record PMID- 28004951 TI - Age-related impairment on a forced-choice version of the Mnemonic Similarity Task. AB - Previous studies from our lab have indicated that healthy older adults are impaired in their ability to mnemonically discriminate between previously viewed objects and similar lure objects in the Mnemonic Similarity Task (MST). These studies have used either old/similar/new or old/new test formats. The forced choice test format (e.g., "Did you see object A or object A' during the encoding phase?") relies on different assumptions than the old/new test format (e.g., "Did you see this object during the encoding phase?"); hence, converging evidence from these approaches would bolster the conclusion that healthy aging is accompanied by impaired performance on the MST. Consistent with our hypothesis, healthy older adults exhibited impaired performance on a forced-choice test format that required discriminating between a target and a similar lure. We also tested the hypothesis that age-related impairments on the MST could be modeled within a global matching computational framework. We found that decreasing the probability of successful feature encoding in the models caused changes that were similar to the empirical data in healthy older adults. Collectively, our behavioral results using the forced-choice format extend the finding that healthy aging is accompanied by an impaired ability to discriminate between targets and similar lures, and our modeling results suggest that a diminished probability of encoding stimulus features is a candidate mechanism for memory changes in healthy aging. We also discuss the ability of global matching models to account for findings in other studies that have used variants on mnemonic similarity tasks. (PsycINFO Database Record PMID- 28004952 TI - The ventral dentate gyrus mediates pattern separation for reward value. AB - Rats with ventral dentate gyrus (DG) lesions, sham lesions, and controls were run in a runway for 20 pellets of food. After reaching running speed asymptote, the number of pellets was reduced to 1, 9, or 17 pellets. The purpose of the present experiment was to determine whether the ventral DG subregion of the hippocampus plays a role in pattern separation for reward value. The results indicated that sham lesioned and control rats displayed a graded decrease in runway velocities, supporting a pattern separation process. In contrast, ventral DG lesioned rats continued to maintain runway velocities regardless of the reward-value shifts. The ventral DG lesion results do not appear to be due to hyperactivity but could be based on the idea that the ventral DG is part of a decision-making circuitry to predict goal-relevant reward outcomes. (PsycINFO Database Record PMID- 28004953 TI - Phosphorylation of tyrosine receptor kinase B in the dorsal striatum and dorsal hippocampus is associated with response learning in a water plus maze. AB - The dorsal hippocampus and dorsal striatum have dissociable roles in learning and memory that are related to region-specific changes in proteins necessary for neuronal plasticity and memory formation. There is additional evidence that the hippocampus and striatum can interact during memory formation. Phosphorylation of tyrosine receptor kinase B is important for memory formation in the hippocampus, but whether or not it has a role in striatum-dependent learning, or in interactions between the hippocampus and striatum, has not been examined. In the present study, we tested the hypothesis that response training increases pTrkB in the dorsal striatum, but decreases pTrkB in dorsal hippocampus, due to an interaction between the systems during memory formation. Results show a significant decrease in pTrkB levels in the dorsal hippocampus of rats trained on the response task compared with swim controls. Response training did not increase pTrkB levels in the dorsal striatum. Positive correlations were found between response learning and the total area of cells expressing pTrkB in the dorsal striatum, while no correlations were found in swim controls. Our results partially support our hypothesis and indicate that response learning is associated with a decrease in hippocampal pTrkB, while phosphorylation of TrkB in the dorsal striatum remains constant. This indicates that suppression of hippocampal pTrkB during response learning may be involved in striatum-dependent memory formation. Additionally, our findings suggest that activation of TrkB in a sparse arrangement of cells may be associated with faster acquisition of a response task. (PsycINFO Database Record PMID- 28004954 TI - Successful and unsuccessful response inhibitions differentially affect the effective connectivity between insular, presupplementary-motor, and striatal areas. AB - Successful response inhibition depends upon the delay between the cues that signal a response and its subsequent inhibition. Previous studies report activity in the right presupplementary motor area (rPreSMA), right anterior insula (rAI), and the right striatum (rSTR) when subjects attempt to inhibit responses. Although these regions are anatomically connected, how they interact during successful and unsuccessful inhibitions has not been studied. In this work, we used a temporal prediction task, functional MRI, and dynamic causal modeling to solve this question. We found selective direct activation of both the rPreSMA and the rAI during successful and unsuccessful inhibitions which also were associated with opposite modulatory effects on insular-striatal and presupplementary-motor striatal descending connections. Moreover, inputs to the rPreSMA during successful inhibitions were propagated to the rAI whereas inputs to the rAI during unsuccessful inhibitions were propagated to the rPreSMA. We interpret that the direct perturbation in the rPreSMA and the modulation of the rPreSMA -> rSTR connections would facilitate response inhibition whereas weak insular activity would cause response inhibition to fail despite the existence of strong rAI -> rSTR modulations. We discuss that descending connections could be nonlinearly modulated via activity of either the right inferior frontal gyrus or the left anterior cingulate cortex. From a predictive coding perspective, rAI activity during successful and unsuccessful inhibition would signal interoceptive information when subjects unexpectedly need to change behaviors. (PsycINFO Database Record PMID- 28004955 TI - Medial orbitofrontal cortex modulates associative learning between environmental cues and reward probability. AB - It has recently been recognized that orbitofrontal cortex has 2 subdivisions that are anatomically and functionally distinct. Most rodent research has focused on the lateral subdivision, leaving the medial subdivision (mOFC) relatively unexplored. We recently showed that inhibiting mOFC neurons eliminated the differential impact of reward probability cues on discrimination accuracy in a sustained attention task. In the present study, we tested whether increasing mOFC neuronal activity in rats would accelerate acquisition of reward contingencies. mOFC neuronal activity was increased using the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) method, in which clozapine-N-oxide administration leads to neuronal modulation by acting on synthetic receptors not normally expressed in the rat brain. We predicted that rats with neuronal activation in mOFC would require fewer sessions than controls for acquisition of a task in which visual cues signal the probability of reward for correct discrimination performance. Contrary to this prediction, mOFC neuronal activation impaired task acquisition, suggesting mOFC may play a role in learning relationships between environmental cues and reward probability or for using that information in adaptive decision-making. In addition, disrupted mOFC activity may contribute to psychiatric conditions in which learning associations between environmental cues and reward probability is impaired. (PsycINFO Database Record PMID- 28004947 TI - A hierarchical causal taxonomy of psychopathology across the life span. AB - We propose a taxonomy of psychopathology based on patterns of shared causal influences identified in a review of multivariate behavior genetic studies that distinguish genetic and environmental influences that are either common to multiple dimensions of psychopathology or unique to each dimension. At the phenotypic level, first-order dimensions are defined by correlations among symptoms; correlations among first-order dimensions similarly define higher-order domains (e.g., internalizing or externalizing psychopathology). We hypothesize that the robust phenotypic correlations among first-order dimensions reflect a hierarchy of increasingly specific etiologic influences. Some nonspecific etiologic factors increase risk for all first-order dimensions of psychopathology to varying degrees through a general factor of psychopathology. Other nonspecific etiologic factors increase risk only for all first-order dimensions within a more specific higher-order domain. Furthermore, each first-order dimension has its own unique causal influences. Genetic and environmental influences common to family members tend to be nonspecific, whereas environmental influences unique to each individual are more dimension-specific. We posit that these causal influences on psychopathology are moderated by sex and developmental processes. This causal taxonomy also provides a novel framework for understanding the heterogeneity of each first-order dimension: Different persons exhibiting similar symptoms may be influenced by different combinations of etiologic influences from each of the 3 levels of the etiologic hierarchy. Furthermore, we relate the proposed causal taxonomy to transdimensional psychobiological processes, which also impact the heterogeneity of each psychopathology dimension. This causal taxonomy implies the need for changes in strategies for studying the etiology, psychobiology, prevention, and treatment of psychopathology. (PsycINFO Database Record PMID- 28004956 TI - Overlearned responses hinder S-R binding. AB - Two mechanisms that are important for human action control are the integration of individual action plans (see Hommel, Musseler, Aschersleben, & Prinz, 2001) and the automatization of overlearned actions to familiar stimuli (see Logan, 1988). In the present study, we analyzed the influence of automatization on action plan integration. Integration with pronunciation responses were compared for response incompatible word and nonword stimuli. Stimulus-response binding effects were observed for nonwords. In contrast, words that automatically triggered an overlearned pronunciation response were not integrated with pronunciation of a different word. That is, automatized response retrieval hindered binding effects regarding the retrieving stimulus and a new response. The results are a first indication of the way that binding and learning processes interact, and might also be a first step to understanding the more complex interdependency of the processes responsible for stimulus-response binding in action control and stimulus-response associations in learning research. (PsycINFO Database Record PMID- 28004958 TI - Associative judgment and vector space semantics. AB - I study associative processing in high-level judgment using vector space semantic models. I find that semantic relatedness, as quantified by these models, is able to provide a good measure of the associations involved in judgment, and, in turn, predict responses in a large number of existing and novel judgment tasks. My results shed light on the representations underlying judgment, and highlight the close relationship between these representations and those at play in language and in the assessment of word meaning. In doing so, they show how one of the best known and most studied theories in decision making research can be formalized to make quantitative a priori predictions, and how this theory can be rigorously tested on a wide range of natural language judgment problems. (PsycINFO Database Record PMID- 28004957 TI - Accounting for stimulus-specific variation in precision reveals a discrete capacity limit in visual working memory. AB - If we view a visual scene that contains many objects, then momentarily close our eyes, some details persist while others seem to fade. Discrete models of visual working memory (VWM) assume that only a few items can be actively maintained in memory, beyond which pure guessing will emerge. Alternatively, continuous resource models assume that all items in a visual scene can be stored with some precision. Distinguishing between these competing models is challenging, however, as resource models that allow for stochastically variable precision (across items and trials) can produce error distributions that resemble random guessing behavior. Here, we evaluated the hypothesis that a major source of variability in VWM performance arises from systematic variation in precision across the stimuli themselves; such stimulus-specific variability can be incorporated into both discrete-capacity and variable-precision resource models. Participants viewed multiple oriented gratings, and then reported the orientation of a cued grating from memory. When modeling the overall distribution of VWM errors, we found that the variable-precision resource model outperformed the discrete model. However, VWM errors revealed a pronounced "oblique effect," with larger errors for oblique than cardinal orientations. After this source of variability was incorporated into both models, we found that the discrete model provided a better account of VWM errors. Our results demonstrate that variable precision across the stimulus space can lead to an unwarranted advantage for resource models that assume stochastically variable precision. When these deterministic sources are adequately modeled, human working memory performance reveals evidence of a discrete capacity limit. (PsycINFO Database Record PMID- 28004959 TI - Modeling visual problem solving as analogical reasoning. AB - We present a computational model of visual problem solving, designed to solve problems from the Raven's Progressive Matrices intelligence test. The model builds on the claim that analogical reasoning lies at the heart of visual problem solving, and intelligence more broadly. Images are compared via structure mapping, aligning the common relational structure in 2 images to identify commonalities and differences. These commonalities or differences can themselves be reified and used as the input for future comparisons. When images fail to align, the model dynamically rerepresents them to facilitate the comparison. In our analysis, we find that the model matches adult human performance on the Standard Progressive Matrices test, and that problems which are difficult for the model are also difficult for people. Furthermore, we show that model operations involving abstraction and rerepresentation are particularly difficult for people, suggesting that these operations may be critical for performing visual problem solving, and reasoning more generally, at the highest level. (PsycINFO Database Record PMID- 28004961 TI - Rethinking the transmission gap: What behavioral genetics and evolutionary psychology mean for attachment theory: A comment on Verhage et al. (2016). AB - Traditional attachment theory posits that attachment in infancy and early childhood is the result of intergenerational transmission of attachment from parents to offspring. Verhage et al. (2016) present meta-analytic evidence addressing the intergenerational transmission of attachment between caregivers and young children. In this commentary, we argue that their appraisal of the behavioral genetics literature is incomplete. The suggested research focus on shared environmental effects may dissuade the pursuit of profitable avenues of research and may hinder progress in attachment theory. Specifically, further research on the "transmission gap" will continue to limit our understanding of attachment etiology. We discuss recent theoretical developments from an evolutionary psychological perspective that can provide a valuable framework to account for the existing behavioral genetic data. (PsycINFO Database Record PMID- 28004962 TI - Failing the duck test: Reply to Barbaro, Boutwell, Barnes, and Shackelford (2017). AB - In this reply, we respond to the critique by Barbaro, Boutwell, Barnes, and Shackelford (2017) in regard to our recent meta-analysis of intergenerational transmission of attachment (Verhage et al., 2016). Barbaro et al. (2017) claim that the influence of shared environment on attachment decreases with age, whereas unique environmental and genetic influences increase, which they felt was disregarded in our meta-analysis. Their criticisms, we argue, are based on a misunderstanding of the core tenets of attachment theory. Barbaro et al. (2017) unify parent-offspring attachment, attachment representations, and romantic-pair attachment under the same conceptual and empirical umbrella, even though these constructs serve different behavioral systems. We show that excluding the incompatible twin data on pair bonding from their analysis undercuts their argument. Statements about the role of the shared environment in attachment beyond early childhood are highly uncertain at this point. Importantly, even if the role of the shared environment were to wane with age, its effects may still be causally important in later childhood or adult outcomes, as either an indirect factor or as a factor influencing earlier developmental outcomes. (PsycINFO Database Record PMID- 28004960 TI - Self-evaluation of decision-making: A general Bayesian framework for metacognitive computation. AB - People are often aware of their mistakes, and report levels of confidence in their choices that correlate with objective performance. These metacognitive assessments of decision quality are important for the guidance of behavior, particularly when external feedback is absent or sporadic. However, a computational framework that accounts for both confidence and error detection is lacking. In addition, accounts of dissociations between performance and metacognition have often relied on ad hoc assumptions, precluding a unified account of intact and impaired self-evaluation. Here we present a general Bayesian framework in which self-evaluation is cast as a "second-order" inference on a coupled but distinct decision system, computationally equivalent to inferring the performance of another actor. Second-order computation may ensue whenever there is a separation between internal states supporting decisions and confidence estimates over space and/or time. We contrast second-order computation against simpler first-order models in which the same internal state supports both decisions and confidence estimates. Through simulations we show that second-order computation provides a unified account of different types of self-evaluation often considered in separate literatures, such as confidence and error detection, and generates novel predictions about the contribution of one's own actions to metacognitive judgments. In addition, the model provides insight into why subjects' metacognition may sometimes be better or worse than task performance. We suggest that second-order computation may underpin self-evaluative judgments across a range of domains. (PsycINFO Database Record PMID- 28004963 TI - Anisakiasis and intestinal endometriosis: under-recognized conditions in the differential diagnosis of acute abdomen. AB - Anisakiasis and endometriosis is rare cause of intestinal obstruction and even perforation, the latter being extremely rare. We report the case of a patient with intestinal obstruction that progress to perforation and whose differential diagnosis is complex. The interest in this clinical case lies in the unexpected histology of the surgical specimen after the intervention of the patient, because the intestinal endometriosis as intestinal anisakiasis are rare entities that make diagnosis difficult. PMID- 28004964 TI - Patient safety under deep sedation for digestive endoscopic procedures. AB - Deep sedation with Propofol has become popular in recent years. The safety of this technique when administered by non-anaesthesiologists has created much controversy which at times is masked in a contentious debate on the economic sustainability of the health system. In 2011, the Spanish Society of Anaesthesiology, Resuscitation and Pain Therapy, along with 20 other organisations from European countries, revoked the recommendations of the European Society of Gastrointestinal Endoscopy on the administration of Propofol by non-anaesthesiologists, citing that it is "extremely dangerous for the safety and quality of endoscopic procedures". The FDA in 2005 had already rejected the use of Propofol by non-anaesthesiologists in the United States, a prohibition which was reiterated in 2010 and is still in force, basing its evidence, among others, on the recommendations and guidelines of the Joint Commission and the Declaration of Helsinki. In Spain, the data sheet of Propofol restricts the use of the drug to anaesthesiologists and intensivists in intensive care units. In our opinion, the key elements to discuss (which we develop in our paper) are those related to: a) the morbidity and mortality of sedation (which is the same as speaking about the factors that influence its safety); b) the appropriate professionals to use this technique; and c) economic aspects related to the use of said technique. Our conclusion is that a technique cannot be declared safe when a high percentage of patients present with varying respiratory depression (and therefore hypoxaemia) and hypotension. We are confident that the collaboration of the Spanish Society of Digestive Pathology and the Spanish Society of Digestive Endoscopy with the Spanish Society of Anaesthesiology, Resuscitation and Pain Therapy is the first step towards finding a satisfactory solution for everyone, and especially for our patients. PMID- 28004965 TI - Restoration of density of interstitial cells of Cajal in the jejunum of diabetic rats after quercetin supplementation. AB - BACKGROUND: Interstitial cells of Cajal (ICC) are required for normal motility in the gastrointestinal tract. Depletion of ICC has been associated with diabetic gastroenteropathy. PURPOSE: To determine the effect of quercertin supplementation on anoctamin-1 (Ano1) immunoreactive ICC in the myenteric region (ICC-MY) and deep muscular plexus (ICC-DMP) in the jejunum of diabetic rats. METHODS: Thirty two 90-day-old male Wistar rats were distributed into the following groups: normoglycemic (C), normoglycemic supplemented with quercetin (CQ; 40 mg daily), diabetic (D), and diabetic supplemented with quercetin (DQ; 40 mg daily). Diabetes was induced by streptozotocin injection. After 120 days, preparations of the jejunal muscular and submucosal layers were immunostained for Ano1 to visualize ICC. Evaluation of the immunofluorescence intensity as well as density of ICC was performed. RESULTS: The density of ICC-MY was 46% lower in group D compared to group C (p < 0.01); ICC-DMP were reduced by 37% (p > 0.05). After quercertin treatment, the densities of ICC-MY were significantly higher in the DQ group compared to group D (ICC-MY: 58%, p < 0.05). Supplementation with quercetin in normoglycemic animals (CQ) compared with group C did not significantly change the ICC density (p > 0.05). CONCLUSIONS: In STZ-treated diabetic rats, diabetes promoted a reduction in the density of jejunal ICC-MY with no significant effect on ICC-DMP. Supplementation with quercetin (DQ) appeared to protect ICC-MY from depletion in diabetes possibly due to its antioxidant action. PMID- 28004966 TI - A survey-based analysis on endoscopic quality indicators compliance among Spanish endoscopists. AB - INTRODUCTION: Endoscopy plays a key role for the diagnosis and management of gastrointestinal disorders. Therefore, quality indicators have been widely proposed in order to optimize endoscopic practice. The aims of this study, promoted by the Spanish Society of Digestive Diseases (SEPD), were to assess the knowledge and compliance to endoscopy quality indicators among Spanish gastroenterologists. METHODS: A 31-questionnaire survey was created based on the endoscopy quality indicators proposed by international guidelines. The survey was distributed among Spanish gastroenterologists who are members of the society. Using only fully completed surveys, a descriptive analysis was performed. Those factors related with a suboptimal quality performance were also investigated. RESULTS: A total of 1,543 surveys were sent and 281 (18.2%) were received completed. Based on the answers obtained, the management of 14 (70%) out of 20 assessed quality indicators was poor: 5 (83.3%) out of 6 pre-procedure items, 7 (58.3%) out of 12 intra-procedure items and 2 (100%) out of 2 post-procedure items. CONCLUSIONS: A significant proportion of Spanish endoscopists do not comply with main endoscopic quality indicators. Factors such as "young" age, public setting, no colorectal cancer screening program and low volume of procedures/week are related to a poorer management of the assessed quality indicators and should be the target for future formative activities. PMID- 28004967 TI - The Value of the T2-Weighted Multipoint Dixon Sequence in MRI of Sacroiliac Joints for the Diagnosis of Active and Chronic Sacroiliitis. AB - OBJECTIVE: The objective of this study was to determine the value of the T2 weighted multipoint Dixon technique as a single sequence in MRI of the sacroiliac joints for the diagnosis of active and chronic sacroiliitis. SUBJECTS AND METHODS: The T2-weighted multipoint Dixon sequence with water-only, in-phase, opposed-phase, and fat-only images was added to a routine MRI protocol, which included T1-weighted, fat-saturated T2-weighted, and contrast-enhanced fat saturated T1-weighted sequences, for imaging 73 patients. Images obtained as part of the routine protocol were reviewed first by two radiologists. Then, the T2 weighted multipoint Dixon images were reviewed separately. Signs of active inflammation detected on fat-saturated T2-weighted and contrast-enhanced fat saturated T1-weighted images were compared with the water-only images. Signs of chronic sacroiliitis detected on T1-weighted images were compared with the fat only, in-phase, and opposed-phase images. Contrast-to-noise ratios (CNRs) of all lesions were statistically analyzed. ANOVA and posthoc Tukey tests were used to compare CNR data. RESULTS: The mean CNR of 34 lesions with bone marrow edema or osteitis was greater on the water-only images (CNR, 176) than on the fat saturated T2-weighted images (CNR, 82) and the contrast-enhanced fat-saturated T1 weighted images (CNR, 56), and this difference in mean CNRs was statistically significant (p < 0.01). There were also statistically significant differences in CNRs between sequences (p < 0.01). The highest mean CNR for subchondral sclerosis in 23 lesions was noted on in-phase images, and the highest mean CNR for periarticular fat deposition in 29 lesions was noted on opposed-phase images. Qualitative analyses also revealed that T2-weighted multipoint Dixon images were superior in showing signs of both active and chronic sacroiliitis. CONCLUSION: The T2-weighted multipoint Dixon sequence is superior to conventional MRI sequences in depicting diagnostic signs of active and chronic sacroiliitis and therefore may be used as a single sequence. PMID- 28004968 TI - Epinephrine-Enhanced Knee Arthrography Revisited. PMID- 28004969 TI - Management of the Incidental Pulmonary Embolism. AB - OBJECTIVE: The incidental pulmonary embolism (PE) is being identified at an increasing rate because of use of MDCT and presents a management challenge because of a lack of prospective data. Most clinicians treat patients with proximal or segmental incidental PE in the same manner as patients with suspected PE. CONCLUSION: The treatment of subsegmental PE may be guided by an assessment of patient symptoms, risk factors for recurrent venous thrombosis, and concomitant deep venous thrombosis. PMID- 28004971 TI - ACP 30th Annual Congress, November 3-6, 2016. PMID- 28004970 TI - Intraabdominal Lymphatic Malformations: Pearls and Pitfalls of Diagnosis and Differential Diagnoses in Pediatric Patients. AB - OBJECTIVE: The purpose of this article is to review the practical imaging workup and characteristic imaging appearances of intraabdominal lymphatic malformations (LMs) in the pediatric population with a brief discussion of some common differential diagnoses found in a vascular anomaly clinic. CONCLUSION: LMs are uncommon pediatric lesions. Because of their rarity among LMs overall, a tendency to present later in life than superficial LMs, and often incidental identification, intraabdominal LMs pose a particular diagnostic challenge, and pathologic entities that are more prevalent must be carefully excluded first. Although the diagnosis of most intraabdominal LMs can be reliably based on clear understanding of characteristic imaging findings, histologic correlation may be necessary in some cases. PMID- 28004973 TI - Beta-2-glycoprotein-1 and alpha-1-antitrypsin as urinary markers of renal cancer in von Hippel-Lindau patients. AB - CONTEXT: Von Hippel-Lindau disease (VHLD) is a rare inherited neoplastic syndrome. Among all the VHLD-associated tumors, clear cell renal cell carcinoma (ccRCC) is the major cause of death. OBJECTIVE: The aim of this paper is the discovery of new non-invasive biomarker for the monitoring of VHLD patients. MATERIALS AND METHODS: We compared the urinary proteome of VHLD patients, ccRCC patients and healthy volunteers. RESULTS: Among all differentially expressed proteins, alpha-1-antitrypsin (A1AT) and APOH (beta-2-glycoprotein-1) are strongly over-abundant only in the urine of VHLD patients with a history of ccRCC. DISCUSSION AND CONCLUSION: A1AT and APOH could be promising non-invasive biomarkers. PMID- 28004974 TI - Vitamin D3 protects against prednisolone-induced liver injury associated with the impairment of the hepatic NF-kappaB/iNOS/NO pathway. AB - The study was carried out to define whether prednisolone-induced damage to hepatic cells is accompanied by excessive nitric oxide (NO) levels associated with nuclear factor kappa B (NF-kappaB)/inducible NO synthase (iNOS) activation and evaluate the efficacy of the treatment with vitamin D3. Histopathological examination, activities of liver transaminases (alanine aminotransferase and aspartate aminotransferase), and cell death assays consistently showed that prednisolone (5 mg/kg body weight, 30 days) induces chronic liver injury in female Wistar rats. Specifically, increased hepatocellular necrosis and caspase-3 dependent apoptosis were observed. Prednisolone enhanced iNOS protein expression, NO generation, and tyrosine nitration in liver cells. Despite unchanged hepatic level of the NF-kappaB/p65 protein, prednisolone increased inhibitory kappaB alpha (IkappaB-alpha) degradation, nuclear translocation, and phosphorylation of NF-kappaB/p65 at Ser311, indicating that NF-kappaB activation can be involved in the induction of iNOS/NO. All changes were associated with a 2.9-fold decrease in the serum content of 25-hydroxyvitamin D3 and significant reduction of hepatic vitamin D3 receptor (VDR) expression that points reliably to vitamin D3 deficiency and failures in VDR signaling. Vitamin D3 co-administration (100 IU/rat, 30 days) prevented glucocorticoid-evoked abnormalities in hepatic tissue. In conclusion, prednisolone-induced liver disturbances were associated with the impairment of NF-kappaB/iNOS/NO responses that can be ameliorated by vitamin D3 treatment through VDR-mediated mechanisms. PMID- 28004975 TI - Electronic Kiosks for Patient Satisfaction Survey in Radiology. AB - OBJECTIVE: The purpose of this article is to analyze patient satisfaction surveys obtained via electronic kiosks in a tertiary-care academic radiology department to detect potential areas of improvement and to identify ways to improve survey response and completion rates. MATERIALS AND METHODS: All patient satisfaction surveys submitted via electronic kiosks and via online surveys between January 2015 and January 2016 were included in this retrospective study. The surveys consisted of questions regarding the patients' overall experience, cleanliness of the department, and interactions with the receptionist, technologist, nurse, and physician. Ratings were assessed using a 5-point scale (where 1 denotes poor and 5 denotes optimal) with an option for free-text comments. The likelihood of recommendation was regarded as an indicator of satisfaction and was our primary evaluation metric. Surveys with less than optimal ratings were analyzed in detail. RESULTS: Of 99,289 patients who visited the department, 6736 (6.8%) initiated surveys, and 4938 (73.3%) of those completed them; 4257 of 4865 (87.5%) patients reported optimal satisfaction. More patients responded via electronic kiosk compared with the online survey (4564/4938 [92.4%] vs 374/4938 [7.6%]; p < 0.001). The frequency of completion rate was lower for kiosks in changing and waiting areas compared with that for kiosks next to elevators (1509/2365 [63.8%] vs 3059/3927 [77.8%]; p < 0.0001). Cleanliness of the department (329/1656 [19.9%]) and courtesy of the receptionist (299/1656 [18.1%]) were the most frequent reasons for the lowest ratings. Wait time (61/278 [21.9%]) and communication (37/278 [13.3%]) were associated with the most frequent free-text complaints. CONCLUSION: Survey kiosks led to a higher response rate than online surveys. The completion rate can be further improved by placing kiosks next to elevators. Cleanliness, wait time, patient-staff communication, and especially courtesy of the receptionist were found to be important factors for patient satisfaction. PMID- 28004976 TI - Perfusion Parameters on Breast Dynamic Contrast-Enhanced MRI Are Associated With Disease-Specific Survival in Patients With Triple-Negative Breast Cancer. AB - OBJECTIVE: The aim of this study was to investigate the association between perfusion parameters on MRI performed before treatment and survival outcome (disease-free survival [DFS], disease-specific survival [DSS]) in patients with triple-negative breast cancer (TNBC). MATERIALS AND METHODS: Sixty-one patients (median age, 50 years; age range, 27-77 years) with TNBC (tumor size on MRI: median, 25.5 mm; range, 11.0-142.0 mm) were included. We analyzed clinical and pathologic variables and MRI parameters. Cox proportional hazards models were used to determine associations with survival outcome. RESULTS: The median follow up time was 46.1 months (range, 13.9-58.4 months). Eleven of 61 (18.0%) patients had events (i.e., local, regional, or distant recurrence or contralateral breast cancer) and seven (11.5%) died of breast cancer. Among the pretreatment variables, a larger tumor size on MR images (hazard ratio [HR] = 1.024, p = 0.003) was associated with worse DFS at univariate analysis. In multivariate pretreatment models for DSS, a higher fractional volume of extravascular extracellular space per unit volume of tissue (ve) value (HR = 1.658, p = 0.038), higher peak enhancement (HR = 1.843, p = 0.018), and a larger tumor size on MR images (HR = 1.060, p = 0.001) were associated with worse DSS. In multivariate posttreatment models, a larger pathologic tumor size (HR for DFS, 1.074 [p = 0.005]; HR for DSS, 1.050 [p = 0.042]) and metastasis in surgically resected axillary lymph nodes (HR for DFS, 5.789 [p = 0.017]; HR for DSS, 23.717 [p = 0.005]) were associated with worse survival outcome. CONCLUSION: A higher ve value, higher peak enhancement, and larger tumor size of the primary tumor on pretreatment MRI were independent predictors of worse DSS in patients with TNBC. PMID- 28004977 TI - Establishment of Transgenic Porcine Fibroblasts Expressing a Human klotho Gene and Its Effects on Gene Expression and Preimplantation Development of Cloned Embryos. AB - Even though the functions of the klotho gene in aging of small animals such as mice have been well investigated, studies using large animal models such as pigs, which have many similarities to humans, have been limited due to the absence of cell lines or animal models. Therefore, the objective of this study was to generate porcine cell lines overexpressing human klotho (hKlotho) and tetracycline (Tet)-inducible hKlotho and to produce cloned embryos from these cell lines. We designed vectors for hKlotho overexpression (CA-Klotho) under control of CMV enhancer/chicken beta-actin (CAG) promoter and Tet-inducible hKlotho overexpression (Tet-Klotho, under control of doxycycline-dependent promoter). The vectors were transfected into porcine fibroblasts then CA-Klotho and Tet-Klotho cell lines were established. The Tet-Klotho (+) cell line was cultured in the presence of doxycycline (2 MUg/mL), whereas the Tet-Klotho (-) cell line was cultured without doxycycline. In polymerase chain reaction (PCR) and reverse transcription-PCR (RT-PCR) assays, integration and expression of the hKlotho gene were confirmed in CA-Klotho, Tet-Klotho (+), and Tet-Klotho (-) cell lines. The CA-Klotho cell line was subjected to real-time PCR and showed positively changed expression of genes related to aging and cell survival. Somatic cell nuclear transfer was performed to generate hKlotho overexpression cloned embryos by using CA-Klotho and Tet-Klotho (+) cell lines; blastocyst formation frequency was significantly higher in cloned embryos from CA-Klotho and Tet-Klotho (+) (21.5% and 20.2%, respectively) compared with the control (8.4%). In conclusion, we established hKlotho overexpression and Tet-inducible hKlotho overexpression cell lines and porcine embryos cloned from these cell lines. PMID- 28004978 TI - Potential Radiation-Related Effects on Radiologists. AB - OBJECTIVE: The risk of injury associated with long-term occupational exposure to ionizing radiation is low for radiologists. The purpose of this article is to systematically review and inform radiologists about radiation-related effects to which they are potentially susceptible. CONCLUSION: Formal education and training on radiation safety and management, careful attention to good radiation protection habits, and continued emphasis on radiation management and the as low as reasonably achievable principle are recommended for all radiologists. PMID- 28004979 TI - Epigenetic Silencing of the Human 18 kDa Translocator Protein in a T Cell Leukemia Cell Line. AB - The mitochondrial membrane 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is constitutively expressed in most organs, most abundantly in hormonal tissue and cells of mononuclear phagocyte lineage, while in the brain, TSPO expression is induced in the wake of injury, inflammation, and neurodegeneration. Increased TSPO expression is also prominent in several cancerous tissues where it appears to correlate with the degree of malignancy. Currently, TSPO is thus actively investigated as a generic biomarker for disease activity and a therapeutic target for a wide range of diseases. In this study, we report a Jurkat human T cell leukemia cell line that has only trace expression of TSPO mRNA. Through the use of bisulphite genomic sequencing, we show that the Jurkat TSPO promoter is highly methylated except for CpG sites that are adjacent to the transcription start site. Control measurements in HEK 293, HeLa, and U87-MG cells with high TSPO mRNA expression showed low levels of TSPO promoter methylation. Demethylation with 5-aza-2'-deoxycytidine (5-aza-dC) caused a dose-dependent increase in TSPO mRNA with a corresponding demethylation of the TSPO promoter in Jurkat cells. Treating HeLa and U87-MG cells with 5-aza dC caused no change in the level of TSPO mRNA. These observations confirm the epigenetic regulation of TSPO and suggest it to be a more common mechanism by which the differential expression of TSPO in various cell types and in health and disease may be explained. PMID- 28004980 TI - Tele-rehabilitation service delivery journey from prototype to robust in-home use. AB - PURPOSE: The purpose of this study is to present a retrospective study on clients with Acquired Brain Injury (ABI) enrolled in a tele-motion-rehabilitation service program for two or more months. METHODS: Data from 82 clients (46 males; 74 with ABI), aged 22-85 years, are reported. The Kinect-based CogniMotion System (ReAbility Online, Gertner Institute, Tel Hashomer, Israel) provided services that included 30-min biweekly sessions. Participants were evaluated prior to and 2 months following the commencement of service with clinical assessments that measured movements and function of the weaker upper extremity and cognitive abilities. RESULTS: Clients enrolled in the service had intact or mild cognitive impairment, mild-moderate motor impairment but little use of their weak upper extremity for daily activities. They were satisfied with the service and reported high levels of system usability. Post-intervention clinical assessments were performed on about half of the participants after 2 months; significant improvements in active movements of the weak upper extremity, shoulder flexion range of motion and in the Trail Making Test were found (p < 0.05). CONCLUSIONS: The service appears to be feasible for people with ABI and effective in important clinical outcomes related to improvements in upper extremity function. Implications for Rehabilitation Tele-rehabilitation provided with Microsoft Kinect 3D sensor virtual reality tracking system is feasible for people with Acquired Brain Injury. People with Acquired Brain Injury in the chronic stage were satisfied with the tele-rehabilitation service and perceived it as beneficial to improve their motor and cognitive abilities The CogniMotion System service appears to be effective in important clinical outcomes related to improvements in upper extremity function. PMID- 28004981 TI - Comment on "Maximum-Intensity-Projection and Computer-Aided-Detection Algorithms as Stand-Alone Reader Devices in Lung Cancer Screening Using Different Dose Levels and Reconstruction Kernels". PMID- 28004982 TI - Intrusive thoughts in patients with obsessive compulsive disorder and non clinical participants: a comparison using the International Intrusive Thought Interview Schedule. AB - The International Intrusive Thought Interview Schedule (IITIS) was used to assess and compare the unwanted intrusive thoughts (UITs) reported in a group of patients with obsessive compulsive disorder (OCD) and a non-clinical group. Although all participants reported at least one type of intrusion, OCD patients experienced more intrusive thoughts than non-clinical participants, and this difference was statistically significant. In the OCD group, intrusive thoughts were more frequent, interfered more with daily life, were considered to be more important to get out of the mind, and were more difficult to stop than in non clinical participants. The two groups did not differ significantly in terms of five appraisals of the most distressing intrusive thought. One appraisal (importance) was used far more by the OCD group than the non-clinical group. For three appraisals (intolerance of anxiety, need to control, and intolerance of uncertainty), the difference was smaller. Only two of the strategies for controlling the most upsetting intrusive thought (ritual and avoidance) were of value in differentiating between the two groups. The IITIS (an instrument used to assess intrusions in non-clinical samples) appears to be of value for the assessment of patients with OCD. PMID- 28004983 TI - Methicillin-Resistant Staphylococcus aureus Pneumonia in Critically Ill Trauma and Burn Patients: A Retrospective Cohort Study. AB - BACKGROUND: The timing and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in trauma patients are not well characterized. This information is critical for the selection of appropriate empiric antibiotics. The objective of this study was to determine the incidence of MRSA pneumonia in early onset and late-onset pneumonia and to identify risk factors for MRSA in the trauma-burn intensive care unit (ICU). PATIENTS AND METHODS: We conducted a retrospective cohort study from January 2012 to March 2015 of patients in the trauma and burn ICU with clinical and microbiologic evidence of pneumonia. Demographics, injury type and severity, co-morbidities, antimicrobial agents, and MRSA nasal colonization at ICU admission were extracted from the medical record. A multi-variable exact logistic regression was performed to assess predictors of MRSA pneumonia. RESULTS: Eighty patients with 88 episodes of pneumonia were included in the cohort. Ten patients had MRSA pneumonia, an overall incidence of 11.4% of pneumonia episodes with a median onset of seven days. The proportion of MRSA pneumonia episodes was not significantly different in early-onset (<5 days) or late-onset pneumonia, and there were no statistically significant risk factors for developing MRSA pneumonia. The majority of patients with MRSA had at least one known risk factor including homelessness, substance abuse, and receipt of broad-spectrum antibiotic agents. CONCLUSIONS: The 11.4% overall incidence of MRSA pneumonia in this trauma-burn cohort was similar to what has been reported in other trauma populations, although MRSA was equally likely to be identified in early- and late-onset pneumonia. Our results suggest that risk factors other than duration of hospitalization may be important considerations in the decision to initiate MRSA-active empiric therapy for pneumonia in the trauma-burn ICU. PMID- 28004984 TI - Cognitive behavioral therapy in practice: therapist perceptions of techniques, outcome measures, practitioner qualifications, and relation to research. AB - Cognitive behavioral therapy (CBT) has a strong evidence base for several psychiatric disorders, however, it may be argued that currently there is no overall agreement on what counts as 'CBT'. One reason is that CBT is commonly perceived as encompassing a broad range of treatments, from purely cognitive to purely behavioral, making it difficult to arrive at a clear definition. The purpose of the present study was to explore practicing therapists' perceptions of CBT. Three hundred fifty members of two multi-disciplinary interest groups for CBT in Sweden participated. Mean age was 46 years, 68% were females, 63% psychologists and mean number of years of professional experience was 12 years. Participants completed a web-based survey including items covering various aspects of CBT practice. Overall, therapist perceptions of the extent to which different treatment techniques and procedures were consistent with CBT were in line with current evidence-based CBT protocols and practice guidelines, as were therapists' application of the techniques and procedures in their own practice. A majority of participants (78%) agreed that quality of life or level of functioning were the most important outcome measures for evaluating treatment success. Eighty percent of therapists believed that training in CBT at a basic level was a requirement for practicing CBT. There was a medium size Spearman correlation of rs=.46 between the perceived importance of research to practice and the extent to which participants kept themselves updated on research. Implications for training, quality assurance, and the effectiveness of CBT in clinical practice are discussed. PMID- 28004985 TI - Cyclophosphamide enhances anti-tumor effects of a fibroblast activation protein alpha-based DNA vaccine in tumor-bearing mice with murine breast carcinoma. AB - Cyclophosphamide (CY) is a DNA alkylating agent, which is widely used with other chemotherapy drugs in the treatment of various types of cancer. It can be used not only as a chemotherapeutic but also as an immunomodulatory agent to inhibit IL-10 expression and T regulatory cells (Tregs). Fibroblast activation protein alpha (FAPalpha) is expressed in cancer-associated fibroblasts in the tumor microenvironment. Immunotherapy based on FAPalpha, as a tumor stromal antigen, typically induces specific immune response targeting the tumor microenvironment. This study evaluated the efficacy of a previously unreported CY combination strategy to enhance the limited anti-tumor effect of a DNA vaccine targeting FAPalpha. The results suggested CY administration could promote the percentage of splenic CD8+ T cells and decrease the proportion of CD4 + CD25 + Foxp3+ Tregs in spleen. In tumor tissues, levels of immunosuppressive cytokines including IL-10 and CXCL-12 were also reduced. Meanwhile, the CY combination did not impair the FAPalpha-specific immunity induced by the DNA vaccine and further reduced tumor stromal factors. Most importantly, FAP-vaccinated mice also treated with CY chemotherapy showed a marked suppression of tumor growth (inhibition ratio =80%) and a prolongation of survival time. Thus, the combination of FAPalpha immunotherapy and chemotherapy with CY offers new insights into improving cancer therapies. PMID- 28004986 TI - Smoking and Risk of Surgical Site Infection after Spinal Surgery: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The effect of smoking on the risk of surgical site infection (SSI) after spinal surgery remains controversial. Therefore, we conducted a meta analysis to determine whether there is an association between smoking and the risk of SSI and to calculate the relative risk of infections attributable to smoking. METHODS: We performed a literature search of cohort and case-control studies in the MEDLINE, Embase, and ISI Web of Science databases. Sensitivity and subgroup analyses were performed to test the robustness of overall estimates of risk and to investigate potential sources of heterogeneity. We further calculated the population-attributable fraction (PAF) to evaluate the proportion of SSIs associated with smoking. RESULTS: In total, 26 independent observational studies involving 67,405 patients who underwent spinal surgery were analyzed. Smokers had a significantly higher risk of SSI than did nonsmokers (odds ratio [OR] 1.26; 95% confidence interval [CI] 1.05-1.51). Subgroup analysis according to the study design revealed an apparent association between smoking and SSI in the cohort subgroup (OR 1.40; 95% CI 1.17-1.66), but not in the case-control subgroup (OR 0.99; 95% CI 0.64-1.53). After evaluation of the PAF, the proportion of SSIs associated with smoking increased to 10.37%. CONCLUSIONS: This meta-analysis demonstrated that smoking increases the risk of SSI after spinal surgery. False negative associations in other studies may have resulted from defects in the study design. However, because of the heterogeneity among the studies in the present meta-analysis, the results should be interpreted with caution. PMID- 28004987 TI - Determining the level and cost of sickness presenteeism among hospital staff in Turkey. AB - OBJECTIVE: This study aimed to determine the associations between sickness presenteeism and socio-demographic factors, perceived health status and health complaints among hospital staff and to calculate the cost burdens and productivity losses attributed to presenteeism. METHODS: A cross-sectional study was conducted using 951 hospital staff, including physicians, nurses, midwives, other health personnel and administrative staff working in two hospitals located in Kirikkale province in Turkey. The health and work performance questionnaire developed by Kessler et al. was revised to measure sickness presenteeism. RESULTS: After performing Student's t test and a one-way analysis of variance, presenteeism was mostly observed in women, nurse-midwives, young employees, university health staff and health workers with low health status. Average productivity loss and cost of lost productivity per staff member were calculated as 19.92 h/TRY 315.57 for 2 weeks and 478.08 h/TRY 7573.68 for 1 year. CONCLUSIONS: The problem of sickness presenteeism is mostly observed in women and nurses. It causes both financial burdens and productivity losses for hospitals. These survey results are thus expected to provide critically important information on presenteeism for decision-makers and healthcare managers. PMID- 28004988 TI - Biosynthetic Grafts To Replace Infected Prosthetic Vascular Bypasses: A Single Center Experience. AB - BACKGROUND: There are only a few options to replace infected infrainguinal synthetic vascular grafts in the absence of suitable autologous veins. To use a biosynthetic vascular graft (Omniflow(r)II) might be a valuable alternative. METHODS: We retrospectively analyzed the clinical course of 29 patients who underwent replacement of an infected infrainguinal vascular prosthesis (Szilagyi 3) by an Omniflow(r)II graft. RESULTS: Because of the lack of suitable autologous veins, 15 above-knee femoro-popliteal, 5 below-knee femoro-popliteal, and 9 femoro-tibial bypasses were replaced with biosynthetic grafts. There were no in hospital deaths, reinfections, or major amputations. The survival rate was 92% at one year and 87% at two years. During follow-up (median 24 months; range 5-66 months), no reinfections occurred. However, nine patients presented with bypass occlusions (primary patency 67.6% at one year and 61.5% at two years; secondary patency 85.3% at one year and 69% at two years). The limb salvage rate was 89% at one year and 83% at two years. CONCLUSION: Biosynthetic bypass grafts might be valuable to replace infected prosthetic grafts in the absence of a suitable vein. They have excellent re-infection resistance. Limb salvage, morbidity, and the mortality rate are similar to those obtained with autologous vein grafts in infected fields. PMID- 28004989 TI - How Long Is Long Enough to Identify a Surgical Site Infection? AB - BACKGROUND: The U.S. Centers for Disease Control requires 90 days after surgery using an implant to diagnose or show the absence of a surgical site infection (SSI). However, many databases only track outcomes up to 30 days. The cost and effort to increase follow-up to 90 days after surgery is high and the benefit is unclear. We hypothesize that the majority of SSIs after ventral hernia repair occur within 30 days of surgery. PATIENTS AND METHODS: All patients who underwent ventral hernia repair (with or without mesh) from 2010-2015 at a single institution were evaluated for evidence of SSI. The duration between surgery and the diagnosis of a post-operative SSI was assessed. Baseline and operative characteristics were compared between patients with an early SSI (within 30 days of surgery) and those with a late SSI (more than 30 days after surgery). RESULTS: Among 1,635 patients who underwent ventral hernia repair, 117 (7.2%) developed an SSI. The median (range) of days between surgery and SSI was 15 days (range, 2 763). There were 20 (17.1%) late SSIs diagnosed; of these, 17 were diagnosed between 31-90 d and three were diagnosed later than 90 days. Patients with a late SSI were more likely to have had a prior ventral hernia repair and have had biologic mesh (p = 0.001). CONCLUSIONS: Whereas the majority of SSIs after ventral hernia repair occurred within the first 30 days, a substantial number of late SSIs occurred. It is worthwhile to follow patients for at least 90 days post operative in order to capture a more accurate picture of the true rate of SSI. PMID- 28004990 TI - Platelet glycoprotein gene Ia C807T, HPA-3, and Ibalpha VNTR polymorphisms are associated with increased ischemic stroke risk: Evidence from a comprehensive meta-analysis. AB - Background/aims Platelet glycoproteins play a crucial role in the initial stage of thrombus formation and may contribute to the pathophysiology of atherosclerosis. Polymorphisms in glycoprotein genes alter the function of the protein, possibly leading to increased risk of ischemic stroke. However, previous genetic association studies that examined the relationship between glycoprotein genes polymorphisms and ischemic stroke have yielded inconsistent results. This study aimed to evaluate the association between glycoprotein genes and ischemic stroke by the application of meta-analysis. Methods Relevant studies were identified by an extensive search through databases. The quality of included studies was assessed independently using the Newcastle-Ottawa Scale. Allele and genotype frequencies for each included study were extracted. The odds ratio (OR) with 95% confidence interval (95%CI) was calculated using a random-effects or fixed-effects model. Q statistic was used to evaluate homogeneity, and a meta regression model was used to explore the study-level variables and to describe the heterogeneity in included studies. Egger's test and funnel plot were used to assess publication bias. Results A total of 60 studies (9 polymorphisms) were included and identified in the current meta-analysis. The Newcastle-Ottawa Scale scores ranged from 7 to 9 except for two studies with Newcastle-Ottawa Scale scores of 6. The T allele or TT genotype of the glycoprotein Ia C807T polymorphism were associated with an increased susceptibility to ischemic stroke in combined population (807T allele: OR, 95%CI: 1.24, 1.03-1.50, p = 0.02) or Asian populations (807T allele: OR, 95%CI: 1.31, 1.10-1.54, p = 0.002 and 807TT genotype: OR, 95%CI: 1.53, 1.13-2.08, p = 0.006, respectively), and the Ser allele of HPA-3 was associated with increased risk of ischemic stroke in combined population or in Asians (OR, 95%CI: 1.21, 1.04-1.40, p = 0.01 or 1.54, 1.18-2.01, p = 0.001). Of note, the Ser/Ser genotype was more common in Asians (OR, 95%CI: 2.09, 1.40-3.13, p < 0.001). For glycoprotein Ibalpha variable number tandem repeat, only B allele showed a mild significant association with ischemic stroke risk in combined population or in Caucasians (OR, 95%CI: 2.17, 1.04-4.55, p = 0.04 or 1.79, 1.02-3.13, p = 0.04). There was no significant association between HPA-1, HPA-2, HPA-4, HPA-5, glycoprotein Ibalpha-5 T/C as well as Ia G873A polymorphisms and increased risk of ischemic stroke. Conclusions We found that glycoprotein Ia C807T T allele or the TT genotype, the Ser-allele of HPA-3 and B allele of glycoprotein Ibalpha variable number tandem repeat polymorphisms were associated with increased risk for ischemic stroke. Future studies with larger sample sizes will be necessary to confirm the results. In addition, analyses of ischemic stroke subtypes and gene-gene and gene-environment interactions are warranted. PMID- 28004992 TI - Organization of stroke care in Turkey. AB - Stroke is one of the major health problems in Turkey. Since cerebrovascular disease is the second leading cause of death, institutional organizations are important to decrease the burden of stroke in our country. Although the number of comprehensive stroke centers has been increasing constantly and many significant improvements have been realized in last years, there are still some regions without a comprehensive stroke center in Turkey. PMID- 28004991 TI - Bilateral versus ipsilesional cortico-subcortical activity patterns in stroke show hemispheric dependence. AB - Background Understanding of interhemispheric interactions in stroke patients during motor control is an important clinical neuroscience quest that may provide important clues for neurorehabilitation. In stroke patients, bilateral overactivation in both hemispheres has been interpreted as a poor prognostic indicator of functional recovery. In contrast, ipsilesional patterns have been linked with better motor outcomes. Aim We investigated the pathophysiology of hemispheric interactions during limb movement without and with contralateral restraint, to mimic the effects of constraint-induced movement therapy. We used neuroimaging to probe brain activity with such a movement-dependent interhemispheric modulation paradigm. Methods We used an fMRI block design during which the plegic/paretic upper limb was recruited/mobilized to perform unilateral arm elevation, as a function of presence versus absence of contralateral limb restriction ( n = 20, with balanced left/right lesion sites). Results Analysis of 10 right-hemispheric stroke participants yielded bilateral sensorimotor cortex activation in all movement phases in contrast with the unilateral dominance seen in the 10 left-hemispheric stroke participants. Superimposition of contralateral restriction led to a prominent shift from activation to deactivation response patterns, in particular in cortical and basal ganglia motor areas in right hemispheric stroke. Left-hemispheric stroke was in general characterized by reduced activation patterns, even in the absence of restriction, which induced additional cortical silencing. Conclusion The observed hemispheric-dependent activation/deactivation shifts are novel and these pathophysiological observations suggest short-term neuroplasticity that may be useful for hemisphere tailored neurorehabilitation. PMID- 28004994 TI - HJM Barnett 1922-2016. PMID- 28004995 TI - 2017, it begins! PMID- 28004996 TI - Splenic Subcapsular Hematoma After Endoscopic Retrograde Cholangiopancreatography in a Liver Transplant Recipient: Case Report and Literature Review. AB - Splenic injuries after an endoscopic retrograde cholangiopancreatography are a rare but lethal complication. We describe a subcapsular splenic hematoma requiring emergent splenectomy after an endoscopic retrograde cholangiopancreatography in a liver transplant recipient. PMID- 28004997 TI - Effect of Long-Term, Low-Dose Aspirin Therapy on Renal Graft Function. AB - OBJECTIVES: Despite improvements in immunosuppressive protocols for renal transplant, long-term success of renal transplant is still limited by the occurrence of interstitial fibrosis and tubular atrophy. Some studies have shown that aspirin decreases the severity of kidney ischemia-reperfusion injury and the development of tubular atrophy in animal models. This study aimed to assess the effects of aspirin therapy started at the time of transplant on long-term graft function. MATERIALS AND METHODS: We compared renal graft function of 82 patients on low-dose aspirin 75 mg once daily who underwent renal transplant between 1 January 2000 and 31 December 2010 from a single center with 65 patients not taking aspirin. For each patient, the following measurements were collected: age, sex, creatinine level, type of donor, cold ischemia time, occurrence of acute allograft rejections, number of HLA mismatches, first transplant, intake of statins, number of antihypertensive medications, and number of days posttransplant. Patients were excluded from the study who were on aspirin before transplant or who had coronary artery disease. RESULTS: Multilevel modelling was used to compare renal allograft function, as measured by serum creatinine levels, between patients taking and not taking aspirin after kidney transplant. Aspirin was not significantly associated with creatinine levels (P = .59) after adjusting for other relevant variables. CONCLUSIONS: Low-dose aspirin started at the time of transplant has a negligible effect on renal allograft function over the 15 year study period posttransplant. PMID- 28004998 TI - De Novo Vascular Lesions After Liver Transplant in a Case With Hereditary Hemorrhagic Telangiectasia and Fibropolycystic Liver Disease: Long-Term Follow-Up With Magnetic Resonance Imaging and Magnetic Resonance Angiography. AB - We report a case of a 62-year-old woman who received a liver transplant 19 years previously for end-stage liver disease due to hereditary hemorrhagic telangiectasia and fibropolycystic liver disease. During long-term follow-up 8 years after the liver transplant, de novo vascular lesions were detected with magnetic resonance imaging and magnetic resonance angiography. Hepatic vascular lesions had slowly progressed, despite no symptoms. To our knowledge, there are few reports in the English literature of de novo vascular lesions after liver transplant in patients with hepatic telangiectasias. PMID- 28004999 TI - A Follow-Up Study on the Renal Protective Efficacy of Telbivudine for Hepatitis B Virus-Infected Taiwanese Patients After Living Donor Liver Transplant. AB - OBJECTIVES: Preservation of renal function is an important issue after living donor liver transplant. We aimed to examine the renal protective efficacy of telbivudine in hepatitis B virus-infected patients after living donor liver transplant. MATERIALS AND METHODS: In this retrospective study, we compared 18 patients who received telbivudine 600 mg once per day and 23 patients who received entecavir 1 mg once per day after living donor liver transplant. Clinical data were obtained through chart review and included Model for End-Stage Liver Disease score and pre- and postoperative aspartate aminotransferase, alanine aminotransferase, and creatinine levels and estimated glomerular filtration rate. RESULTS: Posttransplant estimated glomerular filtration rates and creatinine levels were calculated, and improvement of renal function was found in the group of patients who received telbivudine. Significant improvements were shown in estimated glomerular filtration rates started after 9 months of administration and creatinine levels after 12 months compared with patients who received entecavir. CONCLUSIONS: In our study, long-term telbivudine therapy is associated with a sustained improvement of renal function in patients with hepatitis B virus infection after living donor liver transplant. PMID- 28005000 TI - Nonsurgically Treated Sigmoid Volvulus in a Young Patient 3 Days After Renal Transplant. AB - Sigmoid volvulus is a rare clinical condition in young individuals. It should be accurately diagnosed and treated in a rapid manner. Surgical and nonsurgical conservative methods are used for the treatment of sigmoid volvulus. Patients having no signs of perforation or peritonitis should be primarily treated by colonoscopic detorsion. A delay in the diagnosis and treatment of this condition may cause significant morbidity and mortality in an immunosuppressed patient with newly performed renal transplant and diffuse abdominal pain. This paper reports a young patient who was diagnosed with sigmoid volvulus during admission with sudden-onset abdominal pain and distension after having undergone renal transplant from a living donor 3 days previously. The patient avoided the burden of a second surgical intervention by a bedside endoscopic detorsion procedure. PMID- 28005001 TI - Recurrent Urinary Tract Infection Among Renal Transplant Recipients: Risk Factors and Long-Term Outcome. AB - OBJECTIVES: Urinary tract infection is the most common type of bacterial infection in kidney transplant procedures, with adverse effects on graft and patient survival. We aimed to evaluate the risk factors of recurrent urinary tract infection in renal transplant recipients and its impact on patient and graft survival. MATERIALS AND METHODS: In a cohort of 1019 patients who were transplanted between 2000 and 2010 at Hamed Al-Essa Organ Transplant Center in Kuwait, 86% developed at least 1 episode of urinary tract infection, with only 6.2% of patients having recurrent infections. We compared patients with recurrent urinary tract infections (group 1) with those who had no recurrence (group 2) regarding their risk factors. RESULTS: Patients in group 1 were significantly younger than those in group 2 (34.9 +/- 23 vs 42.8 +/- 16 y; P < .001), with female preponderance (P < .001). The percentage of patients with thymoglobulin induction (21.5%) was significantly higher in group 1. Patients with pretransplant urologic problems experienced significantly more recurrent urinary tract infections (P < .001). Hepatitis C infections were significantly more prevalent among group 1 (10.8% vs 3.8%; P = .008). Long-term graft outcome (functioning and failed) were 78.5% and 21.5% in group 1 versus 85.1% and 13.9% in group 2 (P = .18). Patient outcomes (living and deceased donors) were 98.4% and 1.6% in group 1 versus 95.7% and 4.3% in group 2 (P = .187). CONCLUSIONS: Adult females, thymoglobulin induction, pretransplant urologic problems, and hepatitis C infection were the risk factors of recurrent urinary tract infection among our renal transplant patients. However, recurrence did not adversely affect graft or patient survival. PMID- 28005002 TI - Zika Virus Vector Competency of Mosquitoes, Gulf Coast, United States. AB - Zika virus has recently spread throughout the Americas. Although Aedes aegypti mosquitoes are considered the primary vector, Culex quinquefasciatus and mosquitoes of other species may also be vectors. We tested Cx. quinquefasciatus and Ae. taeniorhynchus mosquitoes from the US Gulf Coast; both were refractory to infection and incapable of transmission. PMID- 28005003 TI - PLEASANT: Preventing and Lessening Exacerbations of Asthma in School-age children Associated with a New Term - a cluster randomised controlled trial and economic evaluation. AB - BACKGROUND: Asthma episodes and deaths are known to be seasonal. A number of reports have shown peaks in asthma episodes in school-aged children associated with the return to school following the summer vacation. A fall in prescription collection in the month of August has been observed, and was associated with an increase in the number of unscheduled contacts after the return to school in September. OBJECTIVE: The primary objective of the study was to assess whether or not a NHS-delivered public health intervention reduces the September peak in unscheduled medical contacts. DESIGN: Cluster randomised trial, with the unit of randomisation being 142 NHS general practices, and trial-based economic evaluation. SETTING: Primary care. INTERVENTION: A letter sent (n = 70 practices) in July from their general practitioner (GP) to parents/carers of school-aged children with asthma to remind them of the importance of taking their medication, and to ensure that they have sufficient medication prior to the start of the new school year in September. The control group received usual care. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of children aged 5-16 years who had an unscheduled medical contact in September 2013. Supporting end points included the proportion of children who collected prescriptions in August 2013 and unscheduled contacts through the following 12 months. Economic end points were quality-adjusted life-years (QALYs) gained and costs from an NHS and Personal Social Services perspective. RESULTS: There is no evidence of effect in terms of unscheduled contacts in September. Among children aged 5-16 years, the odds ratio (OR) was 1.09 [95% confidence interval (CI) 0.96 to 1.25] against the intervention. The intervention did increase the proportion of children collecting a prescription in August (OR 1.43, 95% CI 1.24 to 1.64) as well as scheduled contacts in the same month (OR 1.13, 95% CI 0.84 to 1.52). For the wider time intervals (September-December 2013 and September-August 2014), there is weak evidence of the intervention reducing unscheduled contacts. The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children collecting prescriptions in August as well as having scheduled contacts in the same month. These unscheduled contacts in September could be a result of the intervention, as GPs may have wanted to see patients before issuing a prescription. The economic analysis estimated a high probability that the intervention was cost-saving, for baseline-adjusted costs, across both base-case and sensitivity analyses. There was no increase in QALYs. LIMITATION: The use of routine data led to uncertainty in the coding of medical contacts. The uncertainty was mitigated by advice from a GP adjudication panel. CONCLUSIONS: The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children both collecting prescriptions and having scheduled contacts in August. After September there is weak evidence in favour of the intervention. The intervention had a favourable impact on costs but did not demonstrate any impact on QALYs. The results of the trial indicate that further work is required on assessing and understanding adherence, both in terms of using routine data to make quantitative assessments, and through additional qualitative interviews with key stakeholders such as practice nurses, GPs and a wider group of children with asthma. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03000938. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 93. See the HTA programme website for further project information. PMID- 28005004 TI - Functional evolution of a morphogenetic gradient. AB - Bone Morphogenetic Proteins (BMPs) pattern the dorsal-ventral axis of bilaterian embryos; however, their roles in the evolution of body plan are largely unknown. We examined their functional evolution in fly embryos. BMP signaling specifies two extraembryonic tissues, the serosa and amnion, in basal-branching flies such as Megaselia abdita, but only one, the amnioserosa, in Drosophila melanogaster. The BMP signaling dynamics are similar in both species until the beginning of gastrulation, when BMP signaling broadens and intensifies at the edge of the germ rudiment in Megaselia, while remaining static in Drosophila. Here we show that the differences in gradient dynamics and tissue specification result from evolutionary changes in the gene regulatory network that controls the activity of a positive feedback circuit on BMP signaling, involving the tumor necrosis factor alpha homolog eiger. These data illustrate an evolutionary mechanism by which spatiotemporal changes in morphogen gradients can guide tissue complexity. PMID- 28005006 TI - Dormancy-specific imprinting underlies maternal inheritance of seed dormancy in Arabidopsis thaliana. AB - Mature seed dormancy is a vital plant trait that prevents germination out of season. In Arabidopsis, the trait can be maternally regulated but the underlying mechanisms sustaining this regulation, its general occurrence and its biological significance among accessions are poorly understood. Upon seed imbibition, the endosperm is essential to repress the germination of dormant seeds. Investigation of genomic imprinting in the mature seed endosperm led us to identify a novel set of imprinted genes that are expressed upon seed imbibition. Remarkably, programs of imprinted gene expression are adapted according to the dormancy status of the seed. We provide direct evidence that imprinted genes play a role in regulating germination processes and that preferential maternal allelic expression can implement maternal inheritance of seed dormancy levels. PMID- 28005005 TI - Immediate perception of a reward is distinct from the reward's long-term salience. AB - Reward perception guides all aspects of animal behavior. However, the relationship between the perceived value of a reward, the latent value of a reward, and the behavioral response remains unclear. Here we report that, given a choice between two sweet and chemically similar sugars-L- and D-arabinose Drosophila melanogaster prefers D- over L- arabinose, but forms long-term memories of L-arabinose more reliably. Behavioral assays indicate that L arabinose-generated memories require sugar receptor Gr43a, and calcium imaging and electrophysiological recordings indicate that L- and D-arabinose differentially activate Gr43a-expressing neurons. We posit that the immediate valence of a reward is not always predictive of the long-term reinforcement value of that reward, and that a subset of sugar-sensing neurons may generate distinct representations of similar sugars, allowing for rapid assessment of the salient features of various sugar rewards and generation of reward-specific behaviors. However, how sensory neurons communicate information about L-arabinose quality and concentration-features relevant for long-term memory-remains unknown. PMID- 28005007 TI - Response repetition biases in human perceptual decisions are explained by activity decay in competitive attractor models. AB - Animals and humans have a tendency to repeat recent choices, a phenomenon known as choice hysteresis. The mechanism for this choice bias remains unclear. Using an established, biophysically informed model of a competitive attractor network for decision making, we found that decaying tail activity from the previous trial caused choice hysteresis, especially during difficult trials, and accurately predicted human perceptual choices. In the model, choice variability could be directionally altered through amplification or dampening of post-trial activity decay through simulated depolarizing or hyperpolarizing network stimulation. An analogous intervention using transcranial direct current stimulation (tDCS) over left dorsolateral prefrontal cortex (dlPFC) yielded a close match between model predictions and experimental results: net soma depolarizing currents increased choice hysteresis, while hyperpolarizing currents suppressed it. Residual activity in competitive attractor networks within dlPFC may thus give rise to biases in perceptual choices, which can be directionally controlled through non invasive brain stimulation. PMID- 28005009 TI - Computer-Aided Classification of Gastrointestinal Lesions in Regular Colonoscopy. AB - We have developed a technique to study how good computers can be at diagnosing gastrointestinal lesions from regular (white light and narrow banded) colonoscopic videos compared to two levels of clinical knowledge (expert and beginner). Our technique includes a novel tissue classification approach which may save clinician's time by avoiding chromoendoscopy, a time-consuming staining procedure using indigo carmine. Our technique also discriminates the severity of individual lesions in patients with many polyps, so that the gastroenterologist can directly focus on those requiring polypectomy. Technically, we have designed and developed a framework combining machine learning and computer vision algorithms, which performs a virtual biopsy of hyperplastic lesions, serrated adenomas and adenomas. Serrated adenomas are very difficult to classify due to their mixed/hybrid nature and recent studies indicate that they can lead to colorectal cancer through the alternate serrated pathway. Our approach is the first step to avoid systematic biopsy for suspected hyperplastic tissues. We also propose a database of colonoscopic videos showing gastrointestinal lesions with ground truth collected from both expert image inspection and histology. We not only compare our system with the expert predictions, but we also study if the use of 3D shape features improves classification accuracy, and compare our technique's performance with three competitor methods. PMID- 28005008 TI - Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII. AB - Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII. PMID- 28005011 TI - Correction for Liang et al., A Novel Function for Hog1 Stress-Activated Protein Kinase in Controlling White-Opaque Switching and Mating in Candida albicans. PMID- 28005010 TI - Simultaneous Quantitative Imaging of Electrical Properties and Proton Density From B1 Maps Using MRI. AB - Electrical conductivity and permittivity of biological tissues are important diagnostic parameters and are useful for calculating subject-specific specific absorption rate distribution. On the other hand, water proton density also has clinical relevance for diagnosis purposes. These two kinds of tissue properties are inevitably associated in the technique of electrical properties tomography (EPT), which can be used to map in vivo electrical properties based on the measured B1 field distribution at Larmor frequency using magnetic resonance imaging (MRI). The signal magnitude in MR images is locally proportional to both the proton density of tissue and the receive B1 field; this is a source of artifact in receive B1-based EPT reconstruction because these two quantities cannot easily be disentangled. In this study, a new method was proposed for simultaneously extracting quantitative conductivity, permittivity and proton density from the measured magnitude of transmit B1 field, proton density-weighted receive B1 field, and transceiver phase, in a multi-channel radiofrequency (RF) coil using MRI, without specific assumptions to derive the proton density distribution. We evaluated the spatial resolution, sensitivity to contrast, and accuracy of the method using numerical simulations of B1 field in a phantom and in a realistic human head model. Using the proposed method, conductivity, permittivity and proton density were then experimentally obtained ex vivo in a pork tissue sample on a 7T MRI scanner equipped with a 16-channel microstrip transceiver RF coil. PMID- 28005012 TI - On the correct use of stepped-sine excitations for the measurement of time varying bioimpedance. AB - OBJECTIVE: When a linear time-varying (LTV) bioimpedance is measured using stepped-sine excitations, a compromise must be made: the temporal distortions affecting the data depend on the experimental time, which in turn sets the data accuracy and limits the temporal bandwidth of the system that needs to be measured. APPROACH: Here, the experimental time required to measure linear time invariant bioimpedance with a specified accuracy is analyzed for different stepped-sine excitation setups. RESULTS: We provide simple equations that allow the reader to know whether LTV bioimpedance can be measured through repeated time invariant stepped-sine experiments. SIGNIFICANCE: Bioimpedance technology is on the rise thanks to a plethora of healthcare monitoring applications. The results presented can help to avoid distortions in the data while measuring accurately non-stationary physiological phenomena. The impact of the work presented is broad, including the potential of enhancing bioimpedance studies and healthcare devices using bioimpedance technology. PMID- 28005013 TI - Antithrombin III deficiency concomitant with atrial fibrillation causes thrombi in all chambers: 2D and 3D echocardiographic evaluation. PMID- 28005015 TI - Simple and inexpensive way for the treatment of guidewire-induced distal coronary perforation: subcutaneous fat tissue embolization. PMID- 28005014 TI - Pectoral muscle hematoma: A rare complication of transradial cardiac catheterization. PMID- 28005016 TI - A challenging case of occlusion of the right femoral and right common iliac arteries: diagnostic intervention does not always innocent. PMID- 28005017 TI - Effect of mean serum potassium level on in-hospital and long-term outcomes in ST segment elevation myocardial infarction. PMID- 28005018 TI - Author's Reply. PMID- 28005019 TI - LA thrombus formation in mitral valve disease. PMID- 28005020 TI - Author's Reply. PMID- 28005021 TI - A citation map. PMID- 28005022 TI - Complex interplay of DNA damage, DNA repair genes, and oxidative stress in coronary artery disease. PMID- 28005023 TI - YKL-40 and its complex association with metabolic syndrome, obesity, and cardiovascular disease. PMID- 28005025 TI - [Acquired immunodeficiency syndrome in Russia]. AB - In 2015, the infection caused by human immunodeficiency virus (HIV) (HIV infection) dominated among life-threatening infections in Russians: it was first diagnosed in 98,177 Russians and 15,530 citizens of the Russian Federation died from HIV/AIDS, amounting to 45% of all deaths from infectious diseases in Russia. By the mid-2016, there were a total of 1,062,476 identified HIV-positive Russians, of whom 225,992 people died. The estimated number of HIV-infected patients in Russia approximated to 1% of the population, the highest prevalence of HIV being found in the age group of 30-40 years. The most active and expensive measures against HIV/AIDS in Russia are to examine the population for anti-HIV antibodies (29 million screenings per year) and to use in HIV-positive people antiretroviral therapy that was free of charge to more than 200,000 patients, i.e. nearly 25% of the registered Russians living with the HIV-infected. However, treatment coverage and quality are far from the target indicators that the international experts consider needed to reduce HIV prevalence and mortality. A wider program on HIV/AIDS, which includes a number of preventive measures with proven efficiency, as well as a program of promising researches and developments should be introduced in Russia. PMID- 28005024 TI - A global perspective on mechanical prosthetic heart valve thrombosis: Diagnostic and therapeutic challenges. AB - Prosthetic valve thrombosis is one of the major causes of primary valve failure, which can be life-threatening. Multimodality imaging is necessary for determination of leaflet immobilization, cause of underlying pathology (thrombus versus pannus or both), and whether thrombolytic therapy attempt in the patient would be successful or surgery is needed. Current guidelines for the management of prosthetic valve thrombosis lack definitive class I recommendations due to lack of randomized controlled trials, and usually leave the choice of treatment to the clinician's experience. In this review, we aimed to summarize the pathogenesis, diagnosis, and management of mechanical prosthetic valve thrombosis. PMID- 28005026 TI - [The sociodemographic portrait of a patient living with HIV and visiting AIDS centers in Russia]. AB - AIM: To study the sociodemographic data of people living with HIV who visit AIDS centers. SUBJECTS AND METHODS: A multicenter open-label study was conducted, which included the retrospective model "A patient's portrait". Outpatient records and questionnaires were analyzed in 7,000 patients older than 18 years of age who had visited AIDS centers in 27 regions of Russia from 1 April to 31 July 2014 and signed their informed consent form to participate in the study. RESULTS: There were women accounting for 49% of the study participants, including one transgender. Their mean age was 35.6 years; the median age was 34 (18-79) years. 77.4% of the women were infected sexually; 57.4% of the men were infected parenterally; the men who had sex with men accounted for 2.5% of the whole group (4.7% among the men). Only 9.8% of the respondents reported that they had used intravenous drugs in the past 6 months. 87.8% of the respondents had secondary and higher education; 68.6% of the patients (73% were male and 64% were female) were employed; 59.3% of the respondents were married or cohabited; 66.2% of the patients reported that they had had sexual contacts with one partner, 14.2% had not had sexual intercourses. 38.3% of the women and 48.8% of the men had a permanent HIV-negative sexual partner. 46% of the study participants had dependent minor children. 30% of the women had given birth to at least one child after the diagnosis of HIV infection. CONCLUSION: People living with HIV in Russia and visiting AIDS centers do not differ in main social and demographic indicators from the Russian Federation citizens of the same age who do not have HIV. They represent an economically and socially active population and participate in demographic processes so one of the public health priorities is to maintain and improve their quality of life. PMID- 28005027 TI - [Evaluation of the pro- and antioxidant status of women with HIV or coinfection]. AB - AIM: To reveal the specific features of changes in the parameters of lipid peroxidation - antioxidant defense and the status of the reproductive system in women of fertile age with monoinfection (HIV) or coinfection (HIV and hepatitis B and/or C). SUBJECTS AND METHODS: 81 reproductive-aged women were examined and divided into 3 groups: 1) 28 apparently healthy women (controls); 2) 26 patients with HIV monoinfection; and 3) 27 patients with HIV coinfection (HIV + hepatitis B and/or C) who had not previously received antiretroviral therapy. RESULTS: The HIV coinfection group showed the higher values of primary (conjugated dienes) and secondary (ketodienes and conjugated trienes) lipid peroxidation products in the presence of lower superoxide dismutase activity and obvious alpha-tocopherol deficiency than the control and HIV monoinfection groups. HIV coinfection in reproductive-aged women was accompanied by the high frequency of luteal phase deficiency. CONCLUSION: HIV coinfection is characterized by a more pronounced oxidative stress, antioxidant factor deficiency, and the high frequency of luteal phase deficiency in the patients. PMID- 28005028 TI - [Causes of T lymphocyte activation in HIV-infected patients coinfected with hepatitis C virus]. AB - AIM: To establish the causes of T lymphocyte activation in human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis C (HCV) who are adherent to their antiretroviral therapy regimen and interferon untreated. SUBJECTS AND METHODS: Examinations were made in 62 people who were HIV+HCV-positive (n=21), HIV+HCV-negative (n=21), and noninfected volunteers (n=20). The activation (CD38+HLA-DR+) and proliferation (Ki-67+) of CD4+ and CD8+ T lymphocytes were estimated. The blood concentration of intestinal fatty acid-binding protein (I FABP) was determined. RESULTS: The proportion of activated cells among the CD4+ T lymphocytes was equal in the HIV+HCV-positive and HIV+HCV-negative groups. But these indicators were statistically significantly higher than those in the controls (HIV- HCV-). CD8+ T cell activation was greater in the HIV/HCV coinfected patients than that in the other groups and that was higher in the HIV monoinfected than in the noninfected. The blood I-FABP concentrations were elevated in the HIV+HCV-positive and HIV+HCV groups compared with those in the HIV-HCV-negative group, but these did not differ among themselves. In the HIV+HCV negative patients, CD4+ and CD8+ T cell activation directly and statistically significantly correlated with blood I-FABP levels. In the HIV+HCV-positive group, this correlation remained only for CD4+ T lymphocytes. CD8+ T cell activation in HIV/HCV-coinfected patients was unrelated to I-FABP concentrations. CONCLUSION: The increased activation of CD4+ and CD8+ T lymphocytes in HIV monoinfection was found to be associated with intestinal epithelial destruction and unrelated to cell division processes. In HIV/HCV coinfection, the activated state of CD4+ T cells is determined by both the level of proliferative processes and impairment of the intestinal barrier and that of CD8+ T cells is only by proliferation. PMID- 28005029 TI - [Insulin resistance and chronic hepatitis C]. AB - AIM: To estimate the spread of insulin resistance (IR) in patients with chronic hepatitis C (CHC) and to define the role of IR in the development of hepatic steatosis (HS) and in the progression of liver fibrosis (LF), as well as the impact of IR on the results of antiviral therapy (AVT). SUBJECTS AND METHODS: A total of 211 patients with CHC were examined. A comparison group consisted of 75 patients with chronic hepatitis B (CHB). The patients were divided according to the presence and absence of IR and type 2 diabetes mellitus (DM). IR was analyzed in patients with CHC with a body mass index (BMI) of <25 kg/m2 and with the initial manifestations of LF. RESULTS: In the patients with CHC, IR without DM was 1.7-fold more common and type 2 DM was 2.6 times more frequently seen than in those with CHB. The highest biochemical activity, subclinical inflammation (as evaluated from ferritin and C-reactive protein levels), and an advanced LF stage were noted in the presence of IR and type DM. IR and type 2 DM were associated with metabolic syndrome and its individual components and with no response to AVT. When the BMI was <25 kg/m2, HS, inadequate 25(OH)D provision, an advanced LF stage, and slowly progressive inflammation were related to IR. In the presence of the initial manifestations of fibrosis, IR was associated with obesity, HS, 25(OH)D deficiency, a rise in C-reactive protein greater than 3 mg/l, and no response to AVT. CONCLUSION: The presence of IR in CHC patients with a BMI of <25 kg/m2 and with the initial manifestations of LF and the association of IR with HS and an advanced LF stage necessitate an examination of all patients with CHC in an effort to identify IR and to perform active therapy of detected abnormalities. PMID- 28005030 TI - [Assessment of awareness about the epidemiology, outcomes, and therapy of chronic hepatitis B and C in adolescents and adults]. AB - AIM: To estimate the level of knowledge in adults and adolescents about the issues related to viral hepatitis B and C: the transmission modes, course, and outcomes of acute and chronic hepatitis B (CHB) and C (CHC), as well as about current measures for their prevention and treatment. SUBJECTS AND METHODS: A total of 850 dwellers of Kirov and the Kirov Region were anomalously surveyed using an original questionnaire in 2013- 2015. The questionnaire included 24 questions on the etiology, epidemiology, outcomes, prevention, and treatment of CHB and CHC and on the sources of information. Persons younger than 16 years, people who had medical specialties, and those who were studying at a higher or secondary medical institution were excluded from the study. RESULTS: Low levels of knowledge about the epidemiology, course, and outcomes of CHB and CHC were found in the adolescents and adults. 76.4% and 73.9% of the respondents had no clear idea as to the modes and factors of transmission of hepatitis B and C, respectively. A lack of knowledge of the issues associated with poor CHB and CHC outcomes (cirrhosis and hepatocellular carcinoma) was revealed in 84.8 and 76.2%, respectively. 81.8% of the respondents were well aware of the existence and necessity of vaccination against hepatitis B. 40.8% of the survey participants misbelieved that hepatitis C vaccine had been designed and used. CONCLUSION: A significant portion of the adult population is poorly aware of the problem of viral hepatitis B and C and needs to continue health education for the development and strengthening of a negative attitude towards narcotics and promiscuity; to combat false ideas about viral hepatitis; and enhance motivation for the specific and nonspecific prevention of hepatitis B and C. PMID- 28005031 TI - [Follow-up of patients with Ixodes tick-borne borrelioses caused by Borrelia miyamotoi or Borrelia burgdorferi sensu lato]. AB - : Ixodes tick-borne borrelioses (ITBB) are caused by two different spirochetes: Borrelia from the group of Borrelia burgdorferi sensu lato, the agents of the classic Lyme borreliosis (LB), and Borrelia miyamotoi that belongs to the group of Borrelia causing tick-borne relapsing fevers. ITBB caused by B. miyamotoi (BM ITBB) is a previously unknown infectious disease discovered in Russia. It is known that the LB sequelae may reduce the long-term life guality of convalescents. AIM: To study the follow-up of those who have recovered from new BM-ITBB infection in comparison with persons who have had LB. SUBJECTS AND METHODS: The investigation enrolled 41 patients with BM-ITBB and 41 patients with LB who were treated at the Republican Infectious Diseases Hospital of Udmurtia. Within a year after the disease, they were followed up through clinical and instrumental examination of cardiac performance, expanded biochemical analysis of blood and urine, which could; estimate kidney and liver functions, and psychological questioning. RESULTS: Asthenic syndrome and complaints about and objective signs of cardiac dysfunctions persisted supraventricular extrasystoles, left ventricular diastolic dysfunction, and elevated and/or unstable systolic blood pressure were detected in 20-30% of the convalescents for a long time. Kidney dysfunctions were manifested in albuminuria and the decrease of glomerular filtration rate. A year following the disease, 10-20% patients had persistently elevated concentrations of alanine aminotransferase, aspartate aminotransferase, and C-reactive protein and had higher levels of total cholesterol and low-density lipoproteins. The pathological consequences of ITBB were polymorphic and varied in different patients; in general, only 68% of them showed health improvement. CONCLUSION: We assume that a significant role in the pathogenesis of BM-ITBB and LB is played by vascular endothelial damage possibly associated with the inflammatory and autoimmune aspects of an immune response in Borrelia infection. The consequences of this damage may persist and even intensify during a year, which provokes chronic dysfunction of the heart, kidney, or liver in a number of convalescents. PMID- 28005032 TI - [Tick-borne neuroinfections: Clinical characteristics, immunopathogenesis, and new pharmacotherapeutic strategies]. AB - AIM: To study the semiotics of neurological lesions in patients with tick-borne encephalitis, Ixodes tick-borne borreliosis (ITBB) and mixed infection (MI), their immunopathogenesis, and the possibilities of current pathogenetic pharmacological correction. SUBJECTS AND METHODS: A total of 220 patients with tick-borne encephalitis, ITBB, and MI concurrent with the syndromes of central nervous system lesions were examined. The immunological studies encompassed the examination of mononuclear cells in the cerebrospinal fluid (CSF), the population and subpopulation composition of lymphocytes, and nitroxidergic processes in the serum and CSF from the total level of final stable nitric oxide metabolites. For pharmacotherapeutic correction, the metabolic drug cytoflavin was used as newly indicated. RESULTS: Cytofluorometric analysis of the CSF cellular composition showed the mononuclear cell predominance of CD3+ (58.6%), CD4+ (57.2%), CD8+ (16.8%) lymphocytes and monocytes (34.4%), which expressed the phenotypic marker CD14+. This reflects the nature of a local immune response: an increase in the immunoregulatory index CD4+/CD8+ from 3.4 to 5.6, respectively, while the normal proportion of these cells in the blood ranges from 1.5 to 2.2. CSF lymphocytes were found to be ready for Fas-mediated apoptosis dependent on the receptor (CD95+ was 64.3%).There was a correlation using the pair correlation coefficient between the total concentration of the metabolites of the nitroxide molecule and the percentage of CD14+ (r=0.5; p<0.05). The paired Wilcoxon test was used to analyze serum NO2, NO3, and NOx, which revealed significant differences in nitrites [2.70 (1.90, 2.95; p=0.001)] and total NO metabolites [18.00 (18.00, 22.60; p=0.006)] and statistically significant changes in nitrates [13.29 (15.70. 20.30; p=0.075)] in patients receiving cytoflavin infusions. CONCLUSION: The immune response of Th-1 forms between the CSF phagocytic, antigen-presenting, and immunocompetent lymphocytes in patients with tick-borne neuroinfections. The use of cytoflavin as an agent for neurotransmitter support to correct nitroxidergic processes is pathogenetically justified. PMID- 28005033 TI - [Infective endocarditis: Importance of molecular biological techniques in etiological diagnosis]. AB - AIM: To investigate the specific features of conventional bacteriological methods and current molecular biological techniques for the etiological diagnosis of infective endocarditis (IE). SUBJECTS AND METHODS: Examinations were made in 53 patients treated at City Clinical Hospital Sixty-Four, Moscow Healthcare Department, in 2012-2015 who underwent simultaneous bacteriological and molecular biological (polymerase chain reaction (PCR) or PCR with further sequencing) examinations of blood or resected cardiac valve tissues. RESULTS: The investigation included 53 patients (31 men; median age, 62 years) with IE (Duke 2009); its primary form was observed in 32 (60.4%) patients. Blood bacteriological tests and PCR assays were positive in 28 (52.8%) and 34 (64.2%) patients, respectively. There were concordant results in 21 of the 28 positive blood culture cases and discordant results in 7 (25%); at the same time 3 cases showed a compete discordance in the detected causative agents (the growth of Enterococcus spp. was revealed by bacteriological examination and that of Staphylococcus spp., Streptococcus spp., and Escherichia coli by DNA PCR) and a pathogen could not be identified by DNA PCR in 4 patients who had positive blood bacteriological results. The positive PCR results for cocci and fungi were obtained in 10 of the 25 (47.2%) examinees with culture-negative IE. Rare causative agents were not revealed. The tissues obtained from 8 resected damaged heart valves displayed a wider spectrum of pathogens than did blood samples, which was associated with the formation of bacterial films. CONCLUSION: The etiological agent of IE was revealed in venous blood by bacteriological examination in 52.8% of the examinees, by PCR in 64.2%, and by either in 71.7%. There were concordant and discordant results in 67.9 and 32.1% of the patients, respectively; among whom 18.9% were found to have pathogen DNA revealed by PCR in culture-negative IE. PMID- 28005034 TI - [Treatment for acute respiratory viral infection and influenza in daily clinical practice: Results of the multicenter international observational FLU-EE study]. AB - PURPOSE: To study the clinical aspects of influenza and acute respiratory viral infection (ARVI) in routine clinical practice, with efficacy and safety of the antiviral therapy evaluation. SUBJECTS AND METHODS: In the large multicenter prospective observational study were enrolled 18,946 patients aged 18 to 93 years with previously determined diagnosis of influenza or ARVI from 262 outpatient sites in Russia, Armenia, Moldova and Georgia. According to study design, 3 visits were evaluated. On each visit the detailed medical examination, determination of individual symptoms' severity and course of disease were made. The dynamic evaluation of prescribed in routine clinical practice therapy of influenza and ARVI and cases of disease exacerbations with antibiotics concomitant therapy were assessed. RESULTS: For the first time in outpatient practice on a large population of adult patients the objective data were obtained and analyzed. This data relating to the timing of access to medical care of patients with influenza and ARVI depending on the age and the disease severity, dynamics of clinical picture of the disease, their outcomes, timing recovery, as well as ongoing drug therapy of ARVI and influenza, allowed to identify patterns of development and course of these diseases. The effectiveness and safety of antiviral drug Kagocel for treatment of ARVI and influenza was shown. This is reflected in the improvement of the clinical picture of the disease; reducing the number of patients with exacerbations, requiring the prescription of systemic antibiotics up to 1.5 times; the acceleration of regression of symptoms and recovery periods. CONCLUSION: This study allows increase the level of objective assessment of the beginning and course of influenza and other ARVIs in outpatient practice, to predict their course and outcome, and to improve the treatment. PMID- 28005035 TI - [Acute respiratory viral infections: Topical issues of diagnosis, prevention and treatment in therapeutic practice]. AB - AIM: to assess the efficacy and safety of the medication Grippferon with loratadine for the prevention of acute respiratory viral infections (ARVI) and influenza during the epidemics. MATERIAL AND METHODS: This study included 103 patients (67 men and 36 women) aged 18 to 52 years (mean age 35.3+/-3.2 years). During the first visit (september 2015), we collected patient history data on the average rate of ARVI and influenza for the past three years, the disease duration and its symptoms, presence of concomitant allergic pathologies (such as vasomotor rhinitis, hay fever and urticaria) and food allergies. Appropriate recommendations for the medication use were given to patients. During the second visit (may 2016), we collected follow-up cards and then analyzed the findings. RESULTS: 33 percent of the patients were fully compliant with the medication dosage regimen. In the first group (68 people with a history of one-two ARVI cases in the autumn-winter period for the past three years) the average number of ARVI cases in previous years was 1,53+/-0,23, by comparing with 0,69+/-0,16 (p<0.01) during the follow-up period, when medication Grippferon with loratadine was used. No ARVI cases were noted in 21 patients. In the second group (35 people with a history of three or more ARVI cases for the past three years) the average number of ARVI cases in previous years was 3,69+/-0,29, by comparing with 2,49+/ 0,22 (p<0.05) during the follow-up period, when nasal ointment Grippferon with loratadine was applied. Two people reported that they did not have ARVI. We noted a positive ARVI symptoms dynamics in patients, who received treatment with the given medication. Specifically, a reduced duration of fever and intoxication periods as well as decreased catarrhal symptoms in the nasopharynx and oropharynx were observed. CONCLUSION: The results of our study allow us to consider a new combined medication Grippferon with loratadine (nasal ointment) as an effective and safe medication for the prevention and treatment of influenza and acute respiratory viral infections in the complex therapy in adult patients, including patients with allergic history. PMID- 28005036 TI - [Evaluation of the pharmacoeconomic efficacy of prestance in the treatment of hypertensive patients on the basis of the results of the POTENTIAL program]. AB - AIM: To pharmacoeconomically estimate the use of a fixed-dose combination of perindopril and amlodipine in the treatment of hypertensive patients. MATERIAL AND METHODS: A pharmacoeconomic study was conducted on the basis of the Russian postmarketing observational open program POTENTIAL, which included the estimation of direct and indirect costs associated with the addition of a fixed-dose combination of perindopril and amlodipine to conventional therapy for hypertension in patients who had not achieved adequate blood pressure (BP) control. Cost-difference, cost-effectiveness, and budget-impact analyses were carried out. RESULTS: The addition of prestance to conventional therapy for hypertension can reduce total costs by 5.-5.8 times, direct costs required to achieve 1% of patients with adequate BP control by 20.5-42.1 times, and direct costs to improve a patient's status by one visual analogue scale score by 1.03 2.11 times. Within a 5-year horizon, the administration of prestance can decrease the cost of therapy for high BP and related strokes by 1.39-1.46 times. CONCLUSION: Due its high efficacy, prestance (amlodipine + perindopril) is a pharmacoeconomically preferred alternative only to the conventional therapy for hypertension even if the least costly generics are used, in both the short and medium term. PMID- 28005037 TI - [A case of progressive multifocal leukoencephalopathy in a HIV-infected female patient]. AB - Progressive multifocal leukoencephalopathy (PML) caused by JC virus is a severe central nervous lesion developing in the presence of obvious immunodeficiency. In most cases, the disease results in a fatal outcome within a few months. Antiretroviral therapy is currently considered to be the only method for the prevention and treatment of PML in HIV-infected patients. The paper describes a positive experience in treating the HIV-infected female patient with the established diagnosis of PML. PMID- 28005038 TI - [Common variable immunodeficiency in adults]. AB - The paper analyzes 7 cases of common variable immune deficiency (CVID), a primary immunodeficiency disease. All the cases were detected in outpatients over the age of 40 years. The diagnosis was based on their history data and general clinical findings with due regard for the results of previously conducted functional studies, expert opinions, and the results of immunological studies including the quantitative and functional indices of T and B cells, phagocytes and the levels of immunoglobulins. The analysis showed that the early signs of impaired immunity in all the patients were seen by physicians of various specialties in both outpatient and inpatient settings. Generalizing of all information about the patient could become the basis for a simple and accessible practical public health study of immunoglobulins levels significantly sooner than this diagnosis being verified. This testifies that the physicians of various specialties are partially aware of the clinical signs of immunodeficiency states and that there is a need for a clinical immunologist in adult healthcare facilities. This is especially important since the early clinical manifestations of both primary immunodeficiency disorders that are increasingly frequently detected and nonhereditary - secondary ones can be very similar. The timely verification of the diagnosis is necessary for prescribing adequate therapy with intravenous immunoglobulins to prevent severe chronic pyoinflammatory lung disease and disability in patients with CVID. PMID- 28005040 TI - [Genetic diversity of human immunodeficiency viruses and antiretroviral therapy]. AB - The lecture is devoted to the analysis of the state-of-the-art of the impact of genetic diversity of human immunodeficiency (HIV) viruses on the pattern of infection and the efficiency of antiretroviral therapy (ART). It provides brief information on the origin and evolution of HIV and on the current classification of their genetic variants. The molecular epidemiological situation of HIV infection in Russia and nearby states and the major molecular HIV variants that are dominant in these countries, as well as their origin and prevalence trends are characterized. How the diversity of HIV can affect the efficiency of diagnosis, the transmission of the virus, and the pattern of HIV pathogenesis are briefly reviewed. The comparative data available in the world's scientific literature on these topics are given. More detailed attention is given to the possible causes of varying therapeutic effects against different HIV subtypes, as well as to the specific features of the formation and phenotyping manifestation of ART drug resistance mutations. There is evidence for the necessity of forming a unified follow-up system for treated HIV-infected patients during ART scaling, including in an effort to evaluate the impact of the specific features of the HIV genome on the efficiency of treatment regimens used in Russia. PMID- 28005039 TI - [Intrauterine Pneumocystis infection]. AB - Pneumocystosis is well known as an opportunistic infection that is presently most frequently registered in patients with HIV infection and in those with other immunodeficiency states. Earlier, after the Second World War, Pneumocystis pneumonia was most commonly detected in debilitated and premature children; nosocomial outbreaks of pneumocystosis were studied in detail in the 1960s and 1970s. The pathogen is transmitted through the air, but a number of references indicate that it can be transmitted through the placenta. Despite the increasing number of publications on pneumocystosis in pediatrics, physicians remain unfamiliar with this disease. The paper provides evidence that Pneumocystis jiroveci can infect the fetus in utero. If unrecognized, the disease can lead to a child's death due to severe respiratory failure. The authors describe their case of generalized pneumocystosis that has developed in a child with evidence of intrauterine infection (detection of the pathogen in the autopsy material and placenta and identification of serological markers in his/her parents). The issues that are associated with intrafamilial infection and a risk for in utero transmission of P. jiroveci are discussed. PMID- 28005042 TI - [Depression and epilepsy: comorbidities, pathogenesis, principles of therapy]. AB - Numerous trials of last years confirm the bilateral link between depression and epilepsy with mutual complication of both diseases. Depression increases the risk of the first unprovoked paroxysm, worsens the compliance of epileptic patients, leads to decrease of the response both to therapeutic and surgical treatment and to increase of side effects of antiepileptic drugs. Depression is associated with high risk of suicidal behavior and reduces the quality of life level. Depression in epileptic patients is characterized by atypical clinical course in most cases what makes its diagnostics difficult and becomes the reason of the absence of the necessary pharmacologic and psychotherapeutic treatment. All of the above creates significant economical burden for the community because the epileptic patient with comorbid depression visits the physicians 2-4 times more often. PMID- 28005041 TI - [Outcomes of surgical treatment of patients with pharmacoresistant epilepsy]. AB - AIM: To evaluate the results of surgical treatment of patients with pharmacoresistant epilepsy. MATERIAL AND METHODS: Examination and surgical treatment of 61 patients with pharmacoresistant forms of symptomatic epilepsy were performed from 01.01.14 to 01.05.16. RESULTS AND CONCLUSION: The results confirmed the safety and efficacy of the surgical treatment of pharmacoresistant epilepsy. After 12 months, seizures were controlled in 69% of operated patients. The necessity of complex examination of all patients with pharmacoresistant epilepsy to make a decision about possible surgery is shown. PMID- 28005044 TI - [Determination and classification of Status Epilepticus (comments to the ILAE report)]. PMID- 28005043 TI - [The changes in cognitive impairment in patients with epilepsy during the disease course (on example of executive functions)]. AB - AIM: To identify the relationship between executive functions (EF), personality traits and clinical characteristics of disease course. MATERIAL AND METHODS: One hundred and five patients with partial epilepsy, including temporal lobe epilepsy (61%), lobe epilepsy (33%) and other forms (6%), were examined. Mean age of the patients was 30.24+/-8,67 years. EF were studied using the the Wisconsin Card Sorting Test (WCST) in 25 out of 105 patients of the main group. The patients were followed-up after 5.5 years. RESULTS: Correlations between the EF decline and the age, illness duration and disability was found. Seizure remission and its duration have a positive effect on EF indices. There were no correlations with the age at seizure onset, severity of seizures, amount of medications used, psychopathological symptoms and left-handedness. The WCST scores were worse in patients with temporal lobe epilepsy and patients with alexithymia. A follow-up examination showed the relationship between the further EF decline and the left sided localization of the epileptic focus as well as the absence of seizure remission. No relationship between the EF deficit and antiepileptic treatment was found. CONCLUSION: The EF deficit was observed in all forms of epilepsy, it was correlated with disability of patients, may be aggravated by personality and neurobiological characteristics and increased with the persistence of seizures. Based on the results of the study, the achievement of remission is needed in treatment tactics for epilepsy to preserve cognitive functioning and social well being of patients. PMID- 28005045 TI - [Treatment of epilepsy in children with brain tumors]. AB - AIM: Symptomatic focal epilepsy is frequently caused by supratentorial brain tumors that may be surgically removed. The authors studied outcomes of surgical treatment depending on the use of electrocorticography c (ECoG). MATERIAL AND METHODS: Seventy-five children, aged 5-7 years, with supratentorial brain tumors were examined. Symptomatic epilepsy was found in 52 (69.3%) patients. Dysembryoplastic neuroepithelial tumors (DNET) and fibrillary astrocytomas were the most epileptogenic tumors. RESULTS AND CONCLUSION: The outcomes on the Engel scale were as follows: in 27 patients with surgical intervention without ECoG: class I - 9 patients, class II - 7 patients, class III - 5 patients, class IV - 6 patients and in 25 patients operated with ECoG: class I - 19 patients, class II - 4 patients and class III - 2 patients. The significant difference (p<0.01) between I+II Engel classes in comparison with III+IV Engel classes in operated patients demonstrated the necessity of ECoG during surgery in the resection of supratentorial brain tumors in patients with symptomatic epilepsy. PMID- 28005046 TI - [A role of antioxidants in the complex treatment of epilepsy]. AB - The article covers the pathogenesis of epilepsy and goals of modern pharmacotherapy. The features of the development of epilepsy of vascular origin are presented as well. The authors describe the ways to increase the efficacy and decrease side-effects of anticonvulsants (a combination with antioxidant and antihypoxant drugs that was confirmed by the data on an important role of free radical processes in the pathogenesis of epilepsy). Mechanisms of action and efficacy of antioxidant treatment (on the example of 2-ethyl-6-methyl-3 hydroxypyridine succinate - mexidol) in the complex treatment of various forms of epilepsy are analyzed. The main advantages of mexidol as an add-on drug in the treatment of various types of epileptic syndrome in adults, taking into account its neuroprotective and antihypoxant action, are considered. Literature results have shown the positive effect of mexidol on the course of disease and its safety in the treatment of epilepsy. PMID- 28005048 TI - [Quality of life of adult patients with cryptogenic epilepsy]. AB - AIM: To determine a position of cryptogenic epilepsy (CE) in relation to idiopathic epilepsy (IE) and symptomatic epilepsy (SE) in the aspect of patients' quality-of-life. MATERIAL AND METHODS: One hundred and fifty patients, including 90 with CE, 30 with SE and 30 with IE, were examined. The severity of epileptic seizures assessed with the NHS3, anxiety and depression assessed with the HADS, sleep disorders, quality-of-life measured with the Qolie-89 were studied. RESULTS AND CONCLUSION: CE was similar to SE in many parameters but had a favorable course. The following factors were similar for CE and IE: family history of disease, differences between the severity of seizures and Qolie-89 scores. Quality-of-life was higher in CE compared to SE, despite the marked anxiety of patients. It has been concluded that CE, which is caused by both genetic and environmental factors, has an interim position between IE and SE. PMID- 28005047 TI - [The diagnosis of idiopathic epilepsy in children based on the algorithm of molecular-genetic studies]. AB - AIM: To study mutations and polymorphisms in the sodium channels genes, determining the development of idiopathic epilepsy (IE). MATERIAL AND METHODS: The study of SCN1A gene by direct Sanger sequencing in 53 patients and targeted resequencing of the regions of 34 genes in 40 patients with different clinical forms of IE was performed. RESULTS: Seven mutations (c.3022G>T, c.3637C>T, c.1144G>T, c.80G>C, c.1603C>T, c.2427G>A and c.1131A>C) were detected among 53 patients by direct Sanger sequencing of SCN1A gene. The mutations of SCN1A gene (2 - nonsense mutation, 5 - missense mutation) were identified in 7/40 (17.5%) patients with epilepsy using high-performance sequencing, Mutations in sodium channel genes encoding other subunits: SCN1B, SCN2A, SCN9A were identified in 6 patients. CONCLUSION: As epileptic encephalopathy is polygenic, it is important to conduct genetic testing of more genes (primarily sodium channel genes - SCN1B, SCN2A, SCN9A etc.) using special gene panels to find the molecular defect in DNA. PMID- 28005049 TI - [Hormonal treatment in West syndrome]. AB - West syndrome is one of the most well-known epileptic encephalopathies, a catastrophic epilepsy syndrome with onset in the first year of life. Prognosis of this condition depends on the etiology and adequate treatment. The authors review the hormonal treatment of West syndrome. Adrenocorticotrophic hormone (ACTH) is used in USA and its synthetic analogue tetracosactide is used in Europe. Both of the drugs are not registered in the Russian Federation. The data on the efficacy of corticosteroids, including prednisolone, are contradictory. Recent results have demonstrated the high efficacy of prednisolone in the treatment of West syndrome. The authors discuss different aspects of hormonal treatment of West syndrome: possible mechanisms, choice of medication, hormone doses, its duration, efficacy ant tolerability. PMID- 28005050 TI - [Genetics and treatment of early infantile epileptic encephalopathies]. AB - Epileptic encephalopathies (EE) are the group of progressive conditions with various etiologies that can produce neurocognitive deficit both per se and due to constant epileptiform discharges. Epileptic encephalopathies constitute about 15% of epilepsy in childhood and 40% of all seizures occurring in the first 3 years of life. Ten syndrome forms of EE are identified. Genetic factors contribute to 70-80% of all epileptic diseases and approximately 40% of idiopathic epilepsies have a monogenic mode of inheritance. Thirty-five genes of EE have been identified and the search is still continuing. The marked genetic heterogeneity of early EE, including 16 with autosomal-dominant-, 13 with autosomal-recessive-, 4 with X-linked recessive- and 2 with X-linked autosomal inheritance, was shown. The article describes differentiated approaches to the treatment of certain EE syndromes. Recent publications record the effectiveness of targeted therapy for certain forms of monogenic early EE (stiripentol in SCN1A mutations, diphenine in SCN8A mutations, levetiracetam in STXBP1 mutations). These results indicate the necessity for accurate diagnosis of genetic variants in early infantile EE for preventive actions in burdened families and for increasing the effectiveness of treatment. PMID- 28005052 TI - [Perampanel in pharmacotherapy of focal epilepsy: the efficacy and tolerability in routine clinical practice]. AB - AIM: To analyze the efficacy and tolerability of the innovative drug perampanel (PER) as add-on treatment of focal epilepsy in patients older than 12 years. MATERIAL AND METHODS: Forty-six patients with focal epilepsy, aged from 12 to 63 years, mean age 31.7 years, were studied. RESULTS AND CONCLUSION: A decrease in the frequency of all types of seizures by >50% was noted in 46,5% of patients. Stopping of all types of seizures was found in 25.6% of patients, i.e. in every fourth patient, stopping of secondary-generalized seizures in 39.5%. Adverse effects (AE) were identified in 13 (28.2%) of patients, including aggressiveness 6 (13.0%); other AE were less frequent (<10%): sleepiness (8.7%), dizziness (4.3%), postural instability (4.3%), irritability (4.3%). PER was withdrawn in 3 (6.5%) patients due to AE. Mean effective dose was 6 mg/day. Quality-of-life improved in the majority of patients (71.7%). PMID- 28005051 TI - [Russian experience of lacosamide (vimpat) usage in treatment of uncontrolled focal epilepsy]. AB - : Many patients with epilepsy receive treatment in polytherapy. Selection of antiepileptic drugs (AEDs) for the combination should be carried out in accordance with the principles of rational polytherapy, taking into account the mechanism of action, pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs. Along with levetiracetam, gabapentin, vigabatrin and pregabalin, lacosamide (LCM) shows superior PK profile in rating of all AED and can be combined with any of them. The goal of this study was to evaluate efficacy and tolerability of LCM in patients with uncontrolled partial onset seizures (POS) in routine clinical practice. METHODS: 181 patient's charts from 14 sites in Russia have been analyzed in retrospective manner. Patients 16 years old and older with POS with or without secondary generalization were included. Documented observation period of up to 12 months after initiation or until discontinuation of LCM therapy. Primary effectiveness variables was retention at Observational Point 3 (approximately 12 months). Other variables were: percentage change from historical baseline in seizure frequency, 50% and 75% treatment response and seizure-free status at the Observational Points 1, 2 and 3 (approximately 3, 6 and 12 months) and incidence and reason of treatment discontinuation. RESULTS: retention rate was high with 89.5% after 12-month observation. The development of seizure frequency showed a continuous decrease in terms of 50%, 75% treatment respond rates and seizure free status. A total of 5 adverse drug reactions leading to discontinuation of LCM therapy were recorded in 5 of 181 patients (2.8%) during the observation period. The high retention rate observed in this retrospective chart review is assumed to indicate a good tolerability and effectiveness of an adjunctive LCM treatment in patients with uncontrolled partial epilepsy in Russia. PMID- 28005053 TI - [Leber's hereditary optic neuropathy and epilepsy: a case report]. AB - A clinical case of a young man with rapid bilateral visual impairment developed 2 months after the onset of generalized convulsive seizures is presented. The replacement of valproate to levetiracetam led to the remission of seizures, but the prognosis for vision remains poor, particularly given the pessimistic results of optical coherence tomography (OCT). PMID- 28005054 TI - [Bioethics in Russian neurology and epileptology]. AB - Historical roots and further development of bioethics in domestic neurology and epileptology are considered. The main bioethical principles were established during the formation of the Russian clinical school and neurosciences. It is most distinctly seen in the development of bioethics in neurology and epileptology. In the author's opinion, the Russian scientist V.M. Bekhterev had played a prominent role in the field. In the time when the term "bioethics" was not coined and its principles were not formulated, V.M. Bekhterev had created the Russian league against epilepsy and established the foundations of the International League Against Epilepsy (ILAE) as the organizations working on the problems of medical and social care to patients with epilepsy. In Russia, the Russian society of neurologists has been doing a great work in the field. PMID- 28005055 TI - GRIL-seq provides a method for identifying direct targets of bacterial small regulatory RNA by in vivo proximity ligation. AB - The first step in the post-transcriptional regulatory function of most bacterial small non-coding RNAs (sRNAs) is base pairing with partially complementary sequences of targeted transcripts. We present a simple method for identifying sRNA targets in vivo and defining processing sites of the regulated transcripts. The technique, referred to as global small non-coding RNA target identification by ligation and sequencing (GRIL-seq), is based on preferential ligation of sRNAs to the ends of base-paired targets in bacteria co-expressing T4 RNA ligase, followed by sequencing to identify the chimaeras. In addition to the RNA chaperone Hfq, the GRIL-seq method depends on the activity of the pyrophosphorylase RppH. Using PrrF1, an iron-regulated sRNA in Pseudomonas aeruginosa, we demonstrated that direct regulatory targets of this sRNA can readily be identified. Therefore, GRIL-seq represents a powerful tool not only for identifying direct targets of sRNAs in a variety of environments, but also for uncovering novel roles for sRNAs and their targets in complex regulatory networks. PMID- 28005056 TI - New CRISPR-Cas systems from uncultivated microbes. AB - CRISPR-Cas systems provide microbes with adaptive immunity by employing short DNA sequences, termed spacers, that guide Cas proteins to cleave foreign DNA. Class 2 CRISPR-Cas systems are streamlined versions, in which a single RNA-bound Cas protein recognizes and cleaves target sequences. The programmable nature of these minimal systems has enabled researchers to repurpose them into a versatile technology that is broadly revolutionizing biological and clinical research. However, current CRISPR-Cas technologies are based solely on systems from isolated bacteria, leaving the vast majority of enzymes from organisms that have not been cultured untapped. Metagenomics, the sequencing of DNA extracted directly from natural microbial communities, provides access to the genetic material of a huge array of uncultivated organisms. Here, using genome-resolved metagenomics, we identify a number of CRISPR-Cas systems, including the first reported Cas9 in the archaeal domain of life, to our knowledge. This divergent Cas9 protein was found in little-studied nanoarchaea as part of an active CRISPR Cas system. In bacteria, we discovered two previously unknown systems, CRISPR CasX and CRISPR-CasY, which are among the most compact systems yet discovered. Notably, all required functional components were identified by metagenomics, enabling validation of robust in vivo RNA-guided DNA interference activity in Escherichia coli. Interrogation of environmental microbial communities combined with in vivo experiments allows us to access an unprecedented diversity of genomes, the content of which will expand the repertoire of microbe-based biotechnologies. PMID- 28005058 TI - A complex dominance hierarchy is controlled by polymorphism of small RNAs and their targets. AB - In diploid organisms, phenotypic traits are often biased by effects known as Mendelian dominant-recessive interactions between inherited alleles. Phenotypic expression of SP11 alleles, which encodes the male determinants of self incompatibility in Brassica rapa, is governed by a complex dominance hierarchy1 3. Here, we show that a single polymorphic 24 nucleotide small RNA, named SP11 methylation inducer 2 (Smi2), controls the linear dominance hierarchy of the four SP11 alleles (S44 > S60 > S40 > S29). In all dominant-recessive interactions, small RNA variants derived from the linked region of dominant SP11 alleles exhibited high sequence similarity to the promoter regions of recessive SP11 alleles and acted in trans to epigenetically silence their expression. Together with our previous study4, we propose a new model: sequence similarity between polymorphic small RNAs and their target regulates mono-allelic gene expression, which explains the entire five-phased linear dominance hierarchy of the SP11 phenotypic expression in Brassica. PMID- 28005060 TI - Secondary metabolism: High cholesterol in tomato. PMID- 28005059 TI - Dominance modifier: Expanding mate options. PMID- 28005057 TI - Observation of the 1S-2S transition in trapped antihydrogen. AB - The spectrum of the hydrogen atom has played a central part in fundamental physics over the past 200 years. Historical examples of its importance include the wavelength measurements of absorption lines in the solar spectrum by Fraunhofer, the identification of transition lines by Balmer, Lyman and others, the empirical description of allowed wavelengths by Rydberg, the quantum model of Bohr, the capability of quantum electrodynamics to precisely predict transition frequencies, and modern measurements of the 1S-2S transition by Hansch to a precision of a few parts in 1015. Recent technological advances have allowed us to focus on antihydrogen-the antimatter equivalent of hydrogen. The Standard Model predicts that there should have been equal amounts of matter and antimatter in the primordial Universe after the Big Bang, but today's Universe is observed to consist almost entirely of ordinary matter. This motivates the study of antimatter, to see if there is a small asymmetry in the laws of physics that govern the two types of matter. In particular, the CPT (charge conjugation, parity reversal and time reversal) theorem, a cornerstone of the Standard Model, requires that hydrogen and antihydrogen have the same spectrum. Here we report the observation of the 1S-2S transition in magnetically trapped atoms of antihydrogen. We determine that the frequency of the transition, which is driven by two photons from a laser at 243 nanometres, is consistent with that expected for hydrogen in the same environment. This laser excitation of a quantum state of an atom of antimatter represents the most precise measurement performed on an anti-atom. Our result is consistent with CPT invariance at a relative precision of about 2 * 10-10. PMID- 28005061 TI - Comparative genomics provides a timeframe for Wolbachia evolution and exposes a recent biotin synthesis operon transfer. AB - The genus Wolbachia (Alphaproteobacteria) comprises the most abundant inherited intracellular bacteria1. Despite their relevance as manipulators of human pathogen transmission2 and arthropod reproduction3, many aspects of their evolutionary history are not well understood4. In arthropods, Wolbachia infections are typically transient on evolutionary timescales5,6 and co divergence between hosts and Wolbachia is supposedly rare. Consequently, much of our knowledge of Wolbachia genome evolution derives from very recently diverged strains, and a timescale for Wolbachia is lacking. Here, we investigated the genomes of four Wolbachia strains that have persisted within and co-diverged with their host lineage for ~2 million years. Although the genomes showed very little evolutionary change on a nucleotide level, we found evidence for a recent lateral transfer of a complete biotin synthesis operon that has the potential to transform Wolbachia-host relationships7. Furthermore, this evolutionary snapshot enabled us to calibrate the divergence times of the supergroup A and B Wolbachia lineages using genome-wide data sets and relaxed molecular clock models. We estimated the origin of Wolbachia supergroups A and B to be ~200 million years ago (Ma), which is considerably older than previously appreciated. This age coincides with the diversification of many insect lineages8 that represent most of Wolbachia's host spectrum. PMID- 28005062 TI - Effects of delivery room quality improvement on premature infant outcomes. AB - OBJECTIVE: Delivery room management interventions have been successfully implemented via collaborative quality improvement (QI) projects. However, it is unknown whether these successes translate to reductions in neonatal morbidity and mortality. STUDY DESIGN: This was a prospective pre-post intervention study of three nonrandomized hospital groups within the California Perinatal Quality Care Collaborative. A collaborative QI model (Collaborative QI) was compared with a single-site QI model (NICU QI) and a non-participant population when implementing evidence-based delivery room practices. The intervention period was between June 2011 and May 2012. Infants born with gestational age between 22 weeks 0 days and 29 weeks 6 days and birth weight ?1500 g were included. Outcomes were mortality and select morbidities (bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC)). Outcomes were compared between the baseline (January 2010 to May 2011) and post-intervention period (June 2012 to May 2013) within each comparison group. RESULTS: Ninety-five hospitals were included with 4222 infants in the baseline period and 4186 infants in the post-intervention period. The Collaborative QI group had significantly reduced odds of developing BPD post intervention (odds ratio (OR) 0.8, 95% confidence interval (CI) 0.65 to 0.99) or composite BPD-death (OR 0.83, 95% CI 0.69 to 1.00). In both the Collaborative QI and non-participants there were also reductions in IVH, severe IVH, composite severe IVH-death, severe ROP and composite severe ROP-death. CONCLUSION: Hospitals dedicated to improving delivery room practices can impact neonatal outcomes. PMID- 28005063 TI - Impact of neonatal early-onset sepsis calculator on antibiotic use within two tertiary healthcare centers. AB - OBJECTIVE: A recently described neonatal early-onset sepsis (EOS) calculator has the potential to reduce newborn antibiotic exposure but real world data from its use remains sparse. The objective of this study was to determine the impact of applying the calculator to infants treated for EOS. STUDY DESIGN: Retrospective review of infants ?34 weeks gestational age who received antibiotics at birth. Subjects were compared according to Centers for Disease Control (CDC) 2010 guideline criteria versus the Kaiser Permanente neonatal EOS calculator recommendations. RESULTS: Of 205 patients, the EOS calculator recommended empiric antibiotics for 23% of those who received therapy, compared with 92% per CDC guidelines (P<0.001). No cases of culture-positive sepsis were identified. CONCLUSION: Use of the neonatal EOS calculator may dramatically reduce the number of infants who require antibiotics at birth, leading to reduced need for laboratory monitoring and improved antimicrobial stewardship. More safety data is needed. PMID- 28005064 TI - Skin care practices in newborn nurseries and mother-baby units in Maryland. AB - OBJECTIVE: Skin provides several important homeostatic functions to the developing neonate. However, no consensus guidelines exist in the United States for skin care in the healthy term newborn. STUDY DESIGN: We performed a study of skin and umbilical cord care (including bathing practices, vernix removal and antiseptic cord application) in newborn nurseries and mother-baby units throughout the state of Maryland to determine practices in a variety of clinical settings and assess if uniformity in skin care exists. These data were then assessed in the context of a review of the current literature. RESULTS: We received responses from over 90% of nurseries across the state. In our cohort, practices varied widely between institutions and specific populations, and often were not evidence-based or were contrary to best practices discussed in the scientific literature. CONCLUSION: The frequent departures from evidence that occur regarding the aforementioned practices are likely due to a lack of consensus on these issues as well as limited data on such practices, further highlighting the need for data-driven guidelines on newborn skin care. PMID- 28005065 TI - The cognitive aids in medicine assessment tool (CMAT) applied to five neonatal resuscitation algorithms. AB - OBJECTIVE: The International Liaison Committee on Resuscitation (ILCOR) provides recommendations on neonatal resuscitation training and practice, which includes a template for a decision-making algorithm. We evaluated the design properties of the ILCOR algorithm and four adaptations by member resuscitation organizations using the validated Cognitive Aids in Medicine Assessment Tool (CMAT). STUDY DESIGN: Two experts rated five neonatal resuscitation algorithms against the CMAT and against medical device design criteria. RESULTS: The ILCOR algorithm scored 32 of a possible 60 CMAT points, showing an adherence rate to CMAT of 53%. The ILCOR algorithm scored higher than the design variations by member organizations. Nonetheless, there are design limitations in the ILCOR algorithm. CONCLUSION: In principle, cognitive aids can improve neonatal resuscitation team performance; however, a considered design process that incorporates the full complexity of the 'procedure as performed' is needed to improve future versions of the algorithm for incorporation in international guidelines. PMID- 28005066 TI - Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism. AB - The amount of cholesterol made by many plants is not negligible. Whereas cholesterogenesis in animals was elucidated decades ago, the plant pathway has remained enigmatic. Among other roles, cholesterol is a key precursor for thousands of bioactive plant metabolites, including the well-known Solanum steroidal glycoalkaloids. Integrating tomato transcript and protein co-expression data revealed candidate genes putatively associated with cholesterol biosynthesis. A combination of functional assays including gene silencing, examination of recombinant enzyme activity and yeast mutant complementation suggests the cholesterol pathway comprises 12 enzymes acting in 10 steps. It appears that half of the cholesterogenesis-specific enzymes evolved through gene duplication and divergence from phytosterol biosynthetic enzymes, whereas others act reciprocally in both cholesterol and phytosterol metabolism. Our findings provide a unique example of nature's capacity to exploit existing protein folds and catalytic machineries from primary metabolism to assemble a new, multi-step metabolic pathway. Finally, the engineering of a 'high-cholesterol' model plant underscores the future value of our gene toolbox to produce high-value steroidal compounds via synthetic biology. PMID- 28005067 TI - Generation of nephron progenitor cells and kidney organoids from human pluripotent stem cells. AB - A variety of protocols have been developed that demonstrate the capability to differentiate human pluripotent stem cells (hPSCs) into kidney structures. Our goal was to develop a high-efficiency protocol to generate nephron progenitor cells (NPCs) and kidney organoids to facilitate applications for tissue engineering, disease modeling and chemical screening. Here, we describe a detailed protocol resulting in high-efficiency production (80-90%) of NPCs from hPSCs within 9 d of differentiation. Kidney organoids were generated from NPCs within 12 d with high reproducibility using 96-well plates suitable for chemical screening. The protocol requires skills for culturing hPSCs and careful attention to morphological changes indicative of differentiation. This kidney organoid system provides a platform for studies of human kidney development, modeling of kidney diseases, nephrotoxicity and kidney regeneration. The system provides a model for in vitro study of kidney intracellular and intercompartmental interactions using differentiated human cells in an appropriate nephron and stromal context. PMID- 28005068 TI - Immuno-engineered organoids for regulating the kinetics of B-cell development and antibody production. AB - Induction of B-cell immunity against infection depends on the initiation of the germinal center (GC) reaction in secondary lymphoid organs. Ex vivo recapitulation of the GC reaction in 2D cultures results in transient cell growth, with poor yield and short-term survival. Furthermore, no reported 2D ex vivo system can modulate the kinetics of a GC-like phenotype or the rate of antibody class switching. This protocol describes a methodology for developing immune organoids that partially mimic the B-cell zone of a lymphoid tissue, for efficient and rapid generation of B cells with a GC-like phenotype from naive murine B cells. The organoid is composed of a bioadhesive protein, gelatin, that is transformed into an ionically cross-linked hydrated network using biocompatible silicate nanoparticles (SiNPs). We explain how to establish the immune organoid culture to sustain immune cell proliferation and transformation into a GC-like phenotype. Starting with cell encapsulation in digested lymphoid tissues, clusters of proliferating B cells with a GC-like phenotype can be generated in the organoids at controlled rates, within ~1 week. The culture methodology described here is currently the only one that allows the accelerated induction of a GC-like phenotype in B cells and supports a controllable immunoglobulin class-switching reaction. This method can be easily implemented in a typical tissue culture room by personnel with standard mammalian cell culture expertise. PMID- 28005069 TI - Depletion of mitochondria in mammalian cells through enforced mitophagy. AB - Mitochondria are not only the 'powerhouse' of the cell; they are also involved in a multitude of processes that include calcium storage, the cell cycle and cell death. Traditional means of investigating mitochondrial importance in a given cellular process have centered upon depletion of mtDNA through chemical or genetic means. Although these methods severely disrupt the mitochondrial electron transport chain, mtDNA-depleted cells still maintain mitochondria and many mitochondrial functions. Here we describe a straightforward protocol to generate mammalian cell populations with low to nondetectable levels of mitochondria. Ectopic expression of the ubiquitin E3 ligase Parkin, combined with short-term mitochondrial uncoupler treatment, stimulates widespread mitophagy and effectively eliminates mitochondria. In this protocol, we explain how to generate Parkin-expressing, mitochondria-depleted cells from scratch in 23 d, as well as offer a variety of methods for confirming mitochondrial clearance. Furthermore, we describe culture conditions to maintain mitochondrial-depleted cells for up to 30 d with minimal loss of viability, for longitudinal studies. This method should prove useful for investigating the importance of mitochondria in a variety of biological processes. PMID- 28005070 TI - Auditory biological marker of concussion in children. AB - Concussions carry devastating potential for cognitive, neurologic, and socio emotional disease, but no objective test reliably identifies a concussion and its severity. A variety of neurological insults compromise sound processing, particularly in complex listening environments that place high demands on brain processing. The frequency-following response captures the high computational demands of sound processing with extreme granularity and reliably reveals individual differences. We hypothesize that concussions disrupt these auditory processes, and that the frequency-following response indicates concussion occurrence and severity. Specifically, we hypothesize that concussions disrupt the processing of the fundamental frequency, a key acoustic cue for identifying and tracking sounds and talkers, and, consequently, understanding speech in noise. Here we show that children who sustained a concussion exhibit a signature neural profile. They have worse representation of the fundamental frequency, and smaller and more sluggish neural responses. Neurophysiological responses to the fundamental frequency partially recover to control levels as concussion symptoms abate, suggesting a gain in biological processing following partial recovery. Neural processing of sound correctly identifies 90% of concussion cases and clears 95% of control cases, suggesting this approach has practical potential as a scalable biological marker for sports-related concussion and other types of mild traumatic brain injuries. PMID- 28005071 TI - Rab8a/Rab11a regulate intercellular communications between neural cells via tunneling nanotubes. AB - Tunneling nanotubes (TNTs) are F-actin-based membrane tubes, and can form between cultured cells and within vital tissues. TNTs mediate intercellular communications that range from electrical signaling to the transfer of organelles. Following peripheral nerve injury, the orchestrated intercellular communications among neural and non-neural cells are required for effective nerve regeneration. It remains unknown whether TNTs exist between neural cells in the peripheral nerve system and how TNTs affect neural regeneration. To address these interesting questions, we investigated the transfer of neurotropic factors, membrane protein, cytoplasmic protein, mitochondria and RNA in functional TNTs formed between cultured Schwann cells (SCs). TNT-like structures were increased not only in cultured SCs after exposure to serum depletion but also in longitudinal sections of proximal sciatic nerve stump harvested after rat peripheral nerve transection. Meanwhile, downregulation of Rab8a or Rab11a in cultured SCs inhibited the formation of functional TNTs and vesicle transfer and led to decrease in cell migration, increase in SCs apoptosis. Likewise, knockdown of Rab8a or Rab11a in primary SCs also suppressed axonal outgrowth from co cultured dorsal root ganglion (DRG) neurons. Overall, our results suggested that the gene of Rab8a or Rab11a might be involved in the formation of TNTs structures in the peripheral nerve system, while TNTs structures were likely to affect peripheral nerve regeneration through the regulation of neural cell communications. PMID- 28005072 TI - Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a long-lasting intractable autoimmune disorder, which has become a substantial public health problem. Despite widespread use of biologic drugs, there have been uncertainties in efficacy and long-term safety. Mesenchymal stem cells (MSCs) have been suggested as a promising alternative for the treatment of RA because of their immunomodulatory properties. However, the precise mechanisms of MSCs on RA-related immune cells are not fully elucidated. The aim of this study was to investigate the therapeutic potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) as a new therapeutic strategy for patients with RA and to explore the mechanisms underlying hUCB-MSC-mediated immunomodulation. Mice with collagen-induced arthritis (CIA) were administered with hUCB-MSCs after the onset of disease, and therapeutic efficacy was assessed. Systemic delivery of hUCB-MSCs significantly ameliorated the severity of CIA to a similar extent observed in the etanercept-treated group. hUCB-MSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hUCB-MSCs on macrophages, macrophages were co-cultured with hUCB-MSCs. The tumor necrosis factor (TNF)-alpha-mediated activation of cyclooxygenase-2 and TNF-stimulated gene/protein 6 in hUCB-MSCs polarized naive macrophages toward an M2 phenotype. In addition, hUCB-MSCs down-regulated the activation of nucleotide binding domain and leucine-rich repeat pyrin 3 inflammasome via a paracrine loop of interleukin-1beta signaling. These immune-balancing effects of hUCB-MSCs were reproducible in co-culture experiments using peripheral blood mononuclear cells from patients with active RA. hUCB-MSCs can simultaneously regulate multiple cytokine pathways in response to pro-inflammatory cytokines elevated in RA microenvironment, suggesting that treatment with hUCB-MSCs could be an attractive candidate for patients with treatment-refractory RA. PMID- 28005073 TI - Rab17 mediates differential antigen sorting following efferocytosis and phagocytosis. AB - Macrophages engulf and destroy pathogens (phagocytosis) and apoptotic cells (efferocytosis), and can subsequently initiate adaptive immune responses by presenting antigens derived from engulfed materials. Both phagocytosis and efferocytosis share a common degradative pathway in which the target is engulfed into a membrane-bound vesicle, respectively, termed the phagosome and efferosome, where they are degraded by sequential fusion with endosomes and lysosomes. Despite this shared maturation pathway, macrophages are immunogenic following phagocytosis but not efferocytosis, indicating that differential processing or trafficking of antigens must occur. Mass spectrometry and immunofluorescence microscopy of efferosomes and phagosomes in macrophages demonstrated that efferosomes lacked the proteins required for antigen presentation and instead recruited the recycling regulator Rab17. As a result, degraded materials from efferosomes bypassed the MHC class II loading compartment via the recycling endosome - a process not observed in phagosomes. Combined, these results indicate that macrophages prevent presentation of apoptotic cell-derived antigens by preferentially trafficking efferocytosed, but not phagocytosed, materials away from the MHC class II loading compartment via the recycling endosome pathway. PMID- 28005075 TI - MicroRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by regulating PPP2R1B expression in colorectal cancer. PMID- 28005074 TI - Smad3-related miRNAs regulated oncogenic TRIB2 promoter activity to effectively suppress lung adenocarcinoma growth. AB - MicroRNAs (miRNAs) and Smad3, as key transcription factors in transforming growth factor-beta1 (TGF-beta1) signaling, help regulate various physiological and pathological processes. We investigated the roles of Smad3-regulated miRNAs with respect to lung adenocarcinoma cell apoptosis, proliferation, and metastasis. We observed that Smad3 and phospho-SMAD3 (p-Smad3) were decreased in miR-206- (or miR-140)-treated cells and there might be a feedback loop between miR-206 (or miR 140) and TGF-beta1 expression. Smad3-related miRNAs affected tribbles homolog 2 (TRIB2) expression by regulating trib2 promoter activity through the CAGACA box. MiR-206 and miR-140 inhibited lung adenocarcinoma cell proliferation in vitro and in vivo by suppressing p-Smad3/Smad3 and TRIB2. Moreover, lung adenocarcinoma data supported a suppressive role for miR-206/miR-140 and an oncogenic role for TRIB2-patients with higher TRIB2 levels had poorer survival. In summary, miR-206 and miR-140, as tumor suppressors, induced lung adenocarcinoma cell death and inhibited cell proliferation by modifying oncogenic TRIB2 promoter activity through p-Smad3. MiR-206 and miR-140 also suppressed lung adenocarcinoma cell metastasis in vitro and in vivo by regulating EMT-related factors. PMID- 28005076 TI - BNC2 is a putative tumor suppressor gene in high-grade serous ovarian carcinoma and impacts cell survival after oxidative stress. PMID- 28005077 TI - Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2. AB - Signal transducer and activator of transcription 5 (STAT5) and nucleophosmin (NPM1) are critical regulators of multiple biological and pathological processes. Although a reciprocal regulatory relationship was established between STAT5A and a NPM-ALK fusion protein in T-cell lymphoma, no direct connection between STAT5 and wild-type NPM1 has been documented. Here we demonstrate a mutually regulatory relationship between STAT5 and NPM1. Induction of STAT5 phosphorylation at Y694 (P-STAT5) diminished NPM1 expression, whereas inhibition of STAT5 phosphorylation enhanced NPM1 expression. Conversely, NPM1 not only negatively regulated STAT5 phosphorylation but also preserved unphosphorylated STAT5 level. Mechanistically, we show that NPM1 downregulation by P-STAT5 is mediated by impairing the BRCA1 BARD1 ubiquitin ligase, which controls the stability of NPM1. In turn, decreased NPM1 levels led to suppression of p53 expression, resulting in enhanced cell survival. This study reveals a new STAT5 signaling pathway regulating p53 expression via NPM1 and uncovers new therapeutic targets for anticancer treatment in tumors driven by STAT5 signaling. PMID- 28005078 TI - Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB. AB - Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques. PMID- 28005079 TI - Everyday bat vocalizations contain information about emitter, addressee, context, and behavior. AB - Animal vocal communication is often diverse and structured. Yet, the information concealed in animal vocalizations remains elusive. Several studies have shown that animal calls convey information about their emitter and the context. Often, these studies focus on specific types of calls, as it is rarely possible to probe an entire vocal repertoire at once. In this study, we continuously monitored Egyptian fruit bats for months, recording audio and video around-the-clock. We analyzed almost 15,000 vocalizations, which accompanied the everyday interactions of the bats, and were all directed toward specific individuals, rather than broadcast. We found that bat vocalizations carry ample information about the identity of the emitter, the context of the call, the behavioral response to the call, and even the call's addressee. Our results underline the importance of studying the mundane, pairwise, directed, vocal interactions of animals. PMID- 28005080 TI - Work with visual display units and musculoskeletal disorders: A cross-sectional study. AB - BACKGROUND: Epidemiological studies have shown that employees working with visual display units (VDU) are more likely to complain about musculoskeletal disorders (MSDs). The aim of this study has been to evaluate associations among MSDs and individuals and work-related factors. MATERIAL AND METHODS: A total of 1032 VDU workers were assessed about their personal (i.e., age, working history, smoking history, physical activity) and work-related factors (i.e., predominant job tasks performed, work posture). Work environment was evaluated regarding fulfillment of the standard ISO 9241-5:1998. The investigation required a direct observation of participants (in order to accurately assess the prevalence of MSDs) and workstations. Adjusted odds ratios (ORa) were calculated by means of the logistic regression model. RESULTS: Prevalence of MSDs was relatively high (53%). In general, MSDs were significantly associated with female sex (OR = 2.832, 95% confidence interval (CI): 2.178-3.683), age >= 50 years old (OR = 2.231, 95% CI: 1.236-4.026), longer exposure to VDU, both as working history (10-14 years: OR = 1.934, 95% CI: 1.301-2.875; >= 15 years: OR = 2.223, 95% CI: 1.510-3.271) and working time (30-39 h/week: OR = 1.537, 95% CI: 1.087-2.273). Inappropriate workstation design was confirmed by the multivariate analysis as a risk factor for MSDs (ORa = 2.375, 95% CI: 1.124-5.018). CONCLUSIONS: Musculoskeletal disorders were significantly associated with individual factors as well as characteristics of work environment. An appropriate design of workstations may significantly reduce their prevalence amongst VDU workers. Med Pr 2016;67(6):707 719. PMID- 28005081 TI - Reliability of the Epworth Sleepiness Scale and the Berlin Questionnaire for screening obstructive sleep apnea syndrome in the context of the examination of candidates for drivers. AB - BACKGROUND: The aim of the study has been to assess the usefulness of the Epworth Sleepiness Scale (ESS) and the Berlin Questionnaire (BQ) for obstructive sleep apnea syndrome (OSAS) screening. The capacity of both tests to discriminate between healthy individuals or with mild OSAS (apnea-hypopnea index (AHI) < 15/h) vs. patients with moderate or severe OSAS (AHI >= 15/h) was evaluated. MATERIAL AND METHODS: The study encompassed 223 patients with a suspicion of the OSAS. The ESS and BQ were completed by patients unassisted. Screening polysomnography was performed using the Porti SleepDoc. The OSAS was diagnosed when AHI >= 15/h or AHI >= 5/h with simultaneous occurrence of clinical symptoms. RESULTS: The ESS score was found to be significantly higher in the study group compared to the control group (8.9+/-5.9 vs. 11.6+/-5.2 pt, p < 0.0001). Otherwise, there were no significant inter-group differences in the percentage of high-risk individuals according to the BQ (83.7% vs. 92.3%, p > 0.05). Sensitivity of the ESS and BQ was 53.2% and 93.1%, respectively while specificity was 58.8% and 16.2%, respectively. Poor correlation between the ESS score and AHI and apnea index were noticed (r = 0.22, p = 0.001 and r = 0.24, p < 0.001, respectively). CONCLUSIONS: Considering its low sensitivity, the ESS should not be used as a screening test for the OSAS diagnosis amongst candidates for drivers. The BQ is characterised by high sensitivity for the OSAS diagnosis with AHI >= 15/h, however, due to low specificity, the questionnaire may increase the number of healthy individuals referred for needless diagnostic procedures. Med Pr 2016;67(6):721-728. PMID- 28005082 TI - Miners' return to work following injuries in coal mines. AB - BACKGROUND: The occupational injuries in mines are common and result in severe socio-economical consequences. Earlier studies have revealed the role of multiple factors such as demographic factors, behavioral factors, health-related factors, working environment, and working conditions for mine injuries. However, there is a dearth of information about the role of some of these factors in delayed return to work (RTW) following a miner's injury. These factors may likely include personal characteristics of injured persons and his or her family, the injured person's social and economic status, and job characteristics. This study was conducted to assess the role of some of these factors for the return to work following coal miners' injuries. MATERIAL AND METHODS: A study was conducted for 109 injured workers from an underground coal mine in the years 2000-2009. A questionnaire, which was completed by the personnel interviews, included among others age, height, weight, seniority, alcohol consumption, sleeping duration, presence of diseases, job stress, job satisfaction, and injury type. The data was analyzed using the Kaplan-Meier estimates and the Cox proportional hazard model. RESULTS: According to Kaplan-Meier estimate it was revealed that a lower number of dependents, longer sleep duration, no job stress, no disease, no alcohol addiction, and higher monthly income have a great impact on early return to work after injury. The Cox regression analysis revealed that the significant risk factors which influenced miners' return to work included presence of disease, job satisfaction and injury type. CONCLUSIONS: The mine management should pay attention to significant risk factors for injuries in order to develop effective preventive measures. Med Pr 2016;67(6):729-742. PMID- 28005083 TI - Attenuating effects of caffeic acid phenethyl ester with intralipid on hepatotoxicity of chlorpyrifos in the case of rats. AB - BACKGROUND: Chlorpyrifos (CPF), insecticide widely used in agriculture, may cause poisonings in the case of humans. As a result, there is a large amount of treatment research underway to focus on the possibility of chlorpyrifos induced poisonings. The aim of this study has been to evaluate the effects of caffeic acid phenethyl ester (CAPE) and intralipid (IL) on hepatotoxicity induced by chlorpyrifos in the case of rats. MATERIAL AND METHODS: The rats in this study were treated with CPF (10 mg/kg body weight (b.w.), orally), CAPE (10 MUmol/kg b.w., intraperitoneally), IL (18.6 ml/kg b.w., orally), CPF+CAPE, CPF+IL, and CPF+CAPE+IL. The plasma total oxidant capacity (TOC), total antioxidant capacity (TAC) were measured and the oxidative stress index (OSI) was calculated. Liver histopathology and immunohistochemical staining were performed. RESULTS: Chlorpyrifos statistically significantly decreased the TAC levels in the rats' plasma and increased the apoptosis and the TOC and OSI levels. In the chlorpyrifos induced liver injury, CAPE and CAPE+IL significantly decreased the plasma OSI levels and the apoptosis, and significantly increased the plasma TAC levels. CONCLUSIONS: This study revealed that CAPE and CAPE+IL attenuate chlorpyrifos induced liver injuries by decreasing oxidative stress and apoptosis. Med Pr 2016;67(6):743-749. PMID- 28005084 TI - [Comorbidity diseases in adults with diagnosed interstitial lung diseases among inhabitants of the Silesian voivodeship, Poland]. AB - BACKGROUND: Interstitial lung diseases form a group of chronic diseases associated with a significant worsening of the quality of life. Proper management of these diseases involves the recognition and treatment of comorbidities, so it implies high direct and indirect costs of therapy. The lack of epidemiological data on the total incidence of interstitial diseases in Poland, as well as of information on their increasing incidence in other European countries justify investigations into epidemiological situation in the Silesian voivodeship (the southern region of Poland). MATERIAL AND METHODS: In a descriptive study registered data provided by the National Health Found in 2006-2010 were used to assess the temporal variability of standardized incidence rates. A data set included interstitial lung diseases and comorbidities in adults aged >= 19 years, residents of the Silesian voivodeship. RESULTS: In the period under study standardized incidence ratios for interstitial lung disease declined from 9.7/100 000 adult population to 7.8/100 000 adult population. The most prevalent comorbidities included cardio-vascular diseases, chronic and infectious respiratory diseases, metabolic diseases and musculoskeletal and connective tissue diseases. Comorbidities were found more frequently in older people >= 65 years, except for sarcoidosis, which was four times more prevalent in younger people (19-64 years) compared to older patients. The estimated costs of treatment of the analysed diseases reached more than 50 mln zlotys (12 mln dollars) per year. CONCLUSIONS: A small but systematic decrease in the value of the standardized incidence rate for interstitial lung disease has been shown within the range of 9.7-7.8/100 000 adult inhabitants. The most frequent comorbidities included cardiovascular or chronic and infectious respiratory diseases. The high cost of therapy of interstitial lung diseases was largely related to simultaneous treatment of comorbidities. Med Pr 2016;67(6):751-763. PMID- 28005085 TI - [Health state assessment in people sentenced to the penalty of restriction of liberty]. AB - BACKGROUND: Assessment of the health state of people sentenced to the penalty of restriction of liberty makes up a significant percentage of cases annually elaborated in the Department of Forensic Medicine, Poznan University of Medical Sciences. The analysis of such cases was accomplished to point out the difficulties that expert physicians could encounter in formulating their opinions. MATERIAL AND METHODS: The analysis involved 1051 medico-legal opinions issued in the years 2004-2013, considering the health state of people performing the duty of free, controlled social labor. The authors collected data on age, sex, type of diseases and the ability to control social work of convicted subjects. RESULTS: Among those sentenced to the penalty of restriction of liberty the men aged 51-60 were in the majority. Individuals able to work only in specified conditions were the most numerous group (56.3%). People able to work in all conditions were the smallest set (9.5%). Light work was the type of work most frequently recommended to the persons able to work only in specific conditions (58.4%). The largest group of diseases comprised spondylopathies and osteoarthropathies (51.4%). It was followed by the group of cardiac diseases and angiopathies, including hypertension (38.7%). CONCLUSIONS: The number of cases concerning the ability of the sentenced persons to serve the penalty of restriction of liberty annually elaborated in the Department of Forensic Medicine, Poznan University of Medical Sciences and the number of sentences imposed on the national scale indicate that medical experts may be obliged to provide opinions of this kind. Assessment of the health state of people sentenced to the penalty of restriction of liberty in some cases can be a difficult task for the expert physicians because of frequent lack of information about a specific type of work performed by the sentenced persons having only the data about their diseases. Med Pr 2016;67(6):765-775. PMID- 28005086 TI - [Evaluation of color perception in individuals addicted to narcotic substances in the Farnsworth-Munsell 100-Hue test]. AB - BACKGROUND: The aim of the study was to assess color perception in the Farnsworth Munsell 100-Hue test in individuals addicted to narcotic substances, and to analyze the acquired color vision disorders, depending on the duration of addiction and abstinence. MATERIAL AND METHODS: Ninety-five persons were qualified for the study. All the subjects were divided into 3 groups. Group I (drug addicts) comprised 45 individuals addicted to narcotic substances and nicotine. Group II (smokers) consisted of 30 individuals addicted only to nicotine, and group III (abstinents) included 20 individuals free of addictions. In all the study groups anamnesis, survey, standard ophthalmological examination and the Farnsworth-Munsell 100-Hue test were performed. RESULTS: In the Farnsworth-Munsell 100-Hue test the mean values of total error score (TES) for the purposes of the analysis, expressed in the values of square root (?TES), proved to be significantly higher in group I than in the two other groups (p < 0.001). In group I, the ?TES values exceeding critical values of age norms occurred significantly more frequently than in groups II (p < 0.01) and III (p < 0.05). A positive correlation between duration of addiction and the ?TES values was indicated (rho = 0.234, p < 0.05). The longer was the period of abstinence, the lower were the ?TES values, indicating the improved ability to distinguish between colors. CONCLUSIONS: The Farnsworth-Munsell 100-Hue test proved useful in the detection and assessment of acquired dyschromatopsy induced by narcotic substances. The observed disorders appeared to be dependent on the duration of addiction and abstinence. Med Pr 2016;67(6):777-785. PMID- 28005087 TI - [Structural empowerment and work-family fit in nurses]. AB - BACKGROUND: The goal of the study was to investigate the relationship between structural empowerment and work-family fit in Polish nurses. Structural empowerment is a strategy for managing by providing the employees with opportunities, information, support and resources essential for the effective performance of work duties. Work-family fit takes 2 forms of relationships between these 2 spheres: conflict (functioning in one role is more difficult because of participation in the other role) and facilitation (fulfilling the duties associated with one role enriches filling up the other role). MATERIAL AND METHODS: A total of 159 nurses employed in hospitals took part in the study. The Polish versions of the Conditions of Work Effectiveness Questionnaire and the Work-Family Fit Questionnaire were used. Hierarchical linear regression analysis was applied for data analysis. RESULTS: The results show statistically signifficant relationships between structural empowerment and work-family fit in nurses. In the hospital environment, characterized by a high degree of empowerment, nurses experience a lower level of work-family conflict and a higher level of facilitation in both directions. CONCLUSIONS: Hospital management strategy based on structural empowerment of nurses favors reconciliation of professional and family roles. Therefore, it is important for hospitals to create appropriate working conditions that allow nurses to effectively deal with demands arising from work and family spheres. Med Pr 2016;67(6):787-800. PMID- 28005088 TI - [Work-related rhinitis - Is it always an occupational disease?] AB - Rhinitis is a chronic inflammatory disease of the upper respiratory tract, characterized by a high prevalence and a complex pathogenesis. Work-related rhinitis (WRR) can be divided into occupational rhinitis (OR) and work exacerbated rhinitis (WER). It is not only considered as a disease entity but also in the context of medical certification as the allergic disease associated with occupational exposure. Epidemiology of work-related rhinitis has been found to vary depending on the occupation and specific exposure, on the other hand the prevalence data may be underestimated due to the lack of uniform diagnostic criteria. This paper reviews the issues comprising the pathogenesis, epidemiology, diagnosis and treatment of patients with work-related rhinitis. It also discusses the significance of the disease in occupational medicine, particularly in terms of preventive worker care, general principles of good practice in primary and secondary WRR prevention and the necessary directions of changes in medical certification in the cases of occupational rhinitis. Med Pr 2016;67(6):801-815. PMID- 28005089 TI - [Fullerenols in therapy and diagnosis of cancer]. AB - Malignant tumors are one of the main causes of death in Poland. One of the objectives of contemporary biomedical research is to maximize the effects of therapeutic strategies. The actions undertaken to improve therapeutic agents are aimed at reducing the side effects of cancer treatments. Another direction of investigations is the search for protective substances that reduce the toxicity of the drug to normal cells. Carbon-based nanomaterials (fullerenes and their derivatives, graphene, carbon nanotubes, nanodiamonds) are a broad class of nanoparticles that have potential biomedical applications in both therapy and diagnostics. The aim of this paper is to review biological properties of fullerenols in the context of their use in various strategies of cancer treatments. The authors also discuss the possibility of simultaneous use of nanoparticles in therapy and diagnosis, that is, in theranostics. Current knowledge indicates that fullerenes and their hydrophilic derivatives, especially fullerenols, show low or no toxicity. They may contribute to the inhibition of tumor growth and protection of normal cells through their antioxidant properties, as well as to the regulation of expression of genes involved in apoptosis and angiogenesis, and stimulation of the immune response. Gadoliniumcontaining endohedral fullerenes are less toxic as a contrast agents in magnetic resonance imaging, and they may also inhibit tumor growth, which is a promising result for theranostics. Med Pr 2016;67(6):817-831. PMID- 28005090 TI - [Guidelines for the use of the International Classification of Radiographs of Pneumoconioses of the International Labour Office (ILO): Substantial changes in the currrent edition]. AB - The International Classification of Radiographs of Pneumoconioses is the scheme worked out by the International Labour Office in Geneva (ILO), to register radiographic chest abnormalities in a well-ordered, reproducible and comparable way. It is used for diagnosing abnormalities caused by dust exposure. Guidelines for the use of the ILO International Classification of Radiographs of Pneumoconioses contain detailed information and recommendations on how to use the classification, as well as how the chest X-ray examination should be performed and recorded. To facilitate the diagnosis of observed abnormalities the classification is completed by the set of standard radiograms illustrating typical irregularities referring to lungs and pleura, included in the classification. The article presents the key information on classification and the most important amendments adopted in the 2000 and 2011 ILO guidelines revisions. These changes refer to radiographs quality assessment, the way of presenting abnormalities registered in standard radiographs (QUAD set, digital images) and registration of failures not related to dust exposure. Particularly important complements result from the development of radiological imaging techniques. They are concerned about the classification of radiographic images of the chest recorded digitally. Med Pr 2016;67(6):833-837. PMID- 28005091 TI - Back to the Future. PMID- 28005092 TI - Preservation of the Anterior Cruciate Ligament: A Treatment Algorithm Based on Tear Location and Tissue Quality. AB - The gold standard of anterior cruciate ligament (ACL) injuries is currently single-bundle autograft reconstruction. However, many disadvantages of reconstructive surgery exist, such as: anterior knee pain, muscle atrophy, and loss of range of motion. In addition, native kinematics are not restored, and osteoarthritis is not prevented. Finally, revision surgery, if necessary, can be problematic due to tunnel widening, tunnel malpositioning, and preexisting hardware. Ligament preservation includes preservation of native tissues in order to optimize the biologic aspects, while decreasing the invasive nature of reconstructive surgery. In the 1970s and 1980s, ACL preservation via open primary repair was widely performed, but the technique was abandoned due to unpredictable results. Unfortunately, the influence of both tear location and tissue quality on primary repair outcomes was not adequately recognized. Augmented repair, essentially a combination of primary repair and reconstruction, was then performed in the 1980s and early 1990s. Despite excellent results, for multiple reasons the surgical community moved on to ACL reconstruction, which was adapted as the gold standard. With the current knowledge of the role of tear location and tissue quality on outcomes of ACL preservation, in combination with modern advances of magnetic resonance imaging, arthroscopic technology, and the benefits of early rehabilitation, there is likely a role for ACL preservation today. In this article, we (I) discuss the history of ACL preservation, (II) discuss how modern advances alter the risk-benefit ratio for ACL preservation, and (III) propose a treatment algorithm for ACL injuries that is based on tear location and tissue quality. PMID- 28005094 TI - Preservation of the Anterior Cruciate Ligament: Surgical Techniques. AB - In the first part of this series, we (I) discussed the history of anterior cruciate ligament (ACL) preservation, (II) discussed how modern advances altered the risk-benefit ratio for ACL preservation, and (III) proposed our treatment algorithm for ACL injuries, which is based on tear location and tissue quality. In the second part of this series, we discuss (I) our proposed modification of the Sherman classification of the different tear types and (II) the surgical techniques and variations that can be used to treat these different tear types. PMID- 28005093 TI - Ultrasound-Guided Percutaneous Reconstruction of the Anterolateral Ligament: Surgical Technique and Case Report. AB - The first noted description of the anterolateral ligament (ALL) is often attributed to Dr. Paul Segond (1879). Segond described a "fibrous, pearly band showing extreme amounts of tension during forced internal rotation" that was responsible for an avulsion at the lateral aspect of the proximal tibia. In 2013, Dr. Steven Claes confirmed the presence of the ALL as the band of tissue detailed by Segond. Recent biomechanical studies have shown that the ALL is a vital stabilizer during internal rotation of the knee. Its contribution to stability during rotational kinematics has been proven to exceed that of the anterior cruciate ligament (ACL). Using the concept of the wheel and axle biomechanical formulas, the ACL endures 6 times greater forces during internal rotation in an ALL-deficient knee. With the recent anatomic and biomechanical findings, the necessity of a technique for reconstruction of the ALL has become increasingly important. The novel use of ultrasound intraoperatively allows for the exact anatomic reconstruction of the lost ligament by identifying the exact anatomic location of both the origin and insertion of the ALL. This article describes a technique for an ultrasound-guided percutaneous reconstruction of the ALL and a case report on one of our patients who required the reconstruction of his ALL. PMID- 28005095 TI - A Guide to Ultrasound of the Shoulder, Part 3: Interventional and Procedural Uses. AB - Ultrasound is an extremely useful diagnostic tool for physicians, but recent advances have found that ultrasound's greatest utility is in interventional and procedural uses. Numerous studies have demonstrated a significant improvement in outcome and patient satisfaction when using ultrasound guidance for injections. Newer techniques are emerging to use ultrasound as an aid to surgery and interventional procedures. This allows the physician to use smaller incisions and less invasive methods, which are also easier to use for the practitioner and more cost-effective. PMID- 28005096 TI - Liposomal Bupivacaine vs Interscalene Nerve Block for Pain Control After Shoulder Arthroplasty: A Retrospective Cohort Analysis. AB - The aim of this study was to compare liposomal bupivacaine and interscalene nerve block (ISNB) for analgesia after shoulder arthroplasty. We compared 37 patients who received liposomal bupivacaine vs 21 who received ISNB after shoulder arthroplasty by length of hospital stay (LOS), opioid consumption, and postoperative pain. Pain was the same in both groups for time intervals of 1 hour and 8 to 14 hours postoperatively. Compared with ISNB patients, liposomal bupivacaine patients reported less pain at 18 to 24 hours (P = .001) and 27 to 36 hours (P = .029) and had lower opioid consumption on postoperative days 2 (P = .001) and 3 (P = .002). Mean LOS for liposomal bupivacaine patients was 46 +/- 20 hours vs 57 +/- 14 hours for ISNB patients (P = .012). Sixteen of 37 liposomal bupivacaine patients vs 2 of 21 ISNB patients were discharged on the first postoperative day (P = .010). Liposomal bupivacaine was associated with less pain, less opioid consumption, and shorter hospital stays after shoulder arthroplasty compared with ISNB. PMID- 28005098 TI - Allografts for Ligament Reconstruction: Where Are We Now? AB - The use of musculoskeletal allografts by orthopedic surgeons continues to rise. The process of procuring and sterilizing allografts is evolving with much consideration to limiting the spread of infectious diseases and preserving tissue integrity. Research involving the application of allografts, particularly for ligament repair, is quite active, necessitating an update for the practicing orthopedist. Avoiding donor site morbidities is one of the most commonly cited advantages of allografts over autografts. There is controversy amongst studies for allografts in terms of their biological incorporation and clinical outcomes compared to autografts. This article focuses on reviewing the most current literature and usage of allograft tissue for ligamentous reconstruction amongst orthopedic surgeons today. It includes an in-depth analysis of the current processing, handling, and safety standards employed today, in addition to the advantages and disadvantages of allograft use. PMID- 28005097 TI - Why Do Lateral Unicompartmental Knee Arthroplasties Fail Today? AB - In large studies, the failure modes of lateral unicompartmental knee arthroplasty (UKA) are usually presented in combination with medial UKA, which is mainly due to low surgical frequency of lateral UKA. Because lateral UKA differs from medial UKA in anatomic and kinematic characteristics, failure modes of lateral UKA should not be presented in combination with medial UKA. Therefore, we performed a systematic review to assess failure modes in lateral UKA and compared failure modes in cohort studies with those found in registry-based studies. A search performed in PubMed, Embase, and Cochrane identified 25 studies (23 cohort studies and 2 registry-based studies) that were eligible in presenting failure modes in lateral UKA. Most common failure modes in lateral UKA were progression of osteoarthritis (OA; 29%), aseptic loosening (23%), and bearing dislocation (10%). In cohort studies, progression of OA was more common (36%) than bearing dislocation (17%) and aseptic loosening (16%), while in the registry-based studies, aseptic loosening (28%) was more common than progression of OA (24%) and bearing dislocation (5%). In conclusion, progression of OA is the most common failure mode in lateral UKA. In the future, both cohort studies and registry based studies should report the failure modes of medial and lateral UKA separately. PMID- 28005099 TI - A New Technique for Obtaining Bone Graft in Cases of Distal Femur Nonunion: Passing a Reamer/Irrigator/Aspirator Retrograde Through the Nonunion Site. AB - Bone grafting is one of the most common orthopedic procedures. We conducted a study to assess the possibility of passing a Reamer/Irrigator/Aspirator (RIA; DePuy Synthes) retrograde through the nonunion site in distal femur cases. This technique would avoid the complications and discomfort associated with a separate entry site for RIA. All patients with a distal femur nonunion treated with RIA bone grafting between 2009 and 2013 were included in the study. Nonunions were mobilized with excision of fibrous tissues. The distal part was angulated into varus, and then the guide wire was passed from the nonunion site laterally. Five patients had a RIA passed retrograde through the nonunion site. Mean age of these patients was 40.4 years (range, 22-66 years). Mean reamer size was 13.4 mm (mode, 14 mm), producing an average bone graft volume of 33 mL. There were no intraoperative or postoperative fractures. In 1 case, the reamer shaft broke. Passing a RIA retrograde through the nonunion site in distal femur cases is reproducible, and the technique avoids the discomfort and pain associated with a separate entry point as well as the complication of eccentric reaming of the proximal and distal part of the femoral canal. PMID- 28005100 TI - Total Knee Arthroplasty With Retained Tibial Implants: The Role of Minimally Invasive Hardware Removal. AB - Patients with retained tibial implants may later undergo total knee arthroplasty (TKA) after tibial osteotomy or fracture. Previous knee surgery can increase the rate of complications of joint replacement. Surgical scars may not be in optimal position for hardware removal and arthroplasty. The need for multiple incisions or larger subcutaneous skin flaps in at-risk areas may increase the possibility of wound complications and infection. In this article, we report 3 cases in which a patient who had knee arthrosis and retained tibial implants underwent single stage conversion to TKA. In each case, selected minimally invasive hardware removal was performed through small incisions under fluoroscopic guidance. For insertion of the tibial base plate, only screws were removed; the retained plates were not disturbed. This technique allowed the TKA to be performed without making significant secondary incisions or raising larger-than-normal skin flaps. PMID- 28005101 TI - Ulnar Collateral Ligament Reconstruction: Current Philosophy in 2016. AB - The ulnar collateral ligament (UCL) is the primary static restraint to valgus stress at the elbow. Since Jobe pioneered reconstruction in 1974, thousands of throwers have undergone UCL reconstruction, and good results have been achieved. The high-profile nature of the elite pitcher has brought this technique into the spotlight, and extensive research has been performed with new techniques emerging. The standard reconstruction, modified only slightly since Jobe's original description, remains the gold standard for treatment of UCL insufficiency. Throwers are able to return to the same or even higher levels of competition in the majority of cases. In this article, we present our standard technique and results and discuss emerging techniques for treatment of UCL injuries. PMID- 28005102 TI - Tibial Tubercle Fracture After Bone-Patellar Tendon-Bone Autograft. AB - Fractures occurring with anterior cruciate ligament (ACL) reconstruction are rare and those that do occur take place on the patellar side of a bone-patellar tendon bone (BPTB) autograft. Here we discuss a far more infrequent occurrence, fracture of the tibial tubercle aspect of the BPTB autograft. This fracture type occurs even more infrequently than tibial plateau fractures after ACL reconstruction based on the published literature. In this article we discuss the third published episode of a tibial tubercle fracture after BPTB allograft. We also discuss the fracture types seen with this method of ACL reconstruction and provide insights into prevention of this occurrence. PMID- 28005103 TI - Fat Embolism Syndrome With Cerebral Fat Embolism Associated With Long-Bone Fracture. AB - Fat embolism syndrome (FES) is a well-known sequela of long-bone fracture and fixation. FES most commonly affects the pulmonary system. Brain emboli may lead to a symptomatic cerebral fat embolism (CFE), which is devastating. In this article, we review the presentation, causes, and management of FES presenting with CFE, report a case, and review the literature. The case involved an otherwise healthy 42-year-old woman who developed CFE after reamed intramedullary nail fixation of femoral and tibial shaft fractures during a single operation. When the patient presented after surgery, she was nonverbal and was having diffuse extremity weakness. The diagnosis was stroke and resultant diffuse encephalopathy secondary to CFE. Within days of urgent management, the patient's cognitive and ophthalmologic deficits were substantially improved. Six months after surgery, cognitive and ophthalmologic recovery was excellent, and the fractures were healing with good functional recovery in the affected limb. PMID- 28005105 TI - Hinged-Knee External Fixator Used to Reduce and Maintain Subacute Tibiofemoral Coronal Subluxation. AB - Dislocation of the knee is a rare phenomenon that is becoming increasingly recognized with the expansion of its definition to include knees presenting with multiligament compromise. Hinged external fixators are now considered a viable supplementary treatment option in the management of acute ligament repair or reconstruction but their use in the management of subacute or chronic tibiofemoral dislocations or subluxations is less well defined. We report a case of a hinged-knee external fixator used to facilitate and maintain reduction of a chronic coronal tibial subluxation that presented after repair of an acute knee dislocation with lateral ligament injury secondary to a motor vehicle accident. At 5-year follow-up, the patient treated with hinged external fixation had a stable joint, was able to tolerate regular aerobic exercise, was minimally symptomatic, and did not require more extensive ligament reconstruction. Although there are reports on postoperative use of hinged external fixation to maintain the reduction of chronic or subacute knee dislocations in the sagittal plane after cruciate ligament repair, there are no reports on management of subacute tibiofemoral subluxation in the coronal plane. PMID- 28005104 TI - Potential Operating Room Fire Hazard of Bone Cement. AB - Approximately 600 cases of operating room (OR) fires are reported annually. Despite extensive fire safety education and training, complete elimination of OR fires still has not been achieved. Each fire requires an ignition source, a fuel source, and an oxidizer. In this case report, we describe the potential fire hazard of bone cement in the OR. A total knee arthroplasty was performed with a standard medial parapatellar arthrotomy. Tourniquet control was used. After bone cement was applied to the prepared tibial surface, the surgeon used an electrocautery device to resect residual lateral meniscus tissue-and started a fire in the operative field. The surgeon suffocated the fire with a dry towel and prevented injury to the patient. We performed a PubMed search with a cross reference search for relevant papers and found no case reports outlining bone cement as a potential fire hazard in the OR. To our knowledge, this is the first case report identifying bone cement as a fire hazard. OR fires related to bone cement can be eliminated by correctly assessing the setting time of the cement and avoiding application sites during electrocautery. PMID- 28005106 TI - Mycotic Septic Arthritis of the Ankle Joint. AB - Septic arthritis is a debilitating acute orthopedic emergency. Unfortunately, the diagnosis can be delayed or missed in immunocompromised patients with diabetes mellitus, and the result can be catastrophic. These patients are also at risk for atypical infections, including mycotic subtypes, which are more insidious than their more aggressive, more common Staphylococcus counterparts. The result is increased morbidity. In this article, we report a case of Candida albicans septic arthritis in a patient with diabetes mellitus and rheumatoid arthritis. Her case highlights the complexities of this specific disease entity. With early diagnosis, treatment is multimodal, involving surgical debridement and prolonged antifungal therapy. PMID- 28005107 TI - Prevalence of Low Vitamin D Levels in Patients With Orthopedic Trauma. AB - Low levels of serum vitamin D have been linked to numerous musculoskeletal and nonmusculoskeletal conditions. Vitamin D deficiency appears relatively high among various patient subpopulations, including patients with fracture nonunion. We conducted a retrospective study to determine the prevalence of vitamin D deficiency and insufficiency in a large population of patients with orthopedic trauma. The study included all patients who were over age 18 years, had no risk factors for vitamin D deficiency, and were treated for an acute fracture at a Level 1 trauma center. Between January 2009 and September 2010, 889 trauma patients had recorded serum 25-hydroxyvitamin D levels. Overall prevalence of combined vitamin D deficiency/insufficiency was 77%; prevalence of vitamin D deficiency alone was 39%. There were no statistically significant (P < .05) age or sex differences among the population. There did not appear to be a seasonal difference. Vitamin D deficiency and insufficiency in acute orthopedic trauma patients appear very common. Further investigation is needed to fully understand the clinical significance. PMID- 28005109 TI - Perceived Leg-Length Discrepancy After Primary Total Knee Arthroplasty: Does Knee Alignment Play a Role? AB - Leg length discrepancy (LLD) is common after total knee arthroplasty (TKA) although its incidence has not been well documented. The purpose of this study was to determine the incidence of perceived LLD before and after primary total knee arthroplasty as well as to determine the correlation between mechanical axis of the knee and perceived LLD. The incidence and time frame of resolution of postoperative LLD was also assessed. Seventy-three patients were prospectively enrolled. Evaluation included patient surveys regarding perceived LLD preoperatively, and at 3- to 6-week, 3-month, 6-month, and 1-year visits. Mechanical axis radiographs were obtained and the relationship of mechanical axis in patients with and without perceived LLD, both before and after surgery, was determined. Analysis was also performed for separate varus and valgus deformities. The effect of surgery on patients' perception of LLD was also determined. Fifty-three patients did not perceive a LLD preoperatively and 18 perceived a LLD preoperatively. Sixty-four patients did not perceive a LLD postoperatively and 7 patients perceived a LLD postoperatively. There was a significant difference in patients who perceived LLD preoperatively and those who perceived LLD postoperatively (P = .035). Of the 7 patients with a perceived LLD postoperatively, all noted resolution of LLD at a mean of 8.5 weeks. There were no statistically significant correlations of knee alignment to perceived LLD in any patient groups. Body mass index and age did not demonstrate any statistical differences between patient groups. Perceived LLD is common in patients undergoing TKA; however, perceived LLD decreases after surgery. Although approximately 10% of patients perceive a LLD after surgery, the vast majority resolve within 3 months. Our study did not show any relationship between mechanical knee alignment and perception of LLD. PMID- 28005108 TI - Comparing Cost, Efficacy, and Safety of Intravenous and Topical Tranexamic Acid in Total Hip and Knee Arthroplasty. AB - We conducted a study to compare the cost, efficacy, and safety of intravenous (IV) tranexamic acid (TXA) and topical TXA in primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). We retrospectively reviewed the cases of 291 patients who received either IV TXA or topical TXA before and after surgery. Significant differences favored topical TXA in reducing the postoperative decrease in hemoglobin levels in THA (P = .031) and TKA (P = .015) and calculated blood loss in TKA (P = .019). The groups did not differ in transfusion requirements for either THA or TKA. Topical TXA cost significantly more than IV TXA (P <= .0001). The benefits of using topical TXA to reduce the perioperative decrease in hemoglobin levels come with increased cost. PMID- 28005110 TI - Biomechanics of Polyhydroxyalkanoate Mesh-Augmented Single-Row Rotator Cuff Repairs. AB - Polyhydroxyalkanoate (PHA) mesh is a bioresorbable scaffold used to reinforce the suture-tendon interface in rotator cuff repairs (RCRs). We conducted a study of cyclic and ultimate failure properties of PHA mesh-augmented single-row RCRs and nonaugmented RCRs. Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female) were tested. Mean (SD) age was 61 (9) years. The supraspinatus tendon was resected and reattached in a single-row configuration using 2 triple-loaded suture anchors and 6 simple stitches. The opposite humerus underwent RCR augmented with 2 strips of 13-mm * 23-mm PHA mesh. Humeri were mounted in an Instron load frame, cycled 1000 times to 1.0 MPa of effective stress, and loaded to failure. Construct gapping and ultimate failure loads/displacements were recorded. Paired t tests compared augmented and nonaugmented RCRs (P <= .05 was significant). There was no difference in gapping over 1000 cycles (P = .879). Mean (SD) failure load was higher for PHA mesh-augmented RCRs, 571 (173) N, than for nonaugmented (control) RCRs, 472 (120) N (P = .042), and failures were consistent within pairs because of tissue failure at the knots or anchor pullout. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure. PMID- 28005111 TI - Instability After Reverse Total Shoulder Arthroplasty: Which Patients Dislocate? AB - Given the increasing use of reverse total shoulder arthroplasty (RTSA), it is important to study the complications associated with this procedure. We conducted a study of the incidence, predisposing factors, and treatment of RTSA dislocations. Using our institutional database, we retrospectively searched for RTSAs performed between September 27, 2010 and December 31, 2013 and identified postoperative dislocations. Four hundred eighty-seven patients underwent 510 RTSAs (393 primary, 117 revision). Fourteen patients had 15 dislocations (5 in primary RTSAs, 10 in revision RTSAs). Mean time from surgery to diagnosis was 58.2 days (range, 0-319 days). One dislocation occurred immediately after surgery, 2 after falls, 4 from low-energy mechanisms of injury, and 8 without known inciting events. Logistic regression analysis revealed revision RTSA (odds ratio [OR] = 7.515; P = .042) and higher body mass index (BMI) (OR = 1.09; P = .047) to be independent risk factors. The diagnosis of primary cuff tear arthropathy (CTA) was independently associated with a lower rate of dislocation (OR = 0.025; P = .008); dislocation occurred in only 1 (0.35%) of 285 patients with CTA. All dislocations were treated in the operating room; no dislocation was successfully treated with simple closed reduction in the clinic. Although dislocation after RTSA is uncommon, the risk is higher for patients with higher BMI and for revision patients. Patients may benefit from lifestyle modifications, preoperative counseling, intraoperative considerations, and rehabilitation modifications. Patients who undergo RTSA for primary CTA can be reassured that the likelihood of dislocation is low. PMID- 28005112 TI - Can a Total Knee Arthroplasty Perioperative Surgical Home Close the Gap Between Primary and Revision TKA Outcomes? AB - Given the steady increase in the number of primary and revision total knee arthroplasties (TKAs) performed in the United States, we wanted to determine if an evidence-based TKA perioperative surgical home could close the perioperative morbidity gap between primary and revision TKAs. We conducted a prospective cross sectional cohort study comparing outcomes of patients who had primary TKA (n = 235) with outcomes of patients who had revision TKA (n = 50). We measured several perioperative outcomes: length of stay, discharge disposition, 30-day readmission rate, and 30-day reoperation rate. Mean length of stay was 2.55 days for primary TKA and 2.92 days for revision TKA (P = .061). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 51 revision TKA patients were discharged to a subacute nursing facility (P = .123). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation (P = .993). There was no difference in perioperative outcomes between the primary and revision TKA groups in our Total Joint Replacement Perioperative Surgical Home (TJR-PSH) cohort. Advances in multidisciplinary co-management of TKA patients are highlighted in the TJR-PSH. The similarity in primary and revision TKA outcomes has significant implications regarding costs and potential increased patient satisfaction. PMID- 28005113 TI - Patient-Reported Outcome Measures: How Do Digital Tablets Stack Up to Paper Forms? A Randomized, Controlled Study. AB - Patient-reported outcomes (PROs) are essential to assessing the effectiveness of care, and many general-health and disease-specific PROs have been developed. Until recently, data were collected predominantly with pen-and-paper questionnaires. Now, though, there is a potential role for electronic medical records in data collection. In this study, patients were randomly assigned to complete either tablet or paper questionnaires. They were surveyed on patient demographics, patterns of electronic device use, general-health and disease specific PROs, and satisfaction. The primary outcome measure was survey completion rate. Secondary outcome measures were total time for completion, number of questions left unanswered on incomplete surveys, patient satisfaction, and survey preferences. The study included 483 patients (258 in tablet group, 225 in paper group), and the overall completion rate was 84.4%. There was no significant difference in PRO completion between the tablet and paper groups. Time to completion did not differ between the groups, but their satisfaction rates were similar. However, more paper group patients reported a preference for a tablet survey. Advantages of digital data collection include simple and reliable data storage, ability to improve completion rates by requiring patients to answer all questions, and development of interface adaptations to accommodate patients with handicaps. Given our data and these theoretical benefits, we recommend using tablet data collection systems for PROs. PMID- 28005114 TI - An Update on Management of Syndesmosis Injury: A National US Database Study. AB - We conducted a study to determine the incidence of syndesmotic injury and stabilization within various ankle fracture patterns along with the rate of syndesmotic implant removal. All data were obtained from a publicly available for fee healthcare database, the PearlDiver Patient Records Database. Current Procedural Terminology (CPT) codes were used to search the database for cases of fixation of lateral malleolus, bimalleolar, and trimalleolar fractures in addition to syndesmotic fixation and implant removal. Open reduction and internal fixation (ORIF) was performed for an ankle injury in 54,767 patients during 2007 to 2011. Total number of ORIF procedures was higher with each decade of life: 3206 cases in patients younger than 20 years, and 10,609 cases in patients 70 to 79 years old. Frequency of syndesmotic fixation increased significantly with ORIF of all ankle fractures (P < .0001). Hardware removal decreased throughout the study period. Incidence of syndesmotic injuries and rate of operative management trended upward over the study period, and rate of hardware removal decreased. PMID- 28005115 TI - Robotic Technology Produces More Conservative Tibial Resection Than Conventional Techniques in UKA. AB - Conversion of unicompartmental knee arthroplasty (UKA) to total knee arthroplasty (TKA) may be relatively simple when tibial resection is conservative during the index UKA. However, with greater tibial resection, conversion to TKA may be complicated by osseous insufficiency, requiring stems and augments, and potentially compromising patient outcomes and TKA durability. Robotic assistance in UKA is shown to enhance the bone preparation accuracy. In our retrospective comparison of polyethylene insert sizes, 8-mm or 9-mm polyethylene inserts were used in 93.6% and 84.5% of robotic (N = 8421) and conventional (N = 27,989) UKAs, respectively. Aggressive tibial resection, requiring tibial inserts >=10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases. Robotic-assisted UKA more reproducibly achieved accurate and precise conservative resection. PMID- 28005116 TI - Arthroscopic Transosseous and Transosseous-Equivalent Rotator Cuff Repair: An Analysis of Cost, Operative Time, and Clinical Outcomes. AB - The incidence of arthroscopic rotator cuff repair (RCR) continues to rise. Given the changing healthcare climate, it is becoming increasingly important to critically evaluate current practice and attempt to make modifications that decrease costs without compromising patient outcomes. We conducted a study of the costs associated with arthroscopic anchorless (transosseous [TO]) RCR and those associated with the more commonly performed anchor-based TO-equivalent (TOE) method to determine whether there are any cost savings with the TO-RCR method. Twenty-one consecutive patients who underwent arthroscopic TO-RCR were prospectively enrolled in the study and matched on tear size and concomitant procedures with patients who underwent arthroscopic TOE-RCR. The groups' implant costs and operative times were obtained and compared. Outcome measures, including scores on the VAS (visual analog scale) for pain, the SANE (Single Assessment Numeric Evaluation), and the SST (Simple Shoulder Test), recorded at 3, 6, and >12 months after surgery, were compared between the TO and TOE groups. Mean implant cost was $946.91 less for the TO group than the TOE group-a significant difference. Mean operative time was not significantly different between the TO and TOE groups. There was significant improvement on all outcomes measures (VAS, SANE, SST) at >12 months, and this improvement was not significantly different between the groups. Arthroscopic TO-RCR provides significant cost savings over TOE-RCR with no significant difference in operative time or short-term outcomes. PMID- 28005117 TI - Tenotomy, Tenodesis, Transfer: A Review of Treatment Options for Biceps-Labrum Complex Disease. AB - Biceps-labrum complex (BLC) disease is a well recognized source of shoulder pain. The BLC can be divided into 3 anatomical zones: inside, junction, and bicipital tunnel. Despite our evolving understanding, diagnosis of BLC pathology through physical examination, standard imaging techniques, and standard diagnostic glenohumeral arthroscopy can be challenging. Selection of the most appropriate surgical technique in refractory cases should take into account decompression of the extra-articular bicipital tunnel. In this article we review the recent literature regarding diagnosis and treatment options for BLC disease. PMID- 28005118 TI - Application of Amniotic Tissue in Orthopedic Surgery. AB - The use of amniotic tissue in orthopedic surgery has increased in recent years. While more studies are needed to fully understand the therapeutic potential and define the appropriate applications of these tissues, basic science and clinical studies are available that indicate promising results. This review will highlight these studies as they relate to the musculoskeletal system. PMID- 28005119 TI - An Overview of the History of Orthopedic Surgery. AB - Orthopedic surgery has a long and rich history. While the modern term orthopedics was coined in the 1700s, orthopedic principles were beginning to be developed and used during primitive times. The Egyptians continued these practices, and described ways to recognize and manage common orthopedic conditions. The Greeks and Romans subsequently began to study medicine in a systematic manner, and greatly improved our understanding of orthopedic anatomy and surgical technique. After a period of little progress during the Middle Ages, rapid advancement was noted during the Renaissance, including the description of various injuries, improvements in surgical technique, and development of orthopedic hospitals. Collectively, these advances provided the foundation for modern orthopedics. Currently, orthopedic surgery is a rapidly developing field that has benefited from the works of numerous scholars and surgeons. It is important to recognize the successes and failures of the past, in order to advance research and practice as well as improve patient care and clinical outcomes. PMID- 28005120 TI - Surgical Simulation in Orthopedic Surgery Residency. PMID- 28005121 TI - Limited-Incision Knotless Achilles Tendon Repair. AB - Acute midsubstance Achilles tendon ruptures, which are increasingly common among athletes, can result in significant functional limitations and decreased quality of life when not managed appropriately. The various surgical techniques for treating Achilles ruptures include open repair with Krackow locking sutures, percutaneous repair, and limited-incision repair with suture-passing jigs. Less invasive techniques have been developed to optimize the functional benefits of surgery while reducing delayed wound healing, infection, and other postoperative complications. An important albeit subjective aspect of Achilles tendon repair is suture knot tying and tensioning around the rupture site. Recently, a limited incision knotless Achilles tendon repair technique (Achilles Midsubstance SpeedBridge; Arthrex) was developed to minimize soft-tissue dissection, restore musculotendinous length, and directly fix tendon to bone to allow for early mobilization and more rapid functional recovery. The indications, contraindications, details, pearls, and pitfalls of this surgical technique are discussed in this article. PMID- 28005122 TI - Opioid-Sparing Pain Control in Outpatient Total Joint Arthroplasty. AB - Postoperative pain management is vital to promoting recovery and improving clinical outcomes. Although improved understanding of pain pathways has led to the development of varied approaches for controlling pain after surgery, some approaches are associated with potentially harmful side effects. Several lines of evidence have demonstrated that opioid analgesics can have unwanted adverse effects on patients having surgery. Similarly, risks associated with femoral nerve blocks have outweighed the benefits. Liposomal bupivacaine has shown efficacy in reducing the need for opioid analgesics and nerve blocks. Specifically, use of liposomal bupivacaine in a multimodal analgesia plan resulted in superior clinical and economic parameters in total joint arthroplasty. These advantages of liposomal bupivacaine are valuable in the current health care environment and in outpatient joint arthroplasty, in which highly effective opioid-sparing pain management is a prerequisite. Thus, liposomal bupivacaine can be used to reduce the burden of opioids and facilitate same-day discharge, thereby addressing some of the challenges associated with implementing short-stay or outpatient total joint arthroplasty. PMID- 28005123 TI - Addressing the Opioid Epidemic With Multimodal Pain Management. AB - The opioid epidemic has become a national public health and safety problem affecting both adults and adolescents. There is little doubt that this epidemic is rooted in the need for pain control after surgery and that orthopedic surgeons have in part contributed to opioid overprescription. Indeed, opioid abuse, misuse, and diversion are associated with increased hospitalizations, emergency department visits, and associated health care costs. In addition, postoperative exposure to opioids correlates with long-term use and abuse.Moreover, opioid related adverse effects are the leading cause of preventable harm in hospitals and can result in unexpected death. As such, there is an urgent need to address the opioid epidemic. Toward that end, several professional and governmental organizations have recommended opioid-sparing pain management approaches for surgeries-approaches that target different pain pathways to achieve adequate pain control. Such multimodal analgesia approaches are expected to reduce the writing of postoperative opioid prescriptions and their related adverse effects. PMID- 28005124 TI - Comprehensive Care for Joint Replacement (CJR) Bundle Expense in Perioperative Pain Management. AB - The implementaion of the Comprehensive Care for Joint Replacement (CJR) model has necessitated value-focused care for a 90-day period. Pain management in joint arthroplasty therefore represents a focused opportunity to achieve lasting change in the delivery of care. To be successful, orthopedic surgeons must integrate approaches that take into account administration route and therapy duration, and various combinations thereof, to achieve improved longer term outcomes for joint arthroplasty patients. In addition, pain management choices must be based on value and not on simple costs, as patient satisfaction scores affect CJR repayments. While the postdischarge time period poses the highest risk, improved collaboration with post-acute care providers, such as hospitalists, pharmacists, and rehabilitation facilities will be crucial to addressing patient comorbidities and ensuring optimal outcomes post-surgery. Furthermore, multimodal pain management strategies associated with optimal pain control and shorter hospital stays are valuable in achieving improved outcome and financial metrics. PMID- 28005125 TI - The Role of Liposomal Bupivacaine in Value-Based Care. AB - Multimodal pain control strategies are crucial in reducing opioid use and delivering effective pain management to facilitate improved surgical outcomes. The utility of liposomal bupivacaine in enabling effective pain control in multimodal strategies has been demonstrated in several studies, but others have found the value of liposomal bupivacaine in such approaches to be insignificant. At New York University Langone Medical Center, liposomal bupivacaine injection and femoral nerve block were compared in their delivery of efficacious and cost effective multimodal analgesia among patients undergoing total joint arthroplasty (TJA). Retrospective analysis revealed that including liposomal bupivacaine in a multimodal pain control protocol for TJA resulted in improved quality and efficiency metrics, decreased narcotic use, and faster mobilization, all relative to femoral nerve block, and without a significant increase in admission costs. In addition, liposomal bupivacaine use was associated with elimination of the need for patient-controlled analgesia in TJA. Thus, at Langone Medical Center, the introduction of liposomal bupivacaine to TJA has been instrumental in achieving adequate pain control, delivering high-level quality of care, and controlling costs. PMID- 28005131 TI - Effect of Strain, Region, and Tissue Composition on Glucose Partitioning in Meniscus Fibrocartilage. AB - A nearly avascular tissue, the knee meniscus relies on diffusive transport for nutritional supply to cells. Nutrient transport depends on solute partitioning in the tissue, which governs the amount of nutrients that can enter a tissue. The purpose of the present study was to investigate the effects of mechanical strain, tissue region, and tissue composition on the partition coefficient of glucose in meniscus fibrocartilage. A simple partitioning experiment was employed to measure glucose partitioning in porcine meniscus tissues from two regions (horn and central), from both meniscal components (medial and lateral), and at three levels of compression (0%, 10%, and 20%). Partition coefficient values were correlated to strain level, water volume fraction, and glycosaminoglycan (GAG) content of tissue specimens. Partition coefficient values ranged from 0.47 to 0.91 (n = 48). Results show that glucose partition coefficient is significantly (p < 0.001) affected by compression, decreasing with increasing strain. Furthermore, we did not find a statistically significant effect of tissue when comparing medial versus lateral (p = 0.181) or when comparing central and horn regions (p = 0.837). There were significant positive correlations between tissue water volume fraction and glucose partitioning for all groups. However, the correlation between GAG content and partitioning was only significant in the lateral horn group. Determining how glucose partitioning is affected by tissue composition and loading is necessary for understanding nutrient availability and related tissue health and/or degeneration. Therefore, this study is important for better understanding the transport and nutrition-related mechanisms of meniscal degeneration. PMID- 28005132 TI - Biomechanical Phenotyping of the Murine Aorta: What Is the Best Control? AB - The availability of diverse mouse models is revealing increasingly greater information on arterial mechanics, including homeostatic adaptations and pathologic maladaptations to genetic, pharmacological, and surgical manipulations. Fundamental to understanding such biomechanical changes, however, is reliable information on appropriate control vessels. In this paper, we contrast 15 different geometrical and mechanical metrics of biaxial wall mechanics for the ascending aorta across seven different types of possible control mice. We show that there is a comforting similarity across these multiple controls for most, though not all, metrics. In particular, three potential controls, namely, noninduced conditional mice, exhibit higher values of distensibility, an important clinical metric of structural stiffness, and two of these potential controls also have higher values of intrinsic circumferential material stiffness. There is motivation, therefore, to understand better the biomechanical changes that can arise with noninduced Cre-lox or similar approaches for generating mutations conditionally. In cases of germline mutations generated by breeding heterozygous +/- mice, however, the resulting homozygous +/+ mice tend to exhibit properties similar to traditional (C57BL/6) controls. PMID- 28005133 TI - Formulation of Generalized Mass Transfer Correlations for Blood Oxygenator Design. AB - This paper numerically investigates non-Newtonian blood flow with oxygen and carbon dioxide transport across and along an array of uniformly square and staggered arranged fibers at various porosity (epsilon) levels, focussing on a low Reynolds number regime (Re < 10). The objective is to establish suitable mass transfer correlations, expressed in the form of Sherwood number (Sh = f(epsilon, Re, Sc)), that identifies the link from local mass transfer investigations to full-device analyses. The development of a concentration field is initially investigated and expressions are established covering the range from a typical deoxygenated condition up to a full oxygenated condition. An important step is identified where a cut-off point in those expressions is required to avoid any under- or over-estimation on the Sherwood number. Geometrical features of a typical commercial blood oxygenator is adopted and results in general show that a balance in pressure drop, shear stress, and mass transfer is required to avoid potential blood trauma or clotting formation. Different definitions of mass transfer correlations are found for oxygen/carbon dioxide, parallel/transverse flow, and square/staggered configurations, respectively. From this set of correlations, it is found that transverse flow has better gas transfer than parallel flow which is consistent with reported literature. The mass transfer dependency on fiber configuration is observed to be pronounced at low porosity. This approach provides an initial platform when one is looking to improve the mass transfer performance in a blood oxygenator without the need to conduct any numerical simulations or experiments. PMID- 28005134 TI - A Validation Study of the Repeatability and Accuracy of Atomic Force Microscopy Indentation Using Polyacrylamide Gels and Colloidal Probes. AB - The elasticity of soft biological materials is a critical property to understand their biomechanical behaviors. Atomic force microscopy (AFM) indentation method has been widely employed to measure the Young's modulus (E) of such materials. Although the accuracy of the method has been recently evaluated based on comparisons with macroscale E measurements, the repeatability of the method has yet to be validated for rigorous biomechanical studies of soft elastic materials. We tested the AFM indentation method using colloidal probes and polyacrylamide (PAAM) gels of E < 20 kPa as a model soft elastic material after having identified optimal trigger force and probe speed. AFM indentations repeated with time intervals show that the method is well repeatable when performed carefully. Compared with the rheometric method and the confocal microscopy indentation method, the AFM indentation method is evaluated to have comparable accuracy and better precision, although these elasticity measurements appear to rely on the compositions of PAAM gels and the length scale of measurement. Therefore, we have confirmed that the AFM indentation method can reliably measure the elasticity of soft elastic materials. PMID- 28005136 TI - Management of Pregnancy in Women Who Have Undergone Bariatric Surgery. AB - Importance: As the problem of obesity continues to grow, more patients are choosing to undergo bariatric surgery to lose weight and treat comorbidities, such as diabetes. Of the more than 200,000 procedures performed each year, 80% are in women, many of reproductive age. Taking care of a pregnant woman who has undergone bariatric surgery requires understanding of the risks, the need for additional surveillance, and the limitations of our knowledge about how bariatric surgery affects pregnancy. Objective: The aims of this study were to review the current literature on bariatric surgery and pregnancy and summarize the important evidence to help the obstetrician care for a pregnant woman after bariatric surgery. Evidence Acquisition: Evidence for this review was acquired using PubMed. Conclusions: Pregnancy after bariatric surgery is safe and may be associated with improved pregnancy outcomes; however, more research is needed to better understand how to manage pregnant women with a history of bariatric surgery. Relevance: Obstetricians will increasingly be caring for women who have undergone bariatric surgery and subsequently become pregnant. PMID- 28005135 TI - Psychopharmacotherapy in Pregnancy and Breastfeeding. AB - Importance: Fifteen percent to 20% of pregnant women suffer from mental disorders, and 86% of them are not treated due to potential teratogenic risks for the fetus. Several drugs seem to be safe during pregnancy but knowledge regarding risks of antenatal exposure to drugs is still limited. Objective: The aim of this article is to provide a review of literature, data, and a clinical guideline concerning the treatment and management of mental disorders during pregnancy and lactation. Evidence Acquisition: Bibliographical research was carried out using Medline and Pubmed (from 2005 until 2015) and articles, books and Websites were consulted. Results: Regarding antidepressants, only paroxetine seems to lead to an increased risk of malformations, whereas fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram and venlafaxine do not appear to increase this risk. The use of duloxetine is associated with an increased risk of miscarriage during pregnancy but not with an increased risk of adverse events, such as birth defects. There is no clear evidence of malformation risk associated with the use of antipsychotics, whereas a risk associated with pregnancy and newborn outcome has been detected. All mood stabilizers are associated with risks of birth defects and perinatal complications. Conclusions and Relevance: Taking psychoactive drugs is possible during pregnancy, but it is important to consider various effects of the drugs. Future research should focus on prospective and longitudinal studies with an adequate evaluation of confounding variables. This should be followed by long-term studies to obtain accurate measures of child development. PMID- 28005137 TI - Adverse Fetal and Neonatal Outcome and an Abnormal Vertebral Pattern: A Systematic Review. AB - Importance: The human vertebral column has a stable number of vertebrae and ribs, which is presumably the result of evolutionary selection. An association between an abnormal vertebral pattern, especially in the cervical region, and congenital anomalies or adverse fetal outcome has been reported. Objective: The aim of this study was to review the current literature concerning an abnormal vertebral pattern and prevalence of cervical ribs in healthy subjects and in subjects with adverse outcome. Evidence Acquisition: Scientific databases were searched systematically. Studies assessing the number of vertebrae and/or ribs were included, and data concerning anomalies and outcome were extracted. Results: Thirty-nine studies including 75,018 healthy subjects and 6130 subjects with structural or chromosomal anomalies or adverse outcome were selected. The majority of these studies focused on the prevalence of cervical ribs. The prevalence of cervical ribs was considerably higher in fetuses with adverse outcome, including aneuploidies, compared with healthy individuals in the vast majority of studies. Studies suggest an association between cervical ribs and other structural anomalies. Conclusions: These results demonstrate that detailed assessment of the fetal vertebral column, especially of the cervicothoracic region, could provide valuable information regarding fetal and neonatal prognosis. Based on the available evidence, the application of 3-dimensional (3D) ultrasound to assess the vertebral column and ribs, in particular the cervical region, warrants further research. Relevance: Prenatal assessment of the ribs and vertebral pattern by 3D ultrasound, which is currently not routinely performed, might be useful in the assessment of the fetus, because this can predict fetal and neonatal outcome in some cases. PMID- 28005139 TI - [Heparin-induced thrombocytopenia type II (HIT II) : A medical-economic view]. AB - BACKGROUND: In the context of inpatient and increasingly ambulatory thrombosis prophylaxis, heparins have been recognised as standard therapy for decades. In addition to the therapeutic benefit, therapy with heparins also entails the risk of undesirable side effects, such as bleeding and thrombocytopenia. Heparin induced thrombocytopenia (HIT II) is deemed a serious side effect. AIM: In the following work, HIT II is subjected to a medico-economic consideration (treatment, pharmaceuticals, subsequent costs due to possible complications) and, with regard to a possible HIT II prophylaxis, aspects of increasingly respected patient safety are also considered. METHODS: In the context of a literature search the active ingredients argatroban and danaparoid, which are approved for HIT II treatment, were evaluated. RESULTS: HIT II - especially in combination with thromboembolic complications - represents a medical-economic burden for the hospital. Although this is only an orientation guide, it shows that HIT II syndrome is not adequately cost-covered by the G-DRG system. An early thrombosis prophylaxis with argatroban/danaparoid for HIT II risk patients should therefore be taken into account for medical-related as well as patient safety-relevant aspects. According to experience, the pharmaceutical supply for these medically needed products (anticoagulants) should be ensured for reasons of patient safety. CONCLUSION: The risk of an immunological response to heparin therapy is known. Within the context of increased patient safety, thrombosis prophylaxis should be issued with a risk-adjusted prophylaxis. PMID- 28005140 TI - [Abdominal pain and hypertension in a 55-year-old male patient]. AB - A 55-year-old male patient under permanent testosterone therapy for hypogonadism presented with abdominal pain and increased blood pressure values. In the physical examination a plethora was noted and laboratory examinations revealed polyglobulia. In the subsequent diagnostic process polycythemia vera and cancer could be excluded as the cause. A secondary polyglobulia due to testosterone substitution was diagnosed. Unphysiologically high testosterone levels represent a rare cause of secondary polyglobulia and with an appropriate medical history should be taken into account at an early stage. PMID- 28005141 TI - Case-related factors affecting cutting errors of the proximal tibia in total knee arthroplasty assessed by computer navigation. AB - PURPOSE: The aim of this study was to determine factors that contribute to bone cutting errors of conventional instrumentation for tibial resection in total knee arthroplasty (TKA) as assessed by an image-free navigation system. The hypothesis is that preoperative varus alignment is a significant contributory factor to tibial bone cutting errors. METHODS: This was a prospective study of a consecutive series of 72 TKAs. The amount of the tibial first-cut errors with reference to the planned cutting plane in both coronal and sagittal planes was measured by an image-free computer navigation system. Multiple regression models were developed with the amount of tibial cutting error in the coronal and sagittal planes as dependent variables and sex, age, disease, height, body mass index, preoperative alignment, patellar height (Insall-Salvati ratio) and preoperative flexion angle as independent variables. RESULTS: Multiple regression analysis showed that sex (male gender) (R = 0.25 p = 0.047) and preoperative varus alignment (R = 0.42, p = 0.001) were positively associated with varus tibial cutting errors in the coronal plane. In the sagittal plane, none of the independent variables was significant. CONCLUSION: When performing TKA in varus deformity, careful confirmation of the bone cutting surface should be performed to avoid varus alignment. The results of this study suggest technical considerations that can help a surgeon achieve more accurate component placement. LEVEL OF EVIDENCE: IV. PMID- 28005142 TI - No correlation between coronal alignment of total knee arthroplasty and clinical outcomes: a prospective clinical study using 3D-CT. AB - PURPOSE: The aim of this study was to evaluate femoral and tibial as well as whole leg coronal TKA alignment using 3D-reconstructed CTs and to assess the relationship of coronal TKA alignment and clinical outcome in a large prospective series of patients. It was hypothesized that a coronal deviation of TKA position and leg alignment from the mechanical axis is correlated with poorer patients' outcome after TKA. METHODS: A total of 81 consecutive patients who underwent primary TKA were prospectively included. The patient's demographics such as age, gender and time from primary TKA were noted. All patients underwent clinical and radiological examination including standardized radiographs (anteroposterior and lateral weight-bearing, patellar skyline view) and CT as part of their postoperative follow-up. For assessment of TKA component position and orientation 3D-reconstructed CT was used. For clinical outcome scoring the Knee Society Score (KSS) was used at 1 and 2 years postoperatively. Linear and quadratic regression models were used to test for correlations between alignment variables and KSS (p < .05). RESULTS: The mean Knee Society Score was 181 +/- 28 (range 52-200) 2 years postoperatively, while 78% of the patients were completely pain free and 22% had some persisting pain interfering with their daily activities. The mean mechanical whole limb alignment (HKA angle), femoral component alignment and tibial component alignment were 0 degrees , 0.1 degrees and -0.7 degrees , respectively. The component position parameters, as well as the whole limb alignment measurements, did not show any statistically significant correlation with the KSS, after 1 and 2 years postoperatively. CONCLUSION: In this prospective study, using 3D-CT to measure the component position, the postoperative outcome was not influenced by coronal TKA component position as well as the whole leg alignment. The findings challenge the current target of neutral coronal alignment and point towards a more individualized mechanical alignment target. LEVEL OF EVIDENCE: Prognostic study, Level I. PMID- 28005144 TI - [Ocular myositis as a rare cause of vision loss]. AB - Ocular myositis is a rare disease characterized by painful diplopia but loss of vision rarely occurs. The article reviews the literature focusing on the differential diagnostics. We report the case of an 80-year-old women suffering from slowly progressive loss of vision in the left eye. Diplopia was only present at the beginning and there was only moderate pain. Computed tomography and magnetic resonance imaging revealed a swelling of the left medial, lateral and inferior rectus muscles of the orbit leading to compression of the optic nerve in the orbital cone. An intravenous prednisolone stoss therapy (1000 mg per day for 3 consecutive days) was initiated, followed by oral medication of 100 mg per day then tapering over 10 weeks. Vision improved and no relapses were observed. Physicians should be aware of this rare disease to ensure quick diagnosis and treatment of ocular myositis. PMID- 28005145 TI - [Nutrition and mental diseases : Focus depressive disorders]. AB - Dietary interventions are currently being discussed as additional treatment options for mental disorders. The pathological mechanisms are not yet fully understood. It is hypothesized that certain nutrients and dietary pattern influence immune and inflammatory processes, the microbiome, the leptin melanocortinergic axis and hypothalamic-pituitary axis, as well as neurotransmitters of the cholinergic, noradrenergic, dopaminergic and serotonergic signaling cascades and neurotrophins. Observational studies have shown that traditional dietary patterns, such as the Mediterranean diet have a protective effect on mental health. Supplementation with long-chain polyunsaturated omega-3 fatty acids showed small to medium but significant effect sizes in meta-analyses from depression trials. The evidence with respect to the antidepressive effect of vitamin D supplementation is currently inconclusive. PMID- 28005143 TI - Acidic cellular microenvironment modifies carcinogen-induced DNA damage and repair. AB - Chronic inflammation creates an acidic microenvironment, which plays an important role in cancer development. To investigate how low pH changes the cellular response to the carcinogen benzo[a]pyrene (B[a]P), we incubated human pulmonary epithelial cells (A549 and BEAS-2B) with nontoxic doses of B[a]P using culturing media of various pH's (extracellular pH (pHe) of 7.8, 7.0, 6.5, 6.0 and 5.5) for 6, 24 and 48 h. In most incubations (pHe 7.0-6.5), the pH in the medium returned to the physiological pH 7.8 after 48 h, but at the lowest pH (pHe < 6.0), this recovery was incomplete. Similar changes were observed for the intracellular pH (pHi). We observed that acidic conditions delayed B[a]P metabolism and at t = 48 h, and the concentration of unmetabolized extracellular B[a]P and B[a]P-7,8-diol was significantly higher in acidic samples than under normal physiological conditions (pHe 7.8) for both cell lines. Cytochrome P450 (CYP1A1/CYP1B1) expression and its activity (ethoxyresorufin-O-deethylase activity) were repressed at low pHe after 6 and 24 h, but were significantly higher at t = 48 h. In addition, a DNA repair assay showed that the incision activity was ~80% inhibited for 6 h at low pHe and concomitant exposure to B[a]P. However, at t = 48 h, the incision activity recovered to more than 100% of the initial activity observed at neutral pHe. After 48 h, higher B[a]P-DNA adduct levels and gamma H2AX foci were observed at low pH samples than at pHe 7.8. In conclusion, acidic pH delayed the metabolism of B[a]P and inhibited DNA repair, ultimately leading to increased B[a]P-induced DNA damage. PMID- 28005147 TI - Erratum to: An ecophysiological background for biogeographic patterns of two island lizards? PMID- 28005146 TI - [Diagnostics of drug hypersensitivity reactions]. AB - Drug hypersensitivity reactions comprise approximately 25% of all adverse drug reactions and can be classified into allergic and pseudoallergic drug reactions. Immediate type anaphylactic and delayed type rash reactions of various clinical patterns can be distinguished, depending on the pathogenesis and clinical symptoms. The diagnostic work-up encompasses a thorough but also focused evaluation of the medical history, skin tests and when indicated challenge tests. Furthermore, in vitro tests, such as basophil activation tests and T cell assays not only add valuable additional information but can also yield decisive results for the diagnosis, especially in cases of severe drug reactions or reactions which cannot be further clarified by provocation tests. The aim of these measurements is not only the proof of drug intolerance and the detection of the causal drug but also the disclosure of the type of adverse reaction and the identification of potential, tolerated alternative drugs. This information is very important for the counseling of the patient and for prevention of new drug hypersensitivity reactions in the future. PMID- 28005148 TI - Microanatomy and life history in Palaeopleurosaurus (Rhynchocephalia: Pleurosauridae) from the Early Jurassic of Germany. AB - The tuatara (Sphenodon punctatus) from New Zealand is often-erroneously identified as a 'living fossil', although it is the lone survivor of a large, successful radiation of Rhynchocephalia, sister taxon to squamates (lizards and snakes), that thrived through the Mesozoic and Cenozoic and experienced an intricate evolution of life histories and feeding habits. Within Rhynchocephalia, only Pleurosauridae are thought to be marine and piscivorous. Here, we present bone histological data of the Jurassic pleurosaurid Palaeopleurosaurus, showing osteosclerosis (i.e. bone mass increase) in its gastralia, and some osteosclerosis in its rib but no increase in bone mass in the femur, supporting a gradual skeletal specialization for an aquatic way of life. Similar to Sphenodon, the bone tissue deposited in Palaeopleurosaurus is lamellar zonal bone. The femoral growth pattern in Palaeopleurosaurus differs from that of terrestrial Sphenodon in a more irregular spacing of growth marks and deposition of non annual (i.e. non-continuous) rest lines, indicating strong dependency on exogenous factors. The annual growth mark count in adult but not yet fully grown Palaeopleurosaurus is much lower when compared to adult individuals of Sphenodon, which could indicate a lower lifespan for Palaeopleurosaurus. Whereas the gastral ribs of Palaeopleurosaurus and Sphenodon are similar in composition, the ribs of Sphenodon differ profoundly in being separated into a proximal tubular rib part with a thick cortex, and an elliptical, flared ventral part characterised by extremely thin cortical bone. The latter argues against a previously inferred protective function of the ventral rib parts for the vulnerable viscera in Sphenodon. PMID- 28005149 TI - Non-steroidal Anti-inflammatory Drugs may Worsen the Course of Community-Acquired Pneumonia: A Cohort Study. AB - PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed or used as self-medication in cases of community-acquired pneumonia (CAP). Nevertheless, the consequences of such medication on the risk of pleuroparenchymal complications are not well known. The aim was to investigate whether exposure to NSAIDs prior to hospital admission among patients suffering from CAP is associated with the development of pleural complications or a lung abscess. METHODS: All consecutive non-immunocompromised patients with CAP and admitted to a university hospital were prospectively included (2-year period). The risk of pleuropulmonary complications was analyzed according to previous exposure to NSAIDs. RESULTS: Of the 221 included patients, 40 (18.1%) had developed a pleuropulmonary complication. NSAIDs intake prior to admission was reported for 24 patients (10.9%) who were younger (50.6 +/- 18.5 vs. 66.5 +/- 16.4 years; p = 0.001), had less comorbidities (60 vs. 25.1%; p = 0.001), had a longer duration between the first symptoms of CAP and the start of an antibiotic therapy (6.1 +/- 7.6 vs. 2.8 +/- 3.8 days; p = 0.001), and who had a higher incidence of pleuropulmonary complications (33.3 vs. 16.2%; p = 0.048). In multivariate analyses, two factors were independently associated with the development of pleuroparenchymal complications: NSAIDs intake [Odds Ratio (OR) = 2.57 [1.02-6.64]; p = 0.049] and alcohol abuse (OR = 2.68 [1.27-5.69]; p = 0.01). CONCLUSIONS: Our findings suggest that NSAIDs, often taken by young and healthy patients, may worsen the course of CAP with delayed therapy and a higher rate of pleuropulmonary complications. PMID- 28005150 TI - Early Trends in Bronchoscopic Lung Volume Reduction: A Systematic Review and Meta analysis of Efficacy Parameters. AB - INTRODUCTION: The goal of our systematic review and meta-analysis is to examine the therapeutic effectiveness of bronchoscopic lung volume reduction (BLVR), and to compare it with medical management and lung volume reduction surgery. METHODS: Variables of interest were absolute change in FEV1, 6MWT, and SGRQ. Meta-analysis was performed for the BLVR modalities with >=3 trials. Of the 18 shortlisted publications, only valves (four trials; n = 159) and coils (six trials; n = 194) qualified for meta-analysis. To avoid redundant reporting for valves, only the data for intact fissure subjects were analyzed. Outcome data are presented as the mean difference from baseline with 95% confidence interval at 6-months follow-up. RESULTS: For BLVR using valves, the pooled mean difference (PMD) for FEV1 was 0.146 L (95% CI 0.111-0.181; p < 0.001), 6MWT was 45.225 meters (95% CI 26.954 63.495; p < 0.001), and SGRQ was -8.825 points (95% CI -14.824 to -2.825; p = 0.004). All the PMDs were statistically significant and higher than their respective minimal clinically important difference (MCID). For BLVR using coils, the PMD for FEV1 was 0.080 L (95% CI 0.057-0.104; p < 0.001), 6MWT was 45.320 meters (95% CI 28.040-62.600; p < 0.001), and SGRQ was -10.570 points (95% CI 13.299 to -7.841; p < 0.001). All three variables showed statistically significant PMDs but that for FEV1 was smaller than the MCID. Data from BLVR modalities with <3 major publications are reviewed in the discussion section. CONCLUSIONS: BLVR offers early promise in the palliation of advanced emphysema. Better characterization of patients to identify phenotypes that will derive sustained benefit is needed. PMID- 28005151 TI - Activated protein C binds directly to Tie2: possible beneficial effects on endothelial barrier function. AB - Activated protein C (APC) is a natural anticoagulant with strong anti inflammatory, anti-apoptotic, and barrier stabilizing properties. These cytoprotective properties of APC are thought to be exerted through its pathway involving the binding of APC to endothelial protein C receptor and cleavage of protease-activated receptors. In this study, we found that APC enhanced endothelial barrier integrity via a novel pathway, by binding directly to and activating Tie2, a transmembrane endothelial tyrosine kinase receptor. Binding assays demonstrated that APC competed with the only known ligands of Tie2, the angiopoietins (Angs). APC bound directly to Tie2 (Kd ~3 nM), with markedly stronger binding affinity than Ang2. After binding, APC rapidly activated Tie2 to enhance endothelial barrier function as shown by Evan's blue dye transfer across confluent cell monolayers and in vivo studies. Blocking Tie2 restricted endothelial barrier integrity. This study highlights a novel mechanism by which APC binds directly to Tie2 to enhance endothelial barrier integrity, which helps to explain APC's protective effects in vascular leakage-related pathologies. PMID- 28005152 TI - Incidence of sialolithiasis in Denmark: a nationwide population-based register study. AB - Sialolithiasis is a frequent disorder affecting the salivary glands. The incidence rate (IR) has been reported to be 2.9-5.5 per 100,000 person-years, but all previous studies have been based on selected hospital data. In this study, we conducted a population-based study evaluating the IR of sialolithiasis and the IR variation according to age, gender and geography in Denmark. We included data from hospitals as well as from private ear, nose and throat (ENT) clinics. The study was based on registry data on all sialolithiasis cases in Denmark between 2003 and 2009 extracted from the Danish National Patient Registry (hospital cohort) and the Danish Regions Centre for Healthcare Statistics (private ENT clinic cohort). To validate the diagnosis, the proportion of visually confirmed cases was estimated based on patient records from subsamples of the two cohorts. The IR was 7.27 and 14.10 per 100,000 person-years based on visually confirmed cases only and on all cases, respectively. The highest IR was observed among 60- to 70-year-olds, in the North Denmark region and among females. In the validation subsamples, 35% of assumed sialoliths were visually confirmed in the private ENT clinic cohort and 59% in the hospital cohort. In this first population-based study of IR on sialolithiasis, we found a substantially higher IR. With respect to both visually confirmed cases and all cases, this is higher than previously reported from studies based on selected hospital data. PMID- 28005153 TI - [Significance of PSMA imaging in prostate cancer]. AB - BACKGROUND: Prostate cancer (PCa) is one of the most common malignancies of men in developed countries. To improve clinical diagnostics of PCa, 68Ga-PSMA-11 was recently introduced as a new PET tracer. 68Ga-PSMA-11 is able to specifically bind to the prostate-specific membrane antigen (PSMA), which is upregulated on the surface of prostate cancer cells in most patients. OBJECTIVES: To analyse the current significance of 68Ga-PSMA-11 PET imaging in prostate cancer in relation to staging of men with initial diagnosis, biochemical recurrence and metastatic disease. MATERIALS AND METHODS: Retrospective analysis of current literature (PubMed search) regarding 68Ga-PSMA-11 PET diagnostics in primary staging, in biochemical recurrence and in metastasized disease. RESULTS: Compared to conventional imaging, 68Ga-PSMA-11 PET/CT reaches a higher sensitivity with an excellent specificity in the clinical diagnosis of primary staging as well as staging for recurrence and advanced, metastasized disease. In biochemical recurrence, 68Ga-PSMA-11 PET/CT shows significantly higher detection rates in comparison to choline PET/CT, especially in patients with low PSA values. In the clinical diagnosis of recurrent disease, therapy concepts were changed in more than a quarter of the patients due to the use of 68Ga-PSMA-11 PET/CT. The significance of staging with 68Ga-PSMA-11 PET/CT in advanced metastasized patients remains uncertain. CONCLUSIONS: Due to the excellent results of 68Ga PSMA-11 PET imaging, even in patients with slightly elevated PSA levels, it will continue to play an important role in clinical diagnostics of prostate cancer and, thus, its clinical utilization will become more widely spread. PMID- 28005154 TI - [Pathogenesis of urological complications after radiation therapy]. AB - Radiation therapy is a treatment modality that is often used in the uro oncological setting. The common indication for the radiation therapy in the urological sphere is prostate cancer, whether it is used primarily as a radical approach, or postoperatively as adjuvant or salvage therapy. All urological organs are sensitive to radiation injury with the urinary bladder being the most susceptible with a typical cascade including acute and late changes, arising in the dose-dependent manner. The common indication for radiation therapy in urology is prostate cancer, which collaterally affects the urinary bladder and rarely urethra (especially the bulbo-membranous urethra). Ureteral damage and stricture formation is almost always restricted to the cases of intraoperative therapy and external beam radiation therapy for other urological malignancies (gynecological organs, rectum, retroperitoneal soft tissue tumors) and should not be underestimated. Postradiotherapeutic tissue changes, especially of the prostate, can cause difficulties for pathologists and urologists with regard to diagnosis of prostate cancer recurrence and salvage therapy. PMID- 28005155 TI - On-scene treatment of spinal injuries in motor sports. AB - Because spinal cord injuries can have fatal consequences for injured race car drivers, prehospital treatment of spinal injuries is a major concern in motor sports. A structured procedure for assessing trauma patients and their treatment should follow established ABCDE principles. Only then, a stable patient could be further examined and appropriate measures can be undertaken. For patients in an acute life-threatening condition, rapid transport must be initiated and should not be delayed by measures that are not indicated. If a competitor must first be extricated from the racing vehicle, the correct method of extrication must be chosen. To avoid secondary injury to the spine after a racing accident, in-line extrication from the vehicle and immobilization of the patient are standard procedures in motor sports and have been used for decades. Since immobilization can be associated with disadvantages and complications, the need for immobilization of trauma patients outside of motor sports medicine has become the subject of an increasing number of reports in the scientific literature. Even in motor sports, where specific safety systems that offer spinal protection are present, the indications for spinal immobilization need to be carefully considered rather than being blindly adopted as a matter of course. The aim of this article is to use recent literature to present an overview about the treatment of spinal injuries in motor sports. Further, we present a new protocol for indications for immobilizing the spine in motor sports that is based on the ABCDE principles and takes into account the condition of the patient. PMID- 28005156 TI - Institution of Veno-arterial Extracorporeal Membrane Oxygenation Does Not Lead to Increased Wall Stress in Patients with Impaired Myocardial Function. AB - The effect of veno-arterial extracorporeal membrane oxygenation (VA ECMO) on wall stress in patients with cardiomyopathy, myocarditis, or other cardiac conditions is unknown. We set out to determine the circumferential and meridional wall stress (WS) in patients with systemic left ventricles before and during VA ECMO. We established a cohort of patients with impaired myocardial function who underwent VA ECMO therapy from January 2000 to November 2013. Demographic and clinical data were collected and inotropic score calculated. Measurements were taken on echocardiograms prior to the initiation of VA ECMO and while on full flow VA ECMO, in order to derive wall stress (circumferential and meridional), VCFc, ejection fraction, and fractional shortening. A post hoc sub-analysis was conducted, separating those with pulmonary hypertension (PH) and those with impaired systemic output. Thirty-three patients met inclusion criteria. The patients' median age was 0.06 years (range 0-18.7). Eleven (33%) patients constituted the organ failure group (Gr2), while the remaining 22 (66%) patients survived to discharge (Gr1). WS and all other echocardiographic measures were not different when comparing patients before and during VA ECMO. Ejection and shortening fraction, WS, and VCFc were not statistically different comparing the survival and organ failure groups. The patients' position on the VCFc-WS curve did not change after the initiation of VA ECMO. Those with PH had decreased WS as well as increased EF after ECMO initiation, while those with impaired systemic output showed no difference in those parameters with initiation of ECMO. The external workload on the myocardium as indicated by WS is unchanged by the institution of VA ECMO support. Furthermore, echocardiographic measures of cardiac function do not reflect the changes in ventricular performance inherent to VA ECMO support. These findings are informative for the interpretation of echocardiograms in the setting of VA ECMO. ECMO may improve ventricular mechanics in those with PH as the primary diagnosis. PMID- 28005157 TI - Liquid chromatography-atmospheric pressure laser ionization-mass spectrometry (LC APLI-MS) analysis of polycyclic aromatic hydrocarbons with 6-8 rings in the environment. AB - A method has been developed for the sensitive and rapid analysis of polycyclic aromatic hydrocarbons (PAHs) in environmental samples using liquid chromatography time-of-flight mass spectrometry as well as the selective atmospheric pressure laser ionization (APLI) process (LC-APLI-MS). Upon analyzing 34 PAHs, the limits of detection of this method were found to range from 0.008 to 1.824 pg (0.024 pg for benzo[a]pyrene). The method therefore provides 30-fold to 5,400-fold increased sensitivity compared with the established GC-MS technique. This LC-APLI MS method was optimized for higher molecular weight PAHs (C24-C30 PAHs with 6-8 rings), which are difficult to detect or cannot be detected by GC-MS. Using the LC-APLI-MS method, various 6- to 8-ring PAHs were detected in environmental samples for the first time. After developing the method, it was successfully validated in ruggedness tests. The concentrations determined by the LC-APLI-MS method were in good accord with the certified concentrations in three certified reference materials (contaminated soils and sediments). Upon applying the method to environmental samples, it was found that (1) the presence of dibenzo[a,i]pyrene and dibenzo[a,h]pyrene in urban soil samples could only be detected using LC-APLI-MS (i.e., not GC-MS) due to its high sensitivity, (2) a bituminous coal sample yielded 211 tentative peaks from aromatic compounds in the C24-C30 range, and (3) eleven of those compounds occurred in different environmental samples in similar patterns. Hence, 6- to 8-ring PAHs occur in solid environmental samples in which other 6-ring PAHs such as indeno[1,2,3 cd]pyrene or benzo[ghi]perylene may also be present. Some of these numerous higher molecular weight PAH compounds could have very high carcinogenic potential, which will need to be elucidated to ensure the reliability of PAH risk assessments. PMID- 28005158 TI - Development of a GC-APCI-QTOFMS library for new psychoactive substances and comparison to a commercial ESI library. AB - Gas chromatography coupled to atmospheric pressure chemical ionization quadrupole time-of-flight mass spectrometry (GC-APCI-QTOFMS) was evaluated for the identification of new psychoactive substances (NPS). An in-house high mass resolution GC-APCI-QTOFMS test library was developed for 29 nitrogen-containing drugs belonging mostly to synthetic stimulants. The library was based on 12 intra day measurements of each compound at three different collision energies, 10, 20 and 40 eV. The in-house library mass spectra were compared to mass spectra from a commercial library constructed by liquid chromatography-electrospray ionization (LC-ESI) QTOFMS. The reversed library search scores between the in-house GC-APCI library and the commercial LC-ESI library were compared once a week during a 5 week period by using data measured by GC-APCI-QTOFMS. The protonated molecule was found for all drugs in the full scan mode, and the drugs were successfully identified by both libraries in the targeted MS/MS mode. The GC-APCI library score averaged over all collision energies was as high as 94.4/100 with a high repeatability, while the LC-ESI library score was also high (89.7/100) with a repeatability only slightly worse. These results highlight the merits of GC-APCI QTOFMS in the analysis of NPS even in situations where the reference standards are not immediately available, taking advantage of the accurate mass measurement of the protonated molecule and product ions, and comparison to existing soft ionization mass spectral libraries. Graphical abstract Tandem mass spectra obtained from GC-APCI-QTOFMS are comparable to LC-ESI-QTOFMS library spectra. PMID- 28005159 TI - Determination of labile species of As(V), Ba, Cd, Co, Cr(III), Cu, Mn, Ni, Pb, Sr, V(V), and Zn in natural waters using diffusive gradients in thin-film (DGT) devices modified with montmorillonite. AB - A binding phase based on the clay mineral montmorillonite (MT) was used as a sorbent in this work, which employed diffusive gradients in thin-film (DGT) devices to determine the lability of trace elements in natural waters. Montmorillonite exhibits low cost, wide availability, ease of handling, high ion exchange capacity, and reusability. As(V), Ba2+, Cd2+, Co2+, Cr(III), Cu2+, Mn2+, Ni2+, Pb2+, Sr2+, V(V), and Zn2+ were quantitatively sorbed by MT and eluted with 1.0 mol L-1 HNO3, which provided efficiency above 70% of recovery. Validation tests were performed with synthetic solutions. The recovery of known concentrations ranged from 83 to 110%. The performance of modified DGT was compared with conventional DGT devices in experiments lasting 6 and 48 h. The results obtained with both DGT devices showed no significant differences with 95% confidence. DGT samplers with MT were deployed in the determination of labile forms of the elements in water samples from Iguacu River (Parana, Brazil). The measured masses of elements in MT for various durations showed good fit to a theoretical line, indicating that the results agreed with the principle of the DGT technique. The concentrations of labile species in the sample proceeded as follows; Sr > Cd > Ba > Cu > Cr > Mn > Zn > Pb. The results suggest that DGT devices with MT are an effective alternative for speciation analysis of a wide range of elements (cations as well as anions) in natural waters. PMID- 28005161 TI - [Epidural anesthesia for fetoscopy : Retrospective analysis of a one-year cohort]. AB - BACKGROUND: The introduction of routine prenatal screening using ultrasound has led to a substantial increase in diagnoses of fetal disorders that are amenable to intrauterine treatment. While an ultrasound guided insertion of small bore cannulas can be performed under local anesthesia, insertion of a fetoscope usually requires anesthetic management for the mother and the fetus. Additionally, the fetus' intrauterine position may have to be manipulated in order to enable access. Such manoeuvres depend on relaxation of the mother's abdominal wall. General anesthesia has been the preferred method, but it involves substantial risks both to the mother and possibly the fetus, especially when combined with aggressive uterine relaxation. Epidural anesthesia (EA) may provide an alternative. Only little systematic data on the efficacy, requirements or untoward effects of epidural anesthesia for fetoscopy exists in the literature, yet a high rate of arterial hypotension following EA has been reported. We therefore aimed to assess the hemodynamic reaction to EA in a mixed population of pregnant women undergoing fetoscopy for a variety of fetal conditions and performed a retrospective analysis of a one-year cohort in a single university hospital. METHODS: The local ethics committee approved this retrospective analysis and waived patient consent (local study identifier 304/14). We extracted anesthesiologic and hemodynamic data from the anesthesia charts of 23 consecutive cases of elective fetoscopic procedures requiring anesthesia between May 2011 and 2012 at a German university medical centre. RESULTS: Twenty-three cases of fetoscopy were included in this study. Indications for fetoscopy were congenital diaphragmatic hernia (n = 9), aortic valve stenosis (n = 8), and feto-fetal transfusion syndrome (n = 6). Median gestational age was 26 (8, interquartile range) weeks. Lumbar epidural catheters were injected with a median dose of 0.09 (0.02, interquartile range) ml ropivacaine 0.75% per cm maternal height. In 11 patients, EA was titrated to a sufficient height whereas 12 patients received a single dose with a median volume of 0.08 (0.02) ml/cm maternal height. After injection, systolic arterial pressure did not change significantly, mean arterial pressure dropped from 93 (14) mm Hg to 88 (15) mm Hg (p = 0.03). Heart rate fell from 96 (29) to 89 (20) beats per minute (p = 0.02). At incision, neither blood pressure nor heart rate changed significantly. For hemodynamic support during the procedure, cafedrine/theodrenaline (AkrinorTM) was injected in five patients (median dose in these patients 0.5 (1.5) ml). One patient carrying a fetus with a poor prognosis and who underwent two separate procedures demanded additional sedation, for which we chose remifentanil. Another patient was hypotensive after intravenous administration of the tocolytic drug atosiban. A stable hemodynamic condition was quickly restored in this patient with administration of cafedrine/theodrenaline and i. v. fluids. All procedures were performed without conversion to general anaesthesia. CONCLUSION: This retrospective study demonstrates that fetoscopic procedures under EA in the range of indications treated in our institution can be performed safely. EA was associated with stable hemodynamic conditions in this mixed cohort of pregnant women. EA appears thus to be a suitable technique for fetoscopy, avoiding the risks inherent to general anesthesia in pregnant women. PMID- 28005162 TI - ? PMID- 28005160 TI - A contemporary framework of language processing in the human brain in the context of preoperative and intraoperative language mapping. AB - INTRODUCTION: The emergence of advanced in vivo neuroimaging methods has redefined the understanding of brain function with a shift from traditional localizationist models to more complex and widely distributed neural networks. In human language processing, the traditional localizationist models of Wernicke and Broca have fallen out of favor for a dual-stream processing system involving complex networks organized over vast areas of the dominant hemisphere. The current review explores the cortical function and white matter connections of human language processing, as well as their relevance to surgical planning. METHODS: We performed a systematic review of the literature with narrative data analysis. RESULTS: Although there is significant heterogeneity in the literature over the past century of exploration, modern evidence provides new insight into the true cortical function and white matter anatomy of human language. Intraoperative data and postoperative outcome studies confirm a widely distributed language network extending far beyond the traditional cortical areas of Wernicke and Broca. CONCLUSIONS: The anatomic distribution of language networks, based on current theories, is explored to present a modern and clinically relevant interpretation of language function. Within this framework, we present current knowledge regarding the known effects of damage to both cortical and subcortical components of these language networks. Ideally, we hope this framework will provide a common language for which to base future clinical studies in human language function. PMID- 28005164 TI - [Psychosocial counselling in gynecological practices : Results from a nationwide, representative survey of gynecologists in Germany]. AB - BACKGROUND: Due to their high social acceptance gynecologists provide ideal conditions for approaching families. Psychosocial stress (PSS), e. g. in the context of partnership conflicts, poverty or social isolation can be identified and support can be initiated. OBJECTIVES: The aim of the study was to capture attitudes and engagement of gynecologists dealing with patients with PSS in gynecological practices in Germany. METHODS: Out of 3000 randomly selected gynecologists in private practices, 1034 (response rate: 35%) took part in a Germany-wide questionnaire study on gynecologists' sense of responsibility, procedures and barriers when dealing with women with PSS. RESULTS: Ninety-six percent of the surveyed gynecologists felt responsible for patients with PSS. On average, gynecologists assumed PSS in 23% of their patients. Most of the gynecologists counseled patients with PSS and referral into the regional help system often occurred. When asked about the German early intervention system, 74% responded that they could imagine their own practice participating in this system. A need for improvement was observed in networking and financing. Significant differences in screening and interventions were found mainly in terms of professional experience, old vs. new federal states as well as between single and joint practices. CONCLUSIONS: Surprisingly, openness and engagement for patients with PSS were found in gynecological practices. The majority of gynecologists already offered psychosocial interventions. It may be deduced from these results that gynecologists in practices would contribute to the psychosocial aid network if key basic conditions including the financing were fulfilled. PMID- 28005163 TI - Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer. AB - Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-gamma, soluble TNF-R75 and IL-2Ralpha) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-gamma (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p < 0.001) compared to non-responders. GATA3/T-bet ratio correlated positively with serum neopterin (p = 0.008), IFN-gamma (p = 0.013) and KTR (p = 0.018) after the first BCG instillation. We observed a significant increase in CD4 expression in the Th cell population (p < 0.05), with only a modest tendency toward higher frequency in responders compared to non-responders (p = 0.303). The combined assessment of GATA3/T-bet ratio, neopterin and KTR may be a useful biomarker in predicting BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success. PMID- 28005165 TI - Free lateral tarsal artery perforator flap with functioning extensor digitorum brevis muscle for thenar reconstruction: a case report. AB - In this case report, we describe reconstructive surgery in one patient using a free lateral tarsal artery perforator flap with a functioning extensor digitorum brevis muscle. A 47-year-old woman sustained a crush-avulsion injury to her dominant right hand while working in a factory. A large thenar skin and muscle defect (5.5 cm * 4.0 cm) occurred as a consequence of surgical debridement. The skin and muscle defect was repaired using a free lateral tarsal artery perforator flap with a functioning extensor digitorum brevis muscle in a single operation. The donor site defect was repaired using a full-thickness skin graft. The patient recovered without postoperative complications. The patient showed satisfactory functional gain without significant donor site morbidity at the 4-year follow-up visit. Thus, we have demonstrated that a functional reconstruction of a thenar skin defect complicated by muscle loss is possible by transferring a free lateral tarsal artery perforator flap with the underlying extensor digitorum brevis muscle. PMID- 28005166 TI - Anatomic dissection of the anterolateral ligament (ALL) in paired fresh-frozen cadaveric knee joints. AB - INTRODUCTION: Different dissection studies as well as comparative studies about the anterolateral ligament of the knee (ALL) already exist and the structure's topology and properties have been shown. However, most of the studies investigating the ligament were performed in embalmed knees, which is thought to change the structural integrity of ligaments and thus the topologic and dynamic measurements. Since the biomechanical function of the ALL is not fully understood until today and a correlation with the pivot shift phenomenon is yet speculative, further studies will have to clarify its definitive importance. Its function as a limiter of internal rotation and lateral meniscal extrusion leads to the assumption of a secondary knee stabilizer. METHODS: Twenty paired fresh-frozen cadaveric knees of ten donors have been dissected in a layerwise fashion. After identification of the ALL, topologic measurements were undertaken using a digital caliper. RESULTS: The ALL could be identified as a tender, pearly structure in front of the anterolateral joint capsule in only 60% of the dissected knee joints. Only 20% of donors had a bilateral ALL while 80% had an ALL only in one side. Mean length, thickness and width as well as topographic measurements were comparable to other available studies investigating fresh-frozen cadavers. CONCLUSION: Anatomy and topography of the ALL seem to be highly variable, but consistent within certain borders. Prevalence has to be argued though as it strongly differs between studies. The impact of an ALL absence, even if only unilateral, needs to be investigated in clinical and imaging studies to finally clarify its importance. PMID- 28005167 TI - Patient-specific instrumentation development in TKA: 1st and 2nd generation designs in comparison with conventional instrumentation. AB - INTRODUCTION: This study was conducted to determine if the difference in magnetic resonance imaging (MRI)-based 2nd generation patient-specific instrumentation (PSI) design affects post-operative restoration of neutral mechanical alignment in total knee arthroplasty (TKA) compared with the 1st generation PSI design and conventional surgical techniques. In addition, it is aimed at elucidating whether PSI improves surgical efficiency with respect to operating room time, estimated blood loss and the number of instrument trays used intra-operatively. MATERIALS AND METHODS: We report our experience in TKA using PSI techniques in 234 patients from August 2012 to March 2015. The patients were divided into 1st (n = 64) and 2nd (n = 70) generation PSI design. The control group (n = 100) underwent TKA with the conventional instrument technique. RESULTS: The mean surgical time was significantly shorter in the 2nd generation PSI design (62.1 +/- 12.1 min) than in the control group (80.6 +/- 21.7 min; P < 0.001). A mechanical axis malalignment of >3 degrees of the lower limb was observed in 5.7% of the patients in 2nd generation PSI design compared with 26.0% of the control group (P = 0.006). No significant difference in mechanical alignment on post-operative long alignment radiography was found between 20.3% of the patients in 1st generation PSI design and the control group (P = 0.584). CONCLUSION: The 1st generation PSI design did not have a shorter surgical time or improved alignment compared with conventional instrumentation (CI). However, the use of the perfectly fitted 2nd generation PSI design was associated with improvements in both of these measurements. This study emphasizes the importance of PSI design in intra-operative and post-operative outcomes of TKA. PMID- 28005168 TI - PEEK versus titanium locking plates for proximal humerus fracture fixation: a comparative biomechanical study in two- and three-part fractures. AB - INTRODUCTION: The high rigidity of metal implants may be a cause of failure after fixation of proximal humerus fractures. Carbon fiber-reinforced polyetheretherketone (PEEK) plates with a modulus similar to human cortical bone may help to overcome this problem. The present study assesses the biomechanical behavior of a PEEK plate compared with a titanium locking plate. MATERIALS AND METHODS: Unstable two- and three-part fractures were simulated in 12 pairs of cadaveric humeri and were fixed with either a PEEK or a titanium locking plate using a pairwise comparison. With an optical motion capture system, the stiffness, failure load, plate bending, and the relative motion at the bone implant interface and at the fracture site were evaluated. RESULTS: The mean load to failure for two- and three-part fracture fixations was, respectively, 191 N (range 102-356 N) and 142 N (range 102-169 N) in the PEEK plate group compared with 286 N (range 191-395 N) and 258 N (range 155-366 N) in the titanium locking plate group. The PEEK plate showed significantly more bending in both the two- and three-part fractures (p < 0.05), an increased relative motion at the bone implant interface and lower stiffness values (p < 0.05). CONCLUSION: In this biomechanical study on unstable proximal humerus fractures, fixation with a PEEK plate showed lower fixation strength and increased motion at the bone-implant interface compared with a titanium locking plate. PMID- 28005170 TI - IMPROV-ED study: outcomes after discharge for an episode of acute-decompensated heart failure and comparison between patients discharged from the emergency department and hospital wards. AB - OBJECTIVE: To define the short- and mid-term outcomes of patients discharged after an episode of acute-decompensated heart failure (ADHF) and evaluate the differences between patients discharged directly from the emergency department (ED) and those discharged after hospitalization. METHODS: We performed a prospective, multicenter, cohort-designed study, including consecutive patients diagnosed with ADHF in 27 Spanish EDs. Thirty-four variables on epidemiology, comorbidity, baseline status, vital signs, signs of congestion, laboratory tests, and treatment were collected in every patient. The primary outcome was a combined endpoint of ED revisit (without hospitalization) or hospitalization due to ADHF, or all-cause death. Secondary outcomes were each of these three events individually. Outcomes were obtained by survival analysis at different timepoints in the entire cohort, and crude and adjusted comparisons were carried out between patients discharged directly from the ED and after hospitalization. RESULTS: Of the 3233 patients diagnosed with ADHF during a 2-month period, we analyzed 2986 patients discharged alive: 787 (26.4%) discharged from the ED and 2199 (73.6%) after hospitalization. The cumulative percentages of events for the whole cohort (at 7/30/180 days) for the combined endpoint were 7.8/24.7/57.8; for ED revisit 2.5/9.4/25.5; for hospitalization 4.6/15.3/40.7; and for death 0.9/4.3/16.8. After adjustment for patient profile and center, significant increases were found in the hazard ratios for ED- compared to hospital-discharged patients in the combined endpoint, ED revisit and hospitalization, being higher at short-term [at 7 days, 2.373 (1.678-3.355), 2.069 (1.188-3.602), and 3.071 (1.915-4.922), respectively] than at mid-term [at 180 days, 1.368 (1.160-1.614), 1.642 (1.265 2.132), and 1.302 (1.044-1.623), respectively]. No significant differences were found in death. CONCLUSIONS: Patients with ADHF discharged from the ED have worse outcomes, especially at short term, than those discharged after hospitalization. The definition and implementation of effective strategies to improve patient selection for direct ED discharge are needed. PMID- 28005171 TI - Parietal intradiploic encephalocele in an adult: a delayed complication of pediatric head injury? PMID- 28005169 TI - Paroxysmal atrial fibrillation during intracoronary acetylcholine provocation test. AB - Intracoronary acetylcholine (ACh) provocation test is useful to diagnose vasospastic angina. However, paroxysmal atrial fibrillation (AF) often occurs during intracoronary ACh provocation test, leading to disabling symptoms. The aim of this study was to investigate the incidence and predictors of paroxysmal AF during the test. A total of 377 patients without persistent AF who underwent intracoronary ACh provocation test were included. Paroxysmal AF during ACh provocation test was defined as documented AF on electrocardiogram during the procedure. There were 31 patients (8%) with paroxysmal AF during the test. Of these, 11 (35%) required antiarrhythmic drugs, but none received electrical cardioversion. All of them recovered sinus rhythm within 48 h. At procedure, paroxysmal AF occurred mostly during provocation for the right coronary artery (RCA) rather than for the left coronary artery (LCA) (90 vs. 10%). Multivariate logistic regression analysis demonstrated that a history of paroxysmal AF (OR 4.38 CI 1.42-13.51, p = 0.01) and body mass index (OR 0.88 CI 0.78-0.99, p = 0.03) were independent predictors for occurrence of paroxysmal AF during intracoronary ACh provocation test. In conclusions, paroxysmal AF mostly occurs during ACh provocation test for the RCA, especially in patients with a history of paroxysmal AF and lower body mass index. It may be better to initially administer intracoronary ACh in the LCA when the provocation test is performed. PMID- 28005172 TI - Postural control is associated with cognition and fear of falling in patients with multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting various neurological domains, such as postural control, cognition, fear of falling, depression-anxiety, and fatigue. This study examined the associations of cognitive functions, fear of falling, depression-anxiety, and fatigue with postural control in patients with MS. Postural control (sway velocity) of 63 patients with MS (age 39.0 +/- 8.9 years; %female 57%; Expanded Disability Status Scale score median (interquartile range) 2.0 (1.5)) was recorded on two platforms at stable and unstable conditions. Cognition, fear of falling, depression anxiety, and fatigue were evaluated by a comprehensive neuropsychological assessment. The associations between these domains and postural control have been measured by multivariable linear regression (adjusted for age, gender, disability, and education). In stable condition, only working memory was associated with postural control (p < 0.05). In unstable condition, working memory, executive functions, attention/processing speed, and fear of falling were associated with postural control (p < 0.05). Specific cognitive domains and fear of falling were associated with postural control in MS patients, particularly in unstable condition. These findings highlight the association of cognitive functions and fear of falling with postural control in MS. PMID- 28005173 TI - Diabetes education of patients and their entourage: out-of-hospital national study (EDUCATED 2). AB - AIMS: To determine the contributing factors in the successful diabetes education of patients and their entourage. METHODS: Prospective observational study conducted in a pre-hospital setting by 17 emergency services across France (September 2009-January 2011) included all insulin-treated patients (>=18 years) provided that at least one family member was present on scene. Data were collected from patients and their entourage: (1) personal details including language proficiency and educational attainment, (2) treatments, (3) diabetes related data (log sheets, glucose meter, glucagon, glycated hemoglobin, prior hypoglycemic episodes); (4) care by diabetologist, general practitioner and/or visiting nurse. The main end points were ability to measure capillary blood sugar (patient) and awareness of hypoglycemia symptoms and ability to administer glucagon (entourage). RESULTS: Overall, 561 patients and 736 family members were included; 343 patients (61%) were experiencing a hypoglycemic episode (<2.5 mmol/L). A total of 141 (75%) patients and 343 (50%) family members could measure capillary blood sugar. They could name a median of 2 [0-30/00] hypoglycemia symptoms although 217 (39%) patients and 262 (39%) family members could name no symptom. Few patients (33%) had glucagon available. In multivariate analyses, the main factor associated with better patient education was care by a diabetologist. Lack of an educational qualification and visits by a nurse were associated with poor patient education, and French mother tongue and care by a diabetologist with better education of the entourage. CONCLUSIONS: In France, diabetic patients and their entourage are inadequately educated. Their education benefits most from care by a diabetologist. PMID- 28005174 TI - Predator identity and time of day interact to shape the risk-reward trade-off for herbivorous coral reef fishes. AB - Non-consumptive effects (NCEs) of predators occur as prey alters their habitat use and foraging decisions to avoid predation. Although NCEs are recognized as being important across disparate ecosystems, the factors influencing their strength and importance remain poorly understood. Ecological context, such as time of day, predator identity, and prey condition, may modify how prey species perceive and respond to risk, thereby altering NCEs. To investigate how predator identity affects foraging of herbivorous coral reef fishes, we simulated predation risk using fiberglass models of two predator species (grouper Mycteroperca bonaci and barracuda Sphyraena barracuda) with different hunting modes. We quantified how predation risk alters herbivory rates across space (distance from predator) and time (dawn, mid-day, and dusk) to examine how prey reconciles the conflicting demands of avoiding predation vs. foraging. When we averaged the effect of both predators across space and time, they suppressed herbivory similarly. Yet, they altered feeding differently depending on time of day and distance from the model. Although feeding increased strongly with increasing distance from the predators particularly during dawn, we found that the barracuda model suppressed herbivory more strongly than the grouper model during mid-day. We suggest that prey hunger level and differences in predator hunting modes could influence these patterns. Understanding how context mediates NCEs provides insight into the emergent effects of predator-prey interactions on food webs. These insights have broad implications for understanding how anthropogenic alterations to predator abundances can affect the spatial and temporal dynamics of important ecosystem processes. PMID- 28005175 TI - Research on kidney and mineral metabolism in Japan: past, present, and future. AB - Since the identification of the kidney was the main site for the synthesis of calcitriol (1alpha, 25-dihydroxycholecalciferol), research on chronic kidney disease (CKD)-associated mineral metabolism disorders and their management has made rapid progress. Various active analogues of calcitriol have clinically become available for treating secondary hyperparathyroidism (SHPT), which is a representative mineral metabolism abnormality in CKD patients. A calcimimetic compound cinacalcet hydrochloride has also been developed for the medical management of SHPT through a different mechanism involving the calcium-sensing receptor. The concept of CKD-mineral and bone disorder (CKD-MBD) was proposed in 2006 to provide a comprehensive understanding of a disorder related to mineral metabolism abnormalities of CKD, based on the fact that these abnormalities are closely associated with cardiovascular disease as well as bone disorders (renal osteodystrophy). There has been a recent surge in the development of phosphate binders for CKD-MBD, focused on an effort to improve mortality. In Japan, high quality basic and clinical research on CKD-MBD has led to the development of novel therapeutic drugs, such as maxacalcitol, falecalcitriol, and bixalomer. New practice guidelines have been published and are widely adapted in clinical practice. PMID- 28005176 TI - The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. AB - BACKGROUND: It has long been known that the majority of patients with multiple sclerosis (MS) display an intrathecal, polyspecific humoral immune response to a broad panel of neurotropic viruses. This response has measles virus, rubella virus and varicella zoster virus as its most frequent constituents and is thus referred to as the MRZ reaction (MRZR). OBJECTIVE: Re-evaluation of the specificity of MRZR as a marker of MS. METHODS: Structured review of the existing English-, German- and Spanish-language literature on MRZR testing, with evaluation of MRZR in a cohort of 43 unselected patients with MS and other neurological diseases as a proof of principle. RESULTS: A positive MRZ reaction, defined as a positive intrathecal response to at least two of the three viral agents, was found in 78% of MS patients but only in 3% of the controls (p < 0.00001), corresponding to specificity of 97%. Median antibody index values were significantly lower in non-MS patients (measles, p < 0.0001; rubella, p < 0.006; varicella zoster, p < 0.02). The 30 identified original studies on MRZR reported results from 1478 individual MRZR tests. A positive MRZR was reported for 458/724 (63.3%) tests in patients with MS but only for 19/754 (2.5%) tests in control patients (p < 0.000001), corresponding to cumulative specificity of 97.5% (CI 95% 96-98.4), cumulative sensitivity of 63.3% (CI 95% 59.6-66.8) (or 67.4% [CI 95% 63.5-71.1] in the adult MS subgroup), a positive likelihood ratio of 25.1 (CI 95% 16-39.3) and a negative likelihood ratio of 0.38 (CI 95% 0.34-0.41). Of particular note, MRZR was absent in 52/53 (98.1%) patients with neuromyelitis optica or MOG-IgG-positive encephalomyelitis, two important differential diagnoses of MS. CONCLUSION: MRZR is the most specific laboratory marker of MS reported to date. If present, MRZR substantially increases the likelihood of the diagnosis of MS. Prospective and systematic studies on the diagnostic and prognostic impact of MRZR testing are highly warranted. PMID- 28005178 TI - [Vogt-Koyanagi-Harada Syndrome : An unusual case with lacquer crack-like retinal findings]. AB - We report the case of a 35-year-old female patient with bilateral and recurrent panuveitis. Diagnosed with Vogt-Koyanagi-Harada syndrome, the patient was treated with corticosteroids, achieving rapid improvement of functional and morphological findings. After recovery of the exudative retinal detachment, peripapillary lacquer crack-like findings were observed. PMID- 28005177 TI - [New approaches to ocular surface reconstruction beyond the cornea]. AB - BACKGROUND: Reconstruction of the conjunctiva is an essential part of ocular surface reconstruction. Clinically applied and experimentally tested tissue- and stem-cell-based approaches are presented and evaluated. MATERIALS AND METHODS: Current literature and our own results will be presented. RESULTS: Autologous conjunctiva, mucous membrane of the mouth or nose, and amniotic membrane are routinely used for conjunctival reconstruction. Limitations are limited availability, involvement in autoimmune diseases, donor heterogeneity, and degradation in an inflamed environment. Experimentally tested matrices as tissues made from extracellular matrix proteins, synthetic polymers, temperature sensitive culture dishes, and decellularized conjunctiva have been tested in vitro and partly in vivo. To replace conjunctival cells, cells of conjunctiva and mucous membrane of mouth and nose have been evaluated and show progenitor cell properties as well as secretory capacity (goblet cell differentiation). CONCLUSIONS: Although different matrices are available for conjunctival reconstruction there is-due to specific limitations of existing tissues-a need for the development of new therapies for conjunctival replacement. Matrices produced in the laboratory have already been partly investigated in vivo and may thus be clinically applicable in the near future. Adult mucous membrane cells show many properties of conjunctival epithelium after expansion in vitro and thus are a promising cell source for conjunctival tissue engineering. Other stem cells sources require further evaluation. PMID- 28005179 TI - [Retinal buckling without surgery]. PMID- 28005180 TI - Kinetics of carbendazim degradation in a horizontal tubular biofilm reactor. AB - The fungicide carbendazim is an ecotoxic agent affecting aquatic biota. Due to its suspected hormone-disrupting effects, it is considered a "priority hazard substance" by the Water Framework Directive of the European Commission, and its degradation is of major concern. In this work, a horizontal tubular biofilm reactor (HTBR) operating in plug-flow regime was used to study the kinetics of carbendazim removal by an acclimated microbial consortium. The reactor was operated in steady state continuous culture at eight different carbendazim loading rates. The concentrations of the fungicide were determined at several distances of the HTBR. At the loading rates tested, the highest instantaneous removal rates were observed in the first section of the tubular biofilm reactor. No evidence of inhibition of the catabolic activity of the microbial community was found. Strains of the genera Flectobacillus, Klebsiella, Stenotrophomonas, and Flavobacterium were identified in the biofilm; the last three degrade carbendazim in axenic culture. PMID- 28005181 TI - The natural history of thoracolumbar kyphosis in achondroplasia. AB - There are little published data on the natural history and evolution of thoracolumbar kyphotic deformity in achondroplasia. Furthermore, there are few published reports indicating the probability of symptoms and at what kyphotic angle progressive deformity might occur. The lack of knowledge of the fundamental natural history does not allow firm guidelines for the management of this problem. In this respect the role of bracing remains uncertain both in terms of altering the prognosis for further vertebral wedging and overall sagittal profile. This report describes three illustrative cases of thoracolumbar kyphosis (TLK) that occurred in achondroplastic infants. The long-term outcomes are presented to illustrate the diverse clinical behaviour of TLK in this patient group. PMID- 28005182 TI - Aminoglycoside Increases Permeability of Osseous Spiral Laminae of Cochlea by Interrupting MMP-2 and MMP-9 Balance. AB - The spiral ganglion neurons (SGNs) located in the Rosenthal's canal of cochlea are essential target for cochlear implant. Previous studies found that the canaliculi perforantes, small pores on the surface of the osseous spiral lamina (OSL) of the scala tympanic (ST) of cochlea, may provide communication between the cochlear perilymph and SGNs. In this study, we found that chronic treatment of aminoglycosides antibiotics, which is well known to cause sensory cell damage in the cochlea, induced significant damage of bone lining cells on the OSLs and increased the permeability of the Rosenthal's canal. The pores among the bone lining cells became significantly wider after chronic treatment of amikacin (100 mg/kg/day for 3-7 days). Injection of Evans Blue in the ST resulted in significant increase in its migration in the modulus in the amikacin-treated cochlea compared to the control ears, suggesting increased permeability of these passages. Treatment of amikacin with oxytetracycline, an inhibitor of matrix metalloproteases (MMPs), significantly reduced the amount of dye migrated from the ST to the modiolus. These results suggest that amikacin enhanced the permeability between the ST and SGNs by increasing MMPs. Aggregating the permeability of the bone lining cells on the OSLs may benefit gene and stem cell delivery to the SGNs in the cochlea. PMID- 28005185 TI - Mental health issues of refugee children: lessons from Croatia. PMID- 28005183 TI - Altered Gray Matter Volume in Stable Chronic Obstructive Pulmonary Disease with Subclinical Cognitive Impairment: an Exploratory Study. AB - Gray matter volume deficits have been identified in cognitively impaired patients with chronic obstructive pulmonary disease (COPD). However, it remains unknown whether the gray matter volume is altered in COPD patients with subclinical cognitive impairment. To determine whether any gray matter abnormalities are present in these patients, neuropsychological tests and structural MRI data were analyzed from 60 patients with COPD and 60 age-, gender-, education-, and handedness-matched normal controls (NCs). The COPD patients had similar Mini Mental State Examination (MMSE) scores compared with the NCs. However, they had reduced Montreal Cognitive Assessment (MoCA) scores for visuospatial and executive and naming and memory functions (P < 0.001). Voxel-based morphometry (VBM) analysis revealed that the COPD patients had significantly lowered gray matter volumes in several brain regions, including the left precuneus (PrCU), bilateral calcarine (CAL), right superior temporal gyrus/middle temporal gyrus (STG/MTG), bilateral fusiform gyrus (FG), and right inferior parietal lobule (IPL) (P < 0.01, corrected). Importantly, the forced vital capacity (FVC) was found to be associated with the gray matter volume in the calcarine. The present study confirmed that brain structural changes were present in stable COPD patients with subclinical cognitive impairment. These findings may provide new insights into the pathogenesis of COPD. PMID- 28005184 TI - Association of ARMS2/LOC387715 A69S, CFH Y402H, and CFH I62V polymorphisms with retinal angiomatous proliferation compared with typical age-related macular degeneration: a meta-analysis. AB - PURPOSE: To compare the published results of studies on the genotype association of ARMS2/LOC387715 A69S, CFH Y402H, and CFH I62V in cases diagnosed as retinal angiomatous proliferation (RAP) versus neovascular age-related macular degeneration (AMD) or healthy controls. METHODS: Heterogeneity of studies was evaluated using Cochran's Q test and I-square index. To modify the heterogeneity in the variables, we used random effects model. Meta-analysis was performed using STATA. RESULTS: Four studies were included with 1076 neovascular AMD patients, 222 RAP cases, and 2276 control subjects. Pooled overall odds ratios for RAP/AMD were 1.15 (95% CI 0.60-2.18) for GT versus GG, 3.52 (95% CI 1.25-9.91) for TT versus GG ARMS2, 0.98 (95% CI 0.22-4.29) for GA versus AA, 1.00 (95% CI 0.25 4.02) for GG versus AA CFHI62V, 0.57 (95% CI 0.35-0.93) for CT versus TT CFH Y402H, and 0.40 (95% CI 0.22-0.74) for CC versus TT CFH Y402H. Regression analysis showed that ARMS2 TT genotype has a statistically significant effect on RAP versus AMD compared to CFH genotypes (P < 0.001). CONCLUSION: This meta analysis disclosed a stronger effect of ARMS2 genotypes in RAP cases compared with CFH Y402H and I62V genotypes. PMID- 28005186 TI - Reengineering of the feedback-inhibition enzyme N-acetyl-L-glutamate kinase to enhance L-arginine production in Corynebacterium crenatum. AB - N-acetyl-L-glutamate kinase (NAGK) catalyzes the second step of L-arginine biosynthesis and is inhibited by L-arginine in Corynebacterium crenatum. To ascertain the basis for the arginine sensitivity of CcNAGK, residue E19 which located at the entrance of the Arginine-ring was subjected to site-saturated mutagenesis and we successfully illustrated the inhibition-resistant mechanism. Typically, the E19Y mutant displayed the greatest deregulation of L-arginine feedback inhibition. An equally important strategy is to improve the catalytic activity and thermostability of CcNAGK. For further strain improvement, we used site-directed mutagenesis to identify mutations that improve CcNAGK. Results identified variants I74V, F91H and K234T display higher specific activity and thermostability. The L-arginine yield and productivity of the recombinant strain C. crenatum SYPA-EH3 (which possesses a combination of all four mutant sites, E19Y/I74V/F91H/K234T) reached 61.2 and 0.638 g/L/h, respectively, after 96 h in 5 L bioreactor fermentation, an increase of approximately 41.8% compared with the initial strain. PMID- 28005187 TI - Improved pestalotiollide B production by deleting competing polyketide synthase genes in Pestalotiopsis microspora. AB - Pestalotiollide B, an analog of dibenzodioxocinones which are inhibitors of cholesterol ester transfer proteins, is produced by Pestalotiopsis microspora NK17. To increase the production of pestalotiollide B, we attempted to eliminate competing polyketide products by deleting the genes responsible for their biosynthesis. We successfully deleted 41 out of 48 putative polyketide synthases (PKSs) in the genome of NK17. Nine of the 41 PKS deleted strains had significant increased production of pestalotiollide B (P < 0.05). For instance, deletion of pks35, led to an increase of pestalotiollide B by 887%. We inferred that these nine PKSs possibly lead to branch pathways that compete for precursors with pestalotiollide B, or that convert the product. Deletion of some other PKS genes such as pks8 led to a significant decrease of pestalotiollide B, suggesting they are responsible for its biosynthesis. Our data demonstrated that improvement of pestalotiollide B production can be achieved by eliminating competing polyketides. PMID- 28005188 TI - Expanding the plant non-coding RNA world. PMID- 28005189 TI - Cardiovascular profile in postural orthostatic tachycardia syndrome and Ehlers Danlos syndrome type III. AB - The cardiovascular profile of postural orthostatic tachycardia syndrome + Ehlers Danlos syndrome hypermobility type (POTS + EDSIII) has not been described, despite suggestions that it plays a role in orthostatic intolerance. We studied nine individuals diagnosed with POTS + EDSIII and found that the arterial stiffness and cardiac profiles of patients with POTS + EDSIII were comparable to those of age- and sex-matched controls, suggesting an alternate explanation for orthostatic intolerance. PMID- 28005190 TI - Step Counting: A Review of Measurement Considerations and Health-Related Applications. AB - Step counting has long been used as a method of measuring distance. Starting in the mid-1900s, researchers became interested in using steps per day to quantify ambulatory physical activity. This line of research gained momentum after 1995, with the introduction of reasonably accurate spring-levered pedometers with digital displays. Since 2010, the use of accelerometer-based "activity trackers" by private citizens has skyrocketed. Steps have several advantages as a metric for assessing physical activity: they are intuitive, easy to measure, objective, and they represent a fundamental unit of human ambulatory activity. However, since they measure a human behavior, they have inherent biological variability; this means that measurements must be made over 3-7 days to attain valid and reliable estimates. There are many different kinds of step counters, designed to be worn on various sites on the body; all of these devices have strengths and limitations. In cross-sectional studies, strong associations between steps per day and health variables have been documented. Currently, at least eight prospective, longitudinal studies using accelerometers are being conducted that may help to establish dose-response relationships between steps/day and health outcomes. Longitudinal interventions using step counters have shown that they can help inactive individuals to increase by 2500 steps per day. Step counting is useful for surveillance, and studies have been conducted in a number of countries around the world. Future challenges include the need to establish testing protocols and accuracy standards, and to decide upon the best placement sites. These challenges should be addressed in order to achieve harmonization between studies, and to accurately quantify dose-response relationships. PMID- 28005192 TI - The robotic approach for enucleation of a giant esophageal lipoma. AB - An 87-year-old man, who had been experiencing progressive dysphagia and slight chest discomfort for 12 months, presented for an esophagram with a diagnosis of achalasia. A giant esophageal lipoma (14.5- * 4.5- * 3.5-cm) that caused symptomatic dysphagia and a dilated esophagus was revealed by computed tomography and endoscopic esophageal ultrasound. For such a huge esophageal lipoma in a geriatric patient, we successfully enucleated the mediastinal lesion via a minimally invasive approach using the da Vinci S Surgical System. PMID- 28005191 TI - Central Nervous System Adaptation After Ligamentous Injury: a Summary of Theories, Evidence, and Clinical Interpretation. AB - The array of dysfunction occurring after ligamentous injury is tied to long-term clinical impairments in functional performance, joint stability, and health related quality of life. To appropriately treat individuals, and in an attempt to avoid sequelae such as post-traumatic osteoarthritis, investigators have sought to better establish the etiology of the persistent dysfunction present in patients who have sustained joint ligament injuries to the lower extremities. Recent evidence has suggested that changes within the brain and central nervous system may underlie these functional deficits, with support arising from direct neurophysiologic measures of somatosensory dysfunction, motor system excitability, and plasticity of neural networks. As research begins to utilize these findings to develop targeted interventions to enhance patient outcomes, it is crucial for sports medicine professionals to understand the current body of evidence related to neuroplasticity after ligamentous injury. Therefore, this review provides (1) a comprehensive and succinct overview of the neurophysiologic techniques utilized in assessing central nervous system function after ligamentous injury, (2) a summary of the findings of previous investigations utilizing these techniques, and (3) direction for further application of these techniques in the prevention and rehabilitation of joint injury. PMID- 28005193 TI - TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2P2.1) K+ channels contributes to electrical remodeling during AF with HF, and that TREK-1 gene transfer would provide rhythm control via normalization of atrial effective refractory periods in this AF subset. In patients with chronic AF and HF, atrial TREK-1 mRNA levels were reduced by 82% (left atrium) and 81% (right atrium) compared with sinus rhythm (SR) subjects. Human findings were recapitulated in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. TREK-1 mRNA (-66%) and protein (-61%) was suppressed in AF animals at 14-day follow-up compared with SR controls. Downregulation of repolarizing TREK-1 channels was associated with prolongation of atrial effective refractory periods versus baseline conditions, consistent with prior observations in humans with HF. In a preclinical therapeutic approach, pigs were randomized to either atrial Ad TREK-1 gene therapy or sham treatment. Gene transfer effectively increased TREK-1 protein levels and attenuated atrial effective refractory period prolongation in the porcine AF model. Ad-TREK-1 increased the SR prevalence to 62% during follow up in AF animals, compared to 35% in the untreated AF group. In conclusion, TREK 1 downregulation and rhythm control by Ad-TREK-1 transfer suggest mechanistic and potential therapeutic significance of TREK-1 channels in a subgroup of AF patients with HF and prolonged atrial effective refractory periods. Functional correction of ionic remodeling through TREK-1 gene therapy represents a novel paradigm to optimize and specify AF management. PMID- 28005194 TI - Dapsone 7.5% Gel: A Review in Acne Vulgaris. AB - Dapsone 7.5% gel (Aczone(r)) is indicated for the once-daily topical treatment of acne vulgaris in patients aged >=12 years. Dapsone is a sulfone antibacterial with anti-inflammatory actions, which are thought to be largely responsible for its efficacy in treating acne vulgaris. In two phase III trials of 12 weeks' duration in patients aged >=12 years with moderate acne vulgaris, once-daily dapsone 7.5% gel reduced acne severity (as per the Global Acne Assessment Score) and lesion counts versus vehicle. The benefits of dapsone 7.5% gel over vehicle were seen as early as week 2 for inflammatory lesion counts, and from week 4 or 8 for other outcomes. Dapsone 7.5% gel was well tolerated, with a low incidence of treatment-related adverse events, with the majority of adverse events being administration-site related and mild or moderate in severity. Thus, dapsone 7.5% gel is an effective and well tolerated option for the topical treatment of acne vulgaris in patients aged >=12 years, with the convenience of once-daily application. PMID- 28005196 TI - Pausing to reflect in a high-volume clinical milieu. PMID- 28005195 TI - Incidence of hepatitis C in HIV positive and negative men who have sex with men 2000-2016: a systematic review and meta-analysis. AB - BACKGROUND: There is a need for systematic reviews and meta-analyses to synthesize the epidemiology, and the riskfactors for hepatitis C virus (HCV) among HIV-coinfected and HIV negative men who have sex with men (MSM). METHODS: A meta-analysis of 28 studies was carried out by pooling HCV incidence data of HIV coinfected and HIV negative MSM. Differences in incidence outcome depending on the prospective or retrospective nature of the individual studies were investigated. RESULTS: The pooled incidence of HCV in MSM was 6.3 per 1000 person years (95% CI 5.0-7.5). The overall estimated incidence was 19-fold higher in HIV positive compared to HIV negative MSM living in resource-rich countries. This result was confirmed when the analysis was restricted to high-quality studies. Factors associated with an increased risk for incident HCV included behavioural factors (sexual risk behaviour and recreational drug use) as well as biological characteristics (HIV coinfection and a recent history of syphilis). CONCLUSION: In conclusion, incident HCV predominantly affects HIV positive MSM. The incidence rate varied largely between studies, factors such as study design might play an important role. PMID- 28005197 TI - SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement. AB - Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3. PMID- 28005210 TI - AKT capture by feline leukemia virus. AB - Oncogene-containing retroviruses are generated by recombination events between viral and cellular sequences, a phenomenon called "oncogene capture". The captured cellular genes, referred to as "v-onc" genes, then acquire new oncogenic properties. We report a novel feline leukemia virus (FeLV), designated "FeLV AKT", that has captured feline c-AKT1 in feline lymphoma. FeLV-AKT contains a gag AKT fusion gene that encodes the myristoylated Gag matrix protein and the kinase domain of feline c-AKT1, but not its pleckstrin homology domain. Therefore, it differs structurally from the v-Akt gene of murine retrovirus AKT8. AKT may be involved in the mechanisms underlying malignant diseases in cats. PMID- 28005209 TI - The effect of consolidation chemotherapy after concurrent chemoradiotherapy on the survival of patients with locally advanced non-small cell lung cancer: a meta analysis. AB - Whether consolidation chemotherapy (CCT) after chemoradiotherapy (CRT) helps in the treatment of locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. The aim of this meta-analysis was to evaluate the impact of CCT on overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities in patients with inoperable LA-NSCLC. PubMed, Embase, The Cochrane Library, WanFang, VIP, and CNKI were searched to identify any relevant publications. After screening the literature and completing quality assessment and data extraction, the meta-analysis was performed using RevMan5.3 software. Ultimately, 5 eligible studies with a total of 1036 patients were selected for the present meta-analysis. The results of the analysis indicated that treatment of LA-NSCLC patients with CRT followed by CCT improved OS (pooled HR 0.85; 95% CI 0.73-0.99; P = 0.03), but did not improve PFS (pooled HR 0.78; 95% CI 0.60-1.02; P = 0.07) and ORR (P = 0.26). Although it could increase the risk of grade >=3 infection (P = 0.04), it may not increase the risk of grade >=3 radiation pneumonitis (P = 0.09) during the CCT period. CCT after concurrent CRT may provide additional benefits in the treatment of LA-NSCLC. Although this therapeutic strategy did not prolong PFS, further assessment is warranted. PMID- 28005211 TI - Restricted replication of viral hemorrhagic septicemia virus (VHSV) in a birnavirus-carrier cell culture. AB - Viral hemorrhagic septicemia virus (VHSV) and infectious pancreatic necrosis virus (IPNV) are economically important pathogens of the salmonid aquaculture industry. In previous work we demonstrated that a cell line persistently infected with IPNV (EPCIPNV) exhibited antiviral activity against superinfection with the heterologous virus VHSV. This work extends our study by analyzing the replication of VHSV in the IPNV-persistently infected cells. At early and late stages of infection VHSV RNA synthesis, as well as VHSV-induced syncytia formation, were examined in EPCIPNV cultures. During the course of VHSV infection the accumulation of VHSV RNA is inhibited in EPCIPNV cells. Typical VHSV-induced membrane fusion at the late stages of infection is also absent in the IPNV carrier cultures. VHSV binding and fusion to EPCIPNV cells did not appear to be impaired, but a potent inhibitory effect on VHSV RNA synthesis is exerted at early times of infection in the IPNV carrier culture. In conclusion, the EPCIPNV cells are considered to be a useful system to study viral interference as well to analyze the mechanisms underlying the phenomenon of superinfection exclusion. PMID- 28005212 TI - Genetic characterization of a second novel picornavirus from an amphibian host, smooth newt (Lissotriton vulgaris). AB - In this study, a novel picornavirus was identified in faecal samples from smooth newts (Lissotriton vulgaris). The complete genome of picornavirus strain newt/II 5-Pilis/2014/HUN (KX463670) is 7755 nt long with type-IV IRES and has 39.6% aa sequence identity in the protein P1 to the corresponding protein of bat picornavirus (KJ641686, unassigned) and 42.7% and 53.5% aa sequence identity in the 2C and 3CD protein, respectively, to oscivirus (GU182410, genus Oscivirus). Interestingly, the L-protein of newt/II-5-Pilis/2014/HUN has conserved aa motifs that are similar to those found in phosphatase-1 catalytic (PP1C) subunit binding region (pfam10488) proteins. This second amphibian-origin picornavirus could represent a novel species and could be a founding member of a potential novel picornavirus genus. PMID- 28005213 TI - Impact of Veterinary Pharmaceuticals on the Agricultural Environment: A Re inspection. AB - The use of veterinary pharmaceuticals (VPs) is a result of growing animal production. Manure, a great crop fertilizer, contains a significant amount of VPs. The investigation of VPs in manure is prevalent, because of the potential risk for environmental organisms, as well as human health. A re-evaluation of the impact of veterinary pharmaceuticals on the agricultural environment is needed, even though several publications appear every year. The aim of this review was to collate the data from fields investigated for the presence of VPs as an inevitable component of manure. Data on VP concentrations in manure, soils, groundwater and plants were collected from the literature. All of this was connected with biotic and abiotic degradation, leaching and plant uptake. The data showed that the sorption of VPs into soil particles is a process which decreases the negative impact of VPs on the microbial community, the pollution of groundwater, and plant uptake. What was evident was that most of the data came from experiments conducted under conditions different from those in the environment, resulting in an overestimation of data (especially in the case of leaching). The general conclusion is that the application of manure on crop fields leads to a negligible risk for plants, bacteria, and finally humans, but in future every group of compounds needs to be investigated separately, because of the high divergence of properties. PMID- 28005214 TI - Aluminium Toxicity to Plants as Influenced by the Properties of the Root Growth Environment Affected by Other Co-Stressors: A Review. AB - Aluminium toxicity to crops depends on the acidity of the soil and specific plant resistance. However, it is also strongly affected by other environmental factors that have to be considered to properly evaluate the resultant effects on plants. Observed weather perturbations and predicted climate changes will increase the probability of co-occurrence of aluminium toxicity and other abiotic stresses.In this review the mechanisms of plant-aluminium interactions are shown to be influenced by soil mineral nutrients, heavy metals, organic matter, oxidative stress and drought. Described effects of aluminium toxicity include: root growth inhibition, reduction in the uptake of mineral nutrients resulting from the inhibition of transport processes through ion channels; epigenetic changes to DNA resulting in gene silencing. Complex processes occurring in the rhizosphere are highlighted, including the role of soil organic matter and aluminium detoxification by mucilage.There is a considerable research gap in the understanding of root growth in the soil environment in the presence of toxic aluminium concentrations as affected by interactions with abiotic stressors. This knowledge is important for the selection of feasible methods aimed at the reduction of negative consequences of crop production in acidic soils affected by adverse growth environment. PMID- 28005215 TI - ARSENIC: A Review on Exposure Pathways, Accumulation, Mobility and Transmission into the Human Food Chain. AB - This review deals with exposure pathways of arsenic (As), as well as its transfer and uptake processes from its source to the human body. It is proven fact that uptake of inorganic As for a long period can lead to chronic As poisoning and a variety of adverse health effects such as skin, lung and bladder cancer, in addition to cardiovascular diseases, diabetes and gastrointestinal symptoms. As exposure occurs primarily from consumption of potable water containing high amounts of inorganic As and also from consumption of crops cultivated in As contaminated agricultural fields-either naturally or anthropogenically through contaminated air or pesticides-or irrigated with As containing water. In this review, light is shed on the transfer mechanism of As through the food chain and the parameters that enhance mobility of As in the environment. Amounts of As accumulation in plants and the transfer mechanisms are also quite different. These differences in As accumulation, such as in leaves, stems, fruits and roots, are discussed in detail. Moreover, presence of As in some vegetables consumed is given by investigating recent research articles that deal with As concentrations, especially in edible parts. Some comparative data are also presented, concerning the level of concentration of As in rice during washing, cooking and processing stages. PMID- 28005216 TI - Is there a difference between child self-ratings and parent proxy-ratings of the quality of life of children with a diagnosis of attention-deficit hyperactivity disorder (ADHD)? A systematic review of the literature. AB - There are contemporary indicators that parent proxy-ratings and child self ratings of a child's quality of life (QoL) are not interchangeable. This review examines dual informant studies to assess parent-child agreement on the QoL of children with attention-deficit/hyperactivity disorder. A systematic search of four major databases (PsycINFO, MEDLINE, EMBASE and Cochrane databases) was completed, and related peer-reviewed journals were hand-searched. Studies which reported quantitative QoL ratings for matched parent and child dyads were screened in accordance with relevant inclusion and exclusion criteria. Key findings were extracted from thirteen relevant studies, which were rated for conformity to the recommendations of an adapted version of the STROBE statement guidelines for observational studies. In the majority of studies reviewed, children rated their QoL more highly than their parents. There was some evidence for greater agreement on the physical health domain than psychosocial domains. PMID- 28005217 TI - Streptomyces gamaensis sp. nov., a novel actinomycete with antifungal activity isolated from soil in Gama, Chad. AB - During an investigation exploring potential sources of novel species and natural products, a novel actinomycete with antifungal activity, designated strain NEAU Gz11T, was isolated from a soil sample, which was collected from Gama, Chad. The isolate was found to have morphological and chemotaxonomic characteristics typical of members of the genus Streptomyces. 16S rRNA gene sequence similarity studies showed that strain NEAU-Gz11T belongs to the genus Streptomyces with high sequence similarity to Streptomyces hiroshimensis JCM 4098T (98.0 %). Similarities to other type strains of the genus Streptomyces were lower than 98.0 %. However, the physiological and biochemical characteristics and low levels of DNA-DNA relatedness could differentiate the isolate genotypically and phenotypically from S. hiroshimensis JCM 4098T. Therefore, the strain is concluded to represent a novel species of the genus Streptomyces, for which the name Streptomyces gamaensis sp. nov. is proposed. The type strain is NEAU-Gz11T (=CGMCC 4.7304T=DSM 101531T). PMID- 28005218 TI - Impact of surgical pulmonary valve replacement on ventricular mechanics in children with repaired tetralogy of Fallot. AB - Impaired ventricular myocardial mechanics are observed in patients with repaired tetralogy of Fallot (rTOF). Effects of pulmonary valve replacement (PVR) on ventricular remodeling are controversial. The objective was to assess the impact of surgical PVR on ventricular mechanics in pediatric patients after rTOF. Speckle-tracking analysis was performed in 50 rTOF children, aged 12.6 +/- 3.3 years, pre-operatively and 14.5 +/- 2.2 months post-PVR. Early post-operative studies 2.2 +/- 0.6 months post-PVR were performed in 28 patients. Cardiac magnetic resonance (CMR) pre- and post-PVR was collected. Mid-term post-PVR right ventricular (RV) longitudinal strain increased above pre-operative strain (-19.2 +/- 2.7 to -22.0 +/- 3.0%, p < 0.001) with increases observed in individual RV segments. Left ventricular (LV) strain did not differ at medium-term follow-up. LV and RV longitudinal strain was reduced early post-operatively, followed by recovery of biventricular systolic strain by mid-term follow-up. CMR RV end diastolic indexed volumes correlated with RV strain pre-operatively (r = 0.432, p = 0.005) and at mid-term follow-up (r = 0.532, p = 0.001). Volume-loaded RVs had reduced early RV basal longitudinal strain compared to pressure-loading conditions. Reversed basal counterclockwise rotation was associated with lower mid-term global LV and basal RV strain compared to patients with normal rotation. An increase in mid-term global and regional RV strain beyond pre-operative values suggests positive RV remodeling and adaptation occurs in children post-PVR. Patients with larger pre-operative RV volumes had lower RV strain post operatively. The impact of LV rotation on RV mechanics highlights the presence of ventriculo-ventricular interactions. These findings have important clinical implications in pediatric rTOF patients towards identifying pre-operative factors that predict RV post-operative remodeling. PMID- 28005221 TI - Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3beta Signaling Pathway in 6-OHDA-Induced Parkinson's Disease Mice. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder and characterized by motor system disorders resulting in loss of dopaminergic (DA) neurons. CXC195, a novel tetramethylpyrazine derivative, has been shown strongest neuroprotective effects due to its anti-apoptotic activity. However, whether CXC195 protects against DA neuronal damage in PD and the mechanisms underlying its beneficial effects are unknown. The purpose of our study was to investigate the potential neuroprotective role of CXC195 and to elucidate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. CXC195 administration improved DA neurodegeneration in PD mice induced by 6-OHDA. Our further findings confirmed treatment of CXC195 at the dose of 10 mg/kg significantly inhibited the apoptosis by decreasing the level of cleaved caspase 3 and Bax, and increasing the level of Bcl-2 in 6-OHDA-lesioned mice. Meanwhile, 6-OHDA also decreased the amount of phosphorylated Akt while increased GSK-3beta activity (the amount of phosphorylated GSK-3beta at Ser9 was decreased) which was prevented by CXC195. Wortmannin, a specific PI3K inhibitor, dramatically abolished the changes induced by CXC195. Our study firstly demonstrated that CXC195 protected against DA neurodegeneration in 6-OHDA-induced PD model by its anti-apoptotic properties and PI3K/Akt/GSK3beta signaling pathway was involved in it. PMID- 28005222 TI - Effects of Nerve Growth Factor and Basic Fibroblast Growth Factor Promote Human Dental Pulp Stem Cells to Neural Differentiation. AB - Dental pulp stem cells (DPSCs) were the most widely used seed cells in the field of neural regeneration and bone tissue engineering, due to their easily isolation, lack of ethical controversy, low immunogenicity and low rates of transplantation rejection. The purpose of this study was to investigate the role of basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) on neural differentiation of DPSCs in vitro. DPSCs were cultured in neural differentiation medium containing NGF and bFGF alone or combination for 7 days. Then neural genes and protein markers were analyzed using western blot and RT-PCR. Our study revealed that bFGF and NGF increased neural differentiation of DPSCs synergistically, compared with bFGF and NGF alone. The levels of Nestin, MAP-2, betaIII-tubulin and GFAP were the most highest in the DPSCs + bFGF + NGF group. Our results suggested that bFGF and NGF signifiantly up-regulated the levels of Sirt1. After treatment with Sirt1 inhibitor, western blot, RT-PCR and immunofluorescence staining showed that neural genes and protein markers had markedly decreased. Additionally, the ERK and AKT signaling pathway played a key role in the neural differentiation of DPSCs stimulated with bFGF + NGF. These results suggested that manipulation of the ERK and AKT signaling pathway may be associated with the differentiation of bFGF and NGF treated DPSCs. Our date provided theoretical basis for DPSCs to treat neurological diseases and repair neuronal damage. PMID- 28005223 TI - Metastatic breast cancer cells adhere strongly on varying stiffness substrates, initially without adjusting their morphology. AB - We show that metastatic breast cancer cells are quantitatively identifiable from benign cells during adherence onto soft, elastic gels. We identify differences in time-dependent morphology and strength of adherence of single breast cells that are likely related to their malignancy and metastatic potential (MP). Specifically, we compare high and low MP breast cancer cells with benign cells as a control on collagen-coated, polyacrylamide gels with Young's modulus in the physiological range of 2.4-10.6 kPa. We observe that the evaluated metastatic breast cancer cells remain rounded, with small contact area, up to 6.5 h following seeding. In contrast, the benign cells spread and become more elongated on stiffer gels. We identify measurable differences in the two-dimensional, lateral, traction forces exerted by the cells, where the rounded, metastatic cells apply significantly larger, traction forces, as compared to the benign cells, on gels stiffer than 2.4 kPa. The metastatic cell lines exhibited gel stiffness-dependent differences in traction forces, strain energies, and morphologies during the initial stages of adhesion, which may relate to their MP or invasiveness. PMID- 28005224 TI - Effect of pay-for-performance on cervical cancer screening participation in France. AB - Pay-for-performance (P4P) has been increasingly used across different healthcare settings to incentivize the provision of targeted services. In this study, we investigated the effect of a nationwide P4P scheme for general practitioners implemented in 2012 in France, on cervical cancer screening practices. Using data from a nationally representative permanent sample of health insurance beneficiaries, we analyzed smear test use of eligible women for the years 2006 2014. Our longitudinal sample was an unbalanced panel comprising 180,167 women eligible from 1 to 9 years each. We took into account that during our study period some women were exposed to another incentive for screening participation: the implementation in 2010 of organized screening (OS) in a limited number of areas. To evaluate the effect of P4P, we defined three different measures of smear utilization. For each measure, we specified binary panel-data models to estimate annual probabilities and to compare each estimate to the 2011 baseline level. To explore the combined effect of P4P and OS in areas exposed to both incentives, we computed interaction terms between year dummies and area of residence. We found that P4P had a modest positive effect on recommended screening participation. This effect is likely to be transient as annual smear use, both for the whole sample and among women overdue for screening, increased only in 2013 and decreased again in 2014. The combined effect of P4P and OS on screening participation was not cumulative during the first years of coexistence. PMID- 28005225 TI - Improved Pharmacokinetics with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method: A Randomized Pharmacokinetic Study in Patients with Severe Hemophilia A. AB - BACKGROUND: BAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) for the treatment of hemophilia A. OBJECTIVE: The aim of this study was to compare the pharmacokinetic (PK) profile of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) PATIENTS/METHODS: In this phase I, open-label, crossover study, men aged 18-65 years with severe hemophilia A and >=150 exposure days to FVIII were randomized to receive a single intravenous infusion of 50 IU/kg BAY 81-8973 or rAHF-PFM, followed by crossover to a single infusion of the other treatment. FVIII levels were measured in plasma over 48 h using one-stage and chromogenic assays. PK parameters, including area under the curve from time zero to the last data point (AUClast; primary outcome) and half-life (t 1/2) were calculated. A population PK model was developed to simulate various treatment scenarios. RESULTS: Eighteen patients were randomized and analyzed. Using both assays, geometric mean (coefficient of variation [%CV]) AUClast was significantly higher, and t 1/2 was significantly longer, for BAY 81-8973 versus rAHF-PFM (one-stage, AUClast: 1660 IU.h/dL [29.4] vs. 1310 IU.h/dL [29.0], p < 0.0001; one-stage, t 1/2: 14.5 [25.7] vs. 11.7 h [27.3], p < 0.0001). Simulations showed that median time to 1 IU/dL was approximately 27% longer for BAY 81-8973 versus rAHF-PFM over doses of 25-50 IU/kg; plasma levels >1 IU/dL could be maintained with 14.4 IU/kg BAY 81-8973 or 39.1 IU/kg rAHF-PFM 3*/week. CONCLUSIONS: BAY 81-8973 showed a superior PK profile versus rAHF-PFM. The same FVIII trough threshold level could be achieved with lower doses of BAY 81-8973 versus rAHF-PFM. ClinicalTrials.gov: NCT02483208. PMID- 28005226 TI - Serum n-3 Tetracosapentaenoic Acid and Tetracosahexaenoic Acid Increase Following Higher Dietary alpha-Linolenic Acid but not Docosahexaenoic Acid. AB - n-3 Tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n 3, THA) are believed to be important intermediates to docosahexaenoic acid (DHA, 22:6n-3) synthesis. The purpose of this study is to report for the first time serum concentrations of TPAn-3 and THA and their response to changing dietary alpha-linolenic acid (18:3n-3, ALA) and DHA. The responses will then be used in an attempt to predict the location of these fatty acids in relation to DHA in the biosynthetic pathway. Male Long Evans rats (n = 6 per group) were fed either a low (0.1% of total fatty acids), medium (3%) or high (10%) ALA diet with no added DHA, or a low (0%), medium (0.2%) or high (2%) DHA diet with a background of 2% ALA for 8 weeks post-weaning. Serum n-3 and n-6 polyunsaturated fatty acid (PUFA) concentrations (nmol/mL +/- SEM) were determined by gas chromatography-mass spectrometry. Serum THA increases from low (0.3 +/- 0.1) to medium (5.8 +/- 0.7) but not from medium to high (4.6 +/- 0.9) dietary ALA, while serum TPAn-3 increases with increasing dietary ALA from 0.09 +/- 0.04 to 0.70 +/- 0.09 to 1.23 +/- 0.14 nmol/mL. Following DHA feeding, neither TPAn-3 or THA change across all dietary DHA intake levels. Serum TPAn-3 demonstrates a similar response to dietary DHA. In conclusion, this is the first study to demonstrate that increases in dietary ALA but not DHA increase serum TPAn-3 and THA in rats, suggesting that both fatty acids are precursors to DHA in the biosynthetic pathway. PMID- 28005227 TI - In planta production and characterization of a hyperthermostable GH10 xylanase in transgenic sugarcane. AB - Sugarcane (Saccharum sp. hybrids) is one of the most efficient and sustainable feedstocks for commercial production of fuel ethanol. Recent efforts focus on the integration of first and second generation bioethanol conversion technologies for sugarcane to increase biofuel yields. This integrated process will utilize both the cell wall bound sugars of the abundant lignocellulosic sugarcane residues in addition to the sucrose from stem internodes. Enzymatic hydrolysis of lignocellulosic biomass into its component sugars requires significant amounts of cell wall degrading enzymes. In planta production of xylanases has the potential to reduce costs associated with enzymatic hydrolysis but has been reported to compromise plant growth and development. To address this problem, we expressed a hyperthermostable GH10 xylanase, xyl10B in transgenic sugarcane which displays optimal catalytic activity at 105 degrees C and only residual catalytic activity at temperatures below 70 degrees C. Transgene integration and expression in sugarcane were confirmed by Southern blot, RT-PCR, ELISA and western blot following biolistic co-transfer of minimal expression cassettes of xyl10B and the selectable neomycin phosphotransferase II. Xylanase activity was detected in 17 transgenic lines with a fluorogenic xylanase activity assay. Up to 1.2% of the total soluble protein fraction of vegetative progenies with integration of chloroplast targeted expression represented the recombinant Xyl10B protein. Xyl10B activity was stable in vegetative progenies. Tissues retained 75% of the xylanase activity after drying of leaves at 35 degrees C and a 2 month storage period. Transgenic sugarcane plants producing Xyl10B did not differ from non transgenic sugarcane in growth and development under greenhouse conditions. Sugarcane xylan and bagasse were used as substrate for enzymatic hydrolysis with the in planta produced Xyl10B. TLC and HPLC analysis of hydrolysis products confirmed the superior catalytic activity and stability of the in planta produced Xyl10B with xylobiose as a prominent degradation product. These findings will contribute to advancing consolidated processing of lignocellulosic sugarcane biomass. PMID- 28005228 TI - Patterns of Dating Violence Victimization and Perpetration among Latino Youth. AB - Theory and research suggest that there may be significant heterogeneity in the development, manifestation, and consequences of adolescent dating violence that is not yet well understood. The current study contributed to our understanding of this heterogeneity by identifying distinct patterns of involvement in psychological, physical, and sexual dating violence victimization and perpetration in a sample of Latino youth (n = 201; M = 13.87 years; 42% male), a group that is understudied, growing, and at high risk for involvement in dating violence. Among both boys and girls, latent class analyses identified a three class solution wherein the largest class demonstrated a low probability of involvement in dating violence across all indices ("uninvolved"; 56% of boys, 64% of girls) and the smallest class demonstrated high probability of involvement in all forms of dating violence except for sexual perpetration among girls and physical perpetration among boys ("multiform aggressive victims"; 10% of boys, 11% of girls). A third class of "psychologically aggressive victims" was identified for which there was a high probability of engaging and experiencing psychological dating violence, but low likelihood of involvement in physical or sexual dating violence (34% of boys, 24% of girls). Cultural (parent acculturation, acculturation conflict), family (conflict and cohesion) and individual (normative beliefs, conflict resolution skills, self-control) risk and protective factors were associated with class membership. Membership in the multiform vs. the uninvolved class was concurrently associated with emotional distress among girls and predicted emotional distress longitudinally among boys. The results contribute to understanding heterogeneity in patterns of involvement in dating violence among Latino youth that may reflect distinct etiological processes. PMID- 28005231 TI - Life-long tailoring of management for patients with hypertrophic cardiomyopathy : Awareness and decision-making in changing scenarios. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, characterised by complex pathophysiology and extensive genetic and clinical heterogeneity. In most patients, HCM is caused by mutations in cardiac sarcomere protein genes and inherited as an autosomal dominant trait. The clinical phenotype ranges from severe presentations at a young age to lack of left ventricular hypertrophy in genotype-positive individuals. No preventative treatment is available as the sequence and causality of the pathomechanisms that initiate and exacerbate HCM are unknown. Sudden cardiac death and end-stage heart failure are devastating expressions of this disease. Contemporary management including surgical myectomy and implantable cardiac defibrillators has shown significant impact on long-term prognosis. However, timely recognition of specific scenarios - including transition to the end-stage phase - may be challenging due to limited awareness of the progression patterns of HCM. This in turn may lead to missed therapeutic opportunities. To illustrate these difficulties, we describe two HCM patients who progressed from the typical hyperdynamic stage of asymmetric septal thickening to end-stage heart failure with severely reduced ejection fraction. We highlight the different stages of this complex inherited cardiomyopathy based on the clinical staging proposed by Olivotto and colleagues. In this way, we aim to provide a practical guide for clinicians and hope to increase awareness for this common form of cardiac disease. PMID- 28005230 TI - Comparison of free-hand transperineal mpMRI/TRUS fusion-guided biopsy with transperineal 12-core systematic biopsy for the diagnosis of prostate cancer: a single-center prospective study in China. AB - OBJECTIVES: To prospectively compare biopsy outcomes between free-hand transperineal mpMRI/TRUS fusion targeted biopsy (TB) and transperineal systematic biopsy (SB) in patients with first prostate biopsy. PATIENTS AND METHODS: In all, 224 consecutive patients with the suspicion of PCa were investigated. All patients were evaluated by 3.0-T mpMRI applying the ESUR criteria. All patients underwent free-hand transperineal mpMRI/TRUS fusion TB and additionally a transperineal SB. Pathological findings of TB, SB, and step-sectioned RP specimens were analyzed. RESULTS: The median age of the patients was 69 (40-85) years, median PSA level was 10.05 (3.61-78.39) ng/mL, and median prostate volume was 45.5 (22-77) mL. Overall, the PCa detection rate was 50.45% (113/224). TB detected significantly more cancer [44.2% (99/224) vs. 34.8% (78/224); P = 0.001] and clinically significant PCa [75.75% (75/99) vs. 62.82% (49/78); P = 0.005] than SB. For the upgrading of Gleason score, 39.74% (31/78), more clinically significant PCa was detected by using additional TB than by SB alone. Conversely, 5.05% (5/99) more clinically significant PCa was found by SB in addition to that by TB. The location of 96.67% (58/60) and Gleason score of 60% (36/60) of TB proven ITs were correctly identified, as corroborated by RP specimens. The median IT volume was 1.125 (0.21-19.87) ml on MRI and 1.41 (0.13-9.56) ml in RP specimens. CONCLUSIONS: Free-hand transperineal mpMRI/TRUS fusion biopsy was associated with a higher detection rate of clinically significant PCa while taking fewer cores. Moreover, this technique can reliably predict the location, and relatively reliably predict cancer volume and Gleason score of ITs. PMID- 28005233 TI - The Occupational Transition Process to Upper Secondary School, Further Education and/or Work in Sweden: As Described by Young Adults with Asperger Syndrome and Attention Deficit Hyperactivity Disorder. AB - The aim was to describe the occupational transition process to upper secondary school, further education and/or work, and to discover what support influences the process from the perspectives of young adults with Asperger syndrome or attention deficit/hyperactivity disorder. This qualitative study was performed in Sweden and comprised interviews with 15 young adults recruited from community based day centres. Support influencing the process included: occupational transition preparation in compulsory school, practical work experience in a safe environment, and support beyond the workplace. The overall understanding shows that the occupational transition process was a longitudinal one starting as early as in middle school, and continuing until the young adults obtained and were able to remain in employment or further education. PMID- 28005232 TI - HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury. AB - It is widely accepted that human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) plays an important role in HIV-1-induced neural injury and pathogenesis of HIV-1-associated dementia (HAND). Multiple pathways have been proposed for gp120-induced neurotoxicity, amongst is the activation of N-Methyl-D Aspartate receptors (NMDARs). It has been shown that gp120 causes neuronal injury or death and gp120 transgenic mice exhibit neurological similarity to that of HAND, all of which can be blocked or attenuated by NMDAR antagonists. Several lines of evidence indicate the subtype and location of activated NMDARs are key determinants of the nature of NMDAR physiology. To examine the subtype and the location of NMDARs affected by gp120, we studied gp120 on subtype NMDAR-mediated EPSCs in the CA1 region of rat hippocampal slices through "blind" whole-cell patch recordings. Our results showed bath application of gp120 increased both NR2A- and NR2B-mediated EPSCs possibly via a presynaptic mechanism, with much stronger effect on NR2B-mediated EPSCs. In contrast, gp120 failed on enhancing AMPA receptor-mediated EPSCs. Ca2+ imaging studies revealed that gp120 potentiated glutamate-induced increase of intracellular Ca2+ concentration in rat hippocampal neuronal cultures which were blocked by a NMDAR antagonist, but not by an AMPA receptor antagonist, indicating gp120 induces Ca2+ influx through NMDARs. Further investigations demonstrated that gp120 increased the EPSCs mediated by extrasynaptic NR2BRs. Taken together, these results demonstrate that gp120 interacts with both NR2A and NR2B subtypes of NMDARs with a predominant action on the extrasynaptic NR2B, implicating a role NR2B may play in HIV-1 associated neuropathology. PMID- 28005229 TI - Engaging Natural Killer T Cells as 'Universal Helpers' for Vaccination. AB - Conventional vaccine adjuvants enhance peptide-specific T-cell and B-cell responses by modifying peptide stability or uptake or by binding to pattern recognition receptors on antigen-presenting cells (APCs). This article discusses the application of a distinct mechanism of adjuvant activity: the activation of type I, or invariant, natural killer T (iNKT) cells to drive cellular and humoral immune responses. Using a semi-invariant T-cell receptor (TCR), iNKT cells recognize glycolipid antigens presented on cluster of differentiation (CD)-1d molecules. When their ligands are presented in concert with peptides, iNKT cells can provide T-cell help, 'licensing' APCs to augment peptide-specific T-cell and antibody responses. We discuss the potential benefits and limitations of exploiting iNKT cells as 'universal helpers' to enhance vaccine responses for the treatment and prevention of cancer and infectious diseases. PMID- 28005234 TI - The genetic diversity and complete genome analysis of two novel porcine deltacoronavirus isolates in Thailand in 2015. AB - Porcine deltacoronavirus (PDCoV) was identified in intestinal samples collected from piglets with diarrhea in Thailand in 2015. Two Thai PDCoV isolates, P23_15_TT_1115 and P24_15_NT1_1215, were isolated and identified. The full-length genome sequences of the P23_15_TT_1115 and P24_15_NT1_1215 isolates were 25,404 and 25,407 nucleotides in length, respectively, which were relatively shorter than that of US and China PDCoV. The phylogenetic analysis based on the full length genome demonstrated that Thai PDCoV isolates form a new cluster separated from US and China PDCoV but relatively were more closely related to China PDCoV than US isolates. The genetic analyses demonstrated that Thai PDCoVs have 97.0 97.8 and 92.2-94.0% similarities with China PDCoV at nucleotide and amino acid levels, respectively, but share 97.1-97.3 and 92.5-93.0 similarity with US PDCoV at the nucleotide and amino acid levels, respectively. Thai PDCoV possesses two discontinuous deletions of five amino acids in ORF1a/b region. One additional deletion of one amino acid was identified in P23_15_TT_1115. The variation analyses demonstrated that six regions (nt 1317-1436, 2997-3096, 19,737-19,836, 20,277-20,376, 21,177-21,276, and 22,371-22,416) in ORF1a/b and spike genes exhibit high sequence variation between Thai and other PDCoV. The analyses of amino acid changes suggested that they could potentially be from different lineages. PMID- 28005237 TI - Multiple authorship of scientific manuscripts. PMID- 28005235 TI - Examination of the Applicability of the Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire to Patients with Hand Injuries and Diseases Using Rasch Analysis. AB - BACKGROUND: The Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire is the most commonly applied patient-reported outcome measure used to assess disability and functioning in clinical research and practice for patients with injuries and diseases of the upper extremities. The objective of this study was to assess whether the DASH is a valid and reliable questionnaire to measure disability and functioning in patients with hand injuries and diseases using Rasch analysis. METHODS: We performed a psychometric study using data derived from two multicentre studies carried out to develop the International Classification of Functioning, Disability and Health (ICF) Core Sets for Hand Conditions. We analysed the data of 417 patients recruited in a clinical setting and suffering from hand injuries (e.g. finger fracture, flexor tendon injury) or diseases (e.g. carpal tunnel syndrome, rhizarthrosis). We examined whether the DASH fulfilled the assumptions for its use as a measure by applying a partial credit model and testing for differential item functioning for sex and age. RESULTS: Bifactor analysis revealed problems with the underlying latent trait of functioning and disability. Rasch analysis raised further issues, including disordered thresholds for eight items and misfit in nine items. One item showed Differential Item Functioning for sex. CONCLUSION: The study reveals that some DASH items do not fit the underlying trait that the DASH aims to measure. Further studies using Rasch analysis are needed to compare our findings with results of studies involving other target groups (e.g. patients with injuries of the upper arm and shoulder). PMID- 28005238 TI - Comparison between X-rays spectra and their effective energies in small animal CT tomographic imaging and dosimetry. AB - Small animal CT imaging and dosimetry usually rely on X-ray radiation produced by X-ray tubes. These X-rays typically cover a large energy range. In this study, we compared poly-energetic X-ray spectra against estimated equivalent (effective) mono-energetic beams with the same number of simulated photons for small animal CT imaging and dosimetry applications. Two poly-energetic X-ray spectra were generated from a tungsten anode at 50 and 120 kVp. The corresponding effective mono-energetic beams were established as 36 keV for the 50 kVp spectrum and 49.5 keV for the 120 kVp spectrum. To assess imaging applications, we investigated the spatial resolution by a tungsten wire, and the contrast-to-noise ratio in a reference phantom and in a realistic mouse phantom. For dosimetry investigation, we calculated the absorbed dose in a segmented digital mouse atlas in the skin, fat, heart and bone tissues. Differences of 2.1 and 2.6% in spatial resolution were respectively obtained between the 50 and 120 kVp poly-energetic spectra and their respective 36 and 49.5 keV mono-energetic beams. The differences in contrast-to-noise ratio between the poly-energetic 50 kVp spectrum and its corresponding mono-energetic 36 keV beam for air, fat, brain and bone were respectively -2.9, -0.2, 11.2 and -4.8%, and similarly between the 120 kVp and its effective energy 49.5 keV: -11.3, -20.2, -4.2 and -13.5%. Concerning the absorbed dose, for the lower X-ray beam energies, 50 kVp against 36 keV, the poly energetic radiation doses were higher than the mono-energetic doses. Instead, for the higher X-ray beam energies, 120 kVp and 49.5 keV, the absorbed dose to the bones and lungs were higher for the mono-energetic 49.5 keV. The intensity and energy of the X-ray beam spectrum have an impact on both imaging and dosimetry in small animal studies. Simulations with mono-energetic beams should take into account these differences in order to study biological effects or to be compared to experimental data. PMID- 28005240 TI - Complicated pregnancies in inherited distal renal tubular acidosis: importance of acid-base balance. AB - Inherited distal renal tubular acidosis (dRTA) is caused by impaired urinary acid excretion resulting in hyperchloremic metabolic acidosis. Although the glomerular filtration rate (GFR) is usually preserved, and hypertension and overt proteinuria are absent, it has to be considered that patients with dRTA also suffer from chronic kidney disease (CKD) with an increased risk for adverse pregnancy-related outcomes. Typical complications of dRTA include severe hypokalemia leading to cardiac arrhythmias and paralysis, nephrolithiasis and nephrocalcinosis. Several physiologic changes occur in normal pregnancy including alterations in acid-base and electrolyte homeostasis as well as in GFR. However, data on pregnancy in women with inherited dRTA are scarce. We report the course of pregnancy in three women with hereditary dRTA. Complications observed were severe metabolic acidosis, profound hypokalemia aggravated by hyperemesis gravidarum, recurrent urinary tract infection (UTI) and ureteric obstruction leading to renal failure. However, the outcome of all five pregnancies (1 pregnancy each for mothers n. 1 and 2; 3 pregnancies for mother n. 3) was excellent due to timely interventions. Our findings highlight the importance of close nephrologic monitoring of women with inherited dRTA during pregnancy. In addition to routine assessment of creatinine and proteinuria, caregivers should especially focus on acid-base status, plasma potassium and urinary tract infections. Patients should be screened for renal obstruction in the case of typical symptoms, UTI or renal failure. Furthermore, genetic identification of the underlying mutation may (a) support early nephrologic referral during pregnancy and a better management of the affected woman, and (b) help to avoid delayed diagnosis and reduce complications in affected newborns. PMID- 28005239 TI - Combination of cilostazol and probucol protected podocytes from lipopolysaccharide-induced injury by both anti-inflammatory and anti-oxidative mechanisms. AB - Podocytes are essential for maintaining kidney glomerular functions. Injuries to podocyte are closely related to the pathological process of proteinuria. However, a treatment for podocyte injury has still not been established. Cilostazol (CSZ) and probucol (PBC) have been shown to possess renoprotective effects. Therefore, we evaluated these drugs in a lipopolysaccharide (LPS)-induced podocyte injury model. 7-week-old female C57BL/6J mice were fed a normal diet or a diet containing 0.3% CSZ, 0.5% PBC, or both for 10 days. Then, mice were intraperitoneally injected with 13 MUg g-1 body weight LPS. Both CSZ and PBC decreased LPS-induced albuminuria and co-administration was found to be most effective. These treatments ameliorated the upregulation of monocyte chemoattractant protein 1. In cultured podocytes, CSZ suppressed LPS-induced activation of nuclear factor-kappa B (NF-kappaB) and phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). PBC reduced LPS-induced activation of NF kappaB and reactive oxygen species production. Furthermore, PBC decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase4 expression. Our findings suggest that CSZ and PBC are able to inhibit podocyte-injury through different mechanisms, indicating that a combination of these two old drugs is a good treatment option to protect podocytes from injury. PMID- 28005241 TI - Home Environmental Influences on Childhood Obesity in the Latino Population: A Decade Review of Literature. AB - Latinos are the largest and fastest-growing ethnically diverse group in the United States. Latino children are also among the most overweight and obese ethnic groups of children in the United States. Research over the last decade has identified the home environment as a key influence on the diet and physical activity of children. To summarize cross-sectional and longitudinal research that has identified factors within the home environment of Latino families that are associated with childhood obesity and to provide recommendations for future research and intervention development with Latino families. A decade review from 2005 to 2015 was conducted. Studies identifying factors within the home environments of Latino families that were associated with childhood obesity were examined. Five main factors were identified across the literature as home environment factors that are associated with childhood obesity in Latino children. These factors included: parental influences (e.g., parent feeding practices, modeling), screen time, physical activity/sedentary behavior, socioeconomic status/food security and sleep duration. The current review identified several home environment factors that may contribute to the disparities in childhood obesity for Latino children. Results from this review such as, focusing on decreasing controlling parent feeding practices, and increasing parent modeling of healthy behaviors and child sleep duration, can be used in developing culturally-specific interventions for Latino children. PMID- 28005242 TI - Are the EQ-5D-3L and the ICECAP-O responsive among older adults with impaired mobility? Evidence from the Vancouver Falls Prevention Cohort Study. AB - PURPOSE: Preference-based generic measures are gaining increased use in mobility research to assess health-related quality of life and wellbeing. Hence, we examined the responsiveness of these two measures among individuals at risk of mobility impairment among adults aged >=70 years. METHODS: We conducted a 12 month prospective cohort study of community-dwelling older adults (n = 288 to n = 341 depending on analysis) who were seen at the Vancouver Falls Prevention Clinic who had a history of at least one fall in the previous 12 months. We compared the responsiveness of the EuroQol-5 Domain-3 Level (EQ-5D-3L) and the index of capability for older adults (ICECAP-O) by examining changes in these measures over time (i.e., over 6 and 12 months) and by examining whether their changes varied as a function of having experienced 2 or more falls over 6 and 12 months. RESULTS: Only the ICECAP-O showed a significant change over time from baseline through 12 months; however, neither measure showed change that exceeded the standard error of the mean. Both measures were responsive to falls that occurred during the first 6 months of the study (p < .05). These effects appeared to be amplified among individuals identified as having mild cognitive impairment (MCI) at baseline (p < .01). Additionally, the EQ-5D-3L was responsive among fallers who did not have MCI as well as individuals with MCI who did not fall (p < .05). CONCLUSION: This study provides initial evidence suggesting that the EQ-5D-3L is generally more responsive, particularly during the first 6 months of falls tracking among older adults at risk of future mobility impairment. PMID- 28005243 TI - Improving measures of work-related physical functioning. AB - PURPOSE: To expand content of the physical function domain of the Work Disability Functional Assessment Battery (WD-FAB), developed for the US Social Security Administration's (SSA) disability determination process. METHODS: Newly developed questions were administered to 3532 recent SSA applicants for work disability benefits and 2025 US adults. Factor analyses and item response theory (IRT) methods were used to calibrate and link the new items to the existing WD-FAB, and computer-adaptive test simulations were conducted. RESULTS: Factor and IRT analyses supported integration of 44 new items into three existing WD-FAB scales and the addition of a new 11-item scale (Community Mobility). The final physical function domain consisting of: Basic Mobility (56 items), Upper Body Function (34 items), Fine Motor Function (45 items), and Community Mobility (11 items) demonstrated acceptable psychometric properties. CONCLUSIONS: The WD-FAB offers an important tool for enhancement of work disability determination. The FAB could provide relevant information about work-related functioning for initial assessment of claimants; identifying denied applicants who may benefit from interventions to improve work and health outcomes; enhancing periodic review of work disability beneficiaries; and assessing outcomes for policies, programs and services targeting people with work disability. PMID- 28005244 TI - A comparison of children and adolescent's self-report and parental report of the PedsQL among those with and without autism spectrum disorder. AB - PURPOSE: Children and adolescents with autism spectrum disorders (ASD) are understood to experience a reduced quality of life compared to typically developing (TD) peers. The evidence to support this has largely been derived from proxy reports, in turn which have been evaluated by Cronbach's alpha and interrater reliability, neither of which demonstrate unidimensionality of scales, or that raters use the instruments consistently. To redress this, we undertook an evaluation of the Pediatric Quality of Life InventoryTM (PedsQL), a widely used measure of children's quality of life. Three questions were explored: (1). do TD children or adolescents and their parents use the PedsQL differently; (2). do children or adolescents with ASD and their parents use the PedsQL differently, and (3). do children or adolescents with ASD and TD children or adolescents use the PedsQL differently? By using the scales differently, we mean whether respondents endorse items differently contingent by group. METHODS: We recruited 229 children and adolescents with ASD who had an IQ greater than 70, and one of their parents, as well as 74 TD children or adolescents and one of their parents. Children and adolescents with ASD (aged 6-20 years) were recruited from special primary and secondary schools in the Amsterdam region. Children and adolescents were included based on an independent clinical diagnosis established prior to recruitment according to DSM-IV-TR criteria by psychiatrists and/or psychologists, qualified to make the diagnosis. Children or adolescents and parents completed their respective version of the PedsQL. RESULTS: Data were analysed for unidimensionality and for differential item functioning (DIF) across respondent for TD children and adolescents and their parents, for children and adolescents with ASD and their parents, and then last, children and adolescents with ASD were compared to TD children and adolescents for DIF. Following recoding the data, the unidimensional model was found to fit all groups. We found that parents of and TD children and adolescents do not use the PedsQL differently ([Formula: see text] = 64.86, p = ns), consistent with the literature that children and adolescents with ASD and TD children and adolescents use the PedsQL similarly ([Formula: see text] = 92.22, p = ns), though their score levels may differ. However, children and adolescents with ASD and their parents respond to the PedsQL differently ([Formula: see text] = 190.22, p < 0.001) and contingently upon features of the child or adolescent. CONCLUSIONS: We suggest this is due to children or adolescents with ASD being less forthcoming with their parents about their lives. This, however, will require additional research to confirm. Consequently, we conclude that parents of high-functioning children with ASD are unable to act as reliable proxies for their children with ASD. PMID- 28005245 TI - Aspirin/antiplatelet agent use improves disease-free survival and reduces the risk of distant metastases in Stage II and III triple-negative breast cancer patients. AB - PURPOSE: The objective is to define the therapeutic role of antiplatelet agents in a triple-negative breast cancer (TNBC) population. METHODS: We performed retrospective analysis using the UTSW TNBC registry containing data from 222 Stage II-III TNBC patients treated between 1998 and 2016. Univariate analysis and multivariable logistic regression models were constructed to identify factors associated with disease-free survival (DFS), distant metastases rate (DMR), and overall survival outcomes. Antiplatelet drug use was determined by review of electronic medical records. RESULTS: A total of 65 patients used antiplatelet (AP) agents, and 157 patients did not use AP agents. Median follow-up for AP and non-AP groups was 41.3 and 40.9 months, respectively. There was an improvement in the AP group compared with the control group in 5-year DFS (80.4% at 5 years compared with 62.3% in the control group, p = 0.04) and 5-year DMR (8.8 vs. 31.9%, p = 0.007). In multivariate analysis, AP use was found to be significantly associated with improvements in DFS and DMR. CONCLUSIONS: We illustrate that antiplatelet agent use improves DMR and DFS among a stage II and III TNBC population despite our short follow-up evaluation. Longer follow-up evaluation will be required to determine additional outcome advantage for antiplatelet agent use. Our findings support consideration of investigation of antiplatelet therapy as an adjunctive therapy for TNBC at high risk for disease recurrence. PMID- 28005246 TI - An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome. AB - PURPOSE: Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL. PATIENTS AND METHODS: The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERalpha)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices. RESULTS: An AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47-0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48-0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients. CONCLUSIONS: Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence. PMID- 28005247 TI - Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. AB - PURPOSE: The randomized phase III JO21095 trial compared the efficacy and safety of low-dose capecitabine plus docetaxel combination therapy (XT) versus single agent administration of docetaxel in anthracycline-pretreated HER2-negative metastatic breast cancer. METHODS: Patients were randomized to either low-dose XT (capecitabine 825 mg/m2 twice daily, days 1-14; docetaxel 60 mg/m2, day 1 every 3 weeks) or docetaxel (70 mg/m2, day 1 every 3 weeks). The primary objective was to demonstrate superior progression-free survival (PFS) with low-dose XT versus single-agent docetaxel. Overall survival (OS) and safety were secondary endpoints. RESULTS: In total, 162 patients were treated. Median PFS was 10.5 months with low-dose XT and 9.8 months with single-agent docetaxel (hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.40-0.97]; p = 0.03). The OS HR was 0.89 (95% CI 0.52-1.53; p = 0.68). Grade >=3 treatment-related toxicities occurred in 74% of XT-treated patients and 76% of docetaxel-treated patients. The main differences in grade >=3 treatment-related toxicities were hand-foot syndrome (7.3% of XT-treated patients vs 0% receiving docetaxel), fatigue/malaise (2.4 vs 10.0%), and peripheral edema (1.2 vs 7.5%). Dose modifications were required in 100% of low-dose XT and 49% of docetaxel patients. Toxicity-related treatment discontinuations occurred in 18 and 33%, respectively. CONCLUSION: The improved PFS with low-dose XT versus docetaxel alone is consistent with higher-dose XT phase III experience, but the safety profile was more favorable and manageable. PMID- 28005248 TI - Characterizing Architectural Distortion in Mammograms by Linear Saliency. AB - Architectural distortion (AD) is a common cause of false-negatives in mammograms. This lesion usually consists of a central retraction of the connective tissue and a spiculated pattern radiating from it. This pattern is difficult to detect due the complex superposition of breast tissue. This paper presents a novel AD characterization by representing the linear saliency in mammography Regions of Interest (ROI) as a graph composed of nodes corresponding to locations along the ROI boundary and edges with a weight proportional to the line intensity integrals along the path connecting any pair of nodes. A set of eigenvectors from the adjacency matrix is then used to extract discriminant coefficients that represent those nodes with higher salient lines. A dimensionality reduction is further accomplished by selecting the pair of nodes with major contribution for each of the computed eigenvectors. The set of main salient lines is then assembled as a feature vector that inputs a conventional Support Vector Machine (SVM). Experimental results with two benchmark databases, the mini-MIAS and DDSM databases, demonstrate that the proposed linear saliency domain method (LSD) performs well in terms of accuracy. The approach was evaluated with a set of 246 RoI extracted from the DDSM (123 normal tissues and 123 AD) and a set of 38 ROI from the mini-MIAS collections (19 normal tissues and 19 AD) respectively. The classification results showed respectively for both databases an accuracy rate of 89 % and 87 %, a sensitivity rate of 85 % and 95 %, and a specificity rate of 93 % and 84 %. Likewise, the area under curve (A z ) of the Receiver Operating Characteristic (ROC) curve was 0.93 for both databases. PMID- 28005249 TI - Runtime Verification of Pacemaker Functionality Using Hierarchical Fuzzy Colored Petri-nets. AB - Today, implanted medical devices are increasingly used for many patients and in case of diverse health problems. However, several runtime problems and errors are reported by the relevant organizations, even resulting in patient death. One of those devices is the pacemaker. The pacemaker is a device helping the patient to regulate the heartbeat by connecting to the cardiac vessels. This device is directed by its software, so any failure in this software causes a serious malfunction. Therefore, this study aims to a better way to monitor the device's software behavior to decrease the failure risk. Accordingly, we supervise the runtime function and status of the software. The software verification means examining limitations and needs of the system users by the system running software. In this paper, a method to verify the pacemaker software, based on the fuzzy function of the device, is presented. So, the function limitations of the device are identified and presented as fuzzy rules and then the device is verified based on the hierarchical Fuzzy Colored Petri-net (FCPN), which is formed considering the software limits. Regarding the experiences of using: 1) Fuzzy Petri-nets (FPN) to verify insulin pumps, 2) Colored Petri-nets (CPN) to verify the pacemaker and 3) To verify the pacemaker by a software agent with Petri-network based knowledge, which we gained during the previous studies, the runtime behavior of the pacemaker software is examined by HFCPN, in this paper. This is considered a developing step compared to the earlier work. HFCPN in this paper, compared to the FPN and CPN used in our previous studies reduces the complexity. By presenting the Petri-net (PN) in a hierarchical form, the verification runtime, decreased as 90.61% compared to the verification runtime in the earlier work. Since we need an inference engine in the runtime verification, we used the HFCPN to enhance the performance of the inference engine. PMID- 28005250 TI - Gestational Diabetes Testing, Narrative, and Medical Distrust. AB - In this article, we investigate the role of scientific and patient narratives on perceptions of the medical debate around gestational diabetes (GDM) testing. Among medical scientists, we show that the narrative surrounding GDM testing affirms that future research and data will lead to medical consensus. We call this narrative trajectory the "deferred quest." For patients, however, diagnosis and their subsequent discovery that biomedicine does not speak in one voice ruptures their trust in medical authority. This new distrust creates space for patients to develop a Frankian quest narrative where they become the protagonist in their story. Additionally, across these different narratives, we observe how character is constructed and employed to negotiate trust. We conclude that healthcare providers should assess the narrative trajectory adopted by patients after diagnosis. Also, we suggest that providers acknowledge the lack of medical consensus to their patients. This veracity would foster women's sense of trust in their provider as well as allow women to be active interlocutors in a debate that ultimately plays out in their deliberation about their body, pregnancy, and risk. PMID- 28005251 TI - Investigating Trust, Expertise, and Epistemic Injustice in Chronic Pain. AB - Trust is central to the therapeutic relationship, but the epistemic asymmetries between the expert healthcare provider and the patient make the patient, the trustor, vulnerable to the provider, the trustee. The narratives of pain sufferers provide helpful insights into the experience of pain at the juncture of trust, expert knowledge, and the therapeutic relationship. While stories of pain sufferers having their testimonies dismissed are well documented, pain sufferers continue to experience their testimonies as being epistemically downgraded. This kind of epistemic injustice has received limited treatment in bioethics. In this paper, we examine how a climate of distrust in pain management may facilitate what Fricker calls epistemic injustice. We critically interrogate the processes through which pain sufferers are vulnerable to specific kinds of epistemic injustice, such as testimonial injustice. We also examine how healthcare institutions and practices privilege some kinds of evidence and ways of knowing while excluding certain patient testimonies from epistemic consideration. We argue that providers ought to avoid epistemic injustice in pain management by striving toward epistemic humility. Epistemic humility, as a form of epistemic justice, may be the kind disposition required to correct the harmful prejudices that may arise through testimonial exchange in chronic pain management. PMID- 28005253 TI - Diverging Conclusions from the Same Meta-Analysis in Drug Safety: Source of Data (Primary Versus Secondary) Takes a Toll. AB - INTRODUCTION: Meta-analyses of observational studies represent an important tool for assessing efficacy and safety in the pharmacoepidemiologic field. The data from the individual studies are either primary (i.e., collected through interviews or self-administered questionnaires) or secondary (i.e., collected from databases that were established for other purposes). So far, the origin of the data (primary vs. secondary) has not been systematically assessed as a source of heterogeneity in pharmacoepidemiologic meta-analyses. OBJECTIVE: The aim was to assess the impact of considering the source of exposure data as a criterion in sensitivity and subgroup analysis on the conclusions of drug safety meta analyses. METHODS: We selected meta-analyses published between 2013 and 2015 in which the intake of frequently used over-the-counter medicines was either the main exposure or a concomitant treatment and the outcome had short latency and induction periods. We stratified the results by origin of data (primary vs. secondary) and compared the new results to those presented originally in the meta analyses. RESULTS: We used four meta-analyses that fulfilled our criteria of inclusion. The results were selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: original estimate odds ratio (OR) = 1.71 [95% confidence interval (CI) 1.44-2.04], OR primary data = 1.19 (95% CI 0.90-1.58), OR secondary data = 1.81 (95% CI 1.50-2.17); proton pump inhibitors and cardiac events: original estimate hazard ratio (HR) = 1.35 (95% CI 1.18-1.54), HR primary data = 1.05 (95% CI 0.87-1.26), HR secondary data = 1.43 (95% CI 1.23-1.66); non aspirin non-steroidal anti-inflammatory drugs and myocardial infarction: original estimate risk ratio (RR) = 1.08 (95% CI 0.95-1.22), RR primary data = 0.57 (95% CI 0.34-0.96), RR secondary data = 1.15 (95% CI 1.03-1.28); paracetamol during pregnancy and childhood asthma: original estimate OR = 1.32 (95% CI 1.14-1.52), OR primary data = 1.23 (95% CI 1.06-1.42), OR secondary data = 1.53 (95% CI 1.33 1.75). CONCLUSIONS: The results after stratification are considerably modified. It is crucial to explore the origin of the data, either primary or secondary, as a source of heterogeneity in pharmacoepidemiologic meta-analyses to avoid misleading conclusions. PMID- 28005254 TI - The optomotor response of the praying mantis is driven predominantly by the central visual field. AB - The optomotor response has been widely used to investigate insect sensitivity to contrast and motion. Several studies have revealed the sensitivity of this response to frequency and contrast, but we know less about the spatial integration underlying this response. Specifically, few studies have investigated how the horizontal angular extent of stimuli influences the optomotor response. We presented mantises with moving gratings of varying horizontal extents at three different contrasts in the central or peripheral regions of their visual fields. We assessed the relative effectivity of different regions to elicit the optomotor response and modelled the dependency of the response on the angular extent subtended by stimuli at these different regions. Our results show that the optomotor response is governed by stimuli in the central visual field and not in the periphery. The model also shows that in the central region, the probability of response increases linearly with increase in horizontal extent up to a saturation point. Furthermore, the dependency of the optomotor response on the angular extent of the stimulus is modulated by contrast. We discuss the implications of our results for different modes of stimulus presentation and for models of the underlying mechanisms of motion detection in the mantis. PMID- 28005255 TI - The Roles of Implicit Understanding of Engineering Ethics in Student Teams' Discussion. AB - Following previous work that shows engineering students possess different levels of understanding of ethics-implicit and explicit-this study focuses on how students' implicit understanding of engineering ethics influences their team discussion process, in cases where there is significant divergence between their explicit and implicit understanding. We observed student teams during group discussions of the ethical issues involved in their engineering design projects. Through the micro-scale discourse analysis based on cognitive ethnography, we found two possible ways in which implicit understanding influenced the discussion. In one case, implicit understanding played the role of intuitive ethics-an intuitive judgment followed by reasoning. In the other case, implicit understanding played the role of ethical insight, emotionally guiding the direction of the discussion. In either case, however, implicit understanding did not have a strong influence, and the conclusion of the discussion reflected students' explicit understanding. Because students' implicit understanding represented broader social implication of engineering design in both cases, we suggest to take account of students' relevant implicit understanding in engineering education, to help students become more socially responsible engineers. PMID- 28005256 TI - Risk factors for osteoporosis 2000-2012. PMID- 28005258 TI - Pancreatic Cancer Management and Treatment Landscape Awareness of Gastroenterologists: Results from US Physician Surveys Conducted in 2013 and 2015. AB - INTRODUCTION: In the US, gastroenterologists (GIs) often inform patients of the initial diagnosis of pancreatic cancer. Thus, GIs are frequently the first physicians to provide vital information regarding treatment strategies and options to patients which can have significant impact on subsequent clinical decision-making. Since treatments for pancreatic cancer are rapidly evolving, it may be challenging for GIs to maintain an adequate knowledge base required to provide accurate cursory information or avoid providing inaccurate data to patients at a very sensitive point in time in their care. However, little to no published data are available on the treatment awareness, knowledge, and comfort of GIs in the United States who diagnose pancreatic cancer. METHODS: This study evaluated the self-reported management of pancreatic cancer, including patient discussion, familiarity with treatments, and use of guidelines. A survey was developed and fielded to US academic and community GIs in 2013. In 2015, the survey was redistributed as a follow-up to determine whether familiarity and practice has shifted; two questions were added, all other items remained identical. For the 2013 sample, 432 GIs were contacted and 113 valid responses were collected (26.2). For the 2015 sample, 712 GIs were contacted and 126 valid responses were collected (17.7%). Analysis compared differences between academic and community gastroenterologists and gastroenterologists performing endoscopic ultrasound (EUS) versus those that do not. RESULTS: Self-reported familiarity with pancreatic cancer therapies has not significantly increased from 2013 to 2015, as gastroenterologists report highest familiarity with 5-fluorouracil and gemcitabine. In the 2015 sample, 68% of academic and 58% of community gastroenterologists entered gemcitabine when identifying therapies FDA-approved for treatment of pancreatic cancer. However, 16% of academic and 24% of community gastroenterologists indicated that they were unaware of which therapies are approved, and some indicated therapies that are not FDA-approved for the treatment of pancreatic cancer, such as capecitabine (10%) and paclitaxel (7%). Gastroenterologists in 2015 are significantly more likely than in 2013 to discuss clinical trial enrollment with their patients with metastatic pancreatic cancer (5.5 on a 10-point scale vs 4.2, P = .013) but were not more confident in their ability to conduct such discussions. When managing patients with pancreatic cancer, academic, and community gastroenterologists responded that they were most likely to refer to guidelines developed by their professional organizations, such as the AGA and ACG. However, these groups have not developed specific guidelines for the management of patients with pancreatic cancer. CONCLUSIONS: As gastroenterologists are frequently the first physicians to disclose a diagnosis of pancreatic cancer, education is needed to improve familiarity with current available treatments, clinical trials, and emerging therapies and resources to advise their patients. PMID- 28005257 TI - Safety of transsphenoidal microsurgical approach in patients with an ACTH secreting pituitary adenoma. AB - PURPOSE: Patients affected by Cushing's disease often have important comorbidities directly linked to hypercortisolism that might enhance the operative risk. We report the safety of transsphenoidal surgery in patients affected by Cushing's disease as compared with patients with nonfunctioning pituitary adenoma. METHODS: We have retrospectively analyzed 142 patients with Cushing's disease and 299 patients with nonfunctioning pituitary adenoma who underwent transsphenoidal surgery performed by a single experienced neurosurgeon between September 2007 and December 2014. For all of them, an intraoperative computerized anesthetic record for the automatic storage of data was available. RESULTS: The intraoperative vital parameters and the frequency of drugs administered during anesthesia were comparable between Cushing's disease and nonfunctioning pituitary adenoma groups. The duration of surgery was similar between the two groups (41.2 +/- 11.8 vs. 42.9 +/- 15.6 min), while the duration of anesthesia was slightly shorter in Cushing's disease patients (97.6 +/- 18.1 min) than in nonfunctioning pituitary adenoma patients (101.6 +/- 20.6 min, p = 0.04). The total perioperative mortality rate was 0.2% (0% in Cushing's disease vs. 0.3% in nonfunctioning pituitary adenoma). Cushing's disease patients had surgical and medical complication rates of 3.5% each, not different from those occurring in nonfunctioning pituitary adenoma. The postoperative incidence of diabetes insipidus (10.6%) and isolated hyponatremia (10.6%) in Cushing's disease patients was significantly higher than in nonfunctioning pituitary adenoma patients (4.4 and 4.1%; p = 0.02 and p = 0.01, respectively). CONCLUSIONS: In a large series of unselected and consecutive patients with Cushing's disease, transsphenoidal surgery performed by one dedicated experienced neurosurgeon had a reasonably low risk of complications. In particular, despite the higher burden of comorbidities typically associated with hypercortisolism, medical complications are rare and no more frequent than in patients with nonfunctioning pituitary adenoma. PMID- 28005259 TI - Medical oncology future plan of the Spanish Society of Medical Oncology: challenges and future needs of the Spanish oncologists. AB - PURPOSE: The SEOM Future Plan is aimed at identifying the main challenges, trends and needs of the medical oncology speciality over the next years, including potential oncologist workforce shortages, and proposing recommendations to overcome them. METHODS: The estimations of the required medical oncologists workforce are based on an updated Medical Oncologist Register in Spain, Medical Oncology Departments activity data, dedication times and projected cancer incidence. Challenges, needs and future recommendations were drawn from an opinion survey and an advisory board. RESULTS: A shortage of 211 FTE medical oncologist specialists has been established. To maintain an optimal ratio of 158 new cases/FTE, medical oncology workforce should reach 1881 FTE by 2035. CONCLUSIONS: Main recommendations to face the growing demand and complexity of oncology services include a yearly growth of 2.5% of medical oncologist's workforce until 2035, and development and application of more accurate quality indicators for cancer care and health outcomes measure. PMID- 28005260 TI - High early growth response 1 (EGR1) expression correlates with resistance to anti EGFR treatment in vitro and with poorer outcome in metastatic colorectal cancer patients treated with cetuximab. AB - PURPOSE: Biomarkers, such as mutant RAS, predict resistance to anti-EGFR therapy in only a proportion of patients, and hence, other predictive biomarkers are needed. The aims were to identify candidate genes upregulated in colorectal cancer cell lines resistant to anti-EGFR monoclonal antibody treatment, to knockdown (KD) these genes in the resistant cell lines to determine if sensitivity to anti-EGFR antibody was restored, and finally to perform a pilot correlative study of EGR1 expression and outcomes in a cohort of metastatic colorectal cancer (mCRC) patients given cetuximab therapy. METHODS: Comparative expression array analysis of resistant cell lines (SW48, COLO-320DM, and SNU-C1) vs sensitive cell lines (LIM1215, CaCo2, and SW948) was performed. The highest up regulated gene in each resistant cell line was knocked down (KD) using RNA interference, and effect on proliferation was assessed with and without anti-EGFR treatment. Expression of the candidate genes in patients' tumours treated with cetuximab was assessed by immunohistochemistry; survival analyses were performed comparing high vs low expression. RESULTS: Genes significantly upregulated in resistant cell lines were EGR1 (early growth response protein 1), HBEGF (heparin binding epidermal growth factor-like growth factor), and AKT3 (AKT serine/threonine kinase 3). KD of each gene resulted in the respective cells being more sensitive to anti-EGFR treatment, suggesting that the resistant phenotype was reversed. In the pilot study of mCRC patients treated with cetuximab, both median PFS (1.38 months vs 6.79 months; HR 2.77 95% CI 1.2-19.4) and median OS (2.59 months vs 9.82 months; HR 3.0 95% CI 1.3-23.2) were significantly worse for those patients with high EGR1 expression. CONCLUSION: High EGR1 expression may be a candidate biomarker of resistance to anti-EGFR therapy. PMID- 28005262 TI - Synthesis and theoretical studies on nitrogen-rich salts of bis[4 nitraminofurazanyl-3-azoxy]azofurazan (ADNAAF). AB - Multi-furazan compounds bis[4-nitramino- furazanyl-3-azoxy]azofurazan (ADNAAF) and its derivatives were first synthesized by our research group, and their structures were characterized by IR, 1H-NMR, 13C-NMR spectrums, and element analysis. ADNAAF was synthesized by nitration reaction of bis[4-aminofurazanyl-3 azoxy]azofurazan (ADAAF), and then reacted with ammonium hydroxide, hydrazine hydrate, and guanidine nitrate to obtain three salts marked as salt 1, 2, and 3, respectively. The thermal stabilities of the three salts were supported by the results of DSC analysis, which shows the decomposition temperatures are all above 190 degrees C. Their densities, enthalpies of formation, and detonation properties were studied by density functional theory (DFT) method. Salt 1 has the best detonation pressure (P), 37.42 GPa, and detonation velocity (D), 8.88 km/s, while salt 2 has the best nitrogen content and heat of detonation (Q), 1.27 kcal mol-1. The detonation properties of salt 1 is similar to that of 1,3,5-trinitro 1,3,5-triazineane (RDX). It means that the ammonium cation can provide the better D and P than the cation of hydrazine and guanidine. The three cations offer the enthalpies of formations in the order of hydrazinium > guanidinium > ammonium. Graphical Abstract Nitrogen-rich salts of bis[4-nitraminofurazanyl-3 azoxy]azofurazan(ADNAAF). PMID- 28005261 TI - Results of a multicenter survey showing interindividual variability among neurosurgeons when deciding on the radicality of surgical resection in glioblastoma highlight the need for more objective guidelines. AB - PURPOSE: We assessed agreement among neurosurgeons on surgical approaches to individual glioblastoma patients and between their approach and those recommended by the topographical staging system described by Shinoda. METHODS: Five neurosurgeons were provided with pre-surgical MRIs of 76 patients. They selected the surgical approach [biopsy, partial resection, or gross total resection (GTR)] that they would recommend for each patient. They were blinded to each other's response and they were told that patients were younger than 50 years old and without symptoms. Three neuroradiologists classified each case according to the Shinoda staging system. RESULTS: Biopsy was recommended in 35.5-82.9%, partial resection in 6.6-32.9%, and GTR in 3.9-31.6% of cases. Agreement among their responses was fair (global kappa = 0.28). Nineteen patients were classified as stage I, 14 as stage II, and 43 as stage III. Agreement between the neurosurgeons and the recommendations of the staging system was poor for stage I (kappa = 0.14) and stage II (kappa = 0.02) and fair for stage III patients (kappa = 0.29). An individual analysis revealed that in contrast to the Shinoda system, neurosurgeons took into account T2/FLAIR sequences and gave greater weight to the involvement of eloquent areas. CONCLUSIONS: The surgical approach to glioblastoma is highly variable. A staging system could be used to examine the impact of extent of resection, monitor post-operative complications, and stratify patients in clinical trials. Our findings suggest that the Shinoda staging system could be improved by including T2/FLAIR sequences and a more adequate weighting of eloquent areas. PMID- 28005263 TI - Does early onset cataract increase the risk of ischemic stroke? A nationwide retrospective cohort study. AB - This study was attempted to address the association between early onset cataract (EOC) and ischemic stroke. Using the Longitudinal Health Insurance Database 2000, we established an EOC cohort and a comparison cohort by using 4-fold propensity score matching according to age, gender and comorbidities to detect the incidence of ischemic stroke. A Cox model was used to express the risk of ischemic stroke for the EOC patients compared with the comparison cohort. After adjusting for age, gender and comorbidities of hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, asthma, chronic obstructive pulmonary disease, chronic kidney disease, heart failure, obesity, and atrial fibrillation, the EOC patients had a 1.48-fold higher risk of ischemic stroke than the comparison cohort, but it was not statistically significant. A non-significant increase in the risk of subsequent ischemic stroke development for the EOC patients is demonstrated in this study. PMID- 28005264 TI - Mucin 4 and matrix metalloproteinase 7 as novel salivary biomarkers for periodontitis. AB - AIM: Periodontitis is a chronic inflammatory disease, characterized by irreversible destruction of tooth-supporting tissue including alveolar bone. We recently reported mucin 4 (MUC4) and matrix metalloproteinase 7 (MMP7) as highly associated with periodontitis in gingival tissue biopsies. The aim of this study was to further investigate the levels of MUC4 and MMP7 in saliva and gingival crevicular fluid (GCF) samples of patients with periodontitis. MATERIALS AND METHODS: Saliva and GCF samples were collected from periodontitis patients and healthy controls. The levels of MUC4, MMP7, and total protein concentrations were analysed using ELISA or Bradford assay. RESULTS: MUC4 levels were significantly lower in saliva and GCF from periodontitis patients relative to healthy controls. MMP7 levels were significantly higher in saliva and GCF from periodontitis patients. Multivariate analysis revealed that MUC4 was significantly associated with periodontitis after adjusting for age and smoking habits and, moreover, that the combination of MUC4 and MMP7 accurately discriminated periodontitis from healthy controls. CONCLUSIONS: MUC4 and MMP7 may be utilized as possible novel biomarkers for periodontitis. PMID- 28005265 TI - Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma. AB - In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1.3 mg/m2 on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6.6, 7.5 and 7.6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1.13 [0.80-1.59], P = 0.480; tabalumab 300 mg vs. placebo HR [95% CI] = 1.03 [0.72-1.45], P = 0.884). The most commonly-reported treatment emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8.3 [7.0-9.3] months vs. 5.8 [3.7-6.6] months; HR [95% CI] = 1.59 [1.11-2.29], P = 0.015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma. PMID- 28005266 TI - Enhanced activation of eosinophils in peripheral blood and implications for eosinophilic esophagitis diagnosis. AB - BACKGROUND AND AIM: Eosinophils are markers of the eosinophilic esophagitis (EoE) disease, and this work aimed to assess whether activation of eosinophils could be a noninvasive test to contribute for EoE diagnosis. METHODS: The activation state of peripheral blood eosinophils in EoE patients and control subjects was assessed based on the morphological aspects of the eosinophil after adherence to slide. Cyclooxygenase-2 and 5-lipoxygenase expressions were evaluated by means of immunofluorescence microscopy to verify if and which eicosanoid pathway is triggered in eosinophils in blood in EoE. RESULTS: The eosinophils of patients with EoE were significantly more activated than those of control individuals. The lowest percentage of normal eosinophils for control subjects was 40%, while the highest percentage of eosinophils of normal aspect for patients with EoE was 32%. Considering 36% as a cutoff for normal eosinophils, this value differentiated all individuals with EoE from individuals without the disease with a sensitivity of 100%, considering the diagnosis of EoE as currently defined. Eosinophils of EoE patients showed higher expression of cyclooxygenase-2 than those of control subjects. CONCLUSIONS: The quantification of morphological changes in eosinophils is a feasible, easy, and reliable manner to identify EoE patients. Therefore, patients with symptoms of esophageal dysfunction showing higher than 36% activated eosinophils in peripheral blood could be a useful way to help definition and diagnostic criterion for EoE. PMID- 28005267 TI - Human gingiva transcriptome during wound healing. AB - OBJECTIVES: To investigate the gene expression profile of human gingiva following surgical wounding. METHODS: Ten volunteers had one side of the palate wounded. Five days later, biopsies were harvested from both wounded (healing gingiva) and contra-lateral site (normal gingiva). Tissue samples were processed for gene expression (RNA-Seq, real-time PCR) and immunohistochemistry. Gene set enrichment/pathway analysis was also performed. RESULTS: Seven hundred genes were significantly differentially expressed in healing gingiva. Among genes with >twofold change (FC) in expression, 399 genes were up-regulated and 88 down regulated, several not previously reported expressed in gingiva. Most increased in expression (>=30-FC) were MMP1, CCL18, SPP1, MUC21, CTHRC1, MMP10, and SERPINE1; most decreased (>=7-FC) were COCH, SIAH3, MT4, IGFL3, KY, and SYT16. Real-time PCR confirmed significantly changed mRNA levels for selective genes tested. Gene set enrichment analysis revealed several significantly enriched biological pathways. Immunohistochemistry confirmed protein expression of MUC21, CTHRC1, CTGF, and SYT16 in normal and healing gingiva. CONCLUSIONS: This first comprehensive analysis of the human gingival transcriptome during surgical wound healing offers novel insights into the participating molecular and biological mechanisms. The present results could serve as basis for future investigations into gingival wound healing following surgical, traumatic, or other type of injury. PMID- 28005268 TI - Health information quality of websites on periodontology. AB - AIM: This study aimed to assess the quality of the information available on the Web on gum disease. METHODS: The term "gum disease" was searched in Google and in MedlinePlus. The first 200 websites were analysed by the Journal of the American Medical Association (JAMA) criteria and the Health On the Net Foundation (HONCode) certification, instruments for assessing quality of health information. Data were analysed the Mann-Whitney test or Kruskal-Wallis test, followed by the Dunn's test, using the GraphPad Prism Software version 6. RESULTS: MedlinePlus presented a significantly higher JAMA score than Google. Google's first 10 results had a higher JAMA score than the remaining websites. Journalism and health portals the most reliable affiliations, while commercial and dental practices had low JAMA scores. JAMA score was significantly higher in websites with the HONCode certification compared to the ones without it. CONCLUSION: Currently, there are concerns regarding patients' use of the Internet for accessing health information. However, the conclusion we can make is that Google seems to favour websites with high quality information, at least in terms of JAMA score or HONCode accreditation. The JAMA score of dental practices' websites could be improved by providing basic information such as authorship and date. PMID- 28005269 TI - From the Editors. PMID- 28005270 TI - JAZ2 controls stomata dynamics during bacterial invasion. AB - Coronatine (COR) facilitates entry of bacteria into the plant apoplast by stimulating stomata opening. COR-induced signaling events at stomata remain unclear. We found that the COR and jasmonate isoleucine (JA-Ile) co-receptor JAZ2 is constitutively expressed in guard cells and modulates stomatal dynamics during bacterial invasion We analyzed tissue expression patterns of AtJAZ genes and measured stomata opening and pathogen resistance in loss- and gain-of-function mutants. Arabidopsis jaz2 mutants are partially impaired in pathogen-induced stomatal closing and more susceptible to Pseudomonas. Gain-of-function mutations in JAZ2 prevent stomatal reopening by COR and are highly resistant to bacterial penetration. The JAZ2 targets MYC2, MYC3 and MYC4 directly regulate the expression of ANAC19, ANAC55 and ANAC72 to modulate stomata aperture. Due to the antagonistic interactions between the salicylic acid (SA) and JA defense pathways, efforts to increase resistance to biotrophs result in enhanced susceptibility to necrotrophs, and vice versa. Remarkably, dominant jaz2Deltajas mutants are resistant to Pseudomonas syringae but retain unaltered resistance against necrotrophs. Our results demonstrate the existence of a COI1-JAZ2 MYC2,3,4-ANAC19,55,72 module responsible for the regulation of stomatal aperture that is hijacked by bacterial COR to promote infection. They also provide novel strategies for crop protection against biotrophs without compromising resistance to necrotrophs. PMID- 28005271 TI - Progesterone for acute traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability, and the identification of effective, inexpensive and widely practicable treatments for brain injury is of great public health importance worldwide. Progesterone is a naturally produced hormone that has well-defined pharmacokinetics, is widely available, inexpensive, and has steroidal, neuroactive and neurosteroidal actions in the central nervous system. It is, therefore, a potential candidate for treating TBI patients. However, uncertainty exists regarding the efficacy of this treatment. This is an update of our previous review of the same title, published in 2012. OBJECTIVES: To assess the effects of progesterone on neurologic outcome, mortality and disability in patients with acute TBI. To assess the safety of progesterone in patients with acute TBI. SEARCH METHODS: We updated our searches of the following databases: the Cochrane Injuries Group's Specialised Register (30 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2016), MEDLINE (Ovid; 1950 to 30 September 2016), Embase (Ovid; 1980 to 30 September 2016), Web of Science Core Collection: Conference Proceedings Citation Index-Science (CPCI S; 1990 to 30 September 2016); and trials registries: Clinicaltrials.gov (30 September 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform (30 September 2016). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. DATA COLLECTION AND ANALYSIS: Two review authors screened search results independently to identify potentially relevant studies for inclusion. Independently, two review authors selected trials that met the inclusion criteria from the results of the screened searches, with no disagreement. MAIN RESULTS: We included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data.All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I2 = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies.There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I2 = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies.Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events. AUTHORS' CONCLUSIONS: This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results.There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone).There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions.Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling. PMID- 28005272 TI - Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy. AB - BACKGROUND: Pregnant women with sickle cell disease (HbSS, HbSC and HbSbetaThal) may require blood transfusion to prevent severe anaemia or to manage potential medical complications. Preventive blood transfusion in the absence of complications starting from the early weeks of pregnancy or blood transfusion only for medical or obstetric indications have been used as management policies. There is currently no consensus on the blood transfusion policy that guarantees optimal clinical benefits with minimal risks for such women and their babies. This is an update of a Cochrane review that was published in 2013. OBJECTIVES: To assess the benefits and harms of a policy of prophylactic versus selective blood transfusion in pregnant women with sickle cell disease. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 May 2016) and reference lists of retrieved studies. We did not apply any language or date restrictions. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of prophylactic versus selective (emergency) blood transfusion in pregnant women with sickle cell disease (SCD). Quasi-randomised trials and trials using a cluster-randomised design were eligible for inclusion but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two review authors independently assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Out of six relevant reports identified by the search strategy, one trial involving 72 women with sickle cell anaemia (HbSS) met our inclusion criteria. The trial was at unclear risk of bias. Overall, there were few events for most of the reported outcomes and the results were generally imprecise. The included trial reported no maternal mortality occurring in women who received either prophylactic or selective blood transfusion. Very low-quality evidence indicated no clear differences in maternal mortality, perinatal mortality (risk ratio (RR) 2.85, 95% confidence interval (CI) 0.61 to 13.22; very low-quality evidence) or markers of severe maternal morbidity (pulmonary embolism (no events); congestive cardiac failure (RR 1.00, 95% CI 0.07 to 15.38; very low-quality evidence); acute chest syndrome (RR 0.67, 95% CI 0.12 to 3.75)) between the treatment groups (prophylactic blood transfusion versus selective blood transfusion). Low-quality evidence indicated that prophylactic blood transfusion reduced the risk of pain crisis compared with selective blood transfusion (RR 0.28, 95% CI 0.12 to 0.67, one trial, 72 women; low-quality evidence), and no differences in the occurrence of acute splenic sequestration (RR 0.33, 95% CI 0.01 to 7.92; low-quality evidence), haemolytic crises (RR 0.33, 95% CI 0.04 to 3.06) or delayed blood transfusion reaction (RR 2.00, 95% CI 0.54 to 7.39; very low-quality evidence) between the comparison groups.Other relevant maternal outcomes pre-specified for this review such as cumulative duration of hospital stay, postpartum haemorrhage and iron overload, and infant outcomes, admission to neonatal intensive care unit (NICU) and haemolytic disease of the newborn, were not reported by the trial. AUTHORS' CONCLUSIONS: Evidence from one small trial of very low quality suggests that prophylactic blood transfusion to pregnant women with sickle cell anaemia (HbSS) confers no clear clinical benefits when compared with selective transfusion. Currently, there is no evidence from randomised or quasi-randomised trials to provide reliable advice on the optimal blood transfusion policy for women with other variants of sickle cell disease (i.e. HbSC and HbSbetaThal). The available data and quality of evidence on this subject are insufficient to advocate for a change in existing clinical practice and policy. PMID- 28005273 TI - Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety. AB - The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy. PMID- 28005274 TI - Neutrophilic eccrine hidradenitis in two patients treated with BRAF inhibitors: a new cutaneous adverse event. AB - Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis, first described in patients undergoing chemotherapy for a malignant haemopathy. It has polymorphous clinical features and the association of both clinical and histological features is necessary to make a diagnosis. We report the first two cases of NEH in patients treated with a BRAF inhibitor (BRAFi), either dabrafenib or vemurafenib, for a stage IV metastatic melanoma. Disseminated erythematous plaques associated with fever and polyarthralgia occurred early after the initiation of treatment and were badly tolerated. Histological analyses confirmed the diagnosis of NEH. Symptoms disappeared a few days after the cessation of treatment and introduction of topical steroids. The replacement of one BRAFi with another is a therapeutic alternative as it is not necessarily associated with a relapse of NEH. NEH can be added to the spectrum of neutrophilic dermatoses induced by BRAFis. It occurs earlier (3-4 days) than previously described drug induced NEH (9-12 days) and may be an earlier stage of eccrine squamous syringometaplasia, which has already been reported in the context of BRAFi treated patients. PMID- 28005275 TI - Urgency to treat patients with chronic hepatitis C in Asia. AB - Chronic hepatitis C (CHC) infection poses a global healthcare burden, being associated with serious complications if untreated. The prevalence of hepatitis C virus (HCV) infection is highest in areas of Central, South, and East Asia; over 50% of HCV patients worldwide live in the region, where HCV genotypes 1b, 2, 3, and 6 are the most prevalent. Treatment outcomes for chronic hepatitis C vary by ethnicity, and Asian patients achieve higher sustained virologic response rates following interferon (IFN)-based therapy than non-Asians. However, low efficacy, poor safety profile, and subcutaneous administration limit the use of IFN-based therapies. Superior virologic outcomes have been observed with different classes of direct-acting antivirals (DAAs) alone or in combination, and several all-oral DAA regimens are available in Asia. These regimens have shown excellent efficacy and favorable tolerability in clinical trials, yet there is a need for further studies of DAAs in a real world context, particularly in Asia. Furthermore, IFN free treatment may not be accessible for many patients in the region, and IFN based regimens remain an option in some countries. There is a need to improve current clinical practices for HCV management in Asia, including effective screening, disease awareness, and prevention programs, and to further understand the cost-effectiveness of IFN-free regimens. The evolution of potent treatments makes HCV eradication a possibility that should be available to all patients. However, access to these therapies in Asian countries has been slow, primarily because of economic barriers that continue to present a hurdle to optimal treatment. PMID- 28005276 TI - Treatment of severe atopic dermatitis with ustekinumab: a case series of 10 patients. PMID- 28005277 TI - Health-related quality of life and psychological well-being in adults with differences/disorders of sex development. AB - OBJECTIVE: Rare congenital conditions with incongruence of chromosomal, gonadal and phenotypic sex have been classified as differences/disorders of sex development (DSD). Included in DSD are conditions with diverse genetic aetiology, varying levels of prenatal androgen effects, phenotypes and, subsequently, different medical treatments. Quality of life (QoL) and psychological well-being are indicators of successful psychosocial adaptation to the conditions. We sought to investigate the HRQoL and psychological well-being in this population. DESIGN: This multicentre clinical evaluation study was part of a German network related to DSD funded by the German Ministry of Science and Education (BMBF 2003 to 2007). METHODS: To assess health-related quality of life (HRQoL), we used the Short Form Health Survey (SF-36), and for psychological well-being, the Brief Symptom Inventory (BSI). Participants were classified into five groups: females with CAH, females with XY DSD conditions where there is a partial androgen effect (partial androgen insensitivity, mixed/partial gonadal dysgenesis, disorders of androgen biosynthesis), females with XY DSD without androgen effect (complete androgen insensitivity, complete gonadal dysgenesis), males with XY DSD, and individuals with DSD conditions and other gender. RESULTS: Participants included 110 adults with DSD (age range 17-62). We found a trend of lowered mental HRQoL and significant higher physical HRQoL for participants as compared to the norm. The high physical HRQoL especially applied to females with androgen effect and XY karyotype. Participants reported significant higher psychological distress compared to the norm. Forty-seven participants (42.7%) reported distress in a clinically relevant range on the BSI. CONCLUSIONS: Although we did not find significant impairments in overall HRQoL, participants reported significant impaired psychological well-being. Specialized interdisciplinary care should focus in particular on psychological issues to ensure good overall health and well-being. PMID- 28005278 TI - IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series. AB - OBJECTIVE: To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE. METHOD: Comparative case series of 31 patients with IgG4-RD and 13 patients with L-HES. RESULTS: Peripheral blood eosinophilia was present in eight of 31 patients with IgG4-RD compared to 13 of 13 patients with L-HES (median eosinophils 0.4 vs 7.0 giga/L, P=.001) and 12 of 20 patients with IgG4-RD had increased serum IgE compared to eight of 13 patients with L-HES, P=.930. Twenty-seven of 30 patients with IgG4-RD had elevated serum IgG4 compared to five of 12 patients with L-HES (median IgG4 9.6 g/L vs 0.80 g/L, P=.002). Flow cytometry demonstrated an aberrant T-cell phenotype in 7 of 23 patients with IgG4-RD and 13 of 13 patients with L-HES (P<.001). T-cell clonality by PCR was positive in 12 of 23 patients with IgG4-RD vs 10 of 13 patients with L HES (P=.143). Patients in both groups received corticosteroids as first-line therapy. For refractory disease in IgG4-RD, rituximab was the most common steroid sparing agent, whereas in L-HES, it was pegylated interferon-alpha-2a. CONCLUSION: The overlapping features of these two diseases with divergent treatment options demonstrate the importance of familiarity with both entities to optimize diagnosis and treatment. PMID- 28005279 TI - Fatigue as a symptom in psoriasis and psoriatic arthritis: an observational study. PMID- 28005280 TI - ABCG2/BCRP: Specific and Nonspecific Modulators. AB - Multidrug resistance (MDR) in cancer cells is the development of resistance to a variety of structurally and functionally nonrelated anticancer drugs. This phenomenon has become a major obstacle to cancer chemotherapy seriously affecting the clinical outcome. MDR is associated with increased drug efflux from cells mediated by an energy-dependent mechanism involving the ATP-binding cassette (ABC) transporters, mainly P-glycoprotein (ABCB1), the MDR-associated protein-1 (ABCC1), and the breast cancer resistance protein (ABCG2). The first two transporters have been widely studied already and reviews summarized the results. The ABCG2 protein has been a subject of intense study since its discovery as its overexpression has been detected in resistant cell lines in numerous types of human cancers. To date, a long list of modulators of ABCG2 exists and continues to increase. However, little is known about the clinical consequences of ABCG2 modulation. This makes the design of novel, potent, and nontoxic inhibitors of this efflux protein a major challenge to reverse MDR and thereby increase the success of chemotherapy. The aim of the present review is to describe and highlight specific and nonspecific modulators of ABCG2 reported to date based on the selectivity of the compounds, as many of them are effective against one or more ABC transport proteins. PMID- 28005281 TI - Harnessing self-assembly to enable modular vaccine design. PMID- 28005283 TI - Biotechnology and Bioengineering: Volume 114, Number 2, February 2017. PMID- 28005282 TI - Paradigm shift in virus-like particle bioprocessing. PMID- 28005284 TI - Multiplex PNA-fish to detect cystic fibrosis polymicrobial communities. PMID- 28005285 TI - Modeling hydrogen photoproduction systems in cells. PMID- 28005287 TI - In memoriam: Wayne Akeson, MD (1928-2016). PMID- 28005288 TI - 2016-The year in review at the JOR. PMID- 28005291 TI - In memoriam: Klaus Kuettner, PhD (1933-2016). PMID- 28005290 TI - Collagen V expression is crucial in regional development of the supraspinatus tendon. AB - Manipulations in cell culture and mouse models have demonstrated that reduction of collagen V results in altered fibril structure and matrix assembly. A tissue dependent role for collagen V in determining mechanical function was recently established, but its role in determining regional properties has not been addressed. The objective of this study was to define the role(s) of collagen V expression in establishing the site-specific properties of the supraspinatus tendon. The insertion and midsubstance of tendons from wild type, heterozygous and tendon/ligament-specific null mice were assessed for crimp morphology, fibril morphology, cell morphology, as well as total collagen and pyridinoline cross link (PYD) content. Fibril morphology was altered at the midsubstance of both groups with larger, but fewer, fibrils and no change in cell morphology or collagen compared to the wild type controls. In contrast, a significant disruption of fibril assembly was observed at the insertion site of the null group with the presence of structurally aberrant fibrils. Alterations were also present in cell density and PYD content. Altogether, these results demonstrate that collagen V plays a crucial role in determining region-specific differences in mouse supraspinatus tendon structure. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2154-2161, 2016. PMID- 28005292 TI - Early results using a biodegradable magnesium screw for modified chevron osteotomies. AB - This is the first larger study analyzing the use of magnesium-based screws for fixation of modified Chevron osteotomies in hallux valgus surgery. Forty-four patients (45 feet) were included in this prospective study. A modified Chevron osteotomy was performed on every patient and a magnesium screw used for fixation. The mean clinical follow up was 21.4 weeks. The mean age of the patients was 45.5 years. Forty patients could be provided with the implant, in four patients the surgeon decided to change to a standard metallic implant. The AOFAS, FAAM and pain NRS-scale improved markedly. The hallux valgus angle, intermetatarsal angle and sesamoid position improved significantly. Seven patients showed dorsal subluxation, rotation or medial shifting of the metatarsal heads within the first 3 months. One of these patients was revised, in all others the findings were considered clinically not significant or the patients refused revision. This study shows the feasibility of using magnesium screws in hallux valgus-surgery. Surgeons starting with the use of these implants should be aware of the proper handling of these implants and should know about corrosion effects during healing and its radiographic appearance. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2207-2214, 2016. PMID- 28005293 TI - The diagnosis and management of primary autoimmune haemolytic anaemia. PMID- 28005294 TI - Water supply and demand remain coordinated during breakdown of the global scaling relationship between leaf size and major vein density. AB - Vein networks that disobey the global scaling of major vein density with leaf size shed light on functional constraints of vein network formation in dicotyledons. Understanding their evolution, distribution and impact on vein stomata-climate associations is an important contribution to our global view of vein network organization. Based on vein traits of 55 species of pantropical Ochnaceae, stomata and climatic niche data, and a dated molecular phylogeny, we unveil major structural shifts in vein networks through deep time, relationships between leaf size, vein and stomata traits, and their interplay with climate. Dense 2 degrees veins, reduction of minor veins and the associated breakdown of vein-leaf size scaling evolved multiple times independently in Ochnaceae. In spite of the drastic changes in vein architecture in this venation type, vein and stomatal densities remain correlated. Our study demonstrates that shortening the major vein-stomata distance is economically not less advantageous than by increasing minor vein density, as illustrated by the same degree of coordination between vein and stomatal densities and the similar construction costs across networks with dense 2 degrees veins and those with 'normally' spaced 2 degrees veins. PMID- 28005295 TI - Antibiotics in Endodontics: a review. AB - The overuse of antibiotics and the emergence of antibiotic-resistant bacterial strains is a global concern. This concern is also of importance in terms of the oral microbiota and the use of antibiotics to deal with oral and dental infections. The aim of this paper was to review the current literature on the indications and use of antibiotics and to make recommendations for their prescription in endodontic patients. Odontogenic infections, including endodontic infections, are polymicrobial, and in most cases, the prescription of antibiotics is empirical. This has led to the increasing use of broad-spectrum antibiotics even in cases where antibiotics are not indicated, such as symptomatic irreversible pulpitis, necrotic pulps and localized acute apical abscesses. In case of discrete and localized swelling, the primary aim is to achieve drainage without additional antibiotics. Adjunctive antibiotic treatment may be necessary in the prevention of the spread of infection, in acute apical abscesses with systemic involvement and in progressive and persistent infections. Medically compromised patients are more susceptible to complication arising from odontogenic infections and antimicrobials have a more specific role in their treatment. Therefore, antibiotics should be considered in patients having systemic diseases with compromised immunity or in patients with a localized congenital or acquired altered defence capacity, such as patients with infective endocarditis, prosthetic cardiac valves or recent prosthetic joint replacement. Penicillin VK, possibly combined with metronidazole to cover anaerobic strains, is still effective in most cases. However, amoxicillin (alone or together with clavulanic acid) is recommended because of better absorption and lower risk of side effects. In case of confirmed penicillin allergy, lincosamides such as clindamycin are the drug of choice. PMID- 28005296 TI - Current wheeze, asthma, respiratory infections, and rhinitis among adults in relation to inspection data and indoor measurements in single-family houses in Sweden-The BETSI study. AB - In the Swedish Building Energy, Technical Status and Indoor environment study, a total of 1160 adults from 605 single-family houses answered a questionnaire on respiratory health. Building inspectors investigated the homes and measured temperature, air humidity, air exchange rate, and wood moisture content (in attic and crawl space). Moisture load was calculated as the difference between indoor and outdoor absolute humidity. Totally, 7.3% were smokers, 8.7% had doctor' diagnosed asthma, 11.2% current wheeze, and 9.5% current asthma symptoms. Totally, 50.3% had respiratory infections and 26.0% rhinitis. The mean air exchange rate was 0.36/h, and the mean moisture load 1.70 g/m3 . Damp foundation (OR=1.79, 95% CI 1.16-2.78) was positively associated while floor constructions with crawl space (OR=0.49, 95% CI 0.29-0.84) was negatively associated with wheeze. Concrete slabs with overlying insulation (OR=2.21, 95% CI 1.24-3.92) and brick facade (OR=1.71, 95% CI 1.07-2.73) were associated with rhinitis. Moisture load was associated with respiratory infections (OR=1.21 per 1 g/m3 , 95% CI 1.04 1.40) and rhinitis (OR=1.36 per 1 g/m3 , 95% CI 1.02-1.83). Air exchange rate was associated with current asthma symptoms (OR=0.85 per 0.1/h, 95% CI 0.73-0.99). Living in homes with damp foundation, concrete slabs with overlying insulation, brick facade, low ventilation flow, and high moisture load are risk factors for asthma, rhinitis, and respiratory infections. PMID- 28005298 TI - Stimuli-Responsive Self-Assembled DNA Nanomaterials for Biomedical Applications. AB - Stimuli-responsive DNA-based materials represent a major class of remarkable functional nanomaterials for nano-biotechnological applications. In this review, recent progress in the development of stimuli-responsive systems based on self assembled DNA nanostructures is introduced and classified. Representative examples are presented in terms of their design, working principles and mechanisms to trigger the response of the stimuli-responsive DNA system upon expose to a large variety of stimuli including pH, metal ions, oligonucleotides, small molecules, enzymes, heat, and light. Substantial in vitro studies have clearly revealed the advantages of the use of stimuli-responsive DNA nanomaterials in different biomedical applications, particularly for biosensing, drug delivery, therapy and diagnostic purposes in addition to bio-computing. Some of the challenges faced and suggestions for further development are also highlighted. PMID- 28005297 TI - Predicted percentage dissatisfied with ankle draft. AB - Draft is unwanted local convective cooling. The draft risk model of Fanger et al. (Energy and Buildings 12, 21-39, 1988) estimates the percentage of people dissatisfied with air movement due to overcooling at the neck. There is no model for predicting draft at ankles, which is more relevant to stratified air distribution systems such as underfloor air distribution (UFAD) and displacement ventilation (DV). We developed a model for predicted percentage dissatisfied with ankle draft (PPDAD ) based on laboratory experiments with 110 college students. We assessed the effect on ankle draft of various combinations of air speed (nominal range: 0.1-0.6 m/s), temperature (nominal range: 16.5-22.5 degrees C), turbulence intensity (at ankles), sex, and clothing insulation (<0.7 clo; lower legs uncovered and covered). The results show that whole-body thermal sensation and air speed at ankles are the dominant parameters affecting draft. The seated subjects accepted a vertical temperature difference of up to 8 degrees C between ankles (0.1 m) and head (1.1 m) at neutral whole-body thermal sensation, 5 degrees C more than the maximum difference recommended in existing standards. The developed ankle draft model can be implemented in thermal comfort and air diffuser testing standards. PMID- 28005299 TI - Polymeric Selectin Ligands Mimicking Complex Carbohydrates: From Selectin Binders to Modifiers of Macrophage Migration. AB - Novel polymeric cell adhesion inhibitors were developed in which the selectin tetrasaccharide sialyl-LewisX (SLeX ) is multivalently presented on a biocompatible poly(2-hydroxypropyl)methacrylamide (PHPMA) backbone either alone (P1) or in combination with O-sulfated tyramine side chains (P2). For comparison, corresponding polymeric glycomimetics were prepared in which the crucial "single carbohydrate" substructures fucose, galactose, and sialic acid side chains were randomly linked to the PHPMA backbone (P3 or P4 (O-sulfated tyramine)). All polymers have an identical degree of polymerization, as they are derived from the same precursor polymer. Binding assays to selectins, to activated endothelial cells, and to macrophages show that polyHPMA with SLeX is an excellent binder to E-, L-, and P-selectins. However, mimetic P4 can also achieve close to comparable binding affinities in in vitro measurements and surprisingly, it also significantly inhibits the migration of macrophages; this provides new perspectives for the therapy of severe inflammatory diseases. PMID- 28005300 TI - Studies on Cycloalkane-Based Bisamide Organogelators: A New Example of Stochastic Chiral Symmetry-Breaking Induced by Sonication. AB - Enantiomerically pure C16 -alkyl amides derived from cis and trans cycloalkane 1,2-dicarboxylic acids, respectively, have been synthesized and their behavior as organogelators has been investigated. These compounds include cis/trans diastereomeric cyclobutane and cyclohexane derivatives with the aim to explore the influence of the ring size as well as the relative configuration in their hierarchical self-assembly to form gels. High resolution 1 H NMR spectroscopy studies allowed the determination of the dynamics of the gelation process in [D8 ]toluene and the sol-gel transition temperature. The morphology and size of the aggregates have been investigated and results have shown that, in the case of cyclobutane derivatives, the cis/trans stereochemistry is not relevant for the gelation behavior and the properties of the soft-materials obtained, but it is remarkable for cyclohexane diamides, which are better organogelators. The four compounds produce chiral aggregates despite that two of them are meso achiral molecules. We show herein that this fact is an example of stochastic symmetry breaking induced by sonication. The self-assembly of these molecules has been modelled providing information and support about the structure and the chirality of the aggregates. PMID- 28005301 TI - The Origin of MoS2 Significantly Influences Its Performance for the Hydrogen Evolution Reaction due to Differences in Phase Purity. AB - Molybdenum disulfide (MoS2 ) is at the forefront of materials research. It shows great promise for electrochemical applications, especially for hydrogen evolution reaction (HER) catalysis. There is a significant discrepancy in the literature on the reported catalytic activity for HER catalysis on MoS2 . Here we test the electrochemical performance of MoS2 obtained from seven sources and we show that these sources provide MoS2 of various phase purity (2H and 3R, and their mixtures) and composition, which is responsible for their different electrochemical properties. The overpotentials for HER at -10 mA cm-2 for MoS2 from seven different sources range from -0.59 V to -0.78 V vs. reversible hydrogen electrode (RHE). This is of very high importance as with much interest in 2D-MoS2 , the use of the top-down approach would usually involve the application of commercially available MoS2 . These commercially available MoS2 are rarely characterized for composition and phase purity. These key parameters are responsible for large variance of reported catalytic properties of MoS2 . PMID- 28005302 TI - Catalyst-Controlled Multicomponent Aziridination of Chiral Aldehydes. AB - A highly diastereoselective and enantioselective method for the multicomponent aziridination of chiral aldehydes has been developed with BOROX catalysts of the VANOL (3,3'-diphenyl-2,2'-bi-1-naphthol) and VAPOL (2,2'-diphenyl-(4 biphenanthrol)) ligands. Very high to perfect catalyst control is observed with most all substrates examined including aldehydes with chiral centers in the alpha and beta-positions. High catalyst control was also observed for a number of chiral heterocyclic aldehydes allowing for the preparation of epoxy aziridines, bis(aziridines) and ethylene diaziridines. Application of this reaction in the synthesis of beta3 -homo-d-alloisoleucine and beta3 -homo-l-isoleucine is reported. PMID- 28005303 TI - RADIOGRAPHIC APPEARANCE OF PRESUMED NONCARDIOGENIC PULMONARY EDEMA AND CORRELATION WITH THE UNDERLYING CAUSE IN DOGS AND CATS. AB - Noncardiogenic pulmonary edema is an important cause of respiratory disease in dogs and cats but few reports describe its radiographic appearance. The purpose of this retrospective case series study was to describe radiographic findings in a large cohort of dogs and cats with presumed noncardiogenic pulmonary edema and to test associations among radiographic findings versus cause of edema. Medical records were retrieved for dogs and cats with presumed noncardiogenic edema based on history, radiographic findings, and outcome. Radiographs were reviewed to assess lung pattern and distribution of the edema. Correlation with the cause of noncardiogenic pulmonary edema was evaluated with a Fisher's exact test. A total of 49 dogs and 11 cats were included. Causes for the noncardiogenic edema were airway obstruction (n = 23), direct pulmonary injury (n = 13), severe neurologic stimulation (n = 12), systemic disease (n = 6), near-drowning (n = 3), anaphylaxis (n = 2) and blood transfusion (n = 1). Mixed, symmetric, peripheral, multifocal, bilateral, and dorsal lung patterns were observed in 44 (73.3%), 46 (76.7%), 55 (91.7%), 46 (76.7%), 46 (76.7%), and 34 (57.6%) of 60 animals, respectively. When the distribution was unilateral, pulmonary infiltration involved mainly the right lung lobes (12 of 14, 85.7%). Increased pulmonary opacity was more often asymmetric, unilateral, and dorsal for postobstructive pulmonary edema compared to other types of noncardiogenic pulmonary edema, but no other significant correlations could be identified. In conclusion, noncardiogenic pulmonary edema may present with a quite variable radiographic appearance in dogs and cats. PMID- 28005304 TI - Visible-Light-Mediated Two-Fold Unsymmetrical C(sp3 )-H Functionalization and Double C-F Substitution. AB - A visible-light-mediated [3+3] annulation of tertiary amines with alpha trifluoromethyl alkenes was developed. The reaction offers a direct route to fluorinated tetrahydropyridines and azabicyclo[3.m.1] frameworks under very mild conditions. This protocol presents a rare example of dual sp3 C-H functionalization of tertiary amines with the formation of two different C-C bonds (one sp3 -sp3 bond, one sp2 -sp3 bond). Moreover, two consecutive C-F substitutions in a trifluoromethyl group were achieved in one pot using visible light photoredox catalysis, which enables an unprecedented ring construction. PMID- 28005305 TI - 5 nm Silver Nanoparticles Amplify Clinical Features of Atopic Dermatitis in Mice by Activating Mast Cells. AB - The triggering effect of silver nanoparticles (NPs) on the induction of allergic reactions is evaluated, by studying the activation of mast cells and the clinical features of atopic dermatitis in a mouse model. Granule release is induced in RBL 2H3 mast cells by 5 nm, but not 100 nm silver NPs. Increases in the levels of reactive oxygen species (hydrogen peroxide and mitochondrial superoxide) and intracellular Ca++ in mast cells are induced by 5 nm silver NPs. In a mouse model of atopic dermatitis induced by a mite allergen, the skin lesions are more severe and appear earlier in mice treated simultaneously with 5 nm silver NPs and allergen compared with mice treated with allergen alone or 100 nm silver NPs and allergen. The histological findings reveal that number of tryptase-positive mast cells and total IgE levels in the serum increase in mice treated with 5 nm silver NPs and allergen. The results in this study indicate that cotreatment with 5 nm silver NPs stimulates mast cell degranulation and induces earlier and more severe clinical alterations in allergy-prone individuals. PMID- 28005307 TI - Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols Using an Air- and Moisture-Stable Iron Racemization Catalyst. AB - Herein, we report on a metalloenzymatic dynamic kinetic resolution of sec alcohols employing an iron-based racemization catalyst together with a lipase. The iron catalyst was evaluated in racemization and then used in dynamic kinetic resolution of a number of sec-alcohols to give enantiomerically pure products in good to high yields. The iron catalyst is air and moisture stable and is readily accessible. PMID- 28005306 TI - Nonenzymatic glycation interferes with fibronectin-integrin interactions in vascular smooth muscle cells. AB - OBJECTIVE: We aimed to investigate whether advanced nonenzymatic glycation of the ECM protein, fibronectin, impacts its normal integrin-mediated interaction with arteriolar VSMC. METHODS: AFM was performed on cultured VSMC from rat cremaster arterioles to study native and glycated fibronectin (FN and gFN) interactions with cellular integrins. AFM probes were functionalized with FN or gFN or with native or glycated albumin (gAlb) as controls. RESULTS: VSMC showed increased adhesion probability to gFN (72.9+/-3.5%) compared with native FN (63.0+/-1.6%). VSMC similarly showed increased probability of adhesion (63.8+/-1.7%) to gAlb compared with native Alb (40.1+/-4.7%). Adhesion of native FN to VSMC was alpha5 and beta1 integrin dependent whereas adhesion of gFN to VSMC was integrin independent. The RAGE-selective inhibitor, FPS-ZM1, blocked gFN (and gAlb) adhesion, suggesting that adhesion of glycated proteins was RAGE dependent. Interaction of FN with VSMC was not altered by soluble gFN while soluble native FN did not inhibit adhesion of gFN to VSMC. In contrast, gAlb inhibited adhesion of gFN to VSMC in a concentration-dependent manner. CONCLUSIONS: Glycation of FN shifts the nature of cellular adhesion from integrin- to RAGE-dependent mechanisms. PMID- 28005308 TI - Second-Generation Engineering of a Thermostable Transketolase (TKGst ) for Aliphatic Aldehyde Acceptors with Either Improved or Reversed Stereoselectivity. AB - The transketolase from Geobacillus stearothermophilus (TKGst ) is a thermostable enzyme with notable high activity and stability at elevated temperatures, but it accepts non-alpha-hydroxylated aldehydes only with low efficiency. Here we report a protein engineering study of TKGst based on double-site saturation mutagenesis either at Leu191 or at Phe435 in combination with Asp470; these are the residues responsible for substrate binding in the active site. Screening of the mutagenesis libraries resulted in several positive variants with activity towards propanal up to 7.4 times higher than that of the wild type. Variants F435L/D470E and L191V/D470I exhibited improved (73 % ee, 3S) and inverted (74 % ee, 3R) stereoselectivity, respectively, for propanal. L191V, L382F/E, F435L, and D470/D470I were concluded to be positive mutations at Leu191, Leu382, Phe435, and Asp470 both for activity and for stereoselectivity improvement. These results should benefit further engineering of TKGst for various applications in asymmetric carboligation. PMID- 28005309 TI - An Engineered Tryptophan Synthase Opens New Enzymatic Pathways to beta Methyltryptophan and Derivatives. AB - beta-Methyltryptophans (beta-mTrp) are precursors in the biosynthesis of bioactive natural products and are used in the synthesis of peptidomimetic-based therapeutics. Currently beta-mTrp is produced by inefficient multistep synthetic methods. Here we demonstrate how an engineered variant of tryptophan synthase from Salmonella (StTrpS) can catalyse the efficient condensation of l-threonine and various indoles to generate beta-mTrp and derivatives in a single step. Although l-serine is the natural substrate for TrpS, targeted mutagenesis of the StTrpS active site provided a variant (betaL166V) that can better accommodate l Thr as a substrate. The condensation of l-Thr and indole proceeds with retention of configuration at both alpha- and beta-positions to give (2S,3S)-beta-mTrp. The integration of StTrpS (betaL166V) with l-amino acid oxidase, halogenase enzymes and palladium chemocatalysts provides access to further d-configured and regioselectively halogenated or arylated beta-mTrp derivatives. PMID- 28005310 TI - The Lr34 adult plant rust resistance gene provides seedling resistance in durum wheat without senescence. AB - The hexaploid wheat (Triticum aestivum) adult plant resistance gene, Lr34/Yr18/Sr57/Pm38/Ltn1, provides broad-spectrum resistance to wheat leaf rust (Lr34), stripe rust (Yr18), stem rust (Sr57) and powdery mildew (Pm38) pathogens, and has remained effective in wheat crops for many decades. The partial resistance provided by this gene is only apparent in adult plants and not effective in field-grown seedlings. Lr34 also causes leaf tip necrosis (Ltn1) in mature adult plant leaves when grown under field conditions. This D genome encoded bread wheat gene was transferred to tetraploid durum wheat (T. turgidum) cultivar Stewart by transformation. Transgenic durum lines were produced with elevated gene expression levels when compared with the endogenous hexaploid gene. Unlike nontransgenic hexaploid and durum control lines, these transgenic plants showed robust seedling resistance to pathogens causing wheat leaf rust, stripe rust and powdery mildew disease. The effectiveness of seedling resistance against each pathogen correlated with the level of transgene expression. No evidence of accelerated leaf necrosis or up-regulation of senescence gene markers was apparent in these seedlings, suggesting senescence is not required for Lr34 resistance, although leaf tip necrosis occurred in mature plant flag leaves. Several abiotic stress-response genes were up-regulated in these seedlings in the absence of rust infection as previously observed in adult plant flag leaves of hexaploid wheat. Increasing day length significantly increased Lr34 seedling resistance. These data demonstrate that expression of a highly durable, broad spectrum adult plant resistance gene can be modified to provide seedling resistance in durum wheat. PMID- 28005312 TI - Step-Edge Assisted Direct Linear Alkane Coupling. AB - Direct coupling of alkanes via C-H activation of terminal methyl groups has acquired tremendous interests both scientifically and technically. Herein we present the results of linear alkane-coupling at the step edges of Cu surfaces at modulated temperatures. Combining the observations of scanning tunneling microscopy (STM) with density functional theory plus dispersion (DFT-D) calculations, we elucidate the mechanism of the reaction and demonstrate that the low activation barrier relies on heterogeneous catalysis at the upper step edges, where low-coordinated surface atoms are present. We further reveal the generality of the reaction, so that it can be applied on the step edges of different facets of surfaces. PMID- 28005311 TI - Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development. AB - : Essentials Potential neurodevelopmental side effects of thrombopoietin mimetics need to be considered. The effects of eltrombopag (ELT) on neuronal iron status and dendrite development were assessed. ELT crosses the blood-brain barrier and causes iron deficiency in developing neurons. ELT blunts dendrite maturation, indicating a need for more safety studies before neonatal use. SUMMARY: Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g. eltrombopag [ELT]) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective To determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14 DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 MUm ELT increased Tfr1 and Slc11a2 (iron responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 MUm ELT, but not 2 MUm ELT, decreased BdnfVI, Camk2a and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length were reduced in 6 MUm ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions Eltrombopag treatment during development may impair neuronal structure as a result of neuronal ID. Preclinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development. PMID- 28005313 TI - Hydroxylation Induced Alignment of Metal Oxide Nanocubes. AB - Water vapor is ubiquitous under ambient conditions and may alter the shape of nanoparticles. How to utilize water adsorption for nanomaterial functionality and structure formation, however, is a yet unexplored field. Herein, we report the use of water vapor to induce the self-organization of MgO nanocubes into regularly staggered one-dimensional structures. This transformation evolves via an initial alignment of the MgO cubes, the formation of intermediate elongated Mg(OH)2 structures, and their reconversion into MgO cubes arranged in staggered structures. Ab initio DFT modelling identifies surface-energy changes associated with the cube surface hydration and hydroxylation to promote the uncommon staggered stacked assembly of the cubes. This first observation of metal oxide nanoparticle self-organization occurring outside a bulk solution may pave novel routes for inducing texture in ceramics and represents a great test-bed for new surface-science concepts. PMID- 28005314 TI - Special section on STIGMA & substance use diorders. PMID- 28005316 TI - Changing attitudes in graduate medical education: A commentary on Attitudes towards Substance Use and Schizophrenia by Avery et al. PMID- 28005315 TI - Methadone "callbacks" within a veterans affairs opioid treatment program: Detecting methadone misuse. AB - BACKGROUND AND OBJECTIVES: A "callback" requires patients to bring in take-home methadone doses for inspection. An opioid treatment program (OTP) quality improvement project examined random versus "for-cause" callbacks. METHOD: Eighty two random callbacks and 60 for-cause callbacks were conducted among patients enrolled in an OTP (N = 183). RESULTS: Among patients with more take home doses, 6% of random callbacks versus 44% of for-cause callbacks were failed. Among patients with fewer take home doses, 36% of for-cause callbacks were failed. DISCUSSION AND CONCLUSIONS: For-cause callbacks are more useful than random ones. SCIENTIFIC SIGNIFICANCE: For-cause callbacks based on clinical judgment detect methadone misuse. (Am J Addict 2017;26:50-52). PMID- 28005318 TI - Sandwich-Like CNT@Fe3O4@C Coaxial Nanocables with Enhanced Lithium-Storage Capability. AB - Through the combined method of a low-temperature reflux and calcination, porous sandwich-like CNT@Fe3O4@C coaxial nanocables were cleverly constructed, which exhibited a favorable specific capacity of 724.8 mA h g-1 at 1000 mA g-1, a satisfying rate performance and admirable Coulombic efficiency (ca. 100%) for anodes of lithium-ion batteries. Due to the enlarged contact surface area, shortened Li+ diffusion distance, hierarchical porosity, reasonable structural design and good structural stability, the electrochemical performance of the CNT@Fe3O4@C nanocomposites was greatly enhanced in comparison with the traditional iron oxide anodes. So, it is a good candidate for anode materials with high performance. PMID- 28005319 TI - Suppression of Frost Nucleation Achieved Using the Nanoengineered Integral Humidity Sink Effect. AB - Inhibition of frost formation is important for increasing efficiency of refrigeration systems and heat exchangers, as well as for preventing the rapid icing over of water-repellant coatings that are designed to prevent accumulation of rime and glaze. From a thermodynamic point of view, this task can be achieved by either increasing hydrophobicity of the surface or decreasing the concentration of water vapor above it. The first approach has been studied in depth, but so far has not yielded a robust solution to the problem of frost formation. In this work, we systematically explore how frost growth can be inhibited by controlling water vapor concentration using bilayer coatings with a porous exterior covering a hygroscopic liquid-infused layer. We lay the theoretical foundation and provide experimental validation of the mass transport mechanism that governs the integral humidity sink effect based on this coating platform as well as reveal intriguing sizing effects about this system. We show that the concentration profile above periodically spaced pores is governed by the sink and source concentrations and two geometrical parameters: the nondimensional pore size and the ratio of the pore spacing to the boundary layer thickness. We demonstrate that when the ratio of the pore spacing to the boundary layer thickness vanishes, as for the nanoporous bilayer coatings, the entire surface concentration becomes uniform and equal to the concentration set by the hygroscopic liquid. In other words, the surface concentration becomes completely independent of the nanopore size. We identified the threshold geometrical parameters for this condition and show that it can lead to a 65 K decrease in the nucleation onset surface temperature below the dew point. With this fundamental insight, we use bilayer coatings to nanoengineer the integral humidity sink effect to provide extreme antifrosting performance with up to a 2 h delay in nucleation onset at 263 K. The nanoporous bilayer coatings can be designed to combine optimal antifrosting functionality with a superhydrophobic water repelling exterior to provide coatings that can robustly prevent frost, rime, and glaze accumulation. By minimizing the required amount of antifreeze, this anti icing method can have minimal operational cost and environmental impact. PMID- 28005320 TI - Remarkable Conductive Anisotropy of Metallic Microcoil/PDMS Composites Made by Electric Field Induced Alignment. AB - We successfully fabricated a highly anisotropic electrical conductive microcoil/polydimethylsiloxane (PDMS) composite based on helical Spirulina templated metallic particles using an electric field-induced alignment method. The optimized AC electric field (2 kV/cm, 1 kHz) could efficiently assemble the lightweight conductive microcoils into continuous long chains and form unique end to-end physical contacts between adjacent particles in the alignment direction, leading to highly conductive channels. Furthermore, the electrical conductivity in the alignment direction reached up to ~10 S/m for 1 wt % loading and exhibited almost 7-8 orders of magnitude higher than that in perpendicular directions, which is by far the most remarkable conductive anisotropy for anisotropic conductive composites (ACCs). In addition, the anisotropic composites exhibit excellent current-carrying capability in a functional light emitting diode (LED) circuit. Therefore, due to the superior conductive anisotropy and high conductivity, the composites have promising potential in high reliability electrical interconnections and subminiature integrated circuits. PMID- 28005321 TI - In Situ Observation of Single Au Triangular Nanoprism Etching to Various Shapes for Plasmonic Photocatalytic Hydrogen Generation. AB - In situ etching of single Au triangular nanoprism (TNP) was successfully monitored by the plasmonic photoluminescence (PL) spectra using single-particle microscopy, which provides clear results to understand the geometric and anisotropic dependence of surface plasmon resonance in Au nanostructures. Various Au nanostructures (TNP, obtuse TNP (O-TNP) and nanodisk) were obtained to synthesize anisotropic Pt-Au as plasmonic photocatalyts for hydrogen generation. Single-particle PL spectra and finite-difference time-domain simulations demonstrate that the Pt-edged Au O-TNP has larger tip area and higher plasmon enhanced electrical field for hot electron transfer and charge separation, leading to more efficient photocatalytic hydrogen generation. PMID- 28005322 TI - Lanthanoid-Doped Phosphate/Vanadate Mixed Hollow Particles as Ratiometric Luminescent Sensors. AB - Rare earth (RE) phosphates and vanadates are structurally similar compositions that display distinct but complementary luminescent properties. The properties of these phosphors can be combined in REPO4-REVO4 heterostructures during the development of new sensing technologies for biological applications. This work presents the synthesis of hollow RE phosphate/vanadate colloidal particles and evaluates their applicability as luminescent markers. Hydrothermal treatments of RE hydroxycarbonate particles in the presence of the PO43- and VO43- precursors afforded the final REPO4-REVO4 solids in a two-step template synthesis. We converted precursor hydroxycarbonate particles into the final heterostructures and characterized their structure and morphology. According to our detailed study into the spectroscopic properties of Eu3+-doped particles and their luminescence response to several species, the presence of the phosphate and vanadate phases in a single particle provided different chemical environments and enabled the design of a ratiometric approach to detect H2O2. These results open new perspectives for the development of new intracellular luminescent markers. PMID- 28005323 TI - High-Performance Hydrogen Evolution Electrocatalyst Derived from Ni3C Nanoparticles Embedded in a Porous Carbon Network. AB - In this letter, we report a facile self-foaming strategy to synthesize Ni3C nanoparticles embedded in a porous carbon network (Ni3C@PCN) by rationally incorporating a nickel salt precursor into the carbon source. As a novel hydrogen evolution reaction (HER) catalyst, the Ni3C@PCN shows superior catalytic activity with an onset potential of -65 mV, an overpotential of 262 mV to achieve 50 mA cm 2 current density, a Tafel slope of 63.4 mV/dec, and durability over 12 h in acidic media. The excellent performance of the novel 3D composite material along with its low-cost merits is suggestive of great potential for scalable electrocatalytic H2 production. PMID- 28005324 TI - CO2 Capture in Dry and Wet Conditions in UTSA-16 Metal-Organic Framework. AB - Water is the strongest competitor to CO2 in the adsorption on microporous materials, affecting their performances as CO2 scrubbers in processes such as postcombustion carbon capture. The metal-organic framework (MOF) UTSA-16 is considered a promising material for its capacity to efficiently capture CO2 in large quantities, thanks to the presence of open metal sites (OMSs). It is here shown that UTSA-16 is also able to desorb fully water already at room temperature. This property is unique from all the other materials with OMSs reported so far. UTSA-16 retains indeed the 70% of its CO2 separation capacity after admittance of water in a test flow, created to simulate the emissions from a real postcombustion carbon-capture process. This important aspect not yet observed for any other amine-free material, associated with a high material stability-tested for 160 cycles-and a small temperature swing necessary for regeneration, places UTSA-16 in the restrict number of systems with a real technological future for CO2 separation. PMID- 28005325 TI - Cross-Linked Polymer-Stabilized Nanocomposites for the Treatment of Bacterial Biofilms. AB - Infections caused by bacterial biofilms are an emerging threat to human health. Conventional antibiotic therapies are ineffective against biofilms due to poor penetration of the extracellular polymeric substance secreted by colonized bacteria coupled with the rapidly growing number of antibiotic-resistant strains. Essential oils are promising natural antimicrobial agents; however, poor solubility in biological conditions limits their applications against bacteria in both dispersed (planktonic) and biofilm settings. We report here an oil-in-water cross-linked polymeric nanocomposite (~250 nm) incorporating carvacrol oil that penetrates and eradicates multidrug-resistant (MDR) biofilms. The therapeutic potential of these materials against challenging wound biofilm infections was demonstrated through specific killing of bacteria in a mammalian cell-biofilm coculture wound model. PMID- 28005326 TI - Synergistic Effects of Plasmonics and Electron Trapping in Graphene Short-Wave Infrared Photodetectors with Ultrahigh Responsivity. AB - Graphene's unique electronic and optical properties have made it an attractive material for developing ultrafast short-wave infrared (SWIR) photodetectors. However, the performance of graphene SWIR photodetectors has been limited by the low optical absorption of graphene as well as the ultrashort lifetime of photoinduced carriers. Here, we present two mechanisms to overcome these two shortages and demonstrate a graphene-based SWIR photodetector with high responsivity and fast photoresponse. In particular, a vertical built-in field is employed in the graphene channel for trapping the photoinduced electrons and leaving holes in graphene, which results in prolonged photoinduced carrier lifetime. On the other hand, plasmonic effects were employed to realize photon trapping and enhance the light absorption of graphene. Thanks to the above two mechanisms, the responsivity of this proposed SWIR photodetector is up to a record of 83 A/W at a wavelength of 1.55 MUm with a fast rising time of less than 600 ns. This device design concept addresses key challenges for high-performance graphene SWIR photodetectors and is promising for the development of mid/far infrared optoelectronic applications. PMID- 28005327 TI - Construction of PLGA Nanoparticles Coated with Polycistronic SOX5, SOX6, and SOX9 Genes for Chondrogenesis of Human Mesenchymal Stem Cells. AB - Transfection of a cocktail of genes into cells has recently attracted attraction in stem cell differentiation. However, it is not easy to control the transfection rate of each gene. To control and regulate gene delivery into human mesenchymal stem cells (hMSCs), we employed multicistronic genes coupled with a nonviral gene carrier system for stem cell differentiation. Three genes, SOX5, SOX6, and SOX9, were successfully fabricated in a single plasmid. This multicistronic plasmid was complexed with the polycationic polymer polyethylenimine, and poly(lactic-co glycolic) acid (PLGA) nanoparticles were coated with this complex. The uptake of PLGA nanoparticles complexed with the multicistronic plasmid was tested first. Thereafter, transfection of SOX5, SOX6, and SOX9 was evaluated, which increased the potential for chondrogenesis of hMSCs. The expression of specific genes triggered by transfection of SOX5, SOX6, and SOX9 was tested by RT-PCR and real time qPCR. Furthermore, specific proteins related to chondrocytes were investigated by a glycosaminoglycan/DNA assay, Western blotting, histological analyses, and immunofluorescence staining. These methods demonstrated that chondrogenesis of hMSCs treated with PLGA nanoparticles carrying this multicistronic genes was better than that of hMSCs treated with other carriers. Furthermore, the multicistronic genes complexed with PLGA nanoparticles were more simple than that of each single gene complexation with PLGA nanoparticles. Multicistronic genes showed more chondrogenic differentiation than each single gene transfection methods. PMID- 28005328 TI - Nanoporous Tin with a Granular Hierarchical Ligament Morphology as a Highly Stable Li-Ion Battery Anode. AB - Next generation Li-ion batteries will require negative electrode materials with energy densities many-fold higher than that found in the graphitic carbon currently used in commercial Li-ion batteries. While various nanostructured alloying-type anode materials may satisfy that requirement, such materials do not always exhibit long cycle lifetimes and/or their processing routes are not always suitable for large-scale synthesis. Here, we report on a high-performance anode material for next generation Li-ion batteries made of nanoporous Sn powders with hierarchical ligament morphology. This material system combines both long cycle lifetimes (more than 72% capacity retention after 350 cycles), high capacity (693 mAh/g, nearly twice that of commercial graphitic carbon), good charging/discharging capabilities (545 mAh/g at 1 A/g, 1.5C), and a scalable processing route that involves selective alloy corrosion. The good cycling performance of this system is attributed to its nanoporous architecture and its unique hierarchical ligament morphology, which accommodates the large volume changes taking place during lithiation, as confirmed by synchrotron-based ex-situ X-ray 3D tomography analysis. Our findings are an important step for the development of high-performance Li-ion batteries. PMID- 28005329 TI - Quantitative Three-Dimensional Characterization of Block Copolymer Directed Self Assembly on Combined Chemical and Topographical Prepatterned Templates. AB - Characterization of the three-dimensional (3D) structure in directed self assembly (DSA) of block copolymers is crucial for understanding the complex relationships between the guiding template and the resulting polymer structure so DSA could be successfully implemented for advanced lithography applications. Here, we combined scanning transmission electron microscopy (STEM) tomography and coarse-grain simulations to probe the 3D structure of P2VP-b-PS-b-P2VP assembled on prepatterned templates using solvent vapor annealing. The templates consisted of nonpreferential background and raised guiding stripes that had PS-preferential top surfaces and P2VP-preferential sidewalls. The full 3D characterization allowed us to quantify the shape of the polymer domains and the interface between domains as a function of depth in the film and template geometry and offered important insights that were not accessible with 2D metrology. Sidewall guiding was advantageous in promoting the alignment and lowering the roughness of the P2VP domains over the sidewalls, but incommensurate confinement from the increased topography could cause roughness and intermittent dislocations in domains over the background region at the bottom of the film. The 3D characterization of bridge structures between domains over the background and breaks within domains on guiding lines sheds light on possible origins of common DSA defects. The positional fluctuations of the PS/P2VP interface between domains showed a depth-dependent behavior, with high levels of fluctuations near both the free surface of the film and the substrate and lower fluctuation levels in the middle of the film. This research demonstrates how 3D characterization offers a better understanding of DSA processes, leading to better design and fabrication of directing templates. PMID- 28005330 TI - Bilayer Polymer Metacomposites Containing Negative Permittivity Layer for New High-k Materials. AB - Polymer matrix high-k composites are of considerable interest in various electronic devices, such as capacitors, antennas, actuators, etc. However, how to enhance the permittivity without elevating the loss remains a challenge for us. Here we present a novel design of bilayer high-k metacomposites consisting of two stacked single layers with positive permittivity and negative permittivity. Interestingly, the bilayer system shows an obvious permittivity boost effect with a permittivity improved by a 40-fold increase compared with the polymer matrix, while maintaining a loss tangent as low as 0.06. Further calculation results indicate that the permittivity of the bilayer composites could be enhanced by 4000-fold or even a greater increase as compared with the polymer matrix via balancing the dielectric properties of single layers. Insights into how the thickness ratios and dielectric properties of single layers interfere with the dielectric performances of bilayer composites were discussed. This study provides a new route for the design of high-k materials, and it will have great significance on the development of dielectric materials. Hopefully, multilayer high-k metacomposites with fascinating dielectric performances could be achieved via balancing the dielectric properties of single layers. PMID- 28005331 TI - Magnetic and Folate Functionalization Enables Rapid Isolation and Enhanced Tumor Targeting of Cell-Derived Microvesicles. AB - Cell-derived microvesicles (MVs), which are biogenic nanosized membrane-bound vesicles that convey bioactive molecules between cells, have recently received attention for use as natural therapeutic platforms. However, the medical applications of MV-based delivery platforms are limited by the lack of effective methods for the efficient isolation of MVs and the convenient tuning of their targeting properties. Herein, we report the development of magnetic and folate (FA)-modified MVs based on a donor cell-assisted membrane modification strategy. MVs inherit the membrane properties of their donor cells, which allows them to be modified with the biotin and FA on their own membrane. By conjugating with streptavidin-modified iron oxide nanoparticles (SA-IONPs), the MVs can be conveniently, efficiently, and rapidly isolated from the supernatant of their donor cells using magnetic activated sorting. Moreover, the conjugated magnetic nanoparticles and FA confer magnetic and ligand targeting activities on the MVs. Then, the MVs were transformed into antitumor delivery platforms by directly loading doxorubicin via electroporation. The modified MVs exhibited significantly enhanced antitumor efficacy both in vitro and in vivo. Taken together, this study provides an efficient and convenient strategy for the simultaneous isolation of cell-derived MVs and transformation into targeted drug delivery nanovectors, thus facilitating the development of natural therapeutic nanoplatforms. PMID- 28005332 TI - Surface-Imprinted Magnetic Carboxylated Cellulose Nanocrystals for the Highly Selective Extraction of Six Fluoroquinolones from Egg Samples. AB - We herein describe a novel adsorbent based on molecularly imprinted polymers (MIPs) on the surface of magnetic carboxylated cellulose nanocrystals (Fe3O4@CCNs@MIPs) for the separation and purification of six fluoroquinolones (FQs) from egg samples. The obtained Fe3O4@CCNs@MIPs not only exhibited a large surface area and specific recognition toward FQs, but also were easily gathered and separated from the egg samples using an external magnetic field. The morphologies and surface groups of the Fe3O4@CCNs@MIPs were assessed by X-ray photoelectron spectroscopy, transmission electron microscopy, vibrating sample magnetometry, X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, and Brunauer-Emmett-Teller surface area analysis. The Fe3O4@CCNs@MIPs exhibited high selectivity toward six structurally similar FQs. An enrichment approach was established for the measurement of six FQs from egg samples using Fe3O4@CCNs@MIPs coupled to high-performance liquid chromatography. The recovery of spiked FQs ranged from 75.2-104.9% and limit of detection was in the range of 3.6-18.4 ng g-1 for the six FQs. Therefore, the proposed method is a promising technique for the enrichment, separation, and determination of FQs from biomatrices. PMID- 28005333 TI - Spin-Orbit Coupling Induced Gap in Graphene on Pt(111) with Intercalated Pb Monolayer. AB - Graphene is one of the most promising materials for nanoelectronics owing to its unique Dirac cone-like dispersion of the electronic state and high mobility of the charge carriers. However, to facilitate the implementation of the graphene based devices, an essential change of its electronic structure, a creation of the band gap should controllably be done. Brought about by two fundamentally different mechanisms, a sublattice symmetry breaking or an induced strong spin orbit interaction, the band gap appearance can drive graphene into a narrow-gap semiconductor or a 2D topological insulator phase, respectively, with both cases being technologically relevant. The later case, characterized by a spin-orbit gap between the valence and conduction bands, can give rise to the spin-polarized topologically protected edge states. Here, we study the effect of the spin-orbit interaction enhancement in graphene placed in contact with a lead monolayer. By means of angle-resolved photoemission spectroscopy, we show that intercalation of the Pb interlayer between the graphene sheet and the Pt(111) surface leads to formation of a gap of ~200 meV at the Dirac point of graphene. Spin-resolved measurements confirm the splitting to be of a spin-orbit nature, and the measured near-gap spin structure resembles that of the quantum spin Hall state in graphene, proposed by Kane and Mele [ Phys. Rev. Lett. 2005 , 95 , 226801 ]. With a bandstructure tuned in this way, graphene acquires a functionality going beyond its intrinsic properties and becomes more attractive for possible spintronic applications. PMID- 28005334 TI - Design of UV-Absorbing Polypropylene Films with Polymeric Benzotriaziole Based Nano- and Microparticle Coatings. AB - UV-absorbing nanoparticles (NPs) and microparticles (MPs) were prepared by emulsion and dispersion copolymerization of the vinylic monomer 2-(2'-hydroxy-5' methacryloxyethylphenyl)-2H-benzotriazole (Norbloc (NB)) with the crosslinking monomer divinylbenzene. The effect of the initiator concentration on the size and size distribution of the polyNB (PNB) particles was elucidated. Thin coatings of the formed PNB NPs or MPs of 19 +/- 2 and 200 +/- 25 nm dry diameter, respectively, onto polypropylene (PP) films were then prepared and characterized. Increasing the concentration or thickness of the PNB NP or MP thin coatings on the PP films decreased their UV transmittance, up to complete UV blocking with just 2 MUm of a 4% NP coating. Migration of the UV-absorbing agents from the coated PP films was not observed during three years of storage at room temperature, offering a unique solution to current problems of migration of UV absorbing additives. The thin coatings obtained by the PNB NPs were superior to those of the PNB MPs, in that no UV transmittance or loss of optical properties of the PP films were observed for the NP coatings, while the coatings produced by the PNB MPs resulted in damaged optical properties, particularly increasing the haze, and achieved incomplete UV blocking. PMID- 28005335 TI - Tumor-Specific Multiple Stimuli-Activated Dendrimeric Nanoassemblies with Metabolic Blockade Surmount Chemotherapy Resistance. AB - Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs. In the meantime, we proposed a versatile tactic of a tumor-specific metabolism blockade for provoking several pathways (ATP restriction, apoptotic activation, and anti-apoptotic inhibition) to restrain multiple cellular factors of drug resistance. The highly efficient antitumor activity to drug-resistant MCF-7R tumor in vitro and in vivo supports this design and strongly defeats both physiological barriers and cellular factors of chemotherapy resistance. This work sets up an innovative dendrimeric nanosystem to surmount multidrug resistance, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications. PMID- 28005336 TI - Mapping of Molecular Structure of the Nanoscale Surface in Bionanoparticles. AB - Characterizing the orientation of covalently conjugated proteins on nanoparticles, produced for in vitro and in vivo targeting, though an important feature of such a system, has proved challenging. Although extensive physicochemical characterization of targeting nanoparticles can be addressed in detail, relevant biological characterization of the nanointerface is crucial in order to select suitable nanomaterials for further in vitro or in vivo experiments. In this work, we adopt a methodology using antibody fragments (Fab) conjugated to gold nanoparticles (immunogold) to map the available epitopes on a transferrin grafted silica particle (SiO2-PEG8-Tf) as a proxy methodology to predict nanoparticle biological function, and therefore cellular receptor engagement. Data from the adopted method suggest that, on average, only ~3.5% of proteins grafted on the SiO2-PEG8-Tf nanoparticle surface have a favorable orientation for recognition by the cellular receptor. PMID- 28005337 TI - Colloidal Synthesis of Bipolar Off-Stoichiometric Gallium Iron Oxide Spinel-Type Nanocrystals with Near-IR Plasmon Resonance. AB - We report the colloidal synthesis of ~5.5 nm inverse spinel-type oxide Ga2FeO4 (GFO) nanocrystals (NCs) with control over the gallium and iron content. As recently theoretically predicted, some classes of spinel-type oxide materials can be intrinsically doped by means of structural disorder and/or change in stoichiometry. Here we show that, indeed, while stoichiometric Ga2FeO4 NCs are intrinsic small bandgap semiconductors, off-stoichiometric GFO NCs, produced under either Fe-rich or Ga-rich conditions, behave as degenerately doped semiconductors. As a consequence of the generation of free carriers, both Fe-rich and Ga-rich GFO NCs exhibit a localized surface plasmon resonance in the near infrared at ~1000 nm, as confirmed by our pump-probe absorption measurements. Noteworthy, the photoelectrochemical characterization of our GFO NCs reveal that the majority carriers are holes in Fe-rich samples, and electrons in Ga-rich ones, highlighting the bipolar nature of this material. The behavior of such off stoichiometric NCs was explained by our density functional theory calculations as follows: the substitution of Ga3+ by Fe2+ ions, occurring in Fe-rich conditions, can generate free holes (p-type doping), while the replacement of Fe2+ by Ga3+ cations, taking place in Ga-rich samples, produces free electrons (n-type doping). These findings underscore the potential relevance of spinel-type oxides as p-type transparent conductive oxides and as plasmonic semiconductors. PMID- 28005338 TI - Why So Slow? Mechanistic Insights from Studies of a Poor Catalyst for Polymerization of epsilon-Caprolactone. AB - Polymerization of epsilon-caprolactone (CL) using an aluminum alkoxide catalyst (1) designed to prevent unproductive trans binding was monitored at 110 degrees C in toluene-d8 by 1H NMR and the concentration versus time data fit to a first order rate expression. A comparison of t1/2 for 1 to values for many other aluminum alkyl and alkoxide complexes shows much lower activity of 1 toward polymerization of CL. Density functional theory calculations were used to understand the basis for the slow kinetics. The optimized geometry of the ligand framework of 1 was found indeed to make CL trans binding difficult: no trans bound intermediate could be identified as a local minimum. Nor were local minima for cis-bound precomplexes found, suggesting a concerted coordination-insertion for polymer initiation and propagation. The sluggish performance of 1 is attributed to a high-framework distortion energy required to deform the "resting" ligand geometry to that providing optimal catalysis in the corresponding transition-state structure geometry, thus suggesting a need to incorporate ligand flexibility in the design of efficient polymerization catalysts. PMID- 28005339 TI - Laboratory Studies of the Cloud Droplet Activation Properties and Corresponding Chemistry of Saline Playa Dust. AB - Playas emit large quantities of dust that can facilitate the activation of cloud droplets. Despite the potential importance of playa dusts for cloud formation, most climate models assume that all dust is nonhygroscopic; however, measurements are needed to clarify the role of dusts in aerosol-cloud interactions. Here, we report measurements of CCN activation from playa dusts and parameterize these results in terms of both kappa-Kohler theory and adsorption activation theory for inclusion in atmospheric models. kappa ranged from 0.002 +/- 0.001 to 0.818 +/- 0.094, whereas Frankel-Halsey-Hill (FHH) adsorption parameters of AFHH = 2.20 +/- 0.60 and BFHH = 1.24 +/- 0.14 described the water uptake properties of the dusts. Measurements made using aerosol time-of-flight mass spectrometry (ATOFMS) revealed the presence of halite, sodium sulfates, and sodium carbonates that were strongly correlated with kappa underscoring the role that mineralogy, including salts, plays in water uptake by dust. Predictions of kappa made using bulk chemical techniques generally showed good agreement with measured values. However, several samples were poorly predicted suggesting that chemical heterogeneities as a function of size or chemically distinct particle surfaces can determine the hygroscopicity of playa dusts. Our results further demonstrate the importance of dust in aerosol-cloud interactions. PMID- 28005340 TI - Probing the Flexibility of the Catalytic Nucleophile in the Lyase Catalytic Pocket of Human DNA Polymerase beta with Unnatural Lysine Analogues. AB - DNA polymerase beta (Pol beta) is a key enzyme in mammalian base excision repair (BER), contributing stepwise 5'-deoxyribose phosphate (dRP) lyase and "gap filling" DNA polymerase activities. The lyase reaction is believed to occur via a beta-elimination reaction following the formation of a Schiff base between the dRP group at the pre-incised apurinic/apyrimidinic site and the epsilon-amino group of Lys72. To probe the steric constraints on the formation and subsequent resolution of the putative Schiff base intermediate within the lyase catalytic pocket, Lys72 was replaced with each of several nonproteinogenic lysine analogues. The modified Pol beta enzymes were produced by coupled in vitro transcription and translation from a modified DNA template containing a TAG codon at the position corresponding to Lys72. In the presence of a misacylated tRNACUA transcript, suppression of the UAG codon in the transcribed mRNA led to elaboration of full length Pol beta having a lysine analogue at position 72. Replacement of the primary nucleophilic amine with a secondary amine in the form of N-methyllysine (4) affected mainly the stability of the Schiff base intermediate and resulted in relatively moderate inhibition of lyase activity and BER. Elongation of the side chain of the catalytic residue by one methylene group, achieved by introduction of homolysine (6) at position 72, apparently shifted the amino group to a position less favorable for Schiff base formation. Interestingly, this effect was attenuated when the side chain was elongated by replacing one side-chain methylene group with a bridging S atom (thialysine, 2). In comparison, replacement of lysine 72 with an analogue having a guanidine moiety in lieu of an epsilon-amino group (homoarginine, 5) or a sterically constrained secondary amine (piperidinylalanine, 3) led to almost complete suppression of dRP excision activity and the ability of Pol beta to support BER. These results help to define the tolerance of Pol beta to subtle local structural and functional alterations. PMID- 28005341 TI - Sensitive and Accurate 13C Kinetic Isotope Effect Measurements Enabled by Polarization Transfer. AB - Polarization transfer is demonstrated as a sensitive technique for the measurement of isotopic fractionation of protonated carbons at natural abundance. This method allows kinetic isotope effects (KIEs) to be determined with substantially less material or shorter acquisition time compared with traditional experiments. Computations quantitatively reproduce the KIEs in a Diels-Alder reaction and a catalytic glycosylation. The glycosylation is shown to occur by an effectively concerted mechanism. PMID- 28005343 TI - Pump-to-Wheels Methane Emissions from the Heavy-Duty Transportation Sector. AB - Pump-to-wheels (PTW) methane emissions from the heavy-duty (HD) transportation sector, which have climate change implications, are poorly documented. In this study, methane emissions from HD natural gas fueled vehicles and the compressed natural gas (CNG) and liquefied natural gas (LNG) fueling stations that serve them were characterized. A novel measurement system was developed to quantify methane leaks and losses. Engine related emissions were characterized from twenty two natural gas fueled transit buses, refuse trucks, and over-the-road (OTR) tractors. Losses from six LNG and eight CNG stations were characterized during compression, fuel delivery, storage, and from leaks. Cryogenic boil-off pressure rise and pressure control venting from LNG storage tanks were characterized using theoretical and empirical modeling. Field and laboratory observations of LNG storage tanks were used for model development and evaluation. PTW emissions were combined with a specific scenario to view emissions as a percent of throughput. Vehicle tailpipe and crankcase emissions were the highest sources of methane. Data from this research are being applied by the authors to develop models to forecast methane emissions from the future HD transportation sector. PMID- 28005342 TI - Probing Enhanced Double-Strand Break Formation at Abasic Sites within Clustered Lesions in Nucleosome Core Particles. AB - DNA is rapidly cleaved under mild alkaline conditions at apyrimidinic/apurinic sites, but the half-life is several weeks in phosphate buffer (pH 7.5). However, abasic sites are ~100-fold more reactive within nucleosome core particles (NCPs). Histone proteins catalyze the strand scission, and at superhelical location 1.5, the histone H4 tail is largely responsible for the accelerated cleavage. The rate constant for strand scission at an abasic site is enhanced further in a nucleosome core particle when it is part of a bistranded lesion containing a proximal strand break. Cleavage of this form results in a highly deleterious double-strand break. This acceleration is dependent upon the position of the abasic lesion in the NCP and its structure. The enhancement in cleavage rate at an apurinic/apyrimidinic site rapidly drops off as the distance between the strand break and abasic site increases and is negligible once the two forms of damage are separated by 7 bp. However, the enhancement of the rate of double strand break formation increases when the size of the gap is increased from one to two nucleotides. In contrast, the cleavage rate enhancement at 2 deoxyribonolactone within bistranded lesions is more modest, and it is similar in free DNA and nucleosome core particles. We postulate that the enhanced rate of double-strand break formation at bistranded lesions containing apurinic/apyrimidinic sites within nucleosome core particles is a general phenomenon and is due to increased DNA flexibility. PMID- 28005344 TI - Hydrothermal Conversion of Triclosan-The Role of Activated Carbon as Sorbent and Reactant. AB - Triclosan (TCS) was treated under hydrothermal conditions at 240 degrees C for 4 h, either dissolved in aqueous solution or preadsorbed onto activated carbon (AC). Hydrothermal conversion of dissolved TCS led to formation of 2,8 dichlorodibenzo-p-dioxin (DCDD). Its yield was dependent on the pH of the aqueous solution increasing from 38% at pH 4 up to 67% at pH 12. Adsorption of TCS at neutral pH on three different kinds of ACs, powder, granular, and felt, changed the reactivity of the TCS molecule under hydrothermal conditions significantly. The conversion of TCS and, in particular, the formation of DCDD was inhibited in the presence of ACs. When TCS was adsorbed on powdered AC, the preferred reaction pathway was the reductive hydrodechlorination. The findings described herein may be valuable for a potential regeneration method for loaded AC based on hydrothermal treatment. PMID- 28005345 TI - Dioxygen Reactivity of an Iron Complex of 2-Aminophenol-Appended Ligand: Crystallographic Evidence of the Aromatic Ring Cleavage Product of the 2 Aminophenol Unit. AB - 2-Aminophenol appended pentadentate ligand H2GanAP was synthesized by mixing equimolar amounts of 2-[bis(2-pyridylmethyl)aminomethyl]aniline (A) and 3,5-di tert-butyl catechol in hexane in the presence of Et3N under air. The ligand reacted with Fe(ClO4)2.6H2O or Fe(ClO4)3.6H2O in the presence of tetrabutylammonium perchlorate, and Et3N under air and provided a MU2 oxo-bridged dinuclear iron complex (1). X-ray single-crystal analysis of complex 1 revealed the presence of a furan derivative, resulting from the oxidative aromatic C-C bond cleavage product of 2-aminophenol derivative, in the coordination sphere of each iron center. Mechanistic investigation for the formation of complex 1 established that in the absence of molecular oxygen no oxidation of the appended 2-amidophenolate unit took place. An iron(III)-amidophenolate complex, formed initially, further reacted with molecular oxygen and caused oxidative aromatic C C bond cleavage via a putative alkylperoxo species. PMID- 28005347 TI - New Orthogonal Transcriptional Switches Derived from Tet Repressor Homologues for Saccharomyces cerevisiae Regulated by 2,4-Diacetylphloroglucinol and Other Ligands. AB - Here we describe the development of tightly regulated expression switches in yeast, by engineering distant homologues of Escherichia coli TetR, including the transcriptional regulator PhlF from Pseudomonas and others. Previous studies demonstrated that the PhlF protein bound its operator sequence (phlO) in the absence of 2,4-diacetylphloroglucinol (DAPG) but dissociated from phlO in the presence of DAPG. Thus, we developed a DAPG-Off system in which expression of a gene preceded by the phlO-embedded promoter was activated by a fusion of PhlF to a multimerized viral activator protein (VP16) domain in a DAPG-free environment but repressed when DAPG was added to growth medium. In addition, we constructed a DAPG-On system with the opposite behavior of the DAPG-Off system; i.e., DAPG triggers the expression of a reporter gene. Exposure of DAPG to yeast cells did not cause any serious deleterious effect on yeast physiology in terms of growth. Efforts to engineer additional Tet repressor homologues were partially successful and a known mammalian switch, the p-cumate switch based on CymR from Pseudomonas, was found to function in yeast. Orthogonality between the TetR (doxycycline), CamR (d-camphor), PhlF (DAPG), and CymR (p-cumate)-based Off switches was demonstrated by evaluating all 4 ligands against suitably engineered yeast strains. This study expands the toolbox of "On" and "Off" switches for yeast biotechnology. PMID- 28005346 TI - Identification of Crucial Amino Acid Residues Involved in Agonist Signaling at the GPR55 Receptor. AB - GPR55 is a newly deorphanized class A G-protein-coupled receptor that has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Few potent GPR55 ligands have been identified to date. This is largely due to an absence of information about salient features of GPR55, such as residues important for signaling and residues implicated in the GPR55 signaling cascade. The goal of this work was to identify residues that are key for the signaling of the GPR55 endogenous ligand, l-alpha lysophosphatidylinositol (LPI), as well as the signaling of the GPR55 agonist, ML184 {CID 2440433, 3-[4-(2,3-dimethylphenyl)piperazine-1-carbonyl]-N,N-dimethyl 4-pyrrolidin-1-ylbenzenesulfonamide}. Serum response element (SRE) and serum response factor (SRF) luciferase assays were used as readouts for studying LPI and ML184 signaling at the GPR55 mutants. A GPR55 R* model based on the recent delta-opioid receptor (DOR) crystal structure was used to interpret the resultant mutation data. Two residues were found to be crucial for agonist signaling at GPR55, K2.60 and E3.29, suggesting that these residues form the primary interaction site for ML184 and LPI at GPR55. Y3.32F, H(170)F, and F6.55A/L mutation results suggested that these residues are part of the orthosteric binding site for ML184, while Y3.32F and H(170)F mutation results suggest that these two residues are part of the LPI binding pocket. Y3.32L, M3.36A, and F6.48A mutation results suggest the importance of a Y3.32/M3.36/F6.48 cluster in the GPR55 signaling cascade. C(10)A and C(260)A mutations suggest that these residues form a second disulfide bridge in the extracellular domain of GPR55, occluding ligand extracellular entry in the TMH1-TMH7 region of GPR55. Taken together, these results provide the first set of discrete information about GPR55 residues important for LPI and ML184 signaling and for GPR55 activation. This information should aid in the rational design of next-generation GPR55 ligands and the creation of the first high-affinity GPR55 radioligand, a tool that is sorely needed in the field. PMID- 28005348 TI - Ultrahigh-Vacuum Tip-Enhanced Raman Spectroscopy. AB - Molecule-surface interactions and processes are at the heart of many technologies, including heterogeneous catalysis, organic photovoltaics, and nanoelectronics, yet they are rarely well understood at the molecular level. Given the inhomogeneous nature of surfaces, molecular properties often vary among individual surface sites, information that is lost in ensemble-averaged techniques. In order to access such site-resolved behavior, a technique must possess lateral resolution comparable to the size of surface sites under study, analytical power capable of examining chemical properties, and single-molecule sensitivity. Tip-enhanced Raman spectroscopy (TERS), wherein light is confined and amplified at the apex of a nanoscale plasmonic probe, meets these criteria. In ultrahigh vacuum (UHV), TERS can be performed in pristine environments, allowing for molecular-resolution imaging, low-temperature operation, minimized tip and molecular degradation, and improved stability in the presence of ultrafast irradiation. The aim of this review is to give an overview of TERS experiments performed in UHV environments and to discuss how recent reports will guide future endeavors. The advances made in the field thus far demonstrate the utility of TERS as an approach to interrogate single-molecule properties, reactions, and dynamics with spatial resolution below 1 nm. PMID- 28005349 TI - Correction to "Catalytic Asymmetric Synthesis of Chiral gamma-Amino Ketones via Umpolung Reactions of Imines". PMID- 28005350 TI - Responses of the Proteome and Metabolome in Livers of Zebrafish Exposed Chronically to Environmentally Relevant Concentrations of Microcystin-LR. AB - In this study, for the first time, changes in expressions of proteins and profiles of metabolites in liver of the small, freshwater fish [Formula: see text] (zebrafish) were investigated after long-term exposure to environmentally relevant concentrations of microcystin-LR (MC-LR). Male zebrafish were exposed via water to 1 or 10 MUg MC-LR/L for 90 days, and iTRAQ-based proteomics and 1H NMR-based metabolomics were employed. Histopathological observations showed that MC-LR caused damage to liver, and the effects were more pronounced in fish exposed to 10 MUg MC-LR/L. Metabolomic analysis also showed alterations of hepatic function, which included changes in a number of metabolic pathways, including small molecules involved in energy, glucose, lipids, and amino acids metabolism. Concentrations of lactate were significantly greater in individuals exposed to MC-LR than in unexposed controls. This indicated a shift toward anaerobic metabolism, which was confirmed by impaired respiration in mitochondria. Proteomics revealed that MC-LR significantly influenced multiple proteins, including those involved in folding of proteins and metabolism. Endoplasmic reticulum stress contributed to disturbance of metabolism of lipids in liver of zebrafish exposed to MC-LR. Identification of proteins and metabolites in liver of zebrafish responsive to MC-LR provides insights into mechanisms of chronic toxicity of MCs. PMID- 28005351 TI - Annulated Isomeric, Expanded, and Contracted Porphyrins. AB - Compared to porphyrin, its isomeric, expanded, and contracted analogues are less well explored. This contrast is found to be even more drastic in the case of their peripherally annulated counterparts. Nevertheless, the chemistry of annulated isomeric, expanded, and contracted porphyrins started flourishing recently with considerable efforts over the past few years, as evidenced by an increasing number of publications. While keeping the essence of porphyrins, these annulated versions exhibit quite unique properties that have no precedence in their nonannulated counterparts. An in-depth update of research carried out so far in this emerging area will be presented in this review. PMID- 28005352 TI - Active Antibacterial and Antifouling Surface Coating via a Facile One-Step Enzymatic Cross-Linking. AB - Prevention of microbial contamination of surfaces is one of the biggest challenges for biomedical applications. Establishing a stable, easily produced, highly antibacterial surface coating offers an efficient solution but remains a technical difficulty. Here, we report on a new approach to create an in situ hydrogel film-coating on glass surfaces made by enzymatic cross-linking under physiological conditions. The cross-linking is catalyzed by horseradish peroxidase (HRP)/glucose oxidase (GOD)-coupled cascade reactions in the presence of glucose and results in 3D dendritic polyglycerol (dPG) scaffolds bound to the surface of glass. These scaffolds continuously release H2O2 as long as glucose is present in the system. The resultant polymeric coating is highly stable, bacterial-repellent, and functions under physiological conditions. Challenged with high loads of bacteria (OD540 = 1.0), this novel hydrogel and glucose amended coating reduced the cell viability of Pseudomonas putida (Gram-negative) by 100% and Staphylococcus aureus (Gram-positive) by >=40%, respectively. Moreover, glucose-stimulated production of H2O2 by the coating system was sufficient to kill both test bacteria (at low titers) with >99.99% efficiency within 24 h. In the presence of glucose, this platform produces a coating with high effectiveness against bacterial adhesion and survival that can be envisioned for the applications in the glucose-associated medical/oral devices. PMID- 28005353 TI - Ionic Liquids with Symmetric Diether Tails: Bulk and Vacuum-Liquid Interfacial Structures. AB - The behavior in the bulk and at interfaces of biphilic ionic liquids in which either the cation or anion possesses moderately long alkyl tails is to a significant degree well understood. Less clear is what happens when both the cation and anion possess tails that are not apolar, such as in the case of ether functionalities. The current article discusses the structural characteristics of C2OC2OC2-mim+/C2OC2OC2-OSO3- in the bulk and at the vacuum interface. We find that the vacuum interface affects only the nanometer length scale. This is in contrast to what we have recently found in ( J. Phys. Chem. Lett. , 2016 , 7 ( 19 ), 3785 - -3790 ) for isoelectronic C[8]-mim+/C[8]-OSO3-, where the interface effect is long ranged. Interestingly, ions with the diether tail functionality still favor the tail-outward orientation at the vacuum interface and the bulk phase preserves the alternation between charged networks and tails that is commonly observed for biphilic ionic liquids. However, such alternation is less well-defined and results in a significantly diminished first sharp diffraction peak in the bulk liquid structure function. PMID- 28005354 TI - Modeling of Extended N-H Solids at High Pressures. AB - The formation of nitrogen-hydrogen networked compounds is a promising approach for obtaining high energy density materials. Multiple experimental reports indicate that the synthesis pressure and temperature of high-energy nitrogen networked compounds significantly decrease when adding hydrogen to nitrogen. One- and two-dimensional structures of nitrogen-hydrogen mixtures are reported to form during synthesis and have also been observed with simulations; however, the structures are not thoroughly established or well understood. Here, we present results of calculations of nitrogen-hydrogen mixtures at pressures up to 50 GPa and predict their structural transformations upon applying and releasing pressure using density functional theory and evolutionary algorithms. Improvements in the computational procedure resulted in efficient on-the-fly elimination of slowly converging structures during the geometry optimization process. This enabled the continuation of long evolution simulations of the nitrogen-hydrogen structures with N/H ratios of 3:1, 4:1, and 9:1 at high pressures (10-50 GPa). New stable crystalline structures with high symmetry and covalent bonds are predicted that have (i) infinite chains and (ii) two-dimensional sheets of nitrogen-hydrogens. The structure with N/H ratio of 4:1 is found to be metallic at 50 GPa. Some crystalline phases stabilized by high pressure may exist as metastable structures with high symmetry and high mass density after lowering the pressure from 50 GPa down to 10 GPa. Vibration modes of calculated Raman and IR spectra are in agreement with published experimental data. PMID- 28005355 TI - Role of the Recombination Channel in the Reaction between the HO and HO2 Radicals. AB - The kinetics of the gas phase recombination reaction HO + HO2 + He -> HOOOH + He has been studied between 200 and 600 K by using the SACM/CT model and the unimolecular rate theory. The molecular properties of HOOOH were derived at the CCSD(T)/aug-cc-pVTZ ab initio level of theory, while relevant potential energy features of the reaction were calculated at the CCSD(T)/aug-cc-pVTZ//CCSD(T)/aug cc-pVDZ level. The resulting high and low pressure limit rate coefficients are kinfinity = 3.55 * 10-12 (T/300)0.20 cm3 molecule-1 s-1 and k0 = [He] 1.55 * 10 31 (T/300)-3.2 cm3 molecule-1 s-1. The rate coefficients calculated over the 6 * 10-4 - 400 bar range are smaller at least in a factor of about 60 than the consensus value determined for the main reaction channel HO + HO2 -> H2O + O2, indicating that the recombination pathway is irrelevant. PMID- 28005356 TI - Relationship between the Degree of Polymerization of Chitooligomers and Their Activity Affecting the Growth of Wheat Seedlings under Salt Stress. AB - Seven chitooligomers (COSs) with determined degrees of polymerization (DPs) (chitotetraose to chitooctaose, DP 8-10, DP 10-12) and a heterogeneous COS with various DPs were first applied to explore the relationship between the DP of COSs and their effect on the growth of wheat seedlings under salt stress. The results showed that COS could promote the growth of wheat seedlings under salt stress. Moreover, chitohexaose, chitoheptaose, and chitooctaose exhibited stronger activity compared with other COS samples, which suggested that their activity had a close relationship with the DP. After 10 days of treatment with chitohexaose, chitoheptaose, and chitooctaose, the photosynthetic parameters were obviously improved. The soluble sugar and proline contents were improved by 26.7-53.3 and 43.6-70.2%, respectively, whereas the concentration of malondialdehyde (MDA) was reduced by 36.8-49.6%. In addition, the antioxidant enzyme activities were clearly activated. At the molecular level, the results revealed that they could obviously induce the expression of Na+/H+ antiporter genes. PMID- 28005358 TI - Mechanistic Study of Cp*CoIII/RhIII-Catalyzed Directed C-H Functionalization with Diazo Compounds. AB - Density functional theory calculations have been performed to provide mechanistic insight into a series of Cp*CoIII- and Cp*RhIII-catalyzed directed C-H bond functionalizations with diazo-compound substrates. Co-based catalysis proceeds through five steps: C-H bond activation; C-C coupling via a concerted 1,2-aryl transfer; proto-demetalation; nucleophilic addition; and solvent-assisted methanol elimination. C-H bond activation is predicted to be reversible, consistent with deuterium-scrambling experiments. The higher Lewis acidity of Co compared to Rh for two otherwise identical catalysts increases the susceptibility of a coordinated carbonyl group to nucleophilic addition in the former, facilitating the formation of cyclized products not observed for Rh. Methanol elimination is predicted to be the turnover-limiting step for one substrate, and this is facilitated by solvent 2,2,2-trifluoroethanol (TFE) acting as a proton shuttle. Theory suggests that further tuning of acidity may offer opportunities for improving catalysis. We also assess the role of a pyridine group that leads to a different series of final steps in one Rh-based catalytic cycle, thereby enabling access to the otherwise suppressed cyclization product. Our study of an alternative Rh-based system having acetate ligands replaced with MeCN indicates that C-H bond activation is sensitive to those ligands and variation can affect which step is turnover-limiting. PMID- 28005357 TI - Structure-Based Design of Tricyclic NF-kappaB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K). AB - We report here structure-guided optimization of a novel series of NF-kappaB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-kappaB2 (p52/REL-B) but not canonical NF-kappaB1 (REL-A/p50). PMID- 28005360 TI - Relativistic Prolapse-Free Gaussian Basis Sets of Quadruple-zeta Quality: (aug )RPF-4Z. III. The f-Block Elements. AB - The f-block elements are addressed in this third part of a series of prolapse free basis sets of quadruple-zeta quality (RPF-4Z). Relativistic adapted Gaussian basis sets (RAGBSs) are used as primitive sets of functions while correlating/polarization (C/P) functions are chosen by analyzing energy lowerings upon basis set increments in Dirac-Coulomb multireference configuration interaction calculations with single and double excitations of the valence spinors. These function exponents are obtained by applying the RAGBS parameters in a polynomial expression. Moreover, through the choice of C/P characteristic exponents from functions of lower angular momentum spaces, a reduction in the computational demand is attained in relativistic calculations based on the kinetic balance condition. The present study thus complements the RPF-4Z sets for the whole periodic table (Z <= 118). The sets are available as Supporting Information and can also be found at http://basis-sets.iqsc.usp.br . PMID- 28005359 TI - Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines. AB - Purines and related heterocycles substituted at C-2 with 4'-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 MUM) but was ~2000-fold less active toward CDK1 (IC50 86 MUM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2. PMID- 28005361 TI - Lipid Class Specific Quantitative Analysis of n-3 Polyunsaturated Fatty Acids in Food Supplements. AB - Supplementation products containing n-3 PUFA from marine sources serve a large market. Although the amount of eicosapentaenoic acid and docosahexaenoic acid in the products is provided by the manufacturer, no or little information is available on their lipid pattern. Therefore, we quantitatively analyzed the fatty acid pattern in the lipid fractions triglycerides, phospholipids, ethyl esters, and free fatty acids in supplementation products by means of solid phase extraction and gas chromatography. Twelve products from the European and U.S. markets containing fish, krill, algal, or plant oil were analyzed. Total n-3 PUFA content ranged from 68 g/100 g fat (fish oil) to 42 g/100 g fat (algal oil) to 17 g/100 g fat (krill oil). On the basis of the n-3 PUFA containing lipid class, the supplements can be separated dominantly in ethyl ester, re-esterified triglyceride, triglyceride, and phospholipid containing products. Algae-based products contained natural triglycerides, krill oils a complex mixture of phospholipids, triglycerides, and free fatty acids, and fish oil products either ethyl esters, re-esterified triglycerides, or triglycerides. Even products of the same class and source showed distinct differences in their lipid pattern. A specification of the lipid composition of n-3 PUFA products would allow distinguishing the different (qualities of) supplements. PMID- 28005362 TI - Depolymerization Pathways for Branching Lignin Spirodienone Units Revealed with ab Initio Steered Molecular Dynamics. AB - Lignocellulosic biomass is an abundant, rich source of aromatic compounds, but direct utilization of raw lignin has been hampered by both the high heterogeneity and variability of linking bonds in this biopolymer. Ab initio steered molecular dynamics (AISMD) has emerged both as a fruitful direct computational screening approach to identify products that occur through mechanical depolymerization (i.e., in sonication or ball-milling) and as a sampling approach. By varying the direction of force and sampling over 750 AISMD trajectories, we identify numerous possible pathways through which lignin depolymerization may occur in pyrolysis or through catalytic depolymerization as well. Here, we present eight unique major depolymerization pathways discovered via AISMD for the recently characterized spirodienone lignin branching linkage that may comprise around 10% weight of all lignin in some softwoods. We extract representative trajectories from AISMD and carry out reaction pathway analysis to identify energetically favorable pathways for lignin depolymerization. Importantly, we identify dynamical effects that could not be observed through more traditional calculations of bond dissociation energies. Such effects include thermodynamically favorable recovery of aromaticity in the dienone ring that leads to near-barrierless subsequent ether cleavage and hydrogen-bonding effects that stabilize newly formed radicals. Some of the most stable spirodienone fragments that reside at most 1 eV above the reactant structure are formed with only 2 eV barriers for C-C bond cleavage, suggesting key targets for catalyst design to drive targeted depolymerization of lignin. PMID- 28005363 TI - Correction to End-Site-Specific Conjugation of Enoxaparin and Tetradeoxycholic Acid Using Nonenzymatic Glycosylation for Oral Delivery. PMID- 28005364 TI - Automatic Generation of Auxiliary Basis Sets. AB - A procedure was developed to automatically generate auxiliary basis sets (ABSs) for use with the resolution of the identity (RI) approximation, starting from a given orbital basis set (OBS). The goal is to provide an accurate and universal solution for cases where no optimized ABSs are available. In this context, "universal" is understood as the ability of the ABS to be used for Coulomb, exchange, and correlation energy fitting. The generation scheme (denoted AutoAux) works by spanning the product space of the OBS using an even-tempered expansion for each atom in the system. The performance of AutoAux in conjunction with different OBSs [def2-SVP, def2-TZVP, def2-QZVPP, and cc-pwCVnZ (n = D, T, Q, 5)] has been evaluated for elements from H to Rn and compared to existing predefined ABSs. Due to the requirements of simplicity and universality, the generated ABSs are larger than the optimized ones but lead to similar errors in MP2 total energies (on the order of 10-5 to 10-4 Eh/atom). PMID- 28005366 TI - Thermochemical and Kinetics of CH3SH + H Reactions: The Sensitivity of Coupling the Low and High-Level Methodologies. AB - The reaction system formed by the methanethiol molecule (CH3SH) and a hydrogen atom was studied via three elementary reactions, two hydrogen abstractions and the C-S bond cleavage (CH3SH + H -> CH3S + H2 (R1); -> CH2SH + H2 (R2); -> CH3 + H2S (R3)). The stable structures were optimized with various methodologies of the density functional theory and the MP2 method. Two minimum energy paths for each elementary reaction were built using the BB1K and MP2 methodologies, and the electronic properties on the reactants, products, and saddle points were improved with coupled cluster theory with single, double, and connected triple excitations (CCSD(T)) calculations. The sensitivity of coupling the low and high-level methods to calculate the thermochemical and rate constants were analyzed. The thermal rate constants were obtained by means of the improved canonical variational theory (ICVT) and the tunneling corrections were included with the small curvature tunneling (SCT) approach. Our results are in agreement with the previous experimental measurements and the calculated branching ratio for R1:R2:R3 is equal to 0.96:0:0.04, with kR1 = 9.64 * 10-13 cm3 molecule-1 s-1 at 298 K. PMID- 28005365 TI - Synthesis and Characterization of PEGylated Trityl Radicals: Effect of PEGylation on Physicochemical Properties. AB - Tetrathiatriarylmethyl (TAM, trityl) radicals have attracted considerable attention as spin probes for biological electron paramagnetic resonance (EPR) spectroscopy and imaging owing to their sharp EPR singlet signals and high biostability. However, their in vivo applications were limited by the short blood circulation lifetimes and strong binding with albumins. Our previous results showed that PEGylation is a feasible method to overcome the issues facing in vivo applications of TAM radicals. In the present study, we synthesized a series of new PEGylated TAM radicals (TTP1, TPP2, TNP1, TNP2, d-TNP1, and d-TNP3) containing various lengths and numbers of mPEG chains. Our results found that the pattern of PEGylation exerts an important effect on physicochemical properties of the resulting TAM radicals. Dendritic PEGylated TAM radicals, TNP1 and TNP2, have higher water solubility and lower susceptibility for self-aggregation than their linear analogues TPP1 and TPP2. Furthermore, dendritic PEGylated TAM radicals exhibit extremely high stability toward various biological oxidoreductants as well as in rat whole blood, liver homogenate, and following in vivo intravenous administration in mice. Importantly, the deuterated derivatives, especially d TNP3, exhibit excellent properties including the sharp and O2-sensitive EPR singlet signal, good biocompatibility, and prolonged kinetics with half-life time of >=10 h in mice. These PEGylated TAM radicals should be suitable for a wide range of applications in in vivo EPR spectroscopy and imaging. PMID- 28005367 TI - Size-Dependent Structure Relations between Nanotubes and Encapsulated Nanocrystals. AB - The structural organization of compounds in a confined space of nanometer-scale cavities is of fundamental importance for understanding the basic principles for atomic structure design at the nanolevel. Here, we explore size-dependent structure relations between one-dimensional PbTe nanocrystals and carbon nanotube containers in the diameter range of 2.0-1.25 nm using high-resolution transmission electron microscopy and ab initio calculations. Upon decrease of the confining volume, one-dimensional crystals reveal gradual thinning, with the structure being cut from the bulk in either a <110> or a <100> growth direction until a certain limit of ~1.3 nm. This corresponds to the situation when a stoichiometric (uncharged) crystal does not fit into the cavity dimensions. As a result of the in-tube charge compensation, one-dimensional superstructures with nanometer-scale atomic density modulations are formed by a periodic addition of peripheral extra atoms to the main motif. Structural changes in the crystallographic configuration of the composites entail the redistribution of charge density on single-walled carbon nanotube walls and the possible appearance of the electron density wave. The variation of the potential attains 0.4 eV, corresponding to charge density fluctuations of 0.14 e/atom. PMID- 28005368 TI - Spin State Energetics in First-Row Transition Metal Complexes: Contribution of (3s3p) Correlation and Its Description by Second-Order Perturbation Theory. AB - This paper presents an in-depth study of the performance of multiconfigurational second-order perturbation theory (CASPT2, NEVPT2) in describing spin state energetics in first-row transition metal (TM) systems, including bare TM ions, TM ions in a field of point charges (TM/PC), and an extensive series of TM complexes, where the main focus lies on the (3s3p) correlation contribution to the relative energies of different spin states. To the best of our knowledge, this is the first systematic NEVPT2 investigation of TM spin state energetics. CASPT2 has been employed in several previous studies but was regularly found to be biased toward high spin states. The bias was attributed to a too low value of the so-called IPEA shift epsilon, an empirical correction in the CASPT2 zeroth order Hamiltonian with a standard value of 0.25 hartree. Based on comparisons with experiment (TM ions) and calculations with the multireference configuration interaction (TM ions and TM/PC systems) and coupled-cluster (TM complexes) methods, we demonstrate in this work that standard CASPT2 works well for valence correlation and that its bias toward high-spin states is caused by an erratic description of (3s3p) correlation effects. The latter problem only occurs for spin transitions involving a ligand field (de)excitation, not in bare TM ions. At the same time the (3s3p) correlation contribution also becomes strongly epsilon dependent. The error can be reduced by increasing epsilon but only at the expense of deteriorating the CASPT2 description of valence correlation in the TM complexes. The alternative NEVPT2 method works well for bare TM and TM/PC systems, but its results for the TM complexes are disappointing, with large errors both for the valence and (3s3p) correlation contributions to the relative energies of different spin states. PMID- 28005369 TI - pH-Responsive Mechanistic Switch Regulates the Formation of Dendritic and Fibrillar Nanostructures of a Functional Amyloid. AB - In contrast to pathological amyloids, functional amyloids are involved in crucial physiological functions. For instance, the melanosomal protein comprising a highly amyloidogenic polypeptide repeat domain assembles into amyloid fibrils that act as templates for melanin biosynthesis within acidic melanosomes. However, the mechanism-morphology-function relationship of functional amyloids is poorly understood. Here, we demonstrate that the repeat domain of the melanosomal protein exhibits two distinct types of aggregation pathways that display nanoscale polymorphism in acidic pH. In the pH range of 4.5-6, aggregation proceeds via a typical nucleation-dependent mechanism, resulting in the formation of highly ordered beta-rich curvy thread-like fibrils. On the contrary, at pH < 4.5, aggregation occurs through a rapid nucleation-independent isodesmic polymerization process that yields dendritic aggregates having lower degree of internal packing. These dendritic nanostructures can be converted into more stable fibrils by switching the pH. The nanoscale polymorphism associated with the mechanistic switch is likely to be mediated by the altered conformational propensities and intermolecular interactions due to the protonation/deprotonation of critical glutamate residues. We propose that this striking shift in the mechanism that dictates the nanoscale morphology regulates the melanosomal maturation. PMID- 28005370 TI - Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study. AB - Binding free energies of bromodomain inhibitors are calculated with recently formulated approaches, namely ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling). A set of compounds is provided by GlaxoSmithKline, which represents a range of chemical functionality and binding affinities. The predicted binding free energies exhibit a good Spearman correlation of 0.78 with the experimental data from the 3-trajectory ESMACS, and an excellent correlation of 0.92 from the TIES approach where applicable. Given access to suitable high end computing resources and a high degree of automation, we can compute individual binding affinities in a few hours with precisions no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and 1.71 kcal/mol for the 1- and 3 trajectory ESMACS approaches. PMID- 28005371 TI - M3C: A Computational Approach To Describe Statistical Fragmentation of Excited Molecules and Clusters. AB - The Microcanonical Metropolis Monte Carlo method, based on a random sampling of the density of states, is revisited for the study of molecular fragmentation in the gas phase (isolated molecules, atomic and molecular clusters, complex biomolecules, etc.). A random walk or uniform random sampling in the configurational space (atomic positions) and a uniform random sampling of the relative orientation, vibrational energy, and chemical composition of the fragments is used to estimate the density of states of the system, which is continuously updated as the random sampling populates individual states. The validity and usefulness of the method is demonstrated by applying it to evaluate the caloric curve of a weakly bound rare gas cluster (Ar13), to interpret the fragmentation of highly excited small neutral and singly positively charged carbon clusters (Cn, n = 5,7,9 and Cn+, n = 4,5) and to simulate the mass spectrum of the acetylene molecule (C2H2). PMID- 28005372 TI - Scalable Graphene-Based Membranes for Ionic Sieving with Ultrahigh Charge Selectivity. AB - Nanostructured graphene-oxide (GO) laminate membranes, exhibiting ultrahigh water flux, are excellent candidates for next generation nanofiltration and desalination membranes, provided the ionic rejection could be further increased without compromising the water flux. Using microscopic drift-diffusion experiments, we demonstrated the ultrahigh charge selectivity for GO membranes, with more than order of magnitude difference in the permeabilities of cationic and anionic species of equivalent hydration radii. Measuring diffusion of a wide range of ions of different size and charge, we were able to clearly disentangle different physical mechanisms contributing to the ionic sieving in GO membranes: electrostatic repulsion between ions and charged chemical groups; and the compression of the ionic hydration shell within the membrane's nanochannels, following the activated behavior. The charge-selectivity allows us to rationally design membranes with increased ionic rejection and opens up the field of ion exchange and electrodialysis to the GO membranes. PMID- 28005373 TI - Infrared Spectroscopy and Born-Oppenheimer Molecular Dynamics Simulation Study on Deuterium Substitution in the Crystalline Benzoic Acid. AB - In this study we present complementary computational and experimental studies of hydrogen bond interaction in crystalline benzoic acid and its deuterated and partially deuterated derivatives. The experimental part of the presented work includes preparation of partially deuterated samples and measurement of attenuated total reflection (ATR)-FTIR spectra. Analysis of the geometrical parameters and time course of dipole moment of crystalline benzoic acid and its deuterated and partially deuterated derivatives by Born-Oppenheimer molecular dynamics (BOMD) enabled us to deeply analyze the IR spectra. Presented simulations based on BOMD gave us opportunity to investigate individual motion and its contribution to the IR spectra. The band contours calculated using Fourier transform of autocorrelation function are in quantitative agreement with the experimental spectra. Characterization of single bands was carried out by "normal coordinate analysis". The salient point of our study is a comparison of the spectra of the deuterated and partially deuterated crystalline benzoic acid with that of the nondeuterated one. Furthermore, we have applied the principal component analysis for analysis of the number of components in partially deuterated systems. In this study, we reveal that the arrangements of hydrogen and deuterium atoms in partially deuterated samples are random. PMID- 28005374 TI - Intercalation Doped Multilayer-Graphene-Nanoribbons for Next-Generation Interconnects. AB - Copper-based interconnects employed in a wide range of integrated circuit (IC) products are fast approaching a dead-end due to their increasing resistivity and diminishing current carrying capacity with scaling, which severely degrades both performance and reliability. Here we demonstrate chemical vapor deposition synthesized and intercalation-doped multilayer-graphene-nanoribbons (ML-GNRs) with better performance (more than 20% improvement in estimated delay per unit length), 25%/72% energy efficiency improvement at local/global level, and superior reliability w.r.t. Cu for the first time, for dimensions (down to 20 nm width and thickness of 12 nm) suitable for IC interconnects. This is achieved through a combination of GNR interconnect design optimization, high-quality ML GNR synthesis with precisely controlled number of layers, and effective FeCl3 intercalation doping. We also demonstrate that our intercalation doping is stable at room temperature and that the doped ML-GNRs exhibit a unique width-dependent doping effect due to increasingly efficient FeCl3 diffusion in scaled ML-GNRs, thereby indicating that our doped ML-GNRs will outperform Cu even for sub-20 nm widths. Finally, reliability assessment conducted under accelerated stress conditions (temperature and current density) established that highly scaled intercalated ML-GNRs can carry over 2 * 108 A/cm2 of current densities, whereas Cu interconnects suffer from immediate breakdown under the same stress conditions and thereby addresses the key criterion of current carrying capacity necessary for an alternative interconnect material. Our comprehensive demonstration of highly reliable intercalation-doped ML-GNRs paves the way for graphene as the next-generation interconnect material for a variety of semiconductor technologies and applications. PMID- 28005375 TI - ATN-161 Peptide Functionalized Reversibly Cross-Linked Polymersomes Mediate Targeted Doxorubicin Delivery into Melanoma-Bearing C57BL/6 Mice. AB - PHSCN peptide (licensed as ATN-161) is an effective alpha5beta1 integrin inhibitor that has advanced to phase II clinical trials to treat solid tumors. Here we developed ATN-161 functionalized self-cross-linkable and intracellularly de-cross-linkable polymersomes (ATN/SCID-Ps) for highly efficient and targeted delivery of doxorubicin hydrochloride (DOX.HCl) into B16F10 melanoma-bearing C57BL/6 mice. ATN/SCID-Ps exhibited a high loading capacity of DOX.HCl. The size of DOX-loaded ATN/SCID-Ps (DOX-ATN/SCID-Ps) decreased from 150 to 88 nm with increasing ATN surface densities from 0 to 100% (mol/mol). DOX-ATN/SCID-Ps were robust with low drug leakage under physiological conditions while quickly releasing DOX with the addition of 10 mM glutathione. MTT assay results displayed that DOX-ATN/SCID-Ps induced ATN density-dependent antitumor activity to alpha5beta1 integrin overexpressing B16F10 melanoma cells, in which 56% ATN-161 was optimal. Flow cytometry and CLSM studies revealed significantly more efficient internalization and cytoplasmic DOX release in B16F10 cells for DOX ATN/SCID-Ps than for DOX-SCID-Ps (nontargeting control) as well as clinically used pegylated liposomal doxorubicin (DOX-LPs). DOX-ATN/SCID-Ps displayed a long blood circulation time (elimination half-life = 4.13 h) and 4 times higher DOX accumulation in B16F10 bearing C57BL/6 mice than DOX-LPs. Interestingly, DOX ATN/SCID-Ps exhibited a superior maximum-tolerated dose of over 100 mg DOX.HCl/kg, 10 times higher than DOX-LPs. Remarkably, DOX-ATN/SCID-Ps could significantly inhibit the growth of aggressive B16F10 melanoma with little adverse effects via either multiple or single injection of total dosage of 100 mg DOX.HCl/kg, resulting in greatly improved survival rates as compared to DOX-LPs. ATN/SCID-Ps are appealing nanovehicles for targeted chemotherapy of alpha5beta1 integrin positive solid tumors. PMID- 28005376 TI - Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy. AB - Novel principles for optimizing the properties of peptide-based drugs are needed in order to leverage their full pharmacological potential. We present the design, synthesis, and evaluation of a library of neoglycolipidated glucagon-like peptide 1 (GLP-1) analogues, which are valuable drug candidates for treatment of type 2 diabetes and obesity. Neoglycolipidation of GLP-1 balanced the lipophilicity, directed formation of soluble oligomers, and mediated albumin binding. Moreover, neoglycolipidation did not compromise bioactivity, as in vitro potency of neoglycolipidated GLP-1 analogues was maintained or even improved compared to native GLP-1. This translated into pronounced in vivo efficacy in terms of both decreased acute food intake and improved glucose homeostasis in mice. Thus, we propose neoglycolipidation as a novel, general method for modulating the properties of therapeutic peptides. PMID- 28005377 TI - Structural, Viscoelastic, and Electrochemical Characteristics of Self-Assembled Amphiphilic Comblike Copolymers in Aqueous Solutions. AB - Self-assembly in aqueous solutions of an amphiphilic comblike polyelectrolyte (80C12) that consists of a polystyrene (PS) backbone onto which quaternary ammonium pendant moieties have been grafted has been investigated by light scattering and cryo-transmission electron microscopy measurements in the presence of KCl and methylviologen dication (MV2+) under conditions mimicking those for electrochemical measurements. Polymer chains self-assemble within branched cylindrical micelles that display viscoelastic properties, characterized by a relaxation time of 4 s. To tune this time, 80C12 was mixed with a polyoxyethylene nonionic surfactant (Brij C12E10). Relatively increasing the amount of the latter leads to a decrease in the relaxation time of the 80C12 solution. Correlatively, electrochemical experiments with a rotating disk electrode show a transition of the mass transport rate, which deviates from the classical Newtonian behavior in the same velocity domain. This result generalizes what has been already observed with solutions of linear polymers of high molecular weight and wormlike micelles based on surfactants subjected to elongational deformations. Moreover, the critical times derived from rheological and electrochemical experiments display the same trend. PMID- 28005378 TI - Direct Probing of the Electronic Structures of Single-Layer and Bilayer Graphene with a Hexagonal Boron Nitride Tunneling Barrier. AB - The chemical and mechanical stability of hexagonal boron nitride (h-BN) thin films and their compatibility with other free-standing two-dimensional (2D) crystals to form van der Waals heterostructures make the h-BN-2D tunnel junction an intriguing experimental platform not only for the engineering of specific device functionalities but also for the promotion of quantum measurement capabilities. Here, we exploit the h-BN-graphene tunnel junction to directly probe the electronic structures of single-layer and bilayer graphene in the presence and the absence of external magnetic fields with unprecedented high signal-to-noise ratios. At a zero magnetic field, we identify the tunneling spectra related to the charge neutrality point and the opening of the electric field-induced bilayer energy gap. In the quantum Hall regime, the quantization of 2D electron gas into Landau levels (LL) is seen as early as 0.2 T, and as many as 30 well-separated LL tunneling conductance oscillations are observed for both electron- and hole-doped regions. Our device simulations successfully reproduce the experimental observations. Additionally, we extract the relative permittivity of three-to-five layer h-BN and find that the screening capability of thin h-BN films is as much as 60% weaker than bulk h-BN. PMID- 28005379 TI - HIV Peptide-Mediated Binding Behaviors of Nanoparticles on a Lipid Membrane. AB - The bioinspired design of ligands for nanoparticle coating with remarkable precision in controlling anisotropic connectivity and with universal binding efficiency to the membrane has made a great impact on nanoparticle self-assembly. We utilize the HIV-1-derived trans-activator of transcription peptide (TAT), a member of the cell-penetrating peptides, as a soft shell coating on gold nanoparticles (GNPs) and characterize TAT pepide-mediated binding behaviors of GNPs on the lipid membrane. Whereas the peptides enable GNPs to firmly attach to the membrane, the binding structures are driven by two electrostatic forces: the interparticle peptide repulsion and the peptide-membrane attraction. Although transmission electron microscopy images showed that the densities of membrane embedded GNPs were almost equal, X-ray reflectivity revealed a significant difference in binding structures of GNPs along the surface normal upon the increase of charge densities (phi) of the membrane. In particular, GNPs were densely suspended at phi = 70% while they adopted an additional well-defined layer underneath the membrane at phi = 100%, in addition to a translocation of the initially bound particles into the membrane. The observed behaviors of GNPs manifest a 3D to 2D transformation of the self-assembled structures from the diffused state to the closely packed state with the increase in the charge density of the membrane. The present study also provides insights on the binding mechanisms of the cell-penetrating peptide-coated nanoparticles to the lipid membranes, which is a common theme of delivery systems in pharmaceutical research. PMID- 28005380 TI - Hyaluronic-Acid-Hydroxyapatite Colloidal Gels Combined with Micronized Native ECM as Potential Bone Defect Fillers. AB - One of the grand challenges in translational regenerative medicine is the surgical placement of biomaterials. For bone regeneration in particular, malleable and injectable colloidal gelsare frequently designed to exhibit self assembling and shear-response behavior which facilitates biomaterial placement in tissue defects. The current study demonstrated that by combining native extracellular matrix (ECM) microparticles, i.e., demineralized bone matrix (DBM) and decellularized cartilage (DCC), with hyaluronic acid (HA) and hydroxyapatite (HAP) nanoparticles, a viscoelastic colloidal gel consisting exclusively of natural materials was achieved. Rheological testing of HA-ECM suspensions and HA HAP-ECM colloidal gels concluded either equivalent or substantially higher storage moduli (G' ~ 100-10 000 Pa), yield stresses (tauy ~ 100-1000 Pa), and viscoelastic recoveries (G'recovery >= 87%) in comparison with controls formulated without ECM, which indicated a previously unexplored synergy in fluid properties between ECM microparticles and HA-HAP colloidal networks. Notable rheological differences were observed between respective DBM and DCC formulations, specifically in HA-HAP-DBM mixtures, which displayed a mean 3-fold increase in G' and a mean 4-fold increase in tauy from corresponding DCC mixtures. An initial in vitro assessment of these potential tissue fillers as substrates for cell growth revealed that all formulations of HA-ECM and HA-HAP ECM showed no signs of cytotoxicity and appeared to promote cell viability. Both DBM and DCC colloidal gels represent promising platforms for future studies in bone and cartilage tissue engineering. Overall, the current study identified colloidal gels constructed exclusively of natural materials, with viscoelastic properties that may facilitate surgical placement for a wide variety of therapeutic applications. PMID- 28005381 TI - Molecular Characterization of Organosulfur Compounds in Biodiesel and Diesel Fuel Secondary Organic Aerosol. AB - Secondary organic aerosol (SOA), formed in the photooxidation of diesel fuel, biodiesel fuel, and 20% biodiesel fuel/80% diesel fuel mixture, are prepared under high-NOx conditions in the presence and absence of sulfur dioxide (SO2), ammonia (NH3), and relative humidity (RH). The composition of condensed-phase organic compounds in SOA is measured using several complementary techniques including aerosol mass spectrometry (AMS), high-resolution nanospray desorption electrospray ionization mass spectrometry (nano-DESI/HRMS), and ultrahigh resolution and mass accuracy 21T Fourier transform ion cyclotron resonance mass spectrometry (21T FT-ICR MS). Results demonstrate that sulfuric acid and condensed organosulfur species formed in photooxidation experiments with SO2 are present in the SOA particles. Fewer organosulfur species are formed in the high humidity experiments, performed at RH 90%, in comparison with experiments done under dry conditions. There is a strong overlap of organosulfur species observed in this study with previous field and chamber studies of SOA. Many MS peaks of organosulfates (R-OS(O)2OH) previously designated as biogenic or of unknown origin in field studies might have originated from anthropogenic sources, such as photooxidation of hydrocarbons present in diesel and biodiesel fuel. PMID- 28005382 TI - Unexpected Huge Dimerization Ratio in One-Dimensional Carbon Atomic Chains. AB - Peierls theory predicted atomic distortion in one-dimensional (1D) crystal due to its intrinsic instability in 1930. Free-standing carbon atomic chains created in situ in transmission electron microscope (TEM)1-3 are an ideal example to experimentally observe the dimerization behavior of carbon atomic chain within a finite length. We report here a surprisingly huge distortion found in the free standing carbon atomic chains at 773 K, which is 10 times larger than the value expected in the system. Such an abnormally distorted phase only dominates at the elevated temperatures, while two distinct phases, distorted and undistorted, coexist at lower or ambient temperatures. Atom-by-atom spectroscopy indeed shows considerable variations in the carbon 1s spectra at each atomic site but commonly observes a slightly downshifted pi* peak, which proves its sp1 bonding feature. These results suggest that the simple model, relaxed and straight, is not fully adequate to describe the realistic 1D structure, which is extremely sensitive to perturbations such as external force or boundary conditions. PMID- 28005383 TI - Oxidative Azo-Ene Cyclization. AB - An expedient procedure for catalytic oxidative azo-ene cyclization of allylic and homoallylic 1,2-hydrazinedicarboxylates is reported. The reaction produced a wide range of cyclic carbamate derivatives featuring an appended alkene fragment ready for further functionalization. PMID- 28005384 TI - Observation of Mode Splitting in Photoluminescence of Individual Plasmonic Nanoparticles Strongly Coupled to Molecular Excitons. AB - Plasmon-exciton interactions are important for many prominent spectroscopic applications such as surface-enhanced Raman scattering, plasmon-mediated fluorescence, nanoscale lasing, and strong coupling. The case of strong coupling is analogous to quantum optical effects studied in solid state and atomic systems previously. In plasmonics, similar observations have been almost exclusively made in elastic scattering experiments; however, the interpretation of these experiments is often cumbersome. Here, we demonstrate mode splitting not only in scattering, but also in photoluminescence of individual hybrid nanosystems, which manifests a direct proof of strong coupling in plasmon-exciton nanoparticles. We achieved these results due to saturation of the mode volume with molecular J aggregates, which resulted in splitting up to 400 meV, that is, ~20% of the resonance energy. We analyzed the correlation between scattering and photoluminescence and found that splitting in photoluminescence is considerably less than that in scattering. Moreover, we found that splitting in both photoluminescence and scattering signals increased upon cooling to cryogenic temperatures. These findings improve our understanding of strong coupling phenomena in plasmonics. PMID- 28005385 TI - Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid. AB - Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2 carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 MUM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 +/- 2 MUM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14 degrees was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor. PMID- 28005386 TI - Length Scale of Diffusive Phonon Transport in Suspended Thin Silicon Nanowires. AB - Recent experimental advances have revealed that the mean free path (mfp) of phonons contributing significantly to thermal transport in crystalline semiconductors can be several microns long. Almost all of these experiments are based on bulk and thin film materials and use techniques that are not directly applicable to nanowires. By developing a process with which we could fabricate multiple electrically contacted and suspended segments on individual heavily doped smooth Silicon nanowires, we measured phonon transport across varying length scales using a DC self-heating technique. Our measurements show that diffusive thermal transport is still valid across O(100) nm length scales, supporting the diffuse nature of phonon-boundary scattering even on smooth nanowire surfaces. Our work also showcases the self-heating technique as an important alternative to the thermal bridge technique to measure phonon transport across short length scales relevant to mapping the phonon mfp spectrum in nanowires. PMID- 28005387 TI - Dimer Metadynamics. AB - Sampling complex potential energies is one of the most pressing challenges of contemporary computational science. Inspired by recent efforts that use quantum effects and discretized Feynman's path integrals to overcome large barriers we propose a replica exchange method that we expect to be effective at least for systems of up to 150 atoms roughly. In each replica two copies of the same system with halved potential strengths interact via inelastic springs. The strength of the spring is varied in the different replicas so as to bridge the gap between the infinitely strong spring, that corresponds to the Boltzmann replica, and the less tight ones. We enhance the spring length fluctuations using Metadynamics. We test the method on simple yet challenging problems. PMID- 28005389 TI - Identification of Nitration Products during Heterogeneous Reaction of NO2 on Soot in the Dark and under Simulated Sunlight. AB - Author: The present work, involving the formation of NO and nitrous acid (HONO) and the nitration of polycyclic aromatic hydrocarbon (PAHs) to nitro-PAHs as well as the uptake coefficients of NO2, has been performed on a normal-pressure flow reactor to identify the nitration products during the heterogeneous reaction of soot toward NO2 in the dark and under simulated sunlight. Two types of soot particles, namely the commercial black carbon (BC) and the diesel engine soot (ES), were selected as the studied soot to compare the impacts of soot properties on heterogeneous nitration. During the whole reaction on either of the two studied soots in the dark, a fast reversible physical adsorption is observed at the very beginning, followed by a slow irreversible chemical conversion from NO2 to HONO and NO, in good agreement with the "reduction-oxidation" mechanism. HONO is the most abundant product during the nitration reaction on the two studied soots, contributing to 70-90% of consumed NO2 after 50 min exposure. Reaction orders of NO2 for HONO are determined as 1.20 +/- 0.07 and 1.31 +/- 0.04 for BC and ES, respectively, which are both close to first-order. Moreover, four sorts of PAHs compounds and their five nitro-derivatives have been identified and quantified during the reaction. About 40% and 20% of the total four measured PAHs are consumed on BC and ES, respectively, resulting in an increase in the total five measured nitro-PAHs by 21-fold on BC and 2.8-fold on ES. Finally, the impacts of light on gaseous and organics products have been investigated and the results confirm that simulated sunlight can enhance the reactivity of PAHs toward NO2 and cause the photolysis of newly formed nitro-compounds with more HONO formation, strongly suggesting that photochemistry of soot in the presence of NO2 is of great importance to be a photochemical source of HONO and would also influence the fates of PAHs and nitro-PAHs on soot. PMID- 28005390 TI - Field Effect Optoelectronic Modulation of Quantum-Confined Carriers in Black Phosphorus. AB - We report measurements of the infrared optical response of thin black phosphorus under field-effect modulation. We interpret the observed spectral changes as a combination of an ambipolar Burstein-Moss (BM) shift of the absorption edge due to band-filling under gate control, and a quantum confined Franz-Keldysh (QCFK) effect, phenomena that have been proposed theoretically to occur for black phosphorus under an applied electric field. Distinct optical responses are observed depending on the flake thickness and starting carrier concentration. Transmission extinction modulation amplitudes of more than two percent are observed, suggesting the potential for use of black phosphorus as an active material in mid-infrared optoelectronic modulator applications. PMID- 28005388 TI - Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein-Protein Interaction Inhibitors Targeting the EphA2 Receptor. AB - Metadynamics (META-D) is emerging as a powerful method for the computation of the multidimensional free-energy surface (FES) describing the protein-ligand binding process. Herein, the FES of unbinding of the antagonist N-(3alpha-hydroxy-5beta cholan-24-oyl)-l-beta-homotryptophan (UniPR129) from its EphA2 receptor was reconstructed by META-D simulations. The characterization of the free-energy minima identified on this FES proposes a binding mode fully consistent with previously reported and new structure-activity relationship data. To validate this binding mode, new N-(3alpha-hydroxy-5beta-cholan-24-oyl)-l-beta homotryptophan derivatives were designed, synthesized, and tested for their ability to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists, namely compounds 21 and 22, displayed high affinity versus the EphA2 receptor and resulted endowed with better physicochemical and pharmacokinetic properties than the parent compound. These findings highlight the importance of free-energy calculations in drug design, confirming that META-D simulations can be used to successfully design novel bioactive compounds. PMID- 28005391 TI - Cross-Field Comparison of Ethics Education: Golden Rules and Particulars. AB - Research misconduct negatively impacts the scientific community and society in general. Providing training in the responsible conduct of research (RCR) to researchers is one viable approach to minimizing research misconduct. Although recent evidence suggests ethics training can indeed be effective, little empirical work has examined the similarities and differences across fields. In the present study, we analyzed 62 empirical studies in engineering, biomedical science, social science, and mixed fields. The findings suggest certain instructional principles, or "golden rules," apply generally to all fields. These golden rules include maintaining a field-specific or field-general approach and emphasizing processes in training. The findings also suggest that content areas contributing to instructional effectiveness vary as a function of field. Generally, it appears that all fields may benefit from taking a multi-pronged approach to ethics education wherein the salient field issues are covered. Implications for RCR education are discussed. PMID- 28005392 TI - Analytical Methodologies for the Assessment of Phthalate Exposure in Humans. AB - Screening and quantification of phthalate metabolites in biological matrices provide information on the phthalate exposure. The preferred tool for the determination of phthalate metabolites is liquid chromatography-mass spectrometry, typically preceded by a sample extraction step. Method development for the determination of phthalate metabolites by hyphenated techniques faces challenges due to the widespread occurrence of phthalates in the laboratory and sample collection materials that impairs their accurate quantification. Here, the analytical methods that have been developed for the determination of biomarkers of phthalates in various matrices are presented, and limitations and challenges in these applications are discussed. PMID- 28005393 TI - Multiplexed Single-Cell Imaging: Past, Present, and Future. AB - Jia-Ren Lin from the Laboratory of Systems Pharmacology at Harvard Medical School was awarded best poster at the annual Society of Biomolecular Imaging and Informatics meeting held in Boston, September 2016. His work focuses on single cell imaging, especially on developing new methods for simultaneously detecting many antigens, named cyclic immunofluorescence (CycIF). This method could be applied in different stages of drug development, from discovery phase, preclinical research to clinical research. The current works and future directions of CycIF method are summarized in the following overview. PMID- 28005394 TI - The Past and Future of Breastfeeding Medicine: A Journal for a Defined Medical Specialty. PMID- 28005396 TI - The Effect of Canthaxanthin on the Quality of Frozen Ram Spermatozoa. AB - The addition of antioxidants to semen cryopreservation extenders has been employed for combating oxidative damage. This work aimed to evaluate the addition of carotenoid canthaxanthin to a cryopreservation extender of ram semen. Three breeder rams were used and, after semen collection, with 48-hour intervals between collection, the samples were included in the pool formation (n = 6). The experimental groups comprised 0 (control), 0.1, 1, 10, and 25 MUM of canthaxanthin. After thawing (37 degrees C/30 s) and incubation at 37 degrees C for 2 hours, semen aliquots from each group were evaluated for sperm kinetics (CASA), the integrity of the plasma and acrosomal membranes (iPAM), intracellular reactive oxygen species (ROS) production, and lipid peroxidation (LPO) by flow cytometry associated with the image. The control group and canthaxanthin 1 MUM after incubation at 37 degrees C for 2 hours showed increases of curvilinear velocity and amplitude of lateral head displacement with decreases of linearity, straightness, and wobble (p < 0.05), which were not observed for the canthaxanthin 10 and 25 MUM. The supplementation of a Tris-egg yolk extender with canthaxanthin had no effect on the iPAM, intracellular ROS production in viable spermatozoa, or LPO. In conclusion, supplementation with 10 and 25 MUM of canthaxanthin in a Tris-egg yolk extender used for ram semen cryopreservation is able to protect ovine sperm from kinetic changes after incubation at 37 degrees C for 2 hours post-thawing. PMID- 28005395 TI - Conditional Ablation of Progesterone Receptor Membrane Component 2 Causes Female Premature Reproductive Senescence. AB - The nonclassical progesterone receptors progesterone receptor membrane component (PGRMC) 1 and PGRMC2 have been implicated in regulating cell survival of endometrial and ovarian cells in vitro and are abundantly expressed in these cell types. The objective of this study was to determine if Pgrmc1 and Pgrmc2 are essential for normal female reproduction. To accomplish this objective, Pgrmc1 and/or Pgrmc2 floxed mice (Pgrmc2fl/fl and Pgrmc1/2fl/fl) were crossed with Pgr cre mice, which resulted in the conditional ablation of Pgrmc1 and/or Pgrmc2 from female reproductive tissues (i.e.,Pgrmc2d/d and Pgrmc1/2d/d mice). A breeding trial revealed that conditional ablation of Pgrmc2 initially led to subfertility, with Pgrmc2d/d female mice producing 47% fewer pups/litter than Pgrmc2fl/fl mice (P = 0.001). Pgrmc2d/d mice subsequently underwent premature reproductive senescence by parities 2 to 5, producing 37.8% fewer litters overall during the trial compared with Pgrmc2fl/fl mice (P = 0.020). Similar results were observed with Pgrmc1/2d/d mice. Based on ovarian morphology and serum P4, the subfertility/infertility was not due to faulty ovulation or luteal insufficiency. Rather an analysis of midgestation implantation sites revealed that postimplantation embryonic death was the major cause of the subfertility/infertility. As with our previous report of Pgrmc1d/d mice, Pgrmc2d/d and Pgrmc1/2d/d mice developed endometrial cysts consistent with accelerated aging of this tissue. Given the timing of postimplantation embryonic demise, uterine decidualization may be disrupted in mice deficient in PGRMC2 or PGRMC1/2. Overall, this study revealed that Pgrmc1 and/or Pgrmc2 are required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan. PMID- 28005397 TI - Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation. AB - Myofibroblasts, the primary effector cells that mediate matrix remodeling during pulmonary fibrosis, rapidly assemble an extracellular fibronectin matrix. Tensin (TNS) 1 is a key component of specialized cellular adhesions (fibrillar adhesions) that bind to extracellular fibronectin fibrils. We hypothesized that TNS1 may play a role in modulating myofibroblast-mediated matrix formation. We found that TNS1 expression is increased in fibroblastic foci from lungs with idiopathic pulmonary fibrosis. Transforming growth factor (TGF)-beta profoundly up-regulates TNS1 expression with kinetics that parallel the expression of the myofibroblast marker, smooth muscle alpha-actin. TGF-beta-induced TNS1 expression is dependent on signaling through the TGF-beta receptor 1 and is Rho coiled coiled kinase/actin/megakaryoblastic leukemia-1/serum response factor dependent. Small interfering RNA-mediated knockdown of TNS1 disrupted TGF-beta-induced myofibroblast differentiation, without affecting TGF-beta/Smad signaling. In contrast, loss of TNS1 resulted in disruption of focal adhesion kinase phosphorylation, focal adhesion formation, and actin stress fiber development. Finally, TNS1 was essential for the formation of fibrillar adhesions and the assembly of nascent fibronectin and collagen matrix in myofibroblasts. In summary, our data show that TNS1 is a novel megakaryoblastic leukemia-1-dependent gene that is induced during pulmonary fibrosis. TNS1 plays an essential role in TGF-beta-induced myofibroblast differentiation and myofibroblast-mediated formation of extracellular fibronectin and collagen matrix. Targeted disruption of TNS1 and associated signaling may provide an avenue to inhibit tissue fibrosis. PMID- 28005398 TI - The Paracrine Effect of Degenerated Disc Cells on Healthy Human Nucleus Pulposus Cells Is Mediated by MAPK and NF-kappaB Pathways and Can Be Reduced by TGF-beta1. AB - Inflammation is thought to have a major role in the pathogenesis of disc degeneration. Studies have shown that nucleus pulposus cells (NPCs) respond to one or two specific cytokines by regulating cell proliferation or matrix synthesis. However, the effects of a cocktail of factors secreted by degenerated disc cells on transplanted exogenous healthy NPCs remain unknown. Concentrations of multiple cytokines in degenerated disc tissue-conditioned medium (dCM) were measured using enzyme-linked immunosorbent assay (ELISA). 3-(4, 5-Dimethylthiazol 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Ki67 immunofluorescence staining were used to evaluate the proliferation of cells in dCM. The function of exogenous NPCs cultured in dCM was evaluated by examining catabolic markers (ADAMTS-4, ADAMTS-5, MMP-1, MMP-3, and MMP-13), anabolic markers (TIMP-1, TIMP-2, and TIMP-3), and the extracellular matrix protein-aggrecan (ACAN) and collagen II (COL2)-expression with real time polymerase chain reaction (RT-PCR). Mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathway activation was observed using Western blotting. Finally, we examined the role of transforming growth factor (TGF)-beta1 in reducing dCM-mediated exogenous NPC dysfunction. Levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-1alpha, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, interferon-gamma (IFN-gamma), and prostaglandin E2 (PGE2) were higher and TGF-beta1 levels were lower in dCM compared with the control medium. Treatment with dCM increased the proliferation of healthy NPCs. NPCs exhibited significantly higher expression of ADAMTS-4, ADAMTS-5, MMP-1, MMP-3, and MMP-13 and decreased TIMP-2, ACAN, and COL2 expression in the dCM group in a dose- and time-dependent manner. Treatment with dCM moderately increased TIMP-1 expression and had no effect on TIMP-3 mRNA levels. The MAPK and NF-kappaB pathways were implicated in dCM-mediated responses of healthy NPCs. TGF-beta1 partially reversed the dCM-mediated NPC dysfunction. Increased levels of inflammatory factors and decreased TGF-beta1 levels in dCM suggest an inflammatory environment in degenerated disc tissue. The catabolic effect of dCM on human healthy NPCs is mediated by MAPK and NF-kappaB pathways and can be reduced by TGF-beta1. PMID- 28005400 TI - Does Allograft Augmentation of Small-Diameter Hamstring Autograft ACL Grafts Reduce the Incidence of Graft Retear? AB - BACKGROUND: Small-diameter hamstring tendons are frequently encountered during anterior cruciate ligament (ACL) reconstructions in patients with short stature or those who are skeletally immature. The role of augmenting these small-diameter autografts with allograft is unclear. PURPOSE: To assess clinical outcomes and failure rates in adolescent patients with small hamstring tendon autografts (<7 mm) that were either augmented with soft tissue allograft or accepted "as is" and not augmented. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective chart review of all primary ACL reconstructions performed with hamstring autografts identified 385 patients, of whom 50 (13%) had a quadrupled (semitendinosus-gracilis) graft size less than 7 mm. Patients were grouped based on the surgeon's preference either to augment these grafts with allograft (augmented group; n = 26) or to accept the smaller autograft (nonaugmented group; n = 24). Preoperative demographic, injury, and intraoperative data were documented. All patients were contacted to obtain information about outcome scores, subsequent procedures, and complications. Forty patients (20 in each group) were available for 2-year follow-up. RESULTS: The mean age of the entire cohort was 15.7 years (range, 12-18 years), and 38% were male. No between-group differences were found with respect to any of the preoperative or intraoperative variables except extremity side. The mean graft size for the augmented group was 8.9 mm and for the nonaugmented group was 6.4 mm. At a mean follow-up of 3 years, 6 (30%) of the patients in the augmented group had a graft failure, whereas only 1 (5%) in the nonaugmented group had a failure ( P = .04). Five of the 6 augmented failures occurred within 1 year of surgery, whereas the single failure in the nonaugmented group occurred 2.7years postoperatively. No differences were noted in the reported outcomes between patients in the augmented and nonaugmented groups who did not experience graft failure (Lysholm score, 88 vs 92; Tegner score, 6.4 vs 6.3; single-assessment numeric evaluation score, 86 vs 86; satisfaction, 8.4 vs 8.9, respectively). CONCLUSION: Adolescents undergoing an ACL reconstruction frequently have small hamstring tendon autograft size. The augmentation of these small grafts with allograft does not reduce graft failure rates and may in fact lead to higher retear rates, with earlier graft failure. PMID- 28005399 TI - Bisphenol S (BPS) Alters Maternal Behavior and Brain in Mice Exposed During Pregnancy/Lactation and Their Daughters. AB - Estrogenic endocrine disrupting chemicals have been shown to disrupt maternal behavior in rodents. We investigated the effects of an emerging xenoestrogen, bisphenol S (BPS), on maternal behavior and brain in CD-1 mice exposed during pregnancy and lactation (F0 generation) and in female offspring exposed during gestation and perinatal development (F1 generation). We observed different effects in F0 and F1 dams for a number of components of maternal behavior, including time on the nest, time spent on nest building, latency to retrieve pups, and latency to retrieve the entire litter. We also characterized expression of estrogen receptor alpha in the medial preoptic area (MPOA) and quantified tyrosine hydroxylase immunoreactive cells in the ventral tegmental area, 2 brain regions critical for maternal care. BPS-treated females in the F0 generation had a statistically significant increase in estrogen receptor alpha expression in the caudal subregion of the central MPOA in a dose-dependent manner. In contrast, there were no statistically significant effects of BPS on the MPOA in F1 dams or the ventral tegmental area in either generation. This work demonstrates that BPS affects maternal behavior and brain with outcomes depending on generation, dose, and postpartum period. Many studies examining effects of endocrine disrupting chemicals view the mother as a means by which offspring can be exposed during critical periods of development. Here, we demonstrate that pregnancy and lactation are vulnerable periods for the mother. We also show that developmental BPS exposure alters maternal behavior later in adulthood. Both findings have potential public health implications. PMID- 28005401 TI - Improved Algorithm for Automated Glucose Clamps. AB - BACKGROUND: In glucose clamp experiments, blood glucose concentrations (BGs) are kept as close as possible to a predefined target level using variable glucose infusion rates (GIRs). In automated clamps, GIRs are calculated by algorithms implemented in the device (e.g., the Biostator). Low BG- and GIR-variability is needed for high clamp quality. We therefore tried to reduce oscillations in both BG and GIR with an improved algorithm implemented in ClampArt, a modern clamp device. SUBJECTS AND METHODS: The Biostator algorithm was first improved by numerical simulations of glucose clamps (in silico). With the results of the simulations, we started in vitro experiments using the ClampArt device and a container with water and glucose as "test subject." After a small pilot in vivo study, a larger clinical study was performed to compare the original with the optimized algorithm. RESULTS: With the improved algorithm, in silico, in vitro, and in vivo experiments showed reduced oscillations in both BG and GIR. In the clinical study, the coefficient of variation (CV) of BG values was lowered from 6.0% (4.6%-7.8%) [median (interquartile range)] to 4.2% (3.6%-5.0%), P < 0.0001 and the CV of GIR from 60.7% (49.6%-82.0%) to 43.5% (32.8%-57.2%), P < 0.0001. Other clamp quality parameters did not change substantially, median deviation from target slightly increased from 0.6% (0.2%-1.0%) to 1.1% (0.7%-1.5%), P = 0.0005, whereas utility did not change [97.0% (93.4%-100.0%) vs. 97.0% (94.0% 98.8%), P = 0.57]. CONCLUSIONS: With the improved algorithm, all experiments confirmed a reduction in BG- and GIR-oscillations without a major impact on other glucose clamp parameters. The optimized algorithm has been implemented in ClampArt for all future glucose clamp studies. PMID- 28005402 TI - Qualitative Evaluation Methods in Ethics Education: A Systematic Review and Analysis of Best Practices. AB - Although qualitative research offers some unique advantages over quantitative research, qualitative methods are rarely employed in the evaluation of ethics education programs and are often criticized for a lack of rigor. This systematic review investigated the use of qualitative methods in studies of ethics education. Following a review of the literature in which 24 studies were identified, each study was coded based on 16 best practices characteristics in qualitative research. General thematic analysis and grounded theory were found to be the dominant approaches used. Researchers are effectively executing a number of best practices, such as using direct data sources, structured data collection instruments, non-leading questioning, and expert raters. However, other best practices were rarely present in the courses reviewed, such as collecting data using multiple sources, methods, raters, and timepoints, evaluating reliability, and employing triangulation analyses to assess convergence. Recommendations are presented for improving future qualitative research studies in ethics education. PMID- 28005403 TI - Preliminary Randomized Controlled Trial of Habit Reversal Training for Treatment of Hair Pulling in Youth. AB - OBJECTIVES: This study evaluated the treatment efficacy of habit reversal training (HRT) relative to treatment as usual (TAU) for children and adolescents aged 7-17 years with a primary diagnosis of trichotillomania (TTM). METHOD: An initial assessment consisting of semistructured interviews and rating scales was conducted. Participants (N = 40, 85% female) meeting diagnostic criteria for TTM were randomized to either 8 weekly sessions of HRT by trained therapists or 8 weeks of TAU. One week after the final HRT session or final TAU week, patients completed a posttreatment assessment, followed by 1- and 3-month follow-up assessments. All assessments were conducted by a trained rater who was blinded to treatment condition. RESULTS: The group by time analysis of variance yielded a significant interaction on the National Institute of Mental Health Trichotillomania Severity Scale Total Score (F1,38 = 16.47, p < 0.001, eta2p = 0.30). The mean score decreased from 12.67 +/- 4.60 at baseline to 5.62 +/- 4.38 at posttreatment in the HRT group (t20 = 5.99, p < 0.001, d = 1.31), whereas the TAU group changed from 10.42 +/- 4.35 to 9.32 +/- 4.11 (t18 = 1.34, p = 0.20, d = 0.31). The Massachusetts General Hospital-Hair Pulling Scale Total Score decreased from 15.14 +/- 3.86 at baseline to 7.14 +/- 5.54 at posttreatment in the HRT group (t20 = 6.16, p < 0.001, d = 1.34); the TAU group changed from 14.16 +/- 4.51 to 12.26 +/- 4.34 (t18 = 1.50, p = 0.15, d = 0.34). On the Clinical Global Impressions-Improvement, 16/21 participants (76%) were rated as treatment responders in the HRT group versus 4/19 (21%) in the TAU group (chi2 = 12.13, p < 0.001, V = 0.55). At 1-month follow-up, 10-12 treatment responders who completed the assessment maintained improvement. At 3-month follow-up, six of eight maintained improvement. CONCLUSIONS: HRT can be an effective treatment for TTM in youth. PMID- 28005404 TI - Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury. AB - RATIONALE: Acute respiratory distress syndrome is characterized by alveolar epithelial cell injury, edema formation, and intraalveolar contact phase activation. OBJECTIVES: To explore whether C1 esterase inhibitor (C1INH), an endogenous inhibitor of the contact phase, may protect from lung injury in vivo and to decipher the possible underlying mechanisms mediating protection. METHODS: The ability of C1INH to control the inflammatory processes was studied in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: Here, we demonstrate that application of C1INH alleviates bleomycin-induced lung injury via direct interaction with extracellular histones. In vitro, C1INH was found to bind all histone types. Interaction with histones was independent of its protease inhibitory activity, as demonstrated by the use of reactive-center-cleaved C1INH, but dependent on its glycosylation status. C1INH sialylated-N- and -O-glycans were not only essential for its interaction with histones but also to protect against histone-induced cell death. In vivo, histone-C1INH complexes were detected in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome and multiple models of lung injury. Furthermore, reactive-center-cleaved C1INH attenuated pulmonary damage evoked by intravenous histone instillation. CONCLUSIONS: Collectively, C1INH administration provides a new therapeutic option for disorders associated with histone release. PMID- 28005405 TI - Patellofemoral Arthritis After Lateral Patellar Dislocation: A Matched Population Based Analysis. AB - BACKGROUND: The rate of patellofemoral arthritis after lateral patellar dislocation is unknown. Purpose/Hypothesis: The purpose of this study was to compare the risk of patellofemoral arthritis and knee arthroplasty between patients who experienced a lateral patellar dislocation and matched individuals without a patellar dislocation. Additionally, factors predictive of arthritis after patellar dislocation were examined. The hypothesis was that the rate of arthritis is likely higher among patients who experience a patellar dislocation compared with those who do not. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this study, 609 patients who had a first-time lateral patellar dislocation between 1990 and 2010 were compared with an age- and sex-matched cohort of patients who did not have a patellar dislocation. Medical records were reviewed to collect information related to the initial injury, recurrent dislocation, treatment, and progression to clinically significant patellofemoral arthritis (defined as symptoms with degenerative changes on patellar sunrise radiographs). Factors associated with arthritis (age, sex, recurrence, osteochondral injury, trochlear dysplasia) were examined. RESULTS: At a mean follow-up of 12.3 +/- 6.5 years from initial dislocation, 58 patients (9.5%) in the dislocation cohort were diagnosed with patellofemoral arthritis, corresponding to a cumulative incidence of arthritis of 1.2% at 5 years, 2.7% at 10 years, 8.1% at 15 years, 14.8% at 20 years, and 48.9% at 25 years. In the control cohort, 8 patients (1.3%) were diagnosed with arthritis, corresponding to a cumulative incidence of arthritis of 0% at 5 years, 0% at 10 years, 1.3% at 15 years, 2.9% at 20 years, and 8.3% at 25 years. Therefore, patients who experienced a lateral patellar dislocation had a significantly higher risk of developing arthritis (hazard ratio [HR], 7.8; 95% CI, 3.9-17.6; P < .001) than individuals without a patellar dislocation. However, the risk of knee arthroplasty was similar between groups (HR, 2.8; 95% CI, 0.6-19.7; P = .2). Recurrent patellar dislocations (HR, 4.5; 95% CI, 1.6-12.6), osteochondral injury (HR, 11.3; 95% CI, 5.0-26.6), and trochlear dysplasia (HR, 3.6; 95% CI, 1.3-10.0) were associated with arthritis after patellar dislocation. CONCLUSION: Patellar dislocation is a significant risk factor for patellofemoral arthritis, as nearly half of patients have symptoms and radiographic changes consistent with arthritis at 25 years after lateral patellar dislocation. Osteochondral injury, recurrent patellar instability, and trochlear dysplasia are associated with the development of arthritis. PMID- 28005406 TI - A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses. AB - AIM: To test the utility of targeted sequencing as a method of clinical molecular testing in patients diagnosed with inherited retinal degeneration (IRD). METHODS: After genetic counseling, peripheral blood was drawn from 188 probands and 36 carriers of IRD. Single gene testing was performed on each patient in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory. DNA was isolated, and all exons in the gene of interest were analyzed along with 20 base pairs of flanking intronic sequence. Genetic testing was most often performed on ABCA4, CTRP5, ELOV4, BEST1, CRB1, and PRPH2. Pathogenicity of novel sequence changes was predicted by PolyPhen2 and sorting intolerant from tolerant (SIFT). RESULTS: Of the 225 genetic tests performed, 150 were for recessive IRD, and 75 were for dominant IRD. A positive molecular diagnosis was made in 70 (59%) of probands with recessive IRD and 19 (26%) probands with dominant IRD. Analysis confirmed 12 (34%) of individuals as carriers of familial mutations associated with IRD. Thirty-two novel variants were identified; among these, 17 sequence changes in four genes were predicted to be possibly or probably damaging including: ABCA4 (14), BEST1 (2), PRPH2 (1), and TIMP3 (1). CONCLUSIONS: Targeted analysis of clinically suspected genes in 225 subjects resulted in a positive molecular diagnosis in 26% of patients with dominant IRD and 59% of patients with recessive IRD. Novel damaging mutations were identified in four genes. Single gene screening is not an ideal method for diagnostic testing given the phenotypic and genetic heterogeneity among IRD cases. High-throughput sequencing of all genes associated with retinal degeneration may be more efficient for molecular diagnosis. PMID- 28005407 TI - Validation and Use of a Predictive Modeling Tool: Employing Scientific Findings to Improve Responsible Conduct of Research Education. AB - Although recent evidence suggests ethics education can be effective, the nature of specific training programs, and their effectiveness, varies considerably. Building on a recent path modeling effort, the present study developed and validated a predictive modeling tool for responsible conduct of research education. The predictive modeling tool allows users to enter ratings in relation to a given ethics training program and receive instantaneous evaluative information for course refinement. Validation work suggests the tool's predicted outcomes correlate strongly (r = 0.46) with objective course outcomes. Implications for training program development and refinement are discussed. PMID- 28005408 TI - Evaluation of Research Ethics Committees: Criteria for the Ethical Quality of the Review Process. AB - Repeatedly, adequacy, performance and quality of Ethics Committees that oversee medical research trials are being discussed. Although they play a crucial role in reviewing medical research and protecting human subjects, it is far from clear to what degree they fulfill the task they have been assigned to. This eventuates in the call for an evaluation of their activity and, in some places, led to the establishment of accreditation schemes. At the same time, IRBs have become subject of detailed legislation in the process of the ongoing global juridification of medical research. Unsurprisingly, there is a tendency to understand the evaluation of RECs as a question of controlling their legal compliance. This paper discusses the need for a quality evaluation of IRBs from an ethical point of view and, by systematically reviewing the major ethical guidelines for IRBs, proposes a system of criteria that should orientate any evaluation of IRBs. PMID- 28005409 TI - Safe Drilling Paths in the Distal Femoral Epiphysis for Pediatric Medial Patellofemoral Ligament Reconstruction. AB - BACKGROUND: Anatomic surgical reconstruction of the medial patellofemoral ligament (MPFL) has been popularized for the treatment of recurrent patellar instability in the skeletally immature population. Previous anatomic studies have found that the femoral attachment point of the MPFL is very close to the distal femoral physis. PURPOSE: To establish the safe angles for drilling the distal femoral epiphysis for MPFL graft placement. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 23 cadaveric distal femoral epiphyses were scanned into high-resolution 3-dimensional images. Using computer-aided design, we identified and marked the femoral insertion site of the MPFL. Cylinders 8 mm in diameter were placed at varying angles to simulate the drill paths for placement of 6-mm interference screws with a 1-mm buffer. The distance from the MPFL footprint to where the tunnel first violated the physis, the intercondylar notch, or the distal cartilage was measured. We recorded the percentage of tunnels that caused violations before reaching 20 mm, the shortest length of a typical femoral tunnel socket. RESULTS: Measurements indicated that 41% of tunnels angled distally less than 10 degrees violated the physis, 40% of tunnels angled distally more than 10 degrees but anteriorly less than 10 degrees violated the notch, and 27% of tunnels angled distally and anteriorly more than 20 degrees violated the distal femoral cartilage. At least 90% of the tunnels were safe at 20 mm when the drill was angled between 15 degrees and 20 degrees both anteriorly and distally. CONCLUSION: Because of the anatomy of the distal femoral physis, drilling into the epiphysis from the MPFL attachment site at improper trajectories risks damage to sensitive structures. Angling the drill to an acceptable degree distally and anteriorly leads to less risk to the physis and notch, respectively, but angling too much leads to risk to the distal femoral cartilage. Small variations in the sagittal plane were better tolerated than variations in the coronal plane, so we recommend that more attention be paid to the radiographic anteroposterior view intraoperatively. It is safest to angle the drill distally and anteriorly approximately 15 degrees to 20 degrees in each plane from the MPFL attachment site. CLINICAL RELEVANCE: During drilling into the distal femoral epiphysis at the MPFL origin in skeletally immature patients, angling the drill appropriately 15 degrees to 20 degrees both distally and anteriorly minimizes damage to the physis, notch, and distal femoral cartilage. PMID- 28005410 TI - Results of a Medicare Bundled Payments for Care Improvement Initiative for Chronic Obstructive Pulmonary Disease Readmissions. AB - RATIONALE: Approximately 20% of Medicare beneficiaries hospitalized for acute exacerbations of chronic obstructive pulmonary disease (COPD) are readmitted within 30 days of discharge. In addition to implementing penalties for excess readmissions, the U.S. Centers for Medicare and Medicaid Services has developed Bundled Payments for Care Improvement (BPCI) initiatives to improve outcomes and control costs. OBJECTIVES: To evaluate whether a comprehensive COPD multidisciplinary intervention focusing on inpatient, transitional, and outpatient care as part of our institution's BPCI participation would reduce 30 day all-cause readmission rates for COPD exacerbations and reduce overall costs. METHODS: We performed a pre-postintervention study comparing all-cause readmissions and costs after index hospitalization for Medicare-only patients with acute exacerbation of COPD. The primary outcome was the difference in 30-day all-cause readmission rate compared with historical control subjects; secondary outcomes included the 90-day all-cause readmission rate and also health care costs compared with BPCI target prices. RESULTS: Seventy-eight consecutive Medicare patients were prospectively enrolled in the BPCI intervention in 2014 and compared with 109 patients in the historical group from 2012. Patients in BPCI were more likely to receive regular follow-up phone calls, pneumococcal and influenza vaccines, home health care, durable medical equipment, and pulmonary rehabilitation, and to attend pulmonary clinic. There was no difference in all cause readmission rates at 30 days (BPCI, 12 events [15.4%] vs. non-BPCI, 19 events [17.4%]; P = 0.711), and 90 days (21 [26.9%] vs. 37 [33.9%]; P = 0.306). Compared with BPCI target prices, we incurred 4.3% lower 90-day costs before accounting for significant investment from the health system. CONCLUSIONS: A Medicare BPCI intervention did not reduce 30-day all-cause readmission rates or overall costs after hospitalization for acute exacerbation of COPD. Although additional studies enrolling larger numbers of patients at multiple centers may demonstrate the efficacy of our BPCI initiative for COPD readmissions, this is unlikely to be cost effective at any single center. PMID- 28005411 TI - A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice. AB - Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/Galnt3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), Galnt3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. Galnt3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the Galnt3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression. PMID- 28005416 TI - Corrections. PMID- 28005415 TI - Proteome analysis of human serum proteins adsorbed onto different titanium surfaces used in dental implants. AB - Titanium dental implants are commonly used due to their biocompatibility and biochemical properties; blasted acid-etched Ti is used more frequently than smooth Ti surfaces. In this study, physico-chemical characterisation revealed important differences in roughness, chemical composition and hydrophilicity, but no differences were found in cellular in vitro studies (proliferation and mineralization). However, the deposition of proteins onto the implant surface might affect in vivo osseointegration. To test that hypothesis, protein layers formed on discs of both surface type after incubation with human serum were analysed. Using mass spectrometry (LC/MS/MS), 218 proteins were identified, 30 of which were associated with bone metabolism. Interestingly, Apo E, antithrombin and protein C adsorbed mostly onto blasted and acid-etched Ti, whereas the proteins of the complement system (C3) were found predominantly on smooth Ti surfaces. These results suggest that physico-chemical characteristics could be responsible for the differences observed in the adsorbed protein layer. PMID- 28005418 TI - WNT Signaling in Lung Aging and Disease. AB - Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), represent a significant and increasing health burden. Current therapies are largely symptomatic, and novel therapeutic approaches are needed. Aging has emerged as a contributing factor for the development of both IPF and COPD because their prevalence increases with age, and several pathological features of these diseases resemble classical hallmarks of aging. Aging is thought to be driven in part by aberrant activity of developmental signaling pathways that thus might drive pathological changes, a process termed antagonistic pleiotropy or developmental drift. The developmental WNT pathway is fundamental for lung development, and altered WNT activity has been reported to contribute to the pathogenesis of CLD, in particular to COPD and IPF. Although to date only limited data on WNT signaling during lung aging exist, WNT signal regulation during aging and its effects on age-related pathologies in other organs have recently been investigated. In this review, we discuss evidence of dysregulated WNT signaling in CLD in the context of WNT signal alteration in organ aging and its potential impact on age-related cellular mechanisms, such as senescence or stem cell exhaustion. PMID- 28005417 TI - The association between Internet addiction and personality disorders in a general population-based sample. AB - : Background and aims Data on Internet addiction (IA) and its association with personality disorder are rare. Previous studies are largely restricted to clinical samples and insufficient measurement of IA. Methods Cross-sectional analysis data are based on a German sub-sample (n = 168; 86 males; 71 meeting criteria for IA) with increased levels of excessive Internet use derived from a general population sample (n = 15,023). IA was assessed with a comprehensive standardized interview using the structure of the Composite International Diagnostic Interview and the criteria of Internet Gaming Disorder as suggested in DSM-5. Impulsivity, attention deficit hyperactivity disorder, and self-esteem were assessed with the widely used questionnaires. Results Participants with IA showed higher frequencies of personality disorders (29.6%) compared to those without IA (9.3%; p < .001). In males with IA, Cluster C personality disorders were more prevalent than among non-addicted males. Compared to participants who had IA only, lower rates of remission of IA were found among participants with IA and additional cluster B personality disorder. Personality disorders were significantly associated with IA in multivariate analysis. DISCUSSION AND CONCLUSION: Comorbidity of IA and personality disorders must be considered in prevention and treatment. PMID- 28005419 TI - Aging of the Immune System. Mechanisms and Therapeutic Targets. AB - Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference. PMID- 28005421 TI - Is Chronic Obstructive Pulmonary Disease an Accelerated Aging Disease? AB - Aging is one of the most important risk factors for most chronic diseases. The worldwide increase in life expectancy has been accompanied by an increase in the prevalence of age-related diseases that result in significant morbidity and mortality and place an enormous burden on healthcare and resources. Aging is a progressive degeneration of the tissues that has a negative impact on the structure and function of vital organs. The lung ages, resulting in decreased function and reduced capacity to respond to environmental stresses and injury. Many of the changes that occur in the lungs with normal aging, such as decline in lung function, increased gas trapping, loss of lung elastic recoil, and enlargement of the distal air spaces, also are present in chronic obstructive pulmonary disease (COPD). The prevalence of COPD is two to three times higher in people over the age of 60 years than in younger age groups. Indeed, COPD has been considered a condition of accelerated lung aging. Several mechanisms associated with aging are present in the lungs of patients with COPD. Cell senescence is present in emphysematous lungs and is associated with shortened telomeres and decreased antiaging molecules, suggesting accelerated aging in the lungs of patients with COPD. Increasing age leads to elevated basal levels of inflammation and oxidative stress (inflammaging) and to increased immunosenescence associated with changes in both the innate and adaptive immune responses. These changes are similar to those that occur in COPD and may enhance the activity of the disease as well as increase susceptibility to exacerbations in patients with COPD. Understanding the mechanism of age-related changes in COPD may identify novel therapies for this condition. PMID- 28005420 TI - Exposure Memory and Lung Regeneration. AB - Many acute and chronic lung diseases could benefit from improved regeneration therapy. In development and throughout life, genetically encoded exposure memory systems allow environmental exposures, diet, and infectious agents to direct subsequent phenotypic adaptation and responses. The impact of such memory systems on lung regeneration is currently unknown. This article provides a brief overview of advances in redox biology and medicine as a framework for elucidating exposure memory and delineating spatiotemporal responses in lung regeneration. New imaging and omics methods enable precise definition to advance knowledge of development and the cumulative changes in lung biochemistry, structure, and cell populations occurring from prior and ongoing exposures. Importantly, conditioning steps may be needed to reverse exposure memory and enable effective regeneration. Thus, to complement developmental biology and regenerative medicine, research programs are needed to gain systematic knowledge of how lifelong exposures impact lung biology and support transition of lung regeneration from hypothetical to practical medicine. PMID- 28005422 TI - Multilevel, Dynamic Chronic Obstructive Pulmonary Disease Heterogeneity. A Challenge for Personalized Medicine. AB - This article summarizes how the multilevel (clinical, functional, structural, and biological) and dynamic (i.e., subjected to changes with time) heterogeneity of chronic obstructive pulmonary disease challenges a personalized approach for these patients. In particular, the following issues are discussed: (1) the conceptual differences between personalized and precision medicine, (2) how to frame the complexity and heterogeneity of chronic obstructive pulmonary disease by considering the precise meaning of the terms personalized medicine and precision medicine, and (3) how to translate all these novel concepts into clinical practice and move the field forward. PMID- 28005423 TI - Cellular Senescence and Lung Function during Aging. Yin and Yang. AB - Cellular senescence is a cell fate decision and stress response that entails a permanent arrest of cell proliferation coupled to a complex secretory phenotype. Senescent cells increase in number with age in most, if not all, mammalian tissues, including the airways and lungs. They also increase at greater than expected numbers, compared with age-matched controls, at sites of age-related pathologies such as chronic obstructive pulmonary disorder and emphysema. The senescence response is a double-edged sword. The proliferative arrest suppresses the development of cancer by preventing the propagation of stressed or damaged cells that are at risk for neoplastic transformation. However, this arrest can also curtail the proliferation of stem or progenitor cells and thus hamper tissue repair and regeneration. Similarly, the secretory phenotype can promote wound healing by transiently providing growth factors and the initial inflammatory stimulus that is required for tissue repair. However, when chronically present, the secretory phenotype of senescent cells can drive pathological inflammation, which contributes to a host of age-related pathologies, including cancer. There are now transgenes and prototype small molecules that can clear senescent cells, at least in mouse models, and thus improve health span and median life span. The next challenge will be to develop interventions and supplements that can abrogate the deleterious effects of senescent cells while preserving their beneficial effects. PMID- 28005424 TI - The Lung Microbiome and Airway Disease. AB - A growing body of literature has demonstrated relationships between the composition of the airway microbiota (mixed-species communities of microbes that exist in the respiratory tract) and critical features of immune response and pulmonary function. These studies provide evidence that airway inflammatory status and capacity for repair are coassociated with specific taxonomic features of the airway microbiome. Although directionality has yet to be established, the fact that microbes are known drivers of inflammation and tissue damage suggests that in the context of chronic inflammatory airway disease, the composition and, more importantly, the function, of the pulmonary microbiome represent critical factors in defining airway disease outcomes. PMID- 28005426 TI - Purpose of the Conference: 2016 Transatlantic Airway Conference. PMID- 28005425 TI - A Hidden Epithelial Barrier in the Brain with a Central Role in Regulating Brain Homeostasis. Implications for Aging. AB - Despite increasing interest the last years, the choroid plexus still is a relatively understudied tissue in neuroscience. The choroid plexus contains fenestrated capillaries surrounded by tightly connected choroid plexus epithelial cells that form the blood-cerebrospinal fluid barrier. The choroid plexus is the main source of cerebrospinal fluid production, assures removal of toxic waste products, and acts as gatekeeper of the brain by the presence of resident inflammatory cells. Increasing evidence shows that choroid plexus' dysfunction, via altered secretory, transport, immune, and barrier function, plays a central role in a very diverse set of clinical conditions such as aging and the age associated Alzheimer's disease. Indeed, age-related changes may weaken the barrier formed by the choroid plexus epithelial cells and/or impair the choroid plexus' ability to generate cerebrospinal fluid and to produce beneficial factors. Consequently, advanced knowledge of the choroid plexus-cerebrospinal fluid system in aging is essential to better understand age-associated neurological diseases and might open up new therapeutic strategies. PMID- 28005427 TI - Lung Fibroblasts, Aging, and Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is an aging-associated, progressive, and irreversible lung disease of unknown etiology, elusive pathogenesis, and very limited therapeutic options. The hallmarks of IPF are aberrant activation of alveolar epithelial cells and accumulation of fibroblasts and myofibroblasts along with excessive production of extracellular matrix. The linkage of aging with this disorder is uncertain, but a number of changes associated with aging, including telomere attrition, cell senescence, and mitochondrial dysfunction, have been revealed in IPF lungs. Also, aging seems to confer a profibrotic phenotype upon fibroblasts and to increase the severity of the fibrogenic response in non-IPF fibrotic lung disorders. Better knowledge of the pathophysiological mechanisms linking aging to IPF will advance understanding of its pathogenesis and may provide new therapeutic windows to treatment of this devastating disease. PMID- 28005428 TI - Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care. AB - In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care. PMID- 28005430 TI - Chair's Summary: Lung Aging and Regeneration. 2016 Transatlantic Airway Conference. PMID- 28005429 TI - Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging. AB - The mammalian target of rapamycin (mTOR) signaling pathway has been studied in the context of an impressive number of biological processes and disease states, including major diseases of the lung such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, as well as the rare condition lymphangioleiomyomatosis. The involvement of mTOR in so many disease states (in and out of the lung) raises the question how one signaling pathway can have overlapping but diverse roles seemingly everywhere. Findings in the last decade have placed the mTOR pathway in a new context as an important, conserved mediator of the aging process. This offers one explanation for the pleiotropic effects of mTOR: -that many chronic diseases are also diseases of aging and that pathways modulating aging will have widespread effects on associated disease. However, this may not be the entire story, because mTOR is also implicated in a large number of diseases not linked to aging. In this article, we discuss the current state of knowledge regarding mTOR, especially in the context of lung pathologies, and offer a potential explanation for its widespread involvement in human disease. PMID- 28005431 TI - Lung Development and Aging. AB - The onset of chronic obstructive pulmonary disease (COPD) can arise either from failure to attain the normal spirometric plateau or from an accelerated decline in lung function. Despite reports from numerous big cohorts, no single adult life factor, including smoking, accounts for this accelerated decline. By contrast, five childhood risk factors (maternal and paternal asthma, maternal smoking, childhood asthma and respiratory infections) are strongly associated with an accelerated rate of lung function decline and COPD. Among adverse effects on lung development are transgenerational (grandmaternal smoking), antenatal (exposure to tobacco and pollution), and early childhood (exposure to tobacco and pollution including pesticides) factors. Antenatal adverse events can operate by causing structural changes in the developing lung, causing low birth weight and prematurity and altered immunological responses. Also important are mode of delivery, early microbiological exposures, and multiple early atopic sensitizations. Early bronchial hyperresponsiveness, before any evidence of airway inflammation, is associated with adverse respiratory outcomes. Overlapping cohort studies established that spirometry tracks from the preschool years to late middle age, and those with COPD in the sixth decade already had the worst spirometry at age 10 years. Alveolar development is now believed to continue throughout somatic growth and is adversely impacted by early tobacco smoke exposure. Genetic factors are also important, with genes important in lung development and early wheezing also being implicated in COPD. The inescapable conclusion is that the roots of COPD are in early life, and COPD is a disease of childhood adverse factors interacting with genetic factors. PMID- 28005432 TI - (+)-Catechin prevents methylglyoxal-induced mitochondrial dysfunction and apoptosis in EA.hy926 cells. AB - OBJECTIVE: To investigate whether (+)-catechin, a strong antioxidant, can prevent methylglyoxal (MGO)-induced cytotoxicity and its mechanism. METHODS: Cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, hydrogen peroxide (H2O2) formation, mitochondrial membrane potential (MMP) and mitochondrial morphology were measured in EA.hy926 cells. RESULT: MGO (4 mM) induced cytotoxicity was markedly inhibited by (+)-catechin (0.1-4 mM) in 24 h. 1 mM MGO-induced apoptotic cell death (44.7%) was significantly inhibited by 4 mM (+)-catechin (to 24.4%), 1 mM aminoguanidine (AG) (to 28.8%) or 4 mM N acetylcysteine (NAC) (to 24.3%). (+)-Catechin (4 mM) or AG (4 mM) can inhibit the decrease of MMP induced by MGO (2-8 mM) in 3 h. (+)-Catechin (4 mM) or AG (4 mM) can inhibit MGO (4 mM)-induced mitochondrial swelling in 3 h. However, MGO (4 mM) induced ROS and H2O2 generation was not prevented by (+)-catechin (4 mM). CONCLUSIONS: (+)-Catechin prevents MGO-induced cytotoxicity in EA.Hy926 cells through inhibiting apoptosis and mitochondrial damage. PMID- 28005433 TI - Combined Special Capsular Tension Ring and Toric IOL Implantation for Management of Astigmatism and High Axial Myopia with Cataracts. AB - AIM: This study aimed to compare the effects of toric intraocular lens (IOL) implantation with a capsular tension ring and toric IOL implantation only in patients with axial myopic astigmatism who had undergone cataract surgery. METHODS: Of 34 patients with axial myopia, 16 patients who had received IOL and capsular tension ring (CTR) implantation were included in the combined group and 18 patients who received toric IOL implantation only were included in the simple group. Uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) were evaluated by measuring subjective refraction, residual astigmatism, and the toric IOL axis six months post-surgery. RESULTS: At six months postoperatively, the UCVA for the combined and simple groups was 4.6 +/- 0.1 and 4.5 +/- 0.2, respectively, a statistically significant difference (t = 3.531, P<0.05). The toric IOL in all of the cases was located in the capsular sac, but there were more cases with IOL rotation (12 eyes) in the simple group than in the combined group (4 eyes). The rotation angles were 20 degrees ~30 degrees (one eye), 10 degrees ~20 degrees (four eyes), and <10 degrees (seven eyes) compared with 2 degrees ~5 degrees (four eyes). The residual astigmatism was -0.50 +/- 0.25 D in the combined group, not a significant difference from the predicted residual astigmatism (-0.35 +/- 0.13 D). There was a significant difference in the simple group (-1.25 +/- 0.33 D) when the predicted residual astigmatism was compared ( 0.37 +/- 0.11 D) (t = -9.511, P < 0.01). CONCLUSIONS: In patients with axial myopic astigmatism, CTR can effectively increase the rotational stability of a toric IOL, achieving improvement in corneal astigmatism and visual acuity. PMID- 28005434 TI - A feasibility study on smartphone accelerometer-based recognition of household activities and influence of smartphone position. AB - BACKGROUND: Obesity and physical inactivity are the most important risk factors for chronic diseases. The present study aimed at (i) developing and testing a method for classifying household activities based on a smartphone accelerometer; (ii) evaluating the influence of smartphone position; and (iii) evaluating the acceptability of wearing a smartphone for activity recognition. METHODS: An Android application was developed to record accelerometer data and calculate descriptive features on 5-second time blocks, then classified with nine algorithms. Household activities were: sitting, working at the computer, walking, ironing, sweeping the floor, going down stairs with a shopping bag, walking while carrying a large box, and climbing stairs with a shopping bag. Ten volunteers carried out the activities for three times, each one with a smartphone in a different position (pocket, arm, and wrist). Users were then asked to answer a questionnaire. RESULTS: 1440 time blocks were collected. Three algorithms demonstrated an accuracy greater than 80% for all smartphone positions. While for some subjects the smartphone was uncomfortable, it seems that it did not really affect activity. CONCLUSIONS: Smartphones can be used to recognize household activities. A further development is to measure metabolic equivalent tasks starting from accelerometer data only. PMID- 28005435 TI - Is there a 'weight neutral' second-generation antipsychotic for bipolar disorder? AB - INTRODUCTION: Antipsychotic-induced weight gain (WG) and metabolic abnormalities are major concerns. This review was untaken to answer if there is a weight neutral second-generation antipsychotic for bipolar disorder (BPD). Areas covered: English-language literature in MEDLINE was searched with the keywords of antipsychotic/second-generation antipsychotic or generic/brand name of second generation antipsychotic, and BPD/mania/depression or bipolar maintenance, and safety/tolerability or WG/weight increase, and randomized, placebo-controlled trial. Difference between an antipsychotic monotherapy and placebo in absolute weight gain (AWG) and/or >= 7% (WG in three phases of BPD was compared based on the data from original publications. The number needed to treat to harm was used for the comparison of >= 7% WG. Among antipsychotics with short-term (mania and/or bipolar depression) and long-term (maintenance) studies, olanzapine, asenapine, quetiapine, risperidone had significant WG compared to placebo in both short-term and long-term trials. Aripiprazole did not cause significant WG compared to placebo in short-term studies, but caused significant WG in long-term studies. Paliperidone-ER-induced WG was significant in a mania study as measured with AWG, and ziprasidone caused significant WG in a mania study measured with >= 7% WG. Expert commentary: These data suggest that it is unlikely there is a weight-neutral second-generation antipsychotic in BPD. PMID- 28005436 TI - Novel leukotriene biosynthesis inhibitors (2012-2016) as anti-inflammatory agents. AB - INTRODUCTION: Leukotrienes (LTs) are lipid mediators produced from arachidonic acid with a broad variety of bioactivities in allergy and inflammation. The biosynthesis of LTs mainly involves 5-lipoxygenase (5-LO) and its 5-lipoxygenase activating protein (FLAP), LTA4 hydrolase and LTC4 synthase that all may represent potential targets for LT biosynthesis inhibitors. Areas covered: We introduce the LT biosynthetic pathway and its cellular regulation, the diverse biological actions of LTs and their receptors, and we briefly describe the pharmacological strategies for suppression of LT formation as well as the classes of current LT biosynthesis inhibitors. The main focus is placed on the comprehensive discussion of recently reported inhibitors of 5-LO, FLAP, LTA4 hydrolase and LTC4 synthase, based on literature search (PubMed and Thomson Innovation Patents Searches), covering 2012-2016. Expert opinion: Although many new series of 5-LO inhibitors have been presented without patenting, essentially by academia, novel FLAP inhibitors (many patented) are most advanced in clinical development and are apparently the focus of pharmaceutical companies. Only few novel inhibitors of LTA4 hydrolase and LTC4 synthase were reported. Major issues in the development of LT synthesis inhibitors are related to loss of potency in biological relevant environment, poor pharmacokinetics, lack of oral efficacy, and side effects. PMID- 28005437 TI - Self nanoemulsifying granules (SNEGs) of meloxicam: preparation, characterization, molecular modeling and evaluation of in vivo anti-inflammatory activity. AB - Meloxicam, a BCS class II drug belonging to the class of NSAIDs is indicated in conditions of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis in which rapid onset of drug action is desired to reduce inflammation and pain. The objective of the study was to thus develop Self Nanoemulsifying Granules (SNEGs) of Meloxicam (MLX) for enhancement of solubility; and subsequently dissolution rate, thus aiming for a faster onset of action. Preliminary studies along with molecular modeling studies were carried out for selection of appropriate lipids, surfactants and cosurfactants for the development of MLX-loaded Self Nanoemulsifying preconcentrate (SNEP). A charge inducer was incorporated into the formulation so as to increase the solubility of MLX in lipids and hence, drug loading. A three-factor D-optimal mixture design was used for optimization of MLX loaded SNEP. The role of charge inducer in increasing the drug loading of MLX in SNEDDS was studied by molecular dynamics simulation using Desmond. Optimized SNEP was adsorbed onto solid carriers to form SNEGs for improved stability and enhanced flow properties. Physical characterization studies of SNEGs, in vitro release studies, and in vivo evaluation of anti-inflammatory activity of the optimized formulation were performed. All the results indicated that MLX SNEGs can be a promising alternative to conventional oral NSAIDs therapy because of enhanced dissolution characteristics and subsequent rapid onset of action. PMID- 28005438 TI - Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3. AB - 1. The drug-drug interaction (DDI) mediated by organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and OATP2B1 has a major impact on the hepatic clearance of drugs. The effects of tyrosine kinase inhibitors (TKIs) on OATPs have not been well studied. In the present study, we evaluated the contribution of OATPs to the hepatic uptake of crizotinib and gefitinib and the interaction of those TKIs with OATPs to estimate DDIs. 2. To clarify whether crizotinib and gefitinib were substrates for OATPs, we performed uptake studies. We examined the effects of the TKIs on uptake of typical substrates and fluvastatin via OATPs. IC50 and EC50 values of the TKIs were calculated. 3. OATP1B3- and OATP2B1 mediated crizotinib uptake and OATP2B1-mediated gefitinib uptake were observed. Gefitinib accelerated OATP1B3-mediated [3H]TCA uptake and inhibited OATP2B1 mediated [3H]E3S uptake. On the other hand, gefitinib inhibited OATP1B1- and OATP2B1-mediated fluvastatin uptake. 4. We provided basic information to estimate the DDI on OATPs caused by TKIs. The DDI on OATPs caused by gefitinib could occur in a normal clinical situation. And the uptake of crizotinib into the intrahepatocellular environment via OATPs may induce DDI and liver damage. We therefore emphasize the necessity of careful use of TKIs. PMID- 28005439 TI - Early lung cancer detection by low-dose CT screening: therapeutic implications. AB - INTRODUCTION: Lung cancer screening by low-dose chest computed tomography is currently implemented in the U.S. After implementation of screening, a stage shift may be observed from around 15% stage I non-small cell lung cancers (NSCLCs) in routine clinical practice to up to 70% in screening patients. This indicates a move in treatment options from advanced to early lung cancers, especially in those with small suspected intrapulmonary nodules. Areas covered: We have reviewed the current status of lung cancer screening from the different randomized controlled lung cancer screening studies and the clinical evidence so far for both surgical and non-surgical treatment options for (screen-detected) stage I NSCLC. Furthermore, we provide a step-wise approach for the treatment of stage I NSCLC. Expert Commentary: Recommended treatment for stage I NSCLC remains (VATS) lobectomy in case of a medically operable patient, VATS sublobar resection for subcentimeter nodules, and SBRT otherwise. Currently, there is too limited evidence for the value of ablative techniques in curative treatment of early stage NSCLC. Therefore, these therapies should only be used in expert centers for selected patients in clinical studies. PMID- 28005441 TI - Integrated information visualization to support decision-making in order to strengthen communities: Design and usability evaluation. AB - Community well-being refers to the qualities of an optimally healthy community life. This is the ultimate goal of all the various processes and strategies created to meet the needs of people living together in communities. We propose a holistic integrated visualization, in the form of a community well-being assessment system, as a web-based advanced tool to be used by the executive and health officers of the sub-district administration organization (SAO) network to improve decision-making in order to strengthen their communities. Data were obtained from the Family and Community Assessment Program (FAP) and the SAO in nine sub-districts, covering all of the four regions of Thailand. The system incorporates dashboard architecture and assists the executive and health officers in the SAO to achieve better decision-making for the deployment of proper measures in communities. The model was developed for the Pakpoon SAO and was applied to the other eight SAOs. In order to evaluate the model, 243 users, covering all user groups from three sites, were asked to answer 18 questions during a meeting. The overall average score for user satisfaction was 4.12. The results indicate that this model can be used for community well-being assessment, in order to improve decision-making to strengthen communities in Thailand. PMID- 28005440 TI - Effect of a Single Dose of Vitamin D3 on Postprandial Arterial Stiffness and Inflammation in Vitamin D-Deficient Women. AB - Context: Cholecalciferol (vitamin D3) improves vascular function and inflammation, potentially providing an explanation for the proposed cardiovascular protection of vitamin D. Objective: We investigated whether cholecalciferol supplementation reduces postprandial arterial dysfunction and inflammation. Design: Randomized, 1:1, double-blind trial. Setting: Diabetes and Vascular Center, Franciscus Gasthuis, Rotterdam, The Netherlands. Patients: Twenty-four healthy, premenopausal, overweight or obese, vitamin D-deficient women. Interventions: A single high (300,000 IU) or low dose (75,000 IU) of cholecalciferol. Main Outcome Measures: The effect of low- and high-dose cholecalciferol on postprandial leukocyte activation markers, pulse wave velocity (PWV), and augmentation index (AIx) during an oral fat loading test, expressed as area under the curve (AUC). Results: High- and low-dose supplementation increased vitamin D by 163% +/- 134% (P < 0.001) and 66% +/- 59% (P < 0.001), respectively. Monocyte CD11b-AUC slightly increased after low but not high dose (6% +/- 2%, P = 0.012, and 4% +/- 1%, P = 0.339, respectively). There were no significant effects on postprandial PWV or AIx by high- or low-dose vitamin D. Fasting complement component 3 (C3) levels decreased by 5.9% (P = 0.004) in the high-dose group and by 4.0% (P = 0.018) in the low-dose group. Conclusion: A single dose of vitamin D does not seem to reduce arterial stiffness and leukocyte activation in overweight, vitamin D-deficient women. Vitamin D may decrease fasting C3. Possibly, higher vitamin D concentrations may be needed to decrease inflammation and improve vascular function in overweight or obese vitamin D-deficient women. PMID- 28005442 TI - Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation. AB - OBJECTIVE: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. MATERIALS AND METHODS: Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. RESULTS AND DISCUSSION: The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. CONCLUSION: In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM. PMID- 28005443 TI - Identification and characterization of adult mouse meniscus stem/progenitor cells. AB - Meniscal damage is a common problem that accelerates the onset of knee osteoarthritis. Stem cell-based tissue engineering treatment approaches have shown promise in preserving meniscal tissue and restoring meniscal function. The purpose of our study was to identify meniscus-derived stem/progenitor cells (MSPCs) from mouse, a model system that allows for in vivo analysis of the mechanisms underlying meniscal injury and healing. MSPCs were isolated from murine menisci grown in explant culture and characterized for stem cell properties. Flow cytometry was used to detect the presence of surface antigens related to stem cells, and qRT-PCR was used to examine the gene expression profile of MSPCs. Major proteins associated with MSPCs were localized in the adult mouse knee using immunohistochemistry. Our data show that MSPCs have universal stem cell-like properties including clonogenicity and multi potentiality. MSPCs expressed the mesenchymal stem cell markers CD44, Sca-1, CD90, and CD73 and when cultured had elevated levels of biglycan and collagen type I, important extracellular matrix components of adult meniscus. MSPC also expressed significant levels of Lox and Igf-1, genes associated with the embryonic meniscus. Localization studies showed staining for these same proteins in the superficial and outer zones of the adult mouse meniscus, regions thought to harbor endogenous repair cells. MSPCs represent a novel resident stem cell population in the murine meniscus. Analysis of MSPCs in mice will allow for a greater understanding of the cell biology of the meniscus, essential information for enhancing therapeutic strategies for treating knee joint injury and disease. PMID- 28005444 TI - ICT and the future of healthcare: Aspects of pervasive health monitoring. AB - Along with the digital revolution, information and communication technology applications are currently transforming the delivery of health and social care services. This paper investigates prevailing opinions toward future technology based healthcare solutions among Austrian healthcare professionals. During a biphasic online Delphi survey, panelists rated expected outcomes of two future scenarios describing pervasive health monitoring applications. Experts perceived that the scenarios were highly innovative, but only moderately desirable, and that their implementation could especially improve patients' knowledge, quality of healthcare, and living standard. Contrarily, monetary aspects, technical prerequisites, and data security were identified as key obstacles. We further compared the impact of professional affiliation. Clearly, opinions toward pervasive healthcare differed between the interest groups, medical professionals, patient advocates, and administrative personnel. These data suggest closer collaborations between stakeholder groups to harmonize differences in expectations regarding pervasive health monitoring. PMID- 28005445 TI - Preparation and in vivo safety evaluations of antileukemic homoharringtonine loaded PEGylated liposomes. AB - In order to improve the in vivo safety and specific delivery efficiency of the antileukemic homoharringtonine (HHT) at the targets, the long-circulating PEGylated liposomes loaded with HHT (LCLipo-HHT) were prepared. Their physical characteristics, in vitro drug release, in vivo pharmacokinetic properties and elementary toxicity were evaluated. The mean diameter of the prepared LCLipo-HHT is 75.6 +/- 3.2 nm and the zeta potential is -16.9 +/- 2.5 mV. The entrapment efficiency of HHT in the liposomes is 69.5 +/- 1.7%. In pharmacokinetic experiments, an increased plasma concentration as well as blood circulation time was obtained when distearoyl phosphoethanolamine-PEG 2000 lipid was added in the formulation, which results in enhancing drug delivery efficiency. Hemolysis test, vascular irritation test and acute toxicity test were used to demonstrate toxicity of LCLipo-HHT. Compared with clinical HHT injection dosage, LCLipo-HHT indicated no vascular irritation, good hemocompatibility, as well as much better safety. Therefore, the prepared LCLipo-HHT can be used as a promising anticancer formulation for antileukemic therapy in the future. PMID- 28005446 TI - The Effect of Agave tequilana Weber Inulin on Postprandial Ghrelin Concentration in Obese Patients. AB - This study was performed to investigate the effect of Agave tequilana Weber inulin on postprandial ghrelin levels in obese patients. A randomized, double blind, cross-over design was performed. A total of 14 patients were allocated into two groups: one group received a drink that contained 500 mL lemon water, 24 g of A. tequilana Weber inulin, and 75 g glucose and the other group received a placebo drink with 500 mL lemon drink and 75 g of glucose. After a 7-day washout period, the groups were crossed. The primary outcome measure was postprandial ghrelin levels between minute 240 and minute 270. A. tequilana Weber inulin did not change postprandial ghrelin concentration in obese patients. PMID- 28005447 TI - Gynostemma pentaphyllum Ethanolic Extract Protects Against Memory Deficits in an MPTP-Lesioned Mouse Model of Parkinson's Disease Treated with L-DOPA. AB - This study investigated the effects of ethanol extract from Gynostemma pentaphyllum (GP-EX) on memory deficits in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD) (MPTP lesioned mice). MPTP (30 mg/kg/day, 5 days)-lesioned mice showed deficits of habit learning memory and spatial memory, which were further aggravated by treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) (25 mg/kg, 21 days). However, treatment with GP-EX (50 mg/kg, 21 days) ameliorated memory deficits in MPTP-lesioned mice treated with L-DOPA (25 mg/kg): GP-EX prevented the decreases in retention latency time in the passive avoidance test and tyrosine hydroxylase immunopositive cells and dopamine levels in the nigrostriatum. GP-EX also reduced increases in retention transfer latency time of the elevated plus-maze test and expression of N-methyl-D-aspartate (NMDA) receptor and improved decreases in phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP response element binding protein (CREB) in the hippocampus in the same models. By contrast, L-DOPA treatment (10 mg/kg, 21 days) ameliorated memory deficits in MPTP-lesioned mice, which were further improved by GP-EX treatment. These results suggest that GP-EX ameliorates habit learning memory deficits by activating dopaminergic neurons and spatial memory deficits by modulating NMDA receptor ERK1/2-CREB system in MPTP-lesioned mice treated with L-DOPA. GP-EX may serve as an adjuvant phytonutrient for memory deficits in PD. PMID- 28005448 TI - Tear Film and Ocular Surface Evaluation in Gestational Diabetes Mellitus. AB - BACKGROUND: Dry eye syndrome is one of the complaints of diabetic patients. The aim of the present study was to evaluate the tear functions in pregnant women with gestational diabetes mellitus (GDM) using tests: Schirmer, tear break-up time (TBUT), and tear film osmolarity (TFO) tests and the Ocular Surface Disease Index score (OSDI). METHODS: Pregnant women with GDM (Group 1, n=46) and healthy pregnant women (Group 2, n=36) were enrolled. Initially, all participants were asked to answer the OSDI and then they underwent a detailed ophthalmic examination including Schirmer, TBUT, and TFO tests. The individuals with ocular or systemic disorders that might affect the tear function tests and who were using topical medications were excluded. RESULTS: The results of Schirmer, TBUT, TFO tests and OSDI scores were 11.20+/-4.93 mm, 5.59+/-2.16 sec, 309.65+/-14.80 mOsm/L, and 9.59 +/- 9.69 in Group 1, respectively, and 12.33+/-5.33 mm, 5.67+/ 2.68 sec, 308.36+/-16.00 mOsm/L, and 10.62+/-8.66 in Group 2, respectively. There was no significant difference in any of the tear function tests and OSDI scores between the study groups (p>0.05). CONCLUSION: GDM seems to have no negative effects on tear function tests. This may be due to a lack of duration of hyperglycemia long enough to affect the tear function tests of pregnant women. PMID- 28005449 TI - Clinical benefits and drawbacks of local corticosteroids injections in tendinopathies. AB - INTRODUCTION: local glucocorticoids injections are widely administered for the treatment of tendinopathies. positive results have been observed in some tendinopathies but not in others. moreover, worsening of symptoms, and even spontaneous tendon ruptures has been reported. the characteristics of the tendinopathies, the clinical peculiarities of the patient, and the technique used to administer glucocorticoids, can influence the therapeutic response. Areas covered: After reviewing the pertinent literature on the clinical results, basic information, both on the pathogenesis of tendinopathies and the effects of glucocorticoids on tendons, is reported. The pharmacological properties of glucocorticoids are useful to counteract some pathogenetic mechanisms of tendinopathies. However, several experimental studies suggest that the direct action of glucocorticoids on tendons is detrimental. Loss of collagen organization, impaired viability of fibroblasts, depletion of stem cells pool, and reduced mechanical properties have been observed. Expert opinion: Drawbacks of local glucocorticoids injections could be predicted on an individual basis, after a careful appraisal of patient characteristics and concomitant medications, along with the specific stage of tendon disease. PMID- 28005450 TI - The ECG in the differential diagnosis between takotsubo cardiomyopathy and acute coronary syndrome. AB - INTRODUCTION: Takotsubo cardiomyopathy (TC) is an acquired cardiomyopathy affecting mostly postmenopausal women mimicking an acute coronary syndrome (ACS). TC clinical presentation involves chest pain, elevated cardiac enzymes, wall motion abnormalities and electrocardiographic changes, all of which share striking similarities to ACS. Areas covered: Differential diagnosis between TC and ACS can be complex since there are no reliable and widely-accepted electrocardiographic criteria and, at the moment, only coronary angiography can rule out one of the two diagnoses with good certainty. The present review will discuss the pros and cons of the ECG in TC, focusing on how the signal changes through the acute phase, the hospitalization, and after discharge. Specific information will be provided for each component of the ECG trace, and potential pitfalls will be highlighted, in order get to the core of this important unmet clinical issue. Expert commentary: There are at least several reasons why the ECG is still not considered a useful tool in differential diagnosis between TC and ACS. These include recent awareness of the syndrome, lack of evidence-based therapy, and, more importantly, a wide range of ECG features according to race, patient characteristics, wall motion abnormalities, triggers, and time from symptoms onset. PMID- 28005451 TI - Nanoparticles for the delivery of therapeutic antibodies: Dogma or promising strategy? AB - INTRODUCTION: Over the past two decades, therapeutic antibodies have demonstrated promising results in the treatment of a wide array of diseases. However, the application of antibody-based therapy implies multiple administrations and a high cost of antibody production, resulting in costly therapy. Another disadvantage inherent to antibody-based therapy is the limited stability of antibodies and the low level of tissue penetration. The use of nanoparticles as delivery systems for antibodies allows for a reduction in antibody dosing and may represent a suitable alternative to increase antibody stability Areas covered: We discuss different nanocarriers intended for the delivery of antibodies as well as the corresponding encapsulation methods. Recent developments in antibody nanoencapsulation, particularly the possible toxicity issues that may arise from entrapment of antibodies into nanocarriers, are also assessed. In addition, this review will discuss the alterations in antibody structure and bioactivity that occur with nanoencapsulation. Expert opinion: Nanocarriers can protect antibodies from degradation, ensuring superior bioavailability. Encapsulation of therapeutic antibodies may offer some advantages, including potential targeting, reduced immunogenicity and controlled release. Furthermore, antibody nanoencapsulation may aid in the incorporation of the antibodies into the cells, if intracellular components (e.g. intracellular enzymes, oncogenic proteins, transcription factors) are to be targeted. PMID- 28005452 TI - Preparation and evaluation of posaconazole-loaded enteric microparticles in rats. AB - OBJECTIVES: Posaconazole (POS) is an antifungal compound which has a low oral bioavailability. The aim of this study was to prepare POS enteric microparticles to enhance its oral bioavailability. METHODS: POS enteric microparticles were prepared with hypromellose acetate succinate (HPMCAS) via the spray drying method. The solvent mixtures of acetone and ethanol used in the preparation of the microparticles were optimized to produce the ideal POS enteric microparticles. Multivariate data analysis using a principal component analysis (PCA) was used to find the relationship among the HPMCAS molecular characteristics, particle properties and drug release kinetics from the spray dried microparticles. KEY FINDINGS: The optimal spray solvent mixtures were critical to produce the POS microparticles with the defined polymer entanglement index, drug surface enrichment, particle size and drug loading. The HPMCAS molecular characteristics affected the microscopic connectivity and diffusivity of polymer matrix and eventually influenced the drug release behavior, and enhanced the bioavailability of POS. CONCLUSIONS: These studies suggested that the selection of suitable solvent mixtures of acetone and ethanol used in the spray drying of the microparticles was quite important to produce the entangled polymer structures with preferred polymer molecular properties of polymer coiling, overlap concentration and entanglement index. Additional studies on particle size and surface drug enrichment eventually produced HPMCAS-based enteric microparticles to enhance the oral bioavailability of POS. PMID- 28005453 TI - Can We Study Autonomous Driving Comfort in Moving-Base Driving Simulators? A Validation Study. AB - OBJECTIVE: To lay the basis of studying autonomous driving comfort using driving simulators, we assessed the behavioral validity of two moving-base simulator configurations by contrasting them with a test-track setting. BACKGROUND: With increasing level of automation, driving comfort becomes increasingly important. Simulators provide a safe environment to study perceived comfort in autonomous driving. To date, however, no studies were conducted in relation to comfort in autonomous driving to determine the extent to which results from simulator studies can be transferred to on-road driving conditions. METHOD: Participants ( N = 72) experienced six differently parameterized lane-change and deceleration maneuvers and subsequently rated the comfort of each scenario. One group of participants experienced the maneuvers on a test-track setting, whereas two other groups experienced them in one of two moving-base simulator configurations. RESULTS: We could demonstrate relative and absolute validity for one of the two simulator configurations. Subsequent analyses revealed that the validity of the simulator highly depends on the parameterization of the motion system. CONCLUSION: Moving-base simulation can be a useful research tool to study driving comfort in autonomous vehicles. However, our results point at a preference for subunity scaling factors for both lateral and longitudinal motion cues, which might be explained by an underestimation of speed in virtual environments. APPLICATION: In line with previous studies, we recommend lateral- and longitudinal-motion scaling factors of approximately 50% to 60% in order to obtain valid results for both active and passive driving tasks. PMID- 28005454 TI - Preliminary Population Size Estimation of Men Who Have Sex with Men in Kazakhstan: Implications for HIV Testing and Surveillance. AB - PURPOSE: The purpose of this study is to estimate the population size of men who have sex with men (MSM) in Kazakhstan and their HIV testing history. METHODS: We conducted structured interviews with MSM in four geographically disparate cities N = 400 (n = 100/city)-to implement four population estimation methods and ascertain HIV testing history. RESULTS: Approximately 3.2% of men-corresponding to ~154,000 individuals-in Kazakhstan aged 18-59 are MSM. The 49.9% of the sample who reported taking an HIV test far exceeds the <1% reported as MSM in surveillance data. CONCLUSION: HIV testing surveillance in Kazakhstan has underestimated the number of MSM. This underscores the need to redress social and structural barriers to HIV testing and disclosure of sexual behavior experienced by MSM in Kazakhstan. Recommendations include promoting cultural sensitivity among testing staff through quality assurance and regular training, and increasing protection and public awareness through antidiscrimination policy development. PMID- 28005455 TI - Small GTPases controlling autophagy-related membrane traffic in yeast and metazoans. AB - During macroautophagy, the phagophore-mediated formation of autophagosomes and their subsequent fusion with lysosomes requires extensive transformation of the endomembrane system. Membrane dynamics in eukaryotic cells is regulated by small GTPase proteins including Arfs and Rabs. The small GTPase proteins that regulate autophagic membrane traffic are mostly conserved in yeast and metazoans, but there are also several differences. In this mini-review, we compare the small GTPase network of yeast and metazoan cells that regulates autophagy, and point out the similarities and differences in these organisms. PMID- 28005457 TI - Modelling difficulties in abstract thinking in psychosis: the importance of socio developmental background. AB - INTRODUCTION: Abstract thinking is important in modern understanding of neurocognitive abilities, and a symptom of thought disorder in psychosis. In patients with psychosis, we assessed if socio-developmental background influences abstract thinking, and the association with executive functioning and clinical psychosis symptoms. METHODS: Participants (n = 174) had a diagnosis of psychotic or bipolar disorder, were 17-65 years, intelligence quotient (IQ) > 70, fluent in a Scandinavian language, and their full primary education in Norway. Immigrants (N = 58) were matched (1:2) with participants without a history of migration (N = 116). All participants completed a neurocognitive and clinical assessment. Socio developmental background was operationalised as human developmental index (HDI) of country of birth, at year of birth. Structural equation modelling was used to assess the model with best fit. RESULTS: The model with best fit, chi2 = 96.591, df = 33, p < .001, confirmed a significant indirect effect of HDI scores on abstract thinking through executive functioning, but not through clinical psychosis symptoms. CONCLUSIONS: This study found that socio-developmental background influences abstract thinking in psychosis by indirect effect through executive functioning. We should take into account socio-developmental background in the interpretation of neurocognitive performance in patients with psychosis, and prioritise cognitive remediation in treatment of immigrant patients. PMID- 28005456 TI - Physicochemical and biological characterization of SB2, a biosimilar of Remicade(r) (infliximab). AB - A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product. Biosimilarity to the reference product (RP) in terms of quality characteristics, such as physicochemical and biological properties, safety, and efficacy, based on a comprehensive comparability exercise needs to be established. SB2 (Flixabi(r) and Renflexis(r)) is a biosimilar to Remicade(r) (infliximab). The development of SB2 was performed in accordance with relevant guidelines of the International Conference on Harmonisation, the European Medicines Agency, and the United States Food and Drug Administration. To determine whether critical quality attributes meet quality standards, an extensive characterization test was performed with more than 80 lots of EU- and US-sourced RP. The physicochemical characterization study results revealed that SB2 was similar to the RP. Although a few differences in physicochemical attributes were observed, the evidence from the related literature, structure-activity relationship studies, and comparative biological assays showed that these differences were unlikely to be clinically meaningful. The biological characterization results showed that SB2 was similar to the RP in terms of tumor necrosis factor-alpha (TNF-alpha) binding and TNF-alpha neutralization activities as a main mode of action. SB2 was also similar in Fc related biological activities including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, neonatal Fc receptor binding, C1q binding, and Fc gamma receptor binding activities. These analytical findings support that SB2 is similar to the RP and also provide confidence of biosimilarity in terms of clinical safety and efficacy. PMID- 28005458 TI - Discriminating between first- and second-order cognition in first-episode paranoid schizophrenia. AB - INTRODUCTION: An impairment of visually perceiving backward masked stimuli is commonly observed in patients with schizophrenia, yet it is unclear whether this impairment is the result of a deficiency in first or higher order processing and for which subtypes of schizophrenia it is present. METHODS: Here, we compare identification (first order) and metacognitive (higher order) performance in a visual masking paradigm between a highly homogenous group of young first-episode patients diagnosed with paranoid schizophrenia (N = 11) to that of carefully matched healthy controls (N = 13). RESULTS: We find no difference across groups in first-order performance, but find a difference in metacognitive performance, particularly for stimuli with relatively high visibility. CONCLUSIONS: These results indicate that the masking deficit is present in first-episode patients with paranoid schizophrenia, but that it is primarily an impairment of metacognition. PMID- 28005459 TI - Proceedings of the 2016 Clinical Nutrition Week Research Workshop-The Optimal Dose of Protein Provided to Critically Ill Patients. AB - Recent literature has created considerable confusion about the optimal amount of protein/amino acids that should be provided to the critically ill patient. In fact, the evidentiary basis that directly tries to answer this question is relatively small. As a clinical nutrition research community, there is an urgent need to develop the optimal methods to assess the impact of exogenous protein/amino acid administration in the intensive care unit setting. That assessment can be conducted at various levels: (1) impact on stress response pathways, (2) impact on muscle synthesis and protein balance, (3) impact on muscle mass and function, and (4) impact on the patient's recovery. The objective of this research workshop was to review current literature relating to protein/amino acid administration for the critically ill patient and clinical outcomes and to discuss the key measurement and methodological features of future studies that should be done to inform the optimal protein/amino acid dose provided to critically ill patients. PMID- 28005461 TI - The neuroscience of persuasion: A review with an emphasis on issues and opportunities. AB - Persuasion, a prevalent form of social influence in humans, refers to an active attempt to change a person's attitudes, beliefs, or behavior. There is a growing literature on the neural correlates of persuasion. As is often the case in an emerging literature, however, there are a number of questions, concerns, and alternative interpretations that can be raised about the research and interpretations. We provide a critical review of the research, noting potential problems and issues that warrant attention to move the field forward. Among the recommendations are greater integration of neuroimaging approaches with existing behavioral theories and methods on the information processes (cognitive and affective) underlying persuasion, and moving beyond solely correlative approaches for specifying underlying neural mechanisms. Work in this area has the potential to contribute to our understanding of brain-behavior relationships as well as to advance our understanding of persuasion and social influence more generally. PMID- 28005460 TI - The role of alternative splicing in cancer. AB - The functional capacity of cells is defined by the transcriptome. Many recent studies have identified variations in the transcriptome of tumors due to alternative splicing changes, as well as mutations in splicing factors and regulatory signals in most tumor types. Some of these alterations have been linked to tumor progression, metastasis, therapy resistance, and other oncogenic processes. Here, we describe the different mechanisms that drive splicing changes in tumors and their impact in cancer. Motivated by the current evidence, we propose a model whereby a subset of the splicing patterns contributes to the definition of specific tumor phenotypes, and may hold potential for the development of novel clinical biomarkers and therapeutic approaches. PMID- 28005462 TI - Recognition of c9orf72 Mutant RNA by Single-Stranded Silencing RNAs. AB - Mutations within the chromosome 9 open reading frame 72 (c9orf72) gene are associated with both familial amyotrophic lateral sclerosis and frontotemporal dementia. The mutation leads to an expanded GGGGCC hexanucleotide repeat within the first intron of c9orf72 and an expanded CCCCGG repeat within a corresponding antisense transcript. Both the mutant intronic and antisense RNAs have been implicated in disease. We have previously reported that duplex RNAs complementary to the repeats can recognize disease-causing RNA and block detection of nuclear foci formed by the mutant transcripts. Here, we test the hypothesis that inhibition can also be achieved by single-stranded silencing RNAs (ss-siRNAs). ss siRNAs are single-stranded antisense oligonucleotides (ASOs) that function through RNAi interference (RNAi) to silence gene expression. ss-siRNAs can block the expanded repeats within both intronic RNA and the antisense transcripts. Inhibition is more potent than by analogous duplex RNAs. Our data suggest that the potent effects on foci are caused by a combination of mechanisms including RNAi and direct binding of the ss-siRNA to the target transcripts. These findings reinforce the suggestion that ss-siRNAs combine the favorable properties of duplex RNA and single-stranded ASOs. PMID- 28005464 TI - Improvement of darts performance following lucid dream practice depends on the number of distractions while rehearsing within the dream - a sleep laboratory pilot study. AB - In a lucid dream, the dreamer is aware of the dream state and can deliberately practice motor skills. Two field studies indicated that lucid dream practice can improve waking performance in simple motor tasks. The present pilot study investigated the effect of lucid dream practice in a controlled sleep laboratory setting, using a pre-post design with dart throwing in the evening and morning. The experimental group practiced darts in lucid dreams. Because some participants were distracted during lucid dream practice, the group was divided into lucid dreamers with few (n = 4) and many distractions (n = 5). Change of performance was compared to a physical practice group (n = 9) and a control group (n = 9), showing a significant interaction (P = .013, eta2 = .368). Only the lucid dreamers with few distractions improved (18%) significantly over time (P = .005, d = 3.84). Even though these results have to be considered preliminary, the present study indicates that lucid dream practice can be an effective tool in sports practice if lucid dreamers find ways to minimise distractions during lucid dream practice. Moreover, the study emphasises the necessity to investigate lucid dream practice experiences on a qualitative level. PMID- 28005463 TI - CDK regulation of transcription by RNAP II: Not over 'til it's over? AB - Transcription by RNA polymerase (RNAP) II is regulated at multiple steps by phosphorylation, catalyzed mainly by members of the cyclin-dependent kinase (CDK) family. The CDKs involved in transcription have overlapping substrate specificities, but play largely non-redundant roles in coordinating gene expression. Novel functions and targets of CDKs have recently emerged at the end of the transcription cycle, when the primary transcript is cleaved, and in most cases polyadenylated, and transcription is terminated by the action of the "torpedo" exonuclease Xrn2, which is a CDK substrate. Collectively, various functions have been ascribed to CDKs or CDK-mediated phosphorylation: recruiting cleavage and polyadenylation factors, preventing premature termination within gene bodies while promoting efficient termination of full-length transcripts, and preventing extensive readthrough transcription into intergenic regions or neighboring genes. The assignment of precise functions to specific CDKs is still in progress, but recent advances suggest ways in which the CDK network and RNAP II machinery might cooperate to ensure timely exit from the transcription cycle. PMID- 28005465 TI - What can yeast tell us about breast cancer? PMID- 28005466 TI - Seasonal changes in body composition of inter-county Gaelic Athletic Association hurlers. AB - Longitudinal change in body composition for elite-level inter-county hurlers was reported over a single season and four consecutive seasons. Body composition measured by dual-energy x-ray absorptiometry (DXA) of 66 senior, male, outfield players was obtained. Four successive measurements were taken: off-season (OFF1), pre-season (PRE), mid-season (MID) and the off-season of the following season (OFF2). A subsample of 11 hurlers were measured at all time points over 4 consecutive seasons. DXA-derived estimates of fat and lean mass were normalised to stature for analysis (kg?m-2); data are (mean [lower: upper, 95% confidence interval]). A concurrent increase of lean mass (0.31 [0.19: 0.43] kg?m-2) and loss of fat mass occurred (-0.38 [-0.50: -0.26] kg?m-2) OFF1 to PRE. Lean mass accrual was maintained PRE to OFF2 while the initial loss of fat mass was restored MID to OFF2 (0.52 [0.40: 0.64] kg ? m-2), with the trunk acting as the primary region of change. Over the four seasons, a net increase of lean mass was observed (~ 0.9 [0.4: 1.4] kg per annum) with a negligible overall change for fat mass over time. However, the cycling of fat mass (OFF to PRE and MID to OFF) within each season was recurrent season-to-season. PMID- 28005468 TI - Age and Its Impact on Outcomes with Intra-Abdominal Infection. AB - BACKGROUND: Age has been shown to play a significant role in the etiology of complicated intra-abdominal infections (cIAIs), but the correlation between age and outcomes after therapy was not investigated in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial. PATIENTS AND METHODS: Data were obtained by post hoc analysis of the STOP-IT trial database. Patients were stratified by age <65 or >=65 years. Primary outcomes were surgical site infection (SSI), recurrent IAI (recIAI), and death. Multivariable analysis was performed to identify independent predictors of outcomes. RESULTS: There were 398 subjects <65 and 120 >= 65 years. Overall baseline characteristics of the two groups were similar. The site of infection was similar between groups except: Colon or rectum (48.3% vs. 29.9%, p = 0.0002) and biliary tree (16.7% vs. 9.1%, p = 0.02), which were more common in the older group, whereas small intestine (6.7% vs. 16.3%, p = 0.008) and appendix (4.2% vs.17.1%, p = 0.0004) were more common in the younger group. Among the primary outcomes, only death was significantly different between the age groups and was more prevalent in the >=65 years group (4 [3.3%] vs. 1 [0.3%], p = 0.01). Surgical site infection (9.2% vs. 7.3%, p = 0.50), recIAI (15.8% vs. 14.4%, p = 0.69), and a composite outcome (26.7% vs. 20.4%, p = 0.14) were statistically similar between the age groups, and this remained true when controlling for other co-variables. Multivariable analyses did not reveal age as an independent predictor of the composite or individual outcomes. CONCLUSION: Patients with a more advanced age demonstrated variable sources of infection relative to the younger cohort, yet received similar treatments. Patient age was not an independent predictor of the undesired cIAI outcomes. These findings suggest that advanced age itself does not play a significant role in predicting these adverse outcomes for cIAIs and does not necessitate an altered treatment tactic. PMID- 28005467 TI - Defining the purity of exosomes required for diagnostic profiling of small RNA suitable for biomarker discovery. AB - Small non-coding RNAs (ncRNA), including microRNAs (miRNA), enclosed in exosomes are being utilised for biomarker discovery in disease. Two common exosome isolation methods involve differential ultracentrifugation or differential ultracentrifugation coupled with Optiprep gradient fractionation. Generally, the incorporation of an Optiprep gradient provides better separation and increased purity of exosomes. The question of whether increased purity of exosomes is required for small ncRNA profiling, particularly in diagnostic and biomarker purposes, has not been addressed and highly debated. Utilizing an established neuronal cell system, we used next-generation sequencing to comprehensively profile ncRNA in cells and exosomes isolated by these 2 isolation methods. By comparing ncRNA content in exosomes from these two methods, we found that exosomes from both isolation methods were enriched with miRNAs and contained a diverse range of rRNA, small nuclear RNA, small nucleolar RNA and piwi interacting RNA as compared with their cellular counterparts. Additionally, tRNA fragments (30-55 nucleotides in length) were identified in exosomes and may act as potential modulators for repressing protein translation. Overall, the outcome of this study confirms that ultracentrifugation-based method as a feasible approach to identify ncRNA biomarkers in exosomes. PMID- 28005469 TI - Clinical Significance of Dynamics of Programmed Death Ligand-1 Expression on Circulating CD14+ Monocytes and CD19+ B Cells with the Progression of Hepatitis B Virus Infection. AB - Programmed death-1 (PD-1) expression has been revealed to be upregulated on T cells and contributes to T cell exhaustion in patients with hepatitis B virus (HBV) infection. In this study, we investigated the dynamic expression of programmed death ligand-1 (PD-L1), the ligand of PD-1, on circulating CD14+ monocytes and CD19+ B cells of HBV-infected patients at the stages of chronic HBV (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC), respectively. The results showed that compared with healthy controls, the levels of PD-L1 expression on CD14+ and CD19+ populations were both upregulated in CHB, LC, and HCC groups. Although there was no significant difference of PD-L1 expression on CD14+ population among three disease groups, further analysis demonstrated that the frequency of CD14+PD-L1+ population was negatively correlated with HBV DNA load, the levels of alanine aminotransaminase (ALT), and the levels of aspartate aminotransferase (AST), respectively, at CHB stage, while it did not present significant correlation with such parameters at LC stage and was only positively correlated with HBV DNA load at HCC stage. Similarly, the levels of PD-L1 expression on CD19+ population also did not present much difference among three disease groups. Intriguingly, the frequencies of CD19+PD L1+ population at CHB and LCC stages were both positively correlated with the levels of ALT and AST, but they were not significantly correlated with HBV DNA load. Thereby, the current study elucidated the dynamics of PD-L1 expression on monocytes and B cells, along with the dynamic regulation of PD-1 on T cells, which had a close relationship during the progression of HBV infection. Collectively, our findings demonstrated that in the course of HBV infection development, PD-L1 expression on CD14+ monocytes and CD19+ B cells varied and significantly correlated with clinical parameters, which could be utilized as a potential clinical indicator. PMID- 28005470 TI - Fifty Years of Global Immunization at CDC, 1966-2015. PMID- 28005471 TI - In Memoriam. PMID- 28005472 TI - Stepping Into Healthier Communities. PMID- 28005473 TI - Progress on Broadband Access to the Internet and Use of Mobile Devices in the United States. AB - Healthy People 2020 (HP2020) aims to improve population health outcomes through several objectives, including health communication and health information technology. We used 7 administrations of the Health Information National Trends Survey to examine HP2020 goals toward access to the Internet through broadband and mobile devices (N = 34 080). We conducted descriptive analyses and obtained predicted marginals, also known as model-adjusted risks, to estimate the association between demographic characteristics and use of mobile devices. The HP2020 target (7.7% of the US population) for accessing the Internet through a cellular network was surpassed in 2014 (59.7%), but the HP2020 target (83.2%) for broadband access fell short (63.8%). Sex and age were associated with accessing the Internet through a cellular network throughout the years (Wald F test, P <.05). The increase in the percentage of people accessing the Internet through mobile devices presents an opportunity for technology-based health interventions that should be explored. PMID- 28005474 TI - The Influence of Social Support on Dyadic Functioning and Mental Health Among Military Personnel During Postdeployment Reintegration. AB - OBJECTIVES: Although many service members successfully cope with exposure to stress and traumatic experiences, others have symptoms of depression, posttraumatic stress disorder (PTSD), and anxiety; contextual factors may account for the variability in outcomes from these experiences. This work sought to understand mechanisms through which social support influences the mental health of service members and whether dyadic functioning mediates this relationship. METHODS: We collected cross-sectional data as part of a larger study conducted in 2013; 321 military personnel who had at least 1 deployment were included in these analyses. Surveys were completed online; we collected data on demographic characteristics, social support, mental health measures (depression, PTSD, and anxiety), and dyadic functioning. We performed process modeling through mediation analysis. RESULTS: The direct effects of social support on the mental health of military personnel were limited; however, across all types of support networks, greater social support was significantly associated with better dyadic functioning. Dyadic functioning mediated the relationships between social support and depression/PTSD only when social support came from nonmilitary friends or family; dyadic functioning mediated social support and anxiety only when support came from family. We found no indirect effects of support from military peers or military leaders. CONCLUSION: Findings here highlight the need to continue to explore ways in which social support, particularly from family and nonmilitary connected peers, can bolster healthy intimate partner relationships and, in turn, improve the well-being of military service members who are deployed. PMID- 28005475 TI - Parental Deployment, Adolescent Academic and Social-Behavioral Maladjustment, and Parental Psychological Well-being in Military Families. AB - OBJECTIVE: Increases in the frequency and length of military deployments have raised concerns about the well-being of military families. We examined the relationship between a military parent's deployment and (1) adolescent academic and social-behavioral maladjustment and (2) parental psychological well-being. METHODS: We collected data from April 2013 through January 2014 from 1021 families of enlisted US Army personnel with children aged 12 or 13 during the Military Teenagers' Environments, Exercise, and Nutrition Study. Through online parent surveys, we collected data on deployment, adolescent academic and social behavioral maladjustment, and parental psychological well-being. We estimated adjusted logistic and linear regression models for adolescents (all, boys, girls), military parents (all, fathers, mothers), and civilian parents. RESULTS: Compared with no or short deployments, long deployments (>180 days in the past 3 years) were associated with significantly higher odds of decreases in adolescent academic performance (adjusted odds ratio [AOR] = 1.54), independence (AOR = 2.04), and being responsible (AOR = 1.95). These associations were also significant for boys but not for girls. Among parents, long deployments were associated with significantly higher odds of being depressed (AOR = 2.58), even when controlling for adolescent maladjustment (AOR = 2.54). These associations did not differ significantly between military and civilian parents and were significant for military fathers but not military mothers. Recent deployment (in the past 12 months) was not associated with either adolescent or parent outcomes. CONCLUSION: Long deployments are associated with adolescents' academic and social behavioral maladjustments and diminished parental well-being, especially among boys and military fathers. PMID- 28005476 TI - Multi-Angle Imager for Aerosols. PMID- 28005477 TI - Correlates of Hepatitis C Virus Infection in the Targeted Testing Program of the New York City Jail System. AB - OBJECTIVE: The objective of this study was to understand predictors of hepatitis C virus (HCV) antibody positivity in a large urban jail system in New York City. METHODS: We examined demographic characteristics, risk behaviors, and HCV antibody prevalence among 10 790 jail inmates aged 16 to 86 who were screened from June 13, 2013, to June 13, 2014, based on birth cohort or conventional high risk criteria. We used logistic regression analysis to determine predictors of HCV antibody positivity. RESULTS: Of the 10 790 inmates screened, 2221 (20.6%) were HCV antibody positive. In the multivariate analysis, HCV antibody positivity was associated most strongly with injection drug use (IDU; adjusted odds ratio [aOR] = 35.0; 95% confidence interval [CI], 28.5-43.0). Women were more likely than men to be infected with HCV (aOR = 1.3; 95% CI, 1.1-1.5). Compared with non Hispanic black people, Hispanic (aOR = 2.1; 95% CI, 1.8-2.4) and non-Hispanic white (aOR = 1.7; 95% CI, 1.5-2.1) people were more likely to be infected with HCV. Non-IDU, recidivism, HIV infection, homelessness, mental illness, and lower education level were all significantly associated with HCV infection. The prevalence rate of HCV infection among a subset of inmates born after 1965 who denied IDU and were not infected with HIV was 5.6% (198 of 3529). Predictors of HCV infection among this group included non-IDU as well as being non-Hispanic white, Hispanic, recidivist, and homeless. CONCLUSION: These data reveal differences in HCV infection by sex, race/ethnicity, and socioeconomics in a large jail population, suggesting that a focused public health intervention is required and that universal screening may be warranted. Further sensitivity and cost-benefit analyses are needed to make this determination. PMID- 28005478 TI - Promising Strategies to Remove Inexpensive Sweet Tobacco Products From Retail Stores. PMID- 28005479 TI - Exploring Costing Methods for Environmental Health Services in North Carolina. AB - All local health departments in North Carolina are mandated to provide a defined set of environmental health services, yet few have the tools to understand the costs incurred in delivering these services. The objectives of this study were to (1) derive cost estimates for 2 commonly provided environmental health services food and lodging inspections and on-site water services-and (2) explore factors that drive variations in costs, focusing on the roles of economies of scale and scope. Using data from 15 local health departments in North Carolina, we found that costs varied substantially. A bivariate analysis found evidence of economies of scale: higher volumes of services were associated with lower costs per service. Providing a greater scope of services, however, was not consistently associated with reduced costs. In-depth cost data provide public health officials with key information when deciding how to best serve their communities. PMID- 28005481 TI - Trends in Testing for Mycobacterium tuberculosis Complex From US Public Health Laboratories, 2009-2013. AB - OBJECTIVE: We investigated data from US public health laboratories funded through the Centers for Disease Control and Prevention's Tuberculosis Elimination and Laboratory Cooperative Agreement to document trends and challenges in meeting national objectives in tuberculosis (TB) laboratory diagnoses. METHODS: We examined data on workload and turnaround time from public health laboratories' progress reports during 2009-2013. We reviewed methodologies, laboratory roles, and progress toward rapid detection of Mycobacterium tuberculosis complex through nucleic acid amplification (NAA) testing. We compared selected data with TB surveillance reports to estimate public health laboratories' contribution to national diagnostic services. RESULTS: During the study period, culture and drug susceptibility tests decreased, but NAA testing increased. Public health laboratories achieved turnaround time benchmarks for drug susceptibility tests at lower levels than for acid-fast bacilli smear and identification from culture. NAA positivity in laboratories among surveillance-reported culture-positive TB cases increased from 26.6% (2355 of 8876) in 2009 to 40.0% (2948 of 7358) in 2013. Public health laboratories provided an estimated 50.9% (4285 of 8413 in 2010) to 57.2% (4210 of 7358 in 2013) of culture testing and 88.3% (6822 of 7727 in 2011) to 94.4% (6845 of 7250 in 2012) of drug susceptibility tests for all US TB cases. CONCLUSIONS: Public health laboratories contribute substantially to TB diagnoses in the United States. Although testing volumes mostly decreased, the increase in NAA testing indicates continued progress in rapid M tuberculosis complex detection. PMID- 28005483 TI - A Centers for Medicare & Medicaid Services Lens Toward Value-Based Preventive Care and Population Health. PMID- 28005480 TI - HIV-1 Infection and Transmission Networks of Younger People in Chicago, Illinois, 2005-2011. AB - OBJECTIVE: Analysis of HIV nucleotide sequences can be used to identify people with highly similar HIV strains and understand transmission patterns. The objective of this study was to identify groups of people highly connected by HIV transmission and the extent to which transmission occurred within and between geographic areas in Chicago, Illinois. METHODS: We analyzed genetic sequences in the HIV-1 pol region in samples collected from people participating in the VARHS program in Chicago during 2005-2011. We determined pairwise genetic distance, inferred potential transmission events between HIV-infected people whose sequences were <=1.5% genetically distant, and identified clusters of connected people. We used multivariable analysis to determine demographic characteristics and risk attributes associated with degree of connectivity. RESULTS: Of 1154 sequences, 177 (15.3%) were tied to at least 1 other sequence. We determined that younger people, men, non-Hispanic black people, and men who have sex with men were more highly connected than other HIV-infected people. We also identified a high degree of geographic heterogeneity-48 of 67 clusters (71.6%) contained people from >1 Chicago region (north, south, or west sides). CONCLUSION: Our results indicate a need to address HIV transmission through the networks of younger non-Hispanic black men who have sex with men. The high level of geographic heterogeneity observed suggests that HIV prevention programs should be targeted toward networks of younger people rather than geographic areas of high incidence. This study could also guide prevention efforts in other diverse metropolitan regions with characteristics similar to those of Chicago. PMID- 28005484 TI - State Health Department Requirements for Reporting of Antibiotic-Resistant Infections by Providers, United States, 2013 and 2015. AB - Due to the high burden of antibiotic-resistant infections, several US states mandate public reporting of these infections. To examine the extent to which state departments of health require reporting of antibiotic-resistant infections, we abstracted data from lists of reportable conditions from all 50 states at 2 time points, May 2013 and May 2015. Requirements varied substantially by state. In 2015, most states (n = 44) required reporting of at least 1 antibiotic resistant infection; vancomycin-intermediate and/or vancomycin-resistant Staphylococcus aureus was the most frequently reportable infection (n = 40). Few states required reporting of methicillin-resistant S aureus (n = 11), multidrug resistant gram-negative bacteria (n = 9), or vancomycin-resistant enterococci (n = 8). During the 2 years we studied, 2013 and 2015, 4 states removed and 9 added at least 1 reporting requirement. The changes in reporting requirements suggest flexibility in health departments' response to local surveillance needs and emerging threats. Future studies should assess how data on antibiotic-resistant infections through different sources are used at the state level to drive prevention and control efforts. PMID- 28005485 TI - Infectious Disease Hospitalizations Among American Indian/Alaska Native and Non American Indian/Alaska Native Persons in Alaska, 2010-2011. AB - OBJECTIVE: Reports about infectious disease (ID) hospitalization rates among American Indian/Alaska Native (AI/AN) persons have been constrained by data limited to the tribal health care system and by comparisons with the general US population. We used a merged state database to determine ID hospitalization rates in Alaska. METHODS: We combined 2010 and 2011 hospital discharge data from the Indian Health Service and the Alaska State Inpatient Database. We used the merged data set to calculate average annual age-adjusted and age-specific ID hospitalization rates for AI/AN and non-AI/AN persons in Alaska. We stratified the ID hospitalization rates by sex, age, and ID diagnosis. RESULTS: ID diagnoses accounted for 19% (6501 of 34 160) of AI/AN hospitalizations, compared with 12% (7397 of 62 059) of non-AI/AN hospitalizations. The average annual age-adjusted hospitalization rate was >3 times higher for AI/AN persons (2697 per 100 000 population) than for non-AI/AN persons (730 per 100 000 population; rate ratio = 3.7, P < .001). Lower respiratory tract infection (LRTI), which occurred in 38% (2486 of 6501) of AI/AN persons, was the most common reason for ID hospitalization. AI/AN persons were significantly more likely than non-AI/AN persons to be hospitalized for LRTI (rate ratio = 5.2, P < .001). CONCLUSIONS: A substantial disparity in ID hospitalization rates exists between AI/AN and non AI/AN persons, and the most common reason for ID hospitalization among AI/AN persons was LRTI. Public health programs and policies that address the risk factors for LRTI are likely to benefit AI/AN persons. PMID- 28005486 TI - Student Practicum as a Bridge to Governmental Public Health Practice. PMID- 28005487 TI - Perinatal HIV Exposure Surveillance and Reporting in the United States, 2014. AB - OBJECTIVE: We sought to describe the current status of perinatal HIV exposure surveillance (PHES) activities and regulations in the United States and to make recommendations to strengthen PHES. METHODS: In 2014, we sent an online survey to health departments in the 50 states, District of Columbia, Puerto Rico, Virgin Islands, and 6 cities and counties (Chicago, Illinois; Houston, Texas; Los Angeles, California; New York, New York; Philadelphia, Pennsylvania; and San Francisco, California). We analyzed responses from 56 of the 59 (95%) jurisdictions. RESULTS: Thirty-three of 56 jurisdictions (59%) reported conducting PHES and following infants to determine their infection status. Of the 33 jurisdictions performing PHES, 28 (85%) linked maternal and infant data, but only 12 (36%) determined the HIV care status of postpartum women. Themes of respondents' recommendations for strengthening PHES centered on updating laws and regulations to support PHES, reporting all HIV test results and linking vital records with PHES data to identify and follow HIV-exposed infants, communicating with health care providers to improve reporting, training staff, and getting help from experienced jurisdictions to implement PHES. CONCLUSIONS: Our findings indicate that data on perinatal exposure collected through the current system are inadequate to comprehensively monitor and prevent perinatal HIV exposure and transmission. Comprehensive PHES data collection and reporting are needed to sustain the progress that has been made toward lowering perinatal HIV transmission rates. We propose that minimum standards be established for perinatal HIV exposure reporting to improve the completeness, quality, and efficiency of PHES in the United States. PMID- 28005489 TI - MR Neurography of Brachial Plexus at 3.0 T with Robust Fat and Blood Suppression. AB - Purpose To develop and evaluate magnetic resonance (MR) neurography of the brachial plexus with robust fat and blood suppression for increased conspicuity of nerves at 3.0 T in clinically feasible acquisition times. Materials and Methods This prospective study was HIPAA compliant, with institutional review board approval and written informed consent. A low-refocusing-flip-angle three dimensional (3D) turbo spin-echo (TSE) sequence was modified to acquire both in phase and out-of-phase echoes, required for chemical shift (Dixon) reconstruction, in the same repetition by using partial echoes combined with modified homodyne reconstruction with phase preservation. This multiecho TSE modified Dixon (mDixon) sequence was optimized by using simulations and phantom studies and in three healthy volunteers. The sequence was tested in five healthy volunteers and was evaluated in 10 patients who had been referred for brachial plexopathy at 3.0 T. The images were evaluated against the current standard of care, images acquired with a 3D TSE short inversion time inversion recovery (STIR) sequence, qualitatively by using the Wilcoxon signed-rank test and quantitatively by using the Friedman two-way analysis of variance, with P < .05 considered to indicate a statistically significant difference. Results Multiecho TSE-mDixon involving partial-echo and homodyne reconstruction with phase preservation achieved uniform fat suppression in half the imaging time compared with multiacquisition TSE-mDixon. Compared with 3D TSE STIR, fat suppression, venous suppression, and nerve visualization were significantly improved (P < .05), while arterial suppression was better but not significantly so (P = .06), with increased apparent signal-to-noise ratio in the dorsal nerve root ganglion and C6 nerve (P < .001) with the multiecho TSE-mDixon sequence. Conclusion The multiecho 3D TSE-mDixon sequence provides robust fat and blood suppression, resulting in increased conspicuity of the nerves, in clinically feasible imaging times and can be used for MR neurography of the brachial plexus at 3.0 T. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 28005488 TI - Doctor of Public Health Education and Training. PMID- 28005490 TI - Survival Rates of Out-Migrating Yearling Chinook Salmon in the Lower Columbia River and Plume after Exposure to Gas-Supersaturated Water. AB - In 2011, unusually high flows caused total dissolved gas (TDG) levels in the Columbia River, USA, to escalate well above the 120% regulatory limit that was imposed to prevent harmful impacts to aquatic organisms. After observing gas bubble trauma (GBT) in dead yearling Chinook Salmon Oncorhynchus tshawytscha (smolts) held in tanks, we compared estimated survival rates of acoustic-tagged in-river-migrating (IR) and transported (TR) smolts that were released below Bonneville Dam prior to and during the period of elevated TDG (>120%). The log odds of estimated daily survival in the lower river and plume was significantly lower for IR smolts that were released during elevated TDG (maximum possible exposure = 134%) than for IR smolts released when TDG was less than 120%. The TR smolts that were released 10-13 km below Bonneville Dam during elevated TDG had lower maximum possible exposure levels (126% TDG), and the log odds of estimated daily survival in the lower river and plume did not differ from that of TR smolts released when TDG was less than 120%. Direct mortality due to GBT is probably reduced in natural settings relative to laboratory experiments because smolts can move to deeper water, where pressure keeps gasses in solution, and can migrate downstream of the spillway, where TDG levels decrease as the river returns to equilibrium with the atmosphere. However, initially nonlethal GBT may reduce survival rates by increasing smolt susceptibility to predation and infection. Although our findings are limited by the observational nature of the study, our analysis is the first direct assessment of gas supersaturation's potential influence on survival of free-ranging smolts in the river and coastal ocean below a large dam. Experiments using simultaneous releases of control and gas-exposed groups are warranted and should consider the possibility that the chronic effects of TDG exposure on survival are important and persist into the early marine period. Received October 5, 2015; accepted August 18, 2016 Published online October 24, 2016. PMID- 28005491 TI - Effect of an Otic Milbemycin Oxime Formulation on Tegastes acroporanus Infesting Corals. AB - The copepod Tegastes acroporanus is a notorious pest of captive corals in the genus Acropora. In recent years, infestations of T. acroporanus have become widespread among public aquaria and coral propagation facilities and have been largely controlled with the extra-label use of milbemycin oxime formulations (Carl 2008). Many of these drug formulations (which were intended for dogs) have been discontinued by their manufacturers in favor of multidrug products, many of which are unsuitable for corals, forcing experimentation with alternatives. This report provides the first data on populations of T. acroporanus treated with milbemycin oxime and documents the first known use of an otic solution, MilbeMite Otic (Novartis Animal Health U.S., Greensboro, North Carolina), against copepods on live corals. MilbeMite Otic was found to be soluble in seawater and successful at eradicating T. acroporanus in a large exhibit over the course of 6-h waterborne baths (n = 12) at 0.167 ug/L. The resident population of T. acroporanus was also quantified before each treatment to provide the first estimates of coral parasite burden in response to the application of a waterborne chemotherapeutic agent. Received November 19, 2015; accepted June 7, 2016 Published online October 24, 2016. PMID- 28005492 TI - Feline Injection-Site Sarcoma. AB - Feline injection-site sarcoma (FISS) is an aggressive tumor believed to arise from the proliferation of fibroblasts and myofibroblasts in areas of chronic inflammation, particularly at sites of injection. Local recurrence is frequent after surgical excision. Gelatinases (MMP-2 and MMP-9) and their inhibitor (TIMP 2) are endopeptidases pivotal in extracellular matrix remodeling and therefore in tumor invasiveness. The aim of this study was to investigate the immunohistochemical expression of MMP-2, MMP-9, and TIMP-2 in FISS to assess their usefulness as prognostic factors. Size, soft tissue sarcoma (STS) grading system, depth of infiltration, surgical margins, and Ki-67 index were evaluated as additional prognostic markers. Twenty-four cases of primary FISS were classified according to clinical follow-up as nonrecurrent (NR, n = 14; 58.3%) and recurrent (R, n = 10; 41.7%). MMP-2, MMP-9, and TIMP-2 were variably expressed in the FISS examined, confirming their role in tumor invasiveness, yet they did not show significant differences between the R and NR groups. These results could be due to different tumor stages or to the multiple activities of these enzymes, not limited to ECM remodeling. The immunohistochemical expression of these enzymes considered alone does not seem to be useful as a prognostic marker. STS grading system, depth of infiltration, surgical margins, and Ki-67 index did not relate to recurrence. Instead, the size of the tumor, measured after formalin fixation, with an optimal cutoff of 3.75 cm (accuracy = 86%; P < .05), and the mitotic count, with an optimal cutoff of 20 mitoses/10 HPF (accuracy = 80%; P < .05), could be evaluated as useful prognostic markers. PMID- 28005493 TI - Vasa Vasorum Arteriopathy: Relationship With Systemic Arterial Hypertension and Other Vascular Lesions in Cats. AB - The vasa vasorum is a delicate network of small arterioles that supplies nutrients to the adventitia and outer media of large arteries. In humans, dysfunction of the vasa vasorum contributes to the pathogenesis of aortic dissection and atherosclerosis. Twenty-four cats from 1 to 18 years of age were prospectively evaluated. Cases were divided into 3 cohorts-with systemic hypertension, without systemic hypertension, and uncertain. Histologic sections of the aorta and main pulmonary artery, as well as sections of kidney and lung, were blindly examined by 2 pathologists. The severity of vasa vasorum arteriopathy was compared to the presence of renal arteriosclerosis, aortic medial degeneration, subintimal fibroplasia of the main pulmonary artery, and blood pressure. We found that vasa vasorum arteriopathy correlated strongly with hypertensive status, degree of renal arteriosclerosis, and lesions in the great vessels. The positive predictive value of a severe vasa vasorum score for systemic hypertension was 84.6%. Lesions of vasa vasorum arteriopathy were predictive of renal arteriosclerosis with 100% sensitivity and 64.7% specificity. The positive predictive value of a severe vasa vasorum score for the presence of aortic lesions was 69.2% vs 91.6% for lesions in the main pulmonary artery. The vasa vasorum appears to be an important responder to systemic hypertension in cats, and arteriopathy of this vascular bed has significant implications for the integrity of the great vessels. PMID- 28005494 TI - Glomerular Lesions in Proteinuric Miniature Schnauzer Dogs. AB - Miniature Schnauzer dogs are predisposed to idiopathic hypertriglyerceridemia, which increases risk for diseases such as pancreatitis and gallbladder mucocele. Recently, elevated triglyceride concentrations have been associated with proteinuria in this breed, although it is difficult to determine which abnormality is primary. Retrospective review of renal tissue from 27 proteinuric Miniature Schnauzers revealed that 20 dogs had ultrastructural evidence of osmophilic globules consistent with lipid in glomerular tufts. Seven of these dogs had lipid thromboemboli in glomerular capillary loops that distorted their shape and compressed circulating erythrocytes. Triglyceride concentrations were reported in 6 of these 7 dogs, and all were hypertriglyceridemic. In addition, glomerular lipidosis (defined as accumulation of foam cells within peripheral capillary loops) was identified in a single dog. The remaining 12 dogs had smaller amounts of lipid that could only be identified ultrastructurally. Neither signalment data nor clinicopathologic parameters (serum albumin, serum creatinine, urine protein-to-creatinine ratio, and blood pressure) differed among the various types of lipid lesions. During the time course of this study, all dogs diagnosed with glomerular lipid thromboemboli were Miniature Schnauzers, underscoring the importance of recognizing these clear spaces within capillary loops as lipid. PMID- 28005495 TI - Growth Plate Lesions of Fattening Bulls. AB - Lameness related to growth plate lesions is an important problem in the beef industry. This article describes the macroscopic and microscopic lesions in the distal metatarsal physis of bulls from an association of farmers in northeastern Italy. The metatarsal bones of 62 bulls (12 with severe lameness and 50 without lameness), average age 16.44 +/- 1.72 months, were examined at the abattoir. The animals came from the same geographic area and shared intensive husbandry practices and a diet based on maize starch. A total of 124 metatarsal bones were sectioned, and the distal metaphyseal growth plate was grossly examined. Twenty three cases, including 12 lame and 9 nonlame animals with visible lesions on macroscopic examination, and 2 controls (a total of 46 physes) were examined microscopically. Eight of 12 bulls with severe lameness had a chronic purulent physitis in at least 1 limb. Segmental thickening of the hypertrophic zone, consistent with osteochondrosis (OC), was present contralaterally ( n = 3 cases) and bilaterally ( n = 3 cases) in 6 of these animals. In the group of nonlame bulls, 19 of 50 (38%) had similar segmental thickening of the physis consistent with OC. In the remaining bulls, minor findings included partial closure of the physis and a variable degree of metaphyseal hyperemia. A high incidence of OC was found in both lame and nonlame fattening bulls. It is likely that lame animals were clinically more severe due to secondary hematogenous implantation of bacteria, resulting in a purulent physitis and severe lameness that required emergency slaughter in some cases. PMID- 28005496 TI - Lymphocyte Subsets in the Adrenal Glands of Dogs With Primary Hypoadrenocorticism. AB - Primary hypoadrenocorticism, or Addison's disease, is an autoimmune condition common in certain dog breeds that leads to the destruction of the adrenal cortex and a clinical syndrome involving anorexia, gastrointestinal upset, and electrolyte imbalances. Previous studies have demonstrated that this destruction is strongly associated with lymphocytic-plasmacytic inflammation and that the lymphocytes are primarily T cells. In this study, we used both immunohistochemistry and in situ hybridization to characterize the T-cell subtypes involved. We collected postmortem specimens of 5 dogs with primary hypoadrenocorticism and 2 control dogs and, using the aforementioned techniques, showed that the lymphocytes are primarily CD4+ rather than CD8+. These findings have important implications for improving our understanding of the pathogenesis and in searching for the underlying causative genetic polymorphisms. PMID- 28005497 TI - Impact of Sexual Orientation Identity on Medical Morbidities in Male-to-Female Transgender Patients. AB - PURPOSE: We aim to describe the relationship between sexual orientation identity and medical morbidities in a large sample of male-to-female (MTF) transgender patients. METHODS: We reviewed medical records of patients presenting for MTF sex reassignment surgery (SRS) by a single, high-volume surgeon from 2011 to 2015. Sexual attraction to men (heterosexual), women (lesbian), or both (bisexual) was asked of each patient. We examined 16 medical morbidities for this analysis. RESULTS: During the study period, 330 MTF transgender patients presented for SRS. The average age at the time of surgery was 38.9 (range 18-76). One hundred and one patients (32%) reported being heterosexual, 110 patients (34%) reported being lesbian, and 108 patients (34%) reported being bisexual. Lesbian patients presented for SRS at older ages (mean = 43 years old) compared with heterosexual patients (mean = 36 years old) and bisexual patients (mean = 37), P < 0.01. No differences were found in the majority of coexisting medical morbidities by sexual orientation identity. Lesbian patients had greater odds of having a history of depression, age-adjusted odds ratio (aOR) = 2.36, 95% confidence interval (CI) 1.26-4.40, compared with heterosexual patients. Lesbian patients had higher odds of being married or partnered, aOR = 2.31, 95% CI (1.27-4.19), compared with heterosexual patients. Heterosexual patients had higher odds of having human immunodeficiency virus (HIV), aOR = 9.07, 95% CI (1.08-76.5) compared with lesbian patients. CONCLUSIONS: Sexual orientation identity in MTF transgender patients is variable. The majority of medical morbidities are not associated with sexual orientation identity. Although HIV and depression are common morbidities among MTF patients seeking SRS, the prevalence of these morbidities differs by sexual orientation identity, but these findings need replication. Counseling and future research initiatives in transgender care should incorporate sexual orientation identity and associated risk behavior. PMID- 28005498 TI - Gadolinium Retention in the Body and Brain: Is It Time for an International Joint Research Effort? PMID- 28005499 TI - Congenital Brain Abnormalities and Zika Virus. PMID- 28005500 TI - Imaging is Usually Not Necessary When Clinical Scores for the Diagnosis of Appendicitis Are Low. PMID- 28005501 TI - Imaging of Heart Disease in Women. AB - Ischemic heart disease is the number one cause of death of women in the United States, accounting for over a quarter of a million annual female deaths. Evidence within the last several decades supports sex-specific differences in the prevalence, symptoms, and prognosis of ischemic heart disease between men and women. Despite women having a lower burden of obstructive coronary artery disease compared with men, the prevalence of angina and mortality from ischemic heart disease is higher for women than men. In addition to ischemic heart disease, certain nonischemic conditions may also have sex-specific differences in clinical presentation and occurrence. With the rising utilization of noninvasive modalities for the diagnosis and management of ischemic heart disease, it is important for radiologists to be familiar with the unique considerations for imaging women with heart disease. The purpose of this review is to discuss challenges for detection of heart disease in women, examine performance of noninvasive modalities in the detection of ischemic heart disease, and discuss nonischemic cardiomyopathies unique to or prevalent in women. Considerations for cardiac imaging in pregnancy are also discussed. (c) RSNA, 2017. PMID- 28005502 TI - Equivocal Reporting in Pediatric US Does Not Decrease Clinical Certainty. PMID- 28005503 TI - Interpretation of Postoperative Intracranial Abscess. PMID- 28005504 TI - Setting Sail: 2017. PMID- 28005506 TI - Role of MR Sequences in the Assessment of Gadolinium-dependent T1 Signal Intensity Increase after Repeated Exposure to Linear Gadolinium-based Contrast Agents. PMID- 28005507 TI - David A. Bluemke, MD, PhD, Named Editor of Radiology. PMID- 28005509 TI - Radiology Editorial Board 2017. PMID- 28005508 TI - Irreversible Electroporation: Disappearance of Observable Changes at Imaging Does Not Always Imply Complete Reversibility of the Underlying Causal Tissue Changes. PMID- 28005510 TI - Case 237: Renal Cell Carcinoma with Osseous Metaplasia. AB - History A 47-year-old man presented with palpitations and decreased exercise tolerance. A peripheral blood smear revealed anemia, thrombocytopenia, and blast cells, and a diagnosis of acute myeloid leukemia was made. Immunohistochemistry revealed positivity for cluster of differentiation (or CD) markers, which have been reported to be associated with an increased risk of extramedullary leukemic involvement. Thus, contrast material-enhanced computed tomography (CT) of the thorax, abdomen, and pelvis was requested to enable exclusion of any extramedullary extension of leukemia. Unenhanced and contrast-enhanced nephrographic phase CT was performed. Follow-up CT 3 months later showed minimal interval change in the lesion (images not shown). PMID- 28005511 TI - Case 241. PMID- 28005512 TI - Cardiac MR Imaging in Acute Coronary Syndrome: Application and Image Interpretation. AB - Acute coronary syndrome (ACS) is a frequent cause of hospitalization and coronary interventions. Cardiac magnetic resonance (MR) imaging is an increasingly used technique for initial work-up of chest pain and early post-reperfusion and follow up evaluation of ACS to identify patients at high risk of further cardiac events. Cardiac MR imaging can evaluate with accuracy a variety of prognostic indicators of myocardial damage, including regional myocardial dysfunction, infarct distribution, infarct size, myocardium at risk, microvascular obstruction, and intramyocardial hemorrhage in both acute setting and later follow-up examinations. In addition, MR imaging is useful to rule out other causes of acute chest pain in patients admitted to the emergency department. In this article, a brief explanation of the pathophysiology, classification, and treatment options for patients with ACS will be introduced. Indications of cardiac MR imaging in ACS patients will be reviewed and specific cardiac MR protocol, image interpretation, and potential diagnostic pitfalls will be discussed. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28005513 TI - Editor's Recognition Awards. PMID- 28005514 TI - Richard L. Ehman, MD, President, Radiological Society of North America, 2017. PMID- 28005516 TI - Salinovum rubellum gen. nov., sp. nov., isolated from sediment of a saltern. AB - An aerobic, Gram-reaction-negative, oxidase-positive and catalase-positive strain, YCWB25T, was isolated from saltern farm sediment in Jimo-Daqiao of Qingdao, east coast of China. This strain had an absolute requirement for NaCl and was able to grow in the presence of 1-10 % (w/v) NaCl (optimal growth at 3-5 % NaCl). The strain grew at pH 5.0-9.0 (optimal growth at pH 8.0) and 4-42 degrees C (optimal growth at 30 degrees C). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain YCWB25T belonged to the Roseobacter clade of the family Rhodobacteraceae, and the closest species were members of the genus Pseudooceanicola (similarity lower than 95.58 %). However, the novel strain formed a robust, distinct clade different from other members of the Roseobacter clade. The DNA G+C content of strain YCWB25T was 65.6 mol%. The predominant respiratory quinone was Q-10. The dominant cellular fatty acids were C18 : 1omega7c, C16 : 0 and C19 : 0 cyclo omega8c. The phenotypic, chemotaxonomic and phylogenetic data indicated that strain YCWB25T represents a novel species of a new genus, for which the name Salinovum rubellum gen. nov., sp. nov. is proposed. The type strain of Salinovum rubellum is YCWB25T (=MCCC 1K00272T=LMG 25394T). PMID- 28005517 TI - Streptomyces lasiicapitis sp. nov., an actinomycete that produces kanchanamycin, isolated from the head of an ant (Lasius fuliginosus L.). AB - During a screening for novel and biotechnologically useful actinobacteria in insects, a kanchanamycin-producing actinomycete with antifungal activity, designated strain 3H-HV17(2)T, was isolated from the head of an ant (Lasius fuliginosus L.) and characterized using a polyphasic approach. 16S rRNA gene sequence similarity studies showed that strain 3H-HV17(2)T belongs to the genus Streptomyces with the highest sequence similarities to Streptomyces spectabilis NBRC 13424T (98.90 %, with which it phylogenetically clustered, Streptomyces alboflavus NRRL B-2373T (98.65 %) and Streptomyces flavofungini NBRC 13371T (98.36 %). Phylogenetic analysis based on the gyrB gene also supported the close relationship of these strains. The morphological and chemotaxonomic properties of the strain are also consistent with those members of the genus Streptomyces. A combination of DNA-DNA hybridization experiments and phenotypic tests were carried out between strain 3H-HV17(2)T and its phylogenetically closely related strains, which further clarified their relatedness and demonstrated that strain 3H-HV17(2)T could be distinguished from these strains. Therefore, strain 3H HV17(2)T is concluded to represent a novel species of the genus Streptomyces, for which the name Streptomyces lasiicapitis sp. nov. is proposed. The type strain is 3H-HV17(2)T (=CGMCC 4.7349T=DSM 103124T). PMID- 28005518 TI - Nocardioides phosphati sp. nov., an actinomycete isolated from a phosphate mine. AB - A Gram-staining-positive, non-spore-forming and non-motile strain, designated WYH11-7T, was isolated from a phosphate mine in Yunnan Province, PR China. The taxonomic position of WYH11-7T was investigated by polyphasic approaches. Phylogenetic analyses based on 16S rRNA gene sequences indicated that WYH11-7T represents a member of the genus Nocardioides. WYH11-7T was closely related to Nocardioidesjensenii DSM 20641T, Nocardioidesdubius DSM 19084T and Marmoricolaterrae DSM 27141T, and had pairwise 16S rRNA gene sequence similarities of 97.4, 97.2 and 97.0 %, respectively. DNA-DNA relatedness values between WYH11-7T and related type strains N. jensenii DSM 20641T and N. dubius DSM 19084T were found to be 17.6+/-4.9 and 14.6+/-3.1 %, respectively. The respiratory menaquinone of WYH11-7T was MK-8 (H4) while the major fatty acids were C18 : 1omega9c, C16 : 0, C17 : 0, C17 : 1omega8c, C18 : 1 10-methyl and summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and two unidentified phospholipids. Whole-cell hydrolysates contained mannose, ribose, glucose and galactose along with ll-diaminopimelic acid as the diagnostic diamino acid in the peptidoglycan. The DNA G+C content was 71.2 mol%. Phenotypic, phylogenetic and chemotaxonomic data indicated that strain WYH11-7T represents a novel species of the genus Nocardioides, for which the name Nocardioidesphosphatisp. nov. is proposed. The type strain is WYH11-7T (=CGMCC 4.7371T=DSM 104026T). PMID- 28005519 TI - Subtercola lobariae sp. nov., an actinobacterium of the family Microbacteriaceae isolated from the lichen Lobaria retigera. AB - An actinobacterium, designated strain 9583bT, was isolated from the lichen Lobaria retigera collected from Jiaozi Snow Mountain, Yunnan Province, China. Cells of strain 9583bT were Gram-stain-positive, aerobic, catalase-positive and oxidase-negative. The strain have a short rod-shaped, irregular morphology, and could grow at the temperature range of 4 to 28 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 9583bT belonged to the genus Subtercola in the family Microbacteriaceae, and shared highest sequence similarity with the type strains of Subtercola frigoramans and Subtercola boreus (96.8 and 95.6 %, respectively). The peptidoglycan type was B2gamma, with diaminobutyric acid as the diagnostic diamino acid. The polar lipids comprised of phosphatidylglycerol, diphosphatidylglycerol, five unidentified glycolipids and three unidentified phospholipids. The respiratory quinone was determined to be MK 10. While the major fatty acids (>5 %) of strain 9583bT were anteiso-C15 : 0, C14 : 0 2-OH and iso-C16 : 0, the 1,1-dimethoxy-alkanes included a-15 : 0 DMA, i-16 : 0 DMA, a-17 : 0 DMA and i-15 : 0 DMA. The genomic DNA G+C content of strain 9583bT was 66.8 mol%. On the basis of the phylogenetic, phenotypic and chemotaxonomic data in this study, strain 9583bT represents a novel species of the genus Subtercola, for which the name Subtercola lobariae sp. nov. is proposed. The type strain is 9583bT (=CGMCC 1.12976T=DSM 103962T). PMID- 28005520 TI - Proposal of Rhodoplanes tepidamans sp. nov. to accommodate the thermotolerant phototrophic bacterium previously referred to as 'Rhodoplanes (Rhodopseudomonas) cryptolactis'. AB - Previously we proposed the reclassification of a thermotolerant phototrophic bacterium, 'Rhodopseudomonas cryptolactis' Stadtwald-Demchick et al. 1990, as 'Rhodoplanes cryptolactis' nom. rev., comb. nov. with strain DSM 9987T (ATCC 49414T) as the type strain. However, while both the names 'Rhodopseudomonas cryptolactis' and 'Rhodoplanes cryptolactis' have not been validated, strain ATCC 49414T is no longer available from the culture collection. This situation indicates that the taxonomic status of the bacterium with both the names to be validated has been lost. In this study, we re-examined the taxonomic characteristics of strain DSM 9987T (TUT3520T as our own collection number) compared with those of six species of the genus Rhodoplanes with validly published names. The results of 16S rRNA gene sequence comparisons indicated that TUT3520T had a 99.0 % level of similarity to the type strains of Rhodoplanes oryzae and Rhodoplanes elegans as its closest relatives and 98.9-96.2 % similarities to other species of the genus Rhodoplanes. Genomic DNA-DNA similarities between TUT3520T and the type strains of the species of the genus Rhodoplanes were less than 50 %. Results of phenotypic testing indicated that TUT3520T could be differentiated from any species of the genus Rhodoplanes by a combination of in vivo absorption spectra, growth temperature, vitamin requirements, carbon nutrition and some other characteristics. Thus, we propose Rhodoplanes tepidamans sp. nov. to accommodate the bacterium previously referred to as 'Rhodoplanes (Rhodopseudomonas) cryptolactis'. The type strain is strain TUT3520T (=DSM 9987T=NBRC 104267T). PMID- 28005522 TI - Halomonas alkalicola sp. nov., isolated from a household product plant. AB - A Gram-stain-negative, alkaliphilic and moderately halophilic bacterium, designated 56-L4-10aEnT, was isolated from a household product plant in China. Cells of the novel isolate were rod-shaped, non-spore-forming and non-motile. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 56-L4 10aEnT belongs to the genus Halomonas, with the six closest neighbours being Halomonas mongoliensis Z-7009T (97.59 % 16S rRNA gene sequence similarity), Halomonas ventosae Al12T (97.35 %), Halomonas campaniensis 5AGT (97.22 %), Halomonas alimentaria YKJ-16T (97.22 %), Halomonas shengliensis SL014B-85T (97.12 %) and Halomonas fontilapidosi 5CRT (97.09 %). The main polar lipids of strain 56 L4-10aEnT contained diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The predominant respiratory quinone was Q-9, with Q-8 as a minor component. The major fatty acids were C18 : 1omega7c/C18 : 1omega6c and C16 : 0. Strain 56-L4-10aEnT was clearly distinguished from the type strains mentioned above through phylogenetic analysis, DNA-DNA hybridization, fatty acid composition data and a range of physiological and biochemical characteristics comparisons. It is evident from the genotypic and phenotypic data that strain 56 L4-10aEnTcould be classified as a representative of a novel species of the genus Halomonas, for which the name Halomonas alkalicola sp. nov. is proposed. The type strain is 56-L4-10aEnT (=CICC 11012sT=DSM 103354T). PMID- 28005521 TI - Characterization of nasal methicillin-resistant Staphylococcus aureus isolated from international human and veterinary surgeons. AB - PURPOSE: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is poorly described for surgeons, despite the increased exposure to nosocomial pathogens and at-risk patients. This study investigated the molecular epidemiology and antimicrobial resistance of 26 MRSA isolates cultured from the nares of an international cross-sectional study of 1166 human and 60 veterinary surgeons. METHODOLOGY: All isolates were subjected to agr, spa and multilocus sequence typing, and the presence of 22 virulence factors was screened for by PCR. Additionally, biofilm-forming ability, haemolytic activity, staphyloxanthin production and antibiotic resistance were determined. The genome of a rifampicin resistant MRSA was sequenced. RESULTS: Approximately half of the isolates belonged to well-described clonal lineages, ST1, ST5, ST8, ST45 and ST59, that have previously been associated with severe infections and increased patient mortality. Two of the three veterinarian MRSA belonged to epidemic livestock associated MRSA clonal lineages (ST398 and ST8) previously associated with high transmission potential between animals and humans. The isolates did not display any consistent virulence gene pattern, and 35 % of the isolates carried at least one of the Panton-Valentine leukocidin (lukFS-PV), exfoliative toxin (eta) or toxic shock syndrome (tst) genes. Resistance to rifampicin was detected in one veterinarian isolate and was found to be due to three mutations in the rpoB gene. CONCLUSION: Surgeons occupy a critical position in the healthcare profession due to their close contact with patients. In this study, surgeons were found to be colonized with MRSA at low rates, similar to those of the general population, and the colonizing strains were often common clonal lineages. PMID- 28005524 TI - Nonlabens aestuariivivens sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-flagellated, non-gliding, aerobic and rod-shaped bacterium, designated strain OITF-31T, was isolated from a tidal flat in Oido, an island of South Korea, and subjected to a polyphasic taxonomic study. Strain OITF 31T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 1.0-2.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain OITF-31T belonged to the genus Nonlabens, clustering with the type strains of Nonlabens dokdonensis and Nonlabens xylanidelens, sharing 98.1 % sequence similarity with each. Strain OITF-31T exhibited 16S rRNA gene sequence similarities of 93.9-95.8 % to the type strains of other Nonlabens species and less than of 91.8 % to the type strains of other recognized species. Strain OITF 31T contained MK-6 as the predominant menaquinone and iso-C17 : 0 3-OH and iso C15 : 0 as the major fatty acids. The major polar lipids detected in strain OITF 31T were phosphatidylethanolamine, six unidentified lipids and two unidentified aminolipids. The DNA G+C content of strain OITF-31T was 38.1 mol% and its mean DNA-DNA relatedness values with the type strains of N. dokdonensis and N. xylanidelens were 24 and 19 %, respectively. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain OITF-31T is separated from recognized species of the genus Nonlabens. On the basis of the data presented, strain OITF-31T is considered to represent a novel species of the genus Nonlabens, for which the name Nonlabens aestuariivivens sp. nov. is proposed. The type strain is OITF-31T (=KCTC 52502T=NBRC 112459T). PMID- 28005525 TI - CCR6/CCL20 chemokine axis in human immunodeficiency virus immunity and pathogenesis. AB - Recent studies in human immunodeficiency virus (HIV) have garnered interest for the role of CC chemokine receptor 6 (CCR6) and its known ligands, CC chemokine ligand 20 (CCL20) and human beta-defensins, in viral entry, dissemination and antiviral immunity. Several studies have suggested that CCR6 may also act as a weak co-receptor of HIV entry, in addition to the canonical CXC chemokine receptor 4 (CXCR4) and CCR5. However, the pathogenic significance has yet to be demonstrated as the observations for preferential infection of CD4+CCR6+ over CD4+CCR6- T cells appear to be independent of CCR6 expression. This indicates means for preferential infection other than CCR6 co-receptor use. Attention has also turned to the inadvertent role of the CCR6/CCL20 axis in attracting key immune cells, including TH17 cells and dendritic cells, to sites of infection and propagating the virus to other sites of the body. This review article will summarize the latest evidence that the CCR6/CCL20 chemokine axis is playing an important role in HIV pathogenesis and immunity. Further work with in vivo studies is needed to establish the biological and, hence, therapeutic significance of these findings. PMID- 28005526 TI - Introducing EzBioCloud: a taxonomically united database of 16S rRNA gene sequences and whole-genome assemblies. AB - The recent advent of DNA sequencing technologies facilitates the use of genome sequencing data that provide means for more informative and precise classification and identification of members of the Bacteria and Archaea. Because the current species definition is based on the comparison of genome sequences between type and other strains in a given species, building a genome database with correct taxonomic information is of paramount need to enhance our efforts in exploring prokaryotic diversity and discovering novel species as well as for routine identifications. Here we introduce an integrated database, called EzBioCloud, that holds the taxonomic hierarchy of the Bacteria and Archaea, which is represented by quality-controlled 16S rRNA gene and genome sequences. Whole genome assemblies in the NCBI Assembly Database were screened for low quality and subjected to a composite identification bioinformatics pipeline that employs gene based searches followed by the calculation of average nucleotide identity. As a result, the database is made of 61 700 species/phylotypes, including 13 132 with validly published names, and 62 362 whole-genome assemblies that were identified taxonomically at the genus, species and subspecies levels. Genomic properties, such as genome size and DNA G+C content, and the occurrence in human microbiome data were calculated for each genus or higher taxa. This united database of taxonomy, 16S rRNA gene and genome sequences, with accompanying bioinformatics tools, should accelerate genome-based classification and identification of members of the Bacteria and Archaea. The database and related search tools are available at www.ezbiocloud.net/. PMID- 28005527 TI - Characterization of host-dependent mutations of apple fruit crinkle viroid replicating in newly identified experimental hosts suggests maintenance of stem loop structures in the left-hand half of the molecule is important for replication. AB - Apple fruit crinkle viroid (AFCVd) is a tentative member of the genus Apscaviroid, family Pospiviroidae. AFCVd has a narrow host range and is known to infect apple, hop and persimmon as natural hosts. In this study, tomato, cucumber and wild hop have been identified as new experimental herbaceous hosts. Foliar symptoms were very mild or virtually undetectable, but fruits of infected tomato were small, cracked and distorted. These symptoms resemble those observed on some AFCVd-sensitive apple cultivars. After transfer to tomato, cucumber and wild hop, sequence changes were detected in a natural AFCVd isolate from hop, and major variants in tomato, cucumber and wild hop differed in 10, 8 or 2 nucleotides, respectively, from the predominant one in the inoculum. The major variants in tomato and cucumber were almost identical, and the one in wild hop was very similar to the one in cultivated hop. Detailed analyses of the host-dependent sequence changes that appear in a naturally occurring AFCVd isolate from hop after transfer to tomato using small RNA deep sequence data and infectivity studies with dimeric RNA transcripts followed by progeny analysis indicate that the major AFCVd variant in tomato emerged by selection of a minor variant present in the inoculum (i.e. hop) followed by one to two host-dependent de novo mutations. Comparison of the secondary structures of major variants in hop, tomato and persimmon after transfer to tomato suggested that maintenance of stem loop structures in the left-hand half of the molecule is critical for infection. PMID- 28005528 TI - US Adults' Perceptions of the Harmful Effects During Pregnancy of Using Electronic Vapor Products Versus Smoking Cigarettes, Styles Survey, 2015. AB - INTRODUCTION: Research suggests aerosol from electronic vapor products (EVPs) has fewer harmful constituents than conventional cigarette smoke. Even so, EVPs and other nicotine-containing products are not safe to use during pregnancy. We examined perceptions among US adults regarding harm in using EVPs rather than smoking cigarettes during pregnancy. METHODS: Data came from the 2015 Styles Survey, an Internet panel survey of a sample of US adults aged 18 years or older (N = 4,127). Perceived harm was assessed by asking respondents whether using EVPs was less, equally, or more harmful for pregnant women than smoking cigarettes. Descriptive statistics were used to estimate perceived harm overall and by sociodemographic characteristics and tobacco-use status. Perceived harm was assessed among all adults, women of reproductive age (18-44 years, n = 820), and women of nonreproductive age (>=45 years, n = 1,398). RESULTS: Among all adults, 11.1% believed using EVPs during pregnancy was less harmful than smoking conventional cigarettes, 51.0% believed it was equally harmful, 11.6% believed it was more harmful, and 26.2% did not know. Prevalence of perception of less harm, by demographic category, was greatest among adults aged 18 to 24 years, men, non Hispanic whites, adults with less than a high school diploma, current EVP users, and current cigarette smokers (P < .05). Prevalence of perception of less harm was greater among women of reproductive age (9.6%) than among those of nonreproductive age (7.9%) (P < .05). CONCLUSION: US adults have varying levels of perceptions about the harms of EVP use versus cigarette smoking during pregnancy. Efforts are warranted to prevent nicotine exposure during pregnancy and to educate adults on the dangers of using any form of tobacco during pregnancy, including EVPs. PMID- 28005529 TI - A Cooking Intervention to Increase Vegetable Consumption by Parents With Children Enrolled in an Early Head Start Home Visiting Program: A Pilot Study in Portland, Oregon, 2013-2014. AB - INTRODUCTION: Cooking interventions may improve diet quality. Most cooking interventions are delivered in group settings. Home visiting programs may be an appropriate mechanism for delivering such interventions to low-income families with young children. We conducted a pilot study to test the feasibility of using a cooking intervention delivered by home visitors to improve attitudes and behaviors related to vegetable consumption by low-income parents with children enrolled in a home visiting program. METHODS: We invited 121 parents with children enrolled in an Early Head Start Home Visiting program in Portland, Oregon, to participate. During 2013-2014, each month for 8 months, home visitors (n = 14) implemented 1 cooking activity plus 1 complementary activity focused on 12 vegetables. We collected pre- and post-intervention data on participants' cooking confidence and whether they tried and liked the selected vegetables. We also measured fidelity to protocol and home visitors' perception of intervention usability. RESULTS: Of 104 participants, 58 provided pre- and post-intervention data. We observed a significant increase in confidence in baking, roasting or grilling vegetables; cooking 6 of 10 vegetables; and trying 7 of 12 vegetables. Nearly all respondents participated in the monthly cooking activity (96%) and complementary activity (94%). Twelve of 14 home visitors reported that the intervention was acceptable, feasible, and easy to understand, and needed systems supports to implement. CONCLUSION: Cooking interventions may be a feasible approach to improving attitudes and behaviors related to vegetable consumption by low-income families with young children. Additional research is needed to assess the impact of such interventions on vegetable consumption. PMID- 28005530 TI - Concordance Between Life Satisfaction and Six Elements of Well-Being Among Respondents to a Health Assessment Survey, HealthPartners Employees, Minnesota, 2011. AB - INTRODUCTION: We assessed and tracked perceptions of well-being among employees of member companies of HealthPartners, a nonprofit health care provider and health insurance company in Bloomington, Minnesota. The objective of our study was to determine the concordance between self-reported life satisfaction and a construct of subjective well-being that comprised 6 elements of well-being: emotional and mental health, social and interpersonal status, financial status, career status, physical health, and community support. METHODS: We analyzed responses of 23,268 employees (of 37,982 invitees) from 6 HealthPartners companies who completed a health assessment in 2011. We compared respondents' answers to the question, "How satisfied are you with your life?" with their indicators of well-being where "high life satisfaction" was defined as a rating of 9 or 10 on a scale of 0 (lowest) to 10 (highest) and "high level of well being" was defined as a rating of 9 or 10 for 5 or 6 of the 6 indicators of well being. RESULT: We found a correlation between self-reported life satisfaction and the number of well-being elements scored as high (9 or 10) (r = 0.62, P < .001); 73.6% of the respondents were concordant (high on both or high on neither). Although 82.9% of respondents with high overall well-being indicated high life satisfaction, only 34.7% of those indicating high life satisfaction reported high overall well-being. CONCLUSION: The correlation between self-reported life satisfaction and our well-being measure was strong, and members who met our criterion of high overall well-being were likely to report high life satisfaction. However, many respondents who reported high life satisfaction did not meet our criterion for high overall well-being, which suggests that either they adapted to negative life circumstances or that our well-being measure did not identify their sources of life satisfaction. PMID- 28005531 TI - Nutrition Standards for Food Service Guidelines for Foods Served or Sold in Municipal Government Buildings or Worksites, United States, 2014. AB - INTRODUCTION: The Institute of Medicine and Centers for Disease Control and Prevention have recommended that government agencies use nutrition standards for foods and beverages sold and provided at their facilities. In this study, we examine written nutrition standards for foods sold or served in local government buildings or worksites among US municipalities. METHODS: We used data from a 2014 national survey of 1,945 municipal governments serving populations of 1,000 or more to assess the presence of written nutrition standards, the food groups or nutrients addressed by standards, and the populations served by facilities where standards are applied. The prevalence of standards was estimated by municipality population size, rural-urban status, census region, poverty prevalence, education level, and racial/ethnic composition. RESULTS: Overall, 3.2% of US municipalities reported nutrition standards with greater prevalence observed among large municipalities (12.8% of municipalities with >=50,000 people vs 2.2% of municipalities with <2,500 people, P < .001). Prevalence differed by region, and standards were most common in the West (6.6%) and least common in the Midwest (2.0%, P = .003).The most common nutrition topics addressed in standards were offering low-calorie beverages, fruits and vegetables, and free drinking water. Most standards applied to facilities serving government employees (67%) or the general public (66%), with fewer serving institutionalized populations (23%). CONCLUSION: Few municipal governments reported having written nutrition standards for foods and beverages sold in their facilities in 2014. Implementing nutrition standards for foods sold or served by local governments is a strategy for increasing access to healthier foods and beverages among municipal employees and local residents. PMID- 28005532 TI - Designing a Text Messaging Intervention to Improve Physical Activity Behavior Among Low-Income Latino Patients With Diabetes: A Discrete-Choice Experiment, Los Angeles, 2014-2015. AB - INTRODUCTION: Automated text messaging can deliver self-management education to activate self-care behaviors among people with diabetes. We demonstrated how a discrete-choice experiment was used to determine the features of a text-messaging intervention that are important to urban, low-income Latino patients with diabetes and that could support improvement in their physical activity behavior. METHODS: In a discrete-choice experiment from December 2014 through August 2015 we conducted a survey to elicit information on patient preferences for 5 features of a text-messaging intervention. We described 2 hypothetical interventions and in 7 pairwise comparisons asked respondents to indicate which they preferred. Respondents (n = 125) were recruited in person from a diabetes management program of a safety-net ambulatory care clinic in Los Angeles; clinicians referred patients to the research assistant after routine clinic visits. Data were analyzed by using conditional logistic regression. RESULTS: We found 2 intervention features that were considered by the survey respondents to be important: 1) the frequency of text messaging and 2) physical activity behavior change education (the former being more important than the latter). Physical activity goal setting, feedback on physical activity performance, and social support were not significantly important. CONCLUSION: A discrete-choice experiment is a feasible way to elicit information on patient preferences for a text-messaging intervention designed to support behavior change. However, discrepancies may exist between patients' stated preferences and their actual behavior. Future research should validate and expand our findings. PMID- 28005534 TI - Why Are Some HIV-1 Subtypes More "Wimpy" at Causing Disease? PMID- 28005533 TI - Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic beta Cells during Fasting and in Type 2 Diabetes. AB - Glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and beta cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the beta-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-beta cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing beta cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, beta cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both beta cell physiology and the pathogenesis of beta cell dysfunction in type 2 diabetes. PMID- 28005535 TI - Ectopic Adipose Tissue Storage in the Left and the Right Renal Sinus is Asymmetric and Associated With Serum Kidney Injury Molecule-1 and Fibroblast Growth Factor-21 Levels Increase. AB - OBJECTIVE: A potential mechanism by which obesity could promote hypertension and kidney diseases is through accumulation of adipose tissue in the renal sinus (RS). The aim of the study was to quantify RS and abdominal adipose tissue volumes and to evaluate serum kidney injury molecule (sKIM)-1 and fibroblast growth factor (FGF)-21 association with different adipose tissue compartments. METHODS: The cross-sectional study included 280 and follow-up study-40 asymptomatic participants; aged 38.30+/-4.10. For all study participants computed tomography examination was performed, sKIM-1 and FGF-21 levels were measured. RESULTS: The results indicated asymmetrical deposition of adipose tissue into the RS even after corresponding kidney volume adjustment. The cross-sectional and the follow-up studies showed that sKIM-1 level was positively associated with RS adipose tissue volume increase for both genders. FGF-21 was positively associated with RS and retroperitoneal adipose tissue amount. CONCLUSIONS: Regardless of gender adipose tissue in RS accumulates asymmetrically-the left RS accumulates a significantly higher amount of adipose tissue. Thus, primarily RS adipose tissue effects should be assessed on the left kidney. Accumulation of adipose tissue in the RS is related with the visceral adipose amount, KIM-1 and FGF-21 concentration increase in the blood serum. PMID- 28005536 TI - Integrated Care: A Pill for All Ills? AB - There is an increasing policy emphasis on the integration of care, both within the healthcare sector and also between the health and social care sectors, with the simple aim of ensuring that individuals get the right care, in the right place, at the right time. However, implementing this simple aim is rather more complex. In this editorial, we seek to make sense of this complexity and ask: what does integrated care mean in practice? What are the mechanisms by which it is expected to achieve its aim? And what is the nature of the evidence base around the outcomes delivered? PMID- 28005537 TI - Erosion of Trust in the Medical Profession in India: Time for Doctors to Act. AB - In India, over the last decade, a series of stewardship failures in the health system, particularly in the medical profession, have led to a massive erosion of trust in these institutions. In many low- and middle-income countries (LMICs), the situation is similar and has reached crisis proportions; this crisis requires urgent attention. This paper draws on the insights from the recent developments in India, to argue that a purely control-based regulatory response to this crisis in the medical profession, as is being currently envisaged by the Parliament and the Supreme Court of India, runs the risk of undermining the trusting interpersonal relations between doctors and their patients. A more balanced approach which takes into account the differences between system and interpersonal forms of trust and distrust is warranted. Such an approach should on one hand strongly regulate the institutions mandated with the stewardship and qualities of care functions, and simultaneously on the other hand, initiate measures to nurture the trusting interpersonal relations between doctors and patients. The paper concludes by calling for doctors, and those mandated with the stewardship of the profession, to individually and collectively, critically self reflect upon the state of their profession, its priorities and its future direction. PMID- 28005538 TI - Measuring the Capacity Utilization of Public District Hospitals in Tunisia: Using Dual Data Envelopment Analysis Approach. AB - BACKGROUND: Public district hospitals (PDHs) in Tunisia are not operating at full plant capacity and underutilize their operating budget. METHODS: Individual PDHs capacity utilization (CU) is measured for 2000 and 2010 using dual data envelopment analysis (DEA) approach with shadow prices input and output restrictions. The CU is estimated for 101 of 105 PDH in 2000 and 94 of 105 PDH in 2010. RESULTS: In average, unused capacity is estimated at 18% in 2010 vs. 13% in 2000. Of PDHs 26% underutilize their operating budget in 2010 vs. 21% in 2000. CONCLUSION: Inadequate supply, health quality and the lack of operating budget should be tackled to reduce unmet user's needs and the bypassing of the PDHs and, thus to increase their CU. Social health insurance should be turned into a direct purchaser of curative and preventive care for the PDHs. PMID- 28005539 TI - An investigation Into Traditional Chinese Medicine Hospitals in China: Development Trend and Medical Service Innovation. AB - BACKGROUND: This paper aims to investigate the development trend of traditional Chinese medicine (TCM) hospitals in China and explore their medical service innovations, with special reference to the changing co-existence with western medicine (WM) at TCM hospitals. METHODS: Quantitative data at macro level was collected from official databases of China Health Statistical Yearbook and Extracts of Traditional Chinese Medicine Statistics. Qualitative data at micro level was gathered through interviews and second-hand material collection at two of the top-level TCM hospitals. RESULTS: In both outpatient and inpatient sectors of TCM hospitals, drug fees accounted for the biggest part of hospital revenue. Application of WM medical exanimation increased in both outpatient and inpatient services. Even though the demand for WM drugs was much higher in inpatient care, TCM drugs was the winner in the outpatient. Also qualitative evidence showed that TCM dominated the outpatient hospital service with WM incorporated in the assisting role. However, it was in the inpatient medical care that WM prevailed over TCM which was mostly applied to the rehabilitation of patients. CONCLUSION: By drawing on WM while keeping it active in supporting and strengthening the TCM operation in the TCM hospital, the current system accommodates the overriding objective which is for TCM to evolve into a fully informed and more viable medical field. PMID- 28005540 TI - Beyond "Two Cultures": Guidance for Establishing Effective Researcher/Health System Partnerships. AB - BACKGROUND: The current literature proposing criteria and guidelines for collaborative health system research often fails to differentiate between: (a) various types of partnerships, (b) collaborations formed for the specific purpose of developing a research proposal and those based on long-standing relationships, (c) researcher vs. decision-maker initiatives, and (d) the underlying drivers for the collaboration. METHODS: Qualitative interviews were conducted with 16 decision-makers and researchers who partnered on a Canadian major peer-reviewed grant proposal in 2013. Objectives of this exploration of participants' experiences with health system research collaboration were to: (a) explore perspectives and experience with research collaboration in general; (b) identify characteristics and strategies associated with effective partnerships; and (c) provide guidance for development of effective research partnerships. Interviews were audio-recorded and transcribed: transcripts were qualitatively analyzed using a general inductive approach. RESULTS: Findings suggest that the common "two cultures" approach to research/decision-maker collaboration provides an inadequate framework for understanding the complexity of research partnerships. Many commonly-identified challenges to researcher/knowledge user (KU) collaboration are experienced as manageable by experienced research teams. Additional challenges (past experience with research and researchers; issues arising from previous collaboration; and health system dynamics) may be experienced in partnerships based on existing collaborations, and interact with partnership demands of time and communication. Current research practice may discourage KUs from engaging in collaborative research, in spite of strong beliefs in its potential benefits. Practical suggestions for supporting collaborations designed to respond to real-time health system challenges were identified. CONCLUSION: Participants' experience with previous research activities, factors related to the established collaboration, and interpersonal, intra- and inter-organizational dynamics may present additional challenges to research partnerships built on existing collaboration. Differences between researchers and KUs may pose no greater challenges than differences among KUs (at various levels, and representing diverse perspectives and organizations) themselves. Effective "relationship brokering" is essential for meaningful collaboration. PMID- 28005541 TI - Fair Processes for Priority Setting: Putting Theory into Practice Comment on "Expanded HTA: Enhancing Fairness and Legitimacy". AB - Embedding health technology assessment (HTA) in a fair process has great potential to capture societal values relevant to public reimbursement decisions on health technologies. However, the development of such processes for priority setting has largely been theoretical. In this paper, we provide further practical lead ways on how these processes can be implemented. We first present the misconception about the relation between facts and values that is since long misleading the conduct of HTA and underlies the current assessment-appraisal split. We then argue that HTA should instead be explicitly organized as an ongoing evidence-informed deliberative process, that facilitates learning among stakeholders. This has important consequences for whose values to consider, how to deal with vested interests, how to consider all values in the decision-making process, and how to communicate decisions. This is in stark contrast to how HTA processes are implemented now. It is time to set the stage for HTA as learning. PMID- 28005542 TI - Governance Must Dive Into Organizations to Make a Real Difference Comment on "Governance, Government, and the Search for New Provider Models". AB - In their 2016 article, Saltman and Duran provide a thoughtful examination of the governance challenges involved in different care delivery models adopted in primary care and hospitals in two European countries. This commentary examines the limited potential of structural changes to achieve real reform and considers that, unless governance arrangements actually succeed in penetrating organizations, they are unlikely to improve care. It proposes three sets of levers influenced by governance that have potential to influence what happens at the point of care: harnessing the autonomy and expertise of professionals at a collective level to work towards better safety and quality; creating enabling contexts for cross-fertilization of clinical and organizational expertise, notably through teamwork; and patient and public engagement to achieve greater agreement on improvement priorities and overcome provider/manager tensions. Good governance provides guidance at a distance but also goes deep enough to influence clinical habits. PMID- 28005543 TI - The Evolution of the Physician Role in the Setting of Increased Non-physician Clinicians in Sub-Saharan Africa: An Insistence on Timing and Culturally Sensitive, Purposefully Selected Skill Development Comment on "Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians". AB - As Eyal et al put forth in their piece, Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians, task-shifting across sub-Saharan Africa through non-physician clinicians (NPCs) has led to an improvement in access to health services in the context of physician-shortages. Here, we offer a commentary to the piece by Eyal et al, concurring that physician's roles should evolve into specialized medicine and that skills in mentorship, research, management, and leadership may create more holistic physicians clinical services. We believe that learning such non-clinical skills will allow physicians to improve the outcome of their clinical services. However, at the risk of a local, clinical brain drain as physicians shift to explore beyond the clinical sphere, we advocate strongly for increased caution to be exercised by leadership over the encouragement of this evolution. In the context of still-present physician shortages across many developing countries, we advocate to analyze this changing role and to purposefully select each new skill according to the context, giving careful consideration to the timing and degree of its evolution. PMID- 28005544 TI - A New Generation of Physicians in Sub-Saharan Africa? Comment on "Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians". AB - This commentary follows up on an editorial by Eyal and colleagues in which these authors discuss the implications of the emergence of non-physician clinicians (NPCs) on the health labour market for the education of medical doctors. We generally agree with those authors and we want to stress the importance of clarifying the terminology to describe these practitioners and of defining more formally their scope of practice as prerequisites to identifying the new competencies which physicians need to acquire. We add one new competencies domain, the utilization of new communication technologies, to those listed in the editorial. Finally, we identify policy issues which decision-makers will need to address to make medical education reform work. PMID- 28005545 TI - Decentralisation; The Question of Management Capacity: A Response to Recent Commentaries. PMID- 28005546 TI - Health Promotion in an Age of Normative Equity and Rampant Inequality. AB - The world was different when the Ottawa Charter for Health Promotion was released 30 years ago. Concerns over the environment and what we now call the 'social determinants of health' were prominent in 1986. But the acceleration of ecological crises and economic inequalities since then, in a more complex and multi-polar world, pose dramatically new challenges for those committed to the original vision of the Charter. Can the 2015 Sustainable Development Goals (SDGs), agreed to by all the world's governments, offer a new advocacy and programmatic platform for a renewal of health promotion's founding ethos? Critiqued from both the right and the left for, respectively, their aspirational idealism and lack of political analysis, the SDGs are an imperfect but still compelling normative statement of how much of the world thinks the world should look like. Many of the goals and targets provide signals for what we need to achieve, even if there remains a critical lacuna in articulating how this is to be done. The fundamental flaw in the SDGs is the implicit assumption that the same economic system, and its still-present neoliberal governing rules, that have created or accelerated our present era of rampaging inequality and environmental peril can somehow be harnessed to engineer the reverse. This flaw is not irrevocable, however, if health promoters - practitioners, researchers, advocates - focus their efforts on a few key SDGs that, with some additional critique, form a basic blueprint for a system of national and global regulation of capitalism (or even its transformation) that is desperately needed for social and ecological survival into the 22nd century. Whether or not these efforts succeed is a future unknown; but that the efforts are made is a present urgency. PMID- 28005547 TI - The Legal Strength of International Health Instruments - What It Brings to Global Health Governance? AB - Public health instruments have been under constant development and renewal for decades. International legal instruments, with their binding character and strength, have a special place in this development. The start of the 21st century saw, in particular, the birth of the first World Health Organization (WHO)-era health treaties - the WHO Framework Convention on Tobacco Control (WHO FCTC) and its first Protocol. The authors analyze the potential impact of these instruments on global health governance and public health, beyond the traditional view of their impact on tobacco control. Overall, the very fact that globally binding treaties in modern-era health were feasible has accelerated the debate and expectations for an expanded role of international legal regimes in public health. The impact of treaties has also been notable in global health architecture as the novel instruments required novel institutions to govern their implementation. The legal power of the WHO FCTC has enabled rapid adoption of further instruments to promote its implementation, thus, enhancing the international instrumentarium for health, and it has also prompted stronger role for national legislation on health. Notably, the Convention has elevated several traditionally challenging public health features to the level of international legal obligations. It has also revealed how the legal power of the international health instrument can be utilized in safeguarding the interests of health in the face of competing agendas and legal disputes at both the domestic and international levels. Lastly, the legal power of health instruments is associated with their potential impact not only on health but also beyond; the recently adopted Protocol to Eliminate Illicit Trade in Tobacco Products may best exemplify this matter. The first treaty experiences of the 21st century may provide important lessons for the role of legal instruments in addressing the unfolding challenges in global health. PMID- 28005548 TI - Cost-Sharing Rates Increase During Deep Recession: Preliminary Data From Greece. AB - BACKGROUND: Measures taken over the past four years in Greece to reduce pharmaceutical expenditure have led to significant price reductions for medicines, but have also changed patient cost-sharing rates for prescription drugs. This study attempts to capture the resulting increase in patients' out-of pocket (OOP) expenses for prescription drugs during the 2011-2014 period. METHODS: The authors conducted a retrospective review of financial data derived from 39 883 prescriptions, dispensed at three randomly chosen pharmacies located in Lamia, central Greece. RESULTS: The study recorded an average contribution rate per prescription as follows: 11.28% for 2011 (95% CI: 10.76-11.80), 14.10% for 2012, 19.97% for 2013, and 29.08% for 2014. Correspondingly, the mean patient charge per prescription for 2011 was ?6.58 (95% CI: 6.22-6.94), ?8.28 for 2012, ?8.35 for 2013, and ?10.87 for 2014. During the 2011-2014 period, mean percentage rate of patient contribution increased by 157.75%, while average patient charge per prescription in current prices increased by 65.22%. The use of a newly introduced internal reference price (IRP) system increased the level of prescription charge at a rate of 2.41% for 2012 (100% surcharge on patients), 26.24% for 2013 (49.95% on patients and 50.04% on the appropriate health insurance funds), and 47.72% for 2014 (85.06% on patients and 14.94% on funds). CONCLUSION: Increased cost-sharing rates for prescription drugs can reduce public pharmaceutical expenditure, but international experience shows that rising OOP expenses can compromise patients' ability to pay, particularly when it comes to chronic diseases and vulnerable populations. Various suggestions could be effective in refining the cost-sharing approach by giving greater consideration to chronic patients, and to the poor and elderly. PMID- 28005549 TI - Determinants of Healthcare Utilisation and Out-of-Pocket Payments in the Context of Free Public Primary Healthcare in Zambia. AB - BACKGROUND: Access to appropriate and affordable healthcare is needed to achieve better health outcomes in Africa. However, access to healthcare remains low, especially among the poor. In Zambia, poor access exists despite the policy by the government to remove user fees in all primary healthcare facilities in the public sector. The paper has two main objectives: (i) to examine the factors associated with healthcare choices among sick people, and (ii) to assess the determinants of the magnitude of out-of-pocket (OOP) payments related to a visit to a health provider. METHODS: This paper employs a multilevel multinomial logistic regression to model the determinants of an individual's choice of healthcare options following an illness. Further, the study analyses the drivers of the magnitude of OOP expenditure related to a visit to a health provider using a two-part generalised linear model. The analysis is based on a nationally representative healthcare utilisation and expenditure survey that was conducted in 2014. RESULTS: Household per capita consumption expenditure is significantly associated with increased odds of seeking formal care (odds ratio [OR] = 1.12, P = .000). Living in a household in which the head has a higher level of education is associated with increased odds of seeking formal healthcare (OR = 1.54, P = .000) and (OR = 1.55, P = .01), for secondary and tertiary education, respectively. Rural residence is associated with reduced odds of seeking formal care (OR = 0.706, P = .002). The magnitude of OOP expenditure during a visit is significantly dependent on household economic well-being, distance from a health facility, among other factors. A 10% increase in per capita consumption expenditure was associated with a 0.2% increase in OOP health expenditure while every kilometre travelled was associated with a K0.51 increase in OOP health expenditure. CONCLUSION: Despite the removal of user fees on public primary healthcare in Zambia, access to healthcare is highly dependent on an individual's socio-economic status, illness type and region of residence. These findings also suggest that the benefits of free public healthcare may not reach the poorest proportionately, which raise implications for increasing access in Zambia and other countries in sub-Saharan Africa. PMID- 28005550 TI - Analysing the Stewardship Function in Botswana's Health System: Reflecting on the Past, Looking to the Future. AB - BACKGROUND: In many parts of the world, ongoing deficiencies in health systems compromise the delivery of health interventions. The World Health Organization (WHO) identified four functions that health systems need to perform to achieve their goals: Efforts to strengthen health systems focus on the way these functions are carried out. While a number of studies on health systems functions have been conducted, the stewardship function has received limited attention. In this article, we evaluate the extent to which the Botswana Ministry of Health (MoH) undertook its stewardship role. METHODS: We used the WHO Health Systems Performance Assessment Frame (HSPAF) to guide analysis of the stewardship function of the Botswana's MoH focusing on formulation of national health policies, exerting influence through health regulation, and coalition building. Data were abstracted from published and unpublished documents. We interviewed 54 key informants comprising staff of the MoH (N = 40) and stakeholder organizations (N = 14). Data from documents was analyzed through content analysis. Interviews were transcribed and analyzed through thematic analysis. RESULTS: A lack of capacity for health policy development was identified. Significant policy gaps existed in some areas. Challenges were reported in policy implementation. While the MoH made efforts in developing various statutes that regulated different aspects of the health system, some gaps existed in the regulatory framework. Poor enforcement of legislation was a challenge. Although the MoH had a high number of stakeholders, the mechanisms for stakeholder engagement in the planning processes were weak. CONCLUSION: Problems in the exercise of the stewardship function posed challenges in ensuring accountability and limited the health system's ability to benefit from its stakeholders. Ongoing efforts to establish a District Health System under control of the MoH, attempts to improve service delivery at a national level and political will to strengthen public-private engagement mechanisms are some of the prospects that can improve the MoH's stewardship function. PMID- 28005551 TI - Outcomes and Impact of Training and Development in Health Management and Leadership in Relation to Competence in Role: A Mixed-Methods Systematic Review Protocol. AB - BACKGROUND: The need for competence training and development in health management and leadership workforces has been emphasised. However, evidence of the outcomes and impact of such training and development has not been systematically assessed. The aim of this review is to synthesise the available evidence of the outcomes and impact of training and development in relation to the competence of health management and leadership workforces. This is with a view to enhancing the development of evidence-informed programmes to improve competence. METHODS AND ANALYSIS: A systematic review will be undertaken using a mixed-methods research synthesis to identify, assess and synthesise relevant empirical studies. We will search relevant electronic databases and other sources for eligible studies. The eligibility of studies for inclusion will be assessed independently by two review authors. Similarly, the methodological quality of the included studies will be assessed independently by two review authors using appropriate validated instruments. Data from qualitative studies will be synthesised using thematic analysis. For quantitative studies, appropriate effect size estimate will be calculated for each of the interventions. Where studies are sufficiently similar, their findings will be combined in meta-analyses or meta-syntheses. Findings from quantitative syntheses will be converted into textual descriptions (qualitative themes) using Bayesian method. Textual descriptions and results of the initial qualitative syntheses that are mutually compatible will be combined in mixed methods syntheses. DISCUSSION: The outcome of data collection and analysis will lead, first, to a descriptive account of training and development programmes used to improve the competence of health management and leadership workforces and the acceptability of such programmes to participants. Secondly, the outcomes and impact of such programmes in relation to participants' competence as well as individual and organisational performance will be identified. If possible, the relationship between health contexts and the interventions required to improve management and leadership competence will be examined. PMID- 28005552 TI - New Provider Models for Sweden and Spain: Public, Private or Non-profit? Comment on "Governance, Government, and the Search for New Provider Models". AB - Sweden and Spain experiment with different provider models to reform healthcare provision. Both models have in common that they extend the role of the for-profit sector in healthcare. As the analysis of Saltman and Duran demonstrates, privatisation is an ambiguous and contested strategy that is used for quite different purposes. In our comment, we emphasize that their analysis leaves questions open on the consequences of privatisation for the performance of healthcare and the role of the public sector in healthcare provision. Furthermore, we briefly address the absence of the option of healthcare provision by not-for-profit providers in the privatisation strategy of Sweden and Spain. PMID- 28005553 TI - Is the Role of Physicians Really Evolving Due to Non-physician Clinicians Predominance in Staff Makeup in Sub-Saharan African Health Systems? Comment on "Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians". AB - Health workforce shortages in Sub-Saharan Africa are widely recognized, particularly of physicians, leading the training and deployment of Non-physician clinicians (NPCs). The paper by Eyal et al provides interesting and legitimate viewpoints on evolving role of physicians in context of decisive increase of NPCss in Sub-Saharan Africa. Certainly, in short or mid-term, NPCs will continue to be a proxy solution and a valuable alternative to overcome physicians' shortages in sub-Saharan Africa. Indeed, NPCs have an important role at primary healthcare (PHC) level. Physicians at PHC level can certainly have all different roles that were suggested by Eyal et al, including those not directly related to healthcare provision. However, at secondary and higher levels of healthcare, physicians would assume other roles that are mainly related to patient clinical care. Thus, attempting to generalize the role of physicians without taking into account the context where they will work would be not entirely appropriate. It is true that often physicians start the professional carriers at PHC level and progress to other levels of healthcare particularly after clinical post graduation training. Nevertheless, the training programs offered by medical institutions in sub-Saharan Africa need to be periodically reviewed and take into account professional and occupational roles physicians would take in context of evolving health systems in sub-Saharan Africa. PMID- 28005554 TI - Decentralisation - A Portmanteau Concept That Promises Much but Fails to Deliver? Comment on "Decentralisation of Health Services in Fiji: A Decision Space Analysis". AB - Decentralisation has been described as an empty concept that lacks clarity. Yet there is an enduring interest in the process of decentralisation within health systems and public services more generally. Many claims about the benefits of decentralisation are not supported by evidence. It may be useful as an organising framework for analysis of health systems but in this context it lacks conceptual clarity and particularly often ignores level context issues given the focus on a principal-agent/vertical centre/local axis or other aspects of limits on autonomy such as standards for professional practice. Both these aspects are relevant in discussing the establishment of "decentralised" health centres in Fiji. In the end decentralisation may be nothing more than a useful descriptive label that can be used in an increasingly wide range of ways but actually have little meaning in practice as an analytical concept. PMID- 28005555 TI - Provider Governance; A Basic Blackbox Seldom Looked at Properly: A Response to Recent Commentaries. PMID- 28005556 TI - Lamotrigine-Associated Hemophagocytic Lymphohistiocytosis. PMID- 28005557 TI - Preadmission Diuretic Use and Mortality in Patients Hospitalized With Hyponatremia: A Propensity Score-Matched Cohort Study. AB - BACKGROUND: Hyponatremia is associated with increased mortality and is frequently induced by diuretic use. It is uncertain whether diuretic use is linked to mortality risk in patients with hyponatremia. STUDY QUESTION: To measure the prognostic impact of diuretic use on 30-day mortality among patients hospitalized with hyponatremia. STUDY DESIGN: Using population-based registries, we identified all patients with a serum sodium measurement <135 mmol/L within 24 hours after acute hospital admission in western Denmark from 2006 to 2012 (cumulative population of 2.2 million). We categorized patients as current diuretic users (new and long-term), former users or nonusers, and followed them until death, migration or up to 30 days which ever came first. MEASURES AND OUTCOMES: Thirty day cumulative mortality and relative risk with 95% confidence interval (CI) controlled for demographics, previous morbidity, renal function, and co medications. Calculations were also divided by the diuretic type and were repeated after propensity score matching. RESULTS: Thirty-day mortality was 11.4% among current diuretic users (n = 14,635) compared with 6.2% among nonusers, yielding an adjusted relative risk of 1.4 (95% CI, 1.2-1.5). New users were at higher risk (1.7, 95% CI, 1.5-2.0) than long-term users (1.3, 95% CI, 1.2-1.4). In particular, the use of loop diuretics (1.6, 95% CI, 1.4-1.8), potassium sparing diuretics (1.6, 95% CI, 1.2-2.2), and diuretic polytherapy (1.5, 95% CI, 1.3-1.7) were associated with increased risk, whereas thiazide use was not (1.0, 95% CI, 0.9-1.2). Propensity score-matched analyses confirmed the results. CONCLUSIONS: Diuretic use except from thiazides, and particularly if newly initiated, is a negative prognostic factor in patients admitted with hyponatremia. PMID- 28005558 TI - Residual thromboxane activity and oxidative stress: influence on mortality in patients with stable coronary artery disease. AB - BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin. PMID- 28005559 TI - The impact of blood pressure variability on coronary plaque vulnerability in stable angina: an analysis using optical coherence tomography. AB - BACKGROUND: Blood pressure variability (BPV), especially visit-to-visit BPV, has been reported to be a risk factor for cardiovascular disease. The impact of BPV on coronary plaque vulnerability remains uncertain. The aim of this study was to investigate the relationship between BPV and coronary plaque vulnerability. PATIENTS AND METHODS: From August 2013 to May 2014, 36 patients with both hypertension and stable angina pectoris who underwent a percutaneous coronary intervention guided by frequency-domain optical coherence tomography were investigated retrospectively. The size of the lipid cores and the thickness of the fibrous cap covering the lipid core were measured by frequency-domain optical coherence tomography, and we calculated the blood pressure coefficient of variation (CV) and SD as intraindividual visit-to-visit BPV. RESULTS: Both SD and CV of systolic blood pressure (SBP) correlated positively with lipid arc (SBP-SD: r=0.68, P<0.01; SBP-CV: r=0.64, P<0.01) as well as average SBP (r=0.48, P<0.01). Fibrous cap thickness did not correlate with blood pressure variables or BPV. CONCLUSION: BPV is related to coronary plaque volume, but not to coronary plaque vulnerability. In addition to conventional coronary risk factors, BPV may be a therapeutic target for coronary atherosclerosis. PMID- 28005561 TI - Risk Factors for Collegiate Swimmers Hospitalized With Exertional Rhabdomyolysis. AB - OBJECTIVE: To identify midseason risk factors for symptomatic exertional rhabdomyolysis (sER) in swimmers after a novel upper body workout. DESIGN: Retrospective (1) survey and (2) analyses of observational laboratory data conducted over a 16-week training period, 2 months before sER. SETTING: Midwest University. PARTICIPANTS: Thirty-four collegiate swimmers. INDEPENDENT VARIABLES: (1) Motivation, symptoms, and supplements for survey variables. (2) Changes (midseason minus preseason) in body composition, blood pressure (BP), urinary measures, and protein shake ingestion for laboratory variables. MAIN OUTCOME MEASURES: Swimmers were categorized in hospitalized (H), treated and released from hospital (RH), and nonhospitalized (NH) groups for analyses. RESULTS: (1) Six swimmers were in the H group (17.6%; 3 male/3 female) and 7 in the RH group (20.6%; 3 male/4 female). Nonsignificant trend toward H swimmers relating more upper body soreness (>=9/10) than RH (8/10) and NH (6/10) swimmers (P > 0.05) while reporting "felt bad and workout went poorly" (P = 0.009). H and RH swimmers reported more arm locking during the workout (P = 0.04) and brown urine after arm competition compared with NH-group swimmers (P = 0.03). (2) Increases in right systolic (P = 0.01) and left diastolic (P = 0.02) BP, with trends toward decreased left arm lean mass (P = 0.06) in H compared with RH and NH swimmers. Female H swimmers had more acidic urine (pH = 5.50 vs 6.9; P = 0.004), less volume, and higher specific gravity than RH + NH swimmers. All H swimmers regularly ingested protein shakes after workouts. CONCLUSIONS: Risk factors for sER included exceptional motivation, extreme soreness, increased resting BP, acidic urine (females), and regular ingestion of protein shakes. PMID- 28005563 TI - Evaluation of a Novel Communication Application From Nurses' Perspectives. AB - The purpose of this article is to report usability of a computer application, Speak for Myself, from nurses' perspectives. This was a one-group exploratory survey. Nurses included patients in the study who were older than 18 years, could write and speak English, were unable to verbalize needs for any reason, and had a specified sedation-agitation scale (-1 to +1). Patients were excluded if they were younger than 18, could not write and/or speak English, or had a Richmond Agitation-Sedation Scale score exceeding -1 to +1. Twelve RNs from various ICUs in two hospitals in South Florida participated in the study. A person who was a supervisor or clinical specialist was chosen in each participating unit and at each hospital for recruitment of patient participants. Five nurses (41.6%) stated their patients were able to communicate better with the use of Speak for Myself, and all 12 nurses (100%) indicated they would use Speak for Myself again. Suggestions for further development of Speak for Myself were offered from the nurses. Limitations include a small sample in South Florida. The results of this and previous studies about Speak for Myself will be used in further development and testing of the computer application. PMID- 28005562 TI - Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia: How Well Do the Uniform Data Set Measures Differentiate Between Diseases? AB - BACKGROUND/AIMS: Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. OBJECTIVES: To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? METHODS: Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. RESULTS: As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. CONCLUSIONS: Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in differentiating FTLD from AD at the initial visit. These results highlight the difficulty of obtaining an accurate early diagnosis of FTLD and argue for adding supplemental tests to those included in the UDS to assess cognition in FTD and AD patients. PMID- 28005564 TI - Usability Evaluation and Implementation of a Health Information Technology Dashboard of Evidence-Based Quality Indicators. AB - Health information technology dashboards that integrate evidence-based quality indicators can efficiently and accurately display patient risk information to promote early intervention and improve overall quality of patient care. We describe the process of developing, evaluating, and implementing a dashboard designed to promote quality care through display of evidence-based quality indicators within an electronic health record. Clinician feedback was sought throughout the process. Usability evaluations were provided by three nurse pairs and one physician from medical-surgical areas. Task completion times, error rates, and ratings of system usability were collected to compare the use of quality indicators displayed on the dashboard to the indicators displayed in a conventional electronic health record across eight experimental scenarios. Participants rated the dashboard as "highly usable" following System Usability Scale (mean, 87.5 [SD, 9.6]) and Poststudy System Usability Questionnaire (mean, 1.7 [SD, 0.5]) criteria. Use of the dashboard led to reduced task completion times and error rates in comparison to the conventional electronic health record for quality indicator-related tasks. Clinician responses to the dashboard display capabilities were positive, and a multifaceted implementation plan has been used. Results suggest application of the dashboard in the care environment may lead to improved patient care. PMID- 28005565 TI - Comparing the Financial Impact of Several Hospitals on Their Local Markets. AB - Several studies that measured the financial impact of hospitals on their local markets are examined. Descriptive analyses were performed to ascertain if there are any identifying characteristics and emerging patterns in the data. After hospitals were categorized into small, medium, and large classifications based on the number of employees, various predictive insights were discovered. Smaller hospitals could be expected to contribute approximately 7.3% to the local economy, whereas medium-sized hospitals would likely contribute approximately 11.4% to the financial value of the local market. Finally, larger hospitals may contribute approximately 16% to their local economies. PMID- 28005566 TI - Anesthesia for functional endoscopic sinus surgery. AB - PURPOSE OF REVIEW: The present article summarizes anesthetic techniques used during functional endoscopic sinus surgery to decrease bleeding and aid in creating a clear surgical field. The applicable physiology behind these anesthetic techniques is reviewed with emphasis on the effect on bleeding and the surgical field. Deliberate hypotension, reverse Trendelenburg positioning, regional anesthesia, and cerebral monitoring are discussed. RECENT FINDINGS: There are mixed data as to whether traditional inhalation anesthesia or total intravenous anesthesia is superior with respect to better surgical fields and decreased blood loss. A review of the literature tends to favor total intravenous anesthesia. Cerebral oximetry and transcranial Doppler ultrasound are emerging techniques to monitor cerebral perfusion during deliberate hypotension. SUMMARY: Total intravenous anesthesia using propofol and remifentanil is the current favored technique for producing deliberate hypotension during endoscopic sinus surgery due to its hemodynamic stability and smooth rapid emergence. PMID- 28005567 TI - The state of sinus care in 2017. PMID- 28005568 TI - Dilemma in the therapeutic management of low-gradient aortic stenosis. AB - PURPOSE OF REVIEW: Grading of aortic stenosis is essential in aortic stenosis management patients. However, despite clear thresholds provided in the guidelines, up to 30% of patients have discordant grading of aortic stenosis. The management of patients with low gradients/velocity despite tight aortic valve area is challenging. RECENT FINDINGS: Recent studies demonstrated that patients with or without low flow may have a severe aortic stenosis despite a low gradient. Moreover, aortic valve replacement has been shown to improve outcome in low-gradient aortic stenosis patients with or without low flow. Finally, measurement of aortic valve calcification by multidetector computed tomography is an important tool to assess aortic stenosis severity in these patients. SUMMARY: The presence of a low gradient/velocity despite a tight aortic valve area could be linked to low ejection fraction or low flow with preserved ejection fraction but also with normal flow and normal ejection fraction. In each situation, aortic stenosis could be truly severe or pseudosevere, and the severity of aortic stenosis has to be accurately evaluated for clinical decision-making. Nowadays, two types of interventions are available: surgical and transcatheter aortic valve replacement, whereas conservative management should be considered as a palliative treatment in patients with proven severe aortic stenosis and symptoms or left ventricle dysfunction. PMID- 28005570 TI - In Vitro Microbiological Analysis of Bacterial Seal in Hybrid Zirconia Abutment Tapered Connection. AB - PURPOSE: The aim of this study was to evaluate the bacterial seal at the implant hybrid zirconia abutment interface and Morse taper-type connections through in vitro microbiological analysis. MATERIALS AND METHODS: Sixteen implants and their respective abutments were divided into 3 groups: test (10 sets), positive control (3 sets), and negative control (3 sets). In the test group, 10 implants were contaminated with Escherichia coli using a sterile inoculating loop to the inner portion of the implants, followed by torque application to the abutment (30 N.cm). The positive controls were also contaminated, but no torque was applied to the abutment screw. The negative control consisted of uncontaminated sets. All specimens were immersed in test tubes containing 5 mL brain heart infusion (BHI) broth, maintained in a microbiological incubator for 14 days at 37 degrees C under aerobic conditions, and monitored every 24 hours for evidence of bacterial growth. RESULTS: During the 14 days of incubation, no significant increase in the number of cloudy culture media was observed in the test group (P = 0.448). No significant difference in broth turbidity ratio was observed (P > 0.05). CONCLUSION: Hybrid zirconia abutments can create an effective seal at the tapered abutment-implant interface with a 30-N.cm installation torque. PMID- 28005572 TI - Polyreactive natural antibodies in transplantation. AB - PURPOSE OF REVIEW: Antibody-mediated rejection (ABMR), especially in its chronic manifestation, is increasingly recognized as a leading cause of late graft loss following solid organ transplantation. In recent years, autoantibodies have emerged as a significant component of the humoral response to allografts alongside anti-human leukocyte antigen antibodies. These include polyreactive antibodies also known as natural antibodies (Nabs) secreted by innate B cells. A hallmark of Nabs is their capacity to bind altered self such as oxidized lipids on apoptotic cells. This review provides an overview of these overlooked antibodies and their implication in the pathophysiology of ABMR. RECENT FINDINGS: New evidence reported in the past few years support a contribution of immunoglobulin (Ig) G Nabs to ABMR. Serum IgG Nabs levels are significantly higher in patients with ABMR compared with control kidney transplant recipients with stable graft function. Pretransplant IgG Nabs are also associated with ABMR and late graft loss. IgG Nabs are almost exclusively of the IgG1 and IgG3 subclasses and have the capacity to activate complement. SUMMARY: In conclusion, Nabs are important elements in host immune responses to solid organ grafts. The recent description of their implication in ABMR and late kidney graft loss warrants further investigation into their pathogenic potential. PMID- 28005571 TI - Long-term Exposure to PM2.5 and Mortality Among Older Adults in the Southeastern US. AB - BACKGROUND: Little is known about what factors modify the effect of long-term exposure to PM2.5 on mortality, in part because in most previous studies certain groups such as rural residents and individuals with lower socioeconomic status (SES) are under-represented. METHODS: We studied 13.1 million Medicare beneficiaries (age >=65) residing in seven southeastern US states during 2000 2013 with 95 million person-years of follow-up. We predicted annual average of PM2.5 in each zip code tabulation area (ZCTA) using a hybrid spatiotemporal model. We fit Cox proportional hazards models to estimate the association between long-term PM2.5 and mortality. We tested effect modification by individual-level covariates (race, sex, eligibility for both Medicare and Medicaid, and medical history), neighborhood-level covariates (urbanicity, percentage below poverty level, lower education, median income, and median home value), mean summer temperature, and mass fraction of 11 PM2.5 components. RESULTS: The hazard ratio (HR) for death was 1.021 (95% confidence interval: 1.019, 1.022) per 1 MUg m increase in annual PM2.5. The HR decreased with age. It was higher among males, non-whites, dual-eligible individuals, and beneficiaries with previous hospital admissions. It was higher in neighborhoods with lower SES or higher urbanicity. The HR increased with mean summer temperature. The risk associated with PM2.5 increased with relative concentration of elemental carbon, vanadium, copper, calcium, and iron and decreased with nitrate, organic carbon, and sulfate. CONCLUSIONS: Associations between long-term PM2.5 exposure and death were modified by individual-level, neighborhood-level variables, temperature, and chemical compositions. PMID- 28005573 TI - Mesenchymal stromal cell therapy to promote cardiac tissue regeneration and repair. AB - PURPOSE OF REVIEW: This review focuses on articles published from January 2015 to June 2016 on mesenchymal stromal cell (MSC) therapy for cardiac regeneration and repair. RECENT FINDINGS: During this period, reports published on MSCs address the best MSC tissue source for cellular therapy, mechanisms of MSC activity and improving MSC longevity, and homing in vivo. Currently, there is no definitive therapeutic advantage of any one tissue-derived MSC over another, and even combination therapies struggle with conflicting outcomes. MSC activity, persistence in vivo, or homing can be improved by priming strategies, genetic modification, or biomaterials. Despite numerous studies showing improvement in heart function after acute cardiac injury, the reproducibility and efficacy of the therapy remains elusive and falls short of expectations in clinical trials. Although the safety of MSCs is undisputed, the success of MSC preparations in improving cardiac function clinically remains uncertain due to challenges in correlating MSC potency with clinical outcomes, donor-related variation in MSC function, and a profusion of culture methodologies. SUMMARY: Several strategies are available to advance MSC cell therapy for acute cardiac injury to promote cardiac regeneration and repair in rigorous preclinical and clinical studies. PMID- 28005574 TI - Clinical and viro-immunological correlates of HIV associated neurocognitive disorders (HAND) in a cohort of antiretroviral-naive HIV-infected patients. AB - The multifactorial pathogenesis of HIV-associated neurocognitive disorders may explain the inconsistent association between neurocognitive impairment and cerebrospinal fluid (CSF) HIV RNA. Clinical and viro-immunological (CSF and plasma HIV RNA, CSF/plasma HIV RNA ratio, circulating T-cell phenotypes) parameters were investigated in 155 HIV-infected, antiretroviral-naive, asymptomatic study participants undergoing a neuropsychological evaluation. HIV associated neurocognitive disorders (HAND) was independently associated with AIDS events and a CSF/plasma ratio of at least one, after adjustment for CD4 nadir of less than 200 cells/mmc, suggesting a role for active central nervous system (CNS) viral replication in the pathogenesis of neurocognitive impairment. PMID- 28005575 TI - Reduced capacity of autonomic and baroreflex control associated with sleep pattern in spontaneously hypertensive rats with a nondipping profile. AB - OBJECTIVE: Ambulatory blood pressure (BP) monitoring with a lack of nocturnal BP fall (BP nondipping) has been reported to be more prevalent among hypertensive populations and is a risk factor for cardiovascular disease than in patients with dipping pattern. However, its underlying mechanism is not fully understood. This study hypothesized that spontaneously hypertensive rats (SHRs) with a nondipping profile have an exaggerated disruption of both autonomic functioning and sleep compared with Wistar-Kyoto rats (WKYs) with a nondipping profile. METHODS: Continuous power spectral analysis of electroencephalogram, electromyogram, and cardiovascular variability was performed in WKYs and SHRs over 24 h. BP dipping was assessed as the percentage decline in SBP from dark active waking to light quiet sleep (lQS). According to the human definition of BP dipping (10%), we divided WKYs and SHRs into dipper and nondipper groups individually. RESULTS: Of the four groups, both parasympathetic activity and baroreflex sensitivity in sleep were the lowest in the SHR nondippers. Compared with the WKY nondippers, the SHR nondippers spent more time awake and less time asleep during the light period and the opposite during the dark period. Moreover, they showed more interruptions and a lower delta power percentage of lQS. Correlation analysis revealed that baroreflex sensitivity during lQS was correlated with the BP dipping percentage in SHRs. CONCLUSION: SHR nondippers exhibit poor sleep quality and impaired autonomic functioning to a greater degree than do SHR dippers and WKY nondippers, which may account for a higher cardiovascular risk in this population. PMID- 28005576 TI - Surviving Depression: Clinical Qualitative Analysis of Long-Term Survival for Ethnically Diverse, Depressed Patients. AB - Depression is persistent and recurrent across ethnic groups. Few narrative analyses of long-term outcomes for ethnically diverse adults with depression exist. We combined 9 years of quantitative data, qualitative interviews at 10 years, clinician ratings of outcomes, and a community discussion group with the objective of describing long-term recovery and survival of diverse primary care patients after an episode of depression. Nearly half of participants were found to be depressed at some time over a 10-year period, and most cases across ethnic groups were judged to need further treatment. The ethnically diverse community members that analyzed the transcripts emphasized assets that participants showed in surviving multiple life stresses. Different sex and ethnic/racial groups had different characteristics of engaging in care, with Latino women in particular raising concerns about care engagement, coping with stress, and long-term outcomes. PMID- 28005577 TI - Understanding the Impairment Associated With Depressive Symptoms. AB - Relatively little theory or research has addressed the mediating processes through which depressive symptoms lead to impairment. To conceptualize the nature of impairment in depression, we conducted semistructured interviews of 18 psychiatric patients experiencing depressive symptoms about how their depressive symptoms create impairment. Interviews were audio recorded and transcribed, and thematic analysis methods were used to identify content areas and themes. Three content areas were identified: domains of impairment (types of behavior that are impaired), experience of impairment (nature and severity of impairment), and pathways to impairment (processes connecting symptoms to impairment). Pathways included direct connections between symptom and impairment, as well as indirect pathways mediated by other symptoms and by cognitive responses to symptoms. Patients' examples of the impairment phenomena are presented. In addition, patterns of association were observed between particular pathways and symptom type (vegetative versus cognitive/affective). Increased understanding of clients' explanations for impairment may improve clinical intervention and assessments. PMID- 28005578 TI - Paliperidone Palmitate Once-Monthly Treatment in Recent Onset and Chronic Illness Patients With Schizoaffective Disorder. AB - Data from a multiphase schizoaffective disorder study (NCT01193153) were used to examine the effects of paliperidone palmitate once-monthly (PP1M) by subjects' illness duration, defined as recent onset (<=5 years since first psychiatric diagnosis; n = 206) and chronic illness (>5 years; n = 461). Symptom and functioning scores, as measured during open-label PP1M acute and stabilization treatment phases, improved in both subpopulations, with greater improvements in recent onset than chronic illness subjects (p <= 0.022). Relapse rates, examined during the double-blind, placebo-controlled phase, were higher with placebo than PP1M: 30.0% vs. 10.2% (p = 0.014; hazard ratio [HR]: 2.8; 95% confidence interval [CI]: 1.11-7.12; p = 0.029) in the recent onset subpopulation and 35.5% vs. 18.1% (p = 0.001; HR: 2.38; 95% CI: 1.37-4.12; p = 0.002) in the chronic illness subpopulation. Growing evidence in the treatment of schizophrenia and schizoaffective disorder supports early intervention with long-acting antipsychotics. PMID- 28005579 TI - Spontaneous Activation of Antigen-presenting Cells by Genes Encoding Truncated Homo-Oligomerizing Derivatives of CD40. AB - The interaction between the CD40 receptor on antigen-presenting cells (APCs) and its trimeric ligand on CD4 T cells is essential for the initiation and progression of the adaptive immune response. Here we undertook to endow CD40 with the capacity to trigger spontaneous APC activation through ligand-independent oligomerization. To this end we exploited the GCN4 yeast transcriptional activator, which contains a leucine zipper DNA-binding motif that induces homophilic interactions. We incorporated GCN4 variants forming homodimers, trimers, or tetramers at the intracellular domain of human and mouse CD40 and replaced the extracellular portion with peptide-beta2m or other peptide tags. In parallel we examined similarly truncated CD40 monomers lacking a GCN4 motif. The oligomeric products appeared to arrange in high-molecular-weight aggregates and were considerably superior to the monomer in their ability to trigger nuclear factor kB signaling, substantiating the anticipated constitutively active (ca) phenotype. Cumulative results in human and mouse APC lines transfected with caCD40 mRNA revealed spontaneous upregulation of CD80, IL-1beta, TNFalpha, IL-6, and IL-12, which could be further enhanced by caTLR4 mRNA. In mouse bone-marrow derived dendritic cells caCD40 upregulated CD80, CD86, MHC-II, and IL-12 and in human monocyte-derived dendritic cells it elevated surface CD80, CD83 CD86, CCR7, and HLA-DR. Oligomeric products carrying the peptide-beta2m extracellular portion could support MHC-I presentation of the linked peptide up to 4 days post-mRNA transfection. These findings demonstrate that the expression of a single caCD40 derivative in APCs can exert multiple immunostimulatory effects, offering a new powerful tool in the design of gene-based cancer vaccines. PMID- 28005580 TI - UNILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION. AB - PURPOSE: To report a unilateral case of what is named bilateral diffuse uveal melanocytic proliferation and consider the consequences of this finding. METHODS: The ocular findings were investigated with multimodal imaging to include color fundus photography, fluorescein angiography, autofluorescence imaging, and enhanced depth imaging optical coherence tomography. RESULTS: A 66-year-old woman had a history of breast cancer 23 years previously that was treated and the patient was free of disease since. She developed a recent decrease in visual acuity in her left eye prompting referral. She was seen to have an alteration in the pigmentation of the posterior pole of the left eye with dispersed red placoid spots. Autofluorescence imaging showed nummular areas of absent autofluorescence signal, which corresponded to areas of hyperfluorescence during fluorescein angiography. The placoid spots were hyperautofluorescent and hypofluorescent in autofluorescence and fluorescein angiography, respectively. She had diffuse thickening and infiltration of the choroid in the left eye. Because of the ocular findings, the patient underwent a systemic evaluation and was found to have widely metastatic disease with an unknown primary cancer. No progression of disease was seen in the left eye over a 6-month follow-up, and the right eye never showed any abnormality, except for a modest cataract, by any means of examination. CONCLUSION: Bilateral uveal melanocytic proliferation has been attributed to a paraneoplastic process, allegedly from a factor in the IgG fraction of the serum. However, unilateral involvement suggests that there are other factors involved in disease manifestation. PMID- 28005581 TI - RETINAL DEEP CAPILLARY PLEXUS ISCHEMIA IN A CASE WITH ANTIPHOSPHOLIPID SYNDROME. AB - PURPOSE: To report visualization of a case of retinal deep capillary plexus ischemia with antiphospholipid syndrome. METHODS: A 53-year-old woman was referred with a 1-week history of sudden onset of decreased vision in the right eye. Her symptoms were evaluated by clinical examination, infrared reflectance, fundus autofluorescence, fluorescein angiography, spectral-domain optical coherence tomography, microperimetry, and multifocal electroretinography. RESULTS: The patient's visual acuity on presentation was 0.4 (Snellen) in the right eye and 0.7 in the left eye. Spectral-domain optical coherence tomography showed increased reflectivity of inner nuclear and inner plexiform layers of the right eye. Laboratory evaluation revealed abnormal titers of lupus anticoagulant antibodies. After 6 months, her visual acuity was finger counting at 1 m in the right eye and 0.4 in the left eye. Spectral-domain optical coherence tomographic image demonstrated a diffuse thinning of those retinal layers in the right eye. These findings are consistent with the clinical characteristics of retinal deep capillary ischemia in association with antiphospholipid syndrome. CONCLUSION: Deep capillary ischemia has some characteristic findings, and on spectral-domain optical coherence tomography, outcomes in conjunction with multimodal imaging are helpful for the diagnosis of the acute and the chronic stages of retinal deep capillary plexus ischemia. PMID- 28005582 TI - Analysis of Immunogenetic Factors in Idiosyncratic Drug-induced Liver Injury in the Pediatric Population. AB - OBJECTIVES: Idiosyncratic drug-induced liver injury is a multifactorial complex disease, in which the toxic potential of the drug, together with genetic and acquired factors and deficiencies in adaptive processes, which limit the extent of damage, can determine susceptibility, and make individuals unique in their development of hepatotoxicity. The aim of the present study is to analyse the genetic factors (human leukocyte antigen [HLA], cytokine polymorphisms, and killer cell immunoglobulin-like receptor [KIR] genotype) of children who experience an episode of drug-induced liver injury. PATIENTS AND METHODS: Prospective multicentre case-control study. The subjects included in the study were 30 paediatric patients-infants and children ages between 0 and 15 years and who presented possible liver disease associated with the intake of medicines, herbal products, drugs, or toxins. As a control group, 62 subjects were selected. RESULTS: Although HLAC0401 and HLADQB0603 may provide a hepatoprotective mechanism in the paediatric population, HLADQA0102 and HLA-DR12 are more commonly found in sick children and their presence may be related to liver damage. The KIR inhibitor KIR3DL1 was not present in any child in the control group. CONCLUSIONS: Polymorphisms that are low producers of interleukin-10 occur more frequently in children who have experienced hepatotoxicity. PMID- 28005583 TI - The Virtual Hydrostatic Test. AB - The hydrostatic test is used to help determine if there has been a live birth. Computed tomography (CT), with its ability to detect and localize air/gas in the body, offers a rapid, noninvasive tool for assessment.Four baby deaths (20 to 25 weeks' gestation) in which the hydrostatic test, radiographs, and CT were performed before autopsy are presented. In 2 cases, considered stillbirths, the lungs and liver sank, and there was no air seen in the lungs or gas in the liver on CT. Histology of the lungs showed collapsed alveoli. In 1 case, concluded to be a live birth, the lungs floated, the liver sank, and air was seen in the trachea, bronchi, and both lungs on CT. Histology of the lungs showed multiple areas of expanded alveoli. In 1 case, where both the lungs and liver floated, the CT showed gas widely distributed in the soft tissues. This reflected decomposition, and no conclusion could be made regarding birth status.Assessment of live birth is a critical and difficult decision. Postmortem CT offers another technique to consider in this determination, and it has significant advantages over radiography. Continued study and correlation with existing methods seem warranted. PMID- 28005584 TI - Postmortem Increase in Body Core Temperature: How Inaccurate We Can Be in Time Since Death Calculations. AB - Postmortem increase in body core temperature is a well-known phenomenon in forensic practice. Despite this, cases of reliably documented postmortem hyperthermia are rarely reported in the forensic literature, and it is still not clear how frequently postmortem hyperthermia occurs and in which cases we may it predict. In routine forensic practice, the standard course of body cooling is expected, and the prediction of normal body core temperature in the time of death is used for back-calculating the time of death by Henssge method. The unexpected rising in body core temperature may considerably misguide the estimation of time since death in the early postmortem period. We present a rare case of nonviolent death in the hospital with exactly recorded unusual elevation of body core temperature after death, although the body temperature shortly before the death was normal. In the presented case, the "standard" cooling of the body began up to 4 hours after death. PMID- 28005586 TI - Sudden Death From Ruptured Intracranial Vascular Malformations During Mechanical Asphyxia: A Domestic Violence Case Report. AB - Smothering and manual strangulation are not uncommon in domestic violence against women; however, no report on the combination of mechanical asphyxia and intracranial vascular malformations has been previously published. We report a middle-aged woman who was smothered and manually strangled by her husband and subsequently died from subarachnoid hemorrhage due to ruptured intracranial vascular malformations, rather than direct mechanical asphyxiation. Smothering and manual strangulation are considered provocative conditions for rupture and contributory causes of death. In this case study, we underline the importance of meticulous autopsy in cases of mechanical asphyxia and intracranial hemorrhage. Exclusion of underlying diseases that may have caused or contributed to death is also required, despite serious asphyxiation signs and neck injuries. Postmortem angiography is a valuable complement to autopsy to detect vascular pathology, with good prospects for further development in China. PMID- 28005585 TI - Penicillin-Induced Fulminant Myocarditis: A Case Report and Review of the Literature. AB - Drug-induced eosinophilic myocarditis is uncommon with few cases reported in the literature. It is a rare but potentially life-threatening disease.We report the case of an 11-year-old girl without medical history who developed an acute malaise and chills, followed by severe shortness of breath and a cardiopulmonary arrest 1 hour after an intramuscular injection of penicillin.At autopsy, we observed in the external examination nonspecific asphyxia signs, an injection mark, and the absence of traumatic signs. The organs examination showed a heart with a normal shape and a transmural, diffuse, tannish discoloration of the myocardium. The lungs were severely congested with a diffuse edema. Histological examination of the ventricular walls and septum revealed suggestive signs of eosinophilic myocarditis. Immunohistochemical analysis for the phenotypic characterization of the inflammatory cells revealed the positivity of the CD3 antibody without any stain for CD20.The diagnosis of fulminant myocarditis with an eosinophilic infiltrate was established as the cause of death. The manner of death was stated as natural. PMID- 28005587 TI - Diagnosis and Management of HELLP Syndrome Complicated by Liver Hematoma. AB - Subcapsular liver hematoma is a rare but potentially life-threatening complication of preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. It may present with nonspecific signs and symptoms, none of which are diagnostic, and can mimic pulmonary embolism of cholecystitis. There is no consensus on the management of subcapsular liver hematoma. Unruptured liver hematoma can be conservatively managed. When rupture occurs, surgical, endovascular approaches and, rarely, liver transplantation, may be required. Actual literature is scant and retrospective in nature. Data on follow-up, time to resolution and outcome of subsequent pregnancies are very limited. We here review the diagnosis and management of liver hematoma. PMID- 28005589 TI - Transvaginal Ultrasound for the Diagnosis of Abnormal Uterine Bleeding. AB - Transvaginal ultrasound is the first-line imaging test for the evaluation of abnormal uterine bleeding in both premenopausal and postmenopausal women. Transvaginal ultrasound can be used to diagnose structural causes of abnormal bleeding such as polyps, adenomyosis, leiomyomas, hyperplasia, and malignancy, and can also be beneficial in making the diagnosis of ovulatory dysfunction. Traditional 2-dimensional imaging is often enhanced by the addition of 3 dimension imaging with coronal reconstruction and saline infusion sonohysterography. In this article we discuss specific ultrasound findings and technical considerations useful in the diagnosis of abnormal uterine bleeding. PMID- 28005588 TI - Chronic Hypertension in Pregnancy: Diagnosis, Management, and Outcomes. AB - Chronic hypertension affects up to 5% of pregnancies. Women can be stratified into low-risk or high-risk chronic hypertension based on baseline laboratory and diagnostic work-up, comorbid conditions, and outcomes in prior pregnancies. Pregnancies complicated by chronic hypertension are at risk for increased adverse maternal and neonatal outcomes including superimposed preeclampsia, fetal growth restriction, placental abruption, and perinatal death. Mainstays of management include blood pressure control, close monitoring for development of superimposed preeclampsia, serial ultrasound assessment of fetal growth, and antenatal testing after 32 weeks. PMID- 28005590 TI - Low-Molecular-Weight Heparin for the Prevention of Placenta-mediated Pregnancy Complications. AB - During the past decade, prophylactic doses of low-molecular-weight heparin (LMWH) have been suggested to decrease the risk of placental-mediated complications. Herein, we review the prospective randomized trials that addressed the usefulness of LMWH in preventing placental-mediated complications in high-risk women. Inclusion criteria and results of these trials are heterogeneous. Unlike older trials (3 of 4 are single center), recent trials (all are multicenter) do not show beneficial effect of LMWH. There is certainly a need of complementary research before stating on the usefulness of LMWH in the prevention of placenta mediated pregnancy complications in women at high risk. PMID- 28005592 TI - Ultrasound in Assisted Reproductive Technologies and the First Trimester: Is There a Risk? AB - Ultrasound is routinely used in assisted reproductive technology for monitoring of follicular growth, oocyte retrieval and embryo transfer, as well as for the assessment of early embryonic development in the first 5 to 8 weeks of pregnancy. Ultrasound is a form of energy, which will affect live tissues it traverses (bioeffects) by being partially transformed into heat (thermal effect) and by alternating positive and negative pressures (nonthermal or mechanical effect). In the United States 2 indices (thermal and mechanical index) must be displayed on screen to provide the clinicians an indication of possible thermal and nonthermal changes. The thermal index and mechanical index should be kept below 1. The use of Doppler involves much higher levels of energy than B-mode gray scale 2 dimensional or 3-dimensional and special precautions are recommended when utilizing this modality. Information on susceptibility of the oocyte, prefertilization or postfertilization and the possible vulnerability of the very early fetus to such energy is very scarce. Data on whether there is a cumulative effect or an effect of recurrent exposure (eg, oocyte growth follow-up) do not exist. Ultrasound should be used only when medically indicated, for the shortest time and at the lowest intensity compatible with accurate diagnosis, especially when performing Doppler studies. In addition, because of lack of knowledge regarding bioeffects and safety among clinicians, educational effort is needed. PMID- 28005593 TI - The Normal Female Pelvis. AB - This article provides an overview of ultrasonographic evaluation of the normal female pelvis. Pertinent pelvic anatomy is reviewed, and there is an in-depth discussion of the normal appearance of the uterus and ovaries. In addition, the indications and technique for performing 3-dimensional imaging and saline-infused sonohysterography are covered. PMID- 28005594 TI - Controversies Regarding Diagnosis and Treatment of Severe Hypertension in Pregnancy. AB - The objective of management of severe hypertension in pregnancy is not for the return of normal blood pressure but rather reduction of blood pressure to a level associated with a decreased risk of end-organ damage including cerebral, cardiac, or renal dysfunction. The parenteral agents labetalol and hydralazine are currently the most widely recommended antihypertensive agents for acute reductions of elevated blood pressure related to preeclampsia. Overcorrection of blood pressure with any antihypertensive agent is possible resulting in reduced uteroplacental blood flow, but is more likely to be encountered in patients <32 weeks' gestation and in those whose fetuses have intrauterine growth retardation. PMID- 28005595 TI - Pelvic Floor Ultrasound: A Review. AB - Female pelvic floor dysfunction encompasses a number of prevalent conditions and includes pelvic organ prolapse, urinary and fecal incontinence, obstructed defecation, and sexual dysfunction. In most cases neither etiology nor pathophysiology are well understood. Imaging has great potential to enhance both research and clinical management capabilities, and to date this potential is underutilized. Of the available techniques such as x-ray, computed tomography, magnetic resonance imaging, and ultrasound, the latter is generally superior for pelvic floor imaging, especially in the form of perineal or translabial imaging. The technique is safe, simple, cheap, easily accessible and provides high spatial and temporal resolutions. PMID- 28005596 TI - Tubal Disease and Impersonators/Masqueraders. AB - Ultrasound is considered the first-line imaging modality in the evaluation of the fallopian tubes. This chapter reviews both the physiologic and pathologic sonographic findings of the fallopian tubes and how to recognize characteristic entities. Specifically, it describes how to use ultrasound techniques to distinguish between pathologic processes including chronic versus acute pelvic inflammatory disease, as well as infertility, torsion, and malignancy. It also describes how to employ modern ultrasound techniques, such as color Doppler, three-dimensional imaging, and salpingocentesis in clinical practice. PMID- 28005597 TI - Imaging of Adnexal Masses. AB - We review and emphasize the importance of gynecologic ultrasound scan for the preoperative evaluation of adnexal masses. Transvaginal ultrasound performed by a trained clinician has a good sensitivity and specificity for discriminating benign and malignant adnexal masses. In conjunction with a carefully obtained history, assessment of risk factors, a focused physical examination and serum markers, the information obtained by a gynecologic ultrasound evaluation can assist the clinician in the diagnosis and treatment of adnexal masses. PMID- 28005598 TI - Cancer survival in Latin countries: new insight provided by a systematic modelling of the cancer-specific mortality rate. PMID- 28005599 TI - Trends in net survival from 15 cancers in six European Latin countries: the SUDCAN population-based study material. AB - The aim of the SUDCAN collaborative study was to compare the net survival from 15 cancers diagnosed in 2000-2004 in six European Latin countries and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis from 1992 to 2004 in France, Italy, Spain, and Switzerland, and from 2000 to 2004 in Belgium and Portugal. This paper presents a detailed description of the data analyzed and quality indicators. Incident cases from Belgium, France, Italy, Portugal, Spain, and Switzerland were retrieved from 56 general or specialized population-based cancer registries that participated in the EUROCARE 5 database. Fifteen cancer sites were analyzed. The data were checked according to the EUROCARE protocol. The percentages of excluded cases, cases based on death certificate only, cases lost to follow-up at 5 years after diagnosis, and the proportions of microscopically verified cases were evaluated across countries and cancer sites. Data exclusions for major flaws were negligible. Cases based on death-certificate only were quite rare, except for some poor-prognosis cancers in some countries. The site-specific proportions of microscopically verified cases were generally high, but slightly lower in Italy than elsewhere. The percentage of cases lost to follow-up at 5 years after diagnosis was generally low. The net survival analyses in 2000-2004 included 873 314 tumors, whereas trend analyses included 1 426 004 tumors. The quality of the data analyzed was generally good. In fact, the analyzed data have been already checked and accepted for EUROCARE-5. However, slight differences in quality indexes, for some cancers, should be kept in mind in the interpretation of survival comparisons across countries. PMID- 28005600 TI - New insights into survival trend analyses in cancer population-based studies: the SUDCAN methodology. AB - The main objective of the SUDCAN study was to compare, for 15 cancer sites, the trends in net survival and excess mortality rates from cancer 5 years after diagnosis between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. The study period ranged from 6 (Portugal, 2000-2005) to 18 years (Switzerland, 1989 2007). Trend analyses were carried out separately for each country and cancer site; the number of cases ranged from 1500 to 104 000 cases. We developed an original flexible excess rate modelling strategy that accounts for the continuous effects of age, year of diagnosis, time since diagnosis and their interactions. Nineteen models were constructed; they differed in the modelling of the effect of the year of diagnosis in terms of linearity, proportionality and interaction with age. The final model was chosen according to the Akaike Information Criterion. The fit was assessed graphically by comparing model estimates versus nonparametric (Pohar-Perme) net survival estimates. Out of the 90 analyses carried out, the effect of the year of diagnosis on the excess mortality rate depended on age in 61 and was nonproportional in 64; it was nonlinear in 27 out of the 75 analyses where this effect was considered. The model fit was overall satisfactory. We analysed successfully 15 cancer sites in six countries. The refined methodology proved necessary for detailed trend analyses. It is hoped that three-dimensional parametric modelling will be used more widely in net survival trend studies as it has major advantages over stratified analyses. PMID- 28005601 TI - Trends in net survival from head and neck cancer in six European Latin countries: results from the SUDCAN population-based study. AB - The aim of the SUDCAN collaborative study was to compare the trends in 1- and 5 year net survival and the trends in the dynamics of the excess mortality rates in head and neck cancers between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. First, the net survival was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modelling. There were significant differences between countries in 5-year age-standardized net survivals over the 2000-2004 period, ranging from 33 to 34% in France and Portugal from 42 to 44% in Switzerland and Italy, respectively. The age standardized net survival improved considerably from 1992 to 2004 in Italy, Spain and Switzerland, but not in France because of lack of improvement in the elderly. The increase in net survival was linked to a decrease in the excess mortality rate up to 3-4 years after diagnosis. The net survival from head and neck cancers improved over the study period, but significant differences were still observed in 2004. Differences in sex ratio and anatomical distribution contributed only partially towards these disparities. Differences in stage at diagnosis, time to treatment and/or proportion of human papillomavirus-related cases are also probably involved in the survival disparities observed. Overall, the prognosis of these tumours remains poor. PMID- 28005602 TI - Trends in net survival from esophageal cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Esophageal cancer represents a major clinical challenge because of its poor prognosis. The aim of the SUDCAN collaborative study was to compare the net survival from esophageal cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) and report the trends in net survival and the dynamics of excess mortality rates (EMRs) up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results were reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. These trend analyses were carried out using a flexible excess rate modeling strategy. There were some differences between countries in age-standardized net survival (2000-2004). The 5-year net survival ranged between 9 (Spain) and 21% (Belgium). The small increase in net survival from 1992 and 2004 was mostly observed at ages 55 and 65, but was less marked at age 75. There was a slight decrease in EMR between 1992 and 2004 until ~24 months after diagnosis. Beyond this period, the decrease in the EMR was moderate and the same in all countries irrespective of the year of diagnosis. Some improvement in the 5-year net survival was observed in all countries limited to the 24 months after diagnosis. However, survival differences between countries persisted. Further improvement is expected from innovative treatments. PMID- 28005604 TI - Trends in net survival from colon cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Colon cancer represents a major public health issue. The aim of the SUDCAN collaborative study was to compare the net survival from colon cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) and provide trends in net survival and dynamics of the excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results were reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modeling strategy. There were few differences between countries in age-standardized net survivals (2000-2004). During the 2000-2004 period, the 5-year net survival ranged between 57 (Spain and Portugal) and 61% (Belgium and Switzerland). The age-standardized survival at 1 and 5 years after diagnosis increased between 1992 and 2004. This increase was observed at ages 60 and 70, but was less marked at 80. This increase was linked to a marked decrease in the excess mortality rate between 1992 and 2004 until 18 months after diagnosis. Beyond this period, the decrease in the excess mortality rates among countries was modest and nearly the same whatever the year of diagnosis. There were minor differences in survival after colon cancer between European Latin countries. A considerable improvement in the 5-year net survival was observed in all countries, but the gain was mainly limited to the first 18 months after diagnosis. Further improvements are expected through the implementation of mass screening programs. PMID- 28005603 TI - Trends in net survival from stomach cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Gastric cancers are a clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from gastric cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and explore the trends in net survival and in the dynamics of the excess mortality rates (EMRs) up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These trend analyses were carried out using a flexible excess rate modelling strategy. There were little differences between countries in age-standardized net survival for stomach cancer (2000-2004). The 5-year net survival ranged between 26 (Spain) and 32% (Italy). There was a small increase in the age-standardized net survival at 1 year between 1992 and 2004. The increase was also observed in the 5-year net survival, except in France, where the increase was less marked. A slight decrease in the EMR between 1992 and 2004 was limited to the 24 months after diagnosis. In addition, the decrease in the EMR was the same whatever the year of diagnosis. There were minor differences in survival from stomach cancer between European Latin countries. A slight improvement in the 5-year net survival was observed in all countries and the major gain was observed during the 24 months after diagnosis. Development of innovative treatments is needed to improve the prognosis. PMID- 28005605 TI - Trends in net survival from rectal cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Rectal cancer is a common and serious disease. The aim of the SUDCAN collaborative study was to compare the net survival from rectal cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study-period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modeling strategy. There were some differences between countries in age-standardized net survivals (2000-2004). The 5-year survival ranged from 55% (Portugal) to 62% (Belgium). There was an increase in age-standardized survival rates between 1992 and 2004 as observed at 1 and 5 years. This increase was observed in the 60 and 70-year age groups, but was less marked in the 80-year age group. This was related to a decrease in the excess mortality rates between 1992 and 2004, until ~24 months after diagnosis in France and Switzerland, whereas it was continuous over the entire study period in Italy and Spain. Considerable improvements in survival from rectal cancer have been achieved. Further improvements are expected through better adherence to the guidelines and the implementation of mass screening. PMID- 28005606 TI - Trends in net survival from liver cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Liver cancer represents a major clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from liver cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates (EMRs) up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These trend analyses were carried out using a flexible excess-rate modeling strategy. There were little differences between the six countries in the 5-year age standardized net survival (2000-2004): it ranged from 13% (France and Portugal) to 16% (Belgium). An increase in the net age-standardized survival was observed in all countries between 1992 and 2004, both at 1 year and at 5 years (the highest in Spain, the lowest in France). Generally, patients aged 60 years showed the highest increase. There was a progressive decrease in EMR over the 5-year- period following diagnosis. The study confirmed the poor prognosis of liver cancer. Innovative treatments might improve the prognosis as well as preventive screening of cirrhotic patients with good liver function. Efforts are also needed to improve registration practices. PMID- 28005607 TI - Trends in net survival from pancreatic cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Pancreatic cancer represents a real clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from pancreatic cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results were reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modelling strategy. There were little differences between countries in age-standardized net survivals (2000-2004). The 5-year net survival was poor (range: 6-10%). The changes in net survival from 1992 to 2004 were mostly related to early survival and patients aged 60 years. A slight decrease in the excess mortality rate between 1992 and 2004 was observed, limited to the 18 months after diagnosis. This study confirmed that, despite some improvement, survival from pancreatic cancer is still poor throughout European Latin countries. The major improvements in clinical imaging did not result in improvements in prognosis. Development of truly innovative treatments is highly needed to improve prognosis. PMID- 28005608 TI - Trends in net survival lung cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Survival is a key measure of the effectiveness of a healthcare system. European Latin countries have some similarities in their health systems; it is thus interesting to examine their differences in survival from cancer, here, lung cancer. The aim of the SUDCAN collaborative study was to compare the trends in the 1- and 5-year net survival from lung cancer and the trends in the excess mortality rates between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. First, the net survival was studied over the 2000-2004 period using Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modelling. Overall, the 1-year net survival from lung cancer ranged between 36 (Spain) and 43% (Belgium and Switzerland) and the 5-year net survival ranged between 11 (Spain) and 15% (Belgium and Switzerland). Between 1992 and 2004, the age-standardized survival increased considerably at 1 year, but increased less at 5 years after diagnosis. This increase was observed at ages 60 and 70, but was less obvious at age 80. There was little difference in net survival from lung cancer between European Latin countries, particularly in the more recent years. However, survival was slightly lower in Spain and Portugal than in France, Italy, Belgium and Switzerland. High-resolution studies with data on treatment, stage at diagnosis and comorbidities are needed to understand the reasons for these differences. PMID- 28005609 TI - Trends in net survival from skin malignant melanoma in six European Latin countries: results from the SUDCAN population-based study. AB - In Europe as a whole, survival from skin malignant melanoma (SMM) has increased constantly since the 1980s. The aim of the SUDCAN collaborative study was to compare the trends in the 5-year net survival from SMM and in related excess mortality rate between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland). The data were extracted from the EUROCARE-5 database (end of follow-up: 01 January 2009). First, the net survival was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modeling. Over the 2000-2004 period, the 5-year net survival from SMM ranged from 79 (Portugal) to 90% (Switzerland). In all countries, net survival was higher in women versus men and in young versus old age groups. From 1992 to 2004, the 5 year net survival increased the most in the countries with the lowest survivals in 1992 (+9% in Italy and Spain vs. +2% in Switzerland or +4% in France). The differences between countries decreased between 1992 and 2004. Although survival increased to a lower or higher extent in all countries during the period studied, significant differences in net survival from SMM persisted among the six countries studied. Health policies should mainly enhance early diagnosis by increasing public awareness and with screening campaigns. Furthermore, new immunotherapies, which will be approved soon hopefully, should also be used to improve the outcomes of SMM treatment. PMID- 28005610 TI - Trends in net survival from breast cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Survival from breast cancer (BC) is influenced by the timeliness of diagnosis and appropriateness of treatment, and may constitute a measure of the global effectiveness of a healthcare system. As the healthcare systems of several European Latin countries have some similarities, the search for differences in cancer survival may provide interesting information on the efficacy of these systems. The SUDCAN study is a collaboration between the Group for Epidemiology and Cancer Registration in Latin language countries (GRELL) and EUROCARE. BC data from six countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) were extracted from the EUROCARE-5 database. First, we focus on 1- and 5-year age standardized net survival (NS) from BC by country over the 2000-2004 period. Then, trends in NS over the 1989-2004 period and changes in the pattern of cancer excess mortality rate (EMR) up to 5 years after diagnosis were examined using a multivariate EMR model. There were little differences in age-standardized NS from BC. Over the 2000-2004 period, the 5-year survival ranged between 82 (Spain, Belgium, and Portugal) and 86% (France). There was an increase in age standardized survival between 1989 and 2004 at 1 year as well as at 5 years. This increase was observed at all ages and in all countries. There was a decrease in the cancer EMR both immediately after diagnosis and by the second and third year of follow-up. There were only minor differences in survival from BC between European Latin countries. The general improvement in NS is presumably because of advances in early cancer diagnosis and improvements in treatment. PMID- 28005611 TI - Trends in net survival from cervical cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Cancer survival is a key measure of the effectiveness of a healthcare system. As differences in healthcare systems are present among European Latin countries, it is of interest to look specifically at their similarities and differences in terms of cancer survival. Incident cases were extracted from the EUROCARE-V database for France, Italy, Spain, Switzerland, Portugal, and Belgium. One and 5 year net survivals (NS) were calculated for the period 2000-2004 using the Pohar Perme estimator. Trends in NS over the 1992-2004 period and changes in the pattern of cancer excess mortality rate until 5 years after diagnosis were examined using a multivariate excess mortality rate model. There were moderate differences in age-standardized NS between countries (5-year NS range: 83-88%), but significant differences in the age groups 15-54 and 55-74 years (at 5 years up to +16 and +18% between any two countries). During the study period, excess mortality and NS improved in Italy, Spain, and Portugal. In Italy and Portugal, this improvement was slightly similar at ages 40, 55, and 70 whereas, in Spain, there was a sharp increase in NS at age 55. Because of this improvement, excess mortality and NS were similar in all six countries in 2004. Excess mortality peaked around 1 year after diagnosis in the youngest ages, but decreased gradually in the elderly. Detailed analyses showed differences in excess mortality and NS from cervical cancer between European Latin countries. However, these differences decreased over the study period because of the considerable improvement in Spain, Italy, and Portugal. PMID- 28005612 TI - Trends in net survival from corpus uteri cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Corpus uteri cancer is the most common gynaecological cancer in women in Europe, but presents a relatively good prognosis. There were two main objectives in this study: estimate differences between countries in age-standardized net survival (NS) at 1 and 5 years in 2000-2004 and evaluate time trends in NS and excess mortality rates in 1992-2004. Data on corpus uteri malignant tumours (International Classification of Diseases for Oncology, third ed.: C54) were extracted from the EUROCARE database for six European Latin countries: Belgium, France, Italy, Portugal, Spain and Switzerland. NS was estimated for each country using the nonparametric estimator proposed by Pohar-Perme. Trends in NS and excess mortality rates up to 5 years after diagnosis were assessed using a multivariable parametric flexible modelling. The study analysed 25 508 cases for the first objective and 43 550 for the second. Age-standardized 1-year NS ranged from 88% (Portugal and Spain) to 93% (Switzerland), whereas 5-year survival ranged between 72% (Portugal) and 79% (Belgium and Switzerland). From 1992 to 2004, the NS increased in all countries with available information on this period (France, Italy, Spain and Switzerland). Also, in Belgium and Portugal, there was an increase in NS between 2000 and 2004. Improvements in survival were more evident for older ages (75 years). There were some differences in NS between the countries studied (maximum of 5% at 1 year and 7% at 5 years). The NS improved in all countries during the period studied and the differences between countries narrowed. PMID- 28005614 TI - Trends in net survival from prostate cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Cancer survival is a key measure of the effectiveness of a health-care system. European Latin countries have some differences in their health system; therefore, it is of interest to compare them in terms of survival from cancer. Prostate cancer data from six countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) were extracted from the EUROCARE-5 database (end of follow-up: 1 January 2009). First, the net survival (NS) was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Trends in NS over the 1989-2004 period and changes in the pattern of cancer excess mortality rate until 5 years after the diagnosis were examined using a multivariate excess mortality rate model. A striking increase in survival from prostate cancer occurred in European Latin countries at all ages studied. In the last period of the study, there was little difference in age-standardized NSs from prostate cancer between the six countries. The trends of the survival followed those of the incidence (except in Spain in the elderly); the increases in incidence were the highest at ages 60-70 years and, in the elderly (around 80 years), the incidence did not increase in Switzerland. The increases in NS can mainly be explained by lead-time and overdiagnosis effects. The epidemiological interpretability of the changes in prostate cancer survival in Latin countries is strongly compromised by the biases inherent to the extensive prostate-specific antigen testing. PMID- 28005613 TI - Trends in net survival from ovarian cancer in six European Latin countries: results from the SUDCAN population-based study. AB - European Latin countries have some similarities in their health systems. It is thus interesting to look at their differences in cancer survival (here, ovarian cancer) through monitoring of specific indicators of quality care. The aim of this SUDCAN collaborative study was to compare the trends in 1 and 5-year net survival from ovarian cancer and the trends in the excess mortality rates between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. First, the net survival was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland, and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modelling. Over the period 2000-2004, there were slight differences in the 5-year age-standardized net survivals from ovarian cancer; they ranged from 36% in Spain to 42% in Belgium. Net survival was much higher in young than in old age groups, but this difference was more marked in Spain and less marked in France. Between 1992 and 2004, the net survival increased in all countries, mainly in young and middle-aged women. However, the differences in 5-year net survival between these countries were larger in 2004 than in 1992. Slight differences were observed in survival from ovarian cancer between the six European Latin countries. A considerable improvement in survival was observed in all countries, especially in young and middle-aged women. This study highlights the need for further monitoring of ovarian cancer outcomes. PMID- 28005615 TI - Trends in net survival from kidney cancer in six European Latin countries: results from the SUDCAN population-based study. AB - Kidney cancer is a frequent malignant disease. To date, there is no evidence on the effectiveness of early detection and, in most cases, surgery represents the only standard treatment. So far, there is no standardized therapy for localized and locally advanced renal tumors; however, the recent introduction of target therapy has significantly improved the prognosis of metastatic disease. Therefore, survival differences in Europe are deemed to involve differences in diagnostic and therapeutic approaches. The aim of the SUDCAN collaborative study was to compare the net survival from kidney cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analysis, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain, and Switzerland, and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modeling strategy. In 2000-2004, the 5-year net survival ranged between 59% (Spain) and 67% (France and Italy) in men and between 60% (Spain) and 73% (Portugal) in women. There was an increase in the age standardized net survival between 1992 and 2004 at 1 year, as well as at 5 years, in all age groups and countries. Irrespective of the year of diagnosis, the excess mortality rate decreased with time elapsed since diagnosis. There are some differences in survival from kidney cancer between European Latin countries, but a considerable improvement was observed in most countries. PMID- 28005616 TI - Five-Year Reoperation Rates of 2-Level Lumbar Total Disk Replacement Versus Fusion: Results of a Prospective, Randomized Clinical Trial. AB - STUDY DESIGN: Long-term analysis of prospective randomized clinical trial data. SUMMARY OF BACKGROUND DATA: Lumbar total disk replacement (TDR) has been found to have equivalent or superior clinical outcomes compared with fusion and decreased radiographic incidence of adjacent level degeneration in single-level cases. OBJECTIVE: The purpose of this particular analysis was to determine the incidence and risk factors for secondary surgery in patients treated with TDR or circumferential fusion at 2 contiguous levels of the lumbar spine. METHODS: A total of 229 patients were treated and randomized to receive either TDR or circumferential fusion to treat degenerative disk disease at 2 contiguous levels between L3 and S1 (TDR, n=161; fusion, n=68). RESULTS: Overall, at final 5-year follow-up, 9.6% of subjects underwent a secondary surgery in this study. The overall rate of adjacent segment disease was 3.5% (8/229). At 5 years, the percentage of subjects undergoing secondary surgeries was significantly lower in the TDR group versus fusion (5.6% vs. 19.1%, P=0.0027).Most secondary surgeries (65%, 17/26) occurred at the index levels. Index level secondary surgeries were most common in the fusion cohort (16.2%, 11/68 subjects) versus TDR (3.1%, 5/161 subjects, P=0.0009). There no statistically significant difference in the adjacent level reoperation rate between TDR (2.5%, 4/161) and fusion (5.9%, 4/68). The most common reason for index levels reoperation was instrumentation removal (n=9). Excluding the instrumentation removals, there was not a significant difference between the treatments in index level reoperations or in reoperations overall. CONCLUSIONS: There were significantly fewer reoperations in TDR patients compared with fusion patients. However, most of the secondary surgeries were instrumentation removal in the fusion cohort. Discounting the instrumentation removals, there was no significant difference in reoperations between TDR and fusion. These results are indicative that lumbar TDR is noninferior to fusion. PMID- 28005617 TI - Lateral Extracavitary Approach Versus Posterior Extensive Circumferential Decompression in the Treatment of Complicated Thoracic and Lumbar Tuberculous Spondylitis. AB - OBJECTIVES AND STUDY DESIGN: The aim of this study was to retrospectively evaluate 45 patients operated upon either by posterior extensive circumferential decompression (PECD) or by the lateral extracavitary (LEC) technique and compare the clinical, radiologic, laboratory, and functional outcomes. SUMMARY OF BACKGROUND: The debate continues on the best decompression-fusion technique for treating complicated spinal tuberculosis. In recent times, the advantages of combined surgery have been successfully achieved using the 1-stage salvage technique, with enough accessibility to all 3 spinal columns. MATERIALS AND METHODS: From January 2011 to December 2013, 51 patients with complicated spinal tuberculous were surgically treated at our department. After gaining the approval of the local ethics committee, 45 patients and their records were available for evaluation. The patients were divided into 2 groups. Group I included 23 patients treated with PECD and group II included 22 patients treated with LEC. Two authors and an independent observer performed the final clinical assessment by means of clinical examination and by using the Visual Analog Scale and Oswestery Disability Index for determining pain, disability, and quality of life. The radiographs were reviewed independently by 3 authors and a radiologist for fusion, kyphotic angle, and angle loss rate. Neurological assessment using the American Spinal Injury Association motor index was performed by 2 authors and a neurologist independently. RESULTS: The mean follow-up period was 36+/-5.5 months. In all patients, local symptoms were relieved significantly postoperatively. There were no major complications in this series. Three patients contracted superficial wound infection and 2 developed intercostal neuralgia. Both complications resolved uneventfully and did not influence the outcome. Solid interbody fusion was diagnosed in 43 cases (95.6%). Deformity correction and neurological recovery were significantly improved in both groups (P<0.001). PECD showed better results than LEC. CONCLUSIONS: Both procedures attained good results for maintained deformity correction, bony fusion, spinal cord decompression, and neurological improvement in complicated tuberculous spondylitis. However, PECD may be superior to LEC. PMID- 28005618 TI - The impaired and/or disabled anesthesiologist. AB - PURPOSE OF REVIEW: Impairment and/or disability resulting from any of a number of etiologies will afflict a significant number of anesthesiologists at some point during their career. The impaired anesthesiologist can be difficult to identify and challenging to manage. Questions will arise as to if, how, and when colleagues, family members, or friends should intercede if significant impairment is suspected.This review will examine the common sources of impairment among anesthesiologists and the professional implications of these conditions. We will discuss the obligations of an anesthesiologist and his/her colleagues when there is sufficient suspicion that he/she might be impaired. RECENT FINDINGS: Substance use disorder remains one of the commonest sources of impairment among both resident and attending anesthesiologists. Other common etiologies of impairment include various physical ailments, major psychiatric disorders, especially depression and burnout, and age related dementia. Many regulatory organizations, healthcare systems, and state licensing agencies have developed programmes and protocols with which to identify and direct into treatment those suspected of significant impairment. SUMMARY: Some degree of impairment will occur to one third of anesthesiologists during the course of their career. It is important to understand how such impairments might impact the safe practice of anesthesiology. PMID- 28005619 TI - Comparison of Survival Benefits of Combined Chemotherapy and Radiotherapy Versus Chemotherapy Alone for Uterine Serous Carcinoma: A Meta-analysis. AB - OBJECTIVE: To date, there is no convincing evidence comparing the impact of combined chemotherapy and radiotherapy with chemotherapy alone in postoperative uterine serous carcinoma (USC), which remains an unclear issue. We conducted a meta-analysis assessing the impact of combined chemotherapy and radiotherapy compared to chemotherapy alone on overall survival in postoperative USC. METHODS: A comprehensive search was performed in the databases of EMBASE, PubMed, Web of Science, and Cochrane Library from inception to March 2016. Studies comparing survival among patients who underwent combined chemotherapy and radiotherapy or chemotherapy alone after surgery for USC were included. Quality assessments were carried out by the Newcastle-Ottawa Scale. Hazard ratio (HR) for overall survival was extracted, and a random-effects model was used for pooled analysis. Publication bias was assessed using both funnel plot and the Egger regression test. Statistical analyses were performed using Stata version 13.0 software. RESULT: Nine retrospective studies with relatively high quality containing 9354 patients were included for the final meta-analysis. The pooled results demonstrated that combined chemotherapy and radiotherapy significantly reduced the risk of death (HR, 0.72; P < 0.0001) compared to chemotherapy alone with a low heterogeneity (I = 21.0%, P = 0.256). Subgroup analyses indicated that calculating HR by unadjusted method may cause the heterogeneity among studies. Exploratory analyses showed that either patients with early stage disease (HR, 0.73; P = 0.011) or advanced stage disease (HR, 0.80; P < 0.0001) have survival benefits from combined chemotherapy and radiotherapy. No significant evidence of publication bias was found. CONCLUSIONS: This is the first meta-analysis examining the role of combined chemotherapy and radiotherapy compared to chemotherapy alone in USC. Our results suggest the potential survival benefits of combined chemotherapy and radiotherapy. Further studies, preferably randomized clinical trials, are needed to confirm our results. PMID- 28005620 TI - Perioperative Outcomes for Laparotomy Compared to Robotic Surgical Staging of Endometrial Cancer in the Elderly: A Retrospective Cohort. PMID- 28005621 TI - The Ram Relaxation Technique: A Painless Biopsy Method. A Shave Biopsy Approach Without Injectable Anesthesia or Needles. AB - BACKGROUND: Shave skin biopsies are essential procedures wherein physicians diagnose dermatologic lesions. The protocol for skin biopsies entails a lidocaine/epinephrine injection. This study suggests an alternative, novel method of performing a shave biopsy that avoids pain, needles, and injectable anesthesia, termed the Ram Relaxation Technique (RRT). OBJECTIVE: To present a new technique that physicians may chose to form when faced with dermatological biopsies that are painless and needle free. PATIENTS AND METHODS: Randomly selected, patients were presented to the authors' offices with abnormal skin lesions that required a shave biopsy. The patients were offered the choice of having an anesthetic injection (1% lidocaine, 1:100,000 epinephrine) or the alternative method (RRT) before the biopsy. Twenty patients (n = 20, 10 men, 10 women) chose the alternative method (RRT) and were the focus of this study. These patients who chose RRT were asked to scale their pain on a scale of 0 to 10 (0 = no pain, 1-3 = mild, 4-6 = moderate, and 7-10 = severe pain). RESULTS: Fourteen of the 20 patients stated that they experienced no pain (0), 5 experienced mild pain, and 1 patient experienced moderate pain. CONCLUSION: This study demonstrates an alternative and nearly pain-free method for superficial shave biopsies of the skin for certain patients in the appropriate clinical setting with the appropriate, superficial papule lesions. Dermis lesions, melanocytic lesions, and macular lesions are not ideal candidates given the risk for misdiagnosis, and more pain, respectively. PMID- 28005622 TI - Laser Safety in Isotretinoin Use: A Survey of Expert Opinion and Practice. AB - BACKGROUND: Reports of poor wound healing in the setting of isotretinoin treatment have created a conservative standard of care in which laser and phototherapy treatment of patients receiving isotretinoin is relatively contraindicated. OBJECTIVE: A survey of 220 nationally recognized experts in cutaneous laser surgery was conducted to evaluate physician experience and opinion pertaining to laser and light procedures in patients treated with isotretinoin, including perceived risk and actual complications. RESULTS: There was a 42% response rate. Seventy-six percent of respondents have never seen in their own clinical practices any cases of complications arising in patients treated with laser while receiving isotretinoin or within 6 months of completing a course of therapy. Almost half of respondents have treated patients in this subpopulation with laser, although only a small minority have done so with ablative devices. Common concerns among respondents regarding isotretinoin patients are the risks of poor wound healing and scarring, but the most often reported concern is medicolegal risk (74%). CONCLUSION: It would seem that the risk of performing laser procedures on patients receiving isotretinoin or having recently completed a course, as estimated and observed by cutaneous laser experts, is lower than the currently perceived risk among the general medical community. PMID- 28005623 TI - A 12-Month Follow-up, Randomized Comparison of Effectiveness and Safety of Two Hyaluronic Acid Fillers for Treatment of Severe Nasolabial Folds. AB - BACKGROUND: Hyaluronic acid (HA) filler injection is an increasingly popular aesthetic procedure. OBJECTIVE: To compare the effectiveness and safety of two HA fillers (HAED and HAPER) for the treatment of severe nasolabial folds (NLFs). MATERIALS AND METHODS: This was an evaluator-blinded and subject-blinded split face study. At baseline, HAED or HAPER was randomly assigned to the left or right NLF. The follow-up period was 12 months. Effectiveness was assessed using the wrinkle severity rating scale (WSRS) and subject preference. Safety was assessed by adverse events and local tolerability symptoms recorded by subjects during 3 weeks after the treatment. RESULTS: At 6 months, HAED was noninferior to HAPER (assessed by mean change from baseline in WSRS score). There was a significant difference in mean WSRS score change from baseline in favor of HAED at 3 to 12 months, and a majority of subjects preferred HAED over HAPER at 12 months. However, the overall responder rate was similar between products, and it remained high throughout the study. At 12 months, approximately 80% of subjects were still responders. Both products were well tolerated and associated with a few treatment related adverse events. CONCLUSION: To conclude, HAED was at least as effective and well tolerated for the treatment of severe NLFs as HAPER. PMID- 28005624 TI - Dermoscopic Findings in Porocarcinoma. PMID- 28005625 TI - A Prospective Study of Axillary Hair Reduction in Patients Treated With Microwave Technology. AB - BACKGROUND: Removing unwanted body hair is a growing trend in society today, and there are many laser-based devices for hair reduction. There are some limitations to those methods, including the lack of efficacy for lighter color hair. OBJECTIVE: The objective was to quantify hair reduction in the axillae after treatment with a noninvasive microwave energy device. MATERIALS AND METHODS: A prospective, multicenter study was performed at 3 private dermatology clinics. Fifty-six adult subjects seeking axillary hair reduction were enrolled and treated with the device in 1 or 2 treatment sessions 3 months apart at various energy levels, and followed for 12 months. The primary analysis was monitoring reduction of hair counts from baseline to follow-up visits. A subject assessment of overall satisfaction, odor ratings, and sweat reduction ratings was provided at follow-up visits. RESULTS: Fifty-six subjects received treatment, with an average total underarm hair reduction of approximately 70% for both light and dark hair. Percentage of patients with hair reduction of 30% or more was significantly higher than 50% at all follow-up visits. Half of treated subjects reported expected mild transient post-treatment effects such as localized edema, discomfort, and bruising. Other reported events were mild. CONCLUSION: This clinical study provides evidence for safe and permanent axillary hair reduction, showing stable average reduction that lasted through the year of follow-up. Most notably, the study has shown the treatment's efficacy for reduction of light colored axillary hair. PMID- 28005626 TI - Vulvar Varicosities: A Review. AB - BACKGROUND: Vulvar varicosities (VV) are dilated and tortuous veins occurring within the external female genitalia. Patients may seek treatment of these varices for both medical and cosmetic purposes. In some patients, VV may be associated with a chronic pelvic pain syndrome called pelvic congestion syndrome (PCS). OBJECTIVE: To review the English language literature on VV in both pregnant and nonpregnant women. MATERIALS AND METHODS: A literature search pertaining to vulvar varicosities and PCS was performed using PubMed and Google Scholar databases. RESULTS: There is an overall paucity of literature discussing VV, particularly in nonpregnant women without PCS. Management options for VV include compression, sclerotherapy, embolization, and surgical ligation. Treatment can be dependent on the coexistence of pelvic or leg varicosities and may require referral to a vein specialist for advanced imaging techniques and procedures. Direct sclerotherapy to VV may not provide adequate treatment if pelvic or leg varices are also present. CONCLUSION: In women with persistent VV, imaging studies should be obtained before treatment to evaluate the surrounding venous anatomy of the pelvis and leg, as the results often affect the treatment approach. Patients presenting with VV and chronic pelvic pain should be evaluated for PCS. PMID- 28005627 TI - Needling-Assisted Drug Delivery: Enhanced Response to Ingenol Mebutate After Microneedling. PMID- 28005628 TI - Effective Technique for Periosteal Removal During Mohs Micrographic Surgery. PMID- 28005629 TI - Reconstruction of the Nipple-Areola Complex After Mohs Micrographic Surgery. PMID- 28005630 TI - Association Between Scalp Laxity, Elasticity, and Glidability and Donor Strip Scar Width in Hair Transplantation and a New Elasticity Measuring Method. AB - BACKGROUND: Hair transplantation requires precise evaluation of donor site laxity, elasticity, and glidability. OBJECTIVE: The purpose of this study was to examine the relationship between donor strip scar width and preoperative laxity, elasticity, and glidability. MATERIALS AND METHODS: Preoperative measurements of scalp laxity, elasticity, and glidability and of donor site scar width 10 months postoperatively were evaluated in 88 patients who underwent hair transplantation with strip harvesting. Elasticity was measured by firmly pressing the scalp with the fingertips of one hand at 2 points to restrict dermis movement while stretching the skin with the other hand. Glidability was calculated as laxity minus elasticity. RESULTS: Scar width positively correlated with laxity (p < .01) and elasticity (p < .05) but had no relationship with glidability. There was a significant difference between patients in the upper 30th percentile of elasticity (>=10 mm) versus others (<10 mm) in scar width. CONCLUSION: Scalp laxity, elasticity, and glidability are of great clinical importance in hair transplantation. The authors' novel method of measuring elasticity will assist surgeons in predicting donor site scar width. PMID- 28005631 TI - Comparison of Foam Sclerotherapy Alone or Combined With Stripping of the Great Saphenous Vein for Treating Varicose Veins. AB - BACKGROUND: Varicose veins (VVs) have a substantial impact on patients' quality of life. OBJECTIVE: The study aimed to retrospectively compare the short-term clinical outcomes of 2 treatment methods for VVs, namely high ligation and stripping (HL/S) of the great saphenous vein combined with foam sclerotherapy (FS), and FS alone. MATERIALS AND METHODS: Totally, 180 patients with VVs were included and treated with FS alone or HL/S+FS. Assessments included the first injection efficacy, postoperative status, complications, operative time, and recovery time. A follow-up duration was performed. Patient satisfaction was also recorded. RESULTS: No significant differences in the complete occlusion rate of the varicose tributaries, as well as in postoperative complications, were found between the treatment groups (p > 0.05). The complete occlusion rates of the varicose tributaries in the FS and HL/S+FS groups were 90% and 90%, respectively. Although mild phlebitis and local pigmentation were found in both groups, they disappeared during the follow-up period. Operative and recovery times were higher in the HL/S+FS group than in the FS group. CONCLUSION: The HL/S+FS and FS alone showed equivalent efficacy for treating patients with VVs. Considering the increased operative and recovery times, FS alone is recommended to treat VVs in clinical practice. PMID- 28005632 TI - ASSOCIATION BETWEEN THE VITREOMACULAR INTERFACE AND OPTICAL COHERENCE TOMOGRAPHY CHARACTERISTICS IN WET AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To study the effect of the vitreomacular interface on various wet age related macular degeneration (AMD) characteristics including the size and type of choroidal neovascularization (CNV), choroidal thickness, and activity of the CNV. METHODS: This was a retrospective observational cross-sectional study. The study included 43 patients (51 eyes) with treatment-naive age-related macular degeneration. Twenty-six patients with wet AMD in one eye and dry AMD in the other eye were included in a paired-eye analysis. Patients underwent optical coherence tomography examination using Heidelberg Spectralis (spectral domain optical coherence tomography) at presentation to determine the type of CNV and the vitreomacular status. In addition, various parameters were measured including the choroidal thickness and horizontal width and vertical height measurements of the CNV. RESULTS: There was no correlation between the height, width, activity or type of the CNV, and the presence or absence of vitreomacular adhesion. The mean choroidal thickness (using enhanced depth imaging) in cases with vitreomacular adhesion was 272.57 MUm compared with 197.32 MUm in cases with no vitreomacular adhesion, a statistically significant difference (P = 0.003). In the paired-eye study (21 patients), there was no significant difference between the eyes with wet AMD and dry AMD with regard to vitreomacular status or the choroidal thickness. In a subgroup analysis, patients with Type 1 CNV had a significantly higher percentage of vitreomacular adhesion compared with the other eye with dry AMD (P = 0.034). CONCLUSION: In conclusion, the vitreomacular interface does seem to be associated with an increased choroidal thickness in cases of wet AMD. Furthermore, the association between the vitreomacular interface and wet AMD is more significant for Type 1 CNV. PMID- 28005633 TI - TWENTY-FIVE-GAUGE CANNULA-ASSISTED FINE-NEEDLE ASPIRATION BIOPSY OF CHOROIDAL MELANOMA: Cytopathological Analysis. AB - PURPOSE: To report cytopathological observations on the cells retrieved from the 25-G cannula used during prognostic transvitreal fine-needle aspiration biopsy of choroidal melanoma. METHODS: Transvitreal fine-needle aspiration biopsy of choroidal melanoma was performed through a 25-G valved cannula. Twenty samples from 20 consecutive patients were obtained. Most tumors were treated with plaque radiation therapy (16/20, 80%) following standard clinical guidelines. Four enucleated globes (4/20, 20%) were subjected to a similar transvitreal biopsy before enucleation. RESULTS: Cytopathological analysis of the cells retrieved from the cannula revealed the absence of any cells in 4 of 20 samples (20%). In the remaining 16 samples, definite melanoma cells and atypical cells (probable melanoma cells) were observed in 2 samples each (total 4, 25%). Histiocytes (4/16, 25%) and lymphocytes (1/16, 6%) were also observed. Thirteen samples (13/16, 81%) contained conjunctival epithelial epithelium. Prognostication could be performed on all fine-needle aspiration biopsy samples (20, 100%). CONCLUSION: Use of a 25-G valved cannula offers potential advantages by isolating the needle tract and by allowing retrieval of the contaminating cells without affecting the prognostic yield of the fine-needle aspiration biopsy sample. PMID- 28005634 TI - The Role of Esophageal Hypersensitivity in Functional Esophageal Disorders. AB - The Rome IV diagnostic criteria delineates 5 functional esophageal disorders which include functional chest pain, functional heartburn, reflux hypersensitivity, globus, and functional dysphagia. These are a heterogenous group of disorders which, despite having characteristic symptom profiles attributable to esophageal pathology, fail to demonstrate any structural, motility or inflammatory abnormalities on standard clinical testing. These disorders are associated with a marked reduction in patient quality of life, not least considerable healthcare resources. Furthermore, the pathophysiology of these disorders is incompletely understood. In this narrative review we provide the reader with an introductory primer to the structure and function of esophageal perception, including nociception that forms the basis of the putative mechanisms that may give rise to symptoms in functional esophageal disorders. We also discuss the provocative techniques and outcome measures by which esophageal hypersensitivity can be established. PMID- 28005635 TI - Longitudinal Body Composition Changes in NCAA Division I College Football Players. AB - Trexler, ET, Smith-Ryan, AE, Mann, JB, Ivey, PA, Hirsch, KR, and Mock, MG. Longitudinal body composition changes in NCAA Division I college football players. J Strength Cond Res 31(1): 1-8, 2017-Many athletes seek to optimize body composition to fit the physical demands of their sport. American football requires a unique combination of size, speed, and power. The purpose of the current study was to evaluate longitudinal changes in body composition in Division I collegiate football players. For 57 players (mean +/- SD, age = 19.5 +/- 0.9 years, height = 186.9 +/- 5.7 cm, weight = 107.7 +/- 19.1 kg), body composition was assessed via dual-energy x-ray absorptiometry in the off-season (March-Pre), end of off-season (May), mid-July (Pre-Season), and the following March (March-Post). Outcome variables included weight, body fat percentage (BF%), fat mass, lean mass (LM), android and gynoid (GYN) fat, bone mineral content (BMC), and bone mineral density (BMD). For a subset of athletes (n = 13 out of 57), changes over a 4-year playing career were evaluated with measurements taken every March. Throughout a single year, favorable changes were observed for BF% (Delta = -1.3 +/- 2.5%), LM (Delta = 2.8 +/- 2.8 kg), GYN (Delta = -1.5 +/- 3.0%), BMC (Delta = 0.06 +/- 0.14 kg), and BMD (Delta = 0.015 +/- 0.027 g.cm, all p <= 0.05). Across 4 years, weight increased significantly (Delta = 6.6 +/- 4.1 kg) and favorable changes were observed for LM (Delta = 4.3 +/- 3.0 kg), BMC (Delta = 0.18 +/- 0.17 kg), and BMD (Delta = 0.033 +/- 0.039 g.cm, all p <= 0.05). Similar patterns in body composition changes were observed for linemen and non-linemen. Results indicate that well-trained collegiate football players at high levels of competition can achieve favorable changes in body composition, even late in the career, which may confer benefits for performance and injury prevention. PMID- 28005636 TI - Exercise-Induced Hormone Elevations Are Related to Muscle Growth. AB - Mangine, GT, Hoffman, JR, Gonzalez, AM, Townsend, JR, Wells, AJ, Jajtner, AR, Beyer, KS, Boone, CH, Wang, R, Miramonti, AA, LaMonica, MB, Fukuda, DH, Witta, EL, Ratamess, NA, and Stout, JR. Exercise-induced hormone elevations are related to muscle growth. J Strength Cond Res 31(1): 45-53, 2017-Partial least squares regression structural equation modeling (PLS-SEM) was used to examine relationships between the endocrine response to resistance exercise and muscle hypertrophy in resistance-trained men. Pretesting (PRE) measures of muscle size (thickness and cross-sectional area) of the vastus lateralis and rectus femoris were collected in 26 resistance-trained men. Participants were randomly selected to complete a high-volume (VOL, n = 13, 10-12RM, 1-minute rest) or high-intensity (INT, n = 13, 3-5RM, 3-minute rest) resistance training program. Blood samples were collected at baseline, immediately postexercise, 30-minute, and 60-minute postexercise during weeks 1 (week 1) and 8 (week 8) of training. The hormonal responses (testosterone, growth hormone [22 kD], insulin-like growth factor-1, cortisol, and insulin) to each training session were evaluated using area-under the-curve (AUC) analyses. Relationships between muscle size (PRE), AUC values (week 1 + week 8) for each hormone, and muscle size (POST) were assessed using a consistent PLS-SEM algorithm and tested for statistical significance (p <= 0.05) using a 1,000 samples consistent bootstrapping analysis. Group-wise comparisons for each relationship were assessed through independent t-tests. The model explained 73.4% (p < 0.001) of variance in muscle size at POST. Significant pathways between testosterone and muscle size at PRE (p = 0.043) and muscle size at POST (p = 0.032) were observed. The ability to explain muscle size at POST improved when the model was analyzed by group (INT: R = 0.882; VOL: R = 0.987; p < 0.001). No group differences in modal quality were found. Exercise-induced testosterone elevations, independent of the training programs used in this study, seem to be related to muscle growth. PMID- 28005637 TI - Effects of Physical Training and Fitness on Running Injuries in Physically Active Young Men. AB - Grier, TL, Canham-Chervak, M, Anderson, MK, Bushman, TT, and Jones, BH. Effects of physical training and fitness on running injuries in physically active young men. J Strength Cond Res 31(1): 207-216, 2017-The purpose of this investigation was to determine the effects of physical training (PT) and fitness on risks for running-related injuries (RRIs) in physically active young men. Personal characteristics, PT, Army Physical Fitness Test scores, and injury data were obtained by survey. Army Physical Fitness Test variables (push-ups, sit-ups, and 2-mile run) were converted into quartiles (Q), where Q1 = lowest performance and Q4 = highest performance. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression. Over 4,000 (n = 4,236) soldiers were surveyed. Running injury incidence was 14%. A greater risk of an RRI was associated with older age (OR31+/<22 years = 1.62, 95% CI, 1.21-2.18), higher BMI ((Equation is included in full-text article.)), and total distance ran per week during unit PT (OR16.1+/1-5 miles = 1.66, 95% CI, 1.15-2.41). A lower risk of an RRI was associated with total distance run per week during personal PT (OR5.1-10/1-5 miles = 0.70, 95% CI, 0.53-0.91, OR10.1-16 +/1-5 miles = 0.58, 95% CI, 0.35-0.97, OR16.1+/1-5 miles = 0.54, 95% CI, 0.30-0.98), higher aerobic endurance as measured by 2-mile run performance (ORQ4/Q1 = 0.50, 95% CI, 0.35 0.72), and unit resistance training >=3 times a week (OR>=3 times per week/none = 0.46, 95% CI, 0.29-0.73). Greater personal PT running mileage decreased injuries in this population suggesting that the increased protective effect of higher aerobic fitness outweighed the injurious effect of running more miles during personal PT. Countermeasures to prevent RRIs could entail enhancing aerobic endurance, providing opportunities for personal aerobic training, monitoring for excessive unit PT running mileage and encouraging unit resistance training >=3 times per week. PMID- 28005638 TI - MRI and 18F-FDG PET/CT of Laryngeal Cartilaginous Tumor. AB - Cartilaginous tumors of the larynx are uncommon neoplasms that sometimes mimic laryngeal cancers. There has been no report of F-FDG PET/CT for the evaluation of laryngeal cartilaginous tumors. We reported 3 cases of laryngeal cartilaginous tumors with the image findings, including CT, FDG PET/CT, and MRI and reviewed literatures. We concluded that the combination of a very high-signal mass on T2 weighted magnetic resonance images and lower FDG uptake might be diagnostic image characteristics for distinguishing laryngeal cartilaginous tumor from laryngeal cancer. PMID- 28005639 TI - Pancreatic Uptake by 18F-FDOPA PET/CT in Patients With Hypoglycemia After Gastric Bypass Surgery Compared With Controls With or Without Carbidopa Pretreatment. AB - PURPOSE: The use of Fluorine-labeled dihydroxy-phenyl-alanine (F-FDOPA) PET/CT in patients with hypoglycemia suspected to be caused by pancreatic disease can be helpful to localize the source of excess insulin production. In this setting, carbidopa pretreatment is not recommended. However, quantitative comparisons of pancreatic tracer uptake in patients with or without carbidopa pretreatment and in diffuse pancreatic disease are lacking. Therefore, we aimed to describe and quantify pancreatic F-FDOPA uptake in patients without pancreatic disease with or without carbidopa pretreatment and in patients with hypoglycemia after gastric bypass surgery. PATIENTS AND METHODS: This is a retrospective data analysis of F FDOPA PET/CT scans performed at a university medical center in the period from 2009 to 2015. All scans were reconstructed and calculated based on the European Association of Nuclear Medicine/EANM Research Ltd guidelines. Of 358 patients without evidence of pancreatic disease or hypoglycemic disorders, 344 received carbidopa and 14 did not. Another 9 patients had post-gastric bypass hypoglycemia. The main outcome measurement was F-FDOPA SUVmax for pancreatic head, body, and tail regions. RESULTS: Carbidopa pretreated patients had a lower median SUVmax (-1.15, -1.20, and -0.84 in pancreatic head, body, and tail [all P < 0.01]) than patients without carbidopa pretreatment. Patients with post-gastric bypass hypoglycemia scanned without carbidopa pretreatment had higher median SUVmax (+1.18, +1.39, and +1.63, all P < 0.03) compared with controls without pretreatment. CONCLUSIONS: Patients with post-gastric bypass hypoglycemia have increased uptake in all pancreatic regions. Carbidopa pretreatment lowers pancreatic F-FDOPA uptake in the nonaffected pancreas and may therefore mask disease activity in post-gastric bypass hypoglycemia. PMID- 28005641 TI - FDG PET/CT in Malignant Eccrine Spiradenoma. AB - Malignant eccrine spiradenoma is very rare skin appendageal cancer. We report a 64-year-old man who presented with a 6-month history of a rapidly growing mass in his groin. Physical examination revealed a 10-cm, ulcerated, fungating mass involving the entire right ilioinguinal region. PET/CT scan demonstrated intense FDG-avid lesion in the inguinal region. Histopathology of the lesion was compatible with malignant eccrine spiradenoma. He required extensive tumor resection followed by chemotherapy and radiotherapy. PMID- 28005640 TI - Early Detection of Bone Metastasis in Small Cell Neuroendocrine Carcinoma of the Cervix by 68Ga-DOTATATE PET/CT Imaging. AB - The neuroendocrine small cell carcinoma of the cervix is a rare malignancy that has a poor prognosis due to early lymphatic and hematogenous spread. We herein report a case of a 27- year-old woman who was referred for initial staging of a neuroendocrine small cell carcinoma with previous unremarkable structural imaging. Ga-DOTATATE PET/CT revealed focal uptake at the primary tumor and in a solitary pelvic bone lesion suggestive of metastases that was further confirmed by CT-guided biopsy. Somatostatin receptor PET/CT may be a useful image modality for early detection of metastases to guide treatment in these patients. PMID- 28005642 TI - Tumorlike Pigmented Villonodular Synovitis With Atypical Location: Appearance on 3-Phase 99mTc-MDP Bone Scan. AB - Pigmented villonodular synovitis (PVNS) is a proliferative disorder of unknown etiology that originates from the synovial membranes of joints. Some PVNS lesions have been misdiagnosed as malignancy due to their tumorlike imaging findings. There are few reports of PVNS on nuclear 3-phase bone imaging. However, 3-phase Tc-MDP bone scan can offer additional information about the dynamic flow features of the lesion, which may do help in differential benign and malignant. The present report describes 3-phase bone imaging in a surgically proven case of PVNS with tumorlike appearance and atypical location. PMID- 28005643 TI - Fibromatosis Associated With Neuromuscular Choristoma: Evaluation by FDG PET/CT. AB - Neuromuscular choristoma (NMC) is a rare benign peripheral nerve lesion consisting of mature skeletal muscle fibers admixed with nerve fascicles. Aggressive fibromatosis frequently develops in association with NMC, often after surgery or biopsy, but the exact pathogenesis is not known. We present a case of NMC complicated by aggressive fibromatosis evaluated by F-FDG PET/CT and examine the relationship of metabolic activity and MRI signal characteristics. PMID- 28005644 TI - 18F-FDG PET/CT of Seminal Vesicle Metastasis From Ascending Colon Adenocarcinoma. AB - The most common metastatic sites of colorectal cancer are the regional lymph nodes, liver, lungs, and peritoneum. Seminal vesicle metastasis from colon adenocarcinoma is not reported yet; the diagnosis could be challenging. We report a case of seminal vesicle metastasis from a primary ascending colon adenocarcinoma in a 49-year-old man, with elevating carcinoembryonic antigen as the only clinical sign. This also highlights the role of F-FDG PET/CT to detect metastatic adenocarcinoma from colon in the genitourinary system. PMID- 28005645 TI - 68Ga-DOTATATE PET/CT in Primary Hepatic Neuroendocrine Tumor. AB - Primary neuroendocrine tumors of the liver are a diagnostic challenge. We present a rare case of primary hepatic neuroendocrine tumor in which Ga-DOTATATE PET/CT imaging played an important role in the diagnosis and follow-up. PMID- 28005646 TI - Lymphoscintigraphic SPECT/CT-Contralateral Axillary Sentinel Lymph Node Drainage in Breast Cancer. AB - A 58-year-old woman with previous right breast carcinoma treated with lumpectomy, right axillary clearance, chemo-radiotherapy, and adjuvant hormonal therapy underwent a lymphoscintigraphy for a new right breast lesion. On planar images, an alternate route of lymphatic drainage was observed to the right internal mammary chain and the left axilla. A chest SPECT/CT was performed to confirm the location of the sentinel nodes. The patient underwent a right mastectomy and left axillary sentinel lymph node biopsy, which showed no evidence of lymphovascular invasion. Combining planar imaging and SPECT/CT techniques can accurately identify sentinel lymph nodes at their new unpredicted location. PMID- 28005647 TI - The Ethical Use of Mobile Health Technology in Clinical Psychiatry. AB - The rapid rise of mobile health technologies, such as smartphone apps and wearable sensors, presents psychiatry with new tools of potential value in caring for patients. Novel diagnostic and therapeutic applications of these technologies have been developed in private industry and utilized in mental health, although these methods do not yet constitute standard of care. In this article, we provide an ethical perspective on the practical use of this novel modality by psychiatrists. We propose that in the present context of limited scientific research and regulatory oversight, mobile technologies should serve to enhance the psychiatrist-patient relationship, rather than replace it, to minimize potential clinical and ethical harm to vulnerable patients. We analyze areas of possible ethical tension between clinical practice and the consumer-driven mobile industry, and develop a decision-tree model for implementing ethical safeguards in practice, focused on managing risk to the therapeutic relationship, informed consent, confidentiality, and mutual alignment of treatment goals and expectations. PMID- 28005648 TI - Lateral Wall Orbital Decompression: Comparison of Outcomes in Rim Sparing and Temporary Rim Removal Techniques. AB - PURPOSE: To compare exophthalmos reduction in lateral orbital decompressions performed via rim sparing versus temporary rim removal techniques. METHODS: The authors performed a retrospective chart review of all patients who underwent simple lateral or combined medial and lateral wall orbital decompression between 2005 and 2013 by a single surgeon. Nineteen patients (33 orbits) were identified for inclusion in the study. Decompression procedures (1 or 2 orbital walls) involved either a rim sparing or a temporary rim removal technique. Preoperatively, all patients had stable exophthalmos defined as <=1 mm change in exophthalmos over 2 consecutive visits. Measurements were taken again at the 3 to 4 months postoperative visit. Exclusion criteria were acute or unstable exophthalmos, exophthalmos secondary to malignancy, and patients lost to follow up. RESULTS: There were no significant differences in exophthalmos reduction for rim sparing versus temporary rim removal techniques in any of the groups studied. Simple lateral decompression procedures achieved 3.7 and 4.4 mm of exophthalmos reduction in rim sparing versus temporary rim removal techniques, respectively (P = 0.49). Exophthalmos reduction in combined medial and lateral wall orbital decompression was 4.1 mm for rim sparing and 3.5 mm for temporary rim removal techniques (P = 0.75). CONCLUSION: In our experience, orbital decompression approached through rim sparing or temporary rim removal techniques achieves similar results in simple lateral and combined medial and lateral decompressions. Though these techniques generate similar outcomes, temporary rim removal provides for improved visibility and access to deep orbital structures. PMID- 28005649 TI - Cerebral and Spinal Tuberculous Leptomeningitis: Advanced Magnetic Resonance Imaging Findings. AB - At diagnosis of the cerebral and spinal tuberculous meningitis magnetic resonance (MR) imaging is the primary imaging technique. Magnetic resonance images reveal cerebrospinal fluid collection and obliteration of the spinal subarachnoid space. The contrast-enhanced MR imaging shows nodular and thick intradural enhancement. Herein, the authors reported advanced MR imaging findings of the cerebral and spinal tuberculous leptomeningitis. PMID- 28005651 TI - Columellar Reconstruction: A New Technique for Median Cleft Lip Repair. AB - Median cleft lip (MCL), failure of the fusion of the medial nasal prominences in the midline resulting in vertical cleft through the center of the upper lip, can be repaired by various columellar reconstruction approaches depending on the nature of patient. The main drawback of these surgical techniques is the use of healthy neighboring structures that may compromise the process. In this report, the authors present a new approach for repairing MCL which involves simultaneous columellar reconstruction without damaging any nasal units. Briefly, columella was reconstructed with 2 lateral triangular flaps harvested from both cleft sides. They were sutured together and attached to the ventral surface of the nasal dome at the midline. The procedure was resulted in satisfactory clinical and esthetic outcome suggesting this approach may present a better alternative for this condition. PMID- 28005650 TI - Impact of Laryngopharyngeal Reflux on the Levels of Depression and Anxiety in Patients With Obstructive Sleep Apnea Syndrome. AB - OBJECTIVES: The aim of the study was to assess the impact of the presence of laryngopharyngeal reflux (LPR) on the level of depression and anxiety in patients with obstructive sleep apnea syndrome (OSAS). STUDY DESIGN: A nonrandomized, prospective clinical study. METHODS: In total, 62 patients with an apnea-hypopnea index >5 were included in this study. Each patients completed the 21-item Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Epworth Sleepiness Scale (ESS), and Reflux Symptom Index (RSI). Patients were diagnosed with LPR based on laryngeal examination and symptom presentation, with RSI score >13. The patients were divided into 2 groups based on the presence of LPR. In group A, all patients were diagnosed with LPR. In group B, the patients had no diagnosis of reflux disease. RESULTS: The mean RSI was 3.86 +/- 2.46 in group B and 17.2 +/- 6.34 in group A. The mean ESS scores did not differ between the groups (P = 0.107). Mean BAI and BDI scores were both higher in group A than in group B (P = 0.016 and P = 0.011, respectively). There was no correlation between RSI and BAI scores (r = -0.237; P = 0.063), BDI scores (r = 0.191; P = 0.138), or ESS scores (r = 0.210; P = 0.102). A positive correlation was found between RSI and apnea hypopnea index scores (r = 0.338; P = 0.007). CONCLUSION: The authors observed significantly higher levels of depression and anxiety in patients with LPR and OSAS. The authors suggest that the presence of LPR induces depression and anxiety in patients with OSAS and vice versa. Further studies involving larger numbers of patients are needed to confirm these initial findings. PMID- 28005652 TI - Facial Nerve Preservation During Giant Mandibular Tumor Surgery. AB - Marginal mandibular branch of facial nerve is easy to be ignored and injured in patients undergoing giant mandibular tumor resections. In this article, a 30-year old patient with a giant tumor in the left mandible, an operation of segmental mandibulectomy and reconstruction was given, and the surgery was assisted by intraoperative facial nerve monitoring. During surgery, the marginal mandibular branch of the facial nerve was detected and well preserved. The patient showed no facial function injury postoperation. In patients of giant mandibular tumor resection, the anatomic location of the facial nerve may have great changes. Preservation of marginal mandibular branch should be taken seriously. Intraoperative facial nerve monitoring is an effective method for preventing nerve weakness during such mandibular surgeries. PMID- 28005653 TI - Anatomy of the Corrugator Muscle. AB - The aim of this article is to systematically review the anatomy and action of the corrugator muscle. PubMed and Scopus were searched using the terms "corrugator" AND "anatomy." Among the 60 full texts from the 145 relevant abstracts, 34 articles without sufficient content were excluded and 4 articles drawn from the reference lists were added. Among the 30 articles analyzed (721 hemifaces), 28% classified by oblique head and transverse head, and 72% did not. Corrugator originated mostly from the medial supraorbital rim (45%), followed by the medial frontal bone (31%), the medial infraorbital rim (17%), and the upper nasal process (7%). Corrugator extended through the frontalis and orbicularis oculi (41%), only the frontalis (41%), or only the orbicularis oculi (18%). Corrugator ran superolaterally (59%), or laterally (41%). Corrugators inserted mostly to the middle of the eyebrow (57%), or the medial half of the eyebrow (36%), but also to the glabella region (7%). The length of the corrugator ranged 38 to 53 mm. The transverse head (23.38 mm) was longer than the oblique head (19.75 mm). Corrugator was thicker at the medial canthus than at the midpupillary line. Corrugator was innervated by the temporal branch of the facial nerve (66%), the zygomatic branch (17%), or the angular nerve (zygomatic branch and buccal branch, 17%). Supraorbital nerve (60%) or supratrochlear nerve (40%) penetrated the corrugator. The action was depressing, pulling the eyebrow medially (91%), or with medial eyebrow elevation and lateral eyebrow depression (9%). Surgeons must keep this anatomy in mind during surgical procedures. PMID- 28005654 TI - Calvarial Mass Confused With Trichilemmal Cyst: Hepatocellular Cancer Metastasis. AB - The hepatocellular cancer calvarial metastasis is a rare condition that commonly presents cranial swelling. Therefore, calvarial swelling may confuse with frequent lesions of the scalp. The authors' patient was operated as trichilemmal cyst. But, intracranial extension was seen in operation. Calvarial metastasis of hepatocellular cancer was observed by examination of the patient. PMID- 28005655 TI - Columellar Reconstruction After Nasal Continuous Positive Airway Pressure Associated Necrosis. AB - Though a life-saving modality in neonatal intensive care units, nasal continuous positive airway pressure (nCPAP) carries a small risk of irreversible ischemia and necrosis of the columella due to the configuration of the pressure delivery system. Iatrogenic injuries to the columella after nCPAP use result in a spectrum of disfigurement and functional airway obstruction. The authors performed a retrospective review of patients evaluated for nCPAP-related columellar deformities by the Division of Plastic and Reconstructive Surgery at the authors' institution over a 10-year period to assess reconstructive outcomes. Of 7 patients evaluated, 3 underwent reconstruction using a combination of cartilaginous framework reshaping and local tissue flaps. After a mean follow-up period of 78 months, patients had satisfactory aesthetic and functional results. Based on the authors' observations, columellar necrosis secondary to nCPAP can be divided into 3 categories: Type A demonstrates mild notching of the columella; Type B has an absent columella without notable nasal tip depression; Type C has an absent columella with nasal tip depression, with or without external nasal valve obstruction. Reconstructive needs should be individually tailored based on the degree of nasal tip depression, cartilaginous support, and soft tissue availability. PMID- 28005656 TI - Skeletal Changes of an Osteomyocutaneous Facial Allograft Five Years Following Transplantation. AB - BACKGROUND: More than 30 face transplantations have been performed worldwide, most including part of the facial skeletal framework. In this study, the modifications of the skeletal component of a facial allograft were evaluated. METHODS: Standard head computed tomography (CT) scans, CT angiogram, and bone mineral densitometry were evaluated. Cephalometric analysis was performed. The pre and postoperative CT images were overlapped and the skeletal changes were expressed in a numeric and color-coded scale. The values of the serum calcium, phosphate, vitamin D, alkaline phosphatase, thyroid and parathyroid hormones, TSH, FHS, LH, estradiol, total protein and albumin, serum creatinine, and creatinine clearance were reviewed. RESULTS: At 5 years follow-up the patient was 51 years old, asymptomatic and presented good stability of the Le Fort III component of the allograft. Computed tomography images revealed fibrous union of all fixation sites. There was minimal bone resorption at the osteotomy sites, left infraorbital rim and left maxillary buttress, and anterior maxilla (-0.28 mm). Computed tomography angiogram showed segmental absence at the origin of the left external carotid artery, good opacification of the rest of the external carotid arteries and its branches. Bone mineral densitometry evidenced osteopenia of the spine. The patient presented mild hypoalbuminemia (3.4 g/dL) and perimenopausal hormonal levels. CONCLUSIONS: The skeletal component of the facial allograft was stable over time. Minimal bone resorption was discovered at the level of the left infraorbital rim and anterior maxilla. Transplantation of bone within the facial allograft is a viable reconstructive option. PMID- 28005657 TI - Influence of Orbital Implant Length and Diameter on Stress Distribution: A Finite Element Analysis. AB - PURPOSE: A mathematical simulation of stress distribution around orbital implants was used to determine which length and diameter of implants would be best to dissipate stress. METHODS: An integrated system for computed tomography data was utilized to create a 3-dimensional model of craniofacial structures. The model simulated implants placed in the 7, 11, and 12 o'clock positions of the orbital rim. A load of 2 N was applied to the model along the long axis of the implant (model 1) and an angle of 45 degrees with the long axis of the implant (model 2). A model simulating an implant with a diameter of 3.75 mm and lengths of 3, 4, 6, 8, and 10 mm was developed to investigate the influence of the length factor. The influence of different diameters was modeled using implants with a length of 6 mm and diameters of 3.0, 3.75, 4.2, 5.0, and 6.0 mm. Values of von Mises equivalent stress at the implant-bone interface were computed using the finite element analysis for all variations. RESULTS: The elements exposed to the maximum stress were located around the root of the orbital implant in model 1 or between the neck and the first thread of the orbital implant in model 2. An increase in the orbital implant diameter led to a decrease in the maximum von Mises equivalent stress values. In model 1, the reductions were 45.2% (diameter of 3.0 3.75 mm), 25.3% (diameter of 3.75-4.2 mm), 17.2% (diameter of 4.2-5.0 mm), and 5.4% (diameter of 5.0-6.0 mm). In model 2, the reductions of the maximum stress values were 51.9%, 35.4%, 19.7%, and 8.1% respectively. However, the influence of orbital implant length was not as pronounced as that of diameter. In model 1, the reductions were 28.8% (length of 3-4 mm), 19.2% (length of 4-6 mm), 9.6% (length of 6-8 mm), and 4.3% (length of 8-10 mm). In model 2, the reductions of the maximum stress values were 35.5%, 21.1%, 10.9%, and 5.4% respectively. CONCLUSIONS: An increase in the implant diameter decreased the maximum von Mises equivalent stress around the orbital implant more than an increase in the implant length. From a biomechanical perspective, the optimum choice was an orbital implant with no less than 4.2 mm diameter allowed by the anatomy. PMID- 28005658 TI - The International Retinal Imaging Symposium (IRIS IV) 2016. PMID- 28005659 TI - SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY REVEALS CHORIOCAPILLARIS ALTERATIONS IN EYES WITH NASCENT GEOGRAPHIC ATROPHY AND DRUSEN-ASSOCIATED GEOGRAPHIC ATROPHY. AB - PURPOSE: To investigate choriocapillaris (CC) alteration in patients with nascent geographic atrophy (nGA) and/or drusen-associated geographic atrophy (DAGA) using swept-source optical coherence tomography angiography (OCTA). METHODS: A 1,050-nm wavelength, 400 kHz A-scan rate swept-source optical coherence tomography prototype was used to perform volumetric swept-source optical coherence tomography angiography over 6 mm * 6 mm fields of view in patients with nGA and/or DAGA. The resulting optical coherence tomography (OCT) and OCTA data were analyzed using a combination of en face and cross-sectional techniques. Variable interscan time analysis (VISTA) was used to differentiate CC flow impairment from complete CC atrophy. RESULTS: A total of 7 eyes from 6 patients (mean age: 73.8 +/- 5.7 years) were scanned. Seven areas of nGA and three areas of DAGA were identified. Analysis of cross-sectional OCT and OCTA images identified focal alterations of the CC underlying all seven areas of nGA and all three areas of DAGA. En face OCTA analysis of the CC revealed diffuse CC alterations in all eyes. Variable interscan time analysis processing suggested that the observed CC flow alterations predominantly corresponded to flow impairment rather than complete CC atrophy. CONCLUSION: The OCTA imaging of the CC revealed focal CC flow impairment associated with areas of nGA and DAGA, as well as diffuse CC flow impairment throughout the imaged field. En face OCT analysis should prove useful for understanding the pathogenesis of nGA and DAGA and for identifying the formation of nGA and DAGA as endpoints in therapeutic trials. PMID- 28005660 TI - VISUALIZING RETINAL PIGMENT EPITHELIUM PHENOTYPES IN THE TRANSITION TO GEOGRAPHIC ATROPHY IN AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To inform the interpretation of clinical optical coherence tomography and fundus autofluorescence imaging in geographic atrophy (GA) of age-related macular degeneration by determining the distribution of retinal pigment epithelium (RPE) phenotypes in the transition from health to atrophy in donor eyes. METHODS: In RPE-Bruch membrane flat mounts of two GA eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high resolution histological sections of 13 GA eyes, RPE phenotypes were assessed at +/-500 and +/-100 MUm from the descent of the external limiting membrane (ELM) toward Bruch membrane. The ELM descent was defined as curved, reflected, or oblique in shape. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE plus BLamD were measured. RESULTS: A border of atrophy that can be precisely delimited is the ELM descent, as opposed to the termination of the RPE layer itself, because of dissociated RPE in the atrophic area. Approaching the ELM descent, the percentage of abnormal RPE morphologies increases, the percentage of age-normal cells decreases, overall RPE thickens, and BLamD does not thin. The combination of RPE plus BLamD is 19.7% thicker at -100 MUm from the ELM descent than that at 500 MUm (23.1 +/- 10.7 MUm vs. 19.3 +/- 8.2 MUm; P = 0.05). CONCLUSION: The distribution of RPE phenotypes at the GA transition supports the idea that these morphologies represent defined stages of a degeneration sequence. The idea that RPE dysmorphia including rounding and stacking helps explain variable autofluorescence patterns in GA is supported. The ELM descent and RPE plus BLamD thickness profile may have utility as spectral domain optical coherence tomography metrics in clinical trials. PMID- 28005661 TI - VISUALIZING RETINAL PIGMENT EPITHELIUM PHENOTYPES IN THE TRANSITION TO ATROPHY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To enable future studies of retinal pigment epithelium (RPE) fate in the macular atrophy occurring in eyes with neovascular age-related macular degeneration (nvAMD), the authors determined how RPE morphology changes across the transition from health to atrophy in donor eyes with nvAMD. METHOD: In RPE Bruch membrane flat mounts of 5 nvAMD eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histologic sections of 27 nvAMD eyes, RPE phenotypes were assessed at +/-500 MUm and +/-100 MUm from the descent of the external limiting membrane (ELM) toward the Bruch membrane. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE + BLamD were determined. Shapes of the ELM descent were recorded. RESULTS: Approaching the ELM descent, the percentage of different RPE phenotypes and the thickness of RPE, BLamD, and RPE + BLamD each stayed roughly constant. Compared with a separately described cohort of eyes with geographic atrophy, eyes with nvAMD were more likely to have RPE dysmorphia that did not worsen toward the atrophy border, thinner BLamD overall (3.25 +/- 3.46 MUm vs. 7.99 +/- 7.49 MUm for geographic atrophy), and a higher proportion of oblique ELM descents (47.9 vs. 31.9%). CONCLUSION: The distribution of RPE phenotypes at the transition to macular atrophy in eyes with nvAMD differs from that in primary geographic atrophy, likely reflecting greater photoreceptor loss and the effects of exudation in nvAMD. This distribution, the shape of ELM descents, and thickness profiles may be useful metrics in clinical studies of macular atrophy using optical coherence tomography and fundus autofluorescence. PMID- 28005662 TI - AN UPDATED STAGING SYSTEM OF TYPE 3 NEOVASCULARIZATION USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To comprehensively investigate spectral domain optical coherence tomography features associated with Type 3 neovascularization and determine the prevalence of each feature and to develop an updated staging system for Type 3 neovascularization based on spectral domain optical coherence tomography findings. METHODS: The authors retrospectively analyzed 34 eyes with new-onset Type 3 neovascularization. Spectral domain optical coherence tomography images at onset of Type 3 neovascularization, immediately after the first injection, and at the final quiescent visit were analyzed for the presence of specific optical coherence tomography features. In addition, when available, optical coherence tomography images from the visit before onset were studied. RESULTS: Among 18 eyes with preonset optical coherence tomography, 77.8% had preexisting intraretinal hyperreflective foci (precursor lesion). In the same group of eyes, 44.4% and 27.8% exhibited outer plexiform layer disruption and outer plexiform layer downward deflection, respectively. At the onset of detectable Type 3 neovascularization, all 34 eyes demonstrated a hyperreflective focus with cystoid macular edema and 85.3% exhibited disruption of the retinal pigment epithelium. Serous pigment epithelial detachment and subretinal fluid were present in 67.6% and 23.5% of eyes at onset, respectively. The rate of cystoid macular edema decreased from 100% to 17.6% after a single injection. At the final quiescent visit, focal atrophy at the site of Type 3 lesions, as evidenced by outer retinal and retinal pigment epithelium disruption developed in 88.2% and 52.9% of eyes, respectively. CONCLUSION: An updated staging system of Type 3 lesions was developed based on spectral domain optical coherence tomography findings. A precursor stage consists of a punctate hyperreflective focus in the outer retina. The subtle detection of associated outer plexiform layer disruption and downward deflection may indicate that this precursor lesion is more likely to progress to an active Type 3 neovascular lesion. Stage 1 consists of a larger intraretinal hyperreflective lesion associated with cystoid macular edema but without outer retinal disruption. Stage 2 is notable for outer retinal disruption that occurs with retinal pigment epithelium disruption in most of the cases. Stage 3 is defined by an intraretinal hyperreflective lesion that extends through the retinal pigment epithelium to vascularize a drusenoid pigment epithelial detachment creating a serous component of the pigment epithelial detachment. PMID- 28005663 TI - TYPE 1 VERSUS TYPE 3 NEOVASCULARIZATION IN PIGMENT EPITHELIAL DETACHMENTS ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY: A Prospective Study. AB - PURPOSE: To evaluate the response to aflibercept therapy for Type 1 and Type 3 neovascularization in pigment epithelial detachments associated with treatment naive, neovascular age-related macular degeneration. METHODS: In this multicentered, prospective study, eligible eyes underwent an intravitreal aflibercept injection protocol for 12 months. Visual acuity and morphologic features of the pigment epithelial detachments were compared at baseline and follow-up intervals between eyes with Type 1 versus Type 3 neovascularization. RESULTS: Thirty-six eyes were analyzed. At 12 months, Type 1 lesions showed a 4.5 +/- 23 Early Treatment of Diabetic Retinopathy Study letter improvement (P = 0.1665) versus a 14 +/- 11 (P = 0.0072) letter improvement with Type 3 lesions. Both Type 1 and 3 eyes showed a significant decrease in pigment epithelial detachment size, subretinal fluid, and subretinal hyperreflective material; however, Type 3 eyes had a greater reduction in pigment epithelial detachment size and subretinal hyperreflective material, as well as a reduction in central retinal thickness. Type 1 eyes required an average of 1.636 (range, 1-4) injections to resolve fluid, which was greater than Type 3 eyes, which required an average of 1.143 (range, 1-2) injections (P = 0.0251). CONCLUSION: Intravitreal aflibercept injections were efficacious for pigment epithelial detachments, but baseline and follow-up anatomical and functional outcomes differed in Type 1 versus Type 3 neovascularization. The better response of Type 3 eyes with fewer injections suggests that differentiation of the neovascularization subtype at the initial diagnosis may allow for a more tailored, optimal therapy. PMID- 28005664 TI - RETINAL PIGMENT EPITHELIUM APERTURE: A Previously Unreported Finding in the Evolution of Avascular Pigment Epithelium Detachment. AB - PURPOSE: To describe retinal pigment epithelium (RPE) aperture and to generate hypotheses about pathogenesis of this previously unreported finding in the evolution of avascular pigment epithelium detachment (PED) secondary to age related macular degeneration. METHODS: Medical records and multimodal imaging results from 10 patients with RPE apertures were reviewed between January 2009 and December 2014 by 2 institutions. Main outcome measures were analysis of RPE aperture imaging characteristics, including aperture areas and PED diameters, and their temporal course. Lesions preceding RPE aperture development were also evaluated. RESULTS: Eleven RPE apertures were identified in 10 eyes of 10 patients (1 male, 9 females; mean age 73.1 +/- 6.7 years) and included for analysis. The RPE apertures appeared as round discontinuities either at the apex or at the base of avascular PED. No rippling or retraction of the RPE was found at the sites of aperture. The RPE apertures enlarged homogeneously (mean round area of hypoautofluorescence significantly increased from 0.18 +/- 0.13 to 0.93 +/- 1.2; P = 0.005), and PED flattened (PED maximal height on spectral domain optical coherence significantly decreased from 445.2 +/- 259 to 206.4 +/- 218; P = 0.04) after a mean of 38.6 +/- 16.3 months. Analysis of lesions preceding RPE apertures revealed areas of focal hyperautofluorescence at the site of development, in some cases appearing as drusenoid material connected with the base of avascular PED. CONCLUSION: The RPE aperture represents a previously unreported possible evolution of avascular PED, which should be distinguished by typical RPE tears. Analysis of lesions preceding RPE apertures suggests focal atrophic progression of drusenoid material in its pathogenesis. PMID- 28005665 TI - CHOROIDAL MORPHOLOGY IN EYES WITH POLYPOIDAL CHOROIDAL VASCULOPATHY AND NORMAL OR SUBNORMAL SUBFOVEAL CHOROIDAL THICKNESS. AB - PURPOSE: To subsegment the choroid in patients with polypoidal choroidal vasculopathy and to determine whether the ratio of choriocapillaris/Sattler layer thickness to total choroidal thickness is decreased at sites of polypoidal pathology. METHODS: Retrospective, observational, cross-sectional study. A total of 320 eyes of 305 patients with polypoidal choroidal vasculopathy were studied with optical coherence tomography and dye angiography. The ratio of choriocapillaris/Sattler layer thickness to total choroidal thickness was calculated at polypoidal lesion sites in eyes with subfoveal choroidal thickness (SFCT) <=200 MUm. RESULTS: Mean SFCT was 267.7 +/- 118.5 MUm for the entire cohort. Mean SFCT was 151.2 +/- 35.0 MUm in eyes with SFCT <=200 MUm (n = 124, 39%). In this subgroup, dilated Haller vessels (pachyvessels) were identified under the site of neovascular ingrowth in 117 eyes (94%). Choroidal thickness in the pachyvessel zone was greater (213.3 +/- 52.2 MUm) than SFCT (P < 0.001) with a significantly lower choriocapillaris/Sattler layer to total thickness ratio (P < 0.001). Qualitative alterations of the retinal pigment epithelium were observed in 60 eyes (51%). CONCLUSION: Eyes with normal or subnormal SFCT exhibited extrafoveal choroidal thickening at sites of polypoidal disease. The choriocapillaris and Sattler layers were attenuated at these locations, but Haller vessels were markedly dilated. These changes were topographically associated with sites of neovascular ingrowth and support the classification of polypoidal choroidal vasculopathy as a pachychoroid disorder. PMID- 28005666 TI - CLINICAL TRIAL ENDPOINTS FOR OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To describe qualitative and quantitative optical coherence tomography (OCT) angiography (OCTA) parameters for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and their applicability as potential clinical trial endpoints. METHODS: A review of current literature related to the topic of OCTA and AMD. RESULTS: There are a number of promising OCTA parameters that can be used to diagnose the presence of CNV and to monitor the activity and progression of the lesion, pre- and post-treatment morphological characteristics, CNV dimensions, and automated quantitative parameters such as vessel density. CONCLUSION: The OCTA parameters described in this review have promise for the future development of clinical trial endpoints, but require further validation before they can be widely used. PMID- 28005667 TI - AN AUTOMATIC, INTERCAPILLARY AREA-BASED ALGORITHM FOR QUANTIFYING DIABETES RELATED CAPILLARY DROPOUT USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To develop a robust, sensitive, and fully automatic algorithm to quantify diabetes-related capillary dropout using optical coherence tomography (OCT) angiography (OCTA). METHODS: A 1,050-nm wavelength, 400 kHz A-scan rate swept-source optical coherence tomography prototype was used to perform volumetric optical coherence tomography angiography imaging over 3 mm * 3 mm fields in normal controls (n = 5), patients with diabetes without diabetic retinopathy (DR) (n = 7), patients with nonproliferative diabetic retinopathy (NPDR) (n = 9), and patients with proliferative diabetic retinopathy (PDR) (n = 5); for each patient, one eye was imaged. A fully automatic algorithm to quantify intercapillary areas was developed. RESULTS: Of the 26 evaluated eyes, the segmentation was successful in 22 eyes (85%). The mean values of the 10 and 20 largest intercapillary areas, either including or excluding the foveal avascular zone, showed a consistent trend of increasing size from normal control eyes, to eyes with diabetic retinopathy but without diabetic retinopathy, to nonproliferative diabetic retinopathy eyes, and finally to PDR eyes. CONCLUSION: Optical coherence tomography angiography-based screening and monitoring of patients with diabetic retinopathy is critically dependent on automated vessel analysis. The algorithm presented was able to automatically extract an intercapillary area-based metric in patients having various stages of diabetic retinopathy. Intercapillary area-based approaches are likely more sensitive to early stage capillary dropout than vascular density-based methods. PMID- 28005668 TI - CORRELATION BETWEEN CYSTOID SPACES IN CHRONIC DIABETIC MACULAR EDEMA AND CAPILLARY NONPERFUSION DETECTED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To study the relationship between the location of cystoid spaces and retinal capillary nonperfusion areas in diabetic cystoid macular edema (DCME). METHODS: In this retrospective study, 24 eyes of 21 patients with chronic DCME were followed using optical coherence tomography angiography. The capillary density of the superficial capillary plexus and deep capillary plexus was measured using AngioAnalytics software in all DCME eyes and in 20 healthy controls. Diabetic cystoid macular edema improved spontaneously or after treatment in 11 eyes. RESULTS: The intraretinal cystoid spaces were surrounded by capillary-flow void areas in the superficial capillary plexus in 71% of cases and in the deep capillary plexus in 96% of cases. The deep capillary plexus had lost its regular pattern in all cases. The capillary density was decreased in both plexus (mean decrease of -23.0% in the superficial capillary plexus and -12.4% in the deep capillary plexus vs. normal). In the 11 cases with DCME resolution, the capillary did not reperfuse in areas of resolved cystoid spaces, and the capillary density did not change significantly. CONCLUSION: In chronic DCME, cystoid spaces were located within capillary dropout areas. No reperfusion occurred after DCME resolution. The impact of the severity of this nonperfusion on the risk of recurrence of DCME remains to be clarified. PMID- 28005669 TI - CORRELATION OF MULTIMODAL IMAGING IN SICKLE CELL RETINOPATHY. AB - PURPOSE: To correlate macular findings on spectral domain optical coherence tomography (SDOCT) and optical coherence tomography angiography (OCTA) with quantitative ischemic index calculations on ultra-wide-field fluorescein angiography (UWFFA) in patients with sickle cell retinopathy. METHODS: In this retrospective case series, SDOCT, OCTA, and UWFFA images of patients with sickle cell retinopathy were evaluated. Eyes were staged based on the Goldberg classification of proliferative sickle cell retinopathy. Focal areas of macular thinning were assessed on SDOCT, macular vessel density was derived from OCTA, and peripheral ischemic index was calculated from UWFFA. RESULTS: Eighteen eyes of 10 patients were included. Mean age was 36.8 +/- 16.8 years, and 6 patients (11 eyes) were SS, 3 patients (5 eyes) were SC, and 1 patient (2 eyes) was Sbeta thalassemia in hemoglobin electrophoresis. Abnormal macular findings included inner retinal atrophy in 11 eyes (61%) on SDOCT, vascular remodeling and nonperfusion in the superficial and deep retinal capillary plexus in 12 eyes (67%) on OCTA, and macular microvascular abnormalities in 9 eyes (50%) on UWFFA. Sickle cell retinopathy Stage I was identified in 4 eyes (22.2%), Stage II in 8 eyes (44.4%), and Stage III in 6 eyes (33.3%). Mean ischemic index was 14.1 +/- 9.1%. Ischemic index was significantly correlated with hemoglobinopathy subtype (23.7 +/- 9.8%, 9.3 +/- 5.4%, and 16.3 +/- 3.2%, for SC, SS, and Sbeta thalassemia disease, respectively), stage of sickle cell retinopathy (22.5 +/- 9.2%, 12.5 +/- 4.9%, and 4.5 +/- 0.73% for Stages III, II, and I, respectively), and presence of retinal thinning on SDOCT (17.4 +/- 9.7% vs. 8.8 +/- 5.1%, respectively). CONCLUSION: Multimodal imaging can provide a more complete description of the microvascular and structural alterations associated with sickle retinopathy. The correlation between the severity of peripheral nonperfusion and stage and subtype of retinopathy suggests that UWF imaging may be a useful tool in the evaluation of these patients. PMID- 28005670 TI - TOWARD QUANTITATIVE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY: Visualizing Blood Flow Speeds in Ocular Pathology Using Variable Interscan Time Analysis. AB - PURPOSE: Currently available optical coherence tomography angiography systems provide information about blood flux but only limited information about blood flow speed. The authors develop a method for mapping the previously proposed variable interscan time analysis (VISTA) algorithm into a color display that encodes relative blood flow speed. METHODS: Optical coherence tomography angiography was performed with a 1,050 nm, 400 kHz A-scan rate, swept source optical coherence tomography system using a 5 repeated B-scan protocol. Variable interscan time analysis was used to compute the optical coherence tomography angiography signal from B-scan pairs having 1.5 millisecond and 3.0 milliseconds interscan times. The resulting VISTA data were then mapped to a color space for display. RESULTS: The authors evaluated the VISTA visualization algorithm in normal eyes (n = 2), nonproliferative diabetic retinopathy eyes (n = 6), proliferative diabetic retinopathy eyes (n = 3), geographic atrophy eyes (n = 4), and exudative age-related macular degeneration eyes (n = 2). All eyes showed blood flow speed variations, and all eyes with pathology showed abnormal blood flow speeds compared with controls. CONCLUSION: The authors developed a novel method for mapping VISTA into a color display, allowing visualization of relative blood flow speeds. The method was found useful, in a small case series, for visualizing blood flow speeds in a variety of ocular diseases and serves as a step toward quantitative optical coherence tomography angiography. PMID- 28005671 TI - HYPERSPECTRAL AUTOFLUORESCENCE IMAGING OF DRUSEN AND RETINAL PIGMENT EPITHELIUM IN DONOR EYES WITH AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To elucidate the molecular pathogenesis of age-related macular degeneration (AMD) and interpretation of fundus autofluorescence imaging, the authors identified spectral autofluorescence characteristics of drusen and retinal pigment epithelium (RPE) in donor eyes with AMD. METHODS: Macular RPE/Bruch membrane flat mounts were prepared from 5 donor eyes with AMD. In 12 locations (1-3 per eye), hyperspectral autofluorescence images in 10-nm wavelength steps were acquired at 2 excitation wavelengths (lambdaex 436, 480 nm). A nonnegative tensor factorization algorithm was used to recover 5 abundant emission spectra and their corresponding spatial localizations. RESULTS: At lambdaex 436 nm, the authors consistently localized a novel spectrum (SDr) with a peak emission near 510 nm in drusen and sub-RPE deposits. Abundant emission spectra seen previously (S0 in Bruch membrane and S1, S2, and S3 in RPE lipofuscin/melanolipofuscin, respectively) also appeared in AMD eyes, with the same shapes and peak wavelengths as in normal tissue. Lipofuscin/melanolipofuscin spectra localizations in AMD eyes varied widely in their overlap with drusen, ranging from none to complete. CONCLUSION: An emission spectrum peaking at ~510 nm (lambdaex 436 nm) appears to be sensitive and specific for drusen and sub-RPE deposits. One or more abundant spectra from RPE organelles exhibit characteristic relationships with drusen. PMID- 28005673 TI - MULTIMODAL IMAGING OF DISEASE-ASSOCIATED PIGMENTARY CHANGES IN RETINITIS PIGMENTOSA. AB - PURPOSE: Using multiple imaging modalities, we evaluated the changes in photoreceptor cells and retinal pigment epithelium (RPE) that are associated with bone spicule-shaped melanin pigmentation in retinitis pigmentosa. METHODS: In a cohort of 60 patients with retinitis pigmentosa, short-wavelength autofluorescence, near-infrared autofluorescence (NIR-AF), NIR reflectance, spectral domain optical coherence tomography, and color fundus images were studied. RESULTS: Central AF rings were visible in both short-wavelength autofluorescence and NIR-AF images. Bone spicule pigmentation was nonreflective in NIR reflectance, hypoautofluorescent with short-wavelength autofluorescence and NIR-AF imaging, and presented as intraretinal hyperreflective foci in spectral domain optical coherence tomography images. In areas beyond the AF ring outer border, the photoreceptor ellipsoid zone band was absent in spectral domain optical coherence tomography and the visibility of choroidal vessels in short wavelength autofluorescence, NIR-AF, and NIR reflectance images was indicative of reduced RPE pigmentation. Choroidal visibility was most pronounced in the zone approaching peripheral areas of bone spicule pigmentation; here RPE/Bruch membrane thinning became apparent in spectral domain optical coherence tomography. CONCLUSION: These findings are consistent with a process by which RPE cells vacate their monolayer and migrate into inner retina in response to photoreceptor cell degeneration. The remaining RPE spread undergo thinning and consequently become less pigmented. An explanation for the absence of NIR-AF melanin signal in relation to bone spicule pigmentation is not forthcoming. PMID- 28005672 TI - DISCORDANCE BETWEEN BLUE-LIGHT AUTOFLUORESCENCE AND NEAR-INFRARED AUTOFLUORESCENCE IN AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To identify the origin and significance of discordance between blue light autofluorescence (BL-AF; 488 nm) and near-infrared autofluorescence (NI-AF; 787 nm) in patients with age-related macular degeneration (AMD). METHODS: A total of 86 eyes of 59 patients with a diagnosis of AMD were included in this cross sectional study conducted between March 9, 2015 and May 1, 2015. A masked observer examined the BL-AF, NI-AF, and spectral-domain optical coherence tomography images. Areas with discordance of autofluorescence patterns between NI AF and BL-AF images were correlated with structural findings at the corresponding location in optical coherence tomography scans. RESULTS: Seventy-nine eyes had discordance between BL-AF and NI-AF. The most common optical coherence tomography finding accounting for these discrepancies was pigment migration accounting for 35 lesions in 21 eyes. The most clinically relevant finding was geographic atrophy missed on BL-AF in 7 eyes. CONCLUSION: Our findings indicate that variations in the distribution of lipofuscin, melanin and melanolipofuscin account for the majority of discordance between BL-AF and NI-AF. Given our finding of missed geographic atrophy lesions on BL-AF in 24% of eyes with geographic atrophy (7/29 eyes), clinicians should consider multimodal imaging, including NI-AF and optical coherence tomography, especially in clinical trials of geographic atrophy. PMID- 28005674 TI - DIDANOSINE RETINAL TOXICITY. AB - PURPOSE: To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature. METHODS: This was a multicenter, retrospective, observational case study from seven institutions. Medical records of patients who demonstrated well-demarcated severe midperipheral chorioretinal degeneration and who were previously treated with didanosine therapy were collected and the following information was reviewed: age, gender, medical history, detailed medication history including current and previous antiretroviral use, ocular and retinal examination findings, and multimodal imaging findings with optical coherence tomography, fundus photography, wide-field fundus autofluorescence, and wide-field fluorescein angiography. When available, findings with electrophysiology testing and automated perimetry were also collected and reviewed. A literature review was also performed to collect all reported cases of chorioretinal degeneration secondary to didanosine toxicity. RESULTS: Nine patients were identified who had findings consistent with peripheral retinal toxicity secondary to didanosine use. Eight of the 9 patients were men, and the median age was 54 years at the time of presentation (mean: 55 years, range, 42-71 years). Snellen distance acuity ranged from 20/20 to 20/32. At least three of the cases in the series demonstrated progression of the peripheral retinal pigment epithelium and photoreceptor atrophy despite didanosine cessation. A review of the literature revealed 10 additional cases of didanosine toxicity. Seven of the 10 cases were in men (70%), and the average age was 26 years with a wide range (2-54 years). Chorioretinal findings were very similar to this cohort. CONCLUSION: Herein, we report the largest series of nine cases of peripheral chorioretinal degeneration secondary to didanosine toxicity in adults. When combined with the cases in the literature, 19 cases of didanosine toxicity, 4 of which occurred in children, were collected and analyzed. Three of the new cases presented showed clear progression of degeneration despite didanosine cessation. Newer nucleoside reverse transcriptase inhibitors may potentiate mitochondrial DNA damage and lead to continued chorioretinal degeneration. PMID- 28005675 TI - SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF THE OPTIC DISK IN OPTIC NEUROPATHY. AB - PURPOSE: To evaluate the optic nerve head microvasculature in eyes with acute and chronic optic neuropathies using swept-source optical coherence tomography angiography. METHODS: In this cross-sectional, observational study, optical coherence tomography angiography images were obtained from the optic nerve heads of 21 eyes of 12 patients with optic disk edema, pseudoedema and atrophy, and 12 eyes of 6 healthy subjects using a 1,050-nm optical coherence tomography angiography (Topcon DRI OCT; Triton). Peripapillary vasculature was assessed within five horizontal slabs consisting of the nerve fiber layer (NFL), ganglion cell layer, inner nuclear layer, choroidal layer, and full-thickness retinal layer. In addition, prelaminar and laminar slabs were evaluated. Vessel density was measured within a 3.4-mm diameter circle centered on the optic disk. RESULTS: The abnormalities of the peripapillary capillary network were most apparent in the NFL and total retinal slabs. In eyes with disk edema, an increase or decrease in the visibility of the peripapillary capillary network was observed. Eyes with optic atrophy had decreased visibility of peripapillary capillary network corresponding to the region or sector of NFL thinning. Prelaminar capillary network was dilated and tortuous in eyes with disk edema. The mean vessel density was statistically significantly lower and the mean NFL thickness was statistically significantly thinner in eyes with optic atrophy compared with normal eyes (both P < 0.001). Vessel density was significantly correlated with the peripapillary NFL thickness (P < 0.001). CONCLUSION: Optical coherence tomography angiography provides high-resolution, noninvasive visualization of the microvasculature of the optic nerve head and peripapillary region. Changes in the microvasculature in this region may prove useful in better characterization of optic neuropathies. PMID- 28005676 TI - EN FACE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF MULTIPLE EVANESCENT WHITE DOT SYNDROME: New Insights Into Pathogenesis. AB - PURPOSE: To localize the various levels of abnormalities in multiple evanescent white dot syndrome by comparing "en face" optical coherence tomography (OCT) and OCT angiography with various conventional imaging modalities. METHODS: In this retrospective case series, multimodal imaging was performed in 9 retinal centers on 36 patients with multiple evanescent white dot syndrome and included widefield fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography, and B-scan and "en face" C-scan enhanced depth imaging and spectral domain OCT. Optical coherence tomography angiography was also performed at the level of the superficial and deep retinal capillary plexus and choroid. RESULTS: Multiple evanescent white dot syndrome lesions were more numerous and more easily detectable with FA and FAF. Two types of lesions were identified with FAF, FA, and indocyanine green angiography: larger widely scattered "spots" (approximately 200 MU in diameter) that were hyperfluorescent with FA, hyperautofluorescent with FAF, and hyporeflective in indocyanine green angiography, representing abnormalities primarily at the retinal pigment epithelium/photoreceptor junction; and punctate "dots" (less than 100 MU in diameter) that were hyperfluorescent with FA, hyperautofluorescent, or isoautofluorescent with FAF, and hypofluorescent with indocyanine green angiography and that localized to the outer nuclear layer. These lesions colocalized with "en face" OCT. The larger confluent "spots" were hyporeflective and colocalized to the level of the ellipsoid zone, whereas smaller hyperreflective "dots" colocalized to the outer nuclear layer. The location of the "dots" in the outer nuclear layer was further confirmed by structural spectral domain optical coherence tomography which showed coalescence of the dots into hyperreflective lines extending from the external limiting membrane to the outer plexiform layer in certain cases. Optical coherence tomography angiography analysis of the retinal microvasculature and choriocapillaris and choroid were entirely unremarkable in 100% of our patients. CONCLUSION: By combining multimodal imaging, the authors propose that multiple evanescent white dot syndrome is primarily the result of inflammation at the outer photoreceptor level leading to a "photoreceptoritis" and causing loss of the inner and outer segments. Its evanescent nature suggests that the photoreceptor cell bodies remain intact ensuring complete recovery of the photoreceptor inner and outer segments in most cases, compatible with the clinical course of spontaneous resolution of white spots and dots. PMID- 28005677 TI - An exploratory analysis for Lean and Six Sigma implementation in hospitals: Together is better? AB - BACKGROUND: Despite the increasing interest for Lean and Six Sigma implementations in hospitals, there has been little empirical evidence that goes beyond descriptive case studies to address the current status and the effectiveness of the implementations. PURPOSE: The aim of this study was to explore existing patterns of Lean and Six Sigma implementation in U.S. hospitals and compare the performance of the different patterns. METHODOLOGY/APPROACH: We collected data from 215 U.S. hospitals via a survey that includes measurement items developed from related literature. Using the cross-sectional data, we conducted a cluster analysis, followed by t tests, chi-square tests, and regression analyses for cluster verification. RESULTS: The cluster analysis identifies two clusters, a Moderate Six Sigma group and a Lean Six Sigma group. Results show that the Lean Six Sigma group outperforms the Moderate Six Sigma group across many performance dimensions: responsiveness capability, patient safety, and possibly cost saving. In addition, the Lean Six Sigma group tends to be composed of larger, private teaching hospitals located in more urban areas, and they employ more resources for quality improvement. CONCLUSION: Our research contributes to the quality management literature by supporting the possible complementary relationship between Lean and Six Sigma in hospitals. PRACTICE IMPLICATIONS: Our study encourages practitioners and managers to pay more attention to Lean implementation. Although Lean seems to be conducted in a limited fashion in many hospitals, it should be expanded and combined with Six Sigma for better results. PMID- 28005678 TI - From the Editor. PMID- 28005679 TI - Predictors of Cardiac Rehabilitation Initiation and Adherence in a Multiracial Urban Population. AB - BACKGROUND: Lack of initiation and adherence to cardiac rehabilitation (CR) remains a persistent problem. We sought to examine predictors of initiation, adherence, and completion of CR in a unique, minority predominant, urban population. METHODS: We included all patients who were first-time referred to the outpatient CR program at Montefiore Medical Center between 1997 and 2010. The indications for referral included acute myocardial infarction, coronary artery disease, heart failure, stable angina, and valvular heart disease. Adherence was defined as attendance of at least 18 sessions of CR, and completion was defined as attendance of 36 sessions. Multivariable logistic regression was utilized to examine the predictors of initiation, adherence, and completion of CR. RESULTS: A total of 590 patients were included (43.9% white and 56.1% nonwhite patients). Among 400 patients who initiated CR, 229 patients (57.3%) attended at least 18 sessions and 140 patients (35.0%) completed all sessions. Initiation of CR was less likely in patients who were nonwhite (OR = 0.66; 95% CI: 0.44-0.97; P = .04) and those who lacked insurance (OR = 0.54; 95% CI: 0.29-0.83; P = .04). Older age was associated with better adherence (OR = 1.04; 95% CI: 1.02-1.07; P < .001). Requirement of a copayment (OR = 0.57; 95% CI: 0.37-0.87; P = .01) was associated with poor adherence. CONCLUSION: In a multiracial population, nonwhite patients and those who did not have insurance were less likely to initiate CR. Younger age and requirement of copayment were independent predictors for poor adherence. Increasing medical insurance coverage and eliminating copayment may improve the participation and adherence of CR. PMID- 28005680 TI - Resistance Training With Ankle Weight Cuffs Is Feasible in Patients With Acute Exacerbation of COPD. AB - PURPOSE: Quadriceps muscle weakness is a serious complication of physical inactivity following hospitalization due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Preventing strength loss during AECOPD is therefore a high priority. We aimed to evaluate the feasibility of progressive knee-extension resistance training, using ankle weight cuffs on patients with AECOPD, based on prespecified criteria for feasibility. METHODS: Thirty-four patients (18 men, mean age 74 years, forced expiratory volume in 1 second = 33% predicted) with AECOPD participated in daily knee-extension strength training. During training, the patients were seated on the bedside and performed 3 sets of 10-repetition maximum loads, using ankle weight cuffs. The primary outcome was the change in load from the first to last training sessions. The secondary outcomes were changes in maximal isometric knee-extension strength, the Sit-to Stand (STS) and Timed Up and Go (TUG) tests. RESULTS: The training load increased progressively by a mean (standard deviation) of 54% +/- 41% (when calculated on an individual basis), from a mean of 6.5 +/- 3.3 to 9.2 +/- 3.5 kg over the course of 5.6 +/- 2.3 training days (P < .001). Knee-extension strength improved by a mean of 12% (P = .02), whereas the TUG and STS test performances improved by 11% (P = .001) and 19% (P = .03), respectively. Ninety-eight percent of the planned training sessions were completed with no side effects. CONCLUSIONS: Progressive resistance training with ankle weight cuffs is feasible in patients who are severely disabled due to AECOPD. The approach is simple and seems to counteract the loss of muscle strength and function during hospitalization. PMID- 28005681 TI - Outcomes of Pulmonary Rehabilitation After Treatment for Non-Small Cell Lung Cancer Stages I to IIIa: AN OBSERVATIONAL STUDY. AB - PURPOSE: Although rehabilitation after treatment for non-small cell lung cancer (NSCLC) was found to have a beneficial effect on exercise capacity in a number of studies, insight into its effect on quality of life (QoL) and fatigue is limited. The aim of this study was to examine the outcome of pulmonary rehabilitation (PR) regarding fatigue, QoL, and exercise capacity in adult patients curatively treated for NSCLC stages I to IIIa. METHODS: Study data were prospectively and routinely gathered in daily practice in patients taking part in an outpatient PR program after treatment for NSCLC stages I to IIIa. PR consisted of 12 weeks of supervised exercises 3 times a week, supplemented with scheduled visits with members of a multidisciplinary team. Data were gathered at initial assessment and discharge. Outcomes included fatigue (the Functional Assessment of Cancer Therapy Fatigue and the fatigue domain of the Chronic Respiratory Disease Questionnaire); QoL (total CRQ score), Functional Assessment of Cancer Therapy-Lung, and the Short Form 36; and exercise capacity (cardiopulmonary exercise testing). RESULTS: Fifty patients started the program out of the 70 patients referred to PR and 43 (86%) completed the program. Significant (P <= .01) and clinically relevant improvements were observed for all outcome measures. CONCLUSIONS: Rehabilitation after treatment for NSCLC stages I to IIIa showed promising improvements regarding patient fatigue, QoL, and exercise capacity. PR should be considered for patients after treatment for NSCLC stages I to IIIa. PMID- 28005683 TI - Association of Body Length with Ocular Parameters in Mice. AB - PURPOSE: To determine the association between changes in body length with ocular refraction, corneal radii, axial length, and lens thickness in two different mouse strains. METHODS: Body length, ocular refraction, corneal radii, axial length, and lens thickness were measured for two inbred mouse strains: 129S1/SvJ (n = 7) and C57BL/6 J (n = 10) from 4 to 12 weeks of age. Body length, from tip of nose to base of tail, was obtained using a digital camera. Biometric parameters, corneal radii, and refractions were measured using spectral-domain optical coherence tomography, automated keratometry, and infrared photorefraction, respectively. A mixed-model ANOVA was performed to examine the changes in ocular parameters as a function of body length and strain in mice controlling for age, gender, and weight over time. RESULTS: C57BL/6J mice had significantly longer body length (average body length at 10 weeks, 8.60 +/- 0.06 cm) compared to 129S1/SvJ mice (8.31 +/- 0.05 cm) during development (P < .001). C57BL/6J mice had significantly hyperopic refractions compared to 129S1/SvJ mice across age (mean refraction at 10 weeks, 129S1/SvJ: +0.99 +/- 0.44D vs. C57BL/6J: +6.24 +/- 0.38D, P < .001). Corneal radius of curvature, axial length, and lens thickness (except 10 weeks lens thickness) were similar between the two strains throughout the measurement. In the mixed-model ANOVA, changes in body length showed an independent and significant association with the changes in refraction (P = .002) and corneal radii (P = .016) for each mouse strain. No significant association was found between the changes in axial length (P = .925) or lens thickness (P = .973) as a function of body length and strain. CONCLUSIONS: Changes in body length are significantly associated with the changes in ocular refraction and corneal radii in different mouse strains. Future studies are needed to determine if the association between body length and ocular refraction are related to changes in corneal curvature in mice. PMID- 28005684 TI - Large cluster outbreaks sustain the HIV epidemic among MSM in Quebec. AB - OBJECTIVE: HIV-1 epidemics among MSM remain unchecked despite advances in treatment and prevention paradigms. This study combined viral phylogenetic and behavioural risk data to better understand underlying factors governing the temporal growth of the HIV epidemic among MSM in Quebec (2002-2015). METHODS: Phylogenetic analysis of pol sequences was used to deduce HIV-1 transmission dynamics (cluster size, size distribution and growth rate) in first genotypes of treatment-naive MSM (2002-2015, n = 3901). Low sequence diversity of first genotypes (0-0.44% mixed base calls) was used as an indication of early-stage infection. Behavioural risk data were obtained from the Montreal rapid testing site and primary HIV-1-infection cohorts. RESULTS: Phylogenetic analyses uncovered high proportion of clustering of new MSM infections. Overall, 27, 45, 48, 53 and 57% of first genotypes within one (singleton, n = 1359), 2-4 (n = 692), 5-9 (n = 367), 10-19 (n = 405) and 20+ (n = 1277) cluster size groups were early infections (<0.44% diversity). Thirty viruses within large 20+ clusters disproportionately fuelled the epidemic, representing 13, 25 and 42% of infections, first genotyped in 2004-2007 (n = 1314), 2008-2011 (n = 1356) and 2012-2015 (n = 1033), respectively. Of note, 35, 21 and 14% of MSM belonging to 20+, 2-19 and one (singleton) cluster groups were under 30 years of age, respectively. Half of persons seen at the rapid testing site (2009-2011, n = 1781) were untested in the prior year. Poor testing propensity was associated with fewer reported partnerships. CONCLUSION: Addressing the heterogeneity in transmission dynamics among HIV-1-infected MSM populations may help guide testing, treatment and prevention strategies. PMID- 28005685 TI - Is response to anti-hepatitis C virus treatment predictive of mortality in hepatitis C virus/HIV-positive patients? AB - BACKGROUND: Long-term clinical outcomes after hepatitis C virus (HCV) treatment of HIV/HCV patients are not well described. We aimed to compare the risk of all cause and liver-related death (LRD) according to HCV treatment response in HIV/HCV patients in the multicohort study Collaboration of Observational HIV Epidemiological Research in Europe. METHODS: All patients who had started pegylated interferon + ribavirin (baseline) and followed for at least 72 weeks after baseline were included. Patients were categorized into three response groups depending on treatment duration and HCV-RNA measured in the window 24-72 weeks after baseline. Patients who received at least 24 weeks of therapy were defined as responders if their last HCV-RNA measured between 24 and 72 weeks after baseline was negative, and having 'unknown response' if HCV-RNA was unknown. Nonresponders were treated for less than 24 weeks or were HCV-RNA+ between 24 and 72 weeks after baseline. Mortality rates were compared using survival analysis, and Cox regression was used to compare hazard ratios of death between response groups. RESULTS: A total of 3755 patients were included: 1031 (27.5%) responders, 1639 (43.6%) nonresponders and 1085 (28.9%) with unknown response. Rates [per 1000 person-years of follow-up, 95% confidence interval (CI)] of all-cause death were 17.59 (14.88-20.78), 10.43 (7.62-14.28) and 11.00 (8.54-14.23) for nonresponders, responders and unknown responders, respectively. After adjustment, the relative hazard (nonresponders vs. responders) for all cause death, LRD and nonliver-related death was 1.53 (95% CI 1.06-2.22), 3.39 (95% CI 1.32-8.75) and 1.22 (95% CI 0.80-1.84), respectively. CONCLUSION: HIV/HCV patients with a favourable virological response to pegylated interferon + ribavirin had reduced risk of all-cause and LRD, whereas there was no difference in risk of nonliver-related death when comparing responders and nonresponders. PMID- 28005687 TI - Response to Tenofovir Among Lamivudine-experienced Hepatitis B and HIV-coinfected Adolescents. AB - We determined hepatitis B virus (HBV) suppression rates among 18 lamivudine (3TC) experienced HBV-human immunodeficiency virus-coinfected adolescents after treatment with tenofovir disoproxil fumurate (TDF). At TDF initiation, their median age was 17.6 years, and duration of 3TC exposure was 7.3 years. Eleven patients (61%) achieved HBV DNA <60 IU/mL after 48 weeks on TDF and 3TC which was similar to adult studies, although hepatitis B surface antigen loss or hepatitis B envelope antigen seroconversion did not occur. PMID- 28005686 TI - Transcriptome analyses identify key cellular factors associated with HIV-1 associated neuropathogenesis in infected men. AB - OBJECTIVE: HIV-1 viral proteins and host inflammatory factors have a direct role in neuronal toxicity in vitro; however, the contribution of these factors in vivo in HIV-1-associated neurocognitive disorder (HAND) is not fully understood. We applied novel Systems Biology approaches to identify specific cellular and viral factors and their related pathways that are associated with different stages of HAND. DESIGN: A cross-sectional study of individuals enrolled in the Multicenter AIDS Cohort Study including HIV-1-seronegative (N = 36) and HIV-1-seropositive individuals without neurocognitive symptoms (N = 16) or with mild neurocognitive disorder (MND) (N = 8) or HIV-associated dementia (HAD) (N = 16). METHODS: A systematic evaluation of global transcriptome of peripheral blood mononuclear cells (PBMCs) obtained from HIV-1-seronegative individuals and from HIV-1 positive men without neurocognitive symptoms, or MND or HAD was performed. RESULTS: MND and HAD were associated with specific changes in mRNA transcripts and microRNAs in PBMCs. Comparison of upstream regulators and TimePath analyses identified specific cellular factors associated with MND and HAD, whereas HIV-1 viral proteins played a greater role in HAD. In addition, expression of specific microRNAs - miR-let-7a, miR-124, miR-15a and others - were found to correlate with mRNA gene expression and may have a potential protective role in asymptomatic HIV-1-seropositive individuals by regulating cellular signal transduction pathways downstream of chemokines and cytokines. CONCLUSION: These results identify signature transcriptome changes in PBMCs associated with stages of HAND and shed light on the potential contribution of host cellular factors and viral proteins in HAND development. PMID- 28005688 TI - Respiratory Syncytial Virus Infection-associated Hospitalization Rates in Infants and Children With Cystic Fibrosis. AB - BACKGROUND: Infections with respiratory syncytial virus (RSV) are the leading cause for hospital admissions in infants and young children. The incidence of RSV related hospitalizations in patients with cystic fibrosis (CF) is unclear. To date, no effective treatment for RSV infections is available. Thus, prophylaxis with the monoclonal antibody palivizumab is an important option. METHODS: In a retrospective, single-center study at the Department of Pediatrics and Adolescent Medicine of the Medical University Graz, Austria, we analyzed all CF patients born between 1995 and 2012, who were admitted for respiratory problems between 1995 and 2014. We also defined a group of hypothetical RSV infections with the following criteria: admission caused by a respiratory infection during the first RSV season of life when no test for RSV was performed. Furthermore, we assessed the effectiveness of palivizumab as a prevention of RSV-related hospitalizations. RESULTS: A total of 51 patients with CF were identified. The RSV-related hospitalization rate for the first RSV season was 0. Two patients (3.9%) were hospitalized 3 and 4 times, respectively, caused by RSV infections. The mean age at the time of admission was 12.4 +/- 2.5 years. One case (1.9%) met our criteria for hypothetical RSV infections. There was no difference in RSV-related hospitalization rates between patients who received palivizumab and those who did not. CONCLUSIONS: We found a low rate of RSV-related hospitalizations and could not demonstrate a benefit of palivizumab prophylaxis regarding a decrease of RSV related hospital admissions. The role of RSV reinfections in CF patients beyond infancy appears to be underestimated. PMID- 28005689 TI - Epidemiology and Outcomes of Hospitalized Children With Necrotizing Soft-Tissue Infections. AB - OBJECTIVE: The purpose of this study was to evaluate the epidemiology and outcome of hospitalized children with a diagnosis of necrotizing soft-tissue infections (NSTIs). METHODS: Demographic and outcome data of children 1 month to 18 years of age with a diagnosis of NSTI (International Classification of Diseases, 9th revision diagnosis codes 728.86 and 729.4) were extracted from the Kids' Inpatient Database 2009 and 2012. Univariate and multivariate analyses were done to determine the factors affecting mortality. The sample data were weighted to get national estimates. RESULTS: A total of 446 children with NSTI (prevalence of 1.12/10,000 discharges) were included. Males comprised 54%. The median age was 10 (interquartile range 4-16) years. The mortality rate was 6%. In addition, 29.3% of children with NSTI were discharged to either skilled nursing facilities or to home health care compared with 4.5% of children without NSTI (odds ratio 8.9; 95% confidence interval 7.3-10.9; P < 0001). A bacterial infection was reported in 72.1% of children. An infection with Staphylococcus, Streptococcus, Gram-negative bacteria, anaerobic bacteria, methicillin-resistant Staphylococcus areus and polymicrobia was present in 34.5%, 21.8%, 8.6%, 3.9%, 18.7% and 13.6% of cases, respectively. A compartment syndrome, severe sepsis/septic shock and toxic shock were documented in 4.4%, 22.2% and 3.2% of the cases, respectively. Severe sepsis/septic shock, the need for mechanical ventilation and Hispanic race were associated with increased mortality, whereas skin/muscle surgery was associated with lower mortality. CONCLUSIONS: NSTI in children is associated with high morbidity. The mortality is higher with the presence of severe sepsis/septic shock and among Hispanics and lower with surgical intervention. PMID- 28005690 TI - Low Bone Mineral Density in Vertically HIV-infected Children and Adolescents: Risk Factors and the Role of T-cell Activation and Senescence. AB - BACKGROUND: Our aim was to determine the prevalence and risk factors associated with low bone mineral density (BMD) in vertically HIV-infected patients and to investigate whether low BMD is related to immune activation and senescence induced by HIV infection. METHODS: A cross-sectional study was performed in 98 vertically HIV-infected patients. BMD was measured by dual-energy radiograph absorptiometry at lumbar spine. Height adjustment of BMD Z score was performed using height-for-age Z score. T-cell immune activation and senescence were analyzed in a subgroup of 54 patients by flow cytometry. RESULTS: Median age was 15.9 years, 71.4% were Caucasian, 99% received antiretroviral therapy and 80.6% had undetectable viral load. Low BMD (BMD Z score <= -2) was present in 15.3% of cases, but after height adjustment in 4.1% of cases. Height-adjusted BMD Z score was positively correlated with body mass index Z score, CD4/CD8 ratio and nadir CD4, and inversely with duration of severe immunosuppression and parathyroid hormone values. In the multivariate model including age, gender, ethnicity, encephalopathy, Tanner stage, nadir CD4, duration of viral suppression, CD4 count, CD4/CD8 ratio, body mass index, cumulative duration of antiretroviral therapy, tenofovir and protease inhibitors exposure, nadir CD4 was independently associated to height-adjusted BMD Z score. No association was found between height-adjusted BMD Z score and T-cell activation or senescence. CONCLUSIONS: The prevalence of low BMD in vertically HIV-infected patients was low after height adjustment. Nadir CD4, but not T-cell activation or senescence, was an independent predictor for low BMD. Larger and prospective studies are needed to achieve better knowledge of the pathogenesis of low BMD in vertical HIV infection. PMID- 28005691 TI - Clinical and Bacterial Risk Factors for Mortality in Children With Carbapenem resistant Enterobacteriaceae Bloodstream Infections in India. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are an increasing cause of nosocomial infection in hospitalized children worldwide. Few studies have investigated risk factors for mortality in children with CRE bloodstream infection (BSI). Data are particularly scarce in areas where NDM and OXA carbapenemases predominate. Here, we investigate mortality rates, clinical and microbiologic risk factors for mortality in 50 pediatric patients with CRE BSI in India. METHODS: Children younger than 17 years old with meropenem-resistant Klebsiella pneumoniae or Escherichia coli isolated from blood culture in 2014 and 2015 were identified from laboratory records. Clinical records were systematically reviewed for each child to establish mortality at 30 days and clinical details. Bacterial isolates were subjected to meropenem E test and multiplex polymerase chain reaction to determine carbapenemase gene. Data were analyzed to establish clinical and bacterial risk factors for mortality. RESULTS: All CRE BSI were hospital-acquired or associated with healthcare. A total of 84% of children had an underlying comorbidity and 46% had a malignancy. K. pneumoniae was the most common bacteria isolated; NDM was the most common carbapenemase gene detected. The mortality rate was 52%. Significant risk factors for mortality included intensive care admission, intubation, inotropic support and respiratory source. Failure to clear bacteremia and a minimum inhibitory concentration > 8 mg/L for the isolate was associated with a statistically significant increase in mortality. Mortality rates were significantly lower when two or more effective drugs were used in combination. CONCLUSIONS: CRE BSI affects children with multiple comorbidities and repeated admissions to hospital. The mortality rate is high; combination therapy may be beneficial. PMID- 28005692 TI - Nasal Airway Microbiota Profile and Severe Bronchiolitis in Infants: A Case control Study. AB - BACKGROUND: Little is known about the relationship of airway microbiota with bronchiolitis in infants. We aimed to identify nasal airway microbiota profiles and to determine their association with the likelihood of bronchiolitis in infants. METHODS: A case-control study was conducted. As a part of a multicenter prospective study, we collected nasal airway samples from 40 infants hospitalized with bronchiolitis. We concurrently enrolled 110 age-matched healthy controls. By applying 16S ribosomal RNA gene sequencing and an unbiased clustering approach to these 150 nasal samples, we identified microbiota profiles and determined the association of microbiota profiles with likelihood of bronchiolitis. RESULTS: Overall, the median age was 3 months and 56% were male. Unbiased clustering of airway microbiota identified 4 distinct profiles: Moraxella-dominant profile (37%), Corynebacterium/Dolosigranulum-dominant profile (27%), Staphylococcus dominant profile (15%) and mixed profile (20%). Proportion of bronchiolitis was lowest in infants with Moraxella-dominant profile (14%) and highest in those with Staphylococcus-dominant profile (57%), corresponding to an odds ratio of 7.80 (95% confidence interval, 2.64-24.9; P < 0.001). In the multivariable model, the association between Staphylococcus-dominant profile and greater likelihood of bronchiolitis persisted (odds ratio for comparison with Moraxella-dominant profile, 5.16; 95% confidence interval, 1.26-22.9; P = 0.03). By contrast, Corynebacterium/Dolosigranulum-dominant profile group had low proportion of infants with bronchiolitis (17%); the likelihood of bronchiolitis in this group did not significantly differ from those with Moraxella-dominant profile in both unadjusted and adjusted analyses. CONCLUSIONS: In this case-control study, we identified 4 distinct nasal airway microbiota profiles in infants. Moraxella dominant and Corynebacterium/Dolosigranulum-dominant profiles were associated with low likelihood of bronchiolitis, while Staphylococcus-dominant profile was associated with high likelihood of bronchiolitis. PMID- 28005693 TI - Transplantation in Ireland. PMID- 28005695 TI - Foretelling Graft Outcome by Molecular Evaluation of Renal Allograft Biopsies: The GoCAR Study. PMID- 28005697 TI - Checks and Balances-Microbiota Shifts in Immunosuppressed Mice. PMID- 28005698 TI - Prenatal and postnatal exposure to pet ownership, blood pressure, and hypertension in children: the Seven Northeastern Cities study. AB - OBJECTIVE: There is little information about how exposure to pets impacts blood pressure (BP) in children. The objective of the present study was to investigate the association between pet exposure and BP in children. METHODS: A total of 9354 children, aged 5-17 years, from 24 elementary schools and 24 middle schools in the Seven Northeastern Cities were evaluated during 2012-2013. BP measurements were taken using a mercury sphygmomanometer. Hypertension in children was defined as having an average DBP or SBP in the 95th percentile or higher for the child's sex, age, and height. RESULTS: Overall, 2127 of the 9354 participants (22.7%) had current exposures to pets, with 989 of all participants having dogs (10.6%). Pet exposure was negatively associated with hypertension and BP in men and women. Keeping dogs in the home was related to a significantly lower prevalence of hypertension in men [adjusted odds ratio (aOR) = 0.68; 95% confidence interval (CI): 0.49-0.94] and women (aOR = 0.66; 95% CI: 0.48-0.90). When the analysis was stratified by sex, in-utero exposure to pets was negatively associated with hypertension in men (aOR = 0.66; 95% CI: 0.45-0.97), and the associations with lower BP strengthened with higher levels of current pet exposure. As for BP, the associations between pet exposure and DBP were detected more in women; estimated decreases in mean DBP was 1.10 mmHg (95% CI: -1.75 to -0.45) for current pet exposure. CONCLUSION: Pet ownership reduces the odds of hypertension and elevated BP in children. PMID- 28005699 TI - Home versus office blood pressure: longitudinal relations with left ventricular hypertrophy: the Finn-Home study. AB - OBJECTIVES: Electrocardiographically assessed left-ventricular hypertrophy (ECG LVH) is a particularly high-risk phenomenon that is a part of every hypertensive patient's initial work-up. Several cross-sectional studies have demonstrated that home blood pressure (BP) has a stronger relation to LVH than office BP. However, longitudinal evidence on the association between home BP and target organ damage is scarce to nonexistent. METHODS: We studied in a sample of 615 community dwelling participants (mean age at baseline 53.7 +/- 7.2, 58% women) whether change in home BP is more strongly associated with change in ECG-LVH than change in office BP over an 11-year follow-up. RESULTS: Pearson's correlation coefficients between changes in home/office SBP and changes in Sokolow-Lyon index, Cornell voltage, Cornell product and R wave amplitude in aVL were 0.21/0.18, 0.28/0.17, 0.25/0.16, and 0.32/0.20, respectively (asterisk indicates P < 0.05 for between-method difference in correlations with Steiger's z test). For change in home/office DBP and change in the aforementioned ECG-LVH indexes, the correlations were 0.12/0.12, 0.20/0.15, 0.16/0.12, and 0.28/0.19. Multivariable-adjusted regression modelling provided similar results. No clinically significant increase in correlations between home BP and ECG-LVH indexes occurred after the fourth day of home BP measurement. CONCLUSION: Our study demonstrates for the first time the superiority of home BP over office BP in the follow-up of left ventricular mass. The results of this and previous studies underline the importance of using out-of-office BP measurements as the primary method for assessing blood pressure levels. PMID- 28005700 TI - Morning pressor surge, blood pressure variability, and arterial stiffness in essential hypertension. AB - OBJECTIVE: An excess morning blood pressure surge (MBPS) may portend an increased cardiovascular risk, but the mechanisms thereof have been little investigated. The link between MBPS, short-term blood pressure (BP) variability, and arterial stiffness has not been entirely defined. METHODS: In 602 consecutive untreated hypertensive patients (48 +/- 12 years, 61% men, office BP 149/93 +/- 17/10 mmHg), we measured carotid-femoral pulse wave velocity (cf-PWV, SphygmoCor) and 24-h ambulatory BP. Using self-reported sleep and wake times, MBPS was defined as sleep-trough (ST-MBPS), prewaking, rising. Short-term BP variability was calculated as weighted 24-h SBP SD and average real variability of 24-h SBP (ARV), that is, average of absolute differences between consecutive SBP readings. RESULTS: ST-MBPS (r = 0.16, P < 0.001) and rising MBPS (r = 0.12, P = 0.003) showed a direct correlation with cf-PWV, whereas prewaking MBPS had no such relation (r = 0.06, P = 0.14). Only ST-MBPS was independently associated with cf PWV (t = 1.96, P = 0.04) after adjustment for age, sex, height, office mean arterial pressure, heart rate, and renal function. This association was lost after further adjustment for weighted 24-h SBP SD (P = 0.13) or ARV (P = 0.24). ARV was a significant mediator of the relationship between ST-MBPS and cf-PWV (P = 0.003). CONCLUSION: In untreated hypertension, ST-MBPS has a direct relation with aortic stiffness, which is mediated by an increased ARV. The adverse effects of MBPS may be partly explained by its link with arterial stiffness, mediated by short-term SBP variability. PMID- 28005701 TI - Effect of short-term exercise training on brain-derived neurotrophic factor signaling in spontaneously hypertensive rats. AB - OBJECTIVE: Decreased brain-derived neurotrophic factor (BDNF) level has been reported in the hippocampus of hypertensive rats. The present study explored whether brain neurons and/or endothelial cells are targeted by hypertension with respect to BDNF expression and the potential of physical exercise to cope with hypertension. METHODS: Physical exercise was induced in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. The hippocampus of sedentary and exercised rats (n = 6 for each group) were used for western blots to assess proBDNF, mature BDNF (mBDNF), tropomyosin-related kinase B (TrkB), P-TrkB (TrkB phosphorylated at tyrosine 816), synaptophysin, endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated at serine 1177 protein levels. BDNF and proBDNF localization in the hippocampus was studied in WKY rats, SHR and exercised SHR (n = 5 each). mBDNF and proBDNF protein levels were also assessed in hippocampal slices prepared from SHR (n = 10) that were incubated for 24 h with the nitric oxide (NO) donor glyceryl trinitrate. SBP was measured by the tail-cuff method. RESULTS: Exercise modified blood pressure neither in SHR nor WKY. As compared with WKY rats, SHR displayed decreased levels of mBDNF, P-TrkB, synaptophysin, eNOS and eNOS phosphorylated at serine 1177 but no change in proBDNF and TrkB levels. These effects coincided with low BDNF staining in both endothelial cells and neurons. Exercise improved the endothelium-derived NO system and the BDNF pathway in both strains. The NO donor increased mBDNF but decreased proBDNF levels. CONCLUSION: Our results revealed that endothelial and neuronal BDNF expressions were both impaired in hypertension and that physical exercise improved hippocampal mBDNF levels and signaling through blood pressure independent mechanisms. PMID- 28005702 TI - Time to the peak of the aortic forward wave determines the impact of aortic backward wave and pulse pressure on left ventricular mass. AB - AIM: To determine the degree to which an extended time to the peak of the aortic forward wave or early wave reflection time enhance associations between aortic backward wave pressure and hence central aortic pulse pressure (PPc) and left ventricular mass index (LVMI). METHODS: In 701 adult participants from a community sample either receiving no antihypertensive therapy or receiving low dose thiazide diuretic monotherapy for at least a year (the major therapy employed), we assessed aortic haemodynamics (SphygmoCor software and wave separation analysis; AtCor Medical, West Ryder, New South Wales, Australia) and LVMI (echocardiography). RESULTS: An interaction between time to the peak of the aortic forward wave and aortic backward wave pressure was independently associated with aortic augmented pressure (P < 0.01), PPc (P < 0.005), LVMI (P < 0.01), and LV hypertrophy (LVH; P = 0.01). The time to the peak of the aortic forward wave-aortic backward wave pressure interaction translated into a stepwise increase in the independent association between aortic backward wave pressure and aortic augmented pressure or PPc across quartiles of time to the peak of the aortic forward wave (P < 0.05 to < 0.0001 for comparison of slopes of relations). Furthermore, the time to the peak of the aortic forward wave-aortic backward wave pressure interaction translated into an increase in the independent association between PPc or aortic backward wave pressure and LVMI (P < 0.05 to < 0.001 for comparison of slopes and strength of relations) or LVH (P < 0.05 for comparisons of odds ratios), but not between forward wave pressures and LVMI or LVH across quartiles of time to the peak of the aortic forward wave. A markedly better ability of aortic backward wave pressure and PPc, but not forward wave pressures to detect LVH was noted in the highest as compared with the first three quartiles of time to the peak of the aortic forward wave (P < 0.05). In contrast, reflection time failed to influence the impact of aortic backward wave pressure or PPc on LVMI. CONCLUSIONS: Time to the peak of the aortic forward wave, but not early wave reflection markedly influences the impact of aortic backward wave pressure and hence aortic pulse pressure on LVMI and LVH in adults. PMID- 28005703 TI - Do prorenin-synthesizing cells release active, 'open' prorenin? AB - BACKGROUND: The function of prorenin, the inactive precursor of renin, remains unclear after many decades of research. The discovery of a (pro)renin receptor suggested that prorenin, by binding to this receptor, would become active, that is, obtain an 'open' conformation. However, the receptor only interacted with prorenin at levels that were many orders of magnitude above its normal levels, making such interaction in-vivo unlikely. Prorenin occurs in two conformations, an open, active form, and a closed, inactive form. Under physiological conditions (pH 7.4, 37 degrees C), virtually all prorenin occurs in the closed conformation. This study investigated to what degree prorenin-synthesizing cells release prorenin in an open conformation. METHODS AND RESULTS: Renin plus prorenin-synthesizing human mast cells, and prorenin-synthesizing HEK293 cells (transfected with the mammalian expression vector pRhR1100, containing human prorenin) and human decidua cells were incubated with the renin inhibitor VTP 27999. This inhibitor will trap open prorenin, as after VTP-27999 binding, prorenin can no longer return to its closed conformation, thus allowing its detection in a renin immunoradiometric assay. No evidence for the release of open prorenin was found. Moreover, incubating decidua cells with angiotensinogen yielded low angiotensin levels, corresponding with the activity of ~1% of prorenin in the medium, that is, the amount of open prorenin expected based upon the equilibrium between open and closed prorenin under physiological conditions. CONCLUSION: Our study does not reveal evidence for the release of open, active prorenin by prorenin-synthesizing cells, at least under cell culture conditions. This argues against prorenin activity at the site of its release. PMID- 28005704 TI - The antioxidant effects of green tea reduces blood pressure and sympathoexcitation in an experimental model of hypertension. AB - BACKGROUND: Oxidative stress is a key mediator in the maintenance of sympathoexcitation and hypertension in human and experimental models. Green tea is widely known to be potent antioxidant. OBJECTIVE: We aimed to evaluate the effects of green tea in a model of hypertension. METHODS: Hypertension was induced by the nitric oxide synthase inhibitor [N-nitro-L-arginine-methyl-ester (L-NAME); 20 mg/kg per day, orally, for 2 weeks] in male Wistar rats. After the first week of L-NAME treatment, animals received green tea ad libitum for 1 week. At the end of the treatment period, blood pressure, heart rate, baroreflex sensitivity, renal sympathetic nerve activity, and vascular and systemic oxidative stress were assessed. RESULTS: L-NAME-treated animals exhibited an increase in blood pressure (165 +/- 2 mmHg) compared with control rats (103 +/- 1 mmHg) and green tea treatment reduced hypertension (119 +/- 1 mmHg). Hypertensive animals showed a higher renal sympathetic nerve activity (161 +/- 12 spikes/s) than the control group (97 +/- 2 spikes/s), and green tea also decreased this parameter in the hypertensive treated group (125 +/- 5 spikes/s). Arterial baroreceptor function and vascular and systemic oxidative stress were improved in hypertensive rats after green tea treatment. CONCLUSIONS: Taken together, short term green tea treatment improved cardiovascular function in a hypertension model characterized by sympathoexcitation, which may be because of its antioxidant properties. PMID- 28005705 TI - Denervation of the distal renal arterial branches vs. conventional main renal artery treatment: a randomized controlled trial for treatment of resistant hypertension. AB - BACKGROUND: Effective treatment of uncontrolled hypertension using catheter-based percutaneous renal denervation may depend strongly on the anatomic strategy applied when delivering therapy. We hypothesized that concentering renal denervation treatment in the distal region of the artery would improve clinical response. METHODS AND RESULTS: We conducted a single-center, double-blind, randomized, controlled, and parallel group study (ClinicalTrials.gov NCT02667912). Fifty-one treatment-resistant hypertensive patients meeting guideline indications were randomized either to 'conventional' treatment restricted to the main renal artery (n = 26) or to 'distal' treatment applied mainly in the distal branches beyond the main bifurcation (n = 25). Computer based treatment assignment was performed in the catheterization laboratory at the time of the procedure by the interventional radiologist and remained unknown to patients, investigators, and other outcomes assessors for the entire study period. Six months after randomization, the distal therapy group (n = 24) had a significantly greater decrease in the primary outcome, 24-h mean ambulatory SBP, as compared with the conventionally treated group (n = 21): -22.6 +/- 20.0 vs 9.4 +/- 18.7 mmHg; P less than 0.05. No major safety issues were observed in either group. CONCLUSION: Percutaneous renal denervation treatment was significantly less effective at lowering 24-h blood pressure in treatment resistant hypertensive patients when therapy was applied conventionally in the trunk of renal artery as compared with when applied to distal segmental branches. This observation is in accordance with previous surgical and anatomical findings showing that most renal nerve fibers are distant from the lumen proximally and become available for endovascular treatment mainly in the distal portion of the vessel. PMID- 28005706 TI - Endothelin type A receptor blockade reduces vascular calcification and inflammation in rats with chronic kidney disease. AB - OBJECTIVE: Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD. METHODS: CKD was induced in Wistar rats by renal mass ablation. To induce medial vascular calcification, mineral imbalance was established with a identified as calcium rich/phosphate-rich diet and vitamin D supplementation (Ca/P/VitD). One group of CKD + Ca/P/VitD rats was given the ETA receptor antagonist atrasentan (10 mg/kg/day) for 6 weeks. Hemodynamic parameters including SBP, pulse pressure (PP) and pulse wave velocity (PWV) were determined. Vascular calcification, smooth muscle cells osteoblastic differentiation and expression of inflammatory markers such as inflammatory cytokines and calgranulins S100A8 and S100A9 were assessed in the thoracic aorta. RESULTS: As compared with CKD control rats, CKD + Ca/P/VitD rats developed medal vascular calcification that was associated with increased SBP, PP and PWV. These changes were also associated with increased macrophage infiltration and expression of IL-6, calgranulins and osteoblastic markers. Treatment of CKD + Ca/P/VitD rats with atrasentan reduced vascular calcification, SBP, PP and PWV, macrophage infiltration and expression of IL 1beta, IL-6, tumor necrosis factor, calgranulins and osteoblastic markers. CONCLUSION: This study shows that ETA receptor blockade reduced vascular inflammation, smooth muscle cells differentiation, calcification and stiffness indicating a pivotal role for ET-1 in medial vascular calcification in this rat remnant kidney model of CKD with mineral imbalance. Therefore, the endothelin system may be a potential therapeutic target for improving cardiovascular morbidity in patients with CKD. PMID- 28005707 TI - High glomerular filtration rate is associated with arterial stiffness in Chinese population. AB - OBJECTIVES: Decreased glomerular filtration rate (GFR) has been suspected as a risk factor for arterial stiffness. Whether high GFR is the risk factor of arterial stiffness and cardiovascular disease remains uncertain. We aim to evaluate the association between high estimated GFR (eGFR) and arterial stiffness in Chinese adults. METHODS: We performed a cross-sectional study involving 9136 Chinese adults without chronic kidney disease. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV) and pulse pressure (PP). We divided participants into four groups according to age-specific quartiles of eGFR. Renal hyperfiltration (RHF) was defined with the highest age-specific quartile of eGFR. The odds ratios (ORs) of elevated baPWV and PP were estimated using multivariate logistic regression models and were further tested using propensity score matching analysis between participants with or without RHF. RESULTS: RHF was associated with 11 and 32% higher risk of elevated baPWV and PP in age-adjusted models, P = 0.35 and 0.005, respectively. After adjusting for covariates, RHF was significantly associated with 23 and 39% increased risk of elevated baPWV and PP, P = 0.01 and 0.001, respectively. These associations were further confirmed in propensity score matching analysis. The adjusted ORs (95% confidence interval) were 1.17 (1.03-1.30) for elevated baPWV and 1.28 (1.13-1.46) for elevated PP, P = 0.02 and P value less than 0.001, respectively. CONCLUSION: RHF was associated with elevated baPWV and PP, suggesting that RHF might be an early indicator for the detection of arterial stiffness. PMID- 28005708 TI - An early life course association of pulse pressure with adulthood estimated glomerular filtration rate: evidence from a large community-based birth cohort study. AB - BACKGROUND: Little is known about pulse pressure (PP) during early life and its association with renal function at young adulthood. This study describes an early life course association of PP with adult renal function at 30 years from a large community-based birth cohort study in Australia. METHOD: Sample comprises 1169 young adults aged 30 years from the Mater-University of Queensland Study of Pregnancy, whose blood pressure was recorded in at least three follow-ups (5, 14, 21, and 30 years) and renal function was assessed at 30 years. Estimated glomerular filtration rate was estimated to determine the stages of chronic kidney disease (CKD). A group-based trajectory modelling was developed to identify patterns of PP from childhood to adulthood. Multiple logistic regression was used to determine whether PP trajectories predict adult CKD. RESULTS: In total, 7% of participants (91) had mild CKD. Three PP trajectories were identified: 16% were in the high PP trajectory group characterized by substantial increase in PP over time; 58% were in the middle group who had lower PP at 5 years, which increased at 14 years and then gradually declined at 21 and 30 years, and the remaining 26% were in a lower group which remained static. In the adjusted model, significantly higher odds were found for the high [odds ratio: 2.42 (95% confidence interval: 1.02-5.74)] and middle [2.23 (1.19-4.19)] PP trajectory groups for development of mild CKD at 30 years compared with the low (static) group. CONCLUSION: Early life high and middle PP trajectories predict the risk of subclinical renal insufficiency by age 30 years. PMID- 28005709 TI - Associations of socioeconomic status with prevalence, awareness, treatment, and control of hypertension in a general Japanese population: NIPPON DATA2010. AB - OBJECTIVE: To investigate associations between socioeconomic status (SES) and prevalence, awareness, treatment, and control of hypertension in Japan's general population. METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. The cohort included 2623 adults from 300 randomly selected areas across Japan. Using baseline data, four cross sectional analyses were performed: association of SES with prevalent hypertension in 2623 participants; association of SES with unawareness of hypertension and with no treatment in 1282 hypertensive patients; and association of SES with uncontrolled hypertension in 720 treated hypertensive patients. SES was classified according to employment status, length of education, marital and living status, and household expenditure. RESULTS: The overall prevalence of hypertension was 48.9%. Among hypertensive participants, the proportions of unawareness and no treatment were 33.1 and 43.8%, respectively. Target blood pressure levels were not achieved among 61.2% of treated hypertensive patients. Hypertension was more prevalent in the unmarried and living alone group than in the married group (odds ratio 1.76; 95% confidence interval 1.26-2.44), after adjustment for age, sex, BMI, smoking, alcohol consumption, habitual exercise, history of cardiovascular diseases, diabetes mellitus, hypercholesterolemia, dietary sodium, and potassium intake. SES was not clearly associated with unawareness, no treatment, nor poor control of hypertension. CONCLUSION: Being unmarried and living alone was associated with increased prevalence of hypertension. There was no clear association of SES with unaware, untreated, and uncontrolled hypertension. PMID- 28005710 TI - Time trend in hypertension prevalence, awareness, treatment, and control in a contemporary cohort of HIV-infected patients: the HIV and Hypertension Study. AB - BACKGROUND: Hypertension control is often inadequate in HIV patients. In a contemporary, nationwide cohort of Italian HIV-infected adults, we assessed time trends in hypertension prevalence, awareness, treatment, and control. We also evaluated predictors of cardiovascular events and of new-onset hypertension. METHODS: Multicenter prospective cohort study, sampling 961 consecutive HIV patients (71% men, mean age 46 +/- 9 years, 30% hypertensive) examined in 2010 2014 and after a median follow-up of 3.4 years. RESULTS: Among hypertensive patients, hypertension awareness (63% at baseline and 92% at follow-up), treatment (54 vs. 79%), and control (35 vs. 59%) all improved during follow-up. The incidence of new-onset hypertension was 50.1/1000 person-years (95% confidence interval, 41.2-60.3). Multivariable-adjusted predictors of hypertension were age, BMI, estimated cardiovascular risk, blood pressure, and advanced HIV clinical stage.In total, 35 new cardiovascular events were reported during follow-up (11.1/1000 person-years). In a multivariate model, baseline cardiovascular risk and hypertensive status predicted incident cardiovascular events, whereas a higher CD4 cell count had a protective role. In treated hypertensive patients, the use of integrase strand transfer inhibitors at follow up was associated with a lower SBP (average yearly change, -3.8 +/- 1.6 vs. -0.9 +/- 0.5 mmHg in integrase strand transfer inhibitor users vs. nonusers, respectively, P = 0.02). CONCLUSION: Hypertension awareness, treatment, and control rates all improved in adult Italian HIV patients over the last few years, although hypertension remains highly prevalent (41%) in middle-aged HIV patients, and significantly impacts cardiovascular morbidity. Traditional risk factors and advanced HIV disease predict new-onset hypertension, whereas CD4 cell count favorably affects future cardiovascular events. PMID- 28005711 TI - Trauma system regionalization improves mortality in patients requiring trauma laparotomy. AB - INTRODUCTION: This study evaluates the impact of a regional trauma network (RTN) on patient survival, intensive care unit (ICU) length of stay, and hospital length of stay in patients who required trauma laparotomy. METHODS: Patients who required trauma laparotomy from January 2008 to December 2013 were analyzed. Patients admitted during 2008-2009 and 2011-2013 were designated as pre-RTN and RTN groups, respectively. The primary outcome was mortality. RESULTS: A total of 569 patients were analyzed, 231 patients were pre-RTN, and 338 were in the RTN group. Overall, mean age was 35.7 +/- 17.1 and median Injury Severity Score was 16 (25th-75th percentile: 9-26). The two groups were similar with regard to age, Injury Severity Score, Abbreviated Injury Scale abdomen, sex, and mechanism. Overall, there was a 35% relative reduction in mortality from the pre-RTN to RTN group (p = 0.035), and 30% more patients were triaged to a Level 1 trauma center in the RTN group (p < 0.001). Logistic regression showed that being in the RTN group was an independent predictor for survival (p = 0.026) with odds ratio of 0.53 (95% confidence interval, 0.30-0.93). Patients with penetrating trauma had a nonsignificant decrease in mortality and a reduction of 1 day of ICU stay (p = 0.001). Patients with blunt trauma had a significant reduction in mortality from 38% in the pre-RTN group to 23% in the RTN group (p = 0.017). CONCLUSION: This study focused on the unique patient population that required trauma laparotomies. It showed that trauma system regionalization led to a significant increase in the number of patients triaged to a Level 1 trauma center and reduction of ICU length of stay. More importantly, it demonstrated the benefit of regionalization by showing a significant reduction of hospital mortality in this critically injured patient population. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 28005712 TI - Gunshot wound to the chest with retained projectile in intraventricular septum. PMID- 28005716 TI - Pacific Retina Club Meeting. PMID- 28005717 TI - 40TH MEETING OF THE ATLANTIC COAST RETINA CLUB MACULA 2016. PMID- 28005718 TI - PROPORTION OF PATIENTS WITH MACULAR HOLE SURGERY WHO WOULD HAVE BEEN FAVORABLE OCRIPLASMIN CANDIDATES: A Retrospective Analysis. AB - PURPOSE: To identify favorable ocriplasmin candidates from a cohort of idiopathic full thickness macular hole surgery patients. METHODS: The records of patients with full thickness macular hole who underwent pars plana vitrectomy surgery between 2011 and 2015 were reviewed. Clinical data collected included patient demographics, pre- and post-operative Snellen visual acuity, optical coherence tomography findings, and lens status. The authors defined "favorable" ocriplasmin candidates as patients with focal vitreomacular traction, no epiretinal membrane, and hole size <=400 MUm. The authors further categorized "optimal" candidates as age <=65, phakic, no epiretinal membrane, with focal vitreomacular traction, and hole size <=400 MUm. RESULTS: The records of 238 patients were assessed; 30.7% were male while mean age was 68.6 +/- 8.3 years. The mean logMAR acuity was 1.2 (Snellen 20/317) preoperatively and 0.90 (Snellen 20/159) postoperatively. Optical coherence tomography findings indicated that 46.5% of the macular holes studied were less than <=400 MUm in size, 14.8% had an epiretinal membrane, and 25.3% had vitreomacular traction. A total of 17.7% of study patients were found to be favorable candidates, whereas 3.8% were optimal ocriplasmin candidates. CONCLUSION: Only a minority of full thickness macular hole surgical candidates in this cohort would be considered favorable ocriplasmin candidates. PMID- 28005719 TI - AGE-RELATED CLINICAL OUTCOME AFTER MACULAR HOLE SURGERY. AB - PURPOSE: To evaluate functional and anatomical retinal recovery according to patient age using spectral domain optical coherence tomography in eyes with surgically closed macular holes. METHODS: We retrospectively studied 83 eyes with anatomically closed idiopathic macular holes after surgery confirmed by spectral domain optical coherence tomography. Patients were divided into four subgroups based on age (Group 1: <= 60, Group 2: 61-65, Group 3: 66-70, Group 4: > 70). Best-corrected visual acuity and reconstruction of the external limiting membrane and ellipsoid zone after surgery were documented for 12 months. RESULTS: Mean patient age was 64.5 +/- 9.8 years (range 44-81). Mean visual improvement in logMAR units (ETDRS letter score) at 12 months was worse in older age subgroups (Group 1: 0.4 +/- 0.3 [20], Group 2: 0.4 +/- 0.3 [20], Group 3: 0.2 +/- 0.3 [10], Group 4: 0.1 +/- 0.3 [5], P = 0.001). When age was more than 65 years, total number of eyes with restored retinal microstructure after surgery was lower (22 eyes, 53.7%; 32 eyes, 76.2%; P = 0.018) and time (months) to structural recovery was longer (10.2, 7.1, P < 0.001) than age under 65 years. Visual improvement corresponded to recovery of the outer retinal layers. In multivariate analysis, patients of older age (odds ratio, 0.91; 95% CI, 0.89-0.93) had less visual improvement at month 12. CONCLUSION: Poor visual outcomes and delayed microstructural recovery occurred in older subjects after anatomically closed macular hole surgery. Older age may be indicative of poor clinical outcome in repaired macular holes. PMID- 28005720 TI - FUNDUS AUTOFLUORESCENCE IN RUBELLA RETINOPATHY: Correlation With Photoreceptor Structure and Function. AB - PURPOSE: To illustrate altered fundus autofluorescence in rubella retinopathy and to investigate their relationships with photoreceptor structure and function using multimodal imaging. METHODS: The authors report four cases of rubella retinopathy aged 8, 33, 42, and 50 years. All patients had dilated clinical fundus examination; wide-field color photography; blue, green, and near-infrared autofluorescence imaging and spectral domain optical coherence tomography. Two patients also underwent microperimetry and adaptive optics imaging. En face optical coherence tomography, cone mosaic, and microperimetry were coregistered with autofluorescence images. The authors explored the structure-function correlation. RESULTS: All four patients had a "salt-and-pepper" appearance on dilated fundus examination and wide-field color photography. There were variable sized patches of hypoautofluorescence on both blue and near-infrared excitation in all four patients. Wave-guiding cones were visible and retinal sensitivity was intact over these regions. There was no correlation between hypoautofluorescence and regions of attenuated ellipsoid and interdigitation zones. Hyperautofluorescent lesions were also noted and some of these were pseudo vitelliform lesions. CONCLUSION: Patchy hypoautofluorescence on near-infrared excitation can be a feature of rubella retinopathy. This may be due to abnormal melanin production or loss of melanin within retinal pigment epithelium cells harboring persistent rubella virus infection. Preservation of the ellipsoid zone, wave-guiding cones, and retinal sensitivity within hypoautofluorescent lesions suggest that these retinal pigment epithelium changes have only mild impact on photoreceptor cell function. PMID- 28005721 TI - PERMEABILITY AND ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR EFFECTS OF BEVACIZUMAB, RANIBIZUMAB, AND AFLIBERCEPT IN POLARIZED RETINAL PIGMENT EPITHELIAL LAYER IN VITRO. AB - PURPOSE: To determine the effects of bevacizumab, ranibizumab, and aflibercept on the permeability and the effects of anti-vascular endothelial growth factor (VEGF) on highly polarized retinal pigment epithelial cells (RPECs) in vitro. METHODS: Highly polarized RPECs were cultured in the upper chamber of a Transwell system. Anti-VEGF antibodies were added to the upper chamber, and the concentrations of the drugs in the lower chambers were measured. The permeability rates of the three anti-VEGF drugs through the RPEC layer and the concentration of VEGF in each chamber were determined. RESULTS: The permeability of aflibercept was significantly lower by about 40% than that of bevacizumab through the RPEC layer (P < 0.05). Ranibizumab was significantly more permeable through the RPECs than bevacizumab (180% of bevacizumab, P < 0.05). Although VEGF was almost absent in the upper chamber after exposure to the 3 antibodies, it was decreased more significantly with aflibercept than with bevacizumab in the lower chamber (2.8% vs. 65.8% of control; P < 0.01). Ranibizumab also decreased the VEGF level compared with bevacizumab (31.7% vs. 65.8% of control; P < 0.01). CONCLUSION: The greater reduction of the amount of VEGF in the lower chamber by aflibercept and ranibizumab than bevacizumab may explain why aflibercept and ranibizumab are more effective than bevacizumab against type 1 choroidal neovascularization. PMID- 28005722 TI - Intrabursal and Subhyaloid Hemorrhages in Valsalva Retinopathy. PMID- 28005723 TI - Light-Driven Contact Hearing Aid for Broad-Spectrum Amplification: Safety and Effectiveness Pivotal Study. AB - OBJECTIVE: Demonstrate safety and effectiveness of the light-driven contact hearing aid to support FDA clearance. STUDY DESIGN: A single-arm, open-label investigational-device clinical trial. SETTING: Two private-practice and one hospital-based ENT clinics. PATIENTS: Forty-three subjects (86 ears) with mild-to severe bilateral sensorineural hearing impairment. INTERVENTION: Bilateral amplification delivered via a light-driven contact hearing aid comprising a Tympanic Lens (Lens) with a customized platform to directly drive the umbo and a behind-the-ear sound processor (Processor) that encodes sound into light pulses to wirelessly deliver signal and power to the Lens. MAIN OUTCOME MEASURES: The primary safety endpoint was a determination of "no change" (PTA4 < 10 dB) in residual unaided hearing at the 120-day measurement interval. The primary efficacy endpoint was improvement in word recognition using NU-6 at the 30-day measurement interval over the baseline unaided case. Secondary efficacy endpoints included functional gain from 2 to 10 kHz and speech-in-noise improvement over the baseline unaided case using both omnidirectional and directional microphones. RESULTS: The results for the 86 ears in the study determined a mean change of 0.40 dB in PTA4, indicating no change in residual hearing (p < 0.0001). There were no serious device- or procedure-related adverse events, or unanticipated adverse events. Word recognition aided with the Earlens improved significantly (p < 0.0001) over the unaided performance, by 35% rationalized arcsine units on average. Mean functional gain was 31 dB across 2 to 10 kHz. The average speech recognition threshold improvement over the unaided case for the Hearing in Noise Test was 0.75 dB (p = 0.028) and 3.14 dB (p < 0.0001) for the omnidirectional and directional microphone modes, respectively. CONCLUSION: The safety and effectiveness data supported a de novo 510(k) submission that received clearance from the FDA. PMID- 28005724 TI - One Global Community Under God in One Arena: The Spirit of the Olympics Put Us All Together Avoiding Global Diversity To Further Move Forward. PMID- 28005725 TI - Ephemeral or Timeless?: The Bronte Sisters. PMID- 28005726 TI - Teaching Our Patients and Residents: Time's Limitations and Technology's Answer. PMID- 28005727 TI - The Effect of Mandibulectomy and Mandibulotomy on Cochlear Function. AB - Mandibulectomy and mandibulotomy procedures are performed with the oscillating saw and the acoustic energy generated during the osteotomies is transferred to the cochlea via temporomandibular joint and air conduction. The aim of this study was to assess the effect of mandibulectomy and mandibulotomy on cochlear function. This study was carried out on 15 patients who underwent at an otolaryngology department of a tertiary medical center between January 2013 and August 2015. The study was designed as a prospective study. All of the data were prospectively collected. These included demographic data, date of the surgery, type of surgery, preoperative pure-tone audiometry, preoperative and postoperative distortion product otoacoustic emission (DPOAE) measurements. Of the DPOAE measurements, there was a statistically significant difference between the signal-to-noise ratio measurement on the right ear measurement at 4 kHz (P <0.05). Additionally, there was a statistically significant correlation between the signal-to-noise ratio measurements and the side of the osteotomy (P <0.05). In conclusion, it is found that mandibulectomy and mandibulotomy procedure has a negative effect on cochlear function in the early period. The DPOAEs were diminished on the osteotomy site in day one postoperatively. Results with a longer follow-up time can yield more information on the prognosis of the cochlear damage. PMID- 28005728 TI - Osteosarcoma of the Mandible: A Site-Specific Study on Survival and Prognostic Factors. AB - Osteosarcoma of head and neck is a rare condition comprising of <1% of all head and neck cancers, retrospective studies show difference in survival of mandibular osteosarcoma to other head and neck sites, necessitating investigation into site specific survival and recurrence rates. PMID- 28005729 TI - Assessment of Deformational Plagiocephaly Severity and Neonatal Developmental Delay. AB - Deformational plagiocephaly (DP) in infants has been associated with developmental delay that can last until adolescence. Despite this association and a 5-fold increase in incidence of DP over the past 2 decades, there are currently no guidelines regarding screening for developmental delay or identification of which infants with DP are at the greatest risk of delay. A prospective, nonrandomized study was performed. Infants diagnosed with DP who had no prior intervention were eligible for enrollment. Cranial deformity was measured by cross-cranial measurements using calipers, and developmental delay was measured using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III). Correlation between cranial deformity and developmental delay was analyzed using a linear regression. Twenty-seven infants, ages 4.0 to 11.0 months (mean = 6.61 months) diagnosed with DP were studied. Developmental delay was observed on the composite language (n = 3 of 27, 11%), and composite motor (n = 5 of 23, 22%) scales, but not the cognitive scale. Severity of cranial deformity did not correlate with scores on any Bayley-III scales (cognitive R = 0.058, P = 0.238; composite language R = 0.03, P = 0.399; composite motor R = 0.0195, P = 0.536). This study demonstrates that severity of cranial deformity cannot be used to predict presence or degree of developmental delay. Craniofacial surgeons should be aware of this risk and consider developmental screening based on clinical suspicion. PMID- 28005730 TI - Correction of a Long Face: Simultaneous Reduction of the Upper Lip Using a Modified Endonasal Technique and Le Fort I Osteotomy Superior Impaction. AB - BACKGROUND: Although Le Fort I osteotomy superior impaction during bimaxillary surgery is beneficial for patients with a long face, achieving satisfactory results can be challenging due to the redundant upper lip. However, upper-lip reduction has rarely been performed during or following bimaxillary surgery because of the difficulty in estimating the required amount of cutaneous resection needed and the apparent horizontal scars left behind. Therefore, no simultaneous cutaneous upper-lip reduction with orthognathic surgery has been reported. The authors present successful clinical outcomes using a modified endonasal upper-lip reduction technique performed with orthognathic surgery. METHODS: A total of 33 patients underwent simultaneous cutaneous upper-lip reduction with orthognathic surgery. Of those, 15 patients were statistically analyzed. The amount of skin excised was individualized depending on the amount of Le Fort I osteotomy superior impaction and the aesthetic goal. Postoperative changes in upper-lip length were assessed with lateral cephalography. RESULTS: Most patients had satisfactory results without serious complications. Overall lip contours, especially lip height, were greatly improved. The scar was hidden intranasally, aside from inconspicuous scarring in the subalar area. Regarding Le Fort I osteotomy, the amount of superior impaction averaged 3.26 mm (range, 0 6.0). The amount of upper-lip reduction averaged 3.42 mm (range, 3.0-6.0). Upper lip length decreased from 25.27 +/- 0.94 mm preoperatively to 21.22 +/- 0.94 mm postoperatively (P < 0.05). CONCLUSIONS: Upper-lip reduction is essential for achieving desired results during orthognathic surgery for patients with a long face. Our method enables simultaneous maxillary height and cutaneous upper-lip reduction without a continual, visible cicatrix. PMID- 28005731 TI - Publication Rates of Studies Presented at the International Society of Craniofacial Surgery Congress. AB - BACKGROUND: The proportion of presentations achieving publication in a peer review journal has been suggested to demonstrate the quality of research presented at a conference. No data is available examining the publication rate of research presented at Craniofacial Surgery meetings. OBJECTIVE: The aim of the study was to examine the publication rate of abstracts presented at the International Society of Craniofacial Surgery Biennial Congresses from 2003 to 2011. METHODS: A search was made of the PubMed database for publication of podium presentations of International Society of Craniofacial Surgery Congresses between 2003 and 2011. RESULTS: Thirty-five percent of podium presentations were published in a peer-reviewed journal. Thirty-one percent of presentations were published within 4 years, and the rate of publication decreased 2 years following presentation. PMID- 28005732 TI - Assessment of the Relationship Between Clinicophysiologic and Magnetic Resonance Imaging Findings of the Temporomandibular Disorder Patients. AB - Temporomandibular joint disorders (TMJDs) are a complex group of disorders that comprise dysfunctions of the temporomandibular joint (TMJ). In this study, we analyzed the objective and subjective findings of the TMJD patients by using Helkimo anamnesis (Ai) and clinical dysfunction (Di) indices, and tried to document a relation between these findings and magnetic resonance imaging (MRI) results.Ninety-eight patients who were admitted to our clinic were included in the study. The clinical evaluation was performed by using Ai, an 8-question survey based on the objective symptoms of patients; Di, concluded as the score of 5 objective measurements of physical examination. The morphology of the TMJ was evaluated by MRI, and the findings were analyzed and statistically compared with respect to the Di.The most commonly seen symptoms were noise during mandibular movement (58%), pain around the joint (42.5%), and pain with mandibular movements (40%). Seventeen patients (17.3%) were Di0, 47 (48%) were DiI, 24 (24.5%) were DiII, and 10 (10.2%) were DiIII. Thirty-seven patients (37.8%) had abnormal MRI findings, whereas 61 patients (62.2%) had normal MRI. The most commonly encountered pathology was anterior disc displacement with reduction, which was reported in 15 patients. Increased TMJ Di, which points a more progressed TMJD, was found to be significantly related with the pathological MRI findings (P < 0.05).MRI is especially effective in particularly those with high Di; therefore, the results of the study may give a prospect in which types of patients does MRI give a valuable data toward diagnosis, in which stages of the TMJD should we expect pathological findings, and thereby preventing unnecessary use of MRI in patients with symptoms of TMJD. PMID- 28005733 TI - An Ideal Flap Alternative for Closure of Myelomeningocele Defects: Dorsal Intercostal Artery Perforator Flap. AB - BACKGROUND: Dorsal intercostal artery perforator (DICAP) flap is an ideal flap to be used for posterior trunk defects since it leads to lower donor-site morbidity and shorter operative times, offers easy surgical planning, and uses a reliable and easily identifiable artery. MATERIALS AND METHODS: The study retrospectively reviewed 52 patients with meningomyelocele defects that were closed with DICAP flap between January 2007 and May 2015. SURGICAL TECHNIQUE: Each of the 4th to 12th posterior intercostal arteries can be used as dorsal perforators. The dominant direct cutaneous perforators derive from the 4th, 5th, 6th, 10th, and 11th posterior intercostal arteries. These perforators are located 5 cm medial to the spinous processes of the thoracic vertebrae and can be easily identified. CONCLUSION: Dorsal intercostal artery perforator flap is a reliable flap alternative for the defects seen in neonates, including myelomeningocele, oncologic resections, burn defects, and radiation burns since it is a thin flap and offers easy surgical planning and shorter operative times. PMID- 28005734 TI - Risk Factors Leading to Free Flap Failure: Analysis From the National Surgical Quality Improvement Program Database. AB - BACKGROUND: The objective of this study was to identify risk factors for free flap failure among various anatomically based free flap subgroups. METHODS: The 2005 to 2012 American College of Surgeons National Surgical Quality Improvement Program database was queried for patients undergoing microvascular free tissue transfer based on current procedural terminology codes. Univariate analysis was performed to identify any association between flap failure and the following factors: age, gender, race, body mass index (BMI), diabetes, smoking, alcohol use, hypertension, intraoperative transfusion, functional health status, American Society of Anesthesiologists class, operative time, and flap location. Factors yielding a significance of P < 0.20 were included in multivariate logistic regression models in order to identify independent risk factor significance for flap failure. Furthermore, patients were stratified based on recipient site (breast, head and neck, trunk, or extremity), and analysis was repeated in order to identify risk factors specific to each location. RESULTS: A total of 1921 of 2103 patients who underwent microvascular free flap reconstruction met inclusion criteria. Multivariate logistic regression identified BMI (adjusted odds ratio [AOR] = 1.07, P = 0.004) and male gender (AOR = 2.16, P = 0.033) as independent risk factors for flap failure. Among the "breast flaps" subgroup, BMI (AOR = 1.075, P = 0.012) and smoking (AOR = 3.35, P = 0.02) were independent variables associated with flap failure. In "head and neck flaps," operative time (AOR = 1.003, P = 0.018) was an independent risk factor for flap failure. No independent risk factors were identified for the "extremity flaps" or "trunk flaps" subtypes. CONCLUSIONS: BMI, smoking, and operative time were identified as independent risk factors for free flap failure among all flaps or within flap subsets. PMID- 28005735 TI - Subtypes of Maxillomandibular Advancement Surgery for Patients With Obstructive Sleep Apnea. AB - Maxillomandibular advancement (MMA) surgery, which is the most effective treatment modality for patients with moderate-to-severe obstructive sleep apnea with apparent skeletal discrepancies, has been modified in conjunction with segmental osteotomies, counterclockwise rotation of maxillomandibular complex, and other adjunctive procedures. However, any single type of MMA could not treat or cure all the patients with obstructive sleep apnea showing different dentofacial and pharyngeal patterns. We aimed to suggest critical decision factors for the selective application of MMA subtypes, categorized as straight MMA with genioplasty, rotational MMA, segmental MMA, and segmental-rotational MMA, in the surgical treatment objective process: anteroposterior position of maxilla, upper lip projection, overjet, lower incisor inclination as sagittal factors, and upper incisor exposure and occlusal plane angle as vertical factors. This case series deserves a clinical basis on the way of case-by-case application of the optimal MMA subtype based on the successful treatment outcomes with short term stability. PMID- 28005736 TI - Management of the Repeatedly Failed Cranioplasty Following Large Postdecompressive Craniectomy: Establishing the Efficacy of Staged Free Latissimus Dorsi Transfer/Tissue Expansion/Custom Polyetheretherketone Implant Reconstruction. AB - BACKGROUND: Postdecompressive craniotomy defect management following failed prior cranioplastyis challenging. The authors describe a staged technique utilizing free muscle transfer, tissue expansion, and custom polyetheretherketone (PEEK) implants for the management of previously failed cranioplasty sites in patients with complicating local factors. METHODS: Consecutive patients with previously failed cranioplasties following large decompressive craniectomies underwent reconstruction of skull and soft tissue defects with staged free latissimus muscle transfer, tissue expansion, and placement of custom computer-aided design and modeling PEEK implants with a 'temporalis-plus' modification to minimize temporal hollowing. Implants were placed in a vascularized pocket at the third stage by elevating a plane between the previously transferred latissimus superficial fascia (left on the skin) and muscle (left on the dura/bone). Patients were evaluated postoperatively for cranioplasty durability, aesthetic outcome, and complications. RESULTS: Six patients with an average of 1.6 previously failed cranioplasties underwent this staged technique. Average age was 33 years. Average defect size was 139 cm. Average time to procedure series completion was 14.9 months. There were no flap failures. One patient had early postoperative incisional dehiscence following PEEK implant placement that was managed by immediate scalp flap readvancement. At 21.9 month average follow-up, there were no cranioplasty failures. Three patients (50%) underwent 4 subsequent refining outpatient procedures. All patients achieved complete coverage of their craniectomy defect site with hear-bearing skin, acceptable head shape, and normalized head contour. CONCLUSIONS: The described technique resulted in aesthetic, durable craniectomy defect reconstruction with retention of native hear-bearing scalp skin in a challenging patient population. PMID- 28005737 TI - Nasoalveolar Molding Therapy for the Treatment of Unilateral Cleft Lip and Palate Improves Nasal Symmetry and Maxillary Alveolar Dimensions. AB - OBJECTIVE: The aim of this study is to assess the esthetic and morphologic outcomes before surgery using nasoalveolar molding (NAM) therapy in children with unilateral cleft lip and palate. DESIGN: A prospective analysis was performed. SETTING: The study was carried out in the Congenital Malformations Craniofacial and Cleft Lip and Palate Unit, Hospital Virgen de las Nieves, Andalusian Health Service, Granada (Spain). PATIENTS: Twenty consecutively enrolled infants ranging in age from 7 to 30 days with nonsyndromic unilateral cleft lip and palate treated from 2008 to 2012. INTERVENTIONS: All patients were treated with NAM appliances to align the alveolar segments and reduce severity of the nasal deformity. MAIN OUTCOME MEASURE: The extraoral nasal measurements were performed on casts and nasal photographs. The measurements consisted of bialar width (BAW), columellar deviation (CD), cleft nostril height (CNH), cleft nostril width (CNW), non-CNH, non-CNW, and the deviation of the columella to the horizontal line represented by bilateral pupil line (BIA). The authors have made the measurements following Barilla method. Also 2 intraoral measurements were taken. RESULTS: Following NAM the extraoral records showed a statistically significant decrease in CD (P < 0.0001), CNW (P < 0.0001), and BAW (P < 0.001). Furthermore, statistically significant increases in CNH (P < 0.05) and BIA (P < 0.0001) were observed.Following Barilla measurements, the authors have found a high percentage of symmetry in all the nasal measurements after the NAM therapy.Intraoral results showed a statistically significant decrease in the gap between the greater and lesser alveolar segments and a statistically significant increase in maxillary arch width. CONCLUSIONS: Nasoalveolar molding improves nasal symmetry and achieves an improvement of all maxillary alveolar dimensions, increasing alveolar rim width, reducing the size of alveolar cleft gap, and improving shape of the maxillary dental arch. As a consequence of reducing the alveolar and nasal deformities before surgery, it is expected that the primary repair will be easier for the surgeon and more successful. PMID- 28005738 TI - Discussion on: Nasoalveolar Molding Therapy for the Treatment of Unilateral Cleft Lip and Palate Improves Nasal Symmetry and Maxillary Alveolar Dimensions. PMID- 28005739 TI - Minimally Invasive Strip Craniectomy Simplifies Anesthesia Practice in Patients With Isolated Sagittal Synostosis. AB - BACKGROUND: Traditional open corrective surgery for isolated sagittal synostosis entails significant blood loss, transfusion rates, morbidity, and a lengthy hospitalization. Minimally invasive strip craniectomy (MISC) was introduced to avoid the disadvantages of open techniques. OBJECTIVES: The aim of the study was, first, to compare the anesthesia practice in MISC and open extended strip craniectomy (OESC), and, second, to evaluate the incidence of perioperative complications in both surgical procedures. METHODS: A retrospective analysis was conducted for all consecutive patients receiving either OESC or MISC for nonsyndromic isolated sagittal synostosis between January 2006 and February 2014. The primary endpoints were the volume of blood loss, the volume of infused blood products, the duration of surgery, the anesthesia time, the intubation time, and the length of admission to high care units and the hospital. RESULTS: In MISC, the median duration of surgery (90 versus 178 min.), anesthesia time (178 versus 291 min), and intubation time (153 versus 294 min) were all significantly (P < 0.001) shorter than in OESC. Intraoperative blood loss was less in MISC than in OESC (3.8 versus 29.7 mL/kg, P < 0.001), requiring less crystalloids (33.3 versus 76.9 mL/kg, P < 0.001) as well as less erythrocyte transfusions (0.0 versus 19.7 mL/kg, P < 0.001) in a smaller number of patients (2/20 versus 13/15). The improved hemodynamic stability in MISC allowed for placement of less arterial and central venous catheters. After OESC all 15 patients were admitted to high care units, compared with 9 of 20 in MISC. The overall median hospital stay was shorter in MISC than in OESC (4 versus 6 d, P < 0.001). Although the incidence of technical complications was similar in both techniques, patients in MISC were less affected by perioperative electrolyte and acid-base disturbances and postoperative pyrexia. CONCLUSIONS: Minimally invasive strip craniectomy simplifies anesthesia practice relative to OESC with shorter operative times, decreased needs for replacement fluids and blood products, lessened requirements for invasive monitoring, and reduced demands for postoperative high care beds. PMID- 28005740 TI - Anesthesia Management in Patients With Choanal Atresia. AB - BACKGROUND: In this study, the anaesthetic management of newborn and infant patients who underwent surgery for choanal atresia between 2009 and 2016 is discussed in the light of recently published literature. METHODS: The diagnoses, demographic data, anaesthetic risk and duration, additional anomalies, airway management, and complications that arose in 41 patients with choanal atresia who were operated on between 2009 and 2016 were evaluated retrospectively by examining their medical and anaesthesia records. RESULTS: The patients were divided into 2 groups: Group I-bilateral choanal atresia and Group II-unilateral choanal atresia. Of the 41 patients included in the study, 24 (58.53%) were in the bilateral group, and 17 (41.46%) were in the unilateral group. Fifteen (34.1%) of the patients were male, and 26 (59.1%) of the patients were female. The mean age of the 24 patients in Group I was 25.86 days (3-72), and the mean age of the 17 patients in Group II was 171.08 days (81-365). Additional congenital anomalies were present in 13 of the patients in the bilateral choanal atresia group and 3 of the patients in the unilateral choanal atresia group.Seven patients from Groups I and 2 patients from Group II were determined to have difficult airways. The laryngoscopic images from these patients were classified as grades 3 and 4 according to the Cormack-Lehane classification system. When the durations of anesthesia in the groups were compared, the duration of anesthesia in Group I was found to be significantly longer (Table 3). Anesthesia-related complications were observed in 9 patients (37.5%) from the bilateral choanal atresia group and in 4 patients (2.3%) from the unilateral atresia group. Steroids were used as prophylactics in these patients. CONCLUSIONS: Congenital anomalies and their associated risks, as well as intubation and ventilation problems and the complications that might arise, must be considered in addition to anesthetic management when repairing choanal atresia in newborn and infant patients. PMID- 28005741 TI - Two-Thirds Lip Defects: A New Combined Reconstructive Technique for Patients With Epithelial Cancer. AB - BACKGROUND: The lips are a common site prone to squamous cell carcinomas, which arise in the facial region. There are different techniques to reconstruct the excised lip region, according to dimensions, area, and position of the tumor. The authors describe a new technique of lip reconstruction born from a combination between a nasolabial flap and adipose tissue transplant. METHODS: The study was lead in the Plastic and Reconstructive Surgery Department of the University of Catanzaro. It includes 10 patients with squamous and basal cell carcinomas that interested lower or upper lip. The authors used a nasolabial flap to reconstruct two-thirds of the excised lip. All patients were staged and resulted free of disease. As a result of surgery, deformities and depressions persisted in 5 patients. This induced the authors to subject them to transplantation of adipose tissue to maximize results. Aesthetic and functional evaluation was performed with the Patient and Observer Scar Assessment Scale v 2.0 and drooling rating scale questionnaires. Moreover, an anthropometric analysis was performed in patients treated with fat transplant. Data were analyzed using Wilcoxon signed rank test. RESULTS: All patients had an acceptable aesthetic and functional outcome. Oral competence, sensation, and movements of the area were adequate and aesthetic was good. Adipose tissue transplant compared with surgery alone, determine a real modification of various parameters, that was statistically significant (P = 0.043) to our analysis. CONCLUSIONS: The inverted nasolabial flap is versatile and simple. This technique allows to repair large lip defects by maintaining the eurythmia of the face. Autologous fat transplant is a favorable filler. Our data show that surgery alone is unable to restore face eurythmia after a tumor excision. Adipose tissue transplant allows to reach this goal. These 2 techniques, together, may significantly modify the functional and aesthetic result of the lip reconstruction, ensuring an optimal long-term result. PMID- 28005742 TI - Aberrant Internal Carotid Artery in the Tympanic Cavity. AB - OBJECTIVES: Presence of aberrant internal carotid artery (ICA) in the tympanic cavity is a very rare case and therefore the diagnosis is a challenge. Here, the authors aimed to address the importance of the diagnosis since the intervention to the middle ear and implants is increasing in number and this condition may lead to life-threatening bleeding. METHODS: Between 2012 and 2016, among the patients referred to the authors' Radiology Department from the Department of Otolaringology for the evaluation of the temporal region for various indications, the authors reported this anomaly in 6 patients and multidetector computerized tomography of these 6 patients and magnetic resonance imaging of 2 were assessed in detail. RESULTS: The mean age of the 6 patients was 28.8 and aberrant ICA abnormality was observed in 2 patients bilaterally and 4 patients unilaterally on the right side. In 1 patient ICA was not totally regressed and observed as hypoplastic. In one of the patients, dehiscence was evident between ICA and the cochlea. Moreover, in 1 patient the contralateral ICA was not observed. CONCLUSION: Although rare, aberrant ICA is an abnormality that should be kept in mind by the clinicians and the radiologists, since it leads to abundant bleeding when undiagnosed before the surgical interventions. PMID- 28005743 TI - Computer Image-Guided Template for Horizontal Advancement Genioplasty. AB - BACKGROUND: Horizontal advancement genioplasty can be extremely rewarding for microgenia. However, it is challenging for even very experienced surgeon to determine the three-dimensional position of the distant bone fragment during the operation. This study aimed to apply and evaluate computer-aided design (CAD) and computer-aided manufacturing techniques for horizontal advancement genioplasty to improve surgical accuracy. METHODS: Seven patients with microgenia were prospectively enrolled in the study. Preoperative and postoperative computed tomography (CT), photographs, and lateral cephalograms were performed. Computer aided design was done based on preoperative CT data, and then surgical templates (cutting guide templates and fixation templates) were designed accordingly to guide horizontal advancement genioplasty. All surgeries were performed by junior surgeons. The accuracy of the authors' method was evaluated by the relative error (the mean value of discrepancy between postoperative CT and preoperative design at 6 points selected randomly/preoperative design movement * 100%), Pg position error (postoperative Pg Advancement - preoperative CAD Pg Advancement)/preoperative CAD Pg Advancement * 100%), and Me position error (postoperative Me downward movement - preoperative CAD Me downward movement)/preoperative CAD Me downward movement * 100%). They are all calculated by Geomagic automatically. RESULTS: All 7 patients were satisfied with their aesthetic outcomes. The average absolute relative error is 1.8%. The average absolute Pg position error is 1.9% and the average absolute Me position error value is 1.3%. CONCLUSIONS: The authors' study showed that applying computer assisted techniques for horizontal advancement genioplasty provided accurate surgical result. With this technique, best result for horizontal advancement genioplasty could be achieved by even inexperienced surgeons. PMID- 28005744 TI - A New Procedure Assisted by Digital Techniques for Secondary Mandibular Reconstruction With Free Fibula Flap. AB - PURPOSE: To describe a new procedure assisted by digital techniques for secondary mandibular reconstruction with free fibula flap. METHODS: The 3-dimensional (3D) reconstruction images for vessels were used to demonstrate the vascular diameter and location, which help select the most suitable vein and artery for anastomosis. Maxillary and mandibular stone models of the patient were fabricated and a stable occlusal relationship was determined on an articulator. The 3D tooth model data were scanned using a 3D-optical measuring system, and the obtained stereolithographic (STL) data were imported to Geomagic software. Preoperative maxillofacial and fibular noncontrast-enhanced computed tomography scans were acquired, and the data were imported to ProPlan CMF software. The maxilla and mandible were segmented, and STL data were imported to Geomagic software. The registration function was used to determine the ideal mandibular position. First, with the maxillary position fixed, the maxillary and mandibular models were registered with the maxilla. Then, with the tooth model positions fixed, the mandible was registered with the models. The STL data for the mandible were imported to ProPlan CMF software. Virtual plan and surgical navigation were used to design and correct the mandibular and fibular position. RESULTS: Our technique enabled precise recovery of the original mandibular configuration in this patient. The shift in the reconstructed mandible and fibular segment was <5 mm. CONCLUSIONS: The authors described a new procedure for secondary mandibular reconstruction with a free fibular flap using digital techniques involving surgical navigation, which have the potential to improve the clinical outcomes of this procedure. PMID- 28005745 TI - Indian Survey on Practice Patterns of Lacrimal and Eyelid Disorders (iSUPPLE) Report 2: Mitomycin-C and Lacrimal Stents in Dacryocystorhinostomy. AB - PURPOSE: The aim of the study was to assess practice patterns on the use of intraoperative Mitomycin-C (MMC) and lacrimal stents (intubation) in dacryocystorhinostomy (DCR) for nasolacrimal duct obstruction (NLDO) among oculoplastic surgeons in India. The survey was aimed at obtaining data on the duration of stent placement and specifics regarding MMC usage namely, concentration and duration of application. METHODS: A survey that included questions on the management of lacrimal disorders was sent in April 2015 to members of the Oculoplastic Association of India, through an email communication. The results were tabulated and analyzed. RESULTS: External DCR is the preferred surgery of choice to treat NLDO for most oculoplastic surgeons (86%) surveyed. A majority (58%) of the respondents do not place stents during DCR routinely in their practice. Lesser experienced oculoplastic surgeons (<10 years of experience) when compared with more experienced surgeons were more likely to place stents routinely in their DCRs (59% versus 19%; P = 0.0002). Of the special situations that the respondents would consider stent placement, the most common scenarios were the presence of coexisting canalicular pathology followed by cases of previously failed DCRs. The preferred duration for stent removal was 3 months (48%). Intraoperative MMC was used routinely by only 36% of the respondents. The most common condition where they would consider intraoperative MMC was previously failed DCRs. Three minutes (25%) and 0.2 mg/mL (30%) were the preferred duration of application and concentration of MMC, respectively. CONCLUSIONS: External DCR is the most preferred surgery for NLDO; in comparison, endoscopic DCR enjoys less popularity as the surgical procedure of choice in NLDO. Adjunctive procedures, namely intraoperative MMC and stenting of the lacrimal passages, are not routinely performed; however, previously failed DCRs are common indications when the respondents may use MMC and/or lacrimal stents. Three months is the preferred duration for stent removal. The trends regarding the concentration of MMC and the application show considerable variation, underscoring the need for evidence-based guidelines to assist oculoplastic surgeons. PMID- 28005746 TI - Customized Orbital Wall Reconstruction Using Three-Dimensionally Printed Rapid Prototype Model in Patients With Orbital Wall Fracture. AB - BACKGROUND: It is difficult to restore original orbital contours because of their complex 3-dimensional structure. Moreover, slight implant malpositioning can result in enophthalmos or other complications. The authors describe our experience of using individualized prebent titanium-Medpor mesh implants and stereolithographic modeling in a series of patients who underwent orbital wall reconstruction. METHODS: A consecutive series of 104 patients with orbital fractures received computer simulation-designed prebent titanium-Medpor mesh implants insertion. Preoperative computed tomography (CT) data were processed for each patient, and a rapid prototyping (RP) model was produced. The uninjured side was concurrently mirrored and superimposed onto the traumatized side to create a mirror image of the RP model. The authors fabricated the titanium-Medpor implants to intraoperatively reconstruct the 3-dimensional orbital structure. The prefabricated titanium-Medpor implants were inserted into the defective orbital wall and fixed. Postoperative CT images were immediately taken to evaluate the reconstructed contours and compare the preoperative and postoperative intraorbital volumes. RESULTS: All reconstructions were successful without postoperative complications. The implants were correctly positioned in the sagittal, axial, and coronal planes relative to the original orbital contours. The mean preoperative intraorbital volumes of the uninjured and traumatized sides were 21.39 +/- 1.93 and 23.17 +/- 2.00 cm, respectively, and the postoperative mean intraorbital volume was 20.74 +/- 2.07 cm. CONCLUSIONS: Orbital reconstruction can be optimized using individually manufactured rapid prototype skull model and premolded synthetic scaffold by computer-aid of mirroring reconstruction of 3-dimensional images and 3-dimensional printing techniques. PMID- 28005747 TI - A Craniomaxillofacial Surgical Assistance Workstation for Enhanced Single-Stage Reconstruction Using Patient-Specific Implants. AB - BACKGROUND: Craniomaxillofacial reconstruction with patient-specific, customized craniofacial implants (CCIs) is ideal for skeletal defects involving areas of aesthetic concern-the non-weight-bearing facial skeleton, temporal skull, and/or frontal-forehead region. Results to date are superior to a variety of "off-the shelf" materials, but require a protocol computed tomography scan and preexisting defect for computer-assisted design/computer-assisted manufacturing of the CCI. The authors developed a craniomaxillofacial surgical assistance workstation to address these challenges and intraoperatively guide CCI modification for an unknown defect size/shape. METHODS: First, the surgeon designed an oversized CCI based on his/her surgical plan. Intraoperatively, the surgeon resected the bone and digitized the resection using a navigation pointer. Next, a projector displayed the limits of the craniofacial bone defect onto the prefabricated, oversized CCI for the size modification process; the surgeon followed the projected trace to modify the implant. A cadaveric study compared the standard technique (n = 1) to the experimental technique (n = 5) using surgical time and implant fit. RESULTS: The technology reduced the time and effort needed to resize the oversized CCI by an order of magnitude as compared with the standard manual resizing process. Implant fit was consistently better for the computer-assisted case compared with the control by at least 30%, requiring only 5.17 minutes in the computer-assisted cases compared with 35 minutes for the control. CONCLUSION: This approach demonstrated improvement in surgical time and accuracy of CCI-based craniomaxillofacial reconstruction compared with previously reported methods. The craniomaxillofacial surgical assistance workstation will provide craniofacial surgeons a computer-assisted technology for effective and efficient single-stage reconstruction when exact craniofacial bone defect sizes are unknown. PMID- 28005748 TI - Cleft Lip Repair: Through the Looking Glass. AB - The goal of cleft lip repair is an anatomic re-creation of the normal lip elements with no vertical discrepancy between the affected and normal sides of the central philtral element. Frequently, the repaired lip appears short in the vertical dimension despite careful preoperative measurements and intraoperative maneuvers. Some may be due to postoperative scar contraction, but some may be due to a failure to consider the internal surface when reconstructing the lip. Much literature has been dedicated to marking and repairing the skin and muscle of the lip; however, scant consideration has been given to careful reapproximation of the mucosal surface. The present study sought to review the literature, regarding mucosal reapproximation in unilateral cleft lip repair and to better describe closure of the mucosal surface to minimize tension and provide adequate lip length. PMID- 28005749 TI - Effect of Local Rosuvastatin Administration on Calvarial Bone Defects. AB - The purpose of this study is to investigate the potential of the local administration of different doses of rosuvastatin (RSV) on autogenous grafted critical-sized cortical bone defects. Twenty-four rats were divided into 3 groups: Group C (control), Group RSV-0.1, and Group RSV-1. A 5-mm diameter critical-size defect was created in the calvarium of each animal. In Group C, the defect was filled by autogenous graft and sterile saline-treated absorbable collagen sponge (ACS) was applied. Defects in the experimental groups (groups RSV 0.1 and RSV-1) were grafted by autogenous graft and ACS with saline solution containing 0.1- and 1-mg RSV were applied. All animals were euthanized at 28 days after operation. Stereologic and micro-computed tomography (MUCT) analyses were performed. New bone area and connective tissue volumes were measured. Stereologic analysis showed that the difference between group RSV-1 with a mean bone formation of 1.79 +/- 0.06 mm and groups RSV-0.1 and control (C) was statistically significant (P <= 0.05) with a mean bone formation of 1.29 +/- 0.28 mm and 1.08 +/- 0.12 mm, respectively. Connective tissue volume was also significantly higher in 1-mg RSV applicated group. Micro-CT results were similar with stereologic analyses. Local administered 1-mg RSV enhances bone regeneration in critical-size calvarial rat defects filled with autogenous graft. PMID- 28005750 TI - Discussion on: The Effect of Local Rosuvastatin Administration on Calvarial Bone Defects. PMID- 28005751 TI - Postoperative Improvement of Diplopia and Extraocular Muscle Movement in Patients With Reconstructive Surgeries for Orbital Floor Fractures. AB - OBJECTIVE: With orbital floor fracture incidence rates increasing year by year, many patients require surgical treatment to improve diplopia, limitation of extraocular muscle movement (EOM), enophthalmos, and midface appearance. With the use of high-density polyethylene, titanium screws, titanium plate, and titanium mesh to repair an orbital floor fracture, enophthalmos and midfacial deformity correction procedures have made great progress. However, attenuating diplopia and the limitation of EOM are still difficult problems to prevent. METHODS: The clinical data of 92 patients with reconstructive surgeries after orbital floor fracture were prospectively studied. The position, range of fracture, and incarceration of extraocular muscles were determined by computed tomography scanning. A Hess screen and a synoptophore examination were used to determine the EOM and diplopia. The Hess area ratio (HAR%) and the grade of diplopia were measured before and 1, 3, and 6 months after surgery. Diplopia was evaluated, and the severity was recorded accordingly. RESULTS: Diplopia rates in patients with simple orbital floor fracture showed a significant difference preoperatively and postoperatively at 1 and 3 months (P < 0.05) compared with diplopia rates at 6 months and 12 months after operation, which had no significant difference (P > 0.05). There was a statistically significant difference (P < 0. 05) among patients with an orbital floor fracture who had an operation within 3 weeks or more than 3 months after injury. Compared with preoperative and postoperative findings at 1 and 3 months, the limitation of EOM in patients with orbital floor fractures had a significant difference (P < 0.05); however, compared with 3 and 6 months after operation, there was no significant difference (P > 0.05). There was a statistically significant difference (P < 0.05) in patients with orbital floor fractures having had an operation within 3 weeks and more than 3 months after injury. The difference of improvement for diplopia after operation among HAR% < 65%, 65% <= HAR% <= 85%, and HAR% >85% groups were statistically significant (P <0.05). Postsurgically, the HAR% of the patients was improved, and the difference of HAR% between patients before and after the operation was statistically significant (P < 0.05). CONCLUSION: Surgical management can effectively improve diplopia and EOM disorder of patients with orbital floor fractures. Improvement statistics were calculated by a Hess screen and a synoptophore. Hess area ratio is a useful method to convert the Hess screen into a numerical value and can therefore be used to compare patients in clinical treatment of orbital wall fracture. PMID- 28005752 TI - Analysis of Extended Transconjunctival Approach With Lateral Paracanthal Incision: A Study Among Classical Methods of Orbital Approach and New Method. AB - Although the subcilliary or conventional transconjunctival approach has been widely used, it often fails to get acceptable visual fields or scars. This study directly compared the extended transconjunctival approach accompanied by lateral paracanthal incision with other traditional approaches in terms of surgical fields, the outcomes and complications. This retrospective chart review included 113 patients (82 males and 31 females; mean age: 38.7 years; range: 11-87 years), who underwent orbital reduction from November 2009 to September 2013. In extended transconjunctival approach, the external skin of the inferolateral canthal tendon was demarcated in a natural skin crease approximately 5 mm from the lateral canthus. The surgical approach was based on anteroseptal transconjunctival dissection. Paracanthal incision about 5 mm in length was performed. Esthetic and functional complications were evaluated, including the presence of a visible scar, lid retraction, or hypertrophic scar; epiphora, diplopia, global hematoma, persistent enophthamos, or exophthamos; and presence of entropion/ectropion. The extended transconjunctival approach resulted in a significant increase in the area of the surgical field statistically significant (P = 0.002). Complication rates are similar with other approach techniques. Postoperative scarring was confirmed by pictures taken in the outpatient clinic. The physicians' average Vancouver scar scale (VSS) of first physician was 1.26 and second physician was 1.2. Compared with the conventional transconjunctival approach, the extended transconjunctival approach with paracanthal incision had similar complication and scarring rates, as well as a lower scarring rate than the subciliary approach while providing much wider surgical fields. PMID- 28005753 TI - Motor Nerve Preservation and Muscle Atrophy After Pectoralis Major Musculocutaneous Flap Surgery for Oromandibular Reconstruction. AB - OBJECTIVE: The authors investigated the clinical and histopathologic significance of medial pectoral nerve preservation/reinnervation of pectoralis major musculocutaneous flap for oromandibular reconstruction. MATERIALS AND METHODS: The authors compared 13 patients treated with pectoralis major musculocutaneous flap reconstruction and 6 control patients treated by rectus abdominis musculocutaneous flap reconstruction without motor nerve restoration. Subjective awareness was scored to evaluate changes in the facial contour due to muscle atrophy, and objective evaluation was performed in few patients. In addition, the authors performed histopathologic analysis of both muscle atrophy and nerve regeneration in 20 patients from whom samples were available. RESULTS: Subjective awareness of changes in the facial contour induced by muscle atrophy was low among patients with nerve preservation/reinnervation, but there were objective changes at 3 months after surgery among patients who underwent nerve resection. In the patients who had medial pectoral nerve preservation or nerve restoration by nerve suture, favorable facial symmetry was retained at 5 years after surgery. Even though the motor nerve was preserved or restored, fatty degeneration and fibrosis were noted in approximately 30% of the total surface area of the muscle, and type I fibers had decreased to 36% that of control at 7 years after surgery. However, regressive changes were inhibited for 1 year after surgery; in contrast, changes corresponding to those noted at 7 years after surgery were observed by 3 months in the patients with nerve resection. CONCLUSION: Thus, the authors showed that preservation or restoration of nerves can delay muscle and have highlighted the potential benefits of this approach. PMID- 28005754 TI - Cranioplasty: Review of Materials. AB - Cranioplasty remains a difficult procedure for all craniofacial surgeons, particularly when concerning the reconstruction of large lacunae in the skull. Considering the significant clinical and economic impact of the procedure, the search for materials and strategies to provide more comfortable and reliable surgical procedures is one of the most important challenges faced by modern craniofacial medicine.The purpose of this study was to compare the available data regarding the safety and clinical efficacy of materials and techniques currently used for the reconstruction of the skull. Accordingly, the scientific databases were searched for the following keywords autologous bone, biomaterials, cranial reconstruction, cranioplasty, hydroxyapatite, polyetheretherketone, polymethylmethacrylate, and titanium. This literature review emphasizes the benefits and weaknesses of each considered material commonly used for cranioplasty, especially in terms of infectious complications, fractures, and morphological outcomes.As regards the latter, this appears to be very similar among the different materials when custom three-dimensional modeling is used for implant development, suggesting that this criterion is strongly influenced by implant design. However, the overall infection rate can vary from 0% to 30%, apparently dependent on the type of material used, likely in virtue of the wide variation in their chemico-physical composition. Among the different materials used for cranioplasty implants, synthetics such as polyetheretherketone, polymethylmethacrylate, and titanium show a higher primary tear resistance, whereas hydroxyapatite and autologous bone display good biomimetic properties, although the latter has been ascribed a variable reabsorption rate of between 3% and 50%.In short, all cranioplasty procedures and materials have their advantages and disadvantages, and none of the currently available materials meet the criteria required for an ideal implant. Hence, the choice of cranioplasty materials is still essentially reliant on the surgeon's preference. PMID- 28005755 TI - Management of Zygomatic Fractures in Young Patients: Technical Modifications for Aesthetic and Functional Results. AB - INTRODUCTION: The zygomaticomaxillary complex is very vulnerable to injury because of its intrinsically prominent convexity. There are 2 different surgical approaches for the therapy of these fractures: closed reduction and open reduction. In the open reduction 2 or 3 fixation points with related incisions are usually necessary in dislocated fractures: osteosynthesis must be performed starting from zygomaticofrontal suture when dislocated at this site, followed by zygomatic body fixation on the anterior sinus wall, anterior orbital floor margin fixation, and finally orbital floor reconstruction in case of eye globe dislocation with diplopia. AIM: This study evaluated the combination of the transconjunctival (TC) approach without canthotomy in association with the transoral maxillary approach and lateral rim skin incision (SI) without canthotomy for frontozygomatic dislocated fractures to achieve proper reduction and stabilization without any aesthetic decay in young patients. A less invasive and more aesthetic technique is shown for treating dislocated zygomaticomaxillary complex fractures with 2 or 3 fixation points and platelet-rich fibrin (PRF) use to promote tissue healing. MATERIALS AND METHODS: Ten patients (mean age: 32) were referred for dislocated zygomaticomaxillary complex fracture. Five patients were treated by TC approach without canthotomy in association with the transoral maxillary approach and, when needed, eyebrow SI without canthotomy for frontozygomatic dislocated fractures (group 1). Five more patients were treated by traditional subciliar incision at lower eyelid and vertical lateral incision at lateral margin of the orbit (group 2). Autologous PRF for orbital floor reconstruction was used. The follow-up period was 6 months long. Follow-up radiographs (TC) and photos were routinely used to evaluate the adequacy of reduction and lower eyelid right position or retraction. RESULTS: All cases were successful; there were no problems at surgery and postoperative time. During the 6-month follow-up, all 5 patients of group 1 showed satisfactory facial symmetry, no noticeable scarring, no ectropion or lower eyelid significant droop, and no functional impairment. Mean difference for lower eyelid droop between the 2 groups of patients was 1.4 mm at T1 and 1.2 mm at T2. DISCUSSION: Aesthetic result is a priority in the treatment planning of orbitozygomatic fractures because of the fundamental role of the eye and lid area in the aesthetic of the face. In our experience best aesthetic results were achieved through a latero cantal horizontal SI combined to a vertical periosteal incision at the frontozygomatic rim without canthotomy, thus performing a different double-layer incision. In the patients with large orbital floor dislocation, reconstructive titanium mesh was covered by autologous PRF membranes, which can improve the vascularization of the surgical site, by promoting neoangiogenesis. CONCLUSIONS: In young patients these techniques are indicated because of the need of better aesthetic results that can be achieved by preventing postoperative functional impairment with lower eyelid droop and unnatural aesthetic asymmetry of the 2 lower lids. This more conservative technique resulted in better aesthetic results, avoiding most common complications. PMID- 28005756 TI - Reconstructing a Giant Frontal Osteoma With Porex. AB - Osteomas are the most common benign tumors of the paranasal sinuses. They are usually localized in the frontal sinus. Giant osteomas of the frontal sinuses are very rare but readily extend into the intraorbital or intracranial cavity, causing serious complications. This is a report of a 14 year-old boy with a bulging in frontal area and asymptomatic giant osteoma of the frontal sinuses. He had a history of minor trauma that had a bulging after 3 months. However, he referred to a plastic surgeon after 15 months. Computed tomography of the sinuses revealed a 3.5 * 6 cm extremely dense bony mass in the frontal sinus that extended into the left orbit and ethmoid sinus. A bicoronal frontal flap was raised with a V-shaped skin incision starting from the tragus placed 5 cm posterior to the hairline. The osteoma was resected completely in the frontal sinus and the anterior wall of frontal sinus was reconstructed with Porex. The patient has not had any complications until the time of writing this report. Titanium mesh may still be a valuable option, but Medpore Porex has shown to be quite effective in this case. PMID- 28005757 TI - Correction of Pterygium Colli in Turner Syndrome: A Clinical Report and Review of the Surgical Management. AB - The aim of surgery for pterygium colli (PC) is to correct the contour deformity, redistribute or remove the horizontal excess of skin, address the abnormal posterior hairline, avoid excessive scarring, and prevent recurrence. The purpose of this study is to review the available methods to correct the deformity and highlight a recent patient performed by the senior author. A modified bilateral Z plasty technique was used for correcting PC on a 5-year-old African American girl diagnosed with Turner syndrome. The patient had an uneventful postoperative period and satisfactory functional and esthetic results were demonstrated at 1 year follow-up. The approach used was a variation of a lateral approach. Using the proposed approach, excision and complete release of the scar contracture and less tension, which reduces the rate of recurrence compared with the posterior approaches, is achieved. Moreover, the current technique avoids myotomies, which can put the spinal accessory nerve at risk, and lateral Z-plasties which the authors find unnecessary. Instead, the advancement of each anterior flap is limited in the posterosuperior direction so that the flaps do not meet in the posterior midline. This limits the pull and tension on the entire closure. Although several techniques have been described over the years, the search for the ideal type of surgical treatment is still ongoing. PMID- 28005758 TI - Pathological Mandibular Fracture Associated With Diffuse Large B-Cell Lymphoma in HIV-Positive Patient. AB - This article describes the occurrence of diffuse large B-cell lymphoma in a 39 year-old human immunodeficiency virus-positive patient. The patient sought medical care complaining of increased volume in the right mandibular angle and imaging tests showed an extensive radiolucency with undefined boundaries compromising the mandibular border. After the incisional biopsy, the patient had a pathological fracture in the region, which was properly treated in a second surgical procedure using a 2.4-mm reconstruction plate. Immunohistochemical analysis revealed positive marking for CD3, CD79a, Ki67, and Epstein-Barr virus encoded RNA. The treatment consisted of concurrent antiretroviral therapy with chemotherapy with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone. Examinations of images (2 years postoperatively) revealed complete bone repair and absence of injury recurrence. This work is important because it describes an unusual location of diffuse large B-cell lymphoma and shows the importance of diagnosis and treatment of the injury at an early stage in order to promote the prognosis and survival of patients. PMID- 28005759 TI - Correlation Between the Degree of the Mastoid Pneumatization and the Angle and the Length of the Eustachian Tube. AB - OBJECTIVES: The aim of the present study is to explore the correlation between the degree of the mastoid pneumatization and the angle (ETa) and the length of the Eustachian tube (ETl). STUDY DESIGN: The study design consisted of a retrospective clinical chart review. METHODS: In total, 217 patients (110 females and 107 males; average age, 33.14 +/- 12.88 years; age range: 18-65 years) were included in the study. The patients were divided into 3 groups in terms of the degree of the mastoid pneumatization. The mastoid pneumatization was measured between 0 and 5 cm for group A, between 5 and 10 cm for group B, and >=10 cm for group C. The ETa and ETl of each group were compared. RESULTS: The mean mastoid pneumatization of groups A, B, and C was 4.32 +/- 1.96, 8.26 +/- 2.68, and 11.94 +/- 1.28 cm, respectively. The ETl of group A was lower than that of other groups statistically (P = 0.006 and 0.018, respectively). The mean ETl did not differ between the groups B and C (P = 0.698, >0.05, respectively). The ETa of each group did not differ (all P > 0.05). The mastoid pneumatization and the ETl were higher in males than in females (P = 0.004 and 0.001, respectively). The ETa did not differ between males and females (P = 0.0158). There was a positive correlation between the degree of the mastoid pneumatization and the ETl (r = 0.159/P = 0.002, <0.05, respectively). CONCLUSIONS: The present study is thus the first to analyze the relationship between the degree of the mastoid pneumatization and the ETa and the ETl. We found a positive correlation between the degree of the mastoid pneumatization and the ETl. PMID- 28005760 TI - Can a Specific Computed Tomography-Based Assessment Predict the Ophthalmological Outcome in Pure Orbital Floor Blowout Fractures? AB - The aim of this study was to determine the predictive value of a specific computed tomography (CT)-based assessment for the final functional ophthalmological outcome in pure orbital floor blowout fractures. Data of 34 consecutive patients with pure blowout fractures who had undergone a period of at least 6 months of medical and ophthalmological follow-up were analyzed. The following 3 CT scan-based parameters were included: area ratio of the fractured orbital floor (RF), maximum height of periorbital tissue herniation (MH), and a 4 grade muscular subscore (MSS) describing the inferior rectus muscle displacement relative to the orbital floor level. The orthoptic complications (diplopia, enophthalmos, and ocular motility restriction) were evaluated by an experienced strabologist. The CT parameters' predictive value was analyzed using receiver operating characteristic curves and area under the curve (AUC), logistic regression, and Spearman correlation.The RF had a significant predictive value for enophthalmos appearance (AUC = 0.75, P = 0.02), and MH for diplopia (AUC = 0.80, P = 0.03). Among patients with complications, the relevance of MSS and MH as well as the severity of vertical deviation were also clinically strongly associated (rho = -0.52 and -0.56).Our study revealed the significantly predictive value of RF for occurrence of enophthalmos and of MH for diplopia persistence. Although statistically unable to predict the occurrence of ocular motility restriction, MH and MSS were clinically strongly correlated with the severity of ocular deviation limitations. PMID- 28005761 TI - Tick Infestation of the Eyelid and Removal With Forceps and Punch Biopsy. AB - Ocular tick infestation can occur in any age group or sex with exposure in an endemic setting. All parts of the ocular tissue have been reported to be susceptible to tick infestation. The authors present a rare patient with tick infestation of eyelid.An 88-year-old woman was referred for a yellowish lesion of the right upper eyelid. She had a history of sting 2 days before presentation, and developed eyelid swelling with mucopurulent discharge the next day. Slit lamp examination showed blepharitis and revealed that the lesion was the body of a hard tick, firmly attached to eyelid. First, blunt forceps were used for removal of the tick under a surgical microscope. However, attempted removal resulted in the disembodiement of the parasite and retention of the mouthparts in the skin. The retained tick parts were excised en bloc by skin punch biopsy. The tick was identified as Ixodes nipponensis. Subsequent treatment was given for blepharitis and skin lesion.This case introduces a rare patient with tick infestation of eyelid, and the proper management. Less than 20 documented patients with tick infestation of eyelid have been reported worldwide, and this is the first patient from South Korea in ophthalmological society. PMID- 28005762 TI - Jaw in a Day: State of the Art in Maxillary Reconstruction. AB - BACKGROUND: Reconstruction of maxillary defects following tumor extirpation is challenging because of combined aesthetic and functional roles of the maxilla. One-stage reconstruction combining osseous free flaps with immediate osseointegrated implants are becoming the standard for mandibular defects, and have similar potential for maxillary reconstruction. METHODS: A woman with maxillary Ewing sarcoma successfully treated at age 9 with neoadjuvant chemotherapy, right hemimaxillectomy, and obturator prosthetic reconstruction presented for definitive reconstruction, complaining of poor obturator fit, and hypernasality. Her reconstruction was computer-simulated by a multidisciplinary team, consisting of left hemi-Lefort I advancement and right maxillary reconstruction with a free fibula flap with immediate osseointegrated implants and dental prosthesis. RESULTS: Full dental restoration, midface projection, and oral fistula corrections were achieved in 1 operative stage using this approach. CONCLUSIONS: This patient demonstrates a successful approach for maxillary reconstruction using computer-planned orthognathic surgery with free fibula reconstruction and immediate osseointegrated implants with dental prosthesis. PMID- 28005763 TI - Assessment of Surgery Resident Competency Provided by Patients. AB - The objective of this study was to assess the competency of surgery residents from the patient perspective in the current healthcare environment in China. The authors performed an assessment of 508 surgery residents in Liaoning province. Seven patients were as a group to complete the self-administered questionnaires on the survey for each individual corresponding resident. A 5-point rating scale with an unable-to-evaluate category was used to assess surgery resident competency by patients. Reliability and validity were assessed by Cronbach alpha (alpha) and exploratory factor analysis, respectively. Statistical analysis was performed using SPSS 13.0. The surveys on 421 residents were valid, and the valid response rate was 82.8%. A total of 2947 questionnaires from patients were analyzed in this study. The Cronbach alpha coefficient was 0.92. The 4 factors emerging in the exploratory factor analysis reached a cumulative contribution rate of 66.98%. The items of "promotes health maintenance (talks about preventive care)" (206/7.0%), "tells me about any side effects of the medicine" (177/6.0%), "spends enough time with me" (189/6.4%), and "answers my questions thoroughly" (168/5.7%) were scored <4 by higher percentage of patients. The instrument provided an acceptable means for patients to evaluate the competency of Chinese surgery residents. Surgery residents should improve their competencies on preventive care, patient safety, and communication skills. PMID- 28005764 TI - Intracranial Nasal Dermoid Sinus Cyst: Transnasal Endoscopic Resection by Open Rhinoplasty Approach, With Intraoperative Video. AB - Nasal dermoid sinus cysts are rare congenital lesions that may lead to recurrent soft tissue infections and severe intracranial complications. In case of an intracranial extension, the traditional surgical approach includes a frontal craniotomy with significant morbidity. As a less invasive alternative, a transnasal endoscopic approach has been recommended.This report describes the transnasal endoscopic resection of an intracranial nasal dermoid sinus cyst via an open rhinoplasty approach, which achieved a wide surgical exposure with minimal invasivity and ideal aesthetic results. An intraoperative video demonstrates this combination of techniques in this rare skull base/intracranial pathology. PMID- 28005765 TI - Functional Reconstruction in Mandibular Avulsion Injuries. AB - The present report describes the planning and surgery as well as pitfalls and management of a patient with a near total mandibular avulsion injury that was rehabilitated using three-dimensional (3D) laser printing of a titanium lower jaw. Laser-sintering involves zapping layers of powdered metal to recreate a 3D implantable skeletal defect. The process involves using either mirror imaging of the unaffected side or using archival image database of healthy individuals. A 25 year-old man presented with a gunshot injury that left him with a near total avulsed mandible. The patient received state-of-the-art treatment using a laser 3D printed mandible which was connected to the muscles of mastication for functionality. The inner side of the titanium jaw was filled with the patient's comminuted fractured bones in addition to harvested iliac crest bone graft that was covered with the patient's remaining periosteal tissue. The implantation of a near total mandible using 3D laser printing is a fast and predictable process that in selected patients can result in aesthetically as well as functionally excellent results. The authors believe that the future of craniofacial reconstruction will employ these methods for facial bony reconstruction. PMID- 28005766 TI - Three-Dimensional Handheld Scanning to Quantify Head-Shape Changes in Spring Assisted Surgery for Sagittal Craniosynostosis. AB - Three-dimensional (3D) imaging is an important tool for diagnostics, surgical planning, and evaluation of surgical outcomes in craniofacial procedures. Gold standard for acquiring 3D imaging is computed tomography that entails ionizing radiations and, in young children, a general anaesthesia. Three-dimensional photographic imaging is an alternative method to assess patients who have undergone calvarial reconstructive surgery. The aim of this study was to assess the utility of 3D handheld scanning photography in a cohort of patients who underwent spring-assisted correction surgery for scaphocephaly. Pre- and postoperative 3D scans acquired in theater and at the 3-week follow-up in clinic were postprocessed for 9 patients. Cephalic index (CI), head circumference, volume, sagittal length, and coronal width over the head at pre-op, post-op, and follow-up were measured from the 3D scans. Cephalic index from 3D scans was compared with measurements from planar x-rays. Statistical shape modeling (SSM) was used to calculate the 3D mean anatomical head shape of the 9 patients at the pre-op, post-op, and follow-up. No significant differences were observed in the CI between 3D and x-ray. Cephalic index, volume, and coronal width increased significantly over time. Mean shapes from SSM visualized the overall and regional 3D changes due to the expansion of the springs in situ. Three-dimensional handheld scanning followed by SSM proved to be an efficacious and practical method to evaluate 3D shape outcomes after spring-assisted cranioplasty in individual patients and the population. PMID- 28005767 TI - The Clinical Feasibility of Newly Developed Thin Flat-Type Bioresorbable Osteosynthesis Devices for the Internal Fixation of Zygomatic Fractures: Is There a Difference in Healing Between Bioresorbable Materials and Titanium Osteosynthesis? AB - INTRODUCTION: In recent years, bioresorbable plates have undergone remarkable development. However, there has been no attendant improvement in their strength, because strength requires thickness, and complications such as palpability are related to the thickness of bioresorbable plate systems. In this clinical study, we compared the surgical management of zygomatic fractures using newly developed thinner bioresorbable materials or conventional titanium miniplates. METHODS: Twelve patients with zygomatic fractures were randomly divided equally into 2 groups (6 with new bioresorbable osteosynthesis materials and 6 with standard titanium miniplates). Using computed tomography, we evaluated the thickness of the soft tissue and plate at the zygomaticofrontal sutures in each patient with the help of detailed radiographic computed tomography data at 6 months postoperatively. We compared the amount of soft-tissue volume increase between the uninjured healthy and injured operated sides in each patient. RESULTS: Both groups eventually achieved satisfactory healing, with a favorable restoration of form and function and without any complications, including palpability. The amount of soft-tissue volume increase at the operated side relative to the uninjured healthy side using new thin bioresorbable plates was 131.1% (range: 101.5-165.8). On the other hand, that of titanium miniplates was 126.4% (range: 102.2-167.6). There was no statistically significant difference (P > 0.05). CONCLUSION: This newly developed thinner flat-type bioresorbable plate system could be considered clinically useful in the treatment of zygomatic fractures even in easily palpated areas, such as the infraorbital rim or zygomaticofrontal sutures, without any healing differences in skeleton as compared with conventional titanium miniplates. PMID- 28005768 TI - The "Anatomical Balance Correction" for Secondary Cleft Lip Nasal Deformities. AB - Secondary cleft lip nasal deformities corrective procedures are still a major concern for the maxillofacial surgeons. PMID- 28005769 TI - Aberrant Lower Extremity Arterial Anatomy in Microvascular Free Fibula Flap Candidates: Management Algorithm and Case Presentations. AB - An accurate and comprehensive understanding of lower extremity arterial anatomy is essential for the successful harvest and transfer of a free fibula osteoseptocutaneous flap (FFF). Minimum preoperative evaluation includes detailed history and physical including lower extremity pulse examination. Controversy exists regarding whether preoperative angiographic imaging should be performed for all patients. Elevation of an FFF necessitates division of the peroneal artery in the proximal lower leg and eradicates its downstream flow. For patients in whom the peroneal artery comprises the dominant arterial supply to the foot, FFF elevation is contraindicated. Detailed preoperative knowledge of patient specific lower extremity arterial anatomy can help to avoid ischemia or limb loss resulting from FFF harvest. If preoperative angiographic imaging is omitted, careful attention must be paid to intraoperative anatomy. Should pedal perfusion rely on the peroneal artery, reconstructive options other than an FFF must be pursued. Given the complexity of surgical decision making, the authors propose an algorithm to guide the surgeon from the preoperative evaluation of the potential free fibula flap patient to the final execution of the surgical plan. The authors also provide 3 clinical patients in whom aberrant lower extremity anatomy was encountered and describe each patient's surgical course. PMID- 28005770 TI - A New Surgical Approach for Tessier No. 4 Facial Cleft Reconstruction: Lip-Rescue Flap. AB - Craniofacial clefts are rare, severe challenges for surgeons about which there is limited literature. Tessier Number 4 (No. 4) clefts are one of the most complex craniofacial anomalies and present difficulties in surgical treatment. The most common deformities associated with Tessier No. 4 clefts are displacements of the lower eyelids, medial canthus, and ala and decreased distance between the lower eyelids and lips. In surgery to correct these deformities, the greatest challenges are the design and the placement of the landmarks and incisions. Because of its relative rarity and wide range of severity, no definitive operative methods have been accepted for Tessier No. 4 facial cleft. The present study presents a new lip-rescue flap technique as an alternative approach for reconstructing Tessier No. 4 facial clefts. PMID- 28005771 TI - Ocular Reconstruction Using Bone-Anchored Implants in Irradiated Facial Deformities After Tumor Extirpation. AB - BACKGROUND: Surgical resection of ocular malignancies can result in complex craniofacial defects that can be difficult to reconstruct with conventional reconstruction techniques. Craniofacial prosthesis supported by bone-anchored implants has evolved as a reliable alternative in such scenarios. METHODS: The authors describe a patient who underwent extensive facial resection secondary to squamous cell carcinoma resulting in significant facial deformities. A bone anchored osseointegrated implant was used to perform facial reconstruction. RESULTS: The patient had successful reconstruction of her orbit with bone anchored implant. However, her implant needed to be removed 10 months postoperatively secondary to infection. A second attempt at implant placement has been deferred due to osteonecrosis secondary to adjuvant radiotherapy. CONCLUSION: Bone-anchored implants can provide an elegant alternative in the reconstruction of complex facial defects and provide direct access to surveillance for possible tumor recurrence. However, these bone-supported prosthetics should be used with caution in patients undergoing irradiation. PMID- 28005772 TI - Correction of Residual Static and Dynamic Labial Deviations in a Paralyzed Face After Free Gracilis Muscle Transplantation. AB - Free muscle flap transfer is currently the procedure of choice for longstanding facial paralysis to restore symmetry both at rest and when smiling. However, movements obtained are generally localized, unidirectional, and philtrum centralization and lower lip movement is not proportionally achieved. The stability of free flap insertion at the lips also interferes with the results, as gradual disinsertion and shifting of the nasolabial fold can be caused by repetitive movements. Asymmetry of smile can also be caused by lip depressor inactivity due to marginal mandibular paralysis, and both dynamic and static procedures are often required after dynamic reanimation. Here, the authors report a technical refinement that can be used even years after facial reanimation, using concealed scars and with minimal morbidity for correction of static and dynamic labial deviations from the midline. Placement of a transfixed tendon graft in C-fashion tendon graft between the gracilis free flap and the orbicularis oris of the upper and lower lip on the nonparalyzed side allows the forces from muscle contraction to be transferred to the philtrum and lower lip. It allows correction of static and dynamic labial deviations from the midline, reducing rates of inadequate fixation and partial or total disinsertion of the muscle flap in the buccal region. PMID- 28005773 TI - Pedicle Tongue Flap for Palatal Fistula Closure. AB - BACKGROUND: Palatal fistulae are common sequels that appear in patients after surgical procedures in the palate. Considering the difficulty to achieve an effective treatment, there are many techniques to surgically manage fistulae, that is, the pedicle tongue flap. OBJECTIVE: Being so, the main goal of this paper is to report cases of patients with palatal fistulae, from different etiologies, treated with anterior pedicle tongue flap. PATIENTS: Eleven patients, 8 male and 3 female, mean age of 32 years old with palatal fistulae surgically treated with anterior dorsal tongue flaps. No flap was completely lost. There was 1 partial loss and 1 residual buconasal communication. The most common complaints of the patients were difficulty to perform oral hygiene and mild pain. CONCLUSION: The use of anterior pedicle tongue flap for closing palatal fistulae demonstrates to be a safe procedure with high success rates (81% in this paper) when correctly indicated. PMID- 28005774 TI - A Simple Closure Technic for Tracheoesophageal Puncture Failures. AB - Tracheosephageal puncture is the one of the most favorable methods, and widely used by physicians for voice reconstruction after total laryngectomy. Intractable leakages from the tracheosephageal punctures are the most common complication, and management of these fistulas is still troublesome for the patients and physicians. Local surgical sutures, rotational flaps, injections are reported previously, but in this report the authors aimed to mention on a very simple method with silicone septal button. Insertion of a temporary silicone septal button may be well tolerated by patients and can help to manage this complication easily on exact indications. The authors discussed indications and long-term results of this method with different patients. PMID- 28005775 TI - Fully Endoscope-Controlled Clipping Bilateral Middle Cerebral Artery Aneurysm Via Unilateral Supraorbital Keyhole Approach. AB - Clipping bilateral middle cerebral artery (bMCA) aneurysms via unilateral approach in a single-stage operation is considered as a challenge procedure. To our knowledge, there is no study in surgical management of patients with bMCA aneurysms by fully endoscope-controlled techniques. The author reported a patient with bMCA aneurysms who underwent aneurysms clipping via a unilateral supraorbital keyhole approach by endoscope-controlled microneurosurgery, and the patient had an uneventful postoperative course without neurologic impairment and complication. Furthermore, the author discussed the advantages and adaptation of endoscope-controlled clipping bMCA aneurysms via unilateral supraorbital keyhole approach. PMID- 28005776 TI - Hyperbaric Oxygen Therapy to Avoid Blindness From Filler Injection. AB - The most serious complication of filler or fat injection is blindness. According to a recent systematic review of 98 patients of blindness provoked by filler or fat injection, only 2 patients had the outcome of a complete recovery of vision.In the literature, only 2 papers were found in which hyperbaric oxygen therapy (HBOT) was used in ophthalmic artery obstruction. However, no improvement of vision was obtained in either patient. Recently, the authors treated a patient who had central retinal vein occlusion and cilioretinal artery occlusion with HBOT (daily 2-hour sessions at 253 kPa for 14 days), and his visual acuity returned to normal.In central retinal artery obstruction, if the cilioretinal artery is present, it will maintain the thickness of the retina to a variable extent. Though the size of the cilioretinal artery and the area it supplies varies, 36.2% (32.1-40.2%) of people have a cilioretinal artery.Thereafter, HBOT might be applied to patients with central retinal artery occlusion following filler injection. PMID- 28005777 TI - Virtual Surgery Planning in Orthomorphic Correction of Mandibular Dysmorphology. AB - Three-dimensional virtual surgery programs are widely available for orthognathic surgery. The advent of imaging software programs has proved to be useful for diagnosis, treatment planning, outcome measurement, and three-dimensional surgical simulation. Complex maxillofacial malformations continue to present challenges in analysis and correction beyond modern technology. Orthomorphic correction for mandibular dysmorphology refers to basal bone movement without any change in dental component. The purpose of this paper is to present a virtual surgery planning for surgeons to perform the orthomorphic surgery with precision and quantification. Moreover, it provides an essential educational tool for patients to foresee predicted surgical outcome. PMID- 28005778 TI - Alternative Treatment for Blow-In Fracture of Lateral Orbital Wall: Removal of the Fractured Fragment. AB - Blow-in fracture of the zygomaticomaxillary complex that was displaced into the orbital cavity could be associated with ophthalmologic injuries, ranging from visual acuity to ocular motility limitation. Appropriate reduction and realignment of the fractured bone is necessary as early as possible for recovery of function and esthetics. However, limitation of accessibility and visibility makes it difficult for delicate surgery and increases the risk of damage of adjacent anatomic structures, such as optic nerve and extraocular muscles. In this report, the removal of fractured fragment was carried out in 2 patients showing limitation of gaze via orbital rim approach to avoid aggressive surgery and reduce the possibility of injury of vital structures. The postoperative process was uneventful and there were no complications associated with removal of displaced lateral wall. In conclusion, the authors propose that the removal of the fragment that was medially displaced lateral wall of the orbit is a simple and safe method as an alternative treatment in a difficult situation of reduction surgery. PMID- 28005779 TI - A New Approach to the Use of Osseointegrated Implants in Palate Obturator. AB - Osseointegrated implants are regularly used for retention and stability of maxillofacial prosthesis, especially in palatal obturator with large defects and few remaining teeth. In these cases, loads that tissues receive from a prosthesis can cause bone resorption and thus enlarge the defect. Implants may help redistribute the loads on the perimplant bone crest and avoid exacerbating the defect. The authors present a case in which the palatal defect has increased overtime. After placement of a sealing prosthesis with implants, bone and mucosal tissues stability around the defect it is observed during 1 year of follow-up. PMID- 28005780 TI - Morphological Patterns and Variations of the Nasal Septum Components and Their Clinical Implications. AB - The aim of this study was to clarify the morphological patterns and proportions of the components of the nasal septum. Anatomical examinations were performed on 70 nasal septums of embalmed Korean adult cadavers. The septal deviation was checked before cutting the nasal cavity midsagittally with the aid of a laryngoscope. The shape of each component of the nasal septum was identified, and photographs were taken from a midline sagittal view. A line was drawn on each photograph between the septal components, and then the area of each septal component was measured using software. The mean area proportions of the septal cartilage (SC), the perpendicular plate of the ethmoid bone (PPE), the vomer, and the nasal crest of the maxilla relative to the total area of the nasal septum were 25.6%, 43.0%, 25.8%, and 5.6%, respectively. The morphology of the nasal septum was classified into 3 main patterns according to the proportion of each septal component. The proportions of the SC, the PPE, the vomer, and the nasal crest of the maxilla were similar to the mean values of the present study in 45.7%. The proportions of the SC, the PPE, and the vomer were similar to each other (with a difference of <15%) in 24.3%. The proportion of the PPE exceeded 50% of the total area of the nasal septum in 22.9%. The results reported herein provide detailed anatomical knowledge that can be used as a valuable reference for rhinoplasty procedures. PMID- 28005781 TI - Narrow Foramen Ovale and Rotundum: A Role in the Etiology of Trigeminal Neuralgia. AB - Primary trigeminal neuralgia (TN) may occasionally occur in absence of neurovascular compression. A mechanism other than nerovascular compression may play a role in TN. High-resolution computed tomographies (CTs) of 21 consecutive TN patients without vascular compression during surgery and 30 healthy volunteers were retrospectively performed. Measuring parameters (length, width, and aspect ratio) were obtained in the axial plane for foramen ovale, and in the reconstructed coronal plane for foramen rotundum on both sides in each subject. The right-sided foramen ovale is slightly narrower than the left-sided, but no difference was observed between the sides. No correlation was found between the foramen size and the gender in both groups. The affected side with a narrower ovale foramen (>0.5 mm) and a significantly greater aspect ratio compared with the unaffected side may contribute to TN. Meanwhile, no significant correlation, but more likely a tendency, was found between the right and left sides in size of foramen rotundum (P = 0.09). This study has speculatively suggested that a narrow skull foramen may be etiologically important in a small percentage of TN patients. If recurrent or residual TN was encountered in cases of TN without vascular compression during surgery, high-resolution CT may help to evaluate the anatomical morphology of skull foramen in great detail. PMID- 28005782 TI - Post-Levator Aponeurosis Fat Pad. AB - The aim of this study was to examine the superoinferior extension of the post levator aponeurosis fat pad in the upper eyelids of Japanese cadavers. Twenty-six upper eyelids (12 right and 14 left) from 15 Japanese cadavers (6 men and 9 women; average age at death, 82.1 years) were used in this experimental anatomical study. After an orbital exenteration, the tissues were cut sagittally through the center of the orbit, and the superoinferior extension of the post levator aponerosis fat pad was microscopically examined on the sections. Consequently, the fat pad superiorly reached the myotendinous junction between the levator aponeurosis and the levator palpebrae superioris (LPS) muscle in 17 eyelids with the nonbranching LPS muscle. The fat pad extended to the roots of the superior and inferior branches of the LPS muscle in the other 9 eyelids with the branching LPS muscle. Inferiorly, the fat pad was limited to the conjunctival fornix in 13 eyelids, but reached the tarsal plate in the other 13 eyelids. This study showed anatomical variation in the superoinferior extension of the post levator aponerosis fat pad in Japanese cadavers. PMID- 28005783 TI - Florid Cemento-Osseous Dysplasia Simultaneous the Chronic Suppurative Osteomyelitis in Mandible. AB - INTRODUCTION: The florid cemento-osseous dysplasia is an uncommon condition nonneoplastic, of unknown cause with higher prevalence in melanodermic women, limited the maxillary bones, is characterized by the presence of dispersed and diffuse radiopaque calcifications, constituted of bone and dense cemento; however, when the bone is infected it induces the suppuration and formation of osseous sequestra, thus resulting in an osteomyelitis frame. CLINICAL REPORT: The patient was attended in a Dental Specialties Center in the state of Alagoas, Brazil, presenting on clinical examination edema and extra oral fistula with pus drainage in hemiface submandibular of the right side. Radiographically it was possible to observe area of sclerosis and osseous sequestra involving the right side region of the mandible body, and it increases zones of the bone density. In association with clinical data and complementary diagnosis examinations, the option of treatment adopted was the complete removal of the bone fragment, followed by adaptation and plate fixation and titanium screws to reduce the risk of mandibular fracture. OBJECTIVE: The aim of the present paper was to relate a clinical patient of florid cemento-osseous dysplasia simultaneous the chronic suppurative osteomyelitis, highlighting their clinical, radiographic, and histological characteristics, as well as their diagnosis and treatment. PMID- 28005784 TI - Angular Relationship Between the Foramen Ovale and the Trigeminal Impression: Percutaneous Cannulation Trajectories for Trigeminal Neuralgia. AB - The debilitating pain of trigeminal neuralgia often necessitates neurosurgical intervention via percutaneous transovale cannulation. While most percutaneous treatments of trigeminal neuralgia are successful, severe adverse events resulting from failure to properly cannulate the foramen ovale (FO) have been reported. With regard to specific targeting of particular trigeminal divisions (ie, V1, V2, V3, and combinations thereof), operative techniques have been described; however, these descriptions have not included specific angulation data. This anatomic study analyzed the angular relationship between the centroid and anteromedial- and posterolateral-most aspects of the FO and the boundaries of the trigeminal impression. The study is the first to detail the angular relationship between the FO boundaries and the boundaries of the trigeminal impression in dry human skulls relative to the coronal plane. The information may be used to prevent miscannulation and also target specific branches of the trigeminal nerve for optimal operative results. PMID- 28005785 TI - Eyebrow Shapes Over the Last Century. AB - The aim of this study was to analyze eyebrow shapes as represented in the British edition of "Vogue" over the last century (1916-2015). Photographs containing distinguishable eyebrows were selected from a book entitled "Vogue 100: A Century of Style." A total of 120 frontal pictures in which the eye and eyebrows were identifiable were included and analyzed. The relative width of the eyebrow (REW), as well as relative medial (RMH), midpupillary (RPH), and lateral (RLH) eyebrow height were measured in reference to the length of the palpebral fissure. Types of brow arches and arch shapes were also classified. The REW was 1.64 +/- 0.24, and did not differ significantly over time (P = 0.118). The RLH (0.60 +/- 0.09) was significantly greater than the RMH (0.53 +/- 0.17), and the RPH was the shortest of the 3 measures of height (0.36 +/- 0.16) (P < 0.001). The RMH (P = 0.515) and RPH (P = 0.848) did not exhibit significant chronological variation. However, the RLH increased over time (P = 0.007, y = 0.001x - 1.047). The distribution of the 6 eyebrow arch types varied significantly (P < 0.001). The Anastasia type (45.8%) was the most frequent, followed by the Hwang (25.0%) and Schreiber (11.7%) types. The Lamas (8.3%), Brit-Vogue (7.5%), and Westmore (1.7%) types were relatively infrequent. The arched type (31.7%) and the tail-up type (30.0%) were frequent, while the head-up type (26.7%) and the horizontal type (11.6%) were less frequent. The results of this study may be useful for planning facial rejuvenation operations, as well as for clinical practitioners dealing with brow esthetics or the tattooing of eyebrows. PMID- 28005786 TI - The Comparison of the Efficacy of Blue Light-Emitting Diode Light and 980-nm Low Level Laser Light on Bone Regeneration. AB - The aim of this study is to histologically compare effects of blue light-emitting diode (LED) light (400-490 nm) and Ga-Al-As low-level diode laser light (980 nm) on bone regeneration of calvarial critical-sized defects in rats. Thirty Wistar Albino rats were included in the study. The experimental groups were as follows: blue LED light (400-490 nm) group (LED); 980-nm low-level laser light group (LL); and no-treatment, control group (CL). A critical-sized defect of 8 mm was formed on calvaria of rats. Each animal was sacrificed 21 days after defect formation. Calvarias of all rats were dissected and fixated for histological examination. Histomorphometric measurements of total horizontal length of the newly produced bone tissue, total vertical length of the newly produced bone tissue, and diameter of the newly produced longest bone trabecula were performed with a computer program in micrometers. There was a statistically significant increase in the total horizontal length and total vertical length in LL and LED groups compared to that in the CL group (P < 0.05), while there was no statistical difference between LED and LL groups (P > 0.05). A statistically significant difference was observed in the longest bone trabecula and LL groups compared to that in CL (P < 0.05), but not between LED-CL and LED-LL groups (P > 0.05). In conclusion, blue LED light significantly enhances bone regeneration in critical sized defects when compared with CL group, but does not have a statistically significant effect on bone regeneration when compared with 980-nm low-level laser light. PMID- 28005787 TI - Nasopalatine Island Advancement Flap. AB - BACKGROUND: Anterior maxilla is a high esthetic region of the mouth. Some flaps are introduced for bone graft coverage, mainly based on secondary epithelization of connective tissue-periosteal tissues. This article evaluates the versatility of a new mucoperiosteal flap for reproducible coverage in anterior maxilla. METHODS: In 5 mongrel dogs a 5 mm width mucosal defect in labial mucosa was created after extraction of upper jaw incisors. Nasopalatine island advancement flap was used for mucosal replacement. RESULTS: Flap survival and healing was uneventful without necrosis. CONCLUSION: Nasopalatine island advancement flap is a reliable axial island flap for anterior maxillary reconstruction. PMID- 28005788 TI - Bone Marrow Stem Cells and Ear Framework Reconstruction. AB - BACKGROUND: Repair of total human ear loss or congenital lack of ears is one of the challenging issues in plastic and reconstructive surgery. OBJECTIVE: The aim of the present study was 3D reconstruction of the human ear with cadaveric ear cartilages seeded with human mesenchymal stem cells. METHOD: We used cadaveric ear cartilages with preserved perichondrium. The samples were divided into 2 groups: group A (cartilage alone) and group B (cartilage seeded with a mixture of fibrin powder and mesenchymal stem cell [1,000,000 cells/cm] used and implanted in back of 10 athymic rats). After 12 weeks, the cartilages were removed and shape, size, weight, flexibility, and chondrocyte viability were evaluated. P value <0.05 was considered significant. RESULTS: In group A, size and weight of cartilages clearly reduced (P < 0.05) and then shape and flexibility (torsion of cartilages in clockwise and counterclockwise directions) were evaluated, which were found to be significantly reduced (P > 0.05). After staining with hematoxylin and eosin and performing microscopic examination, very few live chondrocytes were found in group A. In group B, size and weight of samples were not changed (P < 0.05); the shape and flexibility of samples were well maintained (P < 0.05) and on performing microscopic examination of cartilage samples, many live chondrocytes were found in cartilage (15-20 chondrocytes in each microscopic field). CONCLUSION: In samples with human stem cell, all variables (size, shape, weight, and flexibility) were significantly maintained and abundant live chondrocytes were found on performing microscopic examination. This method may be used for reconstruction of full defect of auricles in humans. PMID- 28005795 TI - Orbitocranial Fibrous Dysplasia: Outcome of Radical Resection and Immediate Reconstruction With Titanium Mesh and Pericranial Flap. AB - INTRODUCTION: Fibrous dysplasia (FD) is a non-neoplastic developmental fibro osseous disease. It represents 2.5% of all bone tumors and 5% to 7% of the benign bone tumors. Orbitocranial region is involved in about 20% of the patients. The main presentations are craniofacial deformity and headache. Loss of vision is the most devastating result of this disease. There is no medical treatment to cure or prevent FD. Radiation therapy is contraindicated. Surgery for the orbitocranial FD is often challenging because of the proximity of neurovascular and ocular structures. Conservative surgical shaving and recontouring is always associated with suboptimal results. Radical excision is potentially curative with no extra morbidity. Orbital hypertelorism, dystopia, or proptosis can be corrected only by radical excision and reconstruction. AIM: The aim of the study was to evaluate the outcome of radical excision of the orbitocranial FD and immediate reconstruction using titanium mesh and pericranial flap. PATIENTS AND METHODS: This prospective study had been conducted on 22 patients with orbitocranial FD with age range from 17 to 52 years (mean 29.5). Radical excision of the lesions was done for all patients through transcranial approach. Immediate reconstruction was achieved using titanium mesh and pericranial flap. RESULTS: Intraoperative dural tears and cerebrospinal fluid leak were reported in 2 patients and repaired with galeal graft. Supraorbital anesthesia occurred in 6 patients. Of these, 2 patients were transient, while the remaining 4 patients were permanent. Wound infection was noticed in 1 patient who improved by medical treatment. Temporary postoperative diplopia occurred in 1 patient and temporary postoperative impaired vision in 1 other patient. In all patients, acceptable or good aesthetic results were observed. No recurrence was detected in our series during the follow-up period that ranged from 24 to 58 months (mean 37.5 months). CONCLUSION: Radical excision of orbitocranial FD is potentially curative with no extra morbidity. It can achieve good aesthetic and functional results with no recurrence. PMID- 28005796 TI - Tympanic Membrane Perforation Caused by Thunderbolt Strike. AB - Thunderbolt strike is a life-threatening entity. In the patients presenting with thunderbolt strike, the central nervous system and the cardiovascular system should be primarily evaluated, followed by tympanic membrane lesions. The most important symptom connected with ear is the loss of hearing. In this report, a 43 year-old male patient with unilateral tympanic membrane perforation, tinnitus, and bilateral sensorineural hearing loss caused by thunderbolt strike is presented through a review of the literature. PMID- 28005797 TI - Skin Burn Related to Coblation-Assisted Turbinoplasty. AB - Coblation-assisted turbinoplasty is an effective and safe method to manage nasal obstruction. The common complications of the procedure are pain, bleeding, and crust formation. Since coblation does not generate high heat, direct burn injuries by coblation have been rarely reported. Nevertheless, the authors experienced a skin burn injury in a patient, which is the first patient related to coblation-assisted turbinoplasty. Therefore, surgeons need to be careful and prepared for an inadvertent heat injury at the site that touches the coblation device. Here the authors present a patient along with suggestions to prevent the aforesaid accident. PMID- 28005798 TI - Simultaneous Bilateral Endonasal Endoscopic Dacryocystorhinostomy: A Low Cost, Fast, and Successful Method. AB - The etiology of primary nasolacrimal duct obstruction is largely unknown, and this disease may occur bilaterally in a small percentage of patients. In this retrospective study, the authors aimed to discuss the cost, operation time, complications, and success rate of simultaneous bilateral endonasal endoscopic surgery. Twenty-eight patients (16 female, 12 male) were enrolled in this study, with a mean age of 55 years old (range: 43-76). The success rate was 91% (51/56), and the mean operation time was 44 minutes. Only minor and transient complications were observed in 2 of the patients. Overall, the authors believe that a bilateral endoscopic dacryocystorhinostomy would be useful in a single session, based on its advantages of low morbidity, low cost, and high success. PMID- 28005799 TI - Clinical Characteristics and Treatment of Osteopetrosis Complicated by Osteomyelitis of the Mandible. AB - Osteopetrosis represents a heterogeneous group of rare, hereditary bone disorders with variable clinical features, and an increase in bone density. Osteomyelitis of the jaws is a significant complication of osteopetrosis. In this article, a reported patient with osteopetrosis complicated by osteomyelitis of the mandible was examined. The patient was treated with intravenous antibiotic therapy, debridement of necrotic bone and hyperbaric oxygen therapy; in addition, the authors attempted to implant the calcium sulfate and vancomycin to reconstruct the bone defect. The patient demonstrated satisfactory healing, and no recurrence of osteomyelitis was observed during the 6-month follow-up period. The treatment of osteopetrosis complicated by osteomyelitis of the mandible is difficult. The treatment of osteopetrosis complicated by osteomyelitis is controversial. The authors recommend the following sequential treatment of osteopetrosis complicated by osteomyelitis of the mandible: systemic antibiotic therapy and hyperbaric oxygen therapy before and after surgery; debridement of the necrotic bone; sufficient periosteal coverage and adequate soft tissue to cover the wound; implantation with calcium sulfate and vancomycin to reconstruct the bone defect as much as possible, which may be helpful in treating the disease. PMID- 28005800 TI - Microbiological and Histopathological Effects of Nasal Packing Containing Probiotics on Nasal Mucosa. AB - BACKGROUND: Nasal packing is frequently used after surgical interventions to prevent bleeding and synecchia formation and for the treatment of diseases such as epistaxis. One of the most morbid complications of nasal packing applications is the toxic shock syndrome (TSS). Owing to the microbiological structure of nasal mucosa, antibiotics are administered to all patients who are applied nasal packages for prevention of TSS. AIM: The aim of this study is the evaluation of microbiological and histopathological changes taking place in nasal mucosa with nasal packing containing probiotics. METHODS: Three groups were formed with 6 rats in each group. The nasal packings with the same characteristics were applied to nasal cavities of rats in all 3 groups. In group 1, only nasal packs were used. Probiotics or parenteral antibiotics were not used. In group 2, parenteral antibiotics were used along with nasal packs. In group 3, nasal packs with probiotics containing Lactobacillus strains were applied. No parenteral antibiotics were used. After 3 days packages were removed and nasal cavity was irrigated with saline. Both packages and irrigation materials were analyzed for microbiological content. After scarification, nasal and paranasal structures were examined for histopathological changes. RESULTS: In group 3 statistically the total bacteria load was significantly lower in comparison to the other groups. However, in the histopathological evaluation of the mucosa of rats in group 3, bleeding and inflammation findings were significantly higher statistically. CONCLUSIONS: It has been determined that the total microbiological load significantly decreases with the application of packing containing probiotics. So, the use of probiotics along with nasal packings is promising to prevent unnecessary use of medications. PMID- 28005801 TI - Zygomatic Implant Subjected to Immediate Loading for Atrophic Maxilla Rehabilitation. AB - As life expectancy increases, a larger number of elderly people require dental health care attention for implant-supported rehabilitation, with the aim of restoring the function and aesthetics of the oral cavity. Most of these patients have lost their teeth long time ago, causing a severe bone resorption and maxillary sinus pneumatization. Therefore, the current study aims to demonstrate, through the description of the clinical case, the treatment with zygomatic implants as an option for treating severely atrophic maxillas. In this clinical study, the patient presented, in the clinical and image evaluation, severe alveolar bone atrophy, with height and thickness loss, in addition to a high level pneumatization of the maxillary sinus, bilaterally. The classical zygomatic fixation technique was suggested, with 2 anterior conventional implants and 2 zygomatic implants in the posterior region with the placement of implant supported prosthesis with immediate loading. The patient was monitored for 7 years and did not present pain complaints, absence of infection, or implant loss. Based on this clinical case study, it was concluded that the zygomatic implants are satisfactory options to aid the implant-supported rehabilitation of atrophic maxillas. PMID- 28005802 TI - Blue Rubber Bleb Nevus Syndrome Diagnosed Prenatally as an Epignathus. AB - The authors present a clinical report of the giant fetal tumor protruding from the oral cavity diagnosed sonographically at 32 weeks of gestation as an epignathus. After delivery, tumor proved to be a presentation of the blue rubber bleb nevus syndrome. To the best of our knowledge, the literature offers no reports on similar cases. PMID- 28005803 TI - Pre-Expanded Submental Island Flap for Resurfacing Middle and Lower Facial Defect. AB - Resurfacing large facial defect is a continuing challenge for plastic surgeons. Skin graft or free flap is hard to obtain satisfactory results or is beyond the skill of most surgeons. The authors performed 13 expended submental island flaps to resurface middle and lower facial defects and achieved satisfactory results. In the first stage operation, the authors implanted one soft tissue expander in the anterior neck region which was expanded over an average of 3 months. In the second stage operation, the authors elevated the expanded submental island flap to resurface facial defect. For the patients who request aesthetic results and allow 2-stage operation, our method provides more satisfactory results. This technique does not require any special skills and is well within the skill of most plastic surgeons. PMID- 28005804 TI - Permanent Quadriplegia Following Replacement of Voice Prosthesis. AB - The authors presented a patient with quadriplegia caused by cervical spine abscess following voice prosthesis replacement. The authors present the first reported permanent quadriplegia patient caused by voice prosthesis replacement. The authors wanted to emphasize that life-threatening complications may be faced during the replacement of voice prosthesis. Care should be taken during the replacement of voice prosthesis and if some problems have been faced during the procedure patients must be followed closely. PMID- 28005805 TI - Mental Foramen Relation to Mandibular Fracture. AB - OBJECTIVE: To detect site of the mental nerve foramen in patients of mandibular fracture and study its relation to mandibular fracture site using radiology and operative findings during open reduction and internal fixation. PATIENTS AND METHODS: This study was carried out on 46 patients who had traumatic mandibular fractures. All patients were managed by open reduction and internal fixation during which mental foramen site and fracture site were reported and analyzed and compared to preoperative radiography. RESULTS: By both radiology and operative findings, the mental foramen was found in 78.3% between the first and second premolar, and in 21.7% below the first premolar. While no other mental foramen sites were reported. There were no statistically significant differences between both detected sites as regard age and sex. By operative dissection, mental foramen and neurovascular bundle could be detected, dissected, and preserved in all patients. CONCLUSION: To the best of the authors' knowledge, this is the first operative and radiological work that highlights the site and relation of mental foramen site to mandibular fracture in Arab people. The authors' study provides useful data of mental foramen among Arab population for the surgeons, anesthetists, and dentists to carry out procedures without complications. PMID- 28005806 TI - Hydatid Cyst of the Posterior Cervical Region. AB - Hydatid cyst is an endemically seen parasitic disease and caused by the larval form of Echinococcus parasites. The disease is mostly seen in liver and lung, and the other involvement is rarely seen. Head and neck involvement is extremely rarely seen and its frequency in the literature is reported as less than 1%. It is usually asymptomatic and the symptoms are related to the compression to the adjacent structures. In this paper, the authors report a patient of hydatid cyst localized in the posterior cervical region. PMID- 28005807 TI - Suspected Acoustic Neuroma Demyelinating Lesions. AB - Demyelinating lesions were recognized as a kind of rare central nervous system demyelinating lesion. The diagnosis and differential diagnosis of demyelinating lesions is difficult. Once the diagnosis was delayed or incorrect, it will make a great impact on patients.Demyelinating lesions often involved in young and middle aged, but this patient was the aged, which is rare. PMID- 28005808 TI - Spontaneous Epidural Pneumocephalus. AB - Spontaneous epidural pneumocephalus is a rare condition. The authors reported a 35-year-old male patient with tinnutus, dull headache, and swelling on his head. Patient had a history of head trauma and skull fracture from when he was 5 years old. Cranial computed tomography revealed increase in pneumatization of right mastoid air cells and large epidural air in temporoparietal region. Inner table of right temporal bone got thinner, causing communication of mastoid air cells with epidural space. Epidural air had septations and exerted mass effect on the right parietal lobe with minimal midline shift. Thinning of also right parietal bone caused extension of epidural air into the right parietal subcutaneous tissue and hence subcutaneous swelling. There was no obvious fracture line. Spontaneous epidural pneumocephalus is extremely rare condition that may cause severe complications. There are several etiologic factors. Head trauma can be the eliciting factor in the authors' patient. It is important to be familiar with its presentation and imaging findings to make early diagnosis and treatment. PMID- 28005809 TI - Lipoma of the Tympanic Membrane. PMID- 28005810 TI - A Rare Patient With Orbital Apex Syndrome, Anterior Uveitis, and Necrotizing Scleritis Due to Herpes Zoster Ophthalmicus. AB - The purpose of this study was to describe a patient of orbital apex syndrome, anterior uveitis, secondary glaucoma, corneal dellen, and necrotizing scleritis following an attack of herpes zoster ophthalmicus, and the placement of a pericardial patch graft. A 64-year-old male patient with blepharoptosis of his right eye and multiple vesicles on the forehead, nose and cheeks, limitation on all gazes, blepharoptosis, and exophthalmia was eventually diagnosed with ophthalmic zona with orbital apex syndrome. After the treatment with systemic antiviral and steroid, there was complete recovery of the unilateral vesicular eruption, ophthalmoplegia, and ptosis at the third month follow-up. However, anterior uveitis, necrotizing scleritis, secondary glaucoma, and corneal dellen developed during follow-up. At the ninth month, pericardial patch graft (Tutoplast) was placed due to progression of the scleral thinning. Graft vascularization was completed. Careful and long-term follow-up of patients with ophthalmic zona is required for possible ophthalmic complications of varicella zoster virus infections. A pericardial patch graft might be placed due to the development of necrotizing scleritis. PMID- 28005811 TI - The Role of Percutaneous Radiofrequency Thermocoagulation for Persistent or Recurrent Trigeminal Neuralgia After Surgery. AB - Therapeutic strategy is controversial and not yet uniform for patients with trigeminal neuralgia (TN) and persistent or recurrent facial pain after microvascular decompression, percutaneous radiofrequency thermocoagulation (PRT), or Gamma Knife surgery. The outcomes and risks of PRT for these patients are not clearly understood. The authors performed a retrospective study of 84 patients with persistent or recurrent TN after surgery who then underwent PRT between 2007 and 2013. Data were obtained with chart review and telephone interviews. The mean follow-up duration was 44.2 months. The immediate pain relief after PRT was 98%. The survival rates of pain free without medications at 1, 2, and 3 years after PRT were 85%, 68%, and 54%, respectively, with a nearly 80% rate for effective pain control (pain free, or pain controlled with medications) during the study period. The previous surgical method for TN did not have a significant effect on pain-free rates (P >0.05). Ninety-five percent of patients benefited from multiple PRT procedures and were satisfied with their pain relief. Fourteen of 17 patients who required retreatment selected additional PRT, resulting in 8 patients (57%) in excellent outcome and 12 (86%) in effective pain control. Two patients had failed all conventional invasive treatments. All patients experienced numbness of varying degrees, with 2 reporting severe and bothersome numbness. The complication rate was 15%, including 6 patients with masseter weakness, 2 patients with impaired taste acuity, 4 patients with absent or decreased corneal reflex, 1 patient with oculomotor paralysis. Percutaneous radiofrequency thermocoagulation is a safe and efficacious therapeutic method for patients with persistent or recurrent TN after surgery. Percutaneous radiofrequency thermocoagulation can serve as an alternative treatment option for these patients. PMID- 28005812 TI - Microcystic Adnexal Carcinoma of the Nasal Tip Treated With Surgical Excision and Rotational Forehead Skin Flap. AB - Microcystic adnexal carcinoma (MAC) is a rare malignant cutaneous adenocarcinoma that typically occurs in the head and neck, particularly at the central face. There are only slightly more than 300 patients reported worldwide, and most patients occur in Caucasians. A 72-year-old man was referred to our hospital for definitive treatment of known MAC from previous biopsy. Wide excision of nasal tip and reconstruction of nasal defect with paramedian forehead flap and nasolabial flap transposition were performed rather than conventional Mohs surgery, due to grossly evident disease. Pathological examination verified 4.5 * 3 cm sized MAC with free resection margins. The patient is being followed up without any evidence of disease. PMID- 28005813 TI - The Effect of Local Rosuvastatin on Mandibular Fracture Healing. AB - Mandibular fracture is the most common injury seen in facial fractures and plays an important role for oral and maxillofacial surgery department. The purpose of this study is to investigate the potential of the local administration of rosuvastatin (RSV) on mandibular fracture healing in rats. Thirty-two rats were divided into 4 groups: group C-14 (control), group R-14, group C-28 (control), and group R-28. A unilateral standard vertical osteotomy was performed right side of the mandibula extending from the tooth to the mandibular basis for each animal. In groups C-14 and C-28 sterile saline treated absorbable collogen sponge was applied to the fracture area, in groups R-14 and R-28 absorbable collogen sponge with saline solution containing 1 mg RSV was applied to the fracture area. Animals in groups C-14 and R-14 were euthanized on the 14th day, groups C-28 and R-28 were euthanized on the 28th day after operation. Stereologic analyses were performed. New bone area and connective tissue volumes were measured. Stereologic analysis showed that group R-14 had significantly more new bone at 2 weeks compared with group C-14. Connective tissue volumes were also significantly higher in R-14. New bone and connective tissue volume differences were not statistically significant between groups C-28 and R-28. Locally administered RSV enhances early bone regeneration on mandibular fracture in rats. PMID- 28005814 TI - Syngnathia Between the Palate and Mouth Floor, Cleft Palate, and Funnel Chest. AB - Syngnathia is a rare malformation involving soft tissue and/or bony adhesions between the maxilla and mandible. Less than 40 patients have been reported in the literature. Here the authors report a 6-month-old infant diagnosed as syngnathia of the palate and mouth floor combined with cleft palate and funnel chest in the Department of Oral and Maxillofacial Surgery at Henan Provincial People's Hospital in January 2015. The authors discussed and evaluated the diagnostic and treatment difficulties on surgical and anesthetic procedure. There is no standard treatment protocol, but early treatment is necessary to improve airway functions and infant feeding, and to support proper nutrition for the growth of maxillofacial region. PMID- 28005815 TI - Analysis and Long-Term Follow-Up of the Surgical Treatment of Children With Craniopharyngioma. AB - OBJECTIVE: To investigate the relationship between the operative approach, clinical pathological factors, and curative effect of the surgical treatment in the patients with craniopharyngioma; to provide a theoretical basis for determining the prognosis and reducing the recurrence rate during the long-term postoperative follow-up in children. METHODS: This was a retrospective analysis of the clinical data of 92 children who underwent surgical treatment in our department from May 2011 to January 2005. Long-term follow-up was performed from 12 months to 8 years. The pterional approach was used in 49 patients, the interhemispheric approach in 20 patients, the corpus callosum approach in 16 patients, and the butterfly approach in 7 patients. Pathological classification was performed by hematoxylin and eosin stain staining of the pathological tissues and evaluated according to the different surgical approaches, MRI calcification status, calcification type, pathological type, whether radiotherapy was performed, postoperative recurrence, and death. RESULTS: For the pterion approach resection, there was near total resection in 46 patients (93.9%) with the lowest recurrence rate. The operative approach and postoperative recurrence rates were compared; the difference was statistically significant (P <0.05). For comparison of the operative approach and postoperative mortality, the difference was not statistically significant (P >0.05). There was not a significant difference between the MRI classification and postoperative recurrence rate (P >0.05). Comparing the degree of tumor calcification with the recurrence rate after operation and the mortality rate, the difference was statistically significant (P <0.05). The recurrence rate and mortality rate of adamantimous craniopharyngioma and squamous papillary craniopharyngioma in 2 groups following operation were compared, and the differences were statistically significant (P <0.05). Postoperative adjuvant radiotherapy was compared with the postoperative recurrence rate and mortality; the differences were statistically significant (P <0.05). CONCLUSION: The main effects on tumor recurrence include the choice of surgical approach and degree of calcification. The adamantimous craniopharyngioma relapse rate is higher, which could be because invasion of craniopharyngioma only occurs with adamantimous craniopharyngioma. Postoperative radiotherapy can significantly prolong the recurrence time and reduce the mortality rate of patients with craniopharyngioma. PMID- 28005816 TI - Microsurgical Replantation of Two Consecutive Traumatic Total Scalp Avulsions. AB - Total scalp avulsion is a rare but severe injury frequently ending in hair loss, and one that can even be life-threatening. It frequently occurs in women and in men with long hair and as a result of injuries by industrial or agricultural equipment or of animal attacks. The first option in treatment is replantation of hairy skin with microsurgery.The authors report 2 consecutive patients with total scalp avulsion presenting to our clinic. Similar injury mechanisms and total scalp avulsions were present in both patients. However, the noteworthy aspect of this report is the different outcomes in terms of scalp viability, which the authors think depends on the number of vessels repaired. PMID- 28005817 TI - Pemphigus Vulgaris: How to Perform an Oral Biopsy Properly? AB - Oral biopsy of vesiculobullous diseases such as pemphigus vulgaris often raises questions due to some particularities involving this procedure. The adequate selection of the area to be biopsied defines if the final diagnosis will be reached, being the Achiles heel of the proper management of the patient. Here, the authors report a case of a woman who sought for treatment of generalized oral blisters and ulcers that caused severe pain. She had undergone a previous biopsy by other professionals that was inconclusive. The authors' team diagnosed the patient with pemphigus vulgaris and treated her properly. The authors provide a brief discussion about the adequate oral site to be chosen when dealing with vesiculobullous diseases once it still remains a source of doubts for the dental surgeons. PMID- 28005818 TI - Multimodal Neuronavigation in Microsurgery Resection of BrainStem Tumors. AB - BACKGROUND: Microsurgery is a common treatment of brainstem tumors. However, misdirection, vascular damage, nerves injuries, paralysis, even death are all well-known complications, and the risk of adverse events is more likely in less experienced operators. This study was aimed to validate the accuracy of multimodal neuronavigation during microsurgery resection of brainstem tumors. METHODS: Ten patients with brainstem tumors underwent preoperative MRI, diffusion tensor imaging, computed tomography, three-dimensional print, and images loaded into the neuronavigation platform were used for its segmentation and preoperative planning. After patients' registration and subsequent surgical exposure, each segmented brain element was validated by manual placement of the navigation probe to the target. RESULTS: Preoperative images of the brain matched with three dimensional print and neuronavigation played important role in all patients. Excellent correspondence between image-based segmentation and microscope view was also evident at the surface of tumors and at the tumor-normal gland interfaces. CONCLUSION: Multimodal navigation is a safe and effective method in surgery for patients with brain stem tumors. Our preliminary study is conducted to encourage for future more research with larger numbers of patients. PMID- 28005819 TI - Magnetic Resonance Imaging and Magnetic Resonance Angiography Findings of External Carotid Artery Aneurysm and Coexisting Carotid Body Tumor. AB - Carotid body tumors originate from paraganglionic tissue in the bifurcation of the common carotid artery. Magnetic resonance imaging is a frequently used diagnostic method in the preoperative diagnosis of these tumors and provides appropriate information for surgical planning. In this study, the authors emphasize magnetic resonance imaging and magnetic resonance angiography findings of the external carotid artery aneurysm associated with carotid body tumor. This highlights that the diagnosis of carotid artery aneurysms is essential to avoid accidental injury to the vessel during tumor surgery. PMID- 28005820 TI - Brain Abscess Following Intracerebral Hemorrhage in a Patient With Pneumonia. AB - Brain abscess is a rare but potentially lethal infection of brain parenchyma, requiring prompt surgical intervention and high-dose antibiotic therapy. Brain abscess is a known complication of surgically treated intracerebral hemorrhage (ICH), but it is exceptionally rare that it occurs at the same site of a nonoperated ICH. Such cases may result from hematogenous spread from distant foci (pneumonia, infectious endocarditis) or contiguous sites. Herein, the authors report a case of 75-year-old woman presenting with a brain abscess 6 weeks after a nonoperated ICH. As the patient suffered from pneumonia during the course of ICH, the authors suspected that the brain abscess might originate from the pneumonia via hematogenous spread. The awareness of brain abscess formation at the site of ICH is of great importance for early diagnosis and prompt treatment. PMID- 28005821 TI - Strategy for Successful Management of Facial Keloid Using Triamcinolone Injection as Adjunct to Surgery. AB - The literature on keloids is replete with authors expressing frustration with treatment results. Triamcinolone is effective in shrinking keloids and preventing their recurrence following excision, if delivered successfully. Strategies for effective delivery of drug are presented: recommended needle size, use of metal syringe, slow injection to avoid skin rupture, and delayed withdrawal of needle after injection. The futility of expecting pedunculated keloids to be completely flattened by steroid injection alone is mentioned. PMID- 28005822 TI - Osteodistraction With Dental Implant-Borne Devices for Bone Regeneration in Atrophied Premaxilla. AB - Aim of this work is to present the evolution of an innovative technique for tooth/implant supported bone distraction, leading to proper oral rehabilitation in patients with atrophic alveolar bone, even when a complete premaxilla expansion is needed, or in patients in whom implants were already present, but inserted in wrong position.Distraction osteogenesis was selected because of its moderate invasiveness, the few surgical steps needed, and the proper cost/benefits balance. This procedure is particularly suited for young patients with remarkable aesthetic demands related to active social and working life, as for elderly patients expecting lower surgical stress and risks. PMID- 28005823 TI - Diode Laser Clinical Efficacy and Mini-Invasivity in Surgical Exposure of Impacted Teeth. AB - The gold standard to arrange impacted teeth in the dental arch is represented by a surgical approach followed by orthodontic traction force application. In the literature, many surgical approaches are proposed to reach such a scope. The aim of the present study is to demonstrate how laser technique could positively assist surgical approaches.Study population was composed by 16 patients undergoing orthodontic treatment of 20 impacted teeth. In 10 patients (population A) surgical exposure of the impacted teeth was performed using a 980 nm diode laser, while in the other 10 patients (population B), surgical incision was performed using a traditional lancet.Only 3 patients of the population A needed local anesthesia for surgical procedure while the remaining 7 patients reported only faint pain during surgery. Two patients referred postsurgical pain (numerical rating scale average value = 2) and needed to take analgesics. None of the patients showed other postsurgical side effects (bleeding, edema).All population B patients needed infiltrative anesthesia and referred postsurgical pain (numerical rating scale average value >4) treated with analgesics. Moreover, in such population, 4 patients referred lips edema while 4 showed bleeding and 6 needed surgical sutures of soft tissues.The lack of side effects of laser surgical approach to expose impacted teeth must persuade dental practitioners to choose such a clinical approach to closed surgical approach every time it is possible. PMID- 28005824 TI - Anthropometrically-Based Surgical Technique for Tessier 3 Cleft Reconstruction. AB - Craniofacial clefts are rare entities, with an incidence reported as 1.43 to 4.85 per 100,000 births. The Tessier number 3 cleft, the most medial of the oblique clefts, can manifest as clefting of the lip between the canine and lateral incisors, colobomas of the nasal ala and lower eyelid, and inferior displacement of the medial canthus-frequently disrupting the lacrimal system with extreme variability in expressivity (Eppley).Literature on cleft lip repair is extensive and has evolved to incorporate anthropometric techniques, based on identifiable landmarks and anthropometric measurements that are compared with contralateral unaffected anatomy or population means and tracked over time to assess impact on growth. Recent focus has been placed on "subunit" repair that repairs "like with like." These approaches have resulted in a remarkable reproducibility of methods and outcomes.Facial cleft surgery publications are sparse due to the rarity of the disorders, and consensus has yet to develop on standardized landmarks, reference measurements, and principles of repair. The authors describe a method of correcting incomplete unilateral Tessier 3 cleft based on the principles described above. Intraoperative photographs, including secondary revisions, as well as immediate and long-term postoperative results are presented. PMID- 28005825 TI - The Role of Conservative Management in Pneumosinus Dilatans Frontalis With Minimal Bony Deformity. AB - The authors describe the conservative management of 2 rare patients of uncomplicated pneumosinus dilatans of the frontal sinus with minimal bossing of the forehead. Regular nasal hygiene in combination with topical corticosteroids was administered with following complete resolution symptoms. PMID- 28005826 TI - Porous Polyethylene Implant as Aesthetic Complement in Orthognathic Surgery. AB - Porous polyethylene implants have been used as an alternative in the treatment of patients with zygomatic and paranasal projections deficiency. These implants promote a facial rejuvenating effect due to the attenuation of the nasal and chin prominences. The advantages of porous polyethylene include biocompatibility, dimensional stability, easy adaptation and fixation, low complication rate, and its availability in different sizes and shapes. A 27-year-old woman presenting vertical deficiency associated with midface hypoplasia was treated with orthognathic surgery. Clockwise rotation and genioplasty were performed. In order to improve facial aesthetics, porous polyethylene implants were placed in the paranasal area, optimizing the facial contour with the correction of the midface projection. PMID- 28005827 TI - Spontaneous Involution of a Rathke Cleft Cyst. AB - Rathke cleft cysts (RCCs) are nonneoplastic lesions that are thought to be the remnants of Rathke cleft pouch. The authors report a patient presented with a headache and was diagnosed with RCC on imaging. The lesion underwent spontaneous involution. The authors suggest that patients presenting solely with a headache to be treated conservatively, because it is uncertain whether a headache is definitively associated with RCCs and because there is the possibility of spontaneous regression. PMID- 28005828 TI - Evaluation of Eyeball and Orbit in Relation to Gender and Age. AB - The orbital aperture is the entrance to the orbit in which most important visual structures such as the eyeball and the optic nerve are found. It is vital not only for the visual system but also for the evaluation and recognition of the face. Eyeball volume is essential for diagnosing microphthalmos or buphthalmos in several eye disorders. Knowing the length of the optic nerve is necessary in selecting the right instruments for enucleation. Therefore, the aim of this study was to evaluate eyeball volume, orbital aperture, and optic nerve dimensions for a morphological description in a Turkish population sample according to gender and body side.Paranasal sinus computed tomography (CT) scans of 198 individuals (83 females, 115 males) aged between 5 and 74 years were evaluated retrospectively. The dimensions of orbital aperture, axial length and volume of eyeball, and diameter and length of the intraorbital part of the optic nerve were measured. Computed tomography examinations were performed on an Activion 16 CT Scanner (Toshiba Medical Systems, 2008 Japan). The CT measurements were calculated by using OsiriX software on a personal computer. All parameters were evaluated according to gender and right/left sides. A statistically significant difference between genders was found with respect to axial length of eyeball, optic nerve diameter, dimensions of orbital aperture on both sides, and right optic nerve length. Furthermore, certain statistically significant side differences were also found. There were statistically significant correlations between age and the axial length of the eyeball, optic nerve diameter, and the transverse length of the orbital aperture on both sides for the whole study group.In this study we determined certain morphometric parameters of the orbit. These outcomes may be helpful in developing a database to determine normal orbit values for the Turkish population so that quantitative assessment of orbital disease and orbital deformities will be evaluated both for preoperative planning and for assessing postoperative outcomes. PMID- 28005829 TI - Reproducible Measurements of Muscle Characteristics Using the MyotonPRO Device: Comparison Between Individuals With and Without Paratonia. AB - BACKGROUND AND PURPOSE: The MyotonPRO is a portable device that measures muscle tone and biomechanical muscle properties objectively. MyotonPRO has already proven to be effective in measuring muscle properties in healthy and diseased populations. However, to the best of our knowledge, it has never been tested in individuals suffering from paratonia, a form of hypertonia frequently accompanying dementia. The aims of the present study were to (1) compare muscle tone, elasticity, and stiffness between 3 different subpopulations of young and old healthy adults and individuals with paratonia, and (2) investigate the intra- and interrater reproducibility of MyotonPRO measurements of the biceps brachii (BB) muscle in each subpopulation. METHODS: MyotonPRO measurements of muscle tone, elasticity, and dynamic stiffness were carried out by 2 investigators on 2 different days over the BB muscles of 54 participants (18 healthy young adults, 20 healthy older adults, and 16 older individuals with paratonia). Muscle properties were compared between subpopulations using ANOVA/Welch and post hoc tests. Reliability (intraclass correlation coefficient) and agreement parameters (standard error of measurement and the minimal detectable change) were calculated. RESULTS: Statistically significant differences between subpopulations were found in all parameters, except for stiffness between healthy elderly and individuals with paratonia. In the healthy subpopulations, (a) intrarater reliability was very high and intrarater agreement was good between 2 consecutive series, (b) between days intrarater reliability was low to high and intrarater agreement was variable, (c) interrater reliability was high to very high and interrater agreement was good. In individuals with paratonia, (a) intrarater reliability was moderate to high and agreement was variable between series, (b) between days intrarater reliability was poor to moderate and agreement was poor, (c) interrater reliability ranged from low to high with poor agreement. CONCLUSIONS: MyotonPRO measurements of the BB muscle showed good reproducibility in both healthy subpopulations, particularly for measurements performed within the same day. In individuals with paratonia, reliability and agreement were substantially lower. MyotonPRO can be used in clinical assessment and research. However, in individuals with paratonia, careful interpretation of results is required. Research in a larger sample of persons with paratonia at different stages of disease severity is recommended. PMID- 28005830 TI - Do Older Adults Who Meet 2008 Physical Activity Guidelines Have Better Physical Performance Than Those Who Do Not Meet? AB - BACKGROUND AND PURPOSE: An observed consequence of aging is a decline in muscle performance that includes a loss in both muscle strength and muscle power. This decline can lead to loss of function and independence and is a predictor of disability in older adults. Although the 2008 Physical Activity (PA) Guidelines for Americans provides a guideline for muscle strengthening, there is no evidence that performing muscle strengthening 2 times a week for all major muscle groups is related to better performance on measures known to be important factors in development or progression of frailty in older adults. The purposes of this study were to assess muscle-strengthening and aerobic PA behaviors in older adults and to determine the relationship between the PA behaviors and physical performance measures. METHODS: This was a cross-sectional study of 85 community-dwelling, ambulatory adults (50 women, 35 men) with a mean (standard deviation) age of 67.5 (5.6) years. All used an internet-based survey, TREST (Tracking Resistance Exercise and Strength Training), to report muscle-strengthening and aerobic PA behavior. Physical performance measures of grip strength, 10-m walk test (10 MWT), five-time sit-to-stand test (FTSST), and stair climb test (SCT) were obtained following completion of the survey. Participants were grouped by whether they met 2008 PA Guidelines for (1) muscle strengthening 2 or more days per week, (2) muscle strengthening 2 or more days per week using all major muscle groups, or (3) 150 minutes or more per week of aerobic moderate to vigorous physical activity. Comparisons of physical performance measures were conducted between participants who met and did not meet guidelines using multivariate analyses. Significant multivariate results were followed with one-tailed t tests. RESULTS AND DISCUSSION: The participants meeting muscle strengthening 2 or more days per week performed significantly better on measures of grip strength and SCT. Only 27% of participants met the more stringent-strengthening guideline of 2 or more days per week using all major muscle groups, and these individuals performed significantly better on the SCT and FTSST. The participants meeting the aerobic activity guideline performed significantly better on the SCT, the FTSST, and the 10-MWT.However, participants who met both the strengthening and aerobic activity guidelines performed significantly better on all 4 physical performance measures than participants who met neither of the guidelines. CONCLUSIONS: Meeting guidelines for both aerobic and muscle-strengthening activities may be the most effective way of preserving muscle strength, muscle power, and gait velocity in older adults, but this conclusion must be tested with an intervention study. PMID- 28005831 TI - Bronchoscopy Safety in Patients With Chronic Obstructive Lung Disease. AB - BACKGROUND: Flexible bronchoscopy is a safe and minimally invasive diagnostic tool used by pulmonologists, but few studies have prospectively compared outcomes in patients with objectively defined obstructive lung disease to those without obstruction. METHODS: We determined whether complications in patients undergoing moderate sedation bronchoscopy differ in those without obstruction compared with chronic obstructive pulmonary disease (COPD). We prospectively followed all patients undergoing moderate sedation bronchoscopy in an inpatient or outpatient setting. RESULTS: Over 12 months, data were collected prospectively in 258 patients. A total o 151 patients had pulmonary function testing with classification of COPD according to GOLD Criteria. Sixty-seven of those patients (44%) had COPD: 6 mild (9%), 29 moderate (42%), 27 severe (41%), and 5 very severe (8%). COPD patients were more likely to receive outpatient inhaled corticosteroids and long-acting bronchodilators and anticholinergics (P<0.001) as would be clinically appropriate. Among all patients with COPD, there were 13% minor complications and 5% major complications, with no deaths. Respiratory complications occurred more often in patients with severe to very severe COPD (22%) compared with patients without COPD (6%) (P=0.018). When adjusted for age, body mass index, and use of home oxygen, this difference was still significant (P=0.045). CONCLUSION: Bronchoscopy is generally safe with few complications in most patients with COPD. Patients with objectively confirmed severe to very severe COPD had more frequent respiratory complications than patients without COPD. The risks were not prohibitively high, but should be taken into consideration for COPD patients undergoing moderate sedation flexible bronchoscopy. PMID- 28005832 TI - Going Off Road: The First Case Reports of the Use of the Transbronchial Access Tool With Electromagnetic Navigational Bronchoscopy. AB - The ability to reach the peripheral pulmonary nodule/mass with bronchoscopy has improved greatly over the past several years with the use of Electromagnetic navigational bronchoscopy; however, many of these lesions are unable to be adequately sampled due to their location outside the bronchial airways. We report the first use of the transbronchial access tool that creates a pathway from the bronchial airway through the lung parenchyma into the targeted lung abnormality. PMID- 28005833 TI - Pseudoaneurysm of Aorta Presenting as Endobronchial Mass. PMID- 28005834 TI - Primary Non-Hodgkin Lymphoma Presenting as a Carinal Mass. PMID- 28005835 TI - Our Experience on Silicone Y-Stent for Severe COPD Complicated With Expiratory Central Airway Collapse. AB - BACKGROUND: Expiratory central airway collapse (ECAC) is abnormal central airway narrowing during expiration. ECAC involves 2 different pathophysiological entities as tracheobronchomalacia and excessive dynamic airway collapse (EDAC). Although the exact cause is unknown, chronic obstructive pulmonary disease (COPD) is frequently accompanied by ECAC. Although there are various publications on the relationship between COPD and ECAC, there are very few data for stent placement in patients with tracheobronchomalacia accompanied severe COPD. We share our results for stenting in ECAC among patients with severe COPD. METHODS: The data in this case series were collected retrospectively. The ECAC diagnosis was made during flexible bronchoscopy with severe COPD. Silicone Y-stents were placed via rigid bronchoscopy under general anesthesia. RESULTS: A total of 9 patients' (7 men) data were evaluated with an average age of 67+/-10.73 years. One patient experienced stent migration on the second day of stenting prompting stent removal. Another patient died 1 month after stenting. Consequently, we evaluated the follow-up data of remaining 7 patients. The changes in forced expiratory volume 1 was not significant for these 7 cases (P=0.51). The modified Medical Research Council (mMRC) score improvement was statistically significant (P=0.03). Functional status improvement was observed in 4 of 7 patients. Of the 7 patients, mean additional follow-up bronchoscopic interventions requirement was 2.2 times. CONCLUSIONS: Our study showed significant decrease in mMRC score with stenting for ECAC in severe COPD. For 2 patients, we experienced severe complications during short-term follow-up period after stenting. Additional follow-up bronchoscopic interventions were required. PMID- 28005836 TI - Pulmonologist-Performed Per-Esophageal Needle Aspiration of Parenchymal Lung Lesions Using an EBUS Bronchoscope: Diagnostic Utility and Safety. AB - BACKGROUND: Transesophageal introduction of the endobronchial ultrasound (EBUS) videobronchoscope allows pulmonologists to perform endoscopic ultrasound fine needle aspiration (EUS-B-FNA) of mediastinal lesions. Safety, diagnostic accuracy, and feasibility of EUS-B-FNA in evaluation of pulmonary parenchymal lesions are not established. METHODS: All patients undergoing pulmonologist performed EUS-B-FNA of parenchymal lung lesions at 2 tertiary centers were included in this prospective observational cohort study. RESULTS: EUS-B-FNA sampling of parenchymal lesions was performed in 27 patients. Mean (+/-SD) lesion size was 36+/-16 mm. Seven lesions were <=18 mm. Pneumothorax occurred in 1 patient (3.7%, 95% confidence interval, 0.001%-19%). Ten target lesions (36%) were in locations inaccessible to bronchoscopic sampling via the airways, and 9 lesions were inaccessible to EBUS-guided transbronchial needle aspiration and in locations associated with low diagnostic yield from radial EBUS. EUS-B-FNA was diagnostic in 26 patients (96%), and sensitivity of EUS-B-FNA was 100% (95% confidence interval, 87%-100%) for both lung cancer (n=21) and for pulmonary metastatic lesions (n=5). CONCLUSIONS: Pulmonologist-performed EUS-B-FNA is safe and accurate in the evaluation parenchymal lung lesions. Diagnostic accuracy is high. EUS-B-FNA may achieve access to sites not amenable to other forms of bronchoscopic sampling, or increase diagnostic accuracy in patients where anatomic position predicts a low diagnostic yield. PMID- 28005838 TI - Ultra-broadband 16-channel mode division (de)multiplexer utilizing densely packed bent waveguide arrays. AB - We demonstrate an ultra-broadband 16-channel mode division (de)multiplexer utilizing densely packed bent waveguide arrays (DPBWAs). The phase mismatch is realized by using bent waveguides with a different radius instead of changing the waveguide width. The proposed structure shows theoretical insertion losses (ILs) that are <0.1 dB and crosstalk (CT) that is <-30 dB over a 100 nm wavelength range for all the channels. The fabricated device, which consists of a multiplexer, DPBWAs, and a demultiplexer, exhibits ILs that are <1 dB and crosstalk that is <-20 dB over an ~80 nm wavelength band. PMID- 28005837 TI - Multiple Roles of WNT5A in Breast Cancer. AB - Breast cancer is one of the most common malignant tumors of women. Modern combinatorial therapeutic regimens can reduce patient tumor burdens to undetectable levels, yet in many cases these tumors will relapse. Understanding of breast cancer biology, developing more potent therapeutic approaches, and overcoming resistance are of great importance. WNT5A is a non-canonical signaling member of the WNT family. Its role in breast cancer still remains unclear. Most of the evidence shows that WNT5A is a suppressor in breast cancer and loss of its expression is associated with poor prognosis, while some evidence suggests the tumorigenicity of WNT5A. WNT signaling molecules are potent targets for treatment of cancer. Therefore, understanding the role of WNT5A in breast cancer may provide new ideas and methods for breast cancer treatment. We review the evidence concerning WNT5A and breast cancer involving the signaling pathways and the molecular-targeted therapy of WNT5A. Our results show that the role WNT5A plays depends on the availability of key receptors and intercellular interactions among different cell types. PMID- 28005839 TI - Observation of multimode solitons in few-mode fiber. AB - We experimentally isolate and directly observe multimode solitons in few-mode graded-index fiber. We rely on Raman frequency shifts to spectrally isolate these multimode solitons. By varying the input energy and modal composition of the launched pulse, we observe a continuous variation of multimode solitons with different spatiotemporal properties. They exhibit an energy-volume relation that is distinct from those of single-mode and fully spatiotemporal solitons. PMID- 28005840 TI - Extracting the average single-molecule biexciton photoluminescence lifetime from a solution of chromophores. AB - We present a method for obtaining the average single-molecule biexciton lifetime from an ensemble of chromophores in solution. We apply this analysis to a series of core/shell CdSe/CdS quantum dot heterostructures with increasing shell thickness and find that the lifetime of the biexciton increases with increasing shell thickness, consistent with a simultaneous measurement of biexciton quantum yield. PMID- 28005841 TI - Common-path heterodyne self-mixing interferometry with polarization and frequency multiplexing. AB - A heterodyne Nd:YVO4 microchip laser self-mixing interferometry based on frequency and polarization multiplexing has been demonstrated. By using two orthogonally polarized lights to measure the measurement and reference target, the effect of the acousto-optic crystal thermal creep and air disturbance in interference light path is eliminated. In addition, the measurement error caused by the difference between two identical microchip lasers is compensated for by shifted frequency multiplexing technique. A rate equations model with multi channel frequency-shifted feedback is established for interpreting the principle of the interferometry. Due to the ultrahigh sensitivity of the microchip laser, the target used in the experiment is a non-cooperative object which is different from the targets in conventional Michelson interferometers. Under typical room conditions, the short-term resolution is better than 2.5 nm, and the long-term zero drift is less than 60 nm within 7 h. The result shows that this self-mixing interferometry system is feasible and robust in the field of displacement measurement. PMID- 28005842 TI - Highly efficient all-dielectric optical tensor impedance metasurfaces for chiral polarization control. AB - We propose a highly efficient (nearly lossless and impedance-matched) all dielectric optical tensor impedance metasurface that mimics chiral effects at optical wavelengths. By cascading an array of rotated crossed silicon nanoblocks, we realize chiral optical tensor impedance metasurfaces that operate as circular polarization selective surfaces. Their efficiencies are maximized through a nonlinear numerical optimization process in which the tensor impedance metasurfaces are modeled via multi-conductor transmission line theory. From rigorous full-wave simulations that include all material losses, we show field transmission efficiencies of 94% for right- and left-handed circular polarization selective surfaces at 800 nm. PMID- 28005843 TI - Monolithically integrated tunable mode-locked laser diode source with individual pulse selection and post-amplification. AB - We report the generation of high-peak-power picosecond optical pulses in the 1.55 MUm spectral band from a monolithically mode-locked laser integrated with a pulse selector and power booster. High-peak-power (>1 W) pulses with durations of 15.4 ps at a 55 MHz selected rate are demonstrated, indicating that this device shows promise as a high-peak-power pulsed light source for bio-photonic applications. PMID- 28005844 TI - Random Brillouin fiber laser for tunable ultra-narrow linewidth microwave generation. AB - Studies about random lasing phenomena taking place in disordered structures with amplification are gaining great interest, as they can support dual wavelength lasing without cavity length restriction and, hence, the tunable beat frequency in a microwave can be created in a random cavity and be amplified for applications in the information and communication technology. Here, we present a novel random Brillouin fiber laser scheme using the stimulated Brillouin scattering as gain and strong Rayleigh scattering feedback (10 km) in the single mode fiber. The high degree of mutual coherence between the two Stokes beams from two different lasers leads to the generation of tunable ultra-narrow linewidth microwave signals (<10 Hz at 3 dB bandwidth) with a 70 dB contrast. This offers a simple and cost-effective design for microwave sources. PMID- 28005845 TI - Millimeter-wave signal generation for a wireless transmission system based on on chip photonic integrated circuit structures. AB - We demonstrate and compare two different photonic-based signal sources for generating the carrier wave in a wireless communication link operating in the millimeter-wave range. The first signal source uses the optical heterodyne technique to generate a 113 GHz carrier wave frequency, while the second employs a different technique based on a pulsed mode-locked source with 100 GHz repetition rate frequency. The two optical sources were fabricated in a multi project wafer run from an active/passive generic integration platform process using standardized building blocks, including multimode interference reflectors which allow us to define the structures on chip, without the need for cleaved facet mirrors. We highlight the superior performance of the mode-locked sources over an optical heterodyne technique. Error-free transmission was achieved in this experiment. PMID- 28005846 TI - Non-invasive image-guided laser microsurgery by a dual-wavelength fiber laser and an integrated fiber-optic multi-modal system. AB - A new approach to non-invasive image-guided laser micro-treatment is demonstrated by a dual-wavelength fiber laser source and an integrated fiber-based multi-modal system. The fiber-based source, operated in 1.55 and 1.2 MUm simultaneously, was directly connected to an integrated fiber-based multi-modal system for imaging and laser micro-treatment at the same time. The 1.2 MUm radiations, within the 1.2-1.35 MUm bio-penetration window of skin, were utilized for spectral domain optical coherence tomography imaging. The 1.55 MUm radiations, highly absorptive to waters, were utilized for laser microsurgery. The new approach, which is simple in configuration and accurately controls the positions and exposure time of the laser microsurgery, shows great promises for future clinical applications. PMID- 28005847 TI - Compact 3-8 MUm supercontinuum generation in a low-loss As2Se3 step-index fiber. AB - A mid-infrared supercontinuum source spanning from 3 to 8 MUm is demonstrated using a low-loss As2Se3 commercial step-index fiber. A maximum average output power of 1.5 mW is obtained at a low repetition rate of 2 kHz. Thanks to the low NA step-index fiber, the output is single mode for wavelengths above ~5 MUm. The pump source consists of an erbium-doped ZrF4-based in-amplifier supercontinuum source spanning from 3 to 4.2 MUm. The effects of both the pump power and As2Se3 fiber length on the output characteristics are studied. To the best of our knowledge, this is the first compact supercontinuum source ever reported to reach 8 MUm in a standard step-index fiber. PMID- 28005848 TI - Broadband microwave photonic phase shifter based on a feedback-coupled microring resonator with small radio frequency power variations. AB - An on-chip microwave photonic phase shifter based on an electrically tunable feedback-coupled microring resonator (FCMR) is proposed and experimentally demonstrated. By properly adjusting the voltage applied on the FCMR, the transmission spectrum with different optical extinction ratios is realized while the phase shift range remains almost unchanged. This proposal solves the conflict between the large range of phase shift and small radio frequency (RF) power variation in the ring-resonator-based microwave photonics phase shifter. Finally, a microwave photonic phase shifter with phase tuning of over 172 deg from 20 to 30 GHz is obtained, and the RF power variation can be compressed less than 5 dB under a certain status tuned by the bias voltage. PMID- 28005849 TI - Experimental observation of coherent cavity soliton frequency combs in silica microspheres. AB - We report on the experimental observation of coherent cavity soliton frequency combs in silica microspheres. Specifically, we demonstrate that careful alignment of the microsphere relative to the coupling fiber taper allows for the suppression of higher-order spatial modes, reducing mode interactions and enabling soliton formation. Our measurements show that the temporal cavity solitons have sub-100-fs durations, exhibit considerable Raman self-frequency shift, and generally come in groups of three or four, occasionally with equidistant spacing in the time domain. RF amplitude noise measurements and spectral interferometry confirm the high coherence of the observed soliton frequency combs, and numerical simulations show good agreement with experiments. PMID- 28005850 TI - Temperature-insensitive fiber twist sensor based on elliptical-core few-mode fiber. AB - A highly sensitive fiber optics twist sensor is proposed and experimentally demonstrated using elliptical-core few-mode fiber (e-FMF). With the help of a fixed-phase plate for conversion from LP11 to LP01 mode, the twist angle can be linearly mapped to the spatial rotation of LP11 mode profile and consequently discriminated by monitoring the optical power variation at the standard single-mode fiber (SSMF) output. When the optical power at the e-FMF output is 10 mW, the twist angle within the range of +/-39 degrees can be successfully detected with a sensitivity of more than 20 MUW/ degrees . Meanwhile, the twist direction can be identified simultaneously. In particular, when the twist angle ranges from -12.5 degrees to 20.1 degrees , the sensitivity is higher than 100 MUW/ degrees . Both temperature-insensitive operation from 20 degrees C to 150 degrees C and e-FMF length insensitive operation are experimentally verified. PMID- 28005851 TI - Modes and exceptional points in waveguides with impedance boundary conditions. AB - A planar waveguide with an impedance boundary, composed of nonperfect metallic plates, and with passive or active dielectric filling, is considered. We show the possibility of selective mode guiding and amplification when a homogeneous pump is added to the dielectric and analyze differences in TE and TM mode propagation. Such a non-conservative system is also shown to feature exceptional points for specific and experimentally tunable parameters, which are described for a particular case of transparent dielectric. PMID- 28005852 TI - Quantifying Raman OH-band spectra for remote water temperature measurements. AB - Remote water temperature measurements by Raman scattering is a perspective tool for in situ and/or real-time studies for inaccessible areas such as the Arctic region. State-of-the-art laser remote temperature detection techniques are based on temperature-dependent transformation of the Raman OH stretching vibration band. This study compared different approaches quantifying Raman OH-band spectra transformation with temperature: the two-color technique, deconvolution procedure, Raman difference spectroscopy, and centroid technique. Distilled water was probed remotely by compact Raman LIDAR, and the results demonstrated that the Raman OH-band centroid technique achieved the best temperature measurement accuracy (+/-0.15 degrees C). PMID- 28005853 TI - Optical fiber vector flow sensor based on a silicon Fabry-Perot interferometer array. AB - We report a miniature fiber-optic water vector flow sensor based on an array of silicon Fabry-Perot interferometers (FPIs). The flow sensor is composed of four silicon FPIs, one in the center with the other three equally distributed around it. The center FPI is heated by a cw laser at 980 nm, which is guided through the lead-in single mode fiber. The temperature structure established within the sensor head due to laser heating is a function of the flow vector (speed and direction), which can be deduced from the wavelength shifts of the four FPIs. Theoretical analysis has been conducted to illustrate the operating principle and experimental demonstration has been provided. PMID- 28005854 TI - Widely tunable, low phase noise microwave source based on a photonic chip. AB - Spectrally pure microwave sources are highly desired for several applications, ranging from wireless communication to next generation radar technology and metrology. Additionally, to generate very pure signals at even higher frequencies, these advanced microwave sources have to be compact, low in weight, and low energy consumption to comply with in-field applications. A hybrid optical and electronic cavity, known as an optoelectronic oscillator (OEO), has the potential to leverage the high bandwidth of optics to generate ultrapure high frequency microwave signals. Here we present a widely tunable, low phase noise microwave source based on a photonic chip. Using on-chip stimulated Brillouin scattering as a narrowband active filter allows single-mode OEO operation and ultrawide frequency tunability with no signal degeneration. Furthermore, we show very low close-to-carrier phase noise. This Letter paves the way to a compact, fully integrated pure microwave source. PMID- 28005855 TI - Enhanced complexity of optical chaos in a laser diode with phase-conjugate feedback. AB - We demonstrate numerically that a semiconductor laser subjected to phase conjugate feedback (PCF) can exhibit an enhancement in the complexity of chaos by comparison to conventional optical feedback. Using quantifiers from spectral analysis and information theory, we demonstrate that under similar parametric conditions, PCF exhibits a larger chaotic bandwidth and higher spectral flatness and statistical complexity. These properties are of utmost importance for applications in secure communications and random number generation. PMID- 28005856 TI - Single-shot reconstruction of spectral amplitude and phase in a fiber ring cavity at a 80 MHz repetition rate. AB - Femtosecond pulses circulating in a synchronously driven fiber ring cavity have complex amplitude and phase profiles that can change completely from one round trip to the next. We use a recently developed technique, combining dispersive Fourier transformation) with spectral interferometry, to reconstruct the spectral amplitude and phase at each round-trip and, thereby, follow in detail the pulse reorganization that occurs. We focus on two different regimes: a period-two regime in which the pulse alternates between two distinct states and a highly complex regime. We characterize the spectral amplitude and phase of the pulses in both regimes at a repetition rate of 75.6 MHz and find good agreement with modeling of the system based on numerical solutions of the generalized nonlinear Schrodinger equation with feedback. PMID- 28005857 TI - Improving time and space resolution in electro-optic sampling for near-field terahertz imaging. AB - In this Letter, we present a significant improvement to time and space resolutions in electro-optic sampling (EO) for two-dimensional terahertz (THz) near-field imaging. Using a THz microscope, we readapt a recent EO sampling scheme based on optical probe spectrum filtering. Combined with an ultra-thin EO crystal, we achieve record broadband video-rate THz near-field imaging. Particularly, this new scheme improves the THz bandwidth, the imaging contrast, and the spatial resolution. To validate our method, we show THz near-field images ranging from 100 GHz to 4 THz with a spatial resolution up to lambda/600 at 100 GHz. This demonstration positively affects the detection of intense THz pulses derived from the tilted-pulse-front excitation of lithium niobate and will accelerate our understanding of the interaction processes between electromagnetic waves and the conducting electrons of metallic interfaces. PMID- 28005858 TI - Whispering gallery mode temperature sensor of liquid microresonastor. AB - We propose and demonstrate a whispering gallery mode (WGM) resonance-based temperature sensor, where the microresonator is made of a DCM (2-[2-[4 (dimethylamino)phenyl] ethenyl]-6-methyl-4H-pyran-4-ylidene)-doped oil droplet (a liquid material) immersed in the water solution. The oil droplet is trapped, controlled, and located by a dual-fiber optical tweezers, which prevents the deformation of the liquid droplet. We excite the fluorescence and lasing in the oil droplet and measure the shifts of the resonance wavelength at different temperatures. The results show that the resonance wavelength redshifts when the temperature increases. The testing sensitivity is 0.377 nm/ degrees C in the temperature range 25 degrees C-45 degrees C. The results of the photobleaching testing of the dye indicate that measured errors can be reduced by reducing the measured time. As far as we know, this is the first time a WGM temperature sensor with a liquid state microcavity has been proposed. Compared with the solid microresonator, the utilization of the liquid microresonator improves the thermal sensitivity and provides the possibility of sensing in liquid samples or integrating into the chemical analyzers and microfluidic systems. PMID- 28005859 TI - Demonstration of a photonic crystal surface-emitting laser pumped Yb:YAG laser. AB - We developed a cryogenically cooled Yb:YAG continuous wave oscillator directly pumped with a photonic crystal surface-emitting laser (PCSEL). A high slope efficiency of 65.7% was obtained at an output power of 208 mW. The beam quality was close to the diffraction limit, with M2<1.2 in both directions. To the best of our knowledge, this is the first PCSEL pumped solid state laser to be developed. PMID- 28005860 TI - Janus waves. AB - We show the existence of a family of waves that share a common interesting property affecting the way these waves propagate and focus. The waves are a superposition of twin waves, which are conjugate to each other under inversion of the propagation direction. In analogy to holography, these twin "real" and "virtual" waves are related, respectively, to the converging and diverging parts of the beam and can be clearly visualized in real space at two distinct foci under the action of a focusing lens. Analytic formulas for the intensity distribution after focusing are derived, while numerical and experimental demonstrations are given for some of the most interesting members of this family, the accelerating Airy and ring-Airy beams. PMID- 28005861 TI - Mid-infrared self-Q-switched Er, Pr:CaF2 diode-pumped laser. AB - A diode-end-pumped self-Q-switched mid-infrared laser was demonstrated with Er3+, Pr3+ co-doped CaF2 crystal for, to the best of our knowledge, the first time. Maximum average output power of 262 mW was achieved and the corresponding slope efficiency was 14.9%. Stable self-Q-switched laser pulses as short as 718 ns were obtained with a repetition rate of 52.63 kHz at the center wavelength of 2803.7 nm. This highly compact nanosecond laser using a 3 at. % Er3+ and 0.03 at. % Pr3+ co-doped CaF2 crystal is free from any active or passive modulators in cavity, potentially promising for a micro and integrated diode-pumped mid-infrared laser system. PMID- 28005862 TI - Accurate thermometry based on the red and green fluorescence intensity ratio in NaYF4: Yb, Er nanocrystals for bioapplication. AB - A biological temperature measurement method based on the fluorescence intensity ratio (FIR) was developed to reduce uncertainty. The upconversion luminescence of NaYF4:Yb, Er nanocrystals was studied as a function of temperature around the physiologically relevant range of 300-330 K. We found that the green green FIR Fe and red-green FIR (I660/I540) varied linearly as temperature increased. The thermometric uncertainties using the two FIRs were discussed and were determined to be almost constant at 0.6 and 0.09 K for green green and red-green, respectively. The lower thermometric uncertainty comes from the intense signal-to-noise ratio of the measured FIRs owing to their comparable fluorescence intensities. PMID- 28005863 TI - Ho:YLF chirped pulse amplification at kilohertz repetition rates - 4.3 ps pulses at 2 MUm with GW peak power. AB - A 2 MUm chirped pulse amplification source generates 55 mJ picosecond pulses at a 1 kHz repetition rate. The system consists of a high-gain Ho:YLF regenerative amplifier (RA) operating in the single-energy regime and a dual-rod Ho:YLF power amplifier. Pulses of ~10 mJ energy from the RA are linearly scaled up to 55 mJ in the power amplifier, corresponding to a high overall extraction efficiency of >20%. The system displays an exceptional high stability with a pulse-to-pulse rms as low as 0.3%. Pulse compression is performed up to the 25 mJ energy level, resulting in pulses close to the Fourier-transform limit with a duration of 4.3 ps and a peak power of 4.4 GW. PMID- 28005864 TI - Phase rainbow refractometry for accurate droplet variation characterization. AB - We developed a one-dimensional phase rainbow refractometer for the accurate trans dimensional measurements of droplet size on the micrometer scale as well as the tiny droplet diameter variations at the nanoscale. The dependence of the phase shift of the rainbow ripple structures on the droplet variations is revealed. The phase-shifting rainbow image is recorded by a telecentric one-dimensional rainbow imaging system. Experiments on the evaporating monodispersed droplet stream show that the phase rainbow refractometer can measure the tiny droplet diameter changes down to tens of nanometers. This one-dimensional phase rainbow refractometer is capable of measuring the droplet refractive index and diameter, as well as variations. PMID- 28005865 TI - Dual-mode laser diode carrier with orthogonal polarization and single-mode modulation for remote-node heterodyne MMW-RoF. AB - A remote-node heterodyne millimeter-wave radio-over-fiber (MMW-RoF) link was proposed by a dual-mode optical carrier with orthogonal polarizations and single wavelength modulation, which effectively suppresses the chromatic dispersion and four-wave mixing. For optical wireline transmission, the bit error rate (BER) of a 25-km single-mode fiber (SMF) transmitted baseband 24-Gbit/s 64-QAM OFDM can be improved to 5.9*10-4 with an error vector magnitude (EVM) of 7.1%. Moreover, the beat 35-GHz MMW carrier with a 32-dB carrier-to-noise ratio was generated for wireless transmission. The BER and EVM of passband 8-Gbit/s 16-QAM OFDM at 35-GHz MMW carrier were 3.4*10-3 and 17.1%, respectively, after 25-km SMF and 1.6-m free-space transmissions. PMID- 28005866 TI - Demonstration of 20-Gbit/s high-speed Bessel beam encoding/decoding link with adaptive turbulence compensation. AB - By mapping traditional amplitude modulation to spatial modulation and employing adaptive optics compensation technique, we propose and experimentally demonstrate a high-speed Bessel beam encoding/decoding free-space optical link through atmospheric turbulence. The Bessel beam encoding/decoding speed is not limited by the conventional slow switching response of a spatial light modulator (SLM) but is fully determined by the modulation rate of an intensity modulator, which easily supports tens of gigabits per second modulation and resultant encoding/decoding. We use an SLM loaded with a pseudorandom phase mask to emulate atmospheric turbulence in the laboratory environment. An adaptive optics closed loop is used to sense the phase distortion of an extra probe Gaussian beam and then compensate the distorted Bessel beams. A 20-Gbit/s Bessel beam encoding/decoding link with adaptive turbulence compensation is demonstrated in the experiment, showing favorable operation performance. PMID- 28005867 TI - Ultrafast laser plasma doping of Er3+ ions in silica-on-silicon for optical waveguiding applications. AB - An ultrafast laser plasma doping (ULPD) technique is used for high concentration doping of erbium ions into silica-on-silicon substrate. The method uses a femtosecond laser to ablate material from TeO2-ZnO-Na2O Er2O3 (Er-TZN) target glass. The laser-generated plasma modifies the silica network, producing a high-index-contrast optical layer suited to the production of on-chip integrated optical circuits. Cross-sectional analysis using scanning electron microscope with energy dispersive x-ray spectroscopy revealed homogeneous intermixing of the host silica with Er-TZN, which is unique to ULPD. The highly doped layer exhibits spectroscopic characteristics of erbium with photoluminescence lifetimes from 10.79 to 14.07 ms. PMID- 28005868 TI - Reversible photo-bleaching effect in a bismuth/erbium co-doped optical fiber under 830 nm irradiation. AB - We observed photo-bleaching in a bismuth/erbium co-doped optical fiber (BEDF) under 830 nm irradiation. As a result of the photo-bleaching, the absorption at 814 nm and the near-infrared luminescence at 1420 nm are decreased, indicating that the silicon-based bismuth active center (BAC-Si) in a BEDF is bleached in the process. We further found that the photo-bleaching is reversible under room temperature. This is the first time that the BAC-Si could be bleached under 830 nm irradiation, and the photo-bleaching is reversible. The underlying mechanism of the reversible photo-bleaching effect is discussed. PMID- 28005869 TI - Wide-field spontaneous Raman spectroscopy imaging system for biological tissue interrogation. AB - Raman spectroscopy has shown great promise as a method to discriminate between cancerous and normal tissue/cells for a range of oncology applications using microscopy and tissue interrogation instruments such as handheld probes and needles. Here we are presenting preliminary steps toward the development of a practical handheld macroscopic Raman spectroscopy instrument, demonstrating its capabilities to discriminate between different biological tissue types during ex vivo porcine experiments. The novel probe design can image a field of view of 25 mm2 with a spatial resolution <100 MUm and an average spectral resolution of 95 cm-1, covering the fingerprint region between 450 to 1750 cm-1. The ability of the system to produce tissue maps based on molecular characteristics is demonstrated using a neural network machine learning technique. PMID- 28005870 TI - First demonstration and field trial on multi-user UDWDM-PON full duplex PSK-PSK with single monolithic integrated dual-output-DFB-SOA based ONUs. AB - We demonstrate a monolithically integrated dual-output DFB-SOA, and conduct the field trial on a multi-user bidirectional coherent ultradense wavelength division multiplexing-passive optical network (UDWDM-PON). To the best of our knowledge, this is the first achievement of simplified single integrated laser-based neighboring coherent optical network units (ONUs) with a 12.5 GHz channel spaced ultra-dense access network, including both downstream and upstream, taking the benefits of low footprint and low-temperature dependence. PMID- 28005871 TI - Vector self-pulsing in erbium-doped fiber lasers. AB - Insight into instabilities of fiber laser regimes leading to complex self-pulsing operations is an opportunity to unlock the high power and dynamic operation tunability of lasers. Though many models have been suggested, there is no complete covering of self-pulsing complexity observed experimentally. Here, I further generalized our previous vector model of erbium-doped fiber laser and, for the first time, to the best of my knowledge, map tunability of complex vector self-pulsing on Poincare sphere (limit cycles and double scroll polarization attractors) for laser parameters, e.g., power, ellipticity of the pump wave, and in-cavity birefringence. Analysis validated by extensive numerical simulations demonstrates good correspondence to the experimental results on complex self pulsing regimes obtained by many authors during the last 20 years. PMID- 28005872 TI - Flat-top bandpass filters enabled by cascaded resonant gratings. AB - Narrow bandpass filters are applied in laser systems, imaging, telecommunications, and astronomy. Traditionally implemented with thin-film stacks, there is recent interest in alternative means incorporating photonic resonance effects. Here, we demonstrate a new approach to bandpass filters that engages the guided-mode resonance effect working with a cavity-based Fabry-Perot resonance to flatten and steepen the pass band. Both of these resonance mechanisms are native to simple resonant bandpass filters placed in a cascade. Numerical examples provide quantitative spectral properties including pass-band shape and sideband levels. Thus, we compare the spectra of single-layer 1D and 2D resonant gratings with the dual-cascade design incorporating identical gratings. Two- and three-cavity designs are measured against a classic multi-cavity thin film filter with 151 layers. Whereas these initial results show comparable and improved results achieved with sparse structures, the challenge remains of developing a suitable fabrication technology to capitalize on this promise. PMID- 28005873 TI - Tunable filters for precise spectral gain control in ultra-short-pulse laser systems. AB - We present tunable spectral filters (TSFs) as a variable and precisely adjustable method to control the spectral gain of short-pulse laser systems. The TSFs provide a small residual spectral phase and a high damage threshold, and generate no pre- or post-pulses. The method is demonstrated for two different laser materials and can be applied as an intracavity compensation in regenerative amplifiers as well as a method for pre-compensation in high-energy multipass amplifiers. With this method, a full width at half-maximum bandwidth of 23.9 nm could be demonstrated in a diode-pumped, 50 J Yb:CaF2 amplifier. PMID- 28005874 TI - Generation of blue light by sum-frequency generation of a spectrally combined broad-area diode laser array. AB - We present the first demonstration of a spectrally beam combined diode laser array with subsequent sum-frequency generation (SFG). The combined beam of the diode laser array with 19 emitters has the same beam quality as a single emitter, and the wavelength of each emitter is different. The blue light is generated by sum-frequency mixing of pairs of emitters in the diode laser array. About 93 mW of blue light power is produced using a PPLN crystal. Compared with the SFG of two emitters, this approach can increase the number of lasers participating in nonlinear frequency conversion. Thus, it can enhance the available power. PMID- 28005875 TI - Highly efficient Q-switched Yb:YAG channel waveguide laser with 5.6 W of average output power. AB - In this Letter, we present high-power continuous wave (CW) and Q-switched femtosecond laser-written Yb:YAG channel waveguide lasers. In Q-switched operation, obtained by a semiconductor saturable absorber mirror (SESAM), as well as in CW operation, the laser generates average output powers of more than 5.6 W and reaches slope efficiencies above 74%. The Q-switched laser operated at a maximum repetition rate of 5.4 MHz with a minimum pulse duration of 11 ns, and with a maximum pulse energy of 1 MUJ. This laser has almost an order of magnitude higher average output power than previously reported Q-switched channel waveguide lasers. PMID- 28005876 TI - High-power femtosecond Raman frequency shifter. AB - We report on the generation of broadband, high-energy femtosecond pulses centered at 1.28 MUm by stimulated Raman scattering in a pressurized hydrogen cell. Stimulated Raman scattering is performed by two chirped and delayed pulses originating from a multi-mJ Ti:sapphire amplifier. The Stokes pulse carries record-high energy of 4.4 mJ and is recompressed down to 66 fs by a reflective grating pair. We characterized the short-wavelength mid-infrared source in view of energy stability, beam profile, and conversion efficiency at repetition rates of 100 and 10 Hz. The demonstrated high-energy frequency shifter will benefit intense THz sources based on highly nonlinear organic crystals. PMID- 28005877 TI - Dual optical coherence tomography sensor guided, two-motor, horizontal SMART micro-scissors. AB - In microsurgery, the physiological hand tremor of the surgeon remains an important factor affecting procedure efficiency, risk of complications, and ultimately, the efficacy of treatment. The micro-scissors are routinely employed to perform precise sharp dissection of delicate tissues. Here, we present a dual optical coherence tomography (OCT) distance sensor guided, two-motor, horizontal smart micromanipulation aided robotic-surgery tool (SMART) micro-scissors. It is intended to improve surgeon performance by retaining all of the attributes of the horizontal scissors while implementing proof-of-concept use of two functional motors to provide tremor cancellation. PMID- 28005878 TI - Large degree of polarization of photoluminescence caused by anisotropic strain in nonpolar a-plane MgxZn1-xO layers grown by plasma-assisted molecular beam epitaxy. AB - A large degree of polarization (rho) of photoluminescence (PL) approximate to 1 is obtained in each nonpolar a-plane MgxZn1-xO layer grown by plasma-assisted molecular beam epitaxy (MBE) with x=0.01, 0.03, and 0.10, respectively. Anisotropic in-plane strains are selectively introduced by using foreign substrates and doping with different Mg contents, which strongly modify the valence band structures, leading to anisotropic optical properties. A polarized Raman measurement shows that anisotropic in-plane strains along the y and z axes increase with the increasing Mg contents. Polarized PL spectra show that rho gradually increases to 0.97 with decreasing in-plane strains, resulting from an increasing difference in transition energy (DeltaE) between E?c and E||c caused by a lift of the degeneracy of valence band structures. The obtained highly polarized emission is close to linear polarized light, which is desirable in the backlighting of liquid crystal displays. PMID- 28005879 TI - Phase-sensitive amplification via coherent population oscillations in metastable helium at room temperature. AB - In this Letter, we report our experimental results on phase-sensitive amplification (PSA) in a nondegenerate signal-idler configuration using ultranarrow coherent population oscillations in metastable helium at room temperature. We achieved a high PSA gain of nearly 7 with a bandwidth of 200 kHz by using the system at resonance in a single-pass scheme. Further, the measured minimum gain is close to the ideal value, showing that we have a nearly pure PSA. This is also confirmed from our phase-to-phase transfer curves measurements, illustrating that we have a nearly perfect squeezer, which is interesting for a variety of applications. PMID- 28005880 TI - Dominant chiral optical forces in the vicinity of optical nanofibers. AB - Transverse spin angular momentum (SAM) of light and associated transverse chiral optical forces have received tremendous attention recently, as the latter may lead to an optical separation of chiral biomolecules. In this context, the relative magnitude of chiral and non-chiral forces is a challenge when implementing chiral separation schemes. In this work we have demonstrated that, by spatially separating the maxima of transverse spin density from the gradient of field intensity, it is possible to dominate chiral-specific components of the force over non-chiral ones. To that end, we studied optical nanofibers and nanowires as candidates for such a scheme and demonstrated that in their vicinity, chiral optical forces can emerge that are stronger than gradient and scattering forces. This finding may be of significance in the design of improved optical separation schemes for chiral biomolecules. PMID- 28005881 TI - Electro-optic beam deflection based on a lithium niobate waveguide with microstructured serrated electrodes. AB - We report on electro-optic beam deflection using an annealed proton exchange waveguide in lithium niobate (LN) with microstructured serrated array electrodes. Due to the electro-optic effect of the LN material, the experimental results show that the beam deflection and modulation of the LN waveguide can be realized with relatively low voltages. The total length of the serrated prism array electrodes structure is ~5 mm. With 20 V applied to the electrodes of 50, 100, and 150 MUm wide waveguides, ~1.28, ~0.96, and ~0.64 MUm beam deflections were obtained, respectively, which are in accordance with theoretical simulation. This configuration can be potentially applied in optical beam scanning, high-speed switches, and optical beam smoothing technology. PMID- 28005882 TI - Tunable high-efficiency light absorption of monolayer graphene via Tamm plasmon polaritons. AB - Highly efficient absorption of light at telecommunication wavelengths in monolayer graphene is numerically and theoretically investigated in a multi-layer photonic configuration, which consists of an ultrathin metal film coated on a dielectric Bragg mirror and a graphene sheet in a silica spacer. Our results show that the absolute absorption of light in the single-atomic-layer graphene can significantly reach 80% (34.8-fold enhancement compared to the intrinsic value of 2.3%), due to the strong field confinement of Tamm plasmon polaritons in the silica spacer. Moreover, we find that the absorption efficiency of graphene is critically dependent on the position of the graphene in the spacer. The operating wavelength is flexibly tunable by adjusting the incident angle of light and the thicknesses of metal and Bragg mirror layers. The meaningful improvement and tunability of graphene absorption may find favorable applications for the realization of high-performance graphene optoelectronic devices, such as detectors and modulators. PMID- 28005883 TI - Linear-regression-based approach for loss extraction from ring resonators. AB - This Letter proposes and demonstrates a linear-regression-based loss-extraction model that is applicable for all-pass rings and symmetrically and asymmetrically coupled add-drop rings. The model is derived by transforming the transmission spectra of a ring into linear relationships with no approximation. An all-pass ring resonator is fabricated to verify the model, and the experimental results indicate that the proposed model is more reliable than previously reported models [Opt. Express14, 3872 (2006)OPEXFF1094-408710.1364/OE.14.003872; Opt. Express15, 10553 (2007)OPEXFF1094-408710.1364/OE.15.010553; and J. Lightwave Technol.16, 1308 (1998)JLTEDG0733-872410.1109/50.701410]. PMID- 28005884 TI - Measurements of fluence profiles in femtosecond laser filaments in air. AB - We introduce a technique to measure fluence distributions in femtosecond laser beams with peak intensity of up to several hundred terawatts per square centimeter. Our approach is based on the dependence of single-shot laser ablation threshold for gold on the angle of incidence of the laser beam on the gold sample. We apply this technique to the profiling of fluence distributions in femtosecond laser filaments at a wavelength of 800 nm in air. The peak intensity is found to be clamped at a level that depends on the external beam focusing. The limiting value of the peak intensity attainable in long-range 800 nm air filaments, under very loose focusing conditions (f-number above ~500), is about 55 TW/cm2. PMID- 28005885 TI - Efficient quantization of tunable helix phase plates. AB - Helix phase plates are used in a variety of applications from optical trapping to astronomy. Tunable helix phase plates based on the Alvarez-Lohmann principle allow variation of the topological charge of the helix by rotating the phase plates with respect to each other around the optical axis. Current designs generate an undesired inverse phase in the section determined by the rotation angle. We present tunable phase plates that use a special quantization to maintain a uniform phase over the tuning range, suppressing the undesired part. As one benefit, the efficiency of the elements is increased over the whole tuning range. PMID- 28005886 TI - Adapting the HSV polarization-color mapping for regions with low irradiance and high polarization. AB - Many mappings from polarization into color have been developed so that polarization information can be displayed. One of the most common of these maps the angle of linear polarization into color hue and degree of linear polarization into color saturation, while preserving the irradiance information from the polarization data. While this strategy enjoys wide popularity, there is a large class of polarization images for which it is not ideal. It is common to have images where the strongest polarization signatures (in terms of degree of polarization) occur in regions of relatively low irradiance: either in shadow in reflective bands or in cold regions in emissive bands. Since the irradiance is low, the chromatic properties of the resulting images are generally not apparent. Here we present an alternate mapping that uses the statistics of the angle of polarization as a measure of confidence in the polarization signature, then amplifies the irradiance in regions of high confidence, and leaves it unchanged in regions of low confidence. Results are shown from an LWIR and a visible spectrum imager. PMID- 28005887 TI - Programmable long-period grating in a liquid core optical fiber. AB - A programmable fiber long-period grating (LPG) is experimentally demonstrated in a liquid core optical fiber with a low insertion loss. The LPG is dynamically formed by a temperature gradient in real time through a micro-heater array. The transmission spectrum of the LPG can be completely reconfigured by digitally changing the grating period, index contrast, length, and design. The phase shift inside the LPG can also be readily defined to enable advanced spectrum shaping. Owing to the high thermo-optic coefficient of the liquid core, it is possible to achieve high coupling efficiencies with driving powers as low as a few tens of milliwatts. The proposed thermo-programmable device provides a potential design solution for dynamic all-fiber optics components. PMID- 28005888 TI - 10 MUJ dissipative soliton resonance square pulse in a dual amplifier figure-of eight double-clad Er:Yb mode-locked fiber laser. AB - We demonstrate experimentally a double-clad Er:Yb co-doped dual amplifier passive mode-locked figure-of-eight fiber laser that generates high energy, width, and amplitude tunable dissipative soliton resonance square pulses. In our laser system, each loop contains an amplifier that controls a characteristic of the output pulse. The amplitude and width of the output beam can be controlled continuously but, dependently, according to the pump power of each amplifier. The pulse width can be tuned in a range of almost 360 ns while the peak power varies from 8 to 120 W. On maximum possible pumping from both sides without having a pulse break, we report square pulses with 10 MUJ energy per pulse with a signal to-noise ratio of 60 dB. PMID- 28005889 TI - Widefield lensless endoscopy with a multicore fiber. AB - We demonstrate pixelation-free real-time widefield endoscopic imaging through an aperiodic multicore fiber (MCF) without any distal opto-mechanical elements or proximal scanners. Exploiting the memory effect in MCFs, the images in our system are directly obtained without any post-processing using a static wavefront correction obtained from a single calibration procedure. Our approach allows for video-rate 3D widefield imaging of incoherently illuminated objects with imaging speed not limited by the wavefront-shaping device refresh rate. PMID- 28005890 TI - Coherent artifact suppression in line-field reflection confocal microscopy using a low spatial coherence light source. AB - Line-field reflection confocal microscopy (LF-RCM) has the potential to add a dimension of parallelization to traditional confocal microscopy while reducing the need for two-axis beam scanning. LF-RCM systems often employ light sources with a high degree of spatial coherence. This high degree of spatial coherence potentially leads to unwanted coherent artifact in the setting of nontrivial sample scattering. Here, we (a) confirm that a coherent artifact is a nontrivial problem in LF-RCM when using spatially coherent light, and (b) demonstrate that such a coherent artifact can be mitigated through the use of reduced spatial coherence line-field sources. We demonstrate coherent noise suppression in a full pupil line-field confocal microscope using a large number of mutually incoherent emitters from a vertical-cavity surface-emitting lasers (VCSEL) array. The coherent noise from a highly scattering sample is significantly suppressed by the use of this synthesized reduced spatial coherence light source compared to a fully coherent light source. Lastly, with scattering samples, the axial confocality of line-field confocal microscopy is compromised independent of the source spatial coherence, as demonstrated by our experimental result. Our results highlight the importance of spatial coherence engineering in parallelized reflection confocal microscopy. PMID- 28005891 TI - Simultaneous all-optical phase noise mitigation and automatically locked homodyne reception of an incoming QPSK data signal. AB - Simultaneous phase noise mitigation and automatic phase/frequency-locked homodyne reception is demonstrated for a 20-32 Gbaud QPSK signal. A phase quantization function is realized to squeeze the phase noise of the signal by optical wave mixing of the signal, its third-order harmonic, and their corresponding delayed variant conjugates, converting the noisy input into a noise-mitigated signal. In a simultaneous nonlinear process, the noise-mitigated signal is automatically phase- and frequency-locked with a "local" pump laser, avoiding the need for feedback or phase/frequency tracking for homodyne detection. Open eye-diagrams are obtained for in-phase and quadrature-phase components of the signal and ~2 dB OSNR gain is achieved at BER 10-3. PMID- 28005892 TI - Resonant microsphere gyroscope based on a double Faraday rotator system. AB - The resonant microsphere gyroscope is proposed based on a double Faraday rotator system for the resonant microsphere gyroscope (RMSG) that is characterized by low insertion losses and does not destroy the reciprocity of the gyroscope system. Use of the echo suppression structure and the orthogonal polarization method can effectively inhibit both the backscattering noise and the polarization error, and reduce them below the system sensitivity limit. The resonance asymmetry rate dropped from 34.2% to 2.9% after optimization of the backscattering noise and the polarization noise, which greatly improved the bias stability and the scale factor linearity of the proposed system. Additionally, based on the optimum parameters for the double Faraday rotator system, a bias stability of 0.04 degrees /s has been established for an integration time of 10 s in 1000 s in a resonator microsphere gyroscope using a microsphere resonator with a diameter of 1 mm and a Q of 7.2*106. PMID- 28005893 TI - Optical encryption with protection against Dirac delta and plain signal attacks. AB - This Letter proposes an optical encryption technique that disguises the information with modular arithmetic concepts and time-varying noise components that are unknown to the receiver. Optical encryption systems that use these techniques produce a nondeterministic system response, as well as noise like image data that can easily be generated with ordinary spatial light modulators. The principle of this technique is demonstrated for the double random phase encoding (DRPE) method. The conventional DRPE method has major vulnerabilities for Dirac signal and plain signal attacks, making them impractical for secure encryption. It is shown that the proposed encryption technique provides a robustness against these types of attacks, allowing optical DRPE to be employed in secure encryptions. Moreover, applications of this Letter are not limited to DRPE alone but can also be adopted by other optical encryption techniques such as fractional Fourier transform and Fresnel-transform-based techniques. PMID- 28005894 TI - Realizing topological edge states in a silicon nitride microring-based photonic integrated circuit. AB - Topological edge states in a photonic integrated circuit based on the platform of silicon nitride are demonstrated with a two-dimensional coupled resonator optical waveguide array involving the synthetic magnetic field for photons at near infrared wavelengths. Measurements indicate that the topological edge states can be observed at certain wavelengths, with light travelling around the boundary of the array. Combined with the induced disorders in fabrication near the edge, the system shows the defect immunity under the topological protection of edge states. PMID- 28005895 TI - Non-destructive shadowgraph imaging of ultra-cold atoms. AB - An imaging system is presented that is capable of far-detuned non-destructive imaging of a Bose-Einstein condensate with the signal proportional to the second spatial derivative of the density. Whilst demonstrated with application to Rb85, the technique generalizes to other atomic species and is shown to be capable of a signal-to-noise of ~25 at 1 GHz detuning with 100 in-trap images showing no observable heating or atom loss. The technique is also applied to the observation of individual trajectories of stochastic dynamics inaccessible to single shot imaging. Coupled with a fast optical phase locked loop, the system is capable of dynamically switching to resonant absorption imaging during the experiment. PMID- 28005896 TI - Fiber-laser-based, high-repetition-rate, picosecond ultraviolet source tunable across 329-348 nm. AB - We report a compact, fiber-laser-based, high-repetition-rate picosecond source for the ultraviolet (UV), providing multi-tens of milliwatt of average power across 329-348 nm. The source is based on internal sum-frequency-generation (SFG) in a singly resonant optical parametric oscillator (OPO), synchronously pumped at 532 nm by the second harmonic of a picosecond Yb-fiber laser at 80 MHz repetition rate. Using a 30-mm-long single-grating MgO:sPPLT crystal for the OPO and a 5-mm long BiB3O6 crystal for intracavity SFG, we generate up to 115 mW of average UV power at 339.9 nm, with >50 mW over 73% of the tuning range, for 1.6 W of input pump power. The UV output exhibits a passive rms power stability of ~2.9% rms over 1 min and 6.5% rms over 2 h in high beam quality. Angular acceptance bandwidth and cavity detuning effects have also been studied. PMID- 28005897 TI - Phase-sensitive tomography of the joint spectral amplitude of photon pair sources. AB - We present a novel measurement technique to perform full phase-sensitive tomography on the joint spectrum of photon pair sources, using stimulated four wave mixing and phase-sensitive amplification. Applying this method to an integrated silicon nanowire source with a frequency chirped pump laser, we are able to observe a corresponding phase change in the spectral amplitude that would otherwise be hidden in standard intensity measurements. With a highly nonlinear fiber source, we show that phase-sensitive measurements have superior sensitivity to small spectral features when compared to intensity measurements. This technique enables more complete characterization of photon pair sources based on nonlinear photonics. PMID- 28005898 TI - Bandwidth and wavelength tunable optical passband filter based on silicon multiple microring resonators. AB - An ultra-compact silicon bandpass filter with wide bandwidth tunability is proposed and experimentally demonstrated. The filter architecture is based on a multiple micro-ring resonator-cascaded structure. A wide bandwidth tunability (from 75 to 300 GHz) can be achieved by controlling the resonant frequency of the microring resonators when a good shape factor (0.24-0.44) is held. The filter has a wide free spectral range (about 1.2 THz). The center wavelength can be tuned over several nanometers linearly. The footprint is only 0.053 mm2. PMID- 28005899 TI - Quasi-Bessel beams with longitudinally varying polarization state generated by employing spectrum engineering. AB - We report on the generation and control of quasi-Bessel beams having not only a uniform axial intensity but also a longitudinally varying polarization state. Based on the optimization routine of the spatial spectrum of the so-called Durnin ring, we generate quasi-Bessel beams possessing longitudinally variant axial intensity with linear or sinusoidal envelopes. By utilizing a Sagnac interferometer, we create and coaxially composite two orthogonally polarized beams with complementary axial intensities to form quasi-Bessel beams with uniform axial intensity but a longitudinally varying polarization state. Furthermore, we demonstrate the possibility and flexibility of manipulating the trajectory, speed, and period of polarization state transformation upon propagation. Our results may enable Bessel beams to be used in other applications including optical communications, material processing, and polarimetry. PMID- 28005900 TI - Diagnostic Tests to Support Late-Stage Control Programs for Schistosomiasis and Soil-Transmitted Helminthiases. AB - Global efforts to address schistosomiasis and soil-transmitted helminthiases (STH) include deworming programs for school-aged children that are made possible by large-scale drug donations. Decisions on these mass drug administration (MDA) programs currently rely on microscopic examination of clinical specimens to determine the presence of parasite eggs. However, microscopy-based methods are not sensitive to the low-intensity infections that characterize populations that have undergone MDA. Thus, there has been increasing recognition within the schistosomiasis and STH communities of the need for improved diagnostic tools to support late-stage control program decisions, such as when to stop or reduce MDA. Failure to adequately address the need for new diagnostics could jeopardize achievement of the 2020 London Declaration goals. In this report, we assess diagnostic needs and landscape potential solutions and determine appropriate strategies to improve diagnostic testing to support control and elimination programs. Based upon literature reviews and previous input from experts in the schistosomiasis and STH communities, we prioritized two diagnostic use cases for further exploration: to inform MDA-stopping decisions and post-MDA surveillance. To this end, PATH has refined target product profiles (TPPs) for schistosomiasis and STH diagnostics that are applicable to these use cases. We evaluated the limitations of current diagnostic methods with regards to these use cases and identified candidate biomarkers and diagnostics with potential application as new tools. Based on this analysis, there is a need to develop antigen-detecting rapid diagnostic tests (RDTs) with simplified, field-deployable sample preparation for schistosomiasis. Additionally, there is a need for diagnostic tests that are more sensitive than the current methods for STH, which may include either a field deployable molecular test or a simple, low-cost, rapid antigen-detecting test. PMID- 28005902 TI - Animals in the Zika Virus Life Cycle: What to Expect from Megadiverse Latin American Countries. AB - Zika virus (ZIKV) was first isolated in 1947 in primates in Uganda, West Africa. The virus remained confined to the equatorial regions of Africa and Asia, cycling between infecting monkeys, arboreal mosquitoes, and occasionally humans. The ZIKV Asiatic strain was probably introduced into Brazil in or around late 2013. Presently, ZIKV is in contact with the rich biodiversity in all Brazilian biomes, bordering on other Latin American countries. Infections in Brazilian primates have been reported recently, but the overall impact of this virus on wildlife in the Americas is still unknown. The current epidemic in the Americas requires knowledge on the role of mammals, especially nonhuman primates (NHPs), in ZIKV transmission to humans. The article discusses the available data on ZIKV in host animals and issues of biodiversity, rapid environmental change, and impact on human health in megadiverse Latin American countries. The authors reviewed scientific articles and recent news stories on ZIKV in animals, showing that 47 animal species from three orders (mammals, reptiles, and birds) have been investigated for the potential to establish a sylvatic cycle. The review aims to contribute to epidemiological studies and the knowledge on the natural history of ZIKV. The article concludes with questions that require urgent attention in epidemiological studies involving wildlife in order to understand their role as ZIKV hosts and to effectively control the epidemic. PMID- 28005901 TI - Mapping Soil Transmitted Helminths and Schistosomiasis under Uncertainty: A Systematic Review and Critical Appraisal of Evidence. AB - BACKGROUND: Spatial modelling of STH and schistosomiasis epidemiology is now commonplace. Spatial epidemiological studies help inform decisions regarding the number of people at risk as well as the geographic areas that need to be targeted with mass drug administration; however, limited attention has been given to propagated uncertainties, their interpretation, and consequences for the mapped values. Using currently published literature on the spatial epidemiology of helminth infections we identified: (1) the main uncertainty sources, their definition and quantification and (2) how uncertainty is informative for STH programme managers and scientists working in this domain. METHODOLOGY/PRINCIPAL FINDINGS: We performed a systematic literature search using the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) protocol. We searched Web of Knowledge and PubMed using a combination of uncertainty, geographic and disease terms. A total of 73 papers fulfilled the inclusion criteria for the systematic review. Only 9% of the studies did not address any element of uncertainty, while 91% of studies quantified uncertainty in the predicted morbidity indicators and 23% of studies mapped it. In addition, 57% of the studies quantified uncertainty in the regression coefficients but only 7% incorporated it in the regression response variable (morbidity indicator). Fifty percent of the studies discussed uncertainty in the covariates but did not quantify it. Uncertainty was mostly defined as precision, and quantified using credible intervals by means of Bayesian approaches. CONCLUSION/SIGNIFICANCE: None of the studies considered adequately all sources of uncertainties. We highlighted the need for uncertainty in the morbidity indicator and predictor variable to be incorporated into the modelling framework. Study design and spatial support require further attention and uncertainty associated with Earth observation data should be quantified. Finally, more attention should be given to mapping and interpreting uncertainty, since they are relevant to inform decisions regarding the number of people at risk as well as the geographic areas that need to be targeted with mass drug administration. PMID- 28005903 TI - CT Features of Colorectal Schwannomas: Differentiation from Gastrointestinal Stromal Tumors. AB - PURPOSE: To find differential CT features of colorectal schwannomas from gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS: CT features of 13 pathologically proven colorectal schwannomas and 21 GISTs were retrospectively reviewed. The following CT items were analyzed: size, longitudinal and transverse location, shape, margin, homogeneity, necrosis, surface ulceration, calcification, degree of attenuation, the presence of enlarged lymph node (LN), and metastasis. Among the features, significant variables were evaluated using univariate statistical tests. The optimal cut-off point of tumor size was obtained by ROC analysis. Binary logistic regression analysis was used to find the most independent CT variables. RESULTS: Small size, non-rectum location, smooth margin, homogeneous high attenuation without necrosis, and the presence of enlarged LNs were found to be significant variables to differentiate schwannomas from GISTs (P<0.05). The optimized cut-off point for tumor size in distinguishing GISTs from schwannomas was 3.9 cm (AUC = 0.808, sensitivity = 66.7%, specificity = 92.3%, P<0.0001). Binary regression analysis revealed that only non-rectum location remained independent predictor for schwannomas differentiated from GISTs (odds ratio = 31.667, P = 0.001). CONCLUSION: Colorectal schwannomas usually located in non-rectum and appear as small subepithelial nodules showing homogeneous high attenuation and smooth margin. Schwannomas exclusively accompany with enlarged LNs. PMID- 28005904 TI - Epidemiologic Evaluation of Human Papillomavirus Type Competition and the Potential for Type Replacement Post-Vaccination. AB - BACKGROUND: Millions of women have been vaccinated with one of two first generation human papillomavirus (HPV) vaccines. Both vaccines remain in use and target two oncogenic types (HPVs 16 and 18); however, if these types naturally compete with others that are not targeted, type replacement may occur following reductions in the circulating prevalence of targeted types. To explore the potential for type replacement, we evaluated natural HPV type competition in unvaccinated females. METHODS: Valid HPV DNA typing information was available from five epidemiological studies conducted in Canada and Brazil (n = 14,685; enrollment across studies took place between1993 and 2010), which used similar consensus-primer PCR assays, capable of detecting up to 40 HPV types. A total of 38,088 cervicovaginal specimens were available for inclusion in our analyses evaluating HPV type-type interactions involving vaccine-targeted types (6, 11, 16, and 18), and infection with each of the other HPV types. RESULTS: Across the studies, the average age of participants ranged from 21.0 to 43.7 years. HPV16 was the most common type (prevalence range: 1.0% to 13.8%), and in general HPV types were more likely to be detected as part of a multiple infection than as single infections. In our analyses focusing on each of the vaccine-targeted HPV types separately, many significant positive associations were observed (particularly involving HPV16); however, we did not observe any statistically significant negative associations. CONCLUSIONS: Our findings suggest that natural HPV type competition does not exist, and that type replacement is unlikely to occur in vaccinated populations. PMID- 28005905 TI - Activity-Limiting Musculoskeletal Conditions in US Veterans Compared to Non Veterans: Results from the 2013 National Health Interview Survey. AB - Past military service is associated with health outcomes, both positive and negative. In this study we use the 2013 National Health Interview Survey to examine the constellation of conditions referred to as musculoskeletal disorders (MSDs) for Veterans and non-veterans with health conditions that limit their daily activities. Multivariate logistic regression analysis reveal that Veterans are more likely to report MSDs like neck and back problems, fracture bone and joint problems as an activity limiting problem compared to non-veterans. The relationship between age and reports of activity limiting MSDs is moderated by Veteran status. Veterans in this sample report more activity limiting MSDs at younger ages compared to non-veterans and fewer MSDs at older ages. This research contributes to our understanding of potentially limiting health conditions at earlier ages for Veterans. PMID- 28005907 TI - Lifemap: Exploring the Entire Tree of Life. AB - The Tree of Life (ToL) is meant to be a unique representation of the evolutionary relationships between all species on earth. Huge efforts are made to assemble such a large tree, helped by the decrease of sequencing costs and improved methods to reconstruct and combine phylogenies, but no tool exists today to explore the ToL in its entirety in a satisfying manner. By combining methods used in modern cartography, such as OpenStreetMap, with a new way of representing tree like structures, I created Lifemap, a tool allowing the exploration of a complete representation of the ToL (between 800,000 and 2.2 million species depending on the data source) in a zoomable interface. A server version of Lifemap also allows users to visualize their own trees. This should help researchers in ecology and evolutionary biology in their everyday work, but may also permit the diffusion to a broader audience of our current knowledge of the evolutionary relationships linking all organisms. PMID- 28005906 TI - A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways. AB - INTRODUCTION: HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions. METHODS: We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset). RESULTS: We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the "Immunity" metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28-11.91], p = 0.019) than weak expression, and with a better prognosis in HER2-positive/ER-negative breast cancers (HR = 0.58 [0.36-0.94], p = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs). CONCLUSION: The identification of a predictive and prognostic immune module in HER2-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation. PMID- 28005908 TI - A Machine Learning Approach for Using the Postmortem Skin Microbiome to Estimate the Postmortem Interval. AB - Research on the human microbiome, the microbiota that live in, on, and around the human person, has revolutionized our understanding of the complex interactions between microbial life and human health and disease. The microbiome may also provide a valuable tool in forensic death investigations by helping to reveal the postmortem interval (PMI) of a decedent that is discovered after an unknown amount of time since death. Current methods of estimating PMI for cadavers discovered in uncontrolled, unstudied environments have substantial limitations, some of which may be overcome through the use of microbial indicators. In this project, we sampled the microbiomes of decomposing human cadavers, focusing on the skin microbiota found in the nasal and ear canals. We then developed several models of statistical regression to establish an algorithm for predicting the PMI of microbial samples. We found that the complete data set, rather than a curated list of indicator species, was preferred for training the regressor. We further found that genus and family, rather than species, are the most informative taxonomic levels. Finally, we developed a k-nearest- neighbor regressor, tuned with the entire data set from all nasal and ear samples, that predicts the PMI of unknown samples with an average error of +/-55 accumulated degree days (ADD). This study outlines a machine learning approach for the use of necrobiome data in the prediction of the PMI and thereby provides a successful proof-of- concept that skin microbiota is a promising tool in forensic death investigations. PMID- 28005909 TI - Neural Crest Migration and Survival Are Susceptible to Morpholino-Induced Artifacts. AB - The neural crest (NC) is a stem cell-like embryonic population that is essential for generating and patterning the vertebrate body, including the craniofacial skeleton and peripheral nervous system. Defects in NC development underlie many birth defects and contribute to formation of some of the most malignant cancers in humans, such as melanoma and neuroblastoma. For these reasons, significant research efforts have been expended to identify genes that control NC development, as it is expected to lead to a deeper understanding of the genetic mechanisms controlling vertebrate development and identify new treatments for NC derived diseases and cancers. However, a number of inconsistencies regarding gene function during NC development have emerged from comparative analyses of gene function between mammalian and non-mammalian systems (chick, frog, zebrafish). This poses a significant barrier to identification of single genes and/or redundant pathways to target in NC diseases. Here, we determine whether technical differences, namely morpholino-based approaches used in non-mammalian systems, could contribute to these discrepancies, by examining the extent to which NC phenotypes in fascin1a (fscn1a) morphant embryos are similar to or different from fscn1a null mutants in zebrafish. Analysis of fscn1a morphants showed that they mimicked early NC phenotypes observed in fscn1a null mutants; however, these embryos also displayed NC migration and derivative phenotypes not observed in null mutants, including accumulation of p53-independent cell death. These data demonstrate that morpholinos can cause seemingly specific NC migration and derivative phenotypes, and thus have likely contributed to the inconsistencies surrounding NC gene function between species. We suggest that comparison of genetic mutants between different species is the most rigorous method for identifying conserved genetic mechanisms controlling NC development and is critical to identify new treatments for NC diseases. PMID- 28005911 TI - Epistasis and Entropy. AB - Epistasis is a key concept in the theory of adaptation. Indicators of epistasis are of interest for large systems where systematic fitness measurements may not be possible. Some recent approaches depend on information theory. We show that considering shared entropy for pairs of loci can be misleading. The reason is that shared entropy does not imply epistasis for the pair. This observation holds true also in the absence of higher order epistasis. We discuss a method for reducing the number of false positives. However, our main conclusion is that entropy-based approaches have serious limitations in this context. PMID- 28005910 TI - Melioidosis in Malaysia: A Review of Case Reports. AB - BACKGROUND: Melioidosis is a tropical infectious disease associated with significant mortality due to early onset of sepsis. OBJECTIVE: We sought to review case reports of melioidosis from Malaysia. METHODS: We conducted a computerized search of literature resources including PubMed, OVID, Scopus, MEDLINE and the COCHRANE database to identify published case reports from 1975 to 2015. We abstracted information on clinical characteristics, exposure history, comorbid conditions, management and outcome. RESULTS: Overall, 67 cases were reported with 29 (43%) deaths; the median age was 44 years, and a male preponderance (84%) was noted. Forty-one cases (61%) were bacteremic, and fatal septic shock occurred in 13 (19%) within 24-48 hours of admission; nine of the 13 cases were not specifically treated for melioidosis as confirmatory evidence was available only after death. Diabetes mellitus (n = 36, 54%) was the most common risk factor. Twenty-six cases (39%) had a history of exposure to contaminated soil/water or employment in high-risk occupations. Pneumonia (n = 24, 36%) was the most common primary clinical presentation followed by soft tissue abscess (n = 22, 33%). Other types of clinical presentations were less common-genitourinary (n = 5), neurological (n = 5), osteomyelitis/septic arthritis (n = 4) and skin (n = 2); five cases had no evidence of a focus of infection. With regard to internal foci of infection, abscesses of the subcutaneous tissue (n = 14, 21%) was the most common followed by liver (18%); abscesses of the spleen and lung were the third most common (12% each). Seven of 56 males were reported to have prostatic abscesses. Mycotic pseudoaneurysm occurred in five cases. Only one case of parotid abscess was reported in an adult. Of the 67 cases, 13 were children (<= 18 years of age) with seven deaths; five of the 13 were neonates presenting primarily with bronchopneumonia, four of whom died. Older children had a similar presentation as adults; no case of parotid abscess was reported among children. CONCLUSIONS: The clinical patterns of cases reported from Malaysia are consistent for the most part from previous case reports from South and Southeast Asia with regard to common primary presentations of pneumonia and soft tissue abscesses, and diabetes as a major risk factor. Bacteremic melioidosis carried a poor prognosis and septic shock was strong predictor of mortality. Differences included the occurrence of: primary neurological infection was higher in Malaysia compared to reports outside Malaysia; internal foci of infection such as abscesses of the liver, spleen, prostate, and mycotic pseudoaneurysms were higher than previously reported in the region. No parotid abscess was reported among children. Early recognition of the disease is the cornerstone of management. In clinical situations of community-acquired sepsis and/or pneumonia, where laboratory bacteriological confirmation is not possible, empirical treatment with antimicrobials for B. pseudomallei is recommended. PMID- 28005913 TI - Shared Information between Residues Is Sufficient to Detect Pairwise Epistasis in a Protein. PMID- 28005912 TI - Benchmarking Prehospital and Emergency Department Care for Argentine Children with Traumatic Brain Injury: For the South American Guideline Adherence Group. AB - OBJECTIVE: There is little information on the type of early care provided to children with traumatic brain injury (TBI) in low middle income countries. We benchmarked early prehospital [PH] and emergency department [ED] pediatric TBI care in Argentina. METHODS: We conducted a secondary analysis of data from patients previously enrolled in a prospective seven center study of children with TBI. Eligible participants were patients 0-18 years, and had diagnosis of TBI (admission Glasgow Coma scale score [GCS] < 13 or with GCS 14-15 and abnormal head CT scan within 48 hours of admission, and head AIS > 0). Outcomes were transport type, transport time, PH and ED adherence to best practice, and discharge Pediatric Cerebral Performance Category Scale (PCPC) and Pediatric Overall Performance category Scale (POPC). RESULTS: Of the 366 children, mean age was 8.7 (5.0) years, 58% were male, 90% had isolated TBI and 45.4% were transported by private vehicle. 50 (34.7%) of the 144 children with severe TBI (39.3% of all TBI patients) were transported by private vehicle. Most (267; 73%) patients received initial TBI care at an index hospital prior to study center admission, including children with severe (81.9%) TBI. Transport times were shorter for those patients who were directly transported by ambulance to study center than for the whole cohort (1.4 vs.5.5 hours). Ambulance blood pressure data were recorded in 30.9%. ED guideline adherence rate was higher than PH guideline adherence rate (84.8% vs. 26.4%). For patients directly transferred from scene to study trauma centers, longer transport time was associated with worse discharge outcome (PCPC aOR 1.10 [1.04, 1.18] and (POPC aOR 1.10 [1.04, 1.18]). There was no relationship between PH or ED TBI guideline adherence rate and discharge POPC and PCPC. CONCLUSION: This study benchmarks early pediatric TBI care in Argentina and shows that many critically injured children with TBI do not receive timely or best practice PH care, that PH guideline adherence rate is low and that longer transport time was associated with poor discharge outcomes for patients with direct transfer status. There is an urgent need to improve the early care of children with TBI in Argentina, especially timely transportation to a hospital. PMID- 28005914 TI - The Association of Bread and Rice with Metabolic Factors in Type 2 Diabetic Patients. AB - PURPOSE: Carbohydrates are shown to have an important role in blood glucose control, type 2 diabetes and cardiovascular diseases risk. This is even more challenging when considering populations consuming refined grains diets. Bread and rice are staple foods which supply main proportion of Iranian calorie intake. This study was designed to investigate the effect of bread and rice intake on blood glucose control, lipid profile and anthropometric measurements in Iranian type 2 diabetic patients. METHODS: 426 patients with type 2 diabetes were included in this study. Anthropometric measurements were done using standard methods. Dietary information was assessed by a valid and reliable food frequency questionnaire (FFQ). Fasting blood glucose (FBG), glycated hemoglobin (HbA1c), serum triglycride (TG), total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol were examined after 12-hour fasting. RESULTS: The results represented that people in the highest tertile compared to the lowest tertile of calorie adjusted total bread intake have higher FBG. FBG in the highest tertile of calorie adjusted total bread-rice intake was also significantly higher than the lowest. The association remained significant after adjusting for potential confounders. Rice intake showed no association with cardio-metabolic risk factors. CONCLUSION: We founded that higher total bread intake and total bread-rice intake were associated with FBG in type 2 diabetic patients whereas rice intake was not associated with glucose and lipid profile. This result should be confirmed in prospective studies, considering varieties, glycemic index (GI), glycemic load (GL) and cooking method of bread and rice. PMID- 28005915 TI - Goldilocks and the Raster Grid: Selecting Scale when Evaluating Conservation Programs. AB - Access to high quality spatial data raises fundamental questions about how to select the appropriate scale and unit of analysis. Studies that evaluate the impact of conservation programs have used multiple scales and areal units: from 5x5 km grids; to 30m pixels; to irregular units based on land uses or political boundaries. These choices affect the estimate of program impact. The bias associated with scale and unit selection is a part of a well-known dilemma called the modifiable areal unit problem (MAUP). We introduce this dilemma to the literature on impact evaluation and then explore the tradeoffs made when choosing different areal units. To illustrate the consequences of the MAUP, we begin by examining the effect of scale selection when evaluating a protected area in Mexico using real data. We then develop a Monte Carlo experiment that simulates a conservation intervention. We find that estimates of treatment effects and variable coefficients are only accurate under restrictive circumstances. Under more realistic conditions, we find biased estimates associated with scale choices that are both too large or too small relative to the data generating process or decision unit. In our context, the MAUP may reflect an errors in variables problem, where imprecise measures of the independent variables will bias the coefficient estimates toward zero. This problem may be pronounced at small scales of analysis. Aggregation may reduce this bias for continuous variables, but aggregation exacerbates bias when using a discrete measure of treatment. While we do not find a solution to these issues, even though treatment effects are generally underestimated. We conclude with suggestions on how researchers might navigate their choice of scale and aerial unit when evaluating conservation policies. PMID- 28005916 TI - The TRIAGE-ProADM Score for an Early Risk Stratification of Medical Patients in the Emergency Department - Development Based on a Multi-National, Prospective, Observational Study. AB - INTRODUCTION: The inflammatory biomarker pro-adrenomedullin (ProADM) provides additional prognostic information for the risk stratification of general medical emergency department (ED) patients. The aim of this analysis was to develop a triage algorithm for improved prognostication and later use in an interventional trial. METHODS: We used data from the multi-national, prospective, observational TRIAGE trial including consecutive medical ED patients from Switzerland, France and the United States. We investigated triage effects when adding ProADM at two established cut-offs to a five-level ED triage score with respect to adverse clinical outcome. RESULTS: Mortality in the 6586 ED patients showed a step-wise, 25-fold increase from 0.6% to 4.5% and 15.4%, respectively, at the two ProADM cut offs (<=0.75nmol/L, >0.75-1.5nmol/L, >1.5nmol/L, p ANOVA <0.0001). Risk stratification by combining ProADM within cut-off groups and the triage score resulted in the identification of 1662 patients (25.2% of the population) at a very low risk of mortality (0.3%, n = 5) and 425 patients (6.5% of the population) at very high risk of mortality (19.3%, n = 82). Risk estimation by using ProADM and the triage score from a logistic regression model allowed for a more accurate risk estimation in the whole population with a classification of 3255 patients (49.4% of the population) in the low risk group (0.3% mortality, n = 9) and 1673 (25.4% of the population) in the high-risk group (15.1% mortality, n = 252). CONCLUSIONS: Within this large international multicenter study, a combined triage score based on ProADM and established triage scores allowed a more accurate mortality risk discrimination. The TRIAGE-ProADM score improved identification of both patients at the highest risk of mortality who may benefit from early therapeutic interventions (rule in), and low risk patients where deferred treatment without negatively affecting outcome may be possible (rule out). PMID- 28005917 TI - Natural Cellulose Nanofibers As Sustainable Enhancers in Construction Cement. AB - Cement is one of the mostly used construction materials due to its high durability and low cost, but it suffers from brittle fracture and facile crack initiation. This article describes the use of naturally-derived renewable cellulose nanofibers (CNFs) to reinforce cement. The effects of CNFs on the mechanical properties, degree of hydration (DOH), and microstructure of cement pastes have been studied. It is found that an addition of 0.15% by weight of CNFs leads to a 15% and 20% increase in the flexural and compressive strengths of cement paste. The enhancement in mechanical strength is attributed to high DOH and dense microstructure of cement pastes after adding CNFs. PMID- 28005919 TI - Correction: Reference Ranges and Association of Age and Lifestyle Characteristics with Testosterone, Sex Hormone Binding Globulin, and Luteinizing Hormone among 1166 Western Chinese Men. AB - [This corrects the article DOI: 10.1371/journal.pone.0164116.]. PMID- 28005918 TI - The Plant Hormone Cytokinin Confers Protection against Oxidative Stress in Mammalian Cells. AB - Modulating key dynamics of plant growth and development, the effects of the plant hormone cytokinin on animal cells gained much attention recently. Most previous studies on cytokinin effects on mammalian cells have been conducted with elevated cytokinin concentration (in the MUM range). However, to examine physiologically relevant dose effects of cytokinins on animal cells, we systematically analyzed the impact of kinetin in cultured cells at low and high concentrations (1nM 10MUM) and examined cytotoxic and genotoxic conditions. We furthermore measured the intrinsic antioxidant activity of kinetin in a cell-free system using the Ferric Reducing Antioxidant Power assay and in cells using the dihydroethidium staining method. Monitoring viability, we looked at kinetin effects in mammalian cells such as HL60 cells, HaCaT human keratinocyte cells, NRK rat epithelial kidney cells and human peripheral lymphocytes. Kinetin manifests no antioxidant activity in the cell free system and high doses of kinetin (500 nM and higher) reduce cell viability and mediate DNA damage in vitro. In contrast, low doses (concentrations up to 100 nM) of kinetin confer protection in cells against oxidative stress. Moreover, our results show that pretreatment of the cells with kinetin significantly reduces 4-nitroquinoline 1-oxide mediated reactive oxygen species production. Also, pretreatment with kinetin retains cellular GSH levels when they are also treated with the GSH-depleting agent patulin. Our results explicitly show that low kinetin doses reduce apoptosis and protect cells from oxidative stress mediated cell death. Future studies on the interaction between cytokinins and human cellular pathway targets will be intriguing. PMID- 28005920 TI - Fortified Snack Reduced Anemia in Rural School-Aged Children of Haiti: A Cluster Randomized, Controlled Trial. AB - BACKGROUND: Nutrition in the school-aged child matters for brain development and public policy investments globally. Our group previously conducted a trial in urban schools of Haiti to examine the effects of a fortified peanut butter snack, Vita Mamba, with limited findings for anemia. OBJECTIVE: We aimed to test the hypothesis that Vita Mamba, with systematic deworming in both study arms, would significantly reduce anemia among rural, school-aged children. METHODS: A cluster, randomized longitudinal study was conducted in two rural communities of the North-East Department of Haiti, 2014-2015. Healthy children ages 3-16 years were enrolled (n = 321) and assigned by school to intervention (Vita Mamba and deworming) and control (deworming). Vita Mamba contains 260 kcal and meets >75% of the Recommended Dietary Allowance for critical micronutrients. Multivariate regression analyses including propensity score matching techniques to correct for potential group imbalance (Kernel-based Matching and Propensity Score Weighting) were applied to examine difference-in-difference intervention effects. RESULTS: At baseline, 51% of the children were anemic with no significant differences between study groups. Vita Mamba supplementation showed a consistent, positive effect across regression models on increasing Hb concentration and reducing the odds of anemia compared to the control group after adjusting for child age, vitamin A supplementation, milk consumption, and height-for-age z score. The average treatment effect for the treated in the Propensity Score Weighting models was 0.62+/-0.27 grams per 100 milliliters (g/dL) for Hb concentration (F = 4.64, P = 0.001), and the odds of anemia were reduced by 88% (Wald chi2 = 9.77, P = 0.02). No differences in change in anthropometric markers were evident. CONCLUSIONS: School feeding programs that integrate fortified foods with deworming could reduce anemia burden with important implications for learning, health, and well-being. The rural-urban differences in anemia require further study. PMID- 28005921 TI - Association of Functional Impairments and Co-Morbid Conditions with Driving Performance among Cognitively Normal Older Adults. AB - OBJECTIVES: To examine the relationship between key functional impairments, co morbid conditions and driving performance in a sample of cognitively normal older adults. DESIGN: Prospective observational study. SETTING: The Knight Alzheimer's Disease Research Center, Washington University at St. Louis. PARTICIPANTS: Individuals with normal cognition, 64.9 to 88.2 years old (N = 129), with a valid driver's license, who were currently driving at least once per week, and who had participated in longitudinal studies at the Knight Alzheimer's Disease Research Center. MEASUREMENTS: Static visual acuity, contrast sensitivity, physical frailty measures, motor skills, total medical conditions, and the modified Washington University Road Test. RESULTS: When controlling for age, race, gender, APOE, and education the total number of medical conditions was unassociated with both road test scores (pass vs. marginal + fail) and the total driver error count. There were marginal associations of our measure of physical frailty (p = 0.06) and contrast sensitivity score (p = 0.06) with total driving error count. CONCLUSION: Future research that focuses on older adults and driving should consider adopting measures of physical frailty and contrast sensitivity, especially in samples that may have a propensity for disease impacting visual and/or physical function (e.g. osteoarthritis, Parkinson's, eye disorders, advanced age >80 years, etc.). PMID- 28005922 TI - A Study of Memory Effects in a Chess Database. AB - A series of recent works studying a database of chronologically sorted chess games-containing 1.4 million games played by humans between 1998 and 2007- have shown that the popularity distribution of chess game-lines follows a Zipf's law, and that time series inferred from the sequences of those game-lines exhibit long range memory effects. The presence of Zipf's law together with long-range memory effects was observed in several systems, however, the simultaneous emergence of these two phenomena were always studied separately up to now. In this work, by making use of a variant of the Yule-Simon preferential growth model, introduced by Cattuto et al., we provide an explanation for the simultaneous emergence of Zipf's law and long-range correlations memory effects in a chess database. We find that Cattuto's Model (CM) is able to reproduce both, Zipf's law and the long range correlations, including size-dependent scaling of the Hurst exponent for the corresponding time series. CM allows an explanation for the simultaneous emergence of these two phenomena via a preferential growth dynamics, including a memory kernel, in the popularity distribution of chess game-lines. This mechanism results in an aging process in the chess game-line choice as the database grows. Moreover, we find burstiness in the activity of subsets of the most active players, although the aggregated activity of the pool of players displays inter event times without burstiness. We show that CM is not able to produce time series with bursty behavior providing evidence that burstiness is not required for the explanation of the long-range correlation effects in the chess database. Our results provide further evidence favoring the hypothesis that long-range correlations effects are a consequence of the aging of game-lines and not burstiness, and shed light on the mechanism that operates in the simultaneous emergence of Zipf's law and long-range correlations in a community of chess players. PMID- 28005923 TI - Respiration Gates Sensory Input Responses in the Mitral Cell Layer of the Olfactory Bulb. AB - Respiration plays an essential role in odor processing. Even in the absence of odors, oscillating excitatory and inhibitory activity in the olfactory bulb synchronizes with respiration, commonly resulting in a burst of action potentials in mammalian mitral/tufted cells (MTCs) during the transition from inhalation to exhalation. This excitation is followed by inhibition that quiets MTC activity in both the glomerular and granule cell layers. Odor processing is hypothesized to be modulated by and may even rely on respiration-mediated activity, yet exactly how respiration influences sensory processing by MTCs is still not well understood. By using optogenetics to stimulate discrete sensory inputs in vivo, it was possible to temporally vary the stimulus to occur at unique phases of each respiration. Single unit recordings obtained from the mitral cell layer were used to map spatiotemporal patterns of glomerular evoked responses that were unique to stimulations occurring during periods of inhalation or exhalation. Sensory evoked activity in MTCs was gated to periods outside phasic respiratory mediated firing, causing net shifts in MTC activity across the cycle. In contrast, odor evoked inhibitory responses appear to be permitted throughout the respiratory cycle. Computational models were used to further explore mechanisms of inhibition that can be activated by respiratory activity and influence MTC responses. In silico results indicate that both periglomerular and granule cell inhibition can be activated by respiration to internally gate sensory responses in the olfactory bulb. Both the respiration rate and strength of lateral connectivity influenced inhibitory mechanisms that gate sensory evoked responses. PMID- 28005924 TI - Measuring Ethnic Preferences in Bosnia and Herzegovina with Mobile Advertising. AB - We present a field experiment that uses geo-referenced smartphone advertisements to measure ethnic preferences at a highly disaggregated level. Different types of banners advertising a vote matching tool are randomly displayed to mobile Internet users in Bosnia and Herzegovina, while recording their spatial coordinates. Differences in the response (click) rate to different ethnic cues on these banners are used to measure temporal and spatial variation in ethnic preferences among the population of Bosnia and Herzegovina. Our study lays out the theoretical and practical underpinnings of this technology and discusses its potential for future applications, but also highlights limitations of this approach. PMID- 28005925 TI - Understanding the Home Math Environment and Its Role in Predicting Parent Report of Children's Math Skills. AB - There is a growing literature concerning the role of the home math environment in children's math development. In this study, we examined the relation between these constructs by specifically addressing three goals. The first goal was to identify the measurement structure of the home math environment through a series of confirmatory factor analyses. The second goal was to examine the role of the home math environment in predicting parent report of children's math skills. The third goal was to test a series of potential alternative explanations for the relation between the home math environment and parent report of children's skills, specifically the direct and indirect role of household income, parent math anxiety, and parent math ability as measured by their approximate number system performance. A final sample of 339 parents of children aged 3 through 8 drawn from Mechanical Turk answered a questionnaire online. The best fitting model of the home math environment was a bifactor model with a general factor representing the general home math environment, and three specific factors representing the direct numeracy environment, the indirect numeracy environment, and the spatial environment. When examining the association of the home math environment factors to parent report of child skills, the general home math environment factor and the spatial environment were the only significant predictors. Parents who reported doing more general math activities in the home reported having children with higher math skills, whereas parents who reported doing more spatial activities reported having children with lower math skills. PMID- 28005926 TI - The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway Related Traits: Exploring Metaphenotypes. AB - Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway-related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases. PMID- 28005928 TI - Correction: Health, Health Inequality, and Cost Impacts of Annual Increases in Tobacco Tax: Multistate Life Table Modeling in New Zealand. AB - [This corrects the article DOI: 10.1371/journal.pmed.1001856.]. PMID- 28005927 TI - Antiproliferative and Pro-Apoptotic Effects of MiR-4286 Inhibition in Melanoma Cells. AB - INTRODUCTION: MicroRNAs are essential regulators of gene expression at the post transcriptional level. Their expression is altered in cancer tissues, and evaluation of these alterations is considered a promising tool used to diagnose and identify prognostic markers. MATERIALS AND METHODS: The microRNA expression profiles of formalin-fixed, paraffin-embedded melanoma and melanocytic nevi samples were estimated with a microarray and subsequently validated by real-time PCR. Melanoma cells were transfected with miR-4286 inhibitor to evaluate the influence of this microRNA on the viability, proliferation, apoptosis, migration, and invasion of melanoma cells. RESULTS: The microarray revealed that the expression of 1,171 microRNAs was altered in melanoma samples compared to melanocytic nevi. Real-time PCR validation experiments found the microRNA expression levels to correspond to the melanoma/melanocytic nevi microarray results. The pathway analysis identified 52 modulated pathways in melanoma. Moreover, the application of miR-4286 inhibitor to BRO melanoma cells resulted in a 2.6-fold increase in the apoptosis rate and a 1.7-fold decrease in the cell proliferation/viability but did not affect the invasiveness and migration of these cells. Furthermore, the use of miR-4286 inhibitor altered the mRNA expression of several miR-4286 gene targets: folylpolyglutamate synthase, RNA polymerase I-specific transcription initiation factor, apelin, G-protein-coupled receptor 55, and high-mobility group A1 protein, which have been implicated in cell proliferation/apoptosis regulation. Lastly, the transiently transfected SK MEL-1 cells with miR-4286 inhibitor decreased proliferation rate and modulated folylpolyglutamate synthase rates of these cells. CONCLUSION: Our results demonstrate that miR-4286 mediates proliferation and apoptosis in melanoma cells, these findings may represent a novel mechanism underlying these processes. PMID- 28005929 TI - Low Dose PET Image Reconstruction with Total Variation Using Alternating Direction Method. AB - In this paper, a total variation (TV) minimization strategy is proposed to overcome the problem of sparse spatial resolution and large amounts of noise in low dose positron emission tomography (PET) imaging reconstruction. Two types of objective function were established based on two statistical models of measured PET data, least-square (LS) TV for the Gaussian distribution and Poisson-TV for the Poisson distribution. To efficiently obtain high quality reconstructed images, the alternating direction method (ADM) is used to solve these objective functions. As compared with the iterative shrinkage/thresholding (IST) based algorithms, the proposed ADM can make full use of the TV constraint and its convergence rate is faster. The performance of the proposed approach is validated through comparisons with the expectation-maximization (EM) method using synthetic and experimental biological data. In the comparisons, the results of both LS-TV and Poisson-TV are taken into consideration to find which models are more suitable for PET imaging, in particular low-dose PET. To evaluate the results quantitatively, we computed bias, variance, and the contrast recovery coefficient (CRC) and drew profiles of the reconstructed images produced by the different methods. The results show that both Poisson-TV and LS-TV can provide a high visual quality at a low dose level. The bias and variance of the proposed LS-TV and Poisson-TV methods are 20% to 74% less at all counting levels than those of the EM method. Poisson-TV gives the best performance in terms of high-accuracy reconstruction with the lowest bias and variance as compared to the ground truth (14.3% less bias and 21.9% less variance). In contrast, LS-TV gives the best performance in terms of the high contrast of the reconstruction with the highest CRC. PMID- 28005930 TI - Nanoparticle Tracking Analysis for the Enumeration and Characterization of Mineralo-Organic Nanoparticles in Feline Urine. AB - Urinary stone disease, particularly calcium oxalate, is common in both humans and cats. Calcifying nanoparticles (CNP) are spherical nanocrystallite material, and are composed of proteins (fetuin, albumin) and inorganic minerals. CNP are suggested to play a role in a wide array of pathologic mineralization syndromes including urolithiasis. We documented the development of a clinically relevant protocol to assess urinary CNP in 9 healthy cats consuming the same diet in a controlled environment using Nanoparticle Tracking Analysis (NTA(r)). NTA(r) is a novel method that allows for characterization of the CNP in an efficient, accurate method that can differentiate these particles from other urinary submicron particulates. The predominant nanoscale particles in feline urine are characteristic of CNP in terms of their size, their ability to spontaneously form under suitable conditions, and the presence of an outer layer that is rich in calcium and capable of binding to hydroxyapatite binders such as alendronate and osteopontin. The expansion of this particle population can be suppressed by the addition of citrate to urine samples. Further, compounds targeting exosomal surfaces do not label these particulates. As CNP have been associated with a number of significant urologic maladies, the method described herein may prove to be a useful adjunct in evaluating lithogenesis risk in mammals. PMID- 28005931 TI - Far from Naturalness: How Much Does Spatial Ecological Structure of European Tree Assemblages Depart from Potential Natural Vegetation? AB - Contemporaneous plant communities may retain a mark of past disturbances in their ecological patterns. However, unraveling the history of disturbance on natural systems at a large scale is often unfeasible, due to the complexity of the factors involved and lack of historical data. Here we aim at demonstrating how comparing observed spatial structure of tree assemblages with that expected in a hypothetical, undisturbed scenario can shed light on how natural European forests are. Borrowing an analytical approach developed in the field of network analysis, we assessed how much the observed ecological patterns of nestedness (i.e. positive co-occurrence), segregation (i.e. negative co-occurrence), and modularity in tree assemblages deviate from randomness, and from those projected by Potential Natural Vegetation (PNV) geobotanical expert assessments. We found clear evidence that European forests are far from a natural condition, showing only moderate signals (especially at higher latitudes) of the ecological spatial structure typical of undisturbed vegetation (i.e. nestedness). Our results highlight how taking into account spatial structure along with diversity can be a fundamental tool to address this problem and assess the degree of naturalness in species assemblages. PMID- 28005932 TI - The Use of Procalcitonin (PCT) for Diagnosis of Sepsis in Burn Patients: A Meta Analysis. AB - The continuous development of resuscitation techniques and intensive care reduced the mortality rate induced by the initial shock in burn patients and, currently, infections (especially sepsis) are the main causes of mortality of these patients. The misuse of antimicrobial agents is strongly related to antimicrobial and adverse patient outcomes, development of microbial resistance and increased healthcare-related costs. To overcome these risks, antimicrobial stewardship is mandatory and biomarkers are useful to avoid unnecessary medical prescription, to monitor antimicrobial therapy and to support the decision of its stop. Among a large array of laboratory tests, procalcitonin (PCT) emerged as the leading biomarker to accurately and time-effectively indicate the presence of systemic infection. In the presence of systemic infection, PCT blood levels undergo a sudden and dramatic increase, following the course of the infection, and quickly subside after the control of the septic process. This work is a meta-analysis on PCT performance as a biomarker for sepsis. This meta-analysis showed that overall pooled area under the curve (AUC) is 0.83 (95% CI = 0.76 to 0.90); the estimated cut-off is 1.47 ng/mL. The overall sepsis effect in PCT levels is significant and strong (Cohen's d is 2.1 and 95% CI = 1.1 to 3.2). This meta-analysis showed PCT may be considered as a biomarker with a strong diagnostic ability to discriminate between the septic from the non-septic burn patients. Thus, this work encourages the determination of PCT levels in clinical practice for the management of these patients, in order to timely identify the susceptibility to sepsis and to initiate the antimicrobial therapy, improving the patients' outcomes. PMID- 28005933 TI - Differential Regulation of rRNA and tRNA Transcription from the rRNA-tRNA Composite Operon in Escherichia coli. AB - Escherichia coli contains seven rRNA operons, each consisting of the genes for three rRNAs (16S, 23S and 5S rRNA in this order) and one or two tRNA genes in the spacer between 16S and 23S rRNA genes and one or two tRNA genes in the 3' proximal region. All of these rRNA and tRNA genes are transcribed from two promoters, P1 and P2, into single large precursors that are afterward processed to individual rRNAs and tRNAs by a set of RNases. In the course of Genomic SELEX screening of promoters recognized by RNA polymerase (RNAP) holoenzyme containing RpoD sigma, a strong binding site was identified within 16S rRNA gene in each of all seven rRNA operons. The binding in vitro of RNAP RpoD holoenzyme to an internal promoter, referred to the promoter of riRNA (an internal RNA of the rRNA operon), within each 16S rRNA gene was confirmed by gel shift assay and AFM observation. Using this riRNA promoter within the rrnD operon as a representative, transcription in vitro was detected with use of the purified RpoD holoenzyme, confirming the presence of a constitutive promoter in this region. LacZ reporter assay indicated that this riRNA promoter is functional in vivo. The location of riRNA promoter in vivo as identified using a set of reporter plasmids agrees well with that identified in vitro. Based on transcription profile in vitro and Northern blot analysis in vivo, the majority of transcript initiated from this riRNA promoter was estimated to terminate near the beginning of 23S rRNA gene, indicating that riRNA leads to produce the spacer-coded tRNA. Under starved conditions, transcription of the rRNA operon is markedly repressed to reduce the intracellular level of ribosomes, but the levels of both riRNA and its processed tRNAGlu stayed unaffected, implying that riRNA plays a role in the continued steady-state synthesis of tRNAs from the spacers of rRNA operons. We then propose that the tRNA genes organized within the spacers of rRNA-tRNA composite operons are expressed independent of rRNA synthesis under specific conditions where further synthesis of ribosomes is not needed. PMID- 28005934 TI - Obstetrical Complications in Women with Endometriosis: A Cohort Study in Japan. AB - BACKGROUND: Endometriosis, which occurs in approximately 10% of women of reproductive age, is defined as the presence of endometrial tissue outside the uterus. Women with endometriosis are more likely to have difficulty conceiving and tend to receive infertility treatment, including assisted reproductive technology (ART) therapy. There has not yet been a prospective cohort study examining the effects of endometriosis on pregnancy outcome in pregnant Japanese women. METHODOLOGY: This was a prospective cohort study of the incidence of obstetrical complications in women with endometriosis using data of the Japan Environment & Children's Study (JECS). Included in this study were 9,186 pregnant women in the JECS with or without a history of endometriosis who gave birth or stillbirth or whose pregnancy was terminated with abortion between February and December 2011. MAIN OUTCOME MEASURES: The effects of endometriosis on pregnancy outcome. RESULTS: Of the 9,186 pregnant women in the JECS, 4,119 (44.8%) had obstetrical complications; 330 participants reported a diagnosis of endometriosis before pregnancy, and these women were at higher risk for complications of pregnancy than those without a history of endometriosis (odds ratio (OR) = 1.50; 95% confidence interval (CI) 1.20 to 1.87). Logistic regression analyses showed that the adjusted OR for obstetrical complications of pregnant women who conceived naturally and had a history of endometriosis was 1.45 (CI 1.11 to 1.90). Among pregnant women with endometriosis, the ORs of preterm premature rupture of the membranes (PROM) and placenta previa were significantly higher compared with women never diagnosed with endometriosis who conceived naturally or conceived after infertility treatment, except for ART therapy (OR 2.14, CI 1.03 4.45 and OR 3.37, CI 1.32-8.65). CONCLUSIONS: This study showed that endometriosis significantly increased the incidence of preterm PROM and placenta previa after adjusting for confounding of the data by ART therapy. PMID- 28005935 TI - A Biomechanical Stability Study of Extraforaminal Lumbar Interbody Fusion on the Cadaveric Lumbar Spine Specimens. AB - BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) is an effective surgery for lumbar degenerative disease. However, this fusion technique requires resection of inferior facet joint to provide access for superior facet joint resection, which results in reduced lumbar spinal stability and unnecessary trauma. We have previously developed extraforaminal lumbar interbody fusion (ELIF) that can avoid back muscle injury with direct nerve root decompression. This study aims to show that ELIF enhances lumbar spinal stability in comparison to TLIF by comparing lumbar spinal stability of L4-L5 range of motion (ROM) on 12 cadaveric spine specimens after performing TLIF or ELIF. METHODS: 12 cadaveric spine specimens were randomly divided and treated in accordance with the different internal fixations, including ELIF with a unilateral pedicle screw (ELIF+UPS), TLIF with a unilateral pedicle screw (TLIF+UPS), TLIF with a bilateral pedicle screw (TLIF+BPS), ELIF with a unilateral pedicle screw and translaminar facet screw (ELIF+UPS+TLFS) and ELIF with a bilateral pedicle screw (ELIF+BPS). The treatment groups were exposed to a 400-N load and 6 N.m movement force to calculate the angular displacement of L4-L5 during anterior flexion, posterior extension, lateral flexion and rotation operation conditions. RESULTS: The ROM in ELIF+UPS group was smaller than that of TLIF+UPS group under all operating conditions, with the significant differences in left lateral flexion and right rotation by 36.15% and 25.97% respectively. The ROM in ELIF+UPS group was higher than that in TLIF+BPS group. The ROM in the ELIF+UPS+TLFS group was much smaller than that in the ELIF+UPS group, but was not significantly different than that in the TLIF+BPS group. CONCLUSIONS: Despite that TLIF+BPS has great stability, which can be comparable by that of ELIF+UPS. Additionally, ELIF stability can be further improved by using translaminar facet screws without causing more tissue damage to patient. PMID- 28005936 TI - Prevalence and Genetic Diversity of Avipoxvirus in House Sparrows in Spain. AB - Avipoxvirus (APV) is a fairly common virus affecting birds that causes morbidity and mortality in wild and captive birds. We studied the prevalence of pox-like lesions and genetic diversity of APV in house sparrows (Passer domesticus) in natural, agricultural and urban areas in southern Spain in 2013 and 2014 and in central Spain for 8 months (2012-2013). Overall, 3.2% of 2,341 house sparrows visually examined in southern Spain had cutaneous lesions consistent with avian pox. A similar prevalence (3%) was found in 338 birds from central Spain. Prevalence was higher in hatch-year birds than in adults. We did not detect any clear spatial or temporal patterns of APV distribution. Molecular analyses of poxvirus-like lesions revealed that 63% of the samples were positive. Molecular and phylogenetic analyses of 29 DNA sequences from the fpv167 gene, detected two strains belonging to the canarypox clade (subclades B1 and B2) previously found in Spain. One of them appears predominant in Iberia and North Africa and shares 70% similarity to fowlpox and canarypox virus. This APV strain has been identified in a limited number of species in the Iberian Peninsula, Morocco and Hungary. The second one has a global distribution and has been found in numerous wild bird species around the world. To our knowledge, this represents the largest study of avian poxvirus disease in the broadly distributed house sparrow and strongly supports the findings that Avipox prevalence in this species in South and central Spain is moderate and the genetic diversity low. PMID- 28005937 TI - Impact of Socioeconomic Inequality on Access, Adherence, and Outcomes of Antiretroviral Treatment Services for People Living with HIV/AIDS in Vietnam. AB - BACKGROUND: Ensuring an equal benefit across different patient groups is necessary while scaling up free-of-charge antiretroviral treatment (ART) services. This study aimed to measure the disparity in access, adherence, and outcomes of ART in Vietnam and the effects of socioeconomic status (SES) characteristics on the levels of inequality. METHODS: A cross-sectional study was conducted in 1133 PLWH in Vietnam. ART access, adherence, and treatment outcomes were self-reported using a structured questionnaire. Wealth-related inequality was calculated using a concentration index, and a decomposition analysis was used to determine the contribution of each SES variable to inequality in access, adherence, and outcomes of ART. RESULTS: Based on SES, minor inequality was found in ART access and adherence while there was considerable inequality in ART outcomes. Poor people were more likely to start treatment early, while rich people had better adherence and overall treatment outcomes. Decomposition revealed that occupation and education played important roles in inequality in ART access, adherence, and treatment outcomes. CONCLUSION: The findings suggested that health services should be integrated into the ART regimen. Furthermore, occupational orientation and training courses should be provided to reduce inequality in ART access, adherence, and treatment outcomes. PMID- 28005938 TI - Perceptions and Impact of Mandatory eLearning for Foundation Trainee Doctors: A Qualitative Evaluation. AB - BACKGROUND: Junior doctors in the UK must complete various educational components during their two year Foundation training programme. It is important that mandatory learning is informative and engaging. The aim of this study was to evaluate trainee doctors' perceptions of a Technology Enhanced Learning (TEL) programme developed to improve prescribing competency. METHOD: Focus groups and interviews were conducted at three hospital sites in the West Midlands. Codes, sub-themes and themes were determined using deductive and inductive thematic analysis. RESULTS: Data were collected from 38 Foundation trainee doctors. Results revealed major themes relating to prescribing education, the user experience and user engagement. Key findings included the positive impact of preparedness following undergraduate education on the user experience of the TEL programme at the postgraduate level; the impact of content, structure, and individual learning needs and styles on the user experience; and the impact of motivation and time on engagement. Most trainees engaged with the programme owing to its mandatory nature; however, some trainees also used the programme voluntarily, for example, to acquire knowledge prior to starting a new placement. CONCLUSIONS: It is important to ensure that learners are willing to engage with mandatory TEL, and that they have the time and motivation to do so. It is also important to ensure that learners have a positive user experience and that in designing TEL individual differences in learning styles and needs are taken into account. These findings have implications for educators and system developers in the construction and design of mandatory eLearning programmes. PMID- 28005940 TI - Will the Displacement of Zebra Mussels by Quagga Mussels Increase Water Clarity in Shallow Lakes during Summer? Results from a Mesocosm Experiment. AB - Zebra mussels (Dreissena polymorpha) are known to increase water clarity and affect ecosystem processes in invaded lakes. During the last decade, the conspecific quagga mussels (D. rostriformis bugensis) have displaced zebra mussels in many ecosystems including shallow lakes such as Oneida Lake, New York. In this study, an eight-week mesocosm experiment was conducted to test the hypothesis that the displacement of zebra mussels by quagga mussels leads to further decreases in phytoplankton and increases in water clarity resulting in increases in benthic algae. We found that the presence of zebra mussels alone (ZM), quagga mussels alone (QM), or an equal number of both species (ZQ) reduced total phosphorus (TP) and phytoplankton Chl a. Total suspended solids (TSS) was reduced in ZM and ZQ treatments. Light intensity at the sediment surface was higher in all three mussel treatments than in the no-mussel controls but there was no difference among the mussel treatments. There was no increase in benthic algae biomass in the mussel treatments compared with the no-mussel controls. Importantly, there was no significant difference in nutrient (TP, soluble reactive phosphorus and NO3-) levels, TSS, phytoplankton Chl a, benthic algal Chl a, or light intensity on the sediment surface between ZM, QM and ZQ treatments. These results confirm the strong effect of both mussel species on water clarity and indicate that the displacement of zebra mussel by an equivalent biomass of quagga mussel is not likely to lead to further increases in water clarity, at least for the limnological conditions, including summer temperature, tested in this experiment. PMID- 28005939 TI - Muscle Arnt/Hif1beta Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity. AB - Aryl Hydrocarbon Receptor Nuclear Translocator/ hypoxia-inducible factor 1 beta (ARNT/ HIF1beta), a member of bHLH-PAS family of transcriptional factors, plays a critical role in metabolic homeostasis, insulin resistance and glucose intolerance. The contributions of ARNT in pancreas, liver and adipose tissue to energy balance through gene regulation have been described. Surprisingly, the impact of ARNT signaling in the skeletal muscles, one of the major organs involved in glucose disposal, has not been investigated, especially in type II diabetes. Here we report that ARNT is expressed in the skeletal muscles, particularly in the energy-efficient oxidative slow-twitch myofibers, which are characterized by increased oxidative capacity, mitochondrial content, vascular supply and insulin sensitivity. However, muscle-specific deletion of ARNT did not change myofiber type distribution, oxidative capacity, mitochondrial content, capillarity, or the expression of genes associated with these features. Consequently, the lack of ARNT in the skeletal muscle did not affect weight gain, lean/fat mass, insulin sensitivity and glucose tolerance in lean mice, nor did it impact insulin resistance and glucose intolerance in high fat diet-induced obesity. Therefore, skeletal muscle ARNT is dispensable for controlling muscle fiber type and metabolic regulation, as well as diet-induced weight control, insulin sensitivity and glucose tolerance. PMID- 28005941 TI - Norlichexanthone Reduces Virulence Gene Expression and Biofilm Formation in Staphylococcus aureus. AB - Staphylococcus aureus is a serious human pathogen and antibiotic resistant, community-associated strains, such as the methicillin resistant S. aureus (MRSA) strain USA300, continue to spread. To avoid resistance, anti-virulence therapy has been proposed where toxicity is targeted rather than viability. Previously we have shown that norlichexanthone, a small non-reduced tricyclic polyketide produced by fungi and lichens, reduces expression of hla encoding alpha-hemolysin as well as the regulatory RNAIII of the agr quorum sensing system in S. aureus 8325-4. The aim of the present study was to further characterise the mode of action of norlichexanthone and its effect on biofilm formation. We find that norlichexanthone reduces expression of both hla and RNAIII also in strain USA300. Structurally, norlichexanthone resembles omega-hydroxyemodin that recently was shown to bind the agr two component response regulator, AgrA, which controls expression of RNAIII and the phenol soluble modulins responsible for human neutrophil killing. We show that norlichexanthone reduces S. aureus toxicity towards human neutrophils and interferes directly with AgrA binding to its DNA target. In contrast to omega-hydroxyemodin however, norlichexanthone reduces staphylococcal biofilm formation. Transcriptomic analysis revealed that genes regulated by the SaeRS two-component system are repressed by norlichexanthone when compared to untreated cells, an effect that was mitigated in strain Newman carrying a partially constitutive SaeRS system. Our data show that norlichexanthone treatment reduces expression of key virulence factors in CA-MRSA strain USA300 via AgrA binding and represses biofilm formation. PMID- 28005942 TI - Relative Contribution of Matrix Structure, Patch Resources and Management to the Local Densities of Two Large Blue Butterfly Species. AB - The type of matrix, the landscape surrounding habitat patches, may determine the distribution and function of local populations. However, the matrix is often heterogeneous, and its various components may differentially contribute to metapopulation processes at different spatial scales, a phenomenon that has rarely been investigated. The aim of this study was to estimate the relative importance of matrix composition and spatial scale, habitat quality, and management intensity on the occurrence and density of local populations of two endangered large blue butterflies: Phengaris teleius and P. nausithous. Presence and abundance data were assessed over two years, 2011-12, in 100 local patches within two heterogeneous regions (near Krakow and Tarnow, southern Poland). The matrix composition was analyzed at eight spatial scales. We observed high occupancy rates in both species, regions and years. With the exception of area and isolation, almost all of the matrix components contributed to Phengaris sp. densities. The different matrix components acted at different spatial scales (grassland cover within 4 and 3 km, field cover within 0.4 and 0.3 km and water cover within 4 km radii for P. teleius and P. nausithous, respectively) and provided the highest independent contribution to the butterfly densities. Additionally, the effects of a 0.4 km radius of forest cover and a food plant cover on P. teleius, and a 1 km radius of settlement cover and management intensity on P. nausithous densities were observed. Contrary to former studies we conclude that the matrix heterogeneity and spatial scale rather than general matrix type are of relevance for densities of butterflies. Conservation strategies for these umbrella species should concentrate on maintaining habitat quality and managing matrix composition at the most appropriate spatial scales. PMID- 28005943 TI - Interspecific Variation in Bumblebee Performance on Pollen Diet: New Insights for Mitigation Strategies. AB - Bumblebees (i.e. Bombus genus) are major pollinators of flowering wild plants and crops. Although many species are currently in decline, a number of them remain stable or are even expanding. One factor potentially driving changes in bumblebee distribution is the suitability of plant communities. Actually, bees probably have specific nutritional requirements that could shape their floral choices and constraint them in the current context of global change. However, most studies primarily focus on one bumblebee species at a time, making comparative studies scarce. Herein we performed comparative bioassays on three bumblebee species (i.e. Bombus hypnorum, B. pratorum and B. terrestris) fed on three different pollen diets with distinct nutritive content (Cistus, Erica and Salix pollen diets). Micro-colony performance was compared through different developmental and resource collection parameters for understanding the impact of change in pollen diet on different bumblebee species. The evidence suggests that B. terrestris is by far the most competitive species because of its performance compared to the other species, regardless of pollen diet. Our results also highlight a Bombus species effect as pollen diet impacts the micro-colonies in different ways according to the actual bumblebee species. Such interspecific variation in Bombus performance in response to a dietetic change underlines the importance of considering different bumblebee species in mitigation strategies. Such comparative studies are good advice for developing appropriate suites of plant species that can benefit threatened species while supporting stable or expanding ones. PMID- 28005944 TI - Ventricular Dysfunction in Patients with Acute Coronary Syndrome Undergoing Coronary Surgical Revascularization: Prognostic Impact on Long-Term Outcomes. AB - BACKGROUND: Patients with non-ST elevation acute coronary syndrome complicated by left ventricular dysfunction (LVEF) are a poor prognosis group. The aim of our study was to assess the short and long term LEVF prognostic value in a cohort of NSTE-ACS patients undergoing surgical revascularization. METHODS: We performed elective and isolated CABG on a cohort of 206 consecutive patients with LVEF<=0.40 complicating acute coronary syndrome. The case cohort was compared with a cohort of controls (LVEF>0.40) randomly selected (2:1) among patients who underwent the procedure during this period. RESULTS: The Kaplan-Meier 5-year estimated survival rates for patients in the low and normal LVEF groups were 70.8% (95% confidence interval CI: 64.2-77.4) and 81.7% (95%CI: 77.8-85.6), respectively. A low LVEF was associated with both a higher all-cause (HR [95%CI] = 1.84[1.18-2.86]) and a higher cardiovascular mortality (HR = 2.07 [1.27-3.38]) during the first 12 months of follow-up. After adjustment for potential confounders, a low LVEF remained associated with a higher cardiovascular mortality only (1.87[1.03-3.38]) during the first 12 months of follow-up. After 12 months of follow-up, a low LVEF was no more associated with all-cause, nor cardiovascular mortality. CONCLUSION: Patients with low LVEF might require more intensive care than patients with normal LVEF during the year after the surgical procedure, but once the first postoperative year over, the initial low LVEF was no more associated with long term mortality. PMID- 28005945 TI - Repetitive Elements in Mycoplasma hyopneumoniae Transcriptional Regulation. AB - Transcriptional regulation, a multiple-step process, is still poorly understood in the important pig pathogen Mycoplasma hyopneumoniae. Basic motifs like promoters and terminators have already been described, but no other cis regulatory elements have been found. DNA repeat sequences have been shown to be an interesting potential source of cis-regulatory elements. In this work, a genome-wide search for tandem and palindromic repetitive elements was performed in the intergenic regions of all coding sequences from M. hyopneumoniae strain 7448. Computational analysis demonstrated the presence of 144 tandem repeats and 1,171 palindromic elements. The DNA repeat sequences were distributed within the 5' upstream regions of 86% of transcriptional units of M. hyopneumoniae strain 7448. Comparative analysis between distinct repetitive sequences found in related mycoplasma genomes demonstrated different percentages of conservation among pathogenic and nonpathogenic strains. qPCR assays revealed differential expression among genes showing variable numbers of repetitive elements. In addition, repeats found in 206 genes already described to be differentially regulated under different culture conditions of M. hyopneumoniae strain 232 showed almost 80% conservation in relation to M. hyopneumoniae strain 7448 repeats. Altogether, these findings suggest a potential regulatory role of tandem and palindromic DNA repeats in the M. hyopneumoniae transcriptional profile. PMID- 28005946 TI - The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue-Specific Control of Metabolic Homeostasis. AB - The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial function that has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate the pore opening. We previously found that global CypD knockout mice (KO) are protected from diet-induced glucose intolerance; however, the tissue-specific function of CypD and mPTP, particularly in the control of glucose homeostasis, has not been ascertained. To this end, we performed calcium retention capacity (CRC) assay to compare the importance of CypD in the liver versus skeletal muscle. We found that liver mitochondria are more dependent on CypD for mPTP opening than skeletal muscle mitochondria. To ascertain the tissue specific role of CypD in metabolic homeostasis, we generated liver-specific and muscle-specific CypD knockout mice (LKO and MKO, respectively) and fed them either a chow diet or 45% high-fat diet (HFD) for 14 weeks. MKO mice displayed similar body weight gain and glucose intolerance compared with wild type littermates (WT), whereas LKO mice developed greater visceral obesity, glucose intolerance and pyruvate intolerance compared with WT mice. These findings demonstrate that loss of muscle CypD is not sufficient to alter whole body glucose metabolism, while the loss of liver CypD exacerbates obesity and whole body metabolic dysfunction in mice fed HFD. PMID- 28005947 TI - Metabolic Disturbances in Adult-Onset Still's Disease Evaluated Using Liquid Chromatography/Mass Spectrometry-Based Metabolomic Analysis. AB - OBJECTIVE: Liquid chromatography/mass spectrometry (LC/MS)-based comprehensive analysis of metabolic profiles with metabolomics approach has potential diagnostic and predictive implications. However, no metabolomics data have been reported in adult-onset Still's disease (AOSD). This study investigated the metabolomic profiles in AOSD patients and examined their association with clinical characteristics and disease outcome. METHODS: Serum metabolite profiles were determined on 32 AOSD patients and 30 healthy controls (HC) using ultra performance liquid chromatography (UPLC)/MS analysis, and the differentially expressed metabolites were quantified using multiple reactions monitoring (MRM)/MS analysis in 44 patients and 42 HC. Pure standards were utilized to confirm the presence of the differentially expressed metabolites. RESULTS: Eighteen differentially expressed metabolites were identified in AOSD patents using LC/MS-based analysis, of which 13 metabolites were validated by MRM/MS analysis. Among them, serum levels of lysoPC(18:2), urocanic acid and indole were significantly lower, and L-phenylalanine levels were significantly higher in AOSD patients compared with HC. Moreover, serum levels of lysoPC(18:2), PhePhe, uridine, taurine, L-threonine, and (R)-3-Hydroxy-hexadecanoic acid were significantly correlated with disease activity scores (all p<0.05) in AOSD patients. A different clustering of metabolites was associated with a different disease outcome, with significantly lower levels of isovalerylsarcosine observed in patients with chronic articular pattern (median, 77.0AU/ml) compared with monocyclic (341.5AU/ml, p<0.01) or polycyclic systemic pattern (168.0AU/ml, p<0.05). CONCLUSION: Thirteen differentially expressed metabolites identified and validated in AOSD patients were shown to be involved in five metabolic pathways. Significant associations of metabolic profiles with disease activity and outcome of AOSD suggest their involvement in AOSD pathogenesis. PMID- 28005948 TI - The Jujube Genome Provides Insights into Genome Evolution and the Domestication of Sweetness/Acidity Taste in Fruit Trees. AB - Jujube (Ziziphus jujuba Mill.) belongs to the Rhamnaceae family and is a popular fruit tree species with immense economic and nutritional value. Here, we report a draft genome of the dry jujube cultivar 'Junzao' and the genome resequencing of 31 geographically diverse accessions of cultivated and wild jujubes (Ziziphus jujuba var. spinosa). Comparative analysis revealed that the genome of 'Dongzao', a fresh jujube, was ~86.5 Mb larger than that of the 'Junzao', partially due to the recent insertions of transposable elements in the 'Dongzao' genome. We constructed eight proto-chromosomes of the common ancestor of Rhamnaceae and Rosaceae, two sister families in the order Rosales, and elucidated the evolutionary processes that have shaped the genome structures of modern jujubes. Population structure analysis revealed the complex genetic background of jujubes resulting from extensive hybridizations between jujube and its wild relatives. Notably, several key genes that control fruit organic acid metabolism and sugar content were identified in the selective sweep regions. We also identified S locus genes controlling gametophytic self-incompatibility and investigated haplotype patterns of the S locus in the jujube genomes, which would provide a guideline for parent selection for jujube crossbreeding. This study provides valuable genomic resources for jujube improvement, and offers insights into jujube genome evolution and its population structure and domestication. PMID- 28005949 TI - NETosis before and after Hyperglycemic Control in Type 2 Diabetes Mellitus Patients. AB - INTRODUCTION AND OBJECTIVE: Diabetes is characterized by chronic inflammation, endothelial dysfunction, increased risk of infections and early cardiovascular disease. By releasing neutrophil extracellular traps (NETs), neutrophils kill bacteria and exert pro-inflammatory and pro-thrombotic activities. Increased NETosis has been found in cross-sectional studies including treated type 2 diabetes mellitus (T2DM) patients. In this study, we determined whether the ability of neutrophils to form NETs differs in diabetic patients pre- and post hyperglycemic control versus healthy donors (HD), and the relationship between NETosis with pro-thrombotic, pro-inflammatory biomarkers and thrombotic clinical events. METHODS: Diabetic patients recently diagnosed and after 6 and 12 months of treatment (N = 25) and HD (N = 25) were included. NET formation was studied by microscopy and fluorometry. Nucleosomes, HNE-DNA complexes, von Willebrand factor (vWF), IL6 and TNFalpha plasma levels were measured by ELISA and P-selectin on the platelet surface was assessed by cytometry. RESULTS: Basal levels of NETs in recently diagnosed T2DM patients were higher compared to HD. While TNFalpha stimulation of control neutrophils resulted in DNA release, patient neutrophils were not responsive. Although glycemia decreased after 6 months of metformin treatment, basal and TNFalpha and PMA-stimulated NETs reached normal values after 12 months. Compared to controls, nucleosomes, HNE-DNA complexes, IL-6 and TNFalpha levels were increased in recently diagnosed patients and decreased after 12 months of treatment. P-selectin and vWF levels were similar in both populations. CONCLUSION: Our data suggest that NETs could represent a biomarker for T2DM. Increased NETosis in T2DM patients does not appear to be the consequence of impaired glycemic control but rather due to pro-inflammatory cytokines and is not related to thrombotic events. PMID- 28005950 TI - CGG Repeats in the 5'UTR of FMR1 RNA Regulate Translation of Other RNAs Localized in the Same RNA Granules. AB - CGG repeats in the 5'UTR of Fragile X Mental Retardation 1 (FMR1) RNA mediate RNA localization and translation in granules. Large expansions of CGG repeats (> 200 repeats) in FMR1, referred to as full mutations, are associated with fragile X syndrome (FXS). Smaller expansions (55-200 repeats), referred to as premutations, are associated with fragile X tremor ataxia syndrome (FXTAS) and fragile X premature ovarian insufficiency (FXPOI). TMPyP4 is a porphyrin ring compound that destabilizes CGG repeat RNA secondary structure. Here we show that exogenous CGG repeat RNA by itself, lacking the FMRP ORF, microinjected into hippocampal neurons is localized in RNA granules and inhibits translation of ARC RNA, which is localized in the same granules. TMPyP4 rescues translation of ARC RNA in granules. We also show that in human premutation fibroblasts with endogenous CGG repeat expansions in the FMR1 gene, translation of ARC RNA is inhibited and calcium homeostasis is disrupted and both phenotypes are rescued by TMPyP4. Inhibition of granule translation by expanded CGG repeats and rescue of granule translation by TMPy4, represent potential pathogenic mechanism and therapeutic strategy, respectively, for FXTAS and FXPOI. PMID- 28005951 TI - Genetic Diversity of the Critically Endangered Lake Minnow Eupallasella percnurus in Poland and Its Implications for Conservation. AB - The lake minnow (Eupallasella percnurus) is critically endangered. In this paper we characterize the genetic properties of this fish over its range of occurrence in Poland and propose the use of this knowledge in its active protection. Twelve populations of lake minnow from across its range in Poland were investigated. 13 microsatellite loci were investigated to evaluate genetic variation and distance among populations. The magnitude of the genetic bottleneck or founder effects was investigated. In the studied populations, the allelic diversity and heterozygosity showed that genetic variation in this species is low. At most loci, only 2-3 alleles per population were detected. The average number of alleles detected across all loci was 35, and ranged from 24 to 53. The average observed heterozygosity (Ho) across all investigated loci was 0.38 (range 0.21 0.59); the average expected heterozygosity (He) was 0.36 (range 0.18-0.55). The populations remained in Hardy-Weinberg equilibrium. The average Garza-Williamson M index value for all populations was low (0.47), suggesting a reduction in genetic variation due to a founder effect or a genetic bottleneck. Genetic distance among populations was high or very high (FST range: 0.20-0.64; deltaMU2 range: 1.32-16.98); this was likely a consequence of low gene flow among isolated populations, a founder effect or other genetic bottleneck, and strong genetic drift. The large genetic differences among the investigated lake minnow populations are likely to also exist among other populations of this species, and knowledge of these differences should inform active protection programs based on translocation of wild or cultivated fish of this species. The method presented here can potentially be applied to any population of lake minnows or closely related species. PMID- 28005953 TI - Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism. AB - RATIONAL: Homeostasis of vascular barriers depends upon sphingosine 1-phosphate (S1P) signaling via the S1P1 receptor. Accordingly, S1P1 competitive antagonism is known to reduce vascular barrier integrity with still unclear pathophysiological consequences. This was explored in the present study using NIBR-0213, a potent and selective S1P1 competitive antagonist. RESULTS: NIBR-0213 was tolerated at the efficacious oral dose of 30 mg/kg BID in the rat adjuvant induced arthritis (AiA) model, with no sign of labored breathing. However, it induced dose-dependent acute vascular pulmonary leakage and pleural effusion that fully resolved within 3-4 days, as evidenced by MRI monitoring. At the supra maximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (with increased breathing rate and reduced tidal volume) within the first 24 hrs. Two weeks of NIBR-0213 oral dosing at 30, 100 and 300 mg/kg QD induced moderate pulmonary changes, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, micro-hemorrhage, edema and necrosis. In addition to this picture of chronic inflammation, perivascular edema and myofiber degeneration observed in the heart were also indicative of vascular leakage and its consequences. CONCLUSIONS: Overall, these observations suggest that, in the rat, the lung is the main target organ for the S1P1 competitive antagonism-induced acute vascular leakage, which appears first as transient and asymptomatic but could lead, upon chronic dosing, to lung remodeling with functional impairments. Hence, this not only raises the question of organ specificity in the homeostasis of vascular barriers, but also provides insight into the pre-clinical evaluation of a potential safety window for S1P1 competitive antagonists as drug candidates. PMID- 28005952 TI - MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression. AB - Technological and methodological advances in multi-omics data generation and integration approaches help elucidate genetic features of complex biological traits and diseases such as prostate cancer. Due to its heterogeneity, the identification of key functional components involved in the regulation and progression of prostate cancer is a methodological challenge. In this study, we identified key regulatory interactions responsible for primary to metastasis transitions in prostate cancer using network inference approaches by integrating patient derived transcriptomic and miRomics data into gene/miRNA/transcription factor regulatory networks. One such network was derived for each of the clinical states of prostate cancer based on differentially expressed and significantly correlated gene, miRNA and TF pairs from the patient data. We identified key elements of each network using a network analysis approach and validated our results using patient survival analysis. We observed that HOXD10, BCL2 and PGR are the most important factors affected in primary prostate samples, whereas, in the metastatic state, STAT3, JUN and JUNB are playing a central role. Benefiting integrative networks our analysis suggests that some of these molecules were targeted by several overexpressed miRNAs which may have a major effect on the dysregulation of these molecules. For example, in the metastatic tumors five miRNAs (miR-671-5p, miR-665, miR-663, miR-512-3p and miR-371-5p) are mainly responsible for the dysregulation of STAT3 and hence can provide an opportunity for early detection of metastasis and development of alternative therapeutic approaches. Our findings deliver new details on key functional components in prostate cancer progression and provide opportunities for the development of alternative therapeutic approaches. PMID- 28005954 TI - Pneumovirus-Induced Lung Disease in Mice Is Independent of Neutrophil-Driven Inflammation. AB - The human pneumovirus respiratory syncytial virus (RSV) is the most common pathogen causing lower respiratory tract disease in young children worldwide. A hallmark of severe human RSV infection is the strong neutrophil recruitment to the airways and lungs. Massive neutrophil activation has been proven detrimental in numerous diseases, yet in RSV the contribution of neutrophils to disease severity, and thereby, the relevance of targeting them, is largely unknown. To determine the relevance of potential neutrophil targeting therapies, we implemented antibody-mediated neutrophil depletion in a mouse pneumonia virus of mice (PVM) model. PVM is a host specific murine pneumovirus closely related to human RSV, which reproduces many of the features of RSV infection, such as high viral replication and neutrophil recruitment. Clinical disease and markers of lung inflammation and injury were studied in PVM-infected mice treated with either depleting or isotype control antibodies. To confirm our results we performed all experiments in two mice strains: C57Bl6 and BALBc mice. Neutrophil depletion in blood and lungs was efficient throughout the disease. Remarkably, in both mouse strains we found no difference in clinical disease severity between neutrophil-depleted and control arms. In line with this observation, we found no differences between groups in histopathological lung injury and lung viral loads. In conclusion, our study shows that in mice neutrophil recruitment to the lungs does not affect disease outcome or viral clearance during severe PVM infection. As such, this model does not support the notion that neutrophils play a key role in mouse pneumovirus disease. PMID- 28005955 TI - Vegetation Productivity in Natural vs. Cultivated Systems along Water Availability Gradients in the Dry Subtropics. AB - The dry subtropics are subject to a rapid expansion of crops and pastures over vast areas of natural woodlands and savannas. In this paper, we explored the effect of this transformation on vegetation productivity (magnitude, and seasonal and long-term variability) along aridity gradients which span from semiarid to subhumid conditions, considering exclusively those areas with summer rains (>66%). Vegetation productivity was characterized with the proxy metric "Enhanced Vegetation Index" (EVI) (2000 to 2012 period), on 6186 natural and cultivated sampling points on five continents, and combined with a global climatology database by means of additive models for quantile regressions. Globally and regionally, cultivation amplified the seasonal and inter-annual variability of EVI without affecting its magnitude. Natural and cultivated systems maintained a similar and continuous increase of EVI with increasing water availability, yet achieved through contrasting ways. In natural systems, the productivity peak and the growing season length displayed concurrent steady increases with water availability, while in cultivated systems the productivity peak increased from semiarid to dry-subhumid conditions, and stabilized thereafter giving place to an increase in the growing season length towards wetter conditions. Our results help to understand and predict the ecological impacts of deforestation on vegetation productivity, a key ecosystem process linked to a broad range of services. PMID- 28005956 TI - The Intelligent Control System and Experiments for an Unmanned Wave Glider. AB - The control system designing of Unmanned Wave Glider (UWG) is challenging since the control system is weak maneuvering, large time-lag and large disturbance, which is difficult to establish accurate mathematical model. Meanwhile, to complete marine environment monitoring in long time scale and large spatial scale autonomously, UWG asks high requirements of intelligence and reliability. This paper focuses on the "Ocean Rambler" UWG. First, the intelligent control system architecture is designed based on the cerebrum basic function combination zone theory and hierarchic control method. The hardware and software designing of the embedded motion control system are mainly discussed. A motion control system based on rational behavior model of four layers is proposed. Then, combining with the line-of sight method(LOS), a self-adapting PID guidance law is proposed to compensate the steady state error in path following of UWG caused by marine environment disturbance especially current. Based on S-surface control method, an improved S-surface heading controller is proposed to solve the heading control problem of the weak maneuvering carrier under large disturbance. Finally, the simulation experiments were carried out and the UWG completed autonomous path following and marine environment monitoring in sea trials. The simulation experiments and sea trial results prove that the proposed intelligent control system, guidance law, controller have favorable control performance, and the feasibility and reliability of the designed intelligent control system of UWG are verified. PMID- 28005957 TI - The Effects of Stability and Presentation Order of Rewards on Justice Evaluations. AB - Justice research has evolved by elucidating the factors that affect justice evaluations, as well as their consequences. Unfortunately, few researchers have paid attention to the pattern of rewards over time as a predictor of justice evaluations. There are two main objectives of this research. First, it aims to test the effect of reward stability on justice evaluations. Based on justice theory and prospect theory, we assume that an under-reward at one time cannot be fully offset by an equivalent over-reward at another time. Therefore, in unstable reward systems the asymmetry of the effect of unjust rewards with opposite directions will produce a lower level of justice evaluations over time. The second objective of this research is to show the moderating effect of the presentation order (primacy vs. recency) of unstable rewards on justice evaluations. The results from a controlled experiment with five conditions, which presents the instability of rewards in different orders, confirm both the negative effect of unstable rewards and the stronger effect of primacy on justice evaluations. PMID- 28005958 TI - Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing. AB - BACKGROUND: NGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD). METHODS: A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken. RESULTS: Genetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation. CONCLUSION: The diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes. PMID- 28005959 TI - An Intranasal Proteosome-Adjuvanted Trivalent Influenza Vaccine Is Safe, Immunogenic & Efficacious in the Human Viral Influenza Challenge Model. Serum IgG & Mucosal IgA Are Important Correlates of Protection against Illness Associated with Infection. AB - INTRODUCTION: A Proteosome-adjuvanted trivalent inactivated influenza vaccine (P TIV) administered intra-nasally was shown to be safe, well tolerated and immunogenic in both systemic and mucosal compartments, and effective at preventing illness associated with evidence of influenza infection. METHODS: In two separate studies using the human viral challenge model, subjects were selected to be immunologically naive to A/Panama/2007/1999 (H3N2) virus and then dosed via nasal spray with one of three regimens of P-TIV or placebo. One or two doses, 15 MUg or 30 MUg, were given either once only or twice 14 days apart (1 x 30 MUg, 2 x 30 MUg, 2 x 15 MUg) and subjects were challenged with A/Panama/2007/1999 (H3N2) virus. Immune responses to the vaccine antigens were measured by haemagglutination inhibition assay (HAI) and nasal wash secretory IgA (sIgA) antibodies. RESULTS: Vaccine reactogenicity was mild, predictable and generally consistent with earlier Phase I studies with this vaccine. Seroconversion to A/Panama/2007/1999 (H3N2), following vaccination but prior to challenge, occurred in 57% to 77% of subjects in active dosing groups and 2% of placebo subjects. The greatest relative rise in sIgA, following vaccination but prior to challenge, was observed in groups that received 2 doses. CONCLUSION: Intranasal vaccination significantly protected against influenza (as defined by influenza symptoms combined with A/Panama seroconversion) following challenge with A/Panama/2007/1999 (H3N2). When data were pooled from both studies, efficacy ranged from 58% to 82% in active dosing groups for any influenza symptoms with seroconversion, 67% to 85% for systemic or lower respiratory illness and seroconversion, and 65% to 100% for febrile illness and seroconversion. The two dose regimen was found to be superior to the single dose regimen. In this study, protection against illness associated with evidence of influenza infection (evidence determined by seroconversion) following challenge with virus, significantly correlated with pre-challenge HAI titres (p = 0.0003) and mucosal sIgA (p<=0.0001) individually, and HAI (p = 0.028) and sIgA (p = 0.0014) together. HAI and sIgA levels were inversely related to rates of illness. TRIAL REGISTRATION: ClinicalTrials.gov NCT02522754. PMID- 28005960 TI - First-Time Migration in Juvenile Common Cuckoos Documented by Satellite Tracking. AB - Being an obligate parasite, juvenile common cuckoos Cuculus canorus are thought to reach their African wintering grounds from Palearctic breeding grounds without guidance from experienced conspecifics but this has not been documented. We used satellite tracking to study naive migrating common cuckoos. Juvenile cuckoos left breeding sites in Finland moving slowly and less consistently directed than adult cuckoos. Migration of the juveniles (N = 5) was initiated later than adults (N = 20), was directed toward the southwest-significantly different from the initial southeast direction of adults-and included strikingly long Baltic Sea crossings (N = 3). After initial migration of juvenile cuckoos toward Poland, the migration direction changed and proceeded due south, directly toward the winter grounds, as revealed by a single tag transmitting until arrival in Northwest Angola where northern adult cuckoos regularly winter. Compared to adults, the juvenile travelled straighter and faster, potentially correcting for wind drift along the route. That both migration route and timing differed from adults indicates that juvenile cuckoos are able to reach proper wintering grounds independently, guided only by their innate migration programme. PMID- 28005961 TI - Comparative Transcriptomic Study of Muscle Provides New Insights into the Growth Superiority of a Novel Grouper Hybrid. AB - Grouper (Epinephelus spp.) is a group of fish species with great economic importance in Asian countries. A novel hybrid grouper, generated by us and called the Hulong grouper (Hyb), has better growth performance than its parents, E. fuscoguttatus (Efu, ?) and E. lanceolatus (Ela, ?). We previously reported that the GH/IGF (growth hormone/insulin-like growth factor) system in the brain and liver contributed to the superior growth of the Hyb. In this study, using transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR), we analyzed RNA expression levels of comprehensive genes in the muscle of the hybrid and its parents. Our data showed that genes involved in glycolysis and calcium signaling in addition to troponins are up-regulated in the Hyb. The results suggested that the activity of the upstream GH/IGF system in the brain and liver, along with the up-regulated glycolytic genes as well as ryanodine receptors (RyRs) and troponins related to the calcium signaling pathway in muscle, led to enhanced growth in the hybrid grouper. Muscle contraction inducing growth could be the major contributor to the growth superiority in our novel hybrid grouper, which may be a common mechanism for hybrid superiority in fishes. PMID- 28005962 TI - Health-Related Factors Associated with Discrepancies between Children's Potential and Attained Secondary School Level: A Longitudinal Study. AB - OBJECTIVES: This longitudinal study examines children's health-related characteristics in relation to discrepancies between their educational potential assessed by a cognitive test in primary school at age 11 and their attained secondary school level at age 14. METHODS: Data were used from 1510 participants of the Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort. Multiple multinomial logistic regression analyses were used to estimate the associations between indicators of physical health, psychosocial health, lifestyle, sleeping patterns and stressful life events and attending a higher or lower level of secondary education than indicated by the cognitive test. RESULTS: We found no evidence that physical health contributes to discrepancies between the potential and attained level of secondary education, but attention disorders and stressful life events (nasty experiences and parents' divorce) were associated with educational attainment below children's potential level. Furthermore, substance use (alcohol, drugs and smoking) were strongly associated with attending a lower level of secondary education than expected (odds ratios from 2.2 (CI: 1.5-3.3) to 5.0 (CI: 2.8-8.7)). CONCLUSION: In this general population study, attention disorders, stressful life events and especially substance use seemed to be more important than physical health for the discrepancy between expected and attained level of secondary education. The longitudinal design of the present study and the broad range of health-related factors that were studied, adds insights to the process of health-selection. PMID- 28005963 TI - Association of Respiratory Tuberculosis with Incident Bone Fracture: Bridging the Tuberculosis Airway Infection and the Osteoporotic Bone. AB - OBJECTIVE: The relationship between respiratory tuberculosis (RT) and incident fragility fracture and osteoporosis/fragility fracture in the general population is not well determined; therefore, we conducted a nationwide cohort study to investigate this relationship. METHODS: We used the National Health Insurance Research Database of Taiwan to identify 6612 newly diagnosed patients with RT (RT cohort) and 13220 patients without RT (non-RT cohort) from 1999 to 2005. The mean durations of follow-up were (6.73 +/- 4.00 years, 8.11 +/- 3.24 years) in the (RT cohort, non- RT cohort); respectively. The occurrence of incident fragility fracture and osteoporosis/fragility fracture were followed up until the end of 2011. The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) and 98% CIs of incident fragility fracture and osteoporosis/fragility fracture were estimated using the multivariable Cox proportional hazard model after adjusting for age, sex, occupation, drug use, and comorbidities. RESULTS: A Cox proportional hazards regression analysis was performed and showed the aHRs of [incident fragility fracture; osteoporosis/fragility fracture] were [1.69 (95% CI = 1.26-2.28, 98% CI = 1.18-2.44); 1.42 (95% CI = 1.25-1.61, 98% CI = 1.21-1.65)] between the RT and non-RT cohorts. Regarding the sex, the aHRs of the [incident fragility fracture; osteoporosis / fragility fracture] were [1.57 (98% CI = 1.10 2.23, 98% CI = 1.02-2.41); 1.15 (95% CI = 0.97-1.36, 98% CI = 0.94-1.41)] in the men. The aHRs of the RT cohort without oral steroid use in the [incident fragility fracture; osteoporosis / fragility fracture] were [1.87 (95% CI = 1.20 2.90, 98% CI = 1.09-3.19); 1.41 (95% CI = 1.19-1.67, 98% CI = 1.14-1.74)]. CONCLUSION: The RT associated with the incident fragility fracture, either in men or absence of oral steroid use. PMID- 28005964 TI - The Concurrent Programming of Saccades. AB - Sequences of saccades have been shown to be prepared concurrently however it remains unclear exactly what aspects of those saccades are programmed in parallel. To examine this participants were asked to make one or two target driven saccades: a reflexive saccade; a voluntary saccade; a reflexive then a voluntary saccade; or vice versa. During the first response the position of a second target was manipulated. The new location of the second saccade target was found to impact on second saccade latencies and second saccade accuracy showing that some aspects of the second saccade program are prepared in parallel with the first. However, differences were found in the specific pattern of effects for each sequence type. These differences fit well within a general framework for saccade control in which a common priority map for saccade control is computed and the influence of saccade programs on one another depends not so much on the types of saccade being produced but rather on the rate at which their programs develop. PMID- 28005965 TI - Formaldehyde-Induced Aggravation of Pruritus and Dermatitis Is Associated with the Elevated Expression of Th1 Cytokines in a Rat Model of Atopic Dermatitis. AB - Atopic dermatitis is a complex disease of heterogeneous pathogenesis, in particular, genetic predisposition, environmental triggers, and their interactions. Indoor air pollution, increasing with urbanization, plays a role as environmental risk factor in the development of AD. However, we still lack a detailed picture of the role of air pollution in the development of the disease. Here, we examined the effect of formaldehyde (FA) exposure on the manifestation of atopic dermatitis and the underlying molecular mechanism in naive rats and in a rat model of atopic dermatitis (AD) produced by neonatal capsaicin treatment. The AD and naive rats were exposed to 0.8 ppm FA, 1.2 ppm FA, or fresh air (Air) for 6 weeks (2 hours/day and 5 days/week). So, six groups, namely the 1.2 FA-AD, 0.8 FA-AD, Air-AD, 1.2 FA-naive, 0.8 FA-naive and Air-naive groups, were established. Pruritus and dermatitis, two major symptoms of atopic dermatitis, were evaluated every week for 6 weeks. After that, samples of the blood, the skin and the thymus were collected from the 1.2 FA-AD, the Air-AD, the 1.2 FA-naive and the Air-naive groups. Serum IgE levels were quantified with ELISA, and mRNA expression levels of inflammatory cytokines from extracts of the skin and the thymus were calculated with qRT-PCR. The dermatitis and pruritus significantly worsened in 1.2 FA-AD group, but not in 0.8 FA-AD, compared to the Air-AD animals, whereas FA didn't induce any symptoms in naive rats. Consistently, the levels of serum IgE were significantly higher in 1.2 FA-AD than in air-AD, however, there was no significant difference following FA exposure in naive animals. In the skin, mRNA expression levels of Th1 cytokines such as TNF-alpha and IL-1beta were significantly higher in the 1.2 FA-AD rats compared to the air AD rats, whereas mRNA expression levels of Th2 cytokines (IL-4, IL-5, IL-13), IL 17A and TSLP were significantly higher in 1.2 FA-naive group than in the Air naive group. These results suggested that 1.2 ppm of FA penetrated the injured skin barrier, and exacerbated Th1 responses and serum IgE level in the AD rats so that dermatitis and pruritus were aggravated, while the elevated expression of Th2 cytokines by 1.2 ppm of FA in naive rats was probably insufficient for clinical manifestation. In conclusion, in a rat model of atopic dermatitis, exposure to 1.2 ppm of FA aggravated pruritus and skin inflammation, which was associated with the elevated expression of Th1 cytokines. PMID- 28005966 TI - Higher Leptin but Not Human Milk Macronutrient Concentration Distinguishes Normal Weight from Obese Mothers at 1-Month Postpartum. AB - INTRODUCTION: Exclusively breastfed infants born to obese mothers have previously been shown to gain less weight by 1-month postpartum than infants of normal weight mothers. Our hypothesis is that human milk composition and volume may differ between obese and normal-weight mothers. OBJECTIVE: To compare human milk leptin, macronutrient concentration, and volume in obese and normal-weight mothers. Mother and infant characteristics were studied as secondary aims. MATERIALS AND METHODS: This cross-sectional observational study compared 50 obese mothers matched for age, parity, ethnic origin, and educational level with 50 normal-weight mothers. Leptin, macronutrient human milk concentration, and milk volume were determined at 1 month in exclusively breastfed infants. Mother characteristics and infant growth were recorded. RESULTS: Human milk leptin concentration was higher in obese mothers than normal-weight mothers (4.8+/-2.7 vs. 2.5+/-1.5 ng.mL-1, p<0.001). No difference was observed between obese and normal-weight mothers in protein, lipid, carbohydrate content, and volume, nor in infant weight gain. CONCLUSION: Leptin concentration was higher in the milk of obese mothers than that of normal-weight mothers, but macronutrient concentration was not. It remains to be established whether the higher leptin content impacts on infant growth beyond the 1-month of the study period. PMID- 28005967 TI - Prediction of Coronary Artery Disease Extent and Severity Using Pulse Wave Velocity. AB - BACKGROUND: Pulse-wave velocity (PWV) measures aortic stiffness. It is an independent predictor of cardiovascular events and mortality, yet there is paucity in the literature on its association with the severity and extent of coronary artery disease (CAD). METHODS: To examine the utility of PWV in predicting CAD burden in men and women the PWV was determined in 344 patients (Men = 266, Women = 78) presenting for invasive coronary angiography for the assessment of suspected CAD. Pearson correlations and multivariate analysis were used to evaluate the relationship between these coronary scores, PWV and traditional cardiovascular risk factors. RESULTS: Compared to men, women with chest pain had lower mean Extent scores (19.2 vs. 35.6; p = 0.0001) and Gensini scores (23.6 vs. 41.9; p = 0.0001). PWV was similar between men and women (12.35 +/- 3.74 vs. 12.43 +/- 4.58; p = 0.88) and correlated with Extent score (r = 0.21, p = 0.0001) but not Gensini or vessel score (r = 0.03, p = 0.64 and r = 0.06, p = 0.26, respectively). PWV was associated with Extent score in men (B = 2.25 +/- 0.78, p = 0.004 for men and B = 1.50 +/- 0.88, p = 0.09 for women). It was not a predictor of Gensini score (B = -0.10, P = 0.90). CONCLUSION: PWV correlates with the extent of CAD, as measured by the 'Extent' score in men more than women. However, it does not correlate with the severity of obstructive CAD in either gender. PMID- 28005968 TI - Common SNP rs6564851 in the BCO1 Gene Affects the Circulating Levels of beta Carotene and the Daily Intake of Carotenoids in Healthy Japanese Women. AB - The circulating levels of beta-carotene are modulated not only by sex, but also by autosomal gene variations and fruit intake. The aim of this study was to investigate the interactions between beta-carotene metabolism-related gene single nucleotide polymorphisms (SNPs; genetic factors) and nutrient intake (environmental factors) relating to their effects on circulating beta-carotene. The serum concentrations of beta-carotene and the habitual food intake of 92 healthy Japanese adults were examined. All subjects were genotyped for three common SNPs: rs6564851 in the beta-carotene 15,15'-oxygenase 1 (BCO1) gene, rs2278986 in the scavenger receptor class B member 1 (SCARB1) gene and rs362090 in the intestine-specific homeobox (ISX) gene. Univariate analysis revealed that the circulating beta-carotene levels were significantly higher in rs6564851 GG homozygotes (p = 0.003). Additionally, the daily intake of beta-cryptoxanthin was positively associated with the circulating beta-carotene levels in female GG homozygotes of rs6564851 (p = 0.023), and the daily intake of alpha- and beta carotenes, and beta-cryptoxanthin was significantly lower in female rs6564851 T allele carries than in female GG homozygotes (p = 0.009, 0.008, 0.009, respectively). The present study apparently indicates that higher circulating beta-carotene levels in female rs6564851 GG homozygotes depend on carotenoid intake. PMID- 28005971 TI - The Anatomy of American Football: Evidence from 7 Years of NFL Game Data. AB - How much does a fumble affect the probability of winning an American football game? How balanced should your offense be in order to increase the probability of winning by 10%? These are questions for which the coaching staff of National Football League teams have a clear qualitative answer. Turnovers are costly; turn the ball over several times and you will certainly lose. Nevertheless, what does "several" mean? How "certain" is certainly? In this study, we collected play-by play data from the past 7 NFL seasons, i.e., 2009-2015, and we build a descriptive model for the probability of winning a game. Despite the fact that our model incorporates simple box score statistics, such as total offensive yards, number of turnovers etc., its overall cross-validation accuracy is 84%. Furthermore, we combine this descriptive model with a statistical bootstrap module to build FPM (short for Football Prediction Matchup) for predicting future match-ups. The contribution of FPM is pertinent to its simplicity and transparency, which however does not sacrifice the system's performance. In particular, our evaluations indicate that our prediction engine performs on par with the current state-of-the-art systems (e.g., ESPN's FPI and Microsoft's Cortana). The latter are typically proprietary but based on their components described publicly they are significantly more complicated than FPM. Moreover, their proprietary nature does not allow for a head-to-head comparison in terms of the core elements of the systems but it should be evident that the features incorporated in FPM are able to capture a large percentage of the observed variance in NFL games. PMID- 28005970 TI - Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer. AB - AIMS: The mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) occurring downstream in the PI3K/Akt/mTOR pathway, are regarded as potential prognostic markers for gastric cancer (GC). However, the prognostic value of mTOR/p-mTOR expression remains controversial. In this study, we determined the expression of mTOR, p-mTOR, p70S6k, and p-p70S6K in GC, and investigated the correlation between their overexpression, clinicopathological parameters, and overall survival (OS). METHODS: The expression of mTOR, p-mTOR, p70S6k, and p p70S6K was examined in 120 GC patients by immunohistochemistry (IHC). The association of protein expression with clinicopathological features and OS was explored. The p-mTOR expression was detected in normal, adjacent, and GC tissues using Western blot. Eligible studies retrieved from PubMed, Ovid, Web of Science and Cochrane databases, were reviewed in this meta-analysis. RESULTS: IHC showed that the rates of expression of the signal transduction molecules mTOR, p-mTOR, p70S6k and p-p70S6K in GC were 60.8%, 54.2%, 53.3% and 53.3%, respectively. Overexpression of mTOR and p70S6K showed no significant association with clinical variables. Expression of p-mTOR was significantly associated with differentiation (P < 0.01), depth of invasion (P < 0.01), lymph node metastasis (P = 0.04) and TNM stage (P = 0.02). Expression of p-p70S6K was associated with differentiation (P = 0.006), depth of invasion (P < 0.001), and TNM stage (P = 0.02). In survival analysis, differentiation, depth of invasion, lymph node metastasis and TNM stage were not related to OS (all P > 0.05). Furthermore, p-mTOR and p-p70S6K expression, but not mTOR and p70S6K, were tightly associated with OS of GC patients (P = 0.006 and P < 0.001, respectively). In Western blot, p-mTOR was significantly higher in GC tissues than in normal and adjacent tissues. In the present meta-analysis, mTOR overexpression showed no relationship with any clinicopathological variables. However, p-mTOR was correlated with depth of invasion, and TNM stage (all P < 0.05), and its overexpression was associated with a shorter survival time (P < 0.001). CONCLUSION: The results suggest that p mTOR is a more valuable prognostic factor than mTOR in GC. PMID- 28005969 TI - Mixed Infections of Four Viruses, the Incidence and Phylogenetic Relationships of Sweet Potato Chlorotic Fleck Virus (Betaflexiviridae) Isolates in Wild Species and Sweetpotatoes in Uganda and Evidence of Distinct Isolates in East Africa. AB - Viruses infecting wild flora may have a significant negative impact on nearby crops, and vice-versa. Only limited information is available on wild species able to host economically important viruses that infect sweetpotatoes (Ipomoea batatas). In this study, Sweet potato chlorotic fleck virus (SPCFV; Carlavirus, Betaflexiviridae) and Sweet potato chlorotic stunt virus (SPCSV; Crinivirus, Closteroviridae) were surveyed in wild plants of family Convolvulaceae (genera Astripomoea, Ipomoea, Hewittia and Lepistemon) in Uganda. Plants belonging to 26 wild species, including annuals, biannuals and perennials from four agro ecological zones, were observed for virus-like symptoms in 2004 and 2007 and sampled for virus testing. SPCFV was detected in 84 (2.9%) of 2864 plants tested from 17 species. SPCSV was detected in 66 (5.4%) of the 1224 plants from 12 species sampled in 2007. Some SPCSV-infected plants were also infected with Sweet potato feathery mottle virus (SPFMV; Potyvirus, Potyviridae; 1.3%), Sweet potato mild mottle virus (SPMMV; Ipomovirus, Potyviridae; 0.5%) or both (0.4%), but none of these three viruses were detected in SPCFV-infected plants. Co-infection of SPFMV with SPMMV was detected in 1.2% of plants sampled. Virus-like symptoms were observed in 367 wild plants (12.8%), of which 42 plants (11.4%) were negative for the viruses tested. Almost all (92.4%) the 419 sweetpotato plants sampled from fields close to the tested wild plants displayed virus-like symptoms, and 87.1% were infected with one or more of the four viruses. Phylogenetic and evolutionary analyses of the 3'-proximal genomic region of SPCFV, including the silencing suppressor (NaBP)- and coat protein (CP)-coding regions implicated strong purifying selection on the CP and NaBP, and that the SPCFV strains from East Africa are distinguishable from those from other continents. However, the strains from wild species and sweetpotato were indistinguishable, suggesting reciprocal movement of SPCFV between wild and cultivated Convolvulaceae plants in the field. PMID- 28005972 TI - Morphological and Genetic Differentiation within the Southernmost Vector of Chagas Disease: Triatoma patagonica (Hemiptera - Reduviidae). AB - The epidemiological importance of Chagas disease vectors largely depends on their spreading ability and adaptation to domestic habitats. Triatoma patagonica is a secondary vector of Chagas disease endemic of Argentina, and it has been found colonizing domiciles and most commonly peridomiciliary structures in several Argentine provinces and morphological variation along its distribution range have been described. To asses if population differentiation represents geographic variants or true biological species, multiple genetic and phenotypic approaches and laboratory cross-breeding were performed in T. patagonica peridomestic populations. Analyses of chromatic variation of forewings, their size and the content of C-heterochromatin on chromosomes revealed that populations are structured following a North-South latitudinal variation. Cytochrome c oxidase I mitochondrial gene (COI) nucleotide analysis showed a mean genetic distance of 5.2% between the most distant populations. The cross-breeding experiments suggest a partial reproductive isolation between some populations with 40% of couples not laying eggs and low hatching efficiency. Our findings reveal phenotypic and genetic variations that suggest an incipient differentiation processes among T. patagonica populations with a pronounced phenotypic and genetic divergence between the most distant populations. The population differentiation here reported is probably related to differential environmental conditions and it could reflect the occurrence of an incipient speciation process in T. patagonica. PMID- 28005973 TI - Methodological Quality Assessment of Meta-Analyses and Systematic Reviews of Probiotics in Inflammatory Bowel Disease and Pouchitis. AB - BACKGROUND: Probiotics are widely used for the induction and maintenance of remission in inflammatory bowel disease (IBD) and pouchitis. There are a large number of meta-analyses (MAs)/ systematic reviews (SRs) on this subject, the methodological quality of which has not been evaluated. OBJECTIVES: This study aimed to evaluate the methodological quality of and summarize the evidence obtained from MAs/SRs of probiotic treatments for IBD and pouchitis patients. METHODS: The PubMed, EMBASE, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases were searched to identify Chinese and English language MAs/SRs of the use of probiotics for IBD and pouchitis. The Assessment of Multiple Systematic Reviews (AMSTAR) scale was used to assess the methodological quality of the studies. RESULTS: A total of 36 MAs/SRs were evaluated. The AMSTAR scores of the included studies ranged from 1 to 10, and the average score was 5.81. According to the Canadian Agency for Drugs and Technologies in Health, 4 articles were classified as high quality, 24 articles were classified as moderate quality, and 8 articles were classified as low quality. Most of the MAs/SRs suggested that probiotics had potential benefits for patients with ulcerative colitis (UC), but failed to show effectiveness in the induction and maintenance of remission in Crohn's disease (CD). The probiotic preparation VSL#3 may play a beneficial role in pouchitis. CONCLUSION: The overall methodological quality of the current MAs/SRs in the field of probiotics for IBD and pouchitis was found to be low to moderate. More MAs/SRs of high quality are required to support using probiotics to treat IBD and pouchitis. PMID- 28005974 TI - Bibliometrics for Social Validation. AB - This paper introduces a bibliometric, citation network-based method for assessing the social validation of novel research, and applies this method to the development of high-throughput toxicology research at the US Environmental Protection Agency. Social validation refers to the acceptance of novel research methods by a relevant scientific community; it is formally independent of the technical validation of methods, and is frequently studied in history, philosophy, and social studies of science using qualitative methods. The quantitative methods introduced here find that high-throughput toxicology methods are spread throughout a large and well-connected research community, which suggests high social validation. Further assessment of social validation involving mixed qualitative and quantitative methods are discussed in the conclusion. PMID- 28005975 TI - Correction: Modeling Costs and Impacts of Introducing Early Infant Male Circumcision for Long-Term Sustainability of the Voluntary Medical Male Circumcision Program. AB - [This corrects the article DOI: 10.1371/journal.pone.0159167.]. PMID- 28005976 TI - Relationship of Transportation Noise and Annoyance for Two Metropolitan Cities in Korea: Population Based Study. AB - Transportation noise is known to have negative impact on both public health and life quality. This study evaluated the relationship between transportation noise and annoyance levels, and also the difference of annoyance levels in two metropolitan cities based on epidemiologic surveys. Two thousand adult subjects living in Seoul and Ulsan were enrolled by stratified random sampling on the basis of noise maps from July 2015 to January 2016. Individual annoyance in accordance with transportation noise levels in two metropolitan cities were surveyed using an 11-point visual analog scale questionnaire. The results show that transportation noise level was significantly correlated with annoyance in both cities. Logistic regression analysis revealed that the risk of being 'highly annoyed' increased with noise level (Ldn, day-night average sound level) in both cities. After adjusting for age, residence period, sociodemographic factors (sex, education, marriage, income, alcohol, smoking, and exercise) and noise sensitivity, the risk of being 'highly annoyed' was increased with noise levels in both cities. In comparison to those of areas with noise levels below 55 dBA, the adjusted odds ratios of 'highly annoyed' for areas with 55-65 dBA and over 65 dBA were 2.056 (95% confidence interval [CI] 1.225-3.450), 3.519 (95% CI 1.982 6.246) in Seoul and 1.022 (95% CI 0.585-1.785), 1.704 (95% CI 1.005-2.889) in Ulsan, respectively. Based on the results of a population study, we showed that transportation noise levels were significantly associated with annoyance in adults. However, there were some differences between the two cities. In this study, there were differences in transportation noise between the two cities. Seoul has complex noise (traffic and aircraft), compared to single road traffic noise in Ulsan. Therefore, single and complex transportation noise may have different effects on annoyance levels. PMID- 28005977 TI - Should the Prevalence of Incidental Thyroid Cancer Determine the Extent of Surgery in Multinodular Goiter? AB - BACKGROUND: The most appropriate surgical procedure for multinodular goiter (MNG) remains under debate. Incidental thyroid carcinoma (ITC) is often identified on histopathological examination after thyroidectomy performed for presumed benign MNG. AIM OF THE STUDY: The aim of the study was to determine the value of radical surgery for MNG patients considering the prevalence of ITC diagnosed postoperatively. MATERIALS AND METHODS: We conducted retrospective analysis of the medical records of 2,306 patients surgically treated for MNG between 2008 and 2013 at one center. None of the patients presented with any suspicion of malignancy, history of familial thyroid cancer, multiple endocrine neoplasia syndrome or previous head or neck radiation exposure. RESULTS: Among the 2,306 MNG patients, ITC was detected in 49 (2.12%) (44 women and 5 men, with average ages of 52.2 (21-79) and 55.6 (52-62), respectively). Papillary thyroid carcinoma was significantly more frequently observed than other types of ITC (p<0.00001). Among the MNG patients, 866 (37.5%) underwent total/near total surgery, 464 (20.1%) received subtotal thyroidectomy, and 701 (30.3%) received the Dunhill operation. The remaining 275 (11.9%) patients underwent a less radical procedure and were classified as "others." Among the 49 (100%) patients with ITC, 28 (57.1%) underwent radical surgery. Another 21 (42.9%) patients required completion surgery due to an insufficient primary surgical procedure. A total of 21 (2.42%) patients in the total/near total surgery group were diagnosed with ITC, as well as 16 (2.48%) in the subtotal thyroidectomy group and 12 (1.71%) in the Dunhill operation group; 21 (100%), 4 (25%) and 3 (25%) of these patients, respectively, underwent radical surgery; thus, 0 (0%), 12 (75%) and 9 (75%) required completion surgery. The prevalence rates of ITC were comparable between the radical and subtotal surgery groups (2.42% and 3.44%, respectively, p = 0.4046), and the prevalence was higher in the radical surgery group than in the Dunhill operation group (2.42% and 1.71%, respectively, p = 0.0873). A significant difference was observed between the group of patients who underwent total/near total surgery, among whom all of the patients with ITC (100%) received primary radical surgery, and the groups of patients who received the subtotal and Dunhill operations, among whom only 25% of the patients with ITC in each group received primary radical surgery (p<0.0001). CONCLUSIONS: More radical procedures for MNG result in a lower risk of reoperation for ITC. The prevalence of ITC on postoperative histopathological examination should determine the extent of surgery in MNG patients. In the future, total/near total thyroidectomy should be considered for MNG patients due to the increased prevalence of ITC to avoid the necessity for reoperation. PMID- 28005978 TI - Emergence of Exploratory, Technical and Tactical Behavior in Small-Sided Soccer Games when Manipulating the Number of Teammates and Opponents. AB - The effects that different constraints have on the exploratory behavior, measured by the variety and quantity of different responses within a game situation, is of the utmost importance for successful performance in team sports. The aim of this study was to determine how the number of teammates and opponents affects the exploratory behavior of both professional and amateur players in small-sided soccer games. Twenty-two professional (age 25.6 +/- 4.9 years) and 22 amateur (age 23.1 +/- 0.7 years) male soccer players played three small-sided game formats (4 vs. 3, 4 vs. 5, and 4 vs. 7). These trials were video-recorded and a systematic observation instrument was used to notate the actions, which were subsequently analyzed by means of a principal component analysis and the dynamic overlap order parameter (measure to identify the rate and breadth of exploratory behavior on different time scales). Results revealed that a higher the number of opponents required for more frequent ball controls. Moreover, with a higher number of teammates, there were more defensive actions focused on protecting the goal, with more players balancing. In relation to attack, an increase in the number of opponents produced a decrease in passing, driving and controlling actions, while an increase in the number of teammates led to more time being spent in attacking situations. A numerical advantage led to less exploratory behavior, an effect that was especially clear when playing within a team of seven players against four opponents. All teams showed strong effects of the number of teammates on the exploratory behavior when comparing 5 vs 7 or 3 vs 7 teammates. These results seem to be independent of the players' level. PMID- 28005979 TI - Cloning and Functional Analysis of Pax6 from the Hydrothermal Vent Tubeworm Ridgeia piscesae. AB - The paired box 6 (Pax6) gene encodes a transcription factor essential for eye development in a wide range of animal lineages. Here we describe the cloning and characterization of Pax6 gene from the blind hydrothermal vent tubeworm Ridgeia piscesae (RpPax6). The deduced RpPax6 protein shares extensive sequence identity with Pax6 proteins from other species and contains both the paired domain and a complete homeodomain. Phylogenetic analysis indicates that it clusters with the corresponding sequence from the closely related species Platynereis dumerilii (P. dumerilii) of Annelida. Luciferase reporter assay indicate that RpPax6 protein suppresses the transcription of sine oculis (so) in D. melanogaster, interfering with the C-terminal of RpPax6. Taking advantage of Drosophila model, we show that RpPax6 expression is not able to rescue small eye phenotype of ey2 mutant, only to cause a more severe headless phenotype. In addition, RpPax6 expression induced apoptosis and inhibition of apoptosis can partially rescue RpPax6-induced headless phenotype. We provide evidence RpPax6 plays at least two roles: it blocks the expression of later-acting transcription factors in the eye development cascade, and it promotes cell apoptosis. Our results indicate alternation of the Pax6 function may be one of the possible causes that lead the eye absence in vestimentiferan tubeworms. PMID- 28005981 TI - Aspartyl Proteinases of Eukaryotic Microbial Pathogens: From Eating to Heating. PMID- 28005980 TI - The Prognosis of Anti-Angiogenesis Treatments Combined with Standard Therapy for Newly Diagnosed Glioblastoma: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND AND PURPOSE: Although bevacizumab (BV) has been approved as second line therapy for recurrent glioblastoma (GB), the efficacy and safety of BV for patients with newly diagnosed GB remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched electronic databases (PubMed, EMBASE, OVID, etc.) to identify related studies published from January 1966 and August 2016. Eight randomized controlled trials including a total of 2,185 patients with GB were included. We found that the median progression-free survival (PFS) was higher in the BV group than in the standard therapy (ST) group (pooled hazard ratio, 0.73; 95%CI, 0.62-0.86; P = 0.0001). Compared with ST, BV improved the PFS rate at 6 months (OR 3.33, 95% CI 2.73-4.06, p<0.00001) and 12 months (OR 2.10, 95% CI 1.74 2.54, p<0.00001). There were no significant differences in median overall survival between the BV and ST groups (OR, 1.01; 95%CI, 0.83-1.23; P = 0.95). The BV group had higher survival rates at 6 months (OR, 1.41; 95% CI, 1.09-1.84; P = 0.01) and 12 months (OR, 1.23; 95% CI, 1.02-1.48; P = 0.03), but a low survival rate at the 36-month follow-up (OR, 0.57; 95% CI, 0.32-0.98; P = 0.04). For the incidence of adverse events, three adverse outcomes were found to be significantly different between BV and ST groups, including hypertension (8.37% vs. 1.62%, p<0.000001), proteinuria (7.65% vs. 0%, p<0.001), and fatigue (14.54% vs. 9.01%, p = 0.05). CONCLUSIONS/SIGNIFICANCE: Our study indicates that combination of BV with ST for newly diagnosed GB did not improve the median overall survival but result in longer median PFS, maintaining the quality of life and functional status. However, the long-term use of BV is associated with a higher incidence of adverse events and mortality. STUDY REGISTRATION: This research was registered at PROSPERO. (Registration Number: CRD42016038247). PMID- 28005982 TI - Depot Dependent Effects of Dexamethasone on Gene Expression in Human Omental and Abdominal Subcutaneous Adipose Tissues from Obese Women. AB - Glucocorticoids promote fat accumulation in visceral compared to subcutaneous depots, but the molecular mechanisms involved remain poorly understood. To identify long-term changes in gene expression that are differentially sensitive or responsive to glucocorticoids in these depots, paired samples of human omental (Om) and abdominal subcutaneous (Abdsc) adipose tissues obtained from obese women during elective surgery were cultured with the glucocorticoid receptor agonist dexamethasone (Dex, 0, 1, 10, 25 and 1000 nM) for 7 days. Dex regulated 32% of the 19,741 genes on the array, while 53% differed by Depot and 2.5% exhibited a Depot*Dex concentration interaction. Gene set enrichment analysis showed Dex regulation of the expected metabolic and inflammatory pathways in both depots. Cluster analysis of the 460 transcripts that exhibited an interaction of Depot and Dex concentration revealed sets of mRNAs for which the responses to Dex differed in magnitude, sensitivity or direction between the two depots as well as mRNAs that responded to Dex only in one depot. These transcripts were also clearly depot different in fresh adipose tissue and are implicated in processes that could affect adipose tissue distribution or functions (e.g. adipogenesis, triacylglycerol synthesis and storage, insulin action). Elucidation of the mechanisms underlying the depot differences in the effect of Dex on the expression of specific genes and pathways that regulate adipose function may offer novel insights into understanding the biology of visceral adipose tissues and their links to metabolic health. PMID- 28005983 TI - Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model. AB - OBJECTIVES: Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization. METHODS: We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC) MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV) and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections. RESULTS: In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement) was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement) were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology. CONCLUSION: Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development. PMID- 28005984 TI - Knowledge and Skills of Healthcare Providers in Sub-Saharan Africa and Asia before and after Competency-Based Training in Emergency Obstetric and Early Newborn Care. AB - BACKGROUND: Healthcare provider training in Emergency Obstetric and Newborn Care (EmOC&NC) is a component of 65% of intervention programs aimed at reducing maternal and newborn mortality and morbidity. It is important to evaluate the effectiveness of this. METHODS: We evaluated knowledge and skills among 5,939 healthcare providers before and after 3-5 days 'skills and drills' training in emergency obstetric and newborn care (EmOC&NC) conducted in 7 sub-Saharan Africa countries (Ghana, Kenya, Malawi, Nigeria, Sierra Leone, Tanzania, Zimbabwe) and 2 Asian countries (Bangladesh, Pakistan). Standardised assessments using multiple choice questions and objective structured clinical examination (OSCE) were used to measure change in knowledge and skills and the Improvement Ratio (IR) by cadre and by country. Linear regression was performed to identify variables associated with pre-training score and IR. RESULTS: 99.7% of healthcare providers improved their overall score with a median (IQR) increase of 10.0% (5.0% - 15.0%) for knowledge and 28.8% (23.1% - 35.1%) for skill. There were significant improvements in knowledge and skills for each cadre of healthcare provider and for each country (p<0.05). The mean IR was 56% for doctors, 50% for mid-level staff and nurse-midwives and 38% for nursing-aides. A teaching job, previous in service training, and higher percentage of work-time spent providing maternity care were each associated with a higher pre-training score. Those with more than 11 years of experience in obstetrics had the lowest scores prior to training, with mean IRs 1.4% lower than for those with no more than 2 years of experience. The largest IR was for recognition and management of obstetric haemorrhage (49 70%) and the smallest for recognition and management of obstructed labour and use of the partograph (6-15%). CONCLUSIONS: Short in-service EmOC&NC training was associated with improved knowledge and skills for all cadres of healthcare providers working in maternity wards in both sub-Saharan Africa and Asia. Additional support and training is needed for use of the partograph as a tool to monitor progress in labour. Further research is needed to assess if this is translated into improved service delivery. PMID- 28005986 TI - A Systematic Review of Cost-Effectiveness Studies Reporting Cost-per-DALY Averted. AB - INTRODUCTION: Calculating the cost per disability-adjusted life years (DALYs) averted associated with interventions is an increasing popular means of assessing the cost-effectiveness of strategies to improve population health. However, there has been no systematic attempt to characterize the literature and its evolution. METHODS: We conducted a systematic review of cost-effectiveness studies reporting cost-per-DALY averted from 2000 through 2015. We developed the Global Health Cost Effectiveness Analysis (GHCEA) Registry, a repository of English-language cost per-DALY averted studies indexed in PubMed. To identify candidate studies, we searched PubMed for articles with titles or abstracts containing the phrases "disability-adjusted" or "DALY". Two reviewers with training in health economics independently reviewed each article selected in our abstract review, gathering information using a standardized data collection form. We summarized descriptive characteristics on study methodology: e.g., intervention type, country of study, study funder, study perspective, along with methodological and reporting practices over two time periods: 2000-2009 and 2010-2015. We analyzed the types of costs included in analyses, the study quality on a scale from 1 (low) to 7 (high), and examined the correlation between diseases researched and the burden of disease in different world regions. RESULTS: We identified 479 cost-per-DALY averted studies published from 2000 through 2015. Studies from Sub-Saharan Africa comprised the largest portion of published studies. The disease areas most commonly studied were communicable, maternal, neonatal, and nutritional disorders (67%), followed by non-communicable diseases (28%). A high proportion of studies evaluated primary prevention strategies (59%). Pharmaceutical interventions were commonly assessed (32%) followed by immunizations (28%). Adherence to good practices for conducting and reporting cost-effectiveness analysis varied considerably. Studies mainly included formal healthcare sector costs. A large number of the studies in Sub-Saharan Africa addressed high-burden conditions such as HIV/AIDS, tuberculosis, neglected tropical diseases and malaria, and diarrhea, lower respiratory infections, meningitis, and other common infectious diseases. CONCLUSION: The Global Health Cost-Effectiveness Analysis Registry reveals a growing and diverse field of cost-per-DALY averted studies. However, study methods and reporting practices have varied substantially. PMID- 28005985 TI - Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-alpha. AB - Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-alpha agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-alpha in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-alpha antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-alpha agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-alpha treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-alpha treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-alpha treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin. PMID- 28005987 TI - Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration. AB - One hallmark of Alzheimer's disease are senile plaques consisting of amyloid beta (Abeta), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer's disease and both Abeta and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Abeta, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Abeta in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Abeta levels or Abeta alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Abeta levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Abeta-mediated mitochondrial toxicity. Analyzing Abeta localization revealed that intracellular levels of Abeta and an increased spatial association of APP/Abeta with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Abeta accumulation in Alzheimer's disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases. PMID- 28005988 TI - HvDep1 Is a Positive Regulator of Culm Elongation and Grain Size in Barley and Impacts Yield in an Environment-Dependent Manner. AB - Heterotrimeric G proteins are intracellular membrane-attached signal transducers involved in various cellular processes in both plants and animals. They consist of three subunits denoted as alpha, beta and gamma. The gamma-subunits of the so called AGG3 type, which comprise a transmembrane domain, are exclusively found in plants. In model species, these proteins have been shown to participate in the control of plant height, branching and seed size and could therefore impact the harvestable yield of various crop plants. Whether AGG3-type gamma-subunits influence yield in temperate cereals like barley and wheat remains unknown. Using a transgenic complementation approach, we show here that the Scottish malting barley cultivar (cv.) Golden Promise carries a loss-of-function mutation in HvDep1, an AGG3-type subunit encoding gene that positively regulates culm elongation and seed size in barley. Somewhat intriguingly, agronomic field data collected over a 12-year period reveals that the HvDep1 loss-of-function mutation in cv. Golden Promise has the potential to confer either a significant increase or decrease in harvestable yield depending on the environment. Our results confirm the role of AGG3-type subunit-encoding genes in shaping plant architecture, but interestingly also indicate that the impact HvDep1 has on yield in barley is both genotypically and environmentally sensitive. This may explain why widespread exploitation of variation in AGG3-type subunit-encoding genes has not occurred in temperate cereals while in rice the DEP1 locus is widely exploited to improve harvestable yield. PMID- 28005989 TI - Action Video Game Playing Is Reflected In Enhanced Visuomotor Performance and Increased Corticospinal Excitability. AB - Action video game playing is associated with improved visuomotor performance; however, the underlying neural mechanisms associated with this increased performance are not well understood. Using the Serial Reaction Time Task in conjunction with Transcranial Magnetic Stimulation, we investigated if improved visuomotor performance displayed in action video game players (actionVGPs) was associated with increased corticospinal plasticity in primary motor cortex (M1) compared to non-video game players (nonVGPs). Further, we assessed if actionVGPs and nonVGPs displayed differences in procedural motor learning as measured by the SRTT. We found that at the behavioral level, both the actionVGPs and nonVGPs showed evidence of procedural learning with no significant difference between groups. However, the actionVGPs displayed higher visuomotor performance as evidenced by faster reaction times in the SRTT. This observed enhancement in visuomotor performance amongst actionVGPs was associated with increased corticospinal plasticity in M1, as measured by corticospinal excitability changes pre- and post- SRTT and corticospinal excitability at rest before motor practice. Our results show that aVGPs, who are known to have better performance on visual and motor tasks, also display increased corticospinal excitability after completing a novel visuomotor task. PMID- 28005990 TI - Latent Profiles of Posttraumatic Growth and Their Relation to Differences in Resilience among Only-Child-Lost People in China. AB - AIMS: Since the early 1980s, the one-child policy has been implemented nationwide in China. A special group called the "only-child-lost family" (OCL family) has emerged and has become a social phenomenon that cannot be ignored. We report latent profiles of posttraumatic growth and their relation to differences in resilience among OCL people in China. METHODS: A total of 222 OCL people were investigated using the Posttraumatic Growth Inventory and the Connor-Davidson Resilience Scale. Latent profile analysis was applied to explore PTG latent profiles. Multinomial logistic regression was used to analyze the socio demographic variables in each latent profile and the association between profile membership and resilience. RESULTS: Three latent profiles were identified and labeled the "high appreciation-power group" (30.6%), the "general moderate growth group" (47.7%) and the "low growth and extreme possibility group" (21.7%). Compared to those in the high appreciation-power group, individuals with monthly income >2000 ($312) were less likely to be in the general moderate growth group (OR = 0.13, P<0.01), whereas individuals with a spouse were less likely to be in the low growth and extreme possibility group (OR = 0.43, P<0.01). Individuals in the "general moderate growth group"(OR = 0.92, P<0.01, 95%CI:0.89-0.94) and the "low growth and extreme possibility" groups (OR = 0.83, P<0.01, 95%CI:0.79-0.87) demonstrated significantly lower levels of resilience compared to the high appreciation-power group. CONCLUSION: The PTG patterns in only-child-lost parents were varied. Promoting resilience may be a way to foster these parents' PTG. Targeted intervention should be developed based on the characteristics of each latent class, and timely attention must be paid to the mental health of OCL parents who are without a spouse and have low income. PMID- 28005991 TI - Drug Repositioning for Alzheimer's Disease Based on Systematic 'omics' Data Mining. AB - Traditional drug development for Alzheimer's disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy is drug repositioning, redirecting existing drugs for another disease. The large amount of biological data accumulated to date warrants a comprehensive investigation to better understand AD pathogenesis and facilitate the process of anti-AD drug repositioning. Hence, we generated a list of anti-AD protein targets by analyzing the most recent publically available 'omics' data, including genomics, epigenomics, proteomics and metabolomics data. The information related to AD pathogenesis was obtained from the OMIM and PubMed databases. Drug-target data was extracted from the DrugBank and Therapeutic Target Database. We generated a list of 524 AD-related proteins, 18 of which are targets for 75 existing drugs-novel candidates for repurposing as anti-AD treatments. We developed a ranking algorithm to prioritize the anti-AD targets, which revealed CD33 and MIF as the strongest candidates with seven existing drugs. We also found 7 drugs inhibiting a known anti-AD target (acetylcholinesterase) that may be repurposed for treating the cognitive symptoms of AD. The CAD protein and 8 proteins implicated by two 'omics' approaches (ABCA7, APOE, BIN1, PICALM, CELF1, INPP5D, SPON1, and SOD3) might also be promising targets for anti-AD drug development. Our systematic 'omics' mining suggested drugs with novel anti-AD indications, including drugs modulating the immune system or reducing neuroinflammation that are particularly promising for AD intervention. Furthermore, the list of 524 AD-related proteins could be useful not only as potential anti-AD targets but also considered for AD biomarker development. PMID- 28005992 TI - Do Exogenous DNA Double-Strand Breaks Change Incomplete Synapsis and Chiasma Localization in the Grasshopper Stethophyma grossum? AB - Meiotic recombination occurs as a programmed event that initiates by the formation of DNA double-strand breaks (DSBs) that give rise to the formation of crossovers that are observed as chiasmata. Chiasmata are essential for the accurate chromosome segregation and the generation of new combinations of parental alleles. Some treatments that provoke exogenous DSBs also lead to alterations in the recombination pattern of some species in which full homologous synapsis is achieved at pachytene. We have carried out a similar approach in males of the grasshopper Stethophyma grossum, whose homologues show incomplete synapsis and proximal chiasma localization. After irradiating males with gamma rays we have studied the distribution of both the histone variant gamma-H2AX and the recombinase RAD51. These proteins are cytological markers of DSBs at early prophase I. We have inferred synaptonemal complex (SC) formation via identification of SMC3 and RAD 21 cohesin subunits. Whereas thick and thin SMC3 filaments would correspond to synapsed and unsynapsed regions, the presence of RAD21 is only restricted to synapsed regions. Results show that irradiated spermatocytes maintain restricted synapsis between homologues. However, the frequency and distribution of chiasmata in metaphase I bivalents is slightly changed and quadrivalents were also observed. These results could be related to the singular nuclear polarization displayed by the spermatocytes of this species. PMID- 28005993 TI - Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy. AB - The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles. PMID- 28005994 TI - Scaling Laws in City Growth: Setting Limitations with Self-Organizing Maps. AB - Do scaling relations always provide the means to anticipate the relationships between the size of cities, costs of maintenance, and the socio-economic benefits resulting from their growth? Scaling laws are considered a universal principle that describes the development of complex systems such as cities. It seems that regardless of their location or history, the growth of cities is associated with the super-linear or sublinear scaling of features such as the amount of space required, infrastructure, or human activities. However, the results of our research, based on grouping by Self-Organizing Maps, reveal some limitations in the application of scaling laws: the trends of urban growth behave in a different manner when we consider both a large and diverse collection of cities and a subset of cities alike. This finding complements the existing body of knowledge on the growth of cities and allows for a more accurate prediction of their future. PMID- 28005995 TI - Human Commercial Models' Eye Colour Shows Negative Frequency-Dependent Selection. AB - In this study we investigated the eye colour of human commercial models registered in the UK (400 female and 400 male) and Brazil (400 female and 400 male) to test the hypothesis that model eye colour frequency was the result of negative frequency-dependent selection. The eye colours of the models were classified as: blue, brown or intermediate. Chi-square analyses of data for countries separated by sex showed that in the United Kingdom brown eyes and intermediate colours were significantly more frequent than expected in comparison to the general United Kingdom population (P<0.001). In Brazil, the most frequent eye colour brown was significantly less frequent than expected in comparison to the general Brazilian population. These results support the hypothesis that model eye colour is the result of negative frequency-dependent selection. This could be the result of people using eye colour as a marker of genetic diversity and finding rarer eye colours more attractive because of the potential advantage more genetically diverse offspring that could result from such a choice. Eye colour may be important because in comparison to many other physical traits (e.g., hair colour) it is hard to modify, hide or disguise, and it is highly polymorphic. PMID- 28005996 TI - Correction: Factors Associated with Anemia in the Institutionalized Elderly. AB - [This corrects the article DOI: 10.1371/journal.pone.0162240.]. PMID- 28005997 TI - Lack of Ubiquitin Specific Protease 8 (USP8) Mutations in Canine Corticotroph Pituitary Adenomas. AB - PURPOSE: Cushing's disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a shared oncogenetic background. Recently, hotspot recurrent mutations in the gene encoding for ubiquitin specific protease 8 (USP8) have been identified as the main driver behind the formation of ACTH-secreting pituitary adenomas in humans. In this study, we aimed to verify whether USP8 mutations also play a role in the development of such tumours in dogs. METHODS: Presence of USP8 mutations was analysed by Sanger and PCR-cloning sequencing in 38 canine ACTH-secreting adenomas. Furthermore, the role of USP8 and EGFR protein expression was assessed by immunohistochemistry in a subset of 25 adenomas. RESULTS: None of the analysed canine ACTH-secreting adenomas presented mutations in the USP8 gene. In a subset of these adenomas, however, we observed an increased nuclear expression of USP8, a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated ACTH production in those tumours. CONCLUSIONS: Canine ACTH-secreting pituitary adenomas lack mutations in the USP8 gene suggesting a different genetic background of pituitary tumourigenesis in dogs. However, elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species. In order to establish the dog as a useful animal model for the study of CD, further comprehensive studies are needed. PMID- 28005998 TI - Establishment of a 3D In Vitro Model to Accelerate the Development of Human Therapies against Corneal Diabetes. AB - PURPOSE: To establish an in vitro model that would mirror the in vivo corneal stromal environment in diabetes (DM) patients. METHODS: Human corneal fibroblasts from Healthy (HCFs), Type 1DM (T1DM) and Type 2DM (T2DM) donors were isolated and cultured for 4 weeks with Vitamin C stimulation in order to allow for extracellular matrix (ECM) secretion and assembly. RESULTS: Our data indicated altered cellular morphology, increased cellular migration, increased ECM assembly, and severe mitochondrial damage in both T1DM and T2DMs when compared to HCFs. Furthermore, we found significant downregulation of Collagen I and Collagen V expression in both T1DM and T2DMs. Furthermore, a significant up regulation of fibrotic markers was seen, including alpha-smooth muscle actin in T2DM and Collagen III in both T1DM and T2DMs. Metabolic analysis suggested impaired Glycolysis and Tricarboxylic acid cycle (TCA) pathway. CONCLUSION: DM has significant effects on physiological and clinical aspects of the human cornea. The benefits in developing and fully characterizing our 3D in vitro model are enormous and might provide clues for the development of novel therapeutics. PMID- 28005999 TI - Characterization of Chinese Haemophilus parasuis Isolates by Traditional Serotyping and Molecular Serotyping Methods. AB - Haemophilus parasuis is classified mainly through serotyping, but traditional serotyping always yields non-typable (NT) strains and unreliable results via cross-reactions. Here, we surveyed the serotype prevalence of Chinese H. parasuis isolates using traditional serotyping (gel immuno-diffusion test, GID) and molecular serotyping (multiplex PCR, mPCR). We also investigated why discrepant results between these methods were obtained, and investigated mPCR failure through whole-genome sequencing. Of the 100 isolate tested, 73 (73%) and 93 (93%) were serotyped by the GID test and mPCR, respectively, with a concordance rate of 66% (66/100). Additionally, mPCR reduced the number of NT isolates from 27 (27%) for the GID testing, to seven (7%). Eleven isolates were sequenced, including nine serotype-discrepant isolates from mPCR and GID typing (excluding strains that were NT by GID only) and two NT isolates from both methods, and their in silico serotypes were obtained from genome sequencing based on their capsule loci. The mPCR results were supported by the in silico serotyping of the seven serotype-discrepant isolates. The discrepant results and NT isolates determined by mPCR were attributed to deletions and unknown sequences in the serotype specific region of each capsule locus. Compared with previous investigations, this study found a similar predominant serotype profile, but a different prevalence frequency for H. parasuis, and the five most prevalent serotypes or strain groups were serotypes 5, 4, NT, 7 and 13 for mPCR, and serotypes 5, NT, 4, 7 and 13/10/14 for GID. Additionally, serotype 7 was recognized as a principal serotype in this work. PMID- 28006000 TI - Glibenclamide Prevents Diabetes in NOD Mice. AB - Previous work has revealed that Cx36, the sole connexin expressed in the insulin producing beta cells, enhances the secretion of insulin, and promotes the resistance of beta cells against pro-inflammatory cytokines. In parallel, the anti-diabetic sulphonylurea glibenclamide was shown to promote the assembly and function of Cx36 channels. Here, we assessed whether glibenclamide could protect the insulin-producing cells against conditions mimicking those expected at the onset of type 1 diabetes. We found that the drug 1) protected in vitro the mouse MIN6 cells from the apoptosis and loss of Cx36, which are induced by Th1 cytokines; 2) prevented the development of hyperglycemia as well as the loss of beta cells and Cx36, which rapidly develop with aging in untreated NOD mice; 3) modified the proportion of effector CD4+ and CD8+ T cells in pancreatic draining lymph nodes. The data imply that an early glibenclamide treatment may help protecting beta cells against the autoimmune attack, which triggers the development of type 1 diabetes. PMID- 28006001 TI - Detectable Viral Load in Late Pregnancy among Women in the Rwanda Option B+ PMTCT Program: Enrollment Results from the Kabeho Study. AB - There are limited viral load (VL) data available from programs implementing "Option B+," lifelong antiretroviral treatment (ART) to all HIV-positive pregnant and postpartum women, in resource-limited settings. Extent of viral suppression from a prevention of mother-to-child transmission of HIV program in Rwanda was assessed among women enrolled in the Kigali Antiretroviral and Breastfeeding Assessment for the Elimination of HIV (Kabeho) Study. ARV drug resistance testing was conducted on women with VL>2000 copies/ml. In April 2013-January 2014, 608 pregnant or early postpartum HIV-positive women were enrolled in 14 facilities. Factors associated with detectable enrollment VL (>20 copies/ml) were examined using generalized estimating equations. The most common antiretroviral regimen (56.7%, 344/607) was tenofovir/lamivudine/efavirenz. Median ART duration was 13.5 months (IQR 3.0-48.8); 76.1% of women were on ART at first antenatal visit. Half of women (315/603) had undetectable RNA-PCR VL and 84.6% (510) had <1,000 copies/ml. Detectable VL increased among those on ART > 36 months compared to those on ART 4-36 months (72/191, 37.7% versus 56/187, 29.9%), though the difference was not significant. The odds of having detectable enrollment VL decreased significantly as duration on ART at enrollment increased (AOR = 0.99, 95% CI: 0.9857, 0.9998, p = 0.043). There was a higher likelihood of detectable VL for women with lower gravidity (AOR = 0.90, 95% CI: 0.84, 0.97, p = 0.0039), no education (AOR = 2.25, (95% CI: 1.37, 3.70, p = 0.0004), nondisclosure to partner (AOR = 1.97, 95% CI: 1.21, 3.21, p = 0.0063) and side effects (AOR = 2.63, 95% CI: 1.72, 4.03, p<0.0001). ARV drug resistance mutations were detected in all of the eleven women on ART > 36 months with genotyping available. Most women were receiving ART at first antenatal visit, with relatively high viral suppression rates. Shorter ART duration was associated with higher VL, with a concerning increasing trend for higher viremia and drug resistance among women on ART for >3 years. PMID- 28006002 TI - Unbiased RNA Shotgun Metagenomics in Social and Solitary Wild Bees Detects Associations with Eukaryote Parasites and New Viruses. AB - The diversity of eukaryote organisms and viruses associated with wild bees remains poorly characterized in contrast to the well-documented pathosphere of the western honey bee, Apis mellifera. Using a deliberate RNA shotgun metagenomic sequencing strategy in combination with a dedicated bioinformatics workflow, we identified the (micro-)organisms and viruses associated with two bumble bee hosts, Bombus terrestris and Bombus pascuorum, and two solitary bee hosts, Osmia cornuta and Andrena vaga. Ion Torrent semiconductor sequencing generated approximately 3.8 million high quality reads. The most significant eukaryote associations were two protozoan, Apicystis bombi and Crithidia bombi, and one nematode parasite Sphaerularia bombi in bumble bees. The trypanosome protozoan C. bombi was also found in the solitary bee O. cornuta. Next to the identification of three honey bee viruses Black queen cell virus, Sacbrood virus and Varroa destructor virus-1 and four plant viruses, we describe two novel RNA viruses Scaldis River bee virus (SRBV) and Ganda bee virus (GABV) based on their partial genomic sequences. The novel viruses belong to the class of negative-sense RNA viruses, SRBV is related to the order Mononegavirales whereas GABV is related to the family Bunyaviridae. The potential biological role of both viruses in bees is discussed in the context of recent advances in the field of arthropod viruses. Further, fragmentary sequence evidence for other undescribed viruses is presented, among which a nudivirus in O. cornuta and an unclassified virus related to Chronic bee paralysis virus in B. terrestris. Our findings extend the current knowledge of wild bee parasites in general and addsto the growing evidence of unexplored arthropod viruses in valuable insects. PMID- 28006003 TI - Genital Chlamydia trachomatis Infection among Women of Reproductive Age Attending the Gynecology Clinic of Hawassa University Referral Hospital, Southern Ethiopia. AB - BACKGROUND: Urogenital infection with Chlamydia trachomatis(CT) is one of the most common bacterial sexually transmitted infections (STIs) world-wide, especially in developing nations where routine laboratory diagnosis is unavailable. Little is known about the epidemiology of this infection in Ethiopia where other STIs are prevalent. This study was conducted to determine the prevalence and associated factors of CT infection among women of reproductive age. METHODS: A cross-sectional study was conducted among 322 consecutive women aged between 15-49 years at Hawassa University Referral Hospital from November 2014 to April 2015. Data on socio-demography and potential risk factors for genital infection were collected using structured questionnaires. Moreover, endocervical swabs were collected from all participants, screened for CT antigen using rapid immunochromatography assay, and cultured following the standard bacteriological method to isolate Neisseria gonorrhoeae. RESULT: In this study, the overall prevalence of CT antigen and N. gonorrhoeae infection was 61(18.9%) and 1(0.31%), respectively. Women aged 15-24 years had the highest prevalence of CT infection (24.2%), followed by those aged 25-34 years (16.8%) and those aged 35-49 years (9.6%). CTinfection was associated with women who had unprotected sex within the last six months (aOR = 3.459; 95% CI = 1.459-8.222) and were sexually active for 6-10 years (aOR = 3.076; 95% CI = 1.152-8.209). None of the clinical symptoms and diagnoses was significantly associated with CT antigen positivity. CONCLUSIONS: The high prevalence of genital CT infection in this study highlights the need for further large-scale studies on the general population. Thus, screening of women regardless of their symptoms should be in place. PMID- 28006005 TI - Rapid Assessment of Ecosystem Service Co-Benefits of Biodiversity Priority Areas in Madagascar. AB - The importance of ecosystems for supporting human well-being is increasingly recognized by both the conservation and development sectors. Our ability to conserve ecosystems that people rely on is often limited by a lack of spatially explicit data on the location and distribution of ecosystem services (ES), the benefits provided by nature to people. Thus there is a need to map ES to guide conservation investments, to ensure these co-benefits are maintained. To target conservation investments most effectively, ES assessments must be rigorous enough to support conservation planning, rapid enough to respond to decision-making timelines, and often must rely on existing data. We developed a framework for rapid spatial assessment of ES that relies on expert and stakeholder consultation, available data, and spatial analyses in order to rapidly identify sites providing multiple benefits. We applied the framework in Madagascar, a country with globally significant biodiversity and a high level of human dependence on ecosystems. Our objective was to identify the ES co-benefits of biodiversity priority areas in order to guide the investment strategy of a global conservation fund. We assessed key provisioning (fisheries, hunting and non timber forest products, and water for domestic use, agriculture, and hydropower), regulating (climate mitigation, flood risk reduction and coastal protection), and cultural (nature tourism) ES. We also conducted multi-criteria analyses to identify sites providing multiple benefits. While our approach has limitations, including the reliance on proximity-based indicators for several ES, the results were useful for targeting conservation investments by the Critical Ecosystem Partnership Fund (CEPF). Because our approach relies on available data, standardized methods for linking ES provision to ES use, and expert validation, it has the potential to quickly guide conservation planning and investment decisions in other data-poor regions. PMID- 28006004 TI - Downregulation of TGF-beta Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase. AB - Transforming growth factor-beta (TGF-beta) is a multi-functional cytokine implicated in the control of cell growth and differentiation. TGF-beta signals through a complex of TGF-beta receptors 1 and 2 (TGFbetaR1 and TGFbetaR2) that phosphorylate and activate Smad2/3 transcription factors driving transcription of the Smad-target genes. The Na+/K+-ATPase is an integral plasma membrane protein critical for maintaining the electro-chemical gradient of Na+ and K+ in the cell. We found that inhibition of the Na+/K+ ATPase by ouabain results in a dramatic decrease in the expression of TGFbetaR2 in human lung fibrobalsts (HLF) at the mRNA and protein levels. This was accompanied by inhibition of TGF-beta-induced Smad phosphorylation and the expression of TGF-beta target genes, such as fibronectin and smooth muscle alpha-actin. Inhibition of Na+/K+ ATPase by an alternative approach (removal of extracellular potassium) had a similar effect in HLF. Finally, treatment of lung alveolar epithelial cells (A549) with ouabain also resulted in the downregulation of TGFbetaR2, the inhibition of TGF-beta induced Smad phosphorylation and of the expression of mesenchymal markers, vimentin and fibronectin. Together, these data demonstrate a critical role of Na+/K+-ATPase in the control of TGFbetaR2 expression, TGF-beta signaling and cell responses to TGF-beta. PMID- 28006006 TI - The Gulf of Aden Intermediate Water Intrusion Regulates the Southern Red Sea Summer Phytoplankton Blooms. AB - Knowledge on large-scale biological processes in the southern Red Sea is relatively limited, primarily due to the scarce in situ, and satellite-derived chlorophyll-a (Chl-a) datasets. During summer, adverse atmospheric conditions in the southern Red Sea (haze and clouds) have long severely limited the retrieval of satellite ocean colour observations. Recently, a new merged ocean colour product developed by the European Space Agency (ESA)-the Ocean Color Climate Change Initiative (OC-CCI)-has substantially improved the southern Red Sea coverage of Chl-a, allowing the discovery of unexpected intense summer blooms. Here we provide the first detailed description of their spatiotemporal distribution and report the mechanisms regulating them. During summer, the monsoon-driven wind reversal modifies the circulation dynamics at the Bab-el Mandeb strait, leading to a subsurface influx of colder, fresher, nutrient-rich water from the Indian Ocean. Using satellite observations, model simulation outputs, and in situ datasets, we track the pathway of this intrusion into the extensive shallow areas and coral reef complexes along the basin's shores. We also provide statistical evidence that the subsurface intrusion plays a key role in the development of the southern Red Sea phytoplankton blooms. PMID- 28006007 TI - Improving the Diet for the Rearing of Glossina brevipalpis Newstead and Glossina austeni Newstead: Blood Source and Collection - Processing - Feeding Procedures. AB - One of the challenges to maintain tsetse fly (Diptera: Glossinidae) colonies is the sustainable supply of high quality blood meals. The effect of using anticoagulants during collection of the blood, the addition of phagostimulants to the blood meals as well as using mixtures of bovine and porcine blood in different proportions for feeding on colony productivity was assessed. Defibrinated bovine blood was found to be suitable to maintain both the Glossina brevipalpis Newstead and Glossina austeni Newstead colonies. Blood collected with the anticoagulants sodium citrate, citric sodium combination, citrate phosphate dextrose adenine and citric acid did not affect colony performance of both species. Defibrinated bovine and porcine blood in a 1:1 ratio or the feeding of either bovine or porcine blood on alternating days improved pupae production of G. austeni and can be used to enhance colony growth. Bovine blood is appropriate to maintain G. brevipalpis colonies, however, feeding either bovine or porcine blood on alternating days did improve productivity. Adding the phagostimulants inosine tri-phosphate, cytosine mono-phosphate and guanosine mono-phosphate to the blood at a concentration of 10-4 M improved pupae production of the G. brevipalpis colony. The addition of adenosine tri-phosphate and inosine tri phosphate improved the performance of the G. austeni colony. Decisions on the most suitable rearing diet and feeding protocols will not only depend on the biological requirements of the species but also on the continuous supply of a suitable blood source that can be collected and processed in a cost-effective way. PMID- 28006008 TI - Osmotic and Heat Stress Effects on Segmentation. AB - During vertebrate embryonic development, early skin, muscle, and bone progenitor populations organize into segments known as somites. Defects in this conserved process of segmentation lead to skeletal and muscular deformities, such as congenital scoliosis, a curvature of the spine caused by vertebral defects. Environmental stresses such as hypoxia or heat shock produce segmentation defects, and significantly increase the penetrance and severity of vertebral defects in genetically susceptible individuals. Here we show that a brief exposure to a high osmolarity solution causes reproducible segmentation defects in developing zebrafish (Danio rerio) embryos. Both osmotic shock and heat shock produce border defects in a dose-dependent manner, with an increase in both frequency and severity of defects. We also show that osmotic treatment has a delayed effect on somite development, similar to that observed in heat shocked embryos. Our results establish osmotic shock as an alternate experimental model for stress, affecting segmentation in a manner comparable to other known environmental stressors. The similar effects of these two distinct environmental stressors support a model in which a variety of cellular stresses act through a related response pathway that leads to disturbances in the segmentation process. PMID- 28006009 TI - Mode of Delivery and Pregnancy Outcome in Women with Congenital Heart Disease. AB - BACKGROUND: Advances in cardiac surgery and congenital cardiology have led to an increasing number of women with congenital heart disease (CHD) reaching childbearing age. In general, cardiologists recommend vaginal delivery for women with CHD to avoid complications from Caesarean section as many women with CHD tolerate vaginal delivery well. METHODS AND RESULTS: This is a single-center study comparing mode of delivery, pregnancy outcome, indications for Caesarean section and induction of labor between women with and without CHD. A historical cohort study was conducted including 116 patients with CHD. An individual threefold matching with 348 women without CHD was carried out. Caesarean section was performed in 46.6% of pregnancies with CHD (33.6% without CHD, P = 0.012). Primary Caesarean section increases with severity of CHD (P = 0.036), 33.3% of women with CHD had primary planned Caesarean section due to cardiac reasons. Induction of labor was performed in 45.7% of attempted vaginal deliveries in women with CHD (27.9% without CHD, P = 0.001). Lower mean birth weight (P = 0.004) and Small for Gestational Age (SGA) (P < 0.001) were more common in women with CHD. One CHD patient suffered from postpartum hemorrhage. CONCLUSIONS: Concerns about maternal deterioration resulting in higher rates of induction of labor seem unjustified in most cases. Along with a possible reduction of Caesarean section on maternal request, a reduction of planned vaginal delivery may be expedient in reducing the rate of Caesarean section in women with CHD. PMID- 28006010 TI - Is Adjuvant Cellular Immunotherapy Essential after TACE-Predominant Minimally Invasive Treatment for Hepatocellular Carcinoma? A Systematic Meta-Analysis of Studies Including 1774 Patients. AB - PURPOSE: Cellular immunotherapy has appeared to be a promising modality for the treatment of malignant tumor. The objective of this study was to evaluate the efficacy of cellular immunotherapy combined with minimally invasive therapy. METHODS: We searched PubMed, Web of Science and The Cochrane Library through March 2016 for relevant studies. Short-term efficacy (the disease control rate, the control rate of quality life and the AFP descent rate) and long-term efficacy (overall survival (OS) and progression-free survival (PFS) rate) were compared as the major outcome measures. The meta-analysis was performed using Review Manager 5.3. RESULTS: A total of 1174 references in 3 databases were found of which 19 individual studies with 1774 HCC patients enrolled in this meta-analysis. Meta analysis results showed that cellular immunotherapy combined with minimally invasive treatment significantly improved the measures of short-term response (the disease control rate (OR = 5.91, P = 0.007), the control rate of quality lift (OR = 3.38, P = 0.003) and the AFP descent rate (OR = 4.48, P = 0.02)). Also higher 6-month PFS (OR = 2.78, P = 0.05), >=12-month PFS (OR = 3.56, P<0.00001) rate and 6-month OS (OR = 2.81, P = 0.0009), 12-month OS (OR = 3.05, P<0.00001) and 24-month OS (OR = 3.52, P<0.0001) rate were observed in patients undergoing cellular immunotherapy. CONCLUSIONS: This meta-analysis suggested that cellular immunotherapy is a feasible adjuvant treatment that could be beneficial for the improvement of the clinical outcomes for hepatocellular carcinoma (HCC) patients after minimally invasive treatment, including short-term response and long-term survival. PMID- 28006012 TI - Potential Cost-Effectiveness of an Influenza Vaccination Program Offering Microneedle Patch for Vaccine Delivery in Children. AB - OBJECTIVE: The influenza vaccine coverage rate of children is low in Hong Kong. Microneedle patches (MNPs) is a technology under development for painless delivery of vaccines. This study aimed to examine the potential clinical outcomes and direct medical costs of an influenza program offering MNP vaccine to children who have declined intramuscular (IM) vaccine in Hong Kong. METHODS: A decision model was designed to compare potential outcomes between IM vaccine program and a program offering MNP vaccine to those declined IM vaccine (IM/MNP program) in a hypothetical cohort of children over one-year time horizon. The model outcomes included direct medical cost, influenza infection rate, mortality rate, and quality-adjusted life-years (QALYs) loss. Model inputs were retrieved from published literature. Sensitivity analyses were performed to examine the robustness of model results. RESULTS: In base-case analysis, IM/MNP program was more costly per child (USD19.13 versus USD13.69; USD1 = HKD7.8) with lower influenza infection rate (98.9 versus 124.8 per 1,000 children), hospitalization rate (0.83 versus 1.05 per 1,000 children) and influenza-related mortality rate (0.00042 versus 0.00052 per 1,000 children) when compared to IM program. The incremental cost per QALY saved (ICER) of IM/MNP program versus IM program was 27,200 USD/QALY. Using gross domestic product (GDP) per capita of Hong Kong (USD40,594) as threshold of willingness-to-pay (WTP) per QALY, one-way sensitivity analysis found ICER of IM/MNP to exceed WTP when duration of illness in outpatient setting was <5.7 days or cost per MNP vaccine was >1.39-time of IM vaccine cost. In 10,000 Monte Carlo simulations, IM/MNP program was the preferred option in 57.28% and 91.68% of the time, using 1x and 3x GDP per capita as WTP threshold, respectively. CONCLUSION: Acceptance of IM/MNP program as the preferred program was subject to the WTP threshold, duration of illness in outpatient settings, and cost of MNP vaccine. PMID- 28006011 TI - A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence. AB - Different biomolecules have been identified in bacterial pathogens that sense changes in temperature and trigger expression of virulence programs upon host entry. However, the dynamics and quantitative outcome of this response in individual cells of a population, and how this influences pathogenicity are unknown. Here, we address these questions using a thermosensing virulence regulator of an intestinal pathogen (RovA of Yersinia pseudotuberculosis) as a model. We reveal that this regulator is part of a novel thermoresponsive bistable switch, which leads to high- and low-invasive subpopulations within a narrow temperature range. The temperature range in which bistability is observed is defined by the degradation and synthesis rate of the regulator, and is further adjustable via a nutrient-responsive regulator. The thermoresponsive switch is also characterized by a hysteretic behavior in which activation and deactivation occurred on vastly different time scales. Mathematical modeling accurately mirrored the experimental behavior and predicted that the thermoresponsiveness of this sophisticated bistable switch is mainly determined by the thermo-triggered increase of RovA proteolysis. We further observed RovA ON and OFF subpopulations of Y. pseudotuberculosis in the Peyer's patches and caecum of infected mice, and that changes in the RovA ON/OFF cell ratio reduce tissue colonization and overall virulence. This points to a bet-hedging strategy in which the thermoresponsive bistable switch plays a key role in adapting the bacteria to the fluctuating conditions encountered as they pass through the host's intestinal epithelium and suggests novel strategies for the development of antimicrobial therapies. PMID- 28006013 TI - Procarcinogens - Determination and Evaluation by Yeast-Based Biosensor Transformed with Plasmids Incorporating RAD54 Reporter Construct and Cytochrome P450 Genes. AB - In Vietnam, a great number of toxic substances, including carcinogens and procarcinogens, from industrial and agricultural activities, food production, and healthcare services are daily released into the environment. In the present study, we report the development of novel yeast-based biosensor systems to determine both genotoxic carcinogens and procarcinogens by cotransformation with two plasmids. One plasmid is carrying human CPR and CYP (CYP3A4, CYP2B6, or CYP2D6) genes, while the other contains the RAD54-GFP reporter construct. The three resulting coexpression systems bearing both CPR-CYP and RAD54-GFP expression cassettes were designated as CYP3A4/CYP2B6/CYP2D6 + RAD54 systems, respectively and used to detect and evaluate the genotoxic potential of carcinogens and procarcinogens by selective activation and induction of both CPR CYP and RAD54-GFP expression cassettes in response to DNA damage. Procarcinogens were shown to be predominantly, moderately or not bioactivated by one of the CYP enzymes and thus selectively detected by the specific coexpression system. Aflatoxin B1 and benzo(a)pyrene were predominantly detected by the CYP3A4 + RAD54 system, while N-nitrosodimethylamine only moderately activated the CYP2B6 + RAD54 reporter system and none of them was identified by the CYP2D6 + RAD54 system. In contrast, the genotoxic carcinogen, methyl methanesulfonate, was detected by all systems. Our yeast-reporter system can be performed in 384-well microplates to provide efficient genotoxicity testing to identify various carcinogenic compounds and reduce chemical consumption to about 53% as compared with existing 96-well genotoxicity bioassays. In association with a liquid handling robot, this platform enables rapid, cost-effective, and high-throughput screening of numerous analytes in a fully automated and continuous manner without the need for user interaction. PMID- 28006015 TI - Skipping Selected Steps of DWT Computation in Lossless JPEG 2000 for Improved Bitrates. AB - In order to improve bitrates of lossless JPEG 2000, we propose to modify the discrete wavelet transform (DWT) by skipping selected steps of its computation. We employ a heuristic to construct the skipped steps DWT (SS-DWT) in an image adaptive way and define fixed SS-DWT variants. For a large and diverse set of images, we find that SS-DWT significantly improves bitrates of non-photographic images. From a practical standpoint, the most interesting results are obtained by applying entropy estimation of coding effects for selecting among the fixed SS DWT variants. This way we get the compression scheme that, as opposed to the general SS-DWT case, is compliant with the JPEG 2000 part 2 standard. It provides average bitrate improvement of roughly 5% for the entire test-set, whereas the overall compression time becomes only 3% greater than that of the unmodified JPEG 2000. Bitrates of photographic and non-photographic images are improved by roughly 0.5% and 14%, respectively. At a significantly increased cost of exploiting a heuristic, selecting the steps to be skipped based on the actual bitrate instead of an estimated one, and by applying reversible denoising and lifting steps to SS-DWT, we have attained greater bitrate improvements of up to about 17.5% for non-photographic images. PMID- 28006014 TI - Species Sorting of Benthic Invertebrates in a Salinity Gradient - Importance of Dispersal Limitation. AB - The relative importance of environment and dispersal related processes for community assembly has attracted great interest over recent decades, but few empirical studies from the marine/estuarine realm have examined the possible effects of these two types of factors in the same system. Importance of these processes was investigated in a hypothetical metacommunity of benthic invertebrates in 16 micro-tidal estuaries connected to the same open sea area. The estuaries differed in size and connectivity to the open sea and represented a salinity gradient across the estuaries. The Elements of Metacommunity Structure (EMS) approach on estuary scale was complemented with a mechanistic variance partitioning approach on sample scale to disentangle effects of factors affecting assembly of three trait groups of species with different dispersivity. A quasi Clementsian pattern was observed for all three traits, a likely response to some latent gradient. The primary axis in the pattern was most strongly related to gradients in estuary salinity and estuary entrance width and correlation with richness indicated nestedness only in the matrix of the most dispersive trait group. In the variance partitioning approach measures of turnover and nestedness between paired samples each from different estuaries were related to environmental distance in different gradients. Distance between estuaries was unimportant suggesting importance of factors characterizing the estuaries. While the high dispersive species mainly were sorted in the salinity gradient, apparently according to their tolerance ranges towards salinity, the two less dispersive traits were additionally affected by estuary entrance width and possibly also area. The results exemplify a mechanism of community assembly in the marine realm where the niche factor salinity in conjunction with differential dispersal structure invertebrates in a metacommunity of connected estuaries, and support the idea that dispersive species are more controlled by the environment than less dispersive species. PMID- 28006016 TI - Measuring Emotion in Parliamentary Debates with Automated Textual Analysis. AB - An impressive breadth of interdisciplinary research suggests that emotions have an influence on human behavior. Nonetheless, we still know very little about the emotional states of those actors whose daily decisions have a lasting impact on our societies: politicians in parliament. We address this question by making use of methods of natural language processing and a digitized corpus of text data spanning a century of parliamentary debates in the United Kingdom. We use this approach to examine changes in aggregate levels of emotional polarity in the British parliament, and to test a hypothesis about the emotional response of politicians to economic recessions. Our findings suggest that, contrary to popular belief, the mood of politicians has become more positive during the past decades, and that variations in emotional polarity can be predicted by the state of the national economy. PMID- 28006017 TI - Mitochondrial Biomarkers Reflect Semen Quality: Results from the MARCHS Study in Chongqing, China. AB - Unexplained infertility requires that more sensitive and mechanism-based biomarkers should be developed and used independently of or in addition to conventional semen parameters for an infertility diagnosis. In the present study, semen samples were collected from young men participating in the Male Reproductive Health in Chongqing College students (MARCHS) cohort study in the follow-up stage in 2014. Conventional semen parameters were measured in all 656 participants, whereas sperm mitochondrial membrane potential (MMP), mitochondrial DNA copy number (mtDNAcn), mtDNA integrity and apoptotic parameters were measured among 627, 386, 362, and 628 participants, respectively. We found that sperm MMP was significantly positively correlated with all of conventional semen parameters including semen volume (r = 0.090, p = 0.025), sperm concentration (r = 0.301, p<0.01), total sperm count (r = 0.324, p<0.01), and progressive motility (r = 0.399, p<0.01); sperm MMP was also negatively correlated with Annexin V+ sperm (r = -0.553, p<0.01); mtDNAcn was significantly negatively correlated with sperm concentration (r = -0.214, p<0.01), total sperm count (r = -0.232, p<0.01), and progressive motility (r = -0.164, p = 0.01); mtDNA integrity was also significantly positively correlated with sperm concentration (r = 0.195, p<0.01), total sperm count (r = 0.185, p<0.01), and progressive motility (r = 0.106, p = 0.043). After adjusting for potential confounders, these relationships remained significant. Furthermore, we explored the potential effects of lifestyles on such mitochondrial biomarkers and found that the current drinkers displayed a higher level of sperm MMP; additionally, mt DNAcn was increased with age. The results indicated that certain mitochondrial biomarkers could serve as predictors of semen quality in a general population, and the study provides a baseline for the effects of population characteristics and lifestyles on such mitochondrial markers. PMID- 28006018 TI - Potential Host Manipulation by the Aphid Parasitoid Aphidius avenae to Enhance Cold Tolerance. AB - During parasitoid development, the immature parasitoid is confined to the host species. As a result, any potential to modify the physiology or behaviour of the host could play an important role in parasitoid fitness. The potential for host manipulation by the aphid parasitoid Aphidius avenae to increase cold thermotolerance was investigated using the aphid host species Metopolophium dirhodum and Sitobion avenae. Aphids were parasitized at L3/L4 instar stage (5 d old) and allowed to develop into pre-reproductive adults (10 d old) containing a 5 d old parasitoid larva. A control group was created of non-parasitized pre reproductive adults (10 d old). The inherent physiological thermotolerance (LT50) and potential behavioural thermoregulation (behaviour in a declining temperature regime) of parasitized and non-parasitized aphids were investigated. Results revealed no effect of parasitism on the physiological thermotolerance of S. avenae and M. dirhodum. Significant differences in the behaviour of parasitized and non-parasitized aphids were observed, in addition to differences between host species, and such behaviours are discussed in view of the potential for host manipulation. PMID- 28006019 TI - Characteristics and Prognostic Impact of Pneumonitis during Systemic Anti-Cancer Therapy in Patients with Advanced Non-Small-Cell Lung Cancer. AB - BACKGROUND: Data on characteristics, outcomes, and prognosis of advanced non small-cell lung cancer (NSCLC) patients who develop pneumonitis during systemic anti-cancer therapy (pneumonitis) are currently lacking. METHODS: We conducted a retrospective cohort study of 910 consecutive patients diagnosed with advanced NSCLC between January 2004 and January 2014. Of these, 140 patients were excluded because they did not receive systemic anti-cancer therapy at this hospital. RESULTS: A total of 770 patients were included in the study, of whom 44 (6%) were diagnosed with pneumonitis. The mortality rate of pneumonitis was 36%. The incidence of pneumonitis was independently associated with pre-existing ILD (adjusted odds ratio, 2.99, P = 0.008), and survivors were significantly associated with younger age (P = 0.003) and radiographic non-acute interstitial pneumonia pattern (P = 0.004). In all patients, pneumonitis was identified as an independent predictor of overall survival (OS) (adjusted hazard ratio 1.53, 95% CI, 1.09-2.09, P = 0.015). Performance status was poor in 82% of survivors of pneumonitis; in 62% of survivors, the PS worsened after the pneumonitis improved. Additionally, 54% of survivors received no further systemic anti-cancer therapy after pneumonitis. The median survival time of survivors after pneumonitis was 3.5 months (95% CI, 2.3-7.2 months). CONCLUSIONS: Our study indicated that 6% of patients with advanced NSCLC developed pneumonitis during systemic anti-cancer therapy. The early mortality rate of pneumonitis is high, and the survival and PS after pneumonitis is extremely poor. Additionally, pneumonitis has an adverse impact on the survival of patients with advanced NSCLC. These data should be considered for the management of pneumonitis, and we recommend that future work focuses on pneumonitis particularly to improve the survival of patients with advanced NSCLC. PMID- 28006020 TI - Albuminuria Is Associated with Open-Angle Glaucoma in Nondiabetic Korean Subjects: A Cross-Sectional Study. AB - OBJECTIVE: Systemic vascular dysfunction has been suggested to contribute to glaucomatous damage. Albuminuria is a surrogate marker of endothelial injury, including vessels. However, their relationship is not well understood. This study aimed to investigate the association between albuminuria and the prevalence of open-angle glaucoma (OAG) in nondiabetic subjects. METHODS: We conducted a cross sectional study of 4186 nondiabetic participants aged 19 years or older from the 2011-2012 Korea National Health and Nutrition Examination Survey. OAG was defined based on the criteria of the International Society for Geographic and Epidemiologic Ophthalmology. Urinary albumin excretion was assessed by the urinary albumin-to-creatinine ratio (UACR). A multivariate logistic regression analysis was performed to evaluate the relationship between albuminuria and OAG. RESULTS: Among the subjects, 124 had OAG. The weighted prevalences of microalbuminuria (UACR of 30-299 mg/g creatinine [Cr]) and macroalbuminuria (UACR >= 300 mg/g Cr) were 3.2 +/- 0.3% and 0.4 +/- 0.1%, respectively. The percentages of OAG increased in accordance with increasing UACR tertiles. Compared with subjects in the lower UACR tertile, those in the upper tertile showed an increased prevalence of OAG (odds ratio, 1.963; 95% confidence interval 1.072 3.595, P = 0.029) after adjusting for demographic factors, laboratory parameters, kidney function, and intraocular pressure. Furthermore, even after excluding 155 subjects with microalbuminuria and 19 subjects with macroalbuminuria, a positive association persisted between the upper UACR tertile (low-grade albuminuria) and an increased prevalence of OAG (odds ratio, 2.170; 95% confidence interval, 1.174 4.010, P = 0.014). CONCLUSION: Albuminuria, even low-grade, was significantly associated with OAG in nondiabetic subjects. This result implies the role of vascular endothelial dysfunction in the pathogenic mechanism of OAG and suggests that careful monitoring of OAG is required in nondiabetic subjects with albuminuria. PMID- 28006021 TI - The Impact of the Gut Microbiota on Humoral Immunity to Pathogens and Vaccination in Early Infancy. PMID- 28006022 TI - Does External Knowledge Sourcing Enhance Market Performance? Evidence from the Korean Manufacturing Industry. AB - Firms continuously search for external knowledge that can contribute to product innovation, which may ultimately increase market performance. The relationship between external knowledge sourcing and market performance is not well documented. The extant literature primarily examines the causal relationship between external knowledge sources and product innovation performance or to identify factors which moderates the relationship between external knowledge sourcing and product innovation. Non-technological innovations, such as organization and marketing innovations, intervene in the process of external knowledge sourcing to product innovation to market performance but has not been extensively examined. This study addresses two research questions: does external knowledge sourcing lead to market performance and how does external knowledge sourcing interact with a firm's different innovation activities to enhance market performance. This study proposes a comprehensive model to capture the causal mechanism from external knowledge sourcing to market performance. The research model was tested using survey data from manufacturing firms in South Korea and the results demonstrate a strong statistical relationship in the path of external knowledge sourcing (EKS) to product innovation performance (PIP) to market performance (MP). Organizational innovation is an antecedent to EKS while marketing innovation is a consequence of EKS, which significantly influences PIP and MP. The results imply that any potential EKS effort should also consider organizational innovations which may ultimately enhance market performance. Theoretical and practical implications are discussed as well as concluding remarks. PMID- 28006023 TI - Introduction of the Charite Mobility Index (CHARMI) - A Novel Clinical Mobility Assessment for Acute Care Rehabilitation. AB - INTRODUCTION: Mobility is an essential part of a person's functioning and independence. It encompasses locomotive functions, but also the more basic functions of positioning and transferring. Despite the availability of several mobility-related assessment instruments to date, there is a need for assessment instruments with the specific capability to display the full range of mobilisation. Our aim was to develop and validate a scoring instrument with hierarchical composition where every score value stands for a defined mobility level. PARTICIPANTS AND METHODS: A previously developed and validated pilot instrument was applied to assess patients (n = 113) admitted to an acute rehabilitation programme. Mobility was assessed during admission, subsequently at weekly intervals and at discharge to acquire a detailed status of mobility at multiple time points and individual mobilisation profiles over time. The scoring instrument was then remodelled based on clinical criteria to establish an easy-to use scoring system with hierarchical composition. Psychometric properties were calculated using an independent sample of 87 consecutive patients. RESULTS: Content validity could be affirmed. The psychometric tests demonstrated excellent convergent validity with the three mobility items of the Barthel Index (r = 0.93), despite an adequately lower correlation with the whole Barthel Index (r = 0.63). Adequate floor and ceiling effects (20%) and a large responsiveness to change (|d| = 1.7, p < 0.001) between admission and discharge values were demonstrated. Inter-rater reliability was excellent (kappa = 0.88). CONCLUSIONS: The Charite Mobility Index (CHARMI) is a promising, easy-to-use hierarchical scoring instrument assessing the full individual spectrum from immobility to unlimited mobility, including positioning, transfer and locomotion items. It allows for monitoring of mobilisation. PMID- 28006024 TI - A Novel Approach to Identifying Trajectories of Mobility Change in Older Adults. AB - OBJECTIVES: To validate trajectories of late-life mobility change using a novel approach designed to overcome the constraints of modest sample size and few follow-up time points. METHODS: Using clinical reasoning and distribution-based methodology, we identified trajectories of mobility change (Late Life Function and Disability Instrument) across 2 years in 391 participants age >=65 years from a prospective cohort study designed to identify modifiable impairments predictive of mobility in late-life. We validated our approach using model fit indices and comparing baseline mobility-related factors between trajectories. RESULTS: Model fit indices confirmed that the optimal number of trajectories were between 4 and 6. Mobility-related factors varied across trajectories with the most unfavorable values in poor mobility trajectories and the most favorable in high mobility trajectories. These factors included leg strength, trunk extension endurance, knee flexion range of motion, limb velocity, physical performance measures, and the number and prevalence of medical conditions including osteoarthritis and back pain. CONCLUSIONS: Our findings support the validity of this approach and may facilitate the investigation of a broader scope of research questions within aging populations of varied sizes and traits. PMID- 28006025 TI - iTRAQ-Based Quantitative Proteomics Identifies Potential Regulatory Proteins Involved in Chicken Eggshell Brownness. AB - Brown eggs are popular in many countries and consumers regard eggshell brownness as an important indicator of egg quality. However, the potential regulatory proteins and detailed molecular mechanisms regulating eggshell brownness have yet to be clearly defined. In the present study, we performed quantitative proteomics analysis with iTRAQ technology in the shell gland epithelium of hens laying dark and light brown eggs to investigate the candidate proteins and molecular mechanisms underlying variation in chicken eggshell brownness. The results indicated 147 differentially expressed proteins between these two groups, among which 65 and 82 proteins were significantly up-regulated in the light and dark groups, respectively. Functional analysis indicated that in the light group, the down-regulated iron-sulfur cluster assembly protein (Iba57) would decrease the synthesis of protoporphyrin IX; furthermore, the up-regulated protein solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 5 (SLC25A5) and down-regulated translocator protein (TSPO) would lead to increased amounts of protoporphyrin IX transported into the mitochondria matrix to form heme with iron, which is supplied by ovotransferrin protein (TF). In other words, chickens from the light group produce less protoporphyrin IX, which is mainly used for heme synthesis. Therefore, the exported protoporphyrin IX available for eggshell deposition and brownness is reduced in the light group. The current study provides valuable information to elucidate variation of chicken eggshell brownness, and demonstrates the feasibility and sensitivity of iTRAQ based quantitative proteomics analysis in providing useful insights into the molecular mechanisms underlying brown eggshell pigmentation. PMID- 28006026 TI - Model of the Dynamic Construction Process of Texts and Scaling Laws of Words Organization in Language Systems. AB - Scaling laws characterize diverse complex systems in a broad range of fields, including physics, biology, finance, and social science. The human language is another example of a complex system of words organization. Studies on written texts have shown that scaling laws characterize the occurrence frequency of words, words rank, and the growth of distinct words with increasing text length. However, these studies have mainly concentrated on the western linguistic systems, and the laws that govern the lexical organization, structure and dynamics of the Chinese language remain not well understood. Here we study a database of Chinese and English language books. We report that three distinct scaling laws characterize words organization in the Chinese language. We find that these scaling laws have different exponents and crossover behaviors compared to English texts, indicating different words organization and dynamics of words in the process of text growth. We propose a stochastic feedback model of words organization and text growth, which successfully accounts for the empirically observed scaling laws with their corresponding scaling exponents and characteristic crossover regimes. Further, by varying key model parameters, we reproduce differences in the organization and scaling laws of words between the Chinese and English language. We also identify functional relationships between model parameters and the empirically observed scaling exponents, thus providing new insights into the words organization and growth dynamics in the Chinese and English language. PMID- 28006027 TI - Evidence for Weakened Intercellular Coupling in the Mammalian Circadian Clock under Long Photoperiod. AB - For animals living in temperate latitudes, seasonal changes in day length are an important cue for adaptations of their physiology and behavior to the altered environmental conditions. The suprachiasmatic nucleus (SCN) is known as the central circadian clock in mammals, but may also play an important role in adaptations to different photoperiods. The SCN receives direct light input from the retina and is able to encode day-length by approximating the waveform of the electrical activity rhythm to the duration of daylight. Changing the overall waveform requires a reorganization of the neuronal network within the SCN with a change in the degree of synchrony between the neurons; however, the underlying mechanisms are yet unknown. In the present study we used PER2::LUC bioluminescence imaging in cultured SCN slices to characterize network dynamics on the single-cell level and we aimed to provide evidence for a role of modulations in coupling strength in the photoperiodic-induced phase dispersal. Exposure to long photoperiod (LP) induced a larger distribution of peak times of the single-cell PER2::LUC rhythms in the anterior SCN, compared to short photoperiod. Interestingly, the cycle-to-cycle variability in single-cell period of PER2::LUC rhythms is also higher in the anterior SCN in LP, and is positively correlated with peak time dispersal. Applying a new, impartial community detection method on the time series data of the PER2::LUC rhythm revealed two clusters of cells with a specific spatial distribution, which we define as dorsolateral and ventromedial SCN. Post hoc analysis of rhythm characteristics of these clusters showed larger cycle-to-cycle single-cell period variability in the dorsolateral compared to the ventromedial cluster in the anterior SCN. We conclude that a change in coupling strength within the SCN network is a plausible explanation to the observed changes in single-cell period variability, which can contribute to the photoperiod-induced phase distribution. PMID- 28006028 TI - Synergistic Effects and Mechanisms of Budesonide in Combination with Fluconazole against Resistant Candida albicans. AB - Candida albicans is an important opportunistic pathogen, causing both superficial mucosal infections and life-threatening systemic diseases in the clinic. The emergence of drug resistance in Candida albicans has become a noteworthy phenomenon due to the extensive use of antifungal agents and the development of biofilms. This study showed that budesonide potentiates the antifungal effect of fluconazole against fluconazole-resistant Candida albicans strains both in vitro and in vivo. In addition, our results demonstrated, for the first time, that the combination of fluconazole and budesonide can reverse the resistance of Candida albicans by inhibiting the function of drug transporters, reducing the formation of biofilms, promoting apoptosis and inhibiting the activity of extracellular phospholipases. This is the first study implicating the effects and mechanisms of budesonide against Candida albicans alone or in combination with fluconazole, which may ultimately lead to the identification of new potential antifungal targets. PMID- 28006029 TI - Modular Brain Network Organization Predicts Response to Cognitive Training in Older Adults. AB - Cognitive training interventions are a promising approach to mitigate cognitive deficits common in aging and, ultimately, to improve functioning in older adults. Baseline neural factors, such as properties of brain networks, may predict training outcomes and can be used to improve the effectiveness of interventions. Here, we investigated the relationship between baseline brain network modularity, a measure of the segregation of brain sub-networks, and training-related gains in cognition in older adults. We found that older adults with more segregated brain sub-networks (i.e., more modular networks) at baseline exhibited greater training improvements in the ability to synthesize complex information. Further, the relationship between modularity and training-related gains was more pronounced in sub-networks mediating "associative" functions compared with those involved in sensory-motor processing. These results suggest that assessments of brain networks can be used as a biomarker to guide the implementation of cognitive interventions and improve outcomes across individuals. More broadly, these findings also suggest that properties of brain networks may capture individual differences in learning and neuroplasticity. Trail Registration: ClinicalTrials.gov, NCT#00977418. PMID- 28006030 TI - A Speculative History of DNA: What If Oswald Avery Had Died in 1934? AB - This speculative Essay explores the consequences of the imagined premature death of Oswald Avery, who in 1944 provided evidence that genes are made of DNA. Four imaginary alternate routes to the genetic function of DNA are outlined, each of which highlights different aspects of the actual process of discovery. PMID- 28006031 TI - Selection and Characterization of Tau Binding ?-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease. AB - A variety of neurodegenerative disorders, including Alzheimer disease (AD), are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers. Inhibitors of pathological tau aggregation, interrupting tau self-assembly, might be useful for the development of therapeutics. Employing mirror image phage display with a large peptide library (over 109 different peptides), we have identified tau fibril binding peptides consisting of d enantiomeric amino acids. d-enantiomeric peptides are extremely protease stable and not or less immunogenic than l-peptides, and the suitability of d-peptides for in vivo applications have already been demonstrated. Phage display selections were performed using fibrils of the d-enantiomeric hexapeptide VQIVYK, representing residues 306 to 311 of the tau protein, as a target. VQIVYK has been demonstrated to be important for fibril formation of the full lengths protein and forms fibrils by itself. Here, we report on d-enantiomeric peptides, which bind to VQIVYK, tau isoforms like tau3RD (K19) as well as to full lengths tau fibrils, and modulate the aggregation of the respective tau form. The peptides are able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research. PMID- 28006032 TI - Evaluation of Bt Corn with Pyramided Genes on Efficacy and Insect Resistance Management for the Asian Corn Borer in China. AB - A Bt corn hybrid (AcIe) with two Bt genes (cry1Ie and cry1Ac) was derived by breeding stack from line expressing Cry1Ie and a line expressing Cry1Ac. Efficacy of this pyramided Bt corn hybrid against the Asian corn borer (ACB), Ostrinia furnacalis, was evaluated. We conducted laboratory bioassays using susceptible and resistant ACB strains fed on artificial diet or fresh plant tissues. We also conducted field trials with artificial infestations of ACB neonates at the V6 and silk stages. The toxin-diet bioassay data indicated that mixtures of Cry1Ac and Cry1Ie proteins had synergistic insecticidal efficacy. The plant tissue bioassay data indicated that Bt corn hybrids expressing either a single toxin (Cry1Ac or Cry1Ie) or two toxins had high efficacy against susceptible ACB. Damage ratings in the field trials indicated that the Bt corn hybrids could effectively protect against 1st and the 2nd generation ACB in China. The hybrid line with two Bt genes showed a higher efficacy against ACB larvae resistant to Cry1Ac or CryIe than the hybrid containing one Bt gene, and the two gene hybrid would have increased potential for managing or delaying the evolution of ACB resistance to Bt corn plants. PMID- 28006033 TI - Literary Fiction Influences Attitudes Toward Animal Welfare. AB - Literary fiction has been credited with considerable power to improve attitudes toward outgroups. It was even argued that it has been an important factor behind the global decline of violence against various minorities in the last centuries. Could it also help to reduce the human-inflicted suffering of animals? To test this, we studied the attitude toward animal welfare of n = 921 (experimental group) people of both sexes who read a short fragment of an unpublished novel with a motif of the physical abuse of an animal. The control group (n = 912) read a fragment of a similar length but not related to animals. After reading the text all subjects filled out an on-line questionnaire with seven items (camouflaged among many others items) measuring attitudes toward animal welfare. The questionnaire included also demographical questions, such as whether the subject keeps pets. We found that in comparison with the control group, the experimental group was significantly more concerned about animal welfare. This result indicates that literary fiction can influence attitudes toward other species. It is also worth noting that our study is characterized by a high level of ecological validity, i.e. a relatively high extent to which its results can be generalized (or extended) to real-world settings. Due to its specific design, which involved the cooperation of a bestselling author and his publisher, the study approximated the typical conditions in which people read fiction in a remarkably accurate way. Finally, our research has potential practical implications for promoting animal welfare. PMID- 28006038 TI - A Rapidly Expanding Scalp Mass. PMID- 28006039 TI - Longitudinal Examination of Frequency of and Risk Factors for Severe Dry Eye Symptoms in US Veterans. AB - Importance: Dry eye syndrome is a common condition that affects millions of individuals. Many cross-sectional studies have evaluated risk factors for dry eye severity, but few have assessed risk factors or symptom progression over time. Objectives: To assess symptom progression in dry eye syndrome and determine risk factors associated with severe symptoms at 1 year. Design, Setting, and Participants: A longitudinal study was conducted from October 1, 2013, to April 30, 2015, among patients at the Miami Veterans Affairs Hospital with a wide variety of dry eye symptoms and signs (ranging from none to severe). Main Outcomes and Measures: Change in dry eye symptom severity during 1 year, as assessed by responses to dry eye symptom questionnaires administered at the initial visit and 1 year later, as well as baseline risk factor analysis for severe dry eye symptoms at 1 year, defined as a Dry Eye Questionnaire 5 score of 12 or more. Results: Of the 120 patients (mean [SD] age, 64 [11] years; 109 male and 11 female), 26 of 58 (44.8%) with either no symptoms or mild or moderate symptoms at baseline progressed to more severe symptoms at 1 year, while 46 of 62 patients (74.2%) with severe symptoms at baseline reported that severe symptoms persisted at 1 year. Baseline ocular risk factors for severe dry eye symptoms at 1 year included more severe dry eye symptoms, ocular pain, and neuropathic pain like ocular symptoms. Nonocular risk factors included sleep disturbances (eg, sleep apnea and insomnia), mental health status (eg, posttraumatic stress disorder and depression), nonocular pain, and medications (eg, anxiolytics and analgesics). In a multivariable analysis, the most significant risk factors were sleep apnea (odds ratio [OR], 3.80; 95% CI, 1.00-14.49; P = .05), Dry Eye Questionnaire 5 score (OR, 1.15; 95% CI, 1.02-1.30; P = .02), and posttraumatic stress disorder score (OR, 1.04; 95% CI, 1.01-1.08; P = .02). Conclusions and Relevance: Patients with severe dry eye symptoms and ocular pain at baseline were more likely to have persistent severe dry eye symptoms on 1-year follow-up. Furthermore, nonocular risk factors that have been associated with dry eye cross sectionally, such as psychiatric comorbidities and nonocular pain, were also associated with severe dry eye symptoms at 1 year. Although this cohort was limited to US veterans, which may not be generalizable to other populations, our results suggest that pain perception and severity are important when evaluating and managing dry eye. PMID- 28006034 TI - Peripheral Organs of Dengue Fatal Cases Present Strong Pro-Inflammatory Response with Participation of IFN-Gamma-, TNF-Alpha- and RANTES-Producing Cells. AB - Dengue disease is an acute viral illness caused by dengue virus (DENV) that can progress to hemorrhagic stages leading to about 20000 deaths every year worldwide. Despite many clinical investigations regarding dengue, the immunopathogenic process by which infected patients evolve to the severe forms is not fully understood. Apart from differences in virulence and the antibody cross reactivity that can potentially augment virus replication, imbalanced cellular immunity is also seen as a major concern in the establishment of severe dengue. In this context, the investigation of cellular immunity and its products in dengue fatal cases may provide valuable data to help revealing dengue immunopathogenesis. Here, based in four dengue fatal cases infected by the serotype 3 in Brazil, different peripheral organs (livers, lungs and kidneys) were studied to evaluate the presence of cell infiltrates and the patterns of local cytokine response. The overall scenario of the studied cases revealed a considerable systemic involvement of infection with mononuclear cells targeted to all of the evaluated organs, as measured by immunohistochemistry (IHC). Quantification of cytokine-expressing cells in peripheral tissues was also performed to characterize the ongoing inflammatory process by the severe stage of the disease. Increased levels of IFN-gamma- and TNF-alpha-expressing cells in liver, lung and kidney samples of post-mortem subjects evidenced a strong pro inflammatory induction in these tissues. The presence of increased RANTES producing cell numbers in all analyzed organs suggested a possible link between the clinical status and altered vascular permeability. Co-staining of DENV RNA and IFN-gamma or TNF-alpha using in situ hibridization and IHC confirmed the virus-specific trigger of the pro-inflammatory response. Taken together, this work provided additional evidences that corroborated with the traditional theories regarding the "cytokine storm" and the occurrence of uneven cellular immunity in response to DENV as major reasons for progress to severe disease. PMID- 28006040 TI - Molecular Markers Beyond Microsatellite Instability for Assessing Prognosis in Early-Stage Colorectal Cancer: What Happens at Relapse? PMID- 28006041 TI - Efficacy and Safety of Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes in Pediatric Patients: A Randomized Clinical Trial. AB - Importance: Acute otitis media with tympanostomy tubes (AOMT) in children commonly presents with otorrhea and negatively affects their daily activities. Objective: To evaluate the efficacy and safety of topical ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution relative to ciprofloxacin, 0.3%, otic solution alone and fluocinolone acetonide, 0.025%, otic solution alone in the treatment of AOMT in children. Design, Setting, and Participants: Two twin multicenter, randomized, double-blind clinical trials with identical designs were conducted from June 24, 2011, through June 23, 2014, at ear, nose, and throat pediatric practices, general practices, hospitals, and clinical research centers. The study population comprised 662 children (331 in each trial) with AOMT in at least 1 ear who presented with moderate or severe purulent otorrhea for 3 weeks or less. Data analyses were performed on an intention-to-treat basis. Interventions: Patients were randomly assigned to receive ciprofloxacin plus fluocinolone, ciprofloxacin alone, or fluocinolone alone twice daily for 7 days and were evaluated on days 1 (baseline), 3 to 5 (undergoing therapy), 8 to 10 (end of therapy), and 18 to 22 (test of cure). Main Outcomes and Measures: The primary efficacy measure was time to cessation of otorrhea. The principal secondary end point was sustained microbiological cure, defined as eradication or presumed eradication at end-of-therapy and test-of-cure visits. Results: A total of 662 children participating in the 2 studies were randomized to receive ciprofloxacin plus fluocinolone (n = 223), ciprofloxacin alone (n = 221), or fluocinolone alone (n = 218). The median age was 2.5 years (range, 0.6-12.7 years). The median time to cessation of otorrhea was 4.23 days (95% CI, 3.65-4.95 days) in patients receiving ciprofloxacin plus fluocinolone compared with 6.95 days (95% CI, 5.66-8.20 days) in those receiving ciprofloxacin and not estimable findings in those receiving fluocinolone alone (P < .001). The clinical cure rate at the test-of-cure visit was 80.6% in the ciprofloxacin plus fluocinolone group, 67.4% in the ciprofloxacin group (difference, 13.2%; 95% CI, 5.0%-21.4%; P = .002), and 47.6% in the fluocinolone group (difference, 33.0%; 95% CI, 24.0% 42.0%; P < .001). The sustained microbiological cure rate was 79.7% in the ciprofloxacin plus fluocinolone group vs 67.7% in the ciprofloxacin group (difference, 12.0%; 95% CI, 0.8%-23.0%; P = .04) and 37.6% in the fluocinolone group (difference, 42.1%; 95% CI, 29.3%-54.8%; P < .001). Only 7 (3.1%) of the patients receiving ciprofloxacin plus fluocinolone, 8 (3.6%) of the patients receiving ciprofloxacin, and 10 (4.7%) of the patients receiving fluocinolone presented with adverse events related to study medication. Conclusions and Relevance: The combination of ciprofloxacin plus fluocinolone is more effective than treatment with ciprofloxacin or fluocinolone alone for AOMT, and it is safe and well tolerated in children. Trial Registration: clinicaltrials.gov Identifiers: NCT01395966 and NCT01404611. PMID- 28006042 TI - Evaluating Effects of Switching Anti-Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration and Diabetic Macular Edema. AB - Importance: When a patient with neovascular age-related macular degeneration or diabetic macular edema does not respond to an initial anti-vascular endothelial growth factor agent, usually after several injections, ophthalmologists may switch to another anti-vascular endothelial growth factor agent. Authors of case series have suggested beneficial effects from switching. However, to our knowledge, there are no studies with an appropriate control group to evaluate how such patients would do without switching agents. Objective: To assess outcomes in patients who have a poor initial response but continue treatment without switching agents. Design, Setting, and Participants: We obtained data from 2 multicenter clinical trials, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Diabetic Retinopathy Clinical Research Network (DRCR.net). Based on typical clinical reasons for switching agents, we developed "switching rules" at both 3 and 6 months after initiation of treatment. Using these switching rules, we identified a 3-month and a 6-month cohort of "treatment failures" from both CATT and DRCR.net studies. Interventions: Although the cohorts from each study met criteria for switching, they were treated with the initial agent throughout the study (bevacizumab or ranibizumab in CATT and ranibizumab in DRCR.net). Main Outcomes and Measures: Primary outcomes were change in visual acuity and change in central retinal thickness on optical coherence tomography from the 3- or 6-month visit at which switching rules were met. Results: The 126 patients from CATT and the 59 patients from DRCR.net who were selected for the switching analysis were similar in age, sex and race/ethnicity to the overall study populations. Among the participants who met the criteria for switching, the CATT participants were a mean (SD) of 79.7 (7.8) years of age, 65.9% women, and 97.6% white, while the DRCR.net participants were a mean (SD) of 65.5 (9.3) years of age, 44.1% women, and 76.3% white In all 4 cohorts, there was a 3- to 5-letter improvement in mean visual acuity over the 3 months after the switching rules were met, although all patients continued on their originally assigned treatment. Mean central retinal thickness also improved by 40 to 70 MUM. Conclusions and Relevance: These results demonstrate the importance of having a comparison group to evaluate the effect of switching anti vascular endothelial growth factor agents for treatment of neovascular age related macular degeneration or diabetic macular edema. Without a comparison group, it is impossible to know whether any improvement observed after switching was related to the new treatment or was related to regression to the mean and time effects as observed in the 4 cohorts presented here. Randomization to switching or not switching drugs would provide a basis for valid conclusions about the effects of switching. PMID- 28006043 TI - Health Care Resource Use in Patients With and Without 22q11.2 Deletion Syndrome Undergoing Sphincter Pharyngoplasty for Velopharyngeal Insufficiency. AB - Importance: The use of health care resources in patients with velopharyngeal insufficiency undergoing sphincter pharyngoplasty is unknown. Objectives: To examine the use of health care resources by patients with velopharyngeal insufficiency who have undergone sphincter pharyngoplasty and investigate whether patients with 22q11.2 deletion syndrome (22qDS) had a longer length of stay, increased cost of admission, and higher number of complications. Design, Setting, and Participants: Using data from the Kids' Inpatient Database for January 1 to December 31, 2012, we retrospectively analyzed all patients undergoing pharyngoplasty for velopharyngeal insufficiency. In addition, patients were analyzed according to whether or not they had 22qDS. Data were analyzed from January 1 to December 31, 2012. Main Outcomes and Measures: Total cost of admission, length of stay, number of procedures, and number of complications. Results: There were 687 patients: 90 with 22qDS (mean [SD] age, 6.4 [2.7] years; 43 males and 47 females) and 597 without 22qDS (mean [SD] age, 7.5 [4.1] years; 326 males and 271 females). In both groups, patients were predominantly white, had private insurance, were treated in a children's hospital, and were from either the West or Midwest. The median length of stay (2.0 [interquartile range (IQR), 1.0-3.9] vs 1.0 [IQR, 1.0-2.0] days; 95% CI, 1.0-2.0) and total cost of admission ($9269.24 [IQR, $6800.65-$13 189.25] vs $6936.95 [IQR, $5036.71 $9054.98]; 95% CI, $6791.83-$7542.47) were higher for the group with 22qDS than those without 22qDS, while there was no significant difference in the number of procedures performed. In addition, the median number of diagnoses (5.0 [IQR, 3.0 9.0] vs 3.0 [IQR, 2.0-5.0]; 95% CI, 3.0-4.0) and number of chronic conditions (3.0 [IQR, 2.0-5.0] vs 2.0 [IQR, 1.0-2.0]; 95% CI, 2.0-2.0) were higher for the group with 22qDS than those without 22qDS. Furthermore, results of a multiple regression model showed that 22qDS was positively associated with both length of stay (B = 0.92; 95% CI, 0.59-1.24) and total cost (B = $3458.78; 95% CI, $2051.09 $4866.46). Conclusions and Relevance: This study demonstrates that patients with 22qDS undergoing sphincter pharyngoplasty for velopharyngeal insufficiency have more complex medical conditions and require more health care resources than patients without 22qDS. PMID- 28006044 TI - Human red blood cell recognition enhancement with three-dimensional morphological features obtained by digital holographic imaging. AB - The classification of erythrocytes plays an important role in the field of hematological diagnosis, specifically blood disorders. Since the biconcave shape of red blood cell (RBC) is altered during the different stages of hematological disorders, we believe that the three-dimensional (3-D) morphological features of erythrocyte provide better classification results than conventional two dimensional (2-D) features. Therefore, we introduce a set of 3-D features related to the morphological and chemical properties of RBC profile and try to evaluate the discrimination power of these features against 2-D features with a neural network classifier. The 3-D features include erythrocyte surface area, volume, average cell thickness, sphericity index, sphericity coefficient and functionality factor, MCH and MCHSD, and two newly introduced features extracted from the ring section of RBC at the single-cell level. In contrast, the 2-D features are RBC projected surface area, perimeter, radius, elongation, and projected surface area to perimeter ratio. All features are obtained from images visualized by off-axis digital holographic microscopy with a numerical reconstruction algorithm, and four categories of biconcave (doughnut shape), flat disc, stomatocyte, and echinospherocyte RBCs are interested. Our experimental results demonstrate that the 3-D features can be more useful in RBC classification than the 2-D features. Finally, we choose the best feature set of the 2-D and 3-D features by sequential forward feature selection technique, which yields better discrimination results. We believe that the final feature set evaluated with a neural network classification strategy can improve the RBC classification accuracy. PMID- 28006045 TI - Digital holographic microscopy of phase separation in multicomponent lipid membranes. AB - Lateral in-homogeneities in lipid compositions cause microdomains formation and change in the physical properties of biological membranes. With the presence of cholesterol and mixed species of lipids, phospholipid membranes segregate into lateral domains of liquid-ordered and liquid-disordered phases. Coupling of two dimensional intralayer phase separations and interlayer liquid-crystalline ordering in multicomponent membranes has been previously demonstrated. By the use of digital holographic microscopy (DHMicroscopy), we quantitatively analyzed the volumetric dynamical behavior of such membranes. The specimens are lipid mixtures composed of sphingomyelin, cholesterol, and unsaturated phospholipid, 1,2 dioleoyl-sn-glycero-3-phosphocholine. DHMicroscopy in a transmission mode is an effective tool for quantitative visualization of phase objects. By deriving the associated phase changes, three-dimensional information on the morphology variation of lipid stacks at arbitrary time scales is obtained. Moreover, the thickness distribution of the object at demanded axial planes can be obtained by numerical focusing. Our results show that the volume evolution of lipid domains follows approximately the same universal growth law of previously reported area evolution. However, the thickness of the domains does not alter significantly by time; therefore, the volume evolution is mostly attributed to the changes in area dynamics. These results might be useful in the field of membrane-based functional materials. PMID- 28006046 TI - Automated choroid segmentation in three-dimensional 1-MUm wide-view OCT images with gradient and regional costs. AB - Choroid thickness and volume estimated from optical coherence tomography (OCT) images have emerged as important metrics in disease management. This paper presents an automated three-dimensional (3-D) method for segmenting the choroid from 1 - ? m wide-view swept source OCT image volumes, including the Bruch's membrane (BM) and the choroidal-scleral interface (CSI) segmentation. Two auxiliary boundaries are first detected by modified Canny operators and then the optical nerve head is detected and removed. The BM and the initial CSI segmentation are achieved by 3-D multiresolution graph search with gradient-based cost. The CSI is further refined by adding a regional cost, calculated from the wavelet-based gradual intensity distance. The segmentation accuracy is quantitatively evaluated on 32 normal eyes by comparing with manual segmentation and by reproducibility test. The mean choroid thickness difference from the manual segmentation is 19.16 +/- 4.32 ?? ? m , the mean Dice similarity coefficient is 93.17 +/- 1.30 % , and the correlation coefficients between fovea centered volumes obtained on repeated scans are larger than 0.97. PMID- 28006047 TI - The Microbiome and Risk for Obesity and Diabetes. PMID- 28006048 TI - Test-Retest Reliability and Agreement Between In-Person and Video Assessment of Facial Mimetic Function Using the eFACE Facial Grading System. AB - Importance: Use of a robust high-resolution instrument for grading of facial symmetry would enhance reporting the outcomes of facial reanimation interventions. The eFACE is one such tool. Objective: To determine test-retest reliability of the eFACE tool over time and agreement between eFACE assessments made in person vs those made using video of facial mimetic function. Design, Setting, and Participants: A prospective observational study was conducted among 75 consecutive patients with varying degrees of facial palsy who presented between July 1 and December 31, 2014, to an academic tertiary referral hospital. Facial symmetry of all patients was graded in person and via standardized photographic and video documentation of facial mimetic function at the initial visit. Three months after initial presentation, eFACE scores were reassessed by the same raters using the videos of facial mimetic function documented at the initial visit. Main Outcomes and Measures: Individual and subset eFACE scores assessed by 2 facial reanimation surgeons. Results: Among the 75 patients in the study (mean [SD] age, 48.18 [16.60] years; 30 men and 45 women), agreement between in-person and video assessments of facial function using the eFACE scale was excellent (static subset score: mean difference, 0.19; 95% CI, -1.51 to 1.88; P = .83; intraclass correlation coefficient [ICC], 0.85; 95% CI, 0.80 to 0.89; dynamic subset score: mean difference, -0.51; 95% CI, -1.72 to 0.71; P = .41; ICC, 0.96; 95% CI, 0.94 to 0.97; synkinesis subset score: mean difference, -1.14; 95% CI, -2.87 to 0.59; P = .20; ICC, 0.90; 95% CI, 0.86 to 0.93; and composite score: mean difference, -0.41; 95% CI, -1.30 to 0.47; P = .36; ICC, 0.94; 95% CI, 0.92 to 0.96). Agreement between repeated eFACE assessments of video of facial function was excellent (static subset score: ICC, 0.93; 95% CI, 0.87 to 0.96; dynamic subset score: ICC, 0.88; 95% CI, 0.80 to 0.94; synkinesis subset score: ICC, 0.92; 95% CI, 0.86 to 0.96; and composite score: ICC, 0.96; 95% CI, 0.93 to 0.98). Conclusions and Relevance: Strong agreement exists between eFACE scores of facial function assessed in person and from video recordings. Test-retest reliability of eFACE scores is high. The eFACE is a reliable instrument for high resolution assessment of facial mimetic function. Level of Evidence: NA. PMID- 28006049 TI - Further Scrutiny of Vision Outcomes When Aflibercept Is Used as Rescue Treatment for Eyes With Diabetic Macular Edema Treated With Laser. PMID- 28006050 TI - Surgery for Patients With Rectal Cancer-Time to Listen to the Patients and Recognize Reality. PMID- 28006051 TI - Cetuximab and Radiotherapy in Laryngeal Preservanion-Reply. PMID- 28006052 TI - Association of Low Vitamin D Levels With Noninfectious Anterior Uveitis. AB - Importance: Vitamin D plays an important role in both the innate and adaptive immune systems. It has been shown to contribute to the etiology of T-cell mediated autoimmune diseases through the upregulation of type 2 anti-inflammatory T helper cells and the suppression of type 1 T helper cells. Noninfectious uveitis is postulated to be caused by immune dysfunction. Objective: To determine whether there is an association between vitamin D levels and noninfectious anterior uveitis. Design, Setting, and Participants: This was a case-control study. We identified patients with and without noninfectious uveitis using the Massachusetts Eye and Ear Infirmary Ocular Inflammation Database and electronic medical records from March 1, 2008, to December 12, 2015, at the Massachusetts Eye and Ear Infirmary Uveitis and Comprehensive Ophthalmology Clinics. One hundred patients with noninfectious anterior uveitis and 100 patients without uveitis were recruited. Patients with noninfectious uveitis were diagnosed by fellowship-trained uveitis specialists after exclusion of infectious causes and neoplastic masquerades of uveitis. All patients included had a total 25 hydroxyvitamin D level recorded. Multivariate regression models were constructed to determine the association between vitamin D levels and the presence of uveitis. Main Outcome and Measure: Presence of noninfectious anterior uveitis. Results: We identified 100 patients (64 white, 8 African American, 25 Asian, and 3 Hispanic) with a mean (SD) age of 51.8 (15.9) years (26 men) and 100 control individuals (58 white, 23 African American, 8 Asian, and 11 Hispanic) with a mean (SD) age of 53.6 (16.2) years (27 men). Hypovitaminosis D was associated with noninfectious uveitis in the univariate analysis (odds ratio, 2.53; 95% CI, 1.42 4.51; P = .002). The association in multivariate regression after adjusting for age, sex, and race/ethnicity was 2.96 (95% CI, 1.60-5.50; P = .001) The odds of developing uveitis were 4% lower for every 1-ng/mL increase in vitamin D level (odds ratio, 0.96; 95% CI, 0.93-0.99; P = .01) in the main multivariate analysis. Conclusions and Relevance: In this retrospective study, lower vitamin D levels were associated with an increased risk of noninfectious anterior uveitis. However, this does not confirm a causal effect. PMID- 28006053 TI - Cetuximab and Radiotherapy in Laryngeal Preservation. PMID- 28006054 TI - Cognitive Load in Voice Therapy Carry-Over Exercises. AB - Purpose: The cognitive load generated by online speech production may vary with the nature of the speech task. This article examines 3 speech tasks used in voice therapy carry-over exercises, in which a patient is required to adopt and automatize new voice behaviors, ultimately in daily spontaneous communication. Method: Twelve subjects produced speech in 3 conditions: rote speech (weekdays), sentences in a set form, and semispontaneous speech. Subjects simultaneously performed a secondary visual discrimination task for which response times were measured. On completion of each speech task, subjects rated their experience on a questionnaire. Results: Response times from the secondary, visual task were found to be shortest for the rote speech, longer for the semispontaneous speech, and longest for the sentences within the set framework. Principal components derived from the subjective ratings were found to be linked to response times on the secondary visual task. Acoustic measures reflecting fundamental frequency distribution and vocal fold compression varied across the speech tasks. Conclusions: The results indicate that consideration should be given to the selection of speech tasks during the process leading to automation of revised speech behavior and that self-reports may be a reliable index of cognitive load. PMID- 28006056 TI - Vertical Sweep Deformity After Face-lift. PMID- 28006055 TI - Association of DNA Mismatch Repair and Mutations in BRAF and KRAS With Survival After Recurrence in Stage III Colon Cancers : A Secondary Analysis of 2 Randomized Clinical Trials. AB - Importance: The association of biomarkers with patient survival after recurrence (SAR) of cancer is poorly understood but may guide management and treatment. Objective: To determine the association of DNA mismatch repair (MMR) status and somatic mutation in the B-Raf proto-oncogene (c.1799T>A [V600E]; BRAFV600E) or exon 2 of the KRAS proto-oncogene (KRAS) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant chemotherapy. Design, Setting, and Participants: Patients with resected stage III colon cancers were randomized to adjuvant FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) chemotherapy with or without cetuximab (North Central Cancer Treatment Group N0147 trial) or adjuvant FOLFOX chemotherapy with or without bevacizumab (National Surgical Adjuvant Breast and Bowel Project C-08 trial). Associations of biomarkers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features and time to recurrence (data collected February 10, 2004, to August 7, 2015). Main Outcomes and Measures: The primary study outcome was survival after recurrence of cancer. A secondary outcome measure was the effect of the site of the primary tumor on the association of biomarkers with SAR. Results: Among 871 patients with cancer recurrence in the N0147 trial (472 men [54.2%] and 399 women [45.8%]; mean [SD] age, 57.8 [11.2] years) and 524 in the C-08 trial (269 men [51.3%] and 255 women [48.7%]; mean [SD] age, 57.0 [11.7] years), multivariable analysis revealed that patients whose tumors had deficient vs proficient MMR had significantly better SAR (adjusted hazard ratio [AHR], 0.70; 95% CI, 0.52-0.96; P = .03). Patients whose tumors harbored mutant BRAFV600E (AHR, 2.45; 95% CI, 1.85-3.25; P < .001) or mutant KRAS (AHR, 1.21; 95% CI, 1.00-1.47; P = .052) had worse SAR compared with those whose tumors had wild-type copies of both genes, although only results for BRAFV600E achieved statistical significance. Significant interactions were found for MMR (P = .03) and KRAS (P = .02) by primary tumor site for SAR. Improved SAR was observed for patients with deficient MMR tumors of the proximal vs distal colon (AHR, 0.57; 95% CI, 0.40-0.83; P = .003), and worse SAR was observed for tumors of the distal colon with mutant KRAS in codon 12 (AHR, 1.76; 95% CI, 1.30-2.38; P < .001) and codon 13 (AHR, 1.76; 95% CI, 1.08-2.86; P = .02). Conclusions and Relevance: In patients with recurrence of stage III colon cancer, deficient MMR was significantly associated with better SAR, and this benefit was limited to primary tumors of the proximal colon. Mutations in BRAFV600E were significantly associated with worse SAR, and worse SAR for BRAFV600E or KRAS mutant tumors was more strongly associated with distal cancers. These biomarkers have implications for patient management at recurrence. Trial Registration: clinicaltrials.gov Identifiers: NCT00079274 and NCT00096278. PMID- 28006057 TI - Recalcitrant Orbital Pain in a 50-Year-Old Woman. PMID- 28006058 TI - An Expansile Mass of the Sphenoid Sinus or Petrous Apex. PMID- 28006060 TI - The Optimal Body Mass Index Range for Patients With Colorectal Cancer-Reply. PMID- 28006061 TI - The KRAS Variant as a Predictive Biomarker of Cetuximab Response in Head and Neck Cancer. PMID- 28006059 TI - The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment. Objectives: To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor beta1 (TGF-beta1). Design, Setting, and Participants: A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF beta1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model. Main Outcomes and Measures: The correlation of KRAS variant status with cetuximab response and outcome, p16 status, and plasma TGF beta1 levels was tested. Results: Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-beta1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS variant treated without cetuximab had worse PFS than patients without the KRAS variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-beta1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects. Conclusions and Relevance: Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-beta1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-beta1-induced suppression of antitumor immunity. Trial Registration: clinicaltrials.gov Identifier: NCT00265941. PMID- 28006062 TI - Association Between Benign Breast Disease in African American and White American Women and Subsequent Triple-Negative Breast Cancer. AB - Importance: Compared with white American (WA) women, African American (AA) women have a 2-fold higher incidence of breast cancers that are negative for estrogen receptor, progesterone receptor, and ERBB2 (triple-negative breast cancer [TNBC]). Triple-negative breast cancer, compared with non-TNBC, likely arises from different pathogenetic pathways, and benign breast disease (BBD) predicts future non-TNBC. Objective: To determine whether AA identity remains associated with TNBC for women with a prior diagnosis of BBD. Design, Setting, and Participants: This study is a retrospective analysis of data of a cohort of 2588 AA and 3566 WA women aged between 40 and 70 years with a biopsy-proven BBD diagnosis. The data-obtained from the Pathology Information System of Henry Ford Health System (HFHS), an integrated multihospital and multispecialty health care system headquartered in Detroit, Michigan-include specimens of biopsies performed between January 1, 1994, and December 31, 2005. Data analysis was performed from November 1, 2015, to June 15, 2016. Main Outcomes and Measures: Subsequent breast cancer was stratified on the basis of combinations of hormone receptor and ERBB2 expression. Results: Case management, follow-up, and outcomes received or obtained by our cohort of 2588 AA and 3566 WA patients were similar, demonstrating that HFHS delivered care equitably. Subsequent breast cancers developed in 103 (4.1%) of AA patients (mean follow-up interval of 6.8 years) and 143 (4.0%) of WA patients (mean follow-up interval of 6.1 years). More than three quarters of subsequent breast cancers in each subset were ductal carcinoma in situ or stage I. The 10-year probability estimate for developing TNBC was 0.56% (95% CI, 0.32%-1.0%) for AA patients and 0.25% (95% CI, 0.12%-0.53%) for WA patients. Among the 66 AA patients who developed subsequent invasive breast cancer, 16 (24.2%) developed TNBC compared with 7 (7.4%) of the 94 WA patients who developed subsequent invasive breast cancers and had complete biomarker data (P = .01). Conclusions and Relevance: This study is the largest analysis to date of TNBC in the context of racial/ethnic identity and BBD as risk factors. The study found that AA identity persisted as a significant risk factor for TNBC. This finding suggests that AA identity is associated with inherent susceptibility for TNBC pathogenetic pathways. PMID- 28006063 TI - Intravitreal Aflibercept Injection in Eyes With Substantial Vision Loss After Laser Photocoagulation for Diabetic Macular Edema: Subanalysis of the VISTA and VIVID Randomized Clinical Trials. AB - Importance: Information on the effect of anti-vascular endothelial growth factor therapy in eyes with diabetic macular edema (DME) with vision loss after macular laser photocoagulation is clinically valuable. Objective: To evaluate visual and anatomic outcomes in a subgroup of macular laser photocoagulation treatment control (hereafter laser control) eyes with substantial vision loss receiving treatment with intravitreal aflibercept injection. Design, Setting, and Participants: This investigation was a post hoc analysis of a subgroup of laser control eyes in 2 phase 3 trials-VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)-in a multicenter setting. One hundred nine laser control eyes with center-involving DME were included. Interventions: Treatment with intravitreal aflibercept injection (2 mg) every 8 weeks after 5 monthly doses with sham injections on nontreatment visits starting at week 24 was initiated on meeting prespecified criteria of at least a 10-letter visual acuity loss at 2 consecutive visits or at least a 15-letter visual acuity loss from the best previous measurement at 1 visit and vision not better than at baseline. Main Outcomes and Measures: Visual and anatomic outcomes in a subgroup of laser control eyes receiving treatment with intravitreal aflibercept injection. Results: Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 (VISTA) and 83.5 (VIVID) days. In this subgroup, the mean (SD) visual gain from baseline to week 100 was 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters. At the time of intravitreal aflibercept injection initiation, these eyes had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline, and they subsequently gained a mean (SD) of 17.4 (9.7) (VISTA) and 13.6 (8.6) (VIVID) letters from the initiation of treatment with intravitreal aflibercept injection through week 100. There was a minimal mean change in central subfield thickness from baseline in these eyes at the time of intravitreal aflibercept injection initiation (an increase of 3.9 MUm in VISTA and a decrease of 3.0 MUm in VIVID), after which further mean (SD) reductions of 285.6 (202.6) MUm (VISTA) and 313.4 (181.9) MUm (VIVID) occurred through week 100. Conclusions and Relevance: Intravitreal aflibercept injection improves visual and anatomic outcomes in eyes experiencing substantial vision loss after macular laser photocoagulation treatment for DME. Trial Registration: clinicaltrials.gov Identifiers: NCT01363440 and NCT01331681. PMID- 28006064 TI - Evidence in Favor of Standard Surgical Treatment for Rectal Cancer. PMID- 28006065 TI - Predicting individual contrast sensitivity functions from acuity and letter contrast sensitivity measurements. AB - Contrast sensitivity (CS) is widely used as a measure of visual function in both basic research and clinical evaluation. There is conflicting evidence on the extent to which measuring the full contrast sensitivity function (CSF) offers more functionally relevant information than a single measurement from an optotype CS test, such as the Pelli-Robson chart. Here we examine the relationship between functional CSF parameters and other measures of visual function, and establish a framework for predicting individual CSFs with effectively a zero-parameter model that shifts a standard-shaped template CSF horizontally and vertically according to independent measurements of high contrast acuity and letter CS, respectively. This method was evaluated for three different CSF tests: a chart test (CSV-1000), a computerized sine-wave test (M&S Sine Test), and a recently developed adaptive test (quick CSF). Subjects were 43 individuals with healthy vision or impairment too mild to be considered low vision (acuity range of -0.3 to 0.34 logMAR). While each test demands a slightly different normative template, results show that individual subject CSFs can be predicted with roughly the same precision as test retest repeatability, confirming that individuals predominantly differ in terms of peak CS and peak spatial frequency. In fact, these parameters were sufficiently related to empirical measurements of acuity and letter CS to permit accurate estimation of the entire CSF of any individual with a deterministic model (zero free parameters). These results demonstrate that in many cases, measuring the full CSF may provide little additional information beyond letter acuity and contrast sensitivity. PMID- 28006066 TI - Serial dependence promotes object stability during occlusion. AB - Object identities somehow appear stable and continuous over time despite eye movements, disruptions in visibility, and constantly changing visual input. Recent results have demonstrated that the perception of orientation, numerosity, and facial identity is systematically biased (i.e., pulled) toward visual input from the recent past. The spatial region over which current orientations or face identities are pulled by previous orientations or identities, respectively, is known as the continuity field, which is temporally tuned over the past several seconds (Fischer & Whitney, 2014). This perceptual pull could contribute to the visual stability of objects over short time periods, but does it also address how perceptual stability occurs during visual discontinuities? Here, we tested whether the continuity field helps maintain perceived object identity during occlusion. Specifically, we found that the perception of an oriented Gabor that emerged from behind an occluder was significantly pulled toward the random (and unrelated) orientation of the Gabor that was seen entering the occluder. Importantly, this serial dependence was stronger for predictable, continuously moving trajectories, compared to unpredictable ones or static displacements. This result suggests that our visual system takes advantage of expectations about a stable world, helping to maintain perceived object continuity despite interrupted visibility. PMID- 28006067 TI - Motion direction influences surface segmentation in stereo transparency. AB - To perceive multiple overlapping surfaces in the same location of the visual field (transparency), the visual system must determine which surface elements belong together, and should be integrated, and which should be kept apart. Spatial relations between surfaces, such as depth order, must also be determined. This article details two experiments examining the interaction of motion direction and disparity cues on the perception of depth order and surface segmentation in transparency. In Experiment 1, participants were presented with random-dot stereograms, where transparent planes were defined by differences in motion direction and disparity. Participants reported the direction of motion of the front surface. Results revealed marked effects of motion direction on perceived depth order. These biases interact with disparity in an additive manner, suggesting that the visual system integrates motion direction with other available cues to surface segmentation. This possibility was tested further in Experiment 2. Participants were presented with two intervals: one containing motion and disparity defined transparent planes, the other containing a volume of moving dots. Interplane disparity was varied to find thresholds for the correct identification of the transparent interval. Thresholds depended on motion direction: Thresholds were lower when disparities and directions in the transparency interval matched participants' preferred depth order, compared to conditions where disparity and direction were in conflict. These results suggest that motion direction influences the judgment of depth order even in the presence of other visual cues, and that the assignment of depth order may play an important role in segmentation. PMID- 28006068 TI - Orientation discrimination requires coactivation of on- and off-dominated visual channels. AB - Orientation sensitivity depends on the cortical convergence of on- and off-center subcortical neurons. Off-center inputs are faster and stronger than their on center counterparts: How does this asymmetry affect orientation discrimination? We tackled this question psychophysically with grating stimuli that either increased or decreased luminance. The gratings were of low contrast in order to avoid the complicating influences of nonlinearities such as response saturation, masking, and aftereffects. Gratings were presented in either of two locations, and subjects indicated the perceived location. Stimuli were randomly timed, and response correctness and reaction time were recorded. We found the following: (a) Contrast sensitivity was insignificant for a range of contrasts around zero. (b) Outside this range, contrast sensitivity for contrast decrements exceeded that for increments by an average of 15%. (c) Reaction times for contrast decrements were up to 45 ms less than for increments. (d) These findings are reproduced by a signal-detection model which incorporates recent physiological findings: Neurons in primary visual cortex are hyperpolarized at rest; these neurons respond more to darks than to lights; and off-dominated cortical neurons have shorter latencies than their on-dominated neighbors. (e) We tested orientation discrimination by splitting a grating into two components, one containing the light bars and the other the dark, and presenting the two components asynchronously. Discrimination was optimal when light bars preceded dark bars, consistent with coactivation of on- and off-center cortical inputs. We conclude that the ability to discriminate between orientations is intimately connected with the properties of subcortical channels. PMID- 28006069 TI - Expectations and visual aftereffects. AB - The tilt aftereffect (TAE) is traditionally regarded as a consequence of orientation-selective sensory adaptation, a low-level stimulus-driven process. Adaptation has been recently suggested to be the outcome of predictive coding. Here, we tested whether the TAE is modulated by predictability, and specifically, whether TAE depends on the congruency of adapted and expected orientations. Observers were presented with successive pairs of oriented Gabor patches. Pairs were arranged in blocks, forming two conditions with the orientation of the second pair member either predictable or not. For all pairs, the orientation of the first Gabor was tilted clockwise (CW) or counterclockwise (CCW) (+/-20 degrees relative to vertical, randomized). In the "Expected" conditions, the orientation of the second Gabor was fixed relative to the first Gabor (the same or a mirror orientation, blocked). In the "no-expectation" condition, the orientation of the second Gabor was independent of the first Gabor (randomized +/ 20 degrees ). Intermixed test pairs were used to measure observers' perceived vertical, with the second pair member serving as a target, oriented around the vertical, permitting an estimate of the TAE produced by the presentation of the first Gabor. Results show an increase in TAE with the expected orientation matching the inducing orientation, but a decrease with the expected mirror orientation, consistent with additivity of the adaptation and the expectation effects. A second experiment, with the first oriented Gabor replaced by a colored circular blob, showed that expectation alone does not modulate the perceived orientation. These findings indicate a role for expectation in generating the perceptual TAE and are in line with predictive coding models of perception. We suggest that orientation dependent adaptation is affected by both the mean orientation (first order statistics) and by temporal contingencies (second order statistics). PMID- 28006070 TI - Smooth pursuit detection in binocular eye-tracking data with automatic video based performance evaluation. AB - An increasing number of researchers record binocular eye-tracking signals from participants viewing moving stimuli, but the majority of event-detection algorithms are monocular and do not consider smooth pursuit movements. The purposes of the present study are to develop an algorithm that discriminates between fixations and smooth pursuit movements in binocular eye-tracking signals and to evaluate its performance using an automated video-based strategy. The proposed algorithm uses a clustering approach that takes both spatial and temporal aspects of the binocular eye-tracking signal into account, and is evaluated using a novel video-based evaluation strategy based on automatically detected moving objects in the video stimuli. The binocular algorithm detects 98% of fixations in image stimuli compared to 95% when only one eye is used, while for video stimuli, both the binocular and monocular algorithms detect around 40% of smooth pursuit movements. The present article shows that using binocular information for discrimination of fixations and smooth pursuit movements is advantageous in static stimuli, without impairing the algorithm's ability to detect smooth pursuit movements in video and moving-dot stimuli. With an automated evaluation strategy, time-consuming manual annotations are avoided and a larger amount of data can be used in the evaluation process. PMID- 28006071 TI - Lightness perception for surfaces moving through different illumination levels. AB - Lightness perception has mainly been studied with static scenes so far. This study presents four experiments investigating lightness perception under dynamic illumination conditions. We asked participants for lightness matches of a virtual three-dimensional target moving through a light field while their eye movements were recorded. We found that the target appeared differently, depending on the direction of motion in the light field and its precise position in the light field. Lightness was also strongly affected by the choice of fixation positions with the spatiotemporal image sequence. Overall, lightness constancy was improved when observers could freely view the object, over when they were forced to fixate certain regions. Our results show that dynamic scenes and nonuniform light fields are particularly challenging for our visual system. Eye movements in such scenarios are chosen to improve lightness constancy. PMID- 28006073 TI - Accuracy of eye position for saccades and smooth pursuit. AB - In this study, we address the question of whether a target is foveated during smooth pursuit. Specifically, we examine whether smooth pursuit eye movements land near the center-of-mass of the target, as is the case for saccades. To that end, we instructed eight untrained, healthy participants to follow moving targets, presented monocularly in a scanning laser ophthalmoscope. Stimuli moved either in a modified step-ramp (smooth pursuit), or made a single step (saccade), stepping 6 degrees from the center. Targets were ring-shaped and either 0.6 degrees or 1.7 degrees in diameter. In an additional set of experiments, two participants collected more extensive data on smooth pursuit and saccades for a larger range of target sizes (0.6 degrees , 1.7 degrees , or 4.3 degrees ). During pursuit, eyes were rarely placed at target center, even when participants' fixational stability was taken into account. Furthermore, there was a clear tendency for distance from target center to increase with target size. This outcome was in contrast to saccades, where there was no effect of target size across participants. The difference in foveal placement between the two types of eye movements is consistent with their different purposes: closer inspection of the target for saccades versus maintenance of the target in the visual field for smooth pursuit. PMID- 28006072 TI - The time course of binocular rivalry during the phases of the menstrual cycle. AB - Binocular rivalry occurs when markedly different inputs to the two eyes initiate alternations in perceptual dominance between the two eyes' views. A link between individual differences in perceptual dynamics of rivalry and concentrations of GABA, a prominent inhibitory neurotransmitter in the brain, has highlighted binocular rivalry as a potential tool to investigate inhibitory processes in the brain. The present experiment investigated whether previously reported fluctuations of GABA concentrations in a healthy menstrual cycle (Epperson et al., 2002) also are associated with measurable changes in rivalry dynamics within individuals. We obtained longitudinal measures of alternation rate, dominance, and mixture durations in 300 rivalry tracking blocks measured over 5 weeks from healthy female participants who monitored the start of the follicular and luteal phases of their cycle. Although we demonstrate robust and stable individual differences in rivalry dynamics, across analytic approaches and dependent measures, we found no significant change or even trends across menstrual phases in the temporal dynamics of dominance percepts. We found only sparse between phase differences in skew and kurtosis on mixture percepts when data were pooled across sessions and blocks. These results suggest a complex dynamic between hormonal steroids, binocular rivalry, and GABAeric signaling in the brain and thus implicate the need to consider a systemic perspective when linking GABA with perceptual alternations in binocular rivalry. PMID- 28006074 TI - OpenEyeSim: A biomechanical model for simulation of closed-loop visual perception. AB - We introduce OpenEyeSim, a detailed three-dimensional biomechanical model of the human extraocular eye muscles including a visualization of a virtual environment. The main purpose of OpenEyeSim is to serve as a platform for developing models of the joint learning of visual representations and eye-movement control in the perception-action cycle. The architecture and dynamic muscle properties are based on measurements of the human oculomotor system. We show that our model can reproduce different types of eye movements. Additionally, our model is able to calculate metabolic costs of eye movements. It is also able to simulate different eye disorders, such as different forms of strabismus. We propose OpenEyeSim as a platform for studying many of the complexities of oculomotor control and learning during normal and abnormal visual development. PMID- 28006075 TI - A behavioral task sets an upper bound on the time required to access object memories before object segregation. AB - Traditional theories of vision assume that object segregation occurs before access to object memories. Yet, behavioral evidence shows that familiar configuration is a prior for segregation, and electrophysiological experiments demonstrate these memories are accessed rapidly. A behavioral index of the speed of access is lacking, however. Here we asked how quickly behavior is influenced by object memories that are accessed in the course of object segregation. We investigated whether access to object memories on the groundside of a border can slow behavior during a rapid categorization task. Participants viewed two silhouettes that depicted a real-world and a novel object. Their task was to saccade toward the real-world object as quickly as possible. Half of the nontarget novel objects were ambiguous in that a portion of a real-world object was suggested, but not consciously perceived, on the groundside of their borders. The rest of the nontargets were unambiguous. We tested whether saccadic reaction times were perturbed by the real-world objects suggested on the groundside of ambiguous novel silhouettes. In Experiments 1 and 2, saccadic reaction times were slowed when nontargets were ambiguous rather than unambiguous. Experiment 2 set an upper limit of 190 ms on the time required for object memories in grounds to influence behavior. Experiment 3 ruled out factors that could have produced longer latencies other than access to object memories. These results provide the first behavioral index of how quickly memories of objects suggested in grounds can influence behavior, placing the upper limit at 190 ms. PMID- 28006076 TI - Eggs illusion: Local shape deformation generated by a grid pattern. AB - In this study, we report a new visual shape illusion, the eggs illusion, in which circular disks located at the midpoints between adjacent grid intersections are perceived as being deformed to ellipses. In Experiment 1, we examined the eggs illusion by using a matching method and found that grid luminance and patch size play a critical role in producing the illusory deformation. In Experiment 2, we employed several types of elliptic or circular patches to examine the conditions in which the illusory deformation was cancelled or weakened. We observed that the illusory deformation was dependent on local grid orientation. Based on these results, we found several common features between the eggs illusion and the scintillating grid illusion. This resemblance suggests a possibility that similar mechanisms underlie the two phenomena. In addition to the scintillating grid illusion, we also considered several known perceptual phenomena that might be related to the eggs illusion, i.e., the apparent size illusion, the shape contrast effect, and the Orbison illusion. Finally, we discuss the role of orientation processing in generating the eggs illusion. PMID- 28006077 TI - Serial dependence in the perception of attractiveness. AB - The perception of attractiveness is essential for choices of food, object, and mate preference. Like perception of other visual features, perception of attractiveness is stable despite constant changes of image properties due to factors like occlusion, visual noise, and eye movements. Recent results demonstrate that perception of low-level stimulus features and even more complex attributes like human identity are biased towards recent percepts. This effect is often called serial dependence. Some recent studies have suggested that serial dependence also exists for perceived facial attractiveness, though there is also concern that the reported effects are due to response bias. Here we used an attractiveness-rating task to test the existence of serial dependence in perceived facial attractiveness. Our results demonstrate that perceived face attractiveness was pulled by the attractiveness level of facial images encountered up to 6 s prior. This effect was not due to response bias and did not rely on the previous motor response. This perceptual pull increased as the difference in attractiveness between previous and current stimuli increased. Our results reconcile previously conflicting findings and extend previous work, demonstrating that sequential dependence in perception operates across different levels of visual analysis, even at the highest levels of perceptual interpretation. PMID- 28006078 TI - Corrections. PMID- 28006079 TI - The Optimal Body Mass Index Range for Patients With Colorectal Cancer. PMID- 28006081 TI - Consequences of Ca Codoping in YAlO3 :Ce Single Crystals. AB - The influence of Ca codoping on the optical absorption, photo-, radio-, and thermo-luminescence properties of YAlO3 :Ce (YAP:Ce) crystals has been studied for four different calcium concentrations ranging from 0 to 500 ppm. Ca codoping results in a partial oxidation of Ce3+ into Ce4+ , The luminescence time response under pulsed X-ray excitation of the Ce3+ /Ce4+ admixure clearly demonstrates the role of hole migration on both the rise time and the generally observed slow components. From an application point of view, Ca codoping significantly improves the timing performances, but the induced presence of Ce4+ ions is also the cause of a reduction in scintillation efficiency. PMID- 28006080 TI - Crown-rump length audit plots with the use of operator-specific PAPP-A and beta hCG median MoM. AB - OBJECTIVE: Audit the crown-rump length (CRL) measurements taken at 11 to 13 weeks scan, using operator-specific median multiples of the median (MoM) for pregnancy associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) plots, to identify deviations potentially related to a systematic CRL bias. METHODS: Study population included consecutive singleton pregnancies undergoing first trimester combined screening, scanned by sonologists with at least 100 scans, during the 2011 to 2012 period. Previously described plots for PAPP-A and beta-hCG median MoM points, with their 95% confidence intervals circles, in relation with the expected deviation line were used. These plots have been modified to adjust the deviation line to the sonologist-specific expected MoM variation for each CRL millimetre bias according to each sonologist-specific median gestational ages at both blood sampling and ultrasound. RESULTS: Twenty eight sonologists performing 9472 scans were included, accounting for 36% of the 77 sonologists and 70% of the 13 643 scans initially considered. Mean gestational age was 10 + 2 weeks at blood sampling and 12 + 4 weeks at ultrasound. Fifteen sonologists (53%) did not demonstrate any CRL bias, 10 (36%) present with a significant CRL underestimation, being above 2 mm in 6 (21%), and in 3 (11%) the observed deviation could not be explained by a systematic CRL bias. CONCLUSIONS: In sonologists with more than 100 NT measurements, operator-specific PAPP-A and beta-hCG median MoM plots are able to identify deviations potentially related to a systematic CRL bias. Systematic underestimation above 2 mm was observed in 1/5 of them. (c) 2016 John Wiley & Sons, Ltd. PMID- 28006082 TI - Simplified AIP-II Peptidomimetics Are Potent Inhibitors of Staphylococcus aureus AgrC Quorum Sensing Receptors. AB - The bacterial pathogen Staphylococcus aureus controls many aspects of virulence by using the accessory gene regulator (agr) quorum sensing (QS) system. The agr system is activated by a macrocyclic peptide signal known as an autoinducing peptide (AIP). We sought to develop structurally simplified mimetics of AIPs for use as chemical tools to study QS in S. aureus. Herein, we report new peptidomimetic AgrC receptor inhibitors based on a tail-truncated AIP-II peptide that have almost analogous inhibitory activities to the parent peptide. Structural comparison of one of these peptidomimetics to the parent peptide and a highly potent, all-peptide-derived, S. aureus agr inhibitor (AIP-III D4A) revealed a conserved hydrophobic motif and overall amphipathic nature. Our results suggest that the AIP scaffold is amenable to structural mimicry and minimization for the development of synthetic agr inhibitors. PMID- 28006084 TI - Predictive markers for delayed lymph node metastases and survival in early-stage oral squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to identify clinicopathological and immunohistochemical factors predicting delayed lymph node metastases and survival in early oral squamous cell carcinoma (OSCC). METHODS: The study included 85 consecutive patients with clinically T1 to T2N0 OSCC who were primarily surgically treated between 2000 and 2004. RESULTS: There were 68 men and 17 women (median age, 61 years; range, 34-82 years). Of all the patients, 25 (29.4%) developed delayed lymph node metastases within 3 to 42 months after treatment of the primary tumor. Multivariate logistic regression analysis identified poorly differentiated tumors, low laminin, and high fibronectin expression as prognosticators of delayed lymph node metastases. Cox's proportional hazards regression analysis demonstrated that moderately differentiated tumors and delayed lymph node metastases had predictive value regarding survival. CONCLUSION: Large prospective investigations with reproducibility and the clinical translatability of immunohistochemical methods are needed in order to provide new and effective therapeutic strategies in the future. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 694-701, 2017. PMID- 28006083 TI - Definitive carbon-ion radiotherapy for locally advanced parotid gland carcinomas. AB - BACKGROUND: The purpose of this study was to present our evaluation of the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for locally advanced parotid gland carcinomas. METHODS: Clinicopathological features and outcomes were evaluated in 46 patients receiving C-ion RT for parotid gland carcinomas. RESULTS: Sixteen patients had adenoid cystic carcinoma; 8 had adenocarcinoma, 8 had mucoepidermoid carcinoma, and 14 had other carcinomas. T2, T3, T4a, and T4b diseases were diagnosed in 3, 18, 8, and 17 patients, respectively. C-ion RT was provided to 25 patients as the primary treatment, to 20 patients for local recurrences after surgery, and to 1 patient for residual tumor after surgery. During follow-up (median duration, 62 months), 5-year local control and overall survival (OS) rates were 74.5% and 70.1%, respectively. Of the 30 patients without facial nerve palsy before C-ion RT, 25 showed no radiation-induced facial nerve palsy. CONCLUSION: C-ion RT is effective and has acceptable toxicity levels for locally advanced parotid gland carcinomas. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 724-729, 2017. PMID- 28006085 TI - Lymphatic drainage patterns of oral maxillary tumors: Approachable locations of sentinel lymph nodes mainly at the cervical neck level. AB - BACKGROUND: There is debate if the lymphatic drainage pattern of oral maxillary cancer is to the retropharyngeal lymph nodes or to the cervical lymph nodes. Insight in drainage patterns is important for the indication for neck treatment. The purpose of this study was to identify the lymphatic drainage pattern of oral maxillary cancer via preoperative lymphoscintigraphy. METHODS: Eleven consecutive patients with oral maxillary cancer treated in our center between December 1, 2012, and April 22, 2016 were studied. Sentinel lymph nodes identified by preoperative lymphoscintigraphy after injection of 99m Tc-nanocolloid and by intraoperative detection using a gamma-probe, were surgically removed and histopathologically examined. RESULTS: In 10 patients, sentinel lymph nodes were detected and harvested at cervical levels I, II, or III in the neck. In 2 patients, a parapharyngeal sentinel lymph node was detected. One of the harvested sentinel lymph nodes (1/19) was tumor positive. CONCLUSION: This study suggests the likelihood of 73% of exclusively cervical level I to III sentinel lymph nodes in oral maxillary cancer. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 486-491, 2017. PMID- 28006086 TI - Recurrent oral cavity cancer: Patterns of failure after salvage multimodality therapy. AB - BACKGROUND: We focused on a cohort of radiation naive patients who had recurrent oral cavity cancer (recurrent OCC) to assess their outcomes with salvage multimodal therapy. METHODS: A retrospective single institutional study was performed of patients with recurrent OCC. Disease recurrence and survival outcomes were assessed. RESULTS: Seventy-eight patients were analyzed. All patients had salvage surgery and intensity-modulated radiotherapy (IMRT) and 74% had chemotherapy. Five-year overall survival, recurrence-free survival, and locoregional control rates were 59%, 60%, and 74%, respectively. CONCLUSION: Outcomes of radiation naive patients with recurrent OCC are fair, and seem similar with patients with locally advanced nonrecurrent OCC treated with multimodal therapy. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 633-638, 2017. PMID- 28006087 TI - Significant and durable clinical benefit from trastuzumab in 2 patients with HER2 amplified salivary gland cancer and a review of the literature. AB - BACKGROUND: Salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis. The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options. METHODS: We describe 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling. Testing identified human epidermal growth factor receptor 2 (HER2) amplification in both patients, and an additional activating HER2 mutation in the CEPA case. RESULTS: Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (herceptin) plus chemotherapy and experienced rapid responses. Subsequently, both patients were given single-agent maintenance trastuzumab and continue to experience durable disease control. CONCLUSION: Given the poor prognosis for salivary gland cancers and the limited treatment options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations. In cases with HER2 overexpression or activation, targeted therapies, such as trastuzumab are promising. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: E40-E44, 2017. PMID- 28006089 TI - Acute Withdrawal After Dialysis in a Patient With Chronic Stimulation of the GABAergic Receptors. PMID- 28006088 TI - Case of parotid mucoepidermoid carcinoma: Expanding the spectrum of von Hippel Lindau-related neoplasms. AB - BACKGROUND: von Hippel-Lindau (VHL)-related tumors occurring outside the spectrum of VHL-defining tumors are rare, and mucoepidermoid carcinoma (MEC) in the setting of VHL disease has not been described. METHODS AND RESULTS: We describe a patient with confirmed VHL mutation who presented with a parotid mass and a history of 2 central nervous system (CNS) hemangioblastomas and 1 pheochromocytoma. Fine-needle aspiration (FNA) of the mass suggested a benign Warthin tumor. The mass was resected and final pathology revealed a low-grade MEC. Fluorescence in situ hybridization for the MECT1/MAML2 fusion gene frequently associated with MEC was performed and was negative. Molecular testing of tumor cells displayed a likely "second hit" VHL gene mutation. CONCLUSION: There is a possible broader role of VHL mutations in tumorigenesis beyond the development of classically described VHL-defining neoplasms. Our case also demonstrates the importance of always considering the possibility of a parotid malignancy in patients with VHL despite a benign FNA. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: E51-E54, 2017. PMID- 28006090 TI - Self-Harm in Sertraline-Induced Akathisia. PMID- 28006091 TI - Cardiometabolic Assessment, Diagnosis, and Treatment of Chronic Medical Illnesses During an Inpatient Psychiatric Hospitalization: Colocated Medical Care Versus Treatment as Usual. AB - Background: Reverse colocation care models reduce lifestyle risk factors, emergency department visits, and readmissions. Persons with serious mental illness have higher than average rates of cardiovascular disease-related morbidity and mortality, with second-generation antipsychotics (SGAs) conferring added related risks. Little is written about reverse colocated medical care (RCL) in inpatient psychiatric settings. The objective of this study was to identify associations between screening, diagnosis, and treatment of chronic medical comorbidities and mode of medical care for patients discharged from 2 inpatient psychiatric units on SGAs. Methods: This was a cross-sectional retrospective study of medical comorbidities identified and treated for adults consecutively admitted from January 1, 2015, to October 31, 2015, to 2 inpatient psychiatry units of an academic center and discharged on SGAs. One unit has a primary care team consisting of a physician assistant backed up by a medical doctor who provide medical care (RCL). The other unit has medical care provided by psychiatrists with hospitalists as needed (treatment as usual, TAU). We conducted a chart review of demographics, vital signs, laboratory values, diagnoses, and medications with comparative analysis of the evaluation, diagnosis, and treatment for hypertension, diabetes mellitus, hyperlipidemia, obesity, and tobacco use disorder. Results: In total, 232 patients were discharged from the TAU group and 220 from the RCL group. Significantly more screening laboratory values (glucose, hemoglobin A1c, lipids) were obtained in the TAU group, while documented responses to abnormal tests were higher in the RCL group. Patients were more likely in the RCL group to be diagnosed with obesity, tobacco use disorder, and hyperlipidemia and to be treated for hypertension and hyperlipidemia. Conclusions: Reverse colocated medical care is effective in improving screening, diagnosis, and treatment of chronic medical diseases among psychiatric inpatients.. PMID- 28006092 TI - Simultaneous Measurement of the Dissolution Kinetics of Responsive DNA Hydrogels at Multiple Length Scales. AB - Recent years have seen increasing study of stimulus-responsive hydrogels constructed from aptamer-connected DNA building blocks. Presumably due to a lack of simple, quantitative tools with which to measure gel responsiveness, however, the literature describing these materials is largely qualitative. In response, we demonstrate here simple, time-resolved, multiscale methods for measuring the response kinetics of these materials. Specifically, by employing trace amounts of fluorophore-quencher labeled cross-linkers and the rheology of entrapped fluorescent particles, we simultaneously measure dissolution at molecular, hundred-nanometer, and hundred-micron length-scales. For our test-bed system, an adenine-responsive hydrogel, we find biphasic response kinetics dependent on both effector concentration and depth within the gel and a dissolution pattern uniform at scales longer than a few times the monomer-monomer distance. Likewise, we find that, in agreement with theoretical predictions, dissolution kinetics over the hundred nanometer length scale exhibit a power-law-like dependence on the fraction of disrupted cross-links before a distinct crossover from solid-like to liquid-like behavior. PMID- 28006093 TI - Catalase-Modulated Heterogeneous Fenton Reaction for Selective Cancer Cell Eradication: SnFe2O4 Nanocrystals as an Effective Reagent for Treating Lung Cancer Cells. AB - Heterogeneous Fenton reactions have been proven to be an effective and promising selective cancer cell treatment method. The key working mechanism for this method to achieve the critical therapeutic selectivity however remains unclear. In this study, we proposed and demonstrated for the first time the critical role played by catalase in realizing the therapeutic selectivity for the heterogeneous Fenton reaction-driven cancer cell treatment. The heterogeneous Fenton reaction, with the lattice ferric ions of the solid catalyst capable of converting H2O2 to highly reactive hydroxyl radicals, can effectively eradicate cancer cells. In this study, SnFe2O4 nanocrystals, a recently discovered outstanding heterogeneous Fenton catalyst, were applied for selective killing of lung cancer cells. The SnFe2O4 nanocrystals, internalized into the cancer cells, can effectively convert endogenous H2O2 into highly reactive hydroxyl radicals to invoke an intensive cytotoxic effect on the cancer cells. On the other hand, catalase, present at a significantly higher concentration in normal cells than in cancer cells, remarkably can impede the apoptotic cell death induced by the internalized SnFe2O4 nanocrystals. According to the results obtained from the in vitro cytotoxicity study, the relevant oxidative attacks were effectively suppressed by the presence of normal physiological levels of catalase. The SnFe2O4 nanocrystals were thus proved to effect apoptotic cancer cell death through the heterogeneous Fenton reaction and were benign to cells possessing normal physiological levels of catalase. The catalase modulation of the involved heterogeneous Fenton reaction plays the key role in achieving selective cancer cell eradication for the heterogeneous Fenton reaction-driven cancer cell treatment. PMID- 28006094 TI - Responses of MSCs to 3D Scaffold Matrix Mechanical Properties under Oscillatory Perfusion Culture. AB - Both fluid shear stress and matrix stiffness are implicated in bone metabolism and functional adaptation, but the synergistic action of these mechanical cues on the biological behaviors of mesenchymal stem cells (MSCs) is still not well known. In the present work, a homemade oscillatory flow device was applied to investigate the effects of matrix stiffness on MSCs survival, distribution, and osteogenic differentiation in three-dimensional (3D) conditions. Furthermore, the flow field and cell growth in this bioreactor were theoretically simulated. The results demonstrated that oscillatory shear stress significantly increased the viability and distribution uniformity of MSCs throughout the scaffold after culture for 3 weeks. Compared to static culture, oscillatory shear stress could promote the collagen secretion, mineral deposits, and osteogenic differentiation of MSCs. The findings obtained from this work indicate that the oscillatory perfusion not only provides a higher survival rate and a more uniform distribution of cells but also facilitates osteogenic differentiation of MSCs. Oscillating perfusion bioreactor culture of MSCs in 3D scaffold with optimal matrix stiffness could offer an easy-to-use but efficient bioreactor for bone tissue engineering. PMID- 28006095 TI - Zero-Power-Consumption Solar-Blind Photodetector Based on beta-Ga2O3/NSTO Heterojunction. AB - A solar-blind photodetector based on beta-Ga2O3/NSTO (NSTO = Nb:SrTiO3) heterojunctions were fabricated for the first time, and its photoelectric properties were investigated. The device presents a typical positive rectification in the dark, while under 254 nm UV light illumination, it shows a negative rectification, which might be caused by the generation of photoinduced electron-hole pairs in the beta-Ga2O3 film layer. With zero bias, that is, zero power consumption, the photodetector shows a fast photoresponse time (decay time taud = 0.07 s) and the ratio Iphoto/Idark ~ 20 under 254 nm light illumination with a light intensity of 45 MUW/cm2. Such behaviors are attributed to the separation of photogenerated electron-hole pairs driven by the built-in electric field in the depletion region of beta-Ga2O3 and the NSTO interface, and the subsequent transport toward corresponding electrodes. The photocurrent increases linearly with increasing the light intensity and applied bias, while the response time decreases with the increase of the light intensity. Under -10 V bias and 45 MUW/cm2 of 254 nm light illumination, the photodetector exhibits a responsivity Rlambda of 43.31 A/W and an external quantum efficiency of 2.1 * 104 %. The photo to-electric conversion mechanism in the beta-Ga2O3/NSTO heterojunction photodetector is explained in detail by energy band diagrams. The results strongly suggest that a photodetector based on beta-Ga2O3 thin-film heterojunction structure can be practically used to detect weak solar-blind signals because of its high photoconductive gain. PMID- 28006096 TI - Competitive Oxygen Evolution in Acid Electrolyte Catalyzed at Technologically Relevant Electrodes Painted with Nanoscale RuO2. AB - Using a solution-based, non-line-of sight synthesis, we electrolessly deposit ultrathin films of RuO2 ("nanoskins") on planar and 3D substrates and benchmark their activity and stability for oxygen-evolution reaction (OER) in acid electrolyte under device-relevant conditions. When an electrically contiguous ~9 nm thick RuO2 nanoskin is expressed on commercially available, insulating SiO2 fiber paper, the RuO2@SiO2 electrode exhibits high current density at low overpotential (10 mA cm-2 @ eta = 280 mV), courtesy of a catalyst amplified in 3D; however, the mass-normalized activity falls short of that achieved for films deposited on planar, metallic substrates (Ti foil). By wrapping the fibers with a <100 nm thick graphitic carbon layer prior to RuO2 deposition (RuO2@C@SiO2), we retain the high mass activity of the RuO2 (40-60 mA mg-1 @ eta = 330 mV) and preserve the desirable macroscale properties of the 3D scaffold: porous, lightweight, flexible, and inexpensive. The RuO2@C@SiO2 anodes not only achieve the 10 mA cm-2 figure of merit at a low overpotential (eta = ~270 mV), but more importantly they do so while (1) minimizing the mass of catalyst needed to achieve this metric, (2) incorporating the catalyst into a practical electrode design, and (3) improving the long-term stability of the catalyst. Our best performing anodes achieve state-of-the-art or better performance on the basis of area and mass, and do so with a catalyst density 300-580* less than that of bulk RuO2. By limiting the oxidizing potential required to evolve O2 at the electrode, even at 10 mA cm-2, we achieve stable activity for 100+ h. PMID- 28006097 TI - Indole Synthesis via Cyclative Formation of 2,3-Dizincioindoles and Regioselective Electrophilic Trapping. AB - Upon zincation of two acidic protons attached to the nitrogen and the sp-carbon atoms, a N-protected 2-ethynylaniline cyclizes to a 2,3-dizincioindole at 120 degrees C. Driven by the energy gain due to formation of two C-Zn bonds, this reaction occurs smoothly without side reactions, although this transformation is intrinsically endothermic in its bare anionic form. The resulting dizinc intermediate can be functionalized with one or two different electrophiles either inter- or intramolecularly on either C2 or C3 selectively, depending on the choice of catalyst and the electrophiles. This conversion of 2-ethynylaniline to 2,3-dimetalloindole can be applied to an expeditious synthesis of indenoindolone and benzodipyrrole derivatives, which are compounds of interest for medicinal chemistry and materials science, respectively. PMID- 28006098 TI - Regiochemically Controlled Synthesis of a beta-4-beta' [70]Fullerene Bis-Adduct. AB - A beta-4-beta' C70 bis-adduct regioisomer and an uncommon mono-adduct beta malonate C70 derivative were synthesized by using a Diels-Alder cycloaddition followed by an addition-elimination of bromo-ethylmalonate and a retro-Diels Alder cycloaddition reaction. We also report the regioselective synthesis and spectroscopic characterization of Cs-symmetric tris- and C2v-symmetric tetra adducts of C70, which are the precursors of the mono- and bis-adduct final products. PMID- 28006099 TI - Synthesis of Partially Hydrogenated Cycloparaphenylenes with Bent and Fused Structures Bearing Armchair Carbon Nanotube-like Connections. AB - The Diels-Alder reactions between 2 equiv of (E,E)-1,4-bis(4-bromophenyl)-1,3 butadiene and 1,4-benzoquinone led to the formation of a key intermediate with all four 4-bromophenyl substituents cis to one another. The subsequent nickel mediated homocoupling reactions then produced partially hydrogenated cycloparaphenylenes, including a molecule bearing two units of tetrahydro[6]cycloparaphenylene (4H[6]CPP) fused together through two 1,4 dimethoxybenzene units in an armchair (6,6)carbon nanotube-like connection. Similarly, two 6H[9]CPPs were connected through three 1,4-dimethoxybenzene units in an armchair (9,9)carbon nanotube-like arrangement. A bent 8H[12]CPP and a bent 12H[18]CPP, which were fused intramolecularly with two and three 1,4 dimethoxybenzene units, respectively, to create the bent structures, were likewise synthesized. A molecule containing a bent 8H[12]CPP fused to a 4H[6]CPP was likewise constructed. The structures of these partially hydrogenated CPPs were established by X-ray structure analysis, NMR spectroscopy, and additional independent synthetic pathways. PMID- 28006100 TI - Ultrathin Epitaxial Barrier Layer to Avoid Thermally Induced Phase Transformation in Oxide Heterostructures. AB - Incorporating oxides with radically different physical and chemical properties into heterostructures offers tantalizing possibilities to derive new functions and structures. Recently, we have fabricated freestanding 2D oxide membranes using the water-soluble perovskite Sr3Al2O6 as a sacrificial buffer layer. Here, with atomic-resolution spectroscopic imaging, we observe that direct growth of oxide thin films on Sr3Al2O6 can cause complete phase transformation of the buffer layer, rendering it water-insoluble. More importantly, we demonstrate that an ultrathin SrTiO3 layer can be employed as an effective barrier to preserve Sr3Al2O6 during subsequent growth, thus allowing its integration in a wider range of oxide heterostructures. PMID- 28006101 TI - Direct Observation of Energy Detrapping in LH1-RC Complex by Two-Dimensional Electronic Spectroscopy. AB - The purple bacterial core light harvesting antenna-reaction center (LH1-RC) complex is the simplest system able to achieve the entire primary function of photosynthesis. During the past decade, a variety of photosynthetic proteins were studied by a powerful technique, two-dimensional electronic spectroscopy (2DES). However, little attention has been paid to LH1-RC, although its reversible uphill energy transfer, trapping, and backward detrapping processes, represent a crucial step in the early photosynthetic reaction dynamics. Thus, in this work, we employed 2DES to study two LH1-RC complexes of Thermochromatium (Tch.) tepidum. By direct observation of detrapping, the complex reversible process was clearly identified and an overall scheme of the excitation evolution in LH1-RC was obtained. PMID- 28006102 TI - Diverse ortho-C(sp2)-H Functionalization of Benzaldehydes Using Transient Directing Groups. AB - Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho C(sp2)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue. PMID- 28006103 TI - Assessing the Potential of Folded Globular Polyproteins As Hydrogel Building Blocks. AB - The native states of proteins generally have stable well-defined folded structures endowing these biomolecules with specific functionality and molecular recognition abilities. Here we explore the potential of using folded globular polyproteins as building blocks for hydrogels. Photochemically cross-linked hydrogels were produced from polyproteins containing either five domains of I27 ((I27)5), protein L ((pL)5), or a 1:1 blend of these proteins. SAXS analysis showed that (I27)5 exists as a single rod-like structure, while (pL)5 shows signatures of self-aggregation in solution. SANS measurements showed that both polyprotein hydrogels have a similar nanoscopic structure, with protein L hydrogels being formed from smaller and more compact clusters. The polyprotein hydrogels showed small energy dissipation in a load/unload cycle, which significantly increased when the hydrogels were formed in the unfolded state. This study demonstrates the use of folded proteins as building blocks in hydrogels, and highlights the potential versatility that can be offered in tuning the mechanical, structural, and functional properties of polyproteins. PMID- 28006105 TI - Transfer Hydro-dehalogenation of Organic Halides Catalyzed by Ruthenium(II) Complex. AB - A simple and efficient Ru(II)-catalyzed transfer hydro-dehalogenation of organic halides using 2-propanol solvent as the hydride source was reported. This methodology is applicable for hydro-dehalogenation of a variety of aromatic halides and alpha-haloesters and amides without additional ligand, and quantitative yields were achieved in many cases. The potential synthetic application of this method was demonstrated by efficient gram-scale transformation with catalyst loading as low as 0.5 mol %. PMID- 28006104 TI - 13C-Labeled Idohexopyranosyl Rings: Effects of Methyl Glycosidation and C6 Oxidation on Ring Conformational Equilibria. AB - An ensemble of JHH, JCH, and JCC values was measured in aqueous solutions of methyl alpha- and beta-d-idohexopyranosides containing selective 13C-enrichment at various carbons. By comparing these J-couplings to those reported previously in the alpha- and beta-d-idohexopyranoses, methyl glycosidation was found to affect ring conformational equilibria, with the percentages of 4C1 forms based on 3JHH analysis as follows: alpha-d-idopyranose, ~18%; methyl alpha-d idopyranoside, ~42%; methyl beta-d-idopyranoside, ~74%; beta-d-idopyranose, 82%. JCH and JCC values were analyzed with assistance from theoretical values obtained from density functional theory (DFT) calculations. Linearized plots of the percentages of 4C1 against limiting JCH and JCC values in the chair forms were used to (a) determine the compatibility of the experimental JCH and JCC values with 4C1/1C4 ratios determined from JHH analysis and (b) determine the sensitivity of specific JCH and JCC values to ring conformation. Ring conformational equilibria for methyl idohexopyranosides differ significantly from those predicted from recent molecular dynamics (MD) simulations, indicating that equilibria determined by MD for ring configurations with energetically flat pseudorotational itineraries may not be quantitative. J-couplings in methyl alpha l-[6-13C]idopyranosiduronic acid and methyl alpha-d-[6-13C]glucopyranosiduronic acid were measured as a function of solution pH. The ring conformational equilibrium is pH-dependent in the iduronic acid. PMID- 28006106 TI - Interlayer Exciton Optoelectronics in a 2D Heterostructure p-n Junction. AB - Semiconductor heterostructures are backbones for solid-state-based optoelectronic devices. Recent advances in assembly techniques for van der Waals heterostructures have enabled the band engineering of semiconductor heterojunctions for atomically thin optoelectronic devices. In two-dimensional heterostructures with type II band alignment, interlayer excitons, where Coulomb bound electrons and holes are confined to opposite layers, have shown promising properties for novel excitonic devices, including a large binding energy, micron scale in-plane drift-diffusion, and a long population and valley polarization lifetime. Here, we demonstrate interlayer exciton optoelectronics based on electrostatically defined lateral p-n junctions in a MoSe2-WSe2 heterobilayer. Applying a forward bias enables the first observation of electroluminescence from interlayer excitons. At zero bias, the p-n junction functions as a highly sensitive photodetector, where the wavelength-dependent photocurrent measurement allows the direct observation of resonant optical excitation of the interlayer exciton. The resulting photocurrent amplitude from the interlayer exciton is about 200 times smaller than the resonant excitation of intralayer exciton. This implies that the interlayer exciton oscillator strength is 2 orders of magnitude smaller than that of the intralayer exciton due to the spatial separation of electron and hole to the opposite layers. These results lay the foundation for exploiting the interlayer exciton in future 2D heterostructure optoelectronic devices. PMID- 28006107 TI - Classification and Analysis of Attritional Glenoid Bone Loss in Recurrent Anterior Shoulder Instability. AB - BACKGROUND: Recognition and proper treatment of glenoid bone loss (GBL) are important for successful management of anterior shoulder instability. Although GBL has been described as the amount of bony loss from the front of the glenoid, there is also a fragment of bone that is usually displaced and often undergoes attrition. Thus, due to attritional bone loss (ABL) of the fragment, insufficient bone is left to fully reconstruct the glenoid. PURPOSE: To (1) evaluate ABL of the glenoid fragment in recurrent anterior shoulder instability and (2) correlate ABL with clinical history, fragment size, and radiographic findings. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: GBL was evaluated on 3-dimensional computed tomography (3D CT) en-face view and was measured as percentage loss. The bone fragment size was measured, and attrition of the fragment was determined by evaluation of the amount remaining relative to the initial defect; patients were stratified into minimal (<34%), moderate (34% to <67%), and severe (>=67%) attritional loss groups. Clinical history and demographics were correlated to ABL, and GBL and ABL were compared. RESULTS: The overall median percentage GBL was 15.3% (interquartile range [IQR], 9.9%-20.0%), with a mean (+/-SD) percentage GBL of 16.5% +/- 9.0%. Study participants had a corresponding median percentage ABL of 75.8% (IQR, 53.8%-95.7%) and a mean percentage ABL of 72.0% +/- 24.4%. A total of 61.2% of patients (n = 85) exhibited severe ABL, while 30.2% had moderate ABL and 8.6% had minimal ABL. The total time of instability was significantly associated with percentage of attritional bone loss ( P < .05). In addition, the time of instability was greatest in patients in the third tertile of ABL (>=87.5%; P = .08). A significant difference was found in total time of instability among patients in the highest tertile of ABL (38.6 months) versus both the middle (26.7 months) and lowest (32.8 months) tertiles ( P < .05). CONCLUSION: The study results indicate that in the majority of patients with recurrent anterior instability, GBL presents with extensive attrition of the bone fragment independent of initial glenoid bone loss; therefore, surgeons should be cognizant that the remaining bone fragment is unable to reconstitute glenoid bone stock. In addition, the results showed more attritional bone loss in patients with a longer duration of instability symptoms, indicating a role for incorporating symptom duration in determining proper management. PMID- 28006108 TI - Digitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding. AB - RATIONALE: Cystic fibrosis (CF) lung disease progresses by a combination of airway inflammation, bacterial colonization, and infection. Airway inflammation is predominantly neutrophilic and complicates airway clearance therapies through cellular debris; excessive DNA; excessive and viscous mucus; and high concentrations of neutrophils, IL-8, and related cytokines liberated along the nuclear factor-kappaB signaling pathway. OBJECTIVES: We conducted a preliminary, single-site, randomized, double-blind, placebo-controlled study to evaluate the effects over 28 days of two dose levels (0.05 mg and 0.1 mg daily) of an older cardiac glycoside, digitoxin, as compared with placebo, on safety, pharmacokinetics, and inflammatory markers in induced sputum obtained from 24 subjects with mild to moderate CF lung disease. METHODS: Patients with CF 18-45 years old with any genotype combination were eligible. The primary objective was to measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum. Secondary objectives were to measure (1) the pharmacokinetics of digitoxin in sera of patients with stable CF; (2) safety indices, including ECG changes and sputum microbiology; (3) the effect of digitoxin on gene expression in nasal epithelial cells of patients with stable CF; and (4) quality-of-life scores using the Cystic Fibrosis Questionnaire-Revised. MEASUREMENTS AND MAIN RESULTS: It took several weeks to achieve a therapeutic serum level of digitoxin in subjects with CF. No safety concerns emerged during the study. Digitoxin treatment showed a trend toward reduction in sputum free neutrophil elastase and neutrophil counts, but not a reduction in sputum IL-8. Digitoxin treatment did not reach statistical significance for the primary or secondary outcome measures over the 28-day study period. However, the nasal mRNA from the group receiving 0.1 mg of digitoxin daily had a distinct distribution of global gene expression levels as compared with either the 0.05-mg dose or placebo treatment. The mRNAs encoding chemokine/cytokine or cell surface receptors in immune cells were decreased in nasal epithelial cells at the higher dose, leading to pathway mediated reductions in IL-8, IL-6, lung epithelial inflammation, neutrophil recruitment, and mucus hypersecretion. CONCLUSIONS: At a dose of 0.1 mg daily for 28 days, digitoxin was safe for adults with CF lung disease, but it did not achieve a significant decrease in sputum inflammatory markers. Clinical trial registered with www.clinicaltrials.gov (NCT00782288). PMID- 28006109 TI - Joint Loading in the Sagittal Plane During Gait Is Associated With Hip Joint Abnormalities in Patients With Femoroacetabular Impingement. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a morphological abnormality of the hip joint that results in functional impairments during various activities of daily living (ADL) such as walking. Purpose/Hypothesis: The purpose of this study was to determine if lower extremity joint loading differed between patients with FAI and controls and to determine whether these altered biomechanical parameters were associated with intra-articular abnormalities. It was hypothesized that patients with FAI would exhibit altered lower extremity joint loading during walking when compared with healthy controls and that these altered joint loading patterns would be associated with intra-articular abnormalities. STUDY DESIGN: Controlled laboratory study. METHODS: Lower extremity kinetics was assessed during walking at a self-selected speed in 15 presurgical patients with FAI and 34 healthy controls matched for age and body mass index. All participants underwent unilateral hip magnetic resonance imaging (MRI) to assess hip joint abnormalities. Hip joint abnormalities were assessed using a semiquantitative MRI based scoring system. Self-reported outcomes of pain and function were obtained using the Hip disability and Osteoarthritis Outcome Score (HOOS), and physical performance was measured using the 6-minute walk test (6MWT). Group differences were assessed using an independent t test and analysis of variance. In the patients with FAI, associations of joint kinetics with HOOS subscores and intra articular abnormalities were assessed using the Pearson ( r) and Spearman (rho) correlation coefficients, respectively. RESULTS: Compared with the control group, the FAI group exhibited a significantly increased severity of acetabular (FAI: 1.87 +/- 1.55; control: 0.47 +/- 0.79; P < .001) and femoral (FAI: 3.27 +/- 2.79; control: 1.21 +/- 1.55; P = .002) cartilage abnormalities, increased levels of pain (FAI: 65.0 +/- 18.8; control: 98.2 +/- 3.4; P = .001), and reduced function (FAI: 67.2 +/- 21.5; control: 98.9 +/- 3.4; P < .001) but similar walking speeds (FAI: 1.55 +/- 0.19 m/s; control: 1.63 +/- 0.22 m/s; P = .20) and 6MWT performance (FAI: 628.0 +/- 91.2 m; control: 667.2 +/- 73.4 m; P = .13). The FAI group demonstrated increased hip flexion moment impulses (FAI: 0.14 +/- 0.04 N.m.s/kg; control: 0.11 +/- 0.03 N.m.s/kg; P = .03), peak ankle dorsiflexion moments (FAI: 1.64 +/- 0.16 N.m/kg; control: 1.46 +/- 0.31 N.m/kg; P = .04), and ankle dorsiflexion moment impulses (FAI: 0.39 +/- 0.07 N.m.s/kg; control: 0.31 +/ 0.07 N.m.s/kg; P = .01) compared with the control group. Within the FAI group, an increased hip flexion moment impulse during walking was significantly correlated with increased pain ( r = -0.60, P = .03), decreased ADL ( r = -0.57, P = .04), and increased severity of acetabular cartilage abnormalities (rho = 0.82, P < .01). CONCLUSION: Patients with FAI exhibited altered hip and ankle joint loading patterns during walking. These data suggest that patients with FAI demonstrate both local and distal joint alterations during walking and that hip joint loading is directly related to hip joint abnormalities. CLINICAL RELEVANCE: The results of this study suggest that the hip flexion moment impulse may be an important biomechanical parameter to understand FAI, as the hip flexion moment impulse during walking was shown to be directly related to hip joint abnormalities on MRI. PMID- 28006433 TI - Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway. AB - Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age related obesity. PMID- 28006434 TI - Lactate minimum underestimates the maximal lactate steady-state in swimming mice. AB - The intensity of lactate minimum (LM) has presented a good estimate of the intensity of maximal lactate steady-state (MLSS); however, this relationship has not yet been verified in the mouse model. We proposed validating the LM protocol for swimming mice by investigating the relationship among intensities of LM and MLSS as well as differences between sexes, in terms of aerobic capacity. Nineteen mice (male: 10, female: 9) were submitted to the evaluation protocols for LM and MLSS. The LM protocol consisted of hyperlactatemia induction (30 s exercise (13% body mass (bm)), 30 s resting pause and exhaustive exercise (13% bm), 9 min resting pause and incremental test). The LM underestimated MLSS (mice: 17.6%; male: 13.5%; female: 21.6%). Pearson's analysis showed a strong correlation among intensities of MLSS and LM (male (r = 0.67, p = 0.033); female (r = 0.86, p = 0.003)), but without agreement between protocols. The Bland-Altman analysis showed that bias was higher for females (1.5 (0.98) % bm; mean (MLSS and LM): 4.4%-6.4% bm) as compared with males (0.84 (1.24) % bm; mean (MLSS and LM): 4.5% 7.5% bm). The error associated with the estimated of intensity for males was lower when compared with the range of means for MLSS and LM. Therefore, the LM test could be used to determine individual aerobic intensity for males (considering the bias) but not females. Furthermore, the females supported higher intensities than the males. The differences in body mass between sexes could not explain the higher intensities supported by the females. PMID- 28006435 TI - Linking skeletal muscle blood flow and metabolism to the limits of human performance. AB - Over the last 50 years, Bengt Saltin's contributions to our understanding of physiology of the circulation, the matching of the circulation to muscle metabolism, and the underlying mechanisms that set the limits for exercise performance were enormous. His research addressed the key questions in the field using sophisticated experimental methods including field expeditions. From the Dallas Bedrest Study to the 1-leg knee model to the physiology of lifelong training, his prodigious body of work was foundational in the field of exercise physiology and his leadership propelled integrative human physiology into the mainstream of biological sciences. PMID- 28006436 TI - Professor Bengt Saltin Symposium - Environmental challenges to human performance. AB - This short review is from a presentation made at the Bengt Saltin Symposium, October 15-17, at the 2015 Canadian Society for Exercise Physiology conference, Hamilton, Canada. The review provides context of the important work of the late Dr. Saltin's contributions to environmental physiology. In addition to well controlled laboratory experiments to better understand the influence of hypoxia or temperature, or both, Dr. Saltin also led several field expeditions to the North Greenland, Kenya, Himalayas, and the Andes, where he studied several aspects of human adaptation to environment. The 1998 Danish High-Altitude Expedition to the Andes, in particular, resulted in many major contributions to the field of altitude physiology including, but not limited to, mechanisms of reductions in maximal oxygen uptake, the lactate paradox, acclimatization, muscle metabolism, gas exchange, cerebrovascular physiology, etc. Of note, many of these related studies were conducted in both Danish sojourners to altitude and Bolivian altitude natives of Aymara ancestry, thus providing some of the most mechanistic comparisons with high altitude natives to date. A framework of these physiological contributions in terrestrial extremes is provided in this review. PMID- 28006437 TI - Does exercise pose a challenge to glucoregulation after clinical islet transplantation? AB - Islet transplantation (ITx) is effective in preventing severe hypoglycemia by restoring glucose-dependent insulin secretion in type 1 diabetes (T1D), but may not normalize glucose regulation. Studies suggest that physical activity plays a role in maintaining beta-cell mass and function in individuals with type 2 diabetes and animal models of diabetes. This could indicate that physical activity plays a role in graft survival in ITx recipients. This review's objective is to assess current knowledge related to physical activity in ITx recipients. Responses to other challenges in blood glucose control (i.e., hypoglycemia) in human ITx recipients were examined to provide in-depth background information. To identify studies involving exercise in ITx recipients, a systematic search was performed using PubMed, Medline, and Embase, which revealed 277 English language publications. Publications were excluded if they did not involve ITx recipients; did not involve physical activity or hypoglycemia; or did not report on glucose, insulin, or counterregulatory hormones. During induced hypoglycemia, studies indicate normal suppression of insulin in ITx individuals compared with healthy non-T1D controls. Studies involving exercise in ITx animals have conflicting results, with time since transplantation and transplantation site (spleen, liver, kidney, peritoneal cavity) as possible confounders. No study examining blood glucose responses to physical activity in human ITx recipients was identified. A small number of induced-hypoglycemia studies in humans, and exercise studies in animals, would suggest that glucoregulation is greatly improved yet is still imperfect in this population and that ITx does not fully restore counterregulatory responses to challenges in blood glucose homeostasis. PMID- 28006438 TI - Accelerometer thresholds: Accounting for body mass reduces discrepancies between measures of physical activity for individuals with overweight and obesity. AB - The objective of this study was to explore whether accelerometer thresholds that are adjusted to account for differences in body mass influence discrepancies between self-report and accelerometer-measured physical activity (PA) volume for individuals with overweight and obesity. We analyzed 6164 adults from the National Health and Nutrition Examination Survey between 2003-2006. Established accelerometer thresholds were adjusted to account for differences in body mass to produce a similar energy expenditure (EE) rate as individuals with normal weight. Moderate-, vigorous-, and moderate- to vigorous-intensity PA (MVPA) durations were measured using established and adjusted accelerometer thresholds and compared with self-report. Durations of self-report were longer than accelerometer-measured MVPA using established thresholds (normal weight: 57.8 +/- 2.4 vs 9.0 +/- 0.5 min/day, overweight: 56.1 +/- 2.7 vs 7.4 +/- 0.5 min/day, and obesity: 46.5 +/- 2.2 vs 3.7 +/- 0.3 min/day). Durations of subjective and objective PA were negatively associated with body mass index (BMI) (P < 0.05). Using adjusted thresholds increased MVPA durations, and reduced discrepancies between accelerometer and self-report measures for overweight and obese groups by 6.0 +/- 0.3 min/day and 17.7 +/- 0.8 min/day, respectively (P < 0.05). Using accelerometer thresholds that represent equal EE rates across BMI categories reduced the discrepancies between durations of subjective and objective PA for overweight and obese groups. However, accelerometer-measured PA generally remained shorter than durations of self-report within all BMI categories. Further research may be necessary to improve analytical approaches when using objective measures of PA for individuals with overweight or obesity. PMID- 28006649 TI - Serodiagnosis of Zika virus (ZIKV) infections by a novel NS1-based ELISA devoid of cross-reactivity with dengue virus antibodies: a multicohort study of assay performance, 2015 to 2016. AB - Serological diagnosis of Zika virus (ZIKV) infections is challenging due to high cross-reactivity between flaviviruses. We evaluated the diagnostic performance of a novel anti-ZIKV ELISA based on recombinant ZIKV non-structural protein 1 (NS1). Assay sensitivity was examined using sera from 27 patients with reverse transcription (RT)-PCR-confirmed and 85 with suspected ZIKV infection. Specificity was analysed using sera from 1,015 healthy individuals. Samples from 252 patients with dengue virus (n = 93), West Nile virus (n = 34), Japanese encephalitis virus (n = 25), chikungunya virus (n = 19) or Plasmodium spp. (n = 69) infections and from 12 yellow fever-vaccinated individuals were also examined. In confirmed ZIKV specimens collected >= 6 days after symptom onset, ELISA sensitivity was 58.8% (95% confidence interval (CI): 36.0-78.4) for IgM, 88.2% (95% CI: 64.4-98.0) for IgG, and 100% (95% CI: 78.4-100) for IgM/IgG, at 99.8% (95% CI: 99.2-100) specificity. Cross-reactivity with high-level dengue virus antibodies was not detected. Among patients with potentially cross-reactive antibodies anti-ZIKV positive rates were 0.8% (95% CI: 0-3.0) and 0.4% (95% CI: 0 2.4) for IgM and IgG, respectively. Providing high specificity and low cross reactivity, the NS1-based ELISA has the potential to aid in counselling patients, pregnant women and travellers after returning from ZIKV-endemic areas. PMID- 28006650 TI - Rise of multidrug-resistant non-vaccine serotype 15A Streptococcus pneumoniae in the United Kingdom, 2001 to 2014. AB - Conjugate vaccines have reduced pneumococcal disease in vaccinated children and unvaccinated adults, but non-vaccine serotypes are of concern, particularly if antibiotic resistant. We reviewed Streptococcus pneumoniae collected via: (i) the British Society for Antimicrobial Chemotherapy (BSAC) surveillances from 2001 2014; (ii) Public Health England's (PHE) invasive isolate surveillance from 2005 2014 and (iii) referral to PHE for resistance investigation from 2005-2014. Serotype 15A increased in all series, with many representatives showing triple resistance to macrolides, tetracyclines and penicillin. 15A was consistently among the 10 most prevalent serotypes from 2011 in PHE and BSAC invasive isolate/bacteraemia surveillance but never previously; 26-33% of these invasive 15A isolates had triple resistance. BSAC respiratory isolates were only serotyped in 2013/14 and 2014/15 (October to September); 15A was most prevalent serotype in both periods, comprising 9-11% of isolates, 38-48% of them with triple resistance. Serotype 15A represented 0-4% of S. pneumoniae referred to PHE for reference investigation annually until 2008 but rose to 29% (2013) and 32% (2014). Almost all multidrug-resistant 15A isolates were sequence type (ST) 63 variants, whereas susceptible 15A isolates were clonally diverse. The rise of serotype 15A suggests that pneumococcal conjugate vaccines will need ongoing adaptation. PMID- 28006651 TI - Identification of dengue type 2 virus in febrile travellers returning from Burkina Faso to France, related to an ongoing outbreak, October to November 2016. AB - Dengue fever is rarely reported in travellers returning from Africa. We report two cases of dengue fever in travellers returning from Burkina Faso to France. One of them presented a severe dengue fever with ALT > 1,000 IU/L and pericarditis. Serotype 2 was identified. The cases reflect a large ongoing outbreak with over 1,000 reported cases between August and November in the capital city. Clinicians should consider dengue fever in malaria-negative febrile travellers returning from Africa. PMID- 28006652 TI - Letter to the editor: New metrics to monitor progress towards global HIV targets: using the estimated number of undiagnosed HIV-infected individuals as denominator. PMID- 28006653 TI - Evaluation of molecular typing of foodborne pathogens in European reference laboratories from 2012 to 2013. AB - In 2012, the European Centre for Disease Prevention and Control (ECDC) initiated external quality assessment (EQA) schemes for molecular typing including the National Public Health Reference Laboratories in Europe. The overall aim for these EQA schemes was to enhance the European surveillance of food-borne pathogens by evaluating and improving the quality and comparability of molecular typing. The EQAs were organised by Statens Serum Institut (SSI) and included Salmonella enterica subsp. enterica, verocytotoxin-producing Escherichia coli (VTEC) and Listeria monocytogenes. Inter-laboratory comparable pulsed-field gel electrophoresis (PFGE) images were obtained from 10 of 17 of the participating laboratories for Listeria, 15 of 25 for Salmonella, but only nine of 20 for VTEC. Most problems were related to PFGE running conditions and/or incorrect use of image acquisition. Analysis of the gels was done in good accordance with the provided guidelines. Furthermore, we assessed the multilocus variable-number tandem repeat analysis (MLVA) scheme for S. Typhimurium. Of 15 laboratories, nine submitted correct results for all analysed strains, and four had difficulties with one strain only. In conclusion, both PFGE and MLVA are prone to variation in quality, and there is therefore a continuous need for standardisation and validation of laboratory performance for molecular typing methods of food-borne pathogens in the human public health sector. PMID- 28006654 TI - Authors' reply: New metrics to monitor progress towards global HIV targets: using the estimated number of undiagnosed HIV-infected individuals as denominator. PMID- 28006655 TI - Cloning, expression and purification of autolysin from methicillin-resistant Staphylococcus aureus: potency and challenge study in Balb/c mice. AB - Staphylococcus aureus (MRSA) is an opportunistic pathogen which causes a variety of clinical diseases and leads to high rates of morbidity and mortality. Development of an effective vaccine appears to be a useful strategy to control the infection. Here, the internal region of atl was cloned into the pET24a plasmid and expressed in E. coli BL21 (DE3). Cloning of atl was confirmed by colony-PCR, enzymatic digestion and sequencing. Protein expressed in E coli, BL21 DE3 and was confirmed with SDS-PAGE and western blot analysis. Subsequently, BALB/c mice were injected subcutaneously three times with 20MUg of the recombinant autolysin. After Bleeding, autolysin-specific total IgG antibodies and isotypes were evaluated using ELISA. Opsonophagocytic killing assay was performed and experimental challenge was done by intraperitoneal injection with sub lethal doses of MRSA in mice and also survival rate was regularly monitored. Results showed that vaccinated mice could exhibit higher levels of autolysin specific antibodies (P<0.0001) with a predominant IgG1 response versus control group. Results from in vitro experiments indicated that S. aureus opsonized with immunized-mice sera displayed significantly increased phagocytic uptake and effective intracellular killing versus non-immunized mice. The number of viable bacteria in the kidney of immunized mice showed 1000 times less than the control mice; additionally, an increased survival rate was found after immunization with the candidate vaccine versus control group. Results from this study demonstrated that the autolysin is a valuable target for the development of immunotherapeutic strategies against S. aureus and candidate vaccines. PMID- 28006656 TI - Disruption of Serinc1, which facilitates serine-derived lipid synthesis, fails to alter macrophage function, lymphocyte proliferation or autoimmune disease susceptibility. AB - During immune cell activation, serine-derived lipids such as phosphatidylserine and sphingolipids contribute to the formation of protein signaling complexes within the plasma membrane. Altering lipid composition in the cell membrane can subsequently affect immune cell function and the development of autoimmune disease. Serine incorporator 1 (SERINC1) is a putative carrier protein that facilitates synthesis of serine-derived lipids. To determine if SERINC1 has a role in immune cell function and the development of autoimmunity, we characterized a mouse strain in which a retroviral insertion abolishes expression of the Serinc1 transcript. Expression analyses indicated that the Serinc1 transcript is readily detectable and expressed at relatively high levels in wildtype macrophages and lymphocytes. The ablation of Serinc1 expression in these immune cells, however, did not significantly alter serine-derived lipid composition or affect macrophage function and lymphocyte proliferation. Analyses of Serinc1-deficient mice also indicated that systemic ablation of Serinc1 expression did not affect viability, fertility or autoimmune disease susceptibility. These results suggest that Serinc1 is dispensable for certain immune cell functions and does not contribute to previously reported links between lipid composition in immune cells and autoimmunity. PMID- 28006657 TI - The 6-chromanol derivate SUL-109 enables prolonged hypothermic storage of adipose tissue-derived stem cells. AB - Encouraging advances in cell therapy research with adipose derived stem cells (ASC) require an effective short-term preservation method that provides time for quality control and transport of cells from their manufacturing facility to their clinical destination. Hypothermic storage of cells in their specific growth media offers an alternative and simple preservation method to liquid nitrogen cryopreservation or commercial preservation fluids for short-term storage and transport. However, accumulation of cell damage during hypothermia may result in cell injury and death upon rewarming through the production of excess reactive oxygen species (ROS). Here, the ability of the cell culture medium additive SUL 109, a modified 6-chromanol, to protect ASC from hypothermia and rewarming damage is examined. SUL-109 conveys protective effects against cold-induced damage in ASC as is observed by preservation of cell viability, adhesion properties and growth potential. SUL-109 does not reduce the multilineage differentiation capacity of ASC. SUL-109 conveys its protection against hypothermic damage by the preservation of the mitochondrial membrane potential through the activation of mitochondrial membrane complexes I and IV, and increases maximal oxygen consumption in FCCP uncoupled mitochondria. Consequently, SUL-109 alleviates mitochondrial ROS production and preserves ATP production. In summary, here we describe the generation of a single molecule cell preservation agent that protects ASC from hypothermic damage associated with short-term cell preservation that does not affect the differentiation capacity of ASC. PMID- 28006659 TI - An investigation of perceptions of programme quality support of adult basic education programmes. AB - This study was designed to identify the degree to which the directors of adult basic education programs perceive they have program quality support, as evidenced by a well-defined mission and role in the community, a management system, human resources management, and a suitable learning environment. NSCALL's Evidence based program self-assessment (2006) was modified and administered electronically to administrators of adult education programs in a mid-southern state. Findings indicated that most directors perceive they are implementing the indicators of program quality support in all of the areas surveyed. A research-based annual self-study that considers the quality indicators is recommended, leaving a need for an update to the NCSALL assessment for use as a program assessment instrument. PMID- 28006658 TI - Direct induction of neural progenitor cells transiently passes through a partially reprogrammed state. AB - The generation of functional neural progenitor cells (NPCs) holds great promise for both research and clinical applications in neurodegenerative diseases. Traditionally, NPCs are derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or NPCs can be directly converted from somatic cells by sets of transcription factors or by a combination of chemical cocktails and/or hypoxia. However, the ethical issues of ESCs, the risk of tumorigenesis from iPSCs and transgenic integration from exogenous genes as well as complicated manipulation and time-consuming of chemical induced NPCs (ciNPCs) limit the applications of these strategies. Here, we describe a novel method for generating growth factor-induced neural progenitor cells (giNPCs) from mouse embryonic and adult fibroblasts by using inductive and/or permissive signaling culture conditions. These giNPCs closely resemble brain-derived NPCs in terms of transcription networks and neural lineage differentiation potentials. Moreover, this somatic cell to NPC induction is a gradual process that includes initiation, intermediate, maturation and stabilization stages. Importantly, gene expression and histone modification analyses further indicate a partially reprogrammed state during the generation process of induced NPCs, in which lineage specific genes and pluripotency associated genes are transiently activated. Our study therefore describes the potential safety problems that also exist in the transgene-free direct induction strategy and highlights the importance of excluding the possibility of residual partially reprogrammed and/or teratoma-like cells from the generated NPCs for future clinical trials. PMID- 28006660 TI - Elastic constant determination of hardwoods using ultrasonic insertion technique. AB - Ultrasonic insertion technique (IT) is an ultrasonic technique which involves sample immersion in a solution to determine its acoustic properties. IT is normally used to determine the acoustic properties of a medical phantom. We proposed the use of IT as an alternative technique to the common contact ultrasonic technique: through-transmission technique (TT) for determining the elastic constant of hardwoods in longitudinal, tangential and radial directions. The elastic constant of twelve rectangular-shaped Malaysian hardwoods from three different categories; heavy, medium and light with the density ranging from 602 to 992kgm-3 were determined using IT and TT. Both techniques were carried out at 24.0 degrees C surrounding temperature and utilized 2.25MHz ultrasonic transducers. Data from both techniques were compared to validate the use of the proposed technique. Findings indicated that IT offers consistent and accurate results for, tangential and radial elastic constants (TEC and REC) within 8.89% and 5.86% differences, respectively compared to TT for all tested hardwoods. IT offers an alternative technique for TEC and REC determinations of precious wood samples. PMID- 28006661 TI - Pulsed ultrasonic comb filtering effect and its applications in the measurement of sound velocity and thickness of thin plates. AB - An analytical and experimental study of the pulsed ultrasonic comb filtering effect is presented in this work intending to provide a fundamental tool for data analysis and phenomenon understanding in pulsed ultrasonics. The basic types of comb filter, feedforward and feedback filters, are numerically simulated and demonstrated. The characteristic features of comb filters, which include the formula for determining the locations of the spectral peaks or notches and the relationship between its temporal characteristics (relative time delay between constituent pulses) and its spectral characteristics (frequency interval between peaks or notches), are theoretically derived. To demonstrate the applicability of the comb filtering effect, it is applied to measuring the sound velocities and thickness of a thin plate sample. It is proven that the comb filtering effect based method not only is capable of accurate measurements, but also has advantages over the conventional time-of-flight based method in thin plate measurements. Furthermore, the principles developed in this study have potential applications in any pulsed ultrasonic cases where the output signal shows comb filter features. PMID- 28006662 TI - Potent anticancer activity of a new bismuth (III) complex against human lung cancer cells. AB - The aim of this work is experimental study of an interesting bismuth(III) complex derived from pentadentate 2,6-pyridinedicarboxaldehyde bis(4N methylthiosemicarbazone), [BiL(NO3)2]NO3 {L=2,6-pyridinedicarboxaldehyde bis(4N methylthiosemicarbazone)}. A series of in vitro biological studies indicate that the newly prepared [BiL(NO3)2]NO3 greatly suppressed colony formation, migration and significantly induced apoptosis of human lung cancer cells A549 and H460, but did not obviously decrease the cell viability of non-cancerous human lung fibroblast (HLF) cell line, showing much higher anticancer activities than its parent ligands, especially with half maximum inhibitory concentration (IC50) <3.5MUM. Moreover, in vivo study provides enough evidence that the treatment with [BiL(NO3)2]NO3 effectively inhibited A549 xenograft tumor growth on tumor-bearing mice (10mgkg-1, tumor volume reduced by 97.92% and tumor weight lightened by 94.44% compared to control) and did not indicate harmful effect on mouse weight and liver. These results suggest that the coordination of free ligand with Bi(III) might be an interesting and potent strategy in the discovery of new anticancer drug candidates. PMID- 28006663 TI - Studies on the mechanism of action of antitumor bis(aminophenolate) ruthenium(III) complexes. AB - Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands, formulated as [Ru(III)(salan)(PPh3)Cl] (salan is the tetradentate ligand 6,6'-(1S,2S)-cyclohexane-1,2 diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol) in complex 1, or 2,2' (1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol) in complex 2; PPh3 is triphenylphosphane) and found very active against ovarian and breast adenocarcinoma human cells were studied to outline their antitumor mode of action. The human cisplatin-sensitive ovarian adenocarcinoma line A2780 was used herein as the cell model. At a 24h challenge (similarly as found before for 72h) both complexes are active, their cytotoxicity being comparable to that of cisplatin in the same conditions. As a possible target in the cell for their action, the interaction of 1 and 2 with DNA was assessed through displacement of well-established DNA fluorescent probes (ethidium bromide, EB, and 4',6-diamidino 2-phenylindole, DAPI) through steady-state and time-resolved fluorescence spectroscopy. The whole emission spectra were analyzed globally for the binary DNA-probe and ternary DNA-probe-Ru(III) complex systems. Both Ru(III) complexes can displace EB and bind to DNA with similar and moderate strong affinity with conditional stability constants of logK'=(5.05+/-0.01) for 1 and logK'=(4.79+/ 0.01) for 2. The analysis of time-domain fluorescence intensity decays confirmed both qualitatively and quantitatively the model used to describe the binding and competition processes. Cell studies indicated that apoptosis is the major mechanism of cell death for both complexes, with 2 (the more active complex) promoting that process more efficiently than 1. Transmission electron micrographs revealed clear alterations on intracellular organization consistent with the induction of programmed cell death processes. PMID- 28006664 TI - The high burden of traumatic brain injury and comorbidities amongst homeless adults with mental illness. AB - OBJECTIVE: characterize the prevalence of self-reported head injury with loss of consciousness (LOC) and associated demographic, clinical and service use factors in a sample of homeless adults with mental illness. METHOD: Participants in the At Home/Chez Soi study were interviewed at the time of study enrollment regarding their history of head injuries, mental and physical health diagnoses and justice system and healthcare interactions. Sociodemographic and clinical data were also collected. RESULTS: Over half of the 2088 study respondents (52.6%, n = 1098) reported a history of head injury with a LOC, which was associated with several demographic, clinical and service use variables in this population. With respect to specific mental health conditions, a history of head injury with LOC was associated with higher odds of current depression (OR = 2.18, CI: 1.83-2.60), manic episode or hypomanic episode (OR = 1.91, CI: 1.45-2.50), PTSD (OR = 2.98, CI: 2.44-3.65), panic disorder (OR = 2.37, CI:1.91-2.93), mood disorder (OR = 1.78, CI: 1.40-2.26) and alcohol (OR = 2.09, CI: 1.75-2.49) and drug (OR = 1.73, CI: 1.46-2.06) misuse disorders, but reduced odds of having diagnosis of a psychotic disorder (OR = 0.63, CI: 0.53-0.76). A history of head injury with LOC was also associated with increased use of variety of services, including family medicine (OR = 1.33, CI: 1.12-1.59), criminal justice system (OR = 1.50, CI: 1.25 1.80) and the emergency department (OR = 1.03, CI: 1.01-1.05). CONCLUSIONS: Amongst homeless adults with mental illness having a history of head injuries with LOC was independently associated with various adverse outcomes. These individuals constitute a high-risk group who may benefit from specialized services. PMID- 28006665 TI - Alteration of thyroid hormone concentrations in juvenile Chinook salmon (Oncorhynchus tshawytscha) exposed to polybrominated diphenyl ethers, BDE-47 and BDE-99. AB - Polybrominated diphenyl ethers (PBDEs) have been used as flame-retardants in consumer products and are currently detected in salmon globally. The two most predominant PBDE congeners found in salmon are BDE-47 (2,2',4,4' tetrabromodiphenyl ether) and BDE-99 (2,2',4,4',5-pentabromodiphenyl ether). In the present study, groups of juvenile Pacific Chinook salmon were fed five environmentally relevant concentrations of either BDE-47 (0.3-552 ng total PBDEs/g food), BDE-99 (0.3-580 ng total PBDEs/g food), or nearly equal mixtures of both congeners (0.7-690 ng total PBDEs/g food) for 39-40 days. The concentrations of circulating total thyroid hormones, thyroxine (T4) and 3,5,3' triiodothyronine (T3), were measured using a hormone-specific time-resolved fluoroimmunoassay to determine if PBDE exposure disrupts the hypothalamic pituitary-thyroid endocrine axis. The concentrations of both circulating T4 and T3 were altered in juvenile salmon by dietary uptake of BDE-99. Exposure to BDE 47 did not alter either T3 or T4 circulating hormone concentrations. However, exposure to a mixture of BDE-47 and BDE-99 reduced T3 in fish with lower concentrations of total whole body PBDEs than with either congener alone at equivalent PBDE whole body concentrations. Accordingly, the disruption of PBDEs on circulating thyroid hormone concentrations has the potential to impact a number of critical functions in juvenile salmon including growth, parr-smolt transformation, and immunological processes. PMID- 28006666 TI - Key environmental processes affecting the fate of the insecticide chloropyrifos applied to leaves. AB - Chlorpyrifos (CP) is still a commonly employed organophosphorus insecticide worldwide. In semi-arid and Mediterranean climates, applied CP is expected to remain on leaves surfaces for relatively long time due to the lack of summer rains and common use of drip irrigation. The present work examines the loss rate of CP from leaves via different surface processes: evaporation, direct photolysis and reactions with ozone and OH radicals. Laboratory experiments showed that evaporation rate constant of CP increased from 0.109 to 0.492 h-1 with the increase in wind speed up to 4 m/s. First-order rate constant of direct photolysis, measured using a solar simulator, was k'UV = 1.15 (+/-0.01) x 10-20 cm2 photon-1. Second-order rate constants for the reaction of CP with ozone and OH were measured as 6 * 10-20 and 6 * 10-12 cm3 molecule-1 s-1, respectively. The above rate constants were applied successfully in an outdoor experiment to predict the disappearance of chloropyrifos under specific environmental conditions. Further modeling showed that the insecticide half-life time on exposed surfaces under typical Mediterranean environment will be in the range of 0.9-6.9 h. Evaporation is expected to be the dominant removal path under most environmental conditions, followed by direct photolysis and reaction with OH. PMID- 28006667 TI - Alkaline Technosol contaminated by former mining activity and its culturable autochthonous microbiota. AB - Technosols or technogenic substrates contaminated by potentially toxic elements as a result of iron mining causes not only contamination of the surrounding ecosystem but may also lead to changes of the extent, abundance, structure and activity of soil microbial community. Microbial biomass were significantly inhibited mainly by exceeding limits of potentially toxic metals as arsenic (in the range of 343-511 mg/kg), copper (in the range of 7980-9227 mg/kg), manganese (in the range of 2417-2670 mg/kg), alkaline and strong alkaline pH conditions and minimal contents of organic nutrients. All of the 14 bacterial isolates, belonged to 4 bacterial phyla, Actinobacteria, Firmicutes; beta- and gamma-Proteobacteria. Thirteen genera and 20 species of microscopic filamentous fungi were recovered. The most frequently found species belonged to genera Aspergillus (A. clavatus, A. niger, A. flavus, A. versicolor, Aspergillus sp.) with the dominating A. niger in all samples, and Penicillium (P. canescens, P. chrysogenum, P. spinulosum, Penicillium sp.). Fungal plant pathogens occurred in all surface samples. These included Bjerkandera adustata, Bionectria ochloleuca with anamorph state Clonostachys pseudochloleuca, Lewia infectoria, Phoma macrostoma and Rhizoctonia sp. PMID- 28006668 TI - Design and synthesis of novel 7-aminosubstituted pyrido[2,3-b]pyrazines exhibiting anti-breast cancer activity. AB - Breast cancer (BrCa) remains an unmet medical need despite the revolutionary development of antibody treatments and protein kinase inhibitors. In the current study, a series of novel substituted pyridopyrazine derivatives have been rationally designed and evaluated as multi-kinase inhibitors in the PI3K pathway. The target compounds were prepared from 6-amino-2-picoline, which upon nitration and selective reduction was converted to suitably substituted 6-methyl-7 aminopyrido[2,3-b]pyrazines. Suitable manipulation of the former amines provided the designed analogues, which were then assessed in vitro against several BrCa cell lines using the MTT cytotoxicity assay. The most potent compounds underwent evaluation in a broad spectrum of protein kinases, while their pharmacokinetic parameters were measured by LC-MS/MS. In vivo evaluation of a hit compound (14a) was performed in a HER2 amplified BrCa xenograft model (HCC1954) and efficacy was determined using Western blot based phosphokinase assays and immunohistochemistry. This derivative showed low micromolar cytotoxic potency in all BrCa cell lines, a mild inhibition of the PI3Kalpha wild type and H1047R mutated enzyme and excellent pharmacokinetic parameters following oral and intraperitoneal administration at the designed dose of 10 mg/kg, with absence of in vivo phenotypic toxicity. Interestingly, compound 14a inhibited the growth of xenografted tumors. Analysis of excised tumors from the treated animals showed a significantly reduced population of Ki-67 positive cells, as well as downregulated levels of phosphorylated AKT, ERK1/2 and SRC compared to vehicle treated animals. Finally, the specificity of 14a was assessed in a panel of 31 kinases where a mild, but direct, inhibition of the MET receptor tyrosine kinase was observed. PMID- 28006669 TI - Alkynyloxy derivatives of 5,8-quinolinedione: Synthesis, in vitro cytotoxicity studies and computational molecular modeling with NAD(P)H:Quinone oxidoreductase 1. AB - The natural 7-amino-5,8-quinolinodione antibiotics were the substrate for the NQO1 protein. The structure-activity relationship showed that the 5,8 quinolinedione moiety was responsible for the interaction with the enzyme. In our research, we presented the synthesis, cytotoxic activity and theoretical study of a 5,8-quinolinedione compound as a potential inhibitor of the NQO1 enzyme. Mono and disubstituted alkynyloxy derivatives of the 5,8-quinolinedione were synthesized and characterized by 1H, 13C NMR, IR and HR-MS spectra. Newly synthesized derivatives were also tested for their biological activity in vitro against the human cancer cell lines. They showed high cytotoxic activity depending on the type of substituent and the employed tumor cell lines. Moreover, two breast cancer cell lines, MDA-MB-231 and MCF-7, were chosen for analysis as they are characterized by different NQO1 protein levels. It was found that cytotoxic activities of all studied compounds increased against the cell line with a higher NQO1 protein level. The molecular docking was used to examine the probable interaction between the molecules of alkynyloxy derivatives and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the 5,8-quinolinedione moiety of all docked compounds was located deeply in the hydrophobic matrix of the active site near the side chains of aromatic residues in positions Trp 105, Phe 178, Tyr 126 and Tyr 128. In every case, introduction of aromatic moieties into the 5,8-quinolinedione molecule led to an increase in the binding affinity in relation to the 6,7-dichloro-5,8 quinolinedione. PMID- 28006670 TI - New highly divergent Plum pox virus isolates infecting sour cherry in Russia. AB - Unusual Plum pox virus (PPV) isolates (named Tat isolates) were discovered on sour cherry (Prunus cerasus) in Russia. They failed to be recognized by RT-PCR using commonly employed primers specific to the strains C or CR (the only ones that proved able to infect sour cherry) as well as to the strains M and W. Some of them can be detected by RT-PCR using the PPV-D-specific primers P1/PD or by TAS-ELISA with the PPV-C-specific monoclonal antibody AC. Phylogenetic analysis of the 3'-terminal genomic region assigned the Tat isolates into the cluster of cherry-adapted strains. However, they grouped separately from the C and CR strains and from each other as well. The sequence divergence of the Tat isolates is comparable to the differences between the known PPV strains. They may represent new group(s) of cherry-adapted isolates which do not seem to belong to any known strain of the virus. PMID- 28006672 TI - Gene electrotransfer into skin using noninvasive multi-electrode array for vaccination and wound healing. AB - Skin is an attractive target for gene electrotransfer due to its easy accessibility and its interesting immune properties. Since electrodes are often invasive and frequently induce discomfort during pulse application, there is a fundamental need for non-invasive electrodes for skin delivery. We developed circular pin non-invasive multi-electrode array (MEA), suitable for different clinical applications. MEA was first employed to deliver a luciferase reporter gene. Then, it was used to deliver a DNA vaccine coding for ovalbumin or a plasmid encoding hCAP-18/LL-37 for promoting wound healing. The results demonstrated a strong gene expression and an efficient delivery of both, DNA vaccine and wound healing agent, dependent on the pulses applied. The use of MEA to deliver the ovalbumin plasmid demonstrated a strong immune response, as evidenced by the presence of antibodies in sera, the IFN-gamma response and the delayed tumor growth when the mice were subsequently challenged with B16-OVA cells. The delivery of a plasmid encoding hCAP-18/LL-37 significantly accelerated wound closure. The easy applicability and non-invasiveness of MEA make it suitable for various clinical applications that require gene electrotransfer to skin. Specifically, by adapting electric pulses to the expected action of a transgene, non-invasive MEA can be employed either for vaccination or for wound healing. PMID- 28006673 TI - Enhancing purification efficiency of affinity functionalized composite agarose micro beads using Fe3O4 nanoparticles. AB - In this work, a series of magnetic and nonmagnetic agarose matrices were fabricated for protein purification. Certain amounts of Fe3O4 nanoparticles were encapsulated in agarose beads to form composite magnetic matrices with enhanced purification efficiency. Structure and morphology of prepared matrices were studied by optical and scanning electron microscopes, FT-IR, and BET-BJH analysis. The prepared matrices had regular spherical shape, followed by a uniform size distribution. By nanoparticles addition, the number of mesopores decreased while population of pores with radius <=10nm increased; thus, higher specific area achieved. According to VSM results, magnetization degree was one of the characteristics affected by agarose content of the beads. A dye ligand, Cibacron Blue F3GA (CB), was covalently bound to beads to adsorb Bovine serum albumin. CB concentration was determined by elemental analysis. It was shown that magnetic beads hold higher CB concentrations than nonmagnetic ones due to higher specific area. As a result, magnetic 8%-agarose beads had the highest affinity adsorption capacity in static experiments. Moreover, breakthrough curves were monitored to calculate dynamic binding capacity. And, it was shown that magnetic 4%-agarose had the highest adsorbing amount (6.00mg/mL). It was implied that pore diffusion in magnetic 4%-agarose may be the reason for higher dynamic capacity. Plus, column efficiency was evaluated. It was revealed that all magnetic beads had lower HETP (0.11, 0.12 and 0.11cm for magnetic 4, 6, and 8%-agarose beads) than nonmagnetic ones (P-value<0.05). PMID- 28006671 TI - Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection. AB - There are ~350 million chronic carriers of hepatitis B (HBV). While a prophylactic vaccine and drug regimens to suppress viremia are available, chronic HBV infection is rarely cured. HBV's limited host tropism leads to a scarcity of susceptible small animal models and is a hurdle to developing curative therapies. Mice that support engraftment with human hepatoctyes have traditionally been generated through crosses of murine liver injury models to immunodeficient backgrounds. Here, we describe the disruption of fumarylacetoacetate hydrolase directly in the NOD Rag1-/- IL2RgammaNULL (NRG) background using zinc finger nucleases. The resultant human liver chimeric mice sustain persistent HBV viremia for >90 days. When treated with standard of care therapy, HBV DNA levels decrease below detection but rebound when drug suppression is released, mimicking treatment response observed in patients. Our study highlights the utility of directed gene targeting approaches in zygotes to create new humanized mouse models for human diseases. PMID- 28006674 TI - Development of an extraction method and LC-MS analysis for N-acylated-l homoserine lactones (AHLs) in wastewater treatment biofilms. AB - N-Acylated-l-homoserine lactones (AHLs) play a vital role in Gram-negative bacteria communication by promoting the formation of extracellular polymeric substances (EPS) and biofilms. However, the low concentration of these AHL signals makes the process difficult to understand. A robust and sensitive pretreatment method for AHL detection was developed in this work. Compared with eight different solid-phase extraction (SPE) columns and three various solid extraction method, we found that the UE (ultrasonic extraction) and an Oasis hydrophilic-lipophilic-balanced (HLB) sorbent in column format combined with ultra-performance liquid chromatography linked to tandem mass spectrometry (UPLC MS/MS) can be successfully used for systematic pretreating moving bed biofilm reactor (MBBR) biological samples to extract AHLs and determine concentration of AHLs in wastewater treatment biofilms. This easy-to-follow protocol makes it ideal for quantitative analyses of AHLs in wastewater treatment biofilms. PMID- 28006675 TI - The inversion of 2D NMR relaxometry data using L1 regularization. AB - NMR relaxometry has been used as a powerful tool to study molecular dynamics. Many algorithms have been developed for the inversion of 2D NMR relaxometry data. Unlike traditional algorithms implementing L2 regularization, high order Tikhonov regularization or iterative regularization, L1 penalty term is involved to constrain the sparsity of resultant spectra in this paper. Then fast iterative shrinkage-thresholding algorithm (FISTA) is proposed to solve the L1 regularization problem. The effectiveness, noise vulnerability and practical utility of the proposed algorithm are analyzed by simulations and experiments. The results demonstrate that the proposed algorithm has a more excellent capability to reveal narrow peaks than traditional inversion algorithms. The L1 regularization implemented by our algorithm can be a useful complementary to the existing algorithms. PMID- 28006676 TI - Multiple machine learning based descriptive and predictive workflow for the identification of potential PTP1B inhibitors. AB - In insulin and leptin signaling pathway, Protein-Tyrosine Phosphatase 1B (PTP1B) plays a crucial controlling role as a negative regulator, which makes it an attractive therapeutic target for both Type-2 Diabetes (T2D) and obesity. In this work, we have generated classification models by using the inhibition data set of known PTP1B inhibitors to identify new inhibitors of PTP1B utilizing multiple machine learning techniques like naive Bayesian, random forest, support vector machine and k-nearest neighbors, along with structural fingerprints and selected molecular descriptors. Several models from each algorithm have been constructed and optimized, with the different combination of molecular descriptors and structural fingerprints. For the training and test sets, most of the predictive models showed more than 90% of overall prediction accuracies. The best model was obtained with support vector machine approach and has Matthews Correlation Coefficient of 0.82 for the external test set, which was further employed for the virtual screening of Maybridge small compound database. Five compounds were subsequently selected for experimental assay. Out of these two compounds were found to inhibit PTP1B with significant inhibitory activity in in-vitro inhibition assay. The structural fragments which are important for PTP1B inhibition were identified by naive Bayesian method and can be further exploited to design new molecules around the identified scaffolds. The descriptive and predictive modeling strategy applied in this study is capable of identifying PTP1B inhibitors from the large compound libraries. PMID- 28006677 TI - The alienation of affection toward parents and influential factors in Chinese left-behind children. AB - OBJECTIVE: Although alienation toward parents is important for children (for current mental health status or later interpersonal relationships in adulthood), it is undervalued and even lacks a standardized tool of assessment. Moreover, the large number of left-behind children in China is a cause of public concern. However, their experienced alienation toward their parents remains unclear, which may be important for early detection or intervention for behavioral problems in this population. Hence, the current study aimed to develop an alienation inventory for children and then use it to investigate the experienced alienation toward parents in Chinese left-behind children. METHODS: Two studies were carried out. Study 1 was designed to develop a standard inventory of alienation toward parents (IAP). In study 2, 8361 children and adolescents (6704 of them were left behind status) of the Chongqing area, aged between 8 and 19 years old, were recruited for investigation. All participants were surveyed with a standard sociodemographic questionnaire, children's cognitive style questionnaire, children's depression inventory, adolescent self-rating life events checklist, and newly built IAP in study 1. RESULTS: In study 1, we developed a two-component (communication and emotional distance) and 18-item (9 items for maternal or paternal form, respectively) IAP questionnaire. In study 2, exploratory factor analysis indicated an expected two-factor structure of IAP, which was confirmed by confirmatory factor analysis. The Cronbach's alpha coefficients showed a good reliability (0.887 and 0.821 for maternal and paternal form, respectively). Children with absent mother experienced the highest alienation toward parents. Boys as well as children aged 8-10 years old experienced higher alienation toward parents. Poor communication with parents (sparse or no connection), level of left behind condition (parents divorced, been far away from parents), and psychosocial vulnerability (stressful life events, negative cognitive style) were risk factors of alienation toward parents. CONCLUSIONS: The current study develops a two factor (communication and emotional distance) IAP, which offers a reliable tool to assess experienced alienation of affection toward parents in children aged between 8 and 19 years old. Our result is the first investigation of experienced alienation and potential influential factors in Chinese left-behind children. The findings that children with absent mother experience higher alienation toward parents, as well as three recognized risk factors for alienation of affection toward parents (poor communication with absent parents, worse left-behind condition, and psychosocial vulnerability), give valuable guidance for parents who intend to leave or who are already leaving as well as for government policymaking. PMID- 28006678 TI - Rapid and sensitive detection of bisphenol a from serum matrix. AB - Bisphenol A (BPA) is an endocrine disrupting compound that may have adverse developmental, reproductive, neurological, and immune system effects. Low-level exposure to BPA is ubiquitous in human populations due to its widespread use in consumer products. Therefore, highly sensitive methods are needed to quantify BPA in various matrices including water, serum, and food products. In this study, we developed a simple, rapid, highly sensitive and specific sensor based on an aptamer probe and AC electrokinetics capacitive sensing method that successfully detected BPA at femto molar (fM) levels, which is an improvement over prior work by a factor of 10. We were able to detect BPA spiked in human serum as well as in maternal and cord blood within 30s. The sensor is responsive to BPA down to femto molar levels, but not to structurally similar compounds including bisphenol F (BPF) or bisphenol S (BPS) even at much higher concentration. Further development of this platform may prove useful in monitoring exposure to BPA and other small molecules in various matrices. PMID- 28006679 TI - A disposable amperometric dual-sensor for the detection of hemoglobin and glycated hemoglobin in a finger prick blood sample. AB - A disposable microfluidic amperometric dual-sensor was developed for the detection of glycated hemoglobin (HbA1C) and total hemoglobin (Hb), separately, in a finger prick blood sample. The accurate level of total Hb was determined through the measurements of the cathodic currents of total Hb catalyzed by a toluidine blue O (TBO)-modified working electrode. Subsequently, after washing unbound Hb in the fluidic channel of dual sensor with PBS, the cathodic current by only HbA1C captured on aptamer was monitored using another aptamer/TBO modified working electrode in the channel. To modify the sensor probe, poly(2,2':5',5"-terthiophene-3'-p-benzoic acid) and a multi-wall carbon nanotube (MWCNT) composite layer (pTBA@MWCNT) was electropolymerized on a screen printed carbon electrode (SPCE), followed by immobilization of TBO for the total Hb probe and aptamer/TBO for the HbA1C probe, respectively. The characterization of each sensor surface was performed using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS), quartz crystal microbalance (QCM), field-emission scanning electron microscopy (FE-SEM), and transmission electron microscopy (TEM). The experimental conditions affecting the analytical signal were optimized in terms of the amount of TBO, pH, temperature, binding time, applied potential, and the content ratio of monomer and MWCNT. The dynamic ranges of Hb and HbA1C were from 0.1 to 10uM and from 0.006 to 0.74uM, with detection limits of 82(+/-4.2)nM and 3.7(+/-0.8)nM, respectively. The reliability of the proposed microfluidic dual-sensor for a finger prick blood sample (1uL) was evaluated in parallel with a conventional method (HPLC) for point-of-care analysis. PMID- 28006680 TI - The analysis of proteins and small molecules based on sterically tunable nucleic acid hyperbranched rolling circle amplification. AB - In this work, we succeeded in establishing a new method for proteins and small molecules analysis based on the small molecule-linked DNA and nucleic acid hyperbranched rolling circle amplification (HRCA). Small molecule linked DNA by chemical modification was used as a flexible tool to study protein-small molecule interactions. The HRCA reaction which would produce signal amplification was regulated by the steric effect depending on whether the target proteins were present. In the implement of the proposed strategy, streptavidin (SA)-biotin and anti-digoxin antibody (anti-Dig)-digoxin were chosen as two model partners. Experimental results showed that the quantitative detection of SA and anti-Dig was realized both with nanomolar detection limits. The small molecules biotin and digoxin were also detected at nanomolar levels in a wide range of 1nM~100uM and 1nM~10uM, respectively. Meanwhile, the results indicated that the method had a favorable specificity in analyzing proteins or small molecules. Thus, it may be expected to quantitatively analyze some protein markers and small molecular drugs in complex biological samples. PMID- 28006681 TI - Antibiotics mediated facile one-pot synthesis of gold nanoclusters as fluorescent sensor for ferric ions. AB - In this paper, the cheap, easily obtained small antibiotic molecule of vancomycin was employed as reducer/stabilizer for facile one-pot synthesis of water exhibited a bluish fluorescence emission at 410nm within a short synthesis time about 50min. Based on the strong fluorescence quenching due to electron transfer mechanism by the introduction of ferric ions(Fe3+), the Van-AuNCs were interestingly designed for sensitive and selective detecting Fe3+ with a limit of 1.4MUmol L-1 in the linear range of 2-100MUmol L-1 within 20min. The Van-AuNCs based method was successfully applied to determine Fe3+ in tap water, lake water, river water and sea water samples with the quantitative spike recoveries from 97.50-111.14% with low relative standard deviations ranging from 0.49-1.87%, indicating the potential application of this Van-AuNCs based fluorescent sensor for environmental sample analysis. PMID- 28006682 TI - A graphene oxide-based strand displacement amplification platform for ricin detection using aptamer as recognition element. AB - The toxic plant protein ricin is a potential agent for criminal or bioterrorist attacks due to the wide availability and relative ease of preparation. Herein, we developed a novel strategy for the detection of ricin B-chain (RTB) based on isothermal strand-displacement polymerase reaction (ISDPR) by using aptamer as a recognition element and graphene oxide (GO) as a low background platform. In this method, ricin-binding aptamer (RBA) hybridized with a short blocker firstly, and then was immobilized on the surface of streptavidin-coated magnetic beads (MBs). The addition of RTB could release the blocker, which could hybridize with the dye modified hairpin probe and trigger the ISDPR, resulting in high fluorescence intensity. In the absence of RTB, however, the fluorescence of the dye could be quenched strongly by GO, resulting in the extremely low background signal. Thus, RTB could be sensitively detected by the significantly increased fluorescence signal. The linear range of the current analytical system was from 0.75MUg/mL to 100MUg/mL and the limit of detection (3sigma) was 0.6MUg/mL. This method has been successfully utilized for the detection of both the RTB and the entire ricin toxin in real samples, and it could be generalized to any kind of target detection based on an appropriate aptamer. PMID- 28006683 TI - A selective and sensitive optical sensor for dissolved ammonia detection via agglomeration of fluorescent Ag nanoclusters and temperature gradient headspace single drop microextraction. AB - In this paper, a simple sensor platform is presented for highly selective and sensitive detection of dissolved ammonia in aqueous solutions without pretreatment based on temperature gradient headspace single drop microextraction (HS-SDME) technique, and fluorescence and UV-vis spectrophotometry are utilized with the Ag nanoclusters (Ag NCs) functioned by citrate and glutathione as the probe. The sensing mechanism is based on the volatility of ammonia gas and the active response of Ag NCs to pH change caused by the introduction of ammonia. High pH can make the Ag NCs agglomerate and lead to the obvious decrease of fluorescence intensity and absorbance of Ag NCs solution. Moreover, the presented method exhibits a remarkably high selectivity toward dissolved ammonia over most of inorganic ions and amino acid, and shows a good linear range of 10-350MUM (0.14-4.9mgNL-1) with a low detection limit of 336nM (4.70MUgNL-1) at a signal-to noise ratio of 3. In addition, the practical applications of the sensor have been successfully demonstrated by detecting dissolved ammonia in real samples. PMID- 28006684 TI - An efficient ratiometric fluorescence sensor based on metal-organic frameworks and quantum dots for highly selective detection of 6-mercaptopurine. AB - The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed based on a dual-emission nanosensor. The nanosensor was fabricated by combining a blue-emission metal-organic framework (MOF) NH2-MIL-53(Al) (lambdaem=425nm) with green-emission 3-mercaptopropionic acid-capped CdTe quantum dots (MPA-CdTe QDs) (lambdaem=528nm) under a single excitation wavelength (335nm). Upon addition of 6-MP, the fluorescence of NH2-MIL-53(Al) in the nanohybrid was selectively quenched due to strong inner filter effects, while the fluorescence of the MPA-CdTe QDs was enhanced. The novel RF sensor exhibited higher selectivity towards 6-MP than CdTe QDs alone, and higher sensitivity than MOFs alone. 6-MP could be detected in the range of 0-50MUM with a detection limit of 0.15MUM (S/N=3). The developed sensor was applied for the determination of 6 MP in human urine samples and satisfactory results were obtained. Overall, a novel and efficient fluorescence-based method was developed for the detection of 6-MP in biosamples. PMID- 28006685 TI - In vitro selection of DNA aptamers targeting beta-lactoglobulin and their integration in graphene-based biosensor for the detection of milk allergen. AB - Food allergy has increased rapidly in recent years affecting millions of people worldwide. With the increased consumption of packed food nowadays, a sensitive, accurate and rapid screening method for potential food allergens has become an urgent need in order to protect the sensitive consumers from life-threatening reactions. The current detection methods for food allergens are mostly based on immunoassays which are costly and times-consuming. In this work, we developed an aptamer/graphene-based electrochemical biosensor for on-step, sensitive and low cost detection of beta-lactoglobulin (beta-LG) milk protein, one of the most common food allergens specially in infants. The selection of DNA aptamers against the two beta-LG variants A and B was successfully realised using systemic evolution of ligands by exponential enrichment (SELEX) method. Among the selected aptamers, BLG14 aptamer sequence has shown high affinity and specificity to both beta-LG A and B with dissociation constants (Kds) of 82 and 80nM, respectively as calculated using fluorescence binding assays. The aptamer was then integrated in a voltammetric biosensor utilizing graphene-modified screen printed carbon electrodes. The binding is monitored by following the change in the square wave voltammetry (SWV) reduction peak signal of ferrocyanide/ferricyanide redox couple due to the removal of the negatively charged aptamers from the surface upon protein binding. This one-step "signal on" biosensor takes 20min for the sensitive and selective detection of beta-LG without using any labelling or sophisticated designs. The method was also tested in spiked food sample extract achieving good recovery percentage. The integration of the novel aptamer in the graphene biosensor allows a promising way for cost-effective, rapid and sensitive on-site detection of milk allergen in food stuff. PMID- 28006686 TI - Automated microraft platform to identify and collect non-adherent cells successfully gene-edited with CRISPR-Cas9. AB - Microraft arrays have been used to screen and then isolate adherent and non adherent cells with very high efficiency and excellent viability; however, manual screening and isolation limits the throughput and utility of the technology. In this work, novel hardware and software were developed to automate the microraft array platform. The developed analysis software identified microrafts on the array with greater than 99% sensitivity and cells on the microrafts with 100% sensitivity. The software enabled time-lapse imaging and the use of temporally varying characteristics as sort criteria. The automated hardware released microrafts with 98% efficiency and collected released microrafts with 100% efficiency. The automated system was used to examine the temporal variation in EGFP expression in cells transfected with CRISPR-Cas9 components for gene editing. Of 11,499 microrafts possessing a single cell, 220 microrafts were identified as possessing temporally varying EGFP-expression. Candidate cells (n=172) were released and collected from the microraft array and screened for the targeted gene mutation. Two cell colonies were successfully gene edited demonstrating the desired mutation. PMID- 28006687 TI - Ultrasensitive electrochemical DNA biosensor based on functionalized gold clusters/graphene nanohybrids coupling with exonuclease III-aided cascade target recycling. AB - In this work, a novel and ultrasensitive electrochemical biosensor was constructed for DNA detection based on functionalized gold clusters/graphene nanohybrids (AuNCs/GR nanobybrids) and exonuclease III (Exo III)-aided cascade target recycling. By utilizing the capacity of GR as universal template, different metal nanoclusters including AuNCs/GR nanobybrids and PtNCs/GR nanohybrids were synthesized through convenient ultrasonic method. Exo III-aided cascade recycling was initiated by target DNA, generating the final cleavage product (S2), which acted as a linkage between capture probe and the functionalized metal nanoclusters/GR conjugates in the construction of the biosensor. The AuNCs/GR-DNA-enzyme conjugates acted as interfaces of enzyme catalyzed silver deposition reaction, achieving DNA detection ranging from 0.02 fM to 20 pM with a detection limit of 0.057 fM. In addition, PtNCs/GR-DNA conjugates presented peroxidase-like activity and the functionalized PtNCs/GR nanohybrids-based electrochemical biosensor also realized DNA detection by catalyzing the 3,3',5,5'-tetramethylbenzidine-hydrogen peroxide (TMB-H2O2) system to produce electrochemical signal. This metal clusters/GR-based multiple amplified electrochemical biosensor provided an universal method for DNA detection. PMID- 28006688 TI - Cyanine5-doped silica nanoparticles as ultra-bright immunospecific labels for model circulating tumour cells in flow cytometry and microscopy. AB - In this work, ultra-bright fluorescent silica nanoparticles (NPs) labels have been shown to selectively bind to a model circulating tumour cell (CTC) line, MCF 7, a metastatic breast cancer by targeting epithelial cellular adhesion molecule (EpCAM) present on the MCF-7 cell membrane. Silica NPs approximately 40nm in diameter were doped with different concentrations of Cyanine5 dye molecules, using the reverse microemulsion method. The NPs were two orders of magnitude brighter than Cyanine5 free dye and the measured fluorescence intensity matched a homo-Forster Resonance Energy Transfer model. NPs were conjugated with anti-EpCAM antibody to the NP surface for immunospecific targeting. In flow cytometry experiments the NPs were twice as bright as two commercial anti-EpCAM red fluorophore conjugates, APC and AlexaFluor(r)647. This increase is achieved while keeping non-specific binding low as established in control tests with a non metastatic cancer cell line (HeLa). The NPs were also immunospecific in fluorescence microscopy experiments performed at room temperature on non-fixed cells. Confocal microscopy was used to confirm the NPs were located on the surface of the cells, matching with the location of the EpCAM marker. These NPs labels have excellent potential in biomedical diagnostics, particularly when high signal to noise and good photostability are needed, for example, in point-of-care testing. PMID- 28006689 TI - Advantages of time-resolved fluorescent nanobeads compared with fluorescent submicrospheres, quantum dots, and colloidal gold as label in lateral flow assays for detection of ractopamine. AB - Label selection is a critical factor for improving the sensitivity of lateral flow assay. Time-resolved fluorescent nanobeads, fluorescent submicrospheres, quantum dots, and colloidal gold-based lateral flow assay (TRFN-LFA, FM-LFA, QD LFA, and CG-LFA) were first systematically compared for the quantitative detection of ractopamine in swine urine based on competitive format. The limits of detection (LOD) of TRFN-LFA, FM-LFA, QD-LFA, and CG-LFA were 7.2, 14.7, 23.6, and 40.1pg/mL in swine urine samples, respectively. The sensitivity of TRFN-LFA was highest. In the quantitative determination of ractopamine (RAC) in swine urine samples, TRFN-LFA exhibited a wide linear range of 5pg/mL to 2500pg/mL with a reliable coefficient of correlation (R2=0.9803). Relatively narrow linear ranges of 10-500pg/mL (FM-LFA) and 25-2500pg/mL (QD-LFA and CG-LFA) were acquired. Approximately 0.005ug of anti-RAC poly antibody (pAb) was used in each TRFN-LFA test strip, whereas 0.02, 0.054, and 0.15ug of pAb were used in each of the FM-LFA, QD-LFA, and CG-LFA test strips, respectively. In addition, TRFN-LFA required the least RAC-BSA antigens and exhibited the shortest detection time compared with the other lateral flow assays. Analysis of the RAC in swine urine samples showed that the result of TRFN-LFA was consistent with that of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and a commercial enzyme-linked immunosorbent assay (ELISA) kit. PMID- 28006690 TI - Cause or consequence? Investigating attention bias and self-regulation skills in children at risk for obesity. AB - Impaired self-regulation, especially in food-specific situations, has been linked to childhood obesity. These deficits may be acquired during the development of obesity rather than being a prerequisite thereof. The current study, hence, focused on an at-risk population versus controls. Normal-weight children of obese and normal-weight parents were tested regarding attentional flexibility, emotion regulation, and inhibitory control. A sample of 50 preschoolers of obese parents (n=25) or normal-weight parents (n=25) participated in this study. Through eye tracking, attentional bias for food cues was measured during a visual probe task using food and toy images. Emotion regulation was assessed during a distress evoking task, and inhibitory control was examined through a delay-of gratification task. Both tasks are standardized and were conducted in non-food contexts. Results showed no significant group differences in overall attentional bias to food images over toy images. However, children of normal-weight parents showed a preference for toy images. Regarding emotion regulation, children in the risk group expressed significantly less overall emotional distress. In addition, less gaze aversion and bodily sadness could be observed in this group. No differences were found for inhibitory control. Findings suggest that general deficits in self-regulation are not yet present in normal-weight children at risk for obesity. Instead, they might develop as a by-product of unhealthy weight gain. Results indicate, however, that children of obese parents are less emotionally expressive compared with children of normal-weight parents. Furthermore, children of normal-weight parents appeared to be more interested in toy images than in food images. PMID- 28006691 TI - Spontaneous photon emission: A promising non-invasive diagnostic tool for breast cancer. AB - Ultra-weak photon emission (UPE) has attracted significant scientific attention for its potential to monitor the physiological and pathological characteristics of living systems. In this study, we investigated the strength of spontaneous photon emission (SPE) from the right (R) and left (L) side of body surface of human breast cancer-bearing nude mice models, considering the entire breast cancer growth process, and healthy controls using a photon detector. And then we calculated the ratio of the average SPE strength (ratio (R/L)) between the right and left side of each mouse. Cluster analysis was used to evaluate the accuracy rates of strength-R, strength-L, ratio (R/L) and their combination to identify tumor mice from the controls. Our results revealed that the discriminating powers of different parameters were different in different growth stages of tumor: in tumor incubation period, the accuracy rates of strength-R, strength-L, ratio (R/L) and their combination to identify tumor mice from control mice were 63.6%, 40.9%, 81.8% and 86.4%, respectively; For nude mice with tumor diameter <0.5cm, the accuracies were 72.7%, 45.5%, 86.4% and 90.9%; and for nude mice with tumor diameters larger than 1.5cm, the accuracies were 86.4%, 77.3%, 95.5% and 100%, respectively. These results indicated that the SPE from the body surface of the lesion site could significantly distinguish tumor mice from the controls when tumors were obvious or when there were no obvious morphological changes, although the accuracy was relatively low. The results suggest that SPE, as a sensitive and promising optical method, may contribute to the preliminary screening of breast cancer, especially for early diagnosis, and it may play a critical role in curtailing the effects of breast cancer and improving the survival of patients in the future. PMID- 28006692 TI - Norcyanine dyes with benzo[c,d]indolium moiety: Spectral sensitivity with pH change for fluorescence pH imaging in living cells. AB - Fluorescence pH imaging in living cells is a rapidly expanding research direction, however, it relies on the development of pH-sensitive fluorescent imaging agents. Here four norcyanine dyes with benzo[c,d]indolium moiety, exhibiting high spectral sensitivity with pH changes, were synthesized for fluorescence pH imaging in living cells, and characterized by 1H NMR, 13C NMR, IR, UV-Vis and HRMS. The investigation of their spectral properties in methanol and water showed that the absorption and emission maxima were in the region 488 618nm and 583-651nm, respectively, and four dyes exhibited high photostability. The pH spectral titrations showed that selective dye D1 had pH-dependent absorption spectral changes within the pH range of 2.4 to 9.4, and high fluorescent spectral sensitivity at pH5.0-8.0, with a pKa of 5.0. A cell association study indicated that dye D1 exhibited no or mild cytotoxicity at the application dose and duration, and could be accumulated in cells and mainly distributed in the cytoplasm, giving red fluorescence imaging. In particular, dye D1 could achieve pH-dependent fluorescence imaging in living cells with the increase of pH from 3.0 to 8.0, at excitation wavelength of 543nm and receiving wavelength of 655-755nm, which was valuable for studying the weak acidic, neutral and weak alkaline biological tissue compartments. PMID- 28006693 TI - Clinical implication of frailty assessment in older patients with atrial fibrillation. AB - BACKGROUND: We aimed to show the frailty status in older AF patients, and to find the association between frailty and the scores of CHA2DS2-VASc and HAS-BLED. Ultimately, we sought to investigate the impact of frailty on cardiovascular and all-cause mortality in older AF patients. METHODS: We retrospectively evaluated 365 patients (>=65years old) with AF, who underwent comprehensive geriatric assessment (CGA) between 2007 and 2014 in a single tertiary hospital. The CHA2DS2 VASc and HAS-BLED scores were calculated based on the electronic medical records and the frailty index was computed from the CGA data. The primary outcomes were cardiovascular and all-cause mortality. RESULTS: Frailty status was positively associated with the CHA2DS2-VASc score (P<0.001) and the HAS-BLED score (P=0.01). Patients with high CHA2DS2-VASc and HAS-BLED scores were more likely to be treated with anticoagulants rather than antiplatelet agents. However, frailty status was not associated with antithrombotic therapy. During the follow-up period (median [interquartile range], 22.9 [8.4-42.2] months), 141 patients (38.6%) died, of which 48 were due to cardiovascular events. CHA2DS2-VASc score could predict cardiovascular mortality, but not all-cause mortality. In contrast, frailty status was the independent predictor for both cardiovascular and all cause mortality after adjusting for possible confounders (hazard ratio for all cause mortality, 4.549; 95% CI, 2.756-7.509; P<0.001). CONCLUSION: Frailty assessment can be used to predict mortality in older AF patients, and provides additional prognostic value, along with the CHA2DS2-VASc and HAS-BLED scores. PMID- 28006694 TI - Effects and moderators of exercise on quality of life and physical function in patients with cancer: An individual patient data meta-analysis of 34 RCTs. AB - This individual patient data meta-analysis aimed to evaluate the effects of exercise on quality of life (QoL) and physical function (PF) in patients with cancer, and to identify moderator effects of demographic (age, sex, marital status, education), clinical (body mass index, cancer type, presence of metastasis), intervention-related (intervention timing, delivery mode and duration, and type of control group), and exercise-related (exercise frequency, intensity, type, time) characteristics. Relevant published and unpublished studies were identified in September 2012 via PubMed, EMBASE, PsycINFO, and CINAHL, reference checking and personal communications. Principle investigators of all 69 eligible trials were requested to share IPD from their study. IPD from 34 randomised controlled trials (n=4519 patients) that evaluated the effects of exercise compared to a usual care, wait-list or attention control group on QoL and PF in adult patients with cancer were retrieved and pooled. Linear mixed effect models were used to evaluate the effects of the exercise on post intervention outcome values (z-score) adjusting for baseline values. Moderator effects were studies by testing interactions. Exercise significantly improved QoL (beta=0.15, 95%CI=0.10;0.20) and PF (beta=0.18, 95%CI=0.13;0.23). The effects were not moderated by demographic, clinical or exercise characteristics. Effects on QoL (betadifference_in_effect=0.13, 95%CI=0.03;0.22) and PF (betadifference_in_effect=0.10, 95%CI=0.01;0.20) were significantly larger for supervised than unsupervised interventions. In conclusion, exercise, and particularly supervised exercise, effectively improves QoL and PF in patients with cancer with different demographic and clinical characteristics during and following treatment. Although effect sizes are small, there is consistent empirical evidence to support implementation of exercise as part of cancer care. PMID- 28006695 TI - Role of atrial endothelial cells in the development of atrial fibrosis and fibrillation in response to pressure overload. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1)-mediated inflammatory mechanisms have been shown to play a crucial role in atrial fibrosis induced by pressure overload. In the present study, we investigated whether left atrial endothelial cells would quickly respond structurally and functionally to pressure overload to trigger atrial fibrosis and fibrillation. METHODS AND RESULTS: Six week-old male Sprague-Dawley rats underwent suprarenal abdominal aortic constriction (AAC) or a sham operation. By day 3 after surgery, macrophages were observed to infiltrate into the endocardium. The expression of MCP-1 and E selectin in atrial endothelium and the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and ED1 in left atrial tissue were enhanced. Atrial endothelial cells were irregularly hypertrophied with the disarrangement of lines of cells by scanning electron microscopy. Various-sized gap formations appeared along the border in atrial endothelial cells, and several macrophages were located just in the endothelial gap. Along with the development of heterogeneous interstitial fibrosis, interatrial conduction time was prolonged and the inducibility of atrial fibrillation by programmed extrastimuli was increased in the AAC rats compared to the sham-operated rats. CONCLUSIONS: Atrial endothelium responds rapidly to pressure overload by expressing adhesion molecules and MCP-1, which induce macrophage infiltration into the atrial tissues. These processes could be an initial step in the development of atrial remodeling for atrial fibrillation. PMID- 28006696 TI - Post-traumatic stress disorder and depression among adult survivors 8 years after the 2008 Wenchuan earthquake in China. AB - BACKGROUND: The Wenchuan earthquake was China's worst natural disaster of the past three decades. Although the psychological sequelae of disasters can last for many years, the long-term sequelae and their risk factors tend to receive little research attention. OBJECTIVES: The objectives of the present study were to estimate the prevalences of symptomalogical PTSD and depression among survivors 8 years after the Wenchuan earthquake, and to identify the shared and unshared risk factors associated with PTSD and depression, using data from a cross-sectional survey. METHODS: 1369 participants were recruited from two different sites in the areas that were severely affected by the earthquake. Symptomalogical PTSD was assessed by the Impact of Event Scale-Revised (IES-R). The Chinese edition of the Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depression. Traumatic exposure to the Wenchuan earthquake was assessed using an exposure checklist designed by this study. RESULTS: Eight years after the Wenchuan earthquake, 11.8% of the respondents had symptomalogical PTSD, and 24.8% of respondents had probable depression. The results also indicated that female gender, low education, poor perceived health, and traumatic experiences after the earthquake were associated with higher odds of both PTSD and depression among survivors. Direct exposure to the earthquake was associated with comorbid symptomalogical PTSD and depression (OR=1.86; 95% CI=1.42, 2.44). Those having only depression were more likely to be unmarried/divorced/widowed, and to have experienced fear at the time of the earthquake (OR=1.34; 95% CI=1.04, 1.72), while those with only symptomalogical PTSD were likely to be from the township of Yongan as opposed to Guangji (OR=1.86; 95% CI=1.06, 3.31). LIMITATIONS: This is a cross-sectional study, and thus is insufficient for determining causal relationships with regard to chronic PTSD or depression. CONCLUSIONS: The results of this study indicate that symptomalogical PTSD and depression persist among many survivors of the Wenchuan earthquake, 8 eight years later. Objective earthquake exposure is associated with symptomalogical PTSD, while subjective exposure is associated with long-term depression. PMID- 28006697 TI - Diabetes mellitus and cardiovascular clinical characteristics of Spanish women with stable ischaemic heart disease: Data from the SIRENA study. AB - The relationship between diabetes and the cardiovascular clinical characteristics of Spanish women with stable ischaemic heart disease was studied in a nationwide cross-sectional study. Diabetes was related to a higher burden of risk factors, comorbidity, multivessel disease and coronary surgery. PMID- 28006698 TI - Type 2 diabetes mellitus in African women. AB - Compared to global estimates, Sub-Saharan Africa (SSA) has the highest projected rates of increase in type 2 diabetes (T2D) over the next 25years. This is attributed to the ageing population, increasing urbanisation and the associated lifestyle changes. Although the prevalence does not differ by gender, deaths attributable to T2D in SSA are greater in women, likely due to differences in beliefs and access to care. Women in SSA also have greater risk factor burden for T2D than men, in particular obesity, which is explained in part by sociocultural factors. The pathogenesis of diabetes differs between African and Caucasian women, with implications for risk assessment. African women are more insulin resistant than their Caucasian counterparts, despite a more 'favourable' body fat distribution. Notably, women in SSA face the dual burden of T2D and HIV/AIDS. HIV positive women in SSA are typically young and obese, with the latter being exacerbated by anti-retroviral therapy (ART). Cultural perceptions regarding weight loss and limited financial resources are the major limitations to the management of T2D. Hence prevention is vital. However, there is a paucity of studies examining the effectiveness and sustainability of interventions to reduce T2D in SSA. PMID- 28006699 TI - Midwifery students' experiences of simulation- and skills training. AB - BACKGROUND: In Sweden, simulation- and skills training are implemented in midwifery education in order to prepare students for clinical practice. Research regarding the use of both low to high levels of fidelity in simulation in midwifery programme is limited. AIM: The aim of this study was to explore midwifery students' experiences of simulation- and skills training. METHODS: Midwifery students (n=61), at advanced level, were interviewed in 13 group interviews from 2011 to 2105. A semi-structured interview guide was used, and data were analysed by content analysis. RESULTS: The results are presented in four main categories: develops hands on skills and communication, power of collaborative learning, highly valued learning environment and facilitates clinical practice. The majority of students felt that the simulation- and skills training were necessary to become familiar with hands on skills. Having repetitive practices in a safe and secure environment was viewed as important, and students highly valued that mistakes could be made without fear of comprising patient safety. Student's collaboration, reflections and critical thinking increased learning ability. Simulation- and skills training created links between theory and practice, and the lecturer had an important role in providing instructions and feedback. Students felt prepared and confident before their clinical practice, and simulation- and skills training increased safety for all involved, resulting in students being more confident, as patients in clinical practice became less exposed. Furthermore, mentors were satisfied with students' basic skills. CONCLUSION: Simulation- and skills training support the development of midwifery skills. It creates links between theory and practice, which facilitates students' learning ability. Training needs to include reflections and critical thinking in order to develop their learning. The lecturer has an important role in encouraging time for reflections and creating safe environment during the skills and simulation training. PMID- 28006700 TI - Detection of different microenvironments and Lactobacillus sakei biotypes in Ventricina, a traditional fermented sausage from central Italy. AB - The present study evaluated the physico-chemical and microbiological features of Ventricina, considering for the first time the presence of different compartments deriving from the technology of production. In fact meat pieces (pork muscle and fat cut into cubes of about 10-20cm3), mixed with other ingredients and then stuffed into pig bladder, are still distinguishable at the end of the ripening. They appear delimited on the outside by the casing and inside by thin layers consisting of spices (mainly red pepper powder), salt and meat juices. Our results showed that the exterior (portion of the product in contact with the casing), the interstice (area between the different cubes of meat or fat) and the heart (the inner portion of meat cubes) had distinctive values of pH and aw, and a typical microbial progression, so that they can be considered as different ecological niches, here called microenvironments. The study of lactic acid bacteria population, performed with PCR-DGGE and sequence analysis targeting the V1-V3 region of the 16S rRNA gene (rDNA), highlighted the presence of a few species, including Lactobacillus sakei, Lb. plantarum, Weissella hellenica and Leuconostoc mesenteroides. The RAPD-PCR analysis performed on Lb. sakei, recognised as the predominant species, allowed the differentiation into three biotypes, with that characterised by the highest acidifying and proteolytic activities and the highest ability to grow in the presence of sodium chloride prevailing. This leading biotype, detectable in the interstice during the entire ripening period, was isolated in the microenvironments exterior and heart starting from the 30th d of ripening, and it was the sole biotype present at the end of the ripening. The analysis of microenvironments through the scanning electron microscopy (SEM) evidenced the presence of micro-channels, which could favour the microbial flow from the interstice to the exterior and the heart. Moreover, the SEM analysis allowed the detection of biofilms, recognised as responsible for the correct colonisation of the different meat niches. PMID- 28006701 TI - Effects on performance and meat quality of Holstein bulls fed high concentrate diets without implants following immunological castration. AB - The objective of this study was to evaluate the effect of the GnRH vaccine on the performance and meat quality of Holstein bulls fed high concentrate diets. A total of 493 approximately 7month old bulls (initial BW 298+/-1.2kg) were allocated into 3 treatment groups, intact bulls (n=164), animals surgically castrated at 15 to 17d of the study (n=164), and animals vaccinated on 0 and 28d of the study with the GnRH vaccine (n=165). Animals were slaughtered between 131 and 133d and carcass quality was evaluated. Hot carcass weight, dressing percentage, fat classification and meat quality parameters did not differ significantly between surgically castrated and vaccinated animals but differed (P<0.05) from intact bulls. Carcass classification, pH at 26h, and fat color were not affected by treatment. PMID- 28006702 TI - Wrapper-based gene selection with Markov blanket. AB - Gene selection seeks to find a small subset of discriminant genes from the gene expression profiles. Current gene selection methods such as wrapper-based models mainly address the issue of obtaining high-quality gene subsets. However, they are considerably time consuming, due to the existence of irrelevant and redundant genes. In this study, we present an improved wrapper-based gene selection method by introducing the Markov blanket technique to reduce the required wrapper evaluation time. In addition, our method can identify targeting genes while eliminating redundant ones in an efficient way. We use ten publicly available microarray datasets to evaluate the proposed method. The results show that our method can handle gene selection effectively. Our experimental results also show that wrapper-based method combined with the Markov blanket outperforms other competing methods in terms of classification accuracy and time/space complexity. PMID- 28006703 TI - A comparison report of three advanced methods for drug-cyclodextrin interaction measurements. AB - Three advanced methods, high performance affinity chromatography (HPAC), surface plasmon resonance (SPR) and surface plasmon resonance imaging (SPRi) were compared and evaluated for determining the drug-cyclodextrin (CD) interactions herein. In total, 18 sparingly soluble drugs were selected for this comparative study. The three methods share a unique connection in the working principles and strategies. The same strategies of CD fixation onto solid phase were used in HPAC and SPR for the measurements, whereas, the SPR and SPRi share identical working principles. However, whilst these relationships are evident, no strong correlation was found between kinetic constants obtained from the three methods: Four drugs, namely, prednisolone, pseudolaric acid B, diazepam and gramisetron failed to show any response on SPR, whereas, the kinetics parameters from SPRi and HPAC were successfully measured. From a comparative review of all the kinetic data, random results without any trends were observed (ka, kd and KA) regardless of the relationships between the three methods: It is apparent that the measurement conditions (volume, flow rate, buffers), non-specific adsorption and experimental procedures had a strong impact on the generated data. The relative advantages and limitations of each method are critically presented on the basis of generated data. This comparative study provides a basis to further upgrade these techniques for confident measurement of drug-CDs interactions. PMID- 28006704 TI - Combined UV treatment and ozonation for the removal of by-product precursors in swimming pool water. AB - Both UV treatment and ozonation are used to reduce different types of disinfection by-products (DBPs) in swimming pools. UV treatment is the most common approach, as it is particularly efficient at removing combined chlorine. However, the UV treatment of pool water increases chlorine reactivity and the formation of chloro-organic DBPs such as trihalomethanes. Based on the similar selective reactivity of ozone and chlorine, we hypothesised that the created reactivity to chlorine, as a result of the UV treatment of dissolved organic matter in swimming pool water, might also be expressed as increased reactivity to ozone. Moreover, ozonation might saturate the chlorine reactivity created by UV treatment and mitigate increased formation of a range of volatile DBPs. We found that UV treatment makes pool water highly reactive to ozone. The subsequent reactivity to chlorine decreases with increasing ozone dosage prior to contact with chlorine. Furthermore, ozone had a half-life of 5 min in non-UV treated pool water whereas complete consumption of ozone was obtained in less than 2 min in UV treated pool water. The ozonation of UV-treated pool water induced the formation of some DBPs that are not commonly reported in this medium, in particular trichloronitromethane, which is noteworthy for its genotoxicity, though this issue was removed by UV treatment when repeated combined UV/ozone treatment interchanging with chlorination was conducted over a 24-h period. The discovered reaction could form the basis for a new treatment method for swimming pools. PMID- 28006706 TI - Correlating methane production to microbiota in anaerobic digesters fed synthetic wastewater. AB - A quantitative structure activity relationship (QSAR) between relative abundance values and digester methane production rate was developed. For this, 50 triplicate anaerobic digester sets (150 total digesters) were each seeded with different methanogenic biomass samples obtained from full-scale, engineered methanogenic systems. Although all digesters were operated identically for at least 5 solids retention times (SRTs), their quasi steady-state function varied significantly, with average daily methane production rates ranging from 0.09 +/- 0.004 to 1 +/- 0.05 L-CH4/LR-day (LR = Liter of reactor volume) (average +/- standard deviation). Digester microbial community structure was analyzed using more than 4.1 million partial 16S rRNA gene sequences of Archaea and Bacteria. At the genus level, 1300 operational taxonomic units (OTUs) were observed across all digesters, whereas each digester contained 158 +/- 27 OTUs. Digester function did not correlate with typical biomass descriptors such as volatile suspended solids (VSS) concentration, microbial richness, diversity or evenness indices. However, methane production rate did correlate notably with relative abundances of one Archaeal and nine Bacterial OTUs. These relative abundances were used as descriptors to develop a multiple linear regression (MLR) QSAR equation to predict methane production rates solely based on microbial community data. The model explained over 66% of the variance in the experimental data set based on 149 anaerobic digesters with a standard error of 0.12 L-CH4/LR-day. This study provides a framework to relate engineered process function and microbial community composition which can be further expanded to include different feed stocks and digester operating conditions in order to develop a more robust QSAR model. PMID- 28006705 TI - Effect of calcium oxide (CaO) and sawdust on adhesion and cohesion characteristics of sewage sludge under agitated and non-agitated drying conditions. AB - Stickiness phenomenon is widely observed in sewage sludge drying practices. This paper is aimed at demonstrating and comparing the sticky properties of sewage sludge through non-agitated and agitated drying tests specially designed for sewage sludge. Special attentions were paid to the effects of additives, i.e. CaO, fine sawdust (FSD) and coarse sawdust (CSD), on the adhesive and cohesive characteristics of sewage sludge. The results indicated that the sticky properties of the sludge were markedly different under the different testing methods, and was also greatly influenced by CaO or sawdust addition. For instance, in the non-agitated drying tests, CaO can significantly enhance the maximum adhesive and cohesive stresses of the sludge, whereas in the agitated drying tests, the torque of agitation, which strongly correlated with the cohesive stress of the sludge, was lowered by CaO addition. During agitated drying process, sludge lump with CaO addition started to break up at higher moisture content than that of original sludge. On the other hand, sawdust also affected the sticky properties of sludge in a way that was totally different with CaO. After sawdust addition (at 5-10%WS (wet sludge basis)), the cohesive stress of the sludge was markedly increased due to strengthening of mechanical interlocking inside the sludge, whereas the adhesiveness of the sludge was lowered by sawdust addition. The influencing mechanisms of CaO and sawdust under the different testing methods were detailedly discussed in the paper. PMID- 28006707 TI - Role of effluent organic matter in the photochemical degradation of compounds of wastewater origin. AB - The photoreactivity of treated wastewater effluent organic matter differs from that of natural organic matter, and the indirect phototransformation rates of micropollutants originating in wastewater are expected to depend on the fractional contribution of wastewater to total stream flow. Photodegradation rates of four common compounds of wastewater origin (sulfamethoxazole, sulfadimethoxine, cimetidine and caffeine) were measured in river water, treated municipal wastewater effluent and mixtures of both to simulate various effluent stream water mixing conditions that could occur in environmental systems. Compounds were chosen for their unique photodegradation pathways with the photochemically produced reactive intermediates, triplet-state excited organic matter (3OM*), singlet oxygen (1O2), and hydroxyl radicals (OH). For all compounds, higher rates of photodegradation were observed in effluent relative to upstream river water. Sulfamethoxazole degraded primarily via direct photolysis, with some contribution from OH and possibly from carbonate radicals and other unidentified reactive intermediates in effluent-containing samples. Sulfadimethoxine also degraded mainly by direct photolysis, and natural organic matter appeared to inhibit this process to a greater extent than predicted by light screening. In the presence of effluent organic matter, sulfadimethoxine showed additional reactions with OH and 1O2. In all water samples, cimetidine degraded by reaction with 1O2 (>95%) and caffeine by reaction with OH (>95%). In river water mixtures, photodegradation rate constants for all compounds increased with increasing fractions of effluent. A conservative mixing model was able to predict reaction rate constants in the case of hydroxyl radical reactions, but it overestimated rate constants in the case of 3OM* and 1O2 pathways. Finally, compound degradation rate constants normalized to the rate of light absorption by water correlated with E2/E3 ratios (sample absorbance at 254 nm divided by sample absorbance at 365 nm), suggesting that organic matter optical properties may hold promise to predict indirect compound photodegradation rates for various effluent mixing ratios. PMID- 28006708 TI - Integrating physically based simulators with Event Detection Systems: Multi-site detection approach. AB - The Fault Detection (FD) Problem in control theory concerns of monitoring a system to identify when a fault has occurred. Two approaches can be distinguished for the FD: Signal processing based FD and Model-based FD. The former concerns of developing algorithms to directly infer faults from sensors' readings, while the latter uses a simulation model of the real-system to analyze the discrepancy between sensors' readings and expected values from the simulation model. Most contamination Event Detection Systems (EDSs) for water distribution systems have followed the signal processing based FD, which relies on analyzing the signals from monitoring stations independently of each other, rather than evaluating all stations simultaneously within an integrated network. In this study, we show that a model-based EDS which utilizes a physically based water quality and hydraulics simulation models, can outperform the signal processing based EDS. We also show that the model-based EDS can facilitate the development of a Multi-Site EDS (MSEDS), which analyzes the data from all the monitoring stations simultaneously within an integrated network. The advantage of the joint analysis in the MSEDS is expressed by increased detection accuracy (higher true positive alarms and fewer false alarms) and shorter detection time. PMID- 28006709 TI - Unravelling the active microbial community in a thermophilic anaerobic digester microbial electrolysis cell coupled system under different conditions. AB - Thermophilic anaerobic digestion (AD) of pig slurry coupled to a microbial electrolysis cell (MEC) with a recirculation loop was studied at lab-scale as a strategy to increase AD stability when submitted to organic and nitrogen overloads. The system performance was studied, with the recirculation loop both connected and disconnected, in terms of AD methane production, chemical oxygen demand removal (COD) and volatile fatty acid (VFA) concentrations. Furthermore, the microbial population was quantitatively and qualitatively assessed through DNA and RNA-based qPCR and high throughput sequencing (MiSeq), respectively to identify the RNA-based active microbial populations from the total DNA-based microbial community composition both in the AD and MEC reactors under different operational conditions. Suppression of the recirculation loop reduced the AD COD removal efficiency (from 40% to 22%) and the methane production (from 0.32 to 0.03 m3 m-3 d-1). Restoring the recirculation loop led to a methane production of 0.55 m3 m-3 d-1 concomitant with maximum MEC COD and ammonium removal efficiencies of 29% and 34%, respectively. Regarding microbial analysis, the composition of the AD and MEC anode populations differed from really active microorganisms. Desulfuromonadaceae was revealed as the most active family in the MEC (18%-19% of the RNA relative abundance), while hydrogenotrophic methanogens (Methanobacteriaceae) dominated the AD biomass. PMID- 28006710 TI - Predicting scale formation during electrodialytic nutrient recovery. AB - Electro-concentration of nutrients from waste streams is a promising technology to enable resource recovery, but has several operational concerns. One key concern is the formation of inorganic scale on the concentrate side of cation exchange membranes when recovering nutrients from wastewaters containing calcium, magnesium, phosphorous and carbonate, commonly present in anaerobic digester rejection water. Electrodialytic nutrient recovery was trialed on anaerobic digester rejection water in a laboratory scale electro-concentration unit without treatment (A), following struvite recovery (B), and following struvite recovery as well as concentrate controlled at pH 5 for scaling control (C). Treatment A resulted in large amount of scale, while treatment B significantly reduced the amount of scale formation with reduction in magnesium phosphates, and treatment C reduced the amount of scale further by limiting the formation of calcium carbonates. Treatment C resulted in an 87 +/- 7% by weight reduction in scale compared to treatment A. A mechanistic model for the inorganic processes was validated using a previously published general precipitation model based on saturation index. The model attributed the reduction in struvite scale to the removal of phosphate during the struvite pre-treatment, and the reduction in calcium carbonate scale to pH control resulting in the stripping of carbonate as carbon dioxide gas. This indicates that multiple strategies may be required to control precipitation, and that mechanistic models can assist in developing a combined approach. PMID- 28006711 TI - Anaerobic treatment of antibiotic production wastewater pretreated with enhanced hydrolysis: Simultaneous reduction of COD and ARGs. AB - The presence of high concentration antibiotics in wastewater can disturb the stability of biological wastewater treatment systems and promote generation of antibiotic resistance genes (ARGs) during the treatment. To solve this problem, a pilot system consisting of enhanced hydrolysis pretreatment and an up-flow anaerobic sludge bed (UASB) reactor in succession was constructed for treating oxytetracycline production wastewater, and the performance was evaluated in a pharmaceutical factory in comparison with a full-scale anaerobic system operated in parallel. After enhanced hydrolysis under conditions of pH 7 and 85 degrees C for 6 h, oxytetracycline production wastewater with an influent chemical oxygen demand (COD) of 11,086 +/- 602 mg L-1 was directly introduced into the pilot UASB reactor. With the effective removal of oxytetracycline and its antibacterial potency (from 874 mg L-1 to less than 0.61 mg L-1 and from 900 mg L-1 to less than 0.84 mg L-1, respectively) by the enhanced hydrolysis pretreatment, an average COD removal rate of 83.2%, 78.5% and 68.9% was achieved at an organic loading rate of 3.3, 4.8 and 5.9 kg COD m-3 d-1, respectively. At the same time, the relative abundances of the total tetracycline (tet) genes and a mobile element (Class 1 integron (intI1)) in anaerobic sludge on day 96 were one order of magnitude lower than those in inoculated sludge on day 0 (P < 0.01). The reduction of ARGs was further demonstrated by metagenomic sequencing. By comparison, the full-scale anaerobic system treating oxytetracycline production wastewater with an influent COD of 3720 +/- 128 mg L-1 after dilution exhibited a COD removal of 51 +/- 4% at an organic loading rate (OLR) 1.2 +/- 0.2 kg m-3 d-1, and a total tet gene abundance in sludge was five times higher than the pilot scale system (P < 0.01). The above result demonstrated that enhanced hydrolysis as a pretreatment method could enable efficient anaerobic treatment of oxytetracycline production wastewater containing high concentrations of oxytetracycline with significantly lower generation of ARGs. PMID- 28006712 TI - Effect of annealing on the mechanical properties and the degradation of electrospun polydioxanone filaments. AB - Annealing, or heat treatment, has traditionally been used as a treatment to improve the strength and stiffness of electrospun materials. Understanding the extent to which annealing can improve the mechanical properties and alter the degradation rate of electrospun polydioxanone filaments could influence the range of its potential clinical applications. In this study, we investigated the effect of annealing electrospun polydioxanone filaments at varying times and temperatures and subsequently subjecting them to in vitro degradation in phosphate buffer saline for up to 6 weeks. Fibre alignment, tensile strength and thermal properties were assessed. It was determined that annealing at 65 degrees C for 3h only marginally improved the tensile strength (9+/-2%) but had a significant effect on reducing strain and rate of degradation, as well as maintaining fibre alignment within the filament. The filament retained significantly more of its force at failure after 4 weeks (82+/-15%, compared to 61+/-20% for non annealed filaments) and after 6 weeks of degradation (81+/-9%, compared to 55+/-13% for non annealed filaments). Conversely, annealing filaments at 75 degrees C improved the initial tensile strength of the filament (17+/-6%), but over 6 weeks, both samples annealed at 75 degrees C and 85 degrees C otherwise performed similarly or mechanically worse than those not annealed. These findings suggest that annealing at low temperatures is more useful as a method to tailor degradation rate than to improve mechanical properties. The ability to modulate the degradation profile with annealing may become useful to tailor the properties of electrospun materials without altering the chemistry of the polymer used. This might better match the degradation of the implant and gradual loss of mechanical properties with the new matrix deposition within the structure, enabling multiple regenerative strategies within a single biomaterial system. PMID- 28006713 TI - Influence of sodalite zeolite infiltration on the coefficient of thermal expansion and bond strength of all-ceramic dental prostheses. AB - In all-ceramic systems, a high incidence of veneer chip-off has been reported in clinical studies. Coefficient of thermal expansion (CTE) behaviour is one of the factors that may increase residual stress in the interface and influence the veneer/core bond strength. Therefore, this study aimed to evaluate the effect of sodalite zeolite-infiltration on the CTE behaviour and bond strength of different all-ceramic prostheses. The case-study groups were synthesized sodalite zeolite infiltrated alumina (IA-SOD) and synthesized sodalite zeolite-infiltrated zirconia-toughened alumina (ZTA) (IZ-SOD), while the control groups were glass infiltrated alumina (IA-glass) and glass-infiltrated ZTA (IZ-glass). Forty cylindrical-shaped samples measuring 5 mm in diameter and 10 mm in height were tested for CTE using a thermo-mechanical analyser machine, and forty disc-shaped ceramic samples measuring 12 mm in diameter and 1.2 +/- 0.2 mm in thickness were prepared using specially designed stainless steel split mould and veneered by cylinder-shaped (2 mm high * 2 mm diameter) low-fusing porcelain (Vita VM7). The veneer/core samples were sintered and tested for shear bond strength using a high precision universal testing machine. Scanning electron microscope, stereo microscope, atomic force microscope, and energy-dispersive X-ray spectroscopy were used to investigate the structural characteristics of samples at the fracture surface. The collected data were analyzed with a one-way ANOVA and Tukey HSD test (alpha=.05). IZ-SOD revealed highest CTE and shear bond strength values, while the IA-glass revealed the lowest values than the other groups. There was no significant difference in CTE and bond strength among IZ-SOD, IA-SOD and IZ-glass samples (p>0.05). The experimental SOD zeolite-infiltrated samples revealed higher CTE mismatch and bond strength along with a more favourable mode of failure than did the commercial glass-infiltrated samples. Sandblast technique is considered as effective conditioning procedure for enhancing the surface roughness of SOD zeolite-infiltrated frameworks which subsequently improving the bond strength. PMID- 28006715 TI - Effect of personal characteristics, victimization types, and family- and school related factors on psychological distress in adolescents with intellectual disabilities. AB - The purpose of this study was to determine the prevalence of bullying victimization among adolescents with intellectual disabilities and the influence of victimization experience on their mental health in Taiwan. Data on 706 adolescents from the 2011 Special Needs Education Longitudinal Study were analyzed. Multivariate regression analysis was applied to variables comprising 7 items of psychological distress, 4 types of bullying victimization, and family-, school-, and peer-related factors. Approximately 70% of the survey respondents had experienced at least one type of victimization, and 44% of them had experienced at least two types of victimization. Exclusion (50%) and verbal bullying (70%) were the most commonly reported types. In addition, exclusion and verbal bullying were found to be significantly associated with psychological distress in these adolescents. Our findings suggest that victimization is a common experience among adolescents with disabilities, and a notable risk factor for the psychological well-being of adolescents with intellectual disabilities. However, a good relationship with parents and peers can relieve psychological distress and its effect on mental health. PMID- 28006714 TI - "Skinny is prettier and normal: I want to be normal"-Perceived body image of non Western ethnic minority children in the Netherlands. AB - While the prevalence of overweight and obesity is higher among children of some non-Western ethnic minorities than among their Caucasian counterparts, their body image is understudied. The current study examined the body image of Dutch children of non-Western ethnic minorities (i.e., Surinamese, Antillean, Moroccan, and Turkish). Sociocultural influences from school, media and home environments and their perceptions of overweight prevention programs were taken into account. Fifty-two non-Western ethnic minority children (aged 8-12 years) participated in semi-structured interviews and focus groups. Results showed that the children generally underestimated their current body size, which was often overweight, and preferred thin and 'normal' body sizes. Results further revealed important insights into culturally determined themes, relating to perceived preferences in media, peers, parents, and teachers, nutritional habits, and children's beliefs about school-based health interventions. We conclude that targeting culturally sensitive awareness about actual body size and healthy body images seems paramount in future interventions. PMID- 28006716 TI - Biomolecular aspects of depression: A retrospective analysis. AB - OBJECTIVE: The effects of psychological stress, oxidative stress, and chronic low grade inflammation on the neuro-immune connection have been implicated in the pathogenesis of depression. Thus, in the recent past, there has been a growing effort in determining the mechanism of this pathogenesis. While attempting to map out, this mechanism researchers and clinicians have searched for clinically relevant biomarkers for use in the diagnosis and for the assessment of those suffering from depression. In this study, we have performed a retrospective analysis of biomarkers with clinically relevant potentials, including peripheral catecholamines, chemokines, cytokines, and neurotransmitters. METHODS: The retrospective analysis was performed on data collected over a six-year period of time (July 2009 to July 2015), gathered from patients (N=1399; Mage=42, SD=13; 71% female, 29% male) who submitted samples with complaints of feeling hopeless, worthless, isolated, alone, general sadness, overwhelmed, and/or a lack of interest in things they once enjoyed. The data collected consisted of quantitative values of urinary catecholamines and neurotransmitters (peripheral dopamine, epinephrine, histamine, kynurenic acid, norepinephrine, beta-PEA, and serotonin), salivary hormones (peripheral cortisol and melatonin), and peripheral blood mononuclear cell secreted cytokines and chemokines (Interleukins 1beta, 6, 8, 10, MCP-1, GCSF, and TNFalpha). Statistical and clinical significance was assessed by comparison with a control group (N=2395; Mage=42, SD=13; 70% female, 30% male), calculating the percent mean difference, p value, and effect size (Cohen's d) for each parameter between groups. RESULTS: The findings of this study suggested that, in a model of general depression, there is a dysregulation in the enzymatic production and degradation of catecholamines, neurotransmitters, hormones, and immunological proteins. A cycle of interaction was found between all of these biomolecules, where an increase or decrease in one marker could result in a stimulatory or inhibitory effect on others. The mechanism of this was proposed to occur through the interaction of psychological stress, inflammation, and oxidative stress pathways. All of these biomolecules were found to be significantly altered in the general depression group and are key components of the interaction between the neurological and immunological systems. CONCLUSIONS: This study serves to further elucidate the role of biomolecules in the regulation of affective disorders, such as depression. Resulting in providing a network of clinically relevant biomarkers to objectively assess and monitor general depression. PMID- 28006717 TI - Jejunojejunostomy intussusception after gastric bypass: Case report of a rare but serious complication. AB - Obesity, and the comorbidities associated with it, have become endemic within society. Roux-en-Y gastric bypass (RYGB) surgery is an increasingly common procedure with medical and cosmetic benefits (Li et al., 2014) [1]. However, as the case volume increases so do the rate of uncommon complications and it is imperative for surgeons to be aware of management guidelines of these complications. We present a case of Retrograde intussusception (RI) which is a rare complication status post RYGB. It is most commonly reported at the jejunojejunostomy (JJ) site, and it is hypothesized to be secondary to an antiperistaltic (retrograde) telescoping of the common limb going into the jejunal anastomosis (Varban et al., 2013) [2,3]. We present another case study as well as some points to consider in clinical management. PMID- 28006718 TI - Trigger Wrist and Carpal tunnel syndrome caused by a flexor tendon-related ganglion in a teenager: A case report. AB - INTRODUCTION: Trigger wrist is a rare entity and is usually seen in adults. Trigger wrist in children and teenagers is extremely rare. PRESENTATION OF CASE: A case of Trigger wrist and carpal tunnel syndrome in a 16-year-old male is reported. Surgical exploration revealed a ganglion related to the flexor superficialis tendon. After surgical excision, there was complete resolution of symptoms. DISCUSSION: This is a very rare case and there are no similar cases in the literature. The literature is reviewed and a classification of the causes of triggering at the wrist level is offered. The management approach and outcome are also discussed. CONCLUSION: Trigger wrist with concurrent carpal tunnel syndrome is a rare entity. It is usually caused by space occupying lesions. Excision is usually curative. PMID- 28006719 TI - Male breast cancer: Modified radical mastectomy or breast conservation surgery? A case report and review of the literature. AB - INTRODUCTION: Male breast cancer (MBC) is a rare disease that accounts for <1% of breast cancer cases. The most common treatment is modified radical mastectomy (MRM). Recently, breast conservative surgery (BCS) is getting popular for MBC treatment. We report a case and reviewed the literature to investigate whether emerging BCS can be considered as an alternative of a more radical surgery. PRESENTATION OF CASE: A 46 y.o. patient, presented with a painless left breast lump over a period of six months. The patient underwent a quadrantectomy at another institution. Pathology revealed an intraductal carcinoma in close proximity to the margins of excision. Adjuvant hormonal therapy was proposed to the patient, who refused and was referred to our Institution. We performed a MRM and a sentinel lymph node biopsy (SLNB). A contralateral breast liposuction and an adenectomy were also performed. The patient underwent also a nipple-areolar complex reconstruction. The patient didn't receive adjuvant therapy. DISCUSSION: Both oncological safety and satisfactory cosmetic outcomes are the goals of MBC treatment. No specific guidelines for MBC treatment have been proposed. MRM is currently the surgical gold standard of MBC (approximately 70% of all cases). Some authors reported that male BCS associated with radiation therapy is a feasible alternative MRM. Taking into account data from the literature and considering the previous surgery, in the case we report, we offered a MRM, SLNB and a contralateral breast symmetrization. CONCLUSION: MRM with SLNB and reconstruction of male breast asymmetry should be still considered as the treatment of choice of MBC. PMID- 28006720 TI - Isolated primary tuberculosis of spleen-A rare entity in the immuno-competent patient. AB - INTRODUCTION: Tuberculosis is a global public health concern, with 9.6 million affected individuals worldwide. Current screening and diagnostic regimes focus primarily on smear positivity, and hence, the rising numbers of Sputum negative and Extra-Pulmonary Tuberculosis has become a significant set-back to adequate diagnosis, disease notification and treatment, due to the large number of false negatives. PRESENTATION OF CASE: We hereby describe an intriguing presentation of tuberculosis - A 23 yr old lady with no comorbid illness, came to us with ten month history of on and off pyrexia, weakness and left hypochondriac pain. On evaluation, two isolated hypodense lesions in the spleen were detected. Diagnostic laparoscopy and Splenectomy were performed and histopathology revealed features of primary tubercular abscess. DISCUSSION: Commonly, abdominal visceral involvement is seen as a part of miliary tuberculosis in the immuno-compromised patient. However, in the absence of any co-morbidity and preserved immune function, this case depicts the rare possibility of primary isolated Tubercular splenic abscess in the normal healthy individual. CONCLUSION: We require a close eye and a keen sense of clinical acumen to accurately diagnose and treat smear negative and uncommon forms of Tuberculosis. Considering the growing prevalence and difficulty in disease control, there is need for greater knowledge and awareness to help mitigate the global burden of Tuberculosis. PMID- 28006721 TI - Wide local excision for anal GIST: A case report and review of literature. AB - INTRODUCTION: Gastrointestinal stromal tumors (GIST) are tumors of mesenchymal origin commonly detected in stomach and small bowel. GIST arising primarily from the anal canal is extremely rare. Due to the malignant potential, these tumors are treated with radical surgery like abdominoperineal resection. But with the advent of imatinib therapy and a better understanding of the tumor biology, some cases have been successfully treated with wide local excision. PRESENTATION OF CASE: We describe a case of a 70-year-old lady presenting with a 2cm mass in the anal canal. Endoanal ultrasound revealed a well-circumscribed solid nodule in the intersphincteric space. The patient was successfully treated by wide local excision and adjuvant therapy with imatinib mesylate. DISCUSSION: Only 14 confirmed cases of primary anal GIST have been reported in the literature. It appears as a well circumscribed hypoechoic mass arising from the intersphincteric space encroaching into the lumen on endorectal ultrasound. Lymphadenopathy is absent. Anal sphincters get involved as the lesion increases in size. Treatment is often planned based on the extent of the disease, the mitotic rate, patient's general condition and willingness for a permanent colostomy. CONCLUSION: Small lesions (<2cm) with low mitotic rate may be successfully managed by local excision. Radical surgery should be reserved for large, aggressive tumors. PMID- 28006722 TI - New insights into the effects of onion consumption on lipid mediators using a diet-induced model of hypercholesterolemia. AB - The levels and roles of lipid mediators can be modified in response to nutritional stimuli. The aim of this study was to investigate shifts in oxylipin and sphingolipid profiles stimulated by a hypercholesterolemic (HC) diet along with the modulating effects of onion introduced as an antioxidant functional ingredient characterized in the diet (HCO). Oxylipin and sphingolipid profiles were determined in plasma and tissues from Wistar rats using LC-MS/MS. Plasma omega-3 and omega-6 PUFA-derived oxylipins decreased in rats after 7 weeks of HC feeding, but did not evidence a further shift with HCO diet. Onion ingredient supplementation modulated the hepatic concentrations of prostaglandins and enhanced omega-3 oxylipins in the liver of HCO-fed rats relative to the HC group. The HC diet induced shifts in plasma sphingolipids, increasing sphingoid bases, dihydroceramides and ceramides, whilst the sphingomyelin, hexosylceramide and lactosylceramide families decreased. The HCO diet modified some HC diet-induced changes in sphingolipids in liver and spleen tissue. Onion supplementation effected changes in lipid mediator levels in diet-induced hypercholesterolemic Wistar rats. The potential of onion as regulator of pro-inflammatory mediators, and possible enhancer of pro-resolution pathways, warrants further study of the interaction of functional ingredients with bioactive lipid mediators and their potential impact on inflammation, oxidative stress and organ dysfunction. PMID- 28006723 TI - Synthesis of scalable and tunable slightly oxidized graphene via chemical vapor deposition. AB - Semiconducting, large sheets of carbon as an active material in optoelectronic research are missing and reduced graphene oxide (rGO) can be a good candidate. However, chemical synthesis cannot produce large sheets of rGO (i.e. maximum: 20 30MUm) as well as high quality rGO due to the restraints of fabrication method. Thus, a novel strategy for the synthesis of large sheets of semiconducting rGO is urgently required. Large area slightly oxidized graphene (SOG) is fabricated at the interface of silicon dioxide (SiO2) and silicon via Chemical Vapor Deposition (CVD) method, herein for the first time. Carbon atoms bond with oxygen functionalities (i.e. CO, COH) at the time of diffusion in SiO2 allowing for C/O ratios from 7 to 10 adjustable by the variation of SiO2 thickness, indicating the tunable oxidation. Moreover, electronic structure and morphology of SOG are similar to the chemically grown rGO. The fabrication mechanism of SOG is also investigated. PMID- 28006724 TI - Enhanced specific ion effects in ethylene glycol-based thermoresponsive polymer brushes. AB - The thermoresponse of poly(di(ethyleneglycol) methyl ether methacrylate) (PMEO2MA) brushes has been investigated in the presence of monovalent anions at either end of the Hofmeister series using ellipsometry, neutron reflectometry (NR) and colloid probe atomic force microscopy (AFM). NR measurements in deuterium oxide showed no evidence of vertical phase separation perpendicular to the grafting substrate with a gradual transition between a block-like, dense structure at 45 degrees C and an extended, dilute conformation at lower temperatures. All three techniques revealed a shift to a more collapsed state for a given temperature in kosmotropic potassium acetate solutions, while more swollen structures were observed in chaotropic potassium thiocyanate solutions. No difference was observed between 250mM and 500mM thiocyanate for a 540A brush studied by ellipsometry, while the lower molecular weight ~200A brushes used for NR and AFM measurements continued to respond with increasing salt concentration. The effect of thiocyanate on the temperature response was greatly enhanced relative to PNIPAM with the shift in temperature response at 250mM being five times greater than a PNIPAM brush of similar thickness and grafting density. PMID- 28006725 TI - Oxytocin modulates third-party sanctioning of selfish and generous behavior within and between groups. AB - Human groups function because members trust each other and reciprocate cooperative contributions, and reward others' cooperation and punish their non cooperation. Here we examined the possibility that such third-party punishment and reward of others' trust and reciprocation is modulated by oxytocin, a neuropeptide generally involved in social bonding and in-group (but not out group) serving behavior. Healthy males and females (N=100) self-administered a placebo or 24 IU of oxytocin in a randomized, double-blind, between-subjects design. Participants were asked to indicate (incentivized, costly) their level of reward or punishment for in-group (outgroup) investors donating generously or fairly to in-group (outgroup) trustees, who back-transferred generously, fairly or selfishly. Punishment (reward) was higher for selfish (generous) investments and back-transfers when (i) investors were in-group rather than outgroup, and (ii) trustees were in-group rather than outgroup, especially when (iii) participants received oxytocin rather than placebo. It follows, first, that oxytocin leads individuals to ignore out-groups as long as out-group behavior is not relevant to the in-group and, second, that oxytocin contributes to creating and enforcing in-group norms of cooperation and trust. PMID- 28006726 TI - Perfusion deconvolution in DSC-MRI with dispersion-compliant bases. AB - Perfusion imaging of the brain via Dynamic Susceptibility Contrast MRI (DSC-MRI) allows tissue perfusion characterization by recovering the tissue impulse response function and scalar parameters such as the cerebral blood flow (CBF), blood volume (CBV), and mean transit time (MTT). However, the presence of bolus dispersion causes the data to reflect macrovascular properties, in addition to tissue perfusion. In this case, when performing deconvolution of the measured arterial and tissue concentration time-curves it is only possible to recover the effective, i.e. dispersed, response function and parameters. We introduce Dispersion-Compliant Bases (DCB) to represent the response function in the presence and absence of dispersion. We perform in silico and in vivo experiments, and show that DCB deconvolution outperforms oSVD and the state-of-the-art CPI+VTF techniques in the estimation of effective perfusion parameters, regardless of the presence and amount of dispersion. We also show that DCB deconvolution can be used as a pre-processing step to improve the estimation of dispersion-free parameters computed with CPI+VTF, which employs a model of the vascular transport function to characterize dispersion. Indeed, in silico results show a reduction of relative errors up to 50% for dispersion-free CBF and MTT. Moreover, the DCB method recovers effective response functions that comply with healthy and pathological scenarios, and offers the advantage of making no assumptions about the presence, amount, and nature of dispersion. PMID- 28006727 TI - The relationship between MRI quantitative parameters and the expression of hypoxia inducible factor-1 alpha in cerebral astrocytoma. AB - OBJECTIVE: Astrocytoma is the common type of glioma. But the MRI scanning for astrocytoma preoperation pathological diagnosis is not exact. The purpose of this study was to use the MRI multi quantitative parameters to improve the diagnosis of astrocytoma and exploit their molecular mechanism related to the expression of HIF-1alpha. METHODS: Superconducting MR scanner and its work station were used to calculate the MRI multi quantitative parameters of the selected patients in this experiment. Scion Image Beta4.03 software was used to get the cellular density of tumor tissue. The expression of HIF-1alpha in astrocytoma specimens was detected by immunohistochemistry method. The correlation of MRI multi quantitative parameters and the expression of HIF-1alpha was analyzed by statistical software. RESULT: The values of ADC, RSIGd, EP, EI, cellular density and the expression of HIF-1alpha were changed with the malignant degree of astrocytoma to some extent, but not every quantitative parameter was related to the expression of HIF-1alpha. CONCLUSION: The MRI multi quantitative parameters binding with conventional MRI imaging can significantly raise the diagnostic accuracy of astrocytoma preoperatively. MRI features could indirectly reflect the biological behavior of astrocytoma. The peritumoral edema can't be explained by only one theory. PMID- 28006728 TI - Is clipping better than coiling in the treatment of patients with oculomotor nerve palsies induced by posterior communicating artery aneurysms? A systematic review and meta-analysis. AB - OBJECTIVE: Posterior communicating artery aneurysms (PcomAAs) are the second most common aneurysm, accounting for 25% of all aneurysms and 50% of internal carotid artery aneurysms. It has been estimated that oculomotor nerve palsy (ONP) occurs in up to one-third of patients with posterior communicating artery (PcomA) aneurysms. Recent research showed a better outcome of ONP in patients with PcomAA after surgical clipping when compared to endovascular coiling. We compared the effect of clipping and coiling on recovery of ONP in the management of patients with PcomAAs. METHODS: A meta-analysis of studies that compared surgical clipping with endovascular coiling was conducted by searching the literature via Pubmed, Embase and Cochrane Library databases without restricting the publication year. We extracted the following information: author names and publication year; clinical outcome (number of complete and incomplete recovery of ONP); perioperative data (number of pre-operatively complete or incomplete ONP, subarachnoid hemorrhage or not, number of complications (hydrocephalus, recurrence of PcomAA)). Except for author names and publication year, the data was pooled to perform a mean effect size estimate. The effects of two treatment modalities were then analyzed. RESULTS: Nine published reports of eligible studies involving 297 participants met the inclusion criteria. Overall, compared with endovascular coiling, surgical clipping had no statistically significant difference on the complete recovery of ONP, although there was an obvious trend in favor of clipping [RR=1.48, 95%CI (0.95, 2.29), p=0.08]. There was no significant difference in the total efficiency (any degree of change) on ONP [RR=1.08, 95%CI (0.94, 1.25), p>0.05], the overall complications [RR=0.60, 95%CI (0.33, 1.10), p>0.05], the efficacy on the complete recovery of ONP in patients without SAH [RR=0.83, 95%CI (0.53, 1.31), p>0.05], the effect on the complete recovery of ONP in patients with pre-operatively complete or incomplete ONP [RR=1.12, 95%CI (0.68, 1.85), p>0.05], [RR=1.12, 95%CI (0.79, 1.59), p>0.05]. In a comparison of a small cohort of patients that had suffered an SAH (17 vs. 22) there was a significant difference on the effect on complete recovery of ONP between clipping and coiling [RR=1.70, 95%CI (1.08, 2.67), p<0.05]. CONCLUSIONS: A superiority of clipping over coiling for the complete recovery of oculomotor nerve palsy in patients that had suffered an SAH from a ruptured aneurysm of the posterior communicating artery was found in the present meta-analysis. Limited by the relatively small sample sizes included, there were no significant differences observed in the clinical outcome between coiling and clipping in the treatment of unruptured PcomAA causing ONP. More evidence from advanced multi-center studies of large scale is needed to provide insight into the optimal treatment for outcome of ONP caused by PcomAAs. PMID- 28006729 TI - Can observing a Necker cube make you more insightful? AB - It is a compelling idea that an image as simple as a Necker cube, or a duck rabbit illusion, can reveal something about a person's creativity. Surprisingly, there are now multiple examples showing that people who are better at discovering 'hidden' images in a picture, are also better at solving some creative problems. Although this idea goes back at least a century, little is known about how these two tasks-that seem so different on the surface-are related to each other. At least some forms of creativity (and indeed scientific discoveries) may require that we change our perspectives in order to discover a novel solution to a problem. It's possible that such problems involve a similar cognitive process, and perhaps the same cognitive capacities, as switching perspectives in an ambiguous image. We begin by replicating previous work, and also show metacognitive similarities between the sudden appearance of hidden images in consciousness, and the sudden appearance of solutions to verbal insight problems. We then show that simply observing a Necker cube can improve subsequent creative problem-solving and lead to more self-reported insights. We speculate that these results may in part be explained by Conflict Monitoring Theory. PMID- 28006730 TI - Enhancement of microbial 2,4,6-trinitrotoluene transformation with increased toxicity by exogenous nutrient amendment. AB - In this study, the bacterial strain Citrobacter youngae strain E4 was isolated from 2,4,6-trinitrotoluene (TNT)-contaminated soil and used to assess the capacity of TNT transformation with/without exogenous nutrient amendments. C. youngae E4 poorly degraded TNT without an exogenous amino nitrogen source, whereas the addition of an amino nitrogen source considerably increased the efficacy of TNT transformation in a dose-dependent manner. The enhanced TNT transformation of C. youngae E4 was mediated by increased cell growth and up regulation of TNT nitroreductases, including NemA, NfsA and NfsB. This result indicates that the increase in TNT transformation by C. youngae E4 via nitrogen nutrient stimulation is a cometabolism process. Consistently, TNT transformation was effectively enhanced when C. youngae E4 was subjected to a TNT-contaminated soil slurry in the presence of an exogenous amino nitrogen amendment. Thus, effective enhancement of TNT transformation via the coordinated inoculation of the nutrient-responsive C. youngae E4 and an exogenous nitrogen amendment might be applicable for the remediation of TNT-contaminated soil. Although the TNT transformation was significantly enhanced by C. youngae E4 in concert with biostimulation, the 96-h LC50 value of the TNT transformation product mixture on the aquatic invertebrate Tigriopus japonicas was higher than the LC50 value of TNT alone. Our results suggest that exogenous nutrient amendment can enhance microbial TNT transformation; however, additional detoxification processes may be needed due to the increased toxicity after reduced TNT transformation. PMID- 28006731 TI - Selenite modulates the level of phenolics and nutrient element to alleviate the toxicity of arsenite in rice (Oryza sativa L.). AB - Arsenic (As) contamination of paddy rice is a serious threat all over the world particularly in South East Asia. Selenium (Se) plays important role in protection of plants against various abiotic stresses including heavy metals. Moreover, arsenite (AsIII) and selenite (SeIV) can be biologically antagonistic due to similar electronic configuration and sharing the common transporter for their uptake in plant. In the present study, the response of oxidative stress, phenolic compounds and nutrient elements was analyzed to investigate Se mediated As tolerance in rice seedlings during AsIII and SeIV exposure in hydroponics. Selenite (25uM) significantly decreased As accumulation in plant than As (25uM) alone treated plants. Level of oxidative stress related parameters viz., reactive oxygen species (ROS), lipid peroxidation, electrical conductivity, nitric oxide and pro-oxidant enzyme (NADPH oxidase), were in the order of As>As+Se>control>Se. Selenium ameliorated As phytotoxicity by increased level of phenolic compounds particularly gallic acid, protocatechuic acid, ferulic acid and rutin and thiol metabolism related enzymes viz., serine acetyl transferase (SAT) and cysteine synthase (CS). Selenium supplementation enhanced the uptake of nutrient elements viz., Fe, Mn, Co, Cu, Zn, Mo, and improved plant growth. The results concluded that Se addition in As contaminated environment might be an important strategy to reduce As uptake and associated phytotoxicity in rice plant by modulation of phenolic compounds and increased uptake of nutrient elements. PMID- 28006733 TI - Assessing the influence of sustainable trail design and maintenance on soil loss. AB - Natural-surfaced trail systems are an important infrastructure component providing a means for accessing remote protected natural area destinations. The condition and usability of trails is a critical concern of land managers charged with providing recreational access while preserving natural conditions, and to visitors seeking high quality recreational opportunities and experiences. While an adequate number of trail management publications provide prescriptive guidance for designing, constructing, and maintaining natural-surfaced trails, surprisingly little research has been directed at providing a scientific basis for this guidance. Results from a review of the literature and three scientific studies are presented to model and clarify the influence of factors that substantially influence trail soil loss and that can be manipulated by trail professionals to sustain high traffic while minimizing soil loss over time. Key factors include trail grade, slope alignment angle, tread drainage features, and the amount of rock in tread substrates. A new Trail Sustainability Rating is developed and offered as a tool for evaluating or improving the sustainability of existing or new trails. PMID- 28006732 TI - Impact of secondary inorganic aerosol and road traffic at a suburban air quality monitoring station. AB - PM10 from a suburban site in the northwest of Spain was assessed using data from chemical determinations, meteorological parameters, aerosol maps and five-day back trajectories of air masses. Temporal variations in the chemical composition of PM10 were subsequently related to stationary/mobile local sources and long range transport stemming from Europe and North Africa. The presence of secondary inorganic species (sulphates, nitrates and ammonium) in airborne particulate matter constituted one of the main focuses of this study. These chemical species formed 16.5% of PM10 on average, in line with other suburban background sites in Europe. However, a maximum of 47.8% of PM10 were recorded after several days under the influence of European air masses. Furthermore, the highest values of these three chemical species coincided with episodes of poor air circulation and influxes of air masses from Europe. The relationship between SO42- and NH4+ (R2 = 0.57, p-value<0.01) was found to improve considerably in summer and spring (R2 = 0.88 and R2 = 0.87, respectively, p-value<0.01), whereas NO3- and NH4+ (R2 = 0.55, p-value<0.01) reproduced this pattern in winter (R2 = 0.91, p-value<0.01). The application of a receptor model to the dataset led to the identification of notable apportionments due to road traffic and other types of combustion processes. In fact, large amounts of particulate matter were released to the atmosphere during episodes of biomass burning in forest fires. On isolated days, combustion was estimated to contribute up to 21.0 MUg PM/m3 (50.8% of PM10). The contribution from industrial processes to this source is also worth highlighting given the presence of Ni and Co in its profile. Furthermore, African dust outbreaks at the sampling site, characterised by an arc through the Atlantic Ocean, were usually associated with a higher concentration of Al2O3 in PM10. Results evidenced the relevance of stationary (i.e., steelworks and thermal power station) and mobile sources in the air quality at the suburban site under study, with important apportionments of particulate matter coming from road traffic and as consequence of releasing precursor gases of secondary particles to the atmosphere. PMID- 28006734 TI - Magnetic carbon composites with a hierarchical structure for adsorption of tetracycline, prepared from sugarcane bagasse via hydrothermal carbonization coupled with simple heat treatment process. AB - Sugarcane bagasse, an agricultural waste, was successfully converted into novel magnetic carbon composites by low temperature hydrothermal carbonization at 230 degrees C for 24h, followed by heat treatment at 400 degrees C for only 1h in air. Effects of NaOH and iron loading on the chemical properties of the composites were studied. In addition, various techniques were employed to investigate the physicochemical properties of the composites. Adsorption kinetics and isotherms were investigated with tetracycline (TC) for the magnetic composites. The magnetic carbon composite exhibited 48.35mg/g maximum adsorption capacity and was highly stable chemically and mechanically, with also good magnetic properties. The adsorption of TC by the magnetic adsorbent was mainly attributed to H-bonds and pi-pi interactions. The results indicate that waste sugarcane bagasse from the sugar industries can be efficiently transformed to a magnetic adsorbent for TC removal via a facile environmentally friendly method. PMID- 28006735 TI - Hydrothermal processing of cellulose: A comparison between oxidative and non oxidative processes. AB - This study investigates oxidative and non-oxidative hydrothermal processing of cellulose at five different temperatures (180-260 degrees C). Volatile fatty acids (VFAs) concentration, total suspended solid (TSS) degradation, dissolved organic carbon (DOC) and chemical oxygen demand (COD) were measured and compared in both processes. Moreover, the existence of hydrogen peroxide in both oxidative and non-oxidative processes was confirmed experimentally for the first time in literature. At temperatures ?220 degrees C the amount of H2O2 produced in the oxidative process was higher (50 fold) than that of in the non-oxidative while at higher temperatures (?240 degrees C) it was more for non-oxidative (3.5-5 fold). The concentration of VFAs in the non-oxidative process was lower than 10% of that in oxidative process. In both processes soluble COD increased with time and temperature, however at 260 degrees C after reaching a maximum, it decreased with time due to conversion of some soluble intermediates to CO2 and water. PMID- 28006736 TI - Exploitation of rapid acidification phenomena of food waste in reducing the hydraulic retention time (HRT) of high rate anaerobic digester without conceding on biogas yield. AB - The aim of the present work was to study and infer a full scale experience on co digestion of 1000kg of FW (400kg cooked food waste and 600kg uncooked food waste) and 2000L of rice gruel (RG) on daily basis based on a high rate biomethanation technology called "Anaerobic gas lift reactor" (AGR). The pH of raw substrate was low (5.2-5.5) that resulted in rapid acidification phenomena with in 12h in the feed preparation tank that facilitated to obtain a lower hydraulic residence time (HRT) of 10days. At full load, AGR was fed with 245kg of total solids, 205kg of volatile solids (167kg of organic matter in terms of chemical oxygen demand) which resulted in the generation of biogas and bio manure of 140m3/day and 110kg/day respectively. The produced biogas replaced 60-70kg of LPG per day. PMID- 28006737 TI - Effects of spent liquor recirculation in hydrothermal carbonization. AB - In this study, the effect of the recirculation of spent liquor from hydrothermal carbonization was investigated depending on the biomass type (grape pomace, orange pomace and poultry litter). The yield and fuel properties of hydrochars and spent liquor characteristics were determined for each recirculation step. By recirculation, mass and energy yields of the hydrochar increased, but their combustion characteristics changed: the ignition temperature and combustion reactivity decreased. The organic and inorganic load of liquor was increased with recirculation number, but not as much as would be expected after the first recycle. It was concluded that the load of organic and inorganic species in spent liquor decreased the leaching of some inorganics and diffusion of the degraded soluble fragments from biomass in the subsequent hydrothermal carbonization. Overall, this study showed that spent liquor recirculation makes the overall hydrothermal carbonization process environmentally friendly. PMID- 28006738 TI - Biomimetic apatite formed on cobalt-chromium alloy: A polymer-free carrier for drug eluting stent. AB - In this study, sirolimus (SRL) was loaded within biomimetic apatite formed on cobalt-chromium (Co-Cr) alloy, which has been reported for the first time, to inhibit the in-stent restenosis. Two different groups of loading SRL within biomimetic apatite were prepared: Group A (mono-layer of apatite/SRL) and Group B (bi-layer of apatite/SRL). Group A and Group B showed the biphasic pattern of SRL release up to 40 and 90days, respectively. The attachment of human artery smooth muscle cell (HASMC) for both Group A and Group B was significantly inhibited, and proliferation dramatically decreased with the release of SRL. Noteworthily, biomimetic apatite alone also suppressed the SMC proliferation. The porous biomimetic apatite uniformly covered Co-Cr stent without crack or webbings. After balloon expansion, the integrity of biomimetic apatite was sufficient to resist delamination or destruction. Thus, this study demonstrated that biomimetic apatite is a promising drug carrier for potential use in stents. PMID- 28006739 TI - Participatory action inquiry using baccalaureate nursing students: The inclusion of integrative health care modalities in nursing core curriculum. AB - Nurses, nursing educators and students support the inclusion of integrative health care (IHC) into nursing core curriculum as a way to create nurses who deliver nursing care to the full extent of their scope of practice and advance evidenced based IHC. Because of the holistic nature of IHC modalities, research to investigate appropriate teaching strategies and potential efficacy of learning IHC in the baccalaureate core curriculum requires a holistic approach. Therefore a phenomenological exploration using participatory action inquiry was conducted at a large Midwestern university. Eighteen first year nursing students were selected as co-researchers. Their experiences in learning and delivering three 15 min IHC interventions (foot reflexology, lavender aromatherapy and mindful breathing) in an acute care setting were captured using reflexive journaling and participation in structured and organic communicative spaces. Of the patients approached, 67% accepted to receive one or more IHC modalities (147/219). Using van Manen's model for holistic data reduction three themes emerged: The experience of presence, competency and unexpected results. Learning IHC modalities is best supported by a self-reflective process that is constructed and modeled by a nurse faculty member with experience in delivering IHC modalities. PMID- 28006740 TI - Scenario analysis of carbon emissions' anti-driving effect on Qingdao's energy structure adjustment with an optimization model, Part II: Energy system planning and management. AB - In this study, an inexact multistage stochastic mixed-integer programming (IMSMP) method was developed for supporting regional-scale energy system planning (EPS) associated with multiple uncertainties presented as discrete intervals, probability distributions and their combinations. An IMSMP-based energy system planning (IMSMP-ESP) model was formulated for Qingdao to demonstrate its applicability. Solutions which can provide optimal patterns of energy resources generation, conversion, transmission, allocation and facility capacity expansion schemes have been obtained. The results can help local decision makers generate cost-effective energy system management schemes and gain a comprehensive tradeoff between economic objectives and environmental requirements. Moreover, taking the CO2 emissions scenarios mentioned in Part I into consideration, the anti-driving effect of carbon emissions on energy structure adjustment was studied based on the developed model and scenario analysis. Several suggestions can be concluded from the results: (a) to ensure the smooth realization of low-carbon and sustainable development, appropriate price control and fiscal subsidy on high cost energy resources should be considered by the decision-makers; (b) compared with coal, natural gas utilization should be strongly encouraged in order to insure that Qingdao could reach the carbon discharges peak value in 2020; (c) to guarantee Qingdao's power supply security in the future, the construction of new power plants should be emphasised instead of enhancing the transmission capacity of grid infrastructure. PMID- 28006741 TI - Evaluating differences in forest fragmentation and restoration between western natural forests and southeastern plantation forests in the United States. AB - Changes in forest ecosystem structure and functions are considered some of the research issues in landscape ecology. In this study, advancing Forman's theory, we considered five spatially explicit processes associated with fragmentation, including perforation, dissection, subdivision, shrinkage, and attrition, and two processes associated with restoration, i.e., increment and expansion processes. Following this theory, a forest fragmentation and restoration process model that can detect the spatially explicit processes and ecological consequences of forest landscape change was developed and tested in the current analysis. Using the National Land Cover Databases (2001, 2006 and 2011), the forest fragmentation and restoration process model was applied to US western natural forests and southeastern plantation forests to quantify and classify forest patch losses into one of the four fragmentation processes (the dissection process was merged into the subdivision process) and to classify the newly gained forest patches based on the two restoration processes. At the same time, the spatio-temporal differences in fragmentation and restoration patterns and trends between natural forests and plantations were further compared. Then, through overlaying the forest fragmentation/restoration processes maps with targeting year land cover data and land ownership vectors, the results from forest fragmentation and the contributors to forest restoration in federal and nonfederal lands were identified. Results showed that, in natural forests, the forest change patches concentrated around the urban/forest, cultivated/forest, and shrubland/forest interfaces, while the patterns of plantation change patches were scattered sparsely and irregularly. The shrinkage process was the most common type in forest fragmentation, and the average size was the smallest. Expansion, the most common restoration process, was observed in both natural forests and plantations and often occurred around the previous expansion or covered the previous subdivision or shrinkage processes. The overall temporal fragmentation pattern of natural forests had a "perforation-subdivision/shrinkage-attrition" pathway, which corresponded to Forman's landscape fragmentation rule, while the plantation forests did not follow the rule strictly. The main land cover types resulted from forest fragmentation in natural forests and plantation forests were shrubland and herbaceous, mainly through subdivision and shrinkages process. The processes and effects of restoration of plantation forests were more diverse and efficient, compared to the natural forest, which were simpler with a lower regrowth rate. The fragmentation mostly occurred in nonfederal lands. In natural forests, forest fragmentation pattern differed in different land tenures, yet plantations remained the same in federal and nonfederal lands. PMID- 28006742 TI - Fast and efficient adsorption of methylene green 5 on activated carbon prepared from new chemical activation method. AB - Activated carbon (AC) was synthesized from golden shower (GS) through a new chemical activation process. The three-stage process comprised (1) hydrothermal carbonization of GS to produce hydrochar, (2) pyrolysis of hydrochar to produce biochar, and (3) subsequent chemical activation of biochar with K2CO3 to obtain GSHBAC. The traditional synthesis processes (i.e., one-stage and two-stage) were also examined for comparison. In the one-stage process, GS that was impregnated with K2CO3 was directly pyrolyzed (GSAC), and the two-stage process consisted of (1) pyrolytic or hydrothermal carbonization to produce biochar or hydrochar and (2) subsequent chemical activation was defined as GSBAC and GSHAC, respectively. The synthesized ACs were characterized by scanning electron microscope, Brunauer Emmett-Teller (BET) surface area analysis, Fourier transform infrared spectrometry, point zero charge, and Boehm titration. The adsorption results demonstrated that the MG5 adsorption process was not remarkably affected by neither the solution pH (2.0-10) nor ionic strength (0-0.5 M NaCl). Kinetic studies showed that the adsorption equilibrium was quickly established, with a low activation energy required for adsorption (Ea; 3.30-27.8 kJ/mol), and the ACs removed 50-73% of the MG5 concentration from solution within 01 min. Desorption studies confirmed the adsorption was irreversible. Thermodynamic experiments suggested that the MG5 adsorption was spontaneous (-DeltaG degrees ) and endothermic (+DeltaH degrees ), and increased the randomness (+DeltaS degrees ) in the system. Although the specific surface areas of the ACs followed the order GSAC (1,413) > GSHAC (1,238) > GSHBAC (903) > GSBAC (812 m2/g), the maximum adsorption capacities determined from the Langmuir model (Qomax) at 30 degrees C exhibited the following order: GSHBAC (531) > GSAC (344) > GSHAC (332) > GSBAC (253 mg/g). Oxygenation of the ACs' surface through a hydrothermal process with acrylic acid resulted in a decrease in MG5 adsorption and identified the importance of pi-pi interactions to the adsorption process. The primary interactions in MG5 adsorption were pi-pi interactions and pore filling, while hydrogen bonding and n-pi interactions were minor contributors. The three-stage process can be regarded as the effective preparation method of AC with a high adsorption capacity toward the cationic dye. PMID- 28006743 TI - An expert panel process to evaluate habitat restoration actions in the Columbia River estuary. AB - We describe a process for evaluating proposed ecosystem restoration projects intended to improve survival of juvenile salmon in the Columbia River estuary (CRE). Changes in the Columbia River basin (northwestern USA), including hydropower development, have contributed to the listing of 13 salmon stocks as endangered or threatened under the U.S. Endangered Species Act. Habitat restoration in the CRE, from Bonneville Dam to the ocean, is part of a basin wide, legally mandated effort to mitigate federal hydropower impacts on salmon survival. An Expert Regional Technical Group (ERTG) was established in 2009 to improve and implement a process for assessing and assigning "survival benefit units" (SBUs) to restoration actions. The SBU concept assumes site-specific restoration projects will increase juvenile salmon survival during migration through the 234 km CRE. Assigned SBUs are used to inform selection of restoration projects and gauge mitigation progress. The ERTG standardized the SBU assessment process to improve its scientific integrity, repeatability, and transparency. In lieu of experimental data to quantify the survival benefits of individual restoration actions, the ERTG adopted a conceptual model composed of three assessment criteria-certainty of success, fish opportunity improvements, and habitat capacity improvements-to evaluate restoration projects. Based on these criteria, an algorithm assigned SBUs by integrating potential fish density as an indicator of salmon performance. Between 2009 and 2014, the ERTG assessed SBUs for 55 proposed projects involving a total of 181 restoration actions located across 8 of 9 reaches of the CRE, largely relying on information provided in a project template based on the conceptual model, presentations, discussions with project sponsors, and site visits. Most projects restored tidal inundation to emergent wetlands, improved riparian function, and removed invasive vegetation. The scientific relationship of geomorphic and salmonid responses to restoration actions remains the foremost concern. Although not designed to establish a broad strategy for estuary restoration, the scoring process has adaptively influenced the types, designs, and locations of restoration proposals. The ERTG process may be a useful model for others who have unique ecosystem restoration goals and share some of our common challenges. PMID- 28006744 TI - Understanding influential factors on implementing green supply chain management practices: An interpretive structural modelling analysis. AB - In this study, we establish a set of 19 influential factors on the implementation of Green Supply Chain Management (GSCM) practices and analyse the interaction between these factors and their effect on the implementation of GSCM practices using the Interpretive Structural Modelling (ISM) method and the "Matrice d'Impacts Croises Multiplication Appliquee a un Classement" (MICMAC) analysis on data compiled from interviews with supply chain (SC) executives based in the Gulf countries (Middle East region). The study reveals a strong influence and driving power of the nature of the relationships between SC partners on the implementation of GSCM practices. We especially found that dependence, trust, and durability of the relationship with SC partners have a very high influence. In addition, the size of the company, the top management commitment, the implementation of quality management and the employees training and education exert a critical influence on the implementation of GSCM practices. Contextual elements such as the industry sector and region and their effect on the prominence of specific factors are also highlighted through our study. Finally, implications for research and practice are discussed. PMID- 28006745 TI - Structural social capital and local-level forest governance: Do they inter relate? A mushroom permit case in Catalonia. AB - In diffuse forest uses, like non-timber forest products' harvesting, the behavioural alignment of pickers is crucial for avoiding a "tragedy of the commons". Moreover, the introduction of policy tools such as a harvest permit system may help in keeping the activity under control. Besides the official enforcement, pickers' engagement may also derive from the perceived legitimate decision of forest managers and the community pressure to behave according to the shared values. Framed within the social capital theory, this paper examines three types of relations of rural communities in a protected area in Catalonia (Spain) where a system of mushroom picking permits was recently introduced. Through social network analysis, we explore structural changes in relations within the policy network across the policy conception, design and implementation phases. We then test whether social links of the pickers' community relate to influential members of the policy network. Lastly, we assess whether pickers' bonding and bridging structures affect the rate of permit uptake. Our results show that the high degree of acceptance could be explained by an adequate consideration of pickers' preferences within the decision-making group: local pickers show proximity to members of the policy network with medium-high influence during the three policy phases. The policy network also evolves, with some members emerging as key actors during certain phases. Significant differences are found in pickers' relations among and across the involved municipalities following an urban-rural gradient. A preliminary relation is found between social structures and differential pickers' engagement. These results illustrate a case of positive social capital backing policy design and, probably, also implementation. This calls for a meticulous design of forest policy networks with respect to communities of affected forest users. PMID- 28006746 TI - Acetaminophen-induced hepatotoxicity: Preventive effect of trans anethole. AB - The hepatotoxicity induced by APAP is caused by the excessive production of N acetyl-para-benzoquinone imine (NAPQI), which, when reacting with hepatic proteins proved to cause irreversible lesions. Associated with this process, an intense inflammatory process is also evidenced, characterized by the increased cell influx and production/release of inflammatory mediators. Trans anethole, an aromatic compounds has been showed anti-inflammatory efficacy by inhibit the cellular recruitment and synthesis/releases of many proinflammatory mediators such as prostaglandin (PGE2), cytokines (TNF, IL-1) and nitrico oxide (NO). The aim of this study is to investigate the effect of trans anethole on some inflammatory parameters that are involved in hepatotoxicity induced by high doses of acetaminophen. Our results demonstrate that treatment with AN at doses 125 and 250mg/kg once a day for seven days prevented the changes caused by the APAP overdose, showing less intensity in the histological changes (necrosis, size of hepatocyte area and inflammatory infiltration), and corroborating the findings of serum activities of transaminases and phosphatases and the activity of the enzyme myeloperoxidase. In addition, the treatment prevented the up-regulation of proinflammatory mediators such as NO, TNF, IL-1alpha, MIP-1alpha and MCP-1 and induced the up-regulation of anti-inflammatory cytokines (IL-4 and IL-10). Thus, our results demonstrate a possible protective effect of trans anethole on the hepatotoxicity induced by APAP. PMID- 28006747 TI - Role of protease and protease inhibitors in cancer pathogenesis and treatment. AB - Cancer is the second cause of death in 2015, and it has been estimated to surpass heart diseases as the leading cause of death in the next few years. Several mechanisms are involved in cancer pathogenesis. Studies have indicated that proteases are also implicated in tumor growth and progression which is highly dependent on nutrient and oxygen supply. On the other hand, protease inhibitors could be considered as a potent strategy in cancer therapy. On the basis of the type of the key amino acid in the active site of the protease and the mechanism of peptide bond cleavage, proteases can be classified into six groups: cysteine, serine, threonine, glutamic acid, aspartate proteases, as well as matrix metalloproteases. In this review, we focus on the role of different types of proteases and protease inhibitors in cancer pathogenesis. PMID- 28006748 TI - A focus on resveratrol and ocular problems, especially cataract: From chemistry to medical uses and clinical relevance. AB - Low vision and blindness are important health problems that affect millions of people throughout the world. The most common and important pathologies are diabetic retinopathy, age-related macular degeneration, glaucoma as well as cataracts. The latter consists of an opacification of the lens of the eye which impedes the passage of light and represents one of the most important causes of vision loss. Among the risk factors for cataract development, there are life style factors such as the use of tobacco, abuse of alcohol and unhealthy diet. In light of this, dietary components that possess anti-oxidant activity, such as polyphenols for instance, can be considered good candidates for human studies in the prevention and or treatment of such diseases. Among dietary components, the antioxidant capacity of certain polyphenols is well known, and these could be good candidates. In this review we focus our attention on the current scientific literature regarding to the effects of resveratrol on cataracts and other ocular diseases, along with its potential mechanism/s of action. A large number of preclinical studies support the involvement of resveratrol in clinical trials for the prevention and treatment of eye diseases induced by oxidative stress and inflammation, such as age-related cataract. PMID- 28006749 TI - beta-Ag2MoO4 microcrystals: Characterization, antibacterial properties and modulation analysis of antibiotic activity. AB - This study reports the antibacterial properties and modulation analysis of antibiotic activity by beta-Ag2MoO4 microcrystals as well as their structural and vibrational characterization. The silver molybdate was obtained by the conventional hydrothermal method, and the structural, vibrational and morphological properties of the sample were determined using X-ray diffraction, Raman spectroscopy and scanning electron microscopy images. beta-Ag2MoO4 microcrystals obtained show spinel-type cubic structure (Fd-3m) with irregular shapes. The evaluation of antibacterial and modulatory-antibiotic activity was performed using the microdilution method to determine the Minimum Inhibitory Concentration (MIC) of the beta-Ag2MoO4 and antibiotics alone and associated with the silver molybdate. The beta-Ag2MoO4 modulates the antibiotic activity against all bacteria assayed in a synergistic (as the norfloxacin and gentamicin against S. aureus and gentamicin against E. coli) or an antagonistic form (as the norfloxacin against E.coli and P. aeruginosa). The reversion of antibiotic resistance by combinations with Ag2MoO4 could be a novel strategy to combat infections caused by multiple drug resistance (MDR) pathogens. Our results indicate that these silver molybdates present a clinically relevant antibacterial activity and enhanced the antibiotic activity of some antibiotics against MDR strain of S. aureus and E. coli, being an interesting alternative to combat antibiotic-resistant bacterial infectious agents. PMID- 28006750 TI - miR-382 inhibits tumor progression by targeting SETD8 in non-small cell lung cancer. AB - Previous studies showed that miR-382 plays important roles in several types of cancers. Nevertheless, its expression and function in non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that miR-382 expression was evidently downregulated in NSCLC tissue and cell lines in comparison with the adjacent normal tissues and human bronchial epithelial cell line (16HBE). Moreover, the expression levels of miR-382 were significantly associated with last-stage and tumor metastasis in NSCLC patients. In addition, exogenous miR-382 evidently inhibited NSCLC cell proliferation, migration and invasion in vitro. We also revealed SETD8 as a direct target of miR-382 in NSCLC, and restored SETD8 partially reversed the negative effects miR-382 on NSCLC cells. In total, our study demonstrated that miR-382 dysregulated in NSCLC and involved in NSCLC tumorigenesis and metastasis by suppressing SETD8 expression, which may help to identify effective therapies for NSCLC treatment. PMID- 28006751 TI - miR-375 ameliorates sepsis by downregulating miR-21 level via inhibiting JAK2 STAT3 signaling. AB - Accumulating evidences have confirmed that miRNAs have important roles in sepsis. Myeloid-derived suppressor cells (MDSCs) enhance late sepsis development through immunosuppression in mice. Here, the functions and mechanisms of miR-375 in sepsis were revealed. We found that miR-375 level was downregulated but miR-21 level was upregulated in sepsis patients and that their levels were correlated negatively. Importantly, ectopic expression of miR-375 could decrease the number of sepsis Gr1+CD11b+ MDSCs in mice. Mechanistically, miR-375 could target Janus kinase 2 (JAK2) and further impaired signal transducer and activator of transcription 3 (STAT3) in sepsis Gr1+CD11b+ MDSC. Gain and loss of function of experiments showed that upregulation or downregulation of miR-375 level could decrease or increase miR-21 level. Moreover, pretreatment of JAK2 overexpressing vector could abolish the effects of miR-375 on miR-21 level and the amount of sepsis Gr1+CD11b+ MDSCs. Therefore, our results demonstrate that miR-375 could block JAK2-STAT3 pathway and thus modulate miR-21 level, which is involved in regulation of late sepsis. PMID- 28006752 TI - Regulation of miRNAs by herbal medicine: An emerging field in cancer therapies. AB - MicroRNAs' expression profiles have recently gained major attention as far as cancer research is concerned. MicroRNAs are able to inhibit target gene expression via binding to the 3' UTR of target mRNA, resulting in target mRNA cleavage or translation inhibition. MicroRNAs play significant parts in a myriad of biological processes; studies have proven, on the other hand, that aberrant microRNA expression is, more often than not, associated with the growth and progression of cancers. MicroRNAs could act as oncogenes (oncomir) or tumor suppressors and can also be utilized as biomarkers for diagnosis, prognosis, and cancer therapy. Recent studies have shown that such herbal extracts as Shikonin, Sinomenium acutum, curcumin, Olea europaea, ginseng, and Coptidis Rhizoma could alter microRNA expression profiles through inhibiting cancer cell development, activating the apoptosis pathway, or increasing the efficacy of conventional cancer therapeutics. Such findings patently suggest that the novel specific targeting of microRNAs by herbal extracts could complete the restriction of tumors by killing the cancerous cells so as to recover survival results in patients diagnosed with malignancies. In this review, we summarized the current research about microRNA biogenesis, microRNAs in cancer, herbal compounds with anti-cancer effects and novel strategies for employing herbal extracts in order to target microRNAs for a better treatment of patients diagnosed with cancer. PMID- 28006753 TI - Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats. AB - The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis. Day 8 onwards of CFA administration, rats were injected daily with agmatine for next 7days, and arthritis score, body weights and food intake were monitored daily (g). Since cachexia is known to produce severe inflammation, malnutrition and inhibition of albumin gene expression, we have also monitored the total proteins, albumin, TNF alpha and IL-6 levels in arthritic rats and its modulation by agmatine. In the present study, CFA treated rats showed a progressive reduction in both food intake and body weight. In addition analysis of blood serum of arthritis animals showed a significant reduction in proteins and albumin and significant elevation in tumor necrosis factor (TNF)-alpha and Interleukins (IL)-6. Chronic agmatine (20-40mg/kg, ip) treatment not only attenuated the signs of arthritis but also reverses anorexia and body weight loss in CFA treated rats. In addition, agmatine restored total protein and albumin and reduces TNF-alpha and IL-6 levels in arthritis rats. These results suggest that agmatine administration can prevent the body weights loss and symptoms of arthritis via inhibition of inflammatory cytokines. PMID- 28006754 TI - Influence of extracellular polymeric substances (EPS) treated by combined ultrasound pretreatment and chemical re-flocculation on water treatment sludge settling performance. AB - Extracellular polymeric substances (EPS) are high molecular weight polymers and play a significant role in floc stability, floc size, bioflocculation and sludge settleability. The destruction and reconstruction of EPS improve the performance of solid-water separation processes. In this study, the influence of combined ultrasound pretreatment and chemical re-flocculation on the spatial distribution and composition of EPS was examined. Settleability efficiency demonstrated that the optimal operating condition was an ultrasound pretreatment time of 15 min at pH 6. Sludge particles were greatly disintegrated and the protein-like substances were converted into smaller molecules after ultrasound treatment, and pH had important effects on solubilization and degradation of protein-like substances. The flocs of sludge water after addition of polyacrylamide were larger in size and denser in structure than those resulting from addition of polyaluminium chloride. However, polyaluminium chloride had a better capacity for degrading EPS, especially at a dosage of 1.2 g/g total suspended solids. The results of this research show that the combination of ultrasonication and chemical re flocculation is effective in treating sludge water from a drinking water treatment plant. PMID- 28006755 TI - Partitioning of polybrominated biphenyl ethers from mother to fetus and potential health-related implications. AB - Presently, knowledge on the partitioning of polybrominated biphenyl ethers (PBDEs) from mother to fetus and the relationship between PBDE exposure and the levels of thyroid hormones (THs) needs to be extended further. In the present study, we investigated the concentrations of PBDEs in paired mother-fetus samples from 72 pregnant women in Wenling, China. The detection of PBDE concentration suggested that the expectant women living in Wenling for over 20 years might be highly exposed to PBDEs, which is largely ascribed to e-waste recycling activities in the local environment. The median concentration ratios between paired cord serum and maternal serum for higher-brominated BDEs were smaller than those for lower-brominated BDEs (p < 0.05). This result indicated that the placenta could hinder the transfer of PBDEs from mother to fetus, and the hindrance effect increased with higher-brominated congeners. Median ratios of paired placenta vs. maternal serum concentrations varied in a narrow range (0.15 0.25), with significantly lower value for BDE-209 than that for BDE-28 (p < 0.01). The extent of transplacental transfer was larger than that of placental retention for eight BDE congeners (p < 0.01). The concentration of BDE congeners among the paired samples could be fitted by equations, implying that their distribution could be predicted for each other (p < 0.001). There was a significant association between BDE-153 and TT4 levels in maternal serum from Wenling local residents (p < 0.05), suggesting potential implications for fetal development and their mothers' health in e-waste recycling environment. In addition, it was found that the relationship between BDEs and TH levels was likely affected by the exposure duration of the population to PBDEs. PMID- 28006756 TI - Initial biochar properties related to the removal of As, Se, Pb, Cd, Cu, Ni, and Zn from an acidic suspension. AB - This study tests the influence of a diverse set of biochar properties on As(V), Se(IV), Cd(II), Cu(II), Ni(II), Pb(II), or Zn(II) removal from solution at pH 4.5. Six commercial biochars produced using different feedstock and pyrolysis conditions were extensively characterized using physical, chemical, and spectroscopic techniques, and their properties were correlated to anion and cation removal using multiple linear regression. H/total organic C (TOC) ratio and volatile matter were positively correlated to cation removal from solution, which indicate interactions between metals and non-aromatic C. Defining the correlation of ion removal with specific OC functional groups was hindered by the inherent limitations of the spectroscopic techniques, which was exacerbated by the heterogeneity of the biochars. Ash was negatively correlated to Se(IV) and positively correlated to Cd(II), Cu(II), and Ni(II) removal from solution. Interference from soluble P in biochars may partly explain the low Se(IV) removal from solution; and Ca-, P-, and Fe- containing compounds likely sorbed or precipitated Pb(II), Cd(II), Cu(II), Ni(II) and Zn(II). Furthermore, Ca-oxalate identified using X-ray diffraction in willow, may be responsible for willow's increased ability to remove Cd(II), Ni(II), and Zn(II) compared to the other 5 biochars. It was clear that both OC and inorganic biochar components influenced metal(loid) and Se(IV) removal from solution. The non-aromatic and volatile OC correlated to removal from solution may be readily available for microbial degradation, while Mg, N, P, and S are required for biological growth. Biological metabolism and uptake of these compounds may inhibit or destabilize their interaction with contaminants. PMID- 28006757 TI - Development of QSAR model to predict the ecotoxicity of Vibrio fischeri using COSMO-RS descriptors. AB - Ionic liquids (ILs) are class of solvent whose properties can be modified and tuned to meet industrial requirements. However, a high number of potentially available cations and anions leads to an even increasing members of newly synthesized ionic liquids, adding to the complexity of understanding on their impact on aquatic organisms. Quantitative structure activity?property relationship (QSAR?QSPR) technique has been proven to be a useful method for toxicity prediction. In this work,sigma-profile descriptors were used to build linear and non-linear QSAR models to predict the ecotoxicities of a wide variety of ILs towards bioluminescent bacterium Vibrio fischeri. Linear model was constructed using five descriptors resulting in high accuracy prediction of 0.906. The model performance and stability were ascertained using k-fold cross validation method. The selected descriptors set from the linear model was then used in multilayer perceptron (MLP) technique to develop the non-linear model, the accuracy of the model was further enhanced achieving high correlation coefficient with the lowest value being 0.961 with the highest mean square error of 0.157. PMID- 28006758 TI - Effects of brining on the corrosion of ZVI and its subsequent As(III/V) and Se(IV/VI) removal from water. AB - Zero-valent iron (ZVI) has been extensively applied in water remediation, and most of the ZVI materials employed in practical applications are iron scraps, which have usually been corroded to certain extent under different conditions. In this study, the effects of brining with six solutions (NaCl, Na2SO4, NaHCO3, Na2SiO3, NH4Cl, and NaH2PO4) on the corrosion of ZVI and its performance in the removal of As(III/V)/Se(IV/VI) were systematically investigated. All the studied solutions enhanced the corrosion of ZVI except for Na2SiO3, and the degrees of corrosion followed the order of NH4Cl > NaH2PO4 > Na2SO4 > NaCl > NaHCO3 > H2O > Na2SiO3. The corrosion products derived from ZVI were identified by SEM and XRD, and the dominant corrosion products varied with the type of brine solution. The positive correlation between the degree of ZVI corrosion and As(III/V)/Se(IV/VI) removal by the pre-corroded ZVI (pcZVI) was verified. In addition, As and Se removal by pcZVI was realized via a comprehensive process including adsorption and reduction, as further supported by the XPS analysis. We believe this study will shed new light upon the selection of iron materials pre-corroded under different saline conditions for practical water remediation. PMID- 28006759 TI - Distribution of perfluoroalkyl compounds in Osaka Bay and coastal waters of Western Japan. AB - Perfluoroalkyl acids (PFAAs) including perfluoroalkyl sulfonates (PFSAs) and perfluoroalkyl carboxylates (PFCAs) were analyzed in sediment samples taken from Ajifu Waterway in Osaka city, from Osaka Bay, and from Kagoshima Bay, as well as in fifteen seawater samples collected from Osaka Bay and coastal waters of Western Japan. In all sediment samples, only PFCAs were detected, and the highest concentration was determined in Ajifu Waterway, where SigmaPFAA was 58990 ng kg-1 dry weight. The total concentrations of PFAAs in sea water samples ranged between the limit of quantification and 53.4 ng L-1, and perfluorohexanoic acid was the most prevalent and had the highest concentration of 37 ng L-1. The changes in the patterns and concentrations of PFAAs in Osaka Bay and coastal waters of Western Japan indicate that the PFAAs in surface waters are influenced by sources from Keihanshin Metropolitan Area, mainly the Yodo River basin, and the dilution effect which naturally occurs during their transport to the Pacific Ocean. PMID- 28006760 TI - Investigating heritability of cadmium tolerance in Chironomus riparius natural populations: A physiological approach. AB - Physiological responses allow populations to cope with metal contamination and can be involved in the evolution of tolerance under historical metal contamination scenarios. Here we investigate physiological aspects that might be underlying the heritable high tolerance to cadmium (Cd) in two Chironomus riparius populations collected from historically metal contaminated sites in comparison to two populations from reference sites. To evaluate differences in the physiological response to short-term Cd exposure, protein expression profiles, metallothioneins [MTs] and several antioxidant defences such as total glutathione (GSHt), catalase (CAT) and glutathione-S-transferases [GSTs], were measured in all four populations reared for at least 8 generations under laboratory clean conditions. Cd-induced oxidative damage in lipids and energy related parameters (energy consumption and energy reserves) were also assessed. Results showed two major gradients of protein profiles according to Cd concentration and population tolerance. Furthermore, Cd-tolerant populations showed higher baseline levels of MTs and GSHt while Cd-sensitive populations, collected from reference sites, showed significant induction of GSHt levels with Cd exposure that were nonetheless insufficient to avoid increased oxidative damage to lipids. Cd exposure had no clear effects on the antioxidant enzymes or energy reserves but triggered a general increase in energy consumption. Finally, energy consumption was higher in Cd-tolerant populations across experimental conditions. Altogether, results demonstrate that inherited Cd-tolerance in these midge populations is related, at least in part, with different constitutive levels and plasticity of different defence mechanisms confirming the validity of using multiple physiological traits when studying evolution of tolerance. PMID- 28006761 TI - Lemierre Syndrome: A Retrospective Study of the Role of Anticoagulation and Thrombosis Outcomes. AB - Lemierre syndrome (LS) is a multisystemic infection beginning in the oropharynx and leading to thrombosis of the internal jugular vein (IJV) with septic emboli and potential thrombotic extension to the central nervous system. Although patient outcomes have improved with early initiation of antimicrobial therapies, there is no consensus regarding the role of anticoagulation in LS. To better define the role of anticoagulation therapy in LS and determine whether anticoagulation improves thrombosis outcomes, we conducted a retrospective chart review of pediatric and adult patients diagnosed with LS and managed at our institution from January 1998 to December 2014. Eighteen patients (9 females and 9 males) were included in this analysis, 6 of whom received >=4 weeks of anticoagulation therapy (median 23.1 weeks, range 6.9-32.9 weeks). Six patients were in the pediatric age group (<18 years). All patients received broad-spectrum antibiotics. All patients had improvement in their thrombi by 3 months (nonanticoagulated patient group: complete response [CR], n = 9; partial response [PR], n = 3; anticoagulated patient group: CR, n = 2; PR, n = 4). No patient developed recurrent thrombosis or progression during the follow-up period, regardless of anticoagulation status. Our study suggests that anticoagulation in LS may not affect thrombosis outcomes. PMID- 28006762 TI - H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation. AB - BACKGROUND: Hydrogen sulfide (H2S), known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI) induced by endotoxemia. METHODS: Male ICR mice were divided in six groups: (1) Control group; (2) GYY4137treatment group; (3) L-NAME treatment group; (4) lipopolysaccharide (LPS) treatment group; (5) LPS with GYY4137 treatment group; and (6) LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich) reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting. RESULTS: GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC) and theactivities of catalase (CAT) and superoxide dismutase (SOD) but decreased a marker of peroxynitrite (ONOO-) action and 3-nitrotyrosine (3-NT) in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL)-6, IL-8, and myeloperoxidase (MPO) and the increased level of anti inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA), hydrogenperoxide (H2O2) and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio) and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS) expression and nitric oxide (NO) production in the endotoxemia lung. CONCLUSIONS: GYY4137 conferred protection against acute endotoxemia-associated lung injury, which may have beendue to the anti-oxidant, anti-nitrative and anti-inflammatory properties of GYY4137. The present findings warrant further exploration of the clinical applicability of H2S in the prevention and treatment of ALI. PMID- 28006763 TI - Is Fibroblast Growth Factor 23 the New Biomarker for Cardiovascular Mortality in Chronic Kidney Disease Patients? PMID- 28006764 TI - Telomere Dysfunction in Nonalcoholic Fatty Liver Disease and Cryptogenic Cirrhosis. AB - Nonalcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC) are considered preneoplastic conditions that might progress to hepatocellular carcinoma. We evaluated parameters of telomere dysfunction in these patient groups to study the correlation between telomere length and the progression of NAFLD. We analyzed peripheral lymphocytes from 22 patients with NAFLD, 20 patients with CC, and 20 healthy, age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization, and cellular senescence was evaluated by the percentage of cells with senescence-associated heterochromatin foci. The expression of telomerase reverse transcriptase (hTERT) mRNA was measured using polymerase chain reaction, and telomere capture (TC) was assessed with 2 Cytocell probes, 15qter and 13qter. Shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD, compared to the CC patients and healthy controls. While hTERT mRNA was significantly decreased, TC was increased in CC patients, compared to the NAFLD group and healthy individuals. Thus, there is a correlation between hTERT mRNA expression and telomere length in patients with NAFLD, which might be related to associated metabolic disorders and the risk of malignant transformation. Patients with CC, on the contrary, elongate their telomeres through the TC mechanism. PMID- 28006765 TI - Fibroblast Growth Factor 23 Predicts All-Cause Mortality in a Dose-Response Fashion in Pre-Dialysis Patients with Chronic Kidney Disease. AB - BACKGROUND: Quantitative dose-response associations between fibroblast growth factor 23 (FGF23) and risks of mortality, cardiovascular disease (CVD), and renal events in chronic kidney disease (CKD) are not known. This study aimed to summarize and quantify the predictive effects of FGF23 among the pre-dialysis CKD stages 1-5 population. METHODS: Data sources included PubMed, EMBASE, and Web of Science. Prospective cohort studies assessing the associations between FGF23 and all-cause mortality, CVD, and renal events in CKD patients were selected. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. The composite higher or the highest level in FGF23 categories of each study was considered the high level. The reference level was regarded as the low level in the overall analysis. The restricted cubic spline model was used to estimate dose-response associations. RESULTS: Fifteen prospective cohort studies centered around 15,355 subjects were analyzed. A high FGF23 level was associated with increased risks of all-cause mortality (RR 1.46, 95% CI 1.38-1.55, p < 0.001), CVD (RR 1.37, 95% CI 1.15-1.63, p < 0.001), and renal events (RR 1.31, 95% CI 1.07-1.59, p = 0.008), respectively. There was a positive, nonlinear, dose-response relationship between FGF23 and all-cause mortality. The reference level in dose-response analysis was defined as 51 RU/mL of c-terminal FGF23. We then calculated RRs for increments of 20 RU/mL, which was associated with increased risks of mortality (RR 1.04, 95% CI 1.00-1.07, p = 0.038), CVD (RR 1.02, p < 0.001), and renal events (RR 1.01, p < 0.001), respectively. CONCLUSIONS: There may be positive dose-response predictive effects of FGF23 on all-cause mortality, CVD, and renal events in patients with CKD. PMID- 28006766 TI - Is Overexpression of Ki-67 a Prognostic Biomarker of Upper Tract Urinary Carcinoma? A Retrospective Cohort Study and Meta-Analysis. AB - BACKGROUND: Upper tract urinary carcinoma (UTUC) is a relatively uncommon but aggressive disease. The Ki-67 antigen is a classic marker of cellular proliferation, but there is still controversy regarding the significance and importance of Ki-67 in tumor progression. METHODS: In this study, we first detected Ki-67 expression in UTUC patients by immunohistochemistry (IHC). Subsequently, we quantitatively combined the results with those from the published literature in a meta-analysis after searching several databases. RESULTS: IHC results demonstrated that patients with muscle-invasive tumors (T2 T4) had higher Ki-67 expression than those with non-muscle-invasive tumors (Tis T1), suggesting that high Ki-67 expression may be associated with the aggressive form of UTUC. Kaplan-Meier curves showed that patients with high Ki-67 expression had significantly poorer cancer-specific survival (CSS) and disease-free survival (DFS). Furthermore, multivariate analysis suggested that Ki-67 expression was an independent prognostic factor for CSS (hazard ratio, HR=3.196) and DFS (HR=3.517) in UTUC patients. Then, a meta-analysis of the published literature investigating Ki-67 expression and its effects on UTUC prognosis was conducted. After searching the PubMed, Medline, Embase, Cochrane Library and Scopus databases, 12 articles met the eligibility criteria for this analysis. The eligible studies included a total of 1740 patients with a mean number of 82 patients per study (range, 38 475). The combined results showed that increased Ki-67 levels were associated with poor survival and disease progression, with a pooled HR estimate of 2.081 and 2.791, respectively. In subgroup analysis, the pooled HR was statistically significant for cancer-specific survival (HR=2.276), metastasis-free survival (HR=3.008) and disease-free survival (HR=6.336). CONCLUSIONS: In conclusion, high Ki-67 expression was associated with poor survival in patients with UTUC, as well as a high risk of disease progression, although these findings need to be interpreted with caution. Large-scale, adequately designed, prospective trials are needed to further confirm the value of Ki-67 in prognosis of UTUC patients. PMID- 28006768 TI - Outgoing Editor in Chief's Farewell Message. PMID- 28006767 TI - A 2-Year, Longitudinal, Prospective Study of the Effects of Eltrombopag on Bone Marrow in Patients with Chronic Immune Thrombocytopenia. AB - BACKGROUND: The long-term effects of eltrombopag on bone marrow (BM) reticulin and/or collagen deposition in previously treated adults with chronic immune thrombocytopenia (ITP) were assessed. METHODS: Three BM biopsies were collected at baseline and after 1 and 2 years of eltrombopag treatment. Specimens were centrally processed, stained for reticulin and collagen, independently reviewed by 2 hematopathologists, and rated according to the European Consensus 0-3 scale of marrow fibrosis (MF). RESULTS: Of 162 patients enrolled, 93 completed all 3 protocol-specified BM biopsies. All patients with a baseline assessment were negative for collagen. Of 159 patients assessed at baseline, 150 (94%) had normal reticulin (MF-0) and 9 (6%) had minimally increased reticulin (MF-1). After 2 years, 83/93 patients (89%) with BM biopsies had MF-0, 10 (11%) had MF-1, and none had MF-2 or MF-3. Five out of 127 patients (4%) at 1 year and 1 out of 93 (1%) at 2 years had collagen deposition. None of the patients had clinical symptoms typical of BM dysfunction or abnormalities of clinical concern based on white blood cell count or peripheral blood smear. CONCLUSION: For most patients with chronic ITP, eltrombopag is not associated with clinically relevant increases in BM reticulin or collagen formation. PMID- 28006769 TI - Is Menstruation or the Serum Hormone Level a Useful Predictor for Live Birth after Gonadotropin-Releasing Hormone Agonist during Chemotherapy in Young Breast Cancer Patients. AB - AIMS: The study aimed to investigate whether changes in menstruation or hormone levels are useful parameters to assess the efficacy of gonadotropin-releasing hormone (GnRH) agonist co-treatment with chemotherapy. METHODS: This study included women in their reproductive age diagnosed with breast cancer and who received GnRH agonist during chemotherapy for ovarian protection. Women with treatment failure (follicle-stimulating hormone (FSH) level >20 mIU/mL after at least 12 months and failure for becoming pregnant; n = 16) or with treatment success (becoming pregnant spontaneously and having a live birth; n = 20) were selected, and clinical characteristics, resumption of menstruation, and changes in hormone profiles were compared. RESULTS: Resumption of menstruation was observed in 8 (50%) women and the time until resumption was significantly longer in the treatment failure group. Although levels of luteinizing hormone (LH) and FSH at 3 and 6 months after chemotherapy did not differ between the groups, serum FSH levels were significantly higher in the treatment failure group at 12 months. However, levels of LH or estradiol were not different at each time point. CONCLUSION: Changes in menstruation and FSH levels at 12 months or longer may be useful parameters to predict successful spontaneous pregnancy and live birth after GnRH agonist co-treatment for ovarian protection in young breast cancer patients who undergo chemotherapy. PMID- 28006770 TI - Cardiometabolic Risks in Polycystic Ovary Syndrome: Non-Traditional Risk Factors and the Impact of Obesity. AB - Polycystic ovary syndrome (PCOS) is a common and complex endocrinopathy with reproductive, metabolic, and psychological features and significantly increased cardiometabolic risks. PCOS is underpinned by inherent insulin resistance and hyperandrogenism. Obesity, more common in PCOS, plays an important role in the pathophysiology, exacerbating hyperinsulinaemia and hyperandrogenism, leading to recommended first-line lifestyle intervention. Significant traditional and non traditional risk factors are implicated in PCOS in addition to obesity exacerbated cardiometabolic risks and are explored in this review to promote the understanding of this common metabolic and reproductive condition. PMID- 28006771 TI - Preface. PMID- 28006772 TI - Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND/AIMS: Ectopic lipid accumulation in hepatocytes has been identified as a risk factor for the progression of liver fibrosis and is strongly associated with obesity. In particular, the saturated fatty acid palmitate is involved in initiation of liver fibrosis via formation of secondary metabolites by hepatocytes that in turn activate hepatic stellate cells (HSCs) in a paracrine manner. METHODS: alpha-smooth muscle actin-expression (alpha-SMA) as a marker of liver fibrosis was investigated via western blot analysis and immunofluorescence microscopy in HSCs (LX-2). Sphingolipid metabolism and the generation of the bioactive secondary metabolite sphingosine 1-phosphate (S1P) in response to palmitate were analyzed by LC-MS/MS in hepatocytes (HepG2). To identify the molecular mechanism involved in the progression of liver fibrosis real-time PCR analysis and pharmacological modulation of S1P receptors were performed. RESULTS: Palmitate oversupply increased intra- and extracellular S1P-concentrations in hepatocytes. Conditioned medium from HepG2 cells initiated fibrosis by enhancing alpha-SMA-expression in LX-2 in a S1P-dependent manner. In accordance, fibrotic response in the presence of S1P was also observed in HSCs. Pharmacological inhibition of S1P receptors demonstrated that S1P3 is the crucial receptor subtype involved in this process. CONCLUSION: S1P is synthesized in hepatocytes in response to palmitate and released into the extracellular environment leading to an activation of HSCs via the S1P3 receptor. PMID- 28006773 TI - Discrete Distribution Based on Compound Sum to Model Dental Caries Count Data. AB - Methods for analysing dental caries and associated risk indicators have evolved considerably in recent decades. The use of zero-inflated or hurdle models is increasing so as to take account of the decayed, missing, and filled teeth (DMFT) distribution, which is positively skewed and has a high proportion of zero scores. However, there is a need to develop new statistical models that involve pragmatic biological considerations on dental caries in epidemiological surveys. In this paper, we show that the zero-inflated and the hurdle models can both be expressed as a compound sum. Using the same compound sum, we then present the generalized negative binomial (GNB) distribution for dental caries count data, and provide a numerical application using the data of the EPIPAP study. The GNB model generates the best score functions while handling the lifetime dental caries disease process better. In conclusion, the GNB model suits the nature of some count data, in particular when structural zeros are unlikely to occur and when several latent spells can lead to new countable events. For these reasons, the use of the GNB distribution appears to be relevant for the modelling of dental caries count data. PMID- 28006774 TI - The Prevalence of Fabry Disease in Patients with Chronic Kidney Disease in Turkey: The TURKFAB Study. AB - BACKGROUND/AIMS: Fabry disease is a treatable cause of chronic kidney disease (CKD) characterized by a genetic deficiency of alpha-galactosidase A. European Renal Best Practice (ERBP) recommends screening for Fabry disease in CKD patients. However, this is based on expert opinion and there are no reports of the prevalence of Fabry disease in stage 1-5 CKD. Hence, we investigated the prevalence of Fabry disease in CKD patients not receiving renal replacement therapy. METHODS: This prospective study assessed alpha-galactosidase activity in dried blood spots in 313 stage 1-5 CKD patients, 167 males, between ages of 18-70 years whose etiology of CKD was unknown and were not receiving renal replacement therapy. The diagnosis was confirmed by GLA gene mutation analysis. RESULTS: Three (all males) of 313 CKD patients (0.95%) were diagnosed of Fabry disease, for a prevalence in males of 1.80%. Family screening identified 8 aditional Fabry patients with CKD. Of a total of 11 Fabry patients, 7 were male and started enzyme replacement therapy and 4 were female. The most frequent manifestations in male patients were fatigue (100%), tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%), heat intolerance (71%), and abdominal pain (57%). The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). Three patients had severe episodic abdominal pain attacks and proteinuria, and were misdiagnosed as familial Mediterranean fever. CONCLUSIONS: The prevalence of Fabry disease in selected CKD patients is in the range found among renal replacement therapy patients, but the disease is diagnosed at an earlier, treatable stage. These data support the ERBP recommendation to screen for Fabry disease in patients with CKD of unknown origin. PMID- 28006775 TI - FGF-2 Transcriptionally Down-Regulates the Expression of BNIP3L via PI3K/Akt/FoxO3a Signaling and Inhibits Necrosis and Mitochondrial Dysfunction Induced by High Concentrations of Hydrogen Peroxide in H9c2 Cells. AB - BACKGROUND/AIMS: Cardiovascular disease is a growing major global public health problem. Necrosis is one of the main forms of cardiomyocyte death in heart disease. Oxidative stress is regarded as one of the key regulators of cardiac necrosis, which eventually leads to cardiovascular disease. Many pharmacological and in vitro studies have suggested that FGF-2 can act directly on cardiomyocytes to maintain the integrity and function of the myocardium and prevent damage during oxidative stress. However, the mechanisms by which FGF-2 rescues the myocardium from oxidative stress damage in cardiovascular disease remain unclear. The present study explored the protective effects of FGF-2 in the H2O2-induced necrosis of H9C2 cardiomyocytes as well as the possible signaling pathways involved. METHODS: Necrosis of H9c2 cardiomyocytes was induced by H2O2 and assessed using a Cell Counting Kit-8 (CCK8) assay and flow cytometry analysis. The cells were pretreated with the PI3K/Akt inhibitor Wortmannin to investigate the possible involvement of the PI3K/Akt pathway in the protection by FGF-2. The levels of Akt, p-Akt, FoxO3a, p-FoxO3a, and BNIP3L were detected by Western blot. Chromatin immuno-precipitation (ChIP) analysis was used to test whether FoxO3a binds directly to the BNIP3L promoter region. A luciferase assay was used to study the effects of FoxO3a on BNIP3L gene promoter activity. Mitochondrial DeltaPsiM was quantified using tetramethylrhodamine methyl ester perchlorate (TMRM). The mitochondrial oxygen consumption rate (OCR) was assessed with a Seahorse XF24 Analyzer. RESULTS: Treatment with H2O2 decreased the phosphorylation of Akt and FoxO3a, and it induced the nuclear localization of FoxO3a and the necrosis of H9c2 cells. These effects of H2O2 were abrogated by pretreatment with FGF-2. Furthermore, the protective effects of FGF-2 were abolished by the PI3K/Akt inhibitor Wortmannin. ChIP analyses indicated that FoxO3a binds directly to the BNIP3L promoter region. Using a luciferase assay, we further observed that FoxO3a increased BNIP3L gene promoter activity. As expected, overexpression of BNIP3L in H9C2 cardiomyoblast cells reduced the cardioprotection of FGF-2 in H2O2-induced necrosis and mitochondrial dysfunction. CONCLUSIONS: The present data suggest that FGF-2 protects against H2O2-induced necrosis of H9C2 cardiomyocytes via the activation of the PI3K/Akt/FoxO3a pathway. Moreover, the present results demonstrate that FoxO3a is an important transcription factor that acts by binding to the promoter and promoting the transcription of BNIP3L, and it contributes to the necrosis and mitochondrial dysfunction induced by H2O2 in H9c2 cardiomyoblast cells. PMID- 28006776 TI - Risk Factors and Prognosis of Cardiorenal Syndrome Type 1 in Elderly Chinese Patients: A Retrospective Observational Cohort Study. PMID- 28006777 TI - Cellular Innate Immunity: An Old Game with New Players. AB - Innate immunity is a rapidly evolving field with novel cell types and molecular pathways being discovered and paradigms changing continuously. Innate and adaptive immune responses are traditionally viewed as separate from each other, but emerging evidence suggests that they overlap and mutually interact. Recently discovered cell types, particularly innate lymphoid cells and myeloid-derived suppressor cells, are gaining increasing attention. Here, we summarize and highlight current concepts in the field, focusing on innate immune cells as well as the inflammasome and DNA sensing which appear to be critical for the activation and orchestration of innate immunity, and may provide novel therapeutic opportunities for treating autoimmune, autoinflammatory, and infectious diseases. PMID- 28006778 TI - A Systematic Review and Meta-Analysis of the Effects on Dutasteride Treatment for Reducing Surgical Blood Loss during Transurethral Resection of the Prostate. AB - OBJECTIVE: This systematic review and meta-analysis were performed to evaluate the efficacy of preoperative dutasteride treatment for reducing surgical blood loss in patients undergoing transurethral resection of the prostate (TURP). METHODS: A systematic search was performed from the electronic databases including PubMed, EMBASE, and Cochrane Library by May 2016. We followed the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analysis statement when examining the literature. Identified articles were strictly appraised for quality and relevance. RESULTS: Five randomized controlled trials (RCTs) and 5 retrospective cohort studies involving 1,022 patients with benign prostate hyperplasia were analyzed based on the inclusion criteria. Pooled analysis revealed that preoperative treatment with dutasteride had a significantly smaller decrease in hemoglobin (weighted mean difference [WMD] 0.47, 95% CI -0.70 to -0.24, p < 0.0001) and hematocrit levels (WMD -1.03, 95% CI -1.73 to -0.33, p = 0.004); However, no significant difference has been found in terms of the total blood loss during TURP and blood loos per gram of resected prostatic tissue, the weight of resected prostate tissue, the microvessel density of the prostate, and the transfusion rate between the dutasteride and the control group. CONCLUSIONS: This systematic review and meta-analysis indicate that preoperative treatment with dutasteride could reduce surgical bleeding during TURP, but the findings of this study should be further confirmed by well-designed prospective RCTs with a larger patient series. PMID- 28006779 TI - Cardiorenal Syndrome Type 5 in Sepsis: Role of Endotoxin in Cell Death Pathways and Inflammation. AB - BACKGROUND/AIMS: Cardiorenal Syndrome Type 5 (CRS Type 5) is characterized by concomitant cardiac and renal dysfunction in the setting of different systemic disorders, such as sepsis. In this study, we investigated the possible relationship between endotoxin levels, renal cell death and inflammation in septic patients with CRS Type 5. METHODS: We enrolled 11 patients with CRS Type 5. CRS Type 5 was defined according to the current classification system. AKI was defined by Acute Kidney Injury Network (AKIN) criteria. Acute cardiac dysfunction was documented by echocardiography as acute left and/or right ventricular dysfunction leading to decreased ejection fraction. Endotoxin activity was measured by the Endotoxin Activity Assay (EAA). Plasma from CRS Type 5 patients was incubated with renal tubular cells (RTCs) and cell death levels were evaluated. Plasma cytokines levels were measured as well. RESULTS: Accordingly to EAA levels, patients were divided into two groups: 45.4% of patients had low endotoxin activity level (negative EAA), while 54.5% of patients showed high endotoxin activity (positive EAA). RTCs incubated with plasma from EAA positive patients showed significantly higher apoptosis levels and higher caspase-3 activation compared to cells incubated with plasma from EAA negative patients, and a significant positive correlation was observed between EAA levels and RTC apoptosis levels. Furthermore, IL-6 and IFN-gamma levels were significantly higher in CRS Type 5 patients with positive EAA. CONCLUSION: Our data suggest a possible relationship between endotoxin levels and renal cell death in septic patients with CRS Type 5. Furthermore, this study highlights the presence of renal apoptosis, the immune deregulation and the strong inflammation in CRS Type 5 patients, especially in those with high endotoxin activity. PMID- 28006780 TI - Resveratrol Improves Cognitive Impairment by Regulating Apoptosis and Synaptic Plasticity in Streptozotocin-Induced Diabetic Rats. AB - AIMS: To investigate the effects of resveratrol on cognitive impairment in streptozotocin (STZ)-induced diabetic rats and to explore the mechanisms of that phenomenon. METHODS: Sixty healthy male Sprague Dawley rats were randomly divided into four groups: normal control group (Con group, n = 15), Res group (normal Sprague Dawley rats treated with resveratrol, n = 15), diabetes mellitus group (DM group, n = 15) and DM + Res group (diabetic rats treat with resveratrol, n = 15). Streptozotocin (STZ) was injected intraperitoneally to establish the diabetic model. One week after diabetic model induction, the animals in the Res group and the DM + Res group received resveratrol intraperitoneally once a day for consecutive 4 weeks. The Morris water maze test was applied to assess the effect of resveratrol on learning and memory. To explore the mechanisms of resveratrol on cognition, we detected the protein expression levels of Caspase-3, Bcl-2, Bax, NMDAR1 (N-Methyl-d-Aspartate receptor) and BDNF (Brain Derived Neurotrophic Factor) via western blotting analysis. RESULTS: Resveratrol has no obvious effect on normal SD rats. Compared to Con group, cognitive ability was significantly impaired with increased expression of Caspase-3, Bax and down regulation of Bcl-2, NMDAR1 and BDNF in diabetic rats. By contrast, resveratrol treatment improved the cognitive decline. Evidently, resveratrol treatment reversed diabetes-induced changes of protein expression. CONCLUSIONS: Resveratrol significantly ameliorates cognitive decline in STZ-induced diabetic model rats. The potential mechanism underlying the protective effect could be attributed to the inhibition of hippocampal apoptosis through the Bcl-2, Bax and Caspase-3 signaling pathways and improvement of synaptic dysfunction. BDNF may also play an indispensable role in this mechanism. PMID- 28006781 TI - Allogeneic Compact Bone-Derived Mesenchymal Stem Cell Transplantation Attenuates the Severity of Idiopathic Pneumonia Syndrome in a Murine Bone Marrow Transplantation Model. AB - BACKGROUND/AIMS: Idiopathic pneumonia syndrome (IPS) is a serious and life threatening lung complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and currently no effective therapies exist. This study was designed to determine whether transplantation of allogeneic murine compact bone derived- mesenchymal stem cells (CB-MSCs) could prevent the development of IPS. METHODS: We tested the effects of CB-MSCs transplantation on IPS using an established murine model of C57BL/6 (H-2b)->BALB/c (H-2d). Survival rates, body weight change, clinical GVHD scores, lung histological changes were assessed after IPS induction. Mechanistically, concentrations of cytokines (TNF alpha, IFN-gamma and IL-4) and chemokines (CCL5, CXCL9 and CXCL10) in bronchoalveolar lavage fluid (BALF) from the recipient mice were measured at different time point post-transplantation. CD4+CD25+Foxp3+ regulatory T cell (Treg) percentage, CCR5, CXCR3 and CCR7 expression on CD3+ T cells, and lung CXCR3, CCR5, CCR7, T-bet and GATA-3 mRNA levels were also evaluated at different time point post-transplantation. RESULTS: Co-transplantation of CB-MSCs significantly attenuated the severity of lung injuries and increased survival rate of mice compared to non-cotransplanted mice. A higher Treg percentage, reduction of TNF-alpha, IFN-gamma, CCL5, CXCL9 and CXCL10 levels, down-regulation of CXCR3 and CCR5, as well as up-regulation of CCR7, were observed in MSCs co transplantation mice. Also, the prophylactic effect of CB-MSCs was associated with a shift of Th1/Th2 balance toward anti-inflammatory Th2 polarization. CONCLUSIONS: Allogeneic CB-MSCs effectively controlled the occurrence of IPS due to its profound immunomodulatory capacity. This may offer a novel prophylactic approach for IPS after allo-HSCT. PMID- 28006782 TI - Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease. AB - BACKGROUND/AIMS: Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease (CKD). We explored the effect of IS on human early endothelial progenitor cells (EPCs) and analyzed the correlation between serum IS levels and parameters of vascular function, including endothelial function in a CKD-based cohort. METHODS: A cross-sectional study with 128 stable CKD patients was conducted. Flow-mediated dilation (FMD), pulse wave velocity (PWV), ankle brachial index, serum IS and other biochemical parameters were measured and analyzed. In parallel, the activity of early EPCs was also evaluated after exposure to IS. RESULTS: In human EPCs, a concentration dependent inhibitory effect of IS on chemotactic motility and colony formation was observed. Additionally, serum IS levels were significantly correlated with CKD stages. The total IS (T-IS) and free IS (F-IS) were strongly associated with age, hypertension, cardiovascular disease, blood pressure, PWV, blood urea nitrogen, creatine and phosphate but negatively correlated with FMD, the estimated glomerular filtration rate (eGFR), hemoglobin, hematocrit, and calcium. A multivariate linear regression analysis also showed that FMD was significantly associated with IS after adjusting for other confounding factors. CONCLUSIONS: In humans, IS impairs early EPCs and was strongly correlated with vascular dysfunction. Thus, we speculate that this adverse effect of IS may partly result from the inhibition of early EPCs. PMID- 28006783 TI - Altered Long- and Short-Range Functional Connectivity in Patients with Betel Quid Dependence: A Resting-State Functional MRI Study. AB - OBJECTIVE: Addiction is a chronic relapsing brain disease. Brain structural abnormalities may constitute an abnormal neural network that underlies the risk of drug dependence. We hypothesized that individuals with Betel Quid Dependence (BQD) have functional connectivity alterations that can be described by long- and short-range functional connectivity density(FCD) maps. METHODS: We tested this hypothesis using functional magnetic resonance imaging (fMRI) data from subjects of the Han ethnic group in Hainan, China. Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy controls (HCs) (n = 32) in a rs fMRI study to observe FCD alterations associated with the severity of BQD. RESULTS: Compared with HCs, long-range FCD was decreased in the right anterior cingulate cortex (ACC) and increased in the left cerebellum posterior lobe (CPL) and bilateral inferior parietal lobule (IPL) in the BQD group. Short-range FCD was reduced in the right ACC and left dorsolateral prefrontal cortex (dlPFC), and increased in the left CPL. The short-range FCD alteration in the right ACC displayed a negative correlation with the Betel Quid Dependence Scale (BQDS) (r= 0.432, P=0.012), and the long-range FCD alteration of left IPL showed a positive correlation with the duration of BQD(r=0.519, P=0.002) in BQD individuals. CONCLUSIONS: fMRI revealed differences in long- and short- range FCD in BQD individuals, and these alterations might be due to BQ chewing, BQ dependency, or risk factors for developing BQD. PMID- 28006784 TI - Long-Term Energy Deficit in Mice Causes Long-Lasting Hypothalamic Alterations after Recovery. AB - Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1beta mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin. PMID- 28006785 TI - MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis. AB - BACKGROUND/AIMS: Ischemia/reperfusion injury (IRI) plays a crucial role in renal transplantation and can cause renal failure associated with pyroptosis, a pro inflammatory-induced programmed cell death. Small endogenous non-coding RNAs have been shown to be involved in renal ischemia/reperfusion injury. This study was performed to investigate which miRNAs regulate pyroptosis in response to renal ischemia/reperfusion injury and determine the mechanism underlying this regulation. METHODS: An in vivo rat model of renal IRI was established, and the serum and kidneys were harvested 24 h after reperfusion to assess renal function and histological changes. For the in vitro study, the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia (5% CO2, 1% O2, and 94% N2) followed by 12 h of reoxygenation (5% CO2, 21% O2, and 74% N2). The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme linked immunosorbent assay (ELISA). Bioinformatics analyses were applied to predict miR-155 targets, which were then confirmed by a luciferase reporter assay. RESULTS: We found that the levels of pyroptosis-related proteins, including caspase-1, caspase-11, IL-1beta and IL-18, were significantly increased after renal ischemia/reperfusion injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in HK2 cells. Furthermore, our study revealed that miR-155 expression was substantially increased in the renal tissues of IRI rats and in HRI HK2 cells. Up-regulation of miR-155 promoted HK2 cell pyroptosis in HRI; conversely, knockdown of miR-155 attenuated this process. To understand the signaling mechanisms underlying the pro-pyroptotic activity of miR-155, we found that exogenous expression of miR-155 up-regulated the expression of caspase-1 as well as the pro-inflammatory cytokines IL-1beta and IL-18. Moreover, miR-155 directly repressed FoxO3a expression and its downstream protein apoptosis repressor with caspase recruitment domain (ARC). CONCLUSIONS: Our study proposes a new signaling pathway of miR-155/FoxO3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions. PMID- 28006786 TI - Neuropsychological Outcome in Subthalamic Nucleus Stimulation Surgeries with Electrodes Passing through the Caudate Nucleus. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson disease (PD) is associated with postoperative cognitive decline. One of the proposed underlying mechanisms is the surgical procedure with the lead trajectory penetrating the caudate nucleus. OBJECTIVE: To study whether penetration of the caudate nucleus affects neuropsychological outcome. METHODS: Neuropsychological and imaging data of 30 PD patients who underwent bilateral STN DBS were analysed. Lead trajectories were evaluated leading to a group with (n = 10) and a group without penetration of the caudate nucleus (n = 20). The neuropsychological performance of each group was compared to baseline, both at 3 and 12 months postoperatively. RESULTS: Only the Trail-Making Test part B (TMT-B) showed an interaction effect within the groups over time at 3 months postoperatively. At 12 months postoperatively, there was only a main effect of time with a decrease in performance in TMT-B for both groups. Also verbal fluency showed a significant decrease over time for both groups at 3 and 12 months postoperatively. CONCLUSION: Caudate nucleus penetration affects cognitive flexibility only in the short term after surgery. PMID- 28006787 TI - Role of MiR-215 in Hirschsprung's Disease Pathogenesis by Targeting SIGLEC-8. AB - BACKGROUND/AIMS: Hirschsprung's disease (HSCR), known as aganglionosis, is an infrequent congenital gut motility disorder characterized by absence of enteric neurons. In this study, we focus on the role of the intronic miR-215 and its host gene isoleucyl-tRNA synthetase 2 (IARS2) in the pathogenesis of HSCR. METHODS: Quantitative real time PCR and Western blot were used to detect the miRNA, mRNAs, and proteins levels. The dual-luciferase reporter gene assay confirmed the direct regulation of the specific mRNA and miRNAs in cell lines. Transwell assays, CCK8 assay, and flow cytometry were used to measure cell function of the human 293T and SH-SY5Y cells. RESULTS: Expression levels of miR-215 in HSCR patient colon tissues were outstandingly lower than controls, which was positively correlated with expression of the host gene IARS2 and negatively correlated with predicted target gene: sialic acid binding Ig-like lectin 8 (SIGLEC-8). The loss of miR-215 inhibited cell migration and proliferation, which was consistent with the reduction of IARS2. The dual-luciferase reporter gene assay confirmed that miR 215 resulted in the inhibition of SIGLEC-8 by directly binding to the 3'-UTR of SIGLEC-8. Moreover, knocking-down SIGLEC-8 rescued the extent of suppressed cell migration and proliferation that resulted from the diminishment of miR-215. CONCLUSIONS: Our findings indicate that miR-215 acts in concert with the host gene IARS2 to affect neuron migration and proliferation through the target gene SIGLEC-8. We infer that the IARS2-miR-215-SIGLEC-8 pathway may play a crucial role in the pathogenesis of HSCR. PMID- 28006788 TI - Benthic Foraminifera from the Capricorn Group, Great Barrier Reef, Australia. AB - Effective reef management and monitoring has become increasingly important as anthropogenic processes impact upon natural ecosystems. One locality that is under direct threat due to human activities is the Australian Great Barrier Reef (GBR). Marine foraminifera represent an abundant and readily applicable tool that can be used in reef studies to investigate a variety of ecological parameters and assist in understanding reef dynamics and influence management protocols. The first step is to establish a baseline knowledge of taxonomic composition within the region to facilitate comparative studies and monitor how assemblages change in order to maximise effective management. A detailed taxonomic assessment is provided of 133 species of benthic foraminifera in 76 genera from Heron Island, One Tree Island, Wistari and Sykes Reefs, which form the core of the Capricorn Group (CG) at the southern end of the GBR. Of these 133 species, 46% belong to the order Miliolida, 34% to Rotaliida, 7% to Textulariida, 5% to Lagenida, 3% to Lituolida, 3% to Spirillinida, 1% to Loftusiida and 1% to Robertinida. Samples were collected from a variety of shallow shelf reef environments including reef flat, lagoonal and channel environments. Seventy species, representing the most abundant forms, are formally described with detailed distribution data for the remaining 63 species supplied. PMID- 28006789 TI - Taxonomic revision of Perdita subgenus Heteroperdita Timberlake (Hymenoptera: Andrenidae), with descriptions of two ant-like males. AB - Perdita subgenus Heteroperdita Timberlake, a distinctive subgenus of 22 species from the southwestern United States and adjacent Mexico, all specialists on Tiquilia (Boraginaceae), is revised. Nine new species are described: Perdita (Heteroperdita) desdemona Portman, sp. n., P. (H.) exusta Portman & Griswold, sp. n., P. (H.) hippolyta Portman & Griswold, sp. n. (male previously incorrectly described as P. pilonotata Timberlake), P. (H.) hooki Portman & Neff, sp. n., P. (H.) nuttalliae Portman, sp. n., P. (H.) prodigiosa Portman & Griswold, sp. n., P. (H.) sycorax Portman, sp. n., P. (H.) titania Portman & Griswold, sp. n., and P. (H.) yanegai Portman, sp. n. The following sexes are associated and described for the first time: the male of P. (H.) frontalis Timberlake, 1968, the female of P. (H.) optiva Timberlake, 1954, and the true male of P. (H.) pilonotata Timberlake, 1980. Perdita (H.) fasciatella Timberlake, 1980 is proposed as a junior synonym of P. (H.) sexfasciata Timberlake, 1954. A neotype is designated for P. (H.) pilonotata Timberlake, 1980. Two species in particular, P. prodigiosa and P. pilonotata, are sexually dimorphic with distinctive ant-like males. Information is presented on floral relationships, phenology, and geographic distribution. Identification keys for males and females are provided. PMID- 28006790 TI - Revision of the Australian Union-Jack wolf spiders, genus Tasmanicosa (Araneae, Lycosidae, Lycosinae). AB - The Australian wolf spider (Lycosidae Sundevall, 1833) genus Tasmanicosa Roewer, 1959 with Lycosa tasmanica Hogg, 1905 as type species is revised to include 14 species: T. godeffroyi (L. Koch, 1865), comb. nov. (= Lycosa tasmanica Hogg, 1905, syn. nov.; = Lycosa zualella Strand, 1907, syn. nov.; = Lycosa woodwardi Simon, 1909, syn. nov.); T. fulgor sp. nov.; T. gilberta (Hogg, 1905) comb. nov.; T. harmsi sp. nov.; T. hughjackmani sp. nov.; T. kochorum sp. nov.; T. leuckartii (Thorell, 1870), comb. nov. (= Lycosa molyneuxi Hogg, 1905, syn. nov.); T. musgravei (McKay, 1974) comb. nov.; T. phyllis (Hogg, 1905) comb. nov. (= Lycosa stirlingae Hogg, 1905, syn. nov.); T. ramosa (L. Koch, 1877), comb. nov.; T. salmo sp. nov.; T. semicincta (L. Koch, 1877) comb. nov.; T. stella sp. nov.; and T. subrufa (Karsch, 1878) comb. nov. Within the Australian wolf spider fauna, the genus Tasmanicosa can be diagnosed by the distinct pattern of radiating light and dark lines forming a "Union-Jack" pattern on the carapace. Male pedipalp morphology identifies the genus as part of the subfamily Lycosinae Sundevall, 1833 due to the presence of a transverse tegular apophysis with dorsal groove guiding the embolus during copulation. However, genital morphology is variable and a synapomorphy based on male pedipalp or female epigyne morphology could not be identified. Members of Tasmanicosa are comparatively large spiders (body length ca. 12-30 mm), that build a shallow burrow, which is sometimes covered with a flimsy trapdoor. Species of Tasmanicosa are largely a Bassian faunal element with preference for open woodlands and/or floodplains, although some species can be found into the semi-arid Australian interior. Two Australian wolf spider species may represent Tasmanicosa based on their original descriptions, but due to immature types in combination with the somatic similarities of all Tasmanicosa species, cannot be identified with certainty. They are therefore considered nomina dubia: Lycosa excusor L. Koch, 1867 and Lycosa infensa L. Koch, 1877. The type species of Orthocosa Roewer, 1960 is transferred to Tasmanicosa; however, in order to prevent some non-Australian wolf spiders in the genus Orthocosa to be transferred into Tasmanicosa, which is considered endemic to Australia, we here place these species into more appropriate genera based on their original descriptions pending a future revision of these species: Arctosa ambigua Denis, 1947 comb. reval.; Alopecosa orophila (Thorell, 1887) comb. nov.; Hygrolycosa tokinagai Saito, 1936 comb. reval. Orthocosa sternomaculata (Mello Leitao, 1943) is considered a junior synonym of Hogna birabeni (Mello-Leitao, 1943) comb. nov. PMID- 28006791 TI - Distribution, phenology and host plants of Danish bees (Hymenoptera, Apoidea). AB - Based on the examination of 47.629 specimens of bees from Denmark (54.6oN to 57.8oN) we summarize for the first time the distribution, phenology and host plants for all 286 known species occurring in the country. The mapped occurrence records distinguish whether species are found only in 1974 or earlier, 1975 or later, or in both periods. Danish bees are recorded active from February 29 through October 21 and have been collected in 79% of the 10x10 km Universal Transverse Mercator (UTM) squares covering the country; seven UTM squares have over 100 reported species. Some UTM squares are poorly sampled, including less than five species recorded from 31% of the sampled squares. In addition bees are recorded from 282 different plants representing 50 families with the majority of observations from Asteraceae and Fabaceae (Leguminosae). The data, compiled from all major bee collections in the country, will provide policy makers and scientists a tool for establishing strategies for pollinator conservation and further research. PMID- 28006792 TI - The Caucasus as a major hotspot of biodiversity: Evidence from the millipede family Anthroleucosomatidae (Diplopoda, Chordeumatida). AB - Fifteen new genera and 36 new species of the diplopod family Anthroleucosomatidae Verhoeff, 1899 are described from the Caucasus, one of the world's biodiversity hotspots: Golovatchosoma bacillichaetum gen. et sp. nov., G. trichochaetum sp. nov., Alpinella waltheri gen. et sp. nov., Brachychaetosoma turbanovi gen. et sp. nov., Caucaseuma elephantum sp. nov., C. fanagoriyskaya sp. nov., C. glabroscutum sp. nov., C. kelasuri sp. nov., C. minellii sp. nov., C. variabile sp. nov., Caucasominorus billi gen. et sp. nov., C. polylobatus sp. nov., Georgiosoma bicornutum gen. et sp. nov., Heterocaucaseuma feminaepectorum gen. et sp. nov., H. longicorne sp. nov., Paranotosoma attemsi gen. et sp. nov., P. cordatum sp. nov., P. subrotundatum sp. nov., Dentatosoma denticulatum gen. et sp. nov., D. magnum sp. nov., D. zeraboseli sp. nov., Enghoffiella insolita gen. et sp. nov., Metamastigophorophyllon hamatum sp. nov., M. lamellohirsutum sp. nov., M. torsivum sp. nov., Acanthophorella barjadzei gen. et sp. nov., A. chegemi sp. nov., A. irystoni sp. nov., Cryptacanthophorella manubriata gen. et sp. nov., Flagellophorella hoffmani gen. et sp. nov., Pseudoflagellophorella eskovi gen. et sp. nov., P. mirabilis sp. nov., P. papilioformis sp. nov., Herculina oligosagittae gen. et sp. nov., H. polysagittae sp. nov., Vegrandosoma tabacarui gen. et sp. nov. All anthroleucosomatids from the Caucasus, both new and previously described, are classified in eight endemic complexes, arranged as follows in alphabetic order: the Alloiopus complex, the Caucaseuma complex, the Dentatosoma complex, the Enghoffiella complex, the Flagellophorella complex, the Herculina complex, the Ratcheuma complex and the Vegrandosoma complex. The genus Metamastigophorophyllon Ceuca, 1976 (the type-species: Mastigophorophyllon giljarovi Lang, 1959, adequately redescribed from new material), is a new subjective senior synonym of Persedicus Mauries, 1982, syn. nov., being also newly transferred from the family Mastigophorophyllidae to the family Anthroleucosomatidae, comb. nov. The following two new combinations are also proposed: Heterocaucaseuma mauriesi (Golovatch and Makarov, 2011), comb. nov. ex Anamastigona Silvestri, 1898; and Metamastigophorophyllon martensi (Mauries, 1982), comb. nov. ex Persedicus Mauries, 1982. An identification key to and distribution maps for all known species of Caucasian Anthroleucosomatidae are provided, as well as brief remarks on distributions and on cave-dwelling taxa. PMID- 28006793 TI - A revision of the Neogene Conidae and Conorbidae (Gastropoda) of the Paratethys Sea. AB - The Miocene Conidae and Conorbidae of the central- and south-eastern European Paratethys Sea are revised. In total, 74 species are described of which 10 are new species and 5 are documented for the first time from Paratethyan localities. Species descriptions and delimitations are partly based on morphometric data. In addition, colour patterns are described for the first time for the majority of species. In respect to the ongoing discussion on the supraspecific treatment of extant Conidae, we strongly focus on generic allocations and provide a key for the genera as understood herein. Biogeographically, the larger part of the assemblage indicates affiliation with modern western African faunas as indicated by the occurrence of genera such as Lautoconus, Kalloconus, Monteiroconus and Pseudonoduloconus. The relationship with Indo-West Pacific faunas is comparatively low. The high alpha-diversities observed for localities in the Pannonian, Transylvanian and Vienna basins, with up to 44 species, is a marker of tropical conditions in the Paratethys Sea during middle Miocene times. Conasprella minutissima nov. sp., Kalloconus hendricksi nov. sp., Kalloconus letkesensis nov. sp., Kalloconus pseudohungaricus nov. sp., Lautoconus kovacsi nov. sp., Lautoconus pestensis nov. sp., Lautoconus quaggaoides nov. sp., Leporiconus paratethyianus nov. sp., Plagioconus breitenbergeri nov. sp. and Plagioconus bellissimus nov. sp. are described as new species; Conilithes eichwaldi nov. nom. is proposed as new name for Conus exiguus Eichwald, 1830 [non Lamarck, 1810]. PMID- 28006794 TI - Revision of the family Chasmocarcinidae Serene, 1964 (Crustacea, Brachyura, Goneplacoidea). AB - The family Chasmocarcinidae Serene, 1964, is revised based on the examination of the type material of many of its species as well as unidentified and previously identified material from around the world. The revised family now consists of three subfamilies comprising 16 genera (including eight described as new) and 51 species (including 19 described as new). The subfamily Chasmocarciinae Serene, 1964, consists of Amboplax n. gen. with one species; Angustopelta n. gen. with four species, two of which are new; Camatopsis Alcock & Anderson, 1899, with six species, five of which are new; Chasmocarcinops Alcock, 1900, with one species; Chasmocarcinus Rathbun, 1898, with 11 species, one of which is new; Chinommatia n. gen. with five species, two of which are new; Deltopelta n. gen. with one species; Hephthopelta Alcock, 1899, with two species, one of which is new; Microtopsis Komai, Ng & Yamada, 2012, with two species, one of which is new; Notopelta n. gen. with one species; Statommatia n. gen. with five species, two of which are new; and Tenagopelta n. gen. with three species, two of which are new. The subfamily Megaesthesiinae Stevcic, 2005, consists of Alainthesius n. gen. with two species, both of which are new; Megaesthesius Rathbun, 1909, with four species, one of which is new. The subfamily Trogloplacinae Guinot, 1986, consists of Australocarcinus Davie, 1988, with three species, and Trogloplax Guinot, 1986, with one species. A neotype is selected for Chasmocarcinus cylindricus Rathbun, 1901. Three nominal species were found to be junior subjective synonyms of other species: Chasmocarcinus panamensis Serene, 1964, of C. longipes Garth, 1940; Chasmocarcinus rathbuni Bouvier, 1917, of C. typicus Rathbun, 1898; and Hephthopelta superba Boone, 1927, of Deltopelta obliqua (Rathbun, 1898). Thirteen chasmocarcinid genera are exclusively found in the Indo-West Pacific region, one (Chasmocarcinus) in both the Western Atlantic and Tropical Eastern Pacific regions, and two (Deltopelta n. gen. and Amboplax n. gen.) exclusively in the Western Atlantic. Chasmocarcinids are remarkable for occurring from depths exceeding 1000 m to shallow water and completely freshwater habitats: chasmocarcinines and megaesthesiines are found from shallow to deep water marine ecosystems, whereas trogloplacines live in freshwater streams, including cave systems. PMID- 28006795 TI - Integrative taxonomic re-description of Halisarca magellanica and description of a new species of Halisarca (Porifera, Demospongiae) from Chilean Patagonia. AB - A series of recent expeditions in fjords and canals of Southern Chilean Patagonia allowed the re-collection of Halisarca magellanica Topsent, 1901 and the discovery of a new species, Halisarca desqueyrouxae sp. nov. The material studied was collected at depths ranging from 3 to 30 m at latitudes comprised between 42 degrees and 49 degrees S. Both species share the same habitat and show a morphological plasticity, but differ in their colour. Halisarca magellanica is bright pink to whitish with three morphs whereas H. desqueyrouxae sp. nov. is light brown to beige with two morphs. An extensive investigation in TEM and SEM reveals several differences among cell types with inclusions between both species. Three distinct spherulous cells occur. Type 1 is shared by both species, Type 2 is occasional in H. magellanica but absent from H. desqueyrouxae sp. nov. Type 3 is rare in H. magellanica and occurs abundantly in half of the specimens of H. desqueyrouxae sp. nov. Granular cells are shared by both species but do not occur in all specimens. Microgranular cells are characteristic of H. magellanica. Both species also clearly differ by their endobiotic bacteria. Phylogenetic analysis of cox1 sequences places H. magellanica as a sister group to all other previously published Halisarca species sequences (9.1-9.7% difference) except H. harmelini, while H. desqueyrouxae sp. nov. is placed as a sister group to H. dujardini (2.3% difference). PMID- 28006796 TI - A new generic name, Semigothograptus, for Gothograptus? meganassa Rickards & Palmer, 2002, from the Silurian post-lundgreni Biozone recovery phase, and comparative morphology of retiolitids from the lowermost upper Homerian (upper Wenlock). AB - Gothograptus? meganassa Rickards & Palmer, 2002 is assigned to a new genus Semigothograptus. New, well preserved material from the dubius/nassa Biozone (upper Homerian, Silurian) of the Bartoszyce IG-1 drill core Poland is described. This provides a new phylogenetic perspective on the evolution of post-lundgreni Event retiolitines. Semigothograptus meganassa is considered to be a descendant of Gothograptus nassa, although one of the most significant differences between these forms is the position of the nema, and narrow finite tubarium ending in an appendix in G. nassa. S. meganassa possesses looping meshes of the ancora umbrella recognised in Gothograptus, Papiliograptus, and Baculograptus and shares the common characters of all stratigraphical younger retiolitines. It is recognised that the S. meganassa is known from four terrains: Avalonia, Baltica, Bohemia, and Saxo-Thuringia. Analysis of the genicular hoods of nassa type, characteristic of Gothograptus nassa, Gothograptus kozlowskii, Semigothograptus meganassa, and Neogothograptus eximinassa, demonstrates their unique, solid bandage construction. PMID- 28006797 TI - Redescription and Range Extension of Microhyla sholigari Dutta & Ray (Amphibia: Anura: Microhylidae) from South West India. AB - Microhyla sholigari is an endangered frog described in the year 2000. The original description was based on non-adult types and lacked information on several morphological characters, call structure, genetic material and photographs of the animal in life. The absence of such information posed challenges in field identification of this species. Since the original description, there is one other reported sighting of this species from Kerala in 2001. We encountered specimens that we confer to this species based on morphological similarity to the subadult holotype, from several new localities within and outside the Western Ghats of Karnataka. We here redescribe the species based on additional adult vouchers, provide molecular data, describe the advertisement call and report a range extension. Based on its current distribution, we assess the threat status of the species and suggest listing it as Least Concern according to IUCN Red List criteria. Our paper bridges an important gap in the knowledge of the genus Microhyla in India and highlights the importance of systematic surveys in documenting and understanding amphibian diversity in the region. PMID- 28006798 TI - Description of three new species of Crenitis Bedel from China, with additional faunistic records for the genus (Coleoptera: Hydrophilidae: Chaetarthriinae). AB - Three new species of the genus Crenitis Bedel, 1881 are described from China: C. aduncata sp. nov. (Yunnan), C. lianggeqiui sp. nov. (Yunnan and Sichuan) and C. obovata sp. nov. (Guangxi and Guizhou). All three species are assigned to the subgenus Crenitis. New locality records in China are provided for C. apicalis (Reitter, 1896) (from Inner Mongolia) and C. convexa Ji & Komarek, 2003 (from Ningxia, Chongqing). A key to the Chinese species of the subgenus Crenitis is provided. PMID- 28006799 TI - Cobitis nalbanti, a new species of spined loach from South Korea, and redescription of Cobitis lutheri (Teleostei: Cobitidae). AB - Cobitis nalbanti, new species, is described from the South Korean Han and Geum Rivers, draining to the Yellow Sea. It differs from its congeners by having a wide, ovoid lamina circularis; rounded scales with a large, slightly-displaced focal zone; a relatively long, protruded snout; the suborbital spine not reaching the center of the eye; the mandibular barbel not reaching the anterior edge of the eye; usually 12-14 dark brown blotches in the fourth Gambetta's zone; a single elongated black spot on the upper part of the caudal-fin base; the only streak on the head running from the tip of the snout to the nape, across the eye; 2n=48-51 and NF=66. Cobitis nalbanti was previously identified as C. lutheri. Morphological analysis of C. lutheri shows that it is distinct in having a short obtuse snout, the suborbital spine reaching the center of the eye, the mandibular barbel reaching the anterior edge of the eye, usually less than 12 dark brown blotches in the fourth Gambetta's zone, two spots at the caudal-fin base, several dark streaks on the head, and 2n=50, NF=70. A lectotype is selected for C. lutheri. Cobitis lutheri has a wide distribution in the Amur River basin, several rivers flowing into the Sea of Japan (East Sea), and in the northern part of Sakhalin Island. PMID- 28006800 TI - A simple and quick method of displaying liquid-preserved morphological structures for microphotography. AB - Stabilising microstructures and small organisms for microphotography can be frustrating. If it is desired to take photographs in water from structures just cleared in potassium hydroxide, some sort of stabilisation is necessary otherwise the structures drift. Similarly, specimens taken from glycerol or alcohol, or those placed in alcohol, drift even more as the alcohol evaporates. Bits of crushed coverslip, glass beads, micro pins and dobs of Vaseline(r) have all been used to help keep the structures in place. In an attempt to solve the problem of "drifting genitalia" a simple solution was inadvertently discovered. A method used for whole insects by Sam Droege and his colleagues of the United States Geological Survey (Droege 2016; USGS Bee Inventory and Monitoring Lab 2016) was adapted for use with insect genitalia. PMID- 28006801 TI - Replacement names for two homonyms of Liothrips brevitubus Karny: one from California, the other for a species damaging Jatropha crops in Mexico. AB - There are nearly 280 species of Liothrips listed from around the world (ThripsWiki 2016), all of them presumably feeding and breeding on the leaves of higher plants, and sometimes inducing or being associated with galls (Mound 1994). Despite this, for most of these species the identity of the plant species on which they are dependent is rarely known, and a particularly high proportion of the species are based on few specimens or even single individuals (cf Table 1). As a result, the identity of many of these named species continues to be in doubt. Modern identification keys are available only to the 23 Liothrips species known from Japan (Okajima 2006), the four European species known from Iran (Minaei & Mound 2014), and 14 species from Illinois (Stannard 1968). In contrast, the keys to 16 species of Liothrips from Brazil (Moulton 1933), to more than 80 species from Indonesia (Priesner 1968), and to 50 species from India (Ananthakrishnan & Sen 1980), are of little more than archival interest, in that they are based on few specimens with little allowance for intraspecific variation. Mound & Marullo (1996) listed over 80 Liothrips species from the Americas, although some of these are now placed in Pseudophilothrips (see Mound et al. 2010). That list included two homonyms of the Indonesian species Liothrips brevitubus Karny, one from Mexico and one from California. The homonym from Mexico is here recognised as applying to a species that in 2015 caused severe damage to a crop of Jatropha curcas in Chiapas. The objectives here are to provide a valid name for this pest, to facilitate its recognition among the 13 species of Liothrips recorded from Mexico (Table I), and also to replace the homonym from California. PMID- 28006802 TI - Erratum: GIULIA FURFARO, BERNARD PICTON, ALEXANDER MARTYNOV & PAOLO MARIOTTINI (2016) Diaphorodoris alba Portmann & Sandmeier, 1960 is a valid species: molecular and morphological comparison with D. luteocincta (M. Sars, 1870) (Gastropoda: Nudibranchia). Zootaxa, 4193: 304-316. PMID- 28006803 TI - Bythaelurus bachi n. sp., a new deep-water catshark (Carcharhiniformes, Scyliorhinidae) from the southwestern Indian Ocean, with a review of Bythaelurus species and a key to their identification. AB - A new deep-water catshark, Bythaelurus bachi, is described based on 44 specimens caught on the southern Madagascar Ridge in the southwestern Indian Ocean. The new species is the only stout-bodied Bythaelurus with oral papillae in the region and is distinguished from all congeners by the plain beige to light gray-brown coloration, high diversity in dermal denticle morphology, and presence of composite oral papillae. Despite resemblance in body shape, Bythaelurus bachi n. sp. is distinguished from its closest congener, B. naylori Ebert & Clerkin, 2015, by the presence of numerous large, partially composite papillae on the tongue and roof of the mouth (vs. papillae lacking), plain light coloration (vs. medium to dark brown ground color, light fin edges and a distinctly dark dusky-colored snout), only slightly enlarged dermal denticles on the anterior upper caudal-fin margin (vs. dermal denticles distinctly enlarged), a higher diversity in dermal denticle morphology in general, and smaller maximum size and size at maturity. The distinction of both species is also supported by molecular results. The new species differs from all other congeners in the western Indian Ocean in the stout body shape of large specimens, coloration, larger size, as well as several morphometrics, including larger claspers, longer eyes and dorsal fins, and shorter pelvic-anal and pelvic-caudal spaces. The genus is reviewed, a key to its species given. PMID- 28006804 TI - Key to Plecoptera nymphs from the Brazilian Amazon (Insecta). AB - Nymphs of 22 species of Plecoptera from the Brazilian Amazon are keyed and illustrated to enhance their usefulness as water quality indicator taxa. Four described species of Anacroneuria, two species of Macrogynoplax, and two species of Enderleina have been associated with adults: Anacroneuria marlieri, A. manauensis, A. minuta, A. singularis, M. delicata, M. pulchra, E. froehlichi, and E. flinti. Nymphs of 14 additional morphospecies not yet associated with adults are included. Characters of the head, pronotum, mesonotum, and metanotum are used to distinguish late instar nymphs. PMID- 28006805 TI - The ant genus Linepithema (Formicidae: Dolichoderinae) in Colombia. AB - The species of Linepithema Mayr in Colombia are reviewed from collection material. The genus Linepithema comprises 20 species, of which the following are reported in Colombia: L. angulatum (Emery), L. dispertitum (Forel), L. gallardoi (Brethes), L. humile (Mayr), L. iniquum (Mayr), L. neotropicum Wild, L. piliferum (Mayr), L. tsachila Wild, and a new species, Linepithema hirsutum sp. nov. Linepithema dispertitum is a new record for Colombia and South America. A taxonomic key (English and Spanish) and distribution maps to the species of Linepithema in Colombia are provided. PMID- 28006806 TI - Four subgenera of Bracon Fabricius (Hymenoptera, Braconidae, Braconinae) newly recorded from China, with description of five new species. AB - Four subgenera of the genus Bracon Fabricius (Hymenoptera, Braconidae, Braconinae) are newly reported to China, i.e., Ophthalmobracon Tobias, 1957; Orientobracon Tobias, 2000; Punctobracon Papp, 1996; and Sculptobracon Tobias, 1961. Six species are recognized, including five new species, B. (Ophthalmobracon) elevatus sp. nov., B. (Orientobracon) maculaverticalis sp. nov., B. (Orientobracon) laticanaliculatus sp. nov., B. (Punctobracon) rhyacioniainus sp. nov. and B. (Sculptobracon) obsoletus sp. nov., which are described and illustrated. Keys to the newly recorded Chinese subgenera and species are provided. PMID- 28006807 TI - A new species of Neobathyclupea from the northern Indian Ocean with comments on N. malayana (Teleostei, Perciformes, Bathyclupeidae). AB - A new species of Neobathyclupea is described from two specimens collected off Myanmar and off Socotra Island. The new species is most similar to N. malayana, but differs from it and other congeners in having jet-black coloured fins, larger pseudobranch, dorsal-pterygiophore pattern and some body proportions. Neobathyclupea malayana is re-diagnosed. Individual variations in armament of the preopercle and in the dorsal-pterygiophore patterns within Bathyclupeidae are discussed. PMID- 28006808 TI - A new record and two new species of Cryptochironomus Kieffer, 1918 from China (Diptera, Chironomidae). AB - Two new species of the genus Cryptochironomus Kieffer, C. maculus Yan & Wang sp. n. and C. protuberans Yan & Wang sp. n. are described and illustrated as adult males. C. albofasciatus (Staeger) is recorded from China for the first time. A key to the males of Cryptochironomus in China is presented and generic diagnosis is emended. PMID- 28006809 TI - Two new species of Clubiona Latreille (Araneae: Clubionidae) from China. AB - Clubiona Latreille, 1804, comprising approximately 78% of all Clubionidae species described so far, is the largest genus in the family. Of the 476 Clubiona species worldwide, 113 have been reported from China (World Spider Catalog 2016, Li & Lin 2016). However, the diversity of this genus in China is still insufficiently known and several new species have been described in the last few years (Wu & Zhang 2014a; Wu & Zhang 2014b; Dankittipakul & Singtripop 2014; Wang, Wu & Zhang 2015; Wu, Zheng & Zhang 2015). Among several species groups proposed to accommodate the species of the genus (Mikhailov 1995), the Corticalis group is one of the most well known in China, computing 19 species described so far for that country (Wang, Wu & Zhang 2015; Wu, Zheng & Zhang 2015). While examining spiders collected in Yunnan and Hunan provinces, China, we found two new Clubiona species of the Corticalis group, which are described below. PMID- 28006810 TI - Catalog of the Paramacronychiinae of China (Diptera: Sarcophagidae). AB - An updated taxonomic catalog of all 32 species of the subfamily Paramacronychiinae so far known to occur in China is presented. The catalog includes data on type locality, references, distribution and information on type material for nominal species with a Chinese type locality. Additional specimens deposited in the Institute of Zoology, Chinese Academy of Sciences and the Museum of Beijing Forestry University were examined. The genus Wohlfahrtiodes Villeneuve, 1910 and the species Wohlfahrtiodes marzinowskyi Rohdendorf, 1962 are new records from China. Two new synonyms are proposed: Wohlfahrtia Brauer & Bergenstamm, 1889 = Sinotibetomyia Xue in Xue & Fei, 2011, syn. nov., and Wohlfahrtia atra Aldrich, 1926 = Sinotibetomyia curvifemura Xue & Fei, 2011, syn. nov. PMID- 28006811 TI - Seven new species of the genus Xestoleberis (Ostracoda: Podocopida: Cytheroidea) from the Fiji Archipelago. AB - The genus Xestoleberis has a global distribution, and although they are predominant in shallow marine environments adapted to both sediment and algal habitats, only two species of this genus, Xestoleberis curta (Brady, 1866) and Xestoleberis variegata Brady, 1880, have previously been reported from the Fiji archipelago. Herein we report seven new species of the genus Xestoleberis from intertidal environments of fringing reef flats of the Fiji Islands: Xestoleberis becca n. sp., Xestoleberis concava n. sp., Xestoleberis gracilariaii n. sp., Xestoleberis marcula n. sp., Xestoleberis natuvuensis n. sp., Xestoleberis penna n. sp. and Xestoleberis petrosa n. sp. With the exception of X. becca n. sp., Xestoleberis species show restricted distribution within Fijian waters. The possible causes for their distribution patterns are suggested to be physical barriers imposed by the fast flowing Bligh Water currents, and islands separated by deep ocean waters. PMID- 28006812 TI - Coping with brackish water: A new species of cave-dwelling Protosuberites Porifera: Demospongiae: Suberitidae) from the Western Mediterranean and a first contribution to the phylogenetic relationships within the genus. AB - We used both morphological and genetic approaches to investigate and to describe a new Mediterranean sponge species of the genus Protosuberites from the estuarine anchialine Bue Marino Cave of Sardinia (Tyrrhenian Sea). The morphotraits of the specimens were compared versus congeneric species with the strongest affinities, covering the genus geographic range worldwide. Protosuberites mereui sp. nov. is light yellow, thinly encrusting, devoid of any special ectosomal skeleton, with spicular complement of tylostyles of three size classes, single or arranged in bundles/tufts, with round to suboval heads. The new species is characterized by an exclusive diagnostic trait recorded for any cave-dwelling Protosuberites i.e. suboval and basally plated resting bodies with a foraminal aperture ornate by a collar. Resting bodies were found in the basal spongin plate firmly adhering to the substratum singly or in small groups. Also the rare, small tylostyles with a sinuous shaft and a typical mushroom-like head were never recorded in the Western Mediterranean and Atlantic species of the genus. The phylogenetic reconstruction using maximum likelihood (ML) and Bayesian Inference (BI) analyses (COI, 18S rRNA, and 28S rRNA) recovered a robustly supported sister relationship between the Mediterranean P. mereui sp. nov. and Protosuberites sp. 'Panama' from the Eastern Pacific Ocean. The genetic distances based on COI sequences between all compared Protosuberites species were always higher than 2%, a value sufficient to confirm that P. mereui sp. nov. is a distinct species within the genus. Morphological and genetic analyses confirm unanimously P. mereui sp. nov. as a new species. Our results contribute to the assessment of biodiversity in anchialine/estuarine caves and increase data on sponge adaptive strategies in these extreme ecosystems. PMID- 28006813 TI - Myolaimus ibericus sp. n. (Nematoda, Rhabditida, Myolaimidae) from southern Iberian Peninsula, with a key to species of the genus. AB - A new species of the genus Myolaimus is described from agricultural areas in the southeast of the Iberian Peninsula. Myolaimus ibericus sp. n. is characterized by its 560-783 MUm long body in females and 526-731 MUm in males, cuticle often appearing swollen and baggy, lateral field with one longitudinal wing, lip region with six amalgamated lips having ten (6 + 4) setiform papillae, stoma consisting of a wider anterior chamber (cheilo-gymnostom) and a tubular posterior part (stegostom) separated by a well developed dorsal tooth and two small, lateral (one right and another left) teeth, glottoid-like apparatus structure appearing at metastom, pharyngeal corpus 1.7-2.6 times the isthmus length, excretory pore and deirids located at metacorpus level, deirids pore-like in females and seta like in males, female reproductive system monodelphic-prodelphic with antidromous ovary, post-uterine sac 1.7-2.7 times the corresponding body diameter long, V = 50-56, female rectum 1.3-2.0 times the anal body diameter long, female tail conical-elongate (54-70 MUm, c = 9.9-13.1, c' = 4.4-5.8) often enveloped by the baggy cuticle, male tail conoid (8-10 MUm, c = 58.4-73.1, c' = 1.1-1.4) and ventrally constricted at its middle, bursal structure with seven (4+1+2) pairs of genital papillae. This is the first record of the genus from the Iberian Peninsula. Description, measurements and illustrations, including SEM photographs are provided. An illustrated compendium of the posterior ends of males in Myolaimus species is also presented. PMID- 28006814 TI - A new genus and species of Atalophlebiinae (Insecta: Ephemeroptera: Leptophlebiidae) from Palni hills of the southern Western Ghats, India. AB - A new genus and new species of Atalophlebiinae, Klugephlebia kodai Selvakumar, Subramanian & Sivaramakrishnan, are described based on male and female imagos and larvae from Palni hills of the southern Western Ghats of India. The imago of Klugephlebia gen. n. can be differentiated from all other genera of Atalophlebiinae by having the combination of vein MP forked slightly less than half of the distance from base to margin, MP2 attached at base to vein MP1 by a crossvein, a distinctive shape of the hindwing, dissimilar claws on each leg, and distinctive genitalia structures. The larva can be distinguished from other Atalophlebiinae larvae by having the combination of gills present on abdominal segments 1-7, dorsal and ventral portions of lamellae of gills 1 slender and lanceolate with branched tracheae, dorsal and ventral portions of lamellae of gills 2-7 wider & lanceolate and long & suddenly tapering at apex, fore and mid femora with regular rows of long thin setae on outer margins, denticles on claws progressively larger apically, a distinctive labrum, the maxillary palp short with long setae on third segment, and the third segment of the labial palp with distinct setation. The larvae cling to the underside of boulders in the middle of streams where the boulders lie amidst sand and silt. Updated keys to the genera of south Indian Leptophlebiidae are provided. PMID- 28006815 TI - A new species of Moenkhausia Eigenmann, 1903 (Characiformes: Characidae) from Amazon basin, Brazil. AB - A new species of Moenkhausia is described from tributaries of the lower Amazon basin, Para State, Brazil. The new species is morphologically similar to Moenkhausia collettii, M. copei, and M. venerei by the presence of a dark horizontal stripe across the middle portion of the eye, a conspicuous slightly rounded humeral blotch, a dark longitudinal midlateral stripe and a dark stripe along the anal-fin base. However, the new species can be distinguished from M. collettii, M. copei, and M. venerei mainly by the number of cusps on the inner row of the premaxillary, maxillary and dentary teeth, and by the number of scales in transversal series above and below the lateral line. PMID- 28006816 TI - EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6. AB - BACKGROUND: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). METHODS: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. RESULTS: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA- (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. CONCLUSIONS: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status. PMID- 28006817 TI - Tumour microenvironment factors shaping the cancer metabolism landscape. AB - Cancer cells exhibit metabolic alterations that distinguish them from healthy tissues and make their metabolic processes susceptible to pharmacological targeting. Although typical cell-autonomous features of cancer metabolism have been emerging, it is increasingly appreciated that extrinsic factors also influence the metabolic properties of tumours. This review highlights evidence from the recent literature to discuss how conditions within the tumour microenvironment shape the metabolic character of tumours. PMID- 28006818 TI - Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer. AB - BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression. PMID- 28006819 TI - Better resource utilisation and quality of care for ovarian cancer patients using internet-based pathology review. AB - BACKGROUND: The current literature indicates that a considerable number of patients in ovarian carcinoma clinical trials have histopathological diagnoses in conflict with inclusion criteria. It has been suggested that specialised pathology review prior to randomisation should become the standard procedure in study protocols. We hypothesised that our new, internet-based high-throughput infrastructure would be capable of providing specialised pathology review within 10 working days (w.d.). METHODS: Patients scheduled for the AGO OVAR17 ovarian carcinoma chemotherapy trial were registered for expert pathologic case review using a new internet-based central pathology review platform prior to randomisation. All original slides were requested from local pathologists. Slides were scanned and uploaded to a secured internet server. A network of experienced gynaecological pathologists was connected to the server through a custom-designed software platform. If deemed necessary by the expert pathologists, immunohistochemistry was available through a collaborating pathology lab. RESULTS: A total of 880 patients with an original diagnosis of ovarian epithelial carcinoma were registered for expert pathology review from October 2011 to July 2013. For case review, five gynaecopathologists from Austria, Switzerland and Germany were available online. Median number of w.d. required to complete the whole process from patient registration to transmission of final review diagnoses was 4 (range 2-31) (w.d.), and in 848 out of 880 (97.5%) cases, it amounted to ?10 w.d. In 2.5% (n=22) of cases, a major diagnostic discrepancy of potential clinical relevance was found leading to exclusion from the chemotherapy trial. CONCLUSIONS: Our results show that the use of a new internet-based infrastructure makes timely specialised case review, prior to patient randomisation feasible within ?10 w.d. Our new approach helped to protect against overtreatment with chemotherapy of patients with ovarian borderline tumours and inadequate treatment of patients with ovarian metastases, as a result of their inappropriate entry into a clinical trial designed for patients with primary ovarian carcinoma. PMID- 28006820 TI - Entomopathogenic Nematodes Combined with Adjuvants Presents a New Potential Biological Control Method for Managing the Wheat Stem Sawfly, Cephus cinctus (Hymenoptera: Cephidae). AB - The wheat stem sawfly, (Cephus cinctus Norton) Hymenoptera: Cephidae, has been a major pest of winter wheat and barley in the northern Great Plains for more than 100 years. The insect's cryptic nature and lack of safe chemical control options make the wheat stem sawfly (WSS) difficult to manage; thus, biological control offers the best hope for sustainable management of WSS. Entomopathogenic nematodes (EPNs) have been used successfully against other above-ground insect pests, and adding adjuvants to sprays containing EPNs has been shown to improve their effectiveness. We tested the hypothesis that adding chemical adjuvants to sprays containing EPNs will increase the ability of EPNs to enter wheat stems and kill diapausing WSS larvae. This is the first study to test the ability of EPNs to infect the WSS, C. cinctus, and test EPNs combined with adjuvants against C. cinctus in both the laboratory and the field. Infection assays showed that three different species of EPNs caused 60-100% mortality to WSS larvae. Adding Penterra, Silwet L-77, Sunspray 11N, or Syl-Tac to solutions containing EPNs resulted in higher WSS mortality than solutions made with water alone. Field tests showed that sprays containing S. feltiae added to 0.1% Penterra increased WSS mortality up to 29.1%. These results indicate a novel control method for WSS, and represent a significant advancement in the biological control of this persistent insect pest. PMID- 28006821 TI - SRC-1 Regulates Blood Pressure and Aortic Stiffness in Female Mice. AB - Framingham Heart Study suggests that dysfunction of steroid receptor coactivator 1 may be involved in the development of hypertension. However, there is no functional evidence linking steroid receptor coactivator-1 to the regulation of blood pressure. We used immunohistochemistry to map the expression of steroid receptor coactivator-1 protein in mouse brain, especially in regions implicated in the regulation of blood pressure. Steroid receptor coactivator-1 protein was found in central amygdala, medial amygdala, supraoptic nucleus, arcuate nucleus, ventromedial, dorsomedial, paraventricular hypothalamus, and nucleus of the solitary tract. To determine the effects of steroid receptor coactivator-1 protein on cardiovascular system we measured blood pressures, blood flow velocities, echocardiographic parameters, and aortic input impedance in female steroid receptor coactivator-1 knockout mice and their wild type littermates. Steroid receptor coactivator-1 knockout mice had higher blood pressures and increased aortic stiffness when compared to female wild type littermates. Additionally, the hearts of steroid receptor coactivator-1 knockout mice seem to consume higher energy as evidenced by increased impedance and higher heart rate pressure product when compared to female wild type littermates. Our results demonstrate that steroid receptor coactivator-1 may be functionally involved in the regulation of blood pressure and aortic stiffness through the regulation of sympathetic activation in various neuronal populations. PMID- 28006822 TI - Screening for Dementia in Older Adults: Comparison of Mini-Mental State Examination, Mini-Cog, Clock Drawing Test and AD8. AB - This study was conducted to estimate screening performance of dementia screening tools including Mini-Mental State Examination (MMSE), Mini-Cog, Clock Drawing Test (CDT) and Ascertain Dementia 8 questionnaire (AD8) for older adults. 2015 participants aged 65 years or more in eastern China were enrolled. 4 screening tests were administered and scored by specifically trained psychiatrists. We used data from two-by-two tables to calculate the sensitivity, specificity, and positive and negative predictive values (PPV/NPV). Our study showed that dementia was highly prevalent among elderly in Zhejiang province. The Mini-Cog, with excellent screening characteristics and spending less time, could be considered to be used as a screening tool among communities to help to diagnose dementia early. PMID- 28006824 TI - Correction: Curiosity Search: Producing Generalists by Encouraging Individuals to Continually Explore and Acquire Skills Throughout Their Lifetime. AB - [This corrects the article DOI: 10.1371/journal.pone.0162235.]. PMID- 28006823 TI - Effects of Antifouling Biocides on Molecular and Biochemical Defense System in the Gill of the Pacific Oyster Crassostrea gigas. AB - Antifouling biocides such as organotin compounds and their alternatives are potent toxicants in marine ecosystems. In this study, we employed several molecular and biochemical response systems of the Pacific oyster Crassostrea gigas to understand a potential mode of action of antifouling biocides (i.e. tributyltin (TBT), diuron and irgarol) after exposure to different concentrations (0.01, 0.1, and 1 MUg L-1) for 96 h. As a result, all the three antifouling biocides strongly induced the antioxidant defense system. TBT reduced both enzymatic activity and mRNA expression of Na+/K+-ATPase and acetylcholinesterase (AChE). Lower levels of both Na+/K+-ATPase activity and AChE mRNA expression were observed in the diuron-exposed oysters compared to the control, while the irgarol treatment reduced only the transcriptional expression of AChE gene. We also analyzed transcript profile of heat shock protein (Hsp) superfamily in same experimental conditions. All antifouling biocides tested in this study significantly modulated mRNA expression of Hsp superfamily with strong induction of Hsp70 family. Taken together, overall results indicate that representative organotin TBT and alternatives have potential hazardous effects on the gill of C. gigas within relatively short time period. Our results also suggest that analyzing a series of molecular and biochemical parameters can be a way of understanding and uncovering the mode of action of emerging antifouling biocides. In particular, it was revealed that Pacific oysters have different sensitivities depend on the antifouling biocides. PMID- 28006825 TI - Linking Hydroclimate to Fish Phenology and Habitat Use with Ichthyographs. AB - Streamflow and water temperature (hydroclimate) influence the life histories of aquatic biota. The relationship between streamflow and temperature varies with climate, hydrogeomorphic setting, and season. Life histories of native fishes reflect, in part, their adaptation to regional hydroclimate (flow and water temperature), local habitats, and natural disturbance regimes, all of which may be affected by water management. Alterations to natural hydroclimates, such as those caused by river regulation or climate change, can modify the suitability and variety of in-stream habitat for fishes throughout the year. Here, we present the ichthyograph, a new empirically-based graphical tool to help visualize relationships between hydroclimate and fish phenology. Generally, this graphical tool can be used to display a variety of phenotypic traits. We used long-term data sets of daily fish passage to examine linkages between hydroclimate and the expression of life-history phenology by native fishes. The ichthyograph may be used to characterize the environmental phenology for fishes across multiple spatio-temporal domains. We illustrate the ichthyograph in two applications to visualize: 1) river use for the community of fishes at a specific location; and 2) stream conditions at multiple locations within the river network for one species at different life-history stages. The novel, yet simple, ichthyograph offers a flexible framework to enable transformations in thinking regarding relationships between hydroclimate and aquatic species across space and time. The potential broad application of this innovative tool promotes synergism between assessments of physical characteristics and the biological needs of aquatic species. PMID- 28006826 TI - Predictive Performance of the Simplified Acute Physiology Score (SAPS) II and the Initial Sequential Organ Failure Assessment (SOFA) Score in Acutely Ill Intensive Care Patients: Post-Hoc Analyses of the SUP-ICU Inception Cohort Study. AB - PURPOSE: Severity scores including the Simplified Acute Physiology Score (SAPS) II and the Sequential Organ Failure Assessment (SOFA) score are used in intensive care units (ICUs) to assess disease severity, predict mortality and in research. We aimed to assess the predictive performance of SAPS II and the initial SOFA score for in-hospital and 90-day mortality in a contemporary international cohort. METHODS: This was a post-hoc study of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) inception cohort study, which included acutely ill adults from ICUs across 11 countries (n = 1034). We compared the discrimination of SAPS II and initial SOFA scores, compared the discrimination of SAPS II in our cohort with the original cohort, assessed the calibration of SAPS II customised to our cohort, and compared the discrimination for 90-day mortality vs. in hospital mortality for both scores. Discrimination was evaluated using areas under the receiver operating characteristics curves (AUROC). Calibration was evaluated using Hosmer-Lemeshow's goodness-of-fit C-statistic. RESULTS: AUROC for in-hospital mortality was 0.80 (95% confidence interval (CI) 0.77-0.83) for SAPS II and 0.73 (95% CI 0.69-0.76) for initial SOFA score (P<0.001 for the comparison). Calibration of the customised SAPS II for predicting in-hospital mortality was adequate (P = 0.60). Discrimination of SAPS II was reduced compared with the original SAPS II validation sample (AUROC 0.80 vs. 0.86; P = 0.001). AUROC for 90-day mortality was 0.79 (95% CI 0.76-0.82; P = 0.74 for comparison with in-hospital mortality) for SAPS II and 0.71 (95% CI 0.68-0.75; P = 0.66 for comparison with in-hospital mortality) for the initial SOFA score. CONCLUSIONS: The predictive performance of SAPS II was similar for in-hospital and 90-day mortality and superior to that of the initial SOFA score, but SAPS II's performance has decreased over time. Use of a contemporary severity score with improved predictive performance may be of value. PMID- 28006827 TI - An Automated Image Analysis System to Quantify Endosomal Tubulation. AB - Recycling of cargos from early endosomes requires regulation of endosomal tubule formation and fission. This regulation is disrupted in cells depleted of the microtubule severing enzyme spastin, causing elongation of endosomal tubules and mis-trafficking of recycling endosomal cargos such as the transferrin receptor. Spastin is encoded by SPAST, mutations in which are the most frequent cause of autosomal dominant hereditary spastic paraplegia, a condition characterised by a progressive loss of lower limb function resulting from upper motor neuron axonopathy. Investigation of molecular factors involved in endosomal tubule regulation is hindered by the need for manual counting of endosomal tubules. We report here the development of an open source automated system for the quantification of endosomal tubules, using ImageJ and R. We validate the method in cells depleted of spastin and its binding partner IST1. The additional speed and reproducibility of this system compared with manual counting makes feasible screens of candidates to further understand the mechanisms of endosomal tubule formation and fission. PMID- 28006829 TI - Influences of Interelectrode Distance and Innervation Zone on Electromyographic Signals. AB - The purpose of the present study was to examine the effects of electrode placements centered over and offset from the innervation zone (IZ) with different interelectrode distances (IED) on the time and frequency domain parameters of the electromyographic (EMG) signal during a fatiguing submaximal, isometric workout. 11 adults performed an isometric leg extension muscle action at 50% maximal voluntary isometric contraction (MVIC) to exhaustion. Electromyographic amplitude and frequency parameters were determined from electrode placements with different IED centered over, at proximal offset, at distal offset, and away from the IZ at 10, 50, and 100% of the time to exhaustion using an electrode array. There were greater absolute EMG amplitude and lower absolute EMG frequency for electrode placements over and offset from the IZ, but lower absolute EMG amplitude over than offset from the IZ regardless of IED at each time-point during the time to exhaustion. The absolute EMG frequency values were affected by the location relative to the IZ and IED of the electrode placements, and were greater for distal offset vs. proximal offset electrode placements at each time-point. Normalization of the EMG amplitude and EMG frequency values to MVIC eliminated differences due to IED and electrode placements during the fatiguing workout. PMID- 28006828 TI - Outcomes of Bronchial Artery Embolization for Life-Threatening Hemoptysis in Patients with Chronic Pulmonary Aspergillosis. AB - BACKGROUND: Bronchial artery embolization (BAE) is an important treatment option for short-term control of hemoptysis in patients with simple aspergilloma (SA). However, there are no data on the outcomes of BAE in patients with chronic pulmonary aspergillosis (CPA). In this study, the clinical characteristics and outcomes of BAE were investigated and compared in patients with CPA and SA. METHODS: We retrospectively analyzed the clinical data of 64 patients (55 [86%] with CPA and 9 [14%] with SA) who underwent BAE for life-threatening hemoptysis. The clinical characteristics and outcomes of BAE in CPA patients were compared to those of patients with SA. RESULTS: The most common angiographic abnormality was hypervascularity (n = 60, 94%), followed by contrast extravasation (n = 50, 78%) and systemic-pulmonary shunt (n = 48, 75%), with similar incidence rates in both groups. Immediate success was achieved in 41 (64%) BAE procedures, but it was incomplete in 23 (36%) cases due to difficulty with the approach and/or overuse of contrast medium. Clinical failure of BAE was observed in only one (2%) patient. Complications following BAE were observed in four (6%) patients. Recurrence of hemoptysis was seen in a total of 33 patients (52%) within a median of 2.0 (0.3-10.0) months, and repeat BAE was performed in 25 (76%) of these cases. In comparing the outcomes of patients with CPA and SA, there were no differences in the rates of success of initial BAE, incomplete embolization, or clinical failure in the two groups. However, recurrence of hemoptysis tended to be higher in patients with CPA (55%) than in those with SA (33%). In addition, antifungal medications following BAE were more commonly prescribed in the CPA group (56%) compared to the SA group (0%). CONCLUSIONS: BAE was a safe and effective procedure for the management of life-threatening hemoptysis in patients with CPA. However, recurrence of hemoptysis was common, especially in patients with CPA. Therefore, definitive treatment for CPA following successful BAE should be considered to ensure the long-term success of the embolization in these patients. PMID- 28006830 TI - [c-MET Oncogene in Renal Cell Carcinomas]. AB - c-Met plays a significant role in multiple cellular processes. Being encoded by a proto-oncogene, tyrosine kinase supports aggressive tumour behaviour such as tumour invasiveness and formation of metastases. For some subtypes of renal cell carcinoma studies have shown a association between c-Met expression and clinical outcome or prognosis. Therefore, c-Met represents a prognostic marker in renal cell carcinoma.Furthermore, c-MET will play a decisive role as a possible target for targeted therapies in the era of personalised medicine. Especially for RCC, the dual inhibition of VEGF and c-MET tyrosine kinase in cases of metastatic, treatment-resistant tumours is gaining clinical relevance. The role of c-Met has not been fully elucidated for all subtypes of renal cell carcinomas. The relevance of c-Met for the remaining subtypes of renal tumours has yet to be clarified. PMID- 28006831 TI - [Desmopressin in the Treatment of Enuresis: Is Lyophilisate Superior to Tablets?] AB - Background: Prognosis of MNE is good when adequate treatment starts in a timely manner. First-line treatment for monosymptomatic nocturnal enuresis (MNE) includes desmopressin (Grade A/Level 1 recommendation from the ICI). Missing or insufficient response to pharmacological treatment can be caused by incomplete compliance, but might also be associated with differences in bioavailability from the tablet form. This prospective, non-interventional study was designed to compare desmopressin tablets to the newer ,,melt'' formulation, also known as lyophilisate or orally disintegrating tablet (ODT). The primary endpoint of this study was the patients'/parents' acceptance; the secondary end point was a decrease in the number of wet nights. Materials and Methods: Each of the scheduled 100 participating doctors had to recruit two MNE candidates, one for each treatment group, with a planned total of 200 participants. At the end of the treatment period, treatment satisfaction, difficulties in taking the medication, forgotten doses and treatment success were reported. Results: In total, 134 patients were included (49 on tablet and 84 on melt). Difficulties in taking the medication and forgotten doses were significantly less with the melt than with the tablet formulation. Treatment satisfaction was better with melt. After the 3 months study, the number of wet nights was considerably reduced in both groups. With lyophilisate, a statistically significant greater reduction in wet nights was recorded as early as 2 weeks after starting the treatment. Conclusion: Desmopressin as orally disintegrating tablets is an effective treatment and is associated with improved patient compliance. PMID- 28006832 TI - The Dual Edema-Preventing Molecular Mechanism of the Crataegus Extract WS 1442 Can Be Assigned to Distinct Phytochemical Fractions. AB - The hawthorn (Crataegus spp.) extract WS 1442 is used against mild forms of chronic heart failure. This disease is associated with endothelial barrier dysfunction and edema formation. We have recently shown that WS 1442 protects against this dysfunction by a dual mechanism: it both promotes endothelial barrier integrity by activation of a barrier-enhancing pathway (cortactin activation) and inhibits endothelial hyperpermeability by blocking a barrier disruptive pathway (calcium signaling). In this study, we aimed to identify the bioactive compounds responsible for these actions by using a bioactivity-guided fractionation approach. From the four fractions generated from WS 1442 by successive elution with water, 95 % ethanol, methanol, and 70 % acetone, only the water fraction was inactive, whereas the other three triggered a reduction of endothelial hyperpermeability. Analyses of intracellular calcium levels and cortactin phosphorylation were used as readouts to estimate the bioactivity of subfractions and isolated compounds. Interestingly, only the ethanolic fraction interfered with the calcium signaling, whereas only the methanolic fraction led to an activation of cortactin. Thus, the dual mode of action of WS 1442 could be clearly assigned to two distinct fractions. Although the identification of the calcium-active substance(s) was not successful, we could exclude an involvement of phenolic compounds. Cortactin activation, however, could be clearly attributed to oligomeric procyanidins with a distinct degree of polymerization. Taken together, our study provides the first approach to identify the active constituents of WS 1442 that address different cellular pathways leading to the inhibition of endothelial barrier dysfunction. PMID- 28006833 TI - Triterpenoids with Antiplatelet Aggregation Activity from the Roots of Ilex pubescens. AB - Two new triterpenes and five new triterpene saponins, named ilexpusons A-G (1-7), as well as eight known compounds were isolated from Ilex pubescens. The structures of the new compounds were established by a combination of chemical and spectroscopic methods, including HRESIMS, 1H-NMR, 13C-NMR, 1H-1H COSY, HSQC, HMBC, and NOESY. Additionally, the biological activity of compounds 1 - 15 against adenosine diphosphate-induced platelet aggregation in rabbit plasma was determined. Among the tested compounds, 1, 2, 5, 6, 8, 13, 14, and 15 exhibited significant inhibition of platelet aggregation in vitro. PMID- 28006834 TI - Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non-small-cell lung cancer patients with EGFR mutations. AB - This study was designed to examine the prediction of pretreatment circulating bilirubin and cholesterol for overall survival in 459 advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Circulating total bilirubin, direct bilirubin (DB), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured at baseline. The mean age (standard deviation) of all study patients was 58.7 (10.5) years, and 42.9% of them was males. Ever smokers accounted for 27.0% and lung adenocarcinoma for 90.4%. The median follow-up time and survival time were 29.5 and 34.9 months, respectively. Patients with higher DB had a 1.68-fold increased risk of death compared with patients with lower DB (hazard ratio [HR] = 1.68, 95% confidence interval [CI]: 1.22-2.30, p = 0.001), while patients with higher TC were at a 63% reduced risk of death compared with patients with lower TC (HR = 0.37, 95% CI: 0.20-0.67, p = 0.001). As for HDL-C, patients with higher levels had the risk of death reduced by 46% (HR = 0.54, 95% CI: 0.29-1.00, p = 0.049) compared with patients with lower levels. After the Bonferroni correction, only DB and TC were significantly associated with NSCLC survival. Our findings demonstrate for the first time that pretreatment DB was identified as a significant risk factor, yet TC as a protective factor, for overall survival in NSCLC patients with EGFR mutations. PMID- 28006835 TI - Cramp-fasciculation syndrome associated with monofocal motor neuropathy. AB - INTRODUCTION: Cramp-fasciculation syndrome is a peripheral nerve hyperexcitability disorder, which could be caused by inflammatory neuropathy. CASE REPORT: We describe a 51-year-old woman who presented with a 4- to 5-year history of fasciculations and painful cramping of the right thenar eminence. RESULTS: Electrophysiological studies showed motor conduction block in the right median nerve between the axilla and the elbow with fasciculation potentials and cramp discharges on electromyography in the right abductor pollicis brevis muscle. High titers of serum anti-GM1 immunoglobulin M antibodies were detected. CONCLUSIONS: Monofocal motor neuropathy of the right median nerve was diagnosed. Intravenous immunoglobulin treatment led to significant improvement of symptoms and signs. Although fasciculations and cramps have been reported in multifocal motor neuropathy and are considered supporting criteria for the diagnosis, the occurrence of cramp-fasciculation syndrome as the presenting feature and predominant manifestation in monofocal motor neuropathy, a variant of multifocal motor neuropathy, is unique. Muscle Nerve 56: 828-832, 2017. PMID- 28006836 TI - Consider leprosy as an etiology of sensory neuronopathy. PMID- 28006837 TI - Joint associations of smoking and television viewing time on cancer and cardiovascular disease mortality. AB - Excessive sitting time and smoking are pro-inflammatory lifestyle factors that are associated with both cancer and cardiovascular disease (CVD) mortality. However, their joint associations have not been investigated. We examined the associations of television (TV) viewing time with cancer and CVD mortality, according to smoking status, among 7,498 non-smokers (34% ex-smokers) and 1,409 current-smokers in the Australian Diabetes, Obesity and Lifestyle Study. During 117,506 person-years (median 13.6 years) of follow-up, there were 346 cancer and 209 CVD-related deaths. Including an interaction between TV time and smoking status in the model significantly improved the goodness of fit for cancer (p = 0.01) but not CVD mortality (p = 0.053). In the multivariate-adjusted model, every additional hr/d of TV time was associated with increased risk of cancer related (HR 1.23; 95% CI 1.08-1.40), but not CVD-related mortality (HR 1.16; 95% CI 0.97-1.38) in current-smokers. Elevated multivariate-adjusted cancer mortality HRs were observed for current-smokers watching 2 to <4 hr/d (HR 1.45; 95% CI 0.78 2.71) and >=4 hr/d (HR 2.26; 95% CI 1.10-4.64), compared to those watching <2 hr/d. Current-smokers watching 2 to <4 hr/d (HR 1.07; 95% CI 0.45-2.53) and >=4 hr/d (HR 1.92; 95% CI 0.76-4.84) did not have a significantly higher risk of CVD mortality, compared to <2 hr/d. No associations were observed for non-smokers. These findings show an association of TV, a common sedentary behavior, with cancer mortality in current-smokers. The association with CVD mortality was less clear. Further exploration in larger data sets is warranted. Limiting TV viewing time may be of benefit in reducing cancer mortality risk in current-smokers. PMID- 28006838 TI - Menopausal hormone therapy and the risk of esophageal and gastric cancer. AB - A protective effect of female sex hormones has been suggested to explain the male predominance in esophageal and gastric adenocarcinoma, but evidence is lacking. We aimed to test whether menopausal hormone therapy (MHT) decreases the risk of these tumors. For comparison, esophageal squamous cell carcinoma was also assessed. This population-based matched cohort study included all women who had ever used systemic MHT in Sweden in 2005-2012. A comparison cohort of non-users of MHT was matched to the MHT-users regarding age, parity, thrombotic events, hysterectomy, diabetes, obesity, smoking-related diseases and alcohol-related diseases. Individuals with any previous cancer were excluded. Data on MHT use, cancer, comorbidity and mortality were collected from well-established Swedish nationwide registers. Odds ratios (OR) with 95% confidence intervals (CI) were calculated using conditional logistic regression. Different MHT regimens and age groups were compared in sub-group analyses. We identified 290,186 ever-users and 870,165 non-users of MHT. Ever-users had decreased ORs of esophageal adenocarcinoma (OR = 0.62, 95% CI 0.45-0.85, n = 46), gastric adenocarcinoma (OR = 0.61, 95% CI 0.50-0.74, n = 123) and esophageal squamous cell carcinoma (OR = 0.57, 95% CI 0.39-0.83, n = 33). The ORs were decreased for both estrogen-only MHT and estrogen and progestin combined MHT, and in all age groups. The lowest OR was found for esophageal adenocarcinoma in MHT-users younger than 60 years (OR = 0.20, 95% CI 0.06-0.65). Our study suggests that MHT-users are at a decreased risk of esophageal and gastric adenocarcinoma and also of esophageal squamous cell carcinoma. The mechanisms behind these associations remain to be elucidated. PMID- 28006839 TI - High IKKalpha expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer. AB - The aim of our study was to examine the relationship between tumour IKKalpha expression and breast cancer recurrence and survival. Immunohistochemistry was employed in a discovery and a validation tissue microarray to assess the association of tumour IKKalpha expression and clinico-pathological characteristics. After siRNA-mediated silencing of IKKalpha, cell viability and apoptosis were assessed in MCF7 and MDA-MB-231 breast cancer cells. In both the discovery and validation cohorts, associations observed between IKKalpha and clinical outcome measures were potentiated in oestrogen receptor (ER) positive Luminal A tumours. In the discovery cohort, cytoplasmic IKKalpha was associated with disease-free survival (p = 0.029) and recurrence-free survival on tamoxifen (p < 0.001) in Luminal A tumours. Nuclear IKKalpha and a combination of cytoplasmic and nuclear IKKalpha (total tumour cell IKKalpha) were associated with cancer-specific survival (p = 0.012 and p = 0.007, respectively) and recurrence-free survival on tamoxifen (p = 0.013 and p < 0.001, respectively) in Luminal A tumours. In the validation cohort, cytoplasmic IKKalpha was associated with cancer-specific survival (p = 0.023), disease-free survival (p = 0.002) and recurrence-free survival on tamoxifen (p = 0.009) in Luminal A tumours. Parallel experiment with breast cancer cells in vitro demonstrated the non-canonical NF kappaB pathway was inducible by exposure to lymphotoxin in ER-positive MCF7 cells and not in ER-negative MDA-MB-231 cells. Reduction in IKKalpha expression by siRNA transfection increased levels of apoptosis and reduced cell viability in MCF7 but not in MDA-MB-231 cells. IKKalpha is an important determinant of poor outcome in patients with ER-positive invasive ductal breast cancer and thus may represent a potential therapeutic target. PMID- 28006841 TI - Functional and structural microanatomy of the fetal sciatic nerve. AB - INTRODUCTION: The ultrastructure of a nerve has implications for surgical nerve repair. The aim of our study was to characterize the fascicular versus fibrillar anatomy and the autonomic versus somatic nature of the fetal sciatic nerve (SN). METHODS: Immunohistochemistry for vesicular acetylcholine transporter, tyrosine hydroxylase, and peripheral myelin protein 22 was performed to identify cholinergic, adrenergic, and somatic axons, respectively, in the human fetal SN. Two-dimensional (2D) analysis and 3D reconstructions were performed. RESULTS: The fetal SN is composed of one-third stromal tissue and two-thirds neural tissue. Autonomic fibers are predominant over somatic fibers within the neural tissue. The distribution of somatic fibers is initially random, but then become topographically organized after intra- and interfascicular rearrangements have occurred within the nerve. CONCLUSIONS: The fetal model presents limitations but enables illustration of the nature of the nerve fibers and the 3D fascicular anatomy of the SN. Muscle Nerve 56: 787-796, 2017. PMID- 28006840 TI - Copy number variations in DCC/18q and ERBB2/17q are associated with disease-free survival in microsatellite stable colon cancer. AB - We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in Stage II-III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ERBB2/17q and STK6/20q, were detected using a quantitative multiplex polymerase chain reaction of short fluorescent fragment (QMPSF) method. The primary end point was the impact of the CNVs on the 4-year disease-free survival (DFS). The recurrence rate at 4 years was 20.9%, corresponding to 14% Stage II patients versus 31% Stage III patients (p < 0.0001). The 4-year DFS was significantly decreased in patients with a loss at DCC/18q (p = 0.012) and a gain at ERBB2/17q (p = 0.041). The multivariate analysis demonstrated that Stage III, a loss at DCC/18q and a gain at ERBB2/17q were independent factors associated with DFS. A combination of DCC/18q and ERBB2/17q was also associated with relapse, with the hazard ratio increasing from 1 to 2.4 (95% confidence interval (CI), 1.5-4.1) and 3.1 (95% CI, 1.2-8.4) in the presence of 0, 1 or 2 alterations, respectively (p = 0.0013). CNVs in DCC/18q and ERBB2/17q are significantly associated with DFS in Stage II-III MSS colon cancer. PMID- 28006842 TI - Type-specific HPV infection correlates with risk of recurrence of vulvar intraepithelial neoplasia usual type. PMID- 28006843 TI - Identification and prediction of health-related quality of life trajectories after a prostate cancer diagnosis. AB - The aim of our study was to identify physical and mental health-related quality of life (HRQoL) trajectories after a prostate cancer diagnosis and systematically characterize trajectories by behaviours and prognostic factors. Prostate cancer survivors (n = 817) diagnosed between 1997 and 2000 were recruited between 2000 and 2002 into a prospective repeated measurements study. Behavioural/prognostic data were collected through in-person interviews and questionnaires. HRQoL was collected at three post-diagnosis time-points, approximately 2 years apart using the Short Form (SF)-36 validated questionnaire. To identify physical and mental HRQoL trajectories, group-based trajectory modelling was undertaken. Differences between groups were evaluated by assessing influential dropouts (mortality/poor health), behavioural/prognostic factors at diagnosis or during the follow-up. Three trajectories of physical HRQoL were identified including: average maintaining HRQoL (32.2%), low-declining HRQoL (40.5%) and very low-maintaining HRQoL (27.3%). In addition, three trajectories for mental HRQoL were identified: average-increasing HRQoL (66.5%), above average-declining HRQoL (19.7%) and low increasing HRQoL (13.8%). In both physical and mental HRQoL, dropout from mortality/poor health differed between trajectories, thus confirming HRQoL and mortality were related. Furthermore, increased Charlson comorbidity index score was consistently associated with physical and mental HRQoL group membership relative to average maintaining groups, while behaviours such as time-varying physical activity was associated with physical HRQoL trajectories but not mental HRQoL trajectories. It was possible to define three trajectories of physical and mental HRQoL after prostate cancer. These data provide insights regarding means for identifying subgroups of prostate cancer survivors with lower or declining HRQoL after diagnosis whom could be targeted for interventions aimed at improving HRQoL. PMID- 28006844 TI - The thoracic outlet syndromes: Part 1. Overview of the thoracic outlet syndromes and review of true neurogenic thoracic outlet syndrome. AB - The thoracic outlet syndromes (TOSs) are a group of etiologically and clinically distinct disorders with 1 feature in common: compression of 1 or more neurovascular elements as they traverse the thoracic outlet. The medical literature reflects 5 TOSs: arterial; venous; traumatic neurovascular; true neurogenic; and disputed. Of these, the first 4 demonstrate all of the features expected of a syndrome, whereas disputed TOS does not, causing many experts to doubt its existence altogether. Thus, some categorize disputed TOS as a cervicoscapular pain syndrome rather than as a type of TOS. To better understand these disorders, their distinctions, and the reasoning underlying the categorical change of disputed TOS from a form of TOS to a cervicoscapular pain syndrome, a thorough understanding of the pertinent anatomy, pathology, pathophysiology, and the electrodiagnostic manifestations of their pathophysiologies is required. This review of the TOSs is provided in 2 parts. In this first part we address information pertinent to all 5 TOSs and reviews true neurogenic TOS. In part 2 we review the other 4 TOSs. Muscle Nerve 55: 782-793, 2017. PMID- 28006845 TI - Howell-Jolly bodies in acute hemolytic anemia. PMID- 28006846 TI - Myelolipoma among patients with thalassemia major and rare anemia with iron loading: A not so rare entity. PMID- 28006849 TI - Increased healthcare use up to 10 years among relapse-free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy. AB - With today's excellent cure rates for Hodgkin lymphoma (HL), the number of long term survivors is increasing. This study aims to provide a global assessment of late adverse effects for working-age HL survivors treated with contemporary protocols (combination chemotherapy and limited radiotherapy). From Swedish nationwide registers we identified 1017 HL survivors diagnosed in 2000-2009, aged 18-60 years (median 32) and surviving at least one year post-diagnosis, and 4031 age-, sex-, and calendar-year-matched population comparators. Incidence rate ratios (IRR) and 95% confidence intervals (95%CI) for outpatient visits and inpatient bed-days after the first year up to 14 years post-diagnosis (through 2013) were estimated across treatment subgroups, considering relapse-free time and using negative binomial regression. Scheduled outpatient visits for HL were excluded. The rate of outpatient visits was nearly double (IRR = 1.8, 95%CI: 1.6 2.0) that among comparators and higher rates persisted up to 10 years post diagnosis. The rate of inpatient bed-days among relapse-free survivors was more than three-fold (IRR = 3.6, 95%CI: 2.7-4.7) that of comparators and the increase persisted up to four years post-diagnosis. Patients requiring 6-8 chemotherapy courses had higher rates of outpatient visits (IRR = 1.4, 95%CI: 1.1-1.7) and bed days (IRR = 4.7, 95%CI: 2.9-7.8) than patients treated with 2-4 courses + radiotherapy. Previously seldom reported reasons for the excess healthcare use included chest pain, keratitis, asthma, diabetes mellitus, and depression. Contemporary treatment, chemotherapy in particular, was associated with excess healthcare use among HL survivors during the first decade postdiagnosis. The reasons for healthcare visits reflected a wide range of disorders, indicating the need of broad individualized care in addition to specific screening programs. PMID- 28006848 TI - Global methylation of blood leukocyte DNA and risk of melanoma. AB - Global DNA methylation, possibly influenced by lifestyle and environmental factors, has been suggested to play an active role in carcinogenesis. However, its role in melanoma has rarely been explored. The aims of this study were to evaluate the relationship between melanoma risk and levels of 5-methylcytosine (5 mC), a marker for global DNA methylation, in blood leukocyte DNA, and to determine whether this 5-mC level is influenced by pigmentation and sun exposure. This case-control study included 540 melanoma cases and 540 healthy controls. Overall, melanoma cases had significantly lower levels of 5-mC% than healthy controls (median: 3.24 vs. 3.91, p < 0.001). The significant difference between two groups did not differ by pigmentation or sun exposure. Among healthy controls, however, those who had fair skin color (p = 0.041) or light or no tanning after prolonged sun exposure (p = 0.031) or used a sunlamp (p = 0.028) had lower levels of 5-mC% than their counterparts. In addition, those with an intermediate or high phenotypic index, an indicator of cutaneous cancer susceptibility, had 2.58-fold greater likelihood of having a low level of 5-mC% [odds ratio (OR): 2.58; 95% confidence interval (CI): 1.72, 3.96] than those with a low phenotypic index. Lower levels of 5-mC% were associated with a 1.25-fold greater risk of melanoma (OR: 1.25; 95% CI: 1.08, 1.37). A significant dose response relationship was observed in quartile analysis (p = 0.001). Our results suggest that global hypomethylation in blood leukocyte DNA is associated with increased risk of melanoma and that the level of methylation is influenced by pigmentation and sun exposure. PMID- 28006847 TI - Dietary flavonoid intake and colorectal cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort. AB - Flavonoids have been shown to inhibit colon cancer cell proliferation in vitro and protect against colorectal carcinogenesis in animal models. However, epidemiological evidence on the potential role of flavonoid intake in colorectal cancer (CRC) development remains sparse and inconsistent. We evaluated the association between dietary intakes of total flavonoids and their subclasses and risk of development of CRC, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cohort of 477,312 adult men and women were recruited in 10 European countries. At baseline, dietary intakes of total flavonoids and individual subclasses were estimated using centre-specific validated dietary questionnaires and composition data from the Phenol-Explorer database. During an average of 11 years of follow-up, 4,517 new cases of primary CRC were identified, of which 2,869 were colon (proximal = 1,298 and distal = 1,266) and 1,648 rectal tumours. No association was found between total flavonoid intake and the risk of overall CRC (HR for comparison of extreme quintiles 1.05, 95% CI 0.93-1.18; p-trend = 0.58) or any CRC subtype. No association was also observed with any intake of individual flavonoid subclasses. Similar results were observed for flavonoid intake expressed as glycosides or aglycone equivalents. Intake of total flavonoids and flavonoid subclasses, as estimated from dietary questionnaires, did not show any association with risk of CRC development. PMID- 28006850 TI - Bone marrow cellularity at day 14 is the most important predictive factor for response in patients with AML who require double-induction chemotherapy: Analysis from a large, single institution experience. AB - In patients with acute myeloid leukemia (AML), the presence of residual disease at day 14 after primary induction therapy warrants consideration of a second induction cycle. However, data to guide retreatment decisions in such patients are presently limited. Here, we retrospectively reviewed data from 176 patients with AML treated at our institution with a second induction chemotherapy regimen because of day 14 residual disease. Clinical variables and nadir bone marrow features were assessed for correlations with complete remission (CR) and overall survival (OS). In our patient group, 59% achieved CR after a second induction course. Median OS for the entire group was 12.40 months (95% CI, 9.90-14.90) but 19.07 months (95% CI, 13.13-25.01) for those who attained a CR. Nadir marrow hypocellularity (P < 0.001) at day 14, absolute blast reduction of >50% (P = 0.030), and de novo disease status (P = 0.018) were significantly correlated with CR achievement after re-induction. Marrow hypocellularity at day 14 was the most significant predictor of CR on multivariate analysis (P < 0.001). Nadir marrow features did not independently correlate with OS when accounting for CR status. Re-induction was successful in achieving CR in most patients. Study patients who did not achieve CR were more likely to have nonhypocellular marrows. PMID- 28006852 TI - Heavier and lighter load resistance training to momentary failure produce similar increases in strength with differing degrees of discomfort. AB - INTRODUCTION: It has been suggested that disparities in effort and discomfort between high- and low-load resistance training might exist, which in turn have produced unequivocal adaptations between studies. METHODS: Strength responses to heavier load (HL; 80% maximum voluntary isometric torque; MVIT) and lighter load (LL; 50% MVIT) resistance training were examined in addition to acute perceptions of effort and discomfort. Seven men (20.6 +/- 0.5 years, 178.9 +/- 3.2 cm, 77.1 +/- 2.7 kg) performed unilateral resistance training of the knee extensors to momentary failure using HL and LL. RESULTS: Analyses revealed significant pre- to post-intervention increases in strength for both HL and LL, with no significant between-group differences (P > 0.05). Mean repetitions per set, total training time, and discomfort were all significantly higher for LL compared with HL (P < 0.05). CONCLUSION: This study indicates that resistance training with HL and LL produces similar strength adaptations, but discomfort should be considered before selecting a training load. Muscle Nerve 56: 797-803, 2017. PMID- 28006851 TI - Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor. AB - In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5 year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI. PMID- 28006853 TI - Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013. AB - Burkitt's Lymphoma (BL) has three peaks of occurrence, in children, adults and elderly, at 10, 40 and 70 years respectively. To the best of our knowledge, no study has been conducted to assess predictors of survival in the three age groups. We hypothesized that survival predictors may differ by age group. We, therefore, sought to determine survival predictors for BL in these three groups: children (<15 years of age), adults (40-70 years of age) and elderly (>70 years of age). Using the Surveillance, Epidemiology, and End Results (SEER) database covering the years 2000-2013, we identified 797 children, 1,994 adults and 757 elderly patients newly diagnosed with BL. We used adjusted Cox proportional hazards regression models to determine prognostic factors for survival for each age group. Five-year relative survival in BL for children, adults and elderly were 90.4, 47.8 and 28.9%, respectively. Having at least Stage II disease and multiple primaries were associated with higher mortality in the elderly group. In adults, multiple primaries, Stage III or IV disease, African American race and bone marrow primary were associated with increased mortality whereas Stage IV disease and multiple primaries were associated with worse outcome in children. These findings demonstrate commonalities and differences in predictors of survival that may have implications for management of BL patients. PMID- 28006854 TI - Quantification of human upper extremity nerves and fascicular anatomy. AB - INTRODUCTION: In this study we provide detailed quantification of upper extremity nerve and fascicular anatomy. The purpose is to provide values and trends in neural features useful for clinical applications and neural interface device design. METHODS: Nerve cross-sections were taken from 4 ulnar, 4 median, and 3 radial nerves from 5 arms of 3 human cadavers. Quantified nerve features included cross-sectional area, minor diameter, and major diameter. Fascicular features analyzed included count, perimeter, area, and position. RESULTS: Mean fascicular diameters were 0.57 +/- 0.39, 0.6 +/- 0.3, 0.5 +/- 0.26 mm in the upper arm and 0.38 +/- 0.18, 0.47 +/- 0.18, 0.4 +/- 0.27 mm in the forearm of ulnar, median, and radial nerves, respectively. Mean fascicular diameters were inversely proportional to fascicle count. CONCLUSION: Detailed quantitative anatomy of upper extremity nerves is a resource for design of neural electrodes, guidance in extraneural procedures, and improved neurosurgical planning. Muscle Nerve 56: 463 471, 2017. PMID- 28006855 TI - Lenalidomide and low-dose dexamethasone (Rd) versus bortezomib, melphalan, prednisone (VMP) in elderly newly diagnosed multiple myeloma patients: A comparison of two prospective trials. AB - There are currently no direct head-to-head clinical trials evaluating bortezomib melphalan-prednisone (VMP) versus lenalidomide and low-dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively, and were investigated according to treatments administered over a 60-months follow-up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow-up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd-treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long-term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice. PMID- 28006856 TI - The thoracic outlet syndromes: Part 2. The arterial, venous, neurovascular, and disputed thoracic outlet syndromes. AB - The thoracic outlet syndromes (TOSs) are a group of etiologically and clinically distinct disorders with 1 feature in common: compression of 1 or more neurovascular elements as they traverse the thoracic outlet. The medical literature reflects 5 TOSs: arterial; venous; traumatic neurovascular; true neurogenic; and disputed. Of these, the first 4 demonstrate all of the features expected of a syndrome, whereas disputed TOS does not, causing many experts to doubt its existence altogether. Thus, some categorize disputed TOSs as cervicoscapular pain syndrome rather than as a type of TOS. To better understand these disorders, their distinctions, and the reasoning underlying the categorical change of disputed TOS from a form of TOS to a cervicoscapular pain syndrome, a thorough understanding of the pertinent anatomy, pathology, pathophysiology, and electrodiagnostic manifestations of these pathophysiologies is required. This review of the TOSs is provided in 2 parts. In part 1 we covered general information pertinent to all 5 TOSs and reviewed true neurogenic TOS in detail. In part 2, we review the arterial, venous, traumatic neurovascular, and disputed forms of TOS. Muscle Nerve 56: 663-673, 2017. PMID- 28006858 TI - Eurogin 2016 Roadmap: how HPV knowledge is changing screening practice. AB - Human papillomaviruses (HPVs) are the necessary cause of most cervical cancers, a large proportion of other anogenital cancers, and a subset of oropharyngeal cancers. The knowledge about HPV has led to development of novel HPV-based prevention strategies with important impact on clinical and public health practice. Two complementary reviews have been prepared following the 2015 Eurogin Conference to evaluate how knowledge about HPV is changing practice in HPV infection and disease control through vaccination and screening. This review focuses on screening for cervical and anal cancers in increasingly vaccinated populations. The introduction of HPV vaccines a decade ago has led to reductions in HPV infections and early cancer precursors in countries with wide vaccination coverage. Despite the high efficacy of HPV vaccines, cervical cancer screening will remain important for many decades. Many healthcare systems are considering switching to primary HPV screening, which has higher sensitivity for cervical precancers and allows extending screening intervals. We describe different approaches to implementing HPV-based screening efforts in different healthcare systems with a focus in high-income countries. While the population prevalence for other anogenital cancers is too low for population-based screening, anal cancer incidence is very high in HIV-infected men who have sex with men, warranting consideration of early detection approaches. We summarize the current evidence on HPV-based prevention of anal cancers and highlight important evidence gaps. PMID- 28006857 TI - Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV-associated head and neck squamous cell carcinoma cell lines. AB - Recent studies showed that human papillomavirus (HPV) integration contributes to the genomic instability seen in HPV-associated head and neck squamous cell carcinoma (HPV-HNSCC). However, the epigenetic alterations induced after HPV integration remains unclear. To identify the molecular details of HPV16 DNA integration and the ensuing patterns of methylation in HNSCC, we performed next generation sequencing using a target-enrichment method for the effective identification of HPV16 integration breakpoints as well as the characterization of genomic sequences adjacent to HPV16 integration breakpoints with three HPV16 related HNSCC cell lines. The DNA methylation levels of the integrated HPV16 genome and that of the adjacent human genome were also analyzed by bisulfite pyrosequencing. We found various integration loci, including novel integration sites. Integration loci were located predominantly in the intergenic region, with a significant enrichment of the microhomologous sequences between the human and HPV16 genomes at the integration breakpoints. Furthermore, various levels of methylation within both the human genome and the integrated HPV genome at the integration breakpoints in each integrant were observed. Allele-specific methylation analysis suggested that the HPV16 integrants remained hypomethylated when the flanking host genome was hypomethylated. After integration into highly methylated human genome regions, however, the HPV16 DNA became methylated. In conclusion, we found novel integration sites and methylation patterns in HPV HNSCC using our unique method. These findings may provide insights into understanding of viral integration mechanism and virus-associated carcinogenesis of HPV-HNSCC. PMID- 28006859 TI - Pure erythroid leukemia. AB - The category of acute erythroid leukemia was significantly revised in the recently published 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms. In the previous 2008 WHO classification, acute erythroid leukemia was categorized into two subtypes: erythroleukemia and pure erythroid leukemia (PEL), whereas in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL becomes the only type of acute erythroid leukemia. PEL is a rare and aggressive form of acute leukemia whose biology remains poorly characterized. In this review, we discuss the clinicopathologic features, diagnosis, putative pathogenesis, and molecular biology of PEL, with an overview of novel concepts and future directions in this area. PMID- 28006860 TI - Paraneoplastic cerebellar degeneration and lambert-eaton myasthenia in a patient with merkel cell carcinoma and voltage-gated calcium channel antibodies. AB - INTRODUCTION: Merkel cell carcinoma is a rare cutaneous, aggressive tumor. Although it shares many neuroendocrine features with small cell lung carcinoma, it has only occasionally been reported with paraneoplastic neurological syndromes. METHODS: A healthy 67-year-old man developed acute ataxia, vertigo, and nausea. Subsequently he also developed dysarthria, diplopia, xerostomia, fatigability and progressive anorexia. He underwent a full diagnostic workup and was found to have a high titer of voltage-gated calcium channel antibodies in serum and cerebrospinal fluid, neurophysiological findings compatible with Lambert-Eaton myasthenia and neurological signs compatible with cerebellar degeneration. RESULTS: A positron emission tomography study revealed a hypermetabolic lesion in the axilla, subsequently biopsied and consistent with Merkel cell carcinoma. CONCLUSIONS: In most previous reports, neurological symptoms preceded the Merkel cell carcinoma diagnosis, and the primary localization was in lymph nodes. This tumor should be considered in patients with paraneoplastic syndrome, and particularly Lambert-Eaton myasthenia after exclusion of small cell lung carcinoma. Muscle Nerve 56: 998-1000, 2017. PMID- 28006862 TI - Neuromuscular ultrasound for evaluation of scapular winging. AB - INTRODUCTION: Clinicians who treat nerve and muscle disorders may be asked to evaluate patients who have unilateral or bilateral scapular winging. Traditionally, this evaluation has relied upon a thorough history, physical examination, and electrodiagnostic testing to localize the cause of winging and detect the underlying neuromuscular pathology. Neuromuscular ultrasound has emerged as a non-invasive technique that can be used for structural evaluation of nerve and muscle abnormalities. METHODS: Previous studies of imaging in scapular winging and experiences from our diagnostic laboratory are reviewed. RESULTS: Four standard and 4 ancillary ultrasound views are described for evaluation of scapular winging. CONCLUSION: Ultrasound is a non-invasive, painless, and radiation-free technology that can be used to evaluate scapular winging. Muscle Nerve 56: 7-14, 2017. PMID- 28006863 TI - Concordant and discordant familial cancer: Familial risks, proportions and population impact. AB - Relatives of cancer patients are at an increased risk of the same (concordant) cancer but whether they are at a risk for different (discordant) cancers is largely unknown - beyond well characterized hereditary cancer syndromes - but would be of major scientific and clinical interest. We therefore decided to resolve the issue by analyzing familial risks when family members were diagnosed with any discordant cancers. We compared the population impact of concordant to discordant familial cancer. The Swedish Family-Cancer Database (FCD) was used to calculate familial relative risks (RRs) for family members of cancer patients, for the 27 most common cancers. Population attributable fractions (PAFs) were estimated for concordant and discordant family histories. Discordant cancers in the family were detected as significant risk factors for the majority of cancers, although the corresponding RRs were modest compared to RRs for concordant cancers. Risks increased with the number of affected family members with the highest RRs for pancreatic (2.31), lung (1.69), kidney (1.98), nervous system (1.79) and thyroid cancers (3.28), when 5 or more family members were diagnosed with discordant cancers. For most cancers, the PAF for discordant family history exceeded that for concordant family history. Our findings suggest that there is an unspecific genetic predisposition to cancer with clinical consequences. We consider it unlikely that shared environmental risk factors could essentially contribute to the risks for diverse discordant cancers, which are likely driven by genetic predisposition. The identification of genes that moderately increase the risk for many cancers will be a challenge. PMID- 28006864 TI - Is thyrotoxic periodic paralysis a disease caused by muscle membrane dysfunction? AB - INTRODUCTION: Thyrotoxic periodic paralysis (TPP) is characterized by recurrent episodes of reversible paralysis with hyperthyroidism. It is clinically similar to hypokalemic periodic paralysis (HOPP), which features significant ion-channel dysfunction and reduced muscle fiber conduction velocity (MFCV). However, the muscle membrane function in TPP is not known. METHODS: For 13 patients with TPP and 15 age-matched controls, clinical assessment and serial neurophysiological testing, including nerve conduction, prolonged exercise (PE) testing, and MFCV. were performed. RESULTS: MFCV values were elevated up to 1 year from the paralytic attack in TPP patients. In the group with a positive PE test, MFCV values were higher. There was no significant relationship between MFCV values and either hypokalemia or hyperthyroidism. CONCLUSIONS: Although clinical manifestations in TPP are similar to those observed in HOPP, TPP appears to feature an alternate pathogenic mechanism. Specifically, MFCV values increased rather than decreased. Further studies are needed to support these findings. Muscle Nerve, 2016 Muscle Nerve 56: 780-786, 2017. PMID- 28006865 TI - Current status of auxiliary partial orthotopic liver transplantation for acute liver failure. PMID- 28006861 TI - Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts. AB - Several studies have indicated weakly increased risk for kidney cancer among occupational groups exposed to gasoline vapors, engine exhaust, polycyclic aromatic hydrocarbons and other air pollutants, although not consistently. It was the aim to investigate possible associations between outdoor air pollution at the residence and the incidence of kidney parenchyma cancer in the general population. We used data from 14 European cohorts from the ESCAPE study. We geocoded and assessed air pollution concentrations at baseline addresses by land use regression models for particulate matter (PM10 , PM2.5 , PMcoarse , PM2.5 absorbance (soot)) and nitrogen oxides (NO2 , NOx ), and collected data on traffic. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses to calculate summary hazard ratios (HRs). The 289,002 cohort members contributed 4,111,908 person-years at risk. During follow-up (mean 14.2 years) 697 incident cancers of the kidney parenchyma were diagnosed. The meta-analyses showed higher HRs in association with higher PM concentration, e.g. HR = 1.57 (95%CI: 0.81 3.01) per 5 MUg/m3 PM2.5 and HR = 1.36 (95%CI: 0.84-2.19) per 10-5 m-1 PM2.5 absorbance, albeit never statistically significant. The HRs in association with nitrogen oxides and traffic density on the nearest street were slightly above one. Sensitivity analyses among participants who did not change residence during follow-up showed stronger associations, but none were statistically significant. Our study provides suggestive evidence that exposure to outdoor PM at the residence may be associated with higher risk for kidney parenchyma cancer; the results should be interpreted cautiously as associations may be due to chance. PMID- 28006866 TI - Liver splitting during normothermic organ preservation. PMID- 28006867 TI - Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients. AB - Regulatory T cells (Tregs) play a potential role in operational tolerance in liver transplantation (LT) patients, and microRNAs (miRNAs) are known to be involved in immunological responses and tolerance. Thus, we analyzed the implication of different peripheral blood Treg subsets and miRNAs on LT tolerance in 24 tolerant (Tol) and 23 non-tolerant (non-Tol) LT recipients by cellular, genetic, and epigenetic approximation. Non-Tol patients had a lower demethylation rate of the forkhead box P3 (FOXP3) regulatory T cell-specific demethylated region (TSDR) than Tol patients that correlated with the frequency of circulating Tregs. Tol patients presented a different signature of Treg subset markers compared with non-Tol patients with increased expression of HELIOS and FOXP3 and a higher proportion of latency-associated peptide (LAP)+ Tregs and CD45RA- human leukocyte antigen D related (HLA-DR)+ activated effector-memory Tregs. The expression of miR95, miR24, miR31, miR146a, and miR155 was higher in Tol than in non-Tol patients and was positively correlated with activated Treg markers. In conclusion, these data suggest that activated effector-memory Tregs and a TSDR demethylation state of Tregs may play a role in the complex system of regulation of LT tolerance. In addition, we describe a set of miRNAs differentially expressed in human LT Tol patients providing suggestive evidence that miRNAs are implied in the preservation of self-tolerance as mediated by Tregs. Liver Transplantation 23 933-945 2017 AASLD. PMID- 28006868 TI - Impact of emergency adult living donor liver transplantation on the survival of patients with antituberculosis therapy-induced acute liver failure. PMID- 28006869 TI - Living liver donation, donor safety, and social media: Preparing for a new frontier. PMID- 28006870 TI - Transplant-related survival benefit should influence prioritization for liver transplantation especially in patients with hepatocellular carcinoma. AB - Transplant-related survival benefit is calculated as the difference between life expectancy with transplantation and life expectancy without transplantation. Determining eligibility and prioritization for liver transplantation based on the highest survival benefit is a superior strategy to prioritization based on the highest urgency (ie, the highest wait-list mortality) or the highest utility (ie, the highest posttransplant survival) because prioritization based on the highest survival benefit maximizes the overall life expectancy of all patients in need of liver transplantation. Although the Model for End-Stage Liver Disease (MELD) based prioritization system was designed as an urgency-based system, in practice it functions to a large extent as a survival benefit-based system, when the natural MELD score is used without exceptions. Survival benefit considerations should be used to determine the consequences of deviating from prioritization based on the natural MELD score, such as when exception points are awarded to patients with hepatocellular carcinoma (HCC) that are independent of MELD score or tumor burden, or the appropriateness of expanding eligibility for transplantation. The most promising application of survival benefit-based prioritization would be to replace the current system of prioritization of patients with HCC by one that uses their natural MELD score and tumor characteristics such as HCC tumor burden, serum alpha fetoprotein level, and response to locoregional therapies to predict the impact on survival benefit caused by the presence of HCC and adjust the natural MELD score for prioritization accordingly. Liver Transplantation 23 652-662, 2017 AASLD. PMID- 28006871 TI - Budd-chiari syndrome and acute liver failure: A complex condition requiring a rapid response. PMID- 28006872 TI - Management of biliary anastomotic strictures after liver transplantation (BASALT study): A nationwide Italian survey. PMID- 28006873 TI - Can response to locoregional therapy help predict longterm survival after liver transplantation for hepatocellular carcinoma? A systematic review. AB - For a selected group of patients with hepatocellular carcinoma (HCC), liver transplantation (LT) represents the best chance of a cure. Organ shortages necessitate an efficient allocation of resources and careful prioritization on the transplantation waiting list. In this review, we aim to collate and evaluate the published evidence for using response to locoregional therapies (LRTs), measured by modified Response Evaluation Criteria in Solid Tumors (mRECIST), as a predictor of longterm survival after LT. Our aim was to assess whether response to LRTs before LT for HCC, as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) or mRECIST criteria, can help predict recurrence-free and/or longterm survival outcomes. We searched MEDLINE, Embase, and the Cochrane database. We included randomized controlled trials (RCTs), cohort, case control, and case series studies. Poster and conference abstracts were included. Studies were required to use RECIST or mRECIST criteria when assessing tumor response and were limited to LT for HCC only. A total of 15 records were included in the final systematic review: 7 published manuscripts and 8 conference abstracts. No RCTs were identified. Several included articles were conference abstracts with limited data available. No RCTs were found, and no meta-analysis was undertaken. Several retrospective cohort studies were identified that demonstrated statistically significant differences in survival and recurrence between different RECIST criteria after LT. Liver Transplantation 23 375-385 2017 AASLD. PMID- 28006874 TI - Sofosbuvir/ledipasvir and ribavirin tolerability and efficacy in pediatric liver transplant recipients. PMID- 28006875 TI - Neutrophil-to-lymphocyte ratio correlates with proinflammatory neutrophils and predicts death in low model for end-stage liver disease patients with cirrhosis. AB - The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD <= 20. Neutrophil-to lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (>=4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD <= 20 within 90 days of death. Controls were similar LT candidates who were alive for >=90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was >= 4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous >= 1.9, >= 4, >= 6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of >=1.9, >= 4, >= 6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD. Liver Transplantation 23 155-165 2017 AASLD. PMID- 28006877 TI - The first 25 years of Acta Dermatovenerologica Alpina, Pannonica et Adriatica. PMID- 28006876 TI - Health-related quality of life after pediatric liver transplantation: A systematic review. AB - With improved survival rates after pediatric liver transplantation (LT), attention is targeting improving the health-related quality of life (HRQOL) as an outcome metric. We conducted a systematic review of the literature to examine HRQOL after pediatric LT, focusing on assessment tools and factors associated with HRQOL. A literature search was conducted through PubMed, Web of Science, Ovid, and Google Scholar for all studies matching the eligibility criteria between January 2004 and September 2016. Titles and abstracts were screened independently by 2 authors and consensus for included studies was achieved through discussion. A total of 25 (2 longitudinal, 23 cross-sectional) studies were reviewed. HRQOL in pediatric LT recipients is lower than healthy controls, but it is comparable to children with chronic diseases or other pediatric solid organ transplant recipients. Domain scores were lowest in school functioning on the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale 4.0 and general health perception on the Child Health Questionnaire, the 2 most commonly used generic HRQOL instruments. Identified predictors of poor HRQOL include sleep disturbances, medication adherence, and older age at transplantation. Two recently validated disease-specific HRQOL tools, Pediatric Liver Transplant Quality of Life tool and the Pediatric Quality of Life Inventory 3.0 Transplant Module, have enabled enhanced representation of patient HRQOL, when used in conjugation with generic tools. Heterogeneity in study design and instruments prevented a quantitative, meta-analysis of the data. In conclusion, continued optimization of durable outcomes for this population mandates prioritization of research focusing on the gap of targeted intervention studies aimed at specific HRQOL subdomains and longitudinal studies to predict the trajectory of HRQOL over time. Liver Transplantation 23 361-374 2017 AASLD. PMID- 28006878 TI - Development of a novel multiplex type-specific quantitative real-time PCR for detection and differentiation of infections with human papillomavirus types HPV2, HPV27, and HPV57. AB - INTRODUCTION: The present study describes the development and evaluation of the first multiplex type-specific quantitative real-time PCR (RT-PCR), enabling simple, rapid, sensitive, and specific concurrent detection and differentiation of human papillomavirus (HPV) types HPV2, 27, and 57 in a single PCR reaction. RESULTS: The HPV2/27/57 multiplex RT-PCR with a dynamic range of seven orders of magnitude (discriminating 10 to 108 viral genome equivalents/reaction) has an analytical sensitivity of at least 10 viral copies of each targeted HPV type/reaction, and no cross-reactivities were observed among the included targets. All three primer/probe combinations were efficient in amplifying 500 copies of targeted DNA in a background of 108, 107, 500, 100, and 10 copies of non-targeted viral DNA/reaction, and the performance of the HPV2/27/57 multiplex RT-PCR was additionally not affected by the presence of background human genomic DNA. When testing DNA isolates obtained from fresh-frozen tissue specimens of various children's warts, the results of the HPV2/27/57 multiplex RT-PCR were completely in line with the results of the conventional Low-risk Alpha-PV PCR. CONCLUSION: The newly developed HPV2/27/57 multiplex RT-PCR is an appropriate test for use in routine clinical laboratory settings and for studies focusing on the molecular epidemiology, pathogenesis, and natural history of HPV2/27/57 related lesions. PMID- 28006879 TI - Microbiological characteristics of perianal streptococcal dermatitis: a retrospective study of 105 patients in a 10-year period. AB - Beta-hemolytic streptococci (BHS) are the most common causative agents of perianal streptococcal dermatitis (PSD). This study evaluates the distribution of BHS isolates in perianal bacterial cultures. We retrospectively reviewed microbiological results for perianal BHS that were isolated in our laboratory between 2006 and 2015. We identified a total of 105 BHS isolates from rectal swabs and swabs of clinically intact perianal skin. The majority of BHS were of group A (GABHS) (73/105; 69.5%), followed by group B BHS (GBBHS) (27/105; 25.7%), and non-group A or B BHS (5/105; 4.8%). The distribution of GABHS was age specific, with the majority of GABHS obtained from young children. All BHS isolates were susceptible to penicillin. GABHS were universally susceptible to clindamycin, whereas 1.4% were resistant to erythromycin. GBBHS were resistant to erythromycin and clindamycin in 14.8% and 7.4% of cases. In addition, we wanted to emphasize the importance of correct diagnosis of PSD. Hence, we provide a review of protocols that can decrease the time to diagnosis and treatment of PSD, reduce patients' discomfort, and prevent unnecessary diagnostic procedures. PMID- 28006880 TI - Coexistence of erythema dyschromicum perstans and vitiligo: a case report and review of the literature. AB - Erythema dyschromicum perstans is a rare, chronic, pigmentary disorder with unknown etiology. It clinically presents with oval to round, gray, blue, or brown macules of various sizes. The etiology remains unknown; however, cobalt allergy, radio contrast media, intestinal parasites, human immunodeficiency virus, and hypothyroidism have been proposed as causative factors. In addition, vitiligo is characterized by depigmented macules and patches that are widely andsymmetrically distributed. It has been suggested that autoimmune mechanisms play an important role in the etiopathogenesis of vitiligo. Physical and emotional stress can trigger vitiligo in genetically predisposed patients. However, coexistence of erythema dyschromicum perstans and vitiligo is extremely rare, and similar immune mechanisms have been implicated in the pathogenesis of these cutaneous pigmentary disorders. PMID- 28006881 TI - Methotrexate-induced panniculitis in a patient with rheumatoid arthritis. AB - Methotrexate-induced accelerated nodulosis (MIAN) is not an uncommon adverse effect associated with the use of the methotrexate in rheumatoid arthritis. Limited case reports describe panniculitis as a pathological finding in this setting. A 31-year-old female with seropositive rheumatoid arthritis on methotrexate therapy presented with a 2-week history of sudden onset of painful infiltrated subcutaneous nodules on both forearms. Based on clinical and histological findings, a diagnosis of methotrexate-induced panniculitis was made. The majority of MIAN case reports that we reviewed showed characteristic pathological findings of classic rheumatoid nodules; few reported panniculitis as a finding. This case illustrates the importance of recognizing this phenomenon as methotrexate-induced panniculitis should be considered in the differential diagnosis of any patient receiving methotrexate presenting with a recent history of accelerated nodulosis. Discontinuation of methotrexate remains controversial. PMID- 28006882 TI - Erythema exsudativum multiforme induced by a taurine-containing energy drink. AB - Erythema exsudativum multiforme is an immunologically mediated skin condition caused by viruses, bacteria, food, and drugs. There are different forms, and depending on the severity of the disease there is a major and minor form. Whereas the minor form passes without consequences, the major form and Stevens-Johnson syndrome affect the mucosa and may result in death. The disease affects all age groups but is more often observed in young individuals. Typical signs of the disease are skin lesions termed herpes iris. Taurine is an organic compound used in energy drinks and food that can cause many forms of hypersensitivity reactions, and one of these is erythema exsudativum multiforme. As consumption of energy drinks containing taurine increases, the problem of an increase in cases presenting with various forms of hypersensitivity reactions should be considered. Here we present the case of a 19-year-old man with erythema exsudativum multiforme caused by a drink containing taurine. We excluded all other factors that may have caused erythema multiforme and the patient was hospitalized, having been referred to us for the second time presenting with the same problem caused twice by the same drink. PMID- 28006883 TI - Neutrophilic dermatosis of the dorsal hands: a restrictive designation for an acral entity. AB - In 2000, Galaria et al. proposed the designation neutrophilic dermatosis of the dorsal hands (NDDH). The authors describe a case of NDDH with predominant involvement of the palmar aspect of the hands in a patient suffering from lung cancer, a possible paraneoplastic manifestation. Therefore, the term NDDH is not accurate because palmar manifestations of this dermatosis are also possible. PMID- 28006884 TI - An awake videolaryngoscope-assisted intubation in a patient with Madelung disease and a critical airway obstruction. PMID- 28006885 TI - Epidemiology and outcomes of cardiac arrest among children with Down Syndrome: a multicenter analysis. AB - BACKGROUND: With the increasing prevalence of Down Syndrome, it is unknown if children with Down Syndrome are associated with increased incidence of cardiac arrest and poor outcomes after cardiac arrest. The objective of this study was to evaluate the epidemiology of cardiac arrest and mortality after cardiac arrest among critically ill children with and without Down Syndrome. METHODS: Patients <=18 years admitted at a Pediatric Health Information Systems (PHIS) participating Intensive Care Unit were included (2004-2014). Multivariable logistic regression models were fitted to evaluate association of Down Syndrome with study outcomes after adjusting for patient and center characteristics. RESULTS: A total of 849,250 patients from 44 centers were included. Of the 25,143 patients with Down Syndrome, cardiac arrest was noted among 568 (2.3%) patients with an associated mortality at hospital discharge of 248 (43.6%) patients. In contrast, of the 824,107 patients without Down Syndrome, cardiac arrest was noted among 15,822 (1.9%) patients with an associated mortality at hospital discharge of 7775 (49.1%) patients. In adjusted models, patients with Down Syndrome had a higher likelihood of having cardiac arrest as compared to patients without Down Syndrome (with vs. without Down, OR: 1.14, 95% CI: 1.03-1.25, P=0.01). Despite having a higher likelihood of cardiac arrest, patients with Down Syndrome were associated with a lower mortality after cardiac arrest (OR: 0.78, 95% CI: 0.63 0.96, P=0.02). CONCLUSIONS: Both incidence of cardiac arrest, and mortality at hospital discharge in those with cardiac arrest vary substantially in children with and without Down Syndrome. PMID- 28006886 TI - Neuromuscular effect of dexmedetomidine on sevoflurane: an open-label, dose escalation clinical trial. AB - BACKGROUND: Sevoflurane presents reliable central neuromuscular effects. However, little knowledge is available regarding the interaction between sevoflurane and demedetomidine. We evaluated the neuromuscular effect of dexmedetomidine on sevoflurane in patients with normal neuromuscular transmission and calculated the 50% effective concentration (EC50). METHODS: One-hundred and forty-four ASA grade I~II patients with normal neuromuscular transmission, aged 20~60 years old, undergoing lower limbs surgery were enrolled in this open-label, dose-escalation clinical trial. Patients were randomly assigned into 12 groups. Each patient received intravenous 0, 0.5, or 1.0 MUg/kg dexmedetomidine 15 min after inhaling 0.7, 1.0, 1.4, or 2.0 MAC sevoflurane. Neuromuscular monitoring was recorded from the adductor pollicis muscle by using acceleromyography with train-of-four (TOF) stimulation of the ulnar nerve (2 Hz every 20 s). TOF ratio was recorded before inhaling sevoflurane, 15 min after keeping constant at target MAC of sevoflurane, 30 min after receiving target dose of dexmedetomidine, and 15 min after sevoflurane washing out. RESULTS: Sevoflurane produced a concentration-dependent decrease in TOF ratio. Mean TOF ratio in 0.7, 1.0, 1.4, and 2.0 MAC groups was 97.9%, 94.9%, 84.7%, and 77.2%, respectively. Neuromuscular EC50 of sevoflurane was 1.31 MAC (95% CI: 1.236~1.388 MAC). Intravenous 0.5 and 1.0 MUg/kg dexmedetomidine decreased 3.1% (EC50: 1.27 MAC [95% CI: 1.206~1.327 MAC]) and 10.7% (EC50: 1.17 MAC [95% CI: 1.122~1.217 MAC]) of neuromuscular EC50, respectively. CONCLUSIONS: Sevoflurane has a concentration-dependent central neuromuscular effect in patients with normal neuromuscular transmission. Intravenous dexmedetomidine dose-dependently decreases the neuromuscular EC50 of sevoflurane. PMID- 28006887 TI - Palliative sedation: the position statement of the Italian National Committee for Bioethics. AB - In January 2016 the Italian National Bioethics Committee (NBC) published a position statement entitled Deep and continuous palliative sedation in the imminence of death, related to the use of sedation and analgesia for relief from pain and psychological distress in dying patients. In this statement the Committee points out the clinical and ethical appropriateness of palliative sedation as a therapeutic procedure. As a result, today palliative sedation has to be considered useful, scientifically safe and reliable, and acknowledged as an integral part of good clinical practice. At the same time, the position statement, once and for all, makes clear that palliative sedation cannot and must not be equated with the practice of euthanasia. Thus, this document should be known by health professionals caring for dying patients not only in palliative as well as in intensive care settings, but it should be also considered as a milestone aimed to encourage and ease a widespread implementation of this procedure in all health care settings. PMID- 28006888 TI - Iron parameters, prohepcidin and soluble transferrin receptor levels in obese children. AB - BACKGROUND: Iron deficiency is common in obese children although the underlying mechanism is unclear. Several studies have investigated the relation between iron deficiency and obesity, but studies focusing on children are rare. The aim was to investigate the associations between iron parameters, prohepcidin and soluble transferrin receptor levels in obese children. METHODS: A total of 110 children, ranging in age from 6-16, 50 with primary obesity and 60 healthy children and adolescents, were enrolled. Complete blood count, serum iron levels, iron binding capacity, ferritin levels, soluble transferrin receptor, and prohepcidin levels were studied. RESULTS: Serum iron and transferrin saturation index levels were significantly low, red cell distribution width and ferritin levels were significantly high in obese children compared to control group. No association between soluble transferrin receptor, prohepcidin and iron parameters was detected. A positive correlation between ferritin and prohepcidin levels was defined. CONCLUSIONS: Obese children and adolescents were at greater risk for iron deficiency. It should be considered in the diet recommendations. PMID- 28006889 TI - Evaluating self-esteem modifications after a Life Skills-Based Education intervention. AB - BACKGROUND: A satisfactory level of self-esteem has been recognized as crucial factor contributing to healthy lifestyle, especially among children and adolescents. We performed an analysis of the impact of Life-Skills Based Education (LSBE) in a cohort of pupils in a Primary School of Sondrio (Northern Italy) and we made a comparison with a control group in a Primary school of the same province where no intervention was performed. METHODS: Changes in levels of self-esteem were assessed through Italian version of the Multidimensional Self concept Test of Bruce Bracken - T.M.A. For research purpose we used four of the six scales of the Italian version of the Multidimensional Self-esteem Test - T.M.A. RESULTS: The questionnaire was handed out to a total of 318 pupils: 132 students had received a LSBE intervention and 186 had not received any intervention. Median and interquartile range are in the normal range, both for the intervention and control groups. The four subscales showed an improving trend from the beginning (T1) to the end (T2) of the school year, both for the intervention and control groups. Regarding the intervention group, we found statistically significant changes in the subscales of quality of interpersonal relationships (P=0.003) and emotional competencies (P=0.02); regarding the control group, we found statistically significant changes in all the subscales analyzed. Considering the variable "sex", we found a statistically significant improvement only for male students and for the subscale "quality of interpersonal relationships" (P=0.007). CONCLUSIONS: The population trend observed suggests an improvement in competencies and levels of self-esteem in the cohort subjected to a LSBE intervention. Data analysis revealed significant differences in the subscales of quality of interpersonal relationships and emotional competencies, suggesting that LSBE interventions have an higher impact on males than on females. A longer follow-up could be useful in order to provide more reliable and significant data about LSBE programs' real efficacy. PMID- 28006890 TI - Serum cytokines in paediatric neuropsychiatric syndromes: focus on Attention Deficit Hyperactivity Disorder. AB - BACKGROUND: Inflammation may represent a common underlying mechanism in a wide range of diseases, including neuropsychiatric disorders. Cytokine involvement has been investigated in some studies on patients with childhood neuropsychiatric diseases. The aim of this study was to determine whether cytokines are involved in ADHD to provide a rationale for immune-based therapeutic strategies in this disorder. METHODS: Sixty children were studied: 34 consecutive drug-naive children with ADHD (30 males and 4 females; mean age of 10.10 years, sd=2.43 age) and 26 healthy control children (22 males and 4 females; mean age of 10.70 years, sd=1.81). All cytokines but IL-2 (IL4-IL6-IL10- IL17-TNFA and IFNG) were studied by ELISAs; IL-2 was instead studied by means of paired anti-cytokine Abs and cytokine standards obtained from PharMingen. RESULTS: Data reveal higher IL-6 and IL-10 levels in ADHD patients than in the control group (p= .03). No differences emerged between the two groups for the other cytokines. CONCLUSIONS: Our study shows an imbalance between pro- and anti-inflammatory cytokines that may play a pivotal role in the pathogenesis of ADHD. PMID- 28006891 TI - The efficacy of nasal tip hold-press on venous cannulation pain in children: a prospective randomize controlled study. AB - BACKGROUND: Venipuncture is a common and quiet unpleasant experience for pediatric patients. The pain associated with venous cannulation disturbs the children. Different methods have been used to minimize the pain. The present study evaluated the efficacy of holding and pressing the tip of the nose on the venipuncture pain in pediatric patients. METHODS: A prospective randomize controlled study carried out using the Visual analogue scale (YAS) for assessment cannulation pain and the Yale preoperative anxiety scale (YPAS) for the assessment of anxiety before cannulation. 60 patients, 6-12 years old, who needed venipuncture for general anesthesia were divided in to two groups of 30 each: the control and the study group. Nasal tip was held and pressed during venipuncture by the parents in the study group. No intervention was done in the control group. RESULTS: The anxiety scale (YPAS) was not different between the two groups before venous cannulation (P = 0.136). Comparing the two groups. There was no different regarding the change in HR and BP during venous cannulation. There was significantly lower cannulation pain in the study in comparison with the control group (P value = 0.010). CONCLUSIONS: Holding and pressing the tip of the nose during venipuncture reduce the severity of venipuncture pain in pediatric patients. This could be secondary to distraction along with the physiological effect of the valsalva maneuver on pain. Therefore, we recommend that holding and pressing the tip of the nose is a safe and effective method for reducing the severity of pain from venipuncture in pediatric patients. PMID- 28006892 TI - A novel TaqMAMA assay for allelic discrimination of immunoproteasome subunit PSMB8 in pediatric patients. AB - BACKGROUND: A more recent improvement in MAMA was made when the allele selectivity of MAMA primers was combined with the 5' fluorogenic exonuclease (TaqMan) assay. This strategy referred to as TaqMAMA. METHODS: A SNP rs9357155 at the PSMB8 locus (GenBank access number NM_148919.3.) on chromosome 6 showing a C/T transition in position 32842071, has been chosen as model in this study. RESULTS: Tested assays have provided to be linear over two log10 of magnitude and have efficiencies close to the average of 80.3%. Average Interference Limit values of TaqMAMA have been considered around the 0.6%. Coefficient of variation (CV) for PSMB8c and -t was approximatively 1%. CONCLUSIONS: Pre-validation procedure described in this paper can be applied, not only to the allele quantification, but also to many other Real Time PCR applications. PMID- 28006893 TI - Lifestyle and resulting body composition in young athletes. AB - BACKGROUND: Key aspects in a lifestyle analysis are physical activity level and eating habits. An unhealthy lifestyle results in fat mass increase and in a predisposition to non communicable chronic diseases even in young age. The purpose of this study was to investigate the lifestyle and body composition in young athletes. METHODS: The subjects underwent to an assessment of body composition and they completed two questionnaires, one concerning the level of physical activity and the other regarding eating habits. RESULTS: 152 young athletes (63 females and 89 males) aged 8 to 18 years (13.4+/-2.5 years, height 159+/-14 cm) were enrolled in this study. 80.3% of subjects were normal weight (13.4+/-2.6 yrs) and 19.7% subjects (13.5+/-2.5 yrs) were overweight or obese. Greater sedentary behaviors were found in the overweight or obese participants compared to normal weight (618+/-125 vs 523+/-89 min; p<0.001) and a lower consumption of milk and yoghurt (5.0+/-3.2 vs 6.9+/-4.1 times/week; p=0.031). CONCLUSIONS: Although competitive sports often increases physical activity levels in young people, this activity does not seem to reach the daily recommended amount of physical activity during youth. Therefore, it is necessary to have a comprehensive approach to create a primary prevention strategy from even a young age. PMID- 28006894 TI - Evaluation of clinical outcome in children and adolescents receiving vancomycin for invasive infections due to methicillin-resistant Staphylococcus aureus: impact of increasing vancomycin MICs. AB - BACKGROUND: Vancomycin is the preferred drug for the treatment of methicillin resistant Staphylococcus aureus (MRSA) infections in children. In adults, treatment failure with vancomycin has been associated with an area under the curve/24 hrs /MIC (AUC24/MIC) ratio of <=400 and high minimum inhibitory concentrations (MIC >=1.0 mg/L). Vancomycin dosing information to ensure optimal AUC24/MIC in the pediatric population remains limited. METHODS: A retrospective chart review from August 2008 to 2011 and a prospective study from September 2011 to October 2013 was conducted on all pediatric patients at two hospitals in Brooklyn, NY with positive cultures for MRSA who received vancomycin. Treatment failure was defined as persistent positive cultures (>=5 days) or persistence of clinical symptoms. Vancomycin AUC24/MICs were calculated. RESULTS: Twenty-three children with MRSA infection, 0-18 years of age, were identified; 18 of 23 (78.3%) were community acquired. MICs of 91% of the isolates were >=1.5 ug/mL and 9 had MICs of 2 ug/mL. Treatment failure was seen in 12 (52%) patients with MICs of 1.5 ug/mL and above. Vancomycin trough levels >15 ug/mL and AUC24/MIC >400 were achieved in only 18% and 0% of patients, respectively. CONCLUSIONS: High treatment failure rates with vancomycin was associated with MIC >=1.5 ug/mL. Current recommended vancomycin dosing in children did not achieve a trough concentration of >15 ug/mL in majority of the patients and none achieved an AUC24/MIC>400. PMID- 28006895 TI - 17q21 locus rs7216389 polymorphism and childhood asthma risk: a meta-analysis. AB - INTRODUCTION: Recently, a genome-wide association study (GWAS) indicated that rs7216389 polymorphism on chromosome 17q21 was associated with paediatric asthma risk. However, the results remained controversial. Therefore, a meta-analysis was performed. EVIDENCE ACQUISITION: A comprehensive literature retrieve was performed on PubMed, Embase and Science Direct databases up to Feb 20, 2016. The strength of association between 17q21 locus rs7216389 polymorphism and pediatric asthma risk was assessed by computing odds ratio (OR) with its corresponding 95% confidence interval (CI). EVIDENCE SYNTHESIS: A total of 10 studies with 7797 cases and 38757 controls were included. A statistically significant association of rs7216389 polymorphism and pediatric asthma risk was found (OR=1.41, 95%CI=1.34-1.49, P<0.00001). Furthermore, both Caucasians (OR=1.41, 95%CI=1.33 1.49, P<0.00001) and Asians (OR=1.43, 95%CI=1.25-1.63, P<0.00001) with rs7216389 polymorphism showed significant association, respectively. A significantly increased susceptibility was identified in atopic asthma (OR=1.45, 95%CI=1.22 1.72, P<0.00001). In the stratification analysis by study design, both case control studies (OR=1.40, 95%CI=1.33-1.48, P<0.00001) and cohort studies (OR=2.05, 95%CI=1.32-3.17, P=0.001) showed significant association, respectively. CONCLUSIONS: In conclusion, this meta-analysis suggests that 17q21 locus rs7216389 polymorphism was significantly associated with paediatric asthma risk. PMID- 28006896 TI - Overweight/obesity and lifestyle factors among Italian adolescents: the ALIADO study. AB - BACKGROUND: Childhood obesity is associated with many lifestyle factors. The present study aims to evaluate the relationship between overweight/obesity and abdominal obesity and several lifestyle factors in a sample of Italian adolescents. METHODS: A representative cluster sample of 15-16-year-old adolescents in secondary school in the Lazio region (Italy) was recruited. Body weight, height and waist circumference were measured. Ponderal status was assessed by the IOTF and WHO definitions. Waist-to-height ratio (WtHR) cut-off of 0.5 was used to classify subjects with the highest cardiometabolic risk. Selected dietary habits and lifestyle characteristics were assessed by questionnaires. RESULTS: 369 adolescents (162 males and 207 females) were studied. Prevalence of overweight/obesity was 23.3%, according to the IOTF criteria with a higher percentage of males than females (30.2% vs 17.9%; p=0.031), and 26% according to WHO references with significant differences between males and females (respectively, 33.9% vs 19.8%; p=0.002). The WtHR>=0.5 was observed in 12.7% of the total sample with a higher percentage in males than in females (16% vs 10.1%). Males reported an increased likelihood of being overweight or obese, as well as of having a WtHR>=0.5 (aOR 2.76 and 2.18, respectively). Adolescents that had breakfast regularly everyday were less likely to be overweight/obese and to have a WtHR>=0.5 (aOR 0.52 and 0.49, respectively). CONCLUSIONS: These results showed a high prevalence of overweight/obesity in the sample, and food habits and lifestyle not in accordance with recommendations, especially regarding breakfast. A Surveillance System of Italian adolescents should also be implemented through anthropometric measurement data to monitor the effectiveness of the policies to counteract obesity. PMID- 28006898 TI - Activating Cobalt Nanoparticles via the Mott-Schottky Effect in Nitrogen-Rich Carbon Shells for Base-Free Aerobic Oxidation of Alcohols to Esters. AB - Heterogeneous catalysts of inexpensive and reusable transition-metal are attractive alternatives to homogeneous catalysts; the relatively low activity of transition-metal nanoparticles has become the main hurdle for their practical applications. Here, the de novo design of a Mott-Schottky-type heterogeneous catalyst is reported to boost the activity of a transition-metal nanocatalyst through electron transfer at the metal/nitrogen-doped carbon interface. The Mott Schottky catalyst of nitrogen-rich carbon-coated cobalt nanoparticles (Co@NC) was prepared through direct polycondensation of simple organic molecules and inorganic metal salts in the presence of g-C3N4 powder. The Co@NC with controllable nitrogen content and thus tunable Fermi energy and catalytic activity exhibited a high turnover frequency (TOF) value (8.12 mol methyl benzoate mol-1 Co h-1) for the direct, base-free, aerobic oxidation of benzyl alcohols to methyl benzoate; this TOF is 30-fold higher than those of the state of-the-art transition-metal-based nanocatalysts reported in the literature. The presented efficient Mott-Schottky catalyst can trigger the synthesis of a series of alkyl esters and even diesters in high yields. PMID- 28006897 TI - L-Edge X-ray Absorption Spectroscopic Investigation of {FeNO}6: Delocalization vs Antiferromagnetic Coupling. AB - NO is a classic non-innocent ligand, and iron nitrosyls can have different electronic structure descriptions depending on their spin state and coordination environment. These highly covalent ligands are found in metalloproteins and are also used as models for Fe-O2 systems. This study utilizes iron L-edge X-ray absorption spectroscopy (XAS), interpreted using a valence bond configuration interaction multiplet model, to directly experimentally probe the electronic structure of the S = 0 {FeNO}6 compound [Fe(PaPy3)NO]2+ (PaPy3 = N,N-bis(2 pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide) and the S = 0 [Fe(PaPy3)CO]+ reference compound. This method allows separation of the sigma donation and pi-acceptor interactions of the ligand through ligand-to-metal and metal-to-ligand charge-transfer mixing pathways. The analysis shows that the {FeNO}6 electronic structure is best described as FeIII-NO(neutral), with no localized electron in an NO pi* orbital or electron hole in an Fe dpi orbital. This delocalization comes from the large energy gap between the Fe-NO pi-bonding and antibonding molecular orbitals relative to the exchange interactions between electrons in these orbitals. This study demonstrates the utility of L-edge XAS in experimentally defining highly delocalized electronic structures. PMID- 28006900 TI - Phenylpropenes: Occurrence, Distribution, and Biosynthesis in Fruit. AB - Phenylpropenes such as eugenol, chavicol, estragole, and anethole contribute to the flavor and aroma of a number of important herbs and spices. They have been shown to function as floral attractants for pollinators and to have antifungal and antimicrobial activities. Phenylpropenes are also detected as free volatiles and sequestered glycosides in a range of economically important fresh fruit species including apple, strawberry, tomato, and grape. Although they contribute a relatively small percentage of total volatiles compared with esters, aldehydes, and alcohols, phenylpropenes have been shown to contribute spicy anise- and clove like notes to fruit. Phenylpropenes are typically found in fruit throughout development and to reach maximum concentrations in ripe fruit. Genes involved in the biosynthesis of phenylpropenes have been characterized and manipulated in strawberry and apple, which has validated the importance of these compounds to fruit aroma and may help elucidate other functions for phenylpropenes in fruit. PMID- 28006899 TI - In Silico Prediction of Physicochemical Properties of Environmental Chemicals Using Molecular Fingerprints and Machine Learning. AB - There are little available toxicity data on the vast majority of chemicals in commerce. High-throughput screening (HTS) studies, such as those being carried out by the U.S. Environmental Protection Agency (EPA) ToxCast program in partnership with the federal Tox21 research program, can generate biological data to inform models for predicting potential toxicity. However, physicochemical properties are also needed to model environmental fate and transport, as well as exposure potential. The purpose of the present study was to generate an open source quantitative structure-property relationship (QSPR) workflow to predict a variety of physicochemical properties that would have cross-platform compatibility to integrate into existing cheminformatics workflows. In this effort, decades-old experimental property data sets available within the EPA EPI Suite were reanalyzed using modern cheminformatics workflows to develop updated QSPR models capable of supplying computationally efficient, open, and transparent HTS property predictions in support of environmental modeling efforts. Models were built using updated EPI Suite data sets for the prediction of six physicochemical properties: octanol-water partition coefficient (logP), water solubility (logS), boiling point (BP), melting point (MP), vapor pressure (logVP), and bioconcentration factor (logBCF). The coefficient of determination (R2) between the estimated values and experimental data for the six predicted properties ranged from 0.826 (MP) to 0.965 (BP), with model performance for five of the six properties exceeding those from the original EPI Suite models. The newly derived models can be employed for rapid estimation of physicochemical properties within an open-source HTS workflow to inform fate and toxicity prediction models of environmental chemicals. PMID- 28006901 TI - Encapsulation of Antibiotic Levofloxacin in Biocompatible Microemulsion Formulation: Insights from Microstructure Analysis. AB - Microemulsions (MUEs) are unique systems that offer exciting perspectives in biophysical research for mimicing biomembranes at the molecular level. In the present study, biocompatible MUE formulation of a new oil-in-water (o/w) system comprising clove oil/Tween 20/2-propanol/water was accomplished for encapsulating an antibiotic, levofloxacin (LVF). The pseudoternary phase diagram was delineated at a constant cosurfactant/surfactant (2:1) ratio to meet the economic feasibility. The gradual changes occurring in the microstructure of the as formulated four-component MUEs were explored via multiple complementary characterization techniques. The results of electrical conductivity (sigma), viscosity (eta), and optical microscopic measurements suggested the existence of a percolation transition to a bicontinuous structure in the microregions of the as-formulated MUE. LVF displayed a high solubility (5.0 wt %) at the pH of 6.9 in an optimum MUE formulation comprising 2-propanol (36.4%), Tween 20 (18.2%), clove oil (20.7%), and water (24.7%). The LVF-loaded MUE composition showed long-term stability for over 6 months of storage. Fourier transform IR analysis showed that LVF was stable inside the MUE formulation, indicating the absence of any possible aggregation of LVF. Dynamic light scattering revealed that the average particle size of drug-free MUE (64.5 +/- 3.4 nm) increases to 129.7 +/- 5.8 nm upon loading of LVF, suggesting the accumulation of LVF in the interfacial layers of the micelles. Moreover, fluorescence measurements indicated that LVF might be localized in the interfacial film of MUE system, which may result in a controlled release of drug. PMID- 28006902 TI - Investigating the Effect of Substrate Materials on Wearable Immunoassay Performance. AB - Immunoassays are ubiquitous across research and clinical laboratories, yet little attention is paid to the effect of the substrate material on the assay performance characteristics. Given the emerging interest in wearable immunoassay formats, investigations into substrate materials that provide an optimal mix of mechanical and bioanalytical properties are paramount. In the course of our research in developing wearable immunoassays which can penetrate skin to selectively capture disease antigens from the underlying blood vessels, we recently identified significant differences in immunoassay performance between gold and polycarbonate surfaces, even with a consistent surface modification procedure. We observed significant differences in PEG density, antibody immobilization, and nonspecific adsorption between the two substrates. Despite a higher PEG density formed on gold-coated surfaces than on amine-functionalized polycarbonate, the latter revealed a higher immobilized capture antibody density and lower nonspecific adsorption, leading to improved signal-to-noise ratios and assay sensitivities. The major conclusion from this study is that in designing wearable bioassays or biosensors, the design and its effect on the antifouling polymer layer can significantly affect the assay performance in terms of analytical specificity and sensitivity. PMID- 28006903 TI - Structure-Odor Relationships of ( Z)-3-Alken-1-ols, ( Z)-3-Alkenals, and ( Z)-3 Alkenoic Acids. AB - ( Z)-3-Unsaturated volatile acids, alcohols, and aldehydes are commonly found in foods and other natural sources, playing a vital role in the attractiveness of foods but also as compounds with chemocommunicative function in entomology. However, a systematic investigation of their smell properties, especially regarding humans, has not been carried out until today. To close this gap, the odor thresholds in air and odor qualities of homologous series of ( Z)-3-alken-1 ols, ( Z)-3-alkenals, and ( Z)-3-alkenoic acids were determined by gas chromatography-olfactometry. It was found that the odor qualities in the series of the ( Z)-3-alken-1-ols and ( Z)-3-alkenals changed, with increasing chain length, from grassy, green to an overall fatty and citrus-like, soapy character. On the other hand, the odor qualities of the ( Z)-3-alkenoic acids changed successively from cheesy, sweaty via plastic-like, to waxy in their homologous series. With regard to their odor potencies, the lowest thresholds in air were found for ( Z)-3-hexenal, ( Z)-3-octenoic acid, and ( Z)-3-octenal. PMID- 28006904 TI - Resin Glycosides from Ipomoea alba Seeds as Potential Chemosensitizers in Breast Carcinoma Cells. AB - Multidrug resistance is the expression of one or more efflux pumps, such as P glycoprotein, and is a major obstacle in cancer therapy. The use of new potent and noncytotoxic efflux pump modulators, coadministered with antineoplastic agents, is an alternative approach for increasing the success rate of therapy regimes with different drug combinations. This report describes the isolation and structure elucidation of six new resin glycosides from moon vine seeds (Ipomoea alba) as potential mammalian multidrug-resistance-modifying agents. Albinosides IV-IX (1-6), along with the known albinosides I-III (7-9), were purified from the CHCl3-soluble extract. Degradative chemical reactions in combination with NMR spectroscopy and mass spectrometry were used for their structural elucidation. Four new glycosidic acids, albinosinic acids D-G (10-13), were released by saponification of natural products 3-6. They were characterized as tetrasaccharides of either convolvulinolic (11S-hydroxytetradecanoic) or jalapinolic (11S-hydroxyhexadecanoic) acids. The potentiation of vinblastine susceptibility in multidrug-resistant human breast carcinoma cells of albinosides 1-6 was evaluated by modulation assays. The noncytotoxic albinosides VII (4) and VIII (5), at a concentration of 25 MUg/mL, exerted the strongest potentiation of vinblastine susceptibility, with a reversal factor (RFMCF-7/Vin+) of 201- and >2517-fold, respectively. PMID- 28006905 TI - Silychristin: Skeletal Alterations and Biological Activities. AB - Silychristin is the second most abundant flavonolignan (after silybin) present in the fruits of Silybum marianum. A group of compounds containing silychristin (3) and its derivatives such as 2,3-dehydrosilychristin (4), 2,3 dehydroanhydrosilychristin (5), anhydrosilychristin (6), silyhermin (7), and isosilychristin (8) were studied. Physicochemical data of these compounds acquired at high resolution were compared. The absolute configuration of silyhermin (7) was proposed to be identical to silychristin A (3a) in ring D (10R,11S). The preparation of 2,3-dehydrosilychristin (4) was optimized. The Folin-Ciocalteau reduction and DPPH and ABTS radical scavenging assays revealed silychristin and its analogues to be powerful antioxidants, which were found to be more potent than silybin and 2,3-dehydrosilybin. Compounds 4-6 exhibited inhibition of microsomal lipoperoxidation (IC50 4-6 MUM). Moreover, compounds 4-8 were found to be almost noncytotoxic for 10 human cell lines of different histogenetic origins. On the basis of these results, compounds 3-6 are likely responsible for most of the antioxidant properties of silymarin attributed traditionally to silybin (silibinin). PMID- 28006906 TI - Isolation and Characterization of Cyclotides from Brazilian Psychotria: Significance in Plant Defense and Co-occurrence with Antioxidant Alkaloids. AB - Plants from the genus Psychotria include species bearing cyclotides and/or alkaloids. The elucidation of factors affecting the metabolism of these molecules as well as their activities may help to understand their ecological function. In the present study, high concentrations of antioxidant indole alkaloids were found to co-occur with cyclotides in Psychotria leiocarpa and P. brachyceras. The concentrations of the major cyclotides and alkaloids in P. leiocarpa and P. brachyceras were monitored following herbivore- and pathogen-associated challenges, revealing a constitutive, phytoanticipin-like accumulation pattern. Psyleio A, the most abundant cyclotide found in the leaves of P. leiocarpa, and also found in P. brachyceras leaves, exhibited insecticidal activity against Helicoverpa armigera larvae. Addition of ethanol in the vehicle for peptide solubilization in larval feeding trials proved deleterious to insecticidal activity and resulted in increased rates of larval survival in treatments containing indole alkaloids. This suggests that plant alkaloids ingested by larvae might contribute to herbivore oxidative stress detoxification, corroborating, in a heterologous system with artificial oxidative stress stimulation, the antioxidant efficiency of Psychotria alkaloids previously observed in planta. Overall, the present study reports data for eight novel cyclotides, the identification of P. leiocarpa as a cyclotide-bearing species, and the absence of these peptides in P. umbellata. PMID- 28006907 TI - Differences in Metabolism of Ellagitannins by Human Gut Microbiota ex Vivo Cultures. AB - Ellagitannin-rich plant materials are used as popular remedies in the treatment of various inflammatory diseases. Urolithins are gut microbiota metabolites of ellagitannins and are considered responsible for in vivo health effects. Various natural products have been studied that are known sources of urolithins. However, few studies have focused on the metabolism of ellagitannin molecules. The aim of the study was to examine the metabolic fate of select ellagitannins using ex vivo cultures of human gut microbiota. Fifteen monomeric and dimeric ellagitannins, 1 O-galloyl-4,6-(S)-HHDP-beta-d-glucose (2), pedunculagin (3), potentillin (4), casuarictin (5), coriariin B (6), vescalagin (7), castalagin (8), stachyurin (9), casuarinin (10), stenophyllinin A (11), stenophyllanin A (12), salicarinin A (13), gemin A (14), agrimoniin (15), and oenothein B (16), and ellagic acid (1) were studied. The formation of the metabolites in ex vivo human microbiota cultures was monitored using UHPLC-DAD-MS/MS. Ellagitannins possessing hexahydroxydiphenoyl moieties were metabolized to 6H-dibenzo[b,d]pyran-6-one derivatives, i.e., urolithins. The observed differences in amounts of produced urolithins indicated that the individual microbiota composition and type of ingested ellagitannins could determine the rate of urolithin production. When the oral ingestion of natural products containing ellagitannins with hexahydroxydiphenoyl groups is considered, the formation of urolithins and their bioactivity should be addressed. PMID- 28006908 TI - Pallidopenillines: Polyketides from the Alga-Derived Fungus Penicillium thomii Maire KMM 4675. AB - Eleven new polyketides, pallidopenillines 1-11, were isolated from the alga derived fungus Penicillium thomii. The structures of these compounds were established based on spectroscopic methods. The absolute configuration of pallidopenilline A (1) as 4R, 5S, 8S, 9R, 10R, 13R was established using a combination of the modified Mosher's method, X-ray analysis, and NOESY data. The absolute configurations of 2-5 were determined by time-dependent density functional theory calculations of the ECD spectra and ECD and NOESY data. It was shown that 1-acetylpallidopenilline A (2) and pallidopenilline G (10) inhibit the growth of colonies of 22Rv1 cells by 40% at 2 and 1 MUM, respectively. PMID- 28006909 TI - Pterosin Sesquiterpenoids from Pteris cretica as Hypolipidemic Agents via Activating Liver X Receptors. AB - Four new pterosin sesquiterpenoids (1-4), a new ent-kaurane diterpenoid (17), and 18 known compounds were isolated from the aerial parts of Pteris cretica L. The structures of the isolates were elucidated based on spectroscopic data analysis, and their absolute configurations were determined by comparison of experimental and calculated electronic circular dichroism spectra. The compounds were evaluated for lipid-lowering effects in 3T3-L1 adipocytes. Compounds 4, 8, 17, and 22 were more potent than the positive control, berberine, in decreasing triglycerides activity, with compound 4 exerting the most potent activity. Compound 4 activated LXRalpha/beta in a HEK 293T cell-based reporter gene assay. Molecular dynamic simulations revealed that compound 4 activates liver X receptors (LXRs) through hydrogen bonding with the residues of LXRalpha/beta, suggesting that compound 4 reduces total triglycerides through the regulation of LXRalpha/beta. PMID- 28006910 TI - Anthenosides L-U, Steroidal Glycosides with Unusual Structural Features from the Starfish Anthenea aspera. AB - Ten new polyhydroxysteroidal glycosides, anthenosides L-U (1-10), with rare positions of carbohydrate fragment attachments, were isolated from the starfish Anthenea aspera. The structures of 1-10 were established by NMR and ESIMS techniques as well as by chemical transformations. The unoxidized Delta22-24-nor cholestane (1), (24S)-Delta22-24-methylcholestane (2-5), and Delta22-cholestane (7) side chains of the steroidal aglycons, 3-O-methyl-beta-d-galactofuranosyl residue (2, 8), and 5alpha-cholest-8(14)-ene-3alpha,7beta,16alpha trihydroxysteroidal nucleus (9, 10) have not been found previously in starfish polar steroidal compounds. The mixture of glycosides 9 and 10 showed hemolytic activity with an EC50 = 8 MUM. Compound 4 at a dose of 10 MUM exhibited a potential immunomodulatory action, decreasing by 24% the intracellular ROS content in RAW 264.7 murine macrophages, induced by pro-inflammatory endotoxic lipopolysaccharide from E. coli. PMID- 28006911 TI - Polyacetylenic Oleanane-Type Triterpene Saponins from the Roots of Panax japonicus. AB - Three new polyacetylenic oleanane-type triterpenoids, baisanqisaponins A-C (1-3), and one new oleanane-type triterpenoid, chikusetsusaponin-V ethyl ester (4), together with 19 known compounds (5-23), were isolated from the roots of Panax japonicus. The structures were elucidated on the basis of spectroscopic analyses and chemical methods. Compounds 1-3 feature a rare panaxytriol group containing a polyacetylene on the saponin skeleton. Neuroprotective activity was evaluated for compounds 1-17, and angiotensin II-induced vascular smooth muscle cell proliferation inhibition was tested for compounds 5-7 and 10-12. PMID- 28006912 TI - ent-Labdane Diterpenoids from Dodonaea viscosa. AB - Seven new and two known ent-labdane diterpenoids have been isolated from a single plant specimen of Dodonaea viscosa ssp. spatulata, found in Tasmania, Australia. Prior to this study, only seven different labdane diterpenoids had been isolated from D. viscosa. The structures of the natural products were assigned via 1D and 2D NMR spectroscopy and other standard spectroscopic methods. The absolute configuration of three ent-labdane diterpenoids was determined by single-crystal X-ray crystallography of synthetic derivatives. Significantly, the results of this study suggest that the absolute configuration of some known labdane diterpenoids may have been misassigned. PMID- 28006913 TI - Termisoflavones A-C, Isoflavonoid Glycosides from Termite-Associated Streptomyces sp. RB1. AB - Three new isoflavonoid glycosides, termisoflavones A-C (1-3), and eight isoflavonoids (4-11) were isolated from termite-associated Streptomyces sp. RB1 recovered from the cuticle of the South African termite, Macrotermes natalensis. The structures of new compounds were determined by spectroscopic methods including 1D and 2D NMR and HR-MS analysis, as well as comparison of their NMR data with those of related isoflavonoid glycoside derivatives. The absolute configurations of the sugar moieties were clarified by chemical reactions. None of the isolates (1-11) displayed antifungal or antimicrobial activities (MICs > 100 MUg/mL), whereas compounds 6 and 11 ameliorated cisplatin-induced kidney cell damage to 80% of the control value at a cisplatin dose of 25 MUM. PMID- 28006914 TI - Antioxidant Flavonols and Phenolic Compounds from Atraphaxis frutescens and Their Inhibitory Activities against Insect Phenoloxidase and Mushroom Tyrosinase. AB - Chemical investigation of the aerial parts of Atraphaxis frutescens resulted in the isolation of five 7-methoxyflavonols with pyrogallol B-ring moieties (1-5), a fisetinidol glucoside (13), and a benzyl glycoside (18), together with 26 known compounds including flavonoids, phenylpropanoid amides, anthraquinone glycosides, lignans, and a benzyl derivative. The principal chemical structural feature of the isolated compounds was either a pyrogallol or catechol B-ring moiety, and they showed potent 1,1-diphenyl-2-picrylhydrazyl radical scavenging activities. To assess the effects of these antioxidants on biological enzymes, their inhibitory effects against an insect phenoloxidase and a mushroom tyrosinase were evaluated. This study indicated that insect phenoloxidase was inhibited by phenylpropanoid amides and that mushroom tyrosinase was inhibited by the characteristic 7-methoxyflavonol 3-O-rhamnopyranosides. PMID- 28006915 TI - beta-Dihydroagarofuran-Type Sesquiterpenes from the Seeds of Celastrus monospermus and Their Lifespan-Extending Effects on the Nematode Caenorhabditis elegans. AB - Seventeen beta-dihydroagarofuran-type sesquiterpenes were isolated from the seeds of Celastrus monospermus, and, among them, 15 (1-15) were identified as new natural products. Nine isolates were evaluated for their lifespan-extending effect using the standard model animal nematode Caenorhabditis elegans. As a result, all of the tested compounds prolonged the lifespan of C. elegans when compared to the blank control group (p < 0.0001). Among them, celaspermin E (5) extended the average lifespan and maximum lifespan of C. elegans, with effects similar to those of rapamycin, a positive control that has been found experimentally to delay the aging process of yeasts, worms, fruit flies, and mice. PMID- 28006916 TI - Synergistic Combination of CASE Algorithms and DFT Chemical Shift Predictions: A Powerful Approach for Structure Elucidation, Verification, and Revision. AB - Structure elucidation of complex natural products and new organic compounds remains a challenging problem. To support this endeavor, CASE (computer-assisted structure elucidation) expert systems were developed. These systems are capable of generating a set of all possible structures consistent with an ensemble of 2D NMR data followed by selection of the most probable structure on the basis of empirical NMR chemical shift prediction. However, in some cases, empirical chemical shift prediction is incapable of distinguishing the correct structure. Herein, we demonstrate for the first time that the combination of CASE and density functional theory (DFT) methods for NMR chemical shift prediction allows the determination of the correct structure even in difficult situations. An expert system, ACD/Structure Elucidator, was used for the CASE analysis. This approach has been tested on three challenging natural products: aquatolide, coniothyrione, and chiral epoxyroussoenone. This work has demonstrated that the proposed synergistic approach is an unbiased, reliable, and very efficient structure verification and de novo structure elucidation method that can be applied to difficult structural problems when other experimental methods would be difficult or impossible to use. PMID- 28006917 TI - Monoterpene Indole Alkaloids from the Fruit of Tabernaemontana litoralis and Differential Alkaloid Composition in Various Fruit Components. AB - Two new monoterpene indole alkaloids, isoakuammiline (1) and 18 hydroxypseudovincadifformine (2), and five known alkaloids, coronaridine (3), heyneanine (4), 3,19-oxidocoronaridine (5), tabersonine, and strictosidine, were identified from the fruit of Tabernaemontana litoralis. The structures of the alkaloids were determined using NMR and MS data analyses. While 18 hydroxypseudovincadifformine (2) showed a new hydroxylation pattern, isoakuammiline (1) revealed a novel skeleton for monoterpene indole alkaloids. In spite of the isolation of stemmadenine from the fruit tissues in other Tabernaemontana species, this vital biosynthetic precursor of iboga, aspidosperma, and pseudoaspidosperma skeletons was not found in T. litoralis. PMID- 28006918 TI - Ostalactones A-C, beta- and epsilon-Lactones with Lipase Inhibitory Activity from the Cultured Basidiomycete Stereum ostrea. AB - Ostalactones A-C (1-3), three new beta- and epsilon-lactone natural products, were isolated from the culture broth of the basidiomycete Stereum ostrea. The structures were elucidated by interpretation of HRFABMS and 1D and 2D NMR data. The structures of 1 and 2 are characterized by the presence of a beta-lactone containing a fused 4/5 bicyclic core structure. Compound 3 possesses a 2 oxepinone ring system, which is likely to be a biosynthetic precursor of compounds 1 and 2. Ostalactones A (1) and B (2) displayed potent inhibitory activity against human pancreatic lipase. PMID- 28006919 TI - Bacterial analysis by laser desorption ionization mass spectrometry on amorphous silicon. AB - Lipid profiling in nine bacterial species has been accomplished by laser desorption ionization mass spectrometry (LDI-MS) using amorphous silicon (a-Si) thin film with 100 nm thickness. Lipid ions could be generated by LDI on a-Si regardless of ion acquisition modes because of a thermal property of a-Si to govern laser-induced surface heating. In a comparative study of lipid profiling in Bacillus lichemiformis by LDI-MS and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), LDI-MS on a-Si shows a higher efficiency in lipid and lipopeptide detection than MALDI-MS. A total of 53 peaks of lipid ions generated by LDI on a-Si in both acquisition modes for m/z 400-1200 was 1.6 times more than that detected by MALDI-MS using three organic matrices 2,5-dihydroxybenzoic acid, 1,5-diaminonaphthalene, and 2,4,6 trihydroxyacetophenone monohydrate. Also, the authors demonstrate by mass spectrometry imaging (MSI) that LDI-MS provides high detection coverage through whole sample area. MSI results show the detection yield in LDI on a-Si is 94.8% calculated by counting the number of points detected in the analyte ion signal in a whole spot. It means that reproducible detection of lipid ions by LDI-MS is possible even if laser is randomly irradiated at any position within the bacterial sample area applied on a-Si. Lipid profiling by LDI-MS on a-Si was applied to bacterial differentiation of nine bacterial species conducted by performing principal component analysis. Nine bacterial species are successfully distinguishable from each other by LDI-MS lipid profiling. PMID- 28006920 TI - Clip and endoloop lifting technique to assist cannulation of a hardly reachable papilla because of anatomical changes due to surgery. AB - Bile duct cannulation by ERCP can be difficult because of different reasons. We present a patient with a hardly reachable papilla because of anatomical changes due to surgery. A clip, an endoloop and a guide wire were used to lift the papilla and pull it, achieving a successful cannulation. PMID- 28006921 TI - Could viral load combined with indirect serum markers be an option for predicting the degree of liver fibrosis in treatment-naive chronic hepatitis B patients? AB - In a recent issue of the Revista Espanola de Enfermedades Digestivas, we read with interest the article by Coskun et al. "The diagnostic value of a globulin/platelet model for evaluating liver fibrosis in chronic hepatitis B patients". However, we wanted to emphasize some points about the article. PMID- 28006922 TI - Sister Mary Joseph's nodule as initial pancreatic cancer manifestation. AB - We report the case of an 85-year-old female patient who presented with umbilical pain associated with an indurated growth, the whole being apparently consistent with incarcerated umbilical hernia, which prompted an urgent surgical procedure for its removal. The pathology study revealed dermal infiltration by a malignancy. Gland tumor cells expressed an immunohistochemical profile initially consistent with a pancreatic origin. In view of these findings a CT scan was performed, which revealed a pancreatic tail tumor as well as multiple hepatic metastasis. Skin metastasis is a rare sign usually reflecting a carcinoma of unknown origin. Umbilical skin metastasis, called Sister Mary Joseph's nodule, reflect an intra-abdominal tumor, being pancreatic cancer strange. PMID- 28006923 TI - Solutions to physician undersupply in rural areas: from the experience of rural Fukushima. AB - Key words: Fukushima nuclear accident, health care facilities, health education, Japan, manpower and services. PMID- 28006924 TI - In vitro and in vivo experimental hepatotoxic models in liver research: applications to the assessment of potential hepatoprotective drugs. AB - This mini-review highlights our and others' experience about in vitro and in vivo models that are being used to follow up events of liver injuries under various hepatotoxic agents and potential hepatoprotective drugs. Due to limitations of the outcomes in each model, we focus primarily on two models. First, a developed perfusion method for isolated immobilized hepatocytes that improves the process of oxygenation and helps in end-product removal is of considerable value in improving cell maintenance. This cellular model is presented as a short-term research-scale laboratory bioreactor with various physiological, biochemical, molecular, toxicological and pharmacological applications. Second, the in vivo model of D-galactosamine and lipopolysaccharide (D-GalN/LPS) combination-induced liver damage is described with some details. Recently, we have revealed that resveratrol and other natural polyphenols attenuate D-GalN/LPS-induced hepatitis. Moreover, we reported that D-GalN/LPS down-regulates sirtuin 1 in rat liver. Therefore, we discuss here the role of sirtuin 1 modulation in hepatoprotection. A successful development of pharmacotherapy for liver diseases depends on the suitability of in vitro and in vivo hepatic injury systems. Several models are available to screen the hepatotoxic or hepatoprotective activity of any substance. It is important to combine different methods for confirmation of the findings. PMID- 28006925 TI - Bile acids, nuclear receptors and cytochrome P450. AB - This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives. PMID- 28006926 TI - Athymic nude mice as an experimental model for cancer treatment. AB - Athymic nude mice, a murine strain bearing spontaneous deletion in the Foxn1 gene that causes deteriorated or absent thymus (which results in inhibited immune system with reduction of number of T cells), represent a widely used model in cancer research having long lasting history as a tool for preclinical testing of drugs. The review describes three models of athymic mice that utilize cancer cell lines to induce tumors. In addition, various methods that can be applied in order to evaluate activity of anticancer agents in these models are shown and discussed. Although each model has certain disadvantages, they are still considered as inevitable instruments in many fields of cancer research, particularly in finding new drugs that would more effectively combat the cancer disease or enhance the use of current chemotherapy. Finally, the review summarizes strengths and weaknesses as well as future perspectives of the athymic nude mice model in cancer research. PMID- 28006927 TI - The safety of therapeutic monoclonal antibodies: implications for cancer therapy including immuno-checkpoint inhibitors. AB - Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors. In addition to targeting cancer antigens antibodies can also modulate immunological pathways that are critical to immune surveillance. Antibody therapy directed against several negative immunologic regulators (checkpoints) is demonstrating significant success in the past few years. Immune checkpoint inhibitors, ipilimumab, pembrolizumab and nivolumab, have shown significant clinical benefit in several malignancies and are already approved for advanced melanoma and squamous NSCLC. Based on their mechanism of action, these agents can exert toxicities that are unlike conventional cytotoxic chemotherapy, whose nature is close to autoimmune diseases - immune related adverse events (irAEs). In this review we focus on the spectrum of irAEs associated with immune checkpoint antibodies, discussing the pharmacological treatment strategy and possible clinical impact. PMID- 28006928 TI - Sufentanil and midazolam dosing and pharmacogenetic factors in pediatric analgosedation and withdrawal syndrome. AB - Our aim was to describe the effect of dosing and genetic factors on sufentanil- and midazolam-induced analgosedation and withdrawal syndrome (WS) in pediatric population. Analgosedation and withdrawal syndrome development were monitored using COMFORT-neo/-B scores and SOS score. Length of therapy, dosing of sufentanil and midazolam were recorded. Genotypes of selected candidate polymorphisms in CYP3A5, COMT, ABCB1, OPRM1 and PXR were analysed. In the group of 30 neonates and 18 children, longer treatment duration with midazolam of 141 h (2 - 625) vs. 88 h (7 - 232) and sufentanil of 326.5 h (136 - 885) vs. 92 h (22 - 211) (median; range) was found in the patients suffering from WS vs. non-WS group, respectively. Median midazolam cumulative doses were in the respective values of 18.22 mg/kg (6.93 - 51.25) vs. 9.94 mg/kg (2.12 - 49.83); P=0.03, and the respective values for sufentanil were 88.60 microg/kg (20.21 - 918.52) vs. 21.71 microg/kg (4.5 - 162.29); P<0.01. Cut off value of 177 hours for sufentanil treatment duration represented predictive factor for WS development with 81 % sensitivity and 94 % specificity. SNPs in the candidate genes COMT, PXR and ABCB1 affected the dosing of analgosedative drugs, but were not associated with depth of analgosedation or WS. Cumulative dose and length of analgosedative therapy with sufentanil significantly increases the risk of WS in critically ill neonates and children. PMID- 28006929 TI - Sedative effects of intranasal oxytocin in rabbits and rhesus monkeys. AB - Oxytocin is a hormone therapeutically used mainly for its peripheral effects during pregnancy in the uterus and breasts. However, additional central effects, i.e. anxiolytic effect, decreased level of social stress and increased empathy have been also observed. Hence, the aim of our study was to evaluate if nasal oxytocin can be used as anxiolytic substance in rhesus monkeys (n=20) and rabbits (n=20). Simultaneously, mean arterial blood pressure, arterial oxygen saturation of hemoglobin and pulse rate were monitored in all the evaluated animals. While rabbits lost righting reflex, monkeys developed a dose-dependent loss of aggressiveness and/or anxiety as evaluated by behavioral methods (aggressive behavior was classified as non-sedated - sedated - strongly sedated). PMID- 28006931 TI - Pharmacokinetics of boldine in control and Mrp2-deficient rats. AB - The aim of the present study was to describe the currently poorly understood pharmacokinetics (PK) of boldine in control rats (LW, Lewis rats), and Mrp2 transporter-deficient rats (TR(-)). Animals from the LW and TR(-) groups underwent a bolus dose study with 10 mg/kg of boldine applied either orally or intravenously in order to evaluate the major PK parameters. The TR(-) rats demonstrated significantly reduced total clearance with prolonged biological half life (LW 12+/-4.6 versus TR(-) 20+/-4.4 min), decreased volume of distribution (LW 3.2+/-0.4 l/kg versus TR(-) 2.4+/-0.4 l/kg) and reduced bioavailability (LW 7 % versus TR(-) 4.5 %). Another set of LW and TR(-) rats were used for a clearance study with continuous intravenous administration of boldine. The LW rats showed that biliary and renal clearance formed less than 2 % of the total clearance of boldine. The treatment of samples with beta-glucuronidase showed at least a 38 % contribution of conjugation reactions to the overall clearance of boldine. The TR(-) rats demonstrated reduced biliary clearance of boldine and its conjugates, which was partly compensated by their increased renal clearance. In conclusion, this study presents the PK parameters of boldine and shows the importance of the Mrp2 transporter and conjugation reactions in the elimination of the compound. PMID- 28006930 TI - Systemic administration of miRNA mimics by liposomal delivery system in animal model of colorectal carcinoma. AB - MiRNAs are important regulators of gene expression and changes in their levels are linked with various pathological states, including solid tumors. MiR-215 has been identified as a tumor suppressor in colorectal cancer (CRC). Following our previous in vitro and in vivo experiments, the aim of this project was to study the possibility of increasing the levels of miR-215 in tumor cells by systemic administration of miRNA mimics in liposomal delivery system in vivo. By subcutaneous xenotransplantation of human cancer cells to NSG mice, CRC model was established. The treatment (miR-215 mimics in liposomes [20 and 40 microg/mouse], control oligonucleotide in liposomes, or saline) was administered repeatedly by i.v. injection via tail-vein. Animals were sacrificed, tumor were dissected and measured by a caliper. Expression of miR-215 in tumors, lungs and liver was quantified by RT-PCR. There was no significant differences in tumor volume and miR-215 expression between all three treatment groups. Therefore, the decrease in tumor volume was not achieved. By comparing the levels of miR-215 in lungs, liver and tumors after the treatment, we suggest that the liposomes are accumulated in the lungs and do not concentrate sufficiently in the tumor site to exert significant tumor-suppressive effect. PMID- 28006932 TI - The effect of (-)-linalool on the metabolic activity of liver CYP enzymes in rats. AB - (-)-Linalool is the major floral scent occurring mainly in families Lamiaceae, Lauraceae and Rutaceae and is the main active compound of lavender oil. The purpose of this study was to reveal the influence of subchronic systemic treatment with (-)-linalool on the metabolic activity of CYP2A, 2B, 2C6, 2C11 and 3A in rat liver microsomes (RLM). The second aim was to reveal possible inhibitory effect of (-)-linalool on CYP2C6 in vitro. Wistar albino male rats were treated with (-)-linalool intragastrically at the doses of 40, 120, and 360 mg/kg/day for 13 days. Treatment with (-)-linalool at the dose of 360 mg/kg increased the metabolic activity of CYP2A assessed with testosterone as a probe substrate. (-)-Linalool showed weak competitive inhibition of CYP2C6 in rat liver microsomes, with IC(50) of 84 microM with use of diclofenac as a probe substrate. PMID- 28006933 TI - Nilotinib induces ER stress and cell death in H9c2 cells. AB - Tyrosine kinases inhibitors (TKi) represent a relatively novel class of anticancer drugs that target cellular pathways overexpressed in certain types of malignancies, such as chronic myeloid leukaemia (CML). Nilotinib, ponatinib and imatinib exhibit cardiotoxic and vascular effects. In this study, we focused on possible cardiotoxicity of nilotinib using H9c2 cells as a suitable cell model. We studied role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib toxicity using a complex approach. Nilotinib impaired mitochondrial function and induced formation of ROS under clinically relevant concentrations. In addition, ability of nilotinib to induce ER stress has been shown. These events result in apoptotic cell death. All these mechanisms contribute to cytotoxic effect of the drug. In addition, involvement of ER stress in nilotinib toxicity may be important in co-treatment with pharmaceuticals affecting ER and ER stress, e.g. beta-blockers or sartans, and should be further investigated. PMID- 28006934 TI - Hypertriglyceridemic rats fed high fat diet as a model of metabolic syndrome. AB - People with metabolic syndrome have higher risk of cardiovascular diseases then those without. The aim of the work was to investigate whether high fat diet administered to Prague hereditary hypertriglyceridemic (HTG) rats can induce signs of metabolic syndrome (MetS). Our results showed that HTG rats fed high fat diet (HTGch) had disturbed glucose metabolism and also lipid metabolism - increased serum triacylglycerols (TAG), total cholesterol (Ch), low-density lipoprotein-Ch (LDL-Ch), and decreased high-density lipoprotein-Ch (HDL-Ch). Their livers proved markers of developing steatosis. Moreover, HTGch had increased blood pressure, yet the vascular endothelium was not significantly damaged. All these changes were accompanied with oxidative stress and tissue damage identified as increased liver concentrations of thiobarbituric acid reactive substances (TBARS) and activity of the lysosomal enzyme N-acetyl-D glucosaminidase (NAGA). We assume that the model used may be suitable for the study of MetS with no evidence of obesity. Prolongation of the high fat diet duration might have a major impact on all parameters tested, especially on vascular endothelial function. PMID- 28006935 TI - Multiple roles of mitochondria in aging processes. AB - Aging is a multifactorial process influenced by genetic factors, nutrition, and lifestyle. According to mitochondrial theory of aging, mitochondrial dysfunction is widely considered a major contributor to age-related processes. Mitochondria are both the main source and targets of detrimental reactions initiated in association with age-dependent deterioration of the cellular functions. Reactions leading to increased reactive oxygen species generation, mtDNA mutations, and oxidation of mitochondrial proteins result in subsequent induction of apoptotic events, impaired oxidative phosphorylation capacity, mitochondrial dynamics, biogenesis and autophagy. This review summarizes the major changes of mitochondria related to aging, with emphasis on mitochondrial DNA mutations, the role of the reactive oxygen species, and structural and functional changes of mitochondria. PMID- 28006936 TI - Pathophysiology of perinatal hypoxic-ischemic encephalopathy - biomarkers, animal models and treatment perspectives. AB - Hypoxic-ischemic encephalopathy (HIE) is one of the leading pediatric neurological conditions causing long-term disabilities and socio-economical burdens. Nearly 20-50 % of asphyxiated newborns with HIE die within the newborn period and another third will develop severe health consequences and permanent handicaps. HIE is the result of severe systemic oxygen deprivation and reduced cerebral blood flow, commonly occurring in full-term infants. Hypoxic-ischemic changes trigger several molecular and cellular processes leading to cell death and inflammation. Generated reactive oxygen species attack surrounding cellular components resulting in functional deficits and mitochondrial dysfunction. The aim of the present paper is to review present knowledge about the pathophysiology of perinatal hypoxic-ischemic encephalopathy, especially with respect to novel treatment strategies and biomarkers that might enhance early detection of this disorder and thus improve the general outcome of patients. PMID- 28006937 TI - Morphine decreases social interaction of adult male rats, while THC does not affect it. AB - The aim of the present study was to compare effect of three low doses of morphine (MOR) and delta9-tetrahydrocannabinol (THC) on social behavior tested in Social interaction test (SIT). 45 min prior to testing adult male rats received one of the drugs or solvents: MOR (1; 2.5; 5 mg/kg); saline as a solvent for MOR; THC (0.5; 1; 2 mg/kg); ethanol as a solvent for THC. Occurrence and time spent in specific patterns of social interactions (SI) and non-social activities (locomotion and rearing) was video-recorded for 5 min and then analyzed. MOR in doses of 1 and 2.5 mg/kg displayed decreased SI in total. Detailed analysis of specific patterns of SI revealed decrease in mutual sniffing and allo-grooming after all doses of MOR. The highest dose (5 mg/kg) of MOR decreased following and increased genital investigation. Rearing activity was increased by lower doses of MOR (1 and 2.5 mg/kg). THC, in each of the tested doses, did not induce any specific changes when compared to matching control group (ethanol). However, an additional statistical analysis showed differences between all THC groups and their ethanol control group when compared to saline controls. There was lower SI in total, lower mutual sniffing and allo-grooming, but higher rearing in THC and ethanol groups than in saline control group. Thus, changes seen in THC and ethanol groups are seemed to be attributed mainly to the effect of the ethanol. Based on the present results we can assume that opioids affect SI more than cannabinoid. PMID- 28006938 TI - The effect of neonatal maternal stress on plasma levels of adrenocorticotropic hormone, corticosterone, leptin, and ghrelin in adult male rats exposed to acute heterotypic stressor. AB - Activation of the hypothalamic-pituitary-adrenal (HPA) axis is important for maintenance of homeostasis during stress. Recent studies have shown a connection between the HPA axis and adipose tissue. The present study investigated the effect of acute heterotypic stress on plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), leptin, and ghrelin in adult male rats with respect to neonatal maternal social and physical stressors. Thirty rat mothers and sixty of their male progeny were used. Pups were divided into three groups: unstressed control (C), stressed by maternal social stressor (S), stressed by maternal social and physical stressors (SW). Levels of hormones were measured in adult male progeny following an acute swimming stress (10 min) or no stress. ELISA immunoassay was used to measured hormones. The ACTH and CORT levels were significantly increased in all groups of adult progeny after acute stress; however, CORT levels were significantly lower in both neonatally stressed groups compared to controls. After acute stress, plasma leptin levels were decreased in the C and SW groups but increased in the S group. The data suggest that long-term neonatal stressors lead to lower sensitivity of ACTH receptors in the adrenal cortex, which could be a sign of stress adaptation in adulthood. Acute stress in adult male rats changes plasma levels of leptin differently relative to social or physical neonatal stressors. PMID- 28006939 TI - The effect of combined treatment of opioids with methylphenidate on nociception in rats and pain in human. AB - Methylphenidate hydrochloride (MPH/Ritalin) is a stimulant used for off-label management of cancer-related fatigue and sedation; however, its use in pain treatment is still relatively rare. This study 1) compares the antinociceptive effect of MPH and its combination with morphine (MOR) in adult male Wistar rats after a single administration of MPH, MOR or their combination, and 2) compares the analgesic effects of opioids and Ritalin combined therapy with opioid monotherapy in patients with cancer pain. To objectively assess physical activity during a three-week monitoring period, patients were equipped with Actiwatch Score Actigraph. Patients performed daily evaluations of pain intensity and frequency, and the extent to which pain interfered with their daily life. Our research with rats supports the evidence that MPH in lower doses has the ability to enhance the analgesic properties of morphine when the two drugs are used in combination. Results from the patient arm of our study found that short-term treatment had no significant effect on intensity or frequency of pain, however it decreased the overall burden of pain; the combined treatment of opioid and Ritalin also showed anti-sedation effects and resulted in mild improvement in one of our patient's quality of life. PMID- 28006940 TI - Does effect from developmental methamphetamine exposure on spatial learning and memory depend on stage of neuroontogeny? AB - Psychostimulants, including methamphetamine (MA), have neurotoxic effect, especially, if they are targeting CNS during its critical periods of development. The present study was aimed to examine cognitive changes after prenatal and neonatal MA treatment in combination with chronic MA exposure in adulthood of male rats. Eight groups of male rats were tested in adulthood: males whose mothers were exposed to MA (5 mg/kg) or saline (SA, 1 ml/kg) during the first half of gestation period (GD 1-11), the second half of gestation period (GD 12 22) and neonatal period (PD 1-11). In addition, we compared indirect neonatal application via the breast milk with the group of rat pups that received MA or SA directly by injection (PD 1-11). Males were tested in adulthood for cognitive changes in the Morris Water Maze (MWM). MWM experiment lasted for 12 days: Learning (Day 1-6), Probe test (Day 8) and Retrieval Memory test (Day 12). Each day of the MWM animals were injected with MA (1 mg/kg) or SA (1 ml/kg). Prenatal MA exposure did not induce changes in learning abilities of male rats, but neonatal exposure to MA leads to an increase search errors and latencies to find the hidden platform. Prenatal and also neonatal MA exposure impaired cognitive ability to remember the position of the platform in Retrieval Memory test in adulthood. Animals exposed to the prenatal treatment within the second half of gestation (ED 12-22) swam longer, slower and spent more time to find the hidden platform in Retrieval Memory test than animals exposed throughout other periods. The present study demonstrated that stage of development is crucial for determination the cognitive deficits induced by prenatal or neonatal MA exposure. PMID- 28006941 TI - Early changes of brain perfusion after subarachnoid hemorrhage - the effect of sodium nitroprusside. AB - Causes of early hypoperfusion after subarachnoid hemorrhage (SAH) include intracranial hypertension as well as vasoconstriction. The aim of the study was to assess the effect of intracerebroventricular (ICV) administration of sodium nitroprusside (SNP) on early hypoperfusion after SAH. Male Wistar rats (220-240 g) were used, SAH group received 250 microl of fresh autologous arterial blood into the prechiasmatic cistern; sham-operated animals received 250 microl of isotonic solution. Therapeutic intervention: ICV administration of 10 microg SNP; 5 microl 5 % glucose (SNP vehicle) and untreated control. Brain perfusion and invasive blood pressure were monitored for 30 min during and after induction of SAH. Despite SNP caused increase of perfusion in sham-operated animals, no response was observed in half of SAH animals. The other half developed hypotension accompanied by brain hypoperfusion. There was no difference between brain perfusion in SNP-treated, glucose-treated and untreated SAH animals during the monitored period. We did not observe expected beneficial effect of ICV administration of SNP after SAH. Moreover, half of the SNP-treated animals developed serious hypotension which led to brain hypoperfusion. This is the important finding showing that this is not the option for early management in patient after SAH. PMID- 28006942 TI - Propofol-induced mitochondrial and contractile dysfunction of the rat ventricular myocardium. AB - Propofol is a short-acting hypnotic agent used in human medicine for sedation and general anesthesia. Its administration can be associated with serious cardiovascular side-effects that include decrease in arterial blood pressure and cardiac output. The aim of the present study was to evaluate propofol effects on mitochondrial respiration, myocardial contractility and electrophysiology in the same samples isolated from the heart ventricles of adult rats. Mitochondrial oxygen consumption was measured in permeabilized samples dissected from free walls of both ventricles using high-resolution respirometry. State LEAK was determined with malate and glutamate. Active respiration was induced by ADP (state PI) and further by succinate, a Complex II substrate (PI+II). Rotenone was injected to measure state PII. Antimycin A, a Complex III inhibitor was used to determine residual oxygen consumption (ROX). N,N,N',N'-tetramethyl-p phenylenediamine dihydrochloride and ascorbate were injected simultaneously for respirometric assay of cytochrome c oxidase activity (CIV). Isometric contractions and membrane potentials were determined on multicellular preparations isolated from right and left ventricles. Propofol concentrations used ranged from 0.005 to 0.5 mmol/l. All respiratory parameters were significantly higher in the left control ventricles compared to the right ones. Propofol significantly decreased Complex I activity at concentration 0.025 mmol/l and papillary muscle contraction force at 0.1 mmol/l. Propofol did not affect action potential duration at any concentration studied. Our study suggests that mechanisms contributing to the impaired myocardial contraction during propofol anesthesia might include also mitochondrial dysfunction manifested by compromised activity of the respiratory Complex I. PMID- 28006943 TI - Cardioprotection induced by remote ischemic preconditioning preserves the mitochondrial respiratory function in acute diabetic myocardium. AB - A 2*2 factorial design was used to evaluate possible preservation of mitochondrial functions in two cardioprotective experimental models, remote ischemic preconditioning and streptozotocin-induced diabetes mellitus, and their interaction during ischemia/reperfusion injury (I/R) of the heart. Male Wistar rats were randomly allocated into four groups: control (C), streptozotocin induced diabetic (DM), preconditioned (RPC) and preconditioned streptozotocin induced diabetic (DM+RPC). RPC was conducted by 3 cycles of 5-min hind-limb ischemia and 5-min reperfusion. DM was induced by a single dose of 65 mg/kg streptozotocin. Isolated hearts were exposed to ischemia/reperfusion test according to Langendorff. Thereafter mitochondria were isolated and the mitochondrial respiration was measured. Additionally, the ATP synthase activity measurements on the same preparations were done. Animals of all groups subjected to I/R exhibited a decreased state 3 respiration with the least change noted in DM+RPC group associated with no significant changes in state 2 respiration. In RPC, DM and DM+RPC group, no significant changes in the activity of ATP synthase were observed after I/R injury. These results suggest that the endogenous protective mechanisms of RPC and DM do preserve the mitochondrial function in heart when they act in combination. PMID- 28006944 TI - Regional tissue oximetry reflects changes in arterial flow in porcine chronic heart failure treated with venoarterial extracorporeal membrane oxygenation. AB - Venoarterial extracorporeal membrane oxygenation (VA ECMO) is widely used in treatment of decompensated heart failure. Our aim was to investigate its effects on regional perfusion and tissue oxygenation with respect to extracorporeal blood flow (EBF). In five swine, decompensated low-output chronic heart failure was induced by long-term rapid ventricular pacing. Subsequently, VA ECMO was introduced and left ventricular (LV) volume, aortic blood pressure, regional arterial flow and tissue oxygenation were continuously recorded at different levels of EBF. With increasing EBF from minimal to 5 l/min, mean arterial pressure increased from 47+/-22 to 84+/-12 mm Hg (P<0.001) and arterial blood flow increased in carotid artery from 211+/-72 to 479+/-58 ml/min (P<0.01) and in subclavian artery from 103+/-49 to 296+/-54 ml/min (P<0.001). Corresponding brain and brachial tissue oxygenation increased promptly from 57+/-6 to 74+/-3 % and from 37+/-6 to 77+/-6 %, respectively (both P<0.01). Presented results confirm that VA ECMO is a capable form of heart support. Regional arterial flow and tissue oxygenation suggest that partial circulatory support may be sufficient to supply brain and peripheral tissue by oxygen. PMID- 28006945 TI - Neonatal capsaicin administration impairs postnatal development of the cardiac chronotropy and inotropy in rats. AB - The present study evaluated the impact of neonatal administration of capsaicin (neurotoxin from red hot pepper used for sensory denervation) on postnatal development of the heart rate and ventricular contractility. In the rats subjected to capsaicin administration (100 mg/kg) on postnatal days 2 and 3 and their vehicle-treated controls at the ages of 10 to 90 days, function of the sympathetic innervation of the developing heart was characterized by evaluation of chronotropic responses to metipranolol and atropine, norepinephrine concentrations in the heart, and norepinephrine release from the heart atria. Sensory denervation was verified by determination of calcitonin gene-related peptide levels in the heart. Direct cytotoxic effects of capsaicin were assessed on cultured neonatal cardiomyocytes. Capsaicin-treated rats displayed higher resting heart rates, lower atropine effect, but no difference in the effect of metipranolol. Norepinephrine tissue levels and release did not differ from controls. Contraction force of the right ventricular papillary muscle was lower till the age of 60 days. Significantly reduced viability of neonatal cardiomyocytes was demonstrated at capsaicin concentration 100 micromol/l. Our study suggests that neonatal capsaicin treatment leads to impaired maturation of the developing cardiomyocytes. This effect cannot be attributed exclusively to sensory denervation of the rat heart since capsaicin acts also directly on the cardiac cells. PMID- 28006946 TI - A novel experimental model of acute respiratory distress syndrome in pig. AB - Acute respiratory distress syndrome (ARDS) is severe medical condition occurring in critically ill patients and with mortality of 33-52 % is one of the leading causes of death in critically ill patients. To better understand pathophysiology of ARDS and to verify novel therapeutical approaches a reliable animal model is needed. Therefore we have developed modified lavage model of ARDS in the pig. After premedication (ketamine and midazolam) 35 healthy pigs were anesthetized (propofol, midazolam, morphin, pipecuronium) and orotracheally intubated and ventilated. Primary ARDS was induced by repeated cycles of lung lavage with a detergent Triton X100 diluted in saline (0.03 %) heated to 37 degrees C preceded by pre-oxygenation with 100 % O(2). Single cycle included two subsequent lavages followed by detergent suction. Each cycle was followed by hemodynamic and ventilation stabilization for approx. 15 min, with eventual administration of vasopressors according to an arterial blood pressure. The lavage procedure was repeated until the paO(2)/FiO(2) index after stabilization remained below 100 at PEEP 5 cm H(2)O. In 33 pigs we have achieved the desired degree of severe ARDS (PaO(2)/FiO(2)<100). Typical number of lavages was 2-3 (min. 1, max. 5). Hemodynamic tolerance and the need for vasopressors were strongly individual. In remaining two animals an unmanageable hypotension developed. For other subjects the experimental ARDS stability was good and allowed reliable measurement for more than 10 h. The present model of the ARDS is clinically relevant and thus it is suitable for further research of the pathophysiology and management of this serious medical condition. PMID- 28006947 TI - Lung inflammatory and oxidative alterations after exogenous surfactant therapy fortified with budesonide in rabbit model of meconium aspiration syndrome. AB - Meconium aspiration syndrome (MAS) triggers inflammatory and oxidative pathways which can inactivate both pulmonary surfactant and therapeutically given exogenous surfactant. Glucocorticoid budesonide added to exogenous surfactant can inhibit inflammation and thereby enhance treatment efficacy. Neonatal meconium (25 mg/ml, 4 ml/kg) was administered intratracheally (i.t.) to rabbits. When the MAS model was prepared, animals were treated with budesonide i.t. (Pulmicort, 0.25 mg/kg, M+B); with surfactant lung lavage (Curosurf(r), 10 ml/kg, 5 mg phospholipids/ml, M+S) followed by undiluted Curosurf(r) i.t. (100 mg phospholipids/kg); with combination of budesonide and surfactant (M+S+B); or were untreated (M); or served as controls with saline i.t. instead of meconium (C). Animals were oxygen-ventilated for additional 5 h. Cell counts in the blood and bronchoalveolar lavage fluid (BAL), lung edema formation (wet/dry weight ratio), oxidative damage of lipids/ proteins and inflammatory expression profiles (IL-2, IL-6, IL-13, TNF-alpha) in the lung homogenate and plasma were determined. Combined surfactant+budesonide therapy was the most effective in reduction of neutrophil counts in BAL, oxidative damage, levels and mRNA expression of cytokines in the lung, and lung edema formation compared to untreated animals. Curosurf fortified with budesonide mitigated lung inflammation and oxidative modifications what indicate the perspectives of this treatment combination for MAS therapy. PMID- 28006948 TI - Intravenous dexamethasone attenuated inflammation and influenced apoptosis of lung cells in an experimental model of acute lung injury. AB - Acute lung injury (ALI) is characterized by diffuse alveolar damage, inflammation, and transmigration and activation of inflammatory cells. This study evaluated if intravenous dexamethasone can influence lung inflammation and apoptosis in lavage-induced ALI. ALI was induced in rabbits by repetitive saline lung lavage (30 ml/kg, 9+/-3-times). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with dexamethasone i.v. (0.5 mg/kg, Dexamed; ALI+DEX), and healthy non-ventilated controls (Control). After following 5 h of ventilation, ALI animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated. Lung edema was expressed as wet/dry weight ratio. Concentrations of IL-1beta, IL-8, esRAGE, S1PR3 in the lung were analyzed by ELISA methods. In right lung, apoptotic cells were evaluated by TUNEL assay and caspase-3 immunohistochemically. Dexamethasone showed a trend to improve lung functions and histopathological changes, reduced leak of neutrophils (P<0.001) into the lung, decreased concentrations of pro inflammatory IL-1beta (P<0.05) and marker of lung injury esRAGE (P<0.05), lung edema formation (P<0.05), and lung apoptotic index (P<0.01), but increased immunoreactivity of caspase-3 in the lung (P<0.001). Considering the action of dexamethasone on respiratory parameters and lung injury, the results indicate potential of this therapy in ALI. PMID- 28006949 TI - Autism spectrum disorder is associated with autonomic underarousal. AB - Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder, associated with autonomic dysregulation. However, the pathomechanism leading to autonomic abnormalities is still unclear. The aim of this study was to assess autonomic nervous system (ANS) activity during baseline in homogenous group of autistic children using electrodermal activity (EDA), as an index of sympathetic activity and short-term heart rate variability (HRV) reflecting predominantly cardiac vagal control. Fifteen ASD boys and 15 healthy age-matched boys at the age of 7-15 years were examined. The continuous EDA and ECG were recorded during resting phase in a supine position. Evaluated parameters: EDA amplitude (microS), RR interval, spectral power, peak frequency and power spectral density in low (LF HRV: 0.04-0.15 Hz) and high-frequency (HF-HRV: 0.15-0.4 Hz) bands of HRV spectral analysis. In ASD group we found significantly shortened RR intervals (729+/-20 ms vs. 843+/-30 ms, p=0.005), lower mean EDA (0.66+/-0.13 microS vs. 1.66+/-0.42 microS, p=0.033), reduced spectral activity and power spectral density in HF-HRV compared to controls (2.93+/-0.12 ms(2) vs. 3.38+/-0.10 ms(2), p=0.01; 4.12+/ 0.10 ms(2)/Hz vs. 4.56+/-0.11 ms(2)/Hz, p=0.008, respectively). We suggest that impairment in resting autonomic regulation associated with ASD could represent an important pathomechanism leading to potential cardiovascular complications in ASD. PMID- 28006951 TI - Influence of External Subglottic Air Flow on Dysphagic Tracheotomized Patients With Severe Brain Injury. AB - OBJECTIVE: The aim of this study was to determine if external subglottic air flow (ESAF) influences swallowing frequency in severely dysphagic tracheotomized patients with brain injury. METHODS: Ten patients were recruited at the neurological intensive care unit. The ESAF intervention was provided through the standard cuffed suction aid tracheotomy tube, which primarily is used to suction residual secretion volume from the subglottic area. Sessions were 150 minutes, and ESAF was provided at 60-65, 90-95, and 120-125 minutes at 3 L/min. Outcome measures included swallowing frequency (swallows/5 min) at 0-5 minutes (pre baseline), 25-30 and 55-60 minutes (baseline/control), and 85-90, 115-120, and 145-150 minutes (postintervention). The residual secretion volume (ml) from the subglottic area was collected using a syringe at 0 minutes (pre-baseline), 30 and 60 minutes (baseline/ control), and at 90, 120, and 150 minutes (postintervention). RESULTS: The mean (+/-SEM) swallowing frequency (swallows/5 min) increased from 0.60 +/- 0.30 to 2.10 +/- 0.70 during the ESAF intervention ( P < .001). The mean (+/-SEM) residual secretion volume reduced from 3.10 +/- 0.31 ml to 0.50 +/- 0.30 ml after the ESAF intervention ( P < .001). CONCLUSION: The increase in swallowing frequency and reduction in residual secretion volume may indicate that ESAF influences swallowing parameters in patients with tracheotomy tubes. PMID- 28006950 TI - Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function. AB - AIMS: Cigarette smoke (CS)-mediated acquired cystic fibrosis transmembrane conductance regulator (CFTR)-dysfunction, autophagy-impairment, and resulting inflammatory-oxidative/nitrosative stress leads to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Moreover, nitric oxide (NO) signaling regulates lung function decline, and low serum NO levels that correlates with COPD severity. Hence, we aim to evaluate here the effects and mechanism(s) of S nitrosoglutathione (GSNO) augmentation in regulating inflammatory-oxidative stress and COPD-emphysema pathogenesis. RESULTS: Our data shows that cystic fibrosis transmembrane conductance regulator (CFTR) colocalizes with aggresome bodies in the lungs of COPD subjects with increasing emphysema severity (Global Initiative for Chronic Obstructive Lung Disease [GOLD] I - IV) compared to nonemphysema controls (GOLD 0). We further demonstrate that treatment with GSNO or S-nitrosoglutathione reductase (GSNOR)-inhibitor (N6022) significantly inhibits cigarette smoke extract (CSE; 5%)-induced decrease in membrane CFTR expression by rescuing it from ubiquitin (Ub)-positive aggresome bodies (p < 0.05). Moreover, GSNO restoration significantly (p < 0.05) decreases CSE-induced reactive oxygen species (ROS) activation and autophagy impairment (decreased accumulation of ubiquitinated proteins in the insoluble protein fractions and restoration of autophagy flux). In addition, GSNO augmentation inhibits protein misfolding as CSE-induced colocalization of ubiquitinated proteins and LC3B (in autophagy bodies) is significantly reduced by GSNO/N6022 treatment. We verified using the preclinical COPD-emphysema murine model that chronic CS (Ch-CS)-induced inflammation (interleukin [IL]-6/IL-1beta levels), aggresome formation (perinuclear coexpression/colocalization of ubiquitinated proteins [Ub] and p62 [impaired autophagy marker], and CFTR), oxidative/nitrosative stress (p-Nrf2, inducible nitric oxide synthase [iNOS], and 3-nitrotyrosine expression), apoptosis (caspase-3/7 activity), and alveolar airspace enlargement (Lm) are significantly (p < 0.05) alleviated by augmenting airway GSNO levels. As a proof of concept, we demonstrate that GSNO augmentation suppresses Ch-CS-induced perinuclear CFTR protein accumulation (p < 0.05), which restores both acquired CFTR dysfunction and autophagy impairment, seen in COPD-emphysema subjects. INNOVATION: GSNO augmentation alleviates CS-induced acquired CFTR dysfunction and resulting autophagy impairment. CONCLUSION: Overall, we found that augmenting GSNO levels controls COPD-emphysema pathogenesis by reducing CS-induced acquired CFTR dysfunction and resulting autophagy impairment and chronic inflammatory oxidative stress. Antioxid. Redox Signal. 27, 433-451. PMID- 28006952 TI - Comparison of Antibody Responses Induced by RV144, VAX003, and VAX004 Vaccination Regimens. AB - The RV144 prime-boost regimen demonstrated efficacy against HIV acquisition while VAX003 and VAX004 did not. Although these trials differed by risk groups, immunization regimens, and immunogens, antibody responses may have contributed to the differences observed in vaccine efficacy. We assessed HIV-specific IgG, both total and subclass, and IgA binding to HIV envelope (Env): gp120 proteins and Cyclic V2 (CycV2) and CycV3 peptides and gp70 V1 V2 scaffolds in these 3 HIV vaccine trials. After two protein immunizations, IgG responses to 92TH023 gp120 (contained in ALVAC-HIV vaccine) were significantly higher in RV144 but responses to other Env were higher in the VAX trials lacking ALVAC-HIV. IgG responses declined significantly between vaccinations. All trials induced antibodies to gp70 V1 V2 but VAX004 responses to 92TH023 gp70 V1 V2 were weak. All CycV2 responses were undetectable in VAX004 while 92TH023 gp70 V1 V2 was detected in both RV144 and VAX003 but MN CycV2 was detected only in VAX003. Multiple protein vaccinations in VAX trials did not improve magnitude or durability of V1 V2 and CycV2 antibodies. Herpes simplex virus glycoprotein D (gD) peptide at the N terminus of AIDSVAX(r) B/E and B/B gp120 proteins induced antibodies in all trials, although significantly higher in VAX trials. gD peptide induced IgA, IgG1, IgG2, and IgG3 but not IgG4. Multiple protein vaccinations decreased IgG3 and increased IgG4 changing subclass contribution to total IgG. Although confounded by different modes of HIV transmission, higher Env-specific IgA and IgG4 binding antibodies induced in the VAX trials compared to RV144 raises the hypothesis that these differences may have contributed to different vaccine efficacy results. PMID- 28006953 TI - Lymphocyte Communication in Myocardial Ischemia/Reperfusion Injury. AB - SIGNIFICANCE: Myocardial ischemia/reperfusion (I/R) is an important complication of reperfusion therapy for myocardial infarction (MI). It is a complex process involving metabolic and immunological factors. To date, no effective treatment has been identified. Recent Advances: Previous research has focused on the role of innate immune cells in I/R injury. In recent years, increasing evidence has accumulated for an important role for adaptive immune cells, particularly T lymphocytes. Data from ST elevation MI patients have identified prognostic significance for lymphocyte counts, particularly postreperfusion lymphopenia. Dynamic changes in circulating CD4+ T cell subsets occurring early after reperfusion are associated with development of I/R injury in the form of microvascular obstruction. Transcoronary gradients in cell counts suggest sequestration of these cells into the reperfused myocardium. These findings support existing data from mouse models indicating a role for CD4+ T cells in I/R injury. It is clear, however, the effects of lymphocytes in the ischemic myocardium are time and subset specific, with some having protective effects, while others are pathogenic. CRITICAL ISSUES: An understanding of the cellular events that lead to accumulation of lymphocytes in the myocardium, and their actions once there, is key to manipulating this process. Chemokines produced in response to ischemia and cellular injury have an important role, while lymphocyte derived cytokines are critical in the balance between inflammation and healing. FUTURE DIRECTIONS: Further research into the involvement of lymphocytes in myocardial I/R injury may allow development of targeted therapies, opening a new avenue of considerable therapeutic potential. Antioxid. Redox Signal. 26, 660 675. PMID- 28006955 TI - Speechless After a Roller Coaster Ride. PMID- 28006954 TI - The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor kappaB/Nuclear Transcription Factor Related to NF-E2. AB - AIM: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-kappaB (NF-kappaB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. RESULTS: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of alpha-synuclein-positive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN+/Nrf-2+ cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. INNOVATION: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-kappaB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. CONCLUSION: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471. PMID- 28006956 TI - Findings and Impact of Early Imaging After Partial Nephrectomy. AB - INTRODUCTION: American Urological Association guidelines for surveillance of renal-cell carcinoma after partial nephrectomy recommend imaging within 3-12 months of surgery. Imaging following partial nephrectomy may be difficult to interpret due to the surgical defect, the use of surgical material, and normal postoperative fluid collections. Our primary objective was to evaluate the frequency of indeterminate postoperative imaging results and how those radiographic findings altered patient management. METHODS: Retrospective chart review from 2006 to 2013 of patients who had undergone open, laparoscopic, and robotic partial nephrectomy at our institution was completed. There was a minimum of 2 years of follow-up imaging. Radiology reports were reviewed from follow-up imaging and were categorized as "normal" or "abnormal." RESULTS: We identified 180 patients with 127 (70.5%) considered to have normal findings on initial follow-up imaging, and 53 (29.5%) with abnormal findings. Median time to initial postoperative imaging for normal findings was 6.8 months compared with 4.4 months for patients with abnormal postoperative scans (p = 0.02). On subsequent imaging, 60% of abnormal studies were downgraded to normal. The median time to receive a second postoperative image from surgery in the normal and abnormal groups was 13.2 and 10.2 months, respectively. The median time interval to the second imaging study was 6.3 months for normal initial scans compared with 5.2 months for initially abnormal scans (p <= 0.01). CONCLUSIONS: Early postoperative imaging after partial nephrectomy frequently results in "abnormal" findings and more subsequent radiology exams even though the findings rarely represent cancer recurrences. Based on our results, and pending further validation from other centers, we believe postoperative CT or MRI surveillance after partial nephrectomy can be safely deferred until 1 year after surgery. PMID- 28006957 TI - The Role of Robot-Assisted Radical Prostatectomy in High-Risk Prostate Cancer. AB - Prostate cancer (PCa) is stratified into different risk categories based on the patient's prognosis. High-risk disease was formerly characterized by an increased risk of metastasis and lethality, requiring complex treatments. Surgery was recently highlighted to have a pivotal role for the treatment of such cases, even as monotherapy. In the past, open radical prostatectomy was performed for most patients with high-risk PCa; however, robot-assisted radical prostatectomy (RARP) emerged as a reasonable option because it provided optimal outcomes for low- and intermediate-risk PCa. Robust studies are lacking to properly assess the role of RARP for high-risk PCa. We summarize this knowledge and present a literature review on the perioperative recovery and functional and oncologic outcomes of RARP for the treatment of patients with high-risk PCa. PMID- 28006958 TI - Positive and Negative Themes Found in Superhero Films. AB - Superhero films have become incredibly popular. The objective of this study was to determine the positive and negative themes found in a select number of superhero films. A total of 30 superhero films were analyzed. The average numbers of positive and negative themes were 19.4 and 29.5 mean events per hour for all included films, respectively. The most common positive themes were "assisting others/protecting the public," "positive relationships with family/friends," and "teamwork/collaboration." The most common negative themes were "acts of violence/fighting," "use of guns/knives/lethal weapons," and "bullying/intimidation/torture." Based on the superhero films included in our study, the number of negative themes, especially acts of violence, outweighs positive themes. Although an exposure to positive themes found in superhero films may be beneficial to the development of children, pediatric health care providers should counsel children and their families in an attempt to limit their exposure to violence. PMID- 28006959 TI - Severe Anemia and "Splenomegaly". PMID- 28006960 TI - Lower Extremity Fibromuscular Dysplasia: Clinical Manifestations, Diagnostic Testing, and Approach to Management. AB - Fibromuscular dysplasia (FMD), a disease well described in the renal and cerebrovascular circulations, also manifests in the lower extremity (LE) arteries. This study reports on the clinical presentation, imaging findings, and treatment of patients with LE FMD seen at a single center. Over a 7-year span, 100 of 449 patients with FMD had imaging of the LE arteries, of which 62 were found to have LE FMD (13.8% of the entire FMD cohort including patients with and without LE imaging). The majority of patients were women (96.8%), with an average age of 52 +/- 11.3 years at the time of diagnosis. All patients had FMD present in another vascular bed, most commonly in the renal (80.6%) and extracranial carotid arteries (79.0%). Most patients had multifocal FMD (95.2%) and bilateral LE disease (69.4%), with the external (87.1%), common (19.4%), and internal (11.3%) iliac arteries most commonly affected. Presenting symptoms of LE involvement included claudication (22.6%), atypical leg symptoms (14.5%), and dissection (6.5%), but most patients were asymptomatic (71.0%). Nearly all patients were managed conservatively (98.4%) and only 1 patient required intervention. PMID- 28006961 TI - Key Informants' Perceptions on the Implementation of a National Program for Improving Nutritional Status of Children in Iran. AB - INTRODUCTION: Childhood malnutrition is a major public health issue. Multidisciplinary approach for Improvement of Nutritional Status of Children in Iran was implemented in order to reduce malnutrition among children. OBJECTIVE: This study aimed to evaluate the implementation aspect of the program and to explore key informants' perceptions and experience regarding the factors affected its implementation. METHODS: Data were collected through the review of secondary data and semistructured interviews at national, province, and local levels. Four layers of key informants were selected purposefully for interviewing, including policymakers, senior nutrition officers, head of Hygiene, Remedy and Insurance Affairs in Imam Khomeini Relief Foundation, and community health workers. Qualitative content analysis was carried out based on Supporting the Use of Research Evidence framework and Tailored Implementation for Chronic Diseases' checklist to interpret the viewpoints of the study participants. RESULTS: Results showed that the program had successes in improving mother's knowledge on health, nutrition, and child care through health system and increased families' access to food, but there were some aspects that affected program's implementation. Some of these factors are the lack of clarity in the program's protocol and indicators, human shortage and inadequate financial resources, poor facilities, inattention to staff motivation, insufficient commitment among different sections, poor communication and supervision among different executive sections, and program protocols designing regardless of practical condition. CONCLUSION: Based on the results, top-down approach in policymaking and inadequate financial and human resources were responsible for most of the challenges encountered in the implementation. PMID- 28006962 TI - Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease. AB - Collagen is a macromolecule that has versatile roles in physiology, ranging from structural support to mediating cell signaling. Formation of mature collagen fibrils out of procollagen alpha-chains requires a variety of enzymes and chaperones in a complex process spanning both intracellular and extracellular post-translational modifications. These processes include modifications of amino acids, folding of procollagen alpha-chains into a triple-helical configuration and subsequent stabilization, facilitation of transportation out of the cell, cleavage of propeptides, aggregation, cross-link formation, and finally the formation of mature fibrils. Disruption of any of the proteins involved in these biosynthesis steps potentially result in a variety of connective tissue diseases because of a destabilized extracellular matrix. In this review, we give a revised overview of the enzymes and chaperones currently known to be relevant to the conversion of lysine and proline into hydroxyproline and hydroxylysine, respectively, and the O-glycosylation of hydroxylysine and give insights into the consequences when these steps are disrupted. PMID- 28006963 TI - Re: "Polymorphisms of three genes (ACE, AGT and CYP11B2) in the renin-angiotensin aldosterone system are not associated with blood pressure salt sensitivity: a systematic meta-analysis". PMID- 28006964 TI - Virtual rehabilitation in 2016 - a maturing field with a broadening horizon. PMID- 28006965 TI - Nucleolus-like compartmentalization of the transcription machinery in fast growing bacterial cells. AB - We have learned a great deal about RNA polymerase (RNA Pol), transcription factors, and the transcriptional regulation mechanisms in prokaryotes for specific genes, operons, or transcriptomes. However, we have only begun to understand how the transcription machinery is three-dimensionally (3D) organized into bacterial chromosome territories to orchestrate the transcription process and to maintain harmony with the replication machinery in the cell. Much progress has been made recently in our understanding of the spatial organization of the transcription machinery in fast-growing Escherichia coli cells using state-of-the art superresolution imaging techniques. Co-imaging of RNA polymerase (RNA Pol) with DNA and transcription elongation factors involved in ribosomal RNA (rRNA) synthesis, and ribosome biogenesis has revealed similarities between bacteria and eukaryotes in the spatial organization of the transcription machinery for growth genes, most of which are rRNA genes. Evidence supports the notion that RNA Pol molecules are concentrated, forming foci at the clustering of rRNA operons resembling the eukaryotic nucleolus. RNA Pol foci are proposed to be active transcription factories for both rRNA genes expression and ribosome biogenesis to support maximal growth in optimal growing conditions. Thus, in fast-growing bacterial cells, RNA Pol foci mimic eukaryotic Pol I activity, and transcription factories resemble nucleolus-like compartmentation. In addition, the transcription and replication machineries are mostly segregated in space to avoid the conflict between the two major cellular functions in fast-growing cells. PMID- 28006967 TI - Remaining in the nursing profession: The relevance of strong evaluations. AB - BACKGROUND:: Why nurses remain in the profession is a complex question. However, strong values can be grounds for their remaining, meaning nurses evaluate the qualitative worth of different desires and distinguish between senses of what is a good life. RESEARCH QUESTION:: The overall aim is to explore and argue the relevance of strong evaluations for remaining in the nursing profession. RESEARCH DESIGN:: This theoretical article based on a hermeneutical approach introduces the concept strong evaluations as described by the Canadian philosopher Charles Taylor and provides examples of nurses' experiences in everyday nursing care drawn from a Norwegian empirical study. PARTICIPANTS AND RESEARCH CONTEXT:: Data collected in the original study consisted of qualitative interviews and qualitative follow-up interviews with 13 nurses. The research context was the primary and secondary somatic and psychiatric health service, inside as well as outside institutions. ETHICAL CONSIDERATION:: The article uses data from an original empirical study approved by the Norwegian Social Science Data Services. Information was given and consent obtained from the participants. FINDINGS:: Remaining in the nursing profession can be understood as revolving around being a strong evaluator. This has been concretized in issues of being aware of different incidents in life and having capacities as a nurse. DISCUSSION:: Why nurses remain is discussed in relation to how nurses have shaped themselves by reflecting on what is of significance in their life. However, being a strong evaluator cannot be seen as the casual condition for remaining. CONCLUSION:: Remaining in the nursing profession is obviously not a contingent matter, rather it is a matter concerned with the qualitative worth of different desires and values. Nurses' awareness of a life choice impacts on whether they remain or not. Consequently, nurses may need to articulate and reflect on their priorities for remaining. PMID- 28006966 TI - Social Jetlag Among Night Workers is Negatively Associated with the Frequency of Moderate or Vigorous Physical Activity and with Energy Expenditure Related to Physical Activity. AB - This cross-sectional study analyzed the association between physical activity (PA) and social jetlag (SJL) among shift workers. We evaluated 423 employees, aged between 18 and 60 years, who worked in a poultry-processing company in Brazil. Physical activity levels (PAL) were determined by the short form of the International Physical Activity Questionnaire (IPAQ-SF). SJL was calculated as the absolute difference between the time of mid-sleep on work and free days. The percentage of workers insufficiently active was high on all shifts, with no significant differences between the 3 shifts. The amount of time spent in sedentary behavior on workdays did not differ between shifts. Among night-shift workers, negative associations were observed between SJL and 1) the duration and weekly energy expenditure while walking; 2) the frequency of moderate and vigorous PA; and 3) the total energy expenditure related to PA. Even though PAL did not differ among workers on different shifts, we found a high prevalence of subjects who were insufficiently active or too sedentary among all groups. Also, SJL was negatively associated with PA in night-shift workers. These results suggest that PA should be encouraged among shift workers and that SJL may be an important factor in reducing PA in this cohort. PMID- 28006968 TI - The European Union's Ambient and Assisted Living Joint Programme: An evaluation of its impact on population health and well-being. AB - The Ambient Assisted Living Joint Programme, instituted in 2008 by the European Union, aimed to create better living conditions for older adults through the funding of information and communications technology projects. This review aimed to uncover what can be learned from the Ambient Assisted Living Joint Programme by determining (1) the target populations served, (2) technology-based interventions used and (3) effects on health and well-being outcomes. Information from the Ambient Assisted Living catalogue, project websites and deliverables and from papers in PubMed and EMBASE was reviewed. Overall, 152 projects from the first six rounds of funding were identified. Sensors, computers, phones, tablets and televisions were used for various purposes, that is, monitoring, feedback, coaching, reminders and communication. In total, 12 projects reported evaluating health and well-being outcomes; however, these evaluations demonstrated poor methodological quality. Only three projects reported exact values. For all other projects, published evidence on the effect of these projects on health and well being outcomes was not available. PMID- 28006969 TI - Urban and rural mortality and survival in Medieval England. AB - BACKGROUND: Late medieval England underwent intensive urbanisation, particularly in its largest city: London. Urban dwellers were exposed to factors such as high population density, elevated risk of infection, unsanitary living conditions and precarious food supplies. AIM: To assess whether the urban environment was more detrimental to health than the rural environment, this study compares risks of mortality and survival, as proxies for health, in medieval urban vs rural England. SUBJECTS AND METHODS: This study uses samples from rural St. Peter's cemetery in Barton-upon-Humber, Lincolnshire (c. 1150-1500) and urban St. Mary Spital cemetery in London (c. 1120-1539). Cox proportional hazards analysis and Kaplan-Meier survival analysis are used to assess differences in mortality and survival between urban and rural environments, including differences between sexes. RESULTS: The results indicate that urban adults faced elevated risks of dying and reductions in survivorship. Specifically, urban females faced elevated risks of dying and reductions in survivorship, while the risks for males were similar in both environments. DISCUSSION: These results suggest that the effects of urbanisation in medieval England varied by sex. Deleterious conditions associated with urbanisation in London were hazardous for adults, particularly females who may have migrated into London from rural areas for labour opportunities. PMID- 28006970 TI - Phase II Clinical Trial of Atorvastatin in Mild Traumatic Brain Injury. AB - Statins constitute a class of medications commonly used in the treatment of elevated cholesterol. However, in experimental studies, statins also have other non-cholesterol-mediated mechanisms of action, which may have neuroprotective effects. The aim of this study was to determine whether administration of atorvastatin for 7 days post-injury would improve neurological recovery in patients with mild traumatic brain injury (mTBI). The hypothesis was that atorvastatin administration would reduce post-concussion symptoms and also that atorvastatin administration for 1 week post-injury would be safe. One hundred forty patients with mTBI were planned to be enrolled and randomly assigned to receive atorvastatin 1 mg/kg (up to 80 mg/kg) per day or placebo for 7 days starting within 24 h of injury. Assessments of post-concussion syndrome, post traumatic stress and depressive symptoms, cognition, memory, verbal fluency, functional, and work status were performed at baseline, 1 week, and 1 and 3 months. The result on the Rivermead Post-Concussion Symptoms Questionnaire at 3 months was the primary outcome. Enrollment in the trial was stopped early because of difficulty in recruiting sufficient numbers of subjects. Fifty-two patients with mTBI were enrolled; 28 patients received atorvastatin and 24 received placebo. The median Rivermead score was 2 for the atorvastatin group, compared to 3.5 for the placebo group, at 3 months post-injury (chi2(1) = 0.0976; p = 0.7547). The change in the Rivermead score between baseline and 3 months was also analyzed. The median decrease in score was 4 for the atorvastatin group and 10.5 for the placebo group (chi2(1) = 0.8750; p = 0.3496). No serious adverse events occurred, and there was no significant difference in the incidence of adverse events in the two treatment groups. Atorvastatin administration for 7 days post injury was safe, but there were no significant differences in neurological recovery post-mTBI with atorvastatin. PMID- 28006971 TI - Association of clinical headache features with stroke location: An MRI voxel based symptom lesion mapping study. AB - Background We have recently shown that the presence of headache in ischemic stroke is associated with lesions of the insular cortex. The aim of this post-hoc subgroup analysis was to investigate the association of specific headache features with stroke location in patients with acute ischemic stroke. Methods In this observational study, patients (mean age: 61.5, 58% males) with ischemic stroke and acute headache (n = 49) were investigated. Infarcts were manually outlined on 3D diffusion weighted magnetic resonance imaging (MRI) scans and transformed into standard stereotaxic space; lesions of the left hemisphere were mirrored in the x-axis to allow a voxel-wise group analysis of all patients. We analyzed the association of lesion location and the following phenotypical characteristics by voxel-based symptom lesion mapping: Headache intensity, different qualities of headache (pulsating, tension-type like and stabbing), and the presence of nausea, of cranial autonomic symptoms and of light or noise sensitivity. Results Headache intensity was associated with lesions of the posterior insula, the operculum and the cerebellum. "Pulsating" headache occurred with widespread cortical and subcortical strokes. The presence of "tension-like" and "stabbing" headache was not related to specific lesion patterns. Nausea was associated with lesions in the posterior circulation territory. Cranial-autonomic symptoms were related to lesions of the parietal lobe, the somatosensory cortex (SI) and the middle temporal cortex. The presence of noise sensitivity was associated with cerebellar lesions, whereas light sensitivity was not related to specific lesions in our sample. Conclusion Headache phenotype in ischemic stroke appears to be related to specific ischemic lesion patterns. PMID- 28006973 TI - Perceptions of emotion and age among younger, midlife, and older adults. AB - OBJECTIVES: Older adults report greater emotional well-being than younger persons, yet negative stereotypes about aging are pervasive. Little is known about age group perceptions of emotion in adulthood, particularly for familiar persons. Thus, this project determined perceptions of general affect in familiar younger and older adults. METHOD: In two studies, participants (Study 1, younger adult n = 123, older adult n = 43; Study 2, younger adult n = 34, midlife adult n = 41, older adult n = 16) provided self-report data about their affect in general, as well as reported on the affect of a familiar younger person (aged 18- 34) and a familiar older person (aged 65 or older). Emotion scales assessed high- and low-arousal positive and negative affect. RESULTS: Results suggest a less favorable perception of emotion experiences of older adults compared to younger adults. Specifically, participants of all age groups rated older adults as having lower positive emotions and higher negative emotions than is found in self-report data. CONCLUSION: Perceptions of emotion in older adulthood reflect stereotypes of negative functioning. Older adult participants were not immune to holding negative views about older adults. Negative perceptions about emotion experiences in later life may be detrimental to the physical and mental health of older adults. PMID- 28006972 TI - Identifying HIV care enrollees at-risk for cannabis use disorder. AB - Increased scientific attention given to cannabis in the United States has particular relevance for its domestic HIV care population, given that evidence exists for both cannabis as a therapeutic agent and cannabis use disorder (CUD) as a barrier to antiretroviral medication adherence. It is critical to identify relative risk for CUD among demographic subgroups of HIV patients, as this will inform detection and intervention efforts. A Center For AIDS Research Network of Integrated Clinical Systems cohort (N = 10,652) of HIV-positive adults linked to care at seven United State sites was examined for this purpose. Based on a patient-report instrument with validated diagnostic threshold for CUD, the prevalence of recent cannabis use and corresponding conditional probabilities for CUD were calculated for the aggregate sample and demographic subgroups. Generalized estimating equations then tested models directly examining patient demographic indices as predictors of CUD, while controlling for history and geography. Conditional probability of CUD among cannabis-using patients was 49%, with the highest conditional probabilities among demographic subgroups of young adults and those with non-specified sexual orientation (67-69%) and the lowest conditional probability among females and those 50+ years of age (42% apiece). Similarly, youthful age and male gender emerged as robust multivariate model predictors of CUD. In the context of increasingly lenient policies for use of cannabis as a therapeutic agent for chronic conditions like HIV/AIDS, current study findings offer needed direction in terms of specifying targeted patient groups in HIV care on whom resources for enhanced surveillance and intervention efforts will be most impactful. PMID- 28006974 TI - Resilience Style Questionnaire. AB - The present research aims to develop and validate a measure of resilience that reflects the influence of Confucian philosophies and Chinese cultural lay beliefs. Based on a representative sample of 1,419 college students from universities and a clinical sample of 214 cardiac patients in Hong Kong, reliability, construct validity, and criterion validity of the Resilience Style Questionnaire (RSQ) were examined. A two-factor structure of the RSQ was explored and validated in both samples. Results showed that the two factors of the RSQ (i.e., perseverance and optimistic approach to life) were significantly associated with a variety of mental health indicators in both samples. Furthermore, the RSQ explained additional variances above and beyond those explained by the Ego-Resiliency Scale, the Sense of Coherence Scale (SOC), and the Connor-Davidson Resilience Scale in multiple mental health indicators among college students and cardiac patients. These findings showed that the RSQ is a reliable and valid tool in assessing resilience among Chinese and other groups influenced by Confucianism. PMID- 28006975 TI - Positive IgM in Congenital CMV Infection. AB - Neonatal serum detection of cytomegalovirus (CMV) immunoglobulin M (IgM) has low sensitivity in identifying congenital cytomegalovirus (cCMV). Several reports have endeavored to associate the presence/absence of IgM to disease severity. Data were collected for all infants with cCMV followed in our clinic. Infant outcome after birth was compared between infants who tested positive or negative. Sensitivity of positive IgM in diagnosing cCMV was 40.7%. The rate of symptomatic disease in those who tested positive was statistically higher (67.7%, P < .001). Odds ratio for symptomatic disease in infants with positive IgM born after a maternal primary infection was 3.47 (95% confidence interval = 1.7-7.1). Positive IgM was found in only 48.8% of symptomatic and 22.1% of asymptomatic children. Our results demonstrated a low sensitivity of IgM in diagnosing cCMV. However, while a positive IgM antibody for CMV is associated with a more symptomatic disease, it does not serve as a precise laboratory marker for a severity. PMID- 28006977 TI - Age and the experience of strong self-conscious emotion. AB - OBJECTIVES: It remains unclear whether there are age-related changes in the experience of strong self-conscious emotion, such as shame, guilt, pride and embarrassment. Because shame and guilt figure prominently in the aetiology of depressive symptoms and other mental health problems, a better understanding of how age affects the strong experience of these two negative self-conscious emotions is of particular importance. METHODS: Thirty younger, 30 middle-aged and 30 older adults were compared on standardised cognitive assessments, in addition to an interview-based measure that assessed whether there are age differences in the likelihood of strongly experiencing four different types of self-conscious emotion within the past five years (shame, guilt, embarrassment and pride). RESULTS: The three groups did not differ in their likelihood of reporting an event that strongly elicited the positive self-conscious emotion of pride. However, older adults were more likely to report sources of pride that were other (as opposed to self) focused. Older adults were also less likely to report experiencing events that elicited all three negative self-conscious emotions, in particular, shame. CONCLUSIONS: Strong negative self-conscious emotion, and in particular shame, appears to be experienced less by older than younger adults. PMID- 28006978 TI - The stories we tell: how age, gender, and forgiveness affect the emotional content of autobiographical narratives. AB - OBJECTIVES: Researchers have been attempting to understand the variables that predict differences in autobiographical narratives, given that these differences often reveal important information about the psychological characteristics of the person providing the narrative. METHOD: A sample of young adults (n = 80) and older adults (n = 80) completed a battery of self-report measures in addition to an autobiographical narrative task in which they described a negative emotional experience. These narratives were transcribed and entered into a text analysis program. RESULTS: Results indicated a significant three-way interaction (age * gender * forgiveness) for negative emotion words. Results also indicated two significant two-way interactions (age * forgiveness and gender * forgiveness) and one significant main effect for anger words. There were no significant findings related to anxiety or sad words. DISCUSSION: Results are discussed in the context of Socioemotional Selectivity Theory, which asserts that social and emotional goals shift throughout the lifespan such that older adults are more motivated to regulate their emotions than young adults. Clinical applications and future directions are discussed. PMID- 28006976 TI - Contrasting Effects of Posttraumatic Stress Disorder and Mild Traumatic Brain Injury on the Whole-Brain Resting-State Network: A Magnetoencephalography Study. AB - The aim of this study was to evaluate alterations in whole-brain resting-state networks associated with posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Networks were constructed from locations of peak statistical power on an individual basis from magnetoencephalography (MEG) source series data by applying the weighted phase lag index and surrogate data thresholding procedures. Networks representing activity in the alpha bandwidth as well as wideband activity (DC-80 Hz) were created. Statistical comparisons were adjusted for age and education level. Alpha network results demonstrate reductions in network structure associated with PTSD, but no differences associated with mTBI. Wideband network results demonstrate a shift in connectivity from the alpha to theta bandwidth in both PTSD and mTBI. Also, contrasting alterations in network structure are noted, with increased randomness associated with PTSD and increased structure associated with mTBI. These results demonstrate the potential of the analysis of MEG resting-state networks to differentiate two highly comorbid conditions. The importance of the alpha bandwidth to resting-state connectivity is also highlighted, while demonstrating the necessity of considering activity in other bandwidths during network construction. PMID- 28006979 TI - Dyslipidemia Screening of 9- to 11-Year-Olds at Well-Child Visits by Utah Pediatricians. AB - In 2011, an expert National Institutes of Health panel published the "Integrated Guidelines for CV Health and Risk Reduction in Children and Adolescents," which recommended screening all children aged 9 to 11 years for dyslipidemia. It is unknown if this guideline is being followed. We surveyed members of the Utah chapter of the American Academy of Pediatrics to determine whether they performed universal lipid screening at well-child visits (WCV) on their patients at 9,10, or 11 years and how comfortable they were with evaluating and/or managing children with dyslipidemia. Of the 118 respondents who practiced primary care, only 18 (15%) screened all children at WCV; 86 (73%) tested "some," most commonly children who were obese or had a positive family history. 18% were unfamiliar with the guidelines; 28% were familiar with the guidelines but felt they were "inappropriate;" 98 (84%) of the respondents said they were "very or somewhat comfortable" evaluating children with dyslipidemia. PMID- 28006980 TI - Gastric Bezoar Treatment Using Oral Coca-Cola. PMID- 28006981 TI - Accurate Detection of Streptococcus pyogenes at the Point of Care Using the cobas Liat Strep A Nucleic Acid Test. AB - The performance of a polymerase chain reaction-based point-of-care assay, the cobas Strep A Nucleic Acid Test for use on the cobas Liat System (cobas Liat Strep A assay), for the detection of group A Streptococcus bacteria was evaluated in primary care settings. Throat swab specimens from 427 patients were tested with the cobas Liat Strep A assay and a rapid antigen detection test (RADT) by existing medical staff at 5 primary care clinics, and results were compared with bacterial culture. The cobas Liat Strep A assay demonstrated equivalent sensitivity (97.7%) and specificity (93.3%) to reference culture with a 15-minute turnaround time. In comparison to RADTs, the cobas Liat Strep A assay showed improved sensitivity (97.7% Liat vs 84.5% RADT). The Clinical Laboratory Improvement Amendments-waived cobas Liat Strep A assay demonstrated the ease of use and improved turnaround time of RADTs along with the sensitivity of culture. PMID- 28006982 TI - Noninfectious Enterocolitis as Initial Presentation of Chronic Granulomatous Disease. PMID- 28006983 TI - Social networks and alcohol use among older adults: a comparison with middle-aged adults. AB - OBJECTIVES: This study compared the association between social networks and alcohol consumption among middle-aged (MA) and older adults (OA) to better understand the nature of the relationship between those two factors among OA and MA. METHOD: We examined Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Current drinkers aged over 50 were subdivided into two age groups: MA (50-64, n = 5214) and OA (65 and older, n = 3070). Each age group was stratified into drinking levels (low-risk vs. at-risk) based on alcohol consumption. The size and diversity of social networks were measured. Logistic regression models were used to examine age differences in the association between the social networks (size and diversity) and the probability of at-risk drinking among two age groups. RESULTS: A significant association between the social networks diversity and lower odds of at-risk drinking was found among MA and OA. However, the relationship between the diversity of social networks and the likelihood of at-risk drinking was weaker for OA than for MA. The association between social networks size and at-risk drinking was not significant among MA and OA. CONCLUSION: The current study suggests that the association between social networks diversity and alcohol use among OA differs from the association among MA, and few social networks were associated with alcohol use among OA. In the future, research should consider an in-depth exploration of the nature of social networks and alcohol consumption by using longitudinal designs and advanced methods of exploring drinking networks. PMID- 28006984 TI - Illness perception patterns in patients with Coronary Artery Disease. AB - The purpose of this study is to identify patterns of illness perception in patients with angiografically verified Coronary Artery Disease. A total of 166 patients (age: 64.4 +/- 12.1, 80.7% male) were recruited after angiography. Cluster analysis on the items of the Brief Illness Perception Questionnaire was used to identify patterns of illness perception. The resulting groups were characterized with regard to Quality of Life (MacNew), anxiety and depression (GAD-7 and PHQ-9) and resilience (RS-13). The analysis revealed 4 distinct groups differing with regard to the items covering the perception of the physical and emotional impact of disease. Stronger perceptions in these domains were associated with lower Health Related Quality of Life and higher levels of emotional distress. Group 1 (33.1%) reported the strongest perceptions of the physical and emotional impact of disease and expressed low treatment control, high chronic timeline and significantly higher levels of depression than the other groups. Group 2 (27.7%) was characterized by more moderate perceptions of the emotional and physical impact of disease together with low scores on illness coherence and chronic timeline. Groups 3 (25.3%) and 4 (13.9%) reported smaller physical and emotional impact of illness but differed in chronic timeline. Our results correspond largely to recent findings in patients with other chronic diseases. Further research is needed to explore if stratification of patients according patterns of illness perception can help to inform patient-physician communication strategies. PMID- 28006985 TI - Corticosteroid Treatment for Prolonged Fever in Hepatosplenic Cat-Scratch Disease: A Case Study. AB - Hepatosplenic cat-scratch disease (CSD) may cause prolonged fever. We present the case of a 4-year-old boy with confirmed hepatosplenic CSD with fever lasting 3 months despite use of multiple different antimicrobial agents. The patient became afebrile soon after corticosteroid therapy was started. Our case indicates corticosteroids may be useful in patients with hepatosplenic CSD and prolonged fever. PMID- 28006986 TI - Lymphomatoid Papulosis in a 2-Year-Old Girl With Markedly Elevated Antinuclear Antibodies: A Case Report. PMID- 28006987 TI - WITHDRAWN: Poor Feeding, Weight Loss, and Electrolyte Abnormalities in a Term Infant. PMID- 28006988 TI - The use of spirituality and religiosity in coping with colorectal cancer. AB - BACKGROUND: Spirituality and religiosity are reported as important in coping with cancer but rarely explored across cultures. OBJECTIVES: To explore and compare the use of spirituality and religiosity in coping with colorectal cancer in New Zealand and Iran. METHODS: A cross-sectional qualitative approach involving interviews conducted in New Zealand (n = 20) and Iran (n = 20). The data were analysed using thematic analysis. RESULTS: The majority of participants interviewed used religion as a resource in coping with cancer. A minority described spirituality as separate to religion and drew on spirituality either in relation to religion or alone. All Iranian participants viewed spirituality as intertwined with religion. CONCLUSION: Religious and/or spiritual beliefs formed an important source of support for all Iranians and the majority of New Zealand participants living with cancer. The ability of nurses to identify, recognise, and support these beliefs is important in the provision of holistic care. PMID- 28006989 TI - Development of a paradigm for studying the effects of brief Goal Management Training with Implementation Intentions. AB - Cognitive rehabilitation interventions such as Goal Management Training (GMT) and the Implementation Intentions strategy have been developed with the aim of improving prospective memory (PM) in everyday life. The aim of this study was to provide "proof of concept" for an experimental paradigm that could be used to evaluate the effects of Goal Management Implementation Intentions training (GMTii) derived from the principles of GMT and Implementation Intentions. Thirty adults were randomised to either GMTii or a control training condition. A computerised PM task that involved an ongoing task into which a PM task was embedded was completed pre-training and post-training. In addition, a novel yet similar PM task was completed post-training to assess generalisability of any effect. The two groups had similar overall performance pre-training. Post training, the GMTii group demonstrated significantly better performance on the familiar computerised PM task showing less performance decay over time compared to the control group. The GMTii group also showed better performance on the novel task. The results demonstrated that brief GMTii significantly improved PM performance compared to control training and that computerised PM tasks were sensitive to this effect. The results suggest that this paradigm could be used to study the effects of metacognitive rehabilitation interventions. PMID- 28006990 TI - Perioperative tamoxifen use and risk of deep vein thrombosis. PMID- 28006991 TI - Efficacy of Autologous Bone Marrow-Derived Mesenchymal Stem Cell and Mononuclear Cell Transplantation in Type 2 Diabetes Mellitus: A Randomized, Placebo Controlled Comparative Study. AB - Drugs targeting beta-cells have provided new options in the management of T2DM; however, their role in beta-cell regeneration remains elusive. The recent emergence of cell-based therapies such as autologous bone marrow-derived mesenchymal stem cells (ABM-MSCs) and mononuclear cells (ABM-MNCs) seems to offer a pragmatic approach to augment beta-cell function/mass. This study aims to examine the efficacy and safety of ABM-MSC and ABM-MNC transplantation in T2DM and explores alterations in glucose-insulin homeostasis by metabolic studies. Thirty patients of T2DM with duration of disease >=5 years, receiving triple oral antidiabetic drugs along with insulin (>=0.4 IU/Kg/day) with HbA1c <=7.5%(<=58.0 mmol/mol), were randomized to receive ABM-MSCs or ABM-MNCs through targeted approach and a sham procedure (n = 10 each). The primary endpoint was a reduction in insulin requirement by >=50% from baseline, while maintaining HbA1c <7.0% (<53.0 mmol/mol) during 1-year follow-up. Six of 10 (60%) patients in both the ABM-MSC and ABM-MNC groups, but none in the control group, achieved the primary endpoint. At 12 months, there was a significant reduction in insulin requirement in ABM-MSC (P < 0.05) and ABM-MNC groups (P < 0.05), but not in controls (P = 0.447). There was a significant increase in second-phase C-peptide response during hyperglycemic clamp in the ABM-MNC (P < 0.05) group, whereas a significant improvement in insulin sensitivity index (P < 0.05) accompanied with an increase in insulin receptor substrate-1 gene expression was observed in the ABM-MSC group. In conclusion, both ABM-MSCs and ABM-MNCs result in sustained reduction in insulin doses in T2DM. Improvement in insulin sensitivity with MSCs and increase in C-peptide response with MNCs provide newer insights in cell-based therapies. PMID- 28006992 TI - Increasing hip and knee flexion during a drop-jump task reduces tibiofemoral shear and compressive forces: implications for ACL injury prevention training. AB - Although most ACL injury prevention programmes encourage greater hip and knee flexion during landing, it remains unknown how this technique influences tibiofemoral joint forces. We examined whether a landing strategy utilising greater hip and knee flexion decreases tibiofemoral anterior shear and compression. Twelve healthy women (25.9 +/- 3.5 years) performed a drop-jump task before and after a training session (10-15 min) that emphasised greater hip and knee flexion. Peak tibiofemoral anterior shear and compressive forces were calculated using an electromyography (EMG)-driven knee model that incorporated joint kinematics, EMG and participant-specific muscle volumes and patella tendon orientation measured using magnetic resonance imaging (MRI). Participants demonstrated a decrease in peak anterior tibial shear forces (11.1 +/- 3.3 vs. 9.6 +/- 2.7 N . kg-1; P = 0.008) and peak tibiofemoral compressive forces (68.4 +/- 7.6 vs. 62.0 +/- 5.5 N . kg-1; P = 0.015) post-training. The decreased peak anterior tibial shear was accompanied by a decrease in the quadriceps anterior shear force, while the decreased peak compressive force was accompanied by decreased ground reaction force and hamstring forces. Our data provide justification for injury prevention programmes that encourage greater hip and knee flexion during landing to reduce tibiofemoral joint loading. PMID- 28006993 TI - The structural modification of natural products for novel drug discovery. AB - INTRODUCTION: Throughout history, natural products (NPs) have provided a rich source of compounds that have wide applications in the fields of medicine, health sciences, pharmacy and biology. Although naturally active substances are good lead compounds for the discovery of new drugs, most of them suffer from various deficiencies or shortcomings, such as complex structures, poor stability and solubility. Therefore, structural modification of NPs is needed to develop novel compounds with specific properties. Areas covered: This article presents an overview on the structural modifications of NPs in drug development. The application of multiple classes of NPs to the treatment of conditions such as cancers, infection, Alzheimer's and diabetes are discussed. This article also reveals that modification of NPs is a versatile approach to explore their mode of actions, which may lead to the discovery of novel drugs. Expert opinion: NPs are usually described by structural diversity and complexity. The use of isolated NPs as scaffolds for modification is a good approach to drug discovery and development. Despite many limitations associated with NPs, the total synthesis, semisynthetic modification, SAR-based modification, sometimes even a single atom alteration, may lead to the discovery of a novel drug. PMID- 28006994 TI - The role of human epididymis secretory protein E4 in patients with endometrial cancer and premalignant endometrial lesions. AB - We evaluated the concentrations of human epididymis secretory protein E4 (HE4) and Ca-125 in relation to clinicopathologic features in patients with endometrial cancer and premalignant endometrial lesions. Women with abnormal uterine bleeding (n = 167) who underwent endometrial sampling were divided into four groups. Group 1: endometrial cancer (n = 68), group 2: atypical endometrial hyperplasia (n = 12), group 3: endometrial hyperplasia without atypia (n = 39) and group 4: controls (n = 48). Women with endometrial cancer exhibited higher concentrations of HE4 levels than controls (91.4 pmol/L vs. 46.2 pmol/L, p < 0.001). HE4 levels were significantly higher in patients with lymphatic involvement, deep myometrial invasion, lymphovascular space involvement and non-endometrioid histology (p < 0.001). The sensitivity, specificity, positive and negative predictive values for HE4 in detecting endometrial cancer were 72.7%, 84.4%, 80% and 78.4%, respectively. Preoperative HE4 levels are more elevated in women with endometrial cancer than those with benign endometrium as well as in women with prognostic high-risk factors with endometrial cancer. HE4 may be used as an additional marker in combination with other clinicopathologic features for planning the treatment. PMID- 28006995 TI - New lipid formulation of octenidine dihydrochloride. AB - Octenidine dihydrochloride is an effective antiseptic compound which mode of action is based on destabilization plasma membrane of microorganisms. This ensures that microorganisms cannot develop the drug resistance in a straightforward way, as the entire cellular structure, rather than specific molecular target is affected. Since the octenidine is a hydrophobic compound, it requires organic solvent such as phenoxyethanol in order to be effectively administered. However, the presence of phenoxyethanol has strong irritating effect, particularly when applied on open wounds and mucous membranes. Phospholipids are known as neutral excipients free of side effects and in their aggregated form may serve as solvent for octenidine. In this article, we propose a new antiseptic formulation composed of equimolar ratio of lipids and octenidine. The resulting particles are ~4 nm in diameter showing that their topology is different from that known for liposomes. The new formulation has proven to be equally effective as octenidine dihydrochloride formulation marketed under the name of Octenisept(r). The main advantage of the new formulation is that it does not contain phenoxyethanol, which opens new possibilities for broader application spectrum of octenidine, including treatments of mucous membranes and open wounds. PMID- 28006996 TI - Profiles of Co-Occurring Difficulties Identified Through School-Based Screening. AB - OBJECTIVE: This study used latent class analysis to identify patterns of co occurrence among common childhood difficulties (inattention/hyperactivity, internalizing, externalizing, peer problems, and reading difficulties). METHOD: Parents and teachers of 501 children ages 6 to 9 provided mental health and social ratings, and children completed a reading task. RESULTS: Four latent classes were identified in the analysis of parent ratings and reading: one with inattention/hyperactivity, externalizing, peer problems, and internalizing difficulties; one with inattention/hyperactivity and reading difficulties; one with internalizing and peer problems; and one normative class. The analysis of teacher ratings and reading also identified four latent classes: one with inattention/hyperactivity and externalizing, one with inattention/hyperactivity and reading difficulties, one with internalizing problems, and one normative class. Children in latent classes characterized by one or more difficulties were more impaired than children in the normative latent class 1 year later. CONCLUSION: The results highlight the need for multifaceted interventions. PMID- 28006997 TI - Guidelines for biological treatment of substance use and related disorders, part 1: Alcoholism, first revision. AB - These practice guidelines for the biological treatment of alcohol use disorders are an update of the first edition, published in 2008, which was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). For this 2016 revision, we performed a systematic review (MEDLINE/PUBMED database, Cochrane Library) of all available publications pertaining to the biological treatment of alcoholism and extracted data from national guidelines. The Task Force evaluated the identified literature with respect to the strength of evidence for the efficacy of each medication and subsequently categorised it into six levels of evidence (A-F) and five levels of recommendation (1-5). Thus, the current guidelines provide a clinically and scientifically relevant, evidence-based update of our earlier recommendations. These guidelines are intended for use by clinicians and practitioners who evaluate and treat people with alcohol use disorders and are primarily concerned with the biological treatment of adults with such disorders. PMID- 28006998 TI - Supraventricular tachycardia during the first year of life: is subclinical inflammation the trigger? AB - BACKGROUND: Neutrophil/lymphocyte ratio (NLR) and red cell distribution width (RDW) may be associated with the onset of arrhythmias in adults, thus underlining a possible inflammatory etiology. Paroxysmal supraventricular tachycardia (SVT) is the most frequent pathological tachycardia in childhood. AIM: To verify NLR and RDW levels in a group of children (<1 year) affected by SVT with a structurally normal heart and without fever or inflammatory diseases; to compare NLR and RDW before and after SVT resolution, to verify whether the latter was related with the reduction in inflammatory state; to identify - in SVT subtypes caused by a reentry mechanism - an NLR and RDW cutoff point beyond which adenosine was ineffective in preventing SVT recurrence. METHODS: Eighteen SVT patients were recruited (mean age 18.9 +/- 3.2 days; 50% males) and compared with 18 healthy peers. RESULTS: NLR was higher in SVT group than in controls (p < 0.03). A significant difference was revealed between NLR values obtained on admission and at discharge (p < 0.05). On the contrary, no significant differences were found for RDW. It was not possible to identify NLR or RDW cutoffs capable of predicting SVT recurrence. However, all patients featuring SVT recurrence following adenosine injection presented with a lymphocyte count >6000/mm3. CONCLUSIONS: Elevated NLR is associated with an increased risk of SVT during the first year of life, while its decline looks like to lead the SVT resolution. A subclinical inflammatory status, as assessed by lymphocytes count, influences SVT recurrence. These results provide further support for an inflammatory etiology of SVT in babies. PMID- 28007000 TI - Reducing anger outbursts after a severe TBI: a single-case study. AB - Anger outbursts constitute a frequent behavioural issue after a traumatic brain injury (TBI) and have a strong negative impact on the social outcomes resulting from the TBI. However, few studies have examined the efficacy of specific intervention strategies to reduce the frequency and intensity of anger outbursts. We therefore performed a single-case study on this topic by administering two successive and complementary psychological interventions with an AB design with maintenance (first intervention) and an AC design with maintenance plus a one month follow-up (second intervention) to a patient with a severe TBI. Whereas the first intervention focused on improving the recognition and expression of basic emotions, the second consisted of a self-regulation programme, including various features such as psychoeducation about self-control strategies, relaxation and assertiveness training that aimed to establish adequate behaviours, which were further promoted by an implementation intentions strategy in the patient's daily life. The results indicated that all interventions resulted in a reduced frequency and intensity of anger outbursts, and the data upheld the specificity of these effects. In addition, a meta-analytic integration of the effects of both interventions on the outcomes indicated a medium effect size. Further research is needed on other patients who experience long-standing anger outbursts to examine whether the observed gains can be replicated, sustained on a longer-term basis and improved. PMID- 28006999 TI - Caregiver availability for severe stroke results in improved functional ability at discharge from inpatient rehabilitation. AB - PURPOSE: To evaluate the predictive capacity of caregiver availability on functional ability at time of discharge from inpatient rehabilitation in individuals with severe first-time stroke. METHODS: A retrospective chart review was conducted of severe stroke inpatients admitted to a stroke rehabilitation unit between April 2005 and December 2009. Follow-up telephone interviews were conducted with patients to determine caregiver availability at time of discharge. Hierarchical linear regression analysis was performed to assess the predictive capacity of caregiver availability on functional ability at discharge from an inpatient rehabilitation unit after controlling for covariates. RESULTS: Data from 180 individuals were included in the analysis. Individuals with a caregiver had significantly higher levels of functional ability at discharge compared to those without (85.8 +/- 23.6 versus 72.9 +/- 20.3; p < 0.01), although both groups achieved a minimal clinically important difference. After controlling for age, gender, admission Functional Independence Measure, and length of hospital stay, caregiver availability explained 1.3% of additional variance, with the final model explaining 41.3% of total variance for functional ability at discharge (F (5,174) = 26.21, p < 0.001). CONCLUSIONS: The presence of a caregiver at time of discharge from inpatient rehabilitation is predictive of significantly higher functional ability at discharge in individuals with severe stroke. Implications for rehabilitation The availability of a caregiver at time of discharge from inpatient rehabilitation is predictive of improved functional ability at discharge in individuals with severe stroke. The presence of an available caregiver positively influences the functional recovery of individuals with severe stroke and may be an important element to successful rehabilitation. PMID- 28007001 TI - Antioxidant and neuroprotector effect of Lepidium meyenii (maca) methanol leaf extract against 6-hydroxy dopamine (6-OHDA)-induced toxicity in PC12 cells. AB - Reactive oxygen species (ROS) are normally produced during cell metabolism, there is strong evidence to suggest that ROS produced in excess impair the cell and may be etiologically related to various neurodegenerative diseases. This study was undertaken to examine the effects of Lepidium meyenii (MACA) methanol leaf extract on neurotoxicity in PC12 cell exposed to 6-hydroxydopamine (6-OHDA). Fresh samples of "maca" leaves were processed in order to obtain foliar extracts and to evaluate the neurobiological activity on PC12 cells, subjected to the cytotoxic effect of 6-OHDA through the determination of the capacity antioxidant, cell viability and cytotoxicity assays on PC12 cells. The results of the tests of antioxidant activity, showed maximum values of 2262.37 and 1305.36 expressed in Trolox equivalents (TEAC), for the methanolic and aqueous fractions respectively. Cell viability assays at a dose of 10 MUg extract showed an increase of 31% and 60% at 6 and 12 h of pretreatment, respectively. Cytotoxicity assays at the same dose and exposure time showed a 31.4% and 47.8% reduction in lactate dehydrogenase (LDH) activity and an increase in superoxide dismutase (SOD) activity. The results allow us to affirm that the methanolic foliar extract of "maca" presents in vitro neurobiological activity of antioxidant protection, increase in cell viability and reduction of cytotoxicity against oxidative stress generated by 6-OHDA. In conclusion, the present study shows a protective role for Lepidium meyenii leaf extract on 6-OHDA-induced toxicity by an antioxidant effect. PMID- 28007002 TI - Physical therapy and occupational therapy in Parkinson's disease. AB - Current medical management is only partially effective in controlling the symptoms of Parkinson's disease. As part of comprehensive multidisciplinary care, physical therapy and occupational therapy aim to support people with Parkinson's disease in dealing with the consequences of their disease in daily activities. In this narrative review, we address the limitations that people with Parkinson's disease may encounter despite optimal medical management, and we clarify both the unique and shared approaches that physical therapists and occupational therapists can apply in treating these limitations. PMID- 28007003 TI - Sluggish Cognitive Tempo, Internalizing Symptoms, and Executive Function in Adults With ADHD. AB - OBJECTIVE: We sought to characterize relationships between sluggish cognitive tempo (SCT) and both internalizing symptoms and executive functioning in adults with ADHD. METHOD: A total of 102 adults with ADHD completed clinical interviews and clinical rating scales. Hierarchical regression analyses were conducted to ascertain the independent predictive power of SCT symptoms for deficits in executive function (EF) after considering severity of ADHD inattentive and hyperactive-impulsive symptoms and internalizing symptoms. RESULTS: SCT correlated with ADHD inattentive symptoms and dimensional measures of depression and anxiety but not with clinical diagnosis of depression or anxiety. SCT predicted EF deficits over and above the effects of internalizing and ADHD symptoms. This relationship between SCT and EF was limited to the subset of participants ( n = 48) receiving stimulant treatment. CONCLUSION: SCT in adults with ADHD is associated with internalizing symptoms, ADHD inattentive symptoms, and, independently, with EF deficits. Further research is needed to ascertain why this relationship occurred primarily in adults concurrently receiving stimulants. PMID- 28007004 TI - Mallory Weiss syndrome is not associated with hiatal hernia: a matched case control study. AB - BACKGROUND/OBJECTIVE: Hiatal hernia is considered to be a predisposing factor to develop Mallory-Weiss Syndrome (MWS). No large case-control studies verifying this hypothesis have been conducted. METHODS: We reviewed all esophagogastroduodenoscopies with findings of MWS (n = 2342) in a national database and compared with age and gender-matched controls (n = 9368). Demographics, endoscopic characteristics and presence of a hiatal hernia were compared between both groups. Average age was 56.7 +/- 18.6 years, and 72.4% were male. RESULTS: Hiatal hernia was more common in controls, and no significant difference was seen in a multivariate analysis. CONCLUSION: Dynamic changes inducing mucosal tension are more relevant determinants to develop MWS than gastro-esophageal junction location alone. PMID- 28007006 TI - Abstracts From the PRIM&R 2016 Advancing Ethical Research Conference. PMID- 28007005 TI - Analgesic effect of topical oral capsaicin gel in burning mouth syndrome. AB - OBJECTIVE: To investigate the effectiveness of repeated topical application of oral capsaicin gel in two different concentrations for relief of burning/stinging sensations in patients with burning mouth syndrome (BMS). MATERIAL AND METHODS: This randomized double-blind cross-over study included 22 female patients with BMS. The patients were randomized for topical application of either 0.01% or 0.025% oral capsaicin gel on the dorsal part of tongue three times daily for 14 days, followed by 14 days wash-out period, and finally treatment with the other concentration of oral gel three times daily for 14 days. A visual analogue scale (VAS) was used to assess the severity of pain five times during the intervention period. RESULTS: 18 patients completed the intervention. Their VAS score at baseline was 5.5 +/- 0.6 cm (mean +/- SD). Treatment with the two concentrations of capsaicin gels significantly improved the burning/stinging symptoms assessed on VAS compared with baseline (p = 0.002). There was no statistically significant difference between the two concentrations of the gels on relieving symptoms. Four patients dropped out during the intervention period due to gastrointestinal side effects. CONCLUSIONS: Topical capsaicin might be an alternative for the short term treatment of BMS. However, further studies are needed to investigate especially the gastro-intestinal side-effects which may limit its long-term use. PMID- 28007007 TI - To What Extent Do Risks Need to Be Minimized? PMID- 28007008 TI - Positive and negative mood following imaging-guided core needle breast biopsy and receipt of biopsy results. AB - Positive and negative mood are independent psychological responses to stressful events. Negative mood negatively impacts well-being and co-occurring positive mood leads to improved adjustment. Women undergoing core needle breast biopsies (CNB) experience distress during CNB and awaiting results; however, influences of mood are not well known. This longitudinal study examines psychosocial and biopsy and spirituality-related factors associated with mood in patients day of CNB and one week after receiving results. Ninety women undergoing CNB completed questionnaires on psychosocial factors (chronic stress, social support), biopsy experiences (pain, radiologist communication), and spirituality (peace, meaning, faith) day of CNB. Measures of positive and negative mood were completed day of CNB and one week after receiving results (benign n = 50; abnormal n = 25). Multiple linear regression analyses were conducted. Greater positive mood correlated with greater peace (beta = .25, p = .02) day of CNB. Lower negative mood correlated with greater peace (beta = -.29, p = .004) and there was a trend for a relationship with less pain during CNB (beta = .19, p = .07). For patients with benign results, day of CNB positive mood predicted positive mood post results (beta = .31, p = .03) and only chronic stress predicted negative mood (beta = .33, p = .03). For women with abnormal results, greater meaning day of CNB predicted lower negative mood post-results (beta = -.45, p = .03). Meaning and peace may be important for women undergoing CNB and receiving abnormal results. PMID- 28007009 TI - The American Thyroid Association: Statement on Universal Salt Iodization. PMID- 28007010 TI - Genetic analysis of a hereditary factor XII deficiency pedigree of a consanguineous marriage due to a homozygous F12 gene mutation: Gly341Arg. AB - OBJECTIVE AND IMPORTANCE: To study the gene mutations of factor XII (FXII) in a Chinese family of consanguineous marriage with FXII deficiency and illuminate the possible molecular pathogenic mechanism. It will contribute to our comprehension of the pathogenesis of the disease. CLINICAL PRESENTATION: The proband was a 26 year-old Chinese pregnant woman who was discovered, in a pregnancy test, with a prolonged activated partial thromboplastin time (APTT) at 61.6s (reference range, 29.0-43.0s). TECHNIQUES: The FXII activity (FXII:C) and FXII antigen (FXII:Ag) were tested with clotting assay and ELISA, respectively. The FXII gene (F12) was amplified by PCR with direct sequencing. A ClustalX-2.1-win and four online bioinformatics software (PolyPhen-2, PROVEAN, SIFT, and Mutation Taster) were used to study the conservatism and harm of the mutation. The reference range of each test indicator in our laboratory was established with 150 healthy subjects. Conclusion headings: The FXII:C and FXII:Ag of the proband were 12% and 10% (normal range, 72-113%), respectively. Gene sequencing detected a homozygous c.1078G > A point mutation in exon 10 resulting in a substitution of glycine 341 by arginine (Gly341Arg) in the proline-rich domain of FXII. Family study showed that her elder brother had the same phenotype and genotype with her. In addition, there were another six heterozygous members in her family. Both conservatism and bioinformatics results indicated the mutation probably had affected the function of the protein. We thought the Gly341Arg mutation was responsible for the decreased activity of FXII:C and FXII:Ag. And in vitro expression experiment is performed to elucidate the precise pathological mechanism of the mutation. PMID- 28007011 TI - Mimicking the Acute Myeloid Leukemia Niche for Molecular Study and Drug Screening. AB - Bone marrow niche is a major contributing factor in leukemia development and drug resistance in acute myeloid leukemia (AML) patients. Although mimicking leukemic bone marrow niche relies on two-dimensional (2D) culture conditions, it cannot recapitulate complex bone marrow structure that causes introduction of different three-dimensional (3D) scaffolds. Simultaneously, microfluidic platform by perfusing medium culture mimic interstitial fluid flow, along with 3D scaffold would help for mimicking bone marrow microenvironment. In this study TF-1 cells were cocultured with bone marrow mesenchymal stem cells (BM-MSCs) in 2D and 3D microfluidic devices. Phenotype maintenance during cell culture and proliferation rate was assayed and confirmed by cell cycle analysis. Morphology of cells in 2D and 3D culture conditions was demonstrated by scanning electron microscopy. After these experiments, drug screening was performed by applying azacitidine and cytarabine and cytotoxicity assay and quantitative reverse transcription polymerase chain reaction (qRT-PCR) for B cell lymphoma 2 (BCL2) were done to compare drug resistance in 2D and 3D culture conditions. Our result shows leukemic cells in 3D microfluidic device retaining their phenotype and proliferation rate was significantly higher in 3D culture condition in comparison to 2D culture condition (p < 0.05), which was confirmed by cell cycle analysis. Cytotoxicity assay also illustrated drug resistance in 3D culture condition and qRT-PCR demonstrated higher BCL2 expression in 3D microfluidic device in contrast to 2D microfluidic device (p < 0.05). On balance, mimicking bone marrow niche would help the target therapy and specify the role of niche in development of leukemia in AML patients. PMID- 28007012 TI - Effect of socio-demographic characteristics and clinical findings on the quality of life of patients with chronic venous insufficiency. AB - Objective This study was planned and implemented to evaluate the effect of socio demographic characteristics and clinical findings on the quality of life of patients with chronic venous insufficiency. Methods The sample of this cross sectional study consisted of 163 patients that presented with the diagnosis of chronic venous insufficiency to the cardiovascular surgery clinic of an education and research hospital in the west of Turkey. The data were collected during face to-face interviews using a personal information form, clinical, etiology, anatomy, pathophysiology classification, venous insufficiency epidemiological and economic study-quality of life/symptoms scales and the Short Form-36. Descriptive statistics as well as univariate and multivariate analyses were used to analyze the data. Results The chronic venous insufficiency patients were found to have a low quality of life. Advanced age, higher body mass index, longer working times, being on regular medication, hypertension and presence of pigmentation according to the clinical, etiology, anatomy, pathophysiology classification were found to be associated with a reduced physical score in SF-36. Furthermore, longer weekly working hours and presence of pigmentation reduced the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms scores. Undertaking physical exercise at twice and more than twice a week increased the overall physical scores in SF-36. Conclusions The results of the study showed that the quality of life of chronic venous insufficiency patients are affected by not only physical characteristics, working hours and physical activity but also presence of edema and pigmentation. PMID- 28007013 TI - Dynamic Risk Estimates of Outcome in Chinese Patients with Well-Differentiated Thyroid Cancer After Total Thyroidectomy and Radioactive Iodine Remnant Ablation. AB - BACKGROUND: This study was conducted to compare the staging systems for the prediction of long-term disease status in patients with well-differentiated thyroid carcinoma (WDTC), and to find out the earliest postoperative period predictor of long-term persistence/recurrence of disease. METHODS: Patients with WDTC (n = 356; Mage = 41.5 +/- 12.7 years) followed for at least five years (12.3 +/- 5.0 years) after thyroidectomy and 131I remnant ablation at a tertiary regional hospital in Taiwan were retrospectively studied. Each patient was risk stratified using the American Joint Cancer Committee (stage I-IV) and American Thyroid Association (low, intermediate, and high risk) staging systems after operation and first 131I remnant ablation and using response to initial therapy reclassification (RTR; excellent, indeterminate, biochemical incomplete, and structural incomplete response) system, which is determined 6-24 months after the first 131I ablation. The clinical outcome was defined as no evidence of disease (NED; suppressed thyroglobulin [Tg] <0.5 ng/mL, stimulated Tg <1 ng/mL, and no structural detectable disease), biochemical persistent disease (BPD; suppressed Tg >=0.5 ng/mL or stimulated Tg >=1 ng/mL in the absence of structural disease), structural persistent disease (SPD; locoregional or distant metastases with any Tg level), or recurrent disease (RD; biochemical or structural disease identified after a period of NED). RESULTS: At the time of final follow-up, 78.4% (n = 279) of the patients had NED, 9.3% (n = 33) had BPD, 10.1% (n = 36) had SPD, and 2.2% (n = 8) developed RD. All three systems could predict the increasing trend of SPD and the decreasing trend of NED with advancing stage of disease. However, the ATA risk estimates could be significantly refined by the RTR system, especially for the ATA high-risk group, in which 29.2% developed SPD/RD during follow-up. The RTR system reduced the likelihood of finding SPD/RD to 3.7% in those demonstrating an excellent response to therapy, and increased the likelihood to 78.6% in those demonstrating a structural incomplete response. Among the earliest postoperative factors, only the Tg level at the first 131I ablation could predict long-term persistence/recurrence. CONCLUSIONS: The results highly support incorporating the RTR system to modify the initial risk estimate during follow-up among Chinese patients with WDTC. PMID- 28007014 TI - Evaluation of Pepsinogen I as a Biomarker of Drug-induced Gastric Mucosal Injury in Cynomolgus Monkeys. AB - Gastric mucosal injury is frequently observed in nonclinical studies of nonhuman primates. Because microscopic evaluation of stomach is generally a terminal procedure, our objective was to determine whether serum pepsinogen I (PG I) could serve as a noninvasive biomarker for detection of gastric mucosal injury in monkey. Serum PG I was measured using a commercial human immunoassay in cynomolgus monkeys ( n = 166) prior to dosing and/or terminally in 11 studies of up to 1 month duration. Mean ( SD) PG I values (ug/L) for monkeys with ( n = 59) and without ( n = 100) gastric mucosal degeneration were 101 (215) and 28 (12.6), respectively. For monkeys with baseline and terminal PG I data, mean ( SD) fold change (ratio of terminal to baseline PG I) for monkeys with ( n = 57) and without ( n = 76) glandular degeneration were 4.1 (11.3) and 1 (0.28). Receiver operating characteristic area under the curve (AUC) data demonstrated moderate diagnostic accuracy for serum PG I for glandular degeneration, AUC ( SE) 0.789 (0.04), with improved diagnostic accuracy as a fold change of baseline, AUC ( SE) 0.816 (0.04), consistent with the large interindividual but low intraindividual variability of serum PG I values in control monkeys. These data demonstrate that serum PG I is a useful biomarker of drug-induced gastric mucosal injury in the cynomolgus monkey. PMID- 28007017 TI - Research on medical overuse: Overdiagnosis and overtreatment in family medicine and primary care. PMID- 28007015 TI - Family medicine and family medicine research-generalist approach or specialization? PMID- 28007018 TI - Pregnancy after abdominal wall mesh repair in desmoid fibromatosis. PMID- 28007019 TI - The effects of hand force variation on shoulder muscle activation during submaximal exertions. AB - Upper limb injuries are highly prevalent in the workplace and new tools are needed to proactively design workstations to reduce injury risk. The objective was to characterize spatial, load and direction dependency of muscle activity for hand exertions in the upper limb workspace. Electromyographic signals were collected from 14 upper limb muscles during exertions for all combinations of 4 submaximal hand forces (20/30/50/60 N) in 6 cardinal (up/down/left/right/forward/backward) directions at 5 hand locations. Linear muscle activity increases accompanied increased hand forces. Total muscle activity increases between 20 and 60 N hand forces ranged by direction from 92% (downward) to 189% (right). Prediction equations for all muscles depended on hand force, and linear, quadratic and interaction permutations of hand location. Muscle activity associated with manual tasks is load, direction and spatially dependent. Equations developed to describe these complex relationships can be used to better design future and evaluate current occupational activities. PMID- 28007020 TI - Hb A2 Episkopi - a novel delta-globin chain variant [HBD:c.428C>T] in a family of mixed Cypriot-Lebanese descent. AB - OBJECTIVES: Thalassaemia is a potentially lethal inherited anaemia, caused by reduced or absent synthesis of globin chains. Measurement of the minor adult haemoglobin Hb A2, combining alpha- with delta-globin, is critical for the routine diagnosis of carrier status for alpha- or beta-thalassaemia. Here, we aim to characterize a novel delta-globin variant, Hb A2 Episkopi, in a single family of mixed Lebanese and Cypriot ancestry with mild hypochromic anaemia and otherwise normal globin genotype, which also presents with a coincidental 0.78-Mb sequence duplication on chromosome 1 (1q44) and developmental abnormalities. METHODS: Analyses included comprehensive haematological analyses, cation-exchange high-performance liquid chromatography (CE-HPLC), cellulose acetate electrophoresis (CAE), Sanger sequencing and structure-based stability predictions for Hb A2 Episkopi. RESULTS: The GCT > GTT missense mutation, underlying Hb A2 Episkopi, HBD:c.428C > T, introduces a cd142 codon change in the mature protein, resulting in reduced normal Hb A2 amounts and a novel, less abundant Hb A2 variant (HGVS: HBD:p.A143V), detectable as a delayed peak by CE HPLC. The latter was in line with structure-based stability predictions, which indicated that the substitution of a marginal, non-helical and non-interface residue, five amino acids from the delta-globin chain carboxy-terminus, was moderately destabilizing. DISCUSSION: Detection of the new variant depends on the diagnostic set-up and had failed by CAE and on an independent CE-HPLC system, which, in unfavourable circumstances, may lead to misdiagnoses of beta thalassaemia as alpha-thalassaemia. Given the mixed background of the affected family, the ethnic origin of the mutation is unclear, and this study thus suggests awareness for possible detection of Hb A2 Episkopi in both the Cypriot and the Lebanese populations. PMID- 28007022 TI - Impact of obesity and epicardial fat on early left atrial dysfunction assessed by cardiac MRI strain analysis. AB - BACKGROUND: Diastolic dysfunction is a major cause of morbidity in obese individuals. We aimed to assess the ability of magnetic resonance imaging (MRI) derived left atrial (LA) strain to detect early diastolic dysfunction in individuals with obesity and type 2 diabetes, and to explore the association between cardiac adipose tissue and LA function. METHODS: Twenty patients with obesity and T2D (55 +/- 8 years) and nineteen healthy controls (48 +/- 13 years) were imaged using cine steady state free precession and 2-point Dixon cardiovascular magnetic resonance. LA function was quantified using a feature tracking technique with definition of phasic longitudinal strain and strain rates, as well as radial motion fraction and radial velocities. RESULTS: Systolic left ventricular size and function were similar between the obesity and type 2 diabetes and control groups by MRI. All patients except four had normal diastolic assessment by echocardiography. In contrast, measures of LA function using magnetic resonance feature tracking were uniformly altered in the obesity and type 2 diabetes group only. Although there was no significant difference in intra myocardial fat fraction, Dixon 3D epicardial fat volume(EFV) was significantly elevated in the obesity and type 2 diabetes versus control group (135 +/- 31 vs. 90 +/- 30 mL/m2, p < 0.001). There were significant correlations between LA functional indices and both BMI and EFV (p <= 0.007). CONCLUSIONS: LA MRI-strain may be a sensitive tool for the detection of early diastolic dysfunction in individuals with obesity and type 2 diabetes and correlated with BMI and epicardial fat supporting a possible association between adiposity and LA strain. Trials Registration Australian New Zealand Clinical Trials Registry No. ACTRN12613001069741. PMID- 28007021 TI - Implementation of next generation sequencing into pediatric hematology-oncology practice: moving beyond actionable alterations. AB - BACKGROUND: Molecular characterization has the potential to advance the management of pediatric cancer and high-risk hematologic disease. The clinical integration of genome sequencing into standard clinical practice has been limited and the potential utility of genome sequencing to identify clinically impactful information beyond targetable alterations has been underestimated. METHODS: The Precision in Pediatric Sequencing (PIPseq) Program at Columbia University Medical Center instituted prospective clinical next generation sequencing (NGS) for pediatric cancer and hematologic disorders at risk for treatment failure. We performed cancer whole exome sequencing (WES) of patient-matched tumor-normal samples and RNA sequencing (RNA-seq) of tumor to identify sequence variants, fusion transcripts, relative gene expression, and copy number variation (CNV). A directed cancer gene panel assay was used when sample adequacy was a concern. Constitutional WES of patients and parents was performed when a constitutionally encoded disease was suspected. Results were initially reviewed by a molecular pathologist and subsequently by a multi-disciplinary molecular tumor board. Clinical reports were issued to the ordering physician and posted to the patient's electronic medical record. RESULTS: NGS was performed on tumor and/or normal tissue from 101 high-risk pediatric patients. Potentially actionable alterations were identified in 38% of patients, of which only 16% subsequently received matched therapy. In an additional 38% of patients, the genomic data provided clinically relevant information of diagnostic, prognostic, or pharmacogenomic significance. RNA-seq was clinically impactful in 37/65 patients (57%) providing diagnostic and/or prognostic information for 17 patients (26%) and identified therapeutic targets in 15 patients (23%). Known or likely pathogenic germline alterations were discovered in 18/90 patients (20%) with 14% having germline alternations in cancer predisposition genes. American College of Medical Genetics (ACMG) secondary findings were identified in six patients. CONCLUSIONS: Our results demonstrate the feasibility of incorporating clinical NGS into pediatric hematology-oncology practice. Beyond the identification of actionable alterations, the ability to avoid ineffective/inappropriate therapies, make a definitive diagnosis, and identify pharmacogenomic modifiers is clinically impactful. Taking a more inclusive view of potential clinical utility, 66% of cases tested through our program had clinically impactful findings and samples interrogated with both WES and RNA-seq resulted in data that impacted clinical decisions in 75% of cases. PMID- 28007023 TI - Interventions promoting healthy eating as a tool for reducing social inequalities in diet in low- and middle-income countries: a systematic review. AB - INTRODUCTION: Diet is a major risk factor for non-communicable diseases (NCDs) and is also strongly patterned by socioeconomic factors. Whether interventions promoting healthy eating reduce social inequalities in diet in low- and middle income countries (LMICs) remains uncertain. This paper aims to summarize current evidence on interventions promoting healthy eating in LMICs, and to establish whether they reduce social inequalities in diet. METHODS: Systematic review of cross-sectional or quasi-experimental studies (pre- and post-assessment of interventions) in Pubmed, Scielo and Google Scholar databases, including adults in LMICs, assessing at least one outcome of healthy eating and showing results stratified by socioeconomic status. RESULTS: Seven intervention studies including healthy eating promotion, conducted in seven LMICs (Brazil, Chile, Colombia, Iran, Panama, Trinidad and Tobago, and Tunisia), met our inclusion criteria. To promote healthy eating, all interventions used nutrition education and three of them combined nutrition education with improved acces to foods or social support. Interventions targeted mostly women and varied widely regarding communication tools and duration of the nutrition education sessions. Most interventions used printed material, media use or face-to-face training and lasted from 6 weeks to 5 years. Four interventions targeted disadvantaged populations, and three targeted the entire population. In three out of four interventions targeting disadvantaged populations, healthy eating outcomes were improved suggesting they were likely to reduce social inequalities in diet. All interventions directed to the entire population showed improved healthy eating outcomes in all social strata, and were considered as having no impact on social inequalities in diet. CONCLUSION: In LMICs, agentic interventions promoting healthy eating reduced social inequalities in diet when specifically targeting disadvantaged populations. Further research should assess the impact on social inequalities in diet of a combination of agentic and structural approaches in interventions promoting healthy eating. PMID- 28007024 TI - iCAGES: integrated CAncer GEnome Score for comprehensively prioritizing driver genes in personal cancer genomes. AB - Cancer results from the acquisition of somatic driver mutations. Several computational tools can predict driver genes from population-scale genomic data, but tools for analyzing personal cancer genomes are underdeveloped. Here we developed iCAGES, a novel statistical framework that infers driver variants by integrating contributions from coding, non-coding, and structural variants, identifies driver genes by combining genomic information and prior biological knowledge, then generates prioritized drug treatment. Analysis on The Cancer Genome Atlas (TCGA) data showed that iCAGES predicts whether patients respond to drug treatment (P = 0.006 by Fisher's exact test) and long-term survival (P = 0.003 from Cox regression). iCAGES is available at http://icages.wglab.org . PMID- 28007026 TI - Gemcitabine improves survival in patients with recurrent or metastatic nasopharyngeal carcinoma. AB - For decades, the selection of chemotherapeutic regimens for the treatment of recurrent or metastatic nasopharyngeal carcinoma has been mainly empirical. To our knowledge, there is no phase 3 trial that has been conducted to determine the optimal treatment for these patients before our publication. Recently, we published an article in The Lancet entitled "Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial." The results of our study indicate that gemcitabine plus cisplatin could improve the survival of patients with recurrent or metastatic nasopharyngeal carcinoma compared with conventional fluorouracil plus cisplatin. PMID- 28007025 TI - Study protocol of the Asian XELIRI ProjecT (AXEPT): a multinational, randomized, non-inferiority, phase III trial of second-line chemotherapy for metastatic colorectal cancer, comparing the efficacy and safety of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab. AB - BACKGROUND: Capecitabine and irinotecan combination therapy (XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer (mCRC). Recently, in the Association of Medical Oncology of the German Cancer Society (AIO) 0604 trial, tri-weekly XELIRI plus bevacizumab, with reduced doses of irinotecan (200 mg/m2 on day 1) and capecitabine (1600 mg/m2 on days 1-14), repeated every 3 weeks, has shown favorable tolerability and efficacy which were comparable to those of capecitabine and oxaliplatin (XELOX) plus bevacizumab. The doses of capecitabine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab (BIX) as second-line chemotherapy was well tolerated and had promising efficacy in Japanese patients. METHODS: The Asian XELIRI ProjecT (AXEPT) is an East Asian collaborative, open-labelled, randomized, phase III clinical trial which was designed to demonstrate the non inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI (5 fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second-line chemotherapy for patients with mCRC. Patients with 20 years of age or older, histologically confirmed mCRC, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and disease progression or intolerance of the first-line regimen will be eligible. Patients will be randomized (1:1) to receive standard FOLFIRI with or without bevacizumab (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or XELIRI with or without bevacizumab (7.5 mg/kg on day 1), repeated every 3 weeks (XELIRI arm). A total of 464 events were estimated as necessary to show non-inferiority with a power of 80% at a one-sided alpha of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval (CI) upper limit of the hazard ratio was pre-specified as less than 1.3. CONCLUSION: The Asian XELIRI ProjecT is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second-line treatment option of mCRC. Trial registration ClinicalTrials.gov NCT01996306. UMIN000012263. PMID- 28007027 TI - Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis. AB - BACKGROUND: Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS: Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS: The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION: The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693). PMID- 28007028 TI - Phase I/II trial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma. AB - BACKGROUND: After definitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present significant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can benefit from these treatments. Re-irradiation with X-ray-based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radio-resistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an increased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were previously treated for NPC with a definitive dose of IMXT. The short-term response rates at 3-6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can benefit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the benefits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results. METHODS AND DESIGN: The maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 GyE (2.5 GyE * 21-26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Efficacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%. CONCLUSIONS: Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate efficacy but causes potentially severe toxicities. Improved outcomes in terms of efficacy and toxicity profile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose escalating phase I and randomized phase II trials. PMID- 28007029 TI - Arabidopsis PRC1 core component AtRING1 regulates stem cell-determining carpel development mainly through repression of class I KNOX genes. AB - BACKGROUND: Polycomb repressive complex 2 (PRC2)-catalyzed H3K27me3 marks are tightly associated with the WUS-AG negative feedback loop to terminate floral stem cell fate to promote carpel development, but the roles of Polycomb repressive complex 1 (PRC1) in this event remain largely uncharacterized. RESULTS: Here we show conspicuous variability in the morphology and number of carpels among individual flowers in the absence of the PRC1 core components AtRING1a and AtRING1b, which contrasts with the wild-type floral meristem consumed by uniform carpel production in Arabidopsis thaliana. Promoter-driven GUS reporter analysis showed that AtRING1a and AtRING1b display a largely similar expression pattern, except in the case of the exclusively maternal-preferred expression of AtRING1b, but not AtRING1a, in the endosperm. Indeterminate carpel development in the atring1a;atring1b double mutant is due to replum/ovule-to carpel conversion in association with ectopic expression of class I KNOX (KNOX-I) genes. Moreover, AtRING1a and AtRING1b also play a critical role in ovule development, mainly through promoting the degeneration of non-functional megaspores and proper integument formation. Genetic interaction analysis indicates that the AtRING1a/b-regulated KNOX-I pathway acts largely in a complementary manner with the WUS-AG pathway in controlling floral stem cell maintenance and proper carpel development. CONCLUSIONS: Our study uncovers a novel mechanistic pathway through which AtRING1a and AtRING1b repress KNOX-I expression to terminate floral stem cell activities and establish carpel cell fate identities. PMID- 28007030 TI - Ultrasound anatomy of the transversus abdominis plane region in pregnant women before and after cesarean delivery. AB - BACKGROUND: After cesarean delivery, analgesia is often incomplete and a multimodal approach to analgesia is necessary. Transverse abdominal plane (TAP) block has been advocated in this setting, yet no systematic description of the ultrasound anatomy in pregnant women exists in the literature. Therefore, we aimed to describe the sonographical features of relevant structures in pregnant women before and after elective cesarean. METHODS: Sixty women at, or close to term scheduled for elective cesarean delivery underwent a standardized ultrasound examination before and after delivery. We assessed the visibility of the muscular layers and measured the distance from the skin to the layers of the abdominal wall muscles in the region for TAP block before and after cesarean section on both side. RESULTS: The three muscular layers of the lateral abdominal wall (external oblique, internal oblique and transversus abdominis muscle) were visible in all examinations. Before cesarean section the median TAP distance was shorter: 2.9 cm (interquartile range 2.6-3.6) compared to 3.9 cm (3.1-4.5) after cesarean section (left side, p < 0.001). The external and internal oblique muscles were located closer to the skin surface before cesarean section. An increased body mass is associated with increased the TAP distance before and after birth (p < 0.001). CONCLUSION: Relevant anatomical landmarks for a TAP block are sonographically well visible after cesarean delivery. Postoperatively, depth of the TAP as compared to before birth is increased significantly. Scanning the abdominal wall before CD will underestimate the target depth of the TAP after delivery. The obstetric anesthetist needs to be aware of these changes when planning a TAP block in the context of cesarean delivery. PMID- 28007032 TI - Q&A: what are brassinosteroids and how do they act in plants? AB - Brassinosteroids (BRs) are a class of polyhydroxylated steroidal phytohormones in plants with similar structures to animals' steroid hormones. Brassinosteroids regulate a wide range of physiological processes including plant growth, development and immunity. Brassinosteroid signalling and its integration with other signalling pathways have been investigated thoroughly at the molecular level. PMID- 28007031 TI - Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis. AB - BACKGROUND: Although serotonin (5-HT3) receptor antagonists are effective in reducing nausea and vomiting, they may be associated with increased cardiac risk. Our objective was to examine the comparative safety and effectiveness of 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron) alone or combined with steroids for patients undergoing chemotherapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception until December 2015 for studies comparing 5-HT3 receptor antagonists with each other or placebo in chemotherapy patients. The search results were screened, data were abstracted, and risk of bias was appraised by pairs of reviewers, independently. Random-effects meta analyses and network meta-analyses (NMAs) were conducted. RESULTS: After screening 9226 citations and 970 full-text articles, we included 299 studies (n = 58,412 patients). None of the included studies reported harms for active treatment versus placebo. For NMAs on the risk of arrhythmia (primary outcome; three randomized controlled trials [RCTs], 627 adults) and mortality (secondary outcome; eight RCTs, 4823 adults), no statistically significant differences were observed between agents. A NMA on the risk of QTc prolongation showed a significantly greater risk for dolasetron + dexamethasone versus ondansetron + dexamethasone (four RCTs, 3358 children and adults, odds ratio 2.94, 95% confidence interval 2.13-4.17). For NMAs on the number of patients without nausea (44 RCTs, 11,664 adults, 12 treatments), number of patients without vomiting (63 RCTs, 15,460 adults, 12 treatments), and number of patients without chemotherapy induced nausea or vomiting (27 RCTs, 10,924 adults, nine treatments), all agents were significantly superior to placebo. For a NMA on severe vomiting (10 RCTs, 917 adults), all treatments decreased the risk, but only ondansetron and ramosetron were significantly superior to placebo. According to a rank-heat plot with the surface under the cumulative ranking curve results, palonosetron + steroid was ranked the safest and most effective agent overall. CONCLUSIONS: Most 5-HT3 receptor antagonists were relatively safe when compared with each other, yet none of the studies compared active treatment with placebo for harms. However, dolasetron + dexamethasone may prolong the QTc compared to ondansetron + dexamethasone. All agents were effective for reducing risk of nausea, vomiting, and chemotherapy-induced nausea or vomiting. TRIAL REGISTRATION: This study was registered at PROSPERO: ( CRD42013003564 ). PMID- 28007033 TI - Efficacy of therapeutic suggestions under general anesthesia: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: General anesthesia does not block central nervous processing of auditive information. Therefore, positive suggestions even given during surgery might have the potential to encourage well-being and recovery of patients. Aim of this review was to summarize the evidence on the efficacy of therapeutic suggestions under general anesthesia in adults undergoing surgery compared to an attention control (i.e. white noise). METHODS: We included randomized controlled trials that investigated therapeutic suggestions presented during general anesthesia to adult patients undergoing surgery or medical procedures. Outcomes on pain intensity, mental distress, recovery, use of medication, measured postoperatively within hospitalization were considered. Electronic searches were carried out in the following databases (last search February 23, 2015): MEDLINE, CENTRAL, Web of Science, PsycINFO, ProQuest Dissertations and Theses. RESULTS: Thirty-two eligible randomized controlled trials were included, comprising a total of 2102 patients. All studies used taped suggestions. Random effects meta analyses revealed no effects on pain intensity (Hedges' g = 0.04, CI 95% [-0.04; 0.12], number needed to treat [NNT] = 44.3) and mental distress (g = 0.03, CI 95% [-0.11; 0.16], NNT = 68.2). In contrast, we found small but significant positive effects on use of medication (g = 0.19, CI 95% [0.09; 0.29], NNT = 9.2) and on recovery (g = 0.14, CI 95% [0.03; 0.25], NNT = 13.0). All effects were homogeneous and robust. CONCLUSIONS: Even though effects were small, our results provide indications that intraoperative suggestions can have the potential to reduce the need for medication and enhance recovery. Further high quality trials are needed to strengthen the promising evidence on the efficacy of therapeutic suggestions under general anesthesia for patients undergoing surgery. PMID- 28007034 TI - Online psycho-education to the treatment of bipolar disorder: protocol of a randomized controlled trial. AB - BACKGROUND: Bipolar disorder patients frequently present recurrent episodes and often experience subsyndromal symptoms, cognitive impairment and difficulties in functioning, with a low quality of life, illness relapses and recurrent hospitalization. Early diagnosis and appropriate intervention may play a role in preventing neuroprogression in this disorder. New technologies represent an opportunity to develop standardized psychological treatments using internet-based tools that overcome some of the limitations of face-to-face treatments, in that they are readily accessible and the timing of therapy can be tailored to user needs and availability. However, although many psychological programs are offered through the web and mobile devices for bipolar disorder, there is a lack of high quality evidence concerning their efficacy and effectiveness due to the great variability in measures and methodology used. METHODS: This clinical trial is a simple-blind randomized trial within a European project to compare an internet based intervention with treatment as usual. Bipolar disorder patients are to be included and randomly assigned to one of two groups: 1) the experimental group (tele-care support) and 2) the control group. Participants in both groups will be evaluated at baseline (pre-treatment) and post-treatment. DISCUSSION: This study describes the design of a clinical trial based on psychoeducation intervention that may have a significant impact on both prognosis and treatment in bipolar disorder. Specifically, bringing different services together (service aggregation), it is hoped that the approach proposed will significantly increase the impact of information and communication technologies on access and adherence to treatment, quality of the service, patient safety, patient and professional satisfaction, and quality of life of patients. TRIAL REGISTRATION: NCT02924415 . Retrospectively registered 27 September 2016. PMID- 28007035 TI - Sacral agenesis: a pilot whole exome sequencing and copy number study. AB - BACKGROUND: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. METHOD: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. RESULTS: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. CONCLUSION: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients. PMID- 28007036 TI - Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine. AB - BACKGROUND: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC). METHODS: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415 gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC. RESULTS: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy. CONCLUSIONS: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities. PMID- 28007037 TI - Block network mapping approach to quantitative trait locus analysis. AB - BACKGROUND: Advances in experimental biology have enabled the collection of enormous troves of data on genomic variation in living organisms. The interpretation of this data to extract actionable information is one of the keys to developing novel therapeutic strategies to treat complex diseases. Network organization of biological data overcomes measurement noise in several biological contexts. Does a network approach, combining information about the linear organization of genomic markers with correlative information on these markers in a Bayesian formulation, lead to an analytic method with higher power for detecting quantitative trait loci? RESULTS: Block Network Mapping, combining Similarity Network Fusion (Wang et al., NM 11:333-337, 2014) with a Bayesian locus likelihood evaluation, leads to large improvements in area under the receiver operating characteristic and power over interval mapping with expectation maximization. The method has a monotonically decreasing false discovery rate as a function of effect size, unlike interval mapping. CONCLUSIONS: Block Network Mapping provides an alternative data-driven approach to mapping quantitative trait loci that leverages correlations in the sampled genotypes. The evaluation methodology can be combined with existing approaches such as Interval Mapping. Python scripts are available at http://lbm.niddk.nih.gov/vipulp/ . Genotype data is available at http://churchill lab.jax.org/website/GattiDOQTL . PMID- 28007038 TI - Semi-quantitative method for Staphylococci magnetic detection in raw milk. AB - Bovine mastitis is the most costly disease for dairy farmers, hence, control measures to prevent it are crucial for dairy farm sustainability. Staphylococcus aureus is considered a major mastitis pathogen because of its impact on milk quality and low cure rates. Prevention of S. aureus mastitis includes segregation of infected animals, whilst treatment of such animals should be performed for a longer time to improve cure rates. This makes identification of S. aureus infected quarters and animals of significant importance. The experiments reported in this research paper aimed to develop and validate a sensitive method for magnetic detection of S. aureus and of the Staphylococcus genus in raw milk samples. Mastitic milk samples were collected aseptically from 47 cows with subclinical mastitis, from 12 Portuguese dairy farms. Forty nine quarter milk samples were selected based on bacteriological results. All samples were submitted to PCR analysis. In parallel, these milk samples were mixed with a solution combining specific antibodies and magnetic nanoparticles, to be analysed using a lab-on-a-chip magnetoresistive cytometer, with microfluidic sample handling. The antibodies used in this work were a rabbit polyclonal IgG anti-S. aureus ScpA protein and a mouse monoclonal IgM anti-S. aureus ATCC 29740. This paper describes the methodology used for magnetic detection of bacteria, including analysis of false positive/negative results. This immunological recognition was able to detect bacterial presence above 100 cfu/ml, independently of antibody and targeted bacteria used in this work. Comparison with PCR results showed sensitivities of 57.1 and 79.3%, specificity values of 75 and 50%, and PPV values of 40 and 95.8% for magnetic identification of Staphylococci species with an anti-S. aureus antibody and an anti-Staphylococcus spp. antibody, respectively. Some constraints are described as well as the method's limitations in bacterial quantification. Sensitivities and specificities require to be improved, nevertheless, the methodology described may form the basis for a means of identifying S. aureus infected cows at the point of care. PMID- 28007039 TI - Environmental and genetic factors affecting milk yield and quality in three Italian sheep breeds. AB - The aims of the study described in the Research Communication were to determine the level of influence of some environmental factors on milk yield and quality traits, including lactose, and lactation length in ewes belonging to three different Italian breeds and to estimate the heritability for the same traits. A total of 2138 lactation records obtained from 535 ewes belonging to three different Italian breeds (Comisana, Leccese, and Sarda) were used. Breed significantly affected all of the considered traits. Moreover, year of lambing affected milk yield and lactation length without influence on milk quality traits. Parity affected significantly only the milk yield, whereas type of birth showed its effect on milk yield, fat, protein, and lactose yield. On the whole, the presently reported heritability estimates are within the range of those already obtained in other dairy breeds by other authors, with values for lactation length being very low in all the investigated populations. Considering the heritability estimates for lactose content and yield, to the best of our knowledge, there is a lack of information on these parameters in ovine species and this is the first report on heritability of lactose content and yield in dairy sheep breeds. Our results suggest that genetic variability for milk traits other than lactation length is adequate for selection indicating a good response to selection in these breeds. PMID- 28007040 TI - Alterations of antioxidant status markers in dairy cows during lactation and in the dry period. AB - The purpose of the study reported in this Research Communication was to evaluate alterations in concentration of total antioxidant capacity (TAC) of plasma, plasma total thiols as markers of oxidative protein damage and malondialdehyde (as a final product of lipid peroxidation) in samples obtained at different stages of the lactation cycle and dry period of dairy cows. We found that TAC was significantly lower in the primiparous cows compared to multiparous cows. This study clearly demonstrates a need for monitoring primiparous cows during the production cycle, especially when they are faced with severe metabolic conditions. Furthermore, TAC may be a sensitive, reliable and useful indicator for measurement of cumulative effects of antioxidants as an addition to metabolic profile tests, which are currently used to analyse dairy cattle health. PMID- 28007041 TI - Risk factors for adult acquired subglottic stenosis. AB - OBJECTIVE: The aetiology and outcomes for patients with acquired subglottic stenosis are highly variable. This study aimed to identify risk factors for subglottic stenosis and patient characteristics that predict long-term clinical outcomes. METHODS: A retrospective review was performed on 63 patients with subglottic stenosis and 63 age-matched controls. Patient demographics and clinical characteristics were compared. Subglottic stenosis patients were further grouped according to tracheostomy status (i.e. tracheostomy never required, tracheostomy initially required but patient eventually decannulated, and tracheostomy-dependent). Patient factors from these three groups were then compared to evaluate risk factors for long-term tracheostomy dependence. RESULTS: Compared to controls, patients with subglottic stenosis had a significantly higher body mass index (30.8 vs 26.0 kg/m2; p < 0.001) and were more likely to have diabetes (23.8 per cent vs 7.94 per cent; p = 0.01). Comparing tracheostomy outcomes within the subglottic stenosis group, body mass index trended towards significance (p = 0.08). Age, gender, socio-economic status, subglottic stenosis aetiology and other co-morbidities did not correlate with outcome. CONCLUSION: Obesity and diabetes are significant risk factors for acquiring subglottic stenosis. Further investigations are required to determine if obesity is also a predictor for failed tracheostomy decannulation in subglottic stenosis. PMID- 28007042 TI - The value of close monitoring in vestibular rehabilitation therapy. AB - BACKGROUND: Vestibular rehabilitation therapy is a well-established treatment modality for patients with vestibular problems. HYPOTHESIS: Performing vestibular rehabilitation therapy in a closely monitored setting may result in a better outcome than a home exercise programme. METHODS: A retrospective study was conducted of patients undergoing vestibular rehabilitation therapy between June 2005 and November 2012 in a tertiary university hospital. The Dynamic Gait Index, the main outcome measure, was utilised before and after the rehabilitation programme. The magnitude of improvement for all patients was analysed, mainly to compare the home exercise group with the closely monitored therapy group. RESULTS: Only 32 patients underwent the vestibular rehabilitation therapy programme. In all patients, there was significant improvement in the mean Dynamic Gait Index score (from 11.75 to 17.38; p < 0.01). Dynamic Gait Index improvement was significantly higher with closely monitored therapy (mean improvement of 7.83 vs 2.79; p < 0.01). CONCLUSION: The small sample size is a major limitation; nevertheless, closely monitored vestibular rehabilitation therapy resulted in improved performance status. More studies are needed to establish the efficiency of vestibular rehabilitation therapy and compare closely monitored therapy with tailored home exercise rehabilitation. PMID- 28007043 TI - Physiological responses of feedlot heifers provided access to different levels of shade. AB - Heat stress has a significant impact on all livestock and poultry species causing economic losses and animal well-being concerns. Providing shade is one heat abatement strategy that has been studied for years. Material selected to provide shade for animals greatly influences the overall stress reduction provided by shade. A study was conducted to quantify both the environment and animal response, when cattle had no shade access during summertime exposure or were given access to shade provided by three different materials. A total of 32 Black Angus heifers were assigned to one of the four treatment pens according to weight (eight animals per pen). Each pen was assigned a shade treatment: No Shade, Snow Fence, 60% Aluminet Shade Cloth and 100% Shade Cloth. In the shaded treatment pens, the shade structure covered ~40% of the pen (7.5 m2/animal). Animals were moved to a different treatment every 2 weeks in a 4*4 Latin square design to ensure each treatment was applied to each group of animals. Both environmental parameters and physiological responses were measured during the experiment. Environmental parameters included dry-bulb temperature, relative humidity, wind speed, black globe temperature (BGT), solar radiation (SR) and feedlot surface temperature. Animal response measurements included manual respiration rate (RRm), electronic respiration rate (RRe), vaginal temperature (body temperature (BT)), complete blood count (CBC) and plasma cortisol. The environmental data demonstrated changes proportional to the quality of shade offered. However, the animal responses did not follow this same trend. Some of the data suggest that any amount of shade was beneficial to the animals. However, Snow Fence may not offer adequate protection to reduce BT. For some of the parameters (BT, CBC and cortisol), 60% Aluminet and 100% Shade Cloth offers similar protection. The 60% Aluminet lowered RRe the most during extreme conditions. When considering all parameters, environmental and physiological, 60% Aluminet Shade Cloth offered reductions of BGT, SR, feedlot surface temperature and the best (or equal to the best) overall protection for the animals (RRe, RRm, BT, blood parameters). PMID- 28007044 TI - Neurophysiological aspects of brainstem processing of speech stimuli in audiometric-normal geriatric population. AB - OBJECTIVE: Poor auditory speech perception in geriatrics is attributable to neural de-synchronisation due to structural and degenerative changes of ageing auditory pathways. The speech-evoked auditory brainstem response may be useful for detecting alterations that cause loss of speech discrimination. Therefore, this study aimed to compare the speech-evoked auditory brainstem response in adult and geriatric populations with normal hearing. METHODS: The auditory brainstem responses to click sounds and to a 40 ms speech sound (the Hindi phoneme |da|) were compared in 25 young adults and 25 geriatric people with normal hearing. The latencies and amplitudes of transient peaks representing neural responses to the onset, offset and sustained portions of the speech stimulus in quiet and noisy conditions were recorded. RESULTS: The older group had significantly smaller amplitudes and longer latencies for the onset and offset responses to |da| in noisy conditions. Stimulus-to-response times were longer and the spectral amplitude of the sustained portion of the stimulus was reduced. The overall stimulus level caused significant shifts in latency across the entire speech-evoked auditory brainstem response in the older group. CONCLUSION: The reduction in neural speech processing in older adults suggests diminished subcortical responsiveness to acoustically dynamic spectral cues. However, further investigations are needed to encode temporal cues at the brainstem level and determine their relationship to speech perception for developing a routine tool for clinical decision-making. PMID- 28007045 TI - Observation versus thyroidectomy for papillary thyroid microcarcinoma in the elderly. AB - OBJECTIVE: To compare the effectiveness of non-surgical versus surgical therapy in elderly patients with papillary thyroid microcarcinoma. METHODS: The study cohort included 2323 elderly patients (aged 65 years and over) diagnosed with papillary thyroid microcarcinoma between 1988 and 2009, identified in the Surveillance, Epidemiology, and End Results 18 database of the National Cancer Institute. RESULTS: The five-year overall survival rate was 23 per cent for non surgical patients compared with 91 per cent for surgical patients (p < 0.0001). Unadjusted analysis revealed significantly improved survival in surgical patients compared with non-surgical patients (hazard ratio = 0.06; p < 0.0001). Propensity score analysis also revealed significantly improved survival in surgical patients compared with non-surgical patients (hazard ratio = 0.11; p < 0.0001). CONCLUSION: Thyroidectomy appears to provide a survival benefit for elderly patients with papillary thyroid microcarcinoma. High-quality prospective studies are needed to better evaluate the comparative effectiveness of immediate thyroidectomy versus observation for elderly patients with papillary thyroid microcarcinoma. PMID- 28007047 TI - The efficacy of psychotherapy, pharmacotherapy and their combination on functioning and quality of life in depression: a meta-analysis. PMID- 28007046 TI - Maternal effect gene expression in porcine metaphase II oocytes and embryos in vitro: effect of epidermal growth factor, interleukin-1beta and leukemia inhibitory factor. AB - Maternal effect genes (MEG) play a crucial role in early embryogenesis. In vitro culture conditions may affect MEG expression in porcine oocytes and embryos. We investigated whether in vitro culture medium supplementation with epidermal growth factor (EGF), IL-1beta or LIF (leukemia inhibitory factor) affects the mRNA level of ZAR-1 (zygote arrest 1), NPM2 (nucleoplasmin 2) and DPPA3 (developmental associated protein 3) in porcine MII oocytes and embryos. Cumulus oocyte complexes (COCs) were matured in NCSU-37 medium (control) or in NCSU-37 with EGF 10 ng/ml, IL-1beta 10 ng/ml or LIF 50 ng/ml. After maturation for 44-46 h, MII oocytes were preserved for the analysis of MEG mRNA levels (experiment 1). In experiment 2, COCs were fertilized, and the presumptive zygotes were cultured in the same groups. Then, 2-, 4-, 8-cell embryos, morulae and blastocysts were collected for the analysis of MEG mRNA levels. LIF addition to the maturation medium increased MII oocyte numbers (P < 0.05), while EGF and IL-1beta did not affect oocyte maturation. Medium supplementation with EGF resulted in lower DPPA3 mRNA levels in MII oocytes and in 2- and 4-cell embryos versus control embryos (P < 0.05). LIF treatment increased DPPA3 mRNA levels in morulae and blastocysts (P < 0.05). Culture with EGF and IL-1beta decreased ZAR-1 and NPM2 mRNA levels in 2 cell embryos (P < 0.05). The inclusion of EGF or IL-1beta in the porcine in vitro production system influences ZAR-1, NPM2 and DPPA3 mRNA in MII oocytes and embryos but not beyond the 4-cell stage. LIF stimulates oocyte maturation and affects DPPA3 mRNA in porcine morulae and blastocysts in vitro. PMID- 28007048 TI - Non-invasive individual methane measurement in dairy cows. AB - Attempts to lower the environmental footprint of milk production needs a sound understanding of the genetic and nutritional basis of methane (CH4) emissions from the dairy production systems. This in turn requires accurate and reliable techniques for the measurement of CH4 output from individual cows. Many of the available measurement techniques so far are either slow, expensive, labor intensive and are unsuitable for large-scale individual animal measurements. The main objectives of this study were to examine and validate a non-invasive individual cow CH4 measurement system that is based on photoacoustic IR spectroscopy (PAS) technique implemented in a portable gas analysis equipment (F10), referred to as PAS-F10 method and to estimate the magnitude of between animal variations in CH4 output traits. Data were collected from 115 Nordic Red cows of the Minkio experimental dairy farm, at the Natural Resources Institute Finland (Luke). Records on continuous daily measurements of CH4, milk yield, feed intake and BW measurements over 2 years period were compiled for data analysis. The daily CH4 output was calculated using carbon dioxide as a tracer method. Estimates from the non-invasive PAS-F10 technique were then tested against open circuit indirect respiration calorimetric chamber measurements and against estimates from other widely used prediction models. Concordance analysis was used to establish agreement between the chamber and PAS-F10 methods. A linear mixed model was used for the analysis of the large continuous data. The daily CH4 output of cows was 555 l/day and ranged from 330 to 800 l/day. Dry matter intake, level of milk production, lactation stage and diurnal variation had significant effects on daily CH4 output. Estimates of the daily CH4 output from PAS-F10 technique compared relatively well with the other techniques. The concordance correlation coefficient between combined weekly CH4 output estimates of PAS-F10 and chamber was 0.84 with lower and upper confidence limits of 0.65 and 0.93, respectively. Similarly, when chamber CH4 measurements were predicted from PAS F10 measurements, the mean of two separate weekly PAS-F10 measurements gave the lowest prediction error variance than either of the separate weekly PAS-F10 measurements alone. This suggests that every other week PAS-F10 measurements when combined would improve the estimation of CH4 output with PAS-F10 technique. The repeatability of daily CH4 output from PAS-F10 technique ranged from 0.40 to 0.46 indicating that some between-animal variation exist in CH4 output traits. PMID- 28007049 TI - Comparable risk of childhood asthma after vaginal delivery and emergency caesarean section. AB - INTRODUCTION: Caesarean section is thought to be a risk factor for childhood asthma, but this association may be caused by confounding from, for instance, familial factors. To address this problem, we used twin pairs to assess the risk of childhood asthma after emergency caesarean section. METHODS: The study was a register-based nation-wide matched cohort study using twin pairs to minimise residual confounding. Included were twin pairs in which the first twin was delivered vaginally and the second by emergency caesarean section during the study period from January 1997 through December 2012. RESULTS: In total, 464 twin pairs (928 twins) were included. In 30 pairs, the first twin (vaginal delivery) was diagnosed with asthma, but the second twin (emergency caesarean section) was not. In 20 pairs, the second twin (emergency caesarean section) was diagnosed with asthma, but the first twin (vaginal delivery) was not. In 11 pairs, both twins developed asthma. In the unadjusted analysis, emergency caesarean section did not affect the risk of asthma (odds ratio = 0.67 (95% confidence interval: 0.38-1.17); p = 0.16). After adjusting for birth weight, gender, umbilical cord pH, Apgar score at 5 min. and neonatal respiratory morbidity, the risk of childhood asthma following emergency caesarean section remained unchanged. CONCLUSION: Emergency caesarean section was not associated with childhood asthma. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 28007050 TI - An adverse drug event manager facilitates spontaneous reporting of adverse drug reactions. AB - INTRODUCTION: Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assists healthcare professionals in reporting suspected ADRs to the Danish Health Authority. The aim of this retrospective observational study was to quantify and describe ADRs reported via the ADEM in 2014. METHODS: All ADR reports handled by the ADEM in 2014 were recorded anonymously and analysed descriptively. RESULTS: A total of 484 ADRs were reported through the ADEM in 2014 (the median number of reports per month was 37; range: 17-78). The majority of the reports came from departments of internal medicine (61%), psychiatry (14%) and dermatology, ophthalmology or otorhinolaryngology (11%). The drugs most frequently reported were lisdexamphetamine (n = 40), rivaroxaban (n = 16) and warfarin (n = 15) (vaccines excluded). In 13 out of 484 reports, the ADR was associated with a fatal outcome. CONCLUSION: The findings of this study indicate that an ADEM promotes and facilitates spontaneous ADR reporting and helps raise awareness about ADRs, including how and why they should be reported. Hopefully, this will assist national and European spontaneous reporting systems in their work to increase patient safety nationally and abroad. FUNDING: none. TRIAL REGISTRATION: not relevant. . PMID- 28007051 TI - The effect of standardised cancer pathways on Danish cancer patients' dissatisfaction with waiting time. AB - INTRODUCTION: Standardised cancer patient pathways (CPPs) were implemented in Denmark in 2008 to reduce the waiting time during the diagnostic process and hereby improve patient satisfaction. The aim of this study was to investigate whether patient-reported dissatisfaction with long waiting times has changed from "before" to "after" the implementation of CPPs. METHODS: We conducted a comparative cohort study by comparing the patient-reported dissatisfaction with long waiting time before (2004/2005) and after (2010) CPP implementation. Logistic regression was used to estimate the odds ratios (ORs) for patient reported dissatisfaction after CPP implementation compared with before. RESULTS: Fewer patients reported dissatisfaction with long waiting time from the time of referral by their general practitioner (GP) to the first consultation at the hospital across the time of CPP implementation (p < 0.001) (adjusted OR = 0.6 (95% confidence interval (CI): 0.5-0.8)). More patients reported dissatisfaction with long waiting time to get an appointment with their GP across the time of CPP implementation (p < 0.001) (adjusted OR = 3.7 (95% CI: 2.5-5.3)). CONCLUSION: CPP implementation in Denmark was associated with a reduced level of patient-reported dissatisfaction with long waiting time from the time of referral to the first consultation at the hospital. This indicates that the CPP objective of increasing patient satisfaction may have been achieved. Nevertheless, more patients reported dissatisfaction with long waiting time to get an appointment with their GP. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 28007052 TI - Rotavirus is frequent among adults hospitalised for acute gastroenteritis. AB - INTRODUCTION: Rotavirus infection is the most common aetiology of acute gastroenteritis (AGE) among young children. In adults, diagnostics focus mainly on bacterial causes, though recent studies suggest that rotavirus is a frequent agent. The aim of this study was to examine the proportion of rotavirus in adults hospitalised with AGE and to identify possible predictors. METHODS: During a 24 month period from 1 May 2010 adults (> 15 years) with AGE admitted to one of four hospitals in the Central Denmark Region were examined for rotavirus with VIKIA Rota-Adeno rapid test in addition to routine culture for bacterial pathogens. RESULTS: A total of 265 adult patients were included. 9.4% tested positive for rotavirus. Enteropathogenic bacteria were found in 24.5% of the cases. In the majority of cases (62.3%), no pathogen was found. Overall, rotavirus was the second-most frequent pathogen, exceeded only by Campylobacter spp. Immunosuppression and a C-reactive protein (CRP) below 50 mg/l (0-8 mg/l) were associated with rotavirus. The seasonality of rotavirus differed markedly from that of bacterial gastroenteritis. CONCLUSION: Rotavirus is the second-most frequently identified pathogen in adults hospitalised with AGE. Close contact to children or travel activity does not predict rotavirus gastroenteritis, but immunosuppression and a CRP below 50 mg/l do. The seasonality of rotavirus differs from that of bacterial gastroenteritis, making rotavirus the most frequently identified cause of AGE in adults admitted to hospital in the colder months. FUNDING: The trial was funded by an unrestricted grant from Sanofi Pasteur MSD. TRIAL REGISTRATION: not relevant. PMID- 28007053 TI - Specific skin signs as a cutaneous marker of diabetes mellitus and the prediabetic state - a systematic review. AB - INTRODUCTION: Diabetes mellitus and the prediabetic state are associated with a number of skin manifestations. This study is a systematic review of the following manifestations: acanthosis nigricans (AN), skin tags (ST), diabetic dermopathy (DD), rubeosis faciei (RF), pruritus (PR), granuloma annulare (GA), necrobiosis lipoidica (NL), scleroedema diabeticorum (SD) and bullosis diabeticorum (BD). These conditions possibly relate to underlying diabetogenic mechanisms. Our aim was to determine whether skin signs are feasible as cutaneous markers for the prediabetic or diabetic state. METHODS: Data were collected from the databases PubMed, Embase and Cochrane. Articles were excluded if the populations presented with comorbidities or received treatment with drugs affecting the skin. Also, animal studies, studies with poor methodology and pilot studies were excluded. RESULTS: Among the 34 included original articles, an association with diabetes was shown as follows: in eight articles with AN, five articles with ST, three articles with GA, two articles with NL, PR and SD respectively and in one article with RF. Three papers indirectly showed an association of DD with diabetes. Association between bullous skin lesions and diabetes was only documented by case reports and case series. CONCLUSION: The results indicate a benefit of diabetes screening in individuals presenting with AN, ST or BD. Further studies are required to enlighten a possible association with RF, GA, SD or NL. Until such studies are available, it is advisable to screen individuals with the skin lesions presented by measuring their glycated haemoglobin. PMID- 28007054 TI - Antibiotic prophylaxis and complications following prostate biopsies - a systematic review. AB - INTRODUCTION: Transrectal ultrasound-guided biopsies (TRUS-gb) are associated with both mild and serious complications. Prophylactic antibiotics reduce the risk of septicaemia and mortality; however, no international consensus exists on the timing and duration of antibiotics, including the optimal drug strategy. We reviewed the current evidence supporting use of prophylactic antibiotics and the risk of complications following prostate biopsies. METHODS: This review was drafted in accordance with the Prisma Guidelines. The PubMed, Embase and Cochrane databases were searched. RESULTS: A total of 19 eligible trials were identified. One trial demonstrated a significant reduction in the risk of infection after biopsy and reported that oral ciprofloxacin as either a single-dose or a three day regimen was superior to oral chloramphenicol and norfloxacin. Of three studies investigating the timing of the first dose of antibiotic, one study found that administration 24 h before biopsy versus administration immediately before reduced the relative risk of post-biopsy infection by 55%. Seven studies compared different durations of antibiotic prophylaxis. None showed any benefit from continuing prophylaxis beyond a single dose or a one-day regimen. CONCLUSION: Evidence supporting a specific antibiotic regimen for TRUS-gb prophylaxis is scarce. Widespread use of fluoroquinolone prophylaxis may be associated with an increase in resistant Escherichia coli strains, posing a potentially major health issue in the future. . PMID- 28007055 TI - Physiological and pathophysiological aspects of incretin hormones and glucagon. AB - Infusion of oxyntomodulin and the separate and combined infusion of GLP-1 and glucagon inhibited food intake similarly in healthy individuals, with no superior effect of combining GLP-1 and glucagon. We confirm the inhibitory effects of oxyntomodulin and GLP-1, respectively, on GE and appetite scores observed previously, but by adding glucagon to the infusion of GLP-1 we found no additive effects. Unexpectedly, glucagon alone had no effect on GE and appetite scores, but inhibited food intake to the same extent as oxyntomodulin, GLP-1 and GLP-1 + glucagon. Both the GLP-1, oxyntomodulin and GLP-1 + glucagon infusions appeared to increase O2 compared to saline but this observation is most likely confounded by a residual meal-induced thermogenesis because the calorimetry was performed relatively soon after the paracetamol peak indicating that a considerable volume still resided in the stomach and a high rate of nutrient absorption probably was still going on compared to the saline infusion. Flint et al previously concluded from a protocol very similar to ours using GLP-1 infusions, that the observed increases in energy expenditure most likely were linked to the meal. In contrast, we observed no significant changes in O2 from baseline in any of the experiments in our study. The lack of a clear effect on O2 is in contrast to recently reported findings regarding infusions of glucagon and GLP-1. But the dose of glucagon used in that particular study was more than 15-fold higher than ours and associated with large changes in glucose and insulin levels. Such levels are likely to influence REE and offer an explanation of the reported additive effect of combinations of GLP-1 and glucagon. Our conclusion is consistent with recent findings showing no increases after short-term native GLP-1 infusions. Long-term treatment with the GLP-1 analogue liraglutide using 24 h chamber calorimetry has so far shown no differences in energy expenditure following the treatment. Surprisingly, the infusion of glucagon did not change gastric emptying. This finding is controversial since glucagon previously has been used to inhibit bowel motility. However, the doses used to inhibit bowel motility were more than 3,000 fold higher than the dose used in the present study and as mentioned above, such doses might activate the GLP-1 receptor pathway. Interestingly, the glucagon infusion did result in decreased food intake to the same extent as the other peptide infusions despite having no impact on gastric emptying and appetite scores. We found a mean 180 kcal (120 g) difference in food intake following infusions of all the peptides compared to saline. This would roughly sum up to a body weight loss of 402 g of fat per week, which is in the range of what previously has been found in overweight and obese humans with the injection of oxyntomodulin. PMID- 28007056 TI - Mental Health Disparities Among Canadian Transgender Youth. AB - PURPOSE: This study documented the prevalence of mental health problems among transgender youth in Canada and made comparisons with population-based studies. This study also compared gender identity subgroups and age subgroups (14-18 and 19-25). METHODS: A nonprobability sample of 923 transgender youth from Canada completed an online survey. Participants were recruited through community organizations, health care settings, social media, and researchers' networks. Mental health measures were drawn from the British Columbia Adolescent Health Survey and the Canadian Community Health Survey. RESULTS: Transgender youth had a higher risk of reporting psychological distress, self-harm, major depressive episodes, and suicide. For example, 65% of transgender 14- to 18-year olds seriously considered suicide in the past year compared with 13% in the British Columbia Adolescent Health Survey, and only a quarter of participants reported their mental health was good or excellent. Transgender boys/men and nonbinary youth were most likely to report self-harm and overall mental health remained stable across age subgroups. CONCLUSIONS: Although a notable minority of transgender youth did not report negative health outcomes, this study shows the mental health disparities faced by transgender youth in Canada are considerable. PMID- 28007057 TI - Introduction. PMID- 28007058 TI - The 50/50 cc Total Artificial Heart Trial: Extending the Benefits of the Total Artificial Heart to Underserved Populations. AB - While use of the total artificial heart (TAH) is growing, the use of the device is not uniform across the gender and age spectrum because the vast majority of implants are in adult males. SynCardia has recently developed a smaller 50 cc TAH that was designed to accommodate patients with a body surface area as low as 1.2 m2 (potentially even lower using virtual implantation). Herein, we describe the early use of the 50 cc TAH (10 implants in the US and 18 outside the US). Twenty eight devices have been implanted worldwide. Nineteen (68%) patients were female, 4 (14%) were 21 years of age or younger, and 2 (7%) had a diagnosis of congenital heart disease (1 Fontan). The smallest patient, by body surface area, was 1.35 m2. Six patients (21%) have been placed on the Freedom Driver, all of whom have survived. Fourteen patients (50%) have had a positive outcome to date. The development of the 50 cc TAH has expanded the population of patients who may benefit from TAH support and thus may help improve outcomes for patients who have had limited biventricular support options to date. PMID- 28007059 TI - Current Status of Pediatric Ventricular Assist Device Support. AB - The last decade has witnessed significant advancement in the field of ventricular assist device (VAD) support. Although device options for pediatric patients were previously severely limited because of body size constraints, this frustrating situation has gradually been changing, owing to ongoing device miniaturization. Recognition of the superiority of VAD support compared with conventional extracorporeal membrane oxygenation support has spurred enthusiasm for VAD support in children. In this article, we discuss the current status of pediatric VAD support; where do we stand now and where will we be heading? Because this field is rapidly changing, it is anticipated that this article will provide a general overview of what is currently occurring in the field of pediatric VAD support. PMID- 28007060 TI - Mechanical Circulatory Support of the Fontan Patient. AB - Because of the inadequacies inherent to a circulation supported by a single ventricle, many Fontan patients will experience failure of their circulation. To date, there is no medical regimen that reliably and consistently restores circulatory function in these patients. Because of the shortage of donor organs and the fact that many of these patients present with features that either preclude or render heart transplantation a high risk, there is an intense need to better understand how mechanical circulatory support (MCS) may benefit these patients. In this report, we share our experience of successful MCS and transplantation of three patients. Our experience and that of others is very encouraging, but also preliminary. In general, a systemic ventricular assist device, with or without a Fontan fenestration, is a reasonable consideration for a patient presenting with predominantly systolic dysfunction. A pulmonary/systemic venous assist device may be sufficient for the patient with preserved systolic function and failure of the systemic venous/lymphatic system; however, this remains speculative. The more comprehensive approach of a total artificial heart or bilateral support is attractive in theory, but beset by the need for a more complex operation. In all scenarios, early referral, before organ failure, is paramount to successful MCS. PMID- 28007061 TI - The Evolution of an Adult Congenital Heart Surgery Program: The Emory System. AB - The Emory Adult Congenital Heart (Emory University, Atlanta, GA) program was founded in 2001. In 2004, the surgical component transitioned from a pediatric facility to an adult facility. The aim of this article is characterize the program as a whole, outline changes in the program, and discuss the challenges of the transition process. Between 2001 and 2015, changes in program structure and personnel were evaluated. There has been significant growth of the program between 2001 and 2015. There are currently 19 half-day clinics per week, with 2,700 clinic visits per year. There are six cardiologists, three congenital cardiac surgeons, two sonographers, one advanced practice provider, and one social worker dedicated to the program. There are Accreditation Council for Graduate Medical Education-accredited adult congenital cardiology and congenital cardiac surgery fellowships. One thousand forty-four operations were performed between 2001 and 2015. There were 828 open-heart operations, of which 581 (70%) were re-operations. Over the study period, the number of yearly operations increased from 30 to 119, and the mean age at surgery increased from 22 to 35 years. Over time, more of the operations were performed at the adult hospital: increasing from 3% in 2001 to 82% in 2015, and more of the operations were performed by congenital cardiac surgeons: 87% (114 of 131) before the 2004 transition to 97% (881 of 913) afterward. The Emory Adult Congenital Heart program has undergone significant growth and change, including transition of the surgical component from the pediatric to the adult facility. While numerous obstacles have been overcome and great progress has been made, additional challenges remain. PMID- 28007062 TI - Rescuing the Late Failing Fontan: Focus on Surgical Treatment of Dysrhythmias. AB - Patients with a failing Fontan frequently have dysrhythmias. This review will focus on the treatment of those dysrhythmias based on the 140 patients who have had a Fontan conversion with arrhythmia surgery at Ann & Robert H. Lurie Children's Hospital of Chicago (Chicago, IL). Important technical points to be emphasized are the following:* Atrial fibrillation is extremely common in patients with a failing Fontan and strong consideration should be given to a Cox maze III during any Fontan conversion* Sinus node dysfunction is common post conversion and all patients should receive a dual-chamber epicardial pacemaker* Careful preoperative imaging with either computed tomographic or magnetic resonance imaging is needed to predict re-entry problems at the time of repeat sternotomy* If the patient has protein-losing enteropathy, ascites, or a right or indeterminate ventricular morphology, strong consideration should be given to heart transplantation rather than a Fontan conversion and arrhythmia surgery. Freedom from cardiac death or transplant for patients undergoing Fontan conversion with arrhythmia surgery is 84% at 10 years. The effects of atrial arrhythmia operations are durable in most patients. There is increasing evidence that earlier referral of patients with an atriopulmonary Fontan for Fontan conversion will improve long-term results. Fontan conversion should be performed at centers with the institutional expertise to care for these complex patients. Note that this is an eroding patient population. The time to act may be now. PMID- 28007063 TI - The Neonatal Arterial Switch Operation: Technical Pearls. AB - The neonatal arterial switch operation has become the standard of care for transposition of the great arteries, including transposition with intact ventricular septum, transposition with ventricular septal defect with or without aortic arch hypoplasia, and double outlet right ventricle with subpulmonary ventricular septal defect (Taussig-Bing anomaly). While technically demanding, the operation is enormously gratifying and exciting for the congenital heart surgeon. In the current era, outcomes and expectations for the neonatal arterial switch operation are extremely high with many centers, including our own, reporting 30-day or hospital survivorship approaching 100%. Long-term results are also outstanding, although these patients do require lifelong follow-up and have the potential for need of remedial surgical intervention. PMID- 28007064 TI - The Society of Thoracic Surgeons Congenital Heart Surgery Database Public Reporting Initiative. AB - Three basic principles provide the rationale for the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database (CHSD) public reporting initiative: (1) Variation in congenital and pediatric cardiac surgical outcomes exist. (2) Patients and their families have the right to know the outcomes of the treatments that they will receive. (3). It is our professional responsibility to share this information with them in a format they can understand. The STS CHSD public reporting initiative facilitates the voluntary transparent public reporting of congenital and pediatric cardiac surgical outcomes using the STS CHSD Mortality Risk Model. The STS CHSD Mortality Risk Model is used to calculate risk-adjusted operative mortality and adjusts for the following variables: age, primary procedure, weight (neonates and infants), prior cardiothoracic operations, non cardiac congenital anatomic abnormalities, chromosomal abnormalities or syndromes, prematurity (neonates and infants), and preoperative factors (including preoperative/preprocedural mechanical circulatory support [intraaortic balloon pump, ventricular assist device, extracorporeal membrane oxygenation, or cardiopulmonary support], shock [persistent at time of surgery], mechanical ventilation to treat cardiorespiratory failure, renal failure requiring dialysis and/or renal dysfunction, preoperative neurological deficit, and other preoperative factors). Operative mortality is defined in all STS databases as (1) all deaths, regardless of cause, occurring during the hospitalization in which the operation was performed, even if after 30 days (including patients transferred to other acute care facilities); and (2) all deaths, regardless of cause, occurring after discharge from the hospital, but before the end of the 30th postoperative day. The STS CHSD Mortality Risk Model has good model fit and discrimination with an overall C statistics of 0.875 and 0.858 in the development sample and the validation sample, respectively. These C statistics are the highest C statistics ever seen in a pediatric cardiac surgical risk model. Therefore, the STS CHSD Mortality Risk Model provides excellent adjustment for case mix and should mitigate against risk aversive behavior. The STS CHSD Mortality Risk Model is the best available model to date for measuring outcomes after pediatric cardiac surgery. As of March 2016, 60% of participants in STS CHSD have agreed to publicly report their outcomes through the STS Public Reporting Online website (http://www.sts.org/quality-research-patient-safety/sts public-reporting-online). Although several opportunities exist to improve our risk models, the current STS CHSD public reporting initiative provides the tools to report publicly, and with meaning and accuracy, the outcomes of congenital and pediatric cardiac surgery. PMID- 28007065 TI - A Word of Caution in Public Reporting. AB - Public reporting in its current form will lead to confusion amongst physicians, administrators, families, and the media. It is unclear that we are giving the families information they really need. At the current time there is no evidence that public reporting really leads to improved outcomes. Rather, it may lead to risk aversion and limit access to care. This is a problem not just for congenital heart surgery but for the entire field of medicine and the care that we provide to our patients. We must be very careful that we don't create a system where we are afraid to take on a patient with increased risk of mortality because it may affect our overall ranking. PMID- 28007066 TI - Valve-Sparing Aortic Root Replacement in Pediatric Patients: Lessons Learned Over Two Decades. AB - Valve-sparing aortic root replacement has been utilized in children with aneurysms of the proximal aorta as a valid alternative to composite mechanical or biologic prostheses. While the majority of pediatric patients with aortic root aneurysms have various forms of connective tissue disorders, other diagnostic groups have emerged, such as patients with various forms of congenital heart disease and non-syndromic thoracic aortic aneurysms. We present our experience with valve-sparing procedures in pediatric patients, highlighting the technical aspects of the operation as well as some of the pitfalls and complications we have encountered over the last two decades. PMID- 28007067 TI - Aortic Arch Advancement and Ascending Sliding Arch Aortoplasty for Repair of Complex Primary and Recurrent Aortic Arch Obstruction. AB - The optimal treatment of patients with complex coarctation of the aorta and hypoplastic aortic arch is controversial. Children undergoing repair of obstructive arch lesions are at lifelong risk of recurrence. Multiple techniques have been described to address complex primary and recurrent coarctation. Our approach at Texas Children's Hospital (Houston, TX) has been to address these lesions in an anatomic fashion via median sternotomy, under cardiopulmonary bypass using the techniques of aortic arch advancement and ascending sliding arch aortoplasty. Anatomic repair of complex primary or recurrent aortic obstruction is safe and produces a favorable repair with a low rate of recurrence. Both operations restore normal arch contour using native aortic tissue. The decision of which particular surgical strategy to use depends on the patient's age, anatomy, and the elasticity of the tissue. PMID- 28007068 TI - Congenital Heart Surgery Subspecialty Certification: How Is It Working? The American Board of Thoracic Surgery Perspective. AB - Congenital heart surgery is among the most challenging fields in all of medicine. The unique skills and knowledge base required prompted the American Board of Thoracic Surgery (ABTS) to establish the Subspecialty Certificate in Congenital Heart Surgery (CHS). Standards for operative experience and fellowship training programs were established by the ABTS and the Accreditation Council for Graduate Medical Education. Since 2009, 188 Subspecialty Certificates in CHS have been granted, including 38 earned through the fellowship training pathway. Today, the overwhelming majority of congenital heart surgeons in the United States hold a Subspecialty Certificate in CHS. Recent survey data suggests those individuals who have completed Accreditation Council for Graduate Medical Education fellowship training in CHS were satisfied with the operative experience they received during training and the vast majority are practicing CHS. While surgical training and education will always be a work in progress, in the 7 years since its inception, the ABTS Subspecialty Certificate in CHS has achieved the goal of quality control and standardization of CHS training. PMID- 28007069 TI - The ACGME Fellowship in Congenital Cardiac Surgery: The Graduates' Perspective. AB - The creation of structured fellowship programs in congenital heart surgery (CHS) in the United States appears to have improved the training of congenital heart surgeons. However, the transition process between fellowship and clinical practice and the lack of senior mentorship continue to be major problems. We report the results of a survey of all graduates of accredited programs in CHS. A total of 35/51 (69%) graduates responded to the survey. Of 34 that are in practice, 31 (91%) did not feel ready to engage in solo CHS after completion of training. Even though 33 (97%) considered mentorship in the first few years of practice very important, almost 40% indicated inadequate mentorship. Several graduates continue to mainly assist and do not seem to be independent several years after graduating from their fellowship. On an open-ended question for additional comments, 15 respondents volunteered that a 1-year fellowship duration was not enough and seven stressed the importance of mentorship and the need for an adequate transition from fellowship to practice. Based on the results of the survey and our own experience, we propose the creation of a 1- or 2-year transitional junior faculty period to follow the 1-year formal training in CHS. We believe innovative approaches to improve the transition to clinical practice are required to maximize the likelihood of success among congenital heart surgery graduates. PMID- 28007070 TI - The American Board of Thoracic Surgery Congenital Fellowship: Have We Lost Our International Heritage? AB - Since 2005 there have been very few (if any) individuals trained outside of the United States in congenital surgery. Confining congenital training to only programs in the US has with it some unintended consequences. First, we need to recognize that progress is made around the world and not only in the US. Second, we decrease our opportunity to establish international peers, which leads to less opportunity for multi-institutional and multi-national studies and intellectual isolation. Third, we are in a new age of globalization. Advances in technology, E learning platforms, transportation, Internet, and other means of telecommunication have all expedited our capabilities to transmit knowledge and have created for us a "global village." I believe that it is time for us to reorganize and extend our programs beyond our own borders. To do this, we must think about creating Exchange Programs within our congenital fellowships. International fellowships will expose our trainees to new practice environments and help to open our minds to new ways of thinking. To be successful, our current board requirements will need to reflect these changes. The programs will need oversight, coordination, time and resources. In addition, and most importantly, we must make sure that it is a good learning experience. It will not be enough to "just send fellows abroad"; the programs must be guided by specific goals and objectives that need to be continually monitored and revised as needed. PMID- 28007071 TI - Valve-Sparing or Valve Reconstruction Options in Tetralogy of Fallot Surgery. AB - This review deals with a relatively new field in congenital heart surgery, valve preservation or, in cases of more severe pulmonary valve stenosis or dysplasia, valve reconstruction during tetralogy of Fallot repair. We describe the stepwise approach utilized, starting with simple maneuvers such as commissurotomy and valve dilation for mild pulmonary stenosis to commissurotomy and intraoperative balloon dilation for moderate stenosis, and finally transection of the annulus and valve reconstruction using a patch that acts as a modified monocusp. Results are presented and have been gratifying. PMID- 28007072 TI - Tetralogy Surgery - Back To Baltimore 70 Years Later: Melbourne Heritage and Group Tribute to Juan Comas. AB - Surgery for Tetralogy of Fallot progressed rapidly from the palliative arterio pulmonary Blalock-Taussig shunt, introduced in Baltimore 70 years ago, to the "classic" complete transventricular repair technique, with which excellent early results were achieved soon thereafter. However, as duration of follow-up increased, so did the awareness of development of troubling late complications, including severe pulmonary insufficiency, right ventricular dilatation and dysfunction, and tricuspid valve insufficiency, all contributing to increasing incidence of late reoperations, as well as to arrhythmias and sudden death. This realization fueled the initial introduction of the transatrial-transpulmonary repair technique by Kawashima, as well as the subsequent firm establishment of this technique within the framework of an integrated surgical approach by Roger Mee in Melbourne. In turn, Mee's numerous trainees and associates led the dissemination of this approach and provided the impetus for the current wide adoption of a variety of right ventricular and pulmonary valve preservation techniques. In addition to the outstanding surgical results reported by individual centers adopting this surgical strategy, encouraging multi institutional data are emerging regarding the benefits of these approaches for more favorable early and, most importantly, late outcome. One student and strong proponent of the Melbourne approach was our late colleague and friend Juan Comas, to whose memory this article can serve as tribute. PMID- 28007073 TI - Closing in on the PumpKIN Trial of the Jarvik 2015 Ventricular Assist Device. AB - The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device's performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future. PMID- 28007074 TI - Effect of Stent Implantation on the Deformations of the Superficial Femoral Artery and Popliteal Artery: In Vivo Three-Dimensional Deformational Analysis from Two-Dimensional Radiographs. AB - The objective of this work was to develop a system for three-dimensional (3D) reconstruction of the femoropopliteal artery from two angiographic views and to quantify the in vivo 3D deformations in 18 patients before balloon angioplasty and after primary stent implantation. The procedure had an insignificant effect on the bending behavior of the artery, as the average mean curvature change within the lesion remained constant before (0.04 cm-1 +/- 0.03) and after stent implantation (0.03 cm-1 +/- 0.04). A significant effect of stent implantation was measured in terms of a decrease in arterial shortening during leg flexion. PMID- 28007075 TI - Pulmonary Vein Varix with Pulmonary Vein Stenosis. PMID- 28007076 TI - Transcatheter Embolization of an Internal Mammary Artery-to-Pulmonary Artery Fistula Using N-Butyl Cyanoacrylate and Temporary Dual-Balloon Occlusion. PMID- 28007077 TI - The "Never-Ending Coil": Embolization Procedure Complicated by an Unraveled Coil. PMID- 28007078 TI - Re: Abdelaziz O, Sallam K, Mostafa M, Elansary A, Amin A. Hybrid Microsurgical Reconstruction and Percutaneous Endovascular Stent Placement for Management of Dissected Graft Hepatic Artery during Living Donor Liver Transplantation. (J Vasc Interv Radiol 2015;26:916-918). PMID- 28007079 TI - Inferior Epigastric Uterine Artery. PMID- 28007080 TI - Preoperative Embolization of the Celiac Axis or Common Hepatic Artery before Distal Pancreatectomy with Resection of the Celiac Axis. AB - Patients with locally advanced pancreatic cancer who undergo distal pancreatectomy with resection of the celiac axis (CA) are at risk for postoperative hepatic or gastric ischemia if collateral blood flow from the superior mesenteric artery (SMA) via the gastroduodenal artery is insufficient. This study presents a technique for preoperative angiographic evaluation of these collateral vessels by using an AMPLATZER Vascular Plug to temporarily occlude the CA or common hepatic artery while simultaneously performing digital subtraction angiography of the SMA. If collateral vessels are deemed sufficient, the plug can subsequently be released for permanent occlusion with the intent to enhance the blood flow in these collateral vessels. PMID- 28007081 TI - Annals 2017: Maintaining old traditions and developing new ones. PMID- 28007082 TI - A 10-year-old girl with persistent ocular swelling. PMID- 28007083 TI - Anaphylaxis caused by immediate hypersensitivity to topical chlorhexidine in children. PMID- 28007084 TI - Neurologic manifestations of hereditary angioedema. PMID- 28007086 TI - Stinging insect hypersensitivity: A practice parameter update 2016. PMID- 28007085 TI - Deciphering the black box of food allergy mechanisms. AB - OBJECTIVE: To review our current understanding of immunotherapy, the immune mechanisms underlying food allergy, and the methodological advances that are furthering our understanding of the role of immune cells and other molecules in mediating food allergies. DATA SOURCES: Literature searches were performed using the following combination of terms: allergy, immunotherapy, food, and mechanisms. Data from randomized clinical studies using state-of-the-art mechanistic tools were prioritized. STUDY SELECTIONS: Articles were selected based on their relevance to food allergy. RESULTS: Current standard of care for food allergies is avoidance of allergenic foods and the use of epinephrine in case of severe reaction during unintentional ingestion. During the last few decades, great strides have been made in understanding the cellular and molecular mechanisms underlying food allergy, and this information is spearheading the development of exciting new treatments. CONCLUSION: Immunotherapy protocols are effective in desensitizing individuals to specific allergens; however, recurrence of allergic sensitization is common after discontinuation of therapy. Interestingly, in a subset of individuals, immunotherapy is protective against allergens even after discontinuation of immunotherapy. Whether this protection is permanent is currently unknown because of inadequate long-term follow-up data. Research on understanding the underlying mechanisms may assist in modifying protocols to improve outcome and enable sustained unresponsiveness, rather than a temporary relief against food allergies. The cellular changes brought about by immunotherapy are still a black box, but major strides in our understanding are being made at an exciting pace. PMID- 28007087 TI - The year in review: The best of 2016 in the Annals. PMID- 28007089 TI - Epidemiology of anaphylaxis at a tertiary care center: A report of 730 cases. AB - BACKGROUND: Recent data reveal that the rate of anaphylaxis is increasing and suggest that idiopathic anaphylaxis may account for most of these cases. OBJECTIVE: To determine the pattern of anaphylaxis at a tertiary care referral center. METHODS: A retrospective electronic medical record review spanning 12 years (2002-2013) identified patients with anaphylaxis. RESULTS: Of the 4,777 records reviewed, 730 patients met our anaphylaxis definition. Median age was 34.0 years; 72.7% were adults, 58.6% were female, and 86.8% were white. Median time to evaluation by an allergist was 8.8 months. Foods were the most common cause (29.9%), followed by Hymenoptera venom (24.6%), idiopathic anaphylaxis (13.7%), and medications (13.3%). The most common foods were peanuts (23.9%), tree nuts (21.6%), shellfish (16.1%), and egg and milk (both 10.1%). The most common cause of anaphylaxis in adults was Hymenoptera venom. The most frequent symptoms were urticaria and/or angioedema, reported in 84.7% of cases. Atopy was present in 43.8%. In 15.4% of cases, anaphylaxis was not the chief reason for the office visit. CONCLUSION: We found food allergy was the most common overall cause of anaphylaxis, with peanut the most frequent food trigger. Idiopathic anaphylaxis was not the most common cause but accounted for 13.7% of all cases. Approximately 1 in 6 cases of anaphylaxis may be missed if a comprehensive evaluation is not performed. PMID- 28007088 TI - Maternal depressive symptoms, maternal asthma, and asthma in school-aged children. AB - BACKGROUND: Little is known about the joint effects of maternal asthma and maternal depression on childhood asthma. OBJECTIVE: To examine whether maternal depression and maternal asthma lead to greater risk of childhood asthma than maternal asthma alone. METHODS: Cross-sectional studies of children (6-14 years old) in San Juan, Puerto Rico (n = 655) and Sweden (n = 6,887) were conducted. In Puerto Rico, maternal depressive symptoms were defined using the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire. In Sweden, maternal physician-diagnosed depression was derived from national registries, and maternal depressive symptoms were defined using an abbreviated CES-D questionnaire. Childhood asthma was defined as physician-diagnosed asthma plus current wheeze (in Puerto Rico) or plus medication use (in Sweden). Logistic regression was used for multivariable analysis. RESULTS: Compared with Puerto Rican children whose mothers had neither asthma nor depressive symptoms, those whose mothers had asthma but no depressive symptoms had 3.2 times increased odds of asthma (95% confidence interval [CI] = 2.1-4.8) and those whose mothers had asthma and depressive symptoms had 6.5 times increased odds of asthma (95% CI = 3.3-13.0). Similar results were obtained for maternal depression and maternal asthma in the Swedish cohort (odds ratio for maternal asthma without maternal depression = 2.8, 95% CI = 2.1-3.7; odds ratio for maternal asthma and maternal depression = 4.0, 95% CI = 1.7-9.6). Although the estimated effect of maternal asthma on childhood asthma was increased when maternal depressive symptoms (Puerto Rico) or maternal depression (Sweden) was present, there were no statistically significant additive interactions. CONCLUSION: Maternal depression can further increase the risk of asthma in children whose mothers have a history of asthma. PMID- 28007090 TI - Redness response phenotypes of allergic conjunctivitis in an allergen challenge chamber. AB - BACKGROUND: There are few direct data concerning symptom dynamics of allergic conjunctivitis (AC) in an allergen challenge chamber (ACC). OBJECTIVE: To determine the AC dynamics on subsequent exposures to ragweed pollen (RW) in individuals with allergic rhinitis in an ACC. To determine whether consecutive exposures in an ACC have any persistent detrimental ocular physical effects. METHODS: Participants underwent 3 exposures to RW in an ACC. Ocular symptoms of itching and tearing were self-assessed. Ocular redness and lid swelling were assessed by trained ophthalmic technicians. Complete ophthalmic examinations (COEs) were performed by an ophthalmologist. RESULTS: A total of 188 of 201 participants (93%) developed an ocular redness score of 2 or more in each eye in ACC exposure 1. Reproducibility of redness occurred in approximately 70% of individuals completing ACC exposures 1 through 3. There were no significant changes between baseline COE and end of study COE. Phenotypes were identified by redness responses during and after exposure. Baseline total ocular symptom scores, at 24 hours after a priming exposure, were identified as late-phase reactions rather than enhanced sensitivity. CONCLUSION: When assessed by trained professionals, AC was present with a very high frequency in selected individuals allergic to RW monitored in an ACC. Intrasubject reproducibility of redness was consistent across 3 ACC allergen exposures. Phenotypes were identified as early phase responses, protracted early-phase responses, dual responses, and late-phase responses. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02079649. PMID- 28007091 TI - Inhibition effect of blunting Notch signaling on food allergy through improving TH1/TH2 balance in mice. AB - BACKGROUND: Notch signaling regulates proliferation, differentiation, and function of dendritic cells, T cells, and mast cells, as well as many other immune cells, which act as important parts in food allergy, Notch signaling may play an important role in food allergy. OBJECTIVE: To investigate the role of Notch signaling in IgE-mediated food allergy. METHODS: An ovalbumin-induced food allergy mouse model was built (cholera toxin as adjuvant) and Notch signaling was blunted by FLI-06 and MW167, which inhibited Notch receptor-expressing phase and the gamma-secretase-affecting phase, respectively. Then food allergy indicators, including levels of serum antibodies, cytokines, and degranulation, were examined. Meanwhile, clinical features, such as vascular permeability changes, intestinal permeability changes, body temperature changes, and symptoms, were also observed. RESULTS: After blunting Notch signaling, the levels of serum ovalbumin specific IgE and IgG1 were decreased significantly, suggesting that blunting Notch signaling inhibited antibody responses. The levels of TH1 cytokines (interferon-gamma) were increased significantly, whereas the levels of TH2 cytokines (interleukin-4, -5, and -13) were decreased significantly, suggesting TH2 polarization was suppressed after blunting Notch signaling. The expression of T-bet was significantly increased, whereas the expression of Gata-3 was significantly reduced in both messenger RNA and protein levels, indicating TH2 polarization was inhibited and TH1 polarization was enhanced after blunting Notch signaling. Moreover, allergic clinical features of mice were alleviated after blunting Notch signaling. CONCLUSION: Food allergy was inhibited by blunting Notch signaling through suppressing TH2 polarization, enhancing TH1 cell differentiation and promoting TH1/TH2 balance in mice. Notch signaling plays a key role in IgE-mediated food allergy. PMID- 28007092 TI - State of the Journal 2017. PMID- 28007093 TI - Bronchial effects of cryoballoon ablation for atrial fibrillation. AB - BACKGROUND: Damage to extracardiac structures, including the esophagus and phrenic nerve, is a known complication of cryoballoon ablation (CBA) during pulmonary vein (PV) isolation for atrial fibrillation (AF). Other adjacent structures, including the pulmonary bronchi and lung parenchyma, may be affected during CBA at the PV ostia. OBJECTIVE: The purpose of this study was to prospectively study the bronchial effects of CBA in humans undergoing CBA for PV isolation. METHODS: Ten patients undergoing CBA for AF under general anesthesia were enrolled in an institutional review board-approved prospective observational study. Real-time bronchoscopy was performed during cryoablation of PVs adjacent to pulmonary bronchi to monitor for thermal injury. Patients were followed for the development of respiratory complaints postprocedure. RESULTS: In 7 of 10 patients (70%) and in 13 of 22 freezes (59%), ice formation was visualized in the left mainstem bronchus during CBA in the left upper PV. Ice formation was not seen in the right mainstem bronchus during right upper PV CBA. The average time to ice formation was 89 seconds. There was no significant difference (P = -.45) in average minimum balloon temperature during freezes with ice formation (-48.5 degrees C) and freezes without ice formation (-46.3 degrees C). No patients went on to develop respiratory complications. CONCLUSION: Unrecognized ice formation occurs frequently in the left mainstem bronchus during CBA for AF. This information helps explain the source of cough and hemoptysis in some patients who undergo CBA. The long-term consequences of this novel finding and the implications for procedural safety are unknown. PMID- 28007094 TI - I-123-Metaiodobenzylguanidine imaging in patients with atrial fibrillation undergoing cardiac mapping and ablation of autonomic ganglia. PMID- 28007095 TI - Ganglionated plexus ablation for atrial fibrillation: Just because we can, does that mean we should? PMID- 28007096 TI - Heat or cold: Different questions, same doubts. PMID- 28007097 TI - Intangible benefits of volunteering with the Heart Rhythm Society. PMID- 28007098 TI - The Journal of Cataract & Refractive Surgery in 2016: A Momentous Year. PMID- 28007099 TI - In-the-bag nasal intraocular lens optic truncation for treatment of negative dysphotopsia. AB - : We describe in-the-bag nasal intraocular lens (IOL) optic truncation, a new technique for the treatment of negative dysphotopsia. After a plane is created between the nasal capsular bag and the IOL, micrograspers and intraocular scissors are used to amputate the nasal optic edge. The amputation is to reduce the optical impact of the IOL edge and nasal anterior capsule on the occurrence of negative dysphotopsia. The technique addresses many of the proposed mechanisms contributing to the development of negative dysphotopsia and can theoretically be used in all patients with chronic symptomatology. In the case we describe, the dysphotopsia resolved immediately after in-the-bag nasal IOL optic truncation. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007100 TI - Iris fixation of posterior chamber intraocular lenses. AB - : We introduce a technique for iris fixation of a posterior chamber intraocular lens (IOL) in which most of the procedure is done outside the eye. This minimizes intraocular manipulation, maximizes corneal endothelial preservation, and avoids the risk for IOL drop into the vitreous cavity intraoperatively. The IOL is fixated to the most peripheral part of the iris, resulting in a rounder pupil. Sutures are placed at exact positions on the haptics, resulting in a well centered IOL. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007101 TI - Refractive small-incision lenticule extraction: Push-up and push-down techniques. AB - : We describe 2 techniques for manipulating the edge of the lenticule in refractive small-incision lenticule extraction. In the push-up technique, an instrument with a Y-shaped tip is inserted through the incision and used to push the edge of the lenticule up, facilitating visualization of the edge of the lenticule, which might accelerate the learning curve of the beginning surgeon. The push-down technique is used if the surgeon notices that the lenticule is adherent to the cap after 1 surface has been dissected, making dissection of the superficial surface difficult. The same Y-shaped instrument can be used to engage the edge of the lenticule and push it down to make room to introduce the dissector; this is followed by dissection of the lenticule from the cap using the dissector. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 28007102 TI - Suppression of surface light scattering in intraocular lenses manufactured using an improved production process. AB - PURPOSE: To clinically examine the suppression of surface light scattering after implantation of an intraocular lens (IOL) manufactured using an improved production process. SETTING: Miyata Eye Hospital, Miyazaki, Japan. DESIGN: Comparative case series. METHODS: The prospective case series comprised eyes receiving hydrophobic acrylic Acrysof SN60WF IOLs that were manufactured before and after the improvement. Light scattering on the anterior IOL surface was examined up to 3 years postoperatively using an EAS-1000 anterior segment analyzer. The changes during the postoperative period were evaluated and the 2 IOLs compared. The corrected distance visual acuity (CDVA) and contrast sensitivity under photopic and mesopic conditions were also examined 3 years postoperatively. RESULTS: The case series comprised 24 eyes (received IOL before improvement) and 27 eyes (received IOL after improvement). After the improvement, the IOLs showed no increase in surface light scattering up to 2 years, while there were increases after 2 years in the other IOLs. The light scattering with the improved IOL was significantly reduced at all observations (P < .048, t test with Holm correction). No difference was found in the CDVA and contrast sensitivity. CONCLUSIONS: The improvement in the production process effectively decreased and slowed the development of surface light scattering. The slower increase in the improved IOL 3 years postoperatively showed that the development of water aggregates would not be completely prevented. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007103 TI - Comparison of the visual performance and quality of vision with combined symmetrical inferonasal near addition versus inferonasal and superotemporal placement of rotationally asymmetric refractive multifocal intraocular lenses. AB - PURPOSE: To compare the postoperative quality of vision between different bilateral placements of near segments of rotationally asymmetric refractive multifocal intraocular lenses (IOLs) and to determine how this affects visual performance. SETTING: Cathedral Eye Clinic, Belfast, Northern Ireland, United Kingdom. DESIGN: Retrospective comparative case series. METHODS: The study enrolled consecutive patients having refractive lens exchange and implantation of rotationally asymmetric multifocal IOLs. Group 1 received bilateral SBL-3 IOLs and Group 2 received bilateral Lentis Mplus LS-312 MF30 IOLs, with the near segments placed inferonasally in each group. Group 3 received a Lentis Mplus LS 312 MF20 IOL in the dominant eye with the near segment positioned superotemporal and a Lenstec SBL-3 IOL positioned inferonasally in the fellow eye. Binocular uncorrected (UDVA) and corrected distance visual acuities, binocular uncorrected near (UNVA) and intermediate (UIVA) visual acuities, binocular distance-corrected near and intermediate visual acuities, and quality of vision were evaluated over 3 months postoperatively. RESULTS: The study enrolled 180 patients (360 eyes). There was no significant difference between the groups in binocular UDVA, UIVA, and UNVA; however, there was a significant difference between the groups in quality of vision (P <= .001). Group 3 had significantly better overall quality of vision. CONCLUSION: When implanting rotationally asymmetric multifocal IOLs, a combination of superotemporal placement of the near segment (+2.00 diopter [D] addition [add]) in the dominant eye with inferonasal placement of the near segment (+3.00 D add) in the fellow eye yielded consistent, high overall quality of vision and uncorrected visual acuity. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007104 TI - Dose and administration of intracameral moxifloxacin for prophylaxis of postoperative endophthalmitis. AB - PURPOSE: To review current and past practices of intracameral antibiotic administration for infection prophylaxis in cataract surgery; to review the benefits and liabilities of available prophylactic drugs, dosage determination, and administration protocols; and to devise an optimum dose and administration protocol for intracameral moxifloxacin. SETTING: Humber River Hospital and the University of Toronto, Toronto, Ontario, Canada. DESIGN: Retrospective evaluation of treatment modality. METHODS: This study consisted of a detailed review of the history, drugs, and methods of intracameral prophylaxis and microbiological and pharmacodynamics analysis of options. A review of potential drug sources and doses was performed and 1 drug, dose, and administration protocol was selected. The current method's adoption reasons are described followed by the authors' experience. RESULTS: A single infection in 3430 cases occurred with a moxifloxacin-resistant strain of Staphylococcus epidermidis when moxifloxacin 100 mcg in 0.1 mL was used. Increasing the dose and changing the administration technique resulted in no infections in 4601 cases and no detrimental side effects or complications. CONCLUSION: Intracameral moxifloxacin prepared by dilution of 3 cc moxifloxacin 0.5% (Vigamox) with 7 cc balanced salt solution and with the administration of 0.3 to 0.4 cc (450 to 600 mcg.) as the final step in cataract surgery via the side port after the main incision has been sealed and hydrated showed advantages over alternative intracameral antibiotic prophylactic methods, with minimum risk. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 28007105 TI - Outcomes and complications of excimer laser surgery in patients with collagen vascular and other immune-mediated inflammatory diseases. AB - PURPOSE: To assess refractive and visual outcomes and postoperative complications in a large number of patients with well-controlled collagen vascular and other immune-mediated inflammatory diseases. SETTING: Optical Express, Glasgow, United Kingdom. DESIGN: Retrospective case series. METHODS: The files were reviewed of patients who had collagen vascular and other immune-mediated inflammatory diseases and who had excimer laser surgery between 2008 and 2015. In all cases, the disease was well controlled with no flare or symptoms for a minimum of 6 months preoperatively. RESULTS: The study comprised 622 patients (1224 eyes) with 1 of the following underlying diseases: rheumatoid arthritis (50.6% of patients), systemic lupus erythematosus (19.5%), psoriatic arthritis (10.5%), sarcoidosis (10.0%), ankylosing spondylitis (6.4%), multiple sclerosis (1.9%), or scleroderma (1.1%). Laser in situ keratomileusis (LASIK) was performed in 1114 eyes (91.0%) and photorefractive keratectomy (PRK) in 110 eyes (9.0%). The mean follow-up was 10.9 months. The preoperative spherical equivalent ranged between -10.13 diopters (D) and +4.13 D (LASIK) and -9.50 D and +4.00 D (PRK). Postoperatively, 81.8% LASIK eyes and 82.3% PRK eyes were within +/-0.50 D. The uncorrected distance visual acuity was 20/20 or better in 76.8% and 73.4%, respectively. Complications were mostly those that would be expected after excimer laser surgery in a population of patients without disease with the exception of 1 peripheral flap melt that responded to treatment with topical steroids. CONCLUSION: Excimer laser surgery can be safely performed in patients with well-controlled collagen vascular or other immune-mediated inflammatory disease. FINANCIAL DISCLOSURE: Dr. S.C. Schallhorn is a consultant to Abbott Medical Optics, Inc., Acufocus, Inc., and Carl Zeiss Meditec AG, and a global medical director for Optical Express. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 28007106 TI - One-day postoperative intraocular pressure spikes after phacoemulsification cataract surgery in patients taking tamsulosin. AB - PURPOSE: To evaluate the relationship between 1-day postoperative intraocular pressure (IOP) after phacoemulsification cataract surgery and tamsulosin use. SETTING: University of Colorado Health Eye Center, Aurora, Colorado, USA. DESIGN: Retrospective cohort study. METHODS: Registry data from men who had cataract surgery were used. Patients taking tamsulosin at the time of surgery were included as cases, while patients with no history of tamsulosin use were used as controls. The primary outcome was a 1-day postoperative IOP spike defined as an IOP increase greater than 10 mm Hg compared with baseline or a 1-day postoperative IOP of 30 mm Hg or higher. General estimating equations were used for analysis. RESULTS: The study comprised 584 men (864 eyes). An IOP increase greater than 10 mm Hg or IOP 30 mm Hg or higher after cataract surgery occurred in 12.4% and 9.3%, respectively, of eyes in the tamsulosin group versus 4.4% and 2.1%, respectively, in the control group (all P = .001). After adjusting for significant covariates, patients on tamsulosin were 2.6 times (95% confidence interval [CI], 1.2-5.7; P = .01] and 3.8 (95% CI, 1.3-10.9; P = .01) more likely to have a 1-day postoperative IOP increase greater than 10 mm Hg or a 1-day postoperative IOP of 30 mm Hg or higher. CONCLUSION: Patients on tamsulosin had an increased risk of a 1-day postoperative IOP spike after cataract surgery, showing the importance of identifying patients on tamsulosin preoperatively to better manage and potentially mitigate IOP spikes. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007107 TI - Patient-reported outcome measuring tools in cataract surgery: Clinical comparison at a tertiary hospital. AB - PURPOSE: To assess the performance of patient-reported outcome measure questionnaires and determine their appropriateness for routine use in cataract patients. SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Prospective cohort study. METHODS: Patients having cataract surgery between February and March 2013 were recruited. The following 4 questionnaires-Catquest 9SF, EuroQol 5-dimensions questionnaire (EQ-5D) and visual analog scale (EQ-VAS), National Eye Institute Socioemotional Scale (NEI-SES), and short-form Visual Function Index (VF-8R)-were completed preoperatively and 3 weeks and 3 months postoperatively. The questionnaires' performances were then compared. The paired Student t test and Pearson correlations were used for statistical analysis. RESULTS: One hundred twenty-two patients were recruited; 67.2% and 61.8% completed 3-week and 3-month follow-up, respectively. The changes in the mean scores for the Catquest-9SF, EQ-5D, EQ-VAS, NEI-SES, and VF-8R at 3 weeks were 120.86% (P < .0001), 1.61% (P = .61), 3.37% (P = .09), 16.12% (P = .12), and 61.76 % (P < .0001), respectively. At 3 months, the changes were 162.42% (P < .0001), 4.54% (P = .16), 4.84% (P = .09), 54.63% (P < .0001), and 87.55% (P < .0001), respectively. Correlations between patient-reported outcome measure questionnaires and visual acuity measures were variable and weak at best. CONCLUSIONS: It is feasible to assess patient-reported outcomes in cataract surgery as part of routine clinical practice. In addition, visual acuity might not fully reflect patients' visual function. Clinicians should consider using patient-reported outcome measure questionnaires to facilitate surgical decision making and outcome monitoring. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007108 TI - Comparison of the rate of refractive growth in aphakic eyes versus pseudophakic eyes in the Infant Aphakia Treatment Study. AB - PURPOSE: To compare the rate of refractive growth (RRG) between aphakic eyes and pseudophakic eyes in the Infant Aphakia Treatment Study (IATS). SETTING: Twelve clinical sites across the United States. DESIGN: Randomized clinical trial. METHODS: Patients randomized to unilateral cataract extraction with contact lens correction versus intraocular lens (IOL) implantation in the IATS had their rate of refractive growth (RRG3) calculated based on the change in refraction from the 1-month postoperative examination to age 5 years. The RRG3 is a logarithmic formula designed to calculate the RRG in children. Two-group t tests were used to compare the mean refractive growth between the contact lens group and IOL group and outcomes based on age at surgery and visual acuity. RESULTS: Longitudinal refractive data were studied for 108 of 114 patients enrolled in the IATS (contact lens group, n = 54; IOL group, n = 54). The mean RRG3 was similar in the contact lens group (-18.0 diopter [D] +/- 11.0 [SD]) and the IOL group (-19.0 +/- 9.0 D) (P = .49). The RRG3 value was not correlated with age at cataract surgery, glaucoma status, or visual outcome in the IOL group. In the aphakia group, only visual outcome was correlated with refractive growth (P = .01). CONCLUSIONS: Infants' eyes had a similar rate of refractive growth after unilateral cataract surgery whether or not an IOL was implanted. A worse visual outcome was associated with a higher RRG in aphakic, but not pseudophakic, eyes. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007109 TI - Trypan blue as a surgical adjunct in pediatric cataract surgery. AB - PURPOSE: To study the effect of trypan blue on lens capsule elasticity and ease of completing a continuous curvilinear capsulorhexis (CCC) in a sheep lens model and to subsequently observe the effects of trypan blue in the surgical setting of 3 pediatric patients. SETTING: State University of New York, Downstate Medical Center, Brooklyn, New York, USA. DESIGN: Prospective case series. METHODS: Twenty four lenses were excised from fresh sheep globes. Twelve lenses were immersed in trypan blue for 2.5 minutes, and 12 lenses were immersed in a balanced salt solution for 2.5 minutes. Ease of completion of CCC was graded, and intralenticular pressure was quantified. A pediatric cataract surgeon used trypan blue to stain the lens capsules of 3 children during cataract surgery. The surgeon noted the effects of trypan blue on capsule elasticity and on the ease of completion of the CCC. RESULTS: Lenses immersed in trypan blue had a mean score of 2.58 in ease of completion of capsulorhexis compared with the control group (1.5) (P = .031). Capsulorhexis was successfully completed in 91.7% of trypan blue cases compared with 58.3% of controls. Immersion in trypan blue decreased the intralenticular pressure by a mean of 4.5 mm Hg (P = .025). Successful capsulorhexis was completed in the 3 pediatric cases. CONCLUSION: Trypan blue improved the success rate of CCC completion in the sheep lens by decreasing lens capsule elasticity. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007110 TI - Femtosecond laser-assisted cataract surgery versus standard phacoemulsification cataract surgery: Study from the European Registry of Quality Outcomes for Cataract and Refractive Surgery. AB - PURPOSE: To compare the visual, refractive, and adverse outcomes of femtosecond laser-assisted cataract surgery and conventional phacoemulsification cataract surgery. SETTING: Cataract surgery clinics in 9 European countries and Australia (femtosecond-assisted) and 18 European countries and Australia (conventional). DESIGN: Multicenter case-control study. METHODS: Eyes having femtosecond laser assisted cataract surgery were matched to eyes from the European Registry of Quality Outcomes for Cataract and Refractive Surgery phacoemulsification cataract surgery database for preoperative corrected distance visual acuity (CDVA), age, and preoperative risk factors. Intraoperative and postoperative complications, postoperative CDVA, and refractive outcome were compared. The follow-up was 7 to 60 days. RESULTS: The study matched 2814 femtosecond-assisted cases to 4987 conventional phacoemulsification cases. Femtosecond-assisted surgery compared as follows to conventional phacoemulsification: posterior capsule complications, 0.7% versus 0.4%; postoperative logMAR CDVA, 0.05 (6/6-3) versus 0.03 (6/6-2); worse postoperative CDVA at follow-up (by 5 letters or more), 1.0% versus 0.4%; CDVA 0.3 (6/12) or better, 96.3% versus 97.1%; absolute biometry prediction error, 0.43 diopter (D) versus 0.40 D; within +/-0.5 D of target, 72% versus 74.3%; and postoperative complications, 3.4% versus 2.3%. CONCLUSIONS: Femtosecond laser-assisted cataract surgery did not yield better visual or refractive outcomes than conventional phacoemulsification cataract surgery. Intraoperative complications were similar and low in both groups. Postoperative complications were lower in conventional phacoemulsification cataract surgery. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007112 TI - Short-term complications of femtosecond laser-assisted laser in situ keratomileusis cuts: Review of 1210 consecutive cases. AB - PURPOSE: To evaluate short-term complications after femtosecond laser cuts for laser in situ keratomileusis (LASIK). SETTING: Department of Ophthalmology, Goethe University, Frankfurt, Germany. DESIGN: Retrospective consecutive case series. METHODS: Consecutive femtosecond laser cuts (1210 cuts in 624 patients) from LASIK performed with the Intralase FS60 between 2006 and 2014 were analyzed. The analysis looked at intraoperative and postoperative complications at 1 day, 1 week, and 1 month and factors with potential impact on the complication rate, such as ablation depth. RESULTS: No irregular, incomplete, or thin flaps, buttonholes, gas breakthrough, or free caps were observed. Intraoperatively, incomplete side cuts were observed in 4 cases (0.3%). Three of the 4 occurred during the first year of femtosecond laser usage and were explained by a software problem. Epithelial defects, limbal bleeding, and decentered flaps without negative impact on outcome were observed in 45 (3.7%), 12 (1.0%), and 5 (0.4%) eyes, respectively, on the treatment date. Diffuse lamellar keratitis (DLK) stage 1 was observed in 69 (5.7%), 36 (3.0%), and 3 (0.2%) eyes at 1 day, 1 week, and 1 month, respectively, and DLK stage 2 in 20 (1.7%), 6 (0.5%), and 2 (0.2%) eyes, respectively. An increase in total ablation depth resulted in a higher incidence of microstriae (P < .01 at 1 day, 1 week, and 1 month). An increase in the optical zone resulted in a significantly higher incidence of epithelial ingrowth at 1 day and 1 week (P < .01). CONCLUSION: No major cut-related complications were observed. The femtosecond laser is a safe option to create a flap in LASIK. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 28007111 TI - Validation of the Spanish Catquest-9SF in patients with a monofocal or trifocal intraocular lens. AB - PURPOSE: To validate the Spanish Catquest-9SF and study patient-reported visual function after implantation of a trifocal versus a monofocal intraocular lens (IOL). SETTING: Clinica Baviera, Valencia and Madrid, Spain. DESIGN: Prospective case series. METHODS: The Catquest-9SF was translated from English to Spanish according to a standard procedure. The Spanish version was validated through Rasch analysis. Patients completed the Catquest-9SF before cataract surgery and 3 months after the surgery. The change in patient-reported visual function caused by surgery, the level of achieved visual function, and satisfaction with vision after surgery were assessed for bilaterally implanted trifocal IOLs versus monofocal IOLs. RESULTS: The Spanish Catquest-9SF showed very good psychometric properties. Patient-reported achieved visual function was significantly better for those with a trifocal IOL than for those with a monofocal IOL (P < .001). This was also true when the groups were matched for age and ocular comorbidity (P = .006). In multivariate analyses of all cases and matched cases (the same age and no comorbidity), the reported visual function was significantly better with trifocal IOLs than with monofocal IOLs (P = .001 and P = .008, respectively). There was greater improvement after trifocal IOL implantation in the matched cases, although not significant (P = .103). CONCLUSIONS: Results show the Spanish version of Catquest-9SF is a valid patient questionnaire with good psychometric properties. Patients with a trifocal IOL implanted bilaterally reported better visual function than those with a monofocal IOL implanted bilaterally. The change in visual function after surgery was also greater in patients with a trifocal IOL. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007113 TI - Effect of postoperative administration of nonsteroidal antiinflammatory drugs and steroids on the conformational changes in wound healing after cataract surgery. AB - PURPOSE: To assess the changes in clear corneal incision (CCI) healing resulting from the postoperative administration of nonsteroidal antiinflammatory drugs (NSAIDs) or steroids using anterior segment optical coherence tomography (AS OCT). SETTING: Institute of Vision Research, Department of Ophthalmology, Yonsei University, Seoul, South Korea. DESIGN: Prospective randomized comparative study. METHODS: Eyes having cataract surgery were randomly given an NSAID (bromfenac 0.1% [Bronuck]) or a steroid (prednisolone acetate 1.0% [Pred Forte]). Using AS OCT, structural changes of CCIs were examined 1 day and 1, 3.5, and 23 weeks postoperatively. The incidence and size of 5 wound deformities (endothelial gape, Descemet membrane detachment, epithelial detachment or defect, posterior misalignment, loss of coaptation) were analyzed. The correlation between the mean total wound deformity scores (wound instability) and surgically induced astigmatism (SIA) was evaluated. RESULTS: The bromfenac group comprised 29 eyes and the prednisolone group, 30 eyes. During the 6-month follow-up, the overall changes in wound instability were not significantly different between groups, although epithelial detachment or a larger defect was more frequent in the bromfenac group between 1 week and 3.5 weeks postoperatively. The SIA at 1 week was positively correlated with wound instability and wound instability at 1 day was positively correlated with cataract grading in both groups. CONCLUSIONS: No significant difference in the conformational changes of cataract wounds (aside from increased epithelial detachment or defect in bromfenac group) was observed between NSAIDs and steroids administered postoperatively. In the early postoperative period, high wound instability was associated with SIA, possibly contributing to worse visual outcomes. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007114 TI - In vitro delivery performance assessment of a new preloaded intraocular lens delivery system. AB - PURPOSE: To compare the delivery performance of a new preloaded intraocular lens (IOL) delivery system (Ultrasert [system U]) with that of 2 commercially available preloaded systems (iSert [system S] and Tecnis iTec [system T]), and a manual system (Monarch III D). SETTING: Alcon Laboratories, Fort Worth, Texas, USA. DESIGN: Experimental study. METHODS: Freshly excised porcine eyes were randomly assigned to 5 groups of 10 eyes each as follows: preloaded systems U, S, T 2.2 mm incision, T 2.4 mm incision, and manual system. Corneal incision size was measured before and after delivery. The rate of successful in-the-bag IOL delivery, IOL adherence to the plunger tip, trapped trailing haptic, and presence of nozzle tip splitting were assessed. Statistical analysis was performed to determine the significance of differences between groups. RESULTS: All systems successfully placed the IOL in the capsular bag. System U had the least corneal incision enlargement (mean 0.07 mm +/- 0.05 [SD]) and the smallest final incision size (mean 2.31 +/- 0.06 mm) (P < .05). An associated split in the nozzle tip was observed for system S devices (P < .05). Furthermore, in more than 50% of deliveries with system T, the IOL remained adhered to the plunger tip after exiting the nozzle (P < .05). Systems S and T each had 1 occurrence of a trapped trailing haptic during IOL delivery. CONCLUSION: The new design of the system U with a depth-guard nozzle tip allowed for the smallest incision enlargement with an absence of nozzle tip splitting and uneventful IOL delivery compared with the other preloaded systems tested in this study. FINANCIAL DISCLOSURE: Drs. Tjia and Lane are consultants to Alcon Laboratories, Inc. Drs. Wang, Wolfe, Paliwal, and Miss Chernosky are employees of Alcon Laboratories, Inc. PMID- 28007115 TI - Comparison of stability between a modular intraocular lens system and a single piece hydrophobic acrylic intraocular lens. AB - PURPOSE: To compare the movement of a modular intraocular lens (IOL) with that of a standard single-piece hydrophobic acrylic IOL in a human cadaver eye perfusion model. SETTING: Department of Ophthalmology, University of Colorado, Aurora, Colorado, USA. DESIGN: Experimental study. METHODS: Eight phakic human donor eyes of 4 patients had standard phacoemulsification with lens removal. One of 2 IOLs was then implanted in the capsular bag: a modular IOL (Harmoni) or a standard single-piece IOL (Acrysof SN60). Each globe was connected to a programmable perfusion pump with an in-line pressure transducer. Ultrasound biomicroscopy (UBM) was used to evaluate the anterior chamber depth (ACD) in each eye, measuring from the posterior cornea to the anterior surface of the optic at an intraocular pressure (IOP) of 5 mm Hg, 10 mm Hg, 20 mm Hg, and 30 mm Hg. Five consecutive measurements were recorded for all eyes at each pressure, and the results were averaged. RESULTS: There was significantly less movement in eyes with the modular IOL than in eyes with the single-piece IOL. The mean position of the modular IOL varied from a minimum of 0.03 mm to a maximum of 0.07 mm, and the mean position of the single-piece IOL varied from a minimum of 0.26 mm to a maximum of 0.87 mm (P = .002). CONCLUSIONS: The modular IOL showed less movement with changes in IOP than a standard single-piece IOL. Improved IOL stability might allow more accuracy in determining the effective lens position and hence improve the predictability of the refractive target. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 28007116 TI - Accelerated corneal collagen crosslinking: Technique, efficacy, safety, and applications. AB - : Corneal collagen crosslinking (CXL) is an approach used to increase the biomechanical stability of the stromal tissue. Over the past 10 years, it has been used to halt the progression of ectatic diseases. According to the photochemical law of reciprocity, the same photochemical effect is achieved with reduced illumination time and correspondingly increased irradiation intensity. Several new CXL devices offer high ultraviolet-A irradiation intensity with different time settings. The main purpose of this review was to discuss the current use of different protocols of accelerated CXL and compare the efficacy and safety of accelerated CXL with the efficacy and safety of the established conventional method. Accelerated CXL proved to be safe and effective in halting progression of corneal ectasia. Corneal shape responses varied considerably, as did the demarcation line at different irradiance settings; the shorter the exposure time, the more superficial the demarcation line. FINANCIAL DISCLOSURE: Dr. Santhiago is a consultant to Ziemer Ophthalmic Systems AG and Alcon Laboratories, Inc. None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007117 TI - Anaphylactic reaction secondary to topical preoperative moxifloxacin. AB - : We report a case of anaphylactic shock following topical administration of moxifloxacin for endophthalmitis prophylaxis prior to cataract surgery. Immunoglobulin E (IgE) serology and IgE skin testing confirmed the anaphylactic etiology. Phacoemulsification with posterior chamber intraocular lens implantation was later performed with identical preoperative preparation except for the exclusion of moxifloxacin; no anaphylactic response occurred. To our knowledge, this is the first report of an anaphylactic response to topical moxifloxacin. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 28007118 TI - Rapidly progressive cataract formation associated with non-small-cell lung cancer therapy. AB - : We report 6 patients who developed rapidly progressive hypermature cataracts after starting treatment with rociletinib, a non-small-cell lung cancer therapy with known side effects of hyperglycemia, fatigue, and prolonged QT. Early cataract detection and surgery may prevent complications during future cataract removal. Although rociletinib development has been suspended, there are patients who have been treated and will continue to be treated with this medication based on their physician's judgment. These physicians should know about the potential for rapid vision loss due to cataracts as a manageable side effect. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 28007119 TI - Antibiotic susceptibility of bacterial pathogens isolated from the aqueous and vitreous humor in the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study. PMID- 28007120 TI - Transconjunctival intrascleral intraocular lens fixation with double-needle and flanged-haptic technique: Ultrathin line between success and failure. PMID- 28007121 TI - Guidance needle for insertion of intraocular lens haptics into scleral tunnels during intrascleral lens fixation. PMID- 28007122 TI - Highly irregular topography after excimer laser enhancement: December consultation #1. PMID- 28007123 TI - December consultation #3. PMID- 28007124 TI - December consultation #2. PMID- 28007125 TI - December consultation #5. PMID- 28007126 TI - December consultation #4. PMID- 28007127 TI - December consultation #6. PMID- 28007128 TI - December consultation #7. PMID- 28007129 TI - December consultation #8. PMID- 28007130 TI - Reply. PMID- 28007131 TI - Bromfenac ophthalmic solution 0.09% as an adjunctive therapy to topical steroids after cataract surgery in pseudoexfoliation syndrome. PMID- 28007132 TI - Pocket-chop: Combination of Mackool's non-impale chop and Pandit's combo-chop. PMID- 28007134 TI - High-Sensitivity Cardiac Troponin and Primary Prevention: An Important New Role. PMID- 28007133 TI - High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease. AB - BACKGROUND: Cardiac troponin is an independent predictor of cardiovascular mortality in individuals without symptoms or signs of cardiovascular disease. The mechanisms for this association are uncertain, and a role for troponin testing in the prevention of coronary heart disease has yet to be established. OBJECTIVES: This study sought to determine whether troponin concentration could predict coronary events, be modified by statins, and reflect response to therapy in a primary prevention population. METHODS: WOSCOPS (West of Scotland Coronary Prevention Study) randomized men with raised low-density lipoprotein cholesterol and no history of myocardial infarction to pravastatin 40 mg once daily or placebo for 5 years. Plasma cardiac troponin I concentration was measured with a high-sensitivity assay at baseline and at 1 year in 3,318 participants. RESULTS: Baseline troponin was an independent predictor of myocardial infarction or death from coronary heart disease (hazard ratio [HR]: 2.3; 95% confidence interval [CI]: 1.4 to 3.7) for the highest (>=5.2 ng/l) versus lowest (<=3.1 ng/l) quarter of troponin (p < 0.001). There was a 5-fold greater reduction in coronary events when troponin concentrations decreased by more than a quarter, rather than increased by more than a quarter, for both placebo (HR: 0.29; 95% CI: 0.12 to 0.72 vs. HR: 1.95; 95% CI: 1.09 to 3.49; p < 0.001 for trend) and pravastatin (HR: 0.23; 95% CI: 0.10 to 0.53 vs. HR: 1.08; 95% CI: 0.53 to 2.21; p < 0.001 for trend). Pravastatin reduced troponin concentration by 13% (10% to 15%; placebo adjusted, p < 0.001) and doubled the number of men whose troponin fell more than a quarter (p < 0.001), which identified them as having the lowest risk for future coronary events (1.4% over 5 years). CONCLUSIONS: Troponin concentration predicts coronary events, is reduced by statin therapy, and change at 1 year is associated with future coronary risk independent of cholesterol lowering. Serial troponin measurements have major potential to assess cardiovascular risk and monitor the impact of therapeutic interventions. PMID- 28007135 TI - Sex-Based Differences in Outcomes With Transcatheter Aortic Valve Therapy: TVT Registry From 2011 to 2014. AB - BACKGROUND: A differential impact of sex has been observed in transcatheter aortic valve replacement (TAVR) outcomes from small observational studies and subgroup analyses of randomized trials. OBJECTIVES: The goal of this study was to compare the in-hospital and 1-year outcomes in male and female subjects from the U.S. nationwide TAVR registry. METHODS: National data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry were used for in-hospital outcomes, and data linked from the Centers for Medicare & Medicaid Services were used to provide 1-year events. Multivariable logistic regression adjustment was performed for in-hospital outcomes. Fine-Gray models were used for nonfatal 1-year outcomes to account for the competing risk of death. RESULTS: From 2011 to 2014, a total of 11,808 (49.9%) women and 11,844 (51.1%) men underwent TAVR. Compared with male patients, female patients were older, with a lower prevalence of coronary artery disease, atrial fibrillation, and diabetes but a higher rate of porcelain aorta, lower glomerular filtration rate, and higher mean Society of Thoracic Surgeons score (9.0% vs. 8.0%; all p < 0.001). Women were treated more often by using nontransfemoral access than men (45.0% vs. 34.0%). Despite using smaller device sizes, women achieved valve cover index >=8% more often than men (66% vs. 54%). In-hospital vascular complications were higher in women (8.27% vs. 4.39%; adjusted hazard ratio [HR]: 1.70; 95% CI: 1.34 to 2.14; p < 0.001) and a trend toward higher bleeding (8.01% vs 5.96%; adjusted HR: 1.19; 95% CI: 0.99 to 1.44; p = 0.06) was observed; however, 1-year mortality was lower (21.3% vs. 24.5%; adjusted HR: 0.73; 95% CI: 0.63 to 0.85; p < 0.001) in women than in men. CONCLUSIONS: Female patients undergoing TAVR had a different risk profile compared with male patients. Notwithstanding a greater adjusted risk for in-hospital vascular complications, 1-year adjusted survival was superior in female patients. PMID- 28007136 TI - Transcatheter Aortic Valve Replacement: Only One of the Advantages of Being Female. PMID- 28007137 TI - HotBalloon Ablation of the Pulmonary Veins for Paroxysmal AF: A Multicenter Randomized Trial in Japan. AB - BACKGROUND: Point-by-point catheter ablation is an established treatment for drug refractory paroxysmal atrial fibrillation (PAF). However, it is time consuming, requires excellent technique to achieve complete pulmonary vein (PV) isolation, and is associated with severe complications. OBJECTIVES: The purpose of this study was to evaluate the safety and effectiveness of a HotBalloon ablation (HBA) compared with antiarrhythmic drug therapy (ADT) for the treatment of PAF. METHODS: A prospective multicenter randomized controlled study was conducted in Japan. Patients with symptomatic PAF refractory to antiarrhythmic drugs (Class I to IV) were randomized to HBA or ADT at a 2:1 ratio and assessed for effectiveness in a comparable 9-month follow-up period. RESULTS: A total of 100 patients in the HBA group and 43 patients in the ADT group received treatment at 17 sites. HBA procedure produced acute complete PV isolation in 98.0% (392 of 400) of the PVs and in 93.0% (93 of 100) of patients in the HBA group. The chronic success rates after the 9-month effective evaluation period were 59.0% in the HBA group (n = 100) and 4.7% in the ADT group (n = 43; p < 0.001). The incidence of major complications was 11.2% (15 of 134 patients). The incidences of PV stenosis (>70%) and transient phrenic nerve injury were 5.2% and 3.7%, respectively. The mean fluoroscopy time was 49.4 +/- 26.6 min (n = 134), and the mean procedure duration was 113.9 +/- 31.9 min (n = 133). CONCLUSIONS: This study demonstrates the superiority of HBA compared with ADT for treatment of patients with PAF, and a favorable safety profile. PMID- 28007138 TI - Overview of Balloon Approaches to AF Ablation: Some Like it Hot? PMID- 28007140 TI - Using Human Genetics to Predict the Effects and Side Effects of Lipoprotein(a) Lowering Drugs. PMID- 28007139 TI - Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels. AB - BACKGROUND: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases. PMID- 28007142 TI - Targeting Inflammation in Atherosclerosis. PMID- 28007141 TI - Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis. AB - BACKGROUND: Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified. OBJECTIVES: This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses. METHODS: After genetically invalidating Trem-1 in chimeric Ldlr-/-Trem-1-/- mice and double knockout ApoE-/-Trem-1-/- mice, we pharmacologically inhibited Trem-1 using LR12 peptide. RESULTS: Ldlr-/- mice reconstituted with bone marrow deficient for Trem-1 (Trem-1-/-) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem 1+/+ chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem 1 in ApoE-/-/Trem-1-/- mice or pharmacological blockade of Trem-1 in ApoE-/- mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques. CONCLUSIONS: We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis. PMID- 28007143 TI - Genetics: Implications for Prevention and Management of Coronary Artery Disease. AB - An exciting new era has dawned for the prevention and management of coronary artery disease (CAD) utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for CAD confirms not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Last, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers, and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications. PMID- 28007144 TI - Proteomics Research in Cardiovascular Medicine and Biomarker Discovery. AB - Proteomics is a systems physiology discipline to address the large-scale characterization of protein species within a biological system, be it a cell, a tissue, a body biofluid, an organism, or a cohort population. Building on advances from chemical analytical platforms (e.g., mass spectrometry and other technologies), proteomics approaches have contributed powerful applications in cardiovascular biomedicine, most notably in: 1) the discovery of circulating protein biomarkers of heart diseases from plasma samples; and 2) the identification of disease mechanisms and potential therapeutic targets in cardiovascular tissues, in both preclinical models and translational studies. Contemporary proteomics investigations offer powerful means to simultaneously examine tens of thousands of proteins in various samples, and understand their molecular phenotypes in health and disease. This concise review introduces study design considerations, example applications and use cases, as well as interpretation and analysis of proteomics data in cardiovascular biomedicine. PMID- 28007146 TI - The Emerging Role of Metabolomics in the Diagnosis and Prognosis of Cardiovascular Disease. AB - Perturbations in cardiac energy metabolism are major contributors to a number of cardiovascular pathologies. In addition, comorbidities associated with cardiovascular disease (CVD) can alter systemic and myocardial metabolism, often contributing to the worsening of cardiac function and health outcomes. State-of the-art metabolomic technologies give us the ability to measure thousands of metabolites in biological fluids or biopsies, providing us with a metabolic fingerprint of individual patients. These metabolic profiles may serve as diagnostic and/or prognostic tools that have the potential to significantly alter the management of CVD. Herein, the authors review how metabolomics can assist in the interpretation of perturbed metabolic processes, and how this has improved our ability to understand the pathology of ischemic heart disease, atherosclerosis, and heart failure. Taken together, the integration of metabolomics with other "omics" platforms will allow us to gain insight into pathophysiological interactions of metabolites, proteins, genes, and disease states, while advancing personalized medicine. PMID- 28007145 TI - Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders. AB - This is the first of 2 review papers on genetics and genomics appearing as part of the series on "omics." Genomics pertains to all components of an organism's genes, whereas genetics involves analysis of a specific gene or genes in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper. PMID- 28007148 TI - Left Anterior Descending Artery Myocardial Bridging: A Clinical Approach. AB - A myocardial bridge (MB) is the term for the muscle overlying the intramyocardial segment of the epicardial coronary artery (referred to as a tunneled artery). Although MBs can be found in any epicardial artery, most of them involve the left anterior descending artery. These congenital coronary anomalies have long been recognized anatomically, and are traditionally considered a benign condition; however, the association between myocardial ischemia and MBs has increased their clinical relevance. This review summarizes the prevalence, pathophysiology, and diagnostic findings, including morphological, functional assessment, and treatment of patients with MB involving the left anterior descending artery, suggesting a pragmatic clinical approach to this entity. PMID- 28007149 TI - A View From the New Membership Committee. PMID- 28007150 TI - Statin Therapy on the Basis of HOPE: A European Perspective. PMID- 28007147 TI - Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy. AB - Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients. PMID- 28007151 TI - Improving Peer Mentorship: A Novel Fellow "House" Program. PMID- 28007152 TI - Prospective Evaluation of the Eyeball Test for Assessing Frailty in Patients With Valvular Heart Disease. PMID- 28007153 TI - Renin-Angiotensin System Fingerprints of Heart Failure With Reduced Ejection Fraction. PMID- 28007154 TI - Circulating Long Noncoding RNAs in Personalized Medicine: Response to Pioglitazone Therapy in Type 2 Diabetes. PMID- 28007155 TI - Trimethylamine N-Oxide in Seafood: Rotten or Forgotten? PMID- 28007156 TI - Reply: Trimethylamine N-Oxide in Seafood: Rotten or Forgotten? PMID- 28007157 TI - Risk Prediction in Acute Myocardial Infarction. PMID- 28007159 TI - Correction. PMID- 28007158 TI - Reply: Risk Prediction in Acute Myocardial Infarction. PMID- 28007160 TI - Correction. PMID- 28007161 TI - Correction. PMID- 28007162 TI - Correction. PMID- 28007163 TI - Correction. PMID- 28007164 TI - Professor William R. Cullen and arsenic chemistry. PMID- 28007165 TI - Oxidation state specific analysis of arsenic species in tissues of wild-type and arsenic (+3 oxidation state) methyltransferase-knockout mice. AB - Arsenic methyltransferase (As3mt) catalyzes the conversion of inorganic arsenic (iAs) to its methylated metabolites, including toxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII). Knockout (KO) of As3mt was shown to reduce the capacity to methylate iAs in mice. However, no data are available on the oxidation states of As species in tissues of these mice. Here, we compare the oxidation states of As species in tissues of male C57BL/6 As3mt-KO and wild-type (WT) mice exposed to arsenite (iAsIII) in drinking water. WT mice were exposed to 50mg/L As and As3mt-KO mice that cannot tolerate 50mg/L As were exposed to 0, 15, 20, 25 or 30mg/L As. iAsIII accounted for 53% to 74% of total As in liver, pancreas, adipose, lung, heart, and kidney of As3mt-KO mice; tri- and pentavalent methylated arsenicals did not exceed 10% of total As. Tissues of WT mice retained iAs and methylated arsenicals: iAsIII, MAsIII and DMAsIII represented 55%-68% of the total As in the liver, pancreas, and brain. High levels of methylated species, particularly MAsIII, were found in the intestine of WT, but not As3mt-KO mice, suggesting that intestinal bacteria are not a major source of methylated As. Blood of WT mice contained significantly higher levels of As than blood of As3mt-KO mice. This study is the first to determine oxidation states of As species in tissues of As3mt-KO mice. Results will help to design studies using WT and As3mt-KO mice to examine the role of iAs methylation in adverse effects of iAs exposure. PMID- 28007166 TI - Comparative cytotoxicity of fourteen trivalent and pentavalent arsenic species determined using real-time cell sensing. AB - The occurrence of a large number of diverse arsenic species in the environment and in biological systems makes it important to compare their relative toxicity. The toxicity of arsenic species has been examined in various cell lines using different assays, making comparison difficult. We report real-time cell sensing of two human cell lines to examine the cytotoxicity of fourteen arsenic species: arsenite (AsIII), monomethylarsonous acid (MMAIII) originating from the oxide and iodide forms, dimethylarsinous acid (DMAIII), dimethylarsinic glutathione (DMAGIII), phenylarsine oxide (PAOIII), arsenate (AsV), monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), monomethyltrithioarsonate (MMTTAV), dimethylmonothioarsinate (DMMTAV), dimethyldithioarsinate (DMDTAV), 3-nitro-4 hydroxyphenylarsonic acid (Roxarsone, Rox), and 4-aminobenzenearsenic acid (p arsanilic acid, p-ASA). Cellular responses were measured in real time for 72hr in human lung (A549) and bladder (T24) cells. IC50 values for the arsenicals were determined continuously over the exposure time, giving rise to IC50 histograms and unique cell response profiles. Arsenic accumulation and speciation were analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). On the basis of the 24-hr IC50 values, the relative cytotoxicity of the tested arsenicals was in the following decreasing order: PAOIII?MMAIII>=DMAIII>=DMAGIII~DMMTAV>=AsIII?MMTTAV>AsV>DMDTAV>DMAV>MMAV>=Rox>=p ASA. Stepwise shapes of cell response profiles for DMAIII, DMAGIII, and DMMTAV coincided with the conversion of these arsenicals to the less toxic pentavalent DMAV. Dynamic monitoring of real-time cellular responses to fourteen arsenicals provided useful information for comparison of their relative cytotoxicity. PMID- 28007168 TI - Arsenobetaine and thio-arsenic species in marine macroalgae and herbivorous animals: Accumulated through trophic transfer or produced in situ? AB - Arsenobetaine (AB) and thio-arsenoribosides were measured in common macroalgae species (8 phaeophyta, 4 rhodophyta and 2 chlorphyta), along the Australian south east coast line. As well, arsenic species profiles were measured for two common marine herbivores, the sea urchin Centrostephanus rodgersii and the fish Odax cyanomelas that graze on these macroalgae to understand if trophic transfer of these species would account for their presence in marine herbivores. AB was found in seven of the fourteen macroalgae species investigated but does not contributed significantly to any of the macroalgae arsenic content (0.01-1.2MUg/g). AB was found in only two of the brown macroalgae and all the red and green macroalgae (with the exception of Corallina officinalis). Thio-arsenic species were found sporadically, but not in high concentrations in any of the macroalgae investigated. AB present in macroalgae is likely to be associated with epiphytic organisms while thio-arsenoribosides are likely to be produced by decaying parts of damaged macroalgae. A laboratory feeding experiment in which the herbivorous gastropod, Austrocochlea constricta, was fed macroalgae containing thio arsenoribosides for a 24hr period every three days showed that these are readily accumulated over a short period. Thio-arsenoribosides in herbivores are therefore probably obtained through trophic transfer. Some AB is also obtained through trophic transfer; however, the presence of trimethylated arsonioribosides, a hypothesized precursor of AB formation in herbivores, suggests that some AB is produced within herbivores from the transformation of arsenoribosides accumulated from their diet. PMID- 28007167 TI - Examination of in vivo mutagenicity of sodium arsenite and dimethylarsinic acid in gpt delta rats. AB - Arsenic is a well-known human bladder and liver carcinogen, but its exact mechanism of carcinogenicity is not fully understood. Dimethylarsinic acid (DMAV) is a major urinary metabolite of sodium arsenite (iAsIII) and induces urinary bladder cancers in rats. DMAV and iAsIII are negative in in vitro mutagenicity tests. However, their in vivo mutagenicities have not been determined. The purpose of present study is to evaluate the in vivo mutagenicities of DMAV and iAsIII in rat urinary bladder epithelium and liver using gpt delta F344 rats. Ten week old male gpt delta F344 rats were randomized into 3 groups and administered 0, 92mg/L DMAV, or 87mg/L iAsIII (each 50mg/L As) for 13weeks in the drinking water. In the mutation assay, point mutations are detected in the gpt gene by 6 thioguanine selection (gpt assay) and deletion mutations are identified in the red/gam genes by Spi- selection (Spi- assay). Results of the gpt and Spi- assays showed that DMAV and iAsIII had no effects on the mutant frequencies or mutation spectrum in urinary bladder epithelium or liver. These findings indicate that DMAV and iAsIII are not mutagenic in urinary bladder epithelium or liver in rats. PMID- 28007169 TI - Uptake and transformation of arsenic during the reproductive life stage of Agaricus bisporus and Agaricus campestris. AB - Fruiting bodies from the Agaricus genus have been found to contain non-toxic arsenobetaine (AB) as a major compound. It is unknown whether AB is formed during the vegetative or reproductive life stages of the fungus, or by the surrounding microbial community, but AB's structural similarity to glycine betaine has led to the hypothesis that AB may be adventitiously accumulated as an osmolyte. To investigate the potential formation of AB during the reproductive life stage of Agaricus species, growth substrate and fungi were collected during the commercial growth of Agaricus bisporus and analyzed for arsenic speciation using HPLC-ICP MS. AB was found to be the major arsenic compound in the fungus at the earliest growth stage of fruiting (the primordium). The growth substrate mainly contained arsenate (As(V)). The distribution of arsenic in an A. bisporus primordium grown on As(V) treated substrate, and in a mature Agaricus campestris fruiting body collected from arsenic contaminated mine tailings, was mapped using two dimensional XAS imaging. The primordium and stalk of the mature fruiting body were both found to be growing around pockets of substrate material containing higher As concentrations, and AB was found exclusively in the fungal tissues. In the mature A. campestris the highest proportion of AB was found in the cap, supporting the AB as an osmolyte hypothesis. The results have allowed us to pinpoint the fungus life stage at which AB formation takes place, namely reproduction, which provides a direction for further research. PMID- 28007170 TI - The importance of glutathione and phytochelatins on the selenite and arsenate detoxification in Arabidopsis thaliana. AB - We investigated the role of glutathione (GSH) and phytochelatins (PCs) on the detoxification of selenite using Arabidopsis thaliana. The wild-type (WT) of Arabidopsis thaliana and its mutants (glutathione deficient Cad 2-1 and phytochelatins deficient Cad 1-3) were separately exposed to varying concentrations of selenite and arsenate and jointly to both toxicants to determine their sensitivities. The results of the study revealed that, the mutants were about 20-fold more sensitive to arsenate than the WT, an indication that the GSH and PCs affect arsenate detoxification. On the contrary, the WT and both mutants showed a similar level of sensitivity to selenite, an indication that the GSH and PCs do not significantly affect selenite detoxification. However, the WT is about 8 times more sensitive to selenite than to arsenate, and the mutants were more resistant to selenite than arsenate by a factor of 2. This could not be explained by the accumulation of both elements in roots and shoots in exposure experiments. The co-exposure of the WT indicates a synergistic effect with regards to toxicity since selenite did not induce PCs but arsenic and selenium compete in their PC binding as revealed by speciation analysis of the root extracts using HPLC-ICP-MS/ESI-MS. In the absence of PCs an antagonistic effect has been detected which might suggest indirectly that the formation of Se glutathione complex prevent the formation of detrimental selenopeptides. This study, therefore, revealed that PC and GSH have only a subordinate role in the detoxification of selenite. PMID- 28007171 TI - Arsenic methylation by an arsenite S-adenosylmethionine methyltransferase from Spirulina platensis. AB - Arsenic-contaminated water is a serious hazard for human health. Plankton plays a critical role in the fate and toxicity of arsenic in water by accumulation and biotransformation. Spirulina platensis (S. platensis), a typical plankton, is often used as a supplement or feed for pharmacy and aquiculture, and may introduce arsenic into the food chain, resulting in a risk to human health. However, there are few studies about how S. platensis biotransforms arsenic. In this study, we investigated arsenic biotransformation by S. platensis. When exposed to arsenite (As(III)), S. platensis accumulated arsenic up to 4.1mg/kg dry weight. After exposure to As(III), arsenate (As(V)) was the predominant species making up 64% to 86% of the total arsenic. Monomethylarsenate (MMA(V)) and dimethylarsenate (DMA(V)) were also detected. An arsenite S adenosylmethionine methyltransferase from S. platensis (SpArsM) was identified and characterized. SpArsM showed low identity with other reported ArsM enzymes. The Escherichia coli AW3110 bearing SparsM gene resulted in As(III) methylation and conferring resistance to As(III). The in vitro assay showed that SpArsM exhibited As(III) methylation activity. DMA(V) and a small amount of MMA(V) were detected in the reaction system within 0.5hr. A truncated SpArsM derivative lacking the last 34 residues still had the ability to methylate As(III). The three single mutants of SpArsM (C59S, C186S, and C238S) abolished the capability of As(III) methylation, suggesting the three cysteine residues are involved in catalysis. We propose that SpArsM is responsible for As methylation and detoxification of As(III) and may contribute to As biogeochemistry. PMID- 28007172 TI - The role of phosphorus in the metabolism of arsenate by a freshwater green alga, Chlorella vulgaris. AB - A freshwater microalga, Chlorella vulgaris, was grown in the presence of varying phosphate concentrations (<10-500MUg/L P) and environmentally realistic concentrations of arsenate (As(V)) (5-50MUg/L As). Arsenic speciation in the culture medium and total cellular arsenic were measured using AEC-ICP-MS and ICP DRC-MS, respectively, to determine arsenic biotransformation and uptake in the various phosphorus scenarios. At high phosphate concentration in the culture medium, >100MUg/L P, the uptake and biotransformation of As(V) was minimal and dimethylarsonate (DMAs(V)) was the dominant metabolite excreted by C. vulgaris, albeit at relatively low concentrations. At common environmental P concentrations, 0-50MUg/L P, the uptake and biotransformation of As(V) increased. At these higher As-uptake levels, arsenite (As(III)) was the predominant metabolite excreted from the cell. The concentrations of As(III) in these low P conditions were much higher than the concentrations of methylated arsenicals observed at the various P concentrations studied. The switchover threshold between the (small) methylation and (large) reduction of As(V) occurred around a cellular As concentration of 1fg/cell. The observed nearly quantitative conversion of As(V) to As(III) under low phosphate conditions indicates the importance of As(V) bio-reduction at common freshwater P concentrations. These findings on the influence of phosphorus on arsenic uptake, accumulation and excretion are discussed in relation to previously published research. The impact that the two scenarios of As(V) metabolism, As(III) excretion at high As(V) uptake and methylarsenical excretion at low As(V)-uptake, have on freshwater arsenic speciation is discussed. PMID- 28007173 TI - Modification of a magnetic carbon composite for ciprofloxacin adsorption. AB - A magnetic carbon composite, Fe3O4/C composite, was fabricated by one-step hydrothermal synthesis, modified by heat treatment under an inert atmosphere (N2), and then used as an adsorbent for ciprofloxacin (CIP) removal. Conditions for the modification were optimized according to the rate of CIP removal. The adsorbent was characterized by Fourier transform infrared spectroscopy, X-ray diffraction measurements, vibrating-sample magnetometry, scanning electron microscopy, transmission electron microscopy, and N2 adsorption/desorption isotherm measurements. The results indicate that the modified adsorbent has substantial magnetism and has a large specific area, which favor CIP adsorption. The effects of solution pH, adsorbent dose, contact time, initial CIP concentration, ion strength, humic acid and solution temperature on CIP removal were also studied. Our results show that all of the above factors influence CIP removal. The Langmuir adsorption isotherm fits the adsorption process well, with the pseudo second-order model describing the adsorption kinetics accurately. The thermodynamic parameters indicate that adsorption is mainly physical adsorption. Recycling experiments revealed that the behavior of adsorbent is maintained after recycling for five times. Overall, the modified magnetic carbon composite is an efficient adsorbent for wastewater treatment. PMID- 28007174 TI - Characterization of colloidal arsenic at two abandoned gold mine sites in Nova Scotia, Canada, using asymmetric flow-field flow fractionation-inductively coupled plasma mass spectrometry. AB - Asymmetric flow-field flow fractionation-inductively-coupled plasma-mass spectrometry was used to determine whether colloidal arsenic (As) exists in soil pore water and soil extract samples at two arsenic-contaminated abandoned gold mines (Montague and Goldenville, Nova Scotia). Colloidal arsenic was found in 12 out of the 80 collected samples (=15%), and was primarily associated with iron (Fe) in the encountered colloids. The molar Fe/As ratios indicate that the colloids in some samples appeared to be discrete iron-arsenic minerals, whereas in other samples, they were more consistent with As-rich iron (oxy)hydroxides. Up to three discrete size fractions of colloidal As were encountered in the samples, with mean colloid diameters between 6 and 14nm. The pore water samples only contained one size fraction of As-bearing colloids (around 6nm diameter), while larger As-bearing colloids were only encountered in soil extracts. PMID- 28007175 TI - Transformation of hydroxylated and methoxylated 2,2',4,4',5-brominated diphenyl ether (BDE-99) in plants. AB - The occurrence and fate of hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and methoxylated polybrominated diphenyl ethers (MeO-PBDEs) have received significant attention. However, there is limited information on the metabolism relationship between OH-pentaBDEs and MeO-pentaBDEs that were frequently detected with relatively high concentrations in the environment. In this study, the biotransformation between OH-BDE-99 and MeO-BDE-99 was investigated in rice, wheat, and soybean plants. All the three plants can metabolize OH-BDE-99 to corresponding homologous methoxylated metabolites, while the transformation from MeO-BDE-99 to OH-BDE-99 could only be found in soybean. The conversion of parent compounds was the highest in soybean, followed by wheat and rice. Transformation products were found mainly in the roots, with few metabolites being translocated to the shoots and solution after exposure. The results of this study provide valuable information for a better understanding of the accumulation and transformation of OH-PBDEs and MeO-PBDEs in different plants. PMID- 28007176 TI - Potential of capillary electrophoresis mass spectrometry for the characterization and monitoring of amine-derivatized naphthenic acids from oil sands process affected water. AB - Capillary electrophoresis coupled to mass spectrometry (CE-MS) was used for the analysis of naphthenic acid fraction compounds (NAFCs) of oil sands process affected water (OSPW). A standard mixture of amine-derivatized naphthenic acids is injected directly onto the CE column and analyzed by CE-MS in less than 15min. Time of flight MS analysis (TOFMS), optimized for high molecular weight ions, showed NAFCs between 250 and 800m/z. With a quadrupole mass analyzer, only low molecular weight NAFCs (between 100 and 450m/z) are visible under our experimental conditions. Derivatization of NAFCs consisted of two-step amidation reactions mediated by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or mediated by a mixture of EDC and N-hydroxysuccinimide, in dimethyl sulfoxide, dichloromethane or ethyl acetate. The optimum background electrolyte composition was determined to be 30% (V/V) methanol in water and 2% (V/V) formic acid. NAFCs extracted from OSPW in the Athabasca oil sands region were used to demonstrate the feasibility of CE-MS for the analysis of NAFCs in environmental samples, showing that the labeled naphthenic acids are in the mass range of 350 to 1500m/z. PMID- 28007177 TI - Nitro-PAH exposures of occupationally-exposed traffic workers and associated urinary 1-nitropyrene metabolite concentrations. AB - The assessment of occupational exposure to diesel exhaust (DE) is important from an epidemiological perspective. Urinary biomarkers of exposure have been proposed as a novel approach for measuring exposure to DE. In this study, we measured the concentrations of two urinary metabolites of 1-nitropyrene (1NP), a nitrated polycyclic aromatic hydrocarbon that has been suggested as a molecular marker of diesel particulate matter. These two metabolites, 6-hydroxy-1-nitropyrene and 8 hydroxy-1-nitropyrene, were determined in urine samples (10mL) from a small group of workers who were occupationally-exposed to vehicle exhaust in Trujillo, Peru, before and after their workshifts. Workshift exposures to 1NP, as well as PM2.5, 2-nitropyrene and 2-nitrofluoranthene, were also measured. Exposures to 1NP were similar in all studied workers, averaging 105+/-57.9pg/m3 (+/-standard deviation). Median urinary concentrations of the average of the pre- and post exposure samples for 6-hydroxy-1-nitropyrene and 8-hydroxy-1-nitropyrene, were found to be 3.9 and 2.3pgmetabolite/mg creatinine, respectively in the group of occupationally-exposed subjects (n=17) studied. A direct relationship between workshift exposure to 1NP and urinary 1NP metabolites concentrations was not observed. However, the 1NP exposures and the creatinine-corrected urinary concentrations of the hydroxynitropyrene metabolites in these Peruvian traffic workers were similar to occupationally-exposed taxi drivers in Shenyang, China, and were higher than biomarker levels in office workers from Trujillo without occupational exposure to vehicle exhaust. This study provides further evidence that urinary metabolites of 1NP are associated with exposure to DE and may serve as a useful exposure biomarker. PMID- 28007178 TI - Inorganic arsenic: A non-genotoxic carcinogen. AB - Inorganic arsenic induces a variety of toxicities including cancer. The mode of action for cancer and non-cancer effects involves the metabolic generation of trivalent arsenicals and their reaction with sulfhydryl groups within critical proteins in various cell types which leads to the biological response. In epithelial cells, the response is cell death with consequent regenerative proliferation. If this continues for a long period of time, it can result in an increased risk of cancer. Arsenicals do not react with DNA. There is evidence for indirect genotoxicity in various in vitro and in vivo systems, but these involve exposures at cytotoxic concentrations and are not the basis for cancer development. The resulting markers of genotoxicity could readily be due to the cytotoxicity rather than an effect on the DNA itself. Evidence for genotoxicity in humans has involved detection of chromosomal aberrations, sister chromatid exchanges in lymphocytes and micronucleus formation in lymphocytes, buccal mucosal cells, and exfoliated urothelial cells in the urine. Numerous difficulties have been identified in the interpretation of such results, including inadequate assessment of exposure to arsenic, measurement of micronuclei, and potential confounding factors such as tobacco exposure, folate deficiency, and others. Overall, the data strongly supports a non-linear dose response for the effects of inorganic arsenic. In various in vitro and in vivo models and in human epidemiology studies there appears to be a threshold for biological responses, including cancer. PMID- 28007179 TI - Cellular arsenic transport pathways in mammals. AB - Natural contamination of drinking water with arsenic results in the exposure of millions of people world-wide to unacceptable levels of this metalloid. This is a serious global health problem because arsenic is a Group 1 (proven) human carcinogen and chronic exposure is known to cause skin, lung, and bladder tumors. Furthermore, arsenic exposure can result in a myriad of other adverse health effects including diseases of the cardiovascular, respiratory, neurological, reproductive, and endocrine systems. In addition to chronic environmental exposure to arsenic, arsenic trioxide is approved for the clinical treatment of acute promyelocytic leukemia, and is in clinical trials for other hematological malignancies as well as solid tumors. Considerable inter-individual variability in susceptibility to arsenic-induced disease and toxicity exists, and the reasons for such differences are incompletely understood. Transport pathways that influence the cellular uptake and export of arsenic contribute to regulating its cellular, tissue, and ultimately body levels. In the current review, membrane proteins (including phosphate transporters, aquaglyceroporin channels, solute carrier proteins, and ATP-binding cassette transporters) shown experimentally to contribute to the passage of inorganic, methylated, and/or glutathionylated arsenic species across cellular membranes are discussed. Furthermore, what is known about arsenic transporters in organs involved in absorption, distribution, and metabolism and how transport pathways contribute to arsenic elimination are described. PMID- 28007180 TI - Thiolated arsenicals in arsenic metabolism: Occurrence, formation, and biological implications. AB - Arsenic (As) is a notoriously toxic pollutant of health concern worldwide with potential risk of cancer induction, but meanwhile it is used as medicines for the treatment of different conditions including hematological cancers. Arsenic can undergo extensive metabolism in biological systems, and both toxicological and therapeutic effects of arsenic compounds are closely related to their metabolism. Recent studies have identified methylated thioarsenicals as a new class of arsenic metabolites in biological systems after exposure of inorganic and organic arsenicals, including arsenite, dimethylarsinic acid (DMAV), dimethylarsinous glutathione (DMAIIIGS), and arsenosugars. The increasing detection of thiolated arsenicals, including monomethylmonothioarsonic acid (MMMTAV), dimethylmonothioarsinic acid (DMMTAV) and its glutathione conjugate (DMMTAVGS), and dimethyldithioarsinic acid (DMDTAV) suggests that thioarsenicals may be important metabolites and play important roles in arsenic toxicity and therapeutic effects. Here we summarized the reported occurrence of thioarsenicals in biological systems, the possible formation pathways of thioarsenicals, and their toxicity, and discussed the biological implications of thioarsenicals on arsenic metabolism, toxicity, and therapeutic effects. PMID- 28007181 TI - Methylated and thiolated arsenic species for environmental and health research - A review on synthesis and characterization. AB - Hundreds of millions of people around the world are exposed to elevated concentrations of inorganic and organic arsenic compounds, increasing the risk of a wide range of health effects. Studies of the environmental fate and human health effects of arsenic require authentic arsenic compounds. We summarize here the synthesis and characterization of more than a dozen methylated and thiolated arsenic compounds that are not commercially available. We discuss the methods of synthesis for the following 14 trivalent (III) and pentavalent (V) arsenic compounds: monomethylarsonous acid (MMAIII), dicysteinylmethyldithioarsenite (MMAIII(Cys)2), monomethylarsonic acid (MMAV), monomethylmonothioarsonic acid (MMMTAV) or monothio-MMAV, monomethyldithioarsonic acid (MMDTAV) or dithio-MMAV, monomethyltrithioarsonate (MMTTAV) or trithio-MMAV, dimethylarsinous acid (DMAIII), dimethylarsino-glutathione (DMAIII(SG)), dimethylarsinic acid (DMAV), dimethylmonothioarsinic acid (DMMTAV) or monothio-DMAV, dimethyldithioarsinic acid (DMDTAV) or dithio-DMAV, trimethylarsine oxide (TMAOV), arsenobetaine (AsB), and an arsenicin-A model compound. We have reviewed and compared the available methods, synthesized the arsenic compounds in our laboratories, and provided characterization information. On the basis of reaction yield, ease of synthesis and purification of product, safety considerations, and our experience, we recommend a method for the synthesis of each of these arsenic compounds. PMID- 28007182 TI - Recent progress of arsenic adsorption on TiO2 in the presence of coexisting ions: A review. AB - Arsenic (As)-contaminated wastewater and groundwater pose a pressing environmental issue and worldwide concern. Adsorption of As using TiO2 materials, in combination with filtration, introduces a promising technology for the treatment of As-contaminated water. This review presents an overview on the recent progress of the application of TiO2 for removal of As from wastewater and groundwater. The main focus is on the following three pressing issues that limit the field applications of TiO2 for As removal: coexisting ions, simulation of breakthrough curves, and regeneration and reuse of spent TiO2 materials. We first examined how the coexisting ions in water, especially high concentrations of cations in industrial wastewater, affect the efficacy of As removal using the TiO2 materials. We then discussed As breakthrough curves and the effect of compounded ions on the breakthrough curves. We successfully simulated the breakthrough curves by PHREEQC after integrating the CD-MUSIC model. We further discussed challenges facing the regeneration and reuse of TiO2 media for practical applications. We offer our perspectives on remaining issues and future research needs. PMID- 28007183 TI - Role of complex organic arsenicals in food in aggregate exposure to arsenic. AB - For much of the world's population, food is the major source of exposure to arsenic. Exposure to this non-essential metalloid at relatively low levels may be linked to a wide range of adverse health effects. Thus, evaluating foods as sources of exposure to arsenic is important in assessing risk and developing strategies that protect public health. Although most emphasis has been placed on inorganic arsenic as human carcinogen and toxicant, an array of arsenic containing species are found in plants and animals used as foods. Here, we 2evaluate the contribution of complex organic arsenicals (arsenosugars, arsenolipids, and trimethylarsonium compounds) that are found in foods and consider their origins, metabolism, and potential toxicity. Commonalities in the metabolism of arsenosugars and arsenolipids lead to the production of di methylated arsenicals which are known to exert many toxic effects. Evaluating foods as sources of exposure to these complex organic arsenicals and understanding the formation of reactive metabolites may be critical in assessing their contribution to aggregate exposure to arsenic. PMID- 28007184 TI - Preliminary studies on the stability of arsenolipids: Implications for sample handling and analysis. AB - Human health risk assessments concerning arsenic are now estimating exposure through food in addition to exposure through drinking water. Intrinsic to this assessment is sample handling and preparation that maintains the arsenic species in the form that they occur in foods. We investigated the stability of three arsenolipids (two arsenic fatty acids, AsFA-362 and AsFA-388, and one arsenic hydrocarbon AsHC-332), common constituents of fish and algae, relevant to sample storage and transport, and to their preparation for quantitative measurements. The fate of the arsenolipids was followed by high performance liquid chromatography/electrospray triple quadruple mass spectrometry (HPLC/ESIMS) analyses. Storage of the compounds dry as pure compounds or mixed in fish oil at up to 60C did not result in significant changes to the compounds, although losses were observed by apparent adsorption onto the plastic walls of the polypropylene tubes. No losses occurred when the experiment was repeated with glass tubes. When the compounds were stored in ethanol for up to 15 days under acidic, neutral, or alkaline conditions (each at room temperature), no significant decomposition was observed, although esterification of the fatty acids occurred at low pH. The compounds were also stable during a sample preparation step involving passage through a small silica column. The results indicate that these typical arsenolipids are stable when stored in glass at temperatures up to 60C for at least 2 days, and that, consequently, samples of food or extracts thereof can be transported dry at ambient temperatures, i.e. without the need for cool conditions. PMID- 28007185 TI - AJKD on the Move. PMID- 28007186 TI - Increasing the Relevance of Clinical Research for Patients With Kidney Disease. PMID- 28007187 TI - Risk of Tranexamic Acid for Treatment of Postpartum Hemorrhage. PMID- 28007188 TI - In Reply to 'Risk of Tranexamic Acid for Treatment of Postpartum Hemorrhage'. PMID- 28007189 TI - Erratum Regarding "Nephrologist-Facilitated Advance Care Planning for Hemodialysis Patients: A Quality Improvement Project" (Am J Kidney Dis. 2016;68[1]:103-109). PMID- 28007190 TI - Erratum Regarding "Spironolactone in Dialysis: What's Old Is New Again" (Am J Kidney Dis. 2016;68[4]:512-514). PMID- 28007191 TI - Long-term Outcomes of Acute Kidney Injury: The Power and Pitfalls of Observational/Population-Based Studies. PMID- 28007192 TI - Understanding Dialysis Patient Perspectives on Advocacy. PMID- 28007193 TI - The Transition From the Pre-ESRD to ESRD Phase of CKD: Much Remains to Be Learned. PMID- 28007194 TI - Quiz: An Unusual Case of Metabolic Alkalosis in a Patient With CKD. PMID- 28007196 TI - AJKD Atlas of Renal Pathology: Indinavir Nephrotoxicity. PMID- 28007195 TI - AJKD Atlas of Renal Pathology: Lithium Nephrotoxicity. PMID- 28007197 TI - AJKD Atlas of Renal Pathology: Gouty Nephropathy. PMID- 28007198 TI - Transseptal Techniques for Emerging Structural Heart Interventions. AB - The development of new transseptal transcatheter interventions for patients with structural heart disease is fueling increasing interest in transseptal puncture techniques. The authors review contemporary transseptal puncture indications and techniques and provide a step-by-step approach to challenging transseptal access and procedural complications. PMID- 28007200 TI - Coronary Bypass Surgery Versus Percutaneous Coronary Intervention in Left Main and Multivessel Disease: Incremental Data-How Do We Apply It? PMID- 28007199 TI - Coronary Artery Bypass Surgery Versus Drug-Eluting Stent Implantation for Left Main or Multivessel Coronary Artery Disease: A Meta-Analysis of Individual Patient Data. AB - OBJECTIVES: The authors undertook a patient-level meta-analysis to compare long term outcomes after coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in 3,280 patients with left main or multivessel coronary artery disease (CAD). BACKGROUND: The relative efficacy and safety of CABG versus PCI with DES for left main or multivessel CAD remain controversial. METHODS: Data were pooled from the BEST (Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease), PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease), and SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trials. The primary outcome was a composite of all-cause death, myocardial infarction, or stroke. RESULTS: The median follow-up was 60 months, and follow-up was completed for 96.2% of patients. The rate of primary outcome was significantly lower with CABG than with PCI (13.0% vs. 16.0%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.69 to 1.00; p = 0.046). The difference was mainly driven by reduction in myocardial infarction (HR: 0.46; 95% CI: 0.33 to 0.64; p < 0.001). There was significant interaction between treatment effect and types of CAD, showing CABG to be superior compared with PCI with DES in patients with multivessel CAD (p = 0.001), but no between-group difference in those with left main CAD (p = 0.427). The rates for all-cause death and stroke were similar between the 2 groups. By contrast, the need for repeat revascularization was significantly lower in the CABG group compared with the PCI group. CONCLUSIONS: CABG, as compared with PCI with DES, reduced long-term rates of the composite of all-cause death, myocardial infarction, or stroke in patients with left main or multivessel CAD. The advantage of CABG over PCI with DES was particularly pronounced in those with multivessel CAD. PMID- 28007201 TI - Incidence, Characteristics, Predictors, and Outcomes of Repeat Revascularization After Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting: The SYNTAX Trial at 5 Years. AB - OBJECTIVES: The study sought to determine the incidence, predictors, characteristics, and outcomes of repeat revascularization during 5-year follow-up of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) trial. BACKGROUND: Limited in-depth long-term data on repeat revascularization are available from randomized trials comparing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). METHODS: Incidence and timing of repeat revascularization and its relation to the long term composite safety endpoint of death, stroke, and myocardial infarction were analyzed in the SYNTAX trial (n = 1,800) using Kaplan-Meier analysis. RESULTS: At 5 years, repeat revascularization occurred more often after initial PCI than after initial CABG (25.9% vs. 13.7%, respectively; p < 0.001), and more often consisted of multiple repeat revascularizations (9.0% vs. 2.8%, respectively; p = 0.022). Significantly more repeat PCI procedures were performed on de novo lesions in patients after initial PCI than initial CABG (33.3% vs. 13.4%, respectively; p < 0.001). At 5-year follow-up, patients who underwent repeat revascularization versus patients not undergoing repeat revascularization had significantly higher rates of the composite safety endpoint of death, stroke, and myocardial infarction after initial PCI (33.8% vs. 16.6%, respectively; p < 0.001), and a trend was found after initial CABG (22.4% vs. 15.8%, respectively; p = 0.07). After multivariate adjustment, repeat revascularization was an independent predictor of the composite safety endpoint after both initial PCI (hazard ratio [HR]: 2.2; 95% confidence interval [CI]: 1.6 to 3.0; p < 0.001) and initial CABG (HR: 1.8; 95% CI: 1.2 to 2.9; p = 0.011). CONCLUSIONS: Repeat revascularization rates are significantly higher after initial PCI than after initial CABG for complex coronary disease. Repeat revascularization is an independent predictor of death, stroke, and myocardial infarction for myocardial revascularization. PMID- 28007202 TI - CABG Beats Vintage PCI: Does Contemporary PCI Stand a Chance to EXCEL? PMID- 28007204 TI - TAVR: A Good Fix, But It Cannot Fix Everything. PMID- 28007203 TI - Quality of Life After Transcatheter Aortic Valve Replacement: Prospective Data From GARY (German Aortic Valve Registry). AB - OBJECTIVES: This study sought to analyze health-related quality-of-life (HrQoL) outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) based on data from GARY (German Aortic Valve Registry). BACKGROUND: Typically, patients currently referred for and treated by TAVR are elderly with a concomitant variable spectrum of multiple comorbidities, disabilities, and limited life expectancy. Beyond mortality and morbidity, the assessment of HrQoL is of paramount importance not only to guide patient-centered clinical decision making but also to judge this new treatment modality in this high-risk patient population. METHODS: In 2011, 3,875 patients undergoing TAVR were included in the GARY registry. HrQoL was prospectively measured using the EuroQol 5 dimensions questionnaire self-complete version on paper at baseline and 1 year. RESULTS: Complete follow-up EuroQol 5 dimensions questionnaire evaluation was available for 2,288 patients (transvascular transcatheter aortic valve replacement [TAVR TV]: n = 1,626 and transapical TAVR [TAVR-TA]: n = 662). In-hospital mortality was 5.9% (n = 229) and the 1-year mortality was 23% (n = 893). The baseline visual analog scale score for general health status was 52.6% for TAVR-TV and 55.8% for TAVR-TA and, in parallel to an improvement in New York Heart Association functional class, improved to 59.6% and 58.5% at 1 year, respectively (p < 0.001). Between baseline and 1 year, the number of patients reporting no complaints increased by 7.8% (TAVR-TV) and by 3.5% within the mobility dimension, and by 14.1% (TAVR-TV) and 9.2% within the usual activity dimension, whereas only moderate changes were found for the self-care, pain or discomfort, and anxiety or depression dimensions. In a multiple linear regression analysis several pre- and post-operative factors were predictive for less pronounced HrQoL benefits. CONCLUSIONS: TAVR treatment led to improvements in HrQoL, especially in terms of mobility and usual activities. The magnitude of improvements was higher in the TAVR-TV group as compared to the TAVR-TA group. However, there was a sizable group of patients who did not derive any HrQoL benefits. Several independent pre- and post-operative factors were identified being predictive for less pronounced HrQoL benefits. PMID- 28007206 TI - How to Treat Critical Limb Ischemia: The Critical Need for High-Grade Evidence. PMID- 28007205 TI - Endovascular Therapy Versus Bypass Surgery as First-Line Treatment Strategies for Critical Limb Ischemia: Results of the Interim Analysis of the CRITISCH Registry. AB - OBJECTIVES: The most effective first-line treatment between endovascular therapy and bypass surgery for patients with critical limb ischemia (CLI) is still not well defined. The primary aim of the interim analysis of CRITISCH (Registry of First-Line Treatments in Patients With Critical Limb Ischemia) was to compare both treatment options in a prospective confirmatory manner. BACKGROUND: Only 1 randomized controlled trial between endovascular therapy and bypass surgery has been published yet. Several retrospective studies showed comparable outcomes between the 2 treatment strategies, but in the majority of them, current endovascular technologies have not been included. METHODS: Between January 2013 and September 2014, 1,200 CLI patients (Rutherford 4 to 6) from 27 vascular centers were enrolled. The selection of the first-line treatment was left completely to the discretion of the responsible physician. The primary composite endpoint was amputation-free survival (AFS), that is, time to major amputation and/or death from any cause. A pre-specified interim analysis aimed at showing noninferiority of the endovascular therapy versus bypass surgery as to the hazard ratio (HR) of AFS (noninferiority bound = 1.33; interim alpha = 0.0058). Time-to event analyses of major amputation, death, and the composite endpoint of reintervention and/or above-ankle amputation were also conducted. RESULTS: Endovascular therapy was applied to 642 (54%) and bypass surgery to 284 (24%) patients. Median follow-up time was 12 months in both groups. One-year AFS was 75% and 72%, respectively. The noninferiority of endovascular therapy versus bypass surgery for AFS was confirmed (HR: 0.91; upper bound of 1-sided (1 - 0.0058) confidence interval [CI]: 1.29; p = 0.003). An impact of the treatment strategy on time until death (HR: 1.14; 95% CI: 0.80 to 1.63; p = 0.453), major amputation (HR: 0.86; 95% CI:0.56 to 1.30; p = 0.463), and reintervention and/or above-ankle amputation (HR: 0.89; 95% CI: 0.70 to 1.14; p = 0.348) was not observed. CONCLUSIONS: The interim analysis confirmed that when physicians are free to individualize therapy to CLI patients, the endovascular-first approach achieved a noninferior AFS rate compared with bypass surgery. (Registry of First Line Treatments in Patients With Critical Limb Ischemia [CRITISCH]; NCT01877252). PMID- 28007207 TI - Temporal Changes in Outcomes After Stenting or Bypass Surgery for Unprotected Left Main Coronary Artery Disease According to Diabetes Status. PMID- 28007208 TI - Is Multislice Computed Tomography a Feasible Option for Follow-Up of Complex Coronary Lesions Treated With Bioresorbable Scaffolds? PMID- 28007209 TI - Structural Heart Interventional Training: The Next Steps. PMID- 28007210 TI - Avoiding PTSD (Post-Transcatheter Stress Disorder). PMID- 28007211 TI - Perforation of Anterior Mitral Leaflet Due to Mechanical Stimulation Late After Transcatheter Aortic Valve Replacement. PMID- 28007212 TI - Morphological, molecular, and ultrastructural characterization of Rozella rhizoclosmatii, a new species in Cryptomycota. AB - Rozella is a genus of unwalled endoparasites of a variety of hosts including Oomycota (Stramenopiles), Blastocladiomycota and Chytridiomycota (Fungi), and one green alga (Coleochaete, Chlorophyceae). It currently includes more than 20 formally described species, and no new species of Rozella have been described since 1987. We discovered a new Rozella species parasitizing Rhizoclosmatium globosum (Chytridiales, Chytridiomycota) and investigated its morphology, ultrastructure, and phylogenetic position. Herein named as Rozella rhizoclosmatii sp. nov., the organism induces hypertrophy of the host. Its zoospore is ultrastructurally similar to that of Rozella allomycis, although it has a unique zoospore ultrastructural feature, a lattice of perpendicular rods about the nucleus. The 18S rDNA molecular sequence of R. rhizoclosmatii is similar to that of the previously sequenced 'Rozella ex Rhizoclosmatium'. This is the first study to inclusively characterize a new species of Rozella with morphological, ultrastructural and molecular data. As this is only the second Rozella species to be examined ultrastructurally, and because it is parasitic on a member of Chytridiomycota and not Blastocladiomycota, this research supports the conservative nature of zoospore ultrastructure to help define the genus. PMID- 28007213 TI - The Woronin body in the nematophagous fungus Arthrobotrys oligospora is essential for trap formation and efficient pathogenesis. AB - The Woronin body is a unique organelle in Pezizomycotina species. Following the injury of hyphae, it can quickly seal the septal pores to reduce the loss of cytoplasm and promote hyphal healing. The Woronin body is also considered a significant factor in efficient pathogenesis in many fungal pathogens. In this study, we identified AoHex1, a homologue of Neurospora crassa Hex1, a main component of the Woronin body in the genome of the nematode-trapping fungus Arthrobotrys oligospora. To study the biological function of the AoHex1 gene, the gene was deleted and its phenotypes assessed. Inactivation of this gene led to the loss of the Woronin body. The DeltaAoHex1 strain showed compromised growth rate, conidiation, and anti-stress abilities. Moreover, trap formation was completely absent in the mutant strain, which could no longer capture nematodes. Our results suggest that the Woronin body plays an important role in growth, conidiation, anti-stress, trap formation, and virulence against nematodes in A. oligospora. PMID- 28007214 TI - Polyphasic characterisation of Chaetomium species from soil and compost revealed high number of undescribed species. AB - This study investigated 46 Chaetomium strains isolated from soil and compost from China. In total 14 species were recognised, of which seven were described as new species (i.e. Chaetomium angulare, Chaetomium cirrhata, Chaetomium heterothallicum, Chaetomium laterale, Chaetomium longiciliata, Chaetomium microthecia, Chaetomium uniseriatum). Growth temperature profiles of these fungi revealed that 11 species are mesophilic; C. angulare and Chaetomium jodhpurense are thermotolerant; Chaetomium thermophilum var. dissitum is thermophilic, with temperature maxima above 50 degrees C. Among the 46 strains, 39 were shown to be homothallic. Mating experiments were conducted for the remaining seven strains that are morphologically and phylogenetically closely related. The results of the mating experiment, together with the four-locus (ITS, LSU, RPB2, TUB) phylogeny and a pairwise homoplasy index (PHI) test, supported the division of these seven additional strains into two heterothallic species that are herein described as C. heterothallicum and C. uniseriatum. A three-locus (ITS, LSU, TUB) phylogenetic tree based on all currently accepted species that have available type-derived sequences revealed that Chaetomium species clearly grouped in six phylogenetic groups which showed a certain correspondence with their morphology and temperature profiles. PMID- 28007215 TI - Does Gnomoniopsis castanea contribute to the natural biological control of chestnut gall wasp? AB - Gnomoniopsis castanea has been reported as the causal agent of necrosis of chestnut wasp (Dryocosmus kuriphilus) galls. The fungus is frequently observed on galls in chestnut stands infested by the insect in Italy. In the present study the impact of gall necrosis and the dynamic of its development have been studied in mature and young Castanea sativa stands in Central Italy during spring and early summer, before the D. kuriphilus adult flies. Results suggest that gall necrosis develops from resident endophytic inoculum of G. castanea. During the 2 y of monitoring, no differences were found in incidence and severity of the disease. Gall necrosis increased exponentially during the season, reaching 75,4% of galls totally necrotized in the investigated site in mid July. Gall necrosis was shown to have a severe impact on D. kuriphilus vitality, mostly impacting the adults inside the galls. Gall necrosis by G. castanea appears to efficiently control gall wasp in chestnut stands, although the high virulence of the fungus to chestnut fruits precludes its use as biocontrol agent in biological control strategies. PMID- 28007216 TI - Antifungal activity of the cationic antimicrobial polymer-polyhexamethylene guanidine hydrochloride and its mode of action. AB - The antifungal activity of polyhexamethylene guanidine hydrochloride (PHMGH) was studied against various pathogenic fungi. PHMGH had more potent antifungal activity than amphotericin B, which is a commonly used antifungal drug, and also showed no hemolytic and lactate dehydrogenase release activities in the range of 1.25-40.0 MUg mL-1. PHMGH is a cationic polymer containing an amino group and a polymeric guanidine group. Based on its characteristics such as the cationic charge and hydrophobicity, the antifungal mechanism of PHMGH was investigated using Candida albicans, as a model organism. Flow cytometric contour-plot analysis and microscopy showed changes in the size and granularity of the cells after treatment with PHMGH. A membrane study using 1,6-diphenyl-1,3,5-hexatriene labelling indicated a great loss of phospholipid area in the plasma membrane following PHMGH treatment. To investigate the extent of the damage, fluorescein isothiocyanate-labelled dextran leakage from large unilamellar vesicles was observed, indicating that PHMGH acts on the fungal membranes by inducing pore formation, with the majority of pore size being between 2.3 and 3.3 nm. This mechanism was confirmed with ion transition assays using 3,3' dipropylthiacarbocyanine iodide and an ion-selective electrode meter, which indicated that membrane depolarization involving K+ leakage was induced. Taken together, these results show that PHMGH exerts its fungicidal effect by forming pores in the cell membrane. PMID- 28007217 TI - Gene cloning, heterologous expression and characterization of a Coprinopsis cinerea endo-beta-1,3(4)-glucanase. AB - A gene coding endo-beta-1,3(4)-glucanase (ENG16A) was cloned from Coprinopsis cinerea and heterologously expressed in Pichia pastoris. ENG16A only acts on substrates containing beta-1,3 glycosidic bonds but not on substrates containing only beta-1,4- or beta-1,6-glycosidic bonds. Interestingly, compared to the activity of this enzyme towards carboxymethyl (CM)-pachyman containing only beta 1,3-glycosidic bonds, its activity towards barley beta-glucan containing both beta-1,3-glycosidic and beta-1,4-glycosidic bonds was increased by 64.72 %,, its activity towards laminarin containing both beta-1,3-glycosidic and beta-1,6 glycosidic bonds was decreased by 50.83 %. In addition, ENG16A has a higher Km value and Vmax for barley beta-glucan than laminarin, which may be related to the fact that barley beta-glucan contains mainly beta-1,4-glycosidic bonds mixed with a few beta-1,3-glycosidic bonds, whereas laminarin mainly contains beta-1,3 glycosidic bonds with a few beta-1,6-branched glucose residues. The adjacent beta 1,4-glycosidic bond promotes ENG16A to hydrolyse beta-1,3-glycosidic bonds, leading to an increased Vmax; the nearby beta-1,6-glycosidic bonds inhibited its hydrolysis of beta-1,3-glycosidic bonds, resulting in a decreased Vmax. This property is suggested to be related to the mechanism that C. cinerea uses to degrade and utilize hemicellulose in straw medium and to protect its cell wall during the mycelium growth stage. PMID- 28007218 TI - Ecology and population structure of a tree wound-infecting fungus in a native South African forest environment. AB - Ceratocystis tsitsikammensis was first isolated from bark harvesting wounds on two indigenous tree species in the Afromontane forests of the Western Cape Province of South Africa. Inoculation studies indicated that it is a potential pathogen of native Rapanea melanophloeos trees. In this study, we investigated the distribution, ecology and biology of C. tsitsikammensis in the Garden Route National Park of South Africa. Isolates were obtained from wounds on R. melanophloeos, three non-native hosts as well as from nitidulid and staphylinid beetles visiting wounds on these trees. The genetic diversity and population biology of the fungus was examined using microsatellite markers. Its mating strategy was also determined by amplifying its mating type genes and the fungus was shown to be homothallic. Despite the homothallic nature of the fungus, high levels of random mating and absence of genetic structure was found in the investigated population, suggesting a strong effect of gene flow, probably linked to insect dispersal. The gene diversity of C. tsitsikammensis was similar to that of a related fungus, Ceratocystis albifundus, that is known to be native in Africa. This, together with the fact that C. tsitiskamensis is not known elsewhere, within or outside South Africa, suggests that it is native and endemic to the Cape Afromontane region. PMID- 28007219 TI - Putative origins of the fungus Leptographium procerum. AB - Appropriate management of invasive fungi requires adequate understanding of their global diversities and movement histories. The fungus Leptographium procerum is associated with root-colonizing forest insects in pine forests throughout the world, and may have contributed to the aggressive behaviour of the red turpentine beetle (Dendroctonus valens) in the beetle's invasive range in China. We used microsatellites and mating type loci to investigate the global diversity of L. procerum and the source population of L. procerum associated with D. valens in China. Clustering analyses supported the separation of the fungal data set into three genetically and geographically-distinct clusters: Europe, North America, and China. The fungus had the highest genetic diversity in Europe, followed by North America and China. Analyses using Approximate Bayesian Computation supported Europe as the most likely source of the North American and Chinese populations. Overall, the results suggested that Europe is the global centre of diversity of L. procerum. Furthermore, they suggested that L. procerum most likely arrived in China independently of D. valens and adopted this beetle as a vector after its introduction. PMID- 28007220 TI - Structural features of the aromatic/arginine constriction in the aquaglyceroporin GintAQPF2 are responsible for glycerol impermeability in arbuscular mycorrhizal symbiosis. AB - Carbon transport in arbuscular mycorrhizal (AM) symbiosis is of fundamental importance. However, the role of glycerol transport in AM symbiosis has not yet been resolved. Glycerol transport across the cell membrane is mediated by aquaglyceroporins (AQGPs), whereas our previous study revealed that it was disfavoured by GintAQPF2, an AQGP from AM fungi (AMF). Here, we analysed the function of two amino acid residues in the aromatic/arginine (ar/R) constriction known as the major selectivity filter in AQGPs. Replacement of phenylalanine-94 (Phe-94) by alanine (Ala) enlarged the diameter of the ar/R constriction and resulted in an increased intracellular glycerol accumulation and thus survival rate of yeast cells at high glycerol levels, while individual or joint replacement of Phe-94 and Ala-234 by tryptophan and glycine induced a closed state of GintAQPF2, suggesting that the potential double gates (Phe94-Phe243 and arginine-249) of the ar/R constriction also likely determined solute permeability. To figure out whether GintAQPF2 functions were relevant to the establishment of AM symbiosis, genomic analyses of four representative fungi with different lifestyles were performed. We found that glycerol facilitators existed in the facultative fungi (the ectomycorrhizal fungus Laccaria bicolor and hemibiotrophic pathogen Magnaporthe oryzae), but not in the obligatory fungi (the AMF Rhizophagus irregularis and necrotrophic pathogen Fusarium verticillioides), revealing a conserved pattern of glycerol transport in symbionts and pathogens. Our results suggested that glycerol blocks due to the special structural features of the ar/R constriction in the only AMF AQGP could potentially play a role in the establishment of AM symbiosis. PMID- 28007221 TI - Preparing to lead change: An innovative curriculum integrating theory, group skills and authentic presence. PMID- 28007222 TI - Faster Cancer Treatment: Using timestamp data to improve patient journeys. AB - This paper presents a case study of research conducted to improve the delivery of treatment to high priority cancer patients. The authors present a modelling framework that uses time-stamp data collected by the North Shore Hospital IT systems as "business as usual", to describe the patient journey through the cancer-care process. A simulation process is developed that uses this data to estimate the service's performance under current operating practices, and enables "what-if" analysis to identify where changes to current practice can most effectively be applied, ensuring the investment of additional resource can be targeted at the steps of the patient pathway where it can result in the greatest improvement. The process is illustrated using the Breast Cancer stream as a case study, for the initial study period (July 2013 to June 2014), with a follow-up analysis presented briefly for the 3 months from July to the end of September 2014. PMID- 28007223 TI - A hidden opportunity within surgery in low- and middle-income countries. PMID- 28007224 TI - Efficacy of surgical safety checklist: Assessing orthopaedic surgical implant readiness. AB - INTRODUCTION: Our institution employs a Surgical Universal Protocol Preoperative Checklist in accordance with World Health Organization guidelines to promote patient safety. It is used in part to evaluate orthopaedic surgical equipment and implant readiness prior to the initiation of each surgical case. Our goal is to measure the preoperative checklist's efficacy in assessing orthopaedic equipment readiness preoperatively and its ability to prevent orthopaedic equipment failures (OEF). Our study focused on orthopaedic surgery cases as they require a large volume of equipment and implants for successful completion. These cases therefore present an appropriate medium to identify potential weakness in our institution's current surgical safety checklist (SSC). METHODS: Data was collected over a 6 month period of time, broken into 2 distinct periods. The goal during the first 3 months was to observe compliance with the SSC. And during this time, we observed how often the SSC identified an implant or equipment deficiency at the outset of the case. The goal during the second 3 months was to record if orthopaedic surgical equipment issues were occurring that should have been identified by the SSC. During the second 3 months, we continued to utilize the SSC but also added a postsurgical review at the end of each surgical case. The postsurgical review was a one page questionnaire aimed at identifying any orthopaedic equipment failures that had occurred during the surgical case. For the purposes of this study, we defined an intraoperative orthopaedic equipment failure (OEF) as any one of the 6 following categories: (1) surgery delayed due to missing equipment, (2) lack of sterility of equipment, (3) equipment not available, (4) equipment malfunction, and (5) equipment sets incomplete, or (6) additional equipment brought into room necessary for completion of case. The data was collected at a postsurgical review that was performed by the physicians, nurses, and technicians from the surgical team in a nonthreatening manner. We also attempted to quantify the impact that the OEF had upon the surgical case. RESULTS: During the first 3 months of the study (phase 1), we confirmed that our institutional SSCs were completed for all orthopaedic cases, including the specific questions related to implants and equipment. During phase 1, using the SSC alone, no orthopaedic equipment failures were identified. During phase 2, 33% of the reported surgical cases were identified as having started without essential equipment available or operational (defined as an orthopaedic equipment failure) in the operating room. The most common negative impact upon the surgical case was additional time requirement. CONCLUSION: Our institution's current SSC fails to prevent OEF in our operating rooms. These checklist failures and intraoperative equipment deficiencies have measureable negative patient safety and institutional cost implications. IMPLICATIONS: While the SSC is an effective tool it cannot be used alone to prepare for orthopaedic surgical cases. In order to improve patient safety and decrease hospital losses, further research is necessary to implement an effective communication network between surgeons, administrators, operating room nursing and sterile processing to eliminate OEF. LEVEL OF EVIDENCE: Level IV. PMID- 28007225 TI - Essentials for improving service quality in cancer care. PMID- 28007226 TI - Role expansion on interprofessional primary care teams: Barriers of role self efficacy among clinical associates. AB - BACKGROUND: Interprofessional team-based models of primary care that expand the role of clinical associates (CAs) are increasingly adopted in primary care practices. In this study we query team members of a newly implemented patient centered medical home (PCMH) to identify facilitators and barriers of occupational role self-efficacy, a belief of possessing the capacity to execute their new team based role effectively. METHODS: 79 key informants, members of primary care teams at six Veterans Health Administration (VA) clinics, were interviewed to assess their experiences with implementing expanded roles for CAs. All sites had implemented Patient Aligned Care Teams, the VA's version of PCMH. RESULTS: Three themes that produced the self-efficacy necessary for successful role expansion of CAs were identified: (1) role training (2) time and resources for roles and (3) cross-disciplinary role agreement. Sub-themes emerged around role challenges. Training sub themes included incomplete or limited training, inconsistencies in trainings within a site, and not receiving training with team members. Insufficient resources sub-themes included limited time for expanded tasks, inadequate space, low staffing, and poor task mix. Cross-disciplinary agreement failed to occur specifically when there was insufficient coordination between medicine and nursing leadership about staff roles, poor primary care provider (PCPs) knowledge of the boundaries of staff roles, and lack of synchronicity between staff roles and what PCPs would like staff roles to include. CONCLUSIONS: These identified themes have implications for healthcare professionals working in interprofessional teams in a variety of settings and indicate the need for interdisciplinary leadership based solutions. IMPLICATIONS: Clarifying the factors that impact self-efficacy for the role expansion of PACT staff can inform strategies for role transformation for enhanced primary care delivery. PMID- 28007227 TI - The Perioperative Surgical Home model facilitates change implementation in anesthetic technique within a clinical pathway for total knee arthroplasty. AB - BACKGROUND: The challenge of knowledge translation in medical settings is well known, and implementing change in clinical practice can take years. For the increasing number total knee arthroplasty (TKA) patients annually, there is ample evidence to endorse neuraxial anesthesia over general anesthesia. The rate of adoption of this practice, however, is slow at the current time. We hypothesized that a Perioperative Surgical Home (PSH) model facilitates rapid change implementation in anesthesia. METHODS: The PSH clinical pathways workgroup at a tertiary care Veterans Affairs hospital embarked on a 5-month process of changing the preferred anesthetic technique for patients undergoing TKA. This process involved multiple sequential steps: literature review; development of a work document; training of staff; and prospective collection of data. To assess the impact of this change, we examined data 6 months before (PRE, n=90) and after (POST) change implementation (n=128), and our primary outcome was the overall proportion of spinal anesthesia usage for each 6 month period. Secondary outcomes included minor and major complications associated with anesthetic technique. RESULTS: Over a period of one year, there was an increase in the proportion of patients who received spinal anesthesia (13% vs. 63%, p<0.001). For the following year, 53-92% of TKA patients per month received spinal anesthesia. There were no differences in major complications. CONCLUSION: Rapid and sustained change implementation in clinical anesthesia practice based on emerging evidence is feasible. IMPLICATIONS: Perioperative Surgical Home model may facilitate rapid change implementation in surgical care. LEVEL OF EVIDENCE: Cohort study, Level 2. PMID- 28007228 TI - Using active choice within the electronic health record to increase physician ordering and patient completion of high-value cancer screening tests. AB - BACKGROUND: High value screening tests such as colonoscopy and mammography can improve early cancer detection but are often underutilized. METHODS: We evaluated an active choice intervention using the electronic health record (EHR) to confirm patient eligibility for colonoscopy or mammography during the patient's clinic visit and prompt the physician and his/her medical assistant to actively choose to "accept" or "cancel" an order for it. We fit multivariate logistic regression models using a difference-in-differences approach to evaluate changes in physician ordering and patient completion of colonoscopy and mammography at the intervention practice compared to two control practices, adjusting for time trends, patient and clinic visit characteristics. RESULTS: The sample comprised 7560 patients due for colonoscopy and 8337 patients due for mammography. Pre intervention trends between practices did not differ. In the adjusted models, compared to the control group over time, the intervention practice had a significant increase in ordering of colonoscopy (11.8% points, 95% CI: 8.0-15.6, P<0.001) and mammography (12.4% points, 95% CI: 8.7-16.2, P<0.001). There was a significant increase in patient completion of colonoscopy (3.5% points, 95% CI: 1.1-5.9, P<0.01), but no change in mammography (2.2% points, 95% CI: -1.0 to 5.5, P=0.18). CONCLUSIONS: Active choice through the EHR was associated with an increase in physician ordering of colonoscopy and mammography. The intervention was also associated with an increase in patient completion of colonoscopy but no change in patient completion of mammography. PMID- 28007230 TI - Invited Commentary. PMID- 28007232 TI - Invited Commentary. PMID- 28007231 TI - "Think Outside the Box"-Visionary of Cross-Training. PMID- 28007233 TI - Invited Commentary. PMID- 28007234 TI - Type A Aortic Dissection Repair: How I Teach It. PMID- 28007235 TI - Invited Commentary. PMID- 28007229 TI - Sexually transmitted diseases and infertility. AB - Female infertility, including tubal factor infertility, is a major public health concern worldwide. Most cases of tubal factor infertility are attributable to untreated sexually transmitted diseases that ascend along the reproductive tract and are capable of causing tubal inflammation, damage, and scarring. Evidence has consistently demonstrated the effects of Chlamydia trachomatis and Neisseria gonorrhoeae as pathogenic bacteria involved in reproductive tract morbidities including tubal factor infertility and pelvic inflammatory disease. There is limited evidence in the medical literature that other sexually transmitted organisms, including Mycoplasma genitalium, Trichomonas vaginalis, and other microorganisms within the vaginal microbiome, may be important factors involved in the pathology of infertility. Further investigation into the vaginal microbiome and other potential pathogens is necessary to identify preventable causes of tubal factor infertility. Improved clinical screening and prevention of ascending infection may provide a solution to the persistent burden of infertility. PMID- 28007236 TI - Invited Commentary. PMID- 28007237 TI - Invited Commentary. PMID- 28007238 TI - Invited Commentary. PMID- 28007239 TI - Invited Commentary. PMID- 28007240 TI - The Society of Thoracic Surgeons 2017 Clinical Practice Guidelines for the Surgical Treatment of Atrial Fibrillation. AB - EXECUTIVE SUMMARY: Surgical ablation for atrial fibrillation (AF) can be performed without additional risk of operative mortality or major morbidity, and is recommended at the time of concomitant mitral operations to restore sinus rhythm. (Class I, Level A) Surgical ablation for AF can be performed without additional operative risk of mortality or major morbidity, and is recommended at the time of concomitant isolated aortic valve replacement, isolated coronary artery bypass graft surgery, and aortic valve replacement plus coronary artery bypass graft operations to restore sinus rhythm. (Class I, Level B nonrandomized) Surgical ablation for symptomatic AF in the absence of structural heart disease that is refractory to class I/III antiarrhythmic drugs or catheter-based therapy or both is reasonable as a primary stand-alone procedure, to restore sinus rhythm. (Class IIA, Level B randomized) Surgical ablation for symptomatic persistent or longstanding persistent AF in the absence of structural heart disease is reasonable, as a stand-alone procedure using the Cox-Maze III/IV lesion set compared with pulmonary vein isolation alone. (Class IIA, Level B nonrandomized) Surgical ablation for symptomatic AF in the setting of left atrial enlargement (>=4.5 cm) or more than moderate mitral regurgitation by pulmonary vein isolation alone is not recommended. (Class III no benefit, Level C expert opinion) It is reasonable to perform left atrial appendage excision or exclusion in conjunction with surgical ablation for AF for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C limited data) At the time of concomitant cardiac operations in patients with AF, it is reasonable to surgically manage the left atrial appendage for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C expert opinion) In the treatment of AF, multidisciplinary heart team assessment, treatment planning, and long-term follow up can be useful and beneficial to optimize patient outcomes. (Class I, Level C expert opinion). PMID- 28007241 TI - Reply. PMID- 28007242 TI - Differences Between Venovenous and Venoarterial Extracorporeal Membrane Oxygenation in Pregnancies. PMID- 28007243 TI - Is the Standardized Technique to Air Leak Reduction (STAR) a Star for All Pulmonary Resections? PMID- 28007244 TI - Reply. PMID- 28007245 TI - ITA Well Fits as Arterial Conduit for Coronary Bypass Based on Its Histology. PMID- 28007246 TI - Reply. PMID- 28007247 TI - Role of Postoperative Radiation Therapy in Completely Resected Thymoma. PMID- 28007248 TI - Reply. PMID- 28007249 TI - Novel Tricuspid Valve Repair Technique. PMID- 28007250 TI - Successful Evolut R Valve-in-Valve Transcatheter Aortic Valve Replacement. PMID- 28007251 TI - Reply. PMID- 28007252 TI - Reply. PMID- 28007253 TI - Correction. PMID- 28007254 TI - Retraction Notice to "Acute Preoperative Plasmapheresis and Established Blood Conservation Techniques" [Ann Thorac Surg 1990;50(1):62-68]. PMID- 28007255 TI - Invited Commentary. PMID- 28007256 TI - Invited Commentary. PMID- 28007257 TI - Temporary Banking of the Jejunal Flap for a Difficult Esophageal Reconstruction. AB - In this report, we describe a case of difficult esophageal reconstruction using temporary banking of a jejunal free flap. This flap was temporarily placed on the patient's chest wall using the internal mammary vessels (IMVs) as recipient vessels. After 15 days, the jejunal flap was transferred to the neck region, and permanent coverage was provided using a pedicled latissimus dorsi musculocutaneous flap. PMID- 28007258 TI - Outflow Graft Obstruction Treated With Transcatheter Management: A Novel Therapy for a New Diagnosis. AB - The duration of support in patients with HeartMate II implantation as a bridge to transplant or as destination therapy is rising. As clinical experience continues to grow, physiologic changes contributing to pump malfunction are becoming apparent. Once malfunction is noted with increased power spikes, rises in lactate dehydrogenase and low-flow alarms, thrombosis of the pump is at risk. We describe outflow graft compression and offer an expeditious and definitive management strategy. Our novel management stenting strategy for outflow graft compression will continue to evolve as experience is gained. PMID- 28007259 TI - A Standardized Loop Technique for Mitral Valve Repair. AB - The loop technique is widely used for mitral valve repair. However, estimation of the correct loops' length remains challenging. We describe a standardized technique with implantation of standardized 15- and 25-mm loops for posterior and anterior mitral prolapses. The number of loops and the site of their implantation are decided after a careful surgical valve analysis. This has shown reliable results in our initial experience in eight patients both, in sternotomy and minimally invasive surgery repairs, but needs further long-term evaluation. PMID- 28007261 TI - Fulminant Infectious Aortitis With Ascending Aortic Rupture. AB - Infectious aortitis is associated with a high rate of acute aortic adverse events. However, the nonspecificity of symptoms and low sensitivity of blood cultures may delay early recognition of this condition. A 77-year-old man was incidentally found to have aortitis. His disease took a fulminant course and was complicated by dissection and rupture only 4 days after the diagnosis. Serial computed tomographic angiography provided valuable information about the development of aortitis into dissection and rupture. Postdissection histologic analysis revealed gram-positive cocci in the aortic wall. PMID- 28007260 TI - Right Posterior Thoracotomy for Open-Heart Surgery in a Rare Morphology. AB - The closure of atrial septal defects through right-sided limited posterior thoracotomy has been well established in selected subsets. We present a case of large ostium secundum atrial septal defect, pulmonary valvar stenosis, absent right superior vena cava, and isolated left superior vena cava draining to right atrium via coronary sinus. The child successfully underwent total correction through limited posterior thoracotomy with necessary modifications of intraoperative steps. PMID- 28007262 TI - Off-Pump Atrial Septectomy for Infants With Restrictive Atrial Septal Defect. AB - The management of some subsets of patients with an unsuccessful balloon atrial septostomy (BAS) and poor general condition is typically challenging. Our novel technique involves off-pump atrial septectomy using laparoscopic forceps guided by intraoperative direct pericardial echocardiography. The technique was first used in a case of tricuspid atresia in a patient in preshock and was then used in 2 more patients with hypoplastic left heart syndrome (HLHS) (age, 10-116 days; body weight, 2.4-3.7 kg). There were no operative complications of embolism or bleeding in our series. Our off-pump atrial septectomy technique is an effective approach in specific cases. PMID- 28007263 TI - Thymic and Mediastinal Lymph Node Metastasis of Colon Cancer. AB - Most anterior mediastinal tumors are thymomas. Thymic metastasis from other primary cancers is extremely rare. We report the case of a 72-year-old man who developed thymic and mediastinal lymph node metastases of cecum cancer. He had undergone laparoscopic ileocecal resection with regional lymph node dissection for primary cecum cancer 15 months previously. Follow-up computed tomography revealed tumors in the anterior mediastinum. Fluorodeoxyglucose positron emission tomography showed positive uptake in the tumors. Because thymoma or thymic carcinoma was suspected, we performed total thymectomy via a median sternotomy. Histologic findings of the anterior mediastinal tumors were compatible with metastasis of the previously resected cecum cancer. PMID- 28007264 TI - Femorofemoral Shunt During Surgery for Acute DeBakey Type 1 Dissection to Treat Peripheral Extremity Malperfusion. AB - Peripheral extremity ischemia in patients presenting with a DeBakey type 1 aortic dissection is an independent predictor for mortality. We present a patient with a DeBakey type 1 aortic dissection and peripheral extremity malperfusion that underwent simultaneous aortic repair and percutaneous femorofemoral shunt with arterial sidearm. Our approach allows for immediate peripheral extremity reperfusion and subsequent objective determination of the necessity of femorofemoral bypass via perfusion pressures. PMID- 28007265 TI - Prolonged Survival of Pulmonary Artery Sarcoma After Aggressive Surgical Resection. AB - Pulmonary artery sarcomas are rare tumors with a poor prognosis. Presentation is usually with symptoms of cardiorespiratory dysfunction, and although preoperative diagnosis was unusual historically, modern imaging techniques allow a high degree of confidence, and transvenous catheter biopsy can give confirmation of the diagnosis. This patient survived 6 years after surgical resection of the tumor and left lung with pulmonary artery reconstruction followed by postoperative adjuvant chemotherapy. The prolonged survival supports an aggressive approach in suitable cases. PMID- 28007266 TI - Aortoventricular Dissociation and Refractory Fungal Endocarditis Caused by a Rare Pathogen Lichtheimia: A Surgical and Medical Management Strategy. AB - We report a rare case of prosthetic valve fungal endocarditis caused by Lichtheimia, a subspecies of the order Mucorales. The patient experienced complicated prosthetic valve endocarditis less than 2 months after uneventful coronary artery bypass grafting (CABG) and 2 aortic valve replacements. Ultimately surgical management required aortic root replacement and lifelong antimicrobial agents. We believe this is the first case of fungal endocarditis caused by Lichtheimia. PMID- 28007267 TI - Off-Pump NeoChord Mitral Valve Repair to Simultaneously Treat Posterior Leaflet Prolapse and Systolic Anterior Motion. AB - This case represents the first report of complete elimination of systolic anterior motion by beating-heart implantation of artificial chordae tendineae on a prolapsing and redundant posterior leaflet. PMID- 28007268 TI - Small Intestinal Inflammatory Myofibroblastic Metastasis in the Left Ventricle. AB - Inflammatory myofibroblastic tumors (IMTs) are rare and usually appear in childhood and adolescence. These tumors often take a benign course, but tend to reoccur in a quarter of cases and metastasize locally. Distant IMT metastases are extremely uncommon. To our knowledge, metastatic spread to the heart has not been reported. We present a case of a 43-year-old woman with small intestinal IMT metastatic spread to the cavity of the left ventricle, stomach, liver, vertebra, and pelvic bones. The cardiac tumor was resected, and the patient survived for 9 months. She dies because the progression of IMT at other sites. PMID- 28007269 TI - Totally Endoscopic Coronary Artery Bypass for Anomalous Origin of Right Coronary Artery. AB - Anomalous origin of the right coronary artery (ARCA) from the left Valsalva sinus is a rare but known cause of sudden cardiac death. Surgical revascularization techniques include coronary artery bypass grafting, unroofing, and reimplantation. We report 4 patients who underwent robot-assisted totally endoscopic coronary artery bypass (TECAB) for ARCA as an alternative surgical option. In 3 patients, a single aortocoronary saphenous vein bypass was performed, and in 1 patient the right internal mammary artery was used. All grafts are patent as shown by computed tomographic angiography or cardiac catheterization. We claim that totally endoscopic coronary artery bypass is feasible and safe for anomalous origin of the right coronary artery. PMID- 28007270 TI - Implantation of a Left Ventricular Assist Device for Danon Cardiomyopathy. AB - This is the first report of Danon cardiomyopathy managed with a left ventricular assist device (LVAD). Danon disease is an X-linked dominant inheritance disorder. Heart failure with Danon cardiomyopathy results in a poor prognosis, and heart transplantation is the treatment of choice. We present two cases of successful implantation of an LVAD for Danon cardiomyopathy. Patient 1 was in the dilatated phase of hypertrophic cardiomyopathy (HCM) with Danon cardiomyopathy, and she underwent LVAD implantation. She is waiting for transplantation. Patient 2 had dilatated cardiomyopathy with Danon cardiomyopathy and received transplantation 990 days after LVAD implantation without myopathy or intellectual disability. PMID- 28007271 TI - Biatrial High-Grade Leiomyosarcoma With Nine-Year Post-Surgical Survival. AB - Primary cardiac leiomyosarcoma is a rare tumor with poor prognosis. We present a 53-year-old female patient with biatrial leiomyosarcoma with inferior vena cava and coronary sinus involvement who underwent aggressive surgical resection with reconstruction of her left and right atrium and coronary sinus with bovine pericardium followed by adjuvant radiation therapy. She is living well with no recurrence 9 years after diagnosis. PMID- 28007272 TI - Pulmonary Artery Dissection: A Case Treated by Homograft Replacement. AB - Pulmonary artery dissection was diagnosed in a 32-year-old man who was admitted to the emergency department with intense chest pain. He had a history of pulmonary balloon valvuloplasty for congenital pulmonary stenosis at the age of 7 and no pulmonary hypertension. The operation was performed with cardiopulmonary bypass. The dissected pulmonary arterial trunk was removed with the distorted valve, and replaced with a pulmonary artery homograft. The postoperative course was uneventful. Histologic examination revealed medionecrosis. Pulmonary artery dissection is a rare but highly lethal pathology. In the absence of pulmonary hypertension, surgical treatment with homograft replacement can lead to excellent results. PMID- 28007273 TI - Complete Resection of Masaoka Stage IVb Thymic Carcinoma After Chemoradiotherapy. AB - We report a case of Masaoka stage IVb thymic carcinoma that had metastasized to right supraclavicular lymph nodes, where it would have been difficult to achieve complete resection. Thus, we performed concurrent chemoradiotherapy, which decreased the tumor's size and facilitated complete resection. The patient had an uneventful postoperative course and 30 months of recurrence-free survival. Concurrent chemoradiotherapy followed by complete surgical resection may be a useful strategy in cases of stage IVb thymic carcinoma with supraclavicular lymph node metastasis. PMID- 28007274 TI - Survival Following Gastro-Left Ventricular Fistula in a Patient Post Roux-en-Y Gastric Bypass. AB - We report a case of a 55-year old woman with a prior roux-en-Y gastric bypass who survived after surgical repair of a gastro-left ventricular fistula. PMID- 28007275 TI - Atrioventricular Septum Pseudoaneurysm As Late Complication After Repeated Mitral Valve Replacement. AB - We report the case of a pulsatile mass found in a patient who presented for a routine echocardiogram. The mass turned out to be an exceedingly rare mitral subannular pseudoaneurysm involving the membranous atrioventricular septum with systolic expansion protruding into right atrium, discovered late after repeated multiple valve replacement surgery. Although these pseudoaneurysms may present asymptomatically, surgical intervention might be indicated because of the risk of rupture. This report describes this rare finding, discusses possible pathophysiological mechanisms, and underscores the importance of multimodality imaging to achieve correct identification and delimitation to guide surgical intervention in such cases. PMID- 28007276 TI - Mitral Valve Replacement With Sapien 3 Transcatheter Valve in Severe Mitral Annular Calcification. AB - Transcatheter valve implantation in the mitral position with severe calcific mitral stenosis has been described in patients who are at an increased risk for conventional mitral valve surgical procedures. We report the direct deployment of the Sapien 3 valve in the mitral position with severe mitral annular calcification through a sternotomy in an arrested heart in two cases. PMID- 28007277 TI - Random Finding of a Ruptured Kommerell Aneurysm After Stroke. AB - The random finding of a ruptured Kommerell aneurysm (rKA) is exceptional. We report the case of a 74-year-old man who received an incidental diagnosis of a contained rKA involving an aberrant right subclavian artery after a stroke. He underwent successful hybrid repair with the use of thoracic endovascular aortic repair associated with cervical debranching of the left subclavian artery and vascular plug occlusion of both subclavian artery origins. Whereas no early adverse event was reported, the patient experienced a vertebrobasilar insufficiency once he had recovered, requiring an additional right carotid-to subclavian bypass. PMID- 28007278 TI - The Surgical Repair of a Hyperimmunoglobulin E Syndrome Associated Ascending Aortic Aneurysm. AB - Hyperimmunoglobulin E syndrome (HIES) is an immunodeficiency disorder that manifests itself by affecting more than one system. Arterial aneurysms are among the significant complications associated with HIES. Surgical procedures for patients with such aneurysms are uncommon. In this study, we aim to present the case and surgical repair of a male child who was previously diagnosed with HIES and presented with rapidly expanding ascending aortic aneurysm. PMID- 28007279 TI - Recovery of a Missile Embolus From the Right Ventricle. AB - Missile embolism is a clinical entity in which a projectile object enters a blood vessel and is carried to a distant part of the body. We present a case of the discovery of an iliac vein to right ventricle missile embolus in a young man, with successful extraction through a right atriotomy. We provide a historical overview of the literature concerning missile embolism, and we argue that whereas acute embolized projectiles should be removed in almost all cases, it may be reasonable to simply observe an asymptomatic chronic missile embolus. PMID- 28007280 TI - A Papillary Fibroelastoma Involving Aortic and Pulmonary Valves: Findings on Multimodality Imaging. AB - Cardiac papillary fibroelastoma, a rare entity, is the second most common benign primary cardiac tumor. Commonly involving the cardiac valves, this entity is increasingly diagnosed using different imaging modalities. We present a rare case of simultaneous involvement of both the aortic and pulmonary valves in an asymptomatic patient who underwent different imaging modalities, including transthoracic and transesophageal echocardiography, nongated and gated computed tomography, and magnetic resonance imaging. We will discuss the imaging findings and differential diagnosis. PMID- 28007281 TI - Minimally Invasive Esophagectomy in a Patient With Tetralogy of Fallot and Right Sided Aortic Arch. AB - Improvements in surgical technique and perioperative care have resulted in increased long-term survival for patients with congenital heart disease. As these patients begin to reach their later years, clinicians are challenged with determining optimal management of noncardiac diseases in this complex patient population, including surgically treatable malignancies. We present a case of esophageal cancer in a patient with previously repaired tetralogy of Fallot and right-sided aortic arch, treated with neoadjuvant therapy followed by laparoscopic and left thoracoscopic esophagectomy. PMID- 28007282 TI - Anterior Mediastinal Myelolipoma. PMID- 28007283 TI - Posterior Mediastinal Cyst. PMID- 28007284 TI - Reverse Left Ventricular Remodeling Causing Severe Mitral Regurgitation After Bentall Procedure. PMID- 28007285 TI - Giant Thoracic Aortic Aneurysm Manifested as Dysphagia and Dyspnea. PMID- 28007286 TI - Hybrid Management of a Giant Left Main Coronary Artery Aneurysm. PMID- 28007287 TI - Cross-Reactivity Between Heparin and Danaparoid Antibodies in Cardiac Surgery. AB - Management of heparin-induced thrombocytopenia (HIT) entails cessation of heparin and initiation of a nonheparin parenteral anticoagulant such as danaparoid. Danaparoid cross-reactivity with HIT antibodies is an uncommon complication of treatment of HIT. We report the case of confirmed HIT and in vivo cross reactivity with danaparoid, complicating severe sepsis due to an infectious endocarditis treated by cardiac surgery. PMID- 28007288 TI - A Mitral Heart Valve Prosthesis Hidden Under Perivalvular Pannus. PMID- 28007289 TI - A New Method of Chest Drain Wound Closure Using Knotless Suture Material. AB - Removal of a chest tube drain could be distressful experience for many patients. Pain, unsightly scar, and possible complications such as pneumothorax are common after the removal of a chest tube. A new method of chest drain wound closure using knotless suture material has been employed, which could alleviate pain and unsightly scar. This suture utilizes a unidirectional anchoring barb, which eliminates the need to tie and does not slip back. This new method of wound closure for chest tube site is a convenient method with advantages of leaving a less unsightly scar and less pain during the chest tube removal process. PMID- 28007290 TI - Dacron Skirt Reconstruction of the Left Ventricular Outflow Tract: Extending the Capabilities of a Valved Conduit. AB - Aortic root reconstruction in the setting of redo aortic valve procedures or infective endocarditis may be technically challenging, particularly because of variable destruction or distortion of the left ventricular outflow tract. Homograft aortic root replacement is an excellent option for aortic root abscesses but is limited by homograft availability. We describe a simple technique of a bioprosthetic valved conduit constructed on the table using a Dacron (DuPont, Wilmington, DE) skirt below the valve. The use of the Dacron skirt facilitates easy reconstruction of the left ventricular outflow tract. PMID- 28007291 TI - [Complex regional pain syndrome: A review]. AB - BACKGROUND: Complex regional pain syndrome is characterized by spontaneous or induced pain disproportionate in relation to the initial event and is accompanied by a variety of regional and motor disturbances, leading to a variety of clinical presentations. It is often associated with surgery and minor trauma. PATHOPHYSIOLOGY: Three mechanisms are postulated: changes secondary to post traumatic inflammation, peripheral vasomotor dysfunction and structural and functional changes of the central nervous system as a result of maladaptation. DIAGNOSIS: made based on the criteria of Budapest. The patient must have one symptom and sign of each criterion at diagnosis: Continuing pain, disproportionate to any inciting event. A sensory, vasomotor, oedema and motor/trophic change sign and symptoms that are not explained by another diagnosis or cause. TREATMENT: Multimodal treatment is suggested. There is no gold standard. In early stage NSAIDs or steroids can be used. Drugs used for neuropathic pain treatment have been suggested, but there is not enough evidence for any of these. There is low evidence that bisphosphonates, calcitonin, ketamine and mirror therapy are effective compared to placebo. Interventional treatment should be stepped from epidural block, neurostimulation, intrathecal pump to experimental therapies in case of intractable pain. DISCUSSION: Although complex regional pain syndrome has been a recognized entity for over 100 years, no clear evidence exists for first-line treatments; however, new technologies that are applicable in complex regional pain syndrome treatment have been developed. PMID- 28007292 TI - A diagnostic approach to popliteal fossa masses. AB - There is a myriad of potential mass lesions that occur in the popliteal fossa, which present as palpable masses or are found incidentally on imaging. With a thorough knowledge and understanding of the appearances and locations of these different entities, one can narrow the differential diagnoses in the majority of cases. This will eliminate unnecessary additional investigations and enable a more rapid management. We present a review of frequently encountered and less common entities using an anatomical sieve, with the aim of providing a diagnostic approach to popliteal fossa masses. PMID- 28007293 TI - Centripetal and centrifugal forces in the moral circle: Competing constraints on moral learning. AB - The idea of the moral circle pictures the self in the center, surrounded by concentric circles encompassing increasingly distant possible targets of moral concern, including family, local community, nation, all humans, all mammals, all living things including plants, and all things including inanimate objects. The authors develop the idea of two opposing forces in people's moral circles, with centripetal forces pulling inward, urging greater concern for close others than for distant others, and centrifugal forces pushing outward, resisting "drawing the line" anywhere as a form of prejudice and urging egalitarian concern for all regardless of social distance. Review of the developmental literature shows very early emergence of both moral forces, suggesting at least partly intuitive bases for each. Moral education approaches favoring one force over the other are compared, to show how these forces can provide constraints on moral learning. Finally, the centripetal/centrifugal forces view is applied to current moral debates about empathy and about politics. The authors argue that this view helps us see how intercultural and interpersonal disagreements about morality are based in intrapersonal conflicts shared by all people. PMID- 28007294 TI - [The frequency of cancer in France: Most recent data and trends]. AB - We present and discuss recent data on the frequency of cancer in France and on cancer survival. In the male population, the incidence of prostate and head and neck cancers diminishes rapidly and the incidence of the other common cancers: lung and colorectal diminishes less markedly; cancer mortality decreases for most sites. In the female population, the incidence of breast cancer diminishes rapidly, the incidence of colorectal and uterus cancers diminish less markedly and the incidence of lung cancer increases very fast: the mortality trends are similar. Cancer survival has improved in the last 16 years but some of the improvements are an artifact induced by overdiagnosis. PMID- 28007296 TI - [Which recent results in Oncology and Hematology will have an impact on our practices? The point of vue of Bulletin du Cancer editorial board]. AB - Among the results presented at international congresses or published in scientific journals, which are those that have a real impact on daily practice? Every year, the editorial board of the Bulletin du Cancer proposes a selection of key data in oncology and hematology. The objective is to discuss results that change or reinforce the strategies in 2016 but also identify key information for our reflections in 2017. PMID- 28007295 TI - [Obesity and cancer]. AB - The proportion of people affected by obesity is increasing and this finding emphasizes several issues in oncology: obesity as a risk factor for cancer, prognostic value of obesity in cancer patients, nutritional assessment in overweight patients and impact of obesity on treatment management. It is important to remember the common underevaluation of malnutrition in overweight or obese patients. Every caregiver must be especially careful about the management of comorbidities in these patients. PMID- 28007298 TI - Benefit of Final Kissing Balloon Inflation Mandatory After Simple Crossover Stenting for Left Main Bifurcation Narrowing. AB - The role of final kissing balloon (FKB) inflation after simple crossover stenting in unprotected left main (LM) bifurcation stenosis remains unknown. From the Asan Medical Center-Left Main Revascularization (ASAN-MAIN) registry, 413 patients with LM bifurcation stenosis treated by simple crossover stenting with a drug eluting stent were identified. After simple crossover stenting, FKB inflation was performed in 95 patients (FKB group) and 318 patients finished the procedure without FKB (no-FKB group). The primary end points of the 2-year incidence of major adverse cardiac events (death, myocardial infarction, and left main target lesion revascularization [LM-TLR]) were similar between the FKB and no-FKB groups (12.5% vs 8.5%, p = 0.24). After adjustment, the risk of major adverse cardiac event was not significantly different between the FKB and the no-FKB groups (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.49 to 2.49; p = 0.82). The risk of death (HR 1.03, 95% CI 0.28 to 3.82; p = 0.98), the composite of death or myocardial infarction (HR 0.95, 95% CI 0.26 to 3.51; p = 0.96), or LM TLR (HR 1.32, 95% CI 0.46 to 3.75; p = 0.60) were not significantly different between groups. In conclusions, for the treatment for LM bifurcation stenosis, selective, not mandatory, FKB strategy after simple crossover stenting appears to be associated with a favorable outcome. PMID- 28007297 TI - Comparison of Outcomes of Staged Complete Revascularization Versus Culprit Lesion Only Revascularization for ST-Elevation Myocardial Infarction and Multivessel Coronary Artery Disease. AB - The management of noninfarct-related arteries in patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary disease (MVD) is still debated. We evaluated the prognostic impact of staged complete revascularization with percutaneous coronary intervention (PCI) in STEMI patients with MVD admitted to our hospital from 2005 to 2013. Patients undergoing staged complete revascularization (n = 300) were compared with 1:1 propensity score-matched patients with culprit lesion-only treatment (n = 300). We considered a composite primary end point of all-cause death, myocardial infarction, and urgent PCI. Secondary end points included components of the primary, cardiovascular death, any PCI excluding staged PCI. We also performed an analysis including only patients surviving at least 5 days. The median follow-up was 553 days. The primary end point occurred in 10.3% of patients in the staged complete revascularization group and in 16.3% of patients in the culprit lesion-only group (hazard ratio 0.61, 95% CI 0.38 to 0.95, p = 0.031). Although this difference was no longer significant when considering only the survivors at day 5, all-cause and cardiovascular mortalities were still reduced in the staged complete revascularization group. Complete revascularization was associated with a better outcome (hazard ratio 0.35, 95% CI 0.17 to 0.63, p = 0.005) if performed within 30 days of STEMI. In conclusion, compared with culprit lesion-only revascularization, in STEMI patients with MVD undergoing primary PCI, an approach of staged complete revascularization was associated with a better outcome. PMID- 28007300 TI - Method translation and full metadata transfer from thermal to differential flow modulated comprehensive two dimensional gas chromatography: Profiling of suspected fragrance allergens. AB - The possibility to transfer methods from thermal to differential-flow modulated comprehensive two-dimensional gas chromatographic (GC*GC) platforms is of high interest to improve GC*GC flexibility and increase the compatibility of results from different platforms. The principles of method translation are here applied to an original method, developed for a loop-type thermal modulated GC*GC-MS/FID system, suitable for quali-quantitative screening of suspected fragrance allergens. The analysis conditions were translated to a reverse-injection differential flow modulated platform (GC*2GC-MS/FID) with a dual-parallel secondary column and dual detection. The experimental results, for a model mixture of suspected volatile allergens and for raw fragrance mixtures of different composition, confirmed the feasibility of translating methods by preserving 1D elution order, as well as the relative alignment of resulting 2D peak patterns. A correct translation produced several benefits including an effective transfer of metadata (compound names, MS fragmentation pattern, response factors) by automatic template transformation and matching from the original/reference method to its translated counterpart. The correct translation provided: (a) 2D pattern repeatability, (b) MS fragmentation pattern reliability for identity confirmation, and (c) comparable response factors and quantitation accuracy within a concentration range of three orders of magnitude. The adoption of a narrow bore (i.e. 0.1mm dc) first-dimension column to operate under close-to optimal conditions with the differential-flow modulation GC*GC platform was also advantageous in halving the total analysis under the translated conditions. PMID- 28007299 TI - Size exclusion chromatography with superficially porous particles. AB - A comparison is made using size-exclusion chromatography (SEC) of synthetic polymers between fully porous particles (FPPs) and superficially porous particles (SPPs) with similar particle diameters, pore sizes and equal flow rates. Polystyrene molecular weight standards with a mobile phase of tetrahydrofuran are utilized for all measurements conducted with standard HPLC equipment. Although it is traditionally thought that larger pore volume is thermodynamically advantageous in SEC for better separations, SPPs have kinetic advantages and these will be shown to compensate for the loss in pore volume compared to FPPs. The comparison metrics include the elution range (smaller with SPPs), the plate count (larger for SPPs), the rate production of theoretical plates (larger for SPPs) and the specific resolution (larger with FPPs). Advantages to using SPPs for SEC are discussed such that similar separations can be conducted faster using SPPs. SEC using SPPs offers similar peak capacities to that using FPPs but with faster operation. This also suggests that SEC conducted in the second dimension of a two-dimensional liquid chromatograph may benefit with reduced run time and with equivalently reduced peak width making SPPs advantageous for sampling the first dimension by the second dimension separator. Additional advantages are discussed for biomolecules along with a discussion of optimization criteria for size-based separations. PMID- 28007301 TI - Low serum vitamin D, statin associated muscle symptoms, vitamin D supplementation. PMID- 28007302 TI - Can microRNAs improve prediction of abdominal aortic aneurysm growth? PMID- 28007303 TI - Innate immune regulation of autoimmunity in multiple sclerosis: Focus on the role of Toll-like receptor 2. AB - Innate immunity relies on a set of germline-encoded receptors including Toll-like receptors (TLRs) that enable the host to discriminate between self and non-self. Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS). Infections are thought to play an important role in disease susceptibility. The role of innate immunity in MS has been recently appreciated. TLR2, a member of the TLR family, forms heterodimers with either TLR1 or TLR6 and detects a wide range of microbial as well as self-derived molecular structures. It may thus be important both in fighting infection and in activating autoimmunity. In this review, we discuss innate regulation of autoimmunity in MS with a focus on the role of TLR2 signaling. PMID- 28007304 TI - Reply to "Don't throw the baby out with the bathwater: Appropriate or inappropriate shocks after implantable cardioverter-defibrillator". PMID- 28007305 TI - Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with chronic kidney disease: A systematic review and network meta-analysis. AB - BACKGROUND: Currently there is lack of head-to-head comparisons between different Non-Vitamin K Antagonist Oral Anticoagulants (NOACs), especially in more risky subgroups, as those with chronic kidney disease (CKD). METHODS: We assessed the relative efficacy and safety of the four NOACs on the market in a systematic review and network meta-analysis of patients with atrial fibrillation (AF) and moderate CKD enrolled in the phase 3 randomized trials. A Bayesian framework was used to perform the network meta-analysis. Treatment hierarchy was assessed by surface under the cumulative ranking (SUCRA) curves. RESULTS: Five randomized trials including 13,878 AF patients with moderate CKD were identified. Full/Single dose NOACs were associated with significant reductions in the odds of stroke/systemic embolism (odd ratio [OR] 0.79, 95% credible intervals [CrI] 0.67 0.94) and major bleeding (OR 0.74, 95% CrI 0.65-0.86) compared with Warfarin. Dabigatran 150 had the highest probability of being ranked first with respect to efficacy (SUCRA 0.96), whereas Apixaban had the second highest (SUCRA 0.67); Dabigatran 110, Rivaroxaban and Edoxaban High-Dose showed similar probabilities of being ranked first for efficacy (SUCRA 0.54, 0.53, 0.51, respectively); with respect to safety, only Apixaban and Edoxaban High Dose had a probability >50% of being ranked first (SUCRA 0.84 and 0.61, respectively). CONCLUSIONS: Indirect comparisons generated the hypothesis that Apixaban and Edoxaban High-Dose might be more likely associated with a better net clinical profile in AF patients with moderate CKD. These findings may potentially guide physicians in selecting the most appropriate NOAC for each patient, while waiting for dedicated evidences. PMID- 28007306 TI - A Quick Reference on Chloride. AB - Chloride is an essential element, playing important roles in digestion, muscular activity, regulation of body fluids, and acid-base balance. As the most abundant anion in extracellular fluid, chloride plays a major role in maintaining electroneutrality. Chloride is intrinsically linked to sodium in maintaining osmolality and fluid balance and has an inverse relationship with bicarbonate in maintaining acid-base balance. It is likely because of these close ties that chloride does not get the individual attention it deserves; we can use these facts to simplify and interpret changes in serum chloride concentrations. PMID- 28007307 TI - Human-Based Biological and Biomimetic Autologous Therapies for Musculoskeletal Tissue Regeneration. AB - Repairing and regenerating damaged musculoskeletal tissues is one of the greatest challenges in regenerative medicine. Blood contains the essential ingredients to biologically engineer drug delivery devices that provide spatiotemporal control over the availability of a wide range of autologous agents, including small molecules, cytokines, and growth factors. This opinion article summarizes our current knowledge of blood-derived biological drug delivery therapies. The potential mechanisms that control protein release are discussed, along with the biological rationale and effects of their use in different relevant musculoskeletal tissues, including articular cartilage, bone, tendon, muscle, and nerve tissue injuries. Finally, we finally describe the current challenges facing the field and recent advances that should drive novel solutions for the musculoskeletal system. PMID- 28007308 TI - A point-prevalence survey of healthcare-associated infection in fifty-two Chinese hospitals. AB - BACKGROUND: Healthcare-associated infection (HCAI) represents a major problem for patient safety worldwide. AIM: To demonstrate the prevalence, causative agents, and risk factors for HCAI in Chinese hospitals. METHODS: A one-day point prevalence survey was conducted in 52 Chinese hospitals between October 2014 and March 2015. A web-based software system was developed for data entry and management. FINDINGS: Among 53,939 patients surveyed, the prevalence of patients with at least one HCAI was 3.7%. Of 2182 HCAI episodes, the most frequently occurring types were lower respiratory tract infections (47.2%), followed by urinary tract infection (12.3%), upper respiratory tract infection (11.0%), and surgical site infection (6.2%). The prevalence of patients with at least one HCAI in critical care units was highest (17.1%). Device-associated infections, including ventilator-associated pneumonia, catheter-associated urinary tract infection, and central catheter-associated bloodstream infection, accounted for only 7.9% of all HCAIs. The most frequently isolated micro-organisms were Pseudomonas aeruginosa [206 infections (9.4%)], Acinetobacter baumannii [172 infections (7.9%)], Klebsiella pneumoniae [160 infections (7.3%)], and Escherichia coli [145 infections (6.6%)]. Of the survey patients (18,206/53,939), 33.8% were receiving at least one antimicrobial agent at the time of the survey. Risk factors for HCAI included older age (>=80 years), male gender, days of hospital admission, admission into a critical care unit, and device utilization. CONCLUSION: Our study suggests that the overall prevalence of HCAI in surveyed Chinese hospitals was lower than that reported from most European countries and the USA. More attention should be given to the surveillance and prevention of non device-associated HCAI in China. PMID- 28007309 TI - Differential declines in syphilis-related mortality in the United States, 2000 2014. AB - BACKGROUND: After reaching an all time low in 2000, the rate of syphilis in the United States has been steadily increasing. Parallel benchmarking of the disease's mortality burden has not been undertaken. METHODS: Using ICD-10 classification, all syphilis-related deaths in the national Multiple Cause of Death dataset were examined for the period 2000-2014. Descriptive statistics and age-adjusted mortality rates were generated. Poisson regression was performed to analyze trends over time. A matched case-control analysis was conducted to assess the associations between syphilis-related deaths and comorbid conditions listed in the death records. RESULTS: A total of 1,829 deaths were attributed to syphilis; 32% (n = 593) identified syphilis as the underlying cause of death. Most decedents were men (60%) and either black (48%) or white (39%). Decedents aged >=85 years had the highest average mortality rate (0.47 per 100,000 population; 95% confidence interval [CI], 0.42-0.52). For the sampled period, the average annual decline in mortality was -2.90% (95% CI, -3.93% to -1.87%). However, the average annual percent change varied across subgroups of interest. CONCLUSIONS: Declines in U.S. syphilis mortality suggest early detection and improved treatment access likely helped attenuate disease progression; however, increases in the disease rate since 2000 may be offsetting the impact of these advancements. PMID- 28007310 TI - Persistence of Zika virus in semen 93 days after the onset of symptoms. AB - INTRODUCTION: Zika virus is mainly transmitted through the bites of infected Aedes mosquitoes, although mother-to-child and sexual transmission have also been described. The presence of Zika virus in semen after infection seems to be not uncommon, but the duration of viral persistence has not been well-determined. METHODS: Molecular, serological and cell culture methods were used for the diagnosis and follow up of a case of Zika virus infection imported from Venezuela. Serial samples of serum, urine and semen were analyzed to investigate the persistence of the Zika virus. RESULTS: Zika virus was detected in semen samples up to 93 days after the onset of symptoms. CONCLUSIONS: Our results confirm the persistence of Zika virus in semen samples for long periods after infection. PMID- 28007311 TI - [Multivariate Adaptive Regression Splines (MARS), an alternative for the analysis of time series]. AB - Multivariate Adaptive Regression Splines (MARS) is a non-parametric modelling method that extends the linear model, incorporating nonlinearities and interactions between variables. It is a flexible tool that automates the construction of predictive models: selecting relevant variables, transforming the predictor variables, processing missing values and preventing overshooting using a self-test. It is also able to predict, taking into account structural factors that might influence the outcome variable, thereby generating hypothetical models. The end result could identify relevant cut-off points in data series. It is rarely used in health, so it is proposed as a tool for the evaluation of relevant public health indicators. For demonstrative purposes, data series regarding the mortality of children under 5 years of age in Costa Rica were used, comprising the period 1978-2008. PMID- 28007312 TI - [In favour of the pink ribbon and breast cancer prevention: various points of view]. PMID- 28007313 TI - Neuropsychological alterations and neuroradiological findings in patients with post-traumatic concussion: Results of a pilot study. AB - INTRODUCTION: Mild traumatic brain injury (mTBI) has traditionally been considered to cause no significant brain damage since symptoms spontaneously remit after a few days. However, this idea is facing increasing scrutiny. The purpose of this study is to demonstrate the presence of early cognitive alterations in a series of patients with mTBI and to link these findings to different markers of brain damage. METHODS: We conducted a prospective study of a consecutive series of patients with mTBI who were evaluated over a 12-month period. Forty-one (3.7%) of the 1144 included patients had experienced a concussion. Patients underwent a routine clinical evaluation and a brain computed tomography (CT) scan, and were also administered a standardised test for post concussion symptoms within the first 24hours of mTBI and also 1 to 2 weeks later. The second assessment also included a neuropsychological test battery. The results of these studies were compared to those of a control group of 28 healthy volunteers with similar characteristics. Twenty patients underwent an MRI scan. RESULTS: Verbal memory and learning were the cognitive functions most affected by mTBI. Seven out of the 20 patients with normal CT findings displayed structural alterations on MR images, which were compatible with diffuse axonal injury in 2 cases. CONCLUSIONS: Results from this pilot study suggest that early cognitive alterations and structural brain lesions affect a considerable percentage of patients with post-concussion syndrome following mTBI. PMID- 28007315 TI - Does the NBME Surgery Shelf exam constitute a "double jeopardy" of USMLE Step 1 performance? AB - BACKGROUND: Scores from the NBME Subject Examination in Surgery (Surgery Shelf) positively correlate with United States Medical Licensing Examination Step 1 (Step 1). Based on this relationship, the authors evaluated the predictive value of Step 1 on the Surgery Shelf. METHODS: Surgery Shelf standard scores were substituted for Step 1 standard scores for 395 students in 2012-2014 at one medical school. Linear regression was used to determine how well Step 1 scores predicted Surgery Shelf scores. Percent match between original (with Shelf) and modified (with Step 1) clerkship grades were computed. RESULTS: Step 1 scores significantly predicted Surgery Shelf scores, R2 = 0.42, P < 0.001. For every point increase in Step 1, a Surgery Shelf score increased by 0.30 points. Seventy seven percent of original grades matched the modified grades. CONCLUSION: Replacing Surgery Shelf scores with Step 1 scores did not have an effect on the majority of final clerkship grades. This observation raises concern over use of Surgery Shelf scores as a measure of knowledge obtained during the Surgery clerkship. PMID- 28007314 TI - Interspecies discrimination of A. fumigatus and siblings A. lentulus and A. felis of the Aspergillus section Fumigati using the AsperGenius(r) assay. AB - The AsperGenius(r) assay detects several Aspergillus species and the A. fumigatus Cyp51A mutations TR34/L98H/T289A/Y121F that are associated with azole resistance. We evaluated its contribution in identifying A. lentulus and A. felis, 2 rare but intrinsically azole-resistant sibling species within the Aspergillus section Fumigati. Identification of these species with conventional culture techniques is difficult and time-consuming. The assay was tested on (i) 2 A. lentulus and A. felis strains obtained from biopsy proven invasive aspergillosis and (ii) control A. fumigatus (n=3), A. lentulus (n=6) and A. felis species complex (n=12) strains. The AsperGenius(r) resistance PCR did not detect the TR34 target in A. lentulus and A. felis in contrast to A. fumigatus. Melting peaks for L98H and Y121F markers differed and those of the Y121F marker were particularly suitable to discriminate the 3 species. In conclusion, the assay can be used to rapidly discriminate A. fumigatus, A. lentulus and A. felis. PMID- 28007316 TI - Skill learning from kinesthetic feedback. AB - BACKGROUND: It is important for a surgeon to perform surgical tasks under appropriate guidance from visual and kinesthetic feedback. However, our knowledge on kinesthetic (muscle) memory and its role in learning motor skills remains elementary. OBJECTIVES: To discover the effect of exclusive kinesthetic training on kinesthetic memory in both performance and learning. METHODS: In Phase 1, a total of twenty participants duplicated five 2 dimensional movements of increasing complexity via passive kinesthetic guidance, without visual or auditory stimuli. Five participants were asked to repeat the task in the Phase 2 over a period of three weeks, for a total of nine sessions. RESULTS: Subjects accurately recalled movement direction using kinesthetic memory, but recalling movement length was less precise. Over the nine training sessions, error occurrence dropped after the sixth session. CONCLUSIONS: Muscle memory constructs the foundation for kinesthetic training. Knowledge gained helps surgeons learn skills from kinesthetic information in the condition where visual feedback is limited. PMID- 28007317 TI - Examining the role of follow-up skeletal surveys in non-accidental trauma. AB - BACKGROUND: Diagnosing NAT (non-accidental trauma) includes a skeletal survey to identify injuries. A follow-up survey is performed for missed injuries. This study examines the necessity of follow-up surveys. METHODS: The trauma database identified cases of suspected NAT in <4 years olds (2013-2014). Data were stratified by survey, age, injury, then analyzed for the prevalence of findings. All analyses (relative risk, prevalence and odds ratios) utilized RealStats Resource Pack (Trento, Italy). RESULTS: 79% positive initial findings and no new follow up findings. Those with negative initial imaging, had no missed injuries. Initial scans were 27.6X more likely to be positive. Fractured skull (31.3), femur (17.2) and ribs (15.7) were the most prevalent. No pelvic fractures and <1% spinal injuries despite both having the greatest radiation exposure. Repeat scans rarely identify findings for age >12 months. CONCLUSIONS: Follow-up skeletal surveys maybe unnecessary without clinical evidence. Uncommon pelvic and spinal fractures may warrant exclusion from surveys unless clinically indicated. PMID- 28007318 TI - Suberoylanilide hydroxamic Acid, a histone deacetylase inhibitor, alters multiple signaling pathways in hepatocellular carcinoma cell lines. AB - INTRODUCTION: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has preclinical efficacy in hepatocellular carcinoma (HCC), despite an unclear molecular mechanism. We sought to further investigate the effects of SAHA on HCC. We hypothesize SAHA will inhibit HCC cellular proliferation through apoptosis and aid in further profiling SAHA's effect on HCC oncogenic pathways. METHODS: HCC cell lines were treated with various concentrations of SAHA. Cell proliferation was determined by MTT and colonogenic assays. Cell lysates were analyzed via Western blotting for apoptotic and oncogenic pathway markers. Caspase glo-3/7 was used to assess apoptosis. RESULTS: SAHA treatment demonstrated significant (<0.05) reduction in cell growth and colony formation through apoptosis and cell cycle arrest. Western analysis showed reduction in Notch, pAKT and pERK1/2 proteins. Interestingly, phosphorylated STAT3 was increased in all cell lines. CONCLUSIONS: SAHA inhibits Notch, AKT, and Raf-1 pathways but not the STAT3 pathway. We believe that STAT3 may lead to cancer cell progression, reducing SAHA efficacy in HCC. Therefore, combination of SAHA and STAT or Notch inhibition may be a strategy for HCC treatment. PMID- 28007319 TI - Nasal flaring as a clinical sign of respiratory acidosis in patients with dyspnea. AB - OBJECTIVE: To determine whether the presence of nasal flaring is a clinical sign of respiratory acidosis in patients attending emergency departments for acute dyspnea. METHODS: Single-center, prospective, observational study of patients aged over 15 requiring urgent attention for dyspnea, classified as level II or III according to the Andorran Triage Program and who underwent arterial blood gas test on arrival at the emergency department. The presence of nasal flaring was evaluated by two observers. Demographic and clinical variables, signs of respiratory difficulty, vital signs, arterial blood gases and clinical outcome (hospitalization and mortality) were recorded. Bivariate and multivariate analyses were performed using logistic regression models. RESULTS: The sample comprised 212 patients, mean age 78years (SD=12.8), of whom 49.5% were women. Acidosis was recorded in 21.2%. Factors significantly associated with the presence of acidosis in the bivariate analysis were the need for pre-hospital medical care, triage level II, signs of respiratory distress, presence of nasal flaring, poor oxygenation, hypercapnia, low bicarbonates and greater need for noninvasive ventilation. Nasal flaring had a positive likelihood ratio for acidosis of 4.6 (95% CI 2.9-7.4). In the multivariate analysis, triage level II (aOR 5.16; 95% CI: 1.91 to 13.98), the need for oxygen therapy (aOR 2.60; 95% CI: 1.13-5.96) and presence of nasal flaring (aOR 6.32; 95% CI: 2.78-14.41) were maintained as factors independently associated with acidosis. CONCLUSIONS: Nasal flaring is a clinical sign of severity in patients requiring urgent care for acute dyspnea, which has a strong association with acidosis and hypercapnia. PMID- 28007320 TI - Transthoracic echocardiogram in syncope patients with normal initial evaluation: The criteria for an abnormal echocardiogram. PMID- 28007321 TI - A cautionary note on the use of lifetime attributable cancer risks in a low dose cohort. PMID- 28007322 TI - 2016 AHA/ACC Clinical Performance and Quality Measures for Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. PMID- 28007323 TI - ALPPS: The argument against. PMID- 28007324 TI - Renal angiomyolipomas: At least two diseases. A series of patients treated at two European institutions. AB - OBJECTIVE: The aim of this study is to analyze the outcome of renal angiomyolipomas (AML) at two European institutions. METHODS: The data were collected from patients with a primary AML who were treated at Gustave Roussy, Villejuif, France and Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy from 1998 to 2014. The specimens were classified as classic AML (C AML) or epithelioid AML (E AML) based on the percentage of epithelioid cells. RESULTS: There were 40 patients identified for the study (35 C AML, 5 E AML). One patient had an associated tuberous sclerosis complex. Six patients (15%) had bilateral AML. The imaging results were significantly different between C/E AML. E AML was associated with fewer bilateral lesions, more renal vein/vena cava extension, and more poor or non-fatty aspects. Surgery/active surveillance (AS)/chemo radiation were applied for 28/11/1 patients, respectively. The median tumor size was significantly smaller (3.75 cm) in patients receiving AS (median 15 cm when surgically resected). The median patient follow-up was 43 months. The three-year overall survival was significantly better for patients with C AML than E AML (100% versus 50%, p < 0.0001). The univariate analysis identified the OS prognostic factors were E AML histologic subtype (p < 0.001), poor/non fatty features (p = 0.002), and renal vein extension on imaging (p = 0.01). CONCLUSION: AML manifests as at least two different entities with significantly different outcomes. Epithelioid subtype, poor/non-fatty features, and renal vein involvement are all associated with worse survival. PMID- 28007325 TI - Influence of possible predictor variables on the outcome of primary oral squamous cell carcinoma: a retrospective study of 392 consecutive cases at a single centre. AB - The successful treatment of oral squamous cell carcinoma (OSCC) depends on the treatment strategy. The prognosis is most often linked to the stage at initial presentation, but the effect of patient-related parameters on overall survival remains uncertain. In this study, 392 consecutive cases of OSCC seen between 2007 and 2013 at a single centre were analyzed retrospectively. Overall survival was assessed and univariate and multivariate Cox proportional hazards regression was used to identify associations between possible tumour-specific and patient related variables and survival. The 5-year overall survival rate of the 392 patients (T stage 1-4) was 62.5%. Univariate analysis showed that sex, age, T stage, N stage, Union for International Cancer Control (UICC) stage, American Society of Anesthesiologists (ASA) status, operating time >400min, and length of in-patient stay >15 days were significantly associated with overall survival (all P<0.05). Tumour location, alcohol abuse, and smoking were found not to have a significant influence (all P>0.05). Age, T, N, and M stages, UICC stage, residual tumour status, recurrence, ASA status, and operating time >400min were found to have a significant influence on overall survival in the multivariate analysis (each P<0.05). These findings confirm that postoperative survival does not depend only on tumour-related characteristics. ASA status needs to be considered in treatment planning, as it significantly predicts patient survival. PMID- 28007327 TI - Isolated Mammillary Body Infarct Causing Global Amnesia: A Case Report. AB - OBJECTIVES: Mamillary bodies play an important role in human memory and emotions. Vascular lesions causing an isolated mammillary body lesion without affecting the surrounding structures are very rare. METHODS: A 53-year-old male was brought to the emergency department with acute-onset memory problems suggestive of partial anterograde and retrograde amnesia. RESULTS: Magnetic resonance imaging revealed an isolated left mammillary body infarct sparing adjacent structures. CONCLUSION: Mamillary bodies play an intrinsic role in memory formation and retrieval rather than acting as relay-only station for hippocampal projections. Non-hippocampal input from the limbic midbrain via the ventral tegmental nucleus of Gudden could be contributing to its function. PMID- 28007326 TI - Unilateral Vocal Fold Paralysis: A Systematic Review of Speech-Language Pathology Management. AB - OBJECTIVES: Dysphonia due to unilateral vocal fold paralysis (UVFP) can be characterized by hoarseness and weakness, resulting in a significant impact on patients' activity and participation. Voice therapy provided by a speech-language pathologist is designed to maximize vocal function and improve quality of life. The purpose of this paper is to systematically review literature surrounding the effectiveness of speech-language pathology intervention for the management of UVFP in adults. STUDY DESIGN: This is a systematic review. METHODS: Electronic databases were searched using a range of key terms including dysphonia, vocal fold paralysis, and speech-language pathology. Eligible articles were extracted and reviewed by the authors for risk of bias, methodology, treatment efficacy, and clinical outcomes. RESULTS: Of the 3311 articles identified, 12 met the inclusion criteria: seven case series and five comparative studies. All 12 studies subjectively reported positive effects following the implementation of voice therapy for UVFP; however, the heterogeneity of participant characteristics, voice therapy, and voice outcome resulted in a low level of evidence. CONCLUSIONS: There is presently a lack of methodological rigor and clinical efficacy in the speech-language pathology management of dysphonia arising from UVFP in adults. Reasons for this reduced efficacy can be attributed to the following: (1) no standardized speech-language pathology intervention; (2) no consistency of assessment battery; (3) the variable etiology and clinical presentation of UVFP; and (4) inconsistent timing, frequency, and intensity of treatment. Further research is required to develop the evidence for the management of UVFP incorporating controlled treatment protocols and more rigorous clinical methodology. PMID- 28007328 TI - Arterial Stiffness in Subacute Stroke: Changing Pattern and Relationship with Functional Recovery. AB - BACKGROUND: To examine changing patterns in arterial stiffness and functional outcome in patients with subacute stroke, and to determine which parameter shows a strong correlation with the reversal of arterial stiffness, during a 3-month period of comprehensive rehabilitation therapy. METHODS: This descriptive, observational cohort study enrolled 60 patients (43 male and 17 female; average age, 62.7 years), and all received conventional rehabilitation therapy, during a 3-month period. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Functional assessments included the 6-minute walk test (6MWT), Fugl-Meyer Assessment of hemiparetic upper and lower limbs, the functional ambulatory category, the Berg balance scale, the Korean Mini-Mental Status Examination, and the Korean-Modified Barthel Index. All measurements were conducted at baseline and 1 and 3 months after stroke onset. RESULTS: Rehabilitation therapy resulted in a statistically significant improvement in baPWV since 3 months post stroke. Another functional outcome measure showed statistically significant improvements since 1 month after rehabilitation. Multivariable linear regression analysis revealed that a change in baPWV was significantly correlated with changes in the 6MWT. CONCLUSIONS: Three months of comprehensive rehabilitation therapy led to statistically significant improvements in arterial stiffness and functional outcomes during the subacute phase of stroke. Thus, the comprehensive rehabilitation focused on improving gait endurance would be warranted in subacute stroke patients. PMID- 28007329 TI - Feasibility of Real-Time Intraprocedural Temperature Control during Bone Metastasis Thermal Microwave Ablation: A Bicentric Retrospective Study. AB - PURPOSE: To evaluate feasibility of using a thermocouple for temperature monitoring during microwave (MW) ablation of metastatic bone disease. MATERIALS AND METHODS: This retrospective study comprised 16 patients (8 men with mean age 63 y and 8 women with mean age 59 y) with 18 bone metastases treated with MW ablation using a thermocouple between March 2012 and October 2015. The mean maximum tumor size was 29.5 mm. MW ablation power was set between 15 W and 40 W and applied for 1-6 minutes. Thermocouple placements were as follows: epidural space (n = 7 cases), nerve roots (n = 9 cases), pleura (n = 1), and pericardium (n = 1). The procedure was considered technically successful when the MW and the thermocouple probes were accurately placed and thermoablation was initiated. Clinical success was defined as a 50% visual analog scale score decrease at 1 month as assessed by the operators. RESULTS: Mean MW ablation time was 4.3 minutes with a mean energy of 30 W. Procedural success was 100%. In 16 cases with neural structure monitoring, temperature did not increase > 43 degrees C. In 8 cases, MW ablation had to be discontinued because of temperature reaching 42 degrees C. Efficacy of the procedure in regard to pain was achieved in 17 of 18 ablation sessions at 1 month. CONCLUSIONS: Use of a thermocouple during bone MW ablation is a feasible technique and may be a potentially useful tool to help avoid nontarget ablation surrounding tumors. PMID- 28007330 TI - Clinical Outcomes of Transcatheter Arterial Embolization for Adhesive Capsulitis Resistant to Conservative Treatment. AB - PURPOSE: To evaluate clinical outcomes of transcatheter arterial embolization (TAE) for adhesive capsulitis resistant to conservative treatments. MATERIALS AND METHODS: This study comprised 25 patients (18 women and 7 men; mean age, 53.8 y; range, 39-68 y) with adhesive capsulitis resistant to conservative treatments. TAE was performed, and adverse events (AEs), pain visual analog scale (VAS) score changes, range of motion (ROM), and American Shoulder and Elbow Surgeons (ASES) scores were assessed. RESULTS: Abnormal vessels were identified in all patients. No major AEs were associated with TAE. One patient was lost to follow-up. The remaining 24 patients were available for final follow-up (mean, 36.1 months; range, 30-44 months). Of the 24 patients, 16 (67%) experienced quick improvement of nighttime pain (ie, VAS scores decreased > 50% from baseline) within 1 week, and 21 (87%) improved within 1 month. In terms of mean overall pain (ie, pain at its worst), VAS scores significantly decreased at 1, 3, and 6 months after treatment (82 mm before treatment vs 52, 19, and 8 mm after treatment; P < .001). ASES scores significantly improved at 1, 3, and 6 months after treatment (16.1 before treatment vs 41.4, 69.1, and 83.5 after treatment; P < .001). No symptom recurrence or late-onset AEs were observed. Shoulder ROM and function further improved during midterm follow-up. CONCLUSIONS: TAE is a possible treatment option for patients with adhesive capsulitis that has failed to improve with conservative treatments. PMID- 28007332 TI - Predictive Modeling of Response to Pregabalin for the Treatment of Neuropathic Pain Using 6-Week Observational Data: A Spectrum of Modern Analytics Applications. AB - PURPOSE: This post hoc analysis used 11 predictive models of data from a large observational study in Germany to evaluate potential predictors of achieving at least 50% pain reduction by week 6 after treatment initiation (50% pain response) with pregabalin (150-600 mg/d) in patients with neuropathic pain (NeP). METHODS: The potential predictors evaluated included baseline demographic and clinical characteristics, such as patient-reported pain severity (0 [no pain] to 10 [worst possible pain]) and pain-related sleep disturbance scores (0 [sleep not impaired] to 10 [severely impaired sleep]) that were collected during clinic visits (baseline and weeks 1, 3, and 6). Baseline characteristics were also evaluated combined with pain change at week 1 or weeks 1 and 3 as potential predictors of end-of-treatment 50% pain response. The 11 predictive models were linear, nonlinear, and tree based, and all predictors in the training dataset were ranked according to their variable importance and normalized to 100%. FINDINGS: The training dataset comprised 9187 patients, and the testing dataset had 6114 patients. To adjust for the high imbalance in the responder distribution (75% of patients were 50% responders), which can skew the parameter tuning process, the training set was balanced into sets of 1000 responders and 1000 nonresponders. The predictive modeling approaches that were used produced consistent results. Baseline characteristics alone had fair predictive value (accuracy range, 0.61 0.72; kappa range, 0.17-0.30). Baseline predictors combined with pain change at week 1 had moderate predictive value (accuracy, 0.73-0.81; kappa range, 0.37 0.49). Baseline predictors with pain change at weeks 1 and 3 had substantial predictive value (accuracy, 0.83-0.89; kappa range, 0.54-0.71). When variable importance across the models was estimated, the best predictor of 50% responder status was pain change at week 3 (average importance 100.0%), followed by pain change at week 1 (48.1%), baseline pain score (14.1%), baseline depression (13.9%), and using pregabalin as a monotherapy (11.7%). IMPLICATIONS: The finding that pain changes by week 1 or weeks 1 and 3 are the best predictors of pregabalin response at 6 weeks suggests that adhering to a pregabalin medication regimen is important for an optimal end-of-treatment outcome. Regarding baseline predictors alone, considerable published evidence supports the importance of high baseline pain score and presence of depression as factors that can affect treatment response. Future research would be required to elucidate why using pregabalin as a monotherapy also had more than a 10% variable importance as a potential predictor. PMID- 28007333 TI - [Social determinants of contraceptive use in Tunisia]. AB - BACKGROUND: In Tunisia, the "Revolution" of January 2011 highlighted significant regional disparities and social inequalities in access to health care, including reproductive health services. The purpose of this study was to analyze the social determinants of the use of contraception in Tunisia. METHODS: A cross-sectional national study conducted in 2012; on a sample of 15 to 49-year married women (n=4374) drawn by a two levels random sampling. Prevalence of contraception and its association factors were assessed. Logistic regression was used to evaluate the variation of contraception prevalence with area of residence, age, level of education, number of children and household income. RESULTS: The prevalence of contraception was 66.4 %. Eighty-two percent of women used a modern contraceptive method. The use of contraceptive methods was significantly dependent on the age (P<0.001), area of residence (P=0.008), education (P<0.001). The prevalence of contraception was higher in North West (OR=1.1 [0.81-1.5]; P<0.001), among multiparous women (OR=4.49 [3.57-5.66]; P<0.001), among the youngest women (OR=1.4 [0.9-2,19]; P<0.001) and among those with higher levels of education (OR=1.62 [1.19-2.21]; P=0.008). CONCLUSION: Tunisia, precursor Arab country in family planning, is recording a slowdown in the use of contraception in comparison with other countries of North Africa. Social determinants, such as, age, living conditions, area of residence and level of education are indicators to consider when targeting interventions. PMID- 28007331 TI - Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk. AB - PURPOSE: The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed. FINDINGS: The percentage change of LDL-C ranged from -45% to -56% (mean, -51%) in the monotherapy groups and from -58% to -63% (mean, -60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P < 0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy groups and 87% to 95% (mean, 91%) in the combination groups (P = 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups. IMPLICATIONS: Rosuvastatin/ezetimibe combination therapy has better efficacy and target achievement rates than rosuvastatin monotherapy in patients with high cardiovascular risk. PMID- 28007334 TI - Microarray analysis of long noncoding RNA expression patterns in diabetic nephropathy. AB - AIMS: Long noncoding RNAs (lncRNAs) are implicated in various biological processes and human diseases. Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). We explored the potential functions of lncRNAs in DN. METHODS: We established a mouse model of DN and compared lncRNA expression patterns between DN model and db/m control mouse kidney tissues using microarray analysis. lncRNA function was predicted by gene ontology enrichment and KEGG pathway analyses of lncRNAs-coexpressed mRNAs. Quantitative reverse-transcription PCR was used for validation. Cis- and trans-regulation analyses were conducted to reveal potential relationships between lncRNAs and their target genes. RESULTS: In DN, 311 lncRNAs were dysregulated. LncRNA-coexpressed mRNAs were mainly targeted to golgi apparatus (ontology: cellular component), catalytic activity (ontology: molecular function), and mitotic nuclear division (ontology: biological process), and were mostly enriched in glutathione metabolism signaling. One hundred forty-seven lncRNAs were regarded as cis-regulatory. Several groups of lncRNAs may participate in biological pathways related to DN via trans-regulation of protein-coding genes. CONCLUSION: Hundreds of lncRNAs are dysregulated in DN. These lncRNAs might be involved in the pathogenesis of DN by modulating multiple molecular pathways. Our findings provide potential candidate biomarkers for predicting or diagnosing DN. PMID- 28007336 TI - The combined frequency of IGF and myostatin polymorphism among track & field athletes and swimmers. AB - OBJECTIVE: The IGF C-1245T (rs35767) and the myostatin (MSTN) Lys(K)-153Arg(R) genetic polymorphism may influence skeletal muscle phenotypes and athletic performance. Carrying the minor IGF T allele and the myostatin rare R allele was associated with higher circulating IGF-I levels, greater muscle mass and improved performance. The aim of the present study was to assess the combined frequency of the IGF 1245T (rs35767) and MSTN 153Arg(R) polymorphism among Israeli track and field athletes (n=111) and swimmers (n=80). DESIGN: Track & field athletes were divided to long distance runners (major event 5000m-marathon, n=63) and power athletes (major event 100-200m sprints and long jump, n=48). Swimmers were divided into long-distance swimmers (major event: 400-1500m, n=38), and short distance swimmers (major event: 50-100m, n=42). RESULTS: Carrying both mutations was significantly higher (p<0.05) among long distance runners (LDR, 17%) compared to short distance runners (SDR, 10%), long distance swimmers (LDS, 8%), short distance swimmers (SDS, 2%) and controls (n=111, 7%). Carrying both mutations was significantly higher (p<0.05) among LDS compared to SDS (8% versus 2%, p<0.05). Among LDR and LDS carriers of both mutations, 40% and 25% were of elite level, respectively. Despite the fact that carrying both mutations among SDR and SDS was not greater than controls, all SDR and SDS carriers were elite athletes. CONCLUSION: Our finding suggests that carrying both IGF 1245T and MSTN 153Arg(R) polymorphisms may contribute for long distance running success but not necessarily to elite performance. In contrast, although the frequency was not higher than the general population, all carriers of both mutations among short distance runners and swimmers were of elite competitive caliber. Whether evaluation of the IGF 1245T and MSTN 153R polymorphism can be used for sports selection in young athletes needs to be further studied. PMID- 28007335 TI - Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl l-glutamate on mutant CPS1 enzymes. AB - This study documents the disparate therapeutic effect of N-carbamyl-l-glutamate (NCG) in the activation of two different disease-causing mutants of carbamyl phosphate synthetase 1 (CPS1). We investigated the effects of NCG on purified recombinant wild-type (WT) mouse CPS1 and its human corresponding E1034G (increased ureagenesis on NCG) and M792I (decreased ureagenesis on NCG) mutants. NCG activates WT CPS1 sub-optimally compared to NAG. Similar to NAG, NCG, in combination with MgATP, stabilizes the enzyme, but competes with NAG binding to the enzyme. NCG supplementation activates available E1034G mutant CPS1 molecules not bound to NAG enhancing ureagenesis. Conversely, NCG competes with NAG binding to the scarce M792I mutant enzyme further decreasing residual ureagenesis. These results correlate with the respective patient's response to NCG. Particular caution should be taken in the administration of NCG to patients with hyperammonemia before their molecular bases of their urea cycle disorders is known. PMID- 28007338 TI - Cochlear implantation for deafness and deep brain stimulation for movement disorders in children; lessons in shared learning. PMID- 28007337 TI - Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia. AB - BACKGROUND: Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q type) channel alpha1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA). METHODS: We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy. RESULTS: De novo missense mutations of CACNA1A were found in four patients (4/48, ~8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases. CONCLUSION: Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias. PMID- 28007339 TI - A framework for paediatric neuromodulation - Recognising the challenges and a platform for data sharing. PMID- 28007340 TI - Reply to "Prevalence and impact of irritable bowel syndrome in people with epilepsy: Methodological issues". PMID- 28007341 TI - Better late than never: PrEP in England. PMID- 28007342 TI - Will President Trump protect his party's PEPFAR legacy? PMID- 28007343 TI - Family planning for HIV-positive girls and young women. PMID- 28007344 TI - Introducing optimism to models of resource allocation to reduce HIV incidence. PMID- 28007345 TI - Introducing optimism to models of resource allocation to reduce HIV incidence - Authors' reply. PMID- 28007346 TI - A statement on the war in Syria from SIAARTI and partners. PMID- 28007347 TI - Automated insulin delivery: what's new, needed, and next? PMID- 28007349 TI - The temporalis muscle flap for reconstruction of soft palate and lateral oropharyngeal wall after transoral robotic surgery. AB - Trans Oral robotic surgery (TORS) is a prominent surgical approach for the resection of oropharyngeal tumors without division of the lip and mandible. The current practice following TORS is to allow the defect to heal by secondary intention, but some defects following TORS are large and complex enough to benefit soft-tissue coverage. In the free flap era, regional flaps are often overlooked albeit they still represent a valid alternative. In terms of cost effectiveness, the use of alternative pedicled flaps in TORS framework probably reduced the risks of postoperative complications, with consequent expenditure restraints and reducing treatment costs arising from operating room duration and double surgical team. In this report we described the successfully use of the pedicled temporalis muscle flap for the reconstruction of the soft palate and lateral pharyngeal wall following TORS. This versatile and reliable flap may be a valid option in TORS framework. PMID- 28007350 TI - Characteristics and course of chronic hepatitis B e antigen-negative infection. AB - OBJECTIVE: To describe the epidemiological, analytical and histological characteristics and clinical course of hepatitis B virus (HBV) carriers with negative HBe antigen. MATERIAL AND METHODS: Observational, retrospective cohort study of HBV carriers with negative HBe antigen (2005-2012), with no other causes of liver disease. RESULTS: One hundred and thirty-eight patients were included, with mean age 40.5+/-12.2 years; 54% were women, and 38% were of foreign origin; the number of foreign patients significantly increased (P<.001) over the years. Transaminases were normal in nearly 75% and HBV-DNA was <2,000IU/ml in 56% of patients at diagnosis. There was a gradual decrease in HBV-DNA levels in inactive carriers over the study period. Fibrosis study was performed in 47% of patients by Fibroscan(r) or liver biopsy: 55.4% normal histology and 6.1% cirrhosis. Just over three quarters of patients (77.77%) were inactive carriers. Treatment was required in 15.5% of patients (20% because of cirrhosis and 80% HBeAg-negative chronic hepatitis B). Five patients cleared HBsAg (annual rate .94%), all of whom presented HBV-DNA <2,000IU/ml at diagnosis. Five patients developed complications (3.6%), 4 of them hepatocellular carcinoma (HCC), of which only 2 had cirrhosis. There was 1 HBV-related death (.72%). CONCLUSION: Among HBV carriers with negative HBe antigen, inactive HBs-Ag carriers are predominant. HBV-DNA gradually decreases in the first few years after diagnosis. Morbidity and mortality are low, especially if glutamic pyruvic transaminase (GPT) is normal and HBV-DNA levels are low at diagnosis. Treatment is needed in a considerable number of patients. HCC is the most frequent complication, even in the absence of cirrhosis. PMID- 28007351 TI - Evaluation of a Computerized Self-Management Tool for Children with Type 1 Diabetes: A Pilot Project. PMID- 28007348 TI - Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial. AB - BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3.3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7.8 mmol/L (SD 0.6) in the bionic pancreas period versus 9.0 mmol/L (1.6) in the comparator period (difference 1.1 mmol/L, 95% CI 0.7-1.6; p<0.0001), and the mean time with CGM glucose concentration less than 3.3 mmol/L was 0.6% (0.6) in the bionic pancreas period versus 1.9% (1.7) in the comparator period (difference 1.3%, 95% CI 0.8 1.8; p<0.0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0.52 [SD 0.83]) than in the comparator period (0.05 [0.17]; difference 0.47, 95% CI 0.21-0.73; p=0.0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences. PMID- 28007352 TI - Esophageal cancer in high-risk areas of China: research progress and challenges. AB - PURPOSE: The extremely high incidence of esophageal cancer in certain rural areas of China has prompted significant intellectual curiosity and research efforts both in China and abroad. METHODS: We summarize the research progress over the past several decades in high-risk areas (Linxian, Cixian, Shexian, and Yanting) based on literature research and our field trip (2012-2013). RESULTS: Considerable progress in clarifying the environmental risk factors and pathogenesis of esophageal cancer in high-risk areas has been achieved over the past several decades. Epidemiologic evidence suggests that carcinogen exposure and nutritional deficiency, rather than smoking and drinking, may be the major risk factors for esophageal cancer in the Taihang Mountains region, where the incidence of esophageal cancer is among the highest in the world. Two genome-wide association studies have identified variants in PLCE1 at 10q23 that are significantly associated with esophageal cancer risk. Recent whole-exome studies have revealed a comprehensive mutation pattern, in which the C>T transition is the predominant mutation type. CONCLUSIONS: Despite extensive research, the main causative factors that contribute to esophageal cancer in high-risk areas have not yet been elucidated. Challenges in this research area include determining the causative role of nitrosamine, identifying other potential carcinogens, and conducting fruitful international collaborative studies based on a multidisciplinary approach. Increased international collaboration will contribute to a better understanding of the etiology of esophageal cancer. PMID- 28007353 TI - Impact of obstructive sleep apnea on severe asthma exacerbations. AB - BACKGROUND: Patients with asthma have a higher incidence of obstructive sleep apnea (OSA). However, the association between OSA and the exacerbation of severe asthma remains unclear. In this study, we aimed to investigate the prevalence of OSA in a cross-sectional study of asthma patients and to prospectively examine the significance of the effect of OSA on severe asthma exacerbations. METHODS: One hundred and forty-six patients with asthma and 157 matched-controlled individuals were enrolled in this study. The patients with asthma were prospectively studied for one year, and exacerbation episodes were identified based on the patients' medical histories. Lung function and the percentages of eosinophils in induced sputum samples were determined, and the frequencies of severe asthma exacerbations during the previous year were evaluated in the group of patients with asthma. RESULTS: The rates of OSA were 19.2% (28/146) among the patients with asthma and 9.6% (15/157) among the control individuals (p = 0.016). The frequency of severe asthma exacerbations was significantly higher among the asthma patients with OSA compared with those who did not have OSA (p < 0.001). The apnea-hypopnea index (AHI) correlated significantly with the number of severe asthma exacerbations (r = 0.507, 95% confidence interval [CI] 0.357-0.637, p < 0.001). Logistic regression analyses determined that the AHI was significantly associated with the occurrence of severe asthma exacerbations (odds ratio 1.322, 95% CI 1.148-1.523, p < 0.001). CONCLUSIONS: Patients with asthma had a high prevalence of OSA, which was an important factor associated with severe asthma exacerbations. PMID- 28007354 TI - Gut epithelial barrier markers in patients with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is now being recognized as an additional contributing factor to the pathogenesis of obesity-related comorbidities. At the same time, there is now increasing evidence to suggest that intestinal wall permeability plays a role in the development of metabolic syndrome. In the present study, circulating zonulin and fatty acid binding protein (I-FABP) were measured in association with metabolic, hepatic, and inflammatory parameters. RESULTS: Compared with controls, plasma I-FABP levels were significantly higher in patients with OSA (571 pg/mL [IQR 290-950] vs 396 pg/mL [IQR 234-559], p = 0.04). Zonulin levels were similar between groups. Significant relationships were observed between zonulin levels and waist circumference (p < 0.05), glucose (p < 0.05), and insulin (p < 0.05). In addition, in the OSA group, zonulin levels correlated negatively with the mean nocturnal oxygenation saturation (p < 0.05) and positively with total cholesterol (p < 0.05), alanine aminotransferase (ALT) (p < 0.005), aminotransferase (AST) (p < 0.01), gamma glutamyltransferase (GGT) (p < 0.005), and high-sensitivity C reactive protein (hs-CRP) (p < 0.05). Multivariate analysis showed that associations between zonulin and ALT, AST, and hs-CRP were attenuated, but not eliminated, after adjustment for other variables. CONCLUSIONS: The results of this study suggest that OSA is a risk factor for intestinal damage, regardless of metabolic profile, and that intestinal permeability might be a possible contributor to nonalcoholic fatty liver disease in patients with OSA. PMID- 28007355 TI - Isolated rapid eye movement sleep without atonia in amyotrophic lateral sclerosis. AB - OBJECTIVE: The aim of this study was to quantitatively analyze, with the most recent and advanced tools, the presence of periodic leg movements during sleep (PLMS) and/or rapid eye movement (REM) sleep without atonia (RSWA), in a group of patients with amyotrophic lateral sclerosis (ALS), and to assess their eventual correlation with the clinical severity of the disease. METHODS: Twenty-nine ALS patients were enrolled (mean age 63.6 years) along with 28 age-matched "normal" controls (mean age 63.8 years). Functional impairment due to ALS was evaluated using the ALS-Functional Rating Scale-Revised (ALS-FRS) and the ALS severity scale (ALSSS). Full video polysomnographic night recordings were obtained, and PLMS were analyzed by considering their number/hour of sleep and periodicity index, the distribution of intermovement intervals, and the distribution during the night. The characteristics of the chin electromyogram (EMG) amplitude during REM sleep were analyzed by means of the automatic atonia index and the number of chin EMG activations (movements). RESULTS: The ALS patients showed longer sleep latency than the controls, together with an increase in number of stage shifts, increased sleep stage 1, and decreased sleep stage 2. None of the leg PLMS parameters were different between the ALS patients and controls. The REM atonia index was significantly decreased in the ALS patients, and the number of chin movements/hour tended to increase. Both REM atonia index and number of chin movements/hour correlated significantly with the ALS-FRS; REM atonia was higher and chin movements were less in ALS patients with more preserved function (higher scores on the ALS-FRS). CONCLUSION: Abnormal REM sleep atonia seemed to be a genuine effect of ALS pathology per se and correlated with the clinical severity of the disease. It is unclear if this might constitute the basis of a possible risk for the development of REM sleep behavior disorder or represent a form of isolated RSWA in ALS. PMID- 28007356 TI - The AASM 2012 recommended hypopnea criteria increase the incidence of obstructive sleep apnea but not the proportion of positional obstructive sleep apnea. AB - OBJECTIVE/BACKGROUND: This study compared the effects of using the 2007 and 2012 American Academy of Sleep Medicine (AASM) recommended hypopnea criteria on the proportion of positional obstructive sleep apnea (pOSA). The effect of modifying the minimum recording time in each sleeping position on the proportion of pOSA was also investigated. PATIENTS/METHODS: 207 of 303 consecutive patients (91 of 207 were female) participated in polysomnography (PSG) for the suspicion of OSA met the inclusion criteria for this retrospective investigation. PSGs were scored for both the 2007 AASM recommended hypopnea criteria (AASM2007Rec) and the 2012 AASM recommended hypopnea criteria (AASM2012Rec). For each hypopnea criteria OSA patients were grouped as positional [either supine predominant OSA (spOSA) or supine independent OSA (siOSA)] or non-positional. Outcome measures such as SF 36, FOSQ, PVT, and DASS-21 were compared between groups. RESULTS: The AASM2012Rec increased the incidence of OSA compared to AASM2007Rec (84% vs 49% respectively). AASM2012Rec increased the number of patients with supine predominant OSA (spOSA) and supine independent OSA (siOSA) but did not change the proportion (spOSA: 61% AASM2012Rec vs 61% AASM2007Rec, siOSA: 32% AASM2012Rec vs 36% AASM2007Rec). OSA patients diagnosed by AASM2007Rec criteria had similar outcome measures to those diagnosed by the AASM2012Rec criteria. The AASM2012Rec increased the proportion of female OSA patients with spOSA and siOSA. A minimum recording time of 60 minutes in each position decreased the proportion of spOSA, but not siOSA patients when compared to a minimum time of 15 minutes. CONCLUSIONS: This study demonstrates that, compared to AASM2007Rec, AASM2012Rec almost doubles the incidence of OSA but does not alter the proportion of OSA patients with pOSA. The proportion of female OSA patients with pOSA however, increases as a result of AASM2012Rec. Furthermore, the use of different minimum recording times in each sleeping position can alter the proportion of spOSA. PMID- 28007357 TI - The U-shaped association between self-reported sleep duration and visual impairment in Korean adults: a population-based study. AB - OBJECTIVE: This study aimed to investigate the association between self-reported sleep duration and visual impairment (VI) in Korean adults. METHODS: This population-based, cross-sectional study examined ophthalmologic data of 16,374 Koreans aged 19 years and older from the 2010-2012 Korea National Health and Nutrition Examination Survey (KNHNES V). VI data (best-corrected distance visual acuity worse than 0.5 logMAR in the better-seeing eye) were obtained from direct ophthalmologic examinations, and data on self-reported sleep duration (<=5, 6, 7, 8, or >=9 h/night) were obtained using questionnaires. Multiple logistic regression analysis was conducted to examine the association between self reported sleep duration and VI, and we also adjusted for possible covariates. RESULTS: The weighted VI prevalences (95% CIs) were 1.23% (0.70-1.76), 0.40% (0.10-0.70), 0.18% (0.04-0.31), 0.42% (0.26-0.58), and 0.66% (0.25-1.07) for participants who slept <=5, 6, 7, 8, and >=9 h/night, respectively. Even after adjusting for demographic factors (age and sex), lifestyle factors (household income, occupation, smoking status, regular exercise, and suicidal thoughts), and medical factors (diabetes, hypertension, stroke, and history of ocular surgery), greater risk of VI was found in the <=5 h/night (OR = 3.23, 95% CI: 1.43-7.31) and >=9 h/night (OR = 2.56, 95% CI: 1.03-6.41) groups, compared to the 7 h/night group. CONCLUSIONS: In Korean adults, self-reported sleep duration and VI exhibited a U-shaped association. Both very short (<=5 h/night) and very long (>=9 h/night) sleep durations were significantly associated with increased VI. PMID- 28007358 TI - Hypnic jerks are an underestimated sleep motor phenomenon in patients with parkinsonism. A video-polysomnographic and neurophysiological study. AB - INTRODUCTION: Hypnic jerks (HJs) are sudden contractions of one or more body segments occurring mostly at sleep onset. They are highly sporadic and affect all ages and both sexes with prevalence between 60% and 70% in the general population. STUDY OBJECTIVES: This study describes the frequency and the neurophysiological characteristics of HJs in a population of patients with parkinsonism by means of nocturnal video-polysomnographic recordings. METHODS: This is a prospective cohort study and is reported following the STROBE guidelines. We analyzed the clinical and video-polysomnographic data of the first 66 consecutive patients recruited in the ongoing prospective study "Bologna motor and non-motor Prospective study on Parkinsonism at onset" (BoProPark). Each patient underwent a full neurological workup including a whole-night video- polysomnography. Neurophysiological characteristics including the propagation patterns of the HJs were studied with an extended muscle montage polysomnography. RESULTS: We recorded a total of 62 HJs in 16 patients out of 66 (24%). Sleep parameters were not statistically different between patients with and without HJs. All HJs were spontaneous and occurred randomly throughout the night. Electromyographic analysis showed that muscle activity arose from different muscles with no prevalence of one over the other and without any ordered propagation. No recurring motor pattern of the jerks was detected. DISCUSSION AND CONCLUSIONS: Our findings demonstrated that HJs are a frequent, underestimated, sleep-related motor phenomenon in patients with parkinsonism. As they may represent a further cause of sleep disruption and insomnia, HJs should be actively examined. Neurophysiological analysis suggests a subcortical origin of HJs as shown previously for a healthy subject. PMID- 28007359 TI - Neurocognitive function in patients with residual excessive sleepiness from obstructive sleep apnea: a prospective, controlled study. AB - OBJECTIVE: This study aimed to evaluate neurocognitive function in adult patients with residual excessive sleepiness (RES) after appropriate treatment of obstructive sleep apnea (OSA) with CPAP and good adherence to treatment. METHODS: This was a prospective controlled study. We included patients of both sexes, aged 35-60 years with OSA and an apnea-hypopnea index >20 ev/h, effectively treated with CPAP, but with a residual Epworth Sleepiness Scale score >=11. The control group consisted of OSA patients adequately treated with CPAP who did not present with excessive sleepiness after treatment. Both groups underwent the following evaluations: polysomnography, multiple sleep latency testing, depression symptoms, and cognitive assessment. RESULTS: Regarding baseline characteristics, the data were matched for age, years of study, and body mass index. Long-term memory result did not show a significant difference between the two groups (RES group 4.7 +/- 2.0; control group 6.5 +/- 1.9; p = 0.08). The executive functions were the most affected, with alterations in Wisconsin test, number of categories (RES group: 1.6 +/- 1.4; control group: 3.0 +/- 1.4; p = 0.01), and semantic verbal fluency test (RES group: 13.6 +/- 3.3; control group: 16.9 +/- 4.3; p = 0.04). CONCLUSION: In summary, the mean depression scale score in the group with residual excessive sleepiness was significantly higher than that in the control group. Patients with residual excessive sleepiness showed impairment of executive functions but no impairments in other cognitive domains. PMID- 28007360 TI - Protective and risk factors associated with adolescent sleep: findings from Australia, Canada, and The Netherlands. AB - BACKGROUND: Sleep is vital for adolescent functioning. Those with optimal sleep duration have shown improved capacity to learn and decreased rate of motor vehicle accidents. This study explored the influence of numerous protective and risk factors on adolescents' school night sleep (bedtime, sleep latency, total sleep time) simultaneously to assess the importance of each one and compare within three countries. METHOD: Online survey data were collected from Australia, Canada, and The Netherlands. Overall, 325 (137 male), 193 (28 male), and 150 (55 male) contributed to data from Australia, Canada, and The Netherlands, respectively (age range 12-19 years). RESULTS: Regression analyses showed mixed results, when comparing protective and risk factors for sleep parameters within different countries, with combined behavioural factors contributing to small to large shared portions of variance in each regression (9-50%). One consistent finding between countries was found, with increased pre-sleep cognitive emotional sleep hygiene related to decreased sleep latency (beta = -0.25 to -0.33, p < 0.05). Technology use (mobile phone/Internet stop time) was associated with later bedtime, or less total sleep, with the strength of association varying between device and country. CONCLUSION: Results indicate that when designing interventions for adolescent sleep, multiple lifestyle factors need to be considered, whereas country of residence may play a lesser role. PMID- 28007361 TI - A Perfect Storm: Tyrosine Kinase Inhibitor-Associated Polymorphic Ventricular Tachycardia. AB - BACKGROUND: Oral tyrosine kinase inhibitors (TKIs) are becoming increasingly common in oncology practice due to ease of administration and patient preference. This class of medications is relatively unknown to emergency physicians. CASE REPORT: Here we present a case of electrical storm (ES) thought to be associated with ibrutinib, a TKI. The ES was unabated despite antidysrhythmic therapy and electrical cardioversion, and was treated with supportive care, which eventually included the use of extracorporeal membrane oxygenation. This patient had no risk factors or apparent causes of recurrent ventricular tachycardia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ES has not previously been described with ibrutinib, but may be associated with off-target effects of the drug. PMID- 28007362 TI - Best Clinical Practice: Controversies in Outpatient Management of Acute Pulmonary Embolism. AB - BACKGROUND: Pulmonary embolism (PE) is a common condition managed in the emergency department (ED), with a wide range of morbidity and mortality. Patients are classically admitted for treatment and monitoring of anticoagulation. OBJECTIVE: We sought to evaluate the controversy concerning outpatient therapy for patients with acute PE and investigate the feasibility, safety, and efficacy of outpatient management. DISCUSSION: Patients with venous thromboembolism have historically been admitted for treatment and monitoring for concern of worsening disease or side effects of anticoagulation (bleeding). More than 90% of EDs admit patients with PE in the United States. However, close to 50% of patients may be appropriate for discharge and outpatient therapy. The published literature suggests that outpatient treatment is safe, feasible, and efficacious, with similar rates of recurrent venous thromboembolism and all-cause mortality, especially with novel oral anticoagulants. Multiple scoring criteria can be used, including the Pulmonary Embolism Severity Index (PESI), simplified PESI, Hestia criteria, Geneva Prognostic Score, European Society of Cardiology guidelines, Global Registry of Acute Coronary Events, and Aujesky score. Simplified PESI and the European Society of Cardiology guidelines have high-quality evidence, sufficient sensitivity, and ease of use for the ED. Patients considered for outpatient therapy should possess low hemorrhage risk, adequate social situation, negative biomarkers, ability to comply, and no alternate need for admission. CONCLUSIONS: Patients with acute PE are often admitted in the United States, but a significant proportion may be appropriate for discharge. Patients with low risk for adverse events according to clinical scoring criteria, adequate follow-up, ability to comply, and no other need for admission can be discharged with novel oral anticoagulant therapy. PMID- 28007363 TI - An Emergency Medicine-Focused Review of Seizure Mimics. AB - BACKGROUND: Seizures result in a change in motor, sensory, and behavioral symptoms caused by abnormal neurologic electrical activity. The symptoms share similar presentations of several other conditions, leading to difficulties in diagnosis and frequent improper management. OBJECTIVE: This review evaluates adult patients with suspected seizure, signs and symptoms of seizure, mimics of seizure, and an approach to management of seizure mimics. DISCUSSION: A seizure is caused by abnormal neurologic electrical activity resulting in altered motor, sensory, and behavioral symptoms. Other conditions may present similarly, causing a challenge in diagnosis. These conditions include syncope, psychogenic nonepileptic seizures, stroke or transient ischemic attack, sleep disorders, movement disorders, and migraines. Diagnosis of seizures in the emergency department (ED) is often clinical. Differentiation between seizures and other conditions can be difficult. Laboratories and imaging provide little benefit in definitive diagnosis in the emergency setting. For patients that have an apparent seizure, resuscitation and management is precedent while identifying any provoking factors and treatment of those factors. For adults recovering from suspected seizure, the combination of a focused history, physical examination, and additional studies can provide assistance in diagnosis. CONCLUSIONS: Patients with an apparent seizure should be resuscitated with identification of provoking factors. Many conditions can mimic seizures. A focused history, physical examination, and additional studies will assist in differentiating seizures from mimics. PMID- 28007364 TI - Factor Eight Inhibitor Bypassing Agent (FEIBA) for Reversal of Target-Specific Oral Anticoagulants in Life-Threatening Intracranial Bleeding. AB - INTRODUCTION: As increasing number of patients present to emergency departments with life threatening hemorrhages, particularly intracranial hemorrhage on anticoagulation physicians must be cognizant of the limitations of the available reversal options. Based upon the available literature, our institution formulated a reversal algorithm for patients with life-threatening bleeding on factor Xa inhibitors by administering factor eight inhibitor bypassing agent (FEIBA) 20 units/kg. METHODS: A retrospective chart review was performed to include all patients who received FEIBA per institutional protocol. This case series excluded patients who received FEIBA for reversal of dabigatran. Pre and post FEIBA CT scans were compared for changes. Finally, patients were stratified by estimated mortality rates calculated based on pre-intervention characteristics via published risk models. RESULTS: Thirteen patients were initially included in this study yet two patients were excluded because they were on dabigatran. Fifty-five percent of patients demonstrated stable ICH on CT scan after FEIBA administration while thirty-six percent showed worsening scans. Two patients developed thrombotic events after FEIBA administration. DISCUSSION: FEIBA is a treatment option in patients on a TSOA with acute intracranial hemorrhage with evidence of at least partial pharmacologic reversal of their anticoagulation status. There does not appear to be any major risk of thromboembolic complications associated with FEIBA. Much larger study sizes will be necessary to establish statically significant clinical efficacy for FEIBA use in this patient population. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency medicine physicians are first-line caretakers for patients with life threatening intracranial hemorrhages whether spontaneous or traumatic. FEIBA is a potentially safe option to reverse TSOA in this patient population. PMID- 28007365 TI - Reassessing Claims of Noninferiority of Daptomycin. PMID- 28007366 TI - Access to Care and Depression among Emergency Department Patients. AB - BACKGROUND: The prevalence of depression among patients in the emergency department (ED) is significantly higher than in the general population, making the ED a potentially important forum for the identification of depression and intervention. Concomitant to the identification of depression is the issue of patient access to appropriate care. OBJECTIVE: This study sought to establish prevalence estimates of potential barriers to care among ED patients and relate these barriers with symptoms of depression. METHODS: Two medical students conducted brief surveys on all ED patients >= 18 years on demographics, perceived access to care, and depression. RESULTS: A total of 636 participants were enrolled. The percentage of participants with mild or greater depression was 42%. The majority of patients reported experiencing some barriers to care, with the most prominent being difficulty finding transportation, work responsibilities, and the feeling that the doctor is not responsive to their concerns. Higher depression scores were bivariately associated with higher overall barriers to care mean scores (r = 0.44; p < 0.001), suggesting that greater symptoms of depression are associated with greater difficulties accessing care. Particularly strong associations were observed between symptoms of depression and difficulty finding transportation, the feeling that the doctor is not responsive to patients' concerns, embarrassment about a potential illness, and confusion trying to schedule an appointment. CONCLUSIONS: Across all barriers analyzed, there was a greater incidence of depression associated with a greater perception of barriers. These barriers may be used as potential targets for intervention to increase access to health care resources. PMID- 28007367 TI - Exercise Decreases and Smoking Increases Bladder Cancer Mortality. AB - BACKGROUND: The aim of this study was to investigate modifiable lifestyle factors of smoking, exercise, and obesity with bladder cancer mortality. PATIENTS AND METHODS: We used mortality-linked data from the National Health Information Survey from 1998 through 2006. The primary outcome was bladder cancer-specific mortality. The primary exposures were self-reported smoking status (never- vs. former vs. current smoker), self-reported exercise (dichotomized as "did no exercise" vs. "light, moderate, or vigorous exercise in >= 10-minute bouts"), and body mass index. We utilized multivariable adjusted Cox proportional hazards regression models, with delayed entry to account for age at survey interview. RESULTS: Complete data were available on 222,163 participants, of whom 96,715 (44%) were men and 146,014 (66%) were non-Hispanic whites, and among whom we identified 83 bladder cancer-specific deaths. In multivariate analyses, individuals who reported any exercise were 47% less likely (adjusted hazard ratio [HRadj], 0.53; 95% confidence interval [CI], 0.29-0.96; P = .038) to die of bladder cancer than "no exercise". Compared with never-smokers, current (HRadj, 4.24; 95% CI, 1.89-9.65; P = .001) and former (HRadj, 2.95; 95% CI, 1.50-5.79; P = .002) smokers were 4 and 3 times more likely, respectively, to die of bladder cancer. There were no significant associations of body mass index with bladder cancer mortality. CONCLUSION: Exercise decreases and current smoking increases the risk of bladder cancer-specific mortality. These data suggest that exercise and smoking cessation interventions may reduce bladder cancer death. PMID- 28007368 TI - Fluorescent Versus Radioguided Lymph Node Mapping in Bladder Cancer. AB - INTRODUCTION: The aim of the study was to compare 2 methods of the sentinel lymph node biopsy (SLNB) procedure in bladder cancer: we applied technetium radiocolloid (RadCol) detected by a gamma ray detection probe, and indocyanine green (ICG) detected by a near-infrared fluorescent (NIRF) camera. MATERIAL AND METHODS: The SLNB was performed on 50 patients using the RadCol and the ICG, followed by a lymphadenectomy and a pathologic examination. RESULTS: In the analyzed group of 47 patients (3 patients were excluded owing to the lack of lymphatic drainage from the tumor), the SLNB was performed using the 2 methods. The ICG with a NIRF-guided camera detected all sentinel lymph nodes (SLNs) in 46 cases, whereas RadCol detected them in 45 cases. In 12 (25.6%) of 47 patients, the ICG-fluorescent method revealed more SLNs than the RadCol method. In 8 (17%) patients, the SLNs revealed in the ICG fluorescence were metastatic. In 3 (6.4%) patients, we found SLNs outside the standard lymphadenectomy template, but a histopathologic examination showed they were negative for cancer. In 3 (6.4%) patients, the SLNs detected by both methods were negative for cancer, but other resected lymph nodes revealed metastases. CONCLUSION: Our study shows that SLNB procedure with the RadCol or the ICG method is useful for the evaluation of lymph nodes in bladder cancer. The new ICG fluorescent technique with a NIRF camera system is safe, enables live view of the results of the procedure, and does not create additional costs. However, it highlights more lymph nodes than the radioactive method. PMID- 28007369 TI - Pentobarbital in the context of possible suicides: Analysis of a Case. AB - Pentobarbital is a barbiturate, acting as a central nervous system depressant (CNS), being used for its anticonvulsant, sedative, hypnotic and anaesthetic properties. Barbiturates were replaced by benzodiazepines, leading to a decrease in poisoning cases with these compounds. However, pentobarbital is still used in many countries as an anaesthetic in veterinary medicine. Due to its properties, this compound is sought after by people who wish to commit suicide, acquiring it on the black market. The authors present an unusual fatal pentobarbital intoxication case, in a 37 years-old male salesperson, with no known connection with the veterinary field, being more difficult to obtain this compound. Toxicological results in cardiac blood revealed the presence of pentobarbital (111mg/L), ethanol (0.94g/L), diazepam (33ng/mL), nordiazepam (50ng/mL), oxazepam (3.3ng/mL), temazepam (5.3ng/mL), and metoclopramide. No illicit drugs were detected. Pentobarbital analysis in urine and gastric content was also positive, as well as its presence in the glass powder and in the bottle residue sent to the laboratory. In the present case, it was possible to conclude that the death was a suicide due to pentobarbital intoxication in association with other depressants of the CNS (benzodiazepines and ethanol). It is important to search pentobarbital in routine toxicological analyses, since it is one of the drugs most frequently mentioned by entities defending "painless death", advising the simultaneous use of metoclopramide for emesis avoidance. PMID- 28007370 TI - In vivo biodistribution of antihyperglycemic biopolymer-based nanoparticles for the treatment of type 1 and type 2 diabetes. AB - This study aimed to assess the biodistribution of antihyperglycemic insulin loaded alginate/dextran sulfate-based nanoparticles dual coated with chitosan and technetium-99m-albumin (99mTc-BSA) after oral administration. The oral administration of 50IU/kg insulin-loaded nanoparticles to type 1 diabetic rats showed prolonged antihyperglycemic effects up to 12h and relative pharmacological availability of 5.04% comparing to the subcutaneous administration. The oral antihyperglycemic effect was further compared between type 1 and type 2 diabetic models by the intraperitoneal glucose tolerance test, revealing that the effect lasted longer in the type 1 diabetic model. 99mTc-BSA revealed to be a good nanoparticles' tracer since there was no systemic absorption and 99mTc-BSA nanoparticles were capable of increasing their residence time in the intestinal epithelium of balb-c mice when compared with 99mTc-BSA biodistribution. Thus, this biopolymeric-based delivery nanoparticulate system is a promising tool for the therapy of type 1 and type 2 diabetic individuals and prevention of T1D. PMID- 28007371 TI - Knee Kinematic and Clinical Outcomes Evolution Before, 3 Months, and 1 Year After Total Knee Arthroplasty. AB - BACKGROUND: The aim of this study was to describe the evolution of kinematic and clinical outcomes of a large patient cohort with knee osteoarthritis from before surgery (V1) to 3 months (V2) and 1 year (V3) after a total knee arthroplasty (TKA). METHODS: The patients were evaluated at each visit (118 patients at V1, 93 patients at V2, and 79 patients at V3) during a clinical gait analysis and were compared with a matched control group of healthy adults (CG). The kinematic parameters, the Western Ontario and MacMaster Osteoarthritis Index (WOMAC), quality of life, and patient satisfaction were assessed. Gait velocity and knee range of motion (ROM) as well as clinical parameters were compared at each visit with CG was based on the unpaired samples t-test. To determine changes in the data at baseline, 3 months, and 1 year after surgery in the patient groups, repeated-measure analysis of variance was conducted (P < .05). Pearson correlation was used to examine relationships between clinical and biomechanical outcomes. RESULTS: One year after TKA (V3) compared to V1 and V2, the ROM of the operated knee during gait was significantly improved (V1: 44.2 +/- 8.8 degrees vs V3: 47.5 +/- 7.1 degrees , P < .001, and V2: 42.2 +/- 9.3 degrees vs V3: 47.5 +/- 7.1 degrees , P = .001), as was the gait velocity (V1: 1.0 +/- 0.2 and V2: 1.1 +/- 0.2 m/s vs V3: 1.3 +/- 0.2 m/s, P < .001). The WOMAC and knee pain were significantly better 1 year after TKA. No strong relationships have been found between clinical parameters and knee kinematics. CONCLUSION: This study showed that 1 year after TKA, patients exhibited improved gait velocity and ROM and experienced a significant decrease in the level of pain and an increased clinical score (although different from CG). PMID- 28007372 TI - Wear Rates of Larger-Diameter Cross-Linked Polyethylene at 5 to 13 Years: Does Liner Thickness or Component Position Matter? AB - BACKGROUND: Cross-linked polyethylene (XLPE) has demonstrated significantly reduced wear and osteolysis into the second decade for total hip arthroplasty. There is a relative paucity of data with >=36-mm bearings. Issues include potential effects of reduced liner thickness and component position on wear, osteolysis, and mechanical failure of the bearing. METHODS: Radiographs of 48 primary total hip arthroplasties with >=36-mm modular XLPE bearings were analyzed at a minimum 5 years postoperative on serial radiographs using a validated, edge detection-based algorithm. Subgroups were examined to assess the effect of bearing diameter, liner thickness, acetabular abduction angle, and acetabular anteversion on XLPE wear. RESULTS: There was no significant difference in volumetric wear when subgroups were stratified by component factors: liner thickness (<6.5 mm vs >=6.5 mm) 40.69 mm3/y vs 24.47 mm3/y, respectively (P = .315); acetabular component abduction angle (<45 degrees vs >=45 degrees ): 38.68 mm3/y vs 27.8 mm3/y, respectively (P = .522); acetabular anteversion (<20 degrees vs >=20 degrees ): 41.32 mm3/y vs 31.79 mm3/y, respectively (P = .521). There were no dislocations, mechanical failures, or revisions. There were 7 hips with volumetric wear rates >=80 mm3/y; 1 had possible osteolysis. CONCLUSION: Larger-diameter XLPE wear was not measurably affected by liner thickness, acetabular abduction angle, or acetabular anteversion. However, there is a trend for increasing volumetric wear with increasing bearing size. Wear outliers do occur, and continued follow-up of larger-diameter XLPE bearings is warranted. PMID- 28007373 TI - Effect of Inner Taper Angle of Acetabular Metal Shell on the Malseating and Dissociation Force of Ceramic Liner. AB - BACKGROUND: Malseating of ceramic liner appeared as a matter of concern in multibearing metal, although multibearing cup can be coupled with hard liners as well as polyethylene liner. In this metal shell, the inner taper angle should be 10 degrees for the modularity, while standard metal shells for ceramic liner have an inner taper angle of 18 degrees . However, there has been no study in the effect of taper angle to the risk of malseating. We evaluated whether the taper angle of metal shell might affect the malseating of ceramic liner, and dissociation force of ceramic liner from metal shell. METHODS: Three surgeons manually inserted ceramic liners into two designs of metal shell with different tapers angles (10 degrees and 18 degrees ). We compared malseating rates of ceramic liners and push-out strengths, which means dissociation force of the ceramic liner from the metal shell, between these two metal shell designs. RESULTS: The malseating rates in 10 degrees metal shell were higher than those in 18 degrees metal shell (23.3% vs 0%, P < .05). The mean dissociation force (1148.8 +/- 46.7 N) in 10 degrees taper cup was higher than that (389.7 +/- 108.3 N) in 18 degrees taper cup (P < .01). CONCLUSION: Our results suggest that surgeon should be cautious about malseating of ceramic liner when using multi bearing metal shell with inner taper angle of 10 degrees . CLINICAL RELEVANCE: When surgeon use multi-bearing metal shell with inner taper angle of 10 degrees , our results suggest that surgeon should be cautious about malseating of ceramic liner. PMID- 28007374 TI - Response to Letter to the Editor on "Factors Associated With Trunnionosis in the Metal-on-Metal Pinnacle Hip". PMID- 28007375 TI - Combined hamartoma of the retina and retinal pigment epithelium. PMID- 28007376 TI - Epilepsy-associated genes. AB - Development in genetic technology has led to the identification of an increasing number of genes associated with epilepsy. These discoveries will both provide the basis for including genetic tests in clinical practice and improve diagnosis and treatment of epilepsy. By searching through several databases (OMIM, HGMD, and EpilepsyGene) and recent publications on PubMed, we found 977 genes that are associated with epilepsy. We classified these genes into 4 categories according to the manifestation of epilepsy in phenotypes. We found 84 genes that are considered as epilepsy genes: genes that cause epilepsies or syndromes with epilepsy as the core symptom. 73 genes were listed as neurodevelopment-associated genes: genes associated with both brain-development malformations and epilepsy. Several genes (536) were epilepsy-related: genes associated with both physical or other systemic abnormalities and epilepsy or seizures. We found 284 additional genes putatively associated with epilepsy; this requires further verification. These integrated data will provide new insights useful for both including genetic tests in the clinical practice and evaluating the results of genetic tests. We also summarized the epilepsy-associated genes according to their function, with the goal to better characterize the association between genes and epilepsies and to further understand the mechanisms underlying epilepsy. PMID- 28007377 TI - So long, Farewell, Au revoir, Auf Weidersehen. PMID- 28007378 TI - Cost evaluations of radiotherapy: What do we know? An ESTRO-HERO analysis. AB - Although economic evidence is becoming mandatory to support health care decision making, challenges remain in generating high quality cost data, especially for complex and rapidly evolving treatment modalities, such as radiotherapy. The overall aim of this systematic literature review was to critically analyse the type and quality of radiotherapy cost information available in cost calculation studies, from the health care provider's perspective, published since 1981. A selection process, based on strict and explicit criteria, yielded 52 articles. In spite of meeting our criteria these studies displayed large heterogeneity in scope, costing method, inputs and outputs. The limited use of conventional costing methodologies along with insufficient information on resource inputs hampered comparability across studies. A consistent picture of radiotherapy costs, based on methodologically sound costing studies, has yet to emerge. These results call for developing a well-defined and generally accepted cost methodology for performing economic evaluation studies in radiotherapy. PMID- 28007379 TI - Subunit CcoQ is involved in the assembly of the Cbb3-type cytochrome c oxidases from Pseudomonas stutzeri ZoBell but not required for their activity. AB - The Cbb3-type cytochrome c oxidases (Cbb3-CcOs), the second most abundant CcOs, catalyze the reduction of molecular oxygen to water, even at micromolar oxygen concentrations. In Pseudomonas stutzeri ZoBell, two tandemly organized cbb3 operons encode the isoforms Cbb3-1 and Cbb3-2 both possessing subunits CcoN, CcoO and CcoP. However, only the cbb3-2 operon contains an additional ccoQ gene. CcoQ consists of 62 amino acids and is predicted to possess one transmembrane spanning helix. The physiological role of CcoQ was investigated based on a CcoQ-deletion mutant and wild-type Cbb3-2 crystals not containing subunit CcoQ. Cbb3-2 isolated from the deletion mutant is inactive and appears as a dispersed band on blue native-PAGE gels. Surprisingly, in the absence of ccoQ, Cbb3-1 also shows a strongly reduced activity. Our data suggest that CcoQ primarily functions as an assembly factor for Cbb3-2 but is also required for correct assembly of Cbb3-1. In contrast, once correctly assembled, Cbb3-1 and Cbb3-2 possess a full enzymatic activity even in the absence of CcoQ. PMID- 28007380 TI - The Effect of Transesophageal Echocardiography Probe Placement on Intracuff Pressure of an Endotracheal Tube in Infants and Children. AB - OBJECTIVES: To evaluate the effects of transesophageal echocardiography (TEE) probe insertion on the endotracheal cuff pressure (CP). DESIGN: Prospective observational study. SETTING: Single standing, not-for-profit pediatric hospital. PARTICIPANTS: A total of 80 pediatric patients (aged 6 days to 18.4 years) who underwent cardiac surgery and intraoperative TEE. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Following anesthesia induction and endotracheal intubation, the CP was recorded at 4 points: before the insertion of the TEE (P1), at TEE insertion (P2), during TEE examination (P3), and after the probe was advanced into the stomach (P4). Twenty patients were enrolled in each of the following age groups:<1 year of age; 1-4 years of age; 5-8 years of age; and 9-18 years of age. CP was compared between pairs of time points using paired t-tests, and differences in CP over time were compared among age groups using repeated measures analysis of variance. CP at P1, P2, P3, and P4 was 18.7+/-11.6, 26.7+/ 14.4, 22.3+/-12.4, and 20.6+/-12.6 cmH2O, respectively. Although CP significantly increased from P1 to P2 (p<0.001), there was no significant difference between P1 and P4 (95% CI; -0.3 to 4.1; p = 0.083). There was no significant difference in CP change based on the age of the patient. CONCLUSION: Following a transient increase in CP with TEE probe insertion, the CP returned to baseline after the tip of the TEE probe was advanced into the stomach. There was no variation among age groups in the magnitude of the CP change during the study. PMID- 28007381 TI - Microplastic abundance, distribution and composition along a latitudinal gradient in the Atlantic Ocean. AB - Microplastics in the world's oceans are a global concern due to the potential threat they pose to marine organisms. This study investigated microplastic abundance, distribution and composition in the Atlantic Ocean on a transect from the Bay of Biscay to Cape Town, South Africa. Microplastics were sampled from sub surface waters using the underway system of the RV Polarstern. Potential microplastics were isolated from samples and FT-IR spectroscopy was used to identify polymer types. Of the particles analysed, 63% were rayon and 37% were synthetic polymers. The majority of microplastics were identified as polyesters (49%) and blends of polyamide or acrylic/polyester (43%). Overall, fibres (94%) were predominant. Average microplastic abundance in the Atlantic Ocean was 1.15+/ 1.45particlesm-3. Of the 76 samples, 14 were from the Benguela upwelling and there was no statistically significant difference in microplastic abundance between upwelled and non-upwelled sites. PMID- 28007382 TI - Analysis of bloom conditions in fall 2013 in the Strait of Hormuz using satellite observations and model simulations. AB - In this study an algal bloom event in fall 2013 in the Strait of Hormuz was thoroughly investigated using satellite remote sensing and hydrodynamic modeling. The motivation of this study is to deduce ambient conditions prior to and during the bloom outbreak and understand its trigger. Bloom tracking was achieved by sequential MODIS imagery and numerical simulations. Satellite observations showed that the bloom was initiated in late October 2013 and dissipated in early June 2014. Trajectories of bloom patches were simulated using a Lagrangian transport model. Model-based predictions of bloom patches' trajectories were in good agreement with satellite observations with a probability of detection (POD) reaching 0.85. Analysis of ancillary data, including sea surface temperature, ocean circulation, and wind, indicated that the bloom was likely caused by upwelling conditions in the Strait of Hormuz. Combined with numerical models, satellite observations provide an essential tool for investigating bloom conditions. PMID- 28007384 TI - Determination and assessment of phthalate esters content in sediments from Kaohsiung Harbor, Taiwan. AB - Phthalate esters (PAEs) are known organic endocrine disruptors. The distribution of 10 PAEs in sediments of Kaohsiung Harbor of Taiwan was studied using organic solvents extraction and quantified by gas chromatography/mass spectrometry. The average concentration of total PAEs (SigmaPAEs) in the sediment was 8713+/ 11,454ng/g dw with di-(2-ethylhexyl) phthalate (DEHP) (3630ng/g-dw) and diisononyl phthalate (DiNP) (3497ng/g dw) being the major species, which constitutes of 41.7% and 40.1% of SigmaPAEs. PAEs concentration was relatively high near the river mouths, especially in Love River mouth, and diminished toward the harbor. Based on the sediment quality guidelines developed from previous studies, several of the observed PAE levels exceeded the Maximum Contaminant Level, especially for DEHP and thus may cause adverse effect in aquatic organisms. PMID- 28007383 TI - Paralytic shellfish toxins in phytoplankton and shellfish samples collected from the Bohai Sea, China. AB - Phytoplankton and shellfish samples collected periodically from 5 representative mariculture zones around the Bohai Sea, Laishan (LS), Laizhou (LZ), Hangu (HG), Qinhuangdao (QHD) and Huludao (HLD), were analysed for paralytic shellfish toxins (PSTs) using an high-performance liquid chromatography (HPLC) method. Toxins were detected in 13 out of 20 phytoplankton samples, and N-sulfocarbamoyl toxins (C1/2) were predominant components of PSTs in phytoplankton samples with relatively low toxin content. However, two phytoplankton samples with high PST content collected from QHD and LS had unique toxin profiles characterized by high potency carbamoyl toxins (GTX1/4) and decarbamoyl toxins (dcGTX2/3 and dcSTX), respectively. PSTs were commonly found in shellfish samples, and toxin content ranged from 0 to 27.6nmol/g. High level of PSTs were often found in scallops and clams. Shellfish from QHD in spring, and LZ and LS in autumn exhibited high risks of PST contamination. PMID- 28007385 TI - Heavy metals in surface sediments along the Weihai coast, China: Distribution, sources and contamination assessment. AB - The Weihai coast is a representative zone with fifty-year history of mariculture in China. Algae and shellfish are the main cultured species, other species including fish and sea cucumber are also cultivated. In this study, heavy metals in surface sediments, sampled along the Weihai coast during May yearly between 2009 and 2013 were investigated in terms of their contents and spatiotemporal variation. The contents of Zn, Cr, Cu, Cd, Pb and As showed different spatiotemporal variations and ranged between 11.6 and 115.9, 4.15-51.3, 5.2-21.9, 0.02-0.33, 6.0-54.2, and 2.9-18.7MUgg-1, respectively. Among them, Zn, Cu and As declined during the five years. Ecological risk assessment revealed that Cd posed a moderate risk, as compared to other five elements, which were relatively low risks in surface sediments. Source analysis revealed that Zn, Cr and Cd were mainly from lithogenic contribution, while As was likely from anthropogenic discharges. PMID- 28007386 TI - Polycyclic aromatic hydrocarbon pollution in the surface water and sediments of Chabahar Bay, Oman Sea. AB - In the present study, the concentrations and distribution of 16 polycyclic aromatic hydrocarbons (PAHs) in the water and surface sediments from the Chabahar Bay, Oman Sea, were investigated in May (premonsoon) and December (postmonsoon) 2012. The concentrations of PAHs in the surface water samples ranged from 1.7 to 2.8ngl-1 and from 0.04 to 59.6ngl-1 in pre- and postmonsoon, respectively. In general, the PAH levels of the water samples from Chabahar Bay were higher in postmonsoon than in premonsoon (p<0.05). The concentrations of PAHs in the sediment samples varied from undetectable levels to 92.8ngg-1 d.w. in both seasons. The seasonal comparison of the results in sediment samples showed that the overall concentration of PAH compounds was higher in the postmonsoon season (p<0.05). PMID- 28007387 TI - Characteristics of hydrocarbons in sediment core samples from the northern Okinawa Trough. AB - Sediment core samples from the northern Okinawa Trough (OT) were analyzed to determine abundances and distributions of hydrocarbons by gas chromatography-mass spectrometer (GC-MS). The results show that the n-alkanes in this sediment core conform to a bimodal distribution, and exhibit an odd-to-even predominance of high molecular weights compared to an even-to-odd predominance in low molecular weight n-alkanes with maxima at C16 and C18. The concentrations of bitumen, alkanes and polyaromatic hydrocarbons (PAHs) were higher in samples S10-07 than all others. Three maturity parameters as well as the ratios between parent phenanthrenes (Ps) and methylphenanthrenes (MPs) in samples S10-07 and S10-17 were higher. The distribution and composition of hydrocarbons in sample S10-07 suggest that one, or several, undetected hydrothermal fields may be present in the region of this sediment core. Results also suggest that volcanism may be the main reason for the observed distribution and composition of hydrocarbons in S10 17 sample. PMID- 28007388 TI - Geochemical distribution, fractionation and contamination assessment of heavy metals in marine sediments of the Asaluyeh port, Persian Gulf. AB - In this study, total concentration and speciation of heavy metals in sediments of the Asaluyeh, one of the Iran's largest commercial ports, are investigated. 48 sediment samples were collected and analyzed for trace and major elements. Sediment quality guidelines along with calculated enrichment factors and trace metal profiles indicate that Asaluyeh port is threated by contamination, especially with respect to Hg and Cu. Normalization to Sc indicated high enrichment factors in the sediments following the decreasing order of: Hg>Cu>As>Ni>Zn>Pb~Cr~Mn>Co~V~Fe~Al. Hg displayed the greatest potential ecological risk factor among sampling stations. The results of sequential extraction procedure revealed that in some stations >50% of Mn, V, Cu and Zn occur in potentially mobile phases and therefore are more readily mobilized in the sediments of the study area. PMID- 28007389 TI - Relationship between magnitude of phytoplankton blooms and rainfall in a hyper eutrophic lagoon: A continuous monitoring approach. AB - To evaluate the effect of rainfall intensity on phytoplankton blooms, a continuous monitoring system was deployed during 2015 in a hyper-eutrophic lagoon in Taiwan. Intensive rainfall occurs during the wet summer months, from May to September. Salinity in the lagoon was found to decrease with increasing intensity of rainfall. The magnitude of phytoplankton blooms also increased linearly with increasing rainfall intensity. The chlorophyll a concentration rose by an order of magnitude during the heaviest rainfall. Blooms may be fueled by nutrient enrichment caused by drainage or run-off water from surrounding areas that is channeled into the lagoon during rainfall events. During bloom periods, the rates of net primary production and ecosystem respiration were high. However, this ecosystem was autotrophic for most of the year. As extreme rainfall is predicted to increase, the results of this study imply that the frequency and magnitude of phytoplankton blooms may increase in the future. PMID- 28007390 TI - Do Gender and Season Modify the Triggering Effect of Ambient Temperature on Ischemic Stroke? AB - BACKGROUND: Ischemic stroke (IS) is a multifactorial disorder, a leading cause of long-term disability, and the second most common cause of death. Previous studies have examined the association between stroke and weather conditions with conflicting results. In this study we aimed to investigate the association between changes in ambient temperature and risk of IS onset. METHODS: We used a time-stratified case-crossover study design including all patients admitted to Soroka University Medical Center in southern Israel between 2012 and 2014 for IS. Exposure windows of 6, 12, 24, 48, 72, and 96 hours were examined. All patients were assessed and classified by a neurologist. Temperature ( degrees C), and relative humidity (%) were obtained from monitoring stations located in Beer Sheva. RESULTS: A total of 1,174 patients visited Soroka University Medical Center for admission for an IS during the study period. Among them, 56% were male, on average 69.8 +/- 13.1 years old. IS incidence was associated with increase in temperature during the summer and autumn season over the 96 hours preceding symptoms onset; the odds ratio (OR) for an increase of 5 degrees C was 3.10 (95% CI, 1.45-6.61) during the summer and 1.86 (95% CI, 1.15-2.99) in autumn. The association between temperature and stroke onset during the winter was negative (OR, 0.68; 95% CI, 0.48-0.97) for 96-hour moving average temperature exposure. Men were more sensitive to 96-hour exposure window temperature fluctuations (OR, 1.35; 95% CI, 1.01-1.80) than women (OR, 0.96; 95% CI, 0.68 1.36). We did not find any associations between IS onset and differences between the maximum and minimum measurements of temperature. CONCLUSIONS: Our findings showed that short-term exposure to high temperatures is associated with a higher risk of IS in men but not in women. Further study is needed to validate this observation and to understand its pathophysiology. PMID- 28007391 TI - Differences in Depression Care for Men and Women among Veterans with and without Psychiatric Comorbidities. AB - BACKGROUND: Depression is common among primary care patients, affecting more women than men. Women veterans are an extreme but growing minority among patients seeking care from the Department of Veterans Affairs (VA), an organization historically designed to serve men. Little is known about gender differences in depression care quality within the VA primary care population. PURPOSE: This works assesses the gender differences in depression care among veterans using longitudinal electronic measures. METHODS: We undertook a cross-sectional study of all veteran VA primary care users with a new episode of depression from federal fiscal year 2010, covering nine geographically diverse regions. We assessed the quality of depression care based on receipt of minimally appropriate depression treatment within 1 year of a new episode of depression and on receipt of depression-related follow-up visits within 180 days. Minimally appropriate treatment and follow-up were operationalized as meeting or exceeding a minimally appropriate threshold for care, based on national quality measures and expert panel consensus. Regression models were used to produce predicted probabilities for each process outcome accounting for the presence or absence of other psychiatric comorbidities. All models were adjusted for model covariates and clinic clusters (404 sites). MAIN FINDINGS: In 2010, 110,603 veterans with a primary care visit had a new episode of depression; 10,094 (9%) were women. In multivariate analyses, women had modest yet significantly higher rates of minimally appropriate depression treatment than men, whether patients had depression only (79% of women vs. 76% of men; p < .001) or depression along with other psychiatric comorbidities (92% of women vs. 91% or men; p < .001). There were no significant gender differences for rate of receipt of follow-up for depression at 180 days. Interactions between gender and other psychiatric comorbidities were not significant. CONCLUSIONS: Our findings suggest that the VA is achieving comparable depression care between genders at minimally appropriate thresholds. PMID- 28007392 TI - Donor site morbidity and quality of life after microvascular head and neck reconstruction with free fibula and deep-circumflex iliac artery flaps. AB - PURPOSE: Bone defects after resective tumor surgeries often require the use of microvascular reanastomized bone grafts for reconstruction. The decision as to which specific flap is most suitable for the particular patient is dependent on various factors. The aspects donor site morbidity and quality of life are rarely taken into account in this connection. The aim of this study was to analyze whether these factors, in the future, should influence the choice of donor site. MATERIAL AND METHODS: In this study, the donor sites of 46 patients with respect to deep-circumflex iliac artery (DCIA) and fibula flaps were analyzed using subjective and objective parameters. The primary outcome was postoperative pain measured by VAS. Postoperative complication evaluations as well as 2 orthopedic scores were implemented (American Orthopedic Foot and Ankle Society (AOFAS) Ankle Hindfoot Score and Harris Hip Score) and the patients' quality of life was assessed using the 36-Item Short Form (SF-36) questionnaire to quantify donor site impairment. RESULTS: Postoperative pain was rated with a mean value of 42.4 mm (SD 34.8) for the DCIA group and 36.9 mm (SD 37.1) for the fibula group (p = 0.617). After a mean period of 13.72 months, pain was rated with a mean value of 15.3 mm (SD 21.7) for DCIA and 13.3 mm (SD 22.6 mm) for the fibula (p = 0.763). Persistent pain, however, was recorded only in 11.11% of DCIA patients and 5.26% of fibula patients. Furthermore pain intensity was higher in the DCIA group. A changed gait pattern was observed in 59.26% of DCIA patients and 21.05% of fibula patients. DCIA patients required walking aids for walking and stair climbing more often. Looking at the results of the 2 orthopedic scores, fibula patients showed slightly better results. Concerning quality of life, patients after reconstructive surgery with DCIA flaps showed slight better results than patients in the fibula group. CONCLUSIONS: Taking the results of this study into account, the outcome in terms of pain, morbidity and quality of life did not show a significant superiority of any donor site. PMID- 28007393 TI - Fournier's gangrene during ACTH therapy. AB - Fournier's gangrene is an infectious necrotizing fasciitis of the perineal, genital, or perianal regions and is uncommon in children. Adrenocorticotropic hormone (ACTH) is effective for the treatment of infantile spasms; however, suppression of immune function is one of the major adverse effects of this approach. We encountered a 2-month-old boy with infantile spasms that had been treated with ACTH and had developed complicating Fournier's gangrene. Strangulation of a right inguinal hernia was observed after ACTH treatment. Although surgical repair was successful and no intestinal injuries were detected, swelling and discoloration of the right scrotum developed in association with pyrexia and a severe inflammatory response. A scrotal incision revealed pus with a putrid smell. The patient was subsequently diagnosed with Fournier's gangrene complicated by septic shock and disseminated intravascular coagulation. Extensive debridement and intensive care was performed. Enterobactor aerogenes, methicillin resistant Staphylococcus aureus, and Enterococcus faecalis were isolated from the pus. Meropenem, teicoplanin, and clindamycin were administered to control the bacterial infection. The patient was discharged from the intensive care unit without any obvious neurological sequelae. Suppression of immune function associated with ACTH therapy may have been related to the development of Fournier's gangrene in this case. PMID- 28007394 TI - Limited interaction of a self-adhesive flowable composite with dentin/enamel characterized by TEM. AB - OBJECTIVES: A new category of composite which does not require any acid etching or bonding protocol prior to application has been introduced. The purpose of this study was to characterize the interfacial ultra-structure at enamel and dentin surfaces by means of transmission electron microscopy (TEM). METHODS: Non-carious human third molars were randomly divided into 6 groups (bur-cut dentin, SiC ground dentin, fractured dentin, bur-cut enamel, SiC-ground enamel, and un-cut enamel). After preparation of the respective surfaces, the self-adhesive flowable composite (Vertise Flow, Kerr) was applied. Non-demineralized/demineralized and non-stained/stained sections of 70-90nm were prepared following common TEM specimen processing procedures. Additional specimens were immersed in an ammoniacal silver nitrate solution. RESULTS: The composite-dentin interface was free of voids and no de-bonding occurred during specimen preparation. For bur-cut and SiC-ground dentin, no surface demineralization was observed and the smear contained residual hydroxyapatite. On fractured dentin (i.e. without smear interference), a very thin interaction area of 100-200nm without apparent signs of surface demineralization was seen. When the composite was bonded to enamel, a distinct separation between the self-adhesive composite and enamel was present in all three groups. A tight interaction, yet without distinct dissolution of hydroxyapatite, could only be seen in some regions at bur-cut enamel where smear was absent or sparse. Silver nitrate infiltration was associated with the presence of smear. SIGNIFICANCE: The self-adhesive composite showed limited interaction with smear-covered substrates and aprismatic enamel, which explains its inferior diminished bonding capacity in comparison with current adhesives. PMID- 28007395 TI - Preparation and characterization of high radio-opaque E-glass fiber-reinforced composite with iodine containing methacrylate monomer. AB - OBJECTIVE: The purpose of this study was to prepare radio-opaque E-glass fiber reinforced composite (EFRC) with synthesized iodine containing methacrylate monomer. METHODS: The synthesized iodine containing methacrylate monomer 2 hydroxy-3- methacryloyloxypropyl(2,3,5- triiodobenzoate) (HMTIB) was mixed with Bis-GMA and MMA in different mass ratio to prepare resin impregnating solution (RIS), and RIS without HMTIB was used as control. CQ and DMAEMA were added as photoinitiation system. E-glass fiber was thoroughly wetted by resin impregnating solution to prepare radio-opaque EFRC. Degree of double bond conversion (DC) was investigated by FT-IR analysis. Fiber volume fraction was analyzed by combustion and gravimetric analyzes. The Flexural strength (FS) and modulus (FM) of EFRC were measured using a three-point bending set up. Water sorption (WS) and solubility (SL) were measured until the mass variation of EFRC in distilled water kept stable. Radiographs were taken to determine the radiopacity of EFRC. RESULTS: The FT-IR and 1H NMR spectra of HMTIB revealed that it was the same as designed. ANOVA analysis revealed that increasing HMTIB concentration in RIS would decrease DC and increase fiber volume fraction. When compared with control EFRC, all of HMTIB containing EFRCs had higher or comparable FS and FM, no matter before or after water immersion. WS of EFRC decreased with increasing HMTIB concentration, while SL was nearly kept the same. Radiopacity of EFRC increased with increasing HMTIB concentration. SIGNIFICANCE: The synthesized monomer HMTIB could be used to prepare EFRC with high radiopacity. Moreover, HMTIB containing EFRC would also have high mechanical properties and low WS. PMID- 28007396 TI - Academy of Dental Materials guidance on in vitro testing of dental composite bonding effectiveness to dentin/enamel using micro-tensile bond strength (MUTBS) approach. AB - OBJECTIVE: An ideal dental adhesive should provide retentive strength, marginal seal, be relatively simple to achieve and demonstrate clinical durability. Future improvements in adhesive bonding to tooth structure require in vitro test methods that provide reliable data for materials development and/or evaluation of experimental variables. The objective of this project was to identify a test method that is relatively easy to perform, repeatable and ultimately useful for predicting clinical outcomes. METHODS: The Academy of Dental Materials initiated a project to develop and distribute guidance documents on laboratory test methods that are useful for the evaluation of dental adhesives and cements, composite resins and ceramics. RESULTS: The dental adhesive sub-group has identified the micro-tensile bond strength test, especially after subjecting the specimens to a durability challenge, as currently the best practical surrogate measure of dental composite restoration retention. CONCLUSION: The following MUTBS guidance is meant to aid the researcher in conducting the MUTBS test. The authors, while recognizing the limitations of a static, strength-based test method, welcome comments and suggestions for improvements of this guidance document in future revisions. PMID- 28007398 TI - Development of GC-MS based cytochrome P450 assay for the investigation of multi herb interaction. AB - As drug interactions with cytochrome P450 enzymes become increasingly important in the field of drug discovery, a high-throughput screening method for analysing the effects of a drug is needed. We have developed a simple and rapid simultaneous analytical method using a cocktail approach for measuring the activities of seven cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4). Human liver microsomes were used as a source for the seven cytochrome P450 enzymes, and a gas chromatography-mass spectrometry (GC-MS) was used for analysing their activities. Kinetic studies and inhibition assays of CYP enzymes were performed using known substrates and inhibitors for validating and comparing the reaction rates and time-dependent activities between methods using each substrate versus a method using a cocktail solution. The optimized cocktail method was successfully applied to evaluate the effects of the decoction of Socheongryong-tang (SCRT) on cytochrome P450 enzymes. Our cocktail method provides a simultaneous high-throughput activity assay using GC-MS for the first time. This method is applicable for analysing the drug interactions of various plant-derived mixtures. PMID- 28007397 TI - Impact of the national rotavirus vaccination programme on acute gastroenteritis in England and associated costs averted. AB - BACKGROUND: Introduction of infant oral rotavirus vaccination in the UK in July 2013 has resulted in decreased hospitalisations and Emergency Department (ED) visits for acute gastroenteritis (AGE), for both adults and children. We investigated reductions in AGE incidence seen in primary care in the two years after vaccine introduction, and estimated the healthcare costs averted across healthcare settings in the first year of the vaccination programme. METHODS: We used primary care data from the Clinical Practice Research Datalink and age stratified time-series analyses to derive adjusted incidence rate ratios (IRRa) for AGE in the first two years of the post-vaccination era (July 2013-April 2015) compared to the pre-vaccination era (July 2008-June 2013). We estimated cases averted among children aged <5years in the first year of the vaccination programme by comparing observed numbers of AGE cases in 2013-2014 to numbers predicted from the time-series models. We then estimated the healthcare costs averted for general practice consultations, ED visits and hospitalisations. RESULTS: In general practice, AGE rates in infants (the target group for vaccination) decreased by 15% overall after vaccine introduction (IRRa=0.85; 95%CI=0.76-0.95), and by 41% in the months of historically high rotavirus circulation (IRRa=0.59; 95%CI=0.53-0.66). Rates also decreased in other young children and to a lesser degree in older individuals, indicating herd immunity. Across all three settings (general practice, EDs, and hospitalisations) an estimated 87,376 (95% prediction interval: 62,588-113,561) AGE visits by children aged <5years were averted in 2013-14, associated with an estimated L12.5million (9,209-16,198) reduction in healthcare costs. CONCLUSIONS: The marked decreases in the general practice AGE burden after rotavirus vaccine introduction mirror decreases seen in other UK healthcare settings. Overall, these decreases are associated with substantial averted healthcare costs. PMID- 28007399 TI - Evaluating the methylation status of CXCR4 promoter: A cost-effective and sensitive two-step PCR method. AB - The chemokine receptor CXCR4 plays a key role in the bone marrow microenvironment maintenance and in the hematopoietic stem and progenitor cells migration. In addition, CXCR4 is expressed in a broad spectrum of solid tumors where its methylation state has been recently proposed as a biomarker for cancer prognosis. To evaluate methylation status of CXCR4 promoter we developed a sensitive, accurate, specific and cost-effective two-step PCR method that does not require any specific equipment other than a conventional real-time PCR instrument. The principle of the technique relies on a novel normalization strategy which allows the detection and quantification of small methylation differences among pre amplified DNA samples deriving from low amount of starting material. In addition, the analysis of melting curve profiles of PCR products provides additional information about the methylation status of CpG sites in between the primers. Finally, the principle of this technique can potentially be adapted for the investigation of the methylation status of any other DNA region. PMID- 28007401 TI - Increasing the methodological quality and relevance of cost effectiveness analysis. PMID- 28007400 TI - Consequences of acute Nav1.1 exposure to deltamethrin. AB - BACKGROUND: Pyrethroid insecticides are the most popular class of insecticides in the world, despite their near-ubiquity, their effects of delaying the onset of inactivation of voltage-gated sodium (Nav) channels have not been well-evaluated in all the mammalian Nav isoforms. OBJECTIVE: Here we compare the well-studied Nav1.6 isoforms to the less-understood Nav1.1 in their responses to acute deltamethrin exposure. METHODS: We used patch-clamp electrophysiology to record sodium currents encoded by either Nav1.1 or Nav1.6 channels stably expressed in HEK293 cells. Protocols evaluating both resting and use-dependent modification were employed. RESULTS: We found that exposure of both isoforms to 10MUM deltamethrin significantly potentiated persistent and tail current densities without affecting peak transient current densities, and only Nav1.1 maintained these significant effects at 1MUM deltamethrin. Window currents increased for both as well, and while only Nav1.6 displayed changes in activation slope and V1/2 of steady-state inactivation for peak currents, V1/2 of persistent current activation was hyperpolarized of ~10mV by deltamethrin in Nav1.1 cells. Evaluating use-dependence, we found that deltamethrin again potentiated persistent and tail current densities in both isoforms, but only Nav1.6 demonstrated use-dependent enhancement, indicating the primary deltamethrin induced effects on Nav1.1 channels are not use-dependent. CONCLUSION: Collectively, these data provide evidence that Nav1.1 is indeed vulnerable to deltamethrin modification at lower concentrations than Nav1.6, and this effect is primarily mediated during the resting state. GENERAL SIGNIFICANCE: These findings identify Nav1.1 as a novel target of pyrethroid exposure, which has major implications for the etiology of neuropsychiatric disorders associated with loss of Nav1.1-expressing inhibitory neurons. PMID- 28007403 TI - The additive effect on the antiepileptic treatment of ambroxol in type 3 Gaucher patient. The early observation. PMID- 28007402 TI - Performance of screening questionnaires for obstructive sleep apnea during pregnancy: A systematic review and meta-analysis. AB - This review aims to evaluate the performance of obstructive sleep apnea (OSA) screening questionnaires during pregnancy. A systematic review and meta-analysis was performed using MEDLINE Scopus, CINAHL, and the Cochrane library. A bivariate meta-analysis was applied for pooling of diagnostic parameters. Six of the total 4719 articles met the inclusion criteria. The Berlin questionnaire (BQ, N = 604) and Epworth sleepiness scale (ESS, N = 420) were the most frequently used screening tools during pregnancy. The pooled prevalence of OSA during pregnancy was 26.7% (95%CI: 16.9%, 34.4%, I2 = 83.15%). BQ performance was poor to fair with pooled sensitivity and specificity of 0.66 (95%CI: 0.45, 0.83; I2 = 78.65%) and 0.62 (95%CI: 0.48, 0.75; I2 = 81.55%), respectively. BQ performance was heterogeneous depending on type of reference test and pregnancy. Sensitivity increased if diagnosis was based on polysomnography (0.90), and respiratory disturbance index (0.90). However, sensitivity decreased if screening was performed in early pregnancy (<=20 weeks gestation: 0.47), and high-risk pregnancy (0.44). Performance of ESS was poor with pooled sensitivity and specificity of 0.44 (95%CI: 0.33, 0.56; I2 = 32.8%) and 0.62 (95%CI: 0.48, 0.75; I2 = 81.55%), respectively. In conclusion, BQ and ESS showed poor performance during pregnancy, hence a new OSA screening questionnaire is needed. Registration: PROSPERO registration CRD42015025848. PMID- 28007404 TI - 20th Anniversary Meeting of the Meryon Society Worcester College, Oxford. PMID- 28007405 TI - Ephedrine treatment for autoimmune myasthenia gravis. AB - We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout. In each cycle, ephedrine 50 mg daily in 2 doses was compared with placebo in the alternate treatment period. Primary outcome was a change in QMG score. Add-on treatment with ephedrine compared with placebo improved QMG score by 1.0 point (95% confidence interval 0.21-1.79), which was significant for the group of trial patients as well as for the population treatment effect. Ephedrine also showed a significant trial average treatment effect for all secondary outcomes, improving MG Composite by 2.7, MG-ADL by 1.0 and VAS score for muscle strength by 1.1. Adverse events were mild and included palpitations, tremor and restlessness. Although all ECGs were normal, ephedrine prolonged the corrected QT interval. Ephedrine as add-on treatment for myasthenia gravis resulted in a small but consistent reduction of symptoms and weakness in patients with moderate disease severity. PMID- 28007407 TI - Variable selection methods for multiple regressions influence the parsimony of risk prediction models for cardiac surgery. AB - OBJECTIVE: To compare the impact of different variable selection methods in multiple regression to develop a parsimonious model for predicting postoperative outcomes of patients undergoing cardiac surgery. METHODS: Data from 84,135 patients in the Australian and New Zealand Society of Cardiac and Thoracic Surgeons registry between 2001 and 2014 were analyzed. Primary outcome was 30-day mortality. Mixed-effect logistic regressions were used to build the model. Missing values were imputed by the use of multiple imputations. The following 5 variable selection methods were compared: bootstrap receiver-operative characteristic (ROC), bootstrap Akaike information criteria, bootstrap Bayesian information criteria, and stepwise forward and stepwise backward methods. The final model's prediction performance was evaluated by the use of Frank Harrell's calibration curve and using a multifold cross-validation approach. RESULTS: Stepwise forward and backward methods selected same set of 21 variables into the model with the area under the ROC (AUC) of 0.8490. The bootstrap ROC method selected 13 variables with AUC of 0.8450. Bootstrap Bayesian information criteria and Akaike information criteria respectively selected 16 (AUC: 0.8470) and 23 (AUC: 0.8491) variables. Bootstrap ROC model was selected as the final model which showed very good discrimination and calibration power. CONCLUSIONS: Clinical suitability in terms of parsimony and prediction performance can be achieved substantially by using the bootstrap ROC method for the development of risk prediction models. PMID- 28007406 TI - Adipose Tissue: A Safe Haven for Parasites? AB - Adipose tissue (AT) is no longer regarded as an inert lipid storage, but as an important central regulator in energy homeostasis and immunity. Three parasite species are uniquely associated with AT during part of their life cycle: Trypanosoma cruzi, the causative agent of Chagas disease; Trypanosoma brucei, the causative agent of African sleeping sickness; and Plasmodium spp., the causative agents of malaria. In AT, T. cruzi resides inside adipocytes, T. brucei is found in the interstitial spaces between adipocytes, while Plasmodium spp. infect red blood cells, which may adhere to the blood vessels supplying AT. Here, we discuss how each parasite species adapts to this tissue environment and what the implications are for pathogenesis, clinical manifestations, and therapy. PMID- 28007408 TI - Transcriptional abundance of antioxidant enzymes in endometrium and their circulating levels in Zebu cows with and without uterine infection. AB - Oxidative stress during peripartum period may compromise the uterine immunity. In the present study, we assessed the oxidative stress and antioxidant status during peripartum period and studied their relationship with postpartum uterine infection in dairy cows. Peripheral blood concentrations of total antioxidant capacity (TAC), malondialdehyde (MDA) and nitric oxide (NO) were determined (day 21, -7, on the day of calving and day +7, +21, +35) in normal (n=11), puerperal metritic (n=7) and clinical endometritic (n=6) cows. Endometrial biopsy was performed on the day of calving and expression of CAT, GPx4 and SOD2 genes was studied using qRT-PCR. Puerperal metritic cows had significantly (P<0.05) lower TAC (on day -7, day 0, day +7, +21 & +35), higher MDA (on day -21, -7 & on the day of calving) and NO (on day 0, +7 & day +35) concentrations compared to normal cows. Similarly, clinical endometritic cows had significantly (P<0.05) lower TAC (on day -7, 0, +7 & +21), higher MDA (on day -21, -7, +7 and +35) and NO (on day +7, +21 & +35) concentrations compared to normal cows. The expression of CAT and GPx4 genes was lower (P<0.05) and SOD2 gene was higher (P<0.05) in endometrial tissue of cows that developed uterine infection compared to normal cows. The relationship of peripheral levels of MDA and NO with antioxidant enzymes expression in endometrial tissue was found significant. Receiver operator characteristic analysis revealed that the concentrations of TAC on day -7 to day +35, MDA on day -21 to day +7 and NO on the day of calving to day +35 were highly correlated to the development of postpartum uterine infection in cows. It may be inferred that the low serum TAC level and high level of lipid peroxidation and NO during peripartum period influenced the endometrial expression of anitioxidative genes that compromised the uterine health during postpartum period. PMID- 28007409 TI - Sensitivity of Cytology Specimens From Bronchial Aspirate or Washing During Bronchoscopy in the Diagnosis of Lung Malignancies: An Update. AB - BACKGROUND: Routine collection of cytology specimens from bronchial aspirate or washing is thought to increase the sensitivity of bronchoscopy for diagnosing malignant lung lesions. However, the added value of this practice has not been reappraised in a context of changing epidemiology. PATIENTS AND METHODS: In a retrospective monocenter study, all cytology specimens from bronchial aspirate or washing collected between May 2011 and December 2014 and the corresponding patients' files were reviewed. The final diagnosis of malignancy was based on all available pathologic information. RESULTS: Bronchoscopy was performed in 2750 patients, and bronchial cytology specimens were collected during 667 procedures, including 474 aspirate or washing cytology specimens collected during conventional (n = 366) or ultrasound-guided (EBUS) (n = 108) bronchoscopy in 455 patients with malignant lung lesion(s). The predominant histologic types were lung adenocarcinoma (43.9%) and squamous cell carcinoma (25.2%), and 271 tumors (59.6%) were endoscopically visible. At least 1 endoscopic sample (bronchial cytology and/or biopsies and/or endobronchial ultrasound-guided samples) was positive for malignancy during 329 (69.4%) of the 474 endoscopies, including 79 samples obtained in nonvisible lesions. Only 67 bronchial cytology specimens proved positive (sensitivity, 14.7%; 95% confidence interval, 11.8%-18.3%), and only 1 specimen (0.2%) produced a diagnosis not made by other samples during the same procedure. CONCLUSION: In contrast with older studies, the added value of collecting cytology specimens from bronchial aspirate or washing during bronchoscopy in this series proved negligible, reflecting mainly the increasing prevalence of adenocarcinomas. Abandoning this technique could be considered in centers with similar expertise and patient populations. PMID- 28007411 TI - A qualitative analysis of prescribers' and dispensers' views on improving prescription drug monitoring programs. AB - BACKGROUND: Prescription drug abuse is epidemic in the United States (US). To help address the problem, most states operate prescription drug monitoring programs (PDMPs). PDMPs are designed to monitor and help control the distribution of controlled therapeutic medications and to assist prescribers and dispensers in making informed clinical decisions. To this end, PDMPs rely on timely and accurate data submission, as well as review of the data. Consequently, provider acceptance of these systems is essential to maximize their effectiveness. OBJECTIVES: This article explores licensed prescribers' and dispensers' opinions regarding prescription drug monitoring. METHODS: The study surveyed licensed prescribers and dispensers about their experiences and views on drug monitoring, prescribing and dispensing practices, and on prescription drug abuse in general. Two open-ended questions were posed as part of a larger, end-user survey. The analysis culled thematically-coded excerpts to these two questions. RESULTS: Respondents offered a range of comments that unearthed important disagreements among prescribers and dispensers over the administration and ethics pertaining to PDMPs. At the same time, some respondents suggested means to enhance PDMPs functionality. CONCLUSION: Attending to and rectifying providers' views, while considering their improvement suggestions may boost PDMPs effectiveness by maximizing buy-in and utilization. The potential speaks to advancing a tool that intends to help address alarming rates of prescription drug abuse. PMID- 28007410 TI - Clinical Impact of Frequent Surveillance Imaging in the First Year Following Chemoradiation for Locally Advanced Non-small-cell Lung Cancer. AB - OBJECTIVE: Uncertainty exists regarding the optimal surveillance imaging schedule following definitive chemoradiation (CRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) with regards to both frequency and modality. We sought to document the clinical impact of frequent (at least every 4 months) surveillance imaging. MATERIALS AND METHODS: The records of all patients treated with CRT for stage IIIA/IIIB NSCLC between August 1999 and April 2014 were reviewed. Patients were included if they underwent frequent (at least every 4 months) chest computed tomography or positron emission tomography for routine surveillance following CRT for at least 1 year or until progression or death. Radiographic findings and clinical interventions within the first year were identified. RESULTS: We identified 145 patients with LA-NSCLC treated with CRT, 63 with eligible imaging. Median age was 63.6 years (range, 41.0-86.9 years). Asymptomatic recurrence was radiographically detected in 38 (60.3%). Twenty-one (33.3%) initiated systemic therapy. Two (3.2%) underwent definitive-intent treatment for isolated disease, including lobectomy for a histologically distinct primary NSCLC and stereotactic radiotherapy for an isolated recurrence, both of whom subsequently progressed. Eleven patients (17.5%) received no further therapy. Five patients (7.9%) underwent additional diagnostic procedures for false-positive findings. CONCLUSIONS: Frequent surveillance within the first year following CRT for LA NSCLC lung cancer detects asymptomatic recurrence in a high proportion of patients. However, definitive-intent interventions were infrequent. The predominant benefit of frequent surveillance appears to be expedient initiation of palliative systemic therapy. Evidence-based algorithms for surveillance are needed, and should account for expected patient tolerance of and willingness to undergo additional cancer-directed therapies. PMID- 28007412 TI - Adherence to medication and characteristics of Japanese patients with non valvular atrial fibrillation. AB - BACKGROUND: Adherence to medication plays an important role in the prevention of morbidity and mortality in non-valvular atrial fibrillation (NVAF) patients. The aim of this study is to assess adherence to medication and risk factors for non adherence in Japanese NVAF patients who are prescribed anticoagulants. METHODS: A total of 378 outpatients with NVAF who completed self-reported questionnaires were analyzed in this prospective study (mean age 69+/-12 years; 26% female). Self-reported adherence to cardiovascular drugs including anticoagulants was measured with a modified Siegal scale. Depression was defined as a Patient Health Questionnaire-9 score of >=10. Univariate and multivariate analyses were performed on several variables to analyze factors affecting non-adherence. RESULTS: In total, 291 (77%) of our patients received warfarin, and the remainder received direct oral anticoagulants. Fifty-two (14%) patients were defined as non adherent. Univariate analyses showed that age <65 years, >=2 times daily dosing of cardiovascular drugs and employment, but not depression, were significantly associated with non-adherence, 1.87 (95% CI: 1.01-3.42, p=0.04), 2.97 (95% CI: 1.64-5.49, p<0.01), 2.11 (95% CI: 1.16-3.93, p=0.01), and 0.74 (95% CI: 0.26 2.64), respectively. Multivariate analysis showed that only >=2 times daily dosing was a significant independent risk factor (HR 3.06, 95% CI: 1.67-5.69, p<0.01). CONCLUSIONS: Our study showed that the prevalence of non-adherence to medications was 14% in NVAF patients. Frequent daily dosing was an independent risk factor for non-adherence to medication (UMIN-CTR No. UMIN 000023514). PMID- 28007413 TI - Association of ZFHX3 gene variation with atrial fibrillation, cerebral infarction, and lung thromboembolism: An autopsy study. AB - AIM: We aimed to study a single nucleotide polymorphism (SNP), rs2106261, in the transcription factor gene, ZFHX3, in atrial fibrillation (AF) and other related phenotypes by phenome scanning in a Japanese population. METHOD: We retrieved consecutive autopsy data (n=2433, mean age=80 years) from the Japanese SNP database for geriatric diseases (JG-SNP). Clinical data, including an AF diagnosis, were collected from medical charts. Genotyping was performed with the DNA chip method. We also analyzed 42 pathological and 26 clinical phenotypes, including cerebral infarctions (CIs) and lung thromboembolisms (LTs), diagnosed by macroscopic inspection during the autopsy. RESULT: Among the 2433 patients with available data, 18.6% had AF, 29.4% had CI, and 4.9% had LT phenotypes. The A allele of the rs2106261 SNP was significantly associated with AF, after adjusting for age, sex, diabetes, hypertension, and smoking (AA+AG/GG, OR=1.51, 95%CI: 1.16-1.97, p=0.002). In the entire cohort, CI was not associated with rs2106261 (p=0.14). However, among patients under 80 years old, rs2106261 was significantly associated with CI (AA+AG/GG, OR=1.57, 95%CI: 1.09-2.26, p=0.01). LT was also associated with rs2106261 (AA+AG/GG, OR=1.99, 95%CI: 1.31-3.01, p=0.001). Associations between rs2106261 and CI and LT remained positive after adjusting for the presence of AF, which indicated that this SNP variant might serve as an independent risk marker. CONCLUSION: We showed that the ZFHX3 polymorphism, rs2106261 (A allele), was a risk marker for AF and AF-related phenotypes. The roles of this variant in the development of AF and its related phenotypes warrant further investigation. PMID- 28007414 TI - Characterization of lead-containing aerosol particles in Xiamen during and after Spring Festival by single-particle aerosol mass spectrometry. AB - To comparatively analyze lead (Pb)-containing particles during and after the Chinese Spring Festival (SF), real-time single-particle aerosol mass spectrometry (SPAMS) was conducted in Xiamen during February 9-19 and March 4-14, 2013. Pb containing particles were found in 2.4% and 5.3% of the total particle numbers during and after SF, respectively. Based on the SPAMS mass spectral results, the Pb-containing particles were classified into three major types and 11 subtypes: Pb-rich particles comprising Pb-nitrate, Pb-sulfate and Pb-chloride; K-rich particles comprising K-nitrate, K-sulfate, K-metal, K-carbonaceous, K-phosphate, and K-chloride; and metal particles including Fe-rich and Mn-nitrate particles. During SF, lower contributions of Pb-containing particles were due to the effect of the SF holiday. Firework emissions contributed little to the Pb-containing particles. K-rich particles were a major contribution to Pb-containing particles during SF, accounting for approximately 70% of the total number of Pb-containing particles. After SF, significantly increased Pb-containing particles were observed, coincided with NO2 and SO2, due to increased industrial activities and other anthropogenic activities, and Pb-rich particles increased to approximately 50.3% of the total number of Pb-containing particles. Local industrial emissions and the stagnant meteorological conditions resulted in the higher concentrations of Pb-containing particles in the early morning after SF, especially Pb-nitrate particles. This study provides data on the in-situ monitoring of Pb emissions during and after SF and could be helpful for the mitigation of Pb pollution. PMID- 28007415 TI - Characterizing sources and natural attenuation of nitrate contamination in the Baix Ter aquifer system (NE Spain) using a multi-isotope approach. AB - Nitrate pollution is a widespread issue affecting global water resources with significant economic and health effects. Knowledge of both the corresponding pollution sources and of processes naturally attenuating them is thus of crucial importance in assessing water management policies and the impact of anthropogenic activities. In this study, an approach combining hydrodynamic, hydrochemical and multi-isotope systematics (8 isotopes) is used to characterize the sources of nitrate pollution and potential natural attenuation processes in a polluted basin of NE Spain. delta2H and delta18O isotopes were used to further characterize the sources of recharge of the aquifers. Results show that NO3- is not homogeneously distributed and presents a large range of concentrations, from no NO3- to up to 480mgL-1. delta15N and delta18O of dissolved NO3- identified manure as the main source of nitrate, although sewage and mineral fertilizers can also be isotopically detected using boron isotopes (delta11B) and delta34S and delta18O of dissolved sulphate, respectively. The multi-isotope approach proved that natural denitrification is occurring, especially in near-river environments or in areas hydrologically related to fault zones. delta34S and delta18O indicated that denitrification is not driven by pyrite oxidation but rather by the oxidation of organic matter. This could not be confirmed by the study of delta13CHCO3 that was buffered by the entanglement of other processes and sources. PMID- 28007416 TI - A comprehensive methodology for the multidimensional and synchronic data collecting in soundscape. AB - The soundscape paradigm is comprised of complex living systems where individuals interact moment-by-moment among one another and with the physical environment. The real environments provide promising conditions to reveal deep soundscape behavior, including the multiple components involved and their interrelations as a whole. However, measuring and analyzing the numerous simultaneous variables of soundscape represents a challenge that is not completely understood. This work proposes and applies a comprehensive methodology for multidimensional and synchronic data collection in soundscape. The soundscape variables were organized into three main entities: experienced environment, acoustic environment, and extra-acoustic environment, containing, in turn, subgroups of variables called components. The variables contained in these components were acquired through synchronic field techniques that include surveys, acoustic measurements, audio recordings, photography, and video. The proposed methodology was tested, optimized, and applied in diverse open environments, including squares, parks, fountains, university campuses, streets, and pedestrian areas. The systematization of this comprehensive methodology provides a framework for soundscape research, a support for urban and environment management, and a preliminary procedure for standardization in soundscape data collecting. PMID- 28007417 TI - Outcomes of laparoscopic Kasai portoenterostomy for biliary atresia: A systematic review. AB - AIMS: Biliary atresia (BA) is a rare disease for which mainstay of treatment consists of open Kasai portoenterostomy. The aim of this review was to assess the outcomes of laparoscopic Kasai portoenterostomy, which offers potential benefits of minimally invasive surgery. Outcomes identified were postoperative cholangitis rates, incidence of adhesions at subsequent liver transplantation, native liver survival rates and actuarial survival rates. METHODS: A comprehensive systematic literature search was conducted in the PubMed and Cochrane databases using the keywords hepatic portoenterostomy, biliary atresia and laparoscopy. Robotic cases were excluded. RESULTS: Ten studies (n=149 patients) were included in this review. The mean age at the time of operation was 66 (range 14-119) days. The mean operative time was 261 (range 120-662) minutes. The rate of postoperative cholangitis was 34% (range 11%-50%). The mean native liver survival rate was 57% (range 33%-78%) at 6months and 47% (range 8%-76%) at 2years. Mean actuarial survival rate was 87% (range 54%-100%) at 2years. Subsequent adhesions were reported in 4 patients. Two patients had dense adhesions and 2 had no adhesions. CONCLUSIONS: Although laparoscopic Kasai portoenterostomy is a feasible operation, outcomes in terms of native liver survival rates and actuarial survival rates are unfavourable compared to conventional surgery. There is no evidence that laparoscopic Kasai is associated with fewer adhesions at subsequent liver transplantation. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Treatment study. PMID- 28007418 TI - A new and revised diagnostic criterion for neurocysticercosis: Issues about diagnosis are still unresolved. PMID- 28007419 TI - Child and adult exposure and health risk evaluation following the use of metal- and metalloid-containing costume cosmetics sold in the United States. AB - Costume cosmetics (lipstick, body paints, eyeshadow) were analyzed for metals using inductively coupled plasma mass spectrometry (ICP-MS). Sb was detected in all samples (range: 0.12-6.3 mg/kg; d.f. 100%), followed by Pb (<0.15-9.3 mg/kg), Ni (<0.20-6.3 mg/kg), Co (<0.5-2.0 mg/kg); with d.f. 80% each, Hg (<0.00015 0.0020 mg/kg; d.f. 50%) and As (0.53 mg/kg, d.f. 10%). Ingestion and dermal exposures were estimated for child- and adult-intermittent and adult-occupational users. Adult-occupational users exceeded the U.S. EPA Reference Dose (RfD) for Sb and the CA Proposition 65 maximum allowable dose level (MADL) for Pb was exceeded for all user scenarios. The Pb dose from body paint was sufficient to raise blood lead levels (BLL) in all user scenarios above baseline BLLs from 0.2 MUg/dL to 1.9 MUg/dL per the Adult Lead Model (ALM) and child Integrated Exposure Uptake Biokinetic (IEUBK) blood Pb models. Change in BLL was less than 1 MUg/dL amongst the child and adult-intermittent users, the benchmark change in BLL developed for health risk assessments for children. Adult-occupational users exceeded the CA Proposition 65 NSRL intake value of 15 MUg/day, which corresponds to an increase of 1.2 MUg/dL above baseline levels using ALM. Exposure of occupational users of costume cosmetics should be evaluated further to prevent unnecessary metal exposure. PMID- 28007420 TI - Pyruvate dehydrogenase complex regulator (PdhR) gene deletion boosts glucose metabolism in Escherichia coli under oxygen-limited culture conditions. AB - Pyruvate dehydrogenase complex regulator (PdhR) is a transcriptional regulator that negatively regulates formation of pyruvate dehydrogenase complex (PDHc), NADH dehydrogenase (NDH)-2, and cytochrome bo3 oxidase in Escherichia coli. To investigate the effects of a PdhR defect on glucose metabolism, a pdhR deletion mutant was derived from the wild-type E. coli W1485 strain by lambda Red-mediated recombination. While no difference in the fermentation profiles was observed between the two strains under oxygen-sufficient conditions, under oxygen-limited conditions, the growth level of the wild-type strain was significantly decreased with retarded glucose consumption accompanied by by-production of substantial amounts of pyruvic acid and acetic acid. In contrast, the mutant grew and consumed glucose more efficiently than did the wild-type strain with enhanced respiration, little by-production of pyruvic acid, less production yield and rates of acetic acid, thus displaying robust metabolic activity. As expected, increased activities of PDHc and NDH-2 were observed in the mutant. The increased activity of PDHc may explain the loss of pyruvic acid by-production, probably leading to decreased acetic acid formation, and the increased activity of NDH-2 may explain the enhanced respiration. Measurement of the intracellular NAD+/NADH ratio in the mutant revealed more oxidative or more reductive intracellular environments than those in the wild-type strain under oxygen-sufficient and limited conditions, respectively, suggesting another role of PdhR: maintaining redox balance in E. coli. The overall results demonstrate the biotechnological advantages of pdhR deletion in boosting glucose metabolism and also improve our understanding of the role of PdhR in bacterial physiology. PMID- 28007421 TI - Effect of freeze-thaw process on physical properties, microbial activities and population structures of anaerobic sludge. AB - Effects of the freeze-thaw process on physical properties, cell viability, microbial activities and population structures of anaerobic sludge were investigated. It was found that the sludge volume index was greatly reduced from 16.4 mL/g in the original sludge to 4.0 mL/g in the solid fraction of the frozen thawed sludge. Even though the freeze-thaw process decreased cell viability in the solid fraction of the frozen-thawed sludge, microbial activity tests showed that the freeze-thaw process enhanced acidogenic activity approximately 20%. The enhanced acidogenic activity of the solid fraction was in good agreement with the enrichment of Clostridiaceae, Porphyromonadaceae and Propionibacteriaceae found in the solid fraction. The relative abundances of Proteobacteria families Oxalobacteraceae, Moraxellaceae, and Pseudomonadaceae were found to be highest in the liquid fraction where they form a substantial proportion of the bacterial community (a total of 59%). PMID- 28007422 TI - Transulnar approach for coronary catheterization in patients with a harvested ipsilateral radial artery: A case series. AB - Forearm approach for coronary catheterization is associated with better outcomes, compared to the femoral approach. However, the possibility of post catheterization forearm artery occlusion is a medical concern, which leads many patients to be treated transfemorally. We present a case series of patients who had a harvested radial artery and were successfully catheterized from ipsilateral ulnar artery without any complications recorded. PMID- 28007423 TI - RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling. AB - Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho)biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins. PMID- 28007425 TI - Different Golgi ultrastructure across species and tissues: Implications under functional and pathological conditions, and an attempt at classification. AB - The Golgi complex (GC) is the central station of the secretory pathway, through which several paths of intracellular transport are connected. The main function of the GC is glycosylation of proteins and lipids, and their subsequent sorting. The structure of the GC is extremely complicated, although in general it is unbelievably similar across different cells types and under different functional and pathological conditions. However, there are also a lot of differences between the GCs in different cells and under different normal and pathological conditions. Here, we compare the phenotypes of the GCs in different organisms under these different conditions, in particular according to morphological criteria. We propose a classification of the GC types that reflects the different features of the GC, and that depends on the different molecular machines. PMID- 28007424 TI - Recreating the Cardiac Microenvironment in Pluripotent Stem Cell Models of Human Physiology and Disease. AB - The advent of human pluripotent stem cell (hPSC) biology has opened unprecedented opportunities for the use of tissue engineering to generate human cardiac tissue for in vitro study. Engineering cardiac constructs that recapitulate human development and disease requires faithful recreation of the cardiac niche in vitro. Here we discuss recent progress in translating the in vivo cardiac microenvironment into PSC models of the human heart. We review three key physiologic features required to recreate the cardiac niche and facilitate normal cardiac differentiation and maturation: the biochemical, biophysical, and bioelectrical signaling cues. Finally, we discuss key barriers that must be overcome to fulfill the promise of stem cell biology in preclinical applications and ultimately in clinical practice. PMID- 28007426 TI - Tetracyclines metal complexation: Significance and fate of mutual existence in the environment. AB - Concern over tetracyclines (TCs) complexation with metals in the environment is growing as a new class of emerging contaminants. TCs exist as a different net charged species depending on their dissociation constants, pH and the surrounding environment. One of the key concerns about TCs is its strong tendency to interact with various metal ions and form metal complexes. Moreover, co-existence of TCs and metals in the environment and their interactions has shown increased antibiotic resistance. Despite extensive research on TCs complexation, investigations on their antibiotic efficiency and pharmacological profile in bacteria have been limited. In addition, the current knowledge on TCs metal complexation, their fate and risk assessment in the environment are inadequate to obtain a clear understanding of their consequences on living systems. This indicates that vital and comprehensive studies on TCs-metal complexation, especially towards growing antibiotic resistance trends are required. This review summarizes the role of TCs metal complexation on the development of antibiotic resistance. Furthermore, impact of metal complexation on degradation, toxicity and the fate of TCs in the environment are discussed and future recommendations have been made. PMID- 28007427 TI - Prophylaxis with topical azithromycin against Lyme borreliosis. PMID- 28007428 TI - Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial. AB - BACKGROUND: Lyme borreliosis develops in 1-5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings. METHODS: In this randomised, double blind, placebo-controlled, multicentre trial done in 28 study sites in Germany and Austria, adults were equally assigned to receive topical 10% azithromycin or placebo twice daily for 3 consecutive days, within 72 h of a tick bite being confirmed. Randomisation numbers, which were stratified by study site, were accessed in study centres via an interactive voice-response system, by pharmacists not involved in the study. The primary outcome was the number of treatment failures, defined as erythema migrans, seroconversion, or both, in participants who were seronegative at baseline, had no further tick bites during the study, and had serology results available at 8 weeks (intention-to-treat [ITT] population). This study is registered with EudraCT, number 2011-000117-39. FINDINGS: Between July 7, 2011, and Dec 3, 2012, 1371 participants were randomly assigned to treatment, of whom 995 were included in the ITT population. The trial was stopped early because an improvement in the primary endpoint in the group receiving azithromycin was not reached. At 8 weeks, 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure (odds ratio 0.97, 95% CI 0.42-2.26, p=0.47). Topical azithromycin was well tolerated. Similar numbers of patients had adverse events in the two groups (175 [26%] of 505 vs 177 [26%] of 490, p=0.87), and most adverse events were mild. INTERPRETATION: Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks. FUNDING: Ixodes AG. PMID- 28007429 TI - Redescription and molecular phylogeny of the type species for two main metopid genera, Metopus es (Muller, 1776) Lauterborn, 1916 and Brachonella contorta (Levander, 1894) Jankowski, 1964 (Metopida, Ciliophora), based on broad geographic sampling. AB - Metopid ciliates occupy terrestrial, freshwater, and marine habitats worldwide, playing important roles as predominant consumers of bacteria, flagellates, algae, and diatoms in hypoxic environments. Metopus and Brachonella are the most species rich metopid genera, however most of their species have not been studied by modern methods Here, we report the morphologic, morphometric and molecular characterization, and phylogeny of Metopus es and Brachonella contorta, both types of their respective genera, collected in a broad global sampling effort. Five strains of M. es and three strains of B. contorta were studied in detail, providing the first correlation of morphology, morphometrics, and 18S rRNA gene sequencing for both. We submitted 29 new 18S rRNA gene sequences to GenBank. Phylogenetic analyses yielded trees of similar topology. A strongly supported Metopus es clade is sister to the Brachonella contorta clade. Our analysis shows genus Metopus is not monophyletic. The monophyly of Brachonella cannot yet be determined due to lack of sequences for other species of this genus in molecular databases. Both species appear to have a global distribution. Metopus es was not found in Africa, probably reflecting low sampling effort. Strains of both species showed low 18S rRNA gene sequence divergence despite wide geographic separation. PMID- 28007430 TI - Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease. AB - Canavan disease is a fatal neurological disorder caused by defects in the metabolism of N-acetyl-l-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA observed in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-associated enzyme responsible for the synthesis of NAA, aspartate N acetyltransferase (ANAT), has recently been purified and examined (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and soluble form of ANAT we can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compound libraries. Two core structures of these moderate binding compounds have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition constants (Ki values) against ANAT. Slowing the production of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease. PMID- 28007431 TI - Quantifying in vivo murine antigen-specific T cell responses without requirement for prior knowledge of antigen identity. AB - Extracorporeal Photochemotherapy (ECP) is a widely applied anti-cancer immunotherapy for patients with cutaneous T cell lymphoma (CTCL). By using apoptotic malignant cells as a source of patient-specific tumor antigen, it enables clinically relevant and curative anti-CTCL immunity, with potential efficacy in other tumors. Currentmethods to track patient-specific responses are tedious, and new methods are needed to assess putative global immunity. We developed a clinically practical method to assess antigen-specific T cell activation that does not rely on knowledge of the particular antigen, thereby eliminating the requirement for patient-specific reagents. In the OT-I transgenic murine system, we quantified calcium flux to reveal early T cell engagement by antigen presenting cells constitutively displaying a model antigenic peptide, ovalbumin (OVA)-derived SIINFEKL. We detected calcium flux in OVA-specific T cells, triggered by specific T cell receptor engagement by SIINFEKL peptide loaded DC. This approach led to sensitive detection of antigen-specific calcium flux (ACF) down to a peptide-loading concentration of ~10-3uM and at a frequency of ~0.1% OT-I cells among wild-type (WT), non-responding cells. Antigen-specific T cells were detected in spleen, lymph nodes, and peripheral blood after adoptive transfer into control recipient mice. Methods like this for assessing therapeutic response are lacking in patients currently on immune-based therapies, such as ECP, where assessment of clinical response is made by delayed measurement of the size of the malignant clone. These findings suggest an early, practical way to measure therapeutically-induced anti-tumor responses in ECP-treated patients that have been immunized against their malignant cells. PMID- 28007432 TI - 188Re image performance assessment using small animal multi-pinhole SPECT/PET/CT system. AB - PURPOSE: The goal of this study was to investigate the performance of a pre clinical SPECT/PET/CT system for 188Re imaging. METHODS: Phantom experiments were performed aiming to assess the characteristics of two multi-pinhole collimators: ultra-high resolution collimator (UHRC) and high-energy ultra high resolution collimator (HE-URHC) for imaging 188Re. The spatial resolution, image contrast and contrast-to-noise ratio (CNR) were investigated using micro-Jaszczak phantoms. Additionally, the quantification accuracy of 188Re images was evaluated using two custom-designed phantoms. The 188Re images were compared to those obtained with 99mTc (gold standard); the acquired energy spectra were analyzed and Monte-Carlo simulations of the UHRC were performed. To verify our findings, a C57BL/6-mouse was injected with 188Re-microspheres and scanned with both collimators. RESULTS: The spatial resolution achieved in 188Re images was comparable to that of 99mTc. Acquisitions using HE-UHRC yielded 188Re images with higher contrast and CNR than UHRC. Studies of quantitative accuracy of 188Re images resulted in <10% errors for both collimators when the activity was calculated within a small VOI around the object of interest. Similar quantification accuracy was achieved for 99mTc. However, 188Re images showed much higher levels of noise in the background. Monte-Carlo simulations showed that 188Re imaging with UHRC is severely affected by down-scattered photons from high energy emissions. The mouse images showed similar biodistribution of 188Re microspheres for both collimators. CONCLUSIONS: VECTor/CT provided 188Re images quantitatively accurate and with quality comparable to 99mTc. However, due to large penetration of UHRC by high-energy photons, the use of the HE-UHRC for imaging 188Re in VECTor/CT is recommended. PMID- 28007433 TI - Erratum to "A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding" [Neurobiol. Dis. 95 (2016) 54-65]. PMID- 28007434 TI - Corrigendum to "Prospects for mTOR-mediated functional repair after central nervous system trauma" [Neurobiol. Dis. 85 (2016) 99-110]. PMID- 28007435 TI - Abnormal uterine bleeding in premenopausal women and the role of body mass index. PMID- 28007436 TI - Reply. PMID- 28007437 TI - Reply. PMID- 28007438 TI - Progressive uterorenal denervation may contribute to both placental and cardiovascular syndromes? PMID- 28007439 TI - Patients with diabetes are at high risk of serious medication errors at hospital: Interest of clinical pharmacist intervention to improve healthcare. AB - BACKGROUND: Medication errors (ME) are major public health issues in hospitals because of their consequences on patients' morbi-mortality. This study aims to evaluate the prevalence of ME at admission and discharge of hospitalization in diabetic and non-diabetic patients, and determine their potential clinical impact. METHOD: This prospective observational study was conducted at the Endocrinology-Diabetology-Nutrition Department. All adult patients admitted were eligible. A total of 904 patients were included, of which 671 (74.2%) with diabetes mellitus. Clinical pharmacists conducted medication reconciliation: they collected the Best Possible Medication History and then compared it with admission and discharge prescriptions to identify medication discrepancies. ME were defined as unintended medication discrepancies if corrected by the physician. RESULTS: Clinical pharmacists allowed correcting ME in 176/904 (19.5%) patients at admission and in 86/865 (9.9%) patients at discharge. More than half of ME were omissions. Diabetic patients were more affected by ME than non diabetic patients, both at admission (22.1% vs 12.0%, p<0.001) and at discharge (11.4% vs 5.7%, p=0.01). The diabetic group also had more potentially severe and very severe ME. Diabetic patients had on average twice more medications than non diabetic patients (8.7+/-4.5 vs 4.4+/-3.4, p<0.001). The polypharmacy associated with diabetes, but not diabetes mellitus itself, was identified as a risk factor of ME. CONCLUSIONS: The intervention of clinical pharmacists allowed correcting 378 ME in 25.8% of the cohort before they caused harm. Clinicians, pharmacists and other health care providers should therefore work together to improve patients' safety, in particular in high-risk patients such as diabetic patients. PMID- 28007440 TI - Effects of ammonium on uranium partitioning and kaolinite mineral dissolution. AB - Ammonia gas injection is a promising technique for the remediation of uranium within the vadose zone. It can be used to manipulate the pH of a system and cause co-precipitation processes that are expected to remove uranium from the aqueous phase and decrease leaching from the solid phase. The work presented in this paper explores the effects of ammonium and sodium hydroxide on the partitioning of uranium and dissolution of the kaolinite mineral in simplified synthetic groundwaters using equilibrium batch sorption and sequential extraction experiments. It shows that there is a significant increase in uranium removal in systems with divalent cations present in the aqueous phase but not in sodium chloride synthetic groundwaters. Further, the initial conditions of the aqueous phase do not affect the dissolution of kaolinite. However, the type of base treatment does have an effect on mineral dissolution. PMID- 28007441 TI - The behavior of radiogenic particles at solidification fronts. AB - The thermal behavior of insoluble radiogenic particles at the solid-liquid interface of an advancing solidification front and its significance with regard to environmental impact are discussed. It is shown that, unlike classical particles, where the most probable behavior is engulfing by the solidification front, radiogenic particles are more likely to be rejected by the solidification front. Utilizing a simplified physical model, an adaptation of classical theoretical models is performed, where it is shown that, unlike classical particles, for radiogenic particles the mechanism is thermally driven. An analytical expression for the critical velocity of the solidification front for engulfing/rejection to occur is derived. The study could be potentially important to several fields, e.g. in engineering applications where technological processes for the physical removal of radionuclide particles dispersed throughout another substance by inducing solidification could be envisaged, in planetary science where the occurrence of radiogenic concentration could result in the possibility of the eruption of primordial comet/planetoids, or, if specific conditions are suitable, particle ejection may result in an increase in concentration as the front moves, which can translate into the formation of hot spots. PMID- 28007442 TI - Analysis of sheep alpha-synuclein provides a molecular strategy for the reduction of fibrillation. AB - Parkinson's disease (PD) presents with neuropathological inclusions called Lewy bodies, which are primarily composed of fibrillar alpha-synuclein. Recently, we characterized sheep with Gaucher disease and since GBA1 mutations represent the highest genetic risk factor for PD, we have investigated alpha-synuclein fibrillation in the sheep. Here we demonstrate that differences in six amino acid residues between sheep and human alpha-synuclein significantly alter in vitro fibril formation. Circular dichroism of recombinant human and sheep alpha synuclein show that both proteins adopt the same secondary structure. Fibrils from human and sheep alpha-synuclein formed at pH7.0 or 4.5 were analyzed by Transmission Electron Microscopy (TEM). Unexpectedly, sheep alpha-synuclein form fibrils much less readily than human alpha-synuclein and this difference was more pronounced at the lysosomal pH of 4.5. Aggregation-propensity and intrinsic solubility analysis revealed that sheep alpha-synuclein had lower aggregation propensity and higher solubility. As a result of these observations, TEM was used to analyze fibrils formed at pH4.5 of various "sheep-like" human or "human-like" sheep mutant alpha-synucleins, together with their wild-type forms. Thioflavin T was used to monitor in situ alpha-synuclein fibril formation at pH7.0 and 4.5. Results show that "sheep-like" human alpha-synuclein has substantially lower fibril aggregation, and "human-like" sheep alpha-synuclein aggregates faster than wild-type forms, respectively. Seeding with WT human alpha-synuclein showed that "sheep-like" human alpha-synuclein could not be seeded, providing further evidence that sheep sequence is resistant to fibrillation. These findings provide new avenues to prevent/reduce fibrillation in PD, which may aid in the development of therapies. PMID- 28007443 TI - Translational misreading, amino acid misincorporation and misinterpretations. The case of the flavocytochrome b2 H373Q variant. AB - Amino acid misincorporation during protein synthesis occurs naturally at a low level. Protein sequence errors, depending on the level and the nature of the misincorporation, can have various consequences. When site-directed mutagenesis is used as a tool for understanding the role of a side chain in enzyme catalysis, misincorporation in a variant with intrinsically low activity may lead to misinterpretations concerning the enzyme mechanism. We report here one more example of such a problem, dealing with flavocytochrome b2 (Fcb2), a lactate dehydrogenase, member of a family of FMN-dependent L-2-hydroxy acid oxidizing enzymes. Two papers have described the properties of the Fcb2 catalytic base H373Q variant, each one using a different expression system with the same base change for the mutation. The two papers found similar apparent kinetic parameters. But the first one demonstrated the existence of a low level of histidine misincorporation, which led to an important correction of the variant residual activity (Gaume et al. (1995) Biochimie, 77, 621). The second paper did not investigate the possibility of a misincorporation (Tsai et al. (2007) Biochemistry, 46, 7844). The two papers had different mechanistic conclusions. We show here that in this case the misincorporation does not depend on the expression system. We bring the proof that Tsai et al. (2007) were led to an erroneous mechanistic conclusion for having missed the phenomenon as well as for having misinterpreted the crystal structure of the variant. This work is another illustration of the caution one should exercise when characterizing enzyme variants with low activity. PMID- 28007444 TI - Effectiveness of an Educational Intervention on Reducing Misconceptions Among Ethnic Minorities With Complicated Mild to Severe Traumatic Brain Injury. AB - OBJECTIVE: To evaluate the effectiveness of an educational intervention designed to reduce traumatic brain injury (TBI)-related misconceptions among blacks and Latinos with complicated mild to severe TBI. DESIGN: Randomized controlled trial with masked 1-month follow-up. SETTING: Community. PARTICIPANTS: Persons (N=52) with complicated mild to severe TBI (mean best day 1 Glasgow Coma Scale score, 11.27+/-3.89) were randomly recruited from 141 eligible participants (mean age, 37.71+/-13.88y; age range, 19-66y; mean months postinjury, 24.69+/-11.50); 25 participants (48.1%) of participants were black and 27 (51.9%) were Hispanic/Latino. Of the Hispanic/Latino participants, 18 (66.7%) were non-U.S. born and 12 (44.4%) spoke Spanish as their primary language. Twenty-seven individuals were randomized to the educational intervention group and 25 were randomized to the wait-list control group. INTERVENTIONS: Single-session educational intervention with written materials provided in English or Spanish. MAIN OUTCOME MEASURES: Forty-item Common Misconceptions about Traumatic Brain Injury Questionnaire administered at baseline and 1-month follow-up. RESULTS: After controlling for ethnic and language differences, a significant between group main effect (P=.010) and a significant time-group interaction for the Common Misconceptions about Traumatic Brain Injury Questionnaire were noted (Wilks Lambda=.89; F1,46=6.00; P=.02). The intervention group showed a decrease in TBI misconception percentages, whereas the wait-list control group maintained similar percentages. At 1-month follow-up, the wait-list control group reported more misconceptions than did the intervention group (P=.019). CONCLUSIONS: An educational intervention developed to address the recovery process, common symptoms, and ways to handle the symptoms provides promise as a tool to decrease TBI misconceptions among persons from ethnically and educationally diverse backgrounds. The effects of therapist characteristics and the client-therapist relation on outcomes should be further explored. PMID- 28007445 TI - Functional Goals and Predictors of Their Attainment in Low-Income Community Dwelling Older Adults. AB - OBJECTIVE: To describe functional goals and factors associated with goal attainment among low-income older adults with disabilities living in the community. DESIGN: Secondary analysis. SETTING: Participants' homes. PARTICIPANTS: Older adults (N=226) with disability who participated in the Community Aging in Place, Advancing Better Living for Elders trial. INTERVENTIONS: A 5-month, home-based, person-directed, structured program delivered by an interprofessional team: occupational therapist, registered nurse, and handyman. MAIN OUTCOME MEASURES: Process of occupational therapist goal setting and attainment at the final occupational therapist visit. RESULTS: Participants identified 728 functional goals (mean of 3.2 goals per participant), most commonly related to transferring (22.0%; n=160 goals), changing or maintaining body position (21.4%; n=156 goals), and stair climbing (13.0%; n=95 goals). Participants attained 73.5% (n=535) of goals. Goal attainment was highest for stair climbing (86.3%), transferring (85.6%), and self-care (84.6%); walking goals were less likely attained (54.0%). Goal attainment was not associated with age, sex, education, depressive symptoms, function, or health-related quality of life but was less likely among participants who had severe pain compared with those without pain (adjusted odds ratio, 0.38; 95% confidence interval, 0.17 0.86). When participant readiness to change score increases by 1 point on the 4 point scale, goal attainment was 62% more likely (adjusted odds ratio, 1.62; 95% confidence interval, 1.14-2.29). CONCLUSIONS: Home-based collaborative goal setting between older adults and occupational therapists is feasible and particularly effective when individuals are ready or willing to adopt new strategies to achieve identified goals. PMID- 28007446 TI - Delphi Study to Determine Rehabilitation Research Priorities for Older Adults With Cancer. AB - OBJECTIVE: To solicit expert opinions and develop consensus around the research that is needed to improve cancer rehabilitation for older adults. DESIGN: Delphi methods provided a structured process to elicit and prioritize research questions from national experts. SETTING: National, Web-based survey. PARTICIPANTS: Members (N=32) of the American Congress of Rehabilitation Medicine completed at least 1 of 3 investigator-developed surveys. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: In the first survey, participants identified up to 5 research questions that needed to be answered to improve cancer rehabilitation for older adults. In 2 subsequent surveys, participants viewed the compilation of questions, rated the importance of each question, and identified the 5 most important questions. This generated priority scores for each question. Consensus scores were created to describe the degree of agreement around the priority of each question. RESULTS: Highest priority research concerns the epidemiology and measurement of function and disability in older adult cancer survivors; the effects of cancer rehabilitation interventions on falls, disability, participation, survival, costs, quality of care, and health care utilization; and testing models of care that facilitate referrals from oncology to rehabilitation providers as part of coordinated, multicomponent care. CONCLUSIONS: A multipronged approach is needed to fill these gaps, including targeted funding opportunities developed with an advisory panel of cancer rehabilitation experts, development of a research network to facilitate novel collaborations and grant proposals, and coordinated efforts of clinical groups to advocate for funding, practice change, and policy change. PMID- 28007447 TI - Synthesis of some ester derivatives of 4'-demethoxyepipodophyllotoxin/2'-chloro 4'-demethoxyepipodophyllotoxin as insecticidal agents against oriental armyworm, Mythimna separata Walker. AB - Podophyllotoxin is a naturally occurring non-alkaloid toxin isolated from the roots and rhizomes of Podophyllum peltatum and P. hexandrum. In continuation of our program aimed at the discovery and development of natural product-based insecticides, two series of ester derivatives of 4' demethoxyepipodophyllotoxin/2'-chloro-4'-demethoxyepipodophyllotoxin were prepared. The structures of the target compounds were well characterized by 1H NMR, IR, optical rotation and mp. The precise three-dimensional structural information of 8j was further determined by single-crystal X-ray diffraction. Their insecticidal activity was tested against Mythimna separata Walker. These compounds showed delayed insecticidal activity. Among all derivatives, some compounds showed more potent insecticidal activity than toosendanin against M. separata; especially compounds 8k and 9k exhibited the most potent activity with the final mortality rates of 71.4%. Their structure-activity relationships were discussed. PMID- 28007448 TI - Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia. AB - A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50=1.0MUM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50>20MUM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin. PMID- 28007449 TI - Structural studies of influenza virus RNPs by electron microscopy indicate molecular contortions within NP supra-structures. AB - Ribonucleoprotein (RNP) complexes of influenza viruses are composed of multiple copies of the viral nucleoprotein (NP) that can form filamentous supra structures. RNPs package distinct viral genomic RNA segments of different lengths into pleomorphic influenza virions. RNPs also function in viral RNA transcription and replication. Different RNP segments have varying lengths, but all must be incorporated into virions during assembly and then released during viral entry for productive infection cycles. RNP structures serve varied functions in the viral replication cycle, therefore understanding their molecular organization and flexibility is essential to understanding these functions. Here, we show using electron tomography and image analyses that isolated RNP filaments are not rigid helical structures, but instead display variations in lengths, curvatures, and even tolerated kinks and local unwinding. Additionally, we observed NP rings within RNP preparations, which were commonly composed of 5, 6, or 7 NP molecules and were of similar widths to filaments, suggesting plasticity in NP-NP interactions mediate RNP structural polymorphism. To demonstrate that NP alone could generate rings of variable oligomeric state, we performed 2D single particle image analysis on recombinant NP and found that rings of 4 and 5 protomers dominated, but rings of all compositions up to 7 were directly observed with variable frequency. This structural flexibility may be needed as RNPs carry out the interactions and conformational changes required for RNP assembly and genome packaging as well as virus uncoating. PMID- 28007450 TI - A Review of Open and Endovascular Treatment of Superior Vena Cava Syndrome of Benign Aetiology. AB - BACKGROUND: The widespread use of central venous catheters, ports, pacemakers, and defibrillators has increased the incidence of benign superior vena cava syndrome (SVCS). This study aimed at reviewing the results of open and endovascular treatment of SVCS. METHOD: Medical literature databases were searched for relevant studies. Studies with more than five adult patients, reporting separate results for the SVC were included. Nine studies reported the results of endovascular treatment of SVCS including 136 patients followed up for a mean of 11-48 months. Causes of SVCS were central venous catheters and pacemakers (80.6%), mediastinal fibrosis (13.7%), and other (5.6%). Percutaneous transluminal angioplasty (PTA) and stenting was performed in 73.6%, PTA only in 17.3%, and thrombolysis, PTA, and stenting in 9%. Four studies reported the results of open repair of SVCS including 87 patients followed up between 30 months and 10.9 years. The causes were mediastinal fibrosis (58.4%), catheters and pacemakers (28.5%), and other (13%). Operations performed included a spiral saphenous interposition graft, other vein graft, PTFE graft, and human allograft. Thirteen patients required re-operations (15%) before discharge mainly for graft thrombosis. RESULTS: In the endovascular group technical success was 95.6%. Thirty day mortality was 0%. Regression of symptoms was reported in 97.3%. Thirty two patients (26.9%) underwent 58 secondary procedures. In the open group the 30 day mortality was 0%. Symptom regression was reported in 93.5%. Twenty-four patients (28.4%) underwent a total of 33 secondary procedures. CONCLUSIONS: Endovascular is the first line treatment for SVCS caused by intravenous devices, whereas surgery is most often performed for mediastinal fibrosis. Both treatments show good results regarding regression of the symptoms and mid-term primary patency, with a significant incidence of secondary interventions. PMID- 28007451 TI - Quantitative Changes in Pigment Epithelial Detachment Area and Volume Predict Retreatment in Polypoidal Choroidal Vasculopathy. AB - PURPOSE: To determine if changes in pigment epithelial detachment (PED) area and volume predict retreatment in polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective case-control study. METHODS: PCV patients on pro re nata (PRN) anti vascular endothelial growth factor (VEGF) therapy with >1 year follow-up at an academic retina service were included. Monthly anti-VEGF injections were given until a dry macula was achieved, and treatment deferred. Retreatment indication was recurrence of intraretinal or subretinal fluid or new hemorrhage. PED area and volume changes between visits with a dry macula ("D") and immediate preceding visits ("D-1") were analyzed with an automated optical coherence tomography-based software. Univariate and multivariate analyses were conducted to determine associations between changes in PED parameters and retreatment need at immediate subsequent visits ("D+1"). RESULTS: Twenty-two PCV patients (mean age 69.6 years) were included. Of 46 visits D, 11 (23.9%) were followed by retreatment at D+1. An increase in PED area (>0.43 mm2) and volume (>0.0245 mm3) from D-1 to D was associated with 18.2 (95% CI, 3.7-125.6; P < .001) and 101.9 (95% CI, 9.5-14 308.0; P < .001) higher retreatment odds at D+1, respectively. These associations remained significant after multivariate analyses adjusting for baseline PED area or volume, greatest linear dimension, and type of anti-VEGF agent. CONCLUSION: In PCV on PRN anti-VEGF therapy, increases in PED area and volume at one visit, despite achievement of a dry macula, are associated with retreatment at the next visit. Retreatment criteria relying on intraretinal or subretinal fluid or new hemorrhages may be expanded to include PED changes. Studies are needed to determine if using PED parameters in treatment decisions reduces recurrences. PMID- 28007452 TI - Evaluation of hazardous chemicals in edible insects and insect-based food intended for human consumption. AB - Due to the rapid increase in world population, the waste of food and resources, and non-sustainable food production practices, the use of alternative food sources is currently strongly promoted. In this perspective, insects may represent a valuable alternative to main animal food sources due to their nutritional value and sustainable production. However, edible insects may be perceived as an unappealing food source and are indeed rarely consumed in developed countries. The food safety of edible insects can thus contribute to the process of acceptance of insects as an alternative food source, changing the perception of developed countries regarding entomophagy. In the present study, the levels of organic contaminants (i.e. flame retardants, PCBs, DDT, dioxin compounds, pesticides) and metals (As, Cd, Co, Cr, Cu, Ni, Pb, Sn, Zn) were investigated in composite samples of several species of edible insects (greater wax moth, migratory locust, mealworm beetle, buffalo worm) and four insect-based food items currently commercialized in Belgium. The organic chemical mass fractions were relatively low (PCBs: 27-2065 pg/g ww; OCPs: 46-368 pg/g ww; BFRs: up to 36 pg/g ww; PFRs 783-23800 pg/g ww; dioxin compounds: up to 0.25 pg WHO TEQ/g ww) and were generally lower than those measured in common animal products. The untargeted screening analysis revealed the presence of vinyltoluene, tributylphosphate (present in 75% of the samples), and pirimiphos-methyl (identified in 50% of the samples). The levels of Cu and Zn in insects were similar to those measured in meat and fish in other studies, whereas As, Co, Cr, Pb, Sn levels were relatively low in all samples (<0.03 mg/kg ww). Our results support the possibility to consume these insect species with no additional hazards in comparison to the more commonly consumed animal products. PMID- 28007453 TI - Assessment of antimicrobial effects of food contact materials containing silver on growth of Salmonella Typhimurium. AB - Food contact materials containing antibacterial properties are progressively appearing in the market. Items intended to provide antimicrobial effects such as increased shelf life and food safety are incorporating silver materials during the manufacture of such products. This study examined the total silver content, release capacity, and antibacterial activity of three different silver-containing food contact materials: plastic food storage containers, a plastic cutting board, and food wrapping paper. Silver content and release were determined by Inductively Coupled Plasma Mass Spectrometry, and the results showed that, although the amount of silver in each product was similar, migration varied considerably with kind of material and simulant choice. Antimicrobial effect was tested by measuring the growth of Salmonella Typhimurium during or after exposure to the different food contact materials. The results showed that the food storage containers and wrapping paper delayed the growth of S. Typhimurium under certain conditions, but that these effects were short-lived. The strain of S. Typhimurium used in this study was found to be negative for the presence of tested silver resistance genes. The results of this study suggest that a thorough investigation should be required to show/claim the efficacy of silver-containing food contact materials for food safety purposes. PMID- 28007454 TI - Comparative study of hydrolytic metabolism of dimethyl phthalate, dibutyl phthalate and di(2-ethylhexyl) phthalate by microsomes of various rat tissues. AB - Phthalates are used in food packaging, and are transferred to foods as contaminants. In this study, we examined the hydrolytic metabolism of dimethyl phthalate (DMP), dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) by rat tissue microsomes. We found that carboxylesterase and lipase contribute differently to these activities. When DMP, DBP and DEHP were incubated with rat liver microsomes, DBP was most effectively hydrolyzed to the phthalate monoester, followed by DMP, and the activity toward DEHP was marginal. In contrast, small intestinal microsomes exhibited relatively higher activity toward long-side-chain phthalates. Pancreatic microsomes showed high activity toward DEHP and DBP. Liver microsomal hydrolase activity toward DMP was markedly inhibited by bis(4 nitrophenyl)phosphate, and could be extracted with Triton X-100. The activity toward DBP and DEHP was partly inhibited by carboxylesterase inhibitor, and was partly solubilized with Triton X-100. Ces1e, Ces1d and Ces1f expressed in COS cells exhibited the highest hydrolase activity toward DBP, showing a similar pattern to that of liver microsomes. Ces1e showed activity towards DMP and DEHP. Pancreatic lipase also hydrolyzed DBP and DEHP. Thus, carboxylesterase and lipase contribute differently to phthalate hydrolysis: short-side-chain phthalates are mainly hydrolyzed by carboxylesterase and long-side-chain phthalates are mainly hydrolyzed by lipase. PMID- 28007455 TI - Characterization of 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase (IspG) from Plasmodium vivax and it's potential as an antimalarial drug target. AB - The prokaryotic type Methyl Erythritol phosphate (MEP) pathway functional in the apicoplast of Plasmodium is indispensable for the erythrocytic stages of the parasite. It is the sole process of isoprenoids biosynthesis in the parasite and is different from that in humans. Among the seven enzymes known to be functional in the MEP pathway in prokaryotes, most enzymes from Plasmodium are yet uncharacterized. The penultimate enzyme of this pathway 4-hydroxy-3-methylbut-2 en-1-yl diphosphate synthase (IspG), has been shown to act as a key target molecule in prokaryotes, where its deletion results in impairment of many housekeeping functions. The present study is the first detailed report of IspG enzyme from any Plasmodium sp. We report here that the protein is highly conserved across apicomplexans and prokaryotes and it localizes to the apicoplast as evident from the immune-localization studies performed on P. vivax infected blood smears made from clinical patients. The biochemical reconstitution and in silico docking of [4Fe-4S] clusters on the protein indicate their importance for the activity of enzyme. In-silico screening of different drug entities suggested the inhibitory role of alkyne diphosphate analogues and fosmidomycin against the IspG enzyme, suggesting the potential role of this enzyme as an antimalarial target. PMID- 28007456 TI - Low-risk prostate cancer: to treat or not to treat. PMID- 28007457 TI - Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. AB - BACKGROUND: Vascular-targeted photodynamic therapy, a novel tissue-preserving treatment for low-risk prostate cancer, has shown favourable safety and efficacy results in single-arm phase 1 and 2 studies. We compared this treatment with the standard of care, active surveillance, in men with low-risk prostate cancer in a phase 3 trial. METHODS: This randomised controlled trial was done in 47 European university centres and community hospitals. Men with low-risk, localised prostate cancer (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to vascular-targeted photodynamic therapy (4 mg/kg padeliporfin intravenously over 10 min and optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 min 15 s) or active surveillance. Randomisation was done by a web-based allocation system stratified by centre with balanced blocks of two or four patients. Best practice for active surveillance at the time of study design was followed (ie, biopsy at 12-month intervals and prostate specific antigen measurement and digital rectal examination at 3-month intervals). The co-primary endpoints were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24). Analysis was by intention to treat. Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT01310894. FINDINGS: Between March 8, 2011, and April 30, 2013, we randomly assigned 206 patients to vascular-targeted photodynamic therapy and 207 patients to active surveillance. Median follow-up was 24 months (IQR 24-25). The proportion of participants who had disease progression at month 24 was 58 (28%) of 206 in the vascular-targeted photodynamic therapy group compared with 120 (58%) of 207 in the active surveillance group (adjusted hazard ratio 0.34, 95% CI 0.24-0.46; p<0.0001). 101 (49%) men in the vascular-targeted photodynamic therapy group had a negative prostate biopsy result at 24 months post treatment compared with 28 (14%) men in the active surveillance group (adjusted risk ratio 3.67, 95% CI 2.53-5.33; p<0.0001). Vascular-targeted photodynamic therapy was well tolerated. The most common grade 3-4 adverse events were prostatitis (three [2%] in the vascular-targeted photodynamic therapy group vs one [<1%] in the active surveillance group), acute urinary retention (three [2%] vs one [<1%]) and erectile dysfunction (two [1%] vs three [1%]). The most common serious adverse event in the vascular-targeted photodynamic therapy group was retention of urine (15 patients; severe in three); this event resolved within 2 months in all patients. The most common serious adverse event in the active surveillance group was myocardial infarction (three patients). INTERPRETATION: Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy. FUNDING: Steba Biotech. PMID- 28007458 TI - Oxidative stress activates the TRPM2-Ca2+-CaMKII-ROS signaling loop to induce cell death in cancer cells. AB - High intracellular levels of reactive oxygen species (ROS) cause oxidative stress that results in numerous pathologies, including cell death. Transient potential receptor melastatin-2 (TRPM2), a Ca2+-permeable cation channel, is mainly activated by intracellular adenosine diphosphate ribose (ADPR) in response to oxidative stress. Here we studied the role and mechanisms of TRPM2-mediated Ca2+ influx on oxidative stress-induced cell death in cancer cells. We found that oxidative stress activated the TRPM2-Ca2+-CaMKII cascade to inhibit early autophagy induction, which ultimately led to cell death in TRPM2 expressing cancer cells. On the other hand, TRPM2 knockdown switched cells from cell death to autophagy for survival in response to oxidative stress. Moreover, we found that oxidative stress activated the TRPM2-CaMKII cascade to further induce intracellular ROS production, which led to mitochondria fragmentation and loss of mitochondrial membrane potential. In summary, our data demonstrated that oxidative stress activates the TRPM2-Ca2+-CaMKII-ROS signal loop to inhibit autophagy and induce cell death. PMID- 28007460 TI - MRI accelerating progress in functional assessment of cystic fibrosis lung disease. PMID- 28007459 TI - Endothelial markers are associated with pancreatic necrosis and overall prognosis in acute pancreatitis: A preliminary cohort study. AB - BACKGROUND: Endothelial injury is believed to play an important role in the evolution of pancreatic microcirculatory dysfunction and pancreatic necrosis (PN) in patients with acute pancreatitis (AP). The aim of this study was to investigate the role of three endothelial markers (von Willebrand factor, vWF; E selectin; endothelial protein C receptor, EPCR) in the early phase of AP, especially the relationship between endothelial markers and PN. METHODS: From March 2015 to March 2016, 57 AP patients admitted within 72 h of symptom onset in our hospital were included for this study. Blood samples were taken on admission and the clinical characteristics and outcomes of these patients were recorded. The levels of vWF, E-selectin and EPCR were measured using ELISA for analysis and compared with other severity markers of AP. RESULTS: All the three markers were significantly different in healthy control, mild, moderate and severe AP patients. Moreover, the endothelial markers, especially vWF, also showed significant difference in patients with different extent of PN, as well as those with or without MODS. Additionally, the levels of endothelial markers correlated well with other commonly used markers of AP severity. CONCLUSION: Elevated endothelium-related mediators (vWF, E-selectin and EPCR) appear to participate in the development of PN and may be a potential indicator of overall prognosis. Our results may help clinicians better understand the pathophysiological process of the development of PN. PMID- 28007461 TI - Bio-oil extraction of Jatropha curcas with ionic liquid co-solvent: Fate of biomass protein. AB - The fate of oil-seed biomass protein has been tracked through all steps of a multi-phase extraction process using an ionic liquid based co-solvent system previously demonstrated to extract bio-oil and phorbol esters and to recover fermentable sugars from Jatropha oil seed. These analyses, however, did not address the fate of biomass protein. This work demonstrated that the majority of protein (~86%) tracked with the biomass with the balance lost to co-solvent (~12%) and methanol (~2%) washes. A significant portion of the ionic liquid remained with the treated biomass and required aggressive methanol washes to recover. A system analysis showed a net-positive energy balance and thus the potential of this system to produce both bio-oil and protein-rich toxin-free biomass. While these results further support Jatropha as an oil seed crop, the additional costs of solvent recovery will need to be addressed if commercialization is to be realized. PMID- 28007462 TI - Celecoxib inhibits osteoblast maturation by suppressing the expression of Wnt target genes. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to impair bone healing. We previously reported that in colon cancer cells, celecoxib, a COX-2 selective NSAID, inhibited the canonical Wnt/beta-catenin signaling pathway. Since this pathway also plays an important role in osteoblast growth and differentiation, we examined the effect of celecoxib on maturation of osteoblast like cell line MC3T3-E1. Celecoxib induced degradation of transcription factor 7 like 2, a key transcription factor of the canonical Wnt pathway. Subsequently, we analyzed the effect of celecoxib on two osteoblast differentiation markers; runt related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), both of which are the products of the canonical Wnt pathway target genes. Celecoxib inhibited the expression of both RUNX2 and ALP by suppressing their promoter activity. Consistent with these observations, celecoxib also strongly inhibited osteoblast-mediated mineralization. These results suggest that celecoxib inhibits osteoblast maturation by suppressing Wnt target genes, and this could be the mechanism that NSAIDs inhibit bone formation and fracture healing. PMID- 28007463 TI - Electroretinographic anomalies in medicated and drug free patients with major depression: Tagging the developmental roots of major psychiatric disorders. AB - The retina is tagged as an approachable part of the brain due to its common embryonic origin and appears as a promising site of investigation for psychiatric disorders. Retinal function is assessed best with the electroretinogram (ERG), which was obtained in a large sample of patients with major depressive disorder and matched controls. ERG cone and rod luminance response functions were recorded in non-dilated eyes in 100 major depressive disorder patients (MDD) and 100 controls, (mean age of 42.8 and 40.9y. o. respectively). Amongst MDD patients, 17 were drug free (mean age 41.2y. o). In medicated patients, at the cone level, a prolonged b-wave was observed (p<=0.01). In drug free patients a prolonged b-wave was discovered only when averaging the implicit time of the 3 highest b-wave amplitudes of the photopic hill. For the medicated patients, the mixed rods/cones a-wave was reduced (p=0.01) whereas a trend (p=0.06) was observed for the pure rod b-wave (reduced) and the mixed rods/cones (reduced and prolonged; p=0.05). In drug free patients, a similar pattern could be observed in terms of effect sizes. Overall, medicated and drug free MDD patients shared some deficits suggesting that some anomalies are present above and beyond the effect of medication. Of interest, the prolonged cone and reduced rod amplitude were reported by our group in schizophrenia patients, suggesting a common neurodevelopmental root of major psychiatric disorders. PMID- 28007464 TI - Proneness to aggression and its inhibition in schizophrenia: Interconnections between personality traits, cognitive function and emotional processing. AB - OBJECTIVE: Research on aggression in schizophrenia has focused on narrowly defined deficits, while ignoring interconnections among these impairments which provide better explanatory power. Our goal was to investigate interrelations among impairments in important domains related to aggression: personality traits, including psychopathy and impulsivity, cognition and processing of emotions. METHOD: 34 healthy controls, 37 high aggression (HAG) and 31 low aggression (LAG) patients with schizophrenia participated. The Barratt Impulsiveness Scale, Psychopathy Checklist, Wisconsin Card Sorting Test (WCST), and Emotion Recognition Test were administered. Psychiatric symptoms were assessed. Canonical Discriminant Analysis (CDA) was performed to determine how these measures distinguish among the groups and to identify underlying symptom profiles. RESULTS: CDA revealed two statistically significant profiles of deficits which differentiated the groups. The first comprises impulsivity, psychopathy, and impairments in cognition and fear recognition. It indicates proneness to aggression. The second consists of WCST perseverative errors and facial affect processing impairment; it has an inverse relationship with aggression. These profiles are linked to different psychiatric symptoms in the schizophrenic patients: The first to excitement and poor impulse control; the second to blunted affect and motor retardation. HAG's manifested primarily the first; LAG's had a moderate score on the first and a high score on the second. CONCLUSION: Proneness to aggression in schizophrenia is characterized by a multivariate confluence of impulsivity, psychopathy, cognitive difficulties and impairment in fear recognition. There exists, however, a second pattern of psychopathology that may suppress expression of aggression. These opposing patterns have important implications for integrated treatments of aggression. PMID- 28007465 TI - Poly-l-lactic acid injection-induced delayed-onset foreign body granuloma. PMID- 28007466 TI - KRAS mutation in biliary tract cholangiocarcinoma. PMID- 28007467 TI - Mortality and Androgen Deprivation Therapy as Salvage Treatment for Biochemical Recurrence after Primary Therapy for Clinically Localized Prostate Cancer. AB - PURPOSE: Androgen deprivation therapy is often used as salvage treatment in men with rising prostate specific antigen after initial radical prostatectomy or radiotherapy for clinically localized prostate cancer. Given the lack of evidence from general practice, we examined the association of salvage androgen deprivation therapy with mortality in an observational cohort study. MATERIALS AND METHODS: From 3 managed care organizations we assembled a retrospective cohort of all 5,804 men with newly diagnosed localized prostate cancer from 1995 to 2009 who had a prostate specific antigen increase (biochemical recurrence) after primary radical prostatectomy or radiotherapy. The main outcomes were all cause and prostate cancer specific mortality. We used Cox proportional hazards models to estimate mortality with salvage androgen deprivation therapy as a time dependent predictor. RESULTS: Overall salvage androgen deprivation therapy was not associated with all-cause or prostate cancer specific mortality in the prostatectomy cohort (HR 0.97, 95% CI 0.70-1.35 or HR 1.18, 95% CI 0.68-2.07) or in the radiotherapy cohort (HR 0.84, 95% CI 0.70-1.01 or HR 1.06, 95% CI 0.80 1.40, respectively). Among men with prostate specific antigen doubling time less than 9 months after the prostate specific antigen rise, salvage androgen deprivation therapy was statistically significantly associated with a decreased risk of all-cause and prostate cancer specific mortality in the prostatectomy cohort (HR 0.35, 95% CI 0.20-0.63 and HR 0.43, 95% CI 0.21-0.91) and in the radiotherapy cohort (HR 0.62, 95% CI 0.48-0.80 and HR 0.65, 95% CI 0.47-0.90, respectively). CONCLUSIONS: We found no association of salvage androgen deprivation therapy with all-cause or cause specific mortality in most men with biochemical recurrence after primary radical prostatectomy or radiotherapy for clinically localized prostate cancer. Men with quickly progressed disease may derive a clinical benefit from salvage androgen deprivation therapy. PMID- 28007469 TI - TMS combined with EEG in genetic generalized epilepsy: A phase II diagnostic accuracy study. AB - OBJECTIVES: (A) To develop a TMS-EEG stimulation and data analysis protocol in genetic generalized epilepsy (GGE). (B) To investigate the diagnostic accuracy of TMS-EEG in GGE. METHODS: Pilot experiments resulted in the development and optimization of a paired-pulse TMS-EEG protocol at rest, during hyperventilation (HV), and post-HV combined with multi-level data analysis. This protocol was applied in 11 controls (C) and 25 GGE patients (P), further dichotomized into responders to antiepileptic drugs (R, n=13) and non-responders (n-R, n=12).Features (n=57) extracted from TMS-EEG responses after multi-level analysis were given to a feature selection scheme and a Bayesian classifier, and the accuracy of assigning participants into the classes P-C and R-nR was computed. RESULTS: On the basis of the optimal feature subset, the cross-validated accuracy of TMS-EEG for the classification P-C was 0.86 at rest, 0.81 during HV and 0.92 at post-HV, whereas for R-nR the corresponding figures are 0.80, 0.78 and 0.65, respectively. Applying a fusion approach on all conditions resulted in an accuracy of 0.84 for the classification P-C and 0.76 for the classification R-nR. CONCLUSION: TMS-EEG can be used for diagnostic purposes and for assessing the response to antiepileptic drugs. SIGNIFICANCE: TMS-EEG holds significant diagnostic potential in GGE. PMID- 28007470 TI - Tumor necrosis factor-alpha expression in peripheral blood mononuclear cells correlates with early childhood social interaction in autism spectrum disorder. AB - Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Elevated blood levels of pro-inflammatory cytokines have been reported in subjects with autism spectrum disorder. On the other hand, early childhood adverse experience also increases blood levels of these cytokines. Since social experience of children with autism spectrum disorder is generally unlike to typically developing children, we hypothesized that social interaction during childhood contribute to pro-inflammatory cytokine expression in subjects with autism spectrum disorder. We compared revised Autism Diagnostic Interview scores and expression levels of pro-inflammatory cytokines in peripheral blood mononuclear cells of subjects with autism spectrum disorder (n = 30). The score of domain A on the revised Autism Diagnostic Interview, indicating social interaction impairment in early childhood, was negatively correlated with tumor necrosis factor-alpha mRNA expression level in peripheral blood mononuclear cells but not interleukin-1beta or -6. Consistently, tumor necrosis factor-alpha mRNA expression was markedly low in subjects with autism spectrum disorder compared to typically developing children who presumably experienced the regular levels of social interaction. These findings suggest that the low blood levels of tumor necrosis factor-alpha mRNA in subjects with autism spectrum disorder might be due to impaired social interaction in early childhood. PMID- 28007471 TI - Promoting Resilience in Academic Medicine: Fertile Ground for Future Work. PMID- 28007472 TI - Chemical associations and mobilization of heavy metals in fly ash from municipal solid waste incineration. AB - This study focusses on chemical and mineralogical characterization of fly ash and leached filter cake and on the determination of parameters influencing metal mobilization by leaching. Three different leaching processes of fly ash from municipal solid waste incineration (MSWI) plants in Switzerland comprise neutral, acidic and optimized acidic (+ oxidizing agent) fly ash leaching have been investigated. Fly ash is characterized by refractory particles (Al-foil, unburnt carbon, quartz, feldspar) and newly formed high-temperature phases (glass, gehlenite, wollastonite) surrounded by characteristic dust rims. Metals are carried along with the flue gas (Fe-oxides, brass) and are enriched in mineral aggregates (quartz, feldspar, wollastonite, glass) or vaporized and condensed as chlorides or sulphates. Parameters controlling the mobilization of neutral and acidic fly ash leaching are pH and redox conditions, liquid to solid ratio, extraction time and temperature. Almost no depletion for Zn, Pb, Cu and Cd is achieved by performing neutral leaching. Acidic fly ash leaching results in depletion factors of 40% for Zn, 53% for Cd, 8% for Pb and 6% for Cu. The extraction of Pb and Cu are mainly limited due to a cementation process and the formation of a PbCu0-alloy-phase and to a minor degree due to secondary precipitation (PbCl2). The addition of hydrogen peroxide during acidic fly ash leaching (optimized acidic leaching) prevents this reduction through oxidation of metallic components and thus significantly higher depletion factors for Pb (57%), Cu (30%) and Cd (92%) are achieved. The elevated metal depletion using acidic leaching in combination with hydrogen peroxide justifies the extra effort not only by reduced metal loads to the environment but also by reduced deposition costs. PMID- 28007473 TI - Selective leaching of Zn from spent alkaline batteries using environmentally friendly approaches. AB - The main aim of this work was to evaluate the possibility of using microwave or ultrasound to assist the efficient and selective leaching of Zn from spent alkaline batteries and compare the results with those obtained using the conventional method. Two different strategies were applied: acid leaching of a washed residue and alkaline leaching of the original residue. In both (acid and alkaline) approaches, the use of microwave- or ultrasound-assisted leaching increased the extraction of Zn compared with the best results obtained using conventional leaching [acid leaching (1.5mol/L H2SO4, 3h, 80 degrees C), 90% of Zn extracted; alkaline leaching (6mol/L NaOH, 3h, 80 degrees C), 42% of Zn extracted]. With acid leaching, 94% of the Zn was extracted using microwave assisted leaching (1 cycle, 30s, 1mol/L H2SO4), and 92% of the Zn was extracted using ultrasound-assisted leaching (2min, 0.1p, 20% amplitude, 1mol/L H2SO4). Ultrasound-assisted leaching resulted in a more selective (Zn/Mn ratio of 5.1) Zn extraction than microwave-assisted leaching (Zn/Mn ratio of 3.5); both processes generated a concentrated Zn solution (?18.7g/L) with a purity (83.3% and 77.7%, respectively) that was suitable for electrowinning. With alkaline leaching, microwave- (1 cycle, 3 min, 4mol/L NaOH) and ultrasound-assisted (14min, 0.1p, 20% amplitude, 4mol/L NaOH) leaching extracted about 80% of the Zn and less than 0.01% of the Mn, which resulted in lesser concentrated Zn solutions (approximately 16.5g/L) but with high purity (>99.5%) that was suitable for the recovery of Zn by precipitation. The microwave- and ultrasound-assisted leaching strategies used in this work proved to be efficient and environmentally-friendly approaches for the extraction of Zn from spent alkaline residues since a concentrated Zn solution with adequate purity for subsequent Zn recovery was obtained using significantly decreased leaching times and concentrations of chemicals. PMID- 28007474 TI - Response to Hoy, 'Gender Imbalance at Brain Stimulation Conferences: We Have a Problem and It is Everyone's Problem'. PMID- 28007475 TI - Mechanisms of retinoic acid signaling during cardiogenesis. AB - Substantial experimental and epidemiological data have highlighted the interplay between nutritional and genetic factors in the development of congenital heart defects. Retinoic acid (RA), a derivative of vitamin A, plays a key role during vertebrate development including the formation of the heart. Retinoids bind to RA and retinoid X receptors (RARs and RXRs) which then regulate tissue-specific genes. Here, we will focus on the roles of RA signaling and receptors in gene regulation during cardiogenesis, and the consequence of deregulated retinoid signaling on heart formation and congenital heart defects. PMID- 28007476 TI - Human asthma is characterized by more IRF5+ M1 and CD206+ M2 macrophages and less IL-10+ M2-like macrophages around airways compared with healthy airways. PMID- 28007478 TI - National and regional under-5 mortality in China in the past two decades. PMID- 28007477 TI - National and subnational all-cause and cause-specific child mortality in China, 1996-2015: a systematic analysis with implications for the Sustainable Development Goals. AB - BACKGROUND: China has achieved Millennium Development Goal 4 to reduce under-5 mortality rate by two-thirds between 1990 and 2015. In this study, we estimated the national and subnational levels and causes of child mortality in China annually from 1996 to 2015 to draw implications for achievement of the SDGs for China and other low-income and middle-income countries. METHODS: In this systematic analysis, we adjusted empirical data on levels and causes of child mortality collected in the China Maternal and Child Health Surveillance System to generate representative estimates at the national and subnational levels. In adjusting the data, we considered the sampling design and probability, applied smoothing techniques to produce stable trends, fitted livebirth and age-specific death estimates to natvional estimates produced by the UN for international comparison, and partitioned national estimates of infrequent causes produced by independent sources to the subnational level. FINDINGS: Between 1996 and 2015, the under-5 mortality rate in China declined from 50.8 per 1000 livebirths to 10.7 per 1000 livebirths, at an average annual rate of reduction of 8.2%. However, 181 600 children still died before their fifth birthday, with 93 400 (51.5%) deaths occurring in neonates. Great inequity exists in child mortality across regions and in urban versus rural areas. The leading causes of under-5 mortality in 2015 were congenital abnormalities (35 700 deaths, 95% uncertainty range [UR] 28 400-45 200), preterm birth complications (30 900 deaths, 24 200-40 800), and injuries (26 600 deaths, 21 000-33 400). Pneumonia contributed to a higher proportion of deaths in the western region of China than in the eastern and central regions, and injury was a main cause of death in rural areas. Variations in cause-of-death composition by age were also examined. The contribution of preterm birth complications to mortality decreased after the neonatal period; congenital abnormalities remained an important cause of mortality throughout infancy, whereas the contribution of injuries to mortality increased after the first year of life. INTERPRETATION: China has achieved a rapid reduction in child mortality in 1996-2015. The decline has been widespread across regions, urban and rural areas, age groups, and cause-of-death categories, but great disparities remain. The western region and rural areas and especially western rural areas should receive most attention in improving child survival through enhanced policy and programmes in the Sustainable Development Goals era. Continued investment is crucial in primary and secondary prevention of deaths due to congenital abnormalities, preterm birth complications, and injuries nationally, and of deaths due to pneumonia in western rural areas. The study also has implications for improving child survival and civil registration and vital statistics in other low-income and middle-income countries. FUNDING: Bill & Melinda Gates Foundation. PMID- 28007479 TI - Membrane Interactions of Natural Cyclic Lipodepsipeptides of the Viscosin Group. AB - Many Pseudomonas spp. produce cyclic lipodepsipeptides (CLPs), which, besides their role in biological functions such as motility, biofilm formation and interspecies interactions, are antimicrobial. It has been established that interaction with the cellular membrane is central to the mode of action of CLPs. In this work, we focus on the CLPs of the so-called viscosin group, aiming to assess the impact of the main structural variations observed within this group on both the antimicrobial activity and the interaction with model membranes. The antimicrobial activity of viscosin, viscosinamide A, WLIP and pseudodesmin A were all tested on a broad panel of mainly Gram-positive bacteria. Their capacity to permeabilize or fuse PG/PE/cardiolipin model membrane vesicles is assessed using fluorescent probes. We find that the Glu2/Gln2 structural variation within the viscosin group is the main factor that influences both the membrane permeabilization properties and the minimum inhibitory concentration of bacterial growth, while the configuration of the Leu5 residue has no apparent effect. The CLP-membrane interactions were further evaluated using CD and FT-IR spectroscopy on model membranes consisting of PG/PE/cardiolipin or POPC with or without cholesterol. In contrast to previous studies, we observe no conformational change upon membrane insertion. The CLPs interact both with the polar heads and aliphatic tails of model membrane systems, altering bilayer fluidity, while cholesterol reduces CLP insertion depth. PMID- 28007480 TI - Paternal Insulin-like Growth Factor 2 (Igf2) Regulates Stem Cell Activity During Adulthood. AB - Insulin-like Growth Factor 2 (IGF2) belongs to the IGF/Insulin pathway, a highly conserved evolutionarily network that regulates growth, aging and lifespan. Igf2 is highly expressed in the embryo and in cancer cells. During mouse development, Igf2 is expressed in all sites where hematopoietic stem cells (HSC) successively expand, then its expression drops at weaning and becomes undetectable when adult HSC have reached their niches in bones and start to self-renew. In the present study, we aim to discover the role of IGF2 during adulthood. We show that Igf2 is specifically expressed in adult HSC and we analyze HSC from adult mice deficient in Igf2 transcripts. We demonstrate that Igf2 deficiency avoids the age-related attrition of the HSC pool and that Igf2 is necessary for tissue homeostasis and regeneration. Our study reveals that the expression level of Igf2 is critical to maintain the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSC and their niche. Our data have major clinical interest for transplantation: understanding the changes in adult stem cells and their environments will improve the efficacy of regenerative medicine and impact health- and life-span. PMID- 28007481 TI - Looking Into the Crystal Ball: Predicting Non-response to Ursodeoxycholic Acid in Primary Biliary Cholangitis. PMID- 28007482 TI - Gradients of Connectivity in the Cerebral Cortex. AB - The human neocortex is organized with distributed networks that connect distant regions together, but what determines their spatial layout? A recent study sheds light on the topological placement of regions along the cortical surface in relation to gradients of connectivity in both humans and macaques. PMID- 28007483 TI - Bovine trypanosomosis and vector density in Omo-Ghibe tsetse belt, South Ethiopia. AB - African animal trypanosomosis (AAT) is a parasitic disease that causes serious economic losses in livestock from anemia, loss of condition, emaciation and death in untreated cases. It is one of the major constraints to improved livestock production and productivity in Ethiopia. Entomological and parasitological surveys were conducted in the Omo-Ghibe tsetse belt of south Ethiopia to estimate the prevalence of bovine trypanosomosis and the apparent tsetse density (AD), and identify the potential risk factors. For the parasitological study, blood samples were collected from 1508 cattle sampled from 11 districts and assayed using the buffy coat technique and Giemsa-stained thin smears. For the entomological survey, a total of 216 biconical and NGU traps were deployed in all districts. The overall animal-level prevalence of trypanosomosis was 7.8% (95% CI: 6.5, 9.3). The trypanosome species identified were Trypanosoma congolense (75.4%), T. vivax (20.3%), T. brucei brucei (1.7%) and mixed T. congolense/T. vivax (2.6%). Regarding the entomological survey result, a total of 2243 tsetse flies were captured which identified to be Glossina pallidipes (85.1%) and G. f. fuscipes (14.9%). Besides, other biting flies of the genus Stomoxys (n=146) and Tabanus (n=17) were also trapped. The AD noted in the present study was 3.5 flies/trap/day. Both the prevalence of trypanosomosis and AD of tsetse flies were significantly (p<0.05) influenced by altitude. The prevalence of trypanosomosis was also significantly (p<0.05) associated with poor body condition score, black coat color and lower mean packed cell volume while no significant prevalence difference was noted along with age and sex category. In conclusion, the present study suggested that trypanosomosis is an important disease of cattle in the Omo Ghibe tsetse belt in dry season. The disease is mainly caused by the most pathogenic T. congolense and transmission is predominantly by tsetse flies, particularly G. pallidipes. The study warrants the need for strengthening the vector and parasite control interventions in the area. PMID- 28007484 TI - Diagnosis of intestinal parasites in a rural community of Venezuela: Advantages and disadvantages of using microscopy or RT-PCR. AB - A cross-sectional study was carried out to determine the prevalence and diagnostic performance of microscopy and real time PCR (RT-PCR) for 14 intestinal parasites in a Venezuelan rural community with a long history of persistent intestinal parasitic infections despite the implementation of regular anthelminthic treatments. A total of 228 participants were included in this study. A multiplex RT-PCR was used for the detection of Dientamoeba fragilis, Giardia intestinalis, Cryptosporidium sp. and a monoplex RT-PCR for Entamoeba histolytica. Furthermore, a multiplex PCR was performed for detection of Ascaris lumbricoides, Strongyloides stercoralis, Necator americanus and Ancylostoma duodenale. Combined microscopy-PCR revealed prevalences of 49.3% for A. lumbricoides, 10.1% for N. americanus (no A. duodenale was detected), 2.0% for S. stercoralis, 40.4% for D. fragilis, 35.1% for G. intestinalis, and 7.9% for E. histolytica/dispar. Significant increases in prevalence at PCR vs. microscopy were found for A. lumbricoides, G. intestinalis and D. fragilis. Other parasites detected by microscopy alone were Trichuris trichiura (25.7%), Enterobius vermicularis (3.4%), Blastocystis sp. (65.8%), and the non-pathogenic Entamoeba coli (28.9%), Entamoeba hartmanni (12.3%), Endolimax nana (19.7%) and Iodamoeba butschlii (7.5%). Age- but no gender-related differences in prevalences were found for A. lumbricoides, T. trichiura, G. intestinalis, and E. histolytica/dispar. The persistently high prevalences of intestinal helminths are probably related to the high faecal pollution as also evidenced by the high prevalences of non-pathogenic intestinal protozoans. These results highlight the importance of using sensitive diagnostic techniques in combination with microscopy to better estimate the prevalence of intestinal parasites, especially in the case of D. fragilis trophozoites, which deteriorate very rapidly and would be missed by microscopy. In addition, the differentiation between the pathogenic E. histolytica and the non-pathogenic E. dispar can be attained. However, microscopy remains an important diagnostic tool since it can detect other intestinal parasites for which no PCR is available. PMID- 28007485 TI - Viral hemorrhagic septicemia virus (VHSV) infection-mediated sequential changes in microRNAs profile of Epithelioma papulosum cyprini (EPC) cells. AB - MicroRNAs are small non-coding RNAs and are involved in the regulation of wide biological processes. Viral hemorrhagic septicemia virus (VHSV) is the causative agent of viral hemorrhagic septicemia (VHS) disease causing a heavy loss in aquaculture farms. In this study, we tried to explore the effect of VHSV infection on microRNAs profile of Epithelioma papulosum cyprini (EPC) cells at different points of time (0, 3, 12, 24, and 48 h post infection). A total of 355 conserved microRNAs and 3 novel microRNAs were identified, and among them, 103 microRNAs were differentially expressed. The number of differentially expressed microRNAs was highly increased at 24 h.p.i compared to 3 h.p.i and 12 h.p.i., suggesting that EPC cells might not actively respond to VHSV infection at an early infection period, which can allow viruses to transcript and translate their genes enough to produce viral particles that can infect to another cells. Among the differentially expressed microRNAs, 2 miRNAs (miR-735 and miR-738) that were reported only in fish species were highly upregulated, and based on the target prediction, they could regulate several immune pathways. Furthermore, the present results showed the upregulation of representative immune regulating microRNAs such as miR-146a, miR-155, and miR-99. The target prediction of differentially expressed miRNAs, GO, and KEGG pathways analysis revealed that several biological processes and different pathways were affected by the viral infection. The present dynamical changing patterns of differentially expressed microRNAs in response to the progression of VHSV infection suggest that microRNA profile that was analyzed at one time point cannot provide enough information for the interpretation of the disease mechanism. Considering the wide and complex interactions between microRNAs and genes expression, the present results provide the basis for the understanding of VHSV infection-mediated cellular responses and for future investigations on the development of possible control measures. PMID- 28007487 TI - Effects of Hypericum perforatum on the healing of xenografts: a histomorphometric study in rabbits. AB - The aim of this study was to investigate effects of the Hypericum perforatum (St John's Wort) on bone healing in rabbit calvarium. Ten male New Zealand rabbits each had three bicortical defects made in the calvarial bones, which were filled with xenograft, xenograft+H perforatum oil extract, and autogenous graft. Four weeks postoperatively all rabbits were killed and the bony defects examined histomorphometrically. Tissue compartments including new bone (p<0.001), marrow space (p<0.001), and residual bone grafts (p=0.014) differed significantly among groups. The volume of residual graft was significantly decreased in the xenograft/H perforatum group compared with those with xenografts alone (p=0.0147). The differences in microarchitectural variables of de novo bone formation were also significant (trabecular thickness (p<0.001), trabecular width (p<0.001), trabecular separation (p=0.001). There were no significant differences in node:terminus ratio between the xenograft/H perforatum group and the other two groups. However, the difference in node:terminus ratio between the autogenous graft and xenograft group was significant (p=0.001) Oil extracts of H perforatum improved bony healing in defects filled with bovine-derived xenografts. PMID- 28007486 TI - [Trends in computed tomography characteristics, intracranial pressure monitoring and surgical management in severe traumatic brain injury: Analysis of a data base of the past 25 years in a neurosurgery department]. AB - OBJECTIVE: To describe the radiological characteristics, surgical indications, procedures, and intracranial pressure monitoring of a representative cohort of severe traumatic brain injury (sTBI) cases collected over the past 25years, and to analyse the changes that have occurred by dividing the period into 3 equal time periods. METHODS: An observational cohort study was conducted on consecutive adult patients (>14years of age) with severe closed TBI (Glasgow Coma Scale score [GCS]<=8) who were admitted during the first 48hours after injury to the Hospital 12 de Octubre from 1987 to 2012. The most relevant radiological findings, surgical procedures, and intracranial monitoring indications reported in the literature were defined and compared in 3 equal time periods (1987-1995, 1996 2004, and 2005-2014). RESULTS: A significant increase was observed in subdural haematomas with lesions over 25cc, and midline shift in the last period of time. The incidence of subarachnoid haemorrhage increased significantly with time. There was a progression to a worse computed tomography (CT) classification from the initial CT scan in 33% of cases. Surgery was performed on 721 (39.4%) patients. Early surgery (<12hours) was performed on 585 (81.1%) patients, with the most frequent being for extra-cerebral mass lesions (subdural and epidural haematomas), whereas delayed surgery (>12hours) was most frequently performed due to an intracerebral haematoma. Surgical treatment, both early and late was significantly lower with respect to the first time period. Decompressive craniectomy with evacuation of the mass lesion was the preferred procedure in the last time period. Intracranial pressure monitoring (ICP) was carried out on 1049 (57.3%) patients, with a significantly higher frequency in the second period of time. There was adherence to Guidelines in 64.4% of cases. Elevated/uncontrolled ICP was more significant in the first time period. CONCLUSIONS: As a result of the epidemiological changes seen in traumatic brain injury, a different pattern of morphological injury is described, as depicted in the CT, leading to a difference in practice during this period of observation. PMID- 28007488 TI - Hypertension in Latin America: Current perspectives on trends and characteristics. AB - The region of Latin America, which includes Central America, the Caribbean and South America, is one that is rapidly developing. Signified by socio-economic growth, transition and development over the last few decades, living standards in countries like Brazil and Mexico have improved dramatically, including improvements in education and health care. An important marker of socio-economic change has been the epidemiological shift in disease burden. Cardiovascular disease is now the leading cause of death in Latin America, and the drop in prevalence of infectious diseases has been accompanied by a rise in non communicable diseases. Hypertension is the major risk factor driving the cardiovascular disease continuum. In this article we aim to discuss the epidemiological and management trends and patterns in hypertension that may be specific or more common to Latin-American populations - what we term 'Latin American characteristics' of hypertension - via a review of the recent literature. Recognizing that there may be a specific profile of hypertension for Latin-American patients may help to improve their treatment, with the ultimate goal to reduce their cardiovascular risk. We focus somewhat on the countries of Brazil, Mexico and Venezuela, the experience of which may reflect other Latin American countries that currently have less published data regarding epidemiology and management practices. PMID- 28007489 TI - Proposal for a breakfast quality index for brazilian population: Rationale and application in the Brazilian National Dietary Survey. AB - Breakfast has been related to positive nutrition and health outcomes, but criteria for an optimal composition of this meal are not well established. The aim of this study was to propose a breakfast quality index (BQI) for the Brazilian population, and to describe the relationship between breakfast quality, socio-demographic factors, dietary intake at breakfast and for the total day. BQI was constructed based on individual dietary data of 22,279 breakfast consumers, aged 20+ years from the Brazilian National Dietary Survey, a population-based cross-sectional study. The BQI was comprised of food components (cereals, fruit/vegetables, dairy products), and nutrient criteria (energy, fiber, free sugar, saturated fat, calcium and sodium). Mean, percentage and 95% CIs were estimated for variables according to BQI categories. The mean BQI was 4.2, with 71% of individuals falling into medium BQI category and 6% in high category. Individuals in urban areas, in higher categories of income and education and women had higher BQI means. Consumers with high BQI had higher intake of fruits/vegetables and higher breakfast and total daily intake of energy, carbohydrates, fiber, total sugar, sodium, potassium, phosphorus, thiamin, riboflavin, niacin, folate and vitamins B6, A, C, and D, and lower trans fatty acids compared to those in low and medium BQI groups. Promoting a high-quality breakfast may contribute to a better nutrient intake and achievement of daily requirements. PMID- 28007490 TI - Gut-brain nutrient sensing in food reward. AB - For the past several decades, vagal and hormonal gut-brain negative feedback signaling mechanisms that promote satiety and subsequent suppression of food intake have been explored. In addition, a separate positive feedback process termed "appetition," involving postoral signaling from the gut to the brain, has been shown to promote food intake and produce flavor-nutrient preference conditioning. Afferent fibers emerging from the vagus nerve form the main pathway by which information is relayed from the abdominal viscera to the hindbrain and eventually other higher brain regions involved in food intake. Using a specialized subdiaphragmatic vagal deafferentation technique, it was observed that gut vagal and splanchnic afferents play a role in the negative feedback control of satiety after nutrient intake; however, these afferents are not required for nutrient reinforcement or flavor-nutrient preference conditioning, thereby highlighting the distinction between the processes of satiation and appetition. By linking these physiological and behavioral processes to a neurochemical mechanism, it was found that striatal dopamine release induced by intragastric glucose infusion is involved in sweet appetite conditioning. The mechanisms underlying appetition are still being investigated but may involve other nondopaminergic neurochemical systems and/or presently undiscovered hormonal mediators. Future work to delineate the biological mechanisms whereby appetition drives increased intake and conditioned food preference in response to ingestion should take a multifaceted approach by integrating hormonal, neurophysiological, and behavioral techniques. PMID- 28007491 TI - A Novel Experimental Method for Penile Augmentation Urethroplasty With a Combination of Buccal Mucosa and Amniotic Membrane in a Rabbit Model. AB - OBJECTIVE: To investigate the results of penile urethral reconstruction using amniotic membrane (AM) and buccal mucosa (BM) grafts, and the simultaneous use of both in a rabbit model. MATERIALS AND METHODS: A total of 28 male rabbits were divided into 4 groups according to grafting style: group 1 (AM), group 2 (BM), group 3 (BM + AM), and group 4 (sham). A standardized urethral defect was created in the 3 initial groups. The sham group underwent only a ventral vertical urethral incision and primary re-suturation. AM grafts were used in group 1, and BM grafts were used in groups 2 and 3. AM grafts were affixed to the BM grafts in group 3 as a covering tissue. Urethrography and endoscopy were performed after the 1st and 2nd months of grafting. The penises were subjected to histopathologic and immunohistochemical assessment for fibroblast growth factor and vascular endothelial growth factor expression. RESULTS: Dehiscence and fistula developed in group 1, whereas 2 fistulas were observed in group 2. No complications developed in group 3. Epithelization at urethras was observed at 4 weeks in all groups, but transformation to urothelial epithelialization occurred at 8 weeks. Marked amelioration and epithelial transformation were observed in group 3. The most prominent fibroblast growth factor expression was observed in group 3. Vascular endothelial growth factor expression was completely negative in group 3 at 8 weeks, indicating complete healing. CONCLUSION: The simultaneous use of AM and BM for ventral onlay penile urethroplasty provides better tissue healing and lower complication rates in comparison to BM alone. Further animal studies or clinical applications are needed. PMID- 28007492 TI - Prostate Biopsy-related Infection: A Systematic Review of Risk Factors, Prevention Strategies, and Management Approaches. AB - A systematic review to identify risk factors for prostate biopsy-related infection, preventative strategies, and optimal management of infectious complications was conducted. Significant risk factors for postbiopsy infection include urogenital infection, antibiotic use, international travel, hospital exposure, bacteriuria, previous transrectal biopsy, and resistance of fecal flora to antibiotic prophylaxis (especially fluoroquinolones). Patients at risk may benefit from an adjusted biopsy protocol comprising transrectal biopsy under targeted prophylaxis, and/or the use of rectal disinfection techniques or using a transperineal approach. Management of biopsy-related infection should be based on individual risk and local resistance profiles with input from multiple specialties. PMID- 28007493 TI - Association between family history of diabetes and cardiovascular disease and lifestyle risk factors in the United States population: The 2009-2012 National Health and Nutrition Examination Survey. AB - Family history is a well-known risk factor for diabetes and cardiovascular disease (CVD) and modification of lifestyle risk factors can significantly lessen such risk. Our aim was to assess the association between family history of diabetes and/or CVD and lifestyle behaviors and risk factors (smoking, low physical activity, excessive dietary sodium and cholesterol intake and obesity) in a nationally representative sample of U.S. adults. We conducted a cross sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 2009-2012. Family history, lifestyle behaviors and risk factors were defined using self-reported and physical examination data. The study sample included 10,988 participants with a mean age of 47years. Among the U.S. adult population, 29.5%, 5.7% and 6.5% had a family history of diabetes, CVD and both diseases respectively. Compared to participants with no family history, participants with a family history of diabetes, CVD and both diabetes and CVD were more likely to be current smokers (OR=1.18[95% CI, 1.03-1.35], OR=1.68[95% CI, 1.31-2.17] and OR=1.71[95% CI, 1.30-2.26] respectively). Participants with a family history of diabetes (OR=1.42[95% CI, 1.26-1.61]) and both diabetes and CVD were more likely to be overweight/obese (OR=2.06[95% CI, 1.57-2.69]). There was no association between family history and dietary factors or physical activity. In the U.S., there is a high prevalence of modifiable risk factors among persons with a family history of diabetes and/or CVD. Healthcare providers have a significant role to play in targeting these individuals for lifestyle changes. PMID- 28007494 TI - Built environmental factors and adults' travel behaviors: Role of street layout and local destinations. AB - Street layout is consistently associated with adults' travel behaviors, however factors influencing this association are unclear. We examined associations of street layout with travel behaviors: walking for transport (WT) and car use; and, the extent to which these relationships may be accounted for by availability of local destinations. A 24-h travel diary was completed in 2009 by 16,345 adult participants of the South-East Queensland Household Travel Survey, Australia. Three travel-behavior outcomes were derived: any home-based WT; over 30min of home-based WT; and, over 60min of car use. For street layout, a space syntax measure of street integration was calculated for each Statistical Area 1 (SA1, the smallest geographic unit in Australia). An objective measure of availability of destinations - Walk Score - was also derived for each SA1. Logistic regression examined associations of street layout with travel behaviors. Mediation analyses examined to what extent availability of destinations explained the associations. Street integration was significantly associated with travel behaviors. Each one decile increment in street integration was associated with an 18% (95%CI: 1.15, 1.21) higher odds of any home-based WT; a 10% (95%CI: 1.06, 1.15) higher odds of over 30min of home-based WT; and a 5% (95%CI: 0.94, 0.96) lower odds of using a car over 60min. Local destinations partially mediated the effects of street layout on travel behaviors. Well-connected street layout contributes to active travel partially through availability of more local destinations. Urban design strategies need to address street layout and destinations to promote active travel among residents. PMID- 28007495 TI - The 2016 Active Living Research Conference: Equity in active living. PMID- 28007496 TI - Cardiovascular health metrics among South Asian adults in the United States: Prevalence and associations with subclinical atherosclerosis. AB - South Asians, a fast growing ethnic group in the US, have an increased risk for cardiovascular disease compared to the general population. We examined the prevalence and distribution of the American Heart Association's Life's Simple 7 cardiovascular health (CVH) metrics using data from Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, and cross-sectional associations between number of CVH metrics in the ideal range with subclinical atherosclerosis assessed using coronary artery calcium (CAC) measured using cardiac computed tomography and carotid intima media thickness (CIMT) measured using high-resolution B-mode ultrasonography. CAC was modeled as Agatston scores=0, 1-400 and >400; CIMT was examined continuously and as internal CIMT>1.5mm. In the MASALA cohort (N=875; mean age: 55years; 53% men; living in greater San Francisco and Chicago areas; October 2010-March 2013) without prevalent coronary heart disease, no participant had all 7 metrics in ideal range; approximately 20% of the participants had at least 5 metrics in ideal range. Higher number of CVH metrics in the ideal range was inversely associated with subclinical atherosclerosis. A 1 unit increase in the number of CVH metrics in the ideal range was associated with 32% lower odds of CAC=1-400 (vs. CAC=0; OR=0.68, 95% CI: 0.60, 0.78) and 28% lower odds of internal CIMT>1.5mm (OR=72, 95% CI: 0.61, 0.85). These data show the prevalence of CVH metrics among South Asians in the US, and provide empirical evidence on inverse associations of meeting ideal levels for higher number of metrics and subclinical atherosclerosis. PMID- 28007497 TI - A novel method for extraction of neural response from single channel cochlear implant auditory evoked potentials. AB - Cortical auditory evoked potentials (CAEP) are used to evaluate cochlear implant (CI) patient auditory pathways, but the CI device produces an electrical artifact, which obscures the relevant information in the neural response. Currently there are multiple methods, which attempt to recover the neural response from the contaminated CAEP, but there is no gold standard, which can quantitatively confirm the effectiveness of these methods. To address this crucial shortcoming, we develop a wavelet-based method to quantify the amount of artifact energy in the neural response. In addition, a novel technique for extracting the neural response from single channel CAEPs is proposed. The new method uses matching pursuit (MP) based feature extraction to represent the contaminated CAEP in a feature space, and support vector machines (SVM) to classify the components as normal hearing (NH) or artifact. The NH components are combined to recover the neural response without artifact energy, as verified using the evaluation tool. Although it needs some further evaluation, this approach is a promising method of electrical artifact removal from CAEPs. PMID- 28007499 TI - 3'-Hydroxy-4'-methoxy-beta-methyl-beta-nitrostyrene inhibits tumor growth through ROS generation and GSH depletion in lung cancer cells. AB - AIMS: Members of the beta-nitrostyrene family are known to suppress tumor growth, with the underlying mechanisms of beta-nitrostyrene remain mostly unclear. Herein, we synthesized a beta-nitrostyrene derivative, 3'-hydroxy-4'-methoxy-beta methyl-beta-nitrostyrene (CYT-Rx20), and explored its anticancer activities in human lung cancer cells in vitro and in vivo. MAIN METHODS: Cell viability was measured by XTT assay. Apoptosis was detected by Annexin V/PI staining. Caspase activation was determined by western blotting. ROS (reactive oxygen species), MMP (mitochondrial membrane potential) and mitochondrial mass were determined by flow cytometry. GSH level was detected by ELISA assay. KEY FINDINGS: In this study, we found that CYT-Rx20 significantly reduced cell viability, accompanied by G2/M arrest in lung cancer cells. Increased protein levels of cleaved-caspase families indicated apoptotic cell death upon CYT-Rx20 treatment. Furthermore, increased level of intracellular reactive oxygen species (ROS), loss of mitochondrial membrane potential (DeltaPsim), glutathione (GSH) depletion and inhibition of GSH reductase were observed after CYT-Rx20 treatment. The effects of CYT-Rx20 on cell viability and the loss of DeltaPsim were significantly reversed when cells were pretreated with thiol antioxidants NAC, GSH, or 2-ME. Finally, xenograft animal study demonstrated that CYT-Rx20 significantly suppressed lung tumor growth in vivo. SIGNIFICANCE: Our data demonstrated that CYT-Rx20 triggered apoptotic cell death in lung cancer cells and suppressed lung tumor growth through GSH depletion, suggesting that CYT-Rx20 may have the potential to be further developed as an anticancer compound for treating lung cancer. PMID- 28007500 TI - Novel sulfoglycolipid IG20 causes neuroprotection by activating the phase II antioxidant response in rat hippocampal slices. AB - Compound IG20 is a newly synthesised sulphated glycolipid that promotes neuritic outgrowth and myelinisation, at the time it causes the inhibition of glial proliferation and facilitates exocytosis in chromaffin cells. Here we have shown that IG20 at 0.3-10 MUM afforded neuroprotection in rat hippocampal slices stressed with veratridine, glutamate or with oxygen plus glucose deprivation followed by reoxygenation (OGD/reox). Excess production of reactive oxygen species (ROS) elicited by glutamate or ODG/reox was prevented by IG20 that also restored the depressed tissue levels of GSH and ATP in hippocampal slices subjected to OGD/reox. Furthermore, the augmented iNOS expression produced upon OGD/reox exposure was also counteracted by IG20. Additionally, the IG20 elicited neuroprotection was prevented by the presence of inhibitors of the signalling pathways Jak2/STAT3, MEK/ERK1/2, and PI3K/Akt, consistent with the ability of the compound to increase the phosphorylation of Jak2, ERK1/2, and Akt. Thus, the activation of phase II response and the Nrf2/ARE pathway could explain the antioxidant and anti-inflammatory effects and the ensuing neuroprotective actions of IG20. PMID- 28007498 TI - Dietary restriction and lifespan: Lessons from invertebrate models. AB - Dietary restriction (DR) is the most robust environmental manipulation known to increase active and healthy lifespan in many species. Despite differences in the protocols and the way DR is carried out in different organisms, conserved relationships are emerging among multiple species. Elegant studies from numerous model organisms are further defining the importance of various nutrient-signaling pathways including mTOR (mechanistic target of rapamycin), insulin/IGF-1-like signaling and sirtuins in mediating the effects of DR. We here review current advances in our understanding of the molecular mechanisms altered by DR to promote lifespan in three major invertebrate models, the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster. PMID- 28007502 TI - Structure-activity relationship for branched oxyquinoline HIF activators: Effect of modifications to phenylacetamide "tail". AB - HIF prolyl hydroxylase is a major regulator of HIF stability. Branched tail oxyquinolines have been identified as specific inhibitors of HIF prolyl hydroxylase and recently demonstrated clear benefits in various scenarios of neuronal failure. The structural optimization for branched tail oxyquinolines containing an acetamide bond has been performed in the present study using HIF1 ODD-luc reporter assay. The special attention has been paid to the length of a linker between acetamide group and phenyl ring, as well as substitutions in the phenyl ring in the other branch of the tail. The optimized version of branched tail oxyquinolines is 3-fold more potent than the original one identified before and shows a submicromolar EC50 in the reporter assay. The compounds have been studied in a "liver-on-a-chip" device to question their hepatotoxicity towards differentiated human HepaRG "hepatocytes": the absence of hepatotoxicity is observed up to 200 MUM concentrations for all studied derivatives of branched tail oxyquinolines. PMID- 28007501 TI - Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. AB - The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials. PMID- 28007503 TI - Low spontaneous variability in cerebral blood flow velocity in non-survivors after cardiac arrest. AB - OBJECTIVE: To investigate spontaneous variability in the time and frequency domain in mean flow velocity (MFV) and mean arterial pressure (MAP) in comatose patients after cardiac arrest, and determine possible differences between survivors and non-survivors. METHODS: A prospective observational study was performed at the ICU of a tertiary care university hospital in the Netherlands. We studied 11 comatose patients and 10 controls. MFV in the middle cerebral artery was measured with simultaneously recording of MAP. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, the average spectral power of MAP and MFV were calculated in the very low, low and high frequency bands. RESULTS: In survivors CV of MFV increased from 4.66 [3.92-6.28] to 7.52 [5.52-15.23] % at T=72h. In non survivors CV of MFV decreased from 9.02 [1.70-9.36] to 1.97 [1.97-1.97] %. CV of MAP was low immediately after admission (1.46 [1.09-2.25] %) and remained low at 72h (3.05 [1.87-3.63] %) (p=0.13). There were no differences in CV of MAP between survivors and non-survivors (p=0.30). We noticed significant differences between survivors and non-survivors in the VLF band for average spectral power of MAP (p=0.03) and MFV (p=0.003), whereby the power of both MAP and MFV increased in survivors during admission, while remaining low in non-survivors. CONCLUSIONS: Cerebral blood flow is altered after cardiac arrest, with decreased spontaneous fluctuations in non-survivors. Most likely, these changes are the consequence of impaired intrinsic myogenic vascular function and autonomic dysregulation. PMID- 28007505 TI - Where do we go with PoCUS? PMID- 28007504 TI - Prognostic factors for extracorporeal cardiopulmonary resuscitation recipients following out-of-hospital refractory cardiac arrest. A systematic review and meta analysis. AB - PURPOSE: Association estimates between baseline characteristics and outcomes are imprecise and inconsistent among extracorporeal cardiopulmonary resuscitation (ECPR) recipients following refractory out-of-hospital cardiac arrest (OHCA). This systematic review and meta-analysis aimed to investigate the prognostic significance of pre-specified characteristics for OHCA treated with ECPR. METHODS: The Medline electronic database was searched via PubMed for articles published from January 2000 to September 2016. The electronic search was supplemented by scanning the reference lists of retrieved articles and contacting field experts. Eligible studies were historical and prospective cohort studies of adult patients undergoing ECPR following OHCA. RESULTS: Fifteen primary studies were included, totaling 841 participants. The median prevalence of the primary outcome (i.e., short- or long-term survival for five studies and cerebral performance for ten studies) was 15% (range, 0-50%). The primary outcome was associated with an increased odds ratio of initial shockable cardiac rhythm (2.20; 95% confidence interval [CI], 1.30-3.72; P=0.003), shorter low-flow duration (geometric mean ratio, 0.90; 95% CI, 0.81-0.99; P=0.04), higher arterial pH value (difference, 0.12; 95% CI, 0.03-0.22; P=0.01) and lower serum lactate concentration (difference, -3.52mmol/L; 95% CI, -5.05 to -1.99; P<0.001). No significant association was found between the primary outcome and patient age (the odds of female gender and bystander CPR attempt. CONCLUSION: Observational evidence from published primary studies indicates that shorter low-flow duration, shockable cardiac rhythm, higher arterial pH value and lower serum lactate concentration on hospital admission are associated with better outcomes for ECPR recipients after OHCA. PMID- 28007506 TI - Implementing the standardised cardiac arrest call telephone number for all European hospitals - 2222. PMID- 28007507 TI - Need of intraosseous access in advanced life support in the in-hospital setting: Evaluation of difficult vascular access in cardiac arrest. PMID- 28007508 TI - Functional assessment of glottal insufficiency treated by hyaluronic acid injection: Retrospective 20-case series. AB - OBJECTIVES: The objectives of the present study were to describe hyaluronic acid injection to the vocal folds as treatment for glottal insufficiency, assess indications and report vocal results at 1 month and later than 6 months postoperatively. PATIENTS AND METHODS: A single-center retrospective study was performed for the period March 2012 to August 2015. Inclusion criteria comprised: unilateral recurrent nerve palsy or vocal fold closure defect with conserved mobility. Exclusion criteria comprised: previous thyroplasty, severe swallowing disorder, and cognitive disorder hindering subjective vocal assessment. Restylane(r) injection was performed under general or local anesthesia. The Vocal Handicap Index (VHI), maximum phonation time (MPT) and GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) score were assessed preoperatively and at 1 month and more than 6 months postoperatively. RESULTS: Twenty patients were included: 14 with unilateral recurrent nerve palsy and 6 with vocal fold closure defect. Restylane(r) injection was performed under general anesthesia in 16 patients and local anesthesia in 4 (20%). At 1-month assessment, there was significant reduction in VHI (by 36 points; P=0.0001) and GRBAS score (by 6.95 points; P=0.0001) and significant increase in MPT (by 4.95sec; P=0.0001). At 6 months, VHI, MPT and GRBAS scores remained significantly improved (respectively, P=0.0002, P=0.001 and P=0.0001), without significant difference from 1-month levels. Three patients had minor complications; two recovered normal vocal fold mobility. CONCLUSION: Hyaluronic acid injection was effective in treating glottal failure, improving objective and subjective vocal parameters, which remained satisfactory even 6 months postoperatively. PMID- 28007509 TI - Keratoameloblastoma of the mandible. AB - INTRODUCTION: Keratoameloblastoma is an extremely rare odontogenic tumor, as only 18 cases have been reported in the literature. CASE REPORT: The authors report a case of keratoameloblastoma in a 32-year-old woman and review the literature concerning the clinical features, radiological appearance, histopathological findings and treatment options. DISCUSSION: Keratoameloblastoma is a rare tumor observed more frequently in males (sex ratio: 3:1) characterized by extensive keratin production in odontogenic islets and fibrous stroma. PMID- 28007510 TI - [Palliative care for newborn infants with congenital malformations or genetic abnormalities]. AB - The choice of palliative care can be made today in the perinatal period, as it can be made in children and adults. Palliative care, rather than curative treatment, may be considered in three clinical situations: babies born at the limits of viability, withholding/withdrawing treatments in the NICU, and babies with severe malformations of genetic abnormalities identified during pregnancy. Only the last situation is addressed hereafter. In newborn infants as in older patients, palliative care aims at taking care of the baby and at providing comfort and well-being. The presence of human beings by the newborn infant, most importantly the parents and family, is of utmost importance. The available time should not be used only for care and medical treatments. Sufficient time should be kept for the parents to interact with the baby and for human presence and warmth. The best interests of the newborn infant are the main element for guiding appropriate care. Before birth, the choice of palliative care for newborn infants requires successive steps: (1) establishing a diagnosis of malformation(s) or genetic abnormalities; (2) making a prognosis and ruling out intensive treatments at birth and thereafter; (3) giving the parents appropriate information; (4) assisting the pregnant woman in deciding to continue pregnancy while excluding intensive treatment of the newborn baby; (5) dialoguing with parents about the expected duration of the baby's life and the related uncertainty; (6) planning of palliative care to be implemented at birth; (7) preparing a plan with the parents for discharging the infant from the hospital and for taking care of him over a long time, when it is deemed possible that the baby may live for more than a few days. PMID- 28007511 TI - [Neonatal palliative care at home: Contribution of the regional pediatric palliative care team]. AB - The "patients' rights and end-of-life care" act, known as the Leonetti law, has allowed implementation of palliative care in neonatology as an alternative to unreasonable therapeutic interventions. A palliative care project can be offered to newborns suffering from intractable diseases. It must be focused on the newborn's quality of life and comfort and on family support. Palliative care for newborns can be provided in the delivery room, in the neonatal unit, and also at home. Going home is possible but requires medical support. Here we describe the potential benefits of the intervention of a regional team of pediatric palliative care for newborns, both in the hospital and at home. Two clinical situations of palliative care at home started in the neonatal period and the neonatal unit are presented. They are completed by a retrospective national survey focusing on the type of support to newborns in palliative care in 2014, which was conducted in 22 French regional pediatric palliative care teams. It shows that 26 newborns benefited from this support at home in 2014. Sixteen infants were born after a pregnancy with a palliative care birth plan and ten entered palliative care after a decision to limit life-sustaining treatments. Twelve of them returned home before the 20th day of life. Sixteen infants died, six of them at home. The regional pediatric palliative care team first receives in-hospital interventions: providing support for ethical reflection in the development of the infant's life project, meeting with the child and its family, helping organize the care pathway to return home. When the child is at home, the regional pediatric palliative care team can support the caregiver involved, provide home visits to continue the clinical monitoring of the infant, and accompany the family. The follow-up of the bereavement and the analysis of the practices with caregivers are also part of its tasks. PMID- 28007512 TI - [The complex phenotype of ARC syndrome: A new case]. AB - ARC syndrome (arthrogryposis - renal dysfunction - cholestasis) is a rare lethal multisystemic autosomal recessive disease. A newborn of consanguineous parents of Algerian descent presented cholestatic jaundice, dehydration, and Fanconi syndrome at 10 days of life. The blood smear showed a very characteristic gray appearance of platelets. A homozygous mutation was evidenced in the VPS33B gene. This gene codes for a protein involved in trafficking of intracellular vesicles. The mutation (c.604-2A>G) present in the heterozygous state in the parents affects an invariant base of the splice acceptor site and to our knowledge has not been reported yet. This child died at the age of 3 months. Prenatal diagnosis was offered to the family; another pregnancy was carried to completion and a girl was born without the disease. The combination of cholestasis and proximal tubulopathy should suggest the diagnosis in a newborn with orthopedic problems. A blood smear greatly facilitates diagnosis. PMID- 28007513 TI - [Delayed umbilical cord clamping in preterm infants born before 37 weeks of gestation: A prospective observational study]. AB - INTRODUCTION AND OBJECTIVES: Many international studies have demonstrated that delayed umbilical cord clamping reduces neonatal morbidity. However, in France, delayed umbilical cord clamping is still not performed in many neonatal units. The aims of this study were to evaluate the feasibility of developing a protocol of delayed umbilical cord clamping in the maternity ward of the Toulouse university hospital and to evaluate the impact of this new protocol on neonatal mortality. METHODS: We conducted a prospective observational study including 123 preterm infants born before 37 weeks of gestation between June 2012 and June 2013 and hospitalized at birth. Delayed cord clamping was performed for at least 30s after birth; otherwise, it was evaluated as early cord clamping. We excluded twin to-twin transfusion syndrome, congenital abnormalities, alloimmunization, and perinatal asphyxia. We analyzed the reasons why delayed umbilical cord clamping was not performed and then neonatal morbidity in our population. RESULTS: Delayed umbilical cord clamping was performed on 79 infants and 44 infants had early umbilical cord clamping. The two groups had similar baseline characteristics. Preterm infants in the delayed cord-clamping group had a higher level of hemoglobin during the first 24h of life (17.9g/dL versus 16.6g/dL, P=0.005), fewer of them required transfusion (14% versus 35%, P=0.03), and fewer presented late-onset sepsis (8% versus 26%, P=0.02) or bronchopulmonary dysplasia (9% versus 26%, P=0.03). There was no statistically significant increase of hyperbilirubinemia requiring phototherapy. DISCUSSION AND CONCLUSION: Implanting a new protocol of delayed umbilical cord clamping in our maternity ward proved to be possible without difficulty. The advantages of delayed umbilical cord clamping were observed in this prospective study. Today, delayed cord clamping has become a common practice in our maternity unit. PMID- 28007514 TI - Safety and efficacy of self-assembling bubble carriers stabilized with sodium dodecyl sulfate for oral delivery of therapeutic proteins. AB - Sodium dodecyl sulfate (SDS) is generally regarded as a potent permeability enhancer in oral formulations; however, one concern related to the use of any permeation enhancer is its possible absorption of unwanted toxins during the period of epithelial permeability enhancement. In this work, the safety and efficacy of an SDS-containing bubble carrier system that is developed from an orally administered enteric-coated capsule are evaluated. The bubble carriers comprise diethylene triamine pentaacetic acid (DTPA) dianhydride, sodium bicarbonate (SBC), SDS, and insulin. Upon exposure to the intestinal fluid, DTPA dianhydride hydrolyzes to yield acids, and SBC rapidly reacts with these acids to generate CO2, producing bubble carriers, each containing a self-assembling water film. The hydrophilic insulin is entrapped in the self-assembled water film, which is stabilized by SDS. The SDS in the bubble carrier system can act as a dissolution enhancer in the dispersion of insulin molecules, as a surfactant that stabilizes the bubble carriers, as a protease inhibitor that protects the protein drug, and as a permeation enhancer that augments its oral bioavailability. Hence, a significant increase in the plasma insulin level and an excellent blood glucose lowering response in diabetic rats are effectively achieved. Moreover, the enhancement of epithelial permeation by this SDS-containing formulation does not promote the absorption of intestinal endotoxins. The above facts indicate that the bubble carrier system that is stabilized by SDS can be used as a safe and potent carrier in the oral delivery of therapeutic proteins. PMID- 28007515 TI - Measuring MEG closer to the brain: Performance of on-scalp sensor arrays. AB - Optically-pumped magnetometers (OPMs) have recently reached sensitivity levels required for magnetoencephalography (MEG). OPMs do not need cryogenics and can thus be placed within millimetres from the scalp into an array that adapts to the individual head size and shape, thereby reducing the distance from cortical sources to the sensors. Here, we quantified the improvement in recording MEG with hypothetical on-scalp OPM arrays compared to a 306-channel state-of-the-art SQUID array (102 magnetometers and 204 planar gradiometers). We simulated OPM arrays that measured either normal (nOPM; 102 sensors), tangential (tOPM; 204 sensors), or all components (aOPM; 306 sensors) of the magnetic field. We built forward models based on magnetic resonance images of 10 adult heads; we employed a three compartment boundary element model and distributed current dipoles evenly across the cortical mantle. Compared to the SQUID magnetometers, nOPM and tOPM yielded 7.5 and 5.3 times higher signal power, while the correlations between the field patterns of source dipoles were reduced by factors of 2.8 and 3.6, respectively. Values of the field-pattern correlations were similar across nOPM, tOPM and SQUID gradiometers. Volume currents reduced the signals of primary currents on average by 10%, 72% and 15% in nOPM, tOPM and SQUID magnetometers, respectively. The information capacities of the OPM arrays were clearly higher than that of the SQUID array. The dipole-localization accuracies of the arrays were similar while the minimum-norm-based point-spread functions were on average 2.4 and 2.5 times more spread for the SQUID array compared to nOPM and tOPM arrays, respectively. PMID- 28007516 TI - Using transposition to introduce eGFP fusions in Sinorhizobium meliloti: A tool to analyze protein localization patterns in bacteria. AB - Conventional methods used for the in vivo analysis of subcellular protein localizations and their spatio-temporal dynamics in prokaryotes are based on either the engineering of N(amino)- or C(carboxy)-terminal fusions of fluorescent proteins with the protein of interest, or involved probing internal sites for tag integration. In addition, the use of inducible or constitutive promoters for the expression of fluorescent fusion proteins can lead to overexpression and result in localization artifacts. Here, we describe a method for the synthesis of fluorescent fusion proteins using transposable elements, which can randomly integrate in the internal sections of the protein coding sequence to produce full length fluorescent fusion proteins expressed at endogenous levels. The established method was used for investigating subcellular localization of proteins in the soil bacterium and plant symbiont Sinorhizobium meliloti. Two constructs for transposition-based insertion of the enhanced green fluorescent protein (eGFP), as well as for in vivo excision of the selection marker for the production of full-length proteins were engineered. Conjugation with pHB14 plasmid and induction of the transposition in S. meliloti produced approx. 3.22*104 transconjugant colonies harboring the fluorescent marker with the transposition efficiency of 0.8%. Sixteen randomly targeted proteins of diverse functions, fused to the eGFP were identified and analyzed in living cells by epifluorescence microscopy, demonstrating the suitability of the novel tool for massive, random production of fluorescent proteins and for following of these proteins with different localizations inside the prokaryotic cell. PMID- 28007517 TI - Re-emergent tremor in Parkinson's disease. AB - INTRODUCTION: Re-emergent tremor (RET) is a postural tremor that appears after a variable delay in patients with Parkinson's disease (PD). The aim of the present study was to evaluate the occurrence and the clinical characteristics of RET in a population of patients with PD. METHODS: We consecutively assessed 210 patients with PD. We collected the patients' demographic and clinical data. RET was clinically characterized in terms of latency, severity and body side affected. We also investigated a possible relationship with motor and non-motor symptoms and differences in the clinical features in patients with and without RET. RESULTS: RET was present in 42/210 patients. The mean latency of RET was 9.20 +/- 6.8 seconds. Mean severity was 2.4 +/- 1.9. RET was unilateral in 21 patients. Patients with RET had less severe speech, posture and gait disorders and upper limb and global bradykinesia than patients without RET. Similar findings were observed when we compared patients with RET with patients with tremor at rest associated with action tremor, patients with isolated action tremor and patients with no tremor. By contrast, patients with RET tremor did not clinically differ from those with isolated tremor at rest. CONCLUSION: Our results suggest that patients with RET and patients with isolated tremor at rest represent the same clinical subtype, whereas patients with action tremor (whether isolated or associated with tremor at rest) might belong to a distinct subtype that is clinically worse. Patients with RET represents a benign subtype of PD, even within the tremor-dominant phenotype. PMID- 28007518 TI - Understanding falls in progressive supranuclear palsy. AB - INTRODUCTION: Progressive supranuclear palsy (PSP) is characterized by frequent falls which worsen with disease progression, causing substantial morbidity and mortality. Few studies have investigated which factors contribute to falls in PSP, and all have involved few participants, thus lacking necessary statistical power. The aim of this study was to identify clinical parameters most significantly associated with increasing falls in PSP, using the largest sample of patients to date. METHODS: Comprehensive clinical data were collected from 339 not demented PSP patients meeting the NINDS-SPSP criteria, who were divided into two groups - Infrequent Fallers (IF; n = 118) with rare falls, and Frequent Fallers (FF; n = 221) who fell occasionally to multiple times a day. Of 198 clinical parameters, we hypothesized 38 to be correlated with an increasing risk of falls. These 38 parameters were analyzed via univariate regression analysis to determine the strength of their association with fall frequency. Unit odds ratios identified the magnitude with which each parameter resulted in an increasing risk of falls. RESULTS: Twenty-five of 38 parameters analyzed were significantly associated with fall frequency based on univariate analysis. Symptom duration, clinical measures of disease severity, and several motoric and oculomotor clinical parameters were associated with FF. Examined cognitive parameters and slowing of vertical saccades were not. CONCLUSIONS: The clinical parameters identified as associated with increased frequency of falls improve our understanding of why they occur and may help identify not demented PSP patients at risk for increasing falls. PMID- 28007520 TI - Spinal anaesthesia in outpatient and conventional surgery: A point of view from experienced French anaesthetists. AB - INTRODUCTION: The objective of this investigation was to evaluate the practice of spinal anaesthesia among French anaesthetists in inpatient and outpatient settings. METHODS AND MATERIALS: A questionnaire was sent to members of the French Association of Anaesthetists involved in regional anaesthesia during the first 4months of 2015. The questionnaire included items on the practice of spinal anaesthesia (type of needle, local anaesthetic available, puncture and disinfection techniques, etc.) and on the anaesthetic techniques usually used in 5 surgical situations eligible for outpatient surgery (knee arthroscopy, inguinal hernia, transobturator tape, haemorrhoids, varicose veins in the lower limbs). RESULTS: Responses from 703 anaesthesiologists were analysed. Spinal anaesthesia was usually performed in a sitting position (76%) using a Whitacre needle (60%) with a 25 G (57%) diameter. Ultrasound before puncture was reported in 26% of cases due to obesity or spinal abnormalities. Among the 5 surgical situations eligible for outpatient spinal anaesthesia, the technique was typically proposed in 29-49% of cases. Bupivacaine was the most used local anaesthetic. Concerns over delays in attaining readiness for hospital discharge, urine retention, operation length, and surgeon's preference were the main reasons for choosing another anaesthetic technique in these situations. DISCUSSION: New local anaesthetics are beginning to be used for outpatient spinal anaesthesia due to their interesting pharmacodynamic profile in this context. This study will provide a basis for evaluating future changes in practice. PMID- 28007519 TI - Genetic characterisation of carbapenem-resistant Gram-negative bacteria isolated from the University Hospital Mohamed Boudiaf in Ouargla, southern Algeria. AB - OBJECTIVES: The aim of this study was to investigate the molecular epidemiology and the genetic support of carbapenem-resistant Enterobacteriaceae and Acinetobacter spp. isolates collected in the University Hospital of Ouargla, southern Algeria. METHODS: A total of 99 Gram-negative bacteria (GNB) were collected from stool samples of colonised patients and from inanimate surfaces in the hospital environment between December 2014 and August 2015. Selected Enterobacteriaceae and Acinetobacter spp. isolates with reduced susceptibility to carbapenems were subjected to phenotypic study, including antibiotic susceptibility testing according to CA-SFM-EUCAST 2015 guidelines and modified Carba NP test. Genes encoding carbapenemases, extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases were screened by PCR and sequencing. Clonal relatedness was determined by multilocus sequencing typing (MLST). RESULTS: Of the 99 GNB isolates, 10 (10.1%) showed reduced susceptibility to carbapenems were studied further, including 7 Acinetobacter baumannii, 1 Acinetobacter nosocomialis, 1 Escherichia coli and 1 Klebsiella pneumoniae. PCR and sequencing showed that four A. baumannii isolates and the single A. nosocomialis isolate harboured blaNDM-1. In addition, blaOXA-23 was observed in three A. baumannii isolates, and blaOXA-48 was detected in the two Enterobacteriaceae isolates. MLST assigned the K. pneumoniae to ST999 and the E. coli to ST38. The seven A. baumannii isolates belonged to ST85 and ST2. CONCLUSIONS: This study describes the epidemiology of carbapenemases produced by Enterobacteriaceae and Acinetobacter spp. in southern Algeria and reports the first description of metallo-beta-lactamase NDM-1-producing A. nosocomialis in Algeria. PMID- 28007521 TI - Children with challenging airways: What about GlideScope(r) video-laryngoscopy? AB - BACKGROUND: GlideScope(r) video-laryngoscopy is becoming increasingly used, including in paediatrics. However, to date, very few data are available on efficiency during situations involving difficult intubation. Our objective was to describe the usefulness of the GlideScope(r) in children with presumed challenging airway criteria. METHODS: In this observational study, all children with predicted criteria of potential difficult intubation and requiring general anaesthesia with tracheal intubation were prospectively enrolled over a 12-month period. The Cormack and Lehane (CMK) grade was first assessed by direct laryngoscopy. In case of a CMK>=3, the same experienced anaesthesiologist scored the CMK scale under GlideScope(r) videoscopy. Data related to GlideScope(r) use under difficult intubation conditions were analysed. RESULTS: Out of the sixty one patients (median [25th-75th interquartile range] age of 12 [4-37] months) included, 37 (62%) patients have confirmed a high probability of difficult intubation. Compared to direct laryngoscopy, GlideScope(r) video-laryngoscopy was significantly associated with an improved CMK grade (P<0.001). Tracheal intubation with the GlideScope(r) was successful after the first attempt in almost one half of cases and ultimately in 100% of patients. The median time required for successful GlideScope(r) intubation was 42.5 [30-60] s. No per procedure complications were recorded. CONCLUSION: In children with challenging airways, GlideScope(r) video-laryngoscopy resulted in a significant improvement of the glottic view with an excellent success rate and satisfactory time to intubation. How these devices are to be positioned in difficult airway management algorithms and guidelines remain to be defined. PMID- 28007522 TI - The pupillary light reflex for predicting the risk of hypotension after spinal anaesthesia for elective caesarean section. AB - INTRODUCTION: The balance between the sympathetic and parasympathetic systems could be used to predict the onset of hypotension following spinal anaesthesia. The autonomic innervation of the pupil may reflect this balance. The aim of this study was to evaluate the ability of pupillometry to predict the risk of hypotension after spinal anaesthesia for caesarean section. METHODS: Two hundred patients receiving spinal anaesthesia for caesarean section were recruited. Changes in pupillary diameter, pupillary reaction latency, pupil constriction velocity and maximum and minimum pupillary diameters were measured with a pupillometer (Neurolight(r), IDMed) prior to induction of spinal anaesthesia with 10mg bupivacaine and fentanyl 30MUg. Hypotension was defined as a systolic blood pressure drop of > 20% compared with the baseline value. RESULTS: A total of 141 patients (70%) presented at least one episode of hypotension. Pupillary reaction latency can poorly predict hypotension and severe hypotension after spinal anaesthesia. The areas under the receiver-operating characteristic curves were 0.654 (95% confidence interval: 0.584-0.720, P=0.0001) and 0.633 (95% confidence interval: 0.562-0.700, P=0.004) for optimal threshold values of 223 and 231ms, respectively. In multivariate analysis, a baseline systolic blood pressure > 130mmHg (odds ratio: 1.98, P=0.04) and a PRL > 223ms (odds ratio: 3.42, P=0.0002) were independently associated with the risk of spinal anaesthesia-related hypotension. CONCLUSION: Following spinal anaesthesia in patients undergoing caesarean section, though the predictive capacity pupillary reaction latency for the onset of hypotension and severe hypotension is poor, it is nevertheless the strongest predictor of hypotension identified in our study. PMID- 28007524 TI - Microbial metatranscriptomes from the thermally stratified Gulf of Aqaba/Eilat during summer. AB - The water column in the oligotrophic Gulf of Aqaba/Eilat experiences distinct seasonal cycles with the cooling air and water temperatures of late fall and winter destabilizing the thermocline and forming mixed layer depths reaching 300 to 700m. As air temperatures warm thermal re-stratification results in a stable thermocline throughout the summer which physically separates a photic, nutrient poor surface layer from an aphotic, nutrient-rich deep layer. Here we present the first metatranscriptome dataset, and its taxonomic assignments, sampled from three depths of the 700m deep Station A in the Gulf of Aqaba during the summer stratification (surface - 10m, deep chlorophyll maximum (DCM) - 85m, deep aphotic zone -500m). Intensive transcriptional activity was attributed to Prochlorococcus - the most abundant photosynthetic organism in the RNA-seq dataset - both at the surface and at the DCM. In contrast, cDNA reads related to picoeukaryotic algae were detected almost exclusively at the DCM. The metatranscriptomes presented here provide a basis for examining the seasonal differences in microbial gene expression by comparison with the published metatranscriptomes sampled during the winter deep-mixing from the same station. PMID- 28007523 TI - Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia. AB - Neuroinflammation is a major contributor to intracerebral hemorrhage (ICH) progression, but no drug is currently available to reduce this response and protect against ICH-induced injury. Recently, the natural product pinocembrin has been shown to ameliorate neuroinflammation and is undergoing a phase II clinical trial for ischemic stroke treatment. In this study, we examined the efficacy of pinocembrin in an ICH model, and further examined its effect on microglial activation and polarization. In vivo, pinocembrin dose-dependently reduced lesion volume by ~47.5% and reduced neurologic deficits of mice at 72h after collagenase induced ICH. The optimal dose of pinocembrin (5mg/kg) suppressed microglial activation as evidenced by decreases in CD68-positive microglia and reduced proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, and IL-6. Pinocembrin also reduced the number of classically activated M1 like microglia without affecting M2-like microglia in the perilesional region. Additionally, pinocembrin decreased the expression of toll-like receptor (TLR)4 and its downstream target proteins TRIF and MyD88. The protection by pinocembrin was lost in microglia-depleted mice and in TLR4lps-del mice, and pinocembrin failed to decrease the number of M1-like microglia in TLR4lps-del mice. In lipopolysaccharide-stimulated BV-2 cells or primary microglia, pinocembrin decreased M1-related cytokines and markers (IL-1beta, IL-6, TNF-alpha, and iNOS), NF-kappaB activation, and TLR4 expression, but it did not interfere with TLR4/MyD88 and TLR4/TRIF interactions or affect microglial phagocytosis of red blood cells. Inhibition of the TLR4 signaling pathway and reduction in M1-like microglial polarization might be the major mechanism by which pinocembrin protects hemorrhagic brain. With anti-inflammatory properties, pinocembrin could be a promising new drug candidate for treating ICH and other acute brain injuries. PMID- 28007525 TI - The mammalian Cretaceous cochlear revolution. AB - The hearing organs of amniote vertebrates show large differences in their size and structure between the species' groups. In spite of this, their performance in terms of hearing sensitivity and the frequency selectivity of auditory-nerve units shows unexpectedly small differences. The only substantial difference is that therian, defined as live-bearing, mammalian groups are able to hear ultrasonic frequencies (above 15-20 kHz), whereas in contrast monotreme (egg laying) mammals and all non-mammalian amniotes cannot. This review compares the structure and physiology of the cochleae of the main groups and asks the question as to why the many structural differences seen in therian mammals arose, yet did not result in greater differences in physiology. The likely answers to this question are found in the history of the mammals during the Cretaceous period that ended 65 million years ago. During that period, the therian cochlea lost its lagenar macula, leading to a fall in endolymph calcium levels. This likely resulted in a small revolution and an auditory crisis that was compensated for by a subsequent series of structural and physiological adaptations. The end result was a system of equivalent performance to that independently evolved in other amniotes but with the additional - and of course "unforeseen" - advantage that ultrasonic-frequency responses became an available option. That option was not always availed of, but in most groups of therian mammals it did evolve and is used for communication and orientation based on improved sound localization, with micro-bats and toothed whales relying on it for prey capture. PMID- 28007526 TI - Noise-induced cochlear synaptopathy: Past findings and future studies. AB - For decades, we have presumed the death of hair cells and spiral ganglion neurons are the main cause of hearing loss and difficulties understanding speech in noise, but new findings suggest synapse loss may be the key contributor. Specifically, recent preclinical studies suggest that the synapses between inner hair cells and spiral ganglion neurons with low spontaneous rates and high thresholds are the most vulnerable subcellular structures, with respect to insults during aging and noise exposure. This cochlear synaptopathy can be "hidden" because this synaptic loss can occur without permanent hearing threshold shifts. This new discovery of synaptic loss opens doors to new research directions. Here, we review a number of recent studies and make suggestions in two critical future research directions. First, based on solid evidence of cochlear synaptopathy in animal models, it is time to apply molecular approaches to identify the underlying molecular mechanisms; improved understanding is necessary for developing rational, effective therapies against this cochlear synaptopathy. Second, in human studies, the data supporting cochlear synaptopathy are indirect although rapid progress has been made. To fully identify changes in function that are directly related this hidden synaptic damage, we argue that a battery of tests including both electrophysiological and behavior tests should be combined for diagnosis of "hidden hearing loss" in clinical studies. This new approach may provide a direct link between cochlear synaptopathy and perceptual difficulties. PMID- 28007527 TI - Applications of Higenamine in pharmacology and medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum has been used as local and traditional medicines in many asian regions for the treatment of various diseases such as collapse, syncope, painful joints, oedema, bronchial asthma et al. Higenamine, a plant-based alkaloid, was initially isolated from Aconitum and identified as the active cardiotonic component of Aconitum. It has been tested as a candidate of pharmacologic stress agent in the detection of coronary artery diseases (CADs) and now researchers have just accomplished the phase III clinical studies successfully in China. Besides, a large number of studies have revealed the various pharmacological properties and potentially multi-spectral medical applications of higenamine. However, to date, no comprehensive review on higenamine has been published. AIM OF THE REVIEW: This present paper aims to compile a comprehensive update regarding the biochemistry, pharmacokinetic features, pharmacological activities, clinical and potential clinical uses and toxicities on higenamine with the ultimate objective of providing a guide for future research on this drug. MATERIALS AND METHODS: The selection of relevant data was made through a search using the keyword "higenamine" in "Web of science", "Pubmed", and "China Knowledge Resource Integrated (CNKI)". Information was also acquired from local classic herbal literature, government reports and conference papers. RESULTS: In addition to Aconitum, higenamine also exists in many other plants including Tinospora crispa, Nandina domestica THUNBERG, Gnetum Parvifolium C.Y. Cheng, sarum Heterotropoides,Nelumbo nucifera,N.nucifera. The pharmacokinetic studies conducted in animals and humans showed that higenamine conformed to a two-compartment pharmacokinetic model. Studies over the last four decades on higenamine have revealed its various pharmacological properties such as positive inotropic and chronotropic effect, activating slow channel effect, vascular and tracheal relaxation effect, anti-thrombotic, anti-apoptotic and anti oxidative effect, anti-inflammatory and immunomodulatory effect. This phytochemical constituent has shown its potential therapeutic effects for diseases like heart failure, disseminated intravascular coagulation (DIC), shock, arthritis, asthma, ischemia/reperfusion (I/R) injuries and erectile dysfunction. CONCLUSIONS: Extensive basic and clinical studies on higenamine showed valuable therapeutic effects on different disorders. However, the underlying mechanisms of higenamine have not been established. Therefore, the safety, tolerability and efficacy of higenamine are as yet, not fully understood. Additionally, some of the studies were small sample-sized and unreliable. To sum up, there is a need for deeper investigation in the mechanisms of higenamine action, as well as well designed preclinical and clinical trials studies to test the safety and clinical value of the drug. PMID- 28007529 TI - Application of a paper based device containing a new culture medium to detect Vibrio cholerae in water samples collected in Haiti. AB - Cholera is now considered to be endemic in Haiti, often with increased incidence during rainy seasons. The challenge of cholera surveillance is exacerbated by the cost of sample collection and laboratory analysis. A diagnostic tool is needed that is low cost, easy-to-use, and able to detect and quantify Vibrio cholerae accurately in water samples within 18-24h, and perform reliably in remote settings lacking laboratory infrastructure and skilled staff. The two main objectives of this study were to develop and evaluate a new culture medium embedded in a new diagnostic tool (PAD for paper based analytical device) for detecting Vibrio cholerae from water samples collected in Haiti. The intent is to provide guidance for corrective action, such as chlorination, for water positive for V. cholerae epidemic strains. For detecting Vibrio cholerae, a new chromogenic medium was designed and evaluated as an alternative to thiosulfate citrate bile salts sucrose (TCBS) agar for testing raw water samples. Sensitivity and specificity of the medium were assessed using both raw and spiked water samples. The Vibrio cholerae chromogenic medium was proved to be highly selective against most of the cultivable bacteria in the water samples, without loss of sensitivity in detection of V. cholerae. Thus, reliability of this new culture medium for detection of V. cholerae in the presence of other Vibrio species in water samples offers a significant advantage. A new paper based device containing the new chromogenic medium previously evaluated was compared with reference methods for detecting V. cholerae from spiked water sample. The microbiological PAD specifications were evaluated in Haiti. More precisely, a total of 185 water samples were collected at five sites in Haiti, June 2014 and again in June 2015. With this new tool, three V. cholerae O1 and 17 V. cholerae non-O1/O139 strains were isolated. The presence of virulence-associated and regulatory genes, including ctxA, zot, ace, and toxR, was confirmed using multiplex PCR. The three V. cholerae O1 isolates were positive for three of the four virulence-associated and regulatory genes. Twelve of the V. cholerae non-O1/O139 isolates were found to carry toxR, but none were ctxA+, zot+, or ace+. However, six of the V. cholerae non-O1/O139 isolates were resistant to penicillin, ampicillin, trimethoprim/sulfamethoxazole, nalidixic acid, and ciprofloxacin. The paper based analytical device (PAD) provides advantages in that standard culture methods employing agar plates are not required. Also, intermediary isolation steps were not required, including transfer to selective growth media, hence these steps being omitted reduced time to results. Furthermore, experienced technical skills also were not required. Thus, PAD is well suited for resource-limited settings. PMID- 28007530 TI - Utilizing the Carba NP test as an indicator of expression level of carbapenemase genes in Enterobacteriaceae. AB - The Carba NP test was developed to detect carbapenemase-producing Enterobacteriaceae, and uses imipenem as the reaction substrate. In Japan, IMP-6 metallo-beta-lactamase (MBL) producers, which are usually resistant to meropenem but susceptible to imipenem, and IMP-1 MBL producers, which are usually resistant to both carbapenems are prevalent. We performed the Carba NP test with IMP-6 and IMP-1 MBL producers, and both types were detected by the Carba NP test with high sensitivity. All IMP-1 MBL producers were detected by the Carba NP test, but the minimum inhibitory concentrations (MICs) of imipenem varied from 0.25 to >32MUg/mL, and the time to positivity varied from 0 to 30min. Time to positivity was significantly correlated with expression levels of blaIMP-1, but not with MICs of imipenem. These results suggested that the Carba NP test can be used as a screening assay for carbapenemase gene expression levels among producers of the same type of carbapenemase. Using this approach, it is possible to determine whether the carbapenem resistance of each carbapenemase-producing Enterobacteriaceae isolate is primarily due to carbapenemase production, or to another mechanism such as outer membrane impermeability. PMID- 28007528 TI - Puberty and structural brain development in humans. AB - Adolescence is a transitional period of physical and behavioral development between childhood and adulthood. Puberty is a distinct period of sexual maturation that occurs during adolescence. Since the advent of magnetic resonance imaging (MRI), human studies have largely examined neurodevelopment in the context of age. A breadth of animal findings suggest that sex hormones continue to influence the brain beyond the prenatal period, with both organizational and activational effects occurring during puberty. Given the animal evidence, human MRI research has also set out to determine how puberty may influence otherwise known patterns of age-related neurodevelopment. Here we review structural-based MRI studies and show that pubertal maturation is a key variable to consider in elucidating sex- and individual- based differences in patterns of human brain development. We also highlight the continuing challenges faced, as well as future considerations, for this vital avenue of research. PMID- 28007531 TI - 25-hydroxyvitamin D is associated with adiposity and cardiometabolic risk factors in a predominantly vitamin D-deficient and overweight/obese but otherwise healthy cohort. AB - Vitamin D deficiency has reached epidemic proportions worldwide and has recently been linked to cardiometabolic risk factors including obesity, insulin resistance, hypertension, dyslipidemia, as well as type 2 diabetes and cardiovascular disease. The objective of this study was to examine the associations between circulating 25-hydrovitamin D (25(OH)D) levels and cardiometabolic risk factors using direct measures of adiposity, glucose intolerance, and insulin resistance, as well as lipids, blood pressure, and plasma markers of inflammation. We measured circulating 25(OH)D, physical activity (International Physical Activity Questionnaire- IPAQ), anthropometry (body mass index (BMI), waist-to-hip ratio (WHR), % body fat (dual energy X-ray absorptiometry)), metabolic parameters (fasting and 2-h plasma glucose levels during oral glucose tolerance test; insulin sensitivity (M, hyperinsulinaemic euglycaemic clamp), and cardiovascular and inflammatory profiles (blood pressure (BP), pulse pressure (PP), mean arterial pressure (MAP), plasma lipid levels, white blood cell count (WBC), and plasma high-sensitivity C-reactive protein levels (hsCRP)) in 111 healthy, non-diabetic adults (66 males/45 females; age 31.1+/-9.2years; % body fat 36.0+/-10.2%). Mean 25(OH)D was 39.8+/-19.8 nmol/L with no difference between genders (p=0.4). On univariate analysis, 25(OH)D was associated with% body fat (r=-0.27; p=0.005), 2-h glucose (r=-0.21; p=0.03), PP (r=0.26; p=0.006), and insulin sensitivity (r=0.20, p=0.04), but not with age, BMI, WHR, fasting glucose, BP, MAP, lipids, or inflammatory markers (all p>0.05). After adjusting for age and sex, 25(OH)D remained associated with% body fat (beta=-0.12%; p=0.003), 2-h glucose (beta=-0.13mmol/L; p=0.02), PP (beta=0.12mmHg; p=0.009), and insulin sensitivity (beta=0.22mg/kg/min; p=0.03), and became associated with fasting glucose (beta=-0.04mmol/L; p=0.04) and hsCRP (beta=-0.51mg/L; p=0.04). After adjusting for age, sex, and % body fat, 25(OH)D was no longer associated with insulin sensitivity, 2-h glucose, or hsCRP, but remained associated with fasting glucose (beta=-0.05mmol/L; p=0.03) and PP (beta=0.10mmHg; p=0.03). 25(OH)D remained associated with fasting glucose (beta= 0.06mmol/L; p=0.02) after hsCRP and physical activity were added to the model with % body fat, age, and sex. These cross-sectional data suggest that associations between vitamin D and cardiometabolic risk among healthy, non diabetic adults are largely mediated by adiposity. Large-scale intervention and mechanistic studies are needed to further investigate whether vitamin D has an independent role in the prevention and/or management of cardiometabolic risk and disease. PMID- 28007533 TI - Vitamin D metabolite concentrations in umbilical cord blood serum and associations with clinical characteristics in a large prospective mother-infant cohort in Ireland. AB - Vitamin D deficiency is widespread among mothers and neonates and quality clinical and analytical data are lacking. We used a CDC-accredited LC-MS/MS method to analyze vitamin D metabolites in cord sera from 1050 maternal-infant dyads in the prospective SCOPE Ireland Pregnancy and BASELINE Birth cohort studies, based in Cork, Ireland. The mean+/-SD total 25(OH)D was 34.9+/ 18.1nmol/L; 35% of cords (50% during winter) had 25(OH)D <25nmol/L, 46% were <30nmol/L and 80% were <50nmol/L. In this predominantly white cohort, the main predictor of cord 25(OH)D [adj. mean difference in nmol/L (95% CI)] was summer delivery [19.2 (17.4, 20.9), P<0.0001]. Maternal smoking during pregnancy (9% prevalence) was negatively associated (P<0.002) with cord 25(OH)D [-4.83 (-7.9, 1.5) nmol/L]. There were no associations between cord 25(OH)D and birth weight or any anthropometric measures at birth. Despite the high prevalence of vitamin D deficiency at birth, there were no documented musculoskeletal complications during infancy, which was likely due to widespread supplementation with vitamin D. The mean+/-SD concentration of 3-epi-25(OH)D3, detectable in 99.4% of cord samples, was 3.3+/-1.9nmol/L. The proportion of 25(OH)D as 3-epi-25(OH)D3 was 11.2%. Cord 3-epi-25(OH)D3 concentrations were positively predicted by cord 25(OH)D3 [0.101 (0.099, 0.103) nmol/L, P<0.0001] and negatively by gestational age [-0.104 (-0.131, -0.076) nmol/L, P<0.0001] and maternal age [-0.010 (-0.019, 0.001) nmol/L, P<0.05]. 25(OH)D2 was detected in 98% of cord sera (mean+/-SD; 2.2+/-1.9nmol/L) despite low antenatal consumption of vitamin D2 supplements. In conclusion, these first CDC-accredited data of vitamin D metabolites in umbilical cord blood emphasise the high risk of very low vitamin D status in infants born to un-supplemented mothers. Experimental data to define maternal vitamin D requirements for prevention of neonatal deficiency at high latitude are required. PMID- 28007532 TI - Role of G-protein-coupled estrogen receptor (GPER/GPR30) in maintenance of meiotic arrest in fish oocytes. AB - An essential role for GPER (formerly known as GPR30) in regulating mammalian reproduction has not been identified to date, although it has shown to be involved in the regulation a broad range of other estrogen-dependent functions. In contrast, an important reproductive role for GPER in the maintenance of oocyte meiotic arrest has been identified in teleost fishes, which is briefly reviewed here. Recent studies have clearly shown that ovarian follicle production of estradiol-17beta (E2) maintains meiotic arrest in several teleost species through activation of GPER coupled to a stimulatory G protein (Gs) on oocyte plasma membranes resulting in stimulation of cAMP production and maintenance of elevated cAMP levels. Studies with denuded zebrafish oocytes and with microinjection of GPER antisense oligonucleotides into oocytes have demonstrated the requirement for both ovarian follicle production of estrogens and expression of GPER on the oocyte surface for maintenance of meiotic arrest. This inhibitory action of E2 on the resumption of meiosis is mimicked by the GPER-selective agonist G-1, by the GPER agonists and nuclear ER antagonists, ICI 182,780 and tamoxifen, and also by the xenoestrogen bisphenol-A (BPA) and related alkylphenols. GPER also maintains meiotic arrest of zebrafish oocytes through estrogen- and BPA-dependent GPER activation of epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) signaling. Interestingly, progesterone receptor component 1 (PGRMC1) is also involved in estrogen maintenance of meiotic arrest through regulation of EGFR expression on the oocyte plasma membrane. The preovulatory surge in LH secretion induces the ovarian synthesis of progestin hormones that activate a membrane progestin receptor alpha (mPRalpha)/inhibitory G protein (Gi) pathway. It also increases ovarian synthesis of the catecholestrogen, 2-hydroxy estradiol-17beta (2-OHE2) which inhibits the GPER/Gs/adenylyl cyclase pathway. Both of these LH actions cause declines in oocyte cAMP levels resulting in the resumption of meiosis. GPER is also present on murine oocytes but there are no reports of studies investigating its possible involvement in maintaining meiotic arrest in mammals. PMID- 28007534 TI - FKBP5 polymorphism is associated with insulin resistance in children and adolescents with obesity. AB - OBJECTIVE: Since metabolic syndrome shares several clinical features with hypercortisolism, it was hypothesised that genes altering individual glucocorticoid (GC) sensitivity might be implicated in pathogenesis of obesity and its adverse outcomes. FKBP5 gene encodes a chaperon protein in the GC receptor (GR) complex, which modulates steroid action upon target genes. Its functional variant, rs1360780, may enhance FKBP5 gene transcription, affect GR signalling and thereby influence the hypothalamo-pituitary-adrenal axis. We investigated the association of rs1360780 with obesity and metabolic characteristics in 250 obese children and adolescents (mean age 12.3+/-3.6years, BMI >=95th percentile). METHODS: Anthropometric measurements, body composition, biochemical and hormonal results were analysed. Genotyping of rs1360780 was compared with 568 lean controls. RESULTS: Impaired fasting glucose was present in 8.8%, glucose intolerance in 10.4%, diabetes in 2.8% and dyslipidemia in 28.8% obese individuals. Hypertension was diagnosed in 34 out of 143 patients. No difference was found in FKBP5 polymorphism distribution between subjects with obesity and controls (p>0.05). Stratification by rs1360780 revealed no differences in body mass and composition. However, carriers of the minor allele displayed enhanced insulin resistance (p=0.009) and elevated serum triglyceride (p=0.006), whereas cholesterol, HbA1c, and oral glucose challenge results were similar for all genotypes. Morning ACTH and cortisol did not differ but evening cortisol was higher in minor allele carriers (p=0.039), although this association was lost in logistic regression analysis. CONCLUSION: This study does not support the association of FKBP5 with obesity but demonstrates plausible implication of its variant in susceptibility to obesity-related insulin resistance and hypertriglyceridemia. PMID- 28007535 TI - Association between weight status and men's positive mental health: The influence of marital status. AB - The purpose of this study was to (1) examine the association between weight status and men's positive mental health, defined as the presence of symptoms of emotional, psychological, and social well-being, and (2) evaluate the moderating effect of marital status. A total of 645 men aged between 19 and 71 years self reported their height and weight and answered a questionnaire measuring their emotional, psychological, and social well-being. Analysis of variance revealed that mean levels of emotional, psychological, and social well-being did not significantly differ according to men's weight status. Moderation analyses indicated that, for men in a relationship (married or living common-law), there were no significant associations between overweight, obesity, and the three components of positive mental health. However, for single men, overweight was marginally associated with higher emotional well-being, while obesity was associated with lower psychological well-being and marginally associated with lower social well-being. Results of the present study suggest that health professionals and researchers should take the characteristics (such as marital status) of men with obesity and overweight into account when working with them. Mental health researchers may need to examine men in each weight category separately (e.g. obesity vs. overweight), since the association with positive mental health can differ from one category to another. PMID- 28007536 TI - Conspecific alarm substance differently alters group behavior of zebrafish populations: Putative involvement of cholinergic and purinergic signaling in anxiety- and fear-like responses. AB - The zebrafish (Danio rerio) is an emergent model organism for assessing fear and anxiety-like phenotypes. The short fin wild type (WT), and leopard (leo) are two zebrafish populations that present several behavioral differences, in which leo displays pronounced defensive responses. Mounting evidence suggests a modulatory role for cholinergic and purinergic signaling in fear and anxiety, but the involvement of these neurotransmitter systems in the behavioral profile of zebrafish is obscure. Here we tested whether the acute exposure to conspecific alarm substance (AS), an experimental protocol that induces fear, alters shoaling behavior, diving response, acetylcholinesterase (AChE) activity, and nucleotide hydrolysis in brain tissue of WT and leo. When four fish were concomitantly exposed to AS extracted from a donor fish of similar phenotype, both populations presented a significant increase of erratic movements without changes in freezing bouts. An increased shoal cohesion and a decreased vertical distribution were observed only in WT exposed to AS. The respective population also revealed a significant increase in AChE and ecto-5'-nucleotidase activities after the exposure period. The comparison of basal endpoints between populations showed that leo displays a higher social cohesion, few vertical transitions and enhanced AChE and ecto-5'-nucleotidase activities. In conclusion, we suggest that the effects of AS on defensive behaviors depend on the population, indicating the existence of distinct neurochemical mechanisms involved. Furthermore, this report shows the first evidence of a potential role of cholinergic and purinergic systems in fear- and anxiety-like responses of zebrafish populations. PMID- 28007537 TI - Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer's disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis. AB - Stem cell transplantation represents a promising therapy for central nervous system injuries, but its application to Alzheimer's disease (AD) is still limited and the potential mechanism for cognition improvement remains to be elucidated. In the present study, we used Tg2576 mice which express AD-like pathological forms of amyloid precursor protein (APP) to investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) intravenous transplantation on AD mice. Interestingly, hUC-MSCs transplantation significantly ameliorated cognitive function of AD mice without altering Abeta levels in hippocampus. Remarkably, hUC-MSCs transplantation reduced oxidative stress in hippocampus of AD mice by decreasing the level of malondialdehyde (MDA), increasing the level of nitric oxide (NO), enhancing the activity of superoxide dismutase (SOD) and neuronal nitric oxide synthase (nNOS). The mechanisms underlying the improved cognitive function may be linked to hippocampal neurogenesis and an up-regulation of neuronal synaptic plasticity related proteins levels including silent information regulator 1 (Sirt1), brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN). Taken together, our findings suggest that hUC-MSCs can improve cognition of AD mice by decreasing oxidative stress and promoting hippocampal neurogenesis. These results suggest that modulating hUC-MSCs to generate excess neuroprotective factors could provide a viable therapy to treat AD. PMID- 28007538 TI - Adenosine A2A receptor deletion affects social behaviors and anxiety in mice: Involvement of anterior cingulate cortex and amygdala. AB - Blockade of adenosine A2A receptors can potentiate motivation to work for natural reinforcers such as food. Conspecific interaction is a potent natural reinforcer in social animals that can be manifested as preference for social exploration versus other sources of novel stimulation. Deficiencies in this type of motivated behavior (social withdrawal) have been seen in several pathologies such as autism and depression. However, the role of A2A receptors in motivation for social interaction has not been widely explored. Social interaction paradigms evaluate the natural preference of animals for exploring other conspecifics, and the ability to differentiate between familiar versus novel ones. Anxiety is one of the factors that can induce avoidance of social interaction. In the present study, adenosine A2A knockout (A2AKO) and wild-type (WT) mice were assessed for social and anxiety-related behaviors. c-Fos immunoreactivity was evaluated as a measure of neuronal activation in brain areas involved in different aspects of motivation and emotional processes. Although A2AKO mice showed an anxious profile, they displayed higher levels of sociability and were less sensitive to social novelty. WT mice displayed a typical pattern of social recognition 24h later, but not A2AKO mice, which explored equally both conspecifics. There were no differences between strains in aggressiveness, perseverance or social odor preferences. c-Fos immunoreactivity in A2AKO mice was higher in anterior cingulate and amygdala compared to WT mice. Thus, A2A receptors appear to be potential targets for the improvement of pathologies related to social function. PMID- 28007539 TI - Supplementation with copper edetate in control of Haemonchus contortus of sheep, and its effect on cholinesterase's and superoxide dismutase activities. AB - The aim of this study was to evaluate the effect of copper edetate on biochemical parameters, oxidative profile, cholinesterase's activities, as well as its capacity to control gastrointestinal parasites in infected sheep. Thus, Lacaune sheep (n = 18) infected by Haemonchus contortus were used and divided into three groups of six animal each: the group A was composed of untreated animals (the control group), the group B was formed by animals treated with 0.3 mg/kg of copper edetate, and the group C was composed of animals treated with 0.5 mg/kg of copper edetate. Blood collection was performed on days 0, 10, 20 and 30 after mineral supplementation and different variables were measured. Cholinergic system was evaluated to determine the acetylcholinesterase (AChE) activity in total blood and butyrylcholinesterase (BChE) activity in serum. Eggs per gram of feces (EPG) were evaluated. There were no significant differences (P > 0.05) between groups regarding total protein, albumin, globulin and urea levels, GGT activity, as well as the hematocrit, and EPG. ALT activity decreased (P < 0.05) on groups B and C on day 30 compared to the control group (the group A). AChE activity decreased (P < 0.05) in the group C on days 10 and 30 compared to the control group, such decrease (P < 0.05) was also observed for BChE activity in the group C on day 10. ROS levels increased in the group C compared to groups A and B on day 10, while the SOD activity increased in the group C on days 20 and 30 compared to the control group (P < 0.05). CAT activity did not differ between groups (P > 0.05). In summary, the copper edetate was not efficient to control gastrointestinal parasites, but efficiently activated SOD, an important antioxidant enzyme. In addition, copper edetate was able to partially inhibit cholinesterase's activities when supplementated at its highest dose. PMID- 28007540 TI - Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity. AB - Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive pVDC signature was constructed from 124 U.S. EPA ToxCast high-throughput screening (HTS) assays and used to rank 1060 chemicals for their potential to disrupt vascular development. Thirty-seven compounds were selected for targeted testing in transgenic Tg(kdrl:EGFP) and Tg(fli1:EGFP) zebrafish embryos to identify chemicals that impair developmental angiogenesis. We hypothesized that zebrafish angiogenesis toxicity data would correlate with human cell-based and cell-free in vitro HTS ToxCast data. Univariate statistical associations used to filter HTS data based on correlations with zebrafish angiogenic inhibition in vivo revealed 132 total significant associations, 33 of which were already captured in the pVDC signature, and 689 non-significant assay associations. Correlated assays were enriched in cytokine and extracellular matrix pathways. Taken together, the findings indicate the utility of zebrafish assays to evaluate an HTS-based predictive toxicity signature and also provide an experimental basis for expansion of the pVDC signature with novel HTS assays. PMID- 28007542 TI - Thought leaders saving money: One catheter at a time. PMID- 28007543 TI - Orodispersible films based on amorphous solid dispersions of tetrabenazine. AB - In this work, the formation and stability of amorphous solid dispersions (SDs) as orodispersible films (ODF) were investigated using tetrabenazine (TBZ) as a poorly water soluble drug. The influence of polymer nature and pH-modifier incorporation to form and maintain SDs was investigated. TBZ-loaded ODF were formulated using 4 different polymers (HPMC, PVP, Pullulan, and HEC). Binary systems (BS) were obtained mixing the drug with different polymers, while ternary (TS) systems were also obtained by adding citric acid to solubilize TBZ in the mixture. Drug dissolution studies, thermal analysis and X-ray diffraction were carried out to characterize the physical state of API in ODF. ODF made of TS allowed a major improvement of TBZ dissolution profile in buccal conditions compared to a pure drug or BS. DSC and X-ray diffraction revealed that API was in amorphous state in TS while remained crystalline in BS. Following 6 months of storage, TBZ recrystallization occurred for PVP-TS and HEC-TS which induced a decrease of drug release in saliva conditions. HPMC and PUL-TS maintained API in amorphous state during 6 months. Briefly, amorphous SDs were obtained by the pre dissolution of the drug in acidified water and incorporation in polymeric films. The miscibility and potential interaction between TBZ and polymers have been identified as important factor to explain stability differences. PMID- 28007544 TI - Powder compression mechanics of spray-dried lactose nanocomposites. AB - The aim of this study was to investigate the structural impact of the nanofiller incorporation on the powder compression mechanics of spray-dried lactose. The lactose was co-spray-dried with three different nanofillers, that is, cellulose nanocrystals, sodium montmorillonite and fumed silica, which led to lower micron sized nanocomposite particles with varying structure and morphology. The powder compression mechanics of the nanocomposites and physical mixtures of the neat spray-dried components were evaluated by a rational evaluation method with compression analysis as a tool, using the Kawakita equation and the Shapiro Konopicky-Heckel equation. Particle rearrangement dominated the initial compression profiles due to the small particle size of the materials. The strong contribution of particle rearrangement in the materials with fumed silica continued throughout the whole compression profile, which prohibited an in-depth material characterization. However, the lactose/cellulose nanocrystals and the lactose/sodium montmorillonite nanocomposites demonstrated high yield pressure compared with the physical mixtures indicating increased particle hardness upon composite formation. This increase has likely to do with a reinforcement of the nanocomposite particles by skeleton formation of the nanoparticles. In summary, the rational evaluation of mechanical properties done by applying powder compression analysis proved to be a valuable tool for mechanical evaluation for this type of spray-dried composite materials, unless they demonstrate particle rearrangement throughout the whole compression profile. PMID- 28007545 TI - Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties. AB - Pharmacokinetics of cisplatin administered by the pulmonary route were established in mice using dry powders inhaler (DPI) formulations showing immediate (F1) and controlled release (CR, solid lipid microparticles) in vitro, without (F2) or with PEGylated excipients (F3, F4). Formulation administration was realized using dry powder blends (correspondingly named thereafter F1B to F4B) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder InsufflatorTM. Their platinum pharmacokinetics were established over 48h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1B were rapidly distributed from the lungs (t1/2i 2.6 and 5.0min). F2B was eliminated in ~1h (t1/2i 9.0min). F3B lung retention was sustained for ~7h (t1/2i 59.9min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1B and F2B. Total blood tmax were higher and AUC and Cmax lower using the pulmonary route vs. IV. Kidney Cmax was reduced 6-, 2- and 3-fold for F1B, F2B and F3B. AUC in kidneys were 2- to 3-fold lower for F1B and F2Bvs. IV but comparable for IV vs. F3B, probably because of kidney saturation. PEGylated solid lipid microparticles provided cisplatin particles with interesting lung retention and CR properties. PMID- 28007546 TI - Biopolymeric self-assembled nanoparticles for enhanced antibacterial activity of Ag-based compounds. AB - Microbial infections still remain one of the main issues for human health. The rapid development of resistance towards the most common antimicrobial drugs in bacteria represents today a challenge in the infections management. In the present work we have investigated the antibacterial activity of a group of compounds, namely silver N-heterocyclic carbene complexes, against a broad spectrum of bacteria. For the most promising compound, a biopolymeric nanocarrier has been developed, in order to potentiate the metal complex activity against both Gram +ve and Gram -ve. The polymeric nanovehicle is based on dextran, modified with oleic acid residues, that confer amphiphilic properties to the polysaccharide. We have characterized the obtained biomaterial and studied its ability to self-assemble into nanoparticles in aqueous environment. Next, the transdermal diffusion analyses have been carried out to evaluate the ability of the polymeric particles to penetrate tissues. Thanks to the strategy adopted, we have fabricated an antibacterial system to which K. pneumoniae and E. coli are the most sensitive. PMID- 28007547 TI - Microphase separation in solid lipid dosage forms as the cause of drug release instability. AB - Although lipid excipients are of increasing interest for development of taste masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40 degrees C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage. PMID- 28007541 TI - Calcineurin signaling in the heart: The importance of time and place. AB - The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure. PMID- 28007548 TI - Enhanced neuroprotection with decellularized brain extracellular matrix containing bFGF after intracerebral transplantation in Parkinson's disease rat model. AB - Extracellular matrix-based biomaterials have many advantages over synthetic polymer materials for regenerative medicine applications. In central nervous system (CNS), basic fibroblast growth factor (bFGF) is widely studied as a potential agent for Parkinson's disease (PD). However, the poor stability of bFGF hampered its clinical use. In this study, CNS-derived biologic scaffold containing bFGF was used to enhance and extend the neuroprotective effect of bFGF on PD targeted therapy. Decellularized brain extracellular matrix (dcBECM) was prepared by chemical extraction. The biocompatibility of dcBECM was evaluated using CCK-8 assay and magnetic resonance imaging (MRI). The controlled-release behavior of dcBECM containing bFGF (bFGF+dcBECM) was confirmed by ELISA assay. Furthermore, the cytocompatibility and neuroprotective effect of bFGF+dcBECM was evaluated in vitro and in vivo. From results, dcBECM showed a three-dimensional network structure with high biocompatibility. MRI of dcBECM implanted rats showed nearly seamless fusion of dcBECM with the adjoining tissues. The cumulative release rate of bFGF+dcBECM in vitro reached to 75.88% at 10h and maintained sustained release trend during the observation. ELISA results in vivo further confirmed the sustained-release behavior (from 12h to 3d) of bFGF+dcBECM in brain tissues. Among the experimental groups, bFGF+dcBECM group showed the highest cell survival rate of PD model cells, improved behavioral recovery and positive expressions of neurotrophic proteins in PD recovered rats. In conclusion, sustained neuroprotection in PD rats was achieved by using bFGF+dcBECM. The combination of dcBECM and bFGF would be a promising therapeutic strategy to realize an effective and safe alternative for CNS disease treatment. PMID- 28007549 TI - Estimation of age-specific rates of reactivation and immune boosting of the varicella zoster virus. AB - Studies into the impact of vaccination against the varicella zoster virus (VZV) have increasingly focused on herpes zoster (HZ), which is believed to be increasing in vaccinated populations with decreasing infection pressure. This idea can be traced back to Hope-Simpson's hypothesis, in which a person's immune status determines the likelihood that he/she will develop HZ. Immunity decreases over time, and can be boosted by contact with a person experiencing varicella (exogenous boosting) or by a reactivation attempt of the virus (endogenous boosting). Here we use transmission models to estimate age-specific rates of reactivation and immune boosting, exogenous as well as endogenous, using zoster incidence data from the Netherlands (2002-2011, n=7026). The boosting and reactivation rates are estimated with splines, enabling these quantities to be optimally informed by the data. The analyses show that models with high levels of exogenous boosting and estimated or zero endogenous boosting, constant rate of loss of immunity, and reactivation rate increasing with age (to more than 5% per year in the elderly) give the best fit to the data. Estimates of the rates of immune boosting and reactivation are strongly correlated. This has important implications as these parameters determine the fraction of the population with waned immunity. We conclude that independent evidence on rates of immune boosting and reactivation in persons with waned immunity are needed to robustly predict the impact of varicella vaccination on the incidence of HZ. PMID- 28007550 TI - Gemcitabine: Selective cytotoxicity, induction of inflammation and effects on urothelial function. AB - Intravesical gemcitabine has recently been introduced for the treatment of superficial bladder cancer and has a favourable efficacy and toxicity profile in comparison to mitomycin c (MMC), the most commonly used chemotherapeutic agent. The aim of this study was to assess the cytotoxic potency of gemcitabine in comparison to MMC in urothelial cell lines derived from non-malignant (UROtsa) and malignant (RT4 and T24) tissues to assess selectivity. Cells were treated with gemcitabine or mitomycin C at concentrations up to the clinical doses for 1 or 2h respectively (clinical duration). Treatment combined with hyperthermia was also examined. Cell viability, ROS formation, urothelial function (ATP, acetylcholine and PGE2 release) and secretion of inflammatory cytokines were assessed. Gemcitabine displayed a high cytotoxic selectivity for the two malignant cell lines (RT4, T24) compared to the non-malignant urothelial cells (UROtsa, proliferative and non-proliferative). In contrast, the cytotoxic effects of MMC were non-selective with equivalent potency in each of the cell lines. The cytotoxic effect of gemcitabine in the malignant cell lines was associated with an elevation in free radical formation and was significantly decreased in the presence of an equilibrative nucleoside transporter inhibitor. Transient changes in urothelial ATP and PGE2 release were observed, with significant increase in release of interleukin-6, interleukin-8 and interleukin-1beta from urothelial cells treated with gemcitabine. The selectivity of gemcitabine for malignant urothelial cells may account for the less frequent adverse urological effects with comparison to other commonly used chemotherapeutic agents. PMID- 28007552 TI - The potential subunits involved in two subtypes of alpha-Bgt-resistant nAChRs in cockroach dorsal unpaired median (DUM) neurons. AB - The american cockroach (Periplaneta americana) dorsal unpaired median (DUM) neurons provide an native tool to analyze the functional and pharmacological properties of ion channels and membrane receptors, such as nicotine acetylcholine receptors (nAChRs). Here the imidacloprid-activated nAChR subtypes were examined in DUM neurons by the patch-clamp technique and the potential subunits involved in important subtypes were analyzed by combining with RNA interference (RNAi) technique. Imidacloprid exerted agonist activities on one subtype in alpha-Bgt sensitive nAChRs and another subtype in alpha-Bgt-resistant nAChRs, in which the alpha-Bgt-resistant subtype showed much higher sensitivity to imidacloprid than the alpha-Bgt-sensitive subtype, with the difference close to 200-fold. In alpha Bgt-resistant nAChRs, nicotine exerted the agonist activity on two subtypes (nAChR1 and nAChR2), although imidacloprid only activated nAChR1. RNAi against Paalpha3, Paalpha8 and Pabeta1 significantly reduced both imidacloprid- and nicotine-activated currents on nAChR1. In contrast, RNAi against Paalpha1, Paalpha2 and Pabeta1 decreased nicotine-activated currents on nAChR2. The results indicated that, in alpha-Bgt-resistant nAChRs, Paalpha3, Paalpha8 and Pabeta1 might be involved in the subunit composition of nAChR1, and Paalpha1, Paalpha2 and Pabeta1 in nAChR2. In summary, from the present study and previous reports, we deduced that there are at least three nAChR subtypes that are sensitive to imidacloprid in the cockroach DUM neurons. PMID- 28007551 TI - A preliminary investigation of phoshodiesterase 7 inhibitor VP3.15 as therapeutic agent for the treatment of experimental autoimmune encephalomyelitis mice. AB - cAMP plays a significant role in signal transduction pathways controlling multiple cellular processes such as inflammation and immune regulation. cAMP levels are regulated by a family of phosphodiesterases (PDEs). We have studied the effects of a novel PDE7 inhibitor (PDE7i) treatment on mice with experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS) and compared it with another PDE7i. EAE was induced by immunizing C57BL/6J mice with myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Mice were treated daily either from disease onset or from disease peak with each PDE7i and with fingolimod (used in therapy for MS patients) and disease evolution was followed by clinical symptoms. We examined neuropathology of spinal cord, ex vivo lymphocyte proliferation by [3H]-thymidine incorporation, TNFalpha by ELISA and cAMP-PDE mRNAs expression by in situ hybridization histochemistry (ISHH) in spinal cord of EAE mice treated with both PDE7 inhibitors. Treatment of EAE mice with the novel PDE7i, VP3.15 showed more efficacy in reducing clinical signs at 10mgkg-1 than the other PDE7i, BRL50481 and similar to fingolimod. VP3.15 acts on peripheral lymphocytes inhibiting their proliferation and TNFalpha secretion in a dose-dependent manner. PDE7i treatment alters the levels of PDE4B and PDE7 mRNA expression in EAE mice spinal cord. Given the interest in the development of new drugs for MS, including PDE7i as anti-inflammatory drugs, it is important to study the role played by PDE7 in neurodegenerative diseases with inflammatory component to better understand the beneficial and detrimental effects of a future therapy. PMID- 28007553 TI - Shannon information entropy in the canonical genetic code. AB - The Shannon entropy measures the expected information value of messages. As with thermodynamic entropy, the Shannon entropy is only defined within a system that identifies at the outset the collections of possible messages, analogous to microstates, that will be considered indistinguishable macrostates. This fundamental insight is applied here for the first time to amino acid alphabets, which group the twenty common amino acids into families based on chemical and physical similarities. To evaluate these schemas objectively, a novel quantitative method is introduced based the inherent redundancy in the canonical genetic code. Each alphabet is taken as a separate system that partitions the 64 possible RNA codons, the microstates, into families, the macrostates. By calculating the normalized mutual information, which measures the reduction in Shannon entropy, conveyed by single nucleotide messages, groupings that best leverage this aspect of fault tolerance in the code are identified. The relative importance of properties related to protein folding - like hydropathy and size - and function, including side-chain acidity, can also be estimated. This approach allows the quantification of the average information value of nucleotide positions, which can shed light on the coevolution of the canonical genetic code with the tRNA-protein translation mechanism. PMID- 28007554 TI - Further assessment of the protozoal contribution to the nutrition of the ruminant animal. AB - The flow of protozoa from the reticulo-rumen is lower than expected, due to ability of protozoa to prevent washout through sequestration on feed particles and the rumen epithelium. In order to estimate the distribution of protozoa within the reticulo-rumen and passage to the omasum, Czerkawski (1987) developed a model containing pools for the rumen liquid phase, rumen solid phase, and the omasum. This model was used to estimate loss of protozoa in the omasum as well as the amount of protozoal protein available to the animal in the lower gut. A number of assumptions were incorporated into the model, some of which appear unsupported by current research. This paper represents an update, revision, and re-evaluation of Czerkawski's model, where the assumptions that all protozoa in the 'attached' phase are in solid digesta, and that protozoa only leave the rumen in the liquid, have been relaxed. Therefore, the revised model allows for sequestration of protozoa on the rumen epithelium and protozoal passage with particulate outflow. Using experimental observations with inputs within biological limits, the revised model and Czerkawski's original model were verified. The effect of diet on the model was then assessed using inputs from a 100% forage diet and a 35-65% concentrate diet. The extent of sequestration was also varied from complete sequestration, to partial sequestration, and no sequestration. A sensitivity analysis was conducted through a linear regression of perturbed mean inputs versus outputs. The results from the revised model indicate that within the reticulo-rumen, the concentrate diet has a greater fractional flow rate of protozoa from the liquid to solid phase, but a lesser fractional flow rate back to the liquid phase, compared to the forage diet. As well, the concentrate diet has a slower net growth rate of protozoa in the attached phase, compared to the forage diet. In the omasum, the forage diet has a less negative net growth rate, compared to the concentrate diet. The forage diet was also associated with smaller loss of protozoa from the omasum. There are limited data from the omasum to be incorporated into the revised model, especially for quantity of protozoa in the omasum. Further research on quantification of protozoa in the omasum could strengthen the predictions made by the model. Despite this, the revised model found a loss of protozoa in the omasum similar to that suggested by Czerkawski's original model 65-73% versus 66%. The revised model results indicate that efforts to increase protozoal flow to the duodenum should focus on reduced sequestration and increased outflow rate from the rumen, although more research is needed to quantify protozoa in the omasum, and to investigate the role of sequestration onto the wall of the reticulo-rumen. PMID- 28007555 TI - Regular biennial cycles in epidemics caused by parametric resonance. AB - The interaction between nonlinearity and seasonal forcing in childhood infectious diseases often leads to multiyear cycles with large amplitude. Regular biennial cycles in particular were observed in measles reports throughout the world. The objective of this paper is to understand the mechanism of such biennial cycles, especially the conditions under which the large amplitude biennial oscillation might appear. It is proposed that such biennial cycles are caused by parametric resonance, which might occur when varying the parameter at a frequency close to twice the natural frequency of the system. The analysis is carried out by solving an SIR model semi-analytically using method of multiple scales (MMS). This analysis shows how parametric resonance occurs due to the interaction between nonlinearity and periodic forcing. Using the MMS solution, the boundary between the resonance region and the non-resonance region in the parameter space is obtained. The effects of different parameters on the triggering of parametric resonance are studied, such as transmission rate, recovery rate, birth rate and amplitude of seasonality. The effects of stochasticity on the onset of parametric resonance are also studied. PMID- 28007556 TI - Roles of pH and the Na+/H+ exchanger NHE1 in cancer: From cell biology and animal models to an emerging translational perspective? AB - Acidosis is characteristic of the solid tumor microenvironment. Tumor cells, because they are highly proliferative and anabolic, have greatly elevated metabolic acid production. To sustain a normal cytosolic pH homeostasis they therefore need to either extrude excess protons or to neutralize them by importing HCO3-, in both cases causing extracellular acidification in the poorly perfused tissue microenvironment. The Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed acid-extruding membrane transport protein, and upregulation of its expression and/or activity is commonly correlated with tumor malignancy. The present review discusses current evidence on how altered pH homeostasis, and in particular NHE1, contributes to tumor cell motility, invasion, proliferation, and growth and facilitates evasion of chemotherapeutic cell death. We summarize data from in vitro studies, 2D-, 3D- and organotypic cell culture, animal models and human tissue, which collectively point to pH regulation in general, and NHE1 in particular, as potential targets in combination chemotherapy. Finally, we discuss the possible pitfalls, side effects and cellular escape mechanisms that need to be considered in the process of translating the plethora of basic research data into a clinical setting. PMID- 28007557 TI - The Phytol Phosphorylation Pathway Is Essential for the Biosynthesis of Phylloquinone, which Is Required for Photosystem I Stability in Arabidopsis. AB - Phytyl-diphosphate, which provides phytyl moieties as a common substrate in both tocopherol and phylloquinone biosynthesis, derives from de novo isoprenoid biosynthesis or a salvage pathway via phytol phosphorylation. However, very little is known about the role and origin of the phytyl moiety for phylloquinone biosynthesis. Since VTE6, a phytyl-phosphate kinase, is a key enzyme for phytol phosphorylation, we characterized Arabidopsis vte6 mutants to gain insight into the roles of phytyl moieties in phylloquinone biosynthesis and of phylloquinone in photosystem I (PSI) biogenesis. The VTE6 knockout mutants vte6-1 and vte6-2 lacked detectable phylloquinone, whereas the phylloquinone content in the VTE6 knockdown mutant vte6-3 was 90% lower than that in wild-type. In vte6 mutants, PSI function was impaired and accumulation of the PSI complex was defective. The PSI core subunits PsaA/B were efficiently synthesized and assembled into the PSI complex in vte6-3. However, the degradation rate of PSI subunits in the assembled PSI complex was more rapid in vte6-3 than in wild-type. In vte6-3, PSI was more susceptible to high-light damage than in wild-type. Our results provide the first genetic evidence that the phytol phosphorylation pathway is essential for phylloquinone biosynthesis, and that phylloquinone is required for PSI complex stability. PMID- 28007558 TI - Aryl hydrocarbon receptor suppresses the osteogenesis of mesenchymal stem cells in collagen-induced arthritic mice through the inhibition of beta-catenin. AB - The contributions of aryl hydrocarbon receptor (Ahr) to the pathogenesis of rheumatoid arthritis (RA), particularly bone loss, have not been clearly explored. The imbalance between osteoblasts and osteoclasts is a major reason for bone loss. The dysfunction of osteoblasts, which are derived from mesenchymal stem cells (MSCs), induced bone erosion occurs earlier and is characterized as more insidious. Here, we showed that the nuclear expression and translocation of Ahr were both significantly increased in MSCs from collagen-induced arthritis (CIA) mice. The enhanced Ahr suppressed the mRNA levels of osteoblastic markers including Alkaline phosphatase (Alp) and Runt-related transcription factor 2 (Runx2) in the differentiation of MSCs to osteoblasts in CIA. The 2, 3, 7, 8 tetrachlorodibenzo-p-dioxin (TCDD)-mediated activation of Ahr dose-dependently suppressed the expression of osteoblastic markers. In addition, the expression of beta-catenin was reduced in CIA MSCs compared with control, and the TCDD-mediated activation of the Ahr significantly inhibited beta-catenin expression. The Wnt3a induced the activation of Wnt/beta-catenin pathway partly rescued the osteogenesis decline induced by TCDD. Taken together, these results indicate that activated Ahr plays a negative role in CIA MSCs osteogenesis, possibly by suppressing the expression of beta-catenin. PMID- 28007560 TI - Molecular Dynamics of Amorphous Sulfamethazine With Structurally Related Sulfonamide Impurities Evaluated Using Thermal Analysis. AB - In this study, the effects of structurally related organic impurities on the molecular dynamics of amorphous sulfamethazine were evaluated using thermal analysis. Sulfanilamide (SNA), sulfamerazine (SMR), and sulfadimethoxine were used as virtual impurities of sulfamethazine. The amorphous state was prepared in situ in differential scanning calorimetry by quenching the melted physical mixtures of sulfamethazine and each impurity compound in the differential scanning calorimetry pan. In the following heating process, the glass transition temperatures (Tg) of each were measured. The fragility parameters were estimated from the width of Tg. The Tg of amorphous sulfamethazine with those impurities changed in accordance with the manner set forth in the Gordon-Taylor equation. The fragility parameter slightly increased when a small amount of SNA or SMR was incorporated. Moreover, the probability of a measurement in which crystallization of sulfamethazine was observed above its Tg, increased at a low-concentration range of SNA, SMR, or sulfadimethoxine. It was considered that the existence of a small amount of impurity would induce heterogeneity in the molecular density of the amorphous state, which would be associated with the local fluctuation. It was suggested that the change in the molecular dynamics would be related to the probability of crystallization of sulfamethazine. PMID- 28007559 TI - Macrophage-Mediated Clofazimine Sequestration Is Accompanied by a Shift in Host Energy Metabolism. AB - Prolonged (8 weeks) oral administration of clofazimine results in a profound pharmacodynamic response-bioaccumulation in macrophages (including Kupffer cells) as intracellular crystal-like drug inclusions (CLDIs) with an associated increase in interleukin-1 receptor antagonist production. Notably, CLDI formation in Kupffer cells concomitantly occurs with the formation of macrophage-centric granulomas. Accordingly, we sought to understand the impact of these events on host metabolism using 1H-nuclear magnetic resonance metabolomics. Mice received a clofazimine or vehicle-enriched (sham) diet for at least 8 weeks. At 2 weeks, the antimicrobial activity of clofazimine was evident by changes in urine metabolites. From 2 to 8 weeks, there was a striking change in metabolite levels indicative of a reorientation of host energy metabolism paralleling the onset of CLDI and granuloma formation. This was evidenced by a progressive reduction in urine levels of metabolites involved in one-carbon metabolism with corresponding increases in whole blood, and changes in metabolites associated with lipid, nucleotide and amino acid metabolism, and glycolysis. Although clofazimine-fed mice ate more, they gained less weight than control mice. Together, these results indicate that macrophage sequestration of clofazimine as CLDIs and granuloma formation is accompanied by a profound metabolic disruption in energy homeostasis and one-carbon metabolism. PMID- 28007561 TI - Ion-Pairing Contribution to the Liposomal Transport of Topotecan as Revealed by Mechanistic Modeling. AB - Actively loaded liposomal formulations of anticancer agents have been widely explored due to their high drug encapsulation efficiencies and prolonged drug retention. Mathematical models to predict and optimize drug loading and release kinetics from these nanoparticle formulations would be useful in their development and may allow researchers to tune release profiles. Such models must account for the driving forces as influenced by the physicochemical properties of the drug and the microenvironment, and the liposomal barrier properties. This study employed mechanistic modeling to describe the active liposomal loading and release kinetics of the anticancer agent topotecan (TPT). The model incorporates ammonia transport resulting in generation of a pH gradient, TPT dimerization, TPT lactone ring-opening and -closing interconversion kinetics, chloride transport, and transport of TPT-chloride ion-pairs to describe the active loading and release kinetics of TPT in the presence of varying chloride concentrations. Model based predictions of the kinetics of active loading at varying loading concentrations of TPT and release under dynamic dialysis conditions were in reasonable agreement with experiments. These findings identify key attributes to consider in optimizing and predicting loading and release of liposomal TPT that may also be applicable to liposomal formulations of other weakly basic pharmaceuticals. PMID- 28007562 TI - Impact of Sterilization Method on Protein Aggregation and Particle Formation in Polymer-Based Syringes. AB - The effects of sterilization methods on the storage stability of erythropoietin (EPO) in polymer-based syringes were assessed by quantifying protein oxidation, aggregation, and particle formation. Micro-particle counting and size exclusion chromatography coupled with a multi-angle light scattering detector demonstrated much lower levels of protein particles and aggregates for EPO stored for 12 weeks in steam-sterilized than in radiation (Rad)-sterilized syringes. Intermediate levels of damage were observed for EPO stored in ethylene oxide-sterilized syringes. HPLC analysis documented that the Rad-sterilized syringes caused increased oxidation of the protein during storage. In contrast, in the steam- and ethylene oxide-sterilized syringes EPO oxidation did not change. Analysis with electron spin resonance revealed that only Rad-sterilized syringes formed radicals in the syringe body, which persisted over the 12-week storage period. These results demonstrated that Rad-sterilization generated radicals in the syringes which in turn caused increased EPO oxidation, particle formation, and protein aggregation. Therefore, steam sterilization was shown to be a preferable sterilization method for the polymer-based syringe system when using biopharmaceutical drugs highly sensitive to oxidation, and particle formation and aggregation. PMID- 28007563 TI - Crystal Structures, X-Ray Photoelectron Spectroscopy, Thermodynamic Stabilities, and Improved Solubilities of 2-Hydrochloride Salts of Vortioxetine. AB - Two vortioxetine (VOT) salts with hydrochloride (VOT-HCl and VOT-0.5HCl) were prepared and structurally characterized. VOT-HCl features 1-dimensional P/M helical chains through N-H...Cl hydrogen bond interactions, whereas VOT-0.5HCl possesses a 1-dimensional zigzag structure in which 2 VOT molecules share a single proton through N...H+...N interactions. VOT-HCl converts into the monohydrate VOT-HCl.H2O after dissolution in water, whereas VOT-0.5HCl remains stable. The N 1s X-ray photoelectron spectroscopy analysis shows a characteristic binding energy peak at approximately 398.0 eV for VOT. The shift to high energy occurs at 400.3 eV for VOT-HCl and VOT-HBr, and at 399.7 eV for VOT-0.5HCl, which supports the salt formation by the degree of proton transfer and is confirmed by single-crystal X-ray analyses. The apparent equilibrium solubilities of VOT in water are significantly improved to 2.90 mg/mL (approximately a 32.0-fold increase over that of the free base) for VOT-HCl and to 0.59 mg/mL (approximately a 5.7-fold increase over that of the free base) for VOT-0.5HCl at 25 degrees C. PMID- 28007564 TI - Structural Analysis of Heparin-Derived 3-O-Sulfated Tetrasaccharides: Antithrombin Binding Site Variants. AB - Heparin is a polysaccharide that is widely used as an anticoagulant drug. The mechanism for heparin's anticoagulant activity is primarily through its interaction with a serine protease inhibitor, antithrombin III (AT), that enhances its ability to inactivate blood coagulation serine proteases, including thrombin (factor IIa) and factor Xa. The AT-binding site in the heparin is one of the most well-studied carbohydrate-protein binding sites and its structure is the basis for the synthesis of the heparin pentasaccharide drug, fondaparinux. Despite our understanding of the structural requirements for the heparin pentasaccharide AT-binding site, there is a lack of data on the natural variability of these binding sites in heparins extracted from animal tissues. The present work provides a detailed study on the structural variants of the tetrasaccharide fragments of this binding site afforded following treatment of a heparin with heparin lyase II. The 5 most commonly observed tetrasaccharide fragments of the AT-binding site are fully characterized, and a method for their quantification in heparin and low-molecular-weight heparin products is described. PMID- 28007565 TI - Mechanism of Degradation of an alpha-Keto-Epoxide, a Model for the Warhead for Various Proteasome Inhibitor Anticancer Agents. AB - The anticancer agent, carfilzomib, has a unique alpha-keto-epoxide warhead. The model alpha-keto-epoxide, N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan 2-yl)pivalamide (1), along with a few of its degradation products was synthesized and studied. The kinetics of hydrolysis and identification of some of the degradation products of 1 were performed at pH values 2, 4, 5, 7, and 8 at 25 degrees C, 40 degrees C, and 60 degrees C and followed by HPLC and liquid chromatography-mass spectroscopy, respectively. 1 degraded independent of pH between pH values 4-7 but showed some acid catalysis at pH 2 and base catalysis at pH 8. Energy of activation, Ea, values progressed from 16.8 +/- 0.1 at pH 2 to 20.3 +/- 0.1 kcal/mole at pH 8. The major initial degradation products in the pH range 4-5 were the S,R diol (hydrolysis of the epoxide), and S,R chlorohydrin (in the presence of chloride ions). At pH 7-8, the major products were the R,R diastereomer and the S,R and R,R diols. At pH 2, additional unidentified products were seen with relative retention times of 0.28, 0.30, 0.33, and 0.35 and masses equivalent to the diols. The study of 1 provides insight into the degradation of future drugs that use an alpha-keto-epoxide functional group. PMID- 28007566 TI - By how much do we underestimate species diversity of liverworts using morphological evidence? An example from Australasian Plagiochila (Plagiochilaceae: Jungermanniopsida). AB - As a framework for revisionary study of the leafy liverwort Plagiochila in Australia, two methods for species delimitation on molecular sequence data, General Mixed Yule Coalescence model (GMYC) and Automatic Barcode Gap Discovery (ABGD) were applied to a dataset including 265 individuals from Australia, New Zealand, and the Pacific. Groups returned by GMYC and ABGD were incongruent in some lineages, and ABGD tended to lump groups. This may reflect underlying heterogeneity in the history of diversification within different lineages of Plagiochila. GMYC from trees calculated using three different molecular clocks were compared, in some lineages different primary species hypotheses were returned by analyses of trees estimated under different clock models, suggesting clock model selection should be a routine component of phylogeny reconstruction for tree-based species delimitation methods, such as GMYC. Our results suggest that a minimum of 71 Plagiochilaceae species occur in Australasia, 16 more than currently accepted for the region, comprising 8 undetermined species and 8 synonyms requiring reinstatement. Despite modern taxonomic investigation over a four decade period, (1) real diversity is 29% higher than currently recognized; and (2) 12 of 33, or 36%, of currently accepted and previously untested Australasian species have circumscription issues, including polyphyly, paraphyly, internal phylogenetic structure, or combinations of two or more of these issues. These both reflect the many challenges associated with grouping decisions based solely on morphological data in morphologically simple yet polymorphic plant lineages. Our results highlight again the critical need for combined molecular morphological datasets as a basis for resolving robust species hypotheses in species-rich bryophyte lineages. PMID- 28007567 TI - Global phylogeography of Oithona similis s.l. (Crustacea, Copepoda, Oithonidae) - A cosmopolitan plankton species or a complex of cryptic lineages? AB - Traditionally, many small-sized copepod species are considered to be widespread, bipolar or cosmopolitan. However, these large-scale distribution patterns need to be re-examined in view of increasing evidence of cryptic and pseudo-cryptic speciation in pelagic copepods. Here, we present a phylogeographic study of Oithona similis s.l. populations from the Arctic Ocean, the Southern Ocean and its northern boundaries, the North Atlantic and the Mediterrranean Sea. O. similis s.l. is considered as one of the most abundant species in temperate to polar oceans and acts as an important link in the trophic network between the microbial loop and higher trophic levels such as fish larvae. Two gene fragments were analysed: the mitochondrial cytochrome oxidase c subunit I (COI), and the nuclear ribosomal 28 S genetic marker. Seven distinct, geographically delimitated, mitochondrial lineages could be identified, with divergences among the lineages ranging from 8 to 24%, thus representing most likely cryptic or pseudocryptic species within O. similis s.l. Four lineages were identified within or close to the borders of the Southern Ocean, one lineage in the Arctic Ocean and two lineages in the temperate Northern hemisphere. Surprisingly the Arctic lineage was more closely related to lineages from the Southern hemisphere than to the other lineages from the Northern hemisphere, suggesting that geographic proximity is a rather poor predictor of how closely related the clades are on a genetic level. PMID- 28007568 TI - Hyaluronic acid decreases the mechanical stability, but increases the lytic resistance of fibrin matrices. AB - Hyaluronic acid (HA) is a large, non-sulfated glucosaminoglycan abundantly present at sites where fibrin is also formed (during wound healing, in arterial restenotic lesions and eroded atherosclerotic plaques). The aim of the present study was to characterize the structure of composite fibrin-HA clots with scanning electron microscopy (SEM), pressure-driven permeation and small-angle X ray scattering (SAXS) and their viscoelastic properties with an oscillation rheometer. In addition the efficiency of fibrinolysis in these clots was investigated by kinetic turbidimetric and chromogenic assays for dissolution of fibrin and plasminogen activation by tissue-type plasminogen activator (tPA). Fibrin formed in the presence of native (1500kDa) HA and its 500kDa fragments had thicker fibers and larger pores according to the SEM and clot permeation data, whereas the 25kDa HA fragments had only minor effects. SAXS evidenced a mild disarrangement of protofibrils. These structural alterations suggest that HA modifies the pattern of fibrin polymerization favouring lateral association of protofibrils over formation of branching points. Rheometer data showed softer fibrin structures formed with 1500kDa and 500kDa HA and these clots presented with lower dynamic viscosity values and lower critical stress values at gel/fluid transition. tPA-catalysed plasminogen activation was markedly inhibited by HA, both in free solution and on the surface of fibrin clots, in the presence and in the absence of 6-aminohexanoate suggesting a kringle-independent mechanism. HA of 1500 and 500kDa size prolonged clot lysis with both plasmin and tPA and this inhibition was kringle-mediated, because it was abolished by 6-aminohexanoate and was not observed with des-(kringle1-4)-plasmin. Our data suggest that HA size dependently modifies the pattern of fibrin polymerization with consequent inhibition of fibrinolysis. At sites of tissue injury and inflammation, HA could stabilize fibrin through modification of its structure and lysibility. PMID- 28007569 TI - Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1) are two different proteins: Proofs by fluorescent labeling and binding of sigma-2 receptor ligands to PGRMC1. AB - A controversial relationship between sigma-2 and progesterone receptor membrane component 1 (PGRMC1) proteins, both representing promising targets for the therapy and diagnosis of tumors, exists since 2011, when the sigma-2 receptor was reported to be identical to PGRMC1. Because a misidentification of these proteins will lead to biased future research hampering the possible diagnostic and therapeutic exploitation of the two targets, there is the need to solve the debate on their identity. With this aim, we have herein investigated uptake and distribution of structurally different fluorescent sigma-2 receptor ligands by flow cytometry and confocal microscopy in MCF7 cells, where together with intrinsic sigma-2 receptors, PGRMC1 was constitutively present or alternatively silenced or overexpressed. HCT116 cells, with constitutive or silenced PGRMC1, were also studied. These experiments showed that the fluorescent sigma-2 ligands bind to their receptor irrespective of PGRMC1 expression. Furthermore, isothermal titration calorimetry was conducted to examine if DTG and PB28, two structurally distinct nanomolar affinity sigma-2 ligands, bind to purified PGRMC1 proteins that have recently been revealed to form both apo-monomeric and heme-mediated dimeric forms. While no binding to apo-PGRMC1 monomer was detected, a micromolar affinity to heme-mediated dimerized PGRMC1 was demonstrated in DTG but not in PB28. The current data provide evidence that sigma-2 receptor and PGRMC1 are not identical, paving the pathway for future unbiased research in which these two attractive targets are treated as different proteins while the identification of the true sigma-2 protein further needs to be pursued. PMID- 28007570 TI - Dysfunctional oleoylethanolamide signaling in a mouse model of Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is a lipid mediator involved in the control of feeding, body weight and energy metabolism. OEA produced by small-intestinal enterocytes during dietary fat digestion activates type-alpha peroxisome proliferator-activated receptors (PPAR-alpha) to trigger an afferent signal that causes satiety. Emerging evidence from genetic and human laboratory studies suggests that deficits in OEA-mediated signaling might be implicated in human obesity. In the present study, we investigated whether OEA contributes to feeding dysregulation in Magel2m+/p- (Magel2 KO) mice, an animal model of PWS. Fasted/refed male Magel2 KO mice eat more than do their wild-type littermates and become overweight with age. Meal pattern analyses show that hyperphagia in Magel2 KO is due to increased meal size and meal duration rather than to lengthening of the intermeal interval, which is suggestive of a defect in mechanisms underlying satiation. Food-dependent OEA accumulation in jejunum and fasting OEA levels in plasma are significantly greater in Magel2 KO mice than in wild-type controls. Together, these findings indicate that deletion of the Magel2 gene is accompanied by marked changes in OEA signaling. Importantly, intraperitoneal administration of OEA (10mg/kg) significantly reduces food intake in fasted/refed Magel2 KO mice, pointing to a possible use of this natural compound to control hunger in PWS. PMID- 28007571 TI - Multiple nickel-sensitive targets elicit cardiac arrhythmia in isolated mouse hearts after pituitary adenylate cyclase-activating polypeptide-mediated chronotropy. AB - The pituitary adenylate cyclase-activating polypeptide (PACAP)-27 modulates various biological processes, from the cellular level to function specification. However, the cardiac actions of this neuropeptide are still under intense studies. Using control (+|+) and mice lacking (-|-) either R-type (Cav2.3) or T type (Cav3.2) Ca2+ channels, we investigated the effects of PACAP-27 on cardiac activity of spontaneously beating isolated perfused hearts. Superfusion of PACAP 27 (20nM) caused a significant increase of baseline heart frequency in Cav2.3(+|+) (156.9+/-10.8 to 239.4+/-23.4 bpm; p<0.01) and Cav2.3(-|-) (190.3+/ 26.4 to 270.5+/-25.8 bpm; p<0.05) hearts. For Cav3.2, the heart rate was significantly increased in Cav3.2(-|-) (133.1+/-8.5 bpm to 204.6+/-27.9 bpm; p<0.05) compared to Cav3.2(+|+) hearts (185.7+/-11.2 bpm to 209.3+/-22.7 bpm). While the P wave duration and QTc interval were significantly increased in Cav2.3(+|+) and Cav2.3(-|-) hearts following PACAP-27 superfusion, there was no effect in Cav3.2(+|+) and Cav3.2(-|-) hearts. The positive chronotropic effects observed in the four study groups, as well as the effect on P wave duration and QTc interval were abolished in the presence of Ni2+ (50MUM) and PACAP-27 (20nM) in hearts from Cav2.3(+|+) and Cav2.3(-|-) mice. In addition to suppressing PACAP's response, Ni2+ also induced conduction disturbances in investigated hearts. In conclusion, the most Ni2+-sensitive Ca2+ channels (R- and T-type) may modulate the PACAP signaling cascade during cardiac excitation in isolated mouse hearts, albeit to a lesser extent than other Ni2+-sensitive targets. PMID- 28007572 TI - Methane ameliorates spinal cord ischemia-reperfusion injury in rats: Antioxidant, anti-inflammatory and anti-apoptotic activity mediated by Nrf2 activation. AB - Methane is reported to have antioxidant, anti-inflammatory and anti-apoptotic properties. We investigated the potential neuroprotective effects of methane-rich saline (MS) on spinal cord ischemia-reperfusion injury and determined that its therapeutic benefits are associated with the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Rats received 9min of spinal cord ischemia induced by occlusion of the descending thoracic aorta plus systemic hypotension followed by a single MS treatment (10ml/kg, ip) and 72h reperfusion. MS treatment attenuated motor sensory deficits and produced high concentrations of methane in spinal cords during reperfusion, which increased Nrf2 expression and transcriptional activity in neurons, microglia and astrocytes in the ventral, intermediate and dorsal gray matter of lumbar segments. Heme oxygenase-1, superoxide dismutase, catalase and glutathione were upregulated; and glutathione disulfide, superoxide, hydrogen peroxide, malondialdehyde, 8-hydroxy-2 deoxyguanosine and 3-nitrotyrosine were downregulated in MS-treated spinal cords. MS treatment reduced neuronal apoptosis in gray matter zones, which was consistent with the suppression of cytochrome c release to the cytosol from the mitochondria and the activation of caspase-9 and -3. Throughout the gray matter, the activation of microglia and astrocytes was inhibited; the nuclear accumulation of phosphorylated nuclear factor-kappa B p65 was reduced; and tumor necrosis factor alpha, interleukin 1beta, chemokine (C-X-C motif) ligand 1, intercellular adhesion molecule 1 and myeloperoxidase were decreased. MS treatment attenuated blood-spinal cord barrier dysfunction by preventing the expression and activity of matrix metallopeptidase-9 and disrupting tight junction proteins. Consecutive intrathecal injection of specific siRNAs targeting Nrf2 at 24-h intervals 3 days before ischemia reduced the beneficial effects of MS. Our data indicate that MS treatment prevents IR-induced spinal cord damage via antioxidant, anti-inflammatory and anti-apoptotic activities that involve the activation of Nrf2 signaling. Thus, methane may serve as a novel promising therapeutic agent for treating ischemic spinal cord injury. PMID- 28007573 TI - 5,6-delta-DHTL, a stable metabolite of arachidonic acid, is a potential EDHF that mediates microvascular dilation. AB - OBJECTIVE: Prominent among the endothelium-derived hyperpolarizing factors (EDHFs) are the Cytochrome P450 (CYP) epoxygenase-derived arachidonic acid metabolites-the epoxyeicosatrienoic acids (EETs), that are known as vasodilators in the microcirculation. Among the EET isomers, 5,6-EET undergoes rapid lactonization in aqueous solution to the more stable 5,6-delta DHTL (5,6 dihydroxytrienoic lactone) isomer. It is unclear whether this metabolic transformation maintains its vasodilator potential and what is the mechanism of action. Thus, the aim of this study was to investigate the capacity of the lactone isomer, 5,6- delta DHTL, to induce dilation of arterioles and explore the endothelial Ca2+ response mechanism. APPROACH AND RESULTS: In isolated human microvessels 5,6- delta DHTL induced a dose dependent vasodilation, that was inhibited by mechanical denudation of the endothelial layer. This 5,6- delta DHTL -dependent dilation was partially reduced in the presence of L-NAME (NOS inhibitor) or the NO-scavenger, cPTIO (by 19.7%, which was not statistically significantly). In human endothelial cells, 5,6- delta DHTL induced an increase in intracellular Ca2+([Ca2+]i) in a dose dependent manner. This increase in [Ca2+]i was similar to that induced by the 5,6-EET isomer, and significantly higher than observed by administering the hydrolytic dihydroxy isomer, 5,6-DHET. Further experiments aimed to investigate the mechanism of action revealed, that the 5,6-delta DHTL-mediated ([Ca2+]i elevation was reduced by IP3 and ryanodine antagonists, but not by antagonists to the TRPV4 membrane channel. Similar to their effect on the dilation response in the arteries, NO inhibitors reduced the 5,6-delta DHTL-mediated ([Ca2+]i elevation by 20%. Subsequent 5,6-delta DHTL dependent K+ ion efflux from endothelial cells, was abolished by the inhibition of small and intermediate conductance KCa. CONCLUSIONS: The present study shows that 5,6-delta DHTL is a potential EDHF, that dilates microvessels through a mechanism that involves endothelial dependent Ca2+ entry, requiring endothelial hyperpolarization. These results suggest the existence of additional lactone containing metabolites that can be derived from the PUFA metabolism and which may function as novel EDHFs. PMID- 28007574 TI - Physical interaction between the MAPK Slt2 of the PKC1-MAPK pathway and Grx3/Grx4 glutaredoxins is required for the oxidative stress response in budding yeast. AB - This study demonstrates that both monothiol glutaredoxins Grx3 and Grx4 physically interact with the MAPK Slt2 forming a complex involved in the cellular response to oxidative stress. The simultaneous absence of Grx3 and Grx4 provokes a serious impairment in cell viability, Slt2 activation and Rlm1 transcription in response to oxidative stress. Both in vivo and in vitro results clearly show that Slt2 can independently bind either Grx3 or Grx4 proteins. Our results suggest that Slt2 form iron/sulphur bridged clusters with Grx3 and Grx4. For the assembly of this complex, cysteines of the active site of each Grx3/4 glutaredoxins, glutathione and specific cysteine residues from Slt2 provide the ligands. One of the ligands of Slt2 is required for its dimerisation upon oxidative treatment and iron repletion. These interactions are relevant for the oxidative response, given that mutants in the cysteine ligands identified in the complex show a severe impairment of both cell viability and Slt2 phosphorylation upon oxidative stress. Grx4 is the relevant glutaredoxin that regulates Slt2 phosphorylation under oxidative conditions precluding cell survival. Our studies contribute to extend the functions of both monothiol glutaredoxins to the regulation of a MAPK in the context of the oxidative stress response. PMID- 28007575 TI - The mechanism of formation, structure and physiological relevance of covalent hemoglobin attachment to the erythrocyte membrane. AB - Covalent hemoglobin binding to membranes leads to band 3 (AE1) clustering and the removal of erythrocytes from the circulation; it is also implicated in blood storage lesions. Damaged hemoglobin, with the heme being in a redox and oxygen binding inactive hemichrome form, has been implicated as the binding species. However, previous studies used strong non-physiological oxidants. In vivo hemoglobin is constantly being oxidised to methemoglobin (ferric), with around 1% of hemoglobin being in this form at any one time. In this study we tested the ability of the natural oxidised form of hemoglobin (methemoglobin) in the presence or absence of the physiological oxidant hydrogen peroxide to initiate membrane binding. The higher the oxidation state of hemoglobin (from Fe(III) to Fe(V)) the more binding was observed, with approximately 50% of this binding requiring reactive sulphydryl groups. The hemoglobin bound was in a high molecular weight complex containing spectrin, ankyrin and band 4.2, which are common to one of the cytoskeletal nodes. Unusually, we showed that hemoglobin bound in this way was redox active and capable of ligand binding. It can initiate lipid peroxidation showing the potential to cause cell damage. In vivo oxidative stress studies using extreme endurance exercise challenges showed an increase in hemoglobin membrane binding, especially in older cells with lower levels of antioxidant enzymes. These are then targeted for destruction. We propose a model where mild oxidative stress initiates the binding of redox active hemoglobin to the membrane. The maximum lifetime of the erythrocyte is thus governed by the redox activity of the cell; from the moment of its release into the circulation the timer is set. PMID- 28007576 TI - Rifaximin Reduces the Number and Severity of Intestinal Lesions Associated With Use of Nonsteroidal Anti-Inflammatory Drugs in Humans. AB - The intestinal microbiota might contribute to enteropathy associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs), but there have been few human studies of this association. We performed a placebo-controlled study to determine whether a delayed-release antibiotic formulation (rifaximin-extended intestinal release [EIR]) prevents the development of intestinal lesions in subjects taking daily NSAIDs. Sixty healthy volunteers (median age, 26 y; 42% female) were given the NSAID diclofenac (75 mg twice daily) plus omeprazole (20 mg once daily), and either rifaximin-EIR (400 mg) or placebo, twice daily for 14 days. Subjects were assessed by videocapsule endoscopy at baseline and after 2 weeks of treatment. The primary end point was the proportion of subjects developing at least 1 small bowel mucosal break at week 2. Secondary end points were the change in the mean number of mucosal lesions and the number of subjects with large erosions and/or ulcers after 14 days of exposure. We detected mucosal breaks in 20% of subjects given rifaximin and in 43% of subjects given placebo (P = .05 in the post hoc sensitivity analysis). None of the subjects in the rifaximin group developed large lesions, compared with 9 subjects in the placebo group (P < .001). Our findings indicate that intestinal bacteria contribute to the development of NSAID associated enteropathy in human beings. Clinical trial no: EudraCT 2013-000730 36. PMID- 28007577 TI - [Supraventricular tachycardia in newborns and its association with gastroesophageal reflux disease]. AB - INTRODUCTION: Supraventricular tachycardia (SVT) is the most common arrhythmia in the neonatal period, but its association with other triggering processes is not well established. The aim of the study was to analyse the possible relationship between neonatal SVT and gastroesophageal reflux disease (GERD), a condition which was recently linked to atrial arrhythmias. MATERIAL AND METHODS: A retrospective longitudinal descriptive study was conducted over a period of 5years on newborns who were diagnosed with SVT in a level III neonatal unit, assessing morphological aspects, associated symptoms, and treatments received. Its association with GERD and the impact of this on SVT was studied. RESULTS: Eighteen patients (1.2 per 1000 newborns) were diagnosed with SVT. Fifty percent of them were combined with clinically significant GERD (P=.01), and all of them received drug treatment. The average time of control of SVT without GERD since diagnosis was 6 days (95% CI: 2.16-9.84, with a median of 3) and 7.6 days when both pathologies were present (95% CI: 4.14-10.9, with a median of 7) (P=.024). CONCLUSIONS: Patients with SVT in the neonatal period frequently have GERD, and this combination leads to more difficulty in controlling the tachycardia. The reflux could act as a trigger or perpetuator of arrhythmia, therefore it is important to find and treat GERD in infants with SVT. PMID- 28007578 TI - NMR based model of human telomeric repeat G-quadruplex in complex with 2,4,6 triarylpyridine family ligand. AB - G-quadruplexes (G4) are one of the several different forms of non-canonical DNA structures that can occur in our genome. Their existence is thought to be implicated in important biological functions such as positive and negative transcription regulation or telomeric extension. The human telomeric sequence G4 formed by repetitive nucleotide sequences (T2AG3) at each chromosome end is an important example of intramolecular G4. Knowing the atomic details for different families of ligands targeting G-quadruplex structures hypothetically found in the telomeric repeat it is an important step for rational drug design. Especially if the aim is to prevent or interfere with telomerase extending the 3' end of telomeres. In this study, we report the structure of the complex formed between the telomeric repeat sequence (d[AG3(T2AG3)3]) intramolecular G-quadruplex and the 2,4,6-Triarylpyridine compound. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 28007580 TI - Revisiting the logistic map: A closer look at the dynamics of a classic chaotic population model with ecologically realistic spatial structure and dispersal. AB - There is an ongoing debate about the applicability of chaotic and nonlinear models to ecological systems. Initial introduction of chaotic population models to the ecological literature was largely theoretical in nature and difficult to apply to real-world systems. Here, we build upon and expand prior work by performing an in-depth examination of the dynamical complexities of a spatially explicit chaotic population, within an ecologically applicable modeling framework. We pair a classic chaotic growth model (the logistic map) with explicit dispersal length scale and shape via a Gaussian dispersal kernel. Spatio temporal heterogeneity is incorporated by applying stochastic perturbations throughout the spatial domain. We witness a variety of population dynamics dependent on the growth rate, dispersal distance, and domain size. Dispersal serves to eliminate chaotic population behavior for many of the parameter combinations tested. The model displays extreme sensitivity to changes in growth rate, dispersal distance, or domain size, but is robust to low-level stochastic population perturbations. Large and temporally consistent perturbations can lead to a change in population dynamics. Frequent switching occurs between chaotic/non chaotic behaviors as dispersal distance, domain size, or growth rate increases. Small changes in these parameters are easy to imagine in real populations, and understanding or anticipating the abrupt resulting shifts in population dynamics is important for population management and conservation. PMID- 28007579 TI - G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms. AB - BACKGROUND: AS1411 is a 26-mer G-rich DNA oligonucleotide that forms a variety of G-quadruplex structures. It was identified based on its cancer-selective antiproliferative activity and subsequently determined to be an aptamer to nucleolin, a multifunctional protein that preferentially binds quadruplex nucleic acids and which is present at high levels on the surface of cancer cells. AS1411 has exceptionally efficient cellular internalization compared to non-quadruplex DNA sequences. SCOPE OF REVIEW: Recent developments related to AS1411 will be examined, with a focus on its use for targeted delivery of therapeutic and imaging agents. MAJOR CONCLUSIONS: Numerous research groups have used AS1411 as a targeting agent to deliver nanoparticles, oligonucleotides, and small molecules into cancer cells. Studies in animal models have demonstrated that AS1411-linked materials can accumulate selectively in tumors following systemic administration. The mechanism underlying the cancer-targeting ability of AS1411 is not completely understood, but recent studies suggest a model that involves: (1) initial uptake by macropinocytosis, a form of endocytosis prevalent in cancer cells; (2) stimulation of macropinocytosis by a nucleolin-dependent mechanism resulting in further uptake; and (3) disruption of nucleolin-mediated trafficking and efflux leading to cargoes becoming trapped inside cancer cells. SIGNIFICANCE: Human trials have indicated that AS1411 is safe and can induce durable remissions in a few patients, but new strategies are needed to maximize its clinical impact. A better understanding of the mechanisms by which AS1411 targets and kills cancer cells may hasten the development of promising technologies using AS1411-linked nanoparticles or conjugates for cancer-targeted therapy and imaging. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 28007581 TI - Different doses of dexmedetomidine reduce plasma cytokine production, brain oxidative injury, PARP and caspase expression levels but increase liver oxidative toxicity in cerebral ischemia-induced rats. AB - Cerebral ischemia-induced progression of brain, liver, and erythrocyte oxidative injuries might be modulated by dexmedetomidine (DEX) as a potent antioxidant and anti-inflammatory drug. The present study was conducted to explore whether two different doses of DEX protect against plasma cytokine and brain, liver and erythrocyte oxidative toxicity and apoptosis in cerebral ischemia-induced rats. Forty-two rats were equally divided into 7 groups. The first and second groups were used as untreated and sham controls, respectively. The third (DEX4) and fourth (DEX40) groups received 4mg/kg and 40mg/kg DEX treatments. The fifth, sixth and seventh group were operated on to induce cerebral ischemia. The fifth, sixth and seventh groups are used to represent cerebral ischemia, cerebral ischemia+DEX4, and cerebral ischemia+DEX40, respectively. DEX was intraperitoneally given to the DEX groups at the 3rd, 24th and 48th hour. Brain and erythrocyte lipid peroxidation (MDA) levels and plasma IL-1beta and TNF-alpha levels were high in the cerebral ischemia group although they were low in the DEX4 and DEX40 groups. Decreased glutathione peroxidase (GSH-Px) and reduced glutathione (GSH) values in the brain and erythrocyte of the cerebral ischemia group were increased by the DEX treatments, although PARP, and the caspase 3 and 9 expressions in the brain were further decreased. Conversely, the cerebral ischemia-induced decrease in the liver vitamin A, vitamin E, GSH, and GSH-Px were further decreased by the DEX treatments, although MDA level, PARP, and caspase 3 and 9 expressions were further increased by the DEX treatments. In conclusion, DEX induced protective effects against cerebral ischemia-induced brain and erythrocyte oxidative injuries through regulation of the antioxidant level and cytokine production. However, both doses of DEX induced oxidative toxicity and apoptotic effects in the rats' livers. PMID- 28007582 TI - kMEn: Analyzing noisy and bidirectional transcriptional pathway responses in single subjects. AB - MOTIVATION: Understanding dynamic, patient-level transcriptomic response to therapy is an important step forward for precision medicine. However, conventional transcriptome analysis aims to discover cohort-level change, lacking the capacity to unveil patient-specific response to therapy. To address this gap, we previously developed two N-of-1-pathways methods, Wilcoxon and Mahalanobis distance, to detect unidirectionally responsive transcripts within a pathway using a pair of samples from a single subject. Yet, these methods cannot recognize bidirectionally (up and down) responsive pathways. Further, our previous approaches have not been assessed in presence of background noise and are not designed to identify differentially expressed mRNAs between two samples of a patient taken in different contexts (e.g. cancer vs non cancer), which we termed responsive transcripts (RTs). METHODS: We propose a new N-of-1-pathways method, k-Means Enrichment (kMEn), that detects bidirectionally responsive pathways, despite background noise, using a pair of transcriptomes from a single patient. kMEn identifies transcripts responsive to the stimulus through k-means clustering and then tests for an over-representation of the responsive genes within each pathway. The pathways identified by kMEn are mechanistically interpretable pathways significantly responding to a stimulus. RESULTS: In ~9000 simulations varying six parameters, superior performance of kMEn over previous single-subject methods is evident by: (i) improved precision-recall at various levels of bidirectional response and (ii) lower rates of false positives (1 specificity) when more than 10% of genes in the genome are differentially expressed (background noise). In a clinical proof-of-concept, personal treatment specific pathways identified by kMEn correlate with therapeutic response (p value<0.01). CONCLUSION: Through improved single-subject transcriptome dynamics of bidirectionally-regulated signals, kMEn provides a novel approach to identify mechanism-level biomarkers. PMID- 28007583 TI - Towards a privacy preserving cohort discovery framework for clinical research networks. AB - BACKGROUND: The last few years have witnessed an increasing number of clinical research networks (CRNs) focused on building large collections of data from electronic health records (EHRs), claims, and patient-reported outcomes (PROs). Many of these CRNs provide a service for the discovery of research cohorts with various health conditions, which is especially useful for rare diseases. Supporting patient privacy can enhance the scalability and efficiency of such processes; however, current practice mainly relies on policy, such as guidelines defined in the Health Insurance Portability and Accountability Act (HIPAA), which are insufficient for CRNs (e.g., HIPAA does not require encryption of data - which can mitigate insider threats). By combining policy with privacy enhancing technologies we can enhance the trustworthiness of CRNs. The goal of this research is to determine if searchable encryption can instill privacy in CRNs without sacrificing their usability. METHODS: We developed a technique, implemented in working software to enable privacy-preserving cohort discovery (PPCD) services in large distributed CRNs based on elliptic curve cryptography (ECC). This technique also incorporates a block indexing strategy to improve the performance (in terms of computational running time) of PPCD. We evaluated the PPCD service with three real cohort definitions: (1) elderly cervical cancer patients who underwent radical hysterectomy, (2) oropharyngeal and tongue cancer patients who underwent robotic transoral surgery, and (3) female breast cancer patients who underwent mastectomy) with varied query complexity. These definitions were tested in an encrypted database of 7.1 million records derived from the publically available Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS). We assessed the performance of the PPCD service in terms of (1) accuracy in cohort discovery, (2) computational running time, and (3) privacy afforded to the underlying records during PPCD. RESULTS: The empirical results indicate that the proposed PPCD can execute cohort discovery queries in a reasonable amount of time, with query runtime in the range of 165-262s for the 3 use cases, with zero compromise in accuracy. We further show that the search performance is practical because it supports a highly parallelized design for secure evaluation over encrypted records. Additionally, our security analysis shows that the proposed construction is resilient to standard adversaries. CONCLUSIONS: PPCD services can be designed for clinical research networks. The security construction presented in this work specifically achieves high privacy guarantees by preventing both threats originating from within and beyond the network. PMID- 28007584 TI - Neurogenesis upregulation on the healthy hemisphere after stroke enhances compensation for age-dependent decrease of basal neurogenesis. AB - Stroke is a leading cause of death and disability worldwide with no treatment for the chronic phase available. Interestingly, an endogenous repair program comprising inflammation and neurogenesis is known to modulate stroke outcome. Several studies have shown that neurogenesis decreases with age but the therapeutic importance of endogenous neurogenesis for recovery from cerebral diseases has been indicated as its ablation leads to stroke aggravation and worsened outcome. A detailed characterization of the neurogenic response after stroke related to ageing would help to develop novel and targeted therapies. In an innovative approach, we used the DCX-Luc mouse, a transgenic model expressing luciferase in doublecortin-positive neuroblasts, to monitor the neurogenic response following middle cerebral artery occlusion over three weeks in three age groups (2, 6, 12months) by optical imaging while the stroke lesion was monitored by quantitative MRI. The individual longitudinal and noninvasive time profiles provided exclusive insight into age-dependent decrease in basal neurogenesis and neurogenic upregulation in response to stroke which are not accessible by conventional BrdU-based measures of cell proliferation. For cortico-striatal strokes the maximal upregulation occurred at 4days post stroke followed by a continuous decrease to basal levels by three weeks post stroke. Older animals effectively compensated for reduced basal neurogenesis by an enhanced sensitivity to the cerebral lesion, resulting in upregulated neurogenesis levels approaching those measured in young mice. In middle aged and older mice, but not in the youngest ones, additional upregulation of neurogenesis was observed in the contralateral healthy hemisphere. This further substantiates the increased propensity of older brains to respond to lesion situation. Our results clearly support the therapeutic relevance of endogenous neurogenesis for stroke recovery and particularly in older brains. PMID- 28007585 TI - The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations. AB - Heterozygous and rare homozygous mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia episodic ataxia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function. Recently, an important role for PRTT2 in the neurotransmitter release machinery, brain development and synapse formation has been uncovered. In this work, we have characterized the phenotype of a mouse in which the PRRT2 gene has been constitutively inactivated (PRRT2 KO). beta-galactosidase staining allowed to map the regional expression of PRRT2 that was more intense in the cerebellum, hindbrain and spinal cord, while it was localized to restricted areas in the forebrain. PRRT2 KO mice are normal at birth, but display paroxysmal movements at the onset of locomotion that persist in the adulthood. In addition, adult PRRT2 KO mice present abnormal motor behaviors characterized by wild running and jumping in response to audiogenic stimuli that are ineffective in wild type mice and an increased sensitivity to the convulsive effects of pentylentetrazol. Patch-clamp electrophysiology in hippocampal and cerebellar slices revealed specific effects in the cerebellum, where PRRT2 is highly expressed, consisting in a higher excitatory strength at parallel fiber-Purkinje cell synapses during high frequency stimulation. The results show that the PRRT2 KO mouse reproduces the motor paroxysms present in the human PRRT2-linked pathology and can be proposed as an experimental model for the study of the pathogenesis of the disease as well as for testing personalized therapeutic approaches. PMID- 28007587 TI - Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex. AB - Extracellular potassium concentration, [K+]o, is a major determinant of neuronal excitability. In the healthy brain, [K+]o levels are tightly controlled. During seizures, [K+]o increases up to 15mM and is thought to cause seizures due to its depolarizing effect. Although astrocytes have been suggested to play a key role in the redistribution (or spatial buffering) of excess K+ through Connexin-43 (Cx43)-based Gap Junctions (GJs), the relation between this dynamic regulatory process and seizure generation remains unknown. Here we contrasted the role of astrocytic GJs and hemichannels by studying the effect of GJ and hemichannel blockers on [K+]o regulation in vivo. [K+]o was measured by K+-sensitive microelectrodes. Neuronal excitability was estimated by local field potential (LFP) responses to forepaw stimulation and changes in the power of resting state activity. Starting at the baseline [K+]o level of 1.61+/-0.3mM, cortical microinjection of CBX, a broad spectrum connexin channel blocker, increased [K+]o to 11+/-3mM, Cx43 GJ/hemichannel blocker Gap27 increased it from 1.9+/-0.7 to 9+/ 1mM. At these [K+]o levels, no seizures were observed. Cx43 hemichannel blockade with TAT-Gap19 increased [K+]o by only ~1mM. Microinjection of 4-aminopyridine, a known convulsant, increased [K+]o to ~10mM and induced spontaneously recurring seizures, whereas direct application of K+ did not trigger seizure activity. These findings are the first in vivo demonstration that astrocytic GJs are major determinants for the spatial buffering of [K+]o and that an increase in [K+]o alone does not trigger seizures in the neocortex. PMID- 28007586 TI - Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia. AB - Studies of genetics, serum cytokines, and autoimmune illnesses suggest that immune-related abnormalities are involved in the disease process of schizophrenia. Furthermore, direct evidence of cortical immune activation, including markedly elevated levels of many immune-related markers, have been reported in the prefrontal cortex in multiple cohorts of schizophrenia subjects. Within the prefrontal cortex in schizophrenia, deficits in the basilar dendritic spines of layer 3 pyramidal neurons and disturbances in inhibitory inputs to pyramidal neurons have also been commonly reported. Interestingly, microglia, the resident immune-related cells of the brain, also regulate excitatory and inhibitory input to pyramidal neurons. Consequently, in this review, we describe the cytological and molecular evidence of immune activation that has been reported in the brains of individuals with schizophrenia and the potential links between these immune-related disturbances with previously reported disturbances in pyramidal and inhibitory neurons in the disorder. Finally, we discuss the role that activated microglia may play in connecting these observations and as potential therapeutic treatment targets in schizophrenia. PMID- 28007588 TI - Role of Fallopian Tubes in the Development of Ovarian Cancer. AB - Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth cause of cancer death in women in the United States. The most common and lethal histologic subtype of epithelial ovarian cancer is high-grade serous carcinoma (HGSC), which generally presents at an advanced stage. HGSC may be associated with BRCA1 and BRCA2 mutations. Historically, HGSC was believed to originate from the ovarian epithelial cells. However, more recent evidence supports the idea that most ovarian cancers originate in the fallopian tube epithelium in both high-risk women and in the general population. Serous tubal intraepithelial carcinomas may ultimately evolve into ovarian or peritoneal cancer. As a result, prophylactic salpingectomy with conservation of the ovaries has become an increasingly more common practice for premenopausal women undergoing risk-reducing surgery. Because the fallopian tube is now recognized as the most common potential site of origin of ovarian carcinoma, there is ongoing research to explore molecular and genetic factors that may be critical in the development of this disease. Further research is needed to identify novel opportunities for early detection and screening of ovarian cancer with the ultimate goal of increasing overall survival. PMID- 28007589 TI - Rectovaginal Splenosis: An Unexpected Cause of Dyspareunia Approached by Laparoscopy. AB - STUDY OBJECTIVE: To demonstrate the technique of laparoscopic approach in a rare case of rectovaginal splenosis with severe dyspareunia and dyschesia. DESIGN: A step-by-step explanation of the patient's condition, diagnosis, surgical technique, and postoperative results (Canadian Task Force classification II-3). SETTING: Splenosis consists of ectopic functioning splenic tissue that can be located anywhere within the abdomen or pelvis. Fragments are often multiple and range in diameter from a few millimeters to a few centimeters. They are reddish blue and are sessile or pedunculated. Their appearance can mimic that of neoplasms or endometriosis, which are the main differential diagnoses. Trauma and subsequent splenectomy is the cause in most cases. Splenosis is a benign condition usually found incidentally and is usually asymptomatic. The need for therapy is controversial, and treatment is suggested only in symptomatic cases, primarily those related to pelvic or abdominal lesions, as in our patient. The diagnosis of splenosis in a woman complaining of pelvic pain may present diagnostic difficulties. The splenic tissue has the macroscopic appearance of endometriosis, and its position in the pelvis also may suggest this diagnosis. Where excision of splenosis is considered necessary, the approach should be laparoscopic, unless this is considered too risky owing to the proximity of vital structures. INTERVENTION: A 40-year-old woman was referred to our department for severe dyspareunia and dyschezia. The gynecologic examination revealed a painfull nodularity on the posterior vaginal cul de sac. Further evaluation with 2- and 3 dimensional ultrasound and magnetic resonance imaging revealed several soft tissue nodules in the pouch of Douglas (POD), which were enhanced on contrast administration. She had undergone a splenectomy 15 years earlier after a car accident. A laparoscopic approach to a rectovaginal nodularity was performed. Under general anesthesia, the patient was placed in the dorsal decubitus position with her arms alongside her body and her legs in abduction. Pneumoperitoneum was achieved using a Veres needle placed at the umbilicus. Four trocars were placed: a 10-mm trocar at the umbilicus for the 0-degree laparoscope; a 5-mm trocar at the right anterosuperior iliac spine; a 5-mm trocar in the midline between the umbilicus and the pubic symphysis, approximately 8 to 10 cm inferior to the umbilical trocar; and a 5-mm trocar at the left anterosuperior iliac spine. The entire pelvis was inspected for endometriotic lesions. In the pelvis, hypervascular and bluish nodules were visible with extension from the POD into the deep rectovaginal space. The macroscopic appearance was atypical for endometriotic implants. The nodularities were carefully dissected and excised, and histological assessment revealed splenic tissue. At the time of this report, the patient had been asymptomatic for 6 months after surgery. CONCLUSION: Rectovaginal splenosis may mimic endometriosis. The laparoscopic approach to rectovaginal splenosis avoids an abdominal incision, with its associated pain and possible adhesion formation. It also provides a better view for dissection. In this patient, the splenosis was removed by laparoscopy, with no postoperative dyspareunia or dyschesia. PMID- 28007590 TI - The Curious Case of the Uterine Cyst. PMID- 28007591 TI - The Effectiveness of Treatments for Patients With Medication Overuse Headache: A Systematic Review and Meta-Analysis. AB - : Worldwide, approximately 1 to 2% of the adult population suffers from chronic headache due to overuse of pain medication. Guidelines recommend acute withdrawal of medication, but the optimal treatment remains unknown. We aimed to evaluate the benefit of treatments for patients with medication overuse headache (MOH). We performed an extensive literature search until November 2015, selecting randomized controlled trials that evaluated interventions for adults with MOH. Two authors assessed the eligible trials and extracted data. We calculated effect estimates and used the random effects model for the pooled analysis. Our primary outcome measures were 'headache days' and 'days with medication.' Outcome data were categorized as short-term (up to 12 weeks) or long-term (>=12 weeks) outcomes. This review consists of 16 trials including 1,105 patients. Four trials evaluated the use of prednisone with placebo or celecoxib after medication withdrawal; 7 trials evaluated various methods of withdrawal versus other methods of withdrawal, and 5 trials evaluated prophylactic medication compared with placebo or ibuprofen. We found no significant differences in headache days between prednisone versus placebo or between outpatient versus inpatient treatment, but we found a significant difference in days with medication. Overall, we found no benefit of prophylactic medication versus placebo. We found low to very low quality of evidence of no benefit of prednisone, prophylaxis, and various withdrawal interventions. Because the burden of MOH for patients is enormous, larger and high-quality intervention trials are needed. PERSPECTIVE: This article presents a critical look at studies of patients with MOHs. It appears that the withdrawal strategy remains the best treatment option, although there is scant evidence on the efficacy of any treatment options. PMID- 28007592 TI - Colostrum proinflammatory cytokines as biomarkers of bovine immune response to bovine tuberculosis (bTB). AB - Bovine colostrum contains compounds, which provide passive immune protection from mother to newborn calves. Little is known about cytokine levels and their role in bovine colostrum. Moreover, the capacity of bovine colostrum cells to mount specific immune responses after natural exposure to bovine tuberculosis (bTB) antigens in dairy herds has not been studied, thus far. The purpose of this study was to identify biomarkers for bTB infection measurable in bovine colostrum. The present study reveals that isolated-immune colostrum cells can mount a specific immune response against bTB antigens, by measuring the novo IFN-gamma release in cell culture. We found that IFN-gamma levels in the responders (Bov+) to bTB antigen were higher than in non-responders (Bov-). On the other hand, proinflammatory cytokines contained in colostrum's whey were tested in Tuberculin Skin Test (TST) reactor (TST+) and non-reactor (TST-) animals to assess their potential role as biomarker. We observed that IFN-gamma levels were lower or undetectable, as opposed to IL4 levels were measurable, the TNF-alpha level was higher in TST- than TST+, while IL-6 levels showed the opposite reaction and with no statistical significance. Moreover, IL-1alpha mRNA expression levels were higher in colostrum mononuclear cells (CMC) in Bov+ cattle. Collectively, these data suggest that the differential expression of pro and anti-inflammatory cytokines could have relevant value to diagnose bTB in cattle. PMID- 28007593 TI - Down-regulation of MsrB3 induces cancer cell apoptosis through reactive oxygen species production and intrinsic mitochondrial pathway activation. AB - Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically catalyzes the reduction of methionine-R-sulfoxide residues and has an antioxidant function. We have previously shown that depletion of MsrB3 suppresses the proliferation of normal mammalian cells by arresting cell cycle. In this study, we report the crucial role of MsrB3 in cancer cell death. Deficiency of MsrB3 induced cancer cell death, while MsrB3 overexpression stimulated cancer cell proliferation. MsrB3 depletion resulted in apoptotic cancer cell death through the activation of the intrinsic mitochondrial pathway. MsrB3 deficiency increased the levels of cellular reactive oxygen species (ROS) and led to redox imbalance, and also increased the Bax to Bcl-2 ratio and cytochrome c release, leading to caspase activation. Treatment of MsrB3-depleted cells with N-acetylcysteine, an ROS scavenger, prevented cell death, suggesting that MsrB3 deficiency-induced cell death is associated with increased ROS production. In addition, MsrB3 depletion activated poly(ADP ribose) polymerase-1 (PARP-1) and led to the translocation of apoptosis-inducing factor (AIF) to the nucleus. Taken together, our results suggest that MsrB3 plays an important role in cancer cell survival through the modulation of the intrinsic apoptosis pathway. PMID- 28007594 TI - The P20R mutation of alphaB-crystallin diminishes its anti-apoptotic activity in human lens epithelial cells. AB - alphaB-crystallin acts as an anti-apoptosis protein in human lens epithelial (HLE) cells. We recently identified a missense mutation in alphaB-crystallin that changes proline 20 to an arginine (P20R) in a Chinese family with autosomal dominant congenital posterior polar cataract. The impact of the P20R mutation on the anti-apoptosis function remains unclear. To explore the anti-apoptotic activity of alphaB-crystallin wild type (alphaB-wt) and its P20R mutant under oxidative stress, HLE cells were transfected with alphaB-wt and alphaB-P20R constructs and expression was measured by western blotting. Flow cytometry and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP digoxigenin nick end labelling (TUNEL) staining were performed to investigate apoptosis. We found that alphaB-wt performed a dominant role in inhibiting stress-induced apoptosis, but this function was impeded in cells expressing alphaB-P20R. The P20R mutant of alphaB-crystallin exhibits diminished anti-apoptotic activity compared with the native protein. PMID- 28007595 TI - The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice. AB - Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-alpha. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues. Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro, and enhanced tumor growth when inoculated in vivo in mice. The Dll3-mediated proliferation could be due to increased Akt phosphorylation in LLC cells, because an Akt inhibitor counteracted Dll3-induced proliferation. Moreover, Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling. PMID- 28007596 TI - Soft matrices downregulate FAK activity to promote growth of tumor-repopulating cells. AB - Tumor-repopulating cells (TRCs) are a tumorigenic sub-population of cancer cells that drives tumorigenesis. We have recently reported that soft fibrin matrices maintain TRC growth by promoting histone 3 lysine 9 (H3K9) demethylation and Sox2 expression and that Cdc42 expression influences H3K9 methylation. However, the underlying mechanisms of how soft matrices induce H3K9 demethylation remain elusive. Here we find that TRCs exhibit lower focal adhesion kinase (FAK) and H3K9 methylation levels in soft fibrin matrices than control melanoma cells on 2D rigid substrates. Silencing FAK in control melanoma cells decreases H3K9 methylation, whereas overexpressing FAK in tumor-repopulating cells enhances H3K9 methylation. Overexpressing Cdc42 or RhoA in the presence of FAK knockdown restores H3K9 methylation levels. Importantly, silencing FAK, Cdc42, or RhoA promotes Sox2 expression and proliferation of control melanoma cells in stiff fibrin matrices, whereas overexpressing each gene suppresses Sox2 expression and reduces growth of TRCs in soft but not in stiff fibrin matrices. Our findings suggest that low FAK mediated by soft fibrin matrices downregulates H3K9 methylation through reduction of Cdc42 and RhoA and promotes TRC growth. PMID- 28007597 TI - Computational proteome-wide screening predicts neurotoxic drug-protein interactome for the investigational analgesic BIA 10-2474. AB - The investigational compound BIA 10-2474, designed as a long-acting and reversible inhibitor of fatty acid amide hydrolase for the treatment of neuropathic pain, led to the death of one participant and hospitalization of five others due to intracranial hemorrhage in a Phase I clinical trial. Putative off target activities of BIA 10-2474 have been suggested to be major contributing factors to the observed neurotoxicity in humans, motivating our study's proteome wide screening approach to investigate its polypharmacology. Accordingly, we performed an in silico screen against 80,923 protein structures reported in the Protein Data Bank. The resulting list of 284 unique human interactors was further refined using target-disease association analyses to a subset of proteins previously linked to neurological, intracranial, inflammatory, hemorrhagic or clotting processes and/or diseases. Eleven proteins were identified as potential targets of BIA 10-2474, and the two highest-scoring proteins, Factor VII and thrombin, both essential blood-clotting factors, were predicted to be inhibited by BIA 10-2474 and suggest a plausible mechanism of toxicity. Once this small molecule becomes commercially available, future studies will be conducted to evaluate the predicted inhibitory effect of BIA 10-2474 on blood clot formation specifically in the brain. PMID- 28007598 TI - Identification of AcAP5 as a novel factor Xa inhibitor with both direct and allosteric inhibition. AB - Ancylostoma caninum anticoagulant peptide 5 (AcAP5) is a potent inhibitor for coagulation factor Xa (FXa). Previous studies show that AcAP5 binds to FXa at the active site, and/or the exosite. The active site-binding contributes to direct blocking of FXa catalytic activity, but the effect of exosite-binding and the underlying mechanism remain unknown. To investigate whether and how the exosite binding affects FXa function, we prepared several AcAP5 mutants with modifications to the active site-binding or exosite-binding region. Their FXa inhibiting and anticoagulant activities were examined both in vitro and in rabbit plasma, and the interactions with FXa were analyzed using in silico molecular modeling, docking, and molecular dynamics simulation. Mutants abolishing either active site- or exosite-binding resulted in a dramatic decrease in their anti-FXa and anticoagulant activities. Elongation of AcAP5 exosite-binding region also impaired the FXa-inhibiting activity. Computational analysis demonstrated that the conformation of FXa becomes more rigid due to exosite-binding with AcAP5, which consequently affects its catalytic activity. Our results suggest that both active site- and exosite-binding contribute to the FXa inhibitory activity of AcAP5. PMID- 28007599 TI - The structure formed by inverted repeats in p53 response elements determines the transactivation activity of p53 protein. AB - The TP53 gene is the most frequently mutated gene in human cancer and p53 protein plays a crucial role in gene expression and cancer protection. Its role is manifested by interactions with other proteins and DNA. p53 is a transcription factor that binds to DNA response elements (REs). Due to the palindromic nature of the consensus binding site, several p53-REs have the potential to form cruciform structures. However, the influence of cruciform formation on the activity of p53-REs has not been evaluated. Therefore, we prepared sets of p53 REs with identical theoretical binding affinity in their linear state, but different probabilities to form extra helical structures, for in vitro and in vivo analyses. Then we evaluated the presence of cruciform structures when inserted into plasmid DNA and employed a yeast-based assay to measure transactivation potential of these p53-REs cloned at a chromosomal locus in isogenic strains. We show that transactivation in vivo correlated more with relative propensity of an RE to form cruciforms than to its predicted in vitro DNA binding affinity for wild type p53. Structural features of p53-REs could therefore be an important determinant of p53 transactivation function. PMID- 28007600 TI - Sox9 mediated transcriptional activation of FOXK2 is critical for colorectal cancer cells proliferation. AB - FOXK2, which belongs to the fork head DNA binding protein family, has been shown to play a critical role in tumorigenesis. Here, we detected FOXK2 expression and its clinical significance in colorectal cancer, which has not been fully investigated before. Results from public database and our cohort indicated that FOXK2 was transcriptionally activated in colorectal cancer tissues compared to non-cancer tissues. High expression of FOXK2 was significantly correlated with poor survival. In vitro cell experiments suggested that FOXK2 promoted cell proliferation. Furthermore, we found that oncogene SOX9 was responsible for the up-regulation of FOXK2 by directly binding on its promoter. Depletion of FOXK2 attenuated SOX9 induced cell growth. In addition, we observed that the expression of FOXK2 was significantly associated with the expression of SOX9 both in the public database and our colorectal cancer tissues. The patients with SOX9+FOXK2+ had a poor overall survival (p = 0.0084). In conclusion, our data suggested that SOX9 transcriptionally activated FOXK2 was involved in the pathogenesis of colorectal cancer and might be a novel target for colorectal cancer therapy. PMID- 28007601 TI - C1qr and C1qrl redundantly regulate angiogenesis in zebrafish through controlling endothelial Cdh5. AB - Angiogenesis plays central role in the formation of functional circulation system. Characterizations of the involved factors and signaling pathways remain to be the key interest in the angiogenesis research. In this report, we showed that c1qr/cd93 and c1qrl/clec14a are specifically expressed in the vascular endothelial cells during zebrafish development. Single mutation of c1qr or c1qrl is associated with slightly malformation of inter-segmental vessels (ISVs), whereas double mutant exhibits severe defects in the ISVs formation without affecting early vasculogenesis. Further studies reveal that the endothelial endothelial junctional molecule Cdh5 becomes absent in the ISVs of the double mutant. Replenishment of Cdh5 efficiently rescue the impaired angiogenesis in the c1qr/c1qrl double mutant. These data demonstrate that c1qr and c1qrl redundantly regulate angiogenesis through controlling the expression of the endothelial junctional molecule Cdh5, thus playing an important role in angiogenesis. PMID- 28007602 TI - Molecular epidemiology of Coxiella burnetii in French livestock reveals the existence of three main genotype clusters and suggests species-specific associations as well as regional stability. AB - Q fever is a worldwide zoonosis caused by the bacterium Coxiella burnetii. In domestic ruminants, Q fever main clinical manifestations are abortions. Although the clinical signs may differ between ruminant species, C. burnetii's genetic diversity remains understudied in enzootic areas. Here, we focused on France, where Q fever is enzootic, with the aims to (a) identify potential associations between C. burnetii genotypes and ruminant host species; (b) assess the distribution of C. burnetii genotypes both within French farms and across France's major livestock-farming regions; and (c) suggest a subset of markers for future genotypic studies. We used DNA samples collected between 2006 and 2015 from 301 females (160 cows, 76 ewes, 65 goats) aborted of Q fever within 7 different farming regions. C. burnetii diversity was determined using a multiple locus variable-number of tandem repeat analysis (MLVA) considering 17 markers. Using a phylogenetic approach, we identified 3 main genotypic clusters divided into 12 sub-clusters. These clusters were significantly associated with ruminant species: almost all the cattle genotypes were found in a "cattle-specific" cluster whereas small ruminants genotypes essentially grouped into the two other clusters. The clusters also proved stable over space and time, some genotypes being more specifically observed in certain farming regions. We also observed some within-farm diversity but this diversity was restricted to a same genotypic cluster. Finally, we identified 6 MLVA markers that maximized the representativeness of the diversity described. Overall, we highlighted that molecular epidemiology is a relevant approach to assess C. burnetii's genetic diversity and to reveal the existence of species-specific associations and regional stability. These results will be valuable in the field to trace genotype circulation among ruminants and from ruminants to humans. Ultimately, the potential links between genotypes and virulence traits need to be investigated to adapt control measures in livestock farms. PMID- 28007603 TI - Inverse Association Between Basilar Artery Volume and Neuron Density in the Stellate Ganglion Following Bilateral Common Carotid Artery Ligation: An Experimental Study. AB - OBJECTIVE: This study examined the relationship between neuron density in the stellate ganglion and the severity of basilar artery (BA) enlargement after bilateral common carotid artery ligation. METHODS: Rabbits (n = 24) were randomly divided into 3 groups: unoperated control group (n = 4), experimental group subjected to bilateral common carotid artery ligation (n = 15), and sham-operated control group (n = 5). Histologic examination of the BAs and stellate ganglia was performed 2 months later. Permanent bilateral common carotid artery ligation was induced by ligation of common carotid arteries at prebifurcation levels as a model for steno-occlusive carotid artery disease. RESULTS: Mean BA volume and neuron density in stellate ganglia for all animals were 4200 MUm3 +/- 240 and 8325 MUm3 +/- 210. In sham-operated animals, the mean values were 4360 MUm3 +/- 340 and 8250 mm3 +/- 250. For the experimental group, mean volume and density in animals with slight dilatation of the BA (n = 6) were 4948 MUm3 +/- 680 and 10,321 mm3 +/- 120, whereas in animals with severe dilatation (n = 9), the values were 6728 MUm3 +/- 440 and 6300 mm3 +/- 730. An inverse association was observed between degree of BA enlargement and stellate ganglia neuronal density. CONCLUSIONS: High neuron density in stellate ganglia may protect against steno occlusive carotid artery disease by preventing BA dilatation and aneurysm formation in the posterior circulatory arteries. PMID- 28007604 TI - Primary Germinoma Originating from the Insular Lobe: A Case Report and Review of the Literature. AB - BACKGROUND: Primary intracranial germinomas occurring in the cerebral hemisphere are extremely rare, with only a few reported cases in the literature. We describe an unusual case of a primary germinoma that developed in the insular lobe, with little involvement in the basal frontal lobe. CASE DESCRIPTION: A 19-year-old man presented with headache and vomiting. Magnetic resonance imaging showed a solitary, ring-like enhanced lesion in the left hemisphere, and a preliminary diagnosis of glioma was made. Surgery was performed, and the diagnosis of germinoma was made based on the histopathologic results. CONCLUSIONS: The causes of ectopic germinomas of the midline structures of the brain are still unclear, but the theory of misplacement may partially clarify this phenomenon. Reflecting a lack of definitive management guidelines for atypical germinoma, the present patient was treated with focal radiotherapy around the lesion after surgery and achieved remission by 34 months postoperatively. PMID- 28007605 TI - Mitochondrial networking in diabetic left ventricle cardiomyocytes. AB - Cardiomyocyte mitochondria preserve "the quorum sensing" attribute of their aerobic bacterial ancestors, as shown by the transient physical connectivity and communication not only with each other, but also with other intracellular organelles and with cytosol, ensuing cellular homeostasis. In this review, we present original electron microscopy evidence on mitochondrial networking within diabetic left ventricular cardiomyocytes, focusing on: (i) the inter mitochondrial communication, allowing electrochemical signals transfer and outer membrane components or matrix proteins exchange, (ii) the interplay between mitochondria and the cardiomyocyte nucleus, nucleolus, sarcoplasmic reticulum, lysosomes, and lipid droplets viewed as attributes of mitochondrial "quality control" and "retrograde signaling function", and (iii) the crosstalk between mitochondria and cardiomyocyte cytosol, as part of the adaptive responses that allow cells survival. Confirmation of such interactions in diabetic myocardium and identification of molecules involved are ongoing, foreseeing the alleviation of heart contractile dysfunction in cardiomyopathy. PMID- 28007606 TI - Compositional and functional diversity of canonical PRC1 complexes in mammals. AB - The compositional complexity of Polycomb Repressive Complex 1 (PRC1) increased dramatically during vertebrate evolution. What is considered the "canonical" PRC1 complex consists of four subunits originally identified as regulators of body segmentation in Drosophila. In mammals, each of these four canonical subunits consists of two to six paralogs that associate in a combinatorial manner to produce over a hundred possible distinct PRC1 complexes with unknown function. Genetic studies have begun to define the phenotypic roles for different PRC1 paralogs; however, relating these phenotypes to unique biochemical and transcriptional function for the different paralogs has been challenging. In this review, we attempt to address how the compositional diversity of canonical PRC1 complexes relates to unique roles for individual PRC1 paralogs in transcriptional regulation. This review focuses primarily on PRC1 complex composition, genome targeting, and biochemical function. PMID- 28007608 TI - 16p13 microduplication without CREBBP involvement: Moving toward a phenotype delineation. AB - The short arm of chromosome 16 is one of the less stable regions of our genome, as over 10% of the euchromatic region of 16p is composed of highly complex low copy repeats that are known to be predisposed to rearrangements mediated by non allelic homologous recombination. The 16p13.3p13.13 molecular region has been defined as the 16p duplication hotspot, and duplications of chromosome 16p13 have recently been confirmed to cause a recognizable syndrome, with CREBBP being the main phenotype-causing gene. To date, only one case report is present in the literature with a 16p13 duplication without CREBBP involvement; we describe here a second analogous case with a not previously reported 16p13.2p13.13 microduplication. This paper allows us to better delineate the clinical features of 16p13 microduplications that do not encompass CREBBP and, concurrently, to narrow the molecular region responsible for congenital heart defects in 16p duplications as well as to propose GRIN2A as a candidate gene for epilepsy. PMID- 28007607 TI - Reading and Interpreting the Histone Acylation Code. PMID- 28007609 TI - Editorial: Updates in Teratology. PMID- 28007611 TI - Time course and localization of brain activity in humor comprehension: An ERP/sLORETA study. AB - Although a number of studies have investigated the incongruity-detection and resolution process in humor comprehension, it is difficult to functionally and anatomically dissociate these processes. We used event-related potentials (ERP) and standardized low resolution brain electromagnetic tomography analysis (sLORETA) to examine the time course and localization of brain activity during incongruity detection and resolution. We used the same materials as in our previous fMRI study. Eighteen participants read funny and unfunny scenarios and judged whether the target sentence was funny or not. Results indicated that ERPs elicited by a funny punch line showed a P2 component followed by a P600 component over the centro-parietal electrode sites. Our sLORETA analysis of the P2 ERPs revealed a stronger activation for the funny vs. unfunny condition in the superior frontal gyrus (SFG) and medial prefrontal cortex (mPFC). For the P600 ERPs, the funny punch line elicited greater activation in the temporal-parietal regions. These results indicate that incongruity-detection processes activate the SFG and mPFC in the P2 time window, while incongruity-resolution processes generate activation at the temporal-parietal regions in the P600 time window. These results provide the evidence that verbal humor comprehension is processed in steps which start with the incongruity detection in the early P2 time window and followed by a P600 component reflecting incongruity resolution. PMID- 28007612 TI - Low Motivational Incongruence Predicts Successful EEG Resting-state Neurofeedback Performance in Healthy Adults. AB - Neurofeedback is becoming increasingly sophisticated and widespread, although predictors of successful performance still remain scarce. Here, we explored the possible predictive value of psychological factors and report the results obtained from a neurofeedback training study designed to enhance the self regulation of spontaneous EEG microstates of a particular type (microstate class D). Specifically, we were interested in life satisfaction (including motivational incongruence), body awareness, personality and trait anxiety. These variables were quantified with questionnaires before neurofeedback. Individual neurofeedback success was established by means of linear mixed models that accounted for the amount of observed target state (microstate class D contribution) as a function of time and training condition: baseline, training and transfer (results shown in Diaz Hernandez et al.). We found a series of significant negative correlations between motivational incongruence and mean percentage increase of microstate D during the condition transfer, across sessions (36% of common variance) and mean percentage increase of microstate D during the condition training, within-session (42% of common variance). There were no significant correlations related to other questionnaires, besides a trend in a sub-scale of the Life Satisfaction questionnaire. We conclude that motivational incongruence may be a potential predictor for neurofeedback success, at least in the current protocol. The finding may be explained by the interfering effect on neurofeedback performance produced by incompatible simultaneously active psychological processes, which are indirectly measured by the Motivational Incongruence questionnaire. PMID- 28007613 TI - Hemoglobin J-Iran (HBB c.232C>G): Interference with the assay of HbA1c. PMID- 28007610 TI - Structure, biochemistry, and biology of PAK kinases. AB - PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs. PMID- 28007614 TI - Hypertension: The role of biochemistry in the diagnosis and management. AB - Hypertension is defined as a persistently elevated blood pressure >=140/90mmHg. It is an important treatable risk factor for cardiovascular disease, with a high prevalence in the general population. The most common cause, essential hypertension, is a widespread disease - however, secondary hypertension is under investigated and under diagnosed. Collectively, hypertension is referred to as a "silent killer" - frequently it displays no overt symptomatology. It is a leading risk factor for death and disability globally, with >40% of persons aged over 25 having hypertension. A vast spectrum of conditions result in hypertension spanning essential through resistant, to patients with an overt endocrine cause. A significant number of patients with hypertension have multiple cardiovascular risk factors at the time of presentation. Both routine and specialised biochemical investigations are paramount for the evaluation of these patients and their subsequent management. Biochemical testing serves to identify those hypertensive individuals who are at higher risk on the basis of evidence of dysglycaemia, dyslipidaemia, renal impairment, or target organ damage and to exclude identifiable causes of hypertension. The main target of biochemical testing is the identification of patients with a specific and treatable aetiology of hypertension. Information gleaned from biochemical investigation is used to risk stratify patients and tailor the type and intensity of subsequent management and treatment. We review the approach to the biochemical investigation of patients presenting with hypertension and propose a diagnostic algorithm for work up. PMID- 28007616 TI - Role of neuropeptide F in regulating filter feeding of Manila clam, Ruditapes philippinarum. AB - Endogenous signals which may be involved in the regulation of filter feeding in bivalves have never been examined. NPY/NPF homologue has been proved to play an important role in the regulation of food intake in vertebrate and several invertebrates. In this study, a NPF homologue was cloned from visceral ganglia of clam Ruditapes philippinarum. The full-length cDNA sequence was 892bp in length and encoded a precursor of 82 amino acid residues. We then examined the effects of fasting and refeeding on the filtration rates (FR), plasma glucose concentration (PGC), 5-HT, DA and the expression level of the rp-NPF and insulin transcript. The mRNA expression level of rp-NPF in visceral ganglion was increased during fasting, and rose to highest level on 72h after starvation and declined immediately after food had been supplied. Hemocoel injection of rp NPF(5MUg/g)significantly increased FR of clams within 2h. Compared to the controls, a significant increase in insulin mRNA levels was observed at 8h after injection. Contents of 5-HT and DA also increased in the 5MUg/grp-NPF administrated clams at 8 and 24h after injection. These results suggest that, similar to vertebrates, NPF, insulin, 5-HT and DA may play a role in the regulation of feeding in R. philippinarum. PMID- 28007617 TI - A novel tandem mass spectrometry method for first-line screening of mainly beta thalassemia from dried blood spots. AB - : Traditional methods for thalassemia screening are time-consuming and easily affected by cell hemolysis or hemoglobin degradation in stored blood samples. Tandem mass spectrometry (MS/MS) proved to be an effective technology for sickle cell disorders (SCD) screening. Here, we developed a novel MS/MS method for beta thalassemia screening from dried blood spots (DBS). Stable isotopic-labeled peptides were used as internal standards for quantification and calculation of the alpha:beta-globin ratios. We used the alpha:beta-globin ratio cutoffs to differentiate between normal individuals and patients with thalassemia. About 781 patients and 300 normal individuals were analyzed. The alpha:beta-globin ratios showed significant difference between normal and beta-thalassemia patients (P<0.01), particularly when the disease was homozygous or double heterozygous with another alpha- or beta-thalassemia mutation. In the parallel study, all cases screened for suspected thalassemia from six hundred DBS samples by using this MS/MS method were successfully confirmed by genotyping. The intra-assay and inter-assay CVs of the ratios ranged from 2.4% to 3.9% and 4.7% to 7.1%, and there was no significant sample carryover or matrix effect for this MS/MS method. Combined with SCD screening, this MS/MS method could be used as a first-line screening assay for both structural and expression abnormalities of human hemoglobin. BIOLOGICAL SIGNIFICANCE: Traditional methods for thalassemia screening were depending on the structural integrity of tetramers and could be affected by hemolysis and degradation of whole blood samples, especially when stored. We used proteospecific peptides produced by the tryptic digestion of each globin to evaluate the production ratio between alpha- and beta-globin chains, which turned out to be quite stable even when stored for more than two months. Though most of the peptides were specific to alpha-globin or beta-globin, we only chose four most informative peptides and its stable isotopic-labeled peptides as internal standards for analysis, which could obtain a high accuracy. Currently, we are the first to address the application of MS/MS for thalassemia screening, when combined with SCD screening, this MS/MS method could be used as a first-line screening assay for both structural and expression abnormalities of human hemoglobin. PMID- 28007618 TI - Virus-host interactome: Putting the accent on how it changes. AB - Viral infections are extremely complex processes that could only be well understood by precisely characterizing the interaction networks between the virus and the host components. In recent years, much effort has gone in this direction with the aim of unveiling the molecular basis of viral pathology. These networks are mostly formed by viral and host proteins, and are expected to be dynamic both with time and space (i.e., with the progression of infection, as well as with the virus and host genotypes; what we call plastodynamic). This largely overlooked spatio-temporal evolution urgently calls for a change both in the conceptual paradigms and experimental techniques used so far to characterize virus-host interactions. More generally, molecular plasticity and temporal dynamics are unavoidable components of the mechanisms that underlie any complex disease; components whose understanding will eventually enhance our ability to modulate those networks with the aim of improving disease treatments. PMID- 28007619 TI - Malignant Mesothelioma Biomarkers: From Discovery to Use in Clinical Practice for Diagnosis, Monitoring, Screening, and Treatment. AB - Malignant pleural mesothelioma is a highly aggressive tumor associated with asbestos exposure. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis with a median survival of < 12 months from diagnosis. Biomarkers have been proposed as a cost-effective means of cancer management, and the search for a mesothelioma biomarker has been ongoing for the last 30 years. Many traditional soluble (glyco)protein biomarkers have been evaluated over this time, and an ever-increasing list of new biomarkers, including messenger RNA, DNA, microRNA, and antibodies, is being reported from biomarker discovery projects. To date, soluble mesothelin is the only tumor biomarker to receive US Food and Drug Administration approval for clinical use in mesothelioma. Mesothelin is a glycoprotein normally expressed on the surface of mesothelial cells, and in the cancerous state it can be present in circulation. Mesothelin has a limited expression on normal, nonmalignant tissue and is thus an attractive therapeutic target for mesothelin-positive tumors. In this review we will focus on the discovery and clinical usages of mesothelin and provide an update on other mesothelioma biomarkers and show how such biomarker studies might impact on the management of this deadly tumor in the future. PMID- 28007620 TI - Postoperative Oxygen Therapy in Patients With OSA: A Randomized Controlled Trial. AB - BACKGROUND: Surgical patients with OSA are at increased risk for perioperative complications. Postoperative supplemental oxygen is commonly used, but it may contribute to respiratory depression in patients with OSA receiving opioids. The objective of the study is to investigate the effect of postoperative supplemental oxygen on arterial oxygen saturation (Sao2), sleep respiratory events, and CO2 level in patients with untreated OSA. METHODS: Consented patients with an apnea hypopnea index (AHI) > 5 events per hour on a preoperative polysomnography were randomized (1:1) to oxygen (O2 group) or no oxygen (control group). The O2 group received oxygen at 3 L/min via nasal prongs for three postoperative nights. The primary outcomes were polysomnographic parameters measuring Sao2, sleep respiratory events, and Pco2 measured by transcutaneous CO2 monitor (PtcCO2) on nights 1 through 3. The intention-to-treat and per protocol analysis were completed. RESULTS: There were 123 patients randomized (O2 group: n = 62; control group: n = 61). On night 3, the O2 vs control group had a higher average Sao2 (95.2% +/- 3% vs 91.4% +/- 4%, respectively; P < .001) and lower oxygen desaturation index (median, 2.3; 25th-75th percentile, 0.2-13.8 vs median, 18.5; 25th-75th percentile, 8.2-45.9 events per hour, respectively; P < .0001). The O2 group had a decreased AHI (median, 8.0; 25th-75th percentile, 2.1-19.9 vs median, 15.6; 25th-75th percentile, 9.5-45.8, respectively; P = .016), hypopnea index (P < .001), and central apnea index (P = .026) and a shortened longest apnea hypopnea duration (P = .002). Although time percentage with PtcCO2 >= 55 mm Hg >= 10% on postoperative night 1, 2, or 3 was found in 11.4% patients, there was no difference in PtcCO2 between the groups. CONCLUSIONS: Postoperative supplemental oxygen was found to improve oxygenation and decrease the AHI without increasing the duration of apnea-hypopnea event or PtcCO2 level. A small number of patients had significant CO2 retention while receiving supplemental oxygen. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01552304; URL: www.clinicaltrials.gov. PMID- 28007615 TI - Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening. AB - Improved methodologies for modeling cardiac disease phenotypes and accurately screening the efficacy and toxicity of potential therapeutic compounds are actively being sought to advance drug development and improve disease modeling capabilities. To that end, much recent effort has been devoted to the development of novel engineered biomimetic cardiac tissue platforms that accurately recapitulate the structure and function of the human myocardium. Within the field of cardiac engineering, induced pluripotent stem cells (iPSCs) are an exciting tool that offer the potential to advance the current state of the art, as they are derived from somatic cells, enabling the development of personalized medical strategies and patient specific disease models. Here we review different aspects of iPSC-based cardiac engineering technologies. We highlight methods for producing iPSC-derived cardiomyocytes (iPSC-CMs) and discuss their application to compound efficacy/toxicity screening and in vitro modeling of prevalent cardiac diseases. Special attention is paid to the application of micro- and nano engineering techniques for the development of novel iPSC-CM based platforms and their potential to advance current preclinical screening modalities. PMID- 28007621 TI - Instability of Willingness to Accept Life-Sustaining Treatments in Patients With Advanced Chronic Organ Failure During 1 Year. AB - BACKGROUND: For optimal end-of-life decision-making, it is important to understand the stability of patients' treatment preferences. The aim of this paper is to examine the stability of willingness to accept life-sustaining treatments during 1-year follow-up in Dutch patients with advanced chronic organ failure. In addition, we want to explore the association between willingness to accept high-burden treatment and preferences for CPR and mechanical ventilation (MV). METHODS: In this multicenter longitudinal study, 265 clinically stable outpatients with advanced COPD (Global Initiative for Chronic Obstructive Lung Disease stage III/IV [n = 105]), chronic heart failure (New York Heart Association class III/IV [n = 80]), or chronic renal failure (requiring dialysis [n = 80) were visited at baseline and at 4, 8, and 12 months to assess the stability of life-sustaining treatment preferences using the Willingness to Accept Life-sustaining Treatment instrument. RESULTS: Two hundred six patients completed 1-year follow-up (mean age, 67.2 years [SD, 13.1 years]; 64.1% men). Overall, proportions of patients who were willing to accept life-sustaining treatment during 1 year did not change over time. However, individual trajectories showed that about two-thirds of patients changed their preferences at least once during a year. Moreover, there was no association found between the stability of willingness to undergo high-burden therapy and the stability of preferences for CPR and MV. CONCLUSIONS: The current findings show the complexity of preferences for end-of-life care and indicate once again that advance care planning is a continuous process between patients and physicians, in which preferences for specific situations are discussed and that needs to be regularly reevaluated to deliver high-quality end-of-life care. CLINICAL TRIAL REGISTRATION: Netherlands National Trial Register (NTR 1552). PMID- 28007622 TI - Control of Ventilation in Health and Disease. AB - Control of ventilation occurs at different levels of the respiratory system through a negative feedback system that allows precise regulation of levels of arterial carbon dioxide and oxygen. Mechanisms for ventilatory instability leading to sleep-disordered breathing include changes in the genesis of respiratory rhythm and chemoresponsiveness to hypoxia and hypercapnia, cerebrovascular reactivity, abnormal chest wall and airway reflexes, and sleep state oscillations. One can potentially stabilize breathing during sleep and treat sleep-disordered breathing by identifying one or more of these pathophysiological mechanisms. This review describes the current concepts in ventilatory control that pertain to breathing instability during wakefulness and sleep, delineates potential avenues for alternative therapies to stabilize breathing during sleep, and proposes recommendations for future research. PMID- 28007623 TI - Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance). AB - INTRODUCTION: SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis. There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available. SCLC is rarely resected, limiting the number of samples available for genomic analyses of somatic mutations. METHODS: To identify potential driver mutations in human SCLC we sequenced the whole exomes of 18 primary SCLCs and seven cell lines along with matched normal controls. We extended these data by resequencing a panel of genes across 40 primary SCLCs and 48 cell lines. RESULTS: We report frequent mutations in the lysine methyltransferase 2D gene (KMT2D) (also known as MLL2), a key regulator of transcriptional enhancer function. KMT2D exhibited truncating nonsense/frameshift/splice site mutations in 8% of SCLC tumors and 17% of SCLC cell lines. We found that KMT2D mutation in human SCLC cell lines was associated with reduced lysine methyltransferase 2D protein levels and reduced monomethylation of histone H3 lysine 4, a mark associated with transcriptional enhancers. We also found mutations in other genes associated with transcriptional enhancer control, including CREB binding protein gene (CREBBP), E1A binding protein p300 gene (EP300), and chromodomain helicase DNA binding protein 7 gene (CHD7), and we report mutations in additional chromatin remodeling genes such as polybromo 1 gene (PBRM1). CONCLUSIONS: These data indicate that KMT2D is one of the major mutated genes in SCLC, and they point to perturbation of transcriptional enhancer control as potentially contributing to SCLC. PMID- 28007624 TI - Capture-Based Targeted Ultradeep Sequencing in Paired Tissue and Plasma Samples Demonstrates Differential Subclonal ctDNA-Releasing Capability in Advanced Lung Cancer. AB - INTRODUCTION: Circulating tumor DNA (ctDNA), which represents an unbiased way to assess tumor genetic profile noninvasively, facilitates studying intratumor heterogeneity. Although intratumor heterogeneity has been elucidated substantially in a few cancer types, including NSCLC, how it influences the ability of tumor cells harboring different genetic abnormalities in releasing their DNA remains elusive. We designed a capture-based panel targeting NSCLC to detect and quantify genetic alterations from plasma samples by using deep sequencing. By applying the panel to paired biopsy and plasma samples, we imputed and compared the ctDNA-releasing efficiency in subclones harboring distinct genetic variants. METHODS: We collected 40 pairs of matched biopsy and plasma samples from patients with advanced lung cancer and applied capture-based sequencing using our LungPlasma panel, which consists of critical exons and introns of 168 genes. We derived a normalized relative allelic fraction score (NRAFS) to reflect ctDNA-releasing efficiency. RESULTS: By using mutations detected in biopsy samples as a reference, we achieved 87.2% by-variant sensitivity, including for single-nucleotide variants, insertions or deletions, and gene fusions. Furthermore, the by-variant sensitivity for the seven most critical and actionable genes was 96.2%. The average NRAFS for subclones carrying mutations from seven actionable genes was 0.877; in contrast, the average NRAFS for other mutations was 0.658. Mutations from four genes involved in cell cycle pathways had a particularly low NRAFS (0.480) compared with the other two groups (p = 0.07). CONCLUSIONS: We have demonstrated that subclones carrying driver mutations are more prone to release DNA. We have also demonstrated the quantitative ability of capture-based sequencing, paving its way for routine utilization in clinical settings. PMID- 28007625 TI - Size and Growth Assessment of Pulmonary Nodules: Consequences of the Rounding. AB - OBJECTIVES: The aim of this study was to understand the effect of rounding nodule size measurements on the frequency of positive results in the setting of lung cancer screening. METHODS: Four methods for determining nodule size were compared, including rounding each individual length and width measurement and also rounding the overall average. These were applied to the International Early Lung Cancer Action Program database, in which we determined the frequency of a positive result by using standard size thresholds of 6.0 mm on baseline screening and 3.0 mm on repeat scanning. We also explored how rounding influences the ability to measure growth according to a predefined cutoff value of 1.5 mm as required in the Lung Computed Tomography Screening Reporting and Data System (Lung-RADS) (version 1.0). RESULTS: Each method for rounding increased the frequency of positive results compared with that with no rounding. The largest increases-28.9% and 22.3% for the baseline and repeat round, respectively occurred when rounding was used for both the individual length and width measurements and again for the final diameter. If the 1.5-mm increase in size were used for determining growth, a 4-mm nodule would need to have a volume doubling time of 130.6 days or less to demonstrate growth in 6 months (Lung-RADS category 3) whereas a 6-mm nodule would need volume doubling time of 93.2 days to demonstrate growth in 3 months (Lung-RADS category 4A). In addition, rounding can have the effect of having nodules that appear to not be growing meet the criteria for growth and vice versa. CONCLUSIONS: Rounding influences the frequency of positive results and growth assessment, substantially decreasing the efficiency of screening. PMID- 28007626 TI - Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non-Small Cell Lung Cancer. AB - INTRODUCTION: Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment. METHODS: We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI. RESULTS: Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs. CONCLUSIONS: EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment. PMID- 28007627 TI - Clinical Outcome of ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs). AB - INTRODUCTION: NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood. METHODS: Outcomes of patients with metastatic NSCLC de novo co alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed. RESULTS: A total of 14 patients with adenocarcinoma were identified. Five patients had ALK/EGFR co-alterations and nine had ALK/KRAS co-alterations. Six of seven patients with ALK/KRAS co-alterations (86%) were primary refractory to crizotinib. One patient has had ongoing disease stabilization for 26 months. Of the patients with ALK/EGFR co-alterations, one immediately progressed after receiving crizotinib for 1.3 months and two had a partial response for 5.7 and 7.3 months, respectively. Three of four patients with ALK/EGFR co-alterations treated with an EGFR TKI achieved one or more responses in different lines of therapy: four patients had a partial response, three with afatinib and one with osimertinib. One patient achieved a complete remission with osimertinib, and one patient was primary refractory to erlotinib. Median PFS during treatment with a first EGFR TKI was 5.8 months (range 3.0-6.9 months). CONCLUSIONS: De novo concurrent ALK/KRAS co-alterations were associated with resistance to ALK TKI treatment in seven out of eight patients. In patients with ALK/EGFR co alterations, outcomes with ALK and EGFR TKIs seem inferior to what would be expected in patients with either alteration alone, but further studies are needed to clarify which patients with ALK/EGFR co-alterations may still benefit from the respective TKI. PMID- 28007628 TI - A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer. AB - OBJECTIVES: Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC. METHODS: Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma. RESULTS: The median follow-up was 57.8 months (range 1.6-160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate (p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity. CONCLUSIONS: We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens. PMID- 28007629 TI - ALK Rearrangement Detected in a Focus of Pulmonary Atypical Adenomatous Hyperplasia. PMID- 28007631 TI - On-demand drug release and hyperthermia therapy applications of thermoresponsive poly-(NIPAAm-co-HMAAm)/polyurethane core-shell nanofiber mat on non-vascular nitinol stents. AB - A functional cover made up of core-shell nanofibers with a unique combination of thermoresponsive polymeric shell and stretchable polymeric core for non-vascular nitinol stents that uses an alternating magnetic field (AMF) to induce heat in the stent for hyperthermia therapy and simultaneously release 5-fluorouracil and/or paclitaxel was designed. Varying the ratios of NIPAAm to HMAAm monomer resulted in different LCST properties for the synthesized copolymer and further utilized for an on-demand drug release. Biocompatibility test using NIH-3T3 fibroblast cells indicates that the composite with drug content is biocompatible and the in-vitro cancer cytotoxicity test using ESO26 and OE21 cancer cells proved that the material shows cancer cytotoxic properties via combination of dual drug and hyperthermia therapy. With this functional material, we propose a tailorable and on-demand drug release with more control that can be employed for a combination drug therapy/single drug therapy combined with hyperthermia therapy for cancer cytotoxicity effect. PMID- 28007630 TI - Improving the Accuracy of Mesothelioma Diagnosis in China. AB - INTRODUCTION: In the Western world, malignant mesothelioma (MM) is most prevalent in the pleura of older males who have been professionally exposed to asbestos. Information about MM from rapidly industrializing countries such as China is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not have experience diagnosing this rare cancer. We recently reported an unusually high incidence of peritoneal MM among eastern Chinese female patients. Here, we review the accuracy of MM diagnoses in China and provide suggestions to improve the accuracy of diagnosis. METHODS: We reviewed 92 pathological diagnosis of MM in 2002-2015 from two reference centers in the province of Zhejiang in eastern China. We performed a large set of immunohistochemistry analyses to increase the reliability of the diagnosis. RESULTS: We confirmed the MM diagnosis in 12 of 34 of the pleural tumors (35.3%), in 38 of 56 of the peritoneal tumors (67.9%), and in two of two of the MMs of the tunica vaginalis (100%). MMs were characterized by tumor cells showing nuclear Wilms tumor 1 and calretinin staining and by strong membranous staining for cytokeratin CAM5.2. The results of staining for the epithelial markers carcinoembryonic antigen, thyroid transcription factor-1, MOC31, BerEP4, p63, p40, paired box 8, ER and PR were negative. BRCA1 associated protein 1 nuclear staining was lost in percentages similar to what has been reported for samples from Western countries. CONCLUSIONS: Our findings suggest that MM especially in its pleural localization-is often misdiagnosed in eastern China. Identifying pitfalls and possible solutions in the pathological diagnosis of MM will affect both the standard of care and research in China. PMID- 28007632 TI - New perspectives in the topical delivery of optimized amphotericin B loaded nanoemulsions using excipients with innate anti-fungal activities: A mechanistic and histopathological investigation. AB - This study aimed to develop nanoemulsions (NEs) for the topical delivery of Amphotericin B using lipids and surfactants with innate antifungal activity. NEs were formulated by a slow spontaneous titration method and characterized for particle size, polydispersity index, zeta potential, zone of inhibition (ZOI), in vitro release, enhanced ex vivo rat skin permeation-deposition, hemolysis followed by interaction with the skin using scanning electron microscopy, and histopathology. The ZOI values of the optimized NEs (ANE3) were 21.8+/-1.5 and 19.7+/-1.2 mm against A. fumigatus and C. albicans, respectively. The explored excipients and optimized ANE3 elicited hemo-biocompatibility. ANE3 exhibited in vitro sustained release and an enhanced flux value (21.62+/-1.6 MUg/cm2/h) as compared to the drug solution and Fungisome without displaying toxicity. Conclusively, ANE3 could be a promising therapeutic approach with enhanced efficacy and safety for treating a wide range of fungal infections topically. PMID- 28007633 TI - The GO-ACTIWE randomized controlled trial - An interdisciplinary study designed to investigate the health effects of active commuting and leisure time physical activity. AB - Regular physical activity is efficacious for improving metabolic health in overweight and obese individuals, yet, many adults lead sedentary lives. Most exercise interventions have targeted leisure time, but physical activity also takes place in other domains of everyday life. Active commuting represents a promising alternative to increase physical activity, but it has yet to be established whether active commuting conveys health benefits on par with leisure time physical activity (LTPA). A 6-month randomized controlled trial was designed to investigate the effects of increased physical activity in transport (bicycling) or leisure time domains (moderate or vigorous intensity endurance exercise). We included 188 overweight and class 1 obese sedentary women and men (20-45years) of which 130 were randomized to either sedentary controls (n=18), active commuting (n=35) or moderate (n=39) or vigorous (n=38) intensity LTPA. At baseline and after 3 and 6months, participants underwent a rigorous 3-day biomedical test regimen followed by free-living measurements. In a sub-sample, physical activity level and energy expenditure were monitored by means of personal assistive technology and the doubly labeled water technique. Additionally, the delivery, reception and routinization of the exercise regimens were investigated by ethnological fieldwork. One year after termination of the intervention, participants will be invited for a follow-up visit to investigate sustained health effects and continuous physical activity adherence. By combining biomedical, technological and humanistic approaches, we aim to understand the health benefits of physical activity in different domains of everyday life, as well as how to improve adherence to physical activity. PMID- 28007634 TI - 2GETHER - The Dual Protection Project: Design and rationale of a randomized controlled trial to increase dual protection strategy selection and adherence among African American adolescent females. AB - BACKGROUND: African American adolescent females are at elevated risk for unintended pregnancy and sexually transmitted infections (STIs). Dual protection (DP) is defined as concurrent prevention of pregnancy and STIs. This can be achieved by abstinence, consistent condom use, or the dual methods of condoms plus an effective non-barrier contraceptive. Previous clinic-based interventions showed short-term effects on increasing dual method use, but evidence of sustained effects on dual method use and decreased incident pregnancies and STIs are lacking. METHODS/DESIGN: This manuscript describes the 2GETHER Project. 2GETHER is a randomized controlled trial of a multi-component intervention to increase dual protection use among sexually active African American females aged 14-19years not desiring pregnancy at a Title X clinic in Atlanta, GA. The intervention is clinic-based and includes a culturally tailored interactive multimedia component and counseling sessions, both to assist in selection of a DP method and to reinforce use of the DP method. The participants are randomized to the study intervention or the standard of care, and followed for 12months to evaluate how the intervention influences DP method selection and adherence, pregnancy and STI incidence, and participants' DP knowledge, intentions, and self efficacy. DISCUSSION: The 2GETHER Project is a novel trial to reduce unintended pregnancies and STIs among African American adolescents. The intervention is unique in the comprehensive and complementary nature of its components and its individual tailoring of provider-patient interaction. If the trial interventions are shown to be effective, then it will be reasonable to assess their scalability and applicability in other populations. PMID- 28007635 TI - PHARMAID study protocol: Randomized controlled trial to assess the impact of integrated pharmaceutical care at a psychosocial intervention on caregiver's burden in Alzheimer's disease or related diseases. AB - INTRODUCTION: Alzheimer's Disease and Related Diseases (ADRD) are associated with a caregiver burden that increases with the progression of the disease. Psychosocial interventions reported a moderate improvement on caregivers' burden. Patients with ADRD and their older caregivers are also exposed to a higher risk of developing drug-related problems. The main objective of the PHARMAID study is to measure the impact of personalized pharmaceutical collaborative care integrated to a multidisciplinary psychosocial program on the burden of caregivers. METHODS: The PHARMAID study is a 18-month randomized controlled trial that started in September 2016. This paper describes the study protocol. PHARMAID plans to enroll 240 dyads, i.e. ADRD patients and caregivers, whose inclusion criteria are: outpatient with mild or major neurocognitive disorders due to ADRD, living at home, receiving support from a family caregiver. Three parallel groups will compare a control group with two experimental groups: psychosocial intervention and integrated pharmaceutical care at a psychosocial intervention. The main outcome is the caregiver's burden assessed by the Zarit Burden Index at 6, 12 and 18months. DISCUSSION: This is the first trial designed to assess the specific impact of the integration of pharmaceutical care in a multidisciplinary psychosocial program on the caregiver's burden. The results will inform policymakers on strategies to implement in the near future. TRIAL REGISTRATION NUMBER: [ClinicalTrials.gov: NCT02802371] Registered in June 2016. PMID- 28007636 TI - Inflammatory landscape of human brain tumors reveals an NFkappaB dependent cytokine pathway associated with mesenchymal glioblastoma. AB - The tumor microenvironment is being increasingly recognized as a key factor in cancer aggressiveness. In this study, we characterized the inflammatory gene signatures altered in glioma cell lines and tumor specimens of differing histological and molecular subtypes. The results showed that glioblastoma multiforme (GBM) shows upregulation of a subset of inflammatory genes when compared to astrocytomas and oligodendrogliomas. With molecular subtypes of GBM, the expression of inflammatory genes is heterogeneous, being enriched in mesenchymal and downregulated in Proneural/GCIMP. Other inflammation-associated processes such as tumor-associated macrophage (TAM) signatures are upregulated in mesenchymal, and a subset of 33 mesenchymal-enriched inflammatory and TAM markers showed correlation with poor survival. We found that various GBM tumor upregulated genes such as IL6, IL8 and CCL2 are also actively expressed in glioma cell lines, playing differential and cooperative roles in promoting proliferation, invasion, angiogenesis and macrophage polarization in vitro. These genes can be stimulated by pathways typically altered in GBM, including the EGFR, PDGFR, MEK1/2-ERK1/2, PI3K/Akt and NFkappaB cascades. Taken together, the results presented herein depict some inflammatory pathways altered in gliomas and highlight potentially relevant targets to therapy improvement. PMID- 28007637 TI - Reproductive toxicity of linuron following gestational exposure in rats and underlying mechanisms. AB - Linuron is a widely used herbicide in agriculture; its endocrine disruptive toxicity has recently received public attention. This study was designed to examine the developmental toxicity of linuron on the reproductive system of male offspring following maternal exposure. Mother rats received oral gavages of linuron, once daily, at the dose of 0, 50, 100, 150 or 200mg/kg, from gestational day (GD)13 to GD18; gonadal organs from GD20 fetuses were examined. Data indicated that exposed male offspring had a significantly shortened anogenital distance. Pathological examination further revealed a lack of fusion in the urogenital fold in treated fetuses, the damaged seminiferous tubules, and the injured Leydig cell ultrastructure. Analysis of serum testosterone concentrations at postnatal day (PND)2 showed a significant dose-related reduction (about 33.7 58.75%, r=-0.838, p<0.05) as compared to controls. Immunohistochemical results demonstrated a significantly reduced expression of enzymes pertinent to the testosterone production including P450scc, 3beta-HSD, and PCNA in Leydig cells (p<0.05). qPCR studies confirmed decreased levels of mRNAs encoding P450scc, 3beta-HSD and PCNA (p<0.05). Taken together, these data suggest that maternal exposure to linuron hampers the male gonadal organ development; this appears to be due to linuron's direct action on the production of testosterone in fetal and postnatal offspring. PMID- 28007638 TI - Immunotoxicological effects of arsenic bioaccumulation on spatial metallomics and cellular enzyme response in the spleen of male Wistar rats after oral intake. AB - Arsenic (As) is a worldwide environmental contaminant, which compromises immunity and causes various associated disorders. To further investigate its immunotoxicity, male Wistar rats were exposed to 100ppm of sodium arsenite (inorganic AsIII) in drinking water for 2 months. Given that metals are significant immune regulators, their content and distribution were analysed in spleen tissues, to then evaluate subsequent changes of redox enzyme responses in spleen parenchyma cells (splenocytes). X-ray fluorescence spectrometry demonstrated As accumulation in both white and red pulps (p<0.005), and As related pulp-dependent modifications of the content of Cu, Ca, Zn and Fe (p<0.01). Correlational path analysis revealed direct effects of As on their spatial distribution (Cu: -0.76, Ca: -0.61, Zn: 0.38; p<0.02). As-exposed splenocytes showed gamma-glutamyltranspeptidase inhibition, peroxidase induction, and variable responses of nitric oxide synthase (p<0.05). Concanavalin A-treated splenocytes (T cell mitogen) were more susceptible in vitro to these As-related enzymatic changes than those treated with lipopolysaccharide (B cell mitogen) (p<0.05). The study thus established the impact of As bioaccumulation on metallic spatial homeostasis in the spleen, and then identified enzymatic dysfunctions in splenocytes. This suggested that arsenic disrupts biometal-dependent immune pathways and redox homeostasis, with mitogen exposure modifying the toxicological response. PMID- 28007639 TI - In vitro combinatory effects of the Alternaria mycotoxins alternariol and altertoxin II and potentially involved miRNAs. AB - Alternariol (AOH) and altertoxin II (ATX II) are mycotoxins formed by Alternaria spp. Since they are expected to co-occur in Alternaria-infested food and feed, we addressed the question of combinatory effects. In addition, potentially involved regulatory microRNAs were surveyed in an exploratory approach. Cytotoxicity measurements in constant ratio combinations of 1:10 or 1:1 (ATX II: AOH) mainly revealed additive effects in HepG2, HT29 and HCEC-1CT cells. Yet, in specific high doses antagonism was found. Microarray analysis of miRNA expression profiles in HepG2 cells indicated different patterns of miRNA regulation by AOH and ATX II, including several miRNA species for which no distinct functions are currently known. Among others, miR-4654, miR-4715_3p and miR-6720_3p were up-regulated by AOH and miR-5583_5p was down-regulated by ATX II. Additionally, miR-1323, involved in hindering DNA repair mechanisms, was decreased by ATX II. Digital droplet PCR (ddPCR) analysis of selected miRNAs indicated regulation of miR-29a by AOH, which might play a role in AOH-induced apoptosis. miR-192 and miR-224 regulation was associated with antagonistic cytotoxic effects of AOH and ATX II combinations. Our study represents the first evaluation on combinatory effects of AOH and ATX II. PMID- 28007640 TI - The insecticide esfenvalerate modulates neuronal excitability in mammalian central nervous system in vitro. AB - Pyrethroids are neurotoxic insecticides showing significant selective toxicity on insects over mammals, but effects on mammalian nervous system are not negligible. These substances act on the voltage-gated sodium channel, prolonging the duration of the open state. The present study focused on the effect of the pyrethroid esfenvalerate on the excitability of neuronal networks in vitro. From isolated rat brain slices, neocortical and hippocampal evoked field potentials were recorded; four concentrations (5-40MUM) of esfenvalerate were tested using in vitro administration of the commercial product Sumi-Alpha 5 EC(r). Basic excitability and short- and long-term synaptic plasticity were studied. Application of the lowest concentration elicited epileptiform discharges in neocortex, while the highest concentration exerted a strong inhibitory effect on the excitability of both brain areas. The amplitude of population spikes in hippocampal slices was decreased by all applied concentrations. Significant decrease in basic excitability was accompanied by increase of paired-pulse facilitation in hippocampus and decreased efficacy of the development of long term potentiation in both regions. Pyrethroids have been scarcely studied on brain slices so far, but our results are in concordance with literary data obtained on other in vitro neuronal test systems. It has been described previously that lower concentrations of pyrethroids lead to overexcitation of neurons and repetitive firing (which is in the background of hyperexcitatory symptoms occurring in case of in vivo exposure). Higher concentrations, however, may lead to depolarization block and to inhibition of neuronal firing. PMID- 28007641 TI - The association between anemia and neurological outcome in hypoxic ischemic brain injury after cardiac arrest. AB - AIM: To examine the relationship between daily mean hemoglobin concentration and neurological outcome in hypoxic ischemic brain injury (HIBI) following cardiac arrest. METHODS: We conducted a single center retrospective observational study using a database of HIBI patients between March 2009 and December 2014. We included all adults admitted to the intensive care unit following an in-hospital or out-of-hospital cardiac arrest. The primary outcome was neurological outcome measured by the Cerebral Performance Category (CPC) at hospital discharge. Multivariable logistic regression was used to analyze the association of mean hemoglobin concentration over 48h and 7 days after the onset of HIBI and discharge CPC. Favorable and unfavorable neurological outcome was dichotomized for a discharge CPC 1-2 vs 3-5, respectively. RESULTS: 118 patients were included in the analysis. Patients with a favorable neurological outcome had higher mean 7 day hemoglobin (115g/L vs 107g/L; p=0.05) compared to those with unfavorable outcome. Multivariate logistic regression controlling for age, time to return of spontaneous circulation and blood transfusion demonstrated that lower mean 48-h hemoglobin concentration was associated with unfavorable outcome (OR 0.69 per 10 unit change in Hgb, 95% CI 0.54-0.88, p<0.01). A repeated analysis using mean Hgb for the first 7 days yielded similar results for unfavorable outcome (OR 0.75 per 10 unit change in Hgb, 95% CI 0.57-0.97, p=0.03). CONCLUSIONS: Lower mean hemoglobin concentration in the first 48h and 7 days following HIBI is associated with a higher odds of unfavorable outcome at hospital discharge. Further study to examine this association is warranted. PMID- 28007642 TI - Suppressing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on chocolate self-administration and reinstatement of chocolate seeking in rats. AB - Recent lines of experimental evidence have indicated that saikosaponin A (SSA) - a bioactive ingredient of the medicinal plant, Bupleurum falcatum L. - suppressed alcohol, morphine, and cocaine self-administration in rats. The present paper was designed to assess whether the protective properties of SSA on addiction-related behaviors generalize to a hyperpalatable food such as a chocolate-flavored beverage (CFB). To this end, rats were initially trained to lever-respond for CFB [5% (w/v) Nesquik(r) powder in water] under fixed ratio (FR) 10 (FR10) schedule of reinforcement. Once lever-responding reached stable levels, rats were treated acutely with two different dose ranges of SSA (0, 0.25, 0.5, and 1mg/kg; 0, 1, 2.5, and 5mg/kg; i.p.) and exposed to the FR10 and progressive ratio (PR) schedules of reinforcement in four independent experiments. The effect of acutely administered SSA (0, 0.25, 0.5, and 1mg/kg; i.p.) on cue-induced reinstatement of seeking behavior for CFB was also assessed. Under the FR and PR schedules of reinforcement, treatment with SSA diminished lever-responding for CFB, amount of self-administered CFB, and breakpoint for CFB. All variables were virtually completely suppressed after treatment with 5mg/kg SSA. Treatment with SSA also suppressed reinstatement of CFB-seeking behavior. No dose of SSA altered rat motor-performance, evaluated exposing all rats to an inverted screen test immediately after the self-administration session. These results demonstrate that acute treatment with SSA potently suppressed several addictive-like behaviors motivated by highly hedonic nourishment. These data extend to a highly rewarding natural stimulus the anti-addictive properties of SSA recently disclosed in rats self-administering alcohol, morphine, and cocaine. PMID- 28007643 TI - Synergistic effect of olfactory ensheathing cells and alpha-crystallin on restoration of adult rat optic nerve injury. AB - Olfactory enshesathing cells (OECs) and alpha-crystallin all can promote axonal regeneration after optic nerve injury. However, their mechanisms were different. Here, we study the synergistic effect of OECs and alpha-crystallin on the optic nerve regeneration. alpha-Crystallin was injected into vitreous cavity, and OECs were transplanted to the optic nerve injury area. The regeneration length of optic nerve were measured by anterograde tracing using cholera toxin subunit B (CTB). The survival of RGCs were assessed by counting the numbers of betaIII tubulin-labeled RGCs in a retinal whole mount. The results that OECs and alpha crystallin all could promoted RGCs survival and axonal regeneration (P<0.01). Especially in the combination group, the length of axonal regeneration was 5.6mm after optic nerve injury for 3 months. These findings indicated that compared to OECs and alpha-crystallin alone, the combination of OECs and alpha-crystallin could promote axonal regeneration more effectively. PMID- 28007644 TI - Association between HTR1B alleles and suicidal ideation in individuals with major depressive disorder. AB - Serotonin receptors, also known as 5-hydroxytryptamine receptors (HTRs), play a role in individuals' vulnerability to major depressive disorders (MDDs) and/or suicide attempts. In the first part of the study, we recruited 789 Taiwanese participants, which included 285 MDD patients, 191 MDD patients with a history of suicide attempts (MS), and 313 controls. The three groups were genotyped to identify HTR single nucleotide polymorphisms (SNPs) and we analyzed the correlations among the three groups. In the second part of the study, which involved a functional test of HTR1B allelic and haplotype variants, another 113 MDD patients were recruited. The rs6298-T allele was more frequent in the MS group than in the control group. The rs1923885-T allele occurred more frequently in the MS group than in the MDD group. Carriers of haplotype GT were estimated to have a 1.774-fold higher risk of suicide attempts. Younger age, alleles rs6296-C, rs6298-T and rs1923885-C, and haplotype CT were associated with a greater risk of MDD. Haplotypes GC and GT were directly associated with a lower risk of suicidal ideation. Haplotypes GC and GT also associated with higher levels of HTR1B mRNA, and haplotype GC was associated with extraversion, which caused a lower risk of suicidal ideation. The rs6296-C allele have directly and indirectly influenced a greater risk of suicidal ideation, which mediated by its negative effect on extraversion. Haplotype GT can be used to identify patients with a higher risk of suicide attempts. The rs6296-C allele lowered the level of HTR1B mRNA, causing individuals with MDD to display more hostility and aggressive behavior, which may lead to suicidal ideation. PMID- 28007645 TI - Parkinson's disease-associated GPR37 receptor regulates cocaine-mediated synaptic depression in corticostriatal synapses. AB - GPR37 is an orphan G protein-coupled receptor highly expressed in the brain. The precise function of GPR37 is still unknown, but a number of evidences indicate it modulates the dopaminergic system. Here, we aimed to determine the role of GPR37 on the control of cocaine-mediated electrophysiological effects (synaptic transmission and short-term plasticity) in corticostriatal synapses. Accordingly, we evaluated basal synaptic transmission and paired-pulse stimulation (PPS) in wild-type and GPR37KO mice slices. Regardless of the genotype, a low concentration of cocaine (2MUM) did not modify basal synaptic transmission. Conversely, a higher dose of cocaine (30MUM) decreased synaptic transmission in both genotypes, although with different intensities: approximately 30% in slices from wild-type mice and 45% in slices from GPR37-KO mice. On the other hand, no differences in PPS ratio were observed between wild-type and GPR37-KO cocaine treated mice. Overall, our data suggest that GPR37 is involved in cocaine-induced modification of basal synaptic transmission without modifying cocaine effects in short-term plasticity. PMID- 28007646 TI - Assessments of sensory plasticity after spinal cord injury across species. AB - Spinal cord injury (SCI) is a multifaceted phenomenon associated with alterations in both motor function and sensory function. A majority of patients with SCI report sensory disturbances, including not only loss of sensation, but in many cases enhanced abnormal sensation, dysesthesia and pain. Development of therapeutics to treat these abnormal sensory changes require common measurement tools that can enable cross-species translation from animal models to human patients. We review the current literature on translational nociception/pain measurement in SCI and discuss areas for further development. Although a number of tools exist for measuring both segmental and affective sensory changes, we conclude that there is a pressing need for better, integrative measurement of nociception/pain outcomes across species to enhance precise therapeutic innovation for sensory dysfunction in SCI. PMID- 28007648 TI - Minocycline attenuates noise-induced hearing loss in rats. AB - Noise-induced hearing loss (NIHL) is a serious health concern and prevention of hair cell death or therapeutic intervention at the early stage of NIHL is critical to preserve hearing. Minocycline is a semi-synthetic derivative of tetracycline and has been shown to have otoprotective effects in ototoxic drug induced hearing impairment, however, whether minocycline can protect against NIHL has not been investigated. The present study demonstrated elevated ABR (auditory brainstem response) thresholds and outer hair cell loss following traumatic noise exposure, which was mitigated by intraperitoneal administration of minocycline (45mg/kg/d) for 5 consecutive days. In conclusion, the present study demonstrated that minocycline, a clinically approved drug with a good safety profile, can attenuate NIHL in rats and may potentially be used for treatment of hearing loss in clinic. PMID- 28007650 TI - The impact of physical activity on motor preparation in young adults. AB - Regular physical activity benefits brain health and function. Physical activity performed by young adults is declining. However, the influence of diminished physical activity on cognitive performance and motor preparation in young adults remains unclear. This study measured changes in behavior and brain activity during preparation and performance of simple (SRT) and choice (CRT) reaction time tasks in less and more physically active young adults. Electromyograms were obtained from left and right first dorsal interossei muscles. Midline and hemisphere-specific electroencephalograms were analyzed from frontal and central scalp regions in 11 less- and 11 more-active participants. Physical activity level was assessed by questionnaire (IPAQ). Reaction and premotor times were slower for SRT and CRT tasks in less active participants. No statistically significant difference in contingent negative variation (CNV) amplitude was present between groups. Hemisphere-specific CNV amplitude over frontal scalp regions was evident for both less and more active participants for right hand SRT, whereas only the more active group showed hemisphere-specific CNVs for left hand SRT. Decreased levels of physical activity in young adults may be detrimental for cognitive processing and motor function measured by reaction time and changes in brain activity. PMID- 28007649 TI - Nicotinic receptors modulate the onset of reactive oxygen species production and mitochondrial dysfunction evoked by glutamate uptake block in the rat hypoglossal nucleus. AB - In several neurodegenerative diseases, glutamate-mediated excitotoxicity is considered to be a major process to initiate cell degeneration. Indeed, subsequent to excessive glutamate receptor stimulation, reactive oxygen species (ROS) generation and mitochondrial dysfunction are regarded as two major gateways leading to neuron death. These processes are mimicked in an in vitro model of rat brainstem slice when excitotoxicity is induced by DL-threo-beta benzyloxyaspartate (TBOA), a specific glutamate-uptake blocker that increases extracellular glutamate. Our recent study has demonstrated that brainstem hypoglossal motoneurons, which are very vulnerable to this damage, were neuroprotected from excitotoxicity with nicotine application through the activation of nicotinic acetylcholine receptors (nAChRs) and subsequent inhibition of ROS and mitochondrial dysfunction. The present study examined if endogenous cholinergic activity exerted any protective effect in this pathophysiological model and how ROS production (estimated with rhodamine fluorescence) and mitochondrial dysfunction (measured as methyltetrazolium reduction) were time-related during the early phase of excitotoxicity (0-4h). nAChR antagonists did not modify TBOA-evoked ROS production (that was nearly doubled over control) or mitochondrial impairment (25% decline), suggesting that intrinsic nAChR activity was insufficient to contrast excitotoxicity and needed further stimulation with nicotine to become effective. ROS production always preceded mitochondrial dysfunction by about 2h. Nicotine prevented both ROS production and mitochondrial metabolic depression with a delayed action that alluded to a complex chain of events targeting these two lesional processes. The present data indicate a relatively wide time frame during which strong nAChR activation can arrest a runaway neurotoxic process leading to cell death. PMID- 28007651 TI - Alternative splicing in nicotinic acetylcholine receptor subunits from Locusta migratoria and its influence on acetylcholine potencies. AB - Due to the great abundance within insect central nervous system (CNS), nicotinic acetylcholine receptors (nAChRs) play key roles in insect CNS, which makes it to be the targets of several classes of insecticides, such as neonicotinoids. Insect nAChRs are pentameric complexes consisting of five subunits, and a dozen subunits in one insect species can theoretically comprise diverse nAChRs. The alternative splicing in insect nAChR subunits may increase the diversity of insect nAChRs. In the oriental migratory locust (Locusta migratoria manilensis Meyen), a model insect species with agricultural importance, the alternative splicing was found in six alpha subunits among nine alpha and two beta subunits, such as missing conserved residues in Loop D from Localpha1, Localpha6 and Localpha9, a 34 residue insertion in Localpha8 cytoplasmic loop, and truncated transcripts for Localpha4, Localpha7 and Localpha9. Hybrid nAChRs were successfully constructed in Xenopus oocytes through co-expression with rat beta2 and one alpha subunit from L. migratoria, which included Localpha1, Localpha2, Localpha3, Localpha4, Localpha5, Localpha8 and Localpha9. Influences of alternative splicing in Localpha1, Localpha8 and Localpha9 on acetylcholine potency were tested on hybrid nAChRs. The alternative splicing in Localpha1 and Localpha9 could increase acetylcholine sensitivities on recombinant receptors, while the splicing in Localpha8 showed significant influences on the current amplitudes of oocytes. The results revealed that the alternative splicing at or close to the ligand-binding sites, as well as at cytoplasmic regions away from the ligand-binding sites, in insect nAChR subunits would change the agonist potencies on the receptors, which consequently increased nAChR diversity in functional and pharmacological properties. PMID- 28007647 TI - Rewiring the spinal cord: Direct and indirect strategies. AB - Spinal cord injury is currently incurable. Treatment is limited to minimizing secondary complications and maximizing residual function by rehabilitation. Neurologic recovery is prevented by the poor intrinsic regenerative capacity of neurons in the adult central nervous system and by the presence of growth inhibitors in the adult brain and spinal cord. Here we identify three approaches to rewire the spinal cord after injury: axonal regeneration (direct endogenous reconnection), axonal sprouting (indirect endogenous reconnection) and neural stem cell transplantation (indirect exogenous reconnection). Regeneration and sprouting of axonal fibers can be both enhanced through the neutralization of myelin- and extracellular matrix-associated inhibitors described in the first part of this review. Alternatively, in the second part we focus on the formation of a novel circuit through the grafting of neural stem cells in the lesion site. Transplanted neural stem cells differentiate in vivo into neurons and glial cells which form an intermediate station between the rostral and caudal segment of the recipient spinal cord. In particular, here we describe how neural stem cells derived neurons are endowed with the ability to extend long-distance axons to regain the transmission of motor and sensory information. PMID- 28007653 TI - Poststreptococcal syndrome presenting as posterior scleritis in a child. AB - Posterior scleritis in children is very rare. In contrast to the adult form, pediatric posterior scleritis has not previously been associated with any systemic disorder. We describe a case of an 11-year-old girl who presented with left eye pain and redness and was found to have posterior scleritis on ultrasonography. Her laboratory work-up revealed a highly elevated antistreptolysin O titer; the rest of her serologic and radiologic evaluation was unremarkable. She was diagnosed with presumed poststreptococcal posterior scleritis and improved with a slow taper of oral steroids. PMID- 28007652 TI - Characteristics of sulfasalazine-induced cytotoxicity in C6 rat glioma cells. AB - Glioblastoma is the most aggressive primary brain tumor. Surgical resection, radiotherapy and temozolomide (TMZ), an alkylating agent, is the standard of care. Glioma cells may synthetize the antioxidant glutathione by importing cystine through a cystine/glutamate antiporter, which is inhibited by sulfasalazine (SAS). C6 rat glioma cells are largely used in in vitro and in vivo models for developing new glioblastoma treatment strategies. We treated C6 cells with 25MUM TMZ and/or 0.25mM or 0.5mM SAS for 1, 3 or 5days and evaluated viability, apoptosis, total glutathione levels and metalloproteinase MMP2 and MMP9 activities. TMZ treatment slightly reduced cell viability by 9.5% compared with vehicle treatment (0.1% dimethyl sulfoxide) only after 5days. In addition, TMZ did not modify apoptosis, glutathione content or MMP2/MMP9 activities. The 0.25mM SAS treatment reduced cell viability by 31.1% and 19.4% after the first and third days, respectively. This effect was not sustained after the fifth day of treatment. In contrast, 0.5mM SAS caused a reduction in cell viability by nearly 100%, total glutathione depletion and apoptosis induction. Moreover, the effect of 0.5mM SAS was greater than that of TMZ in terms of cell viability reduction, total glutathione depletion and apoptosis induction. MMP9 activity was reduced by 40% after 5days of 25MUM TMZ and 0.5mM SAS co-administration. Considering previous data from our group, we verified that the cellular viability results differed between rat and human cells; C6 cells were more vulnerable to 0.5mM SAS than human A172 and T98G glioblastoma lineages. We propose that C6 cells may not be appropriate for studying human glioblastoma and that the results obtained using these cells should be interpreted with caution. PMID- 28007654 TI - Archaeal phospholipids: Structural properties and biosynthesis. AB - Phospholipids are major components of the cellular membranes present in all living organisms. They typically form a lipid bilayer that embroiders the cell or cellular organelles, constitute a barrier for ions and small solutes and form a matrix that supports the function of membrane proteins. The chemical composition of the membrane phospholipids present in the two prokaryotic domains Archaea and Bacteria are vastly different. Archaeal lipids are composed of highly-methylated isoprenoid chains that are ether-linked to a glycerol-1-phosphate backbone while bacterial phospholipids consist of straight fatty acids bound by ester bonds to the enantiomeric glycerol-3-phosphate backbone. The chemical structure of the archaeal lipids and their compositional diversity ensures the required stability at extreme environmental conditions as many archaea thrive at such conditions including high or low temperature, high salinity and extreme acidic or alkaline pH values. However, not all archaea are extremophiles, and the presence of ether linked phospholipids is a phylogenetic marker that distinguishes Archaea from other life forms. During the past decade, our understanding of the biosynthesis of archaeal lipids has progressed resulting in the characterization of the main biosynthetic steps of the pathway including the reconstitution of lipid biosynthesis in vitro. Here we describe the chemical and physical properties of archaeal lipids and membranes derived thereof, summarize the existing knowledge about the enzymology of the archaeal lipid biosynthetic pathway and discuss evolutionary theories associated with the "Lipid Divide" that resulted in the differentiation of bacterial and archaeal organisms. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID- 28007655 TI - Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion. AB - There is an abiding need for innovative approaches to the prevention of graft versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. We also determined the effects of ixazomib in a murine GvHD model. Although ixazomib suppressed naive human DC maturation, it had only a limited effect on cell viability. Ixazomib decreased pro-inflammatory cytokine production of resting DCs. This effect was diminished or reversed when DCs were pre-stimulated. In vivo, ixazomib administered post-transplantation on days +1 and +4 or days -1, +2, and +5 ameliorated GvHD in comparison to the GvHD group. Although a fraction of mice treated according to the prolonged schedule died abruptly after the day +5 treatment, both schedules resulted in improved overall survival. When we examined the effects of ixazomib on splenic cells and serum cytokines, we found that ixazomib exerted complex schedule-dependent immunomodulatory effects. Our study provides a rationale for the potential use of ixazomib in the prevention of GvHD. PMID- 28007656 TI - Proinsulin C-peptide modulates the expression of ERK1/2, type I collagen and RANKL in human osteoblast-like cells (Saos-2). AB - A lower bone mass accompanied by a higher bone fragility with increased risk of fracture are observed in individuals with type 1 diabetes mellitus. Low C-peptide levels are associated with low lumbar mineral density in postmenopausal woman. In this work, we investigated the role of C-peptide on the osteoblast cell biology in vitro. We examined intracellular pathways and we found that C peptide activates ERK1/2 in human osteoblast-like cells (Saos-2). We also observed that proinsulin C-peptide prevents a reduction of type I collagen expression and decreases, in combination with insulin, receptor activator of nuclear factor kappaB (RANKL) levels. In this work we show for the first time that Cpeptide activates a specific intracellular pathway in osteoblasts and it modulates the expression of protein involved in bone remodeling. Our results suggest that both C-peptide may have a role in bone metabolism. Further studies are needing to fully clarify its role. PMID- 28007658 TI - The role of microRNAs in the pathophysiology of adrenal tumors. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression in a sequence-specific manner. Due to its association with an assortment of diseases, miRNAs have been extensively studied in the last decade. In this review, the current understanding of the role of miRNAs in the pathophysiology of adrenal tumors is discussed. The recent contributions of high-throughput miRNA profiling studies have identified miRNAs that have functional and molecular roles in adrenal tumorigenesis. With respect to the biological heterogeneity of adrenal tumors and the limitations of the current treatments, an improved understanding of miRNAs may hold potential diagnostic and therapeutic value to facilitate better clinical management. PMID- 28007657 TI - Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats. AB - Studies on the role of hormones in male reproductive aging have traditionally focused on testosterone, but estradiol (E2) also plays important roles in the control of masculine physiology and behavior. Our goal was to examine the effects of E2 on the expression of genes selected for E2-sensitivity, involvement in behavioral neuroendocrine functions, and impairments with aging. Mature adult (MAT, 5 mo) and aged (AG, 18 mo) Sprague-Dawley male rats were castrated, implanted with either vehicle or E2 subcutaneous capsules, and euthanized one month later. Bilateral punches were taken from the bed nucleus of the stria terminalis (BnST), posterodorsal medial amygdala (MePD) and the preoptic area (POA). RNA was extracted, and expression of 48 genes analyzed by qPCR using Taqman low-density arrays. Results showed that effects of age and E2 were age- and region-specific. In the POA, 5 genes were increased with E2 compared to vehicle, and there were no age effects. By contrast the BnST showed primarily age related changes, with 6 genes decreasing with age. The MePD had 5 genes that were higher in aged than mature males, and 17 genes with significant interactions between age and E2. Gene families identified in the MePD included nuclear hormone receptors, neurotransmitters and neuropeptides and their receptors. Ten serum hormones were assayed in these same males, with results revealing both age- and E2-effects, in several cases quite profound. These results support the idea that the male brain continues to be highly sensitive to estradiol even with aging, but the nature of the response can be substantially different in mature and aging animals. PMID- 28007659 TI - Retrospective study of clinical and lesion characteristics of patients undergoing surgical treatment for Pulmonary Tuberculosis in Georgia. AB - OBJECTIVES: Our aim was to retrospectively compare clinical data and characteristics of removed lesions of the cohort of patients undergoing therapeutical surgery for their tuberculosis. DESIGN AND METHODS: Demographic and epidemiological details, clinical data, data on the surgery performed, macroscopic characteristics of the TB lesions removed, and outcome were recorded retrospectively from the 137 patients who underwent therapeutical surgery for their TB in Tbilisi, Georgia during 2014 and 2015. RESULTS: Men represented 70% of the included patients, presented more comorbidities and underwent operation earlier in terms of days between diagnostic and surgery. Women underwent operation at younger ages, and in MDR/XDR-TB cases, showed higher percentages of sputum conversion at >2 months and of fresh necrosis in the surgical specimens, suggesting a worse evolution. Half of cases were MDR/XDR-TB cases. In spite of being considered microbiologically cured according to WHO, a non despricable percentage of cases showed viable bacilli in the surgical specimen. Even if no causality could be statistically demonstrated, differences could be encountered according to gender and drug susceptibility of the responsible strains. CONCLUSIONS: According to our results, host factors such as gender, type of necrosis found in the lesions, size of lesions and presence of viable bacilli in the surgical specimen, should be included in future studies on therapeutical surgery of TB. As most of studies are done in MDR/XDR-TB, more data on DS-TB operated cases are needed. Our results also highlight that, in spite of achieving the microbiologically cured status, sterilization might not occur, and thus new biomarkers and new methods to evaluate the healing process of TB patients are urgently needed and radiological assays should be taken into account. PMID- 28007660 TI - Second line drug susceptibility testing to inform the treatment of rifampin resistant tuberculosis: a quantitative perspective. AB - Treatment failure and resistance amplification are common among patients with rifampin-resistant tuberculosis (TB). Drug susceptibility testing (DST) for second-line drugs is recommended for these patients, but logistical difficulties have impeded widespread implementation of second-line DST in many settings. To provide a quantitative perspective on the decision to scale up second-line DST, we synthesize literature on the prevalence of second-line drug resistance, the expected clinical and epidemiologic benefits of using second-line DST to ensure that patients with rifampin-resistant TB receive effective regimens, and the costs of implementing (or not implementing) second-line DST for all individuals diagnosed with rifampin-resistant TB. We conclude that, in most settings, second line DST could substantially improve treatment outcomes for patients with rifampin-resistant TB, reduce transmission of drug-resistant TB, prevent amplification of drug resistance, and be affordable or even cost-saving. Given the large investment made in each patient treated for rifampin-resistant TB, these payoffs would come at relatively small incremental cost. These anticipated benefits likely justify addressing the real challenges faced in implementing second-line DST in most high-burden settings. PMID- 28007662 TI - Nitric oxide-mediated resistance to photodynamic therapy in a human breast tumor xenograft model: Improved outcome with NOS2 inhibitors. AB - Many malignant tumors employ iNOS-derived NO to resist eradication by chemotherapeutic agents or ionizing radiation. In this study, we determined whether human breast carcinoma MDA-MB-231 cells in vitro and in vivo as tumor xenografts would exploit endogenous iNOS/NO to resist the cytotoxic effects of 5 aminolevulinic acid (ALA)-based photodynamic therapy (PDT). Broad band visible irradiation of ALA-treated cells resulted in a marked after-light upregulation of iNOS protein which persisted for at least 24 h. Apoptotic killing of ALA/light challenged cells was significantly enhanced by iNOS inhibitors (1400W, GW274150) and a NO trap (cPTIO), implying that stress-induced iNOS/NO was acting cytoprotectively. We found that cells surviving the photostress proliferated and migrated more rapidly than controls in 1400W- and cPTIO-inhibitable fashion, indicating iNOS/NO involvement. Female SCID mice bearing MDA-MB-231 tumors were used for animal model experiments. ALA-PDT with a 633 nm light source caused a significant reduction in post-irradiation tumor growth relative to light-only controls, which was further reduced by administration of 1400W or GW274150, whereas 1400W had little or no effect on controls. Immunoblot analyses of tumor samples revealed a progressive post-PDT upregulation of iNOS, which reached >5 times the control level after six days. Correspondingly, the nitrite/nitrate level in post-PDT tumor samples was substantially higher than that in controls. In addition, a 1400W-inhibitable upregulation of pro-survival/progression effector proteins such as Bcl-xL, Survivin, and S100A4 was observed after in vitro and in vivo ALA-PDT. This is the first known study to demonstrate iNOS/NO induced resistance to PDT in an in vivo human tumor model. PMID- 28007663 TI - Dynamic interactions between corticosterone, corticosteroid binding globulin and testosterone in response to capture stress in male breeding Eurasian tree sparrows. AB - In birds, corticosterone (CORT), testosterone (T), and corticosteroid binding globulin (CBG) are involved in modulating the trade-off between reproduction and survival. In response to acute stress, increased total plasma CORT is a ubiquitous phenomenon while T levels can decrease, or remain unchanged. Since CORT and T bind competitively with CBG in birds, the underlying regulatory mechanisms and consequences of their dynamic interactions remain largely unknown. Here, we studied the dynamic changes of total CORT, T, and CBG, and estimated free and bound CORT and T in response to capture stress in male Eurasian tree sparrows (Passer montanus) across the nest building, egg-laying, and nestling stages. We predicted that free, bound and total hormone concentrations would increase for CORT and decrease for T in response to acute stress, and the relative magnitude of these changes would vary with life history stage. We found that baseline and stressed-induced CORT values did not vary across breeding sub stages. However, total and bound CORT increased with stress while free remained unchanged. Baseline levels of total, free and bound T were highest during the nest building and it was the only stage in which all measures of T were affected by stress. Regardless of breeding stage or restraint stress, we did not detect a significant correlation between CORT and T. CBG was found to be mostly unoccupied by steroid hormones under stress and stress-free conditions and this likely provided an adequate buffer for changes in free levels of CORT and T during unpredictable environmental perturbations. PMID- 28007661 TI - Development and stem cells of the esophagus. AB - The esophagus is derived from the anterior portion of the developmental intermediate foregut, a structure that also gives rise to other organs including the trachea, lung, and stomach. Genetic studies have shown that multiple signaling pathways (e.g. Bmp) and transcription factors (e.g. SOX2) are required for the separation of the esophagus from the neighboring respiratory system. Notably, some of these signaling pathways and transcription factors continue to play essential roles in the subsequent morphogenesis of the esophageal epithelium which undergoes a simple columnar-to-stratified squamous conversion. Reactivation of the relevant signaling pathways has also been associated with pathogenesis of esophageal diseases that affect the epithelium and its stem cells in adults. In this review we will summarize these findings. We will also discuss new data regarding the cell-of-origin for the striated and smooth muscles surrounding the esophagus and how they are differentiated from the mesenchyme during development. PMID- 28007664 TI - Effects of seasonal acclimatization on action potentials and sarcolemmal K+ currents in roach (Rutilus rutilus) cardiac myocytes. AB - Temperature sensitivity of electrical excitability is a potential limiting factor for high temperature tolerance of ectotherms. The present study examines whether heat resistance of electrical excitability of cardiac myocytes is modified by seasonal thermal acclimatization in roach (Rutilus rutilus), a eurythermal teleost species. To this end, temperature dependencies of ventricular action potentials (APs), and atrial and ventricular K+ currents were measured from winter-acclimatized (WiR) and summer-acclimatized (SuR) roach. Under patch-clamp recording conditions, ventricular APs could be triggered over a wide range of temperatures (4-43 degrees C) with prominent changes in resting membrane potential (RMP), AP duration and amplitude. In general, APs of SuR were slightly more tolerant to high temperatures than those of WiR, e.g. the break point temperature (TBP) of RMP was 37.6+/-0.4 degrees C in WiR and 41+/-1 degrees C in SuR (p<0.05). Of the two major cardiac K+ currents, the inward rectifier K+ current (IK1) was particularly heat resistant in both SuR (TBP 39.4+/-0.4 degrees C) and WiR (TBP 40.0+/-0.4 degrees C) ventricular myocytes. The delayed rectifier K+ current (IKr) was not as heat resistant as IK1. Surprisingly, IKr of WiR tolerated heat better (TBP 31.9+/-0.8 degrees C) than IKr of SuR (TBP 24.1+/-0.5 degrees C) (p<0.05). IKr (Erg2) channel transcripts of both atrial and ventricular myocytes were up-regulated in WiR. IK1 (Kir2) channel transcripts were not affected by seasonal acclimatization, although ventricular IK1 current was up-regulated in summer. Collectively, these findings show that thermal tolerance limits of K+ currents in isolated myocytes between seasonally acclimatized roach are much less pronounced than the heat sensitivity of ECG variables in intact fish. PMID- 28007665 TI - CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation. AB - Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti CD25 therapy may augment alloreactivity and antitumor immunity. PMID- 28007666 TI - Real Time Immunophenotyping of Leukocyte Subsets Early after Double Cord Blood Transplantation Predicts Graft Function. AB - Cord blood transplantation (CBT) recipients are at increased risk for delayed engraftment and primary graft failure, complications that are often indistinguishable early post-transplantation. Current assays fail to accurately identify recipients with slow hematopoietic recovery and distinguish them from those with pending graft failure. To address this, we prospectively examined the kinetics of immune cell subset recovery in the peripheral blood of 39 patients on days +7 and +14 after double-unit CBT (dCBT) by multiparametric flow cytometry analysis, which we term real-time immunophenotyping (RTIP). RTIP analysis at day +14 revealed distinctive patterns of reconstitution and, importantly, identified patients with slow hematopoietic recovery who went on to engraft. Strikingly, higher absolute numbers of circulating monocytes and natural killer cells at day +14 were predictive of engraftment, but only the absolute number of circulating monocytes was significantly correlated with time to engraftment. This is the first evidence that RTIP on patient peripheral blood mononuclear cells early after dCBT is technically feasible and can be used as a "signature" for predicting the kinetics of hematopoietic recovery. Furthermore, RTIP is a time- and cost-efficient methodology that has the potential to become a clinically feasible diagnostic tool to guide therapeutic interventions in high-risk patients; therefore, its utility should be evaluated in a large cohort of patients. PMID- 28007667 TI - Early localised morphea presenting as painful abdominal erythema. PMID- 28007668 TI - Complete remission of angiolymphoid hyperplasia with eosinophilia using topical tacrolimus. PMID- 28007669 TI - A case of aseptic meningitis without neck rigidity occurring in a metastatic melanoma patient treated with ipilimumab. PMID- 28007670 TI - Maculopapular eruption caused by doripenem. PMID- 28007671 TI - Magnesium-based interventions for normal kidney function and chronic kidney disease. AB - Magnesium (Mg) is one of the most important cations in the body, playing an essential role in biological systems as co-factor for more than 300 essential enzymatic reactions. In the general population, low levels of Mg are associated with a high risk of cardio-vascular disease (CVD). Despite the accumulating literature data, the effect of Mg administration on mortality in chronic kidney disease (CKD) patients has never been investigated as a primary end-point. We conducted a systematic search of studies assessing the benefits and harms of Mg in CKD (stages 1 to 5 and 5D), and considered all randomized controlled trials (RCTs) and quasi-RCTs evaluating Mg-based interventions in CKD. As a phosphate binder, Mg salts offer a plausible opportunity for doubly favorable effects via reduction of intestinal phosphate absorption and addition of potentially beneficial effects via increasing circulating Mg levels. Mg supplementation might have a favorable effect on vascular calcification, although evidence for this is very slight. Although longitudinal data describe an association between low serum Mg levels and increased total and cardiovascular mortality, in patients with CKD, the existing RCTs reporting the effect of Mg supplementation on mortality failed to demonstrate any favorable effect. As with many other variables that influence hard end-points in nephrology, the role of Mg in CKD patients needs to be investigated in more depth. Additional research that is well-designed and directly targeting the role of Mg is needed as a consequence of limited existing evidence. PMID- 28007672 TI - Coexistence of acquired perforating dermatosis and bullous pemphigoid: three cases. PMID- 28007673 TI - Rubber: new allergens and preventive measures. AB - Natural rubber latex (NRL) and rubber accelerators are well-known causes of occupational skin diseases. The latest epidemiological data on rubber allergy show that rubber additives are still among the allergens most strongly associated with occupational contact dermatitis, however, a decrease in NRL allergy has been confirmed. A review of recent publications on rubber allergens based on the Pubmed database is presented. New glove manufacturing processes have been developed, such as low-protein natural rubber gloves, vulcanisation accelerator free gloves, or specific-purpose gloves containing antimicrobial agents or moisturisers. Several websites provide information on allergens found in gloves and/or glove choice according to occupation. PMID- 28007674 TI - The current role of in vivo reflectance confocal microscopy within the continuum of actinic keratosis and squamous cell carcinoma: a systematic review. AB - BACKGROUND: Clinical differentiation between actinic keratosis (AK), squamous cell carcinoma (SCC) in situ, and invasive SCC and its variants may be difficult. Reflectance confocal microscopy (RCM) is a non-invasive technique for in vivo skin imaging. OBJECTIVES: To explicate the diagnostic and monitoring use of RCM within the spectrum of AK and SCC, and evaluate the accuracy of RCM for these diagnoses relative to histopathology. MATERIALS & METHODS: A systematic literature search was performed in PubMed, EMBASE, the Cochrane Library, and Web of Science databases. The quality was assessed using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. RESULTS: Twenty-five eligible studies were included. Different diagnostic RCM features have been described for AK, actinic cheilitis (AC), erythroplasia of Queyrat, Bowen disease, invasive SCC, and keratoacanthoma (KA). The overall range of sensitivity and specificity of RCM for the diagnosis of SCC, AK, SCC in situ, and KA was 79-100% and 78-100%, respectively. CONCLUSION: The current literature describes the use of RCM for diagnosing AK, AC, erythroplasia of Queyrat, Bowen disease, invasive SCC, and KA, as well as for monitoring treatments of AK, with good accuracy. Unfortunately, studies with high methodological quality are lacking. Pre-treatment of hyperkeratotic lesions and uniform definitions of RCM features are required to simplify the differentiation between AKs, SCC in situ, and SCC and its variants in clinical practice. PMID- 28007675 TI - Disseminated acantholytic acanthomas in a patient with bullous pemphigoid. PMID- 28007676 TI - Volume 26, 2016. PMID- 28007677 TI - Colonic acute malignant obstructions: effectiveness of self-expanding metallic stent as bridge to surgery. AB - BACKGROUND/AIMS: Bowel obstruction is a frequent event in patients with adenocarcinoma, affecting, in some series, almost one-third of the patients. In the last decades, in addition to surgery, self-expanding metallic stents (SEMSs) are available both as a bridge to surgery (BTS) or palliation. The aim of our study was to demonstrate the safety and efficacy of the use of SEMSs as BTS in selected patients with acute colonic malignant obstructions. MATERIALS AND METHODS: In total, 125 patients with malignant colonic obstruction who underwent emergency surgery or stent insertion were retrospectively enrolled in our study; 62 patients underwent surgery initially, whereas 62 were subjected to stenting as BTS. The 6-month and 1-year survival rates after the procedure (stenting or surgery) and short-term and long-term complication rates were considered as primary endpoints; the recanalization rate after Hartmann's procedure and the length of hospitalization were considered as secondary endpoints. RESULTS: On comparing the surgery group (SG) and the BTS group (BG), we observed a lower short-term complication rate (p<0.05) and a reduction in the mean hospital stay (16.1+/-7.7 vs. 13.5+/-3.0, p<0.05) in the latter. No differences in long-term complications were found. The recanalization rate after Hartmann's procedure was higher in BG than in SG, although this was not statistically significant. CONCLUSION: Our experience shows that SEMS insertion is a safe and effective technique in selected patients with colonic malignant obstruction; the reduction in hospital stay and short-term complications in BG is an important cost-saving aim. PMID- 28007678 TI - Use of probiotics as an adjuvant to sequential H. pylori eradication therapy: impact on eradication rates, treatment resistance, treatment-related side effects, and patient compliance. AB - BACKGROUND/AIMS: To evaluate the effect of probiotics administered as an adjuvant to sequential Helicobacter pylori (H. pylori) eradication therapy on treatment outcome and patient compliance. MATERIALS AND METHODS: In total, 159 patients with H. pylori infection receiving sequential H. pylori eradication therapy were included in this randomized placebo-controlled study. Starting from day 0 of sequential eradication therapy (ERA), patients in the ERA+probiotic group [n=53, mean (SD) age: 47.7 (14.0) years, 54.7% were females] also received a probiotic supplement with Bifidobacterium animalis subsp. lactis B94 (1 capsule/day), patients in the ERA+placebo group [n=52, mean (SD) age: 46.4 (13.4) years, 51.9% were males] received placebo treatment (1 capsule/day), and patients in the ERA only group [n=54, mean (SD) age: 46.3 (11.9) years, 55.6% were females] received no additional treatments. Eradication rates, patient compliance, and side effects of eradication therapy were recorded in each treatment group. RESULTS: Significantly higher eradication rates were noted in the ERA+probiotic group (86.8% vs. 70.8%, p=0.025) than in the combined ERA (ERA-only and ERA-placebo) group. Non-compliance with anti-H. pylori treatment was noted in 24 (15.1%) of 159 patients. Lower rates of first week treatment non-compliance due to diarrhea (1.88% vs. 12.26%, p=0.036) were noted in the ERA+probiotic group than in the combined ERA (ERA-only and ERA-placebo) group. Treatment resistance (p: 0.389) was similar between the groups, indicating pure antibiotic resistance without any compliance problems. The number needed to treat for an additional beneficial outcome (NNTB) was 6.2 (CI 95%, 3.5 to 28.9) for probiotic use. CONCLUSION: In conclusion, adjuvant administration of probiotic (B. animalis subsp. lactis) in 2 week sequential H. pylori eradication therapy is associated with a higher H. pylori eradication rate, lower first week diarrhea-related treatment discontinuation rates, less common self-reported side effects, and higher treatment compliance. PMID- 28007679 TI - Ten-year analysis of hepatitis-related papers in the Middle East: a web of science-based scientometric study. AB - BACKGROUND/AIMS: In the Middle East (ME), the proper understanding of hepatitis, especially viral hepatitis, is considered to be extremely important. However, no published paper has investigated the status of hepatitis-related research in the ME. A scientometric analysis based on the Web of Science database was conducted on hepatitis-related papers in the ME to determine the current status of research on this topic. MATERIALS AND METHODS: A scientometric analysis using the Web of Science database, specifically articles from the Expanded Science Citation Index and Social Sciences Citation Index, was conducted on work published between 2005 and 2014 using the keyword "hepatitis" in conjunction with the names of countries in the ME. RESULTS: Of 103,096 papers that used the word "hepatitis" in their title, abstract, or keywords, only 6,540 papers (6.34%) were associated with countries in the ME. Turkey, Iran, Egypt, Israel, and Saudi Arabia were the top five countries in which hepatitis-related papers were published. Most papers on hepatitis A, B, and D and autoimmune hepatitis were published in Turkey, and most papers on hepatitis C were published in Egypt. CONCLUSION: We believe that both the quantity and the quality of hepatitis-related papers in this region should be improved. Implementing multicenter and international research projects, holding conferences and congress meetings, conducting educational workshops, and establishing high-quality medical research journals in the region will help countries in the ME address this issue effectively. PMID- 28007680 TI - Accurate biopsy of bile duct without destroying duodenal papilla. PMID- 28007681 TI - Lipoma-induced colonic intussusception in mobile cecum syndrome. PMID- 28007682 TI - An inflammatory myofibroblastic tumor of the small intestine in a 15-year-old girl. PMID- 28007683 TI - Narrow band imaging helps identify the ectopic opening of the common bile duct during endoscopic retrograde cholangiopancreatography. PMID- 28007684 TI - Percutaneous ultrasound-guided bowel biopsy of a pseudokidney mass. PMID- 28007685 TI - Early prediction of organ failure under the revised Atlanta classification. AB - BACKGROUND/AIMS: This study aimed to compare the ability of conventional laboratory markers and scoring systems to early predict organ failure (OF) and to differentiate between transient and persistent OF in patients with acute pancreatitis (AP) using the revised Atlanta classification. MATERIALS AND METHODS: We retrospectively analyzed the medical records of 214 patients with AP between January 2014 and July 2015. The predictive values of laboratory markers were analyzed. The predictive accuracy of individual markers, extrapancreatic inflammation on computed tomography (EPIC), acute physiology and chronic health evaluation II (APACHE II), and bedside index for severity in acute pancreatitis (BISAP) scores were measured using the area under the receiver operating characteristic curve (AUROC). RESULTS: OF was diagnosed in 32 (15%) patients and persistent OF in 14 (6.5%). There were statistically significant differences between patients with and without OF with respect to white blood cell count, creatinine, blood urea nitrogen, lactate dehydrogenase, C-reactive protein, calcium (Ca), arterial partial pressure of oxygen (PaO2), base excess (BE), APACHE II, BISAP scores, and EPIC scores. Logistic regression analysis identified Ca, PaO2, and BE as independent predictors of OF. Using AUROC, the EPIC score had the highest accuracy for the early prediction of OF, which was 0.82. No significant differences were detected between patients with transient and persistent OF. CONCLUSION: Several laboratory markers and score systems were useful for the early prediction of OF in patients with AP, of which Ca, PaO2, and BE had highest predicting value, and EPIC score had the highest accuracy. We could not predict the duration of OF using laboratory markers. PMID- 28007686 TI - Sudden-onset sarcoidosis with severe dyspnea developing during pegylated interferon and ribavirin combination therapy for chronic hepatitis C. PMID- 28007687 TI - Reimagining Human Research Protections for 21st Century Science. AB - BACKGROUND: Evolving research practices and new forms of research enabled by technological advances require a redesigned research oversight system that respects and protects human research participants. OBJECTIVE: Our objective was to generate creative ideas for redesigning our current human research oversight system. METHODS: A total of 11 researchers and institutional review board (IRB) professionals participated in a January 2015 design thinking workshop to develop ideas for redesigning the IRB system. RESULTS: Ideas in 5 major domains were generated. The areas of focus were (1) improving the consent form and process, (2) empowering researchers to protect their participants, (3) creating a system to learn from mistakes, (4) improving IRB efficiency, and (5) facilitating review of research that leverages technological advances. CONCLUSIONS: We describe the impetus for and results of a design thinking workshop to reimagine a human research protections system that is responsive to 21st century science. PMID- 28007688 TI - Email Between Patient and Provider: Assessing the Attitudes and Perspectives of 624 Primary Health Care Patients. AB - BACKGROUND: Email between patients and their health care providers can serve as a continuous and collaborative forum to improve access to care, enhance convenience of communication, reduce administrative costs and missed appointments, and improve satisfaction with the patient-provider relationship. OBJECTIVE: The main objective of this study was to investigate the attitudes of patients aged 16 years and older toward receiving email communication for health-related purposes from an academic inner-city family health team in Southern Ontario. In addition to exploring the proportion of patients with a functioning email address and interest in email communication with their health care provider, we also examined patient-level predictors of interest in email communication. METHODS: A cross sectional study was conducted using a self-administered, 1-page survey of attitudes toward electronic communication for health purposes. Participants were recruited from attending patients at the McMaster Family Practice in Hamilton, Ontario, Canada. These patients were aged 16 years and older and were approached consecutively to complete the self-administered survey (N=624). Descriptive analyses were conducted using the Pearson chi-square test to examine correlations between variables. A logistic regression analysis was conducted to determine statistically significant predictors of interest in email communication (yes or no). RESULTS: The majority of respondents (73.2%, 457/624) reported that they would be willing to have their health care provider (from the McMaster Family Practice) contact them via email to communicate health-related information. Those respondents who checked their personal email more frequently were less likely to want to engage in this electronic communication. Among respondents who check their email less frequently (fewer than every 3 days), 46% (37/81) preferred to communicate with the McMaster Family Practice via email. CONCLUSIONS: Online applications, including email, are emerging as a viable avenue for patient communication. With increasing utility of mobile devices in the general population, the proportion of patients interested in email communication with their health care providers may continue to increase. When following best practices and appropriate guidelines, health care providers can use this resource to enhance patient-provider communication in their clinical work, ultimately leading to improved health outcomes and satisfaction with care among their patients. PMID- 28007690 TI - Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT): Study Protocol of a Randomized Controlled Feasibility Trial. AB - BACKGROUND: Essential tremor is a movement disorder that can result in profound disability affecting the quality of life. Medically refractory essential tremor can be successfully reduced by deep brain stimulation (DBS) traditionally targeting the thalamic ventral intermediate nucleus (Vim). Although this structure can be identified with magnetic resonance (MR) imaging nowadays, Vim DBS electrodes are still implanted in the awake patient with intraoperative tremor testing to achieve satisfactory tremor control. This can be attributed to the fact that the more effective target of DBS seems to be the stimulation of fiber tracts rather than subcortical nuclei like the Vim. There is evidence that current coverage of the dentatorubrothalamic tract (DRT) results in good tremor control in Vim-DBS. Diffusion tensor MR imaging (DTI) tractography-assisted stereotactic surgery targeting the DRT would therefore not rely on multiple trajectories and intraoperative tremor testing in the awake patient, bearing the potential of more patient comfort and reduced operation-related risks. This is the first randomized controlled trial comparing DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia with stereotactic surgery of thalamic/subthalamic region as conventionally used. OBJECTIVE: This clinical pilot trial aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional stereotactic surgery with intraoperative testing in the awake patient. METHODS: The Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT) trial is a single-center investigator-initiated, randomized, controlled, observer-blinded trial. A total of 24 patients with medically refractory essential tremor will be randomized to either DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia or stereotactic surgery of the thalamic/subthalamic region as conventionally used. The primary objective is to assess the tremor reduction, obtained by the Fahn-Tolosa-Marin Tremor Rating Scale in the 2 treatment groups. Secondary objectives include (among others) assessing the quality of life, optimal electrode contact positions, and safety of the intervention. The study protocol has been approved by the independent ethics committee of the University of Freiburg. RESULTS: Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment. CONCLUSIONS: The DISTINCT trial is the first to compare DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It can serve as a cornerstone for the evolving technique of DTI tractography-assisted stereotactic surgery. CLINICALTRIAL: ClinicalTrials.gov NCT02491554; https://clinicaltrials.gov/ct2/show/NCT02491554 (Archived by WebCite at http://www.webcitation.org/6mezLnB9D). German Clinical Trials Register DRKS00008913; http://drks-neu.uniklinik freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008913 (Archived by WebCite at http://www.webcitation.org/6mezCtxhS). PMID- 28007689 TI - The Role of Online Social Support in Supporting and Educating Parents of Young Children With Special Health Care Needs in the United States: A Scoping Review. AB - BACKGROUND: When parents of young children with special health care needs (CSHCN) receive their child's diagnosis, they encounter information they may not understand, emotions they may not know how to cope with, and questions about their child's immediate and long-term future that frequently lack answers. The challenge of health care providers is how to prepare parents for caring for their CSHCN, for coping with any resulting challenges, and for accessing the systems and services that can assist them. OBJECTIVE: The purpose of this work was to review evidence of the information and support needs of parents of young CSHCN and to determine whether online social support can serve as an avenue for learning and empowerment for these parents. METHODS: A scoping review identified the challenges, coping mechanisms, and support needs among parents of CSHCN, and the reach and effectiveness of digital technologies with these families and health care providers. We also conducted interviews with professionals serving parents of CSHCN. RESULTS: The literature review and interviews suggested that parents best learn the information they need, and cope with the emotional challenges of raising a CSHCN, with support from other parents of CSHCN, and that young parents in recent years have most often been finding this parent-to-parent support through digital media, particularly social media, consistent with the theory of online social support. Evidence also shows that social media, particularly Facebook, is used by nearly all women aged 18-29 years across racial and socioeconomic lines in the United States. CONCLUSIONS: Parents of young CSHCN experience significant stress but gain understanding, receive support, and develop the ability to care for and be advocates for their child through parent to-parent emotional and informational social support. Online social support is most effective with young adults of childbearing age, with social media and apps being the most useful within the theoretical framework of social support. This opens new opportunities to effectively educate and support parents of young CSHCN. Providers seeking to inform, educate, and support families of CSHCN should develop strategies to help parents find and use social support through digital resources to facilitate their emotional adjustment and practical abilities to care for and access services for their child. PMID- 28007691 TI - Design and Feasibility of a Text Messaging Intervention to Prevent Indoor Tanning Among Young Adult Women: A Pilot Study. AB - BACKGROUND: Although skin cancer is largely preventable, it affects nearly 1 of 5 US adults. There is a need for research on how to optimally design persuasive public health indoor tanning prevention messages. OBJECTIVE: The objective of our study was to examine whether framed messages on indoor tanning behavioral intentions delivered through short message service (SMS) text messaging would produce (1) positive responses to the messages, including message receptivity and emotional response; (2) indoor tanning efficacy beliefs, including response efficacy and self-efficacy; and (3) indoor tanning risk beliefs. METHODS: We conducted a pilot study of indoor tanning prevention messages delivered via mobile phone text messaging in a sample of 21 young adult women who indoor tan. Participants completed baseline measures, were randomly assigned to receive gain , loss-, or balanced-framed text messages, and completed postexposure outcome measures on indoor tanning cognitions and behaviors. Participants received daily mobile phone indoor tanning prevention text messages for 1 week and completed the same postexposure measures as at baseline. RESULTS: Over the 1-week period there were trends or significant changes after receipt of the text messages, including increased perceived susceptibility (P<.001), response efficacy beliefs (P<.001), and message receptivity (P=.03). Ordinary least squares stepwise linear regression models showed an effect of text message exposure on self-efficacy to quit indoor tanning (t6=-2.475, P<.02). Ordinary least squares linear regression including all measured scales showed a marginal effect of SMS texts on self efficacy (t20=1.905, P=.08). Participants endorsed highly favorable views toward the text messaging protocol. CONCLUSIONS: This study supports this use of mobile text messaging as an indoor tanning prevention strategy. Given the nature of skin cancer risk perceptions, the addition of multimedia messaging service is another area of potential innovation for disseminating indoor tanning prevention messages. PMID- 28007692 TI - MicroRNAs Are Stored in Human MII Oocyte and Their Expression Profile Changes in Reproductive Aging. AB - Maternal RNAs are synthesized by the oocyte during its growth; some of them are utilized for oocyte-specific processes and metabolism, others are stored and used during early development before embryonic genome activation. The appropriate expression of complex sets of genes is needed for oocyte maturation and early embryo development. In spite of the basic role of noncoding RNAs in the regulation of gene expression, few studies have analyzed their role in human oocytes. In this study, we identified the microRNAs (miRNAs) expressed in human metaphase II stage oocytes, and found that some of them are able to control pluripotency, chromatin remodeling, and early embryo development. We demonstrated that 12 miRNAs are differentially expressed in women of advanced reproductive age and, by bioinformatics analysis, we identified their mRNA targets, expressed in human oocytes and involved in the regulation of pathways altered in reproductive aging. Finally, we found the upregulation of miR-29a-3p, miR-203a-3p, and miR-494 3p, evolutionarily conserved miRNAs, also in aged mouse oocytes, and demonstrated that their overexpression is antithetically correlated with the downregulation of DNA methyltransferase 3A (Dnmt3a), DNA methyltransferase 3B (Dnmt3b), phosphatase and tensin homolog (Pten), and mitochondrial transcription factor A (Tfam). We propose that oocyte miRNAs perform an important regulatory function in human female germ cells, and their altered regulation could explain the changes occurring in oocyte aging. PMID- 28007694 TI - Recreating the Female Germline In Vitro. PMID- 28007693 TI - PAD4 Deficiency Decreases Inflammation and Susceptibility to Pregnancy Loss in a Mouse Model. AB - Inflammation is thought to play a critical role in the pathogenesis of placentation disorders such as recurrent miscarriages, growth restriction, and preeclampsia. Recently, neutrophil extracellular traps (NETs) have emerged as a potential mechanism for promoting inflammation in both infectious and noninfectious disorders. To investigate a pathogenic role for NETs in placentation disorders, we studied a model of antiangiogenic factor-mediated pregnancy loss in wild-type (WT) mice and in mice deficient in peptidylarginine deiminase 4 (Padi4-/-) that are unable to form NETs. Overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic protein that is pathogenically linked with abnormal placentation disorders during early gestation, resulted in pregnancy loss and large accumulation of neutrophils and NETs in WT placentas. Interestingly, sFlt-1 overexpression in Padi4-/- mice resulted in dramatically lower inflammatory and thrombotic response, which was accompanied by significant reduction in pregnancy losses. Inhibition of NETosis may serve as a novel target in disorders of impaired placentation. PMID- 28007695 TI - Mapping the Origin of the Testis. PMID- 28007696 TI - A New Window into Ovarian Follicle Development. PMID- 28007697 TI - Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing. AB - Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle. PMID- 28007698 TI - Gynaecologist is struck off for dishonesty and intention to cause distress. PMID- 28007699 TI - Pay inequity spells a winter of discontent for junior doctors. PMID- 28007700 TI - Junior doctors raise concerns about pay difference under new contract. PMID- 28007701 TI - Ischaemic colitis. PMID- 28007702 TI - Immunohistochemical Detection of ROS1 Fusion. AB - Objectives: Patients whose tumors harbor ROS1 translocation may benefit from targeted therapy. Detection of ROS1 rearrangement can be done by three methods: immunohistochemistry, fluorescence in situ hybridization, and molecular assays. Immunohistochemistry would be a cost-effective means to screen for ROS1 translocation, which is uncommon. Methods: ROS1 immunostain was performed on cases with known ROS1 translocation status detected either by fluorescence in situ hybridization or next-generation sequencing. Results: Fifty-seven cases, 10 lung carcinomas with ROS1 rearrangement and 47 cases without ROS1 rearrangement (25 lung carcinomas, 13 gastrointestinal carcinomas, three brain tumors, and six miscellaneous tumors), were included. ROS1 immunostain exhibited 100% sensitivity and 85% specificity, with staining seen in 10 (100%) of 10 cases with ROS1 rearrangement and in seven (15%) of 47 lung cases without ROS1 rearrangement. Weak or 1+ staining of reactive pneumocytes was seen in eight (14%) of 57 cases, and strong staining of osteoclast giant cells was seen in one case. Conclusions: Since ROS1 rearrangement is an infrequent event, immunohistochemistry is a cost effective screening method. Confirmation of all positive and equivocal/weak staining with molecular assays would exclude the false-positive cases. PMID- 28007703 TI - Immunohistochemistry Is Rarely Justified for the Diagnosis of Viral Infections. AB - Objectives: To determine the utility of immunohistochemistry (IHC) for the diagnosis of viral infections in surgical pathology specimens lacking characteristic viral cytopathic effects. Methods: Five years of cases at an academic medical center were reviewed for the use of IHC to detect cytomegalovirus (CMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), adenovirus, or polyomavirus (ie, BK or JC). Results: In total, 1,636 viral IHC stains were ordered on 1,099 specimens from 957 cases. Altogether, 134 (8.2%) stains were positive, including 59 (7.9%) of 749 for CMV, 34 (8.9%) of 384 for HSV-1 and HSV-2, 16 (11.5%) of 139 for VZV, three (1.4%) of 210 for adenovirus, and 22 (14.3%) of 154 for polyomavirus. In 101 (75.4%) of 134 cases, viral cytopathic effect (VCPE) was readily identifiable on H&E slides. No significant changes in clinical care occurred in any of the cases without definitive VCPE that had positive staining cells on IHC. Conclusions: These findings suggest that IHC for viral infections without a high degree of clinical or histologic suspicion is unnecessary in most cases. PMID- 28007704 TI - Police officer in minimally conscious state should be allowed to die, says judge. PMID- 28007705 TI - Umberto Veronesi. PMID- 28007706 TI - Validity of three asthma-specific quality of life questionnaires: the patients' perspective. AB - OBJECTIVES: It is not known which of the many asthma-specific quality of life (QoL) questionnaires best capture the lived experience of people with asthma. The objective of this study was to explore patients' views of three commonly used asthma-specific QoL questionnaires. DESIGN: Qualitative study using semistructured interviews. SETTING: Primary and secondary care in Brighton and Hove, UK. PARTICIPANTS: 30 adult people with a physician-diagnosis of asthma who were asked to complete the Juniper Asthma Quality of Life Questionnaire (AQLQ-J), the Sydney Asthma Quality of Life Questionnaire (AQLQ-S) and the Living with Asthma Questionnaire (LWAQ) to elicit their views on the content validity of these. RESULTS: Thematic content analysis revealed a lack of congruence between the concerns of people with asthma and the questionnaire content in terms of missing (eg, allergies) and irrelevant (eg, smoky restaurants) content. The AQLQ J was perceived as a 'narrow', 'medical' questionnaire focused on symptoms, the environment and functional ability. In contrast, the LWAQ and the AQLQ-S were perceived to be 'non-medical'. The LWAQ was described as a 'test' and as a wide ranging, embracing and holistic questionnaire. Its strong emotional focus was irritating to some. The AQLQ-S was described as a simple, quick and easy questionnaire, although there was a perception that it was lacking in depth. CONCLUSIONS: Patient interviews highlighted strengths and shortcomings in the content validity of these three asthma-specific questionnaires. For patients, the AQLQ-S content seemed to be the most pertinent in its adequacy of coverage of medical, social and emotional aspects of health-related QoL in asthma. PMID- 28007707 TI - Social support as a mediator between problem behaviour and gambling: a cross sectional study among 14-16-year-old Finnish adolescents. AB - BACKGROUND: During the adolescent period, risk-taking behaviour increases. These behaviours can compromise the successful transition from adolescence to adulthood. The purpose of this study was to examine social support as a mediator of the relation between problem behaviour and gambling frequency among Finnish adolescents. METHODS: Data were obtained from the national School Health Promotion Study (SHPS) from the years 2010 and 2011 (N=102 545). Adolescents were classified in the most homogeneous groups based on their problem behaviour via latent class analysis. RESULTS: Path analysis indicated that social support was negatively associated with problem behaviour, and problem behaviour and social support were negatively related (except for social support from friends among boys) to gambling. Social support from parents and school mediated, albeit weakly, the relations between problem behaviour and gambling among girls and boys. CONCLUSIONS: Problem behaviour may affect gambling through social support from school and parents. Thus prevention and intervention strategies should focus on strengthening adolescents' social support. In addition, because of the clustering of different problem behaviours instead of concentrating on a single form of problem behaviour multiple-behaviour interventions may have a much greater impact on public health. PMID- 28007709 TI - Medicare finalizes hospital outpatient payment rule for 2017. PMID- 28007710 TI - Pharmacists help small Kansas hospital cut readmissions. PMID- 28007713 TI - Medication errors researcher Flynn dies at 56. PMID- 28007715 TI - Development of a health-system palliative care clinical pharmacist. PMID- 28007716 TI - Optimizing colistin dosing: Is a loading dose necessary? AB - PURPOSE: Published literature on the pharmacokinetics and effectiveness of colistin loading doses is reviewed. SUMMARY: Colistin is increasingly used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria (GNB). A literature search identified seven reports on studies of colistin loading doses. All reviewed studies involved small samples of critically ill patients, with considerable variation in the colistin products and loading doses used. Pharmacokinetic studies indicated that because of the slow rate of conversion of the prodrug colistimethate sodium to the active drug colistin and the long half-life of colistin, it can take two to three days to attain adequate colistin concentrations without a loading dose. The clinical effectiveness of colistin loading doses was evaluated in two studies, neither involving the use of a comparator group. In one of those studies, clinical cure and bacteriological clearance were reported in 82.1% and 73.9% of cases, respectively; in the other, clinical resolution was reported in 77% of patients. Two studies were conducted to compare clinical outcomes of colistin loading-dose regimens and standard regimens with no loading dose; while use of a loading dose was associated with a higher cure rate (63.0% versus 41.3%, p = 0.04) in one study, no improvement in clinical outcomes was reported in the other study. CONCLUSION: Published data on the effectiveness of colistin loading doses are limited. The available evidence suggests that it may be necessary to administer a colistin loading dose in severe and life-threatening infections due to MDR GNB. PMID- 28007717 TI - Perioperative supplementation of polyunsaturated omega-3 fatty acid for the prevention of atrial fibrillation after cardiothoracic surgery. AB - PURPOSE: The effect of perioperative supplementation of polyunsaturated omega-3 fatty acid (PUFA) on the frequency of atrial fibrillation (AF) in patients without a history of AF was evaluated. METHODS: A total of 561 patients were randomized to receive either 1 g of PUFA or placebo twice daily. Treatment was started up to five days before surgery or within 24 hours after surgery, depending on when consent was received. Treatment was continued until the patient's follow-up visit with the cardiologist up to four weeks after surgery. The primary endpoint of the study was AF before hospital discharge. Secondary endpoints included AF within one week after surgery, AF within one month after surgery, length of hospital stay, postoperative bleeding complications, and readmission within one month after surgery. RESULTS: No significant reduction in the risk of AF was observed at hospital discharge (relative risk [RR], 0.98; p = 0.922) or at three weeks after surgery (RR, 0.98; p = 0.844). After restricting the analysis to treatment-adherent patients, the association remained nonsignificant at hospital discharge (RR, 0.90; p = 0.374) and at three weeks after surgery (RR, 0.90; p = 0.330). No significant differences were observed between treatments for rates of readmission, death, and bleeding complications or the length of hospital stay. CONCLUSION: Perioperative supplementation with PUFA did not decrease the risk of AF in the immediate postoperative period. PUFA also had no effect on the length of hospital stay, postoperative bleeding complications, and readmissions within one month after surgery. PMID- 28007719 TI - Evaluation of the "medication fall risk score". AB - PURPOSE: Results of a study evaluating the predictive validity of a fall screening tool in hospitalized patients are reported. METHODS: Administrative claims data from two hospitals were analyzed to determine the discriminatory ability of the "medication fall risk score" (RxFS), a medication review fall-risk screening tool that is designed for use in conjunction with nurse-administered tools such as the Morse Fall Scale (MFS). Through analysis of data on administered medications and documented falls in a population of adults who underwent fall-risk screening at hospital admission over a 15-month period (n = 33,058), the predictive value of admission MFS scores, alone or in combination with retrospectively calculated RxFS-based risk scores, was assessed. Receiver operating characteristic (ROC) curve analysis and net reclassification improvement (NRI) analysis were used to evaluate improvements in risk prediction with the addition of RxFS data to the prediction model. RESULTS: The area under the ROC curve for the predictive model for falls compromising both MFS and RxFS scores was computed as 0.8014, which was greater than the area under the ROC curve associated with use of the MFS alone (0.7823, p = 0.0030). Screening based on MFS scores alone had 81.25% sensitivity and 61.37% specificity. Combined use of RxFS and MFS scores resulted in 82.42% sensitivity and 66.65% specificity (NRI = 0.0587, p = 0.0003). CONCLUSION: Reclassification of fall risk based on coadministration of the MFS and the RxFS tools resulted in a modest improvement in specificity without compromising sensitivity. PMID- 28007718 TI - Correction factor to improve agreement between point-of-care and laboratory International Normalized Ratio values. AB - PURPOSE: Results of a research project to quantify and improve the accuracy of point-of-care (POC) International Normalized Ratio (INR) values are reported. METHODS: The accuracy of POC INR values relative to laboratory-measured INR values was retrospectively assessed in a cohort of patients with same-day INR determinations by both methods. Univariate linear regression was performed to derive a correction factor for POC INR values of >3; this correction factor was validated in a second cohort. RESULTS: In the derivation cohort (259 patients and 344 paired INR results), agreement of POC values with corresponding laboratory INR values at two specified thresholds (+/-15% and +/-25%) was 51.2% and 66.6%, respectively; for POC INR values of >3 (n = 205), agreement was lower (24.9% and 44.9%, respectively). Univariate linear regression yielded a coefficient of 0.77 (95% confidence interval, 0.76-0.79; p < 0.001). Applying a correction factor of 0.8 to POC INR values in a validation cohort (169 patients and 209 paired INR values) significantly improved the accuracy of POC INR values of >3 relative to laboratory values (from 7% to 71.1% at the lower threshold and from 23.5% to 88.8% at the higher threshold, p < 0.0001 for both comparisons). CONCLUSION: Agreement between POC and laboratory INR results in one institution was poor, especially when POC INR values exceeded 3. Application of an institution-specific correction factor to POC INR values of >3 improved agreement with laboratory INR results but would not have significantly reduced differences in protocol-based warfarin dosage adjustments. PMID- 28007720 TI - Robotic i.v. medication compounding: Recommendations from the international community of APOTECAchemo users. AB - PURPOSE: The development of recommendations for advancing automated i.v. medication compounding is described. SUMMARY: Managing the shift from manual to robotic compounding of i.v. therapies requires an awareness of how automation affects practice and how to best implement robotics into current practice. An international panel of pharmacy professionals, researchers, and technology leaders with experience in i.v. robotics collaborated during a two-day meeting in August 2014 to define a general set of principles to broaden the understanding of the fundamental elements of robotic compounding worldwide. Participants were divided into four working groups (technology and safety; drugs and products; personnel; and facilities and quality) to analyze specific aspects of robotic compounding practice. The four working groups produced an initial list of 92 statements. This list was condensed to 35 statements by consolidating similar and overlapping statements from the different work groups. Participants were surveyed again to assess agreement with the 35 statements and solicit additional clarification. Respondents expressed full agreement with 25 recommendations. Six statements received one or more "don't know" responses, with all other respondents in agreement. Four statements had a combination of "don't know" and "disagree" responses. A total of 32 comments were recorded in free-text fields, including requests for clarification and suggestions for rewording the statements. CONCLUSION: An international panel of pharmacy professionals, researchers, and technology leaders with experience in i.v. robotics developed a set of 35 recommendations toward a better understanding of the role of automated i.v. compounding in hospital and health-system pharmacies worldwide. PMID- 28007721 TI - Physical compatibility of ceftolozane-tazobactam with selected i.v. drugs during simulated Y-site administration. AB - PURPOSE: Results of a study to examine the physical compatibility of ceftolozane tazobactam with common i.v. medications during simulated Y-site administration are presented. METHODS: Ceftolozane-tazobactam was reconstituted according to manufacturer recommendations and diluted with 0.9% sodium chloride or 5% dextrose to solutions containing 15 mg (10 mg of ceftolozane and 5 mg of tazobactam)/mL. All other i.v. drugs were prepared according to manufacturer recommendations and diluted with 0.9% sodium chloride or 5% dextrose to standard concentrations used clinically. Y-site administration was simulated by mixing ceftolozane-tazobactam solution with each tested drug solution at a 1:1 ratio. Solutions were inspected for visual, turbidity, and pH changes immediately and 15, 60, and 120 minutes after mixing. Incompatibility was defined as precipitation, color change, a positive Tyndall test, a change in turbidity of >=0.5 nephelometric turbidity unit, or a change in pH of >=1 unit during the 120-minute observation period. RESULTS: Of the 95 i.v. drugs tested, ceftolozane-tazobactam was compatible with 86 drugs in both diluents; notably, it was compatible with metronidazole in both solutions. No substantial pH changes were observed in any tested combination. Ceftolozane-tazobactam was incompatible with albumin, amphotericin B, caspofungin, cyclosporine, nicardipine, and phenytoin sodium due to turbidity changes and with propofol due to formation of an oily layer. CONCLUSION: Ceftolozane-tazobactam 15 mg (10 mg of ceftolozane and 5 mg of tazobactam)/mL was physically compatible with 86 of 95 study drugs tested in both 0.9% sodium chloride injection and 5% dextrose injection during simulated Y-site administration. PMID- 28007722 TI - Physical compatibility of isavuconazonium sulfate with select i.v. drugs during simulated Y-site administration. AB - PURPOSE: The physical compatibility of isavuconazonium sulfate with 95 i.v. drugs during simulated Y-site administration was studied. METHODS: Isavuconazonium sulfate for injection and all other drugs were reconstituted according to the manufacturer's recommendation and further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a final concentration (1.5 mg/mL for isavuconazonium sulfate and standard concentrations used clinically for other drugs). A Y site was simulated in glass culture tubes by mixing 5 mL of the tested drug and isavuconazonium sulfate solutions in each diluent. Incompatibility was defined as changes in visual characteristics or increases in turbidity by greater than 0.5 nephelometric turbidity units over the 120-minute experiment. RESULTS: Of the 95 drugs tested, isavuconazonium sulfate was physically compatible with 66 drugs in 0.9% sodium chloride injection and 60 drugs in 5% dextrose injection. Incompatibility was observed with albumin, amphotericin B deoxycholate, amphotericin B lipid complex, amphotericin B liposome, ampicillin-sulbactam, cefazolin, cefepime, ceftaroline fosamil, ceftazidime, ceftriaxone, cefuroxime, colistimethate sodium, cyclosporine, ertapenem, esomeprazole, filgrastim, fosphenytoin, furosemide, heparin, meropenem, methylprednisolone, micafungin, phenytoin, potassium phosphate, propofol, sodium bicarbonate, sodium phosphate, and tedizolid. Azithromycin, bumetanide, penicillin G potassium, and piperacillin-tazobactam were incompatible with isavuconazonium sulfate in 5% dextrose injection only. CONCLUSION: Of the 95 drugs tested, isavuconazonium sulfate 1.5 mg/mL was physically compatible with 66 drugs in 0.9% sodium chloride injection and 60 drugs in 5% dextrose injection. Incompatibility was observed with 18 antimicrobials, including most cephalosporins tested, and 14 other i.v. drugs in at least 1 of the 2 tested diluents. PMID- 28007723 TI - Stability of sildenafil in combination with heparin and dopamine. AB - PURPOSE: The stability of sildenafil in combination with heparin and dopamine was evaluated. METHODS: A stability-indicating high-performance liquid chromatography method with ultraviolet detection was developed for sildenafil citrate and validated. The method was applied to the investigation of sildenafil alone, sildenafil with heparin, sildenafil with dopamine, and sildenafil with heparin and with dopamine, all in 5% dextrose injection at room temperature and under refrigeration for 30 days. Samples of 100 MUL were pulled from each storage bottle on each sampling day, diluted in mobile phase, and assayed in duplicate. Samples were tested on days 0, 1, 2, 3, 4, 5, 7, 9, 12, 14, 21, and 30. Each preparation was visually inspected for precipitation and color change. The percent recovery in each study sample was determined by comparing the peak area of sildenafil in the sample with the peak area of sildenafil from a freshly prepared 100-MUg/mL standard in mobile phase. RESULTS: The sildenafil alone, sildenafil with heparin, and sildenafil with dopamine remained within 90-110% of the expected sildenafil potency for at least 30 days at both temperatures. The preparation of sildenafil with both heparin and dopamine fell below 90% potency after 3 days at room temperature and 21 days in the refrigerator. CONCLUSION: Sildenafil prepared in 5% dextrose injection alone, with heparin, and with dopamine retained over 90% potency after 30 days of storage at room temperature and under refrigeration. Sildenafil prepared with both heparin and dopamine had a potency of <90% after 3 days of storage at room temperature and 21 days of storage under refrigeration. PMID- 28007724 TI - Use of social media to engage membership of a state health-system pharmacy organization. AB - PURPOSE: The influence of targeted strategies implemented to increase member engagement on a social media page of a professional pharmacy organization was studied. METHODS: The Ohio Society of Health-System Pharmacists (OSHP) implemented posting strategies to increase member engagement with its social media page in late 2013. Data were collected retrospectively for a nine-month period in 2013 (preimplementation) and a matching nine-month period in 2014 (postimplementation). The primary endpoint was reach (as provided by the social media website). Data regarding reach were reported to OSHP page administrators on a weekly basis. Posts during the study period were characterized by the day of week, time of day, type of post, and corresponding reach. Continuous variables were represented using means and standard deviations or medians and interquartile ranges (IQRs); categorical data were represented by percentages. RESULTS: The total reach of posts during the nine-month study period increased postimplementation, from 10,826 to 32,338. Further, the median reach per post on the OSHP Facebook page was higher postimplementation (214; IQR, 107-380) versus preimplementation (152; IQR, 89-224; p = 0.035). Evening posts had significantly greater reach compared with nonevening posts. The median reach for evening posts was 232 (IQR, 143-378) versus 131 (IQR, 77-200) for nonevening posts (p < 0.001). There was no significant difference in the median reach of weekday posts (179.5; IQR, 85.5-339.5) versus weekend posts (192; IQR, 113-252). Posts with photos or pictures had the highest reach of all post types. CONCLUSION: Implementation of targeted strategies resulted in an increase in the number of users reached by a state health-system pharmacy organization's social media page. PMID- 28007725 TI - Implementation of performance metrics to assess pharmacists' activities in ambulatory care clinics. AB - PURPOSE: The development and implementation of performance metrics for assessing the impact of pharmacists' activities in ambulatory care clinics are described. SUMMARY: Ambulatory care clinic pharmacists within an integrated health system were surveyed to ascertain baseline practices for documenting and tracking performance metrics. Through literature review and meetings with various stakeholders, priorities for metric development were identified; measures of care quality, financial impact, and patient experience were developed. To measure the quality of care, pharmacists' interventions at five ambulatory care clinics within the health system were assessed. Correlation of pharmacist interventions with estimated cost avoidance provided a measure of financial impact. Surveys were distributed at the end of clinic visits to measure satisfaction with the patient care experience. An electronic system for metric documentation and automated tabulation of data on quality and financial impact was built. In a 12 week pilot program conducted at three clinic sites, the metrics were used to assess pharmacists' activities. A total of 764 interventions were documented (a mean of 24 accepted recommendations per pharmacist full-time equivalent each week), resulting in estimated cost avoidance of more than $40,000; survey results indicated high patient satisfaction with the services provided by pharmacists. Biweekly report auditing and solicitation of feedback guided metric refinement and further training of pharmacists. Tools and procedures were established for future metric expansion. CONCLUSION: Development and implementation of performance metrics resulted in successful capture and characterization of pharmacists' activities and their impact on patient care in three ambulatory care clinics. PMID- 28007726 TI - Patient blood management: A role for pharmacists. PMID- 28007728 TI - Gallagher R, Collins S, Trujillo J, et al. Characterization of the continuous, differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia. Blood. 1979;54(3):713-733. PMID- 28007729 TI - Pee no more? Urine light chains down the drain. PMID- 28007730 TI - Leukemias and bones: humanizing the niche in mice. PMID- 28007731 TI - Dying a fiery death: pyroptosis in MDS. PMID- 28007732 TI - Trouble in the niche? Send in a statin. PMID- 28007733 TI - A breath of fresh air for umbilical cord blood. PMID- 28007734 TI - Hodgkin lymphoma mimicking lung abscess. PMID- 28007735 TI - A rare histologic variant of a common lymphoma. PMID- 28007736 TI - Cervantes F, Vannucchi AM, Kiladjian J-J, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122(25):4047-4053. PMID- 28007737 TI - Serum FLC measurements for monitoring MM. PMID- 28007738 TI - Malondialdehyde as a Prognostic Factor in Alcoholic Hepatitis. AB - Aims: Alcoholic hepatitis is a severe complication of alcoholism, associated with high short-term mortality. Although pathogenesis remains obscure, it is generally accepted that lipopolysaccharide-induced cytokine secretion with further generation of reactive oxygen species (ROS) play outstanding roles. Prognosis is uncertain, and the usually employed prognostic scores do not include variables related to ROS generation. Therefore, this study was performed to assess short term prognostic value of cytokines, nutritional status, different scores [Maddrey, model for end-stage liver disease (MELD), albumin, bilirubin, INR, creatinine index (ABIC), Lille, Glasgow, MELD-Na, Child-Pugh] and malondialdehyde (MDA, as an indicator of lipid peroxidation) at admission and after 1 week, among patients affected by severe acute alcoholic hepatitis (Maddrey index >32). Methods: Sixty-two patients affected by severe acute alcoholic hepatitis, for whom we calculated Maddrey, MELD, ABIC, Lille, Glasgow, MELD-Na, Child-Pugh, and determined serum MDA and interleukin (IL)-6, IL-8, IL-4, tumor necrosis factor alpha and interferon gamma levels at admission and after 1 week. Results: Twenty four patients died during the follow-up period. MDA showed a better prognostic accuracy than the aforementioned scores, both at admission and after 1 week. Conclusion: Our study supports the importance of including MDA assessment in the prognostic evaluation of patients with alcoholic hepatitis. Short summary: Alcoholic hepatitis is associated with high short-term mortality. Although not included in prognostic scores, lipid peroxidation plays an outstanding role in its pathogenesis. We found that malondialdehyde levels showed a better prognostic accuracy than the usually employed scores. Therefore, it should be included in the prognostic evaluation of these patients. PMID- 28007739 TI - Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy Through G9a-Dependent H3K9 Dimethylation. AB - BACKGROUND: Ischemic preconditioning (IPC) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post-translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning. METHODS AND RESULTS: We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well-studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed ChIP-Seq and transcriptome profiling using microarray. Two hundred thirty-seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor, increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation. CONCLUSIONS: IPC confers an increase of H3K9me2 levels throughout the Mtor gene-a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC-leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC. PMID- 28007740 TI - Early Coronary Reperfusion Facilitates Return of Spontaneous Circulation and Improves Cardiovascular Outcomes After Ischemic Cardiac Arrest and Extracorporeal Resuscitation in Pigs. AB - BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is widely proposed for the treatment of refractory cardiac arrest. It should be associated with coronary angiography if coronary artery disease is suspected. However, the prioritization of care remains unclear in this situation. Our goal was to determine whether coronary reperfusion should be instituted as soon as possible in such situations in a pig model. METHODS AND RESULTS: Anesthetized pigs were instrumented and submitted to coronary artery occlusion and ventricular fibrillation. After 5 minutes of untreated cardiac arrest, conventional cardiopulmonary resuscitation (CPR) was started. Fifteen minutes later, ECPR was initiated for a total duration of 240 minutes. Animals randomly underwent either early or late coronary reperfusion at 20 or 120 minutes of ECPR, respectively. This timing was adapted to the kinetic of infarct extension in pigs. Return of spontaneous circulation was determined as organized electrocardiogram rhythm with systolic arterial pressure above 80 mm Hg. During conventional CPR, hemodynamic parameters were not different between groups. Carotid blood flow then increased by 70% after the onset of ECPR in both groups. No animal (0 of 7) elicited return of spontaneous circulation after late reperfusion versus 4 of 7 after early reperfusion (P=0.025). The hemodynamic parameters, such as carotid blood flow, were also improved in early versus late reperfusion groups (113+/-20 vs 43+/-17 mL/min after 240 minutes of ECPR, respectively; P=0.030), along with infarct size decrease (71+/-4% vs 84+/-2% of the risk zone, respectively; P=0.013). CONCLUSIONS: Early reperfusion improved hemodynamic status and facilitated return of spontaneous circulation in a porcine model of ischemic cardiac arrest treated by ECPR. PMID- 28007741 TI - Predictors and Long-Term Clinical Impact of Acute Stent Malapposition: An Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) Intravascular Ultrasound Substudy. AB - BACKGROUND: The impact of acute stent malapposition (ASM) on long-term clinical outcomes in patients undergoing percutaneous coronary intervention is still controversial. We sought to evaluate predictors and long-term clinical outcomes of ASM. METHODS AND RESULTS: ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a prospective multicenter study of 8663 patients undergoing percutaneous coronary intervention using drug-eluting stents. In a prespecified intravascular ultrasound-guided substudy, 2072 patients with 2446 culprit lesions had post-percutaneous coronary intervention intravascular ultrasound and were classified according to the presence or absence of ASM. After intravascular ultrasound-guided percutaneous coronary intervention, the overall prevalence of ASM after successful drug-eluting stents implantation was 14.4% per patient and 12.6% per lesion. Compared to lesions without ASM, lesions with ASM had larger in-stent lumen areas, larger stent areas, and larger in-stent vessel areas. A larger mean plaque area along with more attenuated plaque was observed in lesions with ASM versus lesions without ASM. Lesions with ASM had greater proximal and distal reference lumen areas and more distal, but not proximal, reference calcium compared to lesions without ASM. At 2-year follow-up, there was no significant difference in the incidence of cardiac death; myocardial infarction; early, late, or very late stent thrombosis; or clinically driven target lesion revascularization in patients with ASM versus those without ASM. Furthermore, ASM was not an independent predictor of 2-year major adverse cardiac events or target lesion revascularization even when forced into the multivariate model. CONCLUSIONS: In patients treated with intravascular ultrasound-guided drug eluting stents implantation, ASM was not associated with adverse clinical events during long-term follow-up including, but not limited to, stent thrombosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00638794. PMID- 28007742 TI - Invasive minimal Microvascular Resistance Is a New Index to Assess Microcirculatory Function Independent of Obstructive Coronary Artery Disease. AB - BACKGROUND: Coronary microcirculatory dysfunction portends a poor cardiovascular outcome. Invasive assessment of microcirculatory dysfunction by coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) is affected by coronary artery disease (CAD). In this study we propose minimal microvascular resistance (mMR) as a new measure of microcirculatory dysfunction and aim to determine whether mMR is influenced by CAD. METHODS AND RESULTS: We obtained 482 simultaneous measurements of intracoronary Doppler flow velocity and pressure. The mMR is defined as the ratio between distal coronary pressure and flow velocity during the hyperemic wave-free period. Measurements were divided into 2 cohorts. Cohort 1 was a paired analysis involving 81 pairs with a vessel with and without CAD to investigate whether HMR, CFR, and mMR are modulated by CAD. CFR was lower, and HMR was higher, in vessels with CAD than in vessels without CAD: 2.12+/-0.79 versus 2.56+/-0.63 mm Hg.cm-1.s, P<0.001, and 2.61+/-1.22 versus 2.31+/-0.89 mm Hg.cm-1.s, P=0.04, respectively. mMR was equal in vessels with and without CAD: 1.54+/-0.77 versus 1.53+/-0.57 mm Hg.cm-1.s, P=0.90. Differences for CFR occurred when FFR was 0.60 to 0.80 or <=0.60 but not when FFR >=0.80. For HMR, the difference occurred only when FFR <=0.60. For mMR, no difference was observed in any FFR stratum. Cohort 2 was used for validation and showed significant relationships for CFR and HMR with FFR: Pearson r=0.488, P<0.001 and 0.159, P=0.03, respectively; mMR had no association with FFR: Pearson r=0.055; P=0.32. CONCLUSIONS: mMR is a novel index to assess microcirculatory dysfunction and is not modified by the presence of obstructive CAD. PMID- 28007743 TI - Revisiting the "Christmas Holiday Effect" in the Southern Hemisphere. AB - BACKGROUND: A "Christmas holiday effect" showing elevated cardiovascular mortality over the Christmas holidays (December 25 to January 7) was demonstrated previously in study from the United States. To separate the effect of seasonality from any holiday effect, a matching analysis was conducted for New Zealand, where the Christmas holiday period falls within the summer season. METHODS AND RESULTS: New Zealand mortality data for a 25-year period (1988-2013) was analyzed based on the same methodology used in the previous study. Locally weighted smoothing was used to calculate an "expected" number of deaths for each day of the year. The expected value was compared with the actual number of deaths. In addition, mean age at death was estimated and used to assess the life-years lost due to excess mortality. There were 738 409 deaths (197 109 coded as cardiac deaths) during the period. We found evidence of a Christmas holiday effect in our of medical facility's cardiac deaths, with an excess event rate of 4.2% (95% CI 0.7-7.7%) leading to ~4 additional deaths per annum. The average age of those with fatal cardiac deaths was 76.8 years (SD 13.5) during the Christmas holiday period, resulting in 148 to 222 years of life lost per annum. CONCLUSIONS: Cardiac mortality is elevated during the Christmas holiday period relative to surrounding time periods. Our findings are consistent with a previously reported study conducted in the United States, suggesting that cardiac mortality does not take a "summer break." PMID- 28007744 TI - Loss of Caspase-Activated DNase Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. AB - BACKGROUND: Atherosclerosis is a chronic disease that is closely related to inflammation and macrophage apoptosis, which leads to secondary necrosis and proinflammatory responses in advanced lesions. Caspase-activated DNase (CAD) is a double-strand specific endonuclease that leads to the subsequent degradation of chromosome DNA during apoptosis. However, whether CAD is involved in the progression of atherosclerosis remains elusive. METHODS AND RESULTS: CAD-/-ApoE-/ and ApoE-/- littermates were fed a high-fat diet for 28 weeks to develop atherosclerosis. Human specimens were collected from coronary heart disease (CHD) patients who were not suitable for transplantation. CAD expression was increased in the atheromatous lesions of CHD patients and high-fat diet-treated ApoE deficient mice. Further investigation demonstrated that CAD deficiency inhibited high-fat diet-induced atherosclerosis, as evidenced by decreased atherosclerotic plaques, inhibited inflammatory response, and macrophage apoptosis, as well as enhanced stability of plaques in CAD-/-ApoE-/- mice compared to the ApoE-/- controls. Bone marrow transplantation verified the effect of CAD on atherosclerosis from macrophages. Mechanically, the decrease in the phosphorylated levels of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-regulated kinase 1 and 2 (MEK-ERK1/2) that resulted from CAD knockout and the activation of nuclear factor kappa B signaling mediated by CAD stimulation that was suppressed by inhibiting ERK1/2 phosphorylation revealed the potential association between the role of CAD in atherosclerosis and the MAPK signaling pathway. CONCLUSIONS: In conclusion, CAD deficiency protects against atherosclerosis through inhibiting inflammation and macrophage apoptosis, which is partially through inactivation of the MEK-ERK1/2 signaling pathway. This finding provides a promising therapeutic target for treating atherosclerosis. PMID- 28007745 TI - Impact of Retinal Vein Occlusion on Stroke Incidence: A Meta-Analysis. AB - BACKGROUND: Considerable controversy exists on the association between retinal vein occlusion (RVO) and stroke risk. Therefore, we conducted a meta-analysis to assess the relationship between RVO and stroke risk. METHODS AND RESULTS: PubMed, EMBASE, and the Cochrane library databases were searched for cohort studies with data on RVO and stroke risk. Studies that reported adjusted relative risks (RRs) with 95% CIs of stroke associated with RVO were included. Stratified analyses were conducted according to key characteristics. A total of 5 articles including results from 6 prospective cohort studies with 431 cases of stroke and 37 471 participants were included in the meta-analysis. Overall, after adjustment for established cardiovascular risk factors, participants with RVO at baseline were considerably more associated with a greater incidence of stroke risk (combined RR: 1.50, 95% CI: 1.19-1.90), compared to participants without RVO. The results were more pronounced for stroke (RR: 1.72, 95% CI: 1.24-2.37) in the stratified with a stroke history. The risk of stroke was nonsignificant in male subjects (RR: 1.20, 95% CI: 0.96-1.49) and in female subjects (RR: 0.93, 95% CI: 0.64 1.34). The presence of both central RVO (RR: 1.90, 95% CI: 1.46-2.48) and branch RVO (RR: 1.79, 95% CI: 1.18-2.72) was associated with increased risk of stroke. Stratifying by age, the associations between RVO and risk of stroke were similar between the age range in the cohorts that ranged from 50 to 59 years and 60 to 69 years. CONCLUSIONS: Exposure to RVO was associated with an increased risk of stroke, especially in subjects aged between 50 and 69 years. Future studies on the effect of RVO treatment and modifiable risk factor reduction on stroke risk in RVO patients are warranted. PMID- 28007746 TI - Optical Coherence Tomography to Evaluate Plaque Burden and Morphology in Patients With Takotsubo Syndrome. AB - BACKGROUND: Disrupted atherosclerotic plaques in the left anterior descending coronary artery are discussed controversially as a potential pathophysiological mechanism in Takotsubo syndrome (TTS). Therefore, the aim of the present study was to assess plaque burden and morphology by using optical coherence tomography in patients with TTS. METHODS AND RESULTS: A total of 23 consecutive TTS patients were included in this single-center study and underwent optical coherence tomography imaging of the left main coronary artery and the left anterior descending coronary artery at acute presentation. All patients fulfilled the established diagnostic criteria for TTS and the diagnosis was confirmed with a multimodality imaging approach including cardiac magnetic resonance in 16 patients (69.6%). Atherosclerotic plaques located in the left anterior descending coronary artery or both the left anterior descending coronary artery and the left main coronary artery were detected in 16 TTS patients (69.6%), with 6 patients exhibiting multiple plaque types. In addition to the predominant fibrocalcific (52.2%) and lipid-rich plaques (30.4%), thin-cap fibroatheromas were also found in 6 patients (26.1%). However, ruptured plaques or intracoronary thrombi were not observed. Vessel stenosis >50% was found in 3 patients (13.0%) by analyzing cross-sectional areas. Clinical characteristics and cardiac magnetic resonance findings did not differ significantly between TTS patients with and without atherosclerotic plaques. CONCLUSIONS: Using optical coherence tomography, the present study revealed a high prevalence of atherosclerotic plaques in patients with TTS, including a considerable number of highly vulnerable thin-cap fibroatheromas. However, ruptured plaques or intracoronary thrombi were not observed and are therefore most likely not the underlying mechanism of TTS. PMID- 28007747 TI - Takotsubo Cardiomyopathy and Coronary Artery Disease: A Meaningful Coincidence? PMID- 28007748 TI - Emerging studies of human visceral nociceptors. AB - Animal studies have led to significant advances in our understanding of pain mechanisms in the intestine that could lead to altered signaling in disorders such as irritable bowel syndrome. However, how these translate to the human afferent nervous system is unclear. Recent studies have demonstrated that it is possible to use a variety of techniques, including electrophysiological recordings, to begin to examine these concepts in humans. This mini-review examines these studies to explore how well animal studies translate to humans suffering from irritable bowel syndrome, highlights some of the advantages and technical limitations of these approaches, and identifies some priorities for future studies using human tissues. PMID- 28007749 TI - Intermuscular technique for implantation of the subcutaneous implantable cardioverter defibrillator: long-term performance and complications. AB - Aims: The subcutaneous cardioverter defibrillator was designed to overcome electrode complications of transvenous defibrillation systems. While largely achieved, pocket complications have increased. Subcutaneous implantation of the pulse generator leaves it prone to erosion, extrusion, discomfort, and poor cosmesis. Methods and results: We use a demonstration electrode and pulse generator with fluoroscopy, prior to prepping and draping, to maximize the left ventricular mass between them. We adapted a submuscular abdominal ICD technique to implant the S-ICD intermuscularly between the anterior surface of serratus anterior and the posterior surface of latissimus dorsi. Surgery in our patients beyond the subcutaneous tissue was bloodless, as muscle layers were carefully separated but not incised, which also protected the long thoracic nerve. Two layers of muscle protect the pulse generator. We have implanted 82 consecutive patients with this technique, taking ~65 min. All patients were converted with 65 J standard polarity shock during induced arrhythmia conversion testing, with six (7.3%) patients requiring a repositioning of the pulse generator prior to successful conversion. Seven spontaneous episodes of ventricular fibrillation were detected in three (3.6%) patients, all successfully converted back to sinus rhythm. Long-term patient outcomes have been good with low complication rates over the mean +/- standard deviation 3.6 +/- 1.2 years. Conclusion: Our intermuscular technique and implant methodology is successful for placement of the subcutaneous defibrillator pulse generator. Our technique leads to an excellent cosmetic result and high levels of patient satisfaction. Rates of first shock conversion during defibrillation testing, inappropriate shocks, and complications during follow-up compare favourably with previous published case series. There were no left arm movement limitations post-operatively. PMID- 28007750 TI - Parent Preferences for Medical Error Disclosure: A Qualitative Study. AB - OBJECTIVE: According to disclosure guidelines, patients experiencing adverse events due to medical errors should be offered full disclosure, whereas disclosure of near misses is not traditionally expected. This may conflict with parental expectations; surveys reveal most parents expect full disclosure whether errors resulted in harm or not. Protocols regarding whether to include children in these discussions have not been established. This study explores parent preferences around disclosure and views on including children. METHODS: Fifteen parents of hospitalized children participated in semistructured interviews. Three hypothetical scenarios of different severity were used to initiate discussion. Interviews were audiotaped, transcribed, and coded for emergent themes. RESULTS: Parents uniformly wanted disclosure if harm occurred, although fewer wanted their child informed. For nonharmful errors, most parents wanted disclosure for themselves but few for their children.With respect to including children in disclosure, parents preferred to assess their children's cognitive and emotional readiness to cope with disclosure, wishing to act as a "buffer" between the health care team and their children. Generally, as event severity decreased, they felt that risks of informing children outweighed benefits. Parents strongly emphasized needing reassurance of a good final outcome and anticipated difficulty managing their emotions. CONCLUSIONS: Parents have mixed expectations regarding disclosure. Although survey studies indicate a stronger desire for disclosure of nonharmful events than for adult patients, this qualitative study revealed a greater degree of hesitation and complexity. Parents have a great need for reassurance and consistently wish to act as a buffer between the health care team and their children. PMID- 28007751 TI - Cytokinesis in Metazoa and Fungi. AB - SUMMARYCell division-cytokinesis-involves large-scale rearrangements of the entire cell. Primarily driven by cytoskeletal proteins, cytokinesis also depends on topological rearrangements of the plasma membrane, which are coordinated with nuclear division in both space and time. Despite the fundamental nature of the process, different types of eukaryotic cells show variations in both the structural mechanisms of cytokinesis and the regulatory controls. In animal cells and fungi, a contractile actomyosin-based structure plays a central, albeit flexible, role. Here, the underlying molecular mechanisms are summarized and integrated and common themes are highlighted. PMID- 28007752 TI - Assessment of the uterus with three-dimensional ultrasound in women undergoing ART. AB - BACKGROUND: A detailed assessment of the uterus forms a pivotal part of the ART treatment process. The emergence of three-dimensional ultrasound (3D US) has provided clinicians with a highly powerful tool in this respect. Assessments with 3D US range from the reconstruction of anatomical planes elusive to conventional US, to the objective measurement of anatomical volumes and vascularization parameters. However, despite the ever increasing number of publications emerging in the literature, the question of which aspects of 3D US are of most clinical value remains a topic of debate. OBJECTIVE AND RATIONALE: The objective of this review is to dissect which aspects of the 3D US assessment of the uterus are supported by a strong level of evidence to date, and should therefore be incorporated into current routine clinical practice. SEARCH METHODS: We conducted a systematic search of the PubMed database up to May 2016, using a combination of text words and Medical Subject Headings (MeSH) pertaining to the 3D US assessment of the uterus. All articles published in the English language were screened to ascertain relevance to women of reproductive age; further citations were retrieved through manual reference list searching. OUTCOMES: A multitude of predominantly observational studies were identified, which concerned a vast variety of 3D US uterine assessments. All articles unequivocally praised the non invasive, cost-effective, highly acceptable and objective nature of 3D US. Studies regarding the value of assessing the endometrial volume and vascularization prior to embryo transfer appeared conflicting and inconsistent. Studies regarding the imaging of uterine pathology and identification of intratubal and intrauterine devices consistently reported high rates of diagnostic accuracy. A recent RCT did not show an improvement in clinical outcomes when comparing 3D versus 2D US during embryo transfer. However, preliminary studies suggested that 3D US is superior in determining the site of implantation, particularly in ambiguous cases such as interstitial and angular pregnancies. Finally, pilot studies have suggested that the further integration of 3D and possibly 4D US with surgical interventions of the uterus may be a promising prospect. WIDER IMPLICATIONS: 3D US may prove to be an invaluable tool in the assessment of the uterus within the context of ART. Currently, the aim should be to highlight the aspects of 3D US that are most evidence-based and valuable for patients, and to incorporate these into routine clinical practice. PMID- 28007753 TI - Perspectives of health care professionals on cancer cachexia: results from three global surveys. AB - BACKGROUND: Cachexia has a high prevalence in cancer patients and negatively impacts prognosis, quality of life (QOL), and tolerance/response to treatments. This study reports the results of three surveys designed to gain insights into cancer cachexia (CC) awareness, understanding, and treatment practices among health care professionals (HCPs). METHODS: Surveys were conducted globally among HCPs involved in CC management. Topics evaluated included definitions and synonyms of CC, diagnosis and treatment practices, and goals and desired improvements of CC treatment. RESULTS: In total, 742 HCPs from 14 different countries participated in the surveys. The majority (97%) of participants were medical oncologists or hematologists. CC was most frequently defined as weight loss (86%) and loss of appetite (46%). The terms loss of weight and decreased appetite (51% and 34%, respectively) were often provided as synonyms of CC. Almost half (46%) of the participants reported diagnosing CC and beginning treatment if a patient experienced a weight loss of 10%. However, 48% of the participants would wait until weight loss was >=15% to diagnose CC and start treatment. HCPs also reported that 61%-77% of cancer patients do not receive any prescription medication for CC before Stage IV of disease is reached. Ability to promote weight gain was rated as the most important factor for selecting CC treatment. Key goals of treatment included ensuring that patients can cope with the cancer and treatment and have a QOL benefit. HCPs expressed desire for treatments with a more CC-specific mode of action and therapies that enhance QOL. CONCLUSIONS: These surveys underscore the need for increased awareness among HCPs of CC and its management. PMID- 28007754 TI - Myeloablative versus reduced intensity allogeneic stem cell transplantation for relapsed/refractory Hodgkin's lymphoma in recent years: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. AB - BACKGROUND: To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years. PATIENTS AND METHODS: A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study. RESULTS: With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT. CONCLUSIONS: With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL. PMID- 28007755 TI - Low immunogenicity of tocilizumab in patients with rheumatoid arthritis. AB - OBJECTIVE: Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK). RESULTS: The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7-2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy. CONCLUSIONS: The immunogenicity risk of TCZ SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety. PMID- 28007757 TI - Statin therapy now more common than steroids in clinical practice. PMID- 28007756 TI - EULAR/EFORT recommendations for management of patients older than 50 years with a fragility fracture and prevention of subsequent fractures. AB - The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of optimal acute care for the patients aged 50 years and over with a recent fragility fracture and the prevention of subsequent fractures in high risk patients, which can be facilitated by close collaboration between orthopaedic surgeons and rheumatologists or other metabolic bone experts. Therefore, the aim was to establish for the first time collaborative recommendations for these patients. According to the EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations, 7 rheumatologists, a geriatrician and 10 orthopaedic surgeons met twice under the leadership of 2 convenors, a senior advisor, a clinical epidemiologist and 3 research fellows. After defining the content and procedures of the task force, 10 research questions were formulated, a comprehensive and systematic literature search was performed and the results were presented to the entire committee. 10 recommendations were formulated based on evidence from the literature and after discussion and consensus building in the group. The recommendations included appropriate medical and surgical perioperative care, which requires, especially in the elderly, a multidisciplinary approach including orthogeriatric care. A coordinator should setup a process for the systematic investigations for future fracture risk in all elderly patients with a recent fracture. High-risk patients should have appropriate non-pharmacological and pharmacological treatment to decrease the risk of subsequent fracture. PMID- 28007758 TI - Drug-free sustained remission or spontaneous remission by natural history in rheumatoid arthritis? An unsolved question: comment on the article of Ajeganova et al. PMID- 28007759 TI - Magnetic resonance perfusion image features uncover an angiogenic subgroup of glioblastoma patients with poor survival and better response to antiangiogenic treatment. AB - Background: In previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies. Methods: Quantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated. Results: A subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (P values <.01; hazard ratios > 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log rank P=.022). Conclusions: Our findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival. PMID- 28007760 TI - Predictive value of work-related self-efficacy change on RTW for employees with common mental disorders. AB - To improve interventions that aim to promote return to work (RTW) of workers with common mental disorders (CMD), insight into modifiable predictors of RTW is needed. This study tested the predictive value of self-efficacy change for RTW in addition to preintervention levels of self-efficacy. RTW self-efficacy was measured 5 times within 9 months among 168 clients of a mental healthcare organisation who were on sick leave due to CMD. Self-efficacy parameters were modelled with multilevel analyses and added as predictors into a Cox regression analysis. Results showed that both high baseline self-efficacy and self-efficacy increase until full RTW were predictive of a shorter duration until full RTW. Both self-efficacy parameters remained significant predictors of RTW when controlled for several relevant covariates and within subgroups of employees with either high or low preintervention self-efficacy levels. This is the first study that demonstrated the prognostic value of self-efficacy change, over and above the influence of psychological symptoms, for RTW among employees with CMD. By showing that RTW self-efficacy increase predicted a shorter duration until full RTW, this study points to the relevance of enhancing RTW self-efficacy in occupational or mental health interventions for employees with CMD. Efforts to improve self-efficacy appear valuable both for people with relatively low and high baseline self-efficacy. PMID- 28007762 TI - Association of Pre-Transplant Dialysis Modality and Post-Transplant Outcomes: A Meta-Analysis. AB - ? BACKGROUND: It remains unclear whether post-transplant outcomes differ according to the pre-transplant dialysis modality (peritoneal dialysis [PD] versus hemodialysis [HD]). We performed a meta-analysis of studies that assessed either post-transplant mortality, graft survival, or delayed graft function (DGF) in both PD and HD patients. ? METHODS: Two independent authors searched English language literature from January 1, 1980, through August 31, 2014, national conference proceedings, and reference lists. We used combinations of terms related to dialysis (hemodialysis, peritoneal dialysis, or renal replacement therapy), kidney transplant, and outcomes. Studies were included if they measured any of the 3 post-transplant study outcomes in both pre-transplant HD and PD. ? RESULTS: A total of 16 studies were included in the final analysis. Of these, 6 studies reported adjusted hazard ratio for mortality, pooled adjusted risk ratio: 0.89 (95% confidence interval [CI] 0.82 - 0.97) in favor of PD (p = 0.006). The same 6 studies reported adjusted hazard ratio for graft survival, pooled adjusted risk ratio: 0.97 (95% CI 0.92 - 1.01, p = 0.16). A total of 13 studies reported unadjusted DGF. Pooled odds ratio: 0.5 (95% CI 0.41 - 0.63) in favor of PD (p < 0.005). Significant heterogeneity observed for all outcomes: I2 = 72.7%, I2 = 59.9%, and I2 = 66.8%, respectively. ? CONCLUSIONS: Based on these results, pre transplant PD is associated with better post-transplant survival than HD. Pre transplant PD was also associated with decreased risk for DGF compared with HD, although these results were unadjusted. There was no significant difference in graft survival between pre-transplant HD and PD. These results suggest that PD may be the preferred dialysis modality for patients expected to receive a transplant. PMID- 28007761 TI - Functional MU-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area. AB - : The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of MU-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT: The MU-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder. PMID- 28007763 TI - Early and Late Patient Outcomes in Urgent-Start Peritoneal Dialysis. AB - BACKGROUND: Significant interest in the practice of urgent-start peritoneal dialysis (PD) is mounting internationally, with several observational studies supporting the safety, efficacy, and feasibility of this approach. However, little is known about the early complication rates and long-term technique and peritonitis-free survival for patients who start PD urgently (i.e. within 2 weeks of catheter insertion), compared to those with a conventional start. METHODS: This single-center, matched case-control study evaluated patients commencing PD between 2010 and 2015. Urgent-start PD patients were matched 1:3 with conventional-start PD controls based on diabetic status and age. The primary outcomes were early complications, both following catheter insertion and PD commencement (within 4 weeks). Secondary outcomes included technique and peritonitis-free survival. RESULTS: A total of 104 patients (26 urgent-start, 78 conventional-start) were included. Urgent-start patients were more likely to be referred late, initiate PD in hospital, and be prescribed lower initial exchange volumes (p < 0.01). They experienced more frequent leaks post-catheter insertion (12% vs 1%, p = 0.047) and more frequent catheter migration following commencement of PD (12% vs 1%, p = 0.047). There were no significant differences in the rates of overall or infectious complications. Kaplan-Meier estimates of technique survival and time to first episode of peritonitis were comparable between the groups. CONCLUSION: Compared with conventional-start PD, urgent-start PD has acceptably low early complication rates and similar long-term technique survival. Urgent-start PD appears to be a safe way to initiate urgent renal replacement therapy in patients without established dialysis access. PMID- 28007764 TI - Crediting animals in scientific literature: Recognition in addition to Replacement, Reduction, & Refinement [4R]. PMID- 28007766 TI - The Efficacy of Shielding Systems for Reducing Operator Exposure during Neurointerventional Procedures: A Real-World Prospective Study. AB - BACKGROUND AND PURPOSE: Neurointerventional surgery may expose patients and physician operators to substantial amounts of ionizing radiation. Although strategies for reducing patient exposure have been explored in the medical literature, there has been relatively little published in regards to decreasing operator exposure. The purpose of this study was to evaluate the efficacy of shielding systems in reducing physician exposure in a modern neurointerventional practice. MATERIALS AND METHODS: Informed consent was obtained from operators for this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved study. Operator radiation exposure was prospectively measured during 60 consecutive neurointerventional procedures from October to November 2013 using a 3-part lead shielding system. Exposure was then evaluated without lead shielding in a second 60-procedure block from April to May 2014. A radiation protection drape was randomly selected for use in half of the cases in each block. Two-way analysis of covariance was performed to test the effect of shielding systems on operator exposure while controlling for other covariates, including procedure dose-area product. RESULTS: Mean operator procedure dose was 20.6 MUSv for the entire cohort and 17.7 MUSv when using some type of shielding. Operator exposure significantly correlated with procedure dose-area product, but not with other covariates. After we adjusted for procedure dose-area product, the use of lead shielding or a radiation protection drape significantly reduced operator exposure by 45% (F = 12.54, P < .0001) and 29% (F = 7.02, P = .009), respectively. The difference in protection afforded by these systems was not statistically significant (P = .46), and their adjunctive use did not provide additional protection. CONCLUSIONS: Extensive lead shielding should be used as much as possible in neurointerventional surgery to reduce operator radiation exposure to acceptable levels. A radiation protection drape is a reasonable alternative when standard lead shielding is unavailable or impractical to use without neglecting strategies to minimize the dose. PMID- 28007765 TI - Changing POU dimerization preferences converts Oct6 into a pluripotency inducer. AB - The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA-binding and reprogramming activity of Oct4 and Oct6. In enhancers of pluripotency genes, Oct4 cooperates with Sox2 on heterodimeric SoxOct elements. By re-analyzing ChIP-Seq data and performing dimerization assays, we found that Oct6 homodimerizes on palindromic OctOct more cooperatively and more stably than Oct4. Using structural and biochemical analyses, we identified a single amino acid directing binding to the respective DNA elements. A change in this amino acid decreases the ability of Oct4 to generate iPSCs, while the reverse mutation in Oct6 does not augment its reprogramming activity. Yet, with two additional amino acid exchanges, Oct6 acquires the ability to generate iPSCs and maintain pluripotency. Together, we demonstrate that cell type-specific POU factor function is determined by select residues that affect DNA-dependent dimerization. PMID- 28007767 TI - Usefulness of Non-Contrast-Enhanced MR Angiography Using a Silent Scan for Follow Up after Y-Configuration Stent-Assisted Coil Embolization for Basilar Tip Aneurysms. AB - BACKGROUND AND PURPOSE: Y-configuration stent-assisted coil embolization is used for treating wide-neck aneurysms. Noninvasive alternatives to x-ray DSA for follow-up after Y-configuration stent-assisted coil embolization treatment are required. This study aimed to assess the usefulness of non-contrast-enhanced MRA by using a Silent Scan (silent MRA) for follow-up after Y-configuration stent assisted coil embolization for basilar tip aneurysms. MATERIALS AND METHODS: Seven patients treated with Y-configuration stent-assisted coil embolization for basilar tip aneurysms underwent silent MRA, 3D TOF-MRA, and DSA. Silent MRA and 3D TOF-MRA images were obtained during the same scan session on a 3T MR imaging system. Two neuroradiologists independently reviewed both types of MRA images and subjectively scored the flow in the stents on a scale of 1 (not visible) to 5 (nearly equal to DSA) by referring to the latest DSA image as a criterion standard. Furthermore, we evaluated the visualization of the neck remnant. RESULTS: In all patients, the 2 observers gave a higher score for the flow in the stents on silent MRA than on 3D TOF-MRA. The average score +/- standard deviation was 4.07 +/- 0.70 for silent MRA and 1.93 +/- 0.80 (P < .05) for 3D TOF-MRA. Neck remnants were depicted by DSA in 5 patients. In silent MRA, neck remnants were depicted in 5 patients, and visualization was similar to DSA; however, in 3D TOF MRA, neck remnants were depicted in only 1 patient. CONCLUSIONS: Silent MRA might be useful for follow-up after Y-configuration stent-assisted coil embolization. PMID- 28007770 TI - Flow Diversion in Ruptured Intracranial Aneurysms: A Meta-Analysis. AB - BACKGROUND: Flow diversion is now an established technique to treat unruptured intracranial aneurysms not readily amenable to endovascular coil embolization or open microsurgical occlusion. The role of flow-diverting devices in treating ruptured aneurysms is less clear. PURPOSE: To estimate rates of angiographic occlusion and good clinical outcome in patients with ruptured intracranial aneurysms treated with flow-diverting devices. DATA SOURCES: Systematic review of Ovid MEDLINE, PubMed, Cochrane databases, and EMBASE from inception to December 2015 for articles that included ruptured aneurysms treated with flow diversion. STUDY SELECTION: One hundred seventy-two records were screened, of which 20 articles contained sufficient patient and outcome data for inclusion. DATA ANALYSIS: Clinical and radiologic characteristics, procedural details, and outcomes were extracted from these reports. Aggregated occlusion rates and clinical outcomes were analyzed by using the Fisher exact test (statistical significance, alpha = .05). DATA SYNTHESIS: Complete occlusion of the aneurysm was achieved in 90% of patients, and favorable clinical outcome was attained in 81%. Aneurysm size greater than 7 mm was associated with less favorable clinical outcomes (P = .027). Aneurysm size greater than 2 cm was associated with a greater risk of rerupture after treatment (P < .001). LIMITATIONS: Observational studies and case reports may be affected by reporting bias. CONCLUSIONS: Although not recommended as a first-line treatment, the use of flow diverters to treat ruptured intracranial aneurysms may allow high rates of angiographic occlusion and good clinical outcome in carefully selected patients. Aneurysm size contributes to treatment risk because the rerupture rate following treatment is higher for aneurysms larger than 2 cm. PMID- 28007769 TI - Surpass Flow Diverter for Treatment of Posterior Circulation Aneurysms. AB - BACKGROUND AND PURPOSE: Flow diverters for the treatment of posterior circulation aneurysms remain controversial. We aimed to identify factors contributing to outcome measures in patients treated with the Surpass flow diverter for aneurysms in this location. MATERIALS AND METHODS: We conducted an observational study of 53 patients who underwent flow-diverter treatment for posterior circulation aneurysms at 15 centers. Key outcome measures were mortality, complete aneurysm occlusion, and modified Rankin Scale score at follow-up. RESULTS: At follow-up (median, 11.3 months; interquartile range, 5.9-12.7 months), 9 patients had died, resulting in an all-cause mortality rate of 17.3% (95% CI, 7%-27.6%); 7 deaths (14%) were directly related to the procedure and none occurred in patients with a baseline mRS score of zero. After adjusting for covariates, a baseline mRS of 3-5 was more significantly (P = .003) associated with a higher hazard ratio for death than a baseline mRS of 0-2 (hazard ratio, 17.11; 95% CI, 2.69-109.02). After adjusting for follow-up duration, a 1-point increase in the baseline mRS was significantly (P < .001) associated with higher values of mRS at follow-up (odds ratio, 2.93; 95% CI, 1.79-4.79). Follow-up angiography in 44 patients (median, 11.3 months; interquartile range, 5.9-12.7 months) showed complete aneurysm occlusion in 29 (66%; 95% CI, 50.1%-79.5%). CONCLUSIONS: Clinical results of flow diverter treatment of posterior circulation aneurysms depend very much on patient selection. In this study, poorer outcomes were related to the treatment of aneurysms in patients with higher baseline mRS scores. Angiographic results showed a high occlusion rate for this subset of complex aneurysms. PMID- 28007768 TI - Toward Precision and Reproducibility of Diffusion Tensor Imaging: A Multicenter Diffusion Phantom and Traveling Volunteer Study. AB - BACKGROUND AND PURPOSE: Precision medicine is an approach to disease diagnosis, treatment, and prevention that relies on quantitative biomarkers that minimize the variability of individual patient measurements. The aim of this study was to assess the intersite variability after harmonization of a high-angular-resolution 3T diffusion tensor imaging protocol across 13 scanners at the 11 academic medical centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury multisite study. MATERIALS AND METHODS: Diffusion MR imaging was acquired from a novel isotropic diffusion phantom developed at the National Institute of Standards and Technology and from the brain of a traveling volunteer on thirteen 3T MR imaging scanners representing 3 major vendors (GE Healthcare, Philips Healthcare, and Siemens). Means of the DTI parameters and their coefficients of variation across scanners were calculated for each DTI metric and white matter tract. RESULTS: For the National Institute of Standards and Technology diffusion phantom, the coefficients of variation of the apparent diffusion coefficient across the 13 scanners was <3.8% for a range of diffusivities from 0.4 to 1.1 * 10-6 mm2/s. For the volunteer, the coefficients of variations across scanners of the 4 primary DTI metrics, each averaged over the entire white matter skeleton, were all <5%. In individual white matter tracts, large central pathways showed good reproducibility with the coefficients of variation consistently below 5%. However, smaller tracts showed more variability, with the coefficients of variation of some DTI metrics reaching 10%. CONCLUSIONS: The results suggest the feasibility of standardizing DTI across 3T scanners from different MR imaging vendors in a large-scale neuroimaging research study. PMID- 28007771 TI - Multivariate Analysis of MRI Biomarkers for Predicting Neurologic Impairment in Cervical Spinal Cord Injury. AB - BACKGROUND AND PURPOSE: Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment. MATERIALS AND METHODS: We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment. RESULTS: Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short term impairment, even when correcting for surgical decompression and degree of cord compression. CONCLUSIONS: This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging. PMID- 28007772 TI - Imaging Carotid Atherosclerosis Plaque Ulceration: Comparison of Advanced Imaging Modalities and Recent Developments. AB - Atherosclerosis remains the leading cause of long-term mortality and morbidity worldwide, despite remarkable advancement in its management. Vulnerable atherosclerotic plaques are principally responsible for thromboembolic events in various arterial territories such as carotid, coronary, and lower limb vessels. Carotid plaque ulceration is one of the key features associated with plaque vulnerability and is considered a notable indicator of previous plaque rupture and possible future cerebrovascular events. Multiple imaging modalities have been used to assess the degree of carotid plaque ulceration for diagnostic and research purposes. Early diagnosis and management of carotid artery disease could prevent further cerebrovascular events. In this review, we highlight the merits and limitations of various imaging techniques for identifying plaque ulceration. PMID- 28007773 TI - Maternal Smoking during Pregnancy, Household Smoking after the Child's Birth, and Childhood Proteinuria at Age 3 Years. AB - BACKGROUND AND OBJECTIVES: Smoking is a well known risk factor of proteinuria in adults; however, clinical studies in children are limited. The purpose of this study is to clarify the associations of maternal smoking during pregnancy and household smoking after the child's birth with the risk of proteinuria at age 3 years old. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a population-based retrospective cohort study on 44,595 children using data on prenatal health checkups, home visit neonatal health checkups, and health checkups at 4, 9, and 18 months and 3 years of age in Kobe City, Japan. Maternal smoking status (nonsmoker, past smoker, or current smoker) was collected with standardized questionnaires. The outcome of interest was the presence of proteinuria at 3 years of age defined as urinary protein >=1+. To evaluate the association between child proteinuria and smoking status, we performed multivariate logistic regression model analyses adjusted for confounding factors. RESULTS: The prevalence rates of children in the maternal smoking groups (none, past, and current) were 78.9%, 4.4%, and 16.7%, respectively. The frequencies of child proteinuria defined as >=1+ urinary protein were 1.7% in the current smoking group, 1.6% in the past smoking group, and 1.3% in the nonsmoking group. Maternal smoking during pregnancy was associated with child proteinuria (odds ratio, 1.24; 95% confidence interval, 1.00 to 1.52; P=0.05) in the multiple logistic regression model, although nonmaternal family smoking during pregnancy was not significantly associated with child proteinuria (odds ratio, 0.97; 95% confidence interval, 0.79 to 1.19; P=0.77). We also found a similar association with household smoking after the child's birth (odds ratio, 1.23; 95% confidence interval, 0.99 to 1.54; P=0.06), although this observation was not significant. CONCLUSIONS: Maternal smoking during pregnancy was one of the risk factors of childhood proteinuria. We also found a similar association with household smoking after the child's birth, although this observation was not significant. PMID- 28007775 TI - Beating the Clock in T-cell Acute Lymphoblastic Leukemia. AB - CDK4/6 inhibition was synergistic with dexamethasone and everolimus but antagonistic with conventional chemotherapy in T-cell acute lymphoblastic leukemia (T-ALL) preclinical models. Cyclin-dependent kinase inhibition in combination with glucocorticoids and mTOR inhibition offers a unique therapeutic opportunity in T-ALL. Clin Cancer Res; 23(4); 873-5. (c)2016 AACRSee related article by Pikman et al., p. 1012. PMID- 28007774 TI - Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab. AB - Purpose: A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.Experimental Design: A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC).Results: A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively.Conclusions: Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy. Clin Cancer Res; 23(12); 2972-80. (c)2016 AACR. PMID- 28007776 TI - Immune Cytolytic Activity Stratifies Molecular Subsets of Human Pancreatic Cancer. AB - Purpose: Immunotherapy has the potential to improve the dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials, including those with single-agent PD-1 or PD-L1 inhibition, have been disappointing. Our aim was to examine the immune landscape of PDA as it relates to aspects of tumor biology, including neoepitope burden.Experimental Design: We used publicly available expression data from 134 primary resection PDA samples from The Cancer Genome Atlas to stratify patients according to a cytolytic T-cell activity expression index. We correlated cytolytic immune activity with mutational, structural, and neoepitope features of the tumor.Results: Human PDA displays a range of intratumoral cytolytic T-cell activity. PDA tumors with low cytolytic activity exhibited significantly increased copy number alterations, including recurrent amplifications of MYC and NOTCH2 and recurrent deletions and mutations of CDKN2A/B In sharp contrast to other tumor types, high cytolytic activity in PDA did not correlate with increased mutational burden or neoepitope load (MHC class I and class II). Cytolytic-high tumors exhibited increased expression of multiple immune checkpoint genes compared to cytolytic-low tumors, except for PD-L1 expression, which was uniformly low.Conclusions: These data identify a subset of human PDA with high cytolytic T-cell activity. Rather than being linked to mutation burden or neoepitope load, immune activation indices in PDA were inversely linked to genomic alterations, suggesting that intrinsic oncogenic processes drive immune inactivity in human PDA. Furthermore, these data highlight the potential importance of immune checkpoints other than PD-L1/PD-1 as therapeutic targets in this lethal disease. Clin Cancer Res; 23(12); 3129-38. (c)2016 AACR. PMID- 28007777 TI - Noninvasive Measurement of mTORC1 Signaling with 89Zr-Transferrin. AB - Purpose: mTOR regulates many normal physiological processes and when hyperactive can drive numerous cancers and human diseases. However, it is very challenging to detect and quantify mTOR signaling noninvasively in clinically relevant animal models of disease or man. We hypothesized that a nuclear imaging tool measuring intracellular mTOR activity could address this unmet need.Experimental Design: Although the biochemical activity of mTOR is not directly amenable to nuclear imaging probe development, we show that the transferrin receptor can be used to indirectly measure intracellular changes in mTOR activity.Results: After verifying that the uptake of radiolabeled transferrin (the soluble ligand of the transferrin receptor) is stimulated by active mTORC1 in vitro, we showed that 89Zr-labeled transferrin (Tf) can measure mTORC1 signaling dynamics in normal and cancerous mouse tissues with PET. Finally, we show that 89Zr-Tf can detect the upregulation of mTORC1 by tumor cells to escape the antitumor effects of a standard-of-care antiandrogen, which is to our knowledge the first example of applying PET to interrogate the biology of treatment resistant cancer.Conclusions: In summary, we have developed the first quantitative assay to provide a comprehensive measurement of mTOR signaling dynamics in vivo, in specific normal tissues, and during tumor development in genetically engineered animal models using a nuclear imaging tool that is readily translatable to man. Clin Cancer Res; 23(12); 3045-52. (c)2016 AACR. PMID- 28007778 TI - Longitudinal Trajectories of Metabolic Control From Childhood to Young Adulthood in Type 1 Diabetes From a Large German/Austrian Registry: A Group-Based Modeling Approach. AB - OBJECTIVE: Worsening of glycemic control in type 1 diabetes during puberty is a common observation. However, HbA1c remains stable or even improves for some youths. The aim is to identify distinct patterns of glycemic control in type 1 diabetes from childhood to young adulthood. RESEARCH DESIGN AND METHODS: A total of 6,433 patients with type 1 diabetes were selected from the prospective, multicenter diabetes patient registry Diabetes-Patienten-Verlaufsdokumentation (DPV) (follow-up from age 8 to 19 years, baseline diabetes duration >=2 years, HbA1c aggregated per year of life). We used latent class growth modeling as the trajectory approach to determine distinct subgroups following a similar trajectory for HbA1c over time. RESULTS: Five distinct longitudinal trajectories of HbA1c were determined, comprising group 1 = 40%, group 2 = 27%, group 3 = 15%, group 4 = 13%, and group 5 = 5% of patients. Groups 1-3 indicated stable glycemic control at different HbA1c levels. At baseline, similar HbA1c was observed in group 1 and group 4, but HbA1c deteriorated in group 4 from age 8 to 19 years. Similar patterns were present in group 3 and group 5. We observed differences in self-monitoring of blood glucose, insulin therapy, daily insulin dose, physical activity, BMI SD score, body-height SD score, and migration background across all HbA1c trajectories (all P <= 0.001). No sex differences were present. Comparing groups with similar initial HbA1c but different patterns, groups with higher HbA1c increase were characterized by lower frequency of self-monitoring of blood glucose and physical activity and reduced height (all P < 0.01). CONCLUSIONS: Using a trajectory approach, we determined five distinct longitudinal patterns of glycemic control from childhood to early adulthood. Diabetes self-care, treatment differences, and demographics were related to different HbA1c courses. PMID- 28007779 TI - Health Care Transition Preparation and Experiences in a U.S. National Sample of Young Adults With Type 1 Diabetes. AB - OBJECTIVE: Young adults with type 1 diabetes transitioning from pediatric to adult care are at risk for adverse outcomes. We developed a survey to evaluate transition experiences in two groups of young adults with type 1 diabetes, before (PEDS) and after (ADULT) transition to adult care. RESEARCH DESIGN AND METHODS: We fielded an electronic survey to young adults (18 to <30 years) at 60 T1D Exchange Clinic Registry centers. RESULTS: Surveys were completed by 602 young adults, 303 in the PEDS group (60% female, age 20 +/- 2 years) and 299 in the ADULT group (62% female, age 24 +/- 3 years). In the PEDS group, mean anticipated transition age was 22 +/- 2 years; 64% remained in pediatric care because of emotional attachment to the provider. The ADULT group transitioned at age 19 +/- 2 years, mainly after pediatric provider recommendation. More than 80% of respondents reported receiving counseling on type 1 diabetes self-management and screening tests from pediatric providers, but less than half (43% PEDS and 33% ADULT) reported discussing reproductive health. In the PEDS group, half had discussed transfer with pediatric providers. Of the ADULT participants, 63% received an adult provider referral, and 66% felt mostly/completely prepared to transition. ADULT participants with fewer pretransition pediatric visits or who felt unprepared for transition had increased odds of gaps >6 months between pediatric and adult care. Receipt of transition preparation counseling was not associated with self-reported hemoglobin A1c <7.0% in either group. CONCLUSIONS: These results support the need for intensive efforts to integrate transition preparation counseling and care coordination into pediatric type 1 diabetes care. PMID- 28007780 TI - Ficin-Treated Red Cells Help Identify Clinically Significant Alloantibodies Masked as Reactions of Undetermined Specificity in Gel Microtubes. AB - Non-specific antibodies or antibodies of undetermined significance (AUS) often pose problems for a blood bank technologist and physician. It is well known that antibodies can weaken and evanesce over time, thus eluding detection by routine blood bank techniques. Special enhancement techniques exist (eg, ficin treatment); however, they are often underutilized due to concerns over expense. Ficin is known to enhance reactivity caused by antibodies in the ABO, Rh, Kidd, Lewis, I, and P blood group systems, while destroying reactivity of antibodies in the Duffy, and MNS blood group systems. Herein, we discuss our protocol for using ficin treatment to determine the specificity of antibodies that would otherwise be classified as AUS. Of the 97 AUS specimens that were treated with ficin, we were able to identify 25 new alloantibodies that would have otherwise been missed without ficin treatment. Thus, we believe our protocol enhances transfusion safety, while minimizing additional workload and cost. PMID- 28007781 TI - Transient receptor potential vanilloid 2 activation by focal mechanical stimulation requires interaction with the actin cytoskeleton and enhances growth cone motility. AB - We have previously reported that transient receptor potential vanilloid 2 (TRPV2) can be activated by mechanical stimulation, which enhances axonal outgrowth in developing neurons; however, the molecular mechanisms that govern the contribution of TRPV2 activation to axonal outgrowth remain unclear. In the present study, we examined this mechanism by using PC12 cells as a neuronal model. Overexpression of TRPV2 enhanced axonal outgrowth in a mechanical stimulus dependent manner. Accumulation of TRPV2 at the cell surface was 4-fold greater in the growth cone compared with the soma. In the growth cone, TRPV2 is not static, but dynamically accumulates (within ~100 ms) to the site of mechanical stimulation. The dynamic and acute clustering of TRPV2 can enhance very weak mechanical stimuli via focal accumulation of TRPV2. Focal application of mechanical stimuli dramatically increased growth cone motility and caused actin reorganization via activation of TRPV2. We also found that TRPV2 physically interacts with actin and that changes in the actin cytoskeleton are required for its activation. Here, we demonstrated for the first time to our knowledge that TRPV2 clustering is induced by mechanical stimulation generated by axonal outgrowth and that TRPV2 activation is triggered by actin rearrangements that result from mechanical stimulation. Moreover, TRPV2 activation enhances growth cone motility and actin accumulation to promote axonal outgrowth. Sugio, S., Nagasawa, M., Kojima, I., Ishizaki, Y., Shibasaki, K. Transient receptor potential vanilloid 2 activation by focal mechanical stimulation requires interaction with the actin cytoskeleton and enhances growth cone motility. PMID- 28007782 TI - Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity. AB - Endogenous fatty acid metabolism that results in elongation and desaturation lipid products is thought to play a role in the development of type 2 diabetes mellitus (T2DM). In this study, we evaluated the potential of estimated elongase and desaturase activities for use as predictive markers for T2DM remission after Roux-en-Y gastric bypass (RYGB). The results of a targeted metabolomics approach from 2 independent studies were used to calculate 24 serum FA concentration ratios (product/precursor). Gene expression data from an open public data set was also analyzed. In a longitudinal study of 38 obese diabetic patients with RYGB, we found higher baseline stearic acid/palmitic acid (S/P) ratio. This ratio reflects an elovl6-encoded elongase enzyme activity that has been found to be associated with greater possibility for diabetes remission after RYGB [odds ratio, 2.16 (95% CI 1.10-4.26)], after adjustment for age, gender, body mass index, diabetes duration, glycosylated hemoglobin A1c, and fasting C-peptide. Our results were validated by examination of postsurgical elovl6 gene expression in morbidly obese patients. The association of S/P with the metabolic status of obese individuals was further validated in a cross-sectional cohort of 381 participants. In summary, higher baseline S/P was associated with greater probability of diabetes remission after RYGB and may serve as a diagnostic marker in preoperative patient assessment. - Zhao, L., Ni, Y., Yu, H., Zhang, P., Zhao, A., Bao, Y., Liu, J., Chen, T., Xie, G., Panee, J., Chen, W., Rajani, C., Wei, R., Su, M., Jia, W., Jia, W. Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity. PMID- 28007784 TI - An ensemble of regulatory elements controls Runx3 spatiotemporal expression in subsets of dorsal root ganglia proprioceptive neurons. AB - The Runx3 transcription factor is essential for development and diversification of the dorsal root ganglia (DRGs) TrkC sensory neurons. In Runx3-deficient mice, developing TrkC neurons fail to extend central and peripheral afferents, leading to cell death and disruption of the stretch reflex circuit, resulting in severe limb ataxia. Despite its central role, the mechanisms underlying the spatiotemporal expression specificities of Runx3 in TrkC neurons were largely unknown. Here we first defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3. Using transgenic mice expressing BAC reporters spanning the Runx3 locus, we discovered three REs-dubbed R1, R2, and R3-that cross-talk with promoter-2 (P2) to drive TrkC neuron-specific Runx3 transcription. Deletion of single or multiple elements either in the BAC transgenics or by CRISPR/Cas9-mediated endogenous ablation established the REs' ability to promote and/or repress Runx3 expression in developing sensory neurons. Our analysis reveals that an intricate combinatorial interplay among the three REs governs Runx3 expression in distinct subtypes of TrkC neurons while concomitantly extinguishing its expression in non TrkC neurons. These findings provide insights into the mechanism regulating cell type-specific expression and subtype diversification of TrkC neurons in developing DRGs. PMID- 28007785 TI - p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis. AB - Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK-hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications. PMID- 28007783 TI - Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. AB - Nonalcoholic fatty liver disease (NAFLD) is widespread in adults and children. Early exposure to maternal obesity or Western-style diet (WD) increases steatosis and oxidative stress in fetal liver and is associated with lifetime disease risk in the offspring. Pyrroloquinoline quinone (PQQ) is a natural antioxidant found in soil, enriched in human breast milk, and essential for development in mammals. We investigated whether a supplemental dose of PQQ, provided prenatally in a mouse model of diet-induced obesity during pregnancy, could protect obese offspring from progression of NAFLD. PQQ treatment given pre- and postnatally in WD-fed offspring had no effect on weight gain but increased metabolic flexibility while reducing body fat and liver lipids, compared with untreated obese offspring. Indices of NAFLD, including hepatic ceramide levels, oxidative stress, and expression of proinflammatory genes (Nos2, Nlrp3, Il6, and Ptgs2), were decreased in WD PQQ-fed mice, concomitant with increased expression of fatty acid oxidation genes and decreased Pparg expression. Notably, these changes persisted even after PQQ withdrawal at weaning. Our results suggest that supplementation with PQQ, particularly during pregnancy and lactation, protects offspring from WD induced developmental programming of hepatic lipotoxicity and may help slow the advancing epidemic of NAFLD in the next generation.-Jonscher, K. R., Stewart, M. S., Alfonso-Garcia, A., DeFelice, B. C., Wang, X. X., Luo, Y., Levi, M., Heerwagen, M. J. R., Janssen, R. C., de la Houssaye, B. A., Wiitala, E., Florey, G., Jonscher, R. L., Potma, E. O., Fiehn, O. Friedman, J. E. Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice. PMID- 28007786 TI - Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self renewal. AB - Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self renewal division. PMID- 28007788 TI - Chemical Identification of "Maternal Signature Odors" in Rat. AB - Newborn altricial mammals need just after birth to locate their mother's nipples for suckling. In this precocious behavior, including for the human baby, maternal odor via the olfactory process plays a major role. Maternal odor emitted by lactating females or by amniotic fluid (AF) attracts pups, but the chemical identity of this attractant has not yet been elucidated. Here, using behavioral tests and gas chromatography coupled with mass spectrometry (GC-MS) techniques, we show that AF extracts from rat pregnant female, nipples, ventral skin, milk, and nest extracts of mother contained 3-6 active substances. AF extracts contained 3 active compounds: ethylbenzene, benzaldehyde, and benzyl alcohol, and their mixture in similar proportions to those found in AF extracts, in a ratio, respectively, of 1:1:12 (700 ng), attracts pups as putative maternal attractant substances (MAS). These 3 AF substances have already been identified in milk, nipples, ventral wash, and nest extracts of mother, but not in feces. Moreover, anethole flavor incorporated in pregnant rat and mother's diet is also detected in AF, nipples, milk, and nest extracts and the pups are attracted to anethole odor, but not in the case of the no-anethole pups. MAS, combined with diet flavors present in the AF bath, represent olfactory signals as "maternal signature odors" (MSO) that are learned by fetus and pups. These findings open the way to improved understanding of the neurobiology of early olfactory learning and of the importance of evolutionarily conserved survival behavior in many mammal species. PMID- 28007787 TI - Factors Associated with Inaccurate Self-Reporting of Olfactory Dysfunction in Older US Adults. AB - Self-reported olfactory function has poor sensitivity (i.e., people with measured olfactory dysfunction are unlikely to accurately report it). We aimed to identify factors associated with lack of awareness of smell dysfunction. Objective odor identification was evaluated using a validated 5-item test in respondents from the National Social Life, Health, and Aging Project, a representative sample of home-dwelling, US adults ages 57-85 (n = 1468). Self-reported olfaction was assessed with a 5-point Likert scale. Using multivariate logistic regression, we tested factors that might influence inaccuracy of self-reported olfaction, including age, gender, race/ethnicity, education, marital status, cognition, comorbidity, smoking, depression, anxiety, self-rated mental and physical health, and social activity. Among older US adults, 12.4% reported their sense of smell as fair or poor, while 22.0% had objective olfactory dysfunction (<=3 items correct out of 5). Among those with measured olfactory dysfunction, 74.2% did not recognize it; these individuals were more likely to be older, Black, never married, and to have worse cognitive function compared to individuals who recognized their dysfunction (P < 0.05, all). Individuals who lacked awareness of their olfactory dysfunction had the greatest cognitive impairment at 5-year follow-up, followed by individuals aware of their dysfunction and finally normosmics (P < 0.001). Older Americans with measured olfactory dysfunction are unlikely to report it, and those who lack awareness of this dysfunction have distinct demographic, social, and cognitive characteristics. Therefore, clinicians should objectively test patients. Individuals who lack awareness of their olfactory dysfunction have poor cognitive outcomes and should receive additional clinical scrutiny. PMID- 28007789 TI - Reproductive hormones of ICSI-conceived young adult men: the first results. AB - STUDY QUESTION: Are reproductive hormone levels (FSH, LH, inhibin B and testosterone) in male offspring conceived by ICSI because of male infertility comparable with those from peers born after spontaneous conception? SUMMARY ANSWER: In this cohort of 54 young men conceived by ICSI because of male-factor infertility, mean and median reproductive hormone levels were found to be comparable with results from spontaneously conceived peers, but ICSI-conceived men were more likely to have low inhibin B (<10th percentile) and high FSH (>90th percentile) levels. WHAT IS KNOWN ALREADY: Since the worldwide oldest ICSI offspring have recently reached young adulthood, their reproductive health can now be investigated. This typically involves semen analysis and a hormonal profiling including the measurement of FSH, LH, inhibin B and testosterone. Circulating levels of FSH and inhibin B are generally known as markers of the exocrine function of the testis, i.e. spermatogenesis, while LH and testosterone reflect its endocrine function. We have previously observed a normal pubertal development and comparable levels of inhibin B and testosterone among pubertal ICSI boys when compared to spontaneously conceived peers. However, at present, information on the gonadal function of ICSI offspring in adulthood is still lacking. STUDY DESIGN, SIZE, DURATION: This study, conducted between March 2013 and April 2016 at the UZ Brussel, is part of a larger follow-up project focusing on reproductive and metabolic health of young adults between 18 and 22 years and conceived after ICSI because of male infertility. The ICSI men are part of a longitudinally followed cohort while the spontaneously conceived controls were recruited cross-sectionally. PARTICIPANTS/MATERIALS, SETTING, METHODS: Results of a single fasting blood sample from 54 young adult ICSI men were compared to that of 57 spontaneously conceived peers. Reproductive hormone analysis involved FSH, LH, testosterone and inhibin B measurement. Furthermore, the association between their reproductive hormones and their sperm parameters was examined. Data were analyzed by multiple linear and logistic regression adjusted for covariates. MAIN RESULTS AND THE ROLE OF CHANCE: ICSI men had comparable mean levels of FSH, LH, testosterone and inhibin B in comparison to spontaneously conceived counterparts, even after adjustment for confounders, such as age, BMI and season. Young ICSI conceived men were more likely to have inhibin B levels below the 10th percentile (<125.2 ng/l; Adjusted Odds Ratio (AOR) 4.0; 95% CI: 0.9-18.4; P = 0.07) compared with spontaneously conceived peers and were more likely to have FSH levels above the 90th percentile (>5.5 IU/L; AOR 3.3; 95% CI: 0.9-11.9; P = 0.06) compared with spontaneously conceived peers, but neither difference reached statistical significance. FSH, LH and inhibin B, but not testosterone, levels were significantly associated with sperm concentration and total sperm count. LIMITATIONS, REASONS FOR CAUTION: The main limitation is the small study population. Furthermore, the results of this study should be interpreted according to the background of the participants: all subjects in our study group were conceived by ICSI because of severe male infertility and hence the results cannot be generalized to all ICSI offspring because the indications for performing ICSI have since been widened. WIDER IMPLICATIONS OF THE FINDINGS: These first results in a small group of ICSI men show reassuring reproductive hormonal levels. However, larger studies are required to confirm our results. Since inhibin B and FSH are consistently correlated with semen characteristics, we would suggest that the reproductive status of young adults conceived by ICSI is explored with a hormonal assessment given its easier acceptance compared to semen sampling. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts, all issued by the Vrije Universiteit Brussel (VUB). A grant from the Belgian Society for Pediatric Endocrinology and Diabetology was received for this project. All co authors, except M.B. and H.T., declare no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Centre for Medical Genetics have received several educational grants from IBSA, Ferring, Organon, Shering-Plough, Merck for establishing the database for follow-up research and organizing the data collection. The institution of HT receives research grants from the 'Research Fund of Flanders' (FWO), an unconditional grant from Ferring for research on testicular stem cells and research grants from Ferring, Merck, MSD, Roche, Besins, Goodlife and Cook for several research projects in female infertility. H.T. has received consultancy fees from Finox, Abbott and ObsEva for research projects in female infertility. TRIAL REGISTRATION NUMBER: N/A. PMID- 28007790 TI - The effect of expressive writing intervention for infertile couples: a randomized controlled trial. AB - STUDY QUESTION: Is expressive writing intervention (EWI) efficacious in reducing distress and improving pregnancy rates for couples going through ART treatment? SUMMARY ANSWER: Compared to controls, EWI statistically significantly reduced depressive symptoms but not anxiety and infertility-related distress. WHAT IS KNOWN ALREADY: ART treatment is considered stressful. So far, various psychological interventions have been tested for their potential in reducing infertility-related distress and the results are generally positive. It remains unclear whether EWI, a brief and potentially cost-effective intervention, could be advantageous. STUDY DESIGN SIZE, DURATION: Between November 2010 and July 2012, a total of 295 participants (163 women, 132 men) were randomly allocated to EWI or a neutral writing control group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were couples undergoing IVF/ICSI treatment. Single women and couples with Preimplantation Genetic Diagnosis or acute change of procedure from insemination to IVF, were excluded. EWI participants participated in three 20-min home-based writing exercises focusing on emotional disclosure in relation to infertility/fertility treatment (two sessions) and benefit finding (one session). Controls wrote non-emotionally in three 20-min sessions about their daily activities. The participants completed questionnaires at the beginning of treatment (t1), prior to the pregnancy test (t2), and 3 months later (t3). In total, 26.8% (79/295) were lost to follow-up. Mixed linear models were chosen to compare the two groups over time for psychological outcomes (depression, anxiety and infertility-related distress), and a Chi2 test was employed in order to examine group differences in pregnancy rates MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and fifty-three participants received EWI (women = 83; men = 70) and 142 participants were allocated to the neutral writing control group (women = 83; men = 62). Both women and partners in the EWI group exhibited greater reductions in depressive symptoms compared with controls (P = 0.049; [CI 95%: -0.04; -0.01] Cohen's d = 0.27). The effect of EWI on anxiety did not reach statistical significance. Overall infertility-related distress increased marginally for the partners in the EWI group compared to the partners in the control group (P = 0.06; Cohen's d = 0.17). However, in relation to the personal subdomain, the increase was statistically significant (P = 0.01; Cohen's d = 0.24). EWI had no statistically significant effect on pregnancy rates with 42/83 (50.6%) achieving pregnancy in the EWI group compared with 40/80 (49.4%) in the control group (RR = 0.99 [CI 95% = 0.725, 1.341]; P = 0.94). LIMITATIONS, REASONS FOR CAUTION: The results for depressive symptoms corresponded to a small effect size and the remaining results failed to reach statistical significance. This could be due to sample characteristics leading to a possible floor-effect, as we did not exclude participants with low levels of emotional distress at baseline. Furthermore, men showed increased infertility-related distress over time. WIDER IMPLICATIONS OF THE FINDINGS: EWI is a potentially cost-effective and easy to implement home based intervention, and even small effects may be relevant. When faced with infertility, EWI could thus be a relevant tool for alleviating depressive symptoms by allowing the expression of feelings about infertility that may be perceived as socially unacceptable. However, the implications do not seem to be applicable for men, who presented with increased infertility-related distress over time. STUDY FUNDING/COMPETING INTERESTS: The present study was supported by research grants from Merck Sharpe and Dohme and The Danish Agency for Science Technology and Innovation as part of a publicly funded PhD. The funding bodies had no influence on the data collection, analysis or conclusions of the study. None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, trial no. NCT01187095. TRIAL REGISTRATION DATE: 7th September 2010 DATE OF FIRST PATIENT'S ENROLMENT: 23rd November 2010. PMID- 28007791 TI - Factors associated with seminal impairment in HIV-infected men under antiretroviral therapy. AB - STUDY QUESTION: How do semen parameters of HIV-infected men under antiretroviral treatment compare with WHO parameters of normal semen, and what factors are associated with any differences? SUMMARY ANSWER: Semen quality in most HIV infected patients under antiretroviral treatment exceeds WHO limits, but the number falling below them is higher than would be expected in a healthy population. Exposure to efavirenz has a significant association with dysmotility. WHAT IS KNOWN ALREADY: Dysmotility is the most frequently described sperm alteration related to HIV infection, and it has recently been linked to treatment with non-nucleoside reverse transcriptase inhibitors, particularly to efavirenz. STUDY DESIGN, SIZE, DURATION: Prospective cohort study. Between March 2002 and December 2013, 139 HIV-infected men undergoing antiretroviral therapy were enrolled. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were male members of serodiscordant couples who attended a clinic for sexually transmitted infections (STIs) in Madrid and requested reproductive counselling. Sociodemographic, behavioural and clinical data were collected. CD4+ lymphocyte count, HIV viral load, serology/viral load of hepatitis B and C viruses, syphilis serology and other STIs diagnosis were performed. Semen parameters were assessed through standard sperm analysis and were compared with WHO 2010 reference values. Factors associated with impaired semen parameters were evaluated by bivariate and multivariate analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The median values of all assessed semen parameters were within a normal range, but in up to 19% of HIV positive males, at least one parameter of semen quality was below the normal range. A significant association between treatment with efavirenz and the presence of dysmotility was detected in the multivariate analysis. LIMITATIONS, REASONS FOR CAUTION: Our results cannot demonstrate a causal relationship between exposure to efavirenz and impaired motility. We do not have a real comparison group as the WHO cohort is international and may not reflect local variations in semen characteristics. Subjects who requested reproductive counselling might not be representative of HIV-positive men in general. WIDER IMPLICATIONS OF THE FINDINGS: Since efavirenz is still widely used in current therapeutic regimens may be affecting fertility in seropositive men who desire procreation. STUDY FUNDING/COMPETING INTERESTS: No external funding was used for this study. The authors have no conflict of interest to declare. PMID- 28007792 TI - Association between sleep apnoea and pulmonary hypertension in Kyrgyz highlanders. AB - This case-control study evaluates a possible association between high altitude pulmonary hypertension (HAPH) and sleep apnoea in people living at high altitude.Ninety highlanders living at altitudes >2500 m without excessive erythrocytosis and with normal spirometry were studied at 3250 m (Aksay, Kyrgyzstan); 34 healthy lowlanders living below 800 m were studied at 760 m (Bishkek, Kyrgyzstan). Echocardiography, polysomnography and other outcomes were assessed. Thirty-six highlanders with elevated mean pulmonary artery pressure (mPAP) >30 mmHg (31-42 mmHg by echocardiography) were designated as HAPH+. Their data were compared to that of 54 healthy highlanders (HH, mPAP 13-28 mmHg) and 34 healthy lowlanders (LL, mPAP 8-24 mmHg).The HAPH+ group (median age 52 years (interquartile range 47-59) had a higher apnoea-hypopnoea index (AHI) of 33.8 events.h-1 (26.9-54.6) and spent a greater percentage of the night-time with an oxygen saturation <90% (T<90; 78% (61-89)) than the HH group (median age 39 years (32-48), AHI 9.0 events.h-1 (3.6-16), T<90 33% (10-69)) and the LL group (median age 40 years (30-47), AHI 4.3 events.h-1 (1.4-12.6), T<90 0% (0-0)); p<0.007 for AHI and T<90, respectively, in HAPH+ versus others. In highlanders, multivariable regression analysis confirmed an independent association between mPAP and both AHI and T<90, when controlled for age, gender and body mass index.Pulmonary hypertension in highlanders is associated with sleep apnoea and hypoxaemia even when adjusted for age, gender and body mass index, suggesting pathophysiologic interactions between pulmonary haemodynamics and sleep apnoea. PMID- 28007793 TI - Policy Diffusion across Disparate Disciplines: Private- and Public-Sector Dynamics Affecting State-Level Adoption of the ACA. AB - The ACA entails a number of provisions that are profoundly changing the way the states ensure access to medical care, including the expansion of Medicaid and the maintenance of health insurance exchanges. Here, we argue that while federal policy is the originating force of whether these provisions are adopted, individual state decisions are made within a larger ecosystem. This ecosystem has two main components: (1) complementary and competing state and federal policies; and (2) medical provision by a variety of suppliers. Specifically, the merits, costs, and uncertainties associated with adopting these provisions cannot be considered by the states in a vacuum-they may interact with a large set of simultaneously launched or existing local, state, and federal policies aimed at ensuring access to medical care. They may also interact with specific state and federal reimbursement policies and other requirements facing local hospitals and medical providers. We illustrate by example how these interactions may have important implications for the diffusion of ACA provisions. One implication of this perspective is that future empirical work on the rate, determinants, and impacts of ACA coverage expansions on individual and aggregate well-being must incorporate systematic study of this complex public-private sector ecosystem. PMID- 28007794 TI - Mere Mortals: Overselling the Young Invincibles. AB - This article traces the emergence of the term "young invincible" in health policy literature, the health insurance industry, and popular media. Young invincible is the label given to adults under thirty-five who opt not to purchase health insurance because they perceive that they will not need it and would rather spend their money elsewhere. As uninsurance rates climbed, policy makers tried to figure out who the uninsured were and why they lacked coverage. Young adults rightly assumed importance in these conversations because they were disproportionately represented among the uninsured and their numbers were growing. However, the term "young invincible" had the contradictory effect of centering a white, male, high-income chooser as the subject of health policy discourses rather than the far more diverse mix of people who make up the uninsured. This character was imputed preferences and tastes based in economic theory and in long-standing cultural ideals: he was a risk taker, overly optimistic, and preferred cash now to security later. We argue that this heightened concern over young invincibles distorts understanding of the demographics of people who do not have health insurance. It also stokes intergenerational conflict, and frames structural constraints and high prices as a simple consumer "choice." PMID- 28007795 TI - The Future of Health Care Reform: What Is Driving Enrollment? AB - Against a backdrop of ongoing operational challenges, insurance market turbulence, and the ever present pull of partisanship, enrollment in the ACA's programs has soared and significant variations have developed across states in terms of their pace of coverage expansion. Our article explores why ACA enrollment has varied so dramatically across states. We explore the potential influence of party control, presidential cueing, administrative capacity, the reverberating effects of ACA policy decisions, affluence, and unemployment on enrollment. Our multivariate analysis finds that party control dominated early state decision making, but that relative enrollment in insurance exchanges and the Medicaid expansion are driven by a changing mix of political and administrative factors. Health politics is entering a new era as Republicans replace the ACA and devolve significant discretion to states to administer Medicaid and other programs. Our findings offer insights into future directions in health reform and in learning and diffusion. PMID- 28007797 TI - Framing, Engagement, and Policy Change: Lessons for the ACA. AB - Supporters of the Patient Protection and Affordable Care Act (ACA) sometimes speculate that public attitudes toward the law will shift if proponents succeed in focusing attention on its more popular components, but the scholarly literature on framing effects provides ample reason to question their assertion. This article contends that engagement, an alternative rhetorical strategy where advocates address the same policy dimensions as their opponents, is a more promising approach. Extending the engagement literature to the elite context in which most ACA-related decisions are made, it argues that elite-level engagement necessitates the additional task of linking policy change to opponents' broader philosophical and policy goals. Current debates surrounding the application of sales taxes to electronic commerce-a policy arena that seems far removed from health care policy but overlaps with the ACA in ways that make it an appropriate source of lesson drawing-illustrate the potential of an engagement strategy. Recently, many conservative lawmakers who previously opposed policy change have instead embraced online sales taxes as a mechanism for additional tax cuts. Analogous connections may facilitate the diffusion of ACA provisions that presently receive hostile receptions in Republican-leaning states. PMID- 28007799 TI - The Seeds of Policy Change: Leveraging Diffusion to Disseminate Policy Innovations. AB - We conduct a series of simulations to compare how various strategies for seeding a policy in the American states affect the rate at which that policy spreads. Using empirically derived parameters of the policy diffusion process, we simulate the diffusion of a hypothetical policy after seeding the policy in just a handful of states. We compare these strategies to seeding the ten states the RWJF monitored during the states' implementation of the Affordable Care Act of 2010. We attempt to mimic the choices that policy advocates make when deciding which states to target with their resources. Our results indicate that focusing on innovative states, that is, those that tend to adopt new policies faster, offers a valuable boost in the speed of diffusion. Even better, though, is a strategy that targets policy leaders. PMID- 28007800 TI - The Role of Public Opinion-Does It Influence the Diffusion of ACA Decisions? AB - We consider two ways that public opinion influenced the diffusion of ACA policy choices from 2010 through 2014. First, we consider the policy feedback mechanism, which suggests that policy decisions have spillover effects that influence opinions in other states; residents in the home state then influence the decisions of elected officials. We find that both gubernatorial ACA announcements and grant activity increased support for the ACA in nearby states. Consistent with our expectations, however, only gubernatorial announcements respond to shifts in ACA support, presumably because it is a more salient policy than grant activity. Second, we test for the opinion learning mechanism, which suggests that shifts in public opinion in other states provide a signal to elected officials about the viability of decisions in their own state. We find evidence that states are more likely to emulate other states with similar ACA policy preferences when deciding about when to announce their decisions. Our results suggest that scholars and policy makers should consider how shifts in public support influence the spread of ideas across the American states. PMID- 28007801 TI - Rhetoric and Reform in Waiver States. AB - Seven states have used Section 1115 waivers to expand Medicaid as part of the Affordable Care Act (ACA). While each state pursued a unique plan, there are similarities in the types of changes each state desired to make. Equally important to how a state modified their Medicaid programs is how a state talked about Medicaid and reform. We investigate whether the rhetoric that emerged in waiver states is unique, analyze whether the rhetoric is associated with particular waiver reforms, and consider the implications of our findings for the future of Medicaid policy making. We find that proponents in waiver states have convinced a conservative legislature that their reform is sufficiently innovative that they are not doing a Medicaid expansion, and not building on the traditional Medicaid program. Particularly striking is that none of these reforms are entirely new to the Medicaid program. While not new, the way in which waiver states have been allowed to implement many of the reforms is new and has become stricter. We find an emerging consensus utilized by conservative policy makers in framing the Medicaid expansion. Expansion efforts by conservative policy makers in other states have subsequently pushed this framing far to the right. PMID- 28007802 TI - Tribute to Andy Hyman. PMID- 28007803 TI - Diffusion of ACA Policies across the American States. PMID- 28007804 TI - Policy Diffusion in Polarized Times: The Case of the Affordable Care Act. AB - With increasing ideological polarization both within states and across states, policy makers face new challenges in developing and refining policies. This essay explores these challenges in the context of the spread of health policies across the states under the Affordable Care Act, highlighting key arguments and findings from the authors in this Special Issue. I discuss how common mechanisms of policy diffusion, the attributes of policies themselves, and the conditional nature of policy diffusion all play somewhat different roles during polarized times. In addition to new challenges to policy makers, polarization offers new opportunities for experimentation and learning that may be valuable to scholars and practitioners alike. PMID- 28007805 TI - Editorial: The Mental Capacity Act 2005-Ten Years On. PMID- 28007806 TI - Best Interests in the Mental Capacity Act: Time to say Goodbye? AB - Article 12 of the United Nations Convention on the Rights of Persons with Disabilities, as interpreted by the Committee on the Rights of Persons with Disabilities in General Comment No. 1, offers a vision for law's response to capacity impairments which differs in crucial ways from that contained in the Mental Capacity Act 2005. The Committee rejects the functional test for capacity and requires that a 'will and preferences' paradigm must replace the 'best interests' paradigm and that all substitute decision-making regimes must be abolished. This article draws on the position adopted in General Comment No. 1 in evaluating the best interests standard in the Mental Capacity Act. It sets out the normative case for a stronger legislative endorsement of will and preferences and the inclusion of greater support mechanisms but rejects the contention that all substitute decision-making can, or should, be abolished. It also argues that the best interests standard in the Mental Capacity Act retains some revolutionary potential and that, pending legislative reform, this can be further developed through the courts. PMID- 28007807 TI - Litigation Friends or Foes? Representation of 'P' before the Court of Protection. AB - This article argues that, properly analysed, the common law and the European Convention on Human Rights (ECHR) march hand in hand with the provisions of the Mental Capacity Act 2005 (MCA 2005) so as to impose a set of requirements on litigation friends acting for the subject of applications of proceedings before the Court of Protection ('P') which are very different to those currently understood by practitioners and the judiciary. The authors examine critically current practice and procedures and provide a set of proposals for reforms. PMID- 28007808 TI - Dangerous Liaisons? Psychiatry and Law in the Court of Protection-Expert Discourses of 'Insight' (and 'Compliance'). AB - A finding that 'P' (as the person who is subject to Court of Protection proceedings is known) lacks mental capacity is the trigger for exposing them to decision-making by others and the powers of the Court of Protection (CoP) which, in the words of Justice Hedley, can be 'invasive and draconian' (Hedley J in PC v City of York Council cited in [2013] EWCA Civ 478 [13]). Whilst the law asserts the upper hand in the assessment of mental capacity for persons who come before the CoP, it is the discipline of psychiatry, which dominates expert witness testimony in these proceedings. There are a number of implications of allowing psychiatry to dominate this terrain, not least that, as will be argued in this article, clinical discourse, which makes reference to non-statutory terminology such as 'lack of insight' and 'non-compliance' are imported into the business of capacity assessment. This terminology, if used lazily and without clear reference to the statutory criteria, has the potential to muddy the waters of assessing P's capacity. At its worst, it can mask value judgements, which threaten to undermine the law's 'autonomy promoting' provisions set out in the Mental Capacity Act 2005. Whilst it is not intended to discredit 'insight' as a concept in psychiatry, this article concludes that it has a proper context and that in the mental capacity context, decision-makers, lawyers, and advocates should exercise careful scrutiny of its use, and CoP judgments should carefully interrogate the language imported by expert witnesses. PMID- 28007809 TI - The Implications of Meno's Paradox for the Mental Capacity Act 2005. AB - Meno's paradox-which asks 'how will you know it is the thing you didn't know?' appears in Plato's dialogue of the same name. This article suggests that a similar question arises in some supportive relationships. Attention to this question clarifies one condition necessary to justify making a best interests decisions against someone's will: the decided-for person must be unable to recognise that they have failed to recognise a need. From this condition, two duties are derived: a duty to ensure that someone cannot recognise that they have failed to recognise a need before making a decision against their will; and a duty to provide consensual support to those who have had decisions made against their will, in order to help them to avoid such second-order failures of recognition in the future. The article assesses the Mental Capacity Act 2005 against each of these duties. For each duty, it finds that the Act allows compliance, but does not robustly require it. PMID- 28007810 TI - Mental Capacity Law, Autonomy, and best Interests: An Argument for Conceptual and Practical Clarity in the Court of Protection. AB - This article examines medical decision-making, arguing that the law, properly understood, requires where possible that equal weight be given to the wishes, feelings, beliefs, and values of patients who have, and patients who are deemed to lack, decision-making capacity. It responds critically to dominant lines of reasoning that are advanced and applied in the Court of Protection, and suggests that for patient-centred practice to be achieved, we do not need to revise the law, but do need to ensure robust interpretation and application of the law. The argument is based on conceptual analysis of the law's framing of patients and medical decisions, and legal analysis of evolving and contemporary norms governing the best interests standard. PMID- 28007811 TI - Continuities of Risk in the Era of the Mental Capacity Act. AB - When compared with the Mental Capacity Act (MCA) 2005, the Mental Health Act (MHA) 1983 seems an outlier. It authorises compulsory treatment of mental disorders on the basis of P's risks. English law, therefore, discriminates between mental and physical disorders. Following the UK's ratification of the Convention on the Rights of Persons with Disabilities (CRPD), the MHA probably also violates international law. Against this backdrop, one might expect that decisions contingent on risk are confined to the MHA and have no relevance elsewhere. This article argues that the opposite is true: risk-based decision making has colonised MCA processes and plays a key role in determining the nature of P's interaction with health services. These 'continuities' of risk are most notable in the Deprivation of Liberty Safeguards (DOLS), where assessments of risk are implicitly significant for best interests and eligibility determinations. Using governmentality theory as an explanatory model, this article claims that the DOLS can be reconstructed as part of a wider legal apparatus for the regulation of the risks of harm associated with mental disorders. The article also argues that the Law Commission's recent proposals to introduce a new 'protective care' scheme and expand the remit of the MHA hint at a 'rehabilitation' of risk as an integral component of mental health and capacity law. The article concludes that the concept's stigmatising potential, lack of definition, and conflict with the CRPD cast doubt on its capacity to reconcile English mental health law with the era of autonomy, capacity, and non discrimination. PMID- 28007812 TI - Anorexia, Capacity, and Best Interests: Developments in the Court of Protection Since the Mental Capacity Act 2005. PMID- 28007813 TI - A Clinician's Brief Guide to the Mental Capacity Act. PMID- 28007816 TI - Reforming abortion services in the UK: less hypocrisy, more acknowledgment of complexity. PMID- 28007817 TI - Contraception in Iran: revolution and evolution. PMID- 28007818 TI - Quality and abortion services. PMID- 28007819 TI - Abortion law reform in Victoria: lessons for the UK. PMID- 28007820 TI - Curbing publicly-funded family planning services in Iran: who is affected? AB - OBJECTIVE: In response to a persistent low fertility rate in the country, the Supreme Leader of Iran in 2012 called for the shift to pronatalist population policies. Consequently, Iran's Parliament proposed a bill to curb the provision of contraceptive knowledge and services as a solution to raising the country's low fertility rate. This study aimed to investigate which groups of women will be adversely affected if the provision of subsidised contraceptive methods [i.e. sterilisation, intrauterine device (IUD) and injections] is curbed. METHODS: This study used recent data from the 2014 Tehran Survey of Fertility (n=3012) conducted among a representative sample of 3012 married women of reproductive age, and used multinomial logistic regression analysis to identify women with a higher likelihood of using government-funded contraceptive methods. RESULTS: Currently 82% of married women living in Tehran use a contraceptive method. The use of long-acting contraception, namely sterilisation and IUDs, declined from 34% in 2000 to 20% in 2014, and the prevalence of male methods (withdrawal and condoms) increased from 33% to 55% in the same period. Multivariate results showed that women who have a large number of children, want no more children, live in poor districts, and have low education are more likely to use long-acting contraceptive methods than withdrawal and condoms. CONCLUSIONS: Women of low socioeconomic status who want to stop childbearing are the most vulnerable subgroups of the population if the publicly-funded family planning services are curbed. PMID- 28007821 TI - The Moral Case for Abortion. PMID- 28007823 TI - My reflections on abortion law reform. PMID- 28007822 TI - Cervical preparation prior to second-trimester surgical abortion and risk of subsequent preterm birth. PMID- 28007824 TI - Learning with patience. PMID- 28007825 TI - Authors' response to 'Cervical grasping and stabilising forceps'. PMID- 28007826 TI - Comments on the first 'Person in Practice' article. PMID- 28007827 TI - WHO classification of FGM omission and failure to recognise some women's vulnerability to cosmetic vaginal surgery. PMID- 28007829 TI - 24 Weeks (24 Wochen). PMID- 28007828 TI - Brazilian women avoiding pregnancy during Zika epidemic. PMID- 28007830 TI - Girl Up. PMID- 28007831 TI - Venus. PMID- 28007832 TI - Peer Reviewers 2016. PMID- 28007833 TI - Insect Resistance Management in Bt Maize: Wild Host Plants of Stem Borers Do Not Serve as Refuges in Africa. AB - Resistance evolution by target pests threatens the sustainability of Bt maize in Africa where insect resistance management (IRM) strategies are faced by unique challenges. The assumptions, on which current IRM strategies for stem borers are based, are not all valid for African maize stem borer species. The high dose refuge strategy which is used to delay resistance evolution relies heavily on the presence of appropriate refuges (non-Bt plants) where pests are not under selection pressure and where sufficient numbers of Bt-susceptible individuals are produced to mate with possible survivors on the Bt maize crop. Misidentification of stem borer species and inaccurate reporting on wild host plant diversity over the past six decades created the perception that grasses will contribute to IRM strategies for these pests in Africa. Desired characteristics of refuge plants are that they should be good pest hosts, implying that larval survival is high and that it produces sufficient numbers of high-quality moths. Refuge plants should also have large cover abundance in areas where Bt maize is planted. While wild host plants may suffice in IRM strategies for polyphagous pests, this is not the case with stenophagous pests. This review discusses data of ecological studies and stem borer surveys conducted over the past decade and shows that wild host plants are unsuitable for development and survival of sufficient numbers of stem borer individuals. These grasses rather act as dead-end-trap plants and do not comply with refuge requirements of producing 500 susceptible individuals for every one resistant individual that survives on Bt maize. PMID- 28007834 TI - Exon-Enriched Libraries Reveal Large Genic Differences Between Aedes aegypti from Senegal, West Africa, and Populations Outside Africa. AB - Aedes aegypti is one of the most studied mosquito species, and the principal vector of several arboviruses pathogenic to humans. Recently failure to oviposit, low fecundity, and poor egg-to-adult survival were observed when Ae. aegypti from Senegal (SenAae) West Africa were crossed with Ae. aegypti (Aaa) from outside of Africa, and in SenAae intercrosses. Fluorescent in situ hybridization analyses indicated rearrangements on chromosome 1, and pericentric inversions on chromosomes 2 and 3. Herein, high throughput sequencing (HTS) of exon-enriched libraries was used to compare chromosome-wide genetic diversity among Aaa collections from rural Thailand and Mexico, a sylvatic collection from southeastern Senegal (PK10), and an urban collection from western Senegal (Kaolack). Sex-specific polymorphisms were analyzed in Thailand and PK10 to assess genetic differences between sexes. Expected heterozygosity was greatest in SenAae FST distributions of 15,735 genes among all six pairwise comparisons of the four collections indicated that Mexican and Thailand collections are genetically similar, while FST distributions between PK10 and Kaolack were distinct. All four comparisons of SenAae with Aaa indicated extreme differentiation. FST was uniform between sexes across all chromosomes in Thailand, but were different, especially on the sex autosome 1, in PK10. These patterns correlate with the reproductive isolation noted earlier. We hypothesize that cryptic Ae. aegypti taxa may exist in West Africa, and the large genic differences between Aaa and SenAae detected in the present study have accumulated over a long period following the evolution of chromosome rearrangements in allopatric populations that subsequently cause reproductive isolation when these populations became sympatric. PMID- 28007836 TI - Single Locus Maintains Large Variation of Sex Reversal in Half-Smooth Tongue Sole (Cynoglossus semilaevis). AB - Sex determination is a fundamental biological process for individual sex development and population sex ratios. However, for some species, the primary sex might be altered during development, and individuals can develop into the opposite sex. Sex reversal may happen in insects, reptiles, amphibians, and fishes. In half-smooth tongue sole (Cynoglossus semilaevis), some genetically female fish irreversibly reverse to pseudomales, resulting in higher costs in aquaculture owing to a lower growth rate of male fish during a 2-yr growth period. Here, we identified a locus with large controlling effect on sex reversal in the half-smooth tongue sole through genome-wide association study with high density single nucleotide polymorphisms (SNPs). This SNP is located at the third intron of the F-box and leucine rich repeat protein 17 (FBXL17) gene on the Z chromosome, and it has two alleles, A and T. Genetic females with ZAW genotypes will never reverse into phenotypic males, but those with ZTW genotypes can sometimes undergo sex reversal. This SNP explains 82.7% of the genetic variation, or 58.4% of the phenotypic variation. Based on our results, a reproductive management program could be developed to improve the phenotypic female ratio in aquaculture, and elucidate the mechanism of sex reversal in half-smooth tongue sole. We expect that these findings will have a substantial impact on the population management in many harvested species where sex reversal occurs. PMID- 28007835 TI - Paralog-Specific Functions of RPL7A and RPL7B Mediated by Ribosomal Protein or snoRNA Dosage in Saccharomyces cerevisiae. AB - Most ribosomal proteins in Saccharomyces cerevisiae are encoded by two paralogs that additively produce the optimal protein level for cell growth. Nonetheless, deleting one paralog of most ribosomal protein gene pairs results in a variety of phenotypes not observed when the other paralog is deleted. To determine whether paralog-specific phenotypes associated with deleting RPL7A or RPL7B stem from distinct functions or different levels of the encoded isoforms, the coding region and introns of one paralog, including an intron-embedded snoRNA (small nucleolar RNA) gene, were exchanged with that of the other paralog. Among mutants harboring a single native or chimeric RPL7 allele, expression from the RPL7A locus exceeded that from the RPL7B locus, and more Rpl7a was expressed from either locus than Rpl7b Phenotypic differences in tunicamycin sensitivity, ASH1 mRNA localization, and mobility of the Ty1 retrotransposon were strongly correlated with Rpl7 and ribosome levels, but not with the Rpl7 or snoRNA isoform expressed. Although Ty1 RNA is cotranslationally localized, depletion of Rpl7 minimally affected synthesis of Ty1 Gag protein, but strongly influenced Ty1 RNA localization. Unlike the other processes studied, Ty1 cDNA accumulation was influenced by both the level and isoform of Rpl7 or snoRNA expressed. These cellular processes had different minimal threshold values for Rpl7 and ribosome levels, but all were functional when isoforms of either paralog were expressed from the RPL7A locus or both RPL7 loci. This study illustrates the broad range of phenotypes that can result from depleting ribosomes to different levels. PMID- 28007837 TI - The Impact of Open Pollination on the Structural Evolutionary Dynamics, Meiotic Behavior, and Fertility of Resynthesized Allotetraploid Brassica napus L. AB - Allopolyploidy, which results from the merger and duplication of two divergent genomes, has played a major role in the evolution and diversification of flowering plants. The genomic changes that occur in resynthesized or natural neopolyploids have been extensively studied, but little is known about the effects of the reproductive mode in the initial generations that may precede its successful establishment. To truly reflect the early generations of a nascent polyploid, two resynthesized allotetraploid Brassica napus populations were obtained for the first time by open pollination. In these populations, we detected a much lower level of aneuploidy (third generation) compared with those previously published populations obtained by controlled successive selfing. We specifically studied 33 resynthesized B. napus individuals from our two open pollinated populations, and showed that meiosis was affected in both populations. Their genomes were deeply shuffled after allopolyploidization: up to 8.5 and 3.5% of the C and A subgenomes were deleted in only two generations. The identified deletions occurred mainly at the distal part of the chromosome, and to a significantly greater extent on the C rather than the A subgenome. Using Fluorescent In Situ Hybridization (BAC-FISH), we demonstrated that four of these deletions corresponded to fixed translocations (via homeologous exchanges). We were able to evaluate the size of the structural variations and their impact on the whole genome size, gene content, and allelic diversity. In addition, the evolution of fertility was assessed, to better understand the difficulty encountered by novel polyploid individuals before the putative formation of a novel stable species. PMID- 28007839 TI - Predictability of Genetic Interactions from Functional Gene Modules. AB - Characterizing genetic interactions is crucial to understanding cellular and organismal response to gene-level perturbations. Such knowledge can inform the selection of candidate disease therapy targets, yet experimentally determining whether genes interact is technically nontrivial and time-consuming. High fidelity prediction of different classes of genetic interactions in multiple organisms would substantially alleviate this experimental burden. Under the hypothesis that functionally related genes tend to share common genetic interaction partners, we evaluate a computational approach to predict genetic interactions in Homo sapiens, Drosophila melanogaster, and Saccharomyces cerevisiae By leveraging knowledge of functional relationships between genes, we cross-validate predictions on known genetic interactions and observe high predictive power of multiple classes of genetic interactions in all three organisms. Additionally, our method suggests high-confidence candidate interaction pairs that can be directly experimentally tested. A web application is provided for users to query genes for predicted novel genetic interaction partners. Finally, by subsampling the known yeast genetic interaction network, we found that novel genetic interactions are predictable even when knowledge of currently known interactions is minimal. PMID- 28007838 TI - A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1). AB - Spongy degeneration with cerebellar ataxia (SDCA) is a severe neurodegenerative disease with monogenic autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. We performed a genetic investigation in six families and seven isolated cases of Malinois dogs with signs of cerebellar dysfunction. Linkage analysis revealed an unexpected genetic heterogeneity within the studied cases. The affected dogs from four families and one isolated case shared a ~1.4 Mb common homozygous haplotype segment on chromosome 38. Whole genome sequence analysis of three affected and 140 control dogs revealed a missense variant in the KCNJ10 gene encoding a potassium channel (c.986T>C; p.Leu329Pro). Pathogenic variants in KCNJ10 were reported previously in humans, mice, and dogs with neurological phenotypes. Therefore, we consider KCNJ10:c.986T>C the most likely candidate causative variant for one subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia 1 (SDCA1). However, our study also comprised samples from 12 Malinois dogs with cerebellar dysfunction which were not homozygous for this variant, suggesting a different genetic basis in these dogs. A retrospective detailed clinical and histopathological analysis revealed subtle neuropathological differences with respect to SDCA1-affected dogs. Thus, our study highlights the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population. These dogs represent an animal model for the human EAST syndrome. PMID- 28007840 TI - Comparative Analysis of Satellite DNA in the Drosophila melanogaster Species Complex. AB - Satellite DNAs are highly repetitive sequences that account for the majority of constitutive heterochromatin in many eukaryotic genomes. It is widely recognized that sequences and locations of satellite DNAs are highly divergent even in closely related species, contributing to the hypothesis that satellite DNA differences may underlie speciation. However, due to its repetitive nature, the mapping of satellite DNAs has been mostly left out of recent genomics analyses, hampering the use of molecular genetics techniques to better understand their role in speciation and evolution. Satellite DNAs are most extensively and comprehensively mapped in Drosophila melanogaster, a species that is also an excellent model system with which to study speciation. Yet the lack of comprehensive knowledge regarding satellite DNA identity and location in its sibling species (D. simulans, D. mauritiana, and D. sechellia) has prevented the full utilization of D. melanogaster in studying speciation. To overcome this problem, we initiated the mapping of satellite DNAs on the genomes of the D. melanogaster species complex (D. melanogaster, D. simulans, D. mauritiana, and D. sechellia) using multi-color fluorescent in situ hybridization (FISH) probes. Our study confirms a striking divergence of satellite DNAs in the D. melanogaster species complex, even among the closely related species of the D. simulans clade (D. simulans, D. mauritiana, and D. sechellia), and suggests the presence of unidentified satellite sequences in these species. PMID- 28007841 TI - A Network of Chromatin Factors Is Regulating the Transition to Postembryonic Development in Caenorhabditis elegans. AB - Mi2 proteins are evolutionarily conserved, ATP-dependent chromatin remodelers of the CHD family that play key roles in stem cell differentiation and reprogramming. In Caenorhabditis elegans, the let-418 gene encodes one of the two Mi2 homologs, which is part of at least two chromatin complexes, namely the Nucleosome Remodeling and histone Deacetylase (NuRD) complex and the MEC complex, and functions in larval development, vulval morphogenesis, lifespan regulation, and cell fate determination. To explore the mechanisms involved in the action of LET-418/Mi2, we performed a genome-wide RNA interference (RNAi) screen for suppressors of early larval arrest associated with let-418 mutations. We identified 29 suppressor genes, of which 24 encode chromatin regulators, mostly orthologs of proteins present in transcriptional activator complexes. The remaining five genes vary broadly in their predicted functions. All suppressor genes could suppress multiple aspects of the let-418 phenotype, including developmental arrest and ectopic expression of germline genes in the soma. Analysis of available transcriptomic data and quantitative PCR revealed that LET 418 and the suppressors of early larval arrest are regulating common target genes. These suppressors might represent direct competitors of LET-418 complexes for chromatin regulation of crucial genes involved in the transition to postembryonic development. PMID- 28007842 TI - MANAGEMENT OF ENDOCRINE DISEASE: The impact of subclinical hypothyroidism on anthropometric characteristics, lipid, glucose and hormonal profile of PCOS patients: a systematic review and meta-analysis. AB - OBJECTIVE: Subclinical hypothyroidism (SCH) is encountered in 10-25% of women with PCOS. To date, it remains unclear whether this coexistence influences the severity of metabolic and hormonal profile of these patients. The purpose of our systematic review is to investigate this potential relation. METHODS: We systematically searched Medline, Scopus, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases together with reference lists from included studies. All prospective and retrospective observational cohort studies that investigated the impact of subclinical hypothyroidism on hormonal and metabolic parameters of PCOS patients were included. The methodological quality of studies was assessed with the Ottawa Newcastle criteria. Statistical meta-analysis was performed with the RevMan 5.3 software. RESULTS: Twelve studies were finally included in the present review, which enrolled 2341 PCOS patients. Among them, 577 had subclinical hypothyroidism, whereas the remaining 2077 were PCOS women with normal thyroid function. The presence of SCH significantly affected HDL (MD -3.92 mg/dL 95% CI: 6.56, -1.29) and triglycerides levels (26.91 mg/dL 95% CI: -3.79, 50.02). HOMA-IR was also affected (MD 0.82 95% CI: 0.15, 1.50). On the other hand, LDL, fasting glucose and 2-h OGTT were not influenced. Similarly, prolactin, FSH, LH, LH/FSH ratio and sex hormone-binding globulin remained unaffected. CONCLUSION: Subclinical hypothyroidism does not influence the hormonal profile of women with PCOS. On the other hand, it results in mild metabolic abnormalities, which are not clinically important in a short-term setting. PMID- 28007843 TI - Clinical characteristics and management of growth hormone excess in patients with McCune-Albright syndrome. AB - OBJECTIVE: McCune-Albright syndrome (MAS) is a sporadic, postzygotic disease presenting with fibrous dysplasia, cafe-au-lait spots and multiple endocrinopathies. Growth hormone (GH) excess is an uncommon but potentially severe complication of MAS. This study aims to describe the clinical manifestations of GH excess in the context of MAS and analyze the responses of these patients to treatments. DESIGN: Retrospective clinical study. METHODS: Clinical data from 52 MAS patients were analyzed. Serum GH and IGF1 levels, as well as nadir GH levels after an oral glucose tolerance test and alkaline phosphatase (ALP) levels were determined before and after the treatment. RESULTS: In total, 13 MAS patients (25%) had the complication of GH excess, including 10 males (76.9%). Among them, all had FD, and 6 patients had sphenoidal bone involvement. Visual deficits were present in 8 patients, and hearing deficits were present in 5. Olfactory dysfunction was observed in 3 patients. Evident pituitary adenomas were confirmed in 9 patients by MRI. These patients underwent surgery with or without pretreatment of long-acting somatostatin analogue octreotide, and 6 achieved complete remission. The serum ALP levels decreased significantly after treatment for GH excess. CONCLUSIONS: MAS with GH excess is more common in male patients. GH excess can lead to more severe skeletal lesions in MAS patients involving more of the craniofacial bones. Complete trans sphenoidal complete tumor excision with neuronavigational guidance is effective and could lower ALP levels. LAR is recommended as a preoperative treatment and when patients fail to achieve complete remission after surgery. PMID- 28007844 TI - Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency. AB - CONTEXT AND AIMS: Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency. METHODS: An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents. RESULTS: In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80-1.41) was observed. Serum of patients with non functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48-0.55) being distinct from normal was observed. CONCLUSIONS: The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients. PMID- 28007845 TI - Cabergoline for Cushing's disease: a large retrospective multicenter study. AB - OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline. PMID- 28007847 TI - Genome Sequence of KP-Rio/2015, a Novel Klebsiella pneumoniae (Podoviridae) Phage. AB - Klebsiella pneumoniae is a pathogen frequently associated with antibiotic resistant nosocomial infections. Here, we describe the genome of KP-Rio/2015, a novel phage of K. pneumoniae belonging to the family Podoviridae. PMID- 28007848 TI - Draft Genome Sequence of the Nonpathogenic, Thermotolerant, and Exopolysaccharide Producing Bacillus anthracis Strain PFAB2 from Panifala Hot Water Spring in West Bengal, India. AB - Bacillus anthracis is the causative agent of fatal anthrax in both animals and humans. It is prevalently pathogenic. Here, we present a Bacillus anthracis PFAB2 strain from a relatively unexplored Panifala hot water spring in West Bengal, India. It is nonpathogenic, exopolysaccharide producing, and thermotolerant in nature. PMID- 28007846 TI - Different origins of lysophospholipid mediators between coronary and peripheral arteries in acute coronary syndrome. AB - Lysophosphatidic acids (LysoPAs) and lysophosphatidylserine (LysoPS) are emerging lipid mediators proposed to be involved in the pathogenesis of acute coronary syndrome (ACS). In this study, we attempted to elucidate how LysoPA and LysoPS become elevated in ACS using human blood samples collected simultaneously from culprit coronary arteries and peripheral arteries in ACS subjects. We found that: 1) the plasma LysoPA, LysoPS, and lysophosphatidylglycerol levels were not different, while the lysophosphatidylcholine (LysoPC), lysophosphatidylinositol, and lysophosphatidylethanolamine (LysoPE) levels were significantly lower in the culprit coronary arteries; 2) the serum autotaxin (ATX) level was lower and the serum phosphatidylserine-specific phospholipase A1 (PS-PLA1) level was higher in the culprit coronary arteries; 3) the LysoPE and ATX levels were significant explanatory factors for the mainly elevated species of LysoPA, except for 22:6 LysoPA, in the peripheral arteries, while the LysoPC and LysoPE levels, but not the ATX level, were explanatory factors in the culprit coronary arteries; and 4) 18:0 and 18:1 LysoPS were significantly correlated with PS-PLA1 only in the culprit coronary arteries. In conclusion, the origins of LysoPA and LysoPS might differ between culprit coronary arteries and peripheral arteries, and substrates for ATX, such as LysoPC and LysoPE, might be important for the generation of LysoPA in ACS. PMID- 28007849 TI - Complete Genome Sequence of Streptococcus sp. Strain NPS 308. AB - Streptococcus sp. strain NPS 308, isolated from an 8-year-old girl diagnosed with infective endocarditis, likely presents a novel species of Streptococcus Here, we present a complete genome sequence of this species, which will contribute to better understanding of the pathogenesis of infective endocarditis. PMID- 28007850 TI - Genome Sequences of a Novel Vietnamese Bat Bunyavirus. AB - To document the viral zoonotic risks in Vietnam, fecal samples were systematically collected from a number of mammals in southern Vietnam and subjected to agnostic deep sequencing. We describe here novel Vietnamese bunyavirus sequences detected in bat feces. The complete L and S segments from 14 viruses were determined. PMID- 28007851 TI - Complete Genome Sequence of Dehalococcoides mccartyi Strain WBC-2, Capable of Anaerobic Reductive Dechlorination of Vinyl Chloride. AB - Dehalococcoides mccartyi strain WBC-2 dechlorinates carcinogen vinyl chloride to ethene in the West Branch Canal Creek (WBC-2) microbial consortium used for bioaugmentation. We assembled and closed the complete genome sequence of this prokaryote using metagenomic sequencing from an enrichment culture. PMID- 28007853 TI - Genome Sequence of the Soviet/Russian Bacillus anthracis Vaccine Strain 55 VNIIVViM. AB - Bacillus anthracis strain 55-VNIIVViM is a live-attenuated nonencapsulated Soviet/Russian veterinary anthrax vaccine strain. We report here the genome of 55 VNIIVViM and confirm its phylogenetic placement in the global population structure of B. anthracis. PMID- 28007852 TI - Whole-Genome Sequences of 26 Vibrio cholerae Isolates. AB - The human pathogen Vibrio cholerae employs several adaptive mechanisms for environmental persistence, including natural transformation and type VI secretion, creating a reservoir for the spread of disease. Here, we report whole genome sequences of 26 diverse V. cholerae isolates, significantly increasing the sequence diversity of publicly available V. cholerae genomes. PMID- 28007854 TI - Draft Genome Sequence of Multitrait Plant Growth-Promoting Bacillus sp. Strain RZ2MS9. AB - Bacillus sp. strain RZ2MS9 is a multitrait soybean and maize growth-promoting bacterium isolated in Brazil from guarana's rhizosphere. Here, we present the draft genome sequence of RZ2MS9 and its genes involved in many features related to plant growth promotion. PMID- 28007855 TI - Complete Genome Sequences of Four Bordetella pertussis Vaccine Reference Strains from Serum Institute of India. AB - Serum Institute of India is among the world's largest vaccine producers. Here, we report the complete genome sequences for four Bordetella pertussis strains used by Serum Institute of India in the production of whole-cell pertussis vaccines. PMID- 28007856 TI - Complete Genome Sequence of a Novel Aquareovirus That Infects the Endangered Fountain Darter, Etheostoma fonticola. AB - Here, we report the complete genome of a novel aquareovirus isolated from clinically normal fountain darters, Etheostoma fonticola, inhabiting the San Marcos River, Texas, USA. The complete genome consists of 23,958 bp consisting of 11 segments that range from 783 bp (S11) to 3,866 bp (S1). PMID- 28007857 TI - Draft Genome Sequence of the Commensal Escherichia coli Strain F-18. AB - Here, we report the draft genome sequence of Escherichia coli strain F-18, originally isolated from the feces of a healthy individual in 1977. The draft genome is 5,246,829 bp, with a G+C content of 50.50%, and it encodes 4,933 predicted coding sequences (CDSs), 10 rRNAs, and 84 tRNAs. PMID- 28007858 TI - Complete Genome Sequence of Lymantria dispar multiple nucleopolyhedrovirus Isolated in Southwestern Poland. AB - We report here the complete genomic sequence of Polish alphabaculovirus isolated from dead gypsy moth caterpillars. Its genome structure and G+C content indicate that it is a Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV) strain which possesses the shortest sequence among eight other (similar to reference sequence AF081810) LdMNPV sequences available in GenBank; it is 159,729 bp long. PMID- 28007859 TI - Novel Observations in 11 Heteroresistant Vancomycin-Intermediate Methicillin Resistant Staphylococcus aureus Strains from South India. AB - We report here the draft genome sequences of 11 heteroresistant vancomycin intermediate Staphylococcus aureus (hVISA) strains from bloodstream infection. All strains harbor mutations in vraSR, graSR, walKR, and/or tcaRAB and are often implicated as the frequently mutated candidate genes in hVISA phenotypes. PMID- 28007860 TI - Complete Genome Sequence of the Industrial Bacterium Ketogulonicigenium vulgare SKV. AB - Ketogulonicigenium vulgare has been widely used in vitamin C two-step fermentation, which converts l-sorbose to 2-keto-l-gluonic acid. Here, the complete genome of K. vulgare SKV, which performs better fermentation production than K. vulgare Hbe602, is deciphered to understand the key differences in metabolism between K. vulgare strains SKV and Hbe602. PMID- 28007861 TI - Complete Genome Sequence of a Mosaic NADC30-Like Porcine Reproductive and Respiratory Syndrome Virus in China. AB - Here, we report the complete genome of an NADC30-like porcine reproductive and respiratory syndrome virus (PRRSV) strain, HNhx, which was isolated from Henan Province, China, in 2016 and was characterized by recombination with JXA1 strain (an epidemic highly pathogenic PRRSV strain in China) in Nsp4 to Nsp9. PMID- 28007862 TI - Genome Sequence of the Acetogenic Bacterium Acetobacterium wieringae DSM 1911T. AB - Here, we report the draft genome sequence of Acetobacterium wieringae DSM 1911T, an anaerobic, autotrophic, acetogenic, d,l-lactate-utilizing bacterium. The genome consists of a chromosome (3.88 Mb) and 3,620 predicted protein-encoding genes. PMID- 28007863 TI - Draft Genome Sequence of the Phosphate-Solubilizing Bacterium Pseudomonas argentinensis Strain SA190 Isolated from the Desert Plant Indigofera argentea. AB - Pseudomonas argentinensis strain SA190 is a plant endophytic-inhabiting bacterium that was isolated from root nodules of the desert plant Indigofera argentea collected from the Jizan region of Saudi Arabia. Here, we report the genome sequence of SA190, highlighting several functional genes related to plant growth promoting activity, environment adaption, and antifungal activity. PMID- 28007864 TI - Draft Genome Sequence of Kluyvera intestini Strain GT-16 Isolated from the Stomach of a Patient with Gastric Cancer. AB - Here, we report the complete genome sequence of the novel, non-spore-forming Kluyvera intestini strain GT-16, isolated from the stomach of a patient with gastric cancer. The genome is 5,868,299 bp in length with a G+C content of 53.0%. It possesses 5,350 predicted protein-coding genes encoding virulence factors and antibiotic resistance proteins. PMID- 28007865 TI - Metagenomics Analysis of Microorganisms in Freshwater Lakes of the Amazon Basin. AB - The Amazon Basin is the largest hydrographic basin on the planet, and the dynamics of its aquatic microorganisms strongly impact global biogeochemical cycles. However, it remains poorly studied. This metagenome project was performed to obtain a snapshot of prokaryotic microbiota from four important lakes in the Amazon Basin. PMID- 28007866 TI - Draft Whole-Genome Sequence of a Catalase-Negative Staphylococcus aureus subsp. aureus (Sequence Type 25) Strain Isolated from a Patient with Endocarditis and Septic Arthritis. AB - Staphylococcus aureus strains without catalase activity are rare, challenging to identify with conventional biochemical methods, and, despite a supposed decreased pathogenicity, can still cause disease. The first whole-genome sequence of a catalase-negative S. aureus isolate causing severe recurrent invasive infection with two novel missense mutations in the katA gene is reported here. PMID- 28007867 TI - Chest wall stabilization in ventilator-dependent traumatic flail chest patients: who benefits? AB - Objectives: Traumatic flail chest is a potentially life threatening injury, often associated with prolonged invasive mechanical ventilation and intensive care unit stay. This study evaluates the usefulness and cost-effectiveness of surgical rib stabilization in patients with flail chest resulting in ventilator dependent respiratory insufficiency. Methods: A retrospective study on a consecutive series of patients with flail chest with the need for mechanical ventilation was performed. Effectiveness of rib fixation was evaluated in terms of predictors for prolonged ventilation, cost-effectiveness and outcome. Results: A total of 61 patients underwent flail chest stabilization using a locked titanium plate fixation system between July 2010 and December 2015 at our institution. 62% ( n = 38) of patients could be weaned from the ventilator within the first 72 h after surgery. Multiple linear regression analysis revealed that closed head injury, bilateral flail chest, number of stabilized ribs and severity of lung contusion were the main independent predictors for prolonged mechanical ventilation (Odds ratio (OR) 6.88; 3.25; 1.52 and 1.42) and tracheostomy (OR 9.17; 2.2; 1.76 and 0.84 ), respectively. Furthermore cost analysis showed that already a two day reduction in ICU stay could outweigh the cost of surgical rib fixation. Conclusions: Operative rib fixation has the potential to reduce ventilator days and ICU stay and subsequently hospital costs in selected patients with severe traumatic flail chest requiring mechanical ventilation. Especially associated closed head injury can adversely affect mechanical ventilation time. Furthermore the subgroups of patients sustaining a fall from a height and those with flail chest after cardiopulmonary re-animation seem to profit only marginally from surgical rib fixation. PMID- 28007868 TI - Systemic right ventricular morphology in the early postoperative course after extracardiac Fontan operation: is there still a need for special care? AB - Objectives: We aimed to compare early postoperative outcome after extracardiac (EC) Fontan operation between patients with right (RV) or left (LV) systemic ventricles. Methods: In total, 173 consecutive patients (median age 4 years, median weight 14 kg) underwent EC Fontan between 1995 and 2013. Pre- and intraoperative data as well as detailed postoperative haemodynamic variables were compared between patients with LV [ n = 109 (63%)] and RV [ n = 64 (37%)]. Results: : RV patients showed significantly lower mean arterial (median 55 vs 59 mmHg, P = 0.04), higher atrial (median 8 vs 6 mmHg, P = 0.03) and comparable pulmonary pressure (median 14 vs 14 mmHg, P = 0.7) as well as lower mean systemic perfusion pressure (median 39 vs 43 mmHg, P = 0.03) on Day 0 after EC Fontan. They suffered from longer intubation time (median 18 vs 12 h, P = 0.008), higher incidence of ascites (46% vs 28%, P = 0.04) and need for dialysis (21% vs 4%, P = 0.003). Prolonged inotropic support (25% vs 8%, P = 0.02) and pharmacological treatment to reduce pulmonary vascular resistance (71% vs 53%, P = 0.002) were more often used in RV patients and they showed more often supraventricular tachyarrhythmia (27% vs 5%, P < 0.001) and a longer intensive care unit-stay (median 4 vs 3 days, P = 0.03). However, early mortality, need for Fontan takedown, use of mechanical circulatory support, pleural effusions and hospital stay were not significantly different between both groups. Conclusions: Patients with systemic RV demonstrate higher morbidity in the early postoperative course compared with patients with systemic LV anatomy and require intensified postoperative management to avoid postoperative Fontan failure. PMID- 28007869 TI - The importance of lymph node dissection accompanying wedge resection for clinical stage IA lung cancer. AB - Objectives: For patients undergoing lobectomy for non-small cell lung cancer (NSCLC), a survival benefit exists with increased number of lymph nodes (LNs) resected. We sought to evaluate the associations of LN removal with outcomes in clinical stage I lung cancer patients undergoing wedge resection. Methods: We evaluated all patients undergoing wedge resection for peripheral, clinical stage IA NSCLC and grouped patients into those with and without LN assessment. Data were compared and survival analysed using Kaplan-Meier, with differences compared using log-rank. Propensity score matching controlling for age, gender, Charlson comorbidity index, patient tolerability of lobectomy, surgery year, tumour size and surgical approach was done (51 patients in each group, caliper 0.2). Results: We identified196 patients undergoing wedge resection, of whom 138 patients (70%) had LNs resected (median = 4 nodes), while the remaining 58 patients (30%) had none. There were no significant differences in the clinical or pathologic characteristics between the two groups. There was no difference in terms of OR time, estimated blood loss, chest tube duration or length of stay. Median pT size was 1.5 cm in each group ( P = 0.73). Among patients with LNs removed, 6 (4.3%) had positive nodes Patients in the LN assessed group had higher probability of freedom from loco-regional recurrence compared to the no lymph node (NLN) group (5-year: 92 vs 74%, P = 0.025).In propensity matched groups, patients who underwent LN dissection also had higher probability of freedom from local recurrence ( P = 0.024). Conclusions: Accompanying wedge resection for lung cancer, LN sampling adds no morbidity and does not increase length of stay. Positive nodes are identified in 4.3% of patients thought eligible for wedge resection. LN removal appears to decrease locoregional recurrence and may be associated with a survival benefit. PMID- 28007870 TI - Off-pump versus on-pump coronary artery bypass grafting: 'there are no facts, only interpretations'. PMID- 28007871 TI - Hypertrophic cardiomyopathy: the edge-to-edge secures the correction of the systolic anterior motion. AB - Objectives: Although septal myectomy is the technique of choice for hypertrophic cardiomyopathy, the surgical management of concomitant mitral valve lesions is controversial. Various complex surgeries have been proposed to address mitral valve lesions. We propose a simple option using an edge-to-edge mitral valve repair through the aortic valve in addition to the septal myectomy. Methods: We performed an observational analysis of our prospectively collected database. The clinical follow-up was done by telephone contact with each patient. The echocardiographic follow-up was performed in our Department of Cardiology or by the referring cardiologist. Results: Between January 2009 and March 2016, we operated 22 symptomatic patients (mean age 48.5 years, males 59%). The mean interventricular septum diameter and resting intraventricular gradient were 25.8 mm and 75.4 mmHg, respectively. The systolic anterior motion was present in every patient. The mean mitral regurgitation grade was 2.4. There were no in-hospital deaths. Two (9%) patients required a pacemaker. After a mean follow-up of 26.3 months, the mean New York Heart Association functional class decreased from 2.5 to 1.2 ( P < 0.001). The echocardiographic follow-up showed a sustained significant reduction of the septal thickness ( P < 0.001), resting intraventricular gradient ( P < 0.001), presence of systolic anterior motion ( P < 0.001) and grade of mitral regurgitation ( P = 0.002). Conclusions: Septal myectomy remains the gold standard of any surgery for hypertrophic cardiomyopathy owing to its good clinical and echocardiographic results. The edge-to-edge mitral valve repair is an additional simple option to avoid the systolic anterior motion and effectively reduce the grade of mitral regurgitation. PMID- 28007872 TI - Operating room scheduling is not associated with early outcome following elective anatomic lung resections: a propensity score case-matched analysis. AB - Objectives: To investigate the effect of operating room scheduling on the outcome of patients undergoing elective lung resection. Methods: In total, 420 patients submitted to anatomical pulmonary resections (363 lobectomies, 35 pneumonectomies, 22 segmentectomies) (April 2014-November 2015) were analysed. Ninety-two patients (22%) were operated on during weekends (Friday or Saturday) and 161 patients (38%) in the afternoon. Propensity score matching was performed to account for possible selection bias between the groups. The matched groups (weekdays versus weekends; morning versus afternoon) were compared in terms of cardiopulmonary complications, in-hospital mortality and length of stay (LOS). Results: In total, 102 (24%) patients developed cardiopulmonary complications and 56 (13%) patients developed major complications. In-hospital mortality was 3.1% (13 patients). The case-matched comparison between patients operated on during the week versus those operated on during weekends (92 pairs) showed no differences of cardiopulmonary morbidity (22 vs 24, P = 0.8), major complications (14 in both groups), mortality (2 vs 4, P = 0.7) and LOS (7 vs 7.5 days, P = 0.6). The case-matched comparison between patients operated on in the morning versus those operated on in the afternoon (161 pairs) showed no differences of cardiopulmonary morbidity (32 vs 33, P = 0.9), major morbidity (17 vs 19, P = 1), mortality (7 vs 4, P = 0.5) and LOS (7.2 vs 5.9 days, P = 0.2). Conclusions: In our setting, operating room scheduling did not affect early outcome following elective lung resections, confirming the appropriate structural and procedural characteristics of a dedicated Thoracic Unit. PMID- 28007873 TI - Re: Excellent outcome of donor lobectomy with various surgical techniques for the interlobar artery. PMID- 28007874 TI - New tubeless video-assisted thoracoscopic surgery for small pulmonary nodules. AB - Objectives: Problems associated with intubation, chest drainage and urinary catheterization can have a negative impact on patient's recovery after thoracic surgery. We therefore evaluated the feasibility of a new tubeless (spontaneous ventilation without tracheal intubation, urinary catheterization, and no post operative chest drain placement) approach to perform video-assisted thoracoscopic surgery (VATS) for small pulmonary nodules (SPN) less than 2cm in diameter. Methods: From 1 January 2012 to 31 December 2014, 34 patients with SPNs were treated using tubeless VATS in our centre. To be eligible for this approach, the patient must have a body mass index (BMI) of less than 25; ASA grade of II or less; no history of prostate or renal disease and no parenchymal air leak at the end of surgery. All operations were performed via an anterior uniportal VATS under spontaneous ventilation without tracheal intubation. Results: All patients [29 male:5 females; average age: 58 +/- 19 years old] completed their operation under spontaneous ventilation, without conversion to endotracheal intubation. There was good operative exposure and definite diagnosis was obtained in all patients. The anaesthesia and operating time were 23 +/- 3 min and 43 +/- 10 min, respectively. No major intra-operative or post-operative complications were seen. Patients recovered from their anaesthesia (fully awake) within a mean time of 18 +/- 3 min after surgery, and were eating 42 normally on an average of 5 +/- 1 h post-operatively. No patients had pain on deep breathing or coughing (Bruggemann Comfort Score < 2). Within 24 h after surgery, 26 patients were discharged, while the remaining 8 patients were discharged on the second day. None of the patients needed re-invention with chest drainage or urinary catheterization even after discharge. All patients remained well at a median [interquartile range] follow-up time of 3[2-5] weeks. Conclusions: Tubeless VATS approach for SPNs is feasible in carefully selected patients. Intubation, chest drainage, and/or urinary catheterization may not be necessary in all patients. PMID- 28007875 TI - In-hospital cost comparison between percutaneous pulmonary valve implantation and surgery. AB - Objectives: Today, both surgical and percutaneous techniques are available for pulmonary valve implantation in patients with right ventricle outflow tract obstruction or insufficiency. In this controlled, non-randomized study the hospital costs per patient of the two treatment options were identified and compared. Methods: During the period of June 2011 until October 2014 cost data in 20 patients treated with the percutaneous technique and 14 patients treated with open surgery were consecutively included. Two methods for cost analysis were used, a retrospective average cost estimate (overhead costs) and a direct prospective detailed cost acquisition related to each individual patient (patient specific costs). Results: The equipment cost, particularly the stents and valve itself was by far the main cost-driving factor in the percutaneous pulmonary valve group, representing 96% of the direct costs, whereas in the open surgery group the main costs derived from the postoperative care and particularly the stay in the intensive care department. The device-related cost in this group represented 13.5% of the direct costs. Length-of-stay-related costs in the percutaneous group were mean $3885 (1618) and mean $17 848 (5060) in the open surgery group. The difference in postoperative stay between the groups was statistically significant ( P <= 0.001). Conclusions: Given the high postoperative cost in open surgery, the percutaneous procedure could be cost saving even with a device cost of more than five times the cost of the surgical device. PMID- 28007876 TI - Cardiac paraganglioma originating from the right coronary artery. PMID- 28007877 TI - Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia. AB - Objectives: Prolonged global cerebral ischaemia leads to irreversible injury, often with lethal outcome. Brain injuries are partly caused by the uncontrolled reperfusion that occurs once the circulation is re-established. Recent animal experiments suggest that controlled reperfusion following lengthy ischaemia might prevent severe brain injury. This study aimed at further exploring cerebral alterations and outcome following prolonged global cerebral ischaemia and mechanically manipulated reperfusion. Methods: Three groups of pigs were included; one sham operated ( n = 3) and two that underwent 30-min global cerebral ischaemia. All vessels that supply the brain were isolated intrathoracically, after which they were occluded for 30 min in the ischaemic groups. In one of the ischaemic groups uncontrolled reperfusion was applied (URep, n = 6), i.e. normal circulation was restored 30 min after arrested cerebral circulation. The second ischaemic group received mechanical reperfusion (MRep, n = 6) with leucocyte-filtered blood at constant flow and pressure for 20 min using extracorporeal circulation following the 30-min ischaemia, after which normal blood flow resumed. All animals were monitored for 3 h after start of uncontrolled reperfusion. Haemodynamic parameters, arterial and sagittal sinus blood gases, cerebral oxygen extraction rates and intraparenchymal biomarkers using microdialysis were measured. Brain histology was performed post-mortem. Results: Global brain ischaemia led to the same extent of severe morphological changes at the level of light microscopy in the two ischaemic experimental groups, regardless of reperfusion protocol. Furthermore, no significant differences were found between the URep and MRep groups regarding cerebral blood gases or microdialysis biomarkers. Conclusions: Mechanical reperfusion following the current protocol does not modify brain alterations caused by 30 min of arrested cerebral circulation. PMID- 28007878 TI - Video-assisted thoracoscopic surgery-taking a step into the future. PMID- 28007879 TI - Transcatheter versus surgical aortic valve replacement in moderate and high-risk patients: a meta-analysis. AB - Objectives: The evidence of the benefits of transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) for patients of high or intermediate surgical risk is not consistent. We performed a meta analysis to compare major adverse outcomes after TAVR or SAVR. Methods: We searched propensity score matched studies or randomized clinical trials comparing the risks of mortality, stroke, major bleeding, acute renal injury, pacemaker implantation, vascular complications and prostheses haemodynamic performance between TAVR and SAVR in patients with moderate or high risk. Combined odds ratios (ORs), relative risk or mean differences with corresponding 95% confidence intervals (CIs) were calculated using a random effects model. Analyses of sensitivity and publication bias were also conducted. Results: We included 5 clinical trials and 37 observational studies, enrolling 20 224 patients (TAVR, n = 9099 and SAVR, n = 11 125). The pooled analysis suggested no differences in early (OR = 1.11, 95% CI 0.9-1.39, P = 0.355) or late mortality (relative risk = 0.91, 95% CI 0.78-1.05, P = 0.194). TAVR was associated with a lower risk of major bleeding (OR = 0.42, 95% CI 0.25-0.69, P < 0.001) and acute kidney injury (OR = 0.51, 95% CI 0.34-0.71) but with an increase in the incidence of pacemaker implantation (OR = 2.31, 95% CI 1.73-3.08) and vascular complications (OR = 4.88, 95% CI 2.84-8.39). Residual aortic regurgitation was more frequent after TAVR (OR= 6.83, 95% CI 4.87-9.6). SAVR prostheses were associated with poor trans prosthetic gradients (mean difference: -2.4 mmHg, 95% CI - 3.27 to - 1.53). Conclusions: TAVR and SAVR have similar short and long-term all-cause mortality and risk of stroke among patients of moderate or high surgical risk. TAVR decreases the risk of major bleeding, acute kidney injury and improves haemodynamic performance compared with SAVR but increases the risk of vascular complications, the need for a pacemaker and residual aortic regurgitation. PMID- 28007880 TI - Residual SYNTAX score following coronary artery bypass grafting. AB - Objectives: To quantify residual coronary artery disease measured using the SYNTAX score (SS) and its relation to outcomes after coronary artery bypass grafting (CABG). Methods: We conducted a retrospective analysis on a consecutive series of 1608 patients [mean age 68 years, standard deviation (SD): 7, F:M, 242:1366] undergoing first-time isolated CABG from 2004 to 2015. The baseline SS was retrospectively determined from preoperative angiograms, and the residual SS (rSS) was measured during assessment of the actual operative report for each patient after CABG. Patients were then stratified according to tercile cut points of low (rSS low 0-11, N = 537), intermediate (rSS mid >11-18.5, N = 539) and high residual SS (rSS high >18.5, N = 532). The Cox regression model was used to investigate the impact of rSS on major adverse cardiac and cerebrovascular events (MACCE) at 1 year. Results: The mean preoperative SS was 26.6 (SD: 9.4) (range 10.1-53), and the residual SS after CABG was 15.3 (SD: 8.4) (range 0-34) ( P < 0.001 versus preoperative). At 1 year, cumulative incidence of MACCE in the low rSS was 1.5% ( N = 8/537), 4.5% ( N = 24/539) in the intermediate and 8.8% ( N = 47/532) in the high rSS group. Kaplan-Meier analysis showed a statistically significant difference of MACCE-free survival between the three groups (log-rank test, P < 0.001). The estimated MACCE-free survival rate at 1 year was 98.1% [standard error (SE): 1.6] for the rSS low , 95.5% (SE: 1.9) for the rSS mid , and 90.5% (SE: 1.3) for the rSS high group, respectively. After multivariable adjustment, the rSS high group was independently associated with a higher incidence of MACCE at 1 year (hazard ratio 1.92, 95% confidence interval 1.21-3.23) compared to the rSS low group. Conclusions: These unanticipated findings suggest that a residual SS may be a useful tool for risk stratification of patients undergoing isolated first-time CABG. Our study may set the stage for further investigations addressing this important clinical question. PMID- 28007881 TI - Platelet function recovery after ticagrelor withdrawal in patients awaiting urgent coronary surgery. AB - Objective: Dual antiplatelet therapy with ticagrelor and aspirin is associated with an increased risk of perioperative bleeding complications. Current guidelines recommend therefore discontinuation of ticagrelor 5 days before surgery to allow sufficient recovery of platelet function. It is not known how the time to recovery varies between individual patients after discontinuation of ticagrelor. Methods: Twenty-five patients accepted for urgent coronary artery bypass surgery and treated with ticagrelor and aspirin were included in a prospective observational study. Platelet aggregation was evaluated with impedance aggregometry at five timepoints 12-96 h after discontinuation of ticagrelor. In a subset of patients ( n = 15), we also tested the ex vivo efficacy of platelet concentrate supplementation on platelet aggregation. Results: There was a gradual increase in mean adenosine diphosphate-induced platelet aggregation after discontinuation of ticagrelor. After 72 h, mean aggregation was 38 +/-23 aggregation units (U), which is above a previously suggested cut-off of 22 U, when patients can be operated without increased bleeding risk. However, there was a large interindividual variability (range 4-88 U at 72 h) and 6/24 patients (25%) had <22 U after 72 h. Ex vivo administration of platelet concentrate did not improve adenosine diphosphate-induced aggregation at any timepoint after ticagrelor discontinuation. Conclusions: Adenosine diphosphate-induced aggregation was acceptable after 72 h in the majority of patients but with a large interindividual variability. Due to the large variability, platelet function testing may prove to be a valuable tool in timing of surgery in patients with ongoing or recently stopped ticagrelor treatment. Adenosine diphosphate-induced aggregation was not improved by addition of platelet concentrate. PMID- 28007882 TI - Redo aortic root replacement reutilizing 22-year patent modified Cabrol grafts. AB - Long-term patency of modified Cabrol technique in composite aortic root replacement is not well documented. We report a unique case in which a patient presented for prosthetic valve dysfunction with patent Cabrol grafts 22 years after composite root replacement requiring redo aortic root. This case also demonstrates how modified Cabrol grafts can be reutilized in aortic root replacement without compromising adequate fluid dynamics. PMID- 28007883 TI - Evidence for Amino Acid Snorkeling from a High-Resolution, In Vivo Analysis of Fis1 Tail-Anchor Insertion at the Mitochondrial Outer Membrane. AB - Proteins localized to mitochondria by a carboxyl-terminal tail anchor (TA) play roles in apoptosis, mitochondrial dynamics, and mitochondrial protein import. To reveal characteristics of TAs that may be important for mitochondrial targeting, we focused our attention upon the TA of the Saccharomyces cerevisiae Fis1 protein. Specifically, we generated a library of Fis1p TA variants fused to the Gal4 transcription factor, then, using next-generation sequencing, revealed which Fis1p TA mutations inhibited membrane insertion and allowed Gal4p activity in the nucleus. Prompted by our global analysis, we subsequently analyzed the ability of individual Fis1p TA mutants to localize to mitochondria. Our findings suggest that the membrane-associated domain of the Fis1p TA may be bipartite in nature, and we encountered evidence that the positively charged patch at the carboxyl terminus of Fis1p is required for both membrane insertion and organelle specificity. Furthermore, lengthening or shortening of the Fis1p TA by up to three amino acids did not inhibit mitochondrial targeting, arguing against a model in which TA length directs insertion of TAs to distinct organelles. Most importantly, positively charged residues were more acceptable at several positions within the membrane-associated domain of the Fis1p TA than negatively charged residues. These findings, emerging from the first high-resolution analysis of an organelle targeting sequence by deep mutational scanning, provide strong, in vivo evidence that lysine and arginine can "snorkel," or become stably incorporated within a lipid bilayer by placing terminal charges of their side chains at the membrane interface. PMID- 28007884 TI - Genomic Trajectories to Desiccation Resistance: Convergence and Divergence Among Replicate Selected Drosophila Lines. AB - Adaptation to environmental stress is critical for long-term species persistence. With climate change and other anthropogenic stressors compounding natural selective pressures, understanding the nature of adaptation is as important as ever in evolutionary biology. In particular, the number of alternative molecular trajectories available for an organism to reach the same adaptive phenotype remains poorly understood. Here, we investigate this issue in a set of replicated Drosophila melanogaster lines selected for increased desiccation resistance-a classical physiological trait that has been closely linked to Drosophila species distributions. We used pooled whole-genome sequencing (Pool-Seq) to compare the genetic basis of their selection responses, using a matching set of replicated control lines for characterizing laboratory (lab-)adaptation, as well as the original base population. The ratio of effective population size to census size was high over the 21 generations of the experiment at 0.52-0.88 for all selected and control lines. While selected SNPs in replicates of the same treatment (desiccation-selection or lab-adaptation) tended to change frequency in the same direction, suggesting some commonality in the selection response, candidate SNP and gene lists often differed among replicates. Three of the five desiccation selection replicates showed significant overlap at the gene and network level. All five replicates showed enrichment for ovary-expressed genes, suggesting maternal effects on the selected trait. Divergence between pairs of replicate lines for desiccation-candidate SNPs was greater than between pairs of control lines. This difference also far exceeded the divergence between pairs of replicate lines for neutral SNPs. Overall, while there was overlap in the direction of allele frequency changes and the network and functional categories affected by desiccation selection, replicates showed unique responses at all levels, likely reflecting hitchhiking effects, and highlighting the challenges in identifying candidate genes from these types of experiments when traits are likely to be polygenic. PMID- 28007885 TI - Inferring Ancestral Recombination Graphs from Bacterial Genomic Data. AB - Homologous recombination is a central feature of bacterial evolution, yet it confounds traditional phylogenetic methods. While a number of methods specific to bacterial evolution have been developed, none of these permit joint inference of a bacterial recombination graph and associated parameters. In this article, we present a new method which addresses this shortcoming. Our method uses a novel Markov chain Monte Carlo algorithm to perform phylogenetic inference under the ClonalOrigin model. We demonstrate the utility of our method by applying it to ribosomal multilocus sequence typing data sequenced from pathogenic and nonpathogenic Escherichia coli serotype O157 and O26 isolates collected in rural New Zealand. The method is implemented as an open source BEAST 2 package, Bacter, which is available via the project web page at http://tgvaughan.github.io/bacter. PMID- 28007886 TI - Different Evolutionary Strategies To Conserve Chromatin Boundary Function in the Bithorax Complex. AB - Chromatin boundary elements subdivide chromosomes in multicellular organisms into physically independent domains. In addition to this architectural function, these elements also play a critical role in gene regulation. Here we investigated the evolution of a Drosophila Bithorax complex boundary element called Fab-7, which is required for the proper parasegment specific expression of the homeotic Abd-B gene. Using a "gene" replacement strategy, we show that Fab-7 boundaries from two closely related species, D. erecta and D. yakuba, and a more distant species, D. pseudoobscura, are able to substitute for the melanogaster boundary. Consistent with this functional conservation, the two known Fab-7 boundary factors, Elba and LBC, have recognition sequences in the boundaries from all species. However, the strategies used for maintaining binding and function in the face of sequence divergence is different. The first is conventional, and depends upon conservation of the 8 bp Elba recognition sequence. The second is unconventional, and takes advantage of the unusually large and flexible sequence recognition properties of the LBC boundary factor, and the deployment of multiple LBC recognition elements in each boundary. In the former case, binding is lost when the recognition sequence is altered. In the latter case, sequence divergence is accompanied by changes in the number, relative affinity, and location of the LBC recognition elements. PMID- 28007887 TI - Correlated Mutations and Homologous Recombination Within Bacterial Populations. AB - Inferring the rate of homologous recombination within a bacterial population remains a key challenge in quantifying the basic parameters of bacterial evolution. Due to the high sequence similarity within a clonal population, and unique aspects of bacterial DNA transfer processes, detecting recombination events based on phylogenetic reconstruction is often difficult, and estimating recombination rates using coalescent model-based methods is computationally expensive, and often infeasible for large sequencing data sets. Here, we present an efficient solution by introducing a set of mutational correlation functions computed using pairwise sequence comparison, which characterize various facets of bacterial recombination. We provide analytical expressions for these functions, which precisely recapitulate simulation results of neutral and adapting populations under different coalescent models. We used these to fit correlation functions measured at synonymous substitutions using whole-genome data on Escherichia coli and Streptococcus pneumoniae populations. We calculated and corrected for the effect of sample selection bias, i.e., the uneven sampling of individuals from natural microbial populations that exists in most datasets. Our method is fast and efficient, and does not employ phylogenetic inference or other computationally intensive numerics. By simply fitting analytical forms to measurements from sequence data, we show that recombination rates can be inferred, and the relative ages of different samples can be estimated. Our approach, which is based on population genetic modeling, is broadly applicable to a wide variety of data, and its computational efficiency makes it particularly attractive for use in the analysis of large sequencing datasets. PMID- 28007888 TI - Stable Binding of the Conserved Transcription Factor Grainy Head to its Target Genes Throughout Drosophila melanogaster Development. AB - It has been suggested that transcription factor binding is temporally dynamic, and that changes in binding determine transcriptional output. Nonetheless, this model is based on relatively few examples in which transcription factor binding has been assayed at multiple developmental stages. The essential transcription factor Grainy head (Grh) is conserved from fungi to humans, and controls epithelial development and barrier formation in numerous tissues. Drosophila melanogaster, which possess a single grainy head (grh) gene, provide an excellent system to study this conserved factor. To determine whether temporally distinct binding events allow Grh to control cell fate specification in different tissue types, we used a combination of ChIP-seq and RNA-seq to elucidate the gene regulatory network controlled by Grh during four stages of embryonic development (spanning stages 5-17) and in larval tissue. Contrary to expectations, we discovered that Grh remains bound to at least 1146 genomic loci over days of development. In contrast to this stable DNA occupancy, the subset of genes whose expression is regulated by Grh varies. Grh transitions from functioning primarily as a transcriptional repressor early in development to functioning predominantly as an activator later. Our data reveal that Grh binds to target genes well before the Grh-dependent transcriptional program commences, suggesting it sets the stage for subsequent recruitment of additional factors that execute stage-specific Grh functions. PMID- 28007889 TI - Spiraling Complexity: A Test of the Snowball Effect in a Computational Model of RNA Folding. AB - Genetic incompatibilities can emerge as a byproduct of genetic divergence. According to Dobzhansky and Muller, an allele that fixes in one population may be incompatible with an allele at a different locus in another population when the two alleles are brought together in hybrids. Orr showed that the number of Dobzhansky-Muller incompatibilities (DMIs) should accumulate faster than linearly i.e., snowball-as two lineages diverge. Several studies have attempted to test the snowball effect using data from natural populations. One limitation of these studies is that they have focused on predictions of the Orr model, but not on its underlying assumptions. Here, we use a computational model of RNA folding to test both predictions and assumptions of the Orr model. Two populations are allowed to evolve in allopatry on a holey fitness landscape. We find that the number of inviable introgressions (an indicator for the number of DMIs) snowballs, but does so more slowly than expected. We show that this pattern is explained, in part, by the fact that DMIs can disappear after they have arisen, contrary to the assumptions of the Orr model. This occurs because DMIs become progressively more complex (i.e., involve alleles at more loci) as a result of later substitutions. We also find that most DMIs involve >2 loci, i.e., they are complex. Reproductive isolation does not snowball because DMIs do not act independently of each other. We conclude that the RNA model supports the central prediction of the Orr model that the number of DMIs snowballs, but challenges other predictions, as well as some of its underlying assumptions. PMID- 28007890 TI - Multiple Transcriptional and Post-transcriptional Pathways Collaborate to Control Sense and Antisense RNAs of Tf2 Retroelements in Fission Yeast. AB - Retrotransposons are mobile genetic elements that colonize eukaryotic genomes by replicating through an RNA intermediate. As retrotransposons can move within the host genome, defense mechanisms have evolved to repress their potential mutagenic activities. In the fission yeast Schizosaccharomyces pombe, the mRNA of Tf2 long terminal repeat retrotransposons is targeted for degradation by the 3'-5' exonucleolytic activity of the exosome-associated protein Rrp6. Here, we show that the nuclear poly(A)-binding protein Pab2 functions with Rrp6 to negatively control Tf2 mRNA accumulation. Furthermore, we found that Pab2/Rrp6-dependent RNA elimination functions redundantly to the transcriptional silencing mediated by the CENP-B homolog, Abp1, in the suppression of antisense Tf2 RNA accumulation. Interestingly, the absence of Pab2 attenuated the derepression of Tf2 transcription and the increased frequency of Tf2 mobilization caused by the deletion of abp1 Our data also reveal that the expression of antisense Tf2 transcripts is developmentally regulated and correlates with decreased levels of Tf2 mRNA. Our findings suggest that transcriptional and post-transcriptional pathways cooperate to control sense and antisense RNAs expressed from Tf2 retroelements. PMID- 28007892 TI - Feeding-Related Traits Are Affected by Dosage of the foraging Gene in Drosophila melanogaster. AB - Nutrient acquisition and energy storage are critical parts of achieving metabolic homeostasis. The foraging gene in Drosophila melanogaster has previously been implicated in multiple feeding-related and metabolic traits. Before foraging's functions can be further dissected, we need a precise genetic null mutant to definitively map its amorphic phenotypes. We used homologous recombination to precisely delete foraging, generating the for0 null allele, and used recombineering to reintegrate a full copy of the gene, generating the {forBAC} rescue allele. We show that a total loss of foraging expression in larvae results in reduced larval path length and food intake behavior, while conversely showing an increase in triglyceride levels. Furthermore, varying foraging gene dosage demonstrates a linear dose-response on these phenotypes in relation to foraging gene expression levels. These experiments have unequivocally proven a causal, dose-dependent relationship between the foraging gene and its pleiotropic influence on these feeding-related traits. Our analysis of foraging's transcription start sites, termination sites, and splicing patterns using rapid amplification of cDNA ends (RACE) and full-length cDNA sequencing, revealed four independent promoters, pr1-4, that produce 21 transcripts with nine distinct open reading frames (ORFs). The use of alternative promoters and alternative splicing at the foraging locus creates diversity and flexibility in the regulation of gene expression, and ultimately function. Future studies will exploit these genetic tools to precisely dissect the isoform- and tissue-specific requirements of foraging's functions and shed light on the genetic control of feeding-related traits involved in energy homeostasis. PMID- 28007891 TI - General Amino Acid Control and 14-3-3 Proteins Bmh1/2 Are Required for Nitrogen Catabolite Repression-Sensitive Regulation of Gln3 and Gat1 Localization. AB - Nitrogen catabolite repression (NCR), the ability of Saccharomyces cerevisiae to use good nitrogen sources in preference to poor ones, derives from nitrogen responsive regulation of the GATA family transcription activators Gln3 and Gat1 In nitrogen-replete conditions, the GATA factors are cytoplasmic and NCR sensitive transcription minimal. When only poor nitrogen sources are available, Gln3 is nuclear, dramatically increasing GATA factor-mediated transcription. This regulation was originally attributed to mechanistic Tor protein kinase complex 1 (mTorC1)-mediated control of Gln3 However, we recently showed that two regulatory systems act cumulatively to maintain cytoplasmic Gln3 sequestration, only one of which is mTorC1. Present experiments demonstrate that the other previously elusive component is uncharged transfer RNA-activated, Gcn2 protein kinase mediated general amino acid control (GAAC). Gcn2 and Gcn4 are required for NCR sensitive nuclear Gln3-Myc13 localization, and from epistasis experiments Gcn2 appears to function upstream of Ure2 Bmh1/2 are also required for nuclear Gln3 Myc13 localization and appear to function downstream of Ure2 Overall, Gln3 phosphorylation levels decrease upon loss of Gcn2, Gcn4, or Bmh1/2 Our results add a new dimension to nitrogen-responsive GATA-factor regulation and demonstrate the cumulative participation of the mTorC1 and GAAC pathways, which respond oppositely to nitrogen availability, in the nitrogen-responsive control of catabolic gene expression in yeast. PMID- 28007893 TI - Young microglia restore amyloid plaque clearance of aged microglia. AB - Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis. PMID- 28007894 TI - The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function. AB - The F-box protein FBXW7 is the substrate-recruiting subunit of an SCF ubiquitin ligase and a major tumor-suppressor protein that is altered in several human malignancies. Loss of function of FBXW7 results in the stabilization of numerous proteins that orchestrate cell proliferation and survival. Little is known about proteins that directly regulate the function of this protein. In the current work, we have mapped the interactome of the enigmatic pseudophosphatase STYX We reasoned that a catalytically inactive phosphatase might have adopted novel mechanisms of action. The STYX interactome contained several F-box proteins, including FBXW7. We show that STYX binds to the F-box domain of FBXW7 and disables its recruitment into the SCF complex. Therefore, STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients, which affects disease prognosis. We propose the STYX-FBXW7 interaction as a promising drug target for future investigations. PMID- 28007895 TI - Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. AB - Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer. PMID- 28007897 TI - Recurrent detection of VIM-1-producing Escherichia coli clone in German pig production. PMID- 28007896 TI - The complete structure of the chloroplast 70S ribosome in complex with translation factor pY. AB - Chloroplasts are cellular organelles of plants and algae that are responsible for energy conversion and carbon fixation by the photosynthetic reaction. As a consequence of their endosymbiotic origin, they still contain their own genome and the machinery for protein biosynthesis. Here, we present the atomic structure of the chloroplast 70S ribosome prepared from spinach leaves and resolved by cryo EM at 3.4 A resolution. The complete structure reveals the features of the 4.5S rRNA, which probably evolved by the fragmentation of the 23S rRNA, and all five plastid-specific ribosomal proteins. These proteins, required for proper assembly and function of the chloroplast translation machinery, bind and stabilize rRNA including regions that only exist in the chloroplast ribosome. Furthermore, the structure reveals plastid-specific extensions of ribosomal proteins that extensively remodel the mRNA entry and exit site on the small subunit as well as the polypeptide tunnel exit and the putative binding site of the signal recognition particle on the large subunit. The translation factor pY, involved in light- and temperature-dependent control of protein synthesis, is bound to the mRNA channel of the small subunit and interacts with 16S rRNA nucleotides at the A-site and P-site, where it protects the decoding centre and inhibits translation by preventing tRNA binding. The small subunit is locked by pY in a non-rotated state, in which the intersubunit bridges to the large subunit are stabilized. PMID- 28007898 TI - Editor's Note. PMID- 28007899 TI - Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines. AB - ISCU myopathy is an inherited disease that primarily affects individuals of northern Swedish descent who share a single point mutation in the fourth intron of the ISCU gene. The current study shows correction of specific phenotypes associated with disease following treatment with an antisense oligonucleotide (ASO) targeted to the site of the mutation. We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion. Upon ASO treatment, levels of SDHB in patient myotubular cell lines increased to levels observed in control myotubular cell lines. Additionally, we have shown that both patient fibroblast and myotubular cell lines displayed an increase in complex II activity with a concomitant decrease in succinate levels in patient myotubular cell lines after ASO treatment. Mitochondrial and cytosolic aconitase activities increased significantly following ASO treatment in patient myotubes. The current study suggests that ASO treatment may serve as a viable approach to correcting ISCU myopathy in patients. PMID- 28007901 TI - A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype. AB - Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder. Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis. Since short term treatment with steroids has been shown to improve the neurological signs in A-T patients we determined if that was also the case for Atm-deficient rats. Betamethasone treatment extended the lifespan of Atm knockout rats, prevented microglial activation and significantly decreased neuroinflammatory changes and motor neuron loss. These results point to unrepaired damage to DNA leading to significant levels of cytosolic DNA in Atm deficient neurons and microglia and as a consequence activation of the cGAS-STING pathway and cytokine production. This in turn would increase the inflammatory microenvironment leading to dysfunction and death of neurons. Thus the rat model represents a suitable one for studying neurodegeneration in A-T and adds support for the use of anti-inflammatory drugs for the treatment of neurodegeneration in A-T patients. PMID- 28007900 TI - Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. AB - Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing dysregulation have been implicated in many human diseases, but the in vivo functions of most RBPs and the splicing outcome upon their loss remain largely unexplored. Here we report that constitutive deletion of Rbm17, which encodes an RBP with a putative role in splicing, causes early embryonic lethality in mice and that its loss in Purkinje neurons leads to rapid degeneration. Transcriptome profiling of Rbm17-deficient and control neurons and subsequent splicing analyses using CrypSplice, a new computational method that we developed, revealed that more than half of RBM17-dependent splicing changes are cryptic. Importantly, RBM17 represses cryptic splicing of genes that likely contribute to motor coordination and cell survival. This finding prompted us to re-analyze published datasets from a recent report on TDP-43, an RBP implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as it was demonstrated that TDP-43 represses cryptic exon splicing to promote cell survival. We uncovered a large number of TDP-43-dependent splicing defects that were not previously discovered, revealing that TDP-43 extensively regulates cryptic splicing. Moreover, we found a significant overlap in genes that undergo both RBM17- and TDP-43-dependent cryptic splicing repression, many of which are associated with survival. We propose that repression of cryptic splicing by RBPs is critical for neuronal health and survival. CrypSplice is available at www.liuzlab.org/CrypSplice. PMID- 28007902 TI - Early born neurons are abnormally positioned in the doublecortin knockout hippocampus. AB - Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. The Dcx protein plays a key role in neuronal migration, and hippocampal pyramidal neurons in Dcx knockout (KO) mice are disorganized. The single CA3 pyramidal cell layer observed in wild type (WT) is present as two abnormal layers in the KO, and CA3 KO pyramidal neurons are more excitable than WT. Dcx KO mice also exhibit spontaneous epileptic activity originating in the hippocampus. It is unknown, however, how hyperexcitability arises and why two CA3 layers are observed.Transcriptome analyses were performed to search for perturbed postnatal gene expression, comparing Dcx KO CA3 pyramidal cell layers with WT. Gene expression changes common to both KO layers indicated mitochondria and Golgi apparatus anomalies, as well as increased cell stress. Intriguingly, gene expression analyses also suggested that the KO layers differ significantly from each other, particularly in terms of maturity. Layer-specific molecular markers and BrdU birthdating to mark the final positions of neurons born at distinct timepoints revealed inverted layering of the CA3 region in Dcx KO animals. Notably, many early-born 'outer boundary' neurons are located in an inner position in the Dcx KO CA3, superficial to other pyramidal neurons. This abnormal positioning likely affects cell morphology and connectivity, influencing network function. Dissecting this Dcx KO phenotype sheds light on coordinated developmental mechanisms of neuronal subpopulations, as well as gene expression patterns contributing to a bi-layered malformation associated with epilepsy. PMID- 28007904 TI - Cellular, biochemical and molecular changes in muscles from patients with X linked myotubular myopathy due to MTM1 mutations. AB - Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN. The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy. Animal models knocked out for MTM1 show severe reduction of ryanodine receptor 1 mediated calcium release but, since knocking out genes in animal models does not necessarily replicate the human phenotype, we considered it important to study directly the effect of MTM1 mutations on patient muscle cells. The results of the present study show that at the level of myotubes MTM1 mutations do not dramatically affect calcium homeostasis and calcium release mediated through the ryanodine receptor 1, though they do affect myotube size and nuclear content. On the other hand, mature muscles such as those obtained from patient muscle biopsies exhibit a significant decrease in expression of the ryanodine receptor 1, a decrease in muscle-specific microRNAs and a considerable up-regulation of histone deacetylase-4. We hypothesize that the latter events consequent to the primary genetic mutation, are the cause of the severe decrease in muscle strength that characterizes these patients. PMID- 28007903 TI - Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model. AB - Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. It is one of the most common heritable human diseases with eventual development of renal failure; however, effective treatment is lacking. While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst expansions in animal models, results from clinical studies are controversial, prompting further mechanistic studies of mTOR-based therapy. Here, we aim to establish autophagy, a downstream pathway of mTOR, as a new therapeutic target for PKD. We generated zebrafish mutants for pkd1 and noted cystic kidney and mTOR activation in pkd1a mutants, suggesting a conserved ADPKD model. Further assessment of the mutants revealed impaired autophagic flux, which was conserved in kidney epithelial cells derived from both Pkd1-null mice and ADPKD patients. We found that inhibition of autophagy by knocking down the core autophagy protein Atg5 promotes cystogenesis, while activation of autophagy using a specific inducer Beclin-1 peptide ameliorates cysts in the pkd1a model. Treatment with compound autophagy activators, including mTOR-dependent rapamycin as well as mTOR independent carbamazepine and minoxidil, markedly attenuated cyst formation and restored kidney function. Finally, we showed that combination treatment with low doses of rapamycin and carbamazepine was able to attenuate cyst formation as effectively as a single treatment with a high dose of rapamycin alone. In summary, our results suggested a modifying effect of autophagy on ADPKD, established autophagy activation as a novel therapy for ADPKD, and presented zebrafish as an efficient vertebrate model for developing PKD therapeutic strategies. PMID- 28007905 TI - Novel UCHL1 mutations reveal new insights into ubiquitin processing. AB - Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 has been implicated in early-onset progressive neurodegeneration (MIM no. 615491), so far only in one family. In this study a second family is characterized, and the functional consequences of the identified mutations in UCHL1 are explored. Three siblings developed childhood-onset optic atrophy, followed by spasticity and ataxia. Whole exome sequencing identified compound heterozygous variants in UCHL1, c.533G > A (p.Arg178Gln) and c.647C > A (p.Ala216Asp), cosegregating with the phenotype. Enzymatic activity of purified recombinant proteins analysed by ubiquitin hydrolase assays showed a 4-fold increased hydrolytic activity of the recombinant UCHL1 mutant Arg178Gln compared to wild type, whereas the Ala216Asp protein was insoluble. Structural 3D analysis of UCHL1 by computer modelling suggests that Arg178 is a rate-controlling residue in catalysis which is partly abolished in the Arg178Gln mutant and, consequently, the Arg178Gln mutant increases the enzymatic turnover. UCHL1 protein levels in fibroblasts measured by targeted mass spectrometry showed a total amount of UCHL1 in control fibroblasts about 4-fold higher than in the patients. Hence, studies of the identified missense variants reveal surprisingly different functional consequences as the insoluble Ala216Asp variant leads to loss of function, whereas the Arg178Gln leads to increased enzyme activity. The reported patients have remarkably preserved cognition, and we propose that the increased enzyme activity of the Arg178Gln variant offers a protective effect on cognitive function. This study establishes the importance of UCHL1 in neurodegeneration, provides new mechanistic insight about ubiquitin processing, and underlines the complexity of the different roles of UCHL1. PMID- 28007906 TI - IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3. AB - Rett syndrome (RTT) is an X-linked neurodevelopmental disorder in which the MECP2 (methyl CpG-binding protein 2) gene is mutated. Recent studies showed that RTT derived neurons have many cellular deficits when compared to control, such as: less synapses, lower dendritic arborization and reduced spine density. Interestingly, treatment of RTT-derived neurons with Insulin-like Growth Factor 1 (IGF1) could rescue some of these cellular phenotypes. Given the critical role of IGF1 during neurodevelopment, the present study used human induced pluripotent stem cells (iPSCs) from RTT and control individuals to investigate the gene expression profile of IGF1 and IGF1R on different developmental stages of differentiation. We found that the thyroid hormone receptor (TRalpha 3) has a differential expression profile. Thyroid hormone is critical for normal brain development. Our results showed that there is a possible link between IGF1/IGF1R and the TRalpha 3 and that over expression of IGF1R in RTT cells may be the cause of neurites improvement in neural RTT-derived neurons. PMID- 28007908 TI - Topoisomerase 1 inhibitor topotecan delays the disease progression in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan. Improvement of behavioural deficits are accompanied with the significant rescue of their progressively decreased body weight, brain weight and striatal volume. Interestingly, topotecan treatment also significantly reduced insoluble mutant huntingtin load in the HD mouse brain. Finally, we show that topotecan treatment to HD mouse not only inhibits the expression of transgenic mutant huntingtin, but also at the same time induces the expression of Ube3a, an ubiquitin ligase linked to the clearance of mutant huntingtin. These findings suggest that topotecan could be a potential therapeutic molecule to delay the progression of HD. PMID- 28007907 TI - H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation. AB - Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dube (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer. PMID- 28007909 TI - Mendelian randomization estimates of alanine aminotransferase with cardiovascular disease: Guangzhou Biobank Cohort study. AB - Observational studies of the association of alanine aminotransferase (ALT) levels with ischaemic heart disease (IHD) and cardiovascular disease (CVD) risk factors are inconsistent, probably because of confounding and reverse causality. Mendelian randomization (MR) provides less confounded results. We used MR analysis to assess the associations of ALT (U/L) with IHD, diabetes and other CVD risk factors. We used instrumental variable analysis based on two single nucleotide polymorphism (SNPs) HSD17B13/MAPK10 (rs6834314) and PNPLA3/SAMM50 (rs738409) to assess the associations of ALT (U/L) with IHD, diabetes and other CVD risk factors in the Guangzhou Biobank Cohort Study (GBCS). Observationally in 19,925 participants ALT levels were strongly positively associated with self reported IHD, systolic and diastolic blood pressure, low-density lipoprotein- and total cholesterol, triglycerides, fasting glucose, body mass index, waist circumference, heart rate (HR) and diabetes, but were not associated with uncorrected QT interval, HR-corrected QT interval or high-density lipoprotein cholesterol. In the MR study, using a credible genetic instrument (F-statistic = 23) for ALT, ALT levels were negatively associated with IHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.87 to 0.97) and triglycerides (beta - 0.08, 95% CI - 0.13 to - 0.03), but were not associated with other CVD risk factors. Our results using Mendelian randomization suggest that ALT reduces the risk of IHD, probably through reducing triglyceride levels. The underlying mechanisms deserve further investigation. PMID- 28007910 TI - Neuronal pentraxin 1 depletion delays neurodegeneration and extends life in Sandhoff disease mice. AB - GM2 gangliosidoses are a group of lysosomal storage disorders which include Sandhoff disease and Tay-Sachs disease. Dysregulation of glutamate receptors has been recently postulated in the pathology of Sandhoff disease. Glutamate receptor association with neuronal pentraxins 1 and 2, and the neuronal pentraxin receptor facilitates receptor potentiation and synaptic shaping. In this study, we have observed an upregulation of a novel form of neuronal pentraxin 1 (NP1-38) in the brains of a mouse model of Sandhoff disease and Tay-Sachs disease. In order to determine the impact of NP1 on the pathophysiology of Sandhoff disease mouse models, we have generated an Np1-/-Hexb-/- double knockout mouse, and observed extended lifespan, improved righting reflex and enhanced body condition relative to Hexb-/- mice, with no effect on gliosis or apoptotic markers in the CNS. Sandhoff mouse brain slices reveals a reduction in AMPA receptor-mediated currents, and increased variability in total glutamate currents in the CA1 region of the hippocampus; Np1-/-Hexb-/- mice show a correction of this phenotype, suggesting NP1-38 may be interfering with glutamate receptor function. Indeed, some of the psychiatric aspects of Sandhoff and Tay-Sachs disease (particularly late onset) may be attributed to a dysfunctional hippocampal glutamatergic system. Our work highlights a potential role for synaptic proteins, such as NP1 and glutamate receptors in lysosomal storage diseases. PMID- 28007911 TI - Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. AB - Hereditary spastic paraplegia, SPG31, is a rare neurological disorder caused by mutations in REEP1 gene encoding the microtubule-interacting protein, REEP1. The mechanism by which REEP1-dependent processes are linked with the disease is unclear. REEP1 regulates the morphology and trafficking of various organelles via interaction with the microtubules. In this study, we collected primary fibroblasts from SPG31 patients to investigate their mitochondrial morphology. We observed that the mitochondrial morphology in patient cells was highly tubular compared with control cells. We provide evidence that these morphological alterations are caused by the inhibition of mitochondrial fission protein, DRP1, due to the hyperphosphorylation of its serine 637 residue. This hyperphosphorylation is caused by impaired interactions between REEP1 and mitochondrial phosphatase PGAM5. Genetically or pharmacologically induced decrease of DRP1-S637 phosphorylation restores mitochondrial morphology in patient cells. Furthermore, ectopic expression of REEP1 carrying pathological mutations in primary neuronal culture targets REEP1 to the mitochondria. Mutated REEP1 proteins sequester mitochondria to the perinuclear region of the neurons and therefore, hamper mitochondrial transport along the axon. Considering the established role of mitochondrial distribution and morphology in neuronal health, our results support the involvement of a mitochondrial dysfunction in SPG31 pathology. PMID- 28007912 TI - GARLIC: a bioinformatic toolkit for aetiologically connecting diseases and cell type-specific regulatory maps. AB - Genome-wide association studies (GWAS) have emerged as a powerful tool to uncover the genetic basis of human common diseases, which often show a complex, polygenic and multi-factorial aetiology. These studies have revealed that 70-90% of all single nucleotide polymorphisms (SNPs) associated with common complex diseases do not occur within genes (i.e. they are non-coding), making the discovery of disease-causative genetic variants and the elucidation of the underlying pathological mechanisms far from straightforward. Based on emerging evidences suggesting that disease-associated SNPs are frequently found within cell type specific regulatory sequences, here we present GARLIC (GWAS-based Prediction Toolkit for Connecting Diseases and Cell Types), a user-friendly, multi-purpose software with an associated database and online viewer that, using global maps of cis-regulatory elements, can aetiologically connect human diseases with relevant cell types. Additionally, GARLIC can be used to retrieve potential disease causative genetic variants overlapping regulatory sequences of interest. Overall, GARLIC can satisfy several important needs within the field of medical genetics, thus potentially assisting in the ultimate goal of uncovering the elusive and complex genetic basis of common human disorders. PMID- 28007913 TI - Vascular Endothelial Growth Factor (VEGF) Promotes Assembly of the p130Cas Interactome to Drive Endothelial Chemotactic Signaling and Angiogenesis. AB - p130Cas is a polyvalent adapter protein essential for cardiovascular development, and with a key role in cell movement. In order to identify the pathways by which p130Cas exerts its biological functions in endothelial cells we mapped the p130Cas interactome and its dynamic changes in response to VEGF using high resolution mass spectrometry and reconstruction of protein interaction (PPI) networks with the aid of multiple PPI databases. VEGF enriched the p130Cas interactome in proteins involved in actin cytoskeletal dynamics and cell movement, including actin-binding proteins, small GTPases and regulators or binders of GTPases. Detailed studies showed that p130Cas association of the GTPase-binding scaffold protein, IQGAP1, plays a key role in VEGF chemotactic signaling, endothelial polarization, VEGF-induced cell migration, and endothelial tube formation. These findings indicate a cardinal role for assembly of the p130Cas interactome in mediating the cell migratory response to VEGF in angiogenesis, and provide a basis for further studies of p130Cas in cell movement. PMID- 28007916 TI - Watching real-time endocytosis in living cells. AB - The precise sequence of events promoting clathrin-coated vesicle assembly is still debated. In this issue, Kadlecova et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608071) test structural models using quantitative microscopy in living cells to investigate the hierarchy and temporal importance of molecular events required for clathrin-coated pit initiation. PMID- 28007915 TI - Podosome assembly is controlled by the GTPase ARF1 and its nucleotide exchange factor ARNO. AB - Podosomes represent a class of integrin-mediated cell-matrix adhesions formed by migrating and matrix-degrading cells. We demonstrate that in macrophage-like THP1 cells and fibroblasts stimulated to produce podosomes, down-regulation of the G protein ARF1 or the ARF1 guanine nucleotide exchange factor, ARNO, by small, interfering RNA or pharmacological inhibitors led to striking podosome elimination. Concomitantly, treatments inducing podosome formation increased the level of guanosine triphosphate (GTP)-bound ARF1. ARNO was found to colocalize with the adhesive rings of podosomes, whereas ARF1 was localized to vesicular structures transiently contacting podosome rings. Inhibition of ARF1 led to an increase in RhoA-GTP levels and triggered assembly of myosin-IIA filaments in THP1 cells, whereas the suppression of myosin-IIA rescued podosome formation regardless of ARF1 inhibition. Finally, expression of constitutively active ARF1 in fibroblasts induced formation of putative podosome precursors: actin-rich puncta coinciding with matrix degradation sites and containing proteins of the podosome core but not of the adhesive ring. Thus, ARNO-ARF1 regulates formation of podosomes by inhibition of RhoA/myosin-II and promotion of actin core assembly. PMID- 28007914 TI - A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib. AB - Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor betaPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration. PMID- 28007918 TI - ARF1 at the crossroads of podosome construction and function. AB - Podosomes are actin-based proteolytic microdomains of the plasma membrane found in cells that travel across tissues. In this issue, Rafiq et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201605104) reveal that the small guanosine triphosphatase ARF1, a well-known orchestrator of membrane traffic at the Golgi, regulates podosome formation, maintenance, and function. PMID- 28007919 TI - Delivery of Parasite RNA Transcripts Into Infected Epithelial Cells During Cryptosporidium Infection and Its Potential Impact on Host Gene Transcription. AB - Cryptosporidium parvum is an important opportunistic parasite pathogen for immunocompromised individuals and a common cause of diarrhea in young children. Previous studies have identified a panel of RNA transcripts of very low protein coding potential in C. parvum. Using an in vitro model of human intestinal cryptosporidiosis, we report here that some of these C. parvum RNA transcripts were selectively delivered into the nuclei of host epithelial cells during C. parvum infection. Nuclear delivery of several such parasitic RNAs, including Cdg7_FLc_0990, involved heat-shock protein 70-mediated nuclear importing mechanism. Overexpression of Cdg7_FLc_0990 in intestinal epithelial cells resulted in significant changes in expression levels of specific genes, with significant overlapping with alterations in gene expression profile detected in host cells after C. parvum infection. Our data demonstrate that C. parvum transcripts of low protein-coding potential are selectively delivered into epithelial cells during infection and may modulate gene transcription in infected host cells. PMID- 28007920 TI - Role of Interleukin 32 in Human Immunodeficiency Virus Reactivation and Its Link to Human Immunodeficiency Virus-Herpes Simplex Virus Coinfection. AB - Background: Herpes simplex virus type 2 (HSV-2; herpes) exacerbates human immunodeficiency virus type 1 (HIV) by unclear mechanisms. These studies tested the impact of HSV-2 on systemic T-cells and HIV reservoirs. Methods: Peripheral blood mononuclear cells from HIV-infected women on antiretroviral therapy who were HSV-2 seropositive or seronegative and HIV-uninfected controls were analyzed by flow cytometry. Cell-associated HIV DNA and RNA were quantified in the absence or presence of activating stimuli, recombinant interleukin 32gamma (IL-32gamma), and a RUNX1 inhibitor. RNA was assessed by nanostring. Results: CD4, but not CD8, T-cell phenotypes differed in HIV+/HSV-2+ versus HIV+/HSV-2- (overall P = .002) with increased frequency of CCR5+, CXCR4+, PD-1+, and CD69+ and decreased frequency of CCR10+ and CCR6+ T-cells. The changes were associated with higher HIV DNA. Paradoxically, IL-32, a proinflammatory cytokine, was lower in subpopulations of CD4+ T-cells in HSV-2+ versus HSV-2- women. Recombinant IL 32gamma blocked HIV reactivation in CD4+ T-cells and was associated with an increase in RUNX1 expression; the blockade was overcome by a RUNX1 inhibitor. Conclusions: Herpes is associated with phenotypic changes in CD4+ T-cells, including a decrease in IL-32, which may contribute to increased HIV reservoirs. Blocking IL-32 may facilitate HIV reactivation to improve shock and kill strategies. PMID- 28007921 TI - Mosquito Behavior Change After Distribution of Bednets Results in Decreased Protection Against Malaria Exposure. AB - Background: Behavioral resilience in mosquitoes poses a significant challenge to mosquito control. Although behavior changes in anopheline vectors have been reported over the last decade, there are no empirical data to suggest they compromise the efficacy of vector control in reducing malaria transmission. Methods: In this study, we quantified human exposure to both bites and infective bites of a major malaria vector in Papua New Guinea over the course of 4 years surrounding nationwide bednet distribution. We also quantified malaria infection prevalence in the human population during the same time period. Results: We observed a shift in mosquito biting to earlier hours of the evening, before individuals are indoors and protected by bednets, followed by a return to preintervention biting rates. As a result, net users and non-net users experienced higher levels of transmission than before the intervention. The personal protection provided by a bednet decreased over the study period and was lowest in the adult population, who may be an important reservoir for transmission. Malaria prevalence decreased in only 1 of 3 study villages after the distribution. Discussion: This study highlights the necessity of validating and deploying vector control measures targeting outdoor exposure to control and eliminate malaria. PMID- 28007923 TI - Phages, Fitness, Virulence, and Synergy: A Novel Approach for the Therapy of Infections Caused by Pseudomonas aeruginosa. PMID- 28007922 TI - Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence. AB - Background: Increasing antibiotic resistance warrants therapeutic alternatives. Here we investigated the efficacy of bacteriophage-therapy (phage) alone or combined with antibiotics against experimental endocarditis (EE) due to Pseudomonas aeruginosa, an archetype of difficult-to-treat infection. Methods: In vitro fibrin clots and rats with aortic EE were treated with an antipseudomonas phage cocktail alone or combined with ciprofloxacin. Phage pharmacology, therapeutic efficacy, and resistance were determined. Results: In vitro, single dose phage therapy killed 7 log colony-forming units (CFUs)/g of fibrin clots in 6 hours. Phage-resistant mutants regrew after 24 hours but were prevented by combination with ciprofloxacin (2.5 * minimum inhibitory concentration). In vivo, single-dose phage therapy killed 2.5 log CFUs/g of vegetations in 6 hours (P < .001 vs untreated controls) and was comparable with ciprofloxacin monotherapy. Moreover, phage/ciprofloxacin combinations were highly synergistic, killing >6 log CFUs/g of vegetations in 6 hours and successfully treating 64% (n = 7/11) of rats. Phage-resistant mutants emerged in vitro but not in vivo, most likely because resistant mutations affected bacterial surface determinants important for infectivity (eg, the pilT and galU genes involved in pilus motility and LPS formation). Conclusions: Single-dose phage therapy was active against P. aeruginosa EE and highly synergistic with ciprofloxacin. Phage-resistant mutants had impaired infectivity. Phage-therapy alone or combined with antibiotics merits further clinical consideration. PMID- 28007925 TI - Long-term Maintenance of the Influenza-Specific Cross-Reactive Memory CD4+ T-Cell Responses Following Repeated Annual Influenza Vaccination. AB - Background: Annual vaccination for healthcare workers and other high-risk groups is the mainstay of the public health strategy to combat influenza. Inactivated influenza vaccines confer protection by inducing neutralizing antibodies efficiently against homologous and closely matched virus strains. In the absence of neutralizing antibodies, cross-reactive T cells have been shown to limit disease severity. However, animal studies and a study in immunocompromised children suggested that repeated vaccination hampers CD8+ T cells. Yet the impact of repeated annual influenza vaccination on both cross-reactive CD4+ and CD8+ T cells has not been explored, particularly in healthy adults. Methods: We assembled a unique cohort of healthcare workers who received a single AS03 adjuvanted H1N1pdm09 vaccine in 2009 and subsequently either repeated annual vaccination or no further vaccination during 2010-2013. Blood samples were collected before the influenza season or vaccination to assess antibody and T cell responses. Results: Antibody titers to H1N1pdm09 persisted above the protective level in both the repeated- and single-vaccination groups. The interferon gamma+ (IFN-gamma+) and multifunctional CD4+ T-cell responses were maintained in the repeated group but declined significantly in the single vaccination group. The IFN-gamma+CD8+ T cells remained stable in both groups. Conclusions: This study provides the immunological evidence base for continuing annual influenza vaccination in adults. PMID- 28007924 TI - Impact of Periodic Presumptive Treatment for Bacterial Vaginosis on the Vaginal Microbiome among Women Participating in the Preventing Vaginal Infections Trial. AB - Background: Evidence suggests that specific vaginal bacteria associated with bacterial vaginosis (BV) may increase the risk of adverse health outcomes in women. Among women participating in a randomized, double-blinded trial, we assessed the effect of periodic presumptive treatment (PPT) on detection of select vaginal bacteria. Methods: High-risk women from the United States and Kenya with a recent vaginal infection received intravaginal metronidazole 750 mg plus miconazole 200 mg or placebo for 5 consecutive nights each month for 12 months. Vaginal fluid specimens were collected via polyester/polyethylene terephthalate swabs every other month and tested for bacteria, using quantitative polymerase chain reaction (PCR) assays targeting the 16S ribosomal RNA gene. The effect of PPT on bacterium detection was assessed among all participants and stratified by country. Results: Of 234 women enrolled, 221 had specimens available for analysis. The proportion of follow-up visits with detectable quantities was lower in the PPT arm versus the placebo arm for the following bacteria: BVAB1, BVAB2, Atopobium vaginae, Leptotrichia/Sneathia, and Megasphaera. The magnitude of reductions was greater among Kenyan participants as compared to US participants. Conclusions: Use of monthly PPT for 1 year reduced colonization with several bacteria strongly associated with BV. The role of PPT to improve vaginal health should be considered, and efforts to improve the impact of PPT regimens are warranted. PMID- 28007927 TI - Managing acute coronary syndromes: troponin and DAPT in the real world. PMID- 28007928 TI - Cardiovascular medicine at the Quebec Heart and Lung Institute. PMID- 28007926 TI - Circadian Regulation of Benzo[a]Pyrene Metabolism and DNA Adduct Formation in Breast Cells and the Mouse Mammary Gland. AB - The circadian clock plays a role in many biologic processes, yet very little is known about its role in metabolism of drugs and carcinogens. The purpose of this study was to define the impact of circadian rhythms on benzo-a-pyrene (BaP) metabolism in the mouse mammary gland and develop a circadian in vitro model for investigating changes in BaP metabolism resulting from cross-talk between the molecular clock and aryl hydrocarbon receptor. Female 129sv mice (12 weeks old) received a single gavage dose of 50 mg/kg BaP at either noon or midnight, and mammary tissues were isolated 4 or 24 hours later. BaP-induced Cyp1a1 and Cyp1b1 mRNA levels were higher 4 hours after dosing at noon than at 4 hours after dosing at midnight, and this corresponded with parallel changes in Per gene expression. In our in vitro model, we dosed MCF10A mammary cells at different times after serum shock to study how time of day shifts drug metabolism in cells. Analysis of CYP1A1 and CYP1B1 gene expression showed the maximum enzyme-induced metabolism response 12 and 20 hours after shock, as determined by ethoxyresorufin-O deethylase activity, metabolism of BaP, and formation of DNA-BaP adducts. The pattern of PER-, BMAL-, and aryl hydrocarbon receptor-induced P450 gene expression and BaP metabolism was similar to BaP-induced Cyp1A1 and Cyp1B1 and molecular clock gene expression in mouse mammary glands. These studies indicate time-of-day exposure influences BaP metabolism in mouse mammary glands and describe an in vitro model that can be used to investigate the circadian influence on the metabolism of carcinogens. PMID- 28007929 TI - Canadian Cardiovascular Society, the power of collaboration. PMID- 28007930 TI - Eva E. Swahn MD PhD. PMID- 28007931 TI - The William Harvey lecture at ESC Congress 2016. PMID- 28007932 TI - An airport meeting that led to bromocriptine use in peripartum cardiomyopathy. PMID- 28007933 TI - Wisdom and heart rate. PMID- 28007934 TI - Should the 1h algorithm for rule in and rule out of acute myocardial infarction be used universally? PMID- 28007935 TI - Frequency doubling in the cyanobacterial circadian clock. AB - Organisms use circadian clocks to generate 24-h rhythms in gene expression. However, the clock can interact with other pathways to generate shorter period oscillations. It remains unclear how these different frequencies are generated. Here, we examine this problem by studying the coupling of the clock to the alternative sigma factor sigC in the cyanobacterium Synechococcus elongatus Using single-cell microscopy, we find that psbAI, a key photosynthesis gene regulated by both sigC and the clock, is activated with two peaks of gene expression every circadian cycle under constant low light. This two-peak oscillation is dependent on sigC, without which psbAI rhythms revert to one oscillatory peak per day. We also observe two circadian peaks of elongation rate, which are dependent on sigC, suggesting a role for the frequency doubling in modulating growth. We propose that the two-peak rhythm in psbAI expression is generated by an incoherent feedforward loop between the clock, sigC and psbAI Modelling and experiments suggest that this could be a general network motif to allow frequency doubling of outputs. PMID- 28007936 TI - Proteomics reveals the effects of sustained weight loss on the human plasma proteome. AB - Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill-defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry-based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual specific protein levels with wide-ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte-secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of -16% and +37%, respectively (P < 10-13), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten-protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases. PMID- 28007937 TI - Directed evolution of P450cin for mediated electron transfer. AB - Directed evolution is a powerful method to optimize enzyme properties for application demands. Interesting targets are P450 monooxygenases which catalyze the stereo- and regiospecific hydroxylation of chemically inert C-H bonds. Synthesis employing P450s under cell-free reaction conditions is limited by low total turnover numbers, enzyme instability, low product yields and the requirement of the expensive co-factor NADPH. Bioelectrocatalysis is an alternative to replace NADPH in cell-free P450-catalyzed reactions. However, natural enzymes are often not suitable for using non-natural electron delivery systems. Here we report the directed evolution of a previously engineered P450 CinA-10aa-CinC fusion protein (named P450cin-ADD-CinC) to use zinc/cobalt(III)sepulchrate as electron delivery system for an increased hydroxylation activity of 1,8-cineole. Two rounds of Sequence Saturation Mutagenesis (SeSaM) each followed by one round of multiple site-saturation mutagenesis of the P450 CinA-10aa-CinC fusion protein generated a variant (Gln385His, Val386Ser, Thr77Asn, Leu88Arg; named KB8) with a 3.8-fold increase in catalytic efficiency (28 uM-1 min-1) compared to P450cin-ADD-CinC (7 uM-1 min-1). Furthermore, variant KB8 exhibited a 1.5-fold higher product formation (500 uM uM 1 P450) compared to the equimolar mixture of CinA, CinC and Fpr using NADPH as co factor (315 uM uM-1 P450). In addition, electrochemical experiments with the electron delivery system platinum/cobalt(III)sepulchrate showed that the KB8 variant had a 4-fold higher product formation rate (0.16 nmol (nmol) P450-1 min-1 cm-2) than the P450cin-ADD-CinC (0.04 nmol (nmol) P450-1 min-1 cm-2). In summary, the current work shows prospects of using directed evolution to generate P450 enzymes suitable for use with alternative electron delivery systems. PMID- 28007938 TI - An updated comprehensive systematic review of Cladophialophora bantiana and analysis of epidemiology, clinical characteristics, and outcome of cerebral cases. AB - Cladophialophora bantiana is a phaeoid fungus that only rarely has been isolated from sources other than the human brain. It has a particular tropism for the central nervous system (CNS). We have integrated and updated large-scale data related to several aspects of C. Bantiana and reviewed all the available reports on its cerebral infections, focusing on their geographical distribution, infection routes, immune status of infected individuals, type and location of infections, clinical manifestations and treatment and outcome, briefly looking over the spectrum of other disease entities associated with C. bantiana, that is, extra-cerebral and animal infections and on the environmental sources of this fungus. Among the agents of phaeohyphomycosis, a term used to describe an infection caused by a dark pigmented fungus, C. bantiana has some significant specific features. A total of 120 case reports were identified with a significantly higher percentage of healthy subjects than immune-debilitated patients (58.3% vs. 41.7%). Infections due to C. bantiana occur worldwide. The main clinical manifestations are brain abscess (97.5%), coinfection of brain tissue and meninges (14.2%) and meningitis alone (2.5%). Among immunocompetent patients, cerebral infection occurred in the absence of pulmonary lesions. The mortality rate is 65.0% regardless of the patient's immune status. The therapeutic options used include surgery or antifungals alone, and the combination of both, in most cases the fatal outcome being rapid after admission. Since the fungus is a true pathogen, laboratory workers should be made aware that BioSafety Level-3 precautions might be necessary. PMID- 28007939 TI - Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B. AB - BACKGROUND: Haemophilia B is caused by genetic aberrations in the F9 gene. The majority of these are non-synonymous mutations that alter the primary structure of blood coagulation factor IX (FIX). However, a synonymous mutation c.459G>A (Val107Val) was clinically reported to result in mild haemophilia B (FIX coagulant activity 15%-20% of normal). The F9 mRNA of these patients showed no skipping or retention of introns and/or change in mRNA levels, suggesting that mRNA integrity does not contribute to the origin of the disease in affected individuals. The aim of this study is to elucidate the molecular mechanisms that can explain disease manifestations in patients with this synonymous mutation. METHODS: We analyse the molecular mechanisms underlying the FIX deficiency through in silico analysis and reproducing the c.459G>A (Val107Val) mutation in stable cell lines. Conformation and non-conformation sensitive antibodies, limited trypsin digestion, activity assays for FIX, interaction with other proteins and post-translation modifications were used to evaluate the biophysical and biochemical consequences of the synonymous mutation. RESULTS: The Val107Val synonymous mutation in F9 was found to significantly diminish FIX expression. Our results suggest that this mutation slows FIX translation and affects its conformation resulting in decreased extracellular protein level. The altered conformation did not change the specific activity of the mutated protein. CONCLUSIONS: The pathogenic basis for one synonymous mutation (Val107Val) in the F9 gene associated with haemophilia B was determined. A mechanistic understanding of this synonymous variant yields potential for guiding and developing future therapeutic treatments. PMID- 28007940 TI - Activation of Sp1-mediated transcription by Rta of Epstein-Barr virus via an interaction with MCAF1. PMID- 28007942 TI - Everolimus Boosts Endocrine Therapy for Breast Cancer. AB - In a phase II trial, the mTOR inhibitor everolimus, combined with the endocrine therapy fulvestrant, improved progression-free survival in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer who had become resistant to aromatase inhibitors. PMID- 28007941 TI - Registry in a tube: multiplexed pools of retrievable parts for genetic design space exploration. AB - Genetic designs can consist of dozens of genes and hundreds of genetic parts. After evaluating a design, it is desirable to implement changes without the cost and burden of starting the construction process from scratch. Here, we report a two-step process where a large design space is divided into deep pools of composite parts, from which individuals are retrieved and assembled to build a final construct. The pools are built via multiplexed assembly and sequenced using next-generation sequencing. Each pool consists of ~20 Mb of up to 5000 unique and sequence-verified composite parts that are barcoded for retrieval by PCR. This approach is applied to a 16-gene nitrogen fixation pathway, which is broken into pools containing a total of 55 848 composite parts (71.0 Mb). The pools encompass an enormous design space (1043 possible 23 kb constructs), from which an algorithm-guided 192-member 4.5 Mb library is built. Next, all 1030 possible genetic circuits based on 10 repressors (NOR/NOT gates) are encoded in pools where each repressor is fused to all permutations of input promoters. These demonstrate that multiplexing can be applied to encompass entire design spaces from which individuals can be accessed and evaluated. PMID- 28007946 TI - "Cures" Act Signed into Law. AB - President Obama has signed the 21st Century Cures Act into law. The bill provides $4.8 billion to three key health-related measures of the outgoing administration: the Beau Biden Cancer Moonshot, the Precision Medicine Initiative, and the BRAIN initiative. PMID- 28007949 TI - Corrigendum. PMID- 28007950 TI - Auxin-induced expression divergence between Arabidopsis species may originate within the TIR1/AFB-AUX/IAA-ARF module. AB - Auxin is an essential regulator of plant growth and development, and auxin signaling components are conserved among land plants. Yet, a remarkable degree of natural variation in physiological and transcriptional auxin responses has been described among Arabidopsis thaliana accessions. As intraspecies comparisons offer only limited genetic variation, we here inspect the variation of auxin responses between A. thaliana and A. lyrata. This approach allowed the identification of conserved auxin response genes including novel genes with potential relevance for auxin biology. Furthermore, promoter divergences were analyzed for putative sources of variation. De novo motif discovery identified novel and variants of known elements with potential relevance for auxin responses, emphasizing the complex, and yet elusive, code of element combinations accounting for the diversity in transcriptional auxin responses. Furthermore, network analysis revealed correlations of interspecies differences in the expression of AUX/IAA gene clusters and classic auxin-related genes. We conclude that variation in general transcriptional and physiological auxin responses may originate substantially from functional or transcriptional variations in the TIR1/AFB, AUX/IAA, and ARF signaling network. In that respect, AUX/IAA gene expression divergence potentially reflects differences in the manner in which different species transduce identical auxin signals into gene expression responses. PMID- 28007948 TI - Genome-metabolite associations revealed low heritability, high genetic complexity, and causal relations for leaf metabolites in winter wheat (Triticum aestivum). AB - We investigated associations between the metabolic phenotype, consisting of quantitative data of 76 metabolites from 135 contrasting winter wheat (Triticum aestivum) lines, and 17 372 single nucleotide polymorphism (SNP) markers. Metabolite profiles were generated from flag leaves of plants from three different environments, with average repeatabilities of 0.5-0.6. The average heritability of 0.25 was unaffected by the heading date. Correlations among metabolites reflected their functional grouping, highlighting the strict coordination of various routes of the citric acid cycle. Genome-wide association studies identified significant associations for six metabolic traits, namely oxalic acid, ornithine, L-arginine, pentose alcohol III, L-tyrosine, and a sugar oligomer (oligo II), with between one and 17 associated SNPs. Notable associations with genes regulating transcription or translation explained between 2.8% and 32.5% of the genotypic variance (pG). Further candidate genes comprised metabolite carriers (pG 32.5-38.1%), regulatory proteins (pG 0.3-11.1%), and metabolic enzymes (pG 2.5-32.5%). The combinatorial use of genomic and metabolic data to construct partially directed networks revealed causal inferences in the correlated metabolite traits and associated SNPs. The evaluated causal relationships will provide a basis for predicting the effects of genetic interferences on groups of correlated metabolic traits, and thus on specific metabolic phenotypes. PMID- 28007951 TI - Interactions between nitrate and ammonium in their uptake, allocation, assimilation, and signaling in plants. AB - Nitrogen (N) availability is a major factor determining plant growth and productivity. Plants acquire inorganic N from the soil, mainly in the form of nitrate and ammonium. To date, researchers have focused on these N sources, and demonstrated that plants exhibit elaborate responses at both physiological and morphological levels. Mixtures of nitrate and ammonium are beneficial in terms of plant growth, as compared to nitrate or ammonium alone, and therefore synergistic responses to both N sources are predicted at different steps ranging from acquisition to assimilation. In this review, we summarize interactions between nitrate and ammonium with respect to uptake, allocation, assimilation, and signaling. Given that cultivated land often contains both nitrate and ammonium, a better understanding of the synergism between these N sources should help to identify targets with the potential to improve crop productivity. PMID- 28007952 TI - Contributions of two cytosolic glutamine synthetase isozymes to ammonium assimilation in Arabidopsis roots. AB - Glutamine synthetase (GS) catalyzes a reaction that incorporates ammonium into glutamate and yields glutamine in the cytosol and chloroplasts. Although the enzymatic characteristics of the GS1 isozymes are well known, their physiological functions in ammonium assimilation and regulation in roots remain unclear. In this study we show evidence that two cytosolic GS1 isozymes (GLN1;2 and GLN1;3) contribute to ammonium assimilation in Arabidopsis roots. Arabidopsis T-DNA insertion lines for GLN1;2 and GLN1;3 (i.e. gln1;2 and gln1;3 single-mutants), the gln1;2:gln1;3 double-mutant, and the wild-type accession (Col-0) were grown in hydroponic culture with variable concentrations of ammonium to compare their growth, and their content of nitrogen, carbon, ammonium, and amino acids. GLN1;2 and GLN1;3 promoter-dependent green fluorescent protein was observed under conditions with or without ammonium supply. Loss of GLN1;2 caused significant suppression of plant growth and glutamine biosynthesis under ammonium-replete conditions. In contrast, loss of GLN1;3 caused slight defects in growth and Gln biosynthesis that were only visible based on a comparison of the gln1;2 single- and gln1;2:gln1;3 double-mutants. GLN1;2, being the most abundantly expressed GS1 isozyme, markedly increased following ammonium supply and its promoter activity was localized at the cortex and epidermis, while GLN1;3 showed only low expression at the pericycle, suggesting their different physiological contributions to ammonium assimilation in roots. The GLN1;2 promoter-deletion analysis identified regulatory sequences required for controlling ammonium responsive gene expression of GLN1;2 in Arabidopsis roots. These results shed light on GLN1 isozyme-specific regulatory mechanisms in Arabidopsis that allow adaptation to an ammonium-replete environment. PMID- 28007953 TI - The function of LHCBM4/6/8 antenna proteins in Chlamydomonas reinhardtii. AB - In eukaryotic autotrophs, photosystems are composed of a core moiety, hosting charge separation and electron transport reactions, and an antenna system, enhancing light harvesting and photoprotection. In Chlamydomonas reinhardtii, the major antenna of PSII is a heterogeneous trimeric complex made up of LHCBM1 LHCBM9 subunits. Despite high similarity, specific functions have been reported for several members including LHCBM1, 2, 7, and 9. In this work, we analyzed the function of LHCBM4 and LHCBM6 gene products in vitro by synthesizing recombinant apoproteins from individual sequences and refolding them with pigments. Additionally, we characterized knock-down strains in vivo for LHCBM4/6/8 genes. We show that LHCBM4/6/8 subunits could be found as a component of PSII supercomplexes with different sizes, although the largest pool was free in the membranes and poorly connected to PSII. Impaired accumulation of LHCBM4/6/8 caused a decreased LHCII content per PSII and a reduction in the amplitude of state 1-state 2 transitions. In addition, the reduction of LHCBM4/6/8 subunits caused a significant reduction of the Non-photochemical quenching activity and in the level of photoprotection. PMID- 28007954 TI - Evolution of jasmonate biosynthesis and signaling mechanisms. AB - Jasmonates are phytohormones that modulate a wide spectrum of plant physiological processes, especially defense against herbivores and necrotrophs. The molecular mechanisms of jasmonate biosynthesis and signaling have been well characterized in model plants. In this review, we provide an in-depth analysis and overview of the origin and evolution of the jasmonate biosynthesis and signaling pathways. Furthermore, we discuss the striking parallels between jasmonate and auxin signaling mechanisms, which reveals a common ancestry of these signaling mechanisms. Finally, we highlight the importance of studying jasmonate biosynthesis and signaling in lower plants. PMID- 28007955 TI - The AFL subfamily of B3 transcription factors: evolution and function in angiosperm seeds. AB - Seed development follows zygotic embryogenesis; during the maturation phase reserves accumulate and desiccation tolerance is acquired. This is tightly regulated at the transcriptional level and the AFL (ABI3/FUS3/LEC2) subfamily of B3 transcription factors (TFs) play a central role. They alter hormone biosynthesis, mainly in regards to abscisic acid and gibberellins, and also regulate the expression of other TFs and/or modulate their downstream activity via protein-protein interactions. This review deals with the origin of AFL TFs, which can be traced back to non-vascular plants such as Physcomitrella patens and achieves foremost expansion in the angiosperms. In green algae, like the unicellular Chlamydomonas reinhardtii or the pluricellular Klebsormidium flaccidum, a single B3 gene and four B3 paralogous genes are annotated, respectively. However, none of them present with the structural features of the AFL subfamily, with the exception of the B3 DNA-binding domain. Phylogenetic analysis groups the AFL TFs into four Major Clusters of Ortologous Genes (MCOGs). The origin and function of these genes is discussed in view of their expression patterns and in the context of major regulatory interactions in seeds of monocotyledonous and dicotyledonous species. PMID- 28007956 TI - Upregulation of RPA2 promotes NF-kappaB activation in breast cancer by relieving the antagonistic function of menin on NF-kappaB-regulated transcription. AB - RPA2, a subunit of the heterotrimeric replication protein A (RPA) complex, is overexpressed in various cancers. In this study, we showed a significant RPA2 upregulation in breast cancer tissues and cell lines. Ectopic expression of RPA2 in MCF7 and MDA-MB-231 cells promoted cell proliferation, adhesion, migration and invasion, and induced epithelial-mesenchymal transition (EMT) of MCF7 cells. Ablation of RPA2 in MDA-MB-231 cells induced apoptosis and suppressed colony formation, EMT and invasion. Binding assays indicated that menin, the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene product, interacted with RPA2. Ectopic expression of RPA2 inhibited the formation of the menin-NK-kappaB p65 complex and repressed the inhibitory effect of menin on expression of NF kappaB-regulated genes that contribute to tumor progression. Conversely, knockdown of RPA2 promoted formation of the menin-p65 complex and repressed the expression of NF-kappaB-mediated genes. RPA2 expression was induced via an E2F1 dependent mechanism in MCF7 and MDA-MB-231 cells treated with NF-kappaB activators, TNF-alpha or lipopolysaccharide (LPS). These results suggested that RPA2-dependent tumorigenicity was mediated via enhancement of NF-kappaB activity by relieving the antagonistic function of menin on NF-kappaB-regulated transcription in breast cancer cells. PMID- 28007957 TI - Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair. AB - BACKGROUND: Unraveling the molecular mechanisms that regulate the biology of metastasis-competent circulating tumor cells (CTCs) is urgently needed to understand metastasis formation and tumor relapse. Our group previously established the first cell line (CTC-MCC-41) derived from metastasis-competent CTCs of a patient with colon cancer. METHODS: In this study, we analyzed the transcriptome of CTC-MCC-41 cells using Human Genome U133 Plus 2.0 microarrays with the aim of unraveling the molecular basis of their special features (stem cell properties and ability to initiate and support metastasis formation). RESULTS: Comparison of the transcriptome data of metastasis-competent CTC-MCC-41 cells and of HT-29 cells (derived from a primary colon cancer) highlights the differential expression of genes that regulate energy metabolism [peroxisome proliferator-activated receptor gamma coactivator 1A (PPARGC1A), peroxisome proliferator-activated receptor gamma coactivator 1B (PPARGC1B), fatty acid binding protein 1 (FABP1), aldehyde dehydrogenase 3 family member A1 (ALDH3A1)], DNA repair [BRCA1 interacting protein C-terminal helicase 1 (BRIP1), Fanconi anemia complementation group B (FANCB), Fanconi anemia complementation group M (FANCM)], and stemness [glutaminase 2 (GLS2), cystathionine-beta-synthase (CBS), and cystathionine gamma-lyase (CTH)]. The differential expression of 20 genes was validated by quantitative reverse transcription PCR. CONCLUSIONS: This study gives a comprehensive outlook on the molecular events involved in colon cancer progression and provides potential CTC biomarkers that may help develop new therapies to specifically target CTCs with stem cell properties that cause metastases and tumor relapse in patients with colon cancer. PMID- 28007958 TI - Polyphosphate and RNA Differentially Modulate the Contact Pathway of Blood Clotting. AB - The contact pathway of the plasma clotting cascade is dispensable for normal hemostasis, but contributes to thrombosis and serves as a bridge between inflammation and coagulation. This pathway is triggered upon exposure of plasma to certain anionic polymers and artificial surfaces. Recently, extracellular nucleic acids and inorganic polyphosphate (polyP) have been implicated as being important (patho)physiologically relevant activators of this pathway. However, mechanistic details regarding how nucleic acids or polyP modulate the individual reactions of the contact pathway have been lacking. In this study, we investigate the ability of RNA homopolymers and polyP to bind the primary constituents of the contact pathway: factor XIa, factor XIIa, and plasma kallikrein, in the presence and absence of high molecular weight kininogen (HK), an important cofactor in this pathway. We examine seven proteolytic activation reactions within the contact pathway and report that polyP greatly enhances the rate of all seven, while RNA is effective in supporting only a subset of these reactions. HK both enhances and suppresses these proteolytic activation reactions, depending on the specific reaction evaluated. Overall, we find that polyP is a potent mediator of contact pathway activation reactions in general, that RNA secondary structure may be important to its procoagulant activity, and that nucleic acids versus polyP may differentially modulate specific enzyme activation events within the contact pathway. PMID- 28007959 TI - RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis. AB - Adult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation. PMID- 28007960 TI - PrenDB, a Substrate Prediction Database to Enable Biocatalytic Use of Prenyltransferases. AB - Prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily catalyze the attachment of prenyl or prenyl-like moieties to diverse acceptor compounds. These acceptor molecules are generally aromatic in nature and mostly indole or indole-like. Their catalytic transformation represents a major skeletal diversification step in the biosynthesis of secondary metabolites, including the indole alkaloids. DMATS enzymes thus contribute significantly to the biological and pharmacological diversity of small molecule metabolites. Understanding the substrate specificity of these enzymes could create opportunities for their biocatalytic use in preparing complex synthetic scaffolds. However, there has been no framework to achieve this in a rational way. Here, we report a chemoinformatic pipeline to enable prenyltransferase substrate prediction. We systematically catalogued 32 unique prenyltransferases and 167 unique substrates to create possible reaction matrices and compiled these data into a browsable database named PrenDB. We then used a newly developed algorithm based on molecular fragmentation to automatically extract reactive chemical epitopes. The analysis of the collected data sheds light on the thus far explored substrate space of DMATS enzymes. To assess the predictive performance of our virtual reaction extraction tool, 38 potential substrates were tested as prenyl acceptors in assays with three prenyltransferases, and we were able to detect turnover in >55% of the cases. The database, PrenDB (www.kolblab.org/prendb.php), enables the prediction of potential substrates for chemoenzymatic synthesis through substructure similarity and virtual chemical transformation techniques. It aims at making prenyltransferases and their highly regio- and stereoselective reactions accessible to the research community for integration in synthetic work flows. PMID- 28007961 TI - c-JUN Dimerization Protein 2 (JDP2) Is a Transcriptional Repressor of Follicle stimulating Hormone beta (FSHbeta) and Is Required for Preventing Premature Reproductive Senescence in Female Mice. AB - Follicle-stimulating hormone (FSH) regulates follicular growth and stimulates estrogen synthesis in the ovaries. FSH is a heterodimer consisting of an alpha subunit, also present in luteinizing hormone, and a unique beta subunit, which is transcriptionally regulated by gonadotropin-releasing hormone 1 (GNRH). Because most FSH is constitutively secreted, tight transcriptional regulation is critical for maintaining FSH levels within a narrow physiological range. Previously, we reported that GNRH induces FSHbeta (Fshb) transcription via induction of the AP-1 transcription factor, a heterodimer of c-FOS and c-JUN. Herein, we identify c-JUN dimerization protein 2 (JDP2) as a novel repressor of GNRH-mediated Fshb induction. JDP2 exhibited high basal expression and bound the Fshb promoter at an AP-1-binding site in a complex with c-JUN. GNRH treatment induced c-FOS to replace JDP2 as a c-JUN binding partner, forming transcriptionally active AP-1. Subsequently, rapid c-FOS degradation enabled reformation of the JDP2 complex. In vivo studies revealed that JDP2 null male mice have normal reproductive function, as expected from a negative regulator of the FSH hormone. Female JDP2 null mice, however, exhibited early puberty, observed as early vaginal opening, larger litters, and early reproductive senescence. JDP2 null females had increased levels of circulating FSH and higher expression of the Fshb subunit in the pituitary, resulting in elevated serum estrogen and higher numbers of large ovarian follicles. Disruption of JDP2 function therefore appears to cause early cessation of reproductive function, a condition that has been associated with elevated FSH in women. PMID- 28007962 TI - Concerted Up-regulation of Aldehyde/Alcohol Dehydrogenase (ADHE) and Starch in Chlamydomonas reinhardtii Increases Survival under Dark Anoxia. AB - Aldehyde/alcohol dehydrogenases (ADHEs) are bifunctional enzymes that commonly produce ethanol from acetyl-CoA with acetaldehyde as intermediate and play a key role in anaerobic redox balance in many fermenting bacteria. ADHEs are also present in photosynthetic unicellular eukaryotes, where their physiological role and regulation are, however, largely unknown. Herein we provide the first molecular and enzymatic characterization of the ADHE from the photosynthetic microalga Chlamydomonas reinhardtii Purified recombinant ADHE catalyzed the reversible NADH-mediated interconversions of acetyl-CoA, acetaldehyde, and ethanol but seemed to be poised toward the production of ethanol from acetaldehyde. Phylogenetic analysis of the algal fermentative enzyme supports a vertical inheritance from a cyanobacterial-related ancestor. ADHE was located in the chloroplast, where it associated in dimers and higher order oligomers. Electron microscopy analysis of ADHE-enriched stromal fractions revealed fine spiral structures, similar to bacterial ADHE spirosomes. Protein blots showed that ADHE is regulated under oxic conditions. Up-regulation is observed in cells exposed to diverse physiological stresses, including zinc deficiency, nitrogen starvation, and inhibition of carbon concentration/fixation capacity. Analyses of the overall proteome and fermentation profiles revealed that cells with increased ADHE abundance exhibit better survival under dark anoxia. This likely relates to the fact that greater ADHE abundance appeared to coincide with enhanced starch accumulation, which might reflect ADHE-mediated anticipation of anaerobic survival. PMID- 28007963 TI - Interaction of p190A RhoGAP with eIF3A and Other Translation Preinitiation Factors Suggests a Role in Protein Biosynthesis. AB - The negative regulator of Rho family GTPases, p190A RhoGAP, is one of six mammalian proteins harboring so-called FF motifs. To explore the function of these and other p190A segments, we identified interacting proteins by tandem mass spectrometry. Here we report that endogenous human p190A, but not its 50% identical p190B paralog, associates with all 13 eIF3 subunits and several other translational preinitiation factors. The interaction involves the first FF motif of p190A and the winged helix/PCI domain of eIF3A, is enhanced by serum stimulation and reduced by phosphatase treatment. The p190A/eIF3A interaction is unaffected by mutating phosphorylated p190A-Tyr308, but disrupted by a S296A mutation, targeting the only other known phosphorylated residue in the first FF domain. The p190A-eIF3 complex is distinct from eIF3 complexes containing S6K1 or mammalian target of rapamycin (mTOR), and appears to represent an incomplete preinitiation complex lacking several subunits. Based on these findings we propose that p190A may affect protein translation by controlling the assembly of functional preinitiation complexes. Whether such a role helps to explain why, unique among the large family of RhoGAPs, p190A exhibits a significantly increased mutation rate in cancer remains to be determined. PMID- 28007965 TI - The Glycosyltransferase QUA1 Regulates Chloroplast-Associated Calcium Signaling During Salt and Drought Stress in Arabidopsis. AB - Cytoplasmic Ca2+ ([Ca2+]cyt) elevation induced by various signals is responsible for appropriate downstream responses. Through a genetic screen of Arabidopsis thaliana mutants defective in stress-induced [Ca2+]cyt elevation, the glycosyltransferase QUASIMODO1 (QUA1) was identified as a regulator of [Ca2+]cyt in response to salt stress. Compared with the wild type, the qua1-4 mutant exhibited a dramatically greater increase in [Ca2+]cyt under NaCl treatment. Functional analysis showed that QUA1 is a novel chloroplast protein that regulates cytoplasmic Ca2+ signaling. QUA1 was detected in chloroplast thylakoids, and the qua1-4 mutant exhibited irregularly stacked grana. The observed greater increase in [Ca2+]cyt was inhibited upon recovery of chloroplast function in the qua1-4 mutant. Further analysis showed that CAS, a thylakoid localized calcium sensor, also displayed irregularly stacked grana, and the chloroplasts of the qua1-4 cas-1 double mutant were similar to those of cas-1 plants. In QUA1-overexpressing plants, the protein level of CAS was decreased, and CAS was readily degraded under osmotic stress. When CAS was silenced in the qua1-4 mutant, the large [Ca2+]cyt increase was blocked, and the higher expression of PLC3 and PLC4 was suppressed. Under osmotic stress, the qua1-4 mutant showed an even greater elevation in [Ca2+]cyt and was hypersensitive to drought stress. However, this sensitivity was inhibited when the increase in [Ca2+]cyt was repressed in the qua1-4 mutant. Collectively, our data indicate that QUA1 may function in chloroplast-dependent calcium signaling under salt and drought stresses. Additionally, CAS may function downstream of QUA1 to mediate these processes. PMID- 28007964 TI - Peroxisome proliferator-activated receptor-alpha accelerates alpha-chlorofatty acid catabolism. AB - alpha-Chlorofatty aldehydes are generated from myeloperoxidase-derived HOCl targeting plasmalogens, and are subsequently oxidized to alpha-chlorofatty acids (alpha-ClFAs). The catabolic pathway for alpha-ClFA is initiated by omega oxidation. Here, we examine PPAR-alpha activation as a mechanism to increase alpha-ClFA catabolism. Pretreating both HepG2 cells and primary mouse hepatocytes with the PPAR-alpha agonist, pirinixic acid (Wy 14643), increased the production of alpha-chlorodicarboxylic acids (alpha-ClDCAs) in cells treated with exogenous alpha-ClFA. Additionally, alpha-ClDCA production in Wy 14643-pretreated wild-type mouse hepatocytes was accompanied by a reduction in cellular free alpha-ClFA. The dependence of PPAR-alpha-accelerated alpha-ClFA catabolism was further demonstrated by both impaired metabolism in mouse PPAR-alpha-/- hepatocytes and decreased clearance of plasma alpha-ClFA in PPAR-alpha-/- mice. Furthermore, Wy 14643 treatments decreased plasma 2-chlorohexadecanoic acid levels in wild-type mice. Additional studies showed that alpha-ClFA increases PPAR-alpha, PPAR-delta, and PPAR-gamma activities, as well as mRNA expression of the PPAR-alpha target genes, CD36, CPT1a, Cyp4a10, and CIDEC. Collectively, these results indicate that PPAR-alpha accelerates important pathways for the clearance of alpha-ClFA, and alpha-ClFA may, in part, accelerate its catabolism by serving as a ligand for PPAR-alpha. PMID- 28007966 TI - Molecular Characterization of LjSWEET3, a Sugar Transporter in Nodules of Lotus japonicus. AB - Symbiotic nitrogen fixation in legumes contributes greatly to the global nitrogen cycle on the earth. In nodules, resident rhizobia supply nitrogen nutrient fixed from atmospheric N2 to the host plant; in turn, the plant provides photosynthetic metabolites to bacteroids as a carbon source. In this process, various transporters are involved at different membrane systems; however, little is known at the molecular level about the flow of carbon from the host cells to the symbiotic bacteria. We have been studying transporters functioning in nodules of Lotus japonicus, and found that out of 13 SWEET genes in the L. japonicus genome LjSWEET3, a member of the SWEET transporter family, is highly expressed in nodules. The SWEET family was first identified in Arabidopsis, where members of the family are involved in phloem loading, nectar secretion, pollen nutrition and seed filling. The expression of LjSWEET3 strongly increased during nodule development and reached the highest level in mature nodules. Histochemical analysis using L. japonicus plants transformed with LjSWEET3 promoter:GUS (beta glucuronidase) showed strong expression in the vascular systems of nodules. Analysis of an LjSWEET3-green fluorescent protein (GFP) fusion expressed in Nicotiana banthamiana and Coptis japonica indicates that LjSWEET3 localizes to the plasma membrane. Together these data are consistent with a role for LjSWEET3 in sugar translocation towards nodules and also suggest the possible existence of multiple routes of carbon supply into nodules. PMID- 28007967 TI - Aberrant Meiotic Modulation Partially Contributes to the Lower Germination Rate of Pollen Grains in Maize (Zea mays L.) Under Low Nitrogen Supply. AB - Pollen germination is an essential step towards successful pollination during maize reproduction. How low niutrogen (N) affects pollen germination remains an interesting biological question to be addressed. We found that only low N resulted in a significantly lower germination rate of pollen grains after 4 weeks of low N, phosphorus or potassium treatment in maize production. Importantly, cytological analysis showed 7-fold more micronuclei in male meiocytes under the low N treatment than in the control, indicating that the lower germination rate of pollen grains was partially due to numerous chromosome loss events resulting from preceding meiosis. The appearance of 10 bivalents in the control and low N cells at diakinesis suggested that chromosome pairing and recombination in meiosis I was not affected by low N. Further gene expression analysis revealed dramatic down-regulation of Nuclear Division Cycle 80 (Ndc80) and Regulator of Chromosome Condensation 1 (Rcc1-1) expression and up-regulation of Cell Division Cycle 20 (Cdc20-1) expression, although no significant difference in the expression level of kinetochore foundation proteins Centromeric Histone H3 (Cenh3) and Centromere Protein C (Cenpc) and cohesion regulators Recombination 8 (Rec8) and Shugoshin (Sgo1) was observed. Aberrant modulation of three key meiotic regulators presumably resulted in a high likelihood of erroneous chromosome segregation, as testified by pronounced lagging chromosomes at anaphase I or cell cycle disruption at meiosis II. Thus, we proposed a cytogenetic mechanism whereby low N affects male meiosis and causes a higher chromosome loss frequency and eventually a lower germination rate of pollen grains in a staple crop plant. PMID- 28007968 TI - Nitrite Protects Mitochondrial Structure and Function under Hypoxia. AB - Oxygen deprivation leads to changes in mitochondrial morphology and impaired flow of reducing equivalents through the electron transport chain. The extent of these changes depends on the duration and severity of the treatment as well as on the species and cell type. Nitrate is known to ameliorate these effects in some instances, but it is possible that it is nitrite, rather than nitrate, that is the key to the mechanism. To test this, mitochondria were isolated from 21-day old pea (Pisum sativum) roots and incubated for 90 min under normoxia or hypoxia in the presence or absence of 0.5 mM nitrite. The supply of nitrite under hypoxia led to nitric oxide production, improved mitochondrial integrity, improved energization of the inner mitochondrial membrane, increased ATP synthesis, decreased production of reactive oxygen species and decreased lipid peroxidation. It also resulted in higher levels and activities of complex I and the supercomplex I + III2. It is concluded that nitrite has an important role in maintaining mitochondrial function under hypoxia, and that it achieves this through the reduction of nitrite to nitric oxide by the mitochondrial electron transport chain. PMID- 28007969 TI - Cyt c6-3: A New Isoform of Photosynthetic Cyt c6 Exclusive to Heterocyst-Forming Cyanobacteria. AB - All known cyanobacteria contain Cyt c6, a small soluble electron carrier protein whose main function is to transfer electrons from the Cyt b6f complex to PSI, although it is also involved in respiration. We have previously described a second isoform of this protein, the Cyt c6-like, whose function remains unknown. Here we describe a third isoform of Cyt c6 (here called Cytc6-3), which is only found in heterocyst-forming filamentous cyanobacteria. Cyt c6-3 is expressed in vegetative cells but is specifically repressed in heterocysts cells under diazotrophic growth conditions. Although there is a close structural similarity between Cyt c6-3 and Cyt c6 related to the general protein folding, Cyt c6-3 presents differential electrostatic surface features as compared with Cyt c6, its expression is not copper dependent and has a low reactivity towards PSI. According to the different expression pattern, functional reactivity and structural properties, Cyt c6-3 has to play an as yet to be defined regulatory role related to heterocyst differentiation. PMID- 28007970 TI - Dual effects of fructose on ChREBP and FoxO1/3alpha are responsible for AldoB up regulation and vascular remodelling. AB - Increased production of methylglyoxal (MG) in vascular tissues is one of the causative factors for vascular remodelling in different subtypes of metabolic syndrome, including hypertension and insulin resistance. Fructose-induced up regulation of aldolase B (AldoB) contributes to increased vascular MG production but the underlying mechanisms are unclear. Serum levels of MG and fructose were determined in diabetic patients with hypertension. MG level had significant positive correlations with blood pressure and fructose level respectively. C57BL/6 mice were fed with control or fructose-enriched diet for 3 months and ultrasonographic and histologic analyses were performed to evaluate arterial structural changes. Fructose-fed mice exhibited hypertension and high levels of serum MG with normal glucose level. Fructose intake increased blood vessel wall thickness and vascular smooth muscle cell (VSMC) proliferation. Western blotting and real-time PCR analysis revealed that AldoB level was significantly increased in both the aorta of fructose-fed mice and the fructose-treated VSMCs, whereas aldolase A (AldoA) expression was not changed. The knockdown of AldoB expression prevented fructose-induced MG overproduction and VSMC proliferation. Moreover, fructose significantly increased carbohydrate-responsive element-binding protein (ChREBP), phosphorylated FoxO1/3alpha and Akt1 levels. Fructose induced translocation of ChREBP from the cytosol to nucleus and activated AldoB gene expression, which was inhibited by the knockdown of ChREBP. Meanwhile, fructose caused FoxO1/3alpha shuttling from the nucleus to cytosol and inhibited its binding to AldoB promoter region. Fructose-induced AldoB up-regulation was suppressed by Akt1 inhibitor but enhanced by FoxO1/3alpha siRNA. Collectively, fructose activates ChREBP and inactivates FoxO1/3alpha pathways to up-regulate AldoB expression and MG production, leading to vascular remodelling. PMID- 28007971 TI - Paediatric emergency department-based carbon monoxide detector intervention: a randomised trial. AB - BACKGROUND: Although non-fire-related carbon monoxide (CO) poisoning is almost entirely preventable, over 400 people die and 20 000 people are injured each year in the USA from unintentional CO poisoning. Thus, there is a critical need for evidence-based interventions for preventing CO poisoning and increasing the proper use and installation of CO detectors. METHODS: A randomised, controlled trial (Project CODE, a Carbon Monoxide Detector Education intervention) with 2 week and 6-month follow-up home observations was conducted in 299 parents of children aged <=18 years recruited in the emergency department of a level 1 paediatric trauma centre. The intervention group received an educational tool, a spiral-bound, laminated booklet that resembled a CO detector containing theory based safety messages based on the precaution adoption process model, a plug-in CO detector and 9 V battery. The control group received a one page flyer on CO poisoning prevention. RESULTS: Although the difference was not statistically significant, mean CO knowledge score increased at a greater rate for the intervention group than the control group. Intervention group parents were more likely to exhibit 'safe' CO detector use than control group parents at the 2-week follow-up (RR: 2.75; 95% CI 2.06 to 3.69) and 6-month follow-up (RR: 2.78; 95% CI 2.06 to 3.76), after adjusting for self-reported CO detector use behaviour at enrolment and annual per capita income. CONCLUSIONS: An emergency department delivered intervention containing a theory-based educational tool paired with a CO detector can be an effective method for increasing knowledge about CO poisoning, for prevention and for appropriate use of a CO detector. TRIAL REGISTRATION NUMBER: NCT00959478. PMID- 28007972 TI - Fitness Trade-Offs Lead to Suppressor Tolerance in Yeast. AB - Genetic variation among individuals within a population provides the raw material for phenotypic diversity upon which natural selection operates. Some given variants can act on multiple standing genomic variations simultaneously and release previously inaccessible phenotypes, leading to increased adaptive potential upon challenging environments. Previously, we identified such a variant related to a tRNA nonsense suppressor in yeast. When introduced into other genetic backgrounds, the suppressor led to an increased population phenotypic variance on various culture conditions, conferring background and environment specific selective advantages. Nonetheless, most isolates are intolerant to the suppressor on rich media due to a severe fitness cost. Here, we found that the tolerance to suppressor is related to a surprising level of fitness outburst, showing a trade-off effect to accommodate the cost of carrying the suppressor. To dissect the genetic basis of such trade-offs, we crossed strains with contrasting tolerance levels on rich media, and analyzed the fitness distribution patterns in the offspring. Combining quantitative tetrad analysis and bulk segregant analysis, we identified two genes, namely MKT1 and RGA1, involved in suppressor tolerance. We showed that alleles from the tolerant parent for both genes conferred a significant gain of fitness, which increased the suppressor tolerance. Our results present a detailed dissection of suppressor tolerance in yeast and provide insights into the molecular basis of trade-offs between fitness and evolutionary potential. PMID- 28007973 TI - Direct Determination of the Mutation Rate in the Bumblebee Reveals Evidence for Weak Recombination-Associated Mutation and an Approximate Rate Constancy in Insects. AB - Accurate knowledge of the mutation rate provides a base line for inferring expected rates of evolution, for testing evolutionary hypotheses and for estimation of key parameters. Advances in sequencing technology now permit direct estimates of the mutation rate from sequencing of close relatives. Within insects there have been three prior such estimates, two in nonsocial insects (Drosophila: 2.8 * 10-9 per bp per haploid genome per generation; Heliconius: 2.9 * 10-9) and one in a social species, the honeybee (3.4 * 10-9). Might the honeybee's rate be ~20% higher because it has an exceptionally high recombination rate and recombination may be directly or indirectly mutagenic? To address this possibility, we provide a direct estimate of the mutation rate in the bumblebee (Bombus terrestris), this being a close relative of the honeybee but with a much lower recombination rate. We confirm that the crossover rate of the bumblebee is indeed much lower than honeybees (8.7 cM/Mb vs. 37 cM/Mb). Importantly, we find no significant difference in the mutation rates: we estimate for bumblebees a rate of 3.6 * 10-9 per haploid genome per generation (95% confidence intervals 2.38 * 10-9 and 5.37 * 10-9) which is just 5% higher than the estimate that of honeybees. Both genomes have approximately one new mutation per haploid genome per generation. While we find evidence for a direct coupling between recombination and mutation (also seen in honeybees), the effect is so weak as to leave almost no footprint on any between-species differences. The similarity in mutation rates suggests an approximate constancy of the mutation rate in insects. PMID- 28007974 TI - Transition from Environmental to Partial Genetic Sex Determination in Daphnia through the Evolution of a Female-Determining Incipient W Chromosome. AB - Sex chromosomes can evolve during the evolution of genetic sex determination (GSD) from environmental sex determination (ESD). Despite theoretical attention, early mechanisms involved in the transition from ESD to GSD have yet to be studied in nature. No mixed ESD-GSD animal species have been reported, except for some species of Daphnia, small freshwater crustaceans in which sex is usually determined solely by the environment, but in which a dominant female sex determining locus is present in some populations. This locus follows Mendelian single-locus inheritance, but has otherwise not been characterized genetically. We now show that the sex-determining genomic region maps to the same low recombining peri-centromeric region of linkage group 3 (LG3) in three highly divergent populations of D. magna, and spans 3.6 Mb. Despite low levels of recombination, the associated region contains signs of historical recombination, suggesting a role for selection acting on several genes thereby maintaining linkage disequilibrium among the 36 associated SNPs. The region carries numerous genes involved in sex differentiation in other taxa, including transformer2 and sox9. Taken together, the region determining the genetic females shows characteristics of a sex-related supergene, suggesting that LG3 is potentially an incipient W chromosome despite the lack of significant additional restriction of recombination between Z and W. The occurrence of the female-determining locus in a pre-existing low recombining region illustrates one possible form of recombination suppression in sex chromosomes. D. magna is a promising model for studying the evolutionary transitions from ESD to GSD and early sex chromosome evolution. PMID- 28007975 TI - CTDGFinder: A Novel Homology-Based Algorithm for Identifying Closely Spaced Clusters of Tandemly Duplicated Genes. AB - Closely spaced clusters of tandemly duplicated genes (CTDGs) contribute to the diversity of many phenotypes, including chemosensation, snake venom, and animal body plans. CTDGs have traditionally been identified subjectively as genomic neighborhoods containing several gene duplicates in close proximity; however, CTDGs are often highly variable with respect to gene number, intergenic distance, and synteny. This lack of formal definition hampers the study of CTDG evolutionary dynamics and the discovery of novel CTDGs in the exponentially growing body of genomic data. To address this gap, we developed a novel homology based algorithm, CTDGFinder, which formalizes and automates the identification of CTDGs by examining the physical distribution of individual members of families of duplicated genes across chromosomes. Application of CTDGFinder accurately identified CTDGs for many well-known gene clusters (e.g., Hox and beta-globin gene clusters) in the human, mouse and 20 other mammalian genomes. Differences between previously annotated gene clusters and our inferred CTDGs were due to the exclusion of nonhomologs that have historically been considered parts of specific gene clusters, the inclusion or absence of genes between the CTDGs and their corresponding gene clusters, and the splitting of certain gene clusters into distinct CTDGs. Examination of human genes showing tissue-specific enhancement of their expression by CTDGFinder identified members of several well-known gene clusters (e.g., cytochrome P450s and olfactory receptors) and revealed that they were unequally distributed across tissues. By formalizing and automating CTDG identification, CTDGFinder will facilitate understanding of CTDG evolutionary dynamics, their functional implications, and how they are associated with phenotypic diversity. PMID- 28007976 TI - Complex Admixture Preceded and Followed the Extinction of Wisent in the Wild. AB - Retracing complex population processes that precede extreme bottlenecks may be impossible using data from living individuals. The wisent (Bison bonasus), Europe's largest terrestrial mammal, exemplifies such a population history, having gone extinct in the wild but subsequently restored by captive breeding efforts. Using low coverage genomic data from modern and historical individuals, we investigate population processes occurring before and after this extinction. Analysis of aligned genomes supports the division of wisent into two previously recognized subspecies, but almost half of the genomic alignment contradicts this population history as a result of incomplete lineage sorting and admixture. Admixture between subspecies populations occurred prior to extinction and subsequently during the captive breeding program. Admixture with the Bos cattle lineage is also widespread but results from ancient events rather than recent hybridization with domestics. Our study demonstrates the huge potential of historical genomes for both studying evolutionary histories and for guiding conservation strategies. PMID- 28007978 TI - The Genetic and Transcriptional Basis of Short and Long Term Adaptation across Multiple Stresses in Escherichia coli. AB - Microbes exhibit short and long term responses when exposed to challenging environmental conditions. To what extent these responses are correlated, what their evolutionary potential is and how they translate to cross-stress fitness is still unclear. In this study, we comprehensively characterized the response of Escherichia coli populations to four abiotic stresses (n-butanol, osmotic, acidic, and oxidative) and their combinations by performing genome-scale transcriptional analysis and growth profiling. We performed an analysis of their cross-stress behavior which identified 15 cases of cross- protection and one case of cross vulnerability. To elucidate the evolutionary potential of stress responses to individual stresses and stress combinations, we re-sequenced E. coli populations evolved in those four environments for 500 generations. We developed and applied a network-driven method that integrates mutations and differential expression to identify core and stress-specific gene communities that are likely to have a phenotypic impact. Our results suggest that beyond what is expected from the general stress response mechanisms, cross-stress behavior arises both from common pathways, several including metal ion binding and glycolysis/gluconeogenesis, and stress-specific expression programs. The stress specific dependences uncovered, argue that cross-stress behavior is ubiquitous and central to understanding microbial physiology under stressful conditions. PMID- 28007977 TI - Genomic Basis of Adaptive Evolution: The Survival of Amur Ide (Leuciscus waleckii) in an Extremely Alkaline Environment. AB - The Amur ide (Leuciscus waleckii) is a cyprinid fish that is widely distributed in Northeast Asia. The Lake Dali Nur population inhabits one of the most extreme aquatic environments on Earth, with an alkalinity up to 50 mmol/L (pH 9.6), thus providing an exceptional model with which to characterize the mechanisms of genomic evolution underlying adaptation to extreme environments. Here, we developed the reference genome assembly for L. waleckii from Lake Dali Nur. Intriguingly, we identified unusual expanded long terminal repeats (LTRs) with higher nucleotide substitution rates than in many other teleosts, suggesting their more recent insertion into the L. waleckii genome. We also identified expansions in genes encoding egg coat proteins and natriuretic peptide receptors, possibly underlying the adaptation to extreme environmental stress. We further sequenced the genomes of 10 additional individuals from freshwater and 18 from Lake Dali Nur populations, and we detected a total of 7.6 million SNPs from both populations. In a genome scan and comparison of these two populations, we identified a set of genomic regions under selective sweeps that harbor genes involved in ion homoeostasis, acid-base regulation, unfolded protein response, reactive oxygen species elimination, and urea excretion. Our findings provide comprehensive insight into the genomic mechanisms of teleost fish that underlie their adaptation to extreme alkaline environments. PMID- 28007979 TI - Secreted Proteins Defy the Expression Level-Evolutionary Rate Anticorrelation. AB - The rates of evolution of the proteins of any organism vary across orders of magnitude. A primary factor influencing rates of protein evolution is expression. A strong negative correlation between expression levels and evolutionary rates (the so-called E-R anticorrelation) has been observed in virtually all studied organisms. This effect is currently attributed to the abundance-dependent fitness costs of misfolding and unspecific protein-protein interactions, among other factors. Secreted proteins are folded in the endoplasmic reticulum, a compartment where chaperones, folding catalysts, and stringent quality control mechanisms promote their correct folding and may reduce the fitness costs of misfolding. In addition, confinement of secreted proteins to the extracellular space may reduce misinteractions and their deleterious effects. We hypothesize that each of these factors (the secretory pathway quality control and extracellular location) may reduce the strength of the E-R anticorrelation. Indeed, here we show that among human proteins that are secreted to the extracellular space, rates of evolution do not correlate with protein abundances. This trend is robust to controlling for several potentially confounding factors and is also observed when analyzing protein abundance data for 6 human tissues. In addition, analysis of mRNA abundance data for 32 human tissues shows that the E-R correlation is always less negative, and sometimes nonsignificant, in secreted proteins. Similar observations were made in Caenorhabditis elegans and in Escherichia coli, and to a lesser extent in Drosophila melanogaster, Saccharomyces cerevisiae and Arabidopsis thaliana. Our observations contribute to understand the causes of the E-R anticorrelation. PMID- 28007980 TI - Archaic Adaptive Introgression in TBX15/WARS2. AB - A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15. PMID- 28007981 TI - Frontline Science: Myeloid-derived suppressor cells (MDSCs) facilitate maternal fetal tolerance in mice. AB - During successful pregnancy, a woman is immunologically tolerant of her genetically and antigenically disparate fetus, a state known as maternal-fetal tolerance. How this state is maintained has puzzled investigators for more than half a century. Diverse, immune and nonimmune mechanisms have been proposed; however, these mechanisms appear to be unrelated and to act independently. A population of immune suppressive cells called myeloid-derived suppressor cells (MDSCs) accumulates in pregnant mice and women. Given the profound immune suppressive function of MDSCs, it has been suggested that this cell population may facilitate successful pregnancy by contributing to maternal-fetal tolerance. We now report that myeloid cells with the characteristics of MDSCs not only accumulate in the circulation and uterus of female mice following mating but also suppress T cell activation and function in pregnant mice. Depletion of cells with the phenotype and function of MDSCs from gestation d 0.5 through d 7.5 resulted in implantation failure, increased T cell activation, and increased T cell infiltration into the uterus, whereas induction of MDSCs restored successful pregnancy and reduced T cell activation. MDSC-mediated suppression during pregnancy was accompanied by the down-regulation of L-selectin on naive T cells and a reduced ability of naive T cells to enter lymph nodes and become activated. Because MDSCs regulate many of the immune and nonimmune mechanisms previously attributed to maternal-fetal tolerance, MDSCs may be a unifying mechanism promoting maternal-fetal tolerance, and their induction may facilitate successful pregnancy in women who spontaneously abort or miscarry because of dysfunctional maternal-fetal tolerance. PMID- 28007982 TI - Generalization of prior information for rapid Bayesian time estimation. AB - To enable effective interaction with the environment, the brain combines noisy sensory information with expectations based on prior experience. There is ample evidence showing that humans can learn statistical regularities in sensory input and exploit this knowledge to improve perceptual decisions and actions. However, fundamental questions remain regarding how priors are learned and how they generalize to different sensory and behavioral contexts. In principle, maintaining a large set of highly specific priors may be inefficient and restrict the speed at which expectations can be formed and updated in response to changes in the environment. However, priors formed by generalizing across varying contexts may not be accurate. Here, we exploit rapidly induced contextual biases in duration reproduction to reveal how these competing demands are resolved during the early stages of prior acquisition. We show that observers initially form a single prior by generalizing across duration distributions coupled with distinct sensory signals. In contrast, they form multiple priors if distributions are coupled with distinct motor outputs. Together, our findings suggest that rapid prior acquisition is facilitated by generalization across experiences of different sensory inputs but organized according to how that sensory information is acted on. PMID- 28007983 TI - Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation. AB - Mutations in PARK2 and PARK6 genes are responsible for the majority of hereditary Parkinson's disease cases. These genes encode the E3 ubiquitin ligase parkin and the protein kinase PTEN-induced kinase 1 (PINK1), respectively. Together, parkin and PINK1 regulate the mitophagy pathway, which recycles damaged mitochondria following oxidative stress. Native parkin is inactive and exists in an autoinhibited state mediated by its ubiquitin-like (UBL) domain. PINK1 phosphorylation of serine 65 in parkin's UBL and serine 65 of ubiquitin fully activate ubiquitin ligase activity; however, a structural rationale for these observations is not clear. Here, we report the structure of the phosphorylated UBL domain from parkin. We find that destabilization of the UBL results from rearrangements to hydrophobic core packing that modify its structure. Altered surface electrostatics from the phosphoserine group disrupt its intramolecular association, resulting in poorer autoinhibition in phosphorylated parkin. Further, we show that phosphorylation of both the UBL domain and ubiquitin are required to activate parkin by releasing the UBL domain, forming an extended structure needed to facilitate E2-ubiquitin binding. Together, the results underscore the importance of parkin activation by the PINK1 phosphorylation signal and provide a structural picture of the unraveling of parkin's ubiquitin ligase potential. PMID- 28007985 TI - Dose-Response Relationship between Inorganic Arsenic Exposure and Lung Cancer among Arseniasis Residents with Low Methylation Capacity. AB - Background: Exposure to inorganic arsenic (InAs) has been documented as a risk factor for lung cancer. This study examined the association between InAs exposure, its metabolism, and lung cancer occurrence.Methods: We followed 1,300 residents from an arseniasis area in Taiwan, determined urinary InAs metabolites, and identified 39 lung cancer cases. Cox proportional hazards model was performed.Results: The results demonstrated that participants with either the primary methylation index [monomethylarsonic acid (MMA)/InAs] or the secondary methylation index [dimethylarsenic acid (DMA)/MMA] lower than their respective median values were at a higher risk of lung cancer (HRs from 3.41 to 4.66) than those with high methylation capacity. The incidence density of lung cancer increased from 79.9/100,000 (year-1) to 467.4/100,000 (year-1) for residents with low methylation capacity and from 0 to 158.5/100,000 (year-1) for residents with high methylation capacity when the arsenic exposure dose increased from 2 to 10 ppb to >=200 ppb, respectively. The analyses revealed a dose-response relationship between lung cancer occurrence and increasing arsenic concentrations in drinking water as well as cumulative arsenic exposure (monotonic trend test; P < 0.05 and P < 0.05, respectively) among the residents with low methylation capacity. The relationship between arsenic exposure and lung cancer among high methylators was not statistically significant.Conclusions: Hypomethylation responses to InAs exposure may dose dependently increase lung cancer occurrence.Impact: The high-risk characteristics observed among those exposed should be considered in future preventive medicine and research on arsenic carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(5); 756-61. (c)2016 AACR. PMID- 28007984 TI - Microbial competition in porous environments can select against rapid biofilm growth. AB - Microbes often live in dense communities called biofilms, where competition between strains and species is fundamental to both evolution and community function. Although biofilms are commonly found in soil-like porous environments, the study of microbial interactions has largely focused on biofilms growing on flat, planar surfaces. Here, we use microfluidic experiments, mechanistic models, and game theory to study how porous media hydrodynamics can mediate competition between bacterial genotypes. Our experiments reveal a fundamental challenge faced by microbial strains that live in porous environments: cells that rapidly form biofilms tend to block their access to fluid flow and redirect resources to competitors. To understand how these dynamics influence the evolution of bacterial growth rates, we couple a model of flow-biofilm interaction with a game theory analysis. This investigation revealed that hydrodynamic interactions between competing genotypes give rise to an evolutionarily stable growth rate that stands in stark contrast with that observed in typical laboratory experiments: cells within a biofilm can outcompete other genotypes by growing more slowly. Our work reveals that hydrodynamics can profoundly affect how bacteria compete and evolve in porous environments, the habitat where most bacteria live. PMID- 28007986 TI - Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. AB - Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2 The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance. PMID- 28007987 TI - Connectomic correlates of response to treatment in first-episode psychosis. AB - Connectomic approaches using diffusion tensor imaging have contributed to our understanding of brain changes in psychosis, and could provide further insights into the neural mechanisms underlying response to antipsychotic treatment. We here studied the brain network organization in patients at their first episode of psychosis, evaluating whether connectome-based descriptions of brain networks predict response to treatment, and whether they change after treatment. Seventy six patients with a first episode of psychosis and 74 healthy controls were included. Thirty-three patients were classified as responders after 12 weeks of antipsychotic treatment. Baseline brain structural networks were built using whole-brain diffusion tensor imaging tractography, and analysed using graph analysis and network-based statistics to explore baseline characteristics of patients who subsequently responded to treatment. A subgroup of 43 patients was rescanned at the 12-week follow-up, to study connectomic changes over time in relation to treatment response. At baseline, those subjects who subsequently responded to treatment, compared to those that did not, showed higher global efficiency in their structural connectomes, a network configuration that theoretically facilitates the flow of information. We did not find specific connectomic changes related to treatment response after 12 weeks of treatment. Our data suggest that patients who have an efficiently-wired connectome at first onset of psychosis show a better subsequent response to antipsychotics. However, response is not accompanied by specific structural changes over time detectable with this method. PMID- 28007988 TI - Reply: Atherosclerosis and vascular cognitive impairment neuropathological guideline. PMID- 28007989 TI - CAD mutations and uridine-responsive epileptic encephalopathy. AB - Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening. PMID- 28007990 TI - Longitudinal course of epilepsy in Rett syndrome and related disorders. AB - Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious. PMID- 28007991 TI - Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder. AB - SEE SCHENCK AND MAHOWALD DOI101093/AWW329 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Idiopathic REM sleep behaviour disorder is characterized by the enactment of violent dreams during paradoxical (REM) sleep in the absence of normal muscle atonia. Accumulating clinical and experimental data suggest that REM sleep behaviour disorder might be due to the neurodegeneration of glutamate neurons involved in paradoxical sleep and located within the pontine sublaterodorsal tegmental nucleus. The purpose of the present work was thus to functionally determine first, the role of glutamate sublaterodorsal tegmental nucleus neurons in paradoxical sleep and second, whether their genetic inactivation is sufficient for recapitulating REM sleep behaviour disorder in rats. For this goal, we first injected two retrograde tracers in the intralaminar thalamus and ventral medulla to disentangle neuronal circuits in which sublaterodorsal tegmental nucleus is involved; second we infused bilaterally in sublaterodorsal tegmental nucleus adeno-associated viruses carrying short hairpin RNAs targeting Slc17a6 mRNA [which encodes vesicular glutamate transporter 2 (vGluT2)] to chronically impair glutamate synaptic transmission in sublaterodorsal tegmental nucleus neurons. At the neuroanatomical level, sublaterodorsal tegmental nucleus neurons specifically activated during paradoxical sleep hypersomnia send descending efferents to glycine/GABA neurons within the ventral medulla, but not ascending projections to the intralaminar thalamus. These data suggest a crucial role of sublaterodorsal tegmental nucleus neurons rather in muscle atonia than in paradoxical sleep generation. In line with this hypothesis, 30 days after adeno-associated virus injections into sublaterodorsal tegmental nucleus rats display a decrease of 30% of paradoxical sleep daily quantities, and a significant increase of muscle tone during paradoxical sleep concomitant to a tremendous increase of abnormal motor dream enacting behaviours. These animals display symptoms and behaviours during paradoxical sleep that closely mimic human REM sleep behaviour disorder. Altogether, our data demonstrate that glutamate sublaterodorsal tegmental nucleus neurons generate muscle atonia during paradoxical sleep likely through descending projections to glycine/GABA premotor neurons in the ventral medulla. Although playing a role in paradoxical sleep regulation, they are, however, not necessary for inducing the state itself. The present work further validates a potent new preclinical REM sleep behaviour disorder model that opens avenues for studying and treating this disabling sleep disorder, and advances potential regions implicated in prodromal stages of synucleinopathies such as Parkinson's disease. PMID- 28007992 TI - Atherosclerosis and vascular cognitive impairment neuropathological guideline. PMID- 28007993 TI - Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. AB - Astrocytes are key players in the pathology of multiple sclerosis and can assume beneficial and detrimental roles during lesion development. The triggers and timing of the different astroglial responses in acute lesions remain unclear. Astrocytes in acute multiple sclerosis lesions have been shown previously to contain myelin debris, although its significance has not been examined. We hypothesized that myelin phagocytosis by astrocytes is an early event during lesion formation and leads to astroglial immune responses. We examined multiple sclerosis lesions and other central nervous system pathologies with prominent myelin injury, namely, progressive multifocal leukoencephalopathy, metachromatic leukodystrophy and subacute infarct. In all conditions, we found that myelin debris was present in most astrocytes at sites of acute myelin breakdown, indicating that astroglial myelin phagocytosis is an early and prominent feature. Functionally, myelin debris was taken up by astrocytes through receptor-mediated endocytosis and resulted in astroglial NF-kappaB activation and secretion of chemokines. These in vitro results in rats were validated in human disease where myelin-positive hypertrophic astrocytes showed increased nuclear localization of NF-kappaB and elevated chemokine expression compared to myelin-negative, reactive astrocytes. Thus, our data suggest that myelin uptake is an early response of astrocytes in diseases with prominent myelin injury that results in recruitment of immune cells. This first line response of astrocytes to myelin injury may exert beneficial or detrimental effects on the lesion pathology, depending on the inflammatory context. Modulating this response might be of therapeutic relevance in multiple sclerosis and other demyelinating conditions. PMID- 28007994 TI - Axonal neuropathy with neuromyotonia: there is a HINT. AB - Recessive mutations in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1) were recently shown to cause a motor-predominant Charcot-Marie Tooth neuropathy. About 80% of the patients exhibit neuromyotonia, a striking clinical and electrophysiological hallmark that can help to distinguish this disease and to guide diagnostic screening. HINT1 neuropathy has worldwide distribution and is particularly prevalent in populations inhabiting central and south-eastern Europe. With 12 different mutations identified in more than 60 families, it ranks among the most common subtypes of axonal Charcot-Marie-Tooth neuropathy. This article provides an overview of the present knowledge on HINT1 neuropathy with the aim to increase awareness and spur interest among clinicians and researchers in the field. We propose diagnostic guidelines to recognize and differentiate this entity and suggest treatment strategies to manage common symptoms. As a recent player in the field of hereditary neuropathies, the role of HINT1 in peripheral nerves is unknown and the underlying disease mechanisms are unexplored. We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies of this peculiar Charcot-Marie-Tooth subtype. PMID- 28007995 TI - Corticosteroids compromise survival in glioblastoma in part through their elevation of blood glucose levels. PMID- 28007996 TI - Reply: Corticosteroids compromise survival in glioblastoma in part through their elevation of blood glucose levels. PMID- 28007997 TI - Stimulating at the right time: phase-specific deep brain stimulation. AB - SEE MOLL AND ENGEL DOI101093/AWW308 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Brain regions dynamically engage and disengage with one another to execute everyday actions from movement to decision making. Pathologies such as Parkinson's disease and tremor emerge when brain regions controlling movement cannot readily decouple, compromising motor function. Here, we propose a novel stimulation strategy that selectively regulates neural synchrony through phase specific stimulation. We demonstrate for the first time the therapeutic potential of such a stimulation strategy for the treatment of patients with pathological tremor. Symptom suppression is achieved by delivering stimulation to the ventrolateral thalamus, timed according to the patient's tremor rhythm. Sustained locking of deep brain stimulation to a particular phase of tremor afforded clinically significant tremor relief (up to 87% tremor suppression) in selected patients with essential tremor despite delivering less than half the energy of conventional high frequency stimulation. Phase-specific stimulation efficacy depended on the resonant characteristics of the underlying tremor network. Selective regulation of neural synchrony through phase-locked stimulation has the potential to both increase the efficiency of therapy and to minimize stimulation induced side effects. PMID- 28007998 TI - Pathological glutamatergic neurotransmission in Gilles de la Tourette syndrome. AB - Gilles de la Tourette syndrome is a hereditary, neuropsychiatric movement disorder with reported abnormalities in the neurotransmission of dopamine and gamma-aminobutyric acid (GABA). Spatially focalized alterations in excitatory, inhibitory and modulatory neurochemical ratios within specific functional subdivisions of the basal ganglia, may lead to the expression of diverse motor and non-motor features as manifested in Gilles de la Tourette syndrome. Current treatment strategies are often unsatisfactory thus provoking the need for further elucidation of the underlying pathophysiology. In view of (i) the close spatio temporal synergy exhibited between excitatory, inhibitory and modulatory neurotransmitter systems; (ii) the crucial role played by glutamate (Glu) in tonic/phasic dopaminergic signalling; and (iii) the interdependent metabolic relationship exhibited between Glu and GABA via glutamine (Gln); we postulated that glutamatergic signalling is related to the pathophysiology of Gilles de la Tourette syndrome. As such, we examined the neurochemical profile of three cortico-striato-thalamo-cortical regions in 37 well-characterized, drug-free adult patients and 36 age/gender-matched healthy control subjects via magnetic resonance spectroscopy at 3 T. To interrogate the influence of treatment on metabolite concentrations, spectral data were acquired from 15 patients undergoing a 4-week treatment with aripiprazole. Test-retest reliability measurements in 23 controls indicated high repeatability of voxel localization and metabolite quantitation. We report significant reductions in striatal concentrations of Gln, Glu + Gln (Glx) and the Gln:Glu ratio, and thalamic concentrations of Glx in Gilles de la Tourette syndrome in comparison to controls. ON-treatment patients exhibited no significant metabolite differences when compared to controls but significant increases in striatal Glu and Glx, and trends for increases in striatal Gln and thalamic Glx compared to baseline measurements. Multiple regression analysis revealed a significant negative correlation between (i) striatal Gln and actual tic severity; and (ii) thalamic Glu and premonitory urges. Our results indicate that patients with Gilles de la Tourette syndrome exhibit an abnormality in the flux of metabolites in the GABA Glu-Gln cycle, thus implying perturbations in astrocytic-neuronal coupling systems that maintain the subtle balance between excitatory and inhibitory neurotransmission within subcortical nuclei. PMID- 28008000 TI - Stroke outcomes are worse with larger leukoaraiosis volumes. AB - Leukoaraiosis or white matter hyperintensities are frequently observed on magnetic resonance imaging of stroke patients. We investigated how white matter hyperintensity volumes affect stroke outcomes, generally and by subtype. In total, 5035 acute ischaemic stroke patients were enrolled. Strokes were classified as large artery atherosclerosis, small vessel occlusion, or cardioembolism. White matter hyperintensity volumes were stratified into quintiles. Mean age (+/- standard deviation) was 66.3 +/- 12.8, 59.6% male. Median (interquartile range) modified Rankin Scale score was 2 (1-3) at discharge and 1 (0-3) at 3 months; 16.5% experienced early neurological deterioration, and 3.3% recurrent stroke. The Cochran-Mantel-Haenszel test with adjustment for age, stroke severity, sex, and thrombolysis status showed that the distributions of 3 month modified Rankin Scale scores differed across white matter hyperintensity quintiles (P < 0.001). Multiple ordinal logistic regression analysis showed that higher white matter hyperintensity quintiles were independently associated with worse 3-month modified Rankin Scale scores; adjusted odds ratios (95% confidence interval) for the second to fifth quintiles versus the first quintile were 1.29 (1.10-1.52), 1.40 (1.18-1.66), 1.69 (1.42-2.02) and 2.03 (1.69-2.43), respectively. For large artery atherosclerosis (39.0%), outcomes varied by white matter hyperintensity volume (P = 0.01, Cochran-Mantel-Haenszel test), and the upper three white matter hyperintensity quintiles (versus the first quintile) had worse 3-month modified Rankin Scale scores; adjusted odds ratios were 1.45 (1.10 1.90), 1.86 (1.41-2.47), and 1.89 (1.41-2.54), respectively. Patients with large artery atherosclerosis were vulnerable to early neurological deterioration (19.4%), and the top two white matter hyperintensity quintiles were more vulnerable still: 23.5% and 22.3%. Moreover, higher white matter hyperintensities were associated with poor modified Rankin Scale improvement: adjusted odds ratios for the upper two quintiles versus the first quintile were 0.66 (0.47-0.94) and 0.62 (0.43-0.89), respectively. For small vessel occlusion (17.8%), outcomes tended to vary by white matter hyperintensitiy volume (P = 0.10, Cochran-Mantel Haenszel test), and the highest quintile was associated with worse 3-month modified Rankin Scale scores: adjusted odds ratio for the fifth quintile versus first quintile, 1.98 (1.23-3.18). In this subtype, worse white matter hyperintensities were associated with worse National Institute of Health Stroke Scale scores at presentation. For cardioembolism (20.6%), outcomes did not vary significantly by white matter hyperintensity volume (P = 0.19, Cochran-Mantel Haenszel test); however, the adjusted odds ratio for the highest versus lowest quintiles was 1.62 (1.09-2.40). Regardless of stroke subtype, white matter hyperintensities were not associated with stroke recurrence within 3 months of follow-up. In conclusion, white matter hyperintensity volume independently correlates with stroke outcomes in acute ischaemic stroke. There are some suggestions that stroke outcomes may be affected by leukoaraiosis differentially depending on stroke subtypes, to be confirmed in future investigations. PMID- 28008001 TI - Detainment of Tam3 Transposase at Plasma Membrane by Its BED-Zinc Finger Domain. AB - Transposable elements (TEs) are considered to be parasites of host genomes because they act as powerful mutagens. If not kept in check, they can cause gene disruption, genome rearrangement, and genomic takeover. Hence, activities of TEs are under the rigid control of hosts. To date, all identified TE regulations have been epigenetic dependent, with the exception of the DNA transposon Tam3. Blocking nuclear translocation of Tam3 transposase (TPase) is consistent with the suppression of Tam3 in Antirrhinum majus In this article, we discovered that epigenetic-independent regulation of Tam3 is mediated by the BED-zinc finger (Znf BED) domain of Tam3 TPase. The host targets the N terminus of the Znf-BED domain, which contains two highly conserved aromatic amino acids, to detain Tam3 TPase at the plasma membrane and to silence Tam3. Zinc finger proteins perform broader functions in transcriptional regulation through their DNA binding ability. Our data revealed that the posttranslational epigenetic-independent silencing against TEs was a result of the protein binding ability of the Znf-BED domain. PMID- 28008002 TI - Pregnancy Outcomes after Clinical Recovery from AKI. AB - The effect of clinically recovered AKI (r-AKI) on future pregnancy outcomes is unknown. We retrospectively studied all women who delivered infants between 1998 and 2007 at Massachusetts General Hospital to assess whether a previous episode of r-AKI associated with subsequent adverse maternal and fetal outcomes, including preeclampsia. AKI was defined as rise in serum creatinine concentration to 1.5-fold above baseline. We compared pregnancy outcomes in women with r-AKI without history of CKD (eGFR>90 ml/min per 1.73 m2 before conception; n=105) with outcomes in women without kidney disease (controls; n=24,640). The r-AKI and control groups had similar prepregnancy serum creatinine measurements (0.70+/ 0.20 versus 0.69+/-0.10 mg/dl; P=0.36). However, women with r-AKI had increased rates of preeclampsia compared with controls (23% versus 4%; P<0.001). Infants of women with r-AKI were born earlier than infants of controls (37.6+/-3.6 versus 39.2+/-2.2 weeks; P<0.001), with increased rates of small for gestational age births (15% versus 8%; P=0.03). After multivariate adjustment, r-AKI associated with increased risk for preeclampsia (adjusted odds ratio [aOR], 5.9; 95% confidence interval [95% CI], 3.6 to 9.7) and adverse fetal outcomes (aOR, 2.4; 95% CI, 1.6 to 3.7). When women with r-AKI and controls were matched 1:2 by age, race, body mass index, diastolic BP, parity, and diabetes status, r-AKI remained associated with preeclampsia (OR, 4.7; 95% CI, 2.1 to 10.1) and adverse fetal outcomes (OR, 2.1; 95% CI, 1.2 to 3.7). Thus, a past episode of AKI, despite return to normal renal function before pregnancy, associated with adverse outcomes in pregnancy. PMID- 28008003 TI - Executive Function in Adolescents With Type 1 Diabetes: Relationship to Adherence, Glycemic Control, and Psychosocial Outcomes. AB - Objective: Impairments in executive function (EF) skills have been observed in youth with type 1 diabetes (T1D), and these skills are critical for following the complex treatment regimen. This study examines parent reports of EF in relation to measures of adherence, glycemic control (A1c), and psychosocial outcomes (depression and quality of life) in adolescents with T1D. A total of 120 adolescents (aged 13-17 years, 52.5% female, 87.5% White) with T1D and their parents completed questionnaires. Glucometers were downloaded and A1c was obtained during clinical visits at the time of enrollment. The prevalence of clinically significant elevated scores on specific EF skills ranged from 11 to 18.6%. In multivariate analyses, parent-reported EF deficits were associated with poorer adherence and lower quality of life, explaining 13 and 12% of the variance, respectively. Adolescents with T1D exhibit specific EF deficits that may negatively impact their quality of life and their ability to engage in self management activities. PMID- 28008004 TI - Adolescent and Parent Treatment Goals in an Internet-Delivered Chronic Pain Self Management Program: Does Agreement of Treatment Goals Matter? AB - Objective: To assess whether adolescent-parent agreement on treatment goals as part of an Internet-delivered cognitive-behavioral pain intervention was associated with adolescent outcomes. 122 adolescent-parent dyads selected two treatment goals. Pain intensity and pain-related disability were assessed at pre treatment, post-treatment, and 6- and 12-month follow-ups. We compared dyads who had goal agreement versus no agreement. 74 dyads (61%) agreed on one or more treatment goals, most commonly going to school, sports, and sleep. In dyads who chose the same goal, regardless of the content, adolescents had lower pain intensity post-treatment and at follow-up. When goals were categorized by domain, in dyads who agreed on physically active goals, adolescents were more likely to report lower pain intensity compared with other groups. Agreement of goals was not associated with changes in pain-related disability. Agreement on treatment goals may be an important treatment process to maximize outcomes in self management therapies. PMID- 28008005 TI - Confirmatory Factor Analysis of Sizing Me Up: Validation of an Obesity-Specific Health-Related Quality of Life Measure in Latino Youth. AB - Objectives: This study aims to validate an obesity-specific health-related quality of life (HRQOL) measure, Sizing Me Up (SMU), in treatment-seeking Latino youth. Pediatric obesity has been associated with reduced HRQOL; therefore, valid measures are important for use in diverse populations that may be at increased risk for obesity and related comorbidities. Methods: Structural equation modeling tested the fit of the 5-subscale, 22-item SMU measure in Latino youth, 5-13 years of age, with obesity ( N = 204). Invariance testing was conducted to examine equivalence between Latino and non-Latino groups ( N = 250). Results: SMU achieved acceptable fit in a Latino population [chi 2 = 428.33, df = 199, p < .001, Root Mean Squared Error of Approximation = 0.072 (0.062-0.082), Comparative Fit Index = 0.915, Tucker-Lewis Index = 0.901, Weighted Root Mean Square Residual = 1.2230]. Additionally, factor structure and factor loadings were invariant across Latino and non-Latino groups, but thresholds were not invariant. Conclusions: SMU is a valid measure of obesity-specific HRQOL in treatment seeking Latino youth with obesity. PMID- 28008007 TI - Erratum for the Report "Local modulation of human brain responses by circadian rhythmicity and sleep debt" by V. Muto, M. Jaspar, C. Meyer, C. Kusse, S. L. Chellappa, C. Degueldre, E. Balteau, A. Shaffii-Le Bourdiec, A. Luxen, B. Middleton, S. N. Archer, C. Phillips, F. Collette, G. Vandewalle, D.-J. Dijk, P. Maquet. PMID- 28008006 TI - The associations between work-life balance behaviours, teamwork climate and safety climate: cross-sectional survey introducing the work-life climate scale, psychometric properties, benchmarking data and future directions. AB - BACKGROUND: Improving the resiliency of healthcare workers is a national imperative, driven in part by healthcare workers having minimal exposure to the skills and culture to achieve work-life balance (WLB). Regardless of current policies, healthcare workers feel compelled to work more and take less time to recover from work. Satisfaction with WLB has been measured, as has work-life conflict, but how frequently healthcare workers engage in specific WLB behaviours is rarely assessed. Measurement of behaviours may have advantages over measurement of perceptions; behaviours more accurately reflect WLB and can be targeted by leaders for improvement. OBJECTIVES: 1. To describe a novel survey scale for evaluating work-life climate based on specific behavioural frequencies in healthcare workers.2. To evaluate the scale's psychometric properties and provide benchmarking data from a large healthcare system.3. To investigate associations between work-life climate, teamwork climate and safety climate. METHODS: Cross-sectional survey study of US healthcare workers within a large healthcare system. RESULTS: 7923 of 9199 eligible healthcare workers across 325 work settings within 16 hospitals completed the survey in 2009 (86% response rate). The overall work-life climate scale internal consistency was Cronbach alpha=0.790. t-Tests of top versus bottom quartile work settings revealed that positive work-life climate was associated with better teamwork climate, safety climate and increased participation in safety leadership WalkRounds with feedback (p<0.001). Univariate analysis of variance demonstrated differences that varied significantly in WLB between healthcare worker role, hospitals and work setting. CONCLUSIONS: The work-life climate scale exhibits strong psychometric properties, elicits results that vary widely by work setting, discriminates between positive and negative workplace norms, and aligns well with other culture constructs that have been found to correlate with clinical outcomes. PMID- 28008008 TI - Spatiotemporal antagonism in mesenchymal-epithelial signaling in sweat versus hair fate decision. AB - The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis. PMID- 28008011 TI - Cover stories: Making the Breakthrough of the Year cover. PMID- 28008010 TI - Genetic identification of familial hypercholesterolemia within a single U.S. health care system. AB - Familial hypercholesterolemia (FH) remains underdiagnosed despite widespread cholesterol screening. Exome sequencing and electronic health record (EHR) data of 50,726 individuals were used to assess the prevalence and clinical impact of FH-associated genomic variants in the Geisinger Health System. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variant carriers had significantly increased risk of coronary artery disease. Only 24% of carriers met EHR-based presequencing criteria for probable or definite FH diagnosis. Active statin use was identified in 58% of carriers; 46% of statin-treated carriers had a low-density lipoprotein cholesterol level below 100 mg/dl. Thus, we find that genomic screening can prompt the diagnosis of FH patients, most of whom are receiving inadequate lipid-lowering therapy. PMID- 28008009 TI - Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. AB - The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery. PMID- 28008013 TI - News at a glance. PMID- 28008012 TI - Awesome universal chirp. PMID- 28008014 TI - XPrize finalists mull payloads to the moon. PMID- 28008015 TI - In India, elite institutes in shady journals. PMID- 28008016 TI - New blood tests make strides in detecting prion disease. PMID- 28008017 TI - Scientists flag new causes for surge in methane levels. PMID- 28008018 TI - Critics assail paper claiming harm from cancer vaccine. PMID- 28008019 TI - Like birds, insects may travel in sync with the seasons. PMID- 28008021 TI - The runners-up. PMID- 28008020 TI - The cosmos aquiver. PMID- 28008022 TI - Scorecard for 2016. PMID- 28008023 TI - Areas to watch in 2017. PMID- 28008024 TI - Breakdowns of the year. PMID- 28008025 TI - Expand innovation finance via crowdfunding. PMID- 28008026 TI - Oceans on the edge of anoxia. PMID- 28008027 TI - A stitch in time saves nine...billion. PMID- 28008028 TI - Optical circulators reach the quantum level. PMID- 28008029 TI - The "tao" of integuments. PMID- 28008030 TI - "Pheno"menal value for human health. PMID- 28008031 TI - More than a day in the life of a comet. PMID- 28008032 TI - Tomorrow's arsenal. PMID- 28008033 TI - Divining science. PMID- 28008034 TI - Forest value: More than commercial. PMID- 28008035 TI - Forest value: More than commercial-Response. PMID- 28008036 TI - Iran's science landscape in context. PMID- 28008037 TI - Comment on "Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2". AB - Jiao and Liu (Research Articles, 16 October 2015, aac4383) reported the crystal structure of the protein complex polycomb repressive complex 2 from Chaetomium thermophilum This landmark structure has brought invaluable insights into the activation mechanism of this essential methyltransferase. However, the analysis of the x-ray data discussed below suggests that the description of oncogenic H3K27M peptide binding to the active site is incorrect. PMID- 28008038 TI - Response to Comment on "Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2". AB - Zhang et al suggested that in the crystal structure of a polycomb repressive complex 2 from Chaetomium thermophilum (ctPRC2), a flexible linker region, but not the H3K27M cancer mutant peptide, better fits the electron density. Based on our new data, we agree with this alternative interpretation and provide the crystal structure of ctPRC2 bound to a bona fide H3K27M sequence. PMID- 28008040 TI - Now you feel it, now you don't. PMID- 28008039 TI - AAAS reaches out to theology students. PMID- 28008041 TI - Rosetta observes sublimating surface ices. PMID- 28008042 TI - Watching Majorana bound states form. PMID- 28008043 TI - Snapshots of bacteriorhodopsin. PMID- 28008044 TI - Boron nitride catalysis. PMID- 28008045 TI - Mass movement of "invisibles". PMID- 28008046 TI - Prohormone processing by subtilases. PMID- 28008047 TI - A balance between staying and leaving. PMID- 28008048 TI - Combining drugs as the doctor ordered. PMID- 28008049 TI - Unleashing the power of precision medicine. PMID- 28008050 TI - How to grow hair or sweat glands. PMID- 28008051 TI - Extending qubit lifetime through a shaped environment. PMID- 28008052 TI - Marine benefits of the Paris Agreement. PMID- 28008054 TI - Probing packing rules. PMID- 28008053 TI - A quantum optical circulator. PMID- 28008055 TI - A closed conformation for Zika virus enzyme. PMID- 28008056 TI - A precarious balance. PMID- 28008057 TI - Unwelcome rifts. PMID- 28008058 TI - Tracking extracellular space in the brain. PMID- 28008059 TI - Blood and brain intertwined during development. PMID- 28008060 TI - Reacting into new frameworks. PMID- 28008061 TI - Tracing the trends in oxygen reduction. PMID- 28008062 TI - Love the one you're with. PMID- 28008063 TI - A view to a kill, preventing collateral damage. PMID- 28008065 TI - Majorana bound state in a coupled quantum-dot hybrid-nanowire system. AB - Hybrid nanowires combining semiconductor and superconductor materials appear well suited for the creation, detection, and control of Majorana bound states (MBSs). We demonstrate the emergence of MBSs from coalescing Andreev bound states (ABSs) in a hybrid InAs nanowire with epitaxial Al, using a quantum dot at the end of the nanowire as a spectrometer. Electrostatic gating tuned the nanowire density to a regime of one or a few ABSs. In an applied axial magnetic field, a topological phase emerges in which ABSs move to zero energy and remain there, forming MBSs. We observed hybridization of the MBS with the end-dot bound state, which is in agreement with a numerical model. The ABS/MBS spectra provide parameters that are useful for understanding topological superconductivity in this system. PMID- 28008064 TI - A three-dimensional movie of structural changes in bacteriorhodopsin. AB - Bacteriorhodopsin (bR) is a light-driven proton pump and a model membrane transport protein. We used time-resolved serial femtosecond crystallography at an x-ray free electron laser to visualize conformational changes in bR from nanoseconds to milliseconds following photoactivation. An initially twisted retinal chromophore displaces a conserved tryptophan residue of transmembrane helix F on the cytoplasmic side of the protein while dislodging a key water molecule on the extracellular side. The resulting cascade of structural changes throughout the protein shows how motions are choreographed as bR transports protons uphill against a transmembrane concentration gradient. PMID- 28008066 TI - Emergence of hierarchical structural complexities in nanoparticles and their assembly. AB - We demonstrate that nanoparticle self-assembly can reach the same level of hierarchy, complexity, and accuracy as biomolecules. The precise assembly structures of gold nanoparticles (246 gold core atoms with 80 p methylbenzenethiolate surface ligands) at the atomic, molecular, and nanoscale levels were determined from x-ray diffraction studies. We identified the driving forces and rules that guide the multiscale assembly behavior. The protecting ligands self-organize into rotational and parallel patterns on the nanoparticle surface via C-H???pi interaction, and the symmetry and density of surface patterns dictate directional packing of nanoparticles into crystals with orientational, rotational, and translational orders. Through hierarchical interactions and symmetry matching, the simple building blocks evolve into complex structures, representing an emergent phenomenon in the nanoparticle system. PMID- 28008067 TI - Mass seasonal bioflows of high-flying insect migrants. AB - Migrating animals have an impact on ecosystems directly via influxes of predators, prey, and competitors and indirectly by vectoring nutrients, energy, and pathogens. Although linkages between vertebrate movements and ecosystem processes have been established, the effects of mass insect "bioflows" have not been described. We quantified biomass flux over the southern United Kingdom for high-flying (>150 meters) insects and show that ~3.5 trillion insects (3200 tons of biomass) migrate above the region annually. These flows are not randomly directed in insects larger than 10 milligrams, which exploit seasonally beneficial tailwinds. Large seasonal differences in the southward versus northward transfer of biomass occur in some years, although flows were balanced over the 10-year period. Our long-term study reveals a major transport process with implications for ecosystem services, processes, and biogeochemistry. PMID- 28008068 TI - Active cortical dendrites modulate perception. AB - There is as yet no consensus concerning the neural basis of perception and how it operates at a mechanistic level. We found that Ca2+ activity in the apical dendrites of a subset of layer 5 (L5) pyramidal neurons in primary somatosensory cortex (S1) in mice is correlated with the threshold for perceptual detection of whisker deflections. Manipulating the activity of apical dendrites shifted the perceptual threshold, demonstrating that an active dendritic mechanism is causally linked to perceptual detection. PMID- 28008069 TI - Large benefits to marine fisheries of meeting the 1.5 degrees C global warming target. AB - Translating the Paris Agreement to limit global warming to 1.5 degrees C above preindustrial level into impact-related targets facilitates communication of the benefits of mitigating climate change to policy-makers and stakeholders. Developing ecologically relevant impact-related targets for marine ecosystem services, such as fisheries, is an important step. Here, we use maximum catch potential and species turnover as climate-risk indicators for fisheries. We project that potential catches will decrease by more than 3 million metric tons per degree Celsius of warming. Species turnover is more than halved when warming is lowered from 3.5 degrees to 1.5 degrees C above the preindustrial level. Regionally, changes in maximum catch potential and species turnover vary across ecosystems, with the biggest risk reduction in the Indo-Pacific and Arctic regions when the Paris Agreement target is achieved. PMID- 28008070 TI - Rescuing my time from science. PMID- 28008071 TI - Distinct Patterns of Cerebral Cortical Thinning in Schizophrenia: A Neuroimaging Data-Driven Approach. AB - Schizophrenia is an etiologically and clinically heterogeneous disorder. Although neuroimaging studies have revealed brain alterations in schizophrenia, most studies have assumed that the disorder is a single entity, neglecting the diversity of alterations observed in the disorder. The current study sought to explore the distinct patterns of altered cortical thickness in patients with schizophrenia and healthy individuals using a data-driven approach. Unsupervised clustering using self-organizing maps followed by a K-means algorithm was applied to regional cortical thickness data in 108 schizophrenia patients and 121 healthy controls. After clustering, the clinical characteristics and cortical thickness patterns of each cluster were assessed. Unsupervised clustering revealed that a 6 cluster solution was the most appropriate in this sample. There was substantial overlap between the patterns of cortical thickness in schizophrenia patients and healthy controls, although the distributions of the patients and controls differed across the clusters. The patterns of altered cortical thickness in schizophrenia exhibited cluster-specific features; patients within a cluster exhibited the most extensive cortical thinning, particularly in the medial prefrontal and temporal regions, while those in other clusters exhibited reduced cortical thickness in the medial frontal region or temporal lobe. Furthermore, in the schizophrenia group, extensive cortical thinning was correlated with a higher dosage of antipsychotic medication, while preserved cortical thickness appeared to be linked to less negative symptoms. This data-driven neuroimaging approach revealed distinct patterns of cortical thinning in schizophrenia, possibly reflecting the etiological heterogeneity of the disorder. PMID- 28008072 TI - My Relationship With My Caregivers. PMID- 28008073 TI - Surviving the Voices. PMID- 28008074 TI - Increased neural and pupillary reactivity to emotional faces in adolescents with current and remitted major depressive disorder. AB - This study combined multiple levels of analysis to examine whether disrupted neural and pupillary reactivity to emotional faces serves as a state- or trait like marker of adolescent major depressive disorder (MDD). The study examined differences in pupil dilation and the event-related potential (ERP) late positive potential (LPP) component to emotional faces before and after a negative mood induction between 71 adolescents (age 11-18 years) with (i) a current diagnosis of MDD, (ii) a past episode of MDD currently in full remission and (iii) no lifetime history of any Axis I disorder. Relative to healthy control (HC) youth, adolescents with current or remitted MDD exhibited an enhanced LPP and pupillary response to all emotional facial expressions (fearful, happy and sad). This difference in reactivity between remitted depressed and HC adolescents persisted following the negative mood induction. Results also revealed that LPP and pupillary responses to emotional faces were significantly related, but only among the currently depressed adolescents. This study suggests that increased physiological and neural activation in response to social-emotional stimuli may not only characterize currently depressed adolescents, but also remains following MDD remission, potentially serving as a mechanism of risk for future depression relapse. PMID- 28008076 TI - Is neutral really neutral? Converging evidence from behavior and corticolimbic connectivity in children and adolescents. AB - Individuals differ in their tendency to perceive negativity in ambiguous situations or facial expressions. Prior research demonstrates that this so-called "negativity bias" is exaggerated in children; for instance, when they rate the emotional content of neutral facial expressions. However, neutral faces are frequently used as a baseline condition in pediatric emotion processing studies, as they are thought to be emotionally neutral. Here, we present data that challenge that notion. We demonstrate that children and adolescents rate neutral faces, particularly of adults, as negative, similar to ratings elicited by angry faces. In addition, we found a lack of age-related decrease in reaction time for neutral adult faces, suggesting that these stimuli remain salient across development. Demonstrating the relevance of individual differences, higher negativity bias was associated with lower self-reported reward sensitivity and increased functional connectivity of the amygdala. Together, these findings indicate that neutral faces are not perceived as emotionally neutral in children, thus discouraging their use as baseline condition in pediatric research. These data also offer a potential neurobiological substrate of the negativity bias in children. The link to corticolimbic emotion-processing circuitry and affective experience implies that exaggerations in these biases may be relevant for the development of emotional psychopathology. PMID- 28008075 TI - Deciphering human motion to discriminate social interactions: a developmental neuroimaging study. AB - Non-verbal communication plays a major role in social interaction understanding. Using functional magnetic resonance imaging, we explored the development of the neural networks involved in social interaction recognition based on human motion in children (8-11), adolescents (13-17), and adults (20-41). Participants watched point-light videos depicting two actors interacting or moving independently and were asked whether these agents were interacting or not. All groups successfully performed the discrimination task, but children had a lower performance and longer response times than the older groups. In all three groups, the posterior parts of the superior temporal sulci and middle temporal gyri, the inferior frontal gyri and the anterior temporal lobes showed greater activation when observing social interactions. In addition, adolescents and adults recruited the caudate nucleus and some frontal regions that are part of the mirror system. Adults showed greater activations in parietal and frontal regions (part of them belonging to the social brain) than adolescents.An increased number of regions that are part of the mirror system network or the social brain, as well as the caudate nucleus, were recruited with age. In conclusion, a shared set of brain regions enabling the discrimination of social interactions from neutral movements through human motion is already present in 8-year-old children. Developmental processes such as refinements in the social brain and mirror system would help grasping subtle cues in non-verbal aspects of social interactions. PMID- 28008077 TI - Anxious anticipation and pain: the influence of instructed vs conditioned threat on pain. AB - Negative emotions such as anxiety enhance pain perception. However, certain threat characteristics are discussed to have different or even divergent effects on pain (hypoalgesia vs hyperalgesia). In order to investigate the neurobiological basis of different threats, we compared the impact of conditioned threat (CT) vs instructed threat (IT) on pain using fMRI. In two groups, participants underwent either Pavlovian threat conditioning or an instructed threat procedure. Afterwards, in an identical test phase participants watched the same visual cues from the previous phase indicating potential threat or safety, and received painful thermal stimulation. In the test phase, pain ratings were increased in both groups under threat. Group comparisons show elevated responses in amygdala and hippocampus for pain under threat in the CT group, and higher activation of the mid-cingulate gyrus (MCC) in the IT group. Psychophysiological interaction analyses in CT demonstrated elevated connectivity of the amygdala and the insula for the comparison of pain under threat vs safety. In IT, the same comparison revealed elevated functional connectivity of the MCC and the insula. The results suggest a similar pain augmenting effect of CT and IT, which, however, seems to rely on different networks mediating the impact of threat on pain. PMID- 28008078 TI - An evil face? Verbal evaluative multi-CS conditioning enhances face-evoked mid latency magnetoencephalographic responses. AB - Humans have a remarkable capacity for rapid affective learning. For instance, using first-order US such as odors or electric shocks, magnetoencephalography (MEG) studies of multi-CS conditioning demonstrate enhanced early (<150 ms) and mid-latency (150-300 ms) visual evoked responses to affectively conditioned faces, together with changes in stimulus evaluation. However, particularly in social contexts, human affective learning is often mediated by language, a class of complex higher-order US. To elucidate mechanisms of this type of learning, we investigate how face processing changes following verbal evaluative multi-CS conditioning. Sixty neutral expression male faces were paired with phrases about aversive crimes (30) or neutral occupations (30). Post conditioning, aversively associated faces evoked stronger magnetic fields in a mid-latency interval between 220 and 320 ms, localized primarily in left visual cortex. Aversively paired faces were also rated as more arousing and more unpleasant, evaluative changes occurring both with and without contingency awareness. However, no early MEG effects were found, implying that verbal evaluative conditioning may require conceptual processing and does not engage rapid, possibly sub-cortical, pathways. Results demonstrate the efficacy of verbal evaluative multi-CS conditioning and indicate both common and distinct neural mechanisms of first- and higher-order multi-CS conditioning, thereby informing theories of associative learning. PMID- 28008079 TI - The effects of stimulus novelty and negativity on BOLD activity in the amygdala, hippocampus, and bed nucleus of the stria terminalis. AB - Key words: novelty; bed nucleus of the stria terminalis; BNST; amygdale; fMRI; BST. PMID- 28008081 TI - Thermotolerance and heat stress responses of Douglas-fir and ponderosa pine seedling populations from contrasting climates. AB - Temperature and the frequency and intensity of heat waves are predicted to increase throughout the 21st century. Germinant seedlings are expected to be particularly vulnerable to heat stress because they are in the boundary layer close to the soil surface where intense heating occurs in open habitats. We quantified leaf thermotolerance and whole-plant physiological responses to heat stress in first-year germinant seedlings in two populations each of Pinus ponderosa P. and C. Lawson (PIPO) and Pseudotsuga menziesii (Mirb.) Franco (PSME) from climates with contrasting precipitation and temperature regimes. Thermotolerance of detached needles was evaluated using chlorophyll fluorescence (FV/FM, FO) and electrolyte leakage. PSME was more heat tolerant than PIPO according to both independent assessments of thermotolerance. Following exposure of whole seedlings to a simulated heat wave at 45 degrees C for 1 h in a growth chamber, we monitored FV/FM, photosynthesis, stomatal conductance, non-structural carbohydrates (NSCs) and carbon isotope ratios (delta13C) for 14 days. Heat treatment induced significant reductions in FV/FM in both species and a transient reduction in photosynthetic gas exchange only in PIPO 1 day after treatment. Heat treatment induced an increase in glucose + fructose concurrent with a decrease in starch in both species, whereas total NSC and sucrose were not affected by heat treatment. The negative relationship between glucose + fructose and starch observed in treated plants may be due to the conversion of starch to glucose + fructose to aid recovery from heat-induced damage. Populations from drier sites displayed greater delta13C values than those from wetter sites, consistent with higher intrinsic water-use efficiency and drought resistance of populations from drier climates. Thermotolerance and heat stress responses appeared to be phenotypically plastic and representative of the environment in which plants were grown, whereas intrinsic water-use efficiency appeared to reflect ecotypic differentiation and the climate of origin. PMID- 28008080 TI - Repetitive transcranial magnetic stimulation modulates the impact of a negative mood induction. AB - High frequency repetitive Transcranial Magnetic Stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) has been found to alleviate depressive symptoms. However, the mechanisms driving these effects are still poorly understood. In the current study, we tested the idea that this intervention protects against negative mood shifts following emotional provocation. We furthermore explored changes in EEG activity (frontal alpha asymmetry) and effects on attentional processing (emotional Stroop). To this end, 23 healthy individuals participated in two sessions separated by one week, whereby they once received 15 min of 10Hz rTMS stimulation (1500 pulses) at 110% of the individual motor threshold, and once sham stimulation. Then, negative mood was induced using sad movie clips. The results revealed a significantly stronger mood decline following rTMS compared to sham stimulation. No changes were observed in frontal alpha asymmetry and attentional processing. Our findings are at odds with the view that high frequency rTMS over the left DLPFC directly protects against the induction of negative mood, but rather suggest that it enhances the effects of emotional provocation. Possibly, in healthy young individuals, this stimulation protocol heightens susceptibility to mood induction procedures in general. PMID- 28008082 TI - Whole-transcriptome response to water stress in a California endemic oak, Quercus lobata. AB - Reduced water availability during drought can create major stress for many plant species. Within a species, populations with a history of seasonal drought may have evolved the ability to tolerate drought more than those in areas of high precipitation and low seasonality. In this study, we assessed response to water stress in a California oak species, Quercus lobata Nee, by measuring changes in gene expression profiles before and after a simulated drought stress treatment through water deprivation of seedlings in a greenhouse setting. Using whole transcriptome sequencing from nine samples from three collection localities, we identified which genes are involved in response to drought stress and tested the hypothesis that seedlings sampled from climatically different regions of the species range respond to water stress differently. We observed a surprisingly massive transcriptional response to drought: 35,347 of 68,434 contigs (52%) were differentially expressed before versus after drought treatment, of which 18,111 were down-regulated and 17,236 were up-regulated. Genes functionally associated with abiotic stresses and death were enriched among the up-regulated genes, whereas metabolic and cell part-related genes were enriched among the down regulated. We found 56 contigs that exhibited significantly different expression responses to the drought treatment among the three populations (treatment * population interaction), suggesting that those genes may be involved in local adaptation to drought stress. These genes have stress response (e.g., WRKY DNA binding protein 51 and HSP20-like chaperones superfamily protein), metabolic (e.g., phosphoglycerate kinase and protein kinase superfamily protein), transport/transfer (e.g., cationic amino acid transporter 7 and K+ transporter) and regulatory functions (e.g., WRKY51 and Homeodomain-like transcriptional regulator). Baseline expression levels of 1310 unique contigs also differed among pairs of populations, and they were enriched for metabolic and cell part-related genes. Out of the large fraction of the transcriptome that was differentially expressed in response to our drought treatment, we identified several novel genes that are candidates for involvement in local adaptation to drought. PMID- 28008083 TI - Infidelity in the outback: climate signal recorded in Delta18O of leaf but not branch cellulose of eucalypts across an Australian aridity gradient. AB - The isotopic composition of leaf water in terrestrial plants is highly dependent upon a plant's environment. This isotopic signature can become integrated into organic molecules, allowing the isotopic composition of biomarkers such as cellulose to be used as sensitive paleo and climatic proxies. However, the mechanisms by which cellulose isotopic composition reflect environmental conditions are complex, and may vary between leaf and woody tissues. To date few empirical tests have been made on the relative roles of leaf-water enrichment and source water on the isotopic composition of leaf and wood cellulose within the same plant. Here, we study both leaf and branch wood cellulose, as well as xylem/source water of eucalypts across a 900 km aridity gradient in NE Australia. Across 11 sites, spanning average annual precipitation of 235-1400 mm and average relative humidity of 33-70%, we found a strong and consistent trend in leaf cellulose. However, once the effect of altered source water was considered we found wood cellulose to show no trend across this environmental gradient. We consider potential mechanisms that could explain the 'damping' of a climatic signal within wood cellulose and consider the implication and limitations on the use of tree-ring cellulose as a climate proxy. PMID- 28008084 TI - Temperature dependence of needle and shoot elongation before bud break in Scots pine. AB - Knowledge about the early part of needle growth is deficient compared with what is known about shoot growth. It is however important to understand growth of different organs to be able to estimate the changes in whole tree growth in a changing environment. The onset of growth in spring has been observed to occur over some certain threshold value of momentary temperature or temperature accumulation. We measured the length growth of Scots pine (Pinus sylvestris L.) needles and shoots from March until bud break over 3 years. We first compared needle growth with concurrent shoot growth. Then, we quantified threshold temperature of growth (i) with a logistic regression based on momentary temperatures and (ii) with the temperature sum accumulation method. Temperature sum was calculated with combinations of various time steps, starting dates and threshold temperature values. Needle elongation began almost concurrently with shoot elongation and proceeded linearly in relation to shoot growth until bud break. When studying the threshold temperature for growth, the method with momentary temperature effect on growth onset yielded ambiguous results in our conditions. The best fit of an exponential regression between needle growth or length and temperature sum was obtained with threshold temperatures -1 to +2 degrees C, with several combinations of starting date and time step. We conclude that although growth onset is a momentary event the process leading to it is a long-term continuum where past time temperatures have to be accounted for, rather than a sudden switch from quiescence to active growth. Further, our results indicate that lower temperatures than the commonly used +5 degrees C are sufficient for actuating the growth process. PMID- 28008085 TI - Strong coupling of a single electron in silicon to a microwave photon. AB - Silicon is vital to the computing industry because of the high quality of its native oxide and well-established doping technologies. Isotopic purification has enabled quantum coherence times on the order of seconds, thereby placing silicon at the forefront of efforts to create a solid-state quantum processor. We demonstrate strong coupling of a single electron in a silicon double quantum dot to the photonic field of a microwave cavity, as shown by the observation of vacuum Rabi splitting. Strong coupling of a quantum dot electron to a cavity photon would allow for long-range qubit coupling and the long-range entanglement of electrons in semiconductor quantum dots. PMID- 28008086 TI - Nanometer resolution imaging and tracking of fluorescent molecules with minimal photon fluxes. AB - We introduce MINFLUX, a concept for localizing photon emitters in space. By probing the emitter with a local intensity minimum of excitation light, MINFLUX minimizes the fluorescence photons needed for high localization precision. In our experiments, 22 times fewer fluorescence photons are required as compared to popular centroid localization. In superresolution microscopy, MINFLUX attained ~1 nm precision, resolving molecules only 6 nanometers apart. MINFLUX tracking of single fluorescent proteins increased the temporal resolution and the number of localizations per trace by a factor of 100, as demonstrated with diffusing 30S ribosomal subunits in living Escherichia coli As conceptual limits have not been reached, we expect this localization modality to break new ground for observing the dynamics, distribution, and structure of macromolecules in living cells and beyond. PMID- 28008087 TI - Evolutionary drivers of thermoadaptation in enzyme catalysis. AB - With early life likely to have existed in a hot environment, enzymes had to cope with an inherent drop in catalytic speed caused by lowered temperature. Here we characterize the molecular mechanisms underlying thermoadaptation of enzyme catalysis in adenylate kinase using ancestral sequence reconstruction spanning 3 billion years of evolution. We show that evolution solved the enzyme's key kinetic obstacle-how to maintain catalytic speed on a cooler Earth-by exploiting transition-state heat capacity. Tracing the evolution of enzyme activity and stability from the hot-start toward modern hyperthermophilic, mesophilic, and psychrophilic organisms illustrates active pressure versus passive drift in evolution on a molecular level, refutes the debated activity/stability trade-off, and suggests that the catalytic speed of adenylate kinase is an evolutionary driver for organismal fitness. PMID- 28008088 TI - Exploring the past and the future of protein evolution with ancestral sequence reconstruction: the 'retro' approach to protein engineering. AB - A central goal in molecular evolution is to understand the ways in which genes and proteins evolve in response to changing environments. In the absence of intact DNA from fossils, ancestral sequence reconstruction (ASR) can be used to infer the evolutionary precursors of extant proteins. To date, ancestral proteins belonging to eubacteria, archaea, yeast and vertebrates have been inferred that have been hypothesized to date from between several million to over 3 billion years ago. ASR has yielded insights into the early history of life on Earth and the evolution of proteins and macromolecular complexes. Recently, however, ASR has developed from a tool for testing hypotheses about protein evolution to a useful means for designing novel proteins. The strength of this approach lies in the ability to infer ancestral sequences encoding proteins that have desirable properties compared with contemporary forms, particularly thermostability and broad substrate range, making them good starting points for laboratory evolution. Developments in technologies for DNA sequencing and synthesis and computational phylogenetic analysis have led to an escalation in the number of ancient proteins resurrected in the last decade and greatly facilitated the use of ASR in the burgeoning field of synthetic biology. However, the primary challenge of ASR remains in accurately inferring ancestral states, despite the uncertainty arising from evolutionary models, incomplete sequences and limited phylogenetic trees. This review will focus, firstly, on the use of ASR to uncover links between sequence and phenotype and, secondly, on the practical application of ASR in protein engineering. PMID- 28008089 TI - Extracellular vesicles: their role in cancer biology and epithelial-mesenchymal transition. AB - Cell-cell communication is critical across an assortment of physiological and pathological processes. Extracellular vesicles (EVs) represent an integral facet of intercellular communication largely through the transfer of functional cargo such as proteins, messenger RNAs (mRNAs), microRNA (miRNAs), DNAs and lipids. EVs, especially exosomes and shed microvesicles, represent an important delivery medium in the tumour micro-environment through the reciprocal dissemination of signals between cancer and resident stromal cells to facilitate tumorigenesis and metastasis. An important step of the metastatic cascade is the reprogramming of cancer cells from an epithelial to mesenchymal phenotype (epithelial-mesenchymal transition, EMT), which is associated with increased aggressiveness, invasiveness and metastatic potential. There is now increasing evidence demonstrating that EVs released by cells undergoing EMT are reprogrammed (protein and RNA content) during this process. This review summarises current knowledge of EV-mediated functional transfer of proteins and RNA species (mRNA, miRNA, long non-coding RNA) between cells in cancer biology and the EMT process. An in-depth understanding of EVs associated with EMT, with emphasis on molecular composition (proteins and RNA species), will provide fundamental insights into cancer biology. PMID- 28008090 TI - Scaling it down: new in vitro tools to get the balance right. AB - Treatments for diabetes and obesity based on enteroendocrine hormones are a focus of research interest, partly due to the successes of glucagon-like peptide-1 (GLP 1) mimetic peptides in the treatment of diabetes and the correlation of altered enteroendocrine profiles with the positive metabolic outcomes of gastric bypass surgery. It is thought that simultaneous stimulation of more than one receptor might mimic the superior efficacy of the latter and dual or triple-agonist peptides are under investigation. An important step in developing multiple agonists is to establish the relative pharmacological potency and efficacy of new molecules at its different target receptors, and to optimise the balance of activities to achieve the desired treatment outcome. In a recent issue of the Biochemical Journal, Naylor et al. described how they used CRISPR technology to modulate endogenous receptor density in insulinoma cells to get the balance right for a dual incretin peptide engaging both GLP-1- and glucose-dependent insulinotropic polypeptide-receptors. PMID- 28008091 TI - Lacunar Infarcts and Intracerebral Hemorrhage Differences: A Nested Case-Control Analysis in the FHS (Framingham Heart Study). AB - BACKGROUND AND PURPOSE: Lacunar stroke (LS) and intracerebral hemorrhage (ICH) are 2 diverse manifestations of small vessel disease. What predisposes some patients to ischemic stroke and others to hemorrhage is not well understood. METHODS: We performed a nested case-control study within the FHS (Framingham Heart Study) comparing people with incident ICH and lacunar ischemic stroke, to age- and sex-matched controls for baseline prevalence and levels of cardiovascular risk factors. RESULTS: We identified 118 LS (mean age 74 years, 51% male) and 108 ICH (75 years, 46% male) events. Hypertension, diabetes mellitus, smoking, and obesity were strongly associated with LS. Hypertension, but not diabetes mellitus, smoking, or cholesterol levels increased the odds of ICH. Contrary to LS, ICH cases had lower body mass index (BMI) than their controls (26 versus 27); BMI <20 was associated with 4-fold higher odds for ICH. In direct comparison, LS cases had higher BMI (28 versus 26) and obesity prevalence (odds ratio, 3.1); BMI <20 was associated with significantly lower odds of LS (odds ratio, 0.1). CONCLUSIONS: LS and ICH share hypertension, but not diabetes mellitus, as a common risk factor. ICH cases had lower BMI compared with not only LS but their controls as well; this finding is unexplained and merits further exploration. PMID- 28008092 TI - AMOBES (Active Mobility Very Early After Stroke): A Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Intensive physical therapy (PT) facilitates motor recovery when provided during a subacute stage after stroke. The efficiency of very early intensive PT has been less investigated. We aimed to investigate whether intensive PT conducted within the first 2 weeks could aid recovery of motor control. METHODS: This multicentre randomized controlled trial compared soft PT (20-min/d apart from respiratory needs) and intensive PT (idem+45 minutes of intensive exercises/day) initiated within the first 72 hours after a first hemispheric stroke. The primary outcome was change in motor control between day (D) 90 and D0 assessed by the Fugl-Meyer score. Main secondary outcomes were number of days to walking 10 m unassisted, balance, autonomy, quality of life, and unexpected medical events. All analyses were by intent to treat. RESULTS: We could analyze data for 103 of the 104 included patients (51 control and 52 experimental group; 64 males; median age overall 67 [interquartile range 59-77], 67 right hemispheric lesions, 80 ischemic lesions, National Institutes of Health Stroke Scale score >=8 for 82%). Fugl-Meyer score increased over time (P<0.0001), with no significant effect of treatment (P=0.29) or interaction between treatment and time (P=0.40). The median change in score between D90 and D0 was 27.5 (12-40) and 22.0 (12-56) for control and experimental groups (P=0.69). Similar results were found for the secondary criteria. CONCLUSIONS: Very early after stroke, intensive exercises may not be efficient in improving motor control. This conclusion may apply to mainly severe stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01520636. PMID- 28008093 TI - Arterial Obstruction on Computed Tomographic or Magnetic Resonance Angiography and Response to Intravenous Thrombolytics in Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data. METHODS: We analyzed angiograms from the IST-3 (Third International Stroke Trial), an international, multicenter, prospective, randomized controlled trial of intravenous alteplase. Readers, masked to clinical, treatment, and outcome data, assessed prerandomization computed tomographic angiography and magnetic resonance angiography for presence, extent, location, and completeness of obstruction and collaterals. We compared angiography findings to 6-month functional outcome (Oxford Handicap Scale) and tested for interactions with alteplase, using ordinal regression in adjusted analyses. We also meta-analyzed all available angiography data from other randomized controlled trials of intravenous thrombolytics. RESULTS: In IST-3, 300 patients had prerandomization angiography (computed tomographic angiography=271 and magnetic resonance angiography=29). On multivariable analysis, more extensive angiographic obstruction and poor collaterals independently predicted poor outcome (P<0.01). We identified no significant interaction between angiography findings and alteplase effect on Oxford Handicap Scale (P>=0.075) in IST-3. In meta-analysis (5 trials of alteplase or desmoteplase, including IST-3, n=591), there was a significantly increased benefit of thrombolytics on outcome (odds ratio>1 indicates benefit) in patients with (odds ratio, 2.07; 95% confidence interval, 1.18-3.64; P=0.011) versus without (odds ratio, 0.88; 95% confidence interval, 0.58-1.35; P=0.566) arterial obstruction (P for interaction 0.017). CONCLUSIONS: Intravenous thrombolytics provide benefit to stroke patients with computed tomographic angiography or magnetic resonance angiography evidence of arterial obstruction, but the sample was underpowered to demonstrate significant treatment benefit or harm among patients with apparently patent arteries. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN25765518. PMID- 28008094 TI - Differences in Acute Ischemic Stroke Quality of Care and Outcomes by Primary Stroke Center Certification Organization. AB - BACKGROUND AND PURPOSE: Primary stroke center (PSC) certification was established to identify hospitals providing evidence-based care for stroke patients. The numbers of PSCs certified by Joint Commission (JC), Healthcare Facilities Accreditation Program, Det Norske Veritas, and State-based agencies have significantly increased in the past decade. This study aimed to evaluate whether PSCs certified by different organizations have similar quality of care and in hospital outcomes. METHODS: The study population consisted of acute ischemic stroke patients who were admitted to PSCs participating in Get With The Guidelines-Stroke between January 1, 2010, and December 31, 2012. Measures of care quality and outcomes were compared among the 4 different PSC certifications. RESULTS: A total of 477 297 acute ischemic stroke admissions were identified from 977 certified PSCs (73.8% JC, 3.7% Det Norske Veritas, 1.2% Healthcare Facilities Accreditation Program, and 21.3% State-based). Composite care quality was generally similar among the 4 groups of hospitals, although State-based PSCs underperformed JC PSCs in a few key measures, including intravenous tissue-type plasminogen activator use. The rates of tissue-type plasminogen activator use were higher in JC and Det Norske Veritas (9.0% and 9.8%) and lower in State and Healthcare Facilities Accreditation Program certified hospitals (7.1% and 5.9%) (P<0.0001). Door-to-needle times were significantly longer in Healthcare Facilities Accreditation Program hospitals. State PSCs had higher in-hospital risk-adjusted mortality (odds ratio 1.23, 95% confidence intervals 1.07-1.41) compared with JC PSCs. CONCLUSIONS: Among Get With The Guidelines-Stroke hospitals with PSC certification, acute ischemic stroke quality of care and outcomes may differ according to which organization provided certification. These findings may have important implications for further improving systems of care. PMID- 28008095 TI - Intracranial Carotid Artery Calcification Relates to Recanalization and Clinical Outcome After Mechanical Thrombectomy. AB - BACKGROUND AND PURPOSE: Intracranial carotid artery calcification (ICAC) is a surrogate marker of intracranial arteriosclerosis, which may impact the revascularization and clinical outcome of acute stroke patients who undergo mechanical thrombectomy. METHODS: We included 194 patients admitted to our Stroke Unit between January 2009 and September 2015 who underwent mechanical thrombectomy for an anterior circulation occlusion. ICAC was quantified in both intracranial carotid arteries on the nonenhanced computed tomographic scan that was acquired before thrombectomy. Complete arterial revascularization was defined as a Thrombolysis in Cerebral Infarction >=2b on the final angiographic examination. Poor functional outcome was defined as a modified Rankin Scale score of >2 at 90 days. We assessed the independent effect of ICAC volume on complete arterial revascularization, functional outcome, and mortality using logistic regression models adjusted for relevant confounders. RESULTS: ICAC was present in 164 (84.5%) patients, with a median volume of 87.1 mm3 (25th-75th quartile: 18.9 254.6 mm3). We found that larger ICAC volumes were associated with incomplete arterial revascularization (adjusted odds ratio per unit increase in ln transformed ICAC volume 0.73 [95% confidence interval, 0.57-0.93]) and with poorer functional outcome (adjusted odds ratio per unit increase in ln transformed ICAC volume 1.31 [95% confidence interval, 1.04-1.66]). CONCLUSIONS: A larger amount of ICAC before mechanical thrombectomy in acute stroke patients is an indicator of worse postprocedural arterial revascularization and poorer functional outcome. PMID- 28008096 TI - Dry Care Versus Antiseptics for Umbilical Cord Care: A Cluster Randomized Trial. AB - BACKGROUND AND OBJECTIVES: In developed countries, where omphalitis has become rare and related mortality nil, benefits of antiseptic use in umbilical cord care have not been demonstrated. We aimed to assess the noninferiority of dry care compared with antiseptics in France where antiseptic use is widespread. METHODS: We conducted a noninferiority, cluster-randomized, 2-period crossover trial, in 6 French university maternity units including all infants born after 36 weeks' gestation. Maternity units were randomly assigned to provide either their usual antiseptic care or a dry care umbilical cord method for a 4-month period, and then units switched to the alternate cord cleansing method for a 4-month period. The primary outcome was neonatal omphalitis, adjudicated by an independent blinded committee based on all available photographs, clinical, and bacteriological data. We used a noninferiority margin of 0.4%. Analysis was performed per protocol and by intention to treat. RESULTS: Among 8698 participants, omphalitis occurred in 3 of 4293 (0.07%) newborns in the dry care group and in none of the 4404 newborns in the antiseptic care group (crude difference: 0.07; 95% confidence interval: -0.03 to 0.21). Late neonatal infection, parental appreciation of difficulty in care, and time to separation of the cord were not significantly different between the 2 groups. CONCLUSIONS: Dry cord was noninferior to the use of antiseptics in preventing omphalitis in full term newborns in a developed country. Antiseptic use in umbilical cord care is therefore unnecessary, constraining, and expensive in high-income countries and may be replaced by dry care. PMID- 28008097 TI - How the Next President Can Build a Foundation for a Healthy Future: Improving Children's Lives. PMID- 28008098 TI - B-type natriuretic peptide increases cortisol and catecholamine concentrations in healthy subjects. AB - B-type natriuretic peptide (BNP) is a hormone released by the heart in response to volume load and exerts natriuretic properties. It is clinically used as a diagnostic and prognostic biomarker and investigated as a pharmacological agent in the therapy of heart failure. Here we investigate the changes in pituitary, adrenal, and thyroid hormones in response to BNP administration in a randomized single-blinded crossover study conducted in ten healthy men aged 21-29 yr. Participants received in two study sessions a continuous intravenous infusion during 4 h (once placebo and once 3 pmol.kg-1.min-1 BNP) and remained in supine position throughout the study. Circulating concentrations of pituitary, adrenal, and thyroid hormones, heart rate, and blood pressure were measured at baseline and hourly afterwards. BNP prevented the physiological decrease in cortisol during the late morning hours leading to elevated serum cortisol levels (P = 0.022) and increased circulating epinephrine and norepinephrine concentrations (P = 0.018 and P = 0.036, respectively). These hormone changes were accompanied by an increase in heart rate (P = 0.019) but no differences in blood pressure. Taken together, the impact of BNP on the endocrine system extends beyond the well-known inhibition of the renin-angiotensin-aldosterone system and includes increased adrenergic activity and cortisol concentrations. This neuroendocrine activation might impact the outcome of therapeutical BNP administrations and should be further investigated in conditions associated with increased BNP secretion.NEW & NOTEWORTHY The heart hormone B-type natriuretic peptide (BNP) is increased in patients with heart failure, where it is thought to have beneficial effects by reducing the preload. Here we report that intravenous administration of BNP in men leads to increases in adrenal hormones cortisol, epinephrine, and norepinephrine. Cortisol and catecholamine levels are independent predictors of increased cardiovascular mortality risk; therefore, drugs targeting the BNP system should be evaluated regarding their effects on the neuroendocrine activation accompanying heart failure. PMID- 28008099 TI - Velopharyngeal mucosal surface topography in healthy subjects and subjects with obstructive sleep apnea. AB - Macroscopic pharyngeal anatomical abnormalities are thought to contribute to the pathogenesis of upper airway (UA) obstruction in obstructive sleep apnea (OSA). Microscopic changes in the UA mucosal lining of OSA subjects are reported; however, the impact of these changes on UA mucosal surface topography is unknown. This study aimed to 1) develop methodology to measure UA mucosal surface topography, and 2) compare findings from healthy and OSA subjects. Ten healthy and eleven OSA subjects were studied. Awake, gated (end expiration), head and neck position controlled magnetic resonance images (MRIs) of the velopharynx (VP) were obtained. VP mucosal surfaces were segmented from axial images, and three dimensional VP mucosal surface models were constructed. Curvature analysis of the models was used to study the VP mucosal surface topography. Principal, mean, and Gaussian curvatures were used to define surface shape composition and surface roughness of the VP mucosal surface models. Significant differences were found in the surface shape composition, with more saddle/spherical and less flat/cylindrical shapes in OSA than healthy VP mucosal surface models (P < 0.01). OSA VP mucosal surface models were also found to have more mucosal surface roughness (P < 0.0001) than healthy VP mucosal surface models. Our novel methodology was utilized to model the VP mucosal surface of OSA and healthy subjects. OSA subjects were found to have different VP mucosal surface topography, composed of increased irregular shapes and increased roughness. We speculate increased irregularity in VP mucosal surface may increase pharyngeal collapsibility as a consequence of friction-related pressure loss.NEW & NOTEWORTHY A new methodology was used to model the upper airway mucosal surface topography from magnetic resonance images of patients with obstructive sleep apnea and healthy adults. Curvature analysis was used to analyze the topography of the models, and a new metric was derived to describe the mucosal surface roughness. Increased roughness was found in the obstructive sleep apnea vs. healthy group, but further research is required to determine the functional effects of the measured difference on upper airway airflow mechanics. PMID- 28008100 TI - Melatonin protects against uric acid-induced mitochondrial dysfunction, oxidative stress, and triglyceride accumulation in C2C12 myotubes. AB - Excess uric acid has been shown to induce oxidative stress, triglyceride accumulation, and mitochondrial dysfunction in the liver and is an independent predictor of type-2 diabetes. Skeletal muscle plays a dominant role in type 2 diabetes and presents a large surface area to plasma uric acid. However, the effects of uric acid on skeletal muscle are underinvestigated. Our aim was therefore to characterize the effects of excessive uric acid on oxidative stress, triglyceride content, and mitochondrial function in skeletal muscle C2C12 myotubes and assess how these are modulated by the antioxidant molecule melatonin. Differentiated C2C12 myotubes were exposed to 750 uM uric acid or uric acid + 10 nM melatonin for 72 h. Compared with control, uric acid increased triglyceride content by ~237%, oxidative stress by 32%, and antioxidant capacity by 135%. Uric acid also reduced endogenous ROUTINE respiration, complex II-linked oxidative phosphorylation, and electron transfer system capacities. Melatonin counteracted the effects of uric acid without further altering antioxidant capacity. Our data demonstrate that excess uric acid has adverse effects on skeletal muscle similar to those previously reported in hepatocytes and suggest that melatonin at a low physiological concentration of 10 nM may be a possible therapy against some adverse effects of excess uric acid.NEW & NOTEWORTHY Few studies have investigated the effects of uric acid on skeletal muscle. This study shows that hyperuricemia induces mitochondrial dysfunction and triglyceride accumulation in skeletal muscle. The findings may explain why hyperuricemia is an independent predictor of diabetes. PMID- 28008106 TI - Badger culls: numerical targets achieved. PMID- 28008114 TI - Invisible horses: who is responsible? AB - 'The invisible horse' was the central topic discussed at a conference organised by the equine charity World Horse Welfare in London last month. Gill Harris reports. PMID- 28008101 TI - Muscle metabolic and neuromuscular determinants of fatigue during cycling in different exercise intensity domains. AB - Lactate or gas exchange threshold (GET) and critical power (CP) are closely associated with human exercise performance. We tested the hypothesis that the limit of tolerance (Tlim) during cycle exercise performed within the exercise intensity domains demarcated by GET and CP is linked to discrete muscle metabolic and neuromuscular responses. Eleven men performed a ramp incremental exercise test, 4-5 severe-intensity (SEV; >CP) constant-work-rate (CWR) tests until Tlim, a heavy-intensity (HVY; GET) CWR test until Tlim, and a moderate intensity (MOD; 0.05) muscle metabolic milieu (i.e., low pH and [PCr] and high [lactate]) was attained at Tlim (approximately 2-14 min) for all SEV exercise bouts. The muscle metabolic perturbation was greater at Tlim following SEV compared with HVY, and also following SEV and HVY compared with MOD (all P < 0.05). The normalized M-wave amplitude for the vastus lateralis (VL) muscle decreased to a similar extent following SEV (-38 +/- 15%), HVY (-68 +/- 24%), and MOD (-53 +/- 29%), (P > 0.05). Neural drive to the VL increased during SEV (4 +/- 4%; P < 0.05) but did not change during HVY or MOD (P > 0.05). During SEV and HVY, but not MOD, the rates of change in M-wave amplitude and neural drive were correlated with changes in muscle metabolic ([PCr], [lactate]) and blood ionic/acid-base status ([lactate], [K+]) (P < 0.05). The results of this study indicate that the metabolic and neuromuscular determinants of fatigue development differ according to the intensity domain in which the exercise is performed.NEW & NOTEWORTHY The gas exchange threshold and the critical power demarcate discrete exercise intensity domains. For the first time, we show that the limit of tolerance during whole-body exercise within these domains is characterized by distinct metabolic and neuromuscular responses. Fatigue development during exercise greater than critical power is associated with the attainment of consistent "limiting" values of muscle metabolites, whereas substrate availability and limitations to muscle activation may constrain performance at lower intensities. PMID- 28008115 TI - Improving the health of pedigree dogs: is enough being done? AB - Controversies at Crufts in recent years have indicated there is still more to do to improve the health of pedigree dogs. Is the Kennel Club doing enough and can the UK learn from international experiences to help take matters forward? These questions were discussed during a session on pedigree dog health at the BVA Congress last month. Georgina Mills reports. PMID- 28008117 TI - 1914-18: the global veterinary war. AB - While France was the main theatre of the First World War, it was also fought globally. The Army Veterinary Corps was involved in 13 of these operations. The most important were protecting British interests in the Middle East and defending Britain's African colonies. Bruce Vivash Jones explains that, along with the fighting, the Corps had to deal with a wide range of diseases, unusual species and extremes of climate. PMID- 28008118 TI - Antibiotic-resistant bacteria in free-living marine species. PMID- 28008120 TI - Should we advocate neutering for all pet rabbits? AB - The neutering of pet rabbits has become more common in recent years due to recognition of the importance of species-specific social contact and the perceived risk of reproductive malignancies in unspayed older females. Here, GUEN BRADBURY: and GREG DICKENS: argue that the benefits of neutering singly housed rabbits (still the majority in the UK) may not outweigh the adverse effects of the procedure. PMID- 28008121 TI - Support for veterinary professionals. PMID- 28008127 TI - Experience beyond value. AB - Grzegorz Dymacz is a poultry vet who works with farmers in central European countries and the Middle East. He took a break while studying veterinary medicine at Wroclaw university to broaden his knowledge and experience as a student volunteer in the UK. The kindness and hospitality he was shown has left a lasting impression. PMID- 28008128 TI - Ten-minute chat. AB - Samantha Goldberg is a small animal vet who is very taken with beagles. She was recently nominated as a finalist for the Kennel Club's Breed Health Coordinator of the Year award. PMID- 28008129 TI - Nesting behavior of Hy-Line hens in modified enriched colony cages. AB - Hens are motivated to seek out an enclosed nest site, but it is unclear whether the single communal nest in enriched colony cages (EC) adequately supports nesting. One method to investigate this is to provide an "alternative nest site" and determine the effects on laying location, timing of oviposition, and pre laying behavior. The objective of this experiment was to determine whether increasing the degree of enclosure in the scratch area would influence egg laying location, time of oviposition, and pre-laying behavior. Hy-Line W-36 hens (n = 1,560) were reared in standard cages and housed in four rooms, each with six Chore-Time EC, at wk 17 (65 birds/cage at 729 cm2 floor space and 62 cm2 nest space per bird). At 21 wk, the scratch area of the enclosed (E; n = 12) treatment cages was fitted with a wire partition and red vinyl curtain; open (O; n = 12) cages were unmodified. The number of eggs laid in each location (nest, middle, scratch) was counted over 4 d. Nest and scratch areas were instantaneously scan sampled every 20min from 0630 h to 1330 h to count the number of sitting hens and the number of eggs. Aggressive pecks, threats, and displacements were counted in each area during a 30 s interval scan (3 scans/time period, 5 periods). Mixed model analyses tested the effect of treatment, time, room, position, and tier. There was no significant main effect of treatment on the percentage of eggs laid in the nest or scratch areas, but E treatment hens were more aggressive (P = 0.027). The numbers of hens sitting and eggs laid in the nest peaked between 0830 h to 0930 h (P < 0.0001), with a peak in displacements between 0800 h to 1000 h (P < 0.0001). Peak laying time occurred later in the scratch area (0930 h to 1030 h). Treatment affected few nesting behavior patterns, and the behavior differences between the nest and scratch areas replicated earlier findings. Hy Line W-36 hens seemed to perceive the existing nest as satisfactory, with little evidence for competition. PMID- 28008130 TI - Effects of dietary methionine on growth performance, meat quality and oxidative status of breast muscle in fast- and slow-growing broilers. AB - This experiment was conducted to investigate the effects of dietary methionine (Met) on growth performance, carcass traits, meat quality and oxidative status of breast muscle in fast- (Arbor Acres, AA) and slow- (Partridge Shank, PS) growing broilers from 1 to 42 d of age. The broilers were divided into a 2 * 3 factorial design with 6 replicates per treatment. Diets were formulated to contain low (LM, 0.35 and 0.31% during 1 to 21 and 22 to 42 d), adequate (AM, 0.50 and 0.44%) and high (HM, 0.65 and 0.57%) Met, respectively. The main effects showed that the AA broilers had superior (P < 0.05) growth performance and carcass traits compared with those of the PS broilers. The breast muscle of the AA broilers had lower (P < 0.05) drip loss and malondialdehyde (MDA) content but higher (P < 0.05) cooking loss and glutathione peroxidase (GPX) activity than that of the PS broilers. Compared with the LM diets, the AM and HM diets increased (P < 0.05) 42-d BW, ADG, eviscerated yield and breast muscle yield only in the AA broilers. The AA broilers fed the HM diets had higher (P < 0.05) pH but lower (P < 0.05) L*, cooking loss and ether extract content in breast muscle than those fed the LM diets. Compared with the LM diets, the HM diets resulted in strain-dependent changes (P < 0.05) in muscle oxidative status, with total antioxidant capacity (T AOC) increased in the AA broilers, GPX activity increased and MDA content decreased in the PS broilers, and superoxide dismutase (SOD) activity increased in both strains of broilers. No differences were observed between the AM and HM diets except for T-AOC in breast muscle. In conclusion, the LM treatment negatively affected broiler growth performance, carcass traits, meat quality and oxidative status of breast muscle in a strain-dependent manner, particularly in the AA broilers, whereas the HM treatment had limited effects compared to the AM treatment. PMID- 28008131 TI - Increased copy number of SOCS2 gene in Chinese gamecocks. AB - As a member of the suppressor of cytokine signaling (SOCS) family, the SOCS2 gene has been associated with negative regulation of the inflammatory immune response and a positive effect on growth when it is overexpressed. In our previous study, using next-generation sequencing, it was found that the Luxi Game (LX, a Chinese indigenous gamecock) had an increased copy number (CN) of the SOCS2 gene. To verify the copy number increase of the SOCS2 gene in gamecocks, we quantified the copy number value in 8 chicken breeds by quantitative PCR. The results showed that the average CN values of the SOCS2 gene were highly variable among the 8 breeds, and the highest was found in LX (CN = 5.0), almost 3.5 folds as many as the lowest in Rhode Island Red (CN = 1.43). All 4 gamecock breeds possessed significantly higher CN values than others, including broilers and commercial breeds. Thus, it is suggested that most Chinese gamecocks possess an increased copy number in the SOCS2 gene, indicating the plausible functions of the SOCS2 gene in inflammation control and increased body size. PMID- 28008132 TI - Conserved residues in Ycf54 are required for protochlorophyllide formation in Synechocystis sp. PCC 6803. AB - Chlorophylls (Chls) are modified tetrapyrrole molecules, essential for photosynthesis. These pigments possess an isocyclic E ring formed by the Mg protoporphyrin IX monomethylester cyclase (MgPME-cyclase). We assessed the in vivo effects of altering seven highly conserved residues within Ycf54, which is required for MgPME-cyclase activity in the cyanobacterium SynechocystisSynechocystis strains harbouring the Ycf54 alterations D39A, F40A and R82A were blocked to varying degrees at the MgPME-cyclase step, whereas the A9G mutation reduced Ycf54 levels by ~75%. Wild-type (WT) levels of the cyclase subunit CycI are present in strains with D39A and F40A, but these strains have lowered cellular Chl and photosystem accumulation. CycI is reduced by ~50% in A9G and R82A, but A9G has no perturbations in Chl or photosystem accumulation, whilst R82A contains very little Chl and few photosystems. When FLAG tagged and used as bait in pulldown experiments, the three mutants D39A, F40A and R82A were unable to interact with the MgPME-cyclase component CycI, whereas A9G pulled down a similar level of CycI as WT Ycf54. These observations suggest that a stable interaction between CycI and Ycf54 is required for unimpeded Pchlide biosynthesis. Crystal structures of the WT, A9G and R82A Ycf54 proteins were solved and analysed to investigate the structural effects of these mutations. A loss of the local hydrogen bonding network and a reversal in the surface charge surrounding residue R82 are probably responsible for the functional differences observed in the R82A mutation. We conclude that the Ycf54 protein must form a stable interaction with CycI to promote optimal Pchlide biosynthesis. PMID- 28008133 TI - Scolopendin, an antimicrobial peptide from centipede, attenuates mitochondrial functions and triggers apoptosis in Candida albicans. AB - Centipedes, a type of arthropod, reportedly produce antimicrobial peptides as part of an innate immune response. Scolopendin (SPSEKAGLQPVGRIGRMLKK) is a novel antimicrobial peptide derived from Scolopendra subspinipes mutilans Many antifungal agents have more than one type of cell death mechanism. Although scolopendin is involved in membrane perturbation, the corresponding intracellular changes require further investigation. Therefore, we assessed the cell morphology and calcium ion concentration of the cytosol and mitochondria of scolopendin treated cells. The treated cells were shrunken, and calcium ion homeostasis was disrupted in both the cytosol and mitochondria. These conditions attenuated mitochondrial homeostasis, disrupting mitochondrial membrane potential and cytochrome c levels. Fungal cells treated with scolopendin exhibited various apoptotic phenotypes such as reactive oxygen species accumulation, phosphatidylserine exposure, chromatin condensation, and nuclear fragmentation. Scolopendin-induced cell death also triggered metacaspase activation. In conclusion, treatment of Candida albicans with scolopendin induced the apoptotic response, which in turn led to mitochondrial dysfunction, metacaspase activation, and cell death. The antimicrobial peptide scolopendin from the centipede S.s. mutilans demonstrated a novel apoptotic mechanism as an antifungal agent. PMID- 28008134 TI - Interacting post-muscarinic receptor signaling pathways potentiate matrix metalloproteinase-1 expression and invasion of human colon cancer cells. AB - M3 muscarinic receptor (M3R) expression is increased in colon cancer; M3R activation stimulates colon cancer cell invasion via cross-talk with epidermal growth factor receptors (EGFR), post-EGFR activation of mitogen-activated protein kinase (MAPK) extracellular signal-related kinase 1/2 (ERK1/2), and induction of matrix metalloproteinase-1 (MMP1) expression. MMP1 expression is strongly associated with tumor metastasis and adverse outcomes. Here, we asked whether other MAPKs regulate M3R agonist-induced MMP1 expression. In addition to activating ERK1/2, we found that treating colon cancer cells with acetylcholine (ACh) stimulated robust time- and dose-dependent phosphorylation of p38 MAPK. Unlike ERK1/2 activation, ACh-induced p38 phosphorylation was EGFR-independent and blocked by inhibiting protein kinase C-alpha (PKC-alpha). Inhibiting activation of PKC-alpha, EGFR, ERK1/2, or p38-alpha/beta alone attenuated, but did not abolish ACh-induced MMP1 expression, a finding that predicted potentiating interactions between these pathways. Indeed, ACh-induced MMP1 expression was abolished by incubating cells with either an EGFR or MEK/ERK1/2 inhibitor combined with a p38-alpha/beta inhibitor. Activating PKC-alpha and EGFR directly with the combination of phorbol 12-myristate 13-acetate (PMA) and EGF potentiated MMP1 gene and protein expression, and cell invasion. PMA- and ACh induced MMP1 expression were strongly diminished by inhibiting Src and abolished by concurrently inhibiting both p38-alpha/beta and Src, indicating that Src mediates the cross-talk between PKC-alpha and EGFR signaling. Using siRNA knockdown, we identified p38-alpha as the relevant p38 isoform. Collectively, these studies uncover novel functional interactions between post-muscarinic receptor signaling pathways that augment MMP1 expression and drive colon cancer cell invasion; targeting these potentiating interactions has therapeutic potential. PMID- 28008135 TI - GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. AB - Activation of AMP-activated protein kinase (AMPK) in endothelial cells regulates energy homeostasis, stress protection and angiogenesis, but the underlying mechanisms are incompletely understood. Using a label-free phosphoproteomic analysis, we identified glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1) as an AMPK substrate. GFAT1 is the rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP) and as such controls the modification of proteins by O linked beta-N-acetylglucosamine (O-GlcNAc). In the present study, we tested the hypothesis that AMPK controls O-GlcNAc levels and function of endothelial cells via GFAT1 phosphorylation using biochemical, pharmacological, genetic and in vitro angiogenesis approaches. Activation of AMPK in primary human endothelial cells by 5-aminoimidazole-4-carboxamide riboside (AICAR) or by vascular endothelial growth factor (VEGF) led to GFAT1 phosphorylation at serine 243. This effect was not seen when AMPK was down-regulated by siRNA. Upon AMPK activation, diminished GFAT activity and reduced O-GlcNAc levels were observed in endothelial cells containing wild-type (WT)-GFAT1 but not in cells expressing non phosphorylatable S243A-GFAT1. Pharmacological inhibition or siRNA-mediated down regulation of GFAT1 potentiated VEGF-induced sprouting, indicating that GFAT1 acts as a negative regulator of angiogenesis. In cells expressing S243A-GFAT1, VEGF-induced sprouting was reduced, suggesting that VEGF relieves the inhibitory action of GFAT1/HBP on angiogenesis via AMPK-mediated GFAT1 phosphorylation. Activation of GFAT1/HBP by high glucose led to impairment of vascular sprouting, whereas GFAT1 inhibition improved sprouting even if glucose level was high. Our findings provide novel mechanistic insights into the role of HBP in angiogenesis. They suggest that targeting AMPK in endothelium might help to ameliorate hyperglycaemia-induced vascular dysfunction associated with metabolic disorders. PMID- 28008136 TI - How does feedback in mini-CEX affect students' learning response? AB - Objective: This study was aimed to explore students' learning response toward feedback during mini-CEX encounter. Methods: This study used a phenomenological approach to identify the students' experiences toward feedback during mini-CEX encounter. Data was collected using Focus Group Discussion (FGD) for all students who were in their final week of clerkship in the internal medicine rotation. There were 4 FGD groups (6 students for each group). All FGD were audio-taped and transcribed verbatim. The FGD transcripts were analyzed thematically and managed using Atlas-ti (version 7.0). Results: Feedback content and the way of providing feedback on mini-CEX stimulated students' internal process, including self reflection, emotional response, and motivation. These internal processes encouraged the students to take action or do a follow-up on the feedback to improve their learning process. In addition, there was also an external factor, namely consequences, which also influenced the students' reaction to the follow up on feedback. In the end, this action caused several learning effects that resulted in the students' increased self-efficacy, attitude, knowledge and clinical skill. Conclusions: Feedback content and the way of providing feedback on mini-CEX stimulates the students' internal processes to do a follow-up on feedback. However, another external factor also affects the students' decision on the follow-up actions. The follow-ups result in various learning effects on the students. Feedback given along with summative assessment enhances learning effects on students, as well. It is suggested that supervisors of clinical education are prepared to comprehend every factor influencing feedback on mini CEX to improve the students' learning response. PMID- 28008137 TI - Impact of a 20-year collaborative approach to increasing the production of rural doctors in Thailand. PMID- 28008138 TI - Medically uncontrolled conjunctival pyogenic granulomas: correlation between clinical characteristics and histological findings. AB - BACKGROUND: Conjunctival pyogenic granulomas are commonly seen after ocular surgeries or at an ocular wound site. The aim of this study is to describe a novel histological classification for medically uncontrolled conjunctival pyogenic granulomas (MUCPG), and to explore whether the diversity in clinical features correlates to different histological subtypes of MUCPG. METHODS: This is an observational cross-section case series. We reviewed 46 consecutive patients with conjunctival pyogenic granulomas who did not respond to topical corticosteroids and underwent surgical excision from January 1, 2006 through December 31, 2015. Clinical features and histological findings were presented and analyzed. RESULTS: Ocular surgery, accidental injury, and chalazion were the main predisposing causes of MUCPG. The lesions tended to occur unilaterally on the bulbar conjunctiva. Forty patients (87%) presented an enrichment of inflammatory cells and proliferated capillaries in their pathological sections (inflammatory pattern). Six patients (13%) showed relatively few inflammatory cells and capillaries within fibrous stroma (fibrous pattern). Patients with the inflammatory pattern were older (p = 0.025) and tended to be located in bulbar conjunctiva (p = 0.002). The predisposing causes were also different between two histological subtypes (p = 0.007). CONCLUSIONS: We found the correlation between clinical presentation and histological subtypes in patients with MUCPG, indicating this disease may need a new classification scheme. PMID- 28008139 TI - Identifying the clonal origin of synchronous multifocal tumors in the hepatobiliary and pancreatic system using multi-omic platforms. AB - Synchronous multifocal tumors often pose a diagnostic challenge for oncologists. The purpose of this study was to determine the clonal origin and metastatic relationship of synchronous multifocal tumors in the hepatobiliary and pancreatic system using multi-omic platforms. DNA samples were extracted from three masses harvested from a 50-year-old Han Chinese male patient who suffered from synchronous multifocal tumors in the pancreatic tail, upper biliary duct, and omentum at the time of diagnosis. The clonal origin of these samples was tested using two platforms: next-generation sequencing (NGS) of 390 key genes harboring cancer-relevant actionable mutations and whole-genome copy number variation (CNV) chip analysis. The NGS approach revealed high mutational concordance, and the gene CNV profiles were similar between lesions. Whole-genome CNVs for the three samples were further investigated using an Affymetrix chip. Using matched CNV chip data from The Cancer Genome Atlas (TCGA), we developed a computational model that generated tissue-specific CNV signatures for hepatocellular carcinoma, pancreatic carcinoma, and cholangiocarcinoma to accurately identify the origin of the tumor samples. After adding the patient's CNV chip data to the model, all three samples were clustered into the pancreatic cancer branch. Both our NGS and CNV chip analyses suggested that clinically diagnosed synchronous pancreatic cancer and cholangiocarcinoma originated from the same cell population in the pancreas in our patient. This study highlights the use of genomic tools to infer the origin of synchronous multifocal tumors, which could help to improve the accuracy of cancer diagnosis. PMID- 28008140 TI - Choroidal microvascular proliferation secondary to diabetes mellitus. AB - Diabetes is a common endocrine disorder associated with peripheral microvascular diseases such as proliferative retinal microangiopathy (or diabetic retinopathy), which may lead to blindness. Unfortunately, diabetic microvascular abnormalities in the choroid are underestimated in clinical practice. Recent literature has revealed that the severity of diabetic retinopathy is aggravated by choroidopathy resulting from hyperglycemia. Here, we introduce a case of diabetic retinopathy with choroidal neovascularization membrane but without signs of retinal microvascular proliferation or drusen. We investigated the pathogenesis of choroidal microvascular proliferation secondary to diabetes. We postulate that choroidal neovascularization is an intraocular microvascular complication of diabetes mellitus. Intravitreal anti-vascular endothelial growth factor therapy may be a treatment option for microvascular proliferation in both retina and choroids. PMID- 28008142 TI - Systematic review of CYFRA 21-1 as a prognostic indicator and its predictive correlation with clinicopathological features in Non-small Cell Lung Cancer: A meta-analysis. AB - AIM: To evaluate the value of Cytokeratin 19 fragment for its survival prognostic indicator and predictive correlation with clinicopathological features in Non small Cell Lung Cancer. METHODS: Eligible studies or databases for articles were retrieved via search systematically. Pooled effect was calculated to evaluate the association between Cytokeratin 19 fragment level and long-term overall survival, as well as the tumor clinicopathological features in Non-small Cell Lung Cancer patients. A fixed-effects or random-effects model was used to calculate the Pooled risk ratios (RRs) and corresponding 95 % confidence intervals (CIs). RESULTS: Six studies were up to the selection criteria. This meta-analysis indicated that Cytokeratin 19 fragment high level expression correlated with lower 2-year overall survival (RR =0.47; 95%CI: 0.28-0.79), higher Tumor Node Metastasis stage (II+III+IV) (RR =1.43; 95%CI: 1.15-1.76) in Non-small Cell Lung Cancer. The pooled RR estimates indicated that there is no statistical significance of Cytokeratin 19 fragment level expression in the advanced Non small Cell Lung Cancer (IIIB+IV) (RR =1.43, 95% CI: 0.85-2.43). CONCLUSION: Cytokeratin 19 fragment is a negative prognosis indicator and its high level expression indicates higher Tumor Node Metastasis pathological stage (II+III+IV) in Non-small Cell Lung Cancer. In advanced Non-small Cell Lung Cancer, the level of serum Cytokeratin 19 fragment appears to provide more prognostic information than it does for clinical Tumor Node Metastasis stage information. Further studies are required to confirm our results. PMID- 28008143 TI - Association between Retinoic acid receptor-beta hypermethylation and NSCLC risk: a meta-analysis and literature review. AB - Emerging evidence indicates that Retinoic acid receptor-beta (RARbeta) is a tumor suppressor in many types of tumor. However, whether or not RARbeta is a risk factor and is correlated to clinicopathological characteristics of non-small cell lung cancer (NSCLC) remains unclear. In this report, we performed a meta-analysis to determine the effects of RARbeta hypermethylation on the incidence of NSCLC and clinicopathological characteristics in human NSCLC patients. Final valuation and analysis of 1780 cancer patients from 16 eligible studies was performed. RARbeta hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue, the pooled OR from 7 studies including 646 NSCLC and 580 normal lung tissues, OR = 6.05, 95% CI = 3.56-10.25, p<0.00001. RARbeta hypermethylation was significantly higher in adenocarcinoma (AC) compared to squamous cell carcinoma (SCC), pooled OR is 0.68 (95% CI = 0.52-0.89, p = 0.005). RARbeta hypermethylation was also found to occur significantly higher in smoker (n = 232) than non-smoker (n = 213) (OR = 2.46, 95% CI = 1.54-3.93, p = 0.0002). Our results indicate that RARbeta hypermethylation correlates well with an increased risk in NSCLC patients. RARbeta geneinactivation caused by RARbeta methylation contributes the NSCLC tumorigenesis and may serve as a potential risk factor, diagnostic marker and drug target of NSCLC. PMID- 28008144 TI - Preoperatively staging liver fibrosis using noninvasive method in hepatitis B virus-infected hepatocellular carcinoma patients. AB - BACKGROUND: Advanced liver fibrosis can result in serious complications (even patient's death) after partial hepatectomy. Preoperatively percutaneous liver biopsy is an invasive and expensive method to assess liver fibrosis. We aim to establish a noninvasive model, on the basis of preoperative biomarkers, to predict liver fibrosis in hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) infection. METHODS: The HBV-infected liver cancer patients who had received hepatectomy were retrospectively and prospectively enrolled in this study. Univariate analysis was used to compare the variables of the patients with mild to moderate liver fibrosis and with severe liver fibrosis. The significant factors were selected into binary logistic regression analysis. Factors determined to be significant were used to establish a noninvasive model. Then the diagnostic accuracy of this novel model was examined based on sensitivity, specificity and area under the receiver-operating characteristic curve (AUC). RESULTS: This study included 2,176 HBV-infected HCC patients who had undergone partial hepatectomy (1,682 retrospective subjects and 494 prospective subjects). Regression analysis indicated that total bilirubin and prothrombin time had positive correlation with liver fibrosis. It also demonstrated that blood platelet count and fibrinogen had negative correlation with liver fibrosis. The AUC values of the model based on these four factors for predicting significant fibrosis, advanced fibrosis and cirrhosis were 0.79-0.83, 0.83-0.85 and 0.85 0.88, respectively. CONCLUSION: The results showed that this novel preoperative model was an excellent noninvasive method for assessing liver fibrosis in HBV infected HCC patients. PMID- 28008141 TI - Chemoresistance and targeted therapies in ovarian and endometrial cancers. AB - Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers. PMID- 28008145 TI - MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early stage lung cancer patients from the IFCT-0002 Phase 3 Trial. AB - INTRODUCTION: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. METHODS: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens. RESULTS: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death. INTERPRETATION: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors. PMID- 28008146 TI - Autologous reconstitution of human cancer and immune system in vivo. AB - Correlative studies from checkpoint inhibitor trials have indicated that better understanding of human leukocytic trafficking into the human tumor microenvironment can expedite the translation of future immune-oncologic agents. In order to directly characterize signaling pathways that can regulate human leukocytic trafficking into the tumor, we have developed a completely autologous xenotransplantation method to reconstitute the human tumor immune microenvironment in vivo. We were able to genetically mark the engrafted CD34+ bone marrow cells as well as the tumor cells, and follow the endogenous leukocytic infiltration into the autologous tumor. To investigate human tumor intrinsic factors that can potentially regulate the immune cells in our system, we silenced STAT3 signaling in the tumor compartment. As expected, STAT3 signaling suppression in the tumor compartment in these autologously reconstituted humanized mice showed increased tumor infiltrating lymphocytes and reduction of arginase-1 in the stroma, which were associated with slower tumor growth rate. We also used this novel system to characterize human myeloid suppressor cells as well as to screen novel agents that can alter endogenous leukocytic infiltration into the tumor. Taken together, we present a valuable method to study individualized human tumor microenvironments in vivo without confounding allogeneic responses. PMID- 28008147 TI - Outcomes of surgery for gastric cancer with distant metastases: a retrospective study from the SEER database. AB - BACKGROUND: The role of surgical therapy in gastric cancer patients with distant metastases remains controversial. This retrospective analysis was performed to identify whether gastric cancer patients with distant metastases might benefit from surgery. PATIENTS AND METHODS: A total of 5185 patients from the SEER database who were initially diagnosed with histologically confirmed gastric cancer with distant metastases from 2004 to 2009 were included. Patients were divided into the following three groups: patients who underwent resection of both the primary tumor and distant metastatic tumors ('PMTR' group), patients who only underwent resection of the primary tumor ('PTR' group) and patients who did not undergo any surgery ('No surgery' group). We employed the Kaplan-Meier analysis, the log-rank test and multivariate Cox proportional hazards regression models to estimate the survival time of the different groups. RESULTS: A total of 5185 patients had a median survival time (MST) of 9.0 months. The improvement in survival of the 'PMTR' and 'PTR' groups was significantly different compared with that of the 'No surgery' group (MST, 12.0 vs 12.0 vs 9.0 months, respectively, P<0.001; 1-year survival rate, 49.6% vs 49.1% vs 30.1%, respectively, P<0.001; 3 year survival rate, 12.5% vs 15.1% vs 5.8%, respectively, P<0.001), whereas no significant difference was found between the 'PMTR' group and 'PTR' group (P=0.642). Multivariate Cox proportional analysis showed that surgery was an independent prognostic factor ('PMTR', hazard ratio (HR) =0.648, 95% confidence interval (CI) 0.574-0.733, P<0.001; 'PTR', HR=0.631, 95% CI 0.583-0.684, P<0.001). CONCLUSIONS: This retrospective analysis demonstrated that combined PTR and metastasectomy or PTR alone were independent prognostic factors for survival improvement in gastric cancer patients with distant metastases. Because no statistically significant difference in survival was observed between the 'PMTR' group and 'PTR' group, PTR, which is a more minor surgery, might be more appropriate than PMTR in clinical practice for gastric cancer patients with distant metastases. PMID- 28008148 TI - Dysbiosis of urinary microbiota is positively correlated with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) may be associated with altered urinary microbiota in female patients. We investigated alterations of urinary microbiota in Chinese female T2DM patients, and explored the associations between urinary microbiota and a patient's fasting blood glucose (FBG), urine glucose (UGLU), age, menstrual status, and body mass index (BMI). Midstream urine was collected from 70 female T2DM patients and 70 healthy females. Microbial diversity and composition were analyzed using the Illumina MiSeq sequencing platform by targeting the hypervariable V3-V4 regions of the 16S rRNA gene. We found that bacterial diversity was decreased in T2DM patients. Increased Actinobacteria phylum was positively correlated with FBG, UGLU, and BMI; Lactobacillus abundance decreased with age and menopause; and increased Lactobacillus correlated positively with FBG and UGLU. Decreased Akkermansia muciniphila was associated with FBG and UGLU. Escherichia coli abundance did not differ between the two cohorts. Carbohydrate and amino acid metabolism was reduced in T2DM patients, which were associated with bacterial richness indices such as Chao1 and ACE. Detailed microbiota analysis of well-characterized T2DM patients and healthy controls indicate that Chinese T2DM female patients exhibit dysbiosis of urinary microbiota. PMID- 28008149 TI - Idelalisib induces PUMA-dependent apoptosis in colon cancer cells. AB - Idelalisib, a PI3K inhibitor, specifically targeting p110delta, has been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. However, the mechanisms of action of idelalisib in colon cancer cells are not well understood. We investigated how idelalisib suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. In this study, we found that idelalisib treatment induces PUMA in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3beta (GSK3beta) activation. PUMA is necessary for idelalisib-induced apoptosis in colon cancer cells. Idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and antitumor effect of idelalisib in xenograft model. These results demonstrate a critical role of PUMA in mediating the anticancer effects of idelalisib in colon cancer cells and suggest that PUMA induction can be used as an indicator of idelalisib sensitivity, and also have important implications for it clinical applications. PMID- 28008150 TI - PRKAR2B plays an oncogenic role in the castration-resistant prostate cancer. AB - Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer. Despite some progresses have been made, the mechanism of CRPC development is still largely unknown, including the genes involved in its development have not been well defined. Here, we identifiedPRKAR2B to be a gene over-expressingin castration-resistant prostate cancer by analyzing the different online databases. Followed functional validation experiments showed that PRKAR2B promoted CRPC cell proliferation and invasion, and inhibited CRPC cell apoptosis. Whole genome transcriptome and GO enrichment analyses of the knock-down of PRKAR2B in CRPC cells showed that PRKAR2B mainly accelerated cell cycle biological process and modulated multiple cell cycle genes, such as CCNB1, MCM2, PLK1 and AURKB. Our study firstly identified PRKAR2B as a novel oncogenic gene involved in CRPC development and suggested it is a promising target for the future investigation and the treatment of CRPC. PMID- 28008151 TI - Tonsillar CD56brightNKG2A+ NK cells restrict primary Epstein-Barr virus infection in B cells via IFN-gamma. AB - Natural killer (NK) cells constitute the first line of defense against viruses and cancers cells. Epstein-Barr virus (EBV) was the first human virus to be directly implicated in carcinogenesis, and EBV infection is associated with a broad spectrum of B cell lymphomas. How NK cells restrict EBV-associated oncogenesis is not understood. Here, we investigated the efficacies and mechanisms of distinct NK cell subsets from tonsils, the portal of entry of EBV, in limiting EBV infection in naive, germinal center-associated and memory B cells. We found that CD56bright and NKG2A expression sufficiently characterizes the potent anti-EBV capacity of tonsillar NK cells. We observed restriction of EBV infection in B cells as early as 18 hours after infection. The restriction was most efficient in naive B cells and germinal center-associated B cells, the B cell subsets that exhibited highest susceptibility to EBV infection in vitro. IFN gamma release by and partially NKp44 engagement of CD56bright and NKG2A positive NK cells mediated the restriction that eventually inhibited B-cell transformation. Thus, harnessing CD56brightNKG2A+ NK cell function might be promising to improve treatment strategies that target EBV-associated B cell lymphomas. PMID- 28008152 TI - Dysregulated miR34a/diacylglycerol kinase zeta interaction enhances T-cell activation in acquired aplastic anemia. AB - Acquired aplastic anemia is an idiopathic paradigm of human bone marrow failure syndrome, which involves active destruction of hematopoietic stem cells and progenitors by cytotoxic T cells in the bone marrow. Aberrant expression of microRNAs in T cells has been shown to lead to development of certain autoimmune diseases. In the present study, we performed a microarray analysis of miRNA expression in bone marrow CD3+ T cells from patients with aplastic anemia and healthy controls. Overexpression of miR34a and underexpression of its target gene diacylglycerol kinase (DGK) zeta in bone marrow mononuclear cells were validated in 41 patients and associated with the severity of aplastic anemia. Further, the level of miR34a was higher in naive T cells from patients than from controls. The role of miR34a and DGKzeta in aplastic anemia was investigated in a murine model of immune-mediated bone marrow failure using miR34a-/- mice. After T-cell receptor stimulation in vitro, lymph node T cells from miR34a-/- mice demonstrated reduced activation and proliferation accompanied with a less profound down-regulation of DGKzeta expression and decreased ERK phosphorylation compared to those from wild-type C57BL6 control mice. Infusion of 5 * 106 miR34a /- lymph node T cells into sublethally irradiated CB6F1 recipients led to increased Lin-Sca1+CD117+ cells and less vigorous expansion of CD8+ T cells than injection of same number of wild-type lymph node cells. Our study demonstrates that the miR34a/DGKzeta dysregulation enhances T-cell activation in aplastic anemia and targeting miR34a may represent a novel molecular therapeutic approach for patients with aplastic anemia. PMID- 28008153 TI - PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression. AB - Despite improvement of therapeutic treatments for breast cancer, the development of brain metastases has become a major limitation to life expectancy for many patients. Brain metastases show very commonly alterations in EGFR and HER2 driven pathways, of which PTEN is an important regulator. Here, we analyzed PTEN expression in 111 tissue samples of breast cancer brain metastases (BCBM). Loss of PTEN was found in a substantial proportion of BCBM samples (48.6%) and was significantly associated with triple-negative breast cancer (67.5%, p = 0.001) and a shorter survival time after surgical resection of brain metastases (p = 0.048). Overexpression of PTEN in brain-seeking MDA-MB-231 BR cells in vitro reduced activation of the AKT pathway, notably by suppression of Akt1 kinase activity. Furthermore, the migration of MDA-MB-231 BR cells in vitro was promoted by co-culturing with both astrocytes and microglial cells. Interestingly, when PTEN was overexpressed the migration was significantly inhibited. Moreover, in an ex vivo organotypic brain slice model, PTEN overexpression reduced invasion of tumor cells. This was accompanied by reduced astrocyte activation that was mediated by autocrine and paracrine activation of GM-CSF/ CSF2RA and AKT/ PTEN pathways. In conclusion, loss of PTEN is frequently detected in triple-negative BCBM patients and associated with poor prognosis. The findings of our functional studies suggest that PTEN loss promotes a feedback loop between tumor cells and glial cells, which might contribute to disease progression. PMID- 28008154 TI - Down-regulation of CITED2 attenuates breast tumor growth, vessel formation and TGF-beta-induced expression of VEGFA. AB - While we previously demonstrated that CITED2 expression in primary breast tumor tissues is elevated relative to normal mammary epithelium and inversely correlated with patient survival, its functional impact on primary tumor development and progression remained unknown. To address this issue, we examined the effect of CITED2 silencing on the growth of human breast cancer cell lines MDA-MB-231 and MDA-MB-468 following orthotopic administration in vivo. Here, we show that CITED2 silencing significantly attenuated MDA-MB-231 primary tumor growth concordant with reduced tumor vascularization, while MDA-MB-468 primary tumor growth and tumor vascularization remained unaffected. Correspondingly, expression of VEGFA was significantly reduced in shCITED2-expressing MDA-MB-231, but not MDA-MB-468 tumors. Consistent with the observed pattern of vascularization and VEGFA expression, we found that TGF-beta stimulation induced expression of VEGFA and enhanced CITED2 recruitment to the VEGFA promoter in MDA MA-231 cells, while failing to induce VEGFA expression in MDA-MB-468 cells. Further supporting its involvement in TGF-beta-induced expression of VEGFA, CITED2 silencing prevented TGF-beta induction of VEGFA expression in MDA-MB-231 cells. Collectively, these data indicate that CITED2 regulates primary breast tumor growth, likely by influencing tumor vasculature via TGF-beta-dependent regulation of VEGFA. PMID- 28008155 TI - Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors. AB - Activation of the PI3K/AKT pathway occurs in the vast majority of advanced prostate cancers (PCas). Activation of fibroblast growth factor receptor (FGFR) signaling occurs in a wide variety of malignancies, including PCa. RNA-Seq of castration resistant PCa revealed expression of multiple FGFR signaling components compatible with FGFR signaling in all cases, with multiple FGF ligands expressed in 90% of cases. Immunohistochemistry confirmed FGFR signaling in the majority of xenografts and advanced PCas. AZD5363, an AKT kinase inhibitor and AZD4547, a FGFR kinase inhibitor are under active clinical development. We therefore sought to determine if these two drugs have additive effects in PCa models. The effect of both agents, singly and in combination was evaluated in a variety of PCa cell lines in vitro and in vivo. All cell lines tested responded to both drugs with decreased invasion, soft agar colony formation and growth in vivo, with additive effects seen with combination treatment. Activation of the FGFR, AKT, ERK and STAT3 pathways was examined in treated cells. AZD5363 inhibited AKT signaling and increased FGFR1 signaling, which partially compensated for decreased AKT kinase activity. While AZD4547 could effectively block the ERK pathway, combination treatment was needed to completely block STAT3 activation. Thus combination treatment with AKT and FGFR kinase inhibitors have additive effects on malignant phenotypes in vitro and in vivo by inhibiting multiple signaling pathways and mitigating the compensatory upregulation of FGFR signaling induced by AKT kinase inhibition. Our studies suggest that co-targeting these pathways may be efficacious in advanced PCa. PMID- 28008156 TI - Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer. AB - PAX8-PPARG fusion protein (PPFP) results from a t(2;3)(q13;p25) chromosomal translocation, is found in 30% of follicular thyroid carcinomas, and demonstrates oncogenic capacity in transgenic mice. A PPARG ligand, pioglitazone, is highly therapeutic in mice with PPFP thyroid cancer. However, only limited data exist to characterize the binding sites and oncogenic function of PPFP, or to explain the observed therapeutic effect of pioglitazone. Here we used our previously characterized transgenic mouse model of PPFP follicular thyroid carcinoma to identify PPFP binding sites in vivo using ChIP-seq, and to distinguish genes and pathways regulated directly or indirectly by PPFP with and without pioglitazone treatment via integration with RNA-seq data. PPFP bound to DNA regions containing the PAX8 and/or the PPARG motif, near genes involved in lipid metabolism, the cell cycle, apoptosis, and cell motility; the binding site distribution was highly concordant with our previous study in a rat PCCL3 cell line. Most strikingly, pioglitazone induced an immune cell infiltration including macrophages and T cells only in the presence of PPFP, which may be central to its therapeutic effect. PMID- 28008157 TI - The tumor-associated YB-1 protein: new player in the circadian control of cell proliferation. AB - Correct spatial and temporal control of cell proliferation is of fundamental importance for tissue homeostasis. Its deregulation has been associated with several pathological conditions. In common with almost every aspect of plant and animal biology, cell proliferation is dominated by day-night rhythms generated by the circadian clock. However, our understanding of the crosstalk between the core clock and cell cycle control mechanisms remains incomplete. In this study, using zebrafish as a vertebrate model system, we show that the nuclear localization of the Y-box binding protein 1 (YB-1), a regulator of cyclin expression and a hallmark of certain cancers, is robustly regulated by the circadian clock. We implicate clock-controlled changes in YB-1 SUMOylation as one of the mechanisms regulating its periodic nuclear entry at the beginning of the light phase. Furthermore, we demonstrate that YB-1 nuclear protein is able to downregulate cyclin A2 mRNA expression in zebrafish via its direct interaction with the cyclin A2 promoter. Thus, by acting as a direct target of cyclic posttranslational regulatory mechanisms, YB-1 serves as one bridge between the circadian clock and its cell cycle control. PMID- 28008158 TI - Similar outcomes between adenoid cystic carcinoma of the breast and invasive ductal carcinoma: a population-based study from the SEER 18 database. AB - Adenoid cystic carcinoma of the breast (breast-ACC) is a rare and indolent tumor with a good prognosis despite its triple-negative status. However, we observed different outcomes in the present study. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we enrolled a total of 89,937 eligible patients with an estimated 86 breast-ACC cases and 89,851 invasive ductal carcinoma (IDC) patients. In our study, breast-ACC among women presented with a higher proportion of triple-negative breast cancer (TNBC), which was more likely to feature well-differentiated tumors, rare regional lymph node involvement and greater application of breast-conserving surgery (BCS). Kaplan Meier analysis revealed that patients with breast-ACC and breast-IDC patients had similar breast cancer-specific survival (BCSS) and overall survival (OS). Moreover, using the propensity score matching method, no significant difference in survival was observed in matched pairs of breast-ACC and breast-IDC patients. Additionally, BCSS and OS did not differ significantly between TNBC-ACC and TNBC IDC after matching patients for age, tumor size, and nodal status. Further subgroup analysis of molecular subtype indicated improved survival in breast-ACC patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/Her2-) tumors compared to IDC patients with HR+/Her2- tumors. However, the survival of ACC-TNBC and IDC-TNBC patients was similar. In conclusion, ACCs have an indolent clinical course and result in similar outcomes compared to IDC. Understanding these clinical characteristics and outcomes will endow doctors with evidence to provide the same intensive treatment for ACC-TNBC as for IDC-TNBC and lead to more individualized and tailored therapies for breast ACC patients. PMID- 28008159 TI - A common CD55 rs2564978 variant is associated with the susceptibility of non small cell lung cancer. AB - CD55, as one of key membrane-bound complement-regulatory proteins (mCRPs), is crucial for the progression of various cancers. This study aims to investigate the role of CD55 variants in the development of non-small cell lung cancer (NSCLC). A case-control study, including 706 lung cancer cases and 706 health controls, was conducted in a Chinese population. The odds ratio (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression. We found that significantly higher lung cancer risk was linked with CD55 rs2564978 CC genotype (OR = 1.52, 95% CI = 1.11-2.07) or CT genotypes (OR = 1.34, 95% CI = 1.05-1.71), compared to the TT genotype. Stratified analysis showed that rs2564978 CC was associated with NSCLC risk among males (OR = 1.69, 95% CI = 1.14 2.49) and older subjects (OR = 1.75, 95% CI = 1.08-2.82). When stratified by smoking status, the risk effect of rs2564978 CC was more evident among smokers (OR = 2.01, 95% CI = 1.18-3.43) than non-smokers (OR = 1.30, 95% CI = 0.88-1.90). We also conducted the stratified analysis by NSCLC histological types and found that CD55 rs2564978 CC increased the risk of adenocarcinoma with OR (95% CI) of 1.35 (1.01-1.80). The reporter gene expression driven by rs2564978T-containing CD55 promoter was respectively 1.48-fold, 1.96-fold and 1.93-fold higher than those driven by the rs2564978C-containing CD55 promoter in A549, NCI-H2030 and NCI-H23 cells (P = 0.045, 0.010 and < 0.001). These findings indicate that CD55 rs2564978 polymorphism may contribute to an increased risk of NSCLC in Chinese population. PMID- 28008160 TI - Highly Expressed Integrin-alpha8 Induces Epithelial to Mesenchymal Transition Like Features in Multiple Myeloma with Early Relapse. AB - Despite recent groundbreaking advances in multiple myeloma (MM) treatment, most MM patients ultimately experience relapse, and the relapse biology is not entirely understood. To define altered gene expression in MM relapse, gene expression profiles were examined and compared among 16 MM patients grouped by 12 months progression-free survival (PFS) after autologous stem cell transplantation. To maximize the difference between prognostic groups, patients at each end of the PFS spectrum (the four with the shortest PFS and four with the longest PFS) were chosen for additional analyses. We discovered that integrin alpha8 (ITGA8) is highly expressed in MM patients with early relapse. The integrin family is well known to be involved in MM progression; however, the role of integrin-alpha8 is largely unknown. We functionally overexpressed integrin alpha8 in MM cell lines, and surprisingly, stemness features including HIF1alpha, VEGF, OCT4, and Nanog, as well as epithelial mesenchymal transition (EMT)-related phenotypes, including N-cadherin, Slug, Snail and CXCR4, were induced. These, consequently, enhanced migration and invasion abilities, which are crucial to MM pathogenesis. Moreover, the gain of integrin-alpha8 expression mediated drug resistance against melphalan and bortezomib, which are the main therapeutic agents in MM. The cBioPortal genomic database revealed that ITGA8 have significant tendency to co-occur with PDGFRA and PDGFRB and their mRNA expression were up-regulated in ITGA8 overexpressed MM cells. In summary, integrin-alpha8, which was up-regulated in MM of early relapse, mediates EMT-like phenotype, enhancing migration and invasion; therefore, it could serve as a potential marker of MM relapse and be a new therapeutic target. PMID- 28008161 TI - Baicalein Inhibits Epithelial to Mesenchymal Transition via Downregulation of Cyr61 and LOXL-2 in MDA-MB231 Breast Cancer Cells. AB - Epithelial-mesenchymal transition (EMT) is a critical step in the acquisition of the migratory and invasive capabilities associated with metastatic competence. Cysteine-rich protein 61 (CCN1/Cyr61) has been implicated as an important mediator in the proliferation and metastasis of breast cancer. Hence, Cyr61 and associated pathways are attractive targets for therapeutic interventions directed against the EMT. In the present study, we report that baicalein significantly inhibits the expression of Cyr61 and migration and invasion of MDA-MB231 human breast cancer cells. Exposure to baicalein led to increased E-cadherin expression, possibly due to the ubiquitination of Snail and Slug, which was mediated by the Cyr61/Akt/glycogen synthase kinase 3beta (GSK3beta) pathway. Further analysis revealed that baicalein inhibited the expression of lysyl oxidase like-2 (LOXL-2), which is a functional collaborator of Snail and Slug, and subsequently attenuated the direct interaction between LOXL-2 and Snail or Slug, thereby enhancing GSK3beta-dependent Snail and Slug degradation. Our findings provide new insights into the antimetastatic mechanism of baicalein and may contribute to its beneficial use in breast cancer therapies. PMID- 28008162 TI - Endoscopic Approach for Major Complications of Bariatric Surgery. AB - As lifestyle and diet patterns have become westernized in East Asia, the prevalence of obesity has rapidly increased. Bariatric surgeries, such as Roux-en Y gastric bypass (RYGB), sleeve gastrectomy (SG), and laparoscopic adjustable gastric banding (LAGB), are considered the first-line treatment option in patients with severe obesity. However, postoperative complications have increased and the proper management of these complications, including the use of endoscopic procedures, has become important. The most serious complications, such as leaks and fistulas, can be treated with endoscopic stent placement and injection of fibrin glue, and a novel full-thickness closure over-the-scope clip (OTSC) has been used for treatment of postoperative leaks. Stricture at the gastrojejunal (GJ) anastomosis site after RYGB or incisura angularis in SG can be managed using stents or endoscopic balloon dilation. Dilation of the GJ anastomosis or gastric pouch may lead to failure of weight loss, and the use of endoscopic sclerotherapy, novel endoscopic suturing devices, and OTSCs have been attempted. Intragastric migration of the gastric band can be successfully treated using various endoscopic tools. Endoscopy plays a pivotal role in the management of post-bariatric complications, and close cooperation between endoscopists and bariatric surgeons may further increase the success rate of endoscopic procedures. PMID- 28008164 TI - Fluoroscopy-Guided Endoscopic Removal of Foreign Bodies. AB - In most cases of ingested foreign bodies, endoscopy is the first treatment of choice. Moreover, emergency endoscopic removal is required for sharp and pointed foreign bodies such as animal or fish bones, food boluses, and button batteries due to the increased risks of perforation, obstruction, and bleeding. Here, we presented two cases that needed emergency endoscopic removal of foreign bodies without sufficient fasting time. Foreign bodies could not be visualized by endoscopy due to food residue; therefore, fluoroscopic imaging was utilized for endoscopic removal of foreign bodies in both cases. PMID- 28008163 TI - Risk Factors for the Presence of Symptoms in Peptic Ulcer Disease. AB - BACKGROUND/AIMS: Peptic ulcer disease (PUD) is a common condition, but is difficult to detect in asymptomatic individuals. We aimed to investigate the prevalence of symptomatic and asymptomatic PUD during screening endoscopy and to identify risk factors for the presence of symptoms in patients with PUD. METHODS: We investigated subjects who underwent a health inspection, including endoscopy of the upper gastrointestinal (GI) tract and a serum anti-Helicobacter pylori IgG assay, and who completed a self-report questionnaire about their symptoms. RESULTS: Of the 12,852 subjects included in the study, 124 (1.0%) had symptomatic PUD and 309 (2.4%) had asymptomatic PUD. Old age, current smoking, and H. pylori infection were independent risk factors for symptomatic and asymptomatic PUD. Use of non-steroidal anti-inflammatory drugs (NSAIDs) was an independent risk factor only for symptomatic PUD (p=0.040). Compared to subjects with asymptomatic PUD, subjects with symptomatic PUD were more likely to have active-stage ulcers (p=0.002) and to drink more heavily (p=0.005). CONCLUSIONS: Use of NSAIDs is a risk factor for symptomatic PUD, but not for asymptomatic PUD. Excessive alcohol consumption and active-stage ulcers in patients with PUD are related to the presence of gastroduodenal symptoms. PMID- 28008165 TI - Tuberculous Meningitis in an Immunocompetent Host: A Case Report. AB - BACKGROUND Tuberculous meningitis is very rare in the United States in immunocompetent hosts. Risk factors are similar to those of pulmonary tuberculosis, including poverty, malnutrition, overcrowding, a compromised immune system, and coming from an endemic area. Meningeal tuberculosis mortality and other outcomes have changed little over time despite effective therapies due to delay in diagnosis because of its rarity, variable presentation, and often indolent course. CASE REPORT We describe a case of a 57-year-old male immigrant from Senegal with no significant past medical history and no previous history of tuberculosis or evidence of immune compromise. He presented to the hospital with headache and altered mental status and was subsequently diagnosed with tuberculous meningitis. CONCLUSIONS This is a rare case of tuberculous meningitis in an immunocompetent host, questioning the conventional view that tuberculous meningitis is a disease of immunocompromised individuals. It emphasizes the importance of maintaining a strong clinical suspicion of tuberculous meningitis even in an immunocompetent patient in a geographical area with low prevalence if the patient has risk factors. Missed or delayed diagnosis is commonly fatal. PMID- 28008166 TI - Effect of Fu-Zheng-Xiao-Liu Granules on Expression of Human Epidermal Growth Factor Receptor 2 (HER-2) and Proliferation and Apoptosis of Breast Cancer Cell Line SKBR-3. AB - BACKGROUND Previous research showed that granulized Fu-Zheng-Xiao-Liu has a significant effect on breast cancer. However, it remains unclear whether HER-2 plays a role in this anti-cancer effect. MATERIAL AND METHODS Serum of male SD rats administered Fu-Zheng-Xiao-Liu granules (SF) was prepared and used to treat HER-2 positive breast cancer cell line SKBR-3. PBS and herceptin were used as negative and positive controls, respectively. MTT was used to detect the proliferation of SKBR-3 cells. Flow cytometry was used to measure the apoptosis of SKBR-3 cells. Western blot and immunofluorescence were used to measure the expression change of HER-2. RESULTS Serum of male SD rats administered Fu-Zheng Xiao-Liu granules had significantly reduced HER-2 expression at both mRNA level and protein level, significantly inhibited proliferation of SKBR-3 cells, and significantly increased apoptosis of SKBR-3 cells, compared to that of the blank control group or serum control group. CONCLUSIONS Fu-Zheng-Xiao-Liu granules affect proliferation and apoptosis through inhibition of HER-2 transcription and translation, providing an experimental basis for further study of the mechanism by which Fu-Zheng-Xiao-Liu granules affect breast cancer. PMID- 28008167 TI - Corrigendum: Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages. PMID- 28008170 TI - Body fat evolution as predictor of retinal microvasculature in children. AB - OBJECTIVES: Microvascular changes may represent an underlying mechanism through which overweight contributes to cardiovascular disease development. Therefore, the aim of this study was to investigate whether changes in children's body fat over time are associated with the retinal microvasculature, a marker of cardiovascular aging. METHODS: In a longitudinal design, 171 healthy Flemish children (53.8% boys) were followed-up for 7 years (2008-2015), aged 2.7-8.1 years at baseline.Z-scores of body mass index (zBMI; 4.1% overweight), waist circumference (zWC) and fat mass index (zFMI by BODPOD) were obtained using standardized protocols during each visit. Retinal arteriolar (central retinal arteriolar equivalent (CRAE)) and venular equivalents (central retinal venular equivalent (CRVE)) were measured from digital retinal photographs (2015) using IVAN software. Cross-sectional and longitudinal associations between changes in body fat and retinal microvasculature were explored using multivariable regression analysis, while controlling for age, sex, mean arterial pressure, alternate retinal caliber, physical activity, diet and birth weight. RESULTS: In cross-sectional analysis, children with high zFMI had a higher CRVE, but only in boys (beta=0.25, P=0.02). In addition, boys with high zFMI had also a lower CRAE to CRVE ratio (beta=-0.26, P=0.03). No associations were seen with the CRAE, or between zBMI or zWC and the retinal microvasculature. Only changes in zFMI over time were found to be positively associated with the CRVE in boys (beta=0.38, P=0.01). CONCLUSIONS: Our analysis over a 7-year period shows that changes in body fat during childhood are already associated with the CRVE (especially in boys). PMID- 28008168 TI - Cornerstones of CRISPR-Cas in drug discovery and therapy. AB - The recent development of CRISPR-Cas systems as easily accessible and programmable tools for genome editing and regulation is spurring a revolution in biology. Paired with the rapid expansion of reference and personalized genomic sequence information, technologies based on CRISPR-Cas are enabling nearly unlimited genetic manipulation, even in previously difficult contexts, including human cells. Although much attention has focused on the potential of CRISPR-Cas to cure Mendelian diseases, the technology also holds promise to transform the development of therapies to treat complex heritable and somatic disorders. In this Review, we discuss how CRISPR-Cas can affect the next generation of drugs by accelerating the identification and validation of high-value targets, uncovering high-confidence biomarkers and developing differentiated breakthrough therapies. We focus on the promises, pitfalls and hurdles of this revolutionary gene-editing technology, discuss key aspects of different CRISPR-Cas screening platforms and offer our perspectives on the best practices in genome engineering. PMID- 28008171 TI - Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype. AB - BACKGROUND/OBJECTIVE: Futile substrate cycling based on lipolytic release of fatty acids (FA) from intracellular triacylglycerols (TAG) and their re esterification (TAG/FA cycling), as well as de novo FA synthesis (de novo lipogenesis (DNL)), represent the core energy-consuming biochemical activities of white adipose tissue (WAT). We aimed to characterize their roles in cold-induced thermogenesis and energy homeostasis. METHODS: Male obesity-resistant A/J and obesity-prone C57BL/6J mice maintained at 30 degrees C were exposed to 6 degrees C for 2 or 7 days. In epididymal WAT (eWAT), TAG synthesis and DNL were determined using in vivo 2H incorporation from 2H2O into tissue TAG and nuclear magnetic resonance spectroscopy. Quantitative real-time-PCR and/or immunohistochemistry and western blotting were used to determine the expression of selected genes and proteins in WAT and liver. RESULTS: The mass of WAT depots declined during cold exposure (CE). Plasma levels of TAG and non-esterified FA were decreased by day 2 but tended to normalize by day 7 of CE. TAG synthesis (reflecting TAG/FA cycle activity) gradually increased during CE. DNL decreased by day 2 of CE but increased several fold over the control values by day 7. Expression of genes involved in lipolysis, glyceroneogenesis, FA re esterification, FA oxidation and mitochondrial biogenesis in eWAT was induced during CE. All these changes were more pronounced in obesity-resistant A/J than in B6 mice and occurred in the absence of uncoupling protein 1 in eWAT. Expression of markers of glyceroneogenesis in eWAT correlated negatively with hepatic FA synthesis by day 7 in both strains. Leptin and fibroblast growth factor 21 plasma levels were differentially affected by CE in the two mouse strains. CONCLUSIONS: Our results indicate integrated involvement of (i) TAG/FA cycling and DNL in WAT, and (ii) hepatic very-low-density lipoprotein-TAG synthesis in the control of blood lipid levels and provision of FA fuels for thermogenesis in cold. They suggest that lipogenesis in WAT contributes to a lean phenotype. PMID- 28008169 TI - Advances in islet encapsulation technologies. AB - Type 1 diabetes is an autoimmune disorder in which the immune system attacks and destroys insulin-producing islet cells of the pancreas. Although islet transplantation has proved to be successful for some patients with type 1 diabetes, its widespread use is limited by islet donor shortage and the requirement for lifelong immunosuppression. An encapsulation strategy that can prevent the rejection of xenogeneic islets or of stem cell-derived allogeneic islets can potentially eliminate both of these barriers. Although encapsulation technology has met several challenges, the convergence of expertise in materials, nanotechnology, stem cell biology and immunology is allowing us to get closer to the goal of encapsulated islet cell therapy for humans. PMID- 28008172 TI - Association of maternal serum 25-hydroxyvitamin D concentrations in second and third trimester with risk of gestational diabetes and other pregnancy outcomes. AB - OBJECTIVES: To evaluate the maternal serum 25(OH)D concentrations and its association with gestational diabetes and other pregnancy outcomes.zMethods:In our nested case-control study, 4718 pregnancy women were included, who were attending second- and third-trimester screening in Nanjing, China. Serum 25(OH)D concentrations were tested by enzyme-linked immunoassay, and the pregnancy and birth outcomes were obtained via electronic medical record collection and information extraction. The associations of 25(OH)D concentrations with gestational diabetes and other pregnancy outcomes were assessed by logistic regression analysis. And receiver-operator characteristic curve analysis was also conducted. RESULTS: For the total population, the median (IQR) concentrations of 25(OH)D was 43.7 (35.5-57.9) nmol l-1, and 63.1% of women had concentrations <50.0 nmol l-1. The 25(OH)D concentrations was significantly lower in gestational diabetes patients than in controls. Moreover, after adjustment for confounders, women with low 25(OH)D concentrations had significantly increased risks of gestational diabetes and some adverse pregnancy outcomes (anemia, macrosomia, abnormal amniotic fluid, and miscarriage or stillbirth). We also observed a threshold for 25(OH)D of 50.0 nmol l-1 for gestational diabetes and a nice predictive accuracy of the 25(OH)D concentrations included panel, with an area under the curve of 0.625 for gestational diabetes. CONCLUSIONS: Low 25(OH)D concentrations (<50.0 nmol l-1) in pregnancy was significantly associated with gestational diabetes risk, and it may serve as biomarkers for the surveillance of high-risk pregnant women. PMID- 28008173 TI - Development of a high-density genetic linkage map and identification of flowering time QTLs in adzuki bean (Vigna angularis). AB - A high-density linkage map is crucial for the identification of quantitative trait loci (QTLs), positional cloning, and physical map assembly. Here, we report the development of a high-density linkage map based on specific length amplified fragment sequencing (SLAF-seq) for adzuki bean and the identification of flowering time-related QTLs. Through SLAF library construction and Illumina sequencing of a recombinant inbred line (RIL) population, a total of 4425 SLAF markers were developed and assigned to 11 linkage groups (LGs). After binning the SLAF markers that represented the same genotype, the final linkage map of 1628.15 cM contained 2032 markers, with an average marker density of 0.80 cM. Comparative analysis showed high collinearity with two adzuki bean physical maps and a high degree of synteny with the reference genome of common bean (Phaseolus vulgaris). Using this map, one major QTL on LG03 and two minor QTLs on LG05 associated with first flowering time (FLD) were consistently identified in tests over a two-year period. These results provide a foundation that will be useful for future genomic research, such as identifying QTLs for other important traits, positional cloning, and comparative mapping in legumes. PMID- 28008174 TI - Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis. AB - In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival 1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival 2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200 mg/m2 and ASCT (MEL200-ASCT) and 261 to CC+R. Median follow-up was 46 months. MEL200-ASCT significantly improved PFS1 (median: 42 vs 24 months, HR 0.53; P<0.001), PFS2 (4 years: 71 vs 54%, HR 0.53, P<0.001) and OS (4 years: 84 vs 70%, HR 0.51, P<0.001) compared with CC+R. The advantage was noticed in good and bad prognosis patients. Only 53% of patients relapsing from CC+R received ASCT at first relapse. Upfront ASCT significantly reduced the risk of death (HR 0.51; P=0.007) in comparison with salvage ASCT. In conclusion, these data confirm the role of upfront ASCT as the standard approach for all young myeloma patients. PMID- 28008175 TI - CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D. PMID- 28008176 TI - Trends in overall survival and costs of multiple myeloma, 2000-2014. AB - Little real-world evidence is available to describe the recent trends in treatment costs and outcomes for patients with multiple myeloma (MM). Using the Truven Health MarketScan Research Databases linked with social security administration death records, this study found that the percentage of MM patients using novel therapy continuously increased from 8.7% in 2000 to 61.3% in 2014. Compared with MM patients diagnosed in earlier years, those diagnosed after 2010 had higher rates of novel therapy use and better survival outcomes; patients diagnosed in 2012 were 1.25 times more likely to survive 2 years than those diagnosed in 2006. MM patients showed improved survival over the study period, with the 2-year survival gap between MM patients and matched controls decreasing at a rate of 3% per year. Total costs among MM patients have increased in all healthcare services over the years; however, the relative contribution of drug costs has remained fairly stable since 2009 despite new novel therapies coming to market. Findings from this study corroborate clinical data, suggesting a paradigm shift in MM treatment over the past decade that is associated with substantial survival gains. Future studies should focus on the impact on specific novel agents on patients' outcomes. PMID- 28008177 TI - Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. AB - Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a common phenomenon of JAK2 hyperactivation. JAK2 has the potential to activate multiple other signaling molecules, either directly through downstream effectors, or indirectly through induction of target gene expression. We have interrogated myeloproliferative signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) patient samples using mass cytometry, which allows the quantitative measurement of multiple signaling molecules simultaneously at the single-cell level, in cell populations representing a nearly complete spectrum of hematopoiesis. MF and sAML malignant cells demonstrated a high prevalence of hyperactivation of the JAK-STAT, MAP kinase, PI3 kinase and NFkappaB signaling pathways. Constitutive NFkappaB signaling was evident across MF and sAML patients. A supporting gene set enrichment analysis (GSEA) of MF showed many NFkappaB target genes to be expressed above normal levels in MF patient CD34+ cells. NFkappaB inhibition suppressed colony formation from MF CD34+ cells. This study indicates that NFkappaB signaling contributes to human myeloproliferative disease and is abnormally activated in MF and sAML. PMID- 28008179 TI - Resolving the cadherin-F-actin connection. AB - Cadherin adhesion complexes have recently emerged as sensors of tissue tension that regulate key developmental processes. Super-resolution microscopy experiments now unravel the spatial organization of the interface between cadherins and the actin cytoskeleton and reveal how vinculin, a central component in cadherin mechanotransduction, is regulated by mechanical and biochemical signals. PMID- 28008178 TI - Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma. AB - The PIM kinase family (PIM1, 2 and 3) have a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2's role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. Treatment with JP11646 in xenogeneic myeloma murine models demonstrated significant reduction in tumor burden and increased median survival. Altogether our findings suggest the existence of previously unrecognized feedback loop(s) where PIM2 kinase activity regulates PIM2 gene expression in malignant cells, and that JP11646 represents a novel class of PIM2 inhibitors that interdicts this feedback. PMID- 28008180 TI - Y chromothripsis? AB - Micronucleation of missegregated chromatin can lead to substantial chromosome rearrangements via chromothripsis. However, the molecular details of micronucleus based chromothripsis are still unclear. Now, an elegant system that specifically induces missegregation of the Y chromosome provides insight into this process, including a role for non-homologous end joining. PMID- 28008181 TI - Haematopoietic stem cells show their true colours. AB - Delineating the behaviour of haematopoietic stem cells (HSCs) in vivo has thus far proven challenging. Two studies in zebrafish and mouse models now track HSCs in vivo using fate mapping with multicolour approaches to provide further insights into clonal events that regulate blood development, HSC function and differentiation during homeostasis and stress conditions. PMID- 28008182 TI - Corrigendum: Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. PMID- 28008183 TI - Retraction: G9a/RelB regulates self-renewal and function of colon-cancer initiating cells by silencing Let-7b and activating the K-RAS/beta-catenin pathway. PMID- 28008185 TI - T cells: Sorting memories. PMID- 28008186 TI - Reproductive immunology: B cells, be shells? PMID- 28008187 TI - The millimeter IRAM-30 m line survey toward IK Tau. AB - AIMS: We aim to investigate the physical and chemical properties of the molecular envelope of the oxygen-rich AGB star IK Tau. METHODS: We carried out a millimeter wavelength line survey between ~79 and 356 GHz with the IRAM-30 m telescope. We analysed the molecular lines detected in IK Tau using the population diagram technique to derive rotational temperatures and column densities. We conducted a radiative transfer analysis of the SO2 lines, which also helped us to verify the validity of the approximated method of the population diagram for the rest of the molecules. RESULTS: For the first time in this source we detected rotational lines in the ground vibrational state of HCO+, NS, NO, and H2CO, as well as several isotopologues of molecules previously identified, namely, C18O, Si17O, Si18O, 29SiS, 30SiS, Si34S, H13CN, 13CS, C34S, H234S, 34SO, and 34SO2. We also detected several rotational lines in vibrationally excited states of SiS and SiO isotopologues, as well as rotational lines of H2O in the vibrationally excited state nu2=2. We have also increased the number of rotational lines detected of molecules that were previously identified toward IK Tau, including vibrationally excited states, enabling a detailed study of the molecular abundances and excitation temperatures. In particular, we highlight the detection of NS and H2CO with fractional abundances of f(NS)~10-8 and f(H2CO)~[10-7-10-8 ]. Most of the molecules display rotational temperatures between 15 and 40 K. NaCl and SiS isotopologues display rotational temperatures higher than the average (~65 K). In the case of SO2 a warm component with Trot~290 K is also detected. CONCLUSIONS: With a total of ~350 lines detected of 34 different molecular species (including different isotopologues), IK Tau displays a rich chemistry for an oxygen-rich circumstellar envelope. The detection of carbon bearing molecules like H2CO, as well as the discrepancies found between our derived abundances and the predictions from chemical models for some molecules, highlight the need for a revision of standard chemical models. We were able to identify at least two different emission components in terms of rotational temperatures. The warm component, which is mainly traced out by SO2, is probably arising from the inner regions of the envelope (at ?8R*) where SO2 has a fractional abundance of f(SO2)~10-6. This result should be considered for future investigation of the main formation channels of this, and other, parent species in the inner winds of O-rich AGB stars, which at present are not well reproduced by current chemistry models. PMID- 28008184 TI - The control of DNA repair by the cell cycle. AB - The correct duplication and transmission of genetic material to daughter cells is the primary objective of the cell division cycle. DNA replication and chromosome segregation present both challenges and opportunities for DNA repair pathways that safeguard genetic information. As a consequence, there is a profound, two way connection between DNA repair and cell cycle control. Here, we review how DNA repair processes, and DNA double-strand break repair in particular, are regulated during the cell cycle to optimize genomic integrity. PMID- 28008188 TI - ALMA high spatial resolution observations of the dense molecular region of NGC 6302. AB - CONTEXT: The mechanism behind the shaping of bipolar planetary nebulae is still poorly understood. It is becoming increasingly clear that the main agents must operate at their innermost regions, where a significant equatorial density enhancement should be present and related to the collimation of light and jet launching from the central star preferentially towards the polar directions. Most of the material in this equatorial condensation must be lost during the asymptotic giant branch as stellar wind and later released from the surface of dust grains to the gas phase in molecular form. Accurately tracing the molecule rich regions of these objects can give valuable insight into the ejection mechanisms themselves. AIMS: We investigate the physical conditions, structure and velocity field of the dense molecular region of the planetary nebula NGC 6302 by means of ALMA band 7 interferometric maps. METHODS: The high spatial resolution of the 12CO and 13CO J=3-2 ALMA data allows for an analysis of the geometry of the ejecta in unprecedented detail. We built a spatio-kinematical model of the molecular region with the software SHAPE and performed detailed non LTE calculations of excitation and radiative transfer with the shapemol plug-in. RESULTS: We find that the molecular region consists of a massive ring out of which a system of fragments of lobe walls emerge and enclose the base of the lobes visible in the optical. The general properties of this region are in agreement with previous works, although the much greater spatial resolution of the data allows for a very detailed description. We confirm that the mass of the molecular region is 0.1 M?. Additionally, we report a previously undetected component at the nebular equator, an inner, younger ring inclined ~60 degrees with respect to the main ring, showing a characteristic radius of 7.5*1016 cm, a mass of 2.7*10-3 M?, and a counterpart in optical images of the nebula. This inner ring has the same kinematical age as the northwest optical lobes, implying it was ejected approximately at the same time, hundreds of years after the ejection of the bulk of the molecular ring-like region. We discuss a sequence of events leading to the formation of the molecular and optical nebulae, and briefly speculate on the origin of this intriguing inner ring. PMID- 28008189 TI - German-Japanese relationships in biochemistry: a personal perspective. AB - The first Institute of Biochemistry in Japan was founded by Leonor Michaelis from Berlin at Nagoya in 1922, and there have been numerous interrelations between Japanese and German biochemists since. Some such relationships are presented here from a personal point of view as one illustrative example, which could be extended amply by the experience of many other scientists from the two countries. Fruitful exchanges are facilitated by organisations such as the Alexander von Humboldt Foundation (AvH) and the Deutscher Akademischer Austauschienst (DAAD) or the Japanese Society for the Promotion of Science (JSPS) and by the many bilateral agreements between universities and research institutions. PMID- 28008190 TI - Central diabetes insipidus. AB - Central diabetes insipidus (CDI), characterized by polyuria and polydipsia, is caused by deficiency of arginine vasopressin (AVP), an antidiuretic hormone which acts on V2 receptors in kidney to promote reabsorption of free water. CDI is classified into three subtypes; idiopathic, secondary and familial. A previous study suggests that infundibulo-neurohypophysitis might be an underlying cause of idiopathic CDI. Among secondary CDI, the tumors in the central nervous system such as craniopharyngioma and germ cell tumors are the most frequent causes. Familial CDI is inherited mostly in an autosomal dominant mode, and the number of causal mutations in the AVP gene locus reported so far exceeds 80. CDI is treated with desmopressin, an analogue of vasopressin, and the tablet is preferred to the nasal form because it is easier to administer. It is also shown that the oral disintegrating tablet formula increases QOL and decreases the incidence of hyponatremia in CDI patients. In some CDI patients, the osmoreceptors in the hypothalamus do not function and patients do not sense thirst. These adipsic CDI patients are treated with desmopressin and adjusting the amount of daily water intake based on body weight measurement; but controlling the water balance is extremely difficult, and morbidity and mortality are shown to be high in these patients. PMID- 28008191 TI - Abnormal urinalysis on day 7 in patients with IgA vasculitis (Henoch-Schonlein purpura). AB - Rare progression to renal failure imposes a burden on children with IgA vasculitis (Henoch-Schonlein purpura, HSP). An abnormal urinalysis on day 7 (7d UA) may be a surrogate marker for persistent nephritis, but this has not been established. We retrospectively analyzed the risk factors for persistent nephritis in a cohort of 138 children. Of 35 children with abnormal 7d-UA, 24 (69%) had an abnormal urinalysis 6 months after the diagnosis of HSP, which was significantly more than 6 of 103 children (6%) with normal 7d-UA (P < 0.0001). The negative predictive values for normal urinalysis and negative proteinuria 6 months after diagnosis were 0.94 (95% confidence interval [CI], 0.90-0.97) and 0.98 (95% CI, 0.95-0.99), respectively. When children with abnormal urinalysis 6 months after diagnosis were compared with those without, the following factors were significantly associated: age at diagnosis, abnormal urinalysis at diagnosis, abnormal 7d-UA, complement C3, steroid treatment, and presence of abdominal pain. However, multivariate analysis revealed that abnormal 7d-UA was the only significant risk factor for abnormal urinalysis 6 months after diagnosis (odds ratio 54.3, 95% CI 15.3-275, P = 1.89 * 10-6). Abnormal 7d-UA may be an independent risk factor for persistent nephritis, but this should be confirmed in a prospective study. PMID- 28008192 TI - The long-term results and changing patterns of biological valves at the mitral position in contemporary practice in Japan. AB - Mitral valve surgery has changed with the wide acceptance of mitral valve repair. The aim of this study is to obtain the long-term results of patients who underwent mitral valve replacement (MVR) using a biological prosthesis in contemporary practice in Japan. From January 1990 to December 2013, 76 patients underwent MVR using a biological prosthesis with or without concomitant surgery. Data were obtained by means of a questionnaire and a telephone interview. The mean follow-up period was 4.26 years. The etiologies of the patients included dilated cardiomyopathy (DCM) (n=20 [26.3%]), ischemic mitral regurgitation (n=7 [9.2%]). There is a trend towards decreasing number of rheumatic and degenerative disease and increasing number of DCM and ischemic mitral regurgitation. Three patients (3.9%) died in the perioperative period. The 5- and 10-year overall survival rates were 69.6% and 31.7%, respectively. The 5- and 10-year freedom from valve related death were 95.6% and 80.6 %, respectively. The linearized rates of valve-related complications were as follows: thromboembolism (0.63%/patient/year), bleeding (1.25%/patient/year). One patient underwent reoperation for structural degeneration 13 years after the first operation. The present study shows the long-term results of mitral valve replacement with bioproshtesis in a contemporary case series. The practice pattern is changing. The low rate of valve-related complication justify the current patient selection. PMID- 28008193 TI - Associations between proteinuria and cardiovascular risk factors among hypertensive patients in Andkhoy, Afghanistan. AB - Proteinuria in hypertension is an early marker of renal disease and a predictor for the progression of end stage renal disease, and cardiovascular diseases. This study was designed to determine the prevalence of proteinuria and its association with cardiovascular risk factors among adult hypertensive patients in Afghanistan. Five hundred fifty-five patients with a high blood pressure recorded in an outpatient clinic in Andkhoy, Afghanistan from December 2014 to May 2015, were included in this study. Data obtained from each patient, included demographic characteristics, body mass index, blood pressure patterns, cardiovascular history, cardiovascular risk factors, comorbidity, and current drug-therapy. Dipstick screening for proteinuria was performed with reagent test strips. The mean age of the patients was 57.9 +/- 13.3 years, and a female predominance was observed (n = 333, 60%). The prevalence of proteinuria was 67.2%. The predictors of proteinuria were found to be age >=65 years (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04), smoking (OR 1.88, 95% CI 1.17 3.02), heart failure (OR 2.23, 95% CI 1.13-4.41), and diabetes mellitus (OR 3.41, 95% CI 1.49-7.81). In conclusion, this study shows that proteinuria is highly prevalent among hypertensive outpatients in an outpatient clinic in Andkhoy, Afghanistan, especially in those with high cardiovascular risk. PMID- 28008194 TI - Role of courtyard counselling meeting in improving household food safety knowledge and practices in Munshiganj district of Bangladesh. AB - Unsafe food is linked to the deaths of an estimated two million people annually. Food containing harmful agents is responsible for more than 200 diseases ranging from diarrhoea to cancers. A one-sample pilot intervention study was conducted to evaluate the role of courtyard counselling meetings as the means of intervention for improving food safety knowledge and practices among household food handlers in a district of Bangladesh. The study was conducted in three phases: a baseline survey, the intervention and an end-line survey between April and November 2015 where 194 food handlers took part. Data were collected through observations and face-to-face interviews. The mean age of the respondents was 38.8 (+/-12.4) years, all of whom were females. Hand washing before eating, and washing utensils with soap were significantly improved at the end-line in comparison to the baseline (57% vs. 40% and 83% vs. 69%, respectively). Hand washing with soap was increased by 4%. The mean score of food handling practices was significantly increased after the intervention (20.5 vs. 22.1; P<0.001). However, hand washing after use of toilet was unchanged after the intervention (75% vs.76%). Knowledge about safe food and the necessity of thorough cooking were significantly increased after the intervention (88% from 64% and 34% from 21%, respectively). Mean scores of knowledge and practice on food safety were significantly increased by 1.9 and 1.6, respectively after the one month intervention. Thus this food safety education in rural communities should be scaled up and, indeed, strengthened using the courtyard counselling meetings in Bangladesh. PMID- 28008195 TI - A multicenter survey of stage T1 glottic cancer treated with radiotherapy delivered in 2.25-Gy fractions in clinical practice: An initial 5-year analysis. AB - The purpose of this study was to evaluate the acute and late toxicity as well as local control (LC) in T1 glottic cancer (GC) patients treated with hypofractionated radiotherapy (RT) in clinical practice. The Tokai Study Group for Therapeutic Radiology and Oncology started RT treatment with a dose of 2.25 Gy for T1 GC in 2011. Ten institutions combined data from 104 patients with T1 squamous cell carcinoma between 2011 and 2015. In total, 104 patients with T1 GC were irradiated with a standard radiation dose of 63 Gy in 28 fractions.The median follow-up duration was 18 (3.7-49.5) months. Acute grade 3 adverse events were observed in 7 patients, with 4 patients (5%) having dermatitis and 3 patients (4%) having mucositis. Late adverse events above grade 3 were not observed. Two patients developed local recurrence. The rates of acute adverse events in the present study were comparable to those in previous studies that have used 2 Gy fractions of RT. PMID- 28008196 TI - Clinical characteristics of primary peritoneal carcinoma patients: a single institution experience involving 8 patients. AB - Primary peritoneal carcinoma (PPC) is treated similarly to advanced epithelial ovarian carcinoma (aEOC); however, the standard approach for the management of PPC is controversial. The objective of this study was to evaluate the clinical features and prognosis of those patients. A retrospective analysis was performed of eight patients with PPC between January 2008 and December 2015. Clinicopathologic parameters, the diagnostic modality, treatment, and oncologic outcome were analyzed. The median age at the time of diagnosis was 72.5 years (range: 55-79), with a median follow-up of 26.5 months (range, 5-74). Most of the PPC developed with carcinomatosis peritonei involving ascites, while some cases developed sporadically in the peritoneal or extraperitoneal cavity without ascites. The most common initial symptom was abdominal fullness, and other symptoms were inguinal tumor, paralysis of the extremities, and respiratory disorder. The preoperative CA125 value was elevated in all patients. In four patients who did not undergo primary surgery, the final diagnoses were determined by the ascites cytology and radiological image. Initial or interval debulking surgery was performed in only two patients. All patients were treated with paclitaxel or docetaxel plus carboplatin. Five showed a complete response (CR), and one showed a partial response (PR). Among the five patients with CR, the median progression-free and overall survival periods were 15 (12-26) and 41.5 (32 74) months, respectively. Three patients without carcinomatosis peritonei showed a relatively favorable prognosis. The management of PPC is generally consistent with that of aEOC; however, in atypical cases, the treatment method should be considered individually. PMID- 28008197 TI - Associations of alcohol use with mental health and alcohol exposure among school going students in Cambodia. AB - The aim of this study was to examine the associations of alcohol use with sociodemographic factors, mental health and alcohol exposure among school-going adolescents in Cambodia. The analysis included 3,806 school children, mean age 15.7 years (SD=1.8), from Cambodia who participated in the "Global School-based Student Health Survey" (GSHS) in 2013. The results indicate that overall, 10.0% of the students reported current alcohol use, 10.8% lifetime drunkenness, and 2.8% problem drinking. In multivariate logistic regression analysis, sociodemographic factors (older age and being male), mental health and other variables (bullying victimization, OR (odds ratio) = 1.99; 95% Confidence Interval (CI) [1.50, 2.65] and OR = 2.15; 95% CI [1.58, 3.21], respectively; having attempted suicide, OR = 2.04; 95% CI [1.35, 3.08] and OR = 2.06; 95% CI [1.29, 3.28], respectively and illicit drug use, OR = 4.97; 95% CI [2.41, 10.24] OR = 5.05; 95% CI [2.14, 11.98], respectively) and alcohol exposure variables (peer influence on drinking alcohol, OR = 6.68; 95% CI [4.75, 9.39] and OR = 7.83; 95% CI [5.73, 10.66], respectively and daily or almost daily to alcohol advertising in the past 30 days OR = 1.61; 95% CI [1.03, 2.51] and OR = 2.30; 95% CI [1.40, 3.77], respectively) were significantly positively associated with current alcohol use and drunkenness. Moreover, older age, being male, bullying victimization, having close friends, suicide attempt, drug use, father or male guardian drinks alcohol and peer influence were associated with problem drinking. There is a need to implement public health interventions with a special focus on the determinants of alcohol consumption, including exposure to alcohol advertising, in this age group. PMID- 28008198 TI - Anticipated stigma in chronic illness patients in Cambodia, Myanmar and Vietnam. AB - The aim of this study was to explore the prevalence and relationship of anticipated chronic illness stigma among patients diagnosed with a variety of chronic diseases in three Southeast Asian countries (Cambodia, Myanmar and Vietnam). A cross-sectional survey was conducted in 4,803 adult chronic disease patients (mean age 49.3 years; SD=16.5) recruited systematically from health facilities. Overall, the results indicate that 20.7% of patients reported that for any of the 12 stigma items, they anticipated they were likely or very likely to experience chronic disease stigma. A multivariate analysis of sociodemographics revealed the following were associated with anticipated chronic disease stigma: older versus younger age, OR (odds ratio) = 0.71; 95% Confidence Interval (CI) [0.58, 0.87]; higher versus lower education, OR = 2.23; 95% CI [1.81, 2.75]; origin from Myanmar or Vietnam, being single, divorced or widowed, rural residence, and health status (having three or more chronic conditions versus having one chronic condition), OR = 1.93; 95% CI [1.58, 2.35]; lower versus higher quality of life, OR = 0.73; 95% CI [0.63, 0.85]); health risk behavior (physical inactivity, poor diet, current smoking, and problem drinking) and low versus medium or high medication adherence (OR = 0.69; 95% CI [0.55,0.86]). This study demonstrated the possible consequences of anticipated stigma on the health and behavior of people living with chronic diseases, and several factors for chronic disease stigma were identified that can help guide interventions to reduce chronic illness stigma in this population. PMID- 28008199 TI - Magnetic resonance imaging of cardiac sarcoidosis: an evaluation of the cardiac segments and layers that exhibit late gadolinium enhancement. AB - Cardiac sarcoidosis (CS) can cause sudden death, which is the leading cause of mortality in patients with sarcoidosis in Japan. However, it is difficult to diagnose CS because of the lack of a sensitive diagnostic method for the condition. Late gadolinium-enhanced cardiac magnetic resonance (MR) imaging demonstrates improved sensitivity for diagnosing CS. Therefore, it is important to know the late gadolinium-enhancement (LGE) characteristics of CS on cardiac MR images in order to diagnose CS accurately. In this study, we investigated the most common sites of LGE on cardiac MR images in CS. Late gadolinium-enhanced MR images of 9 consecutive patients with CS (obtained between August 2009 and July 2015) were reviewed by two radiologists. The distribution of LGE was evaluated using the American Heart Association 17-segment model of the left ventricle. The LGE in each segment was also classified into 4 patterns according to the myocardial layer in which it occurred (the subepicardial, subendocardial, intramural, and transmural layer patterns). All 9 patients exhibited LGE in their left ventricle, and 70 of 153 (46%) myocardial segments were enhanced. All of the patients displayed LGE in the basal septal wall. The patients' LGE layer patterns were as follows: subepicardial: 40% (28/70), intramural: 30% (21/70), subendocardial: 16% (11/70), and transmural: 14% (10/70). The basal septum wall and subepicardial layer often exhibit LGE on cardiac MR images in CS patients. LGE can be observed in other segments and layers in some cases. PMID- 28008200 TI - Comparing surgical outcomes of complete thoracoscopic lobectomy for congenital cystic lung disease between neonatal and infantile patients. AB - Thoracoscopic lobectomy has recently become a widely used surgical treatment for congenital cystic lung disease, but significant issues can arise in some cases, such as a limited working space in neonates, a limited view in cases involving large cystic lesions. We reviewed the treatment outcomes of neonates that underwent complete thoracoscopic lobectomy or segmentectomy and evaluated the operative difficulties. From January 2008 to October 2015, 38 patients under the age of 1 year underwent complete thoracoscopic lobectomy or segmentectomy for cystic lung disease at our institution. We compared the intra- and postoperative data of the neonate group (N group) with those of the infant group (I group). Fourteen and 24 patients underwent thoracoscopic lobectomy or segmentectomy in the N group and I group, respectively. The operative time and amount of intraoperative blood loss did not differ significantly between the two groups (p=0.694 and p=0.878, respectively), but the duration of the postoperative hospitalization period was significantly longer (p<0.01) in the N group. The frequencies of postoperative complications did not differ significantly between the two groups. The operative time of thoracoscopic lobectomy was significantly longer in cases involving incomplete lobar fissures than in those involving normal lobar fissures. Surgical outcomes of complete thoracoscopic lobectomy for neonatal cases are almost equivalent compared with infantile cases, and thoracoscopic lobectomy takes longer in cases involving incomplete lobar fissures. PMID- 28008201 TI - Active brain changes after initiating fingolimod therapy in multiple sclerosis patients using individual voxel-based analyses for diffusion tensor imaging. AB - Voxel-based analysis (VBA) of diffusion tensor images (DTI) and voxel-based morphometry (VBM) in patients with multiple sclerosis (MS) can sensitively detect occult tissue damage that underlies pathological changes in the brain. In the present study, both at the start of fingolimod and post-four months clinical remission, we assessed four patients with MS who were evaluated with VBA of DTI, VBM, and fluid-attenuated inversion recovery (FLAIR). DTI images for all four patients showed widespread areas of increased mean diffusivity (MD) and decreased fractional anisotropy (FA) that were beyond the high-intensity signal areas across images. After four months of continuous fingolimod therapy, DTI abnormalities progressed; in particular, MD was significantly increased, while brain volume and high-intensity signals were unchanged. These findings suggest that VBA of DTI (e.g., MD) may help assess MS demyelination as neuroinflammatory conditions, even though clinical manifestations of MS appear to be in complete remission during fingolimod. PMID- 28008202 TI - Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes. AB - MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of <=1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders. PMID- 28008203 TI - Prevalence and predictors of prediabetes and diabetes among adults in Palau: population-based national STEPS survey. AB - We aimed to investigate the prevalence and predictors of diabetes and prediabetes among adults in Palau. We used data of 1915 adults, aged 25 to 64 years, who participated in the World Health Organization's (WHO) STEPwise Approach to Risk Factor Surveillance (STEPS) study in Palau. Information on behavioral risk factors of NCDs and physical and biochemical measurements were obtained using standard methods of the WHO. The diagnosis of diabetes and prediabetes was based on the recent American Diabetes Association criteria. Predictors of the prevalence of diabetes and prediabetes were identified using multinomial logistic regression analysis. The overall age-standardized prevalence of prediabetes and diabetes were 40.4% (43.6% for men, 37.4% for women) and 17.7% (18.6% for men, 17% for women), respectively. Old age, overall obesity (high BMI), central obesity (large waist circumference or waist-hip ratio), hypertension and hypertriglyceridemia were significant predictors of prediabetes and/or diabetes. Diabetes occurred at a younger age in "obese" individuals than that of their "non obese" counterparts. We confirmed that prediabetes and diabetes are highly prevalent in Palau affecting 40% and 18% adults, respectively. Introducing public health interventions to reduce and prevent obesity as early as possible could prove useful to curb the problem. PMID- 28008204 TI - Novel and recurrent ATP2A2 mutations in Japanese patients with Darier's disease. AB - Darier's disease (DD, keratosis follicularis: OMIM#124200) is an autosomal dominant skin disorder characterized by multiple dark brown keratotic plaques and warty papules covered by thick crusts. Most cases of DD are caused by mutations in ATP2A2, which is expressed in both the skin and the brain. ATP2A2 encodes the cardiac muscle SERCA2a protein and the ubiquitously expressed SERCA2b. SERCA2 plays an important role as a calcium pump. It is thought that a mutation in ATP2A2 causes dyskeratosis and abnormality of cell-cell adhesion. Here, we report five DD patients from five independent families who presented or were referred to the Nagoya University Hospital in the past five years. We detected five mutations in ATP2A2, including a previously unreported mutation. We observed no apparent genotype/phenotype correlation between types and sites of the ATP2A2 mutations and DD phenotypes in the present series of DD patients. Genetic diagnosis from ATP2A2 mutation search is useful for the definite diagnosis of DD, although it is difficult to predict the severity and prognosis of skin symptoms from the results of the ATP2A2 mutation analysis in DD patients. PMID- 28008205 TI - Prevalence and correlates of perceived teeth health status and oral health behavior among school-going adolescents in Cambodia. AB - The purpose of the study was to investigate perceived teeth health status and oral health behavior, as well as their correlates, among adolescents in Cambodia. The analysis included 3806 Cambodian school children (mean age 15.7 years, SD=1.8 years) who took part in the "Global School-based Student Health Survey" (GSHS) in 2013. Overall, 7.8% of the students reported poor perceived teeth status, 18.0% had missed school in the past year because of a toothache, 26.7% engaged in combined oral health behavior (brushing teeth twice daily or more often = 79.8%, using fluoride toothpaste = 59.9%, and drinking soft drinks less than once a day = 53.6%), and 59.9% had never visited a dentist for a routine examination or other dental work. In the multivariate logistic regression analysis, older age, being female, missing school because of a toothache, having a toothache in the past 12 months, poor oral health behavior and sedentary leisure time were associated with poor perceived teeth status. Older age, good perceived teeth status, having had a dental check-up, washing hands before eating and after toilet use, and not eating fast food were associated with a positive oral health behavior (brushing teeth twice daily or more often, using fluoride toothpaste, and drinking soft drinks less than once a day). Significant proportions of poor perceived teeth status and poor oral health behavior were found among school children in Cambodia. Various risk factors (sociodemographic, dental variables, general health risk behaviors) for perceived poor teeth status, oral health behavior and never having had a dental check-up were identified, which can be utilized for intervention programs. PMID- 28008206 TI - Aggressive resection of frequent peritoneal recurrences in colorectal cancer contributes to long-term survival. AB - We report a long-term survivor of colorectal cancer who underwent aggressive, frequent resection for peritoneal recurrences. A 58-year-old woman was diagnosed with descending colon cancer. Resection of the descending colon along with lymph node dissection was performed in September 2006. The pathological findings revealed Stage IIA colorectal cancer. The following peritoneal recurrences were removed: two in July 2007, two in the omental fat and two in the pouch of Douglas in June 2008 resected by low anterior resection of the rectum, one in the uterus and right ovarian recurrence resected via bilateral adnexectomy and Hartmann's procedure in May 2011, and one in the ascending colon by partial resection of the colon wall in December 2011. Postoperative adjuvant chemotherapy (uracil and tegafur/leucovorin, fluorouracil/levofolinate/oxaliplatin/bevacizumab, 5 fluorouracil/leucovorin/bevacizumab, irinotecan/bevacizumab, and irinotecan/panitumumab) was administered. The patient did not desire postoperative adjuvant chemotherapy after the fourth operation. The long-term survival was 6 years and 7 months. PMID- 28008207 TI - What do we know about pulmonary blastoma?: review of literature and clinical case report. AB - Pulmonary blastoma (PB) is a rare form of lung tumour and is accountable for 0.25 0.5% of primary pulmonary malignancies. Initially pulmonary blastoma was divided into three subtypes: biphasic pulmonary blastoma (BPB) consisting of an epithelial and mesenchymal component, well differentiated fetal adenocarcinoma (WDFA) built of well differentiated epithelium and a mesenchymal component and malignant pleuropulmonary blastoma (PPB). Prognosis in this type of cancer is really poor. We present a current review of literature and a clinical case report. Treatment of PB is very difficult. Data and recommendations about the treatment of pulmonary blastoma are still available therefore we should use only observations and clinical case reports. PMID- 28008208 TI - Ruptured partially thrombosed anterior inferior cerebellar artery aneurysms: two case reports and review of literature. AB - Aneurysms arising from the distal anterior inferior cerebellar artery (AICA) are very rare. When the parent artery is an AICA-posterior inferior cerebellar artery (PICA) variant, occlusion of the artery, even distal to the meatal loop, leads to a significant area of cerebellar infarction. We report two cases of ruptured partially thrombosed distal AICA aneurysms. In both cases, the parent artery was an AICA-PICA variant. The aneurysms were clipped in one case and trapped following occipital artery (OA)-AICA anastomosis in another case. It is important to keep the OA as a donor artery for revascularization in the treatment of the AICA-PICA variant aneurysms, especially when the absence of intra-aneurysmal thrombus is not comfirmed preoperatively. PMID- 28008210 TI - Identification and Estimation of Causal Mechanisms in Clustered Encouragement Designs: Disentangling Bed Nets using Bayesian Principal Stratification. AB - Exploration of causal mechanisms is often important for researchers and policymakers to understand how an intervention works and how it can be improved. This task can be crucial in clustered encouragement designs (CED). Encouragement design studies arise frequently when the treatment cannot be enforced because of ethical or practical constrains and an encouragement intervention (information campaigns, incentives, etc) is conceived with the purpose of increasing the uptake of the treatment of interest. By design, encouragements always entail the complication of non-compliance. Encouragements can also give rise to a variety of mechanisms, particularly when encouragement is assigned at cluster level. Social interactions among units within the same cluster can result in spillover effects. Disentangling the effect of encouragement through spillover effects from that through the enhancement of the treatment would give better insight into the intervention and it could be compelling for planning the scaling-up phase of the program. Building on previous works on CEDs and non-compliance, we use the principal stratification framework to define stratum-specific causal effects, that is, effects for specific latent subpopulations, defined by the joint potential compliance statuses under both encouragement conditions. We show how the latter stratum-specific causal effects are related to the decomposition commonly used in the literature and provide flexible homogeneity assumptions under which an extrapolation across principal strata allows one to disentangle the effects. Estimation of causal estimands can be performed with Bayesian inferential methods using hierarchical models to account for clustering. We illustrate the proposed methodology by analyzing a cluster randomized experiment implemented in Zambia and designed to evaluate the impact on malaria prevalence of an agricultural loan program intended to increase the bed net coverage. Farmer households assigned to the program could take advantage of a deferred payment and a discount in the purchase of new bed nets. Our analysis shows a lack of evidence of an effect of the offering of the program to a cluster of households through spillover effects, that is through a greater bed net coverage in the neighborhood. PMID- 28008209 TI - Paradigm Shifts in Ophthalmic Diagnostics. AB - PURPOSE: Future advances in ophthalmology will see a paradigm shift in diagnostics from a focus on dysfunction and disease to better measures of psychophysical function and health. Practical methods to define genotypes will be increasingly important and non-invasive nanotechnologies are needed to detect molecular changes that predate histopathology. METHODS: This is not a review nor meant to be comprehensive. Specific topics have been selected to illustrate the principles of important paradigm shifts that will influence the future of ophthalmic diagnostics. It is our impression that future evaluation of vision will go beyond visual acuity to assess ocular health in terms of psychophysical function. The definition of disease will incorporate genotype into what has historically been a phenotype-centric discipline. Non-invasive nanotechnologies will enable a paradigm shift from disease detection on a cellular level to a sub cellular molecular level. RESULTS: Vision can be evaluated beyond visual acuity by measuring contrast sensitivity, color vision, and macular function, as these provide better insights into the impact of aging and disease. Distortions can be quantified and the psychophysical basis of vision can be better evaluated than in the past by designing tests that assess particular macular cell function(s). Advances in our understanding of the genetic basis of eye diseases will enable better characterization of ocular health and disease. Non-invasive nanotechnologies can assess molecular changes in the lens, vitreous, and macula that predate visible pathology. Oxygen metabolism and circulatory physiology are measurable indices of ocular health that can detect variations of physiology and early disease. CONCLUSIONS: This overview of paradigm shifts in ophthalmology suggests that the future will see significant improvements in ophthalmic diagnostics. The selected topics illustrate the principles of these paradigm shifts and should serve as a guide to further research and development. Indeed, successful implementation of these paradigm shifts in ophthalmology may provide useful guidance for similar developments in all of healthcare. PMID- 28008211 TI - Dynamic tracking of prosthetic valve motion and deformation from bi-plane x-ray views: feasibility study. AB - Transcatheter aortic valve replacement (TAVR) requires navigation and deployment of a prosthetic valve within the aortic annulus under fluoroscopic guidance. To support improved device visualization in this procedure, this study investigates the feasibility of frame-by-frame 3D reconstruction of a moving and expanding prosthetic valve structure from simultaneous bi-plane x-ray views. In the proposed method, a dynamic 3D model of the valve is used in a 2D/3D registration framework to obtain a reconstruction of the valve. For each frame, valve model parameters describing position, orientation, expansion state, and deformation are iteratively adjusted until forward projections of the model match both bi-plane views. Simulated bi-plane imaging of a valve at different signal-difference-to noise ratio (SDNR) levels was performed to test the approach. 20 image sequences with 50 frames of valve deployment were simulated at each SDNR. The simulation achieved a target registration error (TRE) of the estimated valve model of 0.93 +/- 2.6 mm (mean +/- S.D.) for the lowest SDNR of 2. For higher SDNRs (5 to 50) a TRE of 0.04 mm +/- 0.23 mm was achieved. A tabletop phantom study was then conducted using a TAVR valve. The dynamic 3D model was constructed from high resolution CT scans and a simple expansion model. TRE was 1.22 +/- 0.35 mm for expansion states varying from undeployed to fully deployed, and for moderate amounts of inter-frame motion. Results indicate that it is feasible to use bi plane imaging to recover the 3D structure of deformable catheter devices. PMID- 28008212 TI - Consistent model identification of varying coefficient quantile regression with BIC tuning parameter selection. AB - Quantile regression provides a flexible platform for evaluating covariate effects on different segments of the conditional distribution of response. As the effects of covariates may change with quantile level, contemporaneously examining a spectrum of quantiles is expected to have a better capacity to identify variables with either partial or full effects on the response distribution, as compared to focusing on a single quantile. Under this motivation, we study a general adaptively weighted LASSO penalization strategy in the quantile regression setting, where a continuum of quantile index is considered and coefficients are allowed to vary with quantile index. We establish the oracle properties of the resulting estimator of coefficient function. Furthermore, we formally investigate a BIC-type uniform tuning parameter selector and show that it can ensure consistent model selection. Our numerical studies confirm the theoretical findings and illustrate an application of the new variable selection procedure. PMID- 28008213 TI - The surface climatology of the Ross Ice Shelf Antarctica. AB - The University of Wisconsin-Madison Antarctic Automatic Weather Station (AWS) project has been making meteorological surface observations on the Ross Ice Shelf (RIS) for approximately 30 years. This network offers the most continuous set of routine measurements of surface meteorological variables in this region. The Ross Island area is excluded from this study. The surface climate of the RIS is described using the AWS measurements. Temperature, pressure, and wind data are analysed on daily, monthly, seasonal, and annual time periods for 13 AWS across the RIS. The AWS are separated into three representative regions - central, coastal, and the area along the Transantarctic Mountains - in order to describe specific characteristics of sections of the RIS. The climatology describes general characteristics of the region and significant changes over time. The central AWS experiences the coldest mean temperature, and the lowest resultant wind speed. These AWSs also experience the coldest potential temperatures with a minimum of 209.3 K at Gill AWS. The AWS along the Transantarctic Mountains experiences the warmest mean temperature, the highest mean sea-level pressure, and the highest mean resultant wind speed. Finally, the coastal AWS experiences the lowest mean pressure. Climate indices (MEI, SAM, and SAO) are compared to temperature and pressure data of four of the AWS with the longest observation periods, and significant correlation is found for most AWS in sea-level pressure and temperature. This climatology study highlights characteristics that influence the climate of the RIS, and the challenges of maintaining a long-term Antarctic AWS network. Results from this effort are essential for the broader Antarctic meteorology community for future research. PMID- 28008214 TI - Displacement Sensing Based on Resonant Frequency Monitoring of Electrostatically Actuated Curved Micro Beams. AB - The ability to control nonlinear interactions of suspended mechanical structures offers a unique opportunity to engineer rich dynamical behavior that extends the dynamic range and ultimate device sensitivity. We demonstrate a displacement sensing technique based on resonant frequency monitoring of curved, doubly clamped, bistable micromechanical beams interacting with a movable electrode. In this configuration, the electrode displacement influences the nonlinear electrostatic interactions, effective stiffness and frequency of the curved beam. Increased sensitivity is made possible by dynamically operating the beam near the snap-through bistability onset. Various in-plane device architectures were fabricated from single crystal silicon and measured under ambient conditions using laser Doppler vibrometry. In agreement with the reduced order Galerkin based model predictions, our experimental results show a significant resonant frequency reduction near critical snap-through, followed by a frequency increase within the post-buckling configuration. Interactions with a stationary electrode yield a voltage sensitivity up to ~ 560 Hz/V and results with a movable electrode allow motion sensitivity up to ~ 1.5 Hz/nm. Our theoretical and experimental results collectively reveal the potential of displacement sensing using nonlinear interactions of geometrically curved beams near instabilities, with possible applications ranging from highly sensitive resonant inertial detectors to complex optomechanical platforms providing an interface between the classical and quantum domains. PMID- 28008215 TI - Recent approaches for bridging the pressure gap in photoelectron microspectroscopy. AB - Ambient-pressure photoelectron spectroscopy (APPES) and microscopy are at the frontier of modern chemical analysis at liquid-gas, solid-liquid and solid-gas interfaces, bridging science and engineering of functional materials. Complementing the current state-of-the art of the instruments, we survey in this short review several alternative APPES approaches, developed recently in the scanning photoelectron microscope (SPEM) at the Elettra laboratory. In particular, we report on experimental setups for dynamic near-ambient pressure environment, using pulsed-gas injection in the vicinity of samples or reaction cells with very small apertures, allowing for experiments without introducing additional differential pumping stages. The major part of the review is dedicated to the construction and performance of novel environmental cells using ultrathin electron-transparent but molecularly impermeable membranes to isolate the gas or liquid ambient from the electron detector operating in ultra-high vacuum (UHV). We demonstrate that two dimensional materials, such as graphene and derivatives, are mechanically robust to withstand atmospheric - UHV pressure differences and are sufficiently transparent for the photoelectrons emitted from samples immersed in the liquid or gaseous media. There are many unique opportunities for APPES using X-rays over a wide energy range. We show representative results that illustrate the potential of these 'ambient-pressure' approaches. Combined with the ca 100 nm lateral resolution of SPEM, they can overcome the pressure gap challenges and address the evolution of chemical composition and electronic structure at surface and interfaces under realistic operation conditions with unprecedented lateral and spectral resolution. PMID- 28008216 TI - Understanding Genetic Breast Cancer Risk: Processing Loci of the BRCA Gist Intelligent Tutoring System. AB - The BRCA Gist Intelligent Tutoring System helps women understand and make decisions about genetic testing for breast cancer risk. BRCA Gist is guided by Fuzzy-Trace Theory, (FTT) and built using AutoTutor Lite. It responds differently to participants depending on what they say. Seven tutorial dialogues requiring explanation and argumentation are guided by three FTT concepts: forming gist explanations in one's own words, emphasizing decision-relevant information, and deliberating the consequences of decision alternatives. Participants were randomly assigned to BRCA Gist, a control, or impoverished BRCA Gist conditions removing gist explanation dialogues, argumentation dialogues, or FTT images. All BRCA Gist conditions performed significantly better than controls on knowledge, comprehension, and risk assessment. Significant differences in knowledge, comprehension, and fine-grained dialogue analyses demonstrate the efficacy of gist explanation dialogues. FTT images significantly increased knowledge. Providing more elements in arguments against testing correlated with increased knowledge and comprehension. PMID- 28008218 TI - Objective assessment of a preterm infant's nutritive sucking from initiation of feeding through hospitalization and discharge. AB - INTRODUCTION: In 2008, the American Academy of Pediatrics recommended that an infant's ability to feed independently be considered a primary consideration for discharge home. To date, NICU healthcare teams have relied on clinical experience as well as descriptive scales to determine a high risk infant's ability to transition safely from tube feeding to oral feeding. The aim of the current case study was to illustrate the clinical utility of nfant(r) Feeding Solution as a noninvasive and objective instrument for determining a neonate's readiness to begin and advance oral feeding. MATERIALS AND METHODS: We present the case of AC, a female infant born at 28.6 weeks, with an admitting diagnosis of respiratory distress syndrome. Data collection began when AC was declared medical stable by her attending physician and ready to begin oral feedings. Data was captured during hospitalization and at discharge as well as post discharge for a total of eleven (11) data collections. RESULTS: Results suggested that the subject progressed in all sucking metrics over time. Data analyses revealed three general amplitude and temporal patterns against the nipple: disorganized, hypervigilant, and then organized. Real time data was used to gain immediate feedback on the impact of interventions on sucking performance. CONCLUSIONS: Successful infant feeding is a complex process that requires integration of physiologic function and neurobehavioral ability. To model AC's feeding performance over time, we used nfant Feeding Solution which measures tongue movement against the nipple and streams the data to a mobile tablet so it is displayed in real time. Access to real-time data provides caregivers with objective information that can be used to guide bedside care, help clinicians avoid complications and navigate infants to faster oral feeds and subsequently earlier and safer hospital discharge with lowered expense. PMID- 28008217 TI - Anticancer properties of baicalein: a review. AB - The constituents of many traditional Chinese herbal remedies are currently at the forefront of modern cancer research. Baicalein, a bioactive flavone widely used in nutraceuticals and pharmaceuticals, has shown great potential in the treatment and prevention of cancer without causing severe side effects. Baicalein induces cancer cell apoptosis and cause cell cycle arrest. It shows inhibitory effects on angiogenesis, metastasis and inflammation, all of which are necessary for the promotion and progression of cancer. This review presents an overview of the anti cancer effects and mechanisms of baicalein. In addition, the bioavailability of baicalein and approaches to improve it are summarized. Treatments of baicalein in combination with other anti-cancer agents are also mentioned. PMID- 28008219 TI - Introduction to using structured evocative activities in Functional Analytic Psychotherapy. AB - Functional Analytic Psychotherapy (FAP) focuses on what happens in session between clients and therapists in order to create more intense and curative therapeutic relationships. FAP may be used as a standalone treatment or as an adjunct to other therapies in order to maximize therapeutic gains through strengthened alliance and differential reinforcement. When it fits within a client's case conceptualization, FAP clinicians often choose to use structured, evocative activities to progress the therapy at a faster pace. This article provides a rationale for using structured evocative activities in FAP with concrete examples to facilitate clinicians' implementation of the exercises. PMID- 28008220 TI - Prefiltering Model for Homology Detection Algorithms on GPU. AB - Homology detection has evolved over the time from heavy algorithms based on dynamic programming approaches to lightweight alternatives based on different heuristic models. However, the main problem with these algorithms is that they use complex statistical models, which makes it difficult to achieve a relevant speedup and find exact matches with the original results. Thus, their acceleration is essential. The aim of this article was to prefilter a sequence database. To make this work, we have implemented a groundbreaking heuristic model based on NVIDIA's graphics processing units (GPUs) and multicore processors. Depending on the sensitivity settings, this makes it possible to quickly reduce the sequence database by factors between 50% and 95%, while rejecting no significant sequences. Furthermore, this prefiltering application can be used together with multiple homology detection algorithms as a part of a next generation sequencing system. Extensive performance and accuracy tests have been carried out in the Spanish National Centre for Biotechnology (NCB). The results show that GPU hardware can accelerate the execution times of former homology detection applications, such as National Centre for Biotechnology Information (NCBI), Basic Local Alignment Search Tool for Proteins (BLASTP), up to a factor of 4. PMID- 28008221 TI - A Comparison of Different Methodologies for the Measurement of Extracellular Vesicles and Milk-derived Particles in Raw Milk from Cows. AB - Cow's milk is economically important to the agricultural industry with the nutritive value of milk being routinely measured. This does not give full insight into normal mammary tissue turnover during the course of lactation, which could be important for both an understanding of milk production and animal welfare. We have previously demonstrated that submicron particles, including extracellular vesicles (EVs), can be measured in unprocessed cow's milk by flow cytometry and that they correlate with stage of lactation. A number of different techniques are available to measure EVs and other milk-derived particles. The purpose of this study was to compare two different methodologies and the value of fluorescent staining for the phospholipid phosphatidylserine (PS), which is exposed on the surface of EVs (but not other milk-derived particles). We used two different flow cytometers and nanotracker analysis to detect milk-derived particles in whole and skimmed milk samples. Our findings indicate significant correlation, after staining for PS, suggesting potential for larger multicenter studies in the future. PMID- 28008222 TI - Evaluation of peripheral fundus autofluorescence in eyes with wet age-related macular degeneration. AB - PURPOSE: We aimed to evaluate the prevalence of abnormal peripheral fundus autofluorescence (FAF) in wet age-related macular degeneration (AMD) using wide field imaging instrument. PATIENTS AND METHODS: A retrospective, case-controlled study involving 66 eyes of 46 Japanese wet AMD patients and 32 eyes of 20 control patients was performed. Wide-field FAF images were obtained for typical AMD (37 eyes/28 patients), polypoidal choroidal vasculopathy (PCV) (22 eyes/20 patients), and retinal angiomatous proliferation (RAP) (seven eyes/four patients). Two masked ophthalmologists independently graded the images for mottled, granular, and nummular patterns. Main outcome measures were abnormal peripheral FAF frequencies and relative risks by disease subgroups and treatments. RESULTS: Abnormal peripheral FAF patterns were found in 51.5% of wet AMD eyes compared with 18.8% of control eyes (P<0.001). Mottled, granular, and nummular patterns were found in 45.5%, 31.8%, and 16.7%, respectively, of wet AMD eyes. Each disease subgroup (typical AMD, 54.1%; PCV, 36.4%; and RAP, 85.7%) showed significantly higher frequencies of peripheral FAF (P<0.001, P=0.03, and P<0.001, respectively) than control eyes (18.8%). There were no significant differences (P=0.76) between the frequencies in untreated and treated eyes. CONCLUSION: Eyes of Japanese wet AMD patients had a higher abnormal FAF prevalence compared with control eyes. Among the three disease subtypes, abnormal patterns were least prevalent in PCV eyes. PMID- 28008223 TI - Physician, patient, and caregiver experience of different wet age-related macular degeneration anti-VEGF treatment regimens in Japan: a qualitative assessment. AB - PURPOSE: The purpose of this study was to monitor anti-vascular endothelial growth factor (anti-VEGF) treatment regimens for wet age-related macular degeneration (wAMD) in clinical practice and to determine how they impact the physician, patient, and caregiver treatment experience. MATERIALS AND METHODS: This was a qualitative analysis based on semistructured interviews with 20 ophthalmologists who had practiced both pro re nata (PRN) and treat-and-extend (T&E) anti-VEGF regimens for wAMD. Interview questions were constructed to assess how the different regimens affected patient and caregiver experiences (in the opinion of the ophthalmologist) in addition to the ophthalmologist's own experience. The interview included questions relating to 1) issues and benefits of PRN and T&E; 2) logistical and operational issues of introducing proactive therapy, especially T&E, to PRN practice; and 3) actions taken to handle the issues raised in 2). RESULTS: A total of 18 interview results were eligible for analysis. The study demonstrated that the benefits of T&E compared with PRN included decreased burden of patient consultations, decreased patient and caregiver emotional burden, and a sustained period of macular dryness. The issues associated with T&E were increased number of injections and financial burden from prolonged treatment duration. The ophthalmologists also experienced difficulty explaining the significance of proactive injections to patients. Countermeasures to operational issues experienced by ophthalmologists varied by practice. CONCLUSION: Patients, caregivers, and the practicing ophthalmologists experienced benefits associated with a T&E regimen. However, in order to encourage better understanding of the T&E regimen, including its smooth implementation and significance for patients, a formal T&E treatment guideline providing standard practice should be considered. PMID- 28008225 TI - Identifying Cell Type-Specific Transcription Factors by Integrating ChIP-seq and eQTL Data-Application to Monocyte Gene Regulation. AB - We describe a novel computational approach to identify transcription factors (TFs) that are candidate regulators in a human cell type of interest. Our approach involves integrating cell type-specific expression quantitative trait locus (eQTL) data and TF data from chromatin immunoprecipitation-to-tag sequencing (ChIP-seq) experiments in cell lines. To test the method, we used eQTL data from human monocytes in order to screen for TFs. Using a list of known monocyte-regulating TFs, we tested the hypothesis that the binding sites of cell type-specific TF regulators would be concentrated in the vicinity of monocyte eQTLs. For each of 397 ChIP-seq data sets, we obtained an enrichment ratio for the number of ChIP-seq peaks that are located within monocyte eQTLs. We ranked ChIP-seq data sets according to their statistical significances for eQTL overlap, and from this ranking, we observed that monocyte-regulating TFs are more highly ranked than would be expected by chance. We identified 27 TFs that had significant monocyte enrichment scores and mapped them into a protein interaction network. Our analysis uncovered two novel candidate monocyte-regulating TFs, BCLAF1 and SIN3A. Our approach is an efficient method to identify candidate TFs that can be used for any cell/tissue type for which eQTL data are available. PMID- 28008224 TI - Centrosome - a promising anti-cancer target. AB - The centrosome, an organelle discovered >100 years ago, is the main microtubule organizing center in mammalian organisms. The centrosome is composed of a pair of centrioles surrounded by the pericentriolar material (PMC) and plays a major role in the regulation of cell cycle transitions (G1-S, G2-M, and metaphase-anaphase), ensuring the normality of cell division. Hundreds of proteins found in the centrosome exert a variety of roles, including microtubule dynamics, nucleation, and kinetochore-microtubule attachments that allow correct chromosome alignment and segregation. Errors in these processes lead to structural (shape, size, number, position, and composition), functional (abnormal microtubule nucleation and disorganized spindles), and numerical (centrosome amplification [CA]) centrosome aberrations causing aneuploidy and genomic instability. Compelling data demonstrate that centrosomes are implicated in cancer, because there are important oncogenic and tumor suppressor proteins that are localized in this organelle and drive centrosome aberrations. Centrosome defects have been found in pre-neoplasias and tumors from breast, ovaries, prostate, head and neck, lung, liver, and bladder among many others. Several drugs/compounds against centrosomal proteins have shown promising results. Other drugs have higher toxicity with modest or no benefits, and there are more recently developed agents being tested in clinical trials. All of this emerging evidence suggests that targeting centrosome aberrations may be a future avenue for therapeutic intervention in cancer research. PMID- 28008226 TI - Preparation and physicochemical characterization of spray-dried and jet-milled microparticles containing bosentan hydrate for dry powder inhalation aerosols. AB - The objectives of this study were to prepare bosentan hydrate (BST) microparticles as dry powder inhalations (DPIs) via spray drying and jet milling under various parameters, to comprehensively characterize the physicochemical properties of the BST hydrate microparticles, and to evaluate the aerosol dispersion performance and dissolution behavior as DPIs. The BST microparticles were successfully prepared for DPIs by spray drying from feeding solution concentrations of 1%, 3%, and 5% (w/v) and by jet milling at grinding pressures of 2, 3, and 4 MPa. The physicochemical properties of the spray-dried (SD) and jet-milled (JM) microparticles were determined via scanning electron microscopy, atomic force microscopy, dynamic light scattering particle size analysis, Karl Fischer titration, surface analysis, pycnometry, differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. The in vitro aerosol dispersion performance and drug dissolution behavior were evaluated using an Anderson cascade impactor and a Franz diffusion cell, respectively. The JM microparticles exhibited an irregular corrugated surface and a crystalline solid state, while the SD microparticles were spherical with a smooth surface and an amorphous solid state. Thus, the in vitro aerosol dispersion performance and dissolution behavior as DPIs were considerably different due to the differences in the physicochemical properties of the SD and JM microparticles. In particular, the highest grinding pressures under jet milling exhibited excellent aerosol dispersion performance with statistically higher values of 56.8%+/-2.0% of respirable fraction and 33.8%+/-2.3% of fine particle fraction and lower mass median aerodynamic diameter of 5.0+/-0.3 MUm than the others (P<0.05, analysis of variance/Tukey). The drug dissolution mechanism was also affected by the physicochemical properties that determine the dissolution kinetics of the SD and JM microparticles, which were well fitted into the Higuchi and zero-order models, respectively. PMID- 28008227 TI - Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation. AB - OBJECTIVE: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Meniere's disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. METHODS: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc(r) 24 mg tablet in six healthy male volunteers. RESULTS: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. CONCLUSION: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl. PMID- 28008228 TI - Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy. AB - The use of inhaled corticosteroids (ICSs) plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA) to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD) and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF) and the LABA vilanterol trifenatate (VI) with indications for use in both COPD and asthma. This dry powder inhaler (DPI) comes in two doses of FF (100 or 200 MUg) both combined with VI (25 MUg). This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. PMID- 28008229 TI - Design and in vitro/in vivo evaluation of sustained-release floating tablets of itopride hydrochloride. AB - PURPOSE: The aim of the present study was to improve the bioavailability of itopride (ITO) and sustain its action by formulating as a floating dosage form. MATERIALS AND METHODS: Sustained-release floating tablets of ITO hydrochloride (HCl) were prepared by direct compression using different hydrocolloid polymers such as hydroxypropyl methylcellulose and ethylcellulose and/or methacrylic acid polymers Eudragit RSPM and Carbopol 934P. The floating property was achieved using an effervescent mixture of sodium bicarbonate and anhydrous citric acid (1:1 mol/mol). Hardness, friability, content uniformity, and dissolution rate of the prepared floating tablets were evaluated. The formulation F10 composed of 28.5% Eudragit RSPM, 3% NaHCO3, and 7% citric acid provided sustained drug release. RESULTS: In vitro results showed sustained release of F10 where the drug release percentage was 96.51%+/-1.75% after 24 hours (P=0.031). The pharmacokinetic results indicated that the area under the curve (AUC0-infinity) of the prepared sustained-release floating tablets at infinity achieved 93.69 ug.h/mL compared to 49.89 ug.h/mL for the reference formulation (Ganaton(r)) and the relative bioavailability of the sustained-release formulation F10 increased to 187.80% (P=0.022). CONCLUSION: The prepared floating tablets of ITO HCl (F10) could be a promising drug delivery system with sustained-release action and enhanced drug bioavailability. PMID- 28008230 TI - Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with nontransfusion dependent thalassemia syndromes. PMID- 28008231 TI - Protective effects of vitamin C and vitamin E against hysterosalpingography induced epithelial degeneration and proliferation in rat endometrium. AB - AIM: The aim of this study was to examine the protective effects of vitamin C (VC) and vitamin E (VE) against hysterosalpingography (HSG)-induced epithelial degeneration and proliferation in rat endometrium. MATERIALS AND METHODS: A total of 28 female Wistar albino rats were randomized into four groups: G1 (n=7; abdomen was opened and closed), G2 (n=7; 0.1 mL Lipiodol [ethiodized oil] was administered to each uterine horn in conjunction with X-ray irradiation), G3 (n=7; 50 mg/kg of intraperitoneal (ip) VC was administered, followed by the administration of 0.1 mL of ethiodized oil into the uterine horns after 15 minutes), and G4 (n=7; 50 mg/kg of ip VE was administered, followed by the administration of 0.1 mL of ethiodized oil into the uterine horns after 15 minutes). After abdominal closure, rats in G2, G3 and G4 groups were exposed to whole-body X-irradiation three times with 2-minute intervals at a total dose of 15-20 mrad. Three hours after exposure, abdominal cavities of all the rats were reopened and uterine horns were removed. The right uterine horns were embedded into paraffin blocks after fixing in 10% formaldehyde for histopathological and immunohistochemical examination. Uterine horns on the other side were rapidly excised and stored at -80 degrees C for the examination of expression of microRNAs (miRNAs) and oxidant, antioxidant, apoptotic and antiapoptotic gene expression using real-time polymerase chain reaction (RT-PCR) method. RESULTS: No differences were observed in terms of expression of miRNAs and oxidant, antioxidant, apoptotic and anti-apoptotic gene expression between the study groups. Congestion, epithelial degeneration and malondialdehyde immunoreactivity were significantly lower in G3 and G4 groups than in G2 group; no differences were observed between G1, G3 and G4 groups. Ki-67 immunoreactivity score was significantly higher in G2 group when compared with G1, G3 and G4 groups. Caspase 3 immunoreactivity was not statistically different between the groups. CONCLUSION: VC and VE may confer cellular protection against radiation injury induced by HSG in endometrial epithelium. PMID- 28008232 TI - Structure-based virtual screening and characterization of a novel IL-6 antagonistic compound from synthetic compound database. AB - According to the three-dimensional (3D) complex structure of (hIL-6?hIL-6R?gp 130)2 and the binding orientation of hIL-6, three compounds with high affinity to hIL-6R and bioactivity to block hIL-6 in vitro were screened theoretically from the chemical databases, including 3D-Available Chemicals Directory (ACD) and MDL Drug Data Report (MDDR), by means of the computer-guided virtual screening method. Using distance geometry, molecular modeling and molecular dynamics trajectory analysis methods, the binding mode and binding energy of the three compounds were evaluated theoretically. Enzyme-linked immunosorbent assay analysis demonstrated that all the three compounds could block IL-6 binding to IL 6R specifically. However, only compound 1 could effectively antagonize the function of hIL-6 and inhibit the proliferation of XG-7 cells in a dose-dependent manner, whereas it showed no cytotoxicity to SP2/0 or L929 cells. These data demonstrated that the compound 1 could be a promising candidate of hIL-6 antagonist. PMID- 28008233 TI - Folic acid-conjugated amphiphilic alternating copolymer as a new active tumor targeting drug delivery platform. AB - Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4 diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior. Moreover, the structure is stable only at neutral pH and collapses in the acidic tumor microenvironment, releasing drugs on-site from its core. The delivery vehicle is investigated using human pancreatic PANC-1 cancer cells and RAW-BlueTM mouse macrophage reporter cell line, both of which have overly expression of folic acid receptors. To trace the cellular uptake by both cell lines, curcumin was selected as a dye and drug mimic owing to its fluorescence nature and hydrophobic properties. Fluorescent microscopy of FA-DABA SMA loaded with curcumin revealed a significant internalization of the dye by human pancreatic PANC-1 cancer cells compared to those with unfunctionalized polymers (SMA). Moreover, the FA-DABA-SMA polymers exhibit rodlike association specific to the cells. Both empty SMA and FA-DABA-SMA show little toxicity to PANC-1 cells as characterized by WST-1 cell proliferation assay. These results clearly indicate that FA-DABA-SMA polymers show potential as an active tumor targeting drug delivery system with the ability to internalize hydrophobic chemotherapeutics after they specifically attach to cancer cells. PMID- 28008235 TI - Importance of hemodialysis-related outcomes: comparison of ratings by a self-help group, clinicians, and health technology assessment authors with those by a large reference group of patients. AB - BACKGROUND: The selection of important outcomes is a crucial decision for clinical research and health technology assessment (HTA), and there is ongoing debate about which stakeholders should be involved. Hemodialysis is a complex treatment for chronic kidney disease (CKD) and affects many outcomes. Apart from obvious outcomes, such as mortality, morbidity and health-related quality of life (HRQoL), others such as, concerning daily living or health care provision, may also be important. The aim of our study was to analyze to what extent the preferences for patient-relevant outcomes differed between various stakeholders. We compared preferences of stakeholders normally or occasionally involved in outcome prioritization (patients from a self-help group, clinicians and HTA authors) with those of a large reference group of patients. PARTICIPANTS AND METHODS: The reference group consisted of 4,518 CKD patients investigated previously. We additionally recruited CKD patients via a regional self-help group, nephrologists via an online search and HTA authors via an expert database or personal contacts. All groups assessed the relative importance of the 23 outcomes by means of a discrete visual analog scale. We used descriptive statistics to rank outcomes and compare the results between groups. RESULTS: We received completed questionnaires from 49 self-help group patients, 19 nephrologists and 18 HTA authors. Only the following 3 outcomes were ranked within the top 7 outcomes by all 4 groups: safety, HRQoL and emotional state. The ratings by the self-help group were generally more concordant with the reference group ratings than those by nephrologists, while HTA authors showed the least concordance. CONCLUSION: Preferences of CKD patients from a self-help group, nephrologists and HTA authors differ to a varying extent from those of a large reference group of patients with CKD. The preferences of all stakeholders should form the basis of a transparent approach so as to generate a valid list of important outcomes. PMID- 28008234 TI - The Australasian Hepatology Association consensus guidelines for the provision of adherence support to patients with hepatitis C on direct acting antivirals. AB - BACKGROUND: Hepatitis C is a blood-borne virus primarily spread through sharing of drug-injecting equipment. Approximately 150 million people worldwide and 230,000 Australians are living with chronic hepatitis C infection. In March 2016, the Australian government began subsidizing direct acting antivirals (DAAs) for the treatment of hepatitis C, which are highly effective (95% cure rate) and have few side effects. However, there is limited evidence to inform the provision of adherence support to people with hepatitis C on DAAs including the level of medication adherence required to achieve a cure. METHODOLOGY: In February 2016, a steering committee comprising four authors convened an expert panel consisting of six hepatology nurses, a hepatologist, a pharmacist, a consumer with hepatitis C and treatment experience, and a consumer advocate. The expert panel focused on the following criteria: barriers and enablers to DAA adherence; assessment and monitoring of DAA adherence; components of a patient-centered approach to DAA adherence; patients that may require additional adherence support; and interventions to support DAA adherence. The resultant guidelines underwent three rounds of consultation with the expert panel, Australasian Hepatology Association (AHA) members (n=12), and key stakeholders (n=7) in June 2016. Feedback was considered by the steering committee and incorporated if consensus was achieved. RESULTS: Twenty-four guidelines emerged from the evidence synthesis and expert panel discussion. The guidelines focus on the pretreatment assessment and education, assessment of treatment readiness, and monitoring of medication adherence. The guidelines are embedded in a patient-centered approach which highlights that all patients are at risk of nonadherence. The guidelines recommend implementing interventions focused on identifying patients' memory triggers and hooks; use of nonconfrontational and nonjudgmental language by health professionals; and objectively monitoring adherence. CONCLUSION: These are the first guidelines to support patients and health professionals in the delivery of clinical care by identifying practical adherence support interventions for patients taking DAAs. PMID- 28008236 TI - Communicating laboratory test results for rheumatoid factor: what do patients and physicians want? AB - OBJECTIVE: This study aimed to explore patient and physician perspectives on current laboratory test reporting practices and to elicit ideas for improvement. METHODS: Two independent studies were conducted. The first solicited members of an online physician community for opinions on current laboratory test reporting practices and possible improvements. The second addressed the same topic, but solicited patient feedback, and included an evaluation of a mock laboratory test report for the rheumatoid factor blood test. RESULTS: Both physicians and patients expressed a desire for patient-friendly information on laboratory reports. Physicians expressed a need for education for patients around false positive and false-negative results within laboratory reports, while patients sought context around the meaning of results, relevance to other tests, and follow-up steps. CONCLUSION: Physicians and patients see value in enhancing laboratory test reports to improve communication. While reports should include the context that patients value, they should also contain cautionary interpretation emphasized by physicians. Patient consultation on improving laboratory reports may help improve such patient-focused communication and promote greater patient understanding of health information, thereby increasing patient participation in their own health care and improving outcomes. PRACTICE IMPLICATIONS: Laboratory reports are typically designed by experts. Including patients in laboratory report design may facilitate communication and improve outcomes through better patient engagement. PMID- 28008237 TI - Improving doctor-patient communication: content validity examination of a novel urinary system-simulating physical model. AB - Effective doctor-patient communication is essential for establishing a successful doctor-patient relationship and implementing high-quality health care. In this study, a novel urinary system-simulating physical model was designed and fabricated, and its content validity for improving doctor-patient communication was examined by conducting a randomized controlled trial in which this system was compared with photographs. A total of 240 inpatients were randomly selected and assigned to six doctors for treatment. After primary diagnosis and treatment had been determined, these patients were randomly divided into the experimental group and the control group. Patients in the experimental group participated in model based doctor-patient communication, whereas control group patients received picture-based communication. Within 30 min after this communication, a Demographic Information Survey Scale and a Medical Interview Satisfaction Scale (MISS) were distributed to investigate patients' demographic characteristics and their assessments of total satisfaction, distress relief, communication comfort, rapport, and compliance intent. The study results demonstrated that the individual groups were comparable with respect to demographic variables but that relative to patients in the picture-based communication group, patients in the model-based communication group had significantly higher total satisfaction scores and higher ratings for distress relief, communication comfort, rapport, and compliance intent. These results indicate that the physical model is more effective than the pictures at improving doctor-patient communication and patient outcomes. The application of the physical model in doctor-patient communication is helpful and valuable and therefore merits widespread clinical popularization. PMID- 28008238 TI - Communication practices and awareness of resources for acromegaly patients among endocrinologists. AB - PURPOSE: This study was designed to assess the awareness and utilization of resources to improve patients' treatment experiences among endocrinologists who currently treat patients with acromegaly. METHODS: A total of 4,280 US endocrinologists were randomly selected from the CMS National Plan and Provider Enumeration System and were invited by mail to participate in a 20-minute online survey. In order to qualify, respondents had to be the primary physician making treatment decisions for at least one patient for their acromegaly. RESULTS: Results are based on responses from 126 physicians from primarily urban and suburban practices, with a median of five acromegaly patients. A total of 70% of patients are currently receiving drug therapy; among these, 91% are on octreotide (51%), lanreotide (29%), or pasireotide (11%), alone or in combination with another therapy. Nearly half of the respondents thought that the impact of patient adherence on therapy outcome for acromegaly was either not very (40%) or not at all (7%) significant. Respondents who believe patient adherence significantly impacts treatment outcome were significantly more likely to discuss automated adherence reminders (50% vs 26%; P=0.015), mobile administration programs (57% vs 35%; P=0.029), and symptom tracking (72% vs 42%; P=0.002). Overall, 44% of respondents routinely recommend education/emotional support programs, and 25% routinely recommend financial assistance programs. Respondents who believe patient adherence significantly impacts treatment outcome generally were more familiar with individual education and emotional support programs compared to those who do not, although they were not more likely to routinely refer patients to any of these resources. CONCLUSION: There are unmet needs with respect to increasing awareness among physicians of the importance of patient adherence to therapy, resources available to patients, and how collaboration among patients, nurses, and physicians can improve adherence and overall treatment experiences. PMID- 28008239 TI - Effects of different doses of high-speed resistance training on physical performance and quality of life in older women: a randomized controlled trial. AB - OBJECTIVE: This study aimed to compare the effects of two frequencies of high speed resistance training (HSRT) on physical performance and quality of life of older women. METHODS: A total of 24 older women participated in a 12-week HSRT program composed of either two or three sessions/week (equated for volume and intensity). Women were randomized into three arms: a control group (CG, n=8), a resistance training group performing two sessions/week (RT2, n=8), and a resistance training group performing three sessions/week (RT3, n=8). The training program for both experimental groups included exercises that required high-speed concentric muscle actions. RESULTS: No baseline differences were observed among groups. Compared with the CG, both training groups showed similar small to moderate improvements (P<0.05) in muscle strength, power, functional performance, balance, and quality of life. CONCLUSION: These results suggest that equated for volume and intensity, two and three training sessions/week of HSRT are equally effective for improving physical performance and quality of life of older women. PMID- 28008240 TI - A comparison between metatarsal head-resurfacing hemiarthroplasty and total metatarsophalangeal joint arthroplasty as surgical treatments for hallux rigidus: a retrospective study with short- to midterm follow-up. AB - PURPOSE: We evaluated the short- to midterm outcomes of metatarsal head resurfacing hemiarthroplasty and total metatarsophalangeal joint arthroplasty (total joint replacement [TJR]) as surgical treatments for advanced-stage hallux rigidus (HR). PATIENTS AND METHODS: From 2012 to 2014, all data from patients who underwent surgery for the treatment of grades 2-3 HR were retrospectively reviewed, and 45 patients were included in this study. Of these patients, 26 underwent metatarsal head-resurfacing hemiarthroplasty (Group I) and 19 underwent TJR (Group II). All patients were clinically graded prior to surgery and at their final follow-up visits using the American Orthopedic Foot and Ankle Society's (AOFAS) hallux metatarsophalangeal-interphalangeal scale, a visual analog scale (VAS), and the "first metatarsophalangeal joint range of motion" (MTPJ ROM) score. RESULTS: Metatarsal head resurfacing was performed on 26 patients. Two patients underwent bilateral procedures, yielding a total of 28 cases in Group I. TJR was performed on 19 patients in Group II. Of the 26 Group I patients, 12 (46.2%) were male and 14 (53.8%) were female, with a mean age of 56.3+/-4.5 years (range: 47-63 years); the mean follow-up duration was 29.9+/-5.2 months. Of the 19 Group II patients, eight (42.1%) were male and eleven (57.9%) were female, with a mean age of 57.1+/-5.8 years (range: 45-66 years); the mean follow-up duration was 27.1+/-7.5 months. Significant improvements were evident in the AOFAS scores, and the VAS scores decreased, in both groups. No significant difference was evident between groups I and II. CONCLUSION: After failure of conservative treatment in patients with moderate-to-severe HR, both MTPJ hemiarthroplasty and TJR were associated with effective recovery of toe function and MTPJ ROM, as well as good short- to midterm functional outcomes. PMID- 28008241 TI - Erratum: Prevalence of unknown and untreated arrhythmias in an older outpatient population screened by wireless long-term recording ECG [Corrigendum]. AB - [This corrects the article on p. 1083 in vol. 11, PMID: 27570450.]. PMID- 28008242 TI - A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease. AB - Early-onset Alzheimer's disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer's disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer's disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16-17), PSEN1 (exons 3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE epsilon4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE epsilon4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population. PMID- 28008243 TI - Efficacy of tiotropium-olodaterol fixed-dose combination in COPD. AB - Tiotropium-olodaterol, formulated in the Respimat soft-mist inhaler, is an inhaled fixed-dose combination (FDC) of a long-acting muscarinic antagonist (LAMA) and a long-acting beta2-agonist (LABA), commercialized under the name of Spiolto or Stiolto. The efficacy of tiotropium-olodaterol 5-5 MUg once daily in adult patients with COPD was documented in eleven large, multicenter trials of up to 52 weeks duration. Tiotropium-olodaterol 5-5 MUg not only improved spirometric values to a significantly greater extent than placebo but also resulted in statistically significant beneficial effects on dyspnea, markers of hyperinflation, use of rescue medication, health-related quality of life, and exercise endurance. Improvements exceeded the minimal clinically important difference (MCID) for forced expiratory volume in 1 second (FEV1), dyspnea, and quality of life. Differences between tiotropium-olodaterol 5-5 MUg and the respective monocomponents were statistically significant for FEV1, dyspnea, markers of hyperinflation, use of rescue medication, and health-related quality of life, but did not reach the MCID. However, dual bronchodilatation significantly increased the number of patients who exceeded the MCID for dyspnea and quality of life. Moreover, tiotropium-olodaterol 5-5 MUg was significantly more effective than salmeterol-fluticasone (FDC) twice daily at improving pulmonary function. Differences between tiotropium-olodaterol and other LAMA/LABA FDCs were not observed for FEV1 or other efficacy markers. Therefore, tiotropium olodaterol is a valuable option in the treatment of COPD patients who remain symptomatic under monotherapy. PMID- 28008244 TI - Indacaterol/glycopyrronium in symptomatic patients with COPD (GOLD B and GOLD D) versus salmeterol/fluticasone: ILLUMINATE/LANTERN pooled analysis. AB - BACKGROUND: Indacaterol/glycopyrronium (IND/GLY) is approved for maintenance treatment of adult patients with COPD. This post hoc analysis explored the efficacy and safety of IND/GLY versus salmeterol/fluticasone (SFC) in symptomatic (Global Initiative for Chronic Obstructive Lung Disease [GOLD] B and GOLD D) patients with moderate-to-severe COPD. PATIENTS AND METHODS: Data from LANTERN and ILLUMINATE studies were pooled and analyzed. In both studies, symptomatic COPD patients were randomized to once-daily IND/GLY 110 MUg/50 MUg or twice-daily SFC 50 MUg/500 MUg. End points were pre-dose trough forced expiratory volume in one second (FEV1), standardized area under the curve for FEV1 from 0 to 12 hours (FEV1 AUC0-12 hours), peak FEV1, peak forced vital capacity (FVC), pre-dose trough FVC, Transition Dyspnea Index (TDI) total score, St George's Respiratory Questionnaire total score, rescue medication use and safety. RESULTS: A total of 1,263 patients were classified as either GOLD B (n=809) or GOLD D (n=454). At week 26, IND/GLY demonstrated statistically significant improvement in all lung function parameters versus SFC in patients in both the GOLD B and GOLD D subgroups. TDI total score and rescue medication use were significantly improved with IND/GLY versus SFC in the overall population and in the GOLD B (TDI total score only) and GOLD D (rescue medication only) subgroups. IND/GLY also reduced the rate of exacerbations in the pooled population. Overall safety profile was comparable with a higher incidence of pneumonia in the SFC-treated group. CONCLUSION: In this pooled analysis, IND/GLY demonstrated superior efficacy compared with SFC in patients in the GOLD B and GOLD D subgroups and supported its use in symptomatic COPD patients. PMID- 28008245 TI - Rates and predictors of depression status among caregivers of patients with COPD hospitalized for acute exacerbations: a prospective study. AB - BACKGROUND: Hospitalization is common for acute exacerbation of COPD, but little is known about its impact on the mental health of caregivers. OBJECTIVE: The aim of this study was to determine the rates and predictors of depressive symptoms in caregivers at the time of hospitalization for acute exacerbation of COPD and to identify the probability and predictors of subsequent changes in depressive status 3 months after discharge. MATERIALS AND METHODS: This was a prospective study. Depression symptoms were measured in 87 caregivers of patients hospitalized for exacerbation at hospitalization and 3 months after discharge. We measured factors from four domains: context of care, caregiving demands, caregiver resources, and patient characteristics. Univariate and multivariate multiple logistic regressions were used to determine the predictors of depression at hospitalization and subsequent changes at 3 months. RESULTS: A total of 45 caregivers reported depression at the time of hospitalization. After multiple adjustments, spousal relationship, dyspnea, and severe airflow limitation were the strongest independent predictors of depression at hospitalization. Of these 45 caregivers, 40% had a remission of their depression 3 months after discharge. In contrast, 16.7% of caregivers who were not depressive at hospitalization became depressive at 3 months. Caregivers caring >20 hours per week for patients with dependencies had decreased odds of remission, and patients having dependencies after discharge increased the odds of caregivers becoming depressed. CONCLUSION: Depressive symptoms are common among caregivers when patients are hospitalized for exacerbation of COPD. Although illness factors are determinants of depression at hospitalization, patient dependence determines fluctuations in the depressive status of caregivers. PMID- 28008246 TI - The administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to cigarette smoke. AB - This study aimed to evaluate the effects of a high refined carbohydrate diet and pulmonary inflammatory response in C57BL/6 mice exposed to cigarette smoke (CS). Twenty-four male mice were divided into four groups: control group (CG), which received a standard diet; cigarette smoke group (CSG), which was exposed to CS; a high refined carbohydrate diet group (RG), which received a high refined carbohydrate diet; and a high refined carbohydrates diet and cigarette smoke group (RCSG), which received a high refined carbohydrate diet and was exposed to CS. The animals were monitored for food intake and body weight gain for 12 weeks. After this period, the CSG and RCSG were exposed to CS for five consecutive days. At the end of the experimental protocol, all animals were euthanized for subsequent analyses. There was an increase of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of CSG compared to CG and RCSG compared to CG, CSG, and RG. In addition, in the BALF, there was an increase of tumor necrosis factor alpha in RCSG compared to CG, CSG, and RG; interferon gamma increase in RCSG compared to the CSG; and increase in interleukin-10 in RCSG compared to CG and RG. Lipid peroxidation increased in RCSG compared to CG, CSG, and RG. Furthermore, the oxidation of proteins increased in CSG compared to CG. The analysis of oxidative stress showed an increase in superoxide dismutase in RCSG compared to CG, CSG, and RG and an increase in the catalase activity in RCSG compared with CG. In addition, there was a decrease in the glutathione reduced/glutathione total ratio of CSG, RG, and RCSG compared to CG. Therefore, the administration of a high refined carbohydrate diet promoted an increase in pulmonary inflammation and oxidative stress in mice exposed to CS. PMID- 28008247 TI - New silver nanoparticles induce apoptosis-like process in E. coli and interfere with mammalian copper metabolism. AB - Silver nanoparticles (SNPs) are new functional materials that are widely used in biomedical and industrial technologies. Two main features that make SNPs valuable are their strong antibacterial effects and low toxicity to eukaryotes. In this study, SNPs were synthesized using a modified method of reducing the metal ions to their atomic state followed by crystallization. SNPs were characterized by UV/vis spectroscopy, X-ray diffractometry, atomic force microscopy, and transmission electron microscopy (TEM). The SNPs were spherically shaped with an average linear dimension of 20 nm. In aqueous solution, the SNPs were beige yellow in color, and they formed a black color in bacteria-rich growth media. The toxicity and bioavailability of the SNPs were tested using Escherichia coli cells and C57Bl/6 mice. Although the SNPs displayed bactericidal activity, an E. coli cell strain transformed with an expression plasmid carrying a human CTR1 ectodomain with three motives that bind Cu(II), Cu(I), and Ag(I) demonstrated increased resistance to treatment with SNPs. TEM showed that the SNPs were absorbed by the E. coli cell, and flow cytometry showed that the SNPs induced apoptosis-like death. In mice treated with SNPs (daily intraperitoneal injection of 10 MUg SNPs/g body weight over 4 days), the ceruloplasmin (Cp) oxidase activity in the blood serum decreased. However, level of Cp gene expression, the relative contents of the Cp protein in the Golgi complex and in the serum did not change. Treatment with SNPs did not influence the activity of superoxide dismutase 1 in the liver and had no apparent toxic effects in mice. These findings expand the scope of application for the use of new SNPs. The data are discussed in a paradigm, in which the effects of SNPs are caused by the interference of silver ions with copper metabolism. PMID- 28008248 TI - Coalescence of functional gold and monodisperse silver nanoparticles mediated by black Panax ginseng Meyer root extract. AB - A rapid biological synthesis of multifunctional gold nanoparticle (AuNp) and monodisperse silver nanoparticle (AgNp) was achieved by an aqueous extract of black Panax ginseng Meyer root. The physicochemical transformation into black ginseng (BG) greatly enhanced the pharmacological activities of white ginseng and its minor ginsenoside content. The optimal temperature conditions and kinetics of bioreduction were investigated. Formation of BG-AuNps and BG-AgNps was verified by ultraviolet-visible spectrophotometry at 548 and 412 nm, respectively. The biosynthesized BG-AgNps were spherical and monodisperse with narrow distribution, while BG-AuNps were icosahedral-shaped and moderately polydisperse. Synthesized nanoparticles exhibited long-term stability in buffers of pH 7.0-8.0 and biological media (5% bovine serum albumin) at an ambient temperature and at 37 degrees C. BG-AgNps showed effective antibacterial activity against Escherichia coli and Staphylococcus aureus. BG-AuNps and BG-AgNps demonstrated increased scavenging activity against 2,2-diphenyl-1-picrylhydrazyl free radicals. In addition, BG-AuNps and BG-AgNps were nontoxic to HaCaT and MCF-7 cells; the latter showed no cytotoxicity at concentrations lower than 10 ug/mL. At higher concentrations, BG-AgNps exhibited apparent apoptotic activity in MCF-7 breast cancer cell line through reactive oxygen species generation and nuclear fragmentation. PMID- 28008249 TI - A novel hydrodynamic approach of drag-reducing polymers to improve left ventricular hypertrophy and aortic remodeling in spontaneously hypertensive rats. AB - Drag-reducing polymers (DRPs), when added in minute concentrations, have been shown to decrease peripheral vascular resistance. In this study, the effect of DRPs on the hypertension-induced left ventricular hypertrophy and aortic remodeling was evaluated in spontaneously hypertensive rats (SHR). Male SHR and age-matched Wistar rats were divided into four groups and received intravenous injection of normal saline (NS) or DRPs. Body weight (BW), heart rate (HR) and systolic blood pressure (SBP) were measured. Echocardiography was used to evaluate the changes in left ventricle (LV) function and global wall motion. The LV and aorta were stained by hematoxylin and eosin. Cell size of cardiomyocytes and aortic medial thickness were evaluated for each section. The expression of endothelin-1 (ET-1) of LV and aorta was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. There was no significant difference in the increase of SBP among SHR + NS, SHR + 10DRP and SHR + 20DRP groups. SHR + NS group had markedly smaller left ventricular end systolic diameter and left ventricular end-diastolic diameter but bigger anterior and posterior systolic wall thicknesses, while there was no significant difference in fractional shortening and ejection fraction. The cross-sectional areas (CSAs) of cardiomyocytes and the medial thickness of the aorta in SHR + 10 (ppm) DRP and SHR + 20 (ppm) DRP groups were significantly reduced compared with SHR + NS group. The expression of ET-1 in SHR + 10DRP and SHR + 20DRP groups was significantly attenuated. These results suggest that chronic treatment with DRPs can protect against left ventricular hypertrophy and aortic remodeling. DRPs may offer a new approach to the treatment of left ventricular hypertrophy and aortic remodeling caused by hypertension. PMID- 28008250 TI - A polyethylenimine-modified carboxyl-poly(styrene/acrylamide) copolymer nanosphere for co-delivering of CpG and TGF-beta receptor I inhibitor with remarkable additive tumor regression effect against liver cancer in mice. AB - Cancer immunotherapy based on nanodelivery systems has shown potential for treatment of various malignancies, owing to the benefits of tumor targeting of nanoparticles. However, induction of a potent T-cell immune response against tumors still remains a challenge. In this study, polyethylenimine-modified carboxyl-styrene/acrylamide (PS) copolymer nano-spheres were developed as a delivery system of unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides and transforming growth factor-beta (TGF-beta) receptor I inhibitors for cancer immunotherapy. TGF-beta receptor I inhibitors (LY2157299, LY) were encapsulated to the PS via hydrophobic interaction, while CpG oligodeoxynucleotides were loaded onto the PS through electrostatic interaction. Compared to the control group, tumor inhibition in the PS-LY/CpG group was up to 99.7% without noticeable toxicity. The tumor regression may be attributed to T cell activation and amplification in mouse models. The results highlight the additive effect of CpG and TGF-beta receptor I inhibitors co-delivered in cancer immunotherapy. PMID- 28008252 TI - Nanoscaled hydrated antimony (V) oxide as a new approach to first-line antileishmanial drugs. AB - BACKGROUND: Coordination compounds of pentavalent antimony have been, and remain, the first-line drugs in leishmaniasis treatment for >70 years. Molecular forms of Sb (V) complexes are commercialized as sodium stibogluconate (Pentostam(r)) and meglumine antimoniate (MA) (Glucantime(r)). Ever-increasing drug resistance in the parasites limits the use of antimonials, due to the low drug concentrations being administered against high parasitic counts. Sb5+ toxicity provokes severe side effects during treatment. To enhance therapeutic potency and to increase Sb (V) concentration within the target cells, we decided to try a new active substance form, a hydrosol of Sb2O5.nH2O nanoparticles (NPs), instead of molecular drugs. METHODOLOGY/PRINCIPAL FINDINGS: Sb2O5.nH2O NPs were synthesized by controlled SbCl5 hydrolysis in a great excess of water. Sb2O5.nH2O phase formation was confirmed by X-ray diffraction. The surface of Sb (V) NPs was treated with ligands with a high affinity for target cell membrane receptors. The mean particle size determined by dynamic light scattering and transmission electron microscopy was ~35-45 nm. In vitro tests demonstrated a 2.5-3 times higher antiparasitic activity of Sb (V) nanohybrid hydrosols, when compared to MA solution. A similar comparison for in vivo treatment of experimental cutaneous leishmaniasis with Sb5+ nanohybrids showed a 1.75-1.85 times more effective decrease in the lesions. Microimages of tissue fragments confirmed the presence of NPs inside the cytoplasm of infected macrophages. CONCLUSION/SIGNIFICANCE: Sb2O5.nH2O hydrosols are proposed as a new form of treatment for cutaneous leishmaniasis caused by Leishmania amazonensis. The NPs penetrate directly into the affected cells, creating a high local concentration of the drug, a precondition to overcoming the parasite resistance to molecular forms of pentavalent antimonials. The nanohybrids are more effective at a lower dose, when compared to MA, the molecular drug. Our data suggest that the new form of treatment has the potential to reduce and simplify the course of cutaneous leishmaniasis treatment. At the same time, Sb2O5.nH2O hydrosols provide an opportunity to avoid toxic antimony (V) spreading throughout the body. PMID- 28008251 TI - Coating with spermine-pullulan polymer enhances adenoviral transduction of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are adult stem cells with multilineage potential, which makes them attractive tools for regenerative medicine applications. Efficient gene transfer into MSCs is essential not only for basic research in developmental biology but also for therapeutic applications involving gene modification in regenerative medicine. Adenovirus vectors (Advs) can efficiently and transiently introduce an exogenous gene into many cell types via their primary receptors, the coxsackievirus and adenovirus receptors, but not into MSCs, which are deficient in coxsackievirus and adenovirus receptors expression. To overcome this problem, we developed an Adv coated with a spermine-pullulan (SP) cationic polymer and investigated its physicochemical properties and internalization mechanisms. We demonstrated that the SP coating could enhance adenoviral transduction of MSCs without detectable cytotoxicity or effects on differentiation. Our results argue in favor of the potentiality of the SP-coated Adv as a prototype vector for efficient and safe transduction of MSCs. PMID- 28008253 TI - Novel antimicrobial peptide-modified azithromycin-loaded liposomes against methicillin-resistant Staphylococcus aureus. AB - Infections caused by multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), have become a public threat; therefore, development of new antimicrobial drugs or strategies is urgently required. In this study, a new antibacterial peptide DP7-C (Chol-suc-VQWRIRVAVIRK-NH2) and DP7-C-modified azithromycin (AZT)-loaded liposomes (LPs) are developed for the treatment of MRSA infection, and it was found that DP7-C inserted into the LP lipid bilayer not only functioned as a carrier to encapsulate the antibiotic AZT but also synergized the antibacterial effect of the encapsulated AZT. In vitro assays showed that DP7-C-modified LPs possessed sustained drug release profile and immune regulatory effect and did not show obvious cytotoxicity in mammal cells, but they did not possess direct antibacterial activity in vitro. In vivo studies revealed that DP7-C-modified LPs did not exhibit obvious side effects or toxicity in mice but were able to significantly reduce the bacterial counts in an MRSA infectious mouse model and possessed high antibacterial activity. In particular, DP7-C-modified AZT-loaded LPs showed more positive therapeutic effects than either DP7-C-modified blank LPs or nonmodified AZT-loaded LPs treatment alone. Molecular mechanism studies demonstrated that DP7-C formulations effectively upregulated the production of anti-inflammatory cytokines and chemokines without inducing harmful immune response, suggesting that DP7-C was synergistic with AZT against the bacterial infection by activating the innate immune response. Most importantly, although DP7-C activated the innate immune response, it did not possess direct antibacterial activity in vitro, indicating that DP7-C did not possess the potential to induce bacteria resistance. The findings indicate that DP7-C-modified AZT-loaded LPs developed in this study have a great potential required for the clinical treatment of MRSA infections. PMID- 28008254 TI - Rehmannia glutinosa polysaccharide liposome as a novel strategy for stimulating an efficient immune response and their effects on dendritic cells. AB - Nanomedicine, the medical application of nanotechnology, promises a seemingly limitless range of applications from drug delivery to adjuvants and therapeutics. Our current research is focused on natural polymer-based liposome adjuvants. With the aim of inducing protective and long-lasting immunity, the immunological adjuvant activity of Rehmannia glutinosa polysaccharide liposome (RGPL) was investigated. In vivo, the splenic lymphocyte proliferation ratios and ovalbumin specific immunoglobulin G titers of ovalbumin-RGPL-vaccinated mice were significantly upregulated. In draining lymph nodes, the expression of MHC II+CD11c+ and CD86+CD11c+ was increased by RGPL; in addition, the percentages of central memory cells (TCM) and effector memory cells (TEM) were also elevated. RGPL could effectively provide adequate antigen exposure in lymph nodes. In vitro, RGPL could promote dendritic cell maturation and enhance dendritic cell functions, such as the mixed lymphocyte reaction and antigen presentation. Overall, the results demonstrated that RGPL has the potential to act as an effective controlled release vaccine adjuvant. PMID- 28008255 TI - Rescuing cholinergic neurons from apoptotic degeneration by targeting of serotonin modulator-and apolipoprotein E-conjugated liposomes to the hippocampus. AB - beta-Amyloid (Abeta)-targeting liposomes (LIP) with surface serotonin modulator (SM) and apolipoprotein E (ApoE) were utilized to facilitate the delivery of nerve growth factor (NGF) across the blood-brain barrier (BBB) for neuroprotection in the hippocampus. The therapeutic efficacy of SM- and ApoE grafted LIP carrying NGF (NGF-SM-ApoE-LIP) was assessed by an in vitro Alzheimer's disease (AD) model of degenerated SK-N-MC cells and an in vivo AD model of Abeta-insulted Wistar rats. The experimental evidences revealed that the modified SM and ApoE on the surface of LIP increased the permeation of NGF across the BBB without serious damage to structural integrity of tight junction. When compared with free NGF, NGF-SM-ApoE-LIP upregulated the expression of phosphorylated neurotrophic tyrosine kinase receptor type 1 on cholinergic neurons and significantly improved their survival. In addition, NGF-SM-ApoE-LIP could reduce the secretion of acetylcholinesterase and malondialdehyde and rescue hippocampal neurons from apoptosis in rat brains. The synergistic effect of SM and ApoE is promising in the induction of NGF to inhibit the neurotoxicity of Abeta and NGF-SM-ApoE-LIP can be a potent antiapoptotic pharmacotherapy for clinical care of patients with AD. PMID- 28008256 TI - Blonanserin treatment in patients with methamphetamine-induced psychosis comorbid with intellectual disabilities. AB - OBJECTIVE: Methamphetamine (MA) use has recently been associated with high levels of psychiatric hospitalization and serious social dysfunction. MA use causes frequent psychotic symptoms, which can be treated with antipsychotics. However, people with intellectual disabilities (ID) are vulnerable to adverse effects resulting from treatment with antipsychotic medications. METHOD: We report two cases of MA-induced psychosis (MAP) in patients with ID who were treated with the antipsychotic blonanserin. RESULTS: In both the cases presented, symptoms of psychosis were improved by switching medications from other antipsychotic drugs to blonanserin. Despite the presence of ID in these patients, no significant adverse effects, such as sedation, were detected after treatment with blonanserin. CONCLUSION: Blonanserin may be an effective and well-tolerated pharmacotherapeutical treatment for patients with MAP comorbid with ID. However, further work is necessary to validate this claim. PMID- 28008257 TI - Non-24-hour sleep-wake syndrome improved by low-dose valproic acid: a case report. AB - A woman was diagnosed with non-24-hour sleep-wake syndrome and depressive symptoms. Her depressive symptoms did not respond to standard doses of several antidepressants or mood stabilizers. Furthermore, her sleep-wake cycle remained non-entrained despite treatment with a melatonin-related drug, vitamin B12, and phototherapy. Ultimately, her sleep-wake rhythm was restored to a 24-hour pattern with a low dose of valproic acid, and her depressive symptoms tended to improve as a result of synchronization without antidepressants. Low-dose valproic acid appears to be one of the effective means of entraining circadian rhythms in patients with non-24-hour sleep-wake syndrome, which in turn likely improves associated depressive symptoms. PMID- 28008259 TI - Efficacy and tolerability of topiramate-augmentation therapy for schizophrenia: a systematic review and meta-analysis of randomized controlled trials. AB - This study aimed to perform a comprehensive meta-analysis of topiramate augmentation therapy in patients with schizophrenia receiving antipsychotic agents. Data published up to June 20, 2016 were obtained from the PubMed, PsycINFO, and Cochrane Library databases. Twelve randomized controlled trials comparing topiramate to placebo or antipsychotic only were included (n=676 patients). The primary outcome was change in overall symptoms. Relative risk (RR) and standardized mean difference (SMD), along with 95% confidence intervals, were calculated using random effects model for each outcome. Topiramate-augmentation therapy was superior to the control for decreasing overall symptoms (SMD -0.55, 95% confidence interval -0.86 to -0.24; P=0.001; I2=55%, eight comparisons, n=380), positive symptoms (SMD -0.4), negative symptoms (SMD -0.47), and Positive and Negative Syndrome Scale general subscale scores (SMD -0.67). Furthermore, topiramate-augmentation therapy decreased weight (SMD -0.69) and body mass index (SMD -0.95) compared with the control. Topiramate was similar to the control with respect to discontinuation due to all causes (RR 1.19), inefficacy (RR 1.71), and adverse events (RR 1.09). Topiramate was associated with higher incidence of paresthesia (RR 2.67) and attention difficulty (RR 8.97) compared with the control. Our results seemed to suggest that topiramate-augmentation therapy improves the psychopathology of schizophrenia with good tolerability and has the additional advantage of weight maintenance. However, because there were some limitations (numbers of studies and patients included in the meta-analysis were small, some studies used completer analysis, Chinese studies were included in the meta-analysis, and studies that had a risk of bias were included in the meta analysis) in this study, we cannot apply the results of this study in daily clinical practice. PMID- 28008258 TI - Incidence, risk factors, and phenomenological characteristics of postoperative delirium in patients receiving intravenous patient-controlled analgesia: a prospective cohort study. AB - BACKGROUND: Intravenous patient-controlled analgesia (IVPCA) is a common method of relieving pain which is a risk factor of postoperative delirium (POD). However, research concerning POD in IVPCA patients is limited. OBJECTIVE: We aimed to determine the incidence, risk factors, and phenomenological characteristics of POD in patients receiving IVPCA. METHODS: A prospective, cohort study was conducted in post-general anesthesia IVPCA patients aged >=60 years. POD was measured by the Nursing Delirium Screening Scale (NuDESC; 0-10). Delirium, pain severity at rest and/or on movement, and side effects of IVPCA during 3 postoperative days were examined twice-daily by the acute pain service team. Pain severity is measured by an 11-point verbal numerical rating scale (11 point VNRS) (0-10). An 11-point VNRS >3 was considered inadequate pain relief. If POD (detected by NuDESC >=1) is suspected, consulting a neurologist or a psychiatrist to confirm suspected POD is required. RESULTS: In total, 1,608 patients were included. The incidence rate of POD was 2.2%. Age >=70 years and American Society of Anesthesiologists physical status >III were the risk factors of POD in IVPCA patients. Approximately three-quarters of all POD cases occurred within the first 2 postoperative days. For pain at rest, patients with inadequate pain relief had significantly greater rates of POD than patients with adequate pain relief (day 1, 8.4% vs 1.5%, P<0.001; day 2, 9.6% vs 2.0%, P=0.028; day 3, 4.1% vs 2.1%, P=0.412). However, the incidence of POD was not associated with movement-evoked pain relief. Most (79.9%) POD cases in IVPCA patients showed either one or two symptoms. The symptoms of POD were ranked from high to low as disorientation (65.7%), illusions/hallucinations (37.1%), inappropriate communication (31.4%), inappropriate behavior (25.7%), and psychomotor retardation (14.2%). CONCLUSION: The incidence rate of POD in IVPCA patients was low. Further research is warranted concerning POD and IVPCA pain management. PMID- 28008260 TI - Association between the high-dose use of benzodiazepines and rehospitalization in patients with schizophrenia: a 2-year naturalistic study. AB - BACKGROUND: High-dose use of benzodiazepines (BZPs) reportedly causes adverse effects on cognitive function and quality of life in patients with schizophrenia. However, effects of BZPs on the clinical course of schizophrenia have not been clarified. This study was set out to investigate the association between BZPs and rehospitalization of patients with schizophrenia. METHODS: In this retrospective study, patients with schizophrenia who were discharged from Tokyo Medical University Hospital between January 2009 and February 2012 were eligible as subjects. One hundred and eight patients who continued treatment for >2 years after hospital discharge were included in this study. Clinical characteristics, doses of prescribed medication such as BZPs and antipsychotics, and Global Assessment of Functioning scores at discharge were investigated. The primary outcome was rehospitalization of patients for any reason. RESULTS: In a total of 108 subjects with schizophrenia, 44 subjects (40.7%) experienced rehospitalization during the 2-year study period. A multivariate analysis by the Cox proportional hazards model revealed that low educational history (hazard ratio =2.43, P=0.032), younger onset age of schizophrenia (hazard ratio =2.10, P=0.021), and higher diazepam-equivalent dose (hazard ratio =6.53, P=0.011) were significantly associated with the time to rehospitalization after hospital discharge. CONCLUSION: The results of this study suggest that high-dose use of BZPs at discharge in patients with schizophrenia might be associated with a shorter time to rehospitalization. PMID- 28008261 TI - Balanced discussion of second-generation antihistamines' data. PMID- 28008262 TI - Kinetics of circulating endothelial progenitor cells in patients undergoing carotid artery surgery. AB - AIM: Endothelial progenitor cells (EPCs) are primitive cells found in the bone marrow and peripheral blood (PB). In particular, the potential of EPCs to differentiate into mature endothelial cells remains of high interest for clinical applications such as bio-functionalized patches for autologous seeding after implantation. The objective of this study was to determine EPCs' kinetics in patients undergoing carotid artery thromboendarterectomy (CTEA) and patch angioplasty. METHODS: Twenty CTEA patients were included (15 male, mean age 76 years). PB samples were taken at 1 day preoperatively, and at 1, 3, and 5 days postoperatively. Flow cytometric analysis was performed for CD34, CD133, KDR, and CD45. Expression of KDR, SDF-1alpha, and G-CSF was analyzed by means of enzyme linked immunosorbent assay. RESULTS: Fluorescence-activated cell sorting analysis revealed 0.031%+/-0.016% (% of PB mononuclear cells) KDR+ cells and 0.052%+/ 0.022% CD45-/CD34+/CD133+ cells, preoperatively. A 33% decrease of CD45 /CD34+/CD133+ cells was observed at day 1 after surgery. However, a relative number (compared to initial preoperative values) of CD45-/CD34+/CD133+ cells was found on day 3 (82%) and on day 5 (94%) postoperatively. More profound upregulated levels of CD45-CD34+/CD133+ cells were observed for diabetic (+47% compared to nondiabetic) and male (+38% compared to female) patients. No significant postoperative time-dependent differences were found in numbers of KDR+ cells and the concentrations of the cytokines KDR and G-CSF. However, the SDF-1alpha levels decreased significantly on day 1 postoperatively but returned to preoperative levels by day 3. CONCLUSION: CTEA results in short-term downregulation of circulating EPCs and SDF-1alpha levels. Rapid return to baseline levels might indicate participation of EPCs in repair mechanisms following vascular injury. PMID- 28008263 TI - Clinical features of brain metastases in breast cancer: an implication for hippocampal-sparing whole-brain radiation therapy. AB - OBJECTIVE: The objectives of this study were to describe the distribution of brain metastases (BM) in breast cancer patients and investigate the risk factors for perihippocampal metastases (PHM). PATIENTS AND METHODS: Retrospective analysis of the clinicopathological characteristics and patterns of BM was performed. Associations between clinicopathological characteristics and PHM (the hippocampus plus 5 mm margin) were evaluated using logistic regression analyses. RESULTS: A total of 1,356 brain metastatic lesions were identified in 192 patients. Patients with 1-3 BM, 4-9 BM, and >=10 BM accounted for 63.0%, 18.8%, and 18.2%, respectively. There were only 7 (3.6%) patients with hippocampal metastases (HM) and 14 (7.3%) patients with PHM. On logistic regression, the number of BM was an independent risk factor for PHM. Patients with >=10 BM had a significantly higher risk of PHM compared with those with <10 BM. Breast cancer subtype (BCS) was not associated with PHM. The number of BM was significantly correlated with various BCSs. Patients with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+, HR-/HER2+, and HR-/HER2- subtypes had a higher probability of >=10 BM, relative to patients with an HR+/HER2- subtype. CONCLUSION: Our study suggests that a low incidence of PHM may be acceptable to perform hippocampal-sparing whole-brain radiation therapy for breast cancer patients. Patients with extensive diffuse metastases (>=10 BM) were associated with higher odds of PHM. PMID- 28008264 TI - Impact of preoperative chronic renal failure on liver transplantation: a population-based cohort study. AB - PURPOSE: The purpose of this study was to assess whether preoperative chronic renal failure (CRF) affects the rates of postoperative complications and survival after liver transplantation. METHODS: This population-based retrospective cohort study included 2,931 recipients of liver transplantation performed between 1998 and 2012, enrolled from the Taiwan National Health Insurance Research Database. Patients were divided into two groups, based on the presence or absence of preoperative CRF. RESULTS: The overall estimated survival rate of liver transplantation recipients (LTRs) with preoperative CRF was significantly lower than that of patients without preoperative CRF (P=0.0085). There was no significant difference between the groups in terms of duration of intensive care unit stay, total hospital stay, bacteremia, postoperative bleeding, and pneumonia during hospitalization. Long-term adverse effects, including cerebrovascular disease and coronary heart disease, were not different between patients with versus without CRF. CONCLUSION: These findings suggest that LTRs with preoperative CRF have a higher rate of mortality. PMID- 28008265 TI - Prevalence of cardiovascular risk factors among workers at a private tertiary center in Angola. AB - BACKGROUND: The burden of cardiovascular diseases (CVD) is increasing in most countries of sub-Saharan Africa. However, as there is a scarcity of data, little is known about CVD in Angola. This study aimed to determine the prevalence of prehypertension, hypertension, prediabetes, diabetes, overweight, and obesity among workers at a private tertiary center in Angola. METHODS: A cross-sectional study was conducted among 781 workers of Clinica Girassol, a tertiary health care center in Angola, during the month of November 2013. Demographic, anthropometric, and clinical variables were analyzed. RESULTS: Of the 781 participants studied, 50.44% were males and 78.11% were under 40 years old. The prevalence of hypertension and prehypertension was 17.93% (95% confidence interval [CI]: 15.24% 20.74%) and 54.03% (95% CI: 50.58%-57.62%), respectively. Among hypertensive subjects, 83.57% (117) were unaware of the diagnosis. Hypertension was associated with age (>=40 years) (odds ratio [OR]: 6.21; 95% CI: 4.18-9.24; P<0.001) and with overweight and obesity (OR: 2.32; 95% CI: 1.56-3.44; P<0.001). The prevalence of diabetes and prediabetes was 2.69% (95% CI: 1.54%-3.97%) and 7.94% (95% CI: 6.02%-9.99%), respectively. The prevalence of overweight was 34.44% (95% CI: 31.11%-37.90%) and 19.85% (95% CI: 17.03%-22.79%) for obesity. There was an association between overweight and obesity and the female sex (OR: 1.71; 95% CI: 1.29-2.28; P<0.001). The prevalence of family history of CVD, smoking, and alcoholism was 52.24%, 4.87%, and 45.33%, respectively. CONCLUSION: There was a high prevalence of cardiovascular risk factors in apparently healthy workers at the private tertiary center in Angola. PMID- 28008266 TI - Gender Comparison in Referrals and Treatment Completion to Residential and Outpatient Alcohol Treatment. AB - BACKGROUND: Residential treatment for alcoholism is associated with high completion rates for clients, yet there appear to be gender disparities in patient referrals and treatment completion rates. We studied whether (A) gender is associated with differential patient placement to outpatient vs. residential treatment facilities and (B) completion rates differ by gender. METHODS: In this cross-sectional study, we analyzed the admission and discharge data from 185 publicly funded substance abuse treatment facilities across Los Angeles County between 2005 and 2010. RESULTS: Among the 33,745 studied cases, women were referred to residential treatment facilities less frequently than men (75% vs. 66%). The adjusted results derived from logistic regression models confirmed that females were more likely to be referred to outpatient treatment than to residential treatment facilities (odds ratio [OR]: 1.15, 95% confidence interval [CI]: 1.05-1.26). In addition, we observed that compared to White/Caucasian patients, all other races were associated with more referral to outpatient facilities (ie, less referral to residential facilities), indicating a racial disparity on the top of the observed gender disparity. However, there was no significant link between gender and treatment completion rates (OR: 0.93, 95% CI: 0.86-1.00). CONCLUSIONS: Women seem to have treatment completion rates comparable to men, yet they are less likely to be referred to residential treatment facilities. Hence, there still remains a gender disparity in alcoholic patient referrals. Further studies should delineate which specific therapeutic aspects and programmatic components of women-focused treatments are essential to augment positive treatment outcomes. PMID- 28008267 TI - Oncological Outcomes and Complications After Volume Replacement Oncoplastic Breast Conservations-The Glasgow Experience. AB - INTRODUCTION: Oncoplastic breast conservation surgery (OBCS) combines the principles of surgical oncology and plastic surgery. OBCS has now become a growing option for the treatment of breast cancer and forms a part of breast conserving therapy (BCT). We sought to investigate and report our experience in two breast units in Glasgow (Victoria Infirmary and Western Infirmary) on volume replacement OBCS. MATERIALS AND METHODS: Details of patients treated with volume replacement OBCS were identified from a prospectively recorded database from November 2010 to October 2015. The clinical records included in the oncoplastic dataset were analyzed for demographics, tumor, treatment characteristics, and recurrences. The data were analyzed for follow-up to determine the pattern and timing of recurrence up to April 2016. The primary outcome of this study was tumor-free margin resection rates, and the secondary outcomes were locoregional and distant recurrence rates as these correlate with the overall oncological safety of volume replacement oncoplastic breast surgery (OPBS). RESULTS: A total of 30 volume replacement oncoplastic breast conservation procedures have been carried out in this time period. The mean age of the former group was 51 years. Twice as many patients presented symptomatically than had tumors detected on screening. The mean preoperative tumor size on radiology was 25.4 mm. Patients underwent 13 thoracoepigastric flaps, 5 lateral intercostal artery perforator (LICAP) flaps, 2 thoracodorsal artery perforator (TDAP) flaps, 1 lateral thoracic artery perforator (LTAP) flap, 1 crescent flap volume replacement surgery, and 8 matrix rotations. Two patients had neoadjuvant chemotherapy. Fourteen patients had adjuvant chemotherapy, and all patients were treated with adjuvant radiotherapy. Twenty-two patients were treated with hormonal therapy and four patients were treated with Herceptin. The rate of incomplete excision was 10%. Median follow-up time was 48.5 months. Only one regional recurrence was detected. Eight patients encountered some form of complication. CONCLUSION: This study continues to show the relative oncological safety of volume replacement oncoplastic conservations as an option for reconstruction in breast cancer patients. Further research is urgently needed to build robust evidence supporting the long-term oncological safety. PMID- 28008268 TI - Identification of Stevioside Using Tissue Culture-Derived Stevia (Stevia rebaudiana) Leaves. AB - Stevioside is a natural sweetener from Stevia leaf, which is 300 times sweeter than sugar. It helps to reduce blood sugar levels dramatically and thus can be of benefit to diabetic people. Tissue culture is a very potential modern technology that can be used in large-scale disease-free stevia production throughout the year. We successfully produced stevia plant through in vitro culture for identification of stevioside in this experiment. The present study describes a potential method for identification of stevioside from tissue culture-derived stevia leaf. Stevioside in the sample was identified using HPLC by measuring the retention time. The percentage of stevioside content in the leaf samples was found to be 9.6%. This identification method can be used for commercial production and industrialization of stevia through in vitro culture across the world. PMID- 28008269 TI - Perioperative Management of Direct Oral Anticoagulants (DOACs): A Systemic Review. AB - Direct oral anticoagulants (DOACs) are in wide use among patients requiring both short- and long-term anticoagulation, mainly due to their ease of use and the lack of monitoring requirements. With growing use of DOACs, it is imperative that physicians be able to manage patients on these medications, especially in the perioperative period. We aim to provide guidance on the management of DOACs in the perioperative period. In this review, we performed an extensive literature search summarizing the management of patients on direct-acting anticoagulants in the perioperative period. A total of four direct-acting oral anticoagulants were considered appropriate for inclusion in this review. The drugs were dabigatran etexilate mesylate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa). Management of patients on DOACs in the perioperative period involves an assessment of thromboembolic event risk while off anticoagulation compared to the relative risk of bleeding if such drug is continued. DOACs may not need to be discontinued in minor surgeries or procedures, and in major surgeries, they may be discontinued hours prior depending on drug pharmacokinetics and renal function of the patients. PMID- 28008270 TI - Overexpression and clinical significance of MYC-associated zinc finger protein in pancreatic carcinoma. AB - This study aimed to investigate the expression and clinical significance of MYC associated zinc finger protein (MAZ) in pancreatic carcinoma (PC), and the biological functions of MAZ in PC cells. MAZ expression was detected in 57 PC tissues and 41 paired adjacent nontumor tissues by immunohistochemistry. Compared to the expression in adjacent nontumor tissues, MAZ was significantly higher expressed in PC tissues (P<0.0001). In addition, MAZ expression had a significant correlation with certain clinical characteristics of PC patients, such as age, tumor diameter, tumor number, and the serum level of CA199 (P<0.05). The survival analysis showed that the survival time of PC patients with high expression of MAZ was significantly lower than patients with low expression of MAZ (P=0.0365). After MAZ was knocked down in PANC-1 cells by RNA interference, the cells' ability to proliferate, invade, and migrate was decreased significantly (P<0.01). Moreover, MAZ expression was found to be associated with Ki-67, a cell proliferation marker, in PC tissues, further supporting the idea that MAZ promotes PC cell proliferation. Our study clarifies an oncogenic role of MAZ in pathogenesis of PC and provides MAZ as a biomarker in the treatment and prognosis of PC. PMID- 28008271 TI - Early detection of poor outcome in patients with metastatic colorectal cancer: tumor kinetics evaluated by circulating tumor cells. AB - BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer worldwide. New prognostic markers are needed to identify patients with poorer prognosis, and circulating tumor cells (CTCs) seem to be promising to accomplish this. PATIENTS AND METHODS: A prospective study was conducted by blood collection from patients with metastatic CRC (mCRC), three times, every 2 months in conjunction with image examinations for evaluation of therapeutic response. CTC isolation and counting were performed by Isolation by Size of Epithelial Tumor Cells (ISET). RESULTS: A total of 54 patients with mCRC with a mean age of 57.3 years (31-82 years) were included. Among all patients, 60% (n=32) were carriers of wild-type KRAS (WT KRAS) tumors and 90% of them (n=29) were exposed to monoclonal antibodies along with systemic treatment. Evaluating CTC kinetics, when we compared the baseline (pretreatment) CTC level (CTC1) with the level at first follow-up (CTC2), we observed that CTC1-positive patients (CTCs above the median), who became negative (CTCs below the median) had a favorable evolution (n=14), with a median progression-free survival (PFS) of 14.7 months. This was higher than that for patients with an unfavorable evolution (CTC1- that became CTC2+; n=13, 6.9 months; P=0.06). Patients with WT KRAS with favorable kinetics had higher PFS (14.7 months) in comparison to those with WT KRAS with unfavorable kinetics (9.4 months; P=0.02). Moreover, patients whose imaging studies showed radiological progression had an increased quantification of CTCs at CTC2 compared to those without progression (P=0.04). CONCLUSION: This study made possible the presentation of ISET as a feasible tool for evaluating CTC kinetics in patients with mCRC, which can be promising in their clinical evaluation. PMID- 28008272 TI - Different levels of serum microRNAs in prostate cancer and benign prostatic hyperplasia: evaluation of potential diagnostic and prognostic role. AB - INTRODUCTION: Diagnosis of prostate cancer (PCa) is based on prostate biopsy that is performed when prostate specific antigen (PSA) is persistently altered over time and/or abnormal digital rectal examination is found. Serum PSA levels increase in both PCa and benign prostatic hyperplasia, leading to an increased number of unnecessary biopsies. There is an urgent need to unravel PCa-specific molecular signatures. PATIENTS AND METHODS: This study aimed at characterizing a panel of circulating micro RNAs (miRNAs) that could distinguish PCa from benign prostatic hyperplasia in a population of age-matched patients with increased PSA levels. Both miRNAs targeting genes involved in PCa onset and miRNAs whose role in PCa has been highlighted in other studies were included. For this purpose, let 7c, let-7e, let-7i, miR-26a-5p, miR-26b-5p, miR-24-3p, miR-23b-3p, miR-27-b-3p, miR-106a-5p, miR-20b-5p, miR-18b-5p, miR-19b-2-5p, miR-363-3p, miR-497, miR-195, miR-25-3p, miR-30c-5p, miR-622, miR-874-3p, miR-346 and miR-940 were assayed through real-time PCR in 64 patients with PCa and compared with 60 patients with benign prostatic hyperplasia. The ability of miRNAs to predict the stage of disease was also analyzed. RESULTS: Let-7c, let-7e, let-7i, miR-26a-5p, miR-26b 5p, miR-18b-5p and miR-25-3p were able to discriminate patients with PCa from those harboring benign prostatic hyperplasia, both presenting altered PSA levels (>3 ng/mL). MiR-25-3p and miR-18b-5p showed the highest sensitivity and specificity to predict PCa, respectively. The combination of these two miRNAs improved the overall sensitivity. A correlation between pathological Gleason score and miRNA expression levels was reported; miR-363-3p, miR-26a-5p, miR-26b 5p, miR-106a-5p, miR-18b-5p, miR-25-3p and let-7i decreased in expression concomitantly with an increase in malignancy. CONCLUSION: This study confirms serum miRNAs to be reliable candidates for the development of minimally invasive biomarkers for the diagnosis and prognosis of PCa, particularly in those cases where PSA acts as a flawed marker. PMID- 28008273 TI - Evaluation of the efficacy of chemoradiotherapy in cervical cancer using diffusion-weighted imaging and apparent diffusion coefficient. AB - OBJECTIVE: This study aims to evaluate the efficacy of chemoradiotherapy (CRT) in cervical cancer using diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) values. METHODS: A total of 71 patients with cervical cancer were enrolled in this study. All patients underwent conventional magnetic resonance imaging and DWI scanning before CRT and at 7, 14, 21 days, and 6 months after CRT. These patients were divided into the complete response (CR) and non-CR groups according to the response evaluation criteria in solid tumors criteria. Receiver operating characteristic (ROC) curve was used to evaluate the accuracy of ADC values in predicting the efficacy of CRT in cervical cancer. RESULTS: Compared with before-CRT treatment, tumor volumes were reduced and ADC values were elevated in both CR and non-CR groups after CRT treatment. At 21 days after CRT, tumor volumes in the CR group were smaller than those in the non-CR group. During the period of 21 days to 6 months after CRT, tumor regression rate and the increased rate of ADC values in the CR group were higher than those in the non-CR group. ROC curves revealed that the increased rate of ADC values at 21 days after CRT was the optimal time point for the prediction of CRT efficacy in cervical cancer, with the area under the curve, sensitivity, and specificity of 0.775, 92.7%, and 62.5%, respectively. CONCLUSION: Our study provides evidence that the increased rate of ADC at 21 days after CRT might be a promising tool for predicting the efficacy of CRT in cervical cancer. PMID- 28008274 TI - Lipopolysaccharide-induced alpha-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-kappaB signaling-dependent manner. AB - alpha-Catenin is an important molecule involved in the maintenance of cell-cell adhesion and a prognostic marker in cancer since its expression is essential for preventing cancer metastasis. However, the mechanism that leads to the downregulation of alpha-catenin in cancer progression remains unclear. The present study revealed that lipopolysaccharide (LPS)-induced NF-kappaB signaling activation suppressed alpha-catenin expression and motility in SW620 colorectal cancer (CRC) cells, using real-time polymerase chain reaction, Western blotting, and transwell migration assays. LPS treatment reduced both the mRNA and protein expression of alpha-catenin and thereby enhanced cell motility. Conversely, incubating cells with an NF-kappaB inhibitor disrupted these effects. Furthermore, the ectopic expression of p65 alone mimicked the effects of LPS stimulation. In CRC tissues, the presence of enteric bacterial LPS-related neutrophil-enriched foci was correlated with alpha-catenin downregulation. Collectively, these findings suggest that LPS-induced NF-kappaB signaling is related to alpha-catenin suppression and enhanced cell motility in CRC. Therefore, NF-kappaB is a novel potential therapeutic target for CRC metastasis. PMID- 28008275 TI - Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. In advanced setting and after progression to imatinib, the multi-targeted receptor tyrosine kinase inhibitor sunitinib has clearly demonstrated a clinical benefit in terms of response rate and progression-free survival with an acceptable toxicity profile. The recommended schedule for sunitinib administration is 50 mg per day 4 weeks ON and 2 weeks OFF; however, potential alternative schedules are also reviewed in the present article. Several biomarkers have been explored to better select candidates for sunitinib therapy, such as the value of early changes in standardized uptake value assessed by positron emission tomography with 18F-fluorodeoxyglucose, circulating biomarkers, clinical biomarkers such as the appearance of arterial hypertension during treatment that correlates with better outcomes, and the GIST genotype. GISTs with KIT mutations at exon 9 and the so-called wild-type GISTs seem to better respond to sunitinib. Nonetheless, further investigation is required to confirm these findings as well as to understand the mechanisms of sunitinib resistance such as the development of new KIT mutations or conformational changes in KIT receptor. PMID- 28008276 TI - Non-secretory multiple myeloma: from biology to clinical management. AB - Multiple myeloma (MM) is the second most common hematologic malignancy in the US. It is typically characterized by production of large amounts of defective immunoglobulin (Ig). Diagnosing MM and monitoring treatment response, including eventual relapse, are largely based on sequential measurements of Ig. However, a small subset of MM called non-secretory multiple myeloma (NSMM) produces no detectable Ig. This subset of true NSMM has become even smaller over time, as the advent of the serum free light chain assay has resulted in the majority of NSMM patients being recategorized as light-chain MM - that is, MM cells that produce only the light-chain component of Ig. True forms of NSMM, meaning MM that secretes no monoclonal proteins whatsoever, constitute a distinct entity that is reviewed; definition of NSMM using current detection methods, discuss the biology underpinning NSMM development, and share recommendations for how NSMM should be managed clinically with respect to detection, treatment, and monitoring. PMID- 28008277 TI - Technical and clinical validation of an environmental exposure unit for ragweed. AB - BACKGROUND: Allergic rhinitis is a common condition, with ragweed pollen one of the more prevalent aeroallergens. Environmental exposure units such as the Allergen BioCube(r) are valuable models for clinical allergy studies. A study was conducted to validate the Allergen BioCube for uniform ragweed pollen concentrations and clinically relevant sign and symptom responses to ragweed exposure. METHODS: Ragweed pollen concentrations were measured on 3 consecutive days in the Allergen BioCube and verified by Rotorod collection and continuous laser particle count measurements. Subjects (N=10) were exposed to ragweed pollen in the BioCube for 3 hours per day for 3 consecutive days. Subjects assessed their nasal itching, sneezing, rhinorrhea, and nasal congestion during each BioCube exposure; total nasal symptom score was computed. Peak nasal inspiratory flow was also assessed during BioCube exposure. RESULTS: Uniform ragweed pollen concentrations were obtained throughout each of the 3-hour testing periods in the Allergen BioCube, both spatially and temporally, at all subject positions, with a low mean standard deviation of 10%. Pronounced increases in mean total nasal symptom scores (6.7+/-0.94 to 7.6+/-0.86, last 90 minutes of exposure) occurred for all three BioCube ragweed pollen exposure visits. Mean peak nasal inspiratory flow decreased 24% at 3 hours of BioCube exposure on Day 3. No safety issues of concern occurred in this study. CONCLUSION: The Allergen BioCube achieved technical and clinical validation for ragweed allergen. Ragweed pollen concentration was uniform both temporally and spatially. Allergic rhinitis signs and symptoms were induced in subjects during exposure to ragweed in the BioCube at clinically meaningful levels for allergy studies. PMID- 28008278 TI - Acne keloidalis nuchae: prevalence, impact, and management challenges. AB - Acne keloidalis nuchae (AKN) also known as folliculitis keloidalis nuchae (FKN) is a chronic form of scarring folliculitis seen mostly in men of African descent. The term AKN is commonly used even though the condition is not a keloid, and the affected individuals do not have a tendency to develop keloids in other areas of the body. It is seen in post pubertal men and is rare after the age of 55 years. A few cases have been reported in females. which has been classified as a primary cicatricial alopecia since the exact cause of acne keloidalis (AK) remains unknown. However, a few inciting agents have been suggested which include androgens, inflammation, infection, trauma, genetics, and ingrowing hairs. AK shares some similar features with other forms of cicatricial alopecia and may occur together. Papules, pustules, and sometimes tumorous masses in the nuchal or occipital regions of the scalp hence the name "bumps" evolved in the environment. Despite its common occurrence, only a few seek help in hospital when lesions start to unsightly affect the individual's quality of life. The presences of the keloidal lesions are more stressful compared to the resulting alopecia. Various attempts to reduce the bumps with corrosives, acids, and car engine oils lead to larger lesions or unsightly scars. Active lesions produce bleeding during haircuts. This is worrisome as a couple of individuals with active AK share shaving instruments at the barber shop and are at risk of acquiring or transmitting blood-borne infections. There is an urgent need to encourage safe shaving habits and treatment of lesions at onset so as to prevent unsightly lesions. PMID- 28008280 TI - Thicker carotid intima-media thickness and increased plasma VEGF levels suffered by post-acute thrombotic stroke patients. AB - BACKGROUND AND OBJECTIVES: Atherosclerosis causes reduction of the oxygen supply to structures in the far arterial wall, provoking the release of factors that drive angiogenesis of vasa vasorum, including VEGF. Other studies have revealed the inflammatory response in atherosclerosis and the role of platelet factor 4 (PF4) as an anti-angiogenic chemokine through the inhibition of VEGF. This cross sectional study aims at measuring the effect of atherosclerosis assessed through carotid intima-media thickness (CIMT) against plasma VEGF levels in patients with post-acute thrombotic stroke. MATERIALS AND METHODS: CIMT was assessed sonographically using GE Logiq S6 with 13 MHz frequency linear probe. VEGF-A plasma levels were measured using enzyme-linked immunosorbent assay (ELISA) method. Differences among variables were compared statistically. The data were analyzed using Pearson correlation. RESULTS: A total of 25 patients with post acute thrombotic stroke were identified in days 7 to 90. CIMT thickening was indicated in 88% of patients (1.202 +/- 0.312 mm), while an increase in plasma VEGF was identified in all patients (178.28 +/- 93.96 ng/mL). There was no significant correlation between CIMT and plasma VEGF levels in patients with post acute thrombotic stroke (p=0.741). A significant correlation was recognized between CIMT and total cholesterol (p=0.029) and low-density lipoprotein (p=0.018). CONCLUSION: There were no significant correlations between CIMT and plasma VEGF levels in patients with post-acute thrombotic stroke. However, plasma VEGF increased in patients with thrombotic stroke. CIMT measurement is a promising noninvasive modality to assess the vascular condition of patients with stroke and diabetes, while plasma VEGF cannot specifically assess vascular condition as it can be triggered by ischemic conditions in tissues of the whole body. PMID- 28008279 TI - Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. AB - Human mesenchymal stem cells (MSCs) are considered to be a promising source of cells in regenerative medicine. They have large potential to differentiate into various tissue-specific populations and may be isolated from diverse tissues in desired quantities. As cells of potential autologous origin, they allow recipients to avoid the alloantigen responses. They also have the ability to create immunomodulatory microenvironment, and thus help to minimize organ damage caused by the inflammation and cells activated by the immune system. Our knowledge about the reparative, regenerative, and immunomodulatory properties of MSCs is advancing. At present, there is a very comprehensible idea on how MSCs affect the immune system, particularly in relation to the tissue and organ damage on immunological basis. Hitherto a number of effective mechanisms have been described by which MSCs influence the immune responses. These mechanisms include a secretion of soluble bioactive agents, an induction of regulatory T cells, modulation of tolerogenic dendritic cells, as well as induction of anergy and apoptosis. MSCs are thus able to influence both innate and adaptive immune responses. Soluble factors that are released into local microenvironment with their subsequent paracrine effects are keys to the activation. As a result, activated MSCs contribute to the restoration of damaged tissues or organs through various mechanisms facilitating reparative and regenerative processes as well as through immunomodulation itself and differentiation into the cells of the target tissue. PMID- 28008281 TI - Nicoboxil/nonivamide cream effectively and safely reduces acute nonspecific low back pain - a randomized, placebo-controlled trial. AB - BACKGROUND/OBJECTIVE: Low back pain affects many patients and has a high socioeconomic impact. Topical capsaicinoids have been used for decades to treat musculoskeletal pain. This study investigated the effects of the fixed dose combination (FDC) of nonivamide (a capsaicinoid) and nicoboxil (a nicotinic acid ester) cream in the treatment of acute nonspecific low back pain. MATERIALS AND METHODS: This phase III randomized, double-blind, placebo-controlled, multinational, multi-center trial investigated efficacy, safety, and tolerability of topical nicoboxil 1.08%/nonivamide 0.17% (Finalgon(r) cream) in treatment of acute nonspecific low back pain with the endpoints: pain intensity (PI) difference between pre-dose baseline and 8 hours after first application and the end of treatment, mobility score, and efficacy score. RESULTS: Patients (n=138), 21-65 years of age, were treated for up to 4 days with FDC or placebo cream. Mean baseline PI was 6.8 on a 0-10 point numerical rating scale. After 8 hours, pain was more reduced with the FDC than with placebo (adjusted means: 2.824 vs. 0.975 points; p<0.0001). On the last treatment day, mean pain reduction by the FDC was stronger than with placebo (adjusted means: 5.132 vs. 2.174 points; p<0.0001). Mobility on Day 1 was in favor of the FDC when compared to placebo (odds ratio [95% confidence interval {CI}]: 7.200 [3.609, 14.363], p<0.0001). At the end of treatment, patients treated with the FDC rated efficacy significantly higher than placebo (odds ratio [95% CI]: 11.370 [5.342, 24.199], p<0.0001). Both treatments were tolerated well. No serious adverse events were reported. CONCLUSION: Nicoboxil/nonivamide cream is an effective and safe treatment for acute nonspecific low back pain, adding a promising treatment option. PMID- 28008282 TI - Expression and functionality of TRPV1 in breast cancer cells. AB - Transient receptor potential (TRP) channels contribute to the regulation of intracellular calcium, which can promote cancer hallmarks in cases of dysregulation of gene transcription and calcium-dependent pro-proliferative or anti-apoptotic mechanisms. Several studies have begun to elucidate the roles of TRPV1, TRPV6, TRPM8, and TRPC1 in cancer progression; however, no study has examined the expression profiles of human TRP channels in breast cancer on a large scale. This study focused on the expression and functionality of TRPV1, a nonselective cation channel that was found to be expressed in different carcinoma tissues. Next-generation sequencing analyses revealed the expression of TRPV1 in several native breast cancer tissues, which was subsequently validated via reverse transcriptase-polymerase chain reaction. Activation of TRPV1 by its ligand capsaicin was associated with the growth inhibition of some cancer cell types; however, the signaling components involved are complex. In this study, stimulation by the TRPV1 agonist, capsaicin, of SUM149PT cells, a model system for the most aggressive breast cancer subtype, triple-negative breast cancer, led to intracellular calcium signals that were diminished by the specific TRPV1 antagonist, capsazepin. Activation of TRPV1 by capsaicin caused significant inhibition of cancer cell growth and induced apoptosis and necrosis. In conclusion, the current study revealed the expression profiles of human TRP channels in 60 different breast cancer tissues and cell lines and furthermore validated the antitumor activity of TRPV1 against SUM149PT breast cancer cells, indicating that activation of TRPV1 could be used as a therapeutic target, even in the most aggressive breast cancer types. PMID- 28008283 TI - Validation of celiac disease diagnoses recorded in the Danish National Patient Register using duodenal biopsies, celiac disease-specific antibodies, and human leukocyte-antigen genotypes. AB - PURPOSE: The purpose of this study was to validate the celiac disease diagnoses recorded in the Danish National Patient Register. To validate the diagnoses, we used information on duodenal biopsies from a national register of pathology reports (the Patobank) and information on celiac disease-specific antibodies and human leukocyte antigen (HLA) genotypes obtained from patient medical records. PATIENTS AND METHODS: We included all the children who were born from 1995 to 2012 and who were registered as having celiac disease in the Danish National Patient Register. We reviewed all the pathology reports on duodenal biopsies in the Patobank and the information in the medical records on celiac disease specific antibodies (ie, anti-tissue transglutaminase 2 IgA and IgG, endomysial antibodies IgA, and anti-deamidated gliadin peptide IgG) and HLA genotypes. RESULTS: We identified 2,247 children who were registered in the Danish National Patient Register with celiac disease. Duodenal biopsies for 1,555 of the children (69%) were registered in the Patobank; 1,127 (50%) had a biopsy that was compatible with celiac disease (ie, Marsh 2-3). We accessed the medical records of 95% of the children who were registered in the Danish National Patient Register with celiac disease. We found that 1,510 (67%) had one or more positive antibody-test results; 1,120 (50%) had anti-tissue transglutaminase 2, IgA at tenfold or greater the upper limit of the normal range and/or positive endomysial antibody results. The positive predictive value depended on the criteria used for validation and the types and numbers of registrations that were included in the analysis and ranged from 62% (95% confidence interval: 60%-64%) to 86% (95% confidence interval: 84%-87%). CONCLUSION: Our findings indicate that the Danish National Patient Register is a valuable source to identify patients who have been diagnosed with celiac disease. However, validation of the diagnoses is warranted before data on the patients are used for research purposes. PMID- 28008284 TI - Implementation of co-trimoxazole preventive therapy policy for malaria in HIV infected pregnant women in the public health facilities in Tanzania. AB - BACKGROUND: In 2011, Tanzania adopted a policy for provision of daily co trimoxazole prophylaxis to HIV-infected pregnant women for prevention of malaria and other opportunistic infections. As per the policy, HIV-infected pregnant women should not be given sulfadoxine-pyrimethamine (SP) for intermittent preventive therapy. The challenges associated with this policy change and the extent to which the new policy for prevention of malaria in pregnant women coinfected with HIV was implemented need to be assessed. AIM: To assess the implementation of malaria-preventive therapy policy among HIV-infected pregnant women in the public health facilities in Dar es Salaam, Tanzania. METHODOLOGY: The study was conducted in Kinondoni Municipality, Dar es Salaam, Tanzania, from January 2015 to July 2015. Three hundred and fifty-three HIV-infected pregnant women who were attending antenatal clinics (ANCs) and using co-trimoxazole for prevention of malaria were interviewed. Twenty-six health care workers working at the ANCs were also interviewed regarding provision of co-trimoxazole prophylaxis to pregnant women. A knowledge scale was used to grade the level of knowledge of health care providers. Focus group discussions were also conducted with 18 health care workers to assess the level of implementation of the policy and the challenges encountered. RESULTS: Twenty-three (6.5%) pregnant women with known HIV serostatus were using co-trimoxazole for prevention of opportunistic infections even before they became pregnant. Out of the 353 HIV-infected pregnant women, eight (2.5%) were coadministered with both SP and co-trimoxazole. Sixty (16.7%) pregnant women had poor adherence to co-trimoxazole prophylaxis. Out of the 26 interviewed health care providers, 20 had high level of knowledge regarding malaria-preventive therapy in HIV-infected pregnant women. Lack of adequate supply of co-trimoxazole in health facilities and inadequate training of health care providers were among the factors causing poor implementation of co trimoxazole prophylaxis for prevention of malaria in HIV-infected pregnant women. CONCLUSION: There is a need to continue sensitization of pregnant women and communities about the importance of early attendance to the ANCs for testing of HIV and provision of co-trimoxazole prophylaxis. Availability of co-trimoxazole in the health facilities, regular training, and sensitization of health care providers are necessary for effective implementation of this policy. PMID- 28008285 TI - Development and validation of evaluation tools of nursing students' clinical pharmacology unit. AB - INTRODUCTION: The need for valid, reliable, and objective tools has always been emphasized in studies related to the clinical assessment of nursing students. The aims of this study were to develop and assess the validity and reliability of the tools used to evaluate the clinical pharmacology unit. METHODS: This study was a methodological one, conducted in 2016. An item pool was developed based on the literature review and personal interviews with faculty members. The tool's validity was determined through assessment of face validity, content validity, and construct validity, using exploratory factor analysis on the data provided by 264 second- and third-semester nursing students of the Islamic Azad University of Babol University of Medical Sciences. Reliability was determined through internal and external consistency, using a Cronbach's coefficient of the correlation between classes. RESULTS: Based on the exploratory factor analysis, all items with a special value of >1 were grouped into six factors: 1) professional behavior; 2) effective communication; 3) recognition of medical terminology; 4) nursing actions before administering medicine; 5) nursing actions while administering medicine; and 6) nursing actions after administering medicine. These factors explained 77% of the total variance of the concept of assessment of the clinical pharmacology unit. In this study, reliability was demonstrated by a Cronbach's alpha coefficient of 0.96; the correlation coefficient between floors for the total tool was 0.91, ranging from 0.64 to 0.89 in its dimensions. CONCLUSION: The evaluation tool of the clinical pharmacology unit has an acceptable construct validity and satisfactory reliability and validity. Therefore, it can be used to evaluate the clinical pharmacology unit in the nursing education system in Iran. PMID- 28008286 TI - Pregnancy after bariatric surgery: improving outcomes for mother and child. AB - The significant increase in the prevalence of obesity has led to an increase in the number of obese women who become pregnant. In this setting, in recent years, there has been an exponential rise in the number of bariatric procedures, with approximately half of them performed in women of childbearing age, and a remarkable surge in the number of women who become pregnant after having undergone bariatric surgery (BS). These procedures entail the risk of nutritional deficiencies, and nutrition is a crucial aspect during pregnancy. Therefore, knowledge and awareness of the consequences of these techniques on maternal and fetal outcomes is essential. Current evidence suggests a better overall obstetric outcome after BS, in comparison to morbid obese women managed conservatively, with a reduction in the prevalence of gestational diabetes mellitus, pregnancy associated hypertensive disorders, macrosomia, and congenital defects. However, the risk of potential maternal nutritional deficiencies and newborns small for gestational age cannot be overlooked. Results concerning the incidence of preterm delivery and the number of C-sections are less consistent. In this paper, we review the updated evidence regarding the impact of BS on pregnancy. PMID- 28008287 TI - Searching for sex- and gender-sensitive tuberculosis research in public health: finding a needle in a haystack. AB - Despite broadening consideration of sex- and gender-based issues in health research, when seeking information on how sex and gender contribute to disease contexts for specific health or public health topics, a lack of consistent or systematic use of terminology in health literature means that it remains difficult to identify research with a sex or gender focus. These inconsistencies are driven, in part, by the complexity and terminological inflexibility of the indexing systems for gender- and sex-related terms in public health databases. Compounding the issue are authors' diverse vocabularies, and in some cases lack of accuracy in defining and using fundamental sex-gender terms in writing, and when establishing keyword lists and search criteria. Considering the specific case of the tuberculosis (TB) prevention and management literature, an analysis of sex and gender sensitivity in three health databases was performed. While there is an expanding literature exploring the roles of both sex and gender in the trajectory and lived experience of TB, we demonstrate the potential to miss relevant research when attempting to retrieve literature using only the search criteria currently available. We, therefore, argue that for good clinical practice to be achieved; there is a need for both public health researchers and users to be better educated in appropriate usage of the terminology associated with sex and gender. In addition, public health database indexers ought to accept the task of developing and implementing adequate definitions of sex and gender terms so as to facilitate access to sex- and gender-related research. These twin advances will allow clinicians to more readily recognize and access knowledge pertaining to systems of redress that respond to gendered risks that compound existing health inequalities in disease management and control, particularly when dealing with already complex diseases. Given the methodological and linguistic challenges presented by the multidimensional and highly contextual nature of definitions of sex and gender, it will be important that this review task be undertaken using a multidisciplinary approach. PMID- 28008288 TI - A case of probable esomeprazole-induced transient liver injury in a pregnant woman with hyperemesis. AB - We report a case of 22-year-old primigravida presented to Women's Hospital - Hamad Medical Corporation emergency with severe epigastric pain, nausea, and vomiting. On admission, she was dehydrated with remarkably worsening symptoms. Laboratory findings revealed significantly elevated liver enzymes with unknown etiology. Her past medical history showed an admission for nausea and vomiting 3 weeks previously and she was discharged on antiemetics, and esomeprazole for the first time. Due to the predominantly elevated liver enzymes, the clinical pharmacist discussed the possibility of esomeprazole-induced adverse effects and suggested to suspend esomeprazole based on the evidence from literature review. The liver enzymes showed a substantial improvement within days after the discontinuation of the drug; however, a rechallenge was not done since it could have adversely affected the mother or the fetus. Using the Naranjo Adverse Drug Reaction Probability scales, the adverse reaction due to esomeprazole was classified as "probably". PMID- 28008289 TI - A Phase I study evaluating the effect of age and weight on the pharmacokinetics of an injectable formulation of diclofenac solubilized with hydroxypropyl-beta cyclodextrin. AB - PURPOSE: The analgesic and opioid-sparing effects of nonsteroidal anti inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl beta-cyclodextrin (HPbetaCD)-diclofenac is an injectable formulation of diclofenac solubilized with HPbetaCD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HPbetaCD-diclofenac. METHODS: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55-82 years old stratified into three groups and receiving HPbetaCD diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HPbetaCD diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects. RESULTS: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age- and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t1/2), likely due to a decrease in the volume of distribution (Vz) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation. CONCLUSION: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HPbetaCD-diclofenac but indicates that diclofenac CL increases with increasing body weight. PMID- 28008290 TI - In situ gelation properties of a collagen-genipin sol with a potential for the treatment of gastrointestinal ulcers. AB - We investigated the potential of collagen-genipin sols as biomaterials for treating artificial ulcers following endoscopic submucosal dissection. Collagen sol viscosity increased with condensation, allowing retention on tilted ulcers before gelation and resulting in collagen gel deposition on whole ulcers. The 1.44% collagen sols containing genipin as a crosslinker retained sol fluidity at 23 degrees C for >20 min, facilitating endoscopic use. Collagen sols formed gel depositions on artificial ulcers in response to body temperature, and high temperature responsiveness of gelation because of increased neutral phosphate buffer concentration allowed for thick gel deposition on tilted ulcers. Finally, histological observations showed infiltration of gels into submucosal layers. Taken together, the present data show that genipin-induced crosslinking significantly improves the mechanical properties of collagen gels even at low genipin concentrations of 0.2-1 mM, warranting the use of in situ gelling collagen-genipin sols for endoscopic treatments of gastrointestinal ulcers. PMID- 28008291 TI - Knowledge and attitude of health care professionals regarding hepatitis B virus infection and its vaccination, University of Gondar Hospital, Ethiopia. AB - BACKGROUND: Hepatitis B is a global public health problem affecting approximately 10% of the world population. Health care professionals (HCPs) are at an increased risk of acquiring hepatitis B infection due to occupational exposure. Having enough knowledge and proper attitudes toward the infection and its vaccination is crucial in preventing the infection. This study aimed to assess knowledge of and attitudes toward hepatitis B virus (HBV) infection as well as its vaccination among HCPs working in University of Gondar Hospital. METHODS: An institution based cross-sectional study design was employed from April 1 to May 1, 2016 on 297 HCPs working at University of Gondar Hospital. A self-administered questionnaire prepared in the English language was used to collect the data. The questionnaire contained sociodemographic characteristics, knowledge, and attitude related questions. Data were entered and analyzed using SPSS software version 20.1. Descriptive statistics, cross-tabs, and binary logistic regression were utilized. P<0.05 was used to declare association. RESULTS: From a total of 297 HCPs participated in the study 73.1% have good knowledge of HBV transmission, progress, and its vaccination. The majority (91.3%) of the respondents believe that their job puts them at risk of HBV infection. The majority of study participants (94%) believe vaccination is necessary. Medical doctors have 8.4 times better knowledge of HBV and its vaccination than other professionals (adjusted odds ratio =8.399, CI =1.536-45.936). CONCLUSION: The majority of HCPs working in University of Gondar Hospital have good knowledge of HBV transmission, progress, and its vaccination. The majority of HCPs believe that their job puts them at greater risk for HBV and vaccination is necessary. Knowledge of the HCPs significantly varies across professions. PMID- 28008292 TI - Incidence and prevalence of elite male cricket injuries using updated consensus definitions. AB - BACKGROUND: T20 (Twenty20 or 20 over) cricket has emerged in the last decade as the most popular form of cricket (in terms of spectator attendances). International consensus cricket definitions, first published in 2005, were updated in 2016 to better reflect the rise to prominence of T20 cricket. METHODS: Injury incidence and prevalence rates were calculated using the new international methods and units for elite senior male Australian cricketers over the past decade (season 2006-2007 to season 2015-2016 inclusive). RESULTS: Over the past 10 seasons, average match injury incidence, for match time-loss injuries, was 155 injuries/1,000 days of play, with the highest daily rates in 50-over cricket, followed by 20-over cricket and First-Class matches. Annual injury incidence was 64 injuries/100 players per season, and average annual injury prevalence was 12.5% (although fast bowlers averaged 20.6%, much higher than other positions). The most common injury was the hamstring strain (seasonal incidence 8.7 injuries/100 players per season). The most prevalent injury was lumbar stress fractures (1.9% of players unavailable at all times owing to these injuries, which represents 15% of all missed playing time). DISCUSSION: The hamstring strain has emerged from being one of the many common injuries in elite cricket a decade ago to being clearly the most common injury in the sport at the elite level. This is presumably in association with increased T20 cricket. Lumbar stress fractures in fast bowlers are still the most prevalent injury in the sport of cricket at the elite level, although these injuries are more associated with high workloads arising from the longer forms of the game. Domestic and international matches have very similar match injury incidence rates across the formats, but injury prevalence is higher in international players as they play for most of the year without a substantial off-season. PMID- 28008293 TI - Hormonal and echocardiographic abnormalities in adult patients with sickle-cell anemia in Bahrain. AB - BACKGROUND: Adrenal, thyroid, and parathyroid gland hormonal changes are recognized in children with homozygous (HbSS) sickle-cell anemia (SCA), but are not clear in adult patients with SCA. AIM: To assess the metabolic and endocrine abnormalities in adult patients with SCA and evaluate left ventricular (LV) systolic and diastolic functions compared with patients with no SCA and further study the relationship between serum levels of cortisol, free thyroxine (T4), and testosterone with serum ferritin. MATERIALS AND METHODS: The study was conducted on 82 patients with adult HbSS SCA compared with a sex- and age-matched control group. The serum levels of cortisol, parathyroid hormone (PTH), testosterone, thyroid-stimulating hormone (TSH), and free T4 were compared. Blood levels of hemoglobin, reticulocyte count, lactate dehydrogenase (LDH), calcium, alkaline phosphatase (ALP), vitamin D3, and ferritin were also compared. Pulsed Doppler echo was performed to evaluate the LV mass, wall thickness, and cavity dimensions with diastolic filling velocities of early (E) and atria (A) waves. Biometric data were analyzed as mean +/- standard deviation between the two groups. Multiple regression analysis was performed between serum levels of ferritin as independent variable and testosterone, cortisol, and thyroid hormones. RESULTS: A total of 82 adult patients with HbSS SCA were enrolled who had a mean age of 21+/ 5.7 years, with 51 males (62%). Patients with SCA compared with the control group had significantly lower hemoglobin, body mass index, cortisol, vitamin D3, testosterone, and T4. Furthermore, there were significantly high levels of reticulocyte count, PTH, TSH, ferritin, LDH, ALP, and uric acid. The incidence of subclinical hypothyroidism and adrenal insufficiency was 7% and 4.8%, respectively, with hypogonadism 9.8% and vitamin D3 deficiency 61%. There were inverse relationships between ferritin as independent variable and serum levels of testosterone, T4, and cortisol, with regression coefficients of -0.49 (P<0.001), -0.33 (P<0.001), and -0.11 (P<0.92), respectively. CONCLUSION: Patients with adult SCA had a high prevalence of in vivo hypoadrenialism (4.8%), hypogonadism (9.8%), and hypothyroidism (7%). There were significant inverse relationships between serum ferritin as independent variable and cortisol, testosterone, and T4. Pulsed Doppler echocardiography showed increased LV mass, with a restrictive LV diastolic pattern suggestive of diastolic dysfunction. PMID- 28008294 TI - Correction to "Macroscopical, Histological, and In Vitro Characterization of Nonosteoarthritic Versus Osteoarthritic Hip Joint Cartilage". AB - [This corrects the article DOI: 10.4137/CMAMD.S29844.]. PMID- 28008295 TI - Relationship Between Lymph Node Volume and Pain Following Certolizumab Therapy for Rheumatoid Arthritis Flare: A Pilot Study. AB - OBJECTIVES: The mechanisms that trigger flare in rheumatoid arthritis (RA) are unknown. In murine arthritis models, dysfunctional lymph node (LN) drainage is associated with joint flare. To examine if LN alterations are associated with RA flare, we analyzed the change in LN volume via contrast-enhanced magnetic resonance imaging (CE-MRI) in patients with active joint flare at baseline and 16 weeks after certolizumab pegol (CZP) therapy. We also assessed the changes in popliteal or epitrochlear LN volumes versus the Rheumatoid and Arthritis Outcome Score (RAOS) (knee), or the Michigan Hand Questionnaire (MHQ; wrist/hand), and Disease Activity Score 28 (DAS28), at baseline and 16 weeks. RESULTS: Total LN volume in 7 of 10 patients with measurable LN on CE-MRI significantly decreased 16 weeks after CZP therapy (mean decrease 37%; P = 0.0019). Improvement in knee pain measured by the RAOS (P = 0.03) inversely correlated with a decrease in total popliteal LN volume (R2 = 0.94). All patients demonstrated significant improvement in DAS28 (mean decrease 1.48; P = 0.0002). For flare in the hand, significant improvement in activities of daily living (ADL) as measured by the MHQ was observed (left hand mean improvement 20%; P = 0.02; right hand mean improvement 37%; P = 0.03). CONCLUSION: RA patients with the smallest change in LN volume during anti-tumor necrosis factor (anti-TNF) therapy experienced the greatest pain relief in symptomatic knee joints. Moreover, the remarkably linear inverse correlation between LN volume and joint pain observed in this small clinical pilot provides initial evidence to support the concept that dynamic changes in draining LN volume are a biomarker of clinical response to therapy in RA. PMID- 28008296 TI - Point-of-Care, Ultraportable Echocardiography Predicts Diuretic Response in Patients Admitted with Acute Decompensated Heart Failure. AB - BACKGROUND: Routine management of patients with acute decompensated heart failure (ADHF) requires careful attentiveness to fluid status and diuretic treatment efficacy. New advances in ultrasound have made ultraportable echocardiography (UE) available to physicians for point-of-care use. The purpose of this study is to explore physiologic measures of intravascular fluid volume derived from UE and explore predictors of diuretic response in ADHF. METHODS: Various echocardiography imaging measurements, particularly diameter and collapse of inferior vena cava (IVC), were collected from 77 patients admitted with a primary diagnosis of ADHF. Patients were divided into two groups based on whether or not they achieved a net negative fluid output of 3 L within 48 hours. The demographic information, serum laboratory markers, and physical characteristics of the subjects were obtained to correlate with daily ultrasound measurements. Univariate and multivariate analyses were used to compare diuretic "responders" to "nonresponders." RESULTS: A negative change in the IVC diameter at 48 hours was robust in prediction of diuretic response. For every 1 mm decrease in the IVC diameter at 48 hours, there was an odds ratio of 1.62 (95% CI: 1.20-2.19) for responding to diuretic therapy independent of other variables including baseline renal filtration function and blood B-type natriuretic peptide. CONCLUSION: Assessment of central venous pressure as a proxy for passive renal congestion independently predicts initial diuretic response in ADHF. Future research is needed to further understand the individual variation in response to loop diuresis and to identify optimal treatment approaches that utilize anatomic and physiologic measures such as venous ultrasound. PMID- 28008298 TI - Severe, Protracted Spasm of Urinary Bladder and Autonomic Dysreflexia Caused by Changing the Suprapubic Catheter in a Cervical Spinal Cord Injury Patient: Treatment by a Bolus Dose and Increased Total Daily Dose of Intrathecal Baclofen. AB - BACKGROUND: Intrathecal administration of baclofen by implanted pump reduces rigidity and muscle spasms. Its use specifically to control bladder spasms has not been reported. CASE REPORT: A tetraplegic patient developed severe, protracted, bladder spasms, abdominal muscles spasms, and high blood pressure after change of suprapubic catheter; nifedipine, diazepam, and paracetamol did not control spasms; bolus dose of baclofen intrathecally produced prompt relief via baclofen pump. CONCLUSION: Severe, protracted bladder spasms, abdominal muscles spasms, and autonomic dysreflexia, induced by change of suprapubic catheter in a spinal cord injury patient, were treated successfully by a bolus dose and increased total daily dose of intrathecal baclofen. PMID- 28008297 TI - Altered Calcium Handling and Ventricular Arrhythmias in Acute Ischemia. AB - Acute ischemia results in deadly cardiac arrhythmias that are a major contributor to sudden cardiac death (SCD). The electrophysiological changes involved have been extensively studied, yet the mechanisms of ventricular arrhythmias during acute ischemia remain unclear. What is known is that during acute ischemia both focal (ectopic excitation) and nonfocal (reentry) arrhythmias occur, due to an interaction of altered electrical, mechanical, and biochemical properties of the myocardium. There is particular interest in the role that alterations in intracellular calcium handling, which cause changes in intracellular calcium concentration and to the calcium transient, play in ischemia-induced arrhythmias. In this review, we briefly summarize the known contributors to ventricular arrhythmias during acute ischemia, followed by an in-depth examination of the potential contribution of altered intracellular calcium handling, which may include novel targets for antiarrhythmic therapy. PMID- 28008299 TI - KRAS Mutation as a Potential Prognostic Biomarker of Biliary Tract Cancers. AB - BACKGROUND: The aim of this study was to identify the unique molecular characteristics of biliary tract cancer (BTC) for the development of novel molecular-targeted therapies. MATERIALS AND METHODS: We performed mutational analysis of KRAS, BRAF, PIK3CA, and FBXW7 and immunohistochemical analysis of EGFR and TP53 in 63 Japanese patients with BTC and retrospectively evaluated the association between the molecular characteristics and clinicopathological features of BTC. RESULTS: KRAS mutations were identified in 9 (14%) of the 63 BTC patients; no mutations were detected within the analyzed regions of BRAF, PIK3CA, and FBXW7. EGFR overexpression was observed in 5 (8%) of the 63 tumors, while TP53 overexpression was observed in 48% (30/63) of the patients. Overall survival of patients with KRAS mutation was significantly shorter than that of patients with the wild-type KRAS gene (P = 0.005). By multivariate analysis incorporating molecular and clinicopathological features, KRAS mutations and lymph node metastasis were identified to be independently associated with shorter overall survival (KRAS, P = 0.004; lymph node metastasis, P = 0.015). CONCLUSIONS: Our data suggest that KRAS mutation is a poor prognosis predictive biomarker for the survival in BTC patients. PMID- 28008300 TI - Physicians' attitudes toward, use of, and perceived barriers to clinical guidelines: a survey among Swiss physicians. AB - BACKGROUND: Little is known about the attitudes toward, use of, and perceived barriers to clinical guidelines in Switzerland, a country with no national guideline agency. Moreover, there is no available data on the objective assessment of guideline knowledge in Switzerland. Therefore, we conducted a study at a large university's Department of General Internal Medicine in Switzerland to assess physicians' attitudes toward, use of, perceived barriers to, and knowledge of clinical guidelines. PARTICIPANTS AND METHODS: Ninety-six physicians (residents, n=78, and attendings, n=18) were invited to take part in a survey. Attitudes toward, self-reported use of, and barriers hindering adherence to the clinical guidelines were assessed using established scales and frameworks. Knowledge of the guidelines was objectively tested in a written assessment comprising of 14 multiple-choice and 3 short answer case-based questions. RESULTS: Fifty-five participants completed the survey (residents, n=42, and attendings, n=13; overall response rate 57%). Of these, 50 took part in the knowledge assessment (residents, n=37, and attendings, n=13; overall response rate 52%). Attitudes toward guidelines were favorable. They were considered to be a convenient source of advice (94% agreement), good educational tools (89% agreement), and likely to improve patient quality of care (91% agreement). Self reported use of guidelines was limited, with only one-third reporting using guidelines often or very often. The main barriers to guideline adherence were identified as lack of guideline awareness and familiarity, applicability of existing guidelines to multimorbid patients, unfavorable guideline factors, and lack of time as well as inertia toward changing previous practice. In the assessment of guideline knowledge, the scores were rather modest (mean +/- standard deviation: 60.5%+/-12.7% correct answers). CONCLUSION: In general, this study found favorable physician attitudes toward clinical guidelines. However, several barriers hindering guideline implementation were identified. The importance of improving guideline implementation was supported by modest results in a guideline knowledge test. PMID- 28008301 TI - Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy. AB - INTRODUCTION: Schizophrenia is a chronic and debilitating mental disorder that affects the patient's and their family's quality of life, as well as financial costs and health care settings. Despite the variety of available antipsychotics, optimal treatment outcomes are not always achieved. Novel drugs, such as iloperidone, can provide more effective, tolerable and safer strategies. AIM: To review the evidence for the clinical impact of iloperidone on the treatment of patients with schizophrenia. EVIDENCE REVIEW: Clinical trials, observational studies and meta-analyses reached a common consensus that iloperidone is as effective as haloperidol, risperidone and ziprasidone in reducing schizophrenia symptoms. Similar amounts of adverse events and discontinuations were observed with iloperidone compared to placebo and active treatments. Common adverse events are mild and include dizziness, hypotension, dry mouth and weight gain. Iloperidone can induce extension of QTc interval, and clinicians should be aware of its contraindications. In long-term trials, iloperidone also showed promising safety and tolerability profiles. The low propensity to cause akathisia, extrapyramidal symptoms (EPS), increased prolactin levels or changes to metabolic laboratory parameters support its use in practice. Results showed that iloperidone prevents relapse in stabilized patients, with a time to relapse superior to placebo and similar to haloperidol. Patients using a prior antipsychotic (eg, risperidone and aripiprazole) can easily switch to iloperidone with no serious impact on safety or efficacy. However, the acquisition costs of iloperidone may hamper its use. Further evidence comparing iloperidone with other antipsychotics, and pharmacoeconomic studies would be welcome. PLACE IN THERAPY: Considering just the clinical profile of iloperidone, it represents a promising drug for treating schizophrenia, particularly in patients who are intolerant to previous antipsychotics, as well as being suitable as first-line therapy. Cost effectiveness comparisons are needed to justify its use in clinical practice. PMID- 28008303 TI - Regenerated Sciatic Nerve Axons Stimulated through a Chronically Implanted Macro Sieve Electrode. AB - Sieve electrodes provide a chronic interface for stimulating peripheral nerve axons. Yet, successful utilization requires robust axonal regeneration through the implanted electrode. The present study determined the effect of large transit zones in enhancing axonal regeneration and revealed an intimate neural interface with an implanted sieve electrode. Fabrication of the polyimide sieve electrodes employed sacrificial photolithography. The manufactured macro-sieve electrode (MSE) contained nine large transit zones with areas of ~0.285 mm2 surrounded by eight Pt-Ir metallized electrode sites. Prior to implantation, saline, or glial derived neurotropic factor (GDNF) was injected into nerve guidance silicone conduits with or without a MSE. The MSE assembly or a nerve guidance conduit was implanted between transected ends of the sciatic nerve in adult male Lewis rats. At 3 months post-operation, fiber counts were similar through both implant types. Likewise, stimulation of nerves regenerated through a MSE or an open silicone conduit evoked comparable muscle forces. These results showed that nerve regeneration was comparable through MSE transit zones and an open conduit. GDNF had a minimal positive effect on the quality and morphology of fibers regenerating through the MSE; thus, the MSE may reduce reliance on GDNF to augment axonal regeneration. Selective stimulation of several individual muscles was achieved through monopolar stimulation of individual electrodes sites suggesting that the MSE might be an optimal platform for functional neuromuscular stimulation. PMID- 28008302 TI - Benefits of Hormone Therapy Estrogens Depend on Estrogen Type: 17beta-Estradiol and Conjugated Equine Estrogens Have Differential Effects on Cognitive, Anxiety Like, and Depressive-Like Behaviors and Increase Tryptophan Hydroxylase-2 mRNA Levels in Dorsal Raphe Nucleus Subregions. AB - Decreased serotonin (5-HT) function is associated with numerous cognitive and affective disorders. Women are more vulnerable to these disorders and have a lower rate of 5-HT synthesis than men. Serotonergic neurons in the dorsal raphe nucleus (DRN) are a major source of 5-HT in the forebrain and play a critical role in regulation of stress-related disorders. In particular, polymorphisms of tryptophan hydroxylase-2 (TpH2, the brain-specific, rate-limiting enzyme for 5-HT biosynthesis) are implicated in cognitive and affective disorders. Administration of 17beta-estradiol (E2), the most potent naturally circulating estrogen in women and rats, can have beneficial effects on cognitive, anxiety-like, and depressive like behaviors. Moreover, E2 increases TpH2 mRNA in specific subregions of the DRN. Although conjugated equine estrogens (CEE) are a commonly prescribed estrogen component of hormone therapy in menopausal women, there is a marked gap in knowledge regarding how CEE affects these behaviors and the brain 5-HT system. Therefore, we compared the effects of CEE and E2 treatments on behavior and TpH2 mRNA. Female Sprague-Dawley rats were ovariectomized, administered either vehicle, CEE, or E2 and tested on a battery of cognitive, anxiety-like, and depressive-like behaviors. The brains of these animals were subsequently analyzed for TpH2 mRNA. Both CEE and E2 exerted beneficial behavioral effects, although efficacy depended on the distinct behavior and for cognition, on the task difficulty. Compared to CEE, E2 generally had more robust anxiolytic and antidepressant effects. E2 increased TpH2 mRNA in the caudal and mid DRN, corroborating previous findings. However, CEE increased TpH2 mRNA in the caudal and rostral, but not the mid, DRN, suggesting that distinct estrogens can have subregion-specific effects on TpH2 gene expression. We also found differential correlations between the level of TpH2 mRNA in specific DRN subregions and behavior, depending on the type of behavior. These distinct associations imply that cognition, anxiety-like, and depressive-like behaviors are modulated by unique serotonergic neurocircuitry, opening the possibility of novel avenues of targeted treatment for different types of cognitive and affective disorders. PMID- 28008304 TI - Structural Brain Network Reorganization and Social Cognition Related to Adverse Perinatal Condition from Infancy to Early Adolescence. AB - Adverse conditions during fetal life have been associated to both structural and functional changes in neurodevelopment from the neonatal period to adolescence. In this study, connectomics was used to assess the evolution of brain networks from infancy to early adolescence. Brain network reorganization over time in subjects who had suffered adverse perinatal conditions is characterized and related to neurodevelopment and cognition. Three cohorts of prematurely born infants and children (between 28 and 35 weeks of gestational age), including individuals with a birth weight appropriated for gestational age and with intrauterine growth restriction (IUGR), were evaluated at 1, 6, and 10 years of age, respectively. A common developmental trajectory of brain networks was identified in both control and IUGR groups: network efficiencies of the fractional anisotropy (FA)-weighted and normalized connectomes increase with age, which can be related to maturation and myelination of fiber connections while the number of connections decreases, which can be associated to an axonal pruning process and reorganization. Comparing subjects with or without IUGR, a similar pattern of network differences between groups was observed in the three developmental stages, mainly characterized by IUGR group having reduced brain network efficiencies in binary and FA-weighted connectomes and increased efficiencies in the connectome normalized by its total connection strength (FA). Associations between brain networks and neurobehavioral impairments were also evaluated showing a relationship between different network metrics and specific social cognition-related scores, as well as a higher risk of inattention/hyperactivity and/or executive functional disorders in IUGR children. PMID- 28008305 TI - Magnesium Sulfate Prevents Placental Ischemia-Induced Increases in Brain Water Content and Cerebrospinal Fluid Cytokines in Pregnant Rats. AB - Magnesium sulfate (MgSO4) is the most widely used therapy in the clinic to prevent the progression of preeclampsia, a hypertensive disorder of pregnancy, to eclampsia. Eclampsia, manifested as unexplained seizures and/or coma during pregnancy or postpartum, accounts for ~13% of maternal deaths worldwide. While MgSO4 continues to be used in the clinic, the mechanisms by which it exerts its protective actions are not well understood. In this study, we tested the hypothesis that MgSO4 protects against placental ischemia-induced increases in brain water content and cerebrospinal fluid cytokines. To test this hypothesis, MgSO4 was administered via mini-osmotic pump (60 mg/day, i.p.) to pregnant and placental ischemic rats, induced by mechanical reduction of uterine perfusion pressure, from gestational day 14-19. This treatment regimen of MgSO4 led to therapeutic level of 2.8 +/- 0.6 mmol/L Mg in plasma. MgSO4 had no effect on improving placental ischemia-induced changes in mean arterial pressure, number of live fetuses, or fetal and placental weight. Placental ischemia increased, while MgSO4 prevented the increase in water content in the anterior cerebrum. Cytokine and chemokine levels were measured in the cerebrospinal fluid using a multi-plex assay. Results demonstrate that cerebrospinal fluid, obtained via the cisterna magna, had reduced protein, albumin, interleukin (IL)-17A, IL-18, IL-2, eotaxin, fractalkine, interferon gamma, vascular endothelial growth factor (VEGF), and macrophage inflammatory protein (MIP)-2 following MgSO4 treatment. These data support the hypothesis that MgSO4 offers neuroprotection by preventing placental ischemia-induced cerebral edema and reducing levels of cytokines/chemokines in the cerebrospinal fluid. PMID- 28008306 TI - Cutaneous Mechanoreceptor Feedback from the Hand and Foot Can Modulate Muscle Sympathetic Nerve Activity. AB - Stimulation of high threshold mechanical nociceptors on the skin can modulate efferent sympathetic outflow. Whether low threshold mechanoreceptors from glabrous skin are similarly capable of modulating autonomic outflow is unclear. Therefore, the purpose of this study was to examine the effects of cutaneous afferent feedback from the hand palm and foot sole on efferent muscle sympathetic nerve activity (MSNA). Fifteen healthy young participants (9 male; 25 +/- 3 years [range: 22-29]) underwent microneurographic recording of multi-unit MSNA from the right fibular nerve during 2 min of baseline and 2 min of mechanical vibration (150 Hz, 220 MUm peak-to-peak) applied to the left hand or foot. Each participant completed three trials of both hand and foot stimulation, each separated by 5 min. MSNA burst frequency decreased similarly during the 2 min of both hand (20.8 +/- 8.9 vs. 19.3 +/- 8.6 bursts/minute [Delta -8%], p = 0.035) and foot (21.0 +/- 8.3 vs. 19.5 +/- 8.3 bursts/minute [Delta -8%], p = 0.048) vibration but did not alter normalized mean burst amplitude or area (All p > 0.05). Larger reductions in burst frequency were observed during the first 10 s (onset) of both hand (20.8 +/- 8.9 vs. 17.0 +/- 10.4 [Delta -25%], p < 0.001) and foot (21.0 +/- 8.3 vs. 18.3 +/- 9.4 [Delta -16%], p = 0.035) vibration, in parallel with decreases in normalized mean burst amplitude (hand: 0.45 +/- 0.06 vs. 0.36 +/- 0.14% [Delta 19%], p = 0.03; foot: 0.47 +/- 0.07 vs. 0.34 +/- 0.19% [Delta -27%], p = 0.02) and normalized mean burst area (hand: 0.42 +/- 0.05 vs. 0.32 +/- 0.12% [Delta 25%], p = 0.003; foot: 0.47 +/- 0.05 vs. 0.34 +/- 0.16% [Delta -28%], p = 0.01). These results demonstrate that tactile feedback from the hands and feet can influence efferent sympathetic outflow to skeletal muscle. PMID- 28008307 TI - Specific Metabolomics Adaptations Define a Differential Regional Vulnerability in the Adult Human Cerebral Cortex. AB - Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions-entorhinal cortex, hippocampus, and frontal cortex-using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex. These findings, along with the better antioxidant capacity and lower mTOR signaling also seen in frontal cortex, suggest that this brain region is especially resistant to stress compared to the entorhinal cortex and hippocampus, which are more vulnerable regions. Globally, our results show the presence of specific metabolomics adaptations in three mature, healthy human brain regions, confirming the existence of cross-regional differences in cell vulnerability in the human cerebral cortex. PMID- 28008308 TI - The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress. AB - MicroRNAs are small non-coding RNAs that repress the expression of their target proteins. The roles of microRNAs in the development of Alzheimer's disease (AD) are not clear. In this study we show that miR-200c represses the expression of PTEN protein. PTEN downregulation by miR-200c supports the survival and differentiation of cultured neurons. AD is a progressive neurodegenerative disease signified by beta amyloid (Abeta) peptide aggregation and deposition. In a mouse model of AD that is induced by APPswe and PS1DeltaE9 double transgenes, we found Abeta deposition results in neuronal ER stress that induces miR200c. Pharmacological blockade of ER stress inhibited Abeta-induced miR-200c overexpression in AD brains. MiR-200c was detected in the serum of both AD mice and human AD patients. These findings suggest that miR-200c functions as part of the neuronal cell-intrinsic adaptive machinery, and supports neuronal survival and differentiation in response to Abeta induced ER-stress by downregulating PTEN. PMID- 28008310 TI - Corrigendum: Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B. AB - [This corrects the article on p. 116 in vol. 9, PMID: 27867348.]. PMID- 28008309 TI - Role of Drosophila Amyloid Precursor Protein in Memory Formation. AB - The amyloid precursor protein (APP) is a membrane protein engaged in complex proteolytic pathways. APP and its derivatives have been shown to play a central role in Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by memory decline. Despite a huge effort from the research community, the primary cause of AD remains unclear, making it crucial to better understand the physiological role of the APP pathway in brain plasticity and memory. Drosophila melanogaster is a model system well-suited to address this issue. Although relatively simple, the fly brain is highly organized, sustains several forms of learning and memory, and drives numerous complex behaviors. Importantly, molecules and mechanisms underlying memory processes are conserved from flies to mammals. The fly encodes a single non-essential APP homolog named APP-Like (APPL). Using in vivo inducible RNA interference strategies, it was shown that APPL knockdown in the mushroom bodies (MB)-the central integrative brain structure for olfactory memory-results in loss of memory. Several APPL derivatives, such as secreted and full-length membrane APPL, may play different roles in distinct types of memory phases. Furthermore, overexpression of Drosophila amyloid peptide exacerbates the memory deficit caused by APPL knockdown, thus potentiating memory decline. Data obtained in the fly support the hypothesis that APP acts as a transmembrane receptor, and that disruption of its normal function may contribute to cognitive impairment during early AD. PMID- 28008311 TI - Cloning of the GABAB Receptor Subunits B1 and B2 and their Expression in the Central Nervous System of the Adult Sea Lamprey. AB - In vertebrates, gamma-aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system (CNS) acting through ionotropic (GABAA) and metabotropic (GABAB) receptors. The GABAB receptor produces a slow inhibition since it activates second messenger systems through the binding and activation of guanine nucleotide-binding proteins [G-protein-coupled receptors (GPCRs)]. Lampreys are a key reference to understand molecular evolution in vertebrates. The importance of the GABAB receptor for the modulation of the circuits controlling locomotion and other behaviors has been shown in pharmacological/physiological studies in lampreys. However, there is no data about the sequence of the GABAB subunits or their expression in the CNS of lampreys. Our aim was to identify the sea lamprey GABAB1 and GABAB2 transcripts and study their expression in the CNS of adults. We cloned two partial sequences corresponding to the GABAB1 and GABAB2 cDNAs of the sea lamprey as confirmed by sequence analysis and comparison with known GABAB sequences of other vertebrates. In phylogenetic analyses, the sea lamprey GABAB sequences clustered together with GABABs sequences of vertebrates and emerged as an outgroup to all gnathostome sequences. We observed a broad and overlapping expression of both transcripts in the entire CNS. Expression was mainly observed in neuronal somas of the periventricular regions including the identified reticulospinal cells. No expression was observed in identifiable fibers. Comparison of our results with those reported in other vertebrates indicates that a broad and overlapping expression of the GABAB subunits in the CNS is a conserved character shared by agnathans and gnathostomes. PMID- 28008312 TI - Accelerometer-Based Step Regularity Is Lower in Older Adults with Bilateral Knee Osteoarthritis. AB - Purpose: To compare the regularity and symmetry of gait between a cohort of older adults with bilateral knee osteoarthritis (OA) and an age and sex-matched control group of older adults with healthy knees. Methods: Fifteen (8 females) older adults with knee OA (64.7 +/- 6.7 years) and fifteen (8 females) pain-free controls (66.1 +/- 10.0 years) completed a 9-min. walk at a self-selected, comfortable speed while wearing a single waist-mounted tri-axial accelerometer. The following gait parameters were compared between the two groups according to sex: mean step time, mean stride time, stride and step regularity (defined as the consistency of the stride-to-stride or step-to-step pattern) and the symmetry of gait (defined as the difference between step and stride regularity) as determined by an unbiased autocorrelation procedure that analyzed the pattern of acceleration in the vertical, mediolateral and anteroposterior directions. Results: Older adults with knee OA displayed significantly less step regularity in the vertical (p < 0.05) and anteroposterior (p < 0.05) directions than controls. Females with knee OA were also found to have significantly less mediolateral step regularity than female controls (p < 0.05), whereas no difference was found between males. Conclusion: The results showed that the regularity of the step pattern in individuals with bilateral knee OA was less consistent compared to similarly-aged older adults with healthy knees. The findings suggest that future studies should investigate the relationship between step regularity, sex and movement direction as well as the application of these methods to the clinical assessment of knee OA. PMID- 28008313 TI - Effects of the Adult Attachment Projective Picture System on Oxytocin and Cortisol Blood Levels in Mothers. AB - Oxytocin, a small neuropeptide of nine amino acids, has been characterized as the "hormone of affiliation" and is stimulated, for instance, in mothers when interacting with their offspring. Variations in maternal oxytocin levels were reported to predict differences in the quality of care provided by mothers. In this study, the Adult Attachment Projective Picture System (AAP) as a valid measure to assess attachment representations was used as an activating attachment related stimulus. We investigated whether the AAP induces a release of oxytocin in mothers with a secure attachment representation and a stress-related cortisol response in mothers with an insecure attachment representation. Therefore, pre post effects of AAP administration on plasma oxytocin and serum cortisol levels were investigated in n = 44 mothers 3 months after parturition. Oxytocin levels increased from pre to post in the significant majority of 73% participants (p = 0.004) and cortisol decreased in the significant majority of 73% participants (p = 0.004). Interestingly, no association between alterations in oxytocin and cortisol were found; this suggests taking a model of two independent processes into considerations. These results show that the AAP test procedure induces an oxytocin response. Concerning the results within the four AAP representation subgroups, our hypothesis of a particularly strong increase in oxytocin in secure mothers was not confirmed; however, in secure mothers we observed a particularly strong decrease in cortisol. Effect sizes are reported, allowing the replication of results in a larger study with sufficient sample size to draw final conclusions with respect to differences in OT and cortisol alterations depending on attachment representation. When interpreting the results, one should keep in mind that this study investigated lactating mothers. Thus, the generalizability of results is limited and future studies should investigate non-lactating healthy females as well as males and include a control stimulus condition. PMID- 28008314 TI - Cognitive Aging and the Hippocampus in Older Adults. AB - The hippocampus is one of the most well studied structures in the human brain. While age-related decline in hippocampal volume is well documented, most of our knowledge about hippocampal structure-function relationships was discovered in the context of neurological and neurodegenerative diseases. The relationship between cognitive aging and hippocampal structure in the absence of disease remains relatively understudied. Furthermore, the few studies that have investigated the role of the hippocampus in cognitive aging have produced contradictory results. To address these issues, we assessed 93 older adults from the general community (mean age = 71.9 +/- 9.3 years) on the Montreal Cognitive Assessment (MoCA), a brief cognitive screening measure for dementia, and the NIH Toolbox-Cognitive Battery (NIHTB-CB), a computerized neurocognitive battery. High resolution structural magnetic resonance imaging (MRI) was used to estimate hippocampal volume. Lower MoCA Total (p = 0.01) and NIHTB-CB Fluid Cognition (p < 0.001) scores were associated with decreased hippocampal volume, even while controlling for sex and years of education. Decreased hippocampal volume was significantly associated with decline in multiple NIHTB-CB subdomains, including episodic memory, working memory, processing speed and executive function. This study provides important insight into the multifaceted role of the hippocampus in cognitive aging. PMID- 28008315 TI - Plant Protease Inhibitors in Therapeutics-Focus on Cancer Therapy. AB - Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs) which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI) have been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn, and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and therapeutic effects due to their peculiarity and superabundance. PMID- 28008316 TI - Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent. AB - The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-kappaB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV. PMID- 28008317 TI - Chrysophanic Acid Suppresses Adipogenesis and Induces Thermogenesis by Activating AMP-Activated Protein Kinase Alpha In vivo and In vitro. AB - Chrysophanic acid (CA) is a member of the anthraquinone family abundant in rhubarb, a widely used herb for obesity treatment in Traditional Korean Medicine. Though several studies have indicated numerous features of CA, no study has yet reported the effect of CA on obesity. In this study, we tried to identify the anti-obesity effects of CA. By using 3T3-L1 adipocytes and primary cultured brown adipocytes as in vitro models, high-fat diet (HFD)-induced obese mice, and zebrafish as in vivo models, we determined the anti-obesity effects of CA. CA reduced weight gain in HFD-induced obese mice. They also decreased lipid accumulation and the expressions of adipogenesis factors including peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha) in 3T3-L1 adipocytes. In addition, uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha), the brown fat specific thermogenic genes, were up-regulated in brown adipocytes by CA treatment. Furthermore, when co-treated with Compound C, the AMP activated protein kinase (AMPK) inhibitor, the action of CA on AMPKalpha was nullified in both types of adipocytes, indicating the multi-controlling effect of CA was partially via the AMPKalpha pathway. Given all together, these results indicate that CA can ameliorate obesity by controlling the adipogenic and thermogenic pathway at the same time. On these bases, we suggest the new potential of CA as an anti-obese pharmacotherapy. PMID- 28008318 TI - Alterations in Cerebrospinal Fluid in Patients with Bipolar Syndromes. AB - Bipolar disorder (BD) is a severe and lifelong condition. Primary endogenic polygenetic forms are common. Secondary organic forms have received increasing interest recently due to the detection of immunological encephalopathies that mimic various psychiatric syndromes, including BD. However, only limited data about routine findings of cerebrospinal fluid (CSF) analyses in BD are available. Therefore, we investigated the frequency of alterations in the CSF in patients with BD and the association with autoantibodies, cerebral magnetic resonance imaging, and electroencephalography findings. CSF samples of patients with BD collected from January 1998 until December 2015 were analyzed retrospectively. Patients with preexisting causes for alterations in the CSF (e.g., patients with obvious past or current neurological disorders) were excluded. In total, 63 patients with BD fulfilled the inclusion criteria for the study. In 1.6% of the patients with BD, an increased white blood cell count was found in the CSF. Increased albumin quotients were found in 12.9% of the patients, oligoclonal bands (OCBs) in 1.6%, and increased immunoglobulin (Ig) G indices in 3.2% (OCBs were not measured in case of increased IgG indices). No significant differences in CSF findings were found between patients with manic and depressive episodes. The main findings of this open uncontrolled study are that alterations in the CSF may be found in a small, but potentially relevant, subgroup of patients with BD. These findings are discussed in light of the new concepts of mild encephalitis and immunological encephalopathy. The detection of patients with possibly secondary organic bipolar syndromes could open up new causal treatment options with immunomodulatory medication. PMID- 28008319 TI - Commentary: Is there any Influence of Variations in Context on Object-Affordance Effects in Schizophrenia? Perception of Property and Goals of Action. PMID- 28008320 TI - Editorial: Reading Faces and Bodies: Behavioral and Neural Processes Underlying the Understanding of, and Interaction with, Others. PMID- 28008321 TI - Effect of Redundant Haptic Information on Task Performance during Visuo-Tactile Task Interruption and Recovery. AB - Previous studies have revealed that interruption induces disruptive influences on the performance of cognitive tasks. While much research has focused on the use of multimodal channels to reduce the cost of interruption, few studies have utilized haptic information as more than an associative cue. In the present study, we utilized a multimodal task interruption scenario involving the simultaneous presentation of visual information and haptic stimuli in order to investigate how the combined stimuli affect performance on the primary task (cost of interruption). Participants were asked to perform a two-back visuo-tactile task, in which visual and haptic stimuli were presented simultaneously, which was interrupted by a secondary task that also utilized visual and haptic stimuli. Four experimental conditions were evaluated: (1) paired information (visual stimulus + paired haptic stimulus) with interruption; (2) paired information without interruption; (3) non-paired information (visual stimulus + non-paired haptic stimulus) with interruption; and (4) non-paired information without interruption. Our findings indicate that, within a visuo-tactile task environment, redundant haptic information may not only increase accuracy on the primary task but also reduce the cost of interruption in terms of accuracy. These results suggest a new way of understanding the task recovery process within a multimodal environment. PMID- 28008322 TI - The Relationship between Impulsivity and Problem Gambling in Adolescence. AB - Gambling has become one of the most frequently reported addictive behaviors among young people. Understanding risk factors associated with the onset or maintenance of gambling problems in adolescence has implications for its prevention and treatment. The main aim of the present study was to examine the potential relationships between impulsivity and problem gambling in adolescence. Participants were 874 high school students (average age: 15 years old) who were surveyed to provide data on gambling and impulsivity. Self-reported gambling behavior was assessed using the South Oaks Gambling Screen - Revised for Adolescents (SOGS-RA) and impulsivity was measured using the Impulsive Sensation Seeking Questionnaire (ZKPQ), the Barratt Impulsiveness Scale (BIS-11-A), and a delay discounting task. The data were analyzed using both a prospective longitudinal and a cross-sectional design. In the longitudinal analyses, results showed that the impulsivity subscale of the ZKPQ increased the risk of problem gambling (p = 0.003). In the cross-sectional analyses, all the impulsivity measures were higher in at-risk/problem gamblers than in non-problem gamblers (p = 0.04; 0.03; and 0.01, respectively). These findings further support the relationship between impulsivity and gambling in adolescence. Moreover, our findings suggest a bidirectional relationship between impulsivity and problem gambling in adolescence. These results have consequences for the development of prevention and treatment programs for adolescents with gambling problems. PMID- 28008323 TI - Emotional Eating Is Not What You Think It Is and Emotional Eating Scales Do Not Measure What You Think They Measure. AB - In eating research, it is common practice to group people into different eater types, such as emotional, external and restrained eaters. This categorization is generally based on scores on self-report questionnaires. However, recent studies have started to raise questions about the validity of such questionnaires. In the realm of emotional eating, a considerable number of studies, both in the lab and in naturalistic settings, fail to demonstrate increased food intake in emotional situations in self-described emotional eaters. The current paper provides a review of experimental and naturalistic studies investigating the relationships between self-reported emotional eater status, mood, and food consumption. It is concluded that emotional eating scales lack predictive and discriminative validity; they cannot be assumed to measure accurately what they intend to measure, namely increased food intake in response to negative emotions. The review is followed by a discussion of alternative interpretations of emotional eating scores that have been suggested in the past few years, i.e., concerned eating, uncontrolled eating, a tendency to attribute overeating to negative affect, and cue-reactive eating. PMID- 28008324 TI - Vitamin D3 for the Treatment of Epilepsy: Basic Mechanisms, Animal Models, and Clinical Trials. AB - There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D3 is actively under investigation as a potential intervention for epilepsy. Vitamin D3 is fat-soluble steroid, which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D3 may reduce seizures, and animal data support the efficacy of Vitamin D3 in rat and mouse models of epilepsy. Very little clinical data exist to support the treatment of human epilepsy with Vitamin D3, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D3 as a treatment for human epilepsy. PMID- 28008325 TI - Lactobacilli Dominance and Vaginal pH: Why Is the Human Vaginal Microbiome Unique? AB - The human vaginal microbiome is dominated by bacteria from the genus Lactobacillus, which create an acidic environment thought to protect women against sexually transmitted pathogens and opportunistic infections. Strikingly, lactobacilli dominance appears to be unique to humans; while the relative abundance of lactobacilli in the human vagina is typically >70%, in other mammals lactobacilli rarely comprise more than 1% of vaginal microbiota. Several hypotheses have been proposed to explain humans' unique vaginal microbiota, including humans' distinct reproductive physiology, high risk of STDs, and high risk of microbial complications linked to pregnancy and birth. Here, we test these hypotheses using comparative data on vaginal pH and the relative abundance of lactobacilli in 26 mammalian species and 50 studies (N = 21 mammals for pH and 14 mammals for lactobacilli relative abundance). We found that non-human mammals, like humans, exhibit the lowest vaginal pH during the period of highest estrogen. However, the vaginal pH of non-human mammals is never as low as is typical for humans (median vaginal pH in humans = 4.5; range of pH across all 21 non-human mammals = 5.4-7.8). Contrary to disease and obstetric risk hypotheses, we found no significant relationship between vaginal pH or lactobacilli relative abundance and multiple metrics of STD or birth injury risk (P-values ranged from 0.13 to 0.99). Given the lack of evidence for these hypotheses, we discuss two alternative explanations: the common function hypothesis and a novel hypothesis related to the diet of agricultural humans. Specifically, with regard to diet we propose that high levels of starch in human diets have led to increased levels of glycogen in the vaginal tract, which, in turn, promotes the proliferation of lactobacilli. If true, human diet may have paved the way for a novel, protective microbiome in human vaginal tracts. Overall, our results highlight the need for continuing research on non-human vaginal microbial communities and the importance of investigating both the physiological mechanisms and the broad evolutionary processes underlying human lactobacilli dominance. PMID- 28008326 TI - Localization and Transcriptional Responses of Chrysoporthe austroafricana in Eucalyptus grandis Identify Putative Pathogenicity Factors. AB - Chrysoporthe austroafricana is a fungal pathogen that causes the development of stem cankers on susceptible Eucalyptus grandis trees. Clones of E. grandis that are partially resistant and highly susceptible have been identified based on the extent of lesion formation on the stem upon inoculation with C. austroafricana. These interactions have been used as a model pathosystem to enhance our understanding of interactions between pathogenic fungi and woody hosts, which may be different to herbaceous hosts. In previous research, transcriptomics of host responses in these two clones to C. austroafricana suggested roles for salicylic acid and gibberellic acid phytohormone signaling in defense. However, it is unclear how the pathogen infiltrates host tissue and which pathogenicity factors facilitate its spread in the two host genotypes. The aim of this study was to investigate these two aspects of the E. grandis-C. austroafricana interaction and to test the hypothesis that the pathogen possesses mechanisms to modulate the tree phytohormone-mediated defenses. Light microscopy showed that the pathogen occurred in most cell types and structures within infected E. grandis stem tissue. Notably, the fungus appeared to spread through the stem by penetrating cell wall pits. In order to understand the molecular interaction between these organisms and predict putative pathogenicity mechanisms of C. austroafricana, fungal gene expression was studied in vitro and in planta. Fungal genes associated with cell wall degradation, carbohydrate metabolism and phytohormone manipulation were expressed in planta by C. austroafricana. These genes could be involved in fungal spread by facilitating cell wall pit degradation and manipulating phytohormone mediated defense in each host environment, respectively. Specifically, the in planta expression of an ent-kaurene oxidase and salicylate hydroxylase in C. austroafricana suggests putative mechanisms by which the pathogen can modulate the phytohormone-mediated defenses of the host. These mechanisms have been reported in herbaceous plant-pathogen interactions, supporting the notion that these aspects of the interaction are similar in a woody species. This study highlights ent-kaurene oxidase and salicylate hydroxylase as candidates for further functional characterization. PMID- 28008327 TI - In situ Spectroscopy Reveals that Microorganisms in Different Phyla Use Different Electron Transfer Biomolecules to Respire Aerobically on Soluble Iron. AB - Absorbance spectra were collected on 12 different live microorganisms, representing six phyla, as they respired aerobically on soluble iron at pH 1.5. A novel integrating cavity absorption meter was employed that permitted accurate absorbance measurements in turbid suspensions that scattered light. Illumination of each microorganism yielded a characteristic spectrum of electrochemically reduced colored prosthetic groups. A total of six different patterns of reduced minus-oxidized difference spectra were observed. Three different spectra were obtained with members of the Gram-negative eubacteria. Acidithiobacillus, representing Proteobacteria, yielded a spectrum in which cytochromes a and c and a blue copper protein were all prominent. Acidihalobacter, also representing the Proteobacteria, yielded a spectrum in which both cytochrome b and a long wavelength cytochrome a were clearly visible. Two species of Leptospirillum, representing the Nitrospirae, both yielded spectra that were dominated by a cytochrome with a reduced peak at 579 nm. Sulfobacillus and Alicyclobacillus, representing the Gram-positive Firmicutes, both yielded spectra dominated by a type cytochromes. Acidimicrobium and Ferrimicrobium, representing the Gram positive Actinobacteria, also yielded spectra dominated by a-type cytochromes. Acidiplasma and Ferroplasma, representing the Euryarchaeota, both yielded spectra dominated by a ba3-type of cytochrome. Metallosphaera and Sulfolobus, representing the Crenarchaeota, both yielded spectra dominated by the same novel cytochrome as that observed in the Nitrospirae and a new, heretofore unrecognized redox-active prosthetic group with a reduced peak at around 485 nm. These observations are consistent with the hypothesis that individual acidophilic microorganisms that respire aerobically on iron utilize one of at least six different types of electron transfer pathways that are characterized by different redox-active prosthetic groups. In situ absorbance spectroscopy is shown to be a useful complement to existing means of investigating the details of energy conservation in intact microorganisms under physiological conditions. PMID- 28008328 TI - Dietary Administration of Bacillus subtilis Enhances Growth Performance, Immune Response and Disease Resistance in Cherry Valley Ducks. AB - Given the promising results of applying Bacillus subtilis (B.subtilis) as a probiotic in both humans and animals, the aim of this study was to systematically investigate the effects of B. subtilis on growth performance, immune response and disease resistance in Cherry Valley ducks. At 28 d post-hatch (dph), ducks fed a diet with B. subtilis weighed significantly more, had higher relative immune organ weights (e.g., bursa of Fabricius, thymus, and spleen), and exhibited greater villus heights, villus height to crypt depth ratios (duodenum and jejunum), and shallower crypt depths in the duodenum than controls fed a normal diet (p < 0.05). Moreover, the major pro-inflammatory factors and antiviral proteins, as measured in the thymus and the spleen, were higher at 28 dph in ducks fed probiotics than those of 14 dph. After 28 d of feeding, the ducks were challenged with Escherichia coli (E. coli) and novel duck reovirus (NDRV), and ducks fed B. subtilis achieved survival rates of 43.3 and 100%, respectively, which were significantly greater than the control group's 20 and 83.3%. Altogether, diets with B. subtilis can improve Cherry Valley ducks' growth performance, innate immune response, and resistance against E. coli and NDRV. PMID- 28008329 TI - Maternal and Fetal Mechanisms of B Cell Regulation during Pregnancy: Human Chorionic Gonadotropin Stimulates B Cells to Produce IL-10 While Alpha Fetoprotein Drives Them into Apoptosis. AB - Maternal immune tolerance toward the fetus is an essential requisite for pregnancy. While T cell functions are well documented, little is known about the participation of B cells. We have previously suggested that IL-10-producing B cells are involved in pregnancy tolerance in mice and humans. By employing murine and human systems, we report now that fetal trophoblasts positively regulate the generation of IL-10-producing B cells. We next studied the participation of hormones produced by the placenta as well as the fetal protein alpha-fetoprotein (AFP) in B cell modulation. Human chorionic gonadotropin (hCG), but not progesterone, estrogen, or a combination of both, was able to promote changes in B cell phenotype and boost their IL-10 production, which was abolished after blocking hCG. The hCG-induced B cell phenotype was not associated with augmented galactosylation, sialylation, or fucosylation of IgG subclasses in their Fc. In vitro, hCG induced the synthesis of asymmetrically glycosylated antibodies in their Fab region. Interestingly, AFP had dual effects depending on the concentration. At concentrations corresponding to maternal serum levels, it did not modify the phenotype or IL-10 secretion of B cells. At fetal concentrations, however, AFP was able to drive B cells into apoptosis, which may indicate a protective mechanism to avoid maternal B cells to reach the fetus. Our data suggest that the fetus secrete factors that promote a pregnancy-friendly B cell phenotype, unraveling interesting aspects of B cell function, and modulation by pregnancy hormones and fetal proteins. PMID- 28008330 TI - Increased Levels of Circulating and Tumor-Infiltrating Granulocytic Myeloid Cells in Colorectal Cancer Patients. AB - Increased levels of myeloid cells, especially myeloid-derived suppressor cells (MDSCs), have been reported to correlate with bad prognosis and reduced survival in cancer patients. However, limited data are available on their conclusive phenotypes and their correlation with clinical settings. The aim of this study was to investigate levels and phenotype of myeloid cells in peripheral blood and tumor microenvironment (TME) of colorectal cancer (CRC) patients, compared to blood from healthy donors (HDs) and paired, adjacent non-tumor colon tissue. Flow cytometric analysis was performed to examine the expression of different myeloid markers in fresh peripheral blood samples from CRC patients and HDs, and tissue infiltrating immune cells from CRC patients. We found significantly higher levels of cells expressing myeloid markers and lacking the expression of major histocompatibility complex class II molecule HLA-DR in blood and tumor of CRC patients. Further analysis revealed that these cells were granulocytic and expressed Arginase 1 indicative of their suppressive phenotype. These expanded cells could be neutrophils or granulocytic MDSCs, and we refer to them as granulocytic myeloid cells (GMCs) due to the phenotypical and functional overlap between these cell subsets. Interestingly, the expansion of peripheral GMCs correlated with higher stage and histological grade of cancer, thereby suggesting their role in cancer progression. Furthermore, an increase in CD33+CD11b+HLA-DR CD14-CD15- immature myeloid cells was also observed in CRC tumor tissue. Our work shows that GMCs are expanded in circulation and TME of CRC patients, which provides further insights for developing immunotherapeutic approaches targeting these cell subsets to enhance antitumor immune and clinical responses. PMID- 28008331 TI - A Meningococcal Outer Membrane Vesicle Vaccine Incorporating Genetically Attenuated Endotoxin Dissociates Inflammation from Immunogenicity. AB - BACKGROUND: Group B Neisseria meningitidis, an endotoxin-producing Gram-negative bacterium, causes the highest incidence of group B meningococcus (MenB) disease in the first year of life. The Bexsero vaccine is indicated in Europe from 8 weeks of age. Endotoxin components of outer membrane vesicles (OMVs) or soluble lipopolysaccharide (LPS) represent a potential source of inflammation and residual reactogenicity. The purpose of this study was to compare novel candidate MenB vaccine formulations with licensed vaccines, including Bexsero, using age specific human in vitro culture systems. METHODS: OMVs from wild type- and inactivated lpxL1 gene mutant-N. meningitidis strains were characterized in human neonatal and adult in vitro whole blood assays and dendritic cell (DC) arrays. OMVs were benchmarked against licensed vaccines, including Bexsero and whole cell pertussis formulations, with respect to Th-polarizing cytokine and prostaglandin E2 production, as well as cell surface activation markers (HLA-DR, CD86, and CCR7). OMV immunogenicity was assessed in mice. RESULTS: DeltalpxLI native OMVs (nOMVs) demonstrated significantly less cytokine induction in human blood and DCs than Bexsero and most of the other pediatric vaccines (e.g., PedvaxHib, EasyFive, and bacillus Calmette-Guerin) tested. Despite a much lower inflammatory profile in vitro than Bexsero, DeltalpxLI nOMVs still had moderate DC maturing ability and induced robust anti-N. meningitidis antibody responses after murine immunization. CONCLUSION: A meningococcal vaccine comprised of attenuated LPS based OMVs with a limited inflammatory profile in vitro induces robust antigen specific immunogenicity in vivo. PMID- 28008332 TI - Quantitative Proteomic Analyses Identify ABA-Related Proteins and Signal Pathways in Maize Leaves under Drought Conditions. AB - Drought stress is one of major factors resulting in maize yield loss. The roles of abscisic acid (ABA) have been widely studied in crops in response to drought stress. However, more attention is needed to identify key ABA-related proteins and also gain deeper molecular insights about drought stress in maize. Based on this need, the physiology and proteomics of the ABA-deficient maize mutant vp5 and its wild-type Vp5 under drought stress were examined and analyzed. Malondialdehyde content increased and quantum efficiency of photosystem II decreased under drought stress in both genotypes. However, the magnitude of the increase or decrease was significantly higher in vp5 than in Vp5. A total of 7051 proteins with overlapping expression patterns among three replicates in the two genotypes were identified by Multiplex run iTRAQ-based quantitative proteomic and liquid chromatography-tandem mass spectrometry methods, of which the expression of only 150 proteins (130 in Vp5, 27 in vp5) showed changes of at least 1.5-fold under drought stress. Among the 150 proteins, 67 and 60 proteins were up regulated and down-regulated by drought stress in an ABA-dependent way, respectively. ABA was found to play active roles in regulating signaling pathways related to photosynthesis, oxidative phosphorylation (mainly related to ATP synthesis), and glutathione metabolism (involved in antioxidative reaction) in the maize response to drought stress. Our results provide an extensive dataset of ABA-dependent, drought-regulated proteins in maize plants, which may help to elucidate the underlying mechanisms of ABA-enhanced tolerance to drought stress in maize. PMID- 28008333 TI - Calcite Dissolution by Brevibacterium sp. SOTI06: A Futuristic Approach for the Reclamation of Calcareous Sodic Soils. AB - Assessing the ability of soil microorganisms to dissolute poorly soluble native calcite to supply Ca2+ is a new area to be explored in reclaiming sodic soils by supplying adequate Ca2+ and reducing the recurrent sodicity. Hence, the present study aimed to isolate a calcite dissolving bacteria (CDB) from calcareous sodic soils and to understand the mechanism of calcite dissolution. Of the 33 CDB isolates recovered from the calcareous sodic soils of Tamil Nadu (Coimbatore, Ramnad, and Trichy), 11 isolates were screened for calcite dissolution based on titratable acidity. 16S rRNA gene sequence analysis of the three best isolates viz., SORI09, SOTI05, and SOTI06 revealed 99% similarity to Bacillus aryabhattai, 100% to B. megaterium, and 93% to Brevibacterium sp., respectively. Among them, Brevibacterium sp. SOTI06 released more Ca2+ (3.6 g.l-1) by dissolving 18.6% of the native calcite. The spectral data of FTIR also showed reduction in the intensity of calcite (55.36-41.27) by the isolate at a wave number of 1636 cm-1 which confirmed the dissolution. Besides producing organic acids (gluconic acid and acetic acid), Brevibacterium sp. SOTI06 also produced siderophore (91.6%) and extracellular polysaccharides (EPS, 13.3 MUg. ml-1) which might have enhanced the calcite dissolution. PMID- 28008335 TI - Structure and Function of the TIR Domain from the Grape NLR Protein RPV1. AB - The N-terminal Toll/interleukin-1 receptor/resistance protein (TIR) domain has been shown to be both necessary and sufficient for defense signaling in the model plants flax and Arabidopsis. In examples from these organisms, TIR domain self association is required for signaling function, albeit through distinct interfaces. Here, we investigate these properties in the TIR domain containing resistance protein RPV1 from the wild grapevine Muscadinia rotundifolia. The RPV1 TIR domain, without additional flanking sequence present, is autoactive when transiently expressed in tobacco, demonstrating that the TIR domain alone is capable of cell-death signaling. We determined the crystal structure of the RPV1 TIR domain at 2.3 A resolution. In the crystals, the RPV1 TIR domain forms a dimer, mediated predominantly through residues in the alphaA and alphaE helices ("AE" interface). This interface is shared with the interface discovered in the dimeric complex of the TIR domains from the Arabidopsis RPS4/RRS1 resistance protein pair. We show that surface-exposed residues in the AE interface that mediate the dimer interaction in the crystals are highly conserved among plant TIR domain-containing proteins. While we were unable to demonstrate self association of the RPV1 TIR domain in solution or using yeast 2-hybrid, mutations of surface-exposed residues in the AE interface prevent the cell-death autoactive phenotype. In addition, mutation of residues known to be important in the cell death signaling function of the flax L6 TIR domain were also shown to be required for RPV1 TIR domain mediated cell-death. Our data demonstrate that multiple TIR domain surfaces control the cell-death function of the RPV1 TIR domain and we suggest that the conserved AE interface may have a general function in TIR-NLR signaling. PMID- 28008334 TI - Transcriptome Analysis Highlights Defense and Signaling Pathways Mediated by Rice pi21 Gene with Partial Resistance to Magnaporthe oryzae. AB - Rice blast disease is one of the most destructive rice diseases worldwide. The pi21 gene confers partial and durable resistance to Magnaporthe oryzae. However, little is known regarding the molecular mechanisms of resistance mediated by the loss-of-function of Pi21. In this study, comparative transcriptome profiling of the Pi21-RNAi transgenic rice line and Nipponbare with M. oryzae infection at different time points (0, 12, 24, 48, and 72 hpi) were investigated using RNA sequencing. The results generated 43,222 unique genes mapped to the rice genome. In total, 1109 differentially expressed genes (DEGs) were identified between the Pi21-RNAi line and Nipponbare with M. oryzae infection, with 103, 281, 209, 69, and 678 DEGs at 0, 12, 24, 48, and 72 hpi, respectively. Functional analysis showed that most of the DEGs were involved in metabolism, transport, signaling, and defense. Among the genes assigned to plant-pathogen interaction, we identified 43 receptor kinase genes associated with pathogen-associated molecular pattern recognition and calcium ion influx. The expression levels of brassinolide insensitive 1, flagellin sensitive 2, and elongation factor Tu receptor, ethylene (ET) biosynthesis and signaling genes, were higher in the Pi21-RNAi line than Nipponbare. This suggested that there was a more robust PTI response in Pi21-RNAi plants and that ET signaling was important to rice blast resistance. We also identified 53 transcription factor genes, including WRKY, NAC, DOF, and ERF families that show differential expression between the two genotypes. This study highlights possible candidate genes that may serve a function in the partial rice blast resistance mediated by the loss-of-function of Pi21 and increase our understanding of the molecular mechanisms involved in partial resistance against M. oryzae. PMID- 28008336 TI - MICADo - Looking for Mutations in Targeted PacBio Cancer Data: An Alignment-Free Method. AB - Targeted sequencing is commonly used in clinical application of NGS technology since it enables generation of sufficient sequencing depth in the targeted genes of interest and thus ensures the best possible downstream analysis. This notwithstanding, the accurate discovery and annotation of disease causing mutations remains a challenging problem even in such favorable context. The difficulty is particularly salient in the case of third generation sequencing technology, such as PacBio. We present MICADo, a de Bruijn graph based method, implemented in python, that makes possible to distinguish between patient specific mutations and other alterations for targeted sequencing of a cohort of patients. MICADo analyses NGS reads for each sample within the context of the data of the whole cohort in order to capture the differences between specificities of the sample with respect to the cohort. MICADo is particularly suitable for sequencing data from highly heterogeneous samples, especially when it involves high rates of non-uniform sequencing errors. It was validated on PacBio sequencing datasets from several cohorts of patients. The comparison with two widely used available tools, namely VarScan and GATK, shows that MICADo is more accurate, especially when true mutations have frequencies close to backgound noise. The source code is available at http://github.com/cbib/MICADo. PMID- 28008338 TI - Shape-Dependent Relaxivity of Nanoparticle-Based T1 Magnetic Resonance Imaging Contrast Agents. AB - Gold nanostars functionalized with Gd(III) have shown significant promise as contrast agents for magnetic resonance imaging (MRI) because of their anisotropic, branched shape. However, the size and shape polydispersity of as synthesized gold nanostars have precluded efforts to develop a rigorous relationship between the gold nanostar structure (e.g., number of branches) and relaxivity of surface-bound Gd(III). This paper describes the use of a centrifugal separation method that can produce structurally refined populations of gold nanostars and is compatible with Gd(III) functionalization. Combined transmission electron microscopy and relaxivity analyses revealed that the increased number of nanostar branches was correlated with enhanced relaxivity. By identifying the underlying relaxivity mechanisms for Gd(III)-functionalized gold nanostars, we can inform the design of high-performance MRI contrast agents. PMID- 28008337 TI - Statistical challenges in analyzing methylation and long-range chromosomal interaction data. AB - With the rapid development of high throughput technologies such as array and next generation sequencing (NGS), genome-wide, nucleotide-resolution epigenomic data are increasingly available. In recent years, there has been particular interest in data on DNA methylation and 3-dimensional (3D) chromosomal organization, which are believed to hold keys to understand biological mechanisms, such as transcription regulation, that are closely linked to human health and diseases. However, small sample size, complicated correlation structure, substantial noise, biases, and uncertainties, all present difficulties for performing statistical inference. In this review, we present an overview of the new technologies that are frequently utilized in studying DNA methylation and 3D chromosomal organization. We focus on reviewing recent developments in statistical methodologies designed for better interrogating epigenomic data, pointing out statistical challenges facing the field whenever appropriate. PMID- 28008339 TI - Role of nitric oxide in liver transplantation: Should it be routinely used? AB - Ischemia-reperfusion injury (IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized which are more vulnerable to cold and warm ischemia. Nitric oxide (NO.) is highly reactive gaseous molecule found in air and regarded as a pollutant. Not surprising, it is extremely bioactive, and has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions. Under conditions of ischemia, NO. has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation. Clinical studies designed to test this hypothesis have yielded very promising results that includes reduced hepatocellular injury and enhanced graft recovery without any identifiable complications. By what means NO. facilitates extra-pulmonary actions is up for debate and speculation. The general premise is that they are NO. containing intermediates in the circulation, that ultimately mediate either direct or indirect effects. A plethora of data exists explaining how NO.-containing intermediate molecules form in the plasma as S nitrosothiols (e.g., S-nitrosoalbumin), whereas other compelling data suggest nitrite to be a protective mediator. In this article, we discuss the use of inhaled NO. as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation. PMID- 28008340 TI - Fractional excretion of sodium in hepatorenal syndrome: Clinical and pathological correlation. AB - AIM: To determine the accuracy of fractional excretion of sodium (FeNa) in the diagnosis of hepatorenal syndrome (HRS). METHODS: Eighty-eight liver transplantation candidates with renal dysfunction and/or proteinuria were included in the study sample. The baseline characteristics of the patients were obtained. All the 88 patients underwent iothalamate glomerular filtration rate testing, 24-h urine collection for urinary sodium and protein excretions, random urine for sodium and creatinine testing, and percutaneous kidney biopsy. FeNa was calculated using the equation [(urine sodium * serum creatinine)/(serum sodium * urine creatinine)] * 100%. Diuretic use was recorded among the participants. Patients on renal replacement therapy were not included in the original sample. RESULTS: Seventy-seven (87%) of the 88 patients had FeNa < 1%. FeNa < 1% was present in 10/10, 10/12, 11/13, 12/15 and 34/38 in patients with HRS, acute tubular necrosis, membranoproliferative glomerulonephritis, minimal histological findings (<= 30%) and advanced (>= 30%-40%) interstitial fibrosis and/or glomerulosclerosis, respectively (P = 0.4). FeNa < 1% was 100% sensitive and 14% specific in diagnosing HRS. Receiver operating characteristic curve confirmed the poor accuracy of FeNa < 1% in diagnosing HRS (area under the curve = 0.58, P = 0.47). Calculated positive predictive value and negative predictive value for FeNa < 1% in HRS diagnosis were 46% and 100%, respectively. When used as a continuous variable, FeNa did not correlate with kidney biopsy findings (P = 0.41). CONCLUSION: FeNa < 1% was common in cirrhotic patients with renal dysfunction and it did not differentiate between HRS and other causes of renal pathologies. HRS diagnosis should be avoided in patients with FeNa > 1%. PMID- 28008341 TI - Resection margin influences the outcome of patients with bilobar colorectal liver metastases. AB - AIM: To evaluate the outcome of patients with bilobar colorectal liver metastases (CRLM) and identify clinico-pathological variables that influenced survival. METHODS: Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period (January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatin- or Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type. Response to neo-adjuvant therapy was assessed at the multi-disciplinary team meeting and considered for surgery if all macroscopic CRLM were resectable with a clear margin while preserving sufficient liver parenchyma. RESULTS: Of the 136 patients included, thirty-two (23.5%) patients were considered inoperable and referred for palliative chemotherapy, and thirty-four (25%) patients underwent liver resection. Seventy (51.4%) patients underwent down-staging therapy, of which 37 (52.8%) patients responded sufficiently to undergo liver resection. Patients that failed to respond to down staging therapy (n = 33, 47.1%) were referred for palliative therapy. There was a significant difference in overall survival between the three groups (surgery vs down-staging therapy vs inoperable disease, P < 0.001). All patients that underwent hepatic resection, including patients that had down-staging therapy, had a significantly better overall survival compared to patients that were inoperable (P < 0.001). On univariate analysis, only resection margin significantly influenced disease-free survival (P = 0.017). On multi-variate analysis, R0 resection (P = 0.030) and female (P = 0.036) gender significantly influenced overall survival. CONCLUSION: Patients undergoing liver resection with bilobar CRLM have a significantly better survival outcome. R0 resection is associated with improved disease-free and overall survival in this patient group. PMID- 28008342 TI - On-treatment quantitative hepatitis B e antigen predicted response to nucleos(t)ide analogues in chronic hepatitis B. AB - AIM: To investigate potential predictors for treatment response to nucleos(t)ide analogues (NAs) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. METHODS: Seventy-six HBeAg-positive CHB patients received 96-wk NAs optimized therapy (lamivudine and adefovir dipivoxil) were studied retrospectively. Serum hepatitis B surface antigen, HBeAg, hepatitis B core antibody, hepatitis B virus (HBV) DNA and alanine aminotransferase levels were quantitatively measured before and during the treatment at 12 and 24 wk. Stepwise logistic regression analyses were performed to identify predictors for treatment response, and areas under the receiver operating characteristic curves (AUROC) of the independent predictors were calculated. RESULTS: Forty-three CHB patients (56.6%) achieved virological response (VR: HBV DNA <= 300 copies/mL) and 15 patients (19.7%) developed HBeAg seroconversion (SC) after the 96-wk NAs treatment. The HBeAg level (OR = 0.45, P = 0.003) as well as its declined value (OR = 2.03, P = 0.024) at 24-wk independently predicted VR, with the AUROC of 0.788 and 0.736, respectively. The combination of HBeAg titer < 1.3 lg PEIU/mL and its decreased value > 1.6 lg PEIU/mL at 24-wk predicted VR with a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of 85%, 100%, 100% and 83%, respectively, and the AUROC increased to 0.923. The HBeAg level (OR = 0.37, P = 0.013) as well as its declined value (OR = 2.02, P = 0.012) at 24-wk also independently predicted HBeAg SC, with the AUROC of 0.828 and 0.814, respectively. The HBeAg titer < -0.5 lg PEIU/mL combined with its declined value > 2.2 lg PEIU/mL at 24-wk predicted HBeAg SC with a sensitivity, specificity, PPV, NPV of 88%, 98%, 88% and 98%, respectively, and the AUROC reached 0.928. CONCLUSION: The combination of HBeAg level and its declined value at 24-wk may be used as a reference parameter to optimize NAs therapy. PMID- 28008343 TI - Seroprevalence of hepatitis B surface antigen in pregnant women attending antenatal clinic in Honiara Solomon Islands, 2015. AB - AIM: To determine the seroprevalence of hepatitis B surface antigen (HBsAg) among pregnant women attending antenatal clinic in Honiara, Solomon Islands. METHODS: This descriptive cross-sectional study was carried out in seven area health centers in Honiara. From March to June 2015, identification of eligible pregnant women in each site was conducted using systematic random sampling technique. A total of 243 pregnant women who gave written informed consent were enrolled. Standardized tool was used to record demographics, obstetric history and serology results. HBsAg and hepatitis B e antigen (HBeAg) were tested using point-of-care rapid diagnostic test. All HBsAg positive samples were verified using enzyme linked immunosorbent assay. RESULTS: The mean age of participants was 26 +/- 6 years. The overall hepatitis HBsAg prevalence was 13.8% with higher rate (22%) reported in women between 30-34 years of age. Majority of HBsAg positive participants were Melanesians (29 out for 33). None of the pregnant women in the 15-19 years and >= 40 years tested positive for HBsAg. There was no statistically significant difference in HBsAg prevalence by age, ethnicity, education and residential location. The overall HBeAg seroprevalence was 36.7%. Women between 20-24 years of age had the highest rate of 54.5%. Low level of knowledge about hepatitis B vaccination was reputed. Overall, 54.6% of participants were not aware of their hepatitis B vaccination status and only 65.2% of mothers reported their child had been vaccinated. CONCLUSION: Hepatitis B is a disease of public health importance in Solomon Islands and emphasize the need for integrated preventative interventions for its control. PMID- 28008344 TI - Prevalence and risk factors of acute-on-chronic liver failure in a single center from Argentina. AB - AIM: To study the prevalence, characteristics, risk factors and mortality at 28 d of acute-on-chronic liver failure (ACLF). METHODS: A total of 100 cirrhotic patients admitted to our hospital for more than one day were included during the period between June 2013 and December 2015. We used the European Association for the Study of the Liver-Chronic Liver Failure-Consortium diagnostic criteria for ACLF, considering it as the acute decompensation of cirrhosis associated with the presence of one or more organ failure. For the diagnosis of organic failure the Chronic Liver Failure-Sequential Organ Failure Assessment score was used. Our population was divided into patients with and without ACLF. Clinical characteristics, presence of precipitating events, potential risk factors for developing ACLF and causes of mortality were analyzed. Mortality at 28 d was evaluated. RESULTS: Twenty-nine patients (29%) developed ACLF criteria. Alcoholism, detected in 58 patients (58%), was the major etiological agent of cirrhosis. Bacterial infections were recognized as a precipitating event in 41.3% of cases and gastrointestinal bleeding in 27.5%. No precipitating event was identifiable in 27.5% of patients with ACLF. Comparing patients with and without ACLF, statistically significant risk factors were: Child Pugh score 10.2 +/- 2.1 vs 8.4 +/- 1.6 (P ? 0.0001), MELD score 20.7 +/- 8.5 vs 12.3 +/- 4 (P ? 0.0001), presence of ascites 27 (93%) vs 43 (60.5%) (P = 0.001), leukocytosis 15300 +/- 8033 per cubic millimeter vs 10770 +/- 5601 per cubic millimeter (P ? 0.0001), and high plasma levels of C reactive protein values 50.9 +/- 46.4 mg/L vs 28.6 +/ 23.4 mg/L (P ? 0.0019). Mortality rate was 62% (18 patients) vs 5.6% (4 patients), respectively (P < 0.0001). CONCLUSION: We observed that the ACLF is a frequent entity in this group of patients and has a significantly higher mortality rate. PMID- 28008345 TI - Major hepatectomy using the glissonean approach in cases of right umbilical portion. AB - Right umbilical portion (RUP) is a rare congenital anomaly associated with anomalous ramifications of the hepatic vessels and biliary system. As such, major hepatectomy requires a careful approach. We describe the usefulness of the Glissonean approach in two patients with vessel anomalies, such as RUP. The first patient underwent a right anterior sectionectomy for intrahepatic cholangiocarcinoma. We encircled several Glissonean pedicles that entered the right anterior section along the right side of the RUP. We temporarily clamped each pedicle, confirmed the demarcation area, and finally cut them. The operation was performed safely and was successful. The second patient underwent a left trisectionectomy for perihilar cholangiocarcinoma. We secured the right posterior Glissonean pedicle. The vessels in the pedicle were preserved, and the other vessels and contents were resected. Identifying the vessels for preservation facilitated the safe lymphadenectomy and dissection of the vessels to be resected. We successfully performed the operation. PMID- 28008346 TI - Polyelectrolyte multilayer electrostatic gating of graphene field-effect transistors. AB - We apply polyelectrolyte multilayer films by consecutive alternate adsorption of positively charged polyallylamine hydrochloride and negatively charged sodium polystyrene sulfonate to the surface of graphene field effect transistors. Oscillations in the Dirac voltage shift with alternating positive and negative layers clearly demonstrate the electrostatic gating effect in this simple model system. A simple electrostatic model accounts well for the sign and magnitude of the Dirac voltage shift. Using this system, we are able to create p-type or n type graphene at will. This model serves as the basis for understanding the mechanism of charged polymer sensing using graphene devices, a potentially technologically important application of graphene in areas such as DNA sequencing, biomarker assays for cancer detection, and other protein sensing applications. PMID- 28008347 TI - Tree-centric mapping of forest carbon density from airborne laser scanning and hyperspectral data. AB - Forests are a major component of the global carbon cycle, and accurate estimation of forest carbon stocks and fluxes is important in the context of anthropogenic global change. Airborne laser scanning (ALS) data sets are increasingly recognized as outstanding data sources for high-fidelity mapping of carbon stocks at regional scales.We develop a tree-centric approach to carbon mapping, based on identifying individual tree crowns (ITCs) and species from airborne remote sensing data, from which individual tree carbon stocks are calculated. We identify ITCs from the laser scanning point cloud using a region-growing algorithm and identifying species from airborne hyperspectral data by machine learning. For each detected tree, we predict stem diameter from its height and crown-width estimate. From that point on, we use well-established approaches developed for field-based inventories: above-ground biomasses of trees are estimated using published allometries and summed within plots to estimate carbon density.We show this approach is highly reliable: tests in the Italian Alps demonstrated a close relationship between field- and ALS-based estimates of carbon stocks (r2 = 0.98). Small trees are invisible from the air, and a correction factor is required to accommodate this effect.An advantage of the tree centric approach over existing area-based methods is that it can produce maps at any scale and is fundamentally based on field-based inventory methods, making it intuitive and transparent. Airborne laser scanning, hyperspectral sensing and computational power are all advancing rapidly, making it increasingly feasible to use ITC approaches for effective mapping of forest carbon density also inside wider carbon mapping programs like REDD++. PMID- 28008348 TI - Do doctors agree on doses of antipsychotic medications? AB - BACKGROUND: The objective of this study was to investigate the concordance in attitudes of psychiatrists towards the doses of antipsychotics given to stable outpatients with schizophrenia and to examine the psychiatrists' estimates of equally potent doses of haloperidol and olanzapine. METHODS: We asked all 22 doctors serving at the psychiatry department of Jonkoping County Hospital if they considered the combined dose of antipsychotics for 20 individual patients to be 'low', 'medium' or 'high'. We also asked each doctor to state the dose of haloperidol that they considered to be clinically equivalent to 20 mg/day of olanzapine. RESULTS: The inter-rater reliability (Krippendorff's alpha (alpha)) was 0.50, and the mean estimated dose haloperidol considered clinically equivalent to 20 mg/day of olanzapine was 4.45 mg/day. CONCLUSIONS: The inter rater reliability (Krippendorff's alpha) was low, suggesting lack of agreement. The dose of antipsychotics given to a patient might thus be more influenced by which doctor they meet than the severity of the disease. The respondents in this study considered a mean dose of 4.45 mg/day of haloperidol to be clinically equivalent to 20 mg/day of olanzapine. This is a considerably lower dose than was determined by an international consensus study of antipsychotic dosing, and more in line with the available PET studies measuring central dopamine receptor blockage of optimal clinical doses. PMID- 28008349 TI - Dosing patterns and medication adherence in bipolar disorder patients treated with lurasidone: a US retrospective claims database analysis. AB - BACKGROUND: The aim of this study was to describe dosing patterns and medication adherence among bipolar patients who initiated lurasidone in a real-world setting. METHODS: Adult bipolar patients who initiated lurasidone between 1 November 2010 and 31 December 2012 (index period) with 6-month pre- and post index continuous enrollment were identified from the IMS RWD Adjudicated Claims US database. Patients were grouped by starting lurasidone daily dose: 20 mg (7.1%), 40 mg (62.2%), 60-80 mg (28.7%), and 120-160 mg (2.1%). Patient characteristics were compared across doses using Cochran-Armitage trend tests. Multivariable ordinal logistic regression assessed the association between initial lurasidone dose and patient characteristics. Medication adherence was measured using medication possession ratio (MPR). RESULTS: Of 1114 adult bipolar patients (mean age 40.6 years, 70.6% female), 90% initiated lurasidone at 40 mg or 80 mg/day (mean 51.9 mg/day). Of these, 16.2% initiated lurasidone as monotherapy. Mean lurasidone maintenance dose was 55.2 mg/day and mean MPR was 0.53 [standard deviation (SD) = 0.34] over the 6-month follow up. Substance use, hyperglycemia, obesity, and prior antipsychotic use were associated with higher initial lurasidone doses (p < 0.05). Odds of a 20 mg/day increase in initial lurasidone dose was 1.6-times higher for patients with substance use [95% confidence interval (CI): 1.16-2.24], 2.6-times higher with hyperglycemia problems (95% CI: 1.15-5.83), 1.7-times higher with obesity (95% CI: 1.05-2.60), and 1.3 (95% CI: 1.01-1.78) and 1.8-times higher (95% CI: 1.17-2.86) with prior use of second- and first-generation antipsychotics, respectively. CONCLUSIONS: This real-world analysis of bipolar patients indicated that 40 mg or 80 mg/day were the most common starting doses of lurasidone. A majority of patients used concomitant psychiatric medications (polypharmacy). Higher doses of lurasidone were prescribed to patients with comorbidities or prior antipsychotic use. Adherence to lurasidone was comparable to or better than antipsychotic adherence reported in bipolar disorder literature. PMID- 28008351 TI - Methamphetamine addiction: potential substitute treatment. PMID- 28008350 TI - Safety profile of lamotrigine in overdose. AB - BACKGROUND: Lamotrigine is an anticonvulsant as well as a mood stabilizer. Apart from its established use in the treatment of epilepsy, there has been an expansion of its use in the treatment of mental disorders. Patients with epilepsy as well as those with mental disorders are at increased risk of deliberate drug overdoses. An evidence base for the safety profile of lamotrigine in overdose is an essential tool for prescribers. The objective of this study was to carry out a narrative synthesis of the existing evidence for the safety profile of lamotrigine in overdose. METHODS: A systematic search was conducted of EMBASE (1974 to December 2015), MEDLINE (1946 to December 2015), PsycINFO (1806 to December 2015) and CINAHL (1981 to December 2015) databases. Studies were included in which there was a deliberate or accidental single drug overdose of lamotrigine, with its toxic effects described. Studies that did not involve an overdose were excluded. A narrative synthesis of the described toxic effects was carried out. RESULTS: Out of 562 articles identified, 26 studies were included, mainly in the form of case reports and series. The most commonly described toxic effects of lamotrigine were on the central nervous system, specifically seizures, movement disorders and reduced consciousness. Other toxic effects included QTc interval and QRS complex prolongations, hypersensitivity reactions, serotonin syndrome as well as rhabdomyolysis possibly due to seizures and/or agitation. Deaths were recorded in two studies, with cardiovascular and neurological toxic effects described. CONCLUSIONS: Even though lamotrigine has been reported to be well tolerated, there is a risk of toxic effects which can be life threatening in overdose. This needs to be borne in mind when prescribing to patients at an increased risk of deliberate drug overdose. PMID- 28008352 TI - Low-dose quetiapine complements stimulant response in attention deficit hyperactivity disorder and more. PMID- 28008353 TI - Impact of Medicare Part D on Racial and Ethnic Minorities. AB - OBJECTIVES: Prior to the implementation of Medicare Part D in the United States, inequalities were found to exist in the use of medications between minority and white beneficiaries. Despite improvements in medication affordability after Medicare Part D implementation, it is still not clear whether the characteristics of the program have improved drug utilization patterns among minorities to the same degree as whites. This review aims to determine whether there were barriers for Medicare Part D to realize its potential to improve prescription drug utilization patterns among minorities. METHODS: Google Scholar, PubMed, Sciencedirect and Scopus were used to conduct a comprehensive search of the literature published since 2003 when the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) was passed, which authorized the establishment of the Part D program. All studies and documents related to the effects of Medicare Part D on minorities were included to present a relatively comprehensive review on the topic. RESULTS: Evidence indicated that minorities are not equally benefiting from Medicare Part D prescription drug coverage compared to whites. Examples of characteristics of Medicare Part D that caused significant racial differences in drug utilization include the donut hole, the complexity and number of drug plans, and drug utilization management strategies. CONCLUSION: Medicare Part D has increased access to prescription medications for the elderly. However, continued analysis and research of drug utilization patterns among minorities should be conducted to ensure that all enrollees regardless of race are benefiting equally from Medicare Part D. Identification of these barriers can provide insights on how to improve the program to allow minorities to benefit equally from the Medicare Part D program and remove health inequalities. PMID- 28008354 TI - Percutaneous balloon aortic valvuloplasty in the era of transcatheter aortic valve implantation: a narrative review. AB - The role of percutaneous balloon aortic valvuloplasty (BAV) in the management of severe symptomatic aortic stenosis has come under the spotlight following the development of the transcatheter aortic valve implantation (TAVI) technique. Previous indications for BAV were limited to symptom palliation and as a bridge to definitive therapy for patients undergoing conventional surgical aortic valve replacement (AVR). In the TAVI era, BAV may also be undertaken to assess the 'therapeutic response' of a reduction in aortic gradient in borderline patients often with multiple comorbidities, to assess symptomatic improvement prior to consideration of definitive TAVI intervention. This narrative review aims to update the reader on the current indications and practical techniques involved in undertaking a BAV procedure. In addition, a summary of the haemodynamic and clinical outcomes, as well as the frequently encountered procedural complications is presented for BAV procedures conducted during both the pre-TAVI and post-TAVI era. PMID- 28008355 TI - Distinguishing between those dying suddenly or not suddenly from coronary heart disease: long-term prospective results from the Northwick Park Heart Study. AB - AIM: To establish whether ECG findings are associated with subsequent risk of sudden death from coronary heart disease (CHD). METHODS AND RESULTS: Potential risk factors for CHD were measured at entry to the first Northwick Park Heart Study of 2167 men. ECG findings were coded as high or low risk for CHD according to definitions in the Minnesota code. Sudden or non-sudden deaths were defined as occurring in less than or more than 24 hours, respectively. The only factor independently associated with sudden death among the 262 men dying of CHD was high-risk ECG. Of 184 sudden CHD deaths, 34 men (18.5%) had had high-risk ECGs at entry to the study compared with 5 (6.4%) of 78 men who experienced non-sudden deaths (adjusted OR 3.94 (95% CI 1.33 to 11.67)) (p=0.006). Findings were also compared among all 2167 men, where high-risk ECGs were again associated with sudden death. T-wave changes were the main abnormalities associated with a high risk of sudden death. CONCLUSIONS: In a group of men who had not previously experienced major episodes of CHD but who subsequently died from it, there was strong evidence that high-risk ECG changes, mainly T-wave abnormalities, differentiated between those who later died sudden deaths and those who survived for >24 hours. PMID- 28008356 TI - Frailty is associated with delirium and mortality after transcatheter aortic valve implantation. AB - OBJECTIVE: We hypothesised that frailty assessment is of additional value to predict delirium and mortality after transcatheter aortic valve implantation (TAVI). METHODS: Observational study in 89 consecutive patients who underwent TAVI. Inclusion from November 2012 to February 2014, follow-up until April 2014. Measurement of the association of variables from frailty assessment and cardiological assessment with delirium and mortality after TAVI, respectively. RESULTS: Incidence of delirium after TAVI: 25/89 (28%). Variables from frailty assessment protectively associated with delirium were: Mini Mental State Examination, (OR 0.79; 95% CI 0.65 to 0.96; p=0.02), Instrumental Activities of Daily Living (OR 0.79; 95% CI 0.63 to 0.99; p=0.04) and gait speed (OR 0.05; 95% CI 0.01 to 0.50; p=0.01). Timed Up and Go was predictively associated with delirium (OR 1.14; 95% CI 1.03 to 1.26; p=0.01). From cardiological assessment, pulmonary hypertension was protectively associated with delirium (OR 0.34; 95% CI 0.12 to 0.98; p=0.05). Multivariate logistic analysis: Nagelkerke R2=0.359, Mini Mental State Examination was independently associated with delirium. Incidence of mortality: 11/89 (12%). Variables predictively associated with mortality were: the summary score Frailty Index (HR 1.66, 95% CI 1.06 to 2.60; p=0.03), European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (HR 1.14, 95% CI 1.06 to 1.22; p<0.001) and complications (HR 4.81, 95% CI 1.03 to 22.38; p=0.05). Multivariate Cox proportional hazards analysis: Nagelkerke R2=0.271, Frailty Index and EuroSCORE II were independently associated with mortality. CONCLUSIONS: Delirium frequently occurs after TAVI. Variables from frailty assessment are associated with delirium and mortality, independent of cardiological assessment. Thus, frailty assessment may have additional value in the prediction of delirium and mortality after TAVI. PMID- 28008357 TI - Bicuspid aortic valve disease: systematic review and meta-analysis of surgical aortic valve repair. AB - Aortic valve repair is still emerging, and its role in the treatment of bicuspid aortic valve disease (BAVD) is not yet fully understood. Our objective is to synthesise available evidence on outcomes after surgical aortic valve repair in patients with BAVD. We conducted a systematic review of clinical studies using prespecified methods for searching, identifying and selecting eligible studies in 4 databases, and synthesising results (PROSPERO 2014:CRD42014014415). 2 researchers independently reviewed full-text articles and extracted data. The results of included studies were quantitatively synthesised in frequentist meta analyses. We included 11 aortic valve repair studies or study arms with a total of 2010 participants. Pooled estimates for the proportion of patients surviving at 30 days, 1 year, 5 years and 10 years were 0.995 (95% CI 0.991 to 0.995), 0.994 (0.989 to 0.999), 0.945 (0.898 to 0.993) and 0.912 (0.845 to 0.979), respectively. The pooled proportion of late deaths from valve-related causes was 0.008 (0.000 to 0.019) at a mean follow-up of 3.5 years. Proportion of patients with valve-related reinterventions was 0.075 (0.037 to 0.113) at a mean follow-up of 3.9 years, and the linearised reintervention rate was 1.3 (0.7 to 1.9) per 100 patient-years. Outcome reporting was insufficient to pool the results for a number of predefined outcomes. In conclusion, existing evidence on aortic valve repair in BAVD is limited to mostly small case series, case-control and small retrospective cohort studies. Despite the low quality, available evidence suggests favourable survival outcomes after aortic valve repair in selected patients with BAVD. Valve-related reinterventions at follow-up are common in all patients undergoing repair surgery. PMID- 28008359 TI - Editorial: "This is a very dynamic and exciting time for assistive technologies and for tracking rehabilitation practices." PMID- 28008358 TI - Impact of microvascular obstruction on semiautomated techniques for quantifying acute and chronic myocardial infarction by cardiovascular magnetic resonance. AB - AIMS: The four most promising semiautomated techniques (5-SD, 6-SD, Otsu and the full width half maximum (FWHM)) were compared in paired acute and follow-up cardiovascular magnetic resonance (CMR), taking into account the impact of microvascular obstruction (MVO) and using automated extracellular volume fraction (ECV) maps for reference. Furthermore, their performances on the acute scan were compared against manual myocardial infarct (MI) size to predict adverse left ventricular (LV) remodelling (>=20% increase in end-diastolic volume). METHODS: 40 patients with reperfused ST segment elevation myocardial infarction (STEMI) with a paired acute (4+/-2 days) and follow-up CMR scan (5+/-2 months) were recruited prospectively. All CMR analysis was performed on CVI42. RESULTS: Using manual MI size as the reference standard, 6-SD accurately quantified acute (24.9+/-14.0%LV, p=0.81, no bias) and chronic MI size (17.2+/-9.7%LV, p=0.88, no bias). The performance of FWHM for acute MI size was affected by the acquisition sequence used. Furthermore, FWHM underestimated chronic MI size in those with previous MVO due to the significantly higher ECV in the MI core on the follow-up scans previously occupied by MVO (82 (75-88)% vs 62 (51-68)%, p<0.001). 5-SD and Otsu were precise but overestimated acute and chronic MI size. All techniques were performed with high diagnostic accuracy and equally well to predict adverse LV remodelling. CONCLUSIONS: 6-SD was the most accurate for acute and chronic MI size and should be the preferred semiautomatic technique in randomised controlled trials. However, 5-SD, FWHM and Otsu could also be used when precise MI size quantification may be adequate (eg, observational studies). PMID- 28008360 TI - Disrupting the world of Disability: The Next Generation of Assistive Technologies and Rehabilitation Practices. AB - Designing, developing and deploying assistive technologies at a scale and cost which makes them accessible to people is challenging. Traditional models of manufacturing would appear to be insufficient at helping the world's 1 billion disabled people in accessing the technologies they require. In addition, many who receive assistive technologies simply abandon them as they do not meet their needs. In this study the authors explore the changing world of design for disability. A landscape which includes the rise of the maker movement, the role of ubiquitous sensing and the changing role of the 'user' to one of designer and maker. The authors argue they are on the cusp of a revolution in healthcare provision, where the population will soon have the ability to manage their own care with systems in place for diagnosis, monitoring, individualised prescription and action/reaction. This will change the role of the clinician from that of diagnostician, gatekeeper and resource manager/deliverer to that of consultant informatics manager and overseer; perhaps only intervening to promote healthy behaviour, prevent crisis and react at flash moments. PMID- 28008361 TI - Fuzzy logic-based risk of fall estimation using smartwatch data as a means to form an assistive feedback mechanism in everyday living activities. AB - This Letter aims to create a fuzzy logic-based assistive prevention tool for falls, based on accessible sensory technology, such as smartwatch, resulting in monitoring of the risk factors of falls caused by orthostatic hypotension (OH); a drop in systolic blood pressure (DSBP) >20 mmHg due to postural changes. Epidemiological studies have shown that OH is a high risk factor for falls and has a strong impact in quality of life (QoL) of the elderly's, especially for some cases such as Parkinsonians. Based on smartwatch data, it is explored here how statistical features of heart rate variability (HRV) can lead to DSBP prediction and estimation of the risk of fall. In this vein, a pilot study was conducted in collaboration with five Greek Parkinson's Foundation patients and ten healthy volunteers. Taking into consideration, the estimated DSBP and additional statistics of the user's medical/behavioural history, a fuzzy logic inference system was developed, to estimate the instantaneous risk of fall. The latter is fed back to the user with a mechanism chosen by him/her (i.e. vibration and/or sound), to prevent a possible fall, and also sent to the attentive carers and/or healthcare professionals for a home-based monitoring beyond the clinic. The proposed approach paves the way for effective exploitation of the contribution of smartwatch data, such as HRV, in the sustain of QoL in everyday living activities. PMID- 28008362 TI - Sensewheel: an adjunct to wheelchair skills training. AB - The purpose of this Letter was to investigate the influence of real-time verbal feedback to optimise push arc during over ground manual wheelchair propulsion. Ten healthy non-wheelchair users pushed a manual wheelchair for a distance of 25 m on level paving, initially with no feedback and then with real-time verbal feedback aimed at controlling push arc within a range of 85 degrees -100 degrees . The real-time feedback was provided by a physiotherapist walking behind the wheelchair, viewing real-time data on a tablet personal computer received from the Sensewheel, a lightweight instrumented wheelchair wheel. The real-time verbal feedback enabled the participants to significantly increase their push arc. This increase in push arc resulted in a non-significant reduction in push rate and a significant increase in peak force application. The intervention enabled participants to complete the task at a higher mean velocity using significantly fewer pushes. This was achieved via a significant increase in the power generated during the push phase. This Letter identifies that a lightweight instrumented wheelchair wheel such as the Sensewheel is a useful adjunct to wheelchair skills training. Targeting the optimisation of push arc resulted in beneficial changes in propulsion technique. PMID- 28008363 TI - Muscular activity and physical interaction forces during lower limb exoskeleton use. AB - Spinal cord injury (SCI) typically manifests with a loss of sensorimotor control of the lower limbs. In order to overcome some of the disadvantages of chronic wheelchair use by such patients, robotic exoskeletons are an emerging technology that has the potential to transform the lives of patients. However, there are a number of points of contact between the robot and the user, which lead to interaction forces. In a recent study, the authors have shown that peak interaction forces are particularly prominent at the anterior aspect of the right leg. This study uses a similar experimental protocol with additional electromyography (EMG) analysis to examine whether such interaction forces are due to the muscular activity of the participant or the movement of the exoskeleton itself. Interestingly, the authors found that peak forces preceded peak EMG activity. This study did not find a significant correlation between EMG activity and force data, which would indicate that the interaction forces can largely be attributed to the movement of the exoskeleton itself. However, we also report significantly higher correlation coefficients in muscle/force pairs located at the anterior aspect of the right leg. In their previous research, the authors have shown peak interaction forces at the same locations, which suggests that muscular activity of the participant makes a more significant contribution to the interaction forces at these locations. The findings of this study are of significance for incomplete SCI patients, for whom EMG activity may provide an important input to an intuitive control schema. PMID- 28008364 TI - Interfacial pressure and shear sensor system for fingertip contact applications. AB - This Letter presents a capacitive-based sensor system for fingertip contact applications. It is capable of simultaneously measuring normal (pressure) and tangential (shear) stresses at the interface between a fingertip and external objects. This could be potentially exploitable for applications in the fields of upper limb prosthetics, robotics, hand rehabilitation and so on. The system was calibrated and its performance was tested using a test machine. To do so, specific test protocols reproducing typical stress profiles in fingertip contact interactions were designed. Results show the system's capability to measure the applied pressure and stresses, respectively, with high linearity between the measured and applied stresses. Subsequently, as a case study, a 'press-drag-lift' based fingertip contact test was conducted by using a finger of a healthy subject. This was to provide an initial evaluation for real-life applications. The case study results indicate that both interface pressure and shear were indeed measured simultaneously, which aligns well with the designed finger test protocols. The potential applications for the sensor system and corresponding future works are also discussed. PMID- 28008365 TI - Development of a prototype of portable FES rehabilitation system for relearning of gait for hemiplegic subjects. AB - This study aimed at developing a prototype of portable FES rehabilitation system for relearning gait pattern of healthy subjects, which can measure gait information during walking applying electrical stimulation for foot drop correction or providing timing information. A gait event detection method using an inertial sensor attached on the foot was determined based on gait of healthy subjects from simultaneous measurements with pressure sensors. From the result of comparing the detected gait event timings with EMG signal of the tibialis anterior muscle during walking of healthy subjects, the toe off and the foot flat timings detected by the inertial sensor were suggested to be useful to determine the stimulation timing for the foot drop correction. The gait event detection method was implemented in a prototype of portable FES rehabilitation system consisting of an 8-inch tablet-type device, 2 inertial sensors and an electrical stimulator. The portable system was examined with hemiplegic subjects under the conditions of FES foot drop correction and inducing voluntary effort to develop ankle dorsiflexion at the timing given by electrical stimulation with small stimulation intensity. The system was considered to be useful for gait rehabilitation of hemiplegia using FES foot drop correction or inducing voluntary effort. PMID- 28008366 TI - Pervasive assistive technology for people with dementia: a UCD case. AB - Smart mobile and wearable technology offers exciting opportunities to support people with dementia (PwD). Its ubiquity and popularity could even benefit user adoption - a great challenge for assistive technology (AT) for PwD that calls for user-centred design (UCD) methods. This study describes a user-centred approach to developing and testing AT based on off-the-shelf pervasive technologies. A prototype is created by combining a smartphone, smartwatch and various applications to offer six support features. This is tested among five end-users (PwD) and their caregivers. Controlled usability testing was followed by field testing in a real-world context. Data is gathered from video recordings, interaction logs, system usability scale questionnaires, logbooks, application usage logs and interviews structured on the unified theory of acceptance and use of technology model. The data is analysed to evaluate usability, usefulness and user acceptance. Results show some promise for user adoption, but highlight challenges to be overcome, emphasising personalisation and familiarity as key considerations. The complete findings regarding usability issues, usefulness of support features and four identified adoption profiles are used to provide a set of recommendations for practitioners and further research. These contribute toward UCD practices for improved smart, pervasive AT for dementia. PMID- 28008367 TI - Characterisation of rollator use using inertial sensors. AB - The use of walking aids is prevalent among older people and people with mobility impairment. Rollators are designed to support outdoor mobility and require the user to negotiate curbs and slopes in the urban environment. Despite the prevalence of rollators, analysis of their use outside of controlled environments has received relatively little attention. This Letter reports on an initial study to characterise rollator movement. An inertial measurement unit (IMU) was used to measure the motion of the rollator and analytical approaches were developed to extract features characterising the rollator movement, properties of the surface and push events. The analytics were tested in two situations: first, a healthy participant used a rollator in a laboratory using a motion capture system to obtain ground truth. Second, the IMU was used to measure the movement of a rollator being used by a user with multiple sclerosis on a flat surface, cross slope, up and down slopes and up and down a step. The results showed that surface inclination and distance travelled measured by the IMU have close approximation to the results from ground truth; therefore, demonstrating the potential for IMU derived metrics to characterise rollator movement and user's pushing style in the outdoor environment. PMID- 28008368 TI - Anaphylaxis in the community: a questionnaire survey of members of the UK Anaphylaxis Campaign. AB - OBJECTIVES: To examine the circumstances, features and management of anaphylaxis in children and adults. DESIGN: Self-completed questionnaire. PARTICIPANTS: The age of participants ranged from 0 to 72 years. SETTING: We analysed data from self-completed questionnaires collected over a 12-year period, i.e. 2001-2013, available to people by phone and, since 2012, for online completion through the Anaphylaxis Campaign. MAIN OUTCOME MEASURE: We analysed data from self-completed questionnaires collected over a 12- year period, i.e. 2001-2013, available to people by phone and, since 2012, for online completion through the Anaphylaxis Campaign. RESULTS: In total, 356 questionnaires were submitted, of which 54 did not meet the criteria for anaphylaxis. The remaining 302 anaphylactic reactions originated from 243 individuals; 193 (64%) of these reactions were in children. Approximately half of all reactions occurred at home (n = 148; 49%); 61% (n = 193) of reactions occurred in those reporting a history of asthma, and many (n = 76; 41%) of these individuals had asthma that they classified as being severe. In 57% (n = 173) cases, the respondent reacted to a known allergen. Self-injectable adrenaline (epinephrine) was available in 79% of the cases, and it was only used in 38% of episodes. The usage of self-injected adrenaline was lower in children (30%) than in adults (54%), even though 82% of children had adrenaline available at the time of the reaction compared to 74% of adults. CONCLUSIONS: These data suggest that the majority of anaphylaxis reactions are triggered by exposure to known food allergens and that approximately half of these reactions occur at home. Access to self-injectable adrenaline was sub-optimal and when available it was only used in a minority of cases. Avoiding triggers, access to self injectable adrenaline and its prompt use in the context of reactions need to be reinforced. PMID- 28008369 TI - Effect of the economic crisis on the production of immunology patents managed through the Patent Cooperation Treaty agreement from 2004-2011. AB - OBJECTIVES: To determine the evolution of patents in immunology, as a result of research and innovation in the years 2004-2011. DESIGN: The search for patents published internationally in immunology was made by using the SCOPUSTM database. SCOPUS gives information about over 23 million patents. The extracted data from patents were: inventors and applicants; their nationalities; sections, classes and subclasses of the International Patent Classification. PARTICIPANTS: 89 countries. SETTING: Data have been obtained from the database SCOPUS. It has been used for the international patent classification. MAIN OUTCOME MEASURES: Patents by country, Productive sectors, Productive areas. RESULTS: A total of 17,281 patents were applied for immunology during 2004-2011 of which 16,811 were from 30 Organisation for Economic Cooperation and Development countries, and 5326 from 28 countries in the European Union. These patents were granted in 89 countries and 13,699 of them were submitted by researchers from only one country. Private entities applied for 62.45% of all patents, universities 17.48%, hospitals 3.40% and public research organisations and private applicants applied for the rest. The university that made more applications was the University of California with 315 and the company was Genentech Inc. (US) with 302. The reduction in the number of applications of international patents in all disciplines of science also affected the area of immunology. CONCLUSIONS: Collaboration in immunology between universities, companies and hospitals is hard because their interests are different. It is shown in patent applications that the majority of patents in immunology are applied for by only one entity. Patents in immunology are developed, mainly, in aspects such as medical preparations, peptides, mutation or genetic engineering, therapeutic activity of chemical compounds and analysing materials by determining their chemical or physical properties. PMID- 28008370 TI - Sleep paralysis and folklore. AB - Sleep paralysis is a relatively new term to describe what for hundreds of years many believed to be a visitation by a malevolent creature which attacked its victims as they slept. The first clinical description of sleep paralysis was published in 1664 in a Dutch physician's case histories, where it was referred to as, 'Incubus or the Night-Mare [sic]'. In 1977, it was discovered more than 100 previously healthy people from various South East Asian communities had died mysteriously in their sleep. The individuals affected were dying at a rate of 92/100,000 from Sudden Unexplained Nocturnal Death Syndrome. No underlying cause was ever found, only that subsequent studies revealed a high rate of sleep paralysis and belief in the dab tsog (nightmare spirit) amongst members of the community. The nightmare/succubus is descended from Lilith. The earliest reference to Lilith is found in the Sumerian King list of 2400 BC known as Lilitu or she-demon, she bore children from her nocturnal unions with men. In other derivations, she was Adam's first wife who rather than 'obey' became a demon that preyed on women during childbirth. In modern Middle Eastern maternity wards, some women still wear amulets for protection. Today, clinical cause of these disturbances is sleep paralysis due to the unsuitable timing of REM sleep. During the 'Nightmare' episode, the sleeper becomes partially conscious during REM cycle, leaving the individual in a state between dream and wakefulness. For some, culture and the tradition of the nightmare is explanation enough. PMID- 28008372 TI - Persistent cannabis dependence and alcohol dependence represent risks for midlife economic and social problems: A longitudinal cohort study. AB - With the increasing legalization of cannabis, understanding the consequences of cannabis use is particularly timely. We examined the association between cannabis use and dependence, prospectively assessed between ages 18-38, and economic and social problems at age 38. We studied participants in the Dunedin Longitudinal Study, a cohort (n=1,037) followed from birth to age 38. Study members with regular cannabis use and persistent dependence experienced downward socioeconomic mobility, more financial difficulties, workplace problems, and relationship conflict in early midlife. Cannabis dependence was not linked to traffic-related convictions. Associations were not explained by socioeconomic adversity, childhood psychopathology, achievement orientation, or family structure; cannabis related criminal convictions; early onset of cannabis dependence; or comorbid substance dependence. Cannabis dependence was associated with more financial difficulties than alcohol dependence; no difference was found in risks for other economic or social problems. Cannabis dependence is not associated with fewer harmful economic and social problems than alcohol dependence. PMID- 28008371 TI - Mindful Climate Action: Health and Environmental Co-Benefits from Mindfulness Based Behavioral Training. AB - Greenhouse gases from human activities are causing climate change, creating risks for people around the globe. Behaviors involving transportation, diet, energy use, and purchasing drive greenhouse gas emissions, but are also related to health and well-being, providing opportunity for co-benefits. Replacing shorter automobile trips with walking or cycling, or eating plants rather than animals, for example, may increase personal health, while also reducing environmental impact. Mindfulness-based practices have been shown to enhance a variety of health outcomes, but have not been adapted towards environmental purposes. We designed the Mindful Climate Action (MCA) curriculum to help people improve their health while simultaneously lowering their carbon footprints. Combining mindfulness-based practices with the Stages of Change theory, the MCA program aims to: (1) improve personal health and well-being; (2) decrease energy use; (3) reduce automobile use; (4) increase active transport; (5) shift diet towards plant-based foods; and (6) reduce unnecessary purchasing. Mindfulness practices will foster attentional awareness, openness, and response flexibility, supporting positive behavior change. We plan to test MCA in a randomized controlled trial, with rigorous assessment of targeted outcomes. Our long-term goal is to refine and adapt the MCA program to a variety of audiences, in order to enhance public health and environmental sustainability. PMID- 28008374 TI - Comparative proteomics analysis of human osteosarcoma by 2D DIGE with MALDI TOF/TOF MS. AB - Osteosarcoma (OS) is the most common primary malignant tumor of bone and the third most common cancer in childhood and adolescence. However, controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel protein targets will be critical to identify the path toward improving outcomes for patients. We attempted to identify potential protein markers or therapy targets of osteosarcoma and give a glance at tumorigenesis of osteosarcoma. A sensitive and accurate method was employed in comparative proteomic analysis between benign tumor and osteosarcoma. Tumor tissues obtained by open biopsy before induction chemotherapy were investigated With 2D DIGE and MALDI-TOF/TOF MS, 22 differentially expressed proteins were identified after database searching, including 8 up-regulated and 14 down-regulated proteins. We also validated the expression levels of interesting proteins(have higher Ratios(tumor/normal)) by Western blotting assay. Annotating by bioinformatic tools, we found structural and signal transduction associated proteins were in large percentage among altered level proteins. In particular, some low abundant proteins involving translation and transcription, such as EEF2(Elongation Factor 2), LUM Lumican 23 kDa Protein) and GTF2A2(Transcription Initiation Factor Iia Gamma Chain.), were firstly reported by our study comparing to previous observations. Our findings suggest that these differential proteins may be potential biomarkers for diagnosis or molecules for understanding of osteosarcoma tumorigenesis, coming with biologic, preclinical, and clinical trial efforts being described to improve outcomes for patients. PMID- 28008373 TI - Clinical Factors, Disease Parameters, and Molecular Therapies Affecting Osseointegration of Orthopedic Implants. AB - Total hip and knee arthroplasty are effective interventions for management of end stage arthritis. Indeed, about 7 million Americans are currently living with artificial hip and knee joints. The majority of these individuals, however, will outlive their implants and require revision surgeries, mostly due to poor implant osseointegration and aseptic loosening. Revisions are potentially avoidable with better management of patient-related risk factors that affect the osseointegration of orthopedic implants. In this review, we summarize the published clinical literature on the role of demographics, biologic factors, comorbidities, medications and aseptic loosening risk. We focus on several systemic and local factors that are particularly relevant to implant osseointegration. Examples include physiological and molecular processes that are linked to hyperglycemia, oxidative stress, metabolic syndrome and dyslipidemia. We discuss how orthopedic implant osseointegration can be affected by a number of molecular therapies that are antiresorptive or bone anabolic (i.e. calcium, vitamin D, bisphosphonates, calcitonin, strontium, hormone replacement therapy, selective estrogen-receptor modulators). PMID- 28008375 TI - Knockdown of EWSR1/FLI1 expression alters the transcriptome of Ewing sarcoma cells in vitro. AB - Ewing sarcoma breakpoint region 1 (EWSR1) fusion with Friend leukemia integration 1 transcription factor (FLI1) induced by a translocation of chromosome 11 with 22 contributes to Ewing sarcoma development. To date, the precise molecular mechanisms about EWSR1/FLI1 involving in Ewing sarcoma development remains to be defined. This study explored the potential critical gene targets of EWSR1/FLI1 knockdown in Ewing sarcoma cells on the gene expression profile based on online dataset, performed Limma algorithm for differentially expressed genes identification, constructed the transcriptional factor (TF)-gene regulatory network based on integrate transcriptional regulatory element database (TRED). The data showed up- and down-regulation of differentially expressed genes over time and peaked at 72 h after EWSR1/FLI1 knockdown in Ewing sarcoma cells. SMAD3 were up-regulated and FLI1, MYB, E2F1, ETS2, WT1 were down-regulated with more than half of their targets were down-regulated after EWSR1/FLI1 knockdown. The Gene Ontology (GO) and pathway annotation of these differentially expressed genes showed a consistent trend in each group of samples. Totally, there were 355 differentially expressed genes occurring in all five comparison groups of different time points, in which 39 genes constructed a dysregulated TF-gene network in Ewing sarcoma cell line A673 after EWSR1/FLI1 knockdown. These data demonstrated that knockdown of EWSR1/FLI1 expression led to transcriptome changes in Ewing sarcoma cells and that Ewing sarcoma development and progression caused by altered EWSR1/FLI1 expression may be associated with more complex transcriptome changes. PMID- 28008376 TI - Assessment of bone health in breast cancer patients starting adjuvant aromatase inhibitors: A quality improvement clinical audit. AB - INTRODUCTION: Adjuvant Aromatase Inhibitors (AIs) predispose breast cancer patients to accelerated bone loss. Guidelines recommend initial screening and follow up of bone mineral density with dual energy X-ray absorptiometry (DEXA) scan. In this audit we assessed the rate of adherence to these guidelines and introduced awareness measures to improve it. METHODS: All post-menopausal women who started upfront adjuvant AIs (letrozole in all patients) between January 2007 and December 2013 were retrospectively identified. The standard to be audited was "These patients should have a baseline DEXA scan requested within the first 3 months of starting adjuvant AIs therapy". A 90% or more compliance was accepted as satisfactory. Corrective measures in the form of educational and awareness sessions followed by re-auditing of the practice over the subsequent 12 months were planned in case of lower compliance rate. RESULTS: Three hundred and sixty seven eligible patients were identified. Baseline DEXA scan was performed in 188 (51.2%) patients. As planned, this result triggered the conduction of 4 consecutive educational sessions over a period of 2 weeks. Re-auditing the practice in the pre-defined subsequent subjects showed compliance in 47/52 (90.4%) patients. CONCLUSION: This study of a sizable cohort confirms previous observations that adherence to skeletal health guidelines in this patient population is less than adequate. Adherence is improved dramatically by raising the awareness of relevant physicians. PMID- 28008377 TI - Surgical management of proximal fibular tumors: A report of 12 cases. AB - BACKGROUND/AIM: Aggressive benign or malignant tumors in the proximal fibula may require en bloc resection of the fibular head, including the peroneal nerve and lateral collateral ligament. Here, we report the treatment outcomes of 12 patients with aggressive benign or malignant proximal fibula tumors. PATIENTS AND METHODS: Four patients with osteosarcoma and 1 patient with Ewing's sarcoma were treated with intentional marginal resections after effective chemotherapy, and 4 patients underwent fibular head resections without ligamentous reconstruction. Clinical outcomes were investigated. RESULTS: The mean Musculoskeletal Tumor Society scores were 96% and 65% in patients without peroneal nerve resection and those with nerve resection, respectively. No patients complained of knee instability. CONCLUSION: Functional outcomes after resection of the fibular head were primarily influenced by peroneal nerve preservation. If patients are good responders to preoperative chemotherapy, malignant tumors may be treated with marginal excision, resulting in peroneal nerve preservation and good function. PMID- 28008378 TI - Association of circulating miR-125b and survival in patients with osteosarcoma-A single center experience. AB - BACKGROUND: It is known that miRNAs play various roles in malignant tumors. This study is designed to investigate whether miR-125b levels can be used to predict the clinical response of patients with osteosarcoma (OS) to cisplatin-based chemotherapy. METHODS: From January 2010 to July 2015, 82 patients with resectable OS and 56 patients with unresectable OS were enrolled. Blood samples were collected and quantitative real-time PCR was applied to determine miR-125b expression. Clinical data was collected through medical records, and patients were treated according to National Comprehensive Cancer Network guidelines on OS. RESULTS: Our study found that patients with low miR-125b expression had shorter disease-free survival (p<0.001) in the OS group, which was verified by Kaplan Meier analysis and univariate and multivariate Cox analyses (p<0.001). For patients with unresectable OS, low miR-125b expression was found to be associated with advanced tumor stages (p=0.006). No complete remission was observed, and there were 13 patients with partial remission, 21 with stable disease, and 22 with disease progression. Negative correlation was found between miR-125b expression and response to chemotherapy (p<0.001, r=-0.606). Furthermore, ROC analysis indicated that miR-125b at the cut point of 0.61 yielded an area under the ROC curve of 0.793 (p<0.001, 95% CI: 0.664-0.890) in distinguishing chemotherapy-resistant OS from chemotherapy-sensitive OS, with sensitivity and specificity at 76.9% and 79.1%, respectively. Kaplan-Meier analysis and univariate and multivariate Cox analyses showed that patients with low miR-125b expression suffered shorter overall survival (p=0.014, p=0.024, and p=0.049, respectively). CONCLUSION: Down-regulation of circulating miR-125b might have the potential to predict cisplatin-based chemotherapy resistance and poor prognosis in OS. PMID- 28008379 TI - A phase 2 trial exploring the clinical and correlative effects of combining doxycycline with bone-targeted therapy in patients with metastatic breast cancer. AB - BACKGROUND: Bone-targeting agents (BTAs), such as bisphosphonates and denosumab, have demonstrated no discernable effects on tumour response or disease free/overall survival in patients with bone metastases from breast cancer. Doxycycline is both osteotropic and has anti-cancer effects. When combined with zoledronate in animal models, doxycycline showed significantly increased inhibition of tumour burden and increased bone formation. We evaluated the effects of adding doxycycline to ongoing anti-cancer therapy in patients with metastatic breast cancer. METHODS: Breast cancer patients with bone metastases and >=3 months of BTA use, entered this single-arm study. Patients received doxycycline 100 mg orally, twice a day for 12 weeks. The co-primary endpoints were; effect on validated pain scores (FACT-Bone pain and Brief Pain Inventory) and bone resorption markers (serum C-telopeptide, [sCTx]). All endpoints (pain scores, sCTx, bone-specific alkaline phosphatase, skeletal-related events, toxicity) were evaluated at baseline, 4, 8 and 12 weeks. Bone marrow was sampled at baseline and week 12 for exploratory biomarker analysis. RESULTS: Out of 37 enroled patients, 27 (73%) completed 12 weeks of therapy. No significant changes were seen in pain scores or bone turnover markers. Failure to complete treatment: drug toxicity (70%) and disease progression (30%). Sixteen (43%) patients had GI adverse events. CONCLUSIONS: Doxycycline 100 mg twice daily for 12 weeks had no significant effects on either bone pain or bone turnover markers. Its toxicity profile in this patient population would make further evaluation challenging. PMID- 28008380 TI - Strategies for obtaining bone biopsy specimens from breast cancer patients - Past experience and future directions. AB - BACKGROUND: Cancer and its treatment can have multiple effects on the bone. Despite the widespread use of in vivo and in vitro models, it is still necessary to understand these effects in humans. Obtaining human bone biopsies is technically challenging and in this article we review the experiences from the Ottawa Bone Oncology Program. METHODS: A series of bone biopsy studies in breast cancer patients with and without bone metastasis have been performed. We reviewed the results of these studies and present them in a descriptive manner. We discuss lessons learned from each project and how they have affected future directions for research. RESULTS: Since 2009, 5 studies have been performed accruing 97 breast cancer patients. Study endpoints have ranged from comparing the yield of malignant cells from CT-guided versus standard iliac crest biopsies, to studies assessing the feasibility of micro-CT analysis on Jedhadi trephines to evaluate bisphosphonate effects on bone micro-architecture. More recently, we have assessed the feasibility of performing repeat bone biopsies in the same patient as well as evaluating the practicality of obtaining bone tissue at the time of orthopaedic surgery. CONCLUSION: Human bone tissue is an important biological resource. Our experience suggests that obtaining bone biopsies is feasible and can yield adequate amount of tumour cells for many studies. However, these remain technically challenging specimens to obtain and given the rapid advances in cancer therapeutics and the use of potent adjuvant bone-targeted agents, more centres need to be involved in these types of studies. PMID- 28008381 TI - Pathologic fracture and healthcare resource utilisation: A retrospective study in eight European countries. AB - BACKGROUND: Skeletal-related events (SREs; pathologic fracture [PF], spinal cord compression and radiation or surgery to bone) are common complications of bone metastases or bone lesions and can impose a considerable burden on patients and healthcare systems. In this study, the healthcare resource utilisation (HRU) associated with PFs in patients with bone metastases or lesions secondary to solid tumours or multiple myeloma was estimated in eight European countries. METHODS: Eligible patients were identified in Austria, the Czech Republic, Finland, Greece, Poland, Portugal, Sweden and Switzerland. HRU data were extracted from hospital charts from 3.5 months before the index PF (defined as a PF preceded by a 6.5-month period without a SRE) until 3 months after the last SRE during the study period. Changes from baseline in the number and duration of inpatient stays, number of outpatient visits and number of procedures provided were recorded. RESULTS: Overall, 118 patients with PFs of long bones (those longer than they are wide, e.g. the femur) and 241 patients with PFs of other bones were included. Overall, HRU was greater in patients with long bone PFs than in those with PFs of other bones. A higher proportion of patients with long bone PFs had multiple SREs (79.7%), and more of their SREs were considered to be linked (73.4%) compared with patients with PFs of other bones (51.0% and 47.2%, respectively). CONCLUSION: The increased number and duration of inpatient stays for PFs of long bones compared with those for PFs of other bones may be due in part to the requirement for complicated and lengthy rehabilitation in patients with long bone PFs. Implementing strategies to delay or reduce the number of PFs experienced by patients with bone metastases or lesions may therefore reduce the associated HRU and patient burden. PMID- 28008382 TI - Osteochondromyxoma: Review of a rare carney complex criterion. AB - Osteochondromyxoma is an extremely rare bone tumor associated with 1% of Carney complex patients and constitutes one of its 11 diagnostic criteria. This narrative review of osteochondromyxoma is based on a search of all references to the topic in PubMed, Web Of Science, SCOPUS, ScienceDirect, and JSTOR databases. Special attention was focused on case reports, leading to a review encompassing the case reports to date, as well as related animal model studies. This review covers the current understanding of osteochondromyxoma, highlighting its variability while providing consensus on the most common clinical presentation, pathological findings, and genetic features of this rare bone tumor. PMID- 28008383 TI - Better to be alone than in bad company: The antagonistic effect of cisplatin and crizotinib combination therapy in non-small cell lung cancer. AB - AIM: To investigate the potential benefit of combining the cMET inhibitor crizotinib and cisplatin we performed in vitro combination studies. METHODS: We tested three different treatment schemes in four non-small cell lung cancer (NSCLC) cell lines with a different cMET/epidermal growth factor receptor genetic background by means of the sulforhodamine B assay and performed analysis with Calcusyn. RESULTS: All treatment schemes showed an antagonistic effect in all cell lines, independent of the cMET status. Despite their different genetic backgrounds, all cell lines (EBC-1, HCC827, H1975 and LUDLU-1) showed antagonistic combination indexes ranging from 1.3-2.7. These results were independent of the treatment schedule. CONCLUSION: These results discourage further efforts to combine cMET inhibition with cisplatin chemotherapy in NSCLC. PMID- 28008384 TI - Circulating cytokeratin-positive cells and tumor budding in colorectal cancer. AB - AIM: To investigate whether circulating cytokeratin-positive (CK+) cells in the mesenteric blood of resected colorectal specimens are prognostic and correlate with tumor budding. METHODS: Fifty-six colorectal specimens were collected between 9/2007 and 7/2008. Blood from the mesenteric vein was drawn immediately after receiving the fresh and unfixed specimens in the pathology department. After separation of the mononuclear cells by Ficoll-Hypaque density-gradient centrifugation, cytological smears were immunocytochemically stained for CK18. Tumor budding was evaluated on slides stained for pan-cytokeratin. The identification of >= 30 buds/1.3 mm2 was defined as high grade budding. RESULTS: CK+ cells and clusters were identified in 29 (48%) and 14 (25%) of the samples, respectively. Two cells were identified in one of three non-malignant cases. Clusters were found exclusively in malignant cases. The occurrence of CK+ cells or clusters was not associated with any of the evaluated clinicopathological factors, including surgical technique and tumor budding. Moreover, the occurrence of CK+ cells or clusters had no influence on the cancer-specific survival [75 mo (CI: 61; 88) vs 83 mo (CI: 72; 95) and 80 mo (CI: 63; 98) vs 79 mo (CI: 69; 89), respectively]. CONCLUSION: CK+ cells and showed neither prognostic significance nor an association with tumor budding. It is very likely that CK18-staining is not specific enough to identify the relevant cells. PMID- 28008385 TI - Impact of Smoking on Food Expenditure among Tanzanian Households. AB - This study considers the effect of household tobacco expenditure on food consumption in Tanzania. The study hypothesizes that the majority of Tanzanians belong to a low-income group and that any expenditure on cigarettes or tobacco is at the expense of basic necessities, especially food. To verify this hypothesis, we first compared various expenditure patterns as well as household size of nonsmokers and smokers. The results showed that the majority of nonsmokers and smokers belong to a low-income group and that the mean total per capita expenditure (proxy for income) of nonsmokers is slightly higher than that of smokers. Similar results were observed for per capita food expenditure. On the other hand, the mean household size of nonsmokers was smaller than that of smokers suggesting that smokers should have spent more on food. The per capita tobacco expenditure among smokers was 7.73 percent of per capita food expenditure. We estimated a multiple linear regression on the determinants of per capita food expenditure. For each cigarette consumed, per capita food expenditure would decrease by 67.7 Tanzanian shillings (0.08 US dollars). People who smoke and belong to a high-income group (interaction effect) tend to continue to spend less on food. People who are less educated, who are rural dwellers, and people with a large household size, that is, poor people, tend to spend less on food. Given that the majority of all respondents are classified as low-income (more than 54 percent of total expenditure spent on food), one might conclude that expenditure on tobacco in Tanzania is at the expense of basic needs, especially food. PMID- 28008386 TI - The Role of Fibronectin in the Adherence and Inflammatory Response Induced by Enteroaggregative Escherichia coli on Epithelial Cells. AB - Enteroaggregative Escherichia coli (EAEC) infections are still one of the most important etiologic pathogens of diarrhea in children worldwide. EAEC pathogenesis comprises three stages: adherence and colonization, production of toxins, and diarrhea followed by inflammation. Previous studies have demonstrated that EAEC strains have the ability to bind to fibronectin (FN); however, the role this extracellular matrix protein plays in the inflammatory response induced by EAEC remains unknown. In this study, we postulated that FN-mediated adherence of EAEC strains to epithelial cells increases the expression of pro-inflammatory genes. To verify this hypothesis, we infected HEp-2 and HT-29 cells, in both the presence and absence of FN, with EAEC reference strain 042. We quantified IL-8 secretion and the relative expression of a set of genes regulated by the NF kappaB pathway. Although FN increased EAEC adherence, no changes in IL-8 protein secretion or IL8 gene expression were observed. Similar observations were found in HEp-2 cells transfected with FN-siRNA and infected with EAEC. To evaluate the involvement of AAF/II fimbriae, we infected HEp-2 and HT-29 cells, in both the presence and absence of FN, with an EAEC 042aafA mutant strain transformed with a plasmid harboring the native aafA gene with a site-directed mutation in Lys72 residue (K72A and K72R strains). No changes in IL-8 secretion were observed. Finally, SEM immunogold assay of cells incubated with FN and infected with EAEC revealed that AAF fimbriae can bind to cells either directly or mediated by FN. Our data suggests that FN participates in AAF/II fimbriae-mediated adherence of EAEC to epithelial cells, but not in the inflammatory response of cells infected by this pathogen. PMID- 28008387 TI - Role of PH Monitoring in Laryngopharyngeal Reflux Patients with Voice Disorders. AB - INTRODUCTION: Laryngopharyngeal reflux (LPR) is considered an important cause of voice disorder. We aimed to determine the frequency of LPR in patients with voice disorder and the association between Koufman Reflux Symptom Index (RSI), Reflux Finding Score (RFS), gastroesophageal reflux disease (GERD), and proximal acid reflux in these patients. MATERIALS AND METHODS: We performed a prospective study in patients aged more than 18 years presenting at the ear, nose, and throat (ENT) clinic with a change in voice lasting more than 3 weeks. All patients underwent nasopharyngolaryngoscopy and a dual-probe esophageal pH study. LPR was diagnosed by a Koufman RSI of >13 and/or RFS of >7. GERD was diagnosed according to a DeMeester Johnson score of >14.7. Proximal acid reflux was diagnosed if acid exposure time was >0.02% in a proximal pH probe. RESULTS: The study included 30 patients with a voice disorder. The mean age of participants was 38.5 years and 40% of patients were female. Using either of the two criteria, LPR was present in 46.7% of patients, half of whom had GERD. Among the remaining 53.3% patients with a voice disorder and no evidence of LPR, GERD was present in 25%. There was no significant association between the presence of LPR based on RSI (P=1) and GERD or RFS and GERD (P=0.06). Proximal acid reflux was present in only 10% patients with a voice disorder, and there was no significant association of this test with RFS (P=1) or RSI (P=1). CONCLUSIONS: Approximately half of the patients with a voice disorder have LPR, and only a subset of these patients have evidence of GERD. Fiberoptic laryngoscopic findings (RFS) complementing RSI appears to be important in diagnosing possible reflux etiology in voice disorders and can be an indicator for instituting anti-reflux therapy. However, there is no significant association between RSI, RFS, and GERD suggesting that these tests evaluate different features of the disease. Proximal acid reflux is uncommon in patients with voice disorder based on current measurement criteria. Acid exposure time as measured in the proximal probe of a 24-hour dual pH probe may need to be re evaluated as one of the diagnostic criteria for LPR. PMID- 28008388 TI - Pulmonary Function after Adenotonsillectomy. AB - INTRODUCTION: Adenotonsillar hypertrophy is a common disorder among children which, without proper treatment, may lead to considerable problems. Although the consequences of this disorder have been studied in other articles, we decided to evaluate the changes in pulmonary function tests in these children after adenotonsillectomy, and the correlation between clinical and spirometric parameters. MATERIALS AND METHODS: We conducted a before- and after- clinical trial. Forty children (17 females and 23 males) with a diagnosis of upper airway obstruction due to adenotonsillar hypertrophy were enrolled in this study. Mean age of the participants was 6.9+/-1.9 years. Eight spirometric parameters were selected for evaluation pre-operatively and 40 days postoperatively. Besides, symptom scores were defined for each patient to assess their disease severity, pre- and postoperatively. Data were analyzed statistically. RESULTS: Forced vital capacity (FVC) increased from 1.28+/-0.26% pre-operatively to 1.33+/ 0.24%postoperatively (P=0.05). Peak expiratory flow increased from 2.74+/-0.65% pre-operatively to 2.84+/-0.51% postoperatively (P=0.02) and mid expiratory forced expiratory flow (FEF25-75) was 1.81+/-0.48% pre-operatively, increasing to 1.91+/-0.50% postoperatively (P=0.02). Maximal expiratory flow at 25% of FVC (MEF25) increased from 1.09+/-0.36% pre-operatively to 1.21+/-0.34% postoperatively (P=0.02). There was no correlation among the other spirometric parameters (FEV1, FEV1/FVC, MEF50 and MEF75) pre- and post-operatively (P>0.05). Despite some improvements in pulmonary function indices, there was no correlation between changes in spirometric parameters and severity of the snoring (P>0.05). CONCLUSION: Although our findings reveal that adenotonsillectomy had a positive effect on pulmonary function tests, we found no significant correlation between alterations in spirometric parameters and severity of snoring. However, performing a spirometric examination in children with adenotonsillar hypertrophy may be beneficial for assessing the pulmonary status of the affected patient. PMID- 28008390 TI - Fordyce Happiness Program and Happiness in Mothers of Children with a Cleft Lip and Palate. AB - INTRODUCTION: Facial deformities and aesthetic and functional anomalies in children may be a cause of real distress in families. Problems faced by parents in coping with a child's anomaly can be upsetting and lead parents to exhibit over-severe behavior. The present study was conducted in order to study the effect of happiness program on the happiness of the mothers of children with a cleft lip and palate. MATERIALS AND METHODS: In this semi-experimental study, 64 mothers of children with a cleft lip and palate enrolled by convenience random sampling were assigned to an intervention or control group based on a simple random sampling. Then, a program of happiness training was implemented consisting of 10 sessions of 2 hours each. A demographic questionnaire and the Oxford Happiness Questionnaire were completed prior to and 2 months after the last session of intervention. The data were analyzed using descriptive and analytical statistics, consisting of a paired t-test, independent t-test and Chi-square test using SPSS version 20. RESULTS: The independent t-test indicated a significant difference in mean happiness score after training between the intervention and control groups (P<0.05). Moreover, the paired t-test indicated a significant difference in mean happiness score between before and after training in the intervention group, although the difference was not statistically significant for the control group (P>0.05). CONCLUSION: In light of the efficacy of happiness training on the promotion of happiness in the mothers of children with a cleft lip and palate, this model is recommended as a healthcare intervention to decrease stress in mothers following the birth of an infant with a cleft lip and palate. PMID- 28008389 TI - Immunohistochemical Expression of CD56 and ALDH1 in Common Salivary Gland Tumors. AB - INTRODUCTION: Natural killer (NK) cells, of which CD56 is a specific marker, play an important role in host defense against tumors. Cancer stem cells, of which aldehyde dehydrogenase isoform 1 (ALDH1) is an immunohistochemical marker, are a group of tumorigenic cells which are involved in migration and tumor recurrences. We aimed to evaluate the expression of ALDH1 and CD56 in common salivary gland tumors, as well as their relationship with each other and with a number of clinicopathologic factors. MATERIALS AND METHODS: Forty-five paraffin blocks of salivary gland tumors (pleomorphic adenoma, mucoepidermoid carcinoma and adenoid cystic carcinoma, 15 samples each) were selected. Malignant tumors were classified into two groups: low-grade (including mucoepidermoid carcinoma grade I) and high-grade (including mucoepidermoid carcinoma grade III and adenoid cystic carcinoma). Immunohistochemical staining for ALDH1 and CD56 markers was performed. Data were analyzed using SPSS (20) and the Chi-square test. RESULTS: CD56 expression was significantly higher in benign and high-grade malignant tumors (P=0.01). ALDH1 overexpressed in all three salivary tumors, but not to statistically significant degree (P=0.54). There was no statistically significant correlation between ALDH1 and CD56 expression with demographic factors (age, gender, or location of tumor; P>0.05). CONCLUSION: It appears that the number of NK cells and their function change in different types of salivary gland tumors (benign/malignant) and stroma. NK cells are important components of the anti tumor system; therefore immune dysfunction is associated with tumor progression in tumors of the salivary gland. ALDH1 overexpression suggests its role in tumorogenesis, but ALDH1 is not involved in the morphogenesis of salivary gland tumors. PMID- 28008391 TI - Evaluation of the Correlation between CD44, Tumor Prognosis and the 5-Year Survival Rate in Patients with Oral Tongue SCC. AB - INTRODUCTION: 90% of the tumors in the head and neck are squamous-cell carcinomas (HNSCC), which have overall 5- year survival rate between 50% -60%. CD44 has been shown to be associated with the prognosis. MATERIALS AND METHODS: Biopsy specimens of 51 patients with oral tongue SCC were evaluated by Immunohistochemistry (IHC) for the CD44 antibody. RESULTS: There was no significant correlation between CD44 and survival (P=0.77), age (P=0.4), CD44 and lymph node metastasis (P=0.87), sex (P=0.947), smoking (P=0.287) and tumor size (P=0.813). However, there was significant correlation between smoking and survival. CONCLUSION: There are widespread discrepancies among the findings in the literature regarding the prognosis of CD44 expression in OCSCC. Our study shows that the expression of CD44 is not a marker of aggressive behavior in oral tongue SCC. Consequently, CD44 cannot be considered as handy tool to establish the tumor behavior, prognosis and 5- year survival rate of these tumors. PMID- 28008393 TI - Status of Neutrophils, Lymphocytes and Platelets in Patients with Recurrent Aphthous Stomatitis: A Retrospective Study. AB - INTRODUCTION: The aim of this study was to evaluate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV) in patients with recurrent aphthous stomatitis (RAS). MATERIALS AND METHODS: Eighty patients who were diagnosed with RAS between January 2014 and January 2016 were included in this study. Eighty age- and gender-matched healthy subjects were also enrolled as a control group. Neutrophil, lymphocyte, and platelet counts were compared between groups, in addition to NLR, PLR, and MPV values. RESULTS: There was no significant difference in terms of lymphocyte count, platelet count, PLR, or MPV values between the two groups (P>0.05). However, white blood count, neutrophil count, and NLR were significantly higher in patients with RAS compared with the control group (P<0.05). CONCLUSION: The present study revealed an increased NLR among RAS patients compared with healthy controls. This suggests that development of RAS involves an inflammatory process. We believe that NLR could be used as a cheap and simple marker of inflammation. PMID- 28008392 TI - Assessing the Effect of Simultaneous Exposure to Noise and Cigarette Smoke on Workers' Blood Pressure. AB - INTRODUCTION: Noise, as the most common pollutant in the industrial environment, can lead to hearing loss and negatively affect other organs such as the cardiovascular system. Cigarette smoking is a popular habit among some workers, and can also have a negative effect on the cardiovascular system. This study was aimed to investigate the effect of simultaneous exposure to noise and cigarette smoke on the blood pressure of workers at a manufacturing factory. MATERIALS AND METHODS: This cross-sectional study enrolled 604 workers at a steel factory. Information relating to workers' demography, employment, and risk factors were recorded. Based on the level of smoking per day, workers exposed to noise fell into one of the four following groups: 1) Non-smokers exposed to noise <85 DB; 2) Smokers exposed to noise <85 DB; 3) Non-smokers exposed to noise >=85 DB; 4) Smokers exposed to noise >=85 DB. A t-test, analysis of variance (ANOVA), and logistic regression were applied for analysis using SPSS v11.5. RESULTS: The prevalence of hypertension, cigarette smoking, and exposure to noise >=85 DB was 11.6%, 15.3%, and 56.4%, respectively, among the workers. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 112.3 and 73.9 mmHg, respectively. A significant difference was observed between systolic and diastolic blood pressures in four groups (P=0.001). Posthoc test showed a significant difference between groups 1 and 3 (P=0.001). Regression analysis indicated no significant difference in workers who were simultaneously exposed to noise and cigarette smoke. CONCLUSION: This study demonstrates that noise is an important factor in terms of hypertension, with no significant differences observed in the prevalence of hypertension between workers who were simultaneously exposed to noise and cigarette smoke. It is suggested that workers' blood pressure should be regularly monitored in noisy environments. PMID- 28008394 TI - Does Opium Dependency Affect the Pattern of Involvement in Laryngeal Cancer? AB - INTRODUCTION: Laryngeal cancer is the second most common cancer involving the respiratory tract, second only to lung cancer. Previous studies have shown opium dependency to be a possible risk factor for laryngeal cancer. Opium consumption is a major problem in some parts of the world. The aim of this study was to investigate the effect of opium consumption on the pattern of involvement in laryngeal cancer. METHODS AND MATERIALS: In this analytical cross-sectional study, 44 patients diagnosed with laryngeal cancer (41 male and three female) were studied. Data were collected using a questionnaire, physical examination, and paraclinical studies. Patients were defined as opium dependent based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria and duration of opium consumption. RESULTS: Patients were categorized into two groups: opium-dependent (32.6%) and non-opium-dependent (67.4%) patients. The average age of the patients was 58.5+/-3.2 years in the opium dependent group and 60.7+/-2.8 years in the non-opium-dependent group (P=non significant). An analysis of the pattern of involvement in each group showed glottis involvement in 56%, subglottis involvement in 8%, supraglottis involvement in 32%, and hypopharyngeal involvement in 4% of the opium-dependent group compared with glottis involvement in 55.9%, subglottis involvement in 11.8%, supraglottis involvement in 32.4%, and hypopharyngeal involvement in none of the non-opium-dependent group (P=non-significant). CONCLUSION: There was a poor correlation between opium dependency and pattern of involvement in laryngeal cancer. Opium dependency did not lead to the development of laryngeal cancer at a younger age, based on our study. PMID- 28008395 TI - Nasopharynx- The Secret Vault for Lost Foreign Bodies of the Upper Aerodigestive Tract. AB - INTRODUCTION: Foreign bodies in the upper aerodigestive tract often get lost following inappropriate attempts at removal. Children may present late with localized infection, posing a challenge to the otolaryngologists in a referral set-up in diagnosing and retrieving such foreign bodies. CASE REPORT: A two-year old boy presented with refractory purulent rhinorrhea and intermittent low-grade fever. The symptoms suggested rhinosinusitis; however, following a high index of suspicion, he was referred for further evaluation, with the possibility of any hidden foreign object in the upper aerodigestive tract. His soft palate appeared bulged, and his mother informed that he had ingested the cap of a plastic bottle about a month back which could not be retrieved despite several attempts by her. X-ray of soft tissue nasopharynx revealed a radiolucent shadow of a round object resulting in palatal bulging. It was eventually removed by combined endoscopic/transoral approach. CONCLUSION: In a child with a lost foreign body, the nasopharynx should be meticulously explored. This is less common for ingested objects compared to inhaled ones. The diagnosis becomes furthermore challenging when it is not radio-opaque. Naive manipulations must be avoided and prompt referral should be made to the otolaryngologists for guided removal and minimizing complications. PMID- 28008396 TI - Esophageal Foreign Body: A Case Report of a Refractory Croup in a 20-Month-Old Boy. AB - INTRODUCTION: Foreign body ingestion is common among children and more common in boys and in children under the age of 3. It can present with a wide variety of symptoms like dysphagia and drooling or symptoms related to the upper aerodigestive tract. CASE REPORT: A 20-month-old male presented with refractory croup and poor feeding since 2 weeks. Bronchoscopy and esophagoscopy was performed due to suspicious history of eating loquat. The core of the fruit was found in the esophagus. CONCLUSION: Physicians should be aware of the variability of esophageal foreign body presentations to prevent serious complications due to delay in diagnosis. PMID- 28008397 TI - Play Therapy to Control Pain and Suffering in Pediatric Oncology. PMID- 28008398 TI - Dynamic Complexes in the Chaperonin-Mediated Protein Folding Cycle. AB - The GroEL-GroES chaperonin system is probably one of the most studied chaperone systems at the level of the molecular mechanism. Since the first reports of a bacterial gene involved in phage morphogenesis in 1972, these proteins have stimulated intensive research for over 40 years. During this time, detailed structural and functional studies have yielded constantly evolving concepts of the chaperonin mechanism of action. Despite of almost three decades of research on this oligomeric protein, certain aspects of its function remain controversial. In this review, we highlight one central aspect of its function, namely, the active intermediates of its reaction cycle, and present how research to this day continues to change our understanding of chaperonin-mediated protein folding. PMID- 28008400 TI - Obscure Overt Gastrointestinal Bleeding Secondary to Ventral Hernioplasty Mesh Small Bowel Perforation Visualized With Video Capsule Endoscopy. AB - We report a case of a 79-year-old female presenting with hematemesis and melena 9 years after ventral hernioplasty with mesh. After initial normal endoscopy and colonoscopy, video capsule endoscopy revealed a metallic wire mesh perforating the jejunum. Abdominal computed tomography did not identify a perforation although metallic mesh was visualized close to the small bowel. We present the first ventral hernia mesh perforation diagnosed via video capsule endoscopy. Such a finding emphasizes the importance of a complete diagnostic workup when approaching a patient with obscure overt gastrointestinal bleeding. PMID- 28008399 TI - Urinary Phthalate Metabolites and Biomarkers of Oxidative Stress in a Mexican American Cohort: Variability in Early and Late Pregnancy. AB - People are exposed to phthalates through their wide use as plasticizers and in personal care products. Many phthalates are endocrine disruptors and have been associated with adverse health outcomes. However, knowledge gaps exist in understanding the molecular mechanisms associated with the effects of exposure in early and late pregnancy. In this study, we examined the relationship of eleven urinary phthalate metabolites with isoprostane, an established marker of oxidative stress, among pregnant Mexican-American women from an agricultural cohort. Isoprostane levels were on average 20% higher at 26 weeks than at 13 weeks of pregnancy. Urinary phthalate metabolite concentrations suggested relatively consistent phthalate exposures over pregnancy. The relationship between phthalate metabolite concentrations and isoprostane levels was significant for the sum of di-2-ethylhexyl phthalate and the sum of high molecular weight metabolites with the exception of monobenzyl phthalate, which was not associated with oxidative stress at either time point. In contrast, low molecular weight metabolite concentrations were not associated with isoprostane at 13 weeks, but this relationship became stronger later in pregnancy (p-value = 0.009 for the sum of low molecular weight metabolites). Our findings suggest that prenatal exposure to phthalates may influence oxidative stress, which is consistent with their relationship with obesity and other adverse health outcomes. PMID- 28008401 TI - Rectal Blue Nevus: Distinguishing Features of a Rare Entity. AB - A 26-year-old African American man with a history of depression and tuberculosis presented to the gastroenterology department after several months of rectal pain with bowel movements. Colonoscopy revealed hyperpigmentation in the distal rectum and internal hemorrhoids, which resulted in a diagnosis of blue nevi. This is only the third known description of a blue nevus involving the gastrointestinal mucosa. PMID- 28008402 TI - Dapagliflozin-Induced Acute-on-Chronic Liver Injury. AB - Sodium-glucose cotransporter 2 inhibitors are a new class of oral hypoglycemic agents, and thus safety data are limited. We present a 48-year-old woman with type 2 diabetes mellitus and Child's Class A cirrhosis secondary to nonalcoholic steatohepatitis presenting with jaundice and acute cholestatic liver injury. Other than starting dapagliflozin, she reported no medication changes or supplement use. Before treatment, her total bilirubin was 1.2 mg/dL. On admission, her liver values were elevated and liver biopsy was consistent with drug-induced liver injury. This report raises awareness about the potential hepatotoxic effects of dapagliflozin, particularly in patients with chronic liver disease. PMID- 28008403 TI - Endoscopic Ultrasound as a Diagnostic Tool in a Case of Obscure Hemobilia. AB - Hemobilia represents an uncommon cause of gastrointestinal bleeding that can present both diagnostic and therapeutic challenges. The evaluation of hemobilia typically involves cross-sectional imaging and endoscopic retrograde cholangiopancreatography (ERCP). There is limited data regarding the diagnostic utility of endoscopic ultrasound (EUS) in the evaluation of hemobilia. We present a case of a hepatic artery pseudoaneurysm as the etiology of hemobilia that was detected via EUS only. We conclude that EUS can serve as an important diagnostic tool in the evaluation of obscure hemobilia, especially in cases where imaging, ERCP, and percutaneous transhepatic cholangiography have been unsuccessful or inconclusive. PMID- 28008404 TI - Inverted Meckel's Diverticulum with Intussusception and Ulceration Diagnosed after Rectal Double-Balloon Enteroscopy. PMID- 28008405 TI - Renal Vein and Inferior Vena Cava Thrombosis: A Rare Extrasplanchnic Complication of Acute Pancreatitis. AB - Acute pancreatitis is an inflammatory disorder often associated with various complications. Approximately one fourth of patients with acute pancreatitis develop vascular complications, of which venous thrombosis forms a major group. Extrasplanchnic venous thrombosis is less common, and simultaneous renal vein and inferior vena cava thrombosis is reported only twice. We report a case of alcohol related acute pancreatitis complicated by simultaneous renal vein and inferior vena cava thrombosis. PMID- 28008406 TI - Dietary Creatine as a Possible Novel Treatment for Crohn's Ileitis. AB - Creatine, a commonly used dietary supplement, plays an important role in maintaining gut barrier function. Given that dysregulation of the intestinal epithelial barrier is a hallmark of inflammatory bowel disease, it is plausible that creatine supplementation may attenuate disease severity. We present a patient with Crohn's ileitis who responded to creatine supplementation with both symptomatic and endoscopic improvement in disease activity. PMID- 28008407 TI - Severe Hepatopulmonary Syndrome in an Adolescent Patient with Non-Cirrhotic Portal Fibrosis. PMID- 28008408 TI - Sarcoidosis Causing Mid-Esophageal Traction Diverticulum. PMID- 28008409 TI - A Concurrent Case of Menetrier's Disease and Signet Ring Carcinoma. AB - Menetrier's disease, also known as hyperplastic protein-losing gastropathy, is a rare, idiopathic, acquired, premalignant condition associated with gastric carcinoma. Its association with signet ring cell cancer of the stomach has been previously reported only twice. We present the third case of histologically confirmed concurrent Menetrier's disease with signet ring carcinoma of the stomach, interrogated by esophagogastroduodenoscopy and endoscopic ultrasound. PMID- 28008410 TI - Non-Meckel's Small Bowel Diverticular Bleeding: Two Case Reports and a Review of the Literature. AB - Gastrointestinal bleeding from non-Meckel's small bowel diverticulosis is uncommon. Depending on the diverticulum's location, a patient's presentation can suggest either an upper or lower gastrointestinal source. We present two cases of bleeding from non-Meckel's small bowel diverticula. One patient was managed successfully with endoscopic therapy, and the second required surgical resection after two failed attempts at achieving hemostasis endoscopically. PMID- 28008411 TI - Purulent Proctitis Caused by Prevotella bivia in a Homosexual Male. AB - A 32-year-old homosexual male presented with suprapubic pain. Computed tomography showed rectal wall thickening. Flexible sigmoidoscopy showed small pockets of pus that were opened with mucosal biopsies, and additional pus was diffusely expressed from the rectal wall by applying blunt pressure with the biopsy forceps. Cultures from the pus grew Prevotella bivia. Symptoms resolved after treatment with doxycycline and metronidazole. Proctitis due to P. bivia was not previously reported. PMID- 28008412 TI - Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer. AB - Germline mutations in the CDH1 gene that produces E-cadherin have been implicated in the development of early-onset diffuse gastric cancer, termed hereditary diffuse gastric cancer. The mean age of gastric cancer diagnosis in affected individuals is 37 years. By age 80, CDH1 mutation carriers who fulfill the clinical criteria for hereditary diffuse gastric cancer have an estimated lifetime risk of gastric cancer development of 67% for men and 83% for women. Data suggest that endoscopic surveillance for mutation carriers is largely ineffective. Prophylactic total gastrectomy between the ages of 18 and 40 years is recommended in carriers of germline-truncating E-cadherin mutations. PMID- 28008413 TI - Gastrointestinal Symptoms from Left-Ventricular Assist Device External Compression of the Gastric Lumen. AB - A 74-year-old man with a left-ventricular assist device (LVAD) as destination therapy for end-stage ischemic cardiomyopathy presented with acute upper gastrointestinal bleeding. Other symptoms included chronic early satiety, intermittent nausea, and non-specific abdominal discomfort since LVAD implantation 3 years ago. An actively bleeding duodenal arteriovenous malformation was successfully treated with endoscopic coagulation. There was also evidence of moderate external compression of the anterior gastric wall from the LVAD pump with luminal narrowing in the antrum. While bleeding may be the most commonly encountered gastrointestinal manifestation in LVAD patients, other potential complications, including luminal compression by the device, should be recognized. PMID- 28008414 TI - Endoscopic Tattooing: From Blue to Black. PMID- 28008415 TI - Quantitative histological image analyses of reticulin fibers in a myelofibrotic mouse. AB - Bone marrow (BM) reticulin fibrosis (RF), revealed by silver staining of tissue sections, is associated with myeloproliferative neoplasms, while tools for quantitative assessment of reticulin deposition throughout a femur BM are still in need. Here, we present such a method, allowing via analysis of hundreds of composite images to identify a patchy nature of RF throughout the BM during disease progression in a mouse model of myelofibrosis. To this end, initial conversion of silver stained BM color images into binary images identified two limitations: variable color, owing to polychromatic staining of reticulin fibers, and variable background in different sections of the same batch, limiting application of the color deconvolution method, and use of constant threshold, respectively. By blind coding image identities, to allow for threshold input (still within a narrow range), and using shape filtering to further eliminate background we were able to quantitate RF in myelofibrotic Gata-1low (experimental) and wild type (control) mice as a function of animal age. Color images spanning the whole femur BM were batch-analyzed using ImageJ software, aided by our two newly added macros. The results show heterogeneous RF density in different areas of the marrow of Gata-1low mice, with degrees of heterogeneity reduced upon aging. This method can be applied uniformly across laboratories in studies assessing RF remodeling induced by aging or other conditions in animal models. PMID- 28008416 TI - Comorbidities Among Persons With Incident Psychiatric Condition. AB - OBJECTIVE: I sought to determine how medical comorbidities co-exist with incident psychiatric condition. METHOD: I used data from all 11 available waves (1992 2012) of the Health and Retirement Study (HRS). I identified 4,358 index participants with self-reported incident psychiatric condition. I collected comorbidity data from participants preceding, including, and succeeding that incident wave. Comorbidities assessed included high blood pressure (HBP), diabetes mellitus, cancer, lung disease, heart disease, stroke, and arthritis. Modified Poisson regression combined with log-linked binomial regression was used to estimate relative risks (RRs) of reporting a comorbidity preceding and following the incident wave. Multiple comparison testing dictated significance of RRs with p < .007. RESULTS: For the waves preceding the index wave, the RRs of reporting all comorbidities except HBP and cancer were significantly (p < .007) increased. For the waves following incident psychiatric condition, the risks of reporting heart disease, diabetes, and lung disease were significantly (p < .007) increased. These results were adjusted for participant age, race, gender, other comorbidities listed, and the wave in which a comorbidity was reported. CONCLUSION: The bidirectional association between a psychiatric condition and medical illnesses could only be statistically confirmed for lung disease, diabetes, and heart disease. It is of interest to determine how reporting a psychiatric condition may affect the sequelae of health care use and treatment outcomes for patients with either of these comorbidities or a combination of them. PMID- 28008417 TI - Time-domain diffuse correlation spectroscopy. AB - Physiological monitoring of oxygen delivery to the brain has great significance for improving the management of patients at risk for brain injury. Diffuse correlation spectroscopy (DCS) is a rapidly growing optical technology able to non-invasively assess the blood flow index (BFi) at the bedside. The current limitations of DCS are the contamination introduced by extracerebral tissue and the need to know the tissue's optical properties to correctly quantify the BFi. To overcome these limitations, we have developed a new technology for time resolved diffuse correlation spectroscopy. By operating DCS in the time domain (TD-DCS), we are able to simultaneously acquire the temporal point-spread function to quantify tissue optical properties and the autocorrelation function to quantify the BFi. More importantly, by applying time-gated strategies to the DCS autocorrelation functions, we are able to differentiate between short and long photon paths through the tissue and determine the BFi for different depths. Here, we present the novel device and we report the first experiments in tissue like phantoms and in rodents. The TD-DCS method opens many possibilities for improved non-invasive monitoring of oxygen delivery in humans. PMID- 28008418 TI - Regulation of Group I Metabotropic Glutamate Receptors by MAPK/ERK in Neurons. AB - Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are regulated by protein kinases. A recent focus is mitogen-activated protein kinases (MAPK). A prototypic subclass of MAPKs, extracellular signal-regulated kinases (ERK), is densely expressed in adult brain postmitotic neurons. This kinase resides in not only the cytoplasm around the nucleus, also the neuronal peripheral structures such as synapses. Recombinant ERK2 binds to C terminal tails of mGluR1a in vitro and native ERK1/2 forms complexes with mGluR1/5 in neurons in vivo. Association of ERK with mGluR1/5 enables the kinase to phosphorylate mGluR1/5 at a cluster of serine sites in the distal C terminus, including a serine residue within the Homer binding site. The ERK-mediated phosphorylation of mGluR1/5 promotes surface expression of mGluR1a in cerebellar neurons. ERK also regulates mGluR1/5 signaling and functions. Among different functional outputs surveyed, ERK exerts an output-specific role in either potentiating or inhibiting their activities. In sum, synaptic group I mGluRs are sufficient substrates of MAPK/ERK. Phosphorylation of mGluR1/5 by ERK has a significant impact on subcellular expression and function of phospho-modified receptors. PMID- 28008419 TI - Trends in Susceptibility to Aggressive Periodontal Disease. AB - Aggregatibacter actinomycetemcomitans is a gram-negative microbe involved in periodontitis. Strains with varying degrees of virulence have been identified, in healthy and periodontally compromised individuals alike. Hosts mount differential immune responses to its various serotypes and virulence factors. Studies have explored host immune response in terms of antibody titers, leukocyte responses, and specific inflammatory mediators, questioning the ways in which the infectious microorganism survives. This mini-review will identify the key themes in immune response patterns of individuals both affected by and free from aggressive periodontal disease, thereby using it to understand various forms of periodontitis. PMID- 28008420 TI - Challenges influencing next generation technologies for precision medicine. PMID- 28008421 TI - A new Plasmodium vivax reference sequence with improved assembly of the subtelomeres reveals an abundance of pir genes. AB - Plasmodium vivax is now the predominant cause of malaria in the Asia-Pacific, South America and Horn of Africa. Laboratory studies of this species are constrained by the inability to maintain the parasite in continuous ex vivo culture, but genomic approaches provide an alternative and complementary avenue to investigate the parasite's biology and epidemiology. To date, molecular studies of P. vivax have relied on the Salvador-I reference genome sequence, derived from a monkey-adapted strain from South America. However, the Salvador-I reference remains highly fragmented with over 2500 unassembled scaffolds. Using high-depth Illumina sequence data, we assembled and annotated a new reference sequence, PvP01, sourced directly from a patient from Papua Indonesia. Draft assemblies of isolates from China (PvC01) and Thailand (PvT01) were also prepared for comparative purposes. The quality of the PvP01 assembly is improved greatly over Salvador-I, with fragmentation reduced to 226 scaffolds. Detailed manual curation has ensured highly comprehensive annotation, with functions attributed to 58% core genes in PvP01 versus 38% in Salvador-I. The assemblies of PvP01, PvC01 and PvT01 are larger than that of Salvador-I (28-30 versus 27 Mb), owing to improved assembly of the subtelomeres. An extensive repertoire of over 1200 Plasmodium interspersed repeat (pir) genes were identified in PvP01 compared to 346 in Salvador-I, suggesting a vital role in parasite survival or development. The manually curated PvP01 reference and PvC01 and PvT01 draft assemblies are important new resources to study vivax malaria. PvP01 is maintained at GeneDB and ongoing curation will ensure continual improvements in assembly and annotation quality. PMID- 28008422 TI - Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann Pick Type C disease cellular pathway. AB - BACKGROUND: Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. METHODS: The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. RESULTS: Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria from infected host cells. CONCLUSION : These findings provide a novel mechanistic explanation for mycobacterial intracellular persistence, and suggest that targeting interactions between the mycobacteria and host cell pathways may provide a novel avenue for development of anti-TB therapies. PMID- 28008423 TI - FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy. AB - OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM. PMID- 28008424 TI - Correlation of CA-125 serum level and clinico-pathological characteristic of patients with endometriosis. AB - BACKGROUND: Cancer antigen 125 (CA-125) is a glycoprotein biomarker that is used in women with pelvic masses such as endometriosis and maybe is useful in practice of patients suspicious to endometriosis. OBJECTIVE: The aim of this study was to evaluate the association between preoperative serum CA-125 levels and clinic pathological characteristic in women with endometriosis, and find out the best serum CA-125 levels cut-off in pre and post menopause women. MATERIALS AND METHODS: Serum CA-125 levels in 87 women aged 21-54 years suspected to endometriosis with pelvic pain, dysmenorrhea, or dyspareunia were measured preoperatively. Also the association between clinic pathological characteristic and serum CA-125 level were analyzed. RESULTS: The mean age of women was 32.22+/ 6.91. The mean serum CA-125 level was 49.93+/-4.30 U/mL. There was a significant correlation between the endometriosis stage, lesion size, adhesion score and preoperative CA-125 plasma concentration. However, we did not found significant differences in age, marital status, patient's complaints, and pelvic pain associated to Ca125 serum level. The suggested preoperative serum cut-off levels in premenopausal and postmenopausal patients were 37 U/ml and 35 U/ml, respectively. CONCLUSION: According to the results, preoperative serum CA-125 is an important predictor for patients with endometriosis and it should be taken into consideration when surgical management is suspected, especially if stage of disease, lesion size and adhesion score are undertaken. PMID- 28008425 TI - Quantitative PET/MRI Evaluation and Application in Dementia. AB - A recently introduced integrated scanner combining simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) (PET/MRI) acquisition presents a unique set of opportunities for neuroimaging research and dementia in particular [1]. Among these, the intrinsic co-registration of the images has the potential to reduce errors in multi-modality image registration, which could lead to better quantification of longitudinal volumetric changes in neuroanatomical features that are important for assessing disease progression. PET tracers could provide functional information of brain biochemical processes by radio-labeling specific molecular with high sensitivity and specificity, while MRI could provide superior structural information. Applying MRI anatomical priors to reduce the PET partial volume effect is straightforward, and could further be used to improve spatial resolution of PET images [2]. The hardware challenge in integrating PET and MRI system is the interaction of the PET electronics and MRI system [3]. The special deign of the PET/MRI-PET detector (so called "MR transparent") architecture includes integrated cooling features to assure optimal PET performance, as well as specialized shielding to virtually eliminate magnetic field interference in the PET data processing chain [4]. On the MRI side, larger bore size with cylindrically optimized homogeneity volume has been used for better image quality [4]. Another challenge of the PET/MRI scanner is the derivation of attenuation correction (AC) from MRI for PET images reconstruction [2]. Three commonly-used MR-based AC (MRAC) methods had been proposed: template based MRAC, Dixon's method [5] for fat/water separation which assigns AC values based on the segmentation of fat, water and relative bone tissues, as well as dual-echo or multi-echo ultra-short TE (UTE) MRI sequence [6] for delineation of bone, air and software tissue. PMID- 28008426 TI - Editorial: 3D printing in medicine - promise or reality? PMID- 28008427 TI - Social and legal frame conditions for 3D (and) bioprinting in medicine. AB - The beginnings of three-dimensional (3D) printing and bioprinting can be traced to as early as 1984. From printing inorganic models for the generation of biologic scaffolds, additive manufacturing (AM) developed to the direct printing of organic materials, including specialized tissues, proteins, and cells. In recent years, these technologies have gained significantly in relevance, and there have been several innovations, especially in the field of regenerative medicine. It is becoming increasingly important to consider the economic and social aspects of AM, particularly in education and information of medical human resources, society, and politics, as well as for the establishment of homogenous, globally adapted legal regulations. PMID- 28008428 TI - Materials and scaffolds in medical 3D printing and bioprinting in the context of bone regeneration. AB - The structural and functional repair of lost bone is still one of the biggest challenges in regenerative medicine. In many cases, autologous bone is used for the reconstruction of bone tissue; however, the availability of autologous material is limited, which always means additional stress to the patient. Due to this, more and more frequently various biocompatible materials are being used instead for bone augmentation. In this context, in order to ensure the structural function of the bone, scaffolds are implanted and fixed into the bone defect, depending on the medical indication. Nevertheless, for the surgeon, every individual clinical condition in which standardized scaffolds have to be aligned is challenging, and in many cases the alignment is not possible without limitations. Therefore, in the last decades, 3D printing (3DP) or additive manufacturing (AM) of scaffolds has become one of the most innovative approaches in surgery to individualize and improve the treatment of patients. Numerous biocompatible materials are available for 3DP, and various printing techniques can be applied, depending on the process conditions of these materials. Besides these conventional printing techniques, another promising approach in the context of medical AM is 3D bioprinting, a technique which makes it possible to print human cells embedded in special carrier substances to generate functional tissues. Even the direct printing into bone defects or lesions becomes possible. 3DP is already improving the treatment of patients, and has the potential to revolutionize regenerative medicine in future. PMID- 28008429 TI - Applications of patient-specific 3D printing in medicine. AB - Already three decades ago, the potential of medical 3D printing (3DP) or rapid prototyping for improved patient treatment began to be recognized. Since then, more and more medical indications in different surgical disciplines have been improved by using this new technique. Numerous examples have demonstrated the enormous benefit of 3DP in the medical care of patients by, for example, planning complex surgical interventions preoperatively, reducing implantation steps and anesthesia times, and helping with intraoperative orientation. At the beginning of every individual 3D model, patient-specific data on the basis of computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound data is generated, which is then digitalized and processed using computer-aided design/computer-aided manufacturing (CAD/CAM) software. Finally, the resulting data sets are used to generate 3D-printed models or even implants. There are a variety of different application areas in the various medical fields, eg, drill or positioning templates, or surgical guides in maxillofacial surgery, or patient specific implants in orthopedics. Furthermore, in vascular surgery it is possible to visualize pathologies such as aortic aneurysms so as to improve the planning of surgical treatment. Although rapid prototyping of individual models and implants is already applied very successfully in regenerative medicine, most of the materials used for 3DP are not yet suitable for implantation in the body. Therefore, it will be necessary in future to develop novel therapy approaches and design new materials in order to completely reconstruct natural tissue. PMID- 28008430 TI - Surgical and prosthetic dental rehabilitation through a complete digital workflow - A case report. AB - Several aspects of digital dentistry have recently been improved, including new materials, navigated implant placement, digital impression in combination with virtual articulation, and the computer-aided processes of designing and manufacturing of prosthetic restorations. In this case report, the prosthodontic treatment of a patient through a complete digital workflow is presented. A 39 year-old male patient presented for restoration of missing teeth in the posterior maxilla and mandible. In a single-tooth narrow gap (region 15), a Straumann NNC implant was placed by computer-assisted planning and navigation. For the rest of the missing teeth, ZrO2 fixed dental prostheses (FDPs) were manufactured by a computer-aided design/computer- aided manufacturing (CAD/CAM) system after optical impression with an intraoral scanner (iTero), and data transferal to a virtual articulator (Ceramill Artex). Rehabilitation through a complete digital workflow is a promising technology in terms of accuracy, reduced workload, greater control over the final product, and minimally invasive procedures. These advantages may have a potential positive effect with regard to patient satisfaction compared with conventional methods. PMID- 28008431 TI - 3D-printed orthodontic brackets - proof of concept. AB - : Today, orthodontic treatment with fixed appliances is usually carried out using preprogrammed straight-wire brackets made of metal or ceramics. OBJECTIVE: The goal of this study was to determine the possibility of clinically implementing a fully digital workflow with individually designed and three-dimensionally printed (3D-printed) brackets. MATERIALS AND METHODS: Edgewise brackets were designed using computer-aided design (CAD) software for demonstration purposes. After segmentation of the malocclusion model generated based on intraoral scan data, the brackets were digitally positioned on the teeth and a target occlusion model created. The thus-defined tooth position was used to generate a template for an individualized arch form in the horizontal plane. The base contours of the brackets were modified to match the shape of the tooth surfaces, and a positioning guide (fabricated beforehand) was used to ensure that the brackets were bonded at the correct angle and position. The brackets, positioning guide, and retainer splint, digitally designed on the target occlusion model, were 3D printed using a Digital Light Processing (DLP) 3D printer. The archwires were individually pre-bent using the template. RESULTS: In the treatment sequence, it was shown for the first time that, in principle, it is possible to perform treatment with an individualized 3D-printed brackets system by using the proposed fully digital workflow. Technical aspects of the system, problems encountered in treatment, and possible future developments are discussed in this article. PMID- 28008432 TI - Polycrystalline boron-doped diamond electrodes for electrocatalytic and electrosynthetic applications. AB - Boron-doped diamond (BDD) electrodes are recognized as being superior to other electrode materials due to their outstanding chemical and dimensional stability, their exceptionally low background current, the extremely wide potential window for water electrolysis that they have, and their excellent biocompatibility. However, whereas these properties have been utilized in the rapid development of electroanalytical applications, very few studies have been done in relation to their applications in electrocatalysis or electrosynthesis. In this report, following on from reports of the electrosynthesis of various products through anodic and cathodic reactions using BDD electrodes, the potential use of these electrodes in electrosynthesis is discussed. PMID- 28008433 TI - Novel rare earth fluorescent supramolecular polymeric assemblies constructed by orthogonal pillar[5]arene-based molecular recognition, Eu(iii)-coordination and pi-pi donor-acceptor interactions. AB - Here, a facile strategy is provided to prepare pillar[5]arene-based fluorescent supramolecular polymer assemblies by orthogonal Eu(iii)-coordination and two non interfering noncovalent interactions. PMID- 28008434 TI - Carbodiimide insertion into sulfonimides: one-step route to azepine derivatives via a two-atom saccharin ring expansion. AB - A previously unknown insertion of carbodiimides into sulfonimides enables the first one-step, two-atom expansion of the saccharin 5-membered ring into a 7 membered benzo[1,2,4]thiadiazepine, and a two-atom chain extension of a non cyclic sulfonimide. This reaction is enhanced by copper salts, which allow it to be conducted mechanochemically, in a solvent-free manner. PMID- 28008435 TI - Cyclotrimerisation of isocyanates catalysed by low-coordinate Mn(ii) and Fe(ii) m terphenyl complexes. AB - Two- and three-coordinate m-terphenyl complexes of manganese and iron are efficient catalysts for the selective cyclotrimerisation of primary aliphatic isocyanates affording isocyanurates in short reaction times and under mild conditions. PMID- 28008437 TI - N-Doped porous carbon nanotubes: synthesis and application in catalysis. AB - Uniform N-doped carbon nanotubes were obtained for the first time via a morphology-preserving thermal transformation of organic polymer nanotubes without any additional templates. These carbon nanotubes acted as a superior metal-free carbon catalyst for C-H arylation of benzene, reductive hydrogen atom transfer and oxidation reactions. PMID- 28008436 TI - Aptamer-tagged DNA origami for spatially addressable detection of aflatoxin B1. AB - A DNA origami-based platform for detecting aflatoxin B1 has been constructed with the assistance of aptamer probes and its complementary ssDNA-modified gold nanoparticles. This work may open new horizons for the application of DNA origami in the detection of a variety of small molecules. PMID- 28008438 TI - High-speed electrodeposition of copper-tin-zinc stacks from liquid metal salts for Cu2ZnSnSe4 solar cells. AB - Cu2ZnSnSe4-based solar cells with 5.5% power conversion efficiency were fabricated from Cu/Sn/Zn stacks electrodeposited from liquid metal salts. These electrolytes allow metal deposition rates one order of magnitude higher than those of other deposition methods. PMID- 28008439 TI - A sulfonated poly(arylene ether ketone)/polyoxometalate-graphene oxide composite: a highly ion selective membrane for all vanadium redox flow batteries. AB - A highly ion-selective membrane for vanadium redox flow batteries (VRBs) consisting of sulfonated poly(arylene ether ketone) (SPAEK) and polyoxometalate coupled with a graphene oxide was designed and fabricated. The SPAEK/PW-mGO composite membrane showed an effectively low self-discharge rate and excellent Coulombic efficiency (98.73%) in VRBs. PMID- 28008440 TI - Ambiguous reactivity of Li/Cl phosphinidenoid complexes under redox conditions - a novel dichotomy in phosphorus chemistry. AB - A novel ambiguous reactivity of Li/Cl phosphinidenoid complexes under redox conditions is described. The outcome of the reaction with hexafluoroacetone is highly dependent on the P-substituent as fluoride substitution occurred in the case of R = CPh3 and C5Me5via a radical pathway, whereas for R = CH(SiMe3)2 a complex having a novel 1,2-diol-type P-ligand was obtained via a closed-shell pathway. DFT calculations reveal a new SET pathway starting with a noncovalent pi hole complex between the phosphinidenoid anion and hexafluoroacetone followed by an elimination of LiF. The second, closed-shell reaction course is strongly influenced by a noncovalent OSi interaction established after the initial nucleophilic attack. PMID- 28008441 TI - Synthesis and initial transition metal chemistry of the first PGeP pincer-type germylene. AB - A PGeP pincer-type germylene, Ge(NCH2PtBu2)2C6H4, which contains two phosphane groups hanging from the N atoms of an N-heterocyclic germylene fragment, has been isolated for the first time. This compound has already furnished a rich transition metal derivative chemistry (Co, Rh, and Pd) that includes complexes containing bridging P,Ge,P-, chelating P,Ge- and pincer P,Ge,P-ligands. PMID- 28008442 TI - A crystal structure prediction enigma solved: the gallic acid monohydrate system surprises at 10 K. AB - The seemingly unpredictable structure of gallic acid monohydrate form IV has been investigated using accurate X-ray diffraction measurements at temperatures of 10 and 123 K. The measurements demonstrate that the structure is commensurately modulated at 10 K and disordered at higher temperatures. Aided by charge-density modeling and periodic DFT calculations we show that the disorder gives a substantial stabilization of the structure. PMID- 28008443 TI - An easily accessible aggregation-induced emission probe for lipid droplet specific imaging and movement tracking. AB - Lipid droplets (LDs) as dynamic organelles are associated with many metabolic processes. Ideal fluorescent probes for LD-specific imaging require excellent specificity, superior brightness, fast cell permeability, and easy preparation. However, conventional fluorophores for LD imaging suffer from drawbacks of aggregation-caused quenching (ACQ), poor photostability, and difficulty of preparation. To tackle these challenges, herein, we develop an easily accessible aggregation-induced emission (AIE) fluorescent probe for LD-specific imaging and dynamic movement tracking. This AIE probe has significant advantages in terms of fast cell permeability, low cytotoxicity, strong photostability, and high two photon absorption cross-sections in the near infra-red (NIR) range. It is thus expected to have broad applications in the study of LDs' biological functions. PMID- 28008444 TI - A robust and efficient catalyst of CdxZn1-xSe motivated by CoP for photocatalytic hydrogen evolution under sunlight irradiation. AB - CdxZn1-xSe/CoP composites have been well studied as effervescent photocatalysts for H2 evolution. These composites are highly efficient at 45.1 mmol h-1 g-1 and have a high quantum yield of 11.8% at ~520 nm. The tunable energy band of CdxZn1 xSe facilitates photo-electrons transferring to CoP via chemical bonds between components. Advances in CdxZn1-xSe/CoP for photocatalytic H2 evolution provide a new strategy for future splitting of seawater. PMID- 28008445 TI - Asymmetric rhenium tricarbonyl complexes show superior luminescence properties in live cell imaging. AB - The synthesis and photophysical properties of a novel series of rhenium tricarbonyl complexes based on tridentate phenanthridinyl-containing ligands are described. Photophysical data reveal beneficial luminescence behaviour especially for compounds with an asymmetric ligand set. These advantageous properties are not limited to organic solvents, but indeed also improved in aqueous solutions. The suitability of our new rhenium complexes as potent imaging agents has been confirmed by fluorescence microscopy on living cancer cells, which also confirms superior long-time stability under fluorescence microscopy conditions. Colocalisation studies with commercial organelle stains reveal an accumulation of the complexes in the endoplasmic reticulum for all tested cell lines. PMID- 28008446 TI - Copper-catalyzed/mediated borylation reactions of epoxides with diboron reagents: access to beta-hydroxyl boronic esters. AB - We report the first copper-catalyzed/mediated borylative ring opening reaction of epoxides. This process represents a direct borylative C(sp3)-O bond cleavage of terminal epoxide substrates with commercially available diboron reagents. A wide range of epoxides with different functional groups are involved, and were subsequently converted to the corresponding beta-hydroxyl boronic esters smoothly. Moreover, the ring opening product beta-pinacol boronate alcohol provided a more beneficial approach for the formation of C-C and C-N bonds. PMID- 28008447 TI - Toward the detection of intraplaque hemorrhage in carotid artery lesions using photoacoustic imaging. AB - Photoacoustic imaging (PAI) may have the ability to reveal the composition and the anatomical structure of carotid plaques, which determines its mechanical properties and vulnerability. We used PAI and plane wave ultrasound (PUS) imaging to obtain three-dimensional (3-D) images of endarterectomy samples ex vivo and compared the results with histology to investigate the potential of PAI-based identification of intraplaque hemorrhage. Seven carotid plaque samples were obtained from patients undergoing carotid endarterectomy and imaged with a fully integrated hand-held photoacoustic (PA) probe, consisting of a pulsed diode laser ( t pulse = 130 ?? ns , E pulse = 1 ?? mJ , ? = 808 ?? nm ) and a linear array transducer ( f c = 7.5 ?? MHz ). The samples were rotated 360 deg with 10 deg steps, and data were spatially compounded to obtain complete 3-D images of the plaques. Areas of high absorption in the 3-D datasets were identified and compared to histological data of the plaques. Data in six out of seven endarterectomy samples revealed the presence of intraplaque hemorrhages that were not visible in the PUS images. Due to the noninvasive nature of PAI, this ex vivo study may elucidate preclinical studies toward the in vivo, noninvasive, vulnerability assessment of the atherosclerotic carotid plaque. PMID- 28008448 TI - Gas exchange in fruits related to skin condition and fruit ripening studied with diode laser spectroscopy. AB - The concentration of the biologically active molecular oxygen gas is of crucial importance for fruits in the metabolic respiration, maturation, and ripening processes. In our study, oxygen content and oxygen transport in fruits, exemplified by apples and guavas, were studied noninvasively by gas in scattering media absorption spectroscopy. The technique is based on the fact that free gases typically have 10,000 times narrower absorption features than the bulk material. The technique was demonstrated in studies of the influence of the fruit skin in regulating the internal oxygen balance, by observing the signal response of the internal oxygen gas to a transient change in the ambient gas concentration on peeled and unpeeled fruits. In addition, the gas exchange rate at different ripening stages was also studied in intact guavas. PMID- 28008449 TI - On the equivalence and differences between laser Doppler flowmetry and laser speckle contrast analysis. AB - Laser Doppler flowmetry (LDF) and laser speckle contrast analysis (LASCA) both utilize the spatiotemporal properties of laser speckle patterns to assess microcirculatory blood flow in tissue. Although the techniques analyze the speckle pattern differently, there is a close relationship between them. We present a theoretical overview describing how the LDF power spectrum and the LASCA contrast can be calculated from each other, and how both these can be calculated from an optical Doppler spectrum containing various degrees of Doppler shifted light. The theoretical relationships are further demonstrated using time resolved speckle simulations. A wide range of Monte Carlo simulated tissue models is then used to show how perfusion estimates for LDF and LASCA are affected by changes in blood concentration and speed distribution, as well as by geometrical and optical properties. We conclude that perfusion estimates from conventional single exposure time LASCA are in general more sensitive to changes in optical and geometrical properties and are less accurate in the prediction of real perfusion changes, especially speed changes. Since there is a theoretical one-to one relationship between Doppler power spectrum and contrast, one can conclude that those drawbacks with the LASCA technique can be overcome using a multiple exposure time setup. PMID- 28008450 TI - Real-time measurement of the vaginal pressure profile using an optical-fiber based instrumented speculum. AB - Pelvic organ prolapse (POP) occurs when changes to the pelvic organ support structures cause descent or herniation of the pelvic organs into the vagina. Clinical evaluation of POP is a series of manual measurements known as the pelvic organ prolapse quantification (POP-Q) score. However, it fails to identify the mechanism causing POP and relies on the skills of the practitioner. We report on a modified vaginal speculum incorporating a double-helix fiber-Bragg grating structure for distributed pressure measurements along the length of the vagina and include preliminary data in an ovine model of prolapse. Vaginal pressure profiles were recorded at 10 Hz as the speculum was dilated incrementally up to 20 mm. At 10-mm dilation, nulliparous sheep showed higher mean pressures ( 102 +/ 46 ?? mmHg ) than parous sheep ( 39 +/- 23 ?? mmHg ) ( P = 0.02 ), attributable largely to the proximal (cervical) end of the vagina. In addition to overall pressure variations, we observed a difference in the distribution of pressure that related to POP-Q measurements adapted for the ovine anatomy, showing increased tissue laxity in the upper anterior vagina for parous ewes. We demonstrate the utility of the fiber-optic instrumented speculum for rapid distributed measurement of vaginal support. PMID- 28008451 TI - Values of molecular markers in the differential diagnosis of thyroid abnormalities. AB - INTRODUCTION: Thyroid cancer (TC), follicular adenoma (FA) and Hashimoto's thyroiditis (HT) are three of the most frequently reported abnormalities that affect the thyroid gland. A frequent co-occurrence along with similar histopathological features is observed between TC and FA as well as between TC and HT. The conventional diagnostic methods such as histochemical analysis present complications in differential diagnosis when these abnormalities occur simultaneously. Hence, the authors recognize novel methods based on screening genetic defects of thyroid abnormalities as viable diagnostic and prognostic methods that could complement the conventional methods. METHODS: We have extensively reviewed the existing literature on TC, FA and HT and also on three genes, namely braf, nras and ret/ptc, that could be used to differentially diagnose the three abnormalities. Emphasis was also given to the screening methods available to detect the said molecular markers. RESULTS AND CONCLUSION: It can be conferred from the analysis of the available data that the utilization of braf, nras and ret/ptc as markers for the therapeutic evaluation of FA and HT is debatable. However, molecular screening for braf, nras and ret/ptc mutations proves to be a conclusive method that could be employed to differentially diagnose TC from HT and FA in the instance of a suspected co-occurrence. Thyroid cancer patients can be highly benefited from the screening for the said genetic markers, especially the braf gene due to its diagnostic value as well as due to the availability of personalized medicine targeted specifically for braf mutants. PMID- 28008452 TI - Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study. AB - Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone. PMID- 28008454 TI - Intra-arterial contrast-enhanced ultrasound (IA CEUS) for localization of hepatocellular carcinoma (HCC) supply during transarterial chemoembolization (TACE): a case series. AB - Transarterial chemoembolization (TACE) is a proven catheter-based locoregional therapy for treatment of hepatocellular carcinoma (HCC). Drug-eluting bead TACE involves delivering micrometer-sized particles preloaded with doxorubicin directly to the tumor via its arterial blood supply and results in vascular embolization with intra-tumoral drug release. Effective therapy requires mapping of the tumor arterial supply, which in some cases cannot be accomplished with conventional angiographic techniques alone. Contrast-enhanced ultrasound (CEUS) is an imaging technique which utilizes microbubble contrast agents to demonstrate blood flow and tissue perfusion, enabling tumor visualization in real time. CEUS with intravenous contrast administration is well established for evaluation of HCC. Intra-arterial (IA) CEUS, on the other hand, is an emerging technique that allows more selective evaluation of the arterial supply to the tumor. The three cases in this report illustrate the utility of intra-procedural IA CEUS during TACE. Specifically, IA CEUS aided TACE in cases where the HCC showed poor arterial enhancement, an extrahepatic arterial supply, and a portal venous supply, respectively. PMID- 28008453 TI - Association of VDBP and CYP2R1 gene polymorphisms with vitamin D status in women with polycystic ovarian syndrome: a north Indian study. AB - PURPOSE: Polycystic ovarian syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age and is usually associated with oligo ovulation/anovulation, obesity, and insulin resistance. Hypovitaminosis D may also be a primary factor in the initiation and development of PCOS. However, little is known about the role of genetic variation in vitamin D metabolism in PCOS aetiology. Therefore, we studied the genetic polymorphisms of CYP2R1 and vitamin D binding protein (VDBP) in an Indian population. METHODS: Serum vitamin D was measured by ELISA. Genotyping of VDBP single nucleotide polymorphisms (SNPs) rs7041 (HaeIII; G>T) and rs4588 (StyI; A>C) and CYP2R1 SNP rs2060793 (HinfI; A>G) was carried out by restriction fragment length polymorphism in 50 cases of PCOS that were compared with 50 age-matched healthy women. RESULTS: Vitamin D levels were found to be significantly lower in women with PCOS (p = 0.008) than in age-matched controls. There was no significant difference in genotype frequencies of all three polymorphisms (rs7041, rs4588, and rs2060793) between PCOS and control women. In women with a vitamin D deficiency (<20 ng/ml), the GT allele of the VDBP SNP rs7041 (p value =0.04), the VDBP allelic combination Gc1F/1F (T allele of rs4588 and C allele of rs7041) (p value =0.03), and the GA allele of the CYP2R1 SNP rs2060793 (p = 0.05) were associated with an increased risk of developing PCOS. CONCLUSIONS: The present study shows that the GT allele of VDBP SNP rs7041, the VDBP allelic combination (GC1F/1F), and GA allele of CYP2R1 SNP rs2060793 in vitamin D deficient women increase the risk of PCOS. PMID- 28008455 TI - Perfusion CT measurements predict tumor response in rectal carcinoma. AB - PURPOSE: To evaluate the capacity of perfusion CT imaging to distinguish between complete and incomplete responders after neoadjuvant chemoradiation therapy for rectal carcinoma, with particular attention to segmentation technique. MATERIALS AND METHODS: 17 patients were evaluated in this prospective IRB-approved study. For each patient, a perfusion CT acquisition was obtained prior to the initiation of chemoradiation, at 1-2 weeks after the start of chemoradiation, and at 12 weeks after the start of chemoradiation therapy. From each dataset, three perfusion parameters were measured, each in two different ways: a region of interest incorporating only "hot spots" of greatest enhancement and whole-tumor measurements. RESULTS: In univariate analysis, blood volume and permeability differed significantly between responders and non-responders. In logistic regression analysis evaluating predictors of the "complete response" outcome, only two predictors were retained as statistically significant: peak hot spot blood volume 1-2 weeks into therapy (OR 10.25, p = 0.0026) and hot spot permeability decline at 12 weeks after the initiation of therapy (OR 5.62, p = 0.03). The overall likelihood ratio test for this model supported the conclusion that hot spot blood volume and hot spot permeability decline were significant predictors of the complete pathologic response outcome (p < 0.0001). CONCLUSION: In this pilot study, peak tumor blood volume and decline in tumor permeability, when measured in "hot spots" of greatest enhancement, were strong predictors of complete therapeutic response in rectal cancer after neoadjuvant therapy. PMID- 28008456 TI - Mechanical Bowel Preparation Does Not Affect Clinical Severity of Anastomotic Leakage in Rectal Cancer Surgery. AB - BACKGROUND: Previous multicenter randomized trials demonstrated that omitting mechanical bowel preparation (MBP) did not increase anastomotic leakage rates or other infectious complications. However, the most serious concern regarding the omission of MBP is ongoing fecal peritonitis after anastomotic leakage occurs. The aim of this study was to compare the clinical manifestations and severity of anastomotic leakage between patients who underwent MBP and those who did not. METHODS: This study was a single-center retrospective review of a prospectively maintained database. From January 2006 to September 2013, 1369 patients who underwent elective rectal cancer resection with primary anastomosis were identified and analyzed. RESULTS: Anastomotic leakage rates were not significantly different between patients who did not undergo MBP (77/831, 9.27%) and those who did (42/538, 7.81%). However, a significantly lower rate of clinical leakage requiring surgical exploration was observed in the leakage without MBP group (30/77, 39.0%) compared with the leakage with MBP group (30/42, 71.4%) (P = 0.001). There were no significant differences in the clinical severity of anastomotic leakage as assessed by the length of hospital stay, time to resuming a normal diet, length of antibiotic use, ileus rate, transfusion rate, ICU admission rate, and mortality rate between the leakage without MBP and leakage with MBP groups. CONCLUSION: MBP was not found to affect the clinical severity of anastomotic leakage in elective rectal cancer surgery. PMID- 28008457 TI - Arterial hypertension treated with angiotensin converting enzyme inhibitors and glucocorticoids are independent risk factors associated with decreased glomerular filtration rate in systemic sclerosis. AB - The aim of this study was to estimate prevalence and severity of renal insufficiency in systemic sclerosis (SSc) and to assess risk factors associated with reduced glomerular filtration rate (GFR) in SSc patients. Seventy-three consecutive patients with SSc (67 women and 6 men), mean age 56.2 years, mean disease duration 6.7 years, were included in this cross-sectional study. GFR was measured by creatinine clearance (CCr) in all patients, as well as 24-h proteinuria. We assessed frequency and severity of renal insufficiency in our patients with SSc and estimated the association of renal insufficiency with age, disease duration, subtype of the disease, earlier diagnosed arterial hypertension, and medications for which we assumed to affect renal function cytostatics, nonsteroidal anti-inflammatory drugs, glucocorticoids, ACE inhibitors, diuretics, and calcium channel blockers (CCB). Fifty-six out of 73 patients with SSc (76.7%) had reduced GFR (CCr lower than 90 ml/min), compared to 17/73 (23.3%) of patients with normal renal function. Mild renal insufficiency was noticed in 28/73 (38.4%), moderate in 21/73 (28.8%) and severe renal insufficiency in 5/73 (6.8%). End-stage renal disease (CCr < 15 ml/min) was found in 2/73 (2.7%) of patients. Using the univariate general linear statistical model, we have found that previously diagnosed arterial hypertension and treatment with glucocorticoids are independent risk factors for reduced GFR. On the other hand, age, disease duration, disease form, as well as antibodies (anticentromere antibodies-ACA and anti-topoisomerase I antibodies-ATA) were excluded as independent risk factors. Patients with SSc and arterial hypertension treated with CCB had significantly higher mean CCr than patients treated with diuretics (90.4 vs 53.5 ml/min, p = 0.03), or patients treated with ACE inhibitors (90.4 vs 41.7 ml/min, p = 0.001). Decreased GFR is common in SSc. Most of patients have mild or moderate renal insufficiency. Previously diagnosed arterial hypertension, especially when treated with ACE inhibitors or diuretics, and glucocorticoids are independent risk factors associated with reduced GFR in SSc. These medications should be therefore used with caution in SSc patients. PMID- 28008459 TI - Biologic Behavior of Hydroxyapatite Used in Facial Augmentation. AB - INTRODUCTION: The recent finding that shrinkage of key areas of the facial skeleton contributes to the aging appearance of the face has prompted a search for the most appropriate bone-like implant material. Evidence that hydroxyapatite, in granular form, maintains volume in the long term supports its use in the correction of aging, in addition to its use in the correction of inherently deficient areas of the facial skeleton. The biologic response of hydroxyapatite needs to be fully understood for its use to be confidently recommended. MATERIALS AND METHODS: Samples of 'living' hydroxyapatite from the anterior maxilla, zygoma, and mandible of 17 patients were analyzed. These were obtained during revision procedures performed between 6 months and 15 years following original placement on the facial skeleton. RESULTS: Histology showed that in every case, the individual granules were embedded within a mass of collagen that made up about half of the total implant volume. The collagen mass also contained fine elastin, fibroblasts, lymphocytes, occasional granulomas, and vessels. By 2 years, a new compact bone containing osteoblasts and osteocytes was present in all specimens in the deep (osseous) aspect. Bone progressively replaced the original collagen between the granules with a sharply defined transition at the interface. CONCLUSIONS: This study confirmed a two-stage biologic change following onlay placement of hydroxyapatite granules on the facial skeleton, i.e., initial collagen formation with subsequent conversion to bone. This integrates the implant with the host bone which stabilizes the implant position and shape initially and in long term. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors. www.springer.com/00266 . PMID- 28008458 TI - Columellar Scar Perception in Open Rhinoplasty. Interplay of Scar Awareness, Body Cathexis and Patient Satisfaction. AB - INTRODUCTION: Open and closed approaches for rhinoplasty have individual advantages and disadvantages; however, the resultant columellar scar of the open approach is directly considered as a disadvantage. This study focuses on the columellar scar awareness and its implications on overall satisfaction of the patients after open rhinoplasty. PATIENTS AND METHODS: A total of 91 patients who have undergone open rhinoplasty were included in this study. A written questionnaire algorithm consisting of 4 sequential questions was applied. Except for the first question [Do you have any scar(s) caused by any trauma, operation or any other reason on your face?], every question was answered on a scale from 1 to 5. The respondents were given the 25-question "Modified Body Cathexis Scale (MBCS)"and their scars graded using the "Columellar Scar Assessment Scale" (CSAS). The data were statistically interpreted. RESULTS: Of the 91 open rhinoplasty patients, 12 of them responded with a "yes" to the first question reporting their columellar scars. There was no significant difference with regards to patient satisfaction regarding these patients (p > 0.05). However, those who reported the scar yielded a significantly lower MBCS scores. 9 patients declared that they exerted effort to conceal their scars. Those who concealed their scars and those who did not yielded a significant difference in patient satisfaction. The CSAS scores of those who reported the columellar scar were significantly higher than those who did not. CONCLUSION: Our study suggests that MBSC can be a valuable tool for determining the impact of outcomes from the patient's standpoint, and awareness of the columellar scar is not related to patient satisfaction but with bodily perception. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28008460 TI - Treatment of Tear Trough Deformity: Fat Repositioning versus Autologous Fat Grafting. AB - BACKGROUND: Fat-preserving lower blepharoplasty techniques and filling techniques using autologous or non-autologous materials are increasingly used to treat tear trough deformity. However, there has been no definitive comparison of the results of fat repositioning versus autologous fat grafting for this condition. The authors used statistical analysis to compare the results of the two methods. METHODS: From October 2013 to September 2015, a total of 101 patients, aged 20-43 years, underwent fat repositioning or autologous fat grafting in our department. Group 1 (51 patients, 102 eyes) underwent intraorbital fat repositioning with septal reset by transconjunctival lower blepharoplasty. Group 2 (50 patients, 100 eyes) underwent autologous fat grafting by lipoinjection. RESULTS: No significant complications occurred in any patient postoperatively. Four of 102 eyes in Group 1 and seven of 100 eyes in Group 2 had no improvement; the rest had different degrees of improvement. In Grade II and III deformities, fat repositioning resulted in significantly greater improvement of grade compared with autologous fat grafting. The surgical method of Group 1 resulted in better curative effects than that of Group 2. CONCLUSION: In patients with tear trough deformity and without obvious skin or orbicularis oculi muscle laxity, both fat repositioning and autologous fat grafting are acceptable for mild deformity. In patients with higher-grade deformities, fat repositioning produced superior results than autologous fat grafting. LEVEL OF EVIDENCE IV: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 . PMID- 28008461 TI - Lower Leg Augmentation with Fat Grafting, MRI and Histological Examination. AB - INTRODUCTION: Nowadays, there is an increasing demand for contouring of the entire lower leg, in addition to corrections at the level of the muscle only. Accordingly, it becomes advantageous to use fat tissue for this purpose, for its availability in high quantities, potential for its easy implantation in all leg parts, biological compatibility, low antigen potential, and minimal donor morbidity. METHODS: Forty-eight female patients, aged 20-54 (47.1 % younger than 35 and 52.9 % older than 35), underwent lower leg augmentation with autologous fat. We compared pre- and 1, 3, and 6 months postoperative morphological and volumetric characteristics of the recipient region by circumferential measuring of particular parts of the lower legs and evaluating the presence of live transplanted fat by MRI and histological examination. RESULTS: The augmentation of certain circumferences of the lower leg at the 6-month follow-up examination is significantly related to preoperative circumference as well as to the quantity of infiltrated fat. Therefore, lower the baseline circumference, the greater the augmentation, and the greater the quantity of infiltrated fat, the greater the augmentation. CONCLUSION: Ensuring adequate technique in the transfer of fat tissue from the donor region to the recipient region of the lower leg is definitely the least invasive method of lower leg contouring. For patients with muscle dystrophies or those with injuries, this technique could become the first choice for its minimal complications. The simplicity of the procedure invites its wide application in plastic surgery. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A3 online Instructions to Authors. www.springer.com/00266 . PMID- 28008462 TI - Rhinophyma: "Less is More" and "Old is Gold". AB - : Rhinophyma is a deforming disorder of the nose and considered the most severe stage of rosacea. Since 1950, a large variety of surgical and non-surgical treatments have been adopted to treat it. From January 2014 to June 2016, we treated ten patients (average age: 58 years) affected by moderate (4) and severe (6) degrees of rhinophyma. A nasal skin decortication was performed with a loop shaped electrotome (Valleylab E1560 15 x 12 mm) in order to excise the hypertrophic tissue and restore a pleasing appearance to the nose. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A3 online Instructions to Authors. www.springer.com/00266 . PMID- 28008463 TI - A Dark Side of the Cannula Injections: How Arterial Wall Perforations and Emboli Occur. AB - BACKGROUND: Though most injectors prefer to use a cannula rather than a needle, there have been reported cases of blindness following cannula injections. This study investigated possible situations in which a cannula can injure an artery to gain more insight about the vascular complication and its prevention. METHODS: To understand how an arterial injury occurs, five situations favoring vascular injury were simulated and tested. Experiments were performed in 100 arterial segments of 10 soft embalmed cadavers with red latex injections to the arteries. The frontal branch of the superficial temporal artery with a diameter between 1.2 and 1.5 mm was chosen for the experiment with a 25G cannula. Five situations were created to simulate any possibility that the cannula can penetrate through the arterial wall. Two factors were varied for simulation of specific danger situations. Factors that vary were as follows: (1) the angles between the cannula and the artery when the cannula touched the artery, and (2) the segments of the artery with different features. RESULTS: The cannula could penetrate the arterial wall in some specific situations with a different chance in each situation. The perpendicular angle between the artery and the cannula was one of the essential situations for vascular injury. Situations that had a similar effect of the perpendicular arterial surface related to the cannula axis also favored vascular injuries. CONCLUSION: During a blinded insertion of cannula injections to reach the target area, the injector cannot discriminate the sensation at the cannula tip between the resistance of a fibrous septum in the way of the insertion and the resistance of encountering an artery. To prevent arterial emboli, the cannula trajectory should not be close to the main artery in the region. This allows a physician to safely perform an intermittent forceful insertion without an arterial injury during an attempt to perform a gentle cannula insertion. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors. www.springer.com/00266 . PMID- 28008464 TI - Long-Term Effects of the Collagenase of the Bacterium Clostridium histolyticum for the Treatment of Capsular Fibrosis After Silicone Implants. AB - BACKGROUND: Capsular contracture remains the most frequent long-term complication after augmentation mammoplasty with silicone implants. Thereby, the main part of the fibrotic capsule is collagen. The collagenase of the bacterium Clostridium histolyticum is approved for the treatment of fibrotic diseases and has been demonstrated to be effective for capsular fibrosis treatment in the short term. However, long-term effectiveness is currently unknown but mandatory for clinical utilization. MATERIALS AND METHODS: Forty-eight rats received miniature silicone implants and an injection with either collagenase (treatment group) or plain solvent solution (control group) 120 days post insertion. Ten and 60 days after the injections, the rats underwent 7-Tesla magnetic resonance imaging (MRI) and high-resolution ultrasound (HR-US). Capsule tissue was harvested, and capsule thickness and collagen density were evaluated through histology. Furthermore, the expression levels of inflammatory (CD68, IL4, IL10, IL12, IL13), pro-, and anti fibrotic (TGFb1, TGFb3, Smad3, Col1-4) genes were analyzed using qRT-PCR. RESULTS: On days 10 and 60 after injection of collagenase, histology showed that capsule thickness was significantly reduced in the treatment group when compared with the control (p < 0.05). Thickness measurements were verified by MRI and HR US analysis. Skin perforation occurred in two cases after collagenase injection. The initial up-regulation of pro-fibrotic and inflammatory genes 10 days after collagenase injection did not persist in the long term. Contrarily, on day 60, a slight trend towards lower expression levels with a significant down-regulation of TGFb3 was detected in the treatment group. CONCLUSION: The collagenase of the bacterium C. histolyticum effectively degrades capsular fibrosis around silicone implants with stable outcomes throughout 60 days post injection. Skin perforation and adequate and uniform drug distribution within the implant pocket are issues that need to be addressed. Further studies are warranted to clarify whether collagenase injections have the potential to become a viable treatment option for capsular contracture. NO LEVEL ASSIGNED: This journal requires that authors 46 assign a level of evidence to each article. For a full 47 description of these Evidence-Based Medicine ratings, 48 please refer to the Table of Contents or the online 49 Instructions to Authors. www.springer.com/00266 . PMID- 28008465 TI - Five-year results of laparoscopic sleeve gastrectomy for the treatment of severe obesity. AB - BACKGROUND: Since 2011, the most used bariatric technique in France has been the sleeve gastrectomy. There are still few studies exploring the medium and long term results of this technique. OBJECTIVE: To describe medium-long-term (5 years) results of a cohort of CHU Montpellier experience in sleeve gastrectomy for morbid obesity. METHODS: All patients that underwent laparoscopic sleeve gastrectomy (LSG) from January 2005 to June 2013 were included in this study. RESULTS: A total of 1050 patients were operated. 72.86% were women. The mean preoperative BMI was 44.58 kg/m2 (+/-7.71). A total of 183 patients (18.5%) were super-obese (BMI > 50 kg/m2). LSG was proposed as primary procedure, and also after failure of adjustable gastric banding in 169 patients (16.9%) or after vertical banded gastroplasty in 7 cases (0.7%). There were 38 postoperative gastric fistulas (3.8%) and 3 of them required some kind of bypass to be definitively treated. There were also 34 hemorrhages (3.4%) of which 21 were reoperated for hemostasis. Two gastric stenoses at the angulus (0.2%) were managed with dilation or RYGB. Overall reoperative rate was 6.8%. One patient died of pulmonary embolism. Most common late complication was GERD (39.1%). After 3, 4 and 5 years of LSG, the average of %EBL was, respectively, 75.95% (+/-29.16) (382 patients), 73.23% (+/-31.08) (222 patients) and 69.26% (+/-30.86) (144 patients). The success rate at 5 years was 65.97% (95 patients). The improvement or remission of comorbidities was found, respectively, in 88.4 and 57.2% of diabetic patients; 76.9 and 19.2% for hypertensive patients and 98 and 85% for patients with sleep apnea syndrome. CONCLUSION: LSG is a bariatric surgery technique that presents a very good risk/benefit ratio. Five-year results are very convincing. GERD is the main long-term complication. PMID- 28008466 TI - Perioperative hemorrhagic complications after laparoscopic sleeve gastrectomy: four-year experience of a bariatric center of excellence. AB - BACKGROUND: Bleeding and gastric fistula are the most common postoperative complications after laparoscopic sleeve gastrectomy (LSG). The long stapler line represents the most frequent source of bleeding, which ranges between 0 and 20%. The aim of this retrospective study was to analyze the 4-year experience of a high-volume center with respect to the prevention and management of perioperative LSG bleeding. METHODS: The prospectively maintained database from June 2012 to June 2016 was reviewed. Outcomes, especially perioperative bleeding (until patient discharge), its management, and follow-ups, were analyzed. RESULTS: Out of 870 LSG (603 females, 267 males), 31 cases (3.5%) of postoperative complications were registered: bleeding was the most frequent complication (1.9%). Hemoperitoneum was managed laparoscopically in 9/17 patients (52.9%) with only one conversion to laparotomy (11.1%). Conservative treatment successfully controlled bleeding in 8/17 patients (47.1%). However, four patients (50%) developed an infected hematoma; two of them were treated conservatively with a CT guided drainage, and the other two were complicated by late gastric leak treated laparoscopically. No mortalities occurred in the investigated cases. CONCLUSIONS: In a high-volume center, the expected incidence of bleeding after LSG is 1.7% even after the adoption of all preventive strategies. The intraoperative protocol for detecting silent bleeding was effective, and no cases of bleeding were observed since its application. Our findings showed that the conservative management of postoperative bleeding should be considered as a high-risk condition for late leakage. PMID- 28008467 TI - Readmissions after laparoscopic cholecystectomy in a UK District General Hospital. AB - INTRODUCTION: Laparoscopic cholecystectomy is the gold standard for the treatment of symptomatic gallstones and its practice as day case where possible is considered the standard over the last decade. However, readmission after surgery is recognised as a new problem. AIM: The aim of this cohort observational study was to investigate the readmission rate in a district general hospital and identify the causes of readmission in order to explore ways by which this can be reduced or managed more cost effectively. METHOD: Records of patients who had laparoscopic cholecystectomy over 6 months were retrospectively searched. Patients returning to hospital due to symptoms within 30 days of elective and emergency laparoscopic cholecystectomy were included. RESULTS: Three hundred and twenty-eight laparoscopic cholecystectomies were performed within the 6-month period. Twenty-two patients returned within 30 days of surgery making a readmission rate of 6.7%. Reasons for inpatient admission were abdominal pain without any underlying cause 10 (45.5%), wound infection 5 (22.7%), leg swelling 2 (9%), retained stone 1 (4.5%), bile leak 1 (4.5%), pneumonia 1 (4.5%), iatrogenic bowel injury 1 (4.5%) and back pain 1 (4.5%). Readmission rate decreased with longer duration of stay in hospital during primary admission, and 64% of patients returned to the hospital within 7 days of procedure. 50% of patients who returned with abdominal pain without any identifiable cause had a longstanding history of conditions involving chronic pain. CONCLUSION: While the feared intra-abdominal complications of cholecystectomy often come to mind when assessing patients presenting with abdominal pain after surgery, non-specific abdominal pain is consistently shown to be several times more likely. A combination of patient factors and pain control techniques account for this pain. Effective multimodal pain management approach and community primary health care support in the early post-operative period could reduce readmission, save cost and improve patient experience. PMID- 28008468 TI - Localizing small lung lesions in video-assisted thoracoscopic surgery via radiofrequency identification marking. AB - BACKGROUND: To facilitate accurate localization of small lung lesions in thoracoscopic surgery, we employed a micro-radiofrequency identification tag designed to be delivered through the 2-mm working channel of a flexible bronchoscope. This report presents the results of preclinical studies of our novel localizing technique in a canine model. METHODS: To evaluate functional placement, three types of tags [Group A, tag alone (n = 18); Group B, tag + resin anchor (n = 15); and Group C, tag + NiTi coil anchor (n = 15)] were bronchoscopically placed in subpleural areas and subsegmental bronchi via our new delivery device; tags were examined radiographically on days 0-7 and day 14. In addition, eight tags, which were placed at a mean depth of 13.3 mm (range 9-15.7 mm) from visceral pleura in bronchi with a mean diameter of 1.46 mm (range 0.9 2.3 mm), were recovered by partial lung resection under video-assisted thoracoscopic surgery using a 13.56-MHz wand-shaped probe with a 30-mm communication range. RESULTS: Peripheral airway placement: Group C had a significantly higher retention rate than the other two groups (retention rate at day 14: Group A, 11.1 %; Group B, 26.7 %; Group C, 100.0 %; P < 0.0001). Central airway placement: Overall retention rate was 73.3 % in Group C, and placement was possible in bronchi of up to 3.3 mm in diameter. Outcomes of partial resection: Tag recovery rate was 100 %, mean time required for tag detection was 10.8 s (range 8-15 s), and mean surgical margin from the delivered tag was 9.13 mm (range 6-13 mm). CONCLUSION: Radiofrequency identification marking enabled accurate localization with depth, which could ensure effective deep resection margins. PMID- 28008469 TI - Laparoscopic common bile duct exploration: a safe and definitive treatment for elderly patients. AB - BACKGROUND: Common bile duct (CBD) stone is one of the most common diseases among elderly people. In recent decades, there are numerous studies regarding the safety and efficacy of laparoscopic common bile duct exploration (LCBDE). Elderly patients are often regarded as high-risk patients because they are more likely to present with age-specific deterioration of organ function and coexisting chronic diseases, which may reduce their tolerance of laparoscopic surgery. Although laparoscopic surgery for choledocholithiasis is now widely accepted as the treatment for CBD stone, its appropriateness for the treatment of elderly patients or those with coexisting high-risk patients has not been well established. Therefore, the objective of this paper is to analyze the safety and efficacy of LCBDE in elderly patients. METHODS: Between January 2012 and November 2015, 376 patients underwent LCBDE in our center. Based on their ages, they were divided into two groups, and a retrospective study was performed. By making comparisons between younger group who were younger than 70 years (n = 253) and elderly group who were 70 years old or older (n = 123), the demographics, clinical characteristics, laboratory data, operative parameters and outcomes were analyzed. RESULTS: Before operation, elderly patients had more coexisting chronic diseases and risk factors, such as arterial hypertension, heart diseases, pulmonary diseases and previous abdominal surgery (P < 0.05). In both groups, LCBDE was equally successful with a high clearance rate (100 % in elderly patients vs. 98.8 % in younger group, P = 0.554). Besides, the operating time, intraoperative blood loss, postoperative hospital stay, total costs and overall complication showed no significant difference between two groups (P > 0.05). There was no major bile duct injury or death in either group. CONCLUSION: Although elderly patients are frequently confronted with coexisting disorders, LCBDE can be considered as a safe and effective technique in choledocholithiasis treatment for elderly patients. PMID- 28008470 TI - Uptake of enhanced recovery practices by SAGES members: a survey. AB - BACKGROUND: The SAGES Surgical Multimodal Accelerated Recovery Trajectory (SMART) Enhanced Recovery Task Force aims to increase awareness and provide tools for members to successfully implement enhanced recovery pathways (ERPs) to improve clinical outcomes and patient satisfaction. An initial step was to survey SAGES member on their knowledge, use, and impediments to enhanced recovery. METHODS: An online survey designed by SMART committee members to define SAGES member's awareness and use of enhanced recovery principles and practice was emailed to all SAGES members. Reminders were sent 2 and 3 weeks later, encouraging completion of the survey. The web-based survey included 48 questions and took an estimated 20 min to complete. RESULTS: A total of 229 members completed the survey. Respondents were primarily general/MIS surgeons (82.6%) working in an urban location (85.5%), with a bell-shaped age distribution (median 35-44). Almost half regularly used some elements of ERPs (48.7%), but 30% were unfamiliar with the concept. Wide variety in the specific ERP elements used and discharge criteria were reported. The majority had to create and implement their own plan (70.4%). Roadblocks to implementation were inconsistencies with partners/covering physicians (56.3%), nursing education (46.6%), and resources (34.7%). When implemented, members saw improvements in length of stay (88%), patient satisfaction (54.7%), postoperative pain (53.3%), time to return of bowel function (52.7%), and readmissions (16.7%). A need for education and standardization was especially seen in preoperative care, with 74.4% fasting patients from midnight the night before surgery. Wide variations were also reported in pain management practices. An overwhelming majority (89%) reported that having a protocol endorsed by a national organization, such as SAGES, would help with implementation. CONCLUSIONS: From this survey of SAGES members, there is a need for education, tools, and standardized protocols to increase awareness, support implementation, and encourage wider utilization of ERP. The overwhelming majority stated having a protocol endorsed by a national organization, such as SAGES, would facilitate implementation. PMID- 28008472 TI - Interaction of nucleus reuniens and entorhinal cortex projections in hippocampal field CA1 of the rat. AB - The nucleus reuniens (RE) and entorhinal cortex (EC) provide monosynaptic excitatory inputs to the apical dendrites of pyramidal cells and to interneurons with dendrites in stratum lacunosum moleculare (LM) of hippocampal field CA1. However, whether the RE and EC inputs interact at the cellular level is unknown. In this electrophysiological in vivo study, low-frequency stimulation was used to selectively activate each projection at its origin; field excitatory postsynaptic potentials (fEPSPs) were recorded in CA1. We applied (1) paired pulses to RE or EC, (2) combined paired pulses to RE and EC, and (3) simultaneously paired pulses to RE/EC. The main findings are that: (a) stimulation of either RE- or EC-evoked subthreshold fEPSPs, displaying paired pulse facilitation (PPF), (b) subthreshold fEPSPs evoked by combined stimulation did not display heterosynaptic PPF, and (c) simultaneous stimulation of RE/EC resulted in enhanced subthreshold fEPSPs in proximal LM displaying a nonlinear interaction. CSD analyses of RE/EC-evoked depth profiles revealed a nonlinear enlargement of the 'LM sink-radiatum source' configuration and the appearance of an additional small sink-source pair close to stratum pyramidale, likely reflecting (peri)somatic inhibition. The nonlinear interaction between both inputs indicates that RE and EC axons form synapses, at least partly, onto the same dendritic compartments of CA1 pyramidal cells. We propose that low-frequency activation of the RE-CA1 input facilitates the entorhinal-hippocampal dialogue, and may synchronize the neocortical-hippocampal slow oscillation which is relevant for hippocampal-dependent memory consolidation. PMID- 28008473 TI - CYP716A179 functions as a triterpene C-28 oxidase in tissue-cultured stolons of Glycyrrhiza uralensis. AB - KEY MESSAGE: CYP716A179, a cytochrome P450 monooxygenase expressed predominantly in tissue-cultured stolons of licorice ( Glycyrrhiza uralensis ), functions as a triterpene C-28 oxidase in the biosynthesis of oleanolic acid and betulinic acid. Cytochrome P450 monooxygenases (P450s) play key roles in the structural diversification of plant triterpenoids. Among these, the CYP716A subfamily, which functions mainly as a triterpene C-28 oxidase, is common in plants. Licorice (Glycyrrhiza uralensis) produces bioactive triterpenoids, such as glycyrrhizin and soyasaponins, and relevant P450s (CYP88D6, CYP72A154, and CYP93E3) have been identified; however, no CYP716A subfamily P450 has been isolated. Here, we identify CYP716A179, which functions as a triterpene C-28 oxidase, by RNA sequencing analysis of tissue-cultured stolons of G. uralensis. Heterologous expression of CYP716A179 in engineered yeast strains confirmed the production of oleanolic acid, ursolic acid, and betulinic acid from beta-amyrin, alpha-amyrin, and lupeol, respectively. The transcript level of CYP716A179 was about 500 times higher in tissue-cultured stolons than in intact roots. Oleanolic acid and betulinic acid were consistently detected only in tissue-cultured stolons. The discovery of CYP716A179 helps increase our understanding of the mechanisms of tissue-type-dependent triterpenoid metabolism in licorice and provides an additional target gene for pathway engineering to increase the production of glycyrrhizin in licorice tissue cultures by disrupting competing pathways. PMID- 28008471 TI - Microfabricated tissues for investigating traction forces involved in cell migration and tissue morphogenesis. AB - Cell-generated forces drive an array of biological processes ranging from wound healing to tumor metastasis. Whereas experimental techniques such as traction force microscopy are capable of quantifying traction forces in multidimensional systems, the physical mechanisms by which these forces induce changes in tissue form remain to be elucidated. Understanding these mechanisms will ultimately require techniques that are capable of quantifying traction forces with high precision and accuracy in vivo or in systems that recapitulate in vivo conditions, such as microfabricated tissues and engineered substrata. To that end, here we review the fundamentals of traction forces, their quantification, and the use of microfabricated tissues designed to study these forces during cell migration and tissue morphogenesis. We emphasize the differences between traction forces in two- and three-dimensional systems, and highlight recently developed techniques for quantifying traction forces. PMID- 28008475 TI - Existence of Traveling Waves for the Generalized F-KPP Equation. AB - Variation in genotypes may be responsible for differences in dispersal rates, directional biases, and growth rates of individuals. These traits may favor certain genotypes and enhance their spatiotemporal spreading into areas occupied by the less advantageous genotypes. We study how these factors influence the speed of spreading in the case of two competing genotypes under the assumption that spatial variation of the total population is small compared to the spatial variation of the frequencies of the genotypes in the population. In that case, the dynamics of the frequency of one of the genotypes is approximately described by a generalized Fisher-Kolmogorov-Petrovskii-Piskunov (F-KPP) equation. This generalized F-KPP equation with (nonlinear) frequency-dependent diffusion and advection terms admits traveling wave solutions that characterize the invasion of the dominant genotype. Our existence results generalize the classical theory for traveling waves for the F-KPP with constant coefficients. Moreover, in the particular case of the quadratic (monostable) nonlinear growth-decay rate in the generalized F-KPP we study in detail the influence of the variance in diffusion and mean displacement rates of the two genotypes on the minimal wave propagation speed. PMID- 28008474 TI - Making sense of metacommunities: dispelling the mythology of a metacommunity typology. AB - Metacommunity ecology has rapidly become a dominant framework through which ecologists understand the natural world. Unfortunately, persistent misunderstandings regarding metacommunity theory and the methods for evaluating hypotheses based on the theory are common in the ecological literature. Since its beginnings, four major paradigms-species sorting, mass effects, neutrality, and patch dynamics-have been associated with metacommunity ecology. The Big 4 have been misconstrued to represent the complete set of metacommunity dynamics. As a result, many investigators attempt to evaluate community assembly processes as strictly belonging to one of the Big 4 types, rather than embracing the full scope of metacommunity theory. The Big 4 were never intended to represent the entire spectrum of metacommunity dynamics and were rather examples of historical paradigms that fit within the new framework. We argue that perpetuation of the Big 4 typology hurts community ecology and we encourage researchers to embrace the full inference space of metacommunity theory. A related, but distinct issue is that the technique of variation partitioning is often used to evaluate the dynamics of metacommunities. This methodology has produced its own set of misunderstandings, some of which are directly a product of the Big 4 typology and others which are simply the product of poor study design or statistical artefacts. However, variation partitioning is a potentially powerful technique when used appropriately and we identify several strategies for successful utilization of variation partitioning. PMID- 28008476 TI - Development of liposome encapsulated clindamycin for treatment of acne vulgaris. AB - The enhancement of topical delivery of hydrophilic substances by use of multilammelar liposomes was measured ex vivo on pig ear skin and in vivo on hairless mice by electron paramagnetic resonance method (EPR). Multilamellar liposomes with different lipid composition (final concentration of membrane components is 48 mg/ml) were loaded with a hydrophilic spin probe GluSL, which does not penetrate the liposome membrane easily. They were characterized with respect to their stability, entrapped volume and enhancement characteristics. We observed significant differences in the properties of different types of liposomes with respect to their stability when in contact with the skin and their penetration into the skin. The results measured in vivo are consistent with those obtained ex vivo. On the basis of these findings the liposomes with appropriate stability and intradermal penetration characteristics were chosen for the development of liposome-encapsulated 1% clindamycin preparation for therapy of acne vulgaris. A double-blind clinical study was conducted to assess the safety and efficiency of liposome-encapsulated 1% clindamycin solution versus 1% clindamycin solution (Klimicin(r) T, Lek). On the basis of the clinical trial it may be concluded that liposome-encapsulated 1% clindamycin solution was therapeutically superior over conventional 1% clindamycin solution in the treatment of acne vulgaris. PMID- 28008477 TI - Vitamin C induced apoptosis in human articular chondrocytes. AB - Chondrocytes present in articular cartilage survive as a resident cell population throughout the lifespan of the individual organism. However, articular chondrocytes as other cells also undergo apoptosis and there is an ever increasing list of diverse stimuli that can induce this phenomenon in vitro. Our main interest was to investigate potential cytotoxic effects of vitamin C (L ascorbic acid) on human articular chondrocytes. The present study suggests that vitamin C can induce apoptosis in a cell culture of chondrocytes after 18 h of cultivation. Apoptosis-inducing activity of L-ascorbic acid is dose dependent and significantly affected by the presence of serum. The increased number of vitamin C induced apoptotic cells was associated with DNA fragmentation and morphological changes of the cells. PMID- 28008478 TI - In vitro functional tests for evaluation of stimulating capacity of cultured human dendritic cells. AB - Basic functional test for evaluation of in vitro cultured human dendritic cells (DC) is primary allogeneic one-way mixed lymphocyte reaction (MLR). In this way, one can evaluate stimulating capacity, which is a basic characteristic of DC. The proliferation of cells is measured through incorporation of 3H-thymidine. Normally proliferation is measured at days 5-7. We studied kinetics of proliferative responses initiated with different stimulating cell suspensions to evaluate differences and possibly reduce time needed to perform this test.Gradual increase in response from days 1 to 7 and a significant difference from controls (peripheral blood mononuclear cells) seen from day 4 was noted if macrophages were used as stimulators. A consistently higher proliferation, compared to controls, was always found already on day 2 when mature DC were used as stimulators. The reaction peaked 2 to 3 days earlier and was also more than two times more intense.This maximal and significantly higher response, consistently seen already after 48 hours, allows us to confirm the presence of mature DC in stimulating suspensions much earlier than previously. PMID- 28008479 TI - Asymmetrical labeling of giant phospholipid vesicles. AB - The method for labeling of inner membrane leaflet in unilamellar giant POPC vesicles was developed and characterised. Symmetrically NBD-PC labeled vesicles were treated by sodium dithionite, which undergoes an irreversible chemical reaction with NBD-PC molecule making it non-fluorescent. After the addition of dithionite the fluorescence on single vesicles as well as on vesicle suspension showed a 50 % decrease of its initial value corresponding to marker quenching in the outer leaflet. Hence, flourimetry as well as flourescence microscopy prove that dithionite quenching is a suitable method to induce an asymmetrical labeling of the NBD-PC marked giant vesicles. PMID- 28008480 TI - The Str mouse as a model for Incontinentia pigmenti. AB - Striated mouse has been proposed as a model for incontinentia pigmenti (IP) based on the similarities in genetic predisposition and syntenic gene localisation in mouse. IP is considered an ectodermal dysplasia with all four charctarestic structures involved: sweat glands, hair, teeth and nails. Recently mutations have been found in the Nsdhl, encoding an NAD(P)H steroid dehydrogenase-like protein in Str and Bpa mice. We analysed the phenotype of the Str mouse to evaluate the involvement of ectodermally derived tissues. Our results demonstrated that in Str mouse in addition to abnormal coat texture, sweat glands were severely dystrophic or missing. Retinal degeneration and skeletal abnormalities were also found. We conclude that Str mouse is a good model to get new insights in the pathogenesis of ectodermal dysplasias and X linked male lethality in humans. PMID- 28008481 TI - Animal model in the study of colorectal carcinogenesis. AB - Experimental animal models of neoplastic diseases are important in understanding etiological and pathophysiological processes also in humans. In order to investigate whether the mechanism of genomic instability is associated with chemically induced colorectal tumorigenesis in rat we performed the following study: One hundred and fifty Wistar rats (males 220-280 g and females 140-180 g) were used in the study. Colorectal tumors were induced by means of 15 s.c. applications (20 mg/kg) of 1,2-dimethylhydrazine (DMH). On autopsy, all intestinal lesions were assessed by histological criteria used in human pathology. Forty five tumors were found in the large intestine - 30 of these in males and 15 in females, i.e. in 27% of all animals. In four animals multiple primary tumors were found. Histologically 24 tumours were adenocarcinomas, 14 signet-cell carcinoma and 7 adenomas. DNA was extracted from rat neoplastic lesions and adjoining microscopically normal tissues from the same slide and amplified by PCR, using 10 different microsatellite markers from chromosomes 1, 3, 5, 7 and 8. PCR amplicon were analyzed for microsatellite instability with non isotopic method. In 13 adenocarcinomas (29%) microsatellite instability was found at a minimum of 1 locus. Seven tumors (15.5%) showed microsatellite instability at multiple loci. The results of our experiment suggest that genomic instability is an important molecular event in the pathophysiology of DMH induced colorectal carcinogenesis in rats. PMID- 28008482 TI - Human peripheral blood lymphocytes sensitised to PPD respond to in vitro stimulation with increased expression of CD69 and CD134 activation antigens and production of Th-1 type cytokines. AB - Individuals sensitised to Mycobacterium tuberculosis antigens by infection, vaccination or Mantoux test generate specific memory cells. The response to in vitro restimulation with PPD is observed as the lymphoid cell proliferation and production of Th-1 type cytokines. Cell-mediated immune response was measured by Mantoux test, lymphocyte blast transformation test, estimation of IFN-gamma production (Quantiferon, ELISPOT), and expression of CD69 and CD134 molecules on the T-helper lymphocytes (CD4+). All the methods used were compared for parity of the results. According to Mantoux test results, the patients could be distributed into two groups: responder and non-responder group. Induration in Mantoux test after a new contact with PPD in non-responders was smaller than 5 mm, they produced only small amounts of IFN-gamma, lymphocyte blast transformation was poor, and expression of CD69 and CD134 was low. In responders reaction was much more intensive in all tests measured. We conclude that the reactivity of memory cells to M. tuberculosis antigens can be effectively detected by Mantoux test. The same was true also for the in vitro tests presented but in addition the in vitro tests give more information about the mechanism involved in the immune response against M. tuberculosis. PMID- 28008483 TI - Soluble tumor necrosis factor receptor I (sTNFRI) as a prognostic factor in melanoma patients in Slovene population. AB - Tumor necrosis factor alpha (TNF-alpha) and its receptors (TNFRI and TNFRII) which exist in soluble form as a product of cleavage of the extracellular domain of membrane integrated receptors, still rise debate about their importance. It was reported that TNF-alpha has numerous actions in diseases such as inflammation, autoimmunity, infectious diseases, septic shock and many types of cancer [1, 2]. Several authors have reported the significance of sTNFRI level in serum of cancer patients [3, 4]. This study was performed in collaboration with the Institute of Oncology of Slovenia.At least two different mouse monoclonal antibodies (MAbs) against human sTNFRI have been prepared to obtain a sensitive and reliable sandwich ELISA. It was compared with commercially available R&D and Endogen ELISAs for the determination of sTNFRI. Groups of patients with different stages of melanoma and epithelial ovarian carcinoma were tested and their clinical records were reexamined. Levels of sTNFRI were measured and compared with the normal serum levels of sTNFRI. PMID- 28008484 TI - Modulation of tumour necrosis factor production with desmuramyldipeptide analogues. AB - Some synthetic analogues of the immuno-modulatory agent muramyl dipeptide (MDP), i.e. phthalimido- (LK-511, LK-413, LK-512, LK-423, LK-508), adamantyl- (LK-415, LK-517), 7-oxoaIkyl-(LK-409) desmuramylpeptides were assessed for the tumour necrosis factor (TNF) inducing activity and the ability to modulate TNF production in in vitro phorbol 12-myristate 13-acetate (PMA) & ionomycin stimulated cultures of human peripheral blood mononuclear cells. A kinetic study over a 40-hour period indicated that desmuramyldipeptides were weak TNF inducers compared to romurtide, PMA & ionomycin or lipopolysaccharide. By contrast, they showed the potential to up- or down-regulate the production of TNF evoked by PMA & ionomycin, which was strongly dependent on the time of the stimulation. After 4h of stimulation, the TNF secretion was augmented by LK-508, LK-409 and LK-511, after 18 h by LK-409 and LK-423, and after 40 h by LK-423, LK-511, LK-415 and LK 512. However, LK-517 and LK-512 inhibited the secretion of TNF after the 18-h period. PMID- 28008485 TI - Immune response in lymphocyte cultures stimulated by oral bacteria preparations. AB - Lymphocyte cultures were used as an in vitro experimental model to get a deeper insight into immune response to oral bacteria in periapical granulomas. Lymphocytes isolated from leucocyte concentrate were in lymphocyte cultures stimulated by antigen preparations of oral bacteria. Lymphocyte subsets that have developed in lymphocyte cultures after a week of stimulation were analysed by flow cytometry. A significant increase in expression of INF-gamma molecules in CD3+ cells stimulated by antigen preparations of oral streptococci was found, compared with negative control. On the other hand we observed a significant increase in expression of IL-4 in CD3+ cells stimulated by antigens of anaerobic bacteria, compared with negative control. Our results show that antigens of oral streptococci in in vitro lymphocyte cultures induce the differentiation of T helper cells into Th2 cells and that antigen preparations of anaerobic bacteria induce the differentiation of T helper cells into Th1 cells. Furthermore, an increased expression of HLA-DR molecules on CD8+ T cells stimulated by antigens of oral streptococci was found, compared with negative control. PMID- 28008486 TI - Shift from Th2 to Th1 response in immunotherapy with venoms. AB - Cytokines released from T lymphocytes regulate antibody production by B lymphocytes and releasability of mast cells and basophils. Immune tolerance in specific allergen (Ag) immunotherapy (SIT) might be a consequence of decreased Th2 or increased Th1 response of Ag specific T lymphocytes. We compared function of T lymphocytes in 11 patients with Hymenoptera venom allergy and in 7 healthy volunteers. We followed function of T lymphocytes in 6 patients during SIT. We measured released IL-2, IFN-gamma, IL-4 and IL-5 from Ag and mitogens (either with phorbol-miristate-acetate (PMA) and ionomycine or anti-CD3 antibodies) stimulated peripheral blood mononuclear cells (PBMC). After stimulation with Ag PBMC of patients released 86 +/- 133 pg/ml IFN-gamma and 19.7 +/- 20.1 pg/ml IL-4 (Th2 response), PBMCs of healthy controls released 184 +/- 116 pg/ml IFN-gamma and 4.8 +/- 8 pg/ml IL-4 (Th1 response). Spontaneous release of IFN-gamma in cultures of PBMC of patients increased after rush SIT (before: 25 +/- 31 pg/ml, after 241 +/-281 pg/ml, p<0.05). After 6 months of SIT response of PBMCs of patients became similar to response of PBMCs of healthy controls. Time pattern of cytokines secreted from PBMCs after stimulation with PMA and ionomycine was different than after stimulation through T-cell receptor/CD3 complex. PMID- 28008487 TI - lnterleukin-8 and procalcitonin in early diagnosis of early severe bacterial infection in critically ill neonates. AB - We studied the value of serum interleukin-8 (IL-8) and procalcitonin (PCT) in the early diagnosis of early severe bacterial infection in 58 critically ill ventilated neonates. ELISA was used for determining IL-8 and immunoluminometric assay for PCT. IL-8 and PCT were compared with routinely used serum C-reactive protein (CRP). Neonates were divided into four groups: Ia - proven severe bacterial infection (n = 9), Ib - clinical sepsis (n = 16), II - respiratory distress without bacterial infection (n = 12), and III - various types of neonatal distress (n = 21). Sera were collected on admission, at 24 h and 48 h after admission. There was no significant difference between groups Ia and Ib for either parameter at any time interval. Significant difference was found between group Ia+b (septic neonates) and group II for PCT and CRP at 24 and 48 h, but not for IL-8. There was no difference between group Ia+b and group III except for CRP at 24 h. Diagnostic accuracy was best for PCT on admission and for CRP at 24 h. Serum PCT and IL-8 are not specific markers for early severe bacterial infection in critically ill neonates and are not better than CRP. PMID- 28008488 TI - lnterleukin-6 (IL-6) and soluble receptors for interleukin-2 (slL-2R) in the diagnosis of early severe infection in the critically ill newborns. AB - The aim of our study was to evaluate the diagnostic accuracy of serial determination of interleukin-6 (IL-6) and soluble receptors of interleukin-2 (sIL 2R) in the diagnosis of early infection in the critically ill newborns and compare it with the routinely used C-reactive protein (CRP). Fourty-six critically ill newborns (median age 8 h, range 1-96 h), treated at the multidisciplinary intensive care unit, Division for Paediatric Surgery and Intensive Care, University Medical Centre Ljubljana, were included in the study. Newborns were divided into three groups: group I microbiologically confirmed severe infection (n = 14), group II suspected but not confirmed infection (n = 12) and group III respiratory distress syndrome without laboratory signs of infection. Serum concentrations of IL-6, sIL-2R and CRP were determined on admission and at 12 and 24 h after admission. On admission the concentrations of IL-6 and sIL-2R were significantly higher in group I than in group III, but there was no difference between groups I and II. On admission area under receiver operating characteristic (ROC) curve for IL-6 was 0.756, for IL-2R 0.821 and for CRP 0.799. Repeated determination at 12 h improved diagnostic accuracy for sIL-R and CRP but not for IL-6. PMID- 28008489 TI - Murine monoclonal antibodies directed against human recombinant Macrophage Migration Inhibitory Factor. AB - Macrophage Migration Inhibitory Factor (MIF) is a crucial component of the immune system acting together with glucocorticosteroids to regulate immunity and inflammation. Understanding of its many putative functions and action mechanisms is still ambiguous. Due to the newest findings that a local MIF expression is up regulated in allograft rejection and in glomerulonephritis, an interest in MIF research is increasing and is focused on possibilities of anti-MIF treatment.In the present work new murine monoclonal antibodies (MAbs) directed against human recombinant MIF (hrMIF) are described. hrMIF protein used for the immunisation was tested for its biological activity and has evident macrophage migration inhibitory activity. The selected MAbs were purified and further characterised. They recognised MIF in a Western blot experiment after a native IEF. Anti-MIF MAb designated as Ml inhibited MIF activity in the test, which was performed in the 48 well Boyden chamber system. It is presumed that Ml MAb could be used as a potential therapeutic agent. PMID- 28008490 TI - Effects of molgramostim, filgrastim and lenograstim in the treatment of myelokathexis. AB - Myelokathexis is a very rare form of chronic hereditary neutropenia resulting from impaired neutrophil releasing mechanism in the bone marrow. The recombinant human granulocyte-macrophage (molgramostim) and granulocyte (filgrastim, lenograstim) colony stimulating factors release the mature granulocytes from the bone marrow. We describe a 43-year-old woman suffering from myelokathexis, with the absolute neutrophil count ranging between 0.03 and 1.35 * 109/L. In the period before the introduction of cytokines, the patient had more than 80 major infectious episodes. Since 1991, infections in this patient have been treated with cytokines, given in conjunction with antibiotics. Initially, she received molgramostim in a daily dose of 5 MUg/kg subcutaneously, which stimulated the release of granulocytes from her bone marrow, thereby allowing successful treatment of infection. After the development of hypersensitivity, molgramostim was substituted with filgrastim. Finally, lenograstim was given a trial. With all three cytokines, the patient's neutrophil count always attained normal values already 4 hours after subcutaneous application of the drug in a dose of 5 MUg/kg, the highest neutrophil levels were measured at 24 hours post-injection, and the neutrophil count was again close to the baseline value 72 hours after the treatment. A slight neutropenia was present 48 hours after the application of filgrastim. We believe that all three cytokines are equally effective in increasing the neutrophil count in venous blood of patients with myelokathexis. PMID- 28008491 TI - Expression of human lymphotoxin alpha in Aspergillus niger. AB - A gene-fusion expression strategy was applied for heterologous expression of human lymphotoxin alpha (LTalpha) in the Aspergillus niger AB1.13 protease deficient strain. The LTalpha gene was fused with the A. niger glucoamylase GII form as a carrier-gene, behind its transcription control and secretion signals. Special attention was paid to the influence of different codon usage on secretion of protein. In the case of human tumor necrosis factor alpha (TNFalpha) a dramatic change of secretion has been observed when human cDNA sequence was used instead of synthetic E. coli biased codons. In the case of LTalpha such a change of codon usage brought improvement at the RNA level, however, no increase in the quantity of secreted protein was observed, due to the proteolitic activity of the host organism. The estimated yield of secretion of LTalpha from A. niger into the soya medium was 50 pg l-1 of culture. PMID- 28008492 TI - Immune response in chronic periapical parodonititis. AB - The purpose of our study was to investigate the immune response in chronical periapical parodontitis (CPP) by using multidisciplinary approach. 30 CPP samples were obtained after surgical removal - apicoectomy. Each CPP sample was examined by histological, bacteriological and flow cytometrical (FC) analysis of lymphocytes infiltrating CPP samples. Ten percent of bacteriological samples were sterile, others had significant aerobic and anaerobic growth. We used patohistologic and microbiologic findings and compare them to the results of imunological analysis. By FC we found a significant increase in proportions of T lymphocytes expressing interleukin-2 receptors and ICAM-1 compared to peripheral blood lymphocytes. Proportions of T helper cells that produce interferon-gama (IFN-gamma) was higher in CPP samples predominantly colonized by anaerobic bacteria. There were no differences in IL-4 expression by T cells in both groups (anaerobic and streptoccoccal). Among anaerobic CPP samples differences in proportion of T cells that express IL-2 receptors expression was also found between samples colonised by P. acnes and Bacteroides sp. Oral streptococci cause relatively limited tissue destruction and induce Th2 type of immune response accompanied by non-cytotoxic inflammatory reaction. On the contrary, anaerobic bacteria induce Th1 type of immune response that cause more severe inflammatory reaction (type 4 of hypersensitivity that damage the tissue by the action of cytotoxic T cell activation. PMID- 28008493 TI - Diminished Th1-type cytokine production in gastric mucosa T lymphocytes after H. pylori eradication in duodenal ulcer patients. AB - Helicobacter pylori infects an estimated 50% of the world population, however only a small proportion of individuals develop clinical symptoms of gastritis, peptic ulceration or gastric cancer. The variations in disease presentation may be due to differences in bacterial virulence and/or immune response to the pathogen. In the previous study we reported an increased expression of the IL-2 receptor in duodenal ulcer (DU) patients infected with H. pylori. This study examined intracellular lymphokine production in gastric mucosa infiltrating T lymphocytes in DU patients before and after H. pylori eradication. T lymphocytes were isolated from gastric mucosa biopsies by using mechanical and enzymatic tissue desegregation. Ficoll-purified lymphocytes were incubated with monoclonal antibodies and analysed by using 3-colour flow cytometry analysis for intracellular interferon gamma (IFNgamma) and interleukin 4 (IL-4) expression in order to define Th1 and Th2 cell population. We demonstrated a significant decrease in the proportion of Th1 cells infiltrating gastric mucosa 6 and 12 months after H. pylori eradication. Our results suggest the importance of the local immune response in the development of H. pylori related gastritis. PMID- 28008494 TI - A mouse model of chronic bacterial lesions (a cotton trap) for studying oral bacteria - lymphocyte interactions. AB - We established a mouse model of chronic bacterial infection (cotton trap) to get a deeper insight into interactions between immune cells and bacterial strains, that are most commonly isolated from periapical processes. We have used flow cytometry to identify the presence of intracellular cytokines of activated T cells collected from cotton traps, previously infected with different strains of bacteria and implanted subcutaneously into the back of the mice. We provide an evidence that anaerobic bacteria (Bacteroides sp.) and nocardiae are more effective in inducing cytotoxic immunity and Th1 response compared to oral streptococci. Differences in immune response against anaerobic bacteria when compared to streptococci are probably dependent on some non-specific immune cell stimulation (e.g. by bacterial cell wall components), nevertheless the role of specific antigen-dependent immune mechanism can not be excluded. PMID- 28008495 TI - Changes in Th1/Th2 cytokine balance in Graves' desease. AB - Graves' disease (GD) is characterised by hyperthyroidism, caused by stimulatory thyrotropin receptor (TSHR) antibodies. Recent research shows that an important factor in the pathogenesis of autoimmune diseases is the change in the balance between Th1 cytokines, which promote cell mediated immunity, and Th2 cytokines, which promote humoral immunity. There are contradictory data about this balance shift in GD. Our objective was to determine the Th1/Th2 cytokine balance shift in patients with newly diagnosed GD, when compared to the same balance in healthy controls. We isolated mononuclear cells (MNC) from the peripheral blood of healthy donors and from patients with newly diagnosed GD before treatment. The MNC were activated with ionomycin in combination with phorbol 12-myristate 13 acetate (PMA). After 40-hour incubation, the concentrations of the cytokines produced (IFN-gamma, IL-4, IL-10, IL-12) in the culture supernatants were measured by ELISA (Endogen, USA). The MNC cultures from patients with GD produced significantly less IL-12 and significantly more IL-10 and IL-4 than MNC cultures from healthy controls. All calculated ratios of Th1 against Th2 cytokines in MNC cultures from patients with GD were significantly lower than in MNC cultures from healthy controls. Our results show a systemic shift of cytokine production in patients with GD toward the Th2 cytokine response, thus confirming the key role of TSHR antibodies and humoral immunity in the pathogenesis of GD. PMID- 28008496 TI - Cytokine-regulated secretion of nerve growth factor from cultured rat neonatal astrocytes. AB - Interactions involved in the regulation of nerve growth factor (NGF) release by inflammatory cytokines: interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) were examined in rat neonatal cortical astrocytes in primary culture. Abstract Exposure of cultured astrocytes to IL-1beta, IL-6, and TGF-beta1 resulted in the stimulation of NGF secretion. Treatment of cells for 24 h with IL 1beta (10 U/ml), IL-6 (5 ng/ml) and TGF-beta1 (5 ng/ml) caused 3-, 1.8-, and 2.8 fold increase in NGF secretion as compared to the control cells. In contrast, TNF alpha (30 ng/ml) by itself had no stimulatory action on NGF release whereas co stimulation of astrocytes with IL-1beta and TNF-alpha showed a synergistic interaction. Co-treatment of astrocytes with IL-1beta and TGF-beta1 increased NGF secretion in an additive way, whereas simultaneous application of IL-1beta and IL 6 resulted in the inhibitory effect on NGF secretion. Our results suggest that interactions between cytokines used cause the stimulation of NGF secretion through different regulatory mechanisms. PMID- 28008497 TI - The effects of histamine and interleukin-6 on NGF release from cortical astrocytes in primary culture. AB - The influence of neurotransmitter histamine and cytokine interleukin-6 (IL-6) on nerve growth factor (NGF) release was studied in rat neonatal cortical astrocytes in primary culture. Exposure of astrocytes to either histamine or IL-6 resulted in the stimulation of NGF release. Maximal stimulation of NGF release was obtained using histamine at concentration 100 nM after 24 h of treatment (2.3 fold increase over the basal secretion from the control cells). IL-6 (30 ng/ml) induced NGF secretion was 1.66 fold over the basal level. Time course of NGF release, after histamine or IL-6 treatment, showed elevation of NGF level in the culture medium after 8 h or 24 h, respectively. IL-6 antibody effectively blocked the IL-6 stimulatory effect on NGF release, but did not influence NGF release, evoked by histamine. IL-6 antibody alone did not show any influence on NGF release. Our results suggest that IL-6 and histamine stimulate release of NGF by two different and independent molecular pathways. PMID- 28008498 TI - Effects of ammodytin L on miniature and endplate potentials in neuromuscular junction of frog m. cutaneus pectoris. AB - Neurotoxic effects of ammodytin L (AtnL), a potent phospholipase A2 homologue, was studied in frog neuromuscular preparation m. cutaneus pectoris by measuring the influence of the toxin on the amplitude and the frequency of miniature and endplate potentials (MEPPs, EPPs). AtnL, in 100 nM concentration, significantly increases spontaneous quantal acetylcholine release from the motor nerve endings, observed as the increase in MEPPs frequency. At 100 nM or higher concentration the toxin decreases EPPs amplitude and the membrane potential (MP) simultaneously. No significant effect of AtnL on EPPs was observed at any concentration bellow 100 nM. Our results indicate that in frog AtnL shows the typical myotoxic effects, but it also exerts presynaptic effects. PMID- 28008499 TI - Subchronic liver injuries caused by microcystins. AB - The subchronic effects of cyanobacterial lyophilizate (CL) containing microcystins on liver were investigated in female New Zealand rabbits. Sterilised CL containing microcystins was injected i.p. Liver toxicity was assessed by histological examination of liver samples. Non-invasive magnetic resonance imaging (MRI) of liver was also performed in order to assess changes in the homogeneity of liver tissue. Subchronical intoxication with microcystins caused morphological changes of liver tissue that were also detected by use of MRI. Histological analysis showed that changes seen on MRI represent liver injury characterised with fatty infiltration and periportal fibrosis. This demonstrates that subchronic exposure to microcystins can lead to liver degeneration, which can easily be detected in vivo by use of MRI. PMID- 28008500 TI - The influence of quantal content on the time course of the endplate current in frogs. AB - The aim of this study was to find out whether control and facilitated endplate current (EPC) of a curarized frog nerve-muscle preparation stimulated with paired impulses decay at the same time constant. The experiments revealed that the decay of the greater second EPC was slower in nearly half of the cases. This half of the results suggests that a larger quantity of the released transmitter and, consequently, a higher density of open channels promote a cooperative effect among them. The end effect can be a longer mean lifetime of open acetylcholine channels. In the other half of the experiments, the mean lifetime of open channels seems to be independent of the agonist concentration. PMID- 28008501 TI - Sensitivity of peripheral nerve fibres to sodium pentobarbital anaesthesia in rat. AB - The sensitivity of different classes of peripheral nerve fibres to anaesthesia with sodium pentobarbital in rat was tested. The basic approach was to examine changes in compound action potential (CAP) in a rat sural nerve induced by sodium pentobarbital. Rats were either sacrificed by cervical dislocation (control) or anaesthetized with sodium pentobarbital (100 mg/kg, i.p.), and a 30 mm long sural nerve segment excised and placed on electrodes in a thermostatically controlled recording chamber. CAPs were evoked by electrically stimulating the sural nerve segment with supra-threshold stimuli. CAP in control sural nerves consisted of the early component (A axons: 32.73 +/- 2.91 m/s) and the late component (C axons: 0.92 +/- 0.05 m/s) with peak voltage amplitudes 4.9 +/- 1.0 mV and 0.1 +/- 0.03 mV, respectively. Anaesthesia with sodium pentobarbital had no effect on CAP latency. However, the amplitude of CAP of both A and C axons was reduced by approximately 40 % and 50 %, respectively. The depressant effect of pentobarbital on CAPs was statistically significant for both groups of axons (p<0.01). Non selective sensitivity of A and C axons to pentobarbital suggests even distribution of receptors for GABA in these two populations of axons in the rat peripheral nerve. PMID- 28008502 TI - Phosphate metabolism in red blood cells of critically ill neonates. AB - Very few data exist on phosphate metabolism in critically ill neonates. Therefore we studied the incidence of hypophosphataemia, the intracellular metabolism of phosphate by measuring adenosine 5'-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) in red blood cells, and excretion of phosphate in urine. The aims of the study were early detection of changes in phosphate metabolism as possible diagnostic markers of sepsis and defining the cause of hypophosphataemia.Neonates, treated in multidisciplinary paediatric intensive care unit (PICU), included in the study, were less than three days of age. Eighteen of them had respiratory distress syndrome (RDS) and 16 had microbiologically confirmed or clinical sepsis. The overall incidence of hypophosphataemia in critically ill neonates was over 80%, and was more common (88%) and more profound in those with sepsis than in those with RDS (79%). Therefore the septic neonates needed significantly larger amounts of phosphate to maintain normophosphataemia. In septic neonates ATP concentration in red blood cells was significantly lower than in neonates with RDS and controls, while the 2,3-DPG concentration was increased as a result of compensation. In septic neonates urinary losses of inorganic phosphate (Pi) were significantly higher than in neonates with RDS. Hypophosphataemia in critically ill neonates is at least partly due to higher urinary losses of phosphate. PMID- 28008503 TI - Effect of mechanical load on acetylcholinesterase mRNA levels in the slow soleus muscle of the rat. AB - The influence of mechanical load on the levels of acetylcholinesterase (AChE) mRNA was studied in order to examine to which extent different loading conditions may be responsible for differences in AChE regulation between the soleus, which is an antigravity muscle, and the fast EDL muscle. Forty-eight female rats were randomly assigned to three groups: a group with hindlimb suspension producing soleus muscle unloading, a group with ablation of synergistic gastrocnemius muscle causing overload of the soleus muscle, and the control group. The soleus muscles were isolated after 8 days of treatment. AChE mRNA levels were analyzed by Northern blots and evaluated densitometrically. The values were normalized with beta-actin mRNA level, and then a value of 100% was assigned to the mRNA level in the control EDL muscle. Muscle unloading did not produce a significant increase of the AChE transcript levels, but the levels were rather variable. However, a statistically significant increase of AChE mRNA levels was observed in overloaded soleus muscles. These results corroborate the hypothesis that the slow and fast patterns of activity appear more important then muscle loading for the differences in regulation of AChE mRNA levels in fast and slow muscles. PMID- 28008504 TI - Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure. AB - The pentametric assembly of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The receptor from mammalian muscle, with its circular order of homologous subunits (alphagammaalphadeltabeta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaE falling in between. The waglerins show a 2,000-fold preference for alphaE over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaE. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of receptor structure. PMID- 28008505 TI - Cholinesterase: substrate inhibition and substrate activation. AB - The relationship between activities and substrate concentrations (pS-curves) was analysed for reactions of acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase (EC 3.1.1.8). Catalytic constants Km, Kss, Vm, n and b were calculated from the Michaelis, Haldane, Hill and Webb equations in order to assess whether a given substrate also acts as an inhibitor or activator. It is suggested that the term substrate inhibition should only be attributed to substrates revealing bell-shaped pS-curves, while the terms apparent substrate inhibition or apparent substrate activation should relate to calculated values of the catalytic constants. PMID- 28008506 TI - Role of alpha-adrenoceptors in the cutaneous postocclusive reactive hyperaemia. AB - Laser-Doppler (LD) flow measurements reveal typical flow oscillations in the descending part of the cutaneous postocclusive reactive hyperaemia (PRH). The origin of these oscillations is still poorly understood. We tested the hypothesis that the high frequency (HF) components within the frequency band 0.06-0.2 Hz are due to the local myogenic mechanism, whereas the low frequency (LF) components within frequency band 0.01-0.05 Hz reflect sympathetic vasomotor activity. LD flow was monitored on fingertips of 11 healthy volunteers before and after an 8 minute occlusion of digital arteries. We studied the effect of intradermal microinjection (1 MUl) of alpha-antagonists (prazosine, yohimbine) and alpha agonists (phenilephrine, clonidine) on PRH oscillations. We analysed the magnitude of peak flow and its duration and performed spectral power analysis to obtain fundamental HF and LF frequencies (defined as components with the highest amplitude in the part of the respective frequency band). The results (mean +/- SE) for each substance were compared to the control values obtained after microinjection (1 MUl) of 0.9% NaCl. The fundamental HF significantly decreased from 0.11 +/- 0.008 Hz after an injection of saline solution to 0.08 +/- 0.006 Hz after an application of antagonists (p<0.05). The local application of alpha antagonists did not abolished HF oscillations what suggests that activity of local sympathetic nervous system is not essential in generation of these oscillations. However, the significant decrease of fundamental frequency in HF band after application of alpha-antagonists supports the hypothesis of their local origin and could be explained by the effect on pacemaker myogenic mechanism. PMID- 28008507 TI - Spatial resolution of epicardial pace mapping using body surface potentials. AB - Body surface potential maps (BSPMs) recorded during pace mapping provide an important non-invasive means for identifying local cardiac events; recent clinical studies demonstrated that endocardial pacing sites can be resolved within less than 10 mm. We sought to determine whether similar spatial resolution could be achieved during epicardial pacing. Four patients who were undergoing either heart valve replacement (one), aortocoronary bypass graft (one), or both (two) were studied. In each patient, a pair of epicardial electrodes was placed intraoperatively at the middle aspect of the right ventricular free wall. The distance between the neighbouring electrodes was 10 mm. Five days after the surgery, ECGs were acquired from 35 leads during pacing from each epicardial electrode. We determined the distributions of QRS integrals (the net area under the ECG signal) and compared integrals corresponding to pacing from each of the adjacent electrodes using statistical indices. Student's t-test was applied to these indices and in all the patients revealed that differences in distributions of QRS integral maps were statistically significant (p < 0.01). Results of our study indicate that the non-invasive acquisition of body surface ECGs could resolve epicardial breakthrough sites within 10 mm, which may be useful in facilitating therapeutic ablations in patients with ventricular tachycardias. PMID- 28008508 TI - Improvement of early functional atherosclerotic changes in males with hypercholesterolemia after vitamin E supplementation. AB - Vitamin E as an antioxidant vitamin reduces the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation and may have antiatherosclerotic effects. We tested the hypothesis that six months of 400 mg vitamin E supplementation favourably affects early functional changes in atherosclerotic process in subjects with hypercholesterolemia. The diameter of the brachial artery at rest, after reactive hyperemia (representing endothelium -dependent vasodilatation) and after sublingual glyceryl -trinitrate (representing endothelium - independent vasodilatation), were determined by ultrasonographic method (B mode) before and after the intervention period. After the intervention period the brachial endothelium - dependent vasodilatation increased significantly in the vitamin E group while it did not change in the placebo group. In conclusion, six months of oral vitamin E supplementation results in improvement of the endothelium - dependent vasodilatation in men with hypercholesterolemia. PMID- 28008509 TI - Protein-polyphenol interactions and in vivo digestibility of buckwheat groat proteins. AB - A rat model system, based on a diet with (Nb+) or without (Nb-) the inclusion of 0.7% of a 2:1 (w/w) mixture of Bacitracin and Neomycin sulfate (Nebacitin) was used to elucidate interactions of polyphenols with proteins in buckwheat. The treatment with the antibiotic Nebacitin suppresses the microflora in the large intestine and is used to obtain an estimate of the digestion occurring in the small intestine. Experimental buckwheat samples were obtained in order to contain different levels of polyphenol and were subjected to different hydrothermal treatments. It was found that a considerable interaction between polyphenols and proteins appeared during the hydrothermal treatment, and this interaction reduces the digestion of proteins through the small and large intestine. Microbial processes in the colon enhance the digestibility of protein, blocked by polyphenols in hydrothermally processed buckwheat. PMID- 28008510 TI - Measurement of porcine heart temperatures. AB - During cardiac surgery local hypothermia of the heart is used to slow down cellular metabolism. It has been shown by computer simulation that heart muscle is not uniformly cooled to the desired temperatures. The aim of our work was to find out a way for measuring the temperatures of the ventricular wall and the septum with +/- 0.1^C accuracy. The measurement protocol should be applicable during operations on the human heart, during which disturbing factors should be minimized. We have tested the protocol and the equipment on porcine hearts. Two types of probes were tested, the contact-probe, which can be attached to the heart-wall surface, and the needle-probe, which can be inserted into the heart tissue. Before experiments the probes were calibrated and their heat transfer characteristics determined. We conclude that the probes and the protocol are suitable for studying the effects of cardioplegia, and for checking the results previously obtained by computer simulation. PMID- 28008511 TI - Biochemical and biophysical conditions for blood clot lysis. AB - We have studied how pharmacological dissolution of blood clots was affected by clot retraction, the mode of transport of fibrinolytic agents into the clot and the thickness of the composite fibrin fibers. Retracted clots were resistant to fibrinolysis in a milieu without dissolved plasminogen, because the amount of fibrin-bound plasminogen in retracted clots was insufficient for successful clot lysis. In plasma containing plasminogen, retracted clots were successfully lysed with fibrin-specific plasminogen activators, but not with non-fibrin-specific activators. Preincubation of retracted clots in plasma increased their plasminogen content as well as their sensitivity to fibrinolysis. The rate of lysis was increased up to 100-times when plasminogen activator and plasminogen were introduced into cylindrical clots by pressure-induced bulk flow in comparison with diffusion alone. The magnitude of the increase was similar in retracted and nonretracted clots, but the absolute rate of lysis was faster in non-retracted clots. The influence of fibrin fiber thickness on fibrinolysis was studied by atomic force microscopy. The time to complete lateral section of fibers did not differ between thick and thin composite fibers, and the rate of diameter reduction was faster in thick fibers than in thin ones. Taken together our results suggest that lysis of retracted clots proceeds in circular stages: (a) activation of bound plasminogen followed by partial degradation of fibrin, (b) opening of new plasminogen-binding sites on partly degraded fibrin, (c) binding of plasminogen to the new binding sites which enhances the susceptibility of clots to lysis. Lysis is accelerated by bulk flow of plasminogen activator and plasminogen into clots in comparison to diffusion alone. Fibrinolysis of thick composite fibrin fibers proceeds more efficiently than lysis of thin fibers. PMID- 28008512 TI - Possibilities for clinical use of prostacyclin in vascular disease. AB - Currently available drug therapies for patients suffering severe ischaemia with rest pain and trophic lesions of the limbs remain unsatisfactory. Also vascular reopening procedures are suitable in only about half of the patients. In atherosclerotic disease when the vascular endothelium is damaged prostacyclin synthesis is decreased and thromboxane A2 production increases. Prompted by this knowledge of the importance of prostacyclin in pathogenesis of atherosclerotic disease an attempt was made to employ PGI2 clinically - for treatment of advanced forms of peripheral arterial atherosclerotic disease. Favourable effects of the stable analogue of prostacyclin (Iloprost), were reported in various studies, which included patients with peripheral atherosclerotic arterial disease, thromboangiitis obliterans and Raynaud's phenomenon. The use of Iloprost resulted in a significantly superior response than other drugs and placebo in terms of alleviation of rest pain, ulcer healing and decrease of amputation rate of ischaemic limbs. Therefore prostacyclin provides a therapeutic option in patients with advanced forms of arterial disease - including critical ischaemia. PMID- 28008513 TI - Lacidipine decreases the honeybee venom-induced vasoconstriction of the isolated porcine coronary artery. AB - The venom of the honeybee Apis mellifera induces cardiovascular dysfunction. As its effects on coronary arteries have not yet been described, we studied the effects of the whole honeybee venom (non-volatile part) in the isolated porcine left anterior descending coronary artery (LAD) and the influence of L-type Ca2+ channel blocker, lacidipine, upon the venom effects in LAD. The venom produced concentration dependent contractions (7 - 70 MUg/ml) of the porcine LAD; maximal effect of the venom was approximately the same as the effect of 30 mM KCl. Lacidipine concentration dependently (0.1-10 MUM) and significantly (P <= 0.05) decreased the venom-induced vasoconstriction. The results indicate the involvement of L-type Ca2+ channels in coronary contraction, induced by bee venom. PMID- 28008514 TI - Effects of mibefradil and verapamil on ischemic-reperfusion in the hearts of guinea pigs with acute renal failure. AB - Two parameters indicating the ischemic-reperfusion myocardial injury, coronary flow and lactate dehydrogenase (LDH) release rate, were evaluated in guinea pigs with gentamicine-induced acute renal failure (ARF) and compared with those of healthy animals. Isolated Langendorff's hearts were exposed to 50 min of zero flow global ischemia and 60 min of reperfusion. The influences of calcium channel antagonists (of T- and L-type antagonist mibefradil and of L-type antagonist verapamil) in reperfusion solution were evaluated. Our results showed coronary dilatation and higher LDH release rate in ARF than in control hearts before ischemia. Recovery of coronary flow during reperfusion was better and LDH release rate lower in ARF vs. control hearts. Perfusion with mibefradil and verapamil did not additionally increase coronary flow, however 0.1 MUM mibefradil and verapamil decreased LDH release rate during reperfusion in ARF hearts in comparison to control hearts. Our results showed some protective effects of 0.1 MUM mibefradil and verapamil on LDH release rate during reperfusion, but not on coronary flow in guinea pigs hearts with ARF. PMID- 28008515 TI - Thermal conductivity of the porcine heart tissue. AB - The porcine heart was used as a model for studying the thermal changes in myocardium at cooling and re-warming during open heart surgery. A section of the heart septum was excised and tissue was cut into two similar square slices. The same shape of the tissue, cut from the surface from the upper lateral wall of the left ventricle, covered with epicardium and fat, was taken for another measurement. A thin (<0.5 mm) square thermal source of the same length of the side as the tissue samples was put between the two slices of tissue. This set was placed in the middle of two identical copper cylinders (2r=50 mm, height=55 mm) used to keep the outer side of the specimen at controlled room temperature. Thermal conductivity of the heart tissue was determined at controlled thermal power, and known difference of the temperature at the edge of the tissue and at the middle of the heater, when steady state was reached. Thermal conductivity calculated from the temperature difference and the geometry of heater and samples was 0.75 W/m.K for septal heart tissue, and 0.60 W/m.K for the lateral wall ventricle tissue with epicardium and fat. PMID- 28008516 TI - Nicardipine dose-dependently reduces the effect of equinatoxin II on coronary flow in isolated porcine heart. AB - Death after i.v. administration of equinatoxin II (EqT II) has been attributed to the circulatory failure resulting from cardiotoxic effects. The mechanism of action is unknown. The aim of the present work was to study the effects of the toxin on vascular tone in the isolated porcine coronary artery and on coronary flow in the isolated pig heart. EqT II caused concentration-dependent contractions of rings of the isolated epicardial porcine coronary artery with an EC50 value of 89+/-5 nM (n=5-6) and maximal effect of about 140% of the contraction induced by 20 nM KCl. On Langendorff's porcine heart preparation EqT II caused a dose-dependent decrease of coronary flow. At EqT II doses lower than 0.05 MUmol/100 g of heart weight there were no measurable effects of the toxin. At dose 0.5 MUmol/100 g the toxin decreased coronary flow to less than 9.8+/-2.5 % of the control value. The constrictory effect of the toxin on isolated porcine coronary arteries was diminished by the L-type calcium channel antagonist nicardipine (NC). NC in 1 MUM concentration almost completely abolished the effect of EqT II on coronary flow. Our results confirmed involvement of L-type calcium channels in the vasoconstrictory effects of EqT II on epicardial coronary arteries. PMID- 28008517 TI - Action of mibefradil and lacidipine on the isolated human anterior tibial artery. AB - In isolated human anterior tibial artery the effects of two different types of calcium channel antagonists, mibefradil (a selective T-type Ca2+ channel antagonist) and lacidipine (a 1,4 dihydropyridine Ca2+ channel antagonist, acting at L- and T-type, but binds preferentially at L-type Ca2+ channels) were compared. Both drugs reduced the contractions of isolated arteries induced by 60 mM KCl. The potency (IC50) of mibefradil was 6.5 MUM and of lacidipine 82.4 nM. The potencies of both Ca2+ channel antagonists differed significantly (p<0.001 at 0.1 and 1 MUM; p<0.01 at 10 MUM). Lacidipine was 79-times more effective than mibefradil in reducing the vasoconstriction in isolated human anterior tibial artery. One of the reasons for higher potency of lacidipine could be a higher density of L-type than of T-type Ca2+ channels in tissue of the human anterior tibial artery. PMID- 28008519 TI - The importance of hemolysis in the lethal effects of equnatoxin II, a protein from the sea anemone Actinia equina (L.). AB - Equinatoxin II (EqT II) is one of the three isotoxins isolated from the sea anemone Actinia equina (L.). The cause of death due to i.v. application of Eq T II was attributed to its hemolytic activity and hiperkaliemia, and the direct cardio-respiratory effects of the toxin. The toxin also binds to plasma lipids and forms toxic conglomerates with them. In our study we tried to evaluate the importance of interaction of the toxin with blood components in the toxin lethality. Anaesthetized male Wistar rats were used. The respiratory activity, ECG and animal serum ionic composition were monitored. To simulate isolated effects of the toxin hemolytic activity, hemolysed erythrocytes, KCl and mixture of rat serum with the toxin were injected i.v.. It was shown that neither the lysed erythrocytes nor the mixture of rat serum with the toxin were lethal for the experimental animals. Even KCl, in concentrations detected in serum of rats killed by the toxin, did not cause the death of experimental animals. Our results indicate that either a combination of the tested effects of the toxin on blood components or more probably the direct effects of the toxin on vital organs are responsible for the toxin lethality. PMID- 28008518 TI - Comparison of effects of nitrendipine, lacidipine and mibefradil on postischaemic myocardial damage in isolated rat hearts. AB - During ischaemia and reperfusion increased cytosolic Ca2+ is one of the important causes for ischaemic-reperfusion myocardial injury. In the present study we compared effects of preferentially L-type Ca2+ antagonists nitrendipine (NT) and lacidipine (LP), and of mibefradil (MB) a Ca2+ antagonist with higher affinity to T- than to L-type channels on myocardial function during reperfusion. Coronary flow (CF), heart rate (HR), left ventricular pressure (LVP), lactate dehydrogenase (LDH) release rate and ECG were registered during 40 min of reperfusion following 30 min of global zero flow ischaemia in Langendorff's isolated rat hearts. Either NT (100 nmol/L) or LP (10 nmol/L) or MB (100 nmol/L) was added to Krebs-Henseleit solution 10 min before ischaemia till the end of experiments. All three drugs influenced CF, HR and LVP. All of them decreased LDH release rate (P < 0.05, in MUkat/g.min) when compared with control hearts (53.2 +/- 5.1): MB (19.4 +/- 4.3) > LP (30.7 +/- 6.6) > NT (43.3 +/- 2.8). NT reduced the duration of continuous arrhythmias at the beginning of reperfusion (to 59.1 +/- 6.1 % of ischaemic controls) as well as the number of single arrhythmic events arising during the whole period of reperfusion (to 26.1 +/- 6.0 % of ischaemic controls). MB diminished only single arrhythmic events during reperfusion to 39.1 +/- 17.3 % of ischaemic controls. LP did not affect the onset of arrhythmias. Results of our experiments indicate a relatively greater importance of T-type than of L-type Ca2+ channels in the arising of postischaemic myocardial damage. PMID- 28008520 TI - Assessment of kainate toxicity using contrast enhanced magnetic resonance imaging. AB - The purpose of this study was to test the capability of contrast enhanced magnetic resonance imaging (MRI) in assessing lesion formation in rat brain after systemic (i.v.) administration of kainate. MRI was performed with T1 -weighted spin echo sequence before and after the administration of kainate and contrast media. Contrast media used were based on paramagnetic gadolinium (III) ion: Gd DTPA (gadoliniumdiethylene-triaminepentaacetic acid) and prototype agents for blood-pool enhancement Gadomer-17 and polylysine-Gd-DTPA. Enhancement of lesion rims and other brain tissue abnormalities due to kainate with Gd-DTPA, Gadomer-17 and polylysine-Gd-DTPA were observed mainly in the region of hippocampus and in the areas not protected by the blood-brain-barrier (BBB). PMID- 28008521 TI - alpha-Melanocyte stimulating hormone densensitizes the responsiveness of carbon fibres within seconds. AB - We monitored electrooxidation of noradrenaline and alpha-melanocyte stimulating hormone (alpha-MSH) at a carbon-fibre microelectrode (CFME). The solution of noradrenaline (1 mM) or alpha-MSH (1 mM) was applied by a pressure pulse (2 s) from a micropipette to a voltage-clamped (850 mV) CFME immersed into bathing solution of an inverted microscope chamber. The distance between the CFME and micropipette was 2 to 12 MUm. The maximal currents recorded for these two agents were 8.0 +/- 0.5 pA (N = 9) and 3.0 +/- 1.1 pA (N = 9), respectively. Pressure application of control solution did not affect the measured current. The noradrenaline-evoked anodic current was characterized by a monotonic increase that attained the maximum at the end of the pressure pulse. In contrast, the time course of the alpha-MSH-evoked current was biphasic. The maximum amplitude of this current was attained in 0.59 +/- 0.15 s (N = 9) and then it declined with a time constant of 7.5 +/- 4.0 s (N = 9) until the pressure pulse was terminated. We explain this phenomenon to be due to an interaction between the peptide oxidation products and the CFME which results in its desensitization. PMID- 28008522 TI - Selective recording of neuroelectric activity from the peripheral nerve. AB - Electroneurograms (ENGs) from superficial regions of the sciatic nerve of a dog, innervating the tibialis anterior (TA) and gastrocnemius muscles (GM), arising mainly from muscle spindles and Golgi tendon organs were recorded selectively with an implanted 33-electrode spiral cuff (cuff). Relative positions of superficial regions within the cuff were defined by delivering stimulating pulses on groups of three electrodes (GTEs) within the cuff which were in contact with them. It was found that GTEs eliciting maximum contractions of muscles were GTE No. 3 for the TA muscle and GTE No. 8 for the GM muscle. In the first experiment the implanted leg was mounted into a special electronic brace. Extending forces were applied to the ankle rotating it by up to +/-37 degrees according to the neutral position, thus eliciting torques in the TA muscle of up to 1.2Nm. Channel 1 of the 4-channel preamplifier was connected to GTE No. 8, channel 2 to GTE No. 2, channel 3 to GTE No. 11 and channel 4 to GTE No. 5. Results show that only ENG recorded with GTE No. 8, being close to the region innervating the TA muscle, correspond to the mechanical load. In the second experiment the calcanean tendon (CT) of an implanted leg was dissected. The proximal end of the CT was connected to a force transducer and repetitive pull forces (about 12N) were applied to the CT. Channel 1 of the preamplifier was connected to GTE No. 5, channel 2 to GTE No. 1, channel 3 to the GTE No. 11 and channel 4 to GTE No. 8. Results show that only ENG recorded with GTE No. 5, being close to the region innervating the GM muscle, correspond to the mechanical load applied on CT. PMID- 28008523 TI - Seizure-induced changes in energy metabolites and effects of N-tert-butyl-alpha phenylnitrone (PNB) and vitamin E in rats. AB - Impaired energy metabolism may play a critical role in the neuronal injury caused by kainic acid (KA) induced status epilepticus (SE). Following an acute dose of KA (15 mg/kg, sc) rats developed SE within 1 h. Rats were sacrificed 1 or 72 h after the onset of SE using a head focused microwave technique and the brain regions (pyriform cortex, amygdala, and hippocampus) were assayed for energy metabolites: ATP, ADP, AMP, phosphocreatine (PCr) and creatine (Cr) using reversed-phase HPLC (RP-HPLC). Control values were significantly higher in cortex (23-32%) than in other brain regions. Within 1 h, SE caused a marked decline in ATP (44-56%), PCr (49-64%), total adenine nucleotides (TAN, 45-50%) and total creatine compounds (TCC, 32-51%). Within three days, the hippocampus showed the greatest recovery, as the reduced values returned to normal. Pretreatment of rats with an antioxidant (PBN, 200 mg/kg, ip, 30 min prior to KA; or vitamin E (Vit E), 100 mg/kg, ip/day for 3 days), which did not prevent seizure activity, attenuated depletion of high-energy phosphates caused by KA. These findings suggest that the depletion of energy metabolites caused by KA-induced seizures may be linked to oxidative stress mediated toxicity. PMID- 28008524 TI - Neurotransplantation-induced plasticity in the recipient CNS: focusing on the recipient response. AB - In the last two decades, neurotransplantation has gained the status of a potentially valuable treatment option in various central nervous system (CNS) disorders. This technique has provided considerable functional improvement in animal models of neurodegenerative diseases, stroke and trauma. In order to make the best therapeutic use of this treatment option, mechanisms of neurotransplantation-induced recovery need to be better understood.Specific interactions of transplants with the recipient brain, which are prominent in embryonic neural cell grafts, include formation of synapses between grafted neurons and recipient neuronal population with controled release of neurotransmitters. Production and release of specific trophic substances for the recipient neurons by the grafted cells also play a considerable role in some transplants. In the above cases, the functional recovery seems to correlate well with the number of surviving cells in the transplant.There is, however, another component to the graft-induced recovery, best revealed in those graft recipients who display functional improvement although only few or no grafted cells can be found at the post mortem analysis. While psychological factors (placebo effect) have been proposed to play a central role in human graft recipients with functional recovery in the absence of surviving grafts, animal models of neurodegenerative disease have consistently shown the same phenomenon.Our recent results point to the local inflammatory and immune response to transplantation as a key element which induces a trophic response in the CNS parenchyma and stimulates plastic changes of the recipient neural connections. Findings by other investigators, who studied the connections between the inflammatory and neurotrophic responses in vitro 1 and in vivo 2, and glial reaction to CNS trauma and trophic factor synthesis in vivo 3, support such conclusions.Accumulated evidence point to the need for further studies that would elucidate the role of the immune response in connection with CNS transplantation outcome. PMID- 28008525 TI - Biochemical aspects of Salter's osteotomy for treatment of acetabular dysplasia. AB - The center-edge (CE) angle was measured on serial antero-posterior radiographs of 44 hips treated by Salter's innominate osteotomy for developmental dysplasia of the hip. Radiographic examination according to Severin was performed and the peak hip joint pressure was calculated using geometrical parameters determined from radiographs at the most recent follow-up examination, 7 to 13 years postoperatively.At the latest follow-up assessment, there was a positive correlation between the postoperative CE angle and radiographic results. Negative correlation was found between the postoperative CE angle and peak hip joint pressure at the latest follow up.In conclusion, Salter's osteotomy performed to treat developmental dysplasia of the hip should involve radical acetabular correction resulting in maximum increase of the CE angle. PMID- 28008526 TI - The development of the method for the determination of terbinafine in cat's plasma and hair. AB - Clinical investigations of terbinafine indicate its high treatment activity against infections by several dermatophytes. Its efficiency was tested also in the treatment of microsporosis in cats. The distribution of terbinafine in cat's plasma and hair is important for the identification of the drug efficiency. A fast and reliable reversed-phase high performance liquid chromatographic method with appropriate sample preparation has been developed.Reliability, good reproducibility and low detection limit (LOD 0.25 ng/ml) of the method enable determination of terbinafine in hair and also in plasma of cats infected with Microsporum canis treated by Lamisil(r) tablets. PMID- 28008527 TI - Serum T3 and T4 concentrations in the adult rats treated with herbicide 2,4 dichlorophenoxyacetic acid. AB - The influence of sublethal doses of 2,4-dichlorophenoxyacetic acid (2,4-D) on serum T3 and T4 concentrations in Hsd Cpb: Wistar rats of both sexes was studied. The trial was performed on 24 males and females respectively, each divided into three groups of 8 animals (control, groups 1 and 2). Aqueous solution of the compound (11 mg/kg body weight - group 1 and 110 mg/kg body weight - group 2) or clean tap water (control group) was used. Aliquots of 2.4 ml/kg body weight were administered with a stomach tube from the 1st to 10th day of the experiment. Three days before the first treatment and on the 6th and 13th day of the experiment the serum T3 and T4 concentrations were determined by commercial radioimmunoassay kits (Byk-Sangtec Diagnostica), validated for rats. A significant decrease of serum T4 (P < 0.01) and T3 (P < 0.001) was determined in males of groups 1 and 2 during the experiment. On the 6th day of experiment serum T4 and T3 values were significantly lower (P < 0.001 and 0.01 respectively) in group 2 than in the controls and group 1 of both males and females. During the whole experiment serum T4 levels were lower in females than in males (P < 0.05). PMID- 28008528 TI - In vivo effects of head-to-tail 3-alkylpiridinium polymers isolated from the marine sponge Raniera sarai. AB - Water soluble polymeric 3-alkylpyridinium salts (poly APS; MW 18900 and 5520 Da) were isolated from the marine sponge Raniera sarai. In vitro it strongly inhibited acetyl cholinesterase (AChE) from different species (electric eel, horse serum, human erythrocytes). In our experiments the importance of anti AChE activity in the toxin lethality was evaluated. In vivo experiments were performed on male Wistar rats and ECG, blood pressure and breathing pattern were monitored. After i.v. application of lethal doses of the toxin ECG showed signs of hypo perfusion. Arterial blood pressure fell to mid-circulatory pressure, and breathing stopped after a few breaths At sublethal doses the toxin caused an increase of residual volume, prolongation of expiration, and bradycardia. Patho anatomical examination revealed that the plugs in lung circulation may cause the death of experimental animals due to cardiorespiratory failure. PMID- 28008529 TI - Different operative treatment of slipped capital femoral epiphysis: A comparative study of biomechanical status of the hip. AB - The biomechanical status of the hips subject to two different operative treatments was studied. The biomechanical status was determined by the peak stress on the weight bearing area using the 3-d mathematical model. It was found that the procedure according to Imhauser yields considerably and statistically significantly higher peak stress than the procedure according to Dunn-Fish. PMID- 28008530 TI - Peak contact stress in human hip during gait. AB - The contact stress in a human hip is not uniform and it changes with different body positions. The changing location of the peak contact stress during gait may indicate the predilection sites for further development of osteoarthritis in the hip. On the basis of laboratory measurements and by using mathematical models of forces and stresses in human hip we determined the points of the peak contact stress in successive phases of gait. Results show that the peak stress points are mostly located in the posterior-medial portion of the weight bearing area, which corresponds well to the clinical observations. It is also shown that in the pathological conditions of hip dysplasia the peak contact stress trajectory is located more laterally and anteriorly. PMID- 28008531 TI - G-Protein coupled progesterone receptors in the plasma membrane of fungus Rhizopus nigricans. AB - We have demonstrated simultaneous existence of progesterone receptors and GTPase activity in the membranes prepared from the filamentous fungus Rhizopus nigricans. The results obtained with pertussis toxin treated fungal mycelium suggest that these receptors do not couple to Gi-Go-proteins and play a role in the induction of steroid hydroxylating enzyme system by steroid substrates in the fungus. PMID- 28008532 TI - The effect of lamina propria on the growth and differentiation of urothelial cells in vitro. AB - The effect of lamina propria on the growth and differentiation of the mouse urinary bladder urothelial cells in vitro has been studied by light and electron microscopy using morphological and immunohistochemical methods. Three different types of urothelial cultures were maintained on a porous membrane in serum-free medium for 10 days. Our results showed that urothelial cells in culture types I and II were organised as the multilayer epithelium showing terminal differentiation, from the porous membrane toward the surface. On the surface of culture type I and II, superficial urothelial cells were highy differentiated. They formed tight junctions and had plaques of an asymmetric unit membrane, a hallmark of terminal differentiation in bladder superficial cells. These cultured superficial cells were also cytokeratin 20 positive. On the contrary, urothelial cells in culture type III have shown a limited capacity for survival and have grown as poorly differentiated monolayer. These results revealed that reciprocal intercellular signalling between the lamina propria and urothelial cells is essential to achieve terminal differentiation of urothelial cells in vitro. PMID- 28008533 TI - Mouse urothelial cells in early postnatal development - proliferation and apical plasma membrane specialization. AB - The purpose of this work was to investigate proliferation and differentiation of the mouse urothelial cells from the day of birth until the 5th postnatal day. The expression of proliferating cell nuclear antigen (PCNA) was studied immunocytochemically and the differentiation of apical plasma membrane of superficial cells was analysed by scanning microscopy. It was established that proliferation activity is very high during all five days since PCNA positive cells are seen in the superficial and in basal cell layer of the urothelium. Results of scanning microscopy show that the differentiation of superficial urothelial cells is a nonsynchronous process, which gradually progresses from the day of birth and leads into homogeneous population of terminally differentiated superficial cells on the 5th postnatal day. PMID- 28008534 TI - Reticulocyte analysis using light microscopy and two different flow cytometric procedures. AB - The reticulocyte count is a clinically important indirect indicator of erythropoietic activity of the bone marrow. Reticulocyte enumeration by light microscopy is rather inaccurate and has poor reproducibility. Automation of the reticulocyte count by means of flow cytometry has considerably improved the quality of this investigation.In our study, we compared three methods of establishing the blood reticulocyte number: the microscopic brilliant cresyl blue method and two flow cytometric procedures using thiazole orange (TO), namely FACSort (Becton-Dickinson) and EPICS Profile (Coulter). The aims of the study were (1) to select the most suitable TO concentration to be used with the EPICS Profile cytometer, (2) to determine the correlation between the microscopic method and the two flow cytometric procedures, and (3) to appraise the suitability of flow cytometry for reticulocyte analysis in routine clinical work.According to our results, the most appropriate TO concentration for the EPICS Profile counter is 0.1 mg/L . We observed a good correlation between the three methods tested; the correlation coefficients ranged from 0.82 to 0.87. The mean intra-assay coefficients of variation for the microscopic method and the EPICS Profile and FACSort procedures were 27.5%, 8.4% and 6.3%, respectively. PMID- 28008535 TI - The contribution of HLA-Class II antigens in humoral non-response and delayed response to HBsAg vaccination. AB - The variability in the immune response modulated by HLA alleles may be an important factor for the induction of the protective effect of HBsAg vaccines. We present here the analysis of HLA-DRB1, DQB1 and DQA1 alleles and their combinations in the group of 36 individuals with poor humoral immmune response to HBsAg vaccination. Comparison with the control group, consisted of 60 randomly choosen healthy subjects, revealed that the DRB1*1601, DQB1*0502, DQA1*0102 haplotype is overrepresented in the group of hyporesponders and may therefore be regarded as a factor influencing poor antibody responsiveness. We observed that after revaccination two of three individuals who failed to develop anti-HBs antibodies carry the same phenotype DRB1*0101,DRB1*0301;DQB1*0501, DQB1*0201;DQA1*0101,DQA1*0501, which supports the conjecture that immunogenicity of the HBsAg vaccine depends on specific combination of HLA DR and DQ molecules on antigen presenting cells. PMID- 28008536 TI - Hypomethylation of alphoid DNA and classical satellite DNA on chromosome 1, 9, 16 and Y in extraembryonic tissue. AB - The pattern of DNA methylation can be analyzed on methaphase chromosomes with fluorescein labeled antibodies against 5-methylcytosine. In human extraembryonic tissue lower overall intensity of immunofluorescence in centromeric chromosomal regions correspond to hypomethylation of the DNA when compared with normal human lymphocytes. Pericentromeric regions on chromosomes 1,9,16 and heterochromatin on chromosome Y, which reveal lower levels of immunofluorescence, are rich in classical satellite DNA type II and III. In our experiment methylation-sensitive restriction enzymes, alphoid and classical satellite DNA probes specific for chromosomes 1,9,16 and Y were used. Southern blot analysis on cells from extraembryonic tissue revealed different extent of hypomethylation in different chromosomal regions. Our results confirm overall and sequence-specific hypomethylation of DNA in cells from extraembryonic tissue in comparison with somatic cells. PMID- 28008537 TI - Effect of pH on red blood cell deformability. AB - The effect of pH on the red blood cell (RBC) deformability, which is a consequence of a change of cell membrane elastic properties is studied experimentally. With the intention to reduce the effects on deformability of cell geometry and cytoplasmic viscosity, we measured the deformability of the cells with the same volume at various pH of cell suspension from 6.2 to 8.0. Constant cell volume was achieved by varying osmolarity. Deformability was quantified by measuring the elongation of RBCs subjected to velocity gradient in a transparent cone-plate rheoscope. Observed significant decrease of deformability at lower pH leads to the conclusion that membrane elastic properties could be affected by pH changes in the range from 6.2 to 8.0. PMID- 28008538 TI - Weak D and partial D in Slovenian population through serology and genotyping. AB - Weak D red cell phenotype (formerly Du) exhibits weaker serological reaction with anti-D antibodies. Weak D occurs in 0.2% to 1% of whites and is caused by qualitatively altered RhD proteins called partial D or normal, only weakly expressed RhD proteins that are called weak D. Partial D genes are hybrid alleles between RHD an RHCE genes. 23 partial RHD alleles are described. Weak D phenotypes with reduced expression are likely to posses the normal RHD gene, but the latest findings indicate that weak D alleles carry at least one point mutation. The aim of the present work was to answer an important question how to approach partial and weak D identification in diagnostic use and if it is possible to distinguish between partial D and weak D using commercially available anti-D reagents for routine use. We also wanted to evaluate D-screen kit for partial D identification. We compared phenotypes identified by serological testing and genotypes identified by RHD Multiplex PCR and DVII specific ASPA PCR. Our results showed that it is not possible to distinguish between partial and weak D using commercially available anti-D reagents for routine use. D-screen proved to be useful for DVI and DVII identification, whereas for partial DDFR identification we must look for another set of monoclonal antibodies or simply use genotyping methods. In 44 samples with not interpretable serological results out of 80 we found all RHD specific exons present and we classified the samples as weak D. Fourteen types of weak D with at least one point mutation were recently proposed. Designing of allele specific PCRs for identification of proposed types of weak D is in progress. PMID- 28008539 TI - Determining the parameters of concentration-response relationship for histamine on the isolated portion of guinea pig stomach and guinea pig right atrium. AB - In our previous experiments measuring acid secretion in the isolated mouse stomach we found higher EC50 values (agonist concentration, evoking half maximal effect) for histamine than in the experiments on the isolated guinea pig right atrium (contraction frequency). The difference could be due to nonequilibrium conditions in the isolated mouse stomach preparation or to species differences. In order to check this possibility and to test the consistency of concentration response relationship (CRR) parameter determination on an isolated secretory organ, we compared EC50 for histamine and pA2 for famotidine on the two isolated preparations from the same species, guinea pigs.Both, EC50 and pA2 values were significantly different when measuring gastric acid secretion (9.7 MUM and 6.07) from the parameters, found in the isolated right atrium measuring frequency of contractions (1.6 MUM and 7.06).From these results it can be concluded that the isolated portion of guinea pig stomach is suitable for CRR determination; but the parameters obtained are in the range of higher concentrations than the real ones because of kinetic particularities of the preparation. PMID- 28008540 TI - The oxygen uptake threshold during incremental exercise test. AB - The linear relationship between oxygen consumption (Vo2) and exercise intensity is a well established phenomenon observed during incremental exercise. Recently, a non-linear increase in Vo2 has been reported by Zoladz et al., who used a relatively complicated method to describe the phenomenon. In this study, we tried to ascertain whether the same phenomenon, which we named the oxygen uptake threshold (OUT), could be described by a simple method, using the two best fitting lines adopted for the less and more steep parts of the Vo2 increase. Our hypothesis was that the non-linear Vo2 increase was the result of a continuous Vo2 increase (oxygen drift) occurring during the more intense steps only. Therefore, we analysed the Vo2 time course during each step. Six cyclists performed an incremental exercise test on a cyclo - ergometer. The lactate threshold (LT) was calculated by using the intersection point of the two best fitting lines in the diagram of log LA (lactate concentration) dependence on log P (Power). The time course of Vo2 during each step was analysed by an exponential rise to the maximum model. The results showed that OUT could be determined in five of the six subjects, whereas LT could be determined in all six subjects. The power output determined by OUT (168 +/- 13 W) was similar to that determined by LT (180 +/- 25 W). The Vo2 time course during each step showed steady values during low intensity exercise. At intensities above LT and OUT, however, Vo2 increased continuously, showing oxygen drift. It may be concluded that OUT is a realistic phenomenon, which is based on oxygen drift. PMID- 28008541 TI - Evaluation of biomechanical status of dysplastic human hips. AB - The evaluation of the biomechanical status of human hip joint was performed. Required parameters were assessed from standard antero-posterior rentgenographs and the value of contact stress on the weight bearing area is calculated. We analysed 45 dysplastic human hips and compared measured values to 81 healthy hips. The peak contact stress on the weight bearing area is considerably and statistically significantly higher in dysplastic hips compared to healthy hips. The Wiberg centre-edge angle is statistically significantly smaller in group of dysplastic hips compared to healthy hips. PMID- 28008542 TI - The influence of the successive depolymerization and polymerization of cytoskeleton components on the fibroblast shapes. AB - Monitoring the influence of the cytoskeleton polymers on the shape of fibroblasts, performing the experiments of repeated degradation and polymerization of microtubules and microfilaments, we found out that the presence of microtubules is necessary in order to regenerate the proper functional structure of microfilaments, and vice versa. PMID- 28008543 TI - Visual perception in domestic dogs: susceptibility to the Ebbinghaus-Titchener and Delboeuf illusions. AB - Susceptibility to geometrical visual illusions has been tested in a number of non human animal species, providing important information about how these species perceive their environment. Considering their active role in human lives, visual illusion susceptibility was tested in domestic dogs (Canis familiaris). Using a two-choice simultaneous discrimination paradigm, eight dogs were trained to indicate which of two presented circles appeared largest. These circles were then embedded in three different illusory displays; a classical display of the Ebbinghaus-Titchener illusion; an illusory contour version of the Ebbinghaus Titchener illusion; and the classical display of the Delboeuf illusion. Significant results were observed in both the classical and illusory contour versions of the Ebbinghaus-Titchener illusion, but not the Delboeuf illusion. However, this susceptibility was reversed from what is typically seen in humans and most mammals. Dogs consistently indicated that the target circle typically appearing larger in humans appeared smaller to them, and that the target circle typically appearing smaller in humans, appeared larger to them. We speculate that these results are best explained by assimilation theory rather than other visual cognitive theories explaining susceptibility to this illusion in humans. In this context, we argue that our findings appear to reflect higher-order conceptual processing in dogs that cannot be explained by accounts restricted to low-level mechanisms of early visual processing. PMID- 28008544 TI - The Where and How for Reaching Transgender Women and Men Who Have Sex with Men with HIV Prevention Services in Guatemala. AB - This study aims to describe the transgender women and men who have sex with men (MSM) missed through venue-based sampling and illustrate how data on venues can be used to prioritize service delivery. Respondent-driven sampling (RDS) and time location sampling (TLS) were used concurrently in 2010 for behavioral surveillance among MSM and transgender women in Guatemala City. RDS recruits who did not frequent venues (n = 106) were compared to TLS recruits (n = 609). TLS participants recruited at different types of venues were compared. RDS recruits who did not frequent venues were less educated, less likely to identify as gay, more likely to have concurrent partners and female sexual partners. Participants recruited at NGOs, saunas, hotels, streets and parks had more partners, were more likely to receive money for sex or have concurrent partners. Prevention programs for MSM and transgender women should characterize social venues and people that frequent them and improve service coverage through venues and social networks. PMID- 28008545 TI - A Tri-Leaflet Nitinol Mesh Scaffold for Engineering Heart Valves. AB - The epidemiology of valvular heart disease has significantly changed in the past few decades with aging as one of the main contributing factors. The available options for replacement of diseased valves are currently limited to mechanical and bioprosthetic valves, while the tissue engineered ones that are under study are currently far from clinical approval. The main problem with the tissue engineered heart valves is their progressive deterioration that leads to regurgitation and/or leaflet thickening a few months after implantation. The use of bioresorbable scaffolds is speculated to be one factor affecting these valves' failure. We have previously developed a non-degradable superelastic nitinol mesh scaffold concept that can be used for heart valve tissue engineering applications. It is hypothesized that the use of a non-degradable superelastic nitinol mesh may increase the durability of tissue engineered heart valves, avoid their shrinkage, and accordingly prevent regurgitation. The current work aims to study the effects of the design features on mechanical characteristics of this valve scaffold to attain proper function prior to in vivo implantation. PMID- 28008546 TI - Cost-effectiveness analysis of the use of daclatasvir + sofosbuvir + ribavirin (16 weeks and 12 weeks) vs sofosbuvir + ribavirin (16 weeks and 24 weeks) for the treatment of cirrhotic patients affected with hepatitis C virus genotype 3 in Italy. AB - The WHO estimates that more than 185 million people are infected with hepatitis C virus (HCV) worldwide. The aim of the study is to assess the incremental cost effectiveness ratio (ICER) of the use of daclatasvir (DCV) + sofosbuvir (SOF) + ribavirin (RBV) for 12 and 16 weeks vs SOF + RBV for 16 and 24 weeks for the treatment of genotype 3 HCV infected cirrhotic patients from the Italian National Health Service (NHS) perspective. A published cohort-based Markov model was used to perform the analysis estimating the lifetime direct medical costs associated with the management of the pathology and the quality adjusted life years gained by patients. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. SOF + RBV for 16 weeks was excluded from the analysis due to the significant lower effectiveness, compared with SOF + RBV for 24 weeks (51% vs 79%). DCV + SOF + RBV would increase QALYs and costs in all the comparisons: the ICERs obtained comparing DCV + SOF + RBV for 12 and 16 weeks with SOF + RBV for 24 weeks (reference scenario) are 38,572 ?/QALY and 16,436 ?/QALY, respectively, both below the 40,000 ?/QALY threshold identified by the Italian Health Economics Association. Sensitivity analyses confirmed the robustness of the results. The use of DCV + SOF + RBV is likely to be cost effective compared with SOF + RBV (for 24 weeks) for the treatment of cirrhotic patients infected with genotype 3 HCV considering a threshold value of 40,000 ?/QALY. PMID- 28008547 TI - Gender-specific practice styles and ambulatory health care expenditures. AB - This paper explores the role of physician gender in the expenditures for ambulatory care as a potential source of practice style variation. We exploit a large doctor-patient panel dataset based on insurance-claims data from Switzerland to estimate the effect of physician gender on health care expenditures. We find considerable heterogeneity across specialties. In primary care, female doctors are found to produce similar overall expenditures per visit as their male colleagues, but significantly smaller prescribing costs and significantly higher laboratory costs. In secondary-care specialties, we find that women generate lower overall expenditures, which is mainly driven by consultation costs. These findings provide evidence for the existence of sex specific practice styles that translate into different overall expenditures as well as different compositions of these expenditures. PMID- 28008548 TI - Culturable bacterial communities associated to Brazilian Oscarella species (Porifera: Homoscleromorpha) and their antagonistic interactions. AB - Sponges offer an excellent model to investigate invertebrate-microorganism interactions. Furthermore, bacteria associated with marine sponges represent a rich source of bioactive metabolites. The aim of this study was to characterize the bacteria inhabiting a genus of sponges, Oscarella, and their potentiality for antimicrobial production. Bacterial isolates were recovered from different Oscarella specimens, among which 337 were phylogenetically identified. The culturable community was dominated by Proteobacteria and Firmicutes, and Vibrio was the most frequently isolated genus, followed by Shewanella. When tested for antimicrobial production, bacteria of the 12 genera isolated were capable of producing antimicrobial substances. The majority of strains were involved in antagonistic interactions and inhibitory activities were also observed against bacteria of medical importance. It was more pronounced in some isolated genera (Acinetobacter, Bacillus, Photobacterium, Shewanella and Vibrio). These findings suggest that chemical antagonism could play a significant role in shaping bacterial communities within Oscarella, a genus classified as low-microbial abundance sponge. Moreover, the identified strains may contribute to the search for new sources of antimicrobial substances, an important strategy for developing therapies to treat infections caused by multidrug-resistant bacteria. This study was the first to investigate the diversity and antagonistic activity of bacteria isolated from Oscarella spp. It highlights the biotechnological potential of sponge-associated bacteria. PMID- 28008549 TI - Globisporangium oryzicola sp. nov., causing poor seedling establishment of directly seeded rice. AB - A new species, Globisporangium oryzicola, was isolated from directly seeded rice seedlings, and from soils of paddy fields and an uncultivated field. Despite their different origins, five of the seven isolates studied caused poor seedling establishment of rice in a laboratory inoculation experiment. The species is characterized by oogonia with smooth-walled or sometimes one projection, with one to two antheridia, and aplerotic oospores. Hyphal swellings were rarely observed. Phylogenetic analyses based on the internal transcribed spacer region of the ribosomal RNA gene and mitochondrial cytochrome c oxidase subunit 1 and 2 genes confirmed that the species differed from other Globisporangium species. This novel species is described and illustrated in detail. PMID- 28008550 TI - Barriers to Treatment for Female Problem Gamblers: A UK Perspective. AB - There is a paucity of research in the UK which examines problem gambling and that which does exist is mainly quantitative, focuses on male samples and fails to look at treatment seeking populations or obstacles preventing problem gamblers from seeking treatment. This paper presents findings from part of a larger qualitative study that explored the experience of treatment for female problem gamblers. Data were collected using semi-structured interviews with eight women who had received individual cognitive-behavioural therapy in the National Health Service for their gambling problem. An interpretative phenomenological analysis approach was applied in the research process, identifying three main themes, of which the subtheme 'Barriers to Treatment' is examined here. Internal and external barriers to treatment organically emerged in all female participants' accounts and appear to have an impact on service utilisation. Input directly from gamblers can be combined with findings from other studies to devise better ways of reaching female problem gamblers. A better understanding of barriers to treatment can also provide valuable direction for future research and suggest applications in clinical service provision and treatment planning. PMID- 28008552 TI - Erratum to: Airway Management During Upper GI Endoscopic Procedures: State of the Art Review. PMID- 28008551 TI - Surgical treatment of large incisional hernias with intraperitoneal composite mesh: a cohort study. AB - PURPOSE: Patients with large incisional hernias have significant morbidity and their management is a challenge for the surgical team because of the large abdominal wall involvement. The choice of surgical technique is still controversial. The purpose of this study is to analyze the predictive factors for recurrence after intraperitoneal mesh repair in patients with large incisional hernias. METHODS: A retrospective cohort observational study with a prospectively collected database was performed in the Hospital Clinico San Carlos (Madrid, Spain). All consecutive patients operated on from January 2009 to December 2014 with incisional hernia of 10 or more centimeters in its transverse diameter were included. An intraperitoneal repair with a composite mesh fixed with discontinuous absorbable suture and fibrin sealant was performed. Demographic data, comorbidities, and early and long term outcomes were analyzed. The primary outcome was the presence of recurrence. RESULTS: One hundred and twenty patients were included. Mean age was 63.3 years (SD 12.9) and sex ratio was 1.4:1. Seventy two patients (60%) were ASA III-IV. Forty-five patients (37.5%) had recurrent ventral hernias. Mean defect size was 14.7 cm (SD 3.21) of width. Overall postoperative morbidity rate was 25%. Median hospital stay was 6 days (IQR 4-8). Recurrence rate was 8.3%, after a median follow-up of 16 months (IQR 10-25). Multivariate analysis showed significant association between ASA III-IV, use of Composix KugelTM mesh, superficial surgical site infection, and the presence of recurrence. CONCLUSIONS: The recurrence rate after intraperitoneal mesh repair in patients with large incisional hernias might be associated with ASA III-IV, use of Composix KugelTM mesh, and superficial surgical site infection. PMID- 28008553 TI - A Picture Database for Verbs and Nouns with Different Action Content in Turkish. AB - In this study we present a picture database of 160 nouns and 160 verbs. All verbs and nouns are divided into two groups as action and non-action words. Age of acquisition, familiarity, imageability, name agreement and complexity norms are reported alongside frequency, word length and morpheme count for each word. Data were collected from 600 native Turkish adults in total. The results show that although several measures have weak correlations with each other, only age of acquisition had moderate downhill relationships with familiarity and frequency with familiarity and frequency having a rather strong positive correlation with each other. The norms and the picture database are available as supplemental materials for use in psycholinguistic studies in Turkish. PMID- 28008554 TI - Estimation of stature by using the dimensions of the right hand and right foot in Han Chinese adults. AB - The Han Chinese people are the main ethnic group in China and the largest ethnic group in the world. The dimensions of the hands and feet have been successfully used for the estimation of stature. A total of 26,927 healthy adult subjects, comprising 13,221 men and 13,706 women, were recruited. The survey samples were chosen through random cluster sampling. The mean values were significantly higher in men than those in women for all measurements (P<0.001). All the measurements showed a statistically significant correlation with stature (P<0.01). The combination of the right hand length and the right foot length was the best predictor of stature because it had the lowest standard error of estimate. The use of multiple regression equations yielded better results than did the use of linear regression equations. The accuracy of stature prediction ranged from +/ 4.81 to +/-6.39 cm. The present study was of great importance with regards to improving the physical anthropology database of ethnic groups in China. PMID- 28008556 TI - Associations of Affective Responses During Free-Living Physical Activity and Future Physical Activity Levels: an Ecological Momentary Assessment Study. AB - PURPOSE: Affective response during physical activity may influence motivation to perform future physical activity behavior. However, affective response during physical activity is often assessed under controlled laboratory conditions. The current study used ecological momentary assessment (EMA) to capture affective responses during free-living physical activity performed by adults, and determined whether these affective responses predict future moderate-to-vigorous physical activity (MVPA) levels after 6 and 12 months. METHOD: At baseline, electronic EMA surveys were randomly prompted across 4 days asking about current activities and affective states (e.g., happy, stressed, energetic, tired). Affective response during physical activity was operationalized as the level of positive or negative affect reported when concurrent physical activity (e.g., exercise or sports) was also reported. Data were available for 82 adults. Future levels of moderate-to-vigorous physical activity (MVPA) were measured using accelerometers, worn for seven consecutive days at 6 and 12 months after the baseline assessment. RESULTS: Feeling more energetic during physical activity was associated with performing more minutes of daily MVPA after both 6 and 12 months. Feeling less negative affect during physical activity was associated with engaging in more daily MVPA minutes after 12 months only. CONCLUSION: This study demonstrated how EMA can be used to capture affective responses during free living physical activity. Results found that feelings more energetic and less negative during physical activity were associated with more future physical activity, suggesting that positive emotional benefits may reinforce behavior. PMID- 28008555 TI - Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. AB - PURPOSE: Genetic predisposition to male breast cancer (MBC) is not well understood. The aim of this study was to better define the predisposition genes contributing to MBC and the utility of germline multi-gene panel testing (MGPT) for explaining the etiology of MBCs. METHODS: Clinical histories and molecular results were retrospectively reviewed for 715 MBC patients who underwent MGPT from March 2012 to June 2016. RESULTS: The detection rate of MGPT was 18.1% for patients tested for variants in 16 breast cancer susceptibility genes and with no prior BRCA1/2 testing. BRCA2 and CHEK2 were the most frequently mutated genes (11.0 and 4.1% of patients with no prior BRCA1/2 testing, respectively). Pathogenic variants in BRCA2 [odds ratio (OR) = 13.9; p = 1.92 * 10-16], CHEK2 (OR = 3.7; p = 6.24 * 10-24), and PALB2 (OR = 6.6, p = 0.01) were associated with significantly increased risks of MBC. The average age at diagnosis of MBC was similar for patients with (64 years) and without (62 years) pathogenic variants. CHEK2 1100delC carriers had a significantly lower average age of diagnosis (n = 7; 54 years) than all others with pathogenic variants (p = 0.03). No significant differences were observed between history of additional primary cancers (non breast) and family history of male breast cancer for patients with and without pathogenic variants. However, patients with pathogenic variants in BRCA2 were more likely to have a history of multiple primary breast cancers. CONCLUSION: These data suggest that all MBC patients regardless of age of diagnosis, history of multiple primary cancers, or family history of MBC should be offered MGPT. PMID- 28008557 TI - The effects of complex exercise on shoulder range of motion and pain for women with breast cancer-related lymphedema: a single-blind, randomized controlled trial. AB - BACKGROUND: This study was to investigate the effects of complex exercise on shoulder range of motion and pain for women with breast cancer-related lymphedema. METHODS: 69 women participated in this study and then they were randomly allocated to complex exercise group (n = 35) or the conventional decongestive therapy group (n = 34). All subjects received 8 sessions for 4 weeks. To identify the effects on shoulder range of motion and pain, goniometer and visual analog scale were used, respectively. The outcome measurements were performed before and after the 4 week intervention. RESULTS: After 4 weeks, complex exercise group had greater improvements in shoulder range of motion and pain compared with the conventional decongestive therapy group (p < 0.05). CONCLUSION: These results suggest that complex exercise is beneficial to improve shoulder range of motion as well as pain of the women with breast cancer-related lymphedema. Complex exercise would be useful to improve shoulder range of motion and pain of the women with breast cancer-related lymphedema. PMID- 28008558 TI - Erratum to: Perceived Weight Discrimination and 10-year Risk of Allostatic Load Among US Adults. PMID- 28008560 TI - What is this image? 2017: Image 5. PMID- 28008559 TI - Optimal thallium-201 dose in cadmium-zinc-telluride SPECT myocardial perfusion imaging. AB - BACKGROUND: We aimed to determine the optimal thallium 201 chloride (thallium 201) dose using a novel ultrafast cardiac gamma camera with cadmium-zinc telluride (CZT) solid-state semiconductor detectors (D-SPECT). METHODS AND RESULTS: The optimal thallium-201 dose for obtaining left ventricular (LV) myocardial counts was determined from a phantom study. Consecutive 292 patients underwent stress myocardial perfusion imaging with a thallium-201 injection. Stress test comprised exercise or pharmacological (adenosine) provocation. We calculated an optimal thallium-201 dose that resulted in better LV myocardial counts during 6 minutes of acquisition time. We corrected the respective values according to the patient's age, sex, body mass index (BMI), and type of stress test. The lowest thallium-201 dose for obtaining acceptable imaging was 1.2 million counts. Radiopharmaceutical doses showed a positive correlation with the patient's age (P < .001), sex (P = .012), BMI (P < .001), and type of stress test (P < .001). Multivariate analysis revealed that the patient's BMI and the type of stress test were statistically significant factors for determining the correct radiopharmaceutical dose (P < .001 for both). CONCLUSIONS: For clinical use of the CZT SPECT system, the optimal individual thallium-201 doses can be determined based on the patient's BMI and type of stress test. PMID- 28008561 TI - Endpoints for screening thyroid cancer in the Republic of Korea: thyroid specialists' perspectives. AB - Cancer screening is aimed primarily at reducing deaths from the specific cancer. Thyroid-specific cancer mortality may be the most ambitious endpoint for obtaining estimates of screening effect. Numerous observations have accumulated over the years, indicating that thyroid cancer mortality endpoint has been difficult to study and is confounded by population heterogeneity, provision of randomization, and requirement of large cohorts with sufficiently long follow-up due to the excellent prognosis of the cancer. Accordingly, it may be important to reconsider how to best measure thyroid cancer screening efficacy. Recommendations against thyroid cancer screening should be based upon trials designed to evaluate its effectiveness not only in significant reduction in cancer mortality, but also of other distinct endpoints. It is desirable to evaluate derivative endpoints that can reliably predict reductions in mortality. The term "derivative" means a variable that is related to the true endpoint and is likely to be observable before the primary endpoint. Derivative endpoints may include thyroid cancer incidence, the proportion of early-stage tumors detected, more treatable stage, the identification of small tumors (to maintain in observation), decrease in the number of people who develop metastatic disease, the increased chance of lesser extent surgery, and the application of minimally invasive approaches, as well as no need for lifelong thyroid replacement therapy, a consistent follow-up, low dose or no RAI administration and risk factor assessments where case findings should be continuous. The Korean guidelines for thyroid cancer national-level screening were published by a relevant group of multidisciplinary thyroid experts. It was concluded that the evidence is insufficient to balance the benefits and harms of thyroid cancer screening. However, the paper seems to raise the necessary investments in future research and demand a complete analysis for derivative endpoints, and offer screening participants with complete information necessary to make decisions that will provide them with the most value when a small thyroid cancer is screen-identified. PMID- 28008562 TI - Recognizing 2016 Manuscript Reviewers. PMID- 28008564 TI - Apneic oxygenation: Let's all just take a deep breath. PMID- 28008563 TI - Agitation After Subarachnoid Hemorrhage: A Frequent Omen of Hospital Complications Associated with Worse Outcomes. AB - BACKGROUND: Agitated delirium is frequent following acute brain injury, but data are limited in patients with subarachnoid hemorrhage (SAH). We examined incidence, risk factors, and consequences of agitation in these patients in a single-center retrospective study. METHODS: We identified all patients treated with antipsychotics or dexmedetomidine from a prospective observational cohort of patients with spontaneous SAH. Agitation was confirmed by chart review. Outcomes were assessed at 12 months using the modified Rankin Scale (mRS), Telephone Interview for Cognitive Status (TICS), and Lawton IADL (Instrumental Activities of Daily Living) scores. Independent predictors were identified using logistic regression. RESULTS: From 309 SAH patients admitted between January 2011 and December 2015, 52 (17 %) developed agitation, frequently in the first 72 h (50 %) and in patients with Hunt-Hess grades 3-4 (12 % of grades 1-2, 28 % of grades 3 4, 8 % of grade 5). There was also a significant association between agitation and a history of cocaine use or prior psychiatric diagnosis. Agitated patients were more likely to develop multiple hospital complications; and in half of these patients, complications were diagnosed within 24 h of agitation onset. Agitation was associated with IADL impairment at 12 months (Lawton >8; p = 0.03, OR 2.7, 95 % CI, 1.1-6.8) in non-comatose patients (Hunt-Hess 1-4), but not with functional outcome (mRS >3), cognitive impairment (TICS <=30), or ICU/hospital length of stay after controlling for other predictors. CONCLUSION: Agitation occurs frequently after SAH, especially in non-comatose patients with higher clinical grades. It is associated with the development of multiple hospital complications and may have an independent impact on long-term outcomes. PMID- 28008565 TI - Broadband near-infrared spectroscopy can detect cyanide-induced cytochrome aa3 inhibition in rats: a proof of concept study. AB - PURPOSE: Clinically available near-infrared spectroscopy (NIRS) devices use two to five wavelengths of light to measure the relative amounts of oxyhemoglobin and deoxyhemoglobin in tissue to determine tissue hemoglobin oxygen saturation (StO2). In addition to StO2, broadband NIRS devices (using hundreds of wavelengths of light) may be able to measure the oxidation state of mitochondrial cytochrome aa3 (Cytox) which reflects the subcellular energetic state. We hypothesize that broadband NIRS devices can measure Cytox independent of changes in hemoglobin saturation. METHODS: In this prospective non-randomized study, 20 male Sprague-Dawley rats (300 g) were anesthetized with isoflurane, tracheally intubated, and ventilated with 100% O2 containing 2% isoflurane. They were subsequently instrumented with a broadband NIRS device that used a halogen light source coupled to an emitting fibreoptic cable. Three receiving fibreoptic cables were utilized; one analyzed the light source and the other two were directed at the base of the skull. Each receiving fibre was connected to a spectrometer to measure light intensity. Sodium cyanide (NaCN) 5 mg.kg-1 iv was injected in order to produce cytochrome aa3 reduction. Two to three minutes after injection, oxygen was eliminated and 100% nitrogen (i.e., anoxia) was used for ventilation in order to induce a reduction in both cytochrome aa3 and hemoglobin desaturation. Changes in the cytochrome oxidation state and hemoglobin oxygenation were calculated using a broadband algorithm and compared before and after both the NaCN and anoxia interventions. RESULTS: The NaCN injection resulted in a decrease in median [interquartile range (IQR)] deoxyhemoglobin (-0.014 [-0.29 to -0.005] arbitrary units [AU]; P < 0.001), an increase in oxyhemoglobin (0.013 [-0.011 to 0.031] AU; P < 0.001), and a reduction in cytochrome aa3 (-0.015 [-0.020 to 0.011] AU; P < 0.001). Anoxia resulted in an increase in median [IQR] deoxyhemoglobin (0.13 [0.11 to 0.18] AU; P < 0.001), a decrease in oxyhemoglobin (-0.17 [-0.22 to -0.15] AU; P < 0.001), and a reduction in cytochrome aa3 (-0.04 [-0.06 to -0.03] AU; P < 0.001). CONCLUSION: Broadband NIRS can effectively measure the directionality of changes in both Cytox and StO2 by uncoupling the cytochrome and hemoglobin signals through inhibition of the electron transport chain and anoxia. PMID- 28008566 TI - Simulation as an educational modality in an Anesthesiology Resident Wellness Program. PMID- 28008567 TI - Pro: Pure service delivery is still needed in global surgery missions. PMID- 28008568 TI - Development of Calbindin- and Calretinin-Immunopositive Neurons in the Enteric Ganglia of Rats. AB - Calbindin D28 K (CB) and calretinin (CR) are the members of the EF-hand family of calcium-binding proteins that are expressed in neurons and nerve fibers of the enteric nervous system. CB and CR are expressed differentially in neuronal subpopulations throughout the central and peripheral nervous systems and their expression has been used to selectively target specific cell types and isolate neuronal networks. The present study presents an immunohistochemical analysis of CB and CR in the enteric ganglia of small intestine in rats of different ages (newborn, 10-day-old, 20-day-old, 30-day-old, 60-day-old, 1-year-old, and 2-year old). The data obtained suggest a number of age-dependent changes in CB and CR expression in the myenteric and submucous plexuses. In the myenteric plexus, the lowest percentage of CB-immunoreactive (IR) and CR-IR neurons was observed at birth, after which the number of IR cells increased in the first 10 days of life. In the submucous plexus, CB-IR and CR-IR neurons were observed from 10-day-old onwards. The percentage of CR-IR and CB-IR neurons increased in the first 2 months and in the first 20 days, respectively. In all animals, the majority of the IR neurons colocalized CR and CB. From the moment of birth, the mean of the cross-sectional area of the CB-IR and CR-IR neuronal profiles was larger than that of CB- and CR-negative cells. PMID- 28008569 TI - Two misquotes, a letter to the editor regarding the article by Zhanzhan Xu et al. PMID- 28008571 TI - Reliability of the Ki67-Labelling Index in Core Needle Biopsies of Luminal Breast Cancers is Unaffected by Biopsy Volume. AB - BACKGROUND: Assessing prognostic and predictive factors like the Ki67 labelling index (Ki67-LI) in breast cancer core needle biopsies (CNB) may be hampered by undersampling. Our aim was to arrive at a representative assessment of Ki67-LI in CNB of luminal breast cancers by defining optimal cutoffs and establishing the minimum CNB volume needed for highest concordance of Ki67-LI between CNB and subsequent surgical excision biopsy (SEB). METHODS: We assessed the Ki67-LI in CNB and subsequent SEB of 170 luminal breast cancers according to two counting methods recommended by the International Ki67 in Breast Cancer Working Group and applied the cutoffs to distinguish low and high proliferation given by the St Gallen 2013 and 2015 consensus, respectively. We then compared CNB volume characteristics for cases with concordant and discordant Ki67-LI between CNB versus SEB. RESULTS: Highest concordance (75%, kappa = 0.44) between CNB and SEB was achieved using the method that assesses the average tumor Ki67-LI and a cutoff of 20%. No significant differences were found between cases with concordant and discordant Ki67-LI in CNB versus SEB for number of biopsy cores, total core length, tumor tissue length, or total CNB or tumor tissue area size in the CNB for two various cutoffs. CONCLUSIONS: A concordance of 75% between CNB and SEB can be achieved for the Ki67-LI using a method assessing average Ki67-LI at the threshold of 20%. Increasing CNB volume did not result in improved agreement rates, indicating that reliability of Ki67 levels in CNB of luminal breast cancers is unaffected by CNB volume. PMID- 28008570 TI - The role of interventional radiology in the treatment of intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma. Complete surgical resection remains the only potentially curative option for patients with ICC. However, until now, early diagnosis with potential surgical intervention has been the exception rather than the rule with only 30% of patients qualifying for attempted surgical cure. Many patients are unresectable because of disease stage, anatomic conditions, medical comorbidities, and small future remnant liver. Interventional radiology procedures are available for these types of patients with intra arterial therapies and/or ablative treatments both for curative and for palliative treatment. The goals of interventional therapy are to control local tumor growth, to relieve symptoms, and to improve and preserve quality of life. The choice of treatment depends largely on tumor extent and patient performance. No randomized studies exist to compare treatments. The present review describes the current evidence of the interventional treatments in the management of the ICC. Moreover, interventional procedures available to increase the future liver reserve before surgery were analyzed. PMID- 28008572 TI - Prognostic Value of Sterilized Lymph Nodes After Preoperative Chemoradiotherapy for Patients with ypN0 Rectal Cancer. AB - BACKGROUND: Patients with ypN0 rectal cancer who have received preoperative chemoradiotherapy can be divided into those who initially were node negative and those whose positive nodes have been sterilized by preoperative therapy. The long term prognosis for ypN0 patients with sterilized lymph nodes (LNS) is unknown. This study aimed to assess the prognostic value of LNS after preoperative chemoradiotherapy for patients with ypN0 rectal cancer. METHODS: From January 2007 to March 2014, 206 patients with ypN0 tumors of the mid or lower rectum treated by chemoradiotherapy and radical surgery were enrolled in the study. Of these 206 patients, 49 had ypN0 tumors with LNS (LNS+ group), and 157 had ypN0 tumors without LNS (LNS- group). The patients in both groups were comparable in terms of tumor characteristics, type of chemoradiotherapy, type of surgery, R0 resection rate, and postoperative complication rate. RESULTS: The mean follow-up period was 40.5 +/- 27 months. The 1- and 3-year OS rates in the LNS+ group were respectively 100 and 95.5% versus 99.4 and 91.6% in the LNS- group (P = 0.549). The 1- and 3-year DFS rates in the LNS+ group were respectively 100 and 94.2% versus 94.7 and 87.1% in the LNS- group (P = 0.117). The multivariate analysis showed that the presence of LNS did not affect OS (P = 0.918) or DFS (P = 0.209). CONCLUSIONS: The prognosis is excellent for patients with ypN0 rectal cancer who have LNS after preoperative chemoradiotherapy. The presence of LNS in ypN0 rectal cancer patients after chemoradiotherapy should not be considered a factor for a poor prognosis. PMID- 28008573 TI - Management and Survival of Elderly and Very Elderly Patients with Endometrial Cancer: An Age-Stratified Study of 1228 Women from the FRANCOGYN Group. AB - BACKGROUND: Little data exist about the clinical management and survival of elderly patients with endometrial cancer. This study aimed to evaluate the management of elderly and very elderly patients with endometrial cancer as well as the overall survival (OS) rate, disease-free survival (DFS) rate, and cancer specific survival (CSS) rate in a multicenter cohort. METHODS: Data from 1228 patients with endometrial cancer who received primary treatment between January 2001 and December 2012 were collected from a multicenter database. Clinical management, DFS, CSS, and OS were analyzed. RESULTS: Based on the international endometrial cancer risk classification, 36% (212/582) of women age 65 years or younger, 42% (220/526) of women ages 65-80 years, and 48% (58/120) of women older than 80 years showed high-risk endometrial cancer (p < 0.001). Pelvic lymphadenectomy was performed for 85% (230/271) of the women age 65 years or younger and 46% (33/71) of the women older than 80 years (p < 0.001). Radiotherapy was performed for 27% (33/120) of the very elderly and 40% (233/582) of the young patients (p = 0.009). The 3-year CSS rates were 95% (95% confidence interval [CI], 93-97%) for the women age 65 years or younger, 90% (95% CI, 87 94%) for the women ages 65-80 years, and 82% (95% CI, 73-93%) for the women older than 80 years (p < 0.001). CONCLUSIONS: The elderly and very elderly patients with endometrial cancer showed poorer prognosis than young patients. The significant lower CSS rate for the elderly patients could have be due to both the higher rate of high-risk endometrial cancer and undertreatment. Specific guidelines for the management of elderly and very elderly patients with endometrial cancer are needed to improve their prognosis. PMID- 28008575 TI - Response to "Innovation in Hemophilia Therapies-'And Miles to Go, before [We] Sleep'". PMID- 28008574 TI - Use of Tumor Markers in Gastrointestinal Cancers: Surgeon Perceptions and Cost Benefit Trade-Off Analysis. AB - BACKGROUND: Gastrointestinal cancers constitute the third most common cancers worldwide. Tumor markers have long since been used in the postoperative surveillance of these malignancies; however, the true value in clinical practice remains undetermined. OBJECTIVE: This study aimed to evaluate the clinical utility of three tumor markers in colorectal and esophagogastric cancer. METHODS: A systematic review of the literature was undertaken to elicit the sensitivity, specificity, statistical heterogeneity and ability to predict recurrence and metastases for carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9 and CA125. European surgeons were surveyed to assess their current practice and the characteristics of tumor markers they most valued. Data from the included studies and survey were combined in a cost-benefit trade-off analysis to assess which tumor markers are of most use in clinical practice. RESULTS: Diagnostic sensitivity and specificity were ranked the most desirable characteristics of a tumor marker by those surveyed. Overall, 156 studies were included to inform the cost-benefit trade-off. The cost-benefit trade-off showed that CEA outperformed both CA19-9 and CA125, with lower financial cost and a higher sensitivity, and diagnostic accuracy for metastases at presentation (area under the curve [AUC] 0.70 vs. 0.61 vs. 0.46), as well as similar diagnostic accuracy for recurrence (AUC 0.46 vs. 0.48). CONCLUSIONS: Cost-benefit trade-off analysis identified CEA to be the best performing tumor marker. Further studies should seek to evaluate new tumor markers, with investigation tailored to factors that meet the requirements of practicing clinicians. PMID- 28008576 TI - [Barriers to Addressing Pregnant Patients' Cigarette and Alcohol Use: A Focus Group Study with Gynecologists]. AB - Objectives/Purpose: Alcohol drinking and tobacco smoking pose high health risks for the unborn child. Even though routine testing during the course of pregnancy facilitates early intervention, addressing substance use in pregnancy seems to be more difficult. The aim of the study was to identify barriers to addressing pregnant patients' cigarette and alcohol use. Methods: 2 focus groups (in total N=10 participants) were conducted with gynaecologists. The transcripts of the discussions were analysed using Mayring's approach of qualitative text analysis. Results: Avoidance of addressing substance abuse directly, the social and educational background of patients influencing the communication in this matter and the physicians' ambivalence about their limits of responsibility were barriers often mentioned by the participants. Conclusion: In view of the several structural and individual barriers among gynaecologists identified in this study, gynaecologists obviously cannot be the only health professionals taking responsibility for coping with substance abuse among pregnant women. Strategies should be designed, e. g., to standardise the identification, counselling and referral process. Physicians should receive more support in improving their competences, and effective low-threshold treatment programmes for the women affected are required. PMID- 28008577 TI - [Licensing of Pharmaceuticals and Medical Devices in Germany: Weaknesses and Opportunities]. AB - The purpose of this study is to describe and compare the licensing of pharmaceuticals and medical devices in Germany. Weaknesses and opportunities of the respective processes are identified. Methods: To describe and compare the two approaches, a systematic literature review was conducted, followed by an archival analysis, guided by experts. Unstructured interviews were conducted with experts (users, financers, surveillants and producers) personally or by telephone to identify weaknesses and opportunities. The data were evaluated by content analysis according to Mayring and MAXQDA 11. The results were critically assessed by comparing them with the current academic literature. Results: A central market authorization for medical devices was mentioned often, but seems politically not viable. However, quality, methodology and depth of the analyses necessary for the licensing of medical devices, especially for high-risk devices, can and should strive for higher standards, comparable to those of pharmaceuticals. With regard to post-market surveillance, the systems for both pharmaceuticals and medical devices should be improved. Innovativeness and competitiveness of European medical device manufacturers should not be promoted by reduced evidence standards and patient safety. Subsidies or easier licensing procedures for small product lines with particular importance for public health, similar to orphan drug regulations, are more desirable. Conclusion: This study helps to identify areas of improvement for licensing of pharmaceuticals and medical devices. Concrete recommendations were developed. Higher evidence standards should be mandatory especially for high-risk devices, comparable to those of pharmaceuticals. Post marketing surveillance should be improved for pharmaceuticals and medical devices. PMID- 28008578 TI - ? PMID- 28008579 TI - ? AB - The German Society for Social Medicine and Prevention (DGSMP) confers the Salomon Neumann-Medal for outstanding merits in the field of Preventive and Social Medicine. Salomon Neumann (1819-1908) was one of the most renowned representatives of Social Medicine, whose phrase "Medicine is a Social Science" is punched oh the medal. The Salomon Neumann-Medal 2016 was awarded to the Health Monitoring Unit of the Robert Koch-Institute (RKI), i. e. the Department for Epidemiology and Health Monitoring with its head Barbel Maria Kurth. The article documents the honorific speech which stresses the importance of Health Monitoring for evidence informed policy making. PMID- 28008580 TI - [Salomon Neumann (1819-1908) and the Right to Health]. AB - The "Universal Declaration of Human Rights (UDHR)" of the United Nations (UN) of 1948 sets out a right to health as a common ideal and aspiration. In his writings on the reform of the Prussian Medical Charter "Public Health and property" 100 years before the UDHR was set out, the Jewish physician Salomon Neumann had defined health as a right for every citizen, a right that should to be protected by a public system of health care. His reasoning went beyond contemporaneous critical social discussion. Right of humans to health has been acknowledged nationally and internationally; in the Federal Republic of Germany, the question as to whether there is a basic right to health is still open. PMID- 28008582 TI - Breaking up Prolonged Sitting does not Alter Postprandial Glycemia in Young, Normal-Weight Men and Women. PMID- 28008581 TI - [Health care of refugees in 2015 - Evaluation of an ambulance for refugees in a Cologne emergency accommodation (Cologne Model)]. AB - Access to medical care is a core element in the care of refugees and asylum seekers, and should therefore be guaranteed in a barrier-free way. In practice, there are usually numerous access barriers and the first contact with the German Health Care System takes place in form of a statutory examination to exclude infectious diseases. In addition to the introduction of health insurance cards for refugees, an offer of medical consultation for several hours a week in the municipal emergency accommodations provides an opportunity for low threshold access to primary care and a bridging function to the integration into the regular health care system. This offer is independent of the obligatory initial examination according to S 62 Asylum Law (AsylG) 1. The evaluation of the first year of such a health care center is presented. PMID- 28008583 TI - EndoBarrier Gastrointestinal Liner in Type 2 Diabetic Patients Improves Liver Fibrosis as Assessed by Liver Elastography. AB - Many obese people with type 2 diabetes develop non-alcoholic fatty liver disease, which may progress to liver fibrosis. EndoBarrier gastrointestinal liner is an innovative interventional treatment option for type 2 diabetic patients, which could affect diabetes associated liver disease. The aim of this retrospective study was to analyze the effect of 1-year EndoBarrier therapy on liver fibrosis and steatosis. As an indicator of fibrosis, liver stiffness was assessed by liver elastography at baseline, 2 weeks after EndoBarrier implantation and then every 3 months until explantation. 13/19 patients had elevated liver stiffness at baseline, corresponding to liver fibrosis grade 2 to 4. In these patients, liver stiffness reduced significantly during EndoBarrier therapy from 10.4 kPa (IQR 6.0 14.3) at baseline to 5.3 kPa (IQR 4.3-7.7, p<0.01) by the time of EndoBarrier explantation, corresponding to a normalization of the initially pathologic findings in most patients. Liver steatosis was also assessed by elastographic measurements in terms of the controlled attenuation parameter. In all patients, baseline measurements showed high grade steatosis. Improvements were seen from initially 343 dB/m (IQR 326-384) to 317 dB/m (IQR 269-375, p<0.05) by the time of explantation. However, most patients were still classified high grade steatosis after completion of EndoBarrier treatment. In this observational study, we show that liver fibrosis is a common condition in obese patients suffering from type 2 diabetes, and that EndoBarrier gastrointestinal liner substantially improves liver fibrosis in these patients. PMID- 28008584 TI - Changes in Quality of Diabetes Care and Morbidity over 20 Years in People with Type 1 Diabetes and Long Diabetes Duration: The JEVIN Trial. AB - Background: The JEVIN trial started as a cross-sectional study in 1989/90 in Jena, a city of the former German Democratic Republic. At that time, the centralized diabetes care system was broken down and restarted 10 years later; structured treatment and teaching programs were implemented, blood glucose self monitoring, insulin pump-systems and analogue insulin were introduced. We surveyed people with type-1-diabetes of the baseline JEVIN trial in a 20-year follow-up. Methods: 131 patients with type-1-diabetes were analyzed in 1989/90. Of the living population in 2009/10 (n=104), 83 persons were identified and 75 persons with a mean diabetes duration of 35 years were reexamined regarding HbA1c, self-monitoring, diabetes therapy, severe hypoglycemia, diabetic late complications and compared with the results of the same persons in 1989/90. Results: HbA1c decreased from 57.1 mmol/mol in 1989/90 to 52.7 mmol/mol in 2009/10 (7.4 -7.0%; p=0.049). Self-monitoring of blood glucose increased from 2 to 35 tests/week (p<0.001). 100%-use of animal insulin changed to human and analogue insulin therapy. The incidence of severe hypoglycemia increased from 0.1 to 0.16/patient-year. Retinopathy increased from 29 to 69% (p<0.001), nephropathy from 5 to 27% (p<0.001) and neuropathy from 13 to 43% (p<0.001). 17% had no diabetic late complications. Conclusions: The JEVIN trial shows a significant improve in HbA1c in the past 20 years. Severe hypoglycemia occurred rarely and 17% were still free of any diabetic late complication after 35 years of diabetes. This indicates a good quality of diabetes care in a German setting. PMID- 28008585 TI - Glucagon-like Peptide-1 Analogues Inhibit Proliferation and Increase Apoptosis of Human Prostate Cancer Cells in vitro. AB - Background: Research has shown that the incidence of prostate cancer is increased in patients with type 2 diabetes mellitus (T2DM) 1. Glucagon-like peptide-1 (GLP 1) is a gastrointestinal hormone that enhances glucose-dependent insulin secretion and suppresses glucagon release. Method: Here, we examined the effect of exenatide and liraglutide, 2 types of GLP-1 analogues, on prostate cancer cells growth by CCK-8 assay, Hoechst33258 staining assay, and western blot analysis of apoptosis-related proteins Bax and Bcl-2. Also the kinase pathways maybe involved and the expression of GLP-1 receptor (GLP-1 R) in LNCap cells was detected. Results: In our experiments, exenatide and liraglutide significantly inhibited the proliferation of the LNCap cell lines and induced the cell apoptosis. Exenatide (1-100 nmol/L) increased the ratio of Bax/Bcl-2 in a dose dependent manner, whereas liraglutide increased Bax/Bcl-2 ratio only at concentrations of 10 nmol/L. And we found that GLP-1 analogues activate p38 but not ERK1/2 or AKT in LNCap cells. And classical GLP-1 receptor was detected in LNCap cells. Conclusion: These data suggest that exenatide and liraglutide attenuate prostate cancer growth through regulating P38 pathway by binding with GLP-1R. PMID- 28008586 TI - Association of KCNJ2 Genetic Variants with Susceptibility to Thyrotoxic Periodic Paralysis in Patients with Graves' Disease. AB - Objective: Thyrotoxic periodic paralysis (TPP) is characterized by acute onset paralysis and hypokalemia predominantly in male patients with thyrotoxicosis. Recent studies have emphasized the importance of potassium channels, which might explain the underlying mechanism of TPP. The KCNJ2 gene encodes the inward rectifying potassium channel. In this study, we evaluated the role of KCNJ2 in the development of TPP. Design: Case-control analysis of KCNJ2 genetic association with TPP. Patients: 83 male patients with Graves' disease (GD) were recruited for this study; 43 patients had TPP, whereas 40 patients had no history of TPP. Measurements: We analyzed the genotype and allelic frequency of a single nucleotide polymorphism (SNP; rs312691) (C>T) adjacent to the KCNJ2 gene that is known to be related to TPP development. Results: The frequency of the CC genotype of the rs312691 SNP was 0.51 in TPP patients and 0.05 in controls (p value=6.18*10-6). The C allele frequency of the SNP was 0.67 in the TPP group and 0.38 in the control group (odds ratio 3.24; 95% confidence interval 1.65-6.51; p value, 3.1*10-4). The rs312691 SNP was significantly associated with TPP. Conclusions: We demonstrated that the rs312691 SNP was significantly associated with TPP. These findings suggest that KCNJ2 plays an important role in the pathophysiology of TPP in Korean GD patients with TPP. PMID- 28008587 TI - Neutral Ceramidase Secreted Via Exosome Protects Against Palmitate-Induced Apoptosis in INS-1 Cells. AB - Aims: To investigate the effects of neutral ceramidase (NCDase) packaged in exosomes that are secreted from beta-cells on free fatty acid (FFA)-induced beta cells apoptosis and its role in regulation of sphingolipid-mediated signaling pathway. Methods: HPLC and Western blotting were performed to determine NCDase activity and expression. Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis. Electrospray ionization tandem mass spectrometry was used for ceramide (Cer), sphingosine-1-phosphate (S1P), and sphingosine (SPH) determination. Results: INS-1 cells over-expressed NCDase secreted active NCDase via exosomes. Exosomes isolated from the cultured medium of INS-1 cells that oxpressed NCDase could ameliorate palmitate-induced apoptosis. Furthermore, the results showed that exosome-derived NCDase treatment reduced intracellular Cer/S1P ratio. Conclusions: beta-cell secreted active NCDase via exosome, the exosome-packaged-NCDase protected beta-cells from FFA induced apoptosis through regulating sphingolipid metabolites and it might be a potential treatment for beta-cell lipotoxicity and type 2 diabetes. PMID- 28008588 TI - Losartan Improves Palmitate-Induced Insulin Resistance in 3T3-L1 Adipocytes Through Upregulation of Src Phosphorylation. AB - Angiotensin II type 1 receptor blocker losartan has shown strongly anti-insulin resistance properties in vivo and in vitro; however, the underlying mechanisms are poorly understood. In this study, we demonstrate that losartan administration increased phosphorylation of Akt and its downstream Akt substrate of 160 kDa (AS160), enhanced plasma membrane translocation of glucose transporter type 4 (GLUT4), and increased glucose uptake, along with increased Src phosphorylation as well as reduced expression of docking protein 1(DOK1) in palmitate-treated 3T3 L1 adipocytes. The beneficial impacts of losartan on insulin signaling were diminished in Src-deficient 3T3-L1 adipocytes. In addition, suppressed expression of DOK1 by losartan was abolished by Src knockdown. Our results suggest that anti insulin resistance ability of losartan is mediated by Src/DOK1/Akt pathway. PMID- 28008589 TI - Prevalence of Sexual Dysfunction among Expectant Women. AB - Purpose To identify pregnancy as a causative factor of sexual dysfunction among expectant women. Methods A prospective study with 225 expectant mothers seen in the prenatal clinic of a federal university. Sexual function was evaluated by means of the Female Sexual Function Index (FSFI), and all domains were analyzed (desire, arousal, lubrication, orgasm, satisfaction, and pain). Initially, a univariate analysis of the sample was done. The averages for each domain according to the risk of sexual dysfunction (FSFI <= 26.5) were compared using the Student's t-test for independent samples. The strength of the correlation between sexual dysfunction and all sociodemographic, clinical and behavioral variables was measured by the Chi-Square (chi2) test. Then, odds ratios (ORs) and their confidence intervals were assigned to perform a bivariate analysis. Any p values less than 0.05 were considered significant. Results Approximately two thirds of the women (66.7%) showed signs of risk of sexual dysfunction (FSFI <= 26.5). Within these cases, all sexual dysfunction domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) were found to be statistically significant (p < 0.001). The domains most affected were desire (2.67), satisfaction (2.71) and arousal (2.78). Conclusions Pregnancy appears to be an important causative factor of sexual dysfunction among pregnant women. PMID- 28008590 TI - The Effectiveness of Anticholinergic Therapy for Overactive Bladders: Systematic Review and Meta-Analysis. AB - The overactive bladder (OAB) has a significant negative impact on the quality of life of patients. Antimuscarinics have become the pharmacological treatment of choice for this condition. The objective of this systematic review and meta analysis is to examine the evidence from randomized clinical trials about the outcomes of the antimuscarinic drugs available in Brazil on OABs. We searched MEDLINE and the Cochrane Central Register of Controlled Trials from the inception of these databases through to September 2015. The primary outcome measures were the mean decrease in urge urinary incontinence episodes and the mean decrease in the frequency of micturition. The results suggest that there is a moderate to high amount of evidence supporting the benefit of using anticholinergic drugs in alleviating OAB symptoms when compared with placebo. It is still not clear whether any of the specific drugs that are available in Brazil offer advantages over the others. These drugs are associated with adverse effects (dry mouth and constipation), although they are not related to an increase in the number of withdrawals. PMID- 28008591 TI - Mirror Syndrome after Fetoscopic Laser Treatment - A Case Report. AB - Mirror syndrome is a rare disease with unknown pathophysiology that can be present in different diseases that can cause fetal hydrops. The prognosis is usually bad with a high perinatal mortality. We report an unusual form of mirror syndrome that manifested itself only after a successful treatment for fetal hydrops (caused by twin-twin transfusion syndrome, in Quinteros stage IV) was performed. This syndrome was controlled by medical treatment, and despite the usually bad prognosis seen in these cases, we could extend the pregnancy from the 23rd to the 34th week of gestation, resulting in the birth of 2 live infants. PMID- 28008592 TI - Chitooligosaccharide promotes immune organ development in broiler chickens and reduces serum lipid levels. AB - This study investigated the effects of chitooligosaccharide on lipid metabolism, immune organ development, and lymphocyte apoptosis in broiler chickens. A total of 480 one-day-old broiler chickens (Arbor Acres) were randomly and evenly assigned to control group and experimental groups I, II, and III. The control group was given a basic diet, while experimental groups I, II, and III were given basic diets for 42 days, supplemented with 50 mg/kg chlortetracycline, 20, and 40 mg/kg chitooligosaccharide, respectively. We found levels of serum triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) to be significantly reduced in experimental group II after 21 days, while the periarterial lymphatic sheath area of the spleens and the average number of bursa of Fabricius nodes were markedly increased. The serum total protein (TP) and high density lipoprotein cholesterol (HDL-C) levels, bursa of Fabricius index, and bursa of Fabricius lobule areas were additionally increased in experimental group III. After 42 days, the serum TP content had also increased and the bursa of Fabricius lobule area was augmented as well in experimental group II. Moreover, the splenic periarterial lymphatic sheat areas and the average numbers of bursa of Fabricius nodes were significantly increased in experimental group III. At both 21 and 42 days, numbers of Caspase 3-positive cells in spleen and bursa of Fabricius were significantly decreased in experimental groups II and III. Our results show that appropriate supplementation of chitooligosaccharide may improve lipid metabolism, promote immune organ development, and inhibit lymphocyte apoptosis in broilers. PMID- 28008593 TI - Effectiveness of the European chromium(vi) directive for cement implementation on occupational allergic contact dermatitis occurrence: assessment in France and the U.K. PMID- 28008594 TI - Causes of death in critically ill multiple sclerosis patients. AB - BACKGROUND: Patients with multiple sclerosis (MS) experience higher mortality rates as compared to the general population. While the risk of intensive care unit (ICU) admission is also reported to be higher, little is known about causes of death CoD in critically ill MS patients. AIM: To study the causes of death (CoD) in the series of critically ill patients with MS verified by autopsy. METHODS: We reviewed hospital electronic charts of MS patients treated at the neurological ICU of a tertiary care hospital between 2000 and 2015. We compared clinical and pathological CoD for those who were autopsied. RESULTS: Overall, 10 patients were identified (seven female; median age at death 65 years, range 27 80), and six of them were autopsied. The median MS duration prior to ICU admission was 27.5 years (range 1-50), and the median EDSS score at the time of ICU admission was 9 (range 5-9.5). The median length of ICU stay was 3 days (range 2-213). All the individuals in our series had experienced respiratory insufficiency during their ICU stay. The autopsy examination of brain tissue did not reveal evidences of MS lesions in one patient. In another patient, Lewy bodies were found on brain immunohistochemistry. CONCLUSION: Mortality in critically ill MS patients is largely driven by respiratory complications. Sporadic disparities between clinical and pathological findings can be expected. PMID- 28008595 TI - Defective expression of apoptosis-related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation. AB - Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis-related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)-based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL , FAS, FASL, A1, BCL2, BCLXL , CFLIPL and CIAP2 genes were up-regulated after AHSCT. With the exception of BIK, BIMEL and A1, all genes reached levels similar to controls at day + 720 post transplantation. Furthermore, in these patients, we observed increased CD8+ Fas+ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPL and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post-AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl-2 expression before transplantation. At 1 year post AHSCT, expression of Bak, Bim, Bcl-2, Bcl-xL and cFlip-L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis-related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re-establishment of immune tolerance during the first 2 years post-transplantation. PMID- 28008597 TI - Physician Participation in Meaningful Use and Quality of Care for Medicare Fee for-Service Enrollees. AB - OBJECTIVES: The Meaningful Use initiative has made nearly $30 billion available through incentive programs to encourage provider adoption and use of electronic health records. The objective of this study was to evaluate the impact of outpatient physicians' participation in Meaningful Use on the quality of care provided to Medicare fee-for-service (FFS) enrollees. DESIGN: Retrospective cohort study. SETTING: One hundred percent inpatient and outpatient Medicare FFS claims covering the period January 2010 through December 2012. PARTICIPANTS: 303,110 Medicare FFS enrollees from New York State. MEASUREMENTS: Hospitalizations and emergency department (ED) visits for ambulatory care sensitive conditions (ACSCs), diabetic retinopathy screening, diabetic nephropathy screening, colorectal cancer screening, and influenza vaccinations. RESULTS: Physician participation in the Meaningful Use initiative was not associated with reductions in ACSC-related hospitalizations (0.0 percentage points, 95% confidence interval (CI): 0.0-0.1) or ED visits (0.0 percentage points, 95% CI: 0.0-0.1) relative to the comparison group. Meaningful Use participation was associated with higher odds of colorectal cancer screening (odds ratio (OR): 1.2, 95% CI: 1.1-1.4) relative to the comparison group, but not for diabetic retinopathy screening (OR: 1.1, 95% CI: 1.0-1.2), diabetic nephropathy screening (OR: 1.0, 95% CI: 0.8-1.2), or influenza vaccinations (OR: 1.1, 95% CI: 1.0-1.2). Similar results were found in secondary analyses of dually eligible beneficiaries participating in both Medicare and Medicaid. CONCLUSION: Physician participation in Meaningful Use was not associated with substantial improvements on six quality measures. PMID- 28008596 TI - The Association of Vitamin D Deficiency and Incident Frailty in Older Women: The Role of Cardiometabolic Diseases. AB - OBJECTIVES: Evidence suggests vitamin D deficiency is associated with developing frailty. However, cardiometabolic factors are related to both conditions and may confound and/or mediate the vitamin D-frailty association. We aimed to determine the association of vitamin D concentration with incidence of frailty, and the role of cardiometabolic diseases (cardiovascular disease, diabetes, hyperlipidemia, hypertension) in this relationship. DESIGN: Prospective longitudinal cohort study (7 visits from 1994-2008). SETTING: Baltimore, Maryland. PARTICIPANTS: Three hundred sixty-nine women from the Women's Health and Aging Study II aged 70-79 years, free of frailty at baseline. MEASUREMENTS: Serum circulating 25-hydroxyvitamin D (25[OH]D) concentration was assessed at baseline and categorized as: <10; 10-19.9; 20-29.9; and >=30 ng/mL. Frailty incidence was determined based on presence of three or more criteria: weight loss, low physical activity, exhaustion, weakness, and slowness. Cardiometabolic diseases were ascertained at baseline. Analyses included Cox regression models adjusted for key covariates. RESULTS: Incidence rate of frailty was 32.2 per 1,000 person-years in participants with 25(OH)D < 10 ng/mL, compared to 12.9 per 1,000 person-years in those with 25(OH)D >= 30 ng/mL (mean follow-up = 8.5 +/- 3.7 years). In cumulative incidence analyses, those with lower 25(OH)D exhibited higher frailty incidence, though differences were non-significant (P = .057). In regression models adjusted for demographics, smoking, and season, 25(OH)D < 10 ng/mL (vs >=30 ng/mL) was associated with nearly three-times greater frailty incidence (hazard ratio (HR) = 2.77, 95% CI = 1.14, 6.71, P = .02). After adjusting for BMI, the relationship of 25(OH)D < 10 ng/mL (vs >=30 ng/mL) with incident frailty persisted, but was attenuated after further accounting for cardiometabolic diseases (HR = 2.29, 95% CI = 0.92, 5.69, P = .07). CONCLUSION: Low serum vitamin D concentration is associated with incident frailty in older women; interestingly, the relationship is no longer significant after accounting for the presence of cardiometabolic diseases. Future studies should explore mechanisms to explain this relationship. PMID- 28008598 TI - Endometriosis: an old problem without a current solution. PMID- 28008601 TI - An American Headache Doctor in Beijing. PMID- 28008599 TI - Screening Tool of Older Person's Prescriptions/Screening Tools to Alert Doctors to Right Treatment Medication Criteria Modified for U.S. Nursing Home Setting. AB - OBJECTIVES: To develop a set of prescribing indicators measurable with available data from electronic nursing home (NH) databases by adapting the European-based 2014 Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tools to Alert Doctors to Right Treatment (START) criteria of potentially inappropriate and underused medications for the U.S. SETTING: DESIGN: A two-stage expert panel process. In the first stage, the investigator team reviewed 114 criteria for compatibility and measurability. In the second stage, an online modified e-Delphi (OMD) panel was convened to rate the validity of criteria, and two webinars were held to identify criteria with highest relevance to U.S. NHs. PARTICIPANTS: Seventeen experts with recognized reputations in NH care participated in the e Delphi panel and 12 in the webinar. MEASUREMENTS: Compatibility and measurability were assessed by comparing criteria with U.S. terminology and setting standards and data elements in NH databases. Validity was rated using a 9-point Likert-type scale (1 = not valid at all, 9 = highly valid). Mean, median, interpercentile ranges, and agreement were determined for each criterion score. Relevance was determined by ranking the mean panel ratings on criteria that reached agreement; the webinar participants reviewed and approved half of the criteria with the highest mean values. RESULTS: Fifty-three STOPP/START criteria were deemed to be compatible with the U.S. NH setting and measurable using data from electronic NH databases. E-Delphi panelists rated 48 criteria as valid for U.S. NHs. Twenty four criteria were deemed to be most relevant, consisting of 22 measures of potentially inappropriate medications and two measures of underused medications. CONCLUSION: This study created the first explicit criteria for assessing the quality of prescribing in U.S. NHs. PMID- 28008602 TI - MicroRNA-335-5p and -3p synergize to inhibit estrogen receptor alpha expression and promote tamoxifen resistance. AB - microRNAs (miRNAs) are small noncoding RNA molecules involved in the regulation of gene expression and play critical roles in human malignancies. Next-generation sequencing analysis of the MCF-7 breast cancer cell line overexpressing miR-335 5p and miR-335-3p demonstrated that the miRNA duplex repressed genes involved in the ERalpha signaling pathway, and enhanced resistance of MCF-7 cells to the growth inhibitory effects of tamoxifen. These data suggest that despite its conventional role in tumor suppression, the miR-335 transcript can also play an oncogenic role in promoting agonistic estrogen signaling in a cancerous setting. PMID- 28008604 TI - The Persistence of Sperm and the Development of Time Since Intercourse (TSI) Guidelines in Sexual Assault Cases at Forensic Science Ireland, Dublin, Ireland. AB - The persistence of sperm using confirmatory microscopic analysis, the persistence of sperm with tails, time since intercourse (TSI) analysis, and results from the acid phosphatase (AP) reaction from approximately 5581 swabs taken from circa 1450 sexual assault cases are presented. The observed proportions of sperm in the vagina and anus declines significantly after 48 h TSI, and sperm on oral swabs were observed up to 15 h TSI. The AP reaction as a predictor of sperm on intimate swabs is questioned. All AP reaction times gave a low true positive rate; 23% of sperm-positive swabs gave a negative AP reaction time. We show the AP reaction is an unsafe and an unreliable predictor of sperm on intimate swabs. We propose that TSI not AP informs precase assessment and the evaluative approach for sexual assault cases. To help inform an evaluative approach, TSI guidelines are presented. PMID- 28008603 TI - A Pilot Randomized Controlled Trial of the Effects of Chair Yoga on Pain and Physical Function Among Community-Dwelling Older Adults With Lower Extremity Osteoarthritis. AB - OBJECTIVES: To determine effects of Sit 'N' Fit Chair Yoga, compared to a Health Education program (HEP), on pain and physical function in older adults with lower extremity osteoarthritis (OA) who could not participate in standing exercise. DESIGN: Two-arm randomized controlled trial. SETTING: One HUD senior housing facility and one day senior center in south Florida. PARTICIPANTS: Community dwelling older adults (N = 131) were randomly assigned to chair yoga (n = 66) or HEP (n = 65). Thirteen dropped after assignment but prior to the intervention; six dropped during the intervention; 106 of 112 completed at least 12 of 16 sessions (95% retention rate). INTERVENTIONS: Participants attended either chair yoga or HEP. Both interventions consisted of twice-weekly 45-minute sessions for 8 weeks. MEASUREMENTS: Primary: pain, pain interference; secondary: balance, gait speed, fatigue, functional ability measured at baseline, after 4 weeks of intervention, at the end of the 8-week intervention, and post-intervention (1 and 3 months). RESULTS: The chair yoga group showed greater reduction in pain interference during the intervention (P = .01), sustained through 3 months (P = .022). WOMAC pain (P = .048), gait speed (P = .024), and fatigue (P = .037) were improved in the yoga group during the intervention (P = .048) but improvements were not sustained post intervention. Chair yoga had no effect on balance. CONCLUSION: An 8-week chair yoga program was associated with reduction in pain, pain interference, and fatigue, and improvement in gait speed, but only the effects on pain interference were sustained 3 months post intervention. Chair yoga should be further explored as a nonpharmacologic intervention for older people with OA in the lower extremities. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02113410. PMID- 28008605 TI - Immune deficiency augments the prevalence of p53 loss of heterozygosity in spontaneous tumors but not bi-directional loss of heterozygosity in bone marrow progenitors. AB - p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo. Surprisingly, the loss of either the wild-type p53 allele or mutant p53 allele was detected with a three-to-one ratio in favor of losing the mutant allele. In this study, we examined whether the immune-system can affect the LOH directionality in bone marrow progenitors. We found that mesenchymal progenitor cells derived from immune-deficient mice exhibited the same preference of losing the mutant p53 allele as immune-competent matched cells, nevertheless, these animals showed a significantly shorter tumor-free survival, indicating the possible involvement of immune surveillance in this model. Surprisingly, spontaneous tumors of p53 heterozygous immune-deficient mice exhibited a significantly higher incidence of p53 LOH compared to that observed in tumors derived of p53 heterozygous immune-competent mice. These findings indicate that the immune-system may affect the p53 LOH prevalence in spontaneous tumors. Thus suggesting that the immune-system may recognize and clear cells that underwent p53 LOH, whereas in immune-compromised mice, those cells will form tumors with shorter latency. In individuals with a competent immune-system, p53 LOH independent pathways may induce malignant transformation which requires a longer tumor latency. Moreover, this data may imply that the current immunotherapy treatment aimed at abrogating the inhibition of cellular immune checkpoints may be beneficial for LFS patients. PMID- 28008607 TI - MicroRNA-320a and microRNA-4496 attenuate Helicobacter pylori cytotoxin associated gene A (CagA)-induced cancer-initiating potential and chemoresistance by targeting beta-catenin and ATP-binding cassette, subfamily G, member 2. AB - Infection with Helicobacter pylori is closely linked to an increased risk of gastric cancer. Although cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer-initiating cell (CIC)-like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of beta-catenin and its target CIC markers via downregulation of microRNA (miR)-320a and miR-4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR-320a and miR-4496 attenuated the in vitro self-renewal and tumour-initiating capacity of CagA expressing CICs by targeting beta-catenin. Moreover, miR-320a and miR-4496 decreased CagA-induced chemoresistance by targeting ATP-binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post-transcriptional levels, respectively. Combination therapy with 5-fluorouracil and miR-320a/miR 4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA-induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with H. pylori are linked to CagA induced upregulation of beta-catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA-induced carcinogenisis and the therapeutic potential of of miR-320a and miR-4496. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28008608 TI - Increasing pulmonary blood flow at birth: the nerve of the baby. PMID- 28008606 TI - Derivation of marker gene signatures from human skin and their use in the interpretation of the transcriptional changes associated with dermatological disorders. AB - Numerous studies have explored the altered transcriptional landscape associated with skin diseases to understand the nature of these disorders. However, data interpretation represents a significant challenge due to a lack of good maker sets for many of the specialized cell types that make up this tissue, whose composition may fundamentally alter during disease. Here we have sought to derive expression signatures that define the various cell types and structures that make up human skin, and demonstrate how they can be used to aid the interpretation of transcriptomic data derived from this organ. Two large normal skin transcriptomic datasets were identified, one RNA-seq (n = 578), the other microarray (n = 165), quality controlled and subjected separately to network-based analyses to identify clusters of robustly co-expressed genes. The biological significance of these clusters was then assigned using a combination of bioinformatics analyses, literature, and expert review. After cross comparison between analyses, 20 gene signatures were defined. These included expression signatures for hair follicles, glands (sebaceous, sweat, apocrine), keratinocytes, melanocytes, endothelia, muscle, adipocytes, immune cells, and a number of pathway systems. Collectively, we have named this resource SkinSig. SkinSig was then used in the analysis of transcriptomic datasets for 18 skin conditions, providing in-context interpretation of these data. For instance, conventional analysis has shown there to be a decrease in keratinization and fatty metabolism with age; we more accurately define these changes to be due to loss of hair follicles and sebaceous glands. SkinSig also highlighted the over-/under-representation of various cell types in skin diseases, reflecting an influx in immune cells in inflammatory disorders and a relative reduction in other cell types. Overall, our analyses demonstrate the value of this new resource in defining the functional profile of skin cell types and appendages, and in improving the interpretation of disease data. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 28008609 TI - Randomized Trial of the Family Intervention: Telephone Tracking-Caregiver for Dementia Caregivers: Use of Community and Healthcare Resources. AB - OBJECTIVES: To examine the effects of a telephone-delivered intervention, Family Intervention: Telephone Tracking-Caregiver (FITT-C), on community support and healthcare use by dementia caregivers. DESIGN: Randomized, controlled trial. SETTING: Academic medical center. PARTICIPANTS: Dyads (n = 250) of distressed informal dementia caregivers and care recipients. INTERVENTION: Caregivers were randomly assigned to receive the FITT-C (n = 133) or telephone support (TS; n = 117). Both groups received 16 telephone contacts from a master's-level therapist over 6 months. The FITT-C intervention provided psychoeducation, problem solving, and other directive approaches based on assessment of critical areas (e.g., mood, behavior, family functioning, social support). TS provided supportive therapeutic strategies. MEASUREMENTS: Outcome variables were caregiver report of community support service use, number of visits to the emergency department (ED) for caregivers and care recipients, and hospital stays for caregivers during the interventions. RESULTS: Intervention groups did not differ in demographic characteristics, use of support services, or use of healthcare resources at baseline. Caregivers who received the FITT-C used community support services at end of treatment significantly more than those receiving TS (P = .02). FITT-C caregivers had a significantly lower rate of ED visits (rate difference 9.5%, P = .048) and hospital stays (rate difference 11.4%, P = .01) over the 6-month course of the intervention than TS caregivers. Care recipient use of community or medical resources did not differ according to group. CONCLUSION: An entirely telephone-delivered intervention was effective in increasing caregiver engagement in community resources and reducing caregiver use of hospital-based healthcare resources. Results highlight the potential effect of FITT-C on healthcare use. PMID- 28008610 TI - Medicolegal Implications of Nosocomial Infections: A Case Report of Aspergillus Contamination during Cardiac Surgery. AB - Nosocomial infections have become a major issue of public health and lead to an increasing number of suits for damages. We present a rare case of Aspergillus contamination during cardiac surgery, describe the medicolegal investigation, and present the new system for compensation of bodily injury after nosocomial infection in France, based on the law of March 4, 2002 on patient rights and quality in the health system. This case demonstrates the limits of compensation for nosocomial infections on the grounds of national solidarity. The expert report requested by the regional commission for conciliation and compensation is of fundamental importance in enabling the commission to decide between fault and inherent risk of treatment. PMID- 28008611 TI - Nursing student plans for the future after graduation: a multicentre study. AB - BACKGROUND: When modelling the nursing workforce, estimations of the numbers and characteristics of new graduates over the forecast period are assumed on the basis of previous generations; however, new graduates may have different plans for their future than those documented previously in different socio-economical contexts. AIMS: To explore (a) nursing student plans after graduation and factors influencing their plans, and (b) factors associated with the intention to emigrate. METHODS: A survey questionnaire was developed and distributed to students attending their final third year of nursing education in seven universities in Italy in 2015. Nine hundred and twenty-three (90.4%) students participated. FINDINGS: Four different plans after graduation emerged: about two thirds reported an intention to look for a nursing job in Italy; the remaining reported (a) an intention to emigrate, looking for a nursing job abroad, (b) an intention to search for a nursing job in both Italy and abroad, and (c) while a few an intention to continue nursing education in Italy. Having previous experience abroad, the need to grow and be satisfied, trusting the target country and a desire to increase knowledge encouraged an intention to emigrate, whereas the desire to stay in a comfortable environment and nurture personal relationships prevented the desire to migrate. CONCLUSION: Nursing students may have different plans after graduation, and this should be considered when modelling the nursing workforce of the future. IMPLICATIONS FOR NURSING/HEALTH POLICY: Policymakers should be aware of different plans after graduation to guide healthcare human resource strategies. Knowing these trajectories allows policymakers to estimate the appropriate nursing workforce, and also to act at both macro- and meso-levels, on work environments and opportunities for professional development, according to the different levels of expectations. PMID- 28008612 TI - A Large-Sample Test of a Semi-Automated Clavicle Search Engine to Assist Skeletal Identification by Radiograph Comparison. AB - In 2014, a morphometric capability to search chest radiograph databases by quantified clavicle shape was published to assist skeletal identification. Here, we extend the validation tests conducted by increasing the search universe 18 fold, from 409 to 7361 individuals to determine whether there is any associated decrease in performance under these more challenging circumstances. The number of trials and analysts were also increased, respectively, from 17 to 30 skeletons, and two to four examiners. Elliptical Fourier analysis was conducted on clavicles from each skeleton by each analyst (shadowgrams trimmed from scratch in every instance) and compared to the search universe. Correctly matching individuals were found in shortlists of 10% of the sample 70% of the time. This rate is similar to, although slightly lower than, rates previously found for much smaller samples (80%). Accuracy and reliability are thereby maintained, even when the comparison system is challenged by much larger search universes. PMID- 28008614 TI - Unfitness for Detention Among Arrestees with Suspected Mental Disorders in Paris, France. AB - In this retrospective study (11/2013-04/2014), we aimed to identify the factors associated with psychiatric hospitalization among detainees in police custody. We included 137 patients (M/F, 74%/26%; median age, 37 years), and 125 (91%) had a mental disorder. Seventy-seven patients (56%) had involuntary hospitalization. Sixty patients (44%) were declared fit for detention, and 48 (80%) of these patients had a mental disorder. All patients who required urgent psychiatric care and could not provide valid consent for care were declared as requiring involuntary hospitalization. Forty-nine of the 62 patients (79%) who required urgent psychiatric care and were suspected to have committed serious crimes were involuntarily admitted. In conclusion, we commonly found that some individuals with mental disorders were considered fit for detention in police cells. PMID- 28008615 TI - Mn2+ transport by Ca2+ -ATPase of sarcoplasmic reticulum. PMID- 28008616 TI - Identification of an N-acetylglucosamine kinase essential for UDP-N acetylglucosamine salvage synthesis in Arabidopsis. PMID- 28008617 TI - N-Cadherin, a novel and rapidly remodelling site involved in vasoregulation of small cerebral arteries. AB - KEY POINTS: N-cadherin formed punctate adherens junctions (AJ) along the borders between vascular smooth muscle cells (VSMCs) in the pressurized rat superior cerebellar artery. The formation of N-cadherin AJs in the vessel wall depends on the intraluminal pressure and was responsive to treatment with phenylephrine (PE) (10-5 m) and ACh (10-5 m). N-cadherin-coated beads were able to induce clustering of N-cadherin-enhanced green fluorescent protein (EGFP) on the plasma membrane of isolated VSMCs, whereas treatment with PE (10-5 m) or sodium nitroprusside (10-5 m) induced a significant increase or decrease in the N cadherin-EGFP clustering, respectively. Application of pulling force (~1 nN) to the N-cadherin-coated beads via an atomic force microscope induced a localized mechanical response from the VSMCs that opposed the pulling. ABSTRACT: N-cadherin is the major cell-cell adhesion molecule in vascular smooth muscle cells (VSMCs). We tested the hypothesis that N-cadherin is part of a novel mechanosensory mechanism in VSMCs and plays an active role in both the arteriolar myogenic response and during changes in vascular tone induced by vasomotor agonists. Intact and pressurized rat superior cerebellar arteries were labelled for confocal immunofluorescence imaging. N-cadherin formed punctate adherens junctions (AJ) along the borders between VSMCs. When the lumen pressure was raised from 50 to 90 mmHg, both the density and the average size of N-cadherin AJs increased significantly. Similarly, arteriolar constriction with phenylephrine (PE) (10-5 m) induced a significant increase of N-cadherin AJ density at 50 mmHg, whereas vasodilatation induced by ACh (10-5 m) was accompanied by a significant decrease in density and size of N-cadherin AJs. An atomic force microscope (AFM) was employed to further examine the mechano responsive properties of N-cadherin adhesion sites in isolated VSMCs. AFM probes with an attached N-cadherin-coated microbead (5 MUm) induced a progressive clustering of N-cadherin-enhanced green fluorescent protein (EGFP) on the VSMC surface. Application of pulling force (~1 nN) to the N-cadherin-coated-beads with the AFM induced a localized mechanical response from the VSMCs that opposed the pulling. Treatment with PE (10-5 m) or sodium nitroprusside (10-5 m) induced a significant increase or decrease of the N-cadherin-EGFP clustering, respectively. These observations provide compelling evidence that N-cadherin AJs are sensitive to pressure and vasomotor agonists in VSMCs and support a functional role of N cadherin AJs in vasomotor regulation. PMID- 28008618 TI - Quantitative analysis of the Ca2+ -dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes. AB - KEY POINTS: [Ca2+ ]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (IKs ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K+ current (IKr ) amplitude and voltage dependence were unaffected by high [Ca2+ ]i . When measuring or simulating IKs during an action potential, IKs was not different during a physiological Ca2+ transient or when [Ca2+ ]i was buffered to 500 nm. ABSTRACT: The slowly activating delayed rectifier K+ current (IKs ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+ ]i ) and beta-adrenergic receptor (beta-AR) stimulation modulate IKs amplitude and kinetics, but details of these important IKs regulators and their interaction are limited. We assessed the [Ca2+ ]i dependence of IKs in steady-state conditions and with dynamically changing membrane potential and [Ca2+ ]i during an AP. IKs was recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+ ]i , we found that raising [Ca2+ ]i from 100 to 600 nm produced similar increases in IKs as did beta-AR activation, and the effects appeared additive. Both beta-AR activation and high [Ca2+ ]i increased maximally activated tail IKs , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, IKs recorded during a normal physiological Ca2+ transient was similar to IKs measured with [Ca2+ ]i clamped at 500-600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+ ]i regulates IKs amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+ ]i , in the submembrane or junctional cleft space, is not required to maximize [Ca2+ ]i -dependent IKs activation during normal Ca2+ transients. PMID- 28008619 TI - Voice disorders and associated risk markers among young adults in the United States. AB - OBJECTIVES/HYPOTHESIS: To examine the prevalence of voice disorders in young adults and identify sociodemographic factors, health conditions, and behaviors associated with voice disorder prevalence. STUDY DESIGN: Cross-sectional analysis of data from the National Longitudinal Study of Adolescent to Adult Health. METHODS: During home interviews, 14,794 young adults, aged 24 to 34 years, reported their health conditions and behaviors. Presence and duration of voice disorders were reported over the past 12 months. We computed overall and stratified prevalence estimates by age, gender, race/ethnicity, medical conditions, smoking, and alcohol use. Multiple logistic regression was used to identify independent risk factors for a voice disorder while accounting for the complex sample design. RESULTS: Six percent of participants reported a voice disorder lasting at least 3 days. Females had 56% greater odds of voice disorders than males. Number of days drinking alcohol was associated with voice disorders, but number of smoking days was not. Conditions that increased the likelihood of voice disorders included hypertension (OR = 1.42 [95% confidence interval {CI}: 1.07-1.89]), tinnitus (OR = 1.53 [95% CI: 1.06-2.20]), and anxiety/panic disorder (OR = 1.26 [95% CI: 1.00-1.60]). Results were independent of gender, alcohol consumption, upper respiratory symptoms, and lower respiratory conditions including asthma, bronchitis/emphysema, and gastrointestinal symptoms (diarrhea/nausea/vomiting). CONCLUSIONS: Voice disorders in young adulthood were associated with hypertension, tinnitus, and anxiety. Greater awareness of these relationships may facilitate voice evaluation among people who seek healthcare for these chronic conditions. LEVEL OF EVIDENCE: 2b Laryngoscope, 127:2093-2099, 2017. PMID- 28008620 TI - Therapeutic priorities for solitary large hepatocellular carcinoma in a hepatitis B virus endemic area; an analysis of a nationwide cancer registry database. AB - BACKGROUND/AIMS: We compared overall survival (OS) of patients with a solitary large (>5 cm) hepatocellular carcinoma (HCC) treated surgically or by transarterial chemoembolization (TACE). METHODS: The archived records of HCC patients registered at the Korean Central Cancer Registry from 2003 through 2005 (registry A, n = 4 520) or from 2008 through 2010 (registry B, n = 4 596) were retrospectively analyzed. In these registries, 578 and 315 patients had a single large HCC, respectively. In registry A, 442 (cohort A) underwent surgery (n = 96) or TACE (n = 346). In registry B, 253 (cohort B) underwent surgery (n = 110) or TACE (n = 143). Cohort C (n = 695) was constructed by combining cohorts A and B, and thus, 206 and 489 patients received surgery and TACE, respectively. RESULTS: In cohort C, cumulative OS rates at 1-, 3-, and 5-years were significantly higher for surgery than TACE (89.3%, 67.4%, and 58.0% vs 67.7%, 38.2%, and 27.2%, respectively, P < 0.001). Similar results were obtained for cohorts A and B, even after propensity-score matching in three cohorts (P values for all <0.05). TACE (HR 2.18, P < 0.001), serum albumin (HR 0.77, P = 0.015), and tumor size (HR 1.06, P < 0.001) were predictors of post-treatment mortality. CONCLUSIONS: Surgery is associated with improved OS for a solitary large HCC of BCLC stage A. PMID- 28008622 TI - Short-term ammonium supply induces cellular defence to prevent oxidative stress in Arabidopsis leaves. AB - Plants can assimilate nitrogen from soil pools of both ammonium and nitrate, and the relative levels of these two nitrogen sources are highly variable in soil. Long-term ammonium nutrition is known to cause damage to Arabidopsis that has been linked to mitochondrial oxidative stress. Using hydroponic cultures, we analysed the consequences of rapid shifts between nitrate and ammonium nutrition. This did not induce growth retardation, showing that Arabidopsis can compensate for the changes in redox metabolism associated with the variations in nitrogen redox status. During the first 3 h of ammonium treatment, we observed distinct transient shifts in reactive oxygen species (ROS), low-mass antioxidants, ROS scavenging enzymes, and mitochondrial alternative electron transport pathways, indicating rapid but temporally separated changes in chloroplastic, mitochondrial and cytosolic ROS metabolism. The fast induction of antioxidant defences significantly lowered intracellular H2 O2 levels, and thus protected Arabidopsis leaves from oxidative stress. On the other hand elevated extracellular ROS production in response to ammonium supply may be involved in signalling. The response pattern displays an intricate plasticity of Arabidopsis redox metabolism to minimise stress in responses to nutrient changes. PMID- 28008621 TI - Rapid limb-specific modulation of vestibular contributions to ankle muscle activity during locomotion. AB - KEY POINTS: The vestibular influence on human walking is phase-dependent and modulated across both limbs with changes in locomotor velocity and cadence. Using a split-belt treadmill, we show that vestibular influence on locomotor activity is modulated independently in each limb. The independent vestibular modulation of muscle activity from each limb occurs rapidly at the onset of split-belt walking, over a shorter time course relative to the characteristic split-belt error correction mechanisms (i.e. muscle activity and kinematics) associated with locomotor adaptation. Together, the present results indicate that the nervous system rapidly modulates the vestibular influence of each limb separately through processes involving ongoing sensory feedback loops. These findings help us understand how vestibular information is used to accommodate the variable and commonplace demands of locomotion, such as turning or navigating irregular terrain. ABSTRACT: During walking, the vestibular influence on locomotor activity is phase-dependent and modulated in both limbs with changes in velocity. It is unclear, however, whether this bilateral modulation is due to a coordinated mechanism between both limbs or instead through limb-specific processes that remain masked by the symmetric nature of locomotion. Here, human subjects walked on a split-belt treadmill with one belt moving at 0.4 m s-1 and the other moving at 0.8 m s-1 while exposed to an electrical vestibular stimulus. Muscle activity was recorded bilaterally around the ankles of each limb and used to compare vestibulo-muscular coupling between velocity-matched and unmatched tied-belt walking. In general, response magnitudes decreased by ~20-50% and occurred ~13 20% earlier in the stride cycle at the higher belt velocity. This velocity dependent modulation of vestibular-evoked muscle activity was retained during split-belt walking and was similar, within each limb, to velocity-matched tied belt walking. These results demonstrate that the vestibular influence on ankle muscles during locomotion can be adapted independently to each limb. Furthermore, modulation of vestibular-evoked muscle responses occurred rapidly (~13-34 strides) after onset of split-belt walking. This rapid adaptation contrasted with the prolonged adaptation in step length symmetry (~128 strides) as well as EMG magnitude and timing (~40-100 and ~20-70 strides, respectively). These results suggest that vestibular influence on ankle muscle control is adjusted rapidly in sensorimotor control loops as opposed to longer-term error correction mechanisms commonly associated with split-belt adaptation. Rapid limb-specific sensorimotor feedback adaptation may be advantageous for asymmetric overground locomotion, such as navigating irregular terrain or turning. PMID- 28008623 TI - Relevance of CEA and LDH in relation to KRAS status in patients with unresectable colorectal liver metastases. AB - BACKGROUND: While the significance of carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and Kirsten rat sarcoma (KRAS) status as individual prognostic factors for patients with metastatic colorectal cancer has been addressed, the relationship and interdependence between these prognostic factors on survival is limited. METHODS: Patients with unresectable colorectal liver metastases with known KRAS status, and with baseline CEA and LDH levels who were treated with hepatic arterial infusion and systemic chemotherapy were identified. Patients were divided into two groups: hepatic-only disease and extra-hepatic disease. RESULTS: A total of 193 patients were included: 121 with hepatic-only and 72 with extra-hepatic disease. In the hepatic-only group, median overall survival (OS) was 55 months. On multivariate analysis, KRAS mutated tumors (HR 1.7, P < 0.05), LDH >200 U/L (HR 2.0, P < 0.05), and prior chemotherapy (HR 2.1, P < 0.05) had lower OS. In patients with extra-hepatic disease, median OS was 32 months. On multivariate analysis, baseline CEA >200 ng/mL (HR 2.1, P = 0.051), LDH >200 U/L (HR 3.8, P < 0.05), and right-sided tumors (HR 2.8, P < 0.05) had lower OS. CONCLUSIONS: This analysis verifies two distinct patterns in terms of biomarkers in patients with unresectable colorectal liver metastases. In patients with hepatic-only disease, KRAS mutation and elevated LDH negatively influenced survival. In patients with extra-hepatic disease, elevated LDH negatively impacted survival. PMID- 28008624 TI - Gastric cancer in the young: An advanced disease with poor prognostic features. AB - BACKGROUND AND OBJECTIVES: Gastric cancer in young patients is rare. We analyzed the clinicopathological features and prognosis of early-onset gastric carcinoma. METHODS: We retrospectively reviewed patients with gastric adenocarcinoma aged <=45 years and >45 years at our institution over a 17-year period. Clinicopathological features were compared and survival analysis was performed using Kaplan-Meier curves. RESULTS: A total of 121 patients with gastric carcinoma aged <=45 years were identified. The young group (YG) had a higher incidence of stage III/IV disease (86.8% vs. 57.9%, P < 0.001), poorly differentiated carcinoma (95.9% vs. 74.4%, P < 0.001), and signet-cell type tumor (88.4% vs. 32.2%, P < 0.001) relative to the older group (OG). The majority of tumors were in the middle third of the stomach in both groups (P = 0.108). Three year survival in the YG was 87.1%, 32.2%, and 6.9% in stage I/II, III, and IV disease, respectively. Surgical intervention in young patients with advanced carcinoma was not associated with improved survival. Although median survival was shorter in the YG compared to the OG (11.7 vs. 41.0 months, P < 0.001), stage specific survival was similar. CONCLUSION: Early-onset gastric cancer demonstrates advanced stage of disease, and a high incidence of poorly differentiated and signet-cell type carcinoma. Overall survival is poor with no added benefit to surgical intervention in advanced disease. PMID- 28008625 TI - Arterial ligation versus embolization in epistaxis management: Counterintuitive national trends. AB - OBJECTIVES/HYPOTHESIS: Arterial ligation and embolization are treatment modalities indicated in severe and refractory epistaxis. The purpose of this study was to examine temporal trends and compare outcomes in treatment of hospitalized epistaxis patients with ligation or embolization. METHODS: This retrospective cohort analysis utilized the 2008 to 2013 National Inpatient Sample to identify patients admitted with a primary diagnosis of epistaxis, and an associated procedure code for ligation or embolization. RESULTS: A total of 1,813 cases met the inclusion criteria, with 57.1% undergoing ligation. During the study period, treatment with ligation has trended downward, whereas treatment with embolization has remained constant. Overall, ligated patients were older (64.1 vs. 62.4 years; P = 0.027) and had higher rates of congestive heart failure (15.1% vs. 9.8%; P = 0.001). No significant differences in rates of chronic pulmonary disease, coagulopathy, liver disease, or hereditary hemorrhagic telangiectasia were observed between cohorts. No differences were observed in rates of blood transfusion, stroke, blindness, or in-hospital mortality; however, ligated patients had lower rates of intubation/tracheostomy (2.8% vs. 5.3%; P = 0.009). Ligated patients also experienced shorter hospital stays (3.6 vs. 4.0 days; P = 0.014) and incurred lower hospital charges ($33,029 vs. $69,304; P < 0.001). CONCLUSION: Compared to embolization, ligation is associated with significantly decreased hospital charges and shorter hospital stay, without an increase in complication rates. Counterintuitively, ligation appears to be trending downward nationally in its use relative to embolization. LEVEL OF EVIDENCE: 2C Laryngoscope, 127:1017-1020, 2017. PMID- 28008626 TI - Outcomes of surgically treated human papillomavirus-related oropharyngeal squamous cell carcinoma with N3 disease. AB - OBJECTIVES/HYPOTHESIS: To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival. STUDY DESIGN: Retrospective case series with chart review. METHODS: This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates. RESULTS: Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2-147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%-99%), 87% (95% CI: 75%-99%), and 84% (95% CI: 72%-96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS. CONCLUSIONS: Patients with HPV related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2033-2037, 2017. PMID- 28008627 TI - Clinically small tonsils are typically not obstructive in children during drug induced sleep endoscopy. AB - OBJECTIVE: To determine whether the degree of lateral pharyngeal wall (LPW) obstruction on pediatric drug-induced sleep endoscopy (DISE) correlates with preprocedure tonsillar hypertrophy score on physical examination, and to determine if clinically small tonsils are obstructive. METHODS: Retrospective review of 154 patients who underwent DISE at a single pediatric tertiary care center over a 4-year period. Inclusion criteria were documentation of Brodsky tonsil score on preoperative physical examination. Exclusion criteria were previous tonsillectomy, adenoidectomy, or adenotonsillectomy. Lateral pharyngeal wall obstruction was graded for each patient from 0 (no obstruction) to 3 (severe obstruction) using a validated pediatric DISE scoring system known as the Chan Parikh scoring system (C-P). Data were analyzed using multivariate linear regression controlling for age at time of DISE and presence of comorbid conditions. RESULTS: One hundred fifteen patients met criteria for analysis. Median age at DISE was 5.1 years. A moderate positive correlation was calculated between Brodsky score and DISE score, Spearman correlation coefficient 0.55, P = < 0.001. Linear regression modeling determined that for every 1-point increase in tonsil score, there was a 0.7-point increase in C-P LPW score (95% confidence interval [0.45, 0.92]). Sensitivity analysis did not detect a difference in correlation between children with comorbid conditions and children who were otherwise in good health. Of the 65 children with a pre-DISE Brodsky tonsil score of 1, 39 (60%) had a LPW score of 0 (no obstruction); nine (14%) had a score of 1 (< 50% obstruction); 11 (17%) had a score of 2 (> 50% obstruction); and six (9%) had a score of 3 (100% obstruction). CONCLUSION: There is a positive correlation between Brodsky Score and DISE LPW score. The majority of children with sleep disordered breathing with a Brodsky score of 1 did not demonstrate LPW obstruction. These children may benefit from DISE for identification of alternative sites of upper airway obstruction. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1943-1949, 2017. PMID- 28008628 TI - Analysis of four PCR/SNaPshot multiplex assays analyzing 52 SNPforID markers. AB - The SNPforID consortium identified a panel of 52 SNPs for forensic analysis that has been used by several laboratories worldwide. The original analysis of the 52 SNPs was based on a single multiplex reaction followed by two single-base extension (SBE) reactions each of which was analyzed using capillary electrophoresis. The SBE assays were designed for high throughput genetic analyzers and were difficult to use on the single capillary ABI PRISM 310 Genetic Analyzer and the latest generation 3500 Genetic Analyzer, as sensitivity on the 310 was low and separation of products on the 3500 with POP-7TM was poor. We have modified the original assay and split it into four multiplex reactions, each followed by an SBE assay. These multiplex assays were analyzed using polymer POP 4TM on ABI 310 PRISM(r) and polymers POP-4TM, POP-6TM and POP-7TM on the 3500 Genetic Analyzer. The assays were sensitive and reproducible with input DNA as low as 60 pg using both the ABI 310 and 3500. In addition, we found that POP-6TM was most effective with the 3500, based on the parameters that we assessed, achieving better separation of the small SBE products; this conflicted with the recommended use of POP-7TM by the instrument manufacturer. To support the use of the SNP panel in casework in Malaysia we have created an allele frequency database from 325 individuals, representing the major population groups within Malaysia. Population and forensic parameters were estimated for all populations and its efficacy evaluated using 51 forensic samples from challenging casework. PMID- 28008629 TI - Lower airway disease and pituitary surgery: Is there an association with postoperative cerebrospinal fluid leak? AB - OBJECTIVES/HYPOTHESIS: To explore the relationship between lower airway disease and postoperative cerebrospinal fluid (CSF) rhinorrhea among patients undergoing pituitary surgery STUDY DESIGN: Retrospective review. METHODS: A retrospective review of the Healthcare Cost and Utilization Project's 2013 National Inpatient Sample was conducted to characterize the hospital stay and surgical outcomes of patients undergoing pituitary surgery. Patients with lower airway disease (including chronic obstructive pulmonary disease and asthma) were compared to a disease-free population identifying demographics and complications over represented in the lower airway group. RESULTS: The majority of hypophysectomies (92.1%) were performed via a transsphenoidal approach. Among transsphenoidal patients, individuals with asthma (92.8% of the lower airway disease cohort) harbored a greater postoperative CSF leak rate (4.7% vs. 2.7%, P = .022), and were more likely to develop postoperative diabetes insipidus (6.2% vs. 4.1%, P = .024) and neurological complications (13.0% vs. 9.6%, P = .010) when compared to a lower airway disease-free cohort. Patients with CSF rhinorrhea had longer lengths of stay (7.8 days vs. 4.5 days, P < .001) and higher discharge costs ($148,309 vs. $76,246, P < .001). A binary logistic regression model identified having asthma (P = .042), being female (P = .011), and having gastroesophageal reflux disease (P = .006) as independent predictors of postoperative CSF rhinorrhea. CONCLUSIONS: Several patient comorbidities including asthma are associated with a greater risk of postoperative CSF rhinorrhea. Perioperative lower airway assessment and disease control may potentially decrease one's risk of this complication, although further inquiry is urgently needed to identify optimal preventive strategies. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:1543 1550, 2017. PMID- 28008630 TI - Computing conformational free energy differences in explicit solvent: An efficient thermodynamic cycle using an auxiliary potential and a free energy functional constructed from the end points. AB - Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: (1) The conformational free energy changes for alanine dipeptide transitioning from the right-handed free energy basin to the left-handed basin and (2) the free energy difference between the open and closed conformations of beta-cyclodextrin, a "host" molecule that serves as a model for molecular recognition in host-guest binding. beta-cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, making beta-cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with two endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for the beta-cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required. (c) 2016 Wiley Periodicals, Inc. PMID- 28008631 TI - Systematic review with meta-analysis: the management of chronic refractory pouchitis with an evidence-based treatment algorithm. AB - BACKGROUND: Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is considered the procedure of choice in patients with ulcerative colitis (UC) refractory to medical therapy. The incidence of pouchitis is 40% at 5 years. Ten to 15% of patients with pouchitis experience chronic pouchitis. AIM: To determine the efficacy of medical therapies for the treatment of chronic refractory pouchitis in patients undergoing IPAA for UC. METHODS: A systematic computer assisted search of the on-line bibliographic database MEDLINE and EMBASE was performed between 1966 and February 2016. All original studies reporting remission rates following medical treatment for chronic pouchitis were included. All study designs were considered. Remission was defined according to the individual study. Remission endpoints ranged from 15 days to 10 weeks. Chronic pouchitis was defined by each study. RESULTS: Twenty-one papers were considered eligible. Results from all studies combined suggested that overall remission was obtained in 59% of patients (95% CI: 44-73%). Antibiotics significantly induced remission in patients with chronic pouchitis with 74% remission rate (95% CI:56 93%), (P < 0.001). Biologics significantly induced remission in patients with chronic pouchitis with 53% remission rate (95% CI:30-76%), (P < 0.001). Steroids, bismuth, elemental diet and tacrolimus all can induce remission but failed to achieve significance. Faecal microbiota transplantation in a single study was not found to achieve remission. CONCLUSIONS: Treatment of chronic refractory pouchitis remains difficult and is largely empirical. Larger randomised controlled trials will help aid the management of chronic pouchitis. PMID- 28008632 TI - In-capillary approach to eliminate SDS interferences in antibody analysis by capillary electrophoresis coupled to mass spectrometry. AB - Capillary electrophoresis is an important technique for the characterization of monoclonal antibodies (mAbs), especially in the pharmaceutical context. However, identification is difficult as upscaling and hyphenation of used methods directly to mass spectrometry is often not possible due to separation medium components that are incompatible with MS detection. Here a CE-MS method for the analysis of mAbs is presented analyzing SDS-complexed samples. To obtain narrow and intensive peaks of SDS-treated antibodies, an in-capillary strategy was developed based on the co-injection of positively charged surfactants and methanol as organic solvent. For samples containing 0.2% (v/v) of SDS, recovered MS peak intensities up to 97 and 95% were achieved using cetyltrimethylammonium bromide or benzalkonium chloride, respectively. Successful removal of SDS was shown in neutral coated capillaries but also in a capillary with a positively charged coating applying reversed polarity. The usefulness of this in-capillary strategy was demonstrated also for other proteins and for antibodies dissolved in up to 10% v/v SDS solution, and in other SDS-containing matrices, including the sieving matrix used in a standard CE-SDS method and gel-buffers applied in SDS-PAGE methods. The developed CE-MS approaches enable fast and reproducible characterization of SDS-complexed antibodies. PMID- 28008633 TI - A microfluidic paper-based device to assess acetylcholinesterase activity. AB - Neurotransmitters play key roles in cell-to-cell communication. These chemical messengers are involved in many functional processes, including growth, reproduction, memory, and behavior. In this communication, we describe a novel microfluidic paper-based analytical device (MUPAD) to detect acetylcholinesterase (AChE) activity and inhibitor screening through a colorimetric analysis. The MUPAD is easily fabricated via a wax printing process whereby wax is deposited onto the surface of chromatographic paper, and heated to create a hydrophobic barrier. Separate solutions of 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) and samples containing AChE and acetylthiocholine iodide (ATC) (or cysteine, Cys), respectively, are directly spotted onto the MUPAD. DTNB and AChE/ATC (or Cys) flow towards each other where a reaction occurs to form the yellow colored 2 nitro-5-thiobenzoic acid anion (TNB2- ). The device is dried, scanned, and analyzed yielding a linear range of average inverse yellow intensities versus substrate concentration. An IC50 value (0.045 nM) with a known inhibitor, neostigmine bromide (NB), is obtained on the device. MUPADs are low cost and easy to fabricate and have great potential to quantify neurotransmitter activity. PMID- 28008634 TI - A comparison of two models of dental care for Aboriginal communities in New South Wales. AB - BACKGROUND: Aboriginal people, and particularly those in rural areas, continue to suffer very high levels of dental disease despite significant reductions in the wider Australian population in the past 30 years. Until recently, there has been a shortage of oral health clinicians and the majority have provided care in major cities. The NSW Government funded various models of care for rural and regional areas and vulnerable population groups including Aboriginal people. This study utilizes a comparative retrospective analysis to compare two models of oral health care for Aboriginal people including those living in rural NSW to inform future policy decisions. METHODS: Two models (Model A - Fly in Fly out and Model B - Collective impact) of public oral health care for Aboriginal patients in NSW were examined using publicly available descriptive information. Two years of funding and Dental Weighted Activity Units (DWAUs) data were analysed for the two different models and regression analysis was used to compare the trends of monthly time series of DWAUs. CONCLUSIONS: Based on the standardized national weighted pricing for public dentistry, model B offers significantly more services for less financial resources. PMID- 28008635 TI - Regulatory B cell is critical in bone union process through suppressing proinflammatory cytokines and stimulating Foxp3 in Treg cells. AB - Bone fractures may result in delayed union (DU) or non-union (NU) in some patients. Evidence suggests that the skewing of the immune system toward the proinflammatory type is a contributing factor. Because B cells were previously found to infiltrate the fracture healing site at abundant levels, we examined the regulatory B cells (Bregs) in DU/NU patients. In bone fracture patients with normal healing, the frequency of interleukin (IL)-10-expressing B cells was significantly upregulated in the early healing process (6 weeks post-surgery) and was downregulated later on (18 weeks post-surgery), whereas in DU/NU patients, the early upregulation of IL-10-expressing B cells was missing. The majority of IL-10-expressing B cells were concentrated in the IgM+ CD27+ fraction in both controls and patients. IgM+ CD27+ B cells effectively suppressed interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and IL-2 expression from CD4+ T cells, as well as IFN-gamma and TNF-alpha expression from CD8+ T cells. The IgM+ CD27+ B cell-mediated suppression was restricted to the sample from the early healing time point in controls, as the IgM+ CD27+ B cells from normal healing patients later on or from DU/NU patients did not present significant regulatory function. In addition, culturing of CD4+ CD25+ Tregs with IgM+ CD27+ B cells from controls at early healing time point resulted in higher Foxp3 expression, a function absent in controls at later time point, or in DU/NU patients. In conclusion, our results support a role of B cell-mediated regulation early during the bone healing process. PMID- 28008636 TI - Conscientious Objection to Vaccination. AB - Vaccine refusal occurs for a variety of reasons. In this article we examine vaccine refusals that are made on conscientious grounds; that is, for religious, moral, or philosophical reasons. We focus on two questions: first, whether people should be entitled to conscientiously object to vaccination against contagious diseases (either for themselves or for their children); second, if so, to what constraints or requirements should conscientious objection (CO) to vaccination be subject. To address these questions, we consider an analogy between CO to vaccination and CO to military service. We argue that conscientious objectors to vaccination should make an appropriate contribution to society in lieu of being vaccinated. The contribution to be made will depend on the severity of the relevant disease(s), its morbidity, and also the likelihood that vaccine refusal will lead to harm. In particular, the contribution required will depend on whether the rate of CO in a given population threatens herd immunity to the disease in question: for severe or highly contagious diseases, if the population rate of CO becomes high enough to threaten herd immunity, the requirements for CO could become so onerous that CO, though in principle permissible, would be de facto impermissible. PMID- 28008637 TI - The Edge of Human? The Problem with the Posthuman as the 'Beyond'. AB - This article asks whether enhancement can truly lead to something beyond humanity, or whether it is, itself, an inherently human act. The 'posthuman' is an uncertain proposition. What, exactly, would one be? Many commentators suggest it to be an endpoint for the use of enhancement technologies, yet few choose to codify the term outright; which frequently leads to unnecessary confusion. Characterizing and contextualizing the term, particularly its more novel uses, is therefore a valuable enterprise. The abuse of the term 'Human', especially in the context of the enhancement debate and the myriad meanings ascribed to it, could give 'posthuman' very different slants depending on one's assumptions. There are perhaps three main senses in which the term 'human' is employed: the biological, the moral, and the self-idealizing. In the first of these, 'human' is often conflated with Homo sapiens, and used interchangeably to denote species; in the second, 'human' (or 'humanity') generally refers to a community of beings which qualify as having a certain moral value; and the third, the self-idealizing sense, is more descriptive; a label denoting the qualities that make us who we are as beings, or 'what matters about those who matter'. So, what might enhancement make us? A novel species or genus of hominid? Or, perhaps, a morally more valuable being than a regular human? Of course, there's a third option: that a posthuman is a being which embodies our self-ideal more successfully than we do ourselves - one 'more human than human'. Which to choose? PMID- 28008638 TI - When is a Choice not a Choice? 'Sham Offers' and the Asymmetry of Adolescent Consent and Refusal. AB - In some jurisdictions there is a puzzling asymmetry between consent and refusal, where, for some kinds of treatment, the adolescent patient has the power to permit her own treatment but her refusal does not have the same kind of normative significance as refusal of treatment by a competent adult. In this journal I recently offered a clarification and defence of this asymmetry in terms of a paternalistic justification of the sharing of normative powers between adolescents and other parties. Lawlor (2016) offers a number of objections to this account. Three of his objections can be dealt with quickly. But one of them is much more challenging: the asymmetry of consent and refusal entails a practice of making sham offers (offers that purport to be responsive to the patient's choices, but which, in fact, are not). They do not really offer a choice at all. Genuine offers seem to require a commitment to be symmetrically responsive to whatever decision outcome is reached by the recipient of the offer. When we reflect upon the way that offers can be made in complex social contexts, where different parties have a 'say' in what ought to be done, the symmetry of responsiveness need not apply. Offers can be genuine, without being symmetrically responsive. Contrary to the seemingly plausible objection, the asymmetry of consent and refusal does not entail sham offers, or the offer of 'sham choices'. PMID- 28008639 TI - The Invisible Discrimination Before Our Eyes: A Bioethical Analysis. AB - The goal of this article is to introduce a philosophical analysis of a widely neglected condition which affects between 3% and 18% of the population. People affected by this condition (which will be revealed later in the article) experience a lower level of wellbeing than the average population and are discriminated against in both their professional and their personal life. I will argue that this form of discrimination should be taken more seriously in philosophical debate and that social, legal and medical measures ought to be taken in order to improve the quality of life of people affected by this condition. PMID- 28008640 TI - Objection to Conscience: An Argument Against Conscience Exemptions in Healthcare. AB - I argue that appeals to conscience do not constitute reasons for granting healthcare professionals exemptions from providing services they consider immoral (e.g. abortion). My argument is based on a comparison between a type of objection that many people think should be granted, i.e. to abortion, and one that most people think should not be granted, i.e. to antibiotics. I argue that there is no principled reason in favour of conscientious objection qua conscientious that allows to treat these two cases differently. Therefore, I conclude that there is no principled reason for granting conscientious objection qua conscientious in healthcare. What matters for the purpose of justifying exemptions is not whether an objection is 'conscientious', but whether it is based on the principles and values informing the profession. I provide examples of acceptable forms of objection in healthcare. PMID- 28008641 TI - Effects of miRNAs on myocardial apoptosis by modulating mitochondria related proteins. AB - Myocardial apoptosis play a vital role in pathogenesis of cardiovascular diseases. The intrinsic pathway of apoptosis (mitochondrial apoptosis pathway) and abnormal mitochondrial fission and fusion have a detrimental effect on cells under a variety of intracellular stresses including hypoxia, oxidative stress, drug toxicity or DNA damage and contributes to the development of heart failure (HF), myocardial infarction (MI), diabetic cardiomyopathy and ischaemia/reperfusion injury (I/R). MicroRNAs (miRNAs) are endogenous short non coding RNAs, which target 3'-untranslated region of mRNA to switch off gene expression. They play crucial roles in regulating complicated cardiac signalling and transcriptional events during cardiac development as well as in diseased condition. In this review, we summarize the molecular mechanism of mitochondrial apoptosis in cardiac cells and influence of miRNAs on them. MiRNAs regulate cardiac mitochondrial apoptosis by exert their effects on mitochondrial fission and fusion, reactive oxygen species (ROS) generation and Ca2+ homeostasis, Bcl-2 family members, and other mitochondrial function proteins. This advancement in understanding mechanism of cardiac cells death provides us new therapy targets for cardiovascular diseases associated with mitochondrial dysfunctions. PMID- 28008642 TI - The Substance View: A Critique (Part 3). AB - In my articles 'The Substance View: A Critique' and 'The Substance View: A Critique (Part 2),' I raise objections to the substance view (naturally), a theory of intrinsic value and moral standing defended by a number of contemporary moral philosophers, including Robert P. George, Patrick Lee, Christopher Tollefsen, and Francis Beckwith. In part one of my critique of the substance view, I raise reductio-style objections to the substance view's conclusion that the standard human fetus has the same intrinsic value and moral standing as the standard adult human being, among other human beings. In part two, I raise objections to some of the premises invoked in support of that conclusion. Here, in part three, I raise objections to Henrik Friberg-Fernros's attempt to rebut some of the aforementioned objections. PMID- 28008643 TI - Epidermotropic skin involvement of splenic marginal zone B-cell lymphoma: a diagnostic challenge. PMID- 28008644 TI - Test-retest reliability of quantitative sensory testing for mechanical somatosensory and pain modulation assessment of masticatory structures. AB - Assessing the reliability of medical measurements is a crucial step towards the elaboration of an applicable clinical instrument. There are few studies that evaluate the reliability of somatosensory assessment and pain modulation of masticatory structures. This study estimated the test-retest reliability, that is over time, of the mechanical somatosensory assessment of anterior temporalis, masseter and temporomandibular joint (TMJ) and the conditioned pain modulation (CPM) using the anterior temporalis as the test site. Twenty healthy women were evaluated in two sessions (1 week apart) by the same examiner. Mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up ratio (WUR) and pressure pain threshold (PPT) were assessed on the skin overlying the anterior temporalis, masseter and TMJ of the dominant side. CPM was tested by comparing PPT before and during the hand immersion in a hot water bath. anova and intra-class correlation coefficients (ICCs) were applied to the data (alpha = 5%). The overall ICCs showed acceptable values for the test-retest reliability of mechanical somatosensory assessment of masticatory structures. The ICC values of 75% of all quantitative sensory measurements were considered fair to excellent (fair = 8.4%, good = 33.3% and excellent = 33.3%). However, the CPM paradigm presented poor reliability (ICC = 0.25). The mechanical somatosensory assessment of the masticatory structures, but not the proposed CPM protocol, can be considered sufficiently reliable over time to evaluate the trigeminal sensory function. PMID- 28008645 TI - Confidence intervals for directly standardized rates using mid-p gamma intervals. AB - Directly standardized rates continue to be an integral tool for presenting rates for diseases that are highly dependent on age, such as cancer. Statistically, these rates are modeled as a weighted sum of Poisson random variables. This is a difficult statistical problem, because there are k observed Poisson variables and k unknown means. The gamma confidence interval has been shown through simulations to have at least nominal coverage in all simulated scenarios, but it can be overly conservative. Previous modifications to that method have closer to nominal coverage on average, but they do not achieve the nominal coverage bound in all situations. Further, those modifications are not central intervals, and the upper coverage error rate can be substantially more than half the nominal error. Here we apply a mid-p modification to the gamma confidence interval. Typical mid-p methods forsake guaranteed coverage to get coverage that is sometimes higher and sometimes lower than the nominal coverage rate, depending on the values of the parameters. The mid-p gamma interval does not have guaranteed coverage in all situations; however, in the (not rare) situations where the gamma method is overly conservative, the mid-p gamma interval often has at least nominal coverage. The mid-p gamma interval is especially appropriate when one wants a central interval, since simulations show that in many situations both the upper and lower coverage error rates are on average less than or equal to half the nominal error rate. PMID- 28008646 TI - Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage. AB - Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 MUg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI) continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator. PMID- 28008647 TI - Palmoplantar Keratoderma in Costello Syndrome Responsive to Acitretin. AB - Costello syndrome (CS) is a multisystem congenital disorder characterized by coarse facial features, cardiac defects, intellectual disability, and predisposition to malignancies. Dermatologic findings can include cutaneous papillomas, skin redundancy, acanthosis nigricans, and keratosis pilaris. Palmoplantar keratoderma (PPK) is present in approximately 76% of patients with CS, with disabling functional consequences in severe cases. We report a case of CS with severe PPK that improved dramatically with systemic administration of acitretin 0.3 mg/kg/day. PMID- 28008648 TI - Evaluating the effects of triclosan on 3 field crops grown in 4 formulations of biosolids. AB - A growing body of evidence suggests that amending soil with biosolids can be an integral component of sustainable agriculture. Despite strong evidence supporting its beneficial use in agriculture, there are concerns that chemicals, such as pharmaceuticals and personal care products, could present a risk to terrestrial ecosystems and human health. Triclosan is one of the most commonly detected compounds in biosolids. To date, laboratory studies indicate that triclosan likely poses a de minimis risk to field crops; however, these studies were either conducted under unrealistic exposure conditions or only assessed 1 or 2 formulations of biosolids. The purpose of the present study was to characterize the effects of triclosan on field crops in soils amended with 4 different formulations of biosolids (liquid, dewatered, compost, and alkaline-hydrolyzed), containing both background and spiked triclosan concentrations, following best management practices used in the province of Ontario. Three crop species (corn, soybean, and spring wheat) were evaluated using several plant growth endpoints (e.g., root wet mass, shoot length, shoot wet/dry mass) in 70-d to 90-d potted soil tests. The results indicated no adverse impact of triclosan on any crop biosolids combination. Conversely, amending soil with biosolids either enhanced or had no negative effect, on the growth of plants. Results of the present study suggest little risk of triclosan to crops in agricultural fields amended with biosolids. Environ Toxicol Chem 2017;36:1896-1908. (c) 2016 SETAC. PMID- 28008649 TI - Flexible parametric modelling of the cause-specific cumulative incidence function. AB - Competing risks arise with time-to-event data when individuals are at risk of more than one type of event and the occurrence of one event precludes the occurrence of all other events. A useful measure with competing risks is the cause-specific cumulative incidence function (CIF), which gives the probability of experiencing a particular event as a function of follow-up time, accounting for the fact that some individuals may have a competing event. When modelling the cause-specific CIF, the most common model is a semi-parametric proportional subhazards model. In this paper, we propose the use of flexible parametric survival models to directly model the cause-specific CIF where the effect of follow-up time is modelled using restricted cubic splines. The models provide smooth estimates of the cause-specific CIF with the important advantage that the approach is easily extended to model time-dependent effects. The models can be fitted using standard survival analysis tools by a combination of data expansion and introducing time-dependent weights. Various link functions are available that allow modelling on different scales and have proportional subhazards, proportional odds and relative absolute risks as particular cases. We conduct a simulation study to evaluate how well the spline functions approximate subhazard functions with complex shapes. The methods are illustrated using data from the European Blood and Marrow Transplantation Registry showing excellent agreement between parametric estimates of the cause-specific CIF and those obtained from a semi-parametric model. We also fit models relaxing the proportional subhazards assumption using alternative link functions and/or including time-dependent effects. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28008651 TI - Determinants of pre-transplantation pectoralis muscle area (PMA) and post transplantation change in PMA in lung transplant recipients. AB - BACKGROUND: This study aimed to determine predictors of pectoralis muscle area (PMA) and assess change in PMA following lung transplantation and its relationship to outcomes. METHODS: A retrospective review of 88 lung transplant recipients at a single center was performed. PMA was determined on a single axial slice from chest computerized tomography. Pectoralis muscle index (PMI) was calculated from the PMA divided by the height squared. RESULTS: PMI decreased post-transplantation (8.1+/-2.8 cm2 /m2 pre-transplantation, 7.5+/-2.9 cm2 /m2 at 6 months, and 7.6+/-2.7 cm2 /m2 at 12 months, P<.05). Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) were predictors of pre-transplant PMI (beta=-2.3, P=.001 for COPD; beta=2.1, P<.001 for ILD) and percent change in PMI at 12 months post-transplantation relative to baseline (beta=19.2, P=.04 for COPD; beta=-20.1, P=.01 for ILD). Patients in the highest quartile for PMI change at 12 months had fewer ventilator days compared with patients in the other quartiles (P=.03). CONCLUSIONS: Underlying diagnosis was a significant predictor of both pre-transplantation PMI and change in PMI post transplantation. Further studies of PMI are needed to determine its clinical utility in predicting outcomes following lung transplantation. PMID- 28008652 TI - Multiple Milia as an Isolated Skin Manifestation of Dominant Dystrophic Epidermolysis Bullosa: Evidence of Phenotypic Variability. AB - We report a Japanese pedigree with dominant dystrophic epidermolysis bullosa (DDEB) harboring the p.G2251E mutation of COL7A1. The proband of this pedigree presented with multiple milia as an isolated skin manifestation without a history of blistering and subsequently developed generalized intractable blisters, suggesting that multiple milia could be a primary manifestation of DDEB. Her mother exhibited nail dystrophy and pruritic nodules and her elder sister was unaffected, despite having the same COL7A1 mutation. Inter- and intrafamilial clinical variability are often observed in DDEB, so we should be aware of this factor to provide appropriate genetic counselling. PMID- 28008653 TI - Altruistic Lying in an Alibi Corroboration Context: The Effects of Liking, Compliance, and Relationship between Suspects and Witnesses. AB - Police investigators, judges, and jurors are often very skeptical of alibi witness testimony. To investigate when and why individuals lie for one another, we conducted two studies in which witnesses' support of a false alibi was observed. We varied the level of social pressure exerted on witnesses and the level of affinity between suspect-witness pairs. During a study session purportedly intended to investigate dyadic problem-solving ability, a mock theft was staged. When questioned, participants were provided the opportunity to either corroborate or refute a confederate's false alibi that the latter was with them when the theft occurred. Participants were more likely to lie for the confederate when the latter explicitly asked participants to conceal his/her whereabouts during the time of the theft (Study 1). How much participants liked the suspect did not impact lying; however, participants lied for a confederate more often when the latter was a friend rather than a stranger (Study 2). Results show that alibi witnesses often lie and that investigators and jurors may not accurately estimate the likelihood that such witnesses will lie for one another. Witnesses who lied also reported doing so more often because they believed that the suspect was innocent rather than guilty. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28008650 TI - Evolution of body weight parameters up to 3 years after solid organ transplantation: The prospective Swiss Transplant Cohort Study. AB - Obesity and weight gain are serious concerns after solid organ transplantation (Tx); however, no unbiased comparison regarding body weight parameter evolution across organ groups has yet been performed. Using data from the prospective nationwide Swiss Transplant Cohort Study, we compared the evolution of weight parameters up to 3 years post-Tx in 1359 adult kidney (58.3%), liver (21.7%), lung (11.6%), and heart (8.4%) recipients transplanted between May 2008 and May 2012. Changes in mean weight and body mass index (BMI) category were compared to reference values from 6 months post-Tx. At 3 years post-Tx, compared to other organ groups, liver Tx recipients showed the greatest weight gain (mean 4.8+/ 10.4 kg), 57.4% gained >5% body weight, and they had the highest incidence of obesity (38.1%). After 3 years, based on their BMI categories at 6 months, normal weight and obese liver Tx patients, as well as underweight kidney, lung and heart Tx patients had the highest weight gains. Judged against international Tx patient data, the majority of our Swiss Tx recipients' experienced lower post-Tx weight gain. However, our findings show weight gain pattern differences, both within and across organ Tx groups that call for preventive measures. PMID- 28008654 TI - Application of a multi-directional transformable retractor for lymphatic supermicrosurgery using SEKI method. PMID- 28008655 TI - Characterization and functional study of a Cecropin-like peptide from the Chinese oak silkworm, Antheraea pernyi. AB - In present study, a Cecropin-like peptide from Antheraea pernyi (ApCec) was cloned and characterized. The full-length ApCec cDNA encoded a protein with 64 amino acids including a putative 22-amino-acid signal peptide, a 4-amino-acid propeptide, and a 38-amino-acid mature peptide. ApCec gene was highly expressed in Malpighian tubules of A. pernyi after induction for 24 h by Escherichia coli in PBS. Pro-ApCec (including propeptide and mature peptide) and M-ApCec (just mature peptide) were synthesized chemically and analyzed by HPLC and mass spectroscopy. The antibacterial activity of M-ApCec is more potent than pro-ApCec against E. coli K12 or B. subtilus in both minimum inhibitory concentration and inhibition zone assays. Hemolytic assay results showed M-ApCec possessed a low cytotoxicity to mammalian cells. The secondary structure of M-ApCec forms alpha helical structure, shown by circular dichroism spectroscopy. Transmission electron microscopy analysis suggested that M-ApCec killed bacteria by disrupting bacterial cell membrane integrity. Our results indicate ApCec may play an important role in defending from pathogenic bacteria in A. pernyi, and it may be as a potential candidate for applications in antibacterial drug development and agriculture. PMID- 28008656 TI - Human herpesvirus 6 lymphadenitis in drug rash with eosinophilia and systemic symptoms syndrome: a lymphoma mimic. AB - AIMS: Lymphadenopathy, haematological abnormalities and constitutional symptoms are among the non-specific manifestations seen in drug rash with eosinophilia and systemic symptoms (DRESS), an uncommon but potentially fatal cutaneous adverse drug reaction. The ubiquitous human herpesvirus 6 (HHV-6) plays a unique role in the pathogenesis of DRESS, with emerging data suggesting that reactivation occurs in most cases and contributes to the clinical manifestations, including lymphadenopathy. Further, in the appropriate clinical context, demonstration of HHV-6 reactivation may lend support to a diagnosis of DRESS. The histopathology of DRESS-associated HHV-6 lymphadenitis is reported rarely, with morphologic and immunophenotypic characteristics concerning for T cell lymphoma. The aim is to characterize the histopathology of HHV-6 lymphadenitis in the context of DRESS and to highlight this as an important cause of lymphadenopathy that may be a clinical, morphologic and immunophenotypic mimic of lymphoma. METHODS AND RESULTS: We describe a case of lymphoma-mimicking lymphadenitis in which the histopathological demonstration of reactivation of HHV-6 infection lent support to the clinical diagnosis of DRESS. CONCLUSION: Lymph node biopsies concerning for T cell lymphoma should be evaluated for HHV-6 involvement in a clinical context suggestive of DRESS. PMID- 28008657 TI - Bodyweight-adjustments introduce significant correlations between CYP3A metrics and tacrolimus clearance. PMID- 28008658 TI - Hepatic stellate cells secreting WFA+ -M2BP: Its role in biological interactions with Kupffer cells. AB - BACKGROUND AND AIM: Hepatic stellate cells (HSCs) play a central role in hepatic fibrosis and are regulated by Kupffer cells (KCs). Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+ -M2BP) was recently identified as a serum marker for hepatic fibrosis. Although WFA+ -M2BP was identified as a ligand of Mac-2, the function of WFA+ -M2BP in hepatic fibrosis remains unclear. METHODS: Liver specimens were obtained from five patients with cirrhosis, five with chronic hepatitis, and five without hepatic fibrosis. WFA+ -M2BP kinetics were evaluated histologically and in subpopulations of liver cells such as HSCs, KCs, endothelial cells, biliary epithelial cells, and hepatocytes in in vitro culture. The function of WFA+ -M2BP in activated HSCs was evaluated using immunoblot analysis. RESULTS: Numbers of WFA+ -M2BP-positive cells in liver tissues increased with fibrosis stage. There were significant differences in WFA+ -M2BP levels between fibrosis stages F0 and F1-2 (P = 0.012) and between fibrosis stages F1-2 and F3-4 (P < 0.001). HSCs were the source of WFA+ -M2BP secretion in in vitro cultures of liver cells, as determined by sandwich immunoassay. Cells of the human HSC line LX-2 also secreted WFA+ -M2BP. Histologically, tissue sections showed that WFA+ -M2BP was located in Mac-2-expressing KCs. In vitro assays showed that exogenous WFA+ -M2BP stimulation enhanced Mac-2 expression in KCs and that HSCs co-cultured with KCs increased alpha-smooth muscle actin expression. Finally, Mac-2-depleted KCs with short interfering RNA had reduced alpha-smooth muscle actin expression following co-culturing with HSCs. CONCLUSIONS: WFA+ -M2BP from HSCs induces Mac-2 expression in KCs, which in turn activates HSCs to be fibrogenic. PMID- 28008659 TI - BALF cytokines in different phenotypes of chronic lung allograft dysfunction in lung transplant patients. AB - The long-term success of lung transplantation (LT) is limited by chronic lung allograft dysfunction (CLAD). Different phenotypes of CLAD have been described, such as bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). The purpose of this study was to investigate the levels of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) as markers of these CLAD phenotypes. BALF was collected from 51 recipients who underwent (bilateral and unilateral) LT. The study population was divided into three groups: stable (ST), BOS, and RAS. Levels of interleukin (IL)-4, IL-5, IL-6, IL 10, IL-13, tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using the multiplex technology. BALF neutrophilia medians were higher in BOS (38%) and RAS (30%) than in ST (8%) (P=.008; P=.012). Regarding BALF cytokines, BOS and RAS patients showed higher levels of INF-gamma than ST (P=.02; P=.008). Only IL-5 presented significant differences between BOS and RAS (P=.001). BALF neutrophilia is as a marker for both CLAD phenotypes, BOS and RAS, and IL-5 seems to be a potential biomarker for the RAS phenotype. PMID- 28008660 TI - Humidity- and Photo-Induced Mechanical Actuation of Cross-Linked Liquid Crystal Polymers. AB - Azobenzene-containing cross-linked liquid crystal polymer films without hydrophilic groups exhibit dual-responsivity to humidity and UV light. The films realize not only a series of large and sophisticated contactless motions by utilizing moisture, including an inchworm walk, and tumbling locomotion, but also dual-mode actuation that can be applied in flexible electronics. PMID- 28008661 TI - Rescue alemtuzumab for refractory acute cellular rejection and bronchiolitis obliterans syndrome after lung transplantation. AB - Refractory acute cellular rejection (rACR) is associated with death and bronchiolitis obliterans syndrome (BOS) post-lung transplantation. We report the largest cohort of lung transplant recipients (LTRs) treated with rescue alemtuzumab for rACR or BOS. RACR outcomes included burden of ACR 30 days before and 180 days after rescue assessed by a novel composite rejection standardized score (CRSS, range 0-6) and freedom from >=A2 ACR. BOS outcomes included freedom from BOS progression and FEV1 decline >10%. Univariate parametric and nonparametric statistical approaches were used to assess treatment response. Kaplan-Meier method with log rank conversion was used to assess freedom from events. Fifty-seven alemtuzumab doses (ACR 40 and BOS 17) given to 51 patients were included. Median time to rescue was 722 (IQR 42-1403) days. CRSS declined significantly (3 vs 0.67, P<0.001) after rescue. Freedom from >=A2 was 62.5% in rACR. Freedom from BOS progression was 52.9% at 180 days in the BOS cohort. Freedom from FEV1 decline >10% was 70% in BOS grade 1 and 14.3% in advanced BOS grades 2-3. Infections developed in 72.5% and 76.5% of rACR and BOS groups. Rescue alemtuzumab appears useful for rACR. Patients with BOS 1 may have transient benefit, and patients with advanced BOS seem not to respond to alemtuzumab. PMID- 28008662 TI - Efficacy and safety of short-term treatment with isoniazid and rifampicin for latent tuberculosis infection in lung transplant candidates. AB - BACKGROUND: The current recommendation for the treatment of latent tuberculosis infection (LTBI) in solid organ transplant candidates is isoniazid for 9 months, but this treatment has the main problem of frequently reaching the posttransplant period. METHODS: This is the study of efficacy and safety of a 3-month regimen with isoniazid and rifampicin (3HR) in lung transplant candidates in the Reina Sofia Hospital in Cordoba. RESULTS: Three hundred and ninety-eight lung transplant patients were evaluated. Ninety-two (24.9%) had LTBI and just 22 received the 3HR treatment. One additional patient was treated because he had a history of previous incomplete treatment for active TB. None of the treated patients developed posttransplant tuberculosis compared to three of the 62 patients with LTBI who were not treated (4.8%). Three patients could not conclude the 3HR treatment (13%), but only two had adverse effects (8.7%). CONCLUSIONS: Treatment of LTBI in lung transplant candidates using a short course of 3HR appears to be effective and safe in preventing posttransplant TB in lung transplant recipients. PMID- 28008663 TI - Detection of metabolite changes in response to a varying visual stimulation paradigm using short-TE 1 H MRS at 7 T. AB - The two-fold benefit of 1 H magnetic resonance spectroscopy (MRS) at high B0 fields - enhanced sensitivity and increased spectral dispersion - has been used previously to study dynamic changes in metabolite concentrations in the human brain in response to visual stimulation. In these studies, a strong visual on/off stimulus was combined with MRS data acquisition in a voxel location in the occipital cortex determined by an initial functional magnetic resonance imaging experiment. However, 1) to exclude the possibility of systemic effects (heartbeat, blood flow, etc.), which tend to be different for on/off conditions, a modified stimulation condition not affecting the target voxel needs to be employed, and 2) to assess important neurotransmitters of low concentration, in particular gamma-aminobutyric acid (GABA), it may be advantageous to analyze steady-state, rather than dynamic, conditions. Thus, the aim of this study was to use short-TE 1 H MRS methodology at 7 T to detect differences in steady-state metabolite levels in response to a varying stimulation paradigm in the human visual cortex. The two different stimulation conditions were termed voxel and control activation. Localized MR spectra were acquired using the SPECIAL (spin echo full-intensity acquired localized) sequence. Data were analyzed using LCModel. Fifteen individual metabolites were reliably quantified. On comparison of steady-state concentrations for voxel versus control activation, a decrease in GABA of 0.05 mmol/L (5%) and an increase in lactate of 0.04 mmol/L (7%) were found to be the only significant effects. The observed reduction in GABA can be interpreted as reduced neuronal inhibition during voxel activation, whereas the increase in lactate hints at an intensification of anaerobic glycolysis. Differences from previous studies, notably the absence of any changes in glutamate, are attributed to the modified experimental conditions. This study demonstrates that the use of advanced 1 H MRS methodology at 7 T allows the detection of subtle changes in metabolite concentrations involved in neuronal activation and inhibition. PMID- 28008664 TI - Cell count-based triaging of cytology samples for cell block preparation. AB - OBJECTIVE: Cytology samples can sometimes yield cell blocks of low cellularity that are inadequate for cytomorphological evaluation and ancillary studies. The purpose of this study was to analyse the value of cell count based-triaging of samples for cell block preparation. METHODS: Cell blocks were prepared from different cytology samples using HistoGelTM according to the manufacturer's instructions following cell count assessment. The adequacy of cell blocks was semi-quantitatively scored as empty, scanty, moderate or highly cellular by evaluating corresponding haematoxylin and eosin (H&E) sections. Cell blocks with moderate and highly cellular H&E sections were considered adequate whereas cell blocks with empty and scanty cells in H&E sections were inadequate for cytomorphological evaluation. The average, range and a median number of cells (*106 ) embedded in adequate and inadequate cell blocks were compared. RESULTS: Among 54 cell blocks prepared from fine needle aspiration biopsies (FNAs, 32), effusions (4), brushings (13) and cell lines (5), 20 cell blocks (37%) yielded moderate or highly cellular H&E sections and were considered adequate whereas 34 (63%) cell blocks were empty or scanty and thus considered inadequate. The average (+/- SD) number of cells (*106 ) embedded in adequate and inadequate cell blocks was 2.1 +/- 4.3 and 0.5 +/- 0.3, respectively. Samples containing at least 1 * 106 cells yielded adequate cell blocks in 12/16 cases (75%) whereas samples with less than 1 * 106 cells in 13/38 (34%) cases. CONCLUSION: The present study showed that cell count-based triaging of cytology samples could reduce the number of low cellular cell blocks. PMID- 28008665 TI - Discovery of novel potent nuclear factor kappa-B inhibitors (IKK-beta) via extensive ligand-based modeling and virtual screening. AB - Inhibitor kappa-B kinase-beta (IKK-beta) controls the activation of nuclear transcription factor kappa-B and has been linked to inflammation and cancer. Therefore, inhibitors of this kinase should have potent anti-inflammatory and anticancer properties. Accordingly, we explored the pharmacophoric space of 218 IKK-beta inhibitors to identify high-quality binding models. Subsequently, genetic algorithm-based quantitative structure activity relationship (QSAR) analysis was employed to select the best possible combination of pharmacophoric models and physicochemical descriptors that explain bioactivity variation among training compounds. Three successful pharmacophores emerged in 2 optimal QSAR equations (r12175 = 0.733, r12LOO = 0.52, F1 = 65.62, r12PRESS against 43 test inhibitors = 0.63 and r22175 = 0.683, r22LOO = 0.52, F2 = 72.66, r22PRESS against 43 test inhibitors = 0.65). Two pharmacophores were merged in a single binding model. Receiver operating characteristic curve validation proved the excellent qualities of this model. The merged pharmacophore and the associated QSAR equations were applied to screen the National Cancer Institute list of compounds. Ten hits were found to exhibit potent anti-IKK-beta bioactivity, out of which, one illustrates IC50 of 11.0nM. PMID- 28008666 TI - Detection of cryptococcosis in liquid-based sputum cytology. PMID- 28008667 TI - Effect of a brief episode of experimental muscle pain on jaw movement and jaw muscle activity during chewing. AB - The aims of this study were to determine whether: (i) the jaw motor system develops a new pattern of jaw movement and/or jaw-muscle activity after resolution of an acute episode of jaw-muscle pain; and (ii) if jaw-muscle activity and jaw-movement features change progressively with repetition of a chewing sequence. Jaw movement and jaw muscle (masseter, anterior temporalis, and digastric) activity were recorded during free and rate-standardized chewing in eight asymptomatic participants (pain infusion group), before and at three time blocks up to 45 min after a single 0.2-ml bolus infusion of 5% hypertonic saline into the right masseter muscle. The same procedure, without infusion, was performed in another eight participants (control group). There were no significant main effects of group on jaw movement and muscle activity, suggesting that there were no persistent post-pain effects on chewing. Across groups, repetitions of free and unstandardized chewing movements were associated with progressive increases in velocity and amplitude of jaw movement and masseter and temporalis electromyographic (EMG) activity. These findings suggest that factors unrelated to pain, such as practice effects, may be playing a role in the changes in jaw movement and jaw-muscle activity observed after resolution of an acute episode of jaw-muscle pain. PMID- 28008668 TI - Immunoglobulin heavy and light chains and T-cell receptor beta and gamma chains PCR assessment on cytological samples. A study comparing FTA cards and cryopreserved lymph node fine-needle cytology. AB - OBJECTIVES: To evaluate and compare the DNA yield and quality extracted from lymph node fine needle cytology (FNC) samples stored on FTA cards to those cryopreserved, and to assess the immunoglobulin heavy and light chains (IGHK) and T-Cell receptor beta and gamma chains (TCRBG) PCR tests. METHODS: DNA extractions were performed on FNC of 80 non-Hodgkin lymphomas (NHL), four myelomas and 56 benign reactive hyperplasias (BRH) cryopreserved and stored on FTA cards. The JAK2 gene was amplified to assess the DNA integrity and the IGHK/TCRBG clonality status was tested. RESULTS: IGHK monoclonality was found in 99% of B-cell NHL and 100% of myeloma. TCRBG monoclonality was found in 100% of T-cell NHL. TCRBG polyclonality was detected in 97% of B-cell NHL, 100% of myeloma and 96% of BRH. IGHK/TCRBG PCR data were confirmed by histological and/or follow-up controls. No differences were found in the DNA quality between cryopreservation and FTA cards storage methods. CONCLUSIONS: IGHK/TCRBG PCR of the lymphoproliferative process on FTA cards is comparable to those cryopreserved. FTA cards can be used to store lymph node FNC for further molecular investigations. PMID- 28008670 TI - Characterization of a rat orthotopic pancreatic head tumor model using three dimensional and quantitative multi-parametric MRI. AB - The purpose of this study was to investigate the reliability of 3D isotropic MRI and quantitative multi-parametric MRI characterization on an orthotopic pancreatic head tumor model in rats. 3D isotropic T2 -weighted MRI was performed as a routine for tumor longitudinal follow-up and volume estimation. Common bile duct diameter was measured from 3D multiplanar reconstruction. Quantitative multi parametric measurements including pixel-wise T2 , T1 relaxivity, apparent diffusion coefficient (ADC) and apparent diffusion kurtosis mapping were performed twice throughout tumor growth. Semi-quantitative and quantitative analyses based on an extended Tofts model were applied to region-of-interest based dynamic contrast-enhanced imaging, followed by contrast ratio measurement on standard contrast-enhanced imaging. Moreover, low-level texture-based analysis was inspected for T2 , T1 , ADC and contrast ratio measurements. Results indicated that multi-parametric MRI showed good reproducibility for tumor characterization; the measurements were not affected by tumor growth. Tumor growth was further confirmed with histology examinations. To conclude, state-of the-art clinical MRI techniques were translated to this preclinical tumor model with high reliability, and have paved the way for translational oncology studies on this tumor model. PMID- 28008669 TI - R-Type Ca2+ channels couple to inhibitory neurotransmission to the longitudinal muscle in the guinea-pig ileum. AB - NEW FINDINGS: What is the central question of this study? Subtypes of enteric neurons are coded by the neurotransmitters they synthesize, but it is not known whether enteric neuron subtypes might also be coded by other proteins, including calcium channel subtypes controlling neurotransmitter release. What is the main finding and its importance? Our data indicate that guinea-pig ileum myenteric neuron subtypes may be coded by calcium channel subtypes. We found that R-type calcium channels are expressed by inhibitory but not excitatory longitudinal muscle motoneurons. R-Type calcium channels are also not expressed by circular muscle inhibitory motoneurons. Calcium channel subtype-selective antagonists could be used to target subtypes of neurons to treat gastrointestinal motility disorders. There is evidence that R-type Ca2+ channels contribute to synaptic transmission in the myenteric plexus. It is unknown whether R-type Ca2+ channels contribute to neuromuscular transmission. We measured the effects of the nitric oxide synthase inhibitor nitro-l-arginine (NLA), Ca2+ channel blockers and apamin (SK channel blocker) on neurogenic relaxations and contractions of the guinea-pig ileum longitudinal muscle-myenteric plexus (LMMP) in vitro. We used intracellular recordings to measure inhibitory junction potentials. Immunohistochemical techniques localized R-type Ca2+ channel protein in the LMMP and circular muscle. Cadmium chloride (pan-Ca2+ channel blocker) blocked and NLA and NiCl2 (R-type Ca2+ channel blocker) reduced neurogenic relaxations in a non-additive manner. Nickel chloride did not alter neurogenic cholinergic contractions, but it potentiated neurogenic non-cholinergic contractions. Relaxations were inhibited by apamin, NiCl2 and NLA and were blocked by combined application of these drugs. Relaxations were reduced by NiCl2 or omega-conotoxin (N-type Ca2+ channel blocker) and were blocked by combined application of these drugs. Longitudinal muscle inhibitory junction potentials were inhibited by NiCl2 but not MRS 2179 (P2Y1 receptor antagonist). Circular muscle inhibitory junction potentials were blocked by apamin, MRS 2179, omega-conotoxin and CdCl2 but not NiCl2 . We conclude that neuronal R-type Ca2+ channels contribute to inhibitory neurotransmission to longitudinal muscle but less so or not all in the circular muscle of the guinea-pig ileum. PMID- 28008671 TI - Reliability of reporting the presence of transformation zone material in Papanicolaou smears using an automated screening system. AB - OBJECTIVE: This study was conducted to evaluate the reliability of using an interactive automated screening system (IAS) to determine the presence of endocervical and/or metaplastic cells (transformation zone material; TZM) in liquid-based cytology (LBC) Papanicolaou (Pap) smear slides. MATERIALS AND METHODS: A series of LBC Pap smears was manually screened to determine the presence or absence of TZM. The results were compared to those obtained through IAS. RESULTS: ThinPrep(r) Imaging System (Imager)-assisted screening indicated that 22.4% of the slides did not contain TZM in cases in which previous manual screening revealed that 100% of the slides did contain TZM. CONCLUSION: The reliability of determining TZM through IAS is limited. Manual screening of the slides appears to be necessary to report the presence of TZM accurately. PMID- 28008672 TI - The ANGULATA7 gene encodes a DnaJ-like zinc finger-domain protein involved in chloroplast function and leaf development in Arabidopsis. AB - The characterization of mutants with altered leaf shape and pigmentation has previously allowed the identification of nuclear genes that encode plastid localized proteins that perform essential functions in leaf growth and development. A large-scale screen previously allowed us to isolate ethyl methanesulfonate-induced mutants with small rosettes and pale green leaves with prominent marginal teeth, which were assigned to a phenotypic class that we dubbed Angulata. The molecular characterization of the 12 genes assigned to this phenotypic class should help us to advance our understanding of the still poorly understood relationship between chloroplast biogenesis and leaf morphogenesis. In this article, we report the phenotypic and molecular characterization of the angulata7-1 (anu7-1) mutant of Arabidopsis thaliana, which we found to be a hypomorphic allele of the EMB2737 gene, which was previously known only for its embryonic-lethal mutations. ANU7 encodes a plant-specific protein that contains a domain similar to the central cysteine-rich domain of DnaJ proteins. The observed genetic interaction of anu7-1 with a loss-of-function allele of GENOMES UNCOUPLED1 suggests that the anu7-1 mutation triggers a retrograde signal that leads to changes in the expression of many genes that normally function in the chloroplasts. Many such genes are expressed at higher levels in anu7-1 rosettes, with a significant overrepresentation of those required for the expression of plastid genome genes. Like in other mutants with altered expression of plastid encoded genes, we found that anu7-1 exhibits defects in the arrangement of thylakoidal membranes, which appear locally unappressed. PMID- 28008674 TI - Understanding the Effects of Roasting on Antioxidant Components of Coffee Brews by Coupling On-line ABTS Assay to High Performance Size Exclusion Chromatography. AB - INTRODUCTION: Coffee is a widely consumed beverage containing antioxidant active compounds. During roasting the phytochemical composition of the coffee bean changes dramatically and highly polymeric substances are produced. Besides chlorogenic acids that are already present in green coffee beans, melanoidins show antioxidant capacity as well. OBJECTIVE: To employ post-column derivatisation by coupling high performance size exclusion chromatography (HPSEC) to an antioxidant assay to investigate the effect of roasting on the properties of antioxidant active compounds in coffee brews. METHODOLOGY: We have investigated the antioxidant capacity of Coffea arabica (Arabica) and C. canephora (Robusta) beans that were roasted over the full spectrum of roast conditions (four roasting speeds to three roast degrees) by comparing the results from HPSEC coupled on-line to the ABTS assay with those from two batch assays, Folin Ciocalteu (FC) and oxygen radical absorbance capacity (ORAC) assay. RESULTS: The antioxidant capacity showed a general decrease towards slower and darker roasted coffee for all three assays, indicative of heat degradation of active compounds. Hence, low molecular weight (LMW) compounds such as chlorogenic acids (CGAs) decreased progressively already from relatively mild roasting conditions. In contrast, high molecular weight (HMW) compounds (e.g. melanoidins) increased from light to dark roast degrees with lowering magnitude towards slower roasting profiles. CONCLUSION: By coupling HPSEC on-line to the ABTS assay we were able to separately quantify the contribution of HMW and LMW compounds to the total antioxidant capacity, increasing our understanding of the roast process. (c) 2016 The Authors. Phytochemical Analysis Published by John Wiley & Sons Ltd. PMID- 28008673 TI - Daily antecedents and consequences of nightly sleep. AB - Sleep can serve as both cause and consequence of individuals' everyday experiences. We built upon prior studies of the correlates of sleep, which have relied primarily on cross-sectional data, to examine the antecedents and consequences of sleep using a daily diary design. Specifically, we assessed the temporal sequence between nightly sleep and daily psychosocial stressors. Parents employed in a US information technology company (n = 102) completed eight consecutive daily diaries at both baseline and 1 year later. In telephone interviews each evening, participants reported on the previous night's sleep hours, sleep quality and sleep latency. They also reported daily work-to-family conflict and time inadequacy (i.e. perceptions of not having enough time) for their child and for themselves to engage in exercise. Multi-level models testing lagged and non-lagged effects simultaneously revealed that sleep hours and sleep quality were associated with next-day consequences of work-to-family conflict and time inadequacy, whereas psychosocial stressors as antecedents did not predict sleep hours or quality that night. For sleep latency, the opposite temporal order emerged: on days with more work-to-family conflict or time inadequacy for child and self than usual, participants reported longer sleep latencies than usual. An exception to this otherwise consistent pattern was that time inadequacy for child also preceded shorter sleep hours and poorer sleep quality that night. The results highlight the utility of a daily diary design for capturing the temporal sequences linking sleep and psychosocial stressors. PMID- 28008675 TI - Exploring beta-Tubulin Inhibitors from Plant Origin using Computational Approach. AB - INTRODUCTION: beta-Tubulin is an important target for the binding of anti-cancer drugs, in particular, paclitaxel (taxol), vinblastine and epothilone. However, mutations in beta-tubulin structure give resistance to chemotherapeutic agents. Notably, mutations at R306C, F270 V, L217R, L228F, A185T and A248V positions in beta-tubulin give high resistance for paclitaxel binding. OBJECTIVE: To discover novel inhibitors of beta-tubulin from natural sources, particularly alkaloids, using a virtual screening approach. METHODOLOGY: A virtual screening approach was employed to find potent lead molecules from the Naturally-occurring Plant-based Anti-cancer Compound-activity Target (NPACT) database. Alkaloids have great potential to be anti-cancer agents. Therefore, we have screened all alkaloids from a total of 1574 molecules from the NPACT database for our study. Initially, Molinspiration and DataWarrior programs were utilised to calculate pharmacokinetics and toxicity risks of the alkaloids, respectively. Subsequently, AutoDock algorithm was employed to understand the binding efficiency of alkaloids against beta-tubulin. The binding affinity of the docked complex was confirmed by means of an intermolecular interaction study. Moreover, oral toxicity was predicted by using ProTox program. Further, metabolising capacity of drugs was studied by using SmartCYP software. Additionally, scaffold analysis was done with the help of scaffold trees and dendrograms, providing knowledge about the building blocks for parent-compound synthesis. RESULTS: Overall, the results of our computational analysis indicate that isostrychnine, obtained from Strychnosnux-vomica, satisfies pharmacokinetic and bioavailability properties, binds efficiently with beta-tubulin. Thus, it could be a promising lead for the treatment of paclitaxel resistant cancer types. CONCLUSION: This is the first observation of inhibitory activity of isostrychnine against beta-tubulin and warrants further experimental investigation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28008676 TI - Direct mapping of melanoma cell - endothelial cell interactions. AB - The most life-threatening aspect of cancer is metastasis; cancer patient mortality is mainly due to metastasis. Among all metastases, presence of brain metastasis is one with the poorest prognosis; the median survival time can be counted in months. Therefore, prevention or decreasing their incidence would be highly desired both by patients and physicians. Metastatic cells invading the brain must breach the cerebral vasculature, primarily the blood-brain barrier. The key step in this process is the establishment of firm adhesion between the cancer cell and the cerebral endothelial layer. Using the atomic force microscope, a high-resolution force spectrograph, our aim was to explore the connections among the cell morphology, cellular mechanics, and biological function in the process of transendothelial migration of metastatic cancer cells. By immobilization of a melanoma cell to an atomic force microscope's cantilever, intercellular adhesion was directly measured at quasi-physiological conditions. Hereby, we present our latest results by using this melanoma-decorated probe. Binding characteristics to a confluent layer of brain endothelial cells was directly measured by means of single-cell force spectroscopy. Adhesion dynamics and strength were characterized, and we present data about spatial distribution of elasticity and detachment strength. These results highlight the importance of cellular mechanics in brain metastasis formation and emphasize the enormous potential toward exploration of intercellular dynamic-related processes. PMID- 28008677 TI - Emphysema induced by elastase enhances acute inflammatory pulmonary response to intraperitoneal LPS in rats. AB - Abnormalities in lungs caused by emphysema might alter their response to sepsis and the occurrence of acute lung injury (ALI). This study compared the extension of ALI in response to intraperitoneal lipopolysaccharide (LPS) injection in Wistar rats with and without emphysema induced by elastase. Adult male Wistar rats were randomized into four groups: control, emphysema without sepsis, normal lung with sepsis and emphysema with sepsis. Sepsis was induced, and 24 h later the rats were euthanised. The following analysis was performed: blood gas measurements, bronchoalveolar lavage (BAL), lung permeability and histology. Animals that received LPS showed significant increase in a lung injury scoring system, inflammatory cells in bronchoalveolar lavage (BAL) and IL-6, TNF-alpha and CXCL2 mRNA expression in lung tissue. Animals with emphysema and sepsis showed increased alveolocapillary membrane permeability, demonstrated by higher BAL/serum albumin ratio. In conclusion, the presence of emphysema induced by elastase increases the inflammatory response in the lungs to a systemic stimulus, represented in this model by the intraperitoneal injection of LPS. PMID- 28008678 TI - Mast cells are permissive for rhinovirus replication: potential implications for asthma exacerbations. AB - BACKGROUND: Human rhinoviruses (HRVs) are a major trigger of asthma exacerbations, with the bronchial epithelium being the major site of HRV infection and replication. Mast cells (MCs) play a key role in asthma where their numbers are increased in the bronchial epithelium with increasing disease severity. OBJECTIVE: In view of the emerging role of MCs in innate immunity and increased localization to the asthmatic bronchial epithelium, we investigated whether HRV infection of MCs generated innate immune responses which were protective against infection. METHODS: The LAD2 MC line or primary human cord blood-derived MCs (CBMCs) were infected with HRV or UV-irradiated HRV at increasing multiplicities of infection (MOI) without or with IFN-beta or IFN lambda. After 24 h, innate immune responses were assessed by RT-qPCR and IFN protein release by ELISA. Viral replication was determined by RT-qPCR and virion release by TCID50 assay. RESULTS: HRV infection of LAD2 MCs induced expression of IFN-beta, IFN-lambda and IFN-stimulated genes. However, LAD2 MCs were permissive for HRV replication and release of infectious HRV particles. Similar findings were observed with CBMCs. Neutralization of the type I IFN receptor had minimal effects on viral shedding, suggesting that endogenous type I IFN signalling offered limited protection against HRV. However, augmentation of these responses by exogenous IFN-beta, but not IFN-lambda, protected MCs against HRV infection. CONCLUSION AND CLINICAL RELEVANCE: MCs are permissive for the replication and release of HRV, which is prevented by exogenous IFN-beta treatment. Taken together, these findings suggest a novel mechanism whereby MCs may contribute to HRV-induced asthma exacerbations. PMID- 28008679 TI - ZxAKT1 is essential for K+ uptake and K+ /Na+ homeostasis in the succulent xerophyte Zygophyllum xanthoxylum. AB - The inward-rectifying K+ channel AKT1 constitutes an important pathway for K+ acquisition in plant roots. In glycophytes, excessive accumulation of Na+ is accompanied by K+ deficiency under salt stress. However, in the succulent xerophyte Zygophyllum xanthoxylum, which exhibits excellent adaptability to adverse environments, K+ concentration remains at a relatively constant level despite increased levels of Na+ under salinity and drought conditions. In this study, the contribution of ZxAKT1 to maintaining K+ and Na+ homeostasis in Z. xanthoxylum was investigated. Expression of ZxAKT1 rescued the K+ -uptake defective phenotype of yeast strain CY162, suppressed the salt-sensitive phenotype of yeast strain G19, and complemented the low-K+ -sensitive phenotype of Arabidopsis akt1 mutant, indicating that ZxAKT1 functions as an inward rectifying K+ channel. ZxAKT1 was predominantly expressed in roots, and was induced under high concentrations of either KCl or NaCl. By using RNA interference technique, we found that ZxAKT1-silenced plants exhibited stunted growth compared to wild-type Z. xanthoxylum. Further experiments showed that ZxAKT1-silenced plants exhibited a significant decline in net uptake of K+ and Na+ , resulting in decreased concentrations of K+ and Na+ , as compared to wild type Z. xanthoxylum grown under 50 mm NaCl. Compared with wild-type, the expression levels of genes encoding several transporters/channels related to K+ /Na+ homeostasis, including ZxSKOR, ZxNHX, ZxSOS1 and ZxHKT1;1, were reduced in various tissues of a ZxAKT1-silenced line. These findings suggest that ZxAKT1 not only plays a crucial role in K+ uptake but also functions in modulating Na+ uptake and transport systems in Z. xanthoxylum, thereby affecting its normal growth. PMID- 28008680 TI - Perception and signalling of light and temperature cues in plants. AB - Light and temperature patterns are often correlated under natural plant growth conditions. In this review, we analyse the perception and signalling mechanisms shared by both these environmental cues and discuss the functional implications of their convergence to control plant growth. The first point of integration is the phytochrome B (phyB) receptor, which senses light and temperature. Downstream of phyB, the signalling core comprises two branches, one involving PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and the other CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) and ELONGATED HYPOCOTYL 5 (HY5). The dynamics of accumulation and/or localization of each of these core signalling components depend on light and temperature conditions. These pathways are connected through COP1, which enhances the activity of PIF4. The circadian clock modulates this circuit, since EARLY FLOWERING 3 (ELF3), an essential component of the evening complex (EC), represses expression of the PIF4 gene and PIF4 transcriptional activity. Phytochromes are probably not the only entry point of temperature into this network, but other sensors remain to be established. The sharing of mechanisms of action for two distinct environmental cues is to some extent unexpected, as it renders these responses mutually dependent. There are nonetheless many ecological contexts in which such a mutual influence could be beneficial. PMID- 28008681 TI - Prediction Rule for Diagnosis of Pulmonary Embolism Enhanced by Lung and Venous Ultrasound: Making Confusion or Increasing Efficiency? PMID- 28008683 TI - Non-traumatic out-of-hospital cardiac arrest in rural Taiwan: A retrospective study. AB - OBJECTIVE: Out-of-hospital cardiac arrest (OHCA) studies are usually conducted at metropolitan medical centres. Because rural studies are rare, our study aimed to assess non-traumatic OHCA prevalence and resuscitation outcomes in rural Taiwan. DESIGN: A retrospective observational study. SETTING: All seven designated community hospital emergency departments (ED) in Nantou County, Taiwan. PARTICIPANTS: All OHCA patients from May 2011 to March 2013. MAIN OUTCOME MEASURES: Any return of spontaneous circulation (ROSC) and survival for ED discharge. RESULTS: In the 23-month period, 850 OHCA cases were reported; 741 (87.2%) were non-traumatic. The overall ROSC achievement rate was 19.7%, with 16.4% case survival for ED discharge. Logistic regression identified that arrest in public (OR: 2.62, 95% CI: 1.19-5.78), witness when collapsed (OR: 2.14, 95% CI: 1.28-3.60), and cardiopulmonary resuscitation (CPR) by bystander (OR: 2.09, 95% CI: 1.02-4.26) might increase the likelihood of any ROSC; arrest in public (OR: 2.68, 95% CI: 1.10-6.50), witnessed collapse (OR: 2.26, 95% CI: 1.24-4.09) and CPR by bystander (OR: 2.79, 95% CI: 1.28-6.05) might also increase the likelihood of survival. For non-traumatic OHCA patients conveyed to EDs via emergency medical service system (EMS), a shorter response time (OR: 1.09, 95% CI: 1.01-1.18) and travelling time (OR: 1.04, 95% CI: 1.00-1.09) might also increase the chance of survival. CONCLUSION: Compared to previous data from metropolitan areas, ROSC achievement rate was lower in rural Taiwan. Witness presence, response and travelling times affect ROSC achievement in non-traumatic OHCA patients in rural Taiwan. PMID- 28008682 TI - Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis. AB - A 10-month-old spayed female Cane Corso dog was evaluated after a 2-month history of progressive blindness, ataxia, and lethargy. Neurologic examination abnormalities indicated a multifocal lesion with primarily cerebral and cerebellar signs. Clinical worsening resulted in humane euthanasia. On necropsy, there was marked astrogliosis throughout white matter tracts of the cerebrum, most prominently in the corpus callosum. In the cerebral cortex and midbrain, most neurons contained large amounts of autofluorescent storage material in the perinuclear area of the cells. Cerebellar storage material was present in the Purkinje cells, granular cell layer, and perinuclear regions of neurons in the deep nuclei. Neuronal ceroid lipofuscinosis (NCL) was diagnosed. Whole genome sequencing identified a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos. Our findings indicate a novel mutation causing the CLN1 form of NCL in a previously unreported dog breed. A canine model for CLN1 disease could provide an opportunity for therapeutic advancement, benefiting both humans and dogs with this disorder. PMID- 28008684 TI - 'I miss my family, it's been a while...' A qualitative study of clinicians who live and work in rural/remote Australian Aboriginal communities. AB - OBJECTIVES: Dental issues are more prevalent for Aboriginal Australians, especially those living in rural/remote locations, but distribution of clinicians is favoured towards metropolitan areas and are not always culturally competent. This study aimed to document the experiences of dental clinicians who relocated to rural/remote communities to provide dental services to Aboriginal communities in an effort to redress these gaps. SETTING: Clinicians working in a new rural/remote dental service strategy to Aboriginal communities in Northern NSW. DESIGN: Qualitative semi-structured face-to-face interviews and reflective diaries were analysed qualitatively. PARTICIPANTS: Relocating dental clinicians and their support team. RESULTS: Three major themes emerged: Theme one: Mastering the clinical environment through professional experiences: Increasing professional capabilities, clinical environment, valuing team work and gaining community respect. Theme two: Development and growth of the individual through personal and social experiences: culture shock, developing cultural competence, social impact, economic cost and personal adjustments and growth. Theme three: An overarching sense of achievement and advice to new clinicians. CONCLUSION: Relocation to rural and remote communities to provide health services is a complex but rewarding process. Providing personal and professional support, to relocating clinicians resulted in an overall positive experience for the participants, where they increased their professional skills and developed personally. Living and working in the community increased their cultural competence. Barriers were overcome through effective communication, flexibility and teamwork. Funding for rural placements, such as these, is critical for rural and remote health services and should include long-term appropriate funding for mentoring and support. PMID- 28008686 TI - A new theory of plant-microbe nutrient competition resolves inconsistencies between observations and model predictions. AB - Terrestrial plants assimilate anthropogenic CO2 through photosynthesis and synthesizing new tissues. However, sustaining these processes requires plants to compete with microbes for soil nutrients, which therefore calls for an appropriate understanding and modeling of nutrient competition mechanisms in Earth System Models (ESMs). Here, we survey existing plant-microbe competition theories and their implementations in ESMs. We found no consensus regarding the representation of nutrient competition and that observational and theoretical support for current implementations are weak. To reconcile this situation, we applied the Equilibrium Chemistry Approximation (ECA) theory to plant-microbe nitrogen competition in a detailed grassland 15 N tracer study and found that competition theories in current ESMs fail to capture observed patterns and the ECA prediction simplifies the complex nature of nutrient competition and quantitatively matches the 15 N observations. Since plant carbon dynamics are strongly modulated by soil nutrient acquisition, we conclude that (1) predicted nutrient limitation effects on terrestrial carbon accumulation by existing ESMs may be biased and (2) our ECA-based approach may improve predictions by mechanistically representing plant-microbe nutrient competition. PMID- 28008685 TI - Maternal immune correlates of protection from human cytomegalovirus transmission to the fetus after primary infection in pregnancy. AB - Immune control of primary human cytomegalovirus (HCMV) infection appears to depend on the interaction of humoral and T-cell responses. In this review, we have separately explored the 2 arms of the immune response to primary HCMV infection in HCMV-seronegative pregnant women transmitting (T) or not transmitting (NT) the infection to the fetus, with the objective of correlating the immune risk factors associated with vertical HCMV transmission. As for the humoral response, the following findings were documented: (i) in competitive binding assays, antibody titers to different antigenic sites of the gH pentamer complex were significantly lower in T compared with NT women; (ii) in addition, the number of neutralization sites recognized by T was significantly lower compared with NT women; (iii) the plaque formation inhibition assay showed a faster kinetics and a higher titer in NT women. As for T-cell immunity, the delayed expression of 3 immunological parameters (lymphoproliferative response, CD45RA reexpression in both CD4+ and CD8+ HCMV-specific T cells, and interleukin 2 production by HCMV-specific CD4+ T cells) were significantly associated with vertical transmission. This overview provides important information at the population level, which may help to inform the evaluation of interventions such as vaccination or treatments designed to interrupt intrauterine transmission of HCMV during primary infection. However, although we are waiting for an HCMV vaccination to become available, we emphasize that none of these parameters can be prognostically used on an individual basis because of the great variation in values among women. PMID- 28008687 TI - Hot Off the Press: Which Febrile Children With Sickle Cell Disease Need a Chest X Ray? AB - This retrospective chart review examined the rate of acute chest syndrome (ACS) in febrile children (aged 3 months to 21 years) with sickle cell disease and used recursive partitioning to determine which clinical factors were predictive of a diagnosis of ACS. Over the course of 2 years, 697 children made 1,837 visits to one of two pediatric emergency departments. ACS was diagnosed in 185 (10%) of the visits. PMID- 28008688 TI - The Clinical Next-Generation Sequencing Database: A Tool for the Unified Management of Clinical Information and Genetic Variants to Accelerate Variant Pathogenicity Classification. AB - Recent advances in next-generation sequencing (NGS) have given rise to new challenges due to the difficulties in variant pathogenicity interpretation and large dataset management, including many kinds of public population databases as well as public or commercial disease-specific databases. Here, we report a new database development tool, named the "Clinical NGS Database," for improving clinical NGS workflow through the unified management of variant information and clinical information. This database software offers a two-feature approach to variant pathogenicity classification. The first of these approaches is a phenotype similarity-based approach. This database allows the easy comparison of the detailed phenotype of each patient with the average phenotype of the same gene mutation at the variant or gene level. It is also possible to browse patients with the same gene mutation quickly. The other approach is a statistical approach to variant pathogenicity classification based on the use of the odds ratio for comparisons between the case and the control for each inheritance mode (families with apparently autosomal dominant inheritance vs. control, and families with apparently autosomal recessive inheritance vs. control). A number of case studies are also presented to illustrate the utility of this database. PMID- 28008689 TI - Doublet-Mediated DNA Rearrangement-A Novel and Potentially Underestimated Mechanism for the Formation of Recurrent Pathogenic Deletions. AB - Deletions and duplications of genomic DNA contribute to evolution, phenotypic diversity, and human disease. The underlying mechanisms are incompletely understood. We identified deletions of exon 10 of the SPAST gene in two unrelated families with hereditary spastic paraplegia. We excluded a founder event, but observed that the breakpoints map to identical repeat regions. These regions likely represent an intragenic "doublet," that is, an enigmatic class of local duplications. The fusion sequences for both deletions are compatible with recombination-based as well as with replication-based mechanisms. Searching the literature, we identified a partial SLC24A4 deletion that involved two copies of another doublet, and was likely formed in an analogous way. Comparing the SPAST and the SLC24A4 doublets with doublets identified previously suggested that many additional doublets have a high potential for triggering rearrangements. Considering that doublets are still being formed in the human genome, and that they likely create high local instability, we suggest that a two-step mechanism consisting of doublet generation and subsequent doublet-mediated deletion/duplication may underlie certain copy-number changes for which other mechanisms are currently assumed. Further studies are necessary to delineate the significance of the thus-far understudied doublets for the formation of copy number variation. PMID- 28008690 TI - Heavy alcohol use in adolescence is associated with altered cortical activity: a combined TMS-EEG study. AB - Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability. PMID- 28008691 TI - Effects of Functional Analytic Psychotherapy Therapist Training on Therapist Factors Among Therapist Trainees in Singapore: A Randomized Controlled Trial. AB - : Functional Analytic Psychotherapy (FAP) is a behavioral psychotherapy intervention that emphasizes the development of an intimate and intense therapeutic relationship as the vehicle of therapeutic change. Recently, research has provided preliminary support for a FAP therapist training (FAPTT) protocol in enhancing FAP competency. The present study aimed to expand on this research by examining the effects of FAPTT on FAP-specific skills and competencies and a set of broadly desirable therapist qualities (labelled awareness, courage and love in FAPTT) in a sample of therapist trainees in Singapore. The study also evaluated the feasibility and acceptability of FAP in the Singaporean context. Twenty-five students enrolled in a master's in clinical psychology program were recruited and randomly assigned to receive either eight weekly sessions of a FAPTT course or to a waitlist condition. All participants completed measures assessing empathy, compassionate love, trait mindfulness, authenticity and FAP-specific skills and competencies pre- and post-training, and at 2-month follow-up. A post-course evaluation was administered to obtain participants' qualitative feedback. Results indicated that compared with the waitlisted group, FAPTT participants reported significant increases in overall empathy, FAP skill and treatment acceptability from pre- to post-training. Improvements were observed on several outcome variables at 2-month follow-up. Participants reported finding the training to be both feasible and acceptable, although several raised issues related to the compatibility of the treatment with the local cultural context. Overall, the findings suggest that FAPTT is effective for improving specific FAP competencies and selected broadly desirable therapist qualities among therapist trainees. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Functional Analytic Therapy (FAP) therapist training protocol was effective in improving empathy and FAP skills among Singaporean therapist trainees. These improvements were maintained at 2-month follow-up. The training was found to be acceptable in the Singaporean context, although several adaptations were suggested to increase the compatibility between FAP principles and local cultural norms. PMID- 28008692 TI - A Response to "Diagnostic Performance of Wells Score Combined With Point-of-care Lung and Venous Ultrasound in Suspected Pulmonary Embolism". PMID- 28008693 TI - Acute Heart Failure in the Emergency Department: Just a One Night Stand? PMID- 28008695 TI - Family members' experience of intensive care unit support group: qualitative analysis of intervention. AB - BACKGROUND: Family members of intensive care unit patients develop anxiety, depression and/or symptoms suggestive of risk for post-traumatic stress. Nurse led support groups have been recommended and used in a variety of settings as a mechanism to help meet family needs and overcome challenges. These groups have been reported to increase the members' understanding of complex medical issues involved in their situations and to be helpful in identifying practical coping mechanisms. AIM: To investigate the experiences of family members participating in a nurse-social worker led support group in the intensive care unit. METHOD: Study design: prospective collection of family narratives during support group meetings. A qualitative analysis was done of the narratives of weekly routine nurse-social worker led support group for family members of intensive care unit patients. The meeting contents are documented and related in the nursing notes. SETTING: level 1 trauma centre, at a university hospital, with 13-bed intensive care unit. During the past 3 years this family support group has been providing routine intervention with the purpose of calming the families of intensive care unit patients during crisis situations by utilizing nurse, social worker and group dynamics. RESULTS: A qualitative analysis was performed on the content of support group dynamics. The principal themes found were Behavioural, Perceptual, Emotional and Supportive. CONCLUSIONS: The family support group provides the participants with a 'tool box' of coping mechanisms, which they can choose from in this current unfamiliar crisis event. The group provides a supportive environment, mutuality, a sense of belonging, needs of community, unconditional acceptance and information provision for the participants in the group. RELEVANCE TO CLINICAL PRACTICE: In order to provide support for several families, nurses can use the family support group intervention as an effective technique in reaching as many families as possible. Narratives from family members during group meetings may be a good information source providing insights for nursing guidance and patient/family education. PMID- 28008694 TI - A narrow QRS tachycardia and cannon A waves: What is the mechanism? AB - Regular narrow QRS tachycardia, particularly if well-tolerated, is usually considered a "benign" arrhythmia of a supraventricular origin. This case concerns an 82-year-old male with ischemic heart disease who presented with recurrent episodes of a narrow QRS tachycardia that was initially diagnosed and treated as atrial tachyarrhythmia. However, careful physical examination and ECG analysis established the correct diagnosis, and the patient was managed appropriately. Remarkably, the observation of irregular cannon A waves, and Lewis lead recording, confirmed atrioventricular dissociation during tachycardia and indicated its underlying mechanism. PMID- 28008696 TI - Sub-Tenon's injection in equine cadaver eyes: MRI visualization of anesthetic fluid distribution and comparison of two different volumes. AB - OBJECTIVE: To compare the localization and distribution of two different anesthetic fluid volumes around equine cadaver eyes to determine an appropriate volume for a single sub-Tenon's injection in horses. PROCEDURE: A single sub Tenon's injection of 2% lidocaine was performed in 10 equine cadaver heads (20 eyes) using two different volumes (7 mL on one side and 10 mL on the opposite side). The posterior circular distribution of the anesthetic was quantified in sagittal, dorsal, and transverse MRI (T2W-TSE) sequences and evaluated independently by three board-certified radiologists. The distribution of the two fluid volumes was compared via a paired Student's t-test. The interobserver reliability was evaluated via a Kruskal-Wallis test. RESULTS: Extension of the injection fluid was observed along the dorsal and temporal quadrants of the globe within the subconjunctival space, the anterior and posterior sub-Tenon's space, and into the muscle sheaths along the extraocular muscles. Accumulation of anesthetic fluid directly surrounding the optic nerve was detected in three of 20 cadaver eyes. Circular distribution of the 7 and 10 mL anesthetic volumes was not significantly different (P = 0.849). More retrograde leakage of the anesthetic was observed using the 10 mL volume. Evaluation of interobserver reliability revealed no significant differences between observers (P = 0.21-0.92). CONCLUSIONS: Sub-Tenon's anesthesia can have potential as an alternative to retrobulbar anesthesia for ophthalmic surgeries in equines. A 7- to 10-mL injection volume should be appropriate based on the results of this study. The distribution of the anesthetic solution in live tissues, the clinical effects, and the potential for complications will have to be evaluated in vivo. PMID- 28008697 TI - Host cell binding of the flagellar tip protein of Campylobacter jejuni. AB - Flagella are nanofibers that drive bacterial movement. The filaments are generally composed of thousands of tightly packed flagellin subunits with a terminal cap protein, named FliD. Here, we report that the FliD protein of the bacterial pathogen Campylobacter jejuni binds to host cells. Live-cell imaging and confocal microscopy showed initial contact of the bacteria with epithelial cells via the flagella tip. Recombinant FliD protein bound to the surface of intestinal epithelial cells in a dose-dependent fashion. Search for the FliD binding site on the host cell using cells with defined glycosylation defects indicated glycosaminoglycans as a putative target. Heparinase treatment of wild type cells and an excess of soluble heparin abolished FliD binding. Binding assays showed direct and specific binding of FliD to heparin. Addition of an excess of purified FliD or heparin reduced the attachment of viable C. jejuni to the host cells. The host cell binding domain of FliD was mapped to the central region of the protein. Overall, our results indicate that the C. jejuni flagellar tip protein FliD acts as an attachment factor that interacts with cell surface heparan sulfate glycosaminoglycan receptors. PMID- 28008699 TI - Intraocular sarcoma associated with lens capsule rupture and persistent hyperplastic primary vitreous in a dog. AB - This case report describes the clinical findings and ocular pathology in an adult Golden Retriever diagnosed with an intraocular sarcoma. Nineteen s prior to diagnosis with a lens capsule rupture and intraocular sarcoma, the dog was diagnosed with persistent hyperplastic primary vitreous and uveitis based on clinical signs and the ultrasonographic appearance of the eye. Two years after enucleation, there was no evidence of metastatic spread of the sarcoma. The immunohistochemical characteristics of the tumor as well as the limitations and supportive evidence used in attempting to identify the histogenesis of the tumor are outlined. PMID- 28008700 TI - Knowledge level of nurses in Jordan on ventilator-associated pneumonia and preventive measures. AB - BACKGROUND: Ventilator-associated pneumonia is the most prevalent infection in Intensive Care Units, with the highest mortality rate; crude mortality rates may be as high as 20-75%. Many practices such as prevention measures (e.g. hand washing, wearing gloves, suctioning, elevated head of bed between 30 degrees and 45 degrees ) have demonstrated an effect of reducing the incidence of this infection. AIMS: To identify the level of nurses' knowledge of ventilator associated pneumonia and prevention measures before an educational programme, identify the level of nurses' knowledge on ventilator-associated pneumonia and prevention post an educational programme and identify the reasons for not applying ventilator-associated pneumonia prevention measures among nurses in Jordan. DESIGN: Pre- and post-intervention observational study. METHOD: Data based on a self-reported questionnaire from 428 nurses who worked in intensive care units were analysed. PowerPoint lectures, videos, printed materials and electronic materials were used in the intervention. Paired t-tests were used to test research questions. RESULTS: More than three-quarters of nurses had a low knowledge level regarding pathophysiology, risk factors and ventilator-associated pneumonia preventative measures. Nurses showed significant improvements in mean scores on the knowledge level of ventilator-associated pneumonia and prevention measures after an educational programme (p < 0.05). The main reasons for not applying prevention measures were the lack of time and no followed protocols in the units. CONCLUSION: Health education programmes about ventilator-associated pneumonia must be conducted among nurses in Jordan through continuous education. RELEVANCE TO CLINICAL PRACTICE: Hospital and nursing administrators should be actively involved in educational programmes and in assuring support for continuing education. Protocol for ventilator-associated pneumonia prevention should be developed based on current evidence-based guidelines. PMID- 28008698 TI - Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population-based linked electronic health record cohort study in 2.1 million people. AB - AIMS: The prognosis of patients hospitalized for worsening heart failure (HF) is well described, but not that of patients managed solely in non-acute settings such as primary care or secondary outpatient care. We assessed the distribution of HF across levels of healthcare, and assessed the prognostic differences for patients with HF either recorded in primary care (including secondary outpatient care) (PC), hospital admissions alone, or known in both contexts. METHODS AND RESULTS: This study was part of the CALIBER programme, which comprises linked data from primary care, hospital admissions, and death certificates for 2.1 million inhabitants of England. We identified 89 554 patients with newly recorded HF, of whom 23 547 (26%) were recorded in PC but never hospitalized, 30 629 (34%) in hospital admissions but not known in PC, 23 681 (27%) in both, and 11 697 (13%) in death certificates only. The highest prescription rates of ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists was found in patients known in both contexts. The respective 5-year survival in the first three groups was 43.9% [95% confidence interval (CI) 43.2-44.6%], 21.7% (95% CI 21.1-22.2%), and 39.8% (95% CI 39.2-40.5%), compared with 88.1% (95% CI 87.9 88.3%) in the age- and sex-matched general population. CONCLUSION: In the general population, one in four patients with HF will not be hospitalized for worsening HF within a median follow-up of 1.7 years, yet they still have a poor 5-year prognosis. Patients admitted to hospital with worsening HF but not known with HF in primary care have the worst prognosis and management. Mitigating the prognostic burden of HF requires greater consistency across primary and secondary care in the identification, profiling, and treatment of patients. TRIAL REGISTRATION: NCT02551016. PMID- 28008701 TI - Entire nucleotide sequences of Gossypium raimondii and G. arboreum mitochondrial genomes revealed A-genome species as cytoplasmic donor of the allotetraploid species. AB - Cotton (Gossypium spp.) is commonly grouped into eight diploid genomic groups, designated A-G and K, and an allotetraploid genomic group, AD. Gossypium raimondii (D5 ) and G. arboreum (A2 ) are the putative contributors to the progenitor of G. hirsutum (AD1 ), the economically important fibre-producing cotton species. Mitochondrial DNA from week-old etiolated seedlings was extracted from isolated organelles using discontinuous sucrose density gradient method. Mitochondrial genomes were sequenced, assembled, annotated and analysed in orderly. Gossypium raimondii (D5 ) and G. arboreum (A2 ) mitochondrial genomes were provided in this study. The mitochondrial genomes of two diploid species harboured circular genome of 643,914 bp (D5 ) and 687,482 bp (A2 ), respectively. They differ in size and number of repeat sequences, both contain illuminating triplicate sequences with 7317 and 10,246 bp, respectively, demonstrating dynamic difference and rearranged genome organisations. Comparing the D5 and A2 mitogenomes with mitogenomes of tetraploid Gossypium species (AD1 , G. hirsutum; AD2 , G. barbadense), a shared 11 kbp fragment loss was detected in allotetraploid species, three regions shared by G. arboreum (A2 ), G. hirsutum (AD1 ) and G. barbadense (AD2 ), while eight regions were specific to G. raimondii (D5 ). The presence/absence variations and gene-based phylogeny supported that A-genome is a cytoplasmic donor to the progenitor of allotetraploid species G. hirsutum and G. barbadense. The results present structure variations and phylogeny of Gossypium mitochondrial genome evolution. PMID- 28008702 TI - Leaf habit does not determine the investment in both physical and chemical defences and pair-wise correlations between these defensive traits. AB - Plant life-history strategies associated with resource acquisition and economics (e.g. leaf habit) are thought to be fundamental determinants of the traits and mechanisms that drive herbivore pressure, resource allocation to plant defensive traits, and the simultaneous expression (positive correlations) or trade-offs (negative correlations) between these defensive traits. In particular, it is expected that evergreen species - which usually grow slower and support constant herbivore pressure in comparison with deciduous species - will exhibit higher levels of both physical and chemical defences and a higher predisposition to the simultaneous expression of physical and chemical defensive traits. Here, by using a dataset which included 56 oak species (Quercus genus), we investigated whether leaf habit of plant species governs the investment in both physical and chemical defences and pair-wise correlations between these defensive traits. Our results showed that leaf habit does not determine the production of most leaf physical and chemical defences. Although evergreen oak species had higher levels of leaf toughness and specific leaf mass (physical defences) than deciduous oak species, both traits are essentially prerequisites for evergreenness. Similarly, our results also showed that leaf habit does not determine pair-wise correlations between defensive traits because most physical and chemical defensive traits were simultaneously expressed in both evergreen and deciduous oak species. Our findings indicate that leaf habit does not substantially contribute to oak species differences in plant defence investment. PMID- 28008703 TI - An autopsy case of hyperthyroid cardiomyopathy manifesting lethal congestive heart failure. PMID- 28008704 TI - Effect of nursing care given at home on the quality of life of patients with stomach cancer and their family caregivers' nursing care. AB - In Turkey, the high incidences of stomach and oesophageal cancers in East and high incidence of stomach cancer in Northeast regions are remarkable. This study was conducted to identify homecare needs of patients with stomach cancer and their caregivers and the effect of family supportive nursing care on the quality of life of patients and families. The patient and his/her caregiver were assessed with respect to their daily life activities and NANDA was used for the identified nursing diagnoses, NIC for the appropriate interventions and NOC for assessment of the results. This study was conducted in a pre-test, post-test, controlled trial model to identify. The sample of the investigation consisted of 72 patients and 72 caregivers. As a data-collecting instrument, the Quality of Life Scale and Caregiver Quality of Life Index-Cancer were used. The overall quality of life, global health status and emotional and cognitive functions of the patients in the experimental group improved after the interventions. The overall quality of life and global health status was found to be poorer in the control group patients at post-test as compared to pre-test and their physical, role and social functions deteriorated. The caregivers' quality of life in the control group was affected more negatively with respect to the "Disruption in Daily Life" subscale as compared to pre-test values. PMID- 28008705 TI - Navigating the mesentery: part II. Vascular abnormalities and a review of the literature. AB - AIM: Vascular abnormalities present advantages and/or disadvantages for the patient undergoing surgery. The aims of this study were to define, classify and demonstrate the courses, and to assess the clinical value, of arterial and venous abnormalities in the central mesentery. METHOD: We conducted a review of the anatomy of 340 patients planned for enrolment in the 'Safe Radical D3 Right Hemicolectomy for Cancer through Preoperative Biphasic MDCT Angiography' trial, 312 of whom were submitted to surgery. Vascular abnormalities were analysed in context with surgical notes and images. A meta-analysis of the literature was performed. RESULTS: Arterial Abnormalities were found in 28 (8.2%) of the 340 patients and were classified into the following three groups based on anticipated surgical difficulty: group 1, accessory or replaced arteries to solid organs [14 (4.1%)]; group 2, arterial shunts [11 (3.2%)] between the coeliac trunk and the superior mesenteric artery, which resulted in bleeding in three patients; and group 3, common stem abnormalities [3 (0.9%)]. Two groups of superior mesenteric vein abnormalities were noted. The first included morphological abnormalities in a single vein [4 (1.2%)]: aneurysm [1 (0.3%)]; and ring variants of principal tributaries [3 (0.9%)]. The second included double superior mesenteric vein trunks [31 (9.1%)]: genuine bifid [10 (2.9%)]; and pseudo bifid [21 (6.2%)]. The meta-analysis revealed 26 articles, including 10 series of anatomical dissections or angiographies [1970 cases with 205 (10.4%) arterial abnormalities] and 16 case reports, none of which described a clinical or surgical setting. CONCLUSION: Vascular abnormalities occur frequently. Arterial abnormalities are a hazard when inadvertent injury occurs during surgery. Preoperative knowledge of a bifid superior mesenteric vein is useful. PMID- 28008706 TI - Consumer-driven nutrient dynamics in freshwater ecosystems: from individuals to ecosystems. AB - The role of animals in modulating nutrient cycling [hereafter, consumer-driven nutrient dynamics (CND)] has been accepted as an important influence on both community structure and ecosystem function in aquatic systems. Yet there is great variability in the influence of CND across species and ecosystems, and the causes of this variation are not well understood. Here, we review and synthesize the mechanisms behind CND in fresh waters. We reviewed 131 articles on CND published between 1973 and 1 June 2015. The rate of new publications in CND has increased from 1.4 papers per year during 1973-2002 to 7.3 per year during 2003-2015. The majority of investigations are in North America with many concentrating on fish. More recent studies have focused on animal-mediated nutrient excretion rates relative to nutrient demand and indirect impacts (e.g. decomposition). We identified several mechanisms that influence CND across levels of biological organization. Factors affecting the stoichiometric plasticity of consumers, including body size, feeding history and ontogeny, play an important role in determining the impact of individual consumers on nutrient dynamics and underlie the stoichiometry of CND across time and space. The abiotic characteristics of an ecosystem affect the net impact of consumers on ecosystem processes by influencing consumer metabolic processes (e.g. consumption and excretion/egestion rates), non-CND supply of nutrients and ecosystem nutrient demand. Furthermore, the transformation and transport of elements by populations and communities of consumers also influences the flow of energy and nutrients across ecosystem boundaries. This review highlights that shifts in community composition or biomass of consumers and eco-evolutionary underpinnings can have strong effects on the functional role of consumers in ecosystem processes, yet these are relatively unexplored aspects of CND. Future research should evaluate the value of using species traits and abiotic conditions to predict and understand the effects of consumers on ecosystem-level nutrient dynamics across temporal and spatial scales. Moreover, new work in CND should strive to integrate knowledge from disparate fields of ecology and environmental science, such as physiology and ecosystem ecology, to develop a comprehensive and mechanistic understanding of the functional role of consumers. Comparative and experimental studies that develop testable hypotheses to challenge the current assumptions of CND, including consumer stoichiometric homeostasis, are needed to assess the significance of CND among species and across freshwater ecosystems. PMID- 28008707 TI - Comment on 'The effect of (l-)carnitine on weight loss in adults: a systematic review and meta-analysis of randomized controlled trials'. PMID- 28008708 TI - Application of Ethical Principles to Research using Public Health Data in The Global South: Perspectives from Africa. AB - Existing ethics guidelines, influential literature and policies on ethical research generally focus on real-time data collection from humans. They enforce individual rights and liberties, thereby lowering need for aggregate protections. Although dependable, emerging public health research paradigms like research using public health data (RUPD) raise new challenges to their application. Unlike traditional research, RUPD is population-based, aligned to public health activities, and often reliant on pre-collected longitudinal data. These characteristics, when considered in relation to the generally lower protective ethico-legal frameworks of the Global South, including Africa, highlight ethical gaps. Health and demographic surveillance systems are examples of public health programs that accommodate RUPD in these contexts. We set out to explore the perspectives of professionals with a working knowledge of these systems to determine practical ways of appropriating the foundational principles of health research to advance the ever growing opportunities in RUPD. We present their perspectives and in relation to the literature and our ethical analysis, make context relevant recommendations. We further argue for the development of a framework founded on the discussions and recommendations as a minimum base for achieving optimal ethics for optimal RUPD in the Global South. PMID- 28008709 TI - Will you still need me (Ca2+ , TnT, and DHPR), will you still cleave me (calpain), when I'm 64? PMID- 28008710 TI - The Effect of Hierarchical Micro/Nanotextured Titanium Implants on Osseointegration Immediately After Tooth Extraction in Beagle Dogs. AB - BACKGROUND: Owing to simplify the operation and shorten the overall duration of treatment, immediate implantation earned much satisfactory from patients and dentists. The results of immediate implantation determined by osseointegration, we fabricated a micro/nanotextured titanium implants to improve osseointegration immediately after tooth extraction. PURPOSE: The aim of this study was to investigate the effect of hierarchical micro/nanotextured titanium implant on osseointegration immediately after tooth extraction. MATERIAL AND METHODS: The micro/nanotextured titanium implants were fabricated by etching with 0.5 wt% hydrofluoric (HF) acid followed by anodization in HF electrolytes. Implants with a machined surface as well as implants a microtextured surface prepared by 0.5 wt% HF etching served as control groups. The machined, microtextured, and micro/nanotextured implants were inserted into fresh sockets immediately after tooth extraction in beagle dogs. Twelve weeks after implantation, the animals were sacrificed for micro-CT scanning, histological analysis and biomechanical test. RESULTS: The micro-CT imaging revealed that the bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) in the micro/nanotextured group was significantly higher than that in the machined group and microtextured group, and the trabecular separation (Tb.Sp) in the micro/nanotextured group was significantly lower than that in the other groups. For the histological analysis, the bone-to-implant contact in the machined, micro and micro/nanotextured groups were 47.13 +/- 6.2%, 54.29 +/- 4.18%, and 63.38 +/- 7.63%, respectively, and the differences significant. The maximum pull-out force in the machined, micro, and micro/nanotextured groups were 216.58 +/- 38.71 N, 259.42 +/- 28.93 N, and 284.73 +/- 47.09 N, respectively. CONCLUSIONS: The results indicated that implants with a hierarchical micro/nanotextured can promote osseointegration immediately after tooth extraction. PMID- 28008711 TI - A proteomics assay to detect eight CBRN-relevant toxins in food. AB - A proteomics assay was set up to analyze food substrates for eight toxins of the CBRN (chemical, biological, radiological and nuclear) threat, namely ricin, Clostridium perfringens epsilon toxin (ETX), Staphylococcus aureus enterotoxins (SEA, SEB and SED), shigatoxins from Shigella dysenteriae and entero-hemorragic Escherichia coli strains (STX1 and STX2) and Campylobacter jejuni cytolethal distending toxin (CDT). The assay developed was based on an antibody-free sample preparation followed by bottom-up LC-MS/MS analysis operated in targeted mode. Highly specific detection and absolute quantification were obtained using isotopically labeled proteins (PSAQ standards) spiked into the food matrix. The sensitivity of the assay for the eight toxins was lower than the oral LD50 which would likely be used in a criminal contamination of food supply. This assay should be useful in monitoring biological threats. In the public-health domain, it opens the way for multiplex investigation of food-borne toxins using targeted LC-MS/MS. PMID- 28008712 TI - Insight into the da Vinci(r) Xi - technical notes for single-docking left-sided colorectal procedures. AB - BACKGROUND: The adoption of robot-assisted laparoscopic colorectal surgery has been hampered by issues with docking, operative duration, technical difficulties in multi-quadrant access, and cost. The da Vinci(r) Xi has been designed to overcome some of these limitations. We describe our experience with the system and offer technical insights to its application in left-sided colorectal procedures. METHODS: Our initial series of left-sided robotic colorectal procedures was evaluated. Patient demographics and operative outcomes were recorded prospectively using a predefined database. RESULTS: Between March 2015 and April 2016, 54 cases of robot-assisted laparoscopic left-sided colorectal procedures were successfully completed with no cases of conversion. The majority were low anterior resections for colorectal malignancies. Using the da Vinci(r) Xi Surgical System, multi-quadrant surgery involving dissection from the splenic flexure to the pelvis was possible without redocking. CONCLUSIONS: The da Vinci(r) Xi simplifies the docking procedure and makes single-docking feasible for multi-quadrant left-sided colorectal procedures. PMID- 28008713 TI - Engineering Ashbya gossypii strains for de novo lipid production using industrial by-products. AB - Ashbya gossypii is a filamentous fungus that naturally overproduces riboflavin, and it is currently exploited for the industrial production of this vitamin. The utilization of A. gossypii for biotechnological applications presents important advantages such as the utilization of low-cost culture media, inexpensive downstream processing and a wide range of molecular tools for genetic manipulation, thus making A. gossypii a valuable biotechnological chassis for metabolic engineering. A. gossypii has been shown to accumulate high levels of lipids in oil-based culture media; however, the lipid biosynthesis capacity is rather limited when grown in sugar-based culture media. In this study, by altering the fatty acyl-CoA pool and manipulating the regulation of the main ?9 desaturase gene, we have obtained A. gossypii strains with significantly increased (up to fourfold) de novo lipid biosynthesis using glucose as the only carbon source in the fermentation broth. Moreover, these strains were efficient biocatalysts for the conversion of carbohydrates from sugarcane molasses to biolipids, able to accumulate lipids up to 25% of its cell dry weight. Our results represent a proof of principle showing the promising potential of A. gossypii as a competitive microorganism for industrial biolipid production using cost-effective feed stocks. PMID- 28008715 TI - Human epidermal growth factor receptor 2 status of gastric cancer patients in Asia: results from a large, multicountry study. AB - AIM: Current estimates of the human epidermal growth factor receptor 2 (HER2) positivity rate in gastric cancer vary widely in the literature, and there are limited data from countries in Asia. The primary aim of this study was to conduct a clinical audit of laboratories across seven countries in Asia to determine the incidence of HER2-positive gastric cancer in this region. METHODS: Pathologists were asked to collect data on patient gender, age, cancer site, specimen type, tumor spread, type and grade, HER2 test results, including protein and/or gene copy enumeration, and final HER2 status on consecutive gastric cancer cases tested for HER2 in their laboratory over a 2-year period. RESULTS: HER2 results from 5,301 gastric cancers were submitted by 50 laboratories. The overall HER2 positivity rate was 9.7% which, after the exclusion of China, increased to 18.1%. The rate between countries ranged from 0% to 23.1%, and from 0% to 50.0% between laboratories. An equivocal HER2 result was recorded in 19.5% of cases. CONCLUSION: Despite the lack of centralized testing to confirm the accuracy of HER2 diagnoses, the incidence of HER2-positive gastric cancer observed here was comparable to that reported in the literature. Nevertheless, rates were highly variable between countries and laboratories, which suggests a lack of HER2 testing expertise in gastric cancer. Given that the mortality rates for gastric cancer in Eastern Asia are the highest in the world, efforts should focus on improving HER2 testing expertise in the region so that patients receive the appropriate treatment early in their disease. PMID- 28008714 TI - Bioinformatic tools for analysis of CLIP ribonucleoprotein data. AB - Investigating the interactions of RNA-binding proteins (RBPs) with RNAs is a complex task for molecular and computational biologists. The molecular biology techniques and the computational approaches to understand RBP-RNA (or ribonucleoprotein, RNP) interactions have advanced considerably over the past few years and numerous and diverse software tools have been developed to analyze these data. Accordingly, laboratories interested in RNP biology face the challenge of choosing adequately among the available software tools those that best address the biological problem they are studying. Here, we focus on state-of the-art molecular biology techniques that employ crosslinking and immunoprecipitation (CLIP) of an RBP to study and map RNP interactions. We review the different software tools and databases available to analyze the most widely used CLIP methods, HITS-CLIP, PAR-CLIP, and iCLIP. WIREs RNA 2017, 8:e1404. doi: 10.1002/wrna.1404 For further resources related to this article, please visit the WIREs website. PMID- 28008716 TI - So Long Tom! PMID- 28008717 TI - Pharmacokinetics, tissue distribution, and excretion studies of l-isocorypalmine using ultra high performance liquid chromatography with tandem mass spectrometry. AB - l-Isocorypalmine is a newly identified metabolite of l-tetrahydropalmatine with a unique dual pharmacological profile as a partial dopamine receptor 1 agonist and dopamine receptor 2 antagonist properties for treating cocaine use disorder. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, and excretion of l-isocorypalmine in Sprague-Dawley rats. A sensitive and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for determination of l isocorypalmine in biological samples. The biological samples were extracted by liquid-liquid extraction and separated on a Bonshell ASB C18 column (2.1 * 100 mm, 2.7 MUm, Agela) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by positive electrospray ionization with multiple reaction monitoring mode. Satisfactory linearity, precision, accuracy, extraction recovery, and acceptable matrix effect were achieved. The quantitative method was successfully applied to the pharmacokinetics, tissue distribution, and excretion study of l-isocorypalmine. The results showed that l-isocorypalmine was rapidly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 7.5-15 mg/kg. In addition, the results would be helpful for further clinical reference of l-isocorypalmine as a potential candidate drug for the treatment of cocaine addiction. PMID- 28008718 TI - Binary-solvent-based ionic-liquid-assisted surfactant-enhanced emulsification microextraction for the determination of four fungicides in apple juice and apple vinegar. AB - A binary-solvent-based ionic-liquid-assisted surfactant-enhanced emulsification microextraction method was developed for the separation/preconcentration and determination of four fungicides (pyrimethanil, fludioxonil, cyprodynil, pyraclostrobin) in apple juice and apple vinegar. A nonchlorinated solvent amyl acetate, which has a lower density than water, was used as the extraction solvent, and an ionic liquid 1-hexyl-3-methylimidazolium hexafluorophosphate, which has a high density and low toxicity, was used as a secondary solvent mixed with the extraction solvent. After centrifugation, the binary solvent drop with a relatively high density was deposited on the bottom of the tube. Some parameters influencing the extraction efficiency of analytes such as type of extraction solvent, ratio of ionic liquid, volume of mixed solvent, type and concentration of surfactant, sample pH, NaCl concentration, and vortex time were investigated and optimized. Under the optimized conditions, the proposed method provided a good linearity in the range of 5-200 MUg/L. The limits of quantification of the method were in the range of 2-5 MUg/L. The relative standard deviations for interday assays were 1.7-11.9%. The method was applied to the determination of pyrimethanil, fludioxonil, cyprodynil, and pyraclostrobin in apple juice and apple vinegar samples, and the accuracy was evaluated through recovery experiments. PMID- 28008719 TI - One-step isolation of carnosic acid and carnosol from rosemary by centrifugal partition chromatography. AB - Carnosic acid and carnosol are the main bioactive components responsible for the significant antioxidant activity of Rosmarinus officinalis. Nevertheless, they are known for their instability in solutions. Separation of both compounds from crude rosemary extract was successfully achieved by one-step centrifugal partition chromatography without any degradation. A two-phase solvent system, hexane/ethyl acetate/methanol/water (3:2:3:2 v/v) was run on a preparative scale applying the elution-extrusion technique in descending mode. A 900 mg quantity of the crude extract containing 39.7% carnosic acid and 12.3% carnosol was loaded onto a 500 mL column, rotating at 1800 rpm. Carnosic acid and carnosol were obtained at purities of 96.1 +/- 1% and 94.4 +/- 0.9%, with recoveries of 94.3 +/ 4.4% and 94.8 +/- 2.3%, respectively. The compounds were identified by mass spectrometry, tandem mass spectrometry, and comparison with authentic standards. PMID- 28008720 TI - The exon junction complex: a lifelong guardian of mRNA fate. AB - During messenger RNA (mRNA) biogenesis and processing in the nucleus, many proteins are imprinted on mRNAs assembling them into messenger ribonucleoproteins (mRNPs). Some of these proteins remain stably bound within mRNPs and have a long lasting impact on their fate. One of the best-studied examples is the exon junction complex (EJC), a multiprotein complex deposited primarily 24 nucleotides upstream of exon-exon junctions as a consequence of pre-mRNA splicing. The EJC maintains a stable, sequence-independent, hold on the mRNA until its removal during translation in the cytoplasm. Acting as a molecular shepherd, the EJC travels with mRNA across the cellular landscape coupling pre-mRNA splicing to downstream, posttranscriptional processes such as mRNA export, mRNA localization, translation, and nonsense-mediated mRNA decay (NMD). In this review, we discuss our current understanding of the EJC's functions during these processes, and expound its newly discovered functions (e.g., pre-mRNA splicing). Another focal point is the recently unveiled in vivo EJC interactome, which has shed new light on the EJC's location on the spliced RNAs and its intimate relationship with other mRNP components. We summarize new strides being made in connecting the EJC's molecular function with phenotypes, informed by studies of human disorders and model organisms. The progress toward understanding EJC functions has revealed, in its wake, even more questions, which are discussed throughout. WIREs RNA 2017, 8:e1411. doi: 10.1002/wrna.1411 For further resources related to this article, please visit the WIREs website. PMID- 28008721 TI - Therapy of primary and metastatic liver cancer by human iPS cell-derived myeloid cells producing interferon-beta. AB - BACKGROUND: iPS-ML are myeloid lineage cells with a proliferative capacity derived from induced pluripotent stem (iPS) cells. This study aimed to examine therapeutic effect of iPS-ML producing interferon-beta (iPS-ML/IFN-beta) towards primary and metastatic liver cancer and investigate the mechanism of that effect. METHODS: We established a xenograft model of liver metastasis by injecting the spleen of SCID mice with MKN-45 human gastric cancer cells and also a primary liver cancer model by injecting SK-HEP-1 human hepatocellular carcinoma cells into the liver. After cancer lesions were established, iPS-ML/IFN-beta was administered by intraperitoneal injection, and therapeutic effect was evaluated. RESULTS: The i.p. injection of iPS-ML/IFN-beta resulted in a significant retardation of cancer progression and prolonged mouse survival. The infiltration of i.p. administered iPS-ML into tumor lesions located below the liver capsule was observed, suggesting tumor-directed migration and penetration of the liver capsule by iPS-ML. The IFN-beta concentration in the liver was maintained at levels sufficient to exert an anti-cancer effect for at least 3 days post injection, accounting for the potent therapeutic effect obtained by injection two to three times per week. CONCLUSIONS: This study demonstrates the therapeutic potential of the iPS-ML/IFN-beta in patients with liver cancer. PMID- 28008722 TI - Evaluating distribution of the left branch of the middle colic artery and the left colic artery by CT angiography and colonography to classify blood supply to the splenic flexure. AB - INTRODUCTION: CT angiography has gained widespread acceptance for preoperative evaluation of blood supply in patients with colorectal cancer. However, there have been few reports that pertain to the splenic flexure, for which surgery is technically difficult. We used preoperative CT angiography and CT colonography to evaluate blood supply to the splenic flexure. METHODS: We defined the splenic flexure as the junction of the distal third of the transverse colon and the proximal third of the descending colon. We reviewed 191 cases and considered the descending colon as divided into the proximal third and the distal two-thirds; we then determined which part of the descending colon the left colic artery (LCA) entered. We also considered the transverse colon as divided into the proximal two thirds and the distal third, and evaluated which part of the transverse colon the left branch of the middle colic artery entered. RESULT: We classified blood supply to the splenic flexure into six types, described by the feeder vessels: type 1, the LCA (39.7%); type 2, the left branch of the middle colic artery (17.8%); type 3, the LCA and the left branch of the middle colic artery (9.9%); type 4, the accessory left colic artery (4.1%); type 5, the LCA and the accessory left colic artery (2.6%); and type 6, the marginal artery (25.6%). CONCLUSION: We classified blood supply to the splenic flexure into more complex types than previous reports had. Because we dissect the lymph nodes according to the type of blood supply, knowing the type before splenic flexure surgery is crucial. PMID- 28008723 TI - 2016 International Conference on Human Health and Medical Engineering (HHME 2016). PMID- 28008724 TI - Clinical outcomes of laparoscopic cholecystectomy with accidental gallbladder perforation. AB - INTRODUCTION: Accidental gallbladder perforation frequently occurs during laparoscopic cholecystectomy and may increase the risk of infection. However, the necessity of antimicrobial prophylaxis for these patients is unclear. The aim of this study was to examine the clinical outcomes and necessity of antimicrobial prophylaxis after laparoscopic cholecystectomy with gallbladder perforation. METHODS: One hundred patients who underwent laparoscopic cholecystectomy were divided into two groups: patients with gallbladder perforation (Group A, n = 37) and patients without perforation (Group B, n = 63). We compared the white blood cell count and C-reactive protein level the day after the operation, the complication rates of systemic inflammatory response syndrome and surgical-site infection, and postoperative hospital stay between the two groups. All patients received antimicrobial prophylaxis only once before the operation. RESULTS: There were significant differences in every variable with the exception of postoperative hospital stay. Group A had a higher risk of infection, but the postoperative clinical course of Group A was not inferior to that of Group B. CONCLUSION: The clinical outcomes of patients with accidental gallbladder perforation were acceptable, and the use of antimicrobial prophylaxis once before the operation was sufficient. PMID- 28008725 TI - Tenocytic extract and mechanical stimulation in a tissue-engineered tendon construct increases cellular proliferation and ECM deposition. AB - Chemical and mechanical stimulation, when properly utilized, positively influence both the differentiation of in vitro cultured stem cells and the quality of the deposited extracellular matrix (ECM). This study aimed to find if cell-free extract from primary tenocytes can positively affect the development of a tissue engineered tendon construct, consisting of a human umbilical vein (HUV) seeded with mesenchymal stem cells (MSCs) subjected to cyclical mechanical stimulation. The tenocytic cell-free extract possesses biological material from tendon cells that could potentially influence MSC tenocytic differentiation and construct development. We demonstrate that the addition of tenocytic extract in statically cultured tendon constructs increases ECM deposition and tendon-related gene expression of MSCs. The incorporation of mechanical stimulation (2% strain for 30 min/day at 0.5 cycles/min) with tenocytic extract further improved the MSC seeded HUV constructs by increasing cellularity of the construct by 37% and the ultimate tensile strength by 33% compared to the constructs with only mechanical stimulation after 14 days. Furthermore, the addition of mechanical stimulation to the extract supplementation produced longitudinal ECM fibril alignment along with dense connective tissue, reminiscent of natural tendon. PMID- 28008726 TI - Multi-objective global optimization (MOGO): Algorithm and case study in gradient elution chromatography. AB - Biotechnological separation processes are routinely designed and optimized using parallel high-throughput experiments and/or serial experiments. Well characterized processes can further be optimized using mechanistic models. In all these cases - serial/parallel experiments and modeling - iterative strategies are customarily applied for planning novel experiments/simulations based on the previously acquired knowledge. Process optimization is typically complicated by conflicting design targets, such as productivity and yield. We address these issues by introducing a novel algorithm that combines recently developed approaches for utilizing statistical regression models in multi-objective optimization. The proposed algorithm is demonstrated by simultaneous optimization of elution gradient and pooling strategy for chromatographic separation of a three-component system with respect to purity, yield, and processing time. Gaussian Process Regression Models (GPM) are used for estimating functional relationships between design variables (gradient, pooling) and performance indicators (purity, yield, time). The Pareto front is iteratively approximated by planning new experiments such as to maximize the Expected Hypervolume Improvement (EHVI) as determined from the GPM by Markov Chain Monte Carlo (MCMC) sampling. A comprehensive Monte-Carlo study with in-silico data illustrates efficiency, effectiveness and robustness of the presented Multi-Objective Global Optimization (MOGO) algorithm in determining best compromises between conflicting objectives with comparably very low experimental effort. PMID- 28008727 TI - Nutrient composition of premixed and packaged complementary foods for sale in low and middle-income countries: Lack of standards threatens infant growth. AB - Premixed flours for infant porridge are increasingly produced and sold in developing countries to complement continued breastfeeding. Such complementary food (CF) products have known efficacy against malnutrition in children from 6 to 24 months of age, but ingredient ratios and production processes may vary. This study provides the first systematic measurement of their actual nutrient composition. We purchased samples of 108 premixed CF products in 22 low- and middle-income countries, and commissioned blind laboratory measurement of each product's macronutrients and micronutrients. We compared measured contents to nutrient claims on their packaging and to CF standards from the Codex Alimentarius, the Super Cereal Plus product used in nutrition assistance programs, and the Lutter and Dewey (2003) recommendations, as well as our own modeled nutrient requirements for a healthy breastfed child. Actual densities are significantly different from nutrient claims for protein (p = .013) and fat (p = .000). Only 15% of samples met two of the three benchmarks for fat, 32% met the most stringent protein standard, while only 22% met them for iron, and 21% for zinc. The median healthy child consuming breast milk plus enough of these solid foods to meet energy needs would experience deficits of zinc at 6 months, iron at 6 and 9 months, and dietary fat from 12 months of age. In summary, premixed CF products can provide adequate nutrient density but usually do not, revealing the need and opportunity for independent monitoring and quality assurance to help grain millers making premixed foods maintain uniform ingredient ratios and production practices. PMID- 28008728 TI - Recommendations and consensus on the treatment of peritoneal metastases of colorectal origin: a systematic review of national and international guidelines. AB - AIM: This systematic review aimed to provide an overview of (inter)national guidelines on the treatment of peritoneal metastases of colorectal cancer origin (PMCRC) and to determine the degree of consensus and available evidence with identification of topics for future research. METHOD: A systematic search of MEDLINE, Embase, PubMed as well as Tripdatabase, National Guideline Clearinghouse, BMJ Best Practice and Guidelines International Network was performed to identify (inter)national guidelines and consensus statements from oncological or surgical societies on PMCRC. The quality of guidelines was assessed using the AGREE-II score. Topics followed by recommendations were extracted from the guidelines. The recommendations, highest level of supporting evidence and the degree of consensus were determined for each topic. RESULTS: Twenty-one guidelines were included, in most (15) of which cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) was recommended in selected patients based on level 1b evidence. Substantial consensus was also reached on the benefit of multidisciplinary team discussion and the achievability of a (near) complete cytoreduction (CC0-1) without supporting evidence. Both evidence and consensus were lacking regarding other aspects including preoperative positron emission tomography/CT, second look surgery in high risk patients, the optimal patient selection for CRS/HIPEC, procedural aspects of HIPEC and (perioperative) systemic therapy. CONCLUSION: In currently available guidelines, evidence and consensus on the treatment strategy for PMCRC are lacking. Updates of guidelines are ongoing and future (randomized) clinical trials should contribute to multidisciplinary and international consensus on treatment strategies for PMCRC. PMID- 28008730 TI - Large retroperitoneal immature teratoma leading to renovascular hypertension. PMID- 28008729 TI - Parental and child genetic contributions to obesity traits in early life based on 83 loci validated in adults: the FAMILY study. AB - BACKGROUND: The genetic influence on child obesity has not been fully elucidated. OBJECTIVE: This study investigated the parental and child contributions of 83 adult body mass index (BMI)-associated single-nucleotide polymorphisms (SNPs) to obesity-related traits in children from birth to 5 years old. METHODS: A total of 1402 individuals were genotyped for 83 SNPs. An unweighted genetic risk score (GRS) was generated by the sum of BMI-increasing alleles. Repeated weight and length/height were measured at birth, 1, 2, 3 and 5 years of age, and age specific and sex-specific weight and BMI Z-scores were computed. RESULTS: The GRS was significantly associated with birthweight Z-score (P = 0.03). It was also associated with weight/BMI Z-score gain between birth and 5 years old (P = 0.02 and 6.77 * 10-3 , respectively). In longitudinal analyses, the GRS was associated with weight and BMI Z-score from birth to 5 years (P = 5.91 * 10-3 and 5.08 * 10 3 , respectively). The maternal effects of rs3736485 in DMXL2 on weight and BMI variation from birth to 5 years were significantly greater compared with the paternal effects by Z test (P = 1.53 * 10-6 and 3.75 * 10-5 , respectively). CONCLUSIONS: SNPs contributing to adult BMI exert their effect at birth and in early childhood. Parent-of-origin effects may occur in a limited subset of obesity predisposing SNPs. PMID- 28008731 TI - Mitochondrial respiratory chain complex I deficiency causes intractable gastrointestinal symptoms. AB - We report the case of a 13-month-old girl with frequent vomiting, intractable diarrhea, hyperlactatemia, and liver dysfunction. Although the symptoms were treatment resistant, enteral nutrition formula containing medium-chain triglycerides reduced the weight loss, vomiting, and diarrhea. Immunostaining of mitochondrial respiratory chain (MRC) complexes of the colonic mucosa confirmed the diagnosis of MRC complex I deficiency. This case shows that this disease should be included in the differential diagnosis of hyperlactatemia and intractable, cryptogenic gastrointestinal symptoms. In addition, the mucosa of the affected gastrointestinal organ should be analyzed on immunostaining or electron microscopy for MRC complexes. PMID- 28008732 TI - Alveolar capillary dysplasia with misalignment of the pulmonary veins due to novel insertion mutation of FOXF1. PMID- 28008733 TI - Multiple migratory recurrence of Kikuchi-Fujimoto disease. PMID- 28008734 TI - Human herpesvirus-6 and herpes simplex virus-1 as a cause of cardiomyopathy secondary to myocarditis in children. PMID- 28008735 TI - Aorto-pulmonary calcification in twin-twin transfusion: Successful heart surgery. PMID- 28008736 TI - Congenital glucose-galactose malabsorption diagnosed from macrohematuria in an infant. PMID- 28008737 TI - First mixoploid infant with full triploidy in blood cells. PMID- 28008738 TI - Conservative follow-up of fractured percutaneously inserted central venous catheter. PMID- 28008739 TI - Large abdominal protrusion. PMID- 28008741 TI - Acute kidney injury in type 3 Bartter syndrome: Angiotensin-converting enzyme inhibitors as a cause. PMID- 28008742 TI - Hypofibrinogenemia and intra-articular hemorrhage due to valproic acid. PMID- 28008743 TI - Fatal cytomegalovirus infection following cardiac surgery in a neonate with asplenia. PMID- 28008746 TI - Clinical and biochemical factors associated with preeclampsia in women with obesity. AB - OBJECTIVE: To compare early pregnancy clinical and biomarker risk factors for later development of preeclampsia between women with obesity (body mass index, BMI >=30 kg/m2 ) and those with a normal BMI (20-25 kg/m2 ). METHODS: In 3,940 eligible nulliparous women from the Screening for Pregnancy Endpoints (SCOPE) study, a total of 53 biomarkers of glucose and lipid metabolism, placental function, and known markers of preeclampsia were measured at 14 to 16 weeks' gestation. Logistic regression was performed to identify clinical and biomarker risk factors for preeclampsia in women with and without obesity. RESULTS: Among 834 women with obesity and 3,106 with a normal BMI, 77 (9.2%) and 105 (3.4%) developed preeclampsia, respectively. In women with obesity, risk factors included a family history of thrombotic disease, low plasma placental growth factor, and higher uterine artery resistance index at 20 weeks. In women with a normal BMI, a family history of preeclampsia or gestational hypertension, mean arterial blood pressure, plasma endoglin and cystatin C, and uterine artery resistance index were associated with preeclampsia, while high fruit intake was protective. CONCLUSIONS: Women with obesity and a normal BMI have different early pregnancy clinical and biomarker risk factors for preeclampsia. PMID- 28008744 TI - Programmed cell death-ligand 1 (PD-L1) expression and fibroblast growth factor receptor 1 (FGFR1) amplification in stage III/IV lung squamous cell carcinoma (SQC). AB - BACKGROUND: This study was conducted to explore programmed cell death-ligand-1 (PD-L1) expression and fibroblast growth factor receptor 1 (FGFR1) amplification in stage IIIB/IV lung squamous cell carcinoma (SQC). Correlations between PD-L1 and FGFR1, and with clinicopathological characteristics, efficacy of platinum based chemotherapy, and prognosis were analyzed. METHODS: One hundred and twenty eight consecutive stage III/IV SQC patients were enrolled in this study from 2009 to 2014. Seventy-eight patients received platinum-based chemotherapy. Immunohistochemistry was used to assess PD-L1 expression and fluorescence in situ hybridization was applied to detect FGFR1 amplification. RESULTS: PD-L1 expression was detected in 61.7% (79/128) of lung SQC patients. Smokers had significantly higher PD-L1 expression rates than non-smokers (66.1% vs. 44.0%, P = 0.042, respectively). The objective response and disease control rates for platinum-based chemotherapy were not significantly different between PD-L1 negative and positive patients (43.3% vs. 36.2%, P = 0.434; 80.0% vs. 78.7% P = 0.840, respectively); however, overall survival in PD-L1-negative patients was significantly longer than in PD-L1-positive patients (41.5 vs. 19.3 months, P = 0.001). Twenty-five percent (32/128) of patients displayed FGFR1 amplification, with a lower rate in stage III patients compared to stage IV (17.1% vs. 36.5%, P = 0.013, respectively). There was no significant difference in FGFR1 amplification levels between overall response, disease control or overall survival rates. No correlation was observed between PD-L1 expression and FGFR1 amplification ( P = 0.916). CONCLUSION: PD-L1 expression may function as a prognostic factor in Chinese stage III/IV SQC patients. FGFR1 amplification is more prevalent in late stage SQC patients but does not predict chemotherapy response. There is no apparent correlation between PD-L1 expression and FGFR1 amplification. PMID- 28008747 TI - Validation of an instrument to measure moral distress within the Australian residential and community care environments. AB - AIM AND OBJECTIVES: The aim of this study was to gain insight into the experience of moral distress within the aged care workforce. The objective of this study was to use and validate an existing instrument to measure moral distress within the aged care setting. BACKGROUND: Moral distress, a phenomenon associated with worker satisfaction and retention, is common within nursing. Instruments to measure moral distress exist; however, there are no validated instruments to measure moral distress within an aged care setting. DESIGN AND METHOD: An existing instrument, the Moral Distress Scale (Revised) was identified and amended. Amendments were subject to expert review for face and content validity. Data were collected from aged care nurses working in residential and community aged care, in Australia. Reliability was assessed using Cronbach's alpha with exploratory factor analysis undertaken for construct validity. RESULTS: 106 participants completed the survey, 93 (87.7%) identified as female and 13 (12.3%) male. Participants ranged in age from 21 to 73 years, with a mean time working in nursing of 20.6 years. The frequency component of the instrument demonstrated an alpha of 0.89, the intensity component 0.95 and the instrument as a whole 0.94. Three factors were identified and labelled as: Quality of Care, Capacity of Team and Professional Practice. Mean scores indicate a low occurrence of moral distress, but this distress, when experienced, was felt with a moderate level of intensity. Primary causes of moral distress were insufficient staff competency levels, poor quality care because of poor communication and delays in implementing palliation. CONCLUSION: The instrument demonstrates validity and reliability within the Australian aged care setting. Further analysis with larger populations is required to support these findings. IMPLICATIONS FOR PRACTICE: Australian aged care workers do experience moral distress. They suffer adverse consequences of this distress and quality of care is negatively impacted. This newly validated instrument can be used to quantify the occurrence of moral distress and to inform targeted interventions to reduce the occurrence and intensity of the experience. PMID- 28008749 TI - INSIGHT responsive parenting intervention is associated with healthier patterns of dietary exposures in infants. AB - OBJECTIVE: To determine whether a responsive parenting (RP) intervention affects infant dietary patterns. METHODS: Primiparous mother-newborn dyads (n = 291) were randomized to the Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) RP intervention or control. Curricula were delivered at nurse home visits at ages 3, 16, 28, and 40 weeks. RP group feeding guidance advised responsive feeding, delayed introduction of solids, repeated exposure to novel foods, and age-appropriate portion sizes. Latent class analysis identified patterns of dietary exposure at 9 months. Class membership at 9 months was used to predict BMI percentile at 2 years. RESULTS: Five dietary patterns were identified: "Breastfed, Fruits and Vegetables," "Breastfed, Low Variety," "Formula, Fruits and Vegetables," "Formula, Low Variety," and "Formula, High Energy Density." Over 60% of infants had patterns low in fruits and vegetables or high in energy-dense foods. RP group infants were less likely than control to be in the "Formula, Low Variety" class (OR = 0.40, 95% CI 0.23-0.71) or "Formula, High Energy Density" class (OR = 0.28, 95% CI 0.12-0.61) relative to the "Formula, Fruits and Vegetables" class. Dietary pattern at 9 months was significantly associated with BMI percentile at 2 years. CONCLUSIONS: While a majority of infants consumed diets low in fruits and vegetables, the INSIGHT RP intervention was associated with healthier dietary patterns. PMID- 28008750 TI - The additional effects of a probiotic mix on abdominal adiposity and antioxidant Status: A double-blind, randomized trial. AB - OBJECTIVE: To investigate whether a probiotic mix has additional effects when compared with an isolated dietary intervention on the body composition, lipid profile, endotoxemia, inflammation, and antioxidant profile. METHODS: Women who had excess weight or obesity were recruited to a randomized, double-blind trial and received a probiotic mix (Lactobacillus acidophilus and casei; Lactococcus lactis; Bifidobacterium bifidum and lactis; 2 * 1010 colony-forming units/day) (n = 21) or placebo (n = 22) for 8 weeks. Both groups received a dietary prescription. Body composition was assessed by anthropometry and dual-energy X ray absorptiometry. The lipid profile, lipid accumulation product, plasma fatty acids, lipopolysaccharide, interleukin-6, interleukin-10, tumor necrosis factor alpha, adiponectin, and the antioxidant enzymes activities were analyzed. RESULTS: In comparison with the dietary intervention group, the dietary intervention + probiotic mix group showed a greater reduction in the waist circumference (-3.40% vs. -5.48%, P = 0.03), waist-height ratio (-3.27% vs. 5.00%, P = 0.02), conicity index (-2.43% vs. -4.09% P = 0.03), and plasma polyunsaturated fatty acids (5.65% vs. -18.63%, P = 0.04) and an increase in the activity of glutathione peroxidase (-16.67% vs. 15.62%, P < 0.01). CONCLUSIONS: Supplementation of a probiotic mix reduced abdominal adiposity and increased antioxidant enzyme activity in a more effective way than an isolated dietary intervention. PMID- 28008751 TI - New year's resolution: Say no to fake journals and conferences. PMID- 28008748 TI - TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. AB - We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFkappaB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFkappaB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS. PMID- 28008752 TI - High levels of iron supplementation prevents neural tube defects in the Fpn1ffe mouse model. AB - BACKGROUND: Periconception maternal nutrition and folate in particular are important factors influencing the incidence of neural tube defects (NTDs). Many but not all NTDs are prevented by folic acid supplementation and there is a pressing need for additional strategies to prevent these birth defects. Other micronutrients such as iron are potential candidates, yet a clear role for iron deficiency in contributing to NTDs is lacking. Our previous studies with the flatiron (ffe) mouse model of Ferroportin1 (Fpn1) deficiency suggest that iron is required for neural tube closure and forebrain development raising the possibility that iron supplementation could prevent NTDs. METHODS: We determined the effect of periconception iron and/or folic acid supplementation on the penetrance of NTDs in the Fpn1ffe mouse model. Concurrently, measurements of folate and iron were made to ensure supplementation had the intended effects. RESULTS: High levels of iron supplementation significantly reduced the incidence of NTDs in Fpn1ffe mutants. Fpn1 deficiency resulted in reduced folate levels in both pregnant dams and embryos. Yet folic acid supplementation did not prevent NTDs in the Fpn1ffe model. Similarly, forebrain truncations were rescued with iron. Surprisingly, the high levels of iron supplementation used in this study caused folate deficiency in wild-type dams and embryos. CONCLUSION: Our results demonstrate that iron supplementation can prevent NTDs and forebrain truncations in the Fpn1ffe model. Surprisingly, high levels of iron supplementation and iron overload can cause folate deficiency. If iron is essential for neural tube closure, it is possible that iron deficiency might contribute to NTDs. Birth Defects Research 109:81-91, 2017. (c) 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc. PMID- 28008753 TI - Effects of non-woven mesh in preperitoneal tension-free inguinal hernia repair: a retrospective cohort study. AB - BACKGROUND: Tension-free hernia repair has been recognized as the gold standard for the treatment of inguinal hernia. Different mesh has different characteristics that influence the efficiency of surgery. We conducted this study to evaluate the effectiveness of non-woven mesh in preperitoneal tension-free inguinal hernia repair under local anesthesia. METHODS: The medical records of patients who received preperitoneal tension-free inguinal hernia repair under local anesthesia in our hospital from 2012 to 2015 were reviewed. Patients were included if their surgery was conducted using non-woven or woven mesh. Outcome measures were operation time, length of stay in hospital, hospital fees, complications and degree of chronic pain, foreign body sensation and recurrence. A total of 389 cases were included. 186 cases were repaired with non-woven mesh (observation group), and 203 cases were repaired with woven mesh (control group). RESULTS: There were no significant differences in operation time and length of stay in the hospital, but hospital fees were significantly higher in the observation group. Seroma of the inguinal region occurred in 6 cases of the observation group and 8 cases of the control group with no significant difference and no other complications and recurrence in both groups. No cases of chronic pain were recorded in the observation group; 8 cases were recorded in the control group. Foreign body sensation was found in 1 case of the observation group and 9 cases in the control group, which showed attractive advantages of non-woven mesh. CONCLUSIONS: Preperitoneal tension-free repair for inguinal hernia under local anesthesia using non-woven or woven mesh is available. The hospital cost of using non-woven mesh is higher than that of woven mesh, but the incidence rate of chronic pain and foreign body sensation are lower in the use of non-woven mesh. Therefore, non-woven mesh may be worth using in the clinical setting. PMID- 28008754 TI - Risk factors for Gleason Score upgrading following radical prostatectomy. AB - INTRODUCTION: Gleason Score discordance can confound optimal treatment allocation of patients diagnosed with prostate cancer and place these patients at risk of worse oncological outcomes. Its prevalence remains endemic; its exact causation remains unknown. The objective of this review was to examine the observational studies of patient cohorts who have undergone radical prostatectomy with the aim of identifying any preoperative variables that may be associated with an upgrade in final prostatectomy Gleason Score. EVIDENCE ACQUISITION: A non-systematic review of English articles from 2010 to present was performed through a MEDLINE search. Search terms included "Gleason Score," "pathological," "upgrade," and "radical prostatectomy." EVIDENCE SYNTHESIS: All studies included for review were retrospective analyses of radical prostatectomy series that examined factors associated with Gleason Score discordance. CONCLUSIONS: The various studies found that Gleason Score upgrading remains highly prevalent, and that some association can be seen with greater percent positive cores, longer biopsy core lengths, smaller prostate glands, higher percent tumor volume per gland, prostate-specific antigen density and visible lesions on multiparametric magnetic resonance imaging. PMID- 28008755 TI - An exploratory analysis of the association between levels of hormones implied in steroid biosynthesis and activity of abiraterone in patients with metastatic castration-resistant prostate cancer. AB - BACKGROUND: Abiraterone acetate, approved for patients with metastatic castration resistant prostate cancer (mCRPC), blocks androgen byosinthesis. We aimed to describe changes determined by abiraterone in hormones implied in steroid biosynthesis, exploring association between hormonal levels and drug activity. METHODS: Patients with mCRPC, receiving standard abiraterone + prednisone after docetaxel failure, were studied. We determined serum levels of progesterone, 17OH progesterone, cortisol, ACTH, DHEA-sulphate, androstenedione, testosterone, sex hormone-binding globulin, aldosterone, plasma renin activity, and cholesterol, baseline and every 12 weeks. For each hormone, association with treatment activity was tested 1) comparing baseline values in responders vs. non responders; 2) comparing progression-free survival (PFS) of patients with baseline low vs. high values; 3) comparing values after 12 weeks in responders vs. non-responders. RESULTS: Forty-nine patients were analyzed; 26 patients (53.1%) experienced PSA response. Baseline values of all hormones were not statistically different between responders and non-responders. For all hormones, PFS difference of patients with low vs. high baseline values was not statistically significant. Several hormones showed significant and sustained changes vs. baseline, but all significant changes were similar between responders and non-responders. CONCLUSIONS: This analysis does not suggest a significant association between baseline hormonal values, or changes induced by abiraterone, and treatment activity. PMID- 28008756 TI - Cost effectiveness and robot-assisted urologic surgery: does it make dollars and sense? AB - INTRODUCTION: The introduction of the robotic surgical platform has led to distinct changes in practice patterns and the utilization of minimally invasive surgery in urology. While use of the robotic system is associated with improvements in perioperative outcomes such as estimated blood loss and hospital stay, there are significant fixed and variable costs with the purchase, maintenance and use of the robotics system that has led many authors to investigate the cost effectiveness of robotic urologic surgery. We sought to examine the best current available evidence for the cost effectiveness of robotic urologic surgery. EVIDENCE ACQUISITION: Comprehensive electronic literature searches were conducted without language restriction to identify reports of published studies within PubMed/Medline, SCOPUS and Web of Science. Relevant articles were examined and reference lists cross referenced to find additional pertinent publications. EVIDENCE SYNTHESIS: PubMed literature searches of "robot urology cost" (304 articles) "robotic prostatectomy cost" (215 articles), "robotic nephrectomy cost" (87 articles), "robotic cystectomy cost" (44 articles) and "robotic pyeloplasty cost" (41 articles) were initially reviewed in abstract form to find appropriate articles for inclusion. Given that robotic cystectomy (559 articles), robotic pyeloplasty (344 articles) robotic retroperitoneal lymph node dissection (59 articles) are less frequently performed than robotic prostatectomy, all available articles published from January 1st 2000 until July 31st 2016 were reviewed for potential inclusion. After excluding duplicates, appropriate articles were pulled for full text review. 49 articles were used for the final analysis. CONCLUSIONS: The available literature on the cost effectiveness of robotic urologic surgery is somewhat limited by heterogeneity of research methods, local cost variations and methods for determining costs associated with surgical outcomes. The introduction of the robotic surgical platform has led to a dramatic change in the availability and utilization of laparoscopic surgery and is associated with both favorable perioperative outcomes as well as significantly greater fixed costs related to instrumentation and equipment expenses. Well-designed trials comparing open and robotic approaches in the contemporary era of widespread robotic adoption with quality of life and validated economic metrics will be necessary to provide evidence for continued use of this valuable technology. PMID- 28008757 TI - Identification and Quantification of Potential Anti-inflammatory Hydroxycinnamic Acid Amides from Wolfberry. AB - Wolfberry or Goji berry, the fruit of Lycium barbarum, exhibits health-promoting properties that leads to an extensive study of their active components. We synthesized a set of hydroxycinnamic acid amide (HCCA) compounds, including trans caffeic acid, trans-ferulic acid, and 3,4-dihydroxyhydrocinnamic acid, with extended phenolic amine components as standards to identify and quantify the corresponding compounds from wolfberry and to investigate anti-inflammatory properties of these compounds using in vitro model. With optimized LC-MS/MS and NMR analysis, nine amide compounds were identified from the fruits. Seven of these compounds were identified in this plant for the first time. The amide compounds with a tyramine moiety were the most abundant. In vitro studies indicated that five HCCA compounds showed inhibitory effect on NO production inuded by lipopolysaccharides with IC50 less than 15.08 MUM (trans-N-feruloyl dopamine). These findings suggested that wolfberries demonstrated anti inflammatory properties. PMID- 28008758 TI - Force-Field Prediction of Materials Properties in Metal-Organic Frameworks. AB - In this work, MOF bulk properties are evaluated and compared using several force fields on several well-studied MOFs, including IRMOF-1 (MOF-5), IRMOF-10, HKUST 1, and UiO-66. It is found that, surprisingly, UFF and DREIDING provide good values for the bulk modulus and linear thermal expansion coefficients for these materials, excluding those that they are not parametrized for. Force fields developed specifically for MOFs including UFF4MOF, BTW-FF, and the DWES force field are also found to provide accurate values for these materials' properties. While we find that each force field offers a moderately good picture of these properties, noticeable deviations can be observed when looking at properties sensitive to framework vibrational modes. This observation is more pronounced upon the introduction of framework charges. PMID- 28008759 TI - In-Plane Mosaic Potential Growth of Large-Area 2D Layered Semiconductors MoS2 MoSe2 Lateral Heterostructures and Photodetector Application. AB - Considering the unique layered structure and novel optoelectronic properties of individual MoS2 and MoSe2, as well as the quantum coherence or donor-acceptor coupling effects between these two components, rational design and artificial growth of in-plane mosaic MoS2/MoSe2 lateral heterojunctions film on conventional amorphous SiO2/Si substrate are in high demand. In this article, large-area, uniform, high-quality mosaic MoS2/MoSe2 lateral heterojunctions film was successfully grown on SiO2/Si substrate for the first time by chemical vapor deposition (CVD) technique. MoSe2 film was grown along MoS2 triangle edges and occupied the blanks of the substrate, finally leading to the formation of mosaic MoS2/MoSe2 lateral heterojunctions film. The composition and microstructure of mosaic MoS2/MoSe2 lateral heterojunctions film were characterized by various analytic techniques. Photodetectors based on mosaic MoS2/MoSe2 lateral heterojunctions film, triangular MoS2 monolayer, and multilayer MoSe2 film are systematically investigated. The mosaic MoS2/MoSe2 lateral heterojunctions film photodetector exhibited optimal photoresponse performance, giving rise to responsivity, detectivity, and external quantum efficiency (EQE) up to 1.3 A W-1, 2.6 * 1011 Jones, and 263.1%, respectively, under the bias voltage of 5 V with 0.29 mW cm-2 (610 nm), possibly due to the matched band alignment of MoS2 and MoSe2 and strong donor-acceptor delocalization effect between them. Taking into account the similar edge conditions of transition metal dichalcogenides (TMDCs), such a facile and reliable approach might open up a unique route for preparing other 2D mosaic lateral heterojunctions films in a manipulative manner. Furthermore, the mosaic lateral heterojunctions film like MoS2/MoSe2 in the present work will be a promising candidate for optoelectronic fields. PMID- 28008760 TI - Osmotic Ballasts Enhance Faradaic Efficiency in Closed-Loop, Membrane-Based Energy Systems. AB - Aqueous processes for energy storage and conversion based on reverse electrodialysis (RED) require a significant concentration difference across ion exchange membranes, creating both an electrochemical potential and an osmotic pressure difference. In closed-loop RED, which we recently demonstrated as a new means of energy storage, the transport of water by osmosis has a very significant negative impact on the faradaic efficiency of the system. In this work, we use neutral, nonpermeating solutes as "osmotic ballasts" in a closed-loop concentration battery based on RED. We present experimental results comparing two proof-of-concept ballast molecules, and show that the ballasts reduce, eliminate, or reverse the net transport of water through the membranes when cycling the battery. By mitigating osmosis, faradaic and round-trip energy efficiency are more than doubled, from 18% to 50%, and 7% to 15%, respectively in this nonoptimized system. However, the presence of the ballasts has a slightly negative impact on the open circuit voltage. Our results suggest that balancing osmotic pressure using noncharged solutes is a promising approach for significantly reducing faradaic energy losses in closed-loop RED systems. PMID- 28008761 TI - Crystalline Copper Phosphide Nanosheets as an Efficient Janus Catalyst for Overall Water Splitting. AB - Hydrogen is essential to many industrial processes and could play an important role as an ideal clean energy carrier for future energy supply. Herein, we report for the first time the growth of crystalline Cu3P phosphide nanosheets on conductive nickel foam (Cu3P@NF) for electrocatalytic and visible light-driven overall water splitting. Our results show that the Cu3P@NF electrode can be used as an efficient Janus catalyst for both the oxygen evolution reaction (OER) and the hydrogen evolution reaction (HER). For OER catalysis, a current density of 10 mA/cm2 requires an overpotential of only ~320 mV and the slope of the Tafel plot is as low as 54 mV/dec in 1.0 M KOH. For HER catalysis, the overpotential is only ~105 mV to achieve a catalytic current density of 10 mA cm-2. Moreover, overall water splitting can be achieved in a water electrolyzer based on the Cu3P@NF electrode, which showed a catalytic current density of 10 mA/cm2 under an applied voltage of ~1.67 V. The same current density can also be obtained using a silicon solar cell under ~1.70 V for both the HER and the OER. This new Janus Cu3P@NF electrode is made of inexpensive and nonprecious metal-based materials, which opens new possibilities based on copper to exploit overall water splitting for hydrogen production. To the best of our knowledge, such high performance of a copper-based water oxidation and overall water splitting catalyst has not been reported to date. PMID- 28008762 TI - Scalable Synthesis of Honeycomb-like Ordered Mesoporous Carbon Nanosheets and Their Application in Lithium-Sulfur Batteries. AB - There is a growing need to improve the electrical conductivity of the cathode and to suppress the rapid capacity decay during cycling in lithium-sulfur (Li-S) batteries. This can be achieved by developing facile methods for the synthesis of novel nanostructured carbon materials that can function as effective cathode hosts. In this Article, we report the scalable synthesis of ordered mesoporous carbon nanosheets (OMCNS) via the etching of self-assembled iron oxide/carbon hybrid nanosheets (IO-C NS), which serve as an advanced sulfur host for Li-S batteries. The obtained two-dimensional (2D) nanosheets have close-packed uniform cubic mesopores of ~20 nm side length, and the gap between the pores is ~4 nm, which resembles the honeycomb structure consisting of an ordered array of hexagonal pores. We loaded OMCNS with sulfur by a simple melting infusion process and evaluated the performance of the resulting OMCNS-sulfur composites as the cathode material. As a result, the sulfur-loaded OMCNS hybrid (OMCNS-S) electrode infiltrated with 70 wt % sulfur delivers a high and stable reversible capacity of 505.7 mA h g-1 after 500 cycles at 0.5 C-rate with excellent capacity retention (a decay of 0.081% per cycle) and excellent rate capability (580.6 mA h g-1 at a high current density of 2 C). The improved electrochemical properties could be attributed to the fact that the uniform cubic mesopores offer sufficient space for the volume expansion of sulfur inside them and therefore trap the polysulfides during the charging-discharging process. Therefore, these unique structured carbon nanosheets can be promising candidates for other energy-storage applications. PMID- 28008763 TI - The Multisensory Environment (MSE) in Dementia Care: Examining Its Role and Quality From a User Perspective. AB - BACKGROUND: Multisensory environments (MSEs) for people with dementia have been available over 20 years but are used in an ad hoc manner using an eclectic range of equipment. Care homes have endeavored to utilize this approach but have struggled to find a design and approach that works for this setting. AIMS: Study aims were to appraise the evolving concept of MSEs from a user perspective, to study the aesthetic and functional qualities, to identify barriers to staff engagement with a sensory environment approach, and to identify design criteria to improve the potential of MSE for people with dementia. METHODS: Data were collected from 16 care homes with experience of MSE using ethnographic methods, incorporating semi-structured interviews, and observations of MSE design. Analysis was undertaken using descriptive statistics and thematic analysis. RESULTS: Observations revealed equipment that predominantly stimulated vision and touch. Thematic analysis of the semi-structured interviews revealed six themes: not knowing what to do in the room, good for people in the later stages of the disease, reduces anxiety, it's a good activity, design and setting up of the space, and including relatives and care staff. CONCLUSION: Few MSEs in care homes are designed to meet needs of people with dementia, and staff receive little training in how to facilitate sessions. As such, MSEs are often underused despite perceived benefits. Results of this study have been used to identify the design principles that have been reviewed by relevant stakeholders. PMID- 28008764 TI - Use of stent-grafts for the ductus arteriosus and its related lesions. AB - Five cases of ductal lesions with various anatomies have been successfully treated by thoracic endovascular aortic replacement in recent years; 4 using mainly fenestrated stent-grafts, and one using a non-fenestrated stent-graft. Considering the invasive nature of open surgery and the anatomical limitations of the catheter technique for occluding a patent ductus in many adult cases, thoracic endovascular aortic replacement should be the first option because of its broad applicability for ductal lesions. PMID- 28008765 TI - A comparative analysis of the effectiveness of active versus passive atrial lead fixation in Chinese patients with cardiac implantable electrical devices: a long term, retrospective, observational, single-center study. AB - BACKGROUND: Data comparing active atrial lead fixation with passive atrial lead fixation in Chinese patients with cardiovascular implantable electronic devices (CIEDs) for atrial pacing is limited. Our study evaluated the effectiveness of active fixation versus passive fixation of atrial leads by observing the lead performance parameters. METHODS: This retrospective, long-term, single-center study included a cohort of Chinese patients who underwent CIED implantation at the Department of Cardiology of People's Hospital of Yuxi City, China, from 1 March 2010 to 1 March 2015. Efficacy was determined by comparing implantation time, threshold values, incidence of lead dislocation/failure, and lead-related complications between the two groups. RESULTS: Of the 1217 patients, active and passive atrial lead fixation were performed in 530 (mean age, 69.37 +/- 11.44 years) and 497 (mean age, 68.33 +/- 10.96 years). The active fixation group reported significantly lower mean atrial implantation times (P = .0001) and threshold values (P = .044) compared with the passive atrial lead fixation group. In addition, threshold values in the active atrial lead fixation group were stable throughout the observation period. No instances of myocardial perforation, cardiac tamponade, implantation failure, or electrode dislocation/re-fixation were reported in the active atrial lead fixation group. A favorable decrease in patient comfort parameters such as bed rest time (P = .027) and duration of hospital stay (P = .038) were also observed in the active lead fixation group. CONCLUSION: Active atrial lead fixation demonstrated greater stability, steady long-term thresholds and minimal lead-related complications compared to passive lead fixation in Chinese patients with CIEDs. PMID- 28008766 TI - Identification of Tools and Techniques to Enhance Interdisciplinary Collaboration During Design and Construction Projects. AB - The purpose of this study was to collect the perceptions of design professionals and clinicians regarding design process success strategies and elements of interprofessional engagement and communication during healthcare design and construction projects. Additional objectives were to gather best practices to maximize clinician engagement and provide tools and techniques to improve interdisciplinary collaboration for future projects. Strategies are needed to enhance the design and construction process and create interactions that benefit not only the project but the individuals working to see its completion. Meaningful interprofessional collaboration is essential to any healthcare design project and making sure the various players communicate is a critical element. This was a qualitative study conducted via an online survey. Respondents included architects, construction managers, interior designers, and healthcare personnel who had recently been involved in a building renovation or new construction project for a healthcare facility. Responses to open-ended questions were analyzed for themes, and descriptive statistics were used to provide insight into participant demographics. Information on the impressions, perceptions, and opportunities related to clinician involvement in design projects was collected from nurses, architects, interior designers, and construction managers. Qualitative analysis revealed themes of clinician input, organizational dynamics, and a variety of communication strategies to be the most frequently mentioned elements of successful interprofessional collaboration. This study validates the need to include clinician input in the design process, to consider the importance of organizational dynamics on design team functioning, and to incorporate effective communication strategies during design and construction projects. PMID- 28008767 TI - Classic lung bulla. PMID- 28008768 TI - The cost-effectiveness of dulaglutide versus liraglutide for the treatment of type 2 diabetes mellitus in Spain in patients with BMI >=30 kg/m2. AB - OBJECTIVE: Dulaglutide 1.5 mg once weekly is a novel glucagon-like peptide 1 (GLP 1) receptor agonist, for the treatment of type two diabetes mellitus (T2DM). The objective was to estimate the cost-effectiveness of dulaglutide once weekly vs liraglutide 1.8 mg once daily for the treatment of T2DM in Spain in patients with a BMI >=30 kg/m2. METHODS: The IMS CORE Diabetes Model (CDM) was used to estimate costs and outcomes from the perspective of Spanish National Health System, capturing relevant direct medical costs over a lifetime time horizon. Comparative safety and efficacy data were derived from direct comparison of dulaglutide 1.5 mg vs liraglutide 1.8 mg from the AWARD-6 trial in patients with a body mass index (BMI) >=30 kg/m2. All patients were assumed to remain on treatment for 2 years before switching treatment to basal insulin at a daily dose of 40 IU. One way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) were conducted to explore the sensitivity of the model to plausible variations in key parameters and uncertainty of model inputs. RESULTS: Under base case assumptions, dulaglutide 1.5 mg was less costly and more effective vs liraglutide 1.8 mg (total lifetime costs ?108,489 vs ?109,653; total QALYS 10.281 vs 10.259). OWSA demonstrated that dulaglutide 1.5 mg remained dominant given plausible variations in key input parameters. Results of the PSA were consistent with base case results. LIMITATIONS: Primary limitations of the analysis are common to other cost-effectiveness analyses of chronic diseases like T2DM and include the extrapolation of short-term clinical data to the lifetime time horizon and uncertainty around optimum treatment durations. CONCLUSION: The model found that dulaglutide 1.5 mg was more effective and less costly than liraglutide 1.8 mg for the treatment of T2DM in Spain. Findings were robust to plausible variations in inputs. Based on these results, dulaglutide may result in cost savings to the Spanish National Health System. PMID- 28008769 TI - A discrete event simulation to model the cost-utility of fingolimod and natalizumab in rapidly evolving severe relapsing-remitting multiple sclerosis in the UK. AB - OBJECTIVE: Two disease-modifying therapies are licensed in the EU for use in rapidly-evolving severe (RES) relapsing-remitting multiple sclerosis (RRMS), fingolimod and natalizumab. Here a discrete event simulation (DES) model to analyze the cost-effectiveness of natalizumab and fingolimod in the RES population, from the perspective of the National Health Service (NHS) in the UK, is reported. METHODS: A DES model was developed to track individual RES patients, based on Expanded Disability Status Scale scores. Individual patient characteristics were taken from the RES sub-groups of the pivotal trials for fingolimod. Utility data were in line with previous models. Published costs were inflated to NHS cost year 2015. Owing to the confidential patient access scheme (PAS) discount applied to fingolimod in the UK, a range of discount levels were applied to the fingolimod list price, to capture the likelihood of natalizumab being cost-effective in a real-world setting. RESULTS: At the lower National Institute of Health and Care Excellence (NICE) threshold of L20,000/quality adjusted life year (QALY), fingolimod only required a discount greater than 0.8% of list price to be cost-effective. At the upper threshold of L30,000/QALY employed by the NICE, fingolimod was cost-effective if the confidential discount is greater than 2.5%. Sensitivity analyses conducted using fingolimod list-price showed the model to be most sensitive to changes in the cost of each drug, particularly fingolimod. CONCLUSIONS: The DES model shows that only a modest discount to the UK fingolimod list-price is required to make fingolimod a more cost-effective option than natalizumab in RES RRMS. PMID- 28008770 TI - The budget impact and cost-effectiveness of defibrotide for treatment of veno occlusive disease with multi-organ dysfunction in patients post-hematopoietic stem cell transplant. AB - BACKGROUND: A Phase-3 study of defibrotide compared with historical controls demonstrated a 23% improvement in 100-day survival post-hematopoietic stem cell transplantation (HSCT) among patients with veno-occlusive disease with multi organ dysfunction (VOD with MOD). AIM: To estimate the budget impact and cost effectiveness of introducing defibrotide to a transplant center. METHODS: The authors developed a budget impact model from the perspective of a bone-marrow transplant center. It was estimated that 2.3% of adults and 4.2% of children would develop VOD with MOD following HSCT based on a retrospective hospital database analysis and the effect that treating patients with defibrotide would have on costs for adult and pediatric centers was estimated. A cost-utility analysis (CUA) was also developed to capture the long-term cost-effectiveness of defibrotide. Projected life expectancies in the two groups were estimated based on trial data, transplant registry data, studies of long-term survival among HSCT patients, and US population life-tables. RESULTS: There was an estimated 3% increase ($330,706) per year in total adult transplantation center costs associated with adopting defibrotide, and a <1% increase ($106,385) for pediatric transplant centers, assuming 100 transplants per year. In the CUA, the lifetime increase in cost per patient was $106,928, life expectancy increased by 3.74 years, and quality-adjusted life-years (QALYs) increased by 2.24. The incremental cost-effectiveness ratio (ICER) was $47,736 per QALY gained; 88% probability defibrotide was cost-effective at a $100,000/QALY threshold. CONCLUSION: The budget impact of defibrotide for a transplant center is relatively modest compared to the overall cost of transplantation. Defibrotide provides an important survival advantage for VOD with MOD patients, and the life years gained lead to defibrotide being highly cost-effective. PMID- 28008771 TI - Stroke risk reduction outweighed bleeding risk increase from vitamin K antagonist treatment among nonvalvular atrial fibrillation patients with high stroke risk and low bleeding risk. AB - OBJECTIVE: Warfarin is widely used for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We compared the rates of stroke and major bleeding in NVAF patients with a high stroke risk and low bleeding risk profile during warfarin treated (W+) and warfarin untreated (W-) periods. METHOD: Insurance claims from six commercial, Medicaid or Medicare databases were analyzed from 2000 to 2014. NVAF patients treated with warfarin, with a CHADS2/CHA2DS2-VASc score >=2, and an ATRIA score <=3 at baseline were identified. Incidence rate ratios (IRRs) of stroke and major bleeding were calculated for W + versus W- episodes of person-time, as well as for first 30 days versus beyond 30 days of W + episodes. RESULTS: Among 316,145 patients, anticoagulant prophylaxis with warfarin significantly reduced stroke risk, with IRRs ranging from 0.48 (95% CI: 0.46-0.51) to 0.80 (95% CI: 0.70-0.91), and increased major bleeding risk, with IRRs ranging from 1.13 (95% CI: 1.10-1.15) to 1.95 (95% CI: 1.10-3.45). Stroke and major bleeding rates were higher during the first 30 days of W + than beyond. CONCLUSION: In NVAF patients at high risk for stroke and low risk for bleeding, our data confirm the effectiveness of anticoagulation for stroke prevention. The decrease in stroke risk of anticoagulation may outweigh the risk of major bleeding events, particularly among elderly patients. Potential risks of warfarin during initiation warrant attention, especially among patients who stop and start therapy repeatedly. PMID- 28008772 TI - Selective treatment to reduce contamination of propolis by polycyclic aromatic hydrocarbons (PAHs) still preserving its active polyphenol component and antioxidant activity. AB - The adverse effects on health and environment caused by polycyclic aromatic hydrocarbons (PAHs) are critical problems. EFSA has defined 16 priority PAHs that are both genotoxic and carcinogenic, and identified eight (PAH8) priority PAHs as good indicators of the toxicity and occurrence in food. Food supplements containing propolis were also found to contain relatively high quantities of PAHs. We report about an extractive procedure which is able to purify propolis from a high content of PAHs using a balanced mixture of ethanol and water solvents. Extracts were characterised for total content of polyphenols, for in vitro antioxidant activity, and single classes of polyphenols evaluated by HPLC ESI-MS. Obtained propolis extracts were found to have PAH8 and specific benzo[a]pyrene content below limits recommended by EFSA. The reported extractive procedure is easily applicable for possible industrial productions and may also be adopted to the purification of polyphenols from other plant extracts and natural sources. PMID- 28008773 TI - Radiotherapy response evaluation using FDG PET-CT-established and emerging applications. AB - Radiation therapy is a common component of curative cancer treatment. However, there is a significant incidence of treatment failure. In these cases, salvage surgical options are sometimes appropriate. Accurate assessment of response and early recognition of treatment success or failure is therefore critical to guide treatment decisions and impacts on survival and the morbidity of treatment. Traditionally, treatment response has depended upon the anatomical measurement of disease. However, this may not correlate well with the presence of disease, especially after radiotherapy. Combined positron emission tomography (PET) and CT imaging employs radioactive tracers to identify molecular characteristics of tissues. PET imaging exploits the fact that malignancies have characteristic molecular profiles which differ compared with surrounding tissues. The complementary anatomical and functional information facilitates accurate non invasive assessment of surrogate biomarkers of disease activity. PMID- 28008774 TI - Stereotactic ablative body radiotherapy (SAbR) for oligometastatic cancer. AB - The metastatic state of most solid cancers traditionally has been regarded as an incurable dissemination of disease, with treatment focused on delaying progression rather than eliminating all tumour burden. In this setting, local therapies including surgery and radiotherapy are directed at quality of life end points and not at improvement in survival. However, improvements in imaging and systemic therapy have highlighted populations of patients with lower burden of metastatic disease, termed "oligometastatic," who may present an exception. This condition is hypothesized to bridge the gap between incurable metastatic disease and locoregional disease, where miliary spread either has not occurred or remains eradicable. Consequently, elimination of such low-burden residual disease may "cure" some patients or delay further progression. Accordingly, use of local therapies with the intent of improving survival in oligometastatic disease has increased. Technological advances in radiation delivery with stereotactic ablative body radiotherapy (SAbR) in particular have provided a non-invasive and low-morbidity option. While observational studies have provided interesting preliminary data, significant work remains necessary to prove the merits of this treatment paradigm. This review discusses the data for the oligometastatic state and its treatment with SAbR, as well as challenges to its investigation. PMID- 28008775 TI - Development of clinical simultaneous SPECT/MRI. AB - There is increasing clinical use of combined positron emission tomography and MRI, but to date there has been no clinical system developed capable of simultaneous single-photon emission computed tomography (SPECT) and MRI. There has been development of preclinical systems, but there are several challenges faced by researchers who are developing a clinical prototype including the need for the system to be compact and stationary with MRI-compatible components. The limited work in this area is described with specific reference to the Integrated SPECT/MRI for Enhanced stratification in Radio-chemo Therapy (INSERT) project, which is at an advanced stage of developing a clinical prototype. Issues of SPECT/MRI compatibility are outlined and the clinical appeal of such a system is discussed, especially in the management of brain tumour treatment. PMID- 28008776 TI - Lymph node standardized uptake values at pre-treatment 18F-fluorodeoxyglucose positron emission tomography as a valuable prognostic factor for distant metastasis in nasopharyngeal carcinoma. AB - OBJECTIVE: The aim of the present study was to evaluate prognostic values of pre treatment fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET) parameters for predicting the distant metastasis (DM) of nasopharyngeal cancer. METHODS: 73 patients diagnosed with nasopharyngeal cancer with regional lymph node (LN) involvement, who underwent pre-treatment 18F-FDG PET evaluation between January 2005 and December 2012, were retrospectively reviewed. We assessed the 18F-FDG PET parameters of the primary tumours (T-) and regional LNs (N-). For patients with bilateral retropharyngeal, bilateral neck and/or supraclavicular LN involvement, we also assessed the 18F-FDG PET parameters of the farthest LN station [N(f)-]. The following 18F-FDG PET parameters were evaluated: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), peak standardized uptake value (SUVpeak), metabolic tumour volumes (MTVs) (MTV30-MTV70, which were calculated as the tumour volume with 30%, 40%, 50%, 60% and 70% of the SUVmax as the threshold, respectively) and total lesion glycolysis (TLG) (TLG30-TLG70, which were determined by the product of each MTV and the corresponding SUVmean within that MTV). Distant metastasis-free survival (DMFS) rates were estimated from the date of the start of radiotherapy to the date of DM or last follow-up by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify prognostic factors for DMFS. The median follow-up period was 53 months (range 12-110 months). RESULTS: Most patients (95%) received concurrent chemoradiotherapy. The major failure pattern was DM (15 of all patients, 21%) and the 5-year DMFS was 79%. In univariate analysis, the T-SUVmax, T-SUVmean, T-SUVpeak, N-SUVmax, N-SUVpeak, N(f)-SUVmax and N(f)-SUVpeak were significant prognostic factors for DMFS. In multivariate analysis, the T-SUVmax, T-SUVpeak, N(f)-SUVmax and N(f)-SUVpeak were significant prognostic factors for DMFS. Of these parameters, the N(f)-SUVmax (hazard ratio = 6.524; p = 0.001) and N(f)-SUVpeak (hazard ratio = 5.399; p = 0.001) were the strongest prognostic factors for DMFS. CONCLUSION: In patients with nasopharyngeal cancer with LN involvement, the standardized uptake value parameter of the farthest LN station seems to be an important 18F-FDG PET parameter for predicting DM. Further studies are needed to validate its clinical significance. Advances in knowledge: We found that pre-treatment 18F-FDG PET parameters of primary tumours and regional LNs (the SUVmax and SUVpeak of the primary tumour and the farthest LN station) were significant prognostic factors for DMFS in patients with nasopharyngeal carcinoma with LN involvement. PMID- 28008778 TI - Physical Activity During and After Adjuvant Treatment for Breast Cancer: An Integrative Review of Women's Experiences. AB - BACKGROUND: In oncology, physical activity (PA) is recognized to improve psychological and physiological functions. Motivating women with breast cancer to sustain a physically active lifestyle is important for promoting positive health after diagnosis. To review and synthesize what is known about how women with breast cancer experience supervised and unsupervised PA during and after adjuvant treatment. PubMed, PsycINFO, and CINAHL were searched, yielding 994 citations. The final review included 17 articles published between 2004 and 2014 in English. The CASP (Critical Appraisal Skills Programme) instrument was used to appraise quality. RESULTS: Exercise is experienced as a positive element with multiple benefits. However, maintaining a physically active lifestyle during and after chemotherapy is sometimes challenging. Reported benefits of PA include feeling empowered, and improving and reclaiming health. Facilitators to PA comprised exercising with peers and skilled instructors. Barriers included social factors and lack of information. CONCLUSIONS: Findings highlight the importance of incorporating PA programs from a patient experience perspective as routine treatment. Health care professionals play a crucial "gateway" role in providing information on implementation and benefits of PA. Providing support and educated advice about how to safely start or continue regular PA to minimize symptoms, reduce morbidity, and increase well-being during or after treatment is vital for women with breast cancer. IMPLICATIONS FOR PRACTICE: Health care professionals need increased knowledge of the breast cancer patients' perspectives on facilitators and barriers to PA during and after treatment, in order to provide sufficient support for women to stay physically active during a breast cancer illness. PMID- 28008779 TI - The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer. AB - BACKGROUND: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. METHODS: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4 hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. RESULTS: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. CONCLUSIONS: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions. PMID- 28008780 TI - Carnosine Inhibits the Proliferation of Human Cervical Gland Carcinoma Cells Through Inhibiting Both Mitochondrial Bioenergetics and Glycolysis Pathways and Retarding Cell Cycle Progression. AB - Carnosine has been demonstrated to play an antitumorigenic role in certain types of cancer. However, its underlying mechanism is unclear. In this study, the roles of carnosine in cell proliferation and its underlying mechanism were investigated in the cultured human cervical gland carcinoma cells HeLa and cervical squamous carcinoma cells SiHa. The results showed that carnosine exerted a significant inhibitory effect on the proliferation of HeLa cells, whereas its inhibitory action on the proliferation of SiHa cells was much weaker. Carnosine decreased the ATP content through inhibiting both mitochondrial respiration and glycolysis pathways in cultured HeLa cells but not SiHa cells. Carnosine reduced the activities of isocitrate dehydrogenase and malate dehydrogenase in TCA (tricarboxylic acid) cycle and the activities of mitochondrial electron transport chain complex I, II, III, and IV in HeLa cells but not SiHa cells. Carnosine also decreased the mRNA and protein expression levels of ClpP, which plays a key role in maintaining the mitochondrial function in HeLa cells. In addition, carnosine induced G1 arrest by inhibiting the G1-S phase transition in both HeLa and SiHa cells. Taken together, these findings suggest that carnosine has a strong inhibitory action on the proliferation of human cervical gland carcinoma cells rather than cervical squamous carcinoma cells. Mitochondrial bioenergetics and glycolysis pathways and cell cycle may be involved in the carnosine action on the cell proliferation in cultured human cervical gland carcinoma cells HeLa. PMID- 28008781 TI - Impact of intraoperative MRI-guided resection on resection and survival in patient with gliomas: a meta-analysis. AB - OBJECTIVE: This study addressed the benefit of intraoperative magnetic resonance imaging (iMRI) compared with conventional neuronavigation-guided resection in patients with gliomas. RESEARCH DESIGN AND METHODS: The Medline, PubMed, Cochrane, and Google Scholar databases were searched up to 26 September 2015. Randomized controlled trials (RCTs), two-arm prospective studies, and retrospective studies in patients with glioblastoma/glioma who had received surgical treatment were included. MAIN OUTCOME MEASURES: The primary outcome measures were the extent of tumor resection and tumor size reduction for using iMRI-guided or conventional neuronavigation-guided neurosurgery. Secondary outcomes included impact of surgery on 6 month progression-free survival (PFS), 12 month overall survival (OS) rates and surgical duration. RESULTS: We found that iMRI was associated with greater rate of gross total resection (rGTR) compared with conventional neuronavigation procedures (3.16, 95% confidence interval [CI] 2.07-4.83, P < .001). We found no difference between the two neuronavigation approaches in extent of resection (EOR), tumor size reduction, or time required for surgery (P values >=.065). Intraoperative MRI was associated with a higher rate of progression-free survival (PFS) compared with conventional neuronavigation (odds ratio, 1.84; 95% CI 1.15-2.95; P = .012), but the rate of overall survival (OS) between groups was similar (P = .799). Limitations of the study included the fact that data from non-RCTs was used, the small study population, and heterogeneity of outcomes across studies. CONCLUSIONS: Our findings indicate that iMRI more frequently resulted in more complete resections leading to improved PFS in patients with malignant gliomas. PMID- 28008782 TI - Understanding bolus insulin dose timing: the characteristics and experiences of people with diabetes who take bolus insulin. AB - OBJECTIVE: Despite the increased popularity of newer, fast-acting bolus insulin treatment options that allow for more flexibility in the timing of bolus insulin dosing in recent years, relatively little is known about people with diabetes who administer bolus insulin at differing times in relation to their meals. The purpose of this study was to investigate bolus insulin dose timing in relation to meals among people with type 1 (T1D) and type 2 (T2D) diabetes, as well as to better understand the characteristics and experiences of people who bolus dose at differing times. METHODS: A web-based survey of adults with T1D and T2D treated with bolus insulin therapy in Germany, the UK, and USA was conducted. RESULTS: A total of 906 respondents completed the survey (39% T1D; 61% T2D). A majority of respondents reported bolus dosing before meals in the previous week (57.0%), followed by after meals (18.9%), with meals (12.7%), and at varying times (11.5%). Compared to respondents who dosed with or after meals, those who dosed before meals were significantly less likely to experience hypoglycemia (before, 55.7%; with, 72.8%; after, 68.7%; p < .001) in the previous week. Respondents who bolus dosed before meals were significantly more likely to perceive bolus dose timing as flexible (45.5%) compared to those who dosed with (27.8%) or after (35.7%) meals (p < .001). CONCLUSION: Results show that many people with T1D and T2D dose their bolus insulin with or after meals. Key limitations of all self report surveys include potential bias in responses and generalizability of findings. However, the study was designed to help mitigate these limitations. The findings have implications for clinicians and suggest opportunities for improving diabetes education and care. PMID- 28008783 TI - Lactobacillus rhamnosus NCDC17 ameliorates type-2 diabetes by improving gut function, oxidative stress and inflammation in high-fat-diet fed and streptozotocintreated rats. AB - Restoration of dysbiosed gut microbiota through probiotic may have profound effect on type 2 diabetes. In the present study, rats were fed high fat diet (HFD) for 3 weeks and injected with low dose streptozotocin to induce type 2 diabetes. Diabetic rats were then fed Lactobacillus rhamnosus NCDC 17 and L. rhamnosus GG with HFD for six weeks. L. rhamnosus NCDC 17 improved oral glucose tolerance test, biochemical parameters (fasting blood glucose, plasma insulin, glycosylated haemoglobin, free fatty acids, triglycerides, total cholesterol, low density lipoprotein cholesterol and high-density lipoprotein cholesterol), oxidative stress (thiobarbituric acid reactive substance and activities of catalase, superoxide dismutase and glutathione peroxidase in blood and liver), bifidobacteria and lactobacilli in cecum, expression of glucagon like peptide-1 producing genes in cecum, and adiponection in epididymal fat, while decreased propionate proportions (%) in caecum, and expression of tumour necrosis factor alpha and interlukin-6 in epididymal fat of diabetic rats as compared to diabetes control group. These findings offered a base for the use of L. rhamnosus NCDC 17 for the improvement and early treatment of type 2 diabetes. PMID- 28008784 TI - Therapeutic interventions for gut dysbiosis and related disorders in the elderly: antibiotics, probiotics or faecal microbiota transplantation? AB - Ageing and physiological functions of the human body are inversely proportional to each other. The gut microbiota and host immune system co-evolve from infants to the elderly. Ageing is accompanied by a decline in gut microbial diversity, immunity and metabolism, which increases susceptibility to infections. Any compositional change in the gut is directly linked to gastrointestinal disorders, obesity and metabolic diseases. Increase in opportunistic pathogen invasion in the gut like Clostridium difficile leading to C. difficile infection is more common in the elderly population. Frequent hospitalisation and high prevalence of nosocomial infections with the ageing is also well documented. Long-term utilisation of broad-spectrum antibiotic therapy is being followed in order to control these infections. Nosocomial infections and antibiotic therapy in combination or alone is leading to gastroenteritis followed by Clostridium associated diarrhoea or antibiotic associated diarrhoea. Above all, use of broad spectrum antibiotics is highly debated all over the world due to growing antimicrobial resistance. The use of narrow spectrum antibiotics could be helpful to some extent. Dietary supplementation of probiotics with prebiotics (synbiotics) or without prebiotics has improved gut commensal diversity and regulated the immune system. The recent emergence of faecal microbiota transplantation has played an important role in treating recurrent Clostridium associated diarrhoea. This review focuses on various therapeutic interventions for gut dysbiosis and gastrointestinal diseases in the elderly. The possible mechanism for antimicrobial resistance and mechanism of action of probiotics are also discussed in detail. PMID- 28008785 TI - Establishment of Lactobacillus plantarum strain in honey bee digestive tract monitored using gfp fluorescence. AB - Lactic acid bacteria are symbiotic bacteria that naturally reside in the gastrointestinal tract of honey bees. They serve a multitude of functions and are considered beneficial and completely harmless. In our experiments Lactobacillus plantarum strain B35, isolated from honey bee digestive tract, was modified using pAD43-25 plasmid carrying a functional GFP gene sequence (gfpmut3a) and used as a model for monitoring and optimisation of the mode of application. The establishment of this strain in honey bee digestive tract was monitored using GFP fluorescence. Three different modes of oral application of this strain were tested: water suspension of lyophilised bacteria, aerosol application of these bacteria and consumption of sugar honey paste containing the lyophilised lactobacilli. Two days after administration the L. plantarum B35-gfp was present throughout the honey bee digestive tract with 104-105 cfu/bee with highest count observed for aerosol application. PMID- 28008786 TI - A probiotic combination attenuates experimental colitis through inhibition of innate cytokine production. AB - Inflammatory bowel disease (IBD) is a severe immune cell-mediated syndrome characterised by extensive inflammatory and effector mucosal responses leading to tissue destruction in the colon and small intestine. The leading hypothesis is that dysbiosis of the gut flora causes an excessive immune response and inflammation in the gastrointestinal track. Lactic acid bacteria (LAB) can correct dysbiosis of the normal microbiota. In the current study, the therapeutic potential of seven LAB strains in combination to treat IBD was evaluated using experimental colitis model. This LAB cocktail, designated GI7, includes four strains of Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactococcus lactis, two strains of Bifidobacterium bifidum, Bifidobacterium breve, and one strain of Streptococcus thermophilus. We confirmed that GI7 suppressed pro-inflammatory cytokines in Raw264.7 macrophages. When dextran sulphate sodium-induced colitic mice were treated with GI7, their symptoms of colitis, as assessed by body weight, colon length, myeloperoxidase activity, intestinal bleeding, and histological damage, were reduced compared to untreated mice. In addition, GI7 treatment significantly inhibited the production of innate pro-inflammatory cytokines during colitic progression. Therefore, we suggest that GI7, a combination of seven LAB, has a potential role in the treatment of IBD. PMID- 28008787 TI - A review of dose-responses of probiotics in human studies. AB - The probiotic definition requires the administration of an 'adequate amount' in order to obtain a health benefit. What that amount should be is not indicated. Here, an overview is given of studies that investigated the dose-response relation of probiotics in human interventions. Studies were divided in; meta analyses, meta-analyses on specific probiotic strains, and studies testing two or more doses of a probiotic (combination) in the same study. Meta-analyses on the effect of probiotics on antibiotic associated diarrhoea (AAD) suggest a dose response effect; for Clostridium difficile-associated diarrhoea on the other hand no dose-response was observed. For other end-points; such as necrotising enterocolitis, prevention of atopic dermatitis and slow intestinal transit, no dose-response relation was identified in meta-analyses. For prophylaxis in colorectal cancer and relief of irritable bowel syndrome, no dose-response relation was determined. However, for blood pressure, a meta-analysis observed that higher doses (greater than 1011 cfu) were more effective than lower doses. Meta-analyses of specific strains suggest a break-point for effectiveness of Lactobacillus rhamnosus GG in the treatment of acute gastroenteritis in children; no dose-response was observed for two other probiotics assessed. Studies comparing two or more doses indicate that faecal recovery and risk reduction of AAD follow a positive dose-response relationship. Other end-points such as immune markers, general health, and bowel function did not exhibit clear dose-response relations. For AAD, the findings are very compelling; both meta-analyses and dedicated dose-response studies observe a positive correlation between dose and AAD risk. These findings do not allow for extrapolation, but suggest that studying higher doses for this end-point would be worthwhile. The lack of a clear dose-response for other end-points, does not mean it does not exist; present data does just not allow drawing any conclusions. PMID- 28008788 TI - Instantaneous stiffness and hysteresis of dynamic elastic response prosthetic feet. AB - BACKGROUND: Dynamic elastic response prosthetic feet are designed to mimic the functional characteristics of the native foot/ankle joint. Numerous designs of dynamic elastic response feet exist which make the prescription process difficult, especially because of the lack of empirical evidence describing the objective performance characteristics of the feet. OBJECTIVES: To quantify the mechanical properties of available dynamic elastic response prosthetic feet, specifically the stiffness and hysteresis. STUDY DESIGN: Mechanical testing of dynamic elastic response prosthetic feet. METHODS: Static Proof Testing in accordance with ISO 10328 was conducted on seven dynamic elastic response prosthetic feet. Load-displacement data were used to calculate the instantaneous stiffness in both the heel and forefoot regions, as well as hysteresis associated with each foot. RESULTS: Heel stiffness was greater than forefoot stiffness for all feet. The heel of the glass composite prosthetic foot was stiffer than the carbon fiber feet and it exhibited less hysteresis. Two different carbon fiber feet had the stiffest forefoot regions. CONCLUSION: Mechanical testing is a reproducible method that can be used to provide objective evidence about dynamic elastic response prosthetic foot performance and aid in the prescription process. Clinical relevance The quantitative stiffness and hysteresis data from this study can be used by prosthetists to aid the prescription process and make it more objective. PMID- 28008789 TI - A cautionary note to authors on the selection and use of keywords. PMID- 28008790 TI - Critical analysis of e-health readiness assessment frameworks: suitability for application in developing countries. AB - Introduction e-Health is an innovative way to make health services more effective and efficient and application is increasing worldwide. e-Health represents a substantial ICT investment and its failure usually results in substantial losses in time, money (including opportunity costs) and effort. Therefore it is important to assess e-health readiness prior to implementation. Several frameworks have been published on e-health readiness assessment, under various circumstances and geographical regions of the world. However, their utility for the developing world is unknown. Methods A literature review and analysis of published e-health readiness assessment frameworks or models was performed to determine if any are appropriate for broad assessment of e-health readiness in the developing world. A total of 13 papers described e-health readiness in different settings. Results and Discussion Eight types of e-health readiness were identified and no paper directly addressed all of these. The frameworks were based upon varying assumptions and perspectives. There was no underlying unifying theory underpinning the frameworks. Few assessed government and societal readiness, and none cultural readiness; all are important in the developing world. While the shortcomings of existing frameworks have been highlighted, most contain aspects that are relevant and can be drawn on when developing a framework and assessment tools for the developing world. What emerged is the need to develop different assessment tools for the various stakeholder sectors. This is an area that needs further research before attempting to develop a more generic framework for the developing world. PMID- 28008791 TI - Adapting censored regression methods to adjust for the limit of detection in the calibration of diagnostic rules for clinical mass spectrometry proteomic data. AB - In this paper, we consider the problem of calibrating diagnostic rules based on high-resolution mass spectrometry data subject to the limit of detection. The limit of detection is related to the limitation of instruments in measuring low concentration proteins. As a consequence, peak intensities below the limit of detection are often reported as missing during the quantification step of proteomic analysis. We propose the use of censored data methodology to handle spectral measurements within the presence of limit of detection, recognizing that those have been left-censored for low-abundance proteins. We replace the set of incomplete spectral measurements with estimates of the expected intensity and use those as input to a prediction model. To correct for lack of information and measurement uncertainty, we combine this approach with borrowing of information through the addition of an individual-specific random effect formulation. We present different modalities of using the above formulation for prediction purposes and show how it may also allow for variable selection. We evaluate the proposed methods by comparing their predictive performance with the one achieved using the complete information as well as alternative methods to deal with the limit of detection. PMID- 28008792 TI - Directional Atherectomy With Antirestenotic Therapy vs Drug-Coated Balloon Angioplasty Alone for Isolated Popliteal Artery Lesions. AB - PURPOSE: To report a single-center study comparing drug-coated balloon (DCB) angioplasty vs directional atherectomy with antirestenotic therapy (DAART) for isolated lesions of the popliteal artery. METHODS: Seventy-two patients were treated with either DCB angioplasty alone (n=31) or with DAART (n=41) for isolated popliteal artery stenotic disease between October 2009 and December 2015. The majority of patients presented with lifestyle-limiting claudication (74% vs 86%, respectively). Vessel calcification (29% vs 29%, respectively), mean lesion length (47 vs 42 mm, respectively), and number of runoff vessels were comparable between the groups. The primary outcome measure was primary patency; secondary outcomes were technical success (<30% residual stenosis or bailout stenting), secondary patency, and freedom from clinically driven target lesion revascularization (TLR). RESULTS: The technical success rate following DCB was 84% vs 93% (p=0.24) after DAART. The 12-month primary patency rate was significantly higher in the DAART group (65% vs 82%; hazard ratio 2.64, 95% confidence interval 1.09 to 6.37, p=0.021), while freedom from TLR did not differ between the 2 treatment strategies (82% vs 94%, p=0.072). Secondary patency at 12 months was identical for both groups (96% vs 96%). Although not statistically significant, bailout stenting was more common after DCB angioplasty (16% vs 5% for DAART, p=0.13) and aneurysmal degeneration of the popliteal artery was seen more often after DAART (7% vs 0% for DCB alone, p=0.25). Popliteal artery injury was observed in 2 patients treated using DAART (5% vs 0% for DCB alone, p=0.5), whereas distal embolization rates were comparable between the groups (3% for DCB alone vs 5% for DAART, p=0.99). CONCLUSION: In this study, the use of DAART was associated with a higher primary patency rate compared with DCB angioplasty for isolated popliteal lesions. Nonetheless, both treatment options were associated with excellent 12-month secondary patency. Aneurysmal degeneration of the popliteal artery and increased bailout stenting could compromise the outcomes of DAART and DCB, respectively. PMID- 28008794 TI - Power comparison of Cochran-Armitage trend test against allelic and genotypic tests in large-scale case-control genetic association studies. AB - The Cochran-Armitage trend test (CA) has become a standard procedure for association testing in large-scale genome-wide association studies (GWAS). However, when the disease model is unknown, there is no consensus on the most powerful test to be used between CA, allelic, and genotypic tests. In this article, we tackle the question of whether CA is best suited to single-locus scanning in GWAS and propose a power comparison of CA against allelic and genotypic tests. Our approach relies on the evaluation of the Taylor decompositions of non-centrality parameters, thus allowing an analytical comparison of the power functions of the tests. Compared to simulation-based comparison, our approach offers the advantage of simultaneously accounting for the multidimensionality of the set of features involved in power functions. Although power for CA depends on the sample size, the case-to-control ratio and the minor allelic frequency (MAF), our results first show that it is largely influenced by the mode of inheritance and a deviation from Hardy-Weinberg Equilibrium (HWE). Furthermore, when compared to other tests, CA is shown to be the most powerful test under a multiplicative disease model or when the single nucleotide polymorphism largely deviates from HWE. In all other situations, CA lacks in power and differences can be substantial, especially for the recessive mode of inheritance. Finally, our results are illustrated by the comparison of the performances of the statistics in two genome scans. PMID- 28008793 TI - Social isolation alters central nervous system monoamine content in prairie voles following acute restraint. AB - Animal models have shown that social isolation and other forms of social stress lead to depressive- and anxiety-relevant behaviors, as well as neuroendocrine and physiological dysfunction. The goal of this study was to investigate the effects of prior social isolation on neurotransmitter content following acute restraint in prairie voles. Animals were either paired with a same-sex sibling or isolated for 4 weeks. Plasma adrenal hormones and ex vivo tissue concentrations of monoamine neurotransmitters and their metabolites were measured following an acute restraint stressor in all animals. Isolated prairie voles displayed significantly increased circulating adrenocorticotropic hormone levels, as well as elevated serotonin and dopamine levels in the hypothalamus, and potentially decreased levels of serotonin in the frontal cortex. However, no group differences in monoamine levels were observed in the hippocampus or raphe. The results suggest that social stress may bias monoamine neurotransmission and stress hormone function to subsequent acute stressors, such as restraint. These findings improve our understanding of the neurobiological mechanisms underlying the consequences of social stress. PMID- 28008795 TI - A comparison of fate and toxicity of selenite, biogenically, and chemically synthesized selenium nanoparticles to zebrafish (Danio rerio) embryogenesis. AB - Microbial reduction of selenium (Se) oxyanions to elemental Se is a promising technology for bioremediation and treatment of Se wastewaters. But a fraction of biogenic nano-Selenium (nano-Seb) formed in bioreactors remains suspended in the treated waters, thus entering the aquatic environment. The present study investigated the toxicity of nano-Seb formed by anaerobic granular sludge biofilms on zebrafish embryos in comparison with selenite and chemogenic nano-Se (nano-Sec). The nano-Seb formed by granular sludge biofilms showed a LC50 value of 1.77 mg/L, which was 3.2-fold less toxic to zebrafish embryos than selenite (LC50 = 0.55 mg/L) and 10-fold less toxic than bovine serum albumin stabilized nano-Sec (LC50 = 0.16 mg/L). Smaller (nano-Secs; particle diameter range: 25-80 nm) and larger (nano-Secl; particle diameter range: 50-250 nm) sized chemically synthesized nano-Sec particles showed comparable toxicity on zebrafish embryos. The lower toxicity of nano-Seb in comparison with nano-Sec was analyzed in terms of the stabilizing organic layer. The results confirmed that the organic layer extracted from the nano-Seb consisted of components of the extracellular polymeric substances (EPS) matrix, which govern the physiochemical stability and surface properties like zeta-potential of nano-Seb. Based on the data, it is contented that the presence of humic acid like substances of EPS on the surface of nano-Seb plays a major role in lowering the bioavailability (uptake) and toxicity of nano-Seb by decreasing the interactions between nanoparticles and embryos. PMID- 28008796 TI - Isolation and identification of a novel sildenafil analogue adulterant in herbal products. AB - A novel sildenafil analogue found in herbal products by a routine drug adulteration screening programme was isolated by column chromatography. On the basis of extensive 1D- and 2D-nuclear magnetic resonance (NMR) spectroscopy and mass spectral analysis, the structure of a new compound YJ-07 was established as 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5 yl) benzenesulfonamide. It common name is aminosildenafil. PMID- 28008797 TI - IRF8 is the target of SIRT1 for the inflammation response in macrophages. AB - The type III histone deacetylase SIRT1 has recently emerged as a critical immune regulator by suppressing T-cell immunity and macrophage activation during inflammation, but its mechanism in regulating inflammatory response in macrophages remains unclear. Here we show that the expression of SIRT1 in macrophage cells decreased following the release of inflammation cytokines when the cells were stimulated with LPS. IRF8, an important regulator in monocyte differentiation and macrophage polarization, showed the opposite trend, with SIRT1 expression levels increasing after the cells treated with LPS. Co immunoprecipitation and immunofluorescence experiments showed that SIRT1 could not only interact with IRF8, but also deacetylate it. LPS treatment had no effect on the expression of IRF8 in macrophage cells in which sirt1 was specifically deleted. Our results show that IRF8 may be the target of histone deacetylase SIRT1 to regulate the inflammation in the macrophage cells. PMID- 28008798 TI - Risk assessment of dietary exposure to tryptamine for the Austrian population. AB - Tryptamine acts as a neuromodulator and vasoactive agent in the human body. Dose response data on dietary tryptamine are scarce and neither a toxicological threshold value nor tolerable levels in foods have been established so far. This paper reviews dose-response characteristics and toxicological effects of tryptamine as well as tryptamine contents in food, estimates dietary exposure of Austrian consumers, and calculates risk-based maximum tolerable limits for food categories. A dose without effect of 8 mg kg-1 body weight day-1 was derived from literature data. Dietary exposure via fish/seafood, beer, cheese and meat products was estimated for Austrian schoolchildren, female and male consumers, based on 543 food samples analysed in Austria 2010-15 and on food consumption data from 2008. Even worst-case estimates based on very high tryptamine contents reported in the literature did not exceed 5.9 mg kg-1 body weight day-1, and thus were below the dose without effect. Maximum tolerable levels for food commodities were calculated for high-consumption scenarios (95th percentile of female Austrian consumers). For fresh/cooked fish, preserved fish, cheese, raw sausage, condiments, sauerkraut and fermented tofu, maximum tolerable levels were 1650, 3200, 2840, 4800, 14,120, 1740 and 2400 mg kg-1, respectively. For beer, the maximum tolerable limit of 65 mg kg-1 included an uncertainty factor of 10. None of the Austrian occurrence data exceeded these levels (in fact, only 3.3% of samples demonstrated measurable amounts of tryptamine), and just one report was found in the literature on a raw fish sample exceeding the respective tolerable level. In sum, dietary intake of tryptamine should not cause adverse health effects in healthy individuals. The assessment did not take into account the combined effects of simultaneously ingested biogenic amines, and increased susceptibility to tryptamine, e.g., due to reduced monoamine oxidase activity. PMID- 28008799 TI - Subjective Lexical Characteristics: Comparing Ratings of Members of the Target Population and Doctors for Words Stemming from a Medical Context. AB - The present study investigated the subjective lexical characteristics of words stemming from a medical context by comparing estimations of the target population (age range = 46-89) and of doctors. A total of 58 members of the target population and 22 oncologists completed measures of subjective frequency and emotional valence for words previously collected in interviews of announcement of cancer diagnosis. The members of the target population also completed tests of word definitions, without and within context. As expected, most of the words were rated less familiar, more negative and as generating more intense emotions to the target population than to the doctors. Moreover, only a few words were correctly defined by the target population. Adding a context helped the participants to define most of the words correctly. Importantly, we identified words that were rated familiar by the patients although they did not know their exact meaning. Overall, these results highlight the importance of taking into account the subjective lexical characteristics of words used in specific contexts. PMID- 28008800 TI - Informativeness, Timing and Tempo in Lexical Self-Repair. AB - This paper presents a study of the temporal organization of lexical repair in spontaneous Dutch speech. It assesses the extent to which offset-to-repair duration and repair tempo can be predicted on the basis of offset timing, reparandum tempo and measures of the informativeness of the crucial lexical items in the repair. Specifically, we address the expectations that repairs that are initiated relatively early are produced relatively fast throughout, and that relatively highly informative repairs are produced relatively slowly. For informativeness, we implement measures based on repair semantics, lexical frequency counts and cloze probabilities. Our results highlight differences between factual and linguistic error repairs, which have not been consistently distinguished in previous studies, and provide some evidence to support the notion that repairs that are initiated relatively early are produced relatively fast. They confirm that lexical frequency counts are rough measures of contextual predictability at best, and reveal very few significant effects of our informativeness measures on the temporal organization of lexical self-repair. Moreover, although we can confirm that most repairs have a repair portion that is fast relative to its reparandum, this cannot be attributed to the relative informativeness of the two portions. Our findings inform the current debate on the division of labour between inner and overt speech monitoring, and suggest that, although the influence of informativeness on speech production is extensive, it is not ubiquitous. PMID- 28008801 TI - Focus in Corrective Exchanges: Effects of Pitch Accent and Syntactic Form. AB - A dialog consisting of an utterance by one speaker and another speaker's correction of its content seems intuitively to be made more acceptable when the new information is pitch accented or otherwise focused, and when the utterance and correction have the same syntactic form. Three acceptability judgment studies, one written and two auditory, investigated the interaction of focus (manipulated by sentence position and, in Experiments 2 and 3, pitch accent) and syntactic parallelism. Experiment 1 indicated that syntactic parallelism interacted with position of the new (contrastive) term: nonparallel forms were relatively acceptable when the new term appeared in object position, a position that commonly contains new information (a 'default focus' position). Experiments 2 and 3 indicated that presence of a pitch accent and placement in a default focus position had additive effects on acceptability. Surprisingly, spoken dialogs in which the new term appeared in object position were acceptable even when given information carried the most prominent pitch accent. The present studies, and earlier work, suggest that corrected information can be focused either by prosody or position even in spoken English-a language often thought to express focus through pitch accent, not syntactic position. PMID- 28008802 TI - Learning the Marshallese Phonological System: The Role of Cross-language Similarity on the Perception and Production of Secondary Articulations. AB - The current study determines the influence of cross-language similarity on native English speakers' perception and production of Marshallese consonant contrasts. Marshallese provides a unique opportunity to study this influence because all Marshallese consonants have a secondary articulation. Results of discrimination and production tasks indicate that learners more easily acquire sounds if they are perceptually less similar to native language phonemes. In addition, the degree of cross-language similarity seemed to affect perception and production and may also interact with the effect of orthography. PMID- 28008803 TI - Seeking an Anchorage. Stability and Variability in Tonal Alignment of Rising Prenuclear Pitch Accents in Cypriot Greek. AB - Although tonal alignment constitutes a quintessential property of pitch accents, its exact characteristics remain unclear. This study, by exploring the timing of the Cypriot Greek L*+H prenuclear pitch accent, examines the predictions of three hypotheses about tonal alignment: the invariance hypothesis, the segmental anchoring hypothesis, and the segmental anchorage hypothesis. The study reports on two experiments: the first of which manipulates the syllable patterns of the stressed syllable, and the second of which modifies the distance of the L*+H from the following pitch accent. The findings on the alignment of the low tone (L) are illustrative of the segmental anchoring hypothesis predictions: the L persistently aligns inside the onset consonant, a few milliseconds before the stressed vowel. However, the findings on the alignment of the high tone (H) are both intriguing and unexpected: the alignment of the H depends on the number of unstressed syllables that follow the prenuclear pitch accent. The 'wandering' of the H over multiple syllables is extremely rare among languages, and casts doubt on the invariance hypothesis and the segmental anchoring hypothesis, as well as indicating the need for a modified version of the segmental anchorage hypothesis. To address the alignment of the H, we suggest that it aligns within a segmental anchorage-the area that follows the prenuclear pitch accent-in such a way as to protect the paradigmatic contrast between the L*+H prenuclear pitch accent and the L+H* nuclear pitch accent. PMID- 28008804 TI - Alveolar and Velarized Laterals in Albanian and in the Viennese Dialect. AB - A comparison of alveolar and velarized lateral realizations in two language varieties, Albanian and the Viennese dialect, has been performed. Albanian distinguishes the two laterals phonemically, whereas in the Viennese dialect, the velarized lateral was introduced by language contact with Czech immigrants. A categorical distinction between the two lateral phonemes is fully maintained in Albanian. Results are not as straightforward in the Viennese dialect. Most prominently, female speakers, if at all, realize the velarized lateral in word final position, thus indicating the application of a phonetically motivated process. The realization of the velarized lateral by male speakers, on the other hand, indicates that the velarized lateral replaced the former alveolar lateral phoneme. Alveolar laterals are either realized in perceptually salient positions, thus governed by an input-switch rule, or in front vowel contexts, thus subject to coarticulatory influences. Our results illustrate the subtle interplay of phonology, phonetics and sociolinguistics. PMID- 28008805 TI - Eosinophils in Homeostasis and Their Contrasting Roles during Inflammation and Helminth Infections. AB - Eosinophil numbers are highly elevated during helminth infections and a range of allergic and inflammatory disorders, but eosinophils are also present in several tissues in the absence of infection. Indeed, new findings demonstrate that eosinophils may be involved in events as diverse as glucose metabolism, mammary gland development, intestinal health, tissue remodeling, thymic selection, and B cell survival. Although eosinophils often correlate with pathological parameters during conditions such as inflammatory bowel disease and asthma, the evidence for their contribution to tissue pathology remains controversial. Recent research suggests that eosinophils may have additional roles in these settings that are related to control and resolution of inflammation. Controversy also surrounds the involvement of eosinophils in anti-helminth immunity. Their assumed role in fighting parasites has increasingly been questioned, particularly as a result of data from studies of eosinophil-ablated mouse strains in which either no or only very moderate effects on helminth survival has been reported. Helminths are masters of immune regulation, but whether they actively suppress eosinophil function has rarely been considered. Thus, the purpose of this review is threefold: (1) to summarize our knowledge of the wide range of functions of eosinophils during homeostasis, (2) to discuss the role of eosinophil during inflammation and the recent discovery of eosinophils as mediators of inflammatory resolution, and (3) to summarize data on the effect of eosinophils on helminth infections and discuss the possibility of helminth-mediated modulation of eosinophils. PMID- 28008806 TI - Role of IL-26+CD26+CD4 T Cells in Pulmonary Chronic Graft-Versus-Host Disease and Treatment with Caveolin-1-Ig Fc Conjugate. AB - Obliterative bronchiolitis is the primary noninfectious pulmonary complication after allogeneic hematopoietic cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In our recent study, we identified a novel effect of IL-26, which is absent in rodents, on transplant related-obliterative bronchiolitis. Sublethally irradiated NOD/Shi scidIL2rgammanull mice transplanted with human umbilical cord blood gradually exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Moreover, we showed that IL-26 increased collagen synthesis in fibroblasts in vitro and that collagen contents were increased in a murine GVHD model using IL26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by CD4 T cells following CD26 costimulation, while immunoglobulin Fc domain fused with the N-terminal of caveolin-1, the ligand for CD26, (Cav-Ig) effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. We concluded that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy. PMID- 28008807 TI - The Role of HLA-Class I Heavy-Chain Interactions with Killer-Cell Immunoglobulin Like Receptors in Immune Regulation. AB - HLA-class I molecules form trimeric complexes (pMHC) of peptides, class I heavy chains, and beta2microglobulins (beta2m) that regulate immune responses by binding to T cells and other immune receptors. B2m-free class I heavy chains (FHCs) form on cells either as a consequence of the natural turnover of pMHC or, in the case of HLA-F, are expressed without beta2m. Distinct characteristics of certain HLA-class I members, such as HLA-B27 and HLA-F, stabilize these forms facilitating interactions with immune receptors. FHC forms of HLA-class I have been shown to bind to killer-cell immunoglobulin-like receptor (KIR) family members. The binding of FHC forms to KIR3DL2 regulates natural killer (NK) and T cell functiona and promotes lymphocyte survival. KIR3DL2 binding to B27 FHC dimers has been implicated in the pathogenesis of spondyloarthritis (SpA). KIR3DL2 binding FHC forms could also play a role in immune cell recognition of certain tumors and in regulation of immune homeostasis at the maternal-fetal interface. Here, I review the evidence for the functional interaction of cell surface HLA-class I FHCs with KIR family members. I also discuss the relevance of these interactions in immune homeostasis and immune dysfunction in diseases in which FHC-binding KIRs have been implicated. PMID- 28008808 TI - Antitumor Activity of Extracts from Medicinal Basidiomycetes Mushrooms. AB - Aqueous extracts from the vegetative submerged mycelia of cultivated Basidiomycetes Ganoderma lucidum, Lentinus edodes, and Grifola frondosa, as well as from the fruiting bodies of G. lucidum, were found to have antitumor activity. The antitumor effect of the mycelial extracts from all 3 fungal species was ascertained in vivo in rats with implanted kidney cancer. Dystrophic changes in tumor cells and tumor necrosis (up to 90%) were noted. In vitro cytotoxicity studies of the A549 human lung adenocarcinoma cell line and HEp-2 human laryngeal epidermoid carcinoma cells showed that the extracts from the G. lucidum fruiting bodies and from the L. edodes vegetative mycelium were the most effective. The animals' immune systems were activated, and the fungal extracts displayed no toxicity when administered orally. PMID- 28008809 TI - Medicinal Properties of the Genus Clitocybe and of Lectins from the Clouded Funnel Cap Mushroom, C. nebularis (Agaricomycetes): A Review. AB - Current knowledge of the medicinal properties of Basidiomycetes mushroom species of the genus Clitocybe and of the biological activity of C. nebularis fruiting bodies is reviewed. The main focus is the therapeutic potential of lectins from C. nebularis. Species of the genus Clitocybe, including C. nebularis, have not been traditionally considered as medicinal mushrooms; however, recent studies have demonstrated their antitumor, immunomodulatory, and antioxidative properties, their antimicrobial (antiviral, antibacterial, and antifungal) activities against various bacteria and fungi, as well as their potential use in therapy for alcoholism and as psychotropic agents. These activities have been shown to be due to various compounds, either isolated or in extracts, mainly polysaccharides but also phenols, ribonucleosides, and proteins. These include laccase, protease inhibitors, and lectins. C. nebularis has been shown to be rich in a variety of lectins and isolectins with distinct carbohydrate-binding specificities, showing versatile biological activities. They exhibit immunostimulatory and adhesion-/phagocytosis-promoting properties, as well as toxicity in various invertebrates. Mushroom species of the genus Clitocybe, including C. nebularis, thus constitute a valuable source of compounds showing diverse biological activities with a broad potential for applications in biomedicine or biotechnology. On the basis of such evidence reviewed here, we propose that C. nebularis and other Clitocybe species can be considered to be medicinal mushrooms. PMID- 28008810 TI - A Polysaccharide from the Culinary-Medicinal Mushroom Pholiota nameko (Agaricomycetes) Inhibits the NF-kappaB Pathway in Dendritic Cells Through the TLR2 Receptor. AB - A polysaccharide purified from Pholiota nameko (PNPS-1) was found to have anticancer and anti-inflammatory activity. This study investigated the effect of PNPS-1 on the nuclear factor (NF)-kappaB signaling pathway of TLR2 small interfering RNA-silenced murine bone marrow-derived dendritic cells (BMDCs) and relevant mechanisms. The expression of messenger RNA of 4 NF-kappaB-related genes, including MyD88, IKBKB, RelA(p65), and CCL2, was determined by real-time polymerase chain reaction; the expression of the phenotype molecule intercellular adhesion molecule-1 (ICAM-1) by flow cytometry; the protein expression of IKKbeta and p65 by Western blot; the production of p65 by enzyme-linked immunosorbent assay; and the expression of p65 by immunocytochemistry. The results showed that TLR2-specific small interfering RNA could effectively inhibit the decrease in the expression of MyD88, IKBKB, CCL2, p65, and ICAM-1 in BMDCs induced by PNPS-1, and thus the transcription inactivation of NF-kappaB, which obviously suggests that PNPS-1 could downregulate the NF-kappaB signaling pathway via the TLR2 receptor. PMID- 28008811 TI - Evaluation of Antianxiety Potential of Four Ganoderma (Agaricomycetes) Species from India in Mice. AB - The genus Ganoderma consists of widespread polypore mushrooms that have traditionally been used to reduce stress and anxiety. However, scientific evidence for this is not adequate. Hence, this study was designed to investigate the anxiolytic potential of G. applanatum, G. brownii, G. lucidum, and G. philippii collected from Uttarakhand, India. Various extracts of dried, powdered basidiocarps were prepared using different solvents-namely, petroleum ether, chloroform, methanol, and distilled water-by successive Soxhlet extraction. All the extracts were tested for antianxiety activity using the elevated plus maze (EPM) model in Swiss albino mice. The results showed that the methanol extract of G. lucidum at a dose of 200 mg/kg, administered orally, shows a significant increase in the average time spent in the open arms of the EPM when compared with the control; this was comparable to the effect of the standard drug (diazepam, 2 mg/kg by mouth). This bioactive methanol extract was subjected to bioactivity guided fractionation. The results show that the n-butanol fraction of the methanol extract evinced significant antianxiety activity at a dose of 100 mg/kg. This fraction showed the presence of phenols and flavonoids and thus was standardized with respect to total phenol content and total flavonoid content. The antianxiety activity may be the result of the phenols/flavonoids present. This study clearly demonstrated that the n-butanol fraction from the methanol extract of G. lucidum can be developed as source of new anxiolytic agents. PMID- 28008812 TI - Anti-Inflammation Properties of Fruiting Bodies and Submerged Cultured Mycelia of Culinary-Medicinal Higher Basidiomycetes Mushrooms. AB - This research shows the phenolic composition and anti-inflammation properties of fruiting bodies and mycelia of 15 strains of 12 species of higher Basidiomycetes medicinal mushrooms. In this research, 15 extracts were prepared and their effects on inflammation-related mediators in RAW 264.7 cells were evaluated. In the extracts, amounts of total phenols ranged from 8.47 to 70.32 gallic acid equivalents mg/g and amounts of flavonoids ranged from 0.13 to 15.21 rutin equivalents mg/g. The production of nitric oxide, tumor necrosis factor-alpha, and interleukin-6 was decreased at different levels by these extracts, whereas the production of interleukin-10 was increased by 6 of the extracts. Overall, Cordyceps militaris fruiting bodies, Grifola frondosa fruiting bodies, and Ophiocordyceps sinensis mycelia might be used to ameliorate inflammatory responses. PMID- 28008813 TI - Evaluation of Anticholinesterase and Inflammation Inhibitory Activity of Medicinal Mushroom Phellinus pini (Basidiomycetes) Fruiting Bodies. AB - Phellinus pini, a medicinal mushroom, has been used as folk medicine in Asian countries for treating ailments such as cancer and gastrointestinal diseases. In this study we evaluated in vitro the antidementia and anti-inflammatory activities of Ph. Pini fruiting bodies. Eleven phenol compounds were detected by high-performance liquid chromatography analysis. Acetylcholinesterase and butyrylcholinesterase inhibitory effects of a methanol extract and a hot water extract were moderate and comparable with those of galanthamine, the standard drug used to treat the early stages of Alzheimer's disease. The methanol extract had a neuroprotective effect against glutamate-induced cytotoxicity on PC-12 cells at concentration ranging from 20 to 40 ug/mL. The mushroom extracts also inhibited the production of nitric oxide and the expression of inducible nitric oxide synthase in lipopolysaccharide-induced RAW 264.7 macrophages, and they significantly inhibited in vivo carrageenan-induced hind-paw edema in rats. Therefore, it is suggested that Ph. Pini fruiting bodies possess anticholinesterase and anti-inflammatory effects. PMID- 28008814 TI - Comprehensive Evaluation of the Antioxidant Potential of Coastal Dune Mushroom Species from the Southwest of France. AB - Numerous mushroom species are used as food and for medicinal purposes; however, many species that may contain bioactive compounds remain underinvestigated. In this study, the antioxidant properties of extracts sequentially isolated with cyclohexane, dichloromethane, and methanol from 25 costal dune mushroom species collected in the southwestern region of France were evaluated based on their radical scavenging capacity, ferric-reducing antioxidant power, oxygen radical absorbance capacity, and Folin-Ciocalteu-determined total phenolic content. Overall, the antioxidant potential of dried mushrooms was assessed using integrated antioxidant scores. The highest antioxidant capacity values were demonstrated by the Cortinarius infractus, Agaricus coniferarum, A. menieri, and A. freirei species. These results may foster further studies of the selected mushroom species to valorize their nutritional and medicinal properties. PMID- 28008815 TI - In Silico Analysis of Lanostanoids Characterized in Ganoderma Mushrooms (Agaricomycetes) as Potential Ligands of the Vitamin D Receptor. AB - The metabolism of vitamin D is a very important pathway involved in the regulation of sterols and maintenance of cell health. The physiological activity of the human hormone 1alpha,25-dihydroxyvitamin D3, or calcitriol, is mediated by the vitamin D receptor (VDR), an endocrine member of the nuclear receptor superfamily that inhibits cell growth and stimulates cell differentiation, suggesting a potential application in cancer chemoprevention. Since nonpolar extracts obtained from Ganoderma mushrooms have also been shown to exert an antiproliferative effect on several cancer cell lines, it was suggested that at least part of its activity might be mediated by VDR. The aim of this work was to identify possible VDR ligands from an extensive library of lanostanoids isolated from several Ganoderma mushrooms. Using an in silico approach, 30 lanostanoids were found to interact with the VDR ligand-binding pocket in the same way as calcitriol. The possible implications of using these compounds are discussed here. PMID- 28008816 TI - Laccase Production Among Medicinal Mushrooms from the Genus Flammulina (Agaricomycetes) Under Different Treatments in Submerged Fermentation. AB - The laccase activities of 13 strains of medicinal and edible mushrooms from the Flammulina genus (F. velutipes, F. rossica, and F. fennae) were studied. The effects of both fungal isolates and culture media were investigated. The laccase activities indicated significant differences among Flammulina strains (P < 0.001), and the cultural media significantly affected the laccase activities in Flammulina spp. (P < 0.001). The morphological characteristics of the 3 Flammulina species were similar, but differences in phylogenetic analysis and laccase activity existed among different species. Although isolates of each Flammulina species differed, the laccase variables among different Flammulina species were greater than those within the same species. The presence of simple carbon and nitrogen sources increased the maximum laccase enzyme activity, but the occurrence of both laccase activity and maximum laccase enzyme activity was delayed compared with lignocellulosic material. The laccase activities of most Flammulina isolates were increased when exposed to copper ions. Our findings offer insights into laccase productivity in response to different Flammulina species or strains and different submerged fermentation treatments. PMID- 28008817 TI - Midgut-based resistance to oral infection by a nucleopolyhedrovirus in the laboratory-selected strain of the smaller tea tortrix, Adoxophyes honmai (Lepidoptera: Tortricidae). AB - A strain of Adoxophyes honmai resistant to Adoxophyes honmai nucleopolyhedrovirus (AdhoNPV) was established from a field-collected colony by repeated selection. Fifth-instar larvae of this resistant strain (R-strain) had over 66 666-fold greater resistance in terms of 50 % lethal concentration values to oral infection of AdhoNPV than non-selected strain larvae (susceptible for AdhoNPV; S2-strain). In this study, the mechanism of resistance to AdhoNPV was determined in R-strain larvae. An assessment of viral genome replication in AdhoNPV-infected S2- and R strain larvae by quantitative PCR showed no viral genome replication occurring in R-strain larvae. Transcription of AdhoNPV ie-1, vp39 and polyhedrin genes was also not detected in R-strain midgut cells. Besides, a fluorescent brightener had no effect on AdhoNPV infection in either S2- or R-strain. However, binding and fusion of occlusion-derived virus with R-strain were significantly lower than those of S2-strain. These findings suggest that R-strain Adoxophyeshonmai larvae possess a midgut-based resistance to oral infection by AdhoNPV in which midgut epithelial cells are infected less efficiently. PMID- 28008818 TI - Deletion of a putative NlpC/P60 endopeptidase BAS1812 affects germination, long term survival and endospore formation in Bacillus anthracis. AB - Bacillus anthracis, an aetiologic agent of the zoonotic disease anthrax, encodes a putative NlpC/P60 endopeptidase BAS1812. It harbours a signal peptide, three bacterial SH3 domains and an NlpC/P60 family domain. Previous studies showed that BAS1812 is immunogenic in infected hosts and is a potential biomarker for anthrax treatment. To date, however, little information is known about its function and involvement in anthrax pathogenesis. Here we describe the phenotypic effect of BAS1812 deletion in B. anthracis Sterne strain. Transcriptional analysis showed that BAS1812 expression in a host-like environment was enhanced at the end of log phase, started to diminish after entry to stationary phase and increased again late in stationary phase. The constructed BAS1812 mutant showed impaired long term survival in the stationary growth phase, less resilience to detergent, lesser endospore formation and delayed germination. The mutant also showed diminished ability to degrade peptidoglycan, but its ability to produce anthrax exotoxins was not affected. We hypothesize that BAS1812 is a cell wall hydrolase involved in biological activities related to maintaining cell wall integrity, sporulation and spore germination. PMID- 28008820 TI - Streptococcus caviae sp. nov., isolated from guinea pig faecal samples. AB - A novel cellobiose-degrading and lactate-producing bacterium, strain Cavy grass 6T, was isolated from faecal samples of guinea pigs (Cavia porcellus). Cells of the strain were ovalshaped, non-motile, non-spore-forming, Gram-stain-positive and facultatively anaerobic. The strain gr at 25-40 degrees C (optimum 37 degrees C) and pH 4.5-9.5 (optimum 8.0). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain Cavy grass 6T belongs to the genus Streptococcus with its closest relative being Streptococcus devriesei CCUG 47155T with only 96.5 % similarity. Comparing strain Cavy grass 6T and Streptococcus devriesei CCUG 47155T, average nucleotide identity and level of digital DNA-DNA hybridization dDDH were only 86.9 and 33.3 %, respectively. Housekeeping genes groEL and gyrA were different between strain Cavy grass 6T and other streptococci. The G+C content of strain Cavy grass 6T was 42.6+/-0.3 mol%. The major (>10 %) cellular fatty acids of strain Cavy grass 6T were C16:0, C20 : 1omega9c and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). Strain Cavy grass 6T ferment a range of plant mono- and disaccharides as well as polymeric carbohydrates, including cellobiose, dulcitol, d-glucose, maltose, raffinose, sucrose, l-sorbose, trehalose, inulin and dried grass extract, to lactate, formate, acetate and ethanol. Based on phylogenetic and physiological characteristics, Cavy grass 6T can be distinguished from other members of the genus Streptococcus. Therefore, a novel species of the genus Streptococcus, family Streptococcaceae, order Lactobacillales is proposed, Streptococcuscaviae sp. nov. (type strain Cavy grass 6T=TISTR 2371T=DSM 102819T). PMID- 28008821 TI - Cooperative enhancement of translation by two adjacent microRNA-122/Argonaute 2 complexes binding to the 5' untranslated region of hepatitis C virus RNA. AB - The liver-specific microRNA-122 (miR-122) binds to two conserved binding sites in the 5' UTR of hepatitis C virus (HCV) RNA. This binding was reported to enhance HCV RNA replication, translation and stability. We have analysed binding of miR 122/Argonaute 2 (Ago2) complexes to these sites using anti-Ago2 co immunoprecipitation of radioactively labelled HCV RNAs along with ectopic miR-122 in HeLa cells. Our results show that the miR-122 target sites can be addressed separately. When both target sites were addressed simultaneously, we observed a synergistic binding of both miR/Ago2 complexes. Consistently, simultaneous binding of both miR-122/Ago2 complexes results in cooperative translation stimulation. In the binding assays as well as in the translation assays, binding site 1 has a stronger effect than binding site 2. We also analysed the overall RNA stability as well as the 5' end integrity of these HCV RNAs in the presence of miR-122. Surprisingly, using short HCV reporter RNAs, we did not find effects of miR-122 binding on overall RNA stability or 5' end integrity over up to 36 h. In contrast, using full-length HCV genomes that are incapable of replication, we found a positive influence of miR-122 on RNA stability, indicating that features of the full-length HCV genome that do not reside in the 5' and 3' UTRs may render HCV RNA genome stability miR-122 dependent. PMID- 28008819 TI - Effects of PB1-F2 on the pathogenicity of H1N1 swine influenza virus in mice and pigs. AB - Although several studies have exploited the effects of PB1-F2 in swine influenza viruses, its contribution to the pathogenicity of swine influenza viruses remains unclear. Herein, we investigated the effects of PB1-F2 on the pathogenicity of influenza virus using a virulent H1N1 A/swine/Kansas/77778/2007 (KS07) virus, which expresses a full-length PB1-F2, in mice and pigs. Using reverse genetics, we generated the wild-type KS07 (KS07_WT), a PB1-F2 knockout mutant (KS07_K/O) and its N66S variant (KS07_N66S). KS07_K/O showed similar pathogenicity in mice to the KS07_WT, whereas KS07_N66S displayed enhanced virulence when compared to the other two viruses. KS07_WT exhibited more efficient replication in lungs and nasal shedding in infected pigs than the other two viruses. Pigs infected with the KS07_WT had higher pulmonary levels of granulocyte-macrophage colony stimulating factor, IFN-gamma, IL-6 and IL-8 at 3 and 5 days post-infection, as well as lower levels of IL-2, IL-4 and IL-12 at 1 day post-infection compared to those infected with the KS07_K/O. These results indicate that PB1-F2 modulates KS07 H1N1 virus replication, pathogenicity and innate immune responses in pigs and the single substitution at position 66 (N/S) in the PB1-F2 plays a critical role in virulence in mice. Taken together, our results provide new insights into the effects of PB1-F2 on the virulence of influenza virus in swine and support PB1-F2 as a virulence factor of influenza A virus in a strain- and host-dependent manner. PMID- 28008822 TI - Autophagy activated by duck enteritis virus infection positively affects its replication. AB - Duck enteritis virus (DEV) is an acute, septic, sexually transmitted disease that occurs in ducks, geese and other poultry. Autophagy is an evolutionarily ancient pathway that is important in many viral infections. Despite extensive study, the interplay between DEV and autophagy of host cells is not clearly understood. In this study, we found that DEV infection triggers autophagy in duck embryo fibroblast (DEF) cells, as demonstrated by the appearance of autophagosome-like double- or single-membrane vesicles in the cytoplasm of host cells and the number of GFP-LC3 dots. In addition, increased conversion of the autophagy marker protein LC3-I and LC3-II and decreased p62/SQSTM1 indicated complete autophagy flux. Heat-inactivated DEV infection did not induce autophagy, suggesting that the trigger of autophagy in DEF cells depended on DEV replication. When autophagy was pharmacologically inhibited by LY294002 or wortmannin, DEV replication decreased. The DEV offspring yield decreased when small interference RNA was used to interfere with autophagy related to the genes Beclin-1 and ATG5. In contrast, after treating DEF cells with rapamycin, an inducer of autophagy, DEV replication increased. These results indicated that DEV infection induced autophagy in DEF cells and autophagy facilitated DEV replication. PMID- 28008823 TI - Saccharomyces boulardii improves humoral immune response to DNA vaccines against leptospirosis. AB - PURPOSE: Saccharomyces boulardii may improve the immune response by enhancing the production of anti-inflammatory cytokines, T-cell proliferation and dendritic cell activation. The immunomodulator effect of this probiotic has never been tested with DNA vaccines, which frequently induce low antibody titers. This study evaluated the capacity of Saccharomyces boulardii to improve the humoral and cellular immune responses using DNA vaccines coding for the leptospiral protein fragments LigAni and LigBrep. BALB/c mice were fed with rodent-specific feed containing 108 c.f.u. of Saccharomycesboulardii per gram. METHODOLOGY: Animals were immunized three times intramuscularly with 100 ug of pTARGET plasmids containing the coding sequences for the above mentioned proteins. Antibody titers were measured by indirect ELISA. Expression levels of IL-4, IL-10, IL-12, IL-17, IFN-gamma and TGF-beta were determined by quantitative real-time PCR from RNA extracted from whole blood, after an intraperitoneal boost with 50 ug of the recombinant proteins.Results/Key findings. Antibody titers increased significantly after the second and third application when pTARGET/ligAni and pTARGET/ligBrep were used to vaccinate the animals in comparison with the control group (P<0.05). In addition, there was a significant increase in the expression of the IL-10 in mice immunized with pTARGET/ligBrep and fed with Saccharomyces boulardii. CONCLUSION: The results suggested that Saccharomyces boulardii has an immunomodulator effect in DNA vaccines, mainly by stimulating the humoral response, which is often limited in this kind of vaccine. Therefore, the use of Saccharomyces boulardii as immunomodulator represents a new alternative strategy for more efficient DNA vaccination. PMID- 28008824 TI - Triloculotrema euzeti n. sp. (Monogenea, Monocotylidae) from the nasal tissues of the blackspotted smooth-hound Mustelus punctulatus (Carcharhiniformes, Triakidae) from off Tunisia. AB - Triloculotrema euzeti n. sp. (Monogenea, Monocotylidae, Merizocotylinae) is described from the nasal tissues of the blackspotted smooth-hound Mustelus punctulatus collected from the coastal marine waters off Tunisia. The new parasite species is distinguished from the other two species of the genus, T. japanicae Kearn, 1993 and T. chisholmae Justine, 2009, by the morphology of the sclerotised male copulatory organ which has longitudinal ridges. The species is also characterised by its ootype with short descending and ascending limbs (long and more convoluted in the other two species). The presence of three peripheral loculi, which is the main characteristic of the genus Triloculotrema Kearn, 1993, is unconfirmed. This is the first description of a species of this genus in the Mediterranean Sea and the first record from a coastal shark. PMID- 28008826 TI - [The microbiota's challenges]. PMID- 28008825 TI - Simulating the elimination of sleeping sickness with an agent-based model. AB - Although Human African Trypanosomiasis is largely considered to be in the process of extinction today, the persistence of human and animal reservoirs, as well as the vector, necessitates a laborious elimination process. In this context, modeling could be an effective tool to evaluate the ability of different public health interventions to control the disease. Using the Cormas(r) system, we developed HATSim, an agent-based model capable of simulating the possible endemic evolutions of sleeping sickness and the ability of National Control Programs to eliminate the disease. This model takes into account the analysis of epidemiological, entomological, and ecological data from field studies conducted during the last decade, making it possible to predict the evolution of the disease within this area over a 5-year span. In this article, we first present HATSim according to the Overview, Design concepts, and Details (ODD) protocol that is classically used to describe agent-based models, then, in a second part, we present predictive results concerning the evolution of Human African Trypanosomiasis in the village of Lambi (Cameroon), in order to illustrate the interest of such a tool. Our results are consistent with what was observed in the field by the Cameroonian National Control Program (CNCP). Our simulations also revealed that regular screening can be sufficient, although vector control applied to all areas with human activities could be significantly more efficient. Our results indicate that the current model can already help decision-makers in planning the elimination of the disease in foci. PMID- 28008827 TI - [The coordinators' word]. PMID- 28008828 TI - ? PMID- 28008829 TI - [Culturomics: a method to study human gut microbiota]. PMID- 28008830 TI - [Juvenile growth, chronic undernutrition and microbiota: the growth-promoting effect of specific Lactobacilli strains is conserved from fruit flies to mice]. PMID- 28008831 TI - [Maternal obesity alters social brain programming by altering gut microbiota in progeny]. PMID- 28008832 TI - [CARD9 is involved in the recovery of colitis by promoting the production of AhR ligands by the intestinal microbiota]. PMID- 28008834 TI - [Impact of newly developed metagenomic tools on our knowledge of the gut microbiota and its role in human health: diagnostic and therapeutic issues]. AB - Over the last years, our vision of the intestinal microbiota and its contribution to human physiology has been fully revisited, thanks to metagenomics. Next generation sequencing allowed a full characterization of the microbiome. Quantitative metagenomic permitted a deep understanding of the intestinal ecosystem, its structure, and potential dysbiosis in several human pathologies. The microbiome may be used as biomarker of disease or of risk to progress toward a disease. A good understanding of the mechanisms of interaction between gut microbiota and its host is needed; functional metagenomic is a useful tool to identify genes and metabolites able to interact with host's cells. Overall, the microbiome science that is developing opens new avenue for diagnosis, discovery of new drugs and potential therapeutic approaches. It is also a target for modulation by food, with potential impact on health. PMID- 28008833 TI - [Microbiotes and metagenomics]. AB - Major technical advances were introduced in the study of microflora and microbial communities in the nineties. These are essentially analytical approaches conducted as frequently by brute force. What conclusions can be drawn from these analyses twenty years later? In terms of microbial compositions, monitoring and diagnosis, the results are impressive. But what do all these microorganisms do? What are the factors behind their associations and their maintenance? Gene inventories are approaching completion; they allow us to deepen some physiological processes but do not say much more. We have even begun to manipulate microbiota. But as often in the dialectic between theory and practice, it works but we are far from understanding how! PMID- 28008835 TI - [Microbiotes and metabolic diseases: the bases for therapeutic strategies]. AB - After more than one and a half century, i.e. since Louis Pasteur work on microbes, fermentation, and diseases, biological science has made a giant step in bacteria knowledge. Thanks to an ultra-powerful "microscope", i.e. ultra-fast DNA sequencing, scientists have been able to read and group within a catalog over the last decade, the gene code of bacteria, i.e. the metagenome at the surface of our epithelia. More recently, live bacteria within adipose tissue, defining a tissue microbiota, as well as bacterial fragments such as DNA within the liver, the brain and the blood have been identified. Metagenomic analyses from large cohorts of patients have uncovered tight correlations between bacterial genes within our intestine and mouth and diseases such as metabolic diseases, diabetes, obesity, some liver diseases, kidney and heart failure as well as vascular diseases. Some causal mechanisms have been proposed in rodents and can set the soil for novel therapeutic strategies that could interfere with both the microbes and the corresponding host targets. PMID- 28008836 TI - [Gut microbiota and development of the immune system]. AB - During their long co-evolution, bacteria and their animal host have developed mutualistic interactions that are regulated by the immune system of the host. A dialogue between bacteria and the host immune system is initiated at birth during microbial colonization. This colonization induces the recruitment of multiple immune cell types that cooperate with the intestinal epithelium to construct a barrier capable of confining the microbes within the intestinal lumen. Regulatory mechanisms avoid deleterious inflammatory reactions that would harm both the host and its microbiota. In mouse, homeostatic activation of the intestinal immune system is recapitulated by a small number of bacteria, and more particularly by the segmented filamentous bacteria. PMID- 28008837 TI - [Enteric microflora in inflammatory bowel disease patients]. AB - During the last years, the importance of a well equilibrated intestinal microbiota (eubiosis) has become more and more obvious in human health. Dysbiosis is now a well-recognized feature associated with IBD (inflammatory bowel disease). Rupture of the normal microbiota can occur through different mechanisms: (1) by a typical Western diet rich in fat and low in fiber, (2) by an acute disruption of the microbiota (by an acute gastroenteritis or by intake of antibiotics) or (3) by a combination of event in early childhood avoiding the establishment of eubiosis (the hygiene hypothesis). Risk factors for IBD are stated for each disruption mechanism. Dysbiosis can also induce colonization by several pathobionts able to aggravate inflammation. Among the potential candidates in IBD, most attention has been paid on AIEC during the last years. PMID- 28008838 TI - [The role of intestinal microbiota in the response to anti-tumor therapies]. AB - The gut microbiota is involved in a lot of crucial physiological functions and maintains a symbiotic relationship with the host. Lately, in light of new evidences, an unexpected role of commensals has been depicted. Several studies addressing the role of gut microbiota in the immunomodulatory properties of anti cancer regimens, such as immunotherapy and chemotherapy, reveal that commensals are required to mount complete and efficient antitumor immune responses. Therefore, exploration of microbiota-derived compounds in the future could represent a therapeutic option in the armamentarium of cancer treatments. PMID- 28008839 TI - [Microbiota-intestinal stem cells dialog: a key element for intestinal regeneration]. AB - The most abundant and well-studied microbiota on the human body resides in the intestinal tract. Its impact extends the limits of the mucosal interface as it plays an essential role in systemic functions such as development of the immune system. At the level of the intestine, commensal microbes play important metabolic functions and promote the integrity of the mucosal barrier. Moreover, a large number of studies points to a role of the microbiota in intestinal regeneration both under homeostatic conditions and after epithelial damage. As intestinal regeneration is sustained by highly proliferative intestinal stem cells (ISCs), these observations raise the question of a direct impact of commensals on the activity of these cells. Key mediators of the dialog between microbes and the epithelium are the immune cells residing in the gut. Consistently, both innate lymphoid cells and macrophages activated by microbial stimuli have been shown to promote ISCs proliferation by secreting cytokines. More direct routes of communication have been described recently, either through the binding of bacterial ligands to Pattern Recognition Receptors expressed in ISCs, or through the sensing by ISCs of bacterial metabolites. In this review, we explore this stem cell-microbiota dialog and its impact on gut homeostasis. PMID- 28008840 TI - [Fecal microbiota transplantation: indications and perspectives]. AB - Fecal transplantation demonstrated in a randomized trial its superiority compared to antibiotics in recurrent Clostridium difficile (CD) infections. Used in first line treatment, it has reduced the mortality of patients suffering of CD infections caused by ribotype 027 and made it possible to cure patients with severe manifestations of CD infections caused by other ribotypes. The use of frozen microbiota, now validated, facilitates fecal microbiota transplantation. In addition, the frozen microbiota capsules have proven their efficiency. Other indications such as the digestive decolonization of multidrug-resistant bacteria are emerging. Finally, a better knowledge of the gastrointestinal microbiota will lead in the future to new targeted therapies in many indications. PMID- 28008841 TI - [Gut microbiota, the key for a better diet?] AB - Modern life is associated with changes in gut microbial communities, believed to be involved in the emergence of non-communicable chronic diseases. While there is an increasing effort of the scientific community towards designing microbiota targeting therapies aiming to restore the microbiota of diseased patients, there is a lack of approaches designed to prevent the disruption of the symbiosis between human and its microbial symbionts. We discuss in this review how new technologies, tools and models will contribute to identify diet-derived health relevant microbial metabolites, possible targets for dietary recommendations tailored to individuals' physiology, diet, genetics, lifestyle and gut microbiota. PMID- 28008842 TI - [Microbiota and representations of the human body]. AB - Although the presence of an intestinal flora has been known for a long time, the discovery of the role of gut microbiota in human health and disease has been widely recognized as one of the most important advances in the recent years. Chronic diseases may result from dysbiosis, i.e. a disruption of the balance within the bacterial population hosted by the human body. These developments open new prospects in terms of prevention and treatment, including the design of adapted diets, the development of functional foods and fecal transplantation. These discoveries have profoundly altered our view of microbes, of health and disease, of self and non-self, as well as our representations of the body and its relationship with its ecosystem. Gut microbiota is now generally considered as an organ in its own right. A model of the "microbiotic person" thus arises, in which the human organism is defined as an ecosystem, a chimeric superorganism with a double genome, both human and microbial. Thought should be given to the way in which these new paradigms modify lay perceptions of the human body. PMID- 28008843 TI - [Intestinal microbiota and emergence of new representations of the body: a psychosocial approach]. AB - In view of the growing importance attached to the gut microbiota in preventive medicine and treatment, it would seem essential to identify and analyse the modalities of its representation in a psychosocial approach. In the first part of this article, we will discuss the renewal of representations of the digestive tract brought about by scientific discourse on the gut microbiota, mainly regarding the anthropological status of the intestines and faeces. Then in the second part we will focus on ways of taking advantage of the variable nature of the microbiota by food choices, and we will also focus on therapeutic approaches that use transplantations of faecal matter, and the ensuing loss of privacy entailed (an anthropological notion of defil). PMID- 28008844 TI - [Insect mobile elements jump frequently into viral genomes]. PMID- 28008845 TI - [Asporin: the protective wall against triple-negative breast cancer]. PMID- 28008846 TI - [Non alcoholic-fatty liver disease causes selective CD4+ T lymphocytes loss and promotes hepatocarcinogenesis]. PMID- 28008847 TI - [Visual cortex: brain functions between changing and keeping evenness]. PMID- 28008848 TI - [Removal of senescent cells: towards a better future?] PMID- 28008849 TI - [First use of CRISPR for gene therapy]. AB - Two clinical trials using CRISPR technology to engineer the T cells of cancer patients by inactivating the gene for immune checkpoint molecule PD-1 are (almost) underway, one in the USA and the other in China. The less sophisticated Chinese trial seems slated to begin first, in part because of very speedy approval ; it may however trigger autoimmune reactions that could be very serious. PMID- 28008850 TI - Pathogen effectors and plant immunity determine specialization of the blast fungus to rice subspecies. AB - Understanding how fungi specialize on their plant host is crucial for developing sustainable disease control. A traditional, centuries-old rice agro-system of the Yuanyang terraces was used as a model to show that virulence effectors of the rice blast fungus Magnaporthe oryzaeh play a key role in its specialization on locally grown indica or japonica local rice subspecies. Our results have indicated that major differences in several components of basal immunity and effector-triggered immunity of the japonica and indica rice varieties are associated with specialization of M. oryzae. These differences thus play a key role in determining M. oryzae host specificity and may limit the spread of the pathogen within the Yuanyang agro-system. Specifically, the AVR-Pia effector has been identified as a possible determinant of the specialization of M. oryzae to local japonica rice. PMID- 28008851 TI - Functional dichotomy and distinct nanoscale assemblies of a cell cycle-controlled bipolar zinc-finger regulator. AB - Protein polarization underlies differentiation in metazoans and in bacteria. How symmetric polarization can instate functional asymmetry remains elusive. Here, we show by super-resolution photo-activated localization microscopy and edgetic mutations that the bitopic zinc-finger protein ZitP implements specialized developmental functions - pilus biogenesis and multifactorial swarming motility - while shaping distinct nanoscale (bi)polar architectures in the asymmetric model bacterium Caulobacter crescentus. Polar assemblage and accumulation of ZitP and its effector protein CpaM are orchestrated in time and space by conserved components of the cell cycle circuitry that coordinate polar morphogenesis with cell cycle progression, and also act on the master cell cycle regulator CtrA. Thus, this novel class of potentially widespread multifunctional polarity regulators is deeply embedded in the cell cycle circuitry. PMID- 28008852 TI - Modularity and determinants of a (bi-)polarization control system from free living and obligate intracellular bacteria. AB - Although free-living and obligate intracellular bacteria are both polarized it is unclear whether the underlying polarization mechanisms and effector proteins are conserved. Here we dissect at the cytological, functional and structural level a conserved polarization module from the free living alpha-proteobacterium Caulobacter crescentus and an orthologous system from an obligate intracellular (rickettsial) pathogen. The NMR solution structure of the zinc-finger (ZnR) domain from the bifunctional and bipolar ZitP pilus assembly/motility regulator revealed conserved interaction determinants for PopZ, a bipolar matrix protein that anchors the ParB centromere-binding protein and other regulatory factors at the poles. We show that ZitP regulates cytokinesis and the localization of ParB and PopZ, targeting PopZ independently of the previously known binding sites for its client proteins. Through heterologous localization assays with rickettsial ZitP and PopZ orthologs, we document the shared ancestries, activities and structural determinants of a (bi-)polarization system encoded in free-living and obligate intracellular alpha-proteobacteria. PMID- 28008853 TI - Ric-8A, a G protein chaperone with nucleotide exchange activity induces long range secondary structure changes in Galpha. AB - Cytosolic Ric-8A has guanine nucleotide exchange factor (GEF) activity and is a chaperone for several classes of heterotrimeric G protein alpha subunits in vertebrates. Using Hydrogen-Deuterium Exchange-Mass Spectrometry (HDX-MS) we show that Ric-8A disrupts the secondary structure of the Galpha Ras-like domain that girds the guanine nucleotide-binding site, and destabilizes the interface between the Galphai1 Ras and helical domains, allowing domain separation and nucleotide release. These changes are largely reversed upon binding GTP and dissociation of Ric-8A. HDX-MS identifies a potential Galpha interaction site in Ric-8A. Alanine scanning reveals residues crucial for GEF activity within that sequence. HDX confirms that, like G protein-coupled receptors (GPCRs), Ric-8A binds the C terminus of Galpha. In contrast to GPCRs, Ric-8A interacts with Switches I and II of Galpha and possibly at the Galpha domain interface. These extensive interactions provide both allosteric and direct catalysis of GDP unbinding and release and GTP binding. PMID- 28008854 TI - One genome's junk is another's garbage. AB - Experiments on a single-celled ciliate reveal how mobile genetic elements can shape a genome, even one which is not transcriptionally active. PMID- 28008855 TI - Re: Scott P. Kelly, Philip S. Rosenberg, William F. Anderson, et al. Trends in the Incidence of Fatal Prostate Cancer in the United States by Race. Eur Urol 2017;71:195-201. PMID- 28008856 TI - Interaction between airborne copper exposure and ATP7B polymorphisms on inattentiveness in scholar children. AB - Recent research indicates that airborne copper exposure in scholar children negatively affects brain functioning. These effects are likely to be influenced by the efficiency of copper metabolism, which is partly regulated by the ATPase copper transporting beta (ATP7B) gene. We investigated whether indoor and outdoor airborne copper exposure is differentially associated with child inattentiveness depending on genetic variation within the ATP7B gene in 1645 scholar children from the BREATHE project. Outdoor (courtyard) and indoor (classroom) air pollution levels were measured during class hours in each school. Inattentiveness was assessed through a follow-up with four measurements via the Attentional Network Test (4475 observations). Linear mixed models considering repeated measures were conducted to assess genetic and exposure main and interaction effects. Two interactions were detected indicating that ATP7B-rs1061472 (P for interaction 0.016) and ATP7B-rs1801243 (P for interaction 0.003) polymorphisms modified the association between indoor copper exposure and inattentiveness. Stratified analysis by genotypes revealed that both outdoor and indoor copper exposure increased inattentiveness in rs1061472-CC and rs1801243-CC carriers. These findings suggest that the genetic background promotes the association between airborne copper exposure at school with inattentiveness in children. PMID- 28008857 TI - Vitamin D deficiency in pediatric critical illness: Time to move on from observational studies? PMID- 28008858 TI - Unique Presentation of Leukemic Cutaneous CD3/TCR- Phenotype T-Cell Lymphoma with Complete Remission after Allogeneic Stem Cell Transplantation. PMID- 28008859 TI - Subcutaneous Myeloma Deposit in the Region of an Arteriovenous Fistula. PMID- 28008860 TI - Basal Serum Neurokinin B Levels in Differentiating Idiopathic Central Precocious Puberty from Premature Thelarche. AB - OBJECTIVE: To find out the diagnostic role of kisspeptin and neurokinin B in idiopathic central precocious puberty (ICPP) and premature thelarche (PT). METHODS: The girls who presented with early breast development before the age of 8 years were evaluated. Patients with intracranial pathologies were excluded. Basal and stimulated follicle-stimulating hormone/luteinizing hormone (LH) levels and basal neurokinin B/kisspeptin levels were measured. Patients who had peak value of LH >5 mIU/mL and a bone age (BA)/chronological age (CA) ratio >1.1 were diagnosed as central precocious puberty (CPP), while cases who did not meet these criteria were diagnosed as PT. Healthy age-matched prepubertal girls were included as the control group. RESULTS: The study group contained 25 girls with ICPP (7+/-0.8 years), 35 girls with PT (6.8+/-0.7 years), and 30 controls (6.7+/ 0.7 years). Basal serum kisspeptin and neurokinin B levels were 2.36+/-0.47 ng/mL and 2.61+/-0.32 ng/mL, respectively in the ICPP group, 2.23+/-0.43 ng/mL and 2.24+/-0.23 ng/mL, respectively in the PT group, and 1.92+/-0.33 ng/mL and 2.03+/ 0.24 ng/mL, respectively in the controls. Both kisspeptin and neurokinin B levels were higher in the ICPP and PT groups compared to controls (p<0.05). Moreover, basal neurokinin B level was different between ICPP and PT groups (p<0.01). A serum neurokinin B level of 2.42 ng/mL provided the most appropriate level to differentiate ICPP from PT, with a sensitivity of 84% and specificity of 77.1%. CONCLUSION: Differentiation of CPP from PT is sometime difficult, and there is a need for a simple method for the differential diagnosis. Our results suggest that basal serum neurokinin B level can be used as an adjunctive parameter to differentiate ICCP from PT. PMID- 28008861 TI - Delayed Diagnosis of a 17-Hydroxylase/17,20-Lyase Deficient Patient Presenting as a 46,XY Female: A Low Normal Potassium Level Can Be an Alerting Diagnostic Sign. AB - 17-hydroxylase/17,20-lyase deficiency (17-OHD), a rare autosomal recessive defect in adrenal and gonadal steroidogenesis, causes absence of secondary sexual characteristics and frequently associated with hypertension and hypokalemia. Here, we report a 46,XY case who had normal potassium levels and no hypertension. Our patient was a 2.5-year-old female admitted with female external genitalia and inguinal swelling. Pathology of biopsy revealed that this gonad was a testis. Karyotype was 46,XY. She had no hypertension and no hypokalemia. Serum luteinizing hormone and follicle-stimulating hormone levels were high; testosterone, dehydroepiandrosterone sulfate, and androstenedione were low. Human chorionic gonadotrophin stimulation resulted in partial testosterone response. She was initially diagnosed as partial gonadal dysgenesis or testosterone synthesis defect. In her follow-up after noticing low normal potassium levels at age 9 years, progesterone level was measured and detected to be high. Adrenocorticotropic hormone-stimulated steroid measurements were consistent with 17-OHD. Genetic analyses revealed p. R96Q (c.287G>A) homozygous mutation on exon 1 of CYP17A1 gene. In conclusion, evaluation of 46,XY disorder of sex development patients must include serum potassium levels, and near low levels of potassium levels should also suggest 17-OHD despite absence of hypertension or remarkable hypokalemia. Testosterone synthesis defects must be excluded before establishing the diagnosis of partial gonadal dysgenesis. PMID- 28008862 TI - Association of Subclinical Hypothyroidism with Dyslipidemia and Increased Carotid Intima-Media Thickness in Children. AB - OBJECTIVE: Subclinical hypothyroidism (SH) is defined as an elevated serum thyroid-stimulating hormone (TSH) level with free thyroxine (fT4) level in the normal range. There are very few studies in the literature reporting on the effect of SH on lipid metabolism and carotid intima-media thickness (CIMT) in children. METHODS: The study included 38 children diagnosed with SH and a control group comprising 38 healthy, euthyroid children. SH was diagnosed based on an elevated TSH level (4.2-20 mIU/L) and normal fT4 level measured in two morning fasting blood samples obtained at an interval of 2 to 6 weeks. Blood samples were collected by venipuncture in the morning after an overnight fast. RESULTS: The patient group included 38 children (16 male, 22 female) with SH and the control group -38 healthy, euthyroid children (20 male, 18 female). Mean age was 8.1+/ 3.6 (range, 3.5-15) years in the patient group and 8.9+/-2.4 (range, 4.5-15) years in the control group. In the patient group, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C), and LDL-C/HDL-C were higher compared to the control group (p=0.049, p=0.014, p=0.002, and 0.003, respectively). In the patient group, CIMT was also significantly higher compared to the control group (p=0.001). The patient group was further divided into two subgroups based on their serum TSH level: (I) patients with mildly elevated TSH (TSH=4.2+/-10 mIU/L) (n=33) and (II) patients with high TSH (TSH>=10 mIU/L) (n=5). However, no significant difference was found between the patients with mild and severe SH with regard to TC, LDL-C, HDL-C, triglyceride level and CIMT levels (p=0.635, p=0.424, p=0.310, p=0.342, and 0.610, respectively). CONCLUSION: Subclinical hypothyroidism leads to increased dyslipidemia (increased TC and LDL) and increased CIMT, which leads to increased risk of cardiovascular disease. Further studies are needed to substantiate these findings in children with SH. PMID- 28008863 TI - Association between Obesity and Parental Weight Status in Children and Adolescents. AB - OBJECTIVE: This study aims to assess the relationship between body mass index (BMI) of children and that of their parents in a nationally-representative sample of Iranian population. METHODS: This cross-sectional nationwide study was conducted in 2011-2012 among 6-18-year-old students and their parents living in 30 provinces of Iran. Socio-demographic information was collected. The BMI values of the children/adolescents were categorized according to the World Health Organization reference curves. Association between parental and student weight status was examined using ordinal regression models after adjustment for potential confounders. RESULTS: Overall, 23043 children and adolescents and one of their parents participated in this study (50.7% boys, 73.4% urban status). Mean age of the subjects was 12.55+/-3.31 years. Mean BMI values of parents and children/adolescents were 27.0+/-4.57 and 18.8+/-4.4 kg/m2, respectively. After adjusting for confounders, overweight and/or obesity in students of both genders was found to be significantly associated with parental overweight and/or obesity. In those students who had obese parents, the odds ratio (OR) of being obese was 2.79 for boys [OR=2.79; 95% confidence interval (CI)=2.44-3.20] and 3.46 for girls (OR=3.46; 95% CI=3.03-3.94) compared to their peers with normal-weight parents. Boys with overweight parents were 1.7 times more overweight than their counterparts with normal-weight parents (OR=1.70; 95% CI=1.15-1.92). Similarly, girls who had overweight parents were more overweight compared to those with normal-weight parents (OR=2.00; 95% CI=1.77-2.25). CONCLUSION: Our findings highlight the importance of the shared family environment as a multi-factorial contributor to the childhood obesity epidemic and the necessity of implementing family-centered preventive programs. PMID- 28008864 TI - Hypogonadotropic Hypogonadism due to Novel FGFR1 Mutations. AB - OBJECTIVE: The underlying genetic etiology of hypogonadotropic hypogonadism (HH) is heterogeneous. Fibroblast growth factor signaling is pivotal in the ontogeny of gonadotropin-releasing hormone neurons. Loss-of-function mutations in FGFR1 gene cause variable HH phenotypes encompassing pubertal delay to idiopathic HH (IHH) or Kallmann syndrome (KS). As FGFR1 mutations are common, recognizing mutations and associated phenotypes may enhance clinical management. METHODS: Using a candidate gene approach, we screened 52 IHH/KS patients. RESULTS: We identified three novel (IVS3-1G>C and p.W2X, p.R209C) FGFR1 gene mutations. Despite predictive null protein function, patients from the novel mutation families had normosmic IHH without non-reproductive phenotype. CONCLUSION: These findings further emphasize the great variability of FGFR1 mutation phenotypes in IHH/KS. PMID- 28008865 TI - The Relationship between Serum Zonulin Level and Clinical and Laboratory Parameters of Childhood Obesity. AB - OBJECTIVE: To investigate the relationship between zonulin levels and clinical and laboratory parameters of childhood obesity. METHODS: The study included obese children with a body mass index (BMI) >95th percentile and healthy children who were of similar age and gender distribution. Clinical (BMI, waist circumferences, mid-arm circumference, triceps skinfold, percentage of body fat, systolic blood pressure, diastolic blood pressure) and biochemical (glucose, insulin, lipid levels, thyroid function tests, cortisol, zonulin and leptin levels) parameters were measured. RESULTS: A total of 43 obese subjects (23 males, mean age: 11.1+/ 3.1 years) and 37 healthy subjects (18 males, mean age: 11.5+/-3.5 years) were included in this study. Obese children had significantly higher insulin, homeostasis model assessment of insulin resistance, triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), zonulin and leptin levels than healthy children (p<0.05), while glucose levels were not different (p>0.05). Comparison of the obese children with and without insulin resistance showed no statistically significant differences for zonulin levels (p>0.05). Zonulin levels were found to negatively correlate with HDL-C and positively correlate with leptin levels, after adjusting for age and BMI. CONCLUSION: To the best of our knowledge, this is the first study investigating the relationship between circulating zonulin level (as a marker of intestinal permeability) and insulin resistance and leptin (as markers of metabolic disturbances associated with obesity) in childhood obesity. The results showed that zonulin was significantly higher in obese children when compared to healthy children, a finding indicating a potential role of zonulin in the etiopathogenesis of obesity and related disturbances. PMID- 28008866 TI - Antiviral potential and mode of action of Indigofera heterantha against HSV-2 by targeting the early stages of infection. AB - BACKGROUND: The development of antivirals against herpes simplex virus 2 (HSV-2) has a major public health importance because of the wide spectrum of associated clinical disease in both immunocompetent and immunocompromised populations. Even with the extensive use of acyclovir, issues such as emergence of drug-resistant strains, poor oral bioavailability and low effectiveness in recurrent infections have highlighted the requirement for alternate therapies. Plants, which are rich in metabolites and active against viruses, are being explored as one such source. We had earlier reported specific and potent anti-HSV-2 activity from the roots of the plant Indigofera heterantha. Herein, we describe the mechanism by which it exerts this antiviral potential against HSV-2. METHODS: MTT, plaque reduction and immunofluorescence techniques were used for in vitro antiviral studies. Animal studies were carried out in HSV-2-infected mice followed by plaque reduction assays. RESULTS: The extract was found to act at multiple steps of viral entry viz attachment, adsorption and penetration by blocking binding sites present on the viral envelope glycoproteins which eventually blocks its binding with the cell surface receptors present on the host cells. We also showed efficacy of PP9706642 topical application in prohibiting HSV-2 invasion to nearby organs from the site of infection, that is vagina in HSV-2 infected animals. CONCLUSIONS: The extract targets the early and late stages of HSV-2 viral life cycle and thus shows great promise as both a prophylactic as well as therapeutic phytopharmaceutical against HSV-2. PMID- 28008867 TI - Dolutegravir plasma concentrations according to companion antiretroviral drug: unwanted drug interaction or desirable boosting effect? AB - BACKGROUND: Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy. METHODS: Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection. RESULTS: All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012). CONCLUSIONS: Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings. PMID- 28008868 TI - Effect of minor populations of NS5A and NS5B resistance-associated variants on HCV genotype-3 response to daclatasvir plus sofosbuvir, with or without ribavirin. AB - BACKGROUND: Treatment of hepatitis C virus (HCV) genotype 3 (GT3) is a medical priority. All-oral treatment of HCV GT3 with daclatasvir (DCV) and sofosbuvir (SOF), with or without ribavirin (RBV), is recommended by several treatment guidelines. The impact of HCV minority populations at amino acid positions in NS5A and NS5B associated with drug resistance on response to DCV+SOF+/-RBV was assessed in SOF-naive and SOF-experienced HCV patients. METHODS: The presence of baseline NS5A or NS5B polymorphisms was assessed in 227 and 167 HCV-GT3-infected patients, respectively, from four clinical studies of DCV+SOF+/-RBV. Polymorphisms were identified at a sequencing detection threshold of >=10%, and at >=1% by next-generation sequencing (NGS) for a subset. RESULTS: No SOF resistance-associated polymorphisms were detected at baseline. Among 58 patients with prospective baseline sequencing data at >=10% and >=1%, detectable NS5A substitutions at A30 (A30K/R/S/T/V), S62 (S62A/F/K/L/T) or Y93H were 38% more prevalent at >=1% compared with >=10% (55% [32/58] versus 41% [24/58] of patients), although sustained virological response (SVR) in patients with these substitutions remained the same at both sequencing thresholds (88%). Only one additional Y93H was detected at >=1%; the patient achieved SVR. In two virological failures with baseline Y93H, a minority S62L substitution at baseline was enriched from <20% to >=95% at failure. Treatment-emergent minority populations (at A30, L31, P32, P58 and E92) observed by NGS in four virological failures became undetectable by week 24 post-treatment. CONCLUSIONS: Sequencing at a depth of >=10% appears to be sufficient to predict HCV GT3 response to DCV+SOF+/-RBV. PMID- 28008869 TI - Pressure-dependent semiconductor to semimetal and Lifshitz transitions in 2H MoTe2: Raman and first-principles studies. AB - High pressure Raman spectroscopy of bulk 2H-MoTe2 up to ~29 GPa is shown to reveal two phase transitions (at ~6 and 16.5 GPa), which are analyzed using first-principles density functional theoretical calculations. The transition at 6 GPa is marked by changes in the pressure coefficients of A 1g and [Formula: see text] Raman mode frequencies as well as in their relative intensity. Our calculations show that this is an isostructural semiconductor to a semimetal transition. The transition at ~16.5 GPa is identified with the changes in linewidths of the Raman modes as well as in the pressure coefficients of their frequencies. Our theoretical analysis clearly shows that the structure remains the same up to 30 GPa. However, the topology of the Fermi-surface evolves as a function of pressure, and abrupt appearance of electron and hole pockets at [Formula: see text] GPa marks a Lifshitz transition. PMID- 28008870 TI - Detection of phonon and phason modes in intrinsic colloidal quasicrystals by reconstructing their structure in hyperspace. AB - Phasons are additional degrees of freedom which occur in quasicrystals alongside the phonons known from conventional periodic crystals. The rearrangements of particles that are associated with a phason mode are hard to interpret in physical space. We reconstruct the quasicrystal structure by an embedding into extended higher-dimensional space, where phasons correspond to displacements perpendicular to the physical space. In dislocation-free decagonal colloidal quasicrystals annealed with Brownian dynamics simulations, we identify thermal phonon and phason modes. Finite phononic strain is pinned by phasonic excitations even after cooling down to zero temperature. For the phasonic displacements underlying the flip pattern, the reconstruction method gives an approximation within the limits of a multi-mode harmonic ansatz, and points to fundamental limitations of a harmonic picture for phasonic excitations in intrinsic colloidal quasicrystals. PMID- 28008871 TI - Significant performance enhancement of InGaN/GaN nanorod LEDs with multi-layer graphene transparent electrodes by alumina surface passivation. AB - Nanotextured surfaces provide an ideal platform for efficiently capturing and emitting light. However, the increased surface area in combination with surface defects induced by nanostructuring e.g. using reactive ion etching (RIE) negatively affects the device's active region and, thus, drastically decreases device performance. In this work, the influence of structural defects and surface states on the optical and electrical performance of InGaN/GaN nanorod (NR) light emitting diodes (LEDs) fabricated by top-down RIE of c-plane GaN with InGaN quantum wells was investigated. After proper surface treatment a significantly improved device performance could be shown. Therefore, wet chemical removal of damaged material in KOH solution followed by atomic layer deposition of only 10 [Formula: see text] alumina as wide bandgap oxide for passivation were successfully applied. Raman spectroscopy revealed that the initially compressively strained InGaN/GaN LED layer stack turned into a virtually completely relaxed GaN and partially relaxed InGaN combination after RIE etching of NRs. Time-correlated single photon counting provides evidence that both treatments-chemical etching and alumina deposition-reduce the number of pathways for non-radiative recombination. Steady-state photoluminescence revealed that the luminescent performance of the NR LEDs is increased by about 50% after KOH and 80% after additional alumina passivation. Finally, complete NR LED devices with a suspended graphene contact were fabricated, for which the effectiveness of the alumina passivation was successfully demonstrated by electroluminescence measurements. PMID- 28008872 TI - Silver nanoparticles decorated nanoporous gold for surface-enhanced Raman scattering. AB - Raman spectra are considered as signatures of matter and have been widely used to identify several classes of materials. The development of mobile spectrometers further extends applications of Raman spectroscopy, and both indoor/outdoor and in vivo/in vitro measurements have been evaluated on site. However, the finite detection level restricts its application in high density matters. Here we report a facile silver nanoparticle decorated nanoporous gold (NanoAg@NPG) substrate, which can provide high enhancement of the Raman signal from nearby molecules by 785 nm photoexcitation. This enhancement is attributed to the abundant Raman active nanogaps constructed by adjacent nanoparticles and also by the NPG ligaments and adhered nanoparticles. This NanoAg@NPG substrate shows great potential as a reproducible and quantifiable near infrared surface-enhanced Raman scattering probe for various targets, since it performs well in the so-called biological window which can avoid autofluorescence and absorption either from targets or surroundings in the visible optical region. PMID- 28008873 TI - High performance visible-near-infrared PbS-quantum-dots/indium Schottky diodes for photodetectors. AB - Here we fabricate self-powered photodetectors based on PbS-quantum-dots/indium Schottky barrier diodes successfully. These devices exhibit excellent repeatability and stability at a high frequency (up to1 MHz), and show a typical fast rise time/fall time of ~0.8 MUs/3.2 MUs. They also show excellent rectification ratios up to 104 with bias from -0.5 V to +0.5 V in the dark and a pronounced photovoltaic performance under light illumination. Moreover, the devices demonstrate high sensitivity in weak light illumination detection (detectivity) approaching 1012 Jones and low noise currents <1 pAHz-1/2. These findings suggest great application potential of PbS-quantum-dots for advanced fast response, low noise current, high detectivity and high stability photodetectors. PMID- 28008874 TI - Ultra-high resolution electron microscopy. AB - The last two decades have seen dramatic advances in the resolution of the electron microscope brought about by the successful correction of lens aberrations that previously limited resolution for most of its history. We briefly review these advances, the achievement of sub-Angstrom resolution and the ability to identify individual atoms, their bonding configurations and even their dynamics and diffusion pathways. We then present a review of the basic physics of electron scattering, lens aberrations and their correction, and an approximate imaging theory for thin crystals which provides physical insight into the various different imaging modes. Then we proceed to describe a more exact imaging theory starting from Yoshioka's formulation and covering full image simulation methods using Bloch waves, the multislice formulation and the frozen phonon/quantum excitation of phonons models. Delocalization of inelastic scattering has become an important limiting factor at atomic resolution. We therefore discuss this issue extensively, showing how the full-width-half-maximum is the appropriate measure for predicting image contrast, but the diameter containing 50% of the excitation is an important measure of the range of the interaction. These two measures can differ by a factor of 5, are not a simple function of binding energy, and full image simulations are required to match to experiment. The Z dependence of annular dark field images is also discussed extensively, both for single atoms and for crystals, and we show that temporal incoherence must be included accurately if atomic species are to be identified through matching experimental intensities to simulations. Finally we mention a few promising directions for future investigation. PMID- 28008875 TI - A review of dynamical resonances in A + BC chemical reactions. AB - The concept of the transition state has played an important role in the field of chemical kinetics and reaction dynamics. Reactive resonances in the transition state region can dramatically enhance the reaction probability; thus investigation of the reactive resonances has attracted great attention from chemical physicists for many decades. In this review, we mainly focus on the recent progress made in probing the elusive resonance phenomenon in the simple A + BC reaction and understanding its nature, especially in the benchmark F/Cl + H2 and their isotopic variants. The signatures of reactive resonances in the integral cross section, differential cross section (DCS), forward- and backward scattered DCS, and anion photodetachment spectroscopy are comprehensively presented in individual prototype reactions. The dynamical origins of reactive resonances are also discussed in this review, based on information on the wave function in the transition-state region obtained by time-dependent quantum wave packet calculations. PMID- 28008876 TI - Quantum steering: a review with focus on semidefinite programming. AB - Quantum steering refers to the non-classical correlations that can be observed between the outcomes of measurements applied on half of an entangled state and the resulting post-measured states that are left with the other party. From an operational point of view, a steering test can be seen as an entanglement test where one of the parties performs uncharacterised measurements. Thus, quantum steering is a form of quantum inseparability that lies in between the well-known notions of Bell nonlocality and entanglement. Moreover, quantum steering is also related to several asymmetric quantum information protocols where some of the parties are considered untrusted. Because of these facts, quantum steering has received a lot of attention both theoretically and experimentally. The main goal of this review is to give an overview of how to characterise quantum steering through semidefinite programming. This characterisation provides efficient numerical methods to address a number of problems, including steering detection, quantification, and applications. We also give a brief overview of some important results that are not directly related to semidefinite programming. Finally, we make available a collection of semidefinite programming codes that can be used to study the topics discussed in this article. PMID- 28008878 TI - Molecular and atomic manipulation mediated by electronic excitation of the underlying Si(111)-7x7 surface. AB - We report the local atomic manipulation properties of chemisorbed toluene molecules on the Si(111)-7x7 surface and of the silicon adatoms of the surface. Charge injected directly into the molecule, or into its underlying bonding silicon adatom, can induce the molecule to change bonding site. The voltage dependence of the rates of these processes match closely with scanning tunnelling spectroscopy of the toluene and adatom species. The branching ratio between toluene molecules which are moved to a neighbouring site, or those that travel further is invariant to voltage, suggesting a common final manipulation step for both injection into the molecule and into the bonding adatom site. At low temperatures the rate of silicon adatom manipulation matches that of toluene manipulation, further suggesting that all these manipulation processes are driven by electronic excitation of the underlying silicon surface. Our results therefore suggest that a common non-adiabatic process mediates atomic and molecular manipulation induced by the STM on the Si(111)-7x7 surface and may also mediate similar manipulation induced by the laser irradiation of the Si(111)-7x7 surface. PMID- 28008877 TI - Manipulation of cells with laser microbeam scissors and optical tweezers: a review. AB - The use of laser microbeams and optical tweezers in a wide field of biological applications from genomic to immunology is discussed. Microperforation is used to introduce a well-defined amount of molecules into cells for genetic engineering and optical imaging. The microwelding of two cells induced by a laser microbeam combines their genetic outfit. Microdissection allows specific regions of genomes to be isolated from a whole set of chromosomes. Handling the cells with optical tweezers supports investigation on the attack of immune systems against diseased or cancerous cells. With the help of laser microbeams, heart infarction can be simulated, and optical tweezers support studies on the heartbeat. Finally, laser microbeams are used to induce DNA damage in living cells for studies on cancer and ageing. PMID- 28008879 TI - On entropy change measurements around first order phase transitions in caloric materials. AB - In this work we discuss the measurement protocols for indirect determination of the isothermal entropy change associated with first order phase transitions in caloric materials. The magneto-structural phase transitions giving rise to giant magnetocaloric effects in Cu-doped MnAs and FeRh are used as case studies to exemplify how badly designed protocols may affect isothermal measurements and lead to incorrect entropy change estimations. Isothermal measurement protocols which allow correct assessment of the entropy change around first order phase transitions in both direct and inverse cases are presented. PMID- 28008880 TI - Brillouin light scattering studies of 2D magnonic crystals. AB - Magnonic crystals, materials with periodic modulation of their magnetic properties, represent the magnetic counterpart of photonic, phononic and plasmonic crystals, and have been largely investigated in recent years because of the possibility of using spin waves as a new means for carrying and processing information over a very large frequency bandwidth. Here, we review recent Brillouin light scattering studies of 2D magnonic crystals consisting of single- and bi-component arrays of interacting magnetic dots or antidot lattices. In particular, we discuss the principal properties of the magnonic band diagram of such systems, with emphasis given to its dependence on both magnetic and the geometrical parameters. Thanks to the possibility of tailoring their band structure by means of several degrees of freedom, planar magnonic crystals offer a good opportunity to design an innovative class of nanoscale microwave devices. PMID- 28008881 TI - Tuning growth direction of catalyst-free InAs(Sb) nanowires with indium droplets. AB - The need for indium droplets to initiate self-catalyzed growth of InAs nanowires has been highly debated in the last few years. Here, we report on the use of indium droplets to tune the growth direction of self-catalyzed InAs nanowires. The indium droplets are formed in situ on InAs(Sb) stems. Their position is modified to promote growth in the <11-2> or equivalent directions. We also show that indium droplets can be used for the fabrication of InSb insertions in InAsSb nanowires. Our results demonstrate that indium droplets can initiate growth of InAs nanostructures as well as provide added flexibility to nanowire growth, enabling the formation of kinks and heterostructures, and offer a new approach in the growth of defect-free crystals. PMID- 28008882 TI - Strained graphene Hall bar. AB - The effects of strain, induced by a Gaussian bump, on the magnetic field dependent transport properties of a graphene Hall bar are investigated. The numerical simulations are performed using both classical and quantum mechanical transport theory and we found that both approaches exhibit similar characteristic features. The effects of the Gaussian bump are manifested by a decrease of the bend resistance, R B, around zero-magnetic field and the occurrence of side-peaks in R B. These features are explained as a consequence of bump-assisted scattering of electrons towards different terminals of the Hall bar. Using these features we are able to give an estimate of the size of the bump. Additional oscillations in R B are found in the quantum description that are due to the population/depopulation of Landau levels. The bump has a minor influence on the Hall resistance even for very high values of the pseudo-magnetic field. When the bump is placed outside the center of the Hall bar valley polarized electrons can be collected in the leads. PMID- 28008883 TI - Unfolding the band structure of GaAsBi. AB - Typical supercell approaches used to investigate the electronic properties of GaAs(1-x)Bi(x) produce highly accurate, but folded, band structures. Using a highly optimized algorithm, we unfold the band structure to an approximate [Formula: see text] relation associated with an effective Brillouin zone. The dispersion relations we generate correlate strongly with experimental results, confirming that a regime of band gap energy greater than the spin-orbit-splitting energy is reached at around 10% bismuth fraction. We also demonstrate the effectiveness of the unfolding algorithm throughout the Brillouin zone (BZ), which is key to enabling transition rate calculations, such as Auger recombination rates. Finally, we show the effect of disorder on the effective masses and identify approximate values for the effective mass of the conduction band and valence bands for bismuth concentrations from 0-12%. PMID- 28008884 TI - 16 nm-resolution lithography using ultra-small-gap bowtie apertures. AB - Photolithography has long been a critical technology for nanoscale manufacturing, especially in the semiconductor industry. However, the diffractive nature of light has limited the continuous advance of optical lithography resolution. To overcome this obstacle, near-field scanning optical lithography (NSOL) is an alternative low-cost technique, whose resolution is determined by the near-field localization that can be achieved. Here, we apply the newly-developed backside milling method to fabricate bowtie apertures with a sub-15 nm gap, which can substantially improve the resolution of NSOL. A highly confined electric near field is produced by localized surface plasmon excitation and nanofocusing of the closely-tapered gap. We show contact lithography results with a record 16 nm resolution (FWHM). This photolithography scheme promises potential applications in data storage, high-speed computation, energy harvesting, and other nanotechnology areas. PMID- 28008885 TI - Light irradiation tuning of surface wettability, optical, and electric properties of graphene oxide thin films. AB - In this work the preparation of flexible polymeric films with controlled electrical conductivity, light transmission and surface wettability is reported. A drop casted graphene oxide thin film is photo-reduced at different levels by UV light or laser irradiation. Optical microscopy, IR spectroscopy, electrical characterization, Raman spectroscopy and static water contact angle measurements are used in order to characterize the effects of the various reduction methods. Correlations between the optical, electrical and structural properties are reported and compared to previous literature results. These correlations provide a useful tool for independently tuning the properties of these films for specific applications. PMID- 28008886 TI - Modulation of electronic properties of tin oxide nanobelts via thermal control of surface oxygen defects. AB - Nanomaterials made from binary metal oxides are of increasing interest because of their versatility in applications from flexible electronics to portable chemical and biological sensors. Controlling the electrical properties of these materials is the first step in device implementation. Tin dioxide (SnO2) nanobelts (NB) synthesized by the vapor-liquid-solid mechanism have shown much promise in this regard. We explore the modification of devices prepared with single crystalline NBs by thermal annealing in vacuum and oxygen, resulting in a viable field-effect transistor (FET) for numerous applications at ambient temperature. An oxygen annealing step initially increases the device conductance by up to a factor of 105, likely through the modification of the surface defects of the NB, leading to Schottky barrier limited devices. A multi-step annealing procedure leads to further increase of the conductance by approximately 350% and optimization of the electronic properties. The effects of each step is investigated systematically on a single NB. The optimization of the electrical properties of the NBs makes possible the consistent production of channel-limited FETs and control of the device performance. Understanding these improvements on the electrical properties over the as-grown materials provides a pathway to enhance and tailor the functionalities of tin oxide nanostructures for a wide variety of optical, electronic, optoelectronic, and sensing applications that operate at room temperature. PMID- 28008887 TI - The initial value problem as it relates to numerical relativity. AB - Spacetime is foliated by spatial hypersurfaces in the 3+1 split of general relativity. The initial value problem then consists of specifying initial data for all fields on one such a spatial hypersurface, such that the subsequent evolution forward in time is fully determined. On each hypersurface the 3-metric and extrinsic curvature describe the geometry. Together with matter fields such as fluid velocity, energy density and rest mass density, the 3-metric and extrinsic curvature then constitute the initial data. There is a lot of freedom in choosing such initial data. This freedom corresponds to the physical state of the system at the initial time. At the same time the initial data have to satisfy the Hamiltonian and momentum constraint equations of general relativity and can thus not be chosen completely freely. We discuss the conformal transverse traceless and conformal thin sandwich decompositions that are commonly used in the construction of constraint satisfying initial data. These decompositions allow us to specify certain free data that describe the physical nature of the system. The remaining metric fields are then determined by solving elliptic equations derived from the constraint equations. We describe initial data for single black holes and single neutron stars, and how we can use conformal decompositions to construct initial data for binaries made up of black holes or neutron stars. Orbiting binaries will emit gravitational radiation and thus lose energy. Since the emitted radiation tends to circularize the orbits over time, one can thus expect that the objects in a typical binary move on almost circular orbits with slowly shrinking radii. This leads us to the concept of quasi equilibrium, which essentially assumes that time derivatives are negligible in corotating coordinates for binaries on almost circular orbits. We review how quasi-equilibrium assumptions can be used to make physically well motivated approximations that simplify the elliptic equations we have to solve. PMID- 28008888 TI - H2O incorporation in the phosphorene/a-SiO2 interface: a first-principles study. AB - Based on first-principles calculations, we investigate (i) the energetic stability and electronic properties of single-layer phosphorene (SLP) adsorbed on an amorphous SiO2 surface (SLP/a-SiO2), and (ii) the further incorporation of water molecules at the phosphorene/a-SiO2 interface. In (i), we find that the phosphorene sheet binds to a-SiO2 through van der Waals interactions, even in the presence of oxygen vacancies on the surface. The SLP/a-SiO2 system presents a type-I band alignment, with the valence (conduction) band maximum (minimum) of the phosphorene lying within the energy gap of the a-SiO2 substrate. The structure and the surface-potential corrugations promote the formation of electron-rich and electron-poor regions on the phosphorene sheet and at the SLP/a SiO2 interface. Such charge density puddles are strengthened by the presence of oxygen vacancies in a-SiO2. In (ii), because of the amorphous structure of the surface, we consider a number of plausible geometries for H2O embedded in the SLP/a-SiO2 interface. There is an energetic preference for the formation of hydroxyl (OH) groups on the a-SiO2 surface. Meanwhile, in the presence of oxygenated water or interstitial oxygen in the phosphorene sheet, we observe the formation of metastable OH bonded to the phosphorene, and the formation of energetically stable P-O-Si chemical bonds at the SLP/a-SiO2 interface. Further x ray absorption spectra simulations are performed, which aim to provide additional structural/electronic information on the oxygen atoms forming hydroxyl groups or P-O-Si chemical bonds at the interface region. PMID- 28008889 TI - Plasmonic gold helices for the visible range fabricated by oxygen plasma purification of electron beam induced deposits. AB - Electron beam induced deposition (EBID) currently provides the only direct writing technique for truly three-dimensional nanostructures with geometrical features below 50 nm. Unfortunately, the depositions from metal-organic precursors suffer from a substantial carbon content. This hinders many applications, especially in plasmonics where the metallic nature of the geometric surfaces is mandatory. To overcome this problem a post-deposition treatment with oxygen plasma at room temperature was investigated for the purification of gold containing EBID structures. Upon plasma treatment, the structures experience a shrinkage in diameter of about 18 nm but entirely keep their initial shape. The proposed purification step results in a core-shell structure with the core consisting of mainly unaffected EBID material and a gold shell of about 20 nm in thickness. These purified structures are plasmonically active in the visible wavelength range as shown by dark field optical microscopy on helical nanostructures. Most notably, electromagnetic modeling of the corresponding scattering spectra verified that the thickness and quality of the resulting gold shell ensures an optical response equal to that of pure gold nanostructures. PMID- 28008890 TI - High voltage generation from lead-free magnetoelectric coaxial nanotube arrays and their applications in nano energy harvesters. AB - Harvesting energy from surrounding vibrations and developing self-powered portable devices for wireless and mobile electronics have recently become popular. Here the authors demonstrate the synthesis of piezoelectric energy harvesters based on nanotube arrays by a wet chemical route, which requires no sophisticated instruments. The energy harvester gives an output voltage of 400 mV. Harvesting energy from a sinusoidal magnetic field is another interesting phenomenon for which the authors fabricated a magnetoelectric energy harvester based on piezoelectric-magnetostrictive coaxial nanotube arrays. Piezoelectric K0.5Na0.5NbO3 (KNN) is fabricated as the shell and magnetostrictive CoFe2O4 (CFO) as the core of the composite coaxial nanotubes. The delivered voltages are as high as 300 mV at 500 Hz and at a weak ac magnetic field of 100 Oe. Further tailoring of the thickness of the piezoelectric and magnetic layers can enhance the output voltage by several orders. Easy, single-step wet chemical synthesis enhances the industrial upscaling potential of these nanotubes as energy harvesters. In view of the excellent properties reported here, the lead-free piezoelectric component (KNN) in this nanocomposite should be explored for eco friendly piezoelectric as well as magnetoelectric power generators in nanoelectromechanical systems (NEMS). PMID- 28008891 TI - Defect-free functionalized graphene sensor for formaldehyde detection. AB - Graphene has attracted much attention for sensing applications in recent years. Its largest surface-to-volume ratio makes graphene sensors able to potentially detect a single molecule and its extremely high carrier mobility ensures low electrical noise and energy consumption. However, pristine graphene is chemically inert and weakly adsorbs gas molecules, while defective and/or doped graphene has stronger adsorption ability (high sensitivity). The high sensitivity is related to the increased number of defects or traps in graphene where the gas molecules can be readily grafted, changing the sensor resistance. Nonetheless, similar resistance changes could be induced under exposure to different gases, resulting in a lack of selectivity. Functional groups differ drastically from defects or traps since the former selectively anchor specific molecules. Here, we comparatively investigate three functionalization routes and optimize a defect free one (2,3,5,6,-Tetrafluorohydroquinone, TFQ molecules) for the fabrication of graphene gas sensors. We use TFQ organic molecules as chemical recognition links between graphene and formaldehyde, the most common indoor pollutant gas. The sensor demonstrates a high response and a good selectivity for formaldehyde compared with interfering organic vapours. Particularly, the sensor has a strong immunity to humidity. Our results highlight that defect-free functionalization based on organic molecules not only increases the sensor's response but also its selectivity, paving the way to the design of efficient graphene-based sensors. PMID- 28008892 TI - Tunable growth of perpendicular cobalt ferrite nanosheets on reduced graphene oxide for energy storage. AB - Ultrathin cobalt ferrite nanosheets have been successfully assembled on the surface of reduced graphene oxide (rGO) via only adjusting the volume ratio of ethanol and deionized (DI) water and a post calcination treatment. The perpendicular ultrathin cobalt ferrite nanosheets supported by rGO sheets (CoFe2O4 NSs@rGO) can be obtained when the volume ratio of ethanol and DI water is 10:30. Correspondingly, the hierarchical porous films covering the total rGO sheets will be formed nanosheets. When evaluated as the electrodes for lithium ion batteries (LIBs) and supercapacitors (SCs), the resultant CoFe2O4 NSs@rGO hybrids exhibit highly enhanced electrochemical performance. Even after 200 charge-discharge cycles at 400 mA g-1, the electrodes as the anode material for LIBs still exhibit a reversible discharge capacity of 835.6 mAh g-1. In addition, this electrode for SCs also exhibits specific capacitance of ca 1120 F g-1 after 3000 cycles. These superior results imply that CoFe2O4 NSs with novel hybrid structure of rGO could potentially lead to an excellent electrochemical performance for energy storage. PMID- 28008893 TI - Controlled synthesis of metallic iron nanoparticles and their magnetic hyperthermia performance in polyaniline composite nanofibers. AB - Electrospun magnetic iron/polyaniline nanofibers with applicable heating performance in an AC magnetic field were developed. A new and low-cost method was introduced to synthesize metallic iron (Fe0) nanoparticles with uniform size distribution. The Fe0 nanoparticles were synthesized in an aqueous environment at room temperature with the assistance of polyvinylpyrrolidone and sodium citrate to tailor their particle sizes ranging from 10 to 20 nm. The experimental results showed that regulating the free iron ions present in the solution is critical for obtaining Fe0 nanoparticles with narrow size distribution. The Fe0 nanoparticles were subsequently incorporated with conductive polyaniline (PANI) to fabricate Fe0/PANI/polycaprolactone nanofibers using an electrospinning technique. The resultant composite nanofibers have controlled fiber diameters and also show electrochemical redox properties originating from the PANI polymer. The heating performance test concluded that both eddy current loss from PANI and Neel relaxation loss of magnetic Fe0 nanoparticles can contribute to the power dissipation of the prepared composite nanofibers. The optimal heating performance can be obtained by adjusting the composition of Fe0 nanoparticles and PANI in nanofibers. PMID- 28008894 TI - The Specific Protein Kinase R (PKR) Inhibitor C16 Protects Neonatal Hypoxia Ischemia Brain Damages by Inhibiting Neuroinflammation in a Neonatal Rat Model. AB - BACKGROUND Brain injuries induced by hypoxia-ischemia in neonates contribute to increased mortality and lifelong neurological dysfunction. The specific PKR inhibitor C16 has been previously demonstrated to exert a neuroprotective role in adult brain injuries. However, there is no recent study available concerning its protective role in hypoxia-ischemia-induced immature brain damage. Therefore, we investigated whether C16 protects against neonatal hypoxia-ischemia injuries in a neonatal rat model. MATERIAL AND METHODS Postnatal day 7 (P7) rats were used to establish classical hypoxia-ischemia animal models, and C16 postconditioning with 100 ug/kg was performed immediately after hypoxia. Western blot analysis was performed to quantify the phosphorylation of the PKR at 0 h, 3 h, 6 h, 12 h, 24 h, and phosphorylation of NF-kappaB 24h after hypoxia exposure. The TTC stain for infarction area and TUNEL stain for apoptotic cells were assayed 24 h after the brain hypoxia. Gene expression of IL-1beta, IL-6, and TNF-alpha was performed at 3 h, 6 h, 12 h, and 24 h. RESULTS The level of PKR autophosphorylation was increased dramatically, especially at 3 h (C16 group vs. HI group, P<0.01). Intraperitoneal C16 administration reduced the infarct volume and apoptosis ratio after this insult (C16 group vs. HI group<0.01), and C16 reduced proinflammatory cytokines mRNA expression, partly through inhibiting NF-kappaB activation (C16 group vs. HI group<0.05). CONCLUSIONS C16 can protect immature rats against hypoxia-ischemia-induced brain damage by modulating neuroinflammation. PMID- 28008895 TI - [Adenocystic carcinoma of the trachea]. AB - It is presented 40-years experience of tracheal adenocystic carcinoma diagnosis and management in 144 patients. Peculiarities of clinical course and choice of diagnostic and therapeutic measures are discussed in relation to stenosis and hypoxia degree and severity of accompanying inflammatory complications of trachea, bronchi and lungs. Technical tools and original methods of resection and reconstruction of trachea and it's bifurcation after extended lung resection are described. Surgical management is carried out in 96 patients: all patients underwent circular resection of trachea (77) or it's bifurcation (19). Morbidity rate was 22.9% and mortality - 3.1%. Additional radiotherapy was carried out in 50 patients. 41 patients underwent radiotherapy alone. Radiotherapy improves remote results of management. 5-and 10-year survival rate was 78.3+/-6.1 and 45.9+/-7.9% after surgery alone, 92.0+/-3.9 and 77.1+/-6.5% after combined treatment and 76.4+/-6.5 and 55.0+/-10.7% after radiotherapy alone respectively. PMID- 28008896 TI - [Anesthesia during video-assisted thoracoscopic lobectomy using laryngeal ductwork and auxiliary mechanical ventilation]. AB - The article presents the experience of video-assisted thoracoscopic lobectomies in patients without endotracheal intubation and sparing of spontaneous breathing. The results of intraoperative monitoring and laboratory data of all perioperative period are described. In view of these data it was concluded that such approach can decline the severity of stress-response against surgical aggression in this group of patients. PMID- 28008897 TI - [Surgical treatment of thyroid cancer metastases in the 7th (retrosternal) group of lymph nodes]. AB - : The incidence of thyroid cancer (TC) is being significantly increased. A significant percentage consists of metastatic cancer (MCP) in particular in the anterior-superior mediastinal lymph nodes (Group 7). MATERIAL AND METHODS: 153 out of 324 patients with metastatic TC underwent video-assisted lymphadenectomy of group 7 of lymph nodes. The operations were combined with interventions on the primary tumor or on cervical lymph nodes in case of recurrence. RESULTS: The possibility of long-term survival (over 10 years) was studied in more than 80% of cases. Sternotomy is advisable in case of impossible video-assisted procedure. PMID- 28008898 TI - [Argon-laser ablation is a new method of airways recanalization for tumoral stenosis]. AB - AIM: To develop the new method of laser recanalization of airways for tumoral stenosis. MATERIAL AND METHODS: It is proposed to conduct laser effect in the gas environment that does not support combustion (argon). Also the device for these AIM: is suggested. The method is called argon-laser ablation (ALA). A comparison of ALA and conventional high-energy laser exposure (LPD) was performed. RESULTS: ALA and LPD were used in 46 patients and 17 patients with non-small cell lung cancer. The duration of endobronchial operations and incidence of complications were significantly higher in group 2. The incidence of complete remission was significantly higher in group 1. CONCLUSION: Endobronchial argon-laser ablation of tracheal and bronchial tumors removes exophytic tumoral component in more favorable conditions compared with conventional high-energy laser exposure. Also it significantly increases an efficiency and reduces the frequency of complications. PMID- 28008899 TI - [Surgery for non-small cell lung carcinoma after previous chemoradiotherapy alone]. AB - AIM: To investigate early and remote results of surgery in patients with recurrent non-small cell lung carcinoma (NSCLC) after previous chemoradiotherapy alone. MATERIAL AND METHODS: The retrospective study included 14 NSCLC patients (10 men and 4 women, mean age 52.6 years) who were operated in thoracic department for the period June 2008 - December 2013. Histologically squamous cell carcinoma prevailed (64.3%). Prior to surgery stage IIB was diagnosed in 2 patients, IIIA in 11 and IIIB in 1 patient. The dose of radiotherapy ranged from 45 to 70 Gr (median 58Gr). The average number of chemotherapy cycles was 3.8 per patient. Pneumonectomy was performed in all patients except one who underwent left-sided lower lobectomy. In all cases bronchial stump was covered by vascularized muscle flap (intercostal, latissimus dorsi). Postoperative complications were classified by TMM system (Thoracic Morbidity and Mortality System). RESULTS: Postoperative complications were observed in 7 (50.0%) patients including level II in 2 cases, IIIA in 1 case, IVA in 3 patients and V (death) in 1 (7.1%) patient. Postoperative stages of lung cancer were IB in 2 cases, IIA in 1, IIB in 5, IIIA in 4 and IIIB in 2 patients. Overall 1, 2 and 3-year survival rate was 89.1%, 82.0% and 48.0% respectively (median 35.0 months). Recurrence free survival was 84.2%, 72.0% and 24.8%, respectively (median 28.0 months). Overall and recurrence-free 5-year survival rate was 10.8%. CONCLUSION: "Salvage" surgery may be recommended as individual approach in patients with reccurent lung cancer after previous chemoradiotherapy. PMID- 28008900 TI - [Re-operations in thoracic surgery]. AB - AIM: To optimize the outcomes of reoperations for postoperative complications in patients with thoracic diseases and injuries. MATERIAL AND METHODS: The study enrolled 1258 patients with different thoracic diseases and injuries. Postoperatively 58 (4.6%) patients underwent re-thoracotomy and 15 (1.1%) patients - video-assisted interventions for any complications. Indications for re operations were intrapleural bleeding, bronchial stump failure, esophagogastrostomy insufficiency, prolonged air leak through the drains due to unsealed lung parenchyma, clotted hemothorax. Postoperative complications were observed in 16 patients after re-thoracotomy (including 14 deaths), while only 1 patient died after VATS surgery. CONCLUSION: Early diagnosis and rational surgical approach are key for successful surgical treatment of early postoperative complications in thoracic surgery. PMID- 28008901 TI - [The role of plasmapheresis in prevention of complications after thoracoscopic thymectomy in patients with myasthenia combined with thymic hyperplasia]. AB - Surgical indications for thymectomy include thymus tumour of different genesis as well as myasthenia. Minimally invasive methods such as thorascopy and robot assisted thymectomy have been widely used lately as well as standard surgical methods namely sternotomy and thoracotomy. Regardless the type of access in myasthenia patients specific crisis conditions of respiratory failure can appear in postoperative period that usually requires mechanical ventilation. This study was aimed to estimate the efficacy of pre- and postoperative plasmapheresis in prevention of specific myasthenia-associated complications. PMID- 28008902 TI - [Management of post-sternotomy mediastinitis in cardiac patients]. AB - Post-sternotomy mediastinitis is a severe complication of cardiac surgery and accompanied by high mortality and cost of treatment. To date, there are no large clinical trials defining treatment of these patients. In this study the authors offer early postoperative wound sanitation, use of vacuum drainage in all cases and surgical repair with local tissues. Sternal destruction is cured by osteosynthesis with wire sutures and perforated metal plates. Proposed algorithm showed low incidence of reccurent wound infection, mortality and duration of treatment. PMID- 28008903 TI - [Thoracic echinococcosis complicated by arrosive bleeding from great vessels]. PMID- 28008904 TI - [Left atrial rupture during right-sided combined pneumonectomy for cancer]. PMID- 28008905 TI - The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity. AB - Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8+ T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors. PMID- 28008907 TI - Exotic looped trajectories of photons in three-slit interference. AB - The validity of the superposition principle and of Born's rule are well-accepted tenants of quantum mechanics. Surprisingly, it has been predicted that the intensity pattern formed in a three-slit experiment is seemingly in contradiction with the most conventional form of the superposition principle when exotic looped trajectories are taken into account. However, the probability of observing such paths is typically very small, thus rendering them extremely difficult to measure. Here we confirm the validity of Born's rule and present the first experimental observation of exotic trajectories as additional paths for the light by directly measuring their contribution to the formation of optical interference fringes. We accomplish this by enhancing the electromagnetic near-fields in the vicinity of the slits through the excitation of surface plasmons. This process increases the probability of occurrence of these exotic trajectories, demonstrating that they are related to the near-field component of the photon's wavefunction. PMID- 28008906 TI - Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53. AB - The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53 deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5 Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers. PMID- 28008908 TI - Single-cycle surface plasmon polaritons on a bare metal wire excited by relativistic electrons. AB - Terahertz (THz) pulses are applied in areas as diverse as materials science, communication and biosensing. Techniques for subwavelength concentration of THz pulses give access to a rapidly growing range of spatial scales and field intensities. Here we experimentally demonstrate a method to generate intense THz pulses on a metal wire, thereby introducing the possibility of wave-guiding and focussing of the full THz pulse energy to subwavelength spotsizes. This enables endoscopic sensing, single-shot subwavelength THz imaging and study of strongly nonlinear THz phenomena. We generate THz surface plasmon polaritons (SPPs) by launching electron bunches onto the tip of a bare metal wire. Bunches with 160 pC charge and ~6 ps duration yield SPPs with 6-10 ps duration and 0.4+/-0.1 MV m-1 electric field strength on a 1.5 mm diameter aluminium wire. These are the most intense SPPs reported on a wire. The SPPs are shown to propagate around a 90 degrees bend. PMID- 28008909 TI - Catalytic enantioselective addition of Grignard reagents to aromatic silyl ketimines. AB - alpha-Chiral amines are of significant importance in medicinal chemistry, asymmetric synthesis and material science, but methods for their efficient synthesis are scarce. In particular, the synthesis of alpha-chiral amines with the challenging tetrasubstituted carbon stereocentre is a long-standing problem and catalytic asymmetric additions of organometallic reagents to ketimines that would give direct access to these molecules are underdeveloped. Here we report a highly enantioselective catalytic synthesis of N-sulfonyl protected alpha-chiral silyl amines via the addition of inexpensive, easy to handle and readily available Grignard reagents to silyl ketimines. The key to this success was our ability to suppress any unselective background addition reactions and side reduction pathway, through the identification of an inexpensive, chiral Cu complex as the catalytically active structure. PMID- 28008910 TI - Electronically decoupled stacking fault tetrahedra embedded in Au(111) films. AB - Stacking faults are known as defective structures in crystalline materials that typically lower the structural quality of the material. Here, we show that a particular type of defect, that is, stacking fault tetrahedra (SFTs), exhibits pronounced quantized electronic behaviour, revealing a potential synthetic route to decoupled nanoparticles in metal films. We report on the electronic properties of SFTs that exist in Au(111) films, as evidenced by scanning tunnelling microscopy and confirmed by transmission electron microscopy. We find that the SFTs reveal a remarkable decoupling from their metal surroundings, leading to pronounced energy level quantization effects within the SFTs. The electronic behaviour of the SFTs can be described well by the particle-in-a-box model. Our findings demonstrate that controlled preparation of SFTs may offer an alternative way to achieve well-decoupled nanoparticles of high crystalline quality in metal thin films without the need of thin insulating layers. PMID- 28008911 TI - Geometrical vortex lattice pinning and melting in YBaCuO submicron bridges. AB - Since the discovery of high-temperature superconductors (HTSs), most efforts of researchers have been focused on the fabrication of superconducting devices capable of immobilizing vortices, hence of operating at enhanced temperatures and magnetic fields. Recent findings that geometric restrictions may induce self arresting hypervortices recovering the dissipation-free state at high fields and temperatures made superconducting strips a mainstream of superconductivity studies. Here we report on the geometrical melting of the vortex lattice in a wide YBCO submicron bridge preceded by magnetoresistance (MR) oscillations fingerprinting the underlying regular vortex structure. Combined magnetoresistance measurements and numerical simulations unambiguously relate the resistance oscillations to the penetration of vortex rows with intermediate geometrical pinning and uncover the details of geometrical melting. Our findings offer a reliable and reproducible pathway for controlling vortices in geometrically restricted nanodevices and introduce a novel technique of geometrical spectroscopy, inferring detailed information of the structure of the vortex system through a combined use of MR curves and large-scale simulations. PMID- 28008913 TI - Collisional cross-section of water molecules in vapour studied by means of 1H relaxation in NMR. AB - In gas phase, collisions that affect the rotational angular momentum lead to the return of the magnetization to its equilibrium (relaxation) in Nuclear Magnetic Resonance (NMR). To the best of our knowledge, the longitudinal relaxation rates R1 = 1/T1 of protons in H2O and HDO have never been measured in gas phase. We report R1 in gas phase in a field of 18.8 T, i.e., at a proton Larmor frequency nu0 = 800 MHz, at temperatures between 353 and 373 K and pressures between 9 and 101 kPa. By assuming that spin rotation is the dominant relaxation mechanism, we estimated the effective cross-section sigmaJ for the transfer of angular momentum due to H2O-H2O and HDO-D2O collisions. Our results allow one to test theoretical predictions of the intermolecular potential of water in gas phase. PMID- 28008912 TI - Validation of a genome-wide association study implied that SHTIN1 may involve in the pathogenesis of NSCL/P in Chinese population. AB - Orofacial clefts are among the most common birth defects in humans worldwide. A large-scale, genome-wide association study (GWAS) in the Chinese population recently identified several genetic risk variants for nonsyndromic cleft lip with or without cleft palate (NSCL/P). We selected 16 significant SNPs from the GWAS I stage (P < 1.00E-5) that had not been replicated to validate their association with NSCL/P in 1931 NSCL/P cases and 2258 controls. Ultimately, we identified a NSCL/P susceptibility loci (rs17095681 at 10q25.3, intron of SHTN1 and 27.2 kb downstream of VAX1, Pmeta = 3.80E-9, OR = 0.64) in Chinese Han and Hui populations. This locus was not high LD with the reported loci in 10q25.3. It was a newly identified independent locus in 10q25.3 associated with NSCL/P. These results imply that SHTIN1 may involve in the pathogenesis of NSCL/P advance our understanding of the genetic susceptibility to NSCL/P. PMID- 28008914 TI - How to Enhance Gas Removal from Porous Electrodes? AB - This article presents a structure-based modeling approach to optimize gas evolution at an electrolyte-flooded porous electrode. By providing hydrophobic islands as preferential nucleation sites on the surface of the electrode, it is possible to nucleate and grow bubbles outside of the pore space, facilitating their release into the electrolyte. Bubbles that grow at preferential nucleation sites act as a sink for dissolved gas produced in electrode reactions, effectively suctioning it from the electrolyte-filled pores. According to the model, high oversaturation is necessary to nucleate bubbles inside of the pores. The high oversaturation allows establishing large concentration gradients in the pores that drive a diffusion flux towards the preferential nucleation sites. This diffusion flux keeps the pores bubble-free, avoiding deactivation of the electrochemically active surface area of the electrode as well as mechanical stress that would otherwise lead to catalyst degradation. The transport regime of the dissolved gas, viz. diffusion control vs. transfer control at the liquid-gas interface, determines the bubble growth law. PMID- 28008915 TI - Ultrafast infrared observation of exciton equilibration from oriented single crystals of photosystem II. AB - In oxygenic photosynthesis, two photosystems work in series. Each of them contains a reaction centre that is surrounded by light-harvesting antennae, which absorb the light and transfer the excitation energy to the reaction centre where electron transfer reactions are driven. Here we report a critical test for two contrasting models of light harvesting by photosystem II cores, known as the trap limited and the transfer-to-the trap-limited model. Oriented single crystals of photosystem II core complexes of Synechococcus elongatus are excited by polarized visible light and the transient absorption is probed with polarized light in the infrared. The dichroic amplitudes resulting from photoselection are maintained on the 60 ps timescale that corresponds to the dominant energy transfer process providing compelling evidence for the transfer-to-the-trap limitation of the overall light-harvesting process. This finding has functional implications for the quenching of excited states allowing plants to survive under high light intensities. PMID- 28008917 TI - Enhancing photoluminescence yields in lead halide perovskites by photon recycling and light out-coupling. AB - In lead halide perovskite solar cells, there is at least one recycling event of electron-hole pair to photon to electron-hole pair at open circuit under solar illumination. This can lead to a significant reduction in the external photoluminescence yield from the internal yield. Here we show that, for an internal yield of 70%, we measure external yields as low as 15% in planar films, where light out-coupling is inefficient, but observe values as high as 57% in films on textured substrates that enhance out-coupling. We analyse in detail how externally measured rate constants and photoluminescence efficiencies relate to internal recombination processes under photon recycling. For this, we study the photo-excited carrier dynamics and use a rate equation to relate radiative and non-radiative recombination events to measured photoluminescence efficiencies. We conclude that the use of textured active layers has the ability to improve power conversion efficiencies for both LEDs and solar cells. PMID- 28008916 TI - Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. AB - Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis. PMID- 28008918 TI - Measurement of transverse emittance and coherence of double-gate field emitter array cathodes. AB - Achieving small transverse beam emittance is important for high brightness cathodes for free electron lasers and electron diffraction and imaging experiments. Double-gate field emitter arrays with on-chip focussing electrode, operating with electrical switching or near infrared laser excitation, have been studied as cathodes that are competitive with photocathodes excited by ultraviolet lasers, but the experimental demonstration of the low emittance has been elusive. Here we demonstrate this for a field emitter array with an optimized double-gate structure by directly measuring the beam characteristics. Further we show the successful application of the double-gate field emitter array to observe the low-energy electron beam diffraction from suspended graphene in minimal setup. The observed low emittance and long coherence length are in good agreement with theory. These results demonstrate that our all-metal double-gate field emitters are highly promising for applications that demand extremely low electron bunch-phase space volume and large transverse coherence. PMID- 28008919 TI - Ecological networks are more sensitive to plant than to animal extinction under climate change. AB - Impacts of climate change on individual species are increasingly well documented, but we lack understanding of how these effects propagate through ecological communities. Here we combine species distribution models with ecological network analyses to test potential impacts of climate change on >700 plant and animal species in pollination and seed-dispersal networks from central Europe. We discover that animal species that interact with a low diversity of plant species have narrow climatic niches and are most vulnerable to climate change. In contrast, biotic specialization of plants is not related to climatic niche breadth and vulnerability. A simulation model incorporating different scenarios of species coextinction and capacities for partner switches shows that projected plant extinctions under climate change are more likely to trigger animal coextinctions than vice versa. This result demonstrates that impacts of climate change on biodiversity can be amplified via extinction cascades from plants to animals in ecological networks. PMID- 28008920 TI - Acoustic micro-tapping for non-contact 4D imaging of tissue elasticity. AB - Elastography plays a key role in characterizing soft media such as biological tissue. Although this technology has found widespread use in both clinical diagnostics and basic science research, nearly all methods require direct physical contact with the object of interest and can even be invasive. For a number of applications, such as diagnostic measurements on the anterior segment of the eye, physical contact is not desired and may even be prohibited. Here we present a fundamentally new approach to dynamic elastography using non-contact mechanical stimulation of soft media with precise spatial and temporal shaping. We call it acoustic micro-tapping (AMUT) because it employs focused, air-coupled ultrasound to induce significant mechanical displacement at the boundary of a soft material using reflection-based radiation force. Combining it with high speed, four-dimensional (three space dimensions plus time) phase-sensitive optical coherence tomography creates a non-contact tool for high-resolution and quantitative dynamic elastography of soft tissue at near real-time imaging rates. The overall approach is demonstrated in ex-vivo porcine cornea. PMID- 28008921 TI - Reprogramming the immunological microenvironment through radiation and targeting Axl. AB - Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8+ T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment. PMID- 28008922 TI - ATP hydrolysis by UPF1 is required for efficient translation termination at premature stop codons. AB - Nonsense-mediated mRNA decay (NMD) represents a eukaryotic quality control pathway that recognizes and rapidly degrades transcripts harbouring nonsense mutations to limit accumulation of non-functional and potentially toxic truncated polypeptides. A critical component of the NMD machinery is UPF1, an RNA helicase whose ATPase activity is essential for NMD, but for which the precise function and site of action remain unclear. We provide evidence that ATP hydrolysis by UPF1 is required for efficient translation termination and ribosome release at a premature termination codon. UPF1 ATPase mutants accumulate 3' RNA decay fragments harbouring a ribosome stalled during premature termination that impedes complete degradation of the mRNA. The ability of UPF1 to impinge on premature termination, moreover, requires ATP-binding, RNA-binding and NMD cofactors UPF2 and UPF3. Our results reveal that ATP hydrolysis by UPF1 modulates a functional interaction between the NMD machinery and terminating ribosomes necessary for targeting substrates to accelerated degradation. PMID- 28008923 TI - Electromagnetic Performances Analysis of an Ultra-wideband and Flexible Material Antenna in Microwave Breast Imaging: To Implement A Wearable Medical Bra. AB - In this paper, we report a compact and ultra-wide band antenna on a flexible substrate using the 5-(4-(perfluorohexyl)phenyl)thiophene-2-carbaldehyde compound for microwave imaging. In contrast to other microwave based imaging systems, such as an array of 16 antennas, we proposed a bi-static radar based imaging system consisting of two omnidirectional antennas, which reduces complexity and the overall dimension. The proposed compact antennas are 20 * 14 mm2 and designed for operating at frequencies from 4 to 6 GHz. To allow for implantation into a bra, the electromagnetic performances of the antennas must be considered in bending conditions. In comparison with the recently reported flexible antennas, we demonstrated both electromagnetic performance and imaging reconstruction for bending conditions. For the proof of concept, the electromagnetic performances both at flat and bending conditions have been verified using a homogeneous multilayer model of the human breast phantom. Our results demonstrate that the antenna, even at bending conditions, exhibits an excellent omni-directional radiation pattern with an average efficiency above 70% and average gain above 1 dBi, within the operational frequency band. The comprehensive aim of the realized antenna is to design a biodegradable and wearable antenna-based bra for early breast cancer detection in the future. PMID- 28008924 TI - Observation of the topological soliton state in the Su-Schrieffer-Heeger model. AB - The Su-Schrieffer-Heeger (SSH) model, which captures the most striking transport properties of the conductive organic polymer trans-polyacetylene, provides perhaps the most basic model system supporting topological excitations. The alternating bond pattern of polyacetylene chains is captured by the bipartite sublattice structure of the SSH model, emblematic of one-dimensional chiral symmetric topological insulators. This structure supports two distinct nontrivial topological phases, which, when interfaced with one another or with a topologically trivial phase, give rise to topologically protected, dispersionless boundary states. Here, using 87Rb atoms in a momentum-space lattice, we realize fully tunable condensed matter Hamiltonians, allowing us to probe the dynamics and equilibrium properties of the SSH model. We report on the experimental quantum simulation of this model and observation of the localized topological soliton state through quench dynamics, phase-sensitive injection, and adiabatic preparation. PMID- 28008925 TI - Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. AB - Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon gamma production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer. PMID- 28008926 TI - Long-term propagation of tree shrew spermatogonial stem cells in culture and successful generation of transgenic offspring. AB - Tree shrews have a close relationship to primates and have many advantages over rodents in biomedical research. However, the lack of gene manipulation methods has hindered the wider use of this animal. Spermatogonial stem cells (SSCs) have been successfully expanded in culture to permit sophisticated gene editing in the mouse and rat. Here, we describe a culture system for the long-term expansion of tree shrew SSCs without the loss of stem cell properties. In our study, thymus cell antigen 1 was used to enrich tree shrew SSCs. RNA-sequencing analysis revealed that the Wnt/beta-catenin signaling pathway was active in undifferentiated SSCs, but was downregulated upon the initiation of SSC differentiation. Exposure of tree shrew primary SSCs to recombinant Wnt3a protein during the initial passages of culture enhanced the survival of SSCs. Use of tree shrew Sertoli cells, but not mouse embryonic fibroblasts, as feeder was found to be necessary for tree shrew SSC proliferation, leading to a robust cell expansion and long-term culture. The expanded tree shrew SSCs were transfected with enhanced green fluorescent protein (EGFP)-expressing lentiviral vectors. After transplantation into sterilized adult male tree shrew's testes, the EGFP-tagged SSCs were able to restore spermatogenesis and successfully generate transgenic offspring. Moreover, these SSCs were suitable for the CRISPR/Cas9-mediated gene modification. The development of a culture system to expand tree shrew SSCs in combination with a gene editing approach paves the way for precise genome manipulation using the tree shrew. PMID- 28008927 TI - Immunotherapy against cancer-related viruses. AB - Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus (EBV), Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer therapies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establishment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-associated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T cells have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we describe the current status of immunotherapy for virus-associated malignancies and discuss future prospects. PMID- 28008928 TI - Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding. AB - The global outbreak of SARS in 2002-2003 was caused by the infection of a new human coronavirus SARS-CoV. The infection of SARS-CoV is mediated mainly through the viral surface glycoproteins, which consist of S1 and S2 subunits and form trimer spikes on the envelope of the virions. Here we report the ectodomain structures of the SARS-CoV surface spike trimer in different conformational states determined by single-particle cryo-electron microscopy. The conformation 1 determined at 4.3 A resolution is three-fold symmetric and has all the three receptor-binding C-terminal domain 1 (CTD1s) of the S1 subunits in "down" positions. The binding of the "down" CTD1s to the SARS-CoV receptor ACE2 is not possible due to steric clashes, suggesting that the conformation 1 represents a receptor-binding inactive state. Conformations 2-4 determined at 7.3, 5.7 and 6.8 A resolutions are all asymmetric, in which one RBD rotates away from the "down" position by different angles to an "up" position. The "up" CTD1 exposes the receptor-binding site for ACE2 engagement, suggesting that the conformations 2-4 represent a receptor-binding active state. This conformational change is also required for the binding of SARS-CoV neutralizing antibodies targeting the CTD1. This phenomenon could be extended to other betacoronaviruses utilizing CTD1 of the S1 subunit for receptor binding, which provides new insights into the intermediate states of coronavirus pre-fusion spike trimer during infection. PMID- 28008930 TI - Bio-inspired self-shaping ceramics. AB - Shaping ceramics into complex and intricate geometries using cost-effective processes is desirable in many applications but still remains an open challenge. Inspired by plant seed dispersal units that self-fold on differential swelling, we demonstrate that self-shaping can be implemented in ceramics by programming the material's microstructure to undergo local anisotropic shrinkage during heat treatment. Such microstructural design is achieved by magnetically aligning functionalized ceramic platelets in a liquid ceramic suspension, subsequently consolidated through an established enzyme-catalysed reaction. By fabricating alumina compacts exhibiting bio-inspired bilayer architectures, we achieve deliberate control over shape change during the sintering step. Bending, twisting or combinations of these two basic movements can be successfully programmed to obtain a myriad of complex shapes. The simplicity and the universality of such a bottom-up shaping method makes it attractive for applications that would benefit from low-waste ceramic fabrication, temperature-resistant interlocking structures or unusual geometries not accessible using conventional top-down manufacturing. PMID- 28008929 TI - The overexpressed functional transient receptor potential channel TRPM2 in oral squamous cell carcinoma. AB - TRPM2, one member of the transient receptor potential (TRP) protein super-family, is a Ca2+-permeable channel that is activated by oxidative stress and confers susceptibility to cell death. In the human tongue specimens of carcinoma and the tongue carcinoma SCC cell lines, we observed the enhanced expression of TRPM2. By means of the whole-cell electrophysiological recording, the ADPR-induced currents mediated by TRPM2 were recorded in cultured SCC9 cells. Moreover, after H2O2 treatment for 24 hours, the apoptotic number of SCC9 cells was significantly increased. However, the selectively knocked-down TRPM2 with the small interfering RNA technique inhibited the survival and migration of the SCC9 cancer cells, which was independent of the p53-p21 pathway, since the expression of p21 was enhanced after TRPM2 knockdown. Furthermore, the sub-cellular localization of TRPM2 was remarkably different between cancerous and non-cancerous cells. A significant amount of the TRPM2 proteins were located in the nuclei in cancer cells. All these data suggest that TRPM2 is essential for the survival and migration of SCC cancer cells and may be a potential target for the selective treatment of tongue cancer. PMID- 28008931 TI - Evidence for a magma reservoir beneath the Taipei metropolis of Taiwan from both S-wave shadows and P-wave delays. AB - There are more than 7 million people living near the Tatun volcano group in northern Taiwan. For the safety of the Taipei metropolis, in particular, it has been debated for decades whether or not these volcanoes are active. Here I show evidence of a deep magma reservoir beneath the Taipei metropolis from both S-wave shadows and P-wave delays. The reservoir is probably composed of either a thin magma layer overlay or many molten sills within thick partially molten rocks. Assuming that 40% of the reservoir is partially molten, its total volume could be approximately 350 km3. The exact location and geometry of the magma reservoir will be obtained after dense seismic arrays are deployed in 2017-2020. PMID- 28008932 TI - Timing and quality of sleep in a rural Brazilian family-based cohort, the Baependi Heart Study. AB - Sleep is modulated by several factors, including sex, age, and chronotype. It has been hypothesised that contemporary urban populations are under pressure towards shorter sleep duration and poorer sleep quality. Baependi is a small town in Brazil that provides a window of opportunity to study the influence of sleep patterns in a highly admixed rural population with a conservative lifestyle. We evaluated sleep characteristics, excessive daytime sleepiness, and chronotype using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Morningness-Eveningness Questionnaire questionnaires, respectively. The sample consisted of 1,334 subjects from the Baependi Heart study (41.5% male; age: 46.5 +/- 16.2 y, range: 18-89 years). Average self-reported sleep duration was 07:07 +/- 01:31 (bedtime 22:32 +/- 01:27, wake up time: 06:17 +/- 01:25 hh:min), sleep quality score was 4.9 + 3.2, chronotype was 63.6 +/- 10.8 and daytime sleepiness was 7.4 +/- 4.8. Despite a shift towards morningness in the population, chronotype remained associated with reported actual sleep timing. Age and sex modulated the ontogeny of sleep and chronotype, increasing age was associated with earlier sleep time and shorter sleep duration. Women slept longer and later, and reported poorer sleep quality than men (p < 0.0001). This study provides indirect evidence in support of the hypothesis that sleep timing was earlier prior to full urbanisation. PMID- 28008933 TI - Class B beta-arrestin2-dependent CCR5 signalosome retention with natural antibodies to CCR5. AB - CCR5 stimulation with natural ligands, such as RANTES, classically induces short term internalization with transient activation of beta-arrestins and rapidly recycling on the cell surface. Here we discovered that, in T cells, natural CCR5 antibodies induce a CCR5-negative phenotype with the involvement of beta arrestin2, which leads to the formation of a stable CCR5 signalosome with both beta-arrestin2 and ERK1. The activation of beta-arrestin2 is necessary to CCR5 signaling for the signalosome formation and stabilization. When all stimuli were washed out, beta-arrestin1 silencing favors the activity of beta-arrestin2 for the CCR5 signalosome retention. Interestingly, CCR5 turn from Class A trafficking pattern, normally used for its internalization with natural modulating molecules (i.e. RANTES), into a long lasting Class B type specifically induced by stimulation with natural anti-CCR5 antibodies. This new CCR5 pathway is relevant not only to study in depth the molecular basis of all pathologies where CCR5 is involved but also to generate new antidody-based therapeutics. PMID- 28008934 TI - Driver gene classification reveals a substantial overrepresentation of tumor suppressors among very large chromatin-regulating proteins. AB - Compiling a comprehensive list of cancer driver genes is imperative for oncology diagnostics and drug development. While driver genes are typically discovered by analysis of tumor genomes, infrequently mutated driver genes often evade detection due to limited sample sizes. Here, we address sample size limitations by integrating tumor genomics data with a wide spectrum of gene-specific properties to search for rare drivers, functionally classify them, and detect features characteristic of driver genes. We show that our approach, CAnceR geNe similarity-based Annotator and Finder (CARNAF), enables detection of potentially novel drivers that eluded over a dozen pan-cancer/multi-tumor type studies. In particular, feature analysis reveals a highly concentrated pool of known and putative tumor suppressors among the <1% of genes that encode very large, chromatin-regulating proteins. Thus, our study highlights the need for deeper characterization of very large, epigenetic regulators in the context of cancer causality. PMID- 28008935 TI - Corrigendum: UPLC-PDA-QTOFMS-guided isolation of prenylated xanthones and benzoylphloroglucinols from the leaves of Garcinia oblongifolia and their migration-inhibitory activity. PMID- 28008936 TI - Enhanced Locomotion Efficiency of a Bio-inspired Walking Robot using Contact Surfaces with Frictional Anisotropy. AB - Based on the principles of morphological computation, we propose a novel approach that exploits the interaction between a passive anisotropic scale-like material (e.g., shark skin) and a non-smooth substrate to enhance locomotion efficiency of a robot walking on inclines. Real robot experiments show that passive tribologically-enhanced surfaces of the robot belly or foot allow the robot to grip on specific surfaces and move effectively with reduced energy consumption. Supplementing the robot experiments, we investigated tribological properties of the shark skin as well as its mechanical stability. It shows high frictional anisotropy due to an array of sloped denticles. The orientation of the denticles to the underlying collagenous material also strongly influences their mechanical interlocking with the substrate. This study not only opens up a new way of achieving energy-efficient legged robot locomotion but also provides a better understanding of the functionalities and mechanical properties of anisotropic surfaces. That understanding will assist developing new types of material for other real-world applications. PMID- 28008937 TI - Relationship between quantum speed limit time and memory time in a photonic-band gap environment. AB - Non-Markovian effect is found to be able to decrease the quantum speed limit (QSL) time, and hence to enhance the intrinsic speed of quantum evolution. Although a reservoir with larger degree of non-Markovianity may seem like it should cause smaller QSL times, this seemingly intuitive thinking may not always be true. We illustrate this by investigating the QSL time of a qubit that is coupled to a two-band photonic-band-gap (PBG) environment. We show how the QSL time is influenced by the coherent property of the reservoir and the band-gap width. In particular, we find that the decrease of the QSL time is not attributed to the increasing non-Markovianity, while the memory time of the environment can be seen as an essential reflection to the QSL time. So, the QSL time provides a further insight and sharper identification of memory time in a PBG environment. We also discuss a feasible experimental realization of our prediction. PMID- 28008938 TI - Selective in vitro photothermal nano-therapy of MRSA infections mediated by IgG conjugated gold nanoparticles. AB - There are serious systemic infections associated with methicillin-resistant Staphylococcus aureus (MRSA) and several other types of bacteria leading to the deaths of millions of people globally. This type of mortality is generally caused by the increasing number of antibiotic-resistant organisms, a consequence of evolution via natural selection. After the synthesis of gold nanoparticles (GNPs) by wet chemistry, bio-functionalization with IgG molecules was performed. Following administration of IgG-GNPs to MRSA cultures at various concentrations and various incubation time laser irradiation was performed. To assess the selectivity and specificity of the proposed treatment the following methods were used: flow cytometry, contrast phase microscopy, and by fluorescence microscopy. The results in our study indicate that following administration of IgG-GNPs biomolecule an extended and selective bacterial death occurs following laser irradiation in a dose dependent manner. Therefore, the new findings might impel studies on these antibacterial nanomaterials and their biological and medical applications. PMID- 28008939 TI - CsMAP34, a teleost MAP with dual role: A promoter of MASP-assisted complement activation and a regulator of immune cell activity. AB - In teleost fish, the immune functions of mannan-binding lectin (MBL) associated protein (MAP) and MBL associated serine protease (MASP) are scarcely investigated. In the present study, we examined the biological properties both MAP (CsMAP34) and MASP (CsMASP1) molecules from tongue sole (Cynoglossus semilaevis). We found that CsMAP34 and CsMASP1 expressions occurred in nine different tissues and were upregulated by bacterial challenge. CsMAP34 protein was detected in blood, especially during bacterial infection. Recombinant CsMAP34 (rCsMAP34) bound C. semilaevis MBL (rCsBML) when the latter was activated by bacteria, while recombinant CsMASP1 (rCsMASP1) bound activated rCsBML only in the presence of rCsMAP34. rCsMAP34 stimulated the hemolytic and bactericidal activities of serum complement, whereas anti-CsMAP34 antibody blocked complement activities. Knockdown of CsMASP1 in C. semilaevis resulted in significant inhibition of complement activities. Furthermore, rCsMAP34 interacted directly with peripheral blood leukocytes (PBL) and enhanced the respiratory burst, acid phosphatase activity, chemotactic activity, and gene expression of PBL. These results indicate for the first time that a teleost MAP acts one hand as a regulator that promotes the lectin pathway of complement activation via its ability to recruit MBL to MASP, and other hand as a modulator of immune cell activity. PMID- 28008941 TI - Systemic Wound Healing Associated with local sub-Cutaneous Mechanical Stimulation. AB - Degeneration is a hallmark of autoimmune diseases, whose incidence grows worldwide. Current therapies attempt to control the immune response to limit degeneration, commonly promoting immunodepression. Differently, mechanical stimulation is known to trigger healing (regeneration) and it has recently been proposed locally for its therapeutic potential on severely injured areas. As the early stages of healing consist of altered intra- and inter-cellular fluxes of soluble molecules, we explored the potential of this early signal to spread, over time, beyond the stimulation district and become systemic, to impact on distributed or otherwise unreachable injured areas. We report in a model of arthritis in rats how stimulations delivered in the subcutaneous dorsal tissue result, over time, in the control and healing of the degeneration of the paws' joints, concomitantly with the systemic activation of wound healing phenomena in blood and in correlation with a more eubiotic microbiome in the gut intestinal district. PMID- 28008942 TI - Anisotropic optical response of optically opaque elastomers with conductive fillers as revealed by terahertz polarization spectroscopy. AB - Elastomers are one of the most important materials in modern society because of the inherent viscoelastic properties due to their cross-linked polymer chains. Their vibration-absorbing and adhesive properties are especially useful and thus utilized in various applications, for example, tires in automobiles and bicycles, seismic dampers in buildings, and seals in a space shuttle. Thus, the nondestructive inspection of their internal states such as the internal deformation is essential in safety. Generally, industrial elastomers include various kinds of additives, such as carbon blacks for reinforcing them. The additives make most of them opaque in a wide spectral range from visible to mid infrared, resulting in that the nondestructive inspection of the internal deformation is quite difficult. Here, we demonstrate transmission terahertz polarization spectroscopy as a powerful technique for investigating the internal optical anisotropy in optically opaque elastomers with conductive additives, which are transparent only in the terahertz frequency region. The internal deformation can be probed through the polarization changes inside the material due to the anisotropic dielectric response of the conductive additives. Our study about the polarization-dependent terahertz response of elastomers with conductive additives provides novel knowledge for in situ, nondestructive evaluation of their internal deformation. PMID- 28008940 TI - Deficiency of Mkrn2 causes abnormal spermiogenesis and spermiation, and impairs male fertility. AB - Although recent studies have shed insights on some of the potential causes of male infertility, new underlining molecular mechanisms still remain to be elucidated. Makorin-2 (Mkrn2) is an evolutionarily conserved gene whose biological functions are not fully known. We developed an Mrkn2 knockout mouse model to study the role of this gene, and found that deletion of Mkrn2 in mice led to male infertility. Mkrn2 knockout mice produced abnormal sperms characterized by low number, poor motility, and aberrant morphology. Disruption of Mkrn2 also caused failure of sperm release (spermiation failure) and misarrangement of ectoplasmic specialization (ES) in testes, thus impairing spermiogenesis and spermiation. To understand the molecular mechanism, we found that expression of Odf2, a vital protein in spermatogenesis, was significantly decreased. In addition, we found that expression levels of Odf2 were decreased in Mkrn2 knockout mice. We also found that MKRN2 was prominently expressed in the sperm of normal men, but was significantly reduced in infertile men. This result indicates that our finding is clinically relevant. The results of our study provided insights into a new mechanism of male infertility caused by the MKRN2 downregulation. PMID- 28008943 TI - Effect of omega-3 fatty acid supplementation on serum lipids and vascular inflammation in patients with end-stage renal disease: a meta-analysis. AB - Omega-3 fatty acids (O3FAs) are associated with lower cardiovascular disease (CVD) risk in adults. However, this association in patients with end-stage renal disease (ESRD) remains controversial prompting the need for investigation into the role of O3FAs on serum lipids and vascular inflammation markers. The present meta-analysis summarized the effects of O3FA supplementation on serum lipids and vascular inflammatory markers in patients with ESRD. PubMed, EmBase, and the Cochrane Library were searched to identify randomized controlled trials (RCTs) focused on serum lipids and vascular inflammation markers in patients with ESRD. Standard mean differences (SMD) were used to measure the effect of O3FA supplementation on serum lipids and vascular inflammatory markers. The final pooled analysis included 20 RCTs involving 1,461 patients with ESRD. The results indicated that O3FA supplementation reduced TG by 0.61, LDL by 0.35 and CRP by 0.56. However, O3FA had no significant effect on TC, HDL, albumin, hemoglobin, homocysteine, DBP, glucose, lipoprotein(a), and ferritin. O3FA supplementation is associated with lower several serum lipids and vascular inflammation markers in patients with ESRD. PMID- 28008944 TI - Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go coupled JNK pathway. AB - Amyloid precursor protein (APP), commonly associated with Alzheimer's disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Nav1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by constitutively active Go mutant and blocked by a dominant negative mutant. JNK and CDK5 inhibitor attenuated increases in Nav1.6 sodium currents induced by overexpression of APP. Nav1.6 sodium currents were increased by APPT668E (mutant Thr to Glu) and decreased by T668A (mutant Thr to ALa) mutant, respectively. The cell surface expression of Nav1.6 sodium channels in the white matter of spinal cord and the spinal conduction velocity is decreased in APP, p35 and JNK3 knockout mice. Therefore, APP modulates Nav1.6 sodium channels through a Go coupled JNK pathway, which is dependent on phosphorylation of APP at Thr668. PMID- 28008945 TI - Using nearly full-genome HIV sequence data improves phylogeny reconstruction in a simulated epidemic. AB - HIV molecular epidemiology studies analyse viral pol gene sequences due to their availability, but whole genome sequencing allows to use other genes. We aimed to determine what gene(s) provide(s) the best approximation to the real phylogeny by analysing a simulated epidemic (created as part of the PANGEA_HIV project) with a known transmission tree. We sub-sampled a simulated dataset of 4662 sequences into different combinations of genes (gag-pol-env, gag-pol, gag, pol, env and partial pol) and sampling depths (100%, 60%, 20% and 5%), generating 100 replicates for each case. We built maximum-likelihood trees for each combination using RAxML (GTR + Gamma), and compared their topologies to the corresponding true tree's using CompareTree. The accuracy of the trees was significantly proportional to the length of the sequences used, with the gag-pol-env datasets showing the best performance and gag and partial pol sequences showing the worst. The lowest sampling depths (20% and 5%) greatly reduced the accuracy of tree reconstruction and showed high variability among replicates, especially when using the shortest gene datasets. In conclusion, using longer sequences derived from nearly whole genomes will improve the reliability of phylogenetic reconstruction. With low sample coverage, results can be highly variable, particularly when based on short sequences. PMID- 28008946 TI - HtrA2 suppresses autoimmune arthritis and regulates activation of STAT3. AB - Rheumatoid arthritis (RA) is an autoimmune disease that is related to the induction of T helper (Th)17 cells, which secrete interleukin-17, and activation of the signal transducer and activator of transcription (STAT) 3. The expression of high-temperature requirement protein A (HtrA) 2, a serine protease involved in apoptosis, was decreased in RA patients nonresponsive to drug treatment of RA. The aim of this study was to determine whether overexpression of HtrA2 has a therapeutic effect on RA. Th17 differentiation, osteoclastogenesis, and lymphocyte activation are increased in motor neuron degeneration (mnd)2 mice, which lack HtrA2 activity because of a missense mutation (Ser276Cys) in the protease domain of HtrA2. The inhibitor of HtrA2 also increased Th17 differentiation. On the other hand, HtrA2 induced cleavage of STAT3 and overexpression of HtrA2 attenuated CIA in a mouse model. HtrA2 overexpression inhibited plaque development as well as the differentiation of Th17 in ApoE-/- mice after immunization with proteoglycans to induce a hyperlipidemia-based RA animal model. The therapeutic function of HtrA2 in inflammatory diseases is linked with Th17 development and the STAT3 pathway in splenocytes. These results suggest that HtrA2 participates in immunomodulatory activity where the upregulation of HtrA2 may shed light on therapeutic approaches to RA and hyperlipidemia. PMID- 28008947 TI - Self assembly of HIV-1 Gag protein on lipid membranes generates PI(4,5)P2/Cholesterol nanoclusters. AB - The self-assembly of HIV-1 Gag polyprotein at the inner leaflet of the cell host plasma membrane is the key orchestrator of virus assembly. The binding between Gag and the plasma membrane is mediated by specific interaction of the Gag matrix domain and the PI(4,5)P2 lipid (PIP2). It is unknown whether this interaction could lead to local reorganization of the plasma membrane lipids. In this study, using model membranes, we examined the ability of Gag to segregate specific lipids upon self-assembly. We show for the first time that Gag self-assembly is responsible for the formation of PIP2 lipid nanoclusters, enriched in cholesterol but not in sphingomyelin. We also show that Gag mainly partition into liquid disordered domains of these lipid membranes. Our work strongly suggests that, instead of targeting pre-existing plasma membrane lipid domains, Gag is more prone to generate PIP2/Cholesterol lipid nanodomains at the inner leaflet of the plasma membrane during early events of virus assembly. PMID- 28008948 TI - Lotus Base: An integrated information portal for the model legume Lotus japonicus. AB - Lotus japonicus is a well-characterized model legume widely used in the study of plant-microbe interactions. However, datasets from various Lotus studies are poorly integrated and lack interoperability. We recognize the need for a comprehensive repository that allows comprehensive and dynamic exploration of Lotus genomic and transcriptomic data. Equally important are user-friendly in browser tools designed for data visualization and interpretation. Here, we present Lotus Base, which opens to the research community a large, established LORE1 insertion mutant population containing an excess of 120,000 lines, and serves the end-user tightly integrated data from Lotus, such as the reference genome, annotated proteins, and expression profiling data. We report the integration of expression data from the L. japonicus gene expression atlas project, and the development of tools to cluster and export such data, allowing users to construct, visualize, and annotate co-expression gene networks. Lotus Base takes advantage of modern advances in browser technology to deliver powerful data interpretation for biologists. Its modular construction and publicly available application programming interface enable developers to tap into the wealth of integrated Lotus data. Lotus Base is freely accessible at: https://lotus.au.dk. PMID- 28008949 TI - Super-Spreader Identification Using Meta-Centrality. AB - Super-spreaders are the nodes of a network that can maximize their impacts on other nodes, e.g., in the case of information spreading or virus propagation. Many centrality measures have been proposed to identify such nodes from a given network. However, it has been observed that the identification accuracy based on those measures is not always satisfactory among different types of networks. In addition, the nodes identified by using single centrality are not always placed in the top section, where the super-spreaders are supposed to be, of the ranking generated by simulation. In this paper we take a meta-centrality approach by combining different centrality measures using a modified version of Borda count aggregation method. As a result, we are able to improve the performance of super spreader identification for a broad range of real-world networks. While doing so, we discover a pattern in the centrality measures involved in the aggregation with respect to the topological structures of the networks used in the experiments. Further, we study the eigenvalues of the Laplacian matrix, also known as Laplacian spectrum, and by using the Earth Mover's distance as a metric for the spectrum, we are able to identify four clusters to explain the aggregation results. PMID- 28008950 TI - Corrigendum: The developmental effects of pentachlorophenol on zebrafish embryos during segmentation: A systematic view. PMID- 28008951 TI - The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis. AB - Insulin-like growth factor-binding protein 5 (IGFBP-5) plays a role in cell growth, differentiation, and apoptosis. In this study, we found that IGFBP5 was markedly downregulated in ovarian cancer tissue. We investigated the functional significance of IGFBP-5 as a tumor suppressor. To determine functional regions of IGFBP-5, truncation mutants were prepared and were studied the effect on tumor growth. Expression of C-terminal region of IGFBP-5 significantly decreased tumor growth in an ovarian cancer xenograft. A peptide derived from the C-terminus of IGFBP-5 (BP5-C) was synthesized to evaluate the minimal amino acid motif that retained anti-tumorigenic activity and its effect on angiogenesis was studied. BP5-C peptide decreased the expression of VEGF-A and MMP-9, phosphorylation of Akt and ERK, and NF-kB activity, and inhibited angiogenesis in in vitro and ex vivo systems. Furthermore, BP5-C peptide significantly decreased tumor weight and angiogenesis in both ovarian cancer orthotopic xenograft and patient-derived xenograft mice. These results suggest that the C-terminus of IGFBP-5 exerts anti cancer activity by inhibiting angiogenesis via regulation of the Akt/ERK and NF kB-VEGF/MMP-9 signaling pathway, and might be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer. PMID- 28008952 TI - Antibodies from multiple sclerosis patients preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus influenzae. AB - In autoimmune diseases, there have been proposals that exogenous "molecular triggers", i.e., specific 'non-self antigens' accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS. PMID- 28008953 TI - Glycosuria and Renal Outcomes in Patients with Nondiabetic Advanced Chronic Kidney Disease. AB - Sodium glucose cotransporter 2 inhibitors have shown a potential for renoprotection beyond blood glucose lowering. Glycosuria in nondiabetic patients with chronic kidney disease (CKD) is sometimes noted. Whether glycosuria in CKD implies a channelopathy or proximal tubulopathy is not known. The consequence of glycosuria in CKD is also not studied. We performed a cross-sectional study for the association between glycosuria and urine electrolyte excretion in 208 nondiabetic patients. Fractional excretion (FE) of glucose >4% was 3.4%, 6.3% and 62.5% in CKD stage 3, 4 and 5, respectively. These patients with glycosuria had higher FE sodium, FE potassium, FE uric acid, UPCR, and urine NGAL-creatinine ratio. We conducted a longitudinal study for the consequence of glycosuria, defined by dipstick, in 769 nondiabetic patients with stage 4-5 CKD. Glycosuria was associated with a decreased risk for end-stage renal disease (adjusted hazard ratio: 0.77; CI = 0.62-0.97; p = 0.024) and for rapid renal function decline (adjusted odds ratio: 0.63; CI = 0.43-0.95; p = 0.032); but glycosuria was not associated with all-cause mortality or cardiovascular events. The results were consistent in the propensity-score matched cohort. Glycosuria is associated with increased fractional excretion of electrolytes and is related to favorable renal outcomes in nondiabetic patients with stage 5 CKD. PMID- 28008955 TI - Origin of stabilization and destabilization in solid-state redox reaction of oxide ions for lithium-ion batteries. AB - Further increase in energy density of lithium batteries is needed for zero emission vehicles. However, energy density is restricted by unavoidable theoretical limits for positive electrodes used in commercial applications. One possibility towards energy densities exceeding these limits is to utilize anion (oxide ion) redox, instead of classical transition metal redox. Nevertheless, origin of activation of the oxide ion and its stabilization mechanism are not fully understood. Here we demonstrate that the suppression of formation of superoxide-like species on lithium extraction results in reversible redox for oxide ions, which is stabilized by the presence of relatively less covalent character of Mn4+ with oxide ions without the sacrifice of electronic conductivity. On the basis of these findings, we report an electrode material, whose metallic constituents consist only of 3d transition metal elements. The material delivers a reversible capacity of 300 mAh g-1 based on solid-state redox reaction of oxide ions. PMID- 28008954 TI - Sodium selenate regulates the brain ionome in a transgenic mouse model of Alzheimer's disease. AB - Many studies have shown that imbalance of mineral metabolism may play an important role in Alzheimer's disease (AD) progression. It was recently reported that selenium could reverse memory deficits in AD mouse model. We carried out multi-time-point ionome analysis to investigate the interactions among 15 elements in the brain by using a triple-transgenic mouse model of AD with/without high-dose sodium selenate supplementation. Except selenium, the majority of significantly changed elements showed a reduced level after 6-month selenate supplementation, especially iron whose levels were completely reversed to normal state at almost all examined time points. We then built the elemental correlation network for each time point. Significant and specific elemental correlations and correlation changes were identified, implying a highly complex and dynamic crosstalk between selenium and other elements during long-term supplementation with selenate. Finally, we measured the activities of two important anti oxidative selenoenzymes, glutathione peroxidase and thioredoxin reductase, and found that they were remarkably increased in the cerebrum of selenate-treated mice, suggesting that selenoenzyme-mediated protection against oxidative stress might also be involved in the therapeutic effect of selenate in AD. Overall, this study should contribute to our understanding of the mechanism related to the potential use of selenate in AD treatment. PMID- 28008956 TI - Fracture behaviors under pure shear loading in bulk metallic glasses. AB - Pure shear fracture test, as a special mechanical means, had been carried out extensively to obtain the critical information for traditional metallic crystalline materials and rocks, such as the intrinsic deformation behavior and fracture mechanism. However, for bulk metallic glasses (BMGs), the pure shear fracture behaviors have not been investigated systematically due to the lack of a suitable test method. Here, we specially introduce a unique antisymmetrical four point bend shear test method to realize a uniform pure shear stress field and study the pure shear fracture behaviors of two kinds of BMGs, Zr-based and La based BMGs. All kinds of fracture behaviors, the pure shear fracture strength, fracture angle and fracture surface morphology, are systematically analyzed and compared with those of the conventional compressive and tensile fracture. Our results indicate that both the Zr-based and La-based BMGs follow the same fracture mechanism under pure shear loading, which is significantly different from the situation of some previous research results. Our results might offer new enlightenment on the intrinsic deformation and fracture mechanism of BMGs and other amorphous materials. PMID- 28008957 TI - Transurethral enucleation of prostate with button electrode plasmakinetic vaporization for the treatment of Benign Prostatic Hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a common disease in aged men. In this study, we investigated the efficacy and safety of transurethral enucleation of prostate with button electrode plasmakinetic vaporization for the treatment of BPH. 60 patients diagnosed with BPH who were treated in our hospital from August to December, 2014 by enucleation with button electrode were retrospectively reviewed, and operation time, urinary catheter indwelling time, continuous bladder irrigation time, operation related complications, maximum urinary flow rate (Qmax), post-void residual urine volume (PVR), International Prostate Symptom Score (IPSS), quality of life assessment (QOL), perioperative hemoglobin and electrolytes were recorded. All the operations were completed successfully. The operation time and urinary catheter indwelling time were 45.3 +/- 16.2 min and 1.72 +/- 0.32 d, respectively. During the follow-up, urethral stricture (n = 1), and urinary incontinence (n = 2) were found with recovery after 1-month training. Postoperative PVR at 1, 3 and 6 months significantly decreased compared with preoperative ones (P < 0.05). IPSS, Qmax, QOL at 1, 3 and 6 months improved significantly (P < 0.05). There was no significant difference in serum hemoglobin, sodium and potassium before and after the operation. Thus, the study proved that enucleation of prostate with button electrode was efficient and safe, which was worth being recommended. PMID- 28008958 TI - Zika virus infection induces mitosis abnormalities and apoptotic cell death of human neural progenitor cells. AB - Zika virus (ZIKV) infection has been associated with severe complications both in the developing and adult nervous system. To investigate the deleterious effects of ZIKV infection, we used human neural progenitor cells (NPC), derived from induced pluripotent stem cells (iPSC). We found that NPC are highly susceptible to ZIKV and the infection results in cell death. ZIKV infection led to a marked reduction in cell proliferation, ultrastructural alterations and induction of autophagy. Induction of apoptosis of Sox2+ cells was demonstrated by activation of caspases 3/7, 8 and 9, and by ultrastructural and flow cytometry analyses. ZIKV-induced death of Sox2+ cells was prevented by incubation with the pan caspase inhibitor, Z-VAD-FMK. By confocal microscopy analysis we found an increased number of cells with supernumerary centrosomes. Live imaging showed a significant increase in mitosis abnormalities, including multipolar spindle, chromosome laggards, micronuclei and death of progeny after cell division. FISH analysis for chromosomes 12 and 17 showed increased frequency of aneuploidy, such as monosomy, trisomy and polyploidy. Our study reinforces the link between ZIKV and abnormalities in the developing human brain, including microcephaly. PMID- 28008959 TI - Non-invasive imaging using reporter genes altering cellular water permeability. AB - Non-invasive imaging of gene expression in live, optically opaque animals is important for multiple applications, including monitoring of genetic circuits and tracking of cell-based therapeutics. Magnetic resonance imaging (MRI) could enable such monitoring with high spatiotemporal resolution. However, existing MRI reporter genes based on metalloproteins or chemical exchange probes are limited by their reliance on metals or relatively low sensitivity. Here we introduce a new class of MRI reporters based on the human water channel aquaporin 1. We show that aquaporin overexpression produces contrast in diffusion-weighted MRI by increasing tissue water diffusivity without affecting viability. Low aquaporin levels or mixed populations comprising as few as 10% aquaporin-expressing cells are sufficient to produce MRI contrast. We characterize this new contrast mechanism through experiments and simulations, and demonstrate its utility in vivo by imaging gene expression in tumours. Our results establish an alternative class of sensitive, metal-free reporter genes for non-invasive imaging. PMID- 28008961 TI - Human expansion precipitates niche expansion for an opportunistic apex predator (Puma concolor). AB - There is growing recognition that developed landscapes are important systems in which to promote ecological complexity and conservation. Yet, little is known about processes regulating these novel ecosystems, or behaviours employed by species adapting to them. We evaluated the isotopic niche of an apex carnivore, the cougar (Puma concolor), over broad spatiotemporal scales and in a region characterized by rapid landscape change. We detected a shift in resource use, from near complete specialization on native herbivores in wildlands to greater use of exotic and invasive species by cougars in contemporary urban interfaces. We show that 25 years ago, cougars inhabiting these same urban interfaces possessed diets that were intermediate. Thus, niche expansion followed human expansion over both time and space, indicating that an important top predator is interacting with prey in novel ways. Thus, though human-dominated landscapes can provide sufficient resources for apex carnivores, they do not necessarily preserve their ecological relationships. PMID- 28008960 TI - Precipitation and carbon-water coupling jointly control the interannual variability of global land gross primary production. AB - Carbon uptake by terrestrial ecosystems is increasing along with the rising of atmospheric CO2 concentration. Embedded in this trend, recent studies suggested that the interannual variability (IAV) of global carbon fluxes may be dominated by semi-arid ecosystems, but the underlying mechanisms of this high variability in these specific regions are not well known. Here we derive an ensemble of gross primary production (GPP) estimates using the average of three data-driven models and eleven process-based models. These models are weighted by their spatial representativeness of the satellite-based solar-induced chlorophyll fluorescence (SIF). We then use this weighted GPP ensemble to investigate the GPP variability for different aridity regimes. We show that semi-arid regions contribute to 57% of the detrended IAV of global GPP. Moreover, in regions with higher GPP variability, GPP fluctuations are mostly controlled by precipitation and strongly coupled with evapotranspiration (ET). This higher GPP IAV in semi-arid regions is co-limited by supply (precipitation)-induced ET variability and GPP-ET coupling strength. Our results demonstrate the importance of semi-arid regions to the global terrestrial carbon cycle and posit that there will be larger GPP and ET variations in the future with changes in precipitation patterns and dryland expansion. PMID- 28008962 TI - A rapid method for detecting protein-nucleic acid interactions by protein induced fluorescence enhancement. AB - Many fundamental biological processes depend on intricate networks of interactions between proteins and nucleic acids and a quantitative description of these interactions is important for understanding cellular mechanisms governing DNA replication, transcription, or translation. Here we present a versatile method for rapid and quantitative assessment of protein/nucleic acid (NA) interactions. This method is based on protein induced fluorescence enhancement (PIFE), a phenomenon whereby protein binding increases the fluorescence of Cy3 like dyes. PIFE has mainly been used in single molecule studies to detect protein association with DNA or RNA. Here we applied PIFE for steady state quantification of protein/NA interactions by using microwell plate fluorescence readers (mwPIFE). We demonstrate the general applicability of mwPIFE for examining various aspects of protein/DNA interactions with examples from the restriction enzyme BamHI, and the DNA repair complexes Ku and XPF/ERCC1. These include determination of sequence and structure binding specificities, dissociation constants, detection of weak interactions, and the ability of a protein to translocate along DNA. mwPIFE represents an easy and high throughput method that does not require protein labeling and can be applied to a wide range of applications involving protein/NA interactions. PMID- 28008963 TI - Characterization of dorsal root ganglion neurons cultured on silicon micro-pillar substrates. AB - Our study focuses on characterization of dorsal root ganglion (DRG) neurons cultured on silicon micro-pillar substrates (MPS) with the ultimate goal of designing micro-electrode arrays (MEAs) for successful electrophysiological recordings of DRG neurons. Adult and neonatal DRG neurons were cultured on MPS and glass coverslips for 7 days in vitro. DRG neuronal distribution and morphometric analysis, including neurite alignment and length, was performed on MPS areas with different pillar width and spacing. We showed that MPS provide an environment for growth of adult and neonatal DRG neurons as permissive as control glass surfaces. Neonatal DRG neurons were present on MPS areas with narrow pillar spacing, while adult neurons preferred wider pillar spacing. Compared to the control glass surfaces the neonatal and adult DRG neurons in regions with narrow pillar spacing range developed a smaller number of longer neurites. In the same area, neurites were preferentially oriented along three directional axes at 30 degrees , 90 degrees and 150 degrees . MPS architecture influenced growth directionality of all main DRG neuronal subtypes. We can conclude that specific micro-pillar substrate topography affects the morphology of DRG neurons. This knowledge can enable development of MEAs with precisely defined physical features for various neuroscience applications. PMID- 28008964 TI - The direct-to-indirect band gap crossover in two-dimensional van der Waals Indium Selenide crystals. AB - The electronic band structure of van der Waals (vdW) layered crystals has properties that depend on the composition, thickness and stacking of the component layers. Here we use density functional theory and high field magneto optics to investigate the metal chalcogenide InSe, a recent addition to the family of vdW layered crystals, which transforms from a direct to an indirect band gap semiconductor as the number of layers is reduced. We investigate this direct-to-indirect bandgap crossover, demonstrate a highly tuneable optical response from the near infrared to the visible spectrum with decreasing layer thickness down to 2 layers, and report quantum dot-like optical emissions distributed over a wide range of energy. Our analysis also indicates that electron and exciton effective masses are weakly dependent on the layer thickness and are significantly smaller than in other vdW crystals. These properties are unprecedented within the large family of vdW crystals and demonstrate the potential of InSe for electronic and photonic technologies. PMID- 28008965 TI - Neural correlates of maintaining one's political beliefs in the face of counterevidence. AB - People often discount evidence that contradicts their firmly held beliefs. However, little is known about the neural mechanisms that govern this behavior. We used neuroimaging to investigate the neural systems involved in maintaining belief in the face of counterevidence, presenting 40 liberals with arguments that contradicted their strongly held political and non-political views. Challenges to political beliefs produced increased activity in the default mode network-a set of interconnected structures associated with self-representation and disengagement from the external world. Trials with greater belief resistance showed increased response in the dorsomedial prefrontal cortex and decreased activity in the orbitofrontal cortex. We also found that participants who changed their minds more showed less BOLD signal in the insula and the amygdala when evaluating counterevidence. These results highlight the role of emotion in belief change resistance and offer insight into the neural systems involved in belief maintenance, motivated reasoning, and related phenomena. PMID- 28008966 TI - Revisiting the connection between Solar eruptions and primary headaches and migraines using Twitter. AB - Many internal and environmental triggers of primary headaches have been proposed, but establishing firm evidence for any of them has proved elusive. Geomagnetic storms, the disturbances of Earth's magnetic field following Solar eruptions, have been proposed as one such trigger. In this study, we utilized a vast amount of self-reported symptoms from the online social networking service Twitter in order to investigate a purported link between the level of geomagnetic activity and the onset of primary headaches and migraines. We analyzed 63 million keyword bearing messages posted over the three years covering the maximum of Solar Cycle 24. No correlation has been found despite the large sample size. The simulation reveals that the significant correlation would have emerged even if only 1% of headache (2% of migraine) instances were caused by geomagnetic disturbances, thus placing very low upper limits on the prevalence of this trigger among Twitter users. PMID- 28008967 TI - Formation of equiaxed crystal structures in directionally solidified Al-Si alloys using Nb-based heterogeneous nuclei. AB - The design of chemical compositions containing potent nuclei for the enhancement of heterogeneous nucleation in aluminium, especially cast alloys such as Al-Si alloys, is a matter of importance in order to achieve homogeneous properties in castings with complex geometries. We identified that Al3Nb/NbB2 compounds are effective heterogeneous nuclei and are successfully produced in the form of Al 2Nb-xB (x = 0.5, 1 and 2) master alloys. Our study shows that the inoculation of Al-10Si braze alloy with these compounds effectively promotes the heterogeneous nucleation of primary alpha-Al crystals and reduces the undercooling needed for solidification to take place. Moreover, we present evidences that these Nb-based compounds prevent the growth of columnar crystals and permit to obtain, for the first time, fine and equiaxed crystals in directionally solidified Al-10Si braze alloy. As a consequence of the potent heterogeneous particles, the size of the alpha-Al crystals was found to be less dependent on the processing conditions, especially the thermal gradient. Finally, we also demonstrate that the enhanced nucleation leads to the refinement of secondary phases such as eutectic silicon and primary silicon particles. PMID- 28008968 TI - Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. AB - HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation. PMID- 28008969 TI - Determination of equilibrium dissociation constants for recombinant antibodies by high-throughput affinity electrophoresis. AB - High-quality immunoreagents enhance the performance and reproducibility of immunoassays and, in turn, the quality of both biological and clinical measurements. High quality recombinant immunoreagents are generated using antibody-phage display. One metric of antibody quality - the binding affinity - is quantified through the dissociation constant (KD) of each recombinant antibody and the target antigen. To characterize the KD of recombinant antibodies and target antigen, we introduce affinity electrophoretic mobility shift assays (EMSAs) in a high-throughput format suitable for small volume samples. A microfluidic card comprised of free-standing polyacrylamide gel (fsPAG) separation lanes supports 384 concurrent EMSAs in 30 s using a single power source. Sample is dispensed onto the microfluidic EMSA card by acoustic droplet ejection (ADE), which reduces EMSA variability compared to sample dispensing using manual or pin tools. The KD for each of a six-member fragment antigen binding fragment library is reported using ~25-fold less sample mass and ~5-fold less time than conventional heterogeneous assays. Given the form factor and performance of this micro- and mesofluidic workflow, we have developed a sample sparing, high-throughput, solution-phase alternative for biomolecular affinity characterization. PMID- 28008970 TI - High resolution spectroscopy reveals fibrillation inhibition pathways of insulin. AB - Fibril formation implies the conversion of a protein's native secondary structure and is associated with several neurodegenerative diseases. A better understanding of fibrillation inhibition and fibril dissection requires nanoscale molecular characterization of amyloid structures involved. Tip-enhanced Raman scattering (TERS) has already been used to chemically analyze amyloid fibrils on a sub protein unit basis. Here, TERS in combination with atomic force microscopy (AFM), and conventional Raman spectroscopy characterizes insulin assemblies generated during inhibition and dissection experiments in the presence of benzonitrile, dimethylsulfoxide, quercetin, and beta-carotene. The AFM topography indicates formation of filamentous or bead-like insulin self-assemblies. Information on the secondary structure of bulk samples and of single aggregates is obtained from standard Raman and TERS measurements. In particular the high spatial resolution of TERS reveals the surface conformations associated with the specific agents. The insulin aggregates formed under different inhibition and dissection conditions can show a similar morphology but differ in their beta-sheet structure content. This suggests different aggregation pathways where the prevention of the beta-sheet stacking of the peptide chains plays a major role. The presented approach is not limited to amyloid-related reasearch but can be readily applied to systems requiring extremely surface-sensitive characterization without the need of labels. PMID- 28008972 TI - Experimental Demonstration of a Highly Efficient Fan-out Polarization Grating. AB - Highly efficient fan-out elements are crucial in coherent beam combining architectures especially in coupled laser resonators where the beam passes through the fan-out element twice per round trip. Although the theoretical efficiency is usually less than 86%, the Dammann gratings are ubiquitously utilized in a variety of types of coherent beam combining systems due to the facile design and fabrication. In the current paper, we experimentally demonstrate a highly efficient fan-out polarization grating. It is the first time to our knowledge that all the three space-variant parameters of a polarization grating are simultaneously optimized to achieve the function of multi-beam splitting. Besides the high fan-out efficiency, the ability to control the polarization states of individual split beams is another advantage of this polarization grating. The novel polarization grating is promising to find applications in laser beam combining systems. PMID- 28008971 TI - Biochemical and structural characterization of a novel halotolerant cellulase from soil metagenome. AB - Cellulase catalyzes the hydrolysis of beta-1,4-linkages of cellulose to produce industrially relevant monomeric subunits. Cellulases find their applications in pulp and paper, laundry, food and feed, textile, brewing industry and in biofuel production. These industries always have great demand for cellulases that can work efficiently even in harsh conditions such as high salt, heat, and acidic environments. While, cellulases with high thermal and acidic stability are already in use, existence of a high halotolerant cellulase is still elusive. Here, we report a novel cellulase Cel5R, obtained from soil metagenome that shows high halotolerance and thermal stability. The biochemical and functional characterization of Cel5R revealed its endoglucanase activity and high halostability. In addition, the crystal structure of Cel5R determined at 2.2 A resolution reveals a large number of acidic residues on the surface of the protein that contribute to the halophilic nature of this enzyme. Moreover, we demonstrate that the four free and non-conserved cysteine residues (C65, C90, C231 and C273) contributes to the thermal stability of Cel5R by alanine scanning experiments. Thus, the newly identified endoglucanase Cel5R is a promising candidate for various industrial applications. PMID- 28008973 TI - Disentangling genetic and environmental risk factors for individual diseases from multiplex comorbidity networks. AB - Most disorders are caused by a combination of multiple genetic and/or environmental factors. If two diseases are caused by the same molecular mechanism, they tend to co-occur in patients. Here we provide a quantitative method to disentangle how much genetic or environmental risk factors contribute to the pathogenesis of 358 individual diseases, respectively. We pool data on genetic, pathway-based, and toxicogenomic disease-causing mechanisms with disease co-occurrence data obtained from almost two million patients. From this data we construct a multiplex network where nodes represent disorders that are connected by links that either represent phenotypic comorbidity of the patients or the involvement of a certain molecular mechanism. From the similarity of phenotypic and mechanism-based networks for each disorder we derive measure that allows us to quantify the relative importance of various molecular mechanisms for a given disease. We find that most diseases are dominated by genetic risk factors, while environmental influences prevail for disorders such as depressions, cancers, or dermatitis. Almost never we find that more than one type of mechanisms is involved in the pathogenesis of diseases. PMID- 28008974 TI - Drosophila microRNA-34 Impairs Axon Pruning of Mushroom Body gamma Neurons by Downregulating the Expression of Ecdysone Receptor. AB - MicroRNA-34 (miR-34) is crucial for preventing chronic large-scale neurite degeneration in the aged brain of Drosophila melanogaster. Here we investigated the role of miR-34 in two other types of large-scale axon degeneration in Drosophila: axotomy-induced axon degeneration in olfactory sensory neurons (OSNs) and developmentally related axon pruning in mushroom body (MB) neurons. Ectopically overexpressed miR-34 did not inhibit axon degeneration in OSNs following axotomy, whereas ectopically overexpressed miR-34 in differentiated MB neurons impaired gamma axon pruning. Intriguingly, the miR-34-induced gamma axon pruning defect resulted from downregulating the expression of ecdysone receptor B1 (EcR-B1) in differentiated MB gamma neurons. Notably, the separate overexpression of EcR-B1 or a transforming growth factor- beta receptor Baboon, whose activation can upregulate the EcR-B1 expression, in MB neurons rescued the miR-34-induced gamma axon pruning phenotype. Future investigations of miR-34 targets that regulate the expression of EcR-B1 in MB gamma neurons are warranted to elucidate pathways that regulate axon pruning, and to provide insight into mechanisms that control large-scale axon degeneration in the nervous system. PMID- 28008975 TI - Pre-conception and prenatal alcohol exposure from mothers and fathers drinking and head circumference: results from the Norwegian Mother-Child Study (MoBa). AB - Although microcephaly is a feature of Fetal Alcohol Syndrome, it is currently unknown whether low-to-moderate prenatal alcohol exposure affects head circumference. Small magnitude associations reported in observational studies are likely to be misleading due to confounding and misclassification biases. Alternative analytical approaches such as the use of family negative controls (e.g. comparing the effects of maternal and paternal exposure) could help disentangle causal effects. We investigated the association of maternal and paternal alcohol drinking before and early in pregnancy with infant head circumference, using data from 68,244 mother-father-offspring trios from the Norwegian Mother and Child Cohort Study (MoBa) (1999-2009). In analyses adjusted for potential confounders, we found no consistent pattern of association between maternal or paternal alcohol intake before or during pregnancy and offspring head circumference modelled as a continuous outcome. However, we found higher odds of microcephaly at birth for higher paternal, but not maternal, alcohol consumption before pregnancy, and similar but weaker effect estimates for first trimester drinking. Associations with paternal drinking before pregnancy were unexpected and should be regarded as hypothesis generating, until independently replicated, although potentially important given the absence of guidelines on safe drinking levels for men in couples trying for a pregnancy. PMID- 28008976 TI - Effect of high-flux, low-energy He+ ion irradiation on Ta as a plasma-facing material. AB - The goal of this work is to assess Ta as a potential plasma-facing material for future fusion reactors in terms of its response to high-flux, low-energy He+ ion irradiation. Ta samples were irradiated with 100 eV He+ ions at various fluences up to 3.5 * 1025 ions m-2 while simultaneously heated at constant temperatures in the range 823-1223 K. SEM studies show that irradiated Ta surfaces undergo significant morphology changes that have a strong dependence on both ion fluence and sample temperature. Optical reflectivity complements SEM and demonstrates a vertical growth of surface structures with increasing fluence. Ex situ XPS and XRD both show significant oxidation of the irradiated Ta surfaces, giving further qualitative information on the extent of surface modification. Overall, these irradiation-induced structures on Ta are similar to early-stage "fuzz" structures observed in W. However, Ta exhibits a higher fluence threshold for structure formation. While Ta may have less desirable bulk properties (e.g., thermal conductivity) when compared to W, its higher resilience to He+ ion-induced surface modification suggests that surface thermal and mechanical properties may not degrade as quickly in extreme fusion environments; this quality may be a redeeming factor for Ta as a plasma-facing material. PMID- 28008978 TI - Instant snapshot of the internal structure of Unzen lava dome, Japan with airborne muography. AB - An emerging elementary particle imaging technique called muography has increasingly been used to resolve the internal structures of volcanoes with a spatial resolution of less than 100 m. However, land-based muography requires several days at least to acquire satisfactory image contrast and thus, it has not been a practical tool to diagnose the erupting volcano in a real time manner. To address this issue, airborne muography was implemented for the first time, targeting Heisei-Shinzan lava dome of Unzen volcano, Japan. Obtained in 2.5 hours, the resultant image clearly showed the density contrast inside the dome, which is essential information to predict the magnitude of the dome collapse. Since airborne muography is not restricted by topographic conditions for apparatus placements, we anticipate that the technique is applicable to creating images of this type of lava dome evolution from various angles in real time. PMID- 28008977 TI - Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes. AB - Tunneling Nanotubes (TNTs) are actin enriched filopodia-like protrusions that play a pivotal role in long-range intercellular communication. Different pathogens use TNT-like structures as "freeways" to propagate across cells. TNTs are also implicated in cancer and neurodegenerative diseases, making them promising therapeutic targets. Understanding the mechanism of their formation, and their relation with filopodia is of fundamental importance to uncover their physiological function, particularly since filopodia, differently from TNTs, are not able to mediate transfer of cargo between distant cells. Here we studied different regulatory complexes of actin, which play a role in the formation of both these structures. We demonstrate that the filopodia-promoting CDC42/IRSp53/VASP network negatively regulates TNT formation and impairs TNT mediated intercellular vesicle transfer. Conversely, elevation of Eps8, an actin regulatory protein that inhibits the extension of filopodia in neurons, increases TNT formation. Notably, Eps8-mediated TNT induction requires Eps8 bundling but not its capping activity. Thus, despite their structural similarities, filopodia and TNTs form through distinct molecular mechanisms. Our results further suggest that a switch in the molecular composition in common actin regulatory complexes is critical in driving the formation of either type of membrane protrusion. PMID- 28008979 TI - Beef and coal are key drivers of Australia's high nitrogen footprint. AB - Anthropogenic release of reactive nitrogen (Nr; all species of N except N2) to the global nitrogen (N) cycle is substantial and it negatively affects human and ecosystem health. A novel metric, the N footprint, provides a consumer-based perspective for Nr use efficiency and connects lifestyle choices with Nr losses. Here we report the first full-scale assessment of the anthropogenic Nr loss by Australians. Despite its 'clean and green' image, Australia has the largest N footprint (47 kg N cap-1 yr-1) both in food and energy sectors among all countries that have used the N-Calculator model. About 69% of the Australia's N footprint is attributed to food consumption and the associated food production, with the rest from energy consumption. Beef consumption and production is the major contributor of the high food N footprint, while the heavy dependence on coal for electricity explains the large energy N footprint. Our study demonstrates opportunities for managing Nr loss and lifestyle choices to reduce the N footprint. PMID- 28008981 TI - A binder-free sulfur/reduced graphene oxide aerogel as high performance electrode materials for lithium sulfur batteries. AB - Societies' increasing need for energy storage makes it necessary to explore new concepts beyond the traditional lithium ion battery. A promising candidate is the lithium-sulfur technology with the potential to increase the energy density of the battery by a factor of 3-5. However, so far the many problems with the lithium-sulfur system have not been solved satisfactory. Here we report on a new approach utilizing a self-standing reduced graphene oxide based aerogel directly as electrodes, i.e. without further processing and without the addition of binder or conducting agents. We can thereby disrupt the common paradigm of "no battery without binder" and can pave the way to a lithium-sulfur battery with a high practical energy density. The aerogels are synthesized via a one-pot method and consist of more than 2/3 sulfur, contained inside a porous few-layered reduced graphene oxide matrix. By combining the graphene-based aerogel cathode with an electrolyte and a lithium metal anode, we demonstrate a lithium-sulfur cell with high areal capacity (more than 3 mAh/cm2 after 75 cycles), excellent capacity retention over 200 cycles and good sulfur utilization. Based on this performance we estimate that the energy density of this concept-cell can significantly exceed the Department of Energy (DEO) 2020-target set for transport applications. PMID- 28008980 TI - Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity. AB - The introduction of antiretroviral drugs (ARVd) changed the prognosis of HIV infection from a deadly disease to a chronic disease. However, even with undetectable viral loads, patients still develop a wide range of pathologies, including cerebrovascular complications and stroke. It is hypothesized that toxic side effects of ARVd may contribute to these effects. To address this notion, we evaluated the impact of several non-nucleoside reverse transcriptase inhibitors (NNRTI; Efavirenz, Etravirine, Rilpivirine and Nevirapine) on the integrity of the blood-brain barrier, and their impact on severity of stroke. Among studied drugs, Efavirenz, but not other NNRTIs, altered claudin-5 expression, increased endothelial permeability, and disrupted the blood-brain barrier integrity. Importantly, Efavirenz exposure increased the severity of stroke in a model of middle cerebral artery occlusion in mice. Taken together, these results indicate that selected ARVd can exacerbate HIV-associated cerebrovascular pathology. Therefore, careful consideration should be taken when choosing an anti-retroviral therapy regimen. PMID- 28008982 TI - Comparative study on twinning characteristics during two post-weld compression paths and their effects on joint enhancement. AB - Friction stir welding (FSW) has promising application potential in Mg alloys. However, the texture distribution in stir zone (SZ) is usually complicated for Mg alloys, which deterioriates the joint performance. In this study, the texture distribution in SZ was tailored by applying two kinds of post-weld compression deformation along normal direction (ND) or welding direction (WD) of the FSWed AZ31 Mg alloy plates. The twinning behavior and texture change in the various regions of SZ were then evaluated by electron back scatter diffraction (EBSD) characterization. The effect of texture change on the joint performance was discussed in terms of Schmid factors (SFs) for basal slip and extension twinning. The results showed that profuse extension twins were formed through the whole SZ for the sample subjected to compression along ND, whereas they were observed mainly in SZ-side for the sample compressed along WD. Most of the twins were present in the forms of twin bands or chains. The directions of the twin bands or chains were related to the habit plane traces of selected twin variants. The ND post-weld compression had better strengthening effects on the joints compared to the WD compression, and the underline mechanism was discussed. PMID- 28008983 TI - Scaffold Free Bio-orthogonal Assembly of 3-Dimensional Cardiac Tissue via Cell Surface Engineering. AB - There has been tremendous interest in constructing in vitro cardiac tissue for a range of fundamental studies of cardiac development and disease and as a commercial system to evaluate therapeutic drug discovery prioritization and toxicity. Although there has been progress towards studying 2-dimensional cardiac function in vitro, there remain challenging obstacles to generate rapid and efficient scaffold-free 3-dimensional multiple cell type co-culture cardiac tissue models. Herein, we develop a programmed rapid self-assembly strategy to induce specific and stable cell-cell contacts among multiple cell types found in heart tissue to generate 3D tissues through cell-surface engineering based on liposome delivery and fusion to display bio-orthogonal functional groups from cell membranes. We generate, for the first time, a scaffold free and stable self assembled 3 cell line co-culture 3D cardiac tissue model by assembling cardiomyocytes, endothelial cells and cardiac fibroblast cells via a rapid inter cell click ligation process. We compare and analyze the function of the 3D cardiac tissue chips with 2D co-culture monolayers by assessing cardiac specific markers, electromechanical cell coupling, beating rates and evaluating drug toxicity. PMID- 28008984 TI - Melatonin implantation improved the egg-laying rate and quality in hens past their peak egg-laying age. AB - The egg-laying rates of hens approximately 470 days of age exhibited a positive correlation to blood melatonin levels. The hens with an egg-laying rate <30%, 30~90% and >=90% had blood melatonin levels of 5.8 +/- 2.6, 74.0 +/- 32.9 and 445.9 +/- 115.3 ng/ml, respectively. When 10 mg of melatonin was implanted into the hens at 300, 360, 470 and 550 days of age, the egg-laying rates increased 4.63 +/- 0.46%, 8.38 +/- 1.45%, 4.93 +/- 0.85% and 7.93 +/- 0.91%, respectively, compared to that of the controls. Melatonin implantation in hens at 300-470 days of age was observed to enhance egg production and reduce the rate of appearance of sharpei eggs. Melatonin (10 mg) implanted in hens 360 days of age did not influence the blood levels of progesterone (P4) or the gene expression levels of ovarian follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), oestradiol receptor alpha (ERalpha), superoxide dismutase 2 (SOD2) or melatonin receptor 1 (MT1). In contrast, melatonin significantly elevated the serum oestradiol-17beta (E2) content, down-regulated the gene expression of gonadotropin-inhibitory hormone receptor (GnIHR), and enhanced the expression of melatonin receptor 2 (MT2). This result indicates that the improved egg-laying rate by melatonin was the result of increased serum oestradiol and decreased ovarian GnIHR. These alterations may be mediated by MT2 activation. PMID- 28008985 TI - An Exceptionally Facile Two-Step Structural Isomerization and Detoxication via a Water-Assisted Double Lossen Rearrangement. AB - N-hydroxyphthalimide (NHPI), which is best known as an organocatalyst for efficient C-H activation, has been found to be oxidized by quinoid compounds to its corresponding catalytically active nitroxide-radical. Here, we found that NHPI can be isomerized into isatoic anhydride by an unusually facile two-step method using tetrachloro-1,4-benzoquinone (TCBQ, p-chloranil), accompanied by a two-step hydrolytic dechlorination of highly toxic TCBQ into the much less toxic dihydroxylation product, 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid). Interestingly, through the complementary application of oxygen-18 isotope labeling, HPLC combined with electrospray ionization quadrupole time-of-flight and high resolution Fourier transform ion cyclotron resonance mass spectrometric studies, we determined that water was the source and origin of oxygen for isatoic anhydride. Based on these data, we proposed that nucleophilic attack with a subsequent water-assisted Lossen rearrangement coupled with rapid intramolecular addition and cyclization in two consecutive steps was responsible for this unusual structural isomerization of NHPI and concurrent hydroxylation/detoxication of TCBQ. This is the first report of an exceptionally facile double-isomerization of NHPI via an unprecedented water-assisted double Lossen rearrangement under normal physiological conditions. Our findings may have broad implications for future research on hydroxamic acids and polyhalogenated quinoid carcinogens, two important classes of compounds of major chemical and biological interest. PMID- 28008987 TI - A bio-enabled maximally mild layer-by-layer Kapton surface modification approach for the fabrication of all-inkjet-printed flexible electronic devices. AB - A bio-enabled, environmentally-friendly, and maximally mild layer-by-layer approach has been developed to surface modify inherently hydrophobic Kapton HN substrates to allow for great printability of both water- and organic solvent based inks thus facilitating the full-inkjet-printing of flexible electronic devices. Different from the traditional Kapton surface modification approaches which are structure-compromising and use harsh conditions to target, and oxidize and/or remove part of, the surface polyimide of Kapton, the present Kapton surface modification approach targeted the surface electric charges borne by its additive particles, and was not only the first to utilize environmentally friendly clinical biomolecules to build up a thin film of protamine-heparin complex on Kapton, but also the first to be conducted under minimally destructive and maximally mild conditions. Besides, for electrically charged ink particles, the present surface modification method can enhance the uniformity of the inkjet printed films by reducing the "coffee ring effect". As a proof-of-concept demonstration, reduced graphene oxide-based gas sensors, which were flexible, ultra-lightweight, and miniature-sized, were fully-inkjet-printed on surface modified Kapton HN films and tested for their sensitivity to dimethyl methylphosphonate (a nerve agent simulant). Such fabricated sensors survived a Scotch-tape peel test and were found insensitive to repeated bending to a small 0.5 cm radius. PMID- 28008986 TI - Inhibition of farnesyl pyrophosphate synthase improves pressure overload induced chronic cardiac remodeling. AB - Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group. 12 weeks following AAC, mice were sacrificed by cervical dislocation. Histological and echocardiographic assessments showed that inhibition of FPPS improved chronic cardiac remodeling which was induced by AAC. The reductions of Ras farnesylation and GTP-Ras, as well as their downstream extracellular signal-related kinases 1/2 (ERK1/2) expression were observed in the heart of Tg-AAC mice compared with NLC-AAC mice, along with the reduction of fetal gene expression. We provide here important experimental evidence that inhibition of FPPS improves AAC induced chronic cardiac remodeling and fibrosis by the reduction of farnesylated Ras and the downregulation of Ras-ERK1/2 pathway. PMID- 28008988 TI - Prognostic value of inflammation-based scores in patients with osteosarcoma. AB - Systemic inflammation responses have been associated with cancer development and progression. C-reactive protein (CRP), Glasgow prognostic score (GPS), neutrophil lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and neutrophil-platelet score (NPS) have been shown to be independent risk factors in various types of malignant tumors. This retrospective analysis of 162 osteosarcoma cases was performed to estimate their predictive value of survival in osteosarcoma. All statistical analyses were performed by SPSS statistical software. Receiver operating characteristic (ROC) analysis was generated to set optimal thresholds; area under the curve (AUC) was used to show the discriminatory abilities of inflammation-based scores; Kaplan-Meier analysis was performed to plot the survival curve; cox regression models were employed to determine the independent prognostic factors. The optimal cut-off points of NLR, PLR, and LMR were 2.57, 123.5 and 4.73, respectively. GPS and NLR had a markedly larger AUC than CRP, PLR and LMR. High levels of CRP, GPS, NLR, PLR, and low level of LMR were significantly associated with adverse prognosis (P < 0.05). Multivariate Cox regression analyses revealed that GPS, NLR, and occurrence of metastasis were top risk factors associated with death of osteosarcoma patients. PMID- 28008989 TI - The clinical characteristics of corticosteroid-resistant refractory Mycoplasma Pneumoniae pneumonia in children. AB - To analyze the clinical characteristics of corticosteroid-resistant refractory Mycoplasma pneumoniae pneumonia (RMPP) and explore the related factors that predict corticosteroid-resistant RMPP. Retrospective analysis of 183 children with RMPP in our hospital admitted between January 1, 2012, and December 31, 2014 was performed. Of the 183 RMPP cases, 36 (19.7%) were corticosteroid-resistant RMPP cases. Corticosteroid-resistant RMPP cases had a longer duration of fever and hospitalization compared with corticosteroid-sensitive RMPP cases (P < 0.05). The radiographic findings of 123 (83.7%) cases of corticosteroid-sensitive RMPP apparently resolved after one week of corticosteroid treatment compared with 4 (11.1%) corticosteroid-resistant RMPP cases that had apparently resolution (P < 0.01). Twenty-four (75%) corticosteroid-resistant RMPP patients who received bronchoscopy had mucus plug formation while none of the corticosteroid-sensitive RMPP patients had mucus plug formation (P < 0.05). Multiple logistic regression analysis showed that duration of fever >=11 days, percentage of lymphocytes <=32%, CRP >=48.73 mg/L and LDH >= 545.7 U/L were significant predictors of corticosteroid-resistant RMPP. Patients with corticosteroid-resistant RMPP had more severe presentations and more serious radiological findings. Clinicians might use the parameters of duration of fever, CRP, LDH and proportion of lymphocytes to identify children at higher risk of corticosteroid-resistant RMPP. PMID- 28008991 TI - Physical Interaction Is Required in Social Buffering Induced by a Familiar Conspecific. AB - In social animals, signals released from fearless conspecifics attenuate fear responses, namely social buffering. The presence of conspecific odor can suppress the expression of freezing response of conditioned mice. The present study investigated if physical social experience is required for this social buffering effect. The mice were exposed to donors, donor bedding (collected from cages of donors), or fresh bedding as control, respectively, for 10 days (1 hour daily) in prior to fear conditioning test. The fear expression test was examined in presence of donor bedding. The results showed that only the donor group mice showed reduced freezing time than the other two groups in the fear memory test. This phenomenon indicated that physical interaction might be required for the social buffering effect. PMID- 28008990 TI - Experimental immunological demyelination enhances regeneration in autograft repaired long peripheral nerve gaps. AB - Peripheral nerve long gap defects are a clinical challenge in the regeneration field. Despite the wide variety of surgical techniques and therapies, autografting is the "gold standard" for peripheral nerve gap reconstruction. The pathological process of Wallerian degeneration from the time of acute injury to efficient regeneration requires several weeks. Regeneration time is critical for nerve reconstruction. Immunological demyelination induced by anti galactocerebroside antibodies plus guinea pig complement was used to shorten the treatment time. Based on an antigen-antibody complex reaction, the demyelinating agent induced an acute and severe demyelination, leading to the pathological process of Wallerian degeneration during the demyelinating period. This method was used to treat a 12 mm-long sciatic nerve defect in rats. The control groups were injected with one of the demyelinating agent components. The results indicated that anti-galactocerebroside antibodies plus guinea pig complement can significantly shorten treatment time and promote nerve regeneration and functional recovery. In addition, the demyelinating agent can increase the mRNA levels of nerve growth factors and can regulate inflammation. In conclusion, treatment with anti-galactocerebroside antibodies plus guinea pig complement can promote axonal regeneration. This therapy provides a novel method to improve functional recovery in the treatment of long nerve defects. PMID- 28008992 TI - Acylated and desacyl ghrelin are associated with hepatic lipogenesis, beta oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats. AB - Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK activated mitochondrial FFA beta-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA beta-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA beta-oxidation and autophagy in obese rats, thereby ameliorating NAFLD. PMID- 28008993 TI - Expanding the genetic code of Salmonella with non-canonical amino acids. AB - The diversity of non-canonical amino acids (ncAAs) endows proteins with new features for a variety of biological studies and biotechnological applications. The genetic code expansion strategy, which co-translationally incorporates ncAAs into specific sites of target proteins, has been applied in many organisms. However, there have been only few studies on pathogens using genetic code expansion. Here, we introduce this technique into the human pathogen Salmonella by incorporating p-azido-phenylalanine, benzoyl-phenylalanine, acetyl-lysine, and phosphoserine into selected Salmonella proteins including a microcompartment shell protein (PduA), a type III secretion effector protein (SteA), and a metabolic enzyme (malate dehydrogenase), and demonstrate practical applications of genetic code expansion in protein labeling, photocrosslinking, and post translational modification studies in Salmonella. This work will provide powerful tools for a wide range of studies on Salmonella. PMID- 28008994 TI - Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs. PMID- 28008996 TI - The presence of Anf/Hesx1 homeobox gene in lampreys suggests that it could play an important role in emergence of telencephalon. AB - Accumulated evidence indicates that the core genetic mechanisms regulating early patterning of the brain rudiment in vertebrates are very similar to those operating during development of the anterior region of invertebrate embryos. However, the mechanisms underlying the morphological differences between the elaborate vertebrate brain and its simpler invertebrate counterpart remain poorly understood. Recently, we hypothesized that the emergence of the most anterior unit of the vertebrate brain, the telencephalon, could be related to the appearance in vertebrates' ancestors of a unique homeobox gene, Anf/Hesx1(further Anf), which is absent from all invertebrates and regulates the earliest steps of telencephalon development in vertebrates. However, the failure of Anf to be detected in one of the most basal extant vertebrate species, the lamprey, seriously compromises this hypothesis. Here, we report the cloning of Anf in three lamprey species and demonstrate that this gene is indeed expressed in embryos in the same pattern as in other vertebrates and executes the same functions by inhibiting the expression of the anterior general regulator Otx2 in favour of the telencephalic regulator FoxG1. These results are consistent with the hypothesis that the Anf homeobox gene may have been important in the evolution of the telencephalon. PMID- 28008995 TI - Impaired Function of Peripherally Induced Regulatory T Cells in Hosts at High Risk of Graft Rejection. AB - Regulatory T cells (Tregs) are crucial for allograft survival. Tregs can be divided into thymus-derived natural Tregs (tTregs) and peripherally-derived induced Tregs (pTregs). Here, we determine whether the suppressive function of Treg subsets is hampered in hosts who are at high risk for rejecting their graft. To induce graft beds that promote high risk of transplant rejection, intrastromal corneal sutures were placed two weeks prior to the transplant procedure in mice. We demonstrate that in high-risk recipients the frequencies and function of pTregs (but not tTregs) are suppressed. Reduced function of pTregs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-beta. Adoptive transfer of pTregs from mice at low risk of subsequent graft rejection is able to rescue graft survival in recipients that are at high risk of rejecting their grafts. Our data suggest that impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection. PMID- 28008997 TI - Gas entrapment and microbial N2O reduction reduce N2O emissions from a biochar amended sandy clay loam soil. AB - Nitrous oxide (N2O) is a potent greenhouse gas that is produced during microbial nitrogen transformation processes such as nitrification and denitrification. Soils represent the largest sources of N2O emissions with nitrogen fertilizer application being the main driver of rising atmospheric N2O concentrations. Soil biochar amendment has been proposed as a promising tool to mitigate N2O emissions from soils. However, the underlying processes that cause N2O emission suppression in biochar-amended soils are still poorly understood. We set up microcosm experiments with fertilized, wet soil in which we used 15N tracing techniques and quantitative polymerase chain reaction (qPCR) to investigate the impact of biochar on mineral and gaseous nitrogen dynamics and denitrification-specific functional marker gene abundance and expression. In accordance with previous studies our results showed that biochar addition can lead to a significant decrease in N2O emissions. Furthermore, we determined significantly higher quantities of soil-entrapped N2O and N2 in biochar microcosms and a biochar induced increase in typical and atypical nosZ transcript copy numbers. Our findings suggest that biochar-induced N2O emission mitigation is based on the entrapment of N2O in water-saturated pores of the soil matrix and concurrent stimulation of microbial N2O reduction resulting in an overall decrease of the N2O/(N2O + N2) ratio. PMID- 28008998 TI - Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis. AB - Pathogenesis of primary sclerosing cholangitis (PSC) may involve impaired bile acid (BA) homeostasis. We analyzed expressions of factors mediating enterohepatic circulation of BA using ileal and colonic (ascending and sigmoid) biopsies obtained from patients with PSC with and without ulcerative colitis (UC) and explanted PSC livers. Two-fold increase of BA-activated farnesoid X receptor (FXR) protein levels were seen in ascending and sigmoid colon of PSC patients with correspondingly decreased apical sodium-dependent BA transporter (ASBT) gene expression. This was associated with increased OSTbeta protein levels in each part of analyzed gut. An intestinal fibroblast growth factor (FGF19) protein expression was significantly enhanced in ascending colon. Despite increased hepatic nuclear receptors (FXR, CAR, SHP), and FGF19, neither CYP7A1 suppression nor CYP3A4 induction were observed. The lack of negative regulation of BA synthesis may be accountable for lower levels of cholesterol observed in PSC in comparison to primary biliary cholangitis (PBC). In conclusion, chronic cholestasis in PSC induces adaptive changes in expression of BA transporters and FXR in the intestine. However hepatic impairment of expected in chronic cholestasis downregulation of CYP7A1 and upregulation of CYP3A4 may promote BA induced liver injury in PSC. PMID- 28009000 TI - Sex Ratio Elasticity Influences the Selection of Sex Ratio Strategy. AB - There are three sex ratio strategies (SRS) in nature-male-biased sex ratio, female-biased sex ratio and, equal sex ratio. It was R. A. Fisher who first explained why most species in nature display a sex ratio of 1/2. Consequent SRS theories such as Hamilton's local mate competition (LMC) and Clark's local resource competition (LRC) separately explained the observed deviations from the seemingly universal 1:1 ratio. However, to the best of our knowledge, there is not yet a unified theory that accounts for the mechanisms of the three SRS. Here, we introduce the price elasticity theory in economics to define sex ratio elasticity (SRE), and present an analytical model that derives three SRSs based on the following assumption: simultaneously existing competitions for both resources A and resources B influence the level of SRE in both sexes differently. Consequently, it is the difference (between two sexes) in the level of their sex ratio elasticity that leads to three different SRS. Our analytical results demonstrate that the elasticity-based model not only reveals a highly plausible mechanism that explains the evolution of SRS in nature, but also offers a novel framework for unifying two major classical theories (i.e., LMC &LRC) in the field of SRS research. PMID- 28008999 TI - Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population. AB - Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 * 10-11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components. PMID- 28009001 TI - Real-time qPCR improves meningitis pathogen detection in invasive bacterial vaccine preventable disease surveillance in Fiji. AB - As part of the World Health Organization Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) surveillance in Suva, Fiji, cerebrospinal fluid (CSF) samples from suspected meningitis patients of all ages were examined by traditional methods (culture, Gram stain, and latex agglutination for bacterial antigen) and qPCR for Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Of 266 samples tested, pathogens were identified in 47 (17.7%). S. pneumoniae was the most common pathogen detected (n = 17) followed by N. meningitidis (n = 13). The use of qPCR significantly increased detection of IB VPD pathogens (P = 0.0001): of 35 samples that were qPCR positive for S. pneumoniae, N. meningitidis, and H. influenzae, only 10 were culture positive. This was particularly relevant for N. meningitidis, as only 1/13 cases was culture positive. Molecular serotyping by microarray was used to determine pneumococcal serotypes from 9 of 16 (56%) of samples using DNA directly extracted from CSF specimens. Results indicate that qPCR significantly increases detection of S. pneumoniae, N. meningitidis, and H. influenzae in CSF, and that application of molecular diagnostics is a feasible way to enhance local and global surveillance for IB-VPD. PMID- 28009002 TI - Circulating tumor cell detection in hepatocellular carcinoma based on karyoplasmic ratios using imaging flow cytometry. AB - Circulating tumor cells (CTCs) originate from tumor tissues and are associated with cancer prognosis. However, existing technologies for CTC detection are limited owing to a lack of specific or accurate biomarkers. Here, we developed a new method for CTC detection based on the karyoplasmic ratio, without biomarkers. Consecutive patients with liver cancer or non-cancer liver diseases were recruited. CTCs in blood samples were analyzed by imaging flow cytometry based on the karyoplasmic ratio as well as EpCAM and CD45. Microvascular invasion (MVI), tumor recurrence, and survival were recorded for all patients. A total of 56.2 +/ 23.8/100,000 cells with high karyoplasmic ratios (HKR cells) were detected in cancer patients, which was higher than the number of HKR cells in the non-cancer group (7.6 +/- 2.2/100,000). There was also a difference in HKR cells between liver cancer patients with and without MVI. Based on a receiver operating characteristic curve analysis, the threshold was 21.8 HKR cells per 100,000 peripheral blood mononuclear cells, and the area under the curve was higher than those of traditional methods (e.g., CD45 and EpCAM staining). These results indicate that the new CTC detection method was more sensitive and reliable than existing methods. Accordingly, it may improve clinical CTC detection. PMID- 28009003 TI - Acetyl-11-Keto-beta-Boswellic Acid Attenuates Prooxidant and Profibrotic Mechanisms Involving Transforming Growth Factor-beta1, and Improves Vascular Remodeling in Spontaneously Hypertensive Rats. AB - Vascular remodeling is an important complication of hypertension with oxidative stress-related profibrotic pathways involved. The transforming growth factor beta1 (TGF-beta1) has been shown to be a potential target of vasoprotection, and has multiple roles in vascular remodeling. Acetyl-11-Keto-beta-Boswellic Acid (AKBA) is one of the active principles of Boswellic acids, and shows antioxidant activity in many diseases. The study is to determine effects of AKBA on systemic oxidative stress of hypertension and vascular remodeling. In the experiments, spontaneously hypertensive rats (SHR) were used. And in vitro, fibroblast was pretreated with AKBA before Ang II stimuli. In the results, treatment of AKBA markedly reduced oxidative stress, and decreased vascular remodeling by restoring vascular wall parameters and improving vascular reactivity. AKBA dramatically reduced TGF-beta1 and Smad3 expression, as shown in immunofluorescence and immunohistochemistry. In cultured fibroblast, AKBA decreased intracellular ROS levels. Cell viability and proliferation, as well as migration were inhibited by AKBA. Additionally, treatment of AKBA significantly decreased TGF-beta1 secretion in culture supernatant. Expression of TGF-beta1, Smad3, P-Smad3 and Smad7 were also decreased by AKBA in fibroblast. In conclusion, AKBA is able to attenuate oxidative stress and profibrotic mechanisms, and improve vascular remodeling in hypertension through TGF-beta1/Smad3 pathway. PMID- 28009004 TI - Translocation of the thioesterase domain for the redesign of plipastatin synthetase. AB - Non-ribosomal peptide synthetases (NRPSs) are large enzymatic complexes that catalyse the synthesis of biologically active peptides in microorganisms. Genetic engineering has recently been applied to reprogram NRPSs to produce lipopeptides with a new sequence. The carboxyl-terminal thioesterase (TE) domains from NRPSs catalyse cleavage products by hydrolysis or complex macrocyclization. In this study, we modified plipastatin synthetase by moving the intrinsic TE region to the end of the internal thiolation (T) domains, thus generating Bacillus subtilis strains that could produce new truncated cyclic or linear peptides of the predicted sequence, which further provided an important insight into the regioselectivity of plipastatin TE. The TE was capable of recognizing and catalysing the lactone formation between L-Try3 with the last few residues L-Pro7 and L-Gln8 at the C-terminus. Additionally, the unmatched linkers connecting the TE region and T domain resulted in nonproduction strains, suggesting that the native T-TE linker is necessary and sufficient for the TE domain to release the products from the hybrid enzymes. This is the first report to demonstrate truncated cyclic lipopeptides production and module skipping by simply moving the TE domain forward in an NRPS system. PMID- 28009005 TI - Low abundance of Archaeorhizomycetes among fungi in soil metatranscriptomes. AB - The Archaeorhizomycetes are recently discovered fungi with poorly resolved ecology. Even their abundance in soil fungal communities is currently disputed. Here we applied a PCR-independent, RNA-based metatranscriptomic approach to determine their abundance among fungi in eleven different soils across Europe. Using small subunit (SSU) ribosomal RNA transcripts as marker, we detected Archaeorhizomycetes in 17 out of 28 soil metatranscriptomes. They had average relative SSU rRNA abundance of 2.0% with a maximum of 9.4% among fungal SSU rRNAs. Network analysis revealed that they co-occur with arbuscular mycorrhizal Glomerales, which is in line with their previously suggested association with plant roots. Moreover, Archaeorhizomycetes ranked among the potential keystone taxa. This metatranscriptomic survey exemplifies the usage of non-targeted molecular approaches for the study of soil fungi. It provides PCR- and DNA independent evidence for the low abundance of Archaeorhizomycetes in soil fungal communities, although they might be non-negligible players despite their low abundance. PMID- 28009006 TI - Erratum: Coding and decoding libraries of sequence-defined functional copolymers synthesized via photoligation. PMID- 28009007 TI - Shortcut to adiabatic control of soliton matter waves by tunable interaction. AB - We propose a method for shortcut to adiabatic control of soliton matter waves in harmonic traps. The tunable interaction controlled by Feshbach resonance is inversely designed to achieve fast and high-fidelity compression of soliton matter waves as compared to the conventional adiabatic compression. These results pave the way to control the nonlinear dynamics for matter waves and optical solitons by using shortcuts to adiabaticity. PMID- 28009009 TI - Bacteriophage T5 gene D10 encodes a branch-migration protein. AB - Helicases catalyze the unwinding of double-stranded nucleic acids where structure and phosphate backbone contacts, rather than nucleobase sequence, usually determines substrate specificity. We have expressed and purified a putative helicase encoded by the D10 gene of bacteriophage T5. Here we report that this hitherto uncharacterized protein possesses branch migration and DNA unwinding activity. The initiation of substrate unwinding showed some sequence dependency, while DNA binding and DNA-dependent ATPase activity did not. DNA footprinting and purine-base interference assays demonstrated that D10 engages these substrates with a defined polarity that may be established by protein-nucleobase contacts. Bioinformatic analysis of the nucleotide databases revealed genes predicted to encode proteins related to D10 in archaebacteria, bacteriophages and in viruses known to infect a range of eukaryotic organisms. PMID- 28009008 TI - Down-regulation of common NFkappaB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis. AB - Thalidomide can modulate the TNFalpha-NFkappaB and iNOS pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis. In bile duct ligated-cirrhotic rats, the increased circulating CD16+ (inflammatory) monocytes and its intracellular TNFalpha, NFkappaB, monocyte chemotactic protein (MCP-1) and iNOS levels were associated with increased circulating MCP-1/soluable intercellular cell adehesion molecule-1 (sICAM-1), pulmonary TNFalpha/NOx, up-regulated M1 polarization, exacerbated angiogenesis and hypoxemia (increased AaPO2) in bronchoalveolar lavage (BAL) fluid and pulmonary homogenates. Meanwhile, a significant correlation was noted between circulating CD16+ monocyte/M1 (%) macrophages in BAL; M1 (%) macrophages in BAL/pulmonary iNOS mRNA expression; pulmonary iNOS mRNA expression/relative pulmonary MVD; pulmonary NOx level/AaPO2; circulating CD16+ monocyte/M1 (%) macrophages in muscle homogenates; 3-nitrotyrosine (representative of peroxynitrite) concentration/M1 (%) macrophages in muscle homogenates. The in vitro data demonstrated an iNOS-dependent inhibition of thalidomide on the TNFalpha-stimulated angiogenesis and myogenesis in human pulmonary artery endothelial cells (HPAECs) and C2C12 myoblasts. Significantly, the co-culture of CD16+ monocyte from different rats with HPAECs, or co-culture of supernatant of above mixed cultures with HPAECs or C2C12 myoblasts stimulated angiogenesis, migration and myogenesis. Our findings demonstrate that TNFalpha inhibitor thalidomide markedly diminishes the severity of experimental HPS and muscle wasting by down-regulation of common peripheral and local NFkappaB-iNOS pathway. PMID- 28009011 TI - Pulsed photothermal interferometry for spectroscopic gas detection with hollow core optical fibre. AB - Gas detection with hollow-core photonic bandgap fibre (HC-PBF) and pulsed photothermal (PT) interferometry spectroscopy are studied theoretically and experimentally. A theoretical model is developed and used to compute the gas absorption-induced temperature and phase modulation in a HC-PBF filled with low concentration of C2H2 in nitrogen. The PT phase modulation dynamics for different pulse duration, peak power and energy of pump beam are numerically modelled, which are supported by the experimental results obtained around the P(9) absorption line of C2H2 at 1530.371 nm. Thermal conduction is identified as the main process responsible for the phase modulation dynamics. For a constant peak pump power level, the phase modulation is found to increase with pulse duration up to ~1.2 MUs, while it increases with decreasing pulse duration for a constant pulse energy. It is theoretically possible to achieve ppb level detection of C2H2 with ~1 m length HC-PBF and a pump beam with ~10 ns pulse duration and ~100 nJ pulse energy. PMID- 28009010 TI - Structural Insights on PHA Binding Protein PhaP from Aeromonas hydrophila. AB - Phasins or PhaPs are a group of amphiphilic proteins that are found attached to the surface of microbial polyhydroxyalkanoate (PHA) granules. They have both structural and regulatory functions and can affect intracellular PHA accumulation and mediate protein folding. The molecular basis for the diverse functions of the PhaPs has not been fully understood due to the lack of the structural knowledge. Here we report the structural and biochemical studies of the PhaP cloned from Aeromonas hydrophila (PhaPAh), which is utilized in protein and tissue engineering. The crystal structure of PhaPAh was revealed to be a tetramer with 8 alpha-helices adopting a coiled-coil structure. Each monomer has a hydrophobic and a hydrophilic surface, rendering the surfactant properties of the PhaPAh monomer. Based on the crystal structure, we predicted three key amino acid residues and obtained mutants with enhanced stability and improved emulsification properties. The first PhaP crystal structure, as reported in this study, is an important step towards a mechanistic understanding of how PHA is formed in vivo and why PhaP has such unique surfactant properties. At the same time, it will facilitate the study of other PhaP members that may have significant biotechnological potential as bio-surfactants and amphipathic coatings. PMID- 28009012 TI - Strong-field ionization of clusters using two-cycle pulses at 1.8 MUm. AB - The interaction of intense laser pulses with nanoscale particles leads to the production of high-energy electrons, ions, neutral atoms, neutrons and photons. Up to now, investigations have focused on near-infrared to X-ray laser pulses consisting of many optical cycles. Here we study strong-field ionization of rare gas clusters (103 to 105 atoms) using two-cycle 1.8 MUm laser pulses to access a new interaction regime in the limit where the electron dynamics are dominated by the laser field and the cluster atoms do not have time to move significantly. The emission of fast electrons with kinetic energies exceeding 3 keV is observed using laser pulses with a wavelength of 1.8 MUm and an intensity of 1 * 1015 W/cm2, whereas only electrons below 500 eV are observed at 800 nm using a similar intensity and pulse duration. Fast electrons are preferentially emitted along the laser polarization direction, showing that they are driven out from the cluster by the laser field. In addition to direct electron emission, an electron rescattering plateau is observed. Scaling to even longer wavelengths is expected to result in a highly directional current of energetic electrons on a few femtosecond timescale. PMID- 28009013 TI - Global microbial carbonate proliferation after the end-Devonian mass extinction: Mainly controlled by demise of skeletal bioconstructors. AB - Microbial carbonates commonly flourished following mass extinction events. The end-Devonian (Hangenberg) mass extinction event is a first-order mass extinction on the scale of the 'Big Five' extinctions. However, to date, it is still unclear whether global microbial carbonate proliferation occurred after the Hangenberg event. The earliest known Carboniferous stromatolites on tidal flats are described from intertidal environments of the lowermost Tournaisian (Qianheishan Formation) in northwestern China. With other early Tournaisian microbe-dominated bioconstructions extensively distributed on shelves, the Qianheishan stromatolites support microbial carbonate proliferation after the Hangenberg extinction. Additional support comes from quantitative analysis of the abundance of microbe-dominated bioconstructions through the Famennian and early Tournaisian, which shows that they were globally distributed (between 40 degrees latitude on both sides of the palaeoequator) and that their abundance increased distinctly in the early Tournaisian compared to the latest Devonian (Strunian). Comparison of variations in the relative abundance of skeleton- versus microbe dominated bioconstructions across the Hangenberg and 'Big Five' extinctions suggests that changes in abundance of skeletal bioconstructors may play a first order control on microbial carbonate proliferation during extinction transitions but that microbial proliferation is not a general necessary feature after mass extinctions. PMID- 28009015 TI - Neuroimmunology: Could antibodies cause psychosis? PMID- 28009014 TI - Eyeblink Synchrony in Multimodal Human-Android Interaction. AB - As the result of recent progress in technology of communication robot, robots are becoming an important social partner for humans. Behavioral synchrony is understood as an important factor in establishing good human-robot relationships. In this study, we hypothesized that biasing a human's attitude toward a robot changes the degree of synchrony between human and robot. We first examined whether eyeblinks were synchronized between a human and an android in face-to face interaction and found that human listeners' eyeblinks were entrained to android speakers' eyeblinks. This eyeblink synchrony disappeared when the android speaker spoke while looking away from the human listeners but was enhanced when the human participants listened to the speaking android while touching the android's hand. These results suggest that eyeblink synchrony reflects a qualitative state in human-robot interactions. PMID- 28009016 TI - Motor neuron disease: Nusinersen potentially effective in SMA. PMID- 28009017 TI - HbA1c as a Screening tool for Ketosis in Patients with Type 2 Diabetes Mellitus. AB - Ketosis in patients with type 2 diabetes mellitus (T2DM) is overlooked due to atypical symptoms. The objective of this study is to evaluate the value of hemoglobin A1c (HbA1c) as a screening tool for ketosis in T2DM patients. This retrospective study consisted of 253 T2DM patients with ketosis at Shanghai 10th People's Hospital during a period from January 1, 2011 to June 30, 2015. A control group consisted of 221 T2DM patients without ketosis randomly selected from inpatients during the same period. Receiver operating characteristic curve (ROC) analysis was used to examine the sensitivity and specificity of HbA1c as an indicator for ketosis. Higher HbA1c levels were correlated with ketosis. In patients with newly diagnosed T2DM, the area under the curve (AUC) was 0.832, with 95% confidence interval (CI) 0.754-0.911. The optimal threshold was 10.1% (87 mmol/mol). In patients with previously diagnosed T2DM, the AUC was 0.811 (95% CI: 0.767-0.856), with an optimal threshold of 8.6% (70 mmol/mol). HbA1c is a potential screening tool for ketosis in patients with T2DM. Ketosis is much more likely with HbA1c values at >=10.1% in patients with newly diagnosed T2DM and HbA1c values at >=8.6% in patients with previously diagnosed T2DM. PMID- 28009019 TI - Label-free, multi-scale imaging of ex-vivo mouse brain using spatial light interference microscopy. AB - Brain connectivity spans over broad spatial scales, from nanometers to centimeters. In order to understand the brain at multi-scale, the neural network in wide-field has been visualized in detail by taking advantage of light microscopy. However, the process of staining or addition of fluorescent tags is commonly required, and the image contrast is insufficient for delineation of cytoarchitecture. To overcome this barrier, we use spatial light interference microscopy to investigate brain structure with high-resolution, sub-nanometer pathlength sensitivity without the use of exogenous contrast agents. Combining wide-field imaging and a mosaic algorithm developed in-house, we show the detailed architecture of cells and myelin, within coronal olfactory bulb and cortical sections, and from sagittal sections of the hippocampus and cerebellum. Our technique is well suited to identify laminar characteristics of fiber tract orientation within white matter, e.g. the corpus callosum. To further improve the macro-scale contrast of anatomical structures, and to better differentiate axons and dendrites from cell bodies, we mapped the tissue in terms of its scattering property. Based on our results, we anticipate that spatial light interference microscopy can potentially provide multiscale and multicontrast perspectives of gross and microscopic brain anatomy. PMID- 28009018 TI - HBV/HCV dual infection impacts viral load, antibody response, and cytokine expression differently from HBV or HCV single infection. AB - Hepatitis B virus/hepatitis C virus (HBV/HCV) dual infection is common among high risk individuals. To characterize the virological and immunological features of patients with HBV/HCV dual infection, we enrolled 1,049 individuals who have been identified as injection drug users. Patients were divided into single and dual infection groups according to the serological markers. We found the average HCV RNA level was significantly lower; however, HBV viral load was significantly higher in HBV/HCV dual-infected patients (n = 42) comparing HCV single infection (n = 340) or HBV single infection (n = 136). The level of anti-HBs in patients who experienced spontaneous HBV clearance was higher than that in HCV single infected patients with HBV spontaneous clearance. The level of anti-HCV E2 in HBV/HCV dual infection was lower than that detected in HCV single infection. Serum levels of IL-6, IL-8, and TNF-alpha were significantly lower in HBV/HCV dual-infected patients than in patients infected with HBV or HCV alone. Taken together, two viral replications are imbalanced in dual infected patients. The anti-HBs and anti-HCV E2 antibody production were impaired and proinflammatory IL 6, IL-8, and TNF-alpha also downregulated due to dual infection. These findings will help further understanding the pathogenesis of HBV/HCV dual infection. PMID- 28009020 TI - The relationship of cortical folding and brain arteriovenous malformations. AB - BACKGROUND: The pathogenesis of human intracranial arteriovenous malformations (AVMs) is not well understood; this study aims to quantitatively assess cortical folding in patients with these lesions. METHODS: Seven adult participants, 4 male and 3 female, with unruptured, surgically unresectable intracranial AVMs were prospectively enrolled in the study, with a mean age of 42.1 years and Spetzler Martin grade range of II-IV. High-resolution brain MRI T1 and T2 sequences were obtained. After standard preprocessing, segmentation and registration techniques, three measures of cortical folding, the depth difference index (DDI), coordinate distance index (CDI) and gyrification index (GI)), were calculated for the affected and unaffected hemispheres of each subject as well as a healthy control subject set. RESULTS: Of the three metrics, CDI, DDI and GI, used for cortical folding assessment, none demonstrated significant differences between the participants and previously studied healthy adults. There was a significant negative correlation between the DDI ratio between affected and unaffected hemispheres and AVM volume (correlation coefficient r = -0.74, p = 0.04). CONCLUSION: This study is the first to quantitatively assess human brain cortical folding in the presence of intracranial AVMs and no significant differences between AVM-affected versus unaffected hemispheres were found in a small dataset. We suggest longitudinal, larger human MRI-based cortical folding studies to assess whether AVMs are congenital lesions of vascular development or de novo, dynamic lesions. PMID- 28009021 TI - A Trp-BODIPY cyclic peptide for fluorescence labelling of apoptotic bodies. AB - The rational design and synthesis of a Trp-BODIPY cyclic peptide for the fluorescent labelling of apoptotic bodies is described. Affinity assays, confocal microscopy and flow cytometry analysis confirmed the binding of the peptide to negatively-charged phospholipids associated with apoptosis, and its applicability for the detection and characterisation of subcellular structures released by apoptotic cells. PMID- 28009022 TI - Substituent effects on the relaxation dynamics of furan, furfural and beta furfural: a combined theoretical and experimental approach. AB - For the series furan, furfural and beta-furfural we investigated the effect of substituents and their positioning on the photoinduced relaxation dynamics in a combined theoretical and experimental approach. Using time resolved photoelectron spectroscopy with a high intensity probe pulse, we can, for the first time, follow the whole deactivation process of furan through a two photon probe signal. Using the extended 2-electron 2-orbital model [Nenov et al., J. Chem. Phys., 2011, 135, 034304] we explain the formation of one central conical intersection and predict the influence of the aldehyde group of the derivatives on its geometry. This, as well as the relaxation mechanisms from photoexcitation to the final outcome was investigated using a variety of theoretical methods. Complete active space self consistent field was used for on-the-fly calculations while complete active space perturbation theory and coupled cluster theory were used to accurately describe critical configurations. Experiment and theory show the relaxation dynamics of furfural and beta-furfural to be slowed down, and together they disclose an additional deactivation pathway, which is attributed to the nO lonepair state introduced with the aldehyde group. PMID- 28009024 TI - Doping anatase TiO2 with group V-b and VI-b transition metal atoms: a hybrid functional first-principles study. AB - We investigate the role of transition metal atoms of group V-b (V, Nb, and Ta) and VI-b (Cr, Mo, and W) as n- or p-type dopants in anatase TiO2 using thermodynamic principles and density functional theory with the Heyd-Scuseria Ernzerhof HSE06 hybrid functional. The HSE06 functional provides a realistic value for the band gap, which ensures a correct classification of dopants as shallow or deep donors or acceptors. Defect formation energies and thermodynamic transition levels are calculated taking into account the constraints imposed by the stability of TiO2 and the solubility limit of the impurities. Nb, Ta, W and Mo are identified as shallow donors. Although W provides two electrons, Nb and Ta show a considerably lower formation energy, in particular under O-poor conditions. Mo donates in principle one electron, but under specific conditions can turn into a double donor. V impurities are deep donors and Cr shows up as an amphoteric defect, thereby acting as an electron trapping center in n-type TiO2 especially under O-rich conditions. A comparison with the available experimental data yields excellent agreement. PMID- 28009023 TI - An isothermal electrochemical biosensor for the sensitive detection of microRNA based on a catalytic hairpin assembly and supersandwich amplification. AB - A novel isothermal electrochemical biosensor was proposed for the sensitive detection of microRNA (miRNA) based on the ingenious combination of the target catalyzed hairpin assembly (CHA) and supersandwich amplification strategies. Since miRNA-221 has been reported to be overexpressed in cancers and has been a potentially useful biomarker for the diagnosis of the related diseases, miRNA-221 was chosen as a model target miRNA. The target miRNA-221 triggered a toehold strand displacement assembly of the two hairpin substrates, which led to the cyclicality of the target miRNA and the CHA products. Subsequently, the CHA products hybridized with a capture probe on the electrode and the exposed stem of the CHA products was further used to propagate the supersandwich. After this, the signal probe was modified with horseradish peroxidase (HRP) to form a supersandwich multiplex HRP-DNA label, which could achieve an amplified electrochemical signal. Using the isothermal dual signal amplification strategies, miRNA-221 as low as 0.6 pM (3sigma) could be detected. In addition, this biosensor showed high selectivity and could discriminate miRNA-221 from the homologous miRNAs. Note that human miRNA from cancer cells could also be detected and the results were in excellent agreement with those obtained using qRT-PCR. Given that the biosensor avoided the introduction of nanoparticles, the limitation of using the nanoparticles was overcome. The proposed biosensor has great potential for broad applications in the field of clinical analysis. PMID- 28009025 TI - Polyelectrolyte multilayer-cushioned fluid lipid bilayers: a parachute model. AB - Lipid bilayer membranes supported on polyelectrolyte multilayers are widely used as a new biomembrane model that connects biological and artificial materials since these ultrathin polyelectrolyte supports may mimic the role of the extracellular matrix and cell skeleton in living systems. Polyelectrolyte multilayers were fabricated by a layer-by-layer self-assembly technique. A quartz crystal microbalance with dissipation was used in real time to monitor the interaction between phospholipids and polyelectrolytes in situ on a planar substrate. The surface properties of polyelectrolyte films were investigated by the measurement of contact angles and zeta potential. Phospholipid charge, buffer pH and substrate hydrophilicity were proved to be essential for vesicle adsorption, rupture, fusion and formation of continuous lipid bilayers on the polyelectrolyte multilayers. The results clearly demonstrated that only the mixture of phosphatidylcholine and phosphatidic acid (4 : 1) resulted in fluid bilayers on chitosan and alginate multilayers with chitosan as a top layer at pH 6.5. A coarse-grained molecular simulation study elucidated that the exact mechanism of the formation of fluid lipid bilayers resembles a "parachute" model. As the closest model to the real membrane, polyelectrolyte multilayer-cushioned fluid lipid bilayers can be appropriate candidates for application in biomedical fields. PMID- 28009026 TI - Modeling the active sites of Co-promoted MoS2 particles by DFT. AB - The atomic-scale structure of the Co-promoted MoS2 catalyst (CoMoS), used for hydrodesulfurization and as a potential replacement for platinum in the acidic hydrogen evolution reaction has been analyzed by modeling its sites using density functional theory and applying thermochemical corrections to account for different reaction conditions. The equilibrium structures of the edges, basal plane and corners have been found and used to obtain a picture of an ideal CoMoS nanoparticle under hydrodesulfurization and hydrogen evolution reaction conditions. Under hydrodesulfurization conditions small energy differences between structures having an additional or missing sulfur atom relative to the equilibrium structures have been observed for the edges and corners explaining their activity towards hydrodesulfurization at the atomic scale. The lack of these small energy differences at the basal plane explains why it is inert towards hydrodesulfurization. The adsorption free energy of hydrogen was calculated and used as a descriptor for qualifying each site in the context of hydrogen evolution, finding that the corner site should perform better than the edges. PMID- 28009027 TI - X-ray and molecular dynamics studies of butylammonium butanoate-water binary mixtures. AB - The nanostructural organisation of mixtures of the ionic liquid (butylammonium butanoate) and water at several mole fractions of water has been investigated using small and wide angle X-ray scattering (S-WAXS) and molecular dynamics (MD) simulations. The presence of a first sharp diffraction peak (FSDP) in the pure ionic liquid has been observed, experimentally and theoretically, suggesting the possibility of segregation of domains of different polarity in the system. With increasing dilution in water, the prepeak is shifted towards smaller Q values, and becomes very weak, while the principal peak moves towards larger Q values. These phenomena suggest the disruption of the hydrogen-bonded network of the ionic liquid, primarily through hydrogen bonding of the anion to water, a conclusion supported by MD simulations. PMID- 28009028 TI - High-speed phase-shifting common-path quantitative phase imaging with a piezoelectric actuator. AB - We present a phase-shifting quantitative phase imaging technique providing high temporal and spatial phase stability and high acquisition speed. A piezoelectric microfabricated phase modulator allows tunable modulation frequencies up to the kHz range. After assessing the quantitative phase accuracy with technical samples, we demonstrate the high acquisition rate while monitoring cellular processes at temporal scales ranging from milliseconds to hours. PMID- 28009029 TI - Living better and longer with cystic fibrosis. PMID- 28009030 TI - Long term outcome of cystic fibrosis patients with multisystem evaluation. AB - INTRODUCTION: Cystic fibrosis is a chronic disease with multiple organ involvement and chiefly results in chronic respiratory infections, pancreatic insufficiency and associated complications. The age at diagnosis, clinical presentation, rate of disease progression and prognosis is variable among patients. This study is designed to evaluate the behavior of disease to provide epidemiologic data for early recognition and proper management. MATERIAL AND METHODS: The study was designed as an active surveillance of 192 patients diagnosed with cystic fibrosis in a tertiary lung disease centre between 2008 and 2015. The diagnosis of cystic fibrosis was established in all patients accordingly to conventional criteria, including two positive sweat chloride tests and clinical signs and symptoms. Demographic, clinical and laboratory data were obtained from these patients in each hospitalization and also every follow-up visit and carefully evaluated for complications of this chronic disease. RESULTS: The majority of patients showed positive culture for Pseudomonas aeroginosa. Bronchiectasis was the most prevalent finding in chest CT scan. 44.3% of patients had been treated for allergic bronchopulmonary aspergillosis and all had sinus disease. Increased pulmonary artery pressure was observed in 40% of patients with cystic fibrosis. 33 patients died which consisted 17.1% of all the patients.The mean age of mortaliy was 18.15 year. CONCLUSIONS: The clinical outcome of cystic fibrosis is variable in different countries which may reflect environmental influences and the role of early diagnosis on long term outcomes. However, the role of early diagnosis in long-term outcomes of the disease can not be ignored. PMID- 28009032 TI - A clinic-epidemiological study of head and neck tuberculosis - a single-center experience. AB - INTRODUCTION: Extrapulmonary tuberculosis (EPTB) accounts for less than 6% of all tuberculosis (TB) cases in Poland, although in other countries (European in particular) this proportion is much higher. The study was undertaken to evaluate the clinical and epidemiological differences in patients hospitalized in one of Otolaryngology Departments in Poland during 36 years. MATERIAL AND METHODS: In a retrospective study, 71 patients were identified and divided into three groups according to the study period: I - 1978-1989 (30 patients, 42%), II - 1990-2001 (19 patients, 27%) and III - 2002-2013 (22 patients, 31% of all cases). In each case histological examination of biopsy specimens was available. RESULTS: Larynx TB (54.9%) was most common, followed by cervical lymph nodes TB (29.6%) and auris TB (8.5%). In laryngeal TB, glottic region was most often affected (76.9%). Patients with larynx TB were mainly men (87.2%), 10 years older than women in each study period. However, in lymph nodes TB group, women constituted 66.7% of cases and were twice as old as men (64.0 vs. 34.7 yrs). Bacteriological confirmation was made in only one patient. CONCLUSIONS: The number of patients diagnosed in our center declined in the first period of 12 years and remained stable over the last 24 years, as were the common sites of head and neck EPTB (larynx and cervical lymph nodes). In patients with head and neck TB the biopsy specimens should be examined not only histologically but also for the presence of Mycobacterium tuberculosis. PMID- 28009031 TI - Contemporary national trends of cystic fibrosis hospitalizations and co morbidities in the United States. AB - INTRODUCTION: Cystic fibrosis (CF) is a life-limiting multisystemic genetic disease. Patients with CF have a high rate of hospitalization. We attempt to ascertain national trends of inpatient stays, prevalence of various co morbidities during hospitalizations, outcomes and discharge disposition among CF patients. MATERIAL AND METHODS: Data from the National Inpatient Sample (NIS) was used to identify all hospitalizations of patients with CF and their demographic characteristics from 2003 to 2013. Prevalence and effects of various co morbidities like acute kidney injury (AKI) were determined. Detailed sub-group analysis was performed for individuals with lung transplant. RESULTS: The annual rate of hospitalization per 1,000 CF patients in the U.S. increased from 994 in 2003 to 1,072 in 2013. The overall in-hospital mortality was 1.5%; median age at death was 27 years. In-hospital mortality trended down from 1.9% to 1.2% from 2003 to 2013 (p-value for trend: 0.002). The median length of stay was 7 days. The prevalence of chronic liver disease and AKI was 3.7% and 3.8% respectively. Multivariate adjusted odds of mortality for AKI was 1.74 (95% CI 1.57-1.93, p < 0.001). Patients with prior lung transplantation accounted for 6.5% of hospitalizations. These patients had a significantly higher prevalence of AKI. CONCLUSIONS: The annual hospitalization rates of CF patients is increasing over the years. Females with CF constitute a higher proportion of hospitalized patients despite a higher male preponderance of males with CF in the community. AKI is associated with a significantly higher in-hospital mortality. Lung transplant recipients have a higher prevalence of AKI and mortality. PMID- 28009033 TI - Pain management in lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. Not only burdened by the limited overall survival, lung cancer patient also suffer from various symptoms, such as pain, that implicated in the quality of life. Cancer pain is a complicated and transiently dynamic symptom that results from multiple mechanisms. This review will describe the pathophysiology of cancer pain and general approach in managing a patient with lung cancer pain. The use of opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant analgesia, as part of the pharmacology therapy along with interventional strategy, will also be discussed. PMID- 28009034 TI - Fire-eater's lung. AB - Fire eater's lung (FEL) is an acute hydrocarbon pneumonitis caused by aspiration or inhalation into airways of liquid hydrocarbons. This disorder is classified into distinct form of chemical toxic pneumonitis. An amateur fire-eater is presented in this work. He accidentally aspirated into airways about 1/3 of glass of grill lighter fluid composed of mixture of liquid hydrocarbons. A few hours after this incident he had severe symptoms like weakness, high temperature, midsternal pleuritic chest pain, myalgia of the back, shortness of breath, and dry cough. Radiologic examination revealed consolidations with well-defined cavitary lesions (pneumatoceles) in lower lobes mainly in the left lower lobe. After one week of this event clinical improvement was observed. The lesions resolved nearly completly during three months. The review of the literature connected with fire-eater's lung is also presented. PMID- 28009035 TI - Unilateral hypertransparency on chest radiograph: the congenital Poland Syndrome. AB - Unilateral hypertransparent hemithorax requires a particular diagnostic approach as it can be the result of diverse pulmonary diseases, including pneumothorax, large pulmonary embolus, unilateral large bullae, mucous plag, airway obstruction and contralateral pleural effusion. Congenital syndromes with chest wall abnormalities, are rare, but often underdiagnosed causes. Poland Syndrome consists of such a rare, congenital anomaly and is characterized by the absence of the pectoralis major muscle and upper limb ipsilateral abnormalities. We present a case of a patient with acute exacerbation of chronic obstructive pulmonary disease (COPD) and a unilateral hypertransparency on chest radiology, attributed to the underlying Poland Syndrome. PMID- 28009037 TI - [2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS]. PMID- 28009038 TI - Stenosis, more than critical, of the left main coronary artery in an asymptomatic patient. PMID- 28009039 TI - Restenosis of the sole patent internal carotid artery. PMID- 28009040 TI - Bilateral, progressive coronary ostial stenosis following valve sparing aortic root replacement. PMID- 28009041 TI - Left ventricle assist device supported rotational atherectomy of the highly calcified last remaining vessel in a patient with acute myocardial infarction and reduced left ventricular function. PMID- 28009042 TI - Obituary: Robert Wald Sussman (1941-2016). PMID- 28009043 TI - Temperature-dependent molecular dynamics study reveals an ionic liquid induced 310 - to alpha-helical switch in a neurotoxin. AB - Thermal melting and recooling of AuIB, a neurotoxic conopeptide and a highly potent nonaddictive pain reliever is investigated thoroughly in water and an ionic liquid (IL) 1-butyl-3-methylimidazolium Chloride, [Im41 ][Cl] by classical molecular dynamics simulations. Structural evolution of AuIB in water and the IL is observed at different temperatures between 305 and 400 K, to explore how highly viscous ionic solvents affect the peptide structure as compared to conventional solvent water. At 305 K, unlike water, the coercive effect of IL frustrates AuIB secondary structural motifs significantly. As the temperature is raised, a very interesting IL induced conformational transition from 310 - to alpha-helix is noticed in the peptide, presumably triggered by a significant restructuring of the peptide H-bond network. The backbone length distributions of the peptide indicate that the IL induced conformational switching is accompanied by a reduction of the axial rise of the helical region, encompassing the residues Pro-6 to Ala-10. Further, we estimated the void space available to the peptide for its structural relaxation within the first solvation shell of ~5 A in water as well as in IL. A temperature increase by 100 K, opens up an estimated void volume of ~70 A3 , equivalent to the volume of approximately six water molecules, around the peptide in IL. Cooling simulations of AuIB point to the crucial interplay between thermodynamically favored AuIB conformers and their kinetic control. This study provides a comprehensive understanding of the ionic solvation of biomolecules reinforcing previous experimental findings. PMID- 28009044 TI - Disease-Concordant Twins Empower Genetic Association Studies. AB - Genome-wide association studies with moderate sample sizes are underpowered, especially when testing SNP alleles with low allele counts, a situation that may lead to high frequency of false-positive results and lack of replication in independent studies. Related individuals, such as twin pairs concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient population. Simulation was done by assigning various allele frequencies and allelic relative risks for different mode of genetic inheritance. In general, for achieving a power estimate of 80%, the sample sizes needed for dizygotic and monozygotic twin cases were one half and one fourth of the sample size of an ordinary case-control design, with variations depending on genetic mode. Importantly, the enriched power for dizygotic twins also applies to disease-concordant sibling pairs, which largely extends the application of the concordant twin design. Overall, our simulation revealed a high value of disease-concordant twins in genetic association studies and encourages the use of genetically related individuals for highly efficiently identifying both common and rare genetic variants underlying human complex diseases without increasing laboratory cost. PMID- 28009045 TI - Natural selection and type 2 diabetes-associated mortality in an isolated indigenous community in the valley of Oaxaca, southern Mexico. AB - OBJECTIVE: This study tests the hypothesis that natural selection is associated with type 2 diabetes (T2D)-associated mortality and fertility in a rural isolated Zapotec community in the Valley of Oaxaca, southern Mexico. PARTICIPANTS AND METHODS: Mortality data and related demographic and genealogic information were linked with data for fertility, prereproductive mortality and family history of mortality attributed to T2D. Physician verified T2D mortality (n = 27) between 1980 and 2009 and imputed T2D (n = 70) from cardiovascular mortality (68% random sample) and renal failure (44% random sample). Bootstrapping was used to obtain a robust variance estimate in survival analysis and multivariate analysis of variance. RESULTS: Estimated maximum natural selection by Crow's Index occurred circa 1930 and was relaxed after this time in the study population. Cox regression survival analysis of T2D mortality with covariates (family history of T2D, cardiovascular disease, renal failure) indicated a significant hazard ratio (HR = 5.95, 95% CI: 1.38-25.67, p < .008) for the increase in T2D in 2000 to 2009. Survival analysis of imputed T2D resulted in a significant HR of 2.03 (95% CI: 1.08-3.85, p = .01) for the increase in T2D in the 2000 to 2009 cohort (reference group: 1980-1989). Mean number of live born offspring was lower among T2D (n = 27, 4.04 +/- 3.85 SD) compared to non-T2D (n = 199, 5.30 +/- 3.48) groups (p < .08). Mean number of live born offspring was lower (p = .003) among imputed T2D compared to non-T2D groups (4.10 +/- 3.44 vs. 5.62 + 3.50). DISCUSSION: T2D-associated mortality increased in frequency as natural selection decreased, and favored offspring survival of non-T2D descedants. The results indicated statistically significant directional selection against T2D and imputed T2D to this population isolate. PMID- 28009046 TI - Single-step purification of cyclotides using affinity chromatography. AB - Cyclotides are considered promising scaffolds for drug development owing to their inherent host defence activities and highly stable structure, defined by the cyclic cystine knot. These proteins are expressed as complex mixtures in plants. Although several methods have been developed for their isolation and analysis, purification of cyclotides is still a lengthy process. Here, we describe the use of affinity chromatography for the purification of cyclotides using polyclonal IgG antibodies raised in rabbits against cycloviolacin O2 and immobilized on NHS activated Sepharose columns. Cycloviolacin O2 was used as a model substance to evaluate the chromatographic principle, first as a pure compound and then in combination with other cyclotides, that is, bracelet cyclotide cycloviolacin O19 and Mobius cyclotide kalata B1, and in a plant extract. We demonstrate that single-step purification of cyclotides by affinity chromatography is possible but cross reactivity may occur between homologue cyclotides of the bracelet subfamily. PMID- 28009048 TI - Management of drooling in neurological disabilities: more evidence is needed. PMID- 28009047 TI - Longitudinal monitoring of gene expression in ultra-low-volume blood samples self collected at home. AB - Blood transcriptional profiles could serve as biomarkers of clinical changes in subjects at-risk for or diagnosed with diabetes. However, transcriptional variation over time is poorly understood due to the impracticality of frequent longitudinal phlebotomy in large patient cohorts. We have developed a novel transcriptome assessment method that could be applied to fingerstick blood samples self-collected by study volunteers. Fifteen MUL of blood from a fingerstick yielded sufficient RNA to analyse > 176 transcripts by high throughput quantitative polymerase chain reaction (PCR). We enrolled 13 subjects with type 1 diabetes and 14 controls to perform weekly collections at home for a period of 6 months. Subjects returned an average of 24 of 26 total weekly samples, and transcript data were obtained successfully for > 99% of samples returned. A high degree of correlation between fingerstick data and data from a standard 3 mL venipuncture sample was observed. Increases in interferon stimulated gene expression were associated with self-reported respiratory infections, indicating that real-world transcriptional changes can be detected using this assay. In summary, we show that longitudinal monitoring of gene expression is feasible using ultra-low-volume blood samples self-collected by study participants at home, and can be used to monitor changes in gene expression frequently over extended periods. PMID- 28009049 TI - Zebrafish adult pigment stem cells are multipotent and form pigment cells by a progressive fate restriction process: Clonal analysis identifies shared origin of all pigment cell types. AB - Skin pigment pattern formation is a paradigmatic example of pattern formation. In zebrafish, the adult body stripes are generated by coordinated rearrangement of three distinct pigment cell-types, black melanocytes, shiny iridophores and yellow xanthophores. A stem cell origin of melanocytes and iridophores has been proposed although the potency of those stem cells has remained unclear. Xanthophores, however, seemed to originate predominantly from proliferation of embryonic xanthophores. Now, data from Singh et al. shows that all three cell types derive from shared stem cells, and that these cells generate peripheral neural cell-types too. Furthermore, clonal compositions are best explained by a progressive fate restriction model generating the individual cell-types. The numbers of adult pigment stem cells associated with the dorsal root ganglia remain low, but progenitor numbers increase significantly during larval development up to metamorphosis, likely via production of partially restricted progenitors on the spinal nerves. PMID- 28009050 TI - Factors influencing micronutrient bioavailability in biofortified crops. AB - Dietary and human factors have been found to be the major factors influencing the bioavailability of micronutrients, such as provitamin A carotenoid (pVAC), iron, and zinc, in biofortified crops. Dietary factors are related to food matrix structure and composition. Processing can improve pVAC bioavailability by disrupting the food matrix but can also result in carotenoid losses. By degrading antinutrients, such as phytate, processing can also enhance mineral bioavailability. In in vivo interventions, biofortified crops have been shown to be overall efficacious in reducing micronutrient deficiency, with bioconversion factors varying between 2.3:1 and 10.4:1 for trans-beta-carotene and amounts of iron and zinc absorbed varying between 0.7 and 1.1 mg/day and 1.1 and 2.1 mg/day, respectively. Micronutrient bioavailability was dependent on the crop type and the presence of fat for pVACs and on antinutrients for minerals. In addition to dietary factors, human factors, such as inflammation and disease, can affect micronutrient status. Understanding the interactions between micronutrients is also essential, for example, the synergic effect of iron and pVACs or the competitive effect of iron and zinc. Future efficacy trials should consider human status and genetic polymorphisms linked to interindividual variations. PMID- 28009051 TI - A brief primer on genomic epidemiology: lessons learned from Mycobacterium tuberculosis. AB - Genomics is now firmly established as a technique for the investigation and reconstruction of communicable disease outbreaks, with many genomic epidemiology studies focusing on revealing transmission routes of Mycobacterium tuberculosis. In this primer, we introduce the basic techniques underlying transmission inference from genomic data, using illustrative examples from M. tuberculosis and other pathogens routinely sequenced by public health agencies. We describe the laboratory and epidemiological scenarios under which genomics may or may not be used, provide an introduction to sequencing technologies and bioinformatics approaches to identifying transmission-informative variation and resistance associated mutations, and discuss how variation must be considered in the light of available clinical and epidemiological information to infer transmission. PMID- 28009052 TI - Non-pharmacological interventions for alleviating pain during orthodontic treatment. AB - BACKGROUND: Pain is prevalent during orthodontics, particularly during the early stages of treatment. To ensure patient comfort and compliance during treatment, the prevention or management of pain is of major importance. While pharmacological means are the first line of treatment for alleviation of orthodontic pain, a range of non-pharmacological approaches have been proposed recently as viable alternatives. OBJECTIVES: To assess the effects of non pharmacological interventions to alleviate pain associated with orthodontic treatment. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 6 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 9), MEDLINE Ovid (1946 to 6 October 2016), Embase Ovid (1980 to 6 October 2016) and EThOS (to 6 October 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a non-pharmacological orthodontic pain intervention to a placebo, no intervention or another non-pharmacological pain intervention were eligible for inclusion. We included any type of orthodontic treatment but excluded trials involving the use of pre-emptive analgesia or pain relief following orthognathic (jaw) surgery or dental extractions in combination with orthodontic treatment. We excluded split-mouth trials (in which each participant receives two or more treatments, each to a separate section of the mouth) and cross-over trials. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed risk of bias and extracted data. We used the random-effects model and expressed results as mean differences (MD) with 95% confidence intervals (CI). We investigated heterogeneity with reference to both clinical and methodological factors. MAIN RESULTS: We included 14 RCTs that randomised 931 participants. Interventions assessed included: low-level laser therapy (LLLT) (4 studies); vibratory devices (5 studies); chewing adjuncts (3 studies); brain wave music or cognitive behavioural therapy (1 study) and post-treatment communication in the form of a text message (1 study). Twelve studies involved self-report assessment of pain on a continuous scale and two studies used questionnaires to assess the nature, intensity and location of pain.We combined data from two studies involving 118 participants, which provided low-quality evidence that LLLT reduced pain at 24 hours by 20.27 mm (95% CI -24.50 to -16.04, P < 0.001; I2 = 0%). LLLT also appeared to reduce pain at six hours, three days and seven days.Results for the other comparisons assessed are inconclusive as the quality of the evidence was very low. Vibratory devices were assessed in five studies (272 participants), four of which were at high risk of bias and one unclear. Chewing adjuncts (chewing gum or a bite wafer) were evaluated in three studies (181 participants); two studies were at high risk of bias and one was unclear. Brain wave music and cognitive behavioural therapy were evaluated in one trial (36 participants) assessed at unclear risk of bias. Post-treatment text messaging (39 participants) was evaluated in one study assessed at high risk of bias.Adverse effects were not measured in any of the studies. AUTHORS' CONCLUSIONS: Overall, the results are inconclusive. Although available evidence suggests laser irradiation may help reduce pain during orthodontic treatment in the short term, this evidence is of low quality and therefore we cannot rely on the findings. Evidence for other non pharmacological interventions is either very low quality or entirely lacking. Further prospective research is required to address the lack of reliable evidence concerning the effectiveness of a range of non-pharmacological interventions to manage orthodontic pain. Future studies should use prolonged follow-up and should measure costs and possible harms. PMID- 28009053 TI - The Role of Behavioral Responses in the Total Economic Consequences of Terrorist Attacks on U.S. Air Travel Targets. AB - U.S. airports and airliners are prime terrorist targets. Not only do the facilities and equipment represent high-value assets, but the fear and dread that is spread by such attacks can have tremendous effects on the U.S. economy. This article presents the methodology, data, and estimates of the macroeconomic impacts stemming from behavioral responses to a simulated terrorist attack on a U.S. airport and on a domestic airliner. The analysis is based on risk-perception surveys of these two scenarios. The responses relate to reduced demand for airline travel, shifts to other modes, spending on nontravel items, and savings of potential travel expenditures by U.S. resident passengers considering flying domestic routes. We translate these responses to individual spending categories and feed these direct impact results into a computable general equilibrium (CGE) model of the U.S. economy to ascertain the indirect and total impacts on both the airline industry and the economy as a whole. Overall, the estimated impacts on GDP of both types of attacks exceed $10B. We find that the behavioral economic impacts are almost an order of magnitude higher than the ordinary business interruption impacts for the airliner attack and nearly two orders of magnitude higher for the airport attack. The results are robust to sensitivity tests on the travel behavior of U.S. residents in response to terrorism. PMID- 28009054 TI - New icing media for quality enhancement of chilled hake (Merluccius merluccius) using a jumbo squid (Dosidicus gigas) skin extract. AB - BACKGROUND: An advanced strategy for chilled fish preservation, based on the inclusion in ice of an extract of jumbo squid (Dosidicus gigas) skin (JSS), is proposed. Aqueous solutions including acetic acid-ethanol extracts of JSS were tested at two different concentrations as icing media, with the effects on the quality evolution of chilled hake (Merluccius merluccius) being monitored. RESULTS: A significant inhibition (P < 0.05) of microbial activity (aerobes, psychrotrophs, Enterobacteriaceae, proteolytic bacteria; pH, trimethylamine) was obtained in hake corresponding to the icing batch including the highest JSS concentration. Additionally, fish specimens from such icing conditions showed an inhibitory effect (P < 0.05) on lipid hydrolysis development, while no effect (P > 0.05) was depicted for lipid oxidation. Sensory analysis (skin and mucus development; eyes; gills; texture; external odour; raw and cooked flesh odour; flesh taste) indicated a shelf life extension of chilled hake stored in ice including the highest JSS concentration. CONCLUSION: A profitable use of JSS, an industrial by-product during jumbo squid commercialisation, has been developed in the present work, which leads to a remarkable microbial inhibition and a significant shelf life extension of chilled hake. In agreement with previous research, ommochrome pigments (i.e. lipophilic-type compounds) would be considered responsible for this preservative effect. (c) 2016 Society of Chemical Industry. PMID- 28009055 TI - Life history evolution, reproduction, and the origins of sex-dependent aging and longevity. AB - Males and females in many species differ in how they age and how long they live. These differences have motivated much research, concerning both their evolution and the underlying mechanisms that cause them. We review how differences in male and female life histories have evolved to shape patterns of aging and some of the mechanisms and pathways involved. We pay particular attention to three areas where considerable potential for synergy between mechanistic and evolutionary research exists: (1) the role of estrogens, androgens, the growth hormone/insulin like growth factor 1 pathway, and the mechanistic target of rapamycin signaling pathway in sex-dependent growth and reproduction; (2) sexual conflict over mating rate and fertility, and how mate presence or mating can become an avenue for males and females to directly affect each other's life span; and (3) the link between dietary restriction and aging, and the emerging understanding that only the restriction of certain nutrients is involved and that this is linked to reproduction. We suggest that ideas about life histories, sex-dependent selection, and sexual conflict can inform and be informed by the ever more refined and complex understanding of the mechanisms that cause aging. PMID- 28009056 TI - Guidelines for the use of platelet transfusions. PMID- 28009057 TI - Indole: An evolutionarily conserved influencer of behavior across kingdoms. AB - Indole is a key environmental cue that is used by many organisms. Based on its biochemistry, we suggest indole is used so universally, and by such different organisms, because it derives from the metabolism of tryptophan, a resource essential for many species yet rare in nature. These properties make it a valuable, environmental cue for resources almost universally important for promoting fitness. We then describe how indole is used to coordinate actions within organisms, to influence the behavior of conspecifics and can even be used to change the behavior of species that belong to other kingdoms. Drawing on the evolutionary framework that has been developed for understanding animal communication, we show how this is diversely achieved by indole acting as a cue, a manipulative signal, and an honest signal, as well as how indole can be used synergistically to amplify information conveyed by other molecules. Clarifying these distinct functions of indole identifies patterns that transcend different kingdoms of organisms. PMID- 28009058 TI - The Health, Functioning and Wellbeing Summary Traffic Light Communication Tool: a survey of families' views. AB - AIM: To ascertain families' views about the utility of the Health, Functioning and Wellbeing Summary (HFWS) in positively supporting communication in clinics. METHOD: The HFWS was co-developed with families and members of the multidisciplinary team. A sequential convenience sample of 60 families who attended clinics in Sunderland, UK in 2015 agreed to participate and answered eight questions about their views on the tool's usefulness. Data were recorded and analysed in Microsoft Excel. RESULTS: All families agreed that they had been able to discuss everything they had wanted to discuss with the doctor. All of the serious concerns that they had recorded on the HFWS had been addressed in the consultation. Most (58 out of 60; 97%) reported that the tool was easy to understand and complete, and 57 out of 60 (95%) reported that it helped them to gather their thoughts about what they wanted to discuss. Consultations that used the tool were thought to better address the needs of 49 out of 60 families (87.1%), than those in which it was not used. INTERPRETATION: The HFWS was acceptable to most families surveyed, improved communication from their perspective, and ensured that the issues that mattered most to them were addressed in medical consultations. The tool has been translated into a number of other languages. Its acceptability and utility in other settings requires further study. PMID- 28009059 TI - Production of d-allulose from d-glucose by Escherichia coli transformant cells co expressing d-glucose isomerase and d-psicose 3-epimerase genes. AB - BACKGROUND: d-Allulose is a novel and low-calorie rare monosaccharide that is a C 3 epimer of d-fructose. Because of its excellent physiological properties and commercial potential, d-allulose has attracted researchers' interests. Based on the Izumoring strategy, d-allulose is converted from d-fructose by d-psicose 3 epimerase (DPEase), while d-fructose is converted from d-glucose by d-glucose isomerase (GIase). In this study, we created a cellular system capable of converting d-glucose to d-allulose in a one-step process that co-expressed the GIase from Acidothermus cellulolyticus and the DPEase from Dorea sp. CAG. RESULTS: The co-expression plasmid pETDuet-Dosp-DPE/Acce-GI was generated and transformed into Escherichia coli BL21(DE3) cells. The recombinant co-expression cells exhibited maximum catalytic activity at pH 6.5 and 75 degrees C. These cells were thermostable at less than 60 degrees C. The addition of Co2+ significantly increased the catalytic activity by 10.8-fold. When the reaction equilibrium was reached, the ratio of d-glucose, d-fructose and d-allulose was approximately 6.5:7:3, respectively. CONCLUSION: A recombinant co-expression strain that catalysed the bioconversion of d-allulose from d-glucose in a one step process was created and characterised. When adding 500 g L-1 d-glucose as a substrate, 204.3 g L-1 d-fructose and 89.1 g L-1 d-allulose were produced. (c) 2016 Society of Chemical Industry. PMID- 28009060 TI - Identifying people at higher risk of melanoma across the U.K.: a primary-care based electronic survey. AB - BACKGROUND: Melanoma incidence is rising rapidly worldwide among white populations. Defining higher-risk populations using risk prediction models may help targeted screening and early detection approaches. OBJECTIVES: To assess the feasibility of identifying people at higher risk of melanoma using the Williams self-assessed clinical risk estimation model in U.K. primary care. METHODS: We recruited participants from the waiting rooms of 22 general practices covering a total population of > 240 000 in three U.K. regions: Eastern England, North East Scotland and North Wales. Participants completed an electronic questionnaire using tablet computers. The main outcome was the mean melanoma risk score using the Williams melanoma risk model. RESULTS: Of 9004 people approached, 7742 (86%) completed the electronic questionnaire. The mean melanoma risk score for the 7566 eligible participants was 17.15 +/- 8.51, with small regional differences [lower in England compared with Scotland (P = 0.001) and Wales (P < 0.001), mainly due to greater freckling and childhood sunburn among Scottish and Welsh participants]. After weighting to the age and sex distribution, different potential cut-offs would allow between 4% and 20% of the population to be identified as higher risk, and those groups would contain 30% and 60%, respectively of those likely to develop melanoma. CONCLUSIONS: Collecting data on the melanoma risk profile of the general population in U.K. primary care is both feasible and acceptable for patients in a general practice setting, and provides opportunities for new methods of real-time risk assessment and risk stratified cancer interventions. PMID- 28009061 TI - Intra-surgical vs. radiographic bone level assessments in measuring peri-implant bone loss. AB - OBJECTIVE: To evaluate the accuracy between the intra-surgical and the peri apical radiographic measurements of bone loss at implant with peri-implantitis. MATERIALS AND METHODS: A total of 46 Branemark implants in 24 patients with diagnosis of peri-implantitis were included in the study. The amount of peri implant bone loss occurred at those implants was measured during peri-implant surgery and compared to the radiographic bone loss measured by three independent examiners. RESULTS: The mean bone loss measured on radiographs underestimated the intra-surgical bone loss at the correspondent sites (0.7 mm at the mesial and 0.6 mm at the distal sites); this underestimation was found to be a consistent finding in all the three examiners. Only 21% of the radiographic measurements corresponded to the clinical bone loss assessments, while an over- and underestimation within a range of +/- 1-2 mm was recorded in 57% of the cases. There was a moderate positive linear correlation between the radiographic measurements and the clinical bone loss for mesial and distal sites (r = range 0.58-0.65). The variability between the three examiners in the radiographic measurements was frequently on the range of +/- 1-2 mm. CONCLUSION: The radiographic measurements of bone loss at implant affected by peri-implantitis often underestimated the clinical bone loss occurred at the implants. A difference of about +/- 1-2 mm in the estimation of radiographic bone loss could be merely assigned as inter-examiner different assessments. PMID- 28009062 TI - Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model. AB - OBJECTIVES: Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. METHODS: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum. RESULTS: Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G-CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine-induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease-related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury. INTERPRETATION: These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212-226. PMID- 28009064 TI - Preparation of Tremorine and Gemini Surfactant Precursors with Cationic Ethynyl Bridged Digold Catalysts. AB - Tremorine and precursors of gemini surfactants were synthesised in a one-pot, three-step, double-catalytic A3 coupling reaction and characterised by structural and spectroscopic methods. The cationic [AuI (L1)]SbF6 complex is a more active catalyst compared to neutral L2- and L3-AuI bis(trifluoromethanesulfonyl)imidate complexes (L1, L2=Buchwald-type biaryl phosphane; L3=triphenylphosphine) in promoting the double A3 coupling of ethynyltrimethylsilane, secondary amines (cyclic, aliphatic, or aromatic) and formaldehyde. The solvent influences the catalytic performance by desilylation of silyl acetylene or deactivation of the catalyst by a halide anion. Acetylide-bridged cationic digold(I) L1 and L2 complexes were isolated and characterised by means of single-crystal X-ray structure analysis and their spectroscopic properties. Iodine in the acetylene reagent deactivates the AuI catalyst by formation of the less active iodido bridged cationic digold(I) L1 complex, which was fully characterised by single crystal X-ray crystal structure analysis and spectroscopy. The nature of the phosphine ligand of the gold complexes used as catalyst affects the stability and activity of the formed cationic ethynyl-bridged AuI2 -L intermediates, isolation of which lends support to the proposed double A3 coupling mechanism. PMID- 28009063 TI - Lesions causing freezing of gait localize to a cerebellar functional network. AB - OBJECTIVE: Freezing of gait is a disabling symptom in Parkinson disease and related disorders, but the brain regions involved in symptom generation remain unclear. Here we analyze brain lesions causing acute onset freezing of gait to identify regions causally involved in symptom generation. METHODS: Fourteen cases of lesion-induced freezing of gait were identified from the literature, and lesions were mapped to a common brain atlas. Because lesion-induced symptoms can come from sites connected to the lesion location, not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has been recently shown to identify regions involved in symptom generation across a variety of lesion induced disorders. RESULTS: Lesion location was heterogeneous, and no single region could be considered necessary for symptom generation. However, > 90% (13 of 14) of lesions were functionally connected to a focal area in the dorsal medial cerebellum. This cerebellar area overlapped previously recognized regions that are activated by locomotor tasks, termed the cerebellar locomotor region. Connectivity to this region was specific to lesions causing freezing of gait compared to lesions causing other movement disorders (hemichorea or asterixis). INTERPRETATION: Lesions causing freezing of gait are located within a common functional network characterized by connectivity to the cerebellar locomotor region. These results based on causal brain lesions complement prior neuroimaging studies in Parkinson disease patients, advancing our understanding of the brain regions involved in freezing of gait. ANN NEUROL 2017;81:129-141. PMID- 28009065 TI - A Very Short Be-Be Distance but No Bond: Synthesis and Bonding Analysis of Ng-Be2 O2 -Ng' (Ng, Ng'=Ne, Ar, Kr, Xe). AB - Short interatomic distances below standard values for a single bond are usually identified with double or triple bonds. The synthesis and spectroscopic characterization of a molecule is reported where the distance between two beryllium atoms is shorter than a standard double bond but there is no bond. The cyclic diberyllium dioxide Be2 O2 molecule, which is coordinated by two noble gas atoms in Ng-Be2 O2 -Ng' (Ng, Ng'=Ne, Ar, Kr, Xe) was isolated and spectroscopically identified in low-temperature matrices. The complexes possess very short Be-Be distances, but the analysis of the electronic structure reveals that there is no chemical bond. PMID- 28009066 TI - Concise Review: Amniotic Fluid Stem Cells: The Known, the Unknown, and Potential Regenerative Medicine Applications. AB - The amniotic fluid has been identified as an untapped source of cells with broad potential, which possess immunomodulatory properties and do not have the ethical and legal limitations of embryonic stem cells. CD117(c-Kit)+ cells selected from amniotic fluid have been shown to differentiate into cell lineages representing all three embryonic germ layers without generating tumors, making them ideal candidates for regenerative medicine applications. Moreover, their ability to engraft in injured organs and modulate immune and repair responses of host tissues, suggest that transplantation of such cells may be useful for the treatment of various degenerative and inflammatory diseases. Although significant questions remain regarding the origin, heterogeneous phenotype, and expansion potential of amniotic fluid stem cells, evidence to date supports their potential role as a valuable stem cell source for the field of regenerative medicine. Stem Cells 2017;35:1663-1673. PMID- 28009067 TI - Prioritization of polysaccharide utilization and control of regulator activation in Bacteroides thetaiotaomicron. AB - Bacteroides thetaiotaomicron is a human gut symbiotic bacterium that utilizes a myriad of host dietary and mucosal polysaccharides. The proteins responsible for the uptake and breakdown of many of these polysaccharides are transcriptionally regulated by hybrid two-component systems (HTCSs). These systems consist of a single polypeptide harboring the domains of sensor kinases and response regulators, and thus, are thought to autophosphorylate in response to specific signals. We now report that the HTCS BT0366 is phosphorylated in vivo when B. thetaiotaomicron experiences the BT0366 inducer arabinan but not when grown in the presence of glucose. BT0366 phosphorylation and transcription of BT0366 activated genes requires the conserved predicted sites of phosphorylation in BT0366. When chondroitin sulfate is added to arabinan-containing cultures, BT0366 phosphorylation and transcription of BT0366-activated genes are inhibited and the bacterium exhibits diauxic growth. Whereas 20 additional combinations of polysaccharides also give rise to diauxic growth, other combinations result in synergistic or unaltered growth relative to bacteria experiencing a single polysaccharide. The different strategies employed by B. thetaiotaomicron when faced with multiple polysaccharides may aid its competitiveness in the mammalian gut. PMID- 28009068 TI - Development and validation of a food frequency questionnaire to assess omega-3 long chain polyunsaturated fatty acid intake in Australian children aged 9-13 years. AB - BACKGROUND: The present study aimed to develop a food frequency questionnaire (FFQ) assessing dietary omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) intake in Australian children and to validate the FFQ against a 7-day food diary. METHODS: The investigation comprised a cross-sectional and validation study. The study setting was two private primary schools in the in the Illawarra region of New South Wales. Twenty-two Australian children, aged 9-13 years, who were not on a special diet or receiving medical care that limited their food choice in the 3 months prior to recruitment, were recruited into the study. RESULTS: A total of 131 items, classified according to seven food group categories, was included in the n-3 LCPUFA FFQ, as identified from published dietary surveys and a supermarket survey. Good correlations between the FFQ and the 7-day food diary were observed for eicosapentaenoic acid (EPA) [r = 0.691, 95% confidence interval (CI) = 0.51-0.83, P < 0.001], docosahexaenoic acid (DHA) (r = 0.684, 95% CI = 0.45-0.84, P < 0.001) and total n-3 LCPUFA (r = 0.687, 95% CI = 0.48-0.85, P < 0.001). Bland-Altman plots showed an acceptable limit of agreement between the FFQ and the average 7-day food diary. However, the mean EPA, DHA and total n-3 LCPUFA intakes estimated from the FFQ were significantly higher than those from the average 7-day food diary estimates (P < 0.001). CONCLUSIONS: A novel n-3 LCPUFA FFQ that has been developed to estimate dietary n 3 LCPUFA intakes in Australian children has been shown to have relative validity. The FFQ provides a useful contribution to dietary assessment methodology in this age group; however, reproducibility remains to be demonstrated. PMID- 28009069 TI - Test-retest reliability and concurrent validity of in vivo myelin content indices: Myelin water fraction and calibrated T1 w/T2 w image ratio. AB - In an age-heterogeneous sample of healthy adults, we examined test-retest reliability (with and without participant repositioning) of two popular MRI methods of estimating myelin content: modeling the short spin-spin (T2 ) relaxation component of multi-echo imaging data and computing the ratio of T1 weighted and T2 -weighted images (T1 w/T2 w). Taking the myelin water fraction (MWF) index of myelin content derived from the multi-component T2 relaxation data as a standard, we evaluate the concurrent and differential validity of T1 w/T2 w ratio images. The results revealed high reliability of MWF and T1 w/T2 w ratio. However, we found significant correlations of low to moderate magnitude between MWF and the T1 w/T2 w ratio in only two of six examined regions of the cerebral white matter. Notably, significant correlations of the same or greater magnitude were observed for T1 w/T2 w ratio and the intermediate T2 relaxation time constant, which is believed to reflect differences in the mobility of water between the intracellular and extracellular compartments. We conclude that although both methods are highly reliable and thus well-suited for longitudinal studies, T1 w/T2 w ratio has low criterion validity and may be not an optimal index of subcortical myelin content. Hum Brain Mapp 38:1780-1790, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28009071 TI - Controlled Supramolecular Architecture Transformation from Homopolymer to Copolymer through Competitive Self-Sorting Method. AB - Supramolecular copolymers can not only enrich the diversity of the polymer backbone but also exhibit certain special and improved properties compared with supramolecular homopolymers. However, the synthesis procedure of supramolecular copolymers is relatively complicated and time-consuming. Herein, a simple transformation from an AB2 -based supramolecular hyperbranched homopolymer to an AB2 +CD2 -based supramolecular hyperbranched alternating copolymer by the "competitive self-sorting" strategy is reported. After adding CD2 monomer, which bears a competitive neutral guest moiety (TAPN) and two receptive benzo-21-crown 7 host moieties (B21C7), to the as-prepared AB2 -type supramolecular hyperbranched homopolymer constructed by the self-assembly of dialkylammonium salt (DAAS, A group)-functionalized pillar[5]arene (MeP5, B groups) monomers, the initial homopolymer structure is disrupted and then reassemble into a new supramolecular hyperbranched alternating copolymer based on the competitive self sorting interaction between MeP5-TAPN and B21C7-DAAS. This study supplies a convenient approach to directly transform supramolecular homopolymers into supramolecular copolymers. PMID- 28009070 TI - Effects of aripiprazole and haloperidol on neural activation during a simple motor task in healthy individuals: A functional MRI study. AB - The dopaminergic system plays a key role in motor function and motor abnormalities have been shown to be a specific feature of psychosis. Due to their dopaminergic action, antipsychotic drugs may be expected to modulate motor function, but the precise effects of these drugs on motor function remain unclear. We carried out a within-subject, double-blind, randomized study of the effects of aripiprazole, haloperidol and placebo on motor function in 20 healthy men. For each condition, motor performance on an auditory-paced task was investigated. We entered maps of neural activation into a random effects general linear regression model to investigate motor function main effects. Whole-brain imaging revealed a significant treatment effect in a distributed network encompassing posterior orbitofrontal/anterior insula cortices, and the inferior temporal and postcentral gyri. Post-hoc comparison of treatments showed neural activation after aripiprazole did not differ significantly from placebo in either voxel-wise or region of interest analyses, with the results above driven primarily by haloperidol. We also observed a simple main effect of haloperidol compared with placebo, with increased task-related recruitment of posterior cingulate and precentral gyri. Furthermore, region of interest analyses revealed greater activation following haloperidol compared with placebo in the precentral and post-central gyri, and the putamen. These diverse modifications in cortical motor activation may relate to the different pharmacological profiles of haloperidol and aripiprazole, although the specific mechanisms underlying these differences remain unclear. Evaluating healthy individuals can allow investigation of the effects of different antipsychotics on cortical activation, independently of either disease-related pathology or previous treatment. Hum Brain Mapp 38:1833-1845, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28009072 TI - Taking the brakes off the learning curve. AB - Motor learning is characterized by patterns of cerebello-striato-cortical activations shifting in time, yet the early dynamic and function of these activations remains unclear. Five groups of subjects underwent either continuous or intermittent theta-burst stimulation of one cerebellar hemisphere, or no stimulation just before learning a new motor sequence during fMRI scanning. We identified three phases during initial learning: one rapid, one slow, and one quasi-asymptotic performance phase. These phases were not changed by left cerebellar stimulation. Right cerebellar inhibition, however, accelerated learning and enhanced brain activation in critical motor learning-related areas during the first phase, continuing with reduced brain activation but high performance in late phase. Right cerebellar excitation did not affect the early learning process, but slowed learning significantly in late phase, along with increased brain activation. We conclude that the right cerebellum is a key factor coordinating other neuronal loops in the early acquisition of an explicit motor sequential skill. Hum Brain Mapp 38:1676-1691, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28009073 TI - Structural basis for rifamycin resistance of bacterial RNA polymerase by the three most clinically important RpoB mutations found in Mycobacterium tuberculosis. AB - Since 1967, Rifampin (RMP, a Rifamycin) has been used as a first line antibiotic treatment for tuberculosis (TB), and it remains the cornerstone of current short term TB treatment. Increased occurrence of Rifamycin-resistant (RIFR ) TB, ~41% of which results from the RpoB S531L mutation in RNA polymerase (RNAP), has become a growing problem worldwide. In this study, we determined the X-ray crystal structures of the Escherichia coli RNAPs containing the most clinically important S531L mutation and two other frequently observed RIFR mutants, RpoB D516V and RpoB H526Y. The structures reveal that the S531L mutation imparts subtle if any structural or functional impact on RNAP in the absence of RIF. However, upon RMP binding, the S531L mutant exhibits a disordering of the RIF binding interface, which effectively reduces the RMP affinity. In contrast, the H526Y mutation reshapes the RIF binding pocket, generating significant steric conflicts that essentially prevent any RIF binding. While the D516V mutant does not exhibit any such gross structural changes, certainly the electrostatic surface of the RIF binding pocket is dramatically changed, likely resulting in the decreased affinity for RIFs. Analysis of interactions of RMP with three common RIFR mutant RNAPs suggests that modifications to RMP may recover its efficacy against RIFR TB. PMID- 28009075 TI - ASSESSMENT OF SENTINEL LYMPH NODE METASTASIS IN CANINE MAMMARY GLAND TUMORS USING COMPUTED TOMOGRAPHIC INDIRECT LYMPHOGRAPHY. AB - In the staging process of the breast cancer, demonstrating metastasis of the sentinel lymph node (SLN) has an important prognostic value, in both humans and animals. The aim of this prospective case-control study was to determine the diagnostic value of computed tomographic indirect lymphography (CT-LG) for detecting SLN metastasis in dogs with mammary cancer. Thirty-three female dogs with tumors in the abdominal and inguinal mammary glands were prospectively selected and subjected to CT-LG, 1 and 5 min after injection of 1 ml of contrast agent (iopamidol) in the subareolar tissue of the neoplastic and the contralateral normal mammary glands. The pattern of postcontrast opacification, degree of postcontrast enhancement, and size and shape were assessed in 65 SLNs in total and were correlated with histopathological findings. The absence of opacification or heterogeneous opacification 1 min after contrast medium injection showed the highest sensitivity, specificity, and accuracy (93%, 100%, and 98.4%, respectively). In images taken 1 min after injection, an absolute density value lower than 444 Hounsfield units (HU) in the center of the SLN also provided significant sensitivity and specificity (93.8% and 75%, respectively). The size and shape of the SLN (maximum and minimum diameter, maximum/minimum diameter ratio, maximum diameter/height of fifth thoracic vertebral body ratio) showed the lowest sensitivity and specificity. Results of this study support the hypothesis that CT-LG could help in the assessment of SLN metastasis in cases of mammary gland tumors in dogs. PMID- 28009076 TI - Brain regions that show repetition suppression and enhancement: A meta-analysis of 137 neuroimaging experiments. AB - Repetition suppression and enhancement refer to the reduction and increase in the neural responses for repeated rather than novel stimuli, respectively. This study provides a meta-analysis of the effects of repetition suppression and enhancement, restricting the data used to that involving fMRI/PET, visual stimulus presentation, and healthy participants. The major findings were as follows. First, the global topography of the repetition suppression effects was strikingly similar to that of the "subsequent memory" effects, indicating that the mechanism for repetition suppression is the reduced engagement of an encoding system. The lateral frontal cortex effects involved the frontoparietal control network regions anteriorly and the dorsal attention network regions posteriorly. The left fusiform cortex effects predominantly involved the dorsal attention network regions, whereas the right fusiform cortex effects mainly involved the visual network regions. Second, the category-specific meta-analyses and their comparisons indicated that most parts of the alleged category-specific regions showed repetition suppression for more than one stimulus category. In this regard, these regions may not be "dedicated cortical modules," but are more likely parts of multiple overlapping large-scale maps of simple features. Finally, the global topography of the repetition enhancement effects was similar to that of the "retrieval success" effects, suggesting that the mechanism for repetition enhancement is voluntary or involuntary explicit retrieval during an implicit memory task. Taken together, these results clarify the network affiliations of the regions showing reliable repetition suppression and enhancement effects and contribute to the theoretical interpretations of the local and global topography of these two effects. Hum Brain Mapp 38:1894-1913, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28009077 TI - Inflammasomes as therapeutic targets for Alzheimer's disease. AB - Alzheimer's disease is the most common form of progressive dementia, typified initially by short term memory deficits which develop into a dramatic global cognitive decline. The classical hall marks of Alzheimer's disease include the accumulation of amyloid oligomers and fibrils, and the intracellular formation of neurofibrillary tangles of hyperphosphorylated tau. It is now clear that inflammation also plays a central role in the pathogenesis of the disease through a number of neurotoxic mechanisms. Microglia are the key immune regulators of the CNS which detect amyloidopathy through cell surface and cytosolic pattern recognition receptors (PRRs) and respond by initiating inflammation through the secretion of cytokines such as interleukin-1beta (IL-1beta). Inflammasomes, which regulate IL-1beta release, are formed following activation of cytosolic PRRs, and using genetic and pharmacological approaches, NLRP3 and NLRP1 inflammasomes have been found to be integral in pathogenic neuroinflammation in animal models of Alzheimer's disease. Therefore, the inflammasomes are very promising novel pharmacological targets which merit further research in the continued endeavor for efficacious therapeutics for Alzheimer's disease. PMID- 28009074 TI - New Monoclonal Antibodies to Defined Cell Surface Proteins on Human Pluripotent Stem Cells. AB - The study and application of human pluripotent stem cells (hPSCs) will be enhanced by the availability of well-characterized monoclonal antibodies (mAbs) detecting cell-surface epitopes. Here, we report generation of seven new mAbs that detect cell surface proteins present on live and fixed human ES cells (hESCs) and human iPS cells (hiPSCs), confirming our previous prediction that these proteins were present on the cell surface of hPSCs. The mAbs all show a high correlation with POU5F1 (OCT4) expression and other hPSC surface markers (TRA-160 and SSEA-4) in hPSC cultures and detect rare OCT4 positive cells in differentiated cell cultures. These mAbs are immunoreactive to cell surface protein epitopes on both primed and naive state hPSCs, providing useful research tools to investigate the cellular mechanisms underlying human pluripotency and states of cellular reprogramming. In addition, we report that subsets of the seven new mAbs are also immunoreactive to human bone marrow-derived mesenchymal stem cells (MSCs), normal human breast subsets and both normal and tumorigenic colorectal cell populations. The mAbs reported here should accelerate the investigation of the nature of pluripotency, and enable development of robust cell separation and tracing technologies to enrich or deplete for hPSCs and other human stem and somatic cell types. Stem Cells 2017;35:626-640. PMID- 28009078 TI - Isoconversional Kinetics of Polymers: The Decade Past. AB - This article surveys the decade of progress accomplished in the application of isoconversional methods to thermally stimulated processes in polymers. The processes of interest include: crystallization and melting of polymers, gelation of polymer solutions and gel melting, denaturation (unfolding) of proteins, glass transition, polymerization and crosslinking (curing), and thermal and thermo oxidative degradation. Special attention is paid to the kinetics of polymeric nanomaterials. The article discusses basic principles for understanding the variations in the activation energy and emphasizes the possibility of using models for linking such variations to the parameters of individual kinetic steps. It is stressed that many kinetic effects are not linked to a change in the activation energy alone and may arise from changes in the preexponential factor and reaction model. Also noted is that some isoconversional methods are inapplicable to processes taking place on cooling and cannot be used to study such processes as the melt crystallization. PMID- 28009079 TI - Acute disseminated encephalomyelitis in China, Singapore and Japan: a comparison with the USA. AB - BACKGROUND AND PURPOSE: Ethnicity-related differences in the incidence of acute disseminated encephalomyelitis (ADEM) and other demyelinating diseases including multiple sclerosis and neuromyelitis optica spectrum disorders have been reported. Little is reported on the influence of ethnicity and geographical location in ADEM. METHODS: Medical records of patients who presented with ADEM (ICD-9 323.61 and 323.81) at large referral hospitals in China, Singapore and Japan (years 1992-2015) were retrospectively reviewed and data were collected in a centralized database. Presenting features and outcomes of ADEM were compared between this multi-country Asian cohort and a uniformly collected US cohort using risk differences and risk ratios. Both cohorts were standardized to a 35% pediatric population to facilitate the comparison. RESULTS: There were 83 Asian patients (48 male, 16 pediatric) followed for a median of 2 (25th-75th percentile 1-10) months. Asian patients exhibited a 26% higher prevalence of spinal cord involvement on magnetic resonance imaging [95% confidence interval (CI) 0-52%; P = 0.05; 63% vs. 37%], a 39% lower prevalence of preceding events (95% CI 12-65%; P < 0.01; 33% vs. 72%) and a 23% lower prevalence of corpus callosum involvement (95% CI 7-39%; P < 0.01; 8% vs. 31%). No difference was observed between the two cohorts in the probability of relapse over the first year after disease onset. CONCLUSIONS: It is hypothesized that the high proportion of Asian patients with spinal cord lesions relates to genetic vulnerability or the higher incidence of neuromyelitis optica spectrum disorders in Asia or could be a spurious association. ADEM presentations most probably vary across geographical settings or ethnicities. PMID- 28009080 TI - Disruptions in the left frontoparietal network underlie resting state endophenotypic markers in schizophrenia. AB - Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN (P < 0.001), and in particular from the left SMG (P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG (P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG (P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG (P = 0.005) and to the negative symptom score on the PANSS scale (P = 0.001, r = -0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741 1750, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28009081 TI - Mini-symposium: Role of the inflammasome in brain pathogenesis: a potential therapeutic target? - introduction. PMID- 28009084 TI - Breast cancer with an extremely high Ki-67 labeling index despite a low nuclear grade. PMID- 28009082 TI - Patient expectations for management of chronic non-cancer pain: A systematic review. AB - BACKGROUND: Chronic pain is a major economic and social health problem. Up to 79% of chronic pain patients are unsatisfied with their pain management. Meeting patients' expectations is likely to produce greater satisfaction with care. The challenge is to explore patients' genuine expectations and needs. However, the term expectation encompasses several concepts and may concern different aspects of health-care provision. OBJECTIVE: This review aimed to systematically collect information on types and subject of patients' expectations for chronic pain management. SEARCH STRATEGY: We searched for quantitative and qualitative studies. Because of the multidimensional character of the term "expectations," the search included subject headings and free text words related to the concept of expectations. DATA EXTRACTION AND SYNTHESIS: A framework for understanding patients' expectations was used to map types of expectations within structure, process or outcome of health care. MAIN RESULTS: Twenty-three research papers met the inclusion criteria: 18 quantitative and five qualitative. This review found that assessment of patients' expectations for treatment is mostly limited to outcome expectations (all 18 quantitative papers and four qualitative papers). Patients generally have high expectations regarding pain reduction after treatment, but expectations were higher when expressed as an ideal expectation (81-93% relief) than as a predicted expectation (44-64%). DISCUSSION AND CONCLUSIONS: For health-care providers, for pain management and for pain research purposes, the awareness that patients express different types of expectations is important. For shared decision making in clinical practice, it is important that predicted expectations of the patient are known to the treating physician and discussed. Structure and process expectations are under-represented in our findings. However, exploring and meeting patients' expectations regarding structure, process and outcome aspects of pain management may increase patient satisfaction. PMID- 28009083 TI - Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis. AB - OBJECTIVE: Sporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs. METHODS: RVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification. Whole exome sequencing was performed on 62 sIBM patients. Immunofluorescence was performed on patient and mouse skeletal muscle. RESULTS: A total of 213 proteins were enriched by >1.5 -fold in RVs compared to controls and included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Proteins associated with protein folding and autophagy were the largest group represented. One autophagic adaptor protein not previously identified in sIBM was FYCO1. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p = 0.003). FYCO1 colocalized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced colocalization with MAP1LC3 when expressed in mouse muscle. INTERPRETATION: This study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. FYCO1 accumulates at RVs, and rare missense variants in FYCO1 are overrepresented in sIBM patients. These FYCO1 variants may impair autophagic function, leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways, supporting the hypothesis that impaired endolysosomal degradation underlies the pathogenesis of sIBM. Ann Neurol 2017;81:227-239. PMID- 28009085 TI - Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors. AB - The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1 DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064. PMID- 28009086 TI - 1,2-Diacylglycerol choline phosphotransferase catalyzes the final step in the unique Treponema denticola phosphatidylcholine biosynthesis pathway. AB - Treponema denticola synthesizes phosphatidylcholine through a licCA-dependent CDP choline pathway identified only in the genus Treponema. However, the mechanism of conversion of CDP-choline to phosphatidylcholine remained unclear. We report here characterization of TDE0021 (herein designated cpt) encoding a 1,2-diacylglycerol choline phosphotransferase homologous to choline phosphotransferases that catalyze the final step of the highly conserved Kennedy pathway for phosphatidylcholine synthesis in eukaryotes. T. denticola Cpt catalyzed in vitro phosphatidylcholine formation from CDP-choline and diacylglycerol, and full activity required divalent manganese. Allelic replacement mutagenesis of cpt in T. denticola resulted in abrogation of phosphatidylcholine synthesis. T. denticola Cpt complemented a Saccharomyces cerevisiae CPT1 mutant, and expression of the entire T. denticola LicCA-Cpt pathway in E. coli resulted in phosphatidylcholine biosynthesis. Our findings show that T. denticola possesses a unique phosphatidylcholine synthesis pathway combining conserved prokaryotic choline kinase and CTP:phosphocholine cytidylyltransferase activities with a 1,2 diacylglycerol choline phosphotransferase that is common in eukaryotes. Other than in a subset of mammalian host-associated Treponema that includes T. pallidum, this pathway is found in neither bacteria nor Archaea. Molecular dating analysis of the Cpt gene family suggests that a horizontal gene transfer event introduced this gene into an ancestral Treponema well after its divergence from other spirochetes. PMID- 28009088 TI - Horseradish-Peroxidase-Catalyzed Tyrosine Click Reaction. AB - The efficiency of protein chemical modification on tyrosine residues with N methylluminol derivatives was drastically improved by using horseradish peroxidase (HRP). In the previous method, based on the use of hemin and H2 O2 , oxidative side reactions such as cysteine oxidation were problematic for functionalization of proteins selectively on tyrosine residues. Oxidative activation of N-methylluminol derivatives with a minimum amount of H2 O2 prevented the occurrence of oxidative side reactions under HRP-catalyzed conditions. As probes for HRP-catalyzed protein modification, N-methylluminol derivatives showed much higher efficiency than tyramide without inducing oligomerization of probe molecules. Tyrosine modification also proceeded in the presence of beta-nicotinamide adenine dinucleotide (NADH, H2 O2 -free conditions). PMID- 28009087 TI - Distribution and characteristics of transactive response DNA binding protein 43 kDa pathology in progressive supranuclear palsy. AB - BACKGROUND: This study aimed to determine the frequency of transactive response DNA binding protein 43 kDa pathology in PSP, the clinical features of patients with this pathology, and genetic risk factors for it. METHODS: Hippocampal sections were screened with immunohistochemistry for transactive response DNA binding protein 43 kDa in 945 PSP cases. A subset of 261 cases that were negative in hippocampus was screened in the amygdala. The density and disruption of this pathology, as well as regional tau burden, and clinical and genetic characteristics were analyzed. RESULTS: We observed transactive response DNA binding protein 43 kDa pathology in 47 cases in the hippocampus and an additional 9 cases that only affected the amygdala. Hippocampal sclerosis was the strongest risk factor, followed by Alzheimer's disease pathology, argyrophilic grain disease, and older age at death. Five stages of transactive response DNA binding protein 43 kDa pathology were identified in PSP: Stage A had pathology only in the amygdala (16%); stage I had pathology confined to the hippocampus and entorhinal cortex (9%); stage II included both regions of stage A and I (38%); stage III spread further to medial occipitotemporal gyrus (20%); and stage IV had pathology in the dorsolateral frontal lobe (18%). Anatomical areas vulnerable to PSP pathology had varying degrees of this pathology in stage II and later. PSP with transactive response DNA binding protein 43 kDa pathology were older at disease onset and had lower median MMSE scores; however, the latter was driven by concurrent pathologies. CONCLUSIONS: Distribution and clinical characteristics of transactive response DNA binding protein 43 kDa pathology in PSP were influenced by concurrent pathologies. This is the first study to observe that PSP-vulnerable regions are also susceptible to this non-tau pathology. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 28009089 TI - Facet-Dependent Electrical Conductivity Properties of Silver Oxide Crystals. AB - Ag2 O cubes, truncated octahedra, rhombic dodecahedra, and rhombicuboctahedra were synthesized in aqueous solution. Two tungsten probes were brought into contact with a single particle for electrical conductivity measurements. Strongly facet-dependent electrical conductivity behaviors have been observed. The {111} faces are most conductive. The {100} faces are moderately conductive. The {110} faces are nearly non-conductive. When electrodes contacted two different facets of a rhombicuboctahedron, asymmetrical I-V curves were obtained. The {111} and {110} combination gives the best I-V curve expected for a p-n junction with current flowing in one direction through the crystal but not in the opposite direction. Density of states (DOS) plots for varying number of different lattice planes of Ag2 O match with the experimental results, suggesting that the {111} faces are most electrically conductive. The thicknesses of the thin surface layer responsible for the facet-dependent properties of Ag2 O crystals have been determined. PMID- 28009090 TI - Tuberculosis screening using IGRA and chest computed tomography in patients with inflammatory bowel disease: A retrospective study. AB - OBJECTIVES: To assess the prevalence and potential risk factors of latent tuberculosis infection (LTBI) in Chinese patients with inflammatory bowel disease (IBD) and to evaluate the role of chest computed tomography (CT) in the screening of LTBI. METHODS: A single-center retrospective study was conducted and all IBD patients who had been screened for LTBI by T-SPOT.TB between December 2011 and January 2016 were enrolled in the study. Both inpatient and outpatient records were collected and comprehensively reviewed. RESULTS: Altogether 534 IBD patients were included. The positivity rate of T-SPOT.TB was 18.0% overall, 31.9% in IBD unclassified, 22.5% in ulcerative colitis and 13.0% in Crohn's disease patients, respectively. Age, history of TB and the administration of immunosuppressants were significantly associated with T-SPOT.TB positivity. Among 123 patients who underwent serial testing, the conversion and reversion rate of T-SPOT.TB was 10.2% and 42.9%, respectively. Furthermore, 102 of 447 (22.8%) patients who underwent chest computed tomography (CT) were found with abnormal CT findings suggestive of LTBI. The concordance rate was 75% between the T-SPOT.TB and chest CT with a kappa value of 0.25 (95% CI 0.15-0.35). CONCLUSIONS: The prevalence of LTBI in IBD patients is high in China. Chest CT is recommended as an alternative to IGRA for screening LTBI of IBD patients before commencing immunosuppressive therapy in high-prevalence regions. PMID- 28009091 TI - In vitro spontaneous contractile activity of colonic smooth muscle in naive Lewis rats: Acute effect of gonadal hormones. AB - OBJECTIVE: Functional gastrointestinal disorders affect females more often. Changes in colonic motility may be etiological co-factors for the clinical symptoms. The aim of the present study was to analyze the influence of gonadal hormones on colonic contractile activity. METHODS: In vitro measurements of colonic contractile activity in longitudinal smooth muscle strips of female and male Lewis rats were performed in an organ chamber experiment. After the administration of a gonadal hormone estradiol [EST], progesterone [PROG] and testosterone [TEST]) or ethanol solution as control, stimulation with acetylcholine (ACh) or inhibition with norepinephrine (NE) was performed. RESULTS: Compared to the smooth muscle strips of male rats, significantly higher spontaneous colonic contractile activity (SCCA) was observed in female animals. Increasing doses of ACh showed the progressive stimulation of SCCA whereas rising doses of NE resulted in a stepwise inhibition of SCCA, respectively. EST superfusion displayed an inhibitory effect on SCCA in both sexes and inhibited the ACh effect in female rats. Similarly, acute superfusion with high-dose PROG inhibited SCCA in females. Acute TEST superfusion inhibited SCCA in males and led to significant higher colonic contractile activity in males following subsequent stimulation with ACh. In female rats, the inhibitory effect of NE was reduced by prior exposure to TEST. CONCLUSION: In our in vitro study the acute exposure of colonic smooth muscle tissue to gonadal hormones led to sex-dependent changes in SCCA and translated in a modified response of smooth muscle strips to both pro contractile and anti-contractile neurotransmitters. PMID- 28009092 TI - Arthritis management in primary care - A study of physiotherapists' current practice, educational needs and adherence to national guidelines. AB - BACKGROUND: With an increasing number of patients with osteoarthritis (OA) and rheumatoid arthritis (RA) in primary care, our aim was to investigate arthritis related practice in physiotherapy and to study adherence to evidence-based care. METHODS: Seventy physiotherapists (PTs) working in primary care were emailed a questionnaire to investigate current practice and the number of roles assumed by PTs, the degree of confidence, educational needs and adherence to national guidelines in managing patients with OA or RA. Interventions supported by national guidelines were compared with reports of treatment modalities in the questionnaire. RESULTS: Sixty-four (91%) PTs responded, and they reported a higher degree of confidence in assessment, treatment and education of patients with OA than for those with RA (p < 0.001). The total number of roles assumed by the PTs was higher in the management of OA than for RA (p < 0.001). PTs who assumed a greater number of roles also reported a stronger degree of confidence in assessing OA (p = 0.036). Those who assumed fewer roles also reported less confidence in RA treatment (p = 0.045). Recommendations in the guidelines were followed by the majority of PTs for eight of 11 treatment modalities in OA and for six of six in RA. CONCLUSIONS: PTs reported a lower degree of confidence and the assumption of fewer roles in managing patients with RA compared with OA. There was good adherence to the national guidelines for almost all the treatment modalities listed. Even so, the results indicate a need for education, especially in chronic inflammatory arthritis care. PMID- 28009093 TI - Contract theories and partnership in health care. A philosophical inquiry to the philosophy of John Rawls and Seyla Benhabib. AB - Over the last 20 years, a paternalistic view in health care has been losing ground. The question about less asymmetrical positions in the healthcare professional-patient relationship is, for example, being addressed by the increased emphasis on person-centred care, promoted in disciplines such as medicine and nursing. Partnership is considered as a key component in person centred care. Although the previous studies have addressed the attributes inherent in partnership, there is still potential for further discussion on how the various interpretations of partnership influence their use in healthcare literature. A vague understanding might also affect education and evaluation. As we see it, the philosophical underpinnings of the idea of partnership have not been sufficiently explored and discussed. The study reveals that partnership originates in the term "partener" defined as a relationship between individuals or groups characterized by cooperation and responsibility. Etymologically speaking, partnership is hence bound by a contract, which in this study is discussed in the frame of Rawls' contract theory, which in turn intersects with Benhabib and her distinction between "the abstract" and "the concrete Other." Further, the expression "equal partnership," which often appears in the context of person-centredness, is explored in relation to the philosophies of Rawls and Benhabib. The opportunity for partnership, as well as the risk of partnership becoming a tempting magnet with a vague and imprecise meaning, is discussed. Without exploration, reflection and discussion of the philosophical underpinnings, partnership carries a substantial risk of becoming an indistinct idea used in health care. PMID- 28009094 TI - Clinical value of MRI-detected extramural venous invasion in rectal cancer. AB - Extramural venous invasion (EMVI) is associated with a poor prognosis and a poor overall survival rate in rectal cancer. It can independently predict local and distant tumor recurrences. Preoperative EMVI detection in rectal cancer is useful for determining the treatment strategy. EMVI status is beneficial for the post treatment evaluation and analysis of rectal cancer. Magnetic resonance imaging (MRI) is a non-invasive diagnostic modality with no radiation effects. High resolution MRI can detect EMVI with high accuracy. In addition, MRI results are equal to or even better than pathological results in the detection of medium to large EMVI in rectal cancer. MRI-detected EMVI (mrEMVI) can be used as a potential biomarker that facilitates treatment methods. This review highlights the importance of MRI before and after rectal cancer treatment. In addition, we analyze the prognostic correlation between mrEMVI and circulating tumor cells (CTC) in rectal cancer. This article may help shed light on the significance of mrEMVI. PMID- 28009095 TI - Tools of pathway reconstruction and production of economically relevant plant secondary metabolites in recombinant microorganisms. AB - Plant secondary metabolites exhibit a variety of biological activities and therefore serve as valuable therapeutics or flavoring compounds. However, the small amounts isolated from plants often cannot meet market demands. This led to the exploration of other, more profitable methods for their production, including plant cell culture systems, chemical synthesis and biotechnological production in microbial hosts. The biotechnological production can be pursued by reconstructing metabolic pathways in selected microbial systems. But due to their complexity, most of these pathways are not completely understood and require the expression of a multitude of genes in a foreign organism. Recently, next generation sequencing data and advances in gene silencing in plants allowed the elucidation of some biosynthetic pathways in more detail. Thus, the de novo production of some natural products, including morphine, strictosidine, artemisinin, taxol(r) and resveratrol, in extensively engineered microbial hosts has become feasible. This review highlights the reconstruction of these pathways, missing pieces and novel techniques employed. PMID- 28009096 TI - In Vivo Ischemia Detection by Luminescent Nanothermometers. AB - There is an urgent need to develop new diagnosis tools for real in vivo detection of first stages of ischemia for the early treatment of cardiovascular diseases and accidents. However, traditional approaches show low sensitivity and a limited penetration into tissues, so they are only applicable for the detection of surface lesions. Here, it is shown how the superior thermal sensing capabilities of near infrared-emitting quantum dots (NIR-QDs) can be efficiently used for in vivo detection of subcutaneous ischemic tissues. In particular, NIR-QDs make possible ischemia detection by high penetration transient thermometry studies in a murine ischemic hindlimb model. NIR-QDs nanothermometers are able to identify ischemic tissues by means of their faster thermal dynamics. In addition, they have shown to be capable of monitoring both the revascularization and damage recovery processes of ischemic tissues. This work demonstrates the applicability of fluorescence nanothermometry for ischemia detection and treatment, as well as a tool for early diagnosis of cardiovascular disease. PMID- 28009097 TI - Comments to 'Potential Pathogens Reported in Species of the Family Viverridae and Their Implications for Human and Animal Health'. PMID- 28009098 TI - High-speed photoacoustic microscopy of mouse cortical microhemodynamics. AB - We applied high-speed photoacoustic microscopy (PAM) for both cortical microenvironment studies and dynamic brain studies, with micrometer-level optical resolution and a millisecond-level cross-sectional imaging speed over a millimeter-level field of view. We monitored blood flow redistribution in mini stroke mouse models and cerebral autoregulation induced by a vasoactive agent. Our results collectively suggest that high-speed PAM is a promising tool for understanding dynamic neurophysiological phenomena, complementing conventional imaging modalities. PMID- 28009099 TI - Separation of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane and 1,3,5-trinitro 1,3,5- triazacyclohexane by molecularly imprinted solid-phase extraction. AB - Synthesis of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane and 1,3,5-trinitro 1,3,5-triazacyclohexane by the Bachmann process leads to a mixture of both. The separation of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane and 1,3,5-trinitro 1,3,5-triazacyclohexane from their mixture is difficult because the sizes and physical properties of these homologous compounds are similar. For this purpose, seven molecularly imprinted polymers have been synthesized for each explosive, and a selective solid-phase extraction procedure has been developed. A molecularly imprinted polymer, synthesized with 1,3,5,7-tetranitro-1,3,5,7 tetraazacyclooctane as the template, methacrylic acid as the monomer and trimethylolpropane trimethacrylate as the cross-linking agent in a molar ratio of 1:8:8 showed the best separation capability. A packed cartridge containing this polymer can be reused for 23 solid-phase extraction cycles without repacking, and the total separation capability toward 1,3,5,7-tetranitro-1,3,5,7 tetraazacyclooctane reached 6.81 mg per gram of polymer. 1,3,5-Trinitro-1,3,5 triazacyclohexane was not detected in the separated 1,3,5,7-tetranitro-1,3,5,7 tetraazacyclooctane by high-performance liquid chromatography and vice versa. This newly developed method had the advantages of high recovery (100%) and purity, environmental friendliness, and room temperature operability. This study showed that some molecularly imprinted polymers that cannot absorb target analytes well in the solvent in which the polymers were polymerized might have high-binding capacity for the analytes and show imprinting effects in other solvents. PMID- 28009100 TI - Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome. AB - BACKGROUND: Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdevelopment of the right heart structures commonly accompanied by an atrial septal defect. Familial HRHS reports suggest genetic factor involvement. We examined the role of copy number variants (CNVs) in HRHS. METHODS: We genotyped 32 HRHS cases identified from all New York State live births (1998-2005) using Illumina HumanOmni2.5 microarrays. CNVs were called with PennCNV and prioritized if they were >=20 Kb, contained >=10 SNPs and had minimal overlap with CNVs from in-house controls, the Database of Genomic Variants, HapMap3, and Childrens Hospital of Philadelphia database. RESULTS: We identified 28 CNVs in 17 cases; several encompassed genes important for right heart development. One case had a 2p16-2p23 duplication spanning LBH, a limb and heart development transcription factor. Lbh mis-expression results in right ventricular hypoplasia and pulmonary valve defects. This duplication also encompassed SOS1, a factor associated with pulmonary valve stenosis in Noonan syndrome. Sos1-/- mice display thin and poorly trabeculated ventricles. In another case, we identified a 1.5 Mb deletion associated with Williams-Beuren syndrome, a disorder that includes valvular malformations. A third case had a 24 Kb deletion upstream of the TGFbeta ligand ITGB8. Embryos genetically null for Itgb8, and its intracellular interactant Band 4.1B, display lethal cardiac phenotypes. CONCLUSION: To our knowledge, this is the first study of CNVs in HRHS. We identified several rare CNVs that overlap genes related to right ventricular wall and valve development, suggesting that genetics plays a role in HRHS and providing clues for further investigation. Birth Defects Research 109:16-26, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28009101 TI - BDNF Val66Met polymorphism moderates the link between child maltreatment and reappraisal ability. AB - Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype * child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis-stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype * child maltreatment interaction (B = -0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non-maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders. PMID- 28009102 TI - Feeling the HEAT: Using Hourly Emergency Activity Tracking to demonstrate a novel method of describing activity and patient flow. AB - OBJECTIVE: The objective of the present study is to demonstrate a novel method of mapping ED activity to analyse patterns presentations, occupancy and performance trends. METHODS: This was a retrospective, descriptive analysis of de-identified and linked ED presentations across NSW, Australia, over five calendar years, 2010 2014. It was undertaken as part of the Demand for Emergency Services Trend in Years 2010-2014 (DESTINY) study. The DESTINY project analysed 10.8 million presentations during 2010-2014. Hourly Emergency Activity Tracking (HEAT) maps were generated to visually represent and analyse the number of emergency arrivals to ED occupancy and proportion of patients leaving the ED within 4 h per hour of day across consecutive months of the year. RESULTS: HEAT maps provided a means of visually representing ED activity to demonstrate hour-to-hour trends in presentations, occupancy and performance between 2010 and 2014. This analysis has shown that the most marked increase in presentations per hour has occurred during the 10.00-14.00 hour period, associated with an improvement in ED performance during the same period. CONCLUSION: HEAT maps may be used to facilitate further analyses of ED demand, patterns of patient presentations and patient flow and future health system redesign. PMID- 28009104 TI - Deep gray matter atrophy in neuromyelitis optica spectrum disorder and multiple sclerosis. AB - BACKGROUND AND PURPOSE: We investigated changes in deep gray matter (DGM) volume and its relationship to cognition and clinical factors in a large cohort of patients with neuromyelitis optica spectrum disorder (NMOSD) and compared them with results from multiple sclerosis (MS). METHODS: Brain magnetic resonance imaging (3 Tesla) and clinical data from 91 patients with NMOSD, 52 patients with MS and 44 healthy controls (HCs) were prospectively evaluated. Differences in DGM volumes were compared among groups. The relationships between DGM atrophy and clinical variables were also analysed. RESULTS: Patients with NMOSD exhibited significantly reduced thalamic volumes compared with HCs (P = 0.029), although this atrophy was less severe than that seen in patients with MS (P < 0.001). DGM atrophy was restricted to the thalamus in NMOSD, but it was broadly distributed in MS. Patients with NMOSD with cognitive impairment (CI) exhibited more severe thalamic atrophy than those with cognitive preservation (P = 0.017) and HCs (P = 0.003), whereas patients with MS with CI revealed DGM atrophy across the entire structure, with the exception of the bilateral pallidum, left hippocampus and amygdala, relative to HCs. The Expanded Disability Status Scale score was correlated with thalamic atrophy in both NMOSD and MS. Patients with NMOSD with brain lesions demonstrated more severe thalamic atrophy than did those without brain lesions and HCs (P < 0.001). CONCLUSIONS: The DGM atrophy was less severe and more selectively distributed in NMOSD than in MS. Thalamic atrophy was associated with clinical disability, including CI, in both NMOSD and MS. PMID- 28009103 TI - Experts' Perceptions on China's Capacity to Manage Emerging and Re-emerging Zoonotic Diseases in an Era of Climate Change. AB - Zoonotic diseases transmitted by arthropods and rodents are a major public health concern in China. However, interventions in recent decades have helped lower the incidence of several diseases despite the country's large, frequently mobile population and socio-economic challenges. Increasing globalization, rapid urbanization and a warming climate now add to the complexity of disease control and prevention and could challenge China's capacity to respond to threats of emerging and re-emerging zoonoses. To investigate this notion, face-to-face interviews were conducted with 30 infectious disease experts in four cities in China. The case study diseases under discussion were malaria, dengue fever and haemorrhagic fever with renal syndrome, all of which may be influenced by changing meteorological conditions. Data were analysed using standard qualitative techniques. The study participants viewed the current disease prevention and control system favourably and were optimistic about China's capacity to manage climate-sensitive diseases in the future. Several recommendations emerged from the data including the need to improve health literacy in the population regarding the transmission of infectious diseases and raising awareness of the health impacts of climate change amongst policymakers and health professionals. Participants thought that research capacity could be strengthened and human resources issues for front-line staff should be addressed. It was considered important that authorities are well prepared in advance for outbreaks such as dengue fever in populous subtropical areas, and a prompt and coordinated response is required when outbreaks occur. Furthermore, health professionals need to remain skilled in the identification of diseases for which incidence is declining, so that re-emerging or emerging trends can be rapidly identified. Recommendations such as these may be useful in formulating adaptation plans and capacity building for the future control and prevention of climate-sensitive zoonotic diseases in China and neighbouring countries. PMID- 28009105 TI - Prevalence and Antimicrobial Resistance of Salmonella enterica Serovar Indiana in China (1984-2016). AB - Salmonella enterica serovar Indiana, first described in 1955, is generally regarded as having a low frequency worldwide with outbreaks of gastroenteritis and abortions described in North America and Europe. In China, S. Indiana was first reported in 1984 and in the subsequent 71 surveys in 35 cities/municipalities from 18 provinces, 70% of which were after 2012, S. Indiana has been shown to have become widely prevalent in people, animals, food and the environment around abattoirs and meat processing facilities. The organism is now one of the most common serovars found in livestock and raw meat in China with S. Indiana isolates having high levels of drug resistance, especially against tetracyclines, quinolones, folate pathway inhibitors, phenicols, penicillins, monobactams and nitrofurans. Further, S. Indiana isolates that are concurrently resistant to ciprofloxacin and ceftriaxone/cefotaxime have emerged. Studies have suggested the high levels of multidrug resistance of S. Indiana might be associated with the presence of class 1 integrons and plasmids. Unfortunately, information on the high prevalence of S. Indiana and its extensive drug resistance in China has largely escaped international recognition as it largely appears in local reports written in Chinese. To address this situation, we reviewed all the available local Chinese and international publications on the organism in China and report our findings in this review. PMID- 28009106 TI - Metabolic effects of Lactobacillus reuteri DSM 17938 in people with type 2 diabetes: A randomized controlled trial. AB - AIMS: To investigate the metabolic effects of 12-week oral supplementation with Lactobacillus reuteri DSM 17938 in patients with type 2 diabetes on insulin therapy. MATERIALS AND METHODS: In a double-blind trial, we randomized 46 people with type 2 diabetes to placebo or a low (108 CFU/d) or high dose (1010 CFU/d) of L. reuteri DSM 17938 for 12 weeks. The primary endpoint was the effect of supplementation on glycated haemoglobin (HbA1c). Secondary endpoints were insulin sensitivity (assessed by glucose clamp), liver fat content, body composition, body fat distribution, faecal microbiota composition and serum bile acids. RESULTS: Supplementation with L. reuteri DSM 17938 for 12 weeks did not affect HbA1c, liver steatosis, adiposity or microbiota composition. Participants who received the highest dose of L. reuteri exhibited increases in insulin sensitivity index (ISI) and serum levels of the secondary bile acid deoxycholic acid (DCA) compared with baseline, but these differences were not significant in the between-group analyses. Post hoc analysis showed that participants who responded with increased ISI after L. reuteri supplementation had higher microbial diversity at baseline, and increased serum levels of DCA after supplementation. In addition, increases in DCA levels correlated with improvement in insulin sensitivity in the probiotic recipients. CONCLUSIONS: Intake of L. reuteri DSM 17938 for 12 weeks did not affect HbA1c in people with type 2 diabetes on insulin therapy; however, L. reuteri improved insulin sensitivity in a subset of participants and we propose that high diversity of the gut microbiota at baseline may be important. PMID- 28009107 TI - Detection of Salmonella enterica Serovar Montevideo and Newport in Free-ranging Sea Turtles and Beach Sand in the Caribbean and Persistence in Sand and Seawater Microcosms. AB - Salmonellae are Gram-negative zoonotic bacteria that are frequently part of the normal reptilian gastrointestinal flora. The main objective of this project was to estimate the prevalence of non-typhoidal Salmonella enterica in the nesting and foraging populations of sea turtles on St. Kitts and in sand from known nesting beaches. Results suggest a higher prevalence of Salmonella in nesting leatherback sea turtles compared with foraging green and hawksbill sea turtles. Salmonella was cultured from 2/9 and identified by molecular diagnostic methods in 3/9 leatherback sea turtle samples. Salmonella DNA was detected in one hawksbill turtle, but viable isolates were not recovered from any hawksbill sea turtles. No Salmonella was detected in green sea turtles. In samples collected from nesting beaches, Salmonella was only recovered from a single dry sand sample. All recovered isolates were positive for the wzx gene, consistent with the O:7 serogroup. Further serotyping characterized serovars Montevideo and Newport present in cloacal and sand samples. Repetitive-element palindromic PCR (rep-PCR) fingerprint analysis and pulsed-field gel electrophoresis of the 2014 isolates from turtles and sand as well as archived Salmonella isolates recovered from leatherback sea turtles in 2012 and 2013, identified two distinct genotypes and four different pulsotypes, respectively. The genotyping and serotyping were directly correlated. To determine the persistence of representative strains of each serotype/genotype in these environments, laboratory-controlled microcosm studies were performed in water and sand (dry and wet) incubated at 25 or 35 degrees C. Isolates persisted for at least 32 days in most microcosms, although there were significant decreases in culturable bacteria in several microcosms, with the greatest reduction in dry sand incubated at 35 degrees C. This information provides a better understanding of the epizootiology of Salmonella in free-ranging marine reptiles and the potential public health risks associated with human interactions with these animals in the Caribbean. PMID- 28009108 TI - Diabetes prevalence is associated with different community factors in the diabetes belt versus the rest of the United States. AB - OBJECTIVE: To investigate differences in community characteristics associated with diabetes prevalence between the Diabetes Belt and the rest of the contiguous United States (U.S.) METHODS: County-level adult diabetes prevalence estimates (i.e., percent of people [>=20 years] with diagnosed diabetes 2009) were used from the Centers for Disease Control and Prevention, in addition to data from the U.S. Census Bureau, U.S. Department of Agriculture, and U.S. Department of Health and Human Services, to carry out a spatial regime analysis to identify county level factors correlated with diabetes prevalence in the Diabetes Belt versus the remainder of the U.S. RESULTS: Counties outside of the Diabetes Belt demonstrated stronger positive associations between diabetes prevalence and persistent poverty and greater percentages of unemployed labor forces. For counties in the Diabetes Belt, diabetes prevalence showed a stronger positive association with natural amenities (e.g., temperate climate and topographic features) and a stronger negative association with fitness/recreation facility density. CONCLUSIONS: Community-level correlates of diabetes prevalence differed between the Diabetes Belt and elsewhere in the U.S. Economic hardship was shown to be more relevant outside the Diabetes Belt, while recreational context effects were more pronounced among counties within the region. Prevention and treatment targets are geographically unique, and public health efforts should acknowledge these differences in crafting policy. PMID- 28009110 TI - Re: Intimate partner violence during pregnancy and the risk for adverse infant outcomes: a systematic review and meta-analysis: Anxiety and depression may contribute to birth outcome related to intimate partner violence. PMID- 28009111 TI - Authors' reply re: Parental physical and lifestyle factors and their association with newborn body composition. PMID- 28009112 TI - Hyperemersis gravidarum: past hysteria and present needs. PMID- 28009109 TI - Computational models of the neural control of breathing. AB - The ongoing process of breathing underlies the gas exchange essential for mammalian life. Each respiratory cycle ensues from the activity of rhythmic neural circuits in the brainstem, shaped by various modulatory signals, including mechanoreceptor feedback sensitive to lung inflation and chemoreceptor feedback dependent on gas composition in blood and tissues. This paper reviews a variety of computational models designed to reproduce experimental findings related to the neural control of breathing and generate predictions for future experimental testing. The review starts from the description of the core respiratory network in the brainstem, representing the central pattern generator (CPG) responsible for producing rhythmic respiratory activity, and progresses to encompass additional complexities needed to simulate different metabolic challenges, closed loop feedback control including the lungs, and interactions between the respiratory and autonomic nervous systems. The integrated models considered in this review share a common framework including a distributed CPG core network responsible for generating the baseline three-phase pattern of rhythmic neural activity underlying normal breathing. WIREs Syst Biol Med 2017, 9:e1371. doi: 10.1002/wsbm.1371 For further resources related to this article, please visit the WIREs website. PMID- 28009113 TI - Authors' reply re: Incidence of and risk factors for vasa praevia: a systematic review. PMID- 28009114 TI - Guilt, blame and litigation: can an overenthusiastic 'safety culture' cause harm? PMID- 28009115 TI - A report from #BlueJC: Can we include more pregnant women in drug trials? PMID- 28009116 TI - Gestational weight gain: 'tipping the scales' in our favour. PMID- 28009117 TI - Authors' reply re: The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross-sectional study. PMID- 28009118 TI - Re: Time to optimise and enforce training in interpretation of intrapartum cardiotocograph: Time is not ripe for imposing pass/fail licensing examination in cardiotocography interpretation in UK. PMID- 28009120 TI - Re: Intimate partner violence destroys love like tears blur clear vision: Failing our patients. PMID- 28009121 TI - Re: Abnormally invasive placenta-Prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries. PMID- 28009122 TI - Re: Incidence of and risk factors for vasa praevia: a systematic review: Vasa praevia screening. PMID- 28009123 TI - Moving from intra partum to prenatal diagnosis of placenta accreta: a quarter of a century in the making but still a long road to go. PMID- 28009124 TI - Re: The epidemiology and outcomes of women with postpartum haemorrhage requiring massive transfusion with eight or more units of red cells: a national cross sectional study. PMID- 28009125 TI - Author's reply re: Time to optimise and enforce training in interpretation of intrapartum cardiotocograph. PMID- 28009126 TI - Reviews, reviews, reviews. PMID- 28009127 TI - Re: Parental physical and lifestyle factors and their association with newborn body composition. PMID- 28009128 TI - Authors' reply re: Abnormally invasive placenta-Prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries. PMID- 28009129 TI - Never Events - the ongoing problem of the retained vaginal sponge/swab. PMID- 28009130 TI - A useful way to develop effective in vivo skin optical clearing agents. AB - Skin optical clearing has shown tremendous potential in improving various optical imaging performances, but there is some certain blindness in screening out high efficiency in vivo optical clearing methods. In this work, three optical clearing agents: sucrose (Suc), fructose (Fruc) and PEG-400 (PEG), and two chemical penetration enhancers: propylene glycol (PG) and thiazone (Thiaz) were used. PEG was firstly mixed with the two penetration enhancers, respectively, and then mixed with Fruc and Suc, respectively, to obtain six kinds of skin optical clearing agents (SOCAs). Optical coherence tomography angiography was applied to monitor SOCAs-induced changes in imaging performances, skin optical properties, refractive index mismatching extent, and permeability rate. Experimental results demonstrated that PEG+Thiaz+Suc has the optimal capacity in enhancing the imaging performances, decreasing the scattering and the refractive index mismatching since Thiaz is superior to PG, and Suc is superior to Fruc. This study indicates that the optimal SOCA can be obtained directly by means of additionally adding or replacing the similar category substance in preexisting SOCAs with some more effective reagents. It not only provides an optimal SOCA, but also provides a useful way to develop more effective SOCAs. Cross-section skin structural texture (a), reconstructed blood flow distribution information (b), before or after treated with different SOCAs. PMID- 28009131 TI - Comparative study of presurgical skin infiltration depth measurements of melanocytic lesions with OCT and high frequency ultrasound. AB - A reliable, fast, and non-invasive determination of melanoma thickness in vivo is highly desirable for clinical dermatology as it may facilitate the identification of surgical melanoma margins, determine if a sentinel node biopsy should be performed or not, and reduce the number of surgical interventions for patients. In this work, optical coherence tomography (OCT) and high frequency ultrasound (HFUS) are evaluated for quantitative in vivo preoperative assessment of the skin infiltration depth of melanocytic tissue. Both methods allow non-invasive imaging of skin at similar axial resolution. Comparison with the Breslow lesion thickness obtained from histopathology revealed that OCT is slightly more precise in terms of thickness determination while HFUS has better contrast. The latter does not require image post-processing, as necessary for the OCT images. The findings of our pilot study suggest that non-invasive OCT and HFUS are able to determine the infiltration depth of lesions like melanocytic nevi or melanomas preoperatively and in vivo with a precision comparable to invasive histopathology measurements on skin biopsies. In future, to further strengthen our findings a statistically significant study comprising a larger amount of data is required which will be conducted in an extended clinical study in the next step. Comparison of optical coherence tomography and high frequency ultrasound B-Scans and a H&E stained histology of a melanocytic nevus. PMID- 28009132 TI - Tract-specific atrophy in focal epilepsy: Disease, genetics, or seizures? AB - OBJECTIVE: To investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts. METHODS: Medically refractory unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS-TLE, n = 26) was studied as an archetype of focal epilepsy, using fixel-based analysis of diffusion-weighted imaging. A genetic effect was assessed in first-degree relatives of HS-TLE subjects who did not have epilepsy themselves (HS-1 degrees Rel; n = 26). The role of disease process was uncovered by comparing HS-TLE to unilateral TLE with normal clinical magnetic resonance imaging (MRI-neg TLE; n = 26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS-TLE and MRI-neg TLE, in comparison to healthy controls (n = 76). RESULTS: HS-1 degrees Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS-TLE subjects had lateralized atrophy of most temporal lobe tracts, and hippocampal volumes in HS-TLE correlated with parahippocampal cingulum and anterior commissure atrophy, indicating an effect of the underlying pathology. Ipsilateral atrophy of the tapetum, uncinate, and inferior fronto-occipital fasciculus was found in both HS-TLE and MRI-neg TLE, suggesting a common lateralized effect of focal seizures. Both epilepsy groups had bilateral atrophy of the dorsal cingulum and corpus callosum fibers, which we interpret as a consequence of bilateral insults (potentially generalized seizures and/or medications). INTERPRETATION: Underlying pathology, repeated focal seizures, and global insults each contribute to atrophy in specific tracts. Genetic factors make less of a contribution in this cohort. A multifactorial model of white matter atrophy in focal epilepsy is proposed. Ann Neurol 2017;81:240-250. PMID- 28009133 TI - Raman micro-spectroscopy applied to treatment resistant and sensitive human ovarian cancer cells. AB - Despite the many advances intended to enhance the response to treatment, the survival rate of patients with ovarian cancer has only marginally improved in the past few decades. One major cause for this, is the lack of diagnostics for platinum-resistant disease. The goal of this study was to determine whether Raman micro-spectroscopy in conjunction with multivariate statistical analysis could discriminate between chemically fixed cisplatin-resistant (A2780cp) and cisplatin sensitive (A2780s) human ovarian carcinoma cells. Raman spectra collected from individual cells were pre-processed and subsequently analyzed with Principal Component Analysis - Linear Discriminant Analysis (PCA-LDA). Statistically significant differences (P < 0.0001) were observed between the Raman spectra of A2780s and A2780cp cells. A diagnostic accuracy of 82% was obtained using the PCA LDA classifier model for the discrimination between the A2780s and A2780cp cells. The loading plot analysis suggests that relative increases in proteins and glutathione in the cisplatin-resistant cells compared to the cisplatin-sensitive cells are most likely the major source of discrimination between the two types of cells. These results support the potential application of Raman spectroscopy in the identification of chemo-resistant tumors prior to treatment. PMID- 28009134 TI - Raman spectroscopy and PCA-SVM as a non-invasive diagnostic tool to identify and classify qualitatively glycated hemoglobin levels in vivo. AB - In this study we identify and classify high and low levels of glycated hemoglobin (HbA1c) in healthy volunteers (HV) and diabetic patients (DP). Overall, 86 subjects were evaluated. The Raman spectrum was measured in three anatomical regions of the body: index fingertip, right ear lobe, and forehead. The measurements were performed to compare the difference between the HV and DP (22 well controlled diabetic patients (WCDP) (HbA1c <6.5%), and 49 not controlled diabetic patients (NCDP) (HbA1c >=6.5%)). Multivariable methods such as principal components analysis (PCA) combined with support vector machine (SVM) were used to develop effective diagnostic algorithms for classification among these groups. The forehead of HV versus WCDP showed the highest sensitivity (100%) and specificity (100%). Sensitivity (100%) and specificity (60%), were highest in the forehead of WCDP, versus NCDP. In HV versus NCDP, the fingertip had the highest sensitivity (100%) and specificity (80%). The efficacy of the diagnostic algorithm by receiver operating characteristic (ROC) curve was confirmed. Overall, our study demonstrated that the combination of Raman spectroscopy and PCA-SVM are feasible non-invasive diagnostic tool in diabetes to classify qualitatively high and low levels of HbA1c in vivo. PMID- 28009137 TI - Osteonecrosis as a complication in pediatric patients with acute lymphoblastic leukemia. AB - Osteonecrosis is a significant adverse effect of treatment administered to children suffering from acute lymphoblastic leukemia (ALL) that may have a negative effect on the quality of life. The purpose of this study is to evaluate the rate of secondary vascular osteonecrosis (ON) in a population of pediatric patients with ALL treated with corticosteroids and cytostatic agents. A retrospective analysis of prospectively collected data of the medical records of 328 patients with ALL identified 4 cases with ON, corresponding to 1.2% of all cases observed. Of the 4 patients identified in our study 3 were girls and 1 was a boy, aged from 10 to 16 years old (average age at diagnosis, 12 years). Median time between the diagnosis of ALL and ON was 12.5 months (range, 12 to 36 months). Regarding the lesion size of ON, in all cases the femoral head (monolateral in 1 case and bilateral in 3 cases) was involved and was associated with the scapula-humeral joint in one case. ON of the weight-bearing joints has been identified as a severe complication in children with leukemia that may be associated with the development of articular surface collapse, subsequent debilitating arthritis, sometimes needing arthroplasty. For this reason it is very important to implement prevention strategies, especially in adolescent girls treated with steroids and chemotherapy. An early diagnosis of ON and careful orthopedic follow-up are necessary in order to avoid bone deformations related to the late start or the wrong therapy. PMID- 28009135 TI - Diagnostics of femoral head status in humans using laser spectroscopy - In vitro studies. AB - Osteonecrosis of the femoral head (ONFH), a recalcitrant and disabling disease, is caused by inadequate or fully disrupted blood supply to the affected segment of the subchondral bone. Theoretically, there will develop gas-filled pores during the bone decay process due to lacking blood supply. Unfortunately, the relationship between the gas-filled pores and ONFH is still unclear. Here, we have introduced diode laser absorption spectroscopy to detect oxygen and water vapor signals in the femoral heads from hip replacement in 19 patients. Five samples are affected by osteoarthritis (OA) and the others are related to ONFH. Oxygen and water vapor signals could be obtained, demonstrating the presence of gas-filled pores in both the OA and ONFH groups while the measurement results showed no significant difference. A study of gas exchange was also performed on one excised bone sample to study how these gas pores communicate with the ambient air. The results suggested that the obtained oxygen signals inside the bone samples originate from the invasion of ambient air, which is not expected in vivo. In conclusion, the ability to detect the gas signal of laser absorption spectroscopy shows the potential for the medical application of assessing the human femoral head in vivo. PMID- 28009138 TI - Intracorporeal hybrid single port vs conventional laparoscopic appendectomy in children. AB - Transumbilical laparoscopic assisted appendectomy combines laparoscopic single port dissection with open appendectomy after exteriorization of the appendix through the port site. Compared to the conventional three-port approach, this technique provides an alternative with excellent cosmetic outcome. We developed a safe and effective technique to perform an intracorporeal single port appendectomy, using the same laparoscope employed in the extracorporeal procedure. Retrospective review of 71 consecutively performed intracorporeal single port appendectomies and 30 conventional three-port appendectomies in children 6 to 17 years of age. A straight 10-mm Storz telescope with inbuilt 6 mm working channel is used to dissect the appendix, combined with one port-less 2.3 mm percutaneous grasper. Polymer WECK(r) hem-o-lock(r) clips are applied to seal the base of the appendix and the appendiceal vessels. No intraoperative complications were reported with the hybrid intracorporeal single port appendectomy or three-port appendectomy. There were two post-operative complications in the group treated with the single port hybrid technique: one intra-abdominal abscess and one surgical site infection. Groups did not differ in age, weight, and types of appendicitis. Operative times were shorter for the hybrid technique (70 vs 79 minutes) but did not differ significantly (P=0.19). This modified technique to a previously described single port extracorporeal appendectomy is easy to master and implement. It provides exposure similar to a three-port laparoscopic appendectomy, while maintaining virtually scarless results and potentially reduces the risk for surgical site infections compared to the extracorporeal technique. PMID- 28009139 TI - Neonatal gastrointestinal involvement and congenital cytomegalovirus. AB - Cytomegalovirus (CMV) is the most common cause of congenital viral infection, affecting 0.2 to 2.3% of all live births in developed countries. Very low birth weight and extremely low birth weight newborns are at higher risk of symptomatic CMV infection, most commonly secondary and acquired through breast milk. Gastrointestinal involvement is rare in acquired CMV infections, but it could be an important manifestation of postnatal infection in preterm infants admitted to neonatal intensive care units. Early onset of CMV gastrointestinal signs/symptoms is very rare. In a review of the literature it is described in 5 newborns in the first 24 hours of life, and 6 considering the onset in the first week of life. This review describes also a case report of congenital CMV in an immunocompetent newborn with onset of gastrointestinal signs immediately after birth: a possible association between viral infection and enteric manifestations was considered in the differential diagnosis. A review of the literature of the different case reports found has done, with description and comparison of the different patients and clinical presentations. PMID- 28009140 TI - Wandering spleen with a ten-time twisted vascular pedicle. AB - Torsion of a wandering spleen is a rare cause of acute abdomen in children, usually diagnosed with color-Doppler ultrasonography and enhanced computed tomography. We report a pediatric case of torsion of wandering spleen. PMID- 28009141 TI - Operative cystoscopy in the neonatal period. AB - Aim of the study is to report the experience in the last three years about endourological treatment of newborns affected by genito- and urinary malformation, implying critical urinary tract dilatation and bladder mass requiring a neonatal operative management. Seven - four males and three female - patients were treated cystoscopically during the neonatal period. Three newborns with a posterior urethral valves (PUV), underwent a successful ablation of PUV. In a male with infected persistent large mullerian duct and subsequent acute urinary retention, a cystoscopically-assisted catheterization was performed. Two females, one with cloaca and the other with high persistent urogenital sinus and massive associated hydrometrocolpos underwent a cystoscopical drainage of the vagina and a positioning of a balloon catheter into the bladder. Another female with a bladder mass had a endoscopical biopsy. Thanks to modern neonatal operative urethrocystoscope, today is possible to treat early many pathological genito-urinary conditions in newborns. PMID- 28009142 TI - Robotic kidney transplantation: current status and future perspectives. AB - INTRODUCTION: For the treatment of patients with end-stage renal disease, kidney transplantation is preferred to renal replacement modalities such as hemodialysis and peritoneal dialysis. Although open surgery remains the gold standard, minimally invasive approaches have recently been applied in transplant kidney surgery. Despite growing enthusiasm and potential benefits of robotic kidney transplant, many aspects of this novel technique remain controversial. Aim of this study was to analyze the current status and future developments in robotic assisted surgery for kidney transplantation. EVIDENCE ACQUISITION: A systematic PubMed search for peer-reviewed studies was performed using keywords such as "Minimally invasive surgery" or "Robotic" or "Robot assisted" AND "Kidney transplantation". Eligible articles were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. EVIDENCE SYNTHESIS: Eleven studies evaluated reported the feasibility, safety, and reproducibility of robotic kidney transplantation using either a transperitoneal or an extraperitoneal approach. The graft kidney is usually introduced via a periumbilical or Gibson incision. The functional outcomes of the robotic approach are equivalent to those of open kidney transplantation in terms of mean serum creatinine at 6 month and delayed graft function. The benefits of robotic kidney transplantation include easier vascular anastomosis, better cosmetic results, and a lower complication rate, including in the obese population. Many concerns remain over the potential impairment of graft function due to pneumoperitoneum and warm ischemia and the technical difficulties related to the vascular anastomosis. Refinement of the robotic tactile feedback and development of a cold ischemia device may lead to further improvement in this novel technique. CONCLUSIONS: Robotic surgery allows kidney transplantation to be performed under optimal operative conditions, reducing complications while maintaining the functional results achieved by the open approach. The evolution of this technique is in progress. PMID- 28009143 TI - Robotic intracorporeal urinary diversion: practical review of current surgical techniques. AB - In this practical review, we discuss current surgical techniques reported in the literature to perform intracorporeal urinary diversion (ICUD) after robotic radical cystectomy (RARC), emphasizing criticisms of single approaches and making comparisons with extracorporeal urinary diversion (ECUD). Although almost 97% of all RARCs use an ECUD, ICUD is gaining in popularity, in view of its potential benefits (i.e., decreased bowel exposure, etc.), although there are a few studies comparing ICUD and ECUD. Analyzing single experiences and the data from recent metanalyses, we emphasize the current critiques to ICUD, stressing particular technical details which could reduce operative time, lowering the postoperative complications rate, and improving functional outcomes. Only analysis of long-term follow-up data from large-scale homogeneous series can ascertain whether robotic intracorporeal urinary diversion is superior to other approaches. PMID- 28009144 TI - Robot assisted lymphadenectomy in urology: pelvic, retroperitoneal and inguinal. AB - Lymph node dissection represents an essential surgical step in the treatment of the most commonly treated urological cancers. The introduction of robotic surgery has lead to the possibility of treating these diseases with a minimally invasive surgical approach, but the surgical principles of open surgery need to be carefully respected in order to achieve comparable oncological results. Therefore, the robotic approach to urological cancers must include a carefully performed lymph node dissection when indicated. In the current manuscript we reviewed the current indications and extensions of lymph node dissection in prostate, bladder, testicular, upper urinary tract, renal and penile cancers respectively, with a special focus on the state of the art surgical technique for each procedure. PMID- 28009145 TI - Predicting the risk of positive surgical margins following robotic-assisted radical prostatectomy. AB - INTRODUCTION: The number of men receiving radical prostatectomy (RP) in Victoria, Australia, increased seven-fold in the period 1993-2010, and increasingly robotic assisted radical prostatectomy (RARP) is being utilized over the open and laparoscopic approaches. The longer-term oncological outcomes of RARP are beginning to be reported in the literature. The objective of this review was to determine whether any preoperative variables may be associated with the occurrence of positive surgical margins (PSMs) following RARP and how these may translate into subsequent risk of biochemical recurrence (BCR). EVIDENCE ACQUISITION: A systematic review of English articles from 2005 to present was performed through a MEDLINE search. Search terms included "positive surgical margins", "biochemical recurrence", "radical prostatectomy" and "prostate cancer". EVIDENCE SYNTHESIS: All studies included for review were retrospective analyses of series that reported on rates of PSM and BCR achieved with RARP, and considered potential factors that may influence the rates observed. CONCLUSIONS: RARP appears to confer lower rates of PSM when compared to the established approaches. Recent reports included in this review indicate that RARP should be able to provide excellent oncological outcomes as a result. PMID- 28009146 TI - Positive surgical margins and early oncological outcomes of robotic vs open radical prostatectomy at a medium case-load institution. AB - BACKGROUND: The aim of this study was to analyze the rates of positive surgical margins (PSM) after radical prostatectomy in patients undergoing robotic surgery (robot assisted laparoscopic prostatectomy [RALP]) compared with those undergoing open surgery (radical retropubic prostatectomy [RRP]), at an institution with medium case load. METHODS: Retrospective consultation of a perspectively maintained database that stores the data of all the patients submitted to radical prostatectomy at our institution since 1/2008. The indication to RRP vs. RALP was based almost exclusively on the period of the study: RRP was the sole available option between 1/2008 and 3/2010 and afterwards RALP become the standard of treatment, once a learning curve of 50 cases was concluded. A PSM was defined as the presence of cancer at the inked surface of prostate. A univariate and multivariate binary logistic regression estimated which factors were related to PSMs. RESULTS: The data of 576 patients (285 RRP, 291 RALP) were evaluated. The overall PSM rate was 28.1% (162/414 patients; 20.6% for pT2 stage, 51.8% for pT>2); overall PSM rate for RRP vs. RALP was 31.9% vs. 24.4 % (P=0.044). At multivariable analysis the factors related to the risk of PSM were stage pT>2 (RR 2.979, P=0.001), Gleason Score >6 (RR 1.662, P=0.026), the volume of tumor (RR 1.019, P=0.008) and the surgical technique (RALP vs. RRP, RR 0.647, P=0.039). CONCLUSIONS: In a series from a medium case-load institution, once data are adjusted for local staging, tumor volume and Gleason score, the risk of PSM is lower for RALP than RRP. This evidence could be of support for health-care practitioners to introduce robotic systems. PMID- 28009147 TI - Ten-year experience of robot-assisted radical prostatectomy: the road from cherry picking to standard procedure. AB - BACKGROUND: Patients treated with robot-assisted radical prostatectomy (RARP) are frequently selected according to more favorable characteristics. Such patient selection might decrease according to increasing experience. METHODS: We relied on the Martini Clinic Prostate Cancer Center database and focused on patients treated with RARP between 2004 and 2013. Differences in clinical, pathological and surgical characteristics at RARP over time (2004-2010, 2011-2012 and 2013) were assessed. RESULTS: Overall, 1783 RARP patients were identified. Of those, 407 (22.8%), 764 (42.8%) and 612 (34.3%) were treated between 2004 and 2010, in 2011-2012 and in 2013, respectively. Unfavorable characteristics rate, such as biopsy Gleason Score >=4+4 (8 vs. 9 vs. 15%, P<0.001), D'Amico high-risk (12 vs. 14 vs. 19%, P=0.001) and pathological Gleason score >=4+4 (3 vs. 4 vs. 6%, P<0.001) increased over time. Pelvic lymph node dissection (PLND) was more frequently performed over time (62 vs. 83 vs. 84%, P<0.001), especially in D'Amico intermediate or high-risk patients (82 vs. 94 vs. 96%, P<0.001). Lymph node yield increased over time in overall (7 vs. 9 vs. 13, P<0.001), D'Amico intermediate (6 vs. 9 vs. 12, P<0.001) and D'Amico high-risk patients (9 vs. 12 vs. 18, P<0.001). No differences in surgical margin (P=0.7) and nerve sparing rates (P=0.09) were found. CONCLUSIONS: A clear trend towards more unfavorable tumor characteristics over time was recorded. Additionally, the rates and extent of PLND increased with increasing experience. RAR P does not represent a barrier to PLND at our institution. PMID- 28009148 TI - The impact of previous prostate surgery on the outcomes of laparoscopic radical prostatectomy. AB - BACKGROUND: The aim of this study was to evaluate the outcomes in laparoscopic radical prostatectomy (LRP) in patients who had undergone prior prostate surgery (PPS). METHODS: In this study 946 consecutive LR P patients were included and a retrospective comparison between those patients who had received PPS (group A) and those who had not received PPS (group B) was carried out. The preoperative, intraoperative and postoperative data was collected in a prospectively-maintained database. All complications occurring <=30 days after surgery were recorded and defined according to the Dindo-modification of the Clavien system. RESULTS: Longer operative time, greater blood loss, longer catheterization time, higher incidence of lymphocele, rectal injury and anastomotic stricture were found to be more frequent in group A. No statistically significant difference was noted between the two groups in terms of positive surgical margin rate and Biochemical recurrence free survival (BCRFS). Complete urinary continence rate resulted significantly higher in group B patients at both 1-year and 2-year follow-up. Potency rate resulted better in group B patients even if a statistically significant difference for both unilateral and bilateral nerve sparing techniques was not reached. CONCLUSIONS: LRP procedure can be safely performed on patients who have previously undergone PPS without compromising oncologic safety whereas a negative impact on functional outcome in terms of achieving a complete urinary continence rate and sexual potency should be expected. PMID- 28009149 TI - Robotic assisted laparoscopic radical prostatectomy following transrectal compared to transperineal prostate biopsy: surgical, oncological and functional outcomes. AB - BACKGROUND: To assess if transperineal prostate (TP) biopsy affects th e outcome of robotic-assisted laparoscopic prostatectomy (RALP), with particular reference to perioperative complications, oncological results and functional outcomes in the early postoperative setting. METHODS: We identified 61 men who had undergone RALP after TP biopsies, from June 2012 to June 2014 and a control group of 120 men who had undergone RALP after conventional TRUS biopsy in the same period. Data was compared from the pre-operative biopsy, peri- and postoperative period, procedural outcomes including histological, oncological and functional outcomes between the groups. RESULTS: The groups had comparable demographics, with matched median ages and PSA levels. There was a higher incidence of Gleason 6 disease detected in the TRUS group (P=0.01). Mean operative time (146 minutes TRUS vs. 158 minutes TP, P=0.133), blood loss (250 mL TRUS vs. 288 mL TP, P=0.462) and intraoperative complications were not significantly different between groups. Median length of stay (1 day) and median catheter duration (7 days) were identical in both cohorts. PSA failure rate at 6 months was similar (11.7% TRUS vs. 9.8% TP, P=0.904). There were no differences in functional outcomes (potency or continence) between groups at 6 month s follow-up. CONCLUSIONS: RALP is safe after TP biopsy with no adverse impact on oncological or short-term functional outcomes. PMID- 28009150 TI - High intensity focused ultrasound as first line salvage therapy in prostate cancer local relapse after radical prostatectomy: 4-year follow-up outcomes. AB - BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer death in developed countries. Despite the primary treatments, 20-30% of patients experience a recurrence. The main objective of this study was to evaluate the clinical efficacy of salvage high intensity focused ultrasound (HIF U) after radical prostatectomy in terms of biochemical free survival rate (BFSR) and PSA nadir. METHODS: Twenty two patients with local recurrence of Pca after radical prostatectomy underwent HIFU as first line salvage therapy. Considering that in all HIFU experiences, PSA nadir and PSA failure are different and PSA definition of BFSR is unknown, we defined treatment success as a PSA nadir <=0.4 ng/mL 3 months after treatment. All early and late medical and surgical complications were recorded. RESULTS: Ten of the 22 patients (45.5%) were classified as "success" three months after HIFU, showing a nadir PSA<=0.4 ng/mL; 12/22 patients (54.5%) were classified as "failure" during follow up (median follow-up: 48 months). Seventeen of 22 (77%) patients were continent (no-pad) before HIFU. A new diagnosis of stress urinary incontinence was made in 5 cases (early onset) after treatment. A case of vesicoureteral anastomotic stenosis was treated, endoscopically through cold urethrotomy. We did not observe cases of recto-urinary fistula or persistent lower urinary tract symptoms. Two sevenths of the patients complained about de novo erectile dysfunction after HIFU. CONCLUSIONS: The positive oncologic outcomes in the short term anyway obtained in selected patients, associated with documented mild side effects, represent the basis to start more organic, prospective, randomized and multicenter study protocols, that with a long term follow-up could confirm these promising preliminary results. PMID- 28009151 TI - Comparing conventional laparoscopic to robotic-assisted extended pelvic lymph node dissection in men with intermediate and high-risk prostate cancer: a matched pair analysis. AB - BACKGROUND: In intermediate and high-risk prostate cancer patients, a robotic assisted approach is increasingly being used for prostatectomy and extended pelvic lymph node dissection (ePLND). This is reducing the number of conventional laparoscopic radical prostatectomies (LR P) and laparoscopic ePLNDs for prostate cancer in Europe. Aim of this study is to compare laparoscopic ePLND to robotic assisted ePLND in a cohort of patients with intermediate and high risk prostate cancer. METHODS: We performed a matched-pair analysis matching 1:1 70 patients who underwent LRP+ePLND (2004-2009) to 70 who underwent RAR P+ePLND (2010-2014). All patients presented with intermediate or high-risk prostate cancer according to D'Amico classification. Patients were retrospectively analyzed. Differences in pathologic characteristics and postoperative complications across the two groups were assessed using Wilcoxon Rank sum or chi2 Test. RESULTS: LRP was associated with shorter OR times and decreased blood loss (P<0.001). However, in the robotic assisted arm, more lymph nodes were retrieved (18 vs. 12; P<001). No significant difference in positive surgical margins was found across the two techniques (P=0.9). Lymphocele formation and prolonged lymphorrea were specifically addressed as complications, with no significant difference emerging from our analyses (P>0.74). CONCLUSIONS: In this matched-pair analysis comparing patients with intermediate and high-risk prostate cancer, a robotic-assisted approach was associated to a higher lymph node yield compared to conventional laparoscopy. However, this increase in node yield was balanced with longer OR times, increased blood loss, similar postoperative complications and similar oncologic outcomes. Larger and prospective studies in patients at high risk are necessary to validate these findings. PMID- 28009152 TI - Lung tumors, COPD and immune response: is epigenetics the bottom line? AB - NSCLC is a heterogeneous disorder consisting of distinct molecular subtypes which can be treated by using specific drugs targeted to distinct genetic lesions. It is well known that NSCLS incidence is higher in chronic obstructive pulmonary disease (COPD) patients because they share a common risk factor (cigarette smoking) and it is believed that the typical inflammatory microenvironment observed in COPD may influence the molecular mechanisms responsible of carcinogenesis. In the last years, the role of epigenetic processes in cell biology and tissue pathology has been extensively studied both in COPD and NSCLC. The recent paper by Wauters et al. showed a specific pattern of driver mutations and molecular features in NSCLC raising in the context of COPD. All these findings have shown for the first time that lung tumors found in COPD patients differ from those observed in patient without COPD due to the presence of a specific tumor microenvironment which is characterized by reduced CD4+ Treg cells. On this basis, the present work aims at discussing and analyzing the context-specific mechanisms of clonal selection and evolution mainly focusing on the epigenetic alterations and at pointing out the potential therapeutic implications. PMID- 28009153 TI - Is neural drive the missing piece in the puzzle of COPD exacerbation? AB - The decision to discharge in patients affected by acute exacerbation of COPD remains a common problem due to the complexity of the assessment of clinical recovery, with early readmission perceived as a marker of incompleteness of the received treatment. The neural respiratory drive, assessed by parasternal muscle electromyography, represents an estimate of the load imposed to the respiratory muscles and it may identify early clinical deterioration. The test is noninvasive, may be executed bedside, but requires experienced operators. Yet, feasibility and clinical interpretation outside reference centers seem to be the main unsolved issues in the implementation of the technique in clinical practice. PMID- 28009154 TI - High flow nasal cannula oxygen therapy, work in progress in respiratory critical care. AB - After a planned extubation, the re-occurrence of acute respiratory distress needing the restoration of invasive mechanical support is a severe phenomenon associated with several important consequences, including increased morbidity, Intensive Care Unit mortality, and an enormous financial burden. So far, the most commonly used techniques to ameliorate gas exchange in the postextubation period were low-flow oxygen therapy and non-invasive ventilation (NIV). High flows through nasal cannulae (HFNC) is a system which allows increased CO2 wash-out of anatomical dead space, positive nasopharyngeal pressure, a relatively constant FiO2, and an improvement of mucociliary function. In a recently published paper by Hernandez et al. HFNC therapy, compared in the postextubation period to standard oxygen in patients at low risk of re-intubation, was associated with a lower re-intubation rate within 72 hours of extubation, with no evidence of any delays in re-intubation which may prove fatal, as previously reported in the context of NIV. Despite yielding some useful starting points and positive results with HFNC, some discrepancies have emerged in the findings of the studies in this field. As we await further more homogeneous and enlightening studies, at present we can only affirm that HFNC seems to be a useful means to prevent and treat postextubation hypoxemia. In fact no harmful or adverse effects related to HFNC emerged in any of the studies and globally, it was associated with better comfort and tolerance compared with NIV, which justifies its use as a first alternative to standard oxygen therapy. PMID- 28009155 TI - Three-Dimensional Printing of Shape Memory Composites with Epoxy-Acrylate Hybrid Photopolymer. AB - Four-dimensional printing, a new process to fabricate active materials through three-dimensional (3D) printing developed by MIT's Self-Assembly Lab in 2014, has attracted more and more research and development interests recently. In this paper, a type of epoxy-acrylate hybrid photopolymer was synthesized and applied to fabricate shape memory polymers through a stereolithography 3D printing technique. The glass-to-rubbery modulus ratio of the printed sample determined by dynamic mechanical analysis is as high as 600, indicating that it may possess good shape memory properties. Fold-deploy and shape memory cycle tests were applied to evaluate its shape memory performance. The shape fixity ratio and the shape recovery ratio in ten cycles of fold-deploy tests are about 99 and 100%, respectively. The shape recovery process takes less than 20 s, indicating its rapid shape recovery rate. The shape fixity ratio and shape recovery ratio during 18 consecutive shape memory cycles are 97.44 +/- 0.08 and 100.02 +/- 0.05%, respectively, showing that the printed sample has high shape fixity ratio, shape recovery ratio, and excellent cycling stability. A tensile test at 62 degrees C demonstrates that the printed samples combine a relatively large break strain of 38% with a large recovery stress of 4.7 MPa. Besides, mechanical and thermal stability tests prove that the printed sample has good thermal stability and mechanical properties, including high strength and good toughness. PMID- 28009156 TI - Mechanism of Capacity Fade in Sodium Storage and the Strategies of Improvement for FeS2 Anode. AB - Pyrite FeS2 has attracted extensive interest as anode material for sodium-ion batteries due to its high capacity, low cost, and abundant resource. However, the micron-sized FeS2 usually suffers from poor cyclability, which stems from structure collapse, exfoliation of active materials, and sulfur dissolution. Here, we use a synergistic approach to enhance the sodium storage performance of the micron-sized FeS2 through voltage control (0.5-3 V), binder choice, and graphene coating. The FeS2 electrode with the synergistic approach exhibits high specific capacity (524 mA h g-1), long cycle life (87.8% capacity retention after 800 cycles), and excellent rate capability (323 mA h g-1 at 5 A g-1). The results prove that a synergistic approach can be applied in the micron-sized sulfides to achieve high electrochemical performance. PMID- 28009157 TI - Solar Water Splitting and Nitrogen Fixation with Layered Bismuth Oxyhalides. AB - Hydrogen and ammonia are the chemical molecules that are vital to Earth's energy, environmental, and biological processes. Hydrogen with renewable, carbon-free, and high combustion-enthalpy hallmarks lays the foundation of next-generation energy source, while ammonia furnishes the building blocks of fertilizers and proteins to sustain the lives of plants and organisms. Such merits fascinate worldwide scientists in developing viable strategies to produce hydrogen and ammonia. Currently, at the forefronts of hydrogen and ammonia syntheses are solar water splitting and nitrogen fixation, because they go beyond the high temperature and pressure requirements of methane stream reforming and Haber-Bosch reaction, respectively, as the commercialized hydrogen and ammonia production routes, and inherit the natural photosynthesis virtues that are green and sustainable and operate at room temperature and atmospheric pressure. The key to propelling such photochemical reactions lies in searching photocatalysts that enable water splitting into hydrogen and nitrogen fixation to make ammonia efficiently. Although the past 40 years have witnessed significant breakthroughs using the most widely studied TiO2, SrTiO3, (Ga1-xZnx)(N1-xOx), CdS, and g-C3N4 for solar chemical synthesis, two crucial yet still unsolved issues challenge their further progress toward robust solar water splitting and nitrogen fixation, including the inefficient steering of electron transportation from the bulk to the surface and the difficulty of activating the N=N triple bond of N2. This Account details our endeavors that leverage layered bismuth oxyhalides as photocatalysts for efficient solar water splitting and nitrogen fixation, with a focus on addressing the above two problems. We first demonstrate that the layered structures of bismuth oxyhalides can stimulate an internal electric field (IEF) that is capable of efficiently separating electrons and holes after their formation and of precisely channeling their migration from the bulk to the surface along the different directions, thus enabling more electrons to reach the surface for water splitting and nitrogen fixation. Simultaneously, their oxygen termination feature and the strain differences between interlayers and intralayers render the easy generation of surface oxygen vacancies (OVs) that afford Lewis-base and unsaturated-unsaturated sites for nitrogen activation. With these rationales as the guideline, we can obtain striking visible-light hydrogen- and ammonia-evolving rates without using any noble-metal cocatalysts. Then we show how to utilize IEF and OV based strategies to improve the solar water splitting and nitrogen fixation performances of bismuth oxyhalide photocatalysts. Finally, we highlight the challenges remaining in using bismuth oxyhalides for solar hydrogen and ammonia syntheses, and the prospect of further development of this research field. We believe that our mechanistic insights could serve as a blueprint for the design of more efficient solar water splitting and nitrogen fixation systems, and layered bismuth oxyhalides might open up new photocatalyst paradigm for such two solar chemical syntheses. PMID- 28009158 TI - Hyperpolarized Nanodiamond Surfaces. AB - The widespread use of nanodiamond as a biomedical platform for drug-delivery, imaging, and subcellular tracking applications stems from its nontoxicity and unique quantum mechanical properties. Here, we extend this functionality to the domain of magnetic resonance, by demonstrating that the intrinsic electron spins on the nanodiamond surface can be used to hyperpolarize adsorbed liquid compounds at low fields and room temperature. By combining relaxation measurements with hyperpolarization, spins on the surface of the nanodiamond can be distinguished from those in the bulk liquid. These results are likely of use in signaling the controlled release of pharmaceutical payloads. PMID- 28009159 TI - Delocalized Hypervalent Silyl Radical Supported by Amidinate and Imino Substituents. AB - The reaction of the amidinato silylsilylene with a functionalized diaminochlorosilyl substituent, [LSiSi(Cl){(NtBu)2C(H)Ph}] (1; L = PhC(NtBu)2), with ArN?C?NAr (Ar = 2,6-iPr2C6H3) in toluene afforded the delocalized hypervalent silyl radical [LSi*(MU-CNAr)2Si{(NtBu)2C(H)Ph}] (2). It possesses a hypervalent silyl radical that delocalizes throughout the Si2C2 ring. PMID- 28009160 TI - Lead-Free Piezoelectric (Ba,Ca)(Zr,Ti)O3 Thin Films for Biocompatible and Flexible Devices. AB - In this work, we report the synthesis of functional biocompatible piezoelectric (1 - x)Ba(Ti0.8Zr0.2)TiO3-x(Ba0.7Ca0.3)TiO3, x = 0.45 (BCZT45), thin films with high piezoelectric properties. Pulsed-laser-based techniques, classical pulsed laser deposition and matrix-assisted pulsed-laser evaporation, were used to synthesize the BCZT45 thin films. The second technique was employed in order to ensure growth on polymer flexible Kapton substrates. The BCZT45 thin films grown by both techniques show similar structural properties and high piezoelectric coefficient coupling between the mechanical loading and electrical potential. While it has long been shown that the electrical potential favors biological processes like osteogenesis, the assessment of cell adhesion and osteogenic differentiation onto BCZT materials has not yet been demonstrated. We prove here for the first time that BCZT 45 coatings on Kapton polymer substrates provide optimal support for osteogenic differentiation of mesenchymal stem cells in the bone marrow. PMID- 28009161 TI - Concurrent Modulation of Quantum Dot Photoluminescence Using a Combination of Charge Transfer and Forster Resonance Energy Transfer: Competitive Quenching and Multiplexed Biosensing Modality. AB - An emerging trend with semiconductor quantum dots (QDs) is their use as scaffolds to assemble multiple energy transfer pathways. Examples to date have combined various competitive and sequential Forster resonance energy transfer (FRET) pathways between QDs and fluorescent dyes, luminescent lanthanide complexes, and bioluminescent proteins. Here, we show that the photoluminescence (PL) of QD bioconjugates can also be modulated by a combination of FRET and charge transfer (CT), and characterize the concurrent effects of these mechanistically different pathways using PL measurements at both the ensemble and the single particle level. Peptides were distally labeled with either a fluorescent dye that quenched QD PL through FRET or a ruthenium(II) phenanthroline complex that quenched QD PL through electron transfer. The labeled peptides were assembled around a central CdSe/ZnS QD at different ratios, tuning the relative rates of FRET and CT, which were competitive quenching pathways. The concurrent effects of FRET and CT were predictable from a rate analysis that was calibrated to the isolated effects of each of these pathways. Notably, the dye/QD PL intensity ratio reflected changes in the relative rate of FRET but was approximately independent of CT. In turn, the sum of the QD and dye PL intensities, when adjusted for quantum yields, reflected changes in the relative rate of CT quenching, approximately independent of FRET. The capacity for multiplexed sensing of protease activity was demonstrated using these two orthogonal detection channels. Combined CT-FRET configurations with QDs are thus promising for applications in bioanalysis, sensing, and imaging, and may prove useful in other photonic applications. PMID- 28009162 TI - Correction to "Persistent Energetic Electrons in Methylammonium Lead Iodide Perovskite Thin Films". PMID- 28009163 TI - Au-Loaded Hierarchical MoO3 Hollow Spheres with Enhanced Gas-Sensing Performance for the Detection of BTX (Benzene, Toluene, And Xylene) And the Sensing Mechanism. AB - Monodisperse, hierarchical alpha-MoO3 hollow spheres were fabricated using a facile template-free solvothermal method combined with subsequent calcination. Various quantities of Au nanoparticles (NPs) were deposited on the alpha-MoO3 hollow spheres to construct hybrid nanomaterials for chemical gas sensors and their BTX sensing properties were investigated. The 2.04 wt % Au-loaded alpha MoO3 sensor can detect BTX effectively at 250 degrees C, especially, its responses to 100 ppm toluene and xylene are 17.5 and 22.1, respectively, which are 4.6 and 3.9 times higher than those of pure alpha-MoO3 hollow spheres at 290 degrees C. Besides, Au loading decreased the response times to toluene and xylene from 19 and 6 s to 1.6 and 2 s, respectively, lowered the working temperature from 290 to 250 degrees C as compared with those of pure alpha-MoO3. The surface status of Au/alpha-MoO3 hollow spheres before and after contacting with toluene at 250 degrees C was analyzed through XPS technique. Possible oxidization product of toluene was confirmed by GC for the first time. The gas-sensing mechanism of the Au/alpha-MoO3 was speculated as the oxidation of toluene to water and carbon dioxide by chemisorbed oxygen and lattice oxygen. The possible reason related with improved gas-sensing properties of the Au-functionalized alpha-MoO3 was discussed. PMID- 28009164 TI - Gradient and Patterned Protein Films Stabilized via Nanoimprint Lithography for Engineered Interactions with Cells. AB - Protein-based biomaterials provide versatile scaffolds for generating functional surfaces for biomedical applications. However, tailoring the functional and biological properties of protein films remains a challenge. Here, we describe a high-throughput method to designing stable, functional biomaterials by combining inkjet deposition of protein inks with a nanoimprint lithography based methodology. The translation of the intrinsically charged proteins into functional materials properties was demonstrated through controlled cellular adhesion. This modular strategy offers a rapid method to produce customizable biomaterials. PMID- 28009165 TI - Effect of Pellet Boiler Exhaust on Secondary Organic Aerosol Formation from alpha Pinene. AB - Interactions between anthropogenic and biogenic emissions, and implications for aerosol production, have raised particular scientific interest. Despite active research in this area, real anthropogenic emission sources have not been exploited for anthropogenic-biogenic interaction studies until now. This work examines these interactions using alpha-pinene and pellet boiler emissions as a model test system. The impact of pellet boiler emissions on secondary organic aerosol (SOA) formation from alpha-pinene photo-oxidation was studied under atmospherically relevant conditions in an environmental chamber. The aim of this study was to identify which of the major pellet exhaust components (including high nitrogen oxide (NOx), primary particles, or a combination of the two) affected SOA formation from alpha-pinene. Results demonstrated that high NOx concentrations emitted by the pellet boiler reduced SOA yields from alpha-pinene, whereas the chemical properties of the primary particles emitted by the pellet boiler had no effect on observed SOA yields. The maximum SOA yield of alpha pinene in the presence of pellet boiler exhaust (under high-NOx conditions) was 18.7% and in the absence of pellet boiler exhaust (under low-NOx conditions) was 34.1%. The reduced SOA yield under high-NOx conditions was caused by changes in gas-phase chemistry that led to the formation of organonitrate compounds. PMID- 28009166 TI - High-Yield Seeded Growth of Monodisperse Pentatwinned Gold Nanoparticles through Thermally Induced Seed Twinning. AB - We show that thermal treatment of small Au seeds results in extensive twinning and a subsequent drastic improvement in the yield (>85%) of formation of pentatwinned nanoparticles (NPs), with preselected morphology (nanorods, bipyramids, and decahedra) and aspect ratio. The "quality" of the seeds thus defines the yield of the obtained NPs, which in the case of nanorods avoids the need for additives such as Ag+ ions. This modified seeded growth method also improves reproducibility, as the seeds can be stored for extended periods of time without compromising the quality of the final NPs. Additionally, minor modification of the seeds with Pd allows their localization within the final particles, which opens new avenues toward mechanistic studies. Together, these results represent a paradigm shift in anisotropic gold NP synthesis. PMID- 28009167 TI - Enhanced Grain Size, Photoluminescence, and Photoconversion Efficiency with Cadmium Addition during the Two-Step Growth of CH3NH3PbI3. AB - Control over grain size and crystallinity is important for preparation of methylammonium lead iodide (MAPbI3) solar cells. We explore the effects of using small concentrations of Cd2+ and unusually high concentrations of methylammonium iodide during the growth of MAPbI3 in the two-step solution process. In addition to improved crystallinity and an enhancement in the size of the grains, time resolved photoluminescence measurements indicated a dramatic increase in the carrier lifetime. As a result, devices constructed with the Cd-modified perovskites showed nearly a factor of 2 improvement in the power conversion efficiency (PCE) relative to similar devices prepared without Cd addition. The grains also showed a higher degree of orientation in the ?110? direction, indicating a change in the growth mechanism, and the films were compact and smooth. We propose a Cd-modified film growth mechanism that invokes a critical role for low-dimensional Cd perovskites to explain the experimental observations. PMID- 28009168 TI - Uncertainty Assessment of Gaseous Oxidized Mercury Measurements Collected by Atmospheric Mercury Network. AB - Gaseous oxidized mercury (GOM) measurement uncertainties undoubtedly impact the understanding of mercury biogeochemical cycling; however, there is a lack of consensus on the uncertainty magnitude. The numerical method presented in this study provides an alternative means of estimating the uncertainties of previous GOM measurements. Weekly GOM in ambient air was predicted from measured weekly mercury wet deposition using a scavenging ratio approach, and compared against field measurements of 2-4 hly GOM to estimate the measurement biases of the Tekran speciation instruments at 13 Atmospheric Mercury Network (AMNet) sites. Multiyear average GOM measurements were estimated to be biased low by more than a factor of 2 at six sites, between a factor of 1.5 and 1.8 at six other sites, and below a factor of 1.3 at one site. The differences between predicted and observed were significantly larger during summer than other seasons potentially because of higher ozone concentrations that may interfere with GOM sampling. The analysis data collected over six years at multiple sites suggests a systematic bias in GOM measurements, supporting the need for further investigation of measurement technologies and identifying the chemical composition of GOM. PMID- 28009169 TI - Photophysical Properties of S, Se and Te-Substituted Deoxyguanosines: Insight into Their Ability To Act as Chemotherapeutic Agents. AB - Guanine and guanosine derivatives have long been in use as anticancer drugs and recently have been proposed also as photosensitizers in photodynamic therapy. By means of density functional theory and its time-dependent formulation, the potential power as UVA chemotherapeutic agents has been investigated computing the photophysical properties (absorption spectra, excitation energies, and spin orbit matrix elements) of sulfur, selenium, and tellurium-substituted deoxyguanosines. Different pathways for the population of the lowest triplet state have been considered. Results show that all the examined systems have the lowest triplet state lying above the energy required for the production of the highly cytotoxic excited molecular oxygen 1Deltag and that the heavy atom effect ensures an efficient intersystem spin crossing. PMID- 28009171 TI - Stereoselective Synthesis of alpha- and beta-l-Ara4N Glycosyl H-Phosphonates and a Neoglycoconjugate Comprising Glycosyl Phosphodiester Linked beta-l-Ara4N. AB - Stereoselective synthesis of variably protected alpha- and beta-l-Ara4N glycosyl H-phosphonates as key intermediates in the syntheses of beta-l-Ara4N-modified LPS structures and alpha-l-Ara4N-containing biosynthetic precursors is reported. A facile one-pot approach toward beta-l-Ara4N glycosyl H-phosphonates includes anomeric deallylation of protected 4-azido beta-l-Ara4N via terminal olefin isomerization followed by ozonolysis and methanolysis of formyl groups to furnish exclusively beta-configured lactols that are phosphitylated with retention of configuration. The carbohydrate epitope of beta-l-Ara4N-modified Lipid A, betaGlcN(1->6)alphaGlcN(1->P<-1)beta-l-Ara4N, was stereoselectively synthesized and linked to maleimide-activated bovine serum albumin. PMID- 28009170 TI - Modulation of Molecular Flux Using a Graphene Nanopore Capacitor. AB - Modulation of ionic current flowing through nanoscale pores is one of the fundamental biological processes. Inspired by nature, nanopores in synthetic solid-state membranes are being developed to enable rapid analysis of biological macromolecules and to serve as elements of nanofludic circuits. Here, we theoretically investigate ion and water transport through a graphene-insulator graphene membrane containing a single, electrolyte-filled nanopore. By means of all-atom molecular dynamics simulations, we show that the charge state of such a graphene nanopore capacitor can regulate both the selectivity and the magnitude of the nanopore ionic current. At a fixed transmembrane bias, the ionic current can be switched from being carried by an equal mixture of cations and anions to being carried almost exclusively by either cationic or anionic species, depending on the sign of the charge assigned to both plates of the capacitor. Assigning the plates of the capacitor opposite sign charges can either increase the nanopore current or reduce it substantially, depending on the polarity of the bias driving the transmembrane current. Facilitated by the changes of the nanopore surface charge, such ionic current modulations are found to occur despite the physical dimensions of the nanopore being an order of magnitude larger than the screening length of the electrolyte. The ionic current rectification is accompanied by a pronounced electro-osmotic effect that can transport neutral molecules such as proteins and drugs across the solid-state membrane and thereby serve as an interface between electronic and chemical signals. PMID- 28009173 TI - Correction to Enhanced Mobility of Spin-Helical Dirac Fermions in Disordered 3D Topological Insulators. PMID- 28009172 TI - Isochromans and Related Constituents from the Endophytic Fungus Annulohypoxylon truncatum of Zizania caduciflora and Their Anti-Inflammatory Effects. AB - Six new isochroman derivatives (annulohypoxylomans A-C, 1-3; annulohypoxylomanols A and B, 6 and 7; and annulohypoxyloside, 8), an isocoumarin (annulohypoxylomarin A, 4), and an azaphilone derivative (xylariphilone, 5) were isolated from an ethyl acetate extract derived from cultures of the endophytic fungus JS540 found in the leaves of Zizania caduciflora. The JS540 strain was identified as Annulohypoxylon truncatum. The structures of the isolated compounds were elucidated by one- and two-dimensional nuclear magnetic resonance and mass spectrometry and by comparison with related compounds from the literature. The anti-inflammatory activities of the isolated compounds were evaluated in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells. Xylariphilone (5) exhibited significant inhibitory effects on LPS-induced interleukin (IL)-6, IL-12 p40, and tumor necrosis factor (TNF)-alpha production with IC50 values of 5.3, 19.4, and 37.6 MUM, respectively. PMID- 28009174 TI - Organocatalytic Enantioselective Amination of 2-Substituted Indolin-3-ones: A Strategy for the Synthesis of Chiral alpha-Hydrazino Esters. AB - An efficient enantioselective alpha-amination of 2-substituted 3-indolinones has been achieved for the first time using hydroquinidine as a chiral catalyst through an aza-Michael reaction. The desired alpha-hydrazino esters are obtained in excellent yields with high enantiomeric excess leading to a quaternary stereocenter with a broad substrate scope. PMID- 28009175 TI - Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5). AB - The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5 specific PET tracers. In biodistribution studies, highest PDE5-specific retention was observed for [11C]-12 and [18F]-17 in the lungs of wild-type mice and in the myocardium of transgenic mice with cardiomyocyte-specific PDE5 overexpression at 30 min postinjection. In vivo dynamic microPET images in rats revealed that both tracers crossed the blood-brain barrier but brain retention was not PDE5 specific. Both [11C]-12 and [18F]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [18F]-17 showed significantly higher PDE5 specific inhibitable binding than [11C]-12. PMID- 28009176 TI - Spectrally Engineering Photonic Entanglement with a Time Lens. AB - A time lens, which can be used to reshape the spectral and temporal properties of light, requires the ultrafast manipulation of optical signals and presents a significant challenge for single-photon application. In this work, we construct a time lens based on dispersion and sum-frequency generation to spectrally engineer single photons from an entangled pair. The strong frequency anticorrelations between photons produced from spontaneous parametric down-conversion are converted to positive correlations after the time lens, consistent with a negative-magnification system. The temporal imaging of single photons enables new techniques for time-frequency quantum state engineering. PMID- 28009177 TI - Reversion of a Parent {130}?310?_{alpha^{''}} Martensitic Twinning System at the Origin of {332}?113?_{beta} Twins Observed in Metastable beta Titanium Alloys. AB - In bcc metastable beta titanium alloys, and particularly in superelastic alloys, a unique {332}?113? twinning system occurs during plastic deformation. However, in situ synchrotron x-ray diffraction during a tensile test shows that the beta phase totally transforms into alpha^{''} martensite under stress in a Ti-27Nb (at. %) alloy. {332}?113?_{beta} twins are thus not formed directly in the beta phase but are the result of the reversion of {130}?310?_{alpha^{''}} parent twins occurring in martensite under stress. The formation of an interfacial twin boundary omega phase is also observed to accommodate strains induced during the phase reversion. PMID- 28009178 TI - Translocation Time through a Nanopore with an Internal Cavity Is Minimal for Polymers of Intermediate Length. AB - The translocation of polymers through nanopores with large internal cavities bounded by two narrow pores is studied via Langevin dynamics simulations. The total translocation time is found to be a nonmonotonic function of polymer length, reaching a minimum at intermediate length, with both shorter and longer polymers taking longer to translocate. The location of the minimum is shown to shift with the magnitude of the applied force, indicating that the pore can be dynamically tuned to favor different polymer lengths. A simple model balancing the effects of entropic trapping within the cavity against the driving force is shown to agree well with simulations. Beyond the nonmonotonicity, detailed analysis of translocation uncovers rich dynamics in which factors such as going to a high force regime and the emergence of a tail for long polymers dramatically change the behavior of the system. These results suggest that nanopores with internal cavities can be used for applications such as selective extraction of polymers by length and filtering of polymer solutions, extending the uses of nanopores within emerging nanofluidic technologies. PMID- 28009179 TI - Wetting Effect on Torricelli's Law. AB - This Letter presents an experimental study on the effect of wetting on the draining of a tank through an orifice set at its bottom. The investigation focuses on flows of liquids in the inertial regime through an orifice the size on the order of magnitude of the capillary length. The results show that although the flows always follow a Torricelli-like behavior, wetting strongly affects the speed of drainage. Surprisingly, this speed goes through a minimum as the outside surface of the tank bottom plate changes from hydrophilic to hydrophobic. The maximum effect in slowing down the flows (up to 20%) is obtained for a static wetting angle theta_{s} of about 60 degrees . Experiments suggest that the effect of wetting on the exit flows, very likely, is related to the meniscus that forms at the hole's outlet. A simple model is proposed that estimates the variation of kinetic energy within the meniscus. This model captures the main features of the experimental observations, particularly the nonmonotonic variation of the speed of drainage as a function of theta_{s} with a minimum for a static wetting angle of about 60 degrees . PMID- 28009180 TI - Discriminating between Metallic and Semiconducting Single-Walled Carbon Nanotubes Using Physisorbed Adsorbates: Role of Wavelike Charge-Density Fluctuations. AB - Discriminating between metallic (M) and semiconducting (S) single-walled carbon nanotubes (SWNTs) remains a fundamental challenge in the field of nanotechnology. We address this issue by studying the adsorption of the isotropic atoms Xe, Kr, and a highly anisotropic molecule n heptane on M- and S-SWNTs with density functional theory that includes many-body dispersion forces. We find that the distinct polarizabilities of M- and S-SWNTs exhibit significantly different physisorption properties, which are also strongly controlled by the SWNT's diameter, adsorption site, adsorbate coverage, and the adsorbate's anisotropy. These findings stem from the wavelike nature of charge-density fluctuations in SWNTs. Particularly, these results allow us to rationalize the unusual sqrt[3]*sqrt[3]R30^{0} phase of Kr atoms on small gap M-SWNTs and the double desorption peak temperatures of n heptane on M-SWNTs in experiments, and also propose the n heptane as an effective sensor for experimentally discriminating M- and S-SWNTs. PMID- 28009181 TI - Temporal Multimode Storage of Entangled Photon Pairs. AB - Multiplexed quantum memories capable of storing and processing entangled photons are essential for the development of quantum networks. In this context, we demonstrate and certify the simultaneous storage and retrieval of two entangled photons inside a solid-state quantum memory and measure a temporal multimode capacity of ten modes. This is achieved by producing two polarization-entangled pairs from parametric down-conversion and mapping one photon of each pair onto a rare-earth-ion-doped (REID) crystal using the atomic frequency comb (AFC) protocol. We develop a concept of indirect entanglement witnesses, which can be used as Schmidt number witnesses, and we use it to experimentally certify the presence of more than one entangled pair retrieved from the quantum memory. Our work puts forward REID-AFC as a platform compatible with temporal multiplexing of several entangled photon pairs along with a new entanglement certification method, useful for the characterization of multiplexed quantum memories. PMID- 28009182 TI - Orbital-Dependent Band Narrowing Revealed in an Extremely Correlated Hund's Metal Emerging on the Topmost Layer of Sr_{2}RuO_{4}. AB - We use a surface-selective angle-resolved photoemission spectroscopy and unveil the electronic nature on the topmost layer of Sr_{2}RuO_{4} crystal, consisting of slightly rotated RuO_{6} octahedrons. The gamma band derived from the 4d_{xy} orbital is found to be about three times narrower than that for the bulk. This strongly contrasts with a subtle variation seen in the alpha and beta bands derived from the one-dimensional 4d_{xz/yz}. This anomaly is reproduced by the dynamical mean-field theory calculations, introducing not only the on-site Hubbard interaction but also the significant Hund's coupling. We detect a coherence-to-incoherence crossover theoretically predicted for Hund's metals, which has been recognized only recently. The crossover temperature in the surface is about half that of the bulk, indicating that the naturally generated monolayer of reconstructed Sr_{2}RuO_{4} is extremely correlated and well isolated from the underlying crystal. PMID- 28009183 TI - Comment on "Motional Averaging of Nuclear Resonance in a Field Gradient". PMID- 28009184 TI - Golden Probe of Electroweak Symmetry Breaking. AB - The ratio of the Higgs couplings to WW and ZZ pairs, lambda_{WZ}, is a fundamental parameter in electroweak symmetry breaking as well as a measure of the (approximate) custodial symmetry possessed by the gauge boson mass matrix. We show that Higgs decays to four leptons are sensitive, via tree level or one-loop interference effects, to both the magnitude and, in particular, overall sign of lambda_{WZ}. Determining this sign requires interference effects, as it is nearly impossible to measure with rate information. Furthermore, simply determining the sign effectively establishes the custodial representation of the Higgs boson. We find that h->4l (4l=2e2MU, 4e, 4MU) decays have excellent prospects of directly establishing the overall sign at a high luminosity 13 TeV LHC. We also examine the ultimate LHC sensitivity in h->4l to the magnitude of lambda_{WZ}. Our results are independent of other measurements of the Higgs boson couplings and, in particular, largely free of assumptions about the top quark Yukawa couplings which also enter at one loop. This makes h->4l a unique and independent probe of electroweak symmetry breaking and custodial symmetry. PMID- 28009185 TI - Large-Scale Patterns in a Minimal Cognitive Flocking Model: Incidental Leaders, Nematic Patterns, and Aggregates. AB - We study a minimal cognitive flocking model, which assumes that the moving entities navigate using the available instantaneous visual information exclusively. The model consists of active particles, with no memory, that interact by a short-ranged, position-based, attractive force, which acts inside a vision cone (VC), and lack velocity-velocity alignment. We show that this active system can exhibit-due to the VC that breaks Newton's third law-various complex, large-scale, self-organized patterns. Depending on parameter values, we observe the emergence of aggregates or millinglike patterns, the formation of moving locally polar-files with particles at the front of these structures acting as effective leaders, and the self-organization of particles into macroscopic nematic structures leading to long-ranged nematic order. Combining simulations and nonlinear field equations, we show that position-based active models, as the one analyzed here, represent a new class of active systems fundamentally different from other active systems, including velocity-alignment-based flocking systems. The reported results are of prime importance in the study, interpretation, and modeling of collective motion patterns in living and nonliving active systems. PMID- 28009186 TI - Imaging the Temporal Evolution of Molecular Orbitals during Ultrafast Dissociation. AB - We investigate the temporal evolution of molecular frame angular distributions of Auger electrons emitted during ultrafast dissociation of HCl following a resonant single-photon excitation. The electron emission pattern changes its shape from that of a molecular sigma orbital to that of an atomic p state as the system evolves from a molecule into two separated atoms. PMID- 28009187 TI - Quantum Entanglement Swapping between Two Multipartite Entangled States. AB - Quantum entanglement swapping is one of the most promising ways to realize the quantum connection among local quantum nodes. In this Letter, we present an experimental demonstration of the entanglement swapping between two independent multipartite entangled states, each of which involves a tripartite Greenberger Horne-Zeilinger (GHZ) entangled state of an optical field. The entanglement swapping is implemented deterministically by means of a joint measurement on two optical modes coming from the two multipartite entangled states respectively and the classical feedforward of the measurement results. After entanglement swapping the two independent multipartite entangled states are merged into a large entangled state in which all unmeasured quantum modes are entangled. The entanglement swapping between a tripartite GHZ state and an Einstein-Podolsky Rosen entangled state is also demonstrated and the dependence of the resultant entanglement on transmission loss is investigated. The presented experiment provides a feasible technical reference for constructing more complicated quantum networks. PMID- 28009188 TI - Structure of Plasma Heating in Gyrokinetic Alfvenic Turbulence. AB - We analyze plasma heating in weakly collisional kinetic Alfven wave turbulence using high resolution gyrokinetic simulations spanning the range of scales between the ion and the electron gyroradii. Real space structures that have a higher than average heating rate are shown not to be confined to current sheets. This novel result is at odds with previous studies, which use the electromagnetic work in the local electron fluid frame, i.e., J.(E+v_{e}*B), as a proxy for turbulent dissipation to argue that heating follows the intermittent spatial structure of the electric current. Furthermore, we show that electrons are dominated by parallel heating while the ions prefer the perpendicular heating route. We comment on the implications of the results presented here. PMID- 28009189 TI - Temperature-Induced Topological Phase Transitions: Promoted versus Suppressed Nontrivial Topology. AB - Contrary to previous two-band model studies which find increasing temperature would induce a topological phase transition, we show here through first principles calculations that the opposite is also realizable, depending on the material's full band structure and symmetry of the electron-phonon coupling potential. This finding explains recent experimental results by Wojek et al. [Nat. Commun. 6, 8463 (2015)NCAOBW2041-172310.1038/ncomms9463]. We show that the topological phase diagram of BiTl(S_{1-delta}Se_{delta})_{2} as a function of doping and temperature contains two distinct regions with nontrivial topology. In BiTlS_{2}, the phonons promote the topological phase at high temperature, while in BiTlSe_{2}, the system is driven back into the trivial phase. PMID- 28009190 TI - First Liquid Layer Inertial Confinement Fusion Implosions at the National Ignition Facility. AB - The first cryogenic deuterium and deuterium-tritium liquid layer implosions at the National Ignition Facility (NIF) demonstrate D_{2} and DT layer inertial confinement fusion (ICF) implosions that can access a low-to-moderate hot-spot convergence ratio (1230) DT ice layer implosions. Although high CR is desirable in an idealized 1D sense, it amplifies the deleterious effects of asymmetries. To date, these asymmetries prevented the achievement of ignition at the NIF and are the major cause of simulation-experiment disagreement. In the initial liquid layer experiments, high neutron yields were achieved with CRs of 12-17, and the hot spot formation is well understood, demonstrated by a good agreement between the experimental data and the radiation hydrodynamic simulations. These initial experiments open a new NIF experimental capability that provides an opportunity to explore the relationship between hot-spot convergence ratio and the robustness of hot-spot formation during ICF implosions. PMID- 28009191 TI - Experimental Rectification of Entropy Production by Maxwell's Demon in a Quantum System. AB - Maxwell's demon explores the role of information in physical processes. Employing information about microscopic degrees of freedom, this "intelligent observer" is capable of compensating entropy production (or extracting work), apparently challenging the second law of thermodynamics. In a modern standpoint, it is regarded as a feedback control mechanism and the limits of thermodynamics are recast incorporating information-to-energy conversion. We derive a trade-off relation between information-theoretic quantities empowering the design of an efficient Maxwell's demon in a quantum system. The demon is experimentally implemented as a spin-1/2 quantum memory that acquires information, and employs it to control the dynamics of another spin-1/2 system, through a natural interaction. Noise and imperfections in this protocol are investigated by the assessment of its effectiveness. This realization provides experimental evidence that the irreversibility in a nonequilibrium dynamics can be mitigated by assessing microscopic information and applying a feed-forward strategy at the quantum scale. PMID- 28009192 TI - Comment on "Temporal Correlations of the Running Maximum of a Brownian Trajectory". PMID- 28009193 TI - Unveiling Dimensionality Dependence of Glassy Dynamics: 2D Infinite Fluctuation Eclipses Inherent Structural Relaxation. AB - By using large-scale molecular dynamics simulations, the dynamics of two dimensional (2D) supercooled liquids turns out to be dependent on the system size, while the size dependence is not pronounced in three-dimensional (3D) systems. It is demonstrated that the strong system-size effect in 2D amorphous systems originates from the enhanced fluctuations at long wavelengths which are similar to those of 2D crystal phonons. This observation is further supported by the frequency dependence of the vibrational density of states, consisting of the Debye approximation in the low-wave-number limit. However, the system-size effect in the intermediate scattering function becomes negligible when the length scale is larger than the vibrational amplitude. This suggests that the finite-size effect in a 2D system is transient and also that the structural relaxation itself is not fundamentally different from that in a 3D system. In fact, the dynamic correlation lengths estimated from the bond-breakage function, which do not suffer from those enhanced fluctuations, are not size dependent in either 2D or 3D systems. PMID- 28009194 TI - How Bright is the Proton? A Precise Determination of the Photon Parton Distribution Function. AB - It has become apparent in recent years that it is important, notably for a range of physics studies at the Large Hadron Collider, to have accurate knowledge on the distribution of photons in the proton. We show how the photon parton distribution function (PDF) can be determined in a model-independent manner, using electron-proton (ep) scattering data, in effect viewing the ep->e+X process as an electron scattering off the photon field of the proton. To this end, we consider an imaginary, beyond the Standard Model process with a flavor changing photon-lepton vertex. We write its cross section in two ways: one in terms of proton structure functions, the other in terms of a photon distribution. Requiring their equivalence yields the photon distribution as an integral over proton structure functions. As a result of the good precision of ep data, we constrain the photon PDF at the level of 1%-2% over a wide range of momentum fractions. PMID- 28009195 TI - Nanoelectromechanical Heat Engine Based on Electron-Electron Interaction. AB - We theoretically show that a nanoelectromechanical system can be mechanically actuated by a heat flow through it via an electron-electron interaction. In contrast to most known actuation mechanisms in similar systems, this new mechanism does not involve an electronic current nor external ac fields. Instead, the mechanism relies on deflection-dependent tunneling rates and a heat flow which is mediated by an electron-electron interaction while an electronic current through the device is prohibited by, for instance, a spin-valve effect. Therefore, the system resembles a nanoelectromechanical heat engine. We derive a criterion for the mechanical instability and estimate the amplitude of the resulting self-sustained oscillations. Estimations show that the suggested phenomenon can be studied using available experimental techniques. PMID- 28009196 TI - Dissipative Double-Well Potential for Cold Atoms: Kramers Rate and Stochastic Resonance. AB - We experimentally study particle exchange in a dissipative double-well potential using laser-cooled atoms in a hybrid trap. We measure the particle hopping rate as a function of barrier height, temperature, and atom number. Single-particle resolution allows us to measure rates over more than 4 orders of magnitude and distinguish the effects of loss and hopping. Deviations from the Arrhenius-law scaling at high barrier heights occur due to cold collisions between atoms within a well. By driving the system periodically, we characterize the phenomenon of stochastic resonance in the system response. PMID- 28009197 TI - Nuclear Excitation by Two-Photon Electron Transition. AB - A new mechanism of nuclear excitation via two-photon electron transitions (NETP) is proposed and studied theoretically. As a generic example, detailed calculations are performed for the E1E1 1s2s^{1}S_{0}->1s^{2}^{1}S_{0} two-photon decay of a He-like ^{225}Ac^{87+} ion with a resonant excitation of the 3/2+ nuclear state with an energy of 40.09(5) keV. The probability for such a two photon decay via the nuclear excitation is found to be P_{NETP}=3.5*10^{-9} and, thus, is comparable with other mechanisms, such as nuclear excitation by electron transition and by electron capture. The possibility for the experimental observation of the proposed mechanism is thoroughly discussed. PMID- 28009198 TI - Absence of the Thermal Hall Effect in Anomalous Nernst and Spin Seebeck Effects. AB - The anomalous Nernst effect (ANE) and the spin Seebeck effect (SSE) in spin caloritronics are two of the most important mechanisms to manipulate the spin polarized current and pure spin current by thermal excitation. While the ANE in ferromagnetic metals and the SSE in magnetic insulators have been extensively studied, a recent theoretical work suggests that the signals from the thermal Hall effect (THE) have field dependences indistinguishable from, and may even overwhelm, those of the ANE and SSE. Therefore, it is vital to investigate the contribution of the THE in the ANE and SSE. In this work, we systematically study the THE in a ferromagnetic metal, Permalloy (Py), and magnetic insulator, an yttrium iron garnet (YIG), by using different Seebeck coefficients between electrodes and contact wires. Our results demonstrate that the contribution of the THE by the thermal couple effect in the Py and YIG is negligibly small if one includes the thickness dependence of the Seebeck coefficient. Thus, the spin polarized current in the ANE and the pure spin current in the SSE remain indispensable for exploring spin caloritronics phenomena. PMID- 28009199 TI - Storing Light with Subradiant Correlations in Arrays of Atoms. AB - We show how strong light-mediated resonant dipole-dipole interactions between atoms can be utilized in a control and storage of light. The method is based on a high-fidelity preparation of a collective atomic excitation in a single correlated subradiant eigenmode in a lattice. We demonstrate how a simple phenomenological model captures the qualitative features of the dynamics and sharp transmission resonances that may find applications in sensing. PMID- 28009200 TI - Jarenwattananon and Bouchard Reply. PMID- 28009201 TI - Loops and Strings in a Superconducting Lattice Gauge Simulator. AB - We propose an architecture for an analog quantum simulator of electromagnetism in 2+1 dimensions, based on an array of superconducting fluxonium devices. The encoding is in the integer (spin-1) representation of the quantum link model formulation of compact U(1) lattice gauge theory. We show how to engineer Gauss' law via an ancilla mediated gadget construction, and how to tune between the strongly coupled and intermediately coupled regimes. The witnesses to the existence of the predicted confining phase of the model are provided by nonlocal order parameters from Wilson loops and disorder parameters from 't Hooft strings. We show how to construct such operators in this model and how to measure them nondestructively via dispersive coupling of the fluxonium islands to a microwave cavity mode. Numerical evidence is found for the existence of the confined phase in the ground state of the simulation Hamiltonian on a ladder geometry. PMID- 28009202 TI - Quasi-Many-Body Localization in Translation-Invariant Systems. AB - We examine localization phenomena associated with generic, high entropy, states of a translation-invariant, one-dimensional spin ladder. At early times, we find slow growth of entanglement entropy consistent with the known phenomenology of many-body localization in disordered, interacting systems. At intermediate times, however, anomalous diffusion sets in, leading to full spin polarization decay on an exponentially activated time scale. We identify a single length scale which parametrically controls both the spin transport times and the apparent divergence of the susceptibility to spin glass ordering. Ultimately, at the latest times, the exponentially slow anomalous diffusion gives way to diffusive thermal behavior. We dub the intermediate dynamical behavior, which persists over many orders of magnitude in time, quasi-many-body localization. PMID- 28009203 TI - Observation of von Karman Vortex Street in an Atomic Superfluid Gas. AB - We report on the experimental observation of vortex cluster shedding from a moving obstacle in an oblate atomic Bose-Einstein condensate. At low obstacle velocities v above a critical value, vortex clusters consisting of two like-sign vortices are generated to form a regular configuration like a von Karman street, and as v is increased, the shedding pattern becomes irregular with many different kinds of vortex clusters. In particular, we observe that the Stouhal number associated with the shedding frequency exhibits saturation behavior with increasing v. The regular-to-turbulent transition of the vortex cluster shedding reveals remarkable similarities between a superfluid and a classical viscous fluid. Our work opens a new direction for experimental investigations of the superfluid Reynolds number characterizing universal superfluid hydrodynamics. PMID- 28009204 TI - Gaussian Intrinsic Entanglement. AB - We introduce a cryptographically motivated quantifier of entanglement in bipartite Gaussian systems called Gaussian intrinsic entanglement (GIE). The GIE is defined as the optimized mutual information of a Gaussian distribution of outcomes of measurements on parts of a system, conditioned on the outcomes of a measurement on a purifying subsystem. We show that GIE vanishes only on separable states and exhibits monotonicity under Gaussian local trace-preserving operations and classical communication. In the two-mode case, we compute GIE for all pure states as well as for several important classes of symmetric and asymmetric mixed states. Surprisingly, in all of these cases, GIE is equal to Gaussian Renyi-2 entanglement. As GIE is operationally associated with the secret-key agreement protocol and can be computed for several important classes of states, it offers a compromise between computable and physically meaningful entanglement quantifiers. PMID- 28009205 TI - Dynamics of a Ground-State Cooled Ion Colliding with Ultracold Atoms. AB - Ultracold atom-ion mixtures are gaining increasing interest due to their potential applications in ultracold and state-controlled chemistry, quantum computing, and many-body physics. Here, we studied the dynamics of a single ground-state cooled ion during few, to many, Langevin (spiraling) collisions with ultracold atoms. We measured the ion's energy distribution and observed a clear deviation from the Maxwell-Boltzmann distribution, characterized by an exponential tail, to a power-law distribution best described by a Tsallis function. Unlike previous experiments, the energy scale of atom-ion interactions is not determined by either the atomic cloud temperature or the ion's trap residual excess-micromotion energy. Instead, it is determined by the force the atom exerts on the ion during a collision which is then amplified by the trap dynamics. This effect is intrinsic to ion Paul traps and sets the lower bound of atom-ion steady-state interaction energy in these systems. Despite the fact that our system is eventually driven out of the ultracold regime, we are capable of studying quantum effects by limiting the interaction to the first collision when the ion is initialized in the ground state of the trap. PMID- 28009206 TI - Fate of the Tetraquark Candidate Z_{c}(3900) from Lattice QCD. AB - The possible exotic meson Z_{c}(3900), found in e^{+}e^{-} reactions, is studied by the method of coupled-channel scattering in lattice QCD. The interactions among piJ/psi, rhoeta_{c}, and D[over -]D^{*} channels are derived from (2+1) flavor QCD simulations at m_{pi}=410-700 MeV. The interactions are dominated by the off-diagonal piJ/psi-D[over -]D^{*} and rhoeta_{c}-D[over -]D^{*} couplings, which indicates that the Z_{c}(3900) is not a usual resonance but a threshold cusp. Semiphenomenological analyses with the coupled-channel interaction are also presented to confirm this conclusion. PMID- 28009207 TI - Quantum Networks with Chiral-Light-Matter Interaction in Waveguides. AB - We propose a scalable architecture for a quantum network based on a simple on chip photonic circuit that performs loss-tolerant two-qubit measurements. The circuit consists of two quantum emitters positioned in the arms of an on-chip Mach-Zehnder interferometer composed of waveguides with chiral-light-matter interfaces. The efficient chiral-light-matter interaction allows the emitters to perform high-fidelity intranode two-qubit parity measurements within a single chip and to emit photons to generate internode entanglement, without any need for reconfiguration. We show that, by connecting multiple circuits of this kind into a quantum network, it is possible to perform universal quantum computation with heralded two-qubit gate fidelities F~0.998 achievable in state-of-the-art quantum dot systems. PMID- 28009208 TI - Structural Phase Transition and Material Properties of Few-Layer Monochalcogenides. AB - GeSe and SnSe monochalcogenide monolayers and bilayers undergo a two-dimensional phase transition from a rectangular unit cell to a square unit cell at a critical temperature T_{c} well below the melting point. Its consequences on material properties are studied within the framework of Car-Parrinello molecular dynamics and density-functional theory. No in-gap states develop as the structural transition takes place, so that these phase-change materials remain semiconducting below and above T_{c}. As the in-plane lattice transforms from a rectangle into a square at T_{c}, the electronic, spin, optical, and piezoelectric properties dramatically depart from earlier predictions. Indeed, the Y and X points in the Brillouin zone become effectively equivalent at T_{c}, leading to a symmetric electronic structure. The spin polarization at the conduction valley edge vanishes, and the hole conductivity must display an anomalous thermal increase at T_{c}. The linear optical absorption band edge must change its polarization as well, making this structural and electronic evolution verifiable by optical means. Much excitement is drawn by theoretical predictions of giant piezoelectricity and ferroelectricity in these materials, and we estimate a pyroelectric response of about 3*10^{-12} C/K m here. These results uncover the fundamental role of temperature as a control knob for the physical properties of few-layer group-IV monochalcogenides. PMID- 28009209 TI - Decoupling Electronic versus Nuclear Photoresponse of Isolated Green Fluorescent Protein Chromophores Using Short Laser Pulses. AB - The photophysics of a deprotonated model chromophore for the green fluorescent protein is studied by femtosecond laser pulses in an electrostatic ion-storage ring. The laser-pulse duration is much shorter than the time for internal conversion, and, hence, contributions from sequential multiphoton absorption, typically encountered with ns-laser pulses, are avoided. Following single-photon excitation, the action-absorption maximum is shown to be shifted within the S_{0} to S_{1} band from its origin at about 490 to 450 nm, which is explained by the different photophysics involved in the detected action. PMID- 28009210 TI - Nahar and Pradhan Reply. PMID- 28009211 TI - Can Ab Initio Theory Explain the Phenomenon of Parity Inversion in ^{11}Be? AB - The weakly bound exotic ^{11}Be nucleus, famous for its ground-state parity inversion and distinct n+^{10}Be halo structure, is investigated from first principles using chiral two- and three-nucleon forces. An explicit treatment of continuum effects is found to be indispensable. We study the sensitivity of the ^{11}Be spectrum to the details of the three-nucleon force and demonstrate that only certain chiral interactions are capable of reproducing the parity inversion. With such interactions, the extremely large E1 transition between the bound states is reproduced. We compare our photodisintegration calculations to conflicting experimental data and predict a distinct dip around the 3/2_{1}^{-} resonance energy. Finally, we predict low-lying 3/2^{+} and 9/2^{+} resonances that are not or not sufficiently measured in experiments. PMID- 28009212 TI - Laser-Driven Recollisions under the Coulomb Barrier. AB - Photoelectron spectra obtained from the ab initio solution of the time-dependent Schrodinger equation can be in striking disagreement with predictions by the strong-field approximation (SFA), not only at low energy but also around twice the ponderomotive energy where the transition from the direct to the rescattered electrons is expected. In fact, the relative enhancement of the ionization probability compared to the SFA in this regime can be several orders of magnitude. We show for which laser and target parameters such an enhancement occurs and for which the SFA prediction is qualitatively good. The enhancement is analyzed in terms of the Coulomb-corrected action along analytic quantum orbits in the complex-time plane, taking soft recollisions under the Coulomb barrier into account. These recollisions in complex time and space prevent a separation into sub-barrier motion up to the "tunnel exit" and subsequent classical dynamics. Instead, the entire quantum path up to the detector determines the ionization probability. PMID- 28009214 TI - Topological Superfluid in a Fermi-Bose Mixture with a High Critical Temperature. AB - We show that a 2D spin-polarized Fermi gas immersed in a 3D Bose-Einstein condensate constitutes a very promising system for realizing a p_{x}+ip_{y} superfluid. The fermions attract each other via an induced interaction mediated by the bosons, and the resulting pairing is analyzed with retardation effects fully taken into account. This is further combined with Berezinskii-Kosterlitz Thouless (BKT) theory to obtain reliable results for the superfluid critical temperature. We show that both the strength and the range of the induced interaction can be tuned experimentally, which can be used to make the critical temperature approach the maximum value allowed by general BKT theory. Moreover, this is achieved while keeping the Fermi-Bose interaction weak so that three-body losses are small. Our results show that realizing a topological superfluid with atomic Fermi-Bose mixtures is within experimental reach. PMID- 28009213 TI - Geometric Resonance of Composite Fermions near Bilayer Quantum Hall States. AB - Via the application of a parallel magnetic field, we induce a single-layer to bilayer transition in two-dimensional electron systems confined to wide GaAs quantum wells and study the geometric resonance of composite fermions (CFs) with a periodic density modulation in our samples. The measurements reveal that CFs exist close to bilayer quantum Hall states, formed at Landau level filling factors nu=1 and 1/2. Near nu=1, the geometric resonance features are consistent with half the total electron density in the bilayer system, implying that CFs prefer to stay in separate layers and exhibit a two-component behavior. In contrast, close to nu=1/2, CFs appear single-layer-like (single component) as their resonance features correspond to the total density. PMID- 28009215 TI - Bootstrapping a Five-Loop Amplitude Using Steinmann Relations. AB - The analytic structure of scattering amplitudes is restricted by Steinmann relations, which enforce the vanishing of certain discontinuities of discontinuities. We show that these relations dramatically simplify the function space for the hexagon function bootstrap in planar maximally supersymmetric Yang Mills theory. Armed with this simplification, along with the constraints of dual conformal symmetry and Regge exponentiation, we obtain the complete five-loop six particle amplitude. PMID- 28009217 TI - Temporal Quantum Correlations in Inelastic Light Scattering from Water. AB - Water is one of the most prevalent chemicals on our planet, an integral part of both our environment and our existence as a species. Yet it is also rich in anomalous behaviors. Here we reveal that water is a novel-yet ubiquitous-source for quantum correlated photon pairs at ambient conditions. The photon pairs are produced through Raman scattering, and the correlations arise from the shared quantum of a vibrational mode between the Stokes and anti-Stokes scattering events. We confirm the nonclassical nature of the produced photon pairs by showing that the cross-correlation and autocorrelations of the signals violate a Cauchy-Schwarz inequality by over 5 orders of magnitude. The unprecedented degree of violating the inequality in pure water, as well as the well-defined polarization properties of the photon pairs, points to its usefulness in quantum information. PMID- 28009218 TI - Hund's Rule-Driven Dzyaloshinskii-Moriya Interaction at 3d-5d Interfaces. AB - Using relativistic first-principles calculations, we show that the chemical trend of the Dzyaloshinskii-Moriya interaction (DMI) in 3d-5d ultrathin films follows Hund's first rule with a tendency similar to their magnetic moments in either the unsupported 3d monolayers or 3d-5d interfaces. We demonstrate that, besides the spin-orbit coupling (SOC) effect in inversion asymmetric noncollinear magnetic systems, the driving force is the 3d orbital occupations and their spin-flip mixing processes with the spin-orbit active 5d states control directly the sign and magnitude of the DMI. The magnetic chirality changes are discussed in the light of the interplay between SOC, Hund's first rule, and the crystal-field splitting of d orbitals. PMID- 28009219 TI - Controllable Terahertz Radiation from a Linear-Dipole Array Formed by a Two-Color Laser Filament in Air. AB - We demonstrate effective control on the carrier-envelope phase and angular distribution as well as the peak intensity of a nearly single-cycle terahertz pulse emitted from a laser filament formed by two-color, the fundamental and the corresponding second harmonics, femtosecond laser pulses propagating in air. Experimentally, such control has been performed by varying the filament length and the initial phase difference between the two-color laser components. A linear dipole-array model, including the descriptions of both the generation (via laser field ionization) and propagation of the emitted terahertz pulse, is proposed to present a quantitative interpretation of the observations. Our results contribute to the understanding of terahertz generation in a femtosecond laser filament and suggest a practical way to control the electric field of a terahertz pulse for potential applications. PMID- 28009220 TI - Comment on "Large Enhancement in High-Energy Photoionization of Fe XVII and Missing Continuum Plasma Opacity". PMID- 28009221 TI - Testing Lorentz Symmetry with Lunar Laser Ranging. AB - Lorentz symmetry violations can be parametrized by an effective field theory framework that contains both general relativity and the standard model of particle physics called the standard-model extension (SME). We present new constraints on pure gravity SME coefficients obtained by analyzing lunar laser ranging (LLR) observations. We use a new numerical lunar ephemeris computed in the SME framework and we perform a LLR data analysis using a set of 20 721 normal points covering the period of August, 1969 to December, 2013. We emphasize that linear combination of SME coefficients to which LLR data are sensitive and not the same as those fitted in previous postfit residuals analysis using LLR observations and based on theoretical grounds. We found no evidence for Lorentz violation at the level of 10^{-8} for s[over -]^{TX}, 10^{-12} for s[over -]^{XY} and s[over -]^{XZ}, 10^{-11} for s[over -]^{XX}-s[over -]^{YY} and s[over ]^{XX}+s[over -]^{YY}-2s[over -]^{ZZ}-4.5s[over -]^{YZ}, and 10^{-9} for s[over ]^{TY}+0.43s[over -]^{TZ}. We improve previous constraints on SME coefficient by a factor up to 5 and 800 compared to postfit residuals analysis of respectively binary pulsars and LLR observations. PMID- 28009222 TI - Valley Filtering and Electronic Optics Using Polycrystalline Graphene. AB - In this Letter, both the manipulation of valley-polarized currents and the optical-like behaviors of Dirac fermions are theoretically explored in polycrystalline graphene. When strain is applied, the misorientation between two graphene domains separated by a grain boundary can result in a mismatch of their electronic structures. Such a discrepancy manifests itself in a strong breaking of the inversion symmetry, leading to perfect valley polarization in a wide range of transmission directions. In addition, these graphene domains act as different media for electron waves, offering the possibility to modulate and obtain negative refraction indexes. PMID- 28009223 TI - Development of an Enhanced Recovery After Surgery (ERAS) approach for lumbar spinal fusion. AB - OBJECTIVE Over the past decade, Enhancing Recovery After Surgery (ERAS) programs have been implemented throughout the world across multiple surgical disciplines. However, to date no spinal surgery equivalent has been described. In this report the authors review the development and implementation of a "fast track" surgical approach for lumbar fusion. METHODS The first 42 consecutive cases in which patients were treated with the new surgical procedure were reviewed. A combination of endoscopic decompression, expandable cage deployment, and percutaneous screw placement were performed with liposomal bupivacaine anesthesia to allow the surgery to be performed without general endotracheal anesthesia. RESULTS In all cases the surgical procedure was performed successfully without conversion to an open operation. The patients' mean age (+/- SD) was 66.1 +/- 11.7 years, the male/female ratio was 20:22, and a total of 47 levels were treated. The mean operative time was 94.6 +/- 22.4 minutes, the mean intraoperative blood loss was 66 +/- 30 ml, and the mean hospital length of stay was 1.29 +/- 0.9 nights. Early follow-up showed a significant improvement in the mean Oswestry Disability Index score (from 40 +/- 13 to 17 +/- 11, p = 0.0001). Return to the operating room was required in 2 cases due to infection and in 1 case due to cage displacement. An iterative quality improvement program demonstrated areas of improvement, including steps to minimize infection, improve postoperative analgesia, and reduce cage osteolysis. CONCLUSIONS ERAS programs for improving spinal fusion surgery are possible and necessary. This report demonstrates a first foray to apply these principles through 1) a patient-focused approach, 2) reducing the stress of the operation, and 3) an iterative improvement process. PMID- 28009224 TI - Mesenteric ischemia following the correction of adult spinal deformity: case report. AB - Vascular complications are an important adverse event that can be associated with spinal reconstructive surgery. Direct injury of vessels, or indirect traction or compression of vessels, can cause both arterial and venous injury. Indirect compression of the mesenteric vessels is a well-recognized complication of bracing and surgical care of children with spinal deformity (superior mesenteric artery syndrome), but the complication is not common or well recognized in the adult population with spinal deformity. The purpose of this case report is to detail the case of postoperative mesenteric ischemia in a 63-year-old man in whom a posterior approach was used to perform spinal deformity correction. Preoperatively, the patient had had significant lumbar hypolordosis. The reconstructive surgery with the use of posterior-based osteotomies resulted in a shortening of the posterior column of the spine but a relative lengthening of structures anterior to the spine. The significant lordosis achieved by the surgery led to an acute worsening of the mesenteric stenosis suffered by the patient. He required a vascular surgery intervention to restore perfusion to the bowel. Recognition of severe vasculopathy is important in anticipating potential postoperative vascular insufficiency. This case report will inform surgeons and clinicians to have a higher index of suspicion for the exacerbation of vascular insufficiency, including mesenteric pathology, in patients undergoing surgery that involves significant realignment of the spine. Preoperative recognition of vascular insufficiency and treatment of symptomatic disease may limit the occurrence of postoperative vascular complications in spinal reconstructive surgery. PMID- 28009225 TI - Clinical and surgical management of a congenital Type II split cord malformation presenting with progressive cranial neuropathies: case report. AB - Split cord malformation (SCM) is a rare abnormality of notochord development. The majority of cases occur in the thoracolumbar region, with more than 30 cases of cervical SCM reported. The clinical impact of SCMs involving the cervical cord is therefore largely unknown. In addition, the concomitant finding of brainstem involvement is presumably incompatible with life in the majority of patients, resulting in a paucity of data regarding this clinical scenario. In this paper the authors present the first case, to their knowledge, of an incomplete cervical SCM involving the brainstem and discuss its clinical impact, diagnosis, and management. PMID- 28009227 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 28009226 TI - Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response. AB - Brain tumors are the most common solid tumor in childhood, and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specific mutations within tumor subtypes that may represent targets for individualized tumor treatment. The mitogen-activating protein kinase (MAPK) pathway and, more specifically, BRAF mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and may represent one such area to target. Herein, the authors describe 2 cases of inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a documented response to trametinib, an MAPK pathway inhibitor. While these cases were not treated in the setting of a clinical trial, their data support further ongoing clinical trial investigation to evaluate the safety and efficacy of this agent in pediatric low-grade gliomas. PMID- 28009228 TI - Microsurgery for Spetzler-Ponce Class A and B arteriovenous malformations utilizing an outcome score adopted from Gamma Knife radiosurgery: a prospective cohort study. AB - OBJECTIVE The purpose of this study was to adapt and apply the extended definition of favorable outcome established for Gamma Knife radiosurgery (GKRS) to surgery for brain arteriovenous malformations (bAVMs). The aim was to derive both an error around the point estimate and a model incorporating angioarchitectural features in order to facilitate comparison among different treatments. METHODS A prospective microsurgical cohort was analyzed. This cohort included patients undergoing embolization who did not proceed to microsurgery and patients denied surgery because of perceived risk of treatment. Data on bAVM residual and recurrence during long-term follow-up as well as complications of surgery and preoperative embolization were analyzed. Patients with Spetzler-Ponce Class C bAVMs were excluded because of extreme selection bias. First, patients with a favorable outcome were identified for both Class A and Class B lesions. Patients were considered to have a favorable outcome if they were free of bAVM recurrence or residual at last follow-up, with no complication of surgery or preoperative embolization, and a modified Rankin Scale score of more than 1 at 12 months after treatment. Patients who were denied surgery because of perceived risk, but would otherwise have been candidates for surgery, were included as not having a favorable outcome. Second, the authors analyzed favorable outcome from microsurgery by means of regression analysis, using as predictors characteristics previously identified to be associated with complications. Third, they created a prediction model of favorable outcome for microsurgery dependent upon angioarchitectural variables derived from the regression analysis. RESULTS From a cohort of 675 patients who were either treated or denied surgery because of perceived risk of surgery, 562 had Spetzler-Ponce Class A or B bAVMs and were included in the analysis. Logistic regression for favorable outcome found decreasing maximum diameter (continuous, OR 0.62, 95% CI 0.51-0.76), the absence of eloquent location (OR 0.23, 95% CI 0.12-0.43), and the absence of deep venous drainage (OR 0.19, 95% CI 0.10-0.36) to be significant predictors of favorable outcome. These variables are in agreement with previous analyses of microsurgery leading to complications, and the findings support the use of favorable outcome for microsurgery. The model developed for angioarchitectural features predicts a range of favorable outcome at 8 years following microsurgery for Class A bAVMs to be 88%-99%. The same model for Class B bAVMs predicts a range of favorable outcome of 62%-90%. CONCLUSIONS Favorable outcome, derived from GKRS, can be successfully used for microsurgical cohort series to assist in treatment recommendations. A favorable outcome can be achieved by microsurgery in at least 90% of cases at 8 years following microsurgery for patients with bAVMs smaller than 2.5 cm in maximum diameter and, in the absence of either deep venous drainage or eloquent location, patients with Spetzler-Ponce Class A bAVMs of all diameters. For patients with Class B bAVMs, this rate of favorable outcome can only be approached for lesions with a maximum diameter just above 6 cm or smaller and without deep venous drainage or eloquent location. PMID- 28009216 TI - Constraints on Ultrahigh-Energy Cosmic-Ray Sources from a Search for Neutrinos above 10 PeV with IceCube. AB - We report constraints on the sources of ultrahigh-energy cosmic rays (UHECRs) above 10^{9} GeV, based on an analysis of seven years of IceCube data. This analysis efficiently selects very high- energy neutrino-induced events which have deposited energies from 5*10^{5} GeV to above 10^{11} GeV. Two neutrino-induced events with an estimated deposited energy of (2.6+/-0.3)*10^{6} GeV, the highest neutrino energy observed so far, and (7.7+/-2.0)*10^{5} GeV were detected. The atmospheric background-only hypothesis of detecting these events is rejected at 3.6sigma. The hypothesis that the observed events are of cosmogenic origin is also rejected at >99% CL because of the limited deposited energy and the nonobservation of events at higher energy, while their observation is consistent with an astrophysical origin. Our limits on cosmogenic neutrino fluxes disfavor the UHECR sources having a cosmological evolution stronger than the star formation rate, e.g., active galactic nuclei and gamma-ray bursts, assuming proton-dominated UHECRs. Constraints on UHECR sources including mixed and heavy UHECR compositions are obtained for models of neutrino production within UHECR sources. Our limit disfavors a significant part of parameter space for active galactic nuclei and new-born pulsar models. These limits on the ultrahigh-energy neutrino flux models are the most stringent to date. PMID- 28009229 TI - Transoral robotic surgery for sellar tumors: first clinical study. AB - OBJECTIVE The aim of this study was to confirm the feasibility of an innovative transoral robotic surgery (TORS), using the da Vinci Surgical System, for patients with sellar tumors. This technique was designed to offer a new minimally invasive approach, without soft-palate splitting, that avoids the rhinological side effects of classic endonasal approaches. METHODS The authors performed a prospective study of TORS in patients with symptomatic sellar tumors. Specific anatomical features were required for inclusion in the study and were determined on the basis of preoperative open-mouth CT scans of the brain. The main outcome measure was sellar accessibility using the robot. Resection quality, mean operative time, postoperative changes in patients' vision, side effects, and complications were additionally reported. RESULTS Between February and May 2016, 4 patients (all female, mean age 49.5 years) underwent TORS for resection of sellar tumors as participants in this study. All patients presented with symptomatic visual deficits confirmed as bitemporal hemianopsia. All tumors had a suprasellar portion and a cystic part. In all 4 cases, the operation was performed via TORS, without the need for a second surgery. Sella turcica accessibility was satisfactory in all cases. In 3 cases, tumor resection was complete. The mean operative time was 2 hours 43 minutes. Three patients had a significant visual improvement at Day 1. No rhinological side effects or complications in patients occurred. No pathological examination was performed regarding the fluid component of the tumors. There was 1 postoperative delayed CSF leak and 1 case of transient diabetes insipidus. Side effects specific to TORS included minor sore throat, transient hypernasal speech, and 1 case of delayed otitis media. The mean length of hospital stay and mean follow up were 8.25 days and 82 days, respectively. CONCLUSIONS To our knowledge, this is the first report of the surgical treatment of sellar tumors by means of a minimally invasive TORS. This approach using the da Vinci Surgical System seems feasible and constitutes an innovative neurosurgical technique that may avoid the adverse side effects and technical disadvantages of the classic transsphenoidal route. Moreover, TORS allows an inferosuperior approach to the sella turcica, which is a key point, as the tumor is approached in the direction of its growth. PMID- 28009230 TI - Letter to the Editor: Endoscopic transsphenoidal pituitary surgery. PMID- 28009232 TI - Clinical relevance of anterior cerebral artery asymmetry in aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE An asymmetry of the A1 segments (A1SA) of the anterior cerebral arteries (ACAs) is an assumed risk factor for the development of anterior communicating artery aneurysms (ACoAAs). It is unknown whether A1SA is also clinically relevant after aneurysm rupture. The authors of this study investigated the impact of A1SA on the clinical course and outcome of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS The authors retrospectively analyzed data on consecutive SAH patients treated at their institution between January 2005 and December 2012. The occurrence and severity of cerebral infarctions in the ACA territories were evaluated on follow-up CT scans up to 6 weeks after SAH. Moreover, the risk for an unfavorable outcome (defined as > 3 points on the modified Rankin Scale) at 6 months after SAH was assessed. RESULTS A total of 594 patients were included in the final analysis. An A1SA was identified on digital subtraction angiography studies from 127 patients (21.4%) and was strongly associated with ACoAA (p < 0.0001, OR 13.7). An A1SA independently correlated with the occurrence of ACA infarction in patients with ACoAA (p = 0.047) and in those without an ACoAA (p = 0.015). Among patients undergoing ACoAA coiling, A1SA was independently associated with the severity of ACA infarction (p = 0.023) and unfavorable functional outcome (p = 0.045, OR = 2.4). CONCLUSIONS An A1SA is a common anatomical variation in SAH patients and is strongly associated with ACoAA. Moreover, the presence of A1SA independently increases the likelihood of ACA infarction. In SAH patients undergoing ACoAA coiling, A1SA carries the risk for severe ACA infarction and thus an unfavorable outcome. Clinical trial registration no.: DRKS00005486 ( http://www.drks.de/ ). PMID- 28009231 TI - The superior fovea triangle approach: a novel safe entry zone to the brainstem. AB - The authors describe a safe entry zone, the superior fovea triangle, on the floor of the fourth ventricle for resection of deep dorsal pontine lesions at the level of the facial colliculus. Clinical data from a patient undergoing a suboccipital telovelar transsuperior fovea triangle approach to a deep pontine cavernous malformation were reviewed and supplemented with 6 formalin-fixed adult human brainstem and 2 silicone-injected adult human cadaveric heads using the fiber dissection technique to illustrate the utility of this novel safe entry zone. The superior fovea has a triangular shape that is an important landmark for the motor nucleus of the trigeminal, abducens, and facial nerves. The inferior half of the superior fovea triangle may be incised to remove deep dorsal pontine lesions through the floor of the fourth ventricle. The superior fovea triangle may be used as a safe entry zone for dorsally located lesions at the level of the facial colliculus. PMID- 28009233 TI - Contribution of the straightening effect of the parent artery to decreased recanalization in stent-assisted coiling of large aneurysms. AB - OBJECTIVE The durability of embolization of large aneurysms is enhanced by use of the neck-bridging stent. However, it remains unclear what factors contribute to decreased recanalization. The purpose of this study was to demonstrate the contribution of the straightening effect of the parent artery to the durability of stent-assisted coiling for large aneurysms. METHODS Of the 182 aneurysms treated by embolization since the introduction of the neurovascular stent, 82 consecutive unruptured aneurysms with a diameter greater than 7 mm were selected. There were 52 aneurysms treated with a stent (Group S) and 30 treated without a stent (Group NS). Occlusion status was evaluated 12 months after embolization with digital subtraction angiography. The vascular angle of the parent artery was measured before, immediately after, and 12 months after embolization. The rates of recanalization were compared between Group S and Group NS. In Group S, the rates of recanalization were further compared between those aneurysms with and without a significant angle change. RESULTS The rate of major recanalization was 9.6% in Group S and 26.7% in Group NS. The volume embolization ratio was 32.6% in Group S and 31.6% in Group NS, with no statistically significant difference. However, the angulation change before and after coiling was significantly higher in Group S (10.6 degrees ) than in Group NS (0.9 degrees ). The difference in the angulation was more evident 12 months after coiling (19.1 degrees in Group S and 1.5 degrees in Group NS). In Group S, recanalization was found in 14.3% of 35 stented aneurysms without a significant angular change when a significant angular change was defined as more than 20 degrees . In contrast, all 17 aneurysms with >= 20 degrees of angular change remained occluded. CONCLUSIONS Significant angular change of >= 20 degrees most likely leads to decreased recanalization following stent-assisted embolization of large aneurysms. PMID- 28009234 TI - Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats. AB - OBJECTIVE The aim of this study was to evaluate whether combined gene therapy with vascular endothelial growth factor (VEGF) plus apelin during indirect vasoreconstructive surgery enhances brain angiogenesis in a chronic cerebral hypoperfusion model in rats. METHODS A chronic cerebral hypoperfusion model induced by the permanent ligation of bilateral common carotid arteries (CCAs; a procedure herein referred to as "CCA occlusion" [CCAO]) in rats was employed in this study. Seven days after the CCAO procedure, the authors performed encephalo myo-synangiosis (EMS) and injected plasmid(s) into each rat's temporal muscle. Rats were divided into 4 groups based on which plasmid was received (i.e., LacZ group, VEGF group, apelin group, and VEGF+apelin group). Protein levels in the cortex and attached muscle were assessed with enzyme-linked immunosorbent assay (ELISA) on Day 7 after EMS, while immunofluorescent analysis of cortical vessels was performed on Day 14 after EMS. RESULTS The total number of blood vessels in the cortex on Day 14 after EMS was significantly larger in the VEGF group and the VEGF+apelin group than in the LacZ group (p < 0.05, respectively). Larger vessels appeared in the VEGF+apelin group than in the other groups (p < 0.05, respectively). Apelin protein on Day 7 after EMS was not detected in the cortex for any of the groups. In the attached muscle, apelin protein was detected only in the apelin group and the VEGF+apelin group. Immunofluorescent analysis revealed that apelin and its receptor, APJ, were expressed on endothelial cells (ECs) 7 days after the CCAO. CONCLUSIONS Combined gene therapy (VEGF plus apelin) during EMS in a chronic cerebral hypoperfusion model can enhance angiogenesis in rats. This treatment has the potential to be a feasible option in a clinical setting for patients with moyamoya disease. PMID- 28009235 TI - Expression profile of long noncoding RNAs in human cerebral aneurysms: a microarray analysis. AB - OBJECTIVE The pathogenesis of cerebral aneurysms (CAs) remains largely unknown. Long noncoding RNAs (lncRNAs) were reported recently to play crucial roles in many physiological and biological processes. Here, the authors compared the gene expression profiles of CAs and their control arteries to investigate the potential functions of lncRNAs in the formation of CAs. METHODS A prospective case-control study was designed to identify the changes in expression of lncRNAs and mRNAs between 12 saccular CA samples (case group) and 12 paired superficial temporal artery samples (control group). Microarray analysis was performed to investigate the expression of lncRNAs and messenger RNAs (mRNAs), and reverse transcription quantitative polymerase chain reaction was used to validate the microarray analysis findings. Then, an lncRNA target-prediction program and gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to explore potential lncRNA functions. RESULTS A comparison between the case and control groups revealed that 1518 lncRNAs and 2545 mRNAs were expressed differentially. By using target-prediction program analysis, the authors constructed a complex network consisting of 2786 matched lncRNA-mRNA pairs, in which ine1 mRNA was potentially targeted by one to tens of lncRNAs, and vice versa. The results of further gene ontology and KEGG pathway analyses indicated that lncRNAs were involved mainly in regulating immune/inflammatory processes/pathways and vascular smooth muscle contraction, both of which are known to have crucial pathobiological relevance in terms of CA formation. CONCLUSIONS By comparing CAs with their control arteries, the authors created an expression profile of lncRNAs in CAs and propose here their possible roles in the pathogenesis of CAs. The results of this study provide novel insight into the mechanisms of CA pathogenesis and shed light on developing new therapeutic intervention for CAs in the future. PMID- 28009237 TI - Letter to the Editor: Recurrent or residual craniopharyngioma: management options. PMID- 28009236 TI - Increased blood cell phosphatidylserine exposure and circulating microparticles contribute to procoagulant activity after carotid artery stenting. AB - OBJECTIVE Phosphatidylserine (PS) is a major component of the inner leaflet of membrane bilayers. During cell activation or apoptosis, PS is externalized to the outer membrane, providing an important physiological signal necessary for the release of the microparticles (MPs) that are generated through the budding of cellular membranes. MPs express PS and membrane antigens that reflect their cellular origin. PS exposure on the cell surface and the release of MPs provide binding sites for factor Xa and prothrombinase complexes that promote thrombin formation. Relatively little is known about the role of PS exposure on blood cells and MPs in patients with internal carotid artery (ICA) stenosis who have undergone carotid artery stenting (CAS). The authors aimed to investigate the extent of PS exposure on blood cells and MPs and to define its role in procoagulant activity (PCA) in the 7 days following CAS. METHODS The study included patients with ICA stenosis who had undergone CAS (n = 70), matched patients who had undergone catheter angiography only (n = 30), and healthy controls (n = 30). Blood samples were collected from all patients just before the procedure after an overnight fast and at 2, 6, 24, 48, and 72 hours and 7 days after the CAS procedure. Blood was collected from healthy controls after an overnight fast. Phosphatidylserine-positive (PS+) MPs and blood cells were analyzed by flow cytometry, while PCA was assessed with clotting time analysis, purified coagulation complex assays, and fibrin formation assays. RESULTS The authors found that levels of PS+ blood cells and PS+ blood cell-derived MPs (platelets and platelet-derived MPs [PMPs], neutrophils and neutrophil-derived MPs [NMPs], monocytes and monocyte-derived MPs [MMPs], erythrocytes and erythrocyte-derived MPs [RMPs], and endothelial cells and endothelial cell derived MPs [EMPs]) were increased in the 7 days following the CAS procedure. Specifically, elevation of PS exposure on platelets/PMPs, neutrophils/NMPs, and monocytes/MMPs was detected within 2 hours of CAS, whereas PS exposure was delayed on erythrocytes/RMPs and EMPs, with an increase detected 24 hours after CAS. In addition, PS+ platelets/PMPs peaked at 2 hours, while PS+ neutrophils/NMPs, monocytes/MMPs, and erythrocytes/RMPs peaked at 48 hours. After their peak, all persisted at levels above baseline for 7 days post-CAS. Moreover, the level of PS+ blood cells/MPs was correlated with shortened coagulation time and significantly increased intrinsic and extrinsic Xase, thrombin generation, and fibrin formation. Pretreatment of blood cells with lactadherin at their peak time point after CAS blocked PS, resulting in prolonged coagulation times, decreased procoagulant enzyme activation, and fibrin production. CONCLUSIONS The results of this study suggest that increased exposure of PS on blood cells and MPs may contribute to enhanced PCA in patients with ICA stenosis who have undergone CAS, explaining the risk of perioperative thromboembolic complications in these patients. PS on blood cells and MPs may serve as an important biomarker for predicting, and as a pivotal target for monitoring and treating, acute postoperative complications after CAS. ? CLASSIFICATION OF EVIDENCE Type of question: association; study design: prospective cohort trial; evidence: Class I. PMID- 28009238 TI - 3-Tesla MRI in patients with fully implanted deep brain stimulation devices: a preliminary study in 10 patients. AB - OBJECTIVE The aim of this study was to evaluate the safety of 3-T MRI in patients with implanted deep brain stimulation (DBS) systems. METHODS This study was performed in 2 phases. In an initial phantom study, a Lucite phantom filled with tissue-mimicking gel was assembled. The system was equipped with a single DBS electrode connected to an internal pulse generator. The tip of the electrode was coupled to a fiber optic thermometer with a temperature resolution of 0.1 degrees C. Both anatomical (T1- and T2-weighted) and functional MRI sequences were tested. A temperature change within 2 degrees C from baseline was considered safe. After findings from the phantom study suggested safety, 10 patients with implanted DBS systems targeting various brain areas provided informed consent and underwent 3-T MRI using the same imaging sequences. Detailed neurological evaluations and internal pulse generator interrogations were performed before and after imaging. RESULTS During phantom testing, the maximum temperature increase was registered using the T2-weighted sequence. The maximal temperature changes at the tip of the DBS electrode were < 1 degrees C for all sequences tested. In all patients, adequate images were obtained with structural imaging, although a significant artifact from lead connectors interfered with functional imaging quality. No heating, warmth, or adverse neurological effects were observed. CONCLUSIONS To the authors' knowledge, this was the first study to assess the clinical safety of 3-T MRI in patients with a fully implanted DBS system (electrodes, extensions, and pulse generator). It provided preliminary data that will allow further examination and assessment of the safety of 3-T imaging studies in patients with implanted DBS systems. The authors cannot advocate widespread use of this type of imaging in patients with DBS implants until more safety data are obtained. PMID- 28009239 TI - Central nervous system filariasis masquerading as a glioma: case report. AB - Filariasis, an endemic zoonosis in the Southeast Asia region, has been reported to affect various organs as well as the central nervous system (CNS). Inflammatory reactions mimicking those from neoplastic lesions clinically and radiologically have been reported in the breast and urinary bladder. To date, a CNS manifestation of filarial infestation has been reported in the form of meningoencephalitis. The authors here present an interesting case of a young man presenting in status epilepticus, which on radiological evaluation appeared to be a glioma. However, postoperative histopathological examination changed the provisional diagnosis to a filarial infection of the CNS mimicking a primary CNS neoplasm. PMID- 28009240 TI - Venous sinus stenting for reduction of intracranial pressure in IIH: a prospective pilot study. AB - OBJECTIVE Idiopathic intracranial hypertension (IIH) may cause blindness due to elevated intracranial pressure (ICP). Venous sinus stenosis has been identified in select patients, leading to stenting as a potential treatment, but its effects on global ICP have not been completely defined. The purpose of this pilot study was to assess the effects of venous sinus stenting on ICP in a small group of patients with IIH. METHODS Ten patients for whom medical therapy had failed were prospectively followed. Ophthalmological examinations were assessed, and patients with venous sinus stenosis on MR angiography proceeded to catheter angiography, venography with assessment of pressure gradient, and ICP monitoring. Patients with elevated ICP measurements and an elevated pressure gradient across the stenosis were treated with stent placement. RESULTS All patients had elevated venous pressure (mean 39.5 +/- 14.9 mm Hg), an elevated gradient across the venous sinus stenosis (30.0 +/- 13.2 mm Hg), and elevated ICP (42.2 +/- 15.9 mm Hg). Following stent placement, all patients had resolution of the stenosis and gradient (1 +/- 1 mm Hg). The ICP values showed an immediate decrease (to a mean of 17.0 +/- 8.3 mm Hg), and further decreased overnight (to a mean of 8 +/- 4.2 mm Hg). All patients had subjective and objective improvement, and all but one improved during follow-up (median 23.4 months; range 15.7-31.6 months). Two patients developed stent-adjacent stenosis; retreatment abolished the stenosis and gradient in both cases. Patients presenting with papilledema had resolution on follow-up funduscopic imaging and optical coherence tomography (OCT) and improvement on visual field testing. Patients presenting with optic atrophy had optic nerve thinning on follow-up OCT, but improved visual fields. CONCLUSIONS For selected patients with IIH and venous sinus stenosis with an elevated pressure gradient and elevated ICP, venous sinus stenting results in resolution of the venous pressure gradient, reduction in ICP, and functional, neurological, and ophthalmological improvement. As patients are at risk for stent-adjacent stenosis, further follow-up is necessary to determine long-term outcomes and gain an understanding of venous sinus stenosis as a primary or secondary pathological process behind elevated ICP. PMID- 28009241 TI - Letter to the Editor: Dural arteriovenous fistula: a clinical model of thalamic dementia? PMID- 28009242 TI - An analysis of malpractice litigation related to the management of brain aneurysms. AB - OBJECTIVE Given the highly complex and demanding clinical environment in which neurosurgeons operate, the probability of facing a medical malpractice claim is high. Recent emphasis on tort reform within the political sphere has brought this issue to the forefront of medical literature. Despite the widespread fear of litigation in the medical community, few studies have provided an analysis of malpractice litigation in the field. Here, the authors attempt to delineate the medicolegal factors that impel plaintiffs to file medical malpractice claims related to the management of brain aneurysms, and to better characterize the nature of these lawsuits. METHODS The online legal database WestLawNext was searched to find all medical malpractice cases related to brain aneurysms across a 30-year period. All state and federal jury verdicts and settlements relevant to the search criterion were considered. RESULTS Sixty-six cases were obtained. The average age of the patient was 46.7 years. Seventy-one percent were female. The cases were distributed across 16 states. The jury found in favor of the plaintiff in 40.9% of cases, with a mean payout of $8,765,405, and in favor of the defendant in 28.8% of the cases. A failure to diagnose and/or a failure to treat in a timely manner were the 2 most commonly alleged causes of malpractice. Settlements, which were reached in 25.8% of the cases, had a mean payout of $1,818,250. Neurosurgeons accounted for 6.7% of all defendants. CONCLUSIONS Unlike other medical specialties, a majority of the verdicts were not in the defendant's favor. The mean payouts were nearly 5-fold less in cases in which a settlement was reached, as opposed to a summary judgment. Neurosurgeons accounted for a small percentage of all codefendants. PMID- 28009243 TI - Who Should Assess the Needs of and Care for a Dementia Patient's Caregiver? AB - Using a clinical case example, we examine whether health and human service professionals have a moral obligation to assess and address the needs of family caregivers of persons with dementia and, if so, the challenges in doing so under current health care and reimbursement mechanisms. We also discuss specific strategies for involving caregivers. PMID- 28009244 TI - Neuroethics and Disorders of Consciousness: Discerning Brain States in Clinical Practice and Research. AB - Decisions about end-of-life care and participation in clinical research for patients with disorders of consciousness begin with diagnostic discernment. Accurately distinguishing between brain states clarifies clinicians' ethical obligations and responsibilities. Central to this effort is the obligation to provide neuropalliative care for patients in the minimally conscious state who can perceive pain and to restore functional communication through neuroprosthetics, drugs, and rehabilitation to patients with intact but underactivated neural networks. Efforts to bring scientific advances to patients with disorders of consciousness are reviewed, including the investigational use of deep brain stimulation in patients in the minimally conscious state. These efforts help to affirm the civil rights of a population long on the margins. PMID- 28009245 TI - Advancing Ethical Neuroscience Research. AB - As neuroscience research advances, researchers, clinicians, and other stakeholders will face a host of ethical challenges. The Presidential Commission for the Study of Bioethical Issues (Bioethics Commission) has published two reports that provide recommendations on how to advance research endeavors ethically. The commission addressed, among other issues, how to prioritize different types of neuroscience research and how to include research participants who have impaired consent capacity. The Bioethics Commission's recommendations provide a foundation for ethical guidelines as neuroscience research advances and progresses. PMID- 28009246 TI - Locating Risk in the Adolescent Brain: Ethical Challenges in the Use of Biomarkers for Adolescent Health and Social Policy. AB - Technological developments in neuroscience over the last 20 years have generated excitement about the potential of neuroscientific insights for the understanding of and intervention in children's and adolescents' behavior. This article introduces some ways in which new results from developmental cognitive neuroscience have been appropriated in the context of adolescent mental health. We also consider social and interpersonal factors that drive the use of neurobiological markers of mental disorders in pediatric psychiatry. Finally, we outline the current ambitions for using neurobiological biomarkers in adolescent mental health care and discuss some ethical challenges arising from the methodological, political, cultural, and social contexts of their application. PMID- 28009247 TI - The Legal Implications of Detecting Alzheimer's Disease Earlier. AB - Early detection of Alzheimer's disease (AD) raises a number of challenging legal questions. In this essay, we explore some of those questions, such as: Is a neurological indicator of increased risk for AD a legally relevant brain state before there are any outward behavioral manifestations? How should courts address evidentiary challenges to the admissibility of AD-related neuroimaging? How should the government regulate the marketing of neuroimaging diagnostic tools? How should insurance coverage for the use of these new tools be optimized? We suggest that many voices and multidisciplinary perspectives are needed to answer these questions and ensure that legal responses are swift, efficient, and equitable. PMID- 28009248 TI - Promoting Access to School-Based Services for Children's Mental Health. AB - Mental health issues are widespread among children, but many never receive adequate treatment. One political solution proposed to address this disparity would be to fund mental health services through school-based programs and support collaboration among community and health organizations to address the needs of children. Regardless of whether this policy is implemented, health care professionals have a responsibility to promote access to care and patient health, which may include actively participating in the development of programs to provide services to children with mental health disorders. PMID- 28009249 TI - Manipulating Memories: The Ethics of Yesterday's Science Fiction and Today's Reality. AB - The paper addresses recent advances in memory manipulation from the perspective of the four key pillars of neuroethics: the self, social policy, neurotechnology, and education and outreach. We provide examples for each pillar, assess their neuroethical implications, and conclude with a call for an ethics framework that is specifically tailored for the ethical challenges of memory manipulation. PMID- 28009250 TI - Autism, Art, and Accessibility to Theater. AB - Art has the ability to entertain and educate about many vital aspects of the human experience. Recently, innovative endeavors are providing greater accessibility to theatrical productions for people with autism spectrum disorder (ASD), prompting ethical questions about how accommodations to provide access to art and culture should be made, and for whom. This article uses an attributional model of stigma to explain potential differences in knowledge, attitudes, and behavior toward people with mental illness. This social cognitive model also provides clues about how to spur social change through translational education, familiarization, and advocacy to permit greater access to art for people with disabilities. PMID- 28009251 TI - Changing Memories: Between Ethics and Speculation. AB - Over the past decade, a debate has emerged between those who believe that memory modulating technologies are inherently dangerous and need to be regulated and those who believe these technologies present minimal risk and thus view concerns about their use as far-fetched and alarmist. This article tackles three questions central to this debate: (1) Do these technologies jeopardize personhood? (2) Are the risks of these technologies acceptable? (3) Do these technologies require special regulation or oversight? Although concerns about the unethical use of memory-modulating technologies are legitimate, these concerns should not override the responsible use of memory-modulating technologies in clinical contexts. Accordingly, we call for careful comparative analysis of their use on a case-by case basis. PMID- 28009252 TI - Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones. AB - Our previous paper (Wilkinson et al, 2016) used high-resolution cryo-electron microscopy to solve the structure of the Escherichia coli RecBCD complex, which acts in both the repair of double-stranded DNA breaks and the degradation of bacteriophage DNA. To counteract the latter activity, bacteriophage lambda encodes a small protein inhibitor called Gam that binds to RecBCD and inactivates the complex. Here, we show that Gam inhibits RecBCD by competing at the DNA binding site. The interaction surface is extensive and involves molecular mimicry of the DNA substrate. We also show that expression of Gam in E. coli or Klebsiella pneumoniae increases sensitivity to fluoroquinolones; antibacterials that kill cells by inhibiting topoisomerases and inducing double-stranded DNA breaks. Furthermore, fluoroquinolone-resistance in K. pneumoniae clinical isolates is reversed by expression of Gam. Together, our data explain the synthetic lethality observed between topoisomerase-induced DNA breaks and the RecBCD gene products, suggesting a new co-antibacterial strategy. PMID- 28009253 TI - Structural snapshots of Xer recombination reveal activation by synaptic complex remodeling and DNA bending. AB - Bacterial Xer site-specific recombinases play an essential genome maintenance role by unlinking chromosome multimers, but their mechanism of action has remained structurally uncharacterized. Here, we present two high-resolution structures of Helicobacter pylori XerH with its recombination site DNA difH, representing pre-cleavage and post-cleavage synaptic intermediates in the recombination pathway. The structures reveal that activation of DNA strand cleavage and rejoining involves large conformational changes and DNA bending, suggesting how interaction with the cell division protein FtsK may license recombination at the septum. Together with biochemical and in vivo analysis, our structures also reveal how a small sequence asymmetry in difH defines protein conformation in the synaptic complex and orchestrates the order of DNA strand exchanges. Our results provide insights into the catalytic mechanism of Xer recombination and a model for regulation of recombination activity during cell division. PMID- 28009254 TI - Spatiotemporal coupling and decoupling of gene transcription with DNA replication origins during embryogenesis in C. elegans. AB - The primary task of developing embryos is genome replication, yet how DNA replication is integrated with the profound cellular changes that occur through development is largely unknown. Using an approach to map DNA replication at high resolution in C. elegans, we show that replication origins are marked with specific histone modifications that define gene enhancers. We demonstrate that the level of enhancer associated modifications scale with the efficiency at which the origin is utilized. By mapping replication origins at different developmental stages, we show that the positions and activity of origins is largely invariant through embryogenesis. Contrary to expectation, we find that replication origins are specified prior to the broad onset of zygotic transcription, yet when transcription initiates it does so in close proximity to the pre-defined replication origins. Transcription and DNA replication origins are correlated, but the association breaks down when embryonic cell division ceases. Collectively, our data indicate that replication origins are fundamental organizers and regulators of gene activity through embryonic development. PMID- 28009255 TI - Translational control of auditory imprinting and structural plasticity by eIF2alpha. AB - The formation of imprinted memories during a critical period is crucial for vital behaviors, including filial attachment. Yet, little is known about the underlying molecular mechanisms. Using a combination of behavior, pharmacology, in vivo surface sensing of translation (SUnSET) and DiOlistic labeling we found that, translational control by the eukaryotic translation initiation factor 2 alpha (eIF2alpha) bidirectionally regulates auditory but not visual imprinting and related changes in structural plasticity in chickens. Increasing phosphorylation of eIF2alpha (p-eIF2alpha) reduces translation rates and spine plasticity, and selectively impairs auditory imprinting. By contrast, inhibition of an eIF2alpha kinase or blocking the translational program controlled by p-eIF2alpha enhances auditory imprinting. Importantly, these manipulations are able to reopen the critical period. Thus, we have identified a translational control mechanism that selectively underlies auditory imprinting. Restoring translational control of eIF2alpha holds the promise to rejuvenate adult brain plasticity and restore learning and memory in a variety of cognitive disorders. PMID- 28009258 TI - Making Space for Time. PMID- 28009256 TI - Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling. AB - Internal ribosome entry sites (IRESs) are important RNA-based translation initiation signals, critical for infection by many pathogenic viruses. The hepatitis C virus (HCV) IRES is the prototype for the type 3 IRESs and is also invaluable for exploring principles of eukaryotic translation initiation, in general. Current mechanistic models for the type 3 IRESs are useful but they also present paradoxes, including how they can function both with and without eukaryotic initiation factor (eIF) 2. We discovered that eIF1A is necessary for efficient activity where it stabilizes tRNA binding and inspects the codon anticodon interaction, especially important in the IRES' eIF2-independent mode. These data support a model in which the IRES binds preassembled translation preinitiation complexes and remodels them to generate eukaryotic initiation complexes with bacterial-like features. This model explains previous data, reconciles eIF2-dependent and -independent pathways, and illustrates how RNA structure-based control can respond to changing cellular conditions. PMID- 28009259 TI - Principles of Systems Biology, No. 12. AB - This month: Plants take center stage with fascinating insights into disease susceptibility and engineered pathways for photosynthesis. Also, a wearable stethoscope, new noncanonical miRNA targeting rules, Hsf1, and transcription. PMID- 28009260 TI - Entraining Oscillations in the NF-kappaB Signaling System: With a Little Help from Noise. AB - Two studies show that noise is a key ingredient of new mechanisms for entraining the NF-kappaB system. PMID- 28009262 TI - Cell Lineage Trees Bear Fruit. AB - Two inference approaches harness the information present in cell lineage trees to better understand the dynamic transitions between cell states. PMID- 28009257 TI - Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit. AB - The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations. PMID- 28009261 TI - Turning It Up to 11: Modular Proteins Amplify RNA Sensors for Sophisticated Circuitry. AB - Ligand-sensing RNA switches can be enhanced using protein-based amplifiers to deliver sophisticated signal-processing genetic circuitry. PMID- 28009263 TI - The Evolution of the Algorithms for Collective Behavior. AB - Collective behavior is the outcome of a network of local interactions. Here, I consider collective behavior as the result of algorithms that have evolved to operate in response to a particular environment and physiological context. I discuss how algorithms are shaped by the costs of operating under the constraints that the environment imposes, the extent to which the environment is stable, and the distribution, in space and time, of resources. I suggest that a focus on the dynamics of the environment may provide new hypotheses for elucidating the algorithms that produce the collective behavior of cellular systems. PMID- 28009264 TI - Noise Induces Hopping between NF-kappaB Entrainment Modes. AB - Oscillations and noise drive many processes in biology, but how both affect the activity of the transcription factor nuclear factor kappaB (NF-kappaB) is not understood. Here, we observe that when NF-kappaB oscillations are entrained by periodic tumor necrosis factor (TNF) inputs in experiments, NF-kappaB exhibits jumps between frequency modes, a phenomenon we call "cellular mode-hopping." By comparing stochastic simulations of NF-kappaB oscillations to deterministic simulations conducted inside and outside the chaotic regime of parameter space, we show that noise facilitates mode-hopping in all regimes. However, when the deterministic system is driven by chaotic dynamics, hops between modes are erratic and short-lived, whereas in experiments, the system spends several periods in one entrainment mode before hopping and rarely visits more than two modes. The experimental behavior matches our simulations of noise-induced mode hopping outside the chaotic regime. We suggest that mode-hopping is a mechanism by which different NF-kappaB-dependent genes under frequency control can be expressed at different times. PMID- 28009266 TI - Elucidation of Signaling Pathways from Large-Scale Phosphoproteomic Data Using Protein Interaction Networks. AB - Phosphoproteomic experiments typically identify sites within a protein that are differentially phosphorylated between two or more cell states. However, the interpretation of these data is hampered by the lack of methods that can translate site-specific information into global maps of active proteins and signaling networks, especially as the phosphoproteome is often undersampled. Here, we describe PHOTON, a method for interpreting phosphorylation data within their signaling context, as captured by protein-protein interaction networks, to identify active proteins and pathways and pinpoint functional phosphosites. We apply PHOTON to interpret existing and novel phosphoproteomic datasets related to epidermal growth factor and insulin responses. PHOTON substantially outperforms the widely used cutoff approach, providing highly reproducible predictions that are more in line with current biological knowledge. Altogether, PHOTON overcomes the fundamental challenge of delineating signaling pathways from large-scale phosphoproteomic data, thereby enabling translation of environmental cues to downstream cellular responses. PMID- 28009265 TI - RNA Structural Determinants of Optimal Codons Revealed by MAGE-Seq. AB - Synonymous codon choices at the beginning of genes optimize 5' RNA structures for enhanced translation initiation, but less is known about mechanisms that drive codon optimization downstream within the gene. To understand what determines codon choices across a gene, we generated 12,726 in situ codon mutants in the Escherichia coli essential gene infA and measured their fitness by combining multiplex automated genome engineering mutagenesis with amplicon deep sequencing (MAGE-seq). Correlating predicted 5' RNA structure with fitness revealed that codons even far from the start of the gene are deleterious if they disrupt the native 5' RNA conformation. These long-range structural interactions generate context-dependent rules that constrain codon choices beyond intrinsic codon preferences. Genome-wide RNA folding predictions confirm that natural codon choices far from the start codon are optimized in part to prevent disruption of native structures near the 5' UTR. Our results shed light on natural codon distributions and should improve engineering of gene expression for synthetic biology applications. PMID- 28009268 TI - Mitochondria on the Road to Power Axonal Regeneration. AB - In this issue of Neuron, Han et al. (2016) and Cartoni et al. (2016) define a critical role of mitochondrial transport for successful axon regeneration after injury and provide new insights into intrinsic mechanisms controlling neuronal regeneration capacity in worms and mice. PMID- 28009267 TI - Transcription Factor Hand-offs "Enhance" Motor Neuron Differentiation. AB - Rhee et al. (2016) in this issue of Neuron and Velasco et al. (2016) in Cell Stem Cell find that the activity of transcription factors binding sequentially to a series of transient early and late enhancers directs gene expression that is essential for motor neuron differentiation and function. PMID- 28009269 TI - Shaping Early Networks to Rule Mature Circuits: Little MiRs Go a Long Way. AB - Normative cortical processing depends on precise interactions between excitatory and inhibitory neurons. In this issue of Neuron, Lippi et al. (2016) identify miR 101 as a master regulator coordinating molecular programs during development that ultimately impact the activity of mature networks. PMID- 28009270 TI - Healing Pains of the Past Using Neuronal Transplantation. AB - Yang et al. (2016) show that transplantation of GABAergic inhibitory neurons into the amygdala boosts the persistence of fear extinction in mice. Transplantation was found to degrade perineuronal nets on endogenous inhibitory neurons and enhance synaptic plasticity in host amygdala. PMID- 28009271 TI - Bidirectional Transcriptional Inhibition as Therapy for ALS/FTD Caused by Repeat Expansion in C9orf72. AB - Hexanucleotide repeat expansion in the bi-directionally transcribed C9orf72 gene is the most frequent cause of familial ALS and frontotemporal dementia (FTD). Kramer et al. (2016) report in Science that targeted reduction in the transcription elongation factor SUPT4H1/SUPT5H reduces both sense and antisense repeat-containing RNAs and their associated neurodegeneration. PMID- 28009272 TI - Searching for Signatures of Brain Maturity: What Are We Searching For? AB - Evidence of continued neurobiological maturation through adolescence is increasingly invoked in discussions of youth-focused policies. This should motivate neuroscientists to grapple with core issues such as the definition of brain maturation, how to quantify it, and how to precisely translate this knowledge to broader audiences. PMID- 28009273 TI - Life at Low Copy Number: How Dendrites Manage with So Few mRNAs. AB - Most mammalian dendrites have surprisingly few copy numbers of mRNAs relative to the large number of synapses and consequently, at any given moment, the majority of synapses do not have a repertoire of mRNAs within their immediate locale capable of initiating translation-dependent plasticity. The dimensions of the translationally serviceable locale around synapses have boundary parameters that can be estimated. When a synapse receives an input beyond that boundary, the requisite mRNAs for local translation and plasticity may not be there. How a complex dendritic arbor optimizes this paucity of mRNAs opens several functional considerations that are related to the dynamic range of dendritic plasticity, sparse coding, and modifications of firing rates. RNA localization in dendrites may instantiate a neuron's history and establishes a bias toward inputs that synapse on RNA-laden synaptic clusters. Low copy numbers create an element of stochasticity to the induction of translation-dependent plasticity that allows the dendrite opportunities to respond to novel and unexpected inputs. PMID- 28009274 TI - Targeted Intron Retention and Excision for Rapid Gene Regulation in Response to Neuronal Activity. AB - Activity-dependent transcription has emerged as a major source of gene products that regulate neuronal excitability, connectivity, and synaptic properties. However, the elongation rate of RNA polymerases imposes a significant temporal constraint for transcript synthesis, in particular for long genes where new synthesis requires hours. Here we reveal a novel, transcription-independent mechanism that releases transcripts within minutes of neuronal stimulation. We found that, in the mouse neocortex, polyadenylated transcripts retain select introns and are stably accumulated in the cell nucleus. A subset of these intron retention transcripts undergoes activity-dependent splicing, cytoplasmic export, and ribosome loading, thus acutely releasing mRNAs in response to stimulation. This process requires NMDA receptor- and calmodulin-dependent kinase pathways, and it is particularly prevalent for long transcripts. We conclude that regulated intron retention in fully transcribed RNAs represents a mechanism to rapidly mobilize a pool of mRNAs in response to neuronal activity. PMID- 28009275 TI - The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration. AB - Mitochondrial transport is crucial for neuronal and axonal physiology. However, whether and how it impacts neuronal injury responses, such as neuronal survival and axon regeneration, remain largely unknown. In an established mouse model with robust axon regeneration, we show that Armcx1, a mammalian-specific gene encoding a mitochondria-localized protein, is upregulated after axotomy in this high regeneration condition. Armcx1 overexpression enhances mitochondrial transport in adult retinal ganglion cells (RGCs). Importantly, Armcx1 also promotes both neuronal survival and axon regeneration after injury, and these effects depend on its mitochondrial localization. Furthermore, Armcx1 knockdown undermines both neuronal survival and axon regeneration in the high regenerative capacity model, further supporting a key role of Armcx1 in regulating neuronal injury responses in the adult central nervous system (CNS). Our findings suggest that Armcx1 controls mitochondrial transport during neuronal repair. PMID- 28009276 TI - Mitochondria Localize to Injured Axons to Support Regeneration. AB - Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo, single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration. Experimental alterations to axonal mitochondrial distribution or mitochondrial respiratory chain function result in corresponding changes to regeneration outcomes. Axonal mitochondria are specifically required for growth cone migration, identifying a key energy challenge for injured neurons. Finally, mitochondrial localization to the axon after injury is regulated in part by dual leucine zipper kinase 1 (DLK-1), a conserved regulator of axon regeneration. These data identify regulation of axonal mitochondria as a new cell-biological mechanism that helps determine the regenerative response of injured neurons. PMID- 28009277 TI - Movement Initiation Signals in Mouse Whisker Motor Cortex. AB - Frontal cortex plays a central role in the control of voluntary movements, which are typically guided by sensory input. Here, we investigate the function of mouse whisker primary motor cortex (wM1), a frontal region defined by dense innervation from whisker primary somatosensory cortex (wS1). Optogenetic stimulation of wM1 evokes rhythmic whisker protraction (whisking), whereas optogenetic inactivation of wM1 suppresses initiation of whisking. Whole-cell membrane potential recordings and silicon probe recordings of action potentials reveal layer specific neuronal activity in wM1 at movement initiation, and encoding of fast and slow parameters of movements during whisking. Interestingly, optogenetic inactivation of wS1 caused hyperpolarization and reduced firing in wM1, together with reduced whisking. Optogenetic stimulation of wS1 drove activity in wM1 with complex dynamics, as well as evoking long-latency, wM1-dependent whisking. Our results advance understanding of a well-defined frontal region and point to an important role for sensory input in controlling motor cortex. PMID- 28009278 TI - Dysfunction of Rapid Neural Adaptation in Dyslexia. AB - Identification of specific neurophysiological dysfunctions resulting in selective reading difficulty (dyslexia) has remained elusive. In addition to impaired reading development, individuals with dyslexia frequently exhibit behavioral deficits in perceptual adaptation. Here, we assessed neurophysiological adaptation to stimulus repetition in adults and children with dyslexia for a wide variety of stimuli, spoken words, written words, visual objects, and faces. For every stimulus type, individuals with dyslexia exhibited significantly diminished neural adaptation compared to controls in stimulus-specific cortical areas. Better reading skills in adults and children with dyslexia were associated with greater repetition-induced neural adaptation. These results highlight a dysfunction of rapid neural adaptation as a core neurophysiological difference in dyslexia that may underlie impaired reading development. Reduced neurophysiological adaptation may relate to prior reports of reduced behavioral adaptation in dyslexia and may reveal a difference in brain functions that ultimately results in a specific reading impairment. PMID- 28009279 TI - A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication. AB - Case reports of Zika virus (ZIKV) sexual transmission and genital persistence are mounting. Venereal transmission and genital persistence threaten public health within and beyond the range of ZIKV's mosquito vectors. In this study, we administered ZIKV into the vaginas of AG129 mice and LysMCre+IFNARfl/fl C57BL/6 mice after hormonal treatments. Mice infected during estrus-like phase were resistant to vaginal infection. In contrast, when infected during diestrus-like phase, AG129 mice succumbed to infection, whereas LysMCre+IFNARfl/fl mice experienced transient illness. Patency of transgenital transmission (TGT) in diestrus-like mice was demonstrated by detection of viremia and ZIKV replication in spleen and brain, and viral RNA persisted in vaginal washes as late as 10 days post-infection. In these lethal and sublethal mouse models, this study indicates that intravaginal deposition of ZIKV can cause TGT, hormonal changes in the female reproductive tract (FRT) influence transmission, and ZIKV replication persists in the FRT for several days. PMID- 28009280 TI - Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex. AB - BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM) reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm. The location and ubiquitin-binding activity of BRCC45 suggest that it may provide accessory interactions with nucleosome-linked ubiquitin chains that contribute to their efficient processing. Our data also suggest how ataxia telangiectasia mutated (ATM)-dependent BRCA1 dimerization may stabilize self association of the entire BRCA1-A complex. PMID- 28009281 TI - Peroxiredoxin 1 Protects Telomeres from Oxidative Damage and Preserves Telomeric DNA for Extension by Telomerase. AB - Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage have not been described. We analyzed telomeric chromatin composition during the cell cycle and show that the antioxidant enzyme peroxiredoxin 1 (PRDX1) is enriched at telomeres during S phase. Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage at telomeres. We also show that the oxidized nucleotide 8-oxo 2'deoxyguanosine-5'-triphosphate (8oxodGTP) causes premature chain termination when incorporated by telomerase and that some DNA substrates terminating in 8oxoG prevent extension by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase. PMID- 28009282 TI - Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation. AB - Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3-/- mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS. PMID- 28009283 TI - Calcium Imaging Reveals Coordinated Simple Spike Pauses in Populations of Cerebellar Purkinje Cells. AB - The brain's control of movement is thought to involve coordinated activity between cerebellar Purkinje cells. The results reported here demonstrate that somatic Ca2+ imaging is a faithful reporter of Na+-dependent "simple spike" pauses and enables us to optically record changes in firing rates in populations of Purkinje cells in brain slices and in vivo. This simultaneous calcium imaging of populations of Purkinje cells reveals a striking spatial organization of pauses in Purkinje cell activity between neighboring cells. The source of this organization is shown to be the presynaptic gamma-Aminobutyric acid producing (GABAergic) network, and blocking ionotropic gamma-Aminobutyric acid receptor (GABAARs) abolishes the synchrony. These data suggest that presynaptic interneurons synchronize (in)activity between neighboring Purkinje cells, and thereby maximize their effect on downstream targets in the deep cerebellar nuclei. PMID- 28009284 TI - Targeted Inactivation of Bax Reveals a Subtype-Specific Mechanism of Cajal Retzius Neuron Death in the Postnatal Cerebral Cortex. AB - Cajal-Retzius cells (CRs), the first-born neurons in the developing cerebral cortex, coordinate crucial steps in the construction of functional circuits. CRs are thought to be transient, as they disappear during early postnatal life in both mice and humans, where their abnormal persistence is associated with pathological conditions. Embryonic CRs comprise at least three molecularly and functionally distinct subtypes: septum, ventral pallium/pallial-subpallial boundary (PSB), and hem. However, whether subtype-specific features exist postnatally and through which mechanisms they disappear remain unknown. We report that CR subtypes display unique distributions and dynamics of death in the postnatal mouse cortex. Surprisingly, although all CR subtypes undergo cell death, septum, but not hem, CRs die in a Bax-dependent manner. Bax-inactivated rescued septum-CRs maintain immature electrophysiological properties. These results underlie the existence of an exquisitely refined control of developmental cell death and provide a model to test the effect of maintaining immature circuits in the adult neocortex. PMID- 28009285 TI - Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal. AB - Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa. PMID- 28009287 TI - Cdx and T Brachyury Co-activate Growth Signaling in the Embryonic Axial Progenitor Niche. AB - In vertebrate embryos, anterior tissues are generated early, followed by the other axial structures that emerge sequentially from a posterior growth zone. The genetic network driving posterior axial elongation in mice, and its disturbance in mutants with posterior truncation, is not yet fully understood. Here, we show that the combined expression of Cdx2 and T Brachyury is essential to establish the core signature of posterior axial progenitors. Cdx2 and T Brachyury are required for extension of a similar trunk portion of the axis. Simultaneous loss of function of these two genes disrupts axial elongation to a much greater extent than each single mutation alone. We identify and validate common targets for Cdx2 and T Brachyury in vivo, including Wnt and Fgf pathway components active in the axial progenitor niche. Our data demonstrate that integration of the Cdx/Hox and T Brachyury transcriptional networks controls differential axial growth during vertebrate trunk elongation. PMID- 28009286 TI - The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells. AB - The retina of lower vertebrates grows continuously by integrating new neurons generated from progenitors in the ciliary margin zone (CMZ). Whether the mammalian CMZ provides the neural retina with retinal cells is controversial. Live imaging of embryonic retina expressing eGFP in the CMZ shows that cells migrate laterally from the CMZ to the neural retina where differentiated retinal ganglion cells (RGCs) reside. Because Cyclin D2, a cell-cycle regulator, is enriched in ventral CMZ, we analyzed Cyclin D2-/- mice to test whether the CMZ is a source of retinal cells. Neurogenesis is diminished in Cyclin D2 mutants, leading to a reduction of RGCs in the ventral retina. In line with these findings, in the albino retina, the decreased production of ipsilateral RGCs is correlated with fewer Cyclin D2+ cells. Together, these results implicate the mammalian CMZ as a neurogenic site that produces RGCs and whose proper generation depends on Cyclin D2 activity. PMID- 28009288 TI - Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity. AB - Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming. PMID- 28009289 TI - Blood Stage Malaria Disrupts Humoral Immunity to the Pre-erythrocytic Stage Circumsporozoite Protein. AB - Many current malaria vaccines target the pre-erythrocytic stage of infection in the liver. However, in malaria-endemic regions, increased blood stage exposure is associated with decreased vaccine efficacy, thereby challenging current vaccine efforts. We hypothesized that pre-erythrocytic humoral immunity is directly disrupted by blood stage infection. To investigate this possibility, we used Plasmodium-antigen tetramers to analyze B cells after infection with either late liver stage arresting parasites or wild-type parasites that progress to the blood stage. Our data demonstrate that immunoglobulin G (IgG) antibodies against the pre-erythrocytic antigen, circumsporozoite protein (CSP), are generated only in response to the attenuated, but not the wild-type, infection. Further analyses revealed that blood stage malaria inhibits CSP-specific germinal center B cell differentiation and modulates chemokine expression. This results in aberrant memory formation and the loss of a rapid secondary B cell response. These data highlight how immunization with attenuated parasites may drive optimal immunity to malaria. PMID- 28009290 TI - Inhibition of RORgammaT Skews TCRalpha Gene Rearrangement and Limits T Cell Repertoire Diversity. AB - Recent studies have elucidated the molecular mechanism of RORgammaT transcriptional regulation of Th17 differentiation and function. RORgammaT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP) thymocytes. While RORgamma antagonists are currently being developed to treat autoimmunity, it remains unclear how RORgammaT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORgammaT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)alpha selection. Strikingly, pharmacological inhibition of RORgamma skews TCRalpha gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORgammaT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORgamma inhibitors has allowed us to gain a broader perspective of the diverse function of RORgammaT and its impact on T cell biology. PMID- 28009291 TI - Myeloid-Derived Suppressor Cells Are Controlled by Regulatory T Cells via TGF beta during Murine Colitis. AB - Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-beta (TGF-beta). TGF-beta-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-beta-mediated in-vitro differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-beta led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-beta. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions. PMID- 28009292 TI - TGF-beta Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory Inhibitory Synaptic Balance, and Reversal Learning. AB - Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor beta (TGF-beta) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-beta type II receptor in DA neurons also disrupts the balance in TGF-beta1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-beta signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus reward associations. These results support a role for TGF-beta in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders. PMID- 28009293 TI - Calcium Release from Stores Inhibits GIRK. AB - Synaptic transmission is mediated by ionotropic and metabotropic receptors that together regulate the rate and pattern of action potential firing. Metabotropic receptors can activate ion channels and modulate other receptors and channels. The present paper examines the interaction between group 1 mGluR-mediated calcium release from stores and GABAB/D2-mediated GIRK currents in rat dopamine neurons of the Substantia Nigra. Transient activation of mGluRs decreased the GIRK current evoked by GABAB and D2 receptors, although less efficaciously for D2. The mGluR-induced inhibition of GIRK current peaked in 1 s and recovered to baseline after 5 s. The inhibition was dependent on release of calcium from stores, was larger for transient than for tonic currents, and was unaffected by inhibitors of PLC, PKC, PLA2, or calmodulin. This inhibition of GABAB IPSCs through release of calcium from stores is a postsynaptic mechanism that may broadly reduce GIRK dependent inhibition of many central neurons. PMID- 28009294 TI - Synaptic Specializations Support Frequency-Independent Purkinje Cell Output from the Cerebellar Cortex. AB - The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells (PCs). Here, we characterize the properties of the PC-DCN synapse in juvenile and adult mice and find that prolonged high-frequency stimulation leads to steady-state responses that become increasingly frequency independent within the physiological firing range of PCs in older animals, resulting in a linear relationship between charge transfer and activation frequency. We used a low-affinity antagonist to show that GABAA-receptor saturation occurs at this synapse but does not underlie frequency-invariant transmission. We propose that PC-DCN synapses have two components of release: one prominent early in trains and another specialized to maintain transmission during prolonged activation. Short-term facilitation offsets partial vesicle depletion to produce frequency-independent transmission. PMID- 28009295 TI - A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior. AB - The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior. PMID- 28009296 TI - Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells. AB - In the pancreatic islet, serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high fat diet. It is still unclear whether serotonin is relevant for regular islet physiology and hormone secretion. Here, we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cyclic AMP (cAMP) levels in neighboring alpha cells via 5-HT1F receptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT1F receptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity. PMID- 28009298 TI - Adenovirus Protein E4-ORF1 Activation of PI3 Kinase Reveals Differential Regulation of Downstream Effector Pathways in Adipocytes. AB - Insulin activation of phosphatidylinositol 3-kinase (PI3K) regulates metabolism, including the translocation of the Glut4 glucose transporter to the plasma membrane and inactivation of the FoxO1 transcription factor. Adenoviral protein E4-ORF1 stimulates cellular glucose metabolism by mimicking growth-factor activation of PI3K. We have used E4-ORF1 as a tool to dissect PI3K-mediated signaling in adipocytes. E4-ORF1 activation of PI3K in adipocytes recapitulates insulin regulation of FoxO1 but not regulation of Glut4. This uncoupling of PI3K effects occurs despite E4-ORF1 activating PI3K and downstream signaling to levels achieved by insulin. Although E4-ORF1 does not fully recapitulate insulin's effects on Glut4, it enhances insulin-stimulated insertion of Glut4-containing vesicles to the plasma membrane independent of Rab10, a key regulator of Glut4 trafficking. E4-ORF1 also stimulates plasma membrane translocation of ubiquitously expressed Glut1 glucose transporter, an effect that is likely essential for E4-ORF1 to promote an anabolic metabolism in a broad range of cell types. PMID- 28009297 TI - Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis. AB - AMP-activated protein kinase (AMPK) is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGFbeta isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGFbeta signaling. PMID- 28009299 TI - RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements. AB - Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, alphaC helix, and an unconventional activation loop serine phosphorylation site that engages the HRD motif and promotes phospho tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with direct implications for drug discovery. PMID- 28009300 TI - Lineage-Specific and Non-specific Cytokine-Sensing Genes Respond Differentially to the Master Regulator STAT5. AB - STAT5, a member of the family of signal transducers and activators of transcription, senses cytokines and controls the biology of cell lineages, including mammary, liver, and T cells. Here, we show that STAT5 activates lineage specific and widely expressed genes through different mechanisms. STAT5 preferentially binds to promoter sequences of cytokine-responsive genes expressed across cell types and to putative enhancers of lineage-specific genes. While chromatin accessibility of STAT5-based enhancers was dependent on cytokine exposure, STAT5-responsive promoters of widely expressed target genes were generally constitutively accessible. While the contribution of STAT5 to enhancers is well established, its role on promoters is poorly understood. To address this, we focused on Socs2, a widely expressed cytokine-sensing gene. Upon deletion of the STAT5 response elements from the Socs2 promoter in mice, cytokine induction was abrogated, while basal activity remained intact. Our data suggest that promoter-bound STAT5 modulates cytokine responses and enhancer-bound STAT5 is mandatory for gene activation. PMID- 28009301 TI - Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance. AB - Anti-apoptotic BCL-2 family members bind to BH3-only proteins and multidomain BAX/BAK to preserve mitochondrial integrity and maintain survival. Whereas inhibition of these interactions is the biological basis of BH3-mimetic anti cancer therapy, the actual response of membrane-bound protein complexes to these compounds is currently ill-defined. Here, we find that treatment with BH3 mimetics targeting BCL-xL spares subsets of cells with the highest levels of this protein. In intact cells, sequestration of some pro-apoptotic activators (including PUMA and BIM) by full-length BCL-xL is much more resistant to derepression than previously described in cell-free systems. Alterations in the BCL-xL C-terminal anchor that impacts subcellular membrane-targeting and localization dynamics restore sensitivity. Thus, the membrane localization of BCL xL enforces its control over cell survival and, importantly, limits the pro apoptotic effects of BH3 mimetics by selectively influencing BCL-xL binding to key pro-apoptotic effectors. PMID- 28009302 TI - RPA Stabilization of Single-Stranded DNA Is Critical for Break-Induced Replication. AB - DNA double-strand breaks (DSBs) are cytotoxic lesions that must be accurately repaired to maintain genome stability. Replication protein A (RPA) plays an important role in homology-dependent repair of DSBs by protecting the single stranded DNA (ssDNA) intermediates formed by end resection and by facilitating Rad51 loading. We found that hypomorphic mutants of RFA1 that support intra chromosomal homologous recombination are profoundly defective for repair processes involving long tracts of DNA synthesis, in particular break-induced replication (BIR). The BIR defects of the rfa1 mutants could be partially suppressed by eliminating the Sgs1-Dna2 resection pathway, suggesting that Dna2 nuclease attacks the ssDNA formed during end resection when not fully protected by RPA. Overexpression of Rad51 was also found to suppress the rfa1 BIR defects. We suggest that Rad51 binding to the ssDNA formed by excessive end resection and during D-loop migration can partially compensate for dysfunctional RPA. PMID- 28009303 TI - Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain. AB - Organoids derived from human pluripotent stem cells recapitulate the early three dimensional organization of the human brain, but whether they establish the epigenomic and transcriptional programs essential for brain development is unknown. We compared epigenomic and regulatory features in cerebral organoids and human fetal brain, using genome-wide, base resolution DNA methylome and transcriptome sequencing. Transcriptomic dynamics in organoids faithfully modeled gene expression trajectories in early-to-mid human fetal brains. We found that early non-CG methylation accumulation at super-enhancers in both fetal brain and organoids marks forthcoming transcriptional repression in the fully developed brain. Demethylated regions (74% of 35,627) identified during organoid differentiation overlapped with fetal brain regulatory elements. Interestingly, pericentromeric repeats showed widespread demethylation in multiple types of in vitro human neural differentiation models but not in fetal brain. Our study reveals that organoids recapitulate many epigenomic features of mid-fetal human brain and also identified novel non-CG methylation signatures of brain development. PMID- 28009305 TI - Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells. AB - Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is typically an inefficient and asynchronous process. A variety of technological efforts have been made to accelerate and/or synchronize this process. To define a unified framework to study and compare the dynamics of reprogramming under different conditions, we developed an in silico analysis platform based on mathematical modeling. Our approach takes into account the variability in experimental results stemming from probabilistic growth and death of cells and potentially heterogeneous reprogramming rates. We suggest that reprogramming driven by the Yamanaka factors alone is a more heterogeneous process, possibly due to cell-specific reprogramming rates, which could be homogenized by the addition of additional factors. We validated our approach using publicly available reprogramming datasets, including data on early reprogramming dynamics as well as cell count data, and thus we demonstrated the general utility and predictive power of our methodology for investigating reprogramming and other cell fate change systems. PMID- 28009304 TI - Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex. AB - A major technological goal in neuroscience is to enable the interrogation of individual cells across the live brain. By creating a curved glass replacement to the dorsal cranium and surgical methods for its installation, we developed a chronic mouse preparation providing optical access to an estimated 800,000 1,100,000 individual neurons across the dorsal surface of neocortex. Post surgical histological studies revealed comparable glial activation as in control mice. In behaving mice expressing a Ca2+ indicator in cortical pyramidal neurons, we performed Ca2+ imaging across neocortex using an epi-fluorescence macroscope and estimated that 25,000-50,000 individual neurons were accessible per mouse across multiple focal planes. Two-photon microscopy revealed dendritic morphologies throughout neocortex, allowed time-lapse imaging of individual cells, and yielded estimates of >1 million accessible neurons per mouse by serial tiling. This approach supports a variety of optical techniques and enables studies of cells across >30 neocortical areas in behaving mice. PMID- 28009306 TI - Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities. PMID- 28009307 TI - Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma. PMID- 28009308 TI - [TWIN-TO-TWIN TRANSFUSION SYNDROME: THE POSSIBILITY OF LATENT FLOW (CASE REPORT)]. AB - The early diagnosis of the Twin-To-Twin transfusion syndrome (TTTS) carries benefits of the better survivor for the fetus-donor; but at the same time there are obvious practical impediments to diagnose the condition earlier in the course of a pregnancy. That's why this particular problem in practical medicine requires in depth investigation to clarify casual factors, and specify tactical approach to the prospective patients which in turn will lead to prevention of the fetal death and damage and improvement of fetal survivor in any form of TTTS. The TTTS is one of the complications of a monochorionic pregnancy leading to fetal distress and certain developmental abnormalities as well as worse prognosis for the survival for the affected twin. Previous scientific researches established two major forms of TTTS: chronic - which develops over period of time during the course of the pregnancy and acute - which can develop during the labor itself. This scientific article represents description and analysis of the clinical case of the monozygotic (identical) twin pregnancy characterized by antenatal asphyxia of one of the fetuses at the full-term with unclear clinical etiology but with all morphological characteristics specific for TTTS for monochorionic diamniotic pregnancy. Analyzing the data from this clinical case we have decided that there are latent forms of TTTS which can manifest in the third trimester of the pregnancy. PMID- 28009309 TI - [MODERN APPROACHES TO CORRECTION OF HYPERNATREMIA IN NEUROSURGICAL PATIENTS]. AB - The article presents the analysis of the intensive therapy through the correction of persistent hypernatremia in neurosurgical patients after removal of brain tumors. The aim of this work was to evaluate the effectiveness of Sterofundin in the framework of complex therapy of hypernatremia in neurosurgical patients after removal of brain tumors. We analyzed the dynamics of the concentrations of sodium, potassium, chorus of the plasma, anion gap and buffer bases in the postoperative period of these patients. For obtaining reliable results, the patients were divided into groups according to the nature of the treatment: Sterofundin and symptomatic correction of hypotonic solution of sodium chloride, saluretic and Verospiron respectively. In a comparison between the groups, a distinct difference in the speed of regression of hypernatremia and durability of the achieved effect was observed. In case of treatment with Sterofundin there was a significant decrease of hypernatremia by the end of the second day of the postoperative period without tendency to re-raise. The prevalence of hypotonic solutions of sodium chloride and potassium-sparing saluretics in intensive care allowed reducing the sodium concentration non-persistently to the fourth day on the background of significant fluctuations in its concentration. The use of Sterofundin in complex therapy of electrolyte disturbances, particularly of hypernatremia in neurosurgical patients after removal of brain tumors, is reflected in the form of significant regression of increased sodium concentration in plasma compared with the method of use "hypotonic" hemodilution, saluretics and potassium-sparing diuretics. PMID- 28009310 TI - [THE EARLY DIAGNOSTICS OF MULTIPLE PRIMARY TUMORS OF MALE UROGENITAL TRACT (REVIEW OF CLINICAL CASES)]. AB - Multiple primary tumors (MPT) or polyneoplasias significance is very important. MTP are met rarely in male urogenital system; only single cases are described in the literature. Nevertheless, during the last years there has been an increase of their frequency. So, in order to understand are urogenital MPT popular in men, what is the connection between their appearance and whether there is a trend of increase or not, we have decided to investigate the cases histories of 272 oncourological patients between 18-84 years old have been studied in the period of 2013 - 2015. The tumor tissue specimens of 272 oncourological patients have been investigated too, taken after the surgery and do a histological examination. It is well known, that the diagnosis of tumors is heavily based on the study of the surgical material and its histopathology of their sections stained with hematoxylin-eosin. In result we discovered 13 men from different age groups, more often in elderly patients of 55-70 years, in whom 2 urogenital tumors were discovered. Men with multiple primary tumors of the urogenital system have got mainly double synchronous tumor. It is necessary to organize the dynamic control for oncourological patients life after treatment of the first tumor, even in asymptomatic or atypical clinical course with the morphological methods use in CT, ultrasonography. PMID- 28009311 TI - [MALIGNANT TUMORS IN OVARIAN MATURE CYSTIC TERATOMAS INTRAOPERATIVE DIAGNOSTIC BASIS]. AB - Extremely rare ovarian primary tumors formed in a mature cystic teratomaare described in the literature. This research work studies the frequency of malignant mature cystic teratoma, as well as their clinical and morphological features and necessity of intraoperative histological examination of all teratomas. Cases histories of 56 patients, suffering from ovarian mature cystic teratomahave been studied in MC Shengavit in the period of 2003 - 2015. Among them 4 patients with the somatic malignancies were identified. Morphological methods, which are considered to be "gold standard" of tumor investigation, were used in staining the slides with hematoxylin - eosin. According to the literature the secondary malignant transformation rarely occurs and is typical in postmenopausal women, with a frequency of 0.17-3%. According to the results of our study, malignant tumors in mature cystic teratomas were observed in 4 (7,14%) from the total number of mature cystic teratomas (n=56). There was not revealed a correlation between the duration of the complaints, age of the patients, sizes of ovarian mature teratoma and malignization degree. Thus, the greatest difficulties of clinical diagnosis of malignant tumors in the ovarian mature cystic teratomas were in the early stage of the disease, because of a variety of clinical manifestations, not pathognomonic for malignization. All mentioned symptoms may be observed in the patients with usual mature cystic teratomas. This cases confirm the necessity to take tissue samples from the other ovary for intraoperative histopathological evaluation in each case of mature cystic teratomas. It is necessary to examine a large number of tumor sites, to prevent errors in the assessment of the maturity degree of teratoma. PMID- 28009312 TI - CHANGES IN TOOTH HARD TISSUE MINERALI-ZATION AND BLOOD RHEOLOGY IN HEALTHY ADOLESCENTS AND THOSE WITH THYROID DYSFUNCTION. AB - Thyroid dysfunction causes spreading and development of caries in the teeth and changes in periodontal tissues. In addition, it causes changes in peripheral blood flow and mineralization, local transcapillary metabolism causes changes in blood rheology. There are only few works in this direction and, therefore, the purpose of our research was to find out how the mineralization and the rheological properties of blood are changed in lesion of periodontal tissue on a background of thyroid dysfunction. Accordingly, the stomatological study was conducted in 75 adolescents aged 12-18 years by the standard method, recommended by the World Health Organization. According to the study, 45 patients out of them suffered from thyroid dysfunction, in particular from hypothyroidism. The comparator group consisted of 30 children of the same age without endocrine abnormalities. By the gained results it is noted that in spite of different type lesions due to dental caries, the caries incidence and intensiveness is higher in children with hypothyroidism as compared to healthy children. Decrease in saliva excretion rate and increase in oral fluid viscosity was found in children with thyroid and endocrine diseases as compared to healthy children. In children with endocrine disorders concurrent increase in calcium content (1,43+/-0,08 mmol/l) and decrease in inorganic phosphate concentrations (4,54+/-0,15 mmol/l) is reliably established. In children with thyroid disfunction and while periodontal tissue pathology, rheological features are disordered more dramatically than in healthy children. Therefore, it can be said that the changes in the adolescents' thyroid function is one of the reasons for formation of periodontal tissue diseases.Therefore, at detecting even the first signs of the periodontal tissue diseases, it is desirable in adolescents to assess the thyroid functional condition, since it will be the precondition for effective treatment and management of dental disease, in particular, dental caries and lesions of periodontal tissue. PMID- 28009313 TI - CHARACTER AND FREQUENCY OF THE VARIATIONS OF CO- AND POLYMORBID SYNTROPIC EXTRAHEPATIC LESIONS AND THEIR DEPENDENCE ON THE HEPATOPULMONARY SYNDROME SEVERITY DEGREE IN CIRRHOTIC PATIENTS. AB - In this study, we comprehensively examined 93 patients with liver cirrhosis, selected in a randomized manner, with the preliminary stratification by the presence of hepatopulmonary syndrome with the aim to study the nature and frequency of extrahepatic syntropic lesions of organs and systems and their dependence on the severity of lung injury that is necessary for the appointment of the most effective individualized comprehensive treatment. The results of our calculations showed that with the increasing of the hepatopulmonary syndromeseverity degree, the nature and the frequency of the syntropic co- and polymorbid functional and organic extrahepatic lesions of the organs and body systems was significantly (p<0.05) changing. Also some polymorbid disorders' combinations and/or combined variants of the syndromes and nosologies have been increasing in case of growing the severity of the hepatopulmonary syndrome, that shows their significant (p<0.05) dependency. PMID- 28009314 TI - HURTLE CELLS IMMUNOHISTOCHEMICAL ACTIVITIES IN HASHIMOTO THYROIDITIS PARENCHYMA. AB - The present study was designed to evaluate the participation and utility of Hurtle cells morphological requirment and transformation under Hashimoto autoimmune thyroiditis versus Riedel's struma. Several markers have been evaluated to detect induced activities of Hurtle cells. Study subject - specimens (tissue fragments) collected from TG surgery (thyroidectomy) for mollecular (receptor) diagnosis of Hurtle cells activities using routine histological and immunohistochemical samples. 89 cases were selected in Hashimoto thyroiditis diagnosis with Hurtle cells history (adenoma and adenomatous grouth of oncocytes). Markers as: TSH receptors, TTF-1, S-100 protein, also anti-TPO and anti-TG levels in blood plasm were detected. It was shown that solid cell claster nests like agregation of oncocytes and adenomatous growth foci in parafollicular areas with anti-TPO and anti-TG antibodies levels arising while Riedel's struma shown only large intra- and extra glandular inflammatory proliferative fibrosing process. Large positive expression of TTF-1 and S-100 protein and the negative reaction of TSH receptor factor suggest that Thyroid parenchyma disorganization and mollecular biological atypia with Hurtle cells are proceses due to hypothyreoidismus, as well as neuroectodermal cells prominent activities in 70% of Hashimoto cases. PMID- 28009315 TI - DIFFERENCES IN ECG CHARACTERISTICS AND CO-MORBIDITIES AMONG PATIENTS WHO UNDERWENT ELECTIVE SURGICAL REPAIR. AB - The aim of the study was to assess differences in ECG features and prevalence of comorbidies between two groups of patiens: with Abdominal Aortic Aneurism (AAA) and Aorto-Iliac Occlusive Desieses-Lerish Syndrome (LS). Data was collected for all consecutive adult patients who underwent elective surgical repair of AAA (fusiform aneurysm) or LS at "The Center of Vascular and Heart Diseases" (Tbilisi, Georgia) between 2010 and 2014. We studied a prevalence of Arterial Hypertension (AHT); Diabetes mellitus (DM); Renal Failure (RF),Peripheral Artery Disease (PAD), Coronary Artery Disease (CAD) and rate of coronary revascularization in these patients; We also, investigate some of the electrocariographic characteristics: Corrected QT interval(QTC),QT dispersion(QTD). The majority of patients were mail (92% in both groups). Prevalence rate of CAD didn't differ significantly between groups with LS and AAA (37% and 39%P=0.7000 respectively). Rate of revascularization was (7% and 6% P=0.577 respectively). Prevalence rate of DM was higher in patients with LS compared with AAA (27%and 8%P=0.0000 respectively); PAD was more prevalent in LS group (98% and 48% P=0.0000 respectively). RF was less prevalent in patients with LS as compared with AAA (51% and 64%P=0.0200). Prevalence rate of AHT was significantly low in LS than in AAA (49% and 65%P=0.0000 respectively). A prevalence rate of increased QTd (>0.07ms) was high in LS group but the difference between these two groups was not statistically significant (16% and 9% P=0.1563 respectively). Absolute number of prolonged QTd was high in LS group in comparison with AAA and this difference was statistically significant (0.04+/ 0.026 and 0.02+/-0.028 P=0.0092 respectively).QTC remained in normal range in both groups. Rates of CAD and coronary revascularization did not differ between patients with AAA and LS. The high incidence of DM and PAD was found in patients with LS as well as high HR and prolonged QTd. Prevalence Rate of AHT, RF was higher in patients with AAA as compared with LS group. These findings indicates: a)Different composition of risk factors in two groups. However, both groups of patients are at increased risk of development of coronary events and this circumstance may be considered as a predictor of worse prognosis. b) High incidence of renal failure in AAA group may contribute a progression of renal dysfunction in this patients during /after surgery.c) A prolonged QTd was high in LS group which may contribute heightened risk of fatal arrhythmias in this patients. Further studies are needed for evaluation a prevalence rate of prolonged QTd in the large population. PMID- 28009316 TI - [EFFICACY OF COMBINED USE OF ANTIOXIDATIVE AND PHOTOTHERAPY IN THE TREATMENT OF VITILIGO]. AB - Despite of numerous investigations, carried out practically in all countries of the world for the study of vitiligo and the search for its new effective therapies, pathogenic mechanisms of vitiligo are still poorly understood, and the proposed treatments are not perfect. One of the most accepted theories of the pathogenesis of vitiligo is an oxidative stress theory, according to which a series of biochemical anomalies cause oxidative stress, leading to accumulation of melanocytotoxic substances and inhibition of natural processes of detoxification with subsequent destruction of melanocytes in vitiligo focus. On the other hand, the use of antioxidants in combination with ultraviolet therapy of dermatological diseases, has been theoretically proved by biophysical studies, according to which- the antioxidants inhibit the oxidation of products, formed in the skin after ultraviolet irradiation and greatly reduce erythema sensitivity (1.5-2 times). Due to this effect, the power of radiation exposure can be approximately increased many times. Based on the foregoing, the use of antioxidants during phototherapy of vitiligo pathogenetically is justified. The aim of the study was to evaluate the therapeutic efficacy of Se ACE in treatment of patients with various forms of vitiligo. 35 patients (23 women and 12 men) aged 18 to 40 years with duration of the pathological process from 2 months to 15 years were under observation. 17 of these were diagnosed with a form of non segmental vitiligo (NSV), 18- segmental vitiligo. In 11 patients onset of the disease was not connected with any other problem, 24 noted the appearance of white spots after stress. Vitiligo patients were divided into 2 groups: the study group and the group of comparison. The study group included 17 patients (9 women and 8 men) aged 18 to 40 years with duration of the disease from 2 months to 5 years. The comparison group consisted of 18 patients (10 women and 8 men). Distribution of patients in both groups was homologous by the sex, age, duration and clinical forms of dermatosis. All patients underwent phototherapy. In the study group Selenium was used as an antioxidant, which was administered at a dose of 1 capsule 2 times a day for a month. Phototherapy was performed by means of MEDlight OCTAderm (3 times per week, the course of treatment - 15 procedures). After a course of phototherapy in combination with Selenium (study group), 1 patient had complete regimentation, in 43.5%of patients with NSV whisk of regimentation was formed, in 60.9% of patients with partial NSV we observeda partial regimentation in the form of pigmented inclusions withinthe foci of depigmentation. In the group of comparison we did not reveal any case of full regimentation, the whisk of hyperpigmentation was observed only in 34.7%, formation of pigmented inclusions within the foci of depigmentationwere revealed in 29.1% of cases. Thus, the phototherapy of vitiligoin combination with Selenium gives a well pronounced therapeutic effect, the clinical picture of which can be described as the following: high frequency, fast enough occurrence (2-3 months), cosmetic favorability-regimentation has uniform character without noticeable hyperkeratosis and peeling, as well as without any redness and hyperpigmentation. PMID- 28009317 TI - [EVALUATION OF THE REALTIONSHIP OF DIFFERENT PATHOGENIC FACTORS AND ARRHYTHMIAS IN PATIENTS WITH PULMONARY TUBERCULOSIS AND DIABETES]. AB - Definition of the most important factors and their combination, causing the disturbances of heart rhythm in patients with the pulmonary tuberculosis and diabetes, now attracts more and more attention. For this purpose, extensively used the capabilities of multifactorial analysis, which allowed to evaluate the distribution of the pathological factors and their interaction with each other. The objects of the study were complex examination the data of 90 patients with pulmonary tuberculosis and diabetes (insulin-dependent diabetes-27, non-insulin- dependent diabetes-63). In the mathematical processing of the instrumental methods we analyzed the results of echocardiography, indicators of respiratory function and the results of the Holter ECG monitoring. The use multifactorial mathematical analysis has allowed to establish the most significant pathogenetic factors and their combinations, causing disrhythmogenesis. In patients with pulmonary tuberculosis and diabetes with a combinations of right ventricular hypertrophy with a tendency to pulmonary hypertension and respiratory function parameters most commonly observed ventricular arrhythmias. On the occurrence of supraventricular arrhythmia mainly influenced by pulmonary hypertension and left ventricular hypertrophy. PMID- 28009318 TI - INDICATORS OF PHAGOCYTIC COMPONENT AND SECRETORY IGA IN CHILDREN WITH BRONCHIAL ASTHMA SECONDARY TO UNDIFFERENTIATED CONNECTIVE TISSUE DYSPLASIA. AB - Its aim is to improve the diagnostics and treatment of Bronchial Asthma. There were examined 93 children with bronchial asthma at the age of 6-10 years. All patients were diagnosed with partially controlled or uncontrolled clinical course of bronchial asthma and manifestations of undifferentiated connective tissue dysplasia. The control group included 21 practically healthy children of the same age. The diagnosis of bronchial asthma was made, and the clinical course was determined in accordance with the criteria approved by the Order of Ministry of Health of Ukraine of October 08, 2013 No 868 "Unified clinical protocol of primary, secondary (specialized) medical care "Bronchial Asthma in Children" and GINA criteria (updated in 2015). The manifestations of undifferentiated connective tissue dysplasia were diagnosed according to the major and minor criteria of screening diagnostics using the methods ofMiolkovska-Dmitrova T, Karkashov A (1985). The study has revealed the negative impacts of environmental factors and pathological course of pregnancy on the development of bronchial asthma and undifferentiated connective tissue dysplasia. Infectious diseases, acute respiratory viral infection and pneumonia in particular, often triggered the first asthma symptoms in examined children. The direct correlation between the level of the lack of asthma control and undifferentiated connective tissue dysplasia (rphi=0.54; r<0.001) has been proven. In children with bronchial asthma secondary to undifferentiated connective tissue dysplasia the level of sIgA in saliva decreased significantly compared to the control group: 110.23+/-5.37 versus 149.71+/-2.23 mg/l, respectively (r<0.01). The direct correlation between the indicators of phagocytosis and secretory IgA (rs=0.29-0.41, r<0.05) has been proven. PMID- 28009319 TI - [ULTRASOUND MONITORING OF CENTRAL AND CEREBRAL HEMODYNAMICS DURING THE TREATMENT OF ARTERIAL HYPOTENSION IN PRETERM INFANTS]. AB - The purpose of the study was to evaluate and identify patterns of changes in central and cerebral hemodynamics in neonates with low and extremely low birth weight and birth asphyxia, in order to achieve the early diagnosis of disorders of the central hemodynamics and autoregulation of cerebral blood flow, for timely fluid correction and inotropic therapy. Observation data on 44 preterm infants who were treated at the Kharkiv City Perinatal Centre and Regional Children's Clinical Hospital No1 of Kharkiv has been analyzed. Ultrasound control of the central and cerebral hemodynamics needs to be carried out within the first 30 minutes in premature neonates with low and extremely low birth weight who were born with severe asphyxia. This method of the hypotension correction allows to select the volume of fluids and inotropic therapy individually, preventing development of undesirable side effects. PMID- 28009320 TI - [THE FEATURES OF PHARMACOKINETICS ANTIBIOTIC CEFTRIAXONE WITH INTRAVENOUS WAY THAT ARE DEPOSITED IN AUTOLOGOUS ERYTHROCYTES AND LEUKOCYTES OF RABBIT]. AB - In the experiment on 18 rabbits Seftriaxone pharmacokinetics after intravenous injection of the medication deposited in autologous erythrocytes and leukocytes were studied. The features of the pharmacokinetics when administered Seftriaxone in erythrocytes ghost and leukocytes as compared to traditional intravenous drug administration have been determined.It is discussed the possibility of antibiotics transport in the surgical site of infection via cellular carriers in the article. We do the comparative analysis of the main pharmacokinetic parameters of Ceftriaxone in experimental conditions of leukocyte, erythrocyte transport and intravenous way. Based on these results the authors come to the conclusion about the benefits of leukocyte antibiotic transport to the site of surgical infection. PMID- 28009321 TI - [COMPARATIVE ANALYSIS OF ANTIBACTERIAL EFFECT OF PHYTOANTIBIOTICS AND ANTIBIOTICS]. AB - The objective of this study was to determine the antibacterial activity of individual medicines and containing sum of the phyto-extracts against the bacteria causing nosocomial infections in compare to antibiotics. In the investigation were involved four strains of gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Acinetobacter spp. Each object was investigated on antibiotic resistance using Kirby-Bauer diffusion method on 22 types of antibiotics. The objects of the study were: Sanguinarine, Chelerythrine and Berberine hydrochloride (of lab quality); essential oils and aromatic waters of Eucalyptus, Salvia and Lavanda. For determination their antibacterial activity was used Raits serological dilution method with adaptation. The results show that the antibiotic resistant bacteria did not rise in non-diluted and 1:1 diluted test-tubes. In 1:5 diluted test-tubes was observed a little turbidity and growth, as for in other test-tubes - intensive growth. The investigated phyto-medicines show the higher antibacterial activity than the antibiotics. PMID- 28009322 TI - PREDICTING OF RISKS OF GROUNDWATER AND SURFACE WATER POLLUTION WITH DIFFERENT CLASSES OF HERBICIDES IN SOIL IN EASTERN EUROPE CLIMATE CONDITIONS. AB - Application of pesticides in modern agriculture is a powerful permanent risk factor for public health and the natural environment. The aim of the study was a comparative hygienic assessment of the danger of contamination of ground and surface water sources with most widely used herbicides of different chemical classes (sulfonylureas, imidazolinones, pirimidinilkarboksilovye compounds semicarbazones). Field hygienic experiments for studying of the residues dynamics of studied herbicides concentration in agrocenosis objects were made by us in different types of soils: chernozem, sod-podzolic, podzolized forest. Then the half-life periods (DT50) of the substances in the soil were calculated. It was found that according to GUS index there is a high probability of leaching into groundwater of sulfonylureas and imidazolinones; according to LEACH index all investigated substances have a high risk of run-off into groundwater and surface water. PMID- 28009323 TI - [TO A QUESTION OF TREINING OF THE NEONATOLOGISTS IN RESIDENCY]. AB - : In recent years, the world and in Ukraine neonatology evolved into high-tech and quickly progressive section of the medicine, therefore preparation of experts is very important problem. Residency is the form of specialization of doctors on corresponding clinical chairs for reception of high qualifications of neonatology for possibility of competent rendering of competent and highly specialized medical care to newborns in hospitals of 3rd level. Term of training in residency is 2 years. Plan of the residency training offered by the department of neonatology Kharkiv medical academy of postgraduate education consists of sections on the basic speciality, adjacent clinical disciplines and additional programs. The great attention in training is given to innovative techniques: lectures and seminars with use of electronic presentations, seminars-trainings, seminars-discussions, seminars-conferences, and others. The majority of a practical training are spent in simulation center of the department neonatology with using of dummies, anatomic models for working off of practical skills. CONCLUSIONS: 1. Training of doctors in residency on neonatology can occupy a key position in a professional training for maintenance of high standards of the help with newborn and scientific researches in the field of medicine and occurrence Ukrainian neonatology in the European medical community. 2. At the basis of training of the resident on neonatology should be three components: the first - training in internship on pediatric (2-3 years), the second - presence of standard conditions of training on chair neonatology and the third - carrying out of practical preparation on clinical base which is equipped by the modern diagnostic equipment and medical technologies in conformity of the standard reports of rendering of medical aid in establishments of 3rd level. PMID- 28009324 TI - THE IMPACT OF ULTRAVIOLET IRRADIATION ON MORPHO-FUNCTIONAL STATE OF SKIN IN GUINEA PIGS. AB - The purpose of this study was to assess the impact of ultraviolet irradiation (UV) on morphological and functional condition of the skin in guinea pigs. The study involved 30 albino guinea pigs weighing 400-500 g subjected to local exposure to UV irradiation. Control group consisted of intact guinea pigs. Histological studies of the skin were carried out at different stages of the trial (2 hours, 4 hours, 3 days, 8 days following the exposure). Microscopic examination showed morphological signs of acute inflammation in the skin of animals within the first three days following the exposure to UV irradiation. Within 2 hours following the exposure to UV irradiation these changes were minimal with signs of mild exudative changes. In 4 hours after the exposure histological changes increased. The specimens were also found to contain altered apoptotic keratinocytes (sunburn cells). Histopathological changes persisted and reached maximum severity by the 3rd day. Within post-erythema period (the 8th day) proliferative, hyperplastic, degenerative and dystrophic changes in the skin persisted. The prolonged nature of the changes in the skin is suggestive of the development of chronic inflammation in the skin of guinea pigs subjected to local exposure to UV irradiation. PMID- 28009325 TI - CHI3L1 overexpression is associated with metastasis and is an indicator of poor prognosis in papillary thyroid carcinoma. AB - OBJECTIVE: In this study, we examined the relationships between the expression level of CHI3L1 and the clinicopathological characteristics of papillary thyroid carcinoma. METHODS: A total of 322 tissue samples from patients with papillary thyroid carcinoma were collected, and the CHI3L1 expression levels in tumor tissues, matched adjacent noncancerous tissues were detected using immunohistochemistry (IHC) and qRT-PCR. The relationships between CHI3L1 expression levels and the clinical characteristics were evaluated. RESULTS: CHI3L1 expression was significantly increased in papillary thyroid carcinoma compared with matched adjacent noncancerous tissues (P< 0.001), tumor tissues with lymph node metastasis (LNM) compared with tumor tissues without LNM (P< 0.001) and tumor tissues with distant organ metastasis (DOM) compared with tumor tissues without DOM (P< 0.01). CHI3L1 expression was significantly associated with tumor size (P= 0.0001), lymph node metastasis (P< 0.0001), distant organ metastasis (P< 0.0001), extrathyroid invasion (P= 0.0022), vascular invasion (P= 0.0004) and TNM stage (P= 0.0001). CHI3L1 overexpression in papillary thyroid carcinoma tissues correlates with the tumor malignant potential (P< 0.01). More importantly, Cox multifactor analysis indicated that patients with high CHI3L1 expression have lower overall survival, disease-free survival, lymph node recurrence-free survival, and distant recurrence free survival rates than those with low expression (P< 0.05). And our findings were further validated by online Oncomine database. CONCLUSIONS: CHI3L1 is associated with tumor metastasis and might be a prognostic biomarker for papillary thyroid carcinoma. PMID- 28009326 TI - ALK gene copy number in lung cancer: Unspecific polyploidy versus specific amplification visible as double minutes. AB - BACKGROUND: Gains of a gene due to DNA polyploidy versus amplification of the specific locus are distinct molecular alterations in tumors. OBJECTIVE: We quantified copy number gains of ALK gene due to unspecific polyploidy versus amplifications of the specific locus in a series of non-small cell lung cancers. METHODS: The locus specific ALK copy (LSI) number status was evaluated in 205 cases by FISH. Ratio LSI ALK copy number corrected for control probes CEP2, CEP3 and CEP17 (CEPs) was scored. Amplification of the specific ALK locus was defined when ratio set to >= 2 while polyploidy was interpreted when the increase in gene copy resulted < 2 in ratio (LSI/control CEPs). RESULTS: Twenty one cases (10.2%) showed >= 8 ALK signals, 68 cases (33.2%) 3-7 signals and 116 cases (56.6%) a mean of 2 signals. Only 2/21 cases of the cohort harboring >= 8 signals showed a ratio >= 2 after CEPs correction interpretable as amplified, showing numerous doubled fluorescent spots. All the remaining cases showed a mirrored number of fluorescent spots per each CEPs, interpretable as polyploidy. CONCLUSION: We detected a high prevalence of ALK gene copy number usually due to polyploidy rather than ALK locus amplification, the latter visible prevalently as double minutes. PMID- 28009327 TI - SPARC: As a prognostic biomarker in rectal cancer patients treated with chemo radiotherapy. AB - BACKGROUND: The aim of this study is to search the prognostic value of SPARC expression in rectum cancer cases receiving postoperative radiotherapy. METHODS: Forty three rectal cancer patients are recruited to this retrospective study. All patients received postoperative radiotherapy which the median dose was 5040 cGy and concomitant chemotherapy. Samples taken from their paraffin blocks were examined with immunohistochemical procedures. RESULTS: When the association between SPARC expression and the clinicopathological feature was examined, there was a significant association between age and expression levels. Overall survival of patients with low expression was found to be 67 months whereas the overall survival of the patients with high expression was 32 months and the difference was statistically significant. Time to local recurrence of patients with low expression was found to be 74 months whereas time to local recurrence of the patients with high expression was 31 months. Progression free survival of the patients with low expression and high expression were 67 months and 32 months, respectively. In multivariate Cox regression analyses, high expression of SPARC was found to be associated with a statistically significant shorter overall survival and progression free survival. CONCLUSIONS: High expression of SPARC is related to worse prognosis in rectal cancer patients. PMID- 28009328 TI - Seroprevalence and diagnosis of HIV, HBV, HCV and syphilis infections among blood donors. AB - BACKGROUND: Blood transfusion is one of the most important therapeutic options of life-saving intervention for recipients who are in diseased or non-diseased conditions with severe blood loss. However, it is associated with certain risks which can lead to adverse consequences that may cause acute or delayed complications and bring the risk of transfusion-transmissible infections including HIV, Hepatitis B & C and Syphilis. So, there might be a fatal risk instead of life saving. This paper aims to provide a comprehensive and reliable tabulation of available data on seroprevalence and diagnosis of HIV, HBV, HCV and Syphilis infections among blood donors. METHODS: We searched studies reporting the prevalence rate of HIV, HBV, HCV and Syphilis infections among blood donors that were published between October 2009 and June 2016, using databases of PubMed, Scopus, MEDLINE, Elsevier, ScienceDirect, EBSCO, Google Scholar, EMBASE, and Web of Science with keywords: ''Hepatitis C Virus'', ''Hepatitis B Virus'', ''HIV'', ''Syphilis'', ''Seroprevalence'', and ''blood donor''. RESULTS: The seroprevalence of HBV and HCV was highest in African countries as compared to others continents, predominantly the West African region with a range of 10.0% to 14.96% and 1.5% to 8.69%, respectively, while the overall seropositivity of HIV and syphilis infection show a significant declining pattern through successive years globally, even though relatively higher prevalence rate was observed among older age and those with low level of education. CONCLUSION: There is a problem during selection, diagnoses and screening process in developing nations primarily due to shortage of sensitive screening test kits, highly qualified human resource and lack of proper standard operating procedures and hence, the safety of blood and blood products are the primary threats in the region. Proper clinical diagnosis and screening method should be applied during blood donation and therefore, all the donated blood should be screened properly for transfusion transmitted infections. PMID- 28009330 TI - Failure to initiate breastfeeding among high risk obstetrical patients who intended to breastfeed. AB - BACKGROUND: In the US, at the time of discharge from the hospital, 79% of women had initiated breastfeeding. Intention to breastfeed is a strong predictor of breastfeeding initiation; however, we reported initiation failure in 45% of women with pregestational diabetes who intended to breastfeed. Information regarding intention and initiation among women with other high risk obstetrical conditions (HROB) remains scarce. OBJECTIVE: To ascertain demographic and clinical factors associated with breastfeeding initiation failure among women with HROB conditions who intended to breastfeed. METHODS: The study population is comprised of 89 women with diabetes (DM), 57 who were receiving treatment for substance abuse (SA), 51 women diagnosed with miscellaneous (MISC) conditions and 32 with history of preterm labor/delivery (PTL/D). Intention to exclusively breastfeed or in combination with formula (breastfed/FF) was ascertained prenatally. Breastfeeding was considered initiated if at discharge >=50% of their infant feedings were maternal milk. Statistics include chi-square, Wilcoxon's and logistic regression (p < 0.05). RESULTS: Of all women, 59% initiated any breastfeeding. Intention to breastfeed/FF, lack of mother-infant contact during the first hour following birth and limited lactation consultation were predictive of initiation failure. The odds of initiation failure were 2.3 times higher among women who wished to breastfeed/FF as compared to those who wished to exclusively breastfeed. Women from the SA group had lower rates of initiation failure than the other three HROB groups. CONCLUSION: Intention to breastfeed among women with diverse HROB conditions is similar to that of the general population; however, initiation rates are disappointingly low. Intention to exclusively breastfeed results in fewer initiation failures. Prenatal intention to combine breast and formula feeding characterize women who may benefit from specific educational programs. PMID- 28009331 TI - A study of acute kidney injury in hospitalized preterm neonates in NICU. AB - OBJECTIVES: This study was carried out to determine the incidence, clinical features, etiology and outcome of functional and intrinsic acute kidney injury (AKI) in preterm neonates. METHODS: This is a prospective observational study on premature infants admitted to the neonatal intensive care unit (NICU) over an eight month period. All biochemical parameters of renal function tests were monitored and statically analyzed. RESULTS: The study included 450 infants; of them 300 were inborn and 150 infants were outborn and transported to the NICU. Mean gestational age, weight, and age at the time of AKI diagnosis were 32.3 weeks, 1.66 kg and 3.23 days respectively. The male: female ratio was 1.84:1. Incidence of AKI was higher in low birth weight babies. Sluggishness and refusal for feed were most common symptoms. Birth asphyxia and septicemia were the most common early and late cause of AKI. Hyponatremia was the most common electrolyte disturbance. The incidences of AKI, functional renal failure, and intrinsic renal failure were 12%, 48.14%, and 51.85% respectively. CONCLUSIONS: AKI is not uncommon in preterm infants. The early recognition and aggressive management of episodes of shock which often precede AKI could be life-saving. PMID- 28009332 TI - Effect of intrahepatic cholestasis of pregnancy on maternal serum screening tests. AB - OBJECTIVE: In this study, we aimed to evaluate whether the changes in the first and second trimester maternal serum biochemical markers used for prenatal screening are associated with euploid pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP). METHODS: A total of 94 pregnant women were included in this retrospective comparative study. Thirty-seven women whose pregnancy was complicated with ICP constituted the study group whereas 57 of them constituted the control group. All hospital records were examined in terms of combined first trimester screening test and second trimester triple test parameters. Perinatal outcomes were also recorded. RESULTS: No significant difference was observed between the two groups in term of age, BMI, and obstetric history (all p > 0.05). Mean serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and serum bile acid concentrations in the study group were significantly higher than in the controls (p < 0.001). There were no significant differences between the two groups in terms of first and second trimester serum biochemical markers. Newborn gender, route of birth, and NICU admission rates were also similar in the two groups. Mean birth weight of the control group was statistically significantly higher than the ICP group (p = 0.012). CONCLUSION: We report no significant differences between pregnancies complicated by ICP and healthy pregnancies in terms of first and second trimester maternal serum screening test results. PMID- 28009333 TI - Optimizing care of ventilated infants by improving weighing accuracy on incubator scales. AB - OBJECTIVES: To determine the accuracy of weighing ventilated infants on incubator scales and whether the accuracy can be improved by the addition of a ventilator tube compensator (VTC) device to counterbalance the force exerted by the ventilator tubing. STUDY DESIGN: Body weights on integral incubator scales were compared in ventilated infants (with and without a VTC), with body weights on standalone electronic scales (true weight). Individual and series of trend weights were obtained on the infants. The method of Bland and Altman was used to assess the introduced bias. RESULTS: The study included 60 ventilated infants; 66% of them weighed <1000 g. A total of 102 paired-weight datasets for 30 infants undergoing conventional ventilation and 30 undergoing high frequency oscillator ventilation (HFOV) supported by a SensorMedics oscillator, (with and without a VTC) were obtained. The mean differences and (95% CI for the bias) between the integral and true scale weighing methods was 60.8 g (49.1 g to 72.5 g) without and -2.8 g (-8.9 g to 3.3 g) with a VTC in HFOV infants; 41.0 g (32.1 g to 50.0 g) without and -5.1 g (-9.3 g to -0.8 g) with a VTC for conventionally ventilated infants. Differences of greater than 2% were considered clinically relevant and occurred in 93.8% without and 20.8% with a VTC in HFOV infants and 81.5% without and 27.8% with VTC in conventionally ventilated infants. CONCLUSIONS: The use of the VTC device represents a substantial improvement on the current practice for weighing ventilated infants, particularly in the extreme preterm infants where an over- or underestimated weight can have important clinical implications for treatment. A large-scale clinical trial to validate these findings is needed. PMID- 28009334 TI - Challenges, successes and opportunities for reducing readmissions in a referral based children's hospital NICU. AB - AIM: To evaluate readmission data in a level IV neonatal intensive care unit (NICU) to identify patient characteristics and process failures which serve as drivers for readmission. METHODS: Our center is a primary referral center in Central and Southeast Ohio, providing us a unique opportunity to evaluate readmissions. We studied our current discharge process, caregiver perception of discharge readiness, parental comfort and the pre-discharge and post-discharge characteristics of infants. RESULTS: Our readmission rate during the 4 year period has remained stable at 9.8%. 74% of the caregivers rated that their perception of their baby's medical readiness for discharge was good to excellent. Duration of hospitalization and public insurance coverage (Medicaid) were significant risk factors for readmission (p = 0.00). In our setting, the majority of the patients are readmitted through the emergency department and nearly half of all readmissions were for 3 or fewer days. Patients discharged from our Comprehensive Center for BPD had similar readmission rate despite characteristics which should increase their readmission rate. CONCLUSIONS: Readmission rate is a poor indicator of the quality of care provided in the NICU. In addition to patient factors such as longer length of stay and Medicaid, our data suggests that preventing readmission depends on having systems in place to help families cope with transition of care after discharge. PMID- 28009335 TI - Influence of maternal factors on the successful outcome of kangaroo mother care in low birth-weight infants: A randomized controlled trial. AB - BACKGROUND: Kangaroo mother care (KMC) is associated with positive neonatal outcomes. Studies demonstrated significant influence of maternal factors on the success of applying KMC. AIM: To determine maternal factors that influence on anthropometric parameters in low birth weight babies that received kangaroo mother care. METHODS: This is a randomized controlled study that involved low birth weight newborns. We randomly assigned newborns into two groups; a group who received KMC and a group who received conventional care. Maternal factors were recorded. We followed weight, length, and head circumferences of newborns for thirty days. RESULTS: A total of 40 newborns were included. Weight parameters were significantly higher in the KMC group than the conventional group. From maternal characteristics, only gestational age was found to influence increased head circumference in KMC group (p = 0.035); however, it did not affect the increase in weight or length. Maternal age, parity, education, mode of delivery, fetal sex, and initial Apgar score did not influence growth parameters in either groups. CONCLUSION: KMC was associated with increased weight gain in LBW infants. Gestational age influences head growth in infants who received KMC. PMID- 28009336 TI - Hypocortisolism and preterm birth. AB - OBJECTIVE: We sought to determine whether hypocortisolism is associated with preterm birth, using hair cortisol as a marker of long term hypothalamic pituitary-adrenal axis activity. STUDY DESIGN: In a prospective, matched, case control study, 29 women who had a preterm birth at 24-36w5d gestation were compared to 29 women who delivered at term, matched for maternal age, gestational age, and ethnicity. Cases' samples were collected within 72 h of preterm birth and controls at the same gestational age as the corresponding case. Participants completed validated questionnaires regarding general stress and childhood trauma. The Wilcoxon signed-rank test was used to compare the distribution of mean hair cortisol scores between cases and controls. Conditional logistic regression was used to predict case vs. control by hair cortisol score, controlling for relevant covariates. RESULTS: Baseline characteristics of cases and controls did not differ. Hair cortisol levels were significantly lower among cases in the adjusted analysis. Hair cortisol level was a predictor of case versus control. Each 10 pg.mg-1 increase in hair cortisol level was associated with an estimated 33% decreased odds of being a case. The only significant difference in the validated questionnaires was an increased measure of emotional neglect in the preterm group. CONCLUSION: Our study suggests that women who deliver prematurely may have lower hair cortisol levels than women who deliver at term. Normal hypothalamic pituitary-adrenal axis activation is a physiologic, adaptive response to stress. One hypothesis to explain our results are that women who are stressed, but unable to mount an adequate stress response could be at particular risk for preterm birth. PMID- 28009337 TI - Wireless multichannel electroencephalography in the newborn. AB - OBJECTIVES: First, to determine the feasibility of an ultra-compact wireless device (microEEG) to obtain multichannel electroencephalographic (EEG) recording in the Neonatal Intensive Care Unit (NICU). Second, to identify problem areas in order to improve wireless EEG performance. STUDY DESIGN: 28 subjects (gestational age 24-30 weeks, postnatal age <30 days) were recruited at 2 sites as part of an ongoing study of neonatal apnea and wireless EEG. Infants underwent 8-9 hour EEG recordings every 2-4 weeks using an electrode cap (ANT-Neuro) connected to the wireless EEG device (Bio-Signal Group). A 23 electrode configuration was used incorporating the International 10-20 System. The device transmitted recordings wirelessly to a laptop computer for bedside assessment. The recordings were assessed by a pediatric neurophysiologist for interpretability. RESULTS: A total of 84 EEGs were recorded from 28 neonates. 61 EEG studies were obtained in infants prior to 35 weeks corrected gestational age (CGA). NICU staff placed all electrode caps and initiated all recordings. Of these recordings 6 (10%) were uninterpretable due to artifacts and one study could not be accessed. The remaining 54 (89%) EEG recordings were acceptable for clinical review and interpretation by a pediatric neurophysiologist. Of the recordings obtained at 35 weeks corrected gestational age or later only 11 out of 23 (48%) were interpretable. CONCLUSIONS: Wireless EEG devices can provide practical, continuous, multichannel EEG monitoring in preterm neonates. Their small size and ease of use could overcome obstacles associated with EEG recording and interpretation in the NICU. PMID- 28009338 TI - Atrial arrhythmia after newborn eye exam, to caffeine or not to caffeine? AB - Mydriatic drops are routinely administered to premature neonates to screen for retinopathy of prematurity. Adverse anticholinergic side effects, particularly convulsions and tachycardia have been reported in the pediatric age group following instillation of mydriatics for diagnostic fundus examination [1, 2]. Caffeine is frequently used for apnea of prematurity. In the neonatal intensive care unit, the combined use of caffeine and mydriatic drops is a common practice. Here we report two cases of atrial arrhythmias after neonatal eye exam that improved with conservative management. Both patients were receiving caffeine at the time of events. PMID- 28009339 TI - The effects of thyroid function on retinopathy of prematurity. AB - OBJECTIVES: To assess whether TSH and fT4 have a role in the angiogenesis of vaso obliteration and neovascularization which are the basic pathophysiology of ROP. METHODS: In this retrospective case-control study, the control group (n = 56) included preterm newborns with risk for ROP while the laser group (n = 63) was recruited from cases who developed severe neovascularization and needed laser photocoagulation therapy. Considering the first (vaso-obliteration) and second (neovascularization) phases of the disease, in this study we researched the distribution of thyroid function tests between groups. RESULTS: With regard to the first phase of the disease, TSH and fT4 showed no significant differences between the control and laser groups accordingly (P > 0.05). Likewise, in the second phase of ROP, there was no significant difference between the control and laser groups with respect to TSH and fT4 levels (P > 0.05). CONCLUSION: We found that between the study groups, the levels of thyroid function tests did not have any significant differences, either in the first or the second phases of ROP which are the principal pathophysiology of the disease. Therefore, it was concluded that thyroid hormone values were not informative markers in the course of the disease in preterm babies at risk of developing ROP. PMID- 28009341 TI - Keyword Index Volume 9 (2016). PMID- 28009342 TI - Smartphone application for multi-phasic interventional trials in psychiatry: Technical design of a smart server. AB - Smartphones and their accompanying applications are currently widely utilized in various healthcare interventions. Prior to the deployment of these tools for healthcare intervention, typically, proof of concept feasibility studies, as well as randomized trials are conducted to determine that these tools are efficacious prior to their actual implementation. In the field of psychiatry, most of the current interventions seek to compare smartphone based intervention against conventional care. There remains a paucity of research evaluating different forms of interventions using a single smartphone application. In the field of nutrition, there has been recent pioneering research demonstrating how a multi phasic randomized controlled trial could be conducted using a single smartphone application. Despite the innovativeness of the previous smartphone conceptualization, there remains a paucity of technical information underlying the conceptualization that would support a multi-phasic interventional trial. It is thus the aim of the current technical note to share insights into an innovative server design that would enable the delivery of multi-phasic trials. PMID- 28009343 TI - Interaction of radiation therapy and radiofrequency kyphoplasty in the treatment of myeloma patients. AB - BACKGROUND: 30% of myeloma patients suffer from vertebral compression fractures (VCF). Consequently, augmentation often becomes inevitable to prevent further problems. This study evaluated the interaction of radiation therapy (RT) and radiofrequency kyphoplasty (RFK) in the treatment of myeloma associated VCF. METHODS: Eighty-six myeloma patients with VCF were treated with RFK followed by radiation therapy (RFK group) or vice versa (RT group). Visual analgoue scale (VAS), Oswestry-Disability-Index (ODI), vertebral height and kyphosis angle were assessed preoperatively, 3-4 days, 3 and 6 months postoperatively. Adverse events like cement leakage or additional fractures were documented. RESULTS: Both groups achieved comparable outcomes, but the course of VAS and kyphosis angle differed. Early postoperative kyphosis angles improved significantly in the RFK group, but significantly worsened afterwards. The RT group showed a trend towards significantly improvement postoperatively and minor worsening afterwards. VAS remained constant in the RT group and worsened in the RFK group after 6 months. More cement leakages and additional fractures were noted in the RT group. CONCLUSIONS: RFK is an effective method for treating VCF in myeloma patients independent of treatment order with regard to radiation therapy. However, RT should be conducted after RFK to minimize risks of cement extrusion and additional fractures. PMID- 28009344 TI - A model for continuous monitoring of patients with major depression in short and long term periods. AB - BACKGROUND AND OBJECTIVE: Major depressive disorder causes more human suffering than any other disease affecting humankind. It has a high prevalence and it is predicted that it will be among the three leading causes of disease burden by 2030. The prevalence of depression, all of its social and personal costs, and its recurrent characteristics, put heavy constraints on the ability of the public healthcare system to provide sufficient support for patients with depression. In this research, a model for continuous monitoring and tracking of depression in both short-term and long-term periods is presented. This model is based on a new qualitative reasoning approach. METHOD: This paper describes the patient assessment unit of a major depression monitoring system that has three modules: a patient progress module, based on a qualitative reasoning model; an analysis module, based on expert knowledge and a rules-based system; and the communication module. These modules base their reasoning mainly on data of the patient's mood and life events that are obtained from the patient's responses to specific questionnaires (PHQ-9, M.I.N.I. and Brugha). The patient assessment unit provides synthetic and useful information for both patients and physicians, keeps them informed of the progress of patients, and alerts them in the case of necessity. RESULTS: A set of hypothetical patients has been defined based on clinically possible cases in order to perform a complete scenario evaluation. The results that have been verified by psychiatrists suggest the utility of the platform. CONCLUSION: The proposed major depression monitoring system takes advantage of current technologies and facilitates more frequent follow-up of the progress of patients during their home stay after being diagnosed with depression by a psychiatrist. PMID- 28009345 TI - The role of membrane-inner retina adherence in predicting simultaneous internal limiting membrane peeling during idiopathic epiretinal membrane surgery. AB - PurposeTo correlate the frequency and extent of simultaneous inadvertent internal limiting membrane (ILM) peeling during idiopathic epiretinal membrane (ERM) removal with characteristics of ERM adherence demonstrated on pre-operative spectral domain optical coherence tomography (SD-OCT).Patients and methodsThis is a prospective, observational, case series of patients undergoing pars plana vitrectomy for idiopathic ERM. Inner retina-ERM adhesion was categorized as focal, broad or complete in five anatomic locations at macular area based on preoperative SD-OCT findings. The extent of spontaneous ILM peeling was quantified on a scale 0-100% in each of the aforementioned anatomic locations by the operating surgeons who were masked to the OCT characteristics. All operations were recorded with a high definition recording system and the area of simultaneous ILM peel was quantified by a second masked observer. The final extent of spontaneous ILM peel was calculated as the average of the two scores.ResultsThirty consecutive subjects who underwent surgery for idiopathic ERM were included in the study. Evidence of simultaneous ILM peeling was identified in 80.3% of individuals. With regards to the type of ERM-macula adhesion, inadvertent ILM peel was observed in 70% of the patients who pre operatively showed complete adhesion, in 43% with broad adhesion and in only 21% with focal adhesion (P<0.001). The extent of the spontaneous ILM peel during removal of ERM was also significantly dependent on the type of ERM-inner retina adhesion. Total simultaneous ILM peel was observed in 59% of locations with complete ERM-macula adhesion but only in 22% and 7% of locations with broad and focal adhesion respectively (P<0.001).ConclusionsSimultaneous ILM peel is a frequent occurrence during ERM surgery, especially when there is complete or broad ERM adherence to the macula. The type of ERM-inner retina adhesion represents a valid predictor of the extent of simultaneous ILM peel during removal of ERM. Thorough evaluation of preoperative OCT may be a useful tool in determining a safer, more simplistic strategy in ERM surgery. PMID- 28009346 TI - Risk of intraocular hemorrhage with new oral anticoagulants. AB - PurposeTo assess the risk of intraocular hemorrhage with warfarin and new oral anticoagulants (NOACs).MethodsWe ascertained all reported cases of intraocular hemorrhage (vitreous, choroidal, or retinal) with warfarin and NOACs (including dabigatran, rivaroxaban, apixaban) from the World Health Organizations's Vigibase database from 1968-2015. We used a disproportionality analysis to compute reported odds ratios (RORs) and corresponding 95% confidence by comparing the number of events with the study outcomes and study drugs compared with all other drugs reported to Vigibase. A harmful signal was deemed for a lower limit of the 95% confidence interval above 1.ResultsWe identified 80 cases of intraocular hemorrhage (vitreous, choroidal, or retinal) with warfarin in the World Health Organizations's Vigibase database from 1968-2015. A total of 156 cases of intraocular hemorrhage with NOACs (82 with rivaroxaban, 65 with dabigatran, 9 with apixaban). Warfarin had the highest signal of association with choroidal hemorrhage (ROR= 65.40 (33.86-126.30)). Rivaroxaban had the highest signal of association with both retinal and vitreous hemorrhage (ROR=7.41 (5.73-9.59) and ROR= 11.14 (7.37-16.86), respectively). Dabigatran was also significantly associated with retinal and vitreous hemorrhage (ROR= 3.78 (2.82-5.08) and ROR= 5.83 (3.66-9.30), respectively). The number of reports of retinal and vitreous hemorrhage were also significantly higher with apixaban, but the number of cases may be too little to make a meaningful evaluation.ConclusionA signal for risk of intraocular hemorrhage was detected for warfarin, dabigatran, and rivaroxaban. Large epidemiologic studies are needed to further confirm these findings. PMID- 28009347 TI - An integrin approach to axon regeneration. AB - Axon regeneration in the CNS is blocked by inhibitory molecules in the environment and by a developmental loss of regenerative potential in CNS axons. Axon growth is a specialized form of cell migration, and for any cell to migrate there must be an adhesion molecule at the growth tip that recognizes a ligand in the environment, and which is linked to signaling and cytoskeletal mechanisms. The reasons for this loss of regenerative ability in CNS axons are several, but important contributors are the developmental loss of integrins that recognize ligands in the mature CNS environment, and selective trafficking of integrins and other molecules to exclude them from axons and direct them to dendrites. Regeneration of sensory axons in the spinal cord can be achieved by expression of tenascin-binding alpha9-integrin together with the integrin activator kindlin-1. This works because integrins are transported into sensory axons. Transport of integrins into retinal ganglion cell axons is seen in the retina, but may become more restricted in the optic nerve, with a subset of axons containing expressed integrins. Transduction of ganglion cells with alpha9-integrin and kindlin-1 should promote regeneration of this subset of axons, but attention to transport may be required for regeneration of the remaining axons. PMID- 28009348 TI - The state of ocular health among London's homeless population. AB - PurposeTo investigate the demographics, visual impairment, and diagnoses of patients presenting to Vision Care for Homeless People (VCHP), Crisis clinics for London's under-researched homeless population.Patients and methodsTwo hundred eighty-three patients records, including data on sociodemographic, diabetic status, visual acuity, and ocular examination, via a comprehensive eye test were reviewed from the VCHP clinics held at 10 London 'Crisis at Christmas' centres in 2014.ResultsTwo hundred eighty-three individual patients were seen at the VCHP clinics. Eighty-nine percent of patients were male and 11% were female. Thirty two percent (90) patients had an ocular pathology. Lens problems, including cataracts (7%), vitreoretinal (6%), ocular motility (5%), and external eye disease (5%), were the four most common pathologies. In total, 6.4% of the patients reported that they were diabetic and a medical referral letter was given to 10% of the patients seen. Two hundred thirty-three were dispensed glasses (82%). Readers were most common (39%), then distance (28%), bifocals (15%). Presenting visual impairment was 12% in the patients tested. After refractive correction, this dropped to 2.5%.ConclusionThis study shows that there is a high prevalence of uncorrected refractive error among patients attending the Crisis for Christmas eye clinic. These data also show high prevalence of ocular pathology. There is a clear need for the provision of eye tests and spectacles to tackle the issues and prevent visual impairment. More research and eye care services are needed to investigate how this is linked to their living status and enable this vulnerable population to transition out of homelessness. PMID- 28009349 TI - Reply to: 'Comment on: Effect of smoking on retrobulbar blood flow in thyroid eye disease'. PMID- 28009351 TI - S-2HG is an immunometabolite that shapes the T-cell response. PMID- 28009350 TI - HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer. AB - MicroRNAs (miRNAs) have emerged as a major regulator of the initiation and progression of human cancers, including breast cancer. However, the cooperative effects and transcriptional regulation of multiple miRNAs, especially miRNAs that are present in clusters, remain largely undiscovered. Here we showed that all members of the miR-23~27~24 clusters are upregulated and function as oncogenes in breast cancer and simultaneously target HIC1. Furthermore, we found that HIC1 functions as a transcriptional repressor to negatively control the expression of miR-23~27~24 clusters and forms a double-negative (overall positive) feedback loop. This feedback regulatory pathway is important because overexpression of miR 23~27~24 clusters can remarkably accelerate tumor growth, whereas restoration of HIC1 significantly blocks tumor growth in vivo. A mathematical model was created to quantitatively illustrate the regulatory circuit. Our finding highlights the cooperative effects of miRNAs in a cluster and adds another layer of complexity to the miRNA regulatory network. This study may also provide insight into the molecular mechanisms of breast cancer progression. PMID- 28009352 TI - A negative feedback loop of ICER and NF-kappaB regulates TLR signaling in innate immune responses. AB - The NF-kappaB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38 mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-kappaB by direct interaction with the p65 subunit of NF-kappaB. Deficiency in ICER elevated binding of NF-kappaB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation. PMID- 28009353 TI - Pellino-1 promotes lung carcinogenesis via the stabilization of Slug and Snail through K63-mediated polyubiquitination. AB - Pellino-1 is an E3 ubiquitin ligase acting as a critical mediator for a variety of immune receptor signaling pathways, including Toll-like receptors, interleukin 1 receptor and T-cell receptors. We recently showed that the Pellino-1-transgenic (Tg) mice developed multiple tumors with different subtypes in hematolymphoid and solid organs. However, the molecular mechanism underlying the oncogenic role of Pellino-1 in solid tumors remains unknown. Pellino-1-Tg mice developed adenocarcinoma in the lungs, and Pellino-1 expression was higher in human lung adenocarcinoma cell lines compared with non-neoplastic bronchial epithelial cell lines. Pellino-1 overexpression increased the cell proliferation, survival, colony formation, invasion and migration of lung adenocarcinoma cells, whereas Pellino-1 knock-down showed the opposite effect. Pellino-1 overexpression activated PI3K/Akt and ERK signaling pathways and elicited an epithelial mesenchymal transition (EMT) phenotype of lung adenocarcinoma cells. Pellino-1 mediated EMT was demonstrated through morphology, the upregulation of Vimentin, Slug and Snail expression and the downregulation of E-cadherin and beta-catenin expression. Notably, Pellino-1 had a direct effect on the overexpression of Snail and Slug through Lys63-mediated polyubiquitination and the subsequent stabilization of these proteins. Pellino-1 expression level was significantly correlated with Snail and Slug expression in human lung adenocarcinoma tissues, and lung tumors from Pellino-1-Tg mice showed Snail and Slug overexpression. The Pellino-1-mediated increase in the migration of lung adenocarcinoma cells was mediated by Snail and Slug expression. Taken together, these results show that Pellino-1 contributes to lung tumorigenesis by inducing overexpression of Snail and Slug and promoting EMT. Pellino-1 might be a potential therapeutic target for lung cancer. PMID- 28009355 TI - The Refinement-Tree Partition for Parallel Solution of Partial Differential Equations. AB - Dynamic load balancing is considered in the context of adaptive multilevel methods for partial differential equations on distributed memory multiprocessors. An approach that periodically repartitions the grid is taken. The important properties of a partitioning algorithm are presented and discussed in this context. A partitioning algorithm based on the refinement tree of the adaptive grid is presented and analyzed in terms of these properties. Theoretical and numerical results are given. PMID- 28009354 TI - RSK-mediated nuclear accumulation of the cold-shock Y-box protein-1 controls proliferation of T cells and T-ALL blasts. AB - Deregulated proliferation is key to tumor progression. Although unrestricted proliferation of solid tumor cells correlates with the cold-shock protein Y-box (YB)-binding protein-1 accumulation in the nuclei, little is known about its expression and function in hematopoietic malignancies, such as T-cell acute lymphoblastic leukemia (T-ALL). Here we show that YB-1 protein is highly enriched in the nuclei of activated T cells and malignant human T-ALL cell lines but not in resting T cells. YB-1 S102 mutations that either mimic (S102D) or prevent phosphorylation (S102N) led to accumulation of YB-1 in the nucleus of T cells or strictly excluded it, respectively. Inactivation of ribosomal S6 kinase (RSK) was sufficient to abrogate T-cell and T-ALL cell proliferation, suggesting that RSK mediates cell-cycle progression, possibly dependent on YB-1-phosphorylation. Indeed, phosphomimetic YB-1S102D enhanced proliferation implying that S102 phosphorylation is a prerequisite for malignant T-cell proliferation. At initial diagnosis of T-ALL, YB-1 localization was significantly altered in the nuclei of tumor blasts derived from bone marrow or peripheral blood. Our data show deregulated YB-1 in the nucleus as a yet unreported characteristic of T-ALL blasts and may refine strategies to restrict progression of hematopoietic tumors. PMID- 28009356 TI - Comparison of the NIST and ENEA Air Kerma Standards. AB - A comparison was made between the National Institute of Standards and Technology (NIST) and Ente per le Nuove Tecnologie l'Energia e l'Ambiente (ENEA) air kerma standards for medium energy x rays and 60Co gamma rays. The comparison took place at ENEA in June 1994. Two different transfer chambers from NIST were used for the comparison. The measurements were made at radiation qualities similar to those used at the Bureau International des Poids et Mesures (BIPM) (generating voltages of 100 kV, 135 kV, 180 kV and 250 kV, respectively) and with 60Co gamma radiation. The transfer chamber calibration factors obtained at the NIST and at the ENEA agreed with one another to 0.03 % for 60Co gamma radiation and between 0.1 % to 0.8 % for the medium energy x-ray beam codes. PMID- 28009357 TI - Hyperfine Structure Constants for Diatomic Molecules. AB - The multiconfiguration valence-bond method (VB) is applied to diatomic molecules using the Hartree-Fock (HF) atomic basis set. The hyperfine constant, Fermi contact term, is computed as a function of the interatomic separation for the X2? ground state of 17OH and X1? ground state of 107AgH+ molecules. This study leads to a number of conclusions about the influence of correlation and polarization effects on the hyperfine structure of hydrogenic molecules. The calculated values of the Fermi contact term are found to agree within 1 % of the experimental values wherever available. PMID- 28009358 TI - The 1996 North American Interagency Intercomparison of Ultraviolet Monitoring Spectroradiometers. AB - Concern over stratospheric ozone depletion has prompted several government agencies in North America to establish networks of spectroradiometers for monitoring solar ultraviolet irradiance at the surface of the Earth. To assess the ability of spectroradiometers to accurately measure solar ultraviolet irradiance, and to compare the results between instruments of different monitoring networks, the third North American Interagency Intercomparison of Ultraviolet Monitoring Spectroradiometers was held June 17-25, 1996 at Table Mountain outside Boulder, Colorado, USA. This Intercomparison was coordinated by the National Institute of Standards and Technology (NIST) and the National Oceanic and Atmospheric Administration (NOAA). Participating agencies were the Environmental Protection Agency; the National Science Foundation; the Smithsonian Environmental Research Center; the Department of Agriculture; and the Atmospheric Environment Service, Canada. The spectral irradiances of participants' calibrated standard lamps were measured at NIST prior to the Intercomparison. The spectral irradiance scales used by the participants agreed with the NIST scale within the combined uncertainties, and for all lamps the spectral irradiance in the horizontal position was lower than that in the vertical position. Instruments were characterized for wavelength uncertainty, bandwidth, stray-light rejection, and spectral irradiance responsivity, the latter with NIST standard lamps operating in specially designed field calibration units. The spectral irradiance responsivity demonstrated instabilities for some instruments. Synchronized spectral scans of the solar irradiance were performed over several days. Using the spectral irradiance responsivities determined with the NIST standard lamps, the measured solar irradiances had some unexplained systematic differences between instruments. PMID- 28009359 TI - Uncertainty Analysis for Angle Calibrations Using Circle Closure. AB - We analyze two types of full-circle angle calibrations: a simple closure in which a single set of unknown angular segments is sequentially compared with an unknown reference angle, and a dual closure in which two divided circles are simultaneously calibrated by intercomparison. In each case, the constraint of circle closure provides auxiliary information that (1) enables a complete calibration process without reference to separately calibrated reference artifacts, and (2) serves to reduce measurement uncertainty. We derive closed form expressions for the combined standard uncertainties of angle calibrations, following guidelines published by the International Organization for Standardization (ISO) and NIST. The analysis includes methods for the quantitative evaluation of the standard uncertainty of small angle measurement using electronic autocollimators, including the effects of calibration uncertainty and air turbulence. PMID- 28009360 TI - Calculating the Effects of Longitudinal Resistance in Multi-Series-Connected Quantum Hall Effect Devices. AB - Many ac quantized Hall resistance experiments have measured significant values of ac longitudinal resistances under temperature and magnetic field conditions in which the dc longitudinal resistance values were negligible. We investigate the effect of non-vanishing ac longitudinal resistances on measurements of the quantized Hall resistances by analyzing equivalent circuits of quantized Hall effect resistors. These circuits are based on ones reported previously for dc quantized Hall resistors, but use additional resistors to represent longitudinal resistances. For simplification, no capacitances or inductances are included in the circuits. The analysis is performed for many combinations of multi-series connections to quantum Hall effect devices. The exact algebraic solutions for the quantized Hall resistances under these conditions of finite ac longitudinal resistances provide corrections to the measured quantized Hall resistances, but these corrections do not account for the frequency dependences of the ac quantized Hall resistances reported in the literature. PMID- 28009361 TI - An Easy-To-Use Combination Four-Terminal-Pair/Two-Terminal-Pair AC Transformer Bridge. AB - A new four-terminal-pair bridge, capable of achieving a relative standard uncertainty of 1*10-9, was constructed at the National Institute of Standards and Technology by converting a two-terminal-pair bridge. The conversion requires only the addition of components which are easily removed if two-terminal-pair measurements are to be made. The design and testing of this bridge is described. The new four-terminal-pair bridge requires fewer auxiliary balances than the present four-terminal-pair bridge employed at NIST, which makes it much easier to use. This new design can be used to compare capacitance, resistance, and inductance standards. PMID- 28009362 TI - Spectral Response Based Calibration Method of Tristimulus Colorimeters. AB - A new method is described to calibrate tristimulus colorimeters for high accuracy color measurements. Instead of traditional lamp standards, modern, high accuracy detector standards are suggested for calibration. After high accuracy absolute spectral response determination of the tristimulus receivers, color (spectral) correction and peak (amplitude) normalization can minimize uncertainties caused by imperfect realizations of the Commission Internationale de l'Eclairage (CIE) color matching functions. As a result of the corrections, stable light sources of different spectral power distributions can be measured with an accuracy dominated by the sub tenths of a percent uncertainty of novel spectral response determinations. PMID- 28009363 TI - A Problem in AC Quantized Hall Resistance Measurements and a Proposed Solution. AB - In all experiments reported to date the measured values of the ac quantized Hall resistances RH varied with the frequency of the applied current, and differed significantly from the dc values of RH, making it difficult to use the ac quantum Hall effect as an absolute impedance standard. We analyze the effects due to the large capacitances-to-shields existing in the sample probes on measurements of RH to see if this is the source of the problem. Equivalent electrical circuits are utilized; they contain capacitances and leakage resistances to the sample probe shields, longitudinal resistances within the quantized Hall effect devices, and multiple connections to the devices. The algebraic solutions for the RH values in these circuits reveal large out-of-phase contributions to the quantized Hall voltages VH that would make it difficult to do accurate measurements with high precision ac bridges. These large out-of-phase contributions could introduce the linear frequency dependences observed in previous RH measurements. We predict, however, that quadruple-series connections to the quantum Hall devices yield only small out-of-phase contributions to VH which may allow accurate measurements of the quantity RH - Rx , where Rx is the longitudinal resistance along the device. PMID- 28009364 TI - Development of a Bolometer Detector System for the NIST High Accuracy Infrared Spectrophotometer. AB - A bolometer detector system was developed for the high accuracy infrared spectrophotometer at the National Institute of Standards and Technology to provide maximum sensitivity, spatial uniformity, and linearity of response covering the entire infrared spectral range. The spatial response variation was measured to be within 0.1 %. The linearity of the detector output was measured over three decades of input power. After applying a simple correction procedure, the detector output was found to deviate less than 0.2 % from linear behavior over this range. The noise equivalent power (NEP) of the bolometer system was 6 * 10-12 [Formula: see text] at the frequency of 80 Hz. The detector output 3 dB roll-off frequency was 200 Hz. The detector output was stable to within +/- 0.05 % over a 15 min period. These results demonstrate that the bolometer detector system will serve as an excellent detector for the high accuracy infrared spectrophotometer. PMID- 28009365 TI - Accurate Ab Initio Calculation of Molecular Constants. AB - Molecular constants have been computed for the ground states 2? of 17OH and 1Sigma of 107AgH+. The valence-bond method and advanced computational technique were used to perform all-electron ab initio calculation of molecular electronic structures. The basic idea behind the model is to introduce the molecular wave functions in terms of Hartree-Fock many-electron atomic determinants. Full configuration interaction (CI) with nonorthogonal basis leads to the accurate calculation of molecular constants such as dissociation energy, equilibrium bond distance, vibrational and rotational constants with an agreement to the experimental data within a few percent. PMID- 28009366 TI - Chopped Radiation Measurements With Large Area Si Photodiodes. AB - Frequency dependent response characteristics of photocurrent meters using large area, radiometric quality Si photodiodes have been analyzed. The current responsivity, the voltage noise and drift amplification, and the gain and bandwidth of the photocurrent-measuring analog control loop were calculated. The photodiodes were selected for high shunt resistance. The effect of the photodiode junction capacitance on the response characteristics was also analyzed. As a result of photocurrent gain dependent frequency compensations, the noise boosting effect was minimized at the output of the current meter. The loop gain and bandwidth were maximized. High-accuracy photocurrent measurements can be achieved using the described procedures for both dc and modulated optical radiation. PMID- 28009367 TI - Can a Pressure Standard be Based on Capacitance Measurements? AB - We consider the feasibility of basing a pressure standard on measurements of the dielectric constant epsilon and the thermodynamic temperature T of helium near 0 degrees C. The pressure p of the helium would be calculated from fundamental constants, quantum mechanics, and statistical mechanics. At present, the relative standard uncertainty of the pressure ur(p) would exceed 20 * 10-6, the relative uncertainty of the value of the molar polarizability of helium Aepsilon calculated ab initio. If the relativistic corrections to Aepsilon were calculated as accurately as the classical value is now known, a capacitance-based pressure standard might attain ur(p) < 6 * 10-6 for pressures near 1 MPa, a result of considerable interest for pressure metrology. One obtains p by eliminating the density from the virial expansions for p and epsilon - 1. If epsilon - 1 were measured with a very stable, 0.5 pF toroidal cross capacitor, the small capacitance and the small values of epsilon - 1 would require state-of-the-art capacitance measurements to achieve a useful pressure standard. PMID- 28009368 TI - Degradation of GaAs/AlGaAs Quantized Hall Resistors With Alloyed AuGe/Ni Contacts. AB - Careful testing over a period of 6 years of a number of GaAs/AlGaAs quantized Hall resistors (QHR) made with alloyed AuGe/Ni contacts, both with and without passivating silicon nitride coatings, has resulted in the identification of important mechanisms responsible for degradation in the performance of the devices as resistance standards. Covering the contacts with a film, such as a low temperature silicon nitride, that is impervious to humidity and other contaminants in the atmosphere prevents the contacts from degrading. The devices coated with silicon nitride used in this study, however, showed the effects of a conducting path in parallel with the 2-dimensional electron gas (2-DEG) at temperatures above 1.1 K which interferes with their use as resistance standards. Several possible causes of this parallel conduction are evaluated. On the basis of this work, two methods are proposed for protecting QHR devices with alloyed AuGe/Ni contacts from degradation: the heterostructure can be left unpassivated, but the alloyed contacts can be completely covered with a very thick (> 3 MUm) coating of gold; or the GaAs cap layer can be carefully etched away after alloying the contacts and prior to depositing a passivating silicon nitride coating over the entire sample. Of the two, the latter is more challenging to effect, but preferable because both the contacts and the heterostructure are protected from corrosion and oxidation. PMID- 28009369 TI - Aperture Proximity Effects in High Heat Flux Sensors Calibration. AB - In the transfer calibration of heat flux sensors, a correction for the irradiance distribution across the sensing area may be required when the sensing areas of the reference and test sensors are different. A method to calculate this correction using well-known equations for the configuration factors is presented. Also, estimates of the correction for test conditions corresponding to the transfer calibration technique in use at the National Institute of Standards and Technology are given. PMID- 28009370 TI - Calculation of Measurement Uncertainty Using Prior Information. AB - We describe the use of Bayesian inference to include prior information about the value of the measurand in the calculation of measurement uncertainty. Typical examples show this can, in effect, reduce the expanded uncertainty by up to 85 %. The application of the Bayesian approach to proving workpiece conformance to specification (as given by international standard ISO 14253-1) is presented and a procedure for increasing the conformance zone by modifying the expanded uncertainty guard bands is discussed. PMID- 28009371 TI - The 1995 North American Interagency Intercomparison of Ultraviolet Monitoring Spectroradiometers. AB - Concern over stratospheric ozone depletion has prompted several government agencies in North America to establish networks of spectroradiometers for monitoring solar ultraviolet irradiance at the surface of the Earth. To assess the ability of spectroradiometers to accurately measure solar ultraviolet irradiance, and to compare the results between instruments of different monitoring networks, the second North American Intercomparison of Ultraviolet Monitoring Spectroradiometers was held June 12 to 23, 1995 at Table Mountain outside Boulder, Colorado, USA. This Intercomparison was coordinated by the National Institute of Standards and Technology (NIST) and the National Oceanic and Atmospheric Administration (NOAA). Participating agencies were the Environmental Protection Agency; the National Science Foundation; the Smithsonian Environmental Research Center; the Department of Agriculture; and the Atmospheric Environment Service, Canada. Instruments were characterized for wavelength uncertainty, bandwidth, stray-light rejection, and spectral irradiance responsivity, the latter with a NIST standard lamp operating in a specially designed field calibration unit. The spectral irradiance responsivity, determined once indoors and twice outdoors, demonstrated that while the responsivities changed upon moving the instruments, they were relatively stable when the instruments remained outdoors. Synchronized spectral scans of the solar irradiance were performed over several days. Using the spectral irradiance responsivities determined with the NIST standard lamp and three different convolution functions to account for the different bandwidths of the instruments, the measured solar irradiances generally agreed to within 3 %. PMID- 28009372 TI - Metrological Timelines in Traceability. AB - There is a growing requirement for an internationally accepted system of recognition of measurement capabilities and relationships within and among countries, to facilitate seamless global commerce and trade. As a result, metrologists worldwide have recently developed increased interest in the concept and definition of traceability. Classically, traceability provides a way of relating the results of a measurement (or value of a standard) to higher level standards. Such standards are usually national or international standards, and the comparisons used to provide the traceability must have well-understood uncertainties. An additional complexity arises because all instruments and standards are subject to change, however slight, over time. This paper develops approaches for dealing with the effects of such time-dependent changes as a part of traceability statements. The use of metrological time-lines provides a means of effectively visualizing these relationships in a statement of traceability. When the rate of change in the measurement process is sufficiently small, the approach proposed here is less important. However, documented measurement assurance procedures are required at all levels so that appropriate uncertainties may be estimated with confidence. When laboratory or national boundaries are crossed in the traceability process, other factors come into play, and the original concept of traceability can become obscure. It is becoming common to hear the term "equivalence" used to describe these more complex measurement relationships. PMID- 28009373 TI - Conference Report: WORKSHOP ON THIN FILM THERMAL CONDUCTIVITY MEASUREMENT AT THE THIRTEENTH SYMPOSIUM ON THERMOPHYSICAL PROPERTIES Boulder, CO June 25-26, 1997. PMID- 28009374 TI - Acid-Assisted Consolidation of Silver Alloys for Direct Fillings. AB - Silver-rich metal powders cold-welded by consolidation have been investigated as possible direct dental filling material. The surface of the silver powder must undergo an acid treatment to remove existing contaminants and prevent formation of new surface contaminants during consolidation. This study was designed to investigate the effect of the acid treatment on the strength of the consolidated alloy, its reactivity with the surrounding tooth structure, and its reactions with certain cavity liners. This study investigated the effects of pH and concentration of fluoboric acid on the flexural strength of silver powder consolidated into rectangular beams in a partial 4 * 4 design. The study also assessed, by visible and scanning electron microscopy, what effect the acid treated powders had on dentin that had been pre-coated with different cavity liners. Mean flexural strengths for beams consolidated using dental hand instruments were in the range (77.0 +/- 9.28) MPa to (166.1 +/- 17.6) MPa, where the quoted uncertainties are standard uncertainties (i.e., one standard deviation estimates). ANOVA indicated that fluoboric acid pH was highly significant (p < 0.0001) with lower pH values resulting in higher flexural strength. Concentration alone was not a significant factor for flexural strengths, but there was a significant interaction between concentration and pH (p < 0.0001). Microscopy revealed that the acid-treated silver powder demineralized approximately 2 MUm of dentin when used with no liner. The use of copal or polyamide varnishes eliminated most of this demineralization, but the use of a dentin adhesive liner resulted in some dislodgment and breakdown of the adhesive film by the acid. The results of this study indicate that this silver powder when treated with dilute fluoboric acid at a pH of approximately 1.0 can result in a filling material with strength equivalent to currently used conventional amalgam. The demineralization of tooth structure appears to be minimal and can be eliminated with the use of cavity liners. PMID- 28009376 TI - Least-Squares Fitting Algorithms of the NIST Algorithm Testing System. AB - This report describes algorithms for fitting certain curves and surfaces to points in three dimensions. All fits are based on orthogonal distance regression. The algorithms were developed as reference software for the National Institute of Standards and Technology's Algorithm Testing System, which has been used for 5 years by NIST and by members of the American Society of Mechanical Engineers' B89.4.10 standards committee. The Algorithm Testing System itself is described only briefly; the main part of this paper covers the general linear algebra, numerical analysis, and optimization methods it employs. Most of the fitting routines rely on the Levenberg-Marquardt optimization routine. PMID- 28009375 TI - High-Temperature Adiabatic Calorimeter for Constant-Volume Heat Capacity Measurements of Compressed Gases and Liquids. AB - A high-temperature adiabatic calorimeter has been developed to measure the constant-volume specific heat capacities (cV ) of both gases and liquids, especially fluids of interest to emerging energy technologies. The chief design feature is its nearly identical twin bomb arrangement, which allows accurate measurement of energy differences without large corrections for energy losses due to thermal radiation fluxes. Operating conditions for the calorimeter cover a range of temperatures from 250 K to 700 K and at pressures up to 20 MPa. Performance tests were made with a sample of twice-distilled water. Heat capacities for water were measured from 300 K to 420 K at pressures to 20 MPa. The measured heat capacities differed from those calculated with an independently developed standard reference formulation with a root-mean-square fractional deviation of 0.48 %. PMID- 28009377 TI - Moving Particles Through a Finite Element Mesh. AB - We present a new numerical technique for modeling the flow around multiple objects moving in a fluid. The method tracks the dynamic interaction between each particle and the fluid. The movements of the fluid and the object are directly coupled. A background mesh is designed to fit the geometry of the overall domain. The mesh is designed independently of the presence of the particles except in terms of how fine it must be to track particles of a given size. Each particle is represented by a geometric figure that describes its boundary. This figure overlies the mesh. Nodes are added to the mesh where the particle boundaries intersect the background mesh, increasing the number of nodes contained in each element whose boundary is intersected. These additional nodes are then used to describe and track the particle in the numerical scheme. Appropriate element shape functions are defined to approximate the solution on the elements with extra nodes. The particles are moved through the mesh by moving only the overlying nodes defining the particles. The regular finite element grid remains unchanged. In this method, the mesh does not distort as the particles move. Instead, only the placement of particle-defining nodes changes as the particles move. Element shape functions are updated as the nodes move through the elements. This method is especially suited for models of moderate numbers of moderate-size particles, where the details of the fluid-particle coupling are important. Both the complications of creating finite element meshes around appreciable numbers of particles, and extensive remeshing upon movement of the particles are simplified in this method. PMID- 28009378 TI - Ultraviolet Spectral Irradiance Scale Comparison: 210 nm to 300 nm. AB - Comparison of the irradiances from a number of ultraviolet spectral irradiance standards, based on different physical principles, showed agreement to within their combined standard uncertainties as assigned to them by NIST. The wavelength region of the spectral irradiance comparison was from 210 nm to 300 nm. The spectral irradiance sources were: an electron storage ring, 1000 W quartz-halogen lamps, deuterium arc lamps, and a windowless argon miniarc. PMID- 28009380 TI - Algorithms for Fresnel Diffraction at Rectangular and Circular Apertures. AB - This paper summarizes the theory of Fresnel diffraction by plane rectangular and circular apertures with a view toward numerical computations. Approximations found in the earlier literature, and now obsolete, have been eliminated and replaced by algorithms suitable for use on a personal computer. PMID- 28009381 TI - Image Evaluation of the High Resolution VUV Spectrometer at SURF II by Ray Tracing. AB - A high resolution VUV spectroscopic facility has been in use for several years at SURF II, the Synchrotron Ultraviolet Radiation Facility at the National Institute of Standards and Technology in Gaithersburg, Maryland. At this facility, a combination of three cylindrical mirrors is utilized to focus the light originating in the storage ring onto the horizontal entrance slit of the spectrometer. The spectrometer uses a 6.65 m concave grating having a groove density of 4800 lines/mm in the off-plane Eagle mounting. In preparation for the installation of an array detector in the exit image plane, a ray tracing program has been formulated and spot diagrams have been constructed by plotting the coordinates of the points of intersection of the diffracted rays with the image plane, which is tangent to the Rowland circle. In creating the spot diagrams, we have considered both parallel and tilted configurations of the entrance slit with respect to the grating grooves. It is shown that the line widths of the spectral images can be reduced when the entrance slit is properly tilted. Finally, we have estimated the spectral widths of the images when they are recorded on an array detector placed tangent to the Rowland circle. We conclude that an image spectral width of 0.41 pm to 0.88 pm in first order can be achieved over the wavelength region of 40 nm to 120 nm. PMID- 28009379 TI - Experimental Issues in Coherent Quantum-State Manipulation of Trapped Atomic Ions. AB - Methods for, and limitations to, the generation of entangled states of trapped atomic ions are examined. As much as possible, state manipulations are described in terms of quantum logic operations since the conditional dynamics implicit in quantum logic is central to the creation of entanglement. Keeping with current interest, some experimental issues in the proposal for trappedion quantum computation by J. I. Cirac and P. Zoller (University of Innsbruck) are discussed. Several possible decoherence mechanisms are examined and what may be the more important of these are identified. Some potential applications for entangled states of trapped-ions which lie outside the immediate realm of quantum computation are also discussed. PMID- 28009382 TI - Liquidus Diagram of the Ba-Y-Cu-O System in the Vicinity of the Ba2YCu3O6+x Phase Field. AB - This paper describes the melting equilibria in the vicinity of the high Tc phase Ba2YCu3O6+x , including evidence for two Ba-Y-Cu-O immiscible liquids. Melting equilibria have been investigated in purified air using a combination of differential thermal analysis (DTA), thermogravimetric analysis (TGA), powder x ray diffraction (XRD), MgO wick entrapment of liquid for analysis, scanning electron microscopy (SEM) coupled with energy dispersive x-ray analysis (EDS), and hydrogen reduction for determination of copper oxidation state. For relatively barium-rich compositions, it was necessary to prepare the starting materials under controlled atmosphere conditions using BaO. A liquidus diagram was derived from quantitative data for the melts involved in various melting reactions. In general the 1/2(Y2O3) contents of the melts participating in these equilibria were low (mole fraction <4 %). The primary phase field of Ba2YCu3O6+x occurs at a mole fraction of <2.0 % 1/2Y2O3 and lies very close along the BaO-CuO x edge, extending from a mole fraction of ~43 % CuO to a mole fraction of ~76 % CuO. It is divided by a liquid miscibility gap and extends on either side about this gap. The topological sequence of melting reactions associated with the liquidus is presented as a function of temperature. Implications for the growth of Ba2YCu3O6+x crystals are discussed. PMID- 28009383 TI - Thermal Conductivity of Magnesium Oxide From Absolute, Steady-State Measurements. AB - The thermal conductivity of polycrystalline magnesium oxide has been measured over the temperature range from 400 K to 1300 K using a modified guarded-hot plate design. Three different thicknesses of specimens having 93 % of theoretical density were tested to verify the operation, accuracy, and reproducibility of our apparatus. The measured thermal conductivity ranges from 30 W . m-1 . K-1 down to 8 W . m-1 . K-1 and has an inverse-temperature functionality. The results agree well with literature values for this material. PMID- 28009384 TI - Sexual transmission of Zika virus: what is the issue for awareness? PMID- 28009385 TI - A study on "mobbing" in maritime field: a case study in the Turkish maritime industry. AB - Nowadays, there are many reasons for people to be stressful and restless in their working environments. One of the reasons leading to this situation is known as "mobbing". The term "mobbing" means "bullying of an individual by a group". It usually happens among employees. The main effects of mobbing are the generation of stress and reduction of employee performance at work. In general, research shows that mobbing is particularly common in the public sector. The aim of this research is to understand the frequency of mobbing on employees in the Turkish maritime industry as a case study. In this study, a questionnaire survey on ship, shipyard, public and private company workers was applied to understand how often employees are exposed to mobbing. After analysing the results, it is also aimed to obtain information about the reasons and causes of mobbing, and then we can get some advice for this issue. PMID- 28009386 TI - Detection of Giardia intestinalis infections in Polish soldiers deployed to Afghanistan. AB - BACKGROUND: Members of the Polish Military Contingent (PMC) have been stationed in Afghanistan since 2002. They typically serve in areas characterised by low standards of sanitation which often leads to the development of food- and waterborne diseases. The aim of the study was to evaluate the prevalence of Giardia intestinalis infections among Polish soldiers deployed to Afghanistan. The research study was conducted as part of a programme for prevention of parasitic diseases of the gastrointestinal tract run by the Polish Armed Forces. MATERIALS AND METHODS: The study was carried out in August 2011; it involved 630 asymptomatic Polish soldiers serving in the Forward Operational Base (FOB) Ghazni in eastern Afghanistan. Stool specimens obtained from members of the PMC were first tested in FOB Ghazni (detection of Giardia intestinalis by Rida Quick Giardia immunochromatographic tests and Ridascreen Giardia immunoenzymatic tests single samples). Next, the same biological material and two other faecal specimens fixed in 10% formalin were transported to the Military Institute of Medicine in Poland, where they were tested for Giardia intestinalis under light microscopy (direct smear, decantation in distilled water). RESULTS: Parasitological tests performed under light microscopy showed that 2.7% (17/630) of the study group were infected with Giardia intestinalis. Some of these results were confirmed by immunochromatographic tests (6/630). In contrast, immunoenzymatic tests (ELISA) demonstrated a significantly higher detection rate reaching 18.1% (114/630). Immunoenzymatic tests confirmed all the positive results given by light microscopy and by immunochromatographic tests. CONCLUSIONS: The prevalence rate of Giardia intestinalis infections in Polish soldiers deployed to Afghanistan was found to be high. Microscopic methods exhibit low sensitivity and therefore may result in the underestimation of the true parasite prevalence. Immunoenzymatic tests (ELISA) showing a much higher sensitivity in comparison to light microscopy and immunochromatographic tests ought to be applied in screening for intestinal protozoan infections in areas characterised by harsh environmental conditions. PMID- 28009387 TI - Diving exposure and health effects in divers working in different areas of professional diving. AB - BACKGROUND: The aim of the present study was to compare diving exposure and health effects in different areas of professional diving. MATERIALS AND METHODS: The Norwegian Labour Inspection Authority's Diving Register contains data on all professional inshore divers who have held a diving certificate at any time since 1980. Of these divers, the "Norwegian diver 2011" questionnaire was completed by 2848 (48.7%). A total of 1167 male divers reported that they often worked in one area of diving only (rescue diving, diving instruction, fish farming, quay/construction work and offshore/oil related). In the analysis of these divers, rescue divers were used as referents as they reported the lowest number of dives. RESULTS: Age distribution, the proportion of retired divers and the mean number of dives completed varied between the different areas of professional diving. Compared to rescue divers, divers in fish farming, quay/ /construction work and offshore/oil related work more often experienced physically demanding diving. Divers in fish farming more often had no day off after 3 days of physically demanding work compared to rescue divers. All groups except offshore divers reported making further dives after one physically demanding dive on the same day. All groups reported more frequent decompression sickness than did the referents and divers in quay/construction and offshore/oil related diving reported more frequent episodes of unconsciousness during diving than did the referents. Divers in fish farming, in quay/construction work and oil/ /offshore related diving obtained a higher symptom score than the referents and the two latter groups also reported more frequent adverse health effects due to diving than the referents. Health related physical and mental component summary scores were lower in all other groups than in referents. CONCLUSIONS: Compared to the rescue divers, divers in quay/construction work and offshore/oil related divers reported more adverse health effects and obtained a higher symptom score. PMID- 28009388 TI - Acute gastrointestinal haemorrhage on board a cruise ship in the Antarctic Peninsula. AB - Antarctic tourism on board cruise ships has expanded since the 1990s, essentially in the Antarctic Peninsula. Due to remoteness, medical cases may evolve into life threatening conditions as emergency medical evacuations are challenging. We discuss the case of a young crew member who suddenly fainted with an epigastric pain and abundant rectal bleeding while on board a cruise ship heading to the Deception Island (62 degrees 57.6 South, 60 degrees 29.5 West), 44 h away from Ushuaia by sea. A medical evacuation was necessary to save the patient whose haemoglobin level rapidly decreased from 11 g/dL to 8.7 g/dL over an 8 h period due to uncontrolled gastrointestinal bleeding. Following discussions between the French, Chilean and Argentinean Medical Top Side Support and Maritime Rescue Authorities and despite poor weather conditions, an emergency medical evacuation by air to Chile was made possible. The evacuation, which was 2 days shorter compared to an evacuation by sea, allowed the patient to reach a hospital facility in time to save his life whereas he decompensated in haemorrhagic shock. As passengers on cruise ships are typically elderly and often following anticoagulant therapies, the risk of bleeding is most important. Facing a gastric haemorrhage, a transfusion is often required. In remote areas, transfusion of fresh whole blood to stabilize a critical patient until he reaches a hospital must be considered. PMID- 28009389 TI - Fitness to work: a comparison of European guidelines in the offshore wind industry. AB - Occupational medicine must be able to meet the challenges of rapidly changing technologies and innovations, including the implementation of health and safety standards for physically and psychologically demanding work environments. One such challenge is presented by the offshore wind industry. Here, the demand for "Fitness to Work" regulations for potential employees is justified. An appropriate evaluation has to consider the two aspects "fit for task" and "fit for location and conditions". Guidelines for the fitness testing of offshore employees have been created by various national organisations. The guidelines of the industry organisations of the United Kingdom (Oil & Gas UK) and the Netherlands (NOGEPA), as well as the Norwegian Directorate of Health, were developed for employees of offshore oil and gas platforms. In Germany, however, a medical guideline for fitness testing specific to workers in the offshore wind industry has recently been created. Such recommendations should be made on the basis of accident statistics and rescue reports, but there are only limited data available. In this paper, we present, compare and discuss the content and features of the various guidelines, as well as their recommendations for medical assessment. PMID- 28009390 TI - Knowledge, attitudes, and related practices of Filipino seafarers regarding cardiovascular diseases. AB - BACKGROUND: Globally, cardiovascular diseases (CVD) remain the leading cause of mortality. Due to the nature of their work and lifestyle on board, Filipino seafarers have a high propensity towards acquiring CVD. This study aimed to determine the knowledge, attitudes, and practices related to CVD of Filipino seafarers. MATERIALS AND METHODS: This study utilised a descriptive cross sectional study design. Self-administered questionnaires were distributed among 136 male seafarers who went into a private general hospital for their pre employment medical examination. RESULTS: Eating fatty foods (77.0%), cigarette smoking (68.4%) and lack of exercise (65.4%) were identified by the respondents as the top three most common risk factors for CVD. Avoiding fatty or oily foods (85.3%) and exercising regularly (83.1%) were identified by the respondents as preventive measures for CVD. High blood pressure and shortness of breath were identified by more than half of the respondents as a sign and symptom of CVD, respectively. But the respondents failed to identify other equally important signs and symptoms. Majority of the respondents (> 80%) had high level of perception with respect to the six constructs of the health belief model. Some respondents had admitted engagement in risk-taking behaviours such as smoking (36.0%) and physical inactivity (27.2%). Majority were into high fat and salt diet (70.6%) and current alcohol consumption (79.4%). CONCLUSIONS: Although the respondents had favourable attitudes towards CVD, there were knowledge gaps in risk factors, preventive measures, and recognition of signs and symptoms. Hence, some were still engaging in risk-taking behaviours such as smoking, irregular involvement in physical activity, unbalanced diet, and alcohol intake. PMID- 28009391 TI - Oral impacts on daily performances in white-collar port workers in Nellore, India - a cross-sectional study. AB - BACKGROUND: Oral diseases not only cause pain, but severely impair large number of individuals and can affect various aspects of life, including oral functions, appearance and interpersonal relationships. The aim of the study was to assess the interrelationship between oral impact on daily performance (OIDP) scores, socio-demographic characteristics, dental caries experience and periodontal status. MATERIALS AND METHODS: A cross-sectional descriptive epidemiological study was conducted on a sample of 250 white-collar port workers who were willing to participate. OIDP was assessed using pre-validated questionnaire. Oral health status was assessed using modified World Health Organisation (1997) Proforma. Test of association was conducted between the OIDP score, socio-demographic variables, and periodontal status; loss of attachment was determined by using chi square statistics and Mann-Whitney test. Logistic regression was performed to identify significant predictors of OIDP scores by inputting clinical oral examination variables into the equation, stepwise. RESULTS: A total of 250 white collar workers in the port participated in the study with mean age of 34.67 +/- 6.36. Among them, 219 were males and 31 were females. The OIDP items most commonly affected by oral health status were eating and enjoying food (48.4%), cleaning teeth (48%), sleeping and relaxing (44.4%).There was statistically significant relationship between missing teeth in the decayed missing filled teeth component and OIDP score (p < 0.001). The participants with caries have a greater odd (2.11) of having OIDP score >= 1 than those without caries. The participants with missing teeth have a greater odd (3.60) of having OIDP score >= 1. The participants in the age group of 31-40 years had a greater odd (2.80) of having OIDP score >= 1. CONCLUSIONS: Oral health had an impact on the quality of life of white-collar workers in the port. Physical functions of teeth like eating and cleaning of teeth, sleeping and relaxing were more affected. PMID- 28009392 TI - Hypertension among Danish seafarers. AB - BACKGROUND: Due to the high prevalence of arterial hypertension and its role in the development of atherosclerosis, myocardial infarction and stroke, hypertension is a major public health challenge worldwide. There is limited knowledge of the prevalence of hypertension among seafarers who, however, are known to have an excess morbidity and mortality from these disorders. This article addresses the prevalence of hypertension among Danish seafarers and discusses potential risk factors for hypertension in maritime settings. MATERIALS AND METHODS: A representative sample of 629 Danish seafarers who had statutory medical examinations was studied from the beginning of October 2011 to the end of June 2012. The medical examination included measurements of blood pressure. The prevalence of hypertension in the study population was stratified by age, work place on board, smoking status, alcohol intake, and body mass index. RESULTS: The overall prevalence of hypertension in the study population was 44.7% (95% CI 40.8 48.6). In a comparison sample of adult Danes, the crude rate of hypertension was 12.6%. In addition, 41.8% (95% CI 38.0-45.7) of seafarers were pre-hypertensive. Hypertension was particularly increased among younger seafarers. The proportion of seafarers in antihypertensive treatment was low, in particular among the young seafarers. CONCLUSIONS: Hypertension is a major health issue among Danish seafarers. In addition to ensuring antihypertensive treatment when needed, individual and collective prevention should address lifestyle issues as well as physical and psychosocial exposures at sea. PMID- 28009393 TI - A Medical Support in Offshore Racing Workshop, 6 November 2015, Sanya, China. PMID- 28009394 TI - Eighty years of CIRM. A journey of commitment and dedication in providing maritime medical assistance. AB - BACKGROUND: A review of activities of Centro Internazionale Radio Medico (International Radio Medical Centre, CIRM) from its foundation in 1935 until its 80th anniversary in 2015 was accomplished. CIRM was founded in 1935 to provide medical assistance via radio to ships with no doctor on board and other distant patients who cannot be reached by a doctor. In 1950 CIRM was established as a non profit-making foundation and has benefited since 1957 from an annual contribution from the Italian government. METHODS: Review of CIRM case histories and other published material from 1935 to 2015 and presenting them in a scientific yet simplified manner through the use of basic mathematical analysis. All the data was collected from CIRM's official archives in Rome. RESULTS AND CONCLUSIONS: The results achieved by the Centre over 80 years include medical assistance to 81,016 patients on board ships (as well as on small islands and aircraft), with more than 500,000 medical messages received and transmitted. CIRM from its inception was organised into a medical service, a telecommunications service and a studies section. In 2002 the Centre was recognised as the Italian Telemedical Maritime Assistance Service (TMAS). In the 2010 the Centre was reorganised as a structure articulated in 4 departments, namely maritime telemedicine, telecommunication, research and occupational medicine. This was achieved to cover the different activities related to comprehensive health protection of seafarers. The 24-h continuous medical service is provided by doctors at the CIRM headquarters. The doctor on duty gives instructions for managing the case and continues to follow the patient with subsequent appointments until recovery or landing. In case of emergencies CIRM co-ordinates the transfer of patients assisted on board ships to a hospital ashore. CIRM has developed innovative approaches for the treatment of diseases and accidents on board of seagoing vessels by introducing standard telemedicine equipment on board ships, allowing the transmission of biomedical data from ships to the Centre. These new solutions are aimed at bringing a significant improvement of medical care for seafarers. PMID- 28009395 TI - Seeking specialist advice in the context of the pre-employment medical examination. Getting the 'right' answer to the 'right' question. PMID- 28009396 TI - Cruise tap versus handshake: using common sense to reduce hand contamination and germ transmission on cruise ships. AB - A firm handshake is a widely used greeting, but contaminated fingers and palms can also transfer bacteria and virus. Hand sanitation is important to prevent spreading of contagious diseases, but to wash hands properly takes too much time to ensure satisfactory compliance. Banning the handshake from health care settings has been proposed, but an alternative, less contagious form of greeting must be substituted. Cruise ships are particular vulnerable to infectious diseases that are transferred from person to person. The fist bump, common in some subcultures, has become increasing popular as the greeting-of-choice on smaller cruise vessels. To further reduce the contact area, a modification of the fist bump, the 'cruise tap', where only two knuckles briefly touch each other, is recommended. PMID- 28009397 TI - Corneal collagen crosslinking for corneal ectasias: a review. AB - PURPOSE: To review the published literature on corneal collagen crosslinking (CXL). METHODS: Importance has been placed on seminal publications, systemic reviews, meta-analyses, and randomized controlled clinical trials. Where such evidence was not available, cohort studies, case-controlled studies, and case series with follow-up greater than 12 months were examined. RESULTS: Corneal collagen crosslinking with riboflavin and ultraviolet A (UVA) 370 nm radiation appears to be capable of arresting the progression of ectatic corneal disorders, with most studies reporting significant improvements in visual, keratometric, and topographic measurements. Its mode of action at the molecular level is undetermined. Follow-up is limited to 5-10 years but suggests sustained stability and enhancement in corneal shape with time. Nearly all published long-term data and comparative studies are with epithelium-off techniques. Epithelium-on investigations suggest some efficacy but less than with epithelium-off treatments and long-term data are unavailable. Accelerated techniques with higher UVA fluencies and shorter treatments times, delivering the same UVA energy dosage, are the subject of recent investigation, with some laboratory and clinical studies suggesting reduced efficacy compared to the standard 3 mW/cm2 for 30 minutes irradiation procedure. Combined methodologies of CXL with techniques such as photorefractive keratectomy and intrastromal rings show promise but long-term follow-up is indicated. Sight-threatening complications of CXL are rare. CONCLUSIONS: Studies of epithelium-off CXL with irradiation at 3 mW/cm2 for 30 minutes support its efficacy. Refinement in techniques may allow for safer and more rapid procedures with less patient discomfort but require further investigation. PMID- 28009398 TI - Quantification of trabecular-iris contact and its prevalence by optical coherence tomography in a healthy Caucasian population. AB - PURPOSE: To determine the prevalence of trabecular-iris contact (TIC) and quantify this contact in healthy Caucasian individuals using Fourier-domain optical coherence tomography (FD-OCT). METHODS: For this cross-sectional study, 2,012 eyes of 1,006 healthy subjects were recruited among individuals undergoing a routine ophthalmologic checkup. In each participant, age, sex, intraocular pressure, and spherical refractive error were first recorded along with anterior chamber depth and volume, central corneal thickness measured with the Pentacam, and axial length with the IOLMaster. Anterior chamber angle variables and the presence of TIC in the horizontal quadrants were determined by anterior segment FD-OCT (RTVue 100(r)). When TIC was observed, TIC length (TICL) and its percentage in relation to the length of the trabecular meshwork (TICL percentage) were also measured. RESULTS: Trabecular-iris contact in the horizontal quadrants was observed in 34 eyes of 25 patients, representing 1.6% of the total number of eyes examined. In this subgroup of individuals, mean age was 55.8 years, 84% were women, and spherical refractive error ranged from -0.25 to 8.25 D. Eyes with TIC showed an angle width of less than 23.2 degrees and axial length shorter than 23.7 mm. Mean TICL was 239 +/- 79 MUm (103-495 MUm) and mean TICL percentage was 46.9% +/- 13.9% (17.2%-76.3%). CONCLUSIONS: The prevalence of TIC was low in this population. Fourier-domain optical coherence tomography emerged as useful to assess its prevalence and quantify the extent of TIC. PMID- 28009399 TI - Multifocal corneal ablation (Supracor) in hyperopic presbyopia: 1-year results in a cross-sectional study. AB - PURPOSE: To evaluate the efficacy and safety of the multifocal excimer laser corneal ablation profile (the Supracor procedure) in hyperopic presbyopia 1 year after laser treatment. METHODS: This prospective, consecutive, one-center, cross sectional study included 20 patients with hyperopic presbyopia 1 year after treatment with the Supracor procedure. The main outcome measures were monocular uncorrected distance visual acuity (UDVA) and uncorrected near visual acuity (UNVA), photopic contrast sensitivity (Pelli-Robson charts), patient satisfaction, and functioning at 12 months. RESULTS: Thirty-nine eyes of 20 patients (mean age 59 +/- 7.2 years) were treated. Mean UDVA improved from 0.56 +/- 0.31 (mean 0.34 logMAR) preoperatively to 0.9 +/- 0.15 (mean 0.06 logMAR) 12 months after surgery. Mean UNVA increased from 0.15 +/- 0.07 (mean 0.84 logMAR) before surgery to 0.62 +/- 0.24 (mean 0.23 logMAR) 12 months after treatment. Four eyes lost 2 lines of corrected distance visual acuity (10.3%). Monocular photopic contrast sensitivity was within age-correlated normal range (Pelli Robson chart, mean contrast sensitivity 1.83 +/- 0.18). A total of 75% of the patients would undergo Supracor again (1 not, 4 perhaps). The most frequently reported side effects were increased glare, reduced distance vision, and fluctuations in vision. Most patients used artificial tears. CONCLUSIONS: One year after Supracor, UDVA and UNVA improved markedly, photopic contrast sensitivity was in normal age-correlated range, and the majority of patients (75%) was satisfied with the results. Side effects like loss of distance vision, fluctuations of vision, and increased glare have a greater influence on patient satisfaction than the improvement of spectacle-free near vision. PMID- 28009400 TI - Optical coherence tomography imaging in the management of the Argus II retinal prosthesis system. AB - PURPOSE: To report a real-life experience with the Argus II retinal prosthesis system in blind patients with end-stage retinitis pigmentosa (RP) or choroideremia (CHM), focusing on the pivotal role of optical coherence tomography (OCT) in both preoperative and postoperative management. METHODS: This hospital based case series included 3 blind patients who were uneventfully implanted with Argus II epiretinal device. These patients (2 with RP and 1 with CHM) were selected during the ArgusTM II Retinal Prosthesis System PostMarket Surveillance Study Protocol. Complete screening procedures had involved 66 eyes of 33 patients afferent to the Center for Retinitis Pigmentosa of the Veneto Region. RESULTS: Preoperative OCT examination resulted in the exclusion of 8 eyes in 4 patients with bilateral posterior staphyloma diagnosing unexpected staphylomatous macular patterns in 2 patients with RP and no sign of pathologic myopia. Postoperative OCT study of Argus II proximity to retinal surface indicated a plausible correlation between electrode-retina distance and perceptual threshold in 2 of our 3 patients. In particular, during the first 6 months of follow-up, the patient with the closest contact between device and macula showed a continuous vision-related improvement in the performance of several real-life tasks. CONCLUSIONS: The present findings illustrate the modalities by which each different OCT examination is an essential tool to optimize safety and efficacy profiles during Argus II protocol. Optical coherence tomography will be crucial for future investigative approaches on patient selection criteria and next generation implant design. PMID- 28009401 TI - Single-pass four-throw technique for pupilloplasty. AB - PURPOSE: To describe a surgical technique for performing pupilloplasty. METHODS: In this surgical technique for pupilloplasty, after a single pass of needle through the edges of iris defect along the pupillary margin, the suture end is passed through the loop with 4 throws, creating a helical configuration in modified Siepser slipknot technique that is self-retaining and self-locking. RESULTS: The technique was performed in 27 cases and the loop did not open in any of the cases in the 6-month follow-up period. No case of iritis was seen. The iris tissue was seen well approximated to each other in all cases. CONCLUSIONS: The single-pass 4-throw technique serves as an effective method to perform pupilloplasty. PMID- 28009402 TI - Choroidal characteristics of acute and chronic central serous chorioretinopathy using enhanced depth imaging optical coherence tomography. AB - PURPOSE: Central serous chorioretinopathy (CSC) is an idiopathic disorder characterized by serous detachments of the neurosensory retina and/or the retinal pigment epithelium affecting the macular area in the majority of cases. The objective of this study was to describe choroidal findings in patients with acute and chronic CSC based on enhanced depth imaging optical coherence tomography analysis. METHODS: This is a cross-sectional, noninterventional study performed at Luigi Sacco University Hospital of Milan. Inclusion criteria were the presence of diagnosed (acute or chronic) CSC and being 18 years or older. Patients were evaluated with Spectralis spectral-domain optical coherence tomography enhanced depth imaging by 2 operators. The main features analyzed were intrachoroidal hyperreflective spots and hyperreflective choroidal vessel walls, as actual measurements of wall thickness could not be performed. RESULTS: Patients with chronic CSC had hyperreflective spots in 83.3% of the cases and hyperreflective choroidal vessel walls in 75%, whereas patients with acute course had the same alterations in 33% and 6.7% of cases, respectively. CONCLUSIONS: These findings, if proven, may be indicative of chronic forms, thus guiding more accurate treatments and guiding clinicians through more accurate prognosis. PMID- 28009403 TI - Ocular pulse amplitude after panretinal photocoagulation in normotensive eyes with proliferative diabetic retinopathy. AB - PURPOSE: To assess the effect of panretinal laser photocoagulation on ocular pulse amplitude (OPA) in normotensive eyes with proliferative diabetic retinopathy. METHODS: Prospectively, we performed unilateral argon laser panretinal photocoagulation (PRP) in 30 patients with diabetes mellitus type II and previously untreated bilateral proliferative diabetic retinopathy. Before and 7 and 30 days after the treatment, OPA was measured using dynamic contour tonometer. RESULTS: Compared with the untreated contralateral eyes, laser photocoagulation led to a reduction of OPA. Ocular pulse amplitude did not significantly differ in photocoagulated eyes 7 days after the treatment, but there was a significant difference in OPA 30 days after the treatment. The decrease in OPA values was 15% 7 days after PRP and 40% 30 days after PRP. CONCLUSIONS: Ocular pulse amplitude reduction after PRP indirectly informs us about choriocapillary closure, already reported in previous studies. PMID- 28009404 TI - Vogt-Koyanagi-Harada syndrome (uveomeningoencephalitic syndrome). AB - PURPOSE: To report a case of a 29-year-old man who was examined at the Eye Clinic of Central Military University Hospital Prague for a severe headache and acute blurring of vision in both eyes diagnosed as incomplete Vogt-Koyanagi-Harada syndrome (VKH). METHODS: This is a retrospective and descriptive case report based on data from clinical records, patient observation and follow-ups and analysis of acquired diagnostic tests. RESULTS: A 29-year-old man presented with headache and decreased vision in his left eye (LE) for 2 days. Best-corrected visual acuity was 20/20 in both his eyes. Pupillary function, intraocular pressure, results of external segment examinations, and slit-lamp biomicroscopy were normal bilaterally. Right eye funduscopy was normal; in the LE, funduscopy revealed posterior pole exudative retinal detachments. Optical coherence tomography confirmed multiple serous (bullous) retinal detachments and showed thickening of the posterior choroid also revealed by orbital ultrasound. Fluorescein angiography showed angiographic features typical of VKH disease: disseminated spotted choroidal hyperfluorescence and choroidal multifocal hypofluorescence, multifocal profuse leakage in the retina with late phase pooling, serous retinal detachment, and optic disc hyperfluorescence. All serologic tests for the diagnosis of infectious pathologies were negative. Except for severe headache, the patient did not have any neurologic, integumentary, or auditory manifestations. Immediate high-dose systemic corticosteroid treatment was given. CONCLUSIONS: Despite prompt diagnosis, prompt aggressive systemic therapy, and a rapid response in this case, progressive pigmentary changes of retinal pigment epithelium developed shortly thereafter. PMID- 28009405 TI - Fulminant idiopathic intracranial hypertension and venous stasis retinopathy resulting in severe bilateral visual impairment. AB - PURPOSE: To report a complicated case of fulminant idiopathic intracranial hypertension and concomitant venous stasis retinopathy leading to postpapilledema optic atrophy. METHODS: Case report. RESULTS: A 34-year-old morbidly obese woman with a history of idiopathic intracranial hypertension (IIH) presented with a 1 month history of bilateral vision loss, diplopia, and left eye pain after being lost to follow-up for 6 years. Fundus examination revealed florid papilledema with venous tortuosity bilaterally. Brain and orbit magnetic resonance imaging showed bilateral globe flattening, intraocular optic nerve swelling in both eyes, and no abnormality on magnetic resonance venography. After additional workup including lumbar puncture with an opening pressure of 55 cm H2O, a diagnosis of IIH was confirmed. Medical treatment with oral carbonic anhydrase inhibitors was initiated, followed by same-day bilateral optic nerve sheath decompression and ventriculoperitoneal shunt placement the following week. Fundus examination 2 months later revealed a persistent blood and thunder fundus suggestive of bilateral central retinal vein occlusions. Over the course of 6 months, both eyes displayed postpapilledema optic atrophy with light perception and hand motion vision in the right and left eyes, respectively. On Goldmann perimetry, the patient had vague limited isolated responses in both eyes to the largest target. CONCLUSIONS: Fulminant IIH can present with profoundly blinding complications recalcitrant to aggressive medical and surgical intervention. Central retinal vein occlusion is an uncommon blinding complication of IIH. PMID- 28009406 TI - The frequency and causes of abnormal head position based on an ophthalmology clinic's findings: is it overlooked? AB - PURPOSE: To determine the frequency of abnormal head position (AHP) and identify the underlying causes in patients who presented to an ophthalmology clinic due to any ophthalmologic complaint. METHODS: The medical records of patients who presented with any ophthalmologic symptoms during a 6-month period were prospectively evaluated. In all, 2,710 patients (1,492 female and 1,218 male) aged 6 months-91 years were included in the study. Each patient underwent complete ophthalmologic evaluation. RESULTS: Among the 2,710 patients, 30 (1.1%) (7 female and 23 male) with a mean age of 14.62 +/- 17.45 years (range 6 months 60 years) had AHP. In total, 24 (80%) of the patients with AHP were aged <=16 years. The initial complaint in the patients with AHP was ocular misalignment in 18 (60%) patients, AHP in 4 (13.3%), abnormal ocular movements in 4 (13.3%), double vision in 3 (10%), and droopy eyelid in 1 (3.3%). Comitant strabismus, nystagmus, and Duane syndrome were the most common causes of AHP. Other diagnoses included fourth nerve palsy, sixth nerve palsy, Brown syndrome, congenital muscular torticollis, ptosis, and blowout orbital fracture. CONCLUSIONS: The leading underlying causes of AHP in patients who presented to an ophthalmology clinic were ocular and treatable. Of note, in only a minority of these patients AHP was the initial presenting complaint. Clinicians must be aware that observation of any head position that is not normal should prompt additional investigation, as the underlying pathology can cause treatable morbidity or in rare instances mortality, such as in cases of acute cranial nerve palsy. PMID- 28009407 TI - An easy method for intraoperative confirmation of lacrimal sac patency in endoscopic dacryocystorhinostomy. AB - PURPOSE: Few studies have focused on the intranasal localization of the lacrimal sac during endoscopic dacryocystorhinostomy: landmarks in order to find the medial wall of the lacrimal sac have been described, but there is a lack of description of methods for the verification of the complete marsupialization of the lacrimal sac during surgery. In this report, we propose an easy and effective method for certain intraoperative identification of lacrimal sac. METHODS: A method in order to verify the effective marsupialization of the lacrimal sac is applied and described: to ensure that the opening of the sac in the nasal cavity is complete, the surgeon should identify the Rosenmuller valve, which is the end of the common canaliculus in the lacrimal sac. Continuous irrigation with saline solution through the inferior canaliculus can be useful to obtain a clean surgical area and to permit easy intraoperative identification of the valve. RESULTS: Between 2007 and 2015, 193 endoscopic dacryocystorhinostomies were performed in our institutions. Postoperative surgical success at last follow-up (minimum 12 months) was 93.8% (181 out of 193 of cases). No major complications were observed. CONCLUSIONS: Correct and complete exposure of the lacrimal sac during surgery is crucial for a good outcome: when the opening of the common canaliculus is identified, the surgeon is assured that the sac has been correctly and completely marsupialized inside the nasal cavity. PMID- 28009408 TI - Peripapillary choroidal thickness by enhanced depth imaging optical coherence tomography: the impact of metabolic syndrome. AB - PURPOSE: To assess the impact of metabolic syndrome (MetS) on the peripapillary choroidal thickness (PPCT) and to characterize the PPCT in a Portuguese population. METHODS: This prospective study included 104 eyes. Detailed medical and ophthalmic examinations were performed; the PPCT was measured by spectral domain optical coherence tomography (SD-OCT) using enhanced depth imaging (EDI) modality. The PPCT changes with MetS, as well as with other clinical and demographic factors, were investigated. RESULTS: The mean PPCT was 142.4 +/- 54.0 um (58-303 um); it was thickest superiorly, followed by the temporal, nasal, and inferior sectors. The PPCT was significantly associated with axial length (p<0.001), age (p = 0.001), intraocular pressure (IOP) (p = 0.041), weight (p = 0.015), and arterial hypertension (p = 0.044). The presence of MetS was associated with thinner PPCT in all sectors, being statistically significant in the temporal (p = 0.032) and inferotemporal (p = 0.034) sectors. CONCLUSIONS: The choroidal thickness was significantly less in temporal and inferotemporal sectors in patients with MetS than in controls. This may suggest vascular insufficiency around the optic nerve head. PMID- 28009409 TI - A survey of management of congenital nasolacrimal duct obstruction by pediatric primary health care providers in Spain. AB - PURPOSE: To survey the management of congenital nasolacrimal duct obstruction (CNLDO) by pediatric primary health care providers in Spain. METHODS: This was a descriptive study using a web-based questionnaire to evaluate the perceptions of the members of the Pediatric Primary Care Society in Castilla-Leon, Spain (APAPCYL), regarding management of CNLDO. The questionnaire contained 14 direct questions and was sent by e-mail to all the pediatricians. All the responses were analyzed by the frequency of occurrence and percentages. RESULTS: Ninety physicians responded to the questionnaire. Massage 2 or 3 times a day was the initial treatment advised by 60.47% of pediatricians. Nearly half of the pediatricians recommended continuing massage until symptoms resolved. Fewer than 50% of children required referral to an ophthalmologist. Reasons for an ophthalmic consult included persistence of symptoms among 87.21% of pediatricians and parental/guardian request among 10.5% of pediatricians. According to 45.6% of pediatricians, their knowledge about CNLDO is limited, and 92.2% would like to receive further training on CNLDO. CONCLUSIONS: Massage was the main initial treatment for managing CNLDO among pediatricians. The outcomes of this survey indicated that massage fails in fewer than 50% of patients and an ophthalmic referral is required for these cases. PMID- 28009410 TI - Optical coherence tomography angiography findings in laser maculopathy. AB - PURPOSE: Handheld laser pointer thermal injury affects primarily the retinal pigment epithelium (RPE). However, so far no study has reported on the possible effects of laser pointers in the deeper layers, beneath the RPE. Here, we describe the spectral-domain optical coherence tomography angiography findings in the choriocapillaris of a patient with laser maculopathy. METHODS: A 13-year-old boy presented to our department with decreased vision in the left eye 12 hours after having stared at the beam of a laser pointer. RESULTS: Structural optical coherence tomography (OCT) showed 2 focal hyperreflective columns at the fovea extending from the RPE, involving all outer retinal layers, and terminating at the outer plexiform layer. The patient also underwent OCT angiography (OCT-A), which in the choriocapillary segmentation revealed 2 hypointense lesions in correspondence of the focal hyperreflectivities detected on structural OCT. We hypothesize that the OCT-A findings could represent a rarefaction of the choriocapillaris. However, the choriocapillary OCT-A findings could also represent artifacts due to the overlaying hyperreflective lesions. CONCLUSIONS: It is known that the RPE is primarily damaged by the laser injury. Our findings suggest that the thermal injury could involve also the choriocapillaris, and thus not limited to the RPE. Multimodal imaging in laser maculopathy including OCT-A may lead to a better comprehension of the pathogenesis of laser retinal damages. PMID- 28009411 TI - Systematic screening of Retinopathy in Diabetes (REaD project): an Italian implementation campaign. AB - PURPOSE: To evaluate the use of telemedicine retinal screening in Italy and to identify potential elements of implementation of this system. METHODS: Patients with either new-onset diabetes or no ophthalmologic visit over the previous 2 years and attending 33 referral diabetic centers between mid-April 2013 and mid December 2015 were screened. Two partially overlapping nonstereoscopic 45 degrees digital color images were captured from each eye using a fully automated nonmydriatic digital fundus camera. Factors limiting the assessment of retinopathy were explored. RESULTS: Out of 24,473 eligible individuals, 22,466 had complete data. Among them, good-quality images enabling appropriate evaluation of at least one eye were obtained from 19,712 patients (both eyes, n = 18,887). Although nonmydriatic retinographs were provided, 39% of patients were evaluated using mydriasis. The rate of low-quality images in each center was inversely associated with the number of patients assessed. This was more evident for screening in mydriasis: adjusted odds ratio (OR) 0.79 (95% confidence interval (CI) 0.76-0.82) (p<0.001) vs 0.96 (95% CI 0.94-0.97) (p<0.001). Finally, both the number of patients assessed and use of mydriasis were inversely related to the presence of diabetic retinopathy (DR): adjusted OR 0.93 (95% CI 0.92-0.93) (p<0.001) and 0.88 (95% CI 0.82-0.96) (p<0.001), respectively. CONCLUSIONS: This program confirmed a role for teleophthalmology in the systematic screening of DR and provided important suggestions to improve the system deployed. A high level of training is required for operators to optimize imaging. The role of mydriasis should be evaluated further. PMID- 28009412 TI - Optical Coherence Tomography Angiography of Polypoidal Neovascularization Associated with Choroidal Nevus. AB - Purpose To report a case of juxtapapillary polypoidal choroidal neovascularization (PCNV) associated with choroidal nevus investigated by means of optical coherence tomography angiography (OCT-A). Methods Case report. Results A 72-year-old woman presented with visual loss and metamorphopsia in her left eye for 5 days secondary to PCNV that developed on the border of a juxtapapillary choroidal nevus. Fluorescein angiography, indocyanine green angiography, and spectral-domain OCT confirmed the diagnosis. En face OCT-A disclosed a large tangled hyperreflective PCNV spreading from the optic disc at different levels of the choriocapillaris; the polyp lumina appeared hyporeflective. The patient was treated with 3 intravitreal injections of anti-vascular endothelial growth factor with partial functional recovery. Conclusions Our case showed the application of OCT-A in the diagnosis of a case of active PCNV complicating a benign intraocular tumor. PMID- 28009414 TI - Bromfenac eyedrops in the treatment of diabetic macular edema: a pilot study. AB - PURPOSE: To evaluate the efficacy and safety of topical bromfenac in patients with newly diagnosed diabetic macular edema (DME). METHODS: In this pilot study including 17 patients with monocular, newly diagnosed DME, diagnosis of DME was established by the detection of retinal thickening at or within 500 MUm of the center of the macula on ophthalmoscopic examination, according to the Early Treatment Diabetic Retinopathy Study classification. Central macular thickness (CMT) was determined by optical coherence tomography. Bromfenac sodium hydrate 0.9 mg/mL eyedrops were administered in the affected eye twice daily for 30 days. Primary endpoints were changes in best-corrected visual acuity (BCVA) and CMT at the end of therapy. RESULTS: Topical bromfenac significantly reduced mean CMT, from 465.41 +/- 118.47 MUm at baseline to 388.88 +/- 152.63 MUm posttreatment (p = 0.02). There was no significant change in BCVA and differences in mean macular volume fell just short of statistical significance (p = 0.06). Treatment was well tolerated, and there were no topical or systemic side effects. CONCLUSIONS: Topical bromfenac twice daily may play a role in the reduction of DME. These preliminary results warrant further larger multicenter studies to confirm our findings and establish whether topical bromfenac may be of long-term benefit in the treatment of DME. PMID- 28009413 TI - Role of dextran in maintaining adhesive and stiffness properties of prestripped DMEK lenticules. AB - PURPOSE: To investigate the adhesive and stiffness properties of prestripped Descemet membrane endothelial keratoplasty (DMEK) lenticules in different preservation conditions (with and without dextran). METHODS: The study included 3 conditions: (C1) tissues collected from tissue culture media (TCM), stripped and preserved in TCM; (C2) tissues collected from transport media (TM) (TCM supplemented with 6% dextran T-500), stripped and preserved in TM; and (C3) tissues collected from TCM, stripped and preserved in TM. Using a hinge, 9.5-mm stripped DMEK lenticules were restored back on the stroma and preserved for 4 days at room temperature (RT) in different conditions as above. Nine tissues, 3 from each condition, were used to check the adhesive (fibronectin, laminin, and vitronectin) and elastic properties (fibrillin, elastin, and collagen VI) using different antibodies. Six tissues, 2 from each condition, were used to check the stiffness properties after preservation using atomic force microscopy (AFM) nanoindentation method. RESULTS: On the Descemet membrane, fibronectin was strongly expressed in C2 and C3, whereas laminin was intense in C2 postpreservation. Vitronectin was expressed in all the conditions. Elastic proteins were not expressed in either of the conditions apart from collagen VI, which was expressed on the posterior stroma. Atomic force microscopy showed higher stiffness in C3 and an insignificant but lower rigidity in C2 as compared to C1. CONCLUSIONS: The tissues from C2 showed expression of adherent proteins and lower stiffness. Dextran may be suitable in preservation of DMEK grafts before and after preparation. Less stiff tissues may help reduce manipulations required in the recipient eye during DMEK surgery. PMID- 28009415 TI - Dexamethasone intravitreal implant at the time of cataract surgery in eyes with diabetic macular edema. AB - PURPOSE: To determine the potential role of intraoperative dexamethasone intravitreal implant (DEX-I) in reducing diabetic macular edema (DME) worsening after phacoemulsification. METHODS: This was a prospective study on 19 eyes of 19 patients with type 2 diabetes mellitus with DME and cataract. Mean preoperative Early Treatment Diabetic Retinopathy Study visual acuity (VA) was 16.7 letters. Mean foveal thickness (FT) was 451 MUm. The DME was naive in 11 eyes and refractory in 8 eyes. All eyes underwent a standard phacoemulsification and intraocular lens implantation; DEX-I was injected at the end of surgery. Follow up was performed at 1 week and then monthly until DME recurrence (up to 8 months). RESULTS: At 1 week, mean VA improved by 15 letters (range 0-29 letters) and mean FT decreased by 147 MUm (range 69-236 MUm). Improvement consolidated at month 1, with a mean VA improvement of 18 letters (range 3-32 letters) and a mean improvement in FT of 193 MUm (range 76-304 MUm), remaining stable at month 2 after surgery in all eyes. The DME recurred in 1 eye at month 3, in 14 eyes (73.8%) between months 4 and 5, and after month 6 in 4 eyes (21%). Refractory DMEs demonstrated the same benefit but recurred earlier than naive ones (4 months versus 5.8 months, p<0.01). CONCLUSIONS: Intraoperative DEX-I prevents DME worsening after phacoemulsification. Its positive effects last for at least 3 months. PMID- 28009416 TI - Sleep quality and risk factors of atherosclerosis in predialysis chronic kidney disease. AB - INTRODUCTION: Chronic kidney disease (CKD) patients have more frequent sleep disorders and cardiovascular disease than normals. Since arterial stiffness as a risk factor of atherosclerosis can be evaluated with pulse wave velocity (PWV), we aimed to investigate the prevalance of sleep quality (SQ) and the relationship between SQ and risk factors of atherosclerosis and whether there is a relationship between SQ and PWV (the indicator of arterial stiffness) in predialysis CKD patients. METHODS: This cross-sectional study was carried out in CKD patients followed at the Nephrology Department in Konya, Turkey, between November 2014 and March 2015. A total of 484 CKD patients were screened. Of the 484 patients, 285 patients were excluded. The remaining 199 CKD patients without cardiovascular disease at stage 3, 4, and 5 (predialysis) were included in the final study. The SQ of the patients was evaluated by the Pittsburgh Sleep Quality Index (PSQI). PWV was measured by using a single-cuff arteriography device (Mobil O-Graph PWA, a model pulse wave analysis device; IEM). RESULTS: A total of 199 predialysis CKD patients were included in the study, 73 of whom (36.7 %) were 'poor sleepers' (global PSQI >5). Patients with poor SQ were older than those with good SQ (p = 0.077). SQ was worse in female patients compered to male patients (p = 0.001). SQ was worse in obese patients. As laboratory parameters, serum phosphorus, LDL cholesterol, and triglycerides levels correlated positively with SQ (respectively; r = 0.245, p&0.001; r = 0.142, p = 0.049; r = 0.142, p = 0.048). The indicator of arterial stiffness, PWV, was higher in patients with poor SQ (p = 0.033). Hyperphosphatemia and female gender are determined as risk factors for poor SQ in multivariate analysis (p = 0.049, ExpB = 1.477; p = 0.009, ExpB = 0,429, respectively). CONCLUSIONS: Our study showed for the first time that there is a relationship between SQ and risk factors of atherosclerosis in predialysis CKD patients. PMID- 28009417 TI - Multiple chromophobe and clear cell renal cancer in a patient affected by Birt Hogg-Dube syndrome: a case report. AB - OBJECTIVES: Birt-Hogg-Dube syndrome (BHDS) is a rare autosomal dominant characterized by the presence of fibrofolliculomas and/or trichodiscomas, pulmonary cysts, spontaneous pneumothorax, and renal tumors. The syndrome is linked to mutations in the FLCN gene, which is preferentially expressed in the skin, kidney, and lung. The aim of our paper is to describe a case of multiple bilateral renal cancer in a patient affected by BHDS. CASE PRESENTATION: Patient subjected to enucleoresection seven kidney tumors discovered right after ultrasound performed for other reasons. Definitive histologic examination were as follows: multifocal type chromophobe renal cell carcinoma and clear cell. After 1 month, the patient was readmitted for spontaneous pneumothorax. After about a year, the patient was again subjected to resection of multiple renal tumors left. Histological examination proved that it was multifocal renal cell carcinoma, clear cell varieties. The genome analysis highlighted positive for mutation c. 1379_1380 of FLCN gene, BHDS gene. Currently, the patient is under close follow up. After 1 year, the chest computed tomography (CT) confirmed the presence of minute air bubbles scattered on both sides. Instead, the abdominal CT was positive for a small round lesion 6 mm exophytic. CONCLUSIONS: The BHDS is a rare syndrome whose management is extremely complex both in terms of oncological and functional. Kidney tumors associated with BHDS usually have a favorable clinical course. Present evidence suggests a close follow-up of the carriers of the genetic mutation patients whether or not they have expressed the lesions of disease given the high rate of recurrence of renal lesions. PMID- 28009418 TI - Development of polymeric functionally graded scaffolds: a brief review. AB - Over recent years, there has been a growing interest in multilayer scaffolds fabrication approaches. In fact, functionally graded scaffolds (FGSs) provide biological and mechanical functions potentially similar to those of native tissues. Based on the final application of the scaffold, there are different properties (physical, mechanical, biochemical, etc.) which need to gradually change in space. Therefore, a number of different technologies have been investigated, and often combined, to customize each region of the scaffolds as much as possible, aiming at achieving the best regenerative performance.In general, FGSs can be categorized as bilayered or multilayered, depending on the number of layers in the whole structure. In other cases, scaffolds are characterized by a continuous gradient of 1 or more specific properties that cannot be related to the presence of clearly distinguished layers. Since each traditional approach presents peculiar advantages and disadvantages, FGSs are good candidates to overcome the limitations of current treatment options. In contrast to the reviews reported in the literature, which usually focus on the application of FGS, this brief review provides an overview of the most common strategies adopted to prepare FGS. PMID- 28009420 TI - Clinical outcomes of ceramicized ball heads in total hip replacement bearings: a literature review. AB - BACKGROUND: Metallic ball heads for total hip replacement (THR) bearings with ceramicized surfaces were introduced in orthopedics during the second half of the 1980s, with the aim of decreasing the wear of polyethylene cups. METHODS: An analysis was made of the literature regarding outcomes for metallic ball heads with ceramicized surfaces now in clinical use (TiN, TiNbN, ZrN, monoclinic ZrO2), as well as carbon coatings (pyrolytic carbon, diamond-like carbon) and silicon nitride as coatings in ball heads for THR bearings. RESULTS: Notwithstanding the diffusion of ceramicized ball heads in THRs, there are few reports about their clinical outcomes in hip arthroplasty. In addition, several clinical studies and some registry data are putting under scrutiny the clinical advantages of ceramicized ball heads over cobalt chrome (CoCr) alloy and ceramic ball heads. CONCLUSIONS: The wear of THR bearings with ceramicized ball heads looks like it depends more on the behavior of the polyethylene cups than on the treatment of the ball head surface. The risk of coating damage and of its consequences has to be taken into account in selecting this type of bearing. PMID- 28009419 TI - Mesenchymal stem cells from reaming material possess high osteogenic potential and react sensitively to bone morphogenetic protein 7. AB - BACKGROUND: Femoral material harvested using the Reamer-Irrigator-Aspirator (RIA) system is an alternative source for autogenous bone material in the treatment of non-unions, especially in combination with bone morphogenetic proteins (BMP). So far, there is no in vivo evidence of BMP-7 interacting with mesenchymal stem cells (MSCs) from RIA material (RIA-MSCs) and iliac crest autogenous bone (BMSCs). The aim of this study was to compare their osteogenic potential when stimulated with BMP-7 in vivo. METHODS: RIA-MSC and BMSC from 11 donors were isolated and the character of MSCs was investigated in vitro. Constructs consisting of MSC, beta-tricalcium phosphate and 2 concentrations of BMP-7 (0.1 ug/mL and 1 ug/mL) were implanted in mice for 8 weeks. Bone formation in the constructs was analyzed quantitatively and qualitatively. RESULTS: All cell populations used were determined to be MSCs. The qualitative in vivo analysis showed formation of bone tissue. With regard to quantity, bone formation was significantly higher in RIA constructs without or with stimulation with 0.1 ug/mL BMP-7, compared with BMSC constructs. We found no significant differences between constructs stimulated with 1 ug/mL BMP-7. In the RIA group, we observed a significant increase in bone formation after stimulation with 0.1 ug/mL BMP-7. No significant change could be found using a higher concentration. In the BMSC group, we detected a significant increase when using 0.1 ug/mL and 1 ug/mL BMP-7. CONCLUSIONS: RIA material is a source of MSCs with high osteogenic potential. Our results showed that stimulation by BMP-7 leads to an increased osteogenic potential of MSCs. In this respect, RIA-MSCs reacted more sensitively than BMSCs. PMID- 28009421 TI - Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients. AB - PURPOSE: Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. METHODS: This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. RESULTS: The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. CONCLUSIONS: The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time. PMID- 28009422 TI - Position paper of the Italian Association of Medical Oncology on early palliative care in oncology practice (Simultaneous Care). AB - One of the priorities of personalized medicine regards the role of early integration of palliative care with cancer-directed treatments, called simultaneous care. This article, written by the Italian Association of Medical Oncology (AIOM) Simultaneous and Continuous Care Task Force, represents the position of Italian medical oncologists about simultaneous care, and is the result of a 2-step project: a Web-based survey among medical oncologists and a consensus conference. We present the opinion of more than 600 oncologists who helped formulate these recommendations. This document covers 4 main aspects of simultaneous care: 1) ethical, cultural, and relational aspects of cancer and implications for patient communication; 2) training of medical oncologists in palliative medicine; 3) research on the integration between cancer treatments and palliative care; and 4) organizational and management models for the realization of simultaneous care. The resulting recommendations highlight the role of skills and competence in palliative care along with implementation of adequate organizational models to accomplish simultaneous care, which is considered a high priority of AIOM in order to grant the best quality of life for cancer patients and their families. PMID- 28009423 TI - Synchronous pancreatic and pulmonary metastases from solitary fibrous tumor of the pleura: report of a case. AB - INTRODUCTION: Solitary fibrous tumor of the pleura is an uncommon tumor with an indolent course and a good prognosis after surgical resection. However, the tumor occasionally follows an unpredictable clinical course and malignant transformation has been reported to increase the rate of local recurrence. Solitary extrathoracic metastasis from solitary fibrous tumor of the pleura is an uncommon finding. CASE PRESENTATION: In this case report we present the first case of a synchronous single pulmonary and pancreatic metastasis treated with minimally invasive surgery. CONCLUSIONS: Pancreatic recurrence should be considered in the postoperative follow-up in patients with solitary fibrous tumor of the pleura. PMID- 28009424 TI - Addition of docetaxel and/or zoledronic acid to standard of care for hormone naive prostate cancer: a cost-effectiveness analysis. AB - BACKGROUND: The effectiveness of the addition of docetaxel and/or zoledronic acid to the standard of care (SOC) for hormone-naive prostate cancer has been evaluated in the STAMPEDE trial. The object of the present analysis was to evaluate the cost-effectiveness of these treatment options in the treatment of advanced hormone-naive prostate cancer in China. METHODS: A cost-effectiveness analysis using a Markov model was carried out from the Chinese societal perspective. The efficacy data were obtained from the STAMPEDE trial and health utilities were derived from previous studies. Transition probabilities were calculated based on the survival in each group. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by 1-way sensitivity analysis and probabilistic sensitivity analysis. RESULTS: SOC alone generated an effectiveness of 2.65 quality-adjusted life years (QALYs) at a lifetime cost of $20,969.23. At a cost of $25,001.34, SOC plus zoledronic acid was associated with 2.69 QALYs, resulting in an ICER of $100,802.75/QALY compared with SOC alone. SOC plus docetaxel gained an effectiveness of 2.85 QALYs at a cost of $28,764.66, while the effectiveness and cost data in the SOC plus zoledronic acid/docetaxel group were 2.78 QALYs and $32,640.95. CONCLUSIONS: Based on the results of the analysis, SOC plus zoledronic acid, SOC plus docetaxel, and SOC plus zoledronic acid/docetaxel are unlikely to be cost-effective options in patients with advanced hormone-naive prostate cancer compared with SOC alone. PMID- 28009425 TI - Gemcitabine-induced thrombocytosis as a potential predictive factor in non-small cell lung cancer: analysis of 318 patients. AB - INTRODUCTION: In spite of the progress in the treatment of non-small-cell lung cancer (NSCLC), the majority of patients with advanced disease still receive chemotherapy. Gemcitabine alone or combined with a platinum compound is a valid option. Thrombocytosis is a recognized prognostic factor in lung cancer and an adverse event that may occur during gemcitabine infusion. METHODS: We retrospectively evaluated all patients with NSCLC treated with first-line gemcitabine-based chemotherapy in two Italian hospitals. We assessed the onset of thrombocytosis within the third cycle of therapy and the relation between thrombocytosis and survival. RESULTS: We included 318 patients. Thrombocytosis occurred in 156 patients (49.1%). Median progression-free survival (PFS) was 5.6 months (95% CI, 4.7-6.9 months) in patients who developed thrombocytosis versus 6 months (95% CI, 5.1-7.2 months) in patients without thrombocytosis (p = 0.21). Median overall survival (OS) was 11.2 months (95% CI, 9.8-13.4 months) in patients with thrombocytosis versus 12 months (95% CI, 10.1-14.4 months) in patients without thrombocytosis (p = 0.25). We observed no difference in terms of PFS or OS according to age, sex, stage, chemotherapy (single-agent versus combination chemotherapy) and thrombocytosis. CONCLUSIONS: Thrombocytosis is neither a prognostic nor a predictive factor for PFS or OS in patients with advanced NSCLC treated with first-line gemcitabine-based chemotherapy. PMID- 28009427 TI - First Italian Consensus Conference on VATS lobectomy for NSCLC. AB - PURPOSE: Video-assisted thoracoscopic surgery (VATS) lobectomy has become an accepted procedure for the treatment of selected cases of lung cancer. The aim of this project was to establish national practical recommendations for the management of patients suitable for VATS lobectomy. METHODS: The Scientific Committee of the VATS Lobectomy Group (a branch of the Italian Society of Thoracic Surgery) identified the consensus conference as an appropriate tool for a national debate. The consensus conference was organized following indications of the Italian Department of Health: a panel of experts reviewed the literature, the jury board revised the experts' reports, and the national conference discussed and voted on statements. The strength of recommendation for a statement was classified as weak, fair, or high when the total score ranged between 51% and 67%, 68% and 84%, or 85% and 100%, respectively. RESULTS: Eighty-six Italian thoracic surgeons attended the 1st Italian Consensus Conference on VATS lobectomy in Giulianova, Italy, on October 29-30, 2015. Thirty-three topics were discussed: indications, surgical strategy, perioperative management, and training were the main topics. Consensus was reached on 24 statements that were consequently recommended. CONCLUSIONS: The Italian Consensus Conference is the first attempt to discuss VATS lobectomy-related issues in a national scientific community. Such experience determined an improvement in epistemic knowledge among the Italian thoracic surgeons and could be a suggestion for other national communities. PMID- 28009426 TI - "Christmas Balls": a Christmas carol by the adolescent cancer patients of the Milan Youth Project. AB - The Youth Project is a program developed at the Pediatric Oncology Unit at the Istituto Nazionale Tumori in Milan, dedicated to adolescents and young adults with cancer. Among its various goals, the Youth Project organizes structured creative activities with the support of professionals, with the objective of offering young people a new way to express their hopes and fears. This article describes a project centered around music: patients created a Christmas carol with the help of musicians and authors. The adolescents explained with their own words the meaning of the lyrics, telling the story of a Christmas spent in a cancer hospital ward. PMID- 28009428 TI - High-Dose Chemotherapy and Peripheral Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma. AB - Purpose High-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is used to treat patients with relapsed Hodgkin's lymphoma. In this retrospective study we report our experience with patients who underwent HDCT and ASCT. Methods All patients >=15 years old with relapsed/refractory Hodgkin's lymphoma who underwent HDCT and ASCT between June 2001 and December 2013 were included. Results Fifty-four patients were identified. Median age at transplant was 22 years (range 15-49 years); 26 were men and 28 were women. Forty-eight patients (89%) underwent HDCT and ASCT after achieving a radiological response to salvage chemotherapy. The rate of radiological complete response to salvage chemotherapy was 13% and reached 50% within 3 months of ASCT in assessable patients. After a median follow-up of 25 months, 31 patients (57%) were still alive with no evidence of relapse or progression. Median event-free survival (EFS) was 24 months (95% CI 8.7-39.3) and 3-year EFS was 56%. Median overall survival (OS) was not reached and 3-year OS was 82.5%. Bulky mediastinal disease at relapse, hemoglobin level, and number of salvage regimens did not significantly impact EFS in univariate and multivariate analyses. After transplantation there was a trend towards longer EFS (30 vs. 24 months; p = 0.36) in patients with a longer time from the end of first-line treatment until relapse (>=12 vs. <12 months). The 100-day transplant-related mortality was 5.5%. Conclusions HDCT and ASCT for relapsed/refractory Hodgkin's lymphoma is safe. Our findings are consistent with published phase III results. Longer follow-up is warranted. PMID- 28009429 TI - Association between Toll-like receptor and tumor necrosis factor immunological pathways in uterine cervical neoplasms. AB - INTRODUCTION: The immune system plays a critical role in the defense against human papillomavirus (HPV) infection and its persistence. Toll-like receptors (TLRs) are membrane receptors responsible for activation of the innate immune response, and an association between TLR expression and uterine cervical cancer has been shown. Tumor necrosis factors (TNFs) are among the main mediators of skin and mucosa inflammation. The aim of this study was to demonstrate the association between TLR and TNF immune expression and cervical cancer and premalignant cervical lesions. METHODS: A total of 64 embedded tissues were obtained from gynecological procedures, including 35 specimens with cervical intraepithelial neoplasia (CIN) and 10 specimens with cervical squamous cell carcinoma (CSCC) as well as 19 normal cervical samples. The expression of TLR2, TLR3, TLR4, TNF-alpha and TNF-beta was measured by immunohistochemistry and graded into low and high levels of expression. RESULTS: There was an association between the expression levels of TLR2 and those of TNF-alpha and TNF-beta (p = 0.01 and p = 0.021, respectively) in the cervical cancer and CIN groups. TLR4 expression was associated with TNF-alpha and TNF-beta expression (p = 0.016 and p = 0.025, respectively) in these 2 groups. By contrast, TLR3 was not statistically associated with TNF-alpha or TNF-beta in any of the groups. CONCLUSIONS: There might be an association of the TLR2 and TLR4 pathways with the immunological response of TNF-alpha and TNF-beta in cervical cancer. These markers are also expressed at higher levels in cervical cancer and premalignant lesions compared to normal controls. PMID- 28009430 TI - Timing should no longer be an obstacle to oocyte cryopreservation in patients with cancer. AB - PURPOSE: Anticancer treatment-related infertility is preventable with oocyte cryopreservation, but this is often not considered a relevant issue, due to lack of knowledge and time. The aim of this study is to prove that adequate organization of an Oncofertility Unit and the use of new protocols for controlled ovarian stimulation (COS) can reduce the time required by the procedure, encouraging consultants and patients to preserve fertility before gonadotoxic treatments. METHODS: A total of 125 patients diagnosed with malignant tumors were referred to the Oncofertility Unit of San Raffaele Hospital: 52 patients between April 2011 and October 2013 and 73 patients between October 2013 and November 2015. The 2 periods differ in office organization and type of COS protocol used. RESULTS: Between the 2 periods, a reduction in the mean number of days required from first counseling to the initiation (6.45 +/- 1.058 vs 1.61 +/- 0.228) and the end of the COS (17.83 +/- 1.227 vs 13.70 +/- 0.393) was observed (p<0.0001). No differences exist in the groups between the mean time required to complete COS (11.38 +/- 0.360 vs 12.17 +/- 0.309; p = 0.11) and mean number of frozen oocytes (8.458 +/- 1.060 vs 10.30 +/- 0.919; p = 0.22). Furthermore, in the second period, the number of patients who accepted fertility preservation increased (46.15% vs 64.38%; p<0.05). CONCLUSIONS: Renewed organization of the Oncofertility Unit and the newest random-start COS protocol allowed us to shorten the time for oocyte cryopreservation and start anticancer treatment on time. PMID- 28009431 TI - Up-regulation of long noncoding RNA CCAL predicts poor patient prognosis and promotes tumor metastasis in osteosarcoma. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) play essential roles in tumor progression. Aberrant colorectal cancer-associated lncRNA (CCAL) has been found in colorectal cancer. However, the function of lncRNA CCAL in osteosarcoma (OS) remains unclear. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to measure CCAL expression in OS tissues and adjacent nontumor tissues. The correlation betweent CCAL expression and clinicopathological features and prognosis was also analyzed. In addition, the function of CCAL was further evaluated by cell proliferation, migration and invasion assays. RESULTS: We showed that CCAL was significantly up-regulated in OS tissues compared with adjacent nontumor tissues. Increased expression of CCAL was correlated with advanced TNM stage and metastasis. Kaplan-Meier analysis demonstrated that patients with high CCAL expression had lower overall survival than those with low CCAL expression. Multivariate Cox regression analysis indicated that CCAL expression might be an independent prognostic factor for OS patients. In addition, functional assays showed that decreased CCAL expression could inhibit OS cell proliferation, migration and invasion ability. CONCLUSIONS: Our findings suggested that CCAL plays critical roles in OS progression and could act as a therapeutic target in the treatment of OS. PMID- 28009432 TI - Genetic polymorphisms of vitamin D receptor (VDR), CYP27B1 and CYP24A1 genes and the risk of colorectal cancer. AB - INTRODUCTION: Vitamin D receptor (VDR) and proteins encoded by the genes CYP27B2 and CYP24A1 involved in the production and inactivation of vitamin D can influence vitamin D and the susceptibility to colorectal cancer (CRC). The objective of this study was to investigate the relationship between the risk of CRC and polymorphisms in VDR, CYP27B1 and CYP24A1, lifestyle and dietary habits. METHODS: The study included 152 patients with CRC and 321 controls. All participants answered a questionnaire on their dietary habits, alcohol consumption and smoking habits. DNA was extracted from peripheral blood. Polymorphisms of BsmI and ApaI were identified by performing PCR-RFLP. Identification of CYP24A1 (rs6013897, rs158552 and rs17217119) and CYP27B1 (rs10877012) polymorphisms was performed by gene sequencing. RESULTS: Smoking, alcohol use, and low or no consumption of fruit, cereals and dairy products were associated with an increased risk of CRC. A heterozygous genotype Aa or an association genotype aa + Aa of the VDR ApaI polymorphism increased the risk of CRC. The VDR BsmI polymorphism was not significantly associated with the risk of CRC. Multivariate analysis showed that heterozygous and association genotype AT + AA of the rs6013897 polymorphism, genotype CT of the rs158552 polymorphism, association genotype CT + CC and genotypes AA and GG of the rs17217119 polymorphism of CYP24A1, and heterozygous genotype GT and association genotype GT + TT of the rs10877012 polymorphism in CYP27B1 were associated with a higher risk of CRC. CONCLUSIONS: Dietary habits, lifestyle, and polymorphisms in VDR (ApaI), CYP24A1 (rs6013897, rs158552, rs17217119) and CYP27B1 (rs10877012) were associated with a higher risk of CRC. PMID- 28009433 TI - Increased level of annexin A1 in bronchoalveolar lavage fluid as a potential diagnostic indicator for lung cancer. AB - BACKGROUND: Annexin A1 has been implicated in various tumor types, but few studies have investigated its involvement in lung cancer. The purpose of this investigation was to quantify the annexin A1 level in bronchoalveolar lavage fluid (BALF) and analyze its usefulness in lung cancer diagnosis. METHODS: Annexin A1 expression was measured by immunohistochemistry and enzyme immunoassay. The sensitivity and specificity of annexin A1 for distinguishing lung cancer were determined by receiver operator characteristic (ROC) curves. RESULTS: Tumor tissues, BALF and serum of patients with lung cancer contained higher levels of annexin A1 than those of the control group of patients with benign lung diseases. Moreover, an increased level of BALF annexin A1 was closely correlated with lymphatic invasion and malignant progression of lung cancer. The sensitivity and specificity of BALF annexin A1 for distinguishing lung cancer were 94.2% and 90.2%, respectively. CONCLUSIONS: Increased annexin A1 in BALF was correlated with lymphatic invasion and malignant progression of lung cancer, suggesting that it could be an indicator for discerning lung cancer and predicting outcome. PMID- 28009434 TI - Gene polymorphisms of TLR2 and TLR3 in HBV clearance and HBV-related hepatocellular carcinoma in a Chinese male population. AB - BACKGROUND: The Toll-like receptor plays an essential role in controlling immunity and inflammation. This study was to investigate the relationships of genetic variants in TLR2 and TLR3 with hepatitis B virus (HBV) natural clearance and HBV-related hepatocellular carcinoma (HCC) risk in a Chinese male population. METHODS: We analyzed 5 polymorphisms of TLR2 (rs3804099 and rs3804100) and TLR3 (rs5743305, rs3775296 and rs3775291) in a population consisting of 686 participants with HBV natural clearance, 293 chronic HBV carriers and 395 HBV positive HCC patients, using the improved multiplex ligase detection reaction method. RESULTS: After adjustment for age and smoking and drinking status, no associations were observed either between the 5 single-nucleotide polymorphisms (SNPs) and the HBV natural clearance participants, or between the 5 SNPs and HCC patients. Whereas the stratified analysis showed that under the dominant models, nondrinkers with TLR2 rs3804100 and participants younger than 40 years old with TLR3 rs3775291 were significantly associated with HCC risk when compared with persistent HBV carriers (adjusted odd ratio [OR] = 0.49, 95% confidence interval [95% CI], 0.31-0.78, p = 0.003; and adjusted OR = 0.50, 95% CI, 0.29-0.86, p = 0.013, respectively). Furthermore, the TTTCT haplotype was found to promote the progress of HBV clearance and inhibit development of HBV-related HCC (OR = 0.77, 95% CI, 0.61-0.97, p = 0.029; and OR = 0.72, 95% CI, 0.55-0.94, p = 0.016, respectively). And the CCACC and CCTCT haplotypes were observed to decrease susceptibility to HCC (OR = 0.64, 95% CI, 0.40-1.00, p = 0.048; and OR = 0.43, 95% CI, 0.28-0.68, p<0.001, respectively). CONCLUSIONS: This study revealed that TLR2 rs3804100 and TLR3 rs3775291 polymorphisms may be protective factors for HBV related HCC. PMID- 28009435 TI - Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells. AB - BACKGROUND AND PURPOSE: CD22 and CD79b are cell-surface receptors expressed on B cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody drug conjugates (ADCs) were investigated in cynomolgus monkeys. EXPERIMENTAL APPROACH: Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro. KEY RESULTS: Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity. CONCLUSIONS AND IMPLICATIONS: The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics. PMID- 28009436 TI - Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro 1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator. AB - BACKGROUND AND PURPOSE: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application. EXPERIMENTAL APPROACH: [N-[(2S)-5-(6-fluoro-3 pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent. KEY RESULTS: We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg.kg-1 . UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg.kg-1 . CONCLUSION AND IMPLICATIONS: We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation. PMID- 28009438 TI - Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer. AB - AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). RESULTS: A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. CONCLUSIONS: PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed. PMID- 28009437 TI - Serelaxin in clinical development: past, present and future. AB - : The availability of highly purified recombinant human relaxin, serelaxin, has allowed clinical trials to be conducted in several indications and the elucidation of its pharmacology in human subjects. These studies have demonstrated that serelaxin has unique haemodynamic properties that are likely to contribute to organ protection and long-term outcome benefits in acute heart failure. Clinical observations support its consideration for therapeutic use in other patient populations, including those with chronic heart failure, coronary artery disease, portal hypertension and acute renal failure. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. PMID- 28009439 TI - Sudan black: a fast, easy and non-toxic method to assess myelin repair in demyelinating diseases. AB - AIMS: The search for novel drugs that enhance myelin repair in entities such as multiple sclerosis has top priority in neurological research, not least because remyelination can hinder further neurodegeneration in neuro-inflammatory conditions. Recently, several new compounds with the potential to boost remyelination have been identified using high-throughput in vitro screening methods. However, assessing their potential to enhance remyelination in vivo using plastic embedded semi-thin sections or electron microscopy, even though being the gold standard for assessing remyelination, is toxic, extremely time consuming and expensive. METHODS: We screened available myelin dyes for a staining candidate which offers a faster and easier alternative to visualize remyelination in cryo-sections. RESULTS: We identified sudan black as a candidate with excellent myelin resolution and we show that our adapted sudan black staining can demonstrate myelin repair in rodent spinal cord cryosections as reliable as in semithin sections, but much faster, easier, less toxic and less expensive. Besides that, it can resolve the small myelinated axons in the corpus callosum. The staining can yet readily be combined with immunostainings which can be challenging in semithin sections. We validated the method in human spinal cord tissue as well as in experimental demyelination of the rat spinal cord by a lysolecithin time course experiment. As proof-of-principle, we demonstrate that sudan black is able to reliably detect the remyelination enhancing properties of benztropine. CONCLUSION: Our adapted sudan black staining can be used to rapidly and non-toxically screen for remyelinating therapies in demyelinating diseases. PMID- 28009440 TI - Points on the curve: An analysis of methods for assessing the shape of vertebrate claws. AB - The form of amniote claws has been extensively investigated, often with inferences about ecological association being drawn from studies of their geometry. Various methods have been used to quantify differences in the geometry of claws, but rarely have the underlying assumptions of such methods been addressed. Here, we use one set of bird claws and apply six methods (five that have been previously used, and a new one) that are tasked with comparing their shape. In doing so, we compare the (1) ability of these methods to represent the shape of the claw; (2) validity of the assumptions made about underlying claw geometry; (3) their ability to be applied unambiguously; and (4) their ability to differentiate between predetermined functional clusters. We find that of the six methods considered only the geometric morphometric approach reveals differences in the shapes of bird claws. Our comparison shows that geometry-based methods can provide a general estimate of the degree of curvature of claw arcs, but are unable to differentiate between shapes. Of all of the geometry-based approaches, we conclude that the adjusted version of the Zani (2000) method is the most useful because it can be applied without ambiguity, and provides a reliable estimate of claw curvature. The three landmarks that define that method (tip and base of the claw arc, plus the intersection between said claw arc and a line drawn perpendicular from the midpoint of tip and claw base) do not all bear biological significance, but relatively clearly circumscribe the length-to-height ratio of the claw, which relates to its curvature. Overall, our comparisons reveal that the shape of avian claws does not differ significantly between climbing and perching birds, and that the utilization of preordained functional clusters in comparative data analysis can hinder the discovery of meaningful differences in claw shape. J. Morphol. 278:150-169, 2017. (c) 2016 Wiley Periodicals,Inc. PMID- 28009441 TI - Follicular lymphomatoid papulosis with follicular mucinosis: a clinicopathologic study of 3 cases with literature review and conceptual reappraisal. AB - Lymphomatoid papulosis (LyP), characterized by recurring, waxing and waning, cutaneous papulonodules, is increasingly recognized to represent a heterogeneous collection of pathologically dissimilar subtypes. Recently, a follicular LyP variant was proposed, featuring folliculotropism. Folliculotropism by atypical lymphocytes is conventionally associated with follicular mucinosis and mycosis fungoides (MF), and review of the literature suggests co-occurrence of folliculotropism and follicular mucinosis in LyP to be rare, with only 3 cases identified to date. Herein we describe 3 additional cases, each manifesting a typical LyP clinical picture, with the additional element of folliculotropism and follicular mucinosis on pathology. These cases suggest that LyP should be considered alongside MF in the differential diagnosis of follicular mucinosis with accompanying atypical lymphocytic infiltration. As LyP can occur with other lymphoproliferative disorders such as MF, the finding of follicular mucinosis in LyP may further represent a conceptual intersection between the 2 disease processes. PMID- 28009442 TI - Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis. AB - OBJECTIVE: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited. METHODS: Results of ESA therapy were analyzed in 163 MF patients with severe anemia, most of whom had inadequate erythropoietin (EPO) levels (<125 U/L) at treatment start. RESULTS: According to the revised criteria of the International Working Group for Myelofibrosis Treatment and Research, anemia response was achieved in 86 patients (53%). Median response duration was 19.3 months. In multivariate analysis, baseline factors associated with a higher response rate were female sex (P=.007), leukocyte count >=10*109 /L (P=.033), and serum ferritin <200 ng/mL (P=.002). Patients with 2 or 3 of the above features had a significantly higher response rate than the remainder (73% vs 28%, respectively; P<.001). Over the 373 patient-years of follow-up on ESA treatment, nine patients developed thrombotic complications (six arterial, three venous), accounting for 2.41 events per 100 patient-years. Survival time from ESA start was longer in anemia responders than in non-responders (P=.011). CONCLUSION: Besides the already established predictive value of EPO levels, these data can help to identify which MF patients are more likely to benefit from ESA treatment. PMID- 28009443 TI - Myopathology in the times of modern genetics. AB - The advent of Next Generation Sequencing (NGS) technologies has accelerated the rate of novel disease gene discovery. Analysis of the large datasets generated by whole exome sequencing, whole genome sequencing, and other NGS approaches poses a challenge to physicians and pathologists searching for disease causing variants amongst the 50 000-3 million polymorphisms typically seen in these datasets. This review describes strategies that successfully combine classical neuropathological investigation (e.g. histology, immunostaining and electron microscopy) with modern NGS technologies to pinpoint the underlying genetic cause of a disease. We describe filtering techniques and free online bioinformatic tools that can help physicians and researchers establish a molecular diagnosis from NGS data. The ethical issues raised by NGS data are outlined. We provide specific examples that illustrate how traditional and contemporary approaches integrate to solve a difficult diagnosis or to correct initially wrong assumptions based on data generated from one method alone. PMID- 28009444 TI - Medicine information exchange networks among healthcare professionals and prescribing in geriatric medicine wards. AB - AIMS: Effective transfer of information is vital for rational drug therapy. This is particularly important for older patients, who have a high prevalence of polypharmacy and are managed by multidisciplinary teams. We aimed to assess medicine information exchange (MIE) networks in geriatric medicine wards and whether they are associated with prescribing patterns. METHODS: We conducted network analysis in acute geriatric medicine wards from four hospitals to characterize MIE networks among multidisciplinary team members. Corresponding patient data were collected to analyze high-risk prescribing in conjunction with network characteristics. RESULTS: We found that junior doctors, senior nurses and pharmacists were central to MIE across all four hospitals. Doctors were more likely than other professions to receive medicines information in three hospitals. Reciprocity and the tendency to communicate within one's own profession also influenced network formation. No difference was observed in prescribing practice between hospitals. CONCLUSIONS: Understanding MIE networks can identify gaps in multidisciplinary communication that can be addressed. Networks may identify targets for dissemination of interventions to improve prescribing. PMID- 28009445 TI - Stereoselective bioaccumulation, transformation, and toxicity of triadimefon in Scenedesmus obliquus. AB - In this study the stereoselective bioaccumulation and transformation of triadimefon and the toxicity of triadimefon and its metabolite triadimenol to the green algae Scenedesmus obliquus were studied. In growth inhibition experiments, triadimenol was more toxic than triadimefon, and (1S,2R)-triadimenol, which has the largest fungicidal activity, presented the highest toxicity to the algae. In bioaccumulation experiments, triadimefon was rapidly taken up by algae cells, and the decrease in the concentration of triadimefon was accompanied by an increase in triadimenol. The transformation of S-(+)- triadimefon was faster than that of the R-(-)-enantiomer, resulting in four triadimenol stereoisomers at different forming rates: B2 (1S, 2S) > B1 (1R, 2R) > A2 (1S, 2R) > A1 (1R, 2S). Thus, it is necessary to explore the enantioselective toxicology and ecological fate of these chiral pesticides in an environmental risk assessment. Also, their metabolites should be paid specific attention to since they may pose higher ecological risks. PMID- 28009446 TI - Distribution of enantiomers of volatile organic compounds in selected fruit distillates. AB - The enantiomer ratios of chiral volatile organic compounds in fruit distillates were determined by multidimensional gas chromatography using solid-phase microextraction (SPME) as a sample treatment procedure. Linalool and its oxides, limonene, alpha-terpineol, and nerolidol, were present at the highest concentration levels, while significantly lower amounts of beta-citronellol and lactones were found in the studied samples. However, almost all terpenoids mainly occur as a racemic or near-racemic mixture; enantiomer distribution of some chiral organic compounds in fruit distillates correlated to a botanical origin. In particular, a significant enantiomeric excess of (R)-linalool and (S)-alpha terpineol was found only for pear brandy, and likewise the dominance (R)-limonene and the second eluted enantiomer of nerolidol for Sorbus domestica and strawberry, respectively. The distribution of gamma-lactones stereoisomers was more nonspecific, with a general excess of the R-enantiomer. PMID- 28009447 TI - Modified CVAD and modified CBAD compared to high-dose cyclophosphamide for peripheral blood stem cell mobilization in patients with multiple myeloma. AB - BACKGROUND: The optimal regimen for peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (auto-HCT) has not been established. Experience at The University of Texas MD Anderson Cancer Center suggests in addition to single-agent cyclophosphamide (Cy), modified cyclophosphamide, vincristine, doxorubicin, and dexamethasone (mCVAD), and modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone (mCBAD) may be successful chemomobilization regimens. METHODS: This retrospective review included 167 patients (66 with Cy, 74 with mCVAD, and 27 with mCBAD) with multiple myeloma undergoing mobilization for auto-HCT between January 1, 2006 and September 30, 2013. The primary objective was to evaluate and compare the successful mobilization of CD34+ cells among high-dose Cy, mCVAD or mCBAD. RESULTS: Successful mobilization (>=2*106 CD34+ cells/kg) was achieved in all patients, while 65 (98%), 72 (97%), and 27 (100%) patients achieved an optimal mobilization (>=4*106 CD34+ cells/kg) in the Cy, mCVAD, and mCBAD groups, respectively. There was no significant difference in the number of apheresis sessions (P=.63), incidence of febrile neutropenia (P=.57), or hospital admission rates (P=.55). CONCLUSION: Either Cy, mCVAD, or mCBAD can yield successful PBSC mobilization in patients with multiple myeloma undergoing auto-HCT. PMID- 28009448 TI - Rapid determination of oxindole alkaloids in cat's claw by HPLC using ionic liquid-based microwave-assisted extraction and silica monolithic column. AB - Cat's claw is a large woody vine with hook-like thorns, and has been traditionally used to treat inflammatory disorders in South and Central America. In this study, a rapid, validated high-performance liquid chromatographic (HPLC) method using a silica monolithic column was developed for the simultaneous determination of oxindole alkaloids, namely rhynchophylline, pteropodine, isomitraphylline and isopteropodine, in cat's claw. The ionic liquid-based microwave-assisted extraction (ILMAE), considered as an environmentally friendly and powerful tool, was first applied in the extraction of oxindole alkaloids. To optimize the HPLC method, the stationary phases, pH values of mobile phase and flow rates were investigated. The validated HPLC method using a Monolithic RP18e column (100 * 4.6 mm) enables these analytes to be separated almost twice as fast as with a conventional particulate column (~16 vs ~30 min) with limits of quantification and detection of 0.5 and 0.15 MUg/mL, respectively. The ILMAE conditions were optimized by the Taguchi orthogonal array design. In comparison with conventional water boiling extraction, ILMAE offers almost four times higher yields within an extremely short extraction time. The developed HPLC coupled with ILMAE method could be efficient and practical for rapid determination of oxindole alkaloids in cat's claw. PMID- 28009449 TI - The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. AB - INTRODUCTION: The coagulopathy of cirrhosis is complex, placing patients at risk for both bleeding and thrombosis. Direct oral anticoagulants (DOACs) have equivalent or superior efficacy and safety as compared to vitamin K antagonists (VKAs); however, their efficacy and safety in liver cirrhosis has not been studied. To better define this, we evaluated outcomes of patients with cirrhosis prescribed DOACs compared to other anticoagulants at our center. METHODS: Retrospective cohort study of patients with cirrhosis prescribed therapeutic anticoagulation over a 3-year period for thrombosis or prevention of stroke in patients with atrial fibrillation. The primary outcomes of interest were bleeding events and recurrent thrombosis or stroke. RESULTS: During the study period, 27 patients with cirrhosis were prescribed a DOAC and 18 were prescribed VKA or low molecular weight heparin (LMWH). Both groups had similar total bleeding events (8 DOAC vs 10 other, P=.12). There were significantly less major bleeding episodes in the DOAC group (1 [4%] vs 5 [28%], P=.03). Recurrent thrombosis occurred in one patient receiving a DOAC (4%) and one patient (6%) receiving other anticoagulation (P=1.0). CONCLUSIONS: Direct oral anticoagulant use in patients with cirrhosis may be as safe as traditional anticoagulants. Patients with cirrhosis at our center prescribed DOACs had less major bleeding events, while maintaining efficacy at preventing stroke or thrombosis. PMID- 28009450 TI - Multicompartment compliance aids in the community: the prevalence of potentially inappropriate medications. AB - AIMS: To assess the prevalence of potentially inappropriate medications (PIMs) use in a population of community-based multicompartment compliance aid (MCA) users in north-east Scotland. METHODS: Data for MCAs dispensed by 48 of the 50 community pharmacies in Aberdeen City between 1st June to 31st October 2014, together with concurrently prescribed medications, patient demographics and Carstairs index of social deprivation were recorded. Drug-specific quality indicators for PIMs from the Swedish National Board of Health and Welfare were applied and bivariate logistic regression analysis used to assess for associations with demographic variables. RESULTS: The median age was 82 years (range 12-105 years, 59% female). A total of 1977 PIMs were identified affecting 57.8% of patients. A quarter of patients were prescribed >=10 medications and 43% had a prescription containing at least one clinically significant drug-drug interaction (DDI). Ten drug groups accounted for 76% of all DDIs. A significant increase in the risk for at least one PIM was associated with female sex (for all indicators of PIM use), age <80 years (three or more psychotropic medicines [OR 5.88, 2.96-11.70, P < 0.001]) and lower socioeconomic status (prescription of >=10 medications [OR: 1.43, 95% CI: 1.16-1.78], prescription of a long-acting benzodiazepine [OR: 1.84, CI: 1.14-2.98]). CONCLUSIONS: MCA use is associated with a significant incidence of PIMs particularly affecting those younger than 80 years and those living in deprived areas. Our findings indicate the need for a more aggressive multidisciplinary approach to the review of the medications prescribed to MCA users. PMID- 28009451 TI - Sonic hedgehog is present in parotid saliva and is decreased in patients with taste dysfunction. AB - PURPOSE: To demonstrate that sonic hedgehog (Shh) is present in human parotid saliva and is decreased in human taste dysfunction. METHODS: Shh was measured in parotid saliva of 27 normal subjects and 81 patients with taste dysfunction of multiple etiologies using a sensitive spectrophotometric ELISA assay. Taste dysfunction was defined clinically both by subjective decreases of taste acuity and flavor perception and by impaired gustometry. RESULTS: Shh was found in parotid saliva of both normal subjects and patients with taste dysfunction. Levels were significantly lower in patients than in normal subjects. Both subjective loss of taste acuity and flavor perception and impaired gustometry was measured in untreated patients. CONCLUSIONS: This is the first demonstration of Shh in human saliva. As Shh has been related to taste bud growth and development, its presence in saliva is consistent with its role as a cell signaling moiety involved with stimulation of taste bud stem cells to generate taste receptors. Decreased saliva Shh secretion can be considered a marker of taste dysfunction in patients with multiple pathologies for their dysfunction. PMID- 28009452 TI - Metabolic profiles revealed synergistically antidepressant effects of lilies and Rhizoma Anemarrhenae in a rat model of depression. AB - Depression is a major cause of illness and disability. We applied untargeted metabolomics using mass spectrometry to identify metabolic signatures associated with depression in serum and explored the antidepressant effects of lilies and Rhizoma Anemarrhenae on an experimental model of chronic unpredictable mild stress (CUMS). Meanwhile metabolomics based on UHPLC-Q-TOF-MS was used to study the change in metabolites in CUMS rat serum and to evaluate the effects of Rhizoma Anemarrhenae and lilies (alone and in combination). Partial least squares discriminant analysis identified 30 metabolites as decisive marker compounds that discriminated the CUMS rats and the control rats. The majority of these metabolites were involved in amino acid metabolism, the tricarboxylic acid cycle, and phosphoglyceride metabolism. The reliability of the metabolites was evaluated by the administration of lilies, Rhizoma Anemarrhenae, fluoxetine and the combination of lilies and Rhizoma Anemarrhenae to the CUMS rats. Behavior studies demonstrated that treatment with the combination of lilies and Rhizoma Anemarrhenae resulted in optimal antidepressant effects. The combination treatment was almost as effective as fluoxetine. Our results suggest that lilies and Rhizoma Anemarrhenae demonstrate synergistically antidepressant effects in CUMS via the regulation of multiple metabolic pathways. These findings provide insight into the pathophysiological mechanisms underlying CUMS and suggest innovative and effective treatments for this disorder. PMID- 28009453 TI - Reassigning stop codons via translation termination: How a few eukaryotes broke the dogma. AB - The genetic code determines how amino acids are encoded within mRNA. It is universal among the vast majority of organisms, although several exceptions are known. Variant genetic codes are found in ciliates, mitochondria, and numerous other organisms. All revealed genetic codes (standard and variant) have at least one codon encoding a translation stop signal. However, recently two new genetic codes with a reassignment of all three stop codons were revealed in studies examining the protozoa transcriptomes. Here, we discuss this finding and the recent studies of variant genetic codes in eukaryotes. We consider the possible molecular mechanisms allowing the use of certain codons as sense and stop signals simultaneously. The results obtained by studying these amazing organisms represent a new and exciting insight into the mechanism of stop codon decoding in eukaryotes. Also see the video abstract here. PMID- 28009454 TI - Direct estimation for adaptive treatment length policies: Methods and application to evaluating the effect of delayed PEG insertion. AB - Dysphagia is a primary cause of death among patients diagnosed with amyotrophic lateral sclerosis (ALS), and percutaneous endoscopic gastrostomy (PEG) is a procedure to insert a tube into the stomach to assist or replace oral feeding. It is believed that PEG is beneficial and, generally, earlier insertion is preferable to later. However, gathering clinical evidence to support these beliefs on the use and timing of PEG is challenging because controlled clinical trials are not feasible and clinical endpoints are confounded with PEG in observational data. Moreover, the confounders are time-varying and time to PEG insertion may be only partially observed. We show how one can view this problem as an adaptive treatment length policy and propose a new estimator via g computation. We show that our estimator is consistent and asymptotically normal for the causal estimand and explore its finite sample properties in simulation studies. Finally, using more than 10 years of data from Emory ALS clinic registry, we found no evidence to suggest that earlier PEG reduced 4-year mortality; thus, our results do not support the hypothesis and belief that initiating palliative care earlier extends life, on average. At the same, we cannot be certain that all important confounding variables are collected and observed to ensure our modeling assumptions are correct, so more work is needed to address these important end-of-life questions for ALS patients. PMID- 28009455 TI - Emission rates and the personal cloud effect associated with particle release from the perihuman environment. AB - Inhalation exposure to elevated particulate matter levels is correlated with deleterious health and well-being outcomes. Despite growing evidence that identifies humans as sources of coarse airborne particles, the extent to which personal exposures are influenced by particle releases near occupants is unknown. In a controlled chamber, we monitored airborne total particle levels with high temporal and particle-size resolution for a range of simulated occupant activities. We also sampled directly from the subject's breathing zone to characterize exposures. A material-balance model showed that a sitting occupant released 8 million particles/h in the diameter range 1-10 MUm. Elevated emissions were associated with increased intensity of upper body movements and with walking. Emissions were correlated with exposure, but not linearly. The personal PM10 exposure increment above the room-average levels was 1.6-13 MUg/m3 during sitting, owing to spatial heterogeneity of particulate matter concentrations, a feature that was absent during walking. The personal cloud was more discernible among larger particles, as would be expected for shedding from skin and clothing. Manipulating papers and clothing fabric was a strong source of airborne particles. An increase in personal exposure was observed owing to particle mass exchange associated with a second room occupant. PMID- 28009456 TI - The impact of socio-economic factors on treatment choice and mortality in chronic myeloid leukaemia. AB - PURPOSE: To evaluate the influence of socio-economic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML). METHODS: Using information available in population-based Swedish registries, we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2002 and 2012. Apart from internal comparisons, five age-, gender- and region-matched control subjects per patient served as control cohort. Median follow-up time from CML diagnosis was 4.8 years. RESULTS: Among patients with CML, low personal or household income, short education, living alone, poor performance status and high age (>60 years) were significantly associated with an inferior survival (in univariate analyses). However, similar findings were noted also in the matched control group, and in comparisons adjusted for calendar year, age and performance status, socio-economic variables were not significantly associated with CML survival. Meanwhile, both education and income were independently linked to TKI treatment overall and to upfront treatment with second-generation TKIs. CONCLUSIONS: In conclusion, socio-economic conditions were associated with survival in the studied CML cohort but these associations could be explained by differences at baseline. Meanwhile, socio economic conditions appeared to influence treatment choice. PMID- 28009457 TI - Composite Yttrium-Carbonaceous Spheres Templated Multi-Shell YVO4 Hollow Spheres with Superior Upconversion Photoluminescence. AB - Complex oxide YVO4 multi-shell hollow spheres with uniform morphologies and controllable shell numbers are successfully prepared by using a newly developed and general composite yttrium-carbonaceous sphere templated approach. The prominent upconversion luminous intensity of the YVO4 :Yb3+ /Er3+ hollow spheres might be attributed to the enhanced near-infrared excitation light harvesting efficiency originated from the multiple reflections. PMID- 28009458 TI - Multifunctional Carbon-Based Metal-Free Electrocatalysts for Simultaneous Oxygen Reduction, Oxygen Evolution, and Hydrogen Evolution. AB - Rationally designed N, S co-doped graphitic sheets with stereoscopic holes (SHG) act as effective tri-functional catalysts for the oxygen reduction reaction, hydrogen evolution reaction, and oxygen evolution reaction, simultaneously. The multifunctional electrocatalytic activities originate from a synergistic effect of the N, S heteroatom doping and unique SHG architecture, which provide a large surface area and efficient pathways for electron and electrolyte/reactant transports. PMID- 28009459 TI - Efficient Generation of Long-Lived Triplet Excitons in 2D Hybrid Perovskite. AB - Triplet excitons form in quasi-2D hybrid inorganic-organic perovskites and diffuse over 100 nm before radiating with >11% photoluminescence quantum efficiency (PLQE) at low temperatures. PMID- 28009460 TI - Surface-Driven Magnetotransport in Perovskite Nanocrystals. AB - Unique insights into magnetotransport in 20 nm ligand-free La0.67 Sr0.33 MnO3 perovskite nanocrystals of nearly perfect crystalline quality reveal a chemically altered 0.8 nm thick surface layer that triggers exceptionally large magnetoresistance at low temperature, independently of the spin polarization of the ferromagnetic core. This discovery shows how the nanoscale impacts magnetotransport in a material widely spread as electrode in hybrid spintronic devices. PMID- 28009461 TI - Multistaged Nanovaccines Based on Porous Silicon@Acetalated Dextran@Cancer Cell Membrane for Cancer Immunotherapy. AB - Immunoadjuvant porous silicon (PSi)-based nanovaccines are prepared by nanoprecipitation in a glass capillary microfluidics device. Vesicles, derived from cancer cell membranes encapsulating thermally oxidized PSi nanoparticles or PSi-polymer nanosystems binding a model antigen, are biocompatible over a wide range of concentrations, and show immunostimulant properties in human cells, promoting the expression of co-stimulatory signals and the secretion of pro inflammatory cytokines. PMID- 28009462 TI - Green-Light-Emitting Diodes based on Tetrabromide Manganese(II) Complex through Solution Process. AB - Highly phosphorescent (Ph4 P)2 [MnBr4 ] as a low-cost and environmentally benign emitting material achieves peak current efficiency of 25.4 cd A-1 and external quantum efficiency (EQE) of 7.2% for nondoped organic light-emitting diodes, and peak current efficiency of 32.0 cd A-1 and EQE of 9.6% for doped devices with 20% (Ph4 P)2 [MnBr4 ]:27% TCTA:53% 6DCZPPY as a doping emitting layer. PMID- 28009463 TI - Nanosheets of an Organic Molecular Assembly from Aqueous Medium Exhibit High Solid-State Emission and Anisotropic Charge-Carrier Mobility. AB - A pi-conjugated amphiphilic diketopyrrolopyrrole (PDPP-Amphi) forms crystalline 2D supramolecular nanosheets in water when compared to that from methyl cyclohexane. These nanosheets exhibit high fluorescence quantum yield in the solid-state with anisotropic charge-carrier mobility of 0.33 cm2 V-1 s-1 . PMID- 28009464 TI - Effect of Melanotan-II on Brain Fos Immunoreactivity and Oxytocin Neuronal Activity and Secretion in Rats. AB - Melanocortins stimulate the central oxytocin systems that are involved in regulating social behaviours. Alterations in central oxytocin have been linked to neurological disorders such as autism, and melanocortins have been proposed for therapeutic treatment. In the present study, we investigated how systemic administration of melanotan-II (MT-II), a melanocortin agonist, affects oxytocin neuronal activity and secretion in rats. The results obtained show that i.v., but not intranasal, administration of MT-II markedly induced Fos expression in magnocellular neurones of the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, and this response was attenuated by prior i.c.v. administration of the melanocortin antagonist, SHU-9119. Electrophysiological recordings from identified magnocellular neurones of the SON showed that i.v. administration of MT-II increased the firing rate in oxytocin neurones but did not trigger somatodendritic oxytocin release within the SON as measured by microdialysis. Our data suggest that, after i.v., but not intranasal, administration of MT-II, the activity of magnocellular neurones of the SON is increased. Because previous studies showed that SON oxytocin neurones are inhibited in response to direct application of melanocortin agonists, the actions of i.v. MT-II are likely to be mediated at least partly indirectly, possibly by activation of inputs from the caudal brainstem, where MT-II also increased Fos expression. PMID- 28009465 TI - Direct Synthesis of Graphdiyne Nanowalls on Arbitrary Substrates and Its Application for Photoelectrochemical Water Splitting Cell. AB - A general and simple route to fabricate graphdiyne nanowalls on arbitrary substrates is developed by using a copper envelope catalysis strategy. The GDY/BiVO4 system is but one example of combing the unique properites of GDY with those target substrates where GDY improves the photoelectrochemical performance dramatically. PMID- 28009466 TI - Clinical characteristics of urethral prolapse in Japanese children. AB - BACKGROUND: Urethral prolapse (UP) in children is a rare condition and has commonly been reported in black girls. The aim of this study was to clarify the status of medical management for UP in Japanese children. METHODS: A secondary data analysis was conducted in Japanese children <=15 years old with UP. The relationship between initial treatment approach and outcome was investigated, with symptom persistence or recurrence defined as treatment failure. RESULTS: Of 77 cases of UP in Japanese children reported since 1972, initial surgical treatment was performed in 42 cases (55%) and non-surgical treatment in 35 cases (45%). Underlying conditions constituting possible causative factors were present in 26 cases (34%) in total. Treatment outcome was evaluated in 59 cases (surgical treatment, n = 28; non-surgical treatment, n = 31) during a median follow-up period of 10 months. The rate of treatment failure was significantly higher in the non-surgical (81%, 25/31) than in the surgical treatment group (18%, 5/28; risk ratio, 4.2; 95%CI: 2.0-8.9; P < 0.001). Topical estrogen cream, a standard management worldwide, is not available as a prescription drug in Japan, and therefore was able to be used in only seven cases (20%) in the non-surgical treatment group. CONCLUSIONS: Surgical treatment is more effective than non surgical treatment in Japanese children, but both failure rates are high compared with that in non-Asian children. Drug approval revision for prescription use of estrogen cream, centralizing treatment to specialized facilities, and an active policy of surgical management in cases of non-surgical treatment failure may improve treatment outcomes for pediatric UP in Japan. PMID- 28009467 TI - Internet-based cognitive behavior therapy for major depressive disorder: A randomized controlled trial. AB - BACKGROUND: Prior research has shown that the Sadness Program, a technician assisted Internet-based cognitive behavioral therapy (iCBT) intervention developed in Australia, is effective for treating major depressive disorder (MDD). The current study aimed to expand this work by adapting the protocol for an American population and testing the Sadness Program with an attention control group. METHODS: In this parallel-group, randomized controlled trial, adult MDD participants (18-45 years) were randomized to a 10-week period of iCBT (n = 37) or monitored attention control (MAC; n = 40). Participants in the iCBT group completed six online therapy lessons, which included access to content summaries and homework assignments. During the 10-week trial, iCBT and MAC participants logged into the web-based system six times to complete self-report symptom scales, and a nonclinician technician contacted participants weekly to provide encouragement and support. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), and the secondary outcomes were the Patient Health Questionnaire-9 and Kessler-10. RESULTS: Intent-to-treat analyses revealed significantly greater reductions in depressive symptoms in iCBT compared with MAC participants, using both the self-report measures and the clinician-rated HRSD (d = -0.80). Importantly, iCBT participants also showed significantly higher rates of clinical response and remission. Exploratory analyses did not support illness severity as a moderator of treatment outcome. CONCLUSIONS: The Sadness Program led to significant reductions in depression and distress symptoms. With its potential to be delivered in a scalable, cost-efficient manner, iCBT is a promising strategy to enhance access to effective care. PMID- 28009468 TI - Simultaneous automatic scoring and co-registration of hormone receptors in tumor areas in whole slide images of breast cancer tissue slides. AB - Automation of downstream analysis may offer many potential benefits to routine histopathology. One area of interest for automation is in the scoring of multiple immunohistochemical markers to predict the patient's response to targeted therapies. Automated serial slide analysis of this kind requires robust registration to identify common tissue regions across sections. We present an automated method for co-localized scoring of Estrogen Receptor and Progesterone Receptor (ER/PR) in breast cancer core biopsies using whole slide images. Regions of tumor in a series of fifty consecutive breast core biopsies were identified by annotation on H&E whole slide images. Sequentially cut immunohistochemical stained sections were scored manually, before being digitally scanned and then exported into JPEG 2000 format. A two-stage registration process was performed to identify the annotated regions of interest in the immunohistochemistry sections, which were then scored using the Allred system. Overall correlation between manual and automated scoring for ER and PR was 0.944 and 0.883, respectively, with 90% of ER and 80% of PR scores within in one point or less of agreement. This proof of principle study indicates slide registration can be used as a basis for automation of the downstream analysis for clinically relevant biomarkers in the majority of cases. The approach is likely to be improved by implantation of safeguarding analysis steps post registration. (c) 2016 International Society for Advancement of Cytometry. PMID- 28009469 TI - Large-Scale Quantum Many-Body Perturbation on Spin and Charge Separation in the Excited States of the Synthesized Donor-Acceptor Hybrid PBI-Macrocycle Complex. AB - The reliable calculation of the excited states of charge-transfer (CT) compounds poses a major challenge to the ab initio community because the frequently employed method, time-dependent density functional theory (TD-DFT), massively relies on the underlying density functional, resulting in heavily Hartree-Fock (HF) exchange-dependent excited-state energies. By applying the highly sophisticated many-body perturbation approach, we address the encountered unreliabilities and inconsistencies of not optimally tuned (standard) TD-DFT regarding photo-excited CT phenomena, and present results concerning accurate vertical transition energies and the correct energetic ordering of the CT and the first visible singlet state of a recently synthesized thermodynamically stable large hybrid perylene bisimide-macrocycle complex. This is a large-scale application of the quantum many-body perturbation approach to a chemically relevant CT system, demonstrating the system-size independence of the quality of the many-body-based excitation energies. Furthermore, an optimal tuning of the omegaB97X hybrid functional can well reproduce the many-body results, making TD DFT a suitable choice but at the expense of introducing a range-separation parameter, which needs to be optimally tuned. PMID- 28009470 TI - Proportion of circulating tumor cell clusters increases during cancer metastasis. AB - Circulating tumor cell (CTC) clusters are found among CTCs and show significantly greater potential for an important role in cancer metastasis than single CTCs, which have been traditionally believed as the majority of CTCs. The accurate proportion and dynamics of CTC clusters remain unclear due to the fact that CTCs in blood flow are very difficult to detect in vivo and in vitro. CTC clusters are even more difficult to be distinguished from CTCs without perturbation by state of-the-art detection methods. Here, we demonstrate that by using in vivo flow cytometry (IVFC), we can reliably measure the proportion and dynamics of CTC clusters in two murine tumor models. CTC clusters are easily identified by their unique fluorescent pattern with multiple peaks and wider time duration. We find that the proportion of CTC clusters increases significantly during cancer metastasis in both mouse models, the orthotopic liver cancer and the subcutaneous prostate cancer models. Our results suggest that CTC clusters account for a much larger proportion of CTCs than previously anticipated. Hence this report might provide a new-level of understanding of CTCs during cancer development and progression. (c) 2016 International Society for Advancement of Cytometry. PMID- 28009471 TI - Interference of Steroidogenesis by Gold Nanorod Core/Silver Shell Nanostructures: Implications for Reproductive Toxicity of Silver Nanomaterials. AB - As a widely used nanomaterial in daily life, silver nanomaterials may cause great concern to female reproductive system as they are found to penetrate the blood placental barrier and gain access to the ovary. However, it is largely unknown about how silver nanomaterials influence ovarian physiology and functions such as hormone production. This study performs in vitro toxicology study of silver nanomaterials, focusing especially on cytotoxicity and steroidogenesis and explores their underlying mechanisms. This study exposes primary rat granulosa cells to gold nanorod core/silver shell nanostructures (Au@Ag NRs), and compares outcomes with cells exposed to gold nanorods. The Au@Ag NRs generate more reactive oxygen species and reduce mitochondrial membrane potential and less production of adenosine triphosphate. Au@Ag NRs promote steroidogenesis, including progesterone and estradiol, in a time- and dose-dependent manner. Chemical reactivity and transformation of Au@Ag NRs are then studied by electron spin resonance spectroscopy and X-ray absorption near edge structure, which analyze the generation of free radical and intracellular silver species. Results suggest that both particle-specific activity and intracellular silver ion release of Au@Ag NR contribute to the toxic response of granulosa cells. PMID- 28009472 TI - Effects on alpha- and beta-cell function of sequentially adding empagliflozin and linagliptin to therapy in people with type 2 diabetes previously receiving metformin: An exploratory mechanistic study. AB - AIMS: To investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of alpha- and beta-cell function in people with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy. RESEARCH DESIGN AND METHODS: A total of 44 people with T2DM received 25 mg empagliflozin for a duration of 1 month in an open-label fashion (treatment period 1 [TP1]). Thereafter, they were randomized to a double blind add-on therapy with linagliptin 5 mg or placebo (treatment period 2 [TP2]) for 1 additional month. alpha- and beta-cell function was assessed using a standardized liquid meal test and an intravenous (i.v.) glucose challenge. Efficacy measures comprised the areas under the curve for glucose, insulin, proinsulin and glucagon after the liquid meal test and the assessment of fast and late-phase insulin release after an i.v. glucose load with a subsequent hyperglycaemic clamp. RESULTS: Empagliflozin reduced fasting and postprandial plasma glucose levels, associated with a significant reduction in postprandial insulin levels and an improvement in the conversion rate of proinsulin (TP1). The addition of linagliptin during TP2 further improved postprandial glucose levels, probably as a result of a marked reduction in postprandial glucagon concentrations (TP2). The insulin response to an i.v. glucose load increased during treatment with empagliflozin (TP1), and further improved after the addition of linagliptin (TP2). CONCLUSION: After metformin failure, sequential treatment escalation with empagliflozin and linagliptin is an attractive treatment option because of the additive effects on postprandial glucose control, probably mediated by complementary effects on alpha- and beta-cell function. PMID- 28009474 TI - Prostaglandin use is associated with increased vascular endothelial growth factor in the aqueous humor of glaucoma patients. PMID- 28009473 TI - Temporal discounting across three psychiatric disorders: Anorexia nervosa, obsessive compulsive disorder, and social anxiety disorder. AB - BACKGROUND: Temporal discounting refers to the tendency for rewards to lose value as the expected delay to receipt increases. Individuals with anorexia nervosa (AN) have been found to show reduced temporal discounting rates, indicating a greater preference for delayed rewards compared to healthy peers. Obsessive compulsive disorder (OCD) and social anxiety disorder (SAD) commonly co-occur with AN, and anxiety has been related to development and prognosis of AN. We examined whether reduced temporal discounting is present across these potentially related disorders, and explored the relationship between temporal discounting and anxiety transdiagnostically. METHODS: One hundred ninety six individuals (75 healthy controls (HC); 50 OCD; 27 AN; 44 SAD) completed two temporal discounting tasks in which they chose between smaller-sooner and larger-later monetary rewards. Two measures of discounting-discount rate and discount factor-were compared between diagnostic groups, and associations with anxious traits were examined. RESULTS: Individuals with AN showed decreased temporal discounting compared to HC. OCD and SAD groups did not differ significantly from HC. Across the sample, anxiety was associated with decreased discounting; more anxious individuals showed a greater preference for delayed reward. CONCLUSIONS: We replicated the findings that individuals with AN show an increased preference for delayed reward relative to HC and that individuals with OCD do not differ from HC. We also showed that individuals with SAD do not differ from HC in discounting. Across this large sample, two measures of anxious temperament were associated with temporal discounting. These data raise new questions about the relationship between this dimensional trait and psychopathology. PMID- 28009475 TI - Reactivation of Latent HPV Infections After Renal Transplantation. AB - Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)-related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs. PMID- 28009477 TI - Sequential Introduction of Cations Deriving Large-Grain Csx FA1-x PbI3 Thin Film for Planar Hybrid Solar Cells: Insight into Phase-Segregation and Thermal-Healing Behavior. AB - Composition engineering of perovskite materials has been demonstrated to be important for high-performance solar cells. Recently, the energy favorable hybridization of formamidinium (FA) and cesium (Cs) in three dimension lead halide perovskites has been attracting increasing attention due to its potential benefit on durability. Herein, we reported a simple and effective method to produce phase-pure CsxFA1-xPbI3 thin film via sequential introduction of cations, in which the FA cation was introduced by interdiffusion annealing in the presence of N-methylimidazole (NMI). NMI was employed as an additive to slow down the crystallization and thus drive the formation of CsxFA1-xPbI3 with micrometer grain size, which probably facilitate the charge dissociation and transportation in photovoltaic devices. More importantly, composition dependent phase segregation has been revealed and investigated for the first time during the phase-pure mixed-cation perovskites CsxFA1-xPbI3. The present findings demonstrated that suppressing phase-segregation of mixed-cation perovskites by meticulous composition engineering is significant for further development of efficient photovoltaics. It also suggested that phase-pure Cs0.15FA0.85PbI3 may be a promising candidate with superior phase-durability, which performed an efficiency over 16% in planar perovskite solar cells. PMID- 28009476 TI - Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation. AB - One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection. PMID- 28009478 TI - Local Effects on Airway Inflammation and Systemic Uptake of 5 nm PEGylated and Citrated Gold Nanoparticles in Asthmatic Mice. AB - Nanotechnology is showing promise in many medical applications such as drug delivery and hyperthermia. Nanoparticles administered to the respiratory tract cause local reactions and cross the blood-air barrier, thereby providing a means for easy systemic administration but also a potential source of toxicity. Little is known about how these effects are influenced by preexisting airway diseases such as asthma. Here, BALB/c mice are treated according to the ovalbumin (OVA) asthma protocol to promote allergic airway inflammation. Dispersions of polyethylene-glycol-coated (PEGylated) and citrate/tannic-acid-coated (citrated) 5 nm gold nanoparticles are applied intranasally to asthma and control groups, and (i) airway resistance and (ii) local tissue effects are measured as primary endpoints. Further, nanoparticle uptake into extrapulmonary organs is quantified by inductively coupled plasma mass spectrometry. The asthmatic precondition increases nanoparticle uptake. Moreover, systemic uptake is higher for PEGylated gold nanoparticles compared to citrated nanoparticles. Nanoparticles inhibit both inflammatory infiltrates and airway hyperreactivity, especially citrated gold nanoparticles. Although the antiinflammatory effects of gold nanoparticles might be of therapeutic benefit, systemic uptake and consequent adverse effects must be considered when designing and testing nanoparticle-based asthma therapies. PMID- 28009479 TI - How phylogeny and foraging ecology drive the level of chemosensory exploration in lizards and snakes. AB - The chemical senses are crucial for squamates (lizards and snakes). The extent to which squamates utilize their chemosensory system, however, varies greatly among taxa and species' foraging strategies, and played an influential role in squamate evolution. In lizards, 'Scleroglossa' evolved a state where species use chemical cues to search for food (active foragers), whereas 'Iguania' retained the use of vision to hunt prey (ambush foragers). However, such strict dichotomy is flawed as shifts in foraging modes have occurred in all clades. Here, we attempted to disentangle effects of foraging ecology from phylogenetic trait conservatism as leading cause of the disparity in chemosensory investment among squamates. To do so, we used species' tongue-flick rate (TFR) in the absence of ecological relevant chemical stimuli as a proxy for its fundamental level of chemosensory investigation, that is baseline TFR. Based on literature data of nearly 100 species and using phylogenetic comparative methods, we tested whether and how foraging mode and diet affect baseline TFR. Our results show that baseline TFR is higher in active than ambush foragers. Although baseline TFRs appear phylogenetically stable in some lizard taxa, that is a consequence of concordant stability of foraging mode: when foraging mode shifts within taxa, so does baseline TFR. Also, baseline TFR is a good predictor of prey chemical discriminatory ability, as we established a strong positive relationship between baseline TFR and TFR in response to prey. Baseline TFR is unrelated to diet. Essentially, foraging mode, not phylogenetic relatedness, drives convergent evolution of similar levels of squamate chemosensory investigation. PMID- 28009480 TI - A Transparent, Self-Healing, Highly Stretchable Ionic Conductor. AB - Self-healing materials can repair damage caused by mechanical wear, thereby extending lifetime of devices. A transparent, self-healing, highly stretchable ionic conductor is presented that autonomously heals after experiencing severe mechanical damage. The design of this self-healing polymer uses ion-dipole interactions as the dynamic motif. The unique properties of this material when used to electrically activate transparent artificial muscles are demonstrated. PMID- 28009482 TI - Functional specialization of Nicotiana attenuata phytochromes in leaf development and flowering time. AB - Phytochromes mainly function in photoautotrophic organisms to adjust growth in response to fluctuating light signals. The different isoforms of plant phytochromes often display both conserved and divergent roles, presumably to fine tune plant responses to environmental signals and optimize fitness. Here we describe the distinct, yet partially redundant, roles of phytochromes NaPHYA, NaPHYB1 and NaPHYB2 in a wild tobacco species, Nicotiana attenuata using RNAi silenced phytochrome lines. Consistent with results reported from other species, silencing the expression of NaPHYA or NaPHYB2 in N. attenuata had mild or no influence on plant development as long as NaPHYB1 was functional; whereas silencing the expression of NaPHYB1 alone strongly altered flowering time and leaf morphology. The contribution of NaPHYB2 became significant only in the absence of NaPHYB1; plants silenced for both NaPHYB1 and NaPHYB2 largely skipped the rosette-stage of growth to rapidly produce long, slender stalks that bore flowers early: hallmarks of the shade-avoidance responses. The phenotyping of phytochrome-silenced lines, combined with sequence and transcript accumulation analysis, suggest the independent functional diversification of the phytochromes, and a dominant role of NaPHYB1 and NaPHYB2 in N. attenuata's vegetative and reproductive development. PMID- 28009481 TI - Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells. AB - Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4 3.6 * 106 /kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen. PMID- 28009483 TI - The precise regulation of different COR genes by individual CBF transcription factors in Arabidopsis thaliana. AB - The transcription factors CBF1/2/3 are reported to play a dominant role in the cold responsive network of Arabidopsis by directly regulating the expression levels of cold responsive (COR) genes. In this study, we obtained CRISPR/Cas9 mediated loss-of-function mutants of cbf1~3. Over 3,000 COR genes identified by RNA-seq analysis showed a slight but significant change in their expression levels in the mutants compared to the wild-type plants after being treated at 4 degrees C for 12 h. The C-repeat (CRT) motif (5'-CCGAC-3') was enriched in promoters of genes that were up-regulated by CBF2 and CBF3 but not in promoters of genes up-regulated by CBF1. These data suggest that CBF2 and CBF3 play a more important role in directing the cold response by regulating different sets of downstream COR genes. More than 2/3 of COR genes were co-regulated by two or three CBFs and were involved mainly in cellular signal transduction and metabolic processes; less than 1/3 of the genes were regulated by one CBF, and those genes up-regulated were enriched in cold-related abiotic stress responses. Our results indicate that CBFs play an important role in the trade-off between cold tolerance and plant growth through the precise regulation of COR genes in the complicated transcriptional network. PMID- 28009484 TI - HSP90 inhibition suppresses inflammatory response and reduces carotid atherosclerotic plaque formation in ApoE mice. AB - AIM: Emerging evidences indicate that heat-shock protein 90 (HSP90) is associated with atherogenesis. However, the effect of HSP90 on plaque stability is largely unknown. In this study, we explored the role of HSP90 in plaque development and its regulatory mechanisms on vasculature. METHODS: Heat-shock protein90 overexpression lentivirus (Lenti-HSP90) was used to transfect apoE-/- mice after constrictive collars were planted at the right common carotid arteries. RESULTS: As a result, HSP90 gene overexpression led to reduction in en face plaque area and increase in unstable plaque with heavier accumulation of lipids. Concomitantly, more macrophages, less smooth muscle cells, and collagen were generated, suggesting aggravated inflammation. However, inhibition of HSP90 with 17-AAG, a HSP90-inhibitor, induced opposing effects. Moreover, HSP90 upregulated plaque MMP-8, which might be the underlying mechanism of the change in plaque vulnerability index. Further, the translocation of NF-kappaB was promoted by HSP90, while inhibition of NF-kappaB significantly reduced MMP-8 production, which is upregulated by HSP90. CONCLUSIONS: These findings suggested that HSP90 governs plaque development and vulnerability, as well as inflammation, at least in part via MMP-8 and NF-kappaB signaling pathways. PMID- 28009485 TI - Heterogeneity and concordance in locus-specific differentiation and introgression between species of towhees. AB - The maintenance or breakdown of reproductive isolation is an observable outcome of secondary contact between species. In cases where hybrids beyond the F1 are formed, the representation of each species' ancestry can vary dramatically among genomic regions. This genomic heterogeneity in ancestry and introgression can offer insight into evolutionary processes, particularly if introgression is compared in multiple hybrid zones. Similarly, considerable heterogeneity exists across the genome in the extent to which populations and species have diverged, reflecting the combined effects of different evolutionary processes on genetic variation. We studied hybridization across two hybrid zones of two phenotypically well-differentiated bird species in Mexico (Pipilo maculatus and P. ocai), to investigate genomic heterogeneity in differentiation and introgression. Using genotyping-by-sequencing (GBS) and hierarchical Bayesian models, we genotyped 460 birds at over 41 000 single nucleotide polymorphism (SNP) loci. We identified loci exhibiting extreme introgression relative to the genome-wide expectation using a Bayesian genomic cline model. We also estimated locus-specific FST and identified loci with exceptionally high genetic divergence between the parental species. We found some concordance of locus-specific introgression in the two independent hybrid zones (6-20% of extreme loci shared across zones), reflecting areas of the genome that experience similar gene flow when the species interact. Additionally, heterogeneity in introgression and divergence across the genome revealed another subset of loci under the influence of locally specific factors. These results are consistent with a history in which reproductive isolation has been influenced by a common set of loci in both hybrid zones, but where local environmental and stochastic factors also lead to genomic differentiation. PMID- 28009486 TI - Vascular hyperpolarization in human physiology and cardiovascular risk conditions and disease. AB - Hyperpolarization causing smooth muscle relaxation contributes to the maintenance of vascular homeostasis, particularly in small-calibre arteries and arterioles. It may also become a compensatory vasodilator mechanism upregulated in states with impaired nitric oxide (NO) availability. Bioassay of vascular hyperpolarization in the human circulation has been hampered by the complexity of mechanisms involved and the limited availability of investigational tools. Firm evidence, however, supports the notion that hyperpolarization participates in the regulation of resting vasodilator tone and vascular reactivity in healthy subjects. In addition, an enhanced endothelium-derived hyperpolarization contributes to both resting and agonist-stimulated vasodilation in a variety of cardiovascular risk conditions and disease. Thus, hyperpolarization mediated by epoxyeicosatrienoic acids (EETs) and H2 O2 has been observed in coronary arterioles of patients with coronary artery disease. Similarly, ouabain-sensitive and EETs-mediated hyperpolarization has been observed to compensate for NO deficiency in patients with essential hypertension. Moreover, in non-hypertensive patients with multiple cardiovascular risk factors and in hypercholesterolaemia, KCa channel-mediated vasodilation appears to be activated. A novel paradigm establishes that perivascular adipose tissue (PVAT) is an additional regulator of vascular tone/function and endothelium is not the only agent in vascular hyperpolarization. Indeed, some PVAT-derived relaxing substances, such as adiponectin and angiotensin 1-7, may exert anticontractile and vasodilator actions by the opening of KCa channels in smooth muscle cells. Conversely, PVAT derived factors impair coronary vasodilation via differential inhibition of some K+ channels. In view of adipose tissue abnormalities occurring in human obesity, changes in PVAT-dependent hyperpolarization may be relevant for vascular dysfunction also in this condition. PMID- 28009487 TI - Implementation and modification of an anatomy-based integrated curriculum. AB - Morehouse School of Medicine elected to restructure its first-year medical curriculum by transitioning from a discipline-based to an integrated program. The anatomy course, with regional dissection at its core, served as the backbone for this integration by weaving the content from prior traditional courses into the curriculum around the anatomy topics. There were four primary goals for this restructuring process. Goal 1: develop new integrated courses. Course boundaries were established at locations where logical breaks in anatomy content occurred. Four new courses were created, each containing integrated subject content. Goal 2: establish a curriculum management team. The team consisted of course directors, subject specialists, and a curriculum director. This team worked together to efficiently manage the new curriculum. Goal 3: launch contemporary examination and question banking methods. An electronic system, in which images could be included, was implemented for examinations and quizzes, and for storing and refining questions. Goal 4: ensure equitable distribution of standardized examinations and course grading systems among all courses. Assessments included quizzes, in-course examinations, and National Board of Medical Examiners(r) (NBME(r) ) Subject Examinations. A standard plan assigned the contribution of each to the final course grade. Significant improvement was seen on subject examinations. Once the obstacles and challenges of integration were overcome, a robust and efficient education program was developed. The curriculum is expected to continue evolving and improving, while retaining full regional dissection as a core element. Anat Sci Educ 10: 262-275. (c) 2016 American Association of Anatomists. PMID- 28009489 TI - Effects of Orchidectomy and Testosterone Replacement on Numbers of Kisspeptin-, Neurokinin B-, and Dynorphin A-Immunoreactive Neurones in the Arcuate Nucleus of the Hypothalamus in Obese and Diabetic Rats. AB - Neurones expressing kisspeptin, neurokinin B and dynorphin A, located in the arcuate nucleus of the hypothalamus (ARC), are important regulators of reproduction. Their functions depend on metabolic and hormonal status. We hypothesised that male rats with high-fat diet-induced obesity (DIO) and/or streptozotocin-induced diabetes mellitus type 1 (DM1) and type 2 (DM2) will have alterations in numbers of immunoreactive (-IR) cells: kisspeptin-IR and/or neurokinin B-IR and dynorphin A-IR neurones in the ARC in the sham condition. In addition, orchidectomy alone (ORX) and with testosterone treatment (ORX+T) will unmask possible deficits in the response of these neurones in DIO, and/or DM1 and DM2 rats. Rats were assigned to four groups: a control (C) and one diabetic group (DM1) were fed a regular chow diet, whereas the obese group (DIO) and the other diabetic group (DM2) were fed a high-fat diet. To induce diabetes, streptozotocin was injected. After 6 weeks, each group was divided into three subgroups: ORX, ORX+T and sham. After another 2 weeks, metabolic and hormonal profiles were assessed and immunocytochemistry was performed. We found that: (1) under sham conditions: (i) DM1 and DM2 animals had higher numbers of kisspeptin-IR cells than controls and (ii) DM2 rats had increased numbers of neurokinin B-IR and dynorphin A-IR cells compared to C animals; (2) ORX and ORX+T treatments unmasked deficits of the studied neurones in DM1 and DM2 but not in DIO animals; and (3) DIO, DM1 and DM2 rats had altered metabolic and hormonal profiles, in particular decreased levels of testosterone. We concluded that alterations in numbers of kisspeptin-IR and neurokinin B-IR neurones in the ARC and their response to ORX and ORX+T may account for disruptions of metabolic and reproductive functions in diabetic but not in obese rats. PMID- 28009488 TI - Chronic infections with viruses or parasites: breaking bad to make good. AB - Eukaryotic forms of life have been continually invaded by microbes and larger multicellular parasites, such as helminths. Over a billion years ago bacterial endosymbionts permanently colonized eukaryotic cells leading to recognized organelles with a distinct genetic lineage, such as mitochondria and chloroplasts. Colonization of our skin and mucosal surfaces with bacterial commensals is now known to be important for host health. However, the contribution of chronic virus and parasitic infections to immune homeostasis is being increasingly questioned. Persistent infection does not necessarily equate to exhibiting a chronic illness: healthy hosts (e.g. humans) have chronic viral and parasitic infections with no evidence of disease. Indeed, there are now examples of complex interactions between these microbes and hosts that seem to confer an advantage to the host at a particular time, suggesting that the relationship has progressed along an axis from parasitic to commensal to one of a mutualistic symbiosis. This concept is explored using examples from viruses and parasites, considering how the relationships may be not only detrimental but also beneficial to the human host. PMID- 28009490 TI - Exploring the Chemical Reaction Space at the Formation of Chalcogenidometalate Superspheres in Ionic Liquids. AB - The synthesis of anionic chalcogenidometalate superspheres can be achieved from [Ge4 Se10 ]4- salts and SnCl4 in ionic liquids with 1-alkyl-(2,)3 (di)methylimidazolium cations, denoted as (Cn (C1 )C1 Im)+ (alkyl = butyl for n=4, hexyl for n=6, octyl for n=8). Their formation is apparently independent from the lengths of the Cn chain, and the presence or absence of a second methyl group at the ionic liquid cation (that are exchanged for alkali metal cations in precursor compounds during the reactions), although this may appear counterintuitive. In contrast, and equally counterintuitive, the ionic liquid anion was found to play a crucial role for both the general observability as well as the crystal yield and quality of the products, although they are not part of the product: a minimum content of chloride is needed, while ionic liquids with [BF4 ]- anions alone do not support the product formation/crystallization. The observation suggests a subtle equilibrium of SnCl4 with according halidostannate anions that decreases the reactivity of the tin source. The finding is of particular interest, as chloride anions were shown to have been major impurities of former "chloride-free" ionic liquid charges, which potentially led to irreproducible synthesis protocols in the literature. PMID- 28009491 TI - Corrigendum. PMID- 28009492 TI - Phenyl Benzo[b]phenothiazine as a Visible Light Photoredox Catalyst for Metal Free Atom Transfer Radical Polymerization. AB - This paper reports use of phenyl benzo[b]phenothiazine (Ph-benzoPTZ) as a visible light-induced metal-free atom transfer radical polymerization (ATRP) photoredox catalyst. Well-controlled polymerizations of various methacrylate monomers were conducted under a 392 nm visible light LED using Ph-benzoPTZ to activate different alkyl halides. The use of the photocatalyst enabled temporal control over the growth of polymer chains during intermittent on/off periods. The polymerization was initiated and progressed only under stimulation by light and completely stopped in the absence of light. Block copolymers were synthesized to demonstrate high retention of chain end fidelity in the polymers and livingness of the process. PMID- 28009493 TI - Daratumumab and Blood-Compatibility Testing. PMID- 28009494 TI - Andexanet Alfa for Factor Xa Inhibitor Reversal. PMID- 28009495 TI - Andexanet Alfa for Factor Xa Inhibitor Reversal. PMID- 28009496 TI - Andexanet Alfa for Factor Xa Inhibitor Reversal. PMID- 28009497 TI - Screw-Dislocation-Induced Strengthening-Toughening Mechanisms in Complex Layered Materials: The Case Study of Tobermorite. AB - Nanoscale defects such as dislocations have a profound impact on the physics of crystalline materials. Understanding and characterizing the motion of screw dislocation and its corresponding effects on the mechanical properties of complex low-symmetry materials has long been a challenge. Herein, we focus on triclinic tobermorite, as a model system and a crystalline analogue of layered hydrated cement, and report for the first time how the motion of screw dislocation can influence the strengthening-toughening relationship, imparting brittle-to-ductile transitions. By applying shear loading in tobermorite systems with single and dipole screw dislocations, we observe dislocation jogs around the dislocation core, which increases the yield shear stress and the work-of-fracture when the dislocation lines are along the [100] and [010] directions. Our results demonstrate that the dislocation core acts as a bottleneck for the initial straight gliding to induce intralaminar gliding, which consequently leads to a significant improvement in the mechanical properties. Together, the fundamental knowledge gained in this work on the role of the motion of the dislocation core on the mechanical properties provides an improved understanding of deformation mechanisms in cementitious materials and other complex layered systems, providing new hypotheses and design guidelines for the development of strong, ductile, and tough materials. PMID- 28009498 TI - Resonant Gain Singularities in 1D and 3D Metal/Dielectric Multilayered Nanostructures. AB - We present a detailed study on the resonant gain (RG) phenomena occurring in two nanostructures, in which the presence of dielectric singularities is used to reach a huge amplification of the emitted photons resonantly interacting with the system. The presence of gain molecules in the considered nanoresonator systems makes it possible to obtain optical features that are able to unlock several applications. Two noticeable cases have been investigated: a 1D nanoresonator based on hyperbolic metamaterials and a 3D metal/dielectric spherical multishell. The former has been designed in the framework of the effective medium theory, in order to behave as an epsilon-near-zero-and-pole metamaterial, showing extraordinary light confinement and collimation. Such a peculiarity represents the key to lead to a RG behavior, a condition in which the system is demonstrated to behave as a self-amplifying perfect lens. Very high enhancement and spectral sharpness of 1 nm of the emitted light are demonstrated by means of a transfer matrix method simulation. The latter system consists of a metal/doped-dielectric multishell. A dedicated theoretical approach has been set up to finely engineer its doubly tunable resonant nature. The RG condition has been demonstrated also in this case. Finite element method-based simulations, together with an analytical model, clarify the electric field distribution inside the multishell and suggest the opportunity to use this device as a self-enhanced loss compensated multishell, being a favorable scenario for low-threshold SPASER action. Counterintuitively, exceeding the resonant gain amount of molecules in both systems causes a significant drop in the amplitude of the resonance. PMID- 28009499 TI - Electrochemistry of Corroles in Nonaqueous Media. AB - This review describes the known electrochemistry of corroles in nonaqueous media from 1980 until the present. The outline of the review is grouped according to the periodic table, proceeding from left to right, describing first monomeric free-base derivatives and then transition-metal compounds, followed by main-group corroles, before ending with a brief description of lanthanide and actinide corroles. Many similarities exist between the redox properties of metallocorroles and metalloporphyrins, but there are also many differences due, in part, to the different charges of the two conjugated macrocycles and the noninnocence of the corrole ligand in a variety of compounds. One part of this review will focus on describing redox behavior as a function of metal ion and axial ligands, while another will focus on how changes in structure of the macrocycle are associated with changes in redox behavior. It is hoped that this review will answer the majority of the readers' questions as to what has been electrochemically observed for corroles in the past while at the same time enabling the reader to utilize data in the literature to predict and "tune" what might be observed in future electrochemical studies of corroles that have yet to be synthesized and characterized. PMID- 28009500 TI - Anthropogenic Influences of Paved Runoff and Sanitary Sewage on the Dissolved Organic Matter Quality of Wet Weather Overflows: An Excitation-Emission Matrix Parallel Factor Analysis Assessment. AB - The quality of dissolved organic matter (DOM) in a wet weather overflow (WWF) can be broadly influenced by anthropogenic factors, such as nonpoint sources of paved runoff and point sources of sanitary sewage within the drainage networks. This study focused on the anthropogenic influences of the paved runoff and sanitary sewage on the DOM quality of WWF using excitation-emission matrix parallel factor analysis (EEM-PARAFAC). Results show that (1) EEM-PARAFAC fitted terrestrial humic-like, anthropogenic humic-like, tryptophan-like, and tyrosine-like components can be regarded as indicators to identify the types of sewage overflows and the illicit connection status of drainage systems. (2) A short emission wavelength (em: 302-313 nm) peak of the tyrosine-like component occurred in the reserved sanitary sewage, while a type of longer emission wavelength (em: 321-325 nm) peak came from the sump deposit. These tyrosine-like components were gradually evacuated in the initial phase of the overflow process with the fading of their EEM signals. Fluorescence signal transformations of all the components confirmed the potential ability of EEM-PARAFAC to monitor the dynamic changes of the primary pollutant sources. (3) The input of the newly increased sanitary sewage had a dominant influence on the quality and yield of the WWF DOM. PMID- 28009501 TI - Charges in Hydrophobic Environments: A Strategy for Identifying Alternative States in Proteins. AB - In the V23E variant of staphylococcal nuclease, Glu-23 has a pKa of 7.5. At low pH, Glu-23 is neutral and buried in the hydrophobic interior of the protein. Crystal structures and NMR spectroscopy experiments show that when Glu-23 becomes charged, the protein switches into an open state in which strands beta1 and beta2 separate from the beta-barrel; the remaining structure is unaffected. In the open state the hydrophobic interior of the protein is exposed to bulk water, allowing Glu-23 to become hydrated. This illustrates several key aspects of protein electrostatics: (1) The apparent pKa of an internal ionizable group can reflect the average of the very different pKa values (open ~4.5, closed ?7.5) sampled in the different conformational states. (2) The high apparent dielectric constant reported by the pKa value of internal ionizable group reflects conformational reorganization. (3) The apparent pKa of internal groups can be governed by large conformational changes. (4) A single charge buried in the hydrophobic interior of a protein is sufficient to convert what might have been a transient, partially unfolded state into the dominant state in solution. This suggests a general strategy for examining inaccessible regions of the folding landscape and for engineering conformational switches driven by small changes in pH. These data also constitute a benchmark for stringent testing of the ability of computational algorithms to predict pKa values of internal residues and to reproduce pH-driven conformational transitions of proteins. PMID- 28009502 TI - Polyarylenesulfonium Salt as a Novel and Versatile Nonchemically Amplified Negative Tone Photoresist for High-Resolution Extreme Ultraviolet Lithography Applications. AB - The present report demonstrates the potential of a polyarylenesulfonium polymer, poly[methyl(4-(phenylthio)-phenyl)sulfoniumtrifluoromethanesulfonate] (PAS), as a versatile nonchemically amplified negative tone photoresist for next-generation lithography (NGL) applications starting from i-line (lambda ~ 365 nm) to extreme ultraviolet (EUV, lambda ~ 13.5 nm) lithography. PAS exhibited considerable contrast (gamma), 0.08, toward EUV and patterned 20 nm features successfully. PMID- 28009503 TI - Coadministration of Oligomeric Hyaluronic Acid-Modified Liposomes with Tumor Penetrating Peptide-iRGD Enhances the Antitumor Efficacy of Doxorubicin against Melanoma. AB - A safe and efficient tumor-targeting strategy based on oligomeric hyaluronic acid (HA) modification and coadministration of tumor-penetrating peptide-iRGD was successfully developed. In this study, common liposomes (cLip) were modified by oligomeric HA to obtain HA-Lip. After injection into rats, HA-Lip showed good stealth in the bloodstream and lower liver distribution compared with cLip. Moreover, our HA-Lip could be internalized into B16F10 cells (CD44-overexpressing tumor cells) through HA-CD44 interaction. After systemic administration to B16F10 melanoma-bearing mice, HA-Lip showed an increased distribution in tumor due to the prolonged blood circulation time and the enhanced penetration and retention effect. When coadministered with iRGD, the tumor penetration of HA-Lip was significantly enhanced, which could promote HA-Lip internalization by tumors cells located in deep tumor regions through receptor-mediated endocytosis. Furthermore, doxorubicin (DOX)-loaded HA-Lip coadministering with iRGD showed much better antitumor effect compared to DOX-loaded cLip and DOX-loaded cLip in combination with iRGD. In systemic toxicity test, DOX-loaded HA-Lip could significantly decrease the cardiotoxicity and myelosuppression of DOX. Taken together, our results demonstrated that coadministration of oligomeric HA modified liposomes with iRGD could be a promising treatment strategy for targeted therapy of melanoma. PMID- 28009504 TI - Multifunctionalization of Poly(vinylidene fluoride)/Reactive Copolymer Blend Membranes for Broad Spectrum Applications. AB - Simultaneous immobilization and cross-linking of antifouling/low toxic polymers, e.g., poly(ethylenimine) (PEI), dextran (Dex), agarose (Agr), poly(ethylene glycol) (PEG), PEI-Dex, and PEI-PEG conjugates, and stimuli-responsive copolymers on a porous membrane surface in mild reaction conditions is desirable for the enhancement of hydrophilicity, antifouling character, cytocompatibility, and inducing stimuli-responsive behavior. Grafting to technique is required since the precursors of most of these macromolecules are not amenable to surface-initiated polymerization. In this work, we report a versatile process for the simultaneous immobilization and cross-linking of a library of macromolecules on and into the blend membrane (PVDF-blend) of poly(vinylidene fluoride) and poly(methyl methacrylate)-co-poly(chloromethylstyrene). Sequential nucleophilic substitution reaction between activated halide moieties of the copolymer and amine groups of different macromolecules readily provided series of modified membranes. These membranes exhibited antifouling property superior to that of the unmodified membrane. The effectiveness of this technique has been demonstrated by the immobilization of pH or both pH- and temperature-responsive copolymer on PVDF blend membrane for responsive separation of poly(ethylene oxide) and bovine serum albumin. Silver nanoparticles were also anchored on the select modified membranes surfaces for the enhancement of antibiofouling property. Our approach is useful to obtain verities of functional membranes and selection of membrane for a particular application. PMID- 28009505 TI - Life Cycle Assessment of Solar Photovoltaic Microgrid Systems in Off-Grid Communities. AB - Access to a reliable source of electricity creates significant benefits for developing communities. Smaller versions of electricity grids, known as microgrids, have been developed as a solution to energy access problems. Using attributional life cycle assessment, this project evaluates the environmental and energy impacts of three photovoltiac (PV) microgrids compared to other energy options for a model village in Kenya. When normalized per kilowatt hour of electricity consumed, PV microgrids, particularly PV-battery systems, have lower impacts than other energy access solutions in climate change, particulate matter, photochemical oxidants, and terrestrial acidification. When compared to small scale diesel generators, PV-battery systems save 94-99% in the above categories. When compared to the marginal electricity grid in Kenya, PV-battery systems save 80-88%. Contribution analysis suggests that electricity and primary metal use during component, particularly battery, manufacturing are the largest contributors to overall PV-battery microgrid impacts. Accordingly, additional savings could be seen from changing battery manufacturing location and ensuring end of life recycling. Overall, this project highlights the potential for PV microgrids to be feasible, adaptable, long-term energy access solutions, with health and environmental advantages compared to traditional electrification options. PMID- 28009506 TI - Earthicle: The Design of a Conceptually New Type of Particle. AB - The conception and the steps made in the design of a conceptually new type of composite particle, so-called "earthicle", are being described. This particle is meant to roughly mimic the layered structure of the Earth, having zerovalent iron core, silicate mantle, and a thin carbonaceous crust resembling the biosphere and its geological remnants. Particles are made in a stable colloidal form in an aqueous medium, involving chemical precipitation and pyrolysis of citric acid in the solution. The effects of various synthesis parameters were studied, including borohydride and oleate concentrations, APTES/TEOS molar ratio, chemical nature of the carbon precursors, and others. XRD analysis confirmed the predominantly zerovalent iron composition of the core, amorphous silica and crystalline iron silicate/silicide composition of the mesolayer, and the carbonaceous, amorphous graphitic composition of the surface coating. The atomically thin carbon shell was also detected as a distinct shoulder on the broad n-pi* absorption resonance and the peak at ~300 nm, a signature of sp2 hybridized electronic orbitals and the result of the interband pi-pi* transition characteristic of graphitic structures. The irregularity of the shape of generally round Fe0 particles has caused the uniformity of the silica shell to be directly proportional to the particle size. The size of the earthicles ranged from 60 to 500 nm depending on the ionic concentration of the precursors and additives. Silica layer effectively prevented the aggregation of the iron core and increased the biocompatibility of the particles. The point of zero charge first increased from the acidic to the neutral range after coating Fe0 core with the APTES-functionalized, aminated silica shell and then restored its low value after depositing the carboxylated carbonic crust in a charge-reversal process designed to facilitate the formation of core-multishell structures. Tested on K7M2 osteosarcoma cell line and primary kidney and lung fibroblasts, cytotoxicity was cell-line dependent; however, the trend assessed in both planar and 3D cell culture with respect to the three types of particles, Fe0, Fe/SiO2, and Fe/SiO2/C, was general and independent of the cell line. Thus, the pronounced toxicity of Fe0 alone became neutralized after the silica layer was coated around Fe0. The further addition of the carbonic layer reduced the viability as compared to Fe/SiO2, albeit in a statistically significant manner only for K7M2 cell line when compared against the untreated control. Cell response also varied depending on the formulation: while some formulations exhibited lethal effects on kidney fibroblasts, were harmless to lung fibroblasts, and boosted the proliferation of K7M2 osteosarcoma cells, other formulations exhibited the opposite behavior despite being similar in terms of their core/double-shell structure. Compared across three different cancerous cell lines, K7M2 osteosarcoma and U87 and E297 glioblastoma, a similar cell-line dependency in response was observed, yet the viability reduction was consistent for all Fe/SiO2/C particles, ranging from 80% to 85% of the untreated control. Carbon surface layer, albeit of graphitic structural nature, was of a markedly more viable character than that of nanosized graphene oxide. The viability of lung fibroblasts incubated with Fe/SiO2/C particles was reduced in the presence of the alternating magnetic field of 312.75 A/m and 1 MHz, while the viability reduction caused by Fe/SiO2/C particles in kidney fibroblasts and K7M2 cells was converted from statistically insignificant to significant, suggesting that the composite particles could be used for hyperthermia treatments, although their properties should be optimized for a more intense effect. A single-cell immunofluorescent analysis of the interaction of primary kidney fibroblasts and K7M2 osteosarcoma cells with Fe/SiO2/C particles demonstrated that the cell uptake and perinuclear localization may be responsible for the necrotic effects. This analysis also showed that composite Fe/SiO2/C particles may have the ability to cause the rupture of the cancer cell nucleus while having a harmless effect on the primary cells. Such a promising and selective anticancer activity will be investigated in more detail in future studies. PMID- 28009507 TI - Dual-Phase Transformation: Spontaneous Self-Template Surface-Patterning Strategy for Ultra-transparent VO2 Solar Modulating Coatings. AB - Dual-phase transformation has been developed as a template-free surface patterning technique in this study. Ordered VO2 honeycomb structures with a complex hierarchy have been fabricated via this method, and the microstructures of the obtained VO2(M) coatings are tunable by tailoring the pertinent variables. The VO2(M) honeycomb-structured coatings have excellent visible light transmittance at 700 nm (Tvis) up to 95.4% with decent solar modulating ability (DeltaTsol) of 5.5%, creating the potential as ultratransparent smart solar modulating coatings. Its excellent performance has been confirmed by a proof-of principle demonstration. The dual-phase transformation technique has dramatically simplified the conventional colloidal lithography technique as a scalable surface patterning technique for achieving high-performance metal oxide coatings with diverse applications, such as catalysis, sensing, optics, electronics, and superwettable materials. PMID- 28009508 TI - Synthesis and Antibacterial Study of Sulfobetaine/Quaternary Ammonium-Modified Star-Shaped Poly[2-(dimethylamino)ethyl methacrylate]-Based Copolymers with an Inorganic Core. AB - Cationic polymethacrylates are interesting candidates for bacterial disinfectants since they can be made in large-scale by various well-established polymerization techniques such as atom transfer radical polymerization (ATRP). However, they are usually toxic or ineffective in serum and various strategies to improve their biocompatibility or nonfouling property have often resulted in compromised bactericidal activity. Also, star-shaped polymers are less explored than linear polymers for application as antibacterial compounds. In this paper, star polymers with poly[2-(dimethylamino)ethyl methacrylate] (PDMA) as the arms and polyhedral oligomeric silsesquioxane (POSS) as the core (POSS-g-PDMA) were successfully synthesized by ATRP. The minimum inhibition concentrations (MICs) of the synthesized POSS-g-PDMA are in the range of 10-20 MUg/mL. POSS-g-PDMA was further modified by various hydrophilization strategies in attempting to reduce hemolysis. With quaternization of POSS-g-PDMA, the antibacterial activities of the obtained quaternary polymers are almost unchanged and the copolymers become relatively nonhemolytic. We also copolymerized sulfobetaine (SB) with POSS-g-PDMA to obtain random and block PDMA-co-PSB arm structures, where the PDMA and poly(sulfobetaine) were the cationic and zwitterionic blocks, respectively. The random cationic-zwitterionic POSS-g-(PDMA-r-PSB) copolymers showed poor antibacterial activity, while the block POSS-g-(PDMA-b-PSB) copolymers retained the antibacterial and hemolytic activity of the pristine POSS-g-PDMA. Further, the block copolymers of POSS-g-(PDMA-b-PSB) showed enhanced antifouling property and serum stability as seen by their nanoparticle size stability in the presence of serum and reduced red blood cell aggregation; the POSS-g-(PDMA-b-PSB) also somewhat retained its MIC in blood unlike the quaternized or random zwitterionic copolymers. The antibacterial kinetics study showed that Escherichia coli can be killed within 30 min by both random and block copolymers of POSS-g-(PDMA-co-PSB). Finally, our POSS star polymers showed low toxicity to zebrafish embryo and could be potentially used in aquaculture antibacterial applications. PMID- 28009509 TI - Crystal Structure, Defects, Magnetic and Dielectric Properties of the Layered Bi3n+1Ti7Fe3n-3O9n+11 Perovskite-Anatase Intergrowths. AB - The Bi3n+1Ti7Fe3n-3O9n+11 materials are built of (001)p plane-parallel perovskite blocks with a thickness of n (Ti,Fe)O6 octahedra, separated by periodic translational interfaces. The interfaces are based on anatase-like chains of edge sharing (Ti,Fe)O6 octahedra. Together with the octahedra of the perovskite blocks, they create S-shaped tunnels stabilized by lone pair Bi3+ cations. In this work, the structure of the n = 4-6 Bi3n+1Ti7Fe3n-3O9n+11 homologues is analyzed in detail using advanced transmission electron microscopy, powder X-ray diffraction, and Mossbauer spectroscopy. The connectivity of the anatase-like chains to the perovskite blocks results in a 3ap periodicity along the interfaces, so that they can be located either on top of each other or with shifts of +/-ap along [100]p. The ordered arrangement of the interfaces gives rise to orthorhombic Immm and monoclinic A2/m polymorphs with the unit cell parameters a = 3ap, b = bp, c = 2(n + 1)cp and a = 3ap, b = bp, c = 2(n + 1)cp - ap, respectively. While the n = 3 compound is orthorhombic, the monoclinic modification is more favorable in higher homologues. The Bi3n+1Ti7Fe3n-3O9n+11 structures demonstrate intricate patterns of atomic displacements in the perovskite blocks, which are supported by the stereochemical activity of the Bi3+ cations. These patterns are coupled to the cationic coordination of the oxygen atoms in the (Ti,Fe)O2 layers at the border of the perovskite blocks. The coupling is strong in the n = 3, 4 homologues, but gradually reduces with the increasing thickness of the perovskite blocks, so that, in the n = 6 compound, the dominant mode of atomic displacements is aligned along the interface planes. The displacements in the adjacent perovskite blocks tend to order antiparallel, resulting in an overall antipolar structure. The Bi3n+1Ti7Fe3n-3O9n+11 materials demonstrate an unusual diversity of structure defects. The n = 4-6 homologues are robust antiferromagnets below TN = 135, 220, and 295 K, respectively. They show a high dielectric constant that weakly increases with temperature and is relatively insensitive to the Ti/Fe ratio. PMID- 28009510 TI - Lead-Free Perovskite Nanowire Array Photodetectors with Drastically Improved Stability in Nanoengineering Templates. AB - Organometal halide perovskite materials have triggered enormous attention for a wide range of high-performance optoelectronic devices. However, their stability and toxicity are major bottleneck challenges for practical applications. Substituting toxic heavy metal, that is, lead (Pb), with other environmentally benign elements, for example, tin (Sn), could be a potential solution to address the toxicity issue. Nevertheless, even worse stability of Sn-based perovskite material than Pb-based perovskite poses a great challenge for further device fabrication. In this work, for the first time, three-dimensional CH3NH3SnI3 perovskite nanowire arrays were fabricated in nanoengineering templates, which can address nanowire integration and stability issues at the same time. Also, nanowire photodetectors have been fabricated and characterized. Intriguingly, it was discovered that as the nanowires are embedded in mechanically and chemically robust templates, the material decay process has been dramatically slowed down by up to 840 times, as compared with a planar thin film. This significant improvement on stability can be attributed to the effective blockage of diffusion of water and oxygen molecules within the templates. These results clearly demonstrate a new and alternative strategy to address the stability issue of perovskite materials, which is the major roadblock for high-performance optoelectronics. PMID- 28009511 TI - Color Richness in Cephalopod Chromatophores Originating from High Refractive Index Biomolecules. AB - Cephalopods are arguably one of the most photonically sophisticated marine animals, as they can rapidly adapt their dermal color and texture to their surroundings using both structural and pigmentary coloration. Their chromatophore organs facilitate this process, but the molecular mechanism potentiating color change is not well understood. We hypothesize that the pigments, which are localized within nanostructured granules in the chromatophore, enhance the scattering of light within the dermal tissue. To test this, we extracted the phenoxazone-based pigments from the chromatophore and extrapolated their complex refractive index (RI) from experimentally determined real and approximated imaginary portions of the RI. Mie theory was used to calculate the absorbance and scattering cross sections (cm2/particle) across a broad diameter range at lambda = 589 nm. We observed that the pigments were more likely to scatter attenuated light than absorb it and that these characteristics may contribute to the color richness of cephalopods. PMID- 28009512 TI - Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations. AB - Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and generally applicable methodologies are still not available to the computational and medicinal chemistry communities. Absolute binding free energy calculations based on alchemical pathways provide a rigorous framework for affinity predictions and could thus offer a general approach to the problem. We evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromodomain families, and by comparing the results to isothermal titration calorimetry data. Two case studies were considered. In the first one, the affinities of two similar ligands for seven bromodomains were calculated and returned excellent agreement with experiment (mean unsigned error of 0.81 kcal/mol and Pearson correlation of 0.75). In this test case, we also show how the preferred binding orientation of a ligand for different proteins can be estimated via free energy calculations. In the second case, the affinities of a broad-spectrum inhibitor for 22 bromodomains were calculated and returned a more modest accuracy (mean unsigned error of 1.76 kcal/mol and Pearson correlation of 0.48); however, the reparametrization of a sulfonamide moiety improved the agreement with experiment. PMID- 28009514 TI - Theoretical Study on the Reactivity and Regioselectivity of the Diels-Alder Reaction of Fullerene: Effects of Charges and Encapsulated Lanthanum on the Bis Functionalization of C70. AB - Bis-adducts of fullerenes are important for both material and biological science. The first added substituent greatly impacts the reactivity and regioselectivity of fullerene. What determines the bond reactivity and how to control the regioselectivity are two crucial questions in synthesizing bis-adduct of C70. Recently, an unexpected 12 o'clock isomer of anthracene bis-adduct of C70 was prepared with high yield by the Diels-Alder (DA) reaction although three possible isomers (12, 2, and 5 o'clock isomers) may be formed. In the current study, the beneath mechanism is systematically investigated by density functional theory methods. Moreover, effects of charges and encapsulated lanthanum atom on the regioselectivity are reported. The computational results successfully rationalize experimental observations by Venkata et al. A possible way to change the regioselectivity of DA reaction is put forward. The kinetical promotion effect of an encapsulated La atom on the 12 o'clock reaction is elucidated. PMID- 28009515 TI - Efficient Constrained Density Functional Theory Implementation for Simulation of Condensed Phase Electron Transfer Reactions. AB - Constrained density functional theory (CDFT) is a versatile tool for probing the kinetics of electron transfer (ET) reactions. In this work, we present a well scaling parallel CDFT implementation relying on a mixed basis set of Gaussian functions and plane waves, which has been specifically tailored to investigate condensed phase ET reactions using an explicit, quantum chemical representation of the solvent. The accuracy of our implementation is validated against previous theoretical results for predicting electronic couplings and charge transfer energies. Subsequently, we demonstrate the efficiency of our method by studying the intramolecular ET reaction of an organic mixed-valence compound in water using a CDFT based molecular dynamics simulation. PMID- 28009513 TI - Mechanistic Study of an Improved Ni Precatalyst for Suzuki-Miyaura Reactions of Aryl Sulfamates: Understanding the Role of Ni(I) Species. AB - Nickel precatalysts are potentially a more sustainable alternative to traditional palladium precatalysts for the Suzuki-Miyaura coupling reaction. Currently, there is significant interest in Suzuki-Miyaura coupling reactions involving readily accessible phenolic derivatives such as aryl sulfamates, as the sulfamate moiety can act as a directing group for the prefunctionalization of the aromatic backbone of the electrophile prior to cross-coupling. By evaluating complexes in the Ni(0), (I), and (II) oxidation states we report a precatalyst, (dppf)Ni(o tolyl)(Cl) (dppf = 1,1'-bis(diphenylphosphino)ferrocene), for Suzuki-Miyaura coupling reactions involving aryl sulfamates and boronic acids, which operates at a significantly lower catalyst loading and at milder reaction conditions than other reported systems. In some cases it can even function at room temperature. Mechanistic studies on precatalyst activation and the speciation of nickel during catalysis reveal that Ni(I) species are formed in the catalytic reaction via two different pathways: (i) the precatalyst (dppf)Ni(o-tolyl)(Cl) undergoes comproportionation with the active Ni(0) species; and (ii) the catalytic intermediate (dppf)Ni(Ar)(sulfamate) (Ar = aryl) undergoes comproportionation with the active Ni(0) species. In both cases the formation of Ni(I) is detrimental to catalysis, which is proposed to proceed via a Ni(0)/Ni(II) cycle. DFT calculations are used to support experimental observations and provide insight about the elementary steps involved in reactions directly on the catalytic cycle, as well as off-cycle processes. Our mechanistic investigation provides guidelines for designing even more active nickel catalysts. PMID- 28009516 TI - beta-Hexaalkylporphycenes: Positional Effect of Alkyl Groups toward Design and Control of Structural and Photophysical Properties in Isomeric Hexaethylporphycenes. AB - Two novel beta-hexaalkylated porphycenes, i.e., 2,3,7,12,13,17- (HOT) and 2,3,6,12,13,16-hexaethylporphycenes (HIT) were introduced for the first time in porphycene chemistry. These were synthesized through McMurry coupling reactions of new isomeric unsymmetrically substituted triethylbipyrrole dialdehydes. The positional effects of alkyl groups could be manifested through significant alteration in structure of porphycene cores and, as a consequence their photophysical properties, not noticed in beta-octaethylporphycene. HOT displays significant fluorescence accompanied by reasonable singlet oxygen generation ability. PMID- 28009517 TI - Tuning Azoheteroarene Photoswitch Performance through Heteroaryl Design. AB - Photoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one of the aryl rings from the conventional azobenzene class has been replaced with a five-membered heteroaromatic ring. Initial studies have suggested the azoheteroarenes-the arylazopyrazoles in particular-to have excellent photoswitching properties (quantitative switching and long Z isomer half-life). Here we present a systematic computational and experimental study to elucidate the origin of the long thermal half-lives and excellent addressability of the arylazopyrazoles, and apply this understanding to determine important structure-property relationships for a wide array of comparable azoheteroaryl photoswitches. We identify compounds with Z isomer half-lives ranging from seconds to hours, to days and to years, and variable absorption characteristics, all through tuning of the heteraromatic ring. Conformation perhaps plays the largest role in determining such properties: the compounds with the longest isomerization half-lives adopt a T-shaped ground state Z isomer conformation and proceed through a T-shaped isomerization pathway, whereas the most complete photoswitching is achieved for compounds that have a twisted (rather than T shaped) Z isomer conformation. By balancing these factors, we report a new azopyrazole 3pzH, which can be quantitatively switched to its Z isomer (>98%) with 355 nm irradiation, near-quantitatively (97%) switched back to the E isomer with 532 nm irradiation, and has a very long half-life for thermal isomerization (t1/2 = 74 d at 25 degrees C). Given the large tunability of their properties, the predictive nature of their performance, and the other functional opportunities afforded by usage of a heteroaromatic system, we believe the azoheteroaryl photoswitches to have huge potential in a wide range of optically addressable applications. PMID- 28009518 TI - Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract. AB - As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products. PMID- 28009519 TI - Hydrophilicity Reinforced Adhesion of Anodic Alumina Oxide Template Films to Conducting Substrates for Facile Fabrication of Highly Ordered Nanorod Arrays. AB - Arrays of ordered nanorods are of special interest in many fields. However, it remains challenging to obtain such arrays on conducting substrates in a facile manner. In this article, we report the fabrication of highly ordered and vertically standing nanorod arrays of both metals and semiconductors on Au films and indium tin oxide glass substrates without an additional layering. In this approach, following the simple hydrophilic treatment of an anodic aluminum oxide (AAO) membrane and conducting substrates, the AAO membrane was transferred onto the modified substrates with excellent adhesion. Subsequently, nanorod arrays of various materials were electrodeposited on the conducting substrates directly. This method avoids any expensive and tedious lithographic and ion milling process, which provides a simple yet robust route to the fabrication of arrays of 1D materials with high aspect ratio on conducting substrates, which shall pave the way for many practical applications in a range of fields. PMID- 28009520 TI - The Dynamics of Water in Porous Two-Dimensional Crystals. AB - Porous two-dimensional crystals offer many promises for water desalination applications. For computer simulation to play a predictive role in this area, however, one needs to have reliable methods for simulating an atomistic system with hydrodynamic currents and interpretative tools to relate microscopic interactions to emergent macroscopic dynamical quantities, such as friction, slip length, and permeability. In this article, we use Gaussian dynamics, a nonequilibrium molecular dynamics method that provides microscopic insights into the interactions that control the flows of both simple liquids and liquid water through atomically small channels. In simulations of aqueous transport, we mimic the effect of changing the membrane chemical composition by adjusting the attractive strength of the van der Waals interactions between the membrane atoms and water. We find that the wetting contact angle, a common measure of a membrane's hydrophobicity, does not predict the permeability of a membrane. Instead, the hydrophobic effect is subtle, with both static and dynamic effects that can both help and hinder water transport through these materials. The competition between the static and dynamical hydrophobicity balances an atomic membrane's tendency to wet against hydrodynamic friction, and determines an optimal contact angle for water passage through nonpolar membranes. To a reasonable approximation, the optimal contact angle depends only on the aspect ratio of the pore. We also find that water molecules pass through the most hydrophobic membranes in a punctuated series of bursts that are separated by long pauses. A continuous-time Markov model of these data provides evidence of a molecular analogue to the clogging transition, a phenomenon observed in driven granular flows. PMID- 28009521 TI - ent-Strobane and ent-Pimarane Diterpenoids from Siegesbeckia pubescens. AB - Two strobane diterpenoids, strobols A (1) and B (2), 15 new pimarane diterpenoids (3-6 and 8-18), and the known compounds kirenol (19), darutigenol (20), and ent 2beta,15,16,19-tetrahydroxypimar-8(14)-ene (7) were isolated from the aerial parts of Siegesbeckia pubescens Makino. The structures of the new compounds were established based on the interpretation of HRESIMS and NMR analysis. The configurations of 1, 6, and 17 were confirmed by X-ray crystallographic data. Compounds 3, 5, and 11 inhibited the migration of MB-MDA-231 breast cancer cells induced by the chemokine epithelial growth factor, with IC50 values of 4.26, 3.45, and 9.70 MUM, respectively. PMID- 28009522 TI - Chiral Hypervalent Iodine(III) Catalyst Promotes Highly Enantioselective Sulfonyl and Phosphoryl-oxylactonizations. AB - An efficient enantioselective hypervalent iodine promoted oxylactonization of 4 pentenoic acids has been achieved using stoichiometric or a catalytic amount of chiral aryl-lambda3-iodane. This reaction provides straightforward access to a wide range of sulfonyloxy- and phosphoryloxy-gamma-butyrolactones in respectable yields with moderate to excellent enantioselectivities. PMID- 28009523 TI - The Construction of Chiral Fused Azabicycles Using a Pd-Catalyzed Allylic Substitution Cascade and Asymmetric Desymmetrization Strategy. AB - A highly enantioselective Pd-catalyzed asymmetric allylic substitution cascade of cyclic N-sulfonylimines with an accompanying asymmetric desymmetrization has been developed for the construction of fused tetrahydroindole derivatives bearing two chiral centers. Mechanistic studies confirmed that the cascade reaction proceeds by initial allylic alkylation and subsequent allylic amination. The first alkylation is a chirality-control step and represents an asymmetric desymmetrization of cis-cyclic allyl diacetates. The reaction has been performed on a gram scale, and the desired products can take part in several transformations. PMID- 28009524 TI - Minding the Mind-Body Literature: Frontiers in Cancer Treatment. PMID- 28009525 TI - Effects of Alpha-Lipoic Acid Supplementation on Plasma Adiponectin Levels and Some Metabolic Risk Factors in Patients with Schizophrenia. AB - Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and anti-inflammatory properties and is suggested to be a biomarker of metabolic disturbances. The aim of this study was to investigate the effects of alpha lipoic acid (ALA) on plasma adiponectin and some metabolic risk factors in patients with schizophrenia. The plasma adipokine levels (adiponectin and leptin), routine biochemical and anthropometric parameters, markers of oxidative stress, and the serum phospholipid fatty acid profile in eighteen schizophrenic patients at baseline, in the middle, and at the end of a 3-month long supplementation period with ALA (500 mg daily) were determined. A significant increase in the plasma adiponectin concentrations, as well as a decrease in fasting glucose and aspartate aminotransferase activity (AST), was found. Baseline AST activity was independently correlated with the adiponectin concentrations. Our data show that ALA can improve plasma adiponectin levels and may play a potential role in the treatment of metabolic risk factor in patients with schizophrenia. Future randomized controlled trials are needed to confirm these preliminary investigations. PMID- 28009526 TI - Pubertal Progression and Reproductive Hormones in Healthy Girls With Transient Thelarche. AB - Context: Detailed evaluation of pubertal progression in girls from longitudinal studies is sparse, and the phenomenon of transient thelarche (TT), defined as the appearance, regression, and subsequent reappearance of breast buds, in healthy girls remains undescribed. Objective: To describe TT in terms of pubertal progression, growth, genotypes, and reproductive hormones and to apply new puberty nomograms for breast stages, pubic hair, and menarche. Design: A prospective, longitudinal population-based study. Patients or Other Participants: Ninety-eight healthy Danish schoolchildren (Caucasian girls) followed longitudinally as part of the COPENHAGEN Puberty Study were included in the evaluation of TT. A total of 1466 girls from 2 cross-sectional studies were included in the creation of the puberty nomograms. Intervention(s): None. Main Outcome Measure(s): Pubertal progression, specifically thelarche, reproductive hormones, genotype, and growth. Results: Twelve of 98 (12%) girls experienced TT. A larger proportion of girls with TT entered puberty by the pubarche pathway (50%) compared with girls with normal progression (15.4%), P = 0.014. Girls with TT progressed through puberty normally when evaluated using puberty nomograms. Reproductive hormones and growth velocity were lower at the first (transient) thelarche than the second (permanent) thelarche. Conclusion: TT is a frequent phenomenon that appears to be a peripheral occurrence independent of central puberty. It does not appear to affect subsequent pubertal progression as evaluated by our new puberty nomograms. PMID- 28009527 TI - Reg2 Expression Is Required for Pancreatic Islet Compensation in Response to Aging and High-Fat Diet-Induced Obesity. AB - Maintaining pancreatic beta-cell mass and function is essential for normal insulin production and glucose homeostasis. Regenerating islet-derived 2 (Reg2, Reg II, human ortholog Reg1B) gene is normally expressed in pancreatic acinar cells and is significantly induced in response to diabetes, pancreatitis, and high-fat diet (HFD) and during pancreatic regeneration. To evaluate the role of endogenous Reg2 production in normal beta-cell function, we characterized Reg2 gene-deficient (Reg2-/-) mice under normal conditions and when subjected to several pathological challenges. At a young age, Reg2 gene deficiency caused no obvious change in normal islet morphology or glucose tolerance. There was no change in the severity of streptozotocin-induced diabetes or caerulein-induced acute pancreatitis in the Reg2-/- mice, indicating that the increased Reg2 expression under those conditions was not essential to protect the islet or acinar cells. However, 13- to 14-month-old Reg2-/- mice developed glucose intolerance associated with significantly decreased islet beta-cell ratio and serum insulin level. Similarly, after young mice were fed an HFD for 19 weeks, diminished islet mass expansion and serum insulin level were observed in Reg2-/- vs wild-type mice. This was associated with a decline in the rate of individual beta-cell proliferation measured by Ki67 labeling. In both conditions, the beta cells were smaller in gene-deficient vs wild-type mice. Our results indicate that normal expression of Reg2 gene is required for appropriate compensations in pancreatic islet proliferation and expansion in response to obesity and aging. PMID- 28009528 TI - Death as an Intern. PMID- 28009529 TI - High Prevalence of Middle East Respiratory Coronavirus in Young Dromedary Camels in Jordan. AB - Prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) was determined in 45 dromedary camels from two geographically separated herds in Jordan. Virus shedding was only detected in swabs obtained from the respiratory tract and primarily observed in camels younger than 3 years. MERS-CoV seroprevalence increased with age of camels. Bovine and sheep sera were seronegative. Phylogenetic analysis of partial S2 clustered the Jordanian MERS CoV strains with contemporary MERS-CoV strains associated with nosocomial outbreaks. PMID- 28009531 TI - Effect of Retinol Palmitate on Corneal and Conjunctival Mucin Gene Expression in a Rat Dry Eye Model After Injury. AB - PURPOSE: We examined the wound-healing effect of retinol palmitate (VApal) on mucin gene and protein expressions in a rat dry eye model based on lacrimal gland (LG) resection after injury. METHODS: The rat dry eye model was prepared by surgical resection of the main LG in male Long-Evans rats. After alkaline injury of the central part of the lower palpebral conjunctiva bilaterally, VApal eye drops at 1,500 IU/mL in one eye and a vehicle in the fellow eye were both administered 6 times a day for 7 days. The expression of mucin gene and protein was analyzed by real-time polymerase chain reaction or enzyme-linked immunosorbent assay in the cornea and conjunctiva of MUC1, MUC4, MUC16, and MUC5AC after 1, 3, (5), and 7 days of treatment with VApal. RESULTS: Significant decreases in fluorescein-stained areas and rose bengal scores were observed in VApal-treated dry eyes compared with vehicle-treated dry eyes at both 3 (P < 0.05) and 7 days (P < 0.01). Significant increases in corneal rMuc4 and conjunctival rMuc5AC after 1 day (P < 0.01) and conjunctival rMuc16 gene expression after 3 days were observed with VApal treatment (P < 0.05). Furthermore, conjunctival MUC16 expression significantly increased after 3 days of VApal treatment (P < 0.05). CONCLUSIONS: VApal promoted corneal rMuc4, conjunctival rMuc5AC, and conjunctival rMuc16 gene expression in a rat dry eye model after injury. VApal also promoted conjunctival MUC16 expression. These results indicate that VApal has efficacy in improving keratoconjunctival epithelial damage associated with decreased tear production. PMID- 28009530 TI - Maternal Cortisol During Pregnancy and Infant Adiposity: A Prospective Investigation. AB - Context: Glucocorticoids play a key role during intrauterine development in cellular growth and differentiation. Evidence suggests that exposure to inappropriate concentrations of glucocorticoids during sensitive developmental periods may produce alterations in physiological systems that impact obesity risk. Objective: To elucidate the magnitude and stage-of-gestation-specific association of maternal cortisol concentrations during pregnancy with infant adiposity. Design, Participants, and Setting: Sixty-seven mother-child dyads recruited in early pregnancy at university-based obstetric clinics in Southern California were followed with serial assessments from early gestation through birth until 6 months postnatal age. Maternal cumulative cortisol production was assessed over each of 4 consecutive days in early (?13 weeks), mid (?24 weeks), and late pregnancy (?30 weeks) (5 saliva samples/d * 4 days * 3 trimesters = 60 saliva samples/subject). Infant body composition was serially assessed in newborns (at ~25 days postnatal age) and at ~6 months age with dual-energy X-ray absorptiometry imaging. Results: After adjusting for key prenatal, birth, and postnatal covariates, higher maternal cortisol during the early third trimester (conditioned on prior early and midgestation cortisol concentrations) was significantly associated with a greater change in infant percent body fat from 1 to 6 months of age [partial r (adjusted for covariates) = 0.379, P = 0.007], accounting for ~14% of the variance in this measure of childhood obesity risk. Conclusion: The present findings suggest a stage-of-gestation-specific effect of maternal cortisol on infant adiposity gain in early postnatal life and provide evidence in humans to support the role of glucocorticoids in fetal programming of childhood obesity risk. PMID- 28009532 TI - Feed-forward regulation of self-selected exercise intensity in response to different rates of arterial deoxygenation. AB - Arterial desaturation impairs exercise performance in a dose-dependent manner. However, new theories of exercise-induced fatigue suggest that increasing rates of arterial deoxygenation augment the fatigue response during exercise. The purpose of this dissertation is to clarify if self-selected exercise intensity, while exercising at a constant rate of perceived exertion (RPE), is sensitive to alterations in the absolute arterial saturation (SPO2) and/or the rate of change in SPO2. Subjects performed constant RPE exercise for 30 min. They were instructed to adjust their exercise intensity during the trial to maintain their RPE at 5 on Borg's 10-point scale. Subjects engaged in continuous bilateral, isokinetic cycling and intermittent, unilateral, isometric knee-extension. The fraction of inspired oxygen was reduced to desaturate arterial blood from starting values (>98%) to 70%. This desaturation occurred linearly over 3 target time periods (FAST, 5 min; MED, 15 min; SLOW, 25 min). The rate of arterial desaturation was significantly different between each of the 3 conditions. During cycling exercise, PO (FAST = 2.8 +/- 2.1 W.% SPO2-1; MED = 2.5 +/- 1.8 W.% SPO2 1; SLOW = 1.8 +/- 1.6 W.% SPO2-1; P < 0.001) and surface electromyography (sEMG) of the vastus medialis (FAST = 1.3 +/- 0.6%.% SPO2-1; MED = 1.1 +/- 0.5%.% SPO2 1; SLOW = 0.7 +/- 0.7%.% SPO2-1; P < 0.001) decreased at significantly different rates. Post hoc comparisons revealed that the rates of decline in PO and sEMG during FAST and MED were similar, and both were greater than SLOW. However, during isometric knee extension exercise, the level of force production and sEMG remained similar across saturation levels. These results confirm that decreases in absolute SPO2 impair self-selected exercise intensity and that faster desaturation rates magnify that impairment, but only when a large muscle mass is engaged. These findings suggest that the rate of arterial deoxygenation independently influences exercise performance and that the central depressant effect may be a function of the metabolic strain associated with hypoxia, rather than the hypoxia per se. PMID- 28009533 TI - Cardiovascular disease risk in obese adults assessed using established values for cardiorespiratory fitness. AB - The present study was designed to assess the risk of cardiovascular disease as determined by cardiorespiratory fitness (CRF) in a large sample of inactive, obese adults. Cardiovascular disease risk was determined using published age- and sex-adjusted values for low, moderate, and high CRF from the Aerobics Center Longitudinal Study (ACLS). Contrary to expectations, ACLS-CRF classifications identified approximately 60% of our inactive, obese adults as having moderate or high CRF and hence, low cardiovascular disease risk. PMID- 28009535 TI - Optimizing Vancomycin Release from Calcium Phosphate-Based Cement by Carboxymethyl Cellulose for Prevention of Osteomyelitis. PMID- 28009534 TI - LDB1 Regulates Energy Homeostasis During Diet-Induced Obesity. AB - The broadly expressed transcriptional coregulator LDB1 is essential for beta-cell development and glucose homeostasis. However, it is unclear whether LDB1 has metabolic roles beyond the beta-cell, especially under metabolic stress. Global Ldb1 deletion results in early embryonic lethality; thus, we used global heterozygous Ldb1+/- and inducible beta-cell-specific Ldb1-deficient (Ldb1Deltabeta-cell) mice. We assessed glucose and insulin tolerance, body composition, feeding, and energy expenditure during high-fat diet exposure. Brown adipose tissue (BAT) biology was evaluated by thermogenic gene expression and LDB1 chromatin immunoprecipitation analysis. We found that partial loss of Ldb1 does not impair the maintenance of glucose homeostasis; rather, we observed improved insulin sensitivity in these mice. Partial loss of Ldb1 also uncovered defects in energy expenditure in lean and diet-induced obese (DIO) mice. This decreased energy expenditure during DIO was associated with significantly altered BAT gene expression, specifically Cidea, Elovl3, Cox7a1, and Dio2. Remarkably, the observed changes in energy balance during DIO were absent in Ldb1Deltabeta cell mice, despite a similar reduction in plasma insulin, suggesting a role for LDB1 in BAT. Indeed, LDB1 is expressed in brown adipocytes and occupies a regulatory domain of Elovl3, a gene crucial to normal BAT function. We conclude that LDB1 regulates energy homeostasis, in part through transcriptional modulation of critical regulators in BAT function. PMID- 28009538 TI - Excessive Masturbation Association with Mixed Amphetamine Salts. PMID- 28009537 TI - Overweight and Obese Pediatric Patients Have an Increased Risk of Developing a Surgical Site Infection. AB - BACKGROUND: Obesity is a known risk factor in adult surgical site infections (SSIs), but its significance in pediatrics is unclear. We hypothesized that overweight and obese children have increased risk for SSI. PATIENTS AND METHODS: A National Surgical Quality Improvement Program-Pediatric (NSQIP-P) file and single-center reviews identified surgical patients (2-18 years) who developed SSIs. Patients were classified as underweight, normal, overweight, or obese based on body mass index (BMI). Comorbidities associated with SSI were analyzed. Sub specialties and operations were recorded. RESULTS: National Surgical Quality Improvement Program-Pediatric review identified 66,671 patients and 1,380 SSIs. Seven hundred sixty-seven (767) were male and 613 female. Multivariable analysis revealed overweight and obese BMI to be risk factors for SSIs (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.06-1.43; OR 1.43, 95% CI 1.25-1.63). Most commonly, overweight and obese cohorts had superficial incisional SSIs. Pediatric general surgery (3.6%) and cardiothoracic surgery (2.5%) had the highest rates of SSIs. Single-center review identified 115 SSIs. Of these, 29.6% were overweight or obese with few other identifiable SSI risk factors. Sub-specialties with the most SSIs were pediatric surgery and pediatric orthopedics. Appendectomy was the most common procedure associated with SSIs. CONCLUSION: Herein we show elevated BMI to be a significant risk factor for SSIs. This information should be used in assessing and counseling pre-operative pediatric patients and families. PMID- 28009536 TI - Leucine Protects Against Skeletal Muscle Atrophy in Lipopolysaccharide-Challenged Rats. AB - Skeletal muscle atrophy is a decrease in muscle mass that occurs when protein degradation exceeds protein synthesis. Leucine (Leu), an essential branched-chain amino acid in animal nutrition, regulates skeletal muscle protein metabolism. Two experiments were conducted to evaluate whether Leu could alleviate lipopolysaccharide (LPS)-induced skeletal muscle wasting by modulating skeletal muscle protein synthesis and degradation. A total of 24 rats were randomly allocated into three groups (n = 8): (1) non-challenged control; (2) LPS challenged control; and (3) LPS +3.0% Leu. Rats were fed with control or Leu supplemented (part of the casein was replaced with 3.0% Leu) diets throughout the trial and were injected intraperitoneally with sterile saline or LPS at days 6, 11, 16, and 21. On the morning of day 22, serum samples were collected and rats were then sacrificed for liver and muscle analysis. In vitro protein degradation, nuclear factor-kappaB (NF-kappaB) activity, and proteolytic enzyme activities of the muscles from immune-challenged rats were also measured. Our results showed that the LPS challenge resulted in not only enhanced serum interleukin-1 and liver C-reactive protein (CRP) concentrations but also decreased the average daily body weight gain and muscle fiber diameter. However, dietary Leu inclusion attenuated the increase in CRP level and the decrease in muscle fiber diameter. Importantly, the LPS challenge caused a significant elevation in the muscle proteolysis rate, but dietary Leu supplementation significantly blocked the muscle proteolysis. The mRNA expression of NF-kappaB, muscle atrophy F-box (MAFbx), and muscle ring finger 1 (MuRF1) was upregulated by the LPS challenge in gastrocnemius muscles, but was downregulated by Leu supplementation. Interestingly, when muscles from the LPS-challenged rats were incubated with Leu in vitro, proteasome-, calpain-, and cathepsin-L-dependent muscle proteolysis and NF-kappaB activity were decreased. Collectively, the data suggest that Leu supplementation could inhibit excessive skeletal muscle degradation, as well as enhance protein synthesis and, thus, attenuate the negative effects caused by the LPS-induced immune challenge. PMID- 28009539 TI - Sexual temptation: substance abuse, no sex, safe sex, risky sex, and STDs. AB - Background University students' substance abuse and risky sex contribute to sexually transmitted diseases (STDs). Purpose We develop and empirically test a formative theoretical model of sexual temptation involving substance abuse (cigarettes, alcohol, and marijuana), safe sexual behavior (use of condom/barrier for oral and vaginal intercourse), risky sexual behavior (unprotected sex and multiple sexual partners), and STDs: gonorrhea, HIV, and genital herpes. We simultaneously explore these constructs, controlling membership in social groups (fraternity/sorority, varsity athlete, and club sports) and perceived norm of substance abuse. Methods A total of 687 American university students completed the National College Health Assessment (NCHA). We use structural equation modeling (SEM) to test the goodness of fit between our formative theoretical model and actual data. Results Results reveal the following discoveries: membership in campus social groups is positively associated with STDs, whereas perceived norm of peer substance abuse is negatively related to STDs. Under the influence of substance abuse, we test three outcomes of sexual temptation as related to STDs. Those who have no sex do not contract STDs. For those who fall into temptation and have sex, substance abuse is more strongly related to risky sex which leads to STDs than safe sex which does not. Those engaging in risky sex have significantly higher cognitive impairment than those practicing safe sex. Conclusions Substance abuse contributes to STDs through risky sex only. Those having risky sex suffer higher cognitive impairment than those practicing safe sex. We provide novel implications to policy makers, practitioners, and researchers. PMID- 28009540 TI - Knowledge, attitude, self-efficacy and estimation of frequency of condom use among Iranian students based on a crosswise model: more explanation is needed for the crosswise model. PMID- 28009541 TI - X-ray radiation damage to biological macromolecules: further insights. AB - Despite significant progress made over more than 15 years of research, structural biologists are still grappling with the issue of radiation damage suffered by macromolecular crystals which is induced by the resultant radiation chemistry occurring during X-ray diffraction experiments. Further insights into these effects and the possible mitigation strategies for use in both diffraction and SAXS experiments are given in eight papers in this volume. In particular, damage during experimental phasing is addressed, scavengers for SAXS experiments are investigated, microcrystals are imaged, data collection strategies are optimized, specific damage to tyrosine residues is reexamined, and room temperature conformational heterogeneity as a function of dose is explored. The brief summary below puts these papers into perspective relative to other ongoing radiation damage research on macromolecules. PMID- 28009542 TI - OH cleavage from tyrosine: debunking a myth. AB - During macromolecular X-ray crystallography experiments, protein crystals held at 100 K have been widely reported to exhibit reproducible bond scission events at doses on the order of several MGy. With the objective to mitigate the impact of radiation damage events on valid structure determination, it is essential to correctly understand the radiation chemistry mechanisms at play. OH-cleavage from tyrosine residues is regularly cited as amongst the most available damage pathways in protein crystals at 100 K, despite a lack of widespread reports of this phenomenon in protein crystal radiation damage studies. Furthermore, no clear mechanism for phenolic C-O bond cleavage in tyrosine has been reported, with the tyrosyl radical known to be relatively robust and long-lived in both aqueous solutions and the solid state. Here, the initial findings of Tyr -OH group damage in a myrosinase protein crystal have been reviewed. Consistent with that study, at increasing doses, clear electron density loss was detectable local to Tyr -OH groups. A systematic investigation performed on a range of protein crystal damage series deposited in the Protein Data Bank has established that Tyr -OH electron density loss is not generally a dominant damage pathway in protein crystals at 100 K. Full Tyr aromatic ring displacement is here proposed to account for instances of observable Tyr -OH electron density loss, with the original myrosinase data shown to be consistent with such a damage model. Systematic analysis of the effects of other environmental factors, including solvent accessibility and proximity to disulfide bonds or hydrogen bond interactions, is also presented. Residues in known active sites showed enhanced sensitivity to radiation-induced disordering, as has previously been reported. PMID- 28009543 TI - Identification of the point of diminishing returns in high-multiplicity data collection for sulfur SAD phasing. AB - High-quality high-multiplicity X-ray diffraction data were collected on five different crystals of thaumatin using a homogeneous-profile X-ray beam at E = 8 keV to investigate the counteracting effects of increased multiplicity and increased radiation damage on the quality of anomalous diffraction data collected on macromolecular crystals. By comparing sulfur substructures obtained from subsets of the data selected as a function of absorbed X-ray dose with sulfur positions in the respective refined reference structures, the doses at which the highest quality of anomalous differences could be obtained were identified for the five crystals. A statistic sigma{DeltaF}D, calculated as the width sigma of the normalized distribution of a set {DeltaF} of anomalous differences collected at a dose D, is suggested as a measure of anomalous data quality as a function of dose. An empirical rule is proposed to identify the dose at which the gains in data quality due to increased multiplicity are outbalanced by the losses due to decreases in signal-to-noise as a consequence of radiation damage. Identifying this point of diminishing returns allows the optimization of the choice of data collection parameters and the selection of data to be used in subsequent crystal structure determination steps. PMID- 28009545 TI - Comparison of helical scan and standard rotation methods in single-crystal X-ray data collection strategies. AB - X-ray radiation in macromolecular crystallography can chemically alter the biological material and deteriorate the integrity of the crystal lattice with concomitant loss of resolution. Typical alterations include decarboxylation of glutamic and aspartic residues, breaking of disulfide bonds and the reduction of metal centres. Helical scans add a small translation to the crystal in the rotation method, so that for every image the crystal is shifted to expose a fresh part. On beamline PROXIMA 2A at Synchrotron SOLEIL, this procedure has been tested with various parameters in an attempt to understand how to mitigate the effects of radiation damage. Here, the strategies used and the crystallographic metrics for various scenarios are reported. Among these, the loss of bromine from bromophenyl moieties appears to be a useful monitor of radiation damage as the carbon-bromine bond is very sensitive to X-ray irradiation. Two cases are focused on where helical scans are shown to be superior in obtaining meaningful data compared with conventional methods. In one case the initial resolution of the crystal is extended over time, and in the second case the anomalous signal is preserved to provide greater effective multiplicity and easier phasing. PMID- 28009544 TI - Development of a dose-limiting data collection strategy for serial synchrotron rotation crystallography. AB - Serial crystallography, in which single-shot diffraction images are collected, has great potential for protein microcrystallography. Although serial femtosecond crystallography (SFX) has been successfully demonstrated, limited beam time prevents its routine use. Inspired by SFX, serial synchrotron crystallography (SSX) has been investigated at synchrotron macromolecular crystallography beamlines. Unlike SFX, the longer exposure time of milliseconds to seconds commonly used in SSX causes radiation damage. However, in SSX, crystals can be rotated during the exposure, which can achieve efficient coverage of the reciprocal space. In this study, mercury single-wavelength anomalous diffraction (Hg-SAD) phasing of the luciferin regenerating enzyme (LRE) was performed using serial synchrotron rotation crystallography. The advantages of rotation and influence of dose on the data collected were evaluated. The results showed that sample rotation was effective for accurate data collection, and the optimum helical rotation step depended on multiple factors such as multiplicity and partiality of reflections, exposure time per rotation angle and the contribution from background scattering. For the LRE microcrystals, 0.25 degrees was the best rotation step for the achievable resolution limit, whereas a rotation step larger than or equal to 1 degrees was favorable for Hg-SAD phasing. Although an accumulated dose beyond 1.1 MGy caused specific damage at the Hg site, increases in resolution and anomalous signal were observed up to 3.4 MGy because of a higher signal-to-noise ratio. PMID- 28009546 TI - Uridine as a new scavenger for synchrotron-based structural biology techniques. AB - Macromolecular crystallography (MX) and small-angle X-ray scattering (SAXS) studies on proteins at synchrotron light sources are commonly limited by the structural damage produced by the intense X-ray beam. Several effects, such as aggregation in protein solutions and global and site-specific damage in crystals, reduce the data quality or even introduce artefacts that can result in a biologically misguiding structure. One strategy to reduce these negative effects is the inclusion of an additive in the buffer solution to act as a free radical scavenger. Here the properties of uridine as a scavenger for both SAXS and MX experiments on lysozyme at room temperature are examined. In MX experiments, upon addition of uridine at 1 M, the critical dose D1/2 is increased by a factor of ~1.7, a value similar to that obtained in the presence of the most commonly used scavengers such as ascorbate and sodium nitrate. Other figures of merit to assess radiation damage show a similar trend. In SAXS experiments, the scavenging effect of 40 mM uridine is similar to that of 5% v/v glycerol, and greater than 2 mM DTT and 1 mM ascorbic acid. In all cases, the protective effect of uridine is proportional to its concentration. PMID- 28009547 TI - Development of tools to automate quantitative analysis of radiation damage in SAXS experiments. AB - Biological small-angle X-ray scattering (SAXS) is an increasingly popular technique used to obtain nanoscale structural information on macromolecules in solution. However, radiation damage to the samples limits the amount of useful data that can be collected from a single sample. In contrast to the extensive analytical resources available for macromolecular crystallography (MX), there are relatively few tools to quantitate radiation damage for SAXS, some of which require a significant level of manual characterization, with the potential of leading to conflicting results from different studies. Here, computational tools have been developed to automate and standardize radiation damage analysis for SAXS data. RADDOSE-3D, a dose calculation software utility originally written for MX experiments, has been extended to account for the cylindrical geometry of the capillary tube, the liquid composition of the sample and the attenuation of the beam by the capillary material to allow doses to be calculated for many SAXS experiments. Furthermore, a library has been written to visualize and explore the pairwise similarity of frames. The calculated dose for the frame at which three subsequent frames are determined to be dissimilar is defined as the radiation damage onset threshold (RDOT). Analysis of RDOTs has been used to compare the efficacy of radioprotectant compounds to extend the useful lifetime of SAXS samples. Comparison of the RDOTs shows that, for radioprotectant compounds at 5 and 10 mM concentration, glycerol is the most effective compound. However, at 1 and 2 mM concentrations, dithiothreitol (DTT) appears to be most effective. Our newly developed visualization library contains methods that highlight the unusual radiation damage results given by SAXS data collected using higher concentrations of DTT: these observations should pave the way to the development of more sophisticated frame merging strategies. PMID- 28009548 TI - Conformational variation of proteins at room temperature is not dominated by radiation damage. AB - Protein crystallography data collection at synchrotrons is routinely carried out at cryogenic temperatures to mitigate radiation damage. Although damage still takes place at 100 K and below, the immobilization of free radicals increases the lifetime of the crystals by approximately 100-fold. Recent studies have shown that flash-cooling decreases the heterogeneity of the conformational ensemble and can hide important functional mechanisms from observation. These discoveries have motivated increasing numbers of experiments to be carried out at room temperature. However, the trade-offs between increased risk of radiation damage and increased observation of alternative conformations at room temperature relative to cryogenic temperature have not been examined. A considerable amount of effort has previously been spent studying radiation damage at cryo temperatures, but the relevance of these studies to room temperature diffraction is not well understood. Here, the effects of radiation damage on the conformational landscapes of three different proteins (T. danielli thaumatin, hen egg-white lysozyme and human cyclophilin A) at room (278 K) and cryogenic (100 K) temperatures are investigated. Increasingly damaged datasets were collected at each temperature, up to a maximum dose of the order of 107 Gy at 100 K and 105 Gy at 278 K. Although it was not possible to discern a clear trend between damage and multiple conformations at either temperature, it was observed that disorder, monitored by B-factor-dependent crystallographic order parameters, increased with higher absorbed dose for the three proteins at 100 K. At 278 K, however, the total increase in this disorder was only statistically significant for thaumatin. A correlation between specific radiation damage affecting side chains and the amount of disorder was not observed. This analysis suggests that elevated conformational heterogeneity in crystal structures at room temperature is observed despite radiation damage, and not as a result thereof. PMID- 28009550 TI - Design of a prototype split-and-delay unit for XFEL pulses, and their evaluation by synchrotron radiation X-rays. AB - A prototype split-and-delay unit (SDU) for X-ray free-electron laser (XFEL) pulses is proposed based on the Graeff-Bonse four-Bragg-reflection interferometer by installing 12.5 degrees slopes. The SDU can continuously provide a delay time from approximately -20 to 40 ps with a resolution of less than 26 fs. Because the SDU was constructed from a monolithic silicon crystal, alignment is straightforward. The obtained thoroughputs of the SDU reached 0.7% at 7.46 keV and 0.02% at 14.92 keV. The tunability of the delay time using the proposed SDU was demonstrated by finding the interference effects of the split X-rays, and the time resolution of the proposed SDU was evaluated using the width of the interference pattern recorded on the X-ray charge-coupled device camera by changing the energy, i.e. longitudinal coherence length, of the incident X-rays. It is expected that the proposed SDU will be applicable to XFEL experiments using delay times from tens of femtoseconds to tens of picoseconds, e.g. intensity correlation measurements. PMID- 28009549 TI - Bragg coherent diffraction imaging and metrics for radiation damage in protein micro-crystallography. AB - The proliferation of extremely intense synchrotron sources has enabled ever higher-resolution structures to be obtained using data collected from smaller and often more imperfect biological crystals (Helliwell, 1984). Synchrotron beamlines now exist that are capable of measuring data from single crystals that are just a few micrometres in size. This provides renewed motivation to study and understand the radiation damage behaviour of small protein crystals. Reciprocal-space mapping and Bragg coherent diffractive imaging experiments have been performed on cryo-cooled microcrystals of hen egg-white lysozyme as they undergo radiation damage. Several well established metrics, such as intensity-loss and lattice expansion, are applied to the diffraction data and the results are compared with several new metrics that can be extracted from the coherent imaging experiments. Individually some of these metrics are inconclusive. However, combining metrics, the results suggest that radiation damage behaviour in protein micro-crystals differs from that of larger protein crystals and may allow them to continue to diffract for longer. A possible mechanism to account for these observations is proposed. PMID- 28009551 TI - Linear parabolic single-crystal diamond refractive lenses for synchrotron X-ray sources. AB - Linear parabolic diamond refractive lenses are presented, designed to withstand high thermal and radiation loads coming from upgraded accelerator X-ray sources. Lenses were manufactured by picosecond laser treatment of a high-quality single crystal synthetic diamond. Twelve lenses with radius of curvature at parabola apex R = 200 um, geometrical aperture A = 900 um and length L = 1.5 mm were stacked as a compound refractive lens and tested at the ESRF ID06 beamline. A focal spot of size 2.2 um and a gain of 20 were measured at 8 keV. The lens profile and surface quality were estimated by grating interferometry and X-ray radiography. In addition, the influence of X-ray glitches on the focusing properties of the compound refractive lens were studied. PMID- 28009552 TI - Quantitative characterization of the X-ray beam at the Australian Synchrotron Imaging and Medical Beamline (IMBL). AB - A critical early phase for any synchrotron beamline involves detailed testing, characterization and commissioning; this is especially true of a beamline as ambitious and complex as the Imaging & Medical Beamline (IMBL) at the Australian Synchrotron. IMBL staff and expert users have been performing precise experiments aimed at quantitative characterization of the primary polychromatic and monochromatic X-ray beams, with particular emphasis placed on the wiggler insertion devices (IDs), the primary-slit system and any in vacuo and ex vacuo filters. The findings from these studies will be described herein. These results will benefit IMBL and other users in the future, especially those for whom detailed knowledge of the X-ray beam spectrum (or 'quality') and flux density is important. This information is critical for radiotherapy and radiobiology users, who ultimately need to know (to better than 5%) what X-ray dose or dose rate is being delivered to their samples. Various correction factors associated with ionization-chamber (IC) dosimetry have been accounted for, e.g. ion recombination, electron-loss effects. A new and innovative approach has been developed in this regard, which can provide confirmation of key parameter values such as the magnetic field in the wiggler and the effective thickness of key filters. IMBL commenced operation in December 2008 with an Advanced Photon Source (APS) wiggler as the (interim) ID. A superconducting multi-pole wiggler was installed and operational in January 2013. Results are obtained for both of these IDs and useful comparisons are made. A comprehensive model of the IMBL has been developed, embodied in a new computer program named spec.exe, which has been validated against a variety of experimental measurements. Having demonstrated the reliability and robustness of the model, it is then possible to use it in a practical and predictive manner. It is hoped that spec.exe will prove to be a useful resource for synchrotron science in general, and for hard X-ray beamlines, whether they are based on bending magnets or insertion devices, in particular. In due course, it is planned to make spec.exe freely available to other synchrotron scientists. PMID- 28009553 TI - Generation of apodized X-ray illumination and its application to scanning and diffraction microscopy. AB - X-ray science has greatly benefited from the progress in X-ray optics. Advances in the design and the manufacturing techniques of X-ray optics are key to the success of various microscopic and spectroscopic techniques practiced today. Here the generation of apodized X-ray illumination using a two-stage deformable Kirkpatrick-Baez mirror system is presented. Such apodized illumination is marked by the suppression of the side-lobe intensities of the focused beam. Thus generated apodized illumination was employed to improve the image quality in scanning X-ray fluorescence microscopy. Imaging of a non-isolated object by coherent X-ray diffractive imaging with apodized illumination in a non-scanning mode is also presented. PMID- 28009554 TI - X-ray grating interferometer for in situ and at-wavelength wavefront metrology. AB - A wavefront metrology setup based on the X-ray grating interferometry technique for spatially resolved, quantitative, in situ and at-wavelength measurements of the wavefront at synchrotron radiation and hard X-ray free-electron laser beamlines is reported. Indeed, the ever-increasing demands on the optical components to preserve the wavefront shape and the coherence of the delivered X ray beam call for more and more sensitive diagnostic instruments. Thanks to its angular sensitivity, X-ray grating interferometry has been established in recent years as an adequate wavefront-sensing technique for quantitatively assessing the quality of the X-ray wavefront under working conditions and hence for the in situ investigation of X-ray optical elements. In order to characterize the optical elements at any given beamline by measuring the aberrations introduced in the wavefront, a transportable X-ray grating interferometry setup was realised at the Swiss Light Source (SLS). The instrument, which is expected to be a valuable tool for investigating the quality of the X-ray beam delivered at an endstation, will be described hereafter in terms of the hardware setup and the related data analysis procedure. Several exemplary experiments performed at the X05DA Optics beamline of the SLS will be presented. PMID- 28009555 TI - Bunch-by-bunch position measurement and analysis at PLS-II. AB - A bunch-by-bunch measurement system has been developed at Pohang Light Source II. The system consists of a four-channel button pick-up, 20 GHz sampling oscilloscope and an 800 MHz low-pass digital filter. Upon measuring a bunch-by bunch spatio-temporal beam motion matrix over many turns, singular-value decomposition analysis is used to reveal the dominant coupled-bunch modes. The system can diagnose injection oscillations due to kicker errors and the effect of resistive-wall impedance that gives rise to instability during operation. PMID- 28009556 TI - Design of a multilayer-based collimated plane-grating monochromator for tender X ray range. AB - Collimated plane-grating monochromators (cPGMs), consisting of a plane mirror and plane diffraction grating, are essential optics in synchrotron radiation sources for their remarkable flexibility and good optical characteristics in the soft X ray region. However, the poor energy transport efficiency of a conventional cPGM (single-layer-coated) degrades the source intensity and leaves reduced flux at the sample, especially for the tender X-ray range (1-4 keV) that covers a large number of K- and L-edges of medium-Z elements, and M-edges of high-Z elements. To overcome this limitation, the use of a multilayer-based cPGM is proposed, combining a multilayer-coated plane mirror with blazed multilayer gratings. With this combination, the effective efficiency of cPGMs can be increased by an order of magnitude compared with the conventional single-layer cPGMs. In addition, higher resolving power can be achieved with improved efficiency by increasing the blaze angle and working at higher diffraction order. PMID- 28009557 TI - Performance of photoelectron spin polarimeters with continuous and pulsed sources: from storage rings to free electron lasers. AB - In this work the experimental uncertainties concerning electron spin polarization (SP) under various realistic measurement conditions are theoretically derived. The accuracy of the evaluation of the SP of the photoelectron current is analysed as a function of the detector parameters and specifications, as well as of the characteristics of the photoexcitation sources. In particular, the different behaviour of single counter or twin counter detectors when the intensity fluctuations of the source are considered have been addressed, leading to a new definition of the SP detector performance. The widely used parameter called the figure of merit is shown to be inadequate for describing the efficiency of SP polarimeters, especially when they are operated with time-structured excitation sources such as free-electron lasers. Numerical simulations have been performed and yield strong implications in the choice of the detecting instruments in spin polarization experiments, that are constrained in a limited measurement time. Our results are therefore applied to the characteristics of a wide set of state-of the-art spectroscopy facilities all over the world, and an efficiency diagram for SP experiments is derived. These results also define new mathematical instruments for handling the correct statistics of SP measurements in the presence of source intensity fluctuations. PMID- 28009558 TI - Dynamic X-ray diffraction sampling for protein crystal positioning. AB - A sparse supervised learning approach for dynamic sampling (SLADS) is described for dose reduction in diffraction-based protein crystal positioning. Crystal centering is typically a prerequisite for macromolecular diffraction at synchrotron facilities, with X-ray diffraction mapping growing in popularity as a mechanism for localization. In X-ray raster scanning, diffraction is used to identify the crystal positions based on the detection of Bragg-like peaks in the scattering patterns; however, this additional X-ray exposure may result in detectable damage to the crystal prior to data collection. Dynamic sampling, in which preceding measurements inform the next most information-rich location to probe for image reconstruction, significantly reduced the X-ray dose experienced by protein crystals during positioning by diffraction raster scanning. The SLADS algorithm implemented herein is designed for single-pixel measurements and can select a new location to measure. In each step of SLADS, the algorithm selects the pixel, which, when measured, maximizes the expected reduction in distortion given previous measurements. Ground-truth diffraction data were obtained for a 5 um-diameter beam and SLADS reconstructed the image sampling 31% of the total volume and only 9% of the interior of the crystal greatly reducing the X-ray dosage on the crystal. Using in situ two-photon-excited fluorescence microscopy measurements as a surrogate for diffraction imaging with a 1 um-diameter beam, the SLADS algorithm enabled image reconstruction from a 7% sampling of the total volume and 12% sampling of the interior of the crystal. When implemented into the beamline at Argonne National Laboratory, without ground-truth images, an acceptable reconstruction was obtained with 3% of the image sampled and approximately 5% of the crystal. The incorporation of SLADS into X-ray diffraction acquisitions has the potential to significantly minimize the impact of X-ray exposure on the crystal by limiting the dose and area exposed for image reconstruction and crystal positioning using data collection hardware present in most macromolecular crystallography end-stations. PMID- 28009559 TI - Coherent X-ray beam metrology using 2D high-resolution Fresnel-diffraction analysis. AB - Direct metrology of coherent short-wavelength beamlines is important for obtaining operational beam characteristics at the experimental site. However, since beam-time limitation imposes fast metrology procedures, a multi-parametric metrology from as low as a single shot is desirable. Here a two-dimensional (2D) procedure based on high-resolution Fresnel diffraction analysis is discussed and applied, which allowed an efficient and detailed beamline characterization at the SACLA XFEL. So far, the potential of Fresnel diffraction for beamline metrology has not been fully exploited because its high-frequency fringes could be only partly resolved with ordinary pixel-limited detectors. Using the high-spatial frequency imaging capability of an irradiated LiF crystal, 2D information of the coherence degree, beam divergence and beam quality factor M2 were retrieved from simple diffraction patterns. The developed beam metrology was validated with a laboratory reference laser, and then successfully applied at a beamline facility, in agreement with the source specifications. PMID- 28009560 TI - Fast iterative reconstruction of data in full interior tomography. AB - This paper introduces two novel strategies for iterative reconstruction of full interior tomography (FINT) data, i.e. when the field of view is entirely inside the object support and knowledge of the object support itself or the attenuation coefficients inside specific regions of interest are not available. The first approach is based on data edge-padding. The second technique creates an intermediate virtual sinogram, which is, then, reconstructed by a standard iterative algorithm. Both strategies are validated in the framework of the alternate direction method of multipliers plug-and-play with gridding projectors that provide a speed-up of three orders of magnitude with respect to standard operators implemented in real space. The proposed methods are benchmarked on synchrotron-based X-ray tomographic microscopy datasets of mouse lung alveoli. Compared with analytical techniques, the proposed methods substantially improve the reconstruction quality for FINT underconstrained datasets, facilitating subsequent post-processing steps. PMID- 28009561 TI - On the use of flat-fields for tomographic reconstruction. AB - Seeking for quantitative tomographic images, it is of utmost importance to limit reconstruction artifacts. Detector imperfections, inhomogeneity of the incident beam, as classically observed in synchrotron beamlines, and their variations in time are a major cause of reconstruction bias such as 'ring artifacts'. The present study aims at proposing a faithful estimate of the incident beam local intensity for each acquired projection during a scan, without revisiting the process of data acquisition itself. Actual flat-fields (acquired without specimen in the beam) and sinogram borders (when the specimen is present), which are not masked during the scan, are exploited to construct a suited instantaneous detector-wide flat-field. The proposed treatment is fast and simple. Its performance is assessed on a real scan acquired at ESRF ID19 beamline. Different criteria are used including residuals, i.e. difference between projections of reconstruction and actual projections. All confirm the benefit of the proposed procedure. PMID- 28009562 TI - Synchrotron-based phase-sensitive imaging of leaves grown from magneto-primed seeds of soybean. AB - Experiments were conducted to study the effects of static magnetic fields (SMFs) on the venation network of soybean leaves using the synchrotron-based X-ray micro imaging technique. The seeds of soybean (Glycine max, variety JS-335) were pretreated with different SMFs from 50 to 300 mT in steps of 50 mT for 1 h. The phase-contrast images obtained showed that, as the strength of the SMF increased, the area, width of the midrib, area of the midrib and minor vein of the middle leaflets of third trifoliate leaves also increased up to the SMF strength of 200 mT (1 h) and decreased thereafter. Quantification of the major conducting vein also showed the differences in the major and minor vein structures of the soybean leaves as compared with control leaves. Further, the phase-retrieval technique has been applied to make the segmentation process easy and to quantify the major and minor veins in the venation network. The width and area of midrib enhancement by pre-treatment with SMF implies an enhancement in the uptake of water, which in turn causes an increased rate of photosynthesis and stomatal conductance. PMID- 28009563 TI - Development of synchrotron X-ray micro-tomography under extreme conditions of pressure and temperature. AB - X-ray tomography is a non-destructive three-dimensional imaging/microanalysis technique selective to a wide range of properties such as density, chemical composition, chemical states and crystallographic structure with extremely high sensitivity and spatial resolution. Here the development of in situ high-pressure high-temperature micro-tomography using a rotating module for the Paris-Edinburgh cell combined with synchrotron radiation is described. By rotating the sample chamber by 360 degrees , the limited angular aperture of ordinary high-pressure cells is surmounted. Such a non-destructive high-resolution probe provides three dimensional insight on the morphological and structural evolution of crystalline as well as amorphous phases during high pressure and temperature treatment. To demonstrate the potentials of this new experimental technique the compression behavior of a basalt glass is investigated by X-ray absorption tomography, and diffraction/scattering tomography imaging of the structural changes during the polymerization of C60 molecules under pressure is performed. Small size and weight of the loading frame and rotating module means that this apparatus is portable, and can be readily installed on most synchrotron facilities to take advantage of the diversity of three-dimensional imaging techniques available at beamlines. This experimental breakthrough should open new ways for in situ imaging of materials under extreme pressure-temperature-stress conditions, impacting diverse areas in physics, chemistry, geology or materials sciences. PMID- 28009564 TI - Automatic processing of multimodal tomography datasets. AB - With the development of fourth-generation high-brightness synchrotrons on the horizon, the already large volume of data that will be collected on imaging and mapping beamlines is set to increase by orders of magnitude. As such, an easy and accessible way of dealing with such large datasets as quickly as possible is required in order to be able to address the core scientific problems during the experimental data collection. Savu is an accessible and flexible big data processing framework that is able to deal with both the variety and the volume of data of multimodal and multidimensional scientific datasets output such as those from chemical tomography experiments on the I18 microfocus scanning beamline at Diamond Light Source. PMID- 28009565 TI - A practical local tomography reconstruction algorithm based on a known sub region. AB - A new method to reconstruct data acquired in a local tomography setup is proposed. This method uses an initial reconstruction and refines it by correcting the low-frequency artifacts, known as the cupping effect. A basis of Gaussian functions is used to correct the initial reconstruction. The coefficients of this basis are found by optimizing iteratively a fidelity term under the constraint of a known sub-region. Using a coarse basis reduces the degrees of freedom of the problem while actually correcting the cupping effect. Simulations show that the known region constraint yields an unbiased reconstruction, in accordance with uniqueness theorems stated in local tomography. PMID- 28009566 TI - Direct tomography imaging for inelastic X-ray scattering experiments at high pressure. AB - A method to separate the non-resonant inelastic X-ray scattering signal of a micro-metric sample contained inside a diamond anvil cell (DAC) from the signal originating from the high-pressure sample environment is described. Especially for high-pressure experiments, the parasitic signal originating from the diamond anvils, the gasket and/or the pressure medium can easily obscure the sample signal or even render the experiment impossible. Another severe complication for high-pressure non-resonant inelastic X-ray measurements, such as X-ray Raman scattering spectroscopy, can be the proximity of the desired sample edge energy to an absorption edge energy of elements constituting the DAC. It is shown that recording the scattered signal in a spatially resolved manner allows these problems to be overcome by separating the sample signal from the spurious scattering of the DAC without constraints on the solid angle of detection. Furthermore, simple machine learning algorithms facilitate finding the corresponding detector pixels that record the sample signal. The outlined experimental technique and data analysis approach are demonstrated by presenting spectra of the Si L2,3-edge and O K-edge of compressed alpha-quartz. The spectra are of unprecedented quality and both the O K-edge and the Si L2,3-edge clearly show the existence of a pressure-induced phase transition between 10 and 24 GPa. PMID- 28009567 TI - Miniature diamond anvils for X-ray Raman scattering spectroscopy experiments at high pressure. AB - X-ray Raman scattering (XRS) spectroscopy is an inelastic scattering method that uses hard X-rays of the order of 10 keV to measure energy-loss spectra at absorption edges of light elements (Si, Mg, O etc.), with an energy resolution below 1 eV. The high-energy X-rays employed with this technique can penetrate thick or dense sample containers such as the diamond anvils employed in high pressure cells. Here, we describe the use of custom-made conical miniature diamond anvils of less than 500 um thickness which allow pressure generation of up to 70 GPa. This set-up overcomes the limitations of the XRS technique in very high-pressure measurements (>10 GPa) by drastically improving the signal-to-noise ratio. The conical shape of the base of the diamonds gives a 70 degrees opening angle, enabling measurements in both low- and high-angle scattering geometry. This reduction of the diamond thickness to one-third of the classical diamond anvils considerably lowers the attenuation of the incoming and the scattered beams and thus enhances the signal-to-noise ratio significantly. A further improvement of the signal-to-background ratio is obtained by a recess of ~20 um that is milled in the culet of the miniature anvils. This recess increases the sample scattering volume by a factor of three at a pressure of 60 GPa. Examples of X-ray Raman spectra collected at the O K-edge and Si L-edge in SiO2 glass at high pressures up to 47 GPa demonstrate the significant improvement and potential for spectroscopic studies of low-Z elements at high pressure. PMID- 28009568 TI - Determination of copper nanoparticle size distributions with total reflection X ray fluorescence spectroscopy. AB - Total reflection X-ray fluorescence (TXRF) analysis is extensively used by the semiconductor industry for measuring trace metal contamination on silicon surfaces. In addition to determining the quantity of impurities on a surface, TXRF can reveal information about the vertical distribution of contaminants by measuring the fluorescence signal as a function of the angle of incidence. In this study, two samples were intentionally contaminated with copper in non deoxygenated and deoxygenated ultrapure water (UPW) resulting in impurity profiles that were either atomically dispersed in a thin film or particle-like, respectively. The concentration profile of the samples immersed into deoxygenated UPW was calculated using a theoretical concentration profile representative of particles, yielding a mean particle height of 16.1 nm. However, the resulting theoretical profile suggested that a distribution of particle heights exists on the surface. The fit of the angular distribution data was further refined by minimizing the residual error of a least-squares fit employing a model with a Gaussian distribution of particle heights about the mean height. The presence of a height distribution was also confirmed with atomic force microscopy measurements. PMID- 28009569 TI - X-ray fluorescence at nanoscale resolution for multicomponent layered structures: a solar cell case study. AB - The study of a multilayered and multicomponent system by spatially resolved X-ray fluorescence microscopy poses unique challenges in achieving accurate quantification of elemental distributions. This is particularly true for the quantification of materials with high X-ray attenuation coefficients, depth dependent composition variations and thickness variations. A widely applicable procedure for use after spectrum fitting and quantification is described. This procedure corrects the elemental distribution from the measured fluorescence signal, taking into account attenuation of the incident beam and generated fluorescence from multiple layers, and accounts for sample thickness variations. Deriving from Beer-Lambert's law, formulae are presented in a general integral form and numerically applicable framework. The procedure is applied using experimental data from a solar cell with a Cu(In,Ga)Se2 absorber layer, measured at two separate synchrotron beamlines with varied measurement geometries. This example shows the importance of these corrections in real material systems, which can change the interpretation of the measured distributions dramatically. PMID- 28009570 TI - 1s2p resonant inelastic X-ray scattering combined dipole and quadrupole analysis method. AB - In this study an analysis strategy towards using the resonant inelastic X-ray scattering (RIXS) technique more effectively compared with X-ray absorption spectroscopy (XAS) is presented. In particular, the question of when RIXS brings extra information compared with XAS is addressed. To answer this question the RIXS plane is analysed using two models: (i) an exciton model and (ii) a continuum model. The continuum model describes the dipole pre-edge excitations while the exciton model describes the quadrupole excitations. Applying our approach to the experimental 1s2p RIXS planes of VO2 and TiO2, it is shown that only in the case of quadrupole excitations being present is additional information gained by RIXS compared with XAS. Combining this knowledge with methods to calculate the dipole contribution in XAS measurements gives scientists the opportunity to plan more effective experiments. PMID- 28009571 TI - An endstation for resonant inelastic X-ray scattering studies of solid and liquid samples. AB - A novel experimental setup is presented for resonant inelastic X-ray scattering investigations of solid and liquid samples in the soft X-ray region for studying the complex electronic configuration of (bio)chemical systems. The uniqueness of the apparatus is its high flexibility combined with optimal energy resolution and energy range ratio. The apparatus enables investigation of chemical analyses, which reflects the chemical imprints. The endstation is composed of a main sample chamber, a sample holder for either solid or liquid jet delivery system, and a soft X-ray grating spectrometer for 210-1250 eV with a resolving power of ~1000. It combines for the first time liquid jet technology with a soft X-ray spectrometer based on the variable line spacing principle. This setup was commissioned at the soft X-ray beamline P04 at PETRA III of the Deutsches Elektronen-Synchrotron in Hamburg which is currently the most brilliant storage ring-based X-ray radiation source in the world. The first results of liquid and solid samples show that this setup allows the detection of photons across an energy range of ~300 eV. This covers simultaneously the emission lines of life important elements like carbon, nitrogen and oxygen in a shot-based procedure. PMID- 28009572 TI - Synchrotron radiation micro X-ray fluorescence spectroscopy of thin structures in bone samples: comparison of confocal and color X-ray camera setups. AB - In the quest for finding the ideal synchrotron-radiation-induced imaging method for the investigation of trace element distributions in human bone samples, experiments were performed using both a scanning confocal synchrotron radiation micro X-ray fluorescence (SR-uXRF) (FLUO beamline at ANKA) setup and a full-field color X-ray camera (BAMline at BESSY-II) setup. As zinc is a trace element of special interest in bone, the setups were optimized for its detection. The setups were compared with respect to count rate, required measurement time and spatial resolution. It was demonstrated that the ideal method depends on the element of interest. Although for Ca (a major constituent of the bone with a low energy of 3.69 keV for its Kalpha XRF line) the color X-ray camera provided a higher resolution in the plane, for Zn (a trace element in bone) only the confocal SR uXRF setup was able to sufficiently image the distribution. PMID- 28009573 TI - Analytic expressions for the angular and the spectral fluxes at Compton X-ray sources. AB - The goal of this paper is to express simply the number of photons impinging on a target in the framework of accelerator-based Compton X-ray sources. From the basic kinematics of Compton sources, analytic formulas for the angular and the spectral fluxes are established as functions of the energy spread or/and the angular divergence of the electron and the laser beams. Their detailed predictions are compared with Monte Carlo simulations. These analytic expressions allow one to compute in a simple and precise way the X-ray flux in a given angular acceptance and a given energy bandwidth, knowing the characteristics of the incoming beams. PMID- 28009574 TI - P13, the EMBL macromolecular crystallography beamline at the low-emittance PETRA III ring for high- and low-energy phasing with variable beam focusing. AB - The macromolecular crystallography P13 beamline is part of the European Molecular Biology Laboratory Integrated Facility for Structural Biology at PETRA III (DESY, Hamburg, Germany) and has been in user operation since mid-2013. P13 is tunable across the energy range from 4 to 17.5 keV to support crystallographic data acquisition exploiting a wide range of elemental absorption edges for experimental phase determination. An adaptive Kirkpatrick-Baez focusing system provides an X-ray beam with a high photon flux and tunable focus size to adapt to diverse experimental situations. Data collections at energies as low as 4 keV (lambda = 3.1 A) are possible due to a beamline design minimizing background and maximizing photon flux particularly at low energy (up to 1011 photons s-1 at 4 keV), a custom calibration of the PILATUS 6M-F detector for use at low energies, and the availability of a helium path. At high energies, the high photon flux (5.4 * 1011 photons s-1 at 17.5 keV) combined with a large area detector mounted on a 2theta arm allows data collection to sub-atomic resolution (0.55 A). A peak flux of about 8.0 * 1012 photons s-1 is reached at 11 keV. Automated sample mounting is available by means of the robotic sample changer 'MARVIN' with a dewar capacity of 160 samples. In close proximity to the beamline, laboratories have been set up for sample preparation and characterization; a laboratory specifically equipped for on-site heavy atom derivatization with a library of more than 150 compounds is available to beamline users. PMID- 28009575 TI - Medium-energy microprobe station at the SXRMB of the CLS. AB - Micro-XAFS and chemical imaging techniques have been widely applied for studies of heterogeneously distributed systems, mostly in hard X-ray (>5 keV) or in soft X-ray (<1.5 keV) energies. The microprobe endstation of the SXRMB (soft X-ray microcharacterization beamline) at the Canadian Light Source is optimized at the medium energy (1.7-5 keV), and it has been recently commissioned and is available for general users. The technical design and the performance (energy range, beam size and flux) of the SXRMB microprobe are presented. Examples in chemical imaging and micro-XAFS in the medium energy for important elements such as P, S and Ca for soil and biological samples are highlighted. PMID- 28009576 TI - Protein crystallography beamline BL2S1 at the Aichi synchrotron. AB - The protein crystallography beamline BL2S1, constructed at one of the 5 T superconducting bending-magnet ports of the Aichi synchrotron, is available to users associated with academic and industrial organizations. The beamline is mainly intended for use in X-ray diffraction measurements of single-crystals of macromolecules such as proteins and nucleic acids. Diffraction measurements for crystals of other materials are also possible, such as inorganic and organic compounds. BL2S1 covers the energy range 7-17 keV (1.8-0.7 A) with an asymmetric cut curved single-crystal monochromator [Ge(111) or Ge(220)], and a platinum coated Si mirror is used for vertical focusing and as a higher-order cutoff filter. The beamline is equipped with a single-axis goniometer, a CCD detector, and an open-flow cryogenic sample cooler. High-pressure protein crystallography with a diamond anvil cell can also be performed using this beamline. PMID- 28009578 TI - Surface science at the PEARL beamline of the Swiss Light Source. AB - The Photo-Emission and Atomic Resolution Laboratory (PEARL) is a new soft X-ray beamline and surface science laboratory at the Swiss Light Source. PEARL is dedicated to the structural characterization of local bonding geometry at surfaces and interfaces of novel materials, in particular of molecular adsorbates, nanostructured surfaces, and surfaces of complex materials. The main experimental techniques are soft X-ray photoelectron spectroscopy, photoelectron diffraction, and scanning tunneling microscopy (STM). Photoelectron diffraction in angle-scanned mode measures bonding angles of atoms near the emitter atom, and thus allows the orientation of small molecules on a substrate to be determined. In energy scanned mode it measures the distance between the emitter and neighboring atoms; for example, between adsorbate and substrate. STM provides complementary, real-space information, and is particularly useful for comparing the sample quality with reference measurements. In this article, the key features and measured performance data of the beamline and the experimental station are presented. As scientific examples, the adsorbate-substrate distance in hexagonal boron nitride on Ni(111), surface quantum well states in a metal-organic network of dicyano-anthracene on Cu(111), and circular dichroism in the photoelectron diffraction of Cu(111) are discussed. PMID- 28009577 TI - The SPECIES beamline at the MAX IV Laboratory: a facility for soft X-ray RIXS and APXPS. AB - SPECIES is an undulator-based soft X-ray beamline that replaced the old I511 beamline at the MAX II storage ring. SPECIES is aimed at high-resolution ambient pressure X-ray photoelectron spectroscopy (APXPS), near-edge X-ray absorption fine-structure (NEXAFS), X-ray emission spectroscopy (XES) and resonant inelastic X-ray scattering (RIXS) experiments. The beamline has two branches that use a common elliptically polarizing undulator and monochromator. The beam is switched between the two branches by changing the focusing optics after the monochromator. Both branches have separate exit slits, refocusing optics and dedicated permanent endstations. This allows very fast switching between two types of experiments and offers a unique combination of the surface-sensitive XPS and bulk-sensitive RIXS techniques both in UHV and at elevated ambient-pressure conditions on a single beamline. Another unique property of the beamline is that it reaches energies down to approximately 27 eV, which is not obtainable on other current APXPS beamlines. This allows, for instance, valence band studies under ambient-pressure conditions. In this article the main properties and performance of the beamline are presented, together with selected showcase experiments performed on the new setup. PMID- 28009579 TI - AI-BL1.0: a program for automatic on-line beamline optimization using the evolutionary algorithm. AB - In this report, AI-BL1.0, an open-source Labview-based program for automatic on line beamline optimization, is presented. The optimization algorithms used in the program are Genetic Algorithm and Differential Evolution. Efficiency was improved by use of a strategy known as Observer Mode for Evolutionary Algorithm. The program was constructed and validated at the XAFCA beamline of the Singapore Synchrotron Light Source and 1W1B beamline of the Beijing Synchrotron Radiation Facility. PMID- 28009580 TI - Creating a Physical Activity Self-Report Form for Youth Using Rasch Methodology. AB - Measurement of youth's physical activity levels is recommended to ensure that children are meeting recommended activity guidelines. This article describes the creation of an instrument to measure youth's levels of physical activity, where a strong test validation perspective (Benson, 1998) was followed to create the scale. The development process involved a mixed-method (qualitative followed by quantitative) framework. First, focus groups were conducted, where results informed item creation. Next, three alternative forms were created with different response formats to measure childrens' frequency of participation in various physical activities and intensity of participation. Lastly, a sample of over 500 middle school children was obtained, where three different response scales were investigated. The optimal scale considered measurement of physical activity using a three-point Likert frequency; intensity of activity participation did not strongly contribute to the measurement of children's activity levels. The final version form is thought to be acceptable for use with children in surveillance and large-group studies, as well as in smaller sample applications. PMID- 28009581 TI - Examining the Psychometric Quality of Multiple-Choice Assessment Items using Mokken Scale Analysis. AB - The concept of invariant measurement is typically associated with Rasch measurement theory (Engelhard, 2013). Concerned with the appropriateness of the parametric transformation upon which the Rasch model is based, Mokken (1971) proposed a nonparametric procedure for evaluating the quality of social science measurement that is theoretically and empirically related to the Rasch model. Mokken's nonparametric procedure can be used to evaluate the quality of dichotomous and polytomous items in terms of the requirements for invariant measurement. Despite these potential benefits, the use of Mokken scaling to examine the properties of multiple-choice (MC) items in education has not yet been fully explored. A nonparametric approach to evaluating MC items is promising in that this approach facilitates the evaluation of assessments in terms of invariant measurement without imposing potentially inappropriate transformations. Using Rasch-based indices of measurement quality as a frame of reference, data from an eighth-grade physical science assessment are used to illustrate and explore Mokken-based techniques for evaluating the quality of MC items. Implications for research and practice are discussed. PMID- 28009583 TI - Using the Rasch Model and k-Nearest Neighbors Algorithm for Response Classification. AB - In this paper we propose using the k-nearest neighbors (k-NN) algorithm (Cover and Hart, 1967) for classifying and predicting the responses to dichotomous items. We show using the percent correct statistic how k-NN can be used with Rasch model parameter estimation methods such as joint maximum likelihood (JMLE), conditional maximum likelihood estimation (CMLE), marginal maximum likelihood estimation (MMLE), and marginal Bayes modal estimation (MBME). We further suggest how one can use the algorithm to predict responses on future assessments. The empirical data set that we used to illustrate this procedure was the fraction subtraction data set from Tatsuoka (1984). Using R software we show the accuracy and efficacy of k-NN for classifying responses. PMID- 28009582 TI - A Practitioner's Instrument for Measuring Secondary Mathematics Teachers' Beliefs Surrounding Learner-Centered Classroom Practice. AB - In this paper we present the development and validation of a Mathematics Teaching Pedagogical and Discourse Beliefs Instrument (MTPDBI), a 20 item partial-credit survey designed and analyzed using Rasch measurement theory. Items on the MTPDBI address beliefs about the nature of mathematics, teaching and learning mathematics, and classroom discourse practices. A Rasch partial credit model (Masters, 1982) was estimated from the pilot study data. Results show that item separation reliability is .96 and person separation reliability is .71. Other analyses indicate the instrument is a viable measure of secondary teachers' beliefs about reform-oriented mathematics teaching and learning. This instrument is proposed as a useful measure of teacher beliefs for those working with pre service and in-service teacher development. PMID- 28009584 TI - Exploring Aberrant Responses Using Person Fit and Person Response Functions. AB - Person fit statistics provide equivocal interpretations regarding aberrant responses. This study uses person response functions (PRF) to supplement the interpretation of person fit statistics. Sixty-three multiple-choice items were administered to a sample of persons (N=31) who used guessing strategies to answer them. After answering each item, participants indicated which guessing strategy they used. The data were analyzed with a Rasch (1960) model, where the item calibrations were anchored to values obtained when the items were appropriately administered. The participants showed poor model-data fit as expected. Further examination of person misfit using person response functions suggests that PRF can provide information about absolute person fit to a model, whereas fit statistics provide information about relative fit, given the other persons in the testing group. PRF can also provide information about where and how person responses misfit the model. This additional information can assist practitioners in using and interpreting individual scores appropriately. PMID- 28009585 TI - Evaluation of the Bifactor Nominal Response Model Analysis of a Health Efficacy Measure. AB - The bifactor nominal response item response theory (IRT) model, proposed by Cai, Yang and Hansen (2011), provides an extension of Bock's (1972, 1997) unidimensional nominal response model to multidimensional IRT. This model has not been utilized in any published studies since its original development. In this study, the model was applied to data from a sample of college students (N = 799) to evaluate the psychometric properties of a health efficacy measure. The nominal response model has the unique capability to estimate the functioning of each single response category, and higher response categories were found to have better functioning in this study. Poor-functioning categories were identified and combined into their adjacent categories. Items with revised response format showed improved functioning. The bifactor nominal response model is a useful tool for evaluation of bifactor scales with ordered while non-equivalently functioning categories. PMID- 28009586 TI - Measurement Properties of the Nordic Questionnaire for Psychological and Social Factors at Work: A Rasch Analysis. AB - The main aim of this study was to evaluate the measurement properties of the Nordic Questionnaire for Psychological and Social Factors at Work (QPS Nordic) and the domains of demand, control and support. The Rasch analysis (RUMM 2030) was based on responses from 226 subjects with back pain who completed the QPS Nordic dimensions of demand, control, and social support (30 items) at one year follow up. The Rasch analysis revealed disordered thresholds in a total of 25 of the 30 items. The domains of demand, control and support fit the Rasch model when analyzed separately. The demand domain was well targeted, whereas patients with current neck and back pain had lower control and higher support than reflected by the questions. Two items revealed DIF by gender, otherwise invariance to age, gender, occupation and sick-leave was documented. The demand, control support domains of QPS Nordic comprised unidimensional constructs with adequate measurement properties. PMID- 28009587 TI - Ben Wright: A wisp of greatness Brief photographic review of his life and times. PMID- 28009588 TI - Does Instruction Affect the Underlying Dimensionality of a Kinesiology Test? AB - Does effective instruction, which changes students' knowledge and possibly alters their cognitive functions, also affect the dimensionality of an achievement test? This question was examined by the parameterization of kinesiology test items (n = 42) with a Rasch dichotomous model, followed by an investigation of dimensionality in a pre- and post-test quasi-experimental study design. College students (n = 108) provided responses to kinesiology achievement test items. Then the stability of item difficulties, gender differences, and the interaction of item content categories with dimensionality were examined. In addition, a PCA/t test protocol was implemented to examine dimensionality threats from the item residuals. Internal construct validity was investigated by regressing item content components on calibrated item difficulties. Measurement model item residuals were also investigated with statistical decomposition methods. In general, the results showed significant student achievement between pre and post testing, and dimensionality disturbances were relatively minor. The amount of unexpected item "shift" in an un-equated measurement dimension between pre and post testing was less than ten percent of the total items and largely concentrated among several unrelated items. An unexpected finding was a residual cluster consisting of several items testing related technical content. Complicating interpretation, these items tended to appear near the end of the test, which implicates test position as a threat to measurement equivalence. In general, the results across several methods did not tend to identify common threats and instead pointed to multiple sources of threats with varying degree of prominence. These results suggest conventional approaches to measurement equivalence that emphasize expedient overall procedures such as DIF, IRT, and factor analysis are probably capturing isolated sources of variability. Their implementation probably improves measurement equivalence but with substantial residual sources undetected. PMID- 28009589 TI - Sample Size and Statistical Conclusions from Tests of Fit to the Rasch Model According to the Rasch Unidimensional Measurement Model (Rumm) Program in Health Outcome Measurement. AB - Sample size is a major factor in statistical null hypothesis testing, which is the basis for many approaches to testing Rasch model fit. Few sample size recommendations for testing fit to the Rasch model concern the Rasch Unidimensional Measurement Models (RUMM) software, which features chi-square and ANOVA/F-ratio based fit statistics, including Bonferroni and algebraic sample size adjustments. This paper explores the occurrence of Type I errors with RUMM fit statistics, and the effects of algebraic sample size adjustments. Data with simulated Rasch model fitting 25-item dichotomous scales and sample sizes ranging from N = 50 to N = 2500 were analysed with and without algebraically adjusted sample sizes. Results suggest the occurrence of Type I errors with N less then or equal to 500, and that Bonferroni correction as well as downward algebraic sample size adjustment are useful to avoid such errors, whereas upward adjustment of smaller samples falsely signal misfit. Our observations suggest that sample sizes around N = 250 to N = 500 may provide a good balance for the statistical interpretation of the RUMM fit statistics studied here with respect to Type I errors and under the assumption of Rasch model fit within the examined frame of reference (i.e., about 25 item parameters well targeted to the sample). PMID- 28009590 TI - Simultaneous Ability and Difficulty Estimation Via the Linear Discriminant Function. AB - In this paper, parameter estimation of the dichotomous Rasch model (Rasch, 1960) using the linear discriminant function (Fisher, 1936) is presented. This is accomplished by considering the scored item responses to be distinct groups and using a design matrix that is identical to one used in logistic regression for joint maximum likelihood estimation. The real dataset that was examined was the fraction subtraction dataset from Tatsuoka (1984). Through simulation parameter estimation accuracy using the linear discriminant function was compared to joint maximum likelihood estimation using logistic regression. Using the linear discriminant function person ability estimates from perfect total scores and total response scores of zero were estimable without using an ad hoc procedure, which is a well-known shortcoming of logistic regression based joint maximum likelihood estimation. Finally, computation of a closed-form solution for parameter estimation using the linear discriminant function is discussed. PMID- 28009591 TI - Examining Class Differences in Method Effects Related to Negative Wording: An Example using Rasch Mixture Modeling. AB - This study presents a mixture Rasch-based approach to investigating method effects associated with negatively worded items to illustrate how responses to this method effect vary depending on group characteristics. Using college students' responses on the Rosenberg Self-Esteem scale (Rosenberg, M., 1989), four latent classes were identified using six personality measures associated with the presence of this method effect. In addition, Rasch-based parameter estimates suggested latent classes differed in their use of the scale, showing that the method effect associated with negatively worded items may be more prominent for subjects possessing selected personality traits than for others. The mixture model approach to investigating method effects provides a way to address systematic methodological variation that is left unaccounted when a heterogeneous population is analyzed as one group. PMID- 28009592 TI - Assessment of Acute Trauma Exposure Response for FIRE-EMS Personnel. AB - PURPOSE: The purpose of this study was to develop an instrument that measures response to acute trauma exposure for firefighter and emergency medical service (EMS) personnel. The Acute Trauma Exposure Response Scale (ATERS) was intended to assess firefighter and EMS personnel response to acute trauma exposure from analytical, emotional, and physical perspectives. METHODS: Data were analyzed on 97 firefighter and EMS personnel employed by a fire department in a mid-sized city in a western state. Principal component analysis (PCAR) using Winsteps software was employed to discover which variables in the set formed logical subsets that were independent of one another and included item analyses and assessment of internal consistency reliability (Cronbach's alpha). Rasch analysis included examination of dimensionality, person and item reliability, scale use and function, and construct validity including person-item fit statistics. RESULTS: Principal component analyses of residuals (PCAR) revealed three primary scales which were termed Emotional Psyche, Coping Ability, and Support Systems. Rasch analyses showed the ATERS performance to be acceptable as a new pilot measure with three distinct scales through reliability of person separation of .81 for Emotional Psyche, .66 for Coping Ability, and .63 for Support Systems, respectively (Nunnally and Bernstein, 1994; Carmines and Zeller, 1979; Devellis, 2012). The Rasch item reliability was .96 for Emotional Psyche, .95 for Coping Ability, and .97 for Support Systems. Response scale use and function was appropriate for each subscale. Validity was supported through PCA by evidence of good internal consistency. High item correlations indicated the items for each subscale were measuring a single construct. Likewise, Rasch analyses provided evidence of validity through an even spread of person ability to item difficulty for each of the three constructs. Good item fit provided proof of construct relevant variance and the absence of gaps along the unidimensional continuum indicated each construct to be represented adequately. CONCLUSION: The ATERS performs well as a measure of acute trauma exposure response for three primary constructs: Emotional Psyche, Coping Ability, and Support Systems with good Rasch person internal consistency reliability and factor structure. Items were deleted for each scale following PCA and Rasch analyses due to misfit and low loadings. Further research is recommended to optimally represent each construct in regards to person-item fit. Fire departments may utilize results of this study to assess current program effectiveness. Through evaluation, departments may incorporate programs and resources that are more effective at reducing stress associated with acute trauma, thereby increasing employees overall job satisfaction and performance. PMID- 28009593 TI - A Rasch Rating Scale Analysis of the Presence of Nursing Scale-RN. AB - The phenomenon of nursing presence encompasses the emotional connection between nurse and patient, and technical skills performed by the nurse. The Presence of Nursing Scale-RN version (PONS-RN) was developed to measure nurses' perceptions of their ability to be present to their patients. This study summarizes the process of re-evaluation of the psychometric properties of the PONS-RN instrument. A sample of 76 registered nurses providing direct patient care responded to the 31-item questionnaire. The Rasch rating scale model was used for assessing construct validity of PONS-RN data. A principal component analysis (PCA) of residuals supported appropriateness of the subscales defined by a 2 dimensional structure. The results of item and person fit analysis, rating scale functioning analysis and reliability analysis have demonstrated that the thirty one item Presence of Nursing Scale-RN instrument yielded measures with high validity and reliability as two sub-scales. PMID- 28009594 TI - Assessing the Psychometric Properties of Alternative Items for Certification. AB - Alternative items were added as scored items to the National Certification Examination for Nurse Anesthetists (NCE) in 2010. A common concern related to the new items has been their measurement attributes. This study was undertaken to evaluate the psychometric impact of adding these items to the examination. Candidates had a significantly higher ability estimate in alternative items than in multiple choice questions and 6.7 percent of test candidates performed significantly differently in alternative item formats. The ability estimates of multiple choice questions correlated at r = .58. The alternative items took significantly longer time to answer than standard multiple choice questions and discriminated to a higher degree than MCQs. The alternative items exhibited unidimensionality to the same degree as MCQs and the BIC confirmed the Rasch model as acceptable for scoring. The new item types were found to have acceptable attributes for inclusion in the certification program. PMID- 28009595 TI - Likert is Pronounced "LICK-urt" not "LIE-kurt" and the Data are Ordinal not Interval. AB - Likert-type scales are popular in educational research and often times analyzed using parametric tests. Implied in this kind of study is a general assumption that these data are interval in nature. The authors contend that this is an incorrect supposition as Likert type data are actually ordinal, hence any analysis should be restricted to non-parametric investigations. Such confusion is understandable as Likert-type responses are assigned numbers signifying varying degrees of agreement with respect to behaviors or attitudes giving rise to a certain quantitative air to these data. Such responses are qualitative with meaning limited specifically to the choices available to the respondent; no more and no less. The mode is the preferable measure of central tendency instead of the mean or standard deviation. Non-parametric analysis ensures future researchers do not mistakenly infer their results are replicable beyond that of their sample. Regrettably, Likert scales simply cannot meet this standard of reliability. PMID- 28009596 TI - Erratum: Accounting for local dependence with the Rasch model: The paradox of information increase. AB - Contains a correction to Table 5 in original publication appearing in Journal of Applied Measurement, 17, 262-282. PMID- 28009597 TI - A Review of Treatment for Breast Cancer-Related Lymphedema: Paradigms for Clinical Practice. AB - OBJECTIVES: Breast cancer-related lymphedema (BCRL) represents a major complication of breast cancer treatment, impacting the quality of life for breast cancer survivors that develop it. The purpose of this review is to evaluate the literature surrounding BCRL treatment modalities to guide clinicians regarding risk-stratified treatment options. METHODS: A review of studies over a 10-year period (January 2006 to February 2016) was performed. Noninvasive strategies evaluated included compression therapy, manual lymphatic drainage, and complex decongestive therapy (CDT). Invasive modalities evaluated included liposuction and lymphatic bypass/lymph node transfer (LNT). Our search yielded 149 initial results with 45 studies included. RESULTS: A number of prospective studies have found that CDT is associated with volume reduction in the affected limb as well as improved quality of life, particularly in patients with early stage BCRL. With regards to invasive treatment options, data support that lymphatic bypass and LNT are associated with symptomatic and physiologic improvements, particularly in patients with more advanced BCRL. In addition, a small number of studies suggest that liposuction may be an efficacious and safe treatment for moderate to severe BCRL. CONCLUSIONS: CDT is an effective treatment modality for early stage BCRL. For more advanced BCRL, LNT has demonstrated efficacy. Further study is required with respect to comparing BCRL treatment modalities. PMID- 28009598 TI - Streptococcus Pneumoniae Detection Long Time After Death in a Fatal Case of Waterhouse-Friderichsen Syndrome. AB - We report a fatal case of Waterhouse-Friderichsen syndrome in a 64-year-old man. The diagnosis, suspected during the autopsy (performed 63 hours after death), was confirmed through the successful detection of Streptococcus pneumoniae DNA and antigens in samples (blood and liver) collected during the autopsy. These results conformed with blood cultures performed antemortem, which became available only the day after the autopsy. The case underlines the need to collect biological material (liver and blood samples) during autopsy for microbiological investigations, although the collection is performed a long time after the death, suggesting that a liver sample works for DNA and liver and blood work for Streptococcus pneumoniae antigen detection. PMID- 28009599 TI - A National Curriculum of Fundamental Skills for Plastic Surgery Residency: Report of the Inaugural ACAPS Boot Camp. AB - BACKGROUND: The Inaugural American Council of Academic Plastic Surgeons Plastic Surgery Boot Camp program was developed in response to ongoing changes in graduate medical education. The Boot Camp is a hands-on, practicum-based, 3-day course to introduce core concepts in plastic surgery for new plastic surgery residents (in both integrated and independent tracks). METHODS: The course was held in Pittsburgh in July to August 2015. There were 43 attendees (35 integrated/8 independent) representing 22 residency programs across 15 states. Faculty was composed of 8 local personnel and 5 visiting. Lecture topics and practical sessions covered the full spectrum of plastic surgery. All trainees completed an online survey evaluation both during the course and at 6 months. RESULTS: Participant responses were overwhelmingly positive. A total of 72% of respondents rated the Boot Camp >= 8 on a 1 to 10 scale (10 is excellent) for the overall course rating; 79% of respondents agreed or strongly agreed with the statement that the simulation scenarios were realistic; and 75% of participants agreed or strongly agreed with the statement that they found simulation-based training to be a valuable way to teach this material. Respondents reported an increase in comfort and confidence across topics after attending the Boot Camp at both 0- and 6-month time points. Instructors received positive evaluations across all topics. CONCLUSIONS: This successful inaugural course serves as a benchmark for development of a logistical blueprint, business plan, and curriculum for a proposed expansion to regional centers, to potentially encompass all incoming residents in plastic surgery. PMID- 28009600 TI - The Detection, Analysis, and Significance of Physician Clustering in Medical Malpractice Lawsuit Payouts. AB - OBJECTIVES: There is evidence that most adverse events result from individual errors and that most malpractice suits with payouts reflect both patient injury and error. HYPOTHESIS: There are outlier physicians with regard to the frequency and total amount of malpractice payouts. METHODS: Using the public use file of the National Practitioner Data Bank (NPDB), we sought the percentage of physicians who lay above several cutoff points with regard to total amounts of payments and number of payments. We looked at the frequency with which outliers were likely to have additional paid claims and to be disciplined by their hospitals and state boards. RESULTS: Approximately 1.8% of physicians were responsible for half of the $83,368,588,200 reported to the NPDB over 25 years. Within that group, 12.6% had an adverse licensure action reported to the NPDB, and 6.3% had a clinical privileges action reported. Physicians who were in the high dollar payout category and had one malpractice claim payout had a 74.5% chance of another payout, more than twice the rate for all physicians who had a single payout (chi-square, P < 0.0001). The likelihood that that physician would have additional payments increased as the number of previous payments increased. Total dollar payouts per physician better predicted future payouts than numbers of payouts. (For 1, 2, and 3 payouts, the P value was less than 0.0001 for each category.) Limitations: Neither a prospective nor a randomized study was feasible. Sorting by specialty was not done. Malpractice cases are an indirect measure of adverse events. CONCLUSIONS: There is a clustering of payments in medical malpractice cases among a small group of physicians. These findings point up the need to oppose the negative impact of such outlier physicians on the safety of patients. PMID- 28009601 TI - Separate Medication Preparation Rooms Reduce Interruptions and Medication Errors in the Hospital Setting: A Prospective Observational Study. AB - BACKGROUND: Interruptions and errors during the medication process are common, but published literature shows no evidence supporting whether separate medication rooms are an effective single intervention in reducing interruptions and errors during medication preparation in hospitals. We tested the hypothesis that the rate of interruptions and reported medication errors would decrease as a result of the introduction of separate medication rooms. AIM: Our aim was to evaluate the effect of separate medication rooms on interruptions during medication preparation and on self-reported medication error rates. METHODS: We performed a preintervention and postintervention study using direct structured observation of nurses during medication preparation and daily structured medication error self reporting of nurses by questionnaires in 2 wards at a major teaching hospital in Switzerland. RESULTS: A volunteer sample of 42 nurses was observed preparing 1498 medications for 366 patients over 17 hours preintervention and postintervention on both wards. During 122 days, nurses completed 694 reporting sheets containing 208 medication errors. After the introduction of the separate medication room, the mean interruption rate decreased significantly from 51.8 to 30 interruptions per hour (P < 0.01), and the interruption-free preparation time increased significantly from 1.4 to 2.5 minutes (P < 0.05). Overall, the mean medication error rate per day was also significantly reduced after implementation of the separate medication room from 1.3 to 0.9 errors per day (P < 0.05). CONCLUSIONS: The present study showed the positive effect of a hospital-based intervention; after the introduction of the separate medication room, the interruption and medication error rates decreased significantly. PMID- 28009603 TI - Crospovidone and Microcrystalline Cellulose: A Novel Description of Pharmaceutical Fillers in the Gastrointestinal Tract. AB - Crospovidone and microcrystalline cellulose (MCC) are pharmaceutical fillers well known in the pulmonary pathology literature. Fillers are inactive substances incorporated into medications to facilitate drug delivery. By examining 545 consecutive gastrointestinal surgical specimens from 302 patients between September 11, 2015 and October 23, 2015, we identified the fillers in 29 specimens from 26 patients. The control group consisted of an equal number of consecutive site-matched specimens collected during this same time. Pertinent clinicopathologic data were analyzed, and 1 case was subject to special stains. To confirm the histologic diagnosis, a variety of fillers and medications common to the patients were processed. The fillers were found in 9% of all patients, and there were no specific clinicopathologic associations. In the gastrointestinal tract, crospovidone is nonbirefringent and has a coral shape with each segment composed of a pink core and purple coat; MCC is brightly birefringent with matchstick shape and clear color. Identical material was seen in the processed crospovidone and MCC powders, as well as oxycodone-acetaminophen and omeprazole tablets. In summary, crospovidone and MCC are common, biologically inert, and they are most often seen in the small bowel. Their presence outside of the luminal bowel may serve as a surrogate marker for perforation. Awareness of their morphology is important to distinguish fillers from parasites, calcifications, and other medications, particularly those linked to mucosal injury. We report the unique histomorphologic profile of these fillers as a helpful diagnostic aide, and caution that the fillers have slightly divergent features when compared with those described in the lung. PMID- 28009602 TI - EWSR1 Fusions With CREB Family Transcription Factors Define a Novel Myxoid Mesenchymal Tumor With Predilection for Intracranial Location. AB - Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family (ATF1 and CREB1) have been reported in a diverse group of tumors including angiomatoid fibrous histiocytoma (AFH), soft tissue and gastrointestinal clear cell sarcoma, primary pulmonary myxoid sarcoma, and hyalinizing clear cell carcinoma of salivary gland. We have recently encountered a group of 5 myxoid mesenchymal tumors positive for EWSR1 fusions with one of the CREB family member (ATF1, CREB1, and CREM), with histologic features distinct from any of the previously described pathologic entities. Tumors occurred in children or young adults (12 to 23 y; mean, 18 y), with equal sex distribution. All except 1 were intracranial (intra-axial, 2; meningeal, 2), whereas 1 was perirectal. Histologically, the tumors were well circumscribed, often lobulated, composed of uniform ovoid to round cells, and arranged in cord-like or reticular structures in a myxoid background. All except 1 displayed unique sunburst amianthoid fibers. Immunohistochemically, tumors were positive for epithelial membrane antigen (5/5; 4 focal, 1 diffuse) and desmin (3/5). A novel EWSR1-CREM fusion was identified by RNA sequencing in the perirectal tumor, which was further confirmed by fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). A second case with similar EWSR1-CREM fusion was identified by RT-PCR and FISH in a meningeal tumor. The remaining cases studied by FISH showed the presence of EWSR1-CREB1 fusion in 2 cases and EWSR1-ATF1 in 1. In conclusion, we report a distinct group of myxoid mesenchymal neoplasms occurring in children or young adults with a predilection for intracranial locations. Although the immunoprofile [epithelial membrane antigen (EMA), desmin] and the fusion type raise the possibility of a myxoid AFH, none of the typical histologic findings of AFH were present, suggesting a novel entity. PMID- 28009604 TI - Renal Cell Carcinoma With Chromosome 6p Amplification Including the TFEB Gene: A Novel Mechanism of Tumor Pathogenesis? AB - Amplification of chromosome 6p has been implicated in aggressive behavior in several cancers, but has not been characterized in renal cell carcinoma (RCC). We identified 9 renal tumors with amplification of chromosome 6p including the TFEB gene, 3 by fluorescence in situ hybridization, and 6 from the Cancer Genome Atlas (TCGA) databases. Patients' ages were 28 to 78 years (median, 61 y). Most tumors were high stage (7/9 pT3a, 2/9 pN1). Using immunohistochemistry, 2/4 were positive for melanocytic markers and cathepsin K. Novel TFEB fusions were reported by TCGA in 2; however, due to a small composition of fusion transcripts compared with full-length transcripts (0.5/174 and 3.3/132 FPKM), we hypothesize that these represent secondary fusions due to amplification. Five specimens (4 TCGA, 1 fluorescence in situ hybridization) had concurrent chromosome 3p copy number loss or VHL deletion. However, these did not resemble clear cell RCC, had negative carbonic anhydrase IX labeling, lacked VHL mutation, and had papillary or unclassified histology (2/4 had gain of chromosome 7 or 17). One tumor each had somatic FH mutation and SMARCB1 mutation. Chromosome 6p amplification including TFEB is a previously unrecognized cytogenetic alteration in RCC, associated with heterogenous tubulopapillary eosinophilic and clear cell histology. The combined constellation of features does not fit cleanly into an existing tumor category (unclassified), most closely resembling papillary or translocation RCC. The tendency for high tumor stage, varied tubulopapillary morphology, and a subset with melanocytic marker positivity suggests the possibility of a unique tumor type, despite some variation in appearance and genetics. PMID- 28009605 TI - Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion: An Elusive Mimic of Sinonasal Melanoma. AB - Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal tumors with features of both smooth muscle and melanocytic differentiation, with or without true melanin pigment. The highly variable morphology of PEComas results in a broad differential diagnosis that is also dependent on anatomic site. A subset demonstrates rearrangements involving the TFE3 (Xp11) locus, which can be used in diagnostically difficult cases. Here we describe a case of a melanotic PEComa with NONO-TFE3 fusion occurring in the sinonasal mucosa, as demonstrated by both next-generation sequencing and molecular cytogenetic studies. This case is the first of its kind in the literature and only the second documented PEComa harboring a NONO-TFE3 rearrangement. In light of unequivocal molecular ancillary studies, this case illustrates that PEComa must enter the differential for pigmented lesions of the sinonasal mucosa, where malignant melanoma would be much more likely to occur. PMID- 28009606 TI - Hobnail Variant of Papillary Thyroid Carcinoma: Clinicopathologic and Molecular Evidence of Progression to Undifferentiated Carcinoma in 2 Cases. AB - The hobnail variant (HV) of papillary thyroid carcinoma (PTC) is an unusual entity recently proposed as an aggressive variant of PTC. We describe the pathologic and molecular features of 2 cases of HV of PTC. Both tumors presented in stage III (pT3 pN1a M0). The first case was diagnosed in a 62-year-old man, whereas the second was in a 53-year-old woman. Both patients were treated with total thyroidectomy and radioactive iodine. The primary tumors showed a hobnail/micropapillary pattern in >=50% of the neoplasm, and positivity for TTF 1, TTF-2, thyroglobulin (TG), cyclin D1, and p53. The Ki-67 index was 4.6% and 5%, respectively. In case 1, the tumor disclosed BRAFV600E and TERT C228T (124:G>A) promoter gene mutation, negativity for NRAS, HRAS, and KRAS mutations, and negativity for RET/PTC1, RET/PTC3, and PAX8/PPARgamma rearrangements. After 11 years the patient died with cervical lymph node, bone, and liver metastases. In the liver metastasis, the tumor displayed columnar cell PTC areas (positive for TTF-1, TG, and BRAFV600E) merging with undifferentiated carcinoma (UC) areas (positive for TTF-1 and BRAFV600E; negative for TG). In case 2, the patient died 6 years after treatment with local recurrence and disseminated metastases to the lung, pleura, bone, and liver. The tumor recurrence showed a UC component (positive for cyclin D1 and p53; negative for TTF-1 and TG) with a residual HV of PTC (positive for cyclin D1, p53, TTF-1, and TG). No BRAF, TERT, NRAS, HRAS, nor KRAS mutations were detected in the primary tumor or recurrence in case 2. Our findings suggest that p53-positive HV is a very aggressive form of PTC prone to progression to UC. PMID- 28009607 TI - Vascular Injury Characterizes Doxycycline-induced Upper Gastrointestinal Tract Mucosal Injury. AB - Doxycycline is an oral tetracycline antibiotic that has been associated with upper gastrointestinal (GI) mucosal injury. Recently, characteristic vascular degeneration has been reported in the stomach and duodenum in patients with doxycycline-induced injury. Fourteen patients who underwent upper GI endoscopy for nonspecific symptoms and were found to have doxycycline-induced gastric and esophageal injury are described. Most patients showed characteristic vascular injury. A control group of gastric erosions and esophageal ulcers showed no cases with the characteristic vascular changes. Clinical, endoscopic, and pathologic features of doxycycline-induced upper GI tract injury are reviewed, with an emphasis on vascular injury. PMID- 28009608 TI - FOSB is a Useful Diagnostic Marker for Pseudomyogenic Hemangioendothelioma. AB - Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma is a distinctive vascular neoplasm of intermediate biological potential with a predilection for young adults and frequent multifocal presentation. Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindled and epithelioid cells with abundant eosinophilic cytoplasm and coexpression of keratins and endothelial markers. Recently, a SERPINE1-FOSB fusion has been identified as a consistent genetic alteration in pseudomyogenic hemangioendothelioma. FOSB gene fusions have also been reported in a subset of epithelioid hemangiomas. The purpose of this study was to assess the potential diagnostic utility of FOSB immunohistochemistry for pseudomyogenic hemangioendothelioma compared with other endothelial neoplasms and histologic mimics. We evaluated whole-tissue sections from 274 cases including 50 pseudomyogenic hemangioendotheliomas, 84 other vascular tumors (24 epithelioid hemangiomas [including 6 cases with angiolymphoid hyperplasia with eosinophilia histology], 20 epithelioid angiosarcomas, 20 epithelioid hemangioendotheliomas [17 CAMTA1 positive, 2 TFE3 positive], 10 spindle-cell angiosarcomas, and 10 epithelioid angiomatous nodules), and 140 other histologic mimics (20 each epithelioid sarcoma, proliferative fasciitis, nodular fasciitis, cellular benign fibrous histiocytoma, spindle-cell squamous cell carcinoma, spindle-cell rhabdomyosarcoma, and leiomyosarcoma). Immunohistochemistry for FOSB was performed following pressure cooker antigen retrieval using a rabbit monoclonal antibody. Diffuse nuclear immunoreactivity for FOSB (>50% of cells) was observed in 48 of 50 (96%) pseudomyogenic hemangioendotheliomas and 13 of 24 (54%) epithelioid hemangiomas (including all angiolymphoid hyperplasia with eosinophilia type). Both FOSB-negative pseudomyogenic hemangioendothelioma cases were decalcified bone tumors. Only 7 other tumors showed diffuse FOSB expression: 2 proliferative fasciitis, 2 nodular fasciitis, 1 epithelioid angiosarcoma, 1 spindle-cell angiosarcoma, and 1 epithelioid hemangioendothelioma. Of note, the FOSB-positive epithelioid hemangioendothelioma was negative for CAMTA1 and TFE3. Focal weak FOSB staining was observed in a subset of histologic mimics and is therefore not diagnostically meaningful. In conclusion, FOSB is a highly sensitive and diagnostically useful marker for pseudomyogenic hemangioendothelioma. Immunohistochemistry for FOSB may be helpful to distinguish pseudomyogenic hemangioendothelioma from histologic mimics including epithelioid sarcoma and other vascular neoplasms. As expected, a subset of epithelioid hemangiomas expresses FOSB, including angiolymphoid hyperplasia with eosinophilia. Although occasional cases of nodular and proliferative fasciitis are positive for FOSB, distinction between these tumor types and pseudomyogenic hemangioendothelioma is usually straightforward based on morphology and other immunophenotypic findings. PMID- 28009609 TI - Atypical Intraductal Cribriform Proliferations of the Prostate Exhibit Similar Molecular and Clinicopathologic Characteristics as Intraductal Carcinoma of the Prostate. AB - Atypical intraductal cribriform proliferations of the prostate (AIP) are loose cribriform proliferations of luminal cells that exhibit greater architectural complexity and/or nuclear atypia than high-grade prostatic intraepithelial neoplasia (HGPIN), but lack the diagnostic criteria for intraductal carcinoma (IDC). The significance of AIP has not been formally established. We compared the clinical, morphologic, and immunohistochemical characteristics of AIP with classic IDC in 310 radical prostatectomy specimens that were received over an 18 month period. Of the 310 cases, 46 cases had AIP only (n=10), IDC only (n=6), or AIP coexisting with IDC (n=30). The ERG status of all 46 AIP/IDC cases was identical to the nearby acinar carcinoma, contrasted to just 3 cases of HGPIN (7%, P<0.01). The degree of uniform phosphatase and tensin homolog (PTEN) loss in 34 selected cases was identical in AIP and IDC (66.7%). No foci of HGPIN showed uniform PTEN loss; there was only 38% concordance of PTEN expression pattern between HGPIN and the nearby acinar carcinoma, unlike AIP and IDC (77% and 81%, respectively, P<0.01). AIP-associated and/or IDC-associated carcinoma (n=46) showed a higher stage and grade compared with acinar-only carcinoma (n=264, P<0.01). AIP-associated carcinoma had similar clinicopathologic features as IDC associated carcinoma, including preoperative prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis (n=36, P>0.05). In conclusion, AIP shares similar ERG/PTEN immunoprofiles and exhibits similar clinical behavior as IDC, warranting immediate repeat biopsy when AIP is identified on biopsy, as is recommended in the most recent WHO Classification of Tumours of the Urinary System and Male Genital Organs, 2016. PMID- 28009610 TI - Alveolar Soft Part Sarcoma of the Female Genital Tract: A Morphologic, Immunohistochemical, and Molecular Cytogenetic Study of 10 Cases With Emphasis on its Distinction From Morphologic Mimics. AB - Alveolar soft part sarcoma (ASPS) is a morphologically distinctive neoplasm of unknown differentiation that bears a characteristic gene fusion involving ASPSCR1 and TFE3. ASPS can occur in the female genital tract, but is rare. Eleven cases with an initial diagnosis of ASPS at female genital tract sites were evaluated for their morphologic features and immunoprofile using a panel of antibodies (TFE3, HMB45, melan-A, smooth muscle actin, desmin, and h-Caldesmon). In addition, the presence of TFE3 rearrangement and subsequent ASPSCR1-TFE3 fusion were determined by fluorescence in situ hybridization. Ten tumors retained their classification as ASPS based on their morphologic appearance, immunohistochemical profile, and demonstration of ASPSCR1-TFE3 fusion. The remaining case was reclassified as conventional-type PEComa due to its pattern of HMB45, melan-A, and desmin positivity as well as absence of TFE3 rearrangement. Sites of the 10 ASPS were uterine corpus (3), cervix (2), uterus not further specified (2), vagina (2), and vulva (1). The age of the patients ranged from 15 to 68 years (mean 34 y, median 32 y). The tumors demonstrated a spectrum of morphologic features, but all had a consistent immunophenotype of strong TFE3 nuclear expression and lack of muscle (smooth muscle actin, desmin, h-Caldesmon) and melanocytic (melan-A, HMB45) markers, except focal positivity for HMB45 in 1. Follow-up was available for 4 patients ranging from 1 to 35 months (mean 15 mo, median 25 mo) and they were alive and had no evidence of recurrence or metastasis at last follow-up. Distinguishing ASPS from its morphologic mimics, particularly PEComa, is important due to increasingly efficacious targeted agents such as MET selective and VEGF signaling inhibitors in the former and mTOR inhibition therapy in the latter. PMID- 28009611 TI - Pituitary Adenomas Presenting as Sinonasal or Nasopharyngeal Masses: A Case Series Illustrating Potential Diagnostic Pitfalls. AB - We present a series of nonectopic pituitary adenomas presenting as polypoid sinonasal or nasopharyngeal masses. Thirteen cases diagnosed by biopsies from the nasal cavity, sinuses, or nasopharynx were identified from a series of 1288 surgical pituitary specimens. The patients included 5 men and 8 women ranging from 29 to 69 years of age. The presentations included nasal obstruction (4 cases), headaches (3), visual defects (2), recurrent nose bleeds (1), rhinorrhea (1), sepsis (1), fatigue (1), and hyperthyroidism (1). All patients had large tumors involving the sella and extending inferiorly to involve the sphenoid sinus in 10 cases, ethmoid in 8, nasopharynx in 3, nasal cavity in 6, maxillary and frontal sinuses in 1 case each. In 3 patients, the biopsy was from the nasopharynx, in 4 from the nasal cavity, in 4 from the sphenoid sinus, and in 2 from the ethmoid sinus. The correct diagnosis of pituitary adenoma was initially made in 10 cases. In 3 cases the initial diagnosis was incorrect; 2 tumors were classified as olfactory neuroblastoma, one of those was reclassified as neuroendocrine carcinoma, and 1 case was initially diagnosed as neuroendocrine carcinoma with aberrant adrenocorticotrophic hormone expression. Clinical follow up (2 to 25 y) and treatment information was available in 10 cases. All 10 patients were alive, either free of disease (4 cases) or with disease (6 cases). In 2 cases, the wrong diagnoses led to incorrect treatment with significant morbidity. These cases illustrate that pituitary adenomas can invade nasopharynx and sinonasal cavities and when they do, they present a possible diagnostic pitfall with potentially serious consequences. We demonstrate the need to always consider this entity when encountering a nasopharyngeal or sinonasal tumor with neuroendocrine features. PMID- 28009614 TI - Factors Associated With Patient-Initiated Telephone Calls After Orthopaedic Trauma Surgery. AB - OBJECTIVES: The primary aim of this study is to investigate the incidence of early patient-initiated postoperative telephone calls and reasons for those calls. Secondary goals are to determine perioperative predictive factors for calls including the procedures most frequently associated with them. DESIGN: Retrospective chart review. SETTING: Academic Level-1 Trauma Center. PATIENTS/PARTICIPANTS: Six hundred eighty-four patients who underwent surgical treatment by our orthopaedic trauma division between 01/01/2014 and 31/12/2014. MAIN OUTCOME MEASUREMENTS: Patient-initiated telephone call documented within 14 days after discharge. RESULTS: Twenty-nine percent (n = 199) of patients initiated a telephone call within 14 days after discharge. The most common reasons for telephone calls were pain control (22%), bathing/dressing/wound questions (16%), and questions regarding discharge medications (8%). The procedures associated with the highest percentage of telephone calls were tibial shaft intramedullary nailing (36.0%), calcaneus open reduction internal fixation (31.3%), and cephalomedullary nailing for proximal femur fractures (29.3%). Perioperative factors predictive of an increase in phone calls included discharge directly to home, higher baseline level of health of the patient (based on comorbidities and the American Society for Anesthesiologists score), and a more robust support network (based on marital and employment status). CONCLUSIONS: This study identifies the incidence and common reasons for patient-initiated calls after orthopaedic trauma surgery and an analysis of perioperative factors predictive of increased phone calls. These data give direction for communication at the time of discharge to improve efficiency, patient care, and patient satisfaction. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28009615 TI - Healing of Atypical Subtrochanteric Femur Fractures After Cephalomedullary Nailing: Which Factors Predict Union? AB - OBJECTIVES: The purpose of this study was to determine the healing rate and time to union of atypical subtrochanteric fractures treated with cephalomedullary nailing. DESIGN: Retrospective review, descriptive, and analytic study. SETTING: Six level 1 trauma centers. PATIENTS/PARTICIPANTS: The study included 42 patients with 48 displaced, atypical, bisphosphonate-associated subtrochanteric femur fractures who underwent surgical intervention. INTERVENTION: Cephalomedullary femur nailing. MAIN OUTCOME MEASUREMENT: The main outcome measures were radiologic healing and time to union. RESULTS: The primary healing rate after cephalomedullary nailing of bisphosphonate-associated subtrochanteric femur fractures was 68.7% (33/48 patients). Mean time to union was 10.7 months. Malalignment was determined using the differences in neck-shaft angle (the difference between the normal side and the surgically repaired side) and sagittal angulation. These all proved to be significantly correlated with failure and delayed healing time. The cutoff points for neck-shaft angle, difference in neck shaft angle, and sagittal angulation were 125.6, 4.4, and 5.5 degrees, respectively (receiver operating characteristic curve analysis). CONCLUSIONS: The healing rate of atypical subtrochanteric femur fractures treated with cephalomedullary nailing is lower than that previously reported for atypical femur fractures. The quality of fracture reduction proved to be the most important factor in bony union and time to union. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28009616 TI - Spinal Anesthesia Improves Early Pain Levels After Surgical Treatment of Tibial Plateau Fractures. AB - OBJECTIVES: To determine the effect of spinal anesthesia (SA) on short-term outcomes when compared with general anesthesia in operatively managed tibial plateau fractures. DESIGN: This is an institutional review board-approved retrospective review of prospectively collected data. SETTING: Two level-1 trauma centers. PARTICIPANTS: One hundred twelve patients with a surgically managed tibial plateau fracture were identified within a registry of patients. INTERVENTION: Of these, 29 (25.9%) received SA and 83 (74.1%) received general anesthesia in a nonrandomized fashion. MAIN OUTCOME MEASURES: Short Musculoskeletal Functional Assessment scores, pain levels, knee range of motion, complications, and reoperations. RESULTS: SA was found to be a predictor of lower pain scores at 3 months (odds ratio, 0.32; 95% confidence interval, 0.12-0.95; P = 0.039) but not at 6 months (P = 0.266) or the latest follow-up (P = 0.056). In the multivariate Short Musculoskeletal Functional Assessment model, although anesthesia type was not found to be a statistically significant predictor, other predictors were identified. Anesthesia type was not a predictor of complications or reoperations. In the univariate analysis, SA was associated with an increased knee range of motion at 3 months (121 vs. 111 degrees; P = 0.048) but not at 6 months (P = 0.31) or the latest follow-up (P = 0.053). CONCLUSION: In patients who undergo surgical management of a tibial plateau fracture, the use of SA is associated with decreased pain levels in the early postoperative period; however, there was no effect on functional assessment scores. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28009618 TI - Electroconvulsive Therapy Considerations for Transgendered Patients. AB - As the transgender patient population continues to grow, health care providers will need to become aware of elements unique to the transgender community in order to provide the highest quality of care. Neuromuscular blockade with succinylcholine is routinely administered to patients undergoing electroconvulsive therapy (ECT). Decreased amounts or activity of pseudocholinesterase in serum can lead to prolonged duration of muscle paralysis. Causes of reduced action by pseudocholinesterase include genetically abnormal enzymes, reduced hepatic production, pregnancy, and various drug interactions. Estrogen supplementation taken by transitioning patients may affect the duration of neuromuscular blockade.This is a case of a 32-year-old male-to-female transgender patient with prolonged apnea following ECT treatment for severe, refractory depression. Further investigation revealed the patient was on estrogen therapy as a part of her transition and laboratory testing demonstrated reduced serum pseudocholinesterase activity. Further laboratory testing demonstrated reduced serum pseudocholinesterase activity. Succinylcholine dosing was titrated to an appropriate level to avoid prolonged apnea in subsequent ECT treatments. Physicians and other health care providers are faced with a unique population in the transgender community and must be aware of distinctive circumstances when providing care to this group. Of specific interest, many transitioning and transitioned patients can be on chronic estrogen supplementation. Neuromuscular blockade in those patients require attention from the anesthesiology care team as estrogen compounds may decrease pseudocholinesterase levels and lead to prolonged muscle paralysis from succinylcholine. PMID- 28009619 TI - Left Anterior-Right Temporal Electroconvulsive Therapy for Catatonia After Epilepsy Surgery: A Case Report. PMID- 28009620 TI - The Treatment of Disruptive Vocalization in Dementia (Behavioral and Psychological Symptoms of Dementia) With Electroconvulsive Therapy: A Case Series. AB - OBJECTIVE: There is emerging evidence that electroconvulsive therapy (ECT) can help with the behavioral and psychological symptoms of dementia. One of the most distressing behavioral symptoms of dementia is disruptive vocalization. Previous small case series have suggested that antidepressants and ECT can be beneficial for this distressing condition. The aim of this study was to describe the successful use of ECT in treating 5 patients with disruptive vocalization. METHODS: A retrospective chart review of 5 patients with dementia of mixed etiologies was conducted comparing pretreatment and posttreatment scores on the Cohen-Mansfield Agitation Inventory. All 5 patients had unsuccessful treatments with nonpharmacological methods and pharmacotherapy including antidepressants. RESULTS: After completion of a series of ECT, the mean verbal agitation score decreased from 6.8 (95% confidence interval, 6.3-7.3) to 2.3 (95% confidence interval, 1.3-3.3), with both clinical and statistical significance (P < 0.001). CONCLUSIONS: Although further research is needed, these findings support considering the use of ECT for disruptive vocalization in dementia. PMID- 28009621 TI - A Meta-review of the Safety of Electroconvulsive Therapy in Pregnancy. AB - BACKGROUND: Four systematic reviews have examined the safety of electroconvulsive therapy (ECT) in pregnancy. These have varied widely in methods, findings, and conclusions. METHODS: We compared these reviews with regard to search strategy, study selection criteria, total number of studies identified, total number of patients included, findings related to safety and adverse events, and interpretation of results. RESULTS: The number of studies (number of cases) included in the reviews ranged from 16 (n = 300) to 67 (n = 169) with only one review stating reasons for exclusion of nonselected studies. We provide comparisons about how the reviews described patient characteristics, illness characteristics, ECT characteristics, confounder characteristics, and outcome characteristics; there was wide variation in these regards. We list adverse outcomes that were identified by some but not other reviews. We provide a detailed breakdown of the adverse maternal and fetal outcomes identified in each review. Finally, we examine how different reviews interpreted their findings; whereas some reviews provided reasons for ruling out ECT as an explanation for an adverse outcome, one review adopted the stance that all adverse outcomes were potentially ECT-related. CONCLUSIONS: Our meta-review provides readers with comparative information on the strengths and limitations of the 4 systematic reviews, their findings, and their conclusions. It can assist with clinical decision making on the use of ECT in pregnancy by providing a more complete description of the available literature. PMID- 28009622 TI - Procedural Consolidation During Electroconvulsive Therapy for a Patient With Severe Tourette Syndrome. PMID- 28009623 TI - Electroconvulsive Therapy (ECT) and Race: A Report of ECT Use and Sociodemographic Trends in Texas. AB - OBJECTIVES: Minimal research on race and other sociodemographic disparities in patients receiving electroconvulsive therapy (ECT) exists. One previously noted national trend reveals whites receiving ECT disproportionately more than other races. The aim of this study is to determine whether a county ECT program demonstrates similar disparities observed at the state and national levels. METHODS: This study examined 21 years of ECT data, between 1993 and 2014, provided by the Texas Department of State Health Services, focusing on race, sex, age, and payer source and 2.5 years of the same variables from a Harris County hospital ECT program. In addition, population demographic data for Harris County and the state of Texas during the same period were obtained from the Department of State Health Services Web site. RESULTS: Despite an overall decrease in the population of whites countywide and statewide, whites continue to use more ECT than African Americans, Latinos, and Asians in both Harris County and Texas. However, the rates of ECT use in minorities increased overall. Both countywide and statewide, ECT was used more than twice as often in women than men. Statewide, elderly patients (>65 years old) saw decreases in ECT use, and there was an increase in private third-party payer source. CONCLUSIONS: Electroconvulsive therapy remains underused among African Americans, Latinos, and Asians. Hypotheses and areas for future study include cultural beliefs, stigma, patient and provider knowledge of ECT, and access to care. Despite this, the general use of ECT in Texas has increased overall, and minority use is slowly on the rise. PMID- 28009624 TI - Time Trends and Variations in Electroconvulsive Treatment in Denmark 2008 to 2014: A Nationwide Register-Based Study. AB - OBJECTIVE: The aim of this study was to determine status and variations in the practice of electroconvulsive treatment (ECT) in Denmark in patient characteristics, indications, treatment patterns, and hospital region. METHOD: All 140,627 ECTs registered in the Danish National Patient Registry between 2008 and 2014 were retrieved together with information on patient characteristics. Annual treated person rates were calculated for sex, age, admission diagnosis, and region. RESULTS: The overall ECT treatment rate was 36 (95% confidence interval, 34-38) per 100,000 resident population during the study period. The rate was highest in women and increased with age. There were modest, however, stable regional differences in rates (extremal quotient = 1.4). Electroconvulsive treatment was most commonly used in patients with depression with (19.4%) or without (54.9%) psychotic symptoms. The median number of ECTs administered per patient was 10 and highest in patients with schizophrenia, schizoaffective, or bipolar disorders. A total of 51%, 14%, and 33% of ECTs were administered with bilateral, unilateral, and unspecified electrode placement, respectively. There were regional differences in electrode placement specification and use. CONCLUSIONS: Although some variation was seen across hospital regions and electrode placement, ECT in Denmark was provided with relative stability over time and indications compared with most other countries in Europe and North America. PMID- 28009625 TI - An Unwanted Reduction of Seizure Duration During Electroconvulsive Therapy With Diltiazem. PMID- 28009626 TI - A Successful Course of Electroconvulsive Therapy in a Patient With Epilepsy and a Posterior Fossa Titanium Plate. PMID- 28009627 TI - ECT-Related Anxiety: A Systematic Review. AB - BACKGROUND: A significant proportion of electroconvulsive therapy (ECT)-treated patients experience anxiety anticipating the treatment, often to such an extent that they refuse or discontinue a much-needed treatment. Despite its great impact on treatment adherence, anxiety in patients receiving ECT is underexposed in the scientific literature. OBJECTIVES: We aimed to review the prevalence and specific subjects of ECT-related anxiety and therapeutic interventions to reduce it. METHODS: We performed a computerized search (EMBASE, MEDLINE, and PsycINFO) for articles meeting the following inclusion criteria: (1) qualitative (interview) studies, quantitative (questionnaire) studies, or experimental (interventional) studies that (2) report on anxiety that is related to a planned, ongoing, or past ECT treatment. RESULTS: Of 1160 search results, 31 articles were included. Electroconvulsive therapy-related anxiety is estimated to be present in 14% to 75% of patients and is most often linked to worries about memory impairment or brain damage. Only a few interventions (chlorpromazine, meprobamate, propofol, a talking-through technique, an information leaflet, and animal-assisted therapy) have been proposed to reduce patients' ECT-related anxiety. CONCLUSIONS: Electroconvulsive therapy-related anxiety is a highly prevalent phenomenon, and the literature provides little guidance for its clinical management. Most studies are of a low methodological quality and suffer from significant limitations, thereby hampering generalized conclusions. Given the clinical importance of ECT related anxiety, further study on its nature and evolution through the course of treatment and on anxiety-reducing interventions is warranted. PMID- 28009628 TI - Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti-transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity. AB - Neuropathic pain is a major unmet medical need, with only 30% to 35% of patients responding to the current standard of care. The discovery and development of novel therapeutics to address this unmet need have been hampered by poor target engagement, the selectivity of novel molecules, and limited access to the relevant compartments. Biological therapeutics, either monoclonal antibodies (mAbs) or peptides, offer a solution to the challenge of specificity as the intrinsic selectivity of these kinds of molecules is significantly higher than traditional medicinal chemistry-derived approaches. The interleukin-1 receptor system within the spinal cord has been implicated in the amplification of pain signals, and its central antagonism provides relief of neuropathic pain. Targeting the IL-1 system in the spinal cord with biological drugs, however, raises the even greater challenge of delivery to the central compartment. Targeting the transferrin receptor with monoclonal antibodies has proved successful in traversing the endothelial cell-derived blood-brain barrier and delivering proteins to the central nervous system. In this study, we describe a novel construct exemplifying an engineered solution to overcome these challenges. We have generated a novel anti-transferrin receptor-interleukin-1 receptor antagonist fusion that transports to the central nervous system and delivers efficacy in a model of nerve ligation-induced hypersensitivity. Approaches such as these provide promise for novel and selective analgesics that target the central compartment. PMID- 28009633 TI - Use of Smartphones to Prospectively Evaluate Predictors and Outcomes of Caregiver Responses to Pain in Youth with Chronic Disease. AB - This study examined outcomes and predictors of different types of responses to child pain used by caregivers of youth with chronic disease. Sixty-six children and adolescents (ages 7-18) with juvenile idiopathic arthritis answered questions about pain, pain interference in activities, and mood on a smartphone three times per day for one month, while a caregiver contemporaneously answered questions about their own mood and use of protecting, monitoring, minimizing, or distracting responses to their child's pain. Multilevel models were used to evaluate (a) how a child's pain and pain interference changes after a caregiver uses different types of pain responses; (b) the extent to which caregiver responses to pain vary across days; and (c) whether variability in caregiver responses to pain is predicted by changes in child pain characteristics, child mood, and/or caregiver mood. Results showed that children's pain intensity and pain interference increased following moments when caregivers used more protective responses, whereas children's pain interference decreased following times when caregivers responded with minimizing responses. Caregiver pain responses varied considerably across days, with caregivers responding with more protecting and monitoring responses and fewer minimizing responses at moments when their child reported high levels of pain unpleasantness and pain interference. Caregivers also were found to respond with fewer protective responses at moments when they themselves were in a more positive mood. Implications for clinical recommendations and future studies are discussed. PMID- 28009636 TI - Intravenous Clevidipine for Inducing Hypotensive Challenge During Carotid Balloon Test Occlusion. PMID- 28009635 TI - Perioperative and Anesthetic Considerations for Neurosurgical Laser Interstitial Thermal Therapy Ablations. AB - OBJECTIVE: To describe the anesthetic considerations in patients undergoing laser interstitial thermal therapy (LITT) for neurosurgical procedures. BACKGROUND: LITT for neurosurgical procedures is being increasingly used in a variety of central nervous system diseases. Several studies have demonstrated promising results including a shorter hospital stay. Given the rising trend for the use of LITT, anesthesiologists need to be familiar with the anesthetic considerations to provide care for patients undergoing these types of procedures. MATERIALS AND METHODS: PubMed was searched in April 2016 using different combinations of the following MeSH terms: "Central nervous System," "laser therapy," "Ablation Techniques," "Anesthesia," and "Spinal Cord Neoplasms." A total of 54 relevant manuscripts were included in this review article. CONCLUSIONS: LITT is a promising therapeutic approach for multiple central nervous system disorders. Anesthesiologists must be familiar with the anesthetic considerations and the technical aspects of the procedure when providing care for patients undergoing LITT. The literature is scarce on the impact of different anesthesia and analgesia techniques on clinical outcomes. Therefore, studies comparing different anesthetic regimens and the impact on outcomes are needed to make relevant recommendations on the anesthesia care of these patients. PMID- 28009637 TI - Novel needle guide reduces time to perform ultrasound-guided femoral nerve catheter placement: A randomised controlled trial. AB - BACKGROUND: Ultrasound-guided nerve blocks have become the standard when performing regional nerve blocks in anaesthesia. Infiniti Plus (CIVCO Medical Solutions, Kalona, Iowa, USA) is a needle guide that has been recently developed to help clinicians in performing ultrasound-guided nerve blocks. OBJECTIVES: We tested the hypothesis that femoral nerve catheter placement carried out with the Infiniti Plus needle guide will be quicker to perform than without the Infiniti Plus. Secondary aims were to assess whether the Infiniti Plus needle guide decreased the number of block attempts and also whether it improved needle visibility. DESIGN: A randomised, controlled trial. SETTING: Cleveland Clinic, Cleveland, Ohio, USA. PATIENTS: We enrolled adult patients having elective total knee arthroplasty with a femoral nerve block and femoral nerve catheter. Patients, who were pregnant or those who had preexisting neuropathy involving the surgical limb, coagulopathy, infection at the block site or allergy to local anaesthetics were excluded. INTERVENTIONS: Patients were randomised into two groups to receive the ultrasound-guided femoral nerve catheter placement with or without the Infiniti Plus needle guide. MAIN OUTCOME MEASURES: The time taken to place the femoral nerve catheter, the number of attempts, the success rate and needle visibility were recorded. We used an overall alpha of 0.05 for both the primary and secondary analyses; the secondary analyses were Bonferroni corrected to control for multiple comparisons. RESULT: The median (interquartile range Q1 to Q3) time to perform the femoral nerve catheter placement was 118 (100 to 150) s with Infiniti Plus and 177 (130 to 236) s without Infiniti Plus. Infiniti Plus significantly reduced the time spent performing femoral nerve catheterisation, with estimated ratio of means [(95% confidence interval), P value] of 0.67 [(0.60 to 0.75), P < 0.001] with Infiniti Plus compared with no Infiniti Plus. However, Infiniti Plus had no effect on the odds of a successful femoral nerve catheter placement, number of attempts or percentage of perfect needle visibility. CONCLUSION: We found that the use of Infiniti Plus decreased the median time to successfully place a femoral nerve catheter by 33% compared with not using Infiniti Plus. This difference may be more apparent to clinicians undertaking this procedure less often or by those in training as our team was very experienced, had been trained in the technique and was working in a hospital with a large caseload. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02080481. PMID- 28009639 TI - Brief Report: Increased Expression of the Type I Interferon Receptor on CD4+ T Lymphocytes in HIV-1-Infected Individuals. AB - BACKGROUND: Type I interferons (IFN1s; eg, interferon-alpha and interferon-beta) are potent cytokines that inhibit the replication of human immunodeficiency virus 1 (HIV-1) and other viruses. The antiviral and immunoregulatory activities of IFN1 are mediated through ligand-receptor interactions with the IFN1 receptor complex (IFNAR). Variation in the cell-surface density of IFNAR could play a role in HIV-1 pathogenesis. METHODS: In this cross-sectional study of fresh whole blood, we used flow cytometry to evaluate the expression of IFNAR2 on lymphocyte subsets from HIV-1-infected (n = 33) and HIV-1-uninfected (n = 22) individuals. RESULTS: In comparison with healthy blood bank donors, we observed that the HIV-1 infected individuals, particularly those having advanced to disease, exhibited the increased expression of IFNAR2 on CD4 T cells (relative fluorescence intensity 6.9 vs. 9.0; P = 0.027). The CD4:CD4 T-cell IFNAR2 expression-level ratio provides an internally standardized measure of this alteration. The observed increased expression of IFNAR2 was largely restricted to CD4 T cells that expressed the chemokine receptor CXCR4 and lacked the expression of CCR5. CONCLUSIONS: HIV-1-infected individuals exhibit an increased expression of the IFN1 receptor on CD4 T cells. The level of IFNAR2 expression seems to increase with disease progression. These findings provide insight for the immunologic alterations associated with HIV-1 infection and possibly new therapeutic approaches. PMID- 28009638 TI - The effect of head rotation on efficiency of face mask ventilation in anaesthetised apnoeic adults: A randomised, crossover study. AB - BACKGROUND: Upper airway obstruction occurs commonly after induction of general anaesthesia. It is the major cause of difficult mask ventilation. OBJECTIVES: The aim of this study was to determine whether head rotation improves the efficiency of mask ventilation of anaesthetised apnoeic adults. DESIGN: A randomised, crossover study. SETTING: Single university teaching hospital. PATIENTS: Forty patients, aged 18 to 75 years with a BMI 18.5 to 35.0 kg m requiring general anaesthesia for elective surgery were recruited and randomised into two groups. INTERVENTIONS: Once apnoeic after induction of general anaesthesia, face mask ventilation began with pressure controlled ventilation, at a peak inspiratory pressure of 15 cmH2O. Each patient was ventilated for three 1-min intervals with the head position alternated every minute: group A, mask ventilation was performed with a neutral head position for 1 min, followed by an axial head position rotated 45 degrees to the right for 1 min and then returned to the neutral position for another 1 min. In group B, the sequence of head positioning was rotated -> neutral -> rotated. MAIN OUTCOME MEASURES: Expiratory tidal volume, measured with a respiratory inductive plethysmograph. RESULTS: Two patients were excluded due to protocol violation; thus, data from 38 patients were analysed. The mean expiratory tidal volume was significantly higher in the rotated head position than in the neutral position (612.6 vs. 544.0 ml: difference [95% confidence interval], 68.6 [46.8 to 90.4] ml, P < 0.0001). CONCLUSION: Head rotation of 45 degrees in anaesthetised apnoeic adults significantly increases the efficiency of mask ventilation compared with the neutral head position. Head rotation is an effective alternative to improve mask ventilation if airway obstruction is encountered. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02755077. PMID- 28009640 TI - Learning curve using the second-generation cryoballoon ablation. AB - AIMS: To study the learning curve with the second-generation cryoballoon technology focusing on safety, efficacy and procedural characteristics. METHODS: We included 300 patients (men 64.6%, mean age 58.3 +/- 12.4 years), 240 of whom were treated by four operators without prior experience in atrial fibrillation ablation and compared them with 60 consecutive patients treated by senior operator. To study the learning curves, we divided the study period into two trimesters and analyzed procedure duration, fluoroscopy times, complications, characteristics of the freeze-thaw cycles and midterm outcomes. RESULTS: Hands-on help from senior operators to achieve pulmonary vein isolation was needed only in the first study trimester (24.1%), most commonly to achieve right inferior pulmonary vein isolation (55.2%). The mean procedure duration shortened from 76.7 +/- 17.4 to 65.1 +/- 11.4 min (P < 0.0001), and fluoroscopy time decreased from 18.5 +/- 7.3 to 12.1 +/- 4.3 min (P < 0.0001) for first and second trimester, respectively, and approached senior operator's results (58.2 +/- 12.8 and 8.7 +/- 4.5 min). Most of the major complications (one stroke, four pseudoaneurysms and one retroperitoneal hematoma) occurred during the first study trimester. Most characteristics of the freeze cycles remained unchanged in both study periods. Compared with junior operators, the senior operator achieved lower nadir temperatures in both inferior veins. However, there was no significant difference in midterm outcomes between junior and senior operators (79.5 vs 83.3%, P = 0.589). CONCLUSION: The learning curve with the second-generation cryoballoon is steep. Inexperienced operators, trained in high-volume centers, can achieve pulmonary vein isolation safely and efficiently with short procedure and fluoroscopy times after having performed 20-30 cases. PMID- 28009641 TI - Aortoventricular annulus shape as a predictor of pacemaker implantation following transcatheter aortic valve replacement. AB - AIMS: Conduction abnormalities following transcatheter aortic valve replacement (TAVR) are caused by damage of the aortoventricular conduction tissue during positioning of the valve. Therefore, our aim was to assess whether a higher difference between the long and short diameters of the elliptic aortoventricular annulus will possess higher forces on the annulus, and thus will be a predictor of pacemaker need following TAVR. METHODS: We retrospectively analyzed 123 patients who had the aortoventricular annulus measured by computed tomography angiography. The difference between maximal (Dmax) and minimal (Dmin) diameters of the annulus was considered the elliptic factor (ELFA), which was analyzed using t test to evaluate whether it differs between the group who received a pacemaker and the group without the need for a pacemaker. Then, using univariate and multivariate models adjusted for other confounders predicting the need for a pacemaker, we sought to evaluate whether a higher ELFA is a predictor of pacemaker implantation. RESULTS: Mean age was 82.2 +/- 6.4 years, and 62.6% were women. Average Dmax, Dmin and ELFA were 25.8, 20.8 and 5 mm, respectively. Fourteen patients (11.4%) underwent pacemaker implantation. Those patients had an ELFA of 5.9 mm compared with 4.9 mm in those who did not receive a pacemaker (P < 0.01). In multivariate analysis, a higher ELFA remained a statistically significant and independent predictor for the need of a pacemaker (P = 0.046). CONCLUSION: A high ELFA is an independent and significant predictor of the need for pacemaker implantation after TAVR and suggests further investigation whether it should be considered as a factor in managing TAVR patients. PMID- 28009642 TI - Genetic testing in predicting the risk of sudden death. PMID- 28009643 TI - Palliative care and chronic obstructive pulmonary disease: where the lines meet. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and is expected to increase as the population ages. Patients have a high symptom burden, low healthcare quality of life, and unmet needs at the end of life. This review highlights specific palliative care needs of patients with advanced COPD and opportunities to integrate palliative care into standard practice. RECENT FINDINGS: There are many barriers to providing integrated palliative care in COPD, including difficulty with prognostication, communication barriers surrounding advance care planning, and lack of access to specialty palliative care. Because of the unique disease trajectory, emphases on early and primary palliative care are being studied in this patient population. SUMMARY: Palliative care is appropriate for patients with COPD and should be integrated with disease-specific therapies. The line between life prolonging and palliative care undoubtedly overlaps and maximizing quality of life throughout the continuum of care should be prioritized for patients with this progressive illness. PMID- 28009644 TI - Imaging of nontraumatic thoracic emergencies. AB - PURPOSE OF REVIEW: Acute chest symptoms form an important incentive for imaging in the emergency setting. This review discusses the radiologic features of various vascular and pulmonary diseases leading to acute respiratory distress and recent developments on important emergency radiologic examinations. RECENT FINDINGS: Recently, triple-rule-out computed tomography protocol was introduced in diagnosis of chest pain, and advancing computed tomography technology and knowledge have led to discussion on treatment of pulmonary embolism. Diffuse pulmonary opacities remain a diagnostic dilemma in the emergency setting and although imaging findings can often be nonspecific, they help in guiding toward accurate diagnosis and timely management. SUMMARY: Though promising, triple-rule out is not yet justified because of low incidence of additional findings compared with conventional computed tomography angiography in chest pain, but it might be suited for clinical practice in the near future. Relevance of isolated subsegmental pulmonary embolism is unknown and research on this topic is needed and on its way. We provided some key findings in differentiating diffuse pulmonary opacities and describe the additional value of chest ultrasound in this clinical dilemma. A brief sidestep to pneumothorax is made, as this is also a frequent finding in the acute dyspneic patient, as well as in patients with acute chest pain. PMID- 28009645 TI - Obstructive and environmental respiratory diseases: updates and new facets. PMID- 28009646 TI - Lupus anticoagulant - hypoprothrombinemia syndrome: a rare cause of intracranial bleeding. AB - : We report a 14-year-old girl who presented with subdural hematoma and a deranged coagulation profile suggestive of an inhibitor. Investigations revealed prothrombin deficiency along with positivity for antiphospholipid antibodies, which improved with steroid therapy. Bleeding diathesis in children and adolescents commonly results from thrombocytopenia, platelet function disorders, or coagulation factor deficiency; whereas bleeding because of coagulation factor inhibitors are extremely rare in this age group. This case also highlights the uncommon presentation of antiphospholipid antibody syndrome, as they often present with thrombosis or pregnancy complications rather than bleeding. PMID- 28009647 TI - Relation of coagulation factor XI with incident coronary heart disease and stroke: the Cardiovascular Health Study. AB - : The role of coagulation factor XI (FXI) in the cause of arterial thrombotic events remains uncertain. We examined the association of FXI with incident coronary heart disease (CHD), ischemic stroke, and hemorrhagic stroke. Data were from 3394 adults (mean age: 74.5 years) enrolled in the Cardiovascular Health Study who had FXI antigen from plasma samples drawn in 1992-1993 and were followed for cardiovascular events until 30 June 2013. Approximately 63% of participants were women and 17% were black. FXI levels were higher in blacks and women, showed positive associations with high-density lipoprotein and total cholesterol, BMI and diabetes, and negative associations with age and alcohol intake. During median follow-up of 13 years, we identified 1232 incident CHD, 473 ischemic stroke, and 84 hemorrhagic stroke events. In multivariable Cox models adjusted for traditional cardiovascular disease risk factors, the hazard ratio per one SD (32.2 mg/dl) increment of FXI was 1.02 (95% confidence interval: 0.96 1.08) for CHD; 0.94 (0.85-1.04) for ischemic stroke, and 0.85 (0.65-1.10) for hemorrhagic stroke. In this prospective cohort of elderly adults, there was no statistically significant association of higher FXI levels with incident CHD and stroke. PMID- 28009649 TI - Improving the support of the suddenly bereaved. AB - PURPOSE OF REVIEW: It is recognized that death is inevitable but rarely are we prepared for the death of significant persons in our lives. Sudden death is by its nature unexpected and thus shocking for family members and friends of the decedent. Sudden deaths have customarily been divided into four categories based on the cause of death, including natural, accidental, suicidal, or homicidal (NASH) deaths. Supporting the suddenly bereaved can be stressful, for both novice and experienced professionals; this review provides information important to healthcare professionals (HCP) who are often in a position to support family members after a sudden death. RECENT FINDINGS: Evidence suggests that supportive actions for those suddenly bereaved include HCPs conveying empathy, answering questions about the cause of death, allowing family members an opportunity to say goodbye, and providing follow-up over time. Bereaved individuals appreciate ongoing connections with healthcare professionals after the death, and HCPs need to recognize that the bereaved are at increased risk of illness in the months after a sudden death. SUMMARY: Supporting those bereaved after a sudden unexpected death is not easy, even for experienced professionals. This review identifies supportive strategies to use with individuals and family members who are suddenly bereaved. The suggestions in this review can be used in emergency departments and other settings involved with death notifications. Also provided is information that HCPs can use to support bereaved family members. PMID- 28009648 TI - Platelet aggregation and the risk of stent thrombosis or bleeding in elective percutaneous coronary intervention patients. AB - : Platelet aggregation monitoring in patients after stent implantation is a promising way of preventing stent thrombosis and bleeding. The aim of the study was to verify whether clopidogrel (ADPtest) and aspirin (ASPItest) response measured by Multiplate (Dynabyte, Munich, Germany) analyzer in elective percutaneous coronary implantation patients predict the risk of stent thrombosis or other ischemic adverse events and bleeding. In this prospective, observational study 697 elective percutaneous coronary implantation patients were analyzed. The median ASPItest was 86 AU min. In 69 patients (9.9%), an ASPI result of more than 203 AU min was observed. The median ADP-dependent platelet aggregation was 212 AU min. In 36 (5.2%) patients, the result was at least 468 AU min. Cox regression analysis showed the prognostic factors of definite or probable stent thrombosis and cardiac death at 1 year were higher ASPItest result [odds ratio (OR) 1.006, 95% confidence interval (CI) 1.004-1.008, P < 0.001], ASPItest more than 203 AU min (OR 7.61, 95% CI 2.83-20.43, P < 0.001), higher ADPtest result (OR 1.005, 95% CI 1.003-1.007, P < 0.001) and ADPtest at least 468 AU min (OR 12.54, 95% CI 4.56 35.53, P < 0.001). In turn, ADPtest 188 AU min or less predicted GUSTO scale major and moderate bleeding (OR 4.15, 95% CI 1.12-15.32, P = 0.033). There was also a strong trend toward higher rate of major and moderate bleeding for the ASPItest less than 35 AU min (lowest quintile) - (OR 3.04, 95% CI 0.96-9.58, P = 0.058). Lower creatinine clearance and lower hemoglobin level were associated with both ischemic and bleeding complications. The results of this study show that impaired platelet response to clopidogrel and aspirin measured by the Multiplate analyzer results in increased risk of stent thrombosis and cardiac death. Furthermore, the study showed that increased response to clopidogrel is related to major and moderate bleeding events. PMID- 28009650 TI - Cancer-related cognitive impairment in children. AB - PURPOSE OF REVIEW: To review recent research on cancer-related cognitive impairment (CRCI) in children, including correlational studies and interventions in which outcomes have included cognitive test performance, neuroimaging or academic performance. RECENT FINDINGS: Impairments in processing speed, working memory, executive function and attention continue to be demonstrated in survivors of childhood cancers. Children receiving radiation treatment for their cancer demonstrate greater impairment than those who undergo surgery and/or chemotherapy without radiation. However, CRCI still occurs in the absence of radiation treatment, particularly in the domain of attention. Recent neuroimaging studies highlight atypical connectivity of white matter and its associations with cognitive performance. Given impairments in cognitive function and associated neuroanatomical factors, it is not surprising that survivors of childhood cancers experience academic difficulties. However, early intervention may provide one means of improving cognitive and academic outcomes. SUMMARY: Children with cancer are at risk of impairment in the domains of processing speed, attention, working memory and executive function. Those who receive radiation are likely to experience greater CRCI than those who do not receive this treatment. All survivors of childhood cancers should be carefully monitored to provide support and implement evidence-based interventions to ameliorate cognitive late effects. PMID- 28009651 TI - A review of cognitive screening tools in cancer. AB - PURPOSE OF REVIEW: Cancer-related cognitive impairment (CRCI) is highly prevalent, and assessment of cognition is crucial in providing optimal cancer care. Neuropsychological assessment (NPA) can be lengthy and expensive. Cognitive screening tools are plenty but validity has not been thoroughly studied for use in cancer patients. RECENT FINDINGS: Our search of the recent literature revealed that the Montreal Cognitive Assessment, Mini-Mental State Examination, and Clock Draw Test were the most frequently studied objective screening tools. The Functional Assessment of Cancer Therapy-Cognitive Function and the Cognitive Symptom Checklist-Work 21 were the most commonly studied subjective measures of perceived cognitive impairment. Evidence supports using the Montreal Cognitive Assessment or the Clock Draw Test over the Mini-Mental State Examination to screen for cognitive impairment within specific patient populations. In addition, adding a subjective measure of cognitive impairment (e.g., Functional Assessment of Cancer Therapy-Cognitive Function) may increase diagnostic sensitivity. SUMMARY: These suggest that cognitive screening tools may have a role in screening for CRCI, particularly when full NPA is not feasible. Researchers must continue to conduct high-quality studies to build an evidence to guide best practices in screening for CRCI. PMID- 28009652 TI - Positive and Negative Affect Is Related to Experiencing Chest Pain During Exercise-Induced Myocardial Ischemia. AB - OBJECTIVE: Silent myocardial ischemia is thought to be associated with worse cardiovascular outcomes due to a lack of perception of pain cues that initiate treatment seeking. Negative affect (NA) has been associated with increased pain reporting and positive affect (PA) with decreased pain reporting, but these psychological factors have not been examined within the context of myocardial ischemia. This study evaluated the associations between PA, NA, and chest pain reporting in patients with and without ischemia during exercise testing. METHODS: A total of 246 patients referred for myocardial perfusion single-photon emission computed tomography exercise stress testing completed the positive and negative affect schedule-expanded version, a measure of PA and NA. Presence of chest pain and myocardial ischemia were evaluated using standardized protocols. RESULTS: Logistic regression analyses revealed that for every 1-point increase in NA, there was a 13% higher chance for ischemic patients (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.02 to 1.26) and an 11% higher chance in nonischemic patients (OR = 1.11; 95% CI = 1.03 to 1.19) to report chest pain. A significant interaction of PA and NA on chest pain reporting (beta = 0.02; 95% CI = 0.002 to 0.031) was also observed; nonischemic patients with high NA and PA reported more chest pain (57%) versus patients with low NA and low PA (13%), with high NA and low PA (17%), and with high PA and low NA (7%). CONCLUSIONS: Patients who experience higher NA are more likely to report experiencing chest pain. In patients without ischemia, high NA and PA was also associated with a higher likelihood of reporting chest pain. Results suggest that high levels of PA as well as NA may increase the experience and/or reporting of chest pain. PMID- 28009653 TI - Teamwork Assessment Tools in Obstetric Emergencies: A Systematic Review. AB - INTRODUCTION: Team-based training and simulation can improve patient safety, by improving communication, decision making, and performance of team members. Currently, there is no general consensus on whether or not a specific assessment tool is better adapted to evaluate teamwork in obstetric emergencies. The purpose of this qualitative systematic review was to find the tools available to assess team effectiveness in obstetric emergencies. METHODS: We searched Embase, Medline, PubMed, Web of Science, PsycINFO, CINAHL, and Google Scholar for prospective studies that evaluated nontechnical skills in multidisciplinary teams involving obstetric emergencies. The search included studies from 1944 until January 11, 2016. Data on reliability and validity measures were collected and used for interpretation. A descriptive analysis was performed on the data. RESULTS: Thirteen studies were included in the final qualitative synthesis. All the studies assessed teams in the context of obstetric simulation scenarios, but only six included anesthetists in the simulations. One study evaluated their teamwork tool using just validity measures, five using just reliability measures, and one used both. The most reliable tools identified were the Clinical Teamwork Scale, the Global Assessment of Obstetric Team Performance, and the Global Rating Scale of performance. However, they were still lacking in terms of quality and validity. CONCLUSIONS: More work needs to be conducted to establish the validity of teamwork tools for nontechnical skills, and the development of an ideal tool is warranted. Further studies are required to assess how outcomes, such as performance and patient safety, are influenced when using these tools. PMID- 28009654 TI - Does Appearance Matter? Current Issues and Formulation of a Research Agenda for Moulage in Simulation. AB - STATEMENT: The use of moulage is assumed to add realism and authentic context in simulation. Despite the expense required to utilize moulage effectively, there is little exploration in the literature as to both its necessity and its accuracy of portrayal. We explore engagement, authenticity, and realism theories in the context of moulage and highlight the need for more evidence on moulage in simulation-based education, including suggestions for future research. In particular, we urge the simulation community to move beyond descriptive papers to investigate moulage in terms of justification and clarification. PMID- 28009656 TI - Celebrating 20 years of growth and grit. PMID- 28009655 TI - Amiodarone Versus Lidocaine for Pediatric Cardiac Arrest Due to Ventricular Arrhythmias: A Systematic Review. AB - OBJECTIVE: We performed a systematic review as part of the International Liaison Committee on Resuscitation process to create a consensus on science statement regarding amiodarone or lidocaine during pediatric cardiac arrest for the 2015 International Liaison Committee on Resuscitation's Consensus on Science and Treatment Recommendations. DATA SOURCES: Studies were identified from comprehensive searches in PubMed, Embase, and the Cochrane Library. STUDY SELECTION: Studies eligible for inclusion were randomized controlled and observational studies on the relative clinical effect of amiodarone or lidocaine in cardiac arrest. DATA EXTRACTION: Studies addressing the clinical effect of amiodarone versus lidocaine were extracted and reviewed for inclusion and exclusion criteria by the reviewers. Studies were rigorously analyzed thereafter. DATA SYNTHESIS: We identified three articles addressing lidocaine versus amiodarone in cardiac arrest: 1) a prospective study assessing lidocaine versus amiodarone for refractory ventricular fibrillation in out-of-hospital adults; 2) an observational retrospective cohort study of inpatient pediatric patients with ventricular fibrillation or pulseless ventricular tachycardia who received lidocaine, amiodarone, neither or both; and 3) a prospective study of ventricular tachycardia with a pulse in adults. The first study showed a statistically significant improvement in survival to hospital admission with amiodarone (22.8% vs 12.0%; p = 0.009) and a lack of statistical difference for survival at discharge (p = 0.34). The second article demonstrated 44% return of spontaneous circulation for amiodarone and 64% for lidocaine (odds ratio, 2.02; 1.36-3.03) with no statistical difference for survival at hospital discharge. The third article demonstrated 48.3% arrhythmia termination for amiodarone versus 10.3% for lidocaine (p < 0.05). All were classified as lower quality studies without preference for one agent. CONCLUSIONS: The confidence in effect estimates is so low that International Liaison Committee on Resuscitation felt that a recommendation to use of amiodarone over lidocaine is too speculative; we suggest that amiodarone or lidocaine can be used in the setting of pulseless ventricular tachycardia/ventricular fibrillation in infants and children. PMID- 28009657 TI - Meta-aggregation: emergence of the "missing" piece in qualitative synthesis. PMID- 28009658 TI - Collaboration and evidence based innovation in Africa. PMID- 28009659 TI - Collaboration and evidence based innovation in the Americas. PMID- 28009660 TI - Collaboration and evidence based innovation in Asia. PMID- 28009661 TI - Collaboration and evidence based innovation in Australasia. PMID- 28009662 TI - Collaboration and evidence based innovation in Europe. PMID- 28009663 TI - Effectiveness of different minimally invasive epiphysiodesis techniques in the management of pediatric leg length discrepancies: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize the best available evidence on the use of percutaneous epiphysiodesis for the management of pediatric leg length discrepancies (LLDs). The effectiveness of four different percutaneous epiphysiodesis techniques will be compared, including transphyseal screws (percutaneous epiphysiodesis using transphyseal screws), physeal drilling and curettage, physeal stapling and guided growth with eight-Plates.Specific review questions to be addressed include. PMID- 28009664 TI - Effectiveness of non-pharmacological interventions for the prevention and management of psychological and social morbidity in women who have an elective abortion: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize the best available evidence on the effectiveness of non-pharmacological interventions for the prevention and management of psychological and social morbidity in women who have an elective abortion.The specific review question that will be addressed is: In women (aged 13 years or more) with unwanted pregnancies who decide to have an elective abortion, which non-pharmacological interventions should be provided before, during and after the elective abortion procedure both in community and hospital environments to prevent and manage psychological and social morbidity? PMID- 28009665 TI - Capnography compared to pulse oximetry for early detection of respiratory compromise in non-intubated patients undergoing gastrointestinal endoscopy procedures: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: Does the use of capnography versus pulse oximetry increase the early detection of respiratory compromise and improve safety in non intubated patients undergoing moderate sedation for gastrointestinal endoscopy procedures?Respiratory compromise will be detected by alveolar hypoventilation/hyperventilation (EtCO2 < 35 mmHg/EtCO2 > 50 mmHg), arterial oxygen desaturation (defined as a pulse oximetry reading of <95% for >5 s), visual assessments of abnormal ventilation including apnea detection and adverse respiratory events that involve the need for bag-mask ventilation. PMID- 28009666 TI - Effectiveness of prophylactic intravenous immunoglobulins in preventing infection in pediatric oncology patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify the effectiveness of prophylactic intravenous immunoglobulins (IVIGs) for the prevention of infection in pediatric oncology patients, and to identify which types of patients would benefit from the intervention, such as patients with specific diagnoses or those with previous infections. A further objective of this review is to identify the effectiveness of prophylactic IVIGs on the prevention of diffuse interstitial pneumonitis and mortality in pediatric oncology patients.The review questions are. PMID- 28009667 TI - The effectiveness of psychoeducation programs following first episode psychosis: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to establish whether psychoeducational programs can lead to improved outcomes (reduced relapse or readmission) in patients with first-episode psychosis (FEP) compared with usual care. Specifically, the review question is: Are psychoeducational programs for patients with first-episode psychosis effective in improving outcomes compared with those receiving usual care? PMID- 28009668 TI - Long-term topical corticosteroid use and risk of skin cancer: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to synthesize the best available research evidence to determine the risk of skin cancer in patients on long-term use of topical corticosteroids. Specifically the review question is: In people using long-term (regular use over one month) topical corticosteroids, what is the risk of developing skin cancer (clinically or histologically confirmed basal cell carcinoma, squamous cell carcinoma or melanoma)? PMID- 28009669 TI - Effect of peak inspiratory pressure on the development of postoperative pulmonary complications in mechanically ventilated adult surgical patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective is to identify the effect of peak inspiratory pressure on the development of postoperative pulmonary complications.More specifically, the objective is to identify the effect of maintaining intraoperative peak inspiratory pressure less than or equal to 30 cmH2O compared with peak inspiratory pressure greater than 30 cmH2O on the incidence of postoperative atelectasis, pneumonia and acute respiratory distress syndrome in mechanically ventilated adult surgical patients. PMID- 28009670 TI - Effectiveness of intermittent urinary catheterization in patients with neurogenic bladder: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to investigate the effectiveness of the use of intermittent urinary catheterization in improving the quality of life (QoL) of patients with neurogenic bladder. PMID- 28009671 TI - Experiences of African women who migrate to a developed country and encounter domestic violence: a systematic review protocol of qualitative evidence. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to identify, critically appraise and synthesize the literature regarding the experiences of African women who have migrated to a developed country and have encountered domestic violence. PMID- 28009672 TI - Strategies for implementing shared decision making in elective surgery by healthcare practitioners: a systematic review protocol. AB - REVIEW OBJECTIVES/QUESTIONS: The objectives of the review are to:Specifically, the review questions are. PMID- 28009673 TI - Key components and strategies utilized by nurses for de-escalation of aggression in psychiatric in-patients: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: This systematic review aims to identify the effective de-escalation strategies that nurses utilize to prevent aggressive behaviors.Specifically, this review has the following objectives. PMID- 28009674 TI - Experiences of incivility among faculty and students in online nursing education: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize available evidence of nursing faculty's and nursing students' experiences and perceptions of incivility in online education with the objective of identifying the meaning of incivility in online nursing education. The specific questions to be addressed by this review are. PMID- 28009675 TI - Effects of foot and ankle devices on balance, gait and falls in adults with sensory perception loss: a systematic review. AB - BACKGROUND: Foot and ankle devices are being developed as a method of preventing people with sensory perception loss sustaining a fall. Such devices are believed to work by reducing the likelihood of a fall by improving the balance and gait of the user. OBJECTIVES: The objective of the review was to evaluate the effectiveness of foot and ankle devices for the prevention of falls and the improvement of balance and gait in adults with sensory perception loss. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Participants were community-dwelling adults with bilateral pathological sensory perception loss. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST: The current review evaluated any foot or ankle device, including but not restricted to, all types of footwear (therapeutic and retail), insoles (customized and prefabricated) and ankle-foot orthoses (AFOs). TYPES OF STUDIES: In the absence of randomized controlled trials (RCT), the review considered experimental and epidemiological study designs, except case series, individual case reports and descriptive cross-sectional studies. OUTCOMES: The primary outcome was number of falls. Secondary outcome measures were clinical or laboratory measures of balance or gait. SEARCH STRATEGY: A search for published and unpublished literature from inception to March 2015 written in the English language was conducted across a number of major electronic databases. A three-step search strategy was developed using MeSH terminology and keywords to ensure all that relevant materials are captured. METHODOLOGICAL QUALITY: Methodological quality of included studies was assessed by two reviewers, who appraised each study independently, using standardized Joanna Briggs Institute (JBI) critical appraisal tools. DATA EXTRACTION: Quantitative data were extracted from the studies that were identified as meeting the criteria for methodological quality using the standardized JBI data extraction tools. DATA SYNTHESIS: Due to the heterogeneity of populations, interventions and outcome measures, meta-analyses were not possible and results are presented in narrative form. RESULTS: Nine trials (from 10 papers) involving 238 participants, (14 with multiple sclerosis and 16 with idiopathic peripheral neuropathy, 150 with diabetic neuropathy) and 58 controls were included in the review. No study reported falls as an outcome measure. The results of the included studies found that in people with sensory perception loss, postural sway improved with vibrating insoles and AFO, altering the softness and texture of the top cover had no effect on postural sway, wearing footwear over long distances or AFOs improved step-to-step consistency, and no foot and ankle device was reported to have a negative effect on the balance or gait of people with sensory perception loss. The methodological quality of the included studies was poor. No study used a randomized controlled trial (RCT) methodology. No study incorporated a follow-up period or tested the intervention within the context of the intended clinical environment. CONCLUSION: There is limited evidence to suggest that footwear and insole devices can artificially alter postural stability and may reduce the step to-step variability in adults with sensory perception loss. Varying the material properties of an insole does not notably affect static balance or gait. PMID- 28009676 TI - Effectiveness of meaningful occupation interventions for people living with dementia in residential aged care: a systematic review. AB - BACKGROUND: The ability to participate in valued activities, whether for work, leisure or family, is an important aspect of personal identity. In dementia, progressive memory loss means that abilities developed over a lifetime begin to be lost as well, contributing to the loss of self and identity. Some studies have reported that activities or interventions tailored to be meaningful to the person with dementia (defined as any activity important to the individual) are more effective in addressing behavioral and psychological symptoms of dementia (BPSD) and improving quality of life (QoL) than those that are not so tailored. However, the effectiveness of individualizing interventions or activities for this population is not known. OBJECTIVES: In response to consumer feedback by the Consumer Dementia Research Network that this question ought to be addressed, this review was undertaken, the aim of which was to determine the effectiveness of meaningful occupation interventions for people living with dementia in residential aged care facilities (RACFs). INCLUSION CRITERIA: People living with dementia in RACFs (nursing homes).Any intervention that was individualized to be meaningful to the participant, versus any active control condition or usual care.Experimental and observational studies. TYPES OF OUTCOMES: Quality of life, BPSD (such as agitation, aggression, depression, wandering and apathy), mood, function, cognition and sleep. SEARCH STRATEGY: The search strategy aimed to identify both published and unpublished studies, with the following 12 databases extensively searched: PubMed, CINAHL, PsycINFO, ISI Web of Science, OTSeeker, Embase, Cochrane CENTRAL, clinicaltrials.gov, Mednar, OpenSIGLE, New York Academy of Medicine Library Gray Literature Report, ProQuest Dissertations and Theses. The search strategy was limited to papers published in English between 2004 and January 31, 2015. METHODOLOGICAL QUALITY: All studies were assessed independently by two reviewers for relevance, eligibility and methodological quality. DATA EXTRACTION: Data from included papers were extracted using a standard data extraction tool. DATA SYNTHESIS: Where possible, study results were pooled in statistical meta-analysis. Alternatively, results are presented in narrative and tabular form. RESULTS: A total of 5274 citations were identified; after removal of duplicates, assessment for relevance and eligibility, 61 studies underwent critical appraisal. Thirty-four studies met the quality criteria and were included in a quantitative synthesis. A wide range of interventions were evaluated including individualized recreational activities (13 studies), reminiscence therapy (RT) (seven studies), music therapy interventions (six studies), training staff to develop individual care plans using person-centered care (PCC) or similar approaches (three studies), animal-assisted therapy (two studies), multi-sensory interventions (MSIs) (two studies) and social interaction (one study), all of which measured a number of different outcomes. Overall, and in spite of most studies being small-scale and of relatively brief duration, all interventions with the exception of Snoezelen therapy (a MSI) reported some benefits for people with dementia living in RACFs. The most frequently reported benefits were reductions in agitation (the most frequently assessed outcome), passivity and depression, improved QoL and increases in pleasure and interest. However, the majority of studies generally implemented the intervention, whether it was individualized activities, music or RT or other, in conjunction with one to-one social interaction, and the relative importance of the intervention in comparison to one-to-one social contact for effectiveness cannot be determined from this review. CONCLUSION: Providing meaningful or individualized tailored activities for people with dementia living in RACFs appears to be effective for a range of behavioral and psychological symptoms. The strongest evidence was for individualized activities/recreational interventions for a range of BPSD; preferred music for agitation, depression and anxiety; and RT for mood and cognitive functioning. Insufficient evidence precluded making recommendations regarding animal-assisted (dog) therapy and training staff to develop individual care plans using PCC or similar approaches, while there was no good quality evidence to show that Snoezelen was effective for any outcome. What remains unclear, however, is whether any of these interventions is more effective than the provision of one-to-one social interaction. PMID- 28009677 TI - Effectiveness of temporary deafferentation of the arm on somatosensory and motor functions following stroke: a systematic review. AB - BACKGROUND: After stroke, regaining functional use of the upper limb can be challenging. Temporary deafferentation (TD) is a novel approach used in neurorehabilitation to voluntarily reduce the somatosensory input in a body part by temporary anesthesia; which has been shown to improve sensorimotor functions in the affected limb. OBJECTIVES: The primary objective of this systematic review was to present the best available evidence related to the effects of TD of the affected arm on the recovery of motor function and activity of the upper limb (arm and hand) following stroke. Further, this review aimed to assess the effects of TD on sensory function, activities of daily living (ADL) and quality of life following stroke, the acceptability and safety of the intervention as well as adverse events. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Adult patients (18 years and older) with a clinical diagnosis of stroke, either hemorrhagic or ischemic. TYPES OF INTERVENTIONS: Reports of rehabilitation that included the use of a pneumatic tourniquet, regional anesthesia or nerve block to achieve TD of an arm, or the use of TD as a stand-alone intervention. OUTCOMES: Primary outcomes were motor function and activity of the upper limb using assessment scales, motor tests and global motor functions.Secondary outcomes included measures of sensory function, ADL, impact of stroke and quality of life and pain.Additional outcomes were neurophysiological changes as studied with functional magnetic resonance imaging, magnetoencephalography and/or transcranial magnetic stimulation.Acceptability and safety of the intervention as well as adverse events were also included. TYPES OF STUDIES: We included any experimental and epidemiological studies. There were no randomized controlled trials. We included non-randomized controlled trials, quasi-experimental, before and after studies and case-control studies. SEARCH STRATEGY: We searched for both published and unpublished studies in major databases and all reference lists of relevant articles in English, German or French languages. We included studies published from January 1980 to October 2015. DATA EXTRACTION: Data were extracted from included studies using a standardized data extraction tool from the Joanna Briggs Institute. DATA SYNTHESIS: There was heterogeneity in the types of intervention and outcome measures, therefore statistical pooling of the findings was not appropriate. As such, the studies were grouped according to type of outcome where possible. Findings are presented in a narrative form. RESULTS: Eight studies met the eligibility criteria. All outcome parameters related to the primary outcome (motor function and activity of the more affected upper extremity) showed an improvement during or after TD. The sensory functions significantly improved during or after TD when measured either by the grating orienting task or the grating orientation accuracy, and slightly improved when measured using the von Frey hair testing during TD. CONCLUSION: There is evidence supporting the use of TD of the upper extremity in adults after stroke. Temporary deafferentation can be recommended (Grade B). PMID- 28009678 TI - Extravasation management in the pediatric oncology ward of Children's Hospital of Fudan University: a best practice implementation project. AB - BACKGROUND: Extravasation in a pediatric patient can cause a serious adverse event, but many nurses have insufficient experience to deal with it during intravenous administration. Our division implemented a best practice project, which included extravasation kit instruction preparation, staff education and an update of institutional policy and procedures. The project focused on auditing the extent to which the protocol was implemented and promoting its implementation. OBJECTIVES: The objective of the project was to establish an evidence-based policy and procedure for extravasation management, improve knowledge regarding best practice of extravasation management among staff and formalize the documentation template for extravasation events. METHODS: The Joanna Briggs Institute's Practical Application of Clinical Evidence System and Getting Research into Practice were used to examine compliance with criteria based on the best available evidence before and after the implementation of strategies to promote the use of the evidence-based practice protocol. RESULTS: Four criteria showed a noticeable improvement in compliance: increased use of extravasation kit (0-100%), updated policies and procedure (0-94%), staff education (19-94%) and documented outcomes (13-88%). CONCLUSIONS: The project successfully established effective strategies for establishing an extravasation kit instruction sheet, updating policies and procedures, continuous staff education and nursing documentation to ensure best practice and improve patient outcomes. PMID- 28009679 TI - Commentary on Chlorhexidine Keratitis. PMID- 28009680 TI - A Multicenter Controlled Study to Evaluate Multiple Treatments With Nonthermal Focused Ultrasound for Noninvasive Fat Reduction. AB - BACKGROUND: Demand for nonsurgical esthetic body procedures has led to the development of noninvasive techniques for reducing localized subcutaneous adipose tissue. OBJECTIVE: This study assessed multiple treatments with nonthermal focused ultrasound for noninvasive abdominal treatment of excess fat deposits. MATERIALS AND METHODS: Subjects were randomly assigned to Group 1 for a 4-week control phase before undergoing 3 abdominal fat reduction treatments, at 2-week intervals, or to Group 2 for immediate treatment. Weight, abdominal circumference, tolerability to treatment, subject satisfaction, and adverse events were recorded. RESULTS: Weight remained stable in the 126 participants. Mean reduction in midline circumference was 2.5 +/- 2.1 cm in the Group 1 and 3.5 +/- 2.7 cm in the Group 2 at Week 22. The effect of multiple treatments was cumulative with a steady decrease in abdominal circumferences during the study. Erythema was observed in 28% of treatments but was mild and transient in nature. Subjects tolerated the treatments well and were satisfied with treatment outcome. CONCLUSION: The study demonstrated the efficacy and safety of multiple nonthermal focused ultrasound treatments of excess abdominal fat deposits. Although the remodeling effect is minor compared with traditional surgical procedures, successive focused ultrasound treatments significantly reduced treatment area circumference, while avoiding invasive techniques and their associated disadvantages. PMID- 28009681 TI - Use of a Microwave Device for Treatment of Amputation Residual Limb Hyperhidrosis. PMID- 28009682 TI - Outcomes With Fidaxomicin Therapy in Clostridium difficile Infection. AB - BACKGROUND AND GOALS: Fidaxomicin is a new antibiotic used to treat Clostridium difficile infection (CDI). Given limited clinical experience with fidaxomicin, we assessed outcomes in a diverse cohort of patients with CDI treated with fidaxomicin. STUDY: All CDI cases treated with fidaxomicin at 3 referral centers over a 4-year period were included. Response was defined as resolution of diarrhea and recurrence was defined by recurrence of CDI within 8 weeks of the end of treatment. RESULTS: Overall, 81 patients (median age 55.9 y; 53% female; 26% with inflammatory bowel disease) were included. Response occurred in 90%. Responders had fewer prior CDI episodes [median 1 (range, 0 to 8)] than nonresponders [median 2.5 (range, 1 to 8)], P=0.01. Response after a first CDI episode was 100%, 96% after 1 prior episode, and 82% after 2 or more, P=0.02. Recurrence occurred in 19%. Patients without recurrence had fewer prior episodes of CDI [median 1 (range, 0 to 6)] than patients who recurred [median 2 (range, 1 to 8)], P=0.005. Recurrence after a first episode was 0%, 23% after 1 prior episode, and 29% after 2 or more, P=0.005. All patients with inflammatory bowel disease responded either with improvement of symptoms or a negative C. difficile test; 19% recurred. CONCLUSIONS: All patients with a first CDI episode treated with fidaxomicin responded with no recurrences. Patients with prior CDI episodes were less likely to respond (especially with more than 1 prior episode) and more likely to recur, suggesting a greater clinical benefit of fidaxomicin earlier in the course of CDI. PMID- 28009683 TI - Diabetes Mellitus is Associated With Mortality in Acute Pancreatitis. AB - BACKGROUND AND AIM: Predicting severe pancreatitis is important for early aggressive management of patients with acute pancreatitis (AP). Despite the established role of diabetes mellitus (DM) in the risk of AP, the impact of DM on the clinical outcome in AP has not been fully elucidated. The objective of this study was to assess the risk of mortality and severity in AP among patients with type-2 DM. METHODS: Patients diagnosed with first attacks of AP were enrolled from January 2013 to June 2015. RESULTS: A total of 201 patients (63.2% male, mean age, 59.4 y) with AP were included. Etiologies included gallstones (51.2%), alcohol (37.3%), hypertriglyceridemia (2%), and idiopathic causes (9.5%). There were 54 AP patients (26.9%) with type-2 DM. Severity indices in AP, such as Atlanta Classification (severe), Ranson score, and Bedside Index of Severity in Acute Pancreatitis, were higher in subjects with DM than those without DM. Prevalence of intensive care unit admission and mortality were higher in AP patients with DM compared with those without DM. The association between DM and increased risk of mortality in AP remained statistically significant even after adjustments for confounding factors and Atlanta Classification (odds ratio, 7.76, 95% confidence interval, 1.26-47.63, P=0.027). CONCLUSIONS: Type-2 DM was associated with severity and increased mortality in patients with AP. Our findings provide evidence of the potential role of DM in the pathogenesis and management of severe AP. PMID- 28009684 TI - Within-Stool and Within-Day Sample Variability of Fecal Calprotectin in Patients With Inflammatory Bowel Disease: A Prospective Observational Study. AB - BACKGROUND AND GOALS: The use of fecal calprotectin (FC) as a stool biomarker for differentiating inflammatory bowel disease (IBD) from IBS has been well validated, and there is a strong correlation between FC and the presence of endoscopic inflammatory lesions. However, recent studies have demonstrated intraindividual sample variability in patients with IBD, possibly limiting the reliability of using a single sample for monitoring disease activity. Our aim was to assess the within-stool and within-day sample variability of FC concentrations in patients with IBD. STUDY: We examined a cross-sectional cohort of 50 adult IBD patients. Eligible patients were instructed to collect 3 samples from different parts of the stool from their first bowel movement of the day and 3 samples from each of up to 2 additional bowel movements within 24 hours. FC concentrations were measured by a rapid, quantitative point-of-care test using lateral flow technology (Quantum Blue). Descriptive statistics were used to assess FC variability within a single bowel movement and between different movements at different FC positivity cutoffs. RESULTS: Within a single bowel movement, there was clinically significant sample variability ranging from 8% to 23% depending on the time of the day or on the FC positivity cutoff value. Between bowel movements, there was clinically significant sample variability ranging from 13% to 26% depending on the FC positivity cutoff. CONCLUSIONS: Considering a single FC sample, the first sample of the day with an FC positivity cutoff of 250 MUg/g provided the most reliable indication of disease activity. PMID- 28009685 TI - There is Significant Practice Pattern Variability in the Management of the Hospitalized Ulcerative Colitis Patient at a Tertiary Care and IBD Referral Center. AB - BACKGROUND AND GOALS: Despite published clinical guidelines, substantive data underlying the approach to the management of hospitalized ulcerative colitis (UC) patients failing outpatient therapy are lacking. Variability in practice is therefore not uncommon and may impact clinical outcomes. The degree of variability, however, is not well-studied. Our aim was to evaluate variability in management of the hospitalized UC patient to inform future efforts targeting care optimization for this high-risk population. STUDY: An internet survey was distributed among inflammatory bowel disease providers, which included: (1) nonvignette-based questions assessing provider demographics, experience, and practice setting; (2) diagnostic and therapeutic practice patterns based on a vignette of a hospitalized UC patient. Descriptive and univariate analyses were performed. RESULTS: Ninety-one percent of eligible individuals were included. Nearly 97% endorsed confidence in management of hospitalized UC patients. In general, 83% initiate intravenous corticosteroids (IVCS) as initial therapy, whereas 17% initiate infliximab (IFX) (+/-IVCS). At IVCS failure in the vignette, 74% initiated IFX, 15% increased IVCS dose, 7% initiated cyclosporine, and 4% chose colectomy. Of those choosing IFX, 65% chose 5 mg/kg as the initial dose, whereas the remainder chose 10 mg/kg. Twenty-eight percent gave an additional IFX 5 mg/kg and 7% gave an additional 10 mg/kg dose to the patient in the vignette not responding to 5 mg/kg. CONCLUSIONS: Even among experienced inflammatory bowel disease providers, there is significant practice pattern variability in the management of hospitalized UC patients. Future efforts should target this variability. Adjunctively, prospective trials are needed to guide appropriate therapeutic algorithms, especially with respect to positioning and optimally dosing IFX in this population. PMID- 28009686 TI - Etiology and Pathogenesis of Idiopathic Achalasia. AB - This review examines the etiology and pathogenesis of idiopathic achalasia. This disease is clinically characterized by dysphagia of solids and liquids due to the presence of simultaneous or absent esophageal contractions and impaired or absent relaxation of the lower esophageal sphincter. It includes a review of (a) etiology and pathogenesis of this inflammatory process that damage the ganglion cells of the Auerbach plexus that is limited to the esophagus; (b) genetic abnormalities and polymorphisms associated with this disease that may help explain its heterogeneity expressed by the different motility abnormalities of its phenotypes as well as differences in its clinical progression. These different genetic abnormalities may be responsible for the slow progression of types I or II phenotypes; (c) indirect evidence of viruses present in these patients that may initiate its development; (d) the abnormalities of the muscle layer that may be responsible for the dilation of the body of the esophagus that ultimately causes the sigmoid-like esophagus in the very last phase of this disease. This progression to the end-stage phase tends to occur in about 5% of patients. And, (e) the chronic inflammatory abnormalities in the squamous mucosa that may be the cause of the dysplastic and neoplastic changes that may lead to squamous cell carcinoma whose incidence in this disease is increased. These mucosal abnormalities are usually present in patients with markedly dilated body of the esophagus and severe food stasis. PMID- 28009687 TI - EUS-guided Versus Percutaneous Gallbladder Drainage: Isn't It Time to Convert? AB - BACKGROUND AND AIMS: Endoscopic ultrasound-guided drainage (EUS-GLB) is a minimally invasive option for patients with cholecystitis who are poor surgical candidates. Compared with percutaneous drainage (PC-GLB), earlier studies have demonstrated similar efficacy with improved quality of life. We present a multicenter, international experience comparing PC-GLB and EUS-GLB in nonsurgical patients with cholecystitis. METHODS: All patients who underwent either PC-GLB drainage or EUS-GLB drainage from 7 centers between January 2010 and December 2015 were included. Technical success was defined as successful placement of a catheter or stent into the gallbladder. Clinical success was defined as resolution of clinical symptoms after intervention. Adverse events, length of stay, and the need for repeat interventions and/or hospitalizations were recorded for all patients. RESULTS: A total of 155 patients were included (mean age 74+/ 14.24 y; range, 31 to 96; 56% male). Forty-two patients underwent EUS-GLB and 113 patients underwent PC-GLB. Technical success was achieved in 40 patients (95%) in the EUS-GLB group and 112 patients (99%) in the PC-GLB group (P=0.179). Clinical success was achieved in 40 patients (95%) in the EUS-GLB group and 97 patients (86%) in the PC-GLB group (P=0.157). There was no difference in hospital readmission rates between the 2 groups (14% vs. 24%; P=0.194). However, there was significantly higher number of patients requiring repeat interventions in the PC GLB group (n=28, 24%) compared with the EUS-GLB group (n=4, 10%) (P=0.037). There was no difference in adverse events between the 2 groups. CONCLUSIONS: EUS-GLB is safe and efficacious, with comparable technical and clinical success rates and no difference in adverse events. In addition, EUS-GLB offers a potential cost-saving benefit and morbidity benefit by demonstrating a decreased number of repeat interventions. PMID- 28009688 TI - Introduction to Special Issue on Hypertrophic Scars and Keloids. PMID- 28009689 TI - A Comparison of Gene Expression of Decorin and MMP13 in Hypertrophic Scars Treated With Calcium Channel Blocker, Steroid, and Interferon: A Human-Scar Carrying Animal Model Study. AB - BACKGROUND: The formation of hypertrophic scaring (HSc) is an abnormal wound healing response. In a previous study, an animal model with human scar tissue implanted into nude mice (BALB/c) has been successfully established. The effects of verapamil as well as combination therapy with verapamil and kenacort have been studied and compared. OBJECTIVE: To treat persistent hypertrophic scars, local injection of drugs composed of steroids, calcium channel blockers (CCBs), and interferon might be a good method. What is the best dose of the regimen and what are the mechanisms are also a worthwhile study. MATERIALS AND METHODS: Scar specimens were harvested from patients with HSc or Keloid resulting from burn injury, and then implanted to BALB/c-nu nude mice for 4 weeks. Before implantation, the specimen was either injected with or without drugs such as steroids (kenacort), CCBs (verapamil), and interferons (INFalpha2b), respectively. After the removal of implants, quantitative gene expressions of decorin and collagenase (MMP13) were measured using a real-time polymerase chain reaction to detect their mRNAs. Two way-ANOVA and Post Hoc were used for statistical analysis using the software SPSS 15.0. RESULTS: All drug-treated groups increased the expressions of decorin and MMP13 in comparison with those in noninjected group (p < .001) in a dose-dependent manner. Comparing equal amounts of individual drugs, gene expression of decorin was increased with increasing injection amount, and the best result in low amount of injection (0.02 mL of each) was shown in the group injected with INFalpha2b followed by kenacort and verapamil. However, the results were changed while injection amount was up to 0.04 mL and the strongest decorin gene expression was found in kenacort injection. Regarding MMP-13 expression, low-amount injection (0.02 mL) of INFalpha2b has strongest gene expression followed by kenacort and verapamil, but in the large-amount regimes (0.04 mL), verapamil had strongest gene expression followed by INFalpha2b and kenacort. CONCLUSION: This study showed that the kenacort, verapamil, and INFalpha2b all inhibited HSc in a dose-dependent manner through the evidence of gene expression of decorin and MMP13. In comparison with the injections between small amounts of drugs, INFalpha2b potentiated the strongest decorin and MMP13 expression. On the contrary, among the large-amount injection regimes, kenacrot was more effective on decorin expression as verapamil to MMP13 expression. To decrease side effects from the drugs and produce promising results for the clinical practice, it is suggested to maintain the dose of INFalpha2b along with an increased dose of verapamil for HSc improvement. PMID- 28009690 TI - Fractional Erbium-Doped Yttrium Aluminum Garnet Laser Versus Microneedling in Treatment of Atrophic Acne Scars: A Randomized Split-Face Clinical Study. AB - BACKGROUND: Ablative fractional erbium-doped yttrium aluminum garnet (Er:YAG) laser and microneedling have been popularized in recent years and their effectiveness and side effects individually reported. No previous study, however, has directly compared the efficacy and safety between the 2 different treatments. OBJECTIVE: To compare the efficacy and safety of the ablative fractional Er:YAG laser and microneedling for the treatment of atrophic acne scars. MATERIALS AND METHODS: Thirty patients with atrophic acne scars were randomly treated in a split-face manner with a fractional Er:YAG laser on one side and microneedling on the other side. All patients received 5 treatments with a 1-month interval. Objective and subjective assessments were obtained at baseline and at 3 months after the final treatment. RESULTS: At the 3-month follow-up, both treatment modalities induced noticeable clinical and histological improvement, with significantly better results in fractional Er:YAG laser versus microneedling (70% vs 30%), respectively (p < .001). Fractional Er:YAG laser sides had significantly lower pain scores. Total downtime was significantly shorter in microneedling sides. CONCLUSION: Both treatment modalities are effective and safe in the treatment of atrophic acne scars, with significantly higher scar response to the fractional Er:YAG laser treatment. PMID- 28009691 TI - Treatment of Acne Scars on Darker Skin Types Using a Noninsulated Smooth Motion, Electronically Controlled Radiofrequency Microneedles Treatment System. AB - BACKGROUND: Noninvasive technologies for treating acne scars use radiofrequency (RF)-emitting microneedles for both mechanical disruption of fibrotic strands and heat-mediated collagen remodeling. OBJECTIVE: Efficacy and safety evaluation of electronically controlled noninsulated RF microneedling system on acne scars in patients with dark skin. METHODS: Nineteen patients, 24 to 51 years old, skin types III to V, with acne scars were enrolled in the study. Each patient had 3 treatment sessions at monthly intervals using a multisource RF treatment platform with a microneedle RF applicator. Efficacy was evaluated by the Goodman and Barron's Global Qualitative Acne Scarring System. RESULTS: No bleeding points occurred during treatments. Post-treatment erythema was observed immediately after the treatment and lasted up to 10 hours after the treatment. Improvement of at least 1 acne scar grade was noted in 11 of 19 patients (57.9%) after 1 month and in 9 of 9 patients (100%) after 3 months. CONCLUSION: The tested noninsulated electronically controlled RF microneedles were found to be safe and efficient in the treatment of atrophic acne scars in skin types III to V with minimal pain or downtime. PMID- 28009692 TI - Fractional Carbon Dioxide Laser of Recent Surgical Scars in the Head and Neck Region: A Split-Scar, Evaluator-Blinded Study. AB - BACKGROUND: Postoperative scarring is a common cause of patient dissatisfaction. Several strategies have been developed to improve its clinical aspects. OBJECTIVE: To assess efficacy and safety of the 10,600 nm ablative fractional carbon dioxide (CO2) laser in the treatment of recent surgical scars in the head and neck region. METHODS AND MATERIALS: A prospective, randomized, single-blind intrapatient controlled study was conducted on 9 postoperative scars in the head and neck region. On half of the scar, 3 treatment sessions were performed. Physician/Patient Global Assessment (PhGA/PGA) and Patient and Observer Scar Assessment Scales (POSAS) were used to evaluate treatment efficacy. Safety was evaluated by registration of pain and adverse events. RESULTS: No statistically significant differences were noted in terms of PhGA or POSAS (observer). Patient Global Assessment (p = 0.058) and POSAS (patient) (p = 0.091) showed a trend toward better improvement of the treated half. Itch score (p = 0.046) and global end evaluation (patient) (p = 0.026) demonstrated a statistically significant difference in favor of the treated part. Adverse events were minor, and no long term side effects were noted. CONCLUSION: The use of CO2 fractional laser is safe and is associated with high patient satisfaction. However, objective measurements could not confirm its efficacy in the treatment of recent surgical scars. PMID- 28009693 TI - Importance of Scar Prevention and Treatment-An Approach From Wound Care Principles. AB - BACKGROUND: The increased number of cosmetic surgical and nonsurgical procedures has led to a greater demand to achieve aesthetically acceptable scars. Silicone gel (SG) dressings were evaluated in these cases following the principles of wound care and also minimizing abnormal scar formation. PATIENTS AND METHODS: A newly developed solution in wound care in the form of a SG has proven to be a highly effective treatment for a series of 4 clinically challenging cases presented in this article: postprocedure healing after a laser treatment, nonhealing scalp wounds, chronic relapsing xerotic eczematous cheilitis, and the treatment of scars caused by third degree burns. A standard SG was applied to improve the scar outcome of severe burns of a young child. RESULTS: Silicone gels offer excellent clinical results in these 4 cases. In terms of wound care and scar management, they provide a user friendly, convenient application form and increase patient comfort and compliance. CONCLUSION: To pursue these results, further studies need to be conducted but as of now, there is strong suggestive evidence that SGs indicate beneficial properties for wound care management and scar prevention. PMID- 28009694 TI - Can Emergency Department, Hospital Discharge, and Death Data Be Used to Monitor Burden of Drug Overdose in Rhode Island? AB - CONTEXT: Drug overdoses are a growing public health problem in the United States. Rhode Island is also confronted with a serious epidemic of drug overdose deaths and ranks sixth worst in the United States for age-adjusted drug overdose death rate. OBJECTIVE: To monitor trends of drug overdose-related emergency department (ED) visits, hospitalizations, and deaths and classify the drug overdoses by demographics, discharge status, intent, and specific drug involved to plan for health care resource allocation, mental health services, drug abuse treatment, prevention, and policies. DESIGN: Cross-sectional study. SETTING: The 2005-2014 ED, hospital discharge, and death data were used for this study. MAIN OUTCOME MEASURE: Age-adjusted rates were calculated by using age-specific Rhode Island 2010 standard population. Healthcare Cost and Utilization Project cost-to-charge ratios were used to convert total hospital charges to costs. The descriptive analysis was performed. RESULTS: Hospitalizations generally represent the most severe cases; there are substantially fewer cases than are seen in the ED, and their characteristics are different from ED visits. More than half of the ED cases were an unintentional injury by drug overdose, but more than half of the hospital discharge data cases were a suicide/self-inflicted injury by drug overdose. There were typically much more females than males that result in a hospital admission. In Rhode Island, there were 249 drug overdose deaths in 2014. Drug overdose fatalities were more likely to be young, male, white, and those who reside in suburban regions. IMPLICATIONS: Nonfatal and fatal drug overdose data are important for understanding the scope, incidence, and breadth of this public health epidemic and can guide overdose intervention efforts. In Rhode Island, policy makers can use drug overdose data to target high-risk subpopulations to reduce overdose injuries and fatalities. The Rhode Island study can be shared with other states. CONCLUSIONS: Regardless of the type of drug, overdoses remain a public health crisis in Rhode Island. It is a dynamic epidemic and needs partnership among public health, behavioral health, public safety, clinic, pharmacy, and communities. The ability to track drug overdose in real time will be an essential tool to respond to the constantly evolving drug overdose epidemic in Rhode Island quickly and effectively. PMID- 28009695 TI - Elastin Is Differentially Regulated by Pressure Therapy in a Porcine Model of Hypertrophic Scar. AB - Beneficial effects of pressure therapy for hypertrophic scars have been reported, but the mechanisms of action are not fully understood. This study evaluated elastin and its contribution to scar pliability. The relationship between changes in Vancouver Scar Scale (VSS) scores of pressure-treated scars and differential regulation of elastin was assessed. Hypertrophic scars were created and assessed weekly using VSS and biopsy procurement. Pressure treatment began on day 70 postinjury. Treated scars were compared with untreated shams. Treatment lasted 2 weeks, through day 84, and scars were assessed weekly through day 126. Transcript and protein levels of elastin were quantified. Pressure treatment resulted in lower VSS scores compared with sham-treated scars. Pliability (VSSP) was a key contributor to this difference. At day 70 pretreatment, VSSP = 2. Without treatment, sham-treated scars became less pliable, while pressure-treated scars became more pliable. The percentage of elastin in scars at day 70 was higher than in uninjured skin. Following treatment, the percentage of elastin increased and continued to increase through day 126. Untreated sham scars did not show a similar increase. Quantification of Verhoeff-Van Gieson staining corroborated the findings and immunofluorescence revealed the alignment of elastin fibers. Pressure treatment results in increased protein level expression of elastin compared with sham-untreated scars. These findings further characterize the extracellular matrix's response to the application of pressure as a scar treatment, which will contribute to the refinement of rehabilitation practices and ultimately improvements in functional and psychosocial outcomes for patients. PMID- 28009696 TI - Quantitative Analysis of Estimated Burn Size Accuracy for Transfer Patients. AB - The objective of this study was to quantify differences between estimated TBSA from referring hospitals vs calculated TBSA in the burn unit in regards to several variables. We conducted a retrospective review of 735 burn patients admitted over a 17-month period. Three hundred twenty-six patients fit the criteria of transfers with recorded %TBSA estimations from referring hospitals. Referring %TBSA was compared with actual %TBSA, and the difference was expressed as a percentage of actual %TBSA. This was then used to group referring estimations as underestimated (less than -25%), satisfactory (-25 to 25%), or overestimated (greater than 25%). A paired t-test was used to assess the paired differences for significance. Secondary variables were then assessed between groups. When assessing associations of these clinical measures, a one-way analysis of variance was used for continuous variables and Pearson's chi test or Fisher's exact test was used. Of the 326 patients analyzed, 13 were underestimated, 63 were satisfactory, and 250 were overestimated. The ratio of overestimation to underestimation exceeded 19:1 and the ratio of overestimation to satisfactory estimation was nearly 4:1, with a statistically significant difference in referred %TBSA and actual %TBSA (P < .0001). Within the over and underestimated groups, there were significant differences between referred %TBSA and actual %TBSA (P < .0001). Larger burns were more accurately estimated (P < .0001). There are significant inaccuracies between referring hospital estimated %TBSA and actual %TBSA, which consistently and grossly skew toward overestimation. Inaccuracy in burn size estimation is systemic and can affect patient care and burn unit efficiency. PMID- 28009697 TI - An Intervention Bundle to Facilitate Return to Work for Burn-Injured Workers: Report From a Burn Model System Investigation. AB - Rates of return to work (RTW) after burn injury vary. A 2012 systematic review of the burn literature reported that nearly 28% of all adult burn survivors never return to any form of employment. These authors called for interventions designed to assist survivors' ability to function in an employed capacity. In 2010, our burn center outpatient clinic instituted an intervention aimed to return injured workers to employment within 90 days of their insurance claims. The interventions include patient/family education focused on recovery rather than disability, employer contact and education by the vocational rehabilitation (VR) counselor, physician recommendations for work accommodations, provision of employee status letters, and Activity Prescription Forms (APFs). The purpose of this study is to report on the effectiveness of these interventions. Following institutional review board (IRB) approval, medical records of adults with occupation-related burn injuries and receiving care at a single regional burn center from June 2010 to July 2015 were reviewed. Data on patient and injury characteristics and outpatient VR services provided were collected. The primary outcome of interest was the percentage of patients who RTW; 338 individuals met study entry criteria. The VR counselor evaluated all patients. All patients received an employer letter(s) and APF documentation. Workplace accommodations were provided to more than 30% of patients. RTW rate was 93%, with an average of 24 days from injury to RTW. In an intervention bundle involving the patient, employer, Workers' compensation, and the burn clinic staff, injured workers achieved a high rate of RTW. Although we cannot correlate individual bundle components to outcome, we postulate that the combination of employer/employee/insurer engagement and flexibility contributed to the success of this program. PMID- 28009698 TI - The Effect of Illicit Drug Use on Outcomes Following Burn Injury. AB - Illicit drug use is common among patients admitted following burn injury. The authors sought to evaluate whether drug abuse results in worse outcomes. The National Burn Repository (NBR) was queried for data on all patients with drug testing results available. Outcomes included mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, and duration of ventilator support. Propensity score weighting was performed to control for age, alcohol use, burn size, gender, and etiology of burn. A total of 20,989 patients had drug screen data available; 11,642 (55.5%) tested positive for at least one drug of abuse. Illicit drug use was associated with a higher proportion of patients with flame burn (53.2 vs 48.4%) and larger average burn size (11.2 vs 9.5% TBSA, P < .001). Attempted suicide was more likely if the patient had used drugs (2.8 vs 1.7%, P < .001). Drug use resulted in longer hospital and ICU LOS (14.2 vs 11.4 and 8.5 vs 5.6 days, P < .001), but did not increase the risk of mortality (5.7 vs 5.2, P = .08). After propensity score weighting, drug use did not affect mortality, hospital LOS, or duration of ventilator support, but did increase the average ICU LOS by 1.2 days (P = .001). Drug use does not affect mortality, hospital LOS, or duration of ventilator support among burned patients. After controlling for burn size, age, mechanism of injury, and gender, patients with a positive drug screen had an average increase in ICU LOS by 1 day. PMID- 28009699 TI - A 6-Year Case-Control Study of the Presentation and Clinical Sequelae for Noninflicted, Negligent, and Inflicted Pediatric Burns. AB - Inflicted burns are one of the leading causes of abuse-related fatalities in children. Between 30 and 60% of children accidentally returned to abusive homes suffer reabuse. Given the high chance for abuse recurrence and the associated morbidity/mortality, it is critical that inflicted burns are promptly identified to guide appropriate medical and child welfare management. Although previous studies proposed historical and mechanistic features using noncomparative or poorly powered data, this study utilized comparative data from a 6-year period (2009-2014) at a certified burn center along with expert analysis from Child Advocacy and Protective Services (CAPS) to provide higher level evidence supporting classical findings while elucidating new features with respect to burn severity and required interventions. A retrospective chart review of 408 pediatric burns was cross-referenced with the respective CAPS consultations to construct a multidisciplinary, deidentified database. The average age was 2.9 years (0.04-17 years) with 232 (57%) males and 330 (81%) African-Americans. CAPS investigations confirmed burn etiologies: noninflicted (346 [85%]), negligent (30 [7%]), and inflicted (32 [8%]). In comparing the three etiologies, statistical significance (P < .05) was observed for numerous variables including historical inconsistency, burn age, child welfare history, burn size and depth, distribution, concomitant injury rates, number of surgical interventions, infectious complications, and hospital length of stay. In addition to reaffirming classical features of abusive burns to fortify etiologic diagnoses, this study elucidated appreciable differences in burn severity, interventional sequelae, and burn-related complications, which will help guide medical and surgical interventions for future pediatric burn patients. PMID- 28009700 TI - Silver Sulfadiazine Retards Wound Healing and Increases Hypertrophic Scarring in a Rabbit Ear Excisional Wound Model. AB - This study evaluated the effects of topical use of silver sulfadiazine cream (SSD) on wound healing and subsequent scarring in a rabbit ear wound model. Seven millimeter full-thickness excisional wounds were created in rabbit ears. Twenty four rabbits were randomized into four groups in which each group received base cream, 0.01% SSD, 0.1% SSD, or 1% SSD, respectively. Each treatment was applied at 2-day intervals from postoperative days (PODs) 2 to 14. At POD 7, half of the rabbits from each group were killed and tissues were harvested to measure wound healing parameters that included epithelial gap and granulation area. At POD 28, the remaining rabbits from each group were assessed for hypertrophic scarring. Epithelial gaps in SSD-treated groups at concentrations of 0.1 and 1% were significantly larger than those of base cream-treated controls. In contrast, analysis of granulation areas that represent volume of granulation tissue formed during healing did not show any statistical differences between the base cream treated group and all three SSD-treated groups. At POD 28, when compared to the base cream-treated group (1.44 +/- 0.03), SSD-treated-groups (0.1 and 1%) had more (P < .05) hypertrophic scar formation (scar elevation index = 1.65 +/- 0.04, 0.1%; 1.63 +/- 0.06, 1%). The results of this study demonstrate that SSD treatment contributes not only to impaired reepithelialization but also to a greater hypertrophic scar formation. These results also indicate that caution should be exercised when using SSD clinically to prevent or treat wound infections. PMID- 28009701 TI - Burn Shock and Resuscitation: Proceedings of a Symposium Conducted at the Meeting of the American Burn Association, Chicago, IL, 21 April 2015. AB - The Special Interest Groups of the American Burn Association provide a forum for interested members of the multidisciplinary burn team to congregate and discuss matters of mutual interest. At the 47th Annual Meeting of the American Burn Association in Chicago, IL, the Fluid Resuscitation Special Interest Group sponsored a special symposium on burn resuscitation. The purpose of the symposium was to review the history, current status, and future direction of fluid resuscitation of patients with burn shock. The reader will note several themes running through the following presentations. One is the perennial question of the proper role for albumin or other fluid-sparing strategies. Another is the unique characteristics of the pediatric burn patient. A third is the need for multicenter trials of burn resuscitation, while recognizing the obstacles to conducting randomized controlled trials in this setting. PMID- 28009702 TI - Volar, Dorsal, and Lateral Locking Plate Fixation for Pilon Fractures. AB - The more common dorsal fracture subluxations at the base of the middle phalanx have an intact dorsal buttress of articular surface in continuity with the shaft. Capitalizing on this foundation, various fixation methods have met with relatively equivalent success including Kirschner wires, screws only, nonlocking plate and screws, and external fixation. Pilon fractures are complete articular fractures, where the comminuted articular fragments lack any structural connection to the more distal shaft of the middle phalanx, and have largely relied upon external fixation traction systems. The theoretical concept is that axial distraction prevents articular collapse and that the surrounding soft tissue envelope acts to gather the articular fragments; the term "ligamentotaxis" is often applied. Most constructs are founded on a transverse wire through the axis of rotation in the head of the proximal phalanx with the idea that patients will pursue active motion, termed "dynamic fixation." In practice, patients find it difficult to move well while the construct is in place and have rarely achieved much range by the time of removal. These cases are prone to loss of articular reduction leading to posttraumatic arthritis, substantial proximal interphalangeal joint stiffness, and pin-tract infection. Such problems are solved with locking plates that support the articular reduction throughout healing and permit immediate range of motion while avoiding other complications such as pin-tract infection. Outcomes are reported for 40 patients treated with locking plates applied from volar, dorsal, and lateral to treat pilon fractures. PMID- 28009703 TI - Transient receptor potential vanilloid 2 function regulates cardiac hypertrophy via stretch-induced activation. AB - OBJECTIVE: Hypertension (increased afterload) results in cardiomyocyte hypertrophy leading to left ventricular hypertrophy and subsequently, heart failure with preserved ejection fraction. This study was performed to test the hypothesis that transient receptor potential vanilloid 2 subtype (TRPV2) function regulates hypertrophy under increased afterload conditions. METHODS: We used functional (pore specific) TRPV2 knockout mice to evaluate the effects of increased afterload-induced stretch on cardiac size and function via transverse aortic constriction (TAC) as well as hypertrophic stimuli including adrenergic and angiotensin stimulation via subcutaneous pumps. Wild-type animals served as control for all experiments. Expression and localization of TRPV2 was investigated in wild-type cardiac samples. Changes in cardiac function were measured in vivo via echocardiography and invasive catheterization. Molecular changes, including protein and real-time PCR markers of hypertrophy, were measured in addition to myocyte size. RESULTS: TRPV2 is significantly upregulated in wild-type mice after TAC, though not in response to beta-adrenergic or angiotensin stimulation. TAC-induced stretch stimulus caused an upregulation of TRPV2 in the sarcolemmal membrane. The absence of functional TRPV2 resulted in significantly reduced left ventricular hypertrophy after TAC, though not in response to beta-adrenergic or angiotensin stimulation. The decreased development of hypertrophy was not associated with significant deterioration of cardiac function. CONCLUSION: We conclude that TRPV2 function, as a stretch-activated channel, regulates the development of cardiomyocyte hypertrophy in response to increased afterload. PMID- 28009704 TI - Hospital admissions for orthostatic hypotension and syncope in later life: insights from the Malmo Preventive Project. AB - OBJECTIVE(S): We explored incidence, predictors, and long-term prognosis of hospital admissions attributed to reflex syncope and orthostatic hypotension. METHODS: We analyzed a cohort of 32 628 individuals (68.2% men; age, 45.6 +/- 7.4 years) without prevalent cardiovascular disease over a follow-up period of 26.6 +/- 7.5 years. RESULTS: One thousand and fourteen persons (3.1%, 1.2 per 1000 person-years) had at least 1 hospitalization for orthostatic hypotension (n = 462, 1.42%) or syncope (n = 632, 1.94%). Orthostatic hypotension-related hospitalizations were predicted by age [per 1-year increase, hazard ratio 1.14, 95% confidence interval (CI): 1.12-1.16], smoking (hazard ratio 1.35, 95% CI: 1.12-1.64), diabetes (hazard ratio 1.50, 95% CI: 1.00-2.25), baseline orthostatic hypotension (hazard ratio 1.45, 95% CI: 1.05-1.98), in particular, by SBP fall at least 30 mmHg (hazard ratio 3.93, 95% CI: 2.14-7.23), whereas syncope hospitalizations by age (per 1-year increase, hazard ratio 1.09, 95% CI: 1.07 1.11), smoking (hazard ratio 1.27, 95% CI: 1.08-1.49), and hypertension (hazard ratio 1.42, 95% CI: 1.20-1.69). Both syncope-hospitalized and orthostatic hypotension hospitalized patients had higher burden of hospital admissions for other reasons such as cardiovascular, pulmonary, renal disease, or diabetes. During the follow-up, 10 727 (32.9%) died, with 419 deaths preceded by syncope/orthostatic hypotension hospitalization. After adjustment for traditional risk factors, syncope-hospitalization predicted all-cause mortality (hazard ratio 1.16, 95% CI: 1.02-1.31), whereas orthostatic hypotension hospitalization predicted cardiovascular mortality (hazard ratio 1.13, 95% CI: 1.07-1.19). CONCLUSION: Hospital admissions due to syncope and orthostatic hypotension occur in ~3% of older individuals and increase with age and comorbidities. Admissions due to syncope are associated with prevalent hypertension, whereas those due to orthostatic hypotension overlap with diabetes and previously identified orthostatic hypotension. Syncope-related admissions predict higher all-cause mortality, whereas orthostatic hypotension-related admissions herald increased cardiovascular mortality. PMID- 28009705 TI - Positive allosteric modulation of GABAA receptors attenuates high blood pressure in Schlager hypertensive mice. AB - OBJECTIVE: Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors. METHODS: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5 mg/kg per day), or its vehicle, for a period of 2 weeks. In addition to baseline recordings, the response to stress and ganglionic blockade with pentolinium was recorded, before and 7-14 days after minipump implantation. Following treatment, brains were processed for c-Fos immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: Administration of allopregnanolone selectively reduced mean arterial pressure (-8.0 +/- 2.7 mmHg; P = 0.02) and the depressor response to pentolinium (-15.3 +/- 3.2 mmHg; P = 0.001) in BPH/2J mice, with minimal effects observed in BPN/3J mice. Following allopregnanolone treatment, the diminished expression of GABAA delta, alpha4 and beta2 subunits in the hypothalamus (-1.6 to 4.8-fold; Pstrain < 0.05) was abolished. Furthermore, in BPH/2J mice, allopregnanolone treatment reduced the pressor response to dirty cage switch stress (-26.7 +/- 4.5%; P < 0.001) and abolished the elevated c-Fos expression in pre-sympathetic nuclei. CONCLUSION: The selective antihypertensive and stress inhibitory effects of allopregnanolone in BPH/2J mice suggest that allosteric modulation of GABAA receptors, in amygdalo-hypothalamic pathways, may contribute to the development of hypertension in this model and may offer a potential new therapeutic avenue. PMID- 28009706 TI - Pet ownership and survival in the elderly hypertensive population. AB - OBJECTIVES: To assess the association of pet ownership and all-cause and cardiovascular mortality over a long-term follow-up among elderly treated hypertensive participants. METHODS: Pet-ownership data from a subcohort of the Second Australian National Blood Pressure study were used. Participants were aged 65-84 years at enrolment (1995-1997) and responded to a pet-ownership questionnaire during year 2000. Participants' survival information was determined over a median of 10.9 years that includes Second Australian National Blood Pressure in-trial period (median 4.2 years) together with posttrial follow-up period (median 6.9 years). For the current study, end points were any fatal cardiovascular event and all-cause fatal events. RESULTS: Of those who responded to a pet-ownership questionnaire (4039/6018 - 67%), 86% (3490/4039) owned at least one pet at any-time during their life (current or previous pet owner), with 36% (1456/4039) owning at least one pet at the time of the survey. During the follow-up period, 958 participants died including 499 deaths of cardiovascular origin. Using a Cox proportional hazard regression model adjusting for possible confounders, there was a 22 and 26% reduction in cardiovascular mortality observed among previous and current pet owners, respectively, compared with those who had never owned one. A similar nonsignificant trend was observed for all cause mortality once adjusted for potential confounders. CONCLUSION: Pet ownership was associated with an improved cardiovascular disease survival in a treated elderly hypertensive population. PMID- 28009707 TI - The Spine in Patients With Osteogenesis Imperfecta. AB - Osteogenesis imperfecta is a genetic disorder of type I collagen. Although multiple genotypes and phenotypes are associated with osteogenesis imperfecta, approximately 90% of the mutations are in the COL1A1 and COL1A2 genes. Osteogenesis imperfecta is characterized by bone fragility. Patients typically have multiple fractures or limb deformity; however, the spine can also be affected. Spinal manifestations include scoliosis, kyphosis, craniocervical junction abnormalities, and lumbosacral pathology. The incidence of lumbosacral spondylolysis and spondylolisthesis is higher in patients with osteogenesis imperfecta than in the general population. Use of diphosphonates has been found to decrease the rate of progression of scoliosis in patients with osteogenesis imperfecta. A lateral cervical radiograph is recommended in patients with this condition before age 6 years for surveillance of craniocervical junction abnormalities, such as basilar impression. Intraoperative and anesthetic considerations in patients with osteogenesis imperfecta include challenges related to fracture risk, airway management, pulmonary function, and blood loss. PMID- 28009708 TI - Trunnion Corrosion in Metal-on-Polyethylene Total Hip Arthroplasty: A Case Series. AB - INTRODUCTION: Modular total hip arthroplasty implants can help the operating surgeon reproduce the optimum limb length and offset; however, the modularity can lead to fretting and corrosion with associated metal-related problems. Although metal-on-metal bearings are often reported to have problems, recent case reports suggest that the problems can occur with any articulation, usually as a result of problems at the head/neck junction. METHODS: We retrospectively reviewed three cases of a specific implant combination with nontraumatic trunnion failure, with two cases presenting as acute complete dissociation of the femoral head from the neck. RESULTS: All three cases had failure of the Accolade TMZF plus stem and trunnion (Stryker) that progressed rapidly from the onset of symptoms. The most likely contributing factors to failure were large femoral head size, high horizontal offset, a low angled neck, and a beta titanium alloy taper with a cobalt-chromium head. CONCLUSION: We recommend regular follow-up of all patients with Accolade TMZF stems, and patients should be advised to seek immediate medical attention if they have any new mechanical symptoms in a metal-on polyethylene total hip arthroplasty. Providers should specifically look for any alteration of alignment between the femoral head and neck in follow-up radiographs. PMID- 28009709 TI - The Effect of Cervical Interbody Cage Morphology, Material Composition, and Substrate Density on Cage Subsidence. AB - BACKGROUND: Interbody cages used in spinal fusion surgery can subside into the adjacent vertebral bodies after implantation, leading to loss of spinal height, malalignment, and possible radicular symptoms. Several factors may contribute to cage subsidence. METHODS: This in vitro investigation examined the possible contribution of substrate density, cage contact area (ie, cage footprint), cage filling, cage end plate surface texture, and cage material composition on the magnitude of subsidence. Commercially available cervical interbody cages of two sizes (16 * 12 mm and 17 * 14 mm) were implanted between foam blocks of two different densities and were cyclically loaded. Cages were made of titanium alloy (Ti4Al6V), silicon nitride ceramic (Si3N4), or polyether ether ketone (n = 8 cages of each material type). Additional testing was performed on Si3N4 cages of the smaller size with nontextured surfaces and with filled cores. RESULTS: Subsidence measurements showed that lower foam density had the greatest influence on subsidence, followed by smaller cage footprint. Cage material had no effect on subsidence. In the additional testing of small-footprint Si3N4 cages, the cages in which the core was filled with a load-bearing porous material had less subsidence in lower-density foam than the cages with an empty core had, whereas cage end plate surface texture had no effect on subsidence. CONCLUSION: Ranking of the relative impact of these factors indicated that substrate density had the greatest contribution to the measured subsidence (approximately 1.7 times and approximately 67 times greater than the contributions of cage footprint area and material, respectively). The contribution of cage footprint area to subsidence was found to be 40 times greater than the contribution of cage material to subsidence. PMID- 28009710 TI - Subxiphoid Exchange of HeartMate II Left Ventricular Assist Device. AB - With increasing use of left ventricular assist devices (LVADs) for long-term circulatory support comes a growing need for device exchange. The conventional surgical approach for device exchanges has been a reoperative median resternotomy. Less-invasive HeartMate II LVAD exchange via a nonmuscle-dividing subxiphoid incision as an alternative to a left subcostal incision may reduce pain burden and facilitate recovery. From November 2006 to June 2015, 292 patients underwent HeartMate II LVAD placement, of which 30 (10.3%) required an exchange. Twenty-four (80%) LVAD exchanges were performed through a subxiphoid sternal-sparing approach and six (20%) through reoperative sternotomy. Predominant indication for device exchange was suspected or confirmed pump thrombus (73.3%), followed by electromechanical pump dysfunction (16.7%). The subxiphoid approach resulted in significantly shorter median intensive care unit (7 vs. 37 days, p = 0.01) and hospital stay (29 vs. 107 days, p = 0.01) compared with reoperative sternotomy. Kaplan-Meier analysis showed comparable survival between the subgroups (p = 0.15) as well as between the patients with device exchange and the rest of the HeartMate II LVAD patients at our institution (p = 0.12). Subxiphoid device exchange is a viable option, resulting in low operative morbidity and mortality with no adverse effect on late survival. PMID- 28009711 TI - Surgical Technique for Ventricular Device Exchange: From HeartMate II to HVAD. AB - Implantable continuous-flow left ventricular assist devices (LVADs) have improved the survival of end-stage heart failure patients. Recent studies have shown an increased occurrence of device replacement in the axial flow pumps particularly for thrombosis. In some patients, to try and avoid recurrent pump thrombosis, it might be advantageous to switch from the axial flow LVAD to a newer generation centrifugal flow LVAD. Technically, this requires some adaption of the LVAD inflow and outflow connections. We describe our technique and outcomes in patients who underwent the conversion from an axial flow LVAD to a centrifugal flow LVAD. PMID- 28009712 TI - Rehospitalization Patterns in Pediatric Outpatients with Continuous-Flow VADs. AB - As continuous-flow ventricular assist devices (CF-VADs) are used increasingly in children and adolescents, more pediatric patients will be supported as outpatients. Herein we report the patterns of rehospitalization after CF-VAD implantation at a single center. We retrospectively reviewed the medical records of 19 consecutive patients who received CF-VADs between December 6, 2010 and November 5, 2016 and were discharged on device therapy. The frequency, duration, and indications for all hospitalizations between the time of implant hospitalization discharge and January 8, 2016 were analyzed. There were a total of 52 rehospitalization episodes in 16 (84%) patients over 5,101 (median 93, interquartile range [IQR] 38, 226) follow-up days. There were a median of two (IQR 1, 3) hospitalizations per patient. The median time to first hospitalization was 14 (IQR 7, 62) days. The most common admitting diagnoses were suspected infection 13 (28%) and suspected pump thrombosis in 8 (17%). Thirty-one (60%) hospitalizations included procedures, including seven (13%) requiring device related surgery. Overall, 89% of postimplant discharge days were spent outside of the hospital. Children with CF-VADs can be discharged with acceptable readmission rates and significant time spent out of hospital. Most patients will be rehospitalized at least once between implant hospitalization and transplantation, often within 2 weeks of hospital discharge, with the most common indications for admission being suspected infection and suspected pump thrombosis. Device-related complications necessitating surgical intervention most frequently occur in destination therapy patients who are supported for longer periods of time. PMID- 28009713 TI - Outcomes and Trends of Ventricular Assist Device Selection in Children with End Stage Heart Failure. AB - We aimed to examine trends in ventricular assist device (VAD) selection, continuous flow devices (CFD) versus pulsatile flow devices (PFD), and their associated outcomes in children eligible for both device types. To accomplish this, the United Network for Organ Sharing database was reviewed for pediatric patients listed for heart transplant (HT) from January 2007 to June 2014. Patients were included if a durable VAD was present at wait listing or when removed from the waiting list and who met size eligibility for a CFD (BSA > 1.0 m). In total, 253 patients met inclusion criteria, 144 (57%) CFD and 109 (43%) PFD. Device type varied significantly based on year with CFD increasing from 11% in 2007 to 88% in 2014 (p < 0.01). PFD patients were younger, had a lower BSA, and an increased rate of extracorporeal membrane oxygenation and biventricular assist device support at listing. Survival to transplant or recovery was similar for CFDs and PFDs (96 vs. 94%; p = 0.57), as was the post-HT survival, 95% for both device types. Despite PFD patients having more risk factors for a poor outcome, survival was similar between device types. Even so, there is a dramatic trend toward CFD utilization in patients who are large enough to support one. PMID- 28009714 TI - Worldwide Experience with the Syncardia Total Artificial Heart in the Pediatric Population. AB - Individual centers have documented the use of the Syncardia Total Artificial Heart (TAH) in adolescents with heart failure; however, the number of patients at any given center is small. Herein, we describe the worldwide experience for all patients <=21 years old supported with the TAH between May 2005 and May 2015 (n = 43). The number of patients experiencing a positive outcome at 60, 90, and 120 days were 30 (70%), 27 (63%), and 25 (58%), respectively. Successful bridge to transplantation varied by diagnosis, but outcomes reported are similar to adults supported with the TAH or biventricular assist devices. PMID- 28009716 TI - Precursors of pancreatic cancer. AB - Pancreatic cancer (PC) behaves very differently in comparison with other malignancies. Its incidence has been increasing continuously; mortality has not decreased, the diagnosis is frequently late, radical surgery is performed only in 15-20% of patients, and chemotherapy is only palliative. PC occurs in three different forms. Sporadic PC accounts for 90% of all PCs. Its most frequent form is the pancreatic ductal adenocarcinoma. The remaining 10% constitute two minority groups: familial PC (7%) and PC as a manifestation of a genetic cancer syndrome (3%). PCs are preceded by a precancerous lesion (precursor). At present, six different precursors are known. They have different histomorphological characteristics and malignant potential. The recognition and correct interpretation of individual precursors influences adequate clinical decision making. The publication surveys the present knowledge of individual precursors and their role in the early pancreatic carcinogenesis. PMID- 28009715 TI - Impact of LVAD Implantation Site on Ventricular Blood Stagnation. AB - Treatment of end-stage heart failure includes cardiac transplantation or ventricular assist device (VAD) therapy. Although increasingly prevalent, current VAD therapy has inherent complications, including thrombosis. Studies have demonstrated that VAD implantation alters intracardiac blood flow, creating areas of stagnation that predispose to thrombus formation. Two potential surgical configurations exist for VAD implantation: through the apical or diaphragmatic surfaces of the heart. We hypothesized that diaphragmatic implantation causes more stagnation than apical implantation. We also hypothesized that intermittent aortic valve (AV) opening reduces stagnation of blood inside the left ventricle (LV) when compared with a closed AV. To test these hypotheses, a human LV geometry was recreated in silico and a VAD inflow cannula was virtually implanted in each configuration. A computational indicator-dilution study was conducted where "virtually dyed blood" was washed out of the LV by injecting blood with no dye. Simulations demonstrated a substantial reduction in stagnation with intermittent AV opening. In addition, virtual dye was cleared slightly faster in the apical configuration. Simulations from our study demonstrate the clinical importance of VAD management to allow intermittent opening of the AV to prevent subvalvular stagnation, and also suggests that apical configuration might be more hemodynamically favorable. PMID- 28009717 TI - Insulin resistance is associated with elevated transaminases and low aspartate aminotransferase/alanine aminotransferase ratio in young adults with normal weight. AB - OBJECTIVE: The aim of this study is to determine whether insulin resistance is associated with elevation of transaminases levels and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio in normal-weight healthy young adults. PARTICIPANTS AND METHODS: Apparently healthy nonpregnant women and men, aged 18 23 years, were enrolled in a cross-sectional study. According to the homeostasis model assessment of insulin resistance, the participants were allocated into groups of patients with (>2.5) and without (<=2.5) insulin resistance. Normal weight was defined by BMI of at least 18.5 and less than 25.0 kg/m. A multiple logistic regression analysis was carried out to determine the association between insulin resistance and elevated transaminases and AST/ALT ratio of 1 or less. RESULTS: A total of 1732 young adults were enrolled and allocated into groups with (n=287) and without (n=1445) insulin resistance. The prevalence of insulin resistance was 16.6% in the overall population. The multivariate logistic regression analysis adjusted by age, sex, waist circumference, and BMI indicated that the odds ratio (OR) between insulin resistance and elevated ALT concentrations is 1.65 [95% confidence interval (CI): 1.04-2.62, P=0.03], for AST/ALT ratio lower than 1 OR is 1.69 (95% CI: 1.27-2.26, P<0.001), and for elevated AST levels OR is 1.31 (95% CI: 0.71-2.43, P=0.377). CONCLUSION: The results of the present study suggest that insulin resistance is significantly associated with elevated ALT levels and AST/ALT ratio of lower than 1, but not with elevated AST levels. PMID- 28009718 TI - The role of endoscopic intervention in the management of inflammatory pancreatic fluid collections. AB - Pancreatic fluid collections (PFCs) are a frequent complication of pancreatitis, or less commonly, pancreatic trauma or surgery. The revised Atlanta Classification categorizes PFCs as acute or chronic, with further subclassification of acute collections into acute peripancreatic collections and acute necrotic collections and of chronic fluid collections into pseudocysts and walled-off pancreatic necrosis. Acute PFCs are generally only subjected to an intervention when they are infected and not responding to antibiotics and are not managed endoscopically. Chronic PFCs, both pseudocysts and walled-off pancreatic necrosis, require intervention only when symptomatic or enlarging over time. Endoscopic ultrasound-guided drainage has become the mainstay of management for chronic PFCs that require intervention. Developments in medical devices over the past few years have significantly simplified and shortened the duration of the procedure itself, but the optimum choice of stent in different clinical scenarios remains to be defined, as does the place of endoscopic necrosectomy. To optimize outcomes, these patients should undergo a careful preprocedure workup and discussion in a multidisciplinary environment and procedures should be carried out in high-volume pancreatic units. PMID- 28009719 TI - Plagiocephaly and Developmental Delay: A Systematic Review. AB - OBJECTIVE: Deformational plagiocephaly (includes plagiocephaly and brachycephaly) is a common pediatric condition. Infants who present with altered head shape often experience developmental delay. It is uncertain how common developmental delay is in infants with plagiocephaly and how sustained this is, when present. This review explores the association between plagiocephaly and developmental delay to guide clinical practice. STUDY DESIGN: A systematic review was conducted. MEDLINE, EMBASE, CINAHL, and PEDro databases were searched. Data from relevant studies were extracted regarding study: sample, follow-up, design, and findings. Methodological quality of each study was rated using a critical appraisal tool. RESULTS: The search recovered 1315 articles of which 19 met the inclusion criteria. In the included studies, the children's ages ranged from 3 months to 10 years. Study limitations included selection bias, nonblinding of assessors, and reuse of the same study population for multiple papers. Most papers (11/19) rated "moderate" on methodological quality. A positive association between plagiocephaly and developmental delay was reported in 13 of 19 studies, including 4 of 5 studies with "strong" methodological quality. Delay was more frequently in studies with children <=24 months of age (9/12 studies) compared with >24 months of age (3/7 studies). Motor delay was the most commonly affected domain reported in high-quality papers (5/5 studies). CONCLUSION: This review suggests plagiocephaly is a marker of elevated risk of developmental delays. Clinicians should closely monitor infants with plagiocephaly for this. Prompt referral to early intervention services such as physiotherapy may ameliorate motor delays and identify infants with longer term developmental needs. PMID- 28009720 TI - Roscovitine Protects From Arterial Injury by Regulating the Expressions of c-Jun and p27 and Inhibiting Vascular Smooth Muscle Cell Proliferation. AB - PURPOSE: Roscovitine (Rosc) is a selective inhibitor of cyclin-dependent kinases (CDKs) and a promising therapy for various cancers. However, limited information is available on the biological significance of Rosc in vascular smooth muscle cells (VSMCs), the cell type critical for the development of proliferative vascular diseases. In this study, we address the effects of Rosc in regulating VSMC proliferation, both in vitro and in vivo, exploring the underlying molecular mechanisms. METHODS: The proliferations and cell-cycle distributions of in vitro cultured VSMCs, as well as several other cancer cell lines, were examined by cell counting assay and flow cytometry, respectively. Molecular changes in various CDKs, cyclins, and other regulatory molecules were examined by reverse transcription polymerase chain reaction, Western blot, or immunocytochemistry. The in vivo effects of Rosc were examined on a carotid arterial balloon-injury model. RESULTS: Rosc significantly inhibited VSMC proliferation in response to serum or angiotensin II and arrested these cells at the G0/G1 phase. These changes were associated with a specific and robust decrease in CDK4, cyclin E, c Jun, and a dramatic increase in p27kip1 in VSMCs, which was also translated in vivo and correlated with the protection of Rosc on injury-induced neointimal hyperplasia. CONCLUSIONS: Acting on distinct molecular targets in VSMCs versus cancer cells, Rosc inhibits VSMC proliferation and protects from proliferative vascular diseases. PMID- 28009721 TI - Propofol Provides Cardiac Protection by Suppressing the Proteasome Degradation of Caveolin-3 in Ischemic/Reperfused Rat Hearts. AB - The mechanisms underlying propofol's cardioprotective role remain elusive. Caveolin-3 (Cav-3) has been shown to mediate both opioids- and volatile anesthetics-induced cardioprotection against ischemia/reperfusion (I/R) injury. We hypothesize that the cardioprotective role of propofol is mediated through Cav 3 and its regulation of PI3K/Akt/GSK3beta signal pathway. Rats or H9c2 cardiomyocytes were exposed to propofol before I/R or simulated ischemia/reperfusion (SI/R). Propofol pretreatment significantly decreased left ventricle infarct size in vivo (P < 0.05) and terminal deoxynucleotidyl transferase nick-end labeling-positive cells both in vivo and in vitro (P < 0.05), along with an increased Cav-3 protein expression and binding of Cav-3 to p85-subunit of PI3K. No significant change in Cav-3 mRNA expression in left ventricle tissues was found in either I/R or propofol-treated groups. Methyl-beta cyclodextrin or Cav-3 siRNA was used to knockdown Cav-3 expression in vitro, which virtually abolished propofol-induced cardiac protection and PI3K/Akt/GSK3beta pathway activation. In contrast, MG132, a proteasome inhibitor, could significantly restore SI/R-induced Cav-3 decrease. It is concluded that Cav 3 mediates propofol-induced cardioprotection against I/R injury and the relevant PI3K/Akt/GSK3beta activation. The downregulation of Cav-3 under SI/R may be caused by proteasome degradation, and this process can be prevented by propofol. PMID- 28009723 TI - Adults with autism spectrum disorders: a review of outcomes, social attainment, and interventions. AB - PURPOSE OF REVIEW: With the increasing incidence of individuals diagnosed with autism spectrum disorders, there is a need to develop programs to support them throughout their lifespan but research in adulthood support is still scarce. This article aims to provide an up-to-date review of the research on the core characteristics of autism spectrum disorder (ASD), social attainments, and efforts to improve their outcomes. RECENT FINDINGS: The core social communication impairments continue into adulthood among persons with ASD, but the restrictive, repetitive patterns of behavior and activities have received less attention. Adults with ASD experience more behavioral and emotional regulation issues than their peers. In terms of social attainments, adults with ASD have a greater tendency to be overeducated for their jobs and have a lower employment rate. They are also more likely to live with their parents. Interventions make a positive impact upon social communication skills and employment. SUMMARY: Future research could focus on the repetitive behavior of adults with ASD. Likewise, interventions examining the extent to which repetitive behavior and interests can be managed, as well as the degree to which they can be supported in their community access, living arrangements, as well as family quality of life can be further conducted. PMID- 28009724 TI - Current opinion in Alzheimer's disease therapy by nanotechnology-based approaches. AB - PURPOSE OF REVIEW: Nanotechnology typically deals with the measuring and modeling of matter at nanometer scale by incorporating the fields of engineering and technology. The most prominent feature of these engineered materials involves their manipulation/modification for imparting new functional properties. The current review covers the most recent findings of Alzheimer's disease (AD) therapeutics based on nanoscience and technology. RECENT FINDINGS: Current studies involve the application of nanotechnology in developing novel diagnostic and therapeutic tools for neurological disorders. Nanotechnology-based approaches can be exploited for limiting/reversing these diseases for promoting functional regeneration of damaged neurons. These strategies offer neuroprotection by facilitating the delivery of drugs and small molecules more effectively across the blood-brain barrier. SUMMARY: Nanotechnology based approaches show promise in improving AD therapeutics. Further replication work on synthesis and surface modification of nanoparticles, longer-term clinical trials, and attempts to increase their impact in treating AD are required. PMID- 28009725 TI - Cognitive decline and dementia in Down syndrome. AB - PURPOSE OF REVIEW: Alzheimer's disease is most likely universal in older individuals with Down syndrome, due to having three copies of the amyloid precursor protein gene, resulting in amyloid-beta plaque deposition. Down syndrome is an important population in which to consider clinical trials of treatments to prevent or delay the development of dementia. However, assessment of subtler cognitive changes is challenging due to the presence of intellectual disability. RECENT FINDINGS: Recent research confirmed that older adults with Down syndrome often present with cognitive decline: more than 80% may experience dementia by age 65 years. Efforts have been made to improve and validate neuropsychological assessment and to describe the relationship with comorbidities such as epilepsy and haemorrhagic stroke. There have also been advances in biomarkers such as neuroimaging using amyloid PET. SUMMARY: Clinical trials of treatments, particularly in the presymptomatic phase of Alzheimer's disease, are important to consider in individuals with Down syndrome given their high dementia burden, and may also serve as proof of concept for other forms of Alzheimer's disease. However, further work is required to improve outcome measures and better understand the biomarkers of progression of disorder and their relationship with symptom development during the presymptomatic period. PMID- 28009726 TI - The emergence of autism spectrum disorder: insights gained from studies of brain and behaviour in high-risk infants. AB - PURPOSE OF REVIEW: We review studies of infants at risk for autism spectrum disorder (ASD), proposing that the earliest manifestations of disrupted brain development can shed light on prebehavioural markers of risk and mechanisms underlying the heterogeneity of ASD. RECENT FINDINGS: Prospective, longitudinal studies of infants at risk for ASD have revealed that behavioural signs of ASD are generally not observed until the second year of life. The developmental signs within the first year are often subtle and rooted in processes outside the core diagnostic domains of ASD, such as motor and visual perceptual function. However, studies examining early brain development and function have identified a myriad of atypicalities within the first year that are associated with risk for ASD. SUMMARY: Longitudinal studies of high-risk infants provide a unique opportunity to identify and quantify the sources of the atypical development and developmental heterogeneity of ASD. Integration of assays of behaviour and brain in the first year of life, expansion of the definition of high risk, and coordinated efforts in multisite investigations to adequately power integrative studies will lead to new insights into mechanisms of atypical development and, ultimately, the ideal timing and target for interventions that aim to attenuate delays or impairments. PMID- 28009727 TI - Annals of Surgery to offer self-assessment CME. PMID- 28009729 TI - Impact of Enhanced Recovery After Surgery and Fast Track Surgery Pathways on Healthcare-associated Infections: Results From a Systematic Review and Meta analysis. AB - OBJECTIVE: The aim of this study was to establish if enhanced recovery after surgery (ERAS) and fast track surgery (FTS) protocols are associated with reduction in healthcare-associated infection (HAIs). BACKGROUND: Evidence suggests that prevention strategies for HAIs should be multifaceted and transdisciplinary. ERAS and FTS protocols are collaborative approaches to perioperative care which reduce length of stay but may also be an effective strategy for reducing HAIs. METHODS: We performed a meta-analysis of randomized trials involving either ERAS or FTS for abdominal or pelvic surgery. Primary outcome included postoperative incidence of 3 major HAIs: lung infection (LI), urinary tract infection (UTI), and surgical site infection (SSI). RESULTS: Among all included trials, ERAS/FTS was associated with a significant reduction in postoperative LI [risk ratio (RR) = 0.38; 95% confidence interval (CI) = 0.23 0.61; P < 0.0001; I = 0%], UTI (RR = 0.42; 95% CI = 0.23-0.76; P = 0.004; I = 0%), and SSI (RR = 0.75; 95% CI = 0.58-0.98; P = 0.04; I = 0%) compared with conventional controls. Sensitivity analysis performed following the exclusion of high risk of bias publications did not appreciably affect these results. ERAS/FTS was also associated with a significant decrease in hospital length of stay (standard mean difference = -0.83; 95% CI = -0.92 to -0.75; P < 0.0001; P for heterogeneity <0.0001, I = 93%). Subgroup analysis of trials involving colorectal surgery and open incision also resulted in significant reduction in all 3 HAIs among ERAS/FTS compared with conventional counterparts. CONCLUSIONS: Our results suggest ERAS/FTS protocols are powerful tools to prevent HAIs. Further study is needed to establish the mechanism. Providers should consider adoption of similar transdisciplinary programs to reduce perioperative HAIs and at the same time improve the value of surgical care. PMID- 28009728 TI - Medical and Economic Evaluation of FOREseal Bioabsorbable Reinforcement Sleeves Compared With Current Standard of Care for Reducing Air Leakage Duration After Lung Resection for Malignancy: A Randomized Trial. AB - OBJECTIVE: The objective of this study was to determine the efficacy of alginate staple-line reinforcement of fissure openings as compared with stapling alone, with or without tissue sealant or glue, in reducing the incidence and duration of air leakage after pulmonary lobectomy for malignancy. SUMMARY BACKGROUND DATA: No randomized trial evaluating alginate staple-line reinforcement has been performed to date. METHODS: The Staple-line Reinforcement for Prevention of Pulmonary Air Leakage study was a multicenter randomized trial, with blinded evaluation of endpoints. Patients over 18 years of age scheduled for elective open lobectomy or bilobectomy for malignancy were eligible for enrollment. At thoracotomy, patients were deemed ineligible if an unanticipated pneumonectomy was indicated, or if air leakage occurred after the liberation of pleural adhesions. Otherwise, if the fissure was incomplete or the lung had an emphysematous appearance, patients were randomized to either standard management or interventional procedure consisting of fissure opening with linear cutting staplers buttressed with paired alginate sleeves (FOREseal). The number of eligible patients necessary in each randomization arm was estimated to be 190, and an outcomes analysis was performed on an intention-to-treat basis. RESULTS: Of the 611 patients consented to study enrollment, 380 met the inclusion criteria and were randomized. Based on an intention-to-treat analysis, the primary endpoint of air leak duration was not different between the 2 groups: 1 day (range: 0-2 d) in the FOREseal group and 1 day (range: 0-3 d) in the control group (P = 0.8357). In addition, the 2 groups were similar in terms of the proportion of patients presenting with prolonged air leakage (7.8% in the FOREseal group vs 11.3% in the control group, P = 0.264) and the average duration of chest drainage (P = 0.107). Procedure costs were comparable for both groups. CONCLUSIONS: FOREseal did not demonstrate a significant advantage over standard treatment alone. PMID- 28009730 TI - Ventral Hernia Management: Expert Consensus Guided by Systematic Review. AB - OBJECTIVE: To achieve consensus on the best practices in the management of ventral hernias (VH). BACKGROUND: Management patterns for VH are heterogeneous, often with little supporting evidence or correlation with existing evidence. METHODS: A systematic review identified the highest level of evidence available for each topic. A panel of expert hernia-surgeons was assembled. Email questionnaires, evidence review, panel discussion, and iterative voting was performed. Consensus was when all experts agreed on a management strategy. RESULTS: Experts agreed that complications with VH repair (VHR) increase in obese patients (grade A), current smokers (grade A), and patients with glycosylated hemoglobin (HbA1C) >= 6.5% (grade B). Elective VHR was not recommended for patients with BMI >= 50 kg/m (grade C), current smokers (grade A), or patients with HbA1C >= 8.0% (grade B). Patients with BMI= 30-50 kg/m or HbA1C = 6.5-8.0% require individualized interventions to reduce surgical risk (grade C, grade B). Nonoperative management was considered to have a low-risk of short-term morbidity (grade C). Mesh reinforcement was recommended for repair of hernias >= 2 cm (grade A). There were several areas where high-quality data were limited, and no consensus could be reached, including mesh type, component separation technique, and management of complex patients. CONCLUSIONS: Although there was consensus, supported by grade A-C evidence, on patient selection, the safety of short-term nonoperative management, and mesh reinforcement, among experts; there was limited evidence and broad variability in practice patterns in all other areas of practice. The lack of strong evidence and expert consensus on these topics has identified gaps in knowledge where there is need of further evidence. PMID- 28009731 TI - Combining Systems and Teamwork Approaches to Enhance the Effectiveness of Safety Improvement Interventions in Surgery: The Safer Delivery of Surgical Services (S3) Program. AB - IMPORTANCE: Patient safety improvement interventions usually address either work systems or team culture. We do not know which is more effective, or whether combining approaches is beneficial. OBJECTIVE: To compare improvement in surgical team performance after interventions addressing teamwork culture, work systems, or both. DESIGN: Suite of 5 identical controlled before-after intervention studies, with preplanned analysis of pooled data for indirect comparisons of strategies. SETTING: Operating theatres in 5 UK hospitals performing elective orthopedic, plastic, or vascular surgery PARTICIPANTS:: All operating theatres staff, including surgeons, nurses, anaesthetists, and others INTERVENTIONS:: 4 month safety improvement interventions, using teamwork training (TT), systems redesign and standardization (SOP), Lean quality improvement, SOP + TT combination, or Lean + TT combination. MAIN OUTCOMES AND MEASURES: Team technical and nontechnical performance and World Health Organization (WHO) checklist compliance, measured for 3 months before and after intervention using validated scales. Pooled data analysis of before-after change in active and control groups, comparing combined versus single and systems versus teamwork interventions, using 2-way ANOVA. RESULTS: We studied 453 operations, (255 intervention, 198 control). TT improved nontechnical skills and WHO compliance (P < 0.001), but not technical performance; systems interventions (Lean & SOP, 2 & 3) improved nontechnical skills and technical performance (P < 0.001) but improved WHO compliance less. Combined interventions (4 & 5) improved all performance measures except WHO time out attempts, whereas single approaches (1 & 2 & 3) improved WHO compliance less (P < 0.001) and failed to improve technical performance. CONCLUSIONS & RELEVANCE: Safety interventions combining teamwork training and systems rationalization are more effective than those adopting either approach alone. This has important implications for safety improvement strategies in hospitals. PMID- 28009732 TI - Patient-reported Limitations to Surgical Buy-in: A Qualitative Study of Patients Facing High-risk Surgery. AB - OBJECTIVE: To characterize how patients buy-in to treatments beyond the operating room and what limits they would place on additional life-supporting treatments. BACKGROUND: During a high-risk operation, surgeons generally assume that patients buy-in to life-supporting interventions that might be necessary postoperatively. How patients understand this agreement and their willingness to participate in additional treatment is unknown. METHODS: We purposively sampled surgeons in Toronto, Ontario, Boston, Massachusetts, and Madison, Wisconsin, who are good communicators and routinely perform high-risk operations. We audio-recorded their conversations with patients considering high-risk surgery. For patients who were then scheduled for surgery, we performed open-ended preoperative and postoperative interviews. We used directed qualitative content analysis to analyze the interviews and surgeon visits, specifically evaluating the content about the use of postoperative life support. RESULTS: We recorded 43 patients' conversations with surgeons, 34 preoperative, and 27 postoperative interviews. Patients expressed trust in their surgeon to make decisions about additional treatments if a serious complication occurred, yet expressed a preference for significant treatment limitations that were not discussed with their surgeon preoperatively. Patients valued the existence or creation of an advance directive preoperatively, but they did not discuss this directive with their surgeon. Instead they assumed it would be effective if needed and that family members knew their wishes. CONCLUSIONS: Patients implicitly trust their surgeons to treat postoperative complications as they arise. Although patients may buy-in to some additional postoperative interventions, they hold a broad range of preferences for treatment limitations that were not discussed with the surgeon preoperatively. PMID- 28009733 TI - Age of Transfused Blood Impacts Perioperative Outcomes Among Patients Who Undergo Major Gastrointestinal Surgery. AB - OBJECTIVE: To evaluate the impact of transfused packed red blood cell (PRBC) age on perioperative morbidity among patients undergoing major gastrointestinal surgery. BACKGROUND: Patients undergoing major surgery often receive PRBC transfusions. The effect of PRBC age (ie, storage duration before transfusion) on perioperative surgical outcomes remains poorly defined. METHODS: In this study, 1365 patients were identified who underwent a hepato-pancreatic or colorectal resection and received >=1 unit of PRBCs between 2009 and 2014 at the Johns Hopkins Hospital. Data regarding the storage duration of PRBCs, clinicopathologic characteristics, and perioperative outcomes were obtained and analyzed. Multivariable modified Poisson regression analyses were performed to assess the effect of PRBC age on perioperative morbidity. RESULTS: A total of 5901 PRBC units were transfused for a median of 2 (interquartile range 2-4) units transfused per patient. In all, 936 (68.6%) patients received only units of blood that had been stored for less than 35 days ("fresh" blood), whereas 429 (31.4%) patients received at least 1 unit of PRBC that had been stored for >=35 days ("older" blood). Overall postoperative morbidity was 32.8%. The incidence of postoperative complications (42.7% vs 28.3%) was higher among patients who received "older" vs "fresh" blood (P < 0.001). After adjusting for confounders on multivariable analysis, transfusion of "older" blood remained independently associated with an increased risk of perioperative morbidity (Relative Risk 1.20, P = 0.03). CONCLUSIONS: The use of "older" blood was an independent predictor of postoperative morbidity among patients undergoing hepato-pancreatic or colorectal procedures. Transfusion of "older" blood products may contribute to a higher risk of postoperative complications. PMID- 28009734 TI - The Role of PhD Faculty in Advancing Research in Departments of Surgery. AB - OBJECTIVE: To determine the academic contribution as measured by number of publications, citations, and National Institutes of Health (NIH) funding from PhD scientists in US departments of surgery. SUMMARY BACKGROUND DATA: The number of PhD faculty working in US medical school clinical departments now exceeds the number working in basic science departments. The academic impact of PhDs in surgery has not been previously evaluated. METHODS: Academic metrics for 3850 faculties at the top 55 NIH-funded university and hospital-based departments of surgery were collected using NIH RePORTER, Scopus, and departmental websites. RESULTS: MD/PhDs and PhDs had significantly higher numbers of publications and citations than MDs, regardless of academic or institutional rank. PhDs had the greatest proportion of NIH funding compared to both MDs and MD/PhDs. Across all academic ranks, 50.2% of PhDs had received NIH funding compared with 15.2% of MDs and 33.9% of MD/PhDs (P < 0.001). The proportion of PhDs with NIH funding in the top 10 departments did not differ from those working in departments ranked 11 to 50 (P = 0.456). A greater percentage of departmental PhD faculty was associated with increased rates of MD funding. CONCLUSIONS: The presence of dedicated research faculty with PhDs supports the academic mission of surgery departments by increasing both NIH funding and scholarly productivity. In contrast to MDs and MD/PhDs, PhDs seem to have similar levels of academic output and funding independent of the overall NIH funding environment of their department. This suggests that research programs in departments with limited resources may be enhanced by the recruitment of PhD faculty. PMID- 28009735 TI - Mock Pages Are a Valid Construct for Assessment of Clinical Decision Making and Interprofessional Communication. AB - IMPORTANCE: Answering pages from nurses about patients in need of immediate attention is one of the most difficult challenges a resident faces during their first days as a physician. A Mock Page program has been developed and adopted into a national surgical resident preparatory curriculum to prepare senior medical students for this important skill. OBJECTIVE: The purpose of this study is to assess standardized mock page cases as a valid construct to assess clinical decision making and interprofessional communication skills. DESIGN, SETTING, PARTICIPANTS: Mock page cases (n = 16) were administered to 213 senior medical students from 12 medical schools participating in a national surgical resident preparatory curriculum in 2013 and 2014. MAIN OUTCOME MEASURES: Clinical decision making and interprofessional communication were measured by case-specific assessments evaluating these skills which have undergone rigorous standard setting to determine pass/fail cut points. RESULTS: Students' performance improved in general for both communication and clinical decision making over the 4-week course. Cases have been identified that seem to be best suited for differentiating high- from low-performing students. Chest pain, pulmonary embolus, and mental status change cases posed the greatest difficulty for student learners. CONCLUSIONS AND RELEVANCE: Simulated mock pages demonstrate an innovative technique for training students in both effective interprofessional communication and management of common postoperative conditions they will encounter as new surgical interns. PMID- 28009736 TI - Esophageal Cancer: Associations With (pN+) Lymph Node Metastases. AB - OBJECTIVES: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. SUMMARY BACKGROUND DATA: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. METHODS: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques. RESULTS: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. CONCLUSIONS: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status. PMID- 28009737 TI - Clinicopathological Features of Cervical Esophageal Cancer: Retrospective Analysis of 63 Consecutive Patients Who Underwent Surgical Resection. AB - OBJECTIVE: The objectives of this retrospective study were to elucidate the clinicopathological features and recent surgical results of cervical esophageal cancer. SUMMARY BACKGROUND DATA: Cervical esophageal cancer has been reported to have a dismal prognosis. Accurate knowledge of the clinical characteristics of cervical esophageal cancer is warranted to establish appropriate therapeutic strategies. METHODS: The clinicopathological features and treatment results of 63 consecutive patients with cervical esophageal cancer (Ce group) who underwent surgical resection from 1980 to 2013 were analyzed and compared with 977 patients with thoracic or abdominal esophageal cancer (T/A group) who underwent surgical resection during that time. RESULTS: Among the patients who received curative resection, the 5-year overall and disease-specific survival rates of the Ce patients were significantly better than those of the T/A patients (overall: 77.3% vs 46.5%, respectively, P = 0.0067; disease-specific: 81.9% vs 55.8%, respectively, P = 0.0135). Although total pharyngo-laryngo-esophagectomy procedures were less frequently performed in the recent period, the rate of curative surgical procedures was markedly higher in the recent period (2000-1013) than that in the early period (1980-1999) (44.4% vs 88.9%, P = 0.0001). The 5 year overall survival rate in the recent period (71.5%) was significantly better than that in the early period (40.7%, P = 0.0342). CONCLUSIONS: Curative resection for cervical esophageal cancer contributes to favorable outcomes compared with other esophageal cancers. Recent surgical results for cervical esophageal cancer have improved, and include an increased rate of curative resection and decreased rate of extensive surgery. PMID- 28009738 TI - Lymph Node Metastasis in Mucosal Gastric Cancer: Reappraisal of Expanded Indication of Endoscopic Submucosal Dissection. AB - OBJECTIVE: To evaluate risk factors for lymph node (LN) metastasis in mucosal gastric cancer, particularly the effect of cellular differentiation, and implications for the indication of endoscopic submucosal dissection (ESD). SUMMARY BACKGROUND DATA: The indication of ESD has been expanded to undifferentiated-type (UD-type) gastric cancer despite risk of LN metastasis. METHODS: Patients who underwent radical gastrectomy for pT1a stage primary gastric adenocarcinoma between 2008 and 2012 were retrospectively analyzed. We evaluated risk factors of LN metastasis using univariate and multivariate analyses. Pathologic slides of primary tumor and metastatic LNs from LN positive patients were reviewed. RESULTS: A total of 1003 mucosal gastric cancer patients were enrolled, and mean number of retrieved LNs was 35.5. Eighteen (1.8%) among them had LN metastasis: 2 of the 502 differentiated-type (D-type) patients and 16 of the 501 UD-type patients (0.4% vs 3.2%, P < 0.001). Type of cellular differentiation was a significant risk factor for LN metastasis in univariate and multivariate analyses. Of 216 UD-type patients satisfying the expanded indication of ESD, 5 patients (2.3%) showed LN metastasis. Despite more aggressive clinical features such as larger size of tumor and more LN metastasis, the UD-type cancer showed a less invasion into the muscularis mucosae layer than the D-type cancer. CONCLUSIONS: Because UD-type cancer is a risk factor for LN metastasis in mucosal gastric cancer, ESD cannot be concluded to be a better option than surgery in all UD-type cancer patients. Redefinition of the expanded indication of ESD is required. PMID- 28009739 TI - Who Should Get Extended Thromboprophylaxis After Bariatric Surgery?: A Risk Assessment Tool to Guide Indications for Post-discharge Pharmacoprophylaxis. AB - OBJECTIVE: To determine the risk factors for 30-day postdischarge venous thromboembolism (VTE) after bariatric surgery and to identify potential indications for extended pharmacoprophylaxis. BACKGROUND: VTE is among most common causes of death after bariatric surgery. Most VTEs occur after hospital stay; still a few patients receive extended pharmacoprophylaxis postdischarge. METHODS: From American College of Surgeons-National Surgical Quality Improvement Program, we identified 91,963 patients, who underwent elective primary and revisional bariatric surgery between 2007 and 2012. Regression-based techniques were used to create a risk assessment tool to predict risk of postdischarge VTE. The model was validated using the 2013 American College of Surgeons-National Surgical Quality Improvement Program dataset (N = 20,575). Significant risk factors were used to create a user-friendly online risk calculator. RESULTS: The overall 30-day incidence of postdischarge VTE was 0.29% (N = 269). In those experiencing a postdischarge VTE, mortality increased about 28-fold (2.60% vs 0.09%; P < 0.001). Among 45 examined variables, the final risk-assessment model contained 10 categorical variables including congestive heart failure, paraplegia, reoperation, dyspnea at rest, nongastric band surgery, age >=60 years, male sex, BMI >=50 kg/m, postoperative hospital stay >=3 days, and operative time >=3 hours. The model demonstrated good calibration (Hosmer Lemeshow goodness-of-fit test, P = 0.71) and discrimination (c-statistic = 0.74). Nearly 2.5% of patients had a predicted postdischarge VTE risk >1%. CONCLUSIONS: More than 80% of post-bariatric surgery VTE events occurred post-discharge. Congestive heart failure, paraplegia, dyspnea at rest, and reoperation are associated with the highest risk of post-discharge VTE. Routine post-discharge pharmacoprophylaxis can be considered for high-risk patients (ie, VTE risk >0.4%). PMID- 28009740 TI - Surgeon Annual and Cumulative Volumes Predict Early Postoperative Outcomes after Rectal Cancer Resection. AB - OBJECTIVE: To determine if 5-year surgeon cumulative and annual volumes predict improved early postoperative outcomes in patients with rectal cancer. BACKGROUND: Operative experience has been shown to effect surgical outcomes. The differential role of cumulative versus annual volume has not yet been explored for rectal surgery. METHODS: The Statewide Planning and Research Cooperative System database was used to capture patients undergoing surgery in New York State from 2000 to 2013. A population-based sample of patients undergoing major rectal or rectosigmoid resection as their principal procedure during hospitalization between 2000 and 2013 were identified using International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. Surgeons were identified using a unique physician number from 1995 to 2013. RESULTS: The percentage of surgeries performed by high cumulative/high annual (HC/HA) surgeons increased from 38.3% to 58.4% (P < 0.01) with a simultaneous decrease in that performed by low cumulative/low annual (LC/LA) surgeons (52.5% to 29.8%, P < 0.01). HC/HA volume surgeons had a significantly lower rate of surgical complications (odd ratio = 0.71, 95% confidence interval = 0.60-0.83, P < 0.05) as compared with LC/LA volume surgeons. There was no significant difference in rates of anastomotic leak, nonroutine discharges or readmission among all four groups. CONCLUSIONS: The best early postoperative surgical outcomes are achieved in centers where there are high cumulative and high annual volume surgeons caring for these patients. This suggests the need for specialized designation of rectal cancer centers to support ongoing regionalization of care. PMID- 28009741 TI - Colorectal Cancer Liver Metastases and Concurrent Extrahepatic Disease Treated With Resection. AB - OBJECTIVE: The aim of the study was to evaluate outcomes after resection of colorectal liver metastases (CRLM) and concurrent extrahepatic disease (EHD), and to define prognostic factors. BACKGROUND: There is increasing evidence to support resection of liver metastases and concurrent EHD in selected patients. Long-term survival data are lacking, and prognostic factors are not well defined. METHODS: Retrospective review of 219 patients was undertaken between January 1992 and December 2012, who underwent hepatectomy for CRLM and resection of synchronous EHD. Survival outcomes were estimated by the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed. A scoring system for prognostication was developed. RESULTS: The median, 3, 5, and 10-year overall survival were 34.4 months, 49%, 28%, and 10%, respectively. Disease recurred in 185 patients (90.2%) at a median of 8 months. There were 8 actual 10-year survivors. The site of EHD affected survival, with portal, retroperitoneal nodes and multiple sites associated with the worst prognoses. The size of the largest CRLM, the number of CRLM, unfavorable site of EHD, and progression of CRLM on neoadjuvant therapy were associated with overall survival on univariate and multivariate analyses. Three variables, assigned 1 point each, were used to create an EHD risk score: largest CRLM greater than 3 cm, greater than 5 CRLM, and unfavorable site of EHD. The resulting score was prognostic of overall and recurrence-free survival. CONCLUSIONS: Long-term survival is possible after resection of liver metastases and concurrent EHD, but true cure is rare. A proposed scoring system may identify patients most likely to benefit from surgery. PMID- 28009742 TI - Low Platelet Counts and Prolonged Prothrombin Time Early After Operation Predict the 90 Days Morbidity and Mortality in Living-donor Liver Transplantation. AB - OBJECTIVE: The aim of the study was to investigate the association between platelet count/prothrombin time early after transplant and short-term outcomes among living-donor liver transplant (LDLT) recipients. BACKGROUND: Postoperative platelet count and prothrombin time-international normalized ratio (PT-INR) were critical biomarkers in LDLT. METHODS: The study participants consisted of 445 initial LDLT recipients, and perioperative variables, including platelet count and PT-INR, were assessed for their association with severe complications (Clavien-Dindo classification grade IIIb/IV) and mortality within 90 days after operation. RESULTS: Severe complications and operative mortality occurred in 161 (36%) and 23 patients (5%), respectively. Cox regression analysis revealed that a high body mass index [hazard ratio (HR) 1.2; 95% confidence interval (CI), 1.1 1.4; P = 0.004] and low platelet count on postoperative day (POD)3 (HR 0.88; 95% CI, 0.57-0.97; P < 0.001) were independent predictors for grade IIIb/IV complications after LDLT, whereas high PT-INR on POD5 (HR 1.1; 95% CI, 1.1-1.3; P = 0.021) was the only independent factor for operative mortality. In addtion, the progonostic scoring with low platelet count (<50 * 10/L) and prolonged prothrombin time (PT-INR >1.6) within POD5, 1 point for each, was demonstrated to be useful in predicting the development of Clavien-Dindo grade IIIb/IV/V complications after LDLT (30% for score 0, 46% for score 1, and 72% for score 2: 0 vs 1, P = 0.004; 0 vs 2, P < 0.001; 1 vs 2, P = 0.002). CONCLUSIONS: PT-INR above 1.6 and platelet count below 50 * 10/L within POD5 were useful predictors of mortality and severe complications after LDLT. PMID- 28009743 TI - Comparable Short- and Long-term Outcomes in Living Donor and Deceased Donor Liver Transplantations for Patients With Model for End-stage Liver Disease Scores >=35 in a Hepatitis-B Endemic Area. AB - OBJECTIVE: To evaluate if living donor liver transplantation (LDLT) should be offered to patients with Model for End-stage Liver Disease (MELD) scores >=35. BACKGROUND: No data was available to support LDLT of such patients. METHODS: Data of 672 consecutive adult liver transplant recipients from 2005 to 2014 at our center were reviewed. Patients with MELD scores >=35 were divided into the deceased donor liver transplantation (DDLT) group and the LDLT group and were compared. Univariate analysis was performed to identify risk factors affecting survival. RESULTS: The LDLT group (n = 54) had younger (33 yrs vs 50 yrs, P < 0.001) and lighter (56 Kg vs 65 Kg, P = 0.004) donors, lighter grafts (627.5 g vs 1252.5 g, P < 0.001), lower graft-weight-to-recipient-standard-liver-volume rates (51.28% vs 99.76%, P < 0.001), shorter cold ischemic time (106.5 min vs 389 min, P < 0.001), and longer operation time (681.5 min vs 534 min, P < 0.001). The groups were comparable in postoperative complication, hospital mortality, and graft survival and patient survival at one year (88.9% vs 92.5%; 88.9% vs 94.7%), three years (87.0% vs 86.9%; 87.0% vs 88.8%), and five years (84.8% vs 81.8%; 84.8% vs 83.3%). Univariate analysis did not show inferior survival in LDLT recipients. CONCLUSIONS: At centers with experience, the outcomes of LDLT can be comparable with those of DDLT even in patients with MELD scores >=35. When donor risks and recipient benefits are fully considered and balanced, an MELD score >=35 should not be a contraindication to LDLT. In Hong Kong, where most waitlisted patients have acute-on-chronic liver failure from hepatitis B, LDLT is a wise alternative to DDLT. PMID- 28009744 TI - Hospital Outcomes in Inpatient Laparoscopic Cholecystectomy in Medicare Patients. AB - OBJECTIVE: To compare the risk-adjusted outcomes of hospitals in inpatient Medicare laparoscopic cholecystectomy. BACKGROUND: Reduced length-of-stay for inpatient surgical care requires the inclusion of objective postdischarge outcomes to provide a comprehensive assessment of hospital and surgeon performance for quality improvement. METHODS: The 2010 to 2012 Medicare Limited Data Set was used to develop risk-adjusted prediction models of inpatient deaths, prolonged length-of-stay outliers, 90-day postdischarge deaths, and 90-day readmissions for inpatient laparoscopic cholecystectomy. To define the opportunity for improved performance, prediction models were used to compute z scores and risk-adjusted adverse outcome rates for all hospitals in the database that had 20 or more evaluable cases for the study period. RESULTS: A total of 83,274 patients from 1570 hospitals had an overall adverse outcome rate of 20.7%; 48 hospitals had outcomes that were 2 z scores better than predicted and 76 had 2 z scores poorer than predicted. Risk-adjusted adverse outcomes were 10.0 % in the best performing decile of hospitals and were 32.1% in the poorest performing decile. Gastrointestinal, infectious, and cardiopulmonary complications of care were the most common causes of readmissions with 46.3% occurring between days 30 and 90 after discharge. CONCLUSIONS: Comparative analysis of overall risk adjusted inpatient and 90-day postdischarge adverse outcomes identifies considerable opportunity for improved care in this high-risk population of patients. PMID- 28009745 TI - Safety and Feasibility of Minimally Invasive Inguinal Lymph Node Dissection in Patients With Melanoma (SAFE-MILND): Report of a Prospective Multi-institutional Trial. AB - BACKGROUND: Minimally invasive inguinal lymph node dissection (MILND) is a novel approach to inguinal lymphadenectomy. SAFE-MILND (NCT01500304) is a multicenter, phase I/II clinical trial evaluating the safety and feasibility of MILND for patients with melanoma in a group of surgeons newly adopting the procedure. METHODS: Twelve melanoma surgeons from 10 institutions without any previous MILND experience, enrolled patients into a prospective study after completing specialized training including didactic lectures, participating in a hands-on cadaveric laboratory, and being provided an instructional DVD of the procedure. Complications and adverse postoperative events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0. RESULTS: Eighty-seven patients underwent a MILND. Seventy-seven cases (88.5%) were completed via a minimally invasive approach. The median total inguinal lymph nodes pathologically examined (SLN + MILND) was 12.0 (interquartile range 8.0, 14.0). Overall, 71% of patients suffered an adverse event (AE); the majority of these were grades 1 and 2, with 26% of patients experiencing a grade 3 AE. No grade 4 or 5 AEs were observed. CONCLUSIONS: After a structured training program, high-volume melanoma surgeons adopted a novel surgical technique with a lymph node retrieval rate that met or exceeded current oncologic guidelines and published benchmarks, and a favorable morbidity profile. PMID- 28009747 TI - Multicenter, Prospective, Longitudinal Study of the Recurrence, Surgical Site Infection, and Quality of Life After Contaminated Ventral Hernia Repair Using Biosynthetic Absorbable Mesh: The COBRA Study. AB - OBJECTIVE: The aim of the study was to evaluate biosynthetic absorbable mesh in single-staged contaminated (Centers for Disease Control class II and III) ventral hernia (CVH) repair over 24 months. BACKGROUND: CVH has an increased risk of postoperative infection. CVH repair with synthetic or biologic meshes has reported chronic biomaterial infections and high hernia recurrence rates. METHODS: Patients with a contaminated or clean-contaminated operative field and a hernia defect at least 9 cm had a biosynthetic mesh (open, sublay, retrorectus, or intraperitoneal) repair with fascial closure (n = 104). Endpoints included overall Kaplan-Meier estimates for hernia recurrence and postoperative wound infection rates at 24 months, and the EQ-5D and Short Form 12 Health Survey (SF 12). Analyses were conducted on the intent-to-treat population, and health outcome measures evaluated using paired t tests. RESULTS: Patients had a mean age of 58 years, body mass index of 28 kg/m, 77% had contaminated wounds, and 84% completed 24-months follow-up. Concomitant procedures included fistula takedown (n = 24) or removal of infected previously placed mesh (n = 29). Hernia recurrence rate was 17% (n = 16). At the time of CVH repair, intraperitoneal placement of the biosynthetic mesh significantly increased the risk of recurrences (P <= 0.04). Surgical site infections (19/104) led to higher risk of recurrence (P < 0.01). Mean 24-month EQ-5D (index and visual analogue) and SF-12 physical component and mental scores improved from baseline (P < 0.05). CONCLUSIONS: In this prospective longitudinal study, biosynthetic absorbable mesh showed efficacy in terms of long-term recurrence and quality of life for CVH repair patients and offers an alternative to biologic and permanent synthetic meshes in these complex situations. PMID- 28009748 TI - Mortality in Canadian Trauma Systems: A Multicenter Cohort Study. AB - OBJECTIVE: To measure the variation in trauma center mortality across Canadian trauma systems, assess the contribution of traumatic brain injury and thoracoabdominal injury to observed variations, and evaluate whether the presence of recommended trauma system components is associated with mortality. SUMMARY BACKGROUND DATA: Injuries represent one of the leading causes of mortality, disability, and health care costs worldwide. Trauma systems have improved injury outcomes, but the impact of trauma system configuration on mortality is unknown. METHODS: We conducted a retrospective cohort study of adults admitted for major injury to trauma centers across Canada (2006-2012). Multilevel logistic regression was used to estimate risk-adjusted hospital mortality and assess the impact of 13 recommended trauma system components. RESULTS: Of 78,807 patients, 8382 (10.6%) died in hospital including 6516 (78%) after severe traumatic brain injury and 749 (9%) after severe thoracoabdominal injury. Risk-adjusted mortality varied from 7.0% to 14.2% across provinces (P < 0.0001); 11.1% to 26.0% for severe traumatic brain injury (P < 0.0001), and 4.7% to 5.9% for thoracoabdominal injury (P = 0.2). Mortality decreased with increasing number of recommended trauma system elements; adjusted odds ratio = 0.93 (0.87-0.99). CONCLUSIONS: We observed significant variation in trauma center mortality across Canadian provinces, specifically for severe traumatic brain injury. Provinces with more recommended trauma system components had better patient survival. Results suggest that trauma system configuration may be an important determinant of injury mortality. A better understanding of which system processes drive optimal outcomes is required to reduce the burden of injury worldwide. PMID- 28009746 TI - Curative Surgical Resection of Adrenocortical Carcinoma: Determining Long-term Outcome Based on Conditional Disease-free Probability. AB - OBJECTIVE: To evaluate conditional disease-free survival (CDFS) for patients who underwent curative intent surgery for adrenocortical carcinoma (ACC). BACKGROUND: ACC is a rare but aggressive tumor. Survival estimates are usually reported as survival from the time of surgery. CDFS estimates may be more clinically relevant by accounting for the changing likelihood of disease-free survival (DFS) according to time elapsed after surgery. METHODS: CDFS was assessed using a multi institutional cohort of patients. Cox proportional hazards models were used to evaluate factors associated with DFS. Three-year CDFS (CDFS3) estimates at "x" year after surgery were calculated as follows: CDFS3 = DFS(x+3)/DFS(x). RESULTS: One hundred ninety-two patients were included in the study cohort; median patient age was 52 years. On presentation, 36% of patients had a functional tumor and median size was 11.5 cm. Most patients underwent R0 resection (75%) and 9% had N1 disease. Overall 1-, 3-, and 5-year DFS was 59%, 34%, and 22%, respectively. Using CDFS estimates, the probability of remaining disease free for an additional 3 years given that the patient had survived without disease at 1, 3, and 5 years, was 43%, 53%, and 70%, respectively. Patients with less favorable prognosis at baseline demonstrated the greatest increase in CDFS3 over time (eg, capsular invasion: 28%-88%, Delta60% vs no capsular invasion: 51%-87%, Delta36%). CONCLUSIONS: DFS estimates for patients with ACC improved dramatically over time, in particular among patients with initial worse prognoses. CDFS estimates may provide more clinically relevant information about the changing likelihood of DFS over time. PMID- 28009749 TI - Acid Sphingomyelinase Inhibition in Stored Erythrocytes Reduces Transfusion Associated Lung Inflammation. AB - OBJECTIVE: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. SUMMARY BACKGROUND DATA: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. METHODS: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. RESULTS: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. CONCLUSIONS: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood. PMID- 28009752 TI - Exposure to Anticholinergic and Sedative Drugs, Risk of Falls, and Mortality: An Elderly Inpatient, Multicenter Cohort: Erratum. PMID- 28009750 TI - The American Medical Association's Section on Surgery: The Beginnings of the Organization, Professionalization, and Specialization of Surgery in the United States. AB - OBJECTIVE: To explore the founding of the American Medical Association's Section on Surgery in 1859 and how it represented, on a national basis, the beginnings of organized surgery and the formal start of the professionalization and specialization of surgery in the United States. BACKGROUND: The broad social process of organization, professionalization, and specialization that began for various disciplines in America in the mid-19th century was a reaction to emerging economic, political, and scientific influences including industrialization, urbanization, and technology. For surgeons or, at least, those men who performed surgical operations, the efforts toward group organization provided a means to promote their skills and restrict competition. METHODS: An analysis of the published literature, and unpublished documents relating to the creation of the American Medical Association's Section on Surgery. RESULTS: During the 1850s and through the 1870s, a time when surgery was still not considered a separate branch of medicine, the organization of the American Medical Association's Section on Surgery provided the much needed encouragement to surgeons in their quest for professional and specialty recognition. CONCLUSIONS: The establishment of the American Medical Association's Section on Surgery in 1859 helped shape the nationwide future of the craft, in particular, surgery's rise as a specialty and profession. PMID- 28009753 TI - Efficacy and Safety of Selective Arterial Embolization in the Treatment of Aneurysmal Bone Cyst of the Mobile Spine: A Retrospective Observational Study. AB - STUDY DESIGN: A retrospective observational study. OBJECTIVE: Our aim is to define the efficacy and safety of serial selective arterial embolization (SAE) in the treatment of aneurysmal bone cysts (ABCs), to explore potential treatment alternatives, and to define a therapeutic algorithm. SUMMARY OF BACKGROUND DATA: ABC is a benign lesion with an unpredictable behavior. Its treatment is challenging especially in poorly accessible surgical areas, such as spine and pelvis. Currently, the first-line treatment of ABC is repeated SAE until healing. Other options have been used with variable success rates. METHODS: From January 2004 to September 2015, 23 patients affected by ABC of the mobile spine have been treated with SAE and prospectively followed up by computed tomographic scan and magnetic resonance imaging. Signs of neurological deficit, complications, healing of the lesion, and clinical outcomes were registered.Signs of healing are defined as peripheral sclerotic bone rim formation, decrease of the ABC mass, disappearance of the double content image, and bone formation inside the ABC mass, associated with remission of pain. RESULTS: Twenty-three patients underwent SAE according to the protocol. Seventeen patients have healed. The number of procedures necessary to obtain healing (clinical and radiographic) varied from 1 to 10. No complication occurred during the procedure. Follow-up time ranged from 5 to 120 months after the last angiographic procedure. All 17 patients had complete relief of pain symptoms. Six patients did not respond to SAE, presenting a progressive clinical and radiographic worsening, and underwent other medical or minimally invasive treatments. CONCLUSION: Our study confirms the safety of SAE. The efficacy of the treatment was however lower than expected. SAE is indicated when pathological fracture or signs of cord damage are not detected. Infiltration with autologous bone marrow concentrate or administration of Denosumab is under investigation as alternative choices of treatment. LEVEL OF EVIDENCE: 4. PMID- 28009754 TI - Public Solicitation of Anonymous Organ Donors: A Position Paper by the Canadian Society of Transplantation. PMID- 28009755 TI - Predicting Primary Graft Dysfunction After Lung Transplantation: Trying to Catch It Early. PMID- 28009757 TI - Frequency and Outcomes of Patients With Increased Mean Pulmonary Artery Pressure at the Time of Liver Transplantation. AB - BACKGROUND: Pulmonary hypertension (PH) exists when mean pulmonary artery pressure (mPAP) is 25 mm Hg or greater. mPAP of 35 mm Hg or greater, with increased pulmonary vascular resistance from portopulmonary hypertension, has been associated with increased post-liver transplant (LT) mortality. However, mPAP of 35 mm Hg or greater can also occur in the setting of normal pulmonary vascular resistance from a high flow state and/or increased pulmonary venous volume. We describe the frequency of patients with mPAP of 35 mm Hg or greater at LT and correlate their clinical outcomes with hemodynamic characteristics. METHODS: We reviewed hemodynamics of 300 consecutive adult patients undergoing LT. Primary and secondary outcomes were transplant hospitalization mortality and 1-year mortality. RESULTS: Overall, PH was documented in 117 (39%) of 300 transplant recipients. Five patients were receiving ongoing treatment for portopulmonary hypertension at the time of transplant. mPAP of 35 mm Hg or greater was seen in 31 of 300 patients (10.3%; median, 38 mm Hg; range, 35-46 mm Hg). No intraoperative deaths occurred. Transplant hospitalization mortality was 0% for those with mPAP of 35 mm Hg or greater (vs 2.2% if mPAP < 35 mm Hg, P = 1.0). One-year mortality was similar for patients with and without mPAP of 35 mm Hg or greater (3.2% vs 6.0%, P = 1.0). No deaths were associated with right heart failure. CONCLUSIONS: At the time of LT, 39% of recipients had PH (mPAP >= 25 mm Hg) and 10.3% had mPAP >= 35 mm Hg. When associated with a high flow state and/or increased volume, transplant hospitalization and 1-year posttransplant outcomes were not adversely affected. PMID- 28009756 TI - Regeneration and Cell Recruitment in an Improved Heterotopic Auxiliary Partial Liver Transplantation Model in the Rat. AB - BACKGROUND: Auxiliary partial liver transplantation (APLT) in humans is a therapeutic modality used especially to treat liver failure in children or congenital metabolic disease. Animal models of APLT have helped to explore therapeutic options. Though many groups have suggested improvements, standardizing the surgical procedure has been challenging. Additionally, the question of whether graft livers are reconstituted by recipient-derived cells after transplantation has been controversial. The aim of this study was to improve experimental APLT in rats and to assess cell recruitment in the liver grafts. METHODS: To inhibit recipient liver regeneration and to promote graft regeneration, we treated recipients with retrorsine and added arterial anastomosis. Using green fluorescence protein transgenic rats as recipients, we examined liver resident cell recruitment within graft livers by immunofluorescence costaining. RESULTS: In the improved APLT model, we achieved well-regenerated grafts that could maintain regeneration for at least 4 weeks. Regarding the cell recruitment, there was no evidence of recipient-derived hepatocyte, cholangiocyte, or hepatic stellate cell recruitment into the graft. Macrophages/monocytes, however, were consistently recruited into the graft and increased over time, which might be related to inflammatory responses. Very few endothelial cells showed colocalization of markers. CONCLUSIONS: We have successfully established an improved rat APLT model with arterial anastomosis as a standard technique. Using this model, we have characterized cell recruitment into the regenerating grafts. PMID- 28009758 TI - Evidence-Based Surveillance Imaging Schedule After Liver Transplantation for Hepatocellular Carcinoma Recurrence. AB - BACKGROUND: There is presently no evidence-based recommendation for surveillance of recurrent hepatocellular carcinoma after liver transplantation (LT). We aim to evaluate and develop evidence-based alternate surveillance imaging schedules for post-LT hepatocellular carcinoma patients. METHODS: Imaging and pathologic reports for consecutive post-LT patients followed up by regular surveillance imaging from a single institution's prospective database were evaluated with institutional review board approval. Outcome variable was time to diagnosis of first recurrence post-LT by surveillance imaging. Recurrence-free survival times from alternative surveillance schedules were compared with the existing schedule (every 3 months) using a parametric frailty model. Expected delay (EpD) in diagnosis compared to the existing schedule was also computed for the alternate surveillance schedules. A P value less than 0.05 was considered to indicate a significant difference. RESULTS: One hundred twenty-five patients (108 men; 59.4 +/- 16.6 years) underwent 1953 computed tomography and 255 magnetic resonance imaging scans. Recurrence-free survival time was not significantly different in the first 5 years after LT when the imaging interval was extended from current every 3 months to every 6 months (P = 0.786, EpD = 55 days). This alternative schedule incurred 10 (50.0%) fewer surveillance scans than the 20 in the original schedule, and a corresponding reduction in radiation dose (if involved) and cost during the 5-year follow-up period. CONCLUSIONS: In conclusion, modeled alternative surveillance schedules have the potential to reduce the frequency of scans without compromising surveillance benefits. PMID- 28009759 TI - Outcomes of Simultaneous Liver Kidney Transplantation in Patients With Hepatocellular Carcinoma. AB - BACKGROUND: The frequency of simultaneous liver kidney (SLK) transplantation has increased following the implementation of the model for end-stage liver disease system for liver transplantation (LT). There is a paucity of data evaluating SLK outcomes in patients undergoing LT for hepatocellular carcinoma (HCC). Our aim was to compare outcomes between patients with HCC who underwent SLK and those who received SLK for other indications. METHODS: We performed a retrospective analysis of adult recipients receiving SLK between 2002 and 2013 from the United Network for Organ Sharing registry. The primary outcome was posttransplant mortality. Patient survival was determined using Kaplan-Meier analysis and predictors of mortality were identified using proportional Cox hazard regression models. Propensity score matching was performed between SLK-HCC and SLK in the absence of HCC (SLK-A) groups to reduce confounding. RESULTS: Between 2002 and 2013, 186 HCC patients underwent SLK-HCC and 3599 patients underwent SLK-A. The 1 year and 3-year survival rates were 89.0% and 76.7% in the SLK-HCC group and 84.5% and 76.3% in the SLK-A group (P = 0.20). In multivariable Cox regression, HCC was not associated with post-LT survival among all patients (hazard ratio, 1.15; 95% confidence interval, 0.84-1.58) or the propensity score-matched cohort (hazard ratio, 0.97; 95% confidence interval, 0.64-1.47). SLK-HCC patients had similar rates of acute rejection (13.3% vs 10.5%, P = 0.36) and liver graft failure requiring re-transplantation (3.2% vs 2.3%, P = 0.44) compared with SLK-A patients. CONCLUSIONS: Liver transplant candidates with advanced renal dysfunction and HCC may be considered for SLK. PMID- 28009760 TI - Impact of Cytomegalovirus Infection on Severe Hepatitis C Recurrence in Patients Undergoing Liver Transplantation: Erratum. PMID- 28009761 TI - Adherence to and Acceptance of Once-Daily Tacrolimus After Kidney and Liver Transplant: Results From OSIRIS, a French Observational Study: Erratum. PMID- 28009762 TI - Head Injuries Have Vision and Eye Complications. PMID- 28009763 TI - Brain Injury Impact on the Eye and Vision. PMID- 28009765 TI - Autoimmune Encephalitides: A Broadening Field of Treatable Conditions. AB - BACKGROUND: Neurology has been continuously transforming by the refinement of molecular diagnostics and the development of disease-modifying treatments. The discovery of new antibody markers has elucidated the pathogenesis, provided the means of diagnostics, and offered cure or treatment for several immune-mediated neurological and neuropsychiatric disorders. The identification of pathogenic and marker autoantibodies has also facilitated defining the associated phenotypic spectra and the overlap among the phenotypes linked to individual immune markers. REVIEW SUMMARY: This survey presents the list of currently known autoimmune encephalitis entities along with the associated marker autoantibodies, highlights the phenotypic and immune pathogenic relationships, calls attention to the recently described rare syndromes, discusses the biological significance of the autoantibodies and targeted molecules, points out the potential postinfectious origin of immune pathogenesis in several of the disorders, and directs the readers to the latest diagnostic guidelines as well as to the generally used treatment approaches. CONCLUSIONS AND FUTURE DIRECTIONS: Owing to the successful and usually combined use of various methods to detect serum and cerebrospinal fluid autoantibodies on rodent brain sections, in primary neuronal cell culture, in immune precipitation, and cell-based assays, or in other antigen-specific immune assays (Western blot, enzyme-linked immunosorbent assay, and radioimmune assay), the subgroup of antibody marker-negative autoimmune encephalopathy syndromes is contracting, whereas the numbers of entities within the overall group are expanding. Recognition of the correct diagnosis is becoming increasingly rewarding not only for neurologists, but also for pediatric neurologists and psychiatrists. PMID- 28009766 TI - Urgent Bypass Surgery Following Failed Endovascular Treatment in Acute Symptomatic Stroke Patient With MCA Occlusion. AB - INTRODUCTION: Although the benefits of extracranial-intracranial bypass surgery remain controversial, there is some surgical rationale for the augmentation of cerebral blood flow in cases of acute ischemic stroke with hemodynamic instability. CASE REPORT: We report a case of a 62-year-old woman who suddenly developed right hemiplegia and global aphasia. Initial magnetic resonance imaging and magnetic resonance angiography revealed a small acute ischemic lesion in left parietal lobe with occlusion at the left middle cerebral artery. We performed an endovascular thrombectomy, which failed. Her neurological deficits remained unchanged. On the basis of immediate postendovascular magnetic resonance perfusion, diffusion-weighted imaging (DWI), and neurological examination, an obvious clinical-DWI and a DWI-perfusion-weighted imaging mismatch were detected. We decided to perform emergency superficial temporal artery to middle cerebral artery bypass to prevent further progression of cerebral ischemia. On a 3-month follow-up, neurological deficits remained minimal motor aphasia and dysarthria. CONCLUSIONS: Following failed endovascular treatment in patients with acute symptoms attributed to major cerebral artery occlusion, we recommend immediate multimodal neuroimaging. If there are clinical-DWI and DWI-perfusion-weighted imaging mismatch indications, surgical revascularization could be considered as the next salvageable strategy. PMID- 28009767 TI - Transient Sensory Recovery in Stroke Patients After Pulsed Radiofrequency Electrical Stimulation on Dorsal Root Ganglia: A Case Series. AB - INTRODUCTION: The integrity of the somatosensory system is important for motor recovery and neuroplasticity after strokes. Peripheral stimulation or central stimulation in patients with central nervous system lesions can be an effective modality in improving function and in facilitating neuroplasticity. CASE REPORT: We present 2 hemiplegic cases with sensory motor deficit and the result of the pulsed radiofrequency (PRF) electrical stimulation to the dorsal root ganglia. After PRF electrical stimulation, significant improvement was achieved in the examination of patients with superficial and deep sensation. However, during the follow-up visits were observed that the effect of PRF electrical stimulation disappeared. CONCLUSIONS: We believe that these preliminary results could be used in the development of future prospective cohort studies and randomized controlled trials that focus on the effect of PRF electrical stimulation on dorsal root ganglia to treat sensory deficits in poststroke patients. PMID- 28009768 TI - Thrombus in Transit: A Potentially Life-threatening Complication of Cerebral Sinus Thrombosis. AB - We report the case of a 41-year-old, 7-weeks-pregnant patient, presenting with headache and generalized seizure due to cerebral venous thrombosis complicated by jugular thrombosis and thrombus dislocation into right cardiac cavities. The patient was treated with intravenous heparin, and underwent embolectomy in extracorporeal circulation. This case illustrates the variability of cerebral venous thrombosis progression and a potentially life-threatening condition even during anticoagulant therapy. PMID- 28009769 TI - Movement Disorders Induced by the "Atypical" Antipsychotic Aripiprazole. AB - OBJECTIVES: Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors. Because of its partial agonist activity, it was believed that aripiprazole would be less susceptible than typical antipsychotics to induce extrapyramidal side effects. However, a few case-reports and case-series detailing aripiprazole-induced movement disorders have been published, suggesting that aripiprazole-induced movement disorders may arise. Here, we seek to report further cases of aripiprazole-induced movement disorders to raise the awareness of clinicians on this adverse effect. METHODS: Patients referred to the Andre Barbeau Movement Disorder clinic treated with aripiprazole were enrolled in this study. Their charts were retrospectively reviewed and data regarding past psychiatric history, past antipsychotic medication, duration of aripiprazole treatment, daily dose of aripiprazole administered, and resulting movement disorders were collected. RESULTS: We report 14 cases of parkinsonism, tardive dyskinesia and akathisia induced by aripiprazole. Some of these, mostly the parkinsonian phenotype, abated spontaneously following drug discontinuation, whereas others, mostly related to tardive phenomena, persisted after aripiprazole was discontinued, and required treatment. CONCLUSIONS: This case-series adds to the existing literature that suggests that movement disorders may arise following treatment with aripiprazole. Clinicians should be aware of this potential side effect when prescribing aripiprazole to patients. PMID- 28009770 TI - Fatal Morvan Syndrome Associated With Myasthenia Gravis. AB - INTRODUCTION: Morvan syndrome is a rare and complex autoimmune disorder affecting multiple sites of neuraxis. CASE REPORT: We present fulminant Morvan syndrome, developing on a background of chronic myasthenia gravis. A 54-year-old gentleman presented with fluctuating ophthalmoplegia and proximal muscles weakness of 7 years duration that remitted with pyridostigmine and prednisolone. He developed insomnia of 2 months duration, worsening of myasthenic symptoms and respiratory distress, dysautonomia, encephalopathy, and peripheral nerve hyperexcitability. Antibodies against contactin-associated protein (CASPR) 2 were detected in serum. Computed tomography of thorax showed a thymic mass. He received intravenous methyl prednisolone and plasmapheresis. Antibodies against CASPR and thymic lesion reduced with immunotherapy. However, he developed persistent hypotension and expired after 11 weeks of hospital stay. CONCLUSIONS: Clinical clues for diagnosis of Morvan syndrome and therapeutic changes faced by the treating team are highlighted in this report. Increased awareness and prompt testing for CASPR2 antibody is warranted so that early immunotherapy can be initiated. PMID- 28009771 TI - Spontaneous Spinal Subdural Hematoma. AB - OBJECTIVE: Spinal subdural hematomas (SSDHs) are rare. Causes are (1) posttraumatic, (2) iatrogenic (following surgery or lumbar puncture), (3) spontaneous including underlying malformations or coagulation deficits. With a systematic review of literature we want to shed light on the last group: symptomatology, etiology, treatment and outcome will we discussed. METHODS: Systematic review of literature on PubMed for cases of acute nontraumatic noniatrogenic SSDHs in adults (>=18 y of age). A total of 122 cases were reviewed including 2 cases from our hospital. RESULTS: There was a slight preponderance of female patients with spontaneous SSDHs and the mean age was 60 years. Spontaneous SSDHs were mostly located in the thoracic region (40%). Motor symptoms were most frequent (89%), followed by pain. Sensory deficits were present in 64%, of which 81% had a sensory level. In 6% radiculating pain, without any focal neurological deficits, was the presenting symptom. SSDHs were mainly caused by a coagulopathy (48%), predominantly due to the use of coumarins (34%). Other causes were underlying (vascular) malformations and vasculitis. Forty-three percent the SSDHs was idiopathic. 72% of patients underwent a decompressive laminectomy. 59% had a favorable outcome and 34% had a poor outcome. CONCLUSIONS: Spontaneous SSDHs were predominantly located in the thoracic spine, presenting with paraparesis/paraplegia, sensory level and pain. Over 40% was caused by a coagulation defect, most frequently due to coumarins. Six percent of patients presented with radiculating pain without any focal neurological deficits. PMID- 28009772 TI - Acute Kidney Injury Following Exploratory Laparotomy and Temporary Abdominal Closure. AB - BACKGROUND: Acute kidney injury (AKI) following exploratory laparotomy and temporary abdominal closure (TAC) is poorly understood but clinically significant. We hypothesized that the prevalence of AKI would be highest 96 h following TAC, early hypoxemia would predict AKI, and that AKI would be an independent predictor of mortality. METHODS: We performed a retrospective analysis of 251 acute care surgery patients managed with TAC by negative pressure wound therapy (NPWT). Kidney Disease: Improving Global Outcomes AKI stages were assessed on admission, initial TAC, and following TAC at 48 h, 96 h, and 7 d. Multivariate regression was performed to identify risk factors for AKI and inpatient mortality. RESULTS: Fifty-seven percent of all patients developed AKI within 7 days of laparotomy (stage 1: 14%, 2: 21%, 3: 22%). The prevalence of AKI peaked 48 h following TAC, and stage correlated with inpatient mortality (stage 0: 7%, 1: 13%, 2: 19%, 3: 37%, P < 0.001). Overall mortality was 14%. Factors predictive of stage 2 or 3 AKI at 48 h included age >65 years (OR 2.6 [95% CI 1.4 4.9]), NPWT output >30 mL/h from first TAC to 48 h (2.0 [1.1-3.9]), and three parameters at initial laparotomy: mean arterial pressure <60 mm Hg (2.9 [1.0 8.5]), temperature <36 degrees C (2.1 [1.1-3.8]), and anion gap >21 mEq/L (1.9 [1.0-3.7]). AKI was an independent predictor of inpatient mortality (5.5 [2.5 11.8]). CONCLUSIONS: AKI is common following TAC, reaches greatest prevalence 48 h after initial laparotomy, and is associated with increased mortality. NPWT fluid loss is a risk factor for AKI that is unique to TAC patients. PMID- 28009773 TI - IATROGENIC OCCLUSION OF THE OPHTHALMIC ARTERY AFTER SODIUM TETRADECYL SULFATE INJECTION IN THE FOREHEAD. AB - PURPOSE: To describe a patient with ophthalmic artery occlusion after sodium tetradecyl sulfate foam injection in the forehead. METHODS: In this case report, a description of the clinical examination and imaging findings, including fundus photography, spectral-domain optical coherence tomography, and fluorescein angiography are reported. RESULTS: A 33-year-old white woman presented with severe painless vision loss in the left eye after cosmetic treatment of a forehead vein with sodium tetradecyl sulfate foam. Her visual acuity in the left eye was hand motions, and her fundus revealed diffuse retinal whitening in the macula with the absence of a cherry red spot and disruption of the arteriolar blood supply. Spectral-domain optical coherence tomography revealed intense hyperreflectivity of the inner and outer retina with loss of the foveal contour, and fluorescein angiography revealed delayed filling of the choroidal vasculature and cilioretinal artery with incomplete filling of the retinal arterioles in the late frames consistent with ophthalmic artery occlusion. CONCLUSION: This case represents a devastating ocular complication after the inadvertent injection of sodium tetradecyl sulfate into a forehead artery, resulting in occlusion of the ophthalmic artery and severe vision loss. PMID- 28009774 TI - EFFECT OF PLASMAPHERESIS AND PASSAGE OF ANTI-RETINAL ANTIBODIES THROUGH THE PLACENTA IN A CASE OF NON-PARANEOPLASTIC AUTOIMMUNE RETINOPATHY. AB - PURPOSE: To present a case of nonparaneoplastic autoimmune retinopathy in association with myasthenia gravis in a young woman, and to report the effect of plasmapheresis as well as passage of antiretinal antibodies through the placenta. METHODS: Case report. RESULTS: A 31-year-old woman presented with a history of myasthenia gravis and rapidly progressive vision loss at the age of 23. Funduscopic appearance and fluorescein angiographic findings on presentation were consistent with an autoimmune retinopathy. Paraneoplastic etiology was ruled out, and antiretinal antibody testing revealed positivity for autoantibodies against GAPDH, aldolase, enolase, arrestin, as well as unnamed 48-kDa and 60-kDa proteins. ARA Western Blot and immunohistochemistry profiles were unchanged by either plasmapheresis therapy or passage of serum through the maternal placenta. However, the patient's 6-month and 8-year-old daughters appeared unaffected. CONCLUSION: This is the first report of nonparaneoplastic autoimmune retinopathy associated with myasthenia gravis, although a strong history of autoimmune disorders is a known risk factor. Our patient's antiretinal antibody panel was unaffected immediately after plasmapheresis treatment. Antibodies to GAPDH and unnamed 38-kDa and 86-kDa proteins were able to pass through the placenta into the fetal circulation, although their effect on the growing fetus is not clear. PMID- 28009775 TI - CHEMOTHERAPEUTIC NADIR-ASSOCIATED RETINOPATHY. AB - PURPOSE: To describe subinternal limiting membrane hemorrhage as a retinal complication of chemotherapy nadir in a patient with leukemia. METHODS: Case report. RESULTS: A 23-year-old man presented with bilateral subinternal limiting membrane hemorrhages in both eyes as a manifestation of thrombocytopenia secondary to chemotherapy treatment for acute myeloid leukemia. CONCLUSION: Chemotherapeutic nadir-associated retinopathy may present with sub-internal limiting membrane hemorrhages most probably secondary to thrombocytopenia. PMID- 28009776 TI - BILATERAL OCCIPITAL POLE HYPERTENSIVE STROKE DIAGNOSED WITH MACULAR INTEGRITY ASSESSMENT (MAIA) MICROPERIMETRY. AB - PURPOSE: To describe the utility of microperimetry testing in the diagnosis of a bilateral occipital stroke. METHODS: Retrospective case report. RESULTS: A 57 year-old male with hypertension presented with complaints of bilateral blurred central vision and bilateral hypertensive retinopathy with cotton-wool spots. Automated perimetry demonstrated a central scotoma in both eyes that did not respect the vertical midline; however, microperimetry testing revealed a bilateral homonymous hemianopia that suggested cerebrovascular disease which was subsequently confirmed with magnetic resonance imaging. DISCUSSION: In cases of unexplained central visual loss, microperimetry testing may be a useful ancillary test for the diagnosis of cerebrovascular disease. PMID- 28009777 TI - The cardiosplenic axis: another obscure pathophysiological function of the spleen and its investigation using molecular imaging. AB - Splenic pathophysiology has been relatively unstudied, but recently, the spleen has received more attention as a result of the discovery of the 'cardiosplenic axis'. This term describes a role that the spleen plays in the progression of atherosclerosis following acute myocardial infarction. Human studies of this axis have largely used fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT to quantify peri infarction inflammation, arterial wall inflammation and splenic metabolic activity. Most of these studies have quantified arterial wall inflammation and splenic metabolic activity using the standardized uptake value, but this is a semiquantitative measurement with several drawbacks, including overestimation of metabolic activity in overweight individuals and a dependence on blood glucose levels. A better approach to the measurement of metabolic activity using F-FDG is to measure tissue F-FDG clearance from dynamic imaging and Patlak-Rutland graphical analysis. This is the preferred approach for future human studies of the cardiosplenic axis that will be required to better define the nature of the spleen's role. PMID- 28009778 TI - Left Atrium Maximal Axial Cross-Sectional Area is a Specific Computed Tomographic Imaging Biomarker of World Health Organization Group 2 Pulmonary Hypertension. AB - PURPOSE: Left heart disease is associated with left atrial enlargement and is a common cause of pulmonary hypertension (PH). We investigated the relationship between left atrium maximal axial cross-sectional area (LA-MACSA), as measured on chest computed tomography (CT), and PH due to left heart disease (World Health Organization group 2) in patients with right heart catheterization-proven PH. MATERIALS AND METHODS: A total of 165 patients with PH who had undergone right heart catheterization with pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP) measurements and nongated chest CTs were included. LA MACSA, LA anterior-posterior, and LA transverse measurements were independently obtained using the hand-drawn region-of-interest and distance measurement tools on standard PACS by 2 blinded cardiothoracic radiologists. Nonparametric statistical analyses and receiver operating characteristic curve were performed. RESULTS: Forty-three patients had group 2 PH (PCWP>15 mm Hg), and 122 had nongroup 2 PH (PCWP<=15 mm Hg). Median LA-MACSA was significantly different between the group 2 PH and nongroup 2 PH patients (2312 vs. 1762 mm, P<0.001). Interobserver concordance correlation for LA-MACSA was high at 0.91 (P<0.001). At a threshold of 2400 mm, LA-MACSA demonstrated 93% specificity for classifying group 2 PH (area under the curve, 0.73; P<0.001). CONCLUSIONS: LA-MACSA is a readily obtainable and reproducible measurement of left atrial enlargement on CT and can distinguish between group 2 and nongroup 2 PH with high specificity. PMID- 28009779 TI - Carbapenem-Resistant Enterobacteriaceae Acquired Before Liver Transplantation: Impact on Recipient Outcomes. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) is an emergent microorganism of infections after liver transplant (LT). The aim of this study was to analyze the risk factors for CRE acquisition and infection after LT. METHODS: This was a prospective cohort study involving patients who underwent LT in the 2010 to 2014 period. Surveillance cultures for CRE were collected immediately before LT and weekly thereafter until hospital discharge. RESULTS: We analyzed 386 patients undergoing a total of 407 LTs. Before LT, 68 (17.6%) patients tested positive for CRE, 11 (16.2%) of those patients having CRE infection, whereas 119 (30.8%) patients acquired CRE after LT. Post-LT CRE infection was identified in 59 (15.7%) patients: Klebsiella pneumoniae was isolated in 83.2%; surgical site infection was the most common type of infection (46.7%). Multivariate analysis showed that post-LT dialysis was the only risk factor for post-LT CRE acquisition. Eighty-two percent of patients who underwent 3 or more post-LT dialysis sessions and acquired CRE before LT evolved with post LT CRE infection. Other risk factors for CRE infection were acquisition of CRE post-LT, Model for End-Stage Liver Disease score greater than 32, combined transplantation, and reoperation. Patients who acquired CRE before LT had a high risk of developing CRE infection (P < 0.001). CONCLUSIONS: Measures for minimizing that risk, including altering the antibiotic prophylaxis, should be investigated and implemented. PMID- 28009780 TI - Kidney Transplant With Low Levels of DSA or Low Positive B-Flow Crossmatch: An Underappreciated Option for Highly Sensitized Transplant Candidates. AB - BACKGROUND: Avoiding donor-specific antibody (DSA) is difficult for sensitized patients. Improved understanding of the risk of low level DSA is needed. METHODS: We retrospectively compared the outcomes of 954 patients transplanted with varied levels of baseline DSA detected by single antigen beads and B flow cytometric crossmatch (XM). Patients were grouped as follows: -DSA/-XM, +DSA/-XM, +DSA/low +XM, +DSA/high +XM, and -DSA/+XM and followed up for a mean of 4.1 +/- 1.9 years (similar among groups, P = 0.49). RESULTS: Death-censored allograft survival was similar in all groups except the +DSA/high +XM group, which was lower at 79.1% versus 96.2% in the -DSA/-XM group (P < 0.01). The incidence of chronic antibody mediated rejection (CAMR) based on surveillance biopsy was higher with increasing DSA (8.2% -DSA/-XM, 17.0% +DSA/-XM, 30.6% +DSA/low +XM, and 51.2% +DSA/high +XM, P < 0.01), but similar in groups without baseline DSA (8.1% -DSA/-XM vs 15.4% DSA/+XM, P = 0.19). Having a calculated panel-reactive antibody (cPRA) of 80% or greater was independently associated with CAMR (hazard ratio, 5.2; P = 0.03) even when DSA was undetected at baseline. By 2 years posttransplant, the incidence of CAMR was 19.4% in patients with cPRA of 80% or greater and undetected DSA and negative XM at baseline. CONCLUSIONS: Kidney transplantation with low-level DSA with or without a low positive XM is a reasonable option for highly sensitized patients and may be advantageous compared with waiting for a negative XM deceased donor. The risk for CAMR is low in patients with no DSA even if the XM is positive. Patients with cPRA of 80% or greater are at risk for CAMR even if no DSA is detected. PMID- 28009781 TI - Safety and Efficacy of Treatment of Hepatitis C in Kidney Transplant Recipients With Directly Acting Antiviral Agents. AB - BACKGROUND: With the development of all oral, interferon-free directly acting antiviral (DAA) medications, treatment of hepatitis C virus (HCV) infection in renal transplant recipients is possible, but limited data exists on its safety and efficacy. METHODS: We performed a retrospective cohort analysis of patients transplanted at our center with HCV who have been started on DAAs. Primary endpoints included sustained virologic response as defined as negative viral load at 12 weeks postcompletion of therapy and allograft function. RESULTS: A total of 31 patients met inclusion criteria. The most commonly used regimen was sofosbuvir and ledipasvir (n = 21). Of the treated patients, 100% had undetectable viral load at the completion of therapy. Of the 31 patients treated, 30 (97%) achieved sustained virologic response. Both graft and patient survivals at most recent follow-up was 100%. There was no significant change in glomerular filtration rate (GFR) before or after therapy (64.2 +/- 16.5 mL/min per body surface area before vs. 58.9 +/- 17.5 mL/min per body surface area after therapy; P = 0.22); however, 3 patients now have GFR less than 20. A total of 6 (19.3%) of 31 patients had worsening proteinuria during or shortly after therapy. Patients with more than 500 mg/g of proteinuria at the start of treatment were significantly more likely to develop worsening proteinuria than those with less than 500 mg/g of proteinuria at the start of therapy (P < 0.001). Retrospective review of 20 untreated HCV patients did not demonstrate worsening allograft function and proteinuria during a median follow-up time of 1386 days (range, 332-6254). CONCLUSIONS: Our preliminary data demonstrate that DAAs can be used safely and effectively in patients after kidney transplantation. Patients with proteinuria or lower GFR should be monitored more closely. PMID- 28009782 TI - Prolonged EVLP Using OCS Lung: Cellular and Acellular Perfusates. AB - BACKGROUND: We report the ability to extend lung preservation up to 24 hours (24H) by using autologous whole donor blood circulating within an ex vivo lung perfusion (EVLP) system. This approach facilitates donor lung reconditioning in a model of extended normothermic EVLP. We analyzed comparative responses to cellular and acellular perfusates to identify these benefits. METHODS: Twelve pairs of swine lungs were retrieved after cardiac arrest and studied for 24H on the Organ Care System (OCS) Lung EVLP platform. Three groups (n = 4 each) were differentiated by perfusate: (1) isolated red blood cells (RBCs) (current clinical standard for OCS); (2) whole blood (WB); and (3) acellular buffered dextran-albumin solution (analogous to STEEN solution). RESULTS: Only the RBC and WB groups met clinical standards for transplantation at 8 hours; our primary analysis at 24H focused on perfusion with WB versus RBC. The WB perfusate was superior (vs RBC) for maintaining stability of all monitored parameters, including the following mean 24H measures: pulmonary artery pressure (6.8 vs 9.0 mm Hg), reservoir volume replacement (85 vs 1607 mL), and PaO2:FiO2 ratio (541 vs 223). Acellular perfusion was limited to 6 hours on the OCS system due to prohibitively high vascular resistance, edema, and worsening compliance. CONCLUSIONS: The use of an autologous whole donor blood perfusate allowed 24H of preservation without functional deterioration and was superior to both RBC and buffered dextran-albumin solution for extended lung preservation in a swine model using OCS Lung. This finding represents a potentially significant advance in donor lung preservation and reconditioning. PMID- 28009783 TI - Treatment of Acute Antibody-Mediated Renal Allograft Rejection With Cyclophosphamide. AB - BACKGROUND: Antibody-mediated rejection (AMR) is a major risk for renal allograft survival. Throughout decades, cyclophosphamide treatment has been proven to be effective in patients with antibody-associated autoimmune diseases. We investigated whether cyclophosphamide combined with plasmapheresis and intravenous immunoglobulins is an option for patients with AMR. METHODS: Between March 2013 and November 2015, we initiated treatment of 13 consecutive patients with biopsy-proven acute AMR with intravenous cyclophosphamide pulses (15 mg/kg adapted to age and renal function) at 3-week intervals, PPH (6*), and high-dose intravenous immunoglobulin (1.5 g/kg). Treatment was completed after 6 cyclophosphamide pulses or in case of return to baseline serum creatinine together with reduction of donor-specific HLA antibodies (DSA) below 500 mean fluorescence intensity. RESULTS: Eleven of 13 patients completed treatment. Median follow-up was 18 (12-44) months. At the end of follow-up, graft survival was 77% (10/13). The 3 graft losses were caused at least in part by nonadherence and premature termination of treatment. Serum creatinine increased from 1.7+/-0.4 mg/dL at 3 months before diagnosis to 3.7+/-2.4 mg/dL at diagnosis (P = 0.01), and decreased to 2.1 +/- 0.7 mg/dL at 3 months after diagnosis (P = 0.01). In 7 (64%) of 11 patients, who completed treatment, DSA decreased, in 4 (36%) of 11 DSA were below 500 mean fluorescence intensity after treatment. Dose reductions had to be performed in 3 of 13 patients for leukopenia. We observed 14 hospitalizations in 9 of 13 patients. CONCLUSIONS: To our knowledge, this is the first systematic report on cyclophosphamide-based treatment of acute AMR based on modern diagnostics. Treatment was effective and relatively safe. Future studies will show, whether cyclophosphamide proves to be a valuable alternative for the treatment of AMR. PMID- 28009784 TI - Brief Intense Stair Climbing Improves Cardiorespiratory Fitness. AB - PURPOSE: Sprint interval training (SIT) is a time-efficient strategy to improve cardiorespiratory fitness (CRF); however, most protocols have been studied in laboratory settings and require specialized equipment. We investigated the efficacy of brief intense stair climbing as a practical model of SIT to improve CRF. METHODS: Two separate studies, each consisting of an acute and chronic phase, were conducted in a total of 31 sedentary women (age = 24 +/- 10 yr, body mass index = 23 +/- 4 kg.m). RESULTS: The acute phase of study 1 established that the mean HR, blood [lactate], and RPE were similar when participants (n = 8) performed an SIT protocol that involved 3 * 20-s "all-out" efforts of either continuously ascending stairs or cycling. The chronic phase demonstrated that CRF, as determined by peak oxygen uptake (VO2peak), increased by 12% or ~1 MET (8.27 +/- 1.05 to 9.25 +/- 1.01 METs, P = 0.002) when participants (n = 12) performed the 3 * 20-s stair climbing protocol 3 d.wk for 6 wk. The acute phase of study 2 established that HR and RPE were similar when participants (n = 11) performed three different stair climbing protocols: the 3 * 20-s continuous ascent model used in study 1 and two 3 * 60-s models of ascending and descending either one or two flights of stairs (P > 0.05). The chronic phase demonstrated that VO2peak increased by 7% (8.91 +/- 1.30 to 9.51 +/- 1.52 METs, P = 0.01) when the same group of participants performed the one-flight 3 * 60-s protocol 3 d.wk for 6 wk. The Cederholm index determined from an oral glucose tolerance test was 57 +/- 17 and 64 +/- 21 mg.L.mmol.mU.min before and after training, respectively (P = 0.056). CONCLUSION: Brief, intense stair climbing is a practical, time efficient strategy to improve CRF in previously untrained women. PMID- 28009785 TI - Active Workstations Do Not Impair Executive Function in Young and Middle-Age Adults. AB - PURPOSE: This study aimed to examine the effects of self-selected low-intensity walking on an active workstation on executive functions (EF) in young and middle age adults. METHODS: Using a within-subjects design, 32 young (20.6 +/- 2.0 yr) and 26 middle-age (45.6 +/- 11.8 yr) adults performed low-intensity treadmill walking and seated control conditions in randomized order on separate days, while completing an EF test battery. EF was assessed using modified versions of the Stroop (inhibition), Sternberg (working memory), Wisconsin Card Sorting (cognitive flexibility), and Tower of London (global EF) cognitive tasks. Behavioral performance outcomes were assessed using composite task z-scores and traditional measures of reaction time and accuracy. Average HR and step count were also measured throughout. RESULTS: The expected task difficulty effects were found for reaction time and accuracy. No significant main effects or interactions as a function of treadmill walking were found for tasks assessing global EF and the three individual EF domains. Accuracy on the Tower of London task was slightly impaired during slow treadmill walking for both age-groups. Middle-age adults displayed longer planning times for more difficult conditions of the Tower of London during walking compared with sitting. A 50-min session of low-intensity treadmill walking on an active workstation resulted in accruing approximately 4500 steps. CONCLUSIONS: These findings suggest that executive function performance remains relatively unaffected while walking on an active workstation, further supporting the use of treadmill workstations as an effective approach to increase physical activity and reduce sedentary time in the workplace. PMID- 28009786 TI - Low-Force Muscle Activity Regulates Energy Expenditure after Spinal Cord Injury. AB - : Reduced physical activity is a primary risk factor for increased morbidity and mortality. People with spinal cord injury (SCI) have reduced activity for a lifetime, as they cannot volitionally activate affected skeletal muscles. We explored whether low-force and low-frequency stimulation is a viable strategy to enhance systemic energy expenditure in people with SCI. PURPOSE: This study aimed to determine the effects of low stimulation frequency (1 and 3 Hz) and stimulation intensity (50 and 100 mA) on energy expenditure in people with SCI. We also examined the relationship between body mass index and visceral adipose tissue on energy expenditure during low-frequency stimulation. METHODS: Ten individuals with complete SCI underwent oxygen consumption monitoring during electrical activation of the quadriceps and hamstrings at 1 and 3 Hz and at 50 and 100 mA. We calculated the difference in energy expenditure between stimulation and rest and estimated the number of days that would be necessary to burn 1 lb of body fat (3500 kcal) for each stimulation protocol (1 vs 3 Hz). RESULTS: Both training frequencies induced a significant increase in oxygen consumption above a resting baseline level (P < 0.05). Energy expenditure positively correlated with stimulus intensity (muscle recruitment) and negatively correlated with adiposity (reflecting the insulating properties of adipose tissue). We estimated that 1 lb of body fat could be burned more quickly with 1 Hz training (58 d) as compared with 3 Hz training (87 d) if an identical number of pulses were delivered. CONCLUSION: Low-frequency stimulation increased energy expenditure per pulse and may be a feasible option to subsidize physical activity to improve metabolic status after SCI. PMID- 28009787 TI - Prevalence of Exercise-Induced Arterial Hypoxemia in Distance Runners at Sea Level. AB - PURPOSE: It has been reported that ~50% of endurance-trained men demonstrate exercise-induced arterial hypoxemia (EIAH) during heavy exercise. However, this often-cited prevalence rate comes from a single study using a cohort of 25 highly trained men who completed maximal cycle ergometry. As arterial oxyhemoglobin saturation (SpO2) during maximal exercise is reported to be significantly lower during treadmill versus cycle ergometry in the same subjects, we hypothesized that the prevalence of EIAH would be greater than previously reported (and commonly referenced) in a larger cohort of highly endurance-trained men during maximal treadmill running. METHODS: Data from 124 highly trained male distance runners (VO2max range = 60.3-84.7 mL.kg.min) were retrospectively examined from previously published studies completed in the Indiana University Human Performance Laboratory. Subjects completed a constant speed, progressive-grade treadmill exercise test to volitional exhaustion, and arterial oxyhemoglobin saturation (SaO2ear) in all subjects was estimated using the same oximeter (Hewlett Packard 47201A). RESULTS: Using similar inclusion criteria as previously published for highly trained (VO2max > 68 mL.kg.min) and for EIAH (SaO2ear <= 91%), 55 of 79 subjects (70%) exhibited exercise-induced arterial desaturation. Across all 124 subjects, 104 (84%) demonstrated at least moderate EIAH (SaO2ear <= 93%) during maximal treadmill exercise. SaO2ear was significantly yet weakly correlated with VE/VO2 (P < 0.01, r = 0.28) and VE/VCO2 (P < 0.001, r = 0.33) but not with VO2max. CONCLUSION: These results indicate that the prevalence of EIAH in highly trained men during maximal treadmill exercise at sea level is greater compared with previously suggested data, with exercise mode perhaps playing a factor in the number of athletes who experience EIAH. PMID- 28009788 TI - Effect of Load Carriage on Upper Limb Performance. AB - : Carrying heavy backpacks are often associated with shoulder discomfort or pain, loss of sensorimotor functions, and brachial plexus injuries that might hamper performance. On the basis of previous research, the cause of these symptoms could be tissue deformations of the brachial plexus and the subclavian artery caused by the shoulder straps. PURPOSE: This study aimed to evaluate the changes in the upper extremity hemodynamic and neural function and to assess how they are associated with brachial plexus tissue deformation during heavy load carriage. METHODS: Ten young healthy adults carried for 45 min a backpack load (40% of their body weight) while standing freely, followed by 15 min of recovery (unloaded). Index-finger microvascular flow and sensorimotor function were measured before and after carrying the load, and after recovery. The following sensorimotor functions were measured: light touch thresholds by the index finger and little finger, forearm thermal sensation thresholds, and gross motor function. In addition, marksmanship accuracy, as an indication for fine motor function, was tested. RESULTS: Load carriage resulted in an average decrease of ~40% in microvascular flow and a significant decrement in light touch sensation (P < 0.05), but not in thermal sensation and gross motor functions. An increase in the light touch threshold was highly correlated with a reduced index-finger microvascular blood flow (r = 0.79, P = 0.007). These physiological effects were associated with a functional 34% decrement in the accuracy of target acquisition. CONCLUSION: Heavy load carriage resulted in impaired light touch sensitivity and fine motor function, which were associated with reduced finger microvascular blood flow. PMID- 28009789 TI - Heat Strain Is Exacerbated on the Second of Consecutive Days of Fire Suppression. AB - PURPOSE: We tested the hypothesis that physiological and perceptual heat strain is exacerbated on the second of back-to-back days of fire suppression work despite evidence of full recovery. METHODS: Twenty-six career and volunteer firefighters (age = 31 +/- 8 yr) completed 20 min of near maximal fire suppression work on consecutive days. Dependent variables were core temperature, heart rate, perceived exertion, and thermal sensation, which were measured before and after fire suppression. Urine specific gravity and body mass were also measured upon arrival at the fire academy as an index of hydration and recovery between days. RESULTS: Urine specific gravity (1.007 +/- 0.006 vs 1.005 +/- 0.006), body mass (87.7 +/- 16.1 vs 87.8 +/- 16.0 kg), heart rate (77 +/- 14 vs 76 +/- 14 bpm), and core temperature (37.2 degrees C +/- 0.4 degrees C vs 37.1 degrees C +/- 0.7 degrees C) were not different upon arrival on day 1 compared with day 2 (P >= 0.26). The increase in core temperature during fire suppression was higher on day 2 (0.7 degrees C +/- 0.3 degrees C vs 1.1 degrees C +/- 0.5 degrees C, P < 0.01). Heart rate did not differ (after fire suppression: day 1 = 174 +/- 19, day 2 = 169 +/- 30 bpm, P = 0.60). The magnitude of increase in perceived exertion during fire suppression was greater on day 2 (6.7 +/- 1.6 vs 7.4 +/- 1.6 a.u., P < 0.01). Absolute thermal sensation at the end of fire suppression was greater on day 2 (3.8 +/- 0.8 vs 4.3 +/- 0.6 a.u., P < 0.01). CONCLUSIONS: Physiological and perceptual heat strain is higher on the second of back-to-back days of fire suppression work. PMID- 28009790 TI - Exercise Training Reverses Extrapulmonary Impairments in Smoke-exposed Mice. AB - PURPOSE: Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease and emphysema. However, evidence on the extrapulmonary effects of smoke exposure that precede lung impairments remains unclear at present, as are data on nonpharmacological treatments such as exercise training. METHODS: Three groups of mice, including control (n = 10), smoking (n = 10), and smoking with 6 wk of high-intensity interval treadmill running (n = 11), were exposed to 20 wk of fresh air or whole-body cigarette smoke. Exercise capacity (peak oxygen uptake) and lung destruction (histology) were subsequently measured, whereas the heart, peripheral endothelium (aorta), and respiratory (diaphragm) and limb (extensor digitorum longus and soleus) skeletal muscles were assessed for in vivo and in vitro function, in situ mitochondrial respiration, and molecular alterations. RESULTS: Smoking reduced body weight by 26% (P < 0.05) without overt airway destruction (P > 0.05). Smoking impaired exercise capacity by 15% while inducing right ventricular dysfunction by ~20%, endothelial dysfunction by ~20%, and diaphragm muscle weakness by ~15% (all P < 0.05), but these were either attenuated or reversed by exercise training (P < 0.05). Compared with controls, smoking mice had normal limb muscle and mitochondrial function (cardiac and skeletal muscle fibers); however, diaphragm measures of oxidative stress and protein degradation were increased by 111% and 65%, respectively (P < 0.05), but these were attenuated by exercise training (P < 0.05). CONCLUSIONS: Prolonged cigarette smoking reduced exercise capacity concomitant with functional impairments to the heart, peripheral endothelium, and respiratory muscle that preceded the development of overt emphysema. However, high-intensity exercise training was able to reverse these smoke-induced extrapulmonary impairments. PMID- 28009792 TI - Clinical Features in Children with Posterior Polymorphous Corneal Dystrophy. AB - PURPOSE: To describe clinical features in children diagnosed with posterior polymorphous corneal dystrophy (PPCD) in their first or second decade of life. METHODS: A retrospective study was performed with the medical records of seven unrelated Korean pediatric patients who were diagnosed with PPCD and were followed up for a minimum of 3 years. Thorough ocular examinations were performed, including best-corrected visual acuity, intraocular pressure, refractive and keratometric measurements, slit-lamp biomicroscopy, and specular microscopy at all visits. RESULTS: Slit-lamp examinations revealed vesicular lesions in one patient and horizontally parallel band-like endothelial lesions in six patients. Unilateral corneal involvement was displayed in 4 patients, yielding 10 eyes with deep corneal features characteristic of PPCD. Other corneal, iris, or fundus pathologic findings were not detected in all cases. Among four children who were examined in their visual development (approximately under 8 years of age), two cases demonstrated unilateral amblyopia at initial examination and exhibited improved visual acuity after refractive correction and occlusion therapy. Astigmatism more than 1.5D, which is generally considered amblyogenic, was found in 8 among 10 PPCD-affected eyes. A final visual acuity of more than 20/32 was achieved with appropriate refractive correction in all PPCD affected eyes. There was a negative correlation between the corneal astigmatism and the mean endothelial cell density (ECD) (r = -0.655, P = .011). Initial specular microscopic examinations revealed reduced ECD (1733.0 +/- 543.9 cells/mm) composed of enlarged cells (average cell area, 624.8 +/- 182.1 MUm/cell) in PPCD-affected eyes, compared with those in PPCD-unaffected eyes from our study subjects (P < .001 and P = .005, respectively). A statistically significant percent loss in ECD from initial to 3 years was noted in the PPCD affected eyes (P = .03). CONCLUSIONS: The awareness and treatment of refractive error are important, especially in children with early-onset PPCD during the reversible period of amblyopia. Long-term monitoring of corneal endothelium is required in pediatric patients with early-onset PPCD based on a significant endothelial loss over 3 years in PPCD-affected eyes. PMID- 28009791 TI - Deriving a GPS Monitoring Time Recommendation for Physical Activity Studies of Adults. AB - INTRODUCTION: Determining locations of physical activity (PA) is important for surveillance and intervention development, yet recommendations for using location recording tools like global positioning system (GPS) units are lacking. Specifically, no recommendation exists for the number of days study participants should wear a GPS to reliably estimate PA time spent in locations. METHODS: This study used data from participants (N = 224, age = 18-85 yr) in five states who concurrently wore an ActiGraph GT1M accelerometer and a Qstarz BT-Q1000X GPS for three consecutive weeks to construct monitoring day recommendations through variance partitioning methods. PA bouts >=10 min were constructed from accelerometer counts, and the location of GPS points was determined using a hand coding protocol. RESULTS: Monitoring day recommendations varied by the type of location (e.g., participant homes vs parks) and the intensity of PA bouts considered (low and medium cut point moderate to vigorous PA [MVPA] bouts or high cut point vigorous PA [VPA] bouts). In general, minutes of all PA intensities spent in a given location could be measured with >=80% reliability using 1-3 d of GPS monitoring for fitness facilities, schools, and footpaths. MVPA bout minutes in parks and roads required longer monitoring periods of 5-12 d. PA in homes and commercial areas required >19 d of monitoring. CONCLUSIONS: Twelve days of monitoring was found to reliably estimate minutes in both low and medium threshold MVPA as well as VPA bouts for many important built environment locations that can be targeted to increase PA at the population level. Minutes of PA in the home environment and commercial locations may be best assessed through other means given the lengthy estimated monitoring time required. PMID- 28009793 TI - Measurement Duration and Frequency Impact Objective Light Exposure Measures. AB - PURPOSE: To determine the measurement duration and frequency required to reliably quantify the typical personal light exposure patterns of children and young adults. METHODS: Ambient light exposure data were obtained from 31 young adults and 30 children using a wrist-worn light sensor configured to measure ambient light exposure every 30 seconds for 14 days. To examine the influence of measurement duration upon light exposure, the daily time exposed to outdoor light levels (>1000 lux) was initially calculated based upon data from all 14 days and then recalculated from 12, 10, 8, 6, 4, and 2 randomly selected days. To examine the influence of measurement frequency, the outdoor exposure time was calculated for a 30-second sampling rate and again after resampling at 1-, 2-, 3-, 4-, 5-, and 10-minute sampling rates. RESULTS: Children spent significantly greater time outdoors (44 minutes higher [95% CI: 26, 62]) compared to adults (P = .001). Children spent more time outdoors during the weekdays (13 minutes higher [-7, 32]) and adults spent more time outdoors during the weekends (24 minutes higher [7, 40]) (P = .005). Calculating light exposure using a lower number of days and coarser sampling frequencies did not significantly alter the group mean light exposure (P > .05). However, a significant increase in measurement variability occurred for outdoor light exposure derived from less than 8 days and 3 minutes or coarser measurement frequencies in adults, and from less than 8 days and 4 minutes or coarser frequencies in children (all P < .05). Reducing measurement duration seemed to have a greater impact upon measurement variability than reducing the measurement frequency. CONCLUSIONS: These findings suggest that a measurement duration of at least 1 week and a measurement frequency of 2 minutes or finer provides the most reliable estimates of personal outdoor light exposure measures in children and young adults. PMID- 28009794 TI - Ocular Straylight with Different Multifocal Contact Lenses. AB - PURPOSE: Multifocal contact lenses have been growing in popularity as a modality to correct presbyopic eyes, although visual side effects such as disability glare have been reported. The objective of this study was to investigate the effect of multifocal contact lenses on disability glare by means of ocular straylight. METHODS: A prospective randomized, comparative study was performed that included 16 subjects free of ocular pathology. Straylight was measured using a commercial straylight meter with the natural and dilated pupil. Participants were fitted with Proclear Multifocal (Distance/Near), ACUVUE Oasys for Presbyopia, and Air Optix Aqua Multifocal randomized to the left or right eye. Straylight measurements were repeated with the contact lens in situ after the pupil dilation. Results obtained with the dilated pupil without contact lens acted as a control. RESULTS: Diameter of the natural and dilated pupil was 2.87 +/- 0.40 mm and 7.45 +/- 0.86 mm, respectively (P < .001). After pupil dilation, straylight increased from 0.92 +/- 0.13 log(s) to 1.04 +/- 0.11 log(s) (P < .001). Of the four studied lenses, a significant difference was only found between Air Optix and the control group (P = .006). The latter showed also slightly increased light scatter. CONCLUSIONS: A difference in measured straylight was found between the studied multifocal lenses. The observed variability and the straylight-pupil size dependency should be taken into account to avoid elevated straylight in multifocal contact lens wearers. The reason for the observed differences in straylight must be the subject of future studies. PMID- 28009797 TI - What's New in Congenital Scoliosis? AB - BACKGROUND: Congenital scoliosis is a failure of vertebral formation, segmentation, or a combination of the 2 arising from abnormal vertebral development during weeks 4 to 6 of gestation. The associated spinal deformity can be of varying severity and result in a stable or progressive deformity based on the type and location of the anomalous vertebra(e). Bracing for congenital scoliosis is rarely indicated, while recent reports have demonstrated the utility of serial derotational casting for longer curves with multiple anomalous vertebrae as an effective "time buying strategy" to delay the need for surgery. Earlier hemivertebra excision and short-segment posterior spinal fusion have been advocated to prevent future curve progression of the deformity and/or the development of large compensatory curves. It has been shown in recent long-term follow-up studies that growth rates of the vertebral body and spinal canal are not as dramatically affected by pedicle screw instrumentation at a young age as once thought. Growth friendly surgery with either spine-based or rib-based anchors has demonstrated good results with curve correction while maintaining spinal growth. Rib-based anchors are typically more commonly indicated in the setting of chest wall abnormalities and/or when spinal anatomy precludes placement of spinal instrumentation. Recently, magnetically controlled growing rods have shown promising results in several studies that include a small subset of congenital scoliosis cases. METHODS: A literature search was performed to identify existing studies related to the treatment of congenital scoliosis published from January 1, 2005 to June 1, 2016. Databases included PubMed, Medline, and the Cochrane Library. The search was limited to English articles and yielded 36 papers. This project was initiated by the Pediatric Orthopaedic Society of North America Publications Committee and was reviewed and approved by the Pediatric Orthopaedic Society of North America Presidential Line. RESULTS: A total of 36 papers were selected for review based upon new findings. Classic manuscripts on congenital scoliosis are also included to provide sufficient background information. CONCLUSIONS: Congenital scoliosis represents a wide range of pathology from the simple, stable hemivertebra to the complex, progressive spinal deformity with chest wall abnormalities and associated cardiac, renal, and neural axis anomalies. This paper reviews the natural history and associated anomalies with congenital scoliosis as well as the most up-to-date classification schemes and various treatment options for the care of this challenging patient population. LEVEL OF EVIDENCE: Level 5. PMID- 28009798 TI - Vitamin D Deficiency: The Missing Etiological Factor in the Development of Juvenile Osteochondrosis Dissecans? AB - BACKGROUND: Vitamin D deficiency can result in rickets and hypocalcemia during infant and childhood growth. There is an increasing interest in the role of vitamin D with regards to childhood bone health. Osteochondrosis dissecans (OD) is a common disease affecting different joints. To date, the exact etiology of OD still remains unclear. The aim of this study was to evaluate a possible association of vitamin D deficiency and juvenile OD. METHODS: A retrospective chart review of the years 2010 to 2015 of all orthopaedic patients with an initial diagnosis of juvenile OD admitted to undergo operative treatment of the OD was performed. Patient demographics, medical history, information on sports activity (if available) and serum vitamin D (25-OH-D) level on admission date were obtained. For statistical comparison, we measured baseline prevalence of vitamin D insufficiency in age-matched orthopaedic patients presenting at the department of pediatric orthopaedics. RESULTS: A total of 80 patients were included in this study. Overall, 97.5% (n=78) of tested patients in the OD group had serum vitamin D levels below the recommended threshold of 30 ng/mL (mean value of 10.1 ng/mL (+/-6.7 ng/mL)). Over 60% (n=49) were vitamin D deficient, 29 patients (37%) showed serum levels below 10 ng/mL corresponding to a severe vitamin D deficiency. Of note, only 2 patients (2.5%) reached serum vitamin D levels above the recommended threshold of 30 ng/mL. No statistical difference was found in respect to sports activity level before onset of the symptoms (P=0.09). Statistical analysis found a significant difference in vitamin D levels between patients with OD and patients without an OD (P=0.026). CONCLUSIONS: We found an unexpected high prevalence of vitamin D deficiency in juveniles diagnosed with OD presenting with significant lower mean 25-OH-D level compared with a control group. These results suggest that vitamin D deficiency is potentially associated with the development of OD. Thus, vitamin D deficiency might be an important cofactor in the multifactorial development of juvenile OD. For this reason, supplementation of vitamin D might not only be a potential additional therapy but also be a possible preventative factor in patients with juvenile OD. However, future prospective studies are needed to confirm this preliminary data. LEVEL OF EVIDENCE: Level III-this is a case-control study. PMID- 28009799 TI - Percutaneous Hamstring Lengthening Surgery is as Effective as Open Lengthening in Children With Cerebral Palsy. AB - BACKGROUND: Surgical lengthening of the hamstrings is often performed to correct crouch gait in children with cerebral palsy (CP). Previous studies have demonstrated the effectiveness of open hamstring lengthening (oHSL) in improving knee extension static and dynamic range of motion; however, literature regarding percutaneous hamstring lengthening (pHSL) is limited. The purpose of this study was to investigate the effect of open versus pHSL for improving crouch gait and knee function in children with CP. METHODS: This retrospective cohort study included 87 ambulatory children with CP who underwent HLS surgery with both preoperative and postoperative gait analysis (mean time, 29.4+/-19.9 mo after surgery) testing between 1997 and 2015. In total, 65 patients underwent oHLS surgery (mean age, 8.5+/-2.5 y) and 22 patients underwent pHSL surgery (mean age, 8.3+/-2.3 y). Lower extremity three-dimensional kinematic data were collected while subjects walked at a self-selected speed. Outcome variables for operative limbs were compared within and between groups using t tests, chi tests, and multiple regression analysis. RESULTS: Significant postoperative decreases in knee flexion at initial contact were seen for both open (Delta12.7+/-13.4 degrees; P<0.001) and percutaneous (Delta19.1+/-13.1 degrees; P<0.001) groups. Increased postoperative maximum knee extension in stance was found for both open (Delta8.2+/-16.8 degrees; P=0.001) and percutaneous (Delta14.4+/-16.5 degrees; P=0.001) groups. No significant differences between open and percutaneous groups were found when comparing postoperative changes in kinematic variables between groups after adjusting for covariates. Postoperative changes in static range of motion were similar between lengthening groups. CONCLUSIONS: pHSL is as effective as open lengthening in improving stance phase knee kinematics during gait in children with CP. This is the first study to compare the kinematic effects of open versus pHSL in the pediatric population. Percutaneous lengthening is tolerated well by patients, and as it allows for rapid rehabilitation it may be preferable to the open procedure. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 28009800 TI - Is There Value in Having Radiology Provide a Second Reading in Pediatric Orthopaedic Clinic? AB - BACKGROUND: The Joint Commission on Accreditation of Healthcare Organizations specifically mandates the dual interpretation of musculoskeletal radiographs by a radiologist in addition to the orthopaedist in all hospital-based orthopaedic clinics. Previous studies have questioned the utility of this practice. The purpose of this study was to further investigate the clinical significance of having the radiologist provide a second interpretation in a hospital-based pediatric orthopaedic clinic. METHODS: A retrospective review was performed of all patients who had plain radiographs obtained in the pediatric orthopaedic clinic at an academic children's hospital over a 4-month period. For each radiographic series, the orthopaedist's note and the radiology interpretation were reviewed and a determination was made of whether the radiology read provided new clinically useful information and/or a new diagnosis, whether it recommended further imaging, or if it missed a diagnosis that was reflected in the orthopaedist's note. The hospital charges associated with the radiology read for each study were also quantified. RESULTS: The charts of 1570 consecutive clinic patients who were seen in the pediatric orthopaedic clinic from January to April, 2012 were reviewed. There were 2509 radiographic studies performed, of which 2264 had both a documented orthopaedist's note and radiologist's read. The radiologist's interpretation added new, clinically important information in 1.0% (23/2264) of these studies. In 1.7% (38/2264) of the studies, it was determined that the radiologist missed the diagnosis or clinically important information that could affect treatment. The total amount of the professional fees charged for the radiologists' interpretations was $87,362. On average, the hospital charges for each occurrence in which the radiologist's read provided an additional diagnosis or clinically important information beyond the orthopaedist's note were $3798. CONCLUSIONS: The results of this study suggest that eliminating the requirement to have the radiologist interpret radiographs in the pediatric orthopaedic clinic would have few clinical consequences. LEVEL OF EVIDENCE: Level III-This is a diagnostic retrospective cohort study. PMID- 28009801 TI - Classification of Cruciate Ligament Dysplasia and the Severity of Congenital Fibular Deficiency. AB - BACKGROUND: Dysplasia of the cruciate ligaments has been found in many patients with congenital fibular deficiency. A recent classification system has shown that radiographic tibial spine changes can predict the hypoplasia and aplasia of the cruciate ligaments. We used this radiographic classification to determine the frequency of these abnormalities and how they correlate with the severity of fibular deficiency and lateral femoral condylar hypoplasia. METHODS: Using a hospital database search for fibular deficiency, 99 patients >=6 years with unilateral fibular deficiency were identified. Existing radiographs of both knees were available for 75 patients and reviewed for the tibial spine changes and Achterman and Kalamchi classification of the fibular deficiency. Measurements of femoral condyle heights in 74 of 75 patients were recorded before any surgery to the distal femoral physis to assess lateral femoral condylar hypoplasia. RESULTS: Twenty-two patients had hypoplasia of the lateral tibial spine+normal medial spine, 29 had absence of the lateral tibial spine+hypoplastic medial spine, and 11 had absence of both tibial spines. Five tibial spines were normal and 8 were unclassifiable. The severity of the tibial spine dysplasia, particularly absence of the lateral tibial spine, correlated with the severity of the fibular deficiency. (P<0.0001) The mean lateral femoral condylar hypoplasia, measured by involved: uninvolved lateral condyle heights, was 0.85+/-0.11. Those with some preservation of the lateral tibial spine had less lateral femoral condylar hypoplasia (P=0.0009). This lateral femoral condylar hypoplasia was positively associated with the severity of the fibular absence (P=0.039) and foot ray deficiency (P=0.036). CONCLUSIONS: The severity of cruciate ligament dysplasia in fibular deficiency is directly correlated with the severity of fibular absence, lateral femoral condylar hypoplasia, and the absence of foot rays. This suggests that the embryological factors involved have a complex interplay for all of these clinical findings. LEVEL OF EVIDENCE: Level III. PMID- 28009802 TI - Benign Osteolytic Lesions in Children With Previously Normal Radiographs. AB - BACKGROUND: Benign bone tumors are common in children and are usually diagnosed incidentally or after pathologic fractures. However, case reports of children with lytic lesions with previously normal radiographs are rare. This series presents several such cases. METHODS: This was a retrospective case series of 8 benign osteolytic lesions in 8 pediatric patients (5 female and 3 males). All have previous radiographs of the effected extremity showing no pathology. All participants were at a single institution. RESULTS: Eight cases were identified with 2 aneurysmal bone cysts and 6 nonossifying fibromas. Average age at discovery was 10.75 years old. The range of time between normal and pathologic radiographs was from 2.5 to 7.25 years. Both cases of aneurysmal bone cysts were histologically confirmed and treated with curettage and grafting with one recurrence. One of 6 nonossifying fibromas was treated surgically with the remainder treated with casting for pathologic fractures or observation for incidentally identified lesions. CONCLUSIONS: Benign osteolytic lesions such as aneurysmal bone cysts and nonossifying fibromas can arise in a short time period. The average time between normal and pathologic radiographs was 4.6 years. Prelesion radiographs were obtained to evaluate traumas and leg length discrepancies. CLINICAL RELEVANCE: Radiographs taken before diagnosis in children with osseous lesions are rare, but likely under recognized. Further studies of such instances in larger databases may provide a noninvasive means to reach diagnostic or etiologic conclusions. PMID- 28009803 TI - Phylogenetic Relationships of the Fern Cyrtomium falcatum (Dryopteridaceae) from Dokdo Island Based on Chloroplast Genome Sequencing. AB - Cyrtomium falcatum is a popular ornamental fern cultivated worldwide. Native to the Korean Peninsula, Japan, and Dokdo Island in the Sea of Japan, it is the only fern present on Dokdo Island. We isolated and characterized the chloroplast (cp) genome of C. falcatum, and compared it with those of closely related species. The genes trnV-GAC and trnV-GAU were found to be present within the cp genome of C. falcatum, whereas trnP-GGG and rpl21 were lacking. Moreover, cp genomes of Cyrtomium devexiscapulae and Adiantum capillus-veneris lack trnP-GGG and rpl21, suggesting these are not conserved among angiosperm cp genomes. The deletion of trnR-UCG, trnR-CCG, and trnSeC in the cp genomes of C. falcatum and other eupolypod ferns indicates these genes are restricted to tree ferns, non-core leptosporangiates, and basal ferns. The C. falcatum cp genome also encoded ndhF and rps7, with GUG start codons that were only conserved in polypod ferns, and it shares two significant inversions with other ferns, including a minor inversion of the trnD-GUC region and an approximate 3 kb inversion of the trnG-trnT region. Phylogenetic analyses showed that Equisetum was found to be a sister clade to Psilotales-Ophioglossales with a 100% bootstrap (BS) value. The sister relationship between Pteridaceae and eupolypods was also strongly supported by a 100% BS, but Bayesian molecular clock analyses suggested that C. falcatum diversified in the mid-Paleogene period (45.15 +/- 4.93 million years ago) and might have moved from Eurasia to Dokdo Island. PMID- 28009804 TI - Evaluation of Chemical Composition and Antileishmanial and Antituberculosis Activities of Essential Oils of Piper Species. AB - Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC-MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority of species analyzed. The composition of the essential oil of Piper mosenii was described for the first time. The cytotoxicity of the essential oils was evaluated in peritoneal macrophages and the oils of P. rivinoides, P. arboretum, and P. aduncum exhibited the highest values, with cytotoxic concentration at 50% (CC50) > 200 ug/mL. Both P. diospyrifolium and P. aduncum displayed activity against Leishmania amazonensis, and were more selective for the parasite than for the macrophages, with a selectivity index (SI) of 2.35 and >5.52, respectively. These SI values were greater than the 1 for the standard drug pentamidine. The antileishmanial activity of the essential oils of P. diospyrifolium and P. aduncum was described for the first time. P. rivinoides, P. cernuum, and P. diospyrifolium displayed moderate activity against the Mycobacterium tuberculosis H37Rv bacillus, with a minimum inhibitory concentration (MIC) of 125 ug/mL. These results are relevant and suggests their potential for therapeutic purposes. Nevertheless, further studies are required to explain the exact mechanism of action of these essential oils. PMID- 28009805 TI - Wargame Simulation Theory and Evaluation Method for Emergency Evacuation of Residents from Urban Waterlogging Disaster Area. AB - Urban waterlogging seriously threatens the safety of urban residents and properties. Wargame simulation research on resident emergency evacuation from waterlogged areas can determine the effectiveness of emergency response plans for high risk events at low cost. Based on wargame theory and emergency evacuation plans, we used a wargame exercise method, incorporating qualitative and quantitative aspects, to build an urban waterlogging disaster emergency shelter using a wargame exercise and evaluation model. The simulation was empirically tested in Daoli District of Harbin. The results showed that the wargame simulation scored 96.40 points, evaluated as good. From the simulation results, wargame simulation of urban waterlogging emergency procedures for disaster response can improve the flexibility and capacity for command, management and decision-making in emergency management departments. PMID- 28009806 TI - The Relationship between Multiple Substance Use, Perceived Academic Achievements, and Selected Socio-Demographic Factors in a Polish Adolescent Sample. AB - Predictors of high-risk patterns of substance use are often analysed in relation to demographic and school-related factors. The interaction between these factors and the additional impact of family wealth are still new areas of research. The aim of this study was to find determinants of the most common patterns of psychoactive substance use in mid-adolescence, compared to non-users. A sample of 1202 Polish students (46.1% boys, mean age of 15.6 years) was surveyed in 2013/2014. Four patterns of psychoactive substance use were defined using cluster analysis: non-users-71.9%, mainly tobacco and alcohol users-13.7%, high alcohol and cannabis users-7.2%, poly-users-7.2%. The final model contained the main effects of gender and age, and one three-way (perceived academic achievement * gender * family affluence) interaction. Girls with poor perception of school performance (as compared to girls with better achievements) were at significantly higher risk of being poly-users, in both less and more affluent families (adjusted odds ratio (OR) = 5.55 and OR = 3.60, respectively). The impact of family affluence was revealed only in interaction with other factors. Patterns of substance use in mid-adolescence are strongly related to perceived academic achievements, and these interact with selected socio-demographic factors. PMID- 28009807 TI - Social Disparities in Exposure to Point-of-Sale Cigarette Marketing. AB - While most ecological studies have shown that higher levels of point-of-sale (POS) cigarette marketing are associated with larger proportions of residents from lower socioeconomic and minority backgrounds in neighborhoods, there are no studies that examine individual-level social disparities in exposure to POS cigarette marketing among smokers in the United States. Our aim was to examine these disparities in a Midwestern metropolitan area in the United States. We conducted a telephone survey to collect data on 999 smokers. Cigarette marketing was measured by asking respondents three questions about noticing advertisements, promotions, and displays of cigarettes within their respective neighborhoods. The questions were combined to create a summated scale. We estimated ordered logistic regression models to examine the association of sociodemographic variables with exposure to POS cigarette marketing. Adjusted results showed that having a lower income (p < 0.003) and belonging to a race/ethnicity other than "non-Hispanic White" (p = 0.011) were associated with higher levels of exposure to POS cigarette marketing. The results highlight social disparities in exposure to POS cigarette marketing in the United States, which can potentially be eliminated by banning all forms of cigarette marketing. PMID- 28009808 TI - Evaluation of the Treatment Process of Landfill Leachate Using the Toxicity Assessment Method. AB - Landfill leachate is composed of a complex composition with strong biological toxicity. The combined treatment process of coagulation and sedimentation, anaerobics, electrolysis, and aerobics was set up to treat landfill leachate. This paper explores the effect of different operational parameters of coagulation and sedimentation tanks and electrolytic cells, while investigating the combined process for the removal efficiency of physicochemical indices after processing the landfill leachate. Meanwhile, a battery of toxicity tests with Vibrio fischeri, zebrafish larvae, and embryos were conducted to evaluate acute toxicity and calculated the toxicity reduction efficiency after each treatment process. The combined treatment process resulted in a 100% removal efficiency of Cu, Cd and Zn, and a 93.50% and an 87.44% removal efficiency of Ni and Cr, respectively. The overall removal efficiency of chemical oxygen demand (COD), ammonium nitrogen (NH4+-N), and total nitrogen (TN) were 93.57%, 97.46% and 73.60%, respectively. In addition, toxicity test results showed that the acute toxicity of landfill leachate had also been reduced significantly: toxicity units (TU) decreased from 84.75 to 12.00 for zebrafish larvae, from 82.64 to 10.55 for zebrafish embryos, and from 3.41 to 0.63 for Vibrio fischeri. The combined treatment process was proved to be an efficient treatment method to remove heavy metals, COD, NH4+-N, and acute bio-toxicity of landfill leachate. PMID- 28009809 TI - Dietary Fiber Analysis of Four Pulses Using AOAC 2011.25: Implications for Human Health. AB - Chickpeas, common beans, dry peas, and lentils are pulse crops that have been a cornerstone of the human diet since the inception of agriculture. However, the displacement of pulses from the diet by low fiber protein alternatives has resulted in a pervasive deficiency referred to as the dietary fiber gap. Using an analytical method American Association of Analytical Chemists (AOAC) 2011.25 that conforms to the Codex Alimentarius Commission consensus definition for dietary fiber, the fiber content of these pulse crops was evaluated in seed types used for commercial production. These pulse crops have 2 to 3 times more fiber per 100 g edible portion than other dietary staples. Moreover, there is marked variation in fiber content among cultivars of the same crop. We conclude that pulse crop consumption should be emphasized in efforts to close the dietary fiber gap. The substantial differences in fiber content among currently available cultivars within a crop can be used to further improve gains in fiber intake without the need to change dietary habits. This provides a rationale for cultivar-based food labeling. PMID- 28009810 TI - Low Prevalence of Vitamin D Insufficiency among Nepalese Infants Despite High Prevalence of Vitamin D Insufficiency among Their Mothers. AB - BACKGROUND: Describing vitamin D status and its predictors in various populations is important in order to target public health measures. OBJECTIVES: To describe the status and predictors of vitamin D status in healthy Nepalese mothers and infants. METHODS: 500 randomly selected Nepalese mother and infant pairs were included in a cross-sectional study. Plasma 25(OH)D concentrations were measured by LC-MS/MS and multiple linear regression analyses were used to identify predictors of vitamin D status. RESULTS: Among the infants, the prevalence of vitamin D insufficiency (25(OH)D <50 nmol/L) and deficiency (<30 nmol/L) were 3.6% and 0.6%, respectively, in contrast to 59.8% and 14.0% among their mothers. Infant 25(OH)D concentrations were negatively associated with infant age and positively associated with maternal vitamin D status and body mass index (BMI), explaining 22% of the variability in 25(OH)D concentration. Global solar radiation, maternal age and BMI predicted maternal 25(OH)D concentration, explaining 9.7% of its variability. CONCLUSION: Age and maternal vitamin D status are the main predictors of vitamin D status in infants in Bhaktapur, Nepal, who have adequate vitamin D status despite poor vitamin D status in their mothers. PMID- 28009811 TI - Association between Dietary Intakes of Nitrate and Nitrite and the Risk of Hypertension and Chronic Kidney Disease: Tehran Lipid and Glucose Study. AB - BACKGROUND AND AIM: The association of habitual intakes of dietary nitrate (NO3-) and nitrite (NO2-) with blood pressure and renal function is not clear. Here, we investigated a potential effect of dietary NO3- and NO2- on the occurrence of hypertension (HTN) and chronic kidney disease (CKD). METHODS: A total of 2799 Iranian adults aged >=20 years, participating in the Tehran Lipid and Glucose Study (TLGS), were included and followed for a median of 5.8 years. Dietary intakes of NO3- and NO2- were estimated using a semi-quantitative food frequency questionnaire. Demographics, anthropometrics, blood pressure and biochemical variables were evaluated at baseline and during follow-up examinations. To identify the odds ratio (OR) and 95% confidence interval (CI) of HTN and CKD across tertile categories of residual energy-adjusted NO3- and NO2- intakes, multivariate logistic regression models were used. RESULTS: Dietary intake of NO3 had no significant association with the risk of HTN or CKD. Compared to the lowest tertile category (median intake < 6.04 mg/day), the highest intake (median intake >= 12.7 mg/day) of dietary NO2- was accompanied with a significant reduced risk of HTN, in the fully adjusted model (OR = 0.58, 95% CI = 0.33-0.98; p for trend = 0.054). The highest compared to the lowest tertile of dietary NO2- was also accompanied with a reduced risk of CKD (OR = 0.50, 95% CI = 0.24-0.89, p for trend = 0.07). CONCLUSION: Our findings indicated that higher intakes of NO2- might be an independent dietary protective factor against the development of HTN and CKD, which are major risk factors for adverse cardiovascular events. PMID- 28009812 TI - Newborn Care in the Home and Health Facility: Formative Findings for Intervention Research in Cambodia. AB - Global coverage and scale up of interventions to reduce newborn mortality remains low, though progress has been achieved in improving newborn survival in many low income settings. An important factor in the success of newborn health interventions, and moving to scale, is appropriate design of community-based programs and strategies for local implementation. We report the results of formative research undertaken to inform the design of a newborn health intervention in Cambodia. Information was gathered on newborn care practices over a period of three months using multiple qualitative methods of data collection in the primary health facility and home setting. Analysis of the data indicated important gaps, both at home and facility level, between recommended newborn care practices and those typical in the study area. The results of this formative research have informed strategies for behavior change and improving referral of sick infants in the subsequent implementation study. Collection and dissemination of data on newborn care practices from settings such as these can contribute to efforts to advance survival, growth and development of newborns for intervention research, and for future newborn health programming. PMID- 28009814 TI - A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA. AB - About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro transcription of the patient's RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient's transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset. PMID- 28009813 TI - Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery. AB - Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro. The availability of human iPS cell-derived cells, particularly as an alternative for difficult-to-access tissues and organs, is increasing steadily; however, their use in the field of translational medicine remains challenging. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator with which to evaluate pharmacological and toxicological effects in both the preclinical and clinical settings. In general, during the preclinical stage of the drug development process, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. This review provides an overview of current strategies for human iPS cell-based drug discovery from the perspective of translational research, and discusses the importance of early consideration of clinically relevant biomarkers. PMID- 28009815 TI - The Impact of Body Image on the WTP Values for Reduced-Fat and Low-Salt Content Potato Chips among Obese and Non-Obese Consumers. AB - The aim of this study is to assess the influence of body image on consumers' willingness to pay (WTP) for potato chips carrying nutritional claims among obese and non-obese people. About 309 non-clinical individuals participated in a Real Choice Experiment. They were recruited by a company and grouped in: (i) non-obese with good body image; (ii) non-obese with body image dissatisfaction; (iii) obese with good body image; (iv) obese with body image dissatisfaction. Results indicate differences in consumers' willingness to pay among consumer groups. Body image dissatisfaction of normal people did not influence the WTP for healthier chips. Obese people with body image dissatisfaction were willing to pay more for healthier chips (i.e., low-salt content potato chips) than normal ones with body image dissatisfaction. Examining the role of knowledge in the light of how this could impact on body image is relevant to improve the health status of individuals and their diet. Knowledge about nutrition could improve the body image of obese people. PMID- 28009817 TI - Topological Path Planning in GPS Trajectory Data. AB - This paper proposes a novel solution to the problem of computing a set of topologically inequivalent paths between two points in a space given a set of samples drawn from that space. Specifically, these paths are homotopy inequivalent where homotopy is a topological equivalence relation. This is achieved by computing a basis for the group of homology inequivalent loops in the space. An additional distinct element is then computed where this element corresponds to a loop which passes through the points in question. The set of paths is subsequently obtained by taking the orbit of this element acted on by the group of homology inequivalent loops. Using a number of spaces, including a street network where the samples are GPS trajectories, the proposed method is demonstrated to accurately compute a set of homotopy inequivalent paths. The applications of this method include path and coverage planning. PMID- 28009816 TI - The New Role for an Old Kinase: Protein Kinase CK2 Regulates Metal Ion Transport. AB - The pleiotropic serine/threonine protein kinase CK2 was the first kinase discovered. It is renowned for its role in cell proliferation and anti-apoptosis. The complexity of this kinase is well reflected by the findings of past decades in terms of its heterotetrameric structure, subcellular location, constitutive activity and the extensive catalogue of substrates. With the advent of non-biased high-throughput functional genomics such as genome-wide deletion mutant screening, novel aspects of CK2 functionality have been revealed. Our recent discoveries using the model organism Saccharomyces cerevisiae and mammalian cells demonstrate that CK2 regulates metal toxicity. Extensive literature search reveals that there are few but elegant works on the role of CK2 in regulating the sodium and zinc channels. As both CK2 and metal ions are key players in cell biology and oncogenesis, understanding the details of CK2's regulation of metal ion homeostasis has a direct bearing on cancer research. In this review, we aim to garner the recent data and gain insights into the role of CK2 in metal ion transport. PMID- 28009818 TI - Semantic Agent-Based Service Middleware and Simulation for Smart Cities. AB - With the development of Machine-to-Machine (M2M) technology, a variety of embedded and mobile devices is integrated to interact via the platform of the Internet of Things, especially in the domain of smart cities. One of the primary challenges is that selecting the appropriate services or service combination for upper layer applications is hard, which is due to the absence of a unified semantical service description pattern, as well as the service selection mechanism. In this paper, we define a semantic service representation model from four key properties: Capability (C), Deployment (D), Resource (R) and IOData (IO). Based on this model, an agent-based middleware is built to support semantic service enablement. In this middleware, we present an efficient semantic service discovery and matching approach for a service combination process, which calculates the semantic similarity between services, and a heuristic algorithm to search the service candidates for a specific service request. Based on this design, we propose a simulation of virtual urban fire fighting, and the experimental results manifest the feasibility and efficiency of our design. PMID- 28009819 TI - A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network. AB - Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI) performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI) threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance. PMID- 28009820 TI - Development and Validation of a UAV Based System for Air Pollution Measurements. AB - Air quality data collection near pollution sources is difficult, particularly when sites are complex, have physical barriers, or are themselves moving. Small Unmanned Aerial Vehicles (UAVs) offer new approaches to air pollution and atmospheric studies. However, there are a number of critical design decisions which need to be made to enable representative data collection, in particular the location of the air sampler or air sensor intake. The aim of this research was to establish the best mounting point for four gas sensors and a Particle Number Concentration (PNC) monitor, onboard a hexacopter, so to develop a UAV system capable of measuring point source emissions. The research included two different tests: (1) evaluate the air flow behavior of a hexacopter, its downwash and upwash effect, by measuring air speed along three axes to determine the location where the sensors should be mounted; (2) evaluate the use of gas sensors for CO2, CO, NO2 and NO, and the PNC monitor (DISCmini) to assess the efficiency and performance of the UAV based system by measuring emissions from a diesel engine. The air speed behavior map produced by test 1 shows the best mounting point for the sensors to be alongside the UAV. This position is less affected by the propeller downwash effect. Test 2 results demonstrated that the UAV propellers cause a dispersion effect shown by the decrease of gas and PN concentration measured in real time. A Linear Regression model was used to estimate how the sensor position, relative to the UAV center, affects pollutant concentration measurements when the propellers are turned on. This research establishes guidelines on how to develop a UAV system to measure point source emissions. Such research should be undertaken before any UAV system is developed for real world data collection. PMID- 28009822 TI - Pain Neuroscience Education: State of the Art and Application in Pediatrics. AB - Chronic pain is a widespread problem in the field of pediatrics. Many interventions to ameliorate pain-related dysfunction have a biobehavioral focus. As treatments for chronic pain (e.g., increased movement) often stand in stark contrast to treatments for an acute injury (e.g., rest), providing a solid rationale for treatment is necessary to gain patient and parent buy-in. Most pain treatment interventions incorporate psychoeducation, or pain neuroscience education (PNE), as an essential component, and in some cases, as a stand-alone approach. The current topical review focuses on the state of pain neuroscience education and its application to pediatric chronic pain. As very little research has examined pain neuroscience education in pediatrics, we aim to describe this emerging area and catalyze further work on this important topic. As the present literature has generally focused on adults with chronic pain, pain neuroscience education merits further attention in the realm of pediatric pain in order to be tailored and implemented in this population. PMID- 28009821 TI - Insights into Adenovirus Uncoating from Interactions with Integrins and Mediators of Host Immunity. AB - Human adenoviruses are large (150 MDa) nonenveloped double-stranded DNA (dsDNA) viruses that cause acute respiratory, gastrointestinal and ocular infections. Despite these disease associations, adenovirus has aided basic and clinical research efforts through studies of its association with cells and as a target of host antiviral responses. This review highlights the knowledge of adenovirus disassembly and nuclear transport gleaned from structural, biophysical and functional analyses of adenovirus interactions with soluble and membrane associated host molecules. PMID- 28009823 TI - Acute Diarrhoea in Children: Determination of Duration Using a Combined Bismuth Hydroxide Gel and Oral Rehydration Solution Therapy vs. Oral Rehydration Solution. AB - Oral rehydration salt (ORS) treatment in young children with acute diarrhoea (AD) has contributed to decrease mortality associated with dehydration although effective strategies to reduce morbidity associated with this disease are required. The aim of this study was to evaluate the diarrhoea duration when using combined colloidal bismuth hydroxide gel (CBHG) and oral rehydration salt treatment compared with ORS therapy in children with AD. We designed a double blind, randomised prospective study with treatment and control groups. Patients aged one to 12 years, with no prior pathology and with AD of less than 48 h were included. The Chi-squared and Mann-Whitney tests were used, as well as the Cox proportional hazards model and the Kaplan-Meier estimator. Patients were randomised into an ORS and CBHG treatment group and a control group for ORS plus placebo. (Average age: 3.2 years). The result of the post-treatment evaluation with respect to the average duration of AD was 25.5 h for the treated group vs. 41.5 h for the control group (p = 0.015). The average number of stools was 4.8 in the treated group and 8.2 in the control group (p = 0.032). We conclude that the use of CBHG plus ORS significantly reduced the duration of AD, the number of stools and the percentage of children with persistent AD after 24 h of treatment compared to the control group. AD remitted almost twice as fast in patients treated with CBHG and ORS compared to those who received ORS plus placebo. PMID- 28009824 TI - Chitosan Oligosaccharide Reduces Propofol Requirements and Propofol-Related Side Effects. AB - Propofol is one of the main sedatives but its negative side effects limit its clinical application. Chitosan oligosaccharide (COS), a kind of natural product with anti-pain and anti-inflammatory activities, may be a potential adjuvant to propofol use. A total of 94 patients receiving surgeries were evenly and randomly assigned to two groups: 10 mg/kg COS oral administration and/or placebo oral administration before being injected with propofol. The target-controlled infusion of propofol was adjusted to maintain the values of the bispectral index at 50. All patients' pain was evaluated on a four-point scale and side effects were investigated. To explore the molecular mechanism for the functions of COS in propofol use, a mouse pain model was established. The activities of Nav1.7 were analyzed in dorsal root ganglia (DRG) cells. The results showed that the patients receiving COS pretreatment were likely to require less propofol than the patients pretreated with placebo for maintaining an anesthetic situation (p < 0.05). The degrees of injection pain were lower in a COS-pretreated group than in a propofol pretreated group. The side effects were also more reduced in a COS-treated group than in a placebo-pretreated group. COS reduced the activity of Nav1.7 and its inhibitory function was lost when Nav1.7 was silenced (p > 0.05). COS improved propofol performance by affecting Nav1.7 activity. Thus, COS is a potential adjuvant to propofol use in surgical anesthesia. PMID- 28009825 TI - Neuropeptide Y1 Receptor Regulates Glucocorticoid-Induced Inhibition of Osteoblast Differentiation in Murine MC3T3-E1 Cells via ERK Signaling. AB - High dose glucocorticoid (GC) administration impairs the viability and function of osteoblasts, thus causing osteoporosis and osteonecrosis. Neuropeptide Y1 receptor (Y1 receptor) is expressed in bone tissues and cells, and regulates bone remodeling. However, the role of Y1 receptor in glucocorticoid-induced inhibition of osteoblast differentiation remains unknown. In the present study, osteoblastic cell line MC3T3-E1 cultured in osteogenic differentiation medium was treated with or without of 10-7 M dexamethasone (Dex), Y1 receptor shRNA interference, Y1 receptor agonist [Leu31, Pro34]-NPY, and antagonist BIBP3226. Cell proliferation and apoptosis were assessed by cell counting kit-8 (CCK-8) assay and cleaved caspase expression, respectively. Osteoblast differentiation was evaluated by Alizarin Red S staining and osteogenic marker gene expressions. Protein expression was detected by Western blot analysis. Dex upregulated the expression of Y1 receptor in MC3T3-E1 cells associated with reduced osteogenic gene expressions and mineralization. Blockade of Y1 receptor by shRNA transfection and BIBP3226 significantly attenuated the inhibitory effects of Dex on osteoblastic activity. Y1 receptor signaling modulated the activation of extracellular signal regulated kinases (ERK) as well as the expressions of osteogenic genes. Y1 receptor agonist inhibited ERK phosphorylation and osteoblast differentiation, while Y1 receptor blockade exhibited the opposite effects. Activation of ERK signaling by constitutive active mutant of MEK1 (caMEK) abolished Y1 receptor mediated Dex inhibition of osteoblast differentiation in MC3T3-E1 cells. Taken together, Y1 receptor regulates Dex-induced inhibition of osteoblast differentiation in murine MC3T3-E1 cells via ERK signaling. This study provides a novel role of Y1 receptor in the process of GC-induced suppression in osteoblast survival and differentiation. PMID- 28009826 TI - Using "Functional" Target Coordinates of the Subthalamic Nucleus to Assess the Indirect and Direct Methods of the Preoperative Planning: Do the Anatomical and Functional Targets Coincide? AB - OBJECTIVE: To answer the question of whether the anatomical center of the subthalamic nucleus (STN), as calculated indirectly from stereotactic atlases or by direct visualization on magnetic resonance imaging (MRI), corresponds to the best functional target. Since the neighboring red nucleus (RN) is well visualized on MRI, we studied the relationships of the final target to its different borders. METHODS: We analyzed the data of 23 PD patients (46 targets) who underwent bilateral frame-based STN deep brain stimulation (DBS) procedure with microelectrode recording guidance. We calculated coordinates of the active contact on DBS electrode on postoperative MRI, which we referred to as the final "functional/optimal" target. The coordinates calculated by the atlas-based "indirect" and "direct" methods, as well as the coordinates of the different RN borders were compared to these final coordinates. RESULTS: The mean +/- SD of the final target coordinates was 11.7 +/- 1.5 mm lateral (X), 2.4 +/- 1.5 mm posterior (Y), and 6.1 +/- 1.7 mm inferior to the mid-commissural point (Z). No significant differences were found between the "indirect" X, Z coordinates and those of the final targets. The "indirect" Y coordinate was significantly posterior to Y of the final target, with mean difference of 0.6 mm (p = 0.014). No significant differences were found between the "direct" X, Y, and Z coordinates and those of the final targets. CONCLUSIONS: The functional STN target is located in direct proximity to its anatomical center. During preoperative targeting, we recommend using the "direct" method, and taking into consideration the relationships of the final target to the mid-commissural point (MCP) and the different RN borders. PMID- 28009827 TI - Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen Antioxidant Mutual Prodrugs. AB - Dexibuprofen-antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a-c were obtained by reacting its -COOH group with chloroacetyl derivatives 3a-c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a-c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a-c interacts with the residues present in active binding sites of target protein. The stability of drug-target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug. PMID- 28009828 TI - The Causes and Consequences of Topological Stress during DNA Replication. AB - The faithful replication of sister chromatids is essential for genomic integrity in every cell division. The replication machinery must overcome numerous difficulties in every round of replication, including DNA topological stress. Topological stress arises due to the double-stranded helical nature of DNA. When the strands are pulled apart for replication to occur, the intertwining of the double helix must also be resolved or topological stress will arise. This intrinsic problem is exacerbated by specific chromosomal contexts encountered during DNA replication. The convergence of two replicons during termination, the presence of stable protein-DNA complexes and active transcription can all lead to topological stresses being imposed upon DNA replication. Here we describe how replication forks respond to topological stress by replication fork rotation and fork reversal. We also discuss the genomic contexts where topological stress is likely to occur in eukaryotes, focusing on the contribution of transcription. Finally, we describe how topological stress, and the ways forks respond to it, may contribute to genomic instability in cells. PMID- 28009829 TI - Evaluation of Extrusion Technique for Nanosizing Liposomes. AB - The aim of the present study was to study the efficiency of different techniques used for nanosizing liposomes. Further, the aim was also to evaluate the effect of process parameters of extrusion techniques used for nanosizing liposomes on the size and size distribution of the resultant liposomes. To compare the efficiency of different nanosizing techniques, the following techniques were used to nanosize the liposomes: extrusion, ultrasonication, freeze-thaw sonication (FTS), sonication and homogenization. The extrusion technique was found to be the most efficient, followed by FTS, ultrasonication, sonication and homogenization. The extruder used in the present study was fabricated using readily available and relatively inexpensive apparatus. Process parameters were varied in extrusion technique to study their effect on the size and size distribution of extruded liposomes. The results obtained indicated that increase in the flow rate of the extrusion process decreased the size of extruded liposomes however the size homogeneity was negatively impacted. Furthermore, the liposome size and distribution was found to decline with decreasing membrane pore size. It was found that by extruding through a filter with a pore size of 0.2 um and above, the liposomes produced were smaller than the pore size, whereas, when they were extruded through a filter with a pore size of less than 0.2 um the resultant liposomes were slightly bigger than the nominal pore size. Besides that, increment of extrusion temperature above transition temperature of the pro liposome had no effect on the size and size distribution of the extruded liposomes. In conclusion, the extrusion technique was reproducible and effective among all the methods evaluated. Furthermore, processing parameters used in extrusion technique would affect the size and size distribution of liposomes. Therefore, the process parameters need to be optimized to obtain a desirable size range and homogeneity, reproducible for various in vivo applications. PMID- 28009831 TI - Diverse Planning for UAV Control and Remote Sensing. AB - Unmanned aerial vehicles (UAVs) are suited to various remote sensing missions, such as measuring air quality. The conventional method of UAV control is by human operators. Such an approach is limited by the ability of cooperation among the operators controlling larger fleets of UAVs in a shared area. The remedy for this is to increase autonomy of the UAVs in planning their trajectories by considering other UAVs and their plans. To provide such improvement in autonomy, we need better algorithms for generating alternative trajectory variants that the UAV coordination algorithms can utilize. In this article, we define a novel family of multi-UAV sensing problems, solving task allocation of huge number of tasks (tens of thousands) to a group of configurable UAVs with non-zero weight of equipped sensors (comprising the air quality measurement as well) together with two base line solvers. To solve the problem efficiently, we use an algorithm for diverse trajectory generation and integrate it with a solver for the multi-UAV coordination problem. Finally, we experimentally evaluate the multi-UAV sensing problem solver. The evaluation is done on synthetic and real-world-inspired benchmarks in a multi-UAV simulator. Results show that diverse planning is a valuable method for remote sensing applications containing multiple UAVs. PMID- 28009833 TI - Natural History of Asymptomatic and Unrepaired Vascular Rings: Is Watchful Waiting a Viable Option? A New Case and Review of Previously Reported Cases. AB - Vascular rings are a rare form of congenital heart disease in which abnormal aortic arch anatomy leads to encircling of the esophagus and/or trachea by the aortic vasculature. Symptoms can develop from this and prompt the need for surgery. A natural history study has been done on mildly symptomatic patients but no such study has been done on asymptomatic patients. We present a case report of three children with asymptomatic vascular rings who continue to receive follow-up without intervention and review all published cases of asymptomatic or unrepaired vascular rings. Clinical observation of asymptomatic and mildly symptomatic vascular rings, regardless of aortic arch anatomy, seems to be a safe approach. Children with mild symptoms almost invariably seem to have resolution of their symptoms by four years of age. PMID- 28009830 TI - A Brief History of Research on Mitotic Mechanisms. AB - This chapter describes in summary form some of the most important research on chromosome segregation, from the discovery and naming of mitosis in the nineteenth century until around 1990. It gives both historical and scientific background for the nine chapters that follow, each of which provides an up-to date review of a specific aspect of mitotic mechanism. Here, we trace the fruits of each new technology that allowed a deeper understanding of mitosis and its underlying mechanisms. We describe how light microscopy, including phase, polarization, and fluorescence optics, provided descriptive information about mitotic events and also enabled important experimentation on mitotic functions, such as the dynamics of spindle fibers and the forces generated for chromosome movement. We describe studies by electron microscopy, including quantitative work with serial section reconstructions. We review early results from spindle biochemistry and genetics, coupled to molecular biology, as these methods allowed scholars to identify key molecular components of mitotic mechanisms. We also review hypotheses about mitotic mechanisms whose testing led to a deeper understanding of this fundamental biological event. Our goal is to provide modern scientists with an appreciation of the work that has laid the foundations for their current work and interests. PMID- 28009834 TI - Secure and Efficient Key Coordination Algorithm for Line Topology Network Maintenance for Use in Maritime Wireless Sensor Networks. AB - There has been a significant increase in the proliferation and implementation of Wireless Sensor Networks (WSNs) in different disciplines, including the monitoring of maritime environments, healthcare systems, and industrial sectors. It has now become critical to address the security issues of data communication while considering sensor node constraints. There are many proposed schemes, including the scheme being proposed in this paper, to ensure that there is a high level of security in WSNs. This paper presents a symmetric security scheme for a maritime coastal environment monitoring WSN. The scheme provides security for travelling packets via individually encrypted links between authenticated neighbors, thus avoiding a reiteration of a global rekeying process. Furthermore, this scheme proposes a dynamic update key based on a trusted node configuration, called a leader node, which works as a trusted third party. The technique has been implemented in real time on a Waspmote test bed sensor platform and the results from both field testing and indoor bench testing environments are discussed in this paper. PMID- 28009832 TI - NMR Studies of the Structure and Function of the HIV-1 5'-Leader. AB - The 5'-leader of the human immunodeficiency virus type 1 (HIV-1) genome plays several critical roles during viral replication, including differentially establishing mRNA versus genomic RNA (gRNA) fates. As observed for proteins, the function of the RNA is tightly regulated by its structure, and a common paradigm has been that genome function is temporally modulated by structural changes in the 5'-leader. Over the past 30 years, combinations of nucleotide reactivity mapping experiments with biochemistry, mutagenesis, and phylogenetic studies have provided clues regarding the secondary structures of stretches of residues within the leader that adopt functionally discrete domains. More recently, nuclear magnetic resonance (NMR) spectroscopy approaches have been developed that enable direct detection of intra- and inter-molecular interactions within the intact leader, providing detailed insights into the structural determinants and mechanisms that regulate HIV-1 genome packaging and function. PMID- 28009835 TI - Smart Device-Supported BDS/GNSS Real-Time Kinematic Positioning for Sub-Meter Level Accuracy in Urban Location-Based Services. AB - Using mobile smart devices to provide urban location-based services (LBS) with sub-meter-level accuracy (around 0.5 m) is a major application field for future global navigation satellite system (GNSS) development. Real-time kinematic (RTK) positioning, which is a widely used GNSS-based positioning approach, can improve the accuracy from about 10-20 m (achieved by the standard positioning services) to about 3-5 cm based on the geodetic receivers. In using the smart devices to achieve positioning with sub-meter-level accuracy, a feasible solution of combining the low-cost GNSS module and the smart device is proposed in this work and a user-side GNSS RTK positioning software was developed from scratch based on the Android platform. Its real-time positioning performance was validated by BeiDou Navigation Satellite System/Global Positioning System (BDS/GPS) combined RTK positioning under the conditions of a static and kinematic (the velocity of the rover was 50-80 km/h) mode in a real urban environment with a SAMSUNG Galaxy A7 smartphone. The results show that the fixed-rates of ambiguity resolution (the proportion of epochs of ambiguities fixed) for BDS/GPS combined RTK in the static and kinematic tests were about 97% and 90%, respectively, and the average positioning accuracies (RMS) were better than 0.15 m (horizontal) and 0.25 m (vertical) for the static test, and 0.30 m (horizontal) and 0.45 m (vertical) for the kinematic test. PMID- 28009837 TI - Recent Advances in Olefin Metathesis. AB - Olefin metathesis is one of the most significant developments of the last 20 years in the fields of organic chemistry, polymers synthesis, and materials science [1-7]. [...]. PMID- 28009836 TI - Metabolomics with Nuclear Magnetic Resonance Spectroscopy in a Drosophila melanogaster Model of Surviving Sepsis. AB - Patients surviving sepsis demonstrate sustained inflammation, which has been associated with long-term complications. One of the main mechanisms behind sustained inflammation is a metabolic switch in parenchymal and immune cells, thus understanding metabolic alterations after sepsis may provide important insights to the pathophysiology of sepsis recovery. In this study, we explored metabolomics in a novel Drosophila melanogaster model of surviving sepsis using Nuclear Magnetic Resonance (NMR), to determine metabolite profiles. We used a model of percutaneous infection in Drosophila melanogaster to mimic sepsis. We had three experimental groups: sepsis survivors (infected with Staphylococcus aureus and treated with oral linezolid), sham (pricked with an aseptic needle), and unmanipulated (positive control). We performed metabolic measurements seven days after sepsis. We then implemented metabolites detected in NMR spectra into the MetExplore web server in order to identify the metabolic pathway alterations in sepsis surviving Drosophila. Our NMR metabolomic approach in a Drosophila model of recovery from sepsis clearly distinguished between all three groups and showed two different metabolomic signatures of inflammation. Sham flies had decreased levels of maltose, alanine, and glutamine, while their level of choline was increased. Sepsis survivors had a metabolic signature characterized by decreased glucose, maltose, tyrosine, beta-alanine, acetate, glutamine, and succinate. PMID- 28009838 TI - Modeling Driver Behavior near Intersections in Hidden Markov Model. AB - Intersections are one of the major locations where safety is a big concern to drivers. Inappropriate driver behaviors in response to frequent changes when approaching intersections often lead to intersection-related crashes or collisions. Thus to better understand driver behaviors at intersections, especially in the dilemma zone, a Hidden Markov Model (HMM) is utilized in this study. With the discrete data processing, the observed dynamic data of vehicles are used for the inference of the Hidden Markov Model. The Baum-Welch (B-W) estimation algorithm is applied to calculate the vehicle state transition probability matrix and the observation probability matrix. When combined with the Forward algorithm, the most likely state of the driver can be obtained. Thus the model can be used to measure the stability and risk of driver behavior. It is found that drivers' behaviors in the dilemma zone are of lower stability and higher risk compared with those in other regions around intersections. In addition to the B-W estimation algorithm, the Viterbi Algorithm is utilized to predict the potential dangers of vehicles. The results can be applied to driving assistance systems to warn drivers to avoid possible accidents. PMID- 28009839 TI - Parental Perceptions of the Social Environment Are Inversely Related to Constraint of Adolescents' Neighborhood Physical Activity. AB - BACKGROUND: The current study examined relationships between the neighborhood social environment (parental perceived collective efficacy (PCE)), constrained behaviors (e.g., avoidance or defensive behaviors) and adolescent offspring neighborhood physical activity in low- versus high-incivility neighborhoods. METHODS: Adolescents (n = 71; 11-18 years (14.2, SD +/- 1.6); male = 37 (52%); non-white = 24 (33.8%); low-income = 20 (29%); overweight/obese = 40 (56%)) and their parents/guardians enrolled in the Molecular and Social Determinants of Obesity in Developing Youth study were included in the current study. Questionnaires measured parents'/guardians' PCE, constrained outdoor play practices and offspring neighborhood physical activity. Systematic social observation performed at the parcel-level using Google Street View assessed neighborhood incivilities. t-tests and chi-square tests determined differences by incivilities. Multilevel regression models examined relationships between PCE and: (1) constrained behaviors; and (2) neighborhood physical activity. The Hayes (2013) macro determined the mediating role of constrained behaviors. RESULTS: Parents who had higher PCE reported lower levels of avoidance (p = 0.04) and defensive (p = 0.05) behaviors. However, demographic variables (i.e., gender, race and annual household income) limited these results. The direct relationship between PCE and parent-reported neighborhood physical activity was statistically significant in high-incivility neighborhoods only. Neither avoidance nor defensive behavior mediated the relationship between PCE and neighborhood physical activity. CONCLUSIONS: PCE influences parenting behaviors related to youth physical activity. Community-based programs that seek to facilitate social cohesion and control may be needed to increase adolescents' physical activity. PMID- 28009840 TI - Hypervalent Iodine(III)-Induced Domino Oxidative Cyclization for the Synthesis of Cyclopenta[b]furans. AB - A new strategy for cyclopenta[b]furan synthesis mediated by hypervalent iodine(III) has been described. The approach employs diacetoxyiodobenzene-induced initial dehydrogenation to a putative trienone intermediate and triggered sequential cycloisomerization to form the cyclo-penta[b]furan targets. PMID- 28009841 TI - Use of Cellular Decapping Activators by Positive-Strand RNA Viruses. AB - Positive-strand RNA viruses have evolved multiple strategies to not only circumvent the hostile decay machinery but to trick it into being a priceless collaborator supporting viral RNA translation and replication. In this review, we describe the versatile interaction of positive-strand RNA viruses and the 5'-3' mRNA decay machinery with a focus on the viral subversion of decapping activators. This highly conserved viral trickery is exemplified with the plant Brome mosaic virus, the animal Flock house virus and the human hepatitis C virus. PMID- 28009842 TI - Sulfur Atom in its Bound State Is a Unique Element Involved in Physiological Functions in Mammals. AB - It was in the 1950s that the term polysulfide or persulfide was introduced in biological studies. The unfamiliar term "sulfane sulfur" sometimes appeared in papers published in the 1970s, and was defined in the review article by Westley in 1983. In the article, sulfane sulfur is described as sulfur atoms that are covalently bound only with sulfur atoms, and as this explanation was somewhat difficult to comprehend, it was not generally accepted. Thus, in the early 1990s, we redefined these sulfur species as "bound sulfur", which easily converts to hydrogen sulfide on reduction with a thiol reducing agent. In other words, bound sulfur refers to a sulfur atom that exists in a zero to divalent form (0 to -2). The first part of this review focuses on the fluorescent derivatization HPLC method-which we developed for measurement of bound sulfur-and explains the distribution of bound sulfur and the hydrogen sulfide-producing ability of various tissues, as clarified by this method. Next, we discuss diverse physiological functions and involvement of polysulfide, a typical type of bound sulfur, in the redox regulation system. Additionally, we also address its possible physiological role in the central nervous system, based on its action of scavenging reactive carbonyl compounds. PMID- 28009843 TI - Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage. AB - Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non melanoma skin cancer cells (NMSCC) and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II) compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2.5, 5.0 and 7.5 uM) for 24 h resulted in marked decrease in topoisomerase activity, which was associated with substantial DNA damage as detected by the comet assay. Cryptolepine induced DNA damage resulted in: (i) an increase in the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2 and gammaH2AX; (ii) activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii) downregulation of cyclin dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b) leading to cell cycle arrest at S-phase; and (iv) mitochondrial membrane potential was disrupted and cytochrome c released. These changes in NMSCC by cryptolepine resulted in significant reduction in cell viability, colony formation and increase in apoptotic cell death. PMID- 28009844 TI - An Ultrasensitive Long-Period Fiber Grating-Based Refractive Index Sensor with Long Wavelengths. AB - The response of a novel long-period fiber grating (LPFG) with a period of 180 um to a surrounding refractive index (RI) was investigated. The results displayed that, with the increase in RI of the surrounding media of cladding glass in the grating region, the resonant peak located at 1336.4 nm in the transmission spectrum gradually shifts towards a shorter wavelength, while the resonant peak located at 1618 nm gradually shifted towards a longer wavelength. Moreover, the resonant peak at 1618 nm is much more sensitive to the surrounding RI than that of the one at 1336.4 nm. Compared with the conventional LPFG and other types of wavelength-interrogated RI sensors, such as ring resonators, surface plasmon resonance sensors, and Fabry-Perot interferometric sensors, this novel LPFG possesses a higher sensitivity, which achieved 10,792.45 nm/RIU (RI unit) over a RI range of 1.4436-1.4489. PMID- 28009845 TI - Improvement of Depth Profiling into Biotissues Using Micro Electrical Impedance Spectroscopy on a Needle with Selective Passivation. AB - A micro electrical impedance spectroscopy (EIS)-on-a-needle for depth profiling (MUEoN-DP) with a selective passivation layer (SPL) on a hypodermic needle was recently fabricated to measure the electrical impedance of biotissues along with the penetration depths. The SPL of the MUEoN-DP enabled the sensing interdigitated electrodes (IDEs) to contribute predominantly to the measurement by reducing the relative influence of the connection lines on the sensor output. The discrimination capability of the MUEoN-DP was verified using phosphate buffered saline (PBS) at various concentration levels. The resistance and capacitance extracted through curve fitting were similar to those theoretically estimated based on the mixing ratio of PBS and deionized water; the maximum discrepancies were 8.02% and 1.85%, respectively. Depth profiling was conducted using four-layered porcine tissue to verify the effectiveness of the discrimination capability of the MUEoN-DP. The magnitude and phase between dissimilar porcine tissues (fat and muscle) were clearly discriminated at the optimal frequency of 1 MHz. Two kinds of simulations, one with SPL and the other with complete passivation layer (CPL), were performed, and it was verified that the SPL was advantageous over CPL in the discrimination of biotissues in terms of sensor output. PMID- 28009847 TI - New Iridoid Glucosides from Caryopteris incana (Thunb.) Miq. and Their alpha Glucosidase Inhibitory Activities. AB - In our continued investigations of the plant Caryopteris incana, five new iridoid glucosides 1-5, including two cis-trans-isomers, 3 and 4, along with six known compounds 6-11, were isolated from the n-butyl alcohol (n-BuOH) soluble fraction of whole dried material of Caryopteris incana. Their structures were established by a combination of spectroscopic techniques, including 1D and 2D NMR and high resolution electrospray ionization mass spectroscopy (HR-ESI-MS). Furthermore, all isolates were evaluated for their yeast alpha-glucosidase inhibitory effects. Among these compounds, 4-8 and 10 exhibited potent inhibition of alpha glucosidase. PMID- 28009846 TI - Polyphenol Composition, Antioxidant Activity and Cytotoxicity of Seeds from Two Underexploited Wild Licania Species: L. rigida and L. tomentosa. AB - Studies have shown the benefit of antioxidants in the prevention or treatment of human diseases and promoted a growing interest in new sources of plant antioxidants for pharmacological use. This study aimed to add value to two underexploited wild plant species (Licania rigida) and L. tomentosa) from Brazilian flora. Thus, the phenolic compounds profile of their seed ethanol extract and derived fractions were elucidated by HPLC, the antioxidant capacity was assessed by in vitro chemical tests and the cytotoxicity determined using the human carcinoma cell lines MCF-7 and Caco-2. Eleven phenolic compounds were identified in the extracts of each species. The extracts and fractions showed excellent antioxidant activity in the DPPH assay (SC50, ranging from 9.15 to 248.8 ug/mL). The aqueous fraction of L. rigida seeds was most effective in preventing lipid peroxidation under basal conditions (IC50 60.80 ug/mL) whereas, in the presence of stress inducer, the methanolic fraction of L. tomentosa performed best (IC50 8.55 ug/mL). None of the samples showed iron chelating capacity. Ethanolic seed extracts of both species did not reveal any cytotoxicity against MCF-7 and Caco-2 cells. Both plant species showed a promising phenolic profile with potent antioxidant capacity and deserve attention to be sustainably explored. PMID- 28009848 TI - Chemical Fingerprint Analysis and Quantitative Analysis of Rosa rugosa by UPLC DAD. AB - A method based on ultra performance liquid chromatography with a diode array detector (UPLC-DAD) was developed for quantitative analysis of five active compounds and chemical fingerprint analysis of Rosa rugosa. Ten batches of R. rugosa collected from different plantations in the Xinjiang region of China were used to establish the fingerprint. The feasibility and advantages of the used UPLC fingerprint were verified for its similarity evaluation by systematically comparing chromatograms with professional analytical software recommended by State Food and Drug Administration (SFDA) of China. In quantitative analysis, the five compounds showed good regression (R2 = 0.9995) within the test ranges, and the recovery of the method was in the range of 94.2%-103.8%. The similarities of liquid chromatography fingerprints of 10 batches of R. rugosa were more than 0.981. The developed UPLC fingerprint method is simple, reliable, and validated for the quality control and identification of R. rugosa. Additionally, simultaneous quantification of five major bioactive ingredients in the R. rugosa samples was conducted to interpret the consistency of the quality test. The results indicated that the UPLC fingerprint, as a characteristic distinguishing method combining similarity evaluation and quantification analysis, can be successfully used to assess the quality and to identify the authenticity of R. rugosa. PMID- 28009849 TI - Preventive Effects of Catechins on Cardiovascular Disease. AB - Catechins are polyphenolic phytochemicals with many important physiological activities that play a multifaceted health care function in the human body, especially in the prevention of cardiovascular disease. In this paper, various experimental and clinical studies have revealed the role of catechins in the prevention and treatment of cardiovascular disorders, and we review the preventive effects of catechins on cardiovascular disease from the following aspects: Regulating lipid metabolism, regulating blood lipid metabolism, vascular endothelial protection, and reducing blood pressure. PMID- 28009850 TI - What Contributes to the Regularity of Patients with Hypertension or Diabetes Seeking Health Services? A Pilot Follow-Up, Observational Study in Two Sites in Hubei Province, China. AB - Regular maintenance of non-communicable chronic diseases can constrain disease progression in diabetic and hypertensive patients. To identify the individual and social factors that are associated with positive health-seeking behaviors and regular maintenance of chronic diseases, we have conducted a follow up study in 2015 on diabetic and hypertensive patients in Hubei Province. We used binary logistic regression models to determine specific factors associated with diabetic and hypertensive patients that sought healthcare services for their conditions in accordance with current Chinese Centers for Disease Prevention and Control (CDC) guidelines. Our findings show that 42.16% of 510 people living with chronic conditions (PLCDs) sought health services in line with existing guidelines. Findings also show a higher probability (8.418 times) for PLCDs seeking healthcare services at higher-tiered hospitals (secondary and tertiary hospitals) than for PLCDs seeking care at primary hospitals (odds ratio (OR) = 8.418, 95% confidence interval (CI) = 4.82, 14.27, p < 0.001). These analyses underscore the importance of having patient advocates who can provide support, where necessary, and encourage positive health-seeking behavior. The study also shows a negative impact on regular maintenance for PLCDs in households with high financial constraints. In contrast, the study shows positive impacts for increased household income, age, and residency in rural locations. In sum, this study underscores the importance of primary hospitals as key points of care and critical players in care coordination for PLCDs. The study provides more evidence for Chinese policymakers seeking to contain costs and improve population health. The findings also underscore the need for community-based interventions, specifically interventions that link local primary hospitals, friends/family members, and PLCDs. PMID- 28009851 TI - Artificial Diets for Mosquitoes. AB - Mosquito-borne diseases are responsible for more than a million human deaths every year. Modern mosquito control strategies such as sterile insect technique (SIT), release of insects carrying a dominant lethal (RIDL), population replacement strategies (PR), and Wolbachia-based strategies require the rearing of large numbers of mosquitoes in culture for continuous release over an extended period of time. Anautogenous mosquitoes require essential nutrients for egg production, which they obtain through the acquisition and digestion of a protein rich blood meal. Therefore, mosquito mass production in laboratories and other facilities relies on vertebrate blood from live animal hosts. However, vertebrate blood is expensive to acquire and hard to store for longer times especially under field conditions. This review discusses older and recent studies that were aimed at the development of artificial diets for mosquitoes in order to replace vertebrate blood. PMID- 28009852 TI - Inhibition of Hypoxia-Induced Retinal Angiogenesis by Specnuezhenide, an Effective Constituent of Ligustrum lucidum Ait., through Suppression of the HIF 1alpha/VEGF Signaling Pathway. AB - Specnuezhenide (SPN), one of the main ingredients of Chinese medicine "Nu-zhen zi", has anti-angiogenic and vision improvement effects. However, studies of its effect on retinal neovascularization are limited so far. In the present study, we established a vascular endothelial growth factor A (VEGFA) secretion model of human acute retinal pigment epithelial-19 (ARPE-19) cells by exposure of 150 MUM CoCl2 to the cells and determined the VEGFA concentrations, the mRNA expressions of VEGFA, hypoxia inducible factor-1alpha (HIF-1alpha) & prolyl hydroxylases 2 (PHD-2), and the protein expressions of HIF-1alpha and PHD-2 after treatment of 3 (5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1, 1.0 MUg/mL) or SPN (0.2, 1.0 and 5.0 MUg/mL). Furthermore, rat pups with retinopathy were treated with SPN (5.0 and 10.0 mg/kg) in an 80% oxygen atmosphere and the retinal avascular areas were assessed through visualization using infusion of ADPase and H&E stains. The results showed that SPN inhibited VEGFA secretion by ARPE-19 cells under hypoxia condition, down-regulated the mRNA expressions of VEGFA and PHD-2 slightly, and the protein expressions of VEGFA, HIF-1alpha and PHD-2 significantly in vitro. SPN also prevented hypoxia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy in vivo. These results indicate that SPN ameliorates retinal neovascularization through inhibition of HIF-1alpha/VEGF signaling pathway. Therefore, SPN has the potential to be developed as an agent for the prevention and treatment of diabetic retinopathy. PMID- 28009854 TI - Ambulatory Assessment of Instantaneous Velocity during Walking Using Inertial Sensor Measurements. AB - A novel approach for estimating the instantaneous velocity of the pelvis during walking was developed based on Inertial Measurement Units (IMUs). The instantaneous velocity was modeled by the sum of a cyclical component, decomposed in the Medio-Lateral (ML), VerTical (VT) and Antero-Posterior (AP) directions, and the Average Progression Velocity (APV) over each gait cycle. The proposed method required the availability of two IMUs, attached to the pelvis and one shank. Gait cycles were identified from the shank angular velocity; for each cycle, the Fourier series coefficients of the pelvis and shank acceleration signals were computed. The cyclical component was estimated by Fourier-based time integration of the pelvis acceleration. A Bayesian Linear Regression (BLR) with Automatic Relevance Determination (ARD) predicted the APV from the stride time, the stance duration, and the Fourier series coefficients of the shank acceleration. Healthy subjects performed tasks of Treadmill Walking (TW) and Overground Walking (OW), and an optical motion capture system (OMCS) was used as reference for algorithm performance assessment. The widths of the limits of agreements (+/-1.96 standard deviation) were computed between the proposed method and the reference OMCS, yielding, for the cyclical component in the different directions: ML: +/-0.07 m/s (+/-0.10 m/s); VT: +/-0.03 m/s (+/-0.05 m/s); AP: +/ 0.06 m/s (+/-0.10 m/s), in TW (OW) conditions. The ARD-BLR achieved an APV root mean square error of 0.06 m/s (0.07 m/s) in the same conditions. PMID- 28009853 TI - Pharmacological Properties of Riparin IV in Models of Pain and Inflammation. AB - Riparins, natural alkaloids of the alkamide group, can be synthesized by simple methods, enhancing their potential application in pharmaceutical development. Here, the pharmacological properties of riparins were investigated in in vitro and in vivo assays of pain and inflammation in Swiss mice. Inflammatory mediators were measured by radioimmunoassay and Real-Time PCR. Riparins I, II, III and IV (1.56-100 mg/kg; ip) produced dose-related antinociceptive effects in the formalin test, exhibiting ED50 values of 22.93, 114.2, 31.05 and 6.63 mg/kg, respectively. Taking the greater potency as steering parameter, riparin IV was further investigated. Riparin IV did not produce antinociceptive effect on the tail flick, suggesting that its antinociception is not a centrally-mediated action. In fact, riparin IV (1.56-25 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on the complete Freund's adjuvant (CFA)-induced paw inflammation in mice. During CFA-induced inflammation, riparin IV did not modulate either the production of cytokines, TNF-alpha and IL-10, or COX-2 mRNA expression. On the other hand, riparin IV decreased the PGE2 levels in the inflamed paw. In in vitro assays, riparin IV did not exhibit suppressive activities in activated macrophages. These results indicate, for the first time, that riparin IV induces antinociceptive and anti-inflammatory effects, possibly through the inhibition of prostanoid production. PMID- 28009855 TI - Tetramethyl Pyrazine Protects Hippocampal Neurons Against Anoxia/Reoxygenation Injury Through Inhibiting Apoptosis Mediated by JNK/MARK Signal Pathway. AB - BACKGROUND Tetramethyl pyrazine (TMP) is a typical biologically active alkaloid isolated from the Chinese herb Ligusticum walliichi. It has been reported that TMP shows neuroprotective and stroke injury reductive properties in cerebral ischemia/reperfusion (I/R) animal models. In the present study we sought to investigate the effect and potential intervention mechanism of TMP in anoxia/reoxygenation (A/R) rat hippocampal neurons. MATERIAL AND METHODS After being cultured for 7 days, primary hippocampal neurons were randomly assigned into a normal control group (N), a TMP group (C: 0 ug/ml, L: 60 ug/ml, M: 200ug/ml and H: 800 ug/ml), and a JNK inhibitor group (S: SP600125, 10 MUmol/L). A hypoxia/reoxygenation model were prepared 1 h after incubation. Hippocampal neurons were incubated in 90% N2 and 10% CO2 for 2 h, and then reoxygenated for 24 h in an incubator with 5%CO2 at the temperature of 37 degrees C. The apoptosis rate, MKK4 and MKK7 mRNA and JNK kinase protein levels (C-fos, c-jun, and P-JNK) of hippocampal neurons were detected. RESULTS The apoptosis rates of hippocampal neurons induced by A/R showed significant reduction after being pre-treated with JNK inhibitor, TMP 60 ug/ml, 200 ug/ml, and 800 ug/ml. The JNK kinase MKK4mRNA and MKK7mRNA levels, as well as the expressions of C-fos, C-jun, and P-JNK protein levels, were also be reduced. CONCLUSIONS TMP may produce a protective effect in anoxia/reoxygenation-induced primary hippocampal neuronal injury by inhibiting the apoptosis of the hippocampal neurons; the possible mechanism may be inhibition of the JNK signal pathway. PMID- 28009856 TI - Dynamics and thermodynamics of the coronene octamer described by coarse-grained potentials. AB - Coarse-grained models developed for polycyclic aromatic hydrocarbons based on the Paramonov-Yaliraki potential have been employed to investigate the finite temperature thermodynamics, out-of-equilibrium dynamics, energy landscapes, and rearrangement pathways of the coronene octamer. Molecular dynamics simulations are used to address the short-time behaviour, diffusion properties, convergence to equilibrium, and dissociation kinetics. A kinetic transition network composed of a connected database of stationary points provides a consistent picture of the complex potential and free energy landscapes, and enables us to describe rearrangements occurring over long time scales and associated thermal properties. Comparison with reference simulations performed with an all-atom description, indicates satisfactory agreement at moderate energies, especially when quadrupole corrections to the intermolecular potential are included. At higher energies, unimolecular evaporation rates are particularly well reproduced by the coarse grained model. The potential energy landscapes exhibit multiple funnels for all the models, with alternative columnar arrangements competing at low energy. Entropy-driven structural transitions are predicted to involve largely cooperative motion, with entire stacks shifting and rotating around one another. These structural transitions, which were not characterised in earlier parallel tempering Monte Carlo simulations, are well represented by the coarse-grained models, with similar barrier heights but fewer steps. PMID- 28009857 TI - Highly active MoS2/carbon electrocatalysts for the hydrogen evolution reaction - insight into the effect of the internal resistance and roughness factor on the Tafel slope. AB - Molybdenum disulphide (MoS2) nanomaterials are promising non-precious-metal electrocatalysts for the hydrogen evolution reaction. MoS2/carbon electrocatalysts have been synthesized with the carbon component serving the purpose of enhancing electron transport. The impedance method of Tafel analysis has been employed to evaluate the efficiency of various carbon supports in aiding facile electron transport. A MoS2/carbon nanofiber electrocatalyst has been found to be the most active towards hydrogen evolution with the lowest Tafel slope among the investigated electrocatalysts. Tafel analysis indicates that the hydrogen evolution reaction occurs through the Volmer-Heyrovsky mechanism with a rate determining Heyrovsky step in the MoS2 and MoS2/carbon electrocatalysts. Orderly variation of the Tafel slope with the mass loading has been observed in MoS2/Vulcan carbon and the cause for this has been investigated based on roughness factor measurements. A linear dependence of the Tafel slope on the roughness factor points to a concomitant increase in the limitations on mass transport. The results show that the benefit of increasing the roughness factor of the electrocatalyst is counterbalanced by increasing the Tafel slope, and hence the need for designing an optimal HER electrocatalyst balancing the roughness factor and Tafel slope is deduced. PMID- 28009858 TI - On the dielectric decrement of electrolyte solutions: a dressed-ion theory analysis. AB - Based on the dressed-ion theory and a simple physical argument regarding the conductivity of the solution, we derive a relation between the ionic strength and dielectric constant of an electrolyte solution. At its simplest, this model gives the dielectric constant at low ionic strength I as epsilonr(I) = epsilonr(0)(1 + alphaI)-1, where alpha (the excess polarization) is directly related to the dressed-ion charge. One contribution to the origin of the dielectric decrement is thus seen to stem from the electrostatic screening of the ions in solution, with no solvent contributions necessary. PMID- 28009859 TI - Is energy transfer limiting multiphotochromism? answers from ab initio quantifications. AB - Dithienylethenes (DTEs) can be assembled to form supramolecular multiphotochromic systems that are highly functional molecular architectures of potential interest for building complex optoelectronic devices. Yet even simple DTE dimers relying on an organic linker may suffer from a partial photoactivity, i.e., only one of the two switches does isomerise. Experimentally, this limited photochromism has been attributed to an excited state energy transfer (EET) between the two DTEs of the multimer; this EET taking place instead of the desired photoinduced cyclisation of the DTE. However, no clear evidences of this phenomenon have been provided so far. In this work we propose the first rationalisation of this potential parasite photoinduced event using a computational approach based on Time-Dependent Density Functional Theory (TD-DFT) for the calculation of the electronic coupling in DTE dimers. Besides quantifying EET in several systems, we dissect the role of through-bond and through-space mechanisms on this process and clarify their dependence on both the nature and length of the bridge separating the two photochromes. The theoretical data obtained in this framework are in full agreement with the experimental outcomes and pave the way toward a molecular design of coupled, yet fully functionals, DTE-based multiswitches. PMID- 28009860 TI - Pore size and concentration effect of mesoporous silica nanoparticles on the coefficient of thermal expansion and optical transparency of poly(ether sulfone) films. AB - Mesoporous silica nanoparticles (MSNs) with uniform size (<50 nm) yet with different pore diameters were synthesized, and used as fillers in poly(ether sulfone) (PES) films in order to decrease their coefficient of thermal expansion (CTE) without sacrificing optical transparency. Here, both CTE and optical transparency of the MSN/PES nanocomposite films gradually decreased with increasing MSN concentration. The PES films containing MSNs with larger pores showed the best performance in CTE and optical transparency. While the CTE decreased by 32.3% with increasing MSN content up to 0.5 wt%, the optical transparency decreased by only less than 6.9% because of the small and uniform particle size of less than 50 nm, which minimizes light scattering. This pore size effect is more clearly observed via an annealing process, which enables the polymer chains to slowly move and fill in the free volume in the pores of the MSN, and thus restricts the thermal motion. The effect of the silica nanoparticles was investigated not only on the thermal stability but also on the mechanical stability. We expect the MSNs synthesized in this study to be used as a promising filler to enhance the thermal and mechanical stability of the PES substrate without sacrificing its optical transparency. PMID- 28009861 TI - Structures of protonated hydrogen sulfide clusters, H+(H2S)n, highlighting the nature of sulfur-centered intermolecular interactions. AB - Unique intermolecular structures of protonated hydrogen sulfide clusters, H+(H2S)n, are revealed by infrared spectroscopy and ab initio calculations. The identified intermolecular structures are significantly different from those of the corresponding protonated water clusters, H+(H2O)n, in spite of the common hydrogen bond coordination ability between hydrogen sulfide and water. Protonated hydrogen sulfide clusters have the Eigen type ion core, H3S+, in the size range of n = 3-9. After the first hydrogen bonded shell formation is completed at n = 4, further solvation prefers a new shell bound by the charge-dipole interaction rather than the second hydrogen bonded shell. Thus, closely solvated structures, in which 7 molecules, at maximum, directly interact with the Eigen type ion core, are formed. The beginning of the second hydrogen bonded shell is found at n = 9. Competition among intermolecular interactions in H+(H2S)n is discussed. PMID- 28009862 TI - Probing ice VII crystallization from amorphous NaCl-D2O solutions at gigapascal pressures. AB - We probe the possible inclusion of salt (NaCl) in the ice VII lattice over the pressure range from 2 to 4 gigapascal. We combine data from neutron diffraction experiments under pressure and from computational structure searches based on density functional theory. We observe that the high density amorphous precursor (NaCl.10.2D2O) crystallises during annealing at high pressure in the vicinity of the phase boundary between pure ices VII and VIII. The structure formed is very similar to that of pure ice VII. Our simulations indicate that substituting water molecules in the ice VII lattice with Na+ and Cl- ions would lead to a significant expansion of the lattice parameter. Since this expansion was not observed in our experiments, the ice crystallised is likely to be pure D2O or contains only a small fraction of the ions from the salt solution. PMID- 28009863 TI - Organic sensitizers featuring thiophene derivative based donors with improved stability and photovoltaic performance. AB - Thiophene derivatives, including thieno[3,2-b][1]benzothiophene (TBT), benzo[b]thiophene (BT), 2-phenylthieno[3,2-b]thiophene (PTT) and 2 phenylthiophene (PT), have been introduced as donors for the construction of triarylamine organic dyes (M52, M53, M56, M57 and M52A). The absorption, electrochemical and photovoltaic properties as well as the stabilities of these dyes are systematically investigated and compared with the reference dye (M55), whose donor is composed of the hexyloxybenzene (HOB) unit. It is found that introducing the TBT, BT, PTT or PT donors positively shifted the HOMO and LUMO levels of the organic dyes, providing a larger driving force for regeneration and reducing the energy loss for electron injection. In addition, we found that M52, which contains the TBT unit, exhibited better photovoltaic performance and photostability as compared to the reference dye. In contrast, M53 displayed the lowest efficiency and stability of these dyes, indicating that the BT unit is not a good building block for donors. Interestingly, upon the incorporation of the mixed donor (TBT-HOB), M52A achieved a desirable driving force for regeneration without a loss in light absorption, thus resulting in a further improved photovoltaic performance with respect to that of M52. This work demonstrates that introducing donors based on thiophene derivatives is a good strategy for tuning the energy levels and thereby enhancing the efficiency of the resulting devices. PMID- 28009864 TI - Room-temperature ferromagnetism in the two-dimensional layered Cu2MoS4 nanosheets. AB - A room-temperature ferromagnetic behavior was observed in a ternary layered Cu2MoS4 nanosheet. Both the coercivity and magnetization saturation increased with a decrease in temperature. The electron paramagnetic resonance spectroscopy confirmed a high g value. Combined with atomic structural observations, our first principle calculations revealed that the ferromagnetism originated from the edged molybdenum atoms. PMID- 28009865 TI - Two blue-light excitable yellow-emitting LMOF phosphors constructed by triangular tri(4-pyridylphenyl)amine. AB - Two luminescent metal-organic-frameworks (LMOFs) constructed by a molecular chromophore [tri(4-pyridylphenyl)amine] (tppa) were synthesized by solvothermal reactions and characterized by single crystal and powder X-ray diffraction, thermogravimetric analysis, optical diffuse reflection, photoluminescence spectroscopy, and internal quantum yield measurements. Both compound 1 [Zn(tppa)(ndc).(DMF)4] and compound 2 [Zn4(tppa)2(sdc)3(NO3)2.(DMF)4.(ACN)2] (ndc = 2,6-naphthalenedicarboxylic acid, sdc = (E)-4,4'-(ethene-1,2-diyl)dibenzoic acid, DMF = dimethylformamide, ACN = acetonitrile) exhibit intense yellow emission under blue light (455 nm) excitation. The Commission International de I'Eclairage (CIE) coordinates of 1 (0.42, 0.53) and 2 (0.42, 0.54) are close to that of YAG:Ce3+ (0.41, 0.55) (lambdaex = 455 nm). The two phosphor materials show promise for use in phosphor-converted white LEDs (PC-WLEDs). PMID- 28009866 TI - Centrifugal micro-channel array droplet generation for highly parallel digital PCR. AB - Stable water-in-oil emulsion is essential to digital PCR and many other bioanalytical reactions that employ droplets as microreactors. We developed a novel technology to produce monodisperse emulsion droplets with high efficiency and high throughput using a bench-top centrifuge. Upon centrifugal spinning, the continuous aqueous phase is dispersed into monodisperse droplet jets in air through a micro-channel array (MiCA) and then submerged into oil as a stable emulsion. We performed dPCR reactions with a high dynamic range through the MiCA approach, and demonstrated that this cost-effective method not only eliminates the usage of complex microfluidic devices and control systems, but also greatly suppresses the loss of materials and cross-contamination. MiCA-enabled highly parallel emulsion generation combines both easiness and robustness of picoliter droplet production, and breaks the technical challenges by using conventional lab equipment and supplies. PMID- 28009867 TI - Essential oils of three cow parsnips - composition and activity against nosocomial and foodborne pathogens and food contaminants. AB - Although some widespread, native cow parsnips (Heracleum L. spp., Apiaceae) had broad medicinal and culinary applications throughout history, the knowledge about their volatile constituents is insufficient. This work investigates the composition and bioactivities of H. sphondylium L. (HSPH), H. sibiricum L. (HSIB) and H. montanum Schleich. ex Gaudin (HMON) essential oils. The composition was tested by GC and GC-MS. (Z)-beta-Ocimene was the most abundant in HSPH (28.9%) and HMON (20.4%) root oils, while in HSIB root oil, beta-pinene (26.2%), methyl eugenol (22.3%) and elemicin (25.6%) prevailed. Leaf and flower oils were dominated by various sesquiterpenes (germacrene D, beta-sesquiphellandrene, (E) beta-farnesene and/or (E)-caryophyllene) and/or phenylpropanoids (apiole, methyl eugenol, elemicin and/or (Z)-isoelemicin). Octyl acetate (57.5-67.1%) was the main constituent of all fruit oils. The antimicrobial activity was screened by a microdilution method against eight bacteria and eight fungi. The strongest antimicrobial effect, in several cases better than the activity of antibiotics, was shown by HSPH (MICs = 0.12-3.30 mg mL-1) and HMON (MICs = 0.10-1.30 mg mL-1) flower oils against bacteria, and HSIB fruit oil against fungi (MICs = 0.15-0.40 mg mL-1). The MTT test revealed that the oils were not or weakly cytotoxic against human malignant HeLa, LS174 and/or A549 cells (except HSPH root oil; IC50 = 5.72-24.31 MUg mL-1) and that tested oils were not toxic against human normal MRC-5 cells (at 200.00 MUg mL-1). Significant activity observed against microorganisms that are the common cause of foodborne diseases, food contamination and/or hospital-acquired infections justifies certain traditional uses of the investigated plants and represents a good basis for further research of these Heracleum oils. PMID- 28009868 TI - In situ integration of graphene foam-titanium nitride based bio-scaffolds and microfluidic structures for soil nutrient sensors. AB - It is challenging to integrate porous graphene foam (GF) and GF-based nanocomposites into microfluidic channels and even create microfluidic structures within these materials. This is because their irregular interior pore shape and geometry, rough exterior surface, and relatively large material thickness make it difficult to perform conventional photolithography and etching. This challenge has largely hindered the potential of using GF-based materials in microfluidics based sensors. Here we present a simple approach to create well-defined flow through channels within or across the GF-based materials, using a liquid-phase photopolymerization method. This method allows embedding of a nanocomposite-based scaffold of GF and titanium nitride nanofibers (GF-TiN NFs) into a channel structure, to realize flow-through microfluidic electrochemical sensors for detecting nitrate ions in agricultural soils. The unique GF-TiN nanocomposite provides high electrochemical reactivity, high electron transfer rate, improved loading capacity of receptor biomolecules, and large surface area, serving as an efficient electrochemical sensing interface with the help of immobilized specific enzyme molecules. The microfluidic sensor provides an ultralow limit of detection of 0.01 mg L-1, a wide dynamic range from 0.01 to 442 mg L-1, and a high sensitivity of 683.3 MUA mg-1 L cm-2 for nitrate ions in real soil solution samples. The advantageous features of the GF-TiN nanocomposite, in conjunction with the in situ integration approach, will enable a promising microfluidic sensor platform to monitor soil ions for nutrient management towards sustainable agriculture. PMID- 28009869 TI - The protective effect of betulinic acid (BA) diabetic nephropathy on streptozotocin (STZ)-induced diabetic rats. AB - The present study was designed to investigate the protective effect of betulinic acid (BA) on streptozotocin (STZ)-induced diabetic rats. The rats were intraperitoneally injected with STZ (35 mg kg-1). 7 days later, the animals were intragastrically administered with metformin (MET, 150 mg kg-1), BA (20 mg kg-1) or BA (40 mg kg-1) once daily for consecutive 30 days. The blood glucose, the contents of insulin, interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in serum were examined. The levels of IL-6, IL 1beta, TNF-alpha, superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) in kidney tissues were measured. Moreover, the histopathological alteration and the protein expressions of the signaling pathway were detected by hematoxylin and eosin (H&E) staining and western blotting, respectively. BA significantly decreased the levels of serum insulin, IL-6, IL-1beta, TNF-alpha and blood glucose. In addition, BA increased the activities of SOD, CAT and reduced the contents of MDA, IL-6, IL-1beta, and TNF-alpha in kidney tissues. BA also ameliorated the histopathological condition. Furthermore, BA attenuated the phosphorylations of p-adenosine 5'-monophosphate-activated protein kinase (AMPK), nuclear factor kappaB (NF-kappaB), and an inhibitor of NF-kappaB (IkappaBalpha) and the expressions of NF-E2-related factor 2 (Nrf2) and heme oxygenase (HO)-1. These findings demonstrated that BA exhibited a protective effect on diabetic nephropathy in STZ-induced rats possibly through the AMPK/NF-kappaB/Nrf2 pathway. PMID- 28009870 TI - Slow magnetic relaxation based on the anisotropic Ising-type magnetic coupling between the MoIII and MnII centers. AB - Three new complexes containing MnMoIII zigzag chains have been synthesized and structurally characterized. The crystal structure of complex 3 consists of two linkage isomers of the MoIIIMn chains, which correspond to 1 and 2, respectively. Both complex 1 and 3 show slow magnetic relaxation behavior with an energy barrier of Delta/kB = 69.5 K and 68.8 K, respectively, whereas complex 2 is a simple paramagnet. The linear apical MoIII-CN-MnII pairs provide the required magnetic anisotropy for the slow magnetic relaxation. PMID- 28009872 TI - Medium-chain fatty acids reduce serum cholesterol by regulating the metabolism of bile acid in C57BL/6J mice. AB - Hypercholesterolemia is one of the important risk factors of atherosclerosis (AS). The aim of this study is to explore the effect of medium-chain fatty acids (MCFAs) on serum cholesterol levels and their mechanism of action. Hyperlipemia, as a model of abnormal lipid hypermetabolism, was established by using a high fat diet in C57BL/6J mice. Forty eight mice with dyslipidemia were randomly divided into 4 groups, 12 mice per group, including the control group, the 2% caprylic acid (C8:0)-treated group, 2% capric acid (C10:0)-treated group, and 2% oleic acid (C18:1)-treated group. All mice were fed with a high fat diet. After 16 weeks, the mice were anesthetized with chloral hydrate. The mouse portal vein blood, the liver and the start site of the ileum (1 cm) were collected. The body weight of the mice and blood lipid profiles were measured. Gene transcription and the expression level associated with bile acid metabolism in the liver and small intestine were determined by real-time PCR and the western blotting method. The concentrations of bile acid metabolites in bile and feces were analysed. After 16 weeks of treatment, the concentrations of TC and LDL-C in the caprylic acid group were significantly lower than those in the control group (P < 0.05); the transcription and expression level of LXR, CYP7A1, CYP27A1 and ABCG8 in the caprylic acid and capric acid groups were significantly higher than those in the control group in the liver (P < 0.05), however the transcription and expression level of the small heterodimer partner (SHP) were significantly lower than those in the control group (P < 0.05); the transcription and expression level of LXR, ABCG5 and ABCG8 in the caprylic acid, capric acid and oleic acid groups were significantly higher than those in the control group in the small intestine (P < 0.05). The concentrations of total bile acid, mainly cholic acid and cholesterol in bile and feces were significantly higher in the caprylic and capric acid groups than those of in the control group (P < 0.05). Thus, MCFA increased the expression of LXR and ABCG8, enhanced CYP7A1 and CYP27A1 expression, decreased and SHP expression in the liver, thereby promoted liver bile acid synthesis and excretion. In addition MCFA increased the expression of ABCG5, ABCG8 and LXR in the small intestine, thereby inhibiting small intestinal bile acid absorption, increasing the concentrations of cholesterol and bile acid in bile and feces and reducing the level of serum cholesterol. PMID- 28009871 TI - Cocoplum (Chrysobalanus icaco L.) anthocyanins exert anti-inflammatory activity in human colon cancer and non-malignant colon cells. AB - Cocoplum (Chrysobalanus icaco L.) (CP) is an anthocyanin-rich fruit found in tropical areas around the globe. CP polyphenols are associated with beneficial effects on health, including reduction of inflammation and oxidative stress. Due to its functional properties, the consumption of this fruit may be beneficial in the promotion of human health and reduce the risk for chronic diseases. The objective of this study was to assess the anti-inflammatory and anti proliferative activities of anthocyanins extracted from CP (1.0 to 20.0 MUg ml-1 gallic acid equivalents [GAE]) in CCD-18Co non-malignant colonic fibroblasts and HT-29 colorectal adenocarcinoma cells. Tumor necrosis factor alpha (TNF-alpha, 10 ng mL-1) was used to induce inflammation in CCD-18Co cells. CP anthocyanins were identified and quantified using HPLC-ESI-MSn. The chemical analysis of CP extract identified delphinidin, cyanidin, petunidin and peonidin derivatives as major components. Cell proliferation was suppressed in HT-29 cells at 10.0 and 20.0 MUg ml-1 GAE and this was accompanied by increased intracellular ROS production as well as decreased TNF-alpha, IL-1beta, IL-6, and NF-kappaB1 expressions at 20.0 MUg ml-1 GAE. Within the same concentration range, there was no cytotoxic effect of CP anthocyanins in CCD-18Co cells and TNF-alpha-induced intracellular ROS production was decreased by 17.3%. IL-1beta, IL-6 and TNF-alpha protein expressions were also reduced in TNF-alpha-treated CCD-18Co cells by CP anthocyanins at 20.0 MUg ml-1 GAE. These results suggest that cocoplum anthocyanins possess cancer-cytotoxic and anti-inflammatory activities in both inflamed colon and colon cancer cells. PMID- 28009873 TI - The first of the viscoceuticals? A shear thickening gum induces gastric satiety in rats. AB - We examined the effect of gavage of 4 ml of a viscous shear-thickening polysaccharide solution (15% w/w) extracted from the fronds of the mamaku tree fern (Cythea medullaris) in reducing appetite and delaying gastric emptying in twenty six Sprague Dawley rats. After two weeks habituation to a pelleted chow, the rats were gavaged on alternate days with either the mamaku extract or with the same volume of deionised water for a total of five times over a period of two weeks. The body mass and food intake of each rat were determined daily and the weights of their stomach contents determined on euthanasia two hours after the final gavage. The rats gavaged with the mamaku gum consumed significantly lower quantities of chow on the day of gavage. The weights of the stomach contents of rats two hours after gavage with mamaku extract were significantly greater than those following gavage with water. The failure of the rats dosed with mamaku to lose body weight likely resulted from the overall adverse effect of gavage on food intake, the limited numbers of doses of the gum and the rebound hyperphagia on days when the rats were not gavaged. Together the results indicate that gavage with mamaku gum delayed gastric emptying with respect to that of rats dosed with water and supressed appetite for 12-24 hours after dosage. PMID- 28009874 TI - Superfast and high-sensitivity printable strain sensors with bioinspired micron scale cracks. AB - Functional electronics has promising applications, including highly advanced human-interactive devices and healthcare monitoring. Here, we present a unique printable micron-scale cracked strain sensor (PMSCSS), which is bioinspired by a spider's crack-shaped lyriform slit organ. The PMSCSS is fabricated by a facile process that utilizes screen-printing to coat carbon black (CB) ink onto a paper substrate. With a certain bending radius, a cracked morphology emerged on the solidified ink layer. The working principle of the PMSCSS is prominently attributed to the strain-dependent variation in resistance due to the reconnection-disconnection of the crack fracture surfaces. The device shows appealing performances, with superfast response times (~0.625 ms) and high sensitivity (gauge factor = 647). The response time surpasses most recent reports, and the sensitivity is comparable. We demonstrate the application of the PMSCSSs as encoders, which have good linearity and negligible hysteresis. Also, the sensor can be manipulated as a vibration detector by monitoring human-motion disturbances. According to the sensory information, some details of movements can be deduced. PMID- 28009876 TI - In situ thermomechanical testing methods for micro/nano-scale materials. AB - The advance of micro/nanotechnology in energy-harvesting, micropower, electronic devices, and transducers for automobile and aerospace applications has led to the need for accurate thermomechanical characterization of micro/nano-scale materials to ensure their reliability and performance. This persistent need has driven various efforts to develop innovative experimental techniques that overcome the critical challenges associated with precise mechanical and thermal control of micro/nano-scale specimens during material characterization. Here we review recent progress in the development of thermomechanical testing methods from miniaturized versions of conventional macroscopic test systems to the current state of the art of in situ uniaxial testing capabilities in electron microscopes utilizing either indentation-based microcompression or integrated microsystems. We discuss the major advantages/disadvantages of these methods with respect to specimen size, range of temperature control, ease of experimentation and resolution of the measurements. We also identify key challenges in each method. Finally, we summarize some of the important discoveries that have been made using in situ thermomechanical testing and the exciting research opportunities still to come in micro/nano-scale materials. PMID- 28009875 TI - Half-sandwich complexes of iridium and ruthenium containing cysteine-derived ligands. AB - The dimers [{(etan-ring)MCl}2(MU-Cl)2] ((etan-ring)M = (eta5-C5Me5)Ir, (eta6-p MeC6H4iPr)Ru) react with the modified cysteines S-benzyl-l-cysteine (HL1) or S benzyl-alpha-methyl-l-cysteine (HL2) affording cationic complexes of the formula [(etan-ring)MCl(kappa2N,S-HL)]Cl (1, 2) in good yield. Addition of NaHCO3 to complexes 1 and 2 gave equilibrium mixtures of neutral [(etan-ring)MCl(kappa2N,O L)] (3, 4) and cationic [(etan-ring)M(kappa3N,O,S-L)]Cl (6Cl, 7Cl) complexes. Similar mixtures were obtained in one-pot reaction by successive addition of the modified cysteine and NaHCO3 to the above formulated dimers. Addition of the N Boc substituted cysteine derivative S-benzyl-N-Boc-l-cysteine (HL3) and NaHCO3 to the dimers [{(etan-ring)MCl}2(MU-Cl)2] affords the neutral compounds [(etan ring)MCl(kappa2O,S-L3)] ((etan-ring)M = (eta5-C5Me5)Ir (5a), (eta6-p-MeC6H4iPr)Ru (5b)). Complexes of the formula [(etan-ring)MCl(kappa3N,O,S-L)][SbF6] (6Sb-8Sb), in which the cysteine derivative acts as a tridentate chelate ligand, can be prepared by adding one equivalent of AgSbF6 to the solutions of compounds 5 or to the mixtures of complexes 3/6Cl and 4/7Cl. The amide proton of compounds 8aSb and 8bSb can be removed by addition of NaHCO3 affording the neutral complexes [(etan ring)M(kappa3N,O,S-L3-H)] ((etan-ring)M = (eta5-C5Me5)Ir (9a), (eta6-p MeC6H4iPr)Ru (9b)). Complexes 9a and 9b can also be prepared by reacting the dimers [{(etan-ring)MCl}2(MU-Cl)2] with HL3 and two equivalents of NaHCO3. The absolute configuration of the complexes has been established by spectroscopic and diffractometric means including the crystal structure determination of (RIr,RC,RS)-[(eta5-C5Me5)Ir(kappa3N,O,S-L1)][SbF6] (6aSb). The thermodynamic parameters associated with the epimerization at sulphur that the iridium compound [(eta5-C5Me5)Ir(kappa3N,O,S-L3-H)] (9a) undergoes have been determined through variable temperature 1H NMR studies. PMID- 28009877 TI - Effects of reduced dimensionality on the properties of magnesium hydroxide and calcium hydroxide nanostructures. AB - Metal hydroxides are a class of layered materials that contain two-dimensional metal hydroxide layers that can be isolated to form layered nanostructures. In this work, density functional theory (DFT) and self-consistent-charge density functional tight-binding (SCC-DFTB) methods have been used to investigate the properties of magnesium hydroxide and calcium hydroxide nanostructures. The properties of single layer and multi layer structures with up to 10 metal hydroxide sheets and nanoparticles containing more than 2000 atoms have been calculated and compared with the bulk properties of these systems. The accuracy of the DFT methods employed and SCC-DFTB parameters developed in this study were validated against available experimental data. The results of the calculations indicate that significant differences exist between the properties of the nanostructures and the corresponding bulk values. In particular, the interlayer binding energies, electronic band gaps, and spectroscopic features are size dependent and tend to converge to the bulk values as the size of the nanosystem is increased. The calculated binding energies and shear moduli show that all nanostructures are mechanically stable, in agreement with the experimental reports; although, their stabilities may be affected by the presence of intercalated species. Energy decomposition analyses reveal that the intralayer interactions in the investigated systems are predominantly electrostatic in nature, while the interlayer interactions are dominated by dispersion and polarization components. The results presented here quantify various properties of magnesium hydroxide and calcium hydroxide nanostructures, and could be used to understand the properties of other nanosystems containing layers of metal hydroxides in their structure. PMID- 28009878 TI - Motor-assisted chip-in-a-tube (MACT): a new 2- and 3-dimensional centrifugal microfluidic platform for biomedical applications. AB - Currently, centrifuge apparatus is primarily an end-point sample processing piece of equipment. The lack of real-time active control has imposed an inherent limitation such that many delicate sample processing steps requiring immediate and accurate intervention have never been possible. We report herein a motor assisted chip-in-a-tube (MACT) platform in which a microfluidic chip placed inside a common centrifuge canister can be rotated through wireless control in order to manipulate the centrifugal force vector in a 3-dimensional (3D) manner. As a demonstration experiment, we have used our MACT prototype to perform the operation for two common biomedical procedures, namely human blood plasma separation and E. coli plasmid DNA extraction. This simple, yet highly effective and versatile approach may serve as a generic one-for-all platform for a wide range of common laboratory experiments and bioassay applications. PMID- 28009879 TI - Stepwise reversible nanomechanical buckling in a viral capsid. AB - Viruses are nanoscale infectious agents constructed of a proteinaceous capsid that protects the packaged genomic material. Nanoindentation experiments using atomic force microscopy have, in recent years, provided unprecedented insight into the elastic properties, structural stability and maturation-dependent mechanical changes in viruses. However, the dynamics of capsid behavior are still unresolved. Here we used high-resolution nanoindentation experiments on mature, DNA-filled T7 bacteriophage particles. The elastic regime of the nanoindentation force trace contained discrete, stepwise transitions that cause buckling of the T7 capsid with magnitudes that are integer multiples of ~0.6 nm. Remarkably, the transitions are reversible and contribute to the rapid consolidation of the capsid structure against a force during cantilever retraction. The stepwise transitions were present even following the removal of the genomic DNA by heat treatment, indicating that they are related to the structure and dynamics of the capsomeric proteins. Dynamic force spectroscopy experiments revealed that the thermally activated consolidation step is ~104 times faster than spontaneous buckling, suggesting that the capsid stability is under strong dynamic control. Capsid structural dynamics may play an important role in protecting the genomic material from harsh environmental impacts. The nanomechanics approach employed here may be used to investigate the structural dynamics of other viruses and nanoscale containers as well. PMID- 28009880 TI - Ln polyoxocations: yttrium oxide solution speciation & solution deposited thin films. AB - Rare earth oxide materials, including thin film coatings, are critically important in magnetic, luminescent and microelectric devices, and few substitutes have been discovered with comparable performance. Thin film coatings from solution are almost unknown for rare earth oxides, likely due to their high activity towards hydrolysis which yields poor quality thin films. The hexamer [Ln6(O)(OH)8(H2O)12(NO3)6]2+ is a rare example of a metal-oxo cluster isolated and stabilized without additional supporting organic ligands. Herein we report a new method for both the preparation and stabilization in non-aqueous media, which makes these clusters valuable precursors for solution-processed thin films. Solution characterization (NMR, small-angle X-ray scattering and Raman spectroscopy) in wet organic solvents indicated that the clusters evolve via a fragmentation and reaggregation process. This is especially true for hexamers of the smaller Ln3+-ions: the higher charge density yields higher hydration rates. This process produced an entirely new hexadecameric cluster formulated Y16O3(OH)24(NO3)18(OSMe2)16(OCMe2)2(H2O)4. The new structure represents an intermediate hydrolysis product on the pathway from hexanuclear clusters to metal oxyhydroxide bulk solid. DMSO solvent ligands displace aqua ligands on the cluster and likely explain the additional stability observed for these clusters in organic solvents. The enhanced cluster stability in DMF and DMSO also enables solution-processing methods to create high quality thin films. PMID- 28009881 TI - Decoupling energetic modifications to diffusion from free volume in polymer/nanoparticle composites. AB - Diffusion coefficients of small molecules in a model composite of spherical nanoparticles and polymer with attractive interfacial interactions are reduced from that in the pure polymer, to a degree far below the level expected from geometric tortuosity arguments. We determine whether such dramatic reductions are due to modifications to the matrix polymer free volume near the nanoparticle surface, or alternatively are due to energetic attractions between the diffusants and nanoparticle surface. We performed ethyl acetate sorption experiments within the vicinity of the polymer glass transition (Tg <= T <= Tg + 25 K) for a model polymer/nanoparticle composite, silica-filled poly(methyl acrylate). By application of the Vrentas-Duda free volume theory of diffusion we have decoupled the energetic effects from those related to free-volume and segmental dynamics. While the latter is unaffected by addition of nanoparticles, the energy needed for the ethyl acetate diffusant to overcome neighboring attractive forces doubles after adding 40 vol% nanoparticles with a diameter of 14 nm. This is qualitatively consistent with hydrogen bonding interactions between the silica surface and ethyl acetate slowing its rate of diffusion. On the other hand for benzene, which does not hydrogen bond to the silica surface, diffusion coefficients that can be explained by tortuosity effects were obtained. This work provides quantitative evidence that the diffusant-filler energetic interactions and geometric blocking effects can be fully responsible for the substantially reduced diffusivity commonly observed in polymer/nanoparticle composite systems. PMID- 28009882 TI - Inorganically coated colloidal quantum dots in polar solvents using a microemulsion-assisted method. AB - The dielectric nature of organic ligands capping semiconductor colloidal nanocrystals (NCs) makes them incompatible with optoelectronic applications. For this reason, these ligands are regularly substituted through ligand-exchange processes by shorter (even atomic) or inorganic ones. In this work, an alternative path is proposed to obtain inorganically coated NCs. Differently to regular ligand exchange processes, the method reported here produces core-shell NCs and the removal of the original organic shell in a single step. This procedure leads to the formation of connected NCs resembling 1D worm-like networks with improved optical properties and polar solubility, in comparison with the initial CdSe NCs. The nature of the inorganic shell has been elucidated by X-ray Absorption Near Edge Structure (XANES), Extended X-ray Absorption Fine Structure (EXAFS) and X-ray Photoelectron Spectroscopy (XPS). The 1D morphology along with the lack of long insulating organic ligands and the higher solubility in polar media turns these structures very attractive for their further integration into optoelectronic devices. PMID- 28009884 TI - Synthesis and fluorescence properties of dioxa-, dithia-, and diselena [3.3](1,3)pyrenophanes. AB - [3.3](1,3)Pyrenophanes tethered by oxygen (1), sulfur (2) and selenium (3) atoms were synthesized and the structural and physical properties of these substances were determined. The absorption maxima of the [3.3](1,3)pyrenophanes were observed to shift to longer wavelengths in the order of 1 < 2 < 3. The fluorescence spectra of 1-3 contained both monomer and intramolecular excimer emissions, which correspond to anti and syn conformers, respectively. The ratios of the intensities of intramolecular excimer to monomer emission were observed to increase with the increasing solvent polarity. The intensity ratios also depend on temperature. For example, an increase in temperature results in an increase of the ratio of intensities of the intramolecular excimer to monomer fluorescence of 2. The results of 1H NMR spectroscopic investigations show that resonances for the methylene and aromatic hydrogens in these substances coalesce at low temperatures with coalescence temperatures (Tc) that decrease in the order of 1 > 2 > 3. The results of geometry optimization studies using B3LYP/6-31G(d,p) demonstrate that the syn conformers of 1-3 have lower enthalpies than their anti counterparts, but the syn conformer of 1 and the anti conformers of 2-3 are entropically more favorable. These findings suggest that an equilibrium exists between the syn and anti conformers of the [3.3](1,3)pyrenophanes and that the conformer ratios are dependent on both the solvent polarity and temperature in a manner that can be explained in terms of a combination of enthalpies, dipole moments and entropies. The combined results show that the pyrenophanes are interesting substances that emit different fluorescence colors in a manner that is controlled by the surrounding environment. PMID- 28009885 TI - Maximally dense random packings of cubes and cuboids via a novel inverse packing method. AB - The packings of cubes and cuboids (i.e., "elongated" or "compressed" cubes) are ubiquitous in nature. The high symmetry and space-tiling nature of such particles make them easily packable in dense configurations with a high degree of orientational and translational order. In this paper, we devise a novel inverse packing method that enables one to generate dense hard-particle packings with a controllable degree of disorder/order quantified by predefined order metrics via stochastic Monte Carlo optimizations. We employ the inverse packing method to generate and investigate the maximally dense random packings (MDRPs) of hard cubes and cuboids with aspect ratio alpha, in which a series of newly introduced normalized local cubatic order parameters sensitive to the onset of any spatial order in packings of cubes and cuboids is minimized. The density of the MDRP of cubes is phi ~ 0.637, which increases as the shape deviates from the cube limit (alpha = 1) and reaches the maximal values for cuboids with aspect ratios alpha = 0.7 or 1.5. These special alpha values associated with local density extrema are almost identical for those associated with the random packings of spherocylinders, spheroids and superellipsoids, suggesting a universal influence of shape elongation on random packing density. Our inverse packing method can be readily utilized to study the MDRPs of other hard particles and the normalized local cubatic order parameter introduced here is applicable to other shaped particles characterized by three principal axes. PMID- 28009883 TI - Thermoplastic nanofluidic devices for biomedical applications. AB - Microfluidics is now moving into a developmental stage where basic discoveries are being transitioned into the commercial sector so that these discoveries can affect, for example, healthcare. Thus, high production rate microfabrication technologies, such as thermal embossing and/or injection molding, are being used to produce low-cost consumables appropriate for commercial applications. Based on recent reports, it is clear that nanofluidics offers some attractive process capabilities that may provide unique venues for biomolecular analyses that cannot be realized at the microscale. Thus, it would be attractive to consider early in the developmental cycle of nanofluidics production pipelines that can generate devices possessing sub-150 nm dimensions in a high production mode and at low cost to accommodate the commercialization of this exciting technology. Recently, functional sub-150 nm thermoplastic nanofluidic devices have been reported that can provide high process yield rates, which can enable commercial translation of nanofluidics. This review presents an overview of recent advancements in the fabrication, assembly, surface modification and the characterization of thermoplastic nanofluidic devices. Also, several examples in which nanoscale phenomena have been exploited for the analysis of biomolecules are highlighted. Lastly, some general conclusions and future outlooks are presented. PMID- 28009886 TI - Primary photophysical and photochemical processes for hexachloroosmate(iv) in aqueous solution. AB - The photoaquation of the OsIVCl62- complex was studied by means of stationary photolysis, nanosecond laser flash photolysis and ultrafast kinetic spectroscopy. The OsIVCl5(OH)2- complex was found to be the only reaction product. The quantum yield of photoaquation is rather low and wavelength-dependent. No impact of redox processes on photoaquation was revealed. The total characteristic lifetime of the process is about 80 ps. Three intermediates were recorded in the femto- and picosecond time domains and assigned to different Os(iv) species. The nature of intermediates and possible mechanisms of photoaquation are discussed. PMID- 28009887 TI - Responses of Crepis japonica induced by supplemental blue light and UV-A radiation. AB - Crepis japonica (L.) D.C. (Asteraceae), a weed with antioxidant, antiallergenic, antiviral and antitumor properties displays both medicinal properties and nutritional value. This study aims to assess the effects of a supplementation of blue light and UV-A radiation on the growth, leaf anatomical structure and phenolic profile of the aerial parts of Crepis japonica. Plants were grown under two light treatments: W (control - white light), W + B (white light supplemented with blue light) and W + UV-A (white light supplemented with UV-A radiation). We recorded the length, width, and weight of fresh and dry leaves, the thickness of the epidermis and mesophyll, and stomata density. The phenolic profiles of the aqueous extracts of the aerial parts were analyzed by HPLC-DAD. There was an increase in the leaf size, stomatal density, and phenolic production, and a thickening of the mesophyll and epidermis. UV-A radiation increased the phenolic production more than blue light. Blue light and UV-A radiation both improved the production of caffeic acid by about 6 and 3 times, respectively, in comparison to control. This compound was first reported as a constituent of the extract from the aerial parts together with caftaric acid. UV-A also promoted the production of chlorogenic acid (about 1.5 times in comparison to the control). We observed that the morphological and chemical parameters of C. japonica are modified in response to blue light and UV-A radiation, which can be used as tools in the cultivation of this species in order to improve its medicinal properties and nutritional value. PMID- 28009888 TI - Synthesis and characterization of novel Li-stuffed garnet-like Li5+2xLa3Ta2 xGdxO12 (0 <= x <= 0.55): structure-property relationships. AB - In this article, we report the preparation and characterization of novel Li stuffed garnets Li5+2xLa3Ta2-xGdxO12 (0 <= x <= 0.55) for all-solid-state Li ion batteries. The conventional solid-state method was used to prepare Li5La3Ta2O12 in air at 1200 degrees C and Li5+2xLa3Ta2-xGdxO12 at 1150 degrees C. Rietveld refinements for the powder X-ray diffraction (PXRD) patterns confirmed the formation of a cubic garnet-like structure (space group Ia3[combining macron]d) with cell constant increased from 12.8176(4) A (x = 0) to 12.9372(2) A (x = 0.55). However, small amounts of second phases were observed for higher Gd-doped samples. Scanning electron microscopy revealed that Li5.7La3Ta1.65Gd0.35O12 exhibits the highest density among all investigated samples in this study. The AC impedance spectroscopy data of the samples have been analyzed in relation to ionic conductivity, dielectric constants, and loss tangent. Among the investigated electrolytes, the Li5.7La3Ta1.65Gd0.35O12 composition demonstrated the highest bulk ionic conductivity of 8.18 * 10-5 S cm-1 at 25 degrees C, which is significantly higher than that of the parent garnet Li5La3Ta2O12 (1.65 * 10-5 S cm-1 at 25 degrees C). The appearance of a relaxation peak in the loss tangent plots for all samples seems to be due to the dipolar rotations of Li+ ions in Li stuffed garnets. PMID- 28009889 TI - Synthesis and charge storage properties of templated LaMnO3-SiO2 composite materials. AB - Mesoporous LaMnO3 with bulk surface areas in the range 225-300 m2 g-1 were prepared by direct overgrowth around the short-channel version of SBA-15 silica. The extent of LaMnO3 growth was found to be affected by the polarity of solvent system used to impregnate the SBA-15 with La3+ and Mn2+ precursors. The resulting LaMnO3-SiO2 composites were stable in refluxing NaOH, suggesting that the SiO2 was fully encapsulated. The composites were structurally characterized using a range of techniques including 2-D elemental mapping and Raman spectroscopy. The electrochemical behavior of the composites was tested for pseudocapacitance, which revealed normalized specific capacitances over 200 F g-1. PMID- 28009890 TI - The health benefits of UV radiation exposure through vitamin D production or non vitamin D pathways. Blood pressure and cardiovascular disease. AB - The detrimental effects of ultraviolet radiation are well known. Skin cancer, photo-aging, and induction or exacerbation of photosensitive dermatoses have been the focus of most photobiological research since 1928 when Findlay confirmed the carcinogenicity of ultraviolet radiation using a murine model of skin cancer. The epidemiological, mechanistic and clinical trial data have enabled the classification by the International Agency for Research on Cancer of ultraviolet radiation as a Group 1 ('sufficient evidence') carcinogen for human skin. Public health advice in most developed countries with a pale-skinned population following this has advocated limiting exposure to sunlight through use of clothing, sunblock and behavioural alterations. Despite this plethora of data, one striking omission is evidence that ultraviolet radiation shortens life, and as I will lay out in this chapter, epidemiological and now mechanistic data suggest that UV may have significant benefits on health and in particular cardiovascular health. PMID- 28009891 TI - Ultraviolet radiation, vitamin D and the development of obesity, metabolic syndrome and type-2 diabetes. AB - Obesity is increasing in prevalence in many countries around the world. Its causes have been traditionally ascribed to a model where energy intake exceeds energy consumption. Reduced energy output in the form of exercise is associated with less sun exposure as many of these activities occur outdoors. This review explores the potential for ultraviolet radiation (UVR), derived from sun exposure, to affect the development of obesity and two of its metabolic co morbidities, type-2 diabetes and metabolic syndrome. We here discuss the potential benefits (or otherwise) of exposure to UVR based on evidence from pre clinical, human epidemiological and clinical studies and explore and compare the potential role of UVR-induced mediators, including vitamin D and nitric oxide. Overall, emerging findings suggest a protective role for UVR and sun exposure in reducing the development of obesity and cardiometabolic dysfunction, but more epidemiological and clinical research is required that focuses on measuring the direct associations and effects of exposure to UVR in humans. PMID- 28009892 TI - Cytotoxic and antimicrobial effects of indium(iii) complexes with 2 acetylpyridine-derived thiosemicarbazones. AB - Complexes [In(2Ac4oClPh)Cl2(MeOH)] (1), [In(2Ac4pFPh)Cl2(MeOH)] (2), [In(2Ac4pClPh)Cl2(MeOH)] (3) and [In(2Ac4pIPh)Cl2(MeOH)] (4) were obtained with N(4)-ortho-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4oClPh), N(4) para-fluorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pFPh), N(4)-para chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pClPh) and N(4)-para iodophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pIPh). Theoretical studies suggested that the coordinated methanol molecule can be easily replaced by DMSO used in the preparation of stock solutions, with the formation of [In(L)Cl2(DMSO)] (HL = thiosemicarbazonate ligand), and that the replacement of DMSO by water is unfavorable. However, for all complexes the displacement of one or two chloride ligands by water in aqueous solution is extremely favorable. The cytotoxic activity of the compounds was evaluated against HL-60, Jurkat and THP-1 leukemia and against MDA-MB-231 and HCT-116 solid tumor cell lines, as well as against Vero non-malignant cells. The cytotoxicity and selectivity indexes (SI) increased in several cases for the indium(iii) complexes in comparison with the free thiosemicarbazones. The antimicrobial activity of the compounds was investigated against Candida albicans, Candida dubliniensis, Candida lusitaniae and Candida parapsilosis. In many cases complexation resulted in a substantial increase of the antifungal activity. Complexes (1-4) were revealed to be very active against C. lusitaniae and C. dubliniensis. Structure-activity relationship (SAR) studies were carried out to identify the physico-chemical properties that might be involved in the antifungal action, as well as in the cytotoxic effect of the compounds against HL-60 cells. In both cases, correlations between the bioactivity and physico-chemical properties did not appreciably change when the chloride ligands in [In(L)Cl2(DMSO)] were replaced by water molecules, suggesting [In(L)Cl(H2O)(DMSO)]+ or [In(L)(H2O)2(DMSO)]2+ to be the species that interact with the biological media. PMID- 28009893 TI - Inkjet-printed optoelectronics. AB - Inkjet printing is a powerful and cost-effective technique for deposition of liquid inks with high accuracy, which is not only of great significance for graphic applications but also has enormous potential for the direct printing of optoelectronic devices. This review highlights a comprehensive overview of the progress that has been made in optoelectronics fabrication by the inkjet printing technique. The first part briefly covers the droplet-generation process in the nozzles of printheads and the physical properties affecting droplet formation and the profiles of the printed patterns. The second section outlines the recent activities related to applications of inkjet printing in optoelectronics fabrication including solar cells, light-emitting diodes, photodetectors and transparent electrodes. In each application field, the challenges with the inkjet printing process and the possible solutions are discussed before a few remarks. In the last section, a brief summary on the progress of inkjet printing fabrication of optoelectronics and an outlook for future research effort are presented. PMID- 28009894 TI - Correction: Preparation of Pt-Tl clusters showing new geometries. X-ray, NMR and luminescence studies. AB - Correction for 'Preparation of Pt-Tl clusters showing new geometries. X-ray, NMR and luminescence studies by Ursula Belio et al., Dalton Trans., 2014, 43, 10828 10843. PMID- 28009895 TI - Three-dimensional cavity nanoantennas with resonant-enhanced surface plasmons as dynamic color-tuning reflectors. AB - As plasmonic antennas for surface-plasmon-assisted control of optical fields at specific frequencies, metallic nanostructures have recently emerged as crucial optical components for fascinating plasmonic color engineering. Particularly, plasmonic resonant nanocavities can concentrate lightwave energy to strongly enhance light-matter interactions, making them ideal candidates as optical elements for fine-tuning color displays. Inspired by the color mixing effect found on butterfly wings, a new type of plasmonic, multiresonant, narrow-band (the minimum is about 45 nm), high-reflectance (the maximum is about 95%), and dynamic color-tuning reflector is developed. This is achieved from periodic patterns of plasmonic resonant nanocavities in free-standing capped-pillar nanostructure arrays. Such cavity-coupling structures exhibit multiple narrow band selective and continuously tunable reflections via plasmon standing-wave resonances. Consequently, they can produce a variety of dark-field vibrant reflective colors with good quality, strong color signal and fine tonal variation at the optical diffraction limit. This proposed multicolor scheme provides an elegant strategy for realizing personalized and customized applications in ultracompact photonic data storage and steganography, colorimetric sensing, 3D holograms and other plasmon-assisted photonic devices. PMID- 28009896 TI - Correction: Visible-light controlled catalytic Cu2O-Au micromotors. AB - Correction for 'Visible-light controlled catalytic Cu2O-Au micromotors' by Dekai Zhou, et al., Nanoscale, 2017, DOI: 10.1039/c6nr08088j. PMID- 28009897 TI - Formation of a solid solution between [N(C2H5)4][BF4] and [N(C2H5)4][PF6] in crystal and plastic crystal phases. AB - The phase behavior of [N2222][BF4] and [N2222][PF6] (N2222+ = tetraethylammonium cation) binary systems has been investigated in the present study. Differential scanning calorimetry revealed that the crystal-to-plastic-crystal transition temperature decreases upon mixing the two salts, with a minimum at x([N2222][PF6]) = 0.4, where x([N2222][PF6]) denotes the molar fraction of [N2222][PF6]. Powder X-ray diffraction analysis indicated the formation of a solid solution with a rock-salt type structure in the plastic crystal phase at all ratios and the lattice parameter a changes according to Vegard's law. In the crystal phase, two solid solution phases based on the structures of the single salts are observed. Raman spectroscopy confirmed the changes in the solid-solid transition temperature as observed by differential scanning calorimetry. Consequently, in the resulting phase diagram, the solid solution is formed in a wide x([N2222][PF6]) range for both the crystal and plastic crystal phases. PMID- 28009898 TI - 3D-QSAR predictions for bovine serum albumin-water partition coefficients of organic anions using quantum mechanically based descriptors. AB - Ionic organic chemicals are a class of chemicals that is released in the environment in a large amount from anthropogenic sources. Among various chemical and biological processes, binding to serum albumin is particularly relevant for the toxicokinetic behavior of ionic chemicals. Several experimental studies showed that steric effects have a crucial influence on the sorption to bovine serum albumin (BSA). In this study, we investigated whether a 3D quantitative structure-activity relationship (3D-QSAR) model can accurately account for these steric effects by predicting the BSA-water partition coefficients (KBSA/water) of neutral and anionic organic chemicals. The 3D-QSAR tested here uses quantum mechanically derived local sigma profiles as descriptors. In general, the 3D-QSAR model was able to predict the partition coefficients of neutral and anionic chemicals with an acceptable quality (RMSEtest set 0.63 +/- 0.10, Rtest set2 0.52 +/- 0.15, both for log KBSA/water). Particularly notable is that steric effects that cause a large difference in the log KBSA/water values between isomers were successfully reproduced by the model. The prediction of unknown KBSA/water values with the proposed model should contribute to improved environmental and toxicological assessments of chemicals. PMID- 28009899 TI - Controllable reduced black titania with enhanced photoelectrochemical water splitting performance. AB - Black titania prepared by metal-reduction methods is systematically studied and found the best controllable Mg-reduction method. Colored titania products from white, light blue, dark blue, to black were obtained with a crystalline/amorphous core-shell structure. The black titania shows a five times higher H2 production rate in photoelectrochemical (PEC) water splitting. PMID- 28009900 TI - One-pot synthesis of PtRu nanodendrites as efficient catalysts for methanol oxidation reaction. AB - Bimetallic Pt-based nanodendrites are of particular interest in various catalytic applications due to their high surface areas and low densities. Herein, we provide a facile method for one-pot synthesis of PtRu nanodendrites via the co reduction of Pt and Ru precursors in oleylamine by H2. The as-fabricated PtRu nanodendrites exhibit superior catalytic activity and durability compared with PtRu nanocrystals (NCs), synthesized under the same reaction conditions, and the commercial Pt/C catalyst towards the methanol oxidation reaction (MOR). PMID- 28009901 TI - Aloe activated P-glycoprotein and CYP 3A: a study on the serum kinetics of aloe and its interaction with cyclosporine in rats. AB - Aloe, the leaf juice of Aloe vera, is a popular functional food worldwide. The major constituents of aloe are polyphenolic anthranoids such as aloin, aloe emodin and rhein. Cyclosporine (CSP), an immunosuppressant with a narrow therapeutic window, is a probe substrate of P-glycoprotein (P-gp), an efflux pump, and CYP 3A4. This study first investigated the serum kinetics of aloe, then evaluated the modulation effects of aloe on P-gp and CYP 3A through an aloe-CSP interaction study in rats. The serum kinetic study showed that aloe-emodin glucuronides (G) and rhein sulfates/glucuronides (S/G) were major molecules in the bloodstream. The aloe-CSP interaction study showed that the systemic exposure to CSP was significantly decreased by either a single dose or multiple doses of aloe. The results of in vitro studies indicated that aloe activated P-gp and aloe metabolites activated CYP 3A4. In conclusion, aloe ingestion activated the functions of P-gp and CYP 3A in rats. PMID- 28009902 TI - Ternary rare-earth aluminium intermetallics RE10TAl3 (RE = Y, Ho, Tm, Lu; T = Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt) with an ordered anti-Co2Al5 structure. AB - Twenty new rare-earth metal rich intermetallic aluminium compounds, RE10TAl3 (RE = Y, Ho, Tm, Lu; T = Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt), were synthesized by arc melting the elements. The compounds crystallize, in analogy to e.g. the respective Cd representatives, with a ternary ordered structure as anti-type to the hexagonal Co2Al5 type, with the space group P63/mmc. The three crystallographically independent rare-earth metal sites occupy the aluminium positions of the aristotype, while the transition metal and aluminium atoms are ordered on the two cobalt sites. Like other rare-earth rich compounds the RE10TX3 members also exhibit transition-metal-centred T@RE6 trigonal prisms as striking structural building units. The prepared compounds have been investigated by susceptibility measurements and 27Al solid-state MAS-NMR measurements conducted on the Pauli-paramagnetic Y and Lu compounds. Some compounds show a certain amount of disorder as seen from the single crystal structure analysis and from signal broadening in the NMR investigations. By separating Knight shifts from second-order quadrupolar shifts via field dependent measurements, monotonic trends can be discerned regarding the effect of the T atom valence electron concentration and period number, as well as the effect of the closed 4f shell contributed in the Lu compounds. The results confirm that a comparison of Knight shifts within a series of isotypic compounds can reveal important electronic structure information in intermetallic systems. PMID- 28009903 TI - Creep- and fatigue-resistant, rapid piezoresistive responses of elastomeric graphene-coated carbon nanotube aerogels over a wide pressure range. AB - Lightweight, flexible piezoresistive materials with wide operational pressure ranges are in demand for applications such as human physical activity and health monitoring, robotics, and for functional interfacing between living systems and wearable electronics. Piezoresistivity of many elastomeric foams of polymers and carbon allotropes satisfies much of the required characteristics for these applications except creep and fatigue resistance due to their viscoelasticity, critically limiting the reliability and lifetime of integrated devices. We report the piezoresistive responses from aerogels of graphene-coated single-walled carbon nanotubes (SWCNTs), made using a facile and versatile sol-gel method. Graphene crosslinks the junctions of the underlying random network of SWCNTs, generating lightweight elastomeric aerogels with a mass density of ~11 mg mL-1 (volume fraction ~7.7 * 10-3) and a Young's modulus of ~0.4 MPa. The piezoresistivity of these aerogels spans wide compressive pressures up to at least 120 kPa with sensitivity that exhibit ultrafast temporal responses of <27 ms and <3% delay ratio over 104 compressive loading-unloading cycles at rates between 0.1-10 Hz. Most importantly, the piezoresistive responses do not show any creep at least for 1 hour and 80 kPa of compressive static loading. We suggest that the fatigue- and creep-resistant, ultrafast piezoresistive responses of these elastomeric aerogels are highly attractive for use in dynamic and static lightweight, pressure sensing applications such as human activity monitoring and soft robotics. PMID- 28009904 TI - Electrostatic interactions at the microscale modulate dynamics and distribution of lipids in bilayers. AB - For decades, it has been assumed that electrostatic long-range (micron distances) repulsions in lipid bilayers are negligible due to screening from the aqueous milieu. This concept, mostly derived from theoretical calculations, is broadly accepted in the biophysical community. Here we present experimental evidence showing that domain-domain electrostatic repulsions in charged and also in neutral lipid bilayers regulate the diffusion, in-plane structuring and merging of lipid domains in the micron range. All the experiments were performed on both, lipid monolayers and bilayers, and the remarkable similarity in the results found in bilayers compared to monolayers led us to propose that inter-domain repulsions occur mainly within the plane of the membrane. Finally, our results indicate that electrostatic interactions between the species inserted in a cell membrane are not negligible, not only at nanometric but also at larger distances, suggesting another manner for regulating the membrane properties. PMID- 28009905 TI - Syntheses, crystal structures and photophysical properties of Cu(ii) complexes: fine tuning of a coordination sphere for selective binding of azamethiphos. AB - Two copper complexes C1 and C2 have been designed and developed for selective sensing of organophosphates. It is important to develop an efficient method for the detection of these agents for environmental analysis because the overuse of these agents in the environment causes harmful effects on living systems. Our attempts to utilize the copper complexes for the detection of organophosphates remained successful: the C1 complex has shown selective binding for the azamethiphos with a detection limit of 19 nM; while the C2 complex has not revealed any selectivity for any of the tested organophosphates. The results indicated that the coordination sphere of the C1 complex is proficiently engineered in such a way that it offers judicial binding sites for guest molecules. PMID- 28009906 TI - Synthesis and characterization of asymmetrical gemini surfactants. AB - The effect of variation in the length of surfactant hydrocarbon tail groups was tested in a series of dissymmetric gemini surfactants (N1-alkyl N1,N1,N3,N3 tetramethyl-N3-(6-pyren-6yl)-hexyl)propane-1,3-diammonium dibromide designated as CmC3CnBr, with m = hexyl pyrene, and n = 8, 12, 14, 16, and 18. The aggregation properties of these surfactants have been investigated by means of 1H NMR, fluorescence spectroscopy, surface tension and electrical conductivity measurements. The critical micelle concentration (CMC) was determined using surface tension and confirmed using the specific conductance method. Krafft temperatures and the degree of micelle ionization (alpha) were obtained from specific conductance measurements. With an increase of the dissymmetry (m/n) ratio, the CMC decreased linearly and an increase in the Krafft temperatures was observed for all of the gemini surfactants. alpha values for the dissymmetric GS were higher than those of the m-3-m counterparts, which may be attributed to enhanced micelle-micelle interactions that arise from increased hydrophobicity of the hydrocarbon chains. The introduction of the bulky pyrenyl tail group resulted in much lower CMC values compared to their symmetrical counterparts affecting the packing of these surfactants at the air/water interface, which resulted in high ordered structures (lamellar and inverted micelles). This in turn affected the thermodynamic parameters of the micellization. PMID- 28009907 TI - Status and prospects in higher alcohols synthesis from syngas. AB - Higher alcohols are important compounds with widespread applications in the chemical, pharmaceutical and energy sectors. Currently, they are mainly produced by sugar fermentation (ethanol and isobutanol) or hydration of petroleum-derived alkenes (heavier alcohols), but their direct synthesis from syngas (CO + H2) would comprise a more environmentally-friendly, versatile and economical alternative. Research efforts in this reaction, initiated in the 1930s, have fluctuated along with the oil price and have considerably increased in the last decade due to the interest to exploit shale gas and renewable resources to obtain the gaseous feedstock. Nevertheless, no catalytic system reported to date has performed sufficiently well to justify an industrial implementation. Since the design of an efficient catalyst would strongly benefit from the establishment of synthesis-structure-function relationships and a deeper understanding of the reaction mechanism, this review comprehensively overviews syngas-based higher alcohols synthesis in three main sections, highlighting the advances recently made and the challenges that remain open and stimulate upcoming research activities. The first part critically summarises the formulations and methods applied in the preparation of the four main classes of materials, i.e., Rh-based, Mo-based, modified Fischer-Tropsch and modified methanol synthesis catalysts. The second overviews the molecular-level insights derived from microkinetic and theoretical studies, drawing links to the mechanisms of Fischer-Tropsch and methanol syntheses. Finally, concepts proposed to improve the efficiency of reactors and separation units as well as to utilise CO2 and recycle side-products in the process are described in the third section. PMID- 28009908 TI - Exploring the oxidative stress response mechanism triggered by environmental water samples. AB - Environmental waters can contain a wide range of micropollutants. Bioanalytical test batteries using assays indicative of different stages of cellular toxicity pathways, such as adaptive stress responses, have been applied to a range of water samples. Oxidative stress response assays have proven to be sensitive tools, but the mechanism by which water samples are inducing the oxidative stress response remains unclear because both electrophiles and reactive oxygen species (ROS) may activate the Nrf2-antioxidant response element (ARE) pathway. The current study aimed to explore the underlying mechanisms of the oxidative stress response triggered by exposure to surface water extracts previously shown to be active in the ARE GeneBLAzer oxidative stress response assay. ROS formation and changes in glutathione (GSH) concentration were assessed in human liver cells exposed to water extracts from a large river in addition to individual chemicals that were detected in these water extracts and reported to be active in the ARE GeneBLAzer assay in a previous study. Many of the surface water samples induced ROS formation and decreased the GSH to glutathione disulfide (GSSG) ratio, suggesting that the formation of ROS is an important mechanism. However, some of the most responsive samples in the ARE GeneBLAzer assay, as well as the individual chemicals, did not have a significant effect on either ROS formation or the GSH/GSSG ratio, suggesting a different mechanism. Antioxidants can also induce the Nrf2-ARE pathway and the ARE GeneBLAzer assay may also detect compounds that activate ARE by Nrf2-independent mechanisms, thus further research is required to characterise active chemicals in oxidative stress response assays. However, these tests are still useful for quantifying the integrated cellular response to multiple molecular initiating events and can be used complementary to assays indicative of specific effects, such as receptor-mediated assays. PMID- 28009909 TI - Atomic layer deposition of ZnO on carbon black as nanostructured anode materials for high-performance lithium-ion batteries. AB - Although zinc oxide (ZnO), a low-cost and naturally abundant material, has a high theoretical specific capacity of 987 mA h g-1 for hosting lithium ions, its application as an anode material has been hindered by its rapid capacity fading, mainly due to a large volume change (around 228%) upon repeated charge-discharge cycles. Herein, using carbon black (CB) powder as a support, ZnO-carbon black (denoted as ZnO-CB) nanocomposites were successfully fabricated using the atomic layer deposition (ALD) method. This method was able to produce strong interfacial molecular bindings between ZnO nanoclusters and the carbon surface that provide stable and robust electrical contact during lithiation and delithiation processes, as well as ZnO nanoclusters rich in oxygen vacancies (OVs) for faster Li-ion transport. Overall, the nanocomposites were able to deliver a high discharge specific capacity of 2096 mA h g-1ZnO at 100 mA g-1 and stable cyclic stability with a specific capacity of 1026 mA h g-1ZnO maintained after 500 cycles. The composites also have excellent rate capability, and a reversible capacity at a high 1080 mA h g-1ZnO at 2000 mA g-1. The facile but unique synthesis method demonstrated in this work for producing nanostructures rich in OVs and nanocomposites with strong coupling via interfacial molecular bindings could be extended to the synthesis of other oxide based anode materials and therefore could have general significance for developing high energy density lithium ion batteries. PMID- 28009910 TI - Collective interactions in the nucleation and growth of surface droplets. AB - In the process of solvent exchange, oil droplets nucleate and grow on a solid substrate in response to the oversaturation generated through the displacement of a good oil solvent by a poor one. The mean size of the droplets depends on flow rate, flow geometry and solution conditions. In this work, we investigate the surface coverage of the droplets and the correlation between the base area of the droplets and of the bare zone surrounding the droplets for various flow and solution conditions during the solvent exchange. The surface coverage increases with the increase in the flow rate, channel height and the oil concentration, and reaches a plateau between 35% and 50%. The spatial correlation is analysed with the help of the radial distribution function g(r) and a Voronoi tessellation. When the surface coverage reaches ~25-30%, the number density of the droplets starts to drop, reflecting the mutual interaction and merging of the droplets. With further decrease in the droplet spacing and increase in surface coverage, the Voronoi analysis shows that the base area of the droplets increases linearly with the area size of the depleted zone. The collective interaction in the growth of surface nanodroplets is universal, independent of the specific conditions that control the droplet growth. PMID- 28009911 TI - Assessing the relative stability of copper oxide clusters as active sites of a CuMOR zeolite for methane to methanol conversion: size matters? AB - Copper-containing zeolites exhibit high activity in the direct partial oxidation of methane into methanol at relatively low temperatures. Di- and tricopper species have been proposed as active catalytic sites, with recent experimental evidence also suggesting the possibility of the formation of larger copper oxide species. Using density functional theory based global geometry optimization, we were able to identify a general trend of the copper oxide cluster stability increasing with size. For instance, the identified ground-state structures of tetra- and pentamer copper clusters of CunOn2+ and CunOn-12+ stoichiometries embedded in an 8-ring channel of mordenite exhibit higher relative stability compared to smaller clusters. Moreover, the aluminium content and localization in the zeolite pore influence the cluster's stability and its geometrical motif, which offers a perspective of tuning the properties of copper-exchanged zeolites by creating copper oxide clusters of a given structure and size. With the activity of the cluster towards methane being connected to its stability, such tuning will potentially allow the design of catalysts with engineered properties. PMID- 28009912 TI - Spontaneous Si-C bond cleavage in (TriphosSi)-nickel complexes. AB - Herein, we report on the versatile reactions of CH3C(CH2PPh2)3 as well as CH3Si(CH2PPh2)3 derived Ni-complexes. While Ni[CH3C(CH2PPh2)3] complexes reveal high stability, the Ni[CH3Si(CH2PPh2)3] analogs show rapid decomposition at room temperature and afford the unprecedented pseudo-tetrahedral phosphino methanide complex 5. We provide a detailed electronic structure of 5 from X-ray absorption and emission spectroscopy data analysis in combination with DFT calculations, as well as from comparison with structurally related complexes. A mechanistic study for the formation of complex 5 by reaction with BF4- is presented, based on a comparison of experimental data with quantum chemical calculations. We also show a simple route towards isolable Ni(i)-complexes on the gram scale. PMID- 28009913 TI - Facile synthesis of thietanes via ring expansion of thiiranes. AB - Thietanes are pharmaceutically important cores of some biological compounds and intermediates of organic synthesis. Various thietanes were prepared from thiiranes via ring expansion through a reaction with trimethyloxosulfonium iodide in the presence of sodium hydride. The reaction process is a nucleophilic ring opening reaction of thiiranes with dimethyloxosulfonium methylide, generated from trimethyloxosulfonium iodide and sodium hydride, and subsequent intramolecular displacement (cyclization) of thiolates to the dimethyloxosulfonium moiety. The current method provides a new strategy for efficient preparation of thietanes from readily available thiiranes. PMID- 28009914 TI - Whole cell-SELEX of aptamers with a tyrosine-like side chain against live bacteria. AB - In an effort to expand the binding and recognition capabilities of aptamers, a nucleoside triphosphate modified with a phenol that mimics the side chain of tyrosine was used in the selection of DNA aptamers against live bacteria. Of multiple modified aptamers that were isolated against Escherichia coli DH5alpha cells, one aptamer displays high selectivity and affinity for the target cells and is greatly enriched for phenol-modified dU nucleotides (dUy, 47.5%). When the same sequences are synthesized with TTP, no binding is observed. Taken together, these findings highlight the value of using modified nucleotide triphosphates in aptamer selections and portends success in SELEX against an array of whole cells as targets. PMID- 28009915 TI - Evidence of nose-to-brain delivery of nanoemulsions: cargoes but not vehicles. AB - The nose-to-brain pathway has been proven to be a shortcut for direct drug delivery to the brain. However, whether and to what extent nanoparticles can be delivered through this passage is still awaiting validation with evidence. In this study, nose-to-brain transportation of nanoparticles is tracked via fluorescence bioimaging strategies using nanoemulsions (NEs) as model carriers. Identification of NEs in biological tissues is based on the on -> off signal switching of a new type of environment-responsive embedded dyes, P2 and P4, and two conventional probes, DiR and coumarin-6 (C6), are embedded to represent the cargoes. Evidence for the translocation of NEs was collected either via live imaging or ex vivo histological examination in rats after nasal administration. Results suggest that NEs with a particle size of about 100 nm, either naked or coated with chitosan, have longer retention duration in nostrils and slower mucociliary clearance than larger ones. P2 signals, representing integral NEs, can be found in mucosa and trigeminal nerves for all size groups, whereas only weak P2 signals are detected in the olfactory bulb for chitosan-coated NEs of 100 nm. Confocal microscopy further confirms the translocation of integral 100 nm NEs in nasal mucosa and along the trigeminal nerve in decremental intensity. Weak signals of the P4 probe, also representing integral NEs, can be detected in the olfactory bulb but few in the brain. NEs as large as 900 nm cannot be transported to the olfactory bulb. However, the DiR or C6 signals that represent the cargoes can be found in significant amounts along the nose-to-brain pathway and finally reach the brain. Evidence shows that integral NEs can be delivered to the olfactory bulb, but few to the brain, whereas the cargoes can be released and permeated into the brain in greater amounts. PMID- 28009916 TI - Selenium in the prevention of atherosclerosis and its underlying mechanisms. AB - Atherosclerosis and related cardiovascular diseases (CVDs) represent the greatest threats to human health worldwide. Selenium, an essential trace element, is incorporated into selenoproteins that play a crucial role in human health and disease. Although findings from a limited number of randomized trials have been inconsistent and cannot support a protective role of Se supplementation in CVDs, prospective observational studies have generally shown a significant inverse association between selenium or selenoprotein status and CVD risk. Furthermore, a benefit of selenium supplementation in the prevention of CVDs has been seen in population with low baseline selenium status. Evidence from animal studies shows consistent results that selenium and selenoproteins might prevent experimental atherosclerosis, which can be explained by the molecular and cellular effects of selenium observed both in animal models and cell cultures. Selenoproteins of particular relevance to atherosclerosis are glutathione peroxidases, thioredoxin reductase 1, selenoprotein P, selenoprotein S. The present review is focusing on the existing evidence that supports the concept that optimal selenium intake can prevent atherosclerosis. Its underlying mechanisms include inhibiting oxidative stress, modulating inflammation, suppressing endothelial dysfunction, and protecting vascular cells against apoptosis and calcification. However, the benefit of selenium supplementation in the prevention of atherosclerosis remains insufficiently documented so far. Future studies with regard to the effects of selenium supplementation on atherosclerosis should consider many factors, especially the baseline selenium status, the dose and forms of selenium supplementation, and the selenoprotein genotype. Additionally, much more studies are needed to confirm the roles of selenoproteins in atherosclerosis prevention and clarify the underlying mechanisms. PMID- 28009917 TI - Hierarchically structured photonic crystals for integrated chemical separation and colorimetric detection. AB - A SiO2 colloidal photonic crystal film with a hierarchical porous structure is fabricated to demonstrate an integrated separation and colorimetric detection of chemical species for the first time. This new photonic crystal based thin layer chromatography process requires no dyeing, developing and UV irradiation compared to the traditional TLC. The assembling of mesoporous SiO2 particles via a supersaturation-induced-precipitation process forms uniform and hierarchical photonic crystals with micron-scale cracks and mesopores, which accelerate the diffusion of developers and intensify the adsorption/desorption between the analytes and silica for efficient separation. Meanwhile, the chemical substances infiltrated to the voids of photonic crystals cause an increase of the refractive index and a large contrast of structural colors towards the unloaded part, so that the sample spots can be directly recognized with the naked eye before and after separation. PMID- 28009918 TI - Formation and rheological behavior of wormlike micelles in a catanionic system of fluoroacetic acid and tetradecyldimethylaminoxide. AB - From catanionic fluoro-/hydro-carbon mixtures of fluoroacetic acid (CF3COOH) and tetradecyldimethylaminoxide (C14DMAO) in water, viscoelastic wormlike micelles are successfully constructed which are determined by cryo-TEM measurements. It is found that the formation and rheological behavior of the wormlike micelles are greatly affected by the total concentration and mixing ratio of CF3COOH and C14DMAO as well as temperature. The driving force for the formation of wormlike micelles here is considered to be the electrostatic attractive interaction between the two molecules which is confirmed by 1H NMR measurements. As far as we know, such wormlike micelles formed from the catanionic mixtures of fluorofatty acids and hydrocarbon surfactants have been rarely reported. Our work provides a simple method through mixing a perfluorofatty acid with a hydrocarbon surfactant to construct and understand the formation mechanism of catanionic fluoro-/hydro carbon wormlike micelles, which should be a great advance in the fundamental research of wormlike micelles. PMID- 28009919 TI - Two-dimensional hydrogenated molybdenum and tungsten dinitrides MN2H2 (M = Mo, W) as novel quantum spin hall insulators with high stability. AB - Based on first-principles calculations, we predict the existence of the quantum spin Hall (QSH) effect in hydrogenated transition-metal nitrides MN2H2 (M = Mo, W), showing high structural stability. MN2H2 monolayers are identified to be intrinsic topological insulators (TIs) with protected Dirac type topological helical edge states, and show robust topological features against the large stretching strain. Besides, sizeable intrinsic nontrivial band gaps (70-124 meV) ensure the QSH effect in MN2H2 at room temperature. The pure d-d band inversion was revealed. More interestingly, the topological phase transition between a QSH phase and a topological semimetallic phase can be induced by applying in-plane strain. PMID- 28009920 TI - Cu-Catalyzed electrophilic amination of internal alkynes via hydroalumination. AB - A straightforward and efficient method for the synthesis of 1,2-diaryl substituted enamines through the Cu-catalyzed electrophilic amination reaction of O-benzoyl hydroxylamines with vinylaluminum reagents generated in situ from the Ni-catalyzed hydroalumination of readily accessible internal aryl acetylenes is described. The amination is catalyzed by 1 mol% CuCl without any additive at ambient temperature to afford new versatile enamines in good yield (61-91%) with high selectivity (>98% E-enamine). PMID- 28009921 TI - Synthesis of annulated bis-indoles through Au(i)/Bronsted acid-catalyzed reactions of (1H-indol-3-yl)(aryl)methanols with 2-(arylethynyl)-1H-indoles. AB - A general method to access annulated bis-indoles from (1H-indol-3 yl)(aryl)methanols and 2-(arylethynyl)-1H-indoles under the catalysis of the Ph3PAuOTf/Bronsted acid binary catalyst system has been developed. The reaction was found to proceed in a highly efficient manner and benefit from easy-to-make starting materials, broad substrate scope and operational simplicity. The potential of this method has also been exemplified for the synthesis of pyrrole annulated indoles using 2-(phenylethynyl)-1H-indoles and phenyl(1H-pyrrol-2 yl)methanols. Furthermore, the use of a ternary catalyst system, involving PdCl2/Bronsted acid/Ph3PAuOTf catalysts, has been realized for the synthesis of annulated bis-indoles starting directly from 2-(phenylbuta-1,3-diyn-1-yl)aniline and (1H-indol-3-yl)(aryl)methanol. Mechanistically, this reaction is very interesting since the overall process involves three different catalytic cycles catalyzed by three different catalysts in a relay fashion. PMID- 28009922 TI - Luminescence color control and quantum-efficiency enhancement of colloidal Si nanocrystals by pulsed laser irradiation in liquid. AB - We demonstrate the emission color change of white-emitting chlorine-terminated silicon nanocrystals (Cl:Si-ncs) to blue-emitting carbon-terminated silicon nanocrystals (C:Si-ncs), together with the enhancement of the luminescence quantum efficiency from 7% to 13%, by post-laser ablation in 1-octene. Such changes of the PL properties are caused by the size reduction of Si-nc and efficient surface passivation by hydrocarbons, resulting from a high reactivity of 1-octene in the laser-ablation and subsequent nanoparticle-formation processes. Furthermore, the second post-laser irradiation of the C:Si-ncs in trichloroethylene reversibly results in the formation of the Cl:Si-ncs. The preparation yield of C:Si-ncs via the post-laser ablation of Cl:Si-ncs is higher than that of C:Si-ncs directly prepared only by the laser ablation of PSi in 1 octene. This high preparation yield is due to the high laser-ablation efficiency in trichloroethylene compared with 1-octene, which is attributed to the low heat loss of the solvent in the laser-ablation process. PMID- 28009923 TI - Shape-tunable Pt-Ir alloy nanocatalysts with high performance in oxygen electrode reactions. AB - For the first time, shape-tunable Pt-Ir alloy nanocatalysts including both single crystalline (nano-octahedra (NOs), nano-truncated octahedra (NTOs), nanocubes (NCs)) and polycrystalline (nanocluster flowers (NCFs), nanowires (NWs), nano short-chains (NSCs), and nano-octahedral stars (NOSs)) ones were synthesized with a facile one-pot solvothermal method, via precise control of the facet-selective agents (Br- and I-). The surface effects of Pt-Ir alloy nanocatalysts for oxygen electrode reaction in acidic solution were intensively investigated. Pt-Ir alloy nanocatalysts showed enhanced catalytic activities for the oxygen evolution reaction (OER), which were 1.6 to 2.0 times those of the commercial Ir/C catalyst and the Pt/C-Ir/C mixture at an overpotential of 0.25 V. The catalytic activity for the OER exhibited a positive correlation with the proportion of surface IrOx species, but was restricted by the surface alloying effect. Besides the change of the intermediate adsorption state, the dissociation of water was also confirmed to be effective as the rate-determining step of the Pt-Ir alloy nanocatalysts. The catalytic activity for the oxygen reduction reaction (ORR) decreased with the increase of surface IrOx species. Pt-Ir nano-short-chains (NSCs) exhibited 1.3 times the catalytic activity as that of the commercial Pt/C catalyst at 0.80 V and 0.85 V, owing to the higher proportion of the (110) facets with irregular step sites exposed after the annealing treatment at 350 degrees C. The unique structure could prevent the mass transfer process from being obstructed by adsorbed bisulfate anions and oxidized species on the surfaces. Pt-Ir NSCs exhibited a catalytic efficiency of 46.7% and were considered to be a promising URFC catalyst. PMID- 28009924 TI - C-F bond activation of perfluorinated arenes by a bioxazoline-derived N heterocyclic carbene. AB - The N-heterocyclic carbene IBioxMe4 enacts selective single and double C-F bond activation of octafluorotoluene and hexafluorobenzene, respectively. The formation of the fluoroarene substituted, zwitterionic imidazoliumolate products is consistent with a mechanism involving nucleophilic aromatic substitution and subsequent oxazoline ring opening by liberated fluoride. PMID- 28009925 TI - Synthesis, in vitro and in vivo evaluation of new hybrids of millepachine and phenstatin as potent tubulin polymerization inhibitors. AB - In this paper, a series of millepachine derivatives were synthesized and evaluated as tubulin polymerization inhibitors. The optimal compound 5i, (3 hydroxy-4-methoxyphenyl)(5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone, displayed the highest cytotoxicity toward a series of cancer cells (ranging from 18 to 45 nM of IC50). Further investigation revealed that 5i significantly repressed the multidrug resistant cells (A549/CDDP, A2780/TAX) and had little cytotoxicity towards human normal cells (HLF, BJ). Cellular mechanism studies demonstrated that 5i induced G2/M phase arrest and apoptosis, which was associated with the collapse of the mitochondrial membrane potential (MMP). Additionally, western blot analysis showed that 5i could change the levels of cell cycle-related proteins (e.g. Cyclin B1, Cdc25c, Cdc2) and some apoptosis related proteins (e.g. Bax, Bad, Bcl-2, Bcl-xl). Finally, 5i effectively inhibited the growth of xenograft tumours of A549 cells in nude mice. PMID- 28009926 TI - Thin-sheet creation and threshold pressures in drop splashing. AB - A liquid drop impacting a smooth solid substrate splashes by emitting a thin liquid sheet from near the contact line of the spreading liquid. This sheet is lifted from the substrate and ultimately breaks apart. Surprisingly, the splash is caused by the ambient gas, whose properties dictate when and if the sheet is created. Here, I focus on two aspects of this process. Using high-speed imaging I find that the time of thin-sheet creation displays a different quantitative dependence on air pressure if the sheet is created during the early stages of spreading, rather than when the liquid has already spread to a large radius. This result sheds light on previously observed impact velocity regimes. Additionally, by measuring impacts of drops on surfaces comprised of both rough and smooth regions, I identify a new threshold velocity that limits the times at which the thin sheet can be created. This velocity determines the threshold pressure below which splashing is suppressed. PMID- 28009928 TI - Electronic and optical properties of oxygen vacancies in amorphous Ta2O5 from first principles. AB - Oxygen vacancies are important defects considered to play a central role in the electronic and optical properties of tantalum pentoxide (Ta2O5) films and devices. Despite extensive experimental studies on oxygen vacancies in Ta2O5, the reported defect states are ambiguously identified due to the absence of accurate and conclusive theoretical evidence. Here we investigate the thermodynamic, electronic, and optical properties of oxygen vacancies in amorphous Ta2O5 by first-principles calculations based on hybrid-functional density functional theory (DFT). The calculated thermodynamic and optical transition levels are in good agreement with a broad range of diverse measured properties with various experimental methods, providing conclusive evidence for the identification of the defect states observed in experiments as originating from oxygen vacancies. Our calculations also predict the formation of spin-polarized polarons. Our results elucidate the fundamental atomistic properties of oxygen vacancies in various oxidation states as a function of growth conditions and provide guidance to control the properties of Ta2O5 films/devices. PMID- 28009927 TI - Abnormal pH elevation in the Chaobai River, a reclaimed water intake area. AB - The pH is a primary index reflecting water quality in rivers. The Jian River and Chaobai River are two reclaimed water intake areas which have elevated pH. This elevated pH has a marked effect on both the phytoplankton, species in water and vegetation on the shore. Understanding the main reasons causing pH elevation in river water has important implications for river ecosystem management and the improvement of water quality and can provide a theoretical basis for the direction of water quality improvement. For this reason, each biogeochemical and physical process influencing pH changes in water was quantified along the flow direction in the Wenyu to Chaobai reclaimed water diversion project, in which proton consumption and production by such processes were monitored and calculated at five monitoring sections. The calculations indicated that photosynthesis and denitrification were the primary reasons for the increase of pH in the Jian River and Chaobai River. Oppositely, carbonate precipitation and sediment decomposition restricted the increase of pH in both rivers. In addition, CO2 emission to the air also promoted a increase of pH in the Jian River, while CO2 absorption from the air restricted the increase of pH in the Chaobai River. NO3- nitrogen in reclaimed water was not efficiently removed and the reclaimed water flow condition in the intake area created favorable conditions for photosynthesis of algae breeding and denitrification by microorganisms. Therefore, biogeochemical and physical processes that promoted the increase of pH were greater than inhibiting processes and the pH gradually increased along the flow direction. The contribution rates of photosynthesis and denitrification for the increase of pH were 55.48 and 27.09%, respectively, in the Jian River and 78.08 and 21.92%, respectively, in the Chaobai River. In addition, CO2 emission contributed 17.43% of the increase in pH in the Jian River. PMID- 28009929 TI - Solvent effects on the folding of o-phenylene oligomers. AB - ortho-Phenylene oligomers fold into compact helical conformations in solution, and have therefore recently emerged as a class of foldamers. Previous work has shown that their folding is controlled by arene-arene stacking interactions parallel to the helical axis. Such interactions might reasonably be expected to be sensitive to solvent, but little is known of solvent effects in this system. Here, we report on the behavior of a representative set of o-phenylene oligomers in solvents ranging from non-polar (benzene) to polar and protic (methanol and water). The oligomers have been synthesized using post-oligomerization functionalization by click chemistry. Their folding is good in all solvents studied, but becomes measurably worse as the dielectric constant of the solvent increases. Thus, in contrast to the behavior of many other classes of aromatic foldamers, the folding propensity of o-phenylenes does not appear to be strongly affected by the solvophobic effect. Instead, the greater polarity of "frayed end" states governs their behavior. PMID- 28009930 TI - Incorporation of a metabolizing system in biodetection assays for endocrine active substances. AB - The use of in vitro assays is important for the biodetection of endocrine active substances (EAS), reducing and replacing the in vivo studies required for regulatory assessment. However, this approach often fails to take into account the role of biotransformation on the activity of the test substances. A method incorporating an S9 metabolic system into the CALUX-reporter gene assays for estrogen receptor alpha- and anti-androgen receptor -mediated activities has been developed. Methoxychlor, which is known to exhibit increased estrogenic and anti androgenic activities after biotransformation, was used to set up the method in ERa and anti-AR CALUX. For the anti-androgenic assay, stanozolol was used as a competing agonist not metabolized by S9. The method was first applied in both agonist and antagonist modes to methoxychlor and bisphenol A, as positive and negative controls, respectively. Then, benzo(a)pyrene and flutamide were also tested for their potential of bioactivation. Co-treatment with S9 successfully increased the ERalpha agonist and AR antagonist potency of methoxychlor; no change was observed for bisphenol A. Incubation with S9 also enhanced the anti androgenic activity of flutamide. Interestingly, the metabolism of benzo(a)pyrene by the S9 resulted in an increased estrogen receptor-mediated transcriptional activation; any increase in the potency was only minor. It is likely that both enzyme kinetics and metabolite stability have influenced these effects, which would affect the composition of the final metabolite mixture. Together these results demonstrate the relevance of including biotransformation in in vitro bioassays for the detection of EAS. PMID- 28009931 TI - Do more robust prescription drug monitoring programs reduce prescription opioid overdose? AB - BACKGROUND AND AIMS: In the United States, overdose deaths attributed to opioid pain relievers (OPR) have quadrupled since 1999, prompting many states to adopt Prescription Drug Monitoring Programs (PMP). This study aimed to: (1) estimate the relationship of PMP strength with OPR overdose deaths across states and over time; (2) measure what threshold in PMP strength is associated with the greatest reduction in OPR overdose; and (3) assess the relationship of medical marijuana dispensaries with OPR overdose deaths. DESIGN: Panel data from the Centers for Disease Control and Prevention's (CDC's) Wide-ranging Online Data for Epidemiologic Research database (WONDER) were analyzed using fixed effects to regress state-year death rates on an index variable compiled from the Prescription Drug Abuse Policy System (PDAPS) while controlling for PMP administration, demographic factors and laws that might affect OPR overdose. SETTING AND PARTICIPANTS: Age-adjusted opioid overdose death rates for all 50 states and the District of Columbia between 1999 and 2014 for a total of 816 observations. MEASUREMENTS: PMP strength was calculated using legal data compiled by the Prescription Drug Abuse Policy System (PDAPS). In addition to demographic controls, other covariates included laws that regulate pain clinics, access to naloxone, use of emergency services (Good Samaritan Laws) and medical marijuana. FINDINGS: PMP strength was associated negatively with OPR overdose deaths. Every 1-point increase in PMP strength was associated with a 1% [95% confidence interval (CI) = 0.2-2%] reduction in overdose deaths. When collapsed into quartiles, PMPs in the third quartile were associated with an approximately 18% (95% CI = 1.6-29%) reduction in OPR overdose death rates compared with states without a PMP. States with medical marijuana dispensaries reported a 16% (95% CI = 1-30%) reduction in OPR overdoses. CONCLUSIONS: US states that have more robust prescription drug monitoring programs have fewer prescription opioid overdose deaths than states with weaker PMPs. States with medical marijuana dispensaries also report fewer opioid overdose deaths than states without these. PMID- 28009932 TI - Luminescent Metal-Organic Framework Sensor: Exceptional Cd2+ Turn-On Detection and First In Situ Visualization of Cd2+ Ion Diffusion into a Crystal. AB - With regard to fluorescence quenching commonly observed during metal-ion detection, "turn-on" chemical sensing has been rarely reported, but could be extremely important because it facilitates the selective recognition of target objects of interest against a dark background. A metal-organic framework (MOF) chemosensor has been prepared that serves as an efficient platform for the selective detection of Cu2+ and Cd2+ ions over other metal ions. In particular, this framework shows the highest fluorescence enhancement (~60-fold relative to Cd-free MOF) for the hazardous metal ion Cd2+ among luminescent MOFs and displays excellent reusability in repeated cycles. The direct diffusion of Cd2+ into the crystal pores has also been visualized for the first time. PMID- 28009933 TI - Mass spectrometry-driven drug discovery for development of herbal medicine. AB - Herbal medicine (HM) has made a major contribution to the drug discovery process with regard to identifying products compounds. Currently, more attention has been focused on drug discovery from natural compounds of HM. Despite the rapid advancement of modern analytical techniques, drug discovery is still a difficult and lengthy process. Fortunately, mass spectrometry (MS) can provide us with useful structural information for drug discovery, has been recognized as a sensitive, rapid, and high-throughput technology for advancing drug discovery from HM in the post-genomic era. It is essential to develop an efficient, high quality, high-throughput screening method integrated with an MS platform for early screening of candidate drug molecules from natural products. We have developed a new chinmedomics strategy reliant on MS that is capable of capturing the candidate molecules, facilitating their identification of novel chemical structures in the early phase; chinmedomics-guided natural product discovery based on MS may provide an effective tool that addresses challenges in early screening of effective constituents of herbs against disease. This critical review covers the use of MS with related techniques and methodologies for natural product discovery, biomarker identification, and determination of mechanisms of action. It also highlights high-throughput chinmedomics screening methods suitable for lead compound discovery illustrated by recent successes. PMID- 28009934 TI - The prominence of smoking-related mortality among individuals with alcohol- or drug-use disorders. AB - INTRODUCTION AND AIMS: Even though individuals with substance-use disorders have a high prevalence of tobacco smoking, surprisingly little is known about smoking related mortality in these populations. The current retrospective cohort study aims to address this gap. DESIGN AND METHODS: The study sample included cohorts of individuals hospitalised in California between 1990 and 2005 with alcohol- (n = 509 422), cocaine- (n = 35 276), opioid- (n = 53 172), marijuana- (n = 15 995) or methamphetamine-use (n = 36 717) disorders. Death records were linked to inpatient data. Age-, race- and sex-adjusted standardised mortality ratios (SMR) were generated for 19 smoking-related causes of death. RESULTS: Smoking-related conditions comprised 49% (79 188/163 191) of total deaths in the alcohol, 40% (1412/3570) in the cocaine, 39% (4285/11 091) in the opioid, 42% (554/1332) in the methamphetamine and 36% (1122/3095) in the marijuana cohorts. The SMRs for all smoking-linked diseases were: alcohol, 3.57 (95% confidence interval [CI] = 3.55 to 3.58); cocaine, 2.40 (95% CI = 2.39 to 2.41); opioid, 4.26 (95% CI = 4.24 to 4.27); marijuana, 3.73 (95% CI = 3.71 to 3.74); and methamphetamine, 2.58 (95% CI = 2.57 to 2.59). The SMRs for almost all of the 19 cause-specific smoking related outcomes were elevated across cohorts. DISCUSSION AND CONCLUSIONS: Given the current findings, addressing tobacco smoking among persons with substance-use disorders should be a critical concern, especially given the heavy smoking related mortality burden and the currently limited attention devoted to smoking in these populations. [Callaghan RC, Gatley JM, Sykes J, Taylor L. The prominence of smoking-related mortality among individuals with alcohol- or drug-use disorders. Drug Alcohol Rev 2018;37:97-105]. PMID- 28009935 TI - Synthesis and Olfactory Properties of a 6'-Silasubstituted "Spiro[4.5]-delta Damascone". AB - The silicon analogue of the potent spirocyclic delta-damascone odorant 6 was synthesized from allyltrichlorosilane (15) and but-2-en-1-ol (16). The latter was transformed to 3-methylpen-4-enenitrile (11) by Saucy-Marbet reaction with ethoxyethane and subsequent treatment with HONH2 ?HCl. The resulting gamma,delta unsaturated nitrile 11 was silylated with 1-allyl-1-chlorosilolane (14), which was prepared from allyltrichlorosilane (15) and the bis-Grignard reagent of 1,4 dichlorobutane. Metathetic ring closure employing the Grubbs I catalyst, followed by DIBAL reduction with non-aqueous work up, Grignard reaction with prop-1-en-1 ylmagnesium bromide, and Attenburrow MnO2 oxidation concluded the synthesis. The target compound was found to be olfactorily related to the spiro[4.5]-delta damascone lead, but approximately 900 times weaker. In a type of enol Brook rearrangement, it thermally decomposes however to 3,6-dihydro-2H-1,2-oxasilocine (20), which surprisingly is a damascone odorant as well; although, 12 000 times weaker. PMID- 28009936 TI - Double Reduction of 4,4'-Bipyridine and Reductive Coupling of Pyridine by Two Thorium(III) Single-Electron Transfers. AB - The redox chemistry of uranium is burgeoning and uranium(III) complexes have been shown to promote many interesting synthetic transformations. However, their utility is limited by their reduction potentials, which are smaller than many non traditional lanthanide(II) complexes. Thorium(III) has a greater redox potential so it should present unprecedented opportunities for actinide reactivity but as with uranium(II) and thorium(II) chemistry, these have not yet been fully realized. Herein we present reactivity studies of two equivalents of [Th(Cp'')3 ] (1, Cp''={C5 H3 (SiMe3 )2 -1,3}) with 4,4'-bipyridine or two equivalents of pyridine to give [{Th(Cp'')3 }2 {MU-(NC5 H4 )2 }] (2) and [{Th(Cp'')3 }2 {MU-(NC5 H5 )2 }] (3), respectively. As relatively large reduction potentials are required to effect these transformations we have shown that thorium(III) can promote reactions that uranium(III) cannot, opening up promising new reductive chemistry for the actinides. PMID- 28009937 TI - Needle aspiration versus incision and drainage for the treatment of peritonsillar abscess. AB - BACKGROUND: Peritonsillar abscess is a common infection presenting as a collection of pus in the peritonsillar area. The condition is characterised by a severe sore throat, difficulty in swallowing and pain on swallowing, fever and malaise, and trismus. Needle aspiration and incision and drainage are the two main treatment modalities currently used in the treatment of this condition. The effectiveness of one versus the other has not been clearly demonstrated and remains an area of debate. OBJECTIVES: To assess the effectiveness and risks of needle aspiration versus incision and drainage for the treatment of peritonsillar abscess in older children (eight years of age or older), adolescents and adults. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2016, Issue 7); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 25 August 2016. SELECTION CRITERIA: Randomised controlled trials comparing needle aspiration with incision and drainage. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were recurrence rate (proportion of patients needing repeat intervention) and adverse effects associated with the intervention. Secondary outcomes were time to resumption of normal diet, complications of the disease process and symptom scores. We used GRADE to assess the quality of evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 11 studies (674 participants). The risk of bias was high or unclear in all of the included studies. All studies compared needle aspiration to incision and drainage.All but one of the 11 studies reported on the primary outcome of recurrence. When we pooled data from the 10 studies the recurrence rate was higher in the needle aspiration group compared with incision and drainage: risk ratio (RR) 3.74 (95% confidence interval (CI) 1.63 to 8.59; 612 participants). We detected moderate heterogeneity in this analysis (I2 = 48%). In interpreting the pooled result it is important to note that the evidence for this outcome was of very low quality.None of the other outcomes (adverse effects of the intervention, time to resumption of normal diet, complications of the disease process and symptom scores) were consistently measured across all studies.Only three studies reported on adverse effects/events associated with the intervention and only one such event in a single patient was reported (post-procedure bleeding following incision and drainage: 1/28, 3.6%) (very low-quality evidence). Time to resumption of normal diet was compared in two studies; neither found an obvious difference between needle aspiration and incision and drainage (very low-quality evidence).Only three studies stated that they would report complications of the disease process. In these three studies, the only complication reported was admission to hospital for dehydration in two patients who underwent incision and drainage (2/13, 6.7%). Symptom scores were measured in four studies; three evaluated pain using different scales and one other symptoms. The data could not be pooled in a meta-analysis. Two studies evaluating procedural pain reported this to be lower in the needle aspiration groups. One study found comparable rates of pain resolution at five days post-intervention between groups. The quality of the evidence for symptom scores was very low. AUTHORS' CONCLUSIONS: Although a number of studies have sought to evaluate whether or not needle aspiration or incision and drainage is more effective in patients with peritonsillar abscess, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain. Very low-quality evidence suggests that incision and drainage may be associated with a lower chance of recurrence than needle aspiration. There is some very low-quality evidence to suggest that needle aspiration is less painful. PMID- 28009938 TI - Structure and Optical Properties of Carbon Nanoparticles Generated by Laser Treatment of Graphite in Liquids. AB - In this paper, we report the one-step synthesis of luminescent carbon nanoparticles (NPs) via laser irradiation of a graphite target in a solvent [H2 O, ethanol, or a 0.008 m aqueous diethylenetriaminepentaacetic acid (DTPA) solution]. This is a simple approach for the fabrication of carbon dots with tunable photoluminescence (PL) that differs from other preparation methods, as no post-passivation step is required. The unfocused beam of the second harmonic (wavelength 532 nm) of the Nd:YAG laser was used in our experiments. The sizes of the prepared NPs were mainly distributed in the range of 1-8 nm with an average value of 3 nm. Carbon NPs of different inner structure were prepared: hexagonal diamond phase in aqueous DTPA solution, orthorhombic carbon phase in ethanol, and amorphous carbon in water. The synthesized carbon NPs have strong luminescence in the visible region, which makes them attractive for numerous biological applications. The photoluminescence of the synthesized NPs was investigated at different excitation wavelengths, from 260 to 450 nm. The highest intensities of the emission bands were detected for an excitation wavelength of 400 nm. PMID- 28009939 TI - Comparative Efficacy and Tolerability of Antimuscarinic Agents and the Selective beta3-Adrenoceptor Agonist, Mirabegron, for the Treatment of Overactive Bladder: Which is More Preferable as an Initial Treatment? AB - OBJECTIVES: The objective of the present study was to evaluate comparative efficacy and tolerability of antimuscarinics and mirabegron as primary and salvage therapy in patients with overactive bladder (OAB). METHODS: Patients >=50 years with OAB symptoms were enrolled. Patients were initially treated with antimuscrinics or mirabegron for 8 weeks. When patients were refractory or intolerant to an initial treatment, drugs were switched to the other. The initial and second-line efficacy was assessed at baseline, 4 and 8 weeks after the treatment having the following parameters of the International Prostatic Symptom Score (IPSS), quality of life (QOL) index, Overactive Bladder Symptom Score (OABSS) and post-void residual (PVR) urine volume. Dry mouth and constipation were evaluated using dry mouth scale and constipation assessment scale, respectively. RESULTS: A total of 117 patients were enrolled. As an initial treatment, 60 patients were given antimuscarinics and 57 patients received mirabegron. Similar initial treatment efficacy was observed between the two drugs in the whole patients. However, mirabegron was more efficacious to men with OAB unresponsive to prior alpha1-blocker. Dry mouth and constipation were less burdensome in patients treated with mirabegron. Such differences in efficacy and tolerability were associated with significantly greater persistence of mirabegron. As a second-line setting, both drugs appear to be equally effective at least to relieve urgency symptoms remaining after an initial therapy. CONCLUSION: The present study suggests that mirabegron seems to have priority as an initial therapy with a distinct efficacy/tolerability balance. Mirabegron also represents a reasonable alternative to antimuscarinics for patients who had insufficient efficacy and poor tolerability. PMID- 28009940 TI - An in vivo transfection system for inducible gene expression and gene silencing in murine hepatocytes. AB - BACKGROUND: Hydrodynamic tail vein injection (HTVI) of transposon-based integration vectors is an established system for stably transfecting mouse hepatocytes in vivo that has been successfully employed to study key questions in liver biology and cancer. Refining the vectors for transposon-mediated hepatocyte transfection will further expand the range of applications of this technique in liver research. In the present study, we report an advanced transposon-based system for manipulating gene expression in hepatocytes in vivo. METHODS: Transposon-based vector constructs were generated to enable the constitutive expression of inducible Cre recombinase (CreER) together with tetracycline inducible transgene or miR-small hairpin RNA (shRNA) expression (Tet-ON system). Transposon and transposase expression vectors were co-injected into R26R-mTmG reporter mice by HTVI. Cre-mediated gene recombination was induced by tamoxifen, followed by the administration of doxycycline to drive tetracycline-inducible gene or shRNA expression. Expression was visualized by immunofluorescence staining in livers of injected mice. RESULTS: After HTVI, Cre recombination by tamoxifen led to the expression of membrane-bound green fluorescent protein in transfected hepatocytes. Activation of inducible gene or shRNA expression was detected by immunostaining in up to one-third of transfected hepatocytes, with an efficiency dependent on the promoter driving the Tet-ON system. CONCLUSIONS: Our vector system combines Cre-lox mediated gene mutation with inducible gene expression or gene knockdown, respectively. It provides the opportunity for rapid and specific modification of hepatocyte gene expression and can be a useful tool for genetic screening approaches and analysis of target genes specifically in genetically engineered mouse models. PMID- 28009941 TI - Evaluation of Aortic Paravalvular Leak: A Special Reference for Anatomical Localization. AB - BACKGROUND AND AIM OF THE STUDY: Paravalvular leakage (PVL) remains an unavoidable complication of heart valve surgery and in its severe forms may lead to heart failure and hemolysis. The study aim was to evaluate the echocardiographic, clinical, surgical and laboratory characteristics of patients with aortic PVL. METHODS: A total of 77 aortic PVL patients underwent transthoracic and transesophageal echocardiography examinations. Clinical, echocardiographical and surgical findings were also recorded. RESULTS: Among the 77 patients, 21 (27.3%) had mild, 33 (42.8%) had moderate and 23 (29.9%) had severe aortic PVL. Seventeen patients (22.1%) had moderate-to-severe hemolysis and had a higher incidence of multiple PVL compared to those with no or mild hemolysis. Moderate- to-severe PVL was more frequent between the non-coronary and the left coronary sinus annuli, especially adjacent to the left main coronary artery ostium. Percutaneous closure was performed in five patients. Eleven patients underwent surgical repair, and the localizations of PVL were in accordance with echocardiographic findings. CONCLUSIONS: Aortic PVL occurs more frequently between the non-coronary sinus and the left coronary sinus annuli, which may be associated with multiple factors. Difficulties in seating the prosthesis due to the steep angulation of the commissure and annulus, the avoidance of deep sutures, and focal annular calcification may make this region prone to injury and leakage. PMID- 28009942 TI - Morphological Characteristics and Calcification of the Native Aortic Valve and the Relation to Significant Aortic Regurgitation after CoreValve TAVI. AB - BACKGROUND AND AIM OF THE STUDY: Aortic regurgitation (AR) is a frequent and life limiting complication after transcatheter aortic valve implantation (TAVI). The study aim was to relate post-TAVI AR, using a self-expandable stent, to detailed baseline anatomical and morphological characteristics of the native aortic valve. METHODS: A total of 82 patients (40 males, 42 females; mean age 80 +/- 7 years) who received a Medtronic CoreValve implant was included. Aortic root morphology, aortic annulus and implant size mismatch, implant position, extent of aortic annulus and leaflet calcification, the connected sub-annular calcification volume, and their distribution were quantified based on computed tomography scan analysis. AR following TAVI was quantified using standardized angiography and echocardiography. RESULTS: The mean logistic EuroSCORE of all patients was 16.9 +/- 11.1%. According to angiography and echocardiography, 41% and 39% respectively, of the patients had AR grade >=2. The two methods correlated moderately (Spearman's rho = 0.51, p <0.001). The maximal diameter of the native annulus was larger in patients with significant AR after TAVI based on echocardiography (28.0 mm versus 26.8 mm, p = 0.059). Excessive calcification, especially on the left coronary cusp, was present in patients with significant AR, based on angiography (AR >=II 71.0 mm3 versus AR =II 59.9 mm3 versus AR =2nd degree atrioventricular block (AVB) after TAVR was 5%, and the incidence of new left ventricular bundle branch block (LBBB) was 23%. PPMs were implanted in 13 patients (10%) within 30 days after the procedure. Freedom from new >=2nd degree AVB, LBBB and the need for PPM after TAVR was significantly higher among patients with NCcD <6 mm or LCcD <8 mm (90% and 89%, respectively) compared to patients with NCcD >=6 mm or LCcD >=8 mm (53% and 54%, respectively) (p <0.0001). CONCLUSIONS: Prosthesis depth, measured relative to either the NCcD or LCcD, strongly predicted the occurrence of conduction disturbances and the need for PPM following TAVR with the MCV prosthesis. PMID- 28009944 TI - Suture Forces for Closure of Transapical Transcatheter Aortic Valve Replacement: A Mathematical Model. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of severe aortic stenosis in intermediate, high-risk, and inoperable patients. TAVR has multiple access routes, including transfemoral (TF), transapical (TA), direct aortic (DA), axillary, transcarotid, and transcaval. The most commonly applied algorithm is a TF-first approach, where only when patients are unsuitable for TF are alternatives such as TA considered. An infrequent - but dreaded - risk is left ventricular (LV) apical bleeding from tearing or rupture with the TA approach. With burgeoning transcatheter mitral technology that requires a TA approach, the study aim was to develop a mathematical model to determine suture forces for TA closure. METHODS: Preoperative cine-cardiac magnetic resonance imaging (MRI) was used to acquire three-dimensional (3D) LV geometry at end-systole and end-diastole. Endocardial and epicardial boundaries were manually contoured using MeVisLab, a surface reconstruction software. 3D surfaces of endocardium and epicardium were reconstructed, and surfaces at end systole were used to create a 3D LV finite element (FE) mesh. TA access was mimicked by developing a 10-mm defect within the LV FE model. The LV apex was closed using a virtual suture technique in FE analysis with the application of two virtual sutures. After virtual closure, a FE analysis was performed of LV model diastolic filling and systolic contraction. RESULTS: Proof of concept was achieved to develop an LV transapical access site and perform FE analysis to achieve closure. The FE method of virtual suture technique successfully approximated the LV apical defect. The peak axial forces on virtual sutures at end-diastole and end-systole were 0.445N and 0.736N, respectively. CONCLUSIONS: A LV TA access model was mathematically developed that could be used to evaluate the suture tension of the TA closure process. Further development of this approach may be useful to risk-stratify patients in the future for LV apical tearing. Video 1: Cine cardiac magnetic resonance imaging of the left ventricle. Video 2: Slow motion animation of left ventricular baseline simulation. Video 3: Animation of the virtual suturing process. PMID- 28009945 TI - Hospital Readmission after Aortic Valve Replacement: Impact of Preoperative Heart Failure. AB - BACKGROUND AND AIM OF THE STUDY: Large-scale data of heart failure (HF) readmission after aortic valve replacement (AVR) are limited. METHODS: A total of 40,751 Medicare beneficiaries >65 years who underwent primary isolated AVR between 2000 and 2004 were included in the study. Preoperative HF was defined using ICD-9-CM diagnostic codes from the index admission and any hospitalization during the preceding year. Cumulative readmission incidences over five years were computed for those patients with and without preoperative HF, while adjusting for propensity scores. RESULTS: The median patient age was 76 years. At 30 days, all cause readmission was 21.5% and HF readmission was 3.9%. Patients with preoperative HF had higher postoperative HF readmission rates compared to those without (30 days, 6.3% versus 2.2%; one year, 13.9% versus 4.4%; five years, 6.6% versus 10.3%, p = 0.0001). The incremental risk of HF on readmission was >2 following adjustment. In patients with preoperative HF, the number of admissions was associated with increased postoperative HF readmissions. At 30 days, patients with no preoperative HF admissions had a HF readmission rate of 5.3%, while those with one, two, three and four or more preoperative HF admissions had rates of 8.2%, 11.9%, 13.8% and 17.4%, respectively. This trend persisted over the five year follow up period. CONCLUSIONS: Postoperative HF readmission accounted for about one-fifth of all-cause readmissions after AVR in Medicare beneficiaries. Preoperative HF significantly contributed to postoperative readmission, both all cause and HF-specific, which likely limits the symptomatic benefit of surgery. These data support early aortic valve intervention prior to the development of clinically apparent HF. PMID- 28009946 TI - Successful Surgical Treatment of a Huge Candida albicans Aortic Fungus Ball with Pseudoaneurysm. AB - A 70-year-old woman with a history of aortic valve replacement and coronary artery bypass grafting (CABG) was transferred to the authors' hospital for further management of a three-month fever of unknown origin. Computed tomography showed a huge mass in the ascending aorta with pseudoaneurysm. Blood beta-D glucan levels were significantly high, and blood culture showed the growth of Candida albicans. The fungus ball was excised surgically, together with aortic root replacement and CABG, followed by six-month postoperative anti-fungal therapy. Early diagnosis by imaging studies followed by aggressive surgery and long-term postoperative antifungal treatment should result in a favorable outcome. PMID- 28009947 TI - Root Replacement for Graft Infection Using an All-Biologic Xenopericardial Conduit. AB - BACKGROUND AND AIM OF THE STUDY: The management of graft infection following ascending aortic replacement (AAR) and/or aortic valve replacement (AVR) with destruction of the root remains a challenge. Besides technical issues, the choice of graft material is controversial. The study aim was to investigate the initial results of aortic root replacement (ARR) as redo-surgery for infection using the xenopericardial all-biologic conduit (BioIntegral) as an alternative to a homograft or prosthetic material. METHODS: Between February 2013 and January 2015, a total of 18 consecutive patients (16 males, two females; mean age 61 +/- 14 years) were reoperated on for infection at a mean of 55 +/- 61 months (range: 3 to 219 months) following previous AVR (n = 6), supracoronary aortic replacement (SAR, n = 2), AVR + SAR (n = 1), root replacement (n = 7), and root reconstruction (n = 2). Two patients (11%) had undergone more than one previous cardiac operation. Signs of infection were seen on computed tomography (CT) scanning in 17 patients (94%). Additional 18F-FDG PET-CT was performed in nine patients (50%). RESULTS: The cardiopulmonary bypass and crossclamp were 289 +/- 77 min and 187 +/- 59 min, respectively. Hypothermic circulatory arrest (HCA) + selective antegrade cerebral perfusion (SACP) was necessary in nine patients (50%) and concomitant procedures in 11 (61%). Postcardiotomy extracorporeal life support (ECLS) was necessary in five patients, and renal replacement therapy in eight. One patient died intraoperatively, and the overall 30-day mortality was 22% (n = 4) secondary to multi-organ failure. Risk factors for mortality were myocardial failure requiring ECLS (p = 0.02) and the need for root replacement following previous isolated AVR (p = 0.05). The mean follow up was 12 +/- 5 months. Early graft reinfection occurred in one patient (6%), and another presented with pleural empyema without evidence of persisting conduit infection. Thus, freedom from graft reinfection was 94%. No case of structural valve deterioration was seen. CONCLUSIONS: Aortic root replacement using a xenopericardial conduit in patients with graft infection is technically feasible. Hemodynamics and surgical handling are comparable to that of homografts, but the off-the-shelf availability favors this approach. Mortality was substantial but comparable to that of other series and grafts, with low reinfection rates. Long term outcome regarding the eradication of infection and durability of the graft remains to be demonstrated. PMID- 28009948 TI - The Modified Bentall Procedure: A Single-Institution Experience in 249 Patients with a Maximum Follow Up of 21.5 Years. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the long-term clinical outcomes of the modified Bentall procedure (MBP) with a mechanical conduit. METHODS: Between 1993 and 2014, a total of 249 patients (mean age 62 +/- 12 years; range: 25-87 years) underwent a MBP at the authors' institution. The main indication was annuloaortic ectasia in 102 patients (41%), followed by acute aortic dissection in 82 patients (33%); moderate to severe aortic regurgitation was present in 79% of cases. A bicuspid aortic valve was found in 17% of patients, and Marfan syndrome in 7%. The mean NYHA functional class was 2.5 +/- 1.1. Concomitant procedures were performed in 36 patients (14%). The mean follow up was 8.7 +/- 5.0 years (range: 0.3-21.5 years) and was 99% complete. The total follow up was 6.475 patient-years (pt-yr). RESULTS: Operative mortality was 3% in elective cases. Age, prolonged cardiopulmonary bypass times and mechanical ventilation >96 h were independent risk factors for early mortality. Actuarial survival at 15 and 20 years was 62% and 60%, respectively. Risk factors for late mortality were age and emergency operation. Actuarial freedom from thromboembolism (linearized incidence 0.93%/pt-yr) was 82% at 15 years, and 74% at 20 years. Seven patients required reoperation (0.38%/pt-yr), with an actuarial freedom from reoperation of 91% at 15 years and 87% at 20 years. The incidence of overall valve-related complications was 0.32%/pt-yr, with actuarial freedoms of 94% at 15 and 20 years. CONCLUSIONS: The MBP has shown excellent long-term results with a low incidence of procedure-related complications up to 20 years postoperatively. For this reason, it is considered to be a valid option for the treatment of aortic root disease, whenever valvesparing procedures are not indicated. PMID- 28009949 TI - A Patient with Quadricuspid Aortic Valve and Ischemic Stroke. AB - Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect. Aortic regurgitation is the predominant hemodynamically relevant abnormality in patients with QAV, and the main reason for patients requiring valve surgery. Calcific valve disease of the left heart valves is classified as 'low embolic risk' according to current guidelines. However, it remains an important risk factor of cardiovascular events, including ischemic stroke. A 71-year-old woman presented with new-onset aphasia and hemiparesis of the right side of her body. A magnetic resonance imaging scan of the brain showed acute infarction in the supply area of the left middle cerebral artery. Transesophageal echocardiography revealed a QAV with thickening of the leaflet tips and focal calcifications, especially in the coaptation zones. The four cusps were of equal size and symmetrically affected by sclerosis and calcific deposits, and the aortic valve area was 3.2 cm2 with moderate aortic valve regurgitation. PMID- 28009950 TI - Multiple Imaging Modalities Including Three-Dimensional Echocardiography in Left Ventricular Pseudoaneurysm After Mitral Valve Replacement. AB - Left ventricular pseudoaneurysm (LVPA) after mitral valve replacement (MVR) is a rare condition. The diagnosis of LVPA may be difficult, and for accurate diagnosis, two-dimensional (2D) transthoracic echocardiography (TTE) should be used in combination with other imaging modalities such as multiple detector computed tomography (MDCT) and three-dimensional (3D) TTE. Herein is presented a late type of post-MVR pseudoaneurysm in a 72-year-old female who was admitted to the authors' emergency department with complaints of dyspnea. She had undergone MVR five years previously. A diagnosis was made via 2D TTE, supported by 3D TTE and contrast-enhanced CT. Although aneurysmectomy was performed the patient died due to cardiogenic shock. To the authors' knowledge, the present case report provides the most intense investigation, evaluation and assessment of LVPA performed to date, using different imaging modalities and surgical findings. Movie 1(a) Two-dimensional TTE, four-chamber view. Movie 1(b) Two-dimensional TTE, short-axis view. Movie 2(a) Live/real-time 3D TTE, en face view of the LVPA imaged from the lateral side. Movie 2(b) Live/real time 3D TTE, en face view of the LVPA (arrow) imaged from the left ventricular side. PMID- 28009951 TI - Matrix Metalloproteinases (MMPs), Their Genetic Variants and miRNA in Mitral Valve Diseases: Potential Biomarker Tools and Targets for Personalized Treatments. AB - Mitral valve diseases (MVD)s, comprising congenital and acquired forms, are characterized by a diverse etiology, pathophysiology, prevalence, and incidence. In industrialized countries, the acquired forms represent 2.5% of all cardiovascular diseases, with a marked augmentation after the age of 65 years. In addition, all forms of MVDs (i.e., degenerative forms) have a difficult clinical management. The major challenge is 'the early diagnosis', and echocardiographic analysis has been shown inappropriate for diagnosing MVD in moderate forms. Thus, there is a strong need to identify more appropriate biomarker tools to diagnose MVDs at early clinical stage before complications occur and worsen the prognosis. Innovative biomarker tools may particularly be appropriate for the complex treatment of elderly patients, the clinical management of which is very difficult due to the high risk of surgical interventions and no clear benefits in terms of life expectancy or quality of life compared to younger patients. These biomarker tools may be identified as genetic factors and/or components of cellular and molecular pathways related to the mechanisms of MDV pathophysiology. In this review, emphasis is placed on the possibility of proposing matrix metalloproteinase (MMP) pathways, their genetic variants and microRNA as promising predictive, diagnostic and prognostic biomarkers and targets for personalized treatments. Evidence is also provided of the lack of any consistent evidence which actually hampers their clinical application. Thus, criticisms and concerns are underlined, as well as suggestions to close the existing gaps. PMID- 28009952 TI - Hemodynamic Improvement at Three Months after MitraClipA(r) Treatment in End Stage Heart Failure Patients with Functional Mitral Regurgitation. AB - BACKGROUND: Functional mitral regurgitation (FMR) is common in patients with advanced heart failure and impaired left ventricular function. The study aim was to examine functional and hemodynamic effects at three months after MitraClip(r) implantation in high-risk surgical patients with FMR. METHODS: A group of 93 patients was rejected for surgical treatment by heart-team decisions due to an inacceptable risk for conventional mitral valve surgery. Between October 2011 and May 2015, 89 of these patients (96%) were treated successfully with MitraClip implantation. A subsequent complete follow up was performed over three months in 32 patients with FMR, including pro-brain natriuretic peptide (pro-BNP) measurements, six-minute walk test, echocardiography, and right heart catheterization. RESULTS: The patients (mean age 73 +/- 7 years) presented with a mean left ventricular ejection fraction (LVEF) of 32 +/- 13%, and mitral regurgitation (MR) grade >=3 in 30 of 32 cases (93%). All patients suffered from severe FMR and were highly symptomatic (NYHA functional class III or IV). The mean logistic EuroSCORE was 33%. MitraClip implantation resulted in a significant clinical improvement and reverse cardiac remodelling with a decrease in LV end diastolic and LV endsystolic diameters, while LVEF was unchanged. In addition, a statistically relevant reduction of systolic, diastolic and mean pulmonary artery pressures (PAPsystolic -7.2 mmHg, p = 0.011; PAPdiastolic -4.5 mmHg, p = 0.003; and PAPmean -5.3 mmHg, p = 0.007) were measured, while the cardiac index (+0.3 l/min/m2, p <0.001) and cardiac output (+0.5 l/min, p <0.001) were increased significantly. The 30-day mortality was 8.6% (n = 8). CONCLUSIONS: Among the study population, MitraClip implantation led to clinical improvement, reverse cardiac remodeling, and a sustained hemodynamic benefit during the three-month follow up period. PMID- 28009953 TI - Mitral Valve Re-Repair in an Adult Patient Having Undergone Mitral Ring Annuloplasty at Five Years of Age. AB - In adult patients who have undergone mitral annuloplasty with a rigid ring at a young age, the mitral valve may ultimately deform and demonstrate insufficient growth because the valve annulus is fixed to the ring. Mitral valve re-repair, following this scenario, was performed for mitral stenoinsufficiency in a 26-year old female patient who had undergone mitral annuloplasty with a rigid ring at the age of five years. The valve re-repair procedure consisted of decalcification and stripping of the anterior leaflet and annulus, posterior leaflet augmentation using an elliptical autologous pericardial patch, and a posterior strip annuloplasty sparing the anterior annulus and commissures. Using this procedure, the mitral valve recovered sufficient coaptation area for valve competence, and anterior annular motion was resumed with resultant dynamic changes of the septolateral annular dimension. PMID- 28009954 TI - Outcomes of Minimally Invasive Valve Surgery in Patients with Multiple Previous Cardiac Operations. AB - BACKGROUND: The study aim was to evaluate the outcomes of minimally invasive valve surgery, performed via a right anterior thoracotomy approach, in patients with a history of multiple (more than two) prior cardiac surgeries. METHODS: A retrospective review was conducted of all minimally invasive valve operations performed in patients with a prior history of two or more cardiac surgeries, including coronary artery bypass grafting (CABG) and/or valve surgery, at the authors' institution between January 2008 and November 2014. RESULTS: A total of 38 consecutive patients (23 males, 15 females; mean age 65.8 +/- 14.6 years) were identified. Nine patients (24%) had two prior CABG operations, 18 (47%) had more than two prior valve surgeries, and 11 (29%) had a cardiac operative history that included both CABG and valve surgery. A total of 34 (89.5%) isolated valve procedures was identified; these consisted of 24 (64%) mitral valve operations, nine (23.7%) aortic valve replacements, and one (0.3%) tricuspid valve repair. Four patients (10.5%) underwent combined mitral and tricuspid valve surgery. Postoperatively, two patients (5.3%) had cerebrovascular accidents, three (7.9%) required reoperation for bleeding, and three (7.9%) had acute kidney injury. The median hospital length of stay was 9.5 days (IQR: 7-16 days). The 30-day mortality was 7.9%. The cumulative survival at one year was 82%, and was 72% at five years. CONCLUSIONS: Minimally invasive reoperative valve surgery after multiple prior cardiac operations is safe and feasible, with good perioperative outcomes and mid-term survival. PMID- 28009955 TI - A Left-to-Right Shunt After Transfemoral TAVR Using Edwards SAPIEN 3. AB - Transcatheter aortic valve replacement (TAVR) is used for the treatment of aortic stenosis (AS). Besides major bleeding, conduction blocks, stroke or atrial fibrillation, complications include cardiac perforation with possible left-to right-shunts. Herein is reported the sixth case of a left-to-right shunt in an 87 year-old man who underwent TAVR using a 29 mm Edwards SAPIEN S3 prosthesis to treat AS. Soon after the procedure, a small channel evolving from the right coronary cusp could be detected on echocardiography. The patient was managed medically. PMID- 28009956 TI - New-Onset Hemolytic Anemia after Percutaneous Paravalvular Leak Closure. AB - BACKGROUND AND AIM OF THE STUDY: Despite being usually clinically silent, paravalvular leak can present with congestive heart failure (CHF) or haemolytic anemia. Here, the case is reported of a paravalvular leak presenting with CHF, complicated by new-onset severe hemolytic anemia after percutaneous closure with a large ventricular septal duct (VSD) occlude device. METHODS: A 57-year-old patient presented with infectious endocarditis of a native mitral valve with major mitral regurgitation and was submitted for mitral valvuloplasty. However, one month later failure of the valvuloplasty forced the need for mechanical prosthetic valve implantation. Early endocarditis of the mechanical valve with CHF was noted two months later and led to mechanical valve substitution. One year later the patient presented with a major paravalvular leak and CHF recurrence. Hence, percutaneous paravalvular leak closure was proposed. RESULTS: A 16-mm VSD occluder was used, and clinical and echocardiography success was noticed. However, new-onset hemolytic anemia with acute kidney injury forced surgical re intervention, with the successful implantation of a third mechanical valve. CONCLUSIONS: Usually, percutaneous paravalvular leak closure is a safe and successful method to treat high-risk surgical patients. However, hemolytic anemia may develop after a technically successful procedure, forcing surgical intervention. Dedicated devices are needed to overcome this important safety issue. Video 1: Periprocedural acquisition of 3-D transesophageal echocardiography showing two AVP II in the left atrium after unsuccessful deployment. Video 2: Periprocedural imaging of a muscular ventricular septal duct (mVSD) occluder (16 mm), with successful closure of the paravalvular leak. PMID- 28009957 TI - Implantation of a SAPIEN 3 Valve in a Patient with Pure Aortic Regurgitation. AB - Transcatheter aortic valve implantation (TAVI) is an emerging treatment for high risk patients with aortic stenosis. Aortic regurgitation is considered to be a relative contraindication for transcatheter procedures, as a non-calcified aortic annulus poses the risk of an insufficient anchoring of the transcatheter aortic valve prosthesis. Herein is described the case of a patient who suffered from recurrent aortic valve regurgitation after valve-sparing repair, and which was successfully treated by the transcatheter implantation of an Edwards SAPIEN 3TM prosthesis. This case report demonstrated the suitability of this prosthesis to treat pure aortic valve regurgitation, without excessive oversizing of the valve. PMID- 28009958 TI - Retrograde Snare Technique to Overcome Hostile Aortic Arch Anatomy During Transcatheter Aortic Valve Implantation. AB - Percutaneous valve implantation is a recognized therapy for calcific aortic stenosis in those patients who are inoperable or at high surgical risk. The transfemoral approach is the most frequently used method for device delivery, but a tortuous calcific aorta and the inflexibility of large-caliber endovascular equipment can impede progress or even cause the procedure to be abandoned. Herein, the use of a technique employing a snare to safely overcome device obstruction in the aortic arch of an elderly female patient is described. The technique may be of practical value whenever any large-caliber device is obstructed in the circulation. PMID- 28009959 TI - Right Coronary Artery and Left Anterior Descending Artery Occlusion after Aortic Valve Replacement. AB - Coronary artery stenosis is a potentially life-threatening complication after heart valve surgery. The details are presented of a patient with unobstructed coronary arteries, who underwent routine aortic valve replacement and developed dissection of the right coronary artery (RCA) on the third postoperative day, and occlusion of the left anterior descending (LAD) artery one month after surgery. This complication required prompt clinical recognition and diagnosis by repeat coronary angiography, and a rapid intervention with coronary artery bypass grafting or with angioplasty and stenting. PMID- 28009960 TI - Percutaneous Closure of Massive Mitral Paravalvular Leak. AB - A 59-year-old male with a history of mitral valve replacement several years previously was admitted to the authors' institution with symptoms of advanced heart failure. Echocardiography showed a severe paravalvular dehiscence and surgery was discouraged due to high perioperative risk. A first transcatheter leak closure was unsuccessful despite the correct deployment of various occluding devices. A second percutaneous attempt was carried out with implantation of three Amplatzer Vascular Plug(r) III devices (five occluders were positioned in total within the oblong defect), leading to a mild residual leakage. Device embolism occurred twice during the procedure but was resolved using adequate catheter retrieval techniques. PMID- 28009961 TI - A Perceval Valve in Active Infective Bioprosthetic Valve Endocarditis: Case Report. AB - The case is presented of a 72-year-old male patient suffering from active infective aortic prosthetic endocarditis two months after emergency surgery with aortic valve implantation, and who underwent aortic arch reconstruction using a Dacron patch, due to the spontaneous post-procedural migration of a transcatheter implanted aortic valve. The heart team considered transcatheter valve implantation (TAVI) due to the increased operative risk demonstrated by a EuroSCORE II of 10.9%, including chronic obstructive pulmonary disease (GOLD 3), cirrhosis (Child-B), esophageal varicose stage 2, chronic renal failure stage 3, and reduced left ventricular ejection fraction. Subsequently, the EuroSCORE II was extremely high (76%) due to active infective prosthetic endocarditis and the aortic arch reoperation. A sutureless aortic valve was implanted and a pericardial patch repair of the aortic ascending and arch completed. Sternal re stabilization was required postoperatively. The patient was discharged home after 42 days, and no recurrent endocarditis was diagnosed during follow up. PMID- 28009962 TI - Mitral Valve Diverticulum Presenting with Severe Mitral Stenosis: Case Report. AB - The case is presented of a non-infectious anterior mitral valve leaflet diverticulum, which appeared as symptomatic mitral stenosis. Unlike previous reports, there was no histological myxomatous degeneration of the valve. To the authors' knowledge, this is the first time a mitral valve diverticulum resulting in severe mitral stenosis has been reported in the literature. PMID- 28009963 TI - A New Artificial Chordae Implantation Method in Mitral Valve Surgery. AB - A novel method is described for artificial chordae replacement with expanded polytetrafluoroethylene suture in mitral valve repair procedures. The technique does not involve knots over or beneath the free edge of the mitral valve leaflets. Artificial chords suspend the exact free margin of leaflets as if it were a continuation of the free margin, such that the smooth zone of the coapting area can be preserved. This technique is simple, reproducible, and applicable to both anterior and posterior leaflets. Moreover, the length of the artificial chords can be adjusted rapidly and accurately at the first attempt. PMID- 28009964 TI - The Three Players of Mechanical Valve Thrombosis: Cancer, Anticancer Therapy, and Thromboprophylaxis. PMID- 28009965 TI - Chordal Shortening for Anterior Mitral Leaflet Prolapse and the Maze Procedure for Persistent Atrial Fibrillation. PMID- 28009966 TI - Novel approaches in genetic characterization and targeted therapy for brain metastases. AB - Metastases to the brain are a common complication of various cancers and are associated with poor prognosis. Management of these patients requires a multidisciplinary approach including whole-brain radiation therapy, stereotactic radiosurgery, surgical resection, chemotherapy, and supportive treatment. Because of recent technological advancements in genomics, our understanding of the genetics of brain metastases is rapidly advancing. This has led to the discovery of many potential genetic therapeutic targets in metastatic brain lesions. One of the limitations to systemic therapies is their limited ability to cross the blood brain barrier, necessitating the urgency to develop clinical trials to evaluate efficacy. A description of these genetic mutations, targeted therapies, and associated clinical trials in brain metastases from lung cancers, breast cancers, and melanoma is outlined in this review. PMID- 28009967 TI - The role of B cells in multiple sclerosis: more than antibodies. AB - Multiple sclerosis (MS) is a multicomponent disease that is marked by continual inflammation, demyelination and irreparable damage to the central nervous system. While it was long thought to be mediated by T cells, B cells are now understood to be a central component of MS pathology. Dysfunction and aberrant activity of antigen presenting cells, T cells and B cells are all part of the pathophysiology of the disease. B cells and plasma cells contribute to disease progression through multiple mechanisms, including cytokine secretion, antibody production and antigen presentation. More recent evidence suggests that B cells may play a larger role than previously thought in driving acute episodes of MS. In this review we explore the classical understanding of MS, the evidence and current understanding of B cells in the central nervous system in health and disease, and the interactions present between B cells in the central nervous system and the peripheral nervous system. Lastly, we explore targeted immunological treatments which affect B cells and how this has informed our understanding of MS. PMID- 28009968 TI - The dielectrophoretic disassociation of chloride ions and the influence on diamagnetic anisotropy in cell membranes. AB - Chloride channels represent ubiquitously expressed proteins that regulate fundamental cellular processes including membrane potential, maintenance of intracellular pH, and regulation of cell volume. However, mechanisms to modulate this large family of ion channels have remained elusive to date. This large chloride channel family does not appear to operate with selectivity similar to the sodium and potassium channels. These unique channels appear to be bi directional cotransporters of two or more different molecules or ions across a bilayer phospholipid membrane. Here we show how 3 amperes of direct current from a device that generates an electromagnetic field in a 3 mM hypotonic saline solution leads to a dielectrophoretic disassociation of the chloride ion from its chloro-metabolites transforming it into a polymorphic diamagnetically disassociated bio-chloride (bCl-). This field treated aqueous solution appears to continue to induce a magnetic moment change in solution for some hours when no longer under the influence of the direct current; for when this field influenced solution is used to reconstitute growth media of human breast carcinoma (MDA-MB 231) and human breast epithelial (MCF-10A) cells in vitro, significant changes in chloride ion channel expression, membrane potential, cell volume, and a massive transcriptional reprogramming of 2,468 genes expressions by Human Genome U133 Plus 2.0 Gene Chip Array (Affymetrix) analyses occur. We will highlight how the strong changes in chloride ion channel expression and cell physiology could be intricately linked to enhanced diamagnetic anisotropy in cell membranes that occur under the influence of this disassociated polymorphic bCl-. PMID- 28009969 TI - The role of connexin43 in diabetic microvascular complications. AB - Diabetes mellitus is one of the largest global healthcare problems. People with diabetes have high risk of developing any of the microvascularcomplications, including retinopathy, nephropathy, and neuropathy, which can bring much more serious psychological and economic burden for the diabetic patients. As a consequence of its microvascular complications, diabetes has become the leading cause of blindness, end-stage renal disease, and a variety of debilitating neuropathies. Although the mechanisms involved in the development and progression of these three diabetic microvascular complications are different and have not been completely elucidated, some common histopathological features like increased vascular permeability and apoptosis of specific vascular cells are shared in retinopathy and nephropathy. Moreover, epidemiological studies show a significant clinical association between diabetic retinopathy and nephropathy. Connexin43, the most abundant gap junction protein, is ubiquitously expressed in vertebrate tissues and organs including the retina and kidney. Connexin43 has been reported to play a critical role in maintaining vascular homeostasis. In this review, we highlight the role of connexin43 in diabetic microvascular complications, with special focus on diabetic retinopathy and nephropathy. PMID- 28009970 TI - Combined serum and EPS-urine proteomic analysis using iTRAQ technology for discovery of potential prostate cancer biomarkers. AB - Prostate cancer (PCa) is one of the most common malignant tumors and a major cause of cancer-related death for men worldwide. The aim of our study was to identify potential non-invasive serum and expressed prostatic secretion (EPS) urine biomarkers for accurate diagnosis of PCa. Here, we performed a combined isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis to compare protein profiles using pooled serum and EPS-urine samples from 4 groups of patients: benign prostate hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), localized PCa and metastatic PCa. The differentially expressed proteins were rigorously selected and further validated in a large and independent cohort using classical ELISA and Western blot assays. Finally, we established a multiplex biomarker panel consisting of 3 proteins (serum PF4V1, PSA, and urinary CRISP3) with an excellent diagnostic capacity to differentiate PCa from BPH [area under the receiver operating characteristic curve (AUC) of 0.941], which showed an evidently greater discriminatory ability than PSA alone (AUC, 0.757) (P<0.001). Importantly, even when PSA level was in the gray zone (4-10 ng/mL), a combination of PF4V1 and CRISP3 could achieve a relatively high diagnostic efficacy (AUC, 0.895). Furthermore, their combination also had the potential to distinguish PCa from HGPIN (AUC, 0.934). Our results demonstrated that the combined application of serum and EPS-urine biomarkers can improve the diagnosis of PCa and provide a new prospect for non-invasive PCa detection. PMID- 28009971 TI - Dacomitinib, a new pan-EGFR inhibitor, is effective in killing ovarian cancer cells. AB - OBJECTIVE: Aberrant epidermal growth factor receptor (EGFR) is involved in a variety of cancers and its inhibitors have been studied for over a decade. We aim to investigate the effects of dacomitinib, a second generation pan-EGFR inhibitor, on ovarian cancer cells. METHODS: By immunohistochemistry, we studied the clinical significance of EGFR expression in epithelial ovarian cancer (EOC). The correlations between EGFR expression and the clinicopathological variables of patients with EOC were assessed using Pearson's X2 test. Kaplan-Meier analysis was used to compare the postoperative survival between groups of patients with EOC with varying levels of EGFR expression. MTT, caspase assay, cell apoptosis analysis, autophagy analysis, cell cycle analysis, and western blotting were used to investigate various effects of dacomitinib in cell proliferation, apoptosis, and associated molecular pathways. RESULTS: High expression of EGFR was found to be associated with poor prognosis of patients with EOC. EGFR, P-AKT, and P-ERK were inhibited after treatment of dacomitinib in both SKOV3 and OV4 cells. Activations of caspase activities, apoptosis, and autophagy were also observed and confirmed by western blot: caspase 9, LC3, and Bax levels were elevated, while Bcl-2 and Bcl-xl were down-regulated. The percentage of cancer cells in the S and G2 phases of the cell cycle significantly decreased after treatment. Cdk1 and Cdk2 protein levels declined after dacomitinib treatment; epithelial mesenchymal transition (EMT) was inhibited, which was confirmed by observing E cadherin, N-cadherin, and slug inhibition. Additionally, dacomitinib significantly increased chemotherapy sensitivity in chemotherapeutic resistant ovarian cell lines, C13 and 2780CP. CONCLUSION: Our data showed that increased expression of EGFR is associated with poor prognosis of patients with EOC and dacomitinib may act as a novel, useful chemotherapy drug. Further studies are warranted. PMID- 28009973 TI - That's a Wrap! PMID- 28009972 TI - Inhibition of the hedgehog pathway leads to antifibrotic effects in dermal fibrosis. AB - Dermal fibrosis is characterized by the activation of the matrix-producing 'positive' myofibroblasts, and the relentless production and deposition of extracellular matrix. The hedgehog pathway has recently been demonstrated to work in a pro-fibrotic manner in systemic sclerosis (SSc). A negative regulator of the hedgehog pathway (Hh), the suppressor of fused (Sufu), was shown to be involved in the activation of fibrotic diseases. However, the exact role of Sufu in fibrosis has not been investigated so far. In our study, we aimed to define the role of sufu in the process of fibrosis using dermal fibroblasts of healthy donors that were cultured in vitro. Cyclopamine, a Smo antagonist, and Sufu lentivector were used to treat or transfect cells. The expression of fibrosis markers and ERK1/2, Smad2, and GSK3beta at the protein level was determined by Western blot. Fibroblast migration was measured by in vitro wound healing assay. Bleomycin-induced dermal fibrosis mouse model was introduced to assess the effect of cyclopamine on dermal fibrosis in vivo. We found that cyclopamine significantly upregulated the expression of Sufu. Both cyclopamine and Sufu lentivector reduced migration and myofibroblast differentiation of human dermal fibroblasts at a statistically significant level. Furthermore, cyclopamine reversed dermal fibrosis induced by TGF-beta1. Cyclopamine and the overexpression of Sufu inhibited the phosphorylation of GSK-3beta and restrained the migration of fibroblasts. Dermal fibrosis was inhibited by intraperitoneal injection of cyclopamine in a mouse model of scleroderma. Our findings suggest that cyclopamine and Sufu-overexpression may effectively inhibit the endogenous as well as the TGF-beta1-induced activation of fibroblasts through subsequent activation of GSK-3beta. Sufu agonists may be a promising approach in the development of antifibrotic medications for dermal fibrosis and systemic sclerosis. PMID- 28009974 TI - Dissonance Strikes a Chord in Stilbene Synthesizers. AB - In this issue of Cell Chemical Biology, Mori et al. (2016) combine X-ray crystallography and biochemistry to discover a new mechanism for stilbene synthesis in bacteria. The dialkyl-condensing enzyme StlD catalyzes formation of cyclohexanediones using a non-canonical beta-ketosynthase active site. Aromatization by StlC completes production of the stilbene product. PMID- 28009975 TI - PARP Inhibitors: Staying on Target? AB - Successful phase III trials with poly-ADP-ribose (PARP) inhibitors will have implications for stratified cancer therapy. In this issue of Cell Chemical Biology, Knezevic et al. (2016) demonstrate that the existing collection of PARP inhibitors each display distinctive protein interaction profiles, reaching beyond their intended therapeutic target, with implications for metabolic and other disease. PMID- 28009976 TI - Ammosamides Unveil Novel Biosynthetic Machinery. AB - In this issue of Cell Chemical Biology, Jordan and Moore (2016) present a thorough biosynthetic analysis of ammosamides, a bacterial natural product. The work highlights the previously unknown overlap between two natural products families: pyrroloquinoline alkaloids and ribosomally synthesized posttranslationally modified peptides (RiPPs). PMID- 28009977 TI - Glycan Microarray Reveal the Sweet Side of Cancer Vaccines. AB - Advances in genomics and bioinformatics facilitated identification of tumor specific neoantigens as optimal targets for cancer immunotherapy. In this hot topic, most efforts focus on mutant peptide antigens, overlooking tumor associated glycosylation changes. Given the latest progress in glycomics, in this issue of Cell Chemical Biology, Xia et al. (2016) use glyco-antigen microarrays to investigate immune responses to whole cancer vaccines and provide important insights into vaccine efficacy. PMID- 28009978 TI - The secretion and biological function of tumor suppressor maspin as an exosome cargo protein. AB - Maspin is an epithelial-specific tumor suppressor shown to exert its biological effects as an intracellular, cell membrane-associated, and secreted free molecule. A recent study suggests that upon DNA-damaging g-irradiation, tumor cells can secrete maspin as an exosome-associated protein. To date, the biological significance of exosomal secretion of maspin is unknown. The current study aims at addressing whether maspin is spontaneously secreted as an exosomal protein to regulate tumor/stromal interactions. We prepared exosomes along with cell extracts and vesicle-depleted conditioned media (VDCM) from normal epithelial (CRL2221, MCF-10A and BEAS-2B) and cancer (LNCaP, PC3 and SUM149) cell lines. Atomic force microscopy and dynamic light scattering analysis revealed similar size distribution patterns and surface zeta potentials between the normal cells-derived and tumor cells-derived exosomes. Electron microscopy revealed that maspin was encapsulated by the exosomal membrane as a cargo protein. While western blotting revealed that the level of exosomal maspin from tumor cell lines was disproportionally lower relative to the levels of corresponding intracellular and VDCM maspin, as compared to that from normal cell lines, maspin knockdown in MCF-10A cells led to maspin-devoid exosomes, which exhibited significantly reduced suppressive effects on the chemotaxis activity of recipient NIH3T3 fibroblast cells. These data are the first to demonstrate the potential of maspin delivered by exosomes to block tumor-induced stromal response, and support the clinical application of exosomal maspin in cancer diagnosis and treatment. PMID- 28009979 TI - Ablation of hepatic malignant tumors with irreversible electroporation: A systematic review and meta-analysis of outcomes. AB - BACKGROUND: Irreversible electroporation (IRE) ablation is a new technique that is used to eliminate malignant tumors through nonthermal approaches. OBJECTIVE: The purpose of this review was to evaluate the efficiency of IRE for hepatic malignant tumors. METHODS: A systematic search was performed from PubMed, Embase, Web of science, Scopus and other potential literatures from references in relevant articles July 26th, 2016. Overall estimates of pooled standard mean difference (SMD) with 95% confidence interval (CI) were calculated for the changes of the pre- and post-IRE longest diameter, alkaline phosphatase (ALP), aspartate aminotransferase (AST) and serum total bilirubin levels. Sensitivity analysis and publication bias and were performed after the pooled analysis, and the quality of the included literatures was appraised using Newcastle-Ottawa Scale (NOS). RESULTS: We finally included 300 patients (mean age: 51 to 66.6 years; male: 182; female: 118) from 9 studies of hepatic malignant tumors. The meta-analysis showed that comparing with the initial values, the longest diameter of the tumors was significantly decreased at the last follow-up months after IRE. Furthermore, the ALP, AST and total bilirubin levels were increased at 1 day after IRE while returned to baseline at the last follow-up month. No risk of publication bias was found, and all literatures were assessed good quality according to NOS. CONCLUSIONS: The pooled data indicated that IRE could be a minimal invasive and effective approach for patients who had preoperative poor liver function or those whose masses were in refractory locations where surgical resection was unsuitable. PMID- 28009980 TI - A comparison of the clinicopathological features and prognoses of the classical and the tall cell variant of papillary thyroid cancer: a meta-analysis. AB - Papillary thyroid cancer (PTC) accounts for 80-90% of all thyroid malignancies. The tall cell variant (TCV) is a rare aggressive histotype of PTC. We performed a meta-analysis to compare the clinicopathological characteristics and prognostic factors of TCV with those of classical papillary thyroid carcinoma (cPTC). A literature search was performed using the PubMed and EMBASE databases using Medical Subject Headings and keywords. Twenty studies that included 1871 patients with TCV and 75323 patients with cPTC were included in our meta-analysis. Odds ratios and confidence intervals were calculated for each study. Patients with TCV were associated with multifocality, higher TNM stage, extrathyroidal extension, vascular invasion, lymph node metastasis, distant metastasis, BRAF mutation, disease-specific survival, and overall survival. We found that TCV cases were associated with more aggressive clinicopathological characteristics and poorer prognoses than cPTC cases were. Our results suggest that TCV is a high-risk PTC that warrants aggressive treatment and follow-up strategies. PMID- 28009981 TI - MARCKS protein overexpression in inflammatory breast cancer. AB - BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of locally-advanced breast cancer. Identification of new therapeutic targets is crucial. We previously reported MARCKS mRNA overexpression in IBC in the largest transcriptomics study reported to date. Here, we compared MARCKS protein expression in IBC and non-IBC samples, and searched for correlations between protein expression and clinicopathological features. RESULTS: Tumor samples showed heterogeneity with respect to MARCKS staining: 18% were scored as MARCKS positive (stained cells >= 1%) and 82% as MARCKS-negative. MARCKS expression was more frequent in IBC (36%) than in non-IBC (11%; p = 1.4E-09), independently from molecular subtypes and other clinicopathological variables. We found a positive correlation between protein and mRNA expression in the 148/502 samples previously analyzed for MARCKS mRNA expression. MARCKS protein expression was associated with other poor-prognosis features in the whole series of samples such as clinical axillary lymph node or metastatic extension, high pathological grade, ER negativity, PR-negativity, HER2-positivity, and triple-negative and HER2+ statutes. In IBC, MARCKS expression was the sole tested variable associated with poor MFS. MATERIALS AND METHODS: We retrospectively analyzed MARCKS protein expression by immunohistochemistry in 502 tumors, including 133 IBC and 369 non IBC, from Tunisian and French patients. All samples were pre-therapeutic clinical samples. We searched for correlations between MARCKS expression and clinicopathological features including the IBC versus non-IBC phenotype and metastasis-free survival (MFS). CONCLUSIONS: MARCKS overexpression might in part explain the poor prognosis of IBC. As an oncogene associated with poor MFS, MARCKS might represent a new potential therapeutic target in IBC. PMID- 28009982 TI - Precise integrin-targeting near-infrared imaging-guided surgical method increases surgical qualification of peritoneal carcinomatosis from gastric cancer in mice. AB - Peritoneal carcinomatosis from gastric cancer represents a common recurrent gastric cancer that seriously affects the survival, prognosis, and quality of life of patients at its advanced stage. In recent years, complete cytoreduction surgery in combination with hyperthermic intraperitoneal chemotherapy has been demonstrated to improve the survival and prognosis of patients with malignant tumors including peritoneal carcinomatosis from gastric cancer. Establishing viable methods of accurately assessing the tumor burden in patients with peritoneal carcinoma and correctly selecting suitable patients in order to improve cytoreduction surgical outcomes and reduce the risk of postoperative complications has become a challenge in the field of peritoneal carcinoma research. Here, we investigated peritoneal carcinomatosis from gastric cancer in a mouse model by using our self-developed surgical navigation system that combines optical molecular imaging with an integrin-targeting Arg-Gly-Asp indocyanine green (RGD-ICG) molecular probe. The results showed that our diagnostic method could achieve a sensitivity and specificity of up to 93.93% and 100%, respectively, with a diagnostic index (DI) of 193.93% and diagnostic accuracy rate of 93.93%.Furthermore, the minimum tumor diameter measured during the surgery was 1.8 mm and the operative time was shortened by 3.26-fold when compared with the conventionally-treated control group. Therefore, our surgical navigation system that combines optical molecular imaging with an RGD-ICG molecular probe, could improve the diagnostic accuracy rate for peritoneal carcinomatosis from gastric cancer, shorten the operative time, and improve the quality of the cytoreduction surgery for peritoneal carcinomatosis from gastric cancer, thus providing a solid foundation for its future clinical development and application. PMID- 28009983 TI - Abnormal brain functional connectivity leads to impaired mood and cognition in hyperthyroidism: a resting-state functional MRI study. AB - Patients with hyperthyroidism frequently have neuropsychiatric complaints such as lack of concentration, poor memory, depression, anxiety, nervousness, and irritability, suggesting brain dysfunction. However, the underlying process of these symptoms remains unclear. Using resting-state functional magnetic resonance imaging (rs-fMRI), we depicted the altered graph theoretical metric degree centrality (DC) and seed-based resting-state functional connectivity (FC) in 33 hyperthyroid patients relative to 33 healthy controls. The peak points of significantly altered DC between the two groups were defined as the seed regions to calculate FC to the whole brain. Then, partial correlation analyses were performed between abnormal DC, FC and neuropsychological performances, as well as some clinical indexes. The decreased intrinsic functional connectivity in the posterior lobe of cerebellum (PLC) and medial frontal gyrus (MeFG), as well as the abnormal seed-based FC anchored in default mode network (DMN), attention network, visual network and cognitive network in this study, possibly constitutes the latent mechanism for emotional and cognitive changes in hyperthyroidism, including anxiety and impaired processing speed. PMID- 28009984 TI - BRAF-activated lncRNA predicts gastrointestinal cancer patient prognosis: a meta analysis. AB - BRAF activated non-coding RNA (BANCR) is often dysregulated in cancer. We performed a meta-analysis to clarify its functions as a prognostic indicator in malignant tumors. We searched the PubMed, Medline, OVID, Cochrane Library, and Web of Science databases to identify BANCR-related studies. Nine original studies and 898 total patients were included in the meta-analysis. Hazard ratios (HR) and 95% confidence intervals (CI) were extracted from the included studies to determine the relationship between BANCR expression and patient overall survival (OS). Odds ratios (OR) were calculated using RevMan 5.3 software to assess associations between BANCR expression and pathological parameters. High BANCR expression correlated with lymph node metastasis (LNM) (OR = 3.41, 95% CI: 1.82 6.37, P = 0.0001), distant metastasis (DM) (OR = 2.98, 95% CI: 1.76-5.07, P < 0.0001), tumor stage (OR = 3.11, 95% CI: 1.89-5.12, Z = 3.25, P < 0.0001), and poor OS (pooled HR = 1.98, 95% CI: 1.20-3.27, P = 0.008) in gastrointestinal (GI) cancer patients, but not in non-GI cancer patients. Our results support the notion that BANCR as a promising prognostic biomarker in Chinese patients with GI cancer. PMID- 28009985 TI - Diagnostic and prognostic value of circulating tumor DNA in gastric cancer: a meta-analysis. AB - BACKGROUND: Circulating tumor DNA (ctDNA) has offered a minimally invasive approach for detection and measurement of gastric cancer (GC). However, its diagnostic and prognostic value in gastric cancer still remains unclear. RESULTS: A total of 16 studies comprising 1193 GC patients met our inclusion criteria. The pooled sensitivity and specificity were 0.62 (95% confidence intervals (CI) 0.59 0.65) and 0.95 (95% CI 0.93-0.96), respectively. The AUSROC (area under SROC) curve was 0.94 (95% CI 0.89-0.98). The results showed that the presence of certain ctDNA markers was associated with larger tumor size (OR: 0.26, 95% CI 0.11-0.61, p = 0.002), TNM stage (I + II/III + IV, OR: 0.11, 95% CI 0.07-0.17, p = 0.000), as well as H. pylori infection. (H.p negative/H.p positive, OR: 0.57, 95% CI 0.36-0.91, p = 0.018). Moreover, there was also a significant association between the presence of ctDNA and worse overall survival (HR 1.77, 95% CI 1.38 2.28, p < 0.001), as well as disease-free survival (HR 4.36, 95% CI 3.08-6.16, p < 0.001). MATERIALS AND METHODS: Pubmed, Embase, Cochrane Library and Web of Science databases were searched for relating literature published up until November 30, 2016. Diagnostic accuracy variables were pooled by the Meta-Disc software. Engauge Digitizer and Stata software were applied for prognostic data extraction and analysis. CONCLUSIONS: Our meta-analysis indicates the detection of certain ctDNA targets is significantly associated with poor prognosis of GC patients, with high specificity and relatively moderate sensitivity. PMID- 28009986 TI - Conditionally reprogrammed normal and primary tumor prostate epithelial cells: a novel patient-derived cell model for studies of human prostate cancer. AB - Our previous study demonstrated that conditional reprogramming (CR) allows the establishment of patient-derived normal and tumor epithelial cell cultures from a variety of tissue types including breast, lung, colon and prostate. Using CR, we have established matched normal and tumor cultures, GUMC-29 and GUMC-30 respectively, from a patient's prostatectomy specimen. These CR cells proliferate indefinitely in vitro and retain stable karyotypes. Most importantly, only tumor derived CR cells (GUMC-30) produced tumors in xenografted SCID mice, demonstrating maintenance of the critical tumor phenotype. Characterization of cells with DNA fingerprinting demonstrated identical patterns in normal and tumor CR cells as well as in xenografted tumors. By flow cytometry, both normal and tumor CR cells expressed basal, luminal, and stem cell markers, with the majority of the normal and tumor CR cells expressing prostate basal cell markers, CD44 and Trop2, as well as luminal marker, CD13, suggesting a transit-amplifying phenotype. Consistent with this phenotype, real time RT-PCR analyses demonstrated that CR cells predominantly expressed high levels of basal cell markers (KRT5, KRT14 and p63), and low levels of luminal markers. When the CR tumor cells were injected into SCID mice, the expression of luminal markers (AR, NKX3.1) increased significantly, while basal cell markers dramatically decreased. These data suggest that CR cells maintain high levels of proliferation and low levels of differentiation in the presence of feeder cells and ROCK inhibitor, but undergo differentiation once injected into SCID mice. Genomic analyses, including SNP and INDEL, identified genes mutated in tumor cells, including components of apoptosis, cell attachment, and hypoxia pathways. The use of matched patient derived cells provides a unique in vitro model for studies of early prostate cancer. PMID- 28009988 TI - A neutralized human LMP1-IgG inhibits ENKTL growth by suppressing the JAK3/STAT3 signaling pathway. AB - Latent membrane protein 1 (LMP1), which is associated with the development of different types of Epstein-Barr virus (EBV) related lymphoma, has been suggested to be an important oncoprotein. In this study, a human anti-LMP1 IgG antibody (LMP1-IgG) was constructed and characterized by ELISA, western blotting (WB), affinity and immunohistochemistry (IHC) analyses. CCK-8, MTT, apoptosis assays, antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (complement dependent cytotoxicity) assays were performed to evaluate the inhibitory effects of LMP1-IgG on extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTL). Then, the influence of LMP1-IgG on the JAK/STAT signaling pathway was investigated. The results showed that the successfully constructed LMP1-IgG inhibited proliferation, induced apoptosis, and activated ADCC and CDC of ENKTL in a concentration- and time- dependent manner. Moreover, phosphorylation of JAK3 and STAT3 was inhibited by LMP1-IgG. Our data indicate that LMP1-IgG may provide a novel and promising therapeutic strategy for the treatment of LMP1-positive ENKTL. PMID- 28009989 TI - Overexpression of colorectal cancer oncogene CHRDL2 predicts a poor prognosis. AB - Bone morphogenetic proteins (BMPs) both promote and suppress tumorigenesis, and multiple BMP antagonists reportedly contribute to cancer progression. In this study, we demonstrated that the BMP antagonist Chordin-like 2 (CHRDL2) is upregulated in colorectal cancer (CRC) tissues, and that CHRDL2 levels correlate with clinical features of CRC patients, including tumor size, TNM staging, and tumor differentiation. In addition, survival rate and Cox proportional hazards model analyses showed that high CHRDL2 levels correlate with a poor prognosis in CRC. Moreover, CHRDL2 promoted CRC cell proliferation in vitro and in vivo, perhaps through up-regulation of Cyclin D1 and down-regulation of P21. Co immunoprecipitation assays showed that CHRDL2 bound to BMPs, which inhibited p Smad1/5, thereby promoting CRC cell proliferation and inhibiting apoptosis. These results suggest CHRDL2 could serve as a biomarker of poor prognosis in CRC, and provide evidence that CHRDL2 acts as an oncogene in human CRC, making it a novel potential therapeutic target. PMID- 28009990 TI - Metabolic enzymes: key modulators of functionality in cancer stem-like cells. AB - Cancer Stem-like Cells (CSCs) are a subpopulation of cancer cells with self renewal capacity and are important for the initiation, progression and recurrence of cancer diseases. The metabolic profile of CSCs is consistent with their stem like properties. Studies have indicated that enzymes, the main regulators of cellular metabolism, dictate functionalities of CSCs in both catalysis-dependent and catalysis-independent manners. This paper reviews diverse studies of metabolic enzymes, and describes the effects of these enzymes on metabolic adaptation, gene transcription and signal transduction, in CSCs. PMID- 28009991 TI - Low expression of Rap1GAP is associated with epithelial-mesenchymal transition (EMT) and poor prognosis in gastric cancer. AB - Rap1GAP is a crucial tumor suppressor, but its role in gastric cancer (GC) is little investigated. In this study, we found that the expression of Rap1GAP was decreased in GC. Low expression of Rap1GAP was positively correlated with advanced pTNM stage, Borrmann types, tumor diameter and poor prognosis in patients with GC. Low expression of Rap1GAP correlated with loss of E-cadherin expression, and anomalous positivity of MMP2 expression. Multivariate analysis showed that low expression of Rap1GAP was an independent prognostic factor. Ectopic expression of Rap1GAP impaired cell migration and invasion, promoted the expression of E-cadherin and decreased the expression of MMP2. These results suggest that Rap1GAP functions as a novel suppressor of EMT and tumor metastasis in GC, and loss of Rap1GAP predicts poor prognosis in GC. PMID- 28009992 TI - Identification of a synonymous variant in TRIM59 gene for gastric cancer risk in a Chinese population. AB - Tripartite motif 59 (TRIM59) is a novel oncogenic driver in gastric cancer (GC) that is implicated in disease progression as well as dismal survival. Genetic variants in peculiar gene are likely candidates for conferring hereditary susceptibility. The role of TRIM59 polymorphism in predicting the risk of malignant diseases and its relevance to TRIM59 expression have not been discussed. Using a HapMap tagSNPs approach, we screened three tag TRIM59 single nucleotide polymorphisms (SNPs) (rs1141023G>A, rs7629A>G, rs11706810T>C) which were genotyped in 602 GC patients and 868 healthy controls. Our study provided convincing result that carries of variant rs1141023A allele markedly increased GC risk (P=0.006). In comparison with the GG homozygotes, the variant GA heterozygotes demonstrated 1.50-fold elevated risk of GC (p=0.014, 95% confidence interval [CI] = 1.09-2.08). Subjects who carried the (GA+AA) genotypes of rs1141023 were associated with remarkable increased GC risk compared with the common genotype (P = 0.013, adjusted OR = 1.50, 95% CI = 1.09-2.05). Further stratified analyses displayed that the relationship between mutant genotype of rs1141023 and GC risk was more profound in male individuals. Intriguingly, there is no significant distinction of TRIM59 mRNA expression between rs1141023GA genotype and GG genotype in 44 normal gastric tissues. Taken together, our results suggest that rs1141023 polymorphism contributes to increased predisposition to GC and thus may be responsible for predicting early GC. PMID- 28009994 TI - Pol Arch Med Wewn becomes Pol Arch Intern Med. PMID- 28009995 TI - 110th Anniversary of the Polish Society of Internal Medicine. Foundation of the Polish Society of Internal Medicine. PMID- 28009996 TI - Scientific traditions of the Cracow Doctor's Association. PMID- 28009993 TI - Characterization of RNA editome in primary and metastatic lung adenocarcinomas. AB - RNA editing results in post-transcriptional modification and could potentially contribute to carcinogenesis. However, RNA editing in advanced lung adenocarcinomas has not yet been studied. Based on whole genome and transcriptome sequencing data, we identified 1,071,296 RNA editing events from matched normal, primary and metastatic samples contributed by 24 lung adenocarcinoma patients, with 91.3% A-to-G editing on average, and found significantly more RNA editing sites in tumors than in normal samples. To investigate cancer relevant editing events, we detected 67,851 hyper-editing sites in primary and 50,480 hyper editing sites in metastatic samples. 46 genes with hyper-editing in coding regions were found to result in amino acid alterations, while hundreds of hyper editing events in non-coding regions could modulate splicing or gene expression, including genes related to tumor stage or clinic prognosis. Comparing RNA editome of primary and metastatic samples, we also discovered hyper-edited genes that may promote metastasis development. These findings showed a landscape of RNA editing in matched normal, primary and metastatic tissues of lung adenocarcinomas for the first time and provided new insights to understand the molecular characterization of this disease. PMID- 28009997 TI - Myeloid-derived suppressor cells in bronchoalveolar lavage fluid in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION Myeloid-derived suppressor cells (MDSCs) have the potent ability to suppress T-cell function, and are important in the regulation of chronic inflammation and carcinogenesis. MDSCs may influence local and systemic inflammation and carcinogenesis in COPD; however, their presence in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) or their relationship with clinical parameters in COPD has not been studied yet. OBJECTIVES The aim of the study was to assess MDSCs in BALF and PB and to analyze the relationship between MDSCs and clinical parameters in COPD. PATIENTS AND METHODS The study included 64 patients with stable COPD. The clinical parameters of the patients were studied, and MDSCs were assessed using monoclonal antibodies directly conjugated with fluorochromes in flow cytometry. RESULTS The percentage of MDSCs in BALF was lower than that in PB (0.63 +/-0.90 vs 3.94 +/-0.38). In BALF, MDSCs (% of mononuclear cells) correlated with forced expiratory volume in 1 second (rs = -0.30, P = 0.0185), residual volume/total lung capacity (rs = 0.32, P = 0.0148), PaO2 (rs = -0.45, P = 0.0002), arterial oxygen saturation (SaO2; rs = -0.41, P = 0.0008), and diffusion capacity of carbon dioxide (rs = 0.32, P = 0.0211). There was a significant negative correlation between MDSCs (% of all leukocytes) and arterial oxygen pressure (rs = -0.42, P = 0.0006) and SaO2 (rs = -0.37, P = 0.0027). No correlations were found in PB. CONCLUSIONS MDSCs are present in human lung microenvironment and may be involved in local inflammation in COPD. Future studies should focus on a detailed assessment of MDSCs in local and systemic inflammation in COPD. PMID- 28009998 TI - Validation of the Polish version of the Duke University Religion Index (PolDUREL). PMID- 28009999 TI - Heart palpitations as an early presentation of a heart tumor. PMID- 28010000 TI - Abernethy malformation type I (congenital absence of the portal vein) in a patient with chronic kidney disease. PMID- 28010001 TI - Familial chronic thromboembolic pulmonary hypertension in a mother and a son: successful treatment with refined balloon pulmonary angioplasty. PMID- 28010002 TI - Is retraction sufficient for medical papers? PMID- 28010003 TI - Low blood glucose in type 2 diabetes: a lot more to come? PMID- 28010004 TI - The 2016 World Thrombosis Day in Poland. PMID- 28010005 TI - 2015 in hematology and thromboembolism. Dr. Mark Crowther in an interview with Dr. Roman Jaeschke: part 1. PMID- 28010006 TI - Milestones in VTE treatment. Dr. Mark Crowther in an interview with Dr. Roman Jaeschke: part 2. PMID- 28010007 TI - VTE treatment in 201 6 and future challenges Dr. Mark Crowther in an interview with Dr. Roman Jaeschke: part 3. PMID- 28010008 TI - Treatment of asthma: roles of different classes of drugs Dr. Paul O'Byrne in an interview with Dr. Roman Jaeschke: part 1. PMID- 28010009 TI - Treatment of asthma: predicting the future of atopic disease treatment Dr. Paul O'Byrne in an interview with Dr. Roman Jaeschke: part 2. PMID- 28010011 TI - Long-term anticoagulation in questions and answers. PMID- 28010010 TI - HOPE--3, BP treatment, milestones in CV prevention. Dr. Salim Yusuf in an interview with Dr. Akbar Panju and Dr. Roman Jaeschke. PMID- 28010012 TI - Dawn and dusk of internal medicine: a view of a qualified oncologist and hematologist. PMID- 28010014 TI - Internal medicine: the queen of science. PMID- 28010013 TI - Internal medicine: knowledge and practice. PMID- 28010015 TI - The current status and the future of internal medicine: a voice in the discussion. PMID- 28010016 TI - Reflections on internal medicine. PMID- 28010017 TI - Internal medicine: I cannot live without you as you are my destiny. PMID- 28010018 TI - Forum for internal medicine: opinions and controversies. PMID- 28010019 TI - Internal medicine: an indispensable field of medicine. PMID- 28010020 TI - The internal medicine in crisis: the analysis of causes and proposed changes. PMID- 28010021 TI - The role of an internal medicine specialist in the health care system: going back to the past? PMID- 28010022 TI - On the lesser importance of internal medicine: is it right to forget about it? PMID- 28010023 TI - Internal medicine in the future. PMID- 28010024 TI - Forum medycyny wewnetrznej - opinie i kontrowersje. PMID- 28010026 TI - [Editor's Comment]. PMID- 28010025 TI - Evodiamine Prevents Isoproterenol-Induced Cardiac Fibrosis by Regulating Endothelial-to-Mesenchymal Transition. AB - Evodiamine, a major component of Evodia rutaecarpa, can protect the myocardium against injury induced by atherosclerosis and ischemia-reperfusion. However, the effect of evodiamine against cardiac fibrosis remains unclear. This study aims to investigate the possible effect and mechanism involved in the function of evodiamine on isoproterenol-induced cardiac fibrosis and endothelial-to mesenchymal transition. Isoproterenol was used to induce cardiac fibrosis in mice, and evodiamine was gavaged simultaneously. After 14 days, cardiac function was accessed by echocardiography. The extent of cardiac fibrosis and hypertrophy was evaluated by pathological and molecular analyses. The extent of endothelial to-mesenchymal transition was evaluated by the expression levels of CD31, CD34, alpha-smooth muscle actin, and vimentin by immunofluorescence staining and Western blot analysis. After 14 days, the heart weight/body weight ratio and heart weight/tibia length ratio revealed no significant difference between the isoproterenol group and the isoproterenol/evodiamine-treated groups, whereas the increased heart weight was reduced in the isoproterenol/evodiamine-treated groups. Echocardiography revealed that interventricular septal thickness and left ventricular posterior wall thickness at the end diastole decreased in the evodiamine-treated groups. Evodiamine reduced isoproterenol-induced cardiac fibrosis as accessed by normalization in collagen deposition and gene expression of hypertrophic and fibrotic markers. Evodiamine also prevented endothelial-to mesenchymal transition as evidenced by the increased expression levels of CD31 and CD34, decreased expression levels of alpha-smooth muscle actin and vimentin, and increased microvascular density in the isoproterenol/evodiamine-treated mice hearts. Furthermore, isoproterenol-induced activation of transforming growth factor-beta1/Smad signal was also blunted by evodiamine. Therefore, evodiamine may prevent isoproterenol-induced cardiac fibrosis by regulating endothelial-to mesenchymal transition, which is probably mediated by the blockage of the transforming growth factor-beta1/Smad pathway. PMID- 28010027 TI - ? PMID- 28010028 TI - ? PMID- 28010029 TI - [The Anti-Corruption Act comes into force]. PMID- 28010031 TI - ? PMID- 28010030 TI - [Basics of Ear Surgery]. AB - The present article about the basics of ear surgery is a short overview of current indications, the required diagnostics and surgical procedures of common otologic diseases. In addition to plastic and reconstructive surgery of the auricle, principles of surgery of the external auditory canal, basics of middle ear surgery and the tumor surgery of the temporal bone are shown. Additionally, aspects of the surgical hearing rehabilitation (excluding implantable hearing systems) are presented considering current study results. PMID- 28010032 TI - [Endonasale Chirurgie bei benignen Tumoren II]. PMID- 28010033 TI - Performance of induction module cavity ring-down spectroscopy (IM-CRDS) for measuring delta18 O and delta2 H values of soil, stem, and leaf waters. AB - RATIONALE: Induction module cavity ring-down spectroscopy (IM-CRDS) has been proposed as a rapid and cost-effective alternative to cryogenic vacuum distillation (CVD) and isotope ratio mass spectrometry (IRMS) for the measurement of delta18 O and delta2 H values in matrix-bound waters. In the current study, we characterized the performance of IM-CRDS relative to CVD and IRMS and investigated the mechanisms responsible for differences between the methods. METHODS: We collected a set of 75 soil, stem, and leaf water samples, and measured the delta18 O and delta2 H values of each sample with four techniques: CVD and IRMS, CVD and CRDS, CVD and IM-CRDS, and IM-CRDS alone. We then calculated the isotopic errors for each of the three CRDS methods relative to CVD and IRMS, and analyzed the relationships among these errors and suites of diagnostic spectral parameters that are indicative of organic contamination. RESULTS: The IM-CRDS technique accurately assessed the delta18 O and delta2 H values of pure waters, but exhibited progressively increasing errors for soil waters, stem waters, and leaf waters. For soils, the errors were attributable to subsampling of isotopically heterogeneous source material, whereas for stems and leaves, they were attributable to spectral interference. Unexpectedly, the magnitude of spectral interference was higher for the solid samples analyzed directly via IM-CRDS than for those originally extracted via CVD and then analyzed by IM-CRDS. CONCLUSIONS: There are many types of matrix-bound water samples for which IM-CRDS measurements include significant errors from spectral interference. As a result, spectral analysis and validation should be incorporated into IM-CRDS post-processing procedures. In the future, IM-CRDS performance could be improved through: (i) identification of the compounds that cause spectral interference, and either (ii) modification of the combustion step to completely oxidize these compounds to CO2 , and/or (iii) incorporation of corrections for these compounds into the spectral fitting models used by the CRDS analyzers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28010034 TI - Characterization of crude oil asphaltenes by coupling size-exclusion chromatography directly to an ultrahigh-resolution mass spectrometer. AB - RATIONALE: Fossil fuels are one of the most important energy resources until new sustainable materials become available. To optimize the upgrading processes of these materials characterization of the remaining heavy materials is of great importance. METHODS: Asphaltenes are the most difficult fraction of crude oil to process due to the limited number of solvents in which they can be dissolved. Chromatographic separation methods need to consider the difficulties associated with these limitations. Size-exclusion chromatography (SEC) in combination with Fourier transform Orbitrap mass spectrometry (MS) combines the capabilities of ultrahigh resolution and very high mass accuracy with a separation method that allows using solvents as mobile phase for asphaltene separation. RESULTS: A chromatographic method was developed that shows the separation of asphaltenes according to their molecular mass. A simplification of the samples was achieved by reducing the number of compounds present in a single spectrum compared to infusion data. Direct detection by mass spectrometry additionally allows a distinction of different isomers present in the complex samples. CONCLUSIONS: Direct coupling of SEC with ultrahigh-resolution mass spectrometry allows the study of the most difficult to analyze fraction of crude oil, the asphaltene fraction. Separation reduces the complexity of individual spectra and, therefore, also reduces suppression and discrimination effects. The separation of structural isomers which cannot be characterized by MS alone gives an added dimension to the analysis of asphaltenes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28010035 TI - Reply. PMID- 28010036 TI - Effect of metabolic syndrome on cardiovascular, hepatic events, and death in chronic hepatitis B patients: Methodological issues. PMID- 28010037 TI - The added value of detailed early anomaly scan in fetuses with increased nuchal translucency. AB - OBJECTIVE: This study aims to assess the utility of a detailed early fetal anatomy scan prior to karyotyping in the management of pregnancies with an increased nuchal translucency (NT). METHODS: The study included fetuses with NT above the 99th centile. These women were offered the option of an early detailed fetal anatomy scan prior to genetic evaluation. The presence or absence of major sonographic findings was analyzed for its predictive value for fetal aneuploidy. RESULTS: An increased NT >99th centile was detected in 43 fetuses (1.8%). Mean NT was 4.5 mm (range 3.4-9.0), and gestational age at the early fetal anatomy survey was 12.4 weeks (12-13.6). Major sonographic findings were present in 30 fetuses (69.8%); 24 of them underwent karyotyping, and it was abnormal in 14. Among the 13 fetuses without major sonographic findings, 12 had normal karyotype results, and 1 had aneuploidy, yielding a positive predictive value of 58.3% of early fetal anatomy scan for abnormal karyotype results. Multivariate logistic regression analysis showed that the presence of major sonographic findings was as an independent predictor of fetal aneuploidy (adjusted odds ratio 8.15). CONCLUSION: A detailed early anatomy scan upon detection of increased NT has an important value in the prediction of fetal aneuploidy. (c) 2016 John Wiley & Sons, Ltd. PMID- 28010040 TI - Reply. PMID- 28010038 TI - Suppression and synthetic-lethal genetic relationships of DeltagpsB mutations indicate that GpsB mediates protein phosphorylation and penicillin-binding protein interactions in Streptococcus pneumoniae D39. AB - GpsB regulatory protein and StkP protein kinase have been proposed as molecular switches that balance septal and peripheral (side-wall like) peptidoglycan (PG) synthesis in Streptococcus pneumoniae (pneumococcus); yet, mechanisms of this switching remain unknown. We report that DeltadivIVA mutations are not epistatic to DeltagpsB division-protein mutations in progenitor D39 and related genetic backgrounds; nor is GpsB required for StkP localization or FDAA labeling at septal division rings. However, we confirm that reduction of GpsB amount leads to decreased protein phosphorylation by StkP and report that the essentiality of DeltagpsB mutations is suppressed by inactivation of PhpP protein phosphatase, which concomitantly restores protein phosphorylation levels. DeltagpsB mutations are also suppressed by other classes of mutations, including one that eliminates protein phosphorylation and may alter division. Moreover, DeltagpsB mutations are synthetically lethal with Deltapbp1a, but not Deltapbp2a or Deltapbp1b mutations, suggesting GpsB activation of PBP2a activity. Consistent with this result, co-IP experiments showed that GpsB complexes with EzrA, StkP, PBP2a, PBP2b and MreC in pneumococcal cells. Furthermore, depletion of GpsB prevents PBP2x migration to septal centers. These results support a model in which GpsB negatively regulates peripheral PG synthesis by PBP2b and positively regulates septal ring closure through its interactions with StkP-PBP2x. PMID- 28010039 TI - The emotion regulation questionnaire in women with cancer: A psychometric evaluation and an item response theory analysis. AB - OBJECTIVE: Emotion regulation is thought to play an important role in adaptation to cancer. However, the emotion regulation questionnaire (ERQ), a widely used instrument to assess emotion regulation, has not yet been validated in this context. This study addresses this gap by examining the psychometric properties of the ERQ in a sample of Portuguese women with cancer. METHODS: The ERQ was administered to 204 women with cancer (mean age = 48.89 years, SD = 7.55). Confirmatory factor analysis and item response theory analysis were used to examine psychometric properties of the ERQ. RESULTS: Confirmatory factor analysis confirmed the 2-factor solution proposed by the original authors (expressive suppression and cognitive reappraisal). This solution was invariant across age and type of cancer. Item response theory analyses showed that all items were moderately to highly discriminant and that items are better suited for identifying moderate levels of expressive suppression and cognitive reappraisal. Support was found for the internal consistency and test-retest reliability of the ERQ. The pattern of relationships with emotional control, alexithymia, emotional self-efficacy, attachment, and quality of life provided evidence of the convergent and concurrent validity for both dimensions of the ERQ. CONCLUSION: Overall, the ERQ is a psychometrically sound approach for assessing emotion regulation strategies in the oncological context. Clinical implications are discussed. PMID- 28010041 TI - Release of resource constraints allows greater carbon allocation to secondary metabolites and storage in winter wheat. AB - The atmospheric CO2 concentration ([CO2 ]) is rapidly increasing, and this may have substantial impact on how plants allocate metabolic resources. A thorough understanding of allocation priorities can be achieved by modifying [CO2 ] over a large gradient, including low [CO2 ], thereby altering plant carbon (C) availability. Such information is of critical importance for understanding plant responses to global environmental change. We quantified the percentage of daytime whole-plant net assimilation (A) allocated to night-time respiration (R), structural growth (SG), nonstructural carbohydrates (NSC) and secondary metabolites (SMs) during 8 weeks of vegetative growth in winter wheat (Triticum aestivum) growing at low, ambient and elevated [CO2 ] (170, 390 and 680 ppm). R/A remained relatively constant over a large gradient of [CO2 ]. However, with increasing C availability, the fraction of assimilation allocated to biomass (SG + NSC + SMs), in particular NSC and SMs, increased. At low [CO2 ], biomass and NSC increased in leaves but decreased in stems and roots, which may help plants achieve a functional equilibrium, that is, overcome the most severe resource limitation. These results reveal that increasing C availability from rising [CO2 ] releases allocation constraints, thereby allowing greater investment into long term survival in the form of NSC and SMs. PMID- 28010042 TI - Should we 'open the kimono' to release the results of rare autosomal aneuploidies following noninvasive prenatal whole genome sequencing? AB - The metaphor 'open kimono' has been applied in the business world to connote transparency via the release of all available data to an external party. Here, the author uses this term to discuss the relative advantages and disadvantages of reporting on the presence of rare autosomal aneuploidies detected by massively parallel sequencing of placental cell-free DNA in the plasma of pregnant women. Newly presented data sets from multiple laboratories suggest that autosomal aneuploidies such as trisomies 7, 15, 16, 22, and 8 are easily detectable and are potentially associated with fetal growth restriction, pregnancy loss, and maternal preeclampsia. Furthermore, they may explain false positive results for the common autosomal trisomies (13, 18, and 21) as well as test failures. Thus, release of this information may result in improved clinical utility. At the present time, however, professional societies in various parts of the world differ in their recommendations as to whether or not to release expanded autosomal aneuploidy results beyond the common trisomies. (c) 2016 John Wiley & Sons, Ltd. PMID- 28010043 TI - An efficient data-filtering strategy for easy metabolite detection from the direct analysis of a biological fluid using Fourier transform mass spectrometry. AB - RATIONALE: High-throughput analyses require an overall analytical workflow including not only a robust and high-speed technical platform, but also dedicated data-processing tools able to extract the relevant information. This work aimed at evaluating post-acquisition data-mining tools for selective extraction of metabolite species from direct introduction high-resolution mass spectrometry data. METHODS: Investigations were performed on spectral data in which seven metabolites of vinclozolin, a dicarboximide fungicide containing two chloride atoms, were previously manually identified. The spectral data obtained from direct introduction (DI) and high-resolution mass spectrometry (HRMS) detection were post-processed by plotting the mass defect profiles and applying various data-filtering methods based on accurate mass values. RESULTS: Exploration of mass defect profiles highlighted, in a specific plotting region, the presence of compounds containing common chemical elements and pairs of conjugated and non conjugated metabolites resulting from classical metabolic pathways. Additionally, the judicious application of mass defect and/or isotope pattern filters removed many interfering ions from DI-HRMS data, greatly facilitating the detection of vinclozolin metabolites. Compared with previous results obtained by manual data treatment, three additional metabolites of vinclozolin were detected and putatively annotated. CONCLUSIONS: Tracking simultaneously several specific species could be efficiently performed using data-mining tools based on accurate mass values. The selectivity of the data extraction was improved when the isotope filter was used for halogenated compounds, facilitating metabolite ion detection even for low-abundance species. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28010044 TI - The GpsB files: the truth is out there. AB - Peptidoglycan (PG), an essential stress-bearing component of the bacterial cell wall, is synthesised by penicillin binding proteins (PBPs). PG synthesis at the cell division septum is necessary for constructing new poles of progeny cells, and cells cannot elongate without inserting new PG in the side-wall. The cell division regulator GpsB appears to co-ordinate PG synthesis at the septum during division and at the side-wall during elongation in rod-shaped and ovococcoid Gram positive bacteria. How the control over PG synthesis is exerted is unknown. In this issue of Molecular Microbiology, Rued et al. show that in pneumococci GpsB forms complexes with PBP2a and PBP2b, and that deletion or depletion of GpsB prevents closure of the septal ring that in itself is PBP2x-dependent. Loss of GpsB can be suppressed by spontaneous mutations, including within the gene encoding the only PP2C Ser/Thr phosphatase in Streptococcus pneumoniae, indicating that GpsB plays a key - but unknown - role in protein phosphorylation in pneumococci. Rued et al. combine phenotypic and genotypic analyses of mutant strains that suggest discrepancies in the literature concerning GpsB might have arisen from accumulation of unidentified suppressors, highlighting the importance and power of strain validation and whole genome sequencing in this context. PMID- 28010045 TI - Aspirin for cholangiocarcinoma prevention: New targets to shift the dogma from ascertained risk to possible prevention. PMID- 28010046 TI - Development of transgenic crops based on photo-biotechnology. AB - The phenotypes associated with plant photomorphogenesis such as the suppressed shade avoidance response and de-etiolation offer the potential for significant enhancement of crop yields. Of many light signal transducers and transcription factors involved in the photomorphogenic responses of plants, this review focuses on the transgenic overexpression of the photoreceptor genes at the uppermost stream of the signalling events, particularly phytochromes, crytochromes and phototropins as the transgenes for the genetic engineering of crops with improved harvest yields. In promoting the harvest yields of crops, the photoreceptors mediate the light regulation of photosynthetically important genes, and the improved yields often come with the tolerance to abiotic stresses such as drought, salinity and heavy metal ions. As a genetic engineering approach, the term photo-biotechnology has been coined to convey the idea that the greater the photosynthetic efficiency that crop plants can be engineered to possess, the stronger the resistance to biotic and abiotic stresses. Development of GM crops based on photoreceptor transgenes (mainly phytochromes, crytochromes and phototropins) is reviewed with the proposal of photo-biotechnology that the photoreceptors mediate the light regulation of photosynthetically important genes, and the improved yields often come with the added benefits of crops' tolerance to environmental stresses. PMID- 28010048 TI - Liver transplantation for hepatocellular carcinoma through the lens of transplant benefit. PMID- 28010049 TI - Genesis of the Special Issues on Mass Cytometry. PMID- 28010047 TI - Distal and proximal promoters co-regulate pqsR expression in Pseudomonas aeruginosa. AB - The ubiquitous bacterium Pseudomonas aeruginosa is an opportunistic pathogen that can cause serious infections in immunocompromised individuals. P. aeruginosa virulence is controlled partly by intercellular communication, and the transcription factor PqsR is a necessary component in the P. aeruginosa cell-to cell signaling network. PqsR acts as the receptor for the Pseudomonas quinolone signal, and it controls the production of 2-alkyl-4-quinolone molecules which are important for pathogenicity. Previous studies showed that the expression of pqsR is positively controlled by the quorum-sensing regulator LasR, but it was unclear how LasR is able to induce pqsR transcription. In this report, we further investigated the control of pqsR, and discovered two separate promoter sites that contribute to pqsR expression. LasR-mediated activation occurs at the distal promoter site, but this activation can be antagonized by the regulator CysB. The proximal promoter site also contributes to pqsR transcription, but initiation at this site is inhibited by a negative regulatory sequence element, and potentially by the H-NS family members MvaT and MvaU. We propose a model where positive and negative regulatory influences at each promoter site are integrated to modify pqsR expression. This arrangement could allow for information from both environmental signals and cell-to-cell communication to influence PqsR levels. PMID- 28010050 TI - Single-dose intravenous iron infusion versus red blood cell transfusion for the treatment of severe postpartum anaemia: a randomized controlled pilot study. AB - BACKGROUND AND OBJECTIVES: There are no randomized trials comparing intravenous iron to RBC transfusion for the treatment of severe postpartum anaemia. The objectives of this study were to evaluate the feasibility of randomizing women with severe postpartum anaemia secondary to postpartum haemorrhage to RBC transfusion or intravenous iron, and to describe patient-reported outcomes, and haematological and iron parameters. MATERIALS AND METHODS: Women with a postpartum haemorrhage exceeding 1000 ml and an Hb between 5.6 and 8.1 g/dl were randomized to 1500 mg of intravenous iron (n = 7) isomaltoside or RBC transfusion (n = 6). Participants completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and blood samples were drawn at inclusion, daily during the first week and at weeks 3, 8 and 12. RESULTS: We screened 162 women and included 13 (8%). There was no significant difference between groups in fatigue or depression scores. RBC transfusion was associated with a higher Hb on day 1, inhibition of reticulocytosis during the first week and low iron levels. Intravenous iron was associated with increased reticulocytosis during the first week, repleted iron stores and a higher Hb in weeks 3-12. CONCLUSION: This pilot study shows that intravenous iron could be an attractive alternative to RBC transfusion in severe postpartum anaemia, and that a larger trial is needed and feasible. PMID- 28010051 TI - QMG and MG-ADL correlations: Study of eculizumab treatment of myasthenia gravis. AB - INTRODUCTION: A phase 2 study of eculizumab for treating myasthenia gravis (MG) used the quantitative myasthenia gravis score (QMG) and myasthenia gravis activities of daily living profile (MG-ADL) to evaluate baseline disease severity and treatment response. Correlations were then analyzed between these assessments. METHODS: Patients were given eculizumab or placebo during the first 16-week treatment period of the crossover study, with treatment assignments reversed for the second treatment period following a 5-week washout. QMG and MG ADL scores at baseline and endpoint of each treatment period generated correlation coefficients for baseline status and treatment response during eculizumab therapy. RESULTS: Correlation strength between QMG and MG-ADL scores was higher for treatment response (R = 0.726; 95% confidence interval, 0.264 0.907; P = 0.0036) than for assessing baseline disease status (R = 0.552; 95% confidence interval, -0.022-0.839; P = 0.0495). CONCLUSIONS: MG-ADL may be more sensitive for assessing treatment response than point-in-time disease status. Muscle Nerve 56: 328-330, 2017. PMID- 28010053 TI - Peritonitis as a risk factor for long-term cardiovascular mortality in peritoneal dialysis patients: The case of a friendly fire? AB - AIM: Since the impact of peritonitis on long-term non-infectious mortality has not been investigated until the present, the aim of this study was to analyze the impact of peritonitis on long-term cardiovascular (CV) mortality in a large peritoneal dialysis (PD) cohort. METHODS: The analysis was based on BRAZPD II, a national prospective cohort study that recruited patients in Brazilian centres from December 2004 to January 2011. Incident adult PD patients with at least 90 days on treatment were included in the analysis. Cardiovascular death occurring after a minimum of 30 days after a peritonitis episode was considered the primary endpoint. Cox regression analysis for time-dependent variables was used for the adjustments. RESULTS: There were 2405 episodes of peritonitis in 5707 patients (48% males, 44% diabetes, 73% hypertensive). Patients with one episode of peritonitis presented a 22% increase in the hazard ratio of late CV mortality compared to those who never experienced peritonitis (HR1.22; CI95%1.01-1.47). Adjusted hazard for CV mortality showed a stepwise negative effect on survival for each additional peritonitis episode of infection: two episodes (HR1.78; CI95%1.31-2.42), three episodes (HR2.81; CI95%1.83-4.32) and four episodes (HR3.84; CI95%2.01-7.32). CONCLUSION: Peritonitis was an independent predictor of CV mortality and the frequency of peritonitis was strongly associated with an increase in this risk. This is the first study to demonstrate the impact of peritonitis on late cardiovascular mortality of PD patients, suggesting a link between acute inflammation and cardiovascular outcomes. PMID- 28010054 TI - Several Hfq-dependent alterations in physiology of Yersinia enterocolitica O:3 are mediated by derepression of the transcriptional regulator RovM. AB - In bacteria, the RNA chaperone Hfq enables pairing of small regulatory RNAs with their target mRNAs and therefore is a key player of post-transcriptional regulation network. As a global regulator, Hfq is engaged in the adaptation to external environment, regulation of metabolism and bacterial virulence. In this study we used RNA-sequencing and quantitative proteomics (LC-MS/MS) to elucidate the role of this chaperone in the physiology and virulence of Yersinia enterocolitica serotype O:3. This global approach revealed the profound impact of Hfq on gene and protein expression. Furthermore, the role of Hfq in the cell morphology, metabolism, cell wall integrity, resistance to external stresses and pathogenicity was evaluated. Importantly, our results revealed that several alterations typical for the hfq-negative phenotype were due to derepression of the transcriptional factor RovM. The overexpression of RovM caused by the loss of Hfq chaperone resulted in extended growth defect, alterations in the lipid A structure, motility and biofilm formation defects, as well as changes in mannitol utilization. Furthermore, in Y. enterocolitica RovM only in the presence of Hfq affected the abundance of RpoS. Finally, the impact of hfq and rovM mutations on the virulence was assessed in the mouse infection model. PMID- 28010055 TI - [Peristomal cellulitis due to Magnusiomyces capitatus in a woman carrying percutaneous gastrostomy tube]. PMID- 28010052 TI - Adolescents at risk for drug abuse: a 3-year dual-process analysis. AB - AIMS: To test longitudinal additive and synergistic dual-process models in youth at documented risk for drug use. The specific dual-process approach examined suggests that engaging in drug use behaviors results from a dynamic interplay between automatically activated associative memory processes and executive reflective/control processes. DESIGN: This 3-year, three-wave population-based prospective study used mobile computer-based assessments. SETTING: Self-directed computer assessments were completed in school settings in the Los Angeles metropolitan area, California, USA. PARTICIPANTS: Seven hundred and twenty-five at-risk adolescents (44% female) in continuation high schools were recruited during 9th grade (age at recruitment, 14-16). MEASUREMENTS: Key outcome measures included past year alcohol, marijuana and cigarette use at each assessment. Predictors included working memory capacity (WMC), associative memory, the interaction term WMC by associative memory, sex, age, ethnicity and acculturation. FINDINGS: A significant cross-sectional interaction revealed tobacco-relevant associations were weaker predictors of cigarette use among males with higher WMC than among those with lower WMC (P < 0.004). Alternatively, drug relevant associations were stronger predictors of past year alcohol (P < 0.001) and marijuana use (P = 0.02) among females with higher WMC than among those with lower WMC. Longitudinal analyses revealed no significant interactions after adjusting for predictive effects of previous drug use. With respect to WMC, females with higher WMC were less likely to use marijuana at 2-year follow-up (P = 0.03). First-order effects of drug-related associations predicted greater alcohol and marijuana use prospectively in males at 1- and 2-year follow up (P <= 0.03), and greater past year alcohol and marijuana use in females at 1-year follow up (P <= 0.03). CONCLUSIONS: Drug-relevant memory associations play a key role in drug use behavior in at-risk youth. PMID- 28010056 TI - [Comparative study of HIV-1/2 antibody confirmatory assay: GeeniusTM versus INNO LIATM]. AB - OBJECTIVE: The aim of the study is to compare two confirmatory tests for HIV-1/2 infection. METHODS: A prospective study was carried out between 01/01/2015 and 12/31/2015. Serum samples with repeatedly positive results in the Antibody Antigen-HIV-1/2 (Architect, Abbott) screening assay were included. The serum samples corresponding to new diagnosed cases were selected and were used to compare the two confirmatory assays: GeeniusTM HIV-1/2 (Bio-Rad) and INNO-LIATM HIV-1/2 score line-immunoassay (Innogene-tics(r)). The HIV-1 viral load (Cobas(r) AmpliPrepHIV, Ro-che) was performed in discordant or indeterminate cases. RESULTS: Eight five samples were included. The results of both confirmatory assays were concordant in 80/85 samples: 53 HIV-1, 1 HIV-2, 25 negative and one indeterminate. Cohen's Kappa concordance coefficient between GeeniusTM and INNO LIATM techniques was very high (0.878). CONCLUSIONS: The concordance between the two assays is high. The procedure for GeeniusTM is simple and fast. GeeniusTM is a good alternative to include in the HIV-1/2 diagnostic algorithm. PMID- 28010057 TI - [Assessment of antibiotic prophylaxis adequacy in rectal surgery]. AB - OBJECTIVE: Antibiotic prophylaxis is the most suitable tool for preventing surgical site infection (SSI), so the development of guidelines and assessment of its monitoring is essential. In this study protocol compliance of antibiotic prophylaxis in rectal surgery and the effect of its adequacy in terms of pre ention of SSI was assessed. METHODS: Prospective cohort study was conducted from 1 January 2009 to 30 December 2015. The degree of compliance with antibiotic prophylaxis and causes of non-compliance in rectal surgery was evaluated. The incidence of SSI was studied after a maximum period of 30 days of incubation. To assess the effect of prophylaxis non-compliance on SSI the relative risk (RR) adjusted with the aid of a logistic regression model was used. RESULTS: The study covered a total of 244 patients. The patients infected reached 20 cases with a SSI cumulative incidence of 8.2% (CI95%: 4.8-11.6). Antibiotic prophylaxis was indicated in all patients and was administered in 98% of cases, with an overall protocol compliance 92.5%. The principal cause of non-compliance was the choice of antibiotic 55.6% (n=10). The effect of inadequacy of antibiotic prophylaxis on surgical infection was RR=0.58, CI95%: 0.10-4.10 (P>0.05). CONCLUSIONS: Compliance with antibiotic prophylaxis was high. No relationship between the adequacy of prophylaxis and incidence of surgical site infection in rectal surgery was found. PMID- 28010058 TI - [Epidemiology and risk factors of patients with intra-abdominal postsurgical infection treated with tigecycline: a cohort study]. AB - OBJECTIVE: To study a cohort of patients with intra-abdominal postsurgical infection treated with tigecycline to analyze its effectiveness and mortality related factors. METHODS: Prospective study of patients with intra-abdominal postsurgical infection with microbiological isolation and treated with tigecycline. RESULTS: Out of 103 patients only 61 full fit inclusion criteria. Mean age was 67 year-old and 72% were male. Charlson score was >= 3 in 65.5%, being diabetes and colon cancer the most prevalent diseases. Cancer surgery was the most frequent procedure (n=44, 72%) and previous antibiotic administration was present in 43 cases (69%). Pitt score was >= 3 in 69% and most prevalent bacteria were Escherichia coli (38 %), Enterococcus spp. (34%; mainly Enterococcus faecium) and Klebsiella pneumoniae together with Enterobacter cloacae (28%). Tigecycline was prescribed alone (17; 28%) or in combination with other antibiotics (44; 72%), mainly meropenem (25; 57%) or amikacin (19, 43%). 11 patients died (18%), all of which suffered extended cancer surgery and isolation of extended-spectrum betalactamase producing Enterobacteriaceae. Factors statistically associated to death in univariate analysis were Charlson score >3, pH <7.3 and leucocyte count >20.000 cells/mm3. CONCLUSIONS: As being a cohort of patients treated with tigecycline, E. faecium isolation was very frequent. Non fatal evolution was achieved in 82% cases, being tigecycline a potentially good option in the empiric treatment of very severe infections. PMID- 28010059 TI - Development of a Bifunctional Aptamer Targeting the Transferrin Receptor and Epithelial Cell Adhesion Molecule (EpCAM) for the Treatment of Brain Cancer Metastases. AB - The treatment of brain disorders is greatly hindered by the presence of the blood brain barrier, which restricts the overwhelming majority of small molecules from entering the brain. A novel approach by which to overcome this barrier is to target receptor mediated transport mechanisms present on the endothelial cell membranes. Therefore, we fused an aptamer that binds to epithelial cell adhesion molecule-expressing cancer cells to an aptamer targeting the transferrin receptor. This generated a proof of concept bifunctional aptamer that can overcome the blood-brain barrier and potentially specifically target brain disorders. The initial fusion of the two sequences enhanced the binding affinity of both aptamers while maintaining specificity. Additionally, mutations were introduced into both binding loops to determine their effect on aptamer specificity. The ability of the aptamer to transcytose the blood-brain barrier was then confirmed in vivo following a 1 nmol injection. This study has shown that through the fusion of two aptamer sequences, a bifunctional aptamer can be generated that has the potential to be developed for the specific treatment of brain disorders. PMID- 28010060 TI - Polycyclic Ketone Monooxygenase from the Thermophilic Fungus Thermothelomyces thermophila: A Structurally Distinct Biocatalyst for Bulky Substrates. AB - Regio- and stereoselective Baeyer-Villiger oxidations are difficult to achieve by classical chemical means, particularly when large, functionalized molecules are to be converted. Biocatalysis using flavin-containing Baeyer-Villiger monooxygenases (BVMOs) is a well-established tool to address these challenges, but known BVMOs have shortcomings in either stability or substrate selectivity. We characterized a novel BVMO from the thermophilic fungus Thermothelomyces thermophila, determined its three-dimensional structure, and demonstrated its use as a promising biocatalyst. This fungal enzyme displays excellent enantioselectivity, acts on various ketones, and is particularly active on polycyclic molecules. Most notably we observed that the enzyme can perform oxidations on both the A and D ring when converting steroids. These functional properties can be linked to unique structural features, which identify enzymes acting on bulky substrates as a distinct subgroup of the BVMO class. PMID- 28010061 TI - Self-Templating Construction of 3D Hierarchical Macro-/Mesoporous Silicon from 0D Silica Nanoparticles. AB - Porous silicon has found wide applications in many different fields including catalysis and lithium-ion batteries. Three-dimensional hierarchical macro /mesoporous silicon is synthesized from zero-dimensional Stober silica particles through a facile and scalable magnesiothermic reduction process. By systematic structure characterization of the macro-/mesoporous silicon, a self-templating mechanism governing the formation of the porous silicon is proposed. Applications as lithium-ion battery anode and photocatalytic hydrogen evolution catalyst are demonstrated. It is found that the macro-/mesoporous silicon shows significantly improved cyclic and rate performance over the commercial nanosized and micrometer sized silicon particles. After 300 cycles at 0.2 A g-1, the reversible specific capacity is still retained as much as 959 mAh g-1 with a high mass loading density of 1.4 mg cm-2. With the large current density of 2 A g-1, a reversible capacity of 632 mAh g-1 is exhibited. The coexistence of both macro- and mesoporous structures is responsible for the enhanced performance. The macro /mesoporous silicon also shows superior catalytic performance for photocatalytic hydrogen evolution compared to the silicon nanoparticles. PMID- 28010062 TI - Covalent Modulators of the Vacuolar ATPase. AB - The vacuolar H+ ATPase (V-ATPase) is a complex multisubunit machine that regulates important cellular processes through controlling acidity of intracellular compartments in eukaryotes. Existing small-molecule modulators of V ATPase either are restricted to targeting one membranous subunit of V-ATPase or have poorly understood mechanisms of action. Small molecules with novel and defined mechanisms of inhibition are thus needed to functionally characterize V ATPase and to fully evaluate the therapeutic relevance of V-ATPase in human diseases. We have discovered electrophilic quinazolines that covalently modify a soluble catalytic subunit of V-ATPase with high potency and exquisite proteomic selectivity as revealed by fluorescence imaging and chemical proteomic activity based profiling. The site of covalent modification was mapped to a cysteine residue located in a region of V-ATPase subunit A that is thought to regulate the dissociation of V-ATPase. We further demonstrate that a previously reported V ATPase inhibitor, 3-bromopyruvate, also targets the same cysteine residue and that our electrophilic quinazolines modulate the function of V-ATPase in cells. With their well-defined mechanism of action and high proteomic specificity, the described quinazolines offer a powerful set of chemical probes to investigate the physiological and pathological roles of V-ATPase. PMID- 28010063 TI - Construction of Two-Dimensional Chiral Networks through Atomic Bromine on Surfaces. AB - Using atomic bromine and 2,6-diphenylanthracene (DPA), we successfully constructed and characterized the large-area 2D chiral networks on Ag(111) and Cu(111) surfaces by combining molecular beam epitaxy with scanning tunneling microscopy. The Br atoms distribute themselves periodically in the network with the maximum number of -C-H...Br hydrogen bonds. Density functional theory calculations demonstrate that the hydrogen bonds contribute to the stability of the Br-organic networks. In addition, by controlling the ratio of bromine atoms to DPA molecules, different patterns of Br-organic networks were obtained on Ag(111) surfaces. Further experiments with 2,6-di(4-cyclohexylphenyl)anthracene on Ag(111) produced analogous atomic bromine guided 2D chiral networks. PMID- 28010064 TI - Simulations of the Ultrafast Transient Absorption Dynamics of a Donor-Acceptor Biaryl in Solution. AB - A model for simulating the transient electronic absorption spectra of donor acceptor dyads undergoing ultrafast intramolecular charge transfer in solution has been developed. It is based on the stochastic multichannel point-transition approach and includes the reorganization of high-frequency intramolecular modes (treated quantum mechanically) and of low frequency intramolecular and solvent modes (described classically). The relaxation of the slow modes is assumed to be exponential with time constants taken from experiments. The excited-state dynamics is obtained by simulating the population distribution of each quantum state after optical excitation and upon electronic and vibrational transitions. This model was used to simulate the transient electronic absorption spectra measured previously with a pyrylium phenolate in acetonitrile. A very good agreement between the simulated and measured spectra was obtained assuming a three-level model including the ground state, the optically excited state, and a dark state with large charge-transfer character and a substantially different geometry relative to that of the optically excited state. The merit of this approach to disentangle the contributions of both population changes and relaxation processes to the ultrafast spectral dynamics will be discussed. PMID- 28010065 TI - A power series revisit of the PBE exchange density-functional approximation: The PBEpow model. AB - PBEpow is a power series extension of the Perdew-Burke-Ernzerhof (PBE) exchange generalized gradient approximation. This novel variant is constructed by an inductive determination of the power series coefficients to fulfill physical fundamental constants in the slowly and rapidly varying density limits. When combined with the PBE correlation, PBEpow significantly improves the estimation of molecular covalent interactions such as energies of atomization reactions and keeps the line of performance of PBE for noncovalent interactions. More generally this work provides new insights about how to improve the modeling of short- and long-range interactions at the generalized gradient approximation level without the help of any kind of empirical parameterization. PMID- 28010066 TI - Effective scheme for partitioning covalent bonds in density-functional embedding theory: From molecules to extended covalent systems. AB - Density-functional embedding theory provides a general way to perform multi physics quantum mechanics simulations of large-scale materials by dividing the total system's electron density into a cluster's density and its environment's density. It is then possible to compute the accurate local electronic structures and energetics of the embedded cluster with high-level methods, meanwhile retaining a low-level description of the environment. The prerequisite step in the density-functional embedding theory is the cluster definition. In covalent systems, cutting across the covalent bonds that connect the cluster and its environment leads to dangling bonds (unpaired electrons). These represent a major obstacle for the application of density-functional embedding theory to study extended covalent systems. In this work, we developed a simple scheme to define the cluster in covalent systems. Instead of cutting covalent bonds, we directly split the boundary atoms for maintaining the valency of the cluster. With this new covalent embedding scheme, we compute the dehydrogenation energies of several different molecules, as well as the binding energy of a cobalt atom on graphene. Well localized cluster densities are observed, which can facilitate the use of localized basis sets in high-level calculations. The results are found to converge faster with the embedding method than the other multi-physics approach ONIOM. This work paves the way to perform the density-functional embedding simulations of heterogeneous systems in which different types of chemical bonds are present. PMID- 28010067 TI - An efficient quantum mechanical method for radical pair recombination reactions. AB - The standard quantum mechanical expressions for the singlet and triplet survival probabilities and product yields of a radical pair recombination reaction involve a trace over the states in a combined electronic and nuclear spin Hilbert space. If this trace is evaluated deterministically, by performing a separate time dependent wavepacket calculation for each initial state in the Hilbert space, the computational effort scales as O(Z2log?Z), where Z is the total number of nuclear spin states. Here we show that the trace can also be evaluated stochastically, by exploiting the properties of spin coherent states. This results in a computational effort of O(MZlog?Z), where M is the number of Monte Carlo samples needed for convergence. Example calculations on a strongly coupled radical pair with Z>106 show that the singlet yield can be converged to graphical accuracy using just M=200 samples, resulting in a speed up by a factor of >5000 over a standard deterministic calculation. We expect that this factor will greatly facilitate future quantum mechanical simulations of a wide variety of radical pairs of interest in chemistry and biology. PMID- 28010068 TI - Si clusters are more metallic than bulk Si. AB - Dipole polarizabilities were computed using density functional theory for silicon clusters over a broad range of sizes up to N = 147 atoms. The calculated total effective polarizabilities, which include contributions from permanent dipole moments of the clusters, are in very good agreement with recently measured values. We show that the permanent dipole contributions are most important for clusters in the intermediate size range and that the measured polarizabilities can be used to distinguish between energetically nearly degenerate cluster isomers at these sizes. We decompose the computed total polarizabilities alpha into the so-called dipole and charge transfer contributions, alphap and alphaq, using a site-specific analysis. When the per-atom values of these quantities are plotted against N-1/3, clear linear trends emerge that can be extrapolated to the large size limit (N-1/3->0), resulting in a value for alphaN of 30.5 bohrs3/atom that is significantly larger than the per-atom polarizability of semiconducting bulk Si, 25.04 bohrs3/atom. This indicates that Si clusters possess a higher degree of metallicity than bulk Si, a conclusion that is consistent with the strong electrostatic screening of the cluster interiors made evident by the analysis of the calculated atomic polarizabilities. PMID- 28010069 TI - Hyperfine interactions and internal rotation in methanol. AB - We present a rigorous derivation of the nuclear spin-rotation and spin-torsion coupling terms in the hyperfine Hamiltonian for molecules with internal rotation. Our formulas differ from the expressions derived by Heuvel and Dymanus [J. Mol. Spectrosc. 47, 363 (1973)], which these authors used and which were also applied recently by others to interpret experimental hyperfine spectra of such molecules. In the present work, our theoretical results are applied to methanol. We calculate the nuclear spin-spin magnetic dipole-dipole interactions and the nuclear contribution to the spin-torsion coupling vectors from the nuclear coordinates as functions of the internal rotation angle gamma, compute the spin rotation coupling tensors by ab initio electronic structure methods also as functions of gamma, and obtain the missing parameters for the electronic contribution to the spin-torsion coupling from a fit to measured spectra. The resulting hyperfine Hamiltonian is then used to compute hyperfine transition frequencies and intensities for twelve torsion-rotation transitions in methanol. With the use of the ab initio calculated spin-rotation coupling parameters without any modification, and physically reasonable values for the spin-torsion coupling parameters from the fit, we find good agreement with all of the measured spectra. PMID- 28010070 TI - Communication: Many-body stabilization of non-covalent interactions: Structure, stability, and mechanics of Ag3Co(CN)6 framework. AB - Stimuli-responsive metal-organic frameworks (MOFs) and other framework materials exhibit a broad variety of useful properties, which mainly stem from an interplay of strong covalent bonds within the organic linkers with presumably weak van der Waals (vdW) interactions which determine the overall packing of the framework constituents. Using Ag3Co(CN)6 as a fundamental test case-a system with a colossal positive and negative thermal expansion [A. L. Goodwin et al., Science 319, 794 (2008)]-we demonstrate that its structure, stability, dielectric, vibrational, and mechanical properties are critically influenced by many-body electronic correlation contributions to non-covalent vdW interactions. The Ag3Co(CN)6 framework is a remarkable molecular crystal, being visibly stabilized, rather than destabilized, by many-body vdW correlations. A detailed comparison with H3Co(CN)6 highlights the crucial role of strongly polarized metallophilic interactions in dictating the exceptional properties of denser MOFs. Beyond MOFs, our findings indicate that many-body electronic correlations can substantially stabilize polarizable materials, providing a novel mechanism for tuning the properties of nanomaterials with intricate structural motifs. PMID- 28010071 TI - Self-consistent implementation of ensemble density functional theory method for multiple strongly correlated electron pairs. AB - The spin-restricted ensemble-referenced Kohn-Sham (REKS) method is based on an ensemble representation of the density and is capable of correctly describing the non-dynamic electron correlation stemming from (near-)degeneracy of several electronic configurations. The existing REKS methodology describes systems with two electrons in two fractionally occupied orbitals. In this work, the REKS methodology is extended to treat systems with four fractionally occupied orbitals accommodating four electrons and self-consistent implementation of the REKS(4,4) method with simultaneous optimization of the orbitals and their fractional occupation numbers is reported. The new method is applied to a number of molecular systems where simultaneous dissociation of several chemical bonds takes place, as well as to the singlet ground states of organic tetraradicals 2,4 didehydrometaxylylene and 1,4,6,9-spiro[4.4]nonatetrayl. PMID- 28010072 TI - Simulation of the photodetachment spectrum of HHfO- using coupled-cluster calculations. AB - The photodetachment spectrum of HHfO- was simulated using restricted-spin coupled cluster single-double plus perturbative triple {RCCSD(T)} calculations performed on the ground electronic states of HHfO and HHfO-, employing basis sets of up to quintuple-zeta quality. The computed RCCSD(T) electron affinity of 1.67 +/- 0.02 eV at the complete basis set limit, including Hf 5s25p6 core correlation and zero point energy corrections, agrees well with the experimental value of 1.70 +/- 0.05 eV from a recent photodetachment study [X. Li et al., J. Chem. Phys. 136, 154306 (2012)]. For the simulation, Franck-Condon factors were computed which included allowances for anharmonicity and Duschinsky rotation. Comparisons between simulated and experimental spectra confirm the assignments of the molecular carrier and electronic states involved but suggest that the experimental vibrational structure has suffered from poor signal-to-noise ratio. An alternative assignment of the vibrational structure to that suggested in the experimental work is presented. PMID- 28010073 TI - On the tautomerisation of porphycene on copper (111): Finding the subtle balance between van der Waals interactions and hybridisation. AB - We use density-functional theory (DFT) to analyse the interaction of trans- and cis-porphycene with Cu(111) and their interconversion by intramolecular H transfer. This tautomerisation reaction is characterised by small values for the reaction energy and barrier, on the order of ~0.1 eV, where the trans configuration is thermodynamically more stable upon adsorption according to the experiments [J. N. Ladenthin et al., ACS Nano 9, 7287-7295 (2015)]. To gain even a qualitatively correct description of this reaction at the DFT level, an accurate treatment of dispersion interactions and a careful choice of the exchange contribution are required in order to predict the subtle energetics. Analysis of the electronic structure shows that adsorption is contributed by a van der Waals (vdW) interaction, mainly responsible for stabilising the polyaromatic fragments, and by a significant charge redistribution localised between Cu and the unsaturated N atoms of the molecule central cavity. We find that different vdW functionals can produce qualitatively different electronic structures, while yielding small trans vs. cis energy differences. Unlike other functionals surveyed here, vdW-DF with PBE exchange satisfactorily reproduces not only the experimental energetics but also the scanning tunneling microscopy images. This gives us confidence that this functional achieves a reliable balance between the two mechanisms contributing to the adsorption of porphycene. PMID- 28010074 TI - Effect of sequence dispersity on morphology of tapered diblock copolymers from molecular dynamics simulations. AB - Tapered diblock copolymers are similar to typical AB diblock copolymers but have an added transition region between the two blocks which changes gradually in composition from pure A to pure B. This tapered region can be varied from 0% (true diblock) to 100% (gradient copolymer) of the polymer length, and this allows some control over the microphase separated domain spacing and other material properties. We perform molecular dynamics simulations of linearly tapered block copolymers with tapers of various lengths, initialized from fluids density functional theory predictions. To investigate the effect of sequence dispersity, we compare systems composed of identical polymers, whose taper has a fixed sequence that most closely approximates a linear gradient, with sequentially disperse polymers, whose sequences are created statistically to yield the appropriate ensemble average linear gradient. Especially at high segregation strength, we find clear differences in polymer conformations and microstructures between these systems. Importantly, the statistical polymers are able to find more favorable conformations given their sequence, for instance, a statistical polymer with a larger fraction of A than the median will tend towards the A lamellae. The conformations of the statistically different polymers can thus be less stretched, and these systems have higher overall density. Consequently, the lamellae formed by statistical polymers have smaller domain spacing with sharper interfaces. PMID- 28010075 TI - High order path integrals made easy. AB - The precise description of quantum nuclear fluctuations in atomistic modelling is possible by employing path integral techniques, which involve a considerable computational overhead due to the need of simulating multiple replicas of the system. Many approaches have been suggested to reduce the required number of replicas. Among these, high-order factorizations of the Boltzmann operator are particularly attractive for high-precision and low-temperature scenarios. Unfortunately, to date, several technical challenges have prevented a widespread use of these approaches to study the nuclear quantum effects in condensed-phase systems. Here we introduce an inexpensive molecular dynamics scheme that overcomes these limitations, thus making it possible to exploit the improved convergence of high-order path integrals without having to sacrifice the stability, convenience, and flexibility of conventional second-order techniques. The capabilities of the method are demonstrated by simulations of liquid water and ice, as described by a neural-network potential fitted to the dispersion corrected hybrid density functional theory calculations. PMID- 28010076 TI - Communication: Trapping a proton in argon: Spectroscopy and theory of the proton bound argon dimer and its solvation. AB - Ion-molecule complexes of the form H+Arn are produced in pulsed-discharge supersonic expansions containing hydrogen and argon. These ions are analyzed and mass-selected in a reflectron spectrometer and studied with infrared laser photodissociation spectroscopy. Infrared spectra for the n = 3-7 complexes are characterized by a series of strong bands in the 900-2200 cm-1 region. Computational studies at the MP2/aug-cc-pVTZ level examine the structures, binding energies, and infrared spectra for these systems. The core ion responsible for the infrared bands is the proton-bound argon dimer, Ar-H+-Ar, which is progressively solvated by the excess argon. Anharmonic vibrational theory is able to reproduce the vibrational structure, identifying it as arising from the asymmetric proton stretch in combination with multiple quanta of the symmetric argon stretch. Successive addition of argon shifts the proton vibration to lower frequencies, as the charge is delocalized over more ligands. The Ar-H+ Ar core ion has a first solvation sphere of five argons. PMID- 28010077 TI - Characterization of secondary ion emission processes of sub-MeV C60 ion impacts via analysis of statistical distributions of the emitted ion number. AB - We report probability distributions of the number of secondary ions (SIs) emitted by sub-MeV C60 ion impacts on an organic polymer target and the characterization of their emission processes through the analysis of the distributions. The probability distributions were obtained by analyzing experimental SI counting data obtained by a time-of-flight SI mass spectrometer combined with pulsed primary ion beams, using an analytical model developed to derive the distributions from the experimental data. A series of probability distribution functions was investigated for ion impacts of C60 with sub-MeV energies (0.12 0.54 MeV), which can provide sufficient SIs per impact to determine the functions. Their complicated and undefined SI emission processes were characterized based on the determined functions. PMID- 28010079 TI - Erratum: "On the accuracy of surface hopping dynamics in condensed phase non adiabatic problems" [J. Chem. Phys. 144, 094104 (2016)]. PMID- 28010078 TI - A new potential energy surface of LiHCl system and dynamic studies for the Li(2S) + HCl(X1Sigma+) -> LiCl(X1Sigma+) + H(2S) reaction. AB - A new global potential energy surface (PES) is constructed for the ground state of LiHCl system based on high-quality ab initio energy points calculated using multi-reference configuration interaction calculations with the Davidson correction. The AVQZ and WCVQZ basis sets are employed for H and Li atoms, respectively. To compensate the relativistic effects of heavy element, the AWCVQZ DK basis set is employed for Cl atom. The neural network method is used for fitting the PES, and the root mean square error is small (1.36 * 10-2 eV). The spectroscopic constants of the diatoms obtained from the new PES agree well with experimental data. The geometric characteristics of the transition state and the complex are examined and compared with the previous theoretical values. To study the reaction dynamics of the Li(2S) + HCl(X1Sigma+) -> LiCl(X1Sigma+) + H(2S) reaction, quantum reactive scattering dynamics calculations using collection reactant-coordinate-based wave packet method are conducted based on the new PES. The results of the reaction probabilities indicate that a small barrier exists along the reaction path as observed from the PES. The integral cross section curves reveal that the product molecule LiCl is easily excited. In addition, the reaction is dominated by forward scattering, and similar pattern is observed from Becker's experiment. PMID- 28010080 TI - Fragmentation dynamics of carbonyl sulfide in collision with 500 eV electron. AB - The fragmentation dynamics of OCSq+ (q = 2, 3, 4) induced by electron collision at an impact energy of 500 eV is studied. By using the momentum imaging technique, the three dimensional momentum vectors of all the fragments are obtained, which enables us to analyse both the kinetic energy release and the momentum correlations for a certain fragmentation channel. Up to fifteen dissociation channels are analyzed including six, five, and four channels for two body, and incomplete and complete three-body Coulomb fragmentations. For three body dissociation, the fragmentation mechanisms are investigated with the help of Dalitz plot and Newton diagram. It is found that the sequential fragmentation involves in OCS2+->O+C++S+ with S+ emitted first and in OCS3+->O++C++S+ with O-C and C-S bonds breaking first. The remaining channels, however, always dissociate through a concerted mechanism. The relative intensities of the channels are also presented in this work. PMID- 28010081 TI - Analysis of the lattice kinetic Monte Carlo method in systems with external fields. AB - The lattice kinetic Monte Carlo (LKMC) method is studied in the context of Brownian particles subjected to drift forces, here principally represented by external fluid flow. LKMC rate expressions for particle hopping are derived that satisfy detailed balance at equilibrium while also providing correct dynamical trajectories in advective-diffusive situations. Error analyses are performed for systems in which collections of particles undergo Brownian motion while also being advected by plug and parabolic flows. We demonstrate how the flow intensity, and its associated drift force, as well as its gradient, each impact the accuracy of the method in relation to reference analytical solutions and Brownian dynamics simulations. Finally, we show how a non-uniform grid that everywhere retains full microscopic detail may be employed to increase the computational efficiency of lattice kinetic Monte Carlo simulations of particles subjected to drift forces arising from the presence of external fields. PMID- 28010082 TI - Erratum: "Ab initio investigation of structure, stability, thermal behavior, bonding, and infrared spectra of ionized water cluster (H2O)6+" [J. Chem. Phys. 145, 154307 (2016)]. PMID- 28010083 TI - Theory of molecular conductance using a modular approach. AB - This study probes the correlation between the conductance of a molecular wire (the property of a whole system) and its constituent backbone units (modules). By using a tight-binding Hamiltonian combined with single-particle Green's functions, we develop an approach that enables an estimate of a conductance decay constant in terms of the Hamiltonians of molecular backbone units and the couplings between two nearest-neighbor units in the off-resonant tunneling regime. For demonstration, we examine several representative molecular systems in a framework of the Huckel model (the simplest atomistic-level model). The Huckel model can be reduced to a single-orbital-per-site formulation [A. Nitzan, Annu. Rev. Phys. Chem. 52, 681 (2001)], and each energy level in the single-orbital-per site picture can be expressed in an explicit form including the synergistic effect of all molecular orbitals of a molecular backbone unit. Based on the proposed approach, we show the correspondence between the complete destructive quantum interference and an infinite injection gap and derive the preconditions of the modified Simmons equation and the rule of intramolecular series circuits. PMID- 28010084 TI - The role of intramolecular nonbonded interaction and angle sampling in single step free energy perturbation. AB - Single-step free energy perturbation (sFEP) has often been proposed as an efficient tool for a quick free energy scan due to its straightforward protocol and the ability to recycle an existing molecular dynamics trajectory for free energy calculations. Although sFEP is expected to fail when the sampling of a system is inefficient, it is often expected to hold for an alchemical transformation between ligands with a moderate difference in their sizes, e.g., transforming a benzene into an ethylbenzene. Yet, exceptions were observed in calculations for anisole and methylaniline, which have similar physical sizes as ethylbenzene. In this study, we show that such exceptions arise from the sampling inefficiency on an unexpected rigid degree of freedom, namely, the bond angle theta. The distributions of theta differ dramatically between two end states of a sFEP calculation, i.e., the conformation of the ligand changes significantly during the alchemical transformation process. Our investigation also reveals the interrelation between the ligand conformation and the intramolecular nonbonded interactions. This knowledge suggests a best combination of the ghost ligand potential and the dual topology setting, which improves the accuracy in a single reference sFEP calculation by bringing down its error from around 5kBT to kBT. PMID- 28010085 TI - Nuclei-selected atomic-orbital response-theory formulation for the calculation of NMR shielding tensors using density-fitting. AB - An atomic orbital density matrix based response formulation of the nuclei selected approach of Beer, Kussmann, and Ochsenfeld [J. Chem. Phys. 134, 074102 (2011)] to calculate nuclear magnetic resonance (NMR) shielding tensors has been developed and implemented into LSDalton allowing for a simultaneous solution of the response equations, which significantly improves the performance. The response formulation to calculate nuclei-selected NMR shielding tensors can be used together with the density-fitting approximation that allows efficient calculation of Coulomb integrals. It is shown that using density-fitting does not lead to a significant loss in accuracy for both the nuclei-selected and the conventional ways to calculate NMR shielding constants and should thus be used for applications with LSDalton. PMID- 28010086 TI - Targeting excited states in all-trans polyenes with electron-pair states. AB - Wavefunctions restricted to electron pair states are promising models for strongly correlated systems. Specifically, the pair Coupled Cluster Doubles (pCCD) ansatz allows us to accurately describe bond dissociation processes and heavy-element containing compounds with multiple quasi-degenerate single-particle states. Here, we extend the pCCD method to model excited states using the equation of motion (EOM) formalism. As the cluster operator of pCCD is restricted to electron-pair excitations, EOM-pCCD allows us to target excited electron-pair states only. To model singly excited states within EOM-pCCD, we modify the configuration interaction ansatz of EOM-pCCD to contain also single excitations. Our proposed model represents a simple and cost-effective alternative to conventional EOM-CC methods to study singly excited electronic states. The performance of the excited state models is assessed against the lowest-lying excited states of the uranyl cation and the two lowest-lying excited states of all-trans polyenes. Our numerical results suggest that EOM-pCCD including single excitations is a good starting point to target singly excited states. PMID- 28010087 TI - Role of quantum fluctuations in structural dynamics of liquids of light molecules. AB - A possible role of quantum effects, such as tunneling and zero-point energy, in the structural dynamics of supercooled liquids is studied by dielectric spectroscopy. The presented results demonstrate that the liquids, bulk 3-methyl pentane and confined normal and deuterated water, have low glass transition temperature and unusually low for their class of materials steepness of the temperature dependence of structural relaxation (fragility). Although we do not find any signs of tunneling in the structural relaxation of these liquids, their unusually low fragility can be well described by the influence of the quantum fluctuations. Confined water presents an especially interesting case in comparison to the earlier data on bulk low-density amorphous and vapor deposited water. Confined water exhibits a much weaker isotope effect than bulk water, although the effect is still significant. We show that it can be ascribed to the change of the energy barrier for relaxation due to a decrease in the zero-point energy upon D/H substitution. The observed difference in the behavior of confined and bulk water demonstrates high sensitivity of quantum effects to the barrier heights and structure of water. Moreover, these results demonstrate that extrapolation of confined water properties to the bulk water behavior is questionable. PMID- 28010088 TI - Hydrogen-induced atomic structure evolution of the oxygen-chemisorbed Cu(110) surface. AB - Using a combination of scanning tunneling microscopy (STM) and density functional theory (DFT) modeling, we determine the mechanism of the atomic structural evolution of the oxygenated Cu(110) surface induced by the reaction of adsorbed hydrogen with chemisorbed oxygen in the Cu(110)-c(6 * 2)-O structure. Our STM observations show that the reconstructed Cu(110)-c(6 * 2)-O surface undergoes a phase transition to the (2 * 1)-O reconstruction in the course of oxygen loss induced by the reaction with H2 gas. Using DFT modeling, we find that the surface phase transition is initiated via the adsorption of molecular hydrogen on the chemisorbed oxygen, which results in the formation of H2O molecules that desorb spontaneously from the surface. The loss of chemisorbed oxygen induces the c(6 * 2) -> (2 * 1) transition that involves the diffusion of Cu-O-Cu chains along the ?1-10? direction. PMID- 28010089 TI - Deep tunneling in the unimolecular decay of CH3CHOO Criegee intermediates to OH radical products. AB - Unimolecular decay of Criegee intermediates produced in alkene ozonolysis is known to be a significant source of OH radicals in the troposphere. In this work, unimolecular decay of the methyl-substituted Criegee intermediate, syn-CH3CHOO, to OH products is shown to occur at energies significantly below the transition state barrier for a 1,4 hydrogen transfer that leads to these products [Y. Fang et al., J. Chem. Phys. 144, 061102 (2016)]. The rate of appearance of OH products arising from tunneling through the barrier is obtained through direct time-domain measurements following the vibrational activation of syn-CH3CHOO. IR excitation of syn-CH3CHOO at energies nearly 2000 cm-1 below the barrier is achieved through combination bands involving CH stretch and another lower frequency mode, and the resultant OH products are detected by UV laser-induced fluorescence. The observed syn-CH3CHOO combination bands in the 4100-4350 cm-1 region are identified by comparison with the computed IR absorption spectrum. The experimental decay rates are found to be ca. 106 s-1 in this deep tunneling regime, which is approximately 100-times slower than that in the vicinity of the barrier.The experimental results are consistent with statistical Rice-Ramsperger-Kassel-Marcus (RRKM) calculations of the microcanonical decay rates with tunneling through the barrier, and notable deviations may originate from the sparsity in the density of states for syn-CH3CHOO at lower energies. Thermal unimolecular decay of syn CH3CHOO is predicted to have significant contribution from microcanonical rates at energies that are much below the barrier. PMID- 28010090 TI - Lattice thermal expansion and anisotropic displacements in ??-sulfur from diffraction experiments and first-principles theory. AB - Thermal properties of solid-state materials are a fundamental topic of study with important practical implications. For example, anisotropic displacement parameters (ADPs) are routinely used in physics, chemistry, and crystallography to quantify the thermal motion of atoms in crystals. ADPs are commonly derived from diffraction experiments, but recent developments have also enabled their first-principles prediction using periodic density-functional theory (DFT). Here, we combine experiments and dispersion-corrected DFT to quantify lattice thermal expansion and ADPs in crystalline alpha-sulfur (S8), a prototypical elemental solid that is controlled by the interplay of covalent and van der Waals interactions. We begin by reporting on single-crystal and powder X-ray diffraction measurements that provide new and improved reference data from 10 K up to room temperature. We then use several popular dispersion-corrected DFT methods to predict vibrational and thermal properties of alpha-sulfur, including the anisotropic lattice thermal expansion. Hereafter, ADPs are derived in the commonly used harmonic approximation (in the computed zero-Kelvin structure) and also in the quasi-harmonic approximation (QHA) which takes the predicted lattice thermal expansion into account. At the PPBE+D3(BJ) level, the QHA leads to excellent agreement with experiments. Finally, more general implications of this study for theory and experiment are discussed. PMID- 28010091 TI - Effect of alcohol on the structure of cytochrome C: FCS and molecular dynamics simulations. AB - Effect of ethanol on the size and structure of a protein cytochrome C (Cyt C) is investigated using fluorescence correlation spectroscopy (FCS) and molecular dynamics (MD) simulations. For FCS studies, Cyt C is covalently labeled with a fluorescent probe, alexa 488. FCS studies indicate that on addition of ethanol, the size of the protein varies non-monotonically. The size of Cyt C increases (i.e., the protein unfolds) on addition of alcohol (ethanol) up to a mole fraction of 0.2 (44.75% v/v) and decreases at higher alcohol concentration. In order to provide a molecular origin of this structural transition, we explore the conformational free energy landscape of Cyt C as a function of radius of gyration (Rg) at different compositions of water-ethanol binary mixture using MD simulations. Cyt C exhibits a minimum at Rg ~ 13 A in bulk water (0% alcohol). Upon increasing ethanol concentration, a second minimum appears in the free energy surface with gradually larger Rg up to chiEtOH ~ 0.2 (44.75% v/v). This suggests gradual unfolding of the protein. At a higher concentration of alcohol (chiEtOH > 0.2), the minimum at large Rg vanishes, indicating compaction. Analysis of the contact map and the solvent organization around protein indicates a preferential solvation of the hydrophobic residues by ethanol up to chiEtOH = 0.2 (44.75% v/v) and this causes the gradual unfolding of the protein. At high concentration (chiEtOH = 0.3 (58% v/v)), due to structural organization in bulk water-ethanol binary mixture, the extent of preferential solvation by ethanol decreases. This causes a structural transition of Cyt C towards a more compact state. PMID- 28010093 TI - Perturbative triples correction for local pair natural orbital based explicitly correlated CCSD(F12*) using Laplace transformation techniques. AB - We present an implementation of pair natural orbital coupled cluster singles and doubles with perturbative triples, PNO-CCSD(T), which avoids the quasi-canonical triples approximation (T0) where couplings due to off-diagonal Fock matrix elements are neglected. A numerical Laplace transformation of the canonical expression for the perturbative (T) triples correction is used to avoid an I/O and storage bottleneck for the triples amplitudes. Results for a test set of reaction energies show that only very few Laplace grid points are needed to obtain converged energy differences and that PNO-CCSD(T) is a more robust approximation than PNO-CCSD(T0) with a reduced mean absolute deviation from canonical CCSD(T) results. We combine the PNO-based (T) triples correction with the explicitly correlated PNO-CCSD(F12*) method and investigate the use of specialized F12-PNOs in the conventional triples correction. We find that no significant additional errors are introduced and that PNO-CCSD(F12*)(T) can be applied in a black box manner. PMID- 28010092 TI - Lowest bending mode of 13C-substituted C3 and an experimentally derived structure. AB - The nu2 lowest bending mode of linear C3 and of all its 13C-substituted isotopologues was recorded using a terahertz-supersonic jet spectrometer in combination with a laser ablation source. Sixty-five ro-vibrational transitions between 1.8 and 1.9 THz have been assigned to linear C12C12C12, C12C12C13, C12C13C12, C13C13C12, C13C12C13, and C13C13C13. For each isotopologue, molecular parameters were obtained and the C-C-bond length was derived experimentally. All results are in excellent agreement with recent ab initio calculations [B. Schroder and P. Sebald, J. Chem. Phys. 144, 044307 (2016)]. The new measurements explain why the interstellar search for singly substituted C12C12C13 has failed so far. A spectral line list with recommended transition frequencies based on global data fits is given to foster future interstellar detections. PMID- 28010094 TI - Direct observation of ring-opening dynamics in strong-field ionized selenophene using femtosecond inner-shell absorption spectroscopy. AB - Femtosecond extreme ultraviolet transient absorption spectroscopy is used to explore strong-field ionization induced dynamics in selenophene (C4H4Se). The dynamics are monitored in real-time from the viewpoint of the Se atom by recording the temporal evolution of element-specific spectral features near the Se 3d inner-shell absorption edge (~58 eV). The interpretation of the experimental results is supported by first-principles time-dependent density functional theory calculations. The experiments simultaneously capture the instantaneous population of stable molecular ions, the emergence and decay of excited cation states, and the appearance of atomic fragments. The experiments reveal, in particular, insight into the strong-field induced ring-opening dynamics in the selenophene cation, which are traced by the emergence of non cyclic molecules as well as the liberation of Se+ ions within an overall time scale of approximately 170 fs. We propose that both products may be associated with dynamics on the same electronic surfaces but with different degrees of vibrational excitation. The time-dependent inner-shell absorption features provide direct evidence for a complex relaxation mechanism that may be approximated by a two-step model, whereby the initially prepared, excited cyclic cation decays within tau1 = 80 +/- 30 fs into a transient molecular species, which then gives rise to the emergence of bare Se+ and ring-open cations within an additional tau2 = 80 +/- 30 fs. The combined experimental and theoretical results suggest a close relationship between sigma* excited cation states and the observed ring-opening reactions. The findings demonstrate that the combination of femtosecond time-resolved core-level spectroscopy with ab initio estimates of spectroscopic signatures provide new insights into complex, ultrafast photochemical reactions such as ring-opening dynamics in organic molecules in real-time and with simultaneous sensitivity for electronic and structural rearrangements. PMID- 28010095 TI - Glycerol in micellar confinement with tunable rigidity. AB - We investigate the glassy dynamics of glycerol in the confinement of a microemulsion system, which is stable on cooling down to the glass transition of its components. By changing the composition, we vary the viscosity of the matrix, while keeping the confining geometry intact, as is demonstrated by small angle X ray scattering. By means of 2H NMR, differential scanning calorimetry, and triplet solvation dynamics we, thus, probe the dynamics of glycerol in confinements of varying rigidity. 2H NMR results show that, at higher temperatures, the dynamics of confined glycerol is unchanged compared to bulk behavior, while the reorientation of glycerol molecules becomes significantly faster than in the bulk in the deeply supercooled regime. However, comparison of different 2H NMR findings with data from calorimetry and solvation dynamics reveals that this acceleration is not due to the changed structural relaxation of glycerol, but rather due to the rotational motion of essentially rigid glycerol droplets or of aggregates of such droplets in a more fluid matrix. Thus, independent of the matrix mobility, the glycerol dynamics remains unchanged except for the smallest droplets, where an increase of Tg and, thus, a slowdown of the structural relaxation is observed even in a fluid matrix. PMID- 28010096 TI - General formulation of rovibrational kinetic energy operators and matrix elements in internal bond-angle coordinates using factorized Jacobians. AB - We show how inverse metric tensors and rovibrational kinetic energy operators in terms of internal bond-angle coordinates can be obtained analytically following a factorization of the Jacobian worked out by Frederick and Woywod. The structure of these Jacobians is exploited in two ways: On one hand, the elements of the metric tensor as well as its determinant all have the form ?rmsin(alphan)cos(betao). This form can be preserved by working with the adjugate metric tensor that can be obtained without divisions. On the other hand, the adjugate can be obtained with less effort by exploiting the lower triangular structure of the Jacobians. Together with a suitable choice of the wavefunction, we avoid singularities and show how to obtain analytical expressions for the rovibrational kinetic energy matrix elements. PMID- 28010097 TI - On the incorporation of the geometric phase in general single potential energy surface dynamics: A removable approximation to ab initio data. AB - For two electronic states coupled by conical intersections, the line integral of the derivative coupling can be used to construct a complex-valued multiplicative phase factor that makes the real-valued adiabatic electronic wave function single valued, provided that the curl of the derivative coupling is zero. Unfortunately for ab initio determined wave functions, the curl is never rigorously zero. However, when the wave functions are determined from a coupled two diabatic state Hamiltonian Hd (fit to ab initio data), the resulting derivative couplings are by construction curl free, except at points of conical intersection. In this work we focus on a recently introduced diabatization scheme that produces the Hd by fitting ab initio determined energies, energy gradients, and derivative couplings to the corresponding Hd determined quantities in a least squares sense, producing a removable approximation to the ab initio determined derivative coupling. This approach and related numerical issues associated with the nonremovable ab initio derivative couplings are illustrated using a full 33-dimensional representation of phenol photodissociation. The use of this approach to provide a general framework for treating the molecular Aharonov Bohm effect is demonstrated. PMID- 28010098 TI - Ion pairing and phase behaviour of an asymmetric restricted primitive model of ionic liquids. AB - An asymmetric restricted primitive model (ARPM) of electrolytes is proposed as a simple three parameter (charge q, diameter d, and charge displacement b) model of ionic liquids and solutions. Charge displacement allows electrostatic and steric interactions to operate between different centres, so that orientational correlations arise in ion-ion interactions. In this way the ionic system may have partly the character of a simple ionic fluid/solid and of a polar fluid formed from ion pairs. The present exploration of the system focuses on the ion pair formation mechanism, the relative concentration of paired and free ions and the consequences for the cohesive energy, and the tendency to form fluid or solid phase. In contrast to studies of similar (though not identical) models in the past, we focus on behaviours at room temperature. By MC and MD simulations of such systems composed of monovalent ions of hard-sphere (or essentially hard sphere) diameter equal to 5 A and a charge displacement ranging from 0 to 2 A from the hard-sphere origin, we find that ion pairing dominates for b larger than 1 A. When b exceeds about 1.5 A, the system is essentially a liquid of dipolar ion pairs with a small presence of free ions. We also investigate dielectric behaviours of corresponding liquids, composed of purely dipolar species. Many basic features of ionic liquids appear to be remarkably consistent with those of our ARPM at ambient conditions, when b is around 1 A. However, the rate of self diffusion and, to a lesser extent, conductivity is overestimated, presumably due to the simple spherical shape of our ions in the ARPM. The relative simplicity of our ARPM in relation to the rich variety of new mechanisms and properties it introduces, and to the numerical simplicity of its exploration by theory or simulation, makes it an essential step on the way towards representation of the full complexity of ionic liquids. PMID- 28010099 TI - Generalized entropy theory of glass-formation in fully flexible polymer melts. AB - The generalized entropy theory (GET) offers many insights into how molecular parameters influence polymer glass-formation. Given the fact that chain rigidity often plays a critical role in understanding the glass-formation of polymer materials, the GET was originally developed based on models of semiflexible chains. Consequently, all previous calculations within the GET considered polymers with some degree of chain rigidity. Motivated by unexpected results from computer simulations of fully flexible polymer melts concerning the dependence of thermodynamic and dynamic properties on the cohesive interaction strength (epsilon), the present paper employs the GET to explore the influence of epsilon on glass-formation in models of polymer melts with a vanishing bending rigidity, i.e., fully flexible polymer melts. In accord with simulations, the GET for fully flexible polymer melts predicts that basic dimensionless thermodynamic properties (such as the reduced thermal expansion coefficient and isothermal compressibility) are universal functions of the temperature scaled by epsilon in the regime of low pressures. Similar scaling behavior is also found for the configurational entropy density in the GET for fully flexible polymer melts. Moreover, we find that the characteristic temperatures of glass-formation increase linearly with epsilon and that the fragility is independent of epsilon in fully flexible polymer melts, predictions that are again consistent with simulations of glass-forming polymer melts composed of fully flexible chains. Beyond an explanation of these general trends observed in simulations, the GET for fully flexible polymer melts predicts the presence of a positive residual configurational entropy at low temperatures, indicating a return to Arrhenius relaxation in the low temperature glassy state. PMID- 28010100 TI - Performance of a nonempirical density functional on molecules and hydrogen-bonded complexes. AB - Recently, Tao and Mo derived a meta-generalized gradient approximation functional based on a model exchange-correlation hole. In this work, the performance of this functional is assessed on standard test sets, using the 6-311++G(3df,3pd) basis set. These test sets include 223 G3/99 enthalpies of formation, 99 atomization energies, 76 barrier heights, 58 electron affinities, 8 proton affinities, 96 bond lengths, 82 harmonic vibrational frequencies, 10 hydrogen-bonded molecular complexes, and 22 atomic excitation energies. Our calculations show that the Tao Mo functional can achieve high accuracy for most properties considered, relative to the local spin-density approximation, Perdew-Burke-Ernzerhof, and Tao-Perdew Staroverov-Scuseria functionals. In particular, it yields the best accuracy for proton affinities, harmonic vibrational frequencies, hydrogen-bond dissociation energies and bond lengths, and atomic excitation energies. PMID- 28010101 TI - Constant pH simulations of pH responsive polymers. AB - Polyacidic polymers can change structure over a narrow range of pH in a competition between the hydrophobic effect, which favors a compact state, and electrostatic repulsion, which favors an extended state. Constant pH molecular dynamics computer simulations of poly(methacrylic acid) reveal that there are two types of structural changes, one local and one global, which make up the overall response. The local structural response depends on the tacticity of the polymer and leads to different cooperative effects for polymers with different stereochemistries, demonstrating both positive and negative cooperativities. PMID- 28010102 TI - Theoretical investigation of rotationally inelastic collisions of CH(X2Pi) with molecular hydrogen. AB - We report calculations of state-to-state cross sections for collision-induced rotational transitions of CH(X2Pi) with molecular hydrogen. These calculations employed the diabatic matrix elements of the interaction potential determined by Dagdigian [J. Chem. Phys. 145, 114301 (2016)], which employed the multi-reference configuration-interaction method [MRCISD+Q(Davidson)]. Because of the presence of a deep well on the lower potential energy surface, the scattering calculations were carried out using the quantum statistical method of Manolopoulos and co workers [Chem. Phys. Lett. 343, 356 (2001)]. The computed cross sections included contributions from direct scattering, as well as from the formation and decay of a collision complex. The magnitude of latter contribution was found to decrease significantly with increasing collision energy. Rotationally energy transfer rate constants were computed for this system since these are required for astrochemical modeling. PMID- 28010103 TI - Optimized virtual orbital subspace for faster GW calculations in localized basis. AB - The popularity of the GW approximation to the self-energy to access the quasiparticle energies of molecules is constantly increasing. As the other methods addressing the electronic correlation, the GW self-energy unfortunately shows a very slow convergence with respect to the basis complexity, which precludes the calculation of accurate quasiparticle energies for large molecules. Here we propose a method to mitigate this issue that relies on two steps: (i) the definition of a reduced virtual orbital subspace, thanks to a much smaller basis set; (ii) the account of the remainder through the simpler one-ring approximation to the self-energy. We assess the quality of the corrected quasiparticle energies for simple molecules, and finally we show an application to large graphene chunks to demonstrate the numerical efficiency of the scheme. PMID- 28010104 TI - Experimental and ab initio characterization of HC3N+ vibronic structure. II. High resolution VUV PFI-ZEKE spectroscopy. AB - Vacuum-ultraviolet pulsed-field-ionization zero-kinetic-energy photoelectron spectra of X+Pi2<-XSigma+1 and B+Pi2<-XSigma+1 transitions of the HC314N and HC315N isotopologues of cyanoacetylene have been recorded. The resolution of the photoelectron spectra allowed us to resolve the vibrational structures and the spin-orbit splittings in the cation. Accurate values of the adiabatic ionization potentials of the two isotopologues (EI/hc(HC314N)=93 909(2) cm-1 and EI/hc(HC315N)=93 912(2) cm-1), the vibrational frequencies of the nu2, nu6, and nu7 vibrational modes, and the spin-orbit coupling constant (ASO = -44(2) cm-1) of the X+Pi2 cationic ground state have been derived from the measurements. Using ab initio calculations, the unexpected structure of the B+Pi2<-XSigma+1 transition is tentatively attributed to a conical intersection between the A+ and B+ electronic states of the cation. PMID- 28010105 TI - Contact mechanics for poroelastic, fluid-filled media, with application to cartilage. AB - I study a simple contact mechanics model for a poroelastic, fluid-filled solid squeezed against a rigid, randomly rough substrate. I study how the fluid is squeezed out from the interface, and how the area of contact, and the average interfacial separation, change with time. I present numerical results relevant for a human cartilage. I show that for a fluid filled poroelastic solid the probability of cavitation (and the related wear as the cavities implode), and dynamical scraping (defined below and in Hutt and Persson, J. Chem. Phys. 144, 124903 (2016)), may be suppressed by fluid flow from the poroelastic solid into the (roughness induced) interfacial gap between the solids. PMID- 28010106 TI - Experimental and ab initio characterization of HC3N+ vibronic structure. I. Synchrotron-based threshold photo-electron spectroscopy. AB - Threshold-photoionization spectroscopy of cyanoacetylene (HC3N) and its 15N isotopologue has been investigated in the vacuum-ultraviolet range with a synchrotron-based experiment allowing to record threshold-photoelectron spectrum and photoion yield over a large energy range (from 88 500 to 177 500 cm-1, i.e., from 11 to 22 eV). Adiabatic ionization energies towards the three lowest electronic states X+2Pi, A+ Sigma+2, and B+ Pi2 are derived from the threshold photoelectron spectrum. A detailed description of the vibrational structure of these states is proposed leading to the determination of the vibrational frequencies for most modes. The vibrational assignments and the discussion about the electronic structure are supported by multireference ab initio calculations (CASPT2, MRCI). Unprecedented structures are resolved and tentatively assigned in the region of the B+<- X transition. Exploratory calculations highlight the complexity of the electronic landscape of the cation up to approximately 10 eV above its ground state. PMID- 28010107 TI - Matrix effects in the C 1s photoabsorption spectra of condensed naphthalene. AB - High-resolution C 1s near-edge x-ray absorption fine structure (NEXAFS) spectra of naphthalene are investigated. By comparing the spectral signatures of condensed naphthalene molecules with those of naphthalene in the gas phase, we are able to unambiguously identify spectral features which are affected by the intermolecular interactions in the condensed phase. With the help of calculations using time-dependent density-functional theory and the second-order algebraic diagrammatic construction scheme for the polarization propagator, resonances in the relevant energy range can be assigned to valence and Rydberg-like excitations. Thus, we obtain a more detailed identification of NEXAFS resonances beyond the present literature. PMID- 28010108 TI - Analytic solution of the Ornstein-Zernike relation for inhomogeneous liquids. AB - The properties of a classical simple liquid are strongly affected by the application of an external potential that supports inhomogeneity. To understand the nature of these property changes, the equilibrium particle distribution functions of the liquid have, typically, been calculated directly using either integral equation or density functional based analyses. In this study, we develop a different approach with a focus on two distribution functions that characterize the inhomogeneous liquid: the pair direct correlation function c(r1,r2) and the pair correlation function g(r1,r2). With g(r1,r2) considered to be an experimental observable, we solve the Ornstein-Zernike equation for the inhomogeneous liquid to obtain c(r1,r2), using information about the well studied and resolved g(0)(r1,r2) and c(0)(r1,r2) for the parent homogeneous ((0)) system. In practical cases, where g(r1,r2) is available from experimental data in a discrete form, the resulting c(r1,r2) is expressed as an explicit function of g(r1,r2) in a discrete form. A weaker continuous form of solution is also obtained, in the form of an integral equation with finite integration limits. The result obtained with our formulation is tested against the exact solutions for the correlation and distribution functions of a one-dimensional inhomogeneous hard rod liquid. Following the success of that test, the formalism is extended to higher dimensional systems with explicit consideration of the two-dimensional liquid. PMID- 28010109 TI - Naturally occurring branched-chain polyamines induce a crosslinked meshwork structure in a giant DNA. AB - We studied the effect of branched-chain polyamines on the folding transition of genome-sized DNA molecules in aqueous solution by the use of single-molecule observation with fluorescence microcopy. Detailed morphological features of polyamine/DNA complexes were characterized by atomic force microscopy (AFM). The AFM observations indicated that branched-chain polyamines tend to induce a characteristic change in the higher-order structure of DNA by forming bridges or crosslinks between the segments of a DNA molecule. In contrast, natural linear chain polyamines cause a parallel alignment between DNA segments. Circular dichroism measurements revealed that branched-chain polyamines induce the A-form in the secondary structure of DNA, while linear-chain polyamines have only a minimum effect. This large difference in the effects of branched- and linear chain polyamines is discussed in relation to the difference in the manner of binding of these polyamines to negatively charged double-stranded DNA. PMID- 28010110 TI - A molecular theory of the structural dynamics of protein induced by a perturbation. AB - An equation to describe the structural dynamics of protein molecule induced by a perturbation such as a photo-excitation is derived based on the linear response theory, which reads ??alpha(t)=??alpha(t=infinity) 1kBT?gamma?Delta??alpha(t)Delta??gamma?eq(0)???gamma(0). In the equation, alpha and gamma distinguish atoms in protein, ??gamma(0) denotes a perturbation at time t = 0, ??alpha(t) the average position (or structure) of protein atom alpha at time t after the perturbation being applied, and ??a(t=infinity) the position at t=infinity. ?Delta??alpha(t)Delta??gamma?eq(0) is a response function in which Delta??alpha(t) is the fluctuation of atom alpha at time t in the equilibrium system. The perturbation is defined in terms of the free energy difference between perturbed and unperturbed equilibrium-states, which includes interactions between solute and solvent as well as those among solvent molecules in a renormalized manner. The response function signifies the time evolution of the variance-covariance matrix of the structural fluctuation for the unperturbed system. A theory to evaluate the response function ?Delta??alpha(t)Delta??gamma?eq(0) is also proposed based on the Kim-Hirata theory for the structural fluctuation of protein [B. Kim and F. Hirata, J. Chem. Phys. 138, 054108 (2013)]. The problem reduces to a simple eigenvalue problem for a matrix which includes the friction and the second derivative of the free energy surface of protein with respect to its atomic coordinates. PMID- 28010111 TI - Caveats in the interpretation of time-resolved photoionization measurements: A photoelectron imaging study of pyrrole. AB - We report time-resolved photoelectron imaging studies of gas-phase pyrrole over the 267-240 nm excitation region, recorded in conjunction with a 300 nm probe. Of specific interest is the lowest-lying (3s/pisigma*) state, which exhibits very weak oscillator strength but is thought to be excited directly at wavelengths <=254 nm. We conclude, however, that the only significant contribution to our photoelectron data at all wavelengths investigated is from non-resonant ionization. Our findings do not rule out (3s/pisigma*) state excitation (as appears to be confirmed by supporting time-resolved ion-yield measurements) but do potentially highlight important caveats regarding the use and interpretation of photoreactant ionization measurements to interrogate dynamical processes in systems exhibiting significant topological differences between the potential energy surfaces of the neutral and cation states. PMID- 28010112 TI - Peptide engineered microcantilevers for selective chemical force microscopy and monitoring of nanoparticle capture. AB - Engineered peptides capable of binding to silica have been used to provide contrast in chemical force microscopy and tested for their capacity to selectively capture silica nanoparticles (NPs). Gold coated atomic force microscopy (AFM) microcantilevers with integrated tips and colloidal probes were functionalized with engineered peptides through a thiol group of a terminal cysteine which was linked via a glycine trimer to a 12-mer binding sequence. The functionalized probes demonstrated a significantly increased binding force on silicon oxide areas of a gold-patterned silicon wafer, whereas plain gold probes, and those functionalized with a random permutation of the silica binding peptide motif or an all-histidine sequence displayed similar adhesion forces to gold and silicon oxide. As the functionalized probes also allowed contact mode imaging subsequently to the adhesion mapping, also the associated friction contrast was measured and found to be similar to the adhesion contrast. Furthermore, the adsorption of silica NPs onto planar gold surfaces functionalized in the same manner was observed to be selective. Notably, the surface coverage with silica NPs was found to decrease with increasing pH, implying the importance of electrostatic interactions between the peptide and the NPs. Finally, the adsorption of silica NPs was monitored via the decrease in fundamental resonance frequency of an AFM microcantilever functionalized with silica binding peptides. PMID- 28010113 TI - Toward a quantified, validated, and verifiable understanding of the Biointerface. PMID- 28010114 TI - Heterogeneity Coefficients for Mahalanobis' D as a Multivariate Effect Size. AB - The Mahalanobis distance D is the multivariate generalization of Cohen's d and can be used as a standardized effect size for multivariate differences between groups. An important issue in the interpretation of D is heterogeneity, that is, the extent to which contributions to the overall effect size are concentrated in a small subset of variables rather than evenly distributed across the whole set. Here I present two heterogeneity coefficients for D based on the Gini coefficient, a well-known index of inequality among values of a distribution. I discuss the properties and limitations of the two coefficients and illustrate their use by reanalyzing some published findings from studies of gender differences. PMID- 28010117 TI - Out-of-Sync Cancer Care: Health Insurance Companies, Biomedical Practices, and Clinical Time in Colombia. AB - I discuss the physical wearing out of low-income cancer patients in the aftermath of the neoliberal restructuring of the Colombian health care system in 1993. The settings for this struggle are the hospitals and the health insurance companies; the actors are bodies with cancer, the physicians who diagnose people with cancer, and the relatives who care for them. I show how most low-income patients, instead of accessing complete anticancer treatments in a timely fashion, have to negotiate and confront health insurance companies and profit-making. This results in a wait, where the time needs of the bureaucracy of the health care system and the time needs of patients' bodies are discordant, at a cost to patients. PMID- 28010116 TI - CHRONO integrates behavioral stress and epigenetic control of metabolism. AB - Circadian rhythms are a critical part of the body's homeostatic mechanisms. These rhythms repeat with a cycle-length of approximately 24 h and are generated by a transcriptional-translational feedback loop. These rhythms are critical for proper behavioral, physiological, and molecular functions. CHRONO, a novel circadian clock gene, forms a complex with other clock proteins and modulates the circadian machinery. CHRONO also interacts with histone deacetylase (HDAC) to modulate the epigenetic status of the transcriptional regulation. Chrono knockout mice display a longer period of circadian behavior and an elevated stress response. This paper reviews the molecular function of CHRONO with a focus on epigenetic regulation and speculates on the possible function of CHRONO in physiological processes. Key messages Chrono is a circadian clock gene whose transcription exhibits a robust circadian oscillation. CHRONO is a repressor of circadian transcriptional/translational feedback loops. CHRONO may function to link epigenetic control mechanisms to stress responses. PMID- 28010118 TI - Biogovernance Beyond the State: The Shaping of Stem Cell Therapy by Patient Organizations in India. AB - Public engagement through government-sponsored "public consultations" in biomedical innovation, specifically stem cell research and therapy, has been relatively limited in India. However, patient groups are drawing upon collaborations with medical practitioners to gain leverage in promoting biomedical research and the conditions under which patients can access experimental treatments. Based on qualitative fieldwork conducted between 2012 and 2015, I examine the ways in which two patient groups engaged with debates around how experimental stem cell therapy should be regulated, given the current lack of legally binding research guidelines. Such processes of engagement can be seen as an alternative form of biomedical governance which responds to the priorities and exigencies of Indian patients, contrasting with the current measures taken by the Indian state which, instead, are primarily directed at the global scientific and corporate world. PMID- 28010119 TI - Measuring Sexual Orientation: A Review and Critique of U.S. Data Collection Efforts and Implications for Health Policy. AB - The U.S. Department of Health and Human Services' (HHS) Healthy People 2020 goals sought to improve health outcomes among sexual minorities; HHS acknowledged that a dearth of sexual orientation items in federal and state health surveys obscured a broad understanding of sexual minority-related health disparities. The HHS 2011 data progression plan aimed to advance sexual orientation data collection efforts at the national level. Sexual orientation is a complex, multidimensional construct often composed of sexual identity, sexual attraction, and sexual behavior, thus posing challenges to its quantitative and practical measurement and analysis. In this review, we (a) present existing sexual orientation constructs; (b) evaluate current HHS sexual orientation data collection efforts; (c) review post-2011 data progression plan research on sexual minority health disparities, drawing on HHS survey data; (d) highlight the importance of and (e) identify obstacles to multidimensional sexual orientation measurement and analysis; and (f) discuss methods for multidimensional sexual orientation analysis and propose a matrix for addressing discordance/branchedness within these analyses. Multidimensional sexual orientation data collection and analysis would elucidate sexual minority-related health disparities, guide related health policies, and enhance population-based estimates of sexual minority individuals to steer health care practices. PMID- 28010120 TI - Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis. AB - The association of interleukin-6 (IL-6)-174G > C (rs1800795) single nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) is a relevant issue because of conflicting and consensus lacking reports published in literature. We investigated IL-6-174G > C promoter polymorphism in 34 RA patients, attending a tertiary care hospital in north India. We also performed a meta-analysis, of the previously published studies reporting this genetic relationship, in overall population, and independently in Asian and Caucasian ethnicities to further elucidate this association. A total of 13 studies, including the current one, involving 3291 RA cases and 3812 controls were analyzed. Out of the 13 studies, 6 were from Asian, 6 from Caucasian and 1 from a mixed population. Our case-control study showed significant association of IL-6 174G > C SNP with increased RA risk: allelic (OR = 3.750, 95% CI = 1.800-7.813, p < 0.001); dominant (OR = 2.800, 95% CI = 1.167-6.721, p = 0.021); and recessive (OR = 36.72, 95% CI = 2.004-672.7, p = 0.015). The meta-analysis revealed the increased RA risk associated with IL-6-174G > C SNP in overall population: allelic (OR = 1.650, 95% CI = 1.169-2.329, p = 0.004); homozygous (OR = 1.380, 95% CI = 0.906-2.101, p = 0.133); heterozygous (OR = 1.559, 95% CI = 1.001-2.428, p = 0.049); dominant (OR = 1.663, 95% CI = 1.078-2.567, p = 0.022); and recessive (OR = 1.366, 95% CI = 0.964-1.935, p = 0.079). Subgroup analysis also showed this polymorphism to be associated with increased RA risk in Asian population: allelic (OR = 3.724, 95% CI = 1.361-10.190, p = 0.010); dominant (OR = 3.823, 95% CI = 1.320-11.074, p = 0.013); and recessive (OR = 4.357, 95% CI = 1.634-11.623, p = 0.003), but not in Caucasian population. This meta-analysis shows that IL-6-174G > C SNP is significantly associated with increased RA risk in overall, and specifically in Asian population. PMID- 28010121 TI - Emotional eating as a mediator between anxiety and cholesterol in population with overweight and hypertension. AB - Although the relationship between cholesterol and mood states (especially anxiety) has been well studied, few researches have included the role of eating styles in this relationship. This study explored the associations among eating styles, negative emotional symptoms, and levels of cholesterol (and other medical variables) in a population with hypertension and overweight or obesity, analyzing the possible mediation mechanisms involved. A cross-sectional study was conducted in 68 adults with hypertension and overweight/obesity, and stepwise multiple regression analysis and mediation analyses were carried out to test the hypothesis that eating styles mediate the relationship between negative emotional symptoms and cholesterol. Several significant correlations among age, anthropometric, medical, and psychological variables (eating styles and negative emotional symptoms) were found. There was a significant indirect effect of anxiety on total cholesterol and LDL cholesterol through emotional eating. Results suggest that emotional eating has a relevant role in the rise in total and LDL cholesterol, acting as a mediator in the relationship between anxiety and cholesterol. This finding could have important implications, since it introduces a new variable in the relationship between emotions and cholesterol and, therefore, changes the way of understanding this relationship, and of treating high cholesterol in a hypertensive sample. PMID- 28010123 TI - Consequences of Casual Sex Relationships and Experiences on Adolescents' Psychological Well-Being: A Prospective Study. AB - Casual sexual relationships and experiences (CSREs) are still considered to be detrimental to the psychological well-being of youth even though findings remain inconclusive. Most studies have focused on emerging adulthood. Using a prospective design based on a representative sample of high school students in the province of Quebec, we measured sexually active adolescents' (N = 2,304) psychological well-being six months after engaging in these relationships while controlling for prior well-being. We analyzed two forms of CSREs, friends with benefits (FWB) and one-night stand (ONS) relationships, as well as levels of sexual intimacy. The results show that CSREs had a small impact (small effect sizes) on subsequent psychological well-being, especially among girls; FWB relationships involving penetrative contact increased girls' psychological distress and both their alcohol and drug consumption. ONSs including sexual touching increased girls' psychological distress and their drug use. None of the CSREs influenced boys' psychological well-being. The findings underscored the importance of using caution when arguing that CSREs are detrimental or harmless to the psychological well-being of adolescents. The results also highlight the importance of taking into account gender and forms of CSREs in prevention and health interventions. PMID- 28010122 TI - Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK. AB - AIMS: Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H2O2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin. RESULTS: Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with beta-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H2O2 and O2.- levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H2O2 scavenger polyethylene glycol-conjugated catalase (PEG catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice. INNOVATION: We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension. CONCLUSION: LOX up regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379-397. PMID- 28010124 TI - Validation of a protein panel for the noninvasive detection of recurrent non muscle invasive bladder cancer. AB - CONTEXT: About 50-70% of patients with non-muscle invasive bladder cancer (NMIBC) experience relapse of disease. OBJECTIVE: To establish a panel of protein biomarkers incorporated in a multiplexed microarray (BCa chip) and a classifier for diagnosing recurrent NMIBC. MATERIALS AND METHODS: Urine samples from 45 patients were tested. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: A multi biomarker panel (ECadh, IL8, MMP9, EN2, VEGF, past recurrences, BCG therapies and stage at diagnosis) was identified yielding an area under the curve of 0.96. DISCUSSION AND CONCLUSION: This biomarker panel represents a potential diagnostic tool for noninvasive diagnosis of recurrent NMIBC. PMID- 28010126 TI - Quantifying impatience using models of delay discounting in substance use disorders. PMID- 28010125 TI - Proposed association between the hexanucleotide repeat of C9orf72 and opposability index of the thumb. AB - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron and sub-cerebral projection neuron degeneration. We sought to explore the particular susceptibility of humans to neurodegeneration and whether any characteristic human features might predispose to selective vulnerability of the critical motor circuitry in ALS. The pathophysiology of the C9orf72 repeat is not yet understood, despite its role as a common cause of ALS and frontotemporal dementia. METHODS: We examined the development of the monosynaptic cortico motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool BLAST. RESULTS: We found a statistically significant linear relationship between the C9orf72 hexanucleotide bit score, a measure of genomic conservation of the aligned region across different species, and the thumb opposability index (Pearson's correlation coefficient of 0.78, p value 0.023). The C9orf72 hexanucleotide repeat was only found in humans, chimpanzees and gorillas, species with higher opposability indices. CONCLUSIONS: This may support a role of the hexanucleotide repeat in the same developmental pathways in species with higher prehensility, which may be associated with the selective vulnerability of cortico motoneuronal cells in humans, manifested most obviously as the 'split hand' syndrome in ALS. PMID- 28010127 TI - Accommodating Small Sample Sizes in Three-Level Models When the Third Level is Incidental. AB - Small samples sizes are a pervasive problem when modeling clustered data. In two level models, this problem has been well studied, and several resources provide guidance for modeling such data. However, a recent review of small-sample clustered data methods has noted that no studies have investigated methods for modeling three-level data with small sample sizes. Furthermore, strategies for two-level models do not necessarily translate to the three-level context. Moreover, three-level models are prone to small samples because the "small sample" designation is primarily based on the sample size of the highest level, and large samples are increasingly difficult to amass as one progresses up a hierarchy. In this study, we focus on the case when the third level is incidental, meaning that the third level is important to consider but there are no explicit research questions at the third level. This study performs a simulation study to examine the performance of seven methods for modeling three level data with a small sample at the third level. A motivating educational psychology example is also provided to demonstrate how the choice of method can greatly affect results. PMID- 28010128 TI - Procalcitonin for clinical decisions on influenza-like illness in emergency department during influenza a(H1N1)2009 pandemic. AB - PURPOSE: We aimed to determine whether serum procalcitonin (PCT) values could help in identifying flu in patient admitted to the emergency department (ED) with influenza-like illness (ILI) during influenza A(H1N1)2009 pandemic. METHODS: An observational retrospective cohort study was performed in a referral ED for emerging infectious diseases. All patients tested for influenza A(H1N1)2009 by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and procalcitonin between June 2009 and January 2010 were analyzed. PCT was studied for its negative predictive value of bacterial infection. Patients PCT-/RT-PCR + were considered as true positive. RESULTS: On the 80 patients included, 16 were positive for influenza A(H1N1)2009 RT-PCR, all but one of them had low PCT concentrations. Conversely, 19 (30%) of the 64 patients with negative RT-PCR had elevated PCT concentrations. For a PCT threshold <0.25 MUg/L, sensitivity was 0.94, specificity 0.30, positive predictive value 0.25 and negative predictive value 0.95 for the diagnosis of flu. CONCLUSION: In the context of an influenza pandemic, serum PCT measurement may be useful for clinical decisions in the ED as most of RT-PCR confirmed patients have low PCT values. Patients with PCT above 0.25 MUg/L are unlikely to have a unique diagnosis of flu. PMID- 28010129 TI - Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies. AB - OBJECTIVE: A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies. SIGNIFICANCE: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride. METHODS: Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 degrees C, +2-8 degrees C and -20 degrees C. RESULTS: The ASD powder was composed of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at -20 degrees C. CONCLUSIONS: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such. PMID- 28010130 TI - Treatment of alcohol use disorder and co-occurring PTSD. AB - BACKGROUND: Alcohol use disorder (AUD) is a serious psychiatric disorder with medical, psychiatric, and social consequences. In individuals with comorbid post traumatic stress disorder (PTSD), treatment outcomes are notably worse in comparison with treatment outcomes associated with either disorder occurring alone. There is a growing literature evaluating treatments, both pharmacotherapy and psychotherapy focused, in individuals with co-occurring AUD and PTSD. The main objective of this review was to evaluate pharmacotherapy and psychotherapy studies that were specifically designed to evaluate the treatment of individuals with comorbid AUD and PTSD. METHOD: MEDLINE and PUBMED databases were searched with no specific time period. Studies focusing on SUD treatments were excluded. Because the number of random clinical trial (RCT) studies was small, all publications (including open label, single case, and secondary analyses) were included. RESULTS: Sixteen studies met criteria and were organized based on whether they evaluated the efficacy of pharmacotherapy, psychotherapy, or both. Pharmacological interventions with either AUD or PTSD agents were mainly effective in reducing drinking outcomes; only one study using sertraline found that the active study medication was superior to placebo in reducing PTSD symptoms. Psychotherapies were not superior to a comparative treatment in reducing drinking outcomes. Only 1 study showed reduction in PTSD symptoms in a small sample of completers. The single RCT that evaluated the efficacy of naltrexone in combination with psychotherapies (prolonged exposure or supportive counseling) found that naltrexone in combination with prolonged exposure was better for drinking outcomes at follow-up. CONCLUSIONS: Although these studies represent a good start in terms of research in treatment interventions of co occurring AUD and PTSD, the studies are very limited, most lack adequate power, and the majority suffer from inadequate control groups. In particular, there is a strong need to develop and evaluate the combined medication and psychological based treatment interventions for those with comorbid AUD and PTSD. PMID- 28010131 TI - Predicting the clinical outcome of ICSI by sperm head vacuole examination. AB - : To assess whether high magnification sperm head vacuole examination (SHVE) and/or standard sperm morphology assessment can predict ICSI outcomes in terms of fertilization, embryo quality, and delivery rates, a prospective observational bicentric study was conducted in two publicly funded assisted reproductive technology (ART) units in France between January and July of 2012. A total of 111 ICSI cycles for exclusively male infertility factors were included. A Spearman's correlation test was performed to validate SHVE reproducibility between the ART units. The normal morphology rate and SHVE performed on selected spermatozoa were respectively determined according to David's and Vanderzwalmen's classifications used for motile sperm organelle morphology examination (MSOME) on the day of the ICSI. Receiver Operating Characteristic (ROC) curve analysis was performed to determine thresholds associated with the occurrence of a delivery. There was an excellent correlation between the two operators (r=0.98), thus validating the study's SHVE data. Percentages of normal morphology grade spermatozoa using the standard classification and first-best morphology grade spermatozoa determined by SHVE were not significantly associated with (i) delivery (p=0.58; 0.90 /area under curve (AUC) =0.532; 0.507), (ii) fertilization (p=0.88; 0.90), (iii) top quality embryos (p=0.27; 0.98), and (iv) good quality embryo rates (p=0.73; 0.98), respectively. In conclusion, high magnification SHVE and standard sperm morphology assessment cannot predict clinical or biological ICSI outcomes. ABBREVIATIONS: ART: assisted reproductive technology; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; ICSI: intra cytoplasmic sperm injection; IVF: in vitro fertilization; LNVs: large nuclear vacuoles; MSOME: motile sperm organelle morphology examination; SHVE: sperm head vacuole examination; WHO: World Health Organization. PMID- 28010132 TI - The Risk of Sepsis with Inhaled and Oral Corticosteroids in Patients with COPD. AB - The use of oral and inhaled corticosteroids is associated with increases in the risk of infection, especially pneumonia. The risk of sepsis with corticosteroid treatment in patients with chronic obstructive pulmonary disease (COPD) has been little studied, however. We assessed whether the use of inhaled and oral corticosteroids in COPD is associated with an increase in the risk of sepsis. We carried out a retrospective cohort study using the administrative health databases of the province of Quebec, Canada, over the period 1990-2007. The cohort of patients with COPD included patients aged 55 years or older who used respiratory medications. A quasi-cohort analysis was used to estimate the rate ratio (RR) of sepsis in current users of inhaled corticosteroids and oral corticosteroids separately, after adjusting for differences in COPD disease severity and co-morbid conditions. The cohort included 163,514 patients treated for COPD, including 1,704 who were hospitalized for or died with sepsis during follow-up (incidence rate 1.94 per 1000 per year). The RR of sepsis associated with current use of inhaled corticosteroids was 0.98 (95%confidence interval [CI] 0.84-1.14). Current oral corticosteroid use was associated with a 66% increase in the risk of sepsis (RR 1.66; 95% CI: 1.35-2.05). The increase in risk remains for around 5 months after the oral corticosteroid exposure. Among patients treated for COPD, the risk of sepsis is not increased with inhaled corticosteroids, even at high doses, while the risk is increased with oral corticosteroids. This risk should be considered when treating exacerbations of COPD. PMID- 28010133 TI - Designing small molecule CXCR3 antagonists. AB - INTRODUCTION: By virtue of its specificity for chemokines induced in Th1 associated pathologies, CXCR3 has attracted considerable attention as a target for therapeutic intervention. Several pharmacologically distinct small molecules with in vitro and in vivo potency have been described in the literature, although to date, none have shown efficacy in clinical trials. Areas covered: In this article, the author outlines the rationale for targeting CXCR3 and discusses the potential pitfalls in targeting receptors in poorly understood areas of chemokine biology. Furthermore, they cover emerging therapeutic areas outside of the 'traditional' Th1 arena in which CXCR3 antagonists may ultimately bear fruit. Finally, they discuss the design of recently discovered small molecules targeting CXCR3. Expert opinion: CXCR3 and its ligands appear to play roles in a multitude of diverse diseases in humans. In vitro studies suggest that CXCR3 is inherently 'druggable' and that potent, efficacious small molecules targeting CXCR3 antagonists will find a clinical niche. However, the well-trodden path to failure of small molecule chemokine receptor antagonists in clinical trials suggests that a cautious approach should be undertaken. Ideally, unequivocal evidence elucidating the precise role of CXCR3 should be obtained before targeting the receptor in a particular disease cohort. PMID- 28010134 TI - Peer Victimization Trajectories at the Adolescent Transition: Associations Among Chronic Victimization, Peer-Reported Status, and Adjustment. AB - The current study demonstrated that chronic peer victimization, as compared to time-limited victimization, is particularly associated with peer status and peer reported adjustment at the adolescent transition. Using a cohort sequential design, a sample of 653 adolescents (48% female, 87% Caucasian) in Grades 6-8 were assessed at 3 annual time points; data captured indices of peer victimization, likeability, popularity, and several peer-reported indices of internalizing (e.g., sadness, worry) and externalizing (e.g., anger, fighting) symptoms across Grades 6-10. Four trajectories of victimization experiences were identified-chronic, high decreasing, low increasing, and low stable-suggesting instability in victimization experiences over time. Adolescents who experienced chronic victimization, as compared to those with low-stable, decreasing, or increasing levels of victimization, were rated by peers more often on indices of maladjustment and less often on measures of popularity and likeability. Findings highlight negative associations with chronic victimization and underscore the need for targeted interventions to prevent chronic victimization. Overall, findings further emphasize the role of chronicity in victimization and highlight the importance of identifying chronic victims for intervention and prevention efforts. PMID- 28010135 TI - Neutrophils releasing IL-17A into NETs are essential to plasma cell differentiation in inflamed tissue dependent on IL-1R. AB - Interleukin (IL) 17A in chronic inflammation is also produced by innate immune cells as neutrophils. Mice with chronic humoral response induced by venom of Thalassophryne nattereri (VTn) proved to be a good tool for evaluating the impact of IL-17A on the development of long-lived plasma cells in the inflamed peritoneal cavity. Here, we report that VTn induces IL-17A production by neutrophils accumulating in the peritoneal cavity and triggers the extrusion of IL-17A along with neutrophil extracellular traps (NETs). Neutrophil depletion reduced the number of IL17A-producing cells in VTn-immunized mice and blocked the differentiation of long-lived plasma cells. Specific antibody production and survival of long-lived plasma cells was ablated in VTn-immunized mice deficient in CD4, while CD28 signaling had the opposite effect on differentiation of long lived plasma cells. Further, maturation of long-lived plasma cells in inflamed peritoneal cavity was IL-1R1 and COX-2 dependent. Finally, when both the Raf-MEK ERK pathway and the IL-17A or IL-1R1 activities were blocked, neutrophils were unable to promote the differentiation of memory B cells into long-lived plasma cells, confirming the essential role of neutrophils and IL-17A along with NETs in an IL-1/IL-1R-dependent manner as the novel helping partner for plasma cell differentiation in chronically inflamed tissues. PMID- 28010136 TI - Elucidation of the variability in consistency of pharmacopoeia quality petrolatum. AB - The Pharmacopeia monograph for petrolatum poorly defines the material's physical properties. Indeed, differences between petrolatum grades can be substantial; yield stress varies between 65 and 280 Pa which can be compared with the consistency of respectively thin cream or thick ointment. This variation is not only due to differences in composition or refining process but also as a result of different processing; for example, thermal history influences petrolatum structure considerably. Slow cooling of petrolatum resulted in a yield stress of 26 Pa and fast cooling in 79 Pa. X-ray showed that crystallinity was 0.7% for the first cooling case and 1.5% for the second one. Crystallite size was estimated to be 20-50 nm. To investigate if this relatively small difference in crystallinity may induce the difference in consistency, 15 nm SiO2 particles were added to petrolatum. Indeed, a small increase in SiO2 concentration led to a major increase in yield stress. This was argued to be due to the small size of the particles, resulting in a large increase in absolute number of particles. The Pharmacopeia does not unambiguously define the pharmaceutical excipient petrolatum. As a consequence, the formulator has to take care of selecting the appropriate grade as well as to carefully control the processing of the material in order to achieve a consistent pharmaceutical product. PMID- 28010137 TI - Hydronephrosis with ureteritis developed in C57BL/6N mice carrying the congenic region derived from MRL/MpJ-type chromosome 11. AB - Inbred MRL/MpJ mice show several unique phenotypes in tissue regeneration processes and the urogenital and immune systems. Clarifying the genetic and molecular bases of these phenotypes requires the analysis of their genetic susceptibility locus. Herein, hydronephrosis development was incidentally observed in MRL/MpJ-derived chromosome 11 (D11Mit21-212)-carrying C57BL/6N-based congenic mice, which developed bilateral or unilateral hydronephrosis in both males and females with 23.5% and 12.5% prevalence, respectively. Histopathologically, papillary malformations of the transitional epithelium in the pelvic-ureteric junction seemed to constrict the ureter luminal entrance. Characteristically, eosinophilic crystals were observed in the lumen of diseased ureters. These ureters were surrounded by infiltrating cells mainly composed of numerous CD3+ T-cells and B220+ B-cells. Furthermore, several Iba-1+ macrophages, Gr-1+ granulocytes, mast cells and chitinase 3-like 3/Ym1 (an important inflammatory lectin)-positive cells were detected. Eosinophils also accumulated to these lesions in diseased ureters. Some B6.MRL-(D11Mit21-D11Mit212) mice had duplicated ureters. We determined >100 single nucleotide variants between C57BL/6N- and MRL/MpJ-type chromosome 11 congenic regions, which were associated with nonsynonymous substitution, frameshift or stopgain of coding proteins. In conclusion, B6.MRL-(D11Mit21-D11Mit212) mice spontaneously developed hydronephrosis due to obstructive uropathy with inflammation. Thus, this mouse line would be useful for molecular pathological analysis of obstructive uropathy in experimental medicine. PMID- 28010138 TI - Synthesis, molecular modeling and biological evaluation of two new chicoric acid analogs. AB - Two conformationally constrained compounds similar to chicoric acid but lacking the catechol and carboxyl groups were prepared. In these analogues, the single bond between the two caffeoyl fragments has been replaced with a chiral oxirane ring and both aromatic residues modified protecting completely or partially the catechol moiety as methyl ether. Preliminary molecular modelling studies carried out on the two analogues showed interactions near the active site of HIV integrase; however, in comparison with raltegravir, the biological evaluation confirmed that CAA-1 and CAA-2 were unable to inhibit infection at lower concentration. PMID- 28010139 TI - Association of serum leptin with bone mineral density in postmenopausal osteoporotic females. AB - OBJECTIVE: Present study was designed to find out whether leptin is a predictor of bone mass density (BMD) in premenopausal women (PMW) and postmenopausal osteoporotic women (PMOPW) or it has no association with BMD. METHODS: One hundred and ninety two women (98 PMOPW and 94 PMW) were recruited for this study. The control group was BMI matched with osteoporotic subjects. BMD assessment was done on calcaneus by peripheral ultrasound bone densitometry and T scores were determined. Serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum leptin and BMD values were significantly different in both groups (leptin, 18.56 +/- 8.65 ng/ml versus 21.64 +/- 9.80 ng/ml, p = 0.02) and (BMD, -0.70 +/- 0.19 versus -3.17 +/- 0.59, p = 0.000), respectively. In PMOPW serum leptin and BMD were considerably correlated with weight (lep, r = 0.53, p = <0.001; BMD, r = -0.21, p = 0.02), BMI (lep, r = 0.52, p = <0.001; BMD, r = -0.27, p = 0.005), waist circumference (lep, r = 0.61, p = <0.001; BMD, r = 0.18, p = 0.04), hip circumference (lep, r = 0.58, p = <0.001). Multivariate linear stepwise regression analysis showed that weight and BMI in PMW and PMOPW were independent predictors of BMD. Serum leptin level was not found to be the predictor of BMD in both groups. CONCLUSION: The present results indicate that body weight and BMI have an impact on BMD while serum leptin is not associated with BMD in PMW and PMOPW. PMID- 28010141 TI - Differential expression of visfatin, leptin, stromal cell derived factor-1alpha, endothelial nitric oxide synthase, and vascular endothelial growth factor in human leiomyomas. AB - AIM: This study was aimed to understand expressions of the visfatin, leptin, stromal cell derived factor (SDF)-1alpha, endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF) in human uterine leiomyomas (UL) and normal myometrium. METHOD: This study investigated expression of visfatin, leptin, SDF-1alpha, eNOS and VEGF in 23 uterine leiomyoma patients and 10 normal myometrium by RT-PCR and western blot. Messenger RNA transcripts of SDF 1alpha, eNOS, VEGF and hypoxia inducible factor-1alpha (HIF-1alpha) were analyzed according to the size of UL by real-time PCR. RESULTS: There were no significant differences in expressions of visfatin and leptin between UL compared with normal myometrium. However, expressions of eNOS, SDF-1alpha and VEGF were significantly higher in both intramural and subserosal UL compared with normal myometrium. The expression of SDF1-alpha was significantly increased in small UL (<5 cm) compared to the large UL (>=5 cm), whereas the expressions of eNOS, VEGF and HIF-1alpha were higher in large UL than small UL. CONCLUSIONS: This study shows that expression of SDF-1alpha, eNOS and VEGF were significantly higher in UL than myometrium with a different expression pattern according to the size of UL. However, expressions of visfatin and leptin had no significant differences between the two groups. PMID- 28010140 TI - The cellular basis of platelet secretion: Emerging structure/function relationships. AB - Platelet activation has long been known to be accompanied by secretion from at least three types of compartments. These include dense granules, the major source of small molecules; alpha-granules, the major protein storage organelle; and lysosomes, the site of acid hydrolase storage. Despite ~60 years of research, there are still many unanswered questions about the cell biology of platelet secretion: for example, how are these secretory organelles organized to support cargo release and what are the key routes of cargo release, granule to plasma membrane or granule to canalicular system. Moreover, in recent years, increasing evidence points to the platelet being organized for secretion of the contents from other organelles, namely the dense tubular system (endoplasmic reticulum) and the Golgi apparatus. Conceivably, protein secretion is a widespread property of the platelet and its organelles. In this review, we concentrate on the cell biology of the alpha-granule and its structure/function relationships. We both review the literature and discuss the wide array of 3-dimensional, high resolution structural approaches that have emerged in the last few years. These have begun to reveal new and unanticipated outcomes and some of these are discussed. We are hopeful that the next several years will bring rapid advances to this field that will resolve past controversies and be clinically relevant. PMID- 28010142 TI - Outer membrane vesicles: an attractive candidate for pertussis vaccines. PMID- 28010143 TI - Chikungunya Virus Infection Manifesting as Intermediate Uveitis. AB - PURPOSE: To describe a case of intermediate uveitis caused by chikungunya virus infection in the Western Hemisphere. METHODS: Case report of a patient diagnosed with chikungunya infection presenting with blurry vision and floaters. RESULTS: Exam revealed a unilateral intermediate uveitis, with an extensive work-up positive for chikungunya virus immunoglobulin M and G titers. The patient responded to oral corticosteroids with signs and symptoms resolving over the course of 3 months' treatment. CONCLUSIONS: While anterior uveitis and retinitis are the most common ocular manifestations of chikungunya infection, we report here a case of chikungunya infection presenting as an intermediate uveitis, responding well to oral corticosteroids. This case demonstrates the varied presentation of chikungunya-related uveitis and highlights its consideration in the differential diagnoses of those who have had preceding systemic viral symptoms and uveitis. PMID- 28010144 TI - Frosted Branch Angiitis in a Patient with Typhoid Fever. AB - Frosted branch angiitis (FBA), a rare form of retinal vasculitis presenting as bilateral perivascular sheathing, resembling the appearance of frosted tree branches in winter, was first reported by Ito et al.1 in 1976, in a young immunocompetent boy. FBA predominantly affects healthy young patients, the youngest reported in an 11-month-old infant2 and oldest in a 42-year-old patient.3 Classical symptoms include sudden onset of blurred vision with floaters and photopsiae. Fundus examination shows widespread perivascular translucent sheathing affecting both arterioles and venules, more commonly latter. Fluorescein angiography shows late staining of vessels with no obstruction of blood flow. Electroretinogram shows reduced amplitude and visual fields show generalized constriction. Medline search did not show any case of frosted branch angiitis in a patient with typhoid fever. PMID- 28010145 TI - Strategies for overcoming challenges for decentralised diagnostics in resource limited and catastrophe settings. AB - INTRODUCTION: Globally, both communicable and non-communicable diseases pose a serious threat to populations in developed as well as developing countries. Access to reliable diagnostic testing along with qualified health practitioners is severely limited in low resource and very remote areas and following natural catastrophes. Areas covered: This paper provides an overview of the challenges involved and suggests strategies to address them. The emergence of more robust, user-friendly, cost-effective and 'sample-to-result' point-of-care (POC) tools, along with the proliferation of mobile technologies, may provide a practical approach in addressing some of the challenges. Expert commentary: The successful implementation of POC testing requires the availability of versatile diagnostic technologies, improved platforms and back-up infrastructure, successful leveraging of human resources through training and, finally, engagement/coordination of associated stakeholders, including public health agencies, diagnostics companies, healthcare practitioners and local rural authorities. PMID- 28010146 TI - National reimbursement listing determinants of new cancer drugs: a retrospective analysis of 58 cancer treatment appraisals in 2007-2016 in South Korea. AB - BACKGROUND: Since the positive-list system was introduced, concerns have been raised over restricting access to new cancer drugs in Korea. Policy changes in the decision-making process, such as risk-sharing agreement and the waiver of pharmacoeconomic data submission, were implemented to improve access to oncology medicines, and other factors are also involved in the reimbursement for cancer drugs. The aim of this study is to investigate the reimbursement listing determinants of new cancer drugs in Korea. METHODS: All cancer treatment appraisals of Health Insurance Review and Assessment during 2007-2016 were analyzed based on 13 independent variables (comparative effectiveness, cost effectiveness, drug-price comparison, oncology-specific policy, and innovation such as new mode of action). Univariate and multivariate logistic analyses were conducted. RESULTS: Of 58 analyzed submissions, 40% were listed in the national reimbursement formulary. In univariate analysis, four variables were related to listing: comparative effectiveness, drug-price comparison, new mode of action, and risk-sharing agreement. In multivariate logistic analysis, three variables significantly increased the likelihood of listing: clinical improvement, below alternative's price, and risk-sharing arrangement. Cancer drug's listing increased from 17% to 47% after risk-sharing agreement implementation. CONCLUSION: Clinical improvement, cost-effectiveness, and RSA application are critical to successful national reimbursement listing. PMID- 28010147 TI - Adaptive Optics Imaging in Retinal Vasculitis. AB - PURPOSE: To study the sheathing of retinal vasculitis in various systemic autoimmune diseases using adaptive optics imaging (AOI). METHODS: Prospective, observational case series with six patients: Behcet disease (n = 1); systemic lupus erythematosus (n = 1); idiopathic retinal vasculitis (n = 2); granulomatosis with polyangiitis (n = 1); and Takayasu aorta arteritis (n = 1). Fundus photograph (FP), fundus fluorescein angiography (FFA) were done in all cases at presentation. Using the Image J software, perivascular sheathing and wall-to-wall diameter of the vessel involved were measured on AOI at time of presentation and on follow-up. RESULTS: AOI was able to pick the pipe-stem sheathing in SLE and IRV(I) and parallel sheathing in rest, which correlated with FP and FFA. Moreover, the decrease and a complete resolution in the sheathing were also noted by AOI on follow-up. CONCLUSIONS: AOI can be used as an additional investigative tool for diagnosis and to monitor the disease course during the treatment. PMID- 28010148 TI - Bone health of the Ovahimba people of north-western Namibia in the context of urbanization and a change of the sociocultural environment. AB - The prevalence of osteoporosis in Sub-Saharan African (SSA) countries is low, however, as urbanization takes root, it is predicted that bone health will decrease dramatically. The bone health of the semi-nomadic Ovahimba people of Namibia was investigated in the context of urbanization and changes of the sociocultural environment. Furthermore, data on bone health in SSA countries is scarce; there exists no ethnic-specific reference group for people of black origin. Included in the study were 98 urban and rural living Ovahimba people. Quantitative ultrasound was performed, sunrise/sunset saliva cortisol concentrations was measured and a questionnaire was conducted. There was no significant difference in the QUS parameters, however, after adjustment for confounders, SOS and SI differed significantly. The saliva cortisol concentrations differed significantly. After adjustment for confounders, saliva cortisol was significantly negatively correlated to SOS (r= -0.27, p = 0.021) giving an indication for an association between cortisol concentration and QUS parameters. The urban group furthermore showed a nutritional transition. Even though the bone health of the Ovahimba is very good, first signs of the adverse effects of urbanization were detected. Beside changes of lifestyle, this may be attributed to an increased cortisol exposure of the Ovahimba people living in an urban environment due to an increased psychosocial stress. PMID- 28010149 TI - Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis. AB - OBJECTIVES: To examine treatment patterns, treatment effectiveness, and treatment costs for 1 year after patients with rheumatoid arthritis switched from a tumor necrosis factor inhibitor (TNFi) (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab), either cycling to another TNFi ("TNFi cyclers") or switching to a new mechanism of action (abatacept, tocilizumab, or tofacitinib) ("new MOA switchers"). METHODS: This retrospective cohort study used administrative claims data for a national insurer. Treatment persistence (without switching again, restarting, or discontinuing), treatment effectiveness (defined below), and costs were assessed for the 12-month post-switch period. Patients were "effectively treated" if they satisfied all six criteria for a treatment effectiveness algorithm (high adherence, no dose increase, no new conventional synthetic disease-modifying anti-rheumatic drug, no subsequent switch in therapy, no new/increased oral glucocorticoids, and <2 glucocorticoid injections). Multivariable logistic models were used to adjust for baseline factors. RESULTS: The database included 581 new MOA switchers and 935 TNFi cyclers. New MOA switchers were 39% more likely than TNFi cyclers to persist after the switch (odds ratio [OR] = 1.39; 95% confidence interval [CI] = 1.12-1.74; p = .003) and 36% less likely to switch therapy again (OR = 0.64; 95% CI = 0.51-0.81; p < .001). New MOA switchers were 43% more likely than TNFi cyclers to be effectively treated (OR = 1.43; 95% CI = 1.11-1.85; p = .006). New MOA switchers had 16% lower drug costs than TNFi cyclers (cost ratio = 0.84; 95% CI = 0.79-0.88; p < .001) and 11% lower total costs of rheumatoid arthritis-related medical care (cost ratio = 0.89; 95% CI = 0.84-0.94; p < .001). LIMITATIONS: Claims payments may not reflect rebates or other cost offsets. Medical and pharmacy claims do not include clinical end-points or reasons that lead to new MOA switching vs TNFi cycling. CONCLUSIONS: These results support switching to a new MOA after a patient fails treatment with a TNFi, which is consistent with recent guidelines for the pharmacologic management of established rheumatoid arthritis. PMID- 28010150 TI - Repeated doses of GnRH antagonist at midcycle in artificial frozen embryo transfer cycles may not affect pregnancy outcomes. AB - No significant differences in outcomes have been found between protocols of endometrial preparation for frozen embryo transfer (FET), though gonadotropin releasing hormone (GnRH) antagonists may have detrimental effects on the endometrium. We conducted a retrospective cohort noninferiority study at a single academic center of women receiving multiple doses of mid-cycle GnRH antagonist (GAnt) to those receiving GnRH agonist (GAg) to determine if there are detrimental effects of GnRH antagonists. 1047 FET cycles were identified, detailed data was available in 840 cycles: 610 GAg and 230 GAnt cycles. Patients undergoing GAnt cycles were older (40 +/- 6.6 versus 37 +/- 5.1 years, p < 0.0001), more often used donor oocyte (36% versus 18.6%, p < 0.0001), and more often exhibited diminished ovarian reserve (49.1% versus 36.2%, p = 0.0009). Clinical pregnancy rates (CPRs) per transfer and implantation rates (IRs) were similar for GAnt and GAg cycles. There was a trend for higher pregnancy and IRs with GAg cycles in younger women (CPR 38.8% versus 26.7%, p = 0.16; IR 36% versus 23.3%, p = 0.07). Stratifying by diagnosis, CPR and IR were similar in GAnt and GAg cycles. A GAnt protocol of endometrial preparation for FET is not inferior to a GAg protocol regardless of patient age, use of donor oocyte, or infertility diagnosis. PMID- 28010151 TI - The Prevalence of Intraocular Tuberculosis in HIV-positive and HIV-negative Patients in South Africa Using a Revised Classification System. AB - PURPOSE: To report the prevalence of intraocular tuberculosis in South Africa using a revised classification system. METHODS: A prospective study to determine the underlying etiology in patients presenting with uveitis to a tertiary Eye Clinic. RESULTS: A total of 35 out of 106 patients (33.0%) were diagnosed with intraocular tuberculosis, of which 11 (31.4%) had HIV infection; 23 patients (65.7%) had possible intraocular tuberculosis and 12 (34.3%) had probable intraocular tuberculosis. Patients with probable intraocular tuberculosis were younger than those with possible intraocular tuberculosis (p = 0.003). More males (66.7%) had probable intraocular tuberculosis and more females (73.9%) had possible intraocular tuberculosis (p = 0.031). More HIV-positive patients had probable intraocular tuberculosis and more HIV-negative patients had possible intraocular tuberculosis (p = 0.002). CONCLUSIONS: South Africa has a high prevalence of intraocular tuberculosis. Younger, male, HIV-positive patients are more likely to have probable intraocular tuberculosis, while older, female, HIV negative patients are more likely to have possible intraocular tuberculosis. PMID- 28010152 TI - Consider stopping dengvaxia administration without immunological screening. PMID- 28010153 TI - A systematic review and evaluation of inhibitory stimulus control procedures as a treatment for stereotyped behavior among individuals with autism. AB - PURPOSE: Stereotypy is pervasive among persons with autism and may impact negatively on social inclusion and learning. The implementation of resource intensive behavioral interventions to decrease these behaviors has been questioned. Inhibitory stimulus control procedures (ISCPs) comprise a type of antecedent-based intervention that has been proposed as an effective treatment approach for stereotypy but has received limited research attention to date. METHOD: The current systematic review sought to examine and synthesize the literature reporting applications of ISCPs in the treatment of stereotypy among persons with autism. Treatment outcomes were analyzed quantitatively and the status of ISCPs as evidence-based practice was evaluated in accordance with the National Autism Center's National Standards Report guidelines. RESULTS: A total of 11 studies were reviewed with results indicating that ISCPs constituted an emerging treatment for the stereotypy exhibited by persons with autism. CONCLUSIONS: ISCPs comprise a promising intervention for stereotyped behavior but further research is required. PMID- 28010154 TI - Anti-inflammatory drugs as promising cardiovascular treatments. AB - INTRODUCTION: Inflammation is a well-known powerful effector of atherosclerosis development. Cell infiltration induces inflammatory signal increasing plaque formation as well as its destabilization, leading to cardiovascular disease including myocardial infarction. During ischemia, necrotic cardiomyocytes stimulate the inflammatory storm into the myocardium (by chemokines, vascular adhesion molecules, interleukins action) promoting cardiac repair but also remodeling. Areas covered: Herein the authors present each condition (atherosclerosis and myocardial infarction) in two separate parts. Pathophysiology is briefly presented and focused on its implication in inflammation. Non-invasive techniques are presented, which explore inflammation in vivo. Several anti-inflammatory drugs are presented (mechanism of action, already published studies and ongoing trials are summarized). Expert commentary: Whereas atherosclerosis, regarding both the step-by-step pathophysiology and the acute plaque destabilization, is widely recognized as involving inflammatory pathways, the current translations in clinical practice remain poor. However, both basic and clinical research are active in the field, and the first large trials should soon be available, corroborating or not whether modulating inflammatory processes could be of interest in clinical practice. PMID- 28010155 TI - Change in Visual Function in Uveitis Patients after Treatment: An Experience from Nepal. AB - PURPOSE: To assess the change in visual function in uveitis patients after treatment. MATERIALS AND METHODS: This one and a half year prospective study was conducted among 180 new uveitis patients. A questionnaire was used to assess the visual function in uveitis cases and analysis of effect size change was also done. RESULTS: The male to female ratio was 1.3:1. The mean vision at presentation was 0.49 logMAR units, which improved to 0.39 logMAR units and 0.35 logMAR units by the 1st and 4th week but deteriorated to 0.62 logMAR units at the 6th week. Anterior uveitis and posterior uveitis patients had significant improvement (p<=0.001) in all three scales but panuveitis and intermediate uveitis had significant improvement (p<0.05) in two scales. The effect size showed small to large change in all three scales. CONCLUSIONS: Visual function is adversely affected by uveitis, which can be improved after treatment. PMID- 28010156 TI - Bacillus Calmette-Guerin Infection and Cytotoxicity in the Retinal Pigment Epithelium. AB - PURPOSE: To investigate bacillus Calmette-Guerin (BCG) infective capability and cytotoxicity in ARPE-19 cells. METHODS: BCG inoculum was dispensed at a MOI 100:1 for 3 h in 90% confluent ARPE-19 cells. Infection rates at different time points were determined by colony forming units (CFU) count and, in parallel, by the number of microscopically infected cells. WST-1 reagent was used for cytotoxicity assays. RESULTS: A 67-year-old man previously treated with intravesical BCG for bladder carcinoma presented with chronic, refractory, bilateral uveitis with macular edema. Quiescence was achieved only after commencing antituberculous treatment. BCG infection rate by two methods peaked at 48 h (16 +/- 5.7% by CFU count and 40 +/- 7.7% by microscopy; p = 0.058). BCG adhesion, phagocytosis, intracellular proliferation and cytolysis was observed. Cytotoxicity was minimal and did not differ from uninfected cells. CONCLUSIONS: BCG can infect at low rates and proliferate in ARPE-19 cells without toxicity in the surrounding monolayer. PMID- 28010157 TI - Evaluation of immune response in challenged chickens vaccinated with Newcastle disease vaccine using gums from Cedrela odorata and Khaya senegalensis as delivery agents. AB - Immune response of challenged chickens following previous vaccinations with Newcastle disease vaccine using gums from Cedrela odorata and Khaya senegalensis as delivery agent were evaluated. Two hundred and fifty-two one-day old chickens were divided into vaccine-gum oral (GVOR), vaccine-gum ocular (GVOC), vaccine oral (VOR), vaccine ocular (VOC), gum oral (GOR), gum ocular (GOC), No-gum-no vaccine/challenged (NGNV/C), and No-gum-no-vaccine/unchallenged (NGNV/U) groups. They were vaccinated at days 21 & 42 and challenged at day 84. Trachea and intestinal washings were collected at intervals as well as weekly serum samples. These were analyzed using enzyme-linked immunosorbent assay (ELISA) and haemagglutination inhibition (HI) test for mucosal and systemic IgG response (MA and SA). Statistical analysis was done using Omnibus one-way ANOVA. MA and SA were not different (P > 0.05) post first and second vaccination although gum vaccine groups were marginally higher post second vaccination. Post Infection (PI), there was an early and sustained spike in both MA and SA for the GV groups especially GVOR (P < 0.05). MA and SA for the Gum alone (especially GOR) groups also spiked PI (P < 0.05). Therefore, phytogenic polymers used could be said to possess immunopotentiating property with a possible induction of immunologic memory mechanism. PMID- 28010158 TI - Abnormalities of language pathways in schizophrenia patients with and without a lifetime history of auditory verbal hallucinations: A DTI-based tractography study. AB - OBJECTIVES: Auditory verbal hallucinations (AVHs) are frequently observed in patients with schizophrenia (SZ) and could be the result of white matter (WM) fibre abnormalities involved in speech production/comprehension and perception. We evaluated WM integrity changes in SZ with (SZ+) and without (SZ-) lifetime AVHs compared to healthy controls (HCs), using diffusion tensor imaging-based tractography, with a novel focus on the structural connectivity within both intra and interhemispheric fasciculi. METHODS: The study included 27 SZ+, 12 SZ- and 34 HCs. Fractional anisotropy (FA) and mean and radial diffusivities (MD and RD) were extracted in each participant in two left interhemispheric fasciculi and in the interhemispheric auditory pathway (IAP) to test integrity differences among groups. RESULTS: SZ- and SZ + compared to HCs presented increased diffusivities and/or decreased FA in the interhemispheric fasciculi. Decreased FA was significant only between SZ + and HCs for the IAP. CONCLUSIONS: In this first comparison of integrity changes within both intra- and interhemispheric fasciculi, abnormalities in the intrahemispheric fasciculi were observed in both SZ- and SZ+, but an alteration in the IAP was seen only in SZ+. These results suggest that the IAP may be more involved in patients with AVHs-proneness. PMID- 28010159 TI - Adolescent Social Networks and Alcohol Use: Variability by Gender and Type. AB - BACKGROUND: Scientists have established that social networks influence adolescents' substance use behavior, an influence that varies by gender. However, the role of gender in this mechanism of influence remains poorly understood. Particularly, the role an adolescent's gender, alongside the gender composition of his/her network, plays in facilitating or constraining alcohol use is still unclear. OBJECTIVES: This study examined the associations among the gender composition of adolescents' networks, select network characteristics, intrapersonal and interpersonal factors, and alcohol use among a sample of adolescents in the United States. METHODS: We assessed cross-sectional data from a 2010 study of 1,523 high school students from a school district in Los Angeles. Analyses of adolescents' network characteristics were conducted using UCINET 6; and logistic regression analyses testing the associations between gender composition of the network and alcohol use were conducted using SPSS 20. RESULTS: Our results indicate that the gender composition of adolescents' networks in our sample is associated with alcohol use. Adolescents in predominantly female or predominantly male friendship networks were less likely to report alcohol use compared to adolescents in an equal/balanced network. In addition, depending upon the context/type of network, intrapersonal and interpersonal factors varied in their association with alcohol use. Conclusions/Importance: Based on these findings, we make several recommendations for the future research. We call for researchers to further examine gender as a risk factor for alcohol abuse, particularly within the complex interplay between gender and network contexts. PMID- 28010160 TI - Not Only When Feeling Down: The Relationship Between Mood Intensity and Smoking Behavior. AB - BACKGROUND: There is substantial empirical evidence that negative mood triggers smoking behavior, and less support for the similar effect of positive mood. However, the relationship between the intensity of mood and smoking remains relatively under-researched. OBJECTIVES: The present study explored the association between mood intensity and smoking behavior. METHODS: Seventy-three ad libitum smokers recorded their mood and concurrent number of smoked cigarettes three times daily for one week using electronic diary application. Real time assessment in natural environment enabled greater reliability, validity and generalizability of the collected data. RESULTS: We analyzed results using within subjects approach and obtained significant growth trend in smoking behavior that concurred with the increase of mood intensity-smokers tended to increase their consumption of cigarettes when they were feeling either happy or sad in comparison to the situation when they were in neutral mood. IMPORTANCE: These findings raise implications regarding the role of mood intensity in initiating smoking behavior. PMID- 28010161 TI - Convention Versus Deviance: Moral Agency in Adolescent Gang Members' Decision Making. AB - BACKGROUND: Adolescent gang members are a source of concern due to their involvement in criminal activity, violence, substance use, and high-risk sexual behaviors. Adolescent gang theories hypothesize that social institutions, including the family and school, fail to meet the needs of adolescents who therefore feel less attachment to these institutions and find an unconventional institution (i.e. the gang) to meet these needs through the gang. OBJECTIVES: In this paper, we will examine the extent to which social disorganization and social control theories, in particular the rejection of conventional norms and aspirations, match adolescents' subjective reasons for their decisions and their future aspirations. METHODS: Between 2012 and 2013, we conducted in-depth interviews with 58 gang members between the ages of 14 to 19. Interviews were coded for key themes using the constant comparison method. RESULTS: Social disorganization and social control theories have both value and limitations in explaining reasons why adolescents join gangs and engage in criminal behaviors. Participants saw many of their aspirations blocked by negative school experiences and limited economic opportunities. Gangs provided a social organization in which to sell drugs. However, gang members did not reject conventional norms and aspirations. Rather, they view themselves as making decisions to survive in the present while recognizing that these strategies will not continue to work in the future. CONCLUSIONS: Gang members value education and aspire to obtain legal employment. Thus, interventions to help adolescent gang members with the immediate financial pressures that lead them to sell drugs may be particularly effective. PMID- 28010162 TI - Testing the Model of Goal-Directed Behavior for Predicting Binge Drinking Among Young People. AB - BACKGROUND: One of the most problematic modes of alcohol consumption in young adults is risky drinking in single episodes, which typically takes place in social contexts. Several studies have applied the Theory of Planned Behavior to drinking intentions and behavior in young people. However, previous studies show that this model lacks a "bridge" that links a mental process like intentions to a physical process represented by the actual action. OBJECTIVES: The aim of the present study is to test the predictive power of the Model of Goal-Directed Behavior plus social influences in order to overcome theory of planned behavior gaps in predicting binge-drinking behavior in young people. METHODS: 404 undergraduates completed a questionnaire containing measures for the MGB variables, social identity, and group norms. Two weeks later, participants reported how many times they had had five/four or more alcoholic drinks on a single occasion. Structural equation modeling revealed strong support for model validity. RESULTS: The final equation accounted for 66% in intentions to binge drink, and 48% in drinking behavior, while a planned behavior model accounted for the 47% of variance in intentions to binge and 37% of the drinking behavior. Social influences positively affected desire and intentions to drink. CONCLUSIONS: Our findings suggest that, compared to other attitude-behavior frameworks, the MGB is preferable in modeling the proximal determinants of binge drinking. Therefore, the distinction between desire and intention and the consideration of social influences seem to be essential to improve the prediction of binge drinking among young people. PMID- 28010163 TI - Motives for Prescription Stimulant Misuse in a College Sample: Characteristics of Users, Perception of Risk, and Consequences of Use. AB - BACKGROUND: Prescription stimulant misuse is increasingly prevalent in college populations, with some misuse estimates over 40%. Stimulant use is associated with a variety of health and psychological problems. Motives for use may provide insight into problematic trajectories. OBJECTIVES: The purpose of the current study was to evaluate characteristics of users and motives for prescription stimulant misuse in a large southeastern university. METHOD: College students reported on prescription stimulant use, motives for use, consequences associated with use, perceptions of risk, and social norms. We specifically elicited participation from prescription stimulant misusers. Of the 199 participants, 86 reported misusing prescription stimulants in the past 60 days. We assessed motives for use, rates of substance use, risk perception, normative beliefs, and consequences associated with use. We evaluated differences between misusers and non-misusers, differentiate motives subscales, and identify relationships between motives subscales, rates of use, and consequences. RESULTS: Misusers used more alcohol and other drugs, held different normative beliefs regarding stimulants, and had lower risk perceptions than non-misusers. We evaluated seven motives subscales among misusers: coping, social, enhancement, expansion, conformity, academic performance, and weight loss. Enhancement, social, weight loss, and expansion scales were correlated with negative consequences, while social motives were correlated with use. Results from regression analyses revealed positive associations between weight and expansion with negative consequences, and a negative association between conformity and consequences. Conclusions/Importance:Motives for prescription stimulant use and user characteristics may provide insight into prevention and treatment. Continued work is needed to refine item content and replicate findings. PMID- 28010164 TI - Varietal differences in the growth responses of rice to an arbuscular mycorrhizal fungus under natural upland conditions. AB - Seedlings of three rice (Oryza sativa L.) varieties (one indica, ARC5955; and two japonica, Nipponbare and Koshihikari) with or without pre-colonization by the arbuscular mycorrhizal fungus Funneliformis mosseae were transplanted into an upland field and grown to maturity. Pre-colonization had no effect on the yield of Nipponbare or Koshihikari. However, pre-colonized ARC5955 exhibited a strong tendency toward increased yield, which was accompanied by increases in the percentage of ripened grain and the 1000-grain weight. The rice roots were also colonized by indigenous arbuscular mycorrhizal fungi in the field, but these had only limited effects on shoot biomass and grain yields. We speculate that F. mosseae may have exhibited priority effects, allowing it to dominate the rice roots. There was no significant difference in the contents of most mineral elements in the shoots of pre-colonized ARC5955 at harvest, indicating that some other factor is responsible for the observed yield increase. PMID- 28010165 TI - Modular arrangement of regulatory RNA elements. AB - Due to their simple architecture and control mechanism, regulatory RNA modules are attractive building blocks in synthetic biology. This is especially true for riboswitches, which are natural ligand-binding regulators of gene expression. The discovery of various tandem riboswitches inspired the design of combined RNA modules with activities not yet found in nature. Riboswitches were placed in tandem or in combination with a ribozyme or temperature-responsive RNA thermometer resulting in new functionalities. Here, we compare natural examples of tandem riboswitches with recently designed artificial RNA regulators suggesting substantial modularity of regulatory RNA elements. Challenges associated with modular RNA design are discussed. PMID- 28010166 TI - Reappraisal and perspectives of clinical drug-drug interaction potential of alpha glucosidase inhibitors such as acarbose, voglibose and miglitol in the treatment of type 2 diabetes mellitus. AB - 1. Amidst the new strategies being developed for the management of type 2 diabetes mellitus (T2DM) with both established and newer therapies, alpha glucosidase inhibitors (AGIs) have found a place in several treatment protocols. 2. The objectives of the review were: (a) to compile and evaluate the various clinical pharmacokinetic drug interaction data for AGIs such as acarbose, miglitol and voglibose; (b) provide perspectives on the drug interaction data since it encompasses coadministered drugs in several key areas of comorbidity with T2DM. 3. Critical evaluation of the interaction data suggested that the absorption and bioavailability of many coadministered drugs were not meaningfully affected from a clinical perspective. Therefore, on the basis of the current appraisal, none of the AGIs showed an alarming and/or overwhelming trend of interaction potential with several coadministered drugs. Hence, dosage adjustment is not warranted in the use of AGIs in T2DM patients in situations of comorbidity. 4. The newly evolving fixed dose combination strategies with AGIs need to be carefully evaluated to ensure that the absorption and bioavailability of the added drug are not impaired due to concomitant food ingestion. PMID- 28010167 TI - Parental Style and Its Association With Substance Use in Argentinean Youth. AB - BACKGROUND: In Europe and the United States, family relationships and parenting behavior can influence youth substance use, but less is known about their influence in Latin American countries. OBJECTIVE: To explore whether parenting behavior is associated with substance use among Latin American youth. METHODS: A cross-sectional, school-based survey of middle-school youth (n = 3172) in three Argentinian cities queried tobacco, alcohol, and drug use using items adapted from global youth surveys. Parenting behavior was assessed with previously validated items that tapped into demandingness and responsiveness, separately for mothers and fathers. Multilevel logistic regression models assessed associations between parenting behavior and substance use after adjusting for student characteristics, socioeconomic indicators, sensation seeking, and smoking amongst peers and family members. RESULTS: Substance use prevalence was 10% for current smoking, 32% for current drinking alcohol, 17% for past 30-day binge drinking (>=5 drinks), and 8% for previous year illicit drug use (marijuana or cocaine). Greater maternal demandingness was independently associated with lower likelihood of current smoking (adjusted odds ratio [AOR] = 0.77; 95% confidence interval (CI): 0.64-0.92), current drinking (AOR = 0.81; 95% CI: 0.71-0.92), binge drinking (AOR = 0.77; 95% CI: 0.66-0.99, and drug use (AOR = 0.71; 95% CI: 0.61 0.83). No other parenting behavior were independently associated with substance use, except for paternal demandingness and binge drinking (AOR = 0.84; 95% CI: 0.74-0.97). For all outcomes, no interactions were found between parenting behavior and student gender. CONCLUSIONS: Among Argentine adolescents, maternal demandingness was the strongest and most consistent correlate of substance use, regardless of adolescent substance use behavior or gender. PMID- 28010168 TI - Bayesian analysis of piecewise growth mixture models with skew-t distributions: Application to AIDS studies. AB - A major problem in HIV/AIDS studies is the development of drug resistance to antiretroviral (ARV) drug or therapy. Estimating the time at which such drug resistance would develop is usually sought. The goal of this article is to perform this estimation by developing growth mixture models with change-points and skew-t distributions based on longitudinal data. For such data, following ARV treatment, the profile of each subject's viral load tends to follow a 'broken stick' like growth trajectory, indicating multiple phases of decline and increase in viral loads. These multiple phases with multiple change-points are captured by subject-specific random parameters of growth curve models. To account for heterogeneity of drug resistance among subjects, the change-points are also allowed to differ by subgroups (subpopulations) of patients classified into latent classes on the basis of trajectories of observed viral loads. The proposed methods are illustrated using real data from an AIDS clinical study. PMID- 28010169 TI - Consequences of daily corticosteroid dosing with or without pre-treatment with quinidine on the in vivo cytochrome P450 2D (CYP2D) enzyme in rats: effect on O demethylation activity of dextromethorphan and expression levels of CYP2D1 mRNA. AB - 1. Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate. 2. CYP2D1 mRNA was measured in liver homogenate using quantitative real-time polymerase chain reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10 mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10 mg/kg corticosteroids for five days. 3. Five days repeat dosing of dexamethasone or prednisolone decreased the activity of the rat liver CYP2D by 37% and 34%, at 30 min incubation and decreased CYP2D1 mRNA levels by 62% and 61%, respectively. 4. Pre-treatment of quinidine decreased the enzymatic activity of rat CYP2D by 58% and did not potentiate CYP2D inhibition by corticosteroids. This observation was further complemented by qRT-PCR data. 5. Corticosteroids caused CYP2D inhibition in rats vs. literature evidence of CYP2D induction in human hepatocytes/pregnant humans demonstrating lack of concordance. In vivo inhibition should be factored for interpretation of pharmacokinetic data of CYP2D substrates when treated with corticosteroids in rats. PMID- 28010170 TI - Are avoidance and acclimation responses during hypoxic stress modulated by distinct cell-specific mechanisms? AB - Plants respond to hypoxic stress through either acclimation to the stress or avoidance of it, as they do to most environmental stresses. The hypothesis that has general consensus among the community is that ethylene response factors (ERFs) are central elements that control both types of responses to hypoxia. Recent studies suggest that this may not be the case for all cells experiencing hypoxic stress. Mature maize root cells undergoing hypoxic stress were found to undergo acclimation and avoidance mechanisms involving ERFs, whereas meristematic root cells and cells still undergoing differentiation acclimated to the response without the involvement of ethylene synthesis or ERFs. Phytoglobins (PGBs) and NO were demonstrated to be components critical to the acclimation response. These findings are discussed relative to the possibility that PGBs may be acting as molecular switches controlling cellular stress responses and hormonal changes and responses in cells. PMID- 28010171 TI - Neural correlates of prediction violations in boys with Tourette syndrome: Evidence from harmonic expectancy. AB - OBJECTIVES: It has been suggested that Tourette syndrome (TS) might be associated with alterations of the attention system, but the nature of these alterations and the underlying neuroanatomical network remains elusive. We aimed at investigating the functional neuroanatomical modulators of attention allocation towards predictable versus unpredictable stimuli in boys with TS. METHODS: Using functional magnetic resonance imaging, we ran a harmonic expectancy violation paradigm in 17 boys with TS and 23 matched healthy controls (HCs). We presented chord sequence in which the first four chords induced a strong expectancy for a harmonic chord at the next position. In 70% this expectancy was fulfilled (harmonic), in 30% the expectancy was violated (disharmonic). RESULTS: HCs responded faster to the disharmonic compared to harmonic chords, indicating a stronger attention allocation towards unpredictable stimuli, while this effect was not found in boys with TS. HCs showed stronger anterior cingulate cortex (ACC) activation during disharmonic compared to harmonic chords. Boys with TS showed stronger ACC activation during harmonic chords, which was associated with greater tic severity. CONCLUSIONS: Our findings indicate that boys with TS showed altered reactions towards predictable versus unpredictable stimuli in brain regions playing an important role in attention control. This might indicate altered allocation of attention towards those stimuli. PMID- 28010172 TI - RNA biology of angiogenin: Current state and perspectives. AB - Angiogenin (ANG) is a secreted ribonuclease best known for its ability to promote formation of blood vessels. Extensive research over many years has elucidated its structure and biophysical properties, although our knowledge of molecular mechanisms underlying ANG-associated biologic processes remains limited. Intriguingly, many of processes require the ribonuclease activity of ANG, thus highlighting the importance of identifying and characterizing RNA targets and intermediates of ANG-mediated endonucleolytic cleavage. While ANG demonstrates ribonuclease activity toward many RNA substrates in vitro, specific target of ANG, namely mature tRNA, was only recently identified in vivo. ANG-mediated tRNA cleavage is an unorthodox manner of generating non-coding RNAs with diverse biologic activities. In addition, the ribonuclease activity of ANG has been reported to be crucial for rRNA transcription. Here we critically discuss various aspects of ANG biology related to its RNase activity and discuss areas in need of further investigation. PMID- 28010173 TI - Alcohol-Impaired Driving: The Influence of Adverse Rearing Environments, Alcohol, Cannabis Use, and the Moderating Role of Anxiety. AB - BACKGROUND: The rate of alcohol-impaired driving (AID) increases during the college years and students who have reported adverse rearing environments appear to be at increased risk for the development of alcohol and drug use behaviors. Alcohol and cannabis are the most commonly used drugs by college students, and these substances are particularly predictive of substance-impaired driving. OBJECTIVES: The present study aimed to investigate whether adverse rearing environment experiences and level of alcohol and cannabis use are related to the frequency of alcohol-impaired driving and whether anxiety might buffer or accelerate this effect. METHODS: Data regarding adversity, drug use, anxiety, and AID were obtained from 1,265 students annually, from first to final year of college, over four waves (Mean Age at wave 1 = 18.5 years). RESULTS: Structural equation modeling supported associations among childhood adversity, alcohol, cannabis, and anxiety symptoms. A significant mediation effect was found such that adversity was predictive of AID via alcohol use and cannabis use. Among men, anxiety symptoms accelerated the path from increased cannabis use and decelerated the path from increased alcohol use to AID frequency. Conclusions/Importance: Childhood adversity is a developmental risk precursor to drug use and AID, whereas anxiety might serve a risk or protective factor to AID, contingent on the drug used. PMID- 28010174 TI - Iodine in Malt Whisky: A Preliminary Analysis. PMID- 28010175 TI - Particle count and black carbon measurements at schools in Las Vegas, NV and in the greater Salt Lake City, UT area. AB - : As part of two separate studies aimed to characterize ambient pollutant concentrations at schools in urban areas, we compare black carbon and particle count measurements at Adcock Elementary in Las Vegas, NV (April-June 2013), and Hunter High School in the West Valley City area of greater Salt Lake City, UT (February 2012). Both schools are in urban environments, but Adcock Elementary is next to the U.S. 95 freeway. Black carbon (BC) concentrations were 13% higher at Adcock compared to Hunter, while particle count concentrations were 60% higher. When wind speeds were low-less than 2 m/sec-both BC and particle count concentrations were significantly higher at Adcock, while concentrations at Hunter did not have as strong a variation with wind speed. When wind speeds were less than 2 m/sec, emissions from the adjacent freeway greatly affected concentrations at Adcock, regardless of wind direction. At both sites, BC and particle count concentrations peaked in the morning during commute hours. At Adcock, particle count also peaked during midday or early afternoon, when BC was low and conditions were conducive to new particle formation. While this midday peak occurred at Adcock on roughly 45% of the measured days, it occurred on only about 25% of the days at Hunter, since conditions for particle formation (higher solar radiation, lower wind speeds, lower relative humidity) were more conducive at Adcock. Thus, children attending these schools are likely to be exposed to pollution peaks during school drop-off in the morning, when BC and particle count concentrations peak, and often again during lunchtime recess when particle count peaks again. IMPLICATIONS: Particle count concentrations at two schools were shown to typically be independent of BC or other pollutants. At a school in close proximity to a major freeway, particle count concentrations were high during the midday and when wind speeds were low, regardless of wind direction, showing a large area of effect from roadway emissions even when the school was not downwind of the roadway. At the second school, which sits in an urban neighborhood away from freeways, high particle counts occurred even though solar radiation was low during wintertime conditions, meaning that exposure to high particle counts can occur throughout the year. PMID- 28010176 TI - Self-perceived mental well-being amongst Malaysian dentists. AB - PURPOSE: To assess Malaysian dentists' perceptions of their mental well-being. METHODS: A self-administered questionnaire was developed based on a conceptual framework of mental health and well-being model. Two aspects were assessed, namely the physiological (two domains) and the psychological (six domains). Participants were asked to rate their experiences of the aforementioned aspects using a 5-point Likert scale ranging from all the time to never. RESULTS: The response rate was 81%. Most of the dentists (61.7%) perceived having positive mental well-being. Under the physiological aspect, most respondents reported that they were 'generally happy' (93.3%), but about 30% stated they were 'stressed physically and emotionally'. Of the six domains under the psychological aspect, positive well-being was observed in the 'sense of coherence' and 'behavioural stress' domains. Participants who were above 40 years old, married and had children reported having a more positive mental well-being when compared with their counterparts. CONCLUSION: Overall, most Malaysian dentists perceived having a positive mental well-being. It is crucial, however, to closely monitor and initiate early interventions for those with negative symptoms to ensure the safe practice of dentistry. PMID- 28010177 TI - Insight into the Stigma of Suicide Loss Survivors: Factor Analyses of Family Stereotypes, Prejudices, and Discriminations. AB - Families of individuals who die by suicide report public stigma that threatens their well-being. This study used a community-based participatory (CBPR) approach to describe a factor structure for the family stigma of suicide. Candidate items (n = 82) from a previous qualitative study were presented in an online survey format. Members of the public (n = 232) indicated how much they thought items represented public views and behaviors towards family members who lost a loved one to suicide. Factor analyses revealed two factors for stereotypes (dysfunctional, blameworthy), one factor for prejudice (fear and distrust), and three factors for discrimination (exclusion, secrecy, and avoidance). PMID- 28010178 TI - Are there any job resources capable of moderating the effect of physical demands on work ability? A study among kindergarten teachers. AB - BACKGROUND: It is recognized that teaching in a preschool context is physically demanding. Despite this, the consequences of physical demands on psychophysical health (including work ability) are significantly understudied among kindergarten teachers. OBJECTIVES: The aim of the present study is to examine (a) the association between physical demands and work ability and (b) whether psychosocial job resources buffer the negative impact of physical demands among kindergarten teachers. METHOD: A total of 426 kindergarten teachers employed in the municipal educational services of a city in northwest Italy filled out a self reported questionnaire. RESULTS: High association was found between physical demand and work ability. Moderated hierarchical regressions showed that decision authority, skill discretion, reward and meaning of work buffer the hampering effect of physical demands and work ability. No buffering effects were observed for support from superiors and colleagues. CONCLUSION: The present study has relevant, practical implications, highlighting the importance of investing in interventions encompassing a holistic perspective (e.g., psychosocial and ergonomic) in order to effectively combat the hampering effect of physical demands on work ability. PMID- 28010179 TI - Investigation and modeling of the residential infiltration of fine particulate matter in Beijing, China. AB - : The objective of this study was to estimate the residential infiltration factor (Finf) of fine particulate matter (PM2.5) and to develop models to predict PM2.5 Finf in Beijing. Eighty-eight paired indoor-outdoor PM2.5 samples were collected by Teflon filters for seven consecutive days during both non-heating and heating seasons (from a total of 55 families between August, 2013 and February, 2014). The mass concentrations of PM2.5 were measured by gravimetric method, and elemental concentrations of sulfur in filter deposits were determined by energy dispersive x-ray fluorescence (ED-XRF) spectrometry. PM2.5 Finf was estimated as the indoor/outdoor sulfur ratio. Multiple linear regression was used to construct Finf predicting models. The residential PM2.5 Finf in non-heating season (0.70 +/ 0.21, median = 0.78, n = 43) was significantly greater than in heating season (0.54 +/- 0.18, median = 0.52, n = 45, p < 0.001). Outdoor temperature, window width, frequency of window opening, and air conditioner use were the most important predictors during non-heating season, which could explain 57% variations across residences, while the outdoor temperature was the only predictor identified in heating season, which could explain 18% variations across residences. The substantial variations of PM2.5 Finf between seasons and among residences found in this study highlight the importance of incorporating Finf into exposure assessment in epidemiological studies of air pollution and human health in Beijing. The Finf predicting models developed in this study hold promise for incorporating PM2.5 Finf into large epidemiology studies, thereby reducing exposure misclassification. IMPLICATIONS: Failure to consider the differences between indoor and outdoor PM2.5 may contribute to exposure misclassification in epidemiological studies estimating exposure from a central site measurement. This study was conducted in Beijing to investigate residential PM2.5 infiltration factor and to develop a localized predictive model in both nonheating and heating seasons. High variations of PM2.5 infiltration factor between the two seasons and across homes within each season were found, highlighting the importance of including infiltration factor in the assessment of exposure to PM2.5 of outdoor origin in epidemiological studies. Localized predictive models for PM2.5 infiltration factor were also developed. PMID- 28010180 TI - Subjective evaluations of alcohol-related consequences among college students: Experience with consequences matters. AB - OBJECTIVE: Research suggests college students rate some alcohol-related consequences less negatively than others, yet it is unclear how or when these differences in perception develop. The current study compared college students' subjective evaluations of alcohol-related consequences that they had and had not experienced in order to test the hypothesis that students become desensitized to the consequences they experience. PARTICIPANTS: Participants were 269 undergraduate students enrolled at a large, public, Midwestern university. METHODS: Participants completed measures of drinking behaviors, consequences experienced, and subjective evaluations of consequences via an online survey. RESULTS: Participants rated the consequences they had personally experienced more positively than those they had not experienced. Similarly, individuals who reported experiencing consequences rated them as significantly more positive than those who had not experienced the same consequences. CONCLUSIONS: Experience with consequences is associated with more positive evaluations of those consequences. Therefore, it may be important to consider individuals' experiences with, and evaluations of, alcohol-related consequences in college student drinking interventions. PMID- 28010181 TI - "Someone Else's Problem": New Psychoactive Substances in the Online Hungarian Media. AB - Media monitoring is an important method to inform public health and prevention services about emerging health issues, such as new psychoactive substances (NPS). This study assessed the portrayal of NPS in online Hungarian media in 2015 using qualitative content analysis. Hungarian online media considers the dealer to be the main cause of drug use, which is portrayed as a problem for youth, poor people, minorities, and rural populations. The point of view of the articles is externalized, and so is the solution offered by them. From the perspective of the police or using a biomedical approach, the articles suggest that drug use is an individual (someone else's) problem, and the perspectives of insiders (such as users or addiction treatment professionals) are absent. The media portrays low socioeconomic background and the hopelessness of disadvantaged rural and mostly minority populations as the roots of NPS use, and misses the pressing incapability of health care emergency and drug treatment services to cope with the problem. The dominant portrayal of police raids is rarely counterbalanced by voices of active or recovering drug users or professionals in addiction treatment and harm reduction, who could offer a systematic solution to the apparent rapid spread of NPS use. PMID- 28010182 TI - Protocols for the Investigation of Information Processing in Human Assessment of Fundamental Movement Skills. AB - Fundamental movement skill (FMS) assessment remains an important tool in classifying individuals' level of FMS proficiency. The collection of FMS performances for assessment and monitoring has remained unchanged over the last few decades, but new motion capture technologies offer opportunities to automate this process. To achieve this, a greater understanding of the human process of movement skill assessment is required. The authors present the rationale and protocols of a project in which they aim to investigate the visual search patterns and information extraction employed by human assessors during FMS assessment, as well as the implementation of the Kinect system for FMS capture. PMID- 28010184 TI - Prospective memory 7 years after severe childhood traumatic brain injury - the TGE 2 prospective longitudinal study. AB - OBJECTIVE: To investigate the long-term outcome in prospective memory (PM), seven years after childhood severe traumatic brain injury (TBI), in a prospective longitudinal cohort. PARTICIPANTS: 76 young individuals (aged 7-22 years): 39 patients with a severe accidental TBI included prospectively seven years earlier, aged 0-15 years at injury, and 37 controls individually matched on age, gender and parental education. MAIN OUTCOME MEASURES: Three novel short PM tasks varying in the delay, motivation and context (ecological versus paper and pencil task). RESULTS: Individuals with severe TBI showed significantly poorer PM than matched controls in the two low-motivation PM tasks: (1) the ecological long-delay task consisting of sending a letter on a rainy day (p=0.047, odds ratio = 2.6); (2) the non-ecological short-delay task consisting of taking off post-its while identifying facial emotions (p=0.004, r=0.34). Differences in PM on the high motivation were not significant. PM is impaired several years post severe TBI. PMID- 28010185 TI - Methodological, biological and clinical aspects of circulating free DNA in metastatic colorectal cancer. AB - BACKGROUND: Circulating DNA can be used to measure the total cell-free DNA (cfDNA) and for detection and quantification of tumor-specific genetic alterations in the peripheral blood, and the broad clinical potential of circulating DNA has attracted increasing focus over the past decade. Concentrations of circulating DNA are high in metastatic colorectal cancer (CRC), and the total levels of cfDNA have been reported to hold strong prognostic value. Colorectal tumors are characterized by a high frequency of well known, clinically relevant genetic alteration, which is readily detected in the cfDNA and holds potential for tailoring of palliative therapy and for monitoring during treatment. This review aims to present the current literature which has specifically reported data on the potential utility of cfDNA and on tumor specific mutations in metastatic colorectal cancer (mCRC). METHOD: Methodological, biological and clinical aspects are discussed based on the most recent development in this specific setting, and eligible studies were identified by systematic literature searched from Pubmed and EMBASE in addition to conference papers and communications. RESULTS: The literature regarding cfDNA in CRC is broad and heterogeneous concerning aims, nomenclature, methods, cohorts and clinical endpoints and consequently difficult to include in a single systematic search. However, the available data underline a strong clinical value of measuring both total cfDNA levels and tumor-specific mutations in the plasma of patients with mCRC, pre- and during systemic therapy. CONCLUSION: This paper had gathered the most recent literature on several aspects of cfDNA in mCRC, including methodological, biological and clinical aspects, and discussed the large clinical potential in this specific setting, which needs to be validated in carefully designed prospective studies in statistically relevant cohorts. PMID- 28010186 TI - Graphical aids for visualizing and interpreting patterns in departures from agreement in ordinal categorical observer agreement data. AB - When studying the agreement between two observers rating the same n units into the same k discrete ordinal categories, Bangdiwala (1985) proposed using the "agreement chart" to visually assess agreement. This article proposes that often it is more interesting to focus on the patterns of disagreement and visually understanding the departures from perfect agreement. The article reviews the use of graphical techniques for descriptively assessing agreement and disagreements, and also reviews some of the available summary statistics that quantify such relationships. PMID- 28010188 TI - The in vivo genetic toolkit for studying expression and functions of Drosophila melanogaster microRNAs. AB - Since the initial reports that a group of small RNAs, now known as microRNAs (miRNAs), regulates gene expression without being translated into proteins, there has been an explosion of studies on these important expression modulators. Drosophila melanogaster has proven to be one of the most amenable animal models for investigations of miRNA biogenesis and gene regulatory activities. Here, we highlight the publicly available genetic tools and strategies for in vivo functional studies of miRNA activity in D. melanogaster. By coupling genetic approaches using available strain libraries with technologies for miRNA expression analysis and target and pathway prediction, researchers' ability to test functional activities of miRNAs in vivo is now greatly enhanced. We also comment on the tools that need to be developed to aid in comprehensive evaluation of Drosophila miRNA activities that impact traits of interest. PMID- 28010519 TI - Letter from the editor. PMID- 28010247 TI - Circumstances preceding the suicide of Asian Pacific Islander Americans and White Americans. AB - This study examined the circumstances preceding suicide among Asian and Pacific Islander Americans (APIAs) and White American decedents using data from the National Violent Death Reporting System in the United States. After controlling for gender and age, APIAs had lower rates of recent disclosure of suicide ideation, recent mental health treatment, recent mental health problems, and intimate partner problems, but higher rates of school problems than White Americans. There were also significant Race * Age moderation effects for recent mental health, financial, and school problems and a significant Race * Gender moderation effect for intimate partner problems. PMID- 28010187 TI - Components of the SNARE-containing regulon are co-regulated in root cells undergoing defense. AB - The term regulon has been coined in the genetic model plant Arabidopsis thaliana, denoting a structural and physiological defense apparatus defined genetically through the identification of the penetration (pen) mutants. The regulon is composed partially by the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) syntaxin PEN1. PEN1 has homology to a Saccharomyces cerevisae gene that regulates a Secretion (Sec) protein, Suppressor of Sec 1 (Sso1p). The regulon is also composed of the beta-glucosidase (PEN2) and an ATP binding cassette (ABC) transporter (PEN3). While important in inhibiting pathogen infection, limited observations have been made regarding the transcriptional regulation of regulon genes until now. Experiments made using the model agricultural Glycine max (soybean) have identified co-regulated gene expression of regulon components. The results explain the observation of hundreds of genes expressed specifically in the root cells undergoing the natural process of defense. Data regarding additional G. max genes functioning within the context of the regulon are presented here, including Sec 14, Sec 4 and Sec 23. Other examined G. max homologs of membrane fusion genes include an endosomal bromo domain-containing protein1 (Bro1), syntaxin6 (SYP6), SYP131, SYP71, SYP8, Bet1, coatomer epsilon (epsilon-COP), a coatomer zeta (zeta-COP) paralog and an ER to Golgi component (ERGIC) protein. Furthermore, the effectiveness of biochemical pathways that would function within the context of the regulon ave been examined, including xyloglucan xylosyltransferase (XXT), reticuline oxidase (RO) and galactinol synthase (GS). The experiments have unveiled the importance of the regulon during defense in the root and show how the deposition of callose relates to the process. PMID- 28010520 TI - Innovation, urgency and acceptance at the 9th Vaccine Renaissance. PMID- 28010246 TI - Safety and immunogenicity of a recombinant Staphylococcus aureus alpha-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults. AB - We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant alpha-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS PV dosages of 10, 25, 50, and 100 MUg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 MUg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 MUg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p = 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti- rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 MUg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine. PMID- 28010521 TI - Corrigendum. PMID- 28010522 TI - Corrigendum. PMID- 28010570 TI - Cross-national comparisons of college students' attitudes toward diet/fitness apps on smartphones. AB - OBJECTIVE: Based on the technology acceptance model (TAM), we explored the nationally-bounded roles of four predictors (subjective norms, entertainment, recordability, and networkability) in determining the TAM variables of perceived usefulness (PU), perceived ease of use (PEOU), and behavioral intention (BI) to use diet/fitness apps on smartphones. PARTICIPANTS/METHODS: College students in the US and South Korea were invited to participate in a survey. We obtained 508 questionnaires (304 from the US and 204 from Korea). Data were analyzed mainly through path analysis. RESULTS: The four factors positively predicted the PU and PEOU of diet/fitness apps. While the effects of the predictors on the three TAM components were generally stronger among the US students than Korean students, the effect of subjective norms on the BI of diet/fitness apps was weaker among Korean students. CONCLUSION: Findings from the cross-national comparisons were helpful for thoroughly understanding the contextualized mechanisms involved in the adoption of diet/fitness apps. PMID- 28010624 TI - AOSpine Master Series, Volume 6: Thoraco-Lumbar Trauma. PMID- 28010625 TI - An assessment of safety climate, job satisfaction and turnover intention relationships using a national sample of workers from the USA. AB - The association between safety climate, job satisfaction and turnover intention has not been thoroughly researched. This research is needed so that safety researchers and practitioners can begin to delineate the impact of safety on organizational and business outcomes. A path analysis was completed using data from a national sample of workers from the USA (n = 1525). The overall fit of the model was excellent and analyses determined that both training and resource adequacy positively affected safety climate and job satisfaction. Safety climate also positively influenced job satisfaction. Both safety climate and job satisfaction were negatively associated with respondents' turnover intention. In the study, the relationship between job satisfaction and turnover intention is reiterated in a sample of workers across many industries. This study is novel because it is one of the first studies to confirm that turnover intention is reduced with increased safety climate in a diverse sample of workers. PMID- 28010676 TI - Influence of Different Sitting Positions on Healthy Infants' Reaching Movements. AB - The authors analyze the influence of different sitting positions (ring and flexion) on the reaching performance (spatiotemporal variables) of full-term infants 6 and 7 months old. In addition, they correlated level of trunk control, measured by the Segmental Assessment of Trunk Control, with performance during reaching. The different sitting positions only influenced the reaching movements of 6-month-old infants, who showed the best performance in the ring position. However, this influence was observed only for the trunk displacement, deceleration time, movement units, straightness index and mean velocity. In contrast, there was no influence of positions on 7-month-old infants' reaching performance. Regarding the correlations, it was observed that infants with more level of trunk control showed a better performance when reaching, regardless of position and the age assessed. PMID- 28010675 TI - Simultaneous communication supports learning in noise by cochlear implant users. AB - OBJECTIVES: This study sought to evaluate the potential of using spoken language and signing together (simultaneous communication, SimCom, sign-supported speech) as a means of improving speech recognition, comprehension, and learning by cochlear implant (CI) users in noisy contexts. METHODS: Forty eight college students who were active CI users, watched videos of three short presentations, the text versions of which were standardized at the 8th-grade reading level. One passage was presented in spoken language only, one was presented in spoken language with multi-talker babble background noise, and one was presented via simultaneous communication with the same background noise. Following each passage, participants responded to 10 (standardized) open-ended questions designed to assess comprehension. Indicators of participants' spoken language and sign language skills were obtained via self-reports and objective assessments. RESULTS: When spoken materials were accompanied by signs, scores were significantly higher than when materials were spoken in noise without signs. Participants' receptive spoken language skills significantly predicted scores in all three conditions; neither their receptive sign skills nor age of implantation predicted performance. DISCUSSION: Students who are CI users typically rely solely on spoken language in the classroom. The present results, however, suggest that there are potential benefits of simultaneous communication for such learners in noisy settings. For those CI users who know sign language, the redundancy of speech and signs potentially can offset the reduced fidelity of spoken language in noise. CONCLUSION: Accompanying spoken language with signs can benefit learners who are CI users in noisy situations such as classroom settings. Factors associated with such benefits, such as receptive skills in signed and spoken modalities, classroom acoustics, and material difficulty need to be empirically examined. PMID- 28010677 TI - Cochlear implantation in chronic demyelinating inflammatory polyneuropathy. AB - OBJECTIVE: To describe a case of chronic inflammatory demyelinating polyneuropathy (CDIP) with bilateral sudden sensorineural hearing loss who subsequently benefited from unilateral cochlear implantation. METHODS: case history review and review of the literature for the terms CDIP, hearing loss, cochleovestibular dysfunction, and cochlear implantation. RESULTS: A 49-year-old woman presented with bilateral rapidly progressive sensorineural hearing loss (SNHL) 1 month after an upper respiratory tract infection. Hearing loss was not responsive to high-dose steroids and there were no other laboratory abnormalities or physical findings. Within 1 month, she developed ascending motor palsy, requiring long-term ventilator support. This neurologic condition was diagnosed as CDIP and she was successfully treated with plasmapheresis and intravenous immunoglobulin. Her hearing never recovered. At the time of cochlear implant, she had no response at the limits of the audiometer and obtained 0% on AzBio testing. No ABR could be recorded preoperatively. She underwent uneventful cochlear implantation with a perimodilar electrode. One year after activation, she had a PTA of 20 dB and 40% on AzBio sentence testing. Her eABR demonstrated a neuropathy pattern. Only two other cases of CDIP associated with dysfunction of the eighth nerve have been described, and neither had documented profound hearing loss. CONCLUSIONS: Severe SNHL associated with CDIP is rare. Although this patient has good access to sound, speech discrimination is poor at 1-year post implantation. This outcome may be due to incomplete recovery of myelination of the eighth nerve. Other possibilities include loss of peripheral nerve fibers due to the initial viral upper respiratory infection, which may lead to less neural substrate to stimulate. PMID- 28010678 TI - The experience of parental cancer among emerging adult university students. AB - Cancer is a disease that can have negative as well as some positive outcomes for the survivor, caregiver, and offspring. To date, there has been little research on the experiences of emerging adult offspring. When these offspring are also university students, they can experience unique challenges. In this phenomenological study, we explored the lived experience of parental cancer among emerging adult university students by interviewing 17 university students and using thematic analysis. The overarching themes were perceptions and beliefs about cancer, the outcomes of having a parent with cancer, influence of parental cancer on life as a university student, coping with having a parent with cancer, and attitudes and experiences around health and personal lifestyle. These results will be particularly useful to practitioners who provide services to university students experiencing parental cancer. PMID- 28010679 TI - United Kingdom national paediatric bilateral project: Demographics and results of localization and speech perception testing. AB - OBJECTIVES: To assess longitudinal outcomes in a large and varied population of children receiving bilateral cochlear implants both simultaneously and sequentially. METHODS: This observational non-randomized service evaluation collected localization and speech recognition in noise data from simultaneously and sequentially implanted children at four time points: before bilateral cochlear implants or before the sequential implant, 1 year, 2 years, and 3 years after bilateral implants. No inclusion criteria were applied, so children with additional difficulties, cochleovestibular anomalies, varying educational placements, 23 different home languages, a full range of outcomes and varying device use were included. RESULTS: 1001 children were included: 465 implanted simultaneously and 536 sequentially, representing just over 50% of children receiving bilateral implants in the UK in this period. In simultaneously implanted children the median age at implant was 2.1 years; 7% were implanted at less than 1 year of age. In sequentially implanted children the interval between implants ranged from 0.1 to 14.5 years. Children with simultaneous bilateral implants localized better than those with one implant. On average children receiving a second (sequential) cochlear implant showed improvement in localization and listening in background noise after 1 year of bilateral listening. The interval between sequential implants had no effect on localization improvement although a smaller interval gave more improvement in speech recognition in noise. Children with sequential implants on average were able to use their second device to obtain spatial release from masking after 2 years of bilateral listening. Although ranges were large, bilateral cochlear implants on average offered an improvement in localization and speech perception in noise over unilateral implants. CONCLUSION: These data represent the diverse population of children with bilateral cochlear implants in the UK from 2010 to 2012. Predictions of outcomes for individual patients are not possible from these data. However, there are no indications to preclude children with long inter-implant interval having the chance of a second cochlear implant. PMID- 28010680 TI - Ergonomic assessment of airport shuttle driver tasks using an ergonomic analysis toolset. AB - This study aimed to (a) evaluate strength requirements and lower back stresses during lifting and baggage handling tasks with the 3D Static Strength Prediction Program (3DSSPP) and (b) provide additional analyses using rapid entire body assessment (REBA) and the NASA task load index (TLX) to assess the risks associated with the tasks. Four healthy female shuttle drivers of good health aged between 55 and 60 years were observed and interviewed in an effort to determine the tasks required of their occupations. The results indicated that lifting bags and placing them in a shuttle were high risk for injury and possible changes should be further investigated. The study concluded there was a potential for injury associated with baggage storing and retrieval tasks of a shuttle driver. PMID- 28010723 TI - Evaluation of the microgrinding procedure for the microscopic analysis of temporal bones. AB - INTRODUCTION: The microgrinding technique is used to study cochlear implant electrode positioning and cochlear trauma. It may be argued that this technique might cause damage to inner cochlear structures even without a cochlear implant insertion and thus it should not be recommended. Most papers do not explain how microgrinding is performed, referring to older papers for its description. Properly describing the technique and re-evaluating its safety may reassure researchers of their findings when studying trauma after cochlear implant insertion. OBJECTIVE: To accurately describe the microgrinding technique and re evaluate its safety to assess intracochlear trauma by studying non-implanted temporal bones. METHODS: Four fresh temporal bones were removed before 24 hours postmortem and frozen at -20 degrees C. Two were prepared for microgrinding before 24 hours of freezing and the others after 6 months. A descriptive analysis of the microscopic anatomy was performed, as well as a comparison between the bones processed within 24 hours of freezing and the bones frozen for 6 months. RESULTS: A total of 80 surfaces was evaluated. Preservation of even the most delicate intracochlear and vestibular structures was observed, such as the crista ampullaris, Reissner's and basilar membranes, permitting an adequate micro anatomical study. Artifacts were rare and did not interfere with the analysis. Bones studied before 24 hours postmortem exhibited better quality than those frozen for 6 months. CONCLUSIONS: The microgrinding technique accurately preserves the inner ear's membranous microscopic anatomy and thus it is useful to study cochlear implant electrode positioning and trauma inside the cochlea. Studies that aim to evaluate inner ear microanatomy should be performed with fresh bones or bones frozen for less than 24 hours since they exhibit a better micro-anatomical quality. PMID- 28010724 TI - Social Workers Uniquely Positioned to Create and Support Healthcare Systems for Older Adults with Complex Chronic Conditions. PMID- 28010725 TI - Splendor and misery of adaptation, or the importance of neutral null for understanding evolution. AB - The study of any biological features, including genomic sequences, typically revolves around the question: what is this for? However, population genetic theory, combined with the data of comparative genomics, clearly indicates that such a "pan-adaptationist" approach is a fallacy. The proper question is: how has this sequence evolved? And the proper null hypothesis posits that it is a result of neutral evolution: that is, it survives by sheer chance provided that it is not deleterious enough to be efficiently purged by purifying selection. To claim adaptation, the neutral null has to be falsified. The adaptationist fallacy can be costly, inducing biologists to relentlessly seek function where there is none. PMID- 28010726 TI - Increase in circulating Th17 cells during anti-TNF therapy is associated with ultrasonographic improvement of synovitis in rheumatoid arthritis. AB - BACKGROUND: Anti-TNF agents have revolutionised rheumatoid arthritis (RA) treatment; however, a third of patients fail to achieve therapeutic responses. Unexpectedly, studies in murine and human arthritis have indicated that anti-TNF treatment can increase circulating T helper 17 (Th17) cells, but the relationship to treatment response is unclear. To identify immune correlates of anti-TNF treatment response, we conducted a longitudinal study using clinical, ultrasound and T cell assessments. METHODS: Patients with RA (n = 25) were studied at protocol visits during the initial 12 weeks of anti-TNF treatment. Improvement in the disease activity score of 28 joints (DAS28) >1.2 defined treatment responders (n = 16) and non-responders (n = 9). Changes in synovial thickening and vascularity of 10 metacarpophalangeal joints were quantitatively assessed by grey scale and power Doppler ultrasound. The frequency of circulating Th17 cells was determined by IL17 enzyme-linked immunospot assay (Elispot) and flow cytometry (fluorescence-activated cell sorting (FACS)). RESULTS: The frequency of circulating IL17-producing cells increased significantly 12 weeks after anti-TNF initiation (Elispot median (range) specific spot forming cells (spSFC)/106 360 (280-645) vs 632 (367 - 1167), p = 0.003). The increase in CD4 + IL17+ cells at 12 weeks was confirmed by FACS (median (range) %, 0.7 (0.5-0.9) vs 1.05 (0.6 1.3); p = 0.01). The increase in circulating Th17 cells inversely correlated with reduction in synovial vascularity (r = -0.68, p = 0.007) and thickening (r = 0.39; p = 0.04). Higher frequencies of circulating Th17 cells at baseline were associated with poorer anti-TNF treatment response defined by ultrasonographic measures. CONCLUSIONS: These results demonstrate a link between changes in circulating Th17 cells with resolution of ultrasonographic features of synovial inflammation and vascularity during anti-TNF treatment. The findings may reflect redistribution of Th17 cells from inflamed joints or TNF-driven regulation of Th17 cell production. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01060098 . Registered 29 January 2010. PMID- 28010728 TI - Malaria epidemiological research in the Republic of Congo. AB - BACKGROUND: Reliable and comprehensive information on the burden of malaria is critical for guiding national and international efforts in malaria control. The purpose of this review is to provide an overview of published data and available information on malaria resulting from field studies/investigations conducted in the Republic of Congo (RoC) from 1992 to 2015, as baseline for assisting public health authorities and researchers to define future research priorities as well as interventions. METHODS: This review considers data from peer-reviewed articles and information from the National Malaria Control Programme reports, based on field investigations or samples collected from 1992 to 2015. Peer-reviewed papers were searched throughout online bibliographic databases PubMed, HINARI and Google Scholar using the following terms: "malaria", "Congo", "Brazzaville", "prevalence", "antimalarial", "efficacy", "falciparum", "genetic", "diversity". Original articles and reviews were included and selection of relevant papers was made. RESULTS: Twenty-eight published articles were included in this review and two additional records from the National Malaria Control Programme were also considered. The majority of studies were conducted in Brazzaville and Pointe Noire. CONCLUSION: The present systematic review reveals that number of studies have been conducted in the RoC with regard to malaria. However, their results cannot formally be generalized at the country level. This suggests a need for implementing regular multisite investigations and surveys that may be representative of the country, calling for the support and lead of the Ministry of Health. PMID- 28010727 TI - Quantitative imaging of mammalian transcriptional dynamics: from single cells to whole embryos. AB - Probing dynamic processes occurring within the cell nucleus at the quantitative level has long been a challenge in mammalian biology. Advances in bio-imaging techniques over the past decade have enabled us to directly visualize nuclear processes in situ with unprecedented spatial and temporal resolution and single molecule sensitivity. Here, using transcription as our primary focus, we survey recent imaging studies that specifically emphasize the quantitative understanding of nuclear dynamics in both time and space. These analyses not only inform on previously hidden physical parameters and mechanistic details, but also reveal a hierarchical organizational landscape for coordinating a wide range of transcriptional processes shared by mammalian systems of varying complexity, from single cells to whole embryos. PMID- 28010729 TI - Cholesterol levels and long-term rates of community-acquired sepsis. AB - BACKGROUND: Dyslipidemia is a risk factor for cardiovascular disease, with elevated low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C) recognized as risk factors for acute coronary events. Studies suggest an association between low cholesterol levels and poor outcomes in acute sepsis. We sought to determine the relationship between baseline cholesterol levels and long-term rates of sepsis. METHODS: We used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, a population-based cohort of 30,239 community-dwelling adults. The primary outcome was first sepsis event, defined as hospitalization for an infection with the presence of >=2 systemic inflammatory response syndrome criteria (abnormal temperature, heart rate, respiratory rate, white blood cell count) during the first 28 hours of hospitalization. Cox models assessed the association between quartiles of HDL-C or LDL-C and first sepsis event, adjusted for participant demographics, health behaviors, chronic medical conditions, and biomarkers. RESULTS: We included 29,690 subjects with available baseline HDL-C and LDL-C. There were 3423 hospitalizations for serious infections, with 1845 total sepsis events among 1526 individuals. Serum HDL-C quartile was not associated with long-term rates of sepsis (hazard ratio (HR) (95% CI): Q1 (HDL-C 5-40 mg/dl), 1.08 (0.91-1.28); Q2 (HDL-C 41-49 mg/dl), 1.06 (0.90-1.26); Q3 (HDL C 50-61 mg/dl), 1.04 (0.89-1.23); Q4, reference). However, compared with the highest quartile of LDL-C, low LDL-C was associated with higher rates of sepsis (Q1 (LDL-C 3-89 mg/dl), 1.30 (1.10-1.52); Q2 (LDL-C 90-111 mg/dl), 1.24 (1.06 1.47); Q3 (LDL-C 112-135 mg/dl), 1.07 (0.91-1.26); Q4, reference). CONCLUSION: Low LDL-C was associated with higher long-terms rates of community-acquired sepsis. HDL-C level was not associated with long-term sepsis rates. PMID- 28010730 TI - From antiretroviral therapy access to provision of third line regimens: evidence of HIV Drug resistance mutations to first and second line regimens among Ugandan adults. AB - BACKGROUND: HIV care programs in resource-limited settings have hitherto concentrated on antiretroviral therapy (ART) access, but HIV drug resistance is emerging. In a cross-sectional study of HIV-positive adults on ART for >=6 months enrolled into a prospective cohort in Uganda, plasma HIV RNA was measured and genotyped if >=1000 copies/ml. Identified Drug resistance mutations (DRMs) were interpreted using the Stanford database, 2009 WHO list of DRMs and the IAS 2014 update on DRMs, and examined and tabulated by ART drug classes. FINDINGS: Between July 2013 and August 2014, 953 individuals were enrolled, 119 (12.5%) had HIV-RNA >=1000 copies/ml and 110 were successfully genotyped; 74 (67.3%) were on first line and 36 (32.7%) on second-line ART regimens. The predominant HIV-1 subtypes were D (34.5%), A (33.6%) and Recombinant forms (21.8%). The commonest clinically significant major resistance mutations associated with the highest levels of reduced susceptibility or virological response to the relevant Nucleoside Reverse Transcriptase Inhibitor (NRTI) were; the Non-thymidine analogue mutations (Non TAMS) M184V-20.7% and K65R-8.0%; and the TAMs M41L and K70R (both 8.0%). The major Non-NRTI (NNRTI) mutations were K103N-19.0%, G190A-7.0% and Y181C-6.0%. A relatively nonpolymorphic accessory mutation A98G-12.0% was also common. Seven of the 36 patients on second line ART had major Protease Inhibitor (PI) associated DRMS including; V82A-7.0%, I54V, M46I and L33I (all 5.0%). Also common were the accessory PI mutations L10I-27%, L10V-12.0% and L10F-5.0% that either reduce PI susceptibility or increase the replication of viruses containing PI-resistance mutations. Of the 7 patients with major PI DRMs, five had high level resistance to ritonavir boosted Lopinavir and Atazanavir, with Darunavir as the only susceptible PI tested. CONCLUSIONS: In resource-limited settings, HIV care programs that have previously concentrated on ART access, should now consider availing access to routine HIV viral load monitoring, targeted HIV drug resistance testing and availability of third-line ART regimens. PMID- 28010731 TI - A survey of facilitators and barriers to recruitment to the MAGNETIC trial. AB - BACKGROUND: Recruitment to randomised controlled trials with children is challenging. It is imperative to understand the factors that boost or hinder recruitment of children to clinical trials. We conducted a survey of facilitators and barriers to recruitment to the MAGNETIC trial, using a previously developed web-based tool. METHODS: MAGNETIC is a multicentre randomised trial of nebulised magnesium in acute severe asthma, recruiting 508 children from 30 UK sites. Recruiters were asked to grade a list of factors from -3 to +3 depending on whether the factor was perceived as a strong, intermediate or weak barrier (-3 to -1) or facilitator (+1 to + 3), and using (0) if it was thought to be not applicable. Free text responses were invited on strategies applied to counter the identified barriers. RESULTS: The commonly identified facilitators were motivation and experience of study teams, effective communication and coordination between teams at site and between sites and the Clinical Trials Unit, the presence of designated research nurses, good trial management, clinical trial publicity, simple inclusion criteria, effective communication with parents and presentation of trial information in a simple and clear manner. The commonly identified barriers were heavy clinical workload, shift patterns of work, Good Clinical Practice (GCP) training, inadequate number of trained staff, time and setting of consent seeking, non-availability of research staff out of hours and parents' concerns about their child taking an experimental medicine. Having a designated research nurse, arranging GCP training and trial-related training sessions for staff were the most commonly reported interventions. CONCLUSIONS: This study highlights important generic and trial-specific facilitators and barriers to recruitment to a paediatric trial in the acute setting and provides information on the recruitment strategies or interventions that were applied to overcome these barriers. This information can be very useful in informing the design and conduct of future clinical trials with children, particularly in the acute or emergency setting. TRIAL REGISTRATION: ISRCTN, ISRCTN81456894 . Registered on 15 November 2007. PMID- 28010733 TI - Minimally invasive (sinus tarsi) approach for calcaneal fractures. AB - BACKGROUND: According to the anatomic characteristics of the calcaneus and the sinus tarsi approach, we designed a combined plate. The goal of this study was to retrospectively assess the functional outcomes and complications of treatment with our self-designed plate. METHODS: From March 2014 to October 2015, 18 patients with closed calcaneal fractures (14 Sanders type II and 4 type III) were treated with our combined locking plate through a minimally invasive sinus tarsi approach. All patients underwent both clinical and radiological evaluations. RESULTS: The follow-up duration for all patients ranged from 6 to 13.5 months. The radiographs demonstrated significant corrections of the calcaneal width, length, height, Bohler angle, and Gissane angle from preoperatively to 3 months postoperatively and the last follow-up. However, there were no significant differences in the variables between 3 months postoperatively and the last follow up. The mean Maryland foot score was 88.1 +/- 8.8, in which excellent outcomes were achieved in 11 patients, good in 4, and fair in 3 (excellent and good rate, 83.3% (15 of 18)). No statistical significances in the mean Maryland foot score (88.1 +/- 8.8 vs 87.8 +/- 10.1, p = 0.9), and the excellent and good rate (85.7 vs 75.0%, p = 1.0) was found between type II and type III fractures. No complications were observed in all fractured feet. CONCLUSION: Treatment with our self-designed combined plate through a sinus tarsi approach may be safe and effective for type II and type III calcaneal fractures. PMID- 28010732 TI - The effect of a germline mutation in the APC gene on beta-catenin in human embryonic stem cells. AB - BACKGROUND: Most cases of colorectal cancer (CRC) are initiated by inactivation mutations in the APC gene, which is a negative regulator of the Wnt-beta-catenin pathway. Patients with familial adenomatous polyposis (FAP) inherit a germline mutation in one APC allele, and loss of the second allele leads to the development of polyps that will turn malignant if not removed. It is not fully understood which molecular mechanisms are activated by APC loss and when the loss of the second APC allele occurs. METHODS: Two FAP human embryonic stem cell (hESCs) lines were derived from APC mutated embryos following pre-implantation genetic diagnosis (PGD) for FAP. These FAP-hESCs were cultured in vitro and following extended culture: 1) beta-catenin expression was analyzed by Western blot analysis; 2) Wnt-beta-catenin/TCF-mediated transcription luciferase assay was performed; 3) cellular localization of beta-catenin was evaluated by immunoflorecence confocal microscopy; and 4) DNA sequencing of the APC gene was performed. RESULTS: We have established a novel human in-vitro model for studying malignant transformation, using hESCs that carry a germline mutation in the APC gene following PGD for FAP. Extended culturing of FAP1 hESCs led to activation of the Wnt signaling pathway, as demonstrated by enhanced beta-catenin/TCF-mediated activity. Additionally, beta-catenin showed a distinct perinuclear distribution in most (91 %) of the FAP1 hESCs high passage colonies. DNA sequencing of the whole gene detected several polymorphisms in FAP1 hESCs, however, no somatic mutations were discovered in the APC gene. On the other hand, no changes in beta catenin were detected in the FAP2 hESCs, demonstrating the natural diversity of the human FAP population. CONCLUSIONS: Our results describe the establishment of novel hESC lines from FAP patients with a predisposition for cancer mutation. These cells can be maintained in culture for long periods of time and may serve as a platform for studying the initial molecular and cellular changes that occur during early stages of malignant transformation. PMID- 28010734 TI - Proteins adopt functionally active conformations after type III secretion. AB - BACKGROUND: Bacterial production of natively folded heterologous proteins by secretion to the extracellular space can improve protein production by simplifying purification and enabling continuous processing. In a typical bacterial protein production process, the protein of interest accumulates in the cytoplasm of the cell, requiring cellular lysis and extensive purification to separate the desired protein from other cellular constituents. The type III secretion system of Gram-negative bacteria is used to secrete proteins from the cytosol to the extracellular space in one step, but proteins must unfold during translocation, necessitating the folding of secreted proteins in the extracellular space for an efficient production process. We evaluated type III secretion as a protein production strategy by characterizing and quantifying the extent of correct folding after secretion. RESULTS: We probed correct folding by assaying the function after secretion of two enzymes-beta-lactamase and alkaline phosphatase-and one single-chain variable fragment of an antibody. Secreted proteins are correctly folded and functional after unfolding, secretion, and refolding in the extracellular space. Furthermore, structural and chemical features required for protein function, such as multimerization and disulfide bond formation, are evident in the secreted protein samples. Finally, the concentration of NaCl in the culture media affects the folding efficiency of secreted proteins in a protein-specific manner. CONCLUSIONS: In the extracellular space, secreted proteins are able to fold to active conformations, which entails post-translational modifications including: folding, multimerization, acquisition of metal ion cofactors, and formation of disulfide bonds. Further, different proteins have different propensities to refold in the extracellular space and are sensitive to the chemical environment in the extracellular space. Our results reveal strategies to control the secretion and correct folding of diverse target proteins during bacterial cell culture. PMID- 28010735 TI - Several steps of lateral gene transfer followed by events of 'birth-and-death' evolution shaped a fungal sorbicillinoid biosynthetic gene cluster. AB - BACKGROUND: Sorbicillinoids are a family of complex cyclic polyketides produced by only a small number of distantly related ascomycete fungi such as Trichoderma (Sordariomycetes) and Penicillium (Eurotiomycetes). In T. reesei, they are synthesized by a gene cluster consisting of eight genes including two polyketide synthases (PKS). To reconstruct the evolutionary origin of this gene cluster, we examined the occurrence of these eight genes in ascomycetes. RESULTS: A cluster comprising at least six of them was only found in Hypocreales (Acremonium chrysogenum, Ustilaginoidea virens, Trichoderma species from section Longibrachiatum) and in Penicillium rubens (Eurotiales). In addition, Colletotrichum graminicola contained the two pks (sor1 and sor2), but not the other sor genes. A. chrysogenum was the evolutionary eldest species in which sor1, sor2, sor3, sor4 and sor6 were present. Sor5 was gained by lateral gene transfer (LGT) from P. rubens. In the younger Hypocreales (U. virens, Trichoderma spp.), the cluster evolved by vertical transfer, but sor2 was lost and regained by LGT from C. graminicola. SorB (=sor2) and sorD (=sor4) were symplesiomorphic in P. rubens, whereas sorA, sorC and sorF were obtained by LGT from A. chrysogenum, and sorE by LGT from Pestalotiopsis fici (Xylariales). The sorbicillinoid gene cluster in Trichoderma section Longibrachiatum is under strong purifying selection. The T. reesei sor genes are expressed during fast vegetative growth, during antagonism of other fungi and regulated by the secondary metabolism regulator LAE1. CONCLUSIONS: Our findings pinpoint the evolution of the fungal sorbicillinoid biosynthesis gene cluster. The core cluster arose in early Hypocreales, and was complemented by LGT. During further speciation in the Hypocreales, it became subject to birth and death evolution in selected lineages. In P. rubrens (Eurotiales), two cluster genes were symplesiomorphic, and the whole cluster formed by LGT from at least two different fungal donors. PMID- 28010736 TI - Isoprene production by Escherichia coli through the exogenous mevalonate pathway with reduced formation of fermentation byproducts. AB - BACKGROUND: Isoprene, a volatile C5 hydrocarbon, is an important platform chemical used in the manufacturing of synthetic rubber for tires and various other applications, such as elastomers and adhesives. RESULTS: In this study, Escherichia coli MG1655 harboring Populus trichocarpa isoprene synthase (PtispS) and the exogenous mevalonate (MVA) pathway produced 80 mg/L isoprene. Codon optimization and optimal expression of the ispS gene via adjustment of the RBS strength and inducer concentration increased isoprene production to 199 and 337 mg/L, respectively. To augment expression of MVA pathway genes, the MVA pathway was cloned on a high-copy plasmid (pBR322 origin) with a strong promoter (Ptrc), which resulted in an additional increase in isoprene production up to 956 mg/L. To reduce the formation of byproducts derived from acetyl-CoA (an initial substrate of the MVA pathway), nine relevant genes were deleted to generate the E. coli AceCo strain (E. coli MG1655 DeltaackA-pta, poxB, ldhA, dld, adhE, pps, and atoDA). The AceCo strain harboring the ispS gene and MVA pathway showed enhanced isoprene production of 1832 mg/L in flask culture with reduced accumulation of byproducts. CONCLUSIONS: We achieved a 23-fold increase in isoprene production by codon optimization of PtispS, augmentation of the MVA pathway, and deletion of genes involved in byproduct formation. PMID- 28010737 TI - A new generation of nano-structured supramolecular solvents based on propanol/gemini surfactant for liquid phase microextraction. AB - A new supramolecular solvent (SUPRAS) made up of aggregates of gemini surfactant was introduced. A microextraction method, based on the SUPRAS followed with high performance liquid chromatography-ultraviolet detection, was applied for the determination of parabens in cosmetics, beverages and water samples. A SUPRAS is a nano-structured liquid made up of surfactant aggregates synthesized through a self-assembly process. In the present work, a new gemini-based SUPRAS was introduced. Methyl paraben (MP), ethyl paraben (EP), and propyl paraben (PP) were extracted on the basis of pi-cation and Van der Waals interactions into the SUPRAS. The parameter affecting the extraction of target analytes (i.e., the amount of surfactant and volume of propanol as major components comprising the supramolecular solvent, sample solution pH, salt addition, ultrasonic and centrifugation time) were investigated and optimized by one-variable-at-a-time method. Under the optimum conditions, the preconcentration factors of 98, 143 and 156 were obtained for MP, EP and PP, respectively. The linearity ranged from 0.5 to 0.7-200 MUg L-1 with the correlation of determination of (R2) >= 0.9938. The gemini-based SUPRAS followed by HPLC-UV has been found to have excellent detection sensitivity with a limit of detection (LOD, S/N = 3) of 0.5 MUg L-1 for EP and PP, and 0.7 MUg L-1 for MP. Good recoveries over the range of 92.0-108.3% assured the accuracy of the amount of parabens distinguished in the non-spiked samples. PMID- 28010738 TI - Pseudo-absolute quantitative analysis using gas chromatography - Vacuum ultraviolet spectroscopy - A tutorial. AB - The vacuum ultraviolet detector (VUV) is a new non-destructive mass sensitive detector for gas chromatography that continuously and rapidly collects full wavelength range absorption between 120 and 240 nm. In addition to conventional methods of quantification (internal and external standard), gas chromatography - vacuum ultraviolet spectroscopy has the potential for pseudo-absolute quantification of analytes based on pre-recorded cross sections (well-defined absorptivity across the 120-240 nm wavelength range recorded by the detector) without the need for traditional calibration. The pseudo-absolute method was used in this research to experimentally evaluate the sources of sample loss and gain associated with sample introduction into a typical gas chromatograph. Standard samples of benzene and natural gas were used to assess precision and accuracy for the analysis of liquid and gaseous samples, respectively, based on the amount of analyte loaded on-column. Results indicate that injection volume, split ratio, and sampling times for splitless analysis can all contribute to inaccurate, yet precise sample introduction. For instance, an autosampler can very reproducibly inject a designated volume, but there are significant systematic errors (here, a consistently larger volume than that designated) in the actual volume introduced. The pseudo-absolute quantification capability of the vacuum ultraviolet detector provides a new means for carrying out system performance checks and potentially for solving challenging quantitative analytical problems. For practical purposes, an internal standardized approach to normalize systematic errors can be used to perform quantitative analysis with the pseudo-absolute method. PMID- 28010739 TI - Ionic liquids intercalated in montmorillonite as the sorptive phase for the extraction of low-polarity organic compounds from water by rotating-disk sorptive extraction. AB - Montmorillonite (MMT) clays were modified by the intercalation into their galleries of ionic liquids (IL) based on imidazolium quaternary ammonium salts. This new eco-materials exhibited good features for use as a sorptive phase in the extraction of low-polarity analytes from aqueous samples. Spectroscopic analyses of the modified clays were conducted and revealed an increase in the basal spacing and a shifting of the reflection plane towards lower values as a consequence of the effective intercalation of organic cations into the MMT structure. The novel sorbent developed herein was assayed as the sorptive phase in rotating-disk sorptive extraction (RDSE), using polychlorinated biphenyls (PCBs), representative of low-polarity pollutants, as model analytes. The final determination was made by gas chromatography with electron capture detection. Among the synthetized sorptive phases, the selected system for analytical purposes consisted of MMT modified with the 1-hexadecyl-3-methylimidazolium bromide (HDMIM-Br) IL. Satisfactory analytical features were achieved using a sample volume of 5 mL: the relative recoveries from a wastewater sample were higher than 80%, the detection limits were between 3 ng L-1 and 43 ng L-1, the precision (within-run precision) expressed as the relative standard deviation ranged from 2% to 24%, and the enrichment factors ranged between 18 and 28. Using RDSE, the extraction efficiency achieved for the selected MMT-HDMIM-Br phase was compared with other commercial solid phases/supports, such as polypropylene, polypropylene with 1-octanol (as a supported liquid membrane), octadecyl (C18) and octyl (C8), and showed the highest response for all the studied analytes. Under the optimized extraction conditions, this new device was applied in the analysis of the influent of a wastewater treatment plant in Santiago (Chile), demonstrating its applicability through the good recoveries and precision achieved with real samples. PMID- 28010740 TI - Performance evaluation of oxygen adsorbents using negative corona discharge-ion mobility spectrometry. AB - Trace amounts of oxygen was determined using negative corona discharge as an ionization source for ion mobility spectrometry. A point-in-cylinder geometry with novel design was used to establish the corona discharge without interferences of negative ions such as NOX-. The desirable background spectrum shows only electrons peak, providing the instrument capable of trace analysis of oxygen in gaseous samples. The limit of detection and linear dynamic range with high coefficient of determination (r2 = 0.9997), were obtained for oxygen as 8.5 and 28-14204 ppm, respectively. The relative standard deviations of the method for intraday and interday were obtained 4 and 11%, respectively. The satisfactory results revealed the ability of the negative corona discharge ion mobility spectrometry for investigating the performance of synthesized oxygen adsorbents in nitrogen streams. Two oxygen scavengers of MnO and Cu powder were prepared and the optimum temperature of the reactor containing MnO and Cu powder were obtained as 180 and 230 degrees C, respectively. Due to higher lifetime of copper powder, it was selected as the oxygen scavenger and some parameters such as: the type of adsorbent support, the size of adsorbent particles, and the amount of copper were studied for preparation of more efficient oxygen adsorbent. PMID- 28010741 TI - Integrated work-flow for quantitative metabolome profiling of plants, Peucedani Radix as a case. AB - Universal acquisition of reliable information regarding the qualitative and quantitative properties of complicated matrices is the premise for the success of metabolomics study. Liquid chromatography-mass spectrometry (LC-MS) is now serving as a workhorse for metabolomics; however, LC-MS-based non-targeted metabolomics is suffering from some shortcomings, even some cutting-edge techniques have been introduced. Aiming to tackle, to some extent, the drawbacks of the conventional approaches, such as redundant information, detector saturation, low sensitivity, and inconstant signal number among different runs, herein, a novel and flexible work-flow consisting of three progressive steps was proposed to profile in depth the quantitative metabolome of plants. The roots of Peucedanum praeruptorum Dunn (Peucedani Radix, PR) that are rich in various coumarin isomers, were employed as a case study to verify the applicability. First, offline two dimensional LC-MS was utilized for in-depth detection of metabolites in a pooled PR extract namely universal metabolome standard (UMS). Second, mass fragmentation rules, notably concerning angular-type pyranocoumarins that are the primary chemical homologues in PR, and available databases were integrated for signal assignment and structural annotation. Third, optimum collision energy (OCE) as well as ion transition for multiple monitoring reaction measurement was online optimized with a reference compound-free strategy for each annotated component and large-scale relative quantification of all annotated components was accomplished by plotting calibration curves via serially diluting UMS. It is worthwhile to highlight that the potential of OCE for isomer discrimination was described and the linearity ranges of those primary ingredients were extended by suppressing their responses. The integrated workflow is expected to be qualified as a promising pipeline to clarify the quantitative metabolome of plants because it could not only holistically provide qualitative information, but also straightforwardly generate accurate quantitative dataset. PMID- 28010742 TI - Succinyl-beta-cyclodextrin modified gold biochip improved seroimmunological detection sensitivity for Lyme disease. AB - Cyclodextrin (CD) is a kind of cyclic oligosaccharides, which forms host-guest interactions with hydrophobic molecules and is widely applied in capillary electrophoresis and pharmaceutical engineering. In this study, we established a succinyl-beta-CD modified gold biochip for improvement of seroimmunological detection sensitivity of Lyme disease. We found that the CD modified biochip platform presented a stronger affinity property for VlsE protein in conjugation with >0.000475 MUg/mL of antigen immobilization concentration, which was sensitive enough for fluorescence based assay. Detection limit for anti-VlsE IgG antibody was 0.39 MUg/mL. Specificity of VlsE assay on the succinyl-beta-CD modified biochip was successfully confirmed by an immunological block assay. Furthermore, the correlation coefficient (R2) between the fluorescence values by the biochip and the OD values by ELISA assay was 0.904, indicating this biochip based immunological assay might be a potential substitute with the ELISA-based approach. This biochip platform would be not suitable for loading of flagellin and OspC. PMID- 28010743 TI - Direct solubility determination in optically dense solutions of highly soluble chromophores by the optoacoustic technique: Acidity dependence for Phenol Red. AB - The optoacoustic (OA) technique capable for light-absorption measurements in highly concentrated solutions is applied for direct solubility assessment in highly absorbing saturated solutions without any dilution or sample preparation. Maximum solubility of Phenol Red in aqueous solutions at pH>11 is found to be 1.3+/-0.1 g/L. The experimental dependence of solubility of Phenol Red on solution acidity was obtained with optoacoustic and conventional spectrophotometric measurements. The data from both methods show complementary results. The model of the solubility of Phenol Red on solution acidity describing the experimental dependence is proposed, which cannot be attained at pHs above 7 without the OA-technique. PMID- 28010744 TI - Amphiphilic carbon dots for sensitive detection, intracellular imaging of Al3. AB - In this paper, a simple and effective method was designed to synthesize hydrophobic carbon dots. Subsequently, amphiphilic fluorescent carbon dots (A CDs) were synthesized by further surface modification. The result A-CDs show excellent optical properties with a quantum yield of 16.9%. It was interestingly found that morin (MR) and its fluorescent metal-ion complex (MR-Al3+) can successfully coordinate on the surface of A-CDs, the emission of A-CDs completely overlapped the absorption peak of MR-Al3+. Thus, the prepared A-CDs can be used as an effective fluorescent probe for Al3+ based on a fluorescence resonance energy transfer process. The sensing platform can realize real-time detection of Al3+ within 0.5 min. The fluorescence signals of the system were linearly correlated with the concentration of Al3+ over a range of 8-20 MUM, with a detection limit of 0.113 MUM. The method was also successfully applied to image the distribution of Al3+ in Human Umbilical Vein Endothelial Cells. PMID- 28010745 TI - Optical nose based on porous silicon photonic crystal infiltrated with ionic liquids. AB - A photonic-nose for the detection and discrimination of volatile organic compounds (VOCs) was constructed. Each sensing element on the photonic sensor array was formed by infiltrating a specific type of ionic liquid (IL) into the pore channel of a patterned porous silicon (PSi) chip. Upon exposure to VOC, the density of IL dramatically decreased due to the nano-confinement effect. As a result, the IL located in pore channel expanded its volume and protrude out of the pore channel, leading to the formation of microdroplets on the PSi surface. These VOC-stimulated microdroplets could scatter the light reflected from the PSi rugate filter, thereby producing an optical response to VOC. The intensity of the optical response produced by IL/PSi sensor mainly depends on the size and shape of microdroplets, which is related to the concentration of VOC and the physi chemical propertied of ILs. For ethanol vapor, the optical response has linear relationship with its relative vapor pressure within 0-60%. The LOD of the IL/PSi sensor for ethanol detection is calculated to be 1.3 ppm. It takes around 30 s to reach a full optical response, while the time for recovery is less than 1 min. In addition, the sensor displayed good stability and reproducibility. Owing to the different molecular interaction between IL and VOC, the ILs/PSi sensor array can generate a unique cross-reactive "fingerprint" in response to a specific type of VOC analyte. With the assistance of image technologies and principle components analysis (PCA), rapid discrimination of VOC analyte could be achieved based on the pattern recognition of photonic sensor array. The technology established in this work allows monitoring in-door air pollution in a visualized way. PMID- 28010746 TI - Parallel analysis and orthogonal identification of N-glycans with different capillary electrophoresis mechanisms. AB - The deep involvement of glycans or carbohydrate moieties in biological processes makes glycan patterns an important direction for the clinical and medicine researches. A multiplexing CE mapping method for glycan analysis was developed in this study. By applying different CE separation mechanisms, the potential of combined parallel applications of capillary zone electrophoresis (CZE), micellar electrokinetic chromatography (MEKC) and capillary gel electrophoresis (CGE) for rapid and accurate identification of glycan was investigated. The combination of CZE and MEKC demonstrated enhancing chromatography separation capacity without the compromises of sample pre-treatment and glycan concentration. The separation mechanisms for multiplexing platform were selected based on the orthogonalities of the separation of glycan standards. MEKC method exhibited promising ability for the analysis of small GU value glycans and thus complementing the unavailability of CZE. The method established required only small amount of samples, simple instrument and single fluorescent labelling for sensitive detection. This integrated method can be used to search important glycan patterns appearing in biopharmaceutical products and other glycoproteins with clinical importance. PMID- 28010747 TI - Using on-line solid phase extraction for in vivo speciation of diffusible ferrous and ferric iron in living rat brain extracellular fluid. AB - Exploration of brain extracellular non-protein-bound/diffusible iron species remains a critically important issue in investigations of free radical biology and neurodegenerative diseases. In this study, a facile sample pretreatment scheme, involving poly(vinyl chloride)-metal ion interactions as a selective extraction procedure, was optimized in conjunction with microdialysis (MD) sampling and inductively coupled plasma mass spectrometry (ICP-MS) in cool-plasma mode for in vivo online monitoring of rat brain extracellular Fe(II) and Fe(III) species. Optimization of the system provided detection limits in the range 0.9 6.9 MUg Fe L-1, based on a 12-MUL microdialysate, for the tested iron species; relative standard deviations of the signal intensities during 7.8 h of continuous measurement were less than 9.4%-sufficient to determine the basal concentrations of rat brain extracellular Fe(II) and Fe(III) species and to describe their dynamic actions. The method's applicability was verified through (i) spike analyses of offline-collected rat brain microdialysates, (ii) determination of the basal Fe(II) and Fe(III) concentrations of living rat brain extracellular fluids, and (iii) monitoring of the dynamic changes in the Fe(II) and Fe(III) concentrations in response to perfusion of a high-K+ medium. This proposed sample pretreatment scheme, based on polymer-metal ion interactions and hyphenation to an MD sampling device and an ICP-MS system, appears to have great practicality for the online monitoring of rat brain extracellular diffusible iron species. PMID- 28010748 TI - Psychological Manifestations of Early Childhood Adversity in the Context of Chronic Hematologic Malignancy. AB - BACKGROUND: Myeloproliferative neoplasms (MPNs), a group of chronic hematologic malignancies, carry significant physical and psychological symptom burdens that significantly affect patients' quality of life. OBJECTIVES: We sought to identify the relationship between early childhood adversity (ECA) and psychological distress in patients with MPNs, as ECA may compound symptom burden. METHODS: Patients with MPNs were assessed for ECA (i.e., the Risky Families Questionnaire subscales include abuse/neglect/chaotic home environment), distress (i.e., Distress Thermometer and Problem List), anxiety (i.e., Hospital Anxiety and Depression Scale-Anxiety [HADS-A]), depression (i.e., Hospital Anxiety and Depression Scale-Depression [HADS-D]), meeting standardized cutoff thresholds for distress (i.e., Distress Thermometer and Problem List>= 4 or >= 7)/anxiety (HADS A >=8)/depression (HADS-D >= 8), and demographic factors. RESULTS: A total of 117 participants completed the study (78% response rate). ECA was associated with depression (p < 0.000), anxiety (p < 0.000), and distress (p < 0.000) and problem list variables emotional (p < 0.000), physical (p = 0.004), family (p = 0.01), and spiritual (p = 0.01) by bivariate analysis and only with distress (HADS) (p = 0.038) on multivariate analysis. ECA was associated with meeting cutoff threshold criteria for distress (p = 0.007), anxiety (p = 0.001), and depression (p = 0.02). ECA subscale variables abuse and chaotic home environment were associated with psychological outcomes. ECA was higher based on disease subtypes with greater symptom burden (other > polycythemia vera > myelofibrosis > essential thrombocythemia) (p = 0.047) and taking an antidepressant (p = 0.011). CONCLUSION: ECA is associated with psychological distress and meets screening criteria for anxiety and depression in patients with MPNs. ECA may help to explain individual patient trajectories, and further understanding may enhance patient-centered care among patients with MPNs. PMID- 28010749 TI - Special Interest Group-sponsored Updates in Psychosomatics (SIG-UPs): Understanding the Pathophysiology of Catatonia Through Associated Neurological Insults (Neuropsychiatry SIG). PMID- 28010750 TI - Special Interest Groups-Updates in Psychosomatics (SIG-UPs): Alcohol Use Disorders in Women. PMID- 28010751 TI - Salaries in Psychosomatic Medicine: A Cross-Sectional Survey of Practicing Physicians. PMID- 28010752 TI - Baclofen-Induced Manic Symptoms: Case Report and Systematic Review. PMID- 28010753 TI - Demonstrating Conversion in the Clinic. PMID- 28010754 TI - Bipolar Disorder With Mixed Features Associated With Primary Hyperparathyroidism. PMID- 28010755 TI - The Good Life: Dermatologic Research. PMID- 28010756 TI - Deregulation of Adenosine Receptors in Psoriatic Epidermis: An Option for Therapeutic Treatment. AB - Purinergic signaling is involved in psoriasis, a chronic skin disease characterized by increased epidermis cell growth. In particular, Andres et al. focus on the keratinocyte biology modulated by adenosine receptors providing evidence that the A2B subtype plays a prominent role in the reduction of keratinocyte proliferation whereas A2A and A2B agonists have antiinflammatory effects independent of adenosine receptors. The authors report that psoriatic epidermis presents a deregulated adenosine receptor expression profile with reduced A2B and increased A2A. PMID- 28010757 TI - sm"FISH"ing for Hedgehog. AB - Patched (Ptch) receptors are critical negative regulators of Hedgehog signaling, where Ptch1 loss causes basal cell carcinoma and Ptch1;Ptch2 loss disrupts skin and hair follicle development. Adolphe et al. use single molecule fluorescent in situ hybridization to show quantitatively that Ptch receptors create a Hedgehog signaling gradient that may specify hair follicle development. PMID- 28010758 TI - Double Jeopardy: The Rubber Ball Bounces Twice. AB - Soblet et al. describe cis mutations in TEK/Tie-2 in blue rubber bleb nevus and sporadic vascular malformations. This suggests that the remaining normal allele is required for the phenotype. Second, it suggests therapeutic approaches to treatment signal transduction inhibition. PMID- 28010759 TI - Looking Back while Stepping Forward-A Path Made Possible by Serendipity, a Few Good Decisions, and Helpful Colleagues. PMID- 28010760 TI - ACKR2: Nature's Decoy Receptor Lures Unsuspecting Chemokines in Psoriasis. AB - While we know much about the processes mediated by the Th17 inflammatory pathway that is crucial in psoriasis, we actually know little about the processes by which most psoriatic patients maintain what grossly looks like non-inflamed, normal skin in the face of massive inflammatory changes in nearby affected skin. Other molecular regulators that defend the skin from global inflammation are likely to be involved, including molecules such as ACKR2, an atypical chemokine receptor whose role in psoriasiform dermatitis is explored by Shams et al. PMID- 28010761 TI - Research Techniques Made Simple: Mouse Models of Autoimmune Blistering Diseases. AB - Autoimmune blistering diseases are examples of autoantibody-mediated, organ specific autoimmune disorders. Based on a genetic susceptibility, such as a strong HLA-class II association, as yet unknown triggering factors induce the formation of circulating and tissue-bound autoantibodies that are mainly directed against adhesion structures of the skin and mucous membranes. Compared with other autoimmune diseases, especially systemic disorders, the pathogenicity of autoimmune blistering diseases is relatively well described. Several animal models of autoimmune blistering diseases have been established that helped to uncover the immunological and molecular mechanisms underlying the blistering phenotypes. Each in vivo model focuses on specific aspects of the autoimmune cascade, from loss of immunological tolerance on the level of T and B cells to the pathogenic effects of autoantibodies upon binding to their target autoantigen. We discuss current mouse models of autoimmune blistering diseases, including models of pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa acquisita, and dermatitis herpetiformis. PMID- 28010764 TI - A quarter-century of nanoparticle generation by lasers in liquids: Where are we now, and what's next? PMID- 28010765 TI - UV-irradiated parylene surfaces for proliferation and differentiation of PC-12 cells. AB - PC-12 cells originate from neuroblastic cells, which have an ability to differentiate into neuronlike cells. In this work, the purpose was to estimate the influence of microenvironments on cell attachment and neuritogenesis capacity of PC-12 cells on parylene-N and parylene-C films with and without ultraviolet (UV) light treatment. The estimate of total cell number after incubation for 72h, the ratio of adherent to suspended cells, counting of neurite outgrowths on parylene-N or parylene-C films after UV exposure suggested that these films were suitable for proliferation as well as differentiation of PC-12 cells. The differences in surface properties of parylene-N and parylene-C films with and without UV exposure were analyzed by contact angle measurement, Fourier-transform infrared spectrometry, and X-ray photoelectron spectroscopy. According to these analyses, introduction of oxygen-related chemical functional groups was presumed to result in increased hydrophilicity and efficiency of protein immobilization on parylene-N and parylene-C films after UV treatment. According to fluorescent staining, western blotting, and cell cycle analysis, UV-treated parylene-C and parylene-N films appear to effectively facilitate simultaneous proliferation and differentiation of PC-12 cells with neurite outgrowth. PMID- 28010766 TI - Heterologous expression in Pichia pastoris and characterization of a beta glucosidase from the xylophagous cockroach Panesthia angustipennis spadica displaying high specific activity for cellobiose. AB - A beta-glucosidase (BG), PaBG1b, from the xylophagous cockroach Panesthia angustipennis spadica was heterologously expressed in the methylotrophic yeast Pichia pastoris, purified, and biochemically characterized. Post-translational modification and N-terminal sequencing analysis demonstrated that the expression product was comprised of two polypeptides with different N-terminal sequences, presumably due to the presence of lysine-arginine (KR) sequence in the putative mature region. Substrate specificity analysis showed that PaBG1b hydrolyzed a broad range of substrates including cellohexaose, with the preference for aryl beta-d-fucosyl linkage and laminaribiose. Although the glucose tolerance of PaBG1b was moderate (Ki=200.3+/-1.1mM), PaBG1b demonstrated high specific activity and catalytic efficiency towards cellobiose with Vmax and kcat/Km values of 436.7+/-6.3U/mg and 109.8mM-1s-1, respectively. In addition, PaBG1b was not inhibited by cellobiose up to the highest concentration tested (100mM). Collectively, our work demonstrates that PaBG1b is a potentially valuable BG for commercial bioethanol production from cellulose. PMID- 28010767 TI - Enhanced yield of ethylene glycol production from d-xylose by pathway optimization in Escherichia coli. AB - The microbial production of renewable ethylene glycol (EG) has been gaining attention recently due to its growing importance in chemical and polymer industries. EG has been successfully produced biosynthetically from d-xylose through several novel pathways. The first report on EG biosynthesis employed the Dahms pathway in Escherichia coli wherein 71% of the theoretical yield was achieved. This report further improved the EG yield by implementing metabolic engineering strategies. First, d-xylonic acid accumulation was reduced by employing a weak promoter which provided a tighter control over Xdh expression. Second, EG yield was further improved by expressing the YjgB, which was identified as the most suitable aldehyde reductase endogenous to E. coli. Finally, cellular growth, d-xylose consumption, and EG yield were further increased by blocking a competing reaction. The final strain (WTXB) was able to reach up to 98% of the theoretical yield (25% higher as compared to the first study), the highest reported value for EG production from d-xylose. PMID- 28010768 TI - Green production of microalgae-based silver chloride nanoparticles with antimicrobial activity against pathogenic bacteria. AB - Silver nanoparticles are powerful antimicrobial agents. Here, the synthesis of silver chloride nanoparticles (AgCl-NPs) was consistently evidenced from a commercially valuable microalgae species, Chlorella vulgaris. Incubation of C. vulgaris conditioned medium with AgNO3 resulted in a medium color change to yellow/brown (with UV-vis absorbance at 415nm), indicative of silver nanoparticle formation. Energy-dispersive X-ray spectroscopy (EDS) of purified nanoparticles confirmed the presence of both silver and chlorine atoms, and X-ray diffraction (XRD) showed the typical pattern of cubic crystalline AgCl-NPs. Transmission electron microscopy (TEM) showed that most particles (65%) were spherical, with average diameter of 9.8+/-5.7nm. Fourier transform infrared spectroscopy (FTIR) of purified nanoparticle fractions suggested that proteins are the main molecular entities involved in AgCl-NP formation and stabilization. AgCl-NPs (from 10MUg/mL) decreased by 98% the growth of Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae bacterial pathogens, and had a dose-dependent effect on cell viability, which was measured by automated image-based high content screening (HCS). Ultrastructural analysis of treated bacteria by TEM revealed the abnormal arrangement of the chromosomal DNA. Our findings strongly indicated that the AgCl-NPs from C. vulgaris conditioned medium is a promising 'green' alternative for biomedical application as antimicrobials. PMID- 28010769 TI - The Effect of Pelargonium endlicherianum Fenzl. root extracts on formation of nanoparticles and their antimicrobial activities. AB - Herein, we report the biosynthesis of Ag NPs, for the first time, using identified antimicrobial molecules (gallic acid+apocynin) and (gallic acid+apocynin+quercetin) from the medicinal plant Pelargonium endlicherianum Fenzl. and dramatically enhanced antimicrobial activity. We also investigate the role of each molecule on formation Ag NPs and explain the increase in the antimicrobial activity of identified molecules mediated Ag NPs. The extraction protocols, 11% ethanol and 70% methanol, resulted in identification of different constituents of gallic acid+apocynin (M1) and gallic acid+apocynin+quercetin (M2) with respective concentrations. The M1-Ag and M2-Ag NPs exhibit excellent inhibitory activities towards Gram negative bacteria; Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Gram positive bacteria; Staphylococcus epidermidis ATCC 3699 bacterial using in vitro microdilution method. The minimum inhibitory concentration (MIC) values of M1-Ag and M2-Ag NPs were determined to be 7.81 and 6.25ppm for S. epidermidis, respectively. Surprisingly, MIC value for both Ag NPs was indicated to be identical as 9. 37ppm for P. aeruginosa and E., coli. PMID- 28010770 TI - A single and two step isomerization process for d-tagatose and l-ribose bioproduction using l-arabinose isomerase and d-lyxose isomerase. AB - l-ribose and d-tagatose are biochemically synthesized using sugar isomerases. The l-arabinose isomerase gene from Shigella flexneri (Sf-AI) was cloned and expressed in Escherichia coli BL-21. Sf-AI was applied for the bioproduction of d tagatose from d-galactose. l-ribose synthesis was performed by two step isomerization using Sf-AI and d-lyxose/ribose isomerase from Cohnella laevoribosii. The overall 22.3% and 25% conversion rate were observed for d tagatose and l-ribose production from d-galactose and l-arabinose respectively. In the present manuscript, synthesis of rare sugars from naturally available sugars is discussed along with the biochemical characterization of Sf-AI and its efficiency. PMID- 28010771 TI - Highly regioselective hydroxylation of polydatin, a resveratrol glucoside, for one-step synthesis of astringin, a piceatannol glucoside, by P450 BM3. AB - Enzymatic conversion of natural glycosides to their corresponding hydroxylated products using cytochromes P450 has significant advantages over synthetic chemistry and even enzyme-catalyzed glycosylation of chemicals. At present, the basic strategy for making glycosides of stilbenoid compounds is to use the glycosylation activity of enzymes, such as glycosyltransferases. Here, an efficient synthesis of a valuable (E)-astringin, a piceatannol glucoside, was developed using CYP102A1 via the highly regioselective C-3' hydroxylation of polydatin, a resveratrol glucoside. (E)-astringin is a high added value compound found in plants and wine. Benzylic hydroxylation of polydatin provides an attractive route to (E)-astringin, a catechol product. Thus far, chemical and enzymatic methods of producing (E)-astringin have not been developed. In the present study, a set of CYP102A1 mutants from Bacillus megaterium was found to catalyze regioselective hydroxylation of polydatin at the C-3' position to generate an (E)-astringin, a piceatannol glucoside. PMID- 28010772 TI - Characterization of Clostridium thermocellum (B8) secretome and purified cellulosomes for lignocellulosic biomass degradation. AB - The main goal of the present study was a complete proteomic characterization of total proteins eluted from residual substrate-bound proteins (RSBP), and cellulosomes secreted by Clostridium thermocellum B8 during growth in the presence of microcrystalline cellulose as a carbon source. The second goal was to evaluate their potential use as enzymatic blends for hydrolyzing agro-industrial residues to produce fermentable sugars. Protein identification through LC-MS/MS mass spectrometry showed that the RSBP sample, in addition to cellulosomal proteins, contains a wide variety of proteins, including those without a well characterized role in plant cell wall degradation. The RSBP subsample defined as purified cellulosomes (PC) consists mainly of glycoside hydrolases grouped in families 5, 8, 9, 10 and 48. Dynamic light scattering, DLS, analysis of PC resulted in two protein peaks (pi1 and pi2) presenting molecular masses in agreement with those previously described for cellulosomes and polycellulosomes. These peaks weren't detected after PC treatment with 1.0% Tween. PC and RSBP presented maximal activities at temperatures ranging from 60 degrees to 70 degrees C and at pH 5.0. RSBP retained almost all of its activity after incubation at 50, 60 and 70 degrees C and PC showed remarkable thermostability at 50 and 60 degrees C. RSBP holocellullolytic activities were inhibited by phenolic compounds, while PC showed either increasing activity or a lesser degree of inhibition. RSBP and PC hydrolyze sugar cane straw, cotton waste and microcrystalline cellulose, liberating a diversity of saccharides; however, the highest concentration of released sugar was obtained for assays carried out using PC as an enzymatic blend and after ten days at 50 degrees C. PMID- 28010773 TI - Biosynthesis of silver nanoparticles using pre-hydrolysis liquor of Eucalyptus wood and its effective antimicrobial activity. AB - Herein, we described for the first time, biosynthesis of silver nanoparticles (AgNPs) using pre-hydrolyzed liquor of Eucalyptus wood under ambient conditions. The pre-hydrolyzed liquor containing a high amount of metabolites such as polyphenols, hemicelluloses and its derivatives are mainly assisted for the reduction and stabilization process of Ag+ ions to AgNPs. The formation of AgNPs is monitored by recording the UV-vis spectrophotometer for surface plasmon resonance (SPR) peak observed at ~415nm. The intensity of SPR increased linearly with increasing the reaction time at ambient condition. X-ray diffraction (XRD) pattern of AgNPs reveals the formation of face-centered cubic structure. Field emission electron microscopy (FESEM) and transmission electron microscopy (TEM) images show the spherical shaped particles and narrow size distribution with an average diameter of 25-30nm. The elemental analysis by energy dispersive X-ray (EDAX) analysis confirms the presence of Ag as the major amount and is found to be 82%. Analysis of the fourier transform infrared (FT-IR) spectra of the NPs revealed the presence of phytoconstituents from pre-hydrolyzed liquor adsorbed on the surface of AgNPs. Moreover, in vitro, antimicrobial activity is found to be effective for as-synthesized AgNPs on tested bacteria (viz., P. aeruginosa, S. aureus and E. coli) followed by fungus (C. oxysporum, P. chrysogenum, C. albicans and A.niger). Thus, these results suggest the use of biosynthesized AgNPs as effective growth inhibitors for various biomedical applications. PMID- 28010774 TI - Recombinant cellulolytic or xylanolytic complex comprising the full-length scaffolding protein RjCipA and cellulase RjCel5B or xylanase RjXyn10C of Ruminiclostridium josui. AB - Three cellulosomal subunits of Ruminiclostridium josui, the full-length scaffolding protein CipA (RjCipA), a cellulase Cel5B (RjCel5B) and a xylanase Xyn10C (RjXyn10C), were successfully produced by Escherichia coli recombinant clones. RjCel5B and RjXyn10C were characterized as an endoglucanase and an endoxylanase, respectively. RjCipA, RjCel5B and Xyn10C adsorbed to microcrystalline cellulose (Funacel) and rice straw powder. Interaction between RjCel5B and RjCipA, and RjXyn10C and RjCipA were confirmed by qualitative assays. When a fixed amount of RjCel5B was mixed with different amounts of RjCipA, i.e., at the molar ratio of 6:1 or 6:6, the 6:6 complex showed 6.6-fold higher activity toward Funacel and 11.5-fold higher activity toward rice straw powder than RjCel5B, whereas the 6:1 complex showed only 2.8- and 3.9-folds higher activities toward Funacel and rice straw powder, respectively, than RjCel5B. These results suggest that the family-3 carbohydrate binding module (CBM3) of RjCipA in the RjCel5B-RjCipA complex plays an important role for hydrolysis of cellulose and the substrate-targeting effect of the CBM is more significant than the proximity effect caused by the presence of plural catalytic subunits adjoining each other. In contrast, the 6:1 complex of RjXyn10C and RjCipA showed 45% and 28% of the activities of RjXyn10C toward insoluble wheat arabinoxylan and rice straw powder, respectively. These results suggest that both a negative proximity effect and substrate-isolating effect, but not substrate-targeting effect, are caused by the CBM3 with inappropriate polysaccharide specificity. Substrate-targeting, proximity and substrate-isolating effects are discussed. PMID- 28010775 TI - The catalytic domain of Penicillium crustosum endoglucanase EGL1 has cellulose binding capacity and cellulolytic activity. AB - The cellulase-mediated degradation of cellulosic materials, which is initiated by endoglucanases by the random cleavage of the glycosidic bonds between glucose units to break long cellulose molecules into shorter ones, represents a major carbon flow in the global carbon cycle. The structure of a typical endoglucanase contains a classical (alpha/beta)8 barrel fold catalytic domain, a linker region and a cellulose-binding domain. In this study, we found that both the full-length enzyme and the catalytic domain of endoglucanase EGL1 cloned from Penicillium crustosum strain 601 have CMCase and FPase activity. A cellulose-binding assay using green fluorescent protein as a marker further showed that the catalytic domain could also bind the cellulose substrate. The three-dimensional structure of the catalytic domain of EGL1 revealed that this cellulose substrate-binding capacity of the catalytic domain may come from the hydrophobic core formed by aromatic amino acids distributed in or outside the (alpha/beta)8 barrel fold. A glycine scanning mutagenesis assay further found that the aromatic amino acids at the bottom of the barrel fold and those adjacent to the catalytic site significantly affect the cellulolytic activity and the cellulose binding affinity of the catalytic domain. Thus, it could be speculated that the aromatic amino acids in the bottom of the barrel fold might be the main contributors in the binding capacity of the catalytic domain with the cellulose substrate, and those distributed around the active sites on the top of the enzyme might participate in moving the cellulose substrate to the active site in the barrel fold or releasing the hydrolysis products. PMID- 28010776 TI - Rational design for the stability improvement of Armillariella tabescens beta mannanase MAN47 based on N-glycosylation modification. AB - beta-Mannanase has been widely used in industries such as food and feed processing and thus has been a target enzyme for biotechnological development. In this study, we sought to improve the stability and protease resistance of a recombinant beta-mannanase, MAN47 from Armillariella tabescens, through rationally designed N-glycosylation. Based on homology modeling, molecular docking, secondary structure analysis and glycosylation feasibility analysis, an enhanced aromatic sequon sequence was introduced into specific MAN47 loop regions to facilitate N-glycosylation. The mutant enzymes were expressed in Pichia pastoris SMD1168, and their thermal stability, pH stability, trypsin resistance and pepsin resistance were determined. Two mutant MAN47 enzymes, g-123 and g-347, were glycosylated as expected when expressed in yeast, and their thermal stability, pH stability, and protease resistance were significantly improved compared to the wild-type enzyme. An enzyme with multiple stability characterizations has broad prospects in practical applications, and the rational design N-glycosylation strategy may have applications in simultaneously improving several properties of other biotechnological targets. PMID- 28010777 TI - Hypersensitive antibiotic susceptibility test based on a beta-lactamase assay with a parylene-matrix chip. AB - Many kinds of susceptibility test for beta-lactam antibiotics have been used to determine the antibiotic resistance of bacterial strains. Here, a sensitive antibiotic susceptibility test was presented by using a specialized reaction tool for laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS) based on parylene-matrix chip. The beta-lactamase assay was carried out in a specialized reaction tool by (1) concentrating the bacterial strain and (2) incubating the bacteria with penicillin-G. The parylene-matrix chip was produced by deposition of a partially porous parylene-N thin film on a dried organic matrix array, and the products of beta-lactamase reaction in the low range of mass-to-charge ratio (m/z<500) could be effectively analyzed by using a parylene matrix chip. The sensing parameters were compared with conventional chromogenic antibiotic susceptibility test for beta-lactam antibiotics. Finally, LDI-TOF MS with a specialized reaction tool and parylene-matrix chip could achieve a limit of detection as low as 600 cells/spot for penicillin-G. PMID- 28010778 TI - Quantification of immobilized Candida antarctica lipase B (CALB) using ICP-AES combined with Bradford method. AB - The aim of this manuscript was to study the application of a new method of protein quantification in Candida antarctica lipase B commercial solutions. Error sources associated to the traditional Bradford technique were demonstrated. Eight biocatalysts based on C. antarctica lipase B (CALB) immobilized onto magnetite nanoparticles were used. Magnetite nanoparticles were coated with chitosan (CHIT) and modified with glutaraldehyde (GLUT) and aminopropyltriethoxysilane (APTS). Later, CALB was adsorbed on the modified support. The proposed novel protein quantification method included the determination of sulfur (from protein in CALB solution) by means of Atomic Emission by Inductive Coupling Plasma (AE-ICP). Four different protocols were applied combining AE-ICP and classical Bradford assays, besides Carbon, Hydrogen and Nitrogen (CHN) analysis. The calculated error in protein content using the "classic" Bradford method with bovine serum albumin as standard ranged from 400 to 1200% when protein in CALB solution was quantified. These errors were calculated considering as "true protein content values" the results of the amount of immobilized protein obtained with the improved method. The optimum quantification procedure involved the combination of Bradford method, ICP and CHN analysis. PMID- 28010779 TI - Criteria for Recommending a Patient Self-Report Functional Outcome. PMID- 28010780 TI - The Authors Respond. PMID- 28010781 TI - Aquatic Exercise for People With Spinal Cord Injury. PMID- 28010782 TI - Epigenetic inheritance and the responsibility for health in society. PMID- 28010783 TI - Minority underrepresentation in cardiovascular outcome trials for type 2 diabetes. PMID- 28010784 TI - The causal impact of ART on NCDs: leveraging quasi-experiments. PMID- 28010785 TI - Long-term outcomes of kidney transplantation in people with type 2 diabetes: a population cohort study. AB - BACKGROUND: Overall survival for younger patients with type 2 diabetes without kidney disease has improved substantially over time, but whether a similar pattern of improvement is observed in diabetic kidney transplant recipients remained uncertain. We aimed to compare patient outcomes between diabetic and non diabetic transplant recipients, and to determine the effect of age and era on patient survival. METHODS: This population cohort study included all primary kidney-only transplant recipients included in the Australia and New Zealand Dialysis and Transplant registry between Jan 1, 1994, and Dec 31, 2012. The primary outcomes were all-cause mortality and death with functioning graft. Associations between outcomes and diabetes status were examined using adjusted Cox regression, and interactions between diabetes status and transplant era and recipient age were examined. FINDINGS: Of 10 714 transplant recipients, 985 (9%) had type 2 diabetes. Mortality rates in the first 10 years after transplantation were higher in recipients with diabetes (25.3 per 100 recipients) compared to those without diabetes (11.5 per 100 recipients). Compared with recipients without diabetes, the adjusted hazard ratios (HR) for all-cause mortality and death with a functioning graft in recipients with diabetes were 1.60 (95% CI 1.37 1.86; p<0.0001) and 1.54 (1.28-1.85 p<0.0001), respectively. The association between diabetes status, all-cause mortality, and death with a functioning graft was modified by recipient age (pinteraction<0.0001), with the highest risk in recipients with diabetes aged younger than 40 years (adjusted HR 5.16 [95% CI 2.84-9.35], p<0.0001; and 9.83 [4.51-21.43], p<0.0001; for all-cause mortality and death with a functioning graft, respectively). Risk was increased to a lesser extent in recipients with diabetes aged older than 55 years (adjusted HR 1.41 [95% CI 1.17-1.71; p=0.002] and 1.27 [1.02-1.59; p=0.03], for all-cause mortality and death with a functioning graft, respectively). Transplant era did not modify the association between diabetes status and mortality. INTERPRETATION: Kidney transplant recipients with type 2 diabetes had substantially poorer patient survival, with 5-year mortality rates exceeding those for non-diabetic recipients by over two times. The magnitude of this survival disadvantage was greatest in recipients with diabetes aged less than 40 years. By contrast with the general population, there was no evidence of improvement in mortality over time among people with type 2 diabetes following kidney transplantation. FUNDING: None. PMID- 28010786 TI - Type 2 diabetes: a two-headed snake in kidney transplant recipients? PMID- 28010787 TI - The Journal celebrates 85 years. PMID- 28010788 TI - Infection and inflammation are associated with long-term morbidities. PMID- 28010789 TI - 50 Years Ago in The Journal of Pediatrics: Adrenocortical Neoplasms with Hemihypertrophy, Brain Tumors, and Other Disorders. PMID- 28010790 TI - 50 Years Ago in The Journal of Pediatrics: The Diagnosis of Complete Extrahepatic Obstruction by Rose Bengal I131. PMID- 28010791 TI - 50 Years Ago in The Journal of Pediatrics: Conference on Treatment of Phenylketonuria. PMID- 28010792 TI - 50 Years Ago in The Journal of Pediatrics: Dysgammaglobulinemic Antibody Deficiency Syndrome: Increased gammaM-Globulins and Decreased gammaG- and gammaA Globulins. PMID- 28010793 TI - Iron deficiency: a new alternative when oral iron fails. PMID- 28010794 TI - Ventilating smarter, not harder. PMID- 28010795 TI - 50 Years Ago in The Journal of Pediatrics: Pituitary-Adrenal Responsiveness after Corticosteroid Therapy in Children with Nephrosis. PMID- 28010796 TI - Preschool bedtime associated with adolescent obesity. PMID- 28010797 TI - Ibuprofen use in viral infection is associated with subsequent empyema. PMID- 28010798 TI - US Preventive Task Force cites insufficient evidence for pediatric lipid screening. PMID- 28010799 TI - Long-acting beta agonists do not increase serious asthma-related event risk. PMID- 28010801 TI - Correction. PMID- 28010800 TI - Gadolinium magnetic resonance imaging during pregnancy associated with adverse neonatal and post-neonatal outcomes. PMID- 28010802 TI - 50 Years Ago in The Journal of Pediatrics: The Incidence of Neonatal Hypoglycemia A Completed Survey. PMID- 28010803 TI - 50 Years Ago in The Journal of Pediatrics: The Incidence of Neonatal Hypoglycemia A Completed Survey. PMID- 28010804 TI - 50 Years Ago in The Journal of Pediatrics: Salmonellosis in Infants and Children. PMID- 28010805 TI - Hybrid cooling vest for cooling between exercise bouts in the heat: Effects and practical considerations. AB - While continuous cooling strategies may induce some ergonomic problems to occupational workers, cooling between work bouts may be an alternative for cooling them down in hot environments. The purpose of this study was to assess the effects of wearing a newly designed hybrid cooling vest (HCV) between two bouts of exercise. Inside a climatic chamber set at an air temperature of 37 degrees C and a relative humidity of 60%, twelve male participants underwent two bouts of intermittent exercise interspersed with a 30min between-bout recovery session, during which HCV or a passive rest without any cooling (PAS) was administered. The results indicated that thermoregulatory, physiological, and perceptual strains were significantly lower in HCV than those in PAS during the recovery session (p<=0.022), which were accompanied with a large effect of cooling (Cohen's d=0.84-2.11). For the second exercise bout, the exercise time following HCV (22.13+/-12.27min) was significantly longer than that following PAS (11.04+/-3.40min, p=0.005, d=1.23) During this period, core temperature Tc was significantly lower by 0.14+/-0.0.15 degrees C in HCV than that in PAS. The heart rate drift over time was declined by 2+/-2bpmmin-1 (p=0.001, d=1.00) and the rise in physiological strain index was reduced by 0.11+/-0.12unitmin-1 (p=0.010, d=0.96) following the use of HCV. These findings suggested that using HCV could accelerate between-bout recovery and improve subsequent exercise performance by the enlarged body core temperature margin and blunted cardiovascular drift. PMID- 28010806 TI - Cerebral responses to exercise and the influence of heat stress in human fatigue. AB - There are a number of mechanisms thought to be responsible for the onset of fatigue during exercise-induced hyperthermia. A greater understanding of the way in which fatigue develops during exercise could be gleaned from the studies which have examined the maintenance of cerebral blood flow through the process of cerebral autoregulation. Given that cerebral blood flow is a measure of the cerebral haemodynamics, and might reflect a level of brain activation, it is useful to understand the implications of this response during exercise and in the development of fatigue. It is known that cerebral blood flow is significantly altered under certain conditions such as altitude and exacerbated during exercise induced - hyperthermia. In this brief review we consider the processes of cerebral autoregulation predominantly through the measurement of cerebral blood flow and contrast these responses between exercise undertaken in normothermic versus heat stress conditions in order to draw some conclusions about the role cerebral blood flow might play in determining fatigue. PMID- 28010807 TI - Relationships between ambient conditions, thermal status, and feed intake of cattle during summer heat stress with access to shade. AB - Heat stress in feedlot cattle is known to reduce their performance. The challenge comes in determining reliable predictors of current and near-future changes in thermal status and performance. A 42-d study, using crossbred (Bos taurus) steers was conducted during summer months (July through August) to identify best environmental determinants of rumen temperature (Trumen) and feed intake (FI) in feedlot cattle with access to shade. A further goal was to define the relationship between Trumen and FI. Shade coverage was approximately 50%, and all animals were provided standard feedlot diets and water ad libitum. Intraruminal telemetric boluses recorded Trumen several times each hour. Ear tags, telemetrically connected to a feed monitoring system, provided FI data using RFID technology. Data loggers recorded ambient conditions in sun and shade, along with black globe temperature. Regression analyses identified daylight black globe and air temperatures in shade, with one hour delays, as the best predictors of Trumen. Prediction of FI was much less reliable. Unexpectedly, Trumen was not superior to ambient variables in predicting FI. Maximum daily temperature humidity index, calculated using BG in sun with a 5-d lag, was the best significant predictor of FI. These results indicate for feedlot cattle that although air temperature alone in the shade may be the best predictor of Trumen in the heat, black globe temperature in the sun may be a better determinant of feed intake over time. Additional studies are needed to verify the delayed FI response which seems unusually long. PMID- 28010808 TI - Acute effects of temperature and hypercarbia on cutaneous and branchial gas exchange in the South American lungfish, Lepidosiren paradoxa. AB - The South American lungfish, Lepidosiren paradoxa inhabits seasonal environments in the Central Amazon and Parana-Paraguay basins that undergo significant oscillations in temperature throughout the year. They rely on different gas exchange organs, such as gills and skin for aquatic gas exchange while their truly bilateral lungs are responsible for aerial gas exchange; however, there are no data available on the individual contributions of the skin and the gills to total aquatic gas exchange in L. paradoxa. Thus, in the present study we quantify the relative contributions of skin and gills on total aquatic gas exchange during warm (35 degrees C) and cold exposure (20 degrees C) in addition to the effects of aerial and aquatic hypercarbia on aquatic gas exchange and gill ventilation rate (fG; 25 degrees C), respectively. Elevated temperature (35 degrees C) caused a significant increase in the contribution of cutaneous (from 0.61+/-0.13 to 1.34+/-0.26ml. STPD.h-1kg-1) and branchial (from 0.54+/-0.17 to 1.73+/-0.53ml. STPD.h-1kg-1) gas exchange for VCO2 relative to the lower temperature (20 degrees C), while VO2 remained relatively unchanged. L. paradoxa exhibited a greater branchial contribution in relation to total aquatic gas exchange at lower temperatures (20 and 25 degrees C) for oxygen uptake. Aerial hypercarbia decreased branchial VO2 whereas branchial VCO2 was significantly increased. Progressive increases in aquatic hypercarbia did not affect fG. This response is in contrast to increases in pulmonary ventilation that may offset any increase in arterial partial pressure of CO2 owing to CO2 loading through the animals' branchial surface. Thus, despite their reduced contribution to total gas exchange, cutaneous and branchial gas exchange in L. paradoxa can be significantly affected by temperature and aerial hypercarbia. PMID- 28010809 TI - Deeply torpid bats can change position without elevation of body temperature. AB - Because body temperature is tightly coupled to physiological function, hibernating animals entering deep torpor are typically immobile. We analysed thermal behaviour and locomotory activity of hibernating greater mouse-eared bats Myotis myotis and found two types of movement behaviour related to body temperature, i.e. movement at high fur temperature and at low fur temperatures (Tflow; <5 degrees C). First Tflow movements appeared at the beginning of March and often occurred during long torpor bouts. In most cases, Tflow events represented slow displacements between clusters of bats. In several cases, however, departure or arrivals from and into clusters was also recorded without any elevation in body temperature. Distance travelled, flight duration and speed of locomotion during Tflow events was lower than in high fur temperature events. Such behaviour could allow bats to save energy long-term and prolong torpor bouts. Tflow movement in torpid bats significantly changes our understanding of basic hibernation principles and we strongly recommend further studies on the subject. PMID- 28010810 TI - Conventional and novel body temperature measurement during rest and exercise induced hyperthermia. AB - Despite technological advances in thermal sensory equipment, few core temperature (TCORE) measurement techniques have met the established validity criteria in exercise science. Additionally, there is debate as to what method serves as the most practically viable, yet upholds the proposed measurement accuracy. This study assessed the accuracy of current and novel TCORE measurement techniques in comparison to rectal temperature (TREC) as a reference standard. Fifteen well trained subjects (11 male, 4 female) completed 60min of exercise at an intensity equating to the lactate threshold; measured via a discontinuous exercise test. TREC was significantly elevated from resting values (37.2+/-0.3 degrees C) at the end of moderate intensity exercise (39.6+/-0.04 degrees C; P=0.001). Intestinal telemetric pill (TPILL) temperature and temporal artery temperature (TTEM) did not differ significantly from TREC at rest or during exercise (P>0.05). However, aural canal temperature (TAUR) and thermal imaging temperature (TIMA) were both significantly lower than TREC (P<0.05). Bland Altman analysis revealed only TPILL was within acceptable limits of agreement (mean bias; 0.04 degrees C), while TTEM, TAUR and TIMA demonstrated mean bias values outside of the acceptable range (>0.27 degrees C). Against TREC, these results support the use of TPILL over all other techniques as a valid measure of TCORE at rest and during exercise induced hyperthermia. Novel findings illustrate that TIMA (when measured at the inner eye canthus) shows poor agreement to TREC during rest and exercise, which is similar to other 'surface' measures. PMID- 28010811 TI - Using GAMM to examine inter-individual heterogeneity in thermal performance curves for Natrix natrix indicates bet hedging strategy by mothers. AB - The thermal performance curve (TPC) illustrates the dependence on body- and therefore environmental- temperature of many fitness-related aspects of ectotherm ecology and biology including foraging, growth, predator avoidance, and reproduction. The typical thermal performance curve model is linear in its parameters despite the well-known, strong, non-linearity of the response of performance to temperature. In addition, it is usual to consider a single model based on few individuals as descriptive of a species-level response to temperature. To overcome these issues, we used generalized additive mixed modeling (GAMM) to estimate thermal performance curves for 73 individual hatchling Natrix natrix grass snakes from seven clutches, taking advantage of the structure of GAMM to demonstrate that almost 16% of the deviance in thermal performance curves is attributed to inter-individual variation, while only 1.3% is attributable to variation amongst clutches. GAMM allows precise estimation of curve characteristics, which we used to test hypotheses on tradeoffs thought to constrain the thermal performance curve: hotter is better, the specialist generalist trade off, and resource allocation/acquisition. We observed a negative relationship between maximum performance and performance breadth, indicating a specialist-generalist tradeoff, and a positive relationship between thermal optimum and maximum performance, suggesting "hotter is better". There was a significant difference among matrilines in the relationship between Area Under the Curve and maximum performance - relationship that is an indicator of evenness in acquisition or allocation of resources. As we used unfed hatchlings, the observed matriline effect indicates divergent breeding strategies among mothers, with some mothers provisioning eggs unequally resulting in some offspring being better than others, while other mothers provisioned the eggs more evenly, resulting in even performance throughout the clutch. This observation is reminiscent of bet-hedging strategies, and implies the possibility for intra clutch variability in the TPCs to buffer N. natrix against unpredictable environmental variability. PMID- 28010812 TI - Influence of temperature on female, embryonic and hatchling traits in syntopic newts, Ichthyosaura alpestris and Lissotriton vulgaris. AB - Amphibian populations have been declining globally for the last several decades, and climate change is often regarded as one of the most important factors driving these declines. Amphibians are particularly sensitive to climatic changes due to their physiological, ecological and behavioral characteristics. Here we performed a laboratory experiment to investigate how temperature affects ovipositing females, eggs and hatchlings in two syntopic populations of alpine newts, Ichthyosaura alpestris, and smooth newts, Lissotriton vulgaris. Female newts were assigned to two different oviposition temperatures (11 degrees C and 14 degrees C) for the duration of their oviposition period. Deposited eggs were equally divided and assigned to three different incubation temperatures (11 degrees C, 14 degrees C and 17 degrees C). We hypothesized that oviposition will be affected by temperature, that the combination of different oviposition and incubation temperatures may have an effect on embryonic and hatchling traits (embryonic mortality, days to hatch and hatchling length), and that these effects might differ between the two newt species. Temperature affected the number of deposited eggs in smooth newts, but not in alpine newts. Larval hatching success was not affected by oviposition or incubation temperature. Temperature effects on hatching time and hatchling length differed between the two species. These results suggest that temperature changes may have disparate effects on amphibian reproduction, even in syntopic taxa. PMID- 28010813 TI - Changes in systolic arterial pressure variability are associated with the decreased aerobic performance of rats subjected to physical exercise in the heat. AB - Enhanced cardiovascular strain is one of the factors that explains degraded aerobic capacity in hot environments. The cardiovascular system is regulated by the autonomic nervous system, whose activity can be indirectly evaluated by analyzing heart rate variability (HRV) and systolic arterial pressure (SAP) variability. However, no study has addressed whether HRV or SAP variability can predict aerobic performance during a single bout of exercise. Therefore, this study aimed to investigate whether there is an association between cardiovascular variability and performance in rats subjected to treadmill running at two ambient temperatures. In addition, this study investigated whether the heat-induced changes in cardiovascular variability and reductions in performance are associated with each other. Male Wistar rats were implanted with a catheter into their carotid artery for pulsatile blood pressure recordings. After recovery from surgery, the animals were subjected to incremental-speed exercise until they were fatigued under temperate (25 degrees C) and hot (35 degrees C) conditions. Impaired performance and exaggerated cardiovascular responses were observed in the hot relative to the temperate environment. Significant and negative correlations between most of the SAP variability components (standard deviation, variance, very low frequency [VLF], and low frequency [LF]) at the earlier stages of exercise and total exercise time were observed in both environmental conditions. Furthermore, the heat-induced changes in the sympathetic components of SAP variability (VLF and LF) were associated with heat-induced impairments in performance. Overall, the results indicate that SAP variability at the beginning of exercise predicts the acute performance of rats. Our findings also suggest that heat impairments in aerobic performance are associated with changes in cardiovascular autonomic control. PMID- 28010814 TI - Fire service instructor's undergarment choice to reduce Interleukin-6 and minimise physiological and perceptual strain. AB - Fire Service Instructors frequently experience high levels of physiological and perceptual strain during live fire exposures. Instructors are also at risk of cardiovascular illnesses, with cardiac death being the greatest cause of fire fighter death. Current practice for UK instructors is to select undergarment type based on personal preference, between a boiler suit (BOILER) and a wicking base layer (WBL). Research suggests that shorts and t-shirt (SHORTS) may also be a beneficial alternative undergarment choice. The UK South East Fire Service requested an investigation to identify if undergarment selection can lessen the strain experienced by instructors, and reduce the acute inflammatory response to fire exposures. Eight males completed three 45min sessions in a heat chamber (49.5+/-1.4 degrees C and 16.9+/-4.3% RH) whilst performing intermittent walking. At the end of heat exposure change in heart rate was not effected by garment type (p=0.061, etap2=0.373). Change in rectal temperature was different between garments (p=0.009, etap2=0.271), with trends suggesting that BOILER resulted in a greater change (1.03+/-0.60 degrees C) than SHORTS (0.76+/-0.37 degrees C, p=0.589, d=0.21) and WBL (0.72+/-0.33 degrees C, p=0.545, d=0.25). Interleukin-6 post exposure was greater for BOILER (6.96+/-0.28pgmL-1) than both SHORTS (6.59+/ 0.30pgmL-1, p=0.043, d=0.42) and WBL (6.45+/-0.43pgmL-1, p=0.031, d=0.51). Overall, undergarment type had little impact on physiological or perceptual strain. However, wearing WBL or SHORTS may reduce the inflammatory response, and consequently decrease the risk of cardiovascular events. PMID- 28010815 TI - An assessment of skin temperature gradients in a tropical primate using infrared thermography and subcutaneous implants. AB - Infrared thermography has become a useful tool to assess surface temperatures of animals for thermoregulatory research. However, surface temperatures are an endpoint along the body's core-shell temperature gradient. Skin and fur are the peripheral tissues most exposed to ambient thermal conditions and are known to serve as thermosensors that initiate thermoregulatory responses. Yet relatively little is known about how surface temperatures of wild mammals measured by infrared thermography relate to subcutaneous temperatures. Moreover, this relationship may differ with the degree that fur covers the body. To assess the relationship between temperatures and temperature gradients in peripheral tissues between furred and bare areas, we collected data from wild mantled howling monkeys (Alouatta palliata) in Costa Rica. We used infrared thermography to measure surface temperatures of the furred dorsum and bare facial areas of the body, recorded concurrent subcutaneous temperatures in the dorsum, and measured ambient thermal conditions via a weather station. Temperature gradients through cutaneous tissues (subcutaneous-surface temperature) and surface temperature gradients (surface-ambient temperature) were calculated. Our results indicate that there are differences in temperatures and temperature gradients in furred versus bare areas of mantled howlers. Under natural thermal conditions experienced by wild animals, the bare facial areas were warmer than temperatures in the furred dorsum, and cutaneous temperature gradients in the face were more variable than the dorsum, consistent with these bare areas acting as thermal windows. Cutaneous temperature gradients in the dorsum were more closely linked to subcutaneous temperatures, while facial temperature gradients were more heavily influenced by ambient conditions. These findings indicate that despite the insulative properties of fur, for mantled howling monkeys surface temperatures of furred areas still demonstrate a relationship with subcutaneous temperatures. Given that most mammals possess dense fur, this provides insight for using infrared imaging in thermoregulatory studies of wild animals lacking bare skin. PMID- 28010816 TI - Expression of HSP70 genes in skin of zebu (Tharparkar) and crossbred (Karan Fries) cattle during different seasons under tropical climatic conditions. AB - Skin is most important environmental interface providing a protective envelope to animals. It's always under the influence of both internal and external stressors. Heat shock proteins (HSP) are highly conserved stress proteins which play crucial roles in environmental stress tolerance and thermal adaptation. Present study was planned to observe the relative mRNA expression of inducible (HSP70.1 and HSP70.2) and constitutive (HSP70.8) HSP in skin of zebu (Tharparkar) and crossbred (Karan Fries) cattle during different seasons. Skin biopsies were collected from rump region of each animal, aseptically during winter, spring and summer season. Quantitative real time polymerase chain reaction was performed to examine the gene expression of constitutive (HSP70.8) and inducible (HSP70.1 and HSP70.2) HSP in skin of both the breeds during different seasons. Present study observed higher expression of both constitutive and inducible HSP genes in both the breeds during summer and winter than spring season, but magnitude of increase was higher during summer than winter. During summer season, expression pattern of HSPs in skin showed breed differences, where constitutive HSP expression was higher in Tharparkar than Karan Fries and that of inducible HSP was higher in Karan Fries than Tharparkar. Hence, present study suggested that HSP may be conveniently used as biomarkers for assessing protective response of skin against heat stress in zebu and crossbred cattle. Variation in expression between breeds is associated with their heat tolerance and thermal adaptability. In summary, skin of zebu cattle (Tharparkar) is more resistant to summer stress than crossbred (Karan Fries), providing greater protection against heat stress during summer season. Superior skin protective mechanism of zebu (Tharparkar) than crossbred (Karan-Fries) cattle against heat stress may contribute to superior adaptability of zebu cattle to tropical climatic conditions than crossbreed. PMID- 28010817 TI - A critical review of the use and performance of different function types for modeling temperature-dependent development of arthropod larvae. AB - Temperature-dependent development influences production rates of arthropods, including crustaceans important to fisheries and agricultural pests. Numerous candidate equation types (development functions) exist to describe the effect of temperature on development time, yet most studies use only a single type of equation and there is no consensus as to which, if any model predicts development rates better than the others, nor what the consequences of selecting a potentially incorrect model equation are on predicted development times. In this study, a literature search was performed of studies fitting development functions to development data of arthropod larvae (99 species). The published data of most (79) of these species were then fit with 33 commonly-used development functions. Overall performance of each function type and consequences of using a function other than the best one to model data were assessed. Performance was also related to taxonomy and the range of temperatures examined. The majority (91.1%) of studies were found to not use the best function out of those tested. Using the incorrect model lead to significantly less accurate (e.g., mean difference+/-SE 85.9+/-27.4%, range: -1.7 to 1725.5%) predictions of development times than the best function. Overall, more complex functions performed poorly relative to simpler ones. However, performance of some complex functions improved when wide temperature ranges were tested, which tended to be confined to studies of insects or arachnids compared with those of crustaceans. Results indicate the biological significance of choosing the best-fitting model to describe temperature-dependent development time data. PMID- 28010818 TI - Geographic variation and acclimation effects on thermoregulation behavior in the widespread lizard Liolaemus pictus. AB - Populations at the warm range margins of the species distribution may be at the greatest risks of extinction from global warming unless they can tolerate extreme environmental conditions. Yet, some studies suggest that the thermal behavior of some lizard species is evolutionarily rigid. During two successive years, we compared the thermal biology of two populations of Liolaemus pictus living at the northern (warmer) and one population living at the southern (colder) range limits, thus spanning an 800km latitudinal distance. Populations at the two range margins belong to two deeply divergent evolutionary clades. We quantified field body temperatures (Tb), laboratory preferred body temperatures (PBT), and used operative temperature data (Te) to calculate the effectiveness of thermoregulation (E). During one year in all populations, we further exposed half of the lizards to a cold or a hot acclimation treatment to test for plasticity in the thermal behavior. The environment at the southern range limit was characterized by cooler weather and lower Te. Despite that, females had higher Tb and both males and females had higher PBT in the southernmost population (or clade) than in the northernmost populations. Acclimation to cold conditions led to higher PBT in all populations suggesting that plastic responses to thermal conditions, instead of evolutionary history, may contribute to geographic variation. Lizards regulated moderately well their body temperature (E~0.7): they avoided warm microhabitats in the northern range but capitalized on warm microhabitats in the southern range. We review literature data to show that Liolaemus species increase their thermoregulation efficiency in thermally challenging environments. Altogether, this indicates that habitats of low thermal quality generally select against thermoconformity in these lizards. PMID- 28010819 TI - Transition duration of ingested deuterium oxide to eccrine sweat during exercise in the heat. AB - The time necessary for the initial appearance of ingested water as sweat during exercise in the heat remains unknown. Based on the current literature, we estimated fluid transition through the body, from ingestion to appearance as sweat, to have a minimum time duration of approximately three minutes. The purpose of this study was to test this prediction and identify the time necessary for the initial enrichment of deuterium oxide (D2O) in sweat following ingestion during exercise in the heat. Eight participants performed moderate intensity (40% of maximal oxygen uptake) treadmill exercise in an environmental chamber (40 degrees C, 40% rH) to induce active sweating. After fifteen minutes, while continuing to walk, participants consumed D2O (0.15mlkg-1) in a final volume of 50ml water. Scapular sweat samples were collected one minute prior to and ten minutes post-ingestion. Samples were analyzed for sweat D2O concentration using isotope ratio mass spectrometry and compared to baseline. Mean+/-SD ? sweat D2O concentration at minutes one and two post-ingestion were not significantly higher than baseline (0min). Minutes three (9+/-3ppm) through ten (23+/-11ppm) post ingestion had ? sweat D2O concentrations significantly (P<0.05) higher than baseline. Such results suggest that ingested water rapidly transports across the mucosal membrane of the alimentary canal into the vasculature space, enters the extravascular fluid, and is actively secreted by the eccrine sweat glands onto the surface of the skin for potential evaporation in as little as three minutes during exercise in the heat. PMID- 28010820 TI - A parametric study of thermal therapy of skin tissue. AB - A thermal therapy for cancer in skin tissue is numerically investigated using three bioheat conduction models, namely Pennes, thermal wave and dual-phase lag models. A laser is applied at the surface of the skin for cancer ablation, and the temperature and thermal damage distributions are predicted using the three bioheat models and two different modeling approaches of the laser effect. The first one is a prescribed surface heat flux, in which the tissue is assumed to be highly absorbent, while the second approach is a volumetric heat source, which is reasonable if the scattering and absorption skin effects are of similar magnitude. The finite volume method is applied to solve the governing bioheat equation. A parametric study is carried out to ascertain the effects of the thermophysical properties of the cancer on the thermal damage. The temperature distributions predicted by the three models exhibit significant differences, even though the temperature distributions are similar when the laser is turned off. The type of bioheat model has more influence on the predicted thermal damage than the type of modeling approach used for the laser. The phase lags of heat flux and temperature gradient have an important influence on the results, as well as the thermal conductivity of the cancer. In contrast, the uncertainty in the specific heat and blood perfusion rate has a minor influence on the thermal damage. PMID- 28010821 TI - On the Inconsistency of Burnout Conceptualization and Measurement. PMID- 28010822 TI - Defining and Mitigating Burnout: In Reply to Brisson and Bianchi. PMID- 28010823 TI - Effect of Burnout: In Reply to Lefor. PMID- 28010824 TI - Resident Burnout. PMID- 28010825 TI - Surgical Costs. PMID- 28010828 TI - The Use of Hijama (Wet Cupping) in Alternative and Complementary Medicine: Efficacious or Perilous? PMID- 28010827 TI - "Is It All Right for Me to Have a Baby or Not?": Men Living With HIV Discuss Fertility Desires and Interactions With Providers. AB - To our knowledge, no study in the United States has qualitatively examined fertility desires, experiences communicating with health care providers about sexual and reproductive health, and attitudes toward reproductive counseling and services in men living with HIV (MLWH) who have sex with women. We conducted focus groups and interviews with MLWH (N = 17) who have sex with women seeking HIV care in San Francisco. The men conveyed limited awareness of safer conception strategies. While many men expressed the desire to have a child, most reported that their providers had not discussed reproduction with them. Participants highlighted the lack of HIV services for men who have sex with women and the need for improved reproductive counseling. We make recommendations for providers who work with MLWH who have sex with women and for patient-centered materials on safer conception, sexual HIV transmission risk reduction, and family planning strategies. PMID- 28010829 TI - A New Document on Smallpox Vaccination. AB - Modern medicine owes much to the invaluable heritage of the practices of past generations and their achievements that have now become medical rules. In the case of vaccination, there is evidence that the nomads of Baluchistan (Southeast Iran) demonstrated natural immunization against cowpox, a practice that was later introduced to the medical community by Edward Jenner. Although the discoveries of scientists cannot be ignored, they are certainly based on the traditional and indigenous experiences that have been transferred from generation to generation until reaching us. PMID- 28010830 TI - Anatomical Features of the Interscapular Area Where Wet Cupping Therapy Is Done and Its Possible Relation to Acupuncture Meridians. AB - Although wet cupping has been a treatment for centuries, its mechanism of action is not well understood. Because the anatomical features of the wet-cupping area might play a role in its mechanism, we focus on the features of the interscapular area in which a common type of wet-cupping therapy (WCT), called Hijamat-e-Aam in Iranian medicine, is usually applied and discuss the possible relation of those features to the acupuncture meridians. We gathered and analyzed data from reliable textbooks on modern medicine with a focus on the anatomical features of the interscapular area, topics related to WTC in Iranian medicine, and acupuncture sources obtained by searching PubMed, Google-Scholar, and Science Direct. The interscapular area used for WCT was found to have special features: brown adipose tissue, immediate proximity to sympathetic ganglia, passage of the thoracic duct, two important acupuncture meridians, and proximity to the main vessel divisions carrying blood from the heart and the brain. These features indicate that the interscapular application of WCT not only discharges waste materials through a shifting of blood to the site after application of a traction force but also invigorates the body's metabolism, increases immunity, and regulates blood biochemistry, which are desired therapeutic effects of WCT. PMID- 28010831 TI - Technical Challenges in Current Primo Vascular System Research and Potential Solutions. AB - Since Bonghan Kim's discovery of the Bonghan system (BHS) in the 1960s, numerous reports have suggested that the system is fundamental for maintaining mammalian life. The BHS is a circulatory system independent of the blood or the lymphatic system, forms an extensive network throughout the entire mammalian body, has been reported to be the acupuncture meridian, stores distinct types of stem cells, and appears to have some roles in cancer metastasis. Despite Kim's first report having been published as early as 1962, research progress has been rather slow mainly because the system is very small and translucent, making it optically difficult to distinguish it from the hemoglobin-rich surrounding tissues. Unfortunately, Kim did not describe in detail the methods that he used for identifying and harvesting the system and the components of the system. In 2000, Kwang-Sup Soh reopened the BHS research, and since then, new and important scientific findings on the system have been reported, and many of Kim's results have been verified. In 2010, the BHS was renamed the primo vascular system. Nevertheless, good tools to properly deal with this system are still lacking. In this article, we address some of the technical difficulties involved in studying the primo vascular system and attempt to discuss potential ways to overcome those difficulties. PMID- 28010832 TI - Effect of Needling at CV-12 (Zhongwan) on Blood Glucose Levels in Healthy Volunteers: A Pilot Randomized Placebo Controlled Trial. AB - INTRODUCTION: Acupuncture, a key part of traditional Chinese medicine, is used to relieve symptoms of diabetes mellitus. The aim of this study was to evaluate the effect of needling CV-12 (Zhongwan) on blood glucose levels in healthy volunteers. MATERIALS AND METHODS: Thirty-six individuals were recruited and randomized into either the acupuncture group or the placebo control group. The participants in the acupuncture group were needled at CV-12 (4 cun above the center of the umbilicus), and those in the placebo control group were needled at a nonexisting "sham" point on the right side of the abdomen (1 cun beside the CV 12)-a nonacupuncture point. For both groups, the needle was retained for 20 minutes without stimulation. Assessments were performed prior to and after the intervention. Statistical analysis was performed using the Statistical Package for the Social Sciences, version 16. RESULTS: The result of this study showed a mild reduction in random blood glucose (RBG) levels in the acupuncture group and a mild increase in RBG levels in the placebo control group. However, these changes were not statistically significant both within and between groups. CONCLUSION: The result of this study suggests that although 20 minutes of needling at CV-12 without stimulation produced a mild reduction in RBG levels in healthy volunteers, it did not produce a statistically significant result. PMID- 28010833 TI - Effects of Distilled Cervi Pantotrichum Cornu and Rehmannia glutinosa Pharmacopuncture at GB21 (Jianjing) on Heart Rate Variability: A Randomized and Double-blind Clinical Trial. AB - BACKGROUND/PURPOSE: The purpose of this study was to use heart rate variability (HRV) to investigate the effects of distilled Cervi Pantotrichum Cornu pharmacopuncture and Rehmannia glutinosa pharmacopuncture on the autonomic nervous system. MATERIALS AND METHODS: Forty healthy male participants were divided into two groups: the participants of the C-group received distilled Cervi Pantotrichum Cornu pharmacopuncture and those of the R-group received Rehmannia glutinosa pharmacopuncture. The study design was a randomized, double-blind clinical trial. Each participant received one of the two solutions injected at GB21 (Jianjing). The changes in HRV were measured seven times using the QECG-3: LXC3203 system (LAXTHA Inc. Korea). Time-dependent changes in HRV for each group were analyzed using the paired t test (significance level: p < 0.05), and the difference in the HRV fluctuations between the two experimental groups was evaluated using the independent sample test (significance level: p < 0.05). RESULTS AND CONCLUSION: The results showed that Cervi Pantotrichum Cornu pharmacopuncture and Rehmannia glutinosa pharmacopuncture tended to activate the autonomic nervous system within the normal range. Cervi Pantotrichum Cornu pharmacopuncture tended to activate the sympathetic nervous system, whereas Rehmannia glutinosa pharmacopuncture tended to activate both the sympathetic and parasympathetic nervous systems. PMID- 28010834 TI - Acupuncture Treatment of a Metatarsus Proximal End Fracture: A Case Report. AB - A tuberosity fracture is an avulsion fracture in an area 1.5 cm proximal to the fifth metatarsus. Six to eight weeks of immobilization may be required. A patient with a short leg plaster splint came to our clinic because of pain. The patient had a diagnosis of a fifth metatarsus fracture. Significant edema, fluctuation on the dorsolateral section of the left foot, and red color changes (0.2- to 0.3-cm diameter) on the skin of the anterolateral tibial area of the affected leg were noted. The locations of these skin changes corresponded to the GB34 (Yanglingguan) and the ST37 (Shanqiuxu) acupoints. The patient was successfully treated with acupuncture at these and several other acupoints. After 3 weeks (i.e., eight sessions), the patient returned to her routine life without any pain. This interesting case of metatarsus proximal end fracture shows that some acupoints may be visible during the progress of the disease. We used these acupoints in acupuncture treatment. Pain and edema were rapidly relieved, which may be attributable to the recovery of the lymphatic system in the affected area via acupuncture treatment. PMID- 28010835 TI - Treatment of an Adult Patient with Atopic Dermatitis Using Traditional Korean Medicine, Especially Sa-Am Acupuncture. AB - Atopic dermatitis is known not to respond well to many clinical treatments. In this report, we present the case of an adult woman with atopic dermatitis who was effectively treated by using traditional Korean medicine (TKM). The patient was diagnosed with psoriasis based on lung dryness and heat and heart fire. The patient underwent acupuncture treatment based on the theory of Sa-Am acupuncture. Two meridians, the hand tai-yin meridian and the foot tai-yang meridian, were used to control lung dryness, lung heat, and heart fire. Using the LU9 and SP3 acupoints to tonify the hand tai-yin meridian, we could sedate lung dryness and heat, and using the BL67 acupoint to tonify the foot tai-yang bladder meridian, we could sedate heart fire. With this treatment, her symptoms completely disappeared in about 6 months. This case report provides a preliminary indication that TKM, especially Sa-Am acupuncture, can be effective for treating patients with psoriasis. Thus, further study is warranted. PMID- 28010836 TI - Acupuncture in the Management of Intraoperative Nausea and Vomiting. AB - Intraoperative and postoperative nausea and vomiting (IONV and PONV, respectively) are common complications of anesthesia with significant associated morbidity. Strategies for their prevention and treatment have been organized in pharmacological and nonpharmacological measures. Acupuncture at PC6 has demonstrated efficacy in randomized trials, although evidence regarding its efficacy in treating IONV and PONV has not yet been fully established. We present the case of a patient who underwent peripheral vascular surgery on a limb under a subarachnoid block and who developed IONV refractory to conventional pharmacological therapy. Acupuncture at the PC6 and the TF4 points proved to be an effective alternative treatment to conventional pharmacological treatment and resulted in almost immediate cessation of IONV. PMID- 28010838 TI - Microplasma-based flowing atmospheric-pressure afterglow (FAPA) source for ambient desorption-ionization mass spectrometry. AB - A new direct-current microplasma-based flowing atmospheric pressure afterglow (FAPA) source was developed for use in ambient desorption-ionization mass spectrometry. The annular-shaped microplasma is formed in helium between two concentric stainless-steel capillaries that are separated by an alumina tube. Current-voltage characterization of the source shows that this version of the FAPA operates in the normal glow-discharge regime. A glass surface placed in the path of the helium afterglow reaches temperatures of up to approximately 400 degrees C; the temperature varies with distance from the source and helium flow rate through the source. Solid, liquid, and vapor samples were examined by means of a time-of-flight mass spectrometer. Results suggest that ionization occurs mainly through protonation, with only a small amount of fragmentation and adduct formation. The mass range of the source was shown to extend up to at least m/z 2722 for singly charged species. Limits of detection for several small organic molecules were in the sub-picomole range. Examination of competitive ionization revealed that signal suppression occurs only at high (mM) concentrations of competing substances. PMID- 28010837 TI - Raptor Acupuncture for Treating Chronic Degenerative Joint Disease. AB - A permanently captive 21-year-old male bald eagle was diagnosed with chronic degenerative joint disease in the right stifle with severe lameness (Grade 5) based on radiography. Clinical signs included decreased movement, vocalization, non weight-bearing on the affected limb, inappetence, depression, and pododermatitis on the left foot (bumblefoot, Grade 3). The eagle was treated with anti-inflammatory or analgesic drugs including carprofen and celecoxib. As there was no observed clinical improvement with any of the treatments, acupuncture treatment was provided. The eagle was treated with dry needle acupuncture once per week for 2 months and biweekly for another 2 months. The Traditional Eastern Medicine diagnosis of this eagle was Bony Bi syndrome. The selected acupuncture points were ST 36, LI 4, BL 40, BL 60, GB 34, and Ba Feng (Table 3). The lameness score improved from Grade 5 to Grade 1 after 4 months of acupuncture treatment. The observed pododermatitis improved from Grade 3 to Grade 0. Symptoms including inappetence and vocalizations were significantly reduced over the 4 month period. There was no significant improvement in the radiographic signs. In conclusion, acupuncture may be a potential medical option for permanently captive raptors having musculoskeletal conditions, such as degenerative joint disease. PMID- 28010839 TI - A systematic study on the effect of noise and shift on multivariate figures of merit of second-order calibration algorithms. AB - In the present study, multivariate analytical figures of merit (AFOM) for three well-known second-order calibration algorithms, parallel factor analysis (PARAFAC), PARAFAC2 and multivariate curve resolution-alternating least squares (MCR-ALS), were investigated in simulated hyphenated chromatographic systems including different artifacts (e.g., noise and peak shifts). Different two- and three-component systems with interferences were simulated. Resolved profiles from the target components were used to build calibration curves and to calculate the multivariate AFOMs, sensitivity (SEN), analytical sensitivity (gamma), selectivity (SEL) and limit of detection (LOD). The obtained AFOMs for different simulated data sets using different algorithms were used to compare the performance of the algorithms and their calibration ability. Furthermore, phenanthrene and anthracene were analyzed by GC-MS in a mixture of polycyclic aromatic hydrocarbons (PAHs) to confirm the applicability of multivariate AFOMs in real samples. It is concluded that the MCR-ALS method provided the best resolution performance among the tested methods and that more reliable AFOMs were obtained with this method for the studied chromatographic systems with various levels of noise, elution time shifts and presence of unknown interferences. PMID- 28010840 TI - Electrochemical paper-based peptide nucleic acid biosensor for detecting human papillomavirus. AB - A novel paper-based electrochemical biosensor was developed using an anthraquinone-labeled pyrrolidinyl peptide nucleic acid (acpcPNA) probe (AQ-PNA) and graphene-polyaniline (G-PANI) modified electrode to detect human papillomavirus (HPV). An inkjet printing technique was employed to prepare the paper-based G-PANI-modified working electrode. The AQ-PNA probe baring a negatively charged amino acid at the N-terminus was immobilized onto the electrode surface through electrostatic attraction. Electrochemical impedance spectroscopy (EIS) was used to verify the AQ-PNA immobilization. The paper-based electrochemical DNA biosensor was used to detect a synthetic 14-base oligonucleotide target with a sequence corresponding to human papillomavirus (HPV) type 16 DNA by measuring the electrochemical signal response of the AQ label using square-wave voltammetry before and after hybridization. It was determined that the current signal significantly decreased after the addition of target DNA. This phenomenon is explained by the rigidity of PNA-DNA duplexes, which obstructs the accessibility of electron transfer from the AQ label to the electrode surface. Under optimal conditions, the detection limit of HPV type 16 DNA was found to be 2.3 nM with a linear range of 10-200 nM. The performance of this biosensor on real DNA samples was tested with the detection of PCR-amplified DNA samples from the SiHa cell line. The new method employs an inexpensive and disposable device, which easily incinerated after use and is promising for the screening and monitoring of the amount of HPV-DNA type 16 to identify the primary stages of cervical cancer. PMID- 28010841 TI - Hard cap espresso extraction-stir bar preconcentration of polychlorinated biphenyls in soil and sediments. AB - A Nespresso(c) hard cap espresso machine has been employed for the quantitative extraction of polychlorinated biphenyls (PCBs) from sediments and soils. Sample extraction was performed from five grams of sample in less than 40 s, with 200 mL ethanol 40% (v/v) in water and PCBs were concentrated using stir bar sorptive extraction (SBSE) and determined by thermal desorption-gas chromatography-tandem mass spectrometry (TD-GC-MS-MS). Eleven PCB congeners (28, 52, 77, 80, 81, 101, 118, 138, 153,169, and 180) were determined in soils and sediments with limits of quantification in the 0.03-0.08 ng g-1 range. Extraction efficiency was established by the analysis of soil samples spiked with the studied PCBs at concentrations from 0.1 to 10.0 ng g-1, obtaining quantitative recoveries from 81 to 120% and an adequate precision with relative standard deviations lower than 20%. Certified reference materials and natural samples were analyzed by the proposed hard cap espresso extraction and results were compared with those provided by a reference procedure based on pressurized solvent extraction, obtaining statistically comparable results. Therefore, the use of a hard cap espresso machine in tandem with SBSE and TD-GC-MS-MS allowed a simple, sensitive and quantitative determination of PCBs. PMID- 28010842 TI - Ultra-sensitive HPLC-photochemical reaction-luminol chemiluminescence method for the measurement of secondary amines after nitrosation. AB - A novel method for the determination of secondary amines at the nanomolar level was developed. The method is based on the nitrosation reaction of secondary amines, with the generated N-nitrosamines being measured using an HPLC separation, photochemical reaction, and chemiluminescence detection system. The efficient nitrosation of secondary amines was performed using sodium nitrite (200 mM) and acetic acid (0.8 M) at 80 degrees C over 60 min. Although compounds bearing OH and SH functional groups also underwent the nitrosation reaction, the sensitivity of these compounds was 1000 times lower than that of the secondary amines. Our method was applied to the determination of low molecular weight secondary amines, including dimethylamine, morpholine, pyrrolidine, diethylamine, and piperidine, giving method detection limits of 0.7 nM, 0.2 nM, 0.4 nM, 0.7 nM, and 1.5 nM, respectively. The calibration curves were linear in the range of 5 100 nM. We then applied this method for the detection and quantification of these secondary amines in samples of tap water, river water, treated wastewater, and sea water. Dimethylamine was detected at concentrations up to 15.4 nM, <0.7 nM, and 48.5 nM in tap water, river water, and treated wastewater samples, respectively, with recoveries ranging from 94 to 103%. Other amines were also detected at nanomolar levels. These results indicate that our proposed method can be applied to the analysis of secondary amines in various environmental water samples. To the best of our knowledge, the proposed method is one of the most sensitive and selective methods for the determination of secondary amines without pre-concentration steps. PMID- 28010843 TI - An in-source multiple collision-neutral loss filtering based nontargeted metabolomics approach for the comprehensive analysis of malonyl-ginsenosides from Panax ginseng, P. quinquefolius, and P. notoginseng. AB - The simultaneous identification and quantification of target metabolites from herbal medicines are difficult to implement by the full-scan MS based nontargeted metabolomics approaches. Here an in-source multiple collision-neutral loss filtering (IMC-NLF) based nontargeted metabolomics approach is developed and applied to identify and quantify the variations of malonyl-ginsenosides, a common group of acyl saponins with potential anti-diabetic activity, among Panax ginseng, P. quinquefolius, and P. notoginseng. The key steps of the IMC-NLF strategy are the acquisition of specific high-resolution neutral loss data and the efficient filtering of target precursor ions from the full-scan spectra. Using a hybrid LTQ-Orbitrap mass spectrometer after UHPLC separation, abundant in source product ions, [M-H-CO2]- (due to the vulnerability of the carboxyl group) and [M-H-Mal.]-, were generated at the energies of 70 V and 90 V, respectively. After spectral deconvolution, the generated peak list was screened by dual NLF using a Neutral Loss MS Finder software (NL of 43.9898 Da for CO2 and 86.0004 Da for the malonyl substituent). By combining the precursor ions list-triggered HCD MS/MS and basic hydrolysis, a total of 101 malonyl-ginsenosides (including 69 from P. ginseng, 52 from P. quinquefolius, and 44 from P. notoginseng) were identified or tentatively characterized. The variations of 81 characterized malonyl-ginsenosides among 45 batches of Ginseng samples were statistically analyzed disclosing ten potential markers. It is the first systematic analysis of malonyl-ginsenosides. The IMC-NLF approach by a single analytical platform is promising in targeted analyses of modification-specific metabolites in metabolomics and drug metabolism. PMID- 28010844 TI - Pharmacokinetic study based on a matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight imaging mass microscope combined with a novel relative exposure approach: A case of octreotide in mouse target tissues. AB - Application of imaging mass spectrometry in drug pharmacokinetics remains challenging due to its weak quantitative capability. Herein, an imaging mass microscope (iMScope), equipped with an optical microscope, an atmospheric pressure ion-source chamber for matrix-assisted laser desorption/ionization (AP MALDI) and a hybrid quadrupole ion trap time-of-flight (QIT-TOF) analyzer, was first validated and applied to visualize drug disposition in vivo. The distribution and elimination rate of the therapeutic peptide octreotide, a long acting analogue of the natural hormone somatostatin, was first calculated based on the data determined by iMScope system combining a novel relative exposure strategy. Microspotted pixel-to-pixel quantitative iMScope provided a relative amount of octreotide presented in a thin stomach/intestinal section while preserving its original spatial distribution. The images of dosed mouse stomach clearly demonstrated the transport process of octreotide from the mucosal layer to the muscle side. More importantly, octreotide was found to eliminate from the intestines rapidly, the absorption peak time (Tmax) appeared at 40 min and the half-life time (t1/2) was calculated as 37.7 min according to the elimination curves. Comparisons to the LC-MS/MS data adequately indicated that the quantification approach and methodology based on the iMScope was reliable and practicable for drug pharmacokinetic study. PMID- 28010845 TI - Direct immobilization of antibodies on Zn-doped Fe3O4 nanoclusters for detection of pathogenic bacteria. AB - Zinc-doped magnetic nanoclusters (Zn-MNCs) were synthesized and used to detect pathogenic bacteria in milk. Hydrothermally synthesized Zn-MNCs exhibited stronger magnetic properties than pure MNCs, which facilitated the magnetic separation from the sample using a permanent magnet. The presence of accessible Zn sites allows the direct immobilization of half-fragmented antibodies over Zn MNCs through strong ZnS bonds and prevents the tedious multiple steps of molecular functionalization or coating with costly noble metals prior to conjugation with an antibody. After the capture and magnetic separation of Salmonella in milk using the antibody-functionalized Zn-MNCs, the concentration of bacteria was determined with a portable ATP luminometer and the detection limit was found to be 10 CFU/mL. PMID- 28010846 TI - Immobilization of enzyme on chiral polyelectrolyte surface. AB - Chiral D- and L-N-acryloyl aspartic acid (NAsp) polyelectrolyte (PE) surfaces with similar chemical compositions and physical properties but opposite chirality are designed for enzyme immobilization. Enzymes immobilized onto the chiral PE surfaces present high chiral preference, namely L-NAsp PE surface can keep most of the catalytic activity of the immobilized enzymes, however, for enzymes immobilized on D-NAsp PE surface a large decrease in catalytic activity occurred which was 11 times lower compared with L-NAsp PE surface. This phenomenon of chiral effect on enzymes immobilization can be explained by attenuated total reflectance (ATR) and circular dichroism (CD) results. The results exhibited that L-NAsp PE surface could preserve most of the secondary structures of immobilized enzymes while on D-NAsp PE surface with a large conformation alteration. These chiral surface induced differences after enzyme immobilization can be further used for logic operation. These results imply a novel strategy for the design of new enzymes immobilization materials based on the chiral effect and expand the applications of enzymes in biochips, chemical transformations and chiral biodevices. PMID- 28010847 TI - Multivariate statistical process control (MSPC) using Raman spectroscopy for in line culture cell monitoring considering time-varying batches synchronized with correlation optimized warping (COW). AB - Multivariate statistical process control (MSPC) is increasingly popular as the challenge provided by large multivariate datasets from analytical instruments such as Raman spectroscopy for the monitoring of complex cell cultures in the biopharmaceutical industry. However, Raman spectroscopy for in-line monitoring often produces unsynchronized data sets, resulting in time-varying batches. Moreover, unsynchronized data sets are common for cell culture monitoring because spectroscopic measurements are generally recorded in an alternate way, with more than one optical probe parallelly connecting to the same spectrometer. Synchronized batches are prerequisite for the application of multivariate analysis such as multi-way principal component analysis (MPCA) for the MSPC monitoring. Correlation optimized warping (COW) is a popular method for data alignment with satisfactory performance; however, it has never been applied to synchronize acquisition time of spectroscopic datasets in MSPC application before. In this paper we propose, for the first time, to use the method of COW to synchronize batches with varying durations analyzed with Raman spectroscopy. In a second step, we developed MPCA models at different time intervals based on the normal operation condition (NOC) batches synchronized by COW. New batches are finally projected considering the corresponding MPCA model. We monitored the evolution of the batches using two multivariate control charts based on Hotelling's T2 and Q. As illustrated with results, the MSPC model was able to identify abnormal operation condition including contaminated batches which is of prime importance in cell culture monitoring We proved that Raman-based MSPC monitoring can be used to diagnose batches deviating from the normal condition, with higher efficacy than traditional diagnosis, which would save time and money in the biopharmaceutical industry. PMID- 28010848 TI - Visioning Report 2017: A Preferred Path Forward for the Nutrition and Dietetics Profession. PMID- 28010850 TI - Errata. PMID- 28010849 TI - The Route to Practice and the Root of the Profession: 25+ Years of Evolving Nutrition and Dietetics Education at the Academy. PMID- 28010851 TI - Errata. PMID- 28010852 TI - What Do I Tell My Clients Who Want to Follow a Low Glycemic Index Diet? PMID- 28010853 TI - Use MyPlate, MyWins-A Small-Steps Approach-To Set Realistic Solutions for the New Year. PMID- 28010854 TI - A Tale of Two Runners: A Case Report of Athletes' Experiences with Eating Disorders in College. AB - Athletes are at higher risk than the general population for eating disorders, and risk is heightened for athletes in thin-build sports, including track. Collegiate athletes are particularly vulnerable to disordered eating when the transition from home to the college environment adds to the stress of performance pressures and the high demands of the sport environment. Male and female athletes who develop eating disorders share some common characteristics, yet their experiences can be quite different, in part as a consequence of their sex and how eating disorders develop, and are recognized, acknowledged, and treated, within the culture of sports. This case report describes the experiences of two track athletes, one male and one female, who were recruited to the same Division 1 collegiate track program. Both were elite athletes, freshmen in the same year, experiencing the same urban college environment, and experiencing an eating disorder characterized by restrictive eating, significant weight loss, injury, and compromised performance in sport. Both received treatment from a multidisciplinary team of professionals. Both athletes achieved weight restoration, recovery from the disorder, and success in their sport. In spite of the similarities, striking differences were apparent in clinical presentation, predisposing features, onset of symptoms, entry points to treatment, interventions received, and clinical courses through treatment that depict sex differences in how eating disorders present in athletes and are addressed in the sport environment. Findings endorse the need for research and inform prevention strategies, risk assessment, and intervention approaches for nutrition and sports medicine professionals and collegiate athletic departments. PMID- 28010855 TI - Using Our Professional Judgment to Make a Powerful Impact. PMID- 28010856 TI - Corrigendum to "Exploring the protective role of apocynin, a specific NADPH oxidase inhibitor, in cisplatin-induced cardiotoxicity in rats" [Chem. Biol. Interact. 207 (2014) 58-66]. PMID- 28010857 TI - Invited commentary. PMID- 28010858 TI - Invited commentary. PMID- 28010859 TI - Invited commentary. PMID- 28010860 TI - Invited commentary. PMID- 28010861 TI - Invited commentary. PMID- 28010862 TI - Double-lumen atherosclerotic abdominal aortic aneurysm. PMID- 28010863 TI - Meta-analysis of open and endovascular repair of popliteal artery aneurysms. AB - OBJECTIVE: Endovascular popliteal artery aneurysm repair (EPAR) is increasingly used over open surgical repair (OPAR). The purpose of this study was to analyze the available literature on their comparative outcomes. METHODS: The PubMed and Embase databases were searched to identify studies comparing OPAR and EPAR. Studies with only one treatment and fewer than five patients were excluded. Demographics and outcomes were collected. Bias risk was assessed using a modified version of the Newcastle-Ottawa Scale. Results were computed from random-effects meta-analyses using the DerSimonian-Laird algorithm. RESULTS: A total of 14 studies were identified encompassing 4880 popliteal artery aneurysm repairs (OPAR, 3915; EPAR, 1210) during the last decade. OPAR patients were younger (standard mean difference, -0.798 [-0.798 to -1.108]; P < .001) and more likely to have worse tibial runoff (odds ratio [OR], 1.949 (1.15-3.31); P = .013) than EPAR patients. OPAR had higher odds of wound complications (OR, 5.182 [2.191 12.256]; P < .001) and lower odds of thrombotic complications (OR, 0.362 [0.155 0.848]; P < .001). OPAR had longer length of stay (standardized mean difference, 2.158 [1.225-3.090]; P < .001) and fewer reinterventions (OR, 0.275 [0.166 0.454]; P < .001). Primary patency was better for OPAR at 1 year and 3 years (relative risk, 0.607 [P = .01] and 0.580 [P = .006], respectively). There was no difference in secondary patency at 1 year and 3 years (0.770 [P = .458] and 0.642 [P = .073], respectively). CONCLUSIONS: EPAR has a lower wound complication rate and shorter length of hospital stay compared with OPAR. This comes at the cost of inferior primary patency but not secondary patency out to 3 years. Studies reporting long-term outcomes are lacking and necessary. PMID- 28010864 TI - Invited commentary. PMID- 28010865 TI - The modified operative technique of partial eversion carotid endarterectomy. AB - We report a modified operative technique termed partial eversion carotid endarterectomy (PECE). During a 9-year period (2006-2015), 352 patients underwent PECE. Indications for surgery, intraoperative details, and outcomes were recorded. The initial 185 patients had carotid duplex ultrasound imaging at 6 weeks and then at 6, 12, and 24 months. Subsequent patients had carotid imaging at 4 to 6 weeks. Indications included stroke (76), transient ischemic attack (153), and amaurosis fugax (33); 58 patients were asymptomatic, and 32 patients had surgery before cardiac surgery. Median clamp time was 14 minutes (interquartile range, 11.5-17 minutes). Median total operation time was 41 minutes (interquartile range, 31-72 minutes). Outcomes included four transient ischemic attacks (1.2%), five strokes (1.4%), and two deaths at 30 days (0.5%). No significant cranial nerve injuries or carotid restenosis was detected during follow-up. PECE is technically straightforward, with outcomes comparable to those of current operative techniques. Its advantages included reduced operative and carotid clamping time. PMID- 28010866 TI - Fifty-year anniversary of the Vietnam Vascular Registry and a historic look at vascular registries. AB - The management of arterial injuries has evolved from simple cauterization of the time of Ambrose Pare to the more complex repairs of today. Through history there has been much learned from combat regarding the management of vascular injuries. Starting in World War I, vascular registries have been established to further study and refine the management of these injuries. One of the most pivotal registries was the Vietnam Vascular Registry established by Dr Norman Rich. The lessons learned from these registries have been carried on to the current conflicts with the establishment of the Global War on Terror Vascular Initiative. We compare 100 lower extremity vascular injuries from the Vietnam Vascular Registry to 100 injuries in the Global War on Terror Vascular Initiative database as we continue to improve the future with lessons from our past. PMID- 28010867 TI - The diseases one treats: A vascular surgeon's perspective. PMID- 28010868 TI - Correction. PMID- 28010869 TI - Invited commentary. PMID- 28010870 TI - Few internal iliac artery aneurysms rupture under 4 cm. AB - OBJECTIVE: This study investigated the diameter of internal iliac artery (IIA) aneurysms (IIAAs) at the time of rupture to evaluate whether the current threshold diameter for elective repair of 3 cm is reasonable. The prevalence of concomitant aneurysms and results of surgical treatment were also investigated. METHODS: This was a retrospective analysis of patients with ruptured IIAA from seven countries. The patients were collected from vascular registries and patient records of 28 vascular centers. Computed tomography images taken at the time of rupture were analyzed, and maximal diameters of the ruptured IIA and other aortoiliac arteries were measured. Data on the type of surgical treatment, mortality at 30 days, and follow-up were collected. RESULTS: Sixty-three patients (55 men and 8 women) were identified, operated on from 2002 to 2015. The patients were a mean age of 76.6 years (standard deviation, 9.0; range 48-93 years). A concomitant common iliac artery aneurysm was present in 65.0%, 41.7% had a concomitant abdominal aortic aneurysm, and 36.7% had both. IIAA was isolated in 30.0%. The mean maximal diameter of the ruptured artery was 68.4 mm (standard deviation, 20.5 mm; median, 67.0 mm; range, 25-116 mm). One rupture occurred at <3 cm and four at <4 cm (6.3% of all ruptures). All patients were treated, 73.0% by open repair and 27.0% by endovascular repair. The 30-day mortality was 12.7%. Median follow-up was 18.3 months (interquartile range, 2.0-48.3 months). The 1 year Kaplan-Meier estimate for survival was 74.5% (standard error, 5.7%). CONCLUSIONS: IIAA is an uncommon condition and mostly coexists with other aortoiliac aneurysms. Follow-up until a diameter of 4 cm seems justified, at least in elderly men, although lack of surveillance data precludes firm conclusions. The mortality was low compared with previously published figures and lower than mortality in patients with ruptured abdominal aortic aneurysm. PMID- 28010871 TI - Commentary on: Implementing mechanical thrombectomy for acute ischaemic stroke in the UK. PMID- 28010872 TI - Inflammatory Skin Conditions Associated With Radiotherapy. AB - Radiotherapy for cancer is used increasingly. Because skin cells undergo rapid turnover, the ionizing radiation of radiotherapy has collateral effects that are often expressed in inflammatory reactions. Some of these reactions radiodermatitis and recall phenomenon, for example-are very familiar to dermatologists. Other, less common radiotherapy-associated skin conditions are often underdiagnosed but must also be recognized. PMID- 28010873 TI - Paraffin Wax Baths for the Treatment of Chronic Hand Eczema. PMID- 28010874 TI - Predictors of Paravalvular Regurgitation After Transcatheter Aortic Valve Implantation for Aortic Stenosis Using New-Generation Balloon-Expandable SAPIEN 3. AB - Paravalvular regurgitation (PVR) is a common and serious complication after transcatheter aortic valve implantation (TAVI). New-generation balloon-expandable SAPIEN 3 has an outer sealing skirt to minimize PVR. However, the predictors of PVR after SAPIEN 3 transcatheter heart valve (THV) implantation have not been well investigated. We sought to clarify the determinants of PVR after TAVI using SAPIEN 3 with quantitative multidetector computed tomography (MDCT) assessment. This study analyzed 281 patients with severe symptomatic aortic stenosis who underwent TAVI using SAPIEN 3. Quantitative assessment of aortic root dimensions and calcium volume for leaflet, annulus, and left ventricular outflow tract were retrospectively performed with MDCT. MDCT nominal area oversizing was calculated using the following formula: % oversizing = (THV nominal area/MDCT derived annular area - 1) * 100. Logistic regression analysis was performed to determine the predictors of PVR greater than or equal to mild. PVR greater than or equal to mild was observed in 19% (53 of 281). Quantity and asymmetry of aortic valve calcium of annulus, left ventricular outflow tract, and leaflet were associated with higher incidence of PVR greater than or equal to mild, except leaflet asymmetry. Lower percentage of THV oversizing was also associated with PVR. Multivariable logistic regression analysis showed that larger calcification volume of annulus and lower percentage of THV oversizing were independent predictors of PVR greater than or equal to mild. These results suggest that prosthesis/annulus incongruence and aortic annulus calcification predicted PVR greater than or equal to mild after TAVI using SAPIEN 3. PMID- 28010875 TI - Achievements and Limitations of a Strategy of Rehabilitation of Native Pulmonary Vessels in Pulmonary Atresia, Ventricular Septal Defect, and Major Aortopulmonary Collateral Arteries. AB - BACKGROUND: A strategy of rehabilitation for pulmonary atresia, ventricular septal defect, and major aortopulmonary collateral arteries (PA/VSD/MAPCAs) comprises repetitive shunting and patching procedures of the central pulmonary arteries. We wanted to determine the feasibility and limitations of a strategy of rehabilitation. METHODS: The outcomes of 37 consecutive patients operated from June 2003 to December 2014 for PA/VSD/MAPCAs were reviewed. The patients were directed to a rehabilitation strategy, except when they presented in heart failure with very large collaterals. RESULTS: Four patients with very large MAPCAs underwent a one-stage repair with unifocalization of collateral vessels at a median age of 8.6 months. There was no mortality in this group after a median follow-up of 4.6 years. Following a strategy of staged rehabilitation, 33 patients had 2.01 +/- 0.9 procedures before repair. Median age at primary shunting was 3.3 weeks (0.4 to 31.9 weeks). Repair rate was 73% (22 patients), at a median age of 1.7 years. Three patients (10%) were left palliated and 3 patients (10%) died. Median follow-up in this group was 4.5 years. Complementary procedures to the rehabilitation strategy consisted in pulmonary artery reconstruction in 25 patients (76%) and MAPCAs ligation in 7 patients (21%). Pulmonary balloon angioplasty was required in 12 patients (36%) and MAPCAs coil occlusion in 8 patients (24%). CONCLUSIONS: A strategy of rehabilitation can be implemented in almost 90% of the cases, with a low mortality rate. Following this strategy, 73% of the patients can be successfully repaired. PMID- 28010877 TI - Assessment of cancer pain management in ambulatory care in Morocco. PMID- 28010878 TI - [beta-catenin and desmoid tumors: The ideal biomarker?] PMID- 28010876 TI - Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory. AB - BACKGROUND: There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. METHODS: We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. RESULTS: In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. CONCLUSIONS: These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite. PMID- 28010879 TI - Explaining the moral of the story. AB - Although storybooks are often used as pedagogical tools for conveying moral lessons to children, the ability to spontaneously extract "the moral" of a story develops relatively late. Instead, children tend to represent stories at a concrete level - one that highlights surface features and understates more abstract themes. Here we examine the role of explanation in 5- and 6-year-old children's developing ability to learn the moral of a story. Two experiments demonstrate that, relative to a control condition, prompts to explain aspects of a story facilitate children's ability to override salient surface features, abstract the underlying moral, and generalize that moral to novel contexts. In some cases, generating an explanation is more effective than being explicitly told the moral of the story, as in a more traditional pedagogical exchange. These findings have implications for moral comprehension, the role of explanation in learning, and the development of abstract reasoning in early childhood. PMID- 28010880 TI - Assessing the national trends in colon cancer among Native Americans: A 12 year SEER database study. AB - INTRODUCTION: Native Americans (NA) form a unique cohort of colon cancer (CC) patients among whom the variability in demographics and cancer characteristics remains unclear. METHODS: We abstracted the national estimates for NA with CC using the Surveillance, Epidemiology, and End Result (SEER) database. Trend analysis of incidence, variation in location and patient demographic analysis were performed. RESULTS: A total number of 26,674 NA with CC were reported during the 12-year study period. While the overall incidence of CC decreased by 12% during the study period, incidence increased by 38% in NA. Incidence of CC was more prevalent and higher increase (42%) seen in NA females than males (p = 0.02; 34%). Stage III tumors represented 29% of all CC, sigmoid colon the most common site location (38%) with 72% of all tumors being moderately differentiated. 55% tumors were localized in left, 36% in right and 9% in transverse colon. 92% of the NA were insured. CONCLUSION: Incidence of CC continues to rise in NA with majority of CC presented at higher stage and moderate differentiation. PMID- 28010881 TI - Post-hepatectomy hyperbilirubinemia: The point of no return. AB - BACKGROUND: Post-hepatectomy hyperbilirubinemia is associated with liver insufficiency and failure. The highest survivable peak total bilirubin (ptbili) is not defined. This study aimed to identify the postop ptbili beyond which survival is improbable or impossible. METHODS: An institutional database of major hepatectomies (>=3 segments, no biliary resections), 2000-2012 was reviewed. Data were analyzed to find ptbili in the first 45 postop days. Factors associated with 90-day mortality (90 DM) and those predictive of ptbili were determined. RESULTS: 603 pts were analyzed with 90DM of 4.5%. 90 DM for a ptbili >= 18 (n = 15) was 86.6%, but only 2.5% for a ptbili < 18. All 6 pts with a ptbili >= 30 died. On multivariate analysis, postop ptbili >= 18 (HR34.95, CI 3.8-324; p = 0.002) and cirrhosis (HR6.4, CI 1.2-33.2; p = 0.027) were associated with 90DM. Factors associated with a ptbili >= 18 were age >65 (HR14.24, CI 2.9-70.5; p = 0.001), preop chemotherapy (HR4.77, CI 1.3-18.2; p = 0.02) and postop FFP (HR12.5, CI 2.6 56.2; p = 0.001). CONCLUSION: Postop ptbili >= 18 after major hepatectomy has an 86.6% risk of 90DM; there are no survivors for tbili >= 30. These values may guide postop counseling for prognosis. Future studies may evaluate tbili >= 18 as an indication for hepatic replacement therapy. PMID- 28010882 TI - Identifying the source of petroleum pollution in sediment cores of southwest of the Caspian Sea using chemical fingerprinting of aliphatic and alicyclic hydrocarbons. AB - In this study, the concentration and sources of aliphatic and petroleum markers were investigated in 105 samples of Anzali, Rezvanshahr and Astara cores from the southwest of Caspian Sea. Petroleum importation was diagnosed as a main source in most depths of cores by the results of unresolved complex mixture, carbon preference index and hopanes and steranes. From the chemical diagnostic parameters, petroleum inputs in sediment of cores were determined to be different during years and the sources of hydrocarbons in some sections differed than Anzali and Turkmenistan and Azerbaijan oils. Diagenic ratios in most sediments of upper and middle sections in Astara core were determined to be highly similar to those of Azerbaijan oil, while the presence of Turkmenistan and Anzali oils were detected in a few sections of Anzali and Rezvanshahr cores and only five layers of downer section in Anzali core, respectively. PMID- 28010883 TI - Effectiveness and drug survival of TNF-inhibitors in the treatment of psoriatic arthritis: A prospective cohort study. AB - BACKGROUND AND OBJECTIVES: Tumor necrosis factor (TNF)-inhibitors are used to treat psoriatic arthritis (PsA), but only a limited number of observational studies on this subject have been published thus far. The aim of this research was to analyze the effectiveness and drug survival of TNF-inhibitors in the treatment of PsA. METHODS: PsA patients identified from the National Register for Biologic Treatment in Finland (ROB-FIN) starting their first, second, or third TNF-inhibitor treatment between 2004 and 2014 were included. Effectiveness was measured using ACR and EULAR response criteria and modeled using ordinal logistic regression. Treatment persistence was analyzed using Kaplan-Meier survival analysis and Cox proportional hazards model. RESULTS: The study comprised 765 patients and 990 TNF-inhibitor treatment courses. EULAR moderate treatment responses at 6 months were achieved by 68% and 37% of the users of the first and the second or the third biologic, respectively. The probabilities of discontinuing the treatment within 12 and 24 months were 20% and 28%, respectively. Adjusted treatment responses to all TNF-inhibitors were similar; however, co-therapy with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) was not associated with better effectiveness. Adalimumab [hazard ratio (HR) = 0.62; 95% confidence interval (CI): 0.44-0.88] was superior to infliximab in drug survival while etanercept (HR = 0.77, 95% CI: 0.55-1.1) and golimumab (HR = 0.75, 95% CI: 0.46-1.2) did not differ from it. Co-medication with csDMARDs did not statistically improve drug survival. CONCLUSION: All available TNF-inhibitors showed similar treatment responses with or without csDMARDs. Adalimumab was associated with better drug survival when compared to infliximab. PMID- 28010884 TI - Efficacy of lumbar cistern drainage combined with intrathecal antibiotherapy for the treatment of ventriculo-subarachnoid infections following surgery for hypertensive intracerebral hemorrhage. AB - OBJECTIVE: The aim of this study was to investigate the efficacy of lumbar cistern drainage combined with intrathecal injection of antibiotics (LCD-ITI) in treating postoperative intracranial infections of hypertensive intracerebral hemorrhage (pHIH-ICI). METHODS: Sixty pHIH-ICI patients were randomly divided into the control group and the treatment group, with 30 patients in each group. Conventional treatment was performed in the control group, while LCD-ITI was performed in the treatment group. The clinical outcomes, Glasgow Outcome Score (GOS), activities of daily living (ADL) scores, incidence rates of hydrocephalus and other indicators were compared. RESULTS: The improvement time of clinical symptoms, infection control time and hydrocephalus incidence of the treatment group were significantly lower than the control group (P<0.05). Also the infection control rate, GOS score and ADL score of the treatment group were significantly higher or better than the control group (P<0.05). CONCLUSION: LCD ITI could improve clinical treatment and prognosis of pHIH-ICI patients. PMID- 28010885 TI - Gastroprotective effects of hydroethanolic root extract of Arrabidaea brachypoda: Evidences of cytoprotection and isolation of unusual glycosylated polyphenols. AB - The hydroethanolic root extract of Arrabidaea brachypoda, from Bignoniaceae family, a Brazilian medicinal plant, demonstrated significant in vivo gastroprotective effects using different in vivo assays. The activity was evaluated in several models of experimental gastric ulcer in rats (absolute ethanol, glutathione depletion, nitric oxide depletion, non-steroidal anti inflammatory drugs, pylorus ligation and acetic acid). Using 300 mg/kg (p.o.) the extract significantly reduced gastric injury in all models. In depth phytochemical investigation of this extract led to the isolation of two previously undescribed phenylethanoid glycosides derivatives and seven unusual glycosylated dimeric flavonoids. The structures were elucidated using UV, NMR and HRMS analysis. Absolute configuration of the dimeric flavonoids was performed by electronic circular dichroism (ECD) spectroscopy. PMID- 28010887 TI - Obesity and kidney disease: hidden consequences of the epidemic. AB - Obesity is a growing worldwide epidemic. Obesity is one of the strongest risk factors for new-onset chronic kidney disease, and also for nephrolithiasis and for kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option. PMID- 28010886 TI - Reappraisal in two European cohorts of the prognostic power of left ventricular mass index in chronic kidney failure. AB - Left ventricular hypertrophy is a strong causal risk factor of cardiovascular morbidity and death in end stage kidney failure, and its prognostic value is taken for granted in this population. However, the issue has never been formally tested by state-of-art prognostic analyses. Therefore, we determined the prognostic power of the left ventricular mass index (LVMI) for all-cause and cardiovascular death beyond and above that provided by well validated clinical risk scores, the annualized rate of occurrence cohort risk scores (ARO, all cause death risk and cardiovascular risk). Two large cohorts that measured LVMI in 207 hemodialysis patients in the South Italian CREED cohort and 287 patients in the French Hospital Manhes cohort were analyzed. Over a two year follow-up, 123 patients died (cardiovascular death 65%). In Cox models both the LVMI and the ARO risk scores were significantly related to all-cause and cardiovascular death. In prognostic analyses, LVMI per se showed an inferior discriminatory power (Harrell's C index) to that of the ARO risk scores (all-cause death: -10%; cardiovascular death: -5%). LVMI largely failed to improve model calibration based on the ARO risk scores, and added nonsignificant discriminatory power (Integrated Discrimination Index +2% and +3%) and quite limited reclassification ability (Net Reclassification Index +4.3%, and +8.8) to the ARO risk scores. Thus, while left ventricular hypertrophy remains a fundamental treatment target in end stage kidney failure, the measurement of LVMI solely for risk stratification is unwarranted in this condition. PMID- 28010888 TI - Dose-dependent effects of morphine on lipopolysaccharide (LPS)-induced inflammation, and involvement of multixenobiotic resistance (MXR) transporters in LPS efflux in teleost fish. AB - Opioid drugs, such as morphine (MO), detected in aquatic environments worldwide, may harm fish due to their semi-persistence and ability to potently interact with molecular targets conserved across vertebrates. Here, we established a waterborne bacterial lipopolysaccharide (LPS) challenge assay with zebrafish embryos as a model to investigate chemically-induced disruption of the innate immune system, and used it to study the effects of MO exposure. Exposure to 1 mg/L MO resulted in pronounced immunosuppression, reflected in downregulation of several inflammation-related genes, including myd88, trif, traf6, p38, nfkappab2, il 1beta, il-8 and ccl34a. Fish exposed to 1 mg/L MO accumulated 11.7 ng/g (wet weight) of MO, a concentration comparable to that reported in blood of chronic drug abusers subject to higher infection rates. Surprisingly, exposure to lower MO concentrations (100 ng/L-100 MUg/L) led to exacerbation of LPS-induced inflammation. Two ATP-binding cassette (ABC) transporters known to be involved in the xenobiotic efflux - abcb4 and abcc2, also known as multixenobiotic resistance (MXR) transporters - were downregulated at 100 ng/L MO. We hypothesized that ABC/MXR transporters could modulate the severity of inflammation by being involved in efflux of LPS, thus regulating its accumulation in the organism. Indeed, we could demonstrate that blocking of ABC/MXR transporters by an inhibitor, cyclosporine A, results in stronger inflammation, coinciding with higher LPS accumulation, as visualized with fluorescently labeled LPS. Our work demonstrates that MO can disrupt fish innate immune responses at environmentally relevant concentrations. We also provide evidence for a role of ABC/MXR transporters in LPS efflux in fish. These finding may be applicable across other taxa, as ABC transporters are evolutionary conserved. Since diverse environmentally present chemicals are known to interfere with ABC/MXR transporters' expression or activity, our discovery raises concerns about potential adverse effects of such compounds on the immune system responses in aquatic organisms. PMID- 28010889 TI - Nail involvement in systemic sclerosis. AB - BACKGROUND: Nail involvement has rarely been recognized in systemic sclerosis (SSc). Indeed, only a few small series have assessed nail changes in SSc, most of which are case reports. OBJECTIVE: The aims of the current case-control study were to: (1) determine the prevalence of fingernail changes in SSc; and (2) evaluate the correlation between fingernail changes and other features of SSc. METHODS: In all, 129 patients with SSc and 80 healthy control subjects underwent routine fingernail examination. RESULTS: The prevalence of fingernail changes was 80.6% in SSc. Patients with SSc more frequently exhibited: trachyonychia (P = .006), scleronychia (P < .0001), thickened nails (P < .0001), brachyonychia (P = .0004), parrot beaking (P < .0001), pterygium inversum unguis (P < .0001), splinter hemorrhages (P < .0001), and cuticle abnormalities (P < .0001) than healthy control subjects. The presence of fingernail changes was associated with digital ulcers (P < .0001), calcinosis cutis (P = .004), and higher values of mean nailfold videocapillaroscopy score (P = .0009). LIMITATIONS: The cohort originated from a single center. CONCLUSION: This study underlines that fingernail changes are correlated with more severe forms of SSc characterized by digital microangiopathy, including digital ulcers and calcinosis cutis. Nail changes should be systematically checked in all patients with SSc, and may be included in the American College of Rheumatology/European League Against Rheumatism classification criteria for SSc. PMID- 28010890 TI - Hair pull test: Evidence-based update and revision of guidelines. AB - BACKGROUND: The hair pull test lacks validation and has unclear pretest guidelines. OBJECTIVE: We sought to quantify normal hair pull test values and elucidate the effect of pretest hair washing and brushing. The impact of hair texture and lifestyle was also examined. METHODS: Participants (n = 181) completed a questionnaire recording demographics, medications, and hair health/history. A single hair pull test (scalp vertex) was performed. RESULTS: The mean number of hairs removed per pull was 0.44 (SD 0.75). There was no significant difference in the mean number of hairs removed regardless of when participants washed (P = .20) or brushed (P = .25) their hair. Hair pull test values were similar between Caucasian-, Asian-, and Afro-textured hair. There was no significant difference in hair pull values between participants taking medications affecting hair loss and participants not taking these medications (P = .33). Tight hairstyles did not influence hair pull test values. LIMITATIONS: Participant hair washing and brushing could not be controlled during the study, but this information was documented and analyzed. CONCLUSION: Normal values for the hair pull test should be reduced to 2 hairs or fewer (97.2% of participants). The current 5-day restriction on pretest hair washing can be reduced and brushing be made permissible. PMID- 28010891 TI - Use of the extracapsular dissection technique for palatal minor salivary gland benign tumours - a technical note. PMID- 28010893 TI - An exceedingly rare cause of dysphagia. PMID- 28010892 TI - Implementation and evaluation of early gastroscopy for patients with dyspepsia and warning signs in Primary Care. AB - INTRODUCTION: Dyspepsia is a common disorder in both Primary (PC) and Specialised Care (SC). Gastroscopy is recommended at the start of the study if there are warning signs, although it is not always available in PC. OBJECTIVES AND METHODS: We developed a pilot project establishing an early gastroscopy programme for patients with dyspepsia and warning signs in PC, subsequently extending it to the entire healthcare area. The aim was to evaluate the requirements, impact and opinion of this service at the PC level. Demographic, symptomatic and endoscopic variables on the patients referred to SC from the pilot centre were recorded. A satisfaction survey was conducted among the PC physicians. RESULTS: The one-year pilot study and the first year of implementation of the programme were evaluated. A total of 355 patients were included (median age 56.4 years; IQR 45.5-64.3); 61.2% (56.1-66.3%) were women. The waiting time for examination was 1.5 weeks (IQR 1.5-2.5). Gastroscopy was correctly indicated in 82.7% (78.4-86.3%) of patients. The median number of requests per month was 1.1 per 10,000 adults (range 0.8-1.6). Monthly referrals to SC clinics from the pilot centre fell by 11 subjects (95% CI 5.9-16) with respect to the previous median of 58 (IQR 48-64.5). Almost all those polled (98.4%) considered the programme useful in routine practice. CONCLUSIONS: The availability of an early gastroscopy programme in PC for patients with dyspepsia and warning signs reduced the number of referrals to SC. PMID- 28010894 TI - Metabolic hijacking: A survival strategy cancer cells exploit? AB - The majority of human tumours are comprised of cancerous epithelial cells that coexist with a multitude of different cell types and extracellular matrix components creating the cancer microenvironment. Cancer-associated fibroblasts (CAFs) are the most abundant mesenchymal cell types present within most human carcinomas. Recent evidence suggests that nutrient deprived epithelial cancer cells are able to survive these conditions, as a result of their ability to undergo extensive metabolic reprogramming and exploit the metabolic capacities of surrounding CAFs. Although several studies support the role of CAFs in tumour progression and metastasis, the molecular mechanisms underlying this pro tumourigenic interaction remains to be elucidated. This review will discuss the complex metabolic interaction that exists between epithelial cancer cells and CAF's: focussing primarily on their functional role in tumour progression, metastasis and chemotherapeutic resistance. Attempts are made at delineating the molecular mechanisms underlying this pro-tumourigenic interaction, and potential CAF-based targets are suggested. PMID- 28010895 TI - Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies. AB - PURPOSE: To investigate oncogenic platelet-derived growth factor receptor(PDGFR) fusion genes involvement in hematological malignancies, the advances in the PDGFR fusion genes diagnosis and development of PDGFR fusions inhibitors. METHODS: Literature search was done using terms "PDGFR and Fusion" or "PDGFR and Myeloid neoplasm" or 'PDGFR and Lymphoid neoplasm' or "PDGFR Fusion Diagnosis" or "PDGFR Fusion Targets" in databases including PubMed, ASCO.org, and Medscape. RESULTS: Out of the 36 fusions detected, ETV6(TEL)-PDGFRB and FIP1L1-PDGFRA fusions were frequently detected, 33 are as a result of chromosomal translocation, FIP1L1 PDGFRA and EBF1-PDGFRB are the result of chromosomal deletion and CDK5RAP2- PDGFRAlpha is the result of chromosomal insertion. Seven of the 34 rare fusions have detectable reciprocals. CONCLUSION: RNA aptamers are promising therapeutic target of PDGFRs and diagnostic tools of PDGFRs fusion genes. Also, PDGFRs have variable prospective therapeutic strategies including small molecules, RNA aptamers, and interference therapeutics as well as development of adaptor protein Lnk mimetic drugs. PMID- 28010896 TI - New perspectives in the second-line treatment of non squamous NSCLC patients: Results from a large Italian Lung Cancer Working Group. AB - Lung cancer is still considered a big killer among cancer diseases, due to high incidence and mortality rates. The newer frontiers of therapeutic development regard the discovery of oncogene driven tumours: however, the majority of NSCLC patients are wild type and they cannot be treated with targeted based agents. The recent positive results obtained with immunotherapy and with the combination of angiogenesis inhibitors and docetaxel, changed the therapeutic scenario of the second line therapy of non squamous NSCLC without actionable mutations. A major issue is currently the lack of predictive biomarkers that could help the oncologists in the choice of the best second-line treatment. Aim of this project was to define an optimal therapeutic pathway for patients with non-squamous NSCLC, through a working group of a large number of Italian lung cancer oncologists. Panellists have identified and discussed the more significant criteria in the second-line setting for a therapeutic decision between the combination of angiogenesis inhibitors plus chemotherapy or immunotherapy. Finally, they expressed their preference on each criterion, building a proposal of a decision-making tree for a second-line treatment of non-squamous NSCLC. PMID- 28010898 TI - The etiopathogenesis of diffuse low-grade gliomas. AB - The origins of diffuse low-grade gliomas (DLGG) are unknown. Beyond some limited data on their temporal and cellular origins, the mechanisms and risk factors involved are poorly known. First, based on strong relationships between DLGG development and the eloquence of brain regions frequently invaded by these tumors, we propose a "functional theory" to explain the origin of DLGG. Second, the biological pathways involved in DLGG genesis may differ according to tumor location (anatomo-molecular correlations). The cellular and molecular mechanisms of such "molecular theory" will be reviewed. Third, the geographical distribution of diffuse WHO grade II-III gliomas within populations is heterogeneous, suggesting possible environmental risk factors. We will discuss this "environmental theory". Finally, we will summarize the current knowledge on genetic susceptibility in gliomas ("genetic predisposition theory"). These crucial issues illustrate the close relationships between the pathophysiology of gliomagenesis, the anatomo-functional organization of the brain, and personalized management of DLGG patients. PMID- 28010897 TI - Brentuximab vedotin for treatment of non-Hodgkin lymphomas: A systematic review. AB - BACKGROUND: Brentuximab vedotin (BV) is an antibody-drug conjucate (ADC) comprising a CD30-directed antibody, conjugated to the microtubule-disrupting agent MMAE via a protease cleavable linker. BV is FDA approved for use in relapsed classical Hodgkin lymphoma (HL) and relapsed systemic anaplastic large cell lymphoma (sALCL). There are multiple publications for its utility in other malignancies such as diffuse large B-cell lymphoma (DLBCL), mycosis fungoides (MF), Sezary syndrome (SS), T-cell lymphomas (TCL), primary mediastinal lymphoma (PMBL), and post-transplant lymphoproliferative disorders (PTLD). We believe that BV could potentially provide a strong additional treatment option for patients suffering from NHL. OBJECTIVE: Perform a systematic review on the use of BV in non-Hodgkin lymphoma (NHL) and other CD30+ malignancies in humans. DATA SOURCES: We searched various databases including PubMed (1946-2015), EMBASE (1947-2015), and Cochrane Central Register of Controlled Trials (1898-2015). ELIGIBILITY CRITERIA: Inclusion criteria specified all studies and case reports of NHLs in which BV therapy was administered. INCLUDED STUDIES: A total of 28 articles met these criteria and are summarized in this manuscript. CONCLUSION: Our findings indicate that BV induces a variety of responses, largely positive in nature and variable between NHL subtypes. With additional, properly powered prospective studies, BV may prove to be a strong candidate in the treatment of various CD30+ malignancies. PMID- 28010899 TI - SPARCL1 a novel player in cancer biology. AB - Matricellular proteins are secreted, nonstructural proteins, involved in the mediation of molecular interactions between cells and extracellular microenvironment. They include several, structurally unrelated, members and their homologs. Among these a particularly interesting one is SPARCL1 due to its potential interactions in tumor biology. SPARCL1 is a secreted glycoprotein, belonging to SPARC family of matricellular proteins. It is implicated in the regulation of cell adhesion, migration, and proliferation. SPARCL1 is expressed in physiological context, both during embryogenesis and in adult life during tissue remodeling. Its diverse expression pattern in different forms of human cancers has suggested it may play different roles in tumor biology, as both oncogene and tumor suppressor, based on tumor type. Aim of this review is to critically revise current knowledges about the role, played by SPARCL1, in physiological and pathological contexts and highlight its role as a key-gene in the regulation of tumor biology. PMID- 28010901 TI - Clinical relevance of colorectal cancer molecular subtypes. AB - Colorectal cancer (CRC) is characterized by alteration of critical pathways such TP53 inactivation, BRAF, PI3CA mutations, APC inactivation, KRAS, TGF-beta, CTNNB mutations, disregulation of Epithelial to mesnechymal transition (EMT) genes, WNT signaling activation, MYC amplification, and others. Differences in these molecular events results in differences in phenotypic characteristics of CRC, that have been studied and classified by different models of molecular subtypes. It could have potential applications to prognosis, but also to therapeutical approaches of the CRC patients. We review and summarized the different molecular classifications and try to clarify their clinical and therapeutical relevance. PMID- 28010902 TI - Evaluating the effect of synchronized sea lice treatments in Chile. AB - The sea louse is considered an important ectoparasite that affects farmed salmonids around the world. Sea lice control relies heavily on pharmacological treatments in several salmon-producing countries, including Chile. Among options for drug administration, immersion treatments represent the majority of antiparasitic control strategies used in Chile. As a topical procedure, immersion treatments do not induce a long lasting effect; therefore, re-infestation from neighbouring farms may undermine their efficacy. Synchronization of treatments has been proposed as a strategy to improve immersion treatment performance, but it has not been evaluated so far. Using a repeated-measures linear mixed-effect model, we evaluated the impact of treatment synchronization of neighbouring farms (within 10km seaway distance) on the adult lice mean abundance from weeks 2 to 8 post-treatment on rainbow trout and Atlantic salmon farms in Chile, while controlling for external and internal sources of lice before the treatments, and also for environmental and fish-related variables. Results indicate that treatment synchronization was significantly associated with lower adult lice levels from weeks 5 to 7 after treatment. This relationship appeared to be linear, suggesting that higher levels of synchronization may result in lower adult sea lice levels during these weeks. These findings suggest that synchronization can improve the performance of immersion delousing treatments by keeping sea lice levels low for a longer period of time. Our results may be applicable to other regions of the world where immersion treatments are widely used. PMID- 28010900 TI - Emergence of miR-34a in radiation therapy. AB - Expressions of many microRNAs (miRNAs) in response to ionizing radiation (IR) have already been investigated and some of them seem to play an important role in the tumor radioresistance, normal tissue radiotoxicity or as predictive biomarkers to radiation. miR-34a is an emerging miRNA in recent radiobiology studies. Here, we review this miR-34 family member by detailing its different roles in radiation response and we will discuss about the role that it can play in radiation treatment. Thus, we will show that IR regulates miR-34a by increasing its expression. We will also highlight different biological processes involved in cellular response to IR and regulated by miR-34a in order to demonstrate the role it can play in tumor radio-response or normal tissue radiotoxicity as a radiosensitizer or radioprotector. miR-34a is poised to assert itself as an important player in radiobiology and should become more and more important in radiation therapy management. PMID- 28010903 TI - Disease and pharmacologic risk factors for first and subsequent episodes of equine laminitis: A cohort study of free-text electronic medical records. AB - Electronic medical records from first opinion equine veterinary practice may represent a unique resource for epidemiologic research. The appropriateness of this resource for risk factor analyses was explored as part of an investigation into clinical and pharmacologic risk factors for laminitis. Amalgamated medical records from seven UK practices were subjected to text mining to identify laminitis episodes, systemic or intra-synovial corticosteroid prescription, diseases known to affect laminitis risk and clinical signs or syndromes likely to lead to corticosteroid use. Cox proportional hazard models and Prentice, Williams, Peterson models for repeated events were used to estimate associations with time to first, or subsequent laminitis episodes, respectively. Over seventy percent of horses that were diagnosed with laminitis suffered at least one recurrence. Risk factors for first and subsequent laminitis episodes were found to vary. Corticosteroid use (prednisolone only) was only significantly associated with subsequent, and not initial laminitis episodes. Electronic medical record use for such analyses is plausible and offers important advantages over more traditional data sources. It does, however, pose challenges and limitations that must be taken into account, and requires a conceptual change to disease diagnosis which should be considered carefully. PMID- 28010904 TI - Longitudinal study of Salmonella 1,4,[5],12:i:- shedding in five Australian pig herds. AB - The shedding patterns of Salmonella spp. and MLVA profiles of Salmonella enterica subspecies enterica (I) serotype 1,4,[5],12:i:- were monitored in a 12-month longitudinal observational study of five pig herds to inform management; provide indications of potential hazard load at slaughter; and assist evaluation of MLVA for use by animal and public health practitioners. Twenty pooled faecal samples, stratified by age group, were collected quarterly. When Salmonella was cultured, multiple colonies were characterized by serotyping and where S. Typhimurium-like serovars were confirmed, isolates were further characterized by phage typing and multiple locus variable number tandem repeat analysis (MLVA). Salmonella was detected in 43% of samples. Salmonella 1,4,[5],12:i- was one of several serovars that persisted within the herds and was found among colonies from each production stage. Virtually all Salmonella 1,4,[5],12:i:- isolates were phage type 193, but exhibited 12 different, closely-related MLVA profiles. Salmonella 1,4,[5],12:i:- diversity within herds was low and MLVA profiles were stable indicating colonization throughout the herds and suggesting each farm had an endemic strain. High prevalence of S. 1,4,[5],12:i:- specific shedding among terminal animals indicated high hazard load at slaughter, suggesting that primary production may be an important pathway of S. 1,4,[5],12:i:- into the human food chain, this has implications for on-farm management and the application and targeting control measures and further evidence of the need for effective process control procedures to be in place during slaughter and in pork boning rooms. These findings have implications for animal health and food safety risk mitigation and risk management. PMID- 28010905 TI - An investigation of antimicrobial usage patterns by small animal veterinarians in South Africa. AB - AIM: At present very little information is available on antimicrobial use patterns in small animal veterinary practice in South Africa. The aim of this study was firstly to provide some indication of antimicrobial use patterns, and secondly to ascertain if the country's small animal veterinarians make use of prudent use guidelines to optimise their antimicrobial use in order to minimise the development of antimicrobial resistance. METHODOLOGY: In order to understand use patterns, a questionnaire was circulated to registered South African veterinarians, whose responses were evaluated by descriptive statistics. The prevalence of antimicrobial resistance was evaluated for dogs from samples submitted for culture and susceptibility testing for the period 2007-2013 from the only faculty of Veterinary Science in the country. The resistance data was organized into contingency tables and yearly trends in resistance evaluated by means of a chi-square. The use of antimicrobials from the survey were compared to the laboratory result to ascertain the degree of prudent use of the antimicrobials in small animal practice in a developing country. RESULTS: The responses from the questionnaire indicated that South African veterinarians predominantly (91.16%) used antimicrobials empirically before resorting to laboratory testing and that antimicrobial compounding and off label use (86.19%) of human registered medication was common practice. A worrying finding was that a large number of clients attempted antimicrobial treatment of their pets prior to seeking veterinary assistance. In terms of monitored resistance, annual prevalence of resistance was above 10% and multiple drug resistance was above 50% for all the isolates. CONCLUSION: It is concluded that antimicrobial resistant bacteria are present in small companion animal practice in South Africa which requires better implementation of prudent use guidelines. PMID- 28010906 TI - Zoonotic disease risk perceptions in the British veterinary profession. AB - In human and veterinary medicine, reducing the risk of occupationally-acquired infections relies on effective infection prevention and control practices (IPCs). In veterinary medicine, zoonoses present a risk to practitioners, yet little is known about how these risks are understood and how this translates into health protective behaviour. This study aimed to explore risk perceptions within the British veterinary profession and identify motivators and barriers to compliance with IPCs. A cross-sectional study was conducted using veterinary practices registered with the Royal College of Veterinary Surgeons. Here we demonstrate that compliance with IPCs is influenced by more than just knowledge and experience, and understanding of risk is complex and multifactorial. Out of 252 respondents, the majority were not concerned about the risk of zoonoses (57.5%); however, a considerable proportion (34.9%) was. Overall, 44.0% of respondents reported contracting a confirmed or suspected zoonoses, most frequently dermatophytosis (58.6%). In veterinary professionals who had previous experience of managing zoonotic cases, time or financial constraints and a concern for adverse animal reactions were not perceived as barriers to use of personal protective equipment (PPE). For those working in large animal practice, the most significant motivator for using PPE was concerns over liability. When assessing responses to a range of different "infection control attitudes", veterinary nurses tended to have a more positive perspective, compared with veterinary surgeons. Our results demonstrate that IPCs are not always adhered to, and factors influencing motivators and barriers to compliance are not simply based on knowledge and experience. Educating veterinary professionals may help improve compliance to a certain extent, however increased knowledge does not necessarily equate to an increase in risk-mitigating behaviour. This highlights that the construction of risk is complex and circumstance-specific and to get a real grasp on compliance with IPCs, this construction needs to be explored in more depth. PMID- 28010907 TI - Efficacy of vaccination for bluetongue virus serotype 8 performed shortly before challenge and implications for animal trade. AB - Vaccination is the most effective strategy for controlling Bluetongue virus (BTV) spread and economic consequences thereof. In this study we verified in sheep, using one commercially available inactivated vaccine for BTV-8 (BTVPUR AlSap 8), when, during the recommended vaccination schedule, animals start to be effectively protected against challenge with wild-type strain. To this aim, sheep were challenged at different time points shortly after the first vaccine injection. Twenty-four Sarda sheep were divided into four groups vaccinated two weeks before challenge (Group A), one week before challenge (Group B) and concurrently with challenge (Group C). A second vaccine was performed twenty eight days later with respect the first vaccine administration in each experimental group. The last group consisted of six non vaccinated-infected animals (NVIA). Virological and serological examinations were performed before and after challenge up to 42 and 77days post challenge, respectively. The results of the study show that vaccination commenced as little as two weeks before challenge (Group A) prevented viremia and RNAemia in challenged sheep altogether. Conversely, Group B was partially protected from challenge and Group C showed viraemia and RNAemia similar to NVIA. This study indicates that the first administration of inactivated vaccine performed two weeks before challenge was able to prevent viraemia. Overall, our findings may have direct consequences for the management of an unexpected BTV-8 outbreak in sheep and for the legislation on sheep trade from BTV restriction areas. PMID- 28010908 TI - Impact of Mycobacterium avium subspecies paratuberculosis on profit efficiency in semi-extensive dairy sheep and goat farms of Apulia, southern Italy. AB - A recent study on paratubercolosis in semi-extensive dairy sheep and goat farms in Apulia revealed a flock positivity of 60.5% and a seroprevalence of 3.0% for sheep and 14.5% for goat, with peaks of 50%. In such a context, providing detailed economic information is crucial for the implementation of a suitable control plan. In this paper we investigated the impact of Mycobacterium avium subspecies paratuberculosis (MAP) on profit efficiency of the Apulian dairy sheep and goat farms. Empirical results through a stochastic frontier model showed that the uninfected farms had a mean level of profit efficiency of 84%, which dropped to 64% in the presence of paratubercolosis as it negatively affected the productivity of feeding, veterinary and labour factors. Structural, managerial and production aspects were involved in the greater inefficiency of the infected farms compared to the uninfected ones: lower experience and schooling of farmers, no access to credit, fewer family members (women in particular) participating in the farming activities, high density of animals per hectare, small flocks, high number of goats in mixed flocks, no confinement practices for young and purchased animals and no pasture rotation. Hence, targeted interventions on these factors by decision makers can ensure effectiveness and efficiency to veterinary and economic action plans. PMID- 28010909 TI - A meta-analysis of the rates of Staphylococcus aureus and methicillin-resistant S aureus contamination on the surfaces of environmental objects that health care workers frequently touch. AB - BACKGROUND: Health care workers may potentially spread Staphylococcus aureus and methicillin-resistant S aureus (MRSA) to patients by contaminated high-touch items. We aimed to determine the pooled rates of S aureus and MRSA contamination and influencing factors. METHODS: A literature search of the PubMed, ScienceDirect, Embase, Ovid, and Scopus databases was performed. Pooled contamination rates were determined using random effect models. Subgroup and meta regression analyses were conducted to identify factors potentially influencing the rates of S aureus and MRSA contamination. Sensitivity and publication bias analyses were performed. RESULTS: Thirty-eight studies were included in the meta analysis. The pooled contamination rates were 15.0% (95% confidence interval [CI], 9.8%-21.1%) for S aureus and 5.0% (95% CI, 2.7%-7.7%) for MRSA. The subgroup analyses indicated that the pooled rate of S aureus contamination was significantly higher for studies conducted in South America, in developing countries, and during 2010-2015. The pooled rate of MRSA contamination was significantly higher for studies conducted in Africa. The meta-regression analysis suggested that the pooled rate of S aureus contamination was lower for studies conducted in developed countries (odds ratio, 0.664; 95% CI, 0.509-0.867; P = .004). No bias was found in the publication of the rates of S aureus and MRSA contamination. CONCLUSIONS: S aureus and MRSA contamination statuses of high touch items are worrisome and should be paid greater attention. Developing country status was a risk factor for S aureus contamination. PMID- 28010910 TI - Contrast-Enhanced Computed Tomography in Intensive Care Unit Patients With Acute Clinical Deterioration: Impact of Hyperattenuating Adrenal Glands. AB - PURPOSE: The study sought to assess the frequency and prognostic value of hyperattenuating adrenal glands on contrast-enhanced computed tomography (CT) scans of surgical intensive care unit (ICU) patients with acute clinical deterioration. METHODS: Eighty-eight consecutive ICU patients (63.2 +/- 14.5 years of age) were included in this retrospective analysis. All patients underwent biphasic contrast-enhanced CT due to an acute clinical deterioration. Hyperattenuation of the adrenal glands was assessed subjectively and objectively. Subjective presence or absence of hyperattenuating adrenal glands was assessed by 2 blinded radiologists (J.B. and R.S.L.) in consensus. Hounsfield units (HU) were measured in the adrenal glands and in the inferior vena cava. Objective hyperattenuation was defined as HU (adrenal glands) > HU (inferior vena cava) with a 15-HU threshold. Death within 14 days following CT was set as endpoint and acquired from electronic patient data. RESULTS: Thirty-eight patients (43.2%, Group Asubj) exhibited hyperattenuation of the adrenal glands, whereas 50 patients (56.8%, Group Bsubj) did not. Concerning the objective analysis, 31 patients (35.2%, Group Aobj) exhibited hyperdense adrenal glands, whereas 53 patients (64.8%, Group Bobj) did not. Overall 27 of 88 patients (30.6%) died within 14 days following the CT examination. Lethal outcome was significantly more frequent among patients in Group Asubj and Aobj (19 of 38 patients [50.0%] and 15 of 31 patients [48.4%]) as compared with patients in Group Bsubj (8 of 50 patients [16.0%]) and Group Bobj (12 of 57 patients [21.1%]; P < .05). Subjective and objective analysis correlated significantly (P < .05). CONCLUSIONS: Hyperattenuation of adrenal glands on contrast-enhanced CT of ICU patients with acute clinical deterioration is associated with a high mortality and might serve as a prognostic marker for patients' outcome. PMID- 28010911 TI - Variations in Magnetic Resonance Imaging Provision and Processes Among Canadian Academic Centres. AB - PURPOSE: Increasing demand has led to questions regarding the appropriateness of advanced imaging exams, particularly for magnetic resonance imaging (MRI). The study aimed to explore variability in MRI service provision and request variation within Canadian academic medical imaging departments, particularly factors potentially affecting appropriate MRI service provision. METHODS: All Canadian academic centres with medical imaging residency programs were invited to participate. Participation involved completing an institution-level survey and submitting exam requests for all MRI exams completed in a common 24-hour period. The surveys and request forms were analysed and contrasted. RESULTS: The 13 participating institutions reported scanner operating hours per week ranging from 101-672; large urban centres typically had higher hours. A total of 42% of sites housed multiple scanners, and 28% housed a 3-T scanner. Most accept requests from all general practitioners and specialists. Only 1 institution has a solely electronic request submission process. Requisitions are focused on patient safety, including contrast considerations, metallic foreign bodies, and implants. Request prioritization scales vary substantially across institutions. Few use referral guidelines to evaluate request appropriateness. CONCLUSIONS: Our analysis showed great variation among facility-level factors such as hours of operation, request forms, and prioritization scales among institutions and facilities. Opportunities exist to create standardized processes and improve request forms to focus more on specific information required for appropriateness, increase consistency in patient care, and promote demand balancing, minimizing unnecessary exams and therefore reducing wait times. PMID- 28010912 TI - Age as a differential factor in patients with bacteremia. PMID- 28010913 TI - Serum proteome and hepatitis C virus: Further issues to be discussed. PMID- 28010914 TI - Reconstructions Using RIF in Motion Mapping Technique Have Substantially Less Arrhythmogenic Artifacts in Dual-source Coronary CTA. AB - RATIONALE AND OBJECTIVES: Particularly for patients with heart arrhythmias, conventional BestSystole (BS) and BestDiastole (BD) reconstruction techniques in computed tomography (CT) frequently show artifacts that hinder the readability of the coronary tree. To address this problem, this paper presents an alternative reconstruction method that combines the technique "reconstructions with identical filling" (RIF) with motion mapping: This new technique is called "RIF in motion mapping" (RIMM). This study compares the diagnostic quality of images generated with RIMM to that of the other reconstruction techniques. MATERIALS AND METHODS: Having shown major artifacts in standard reconstructions, the CT datasets of 23 patients with suspected coronary artery disease or prior to transcatheter aortic valve replacement were selected manually. Each dataset was evaluated with four reconstruction techniques: BS, BD, RIF, and RIMM. Two radiologists, blinded to the applied reconstruction type, then evaluated the entire coronary tree of each sample using the 15-segment American Heart Association model and the six-grade Likert scale. RESULTS: Of the 345 analyzed coronary segments, the RIMM technique showed a significant number of images with reliable diagnostic quality (n = 228, 66%) as compared to RIF (P = 0.002) and BS/BD reconstructions (P < 0.001). Per coronary segment, vessel, and patient, the RIMM technique scored significantly better than the conventional BS/BD reconstructions (P = 0.003) and better than the RIF reconstructions with regard to the right coronary artery (P = 0.041). CONCLUSIONS: This new technique works: Using RIMM on the worst CT images substantially erased many of these artifacts, thereby enabling the radiologists to clearly visualize these segments. As RIMM considerably eliminates artifacts, this new CT reconstruction technique can help make a fast reliable evaluation of a patient's coronary tree. Thus, this enhanced visualization of cardiac images by RIMM avoids the need for further invasive diagnostic procedures. PMID- 28010915 TI - The Use of Tomosynthesis in the Global Study of Knee Subchondral Insufficiency Fractures. AB - RATIONALE AND OBJECTIVES: Subchondral insufficiency fractures (SIF), previously termed spontaneous osteonecrosis of the knee, are marked by a sudden onset of severe pain. Other than the size of the lesion, prediction for progression to joint replacement is difficult. The objective was to determine if quantitative analysis of bone texture using digital tomosynthesis imaging would be useful in predicting more rapid progression to joint replacement. MATERIALS AND METHODS: Tomosynthesis studies of 30 knees with documented SIF were quantified by fractal, mean intercept length (MIL), and line fraction deviation analyses. Fractal dimension, lacunarity, MIL, and line fraction deviation variables measured from these analyses were then correlated to short interval progression to joint replacement surgery. RESULTS: Higher odds for joint replacement were related to higher values of the standard deviation of slope lacunarity and to morphometric measures (eg, MIL). CONCLUSIONS: Using digital tomosynthesis images for bone texture assessment may help distinguish condylar bone response in SIF, potentially acting as a clinically relevant predictive tool. In the future, contrasting SIF to the more gradual long-term process of osteoarthritis, there may be a better understanding of the different mechanisms for the two conditions. PMID- 28010916 TI - Perspectives on the International Classification of Diseases, 11th Revision, developments in allergy clinical practice in the United States. PMID- 28010917 TI - Technical challenges and safety of magnetic resonance imaging with in situ neuromodulation from spine to brain. PMID- 28010918 TI - Neuroplasticity and neuromodulation in children. PMID- 28010919 TI - Deep Brain Stimulation for Childhood Dystonia: Is "where" as important as in "whom"? PMID- 28010920 TI - Computer aided diagnosis of Coronary Artery Disease, Myocardial Infarction and carotid atherosclerosis using ultrasound images: A review. AB - The diagnosis of Coronary Artery Disease (CAD), Myocardial Infarction (MI) and carotid atherosclerosis is of paramount importance, as these cardiovascular diseases may cause medical complications and large number of death. Ultrasound (US) is a widely used imaging modality, as it captures moving images and image features correlate well with results obtained from other imaging methods. Furthermore, US does not use ionizing radiation and it is economical when compared to other imaging modalities. However, reading US images takes time and the relationship between image and tissue composition is complex. Therefore, the diagnostic accuracy depends on both time taken to read the images and experience of the screening practitioner. Computer support tools can reduce the inter operator variability with lower subject specific expertise, when appropriate processing methods are used. In the current review, we analysed automatic detection methods for the diagnosis of CAD, MI and carotid atherosclerosis based on thoracic and Intravascular Ultrasound (IVUS). We found that IVUS is more often used than thoracic US for CAD. But for MI and carotid atherosclerosis IVUS is still in the experimental stage. Furthermore, thoracic US is more often used than IVUS for computer aided diagnosis systems. PMID- 28010921 TI - Digital breast tomosynthesis: Dose and image quality assessment. AB - The aim of this work was to evaluate how different acquisition geometries and reconstruction parameters affect the performance of four digital breast tomosynthesis (DBT) systems (Senographe Essential - GE, Mammomat Inspiration - Siemens, Selenia Dimensions - Hologic and Amulet Innovality - Fujifilm) on the basis of a physical characterization. Average Glandular Dose (AGD) and image quality parameters such as in-plane/in-depth resolution, signal difference to noise ratio (SDNR) and artefact spread function (ASF) were examined. Measured AGD values resulted below EUREF limits for 2D imaging. A large variability was recorded among the investigated systems: the mean dose ratio DBT/2D ranged between 1.1 and 1.9. In-plane resolution was in the range: 2.2mm-1-3.8mm-1 in chest wall-nipple direction. A worse resolution was found for all devices in tube travel direction. In-depth resolution improved with increasing scan angle but was also affected by the choice of reconstruction and post-processing algorithms. The highest z-resolution was provided by Siemens (50 degrees , FWHM=2.3mm) followed by GE (25 degrees , FWHM=2.8mm), while the Fujifilm HR showed the lowest one, despite its wide scan angle (40 degrees , FWHM=4.1mm). The ASF was dependent on scan angle: smaller range systems showed wider ASF curves; however a clear relationship was not found between scan angle and ASF, due to the different post processing and reconstruction algorithms. SDNR analysis, performed on Fujifilm system, demonstrated that pixel binning improves detectability for a fixed dose/projection. In conclusion, we provide a performance comparison among four DBT systems under a clinical acquisition mode. PMID- 28010922 TI - Risk factors for symptomatic venous and arterial thromboembolism in newborns, children and adolescents - What did we learn within the last 20years? AB - Venous thrombosis (VTE) in children is increasingly diagnosed, as advanced medical care has increased treatment intensity of hospitalized pediatric patients. The aim of this review was to summarize the data available and to discuss the controversial issue of thrombophilia screening in the light of the pediatric data available. Follow-up data for VTE recurrence in children suggest a recurrence rate between 3% (neonates) and 21% in individuals with unprovoked VTE. Apart from underlying medical conditions, recently reported systematic reviews on pediatric VTE (70% provoked) have shown significant associations between thrombosis and presence of protein C-, protein S- and antithrombin deficiency, factor 5 (F5: rs6025), factor 2 (F2: rs1799963), even more pronounced when combined inherited thrombophilias [IT] were involved. The F2 mutation, protein C , protein S-, and antithrombin deficiency did also play a significant role at VTE recurrence. Although we have learned more about the pathophysiology of VTE with the increased discovery of IT evidence is still lacking as to whether IT influence the clinical outcome in pediatric VTE. It still remains controversial as to whether children with VTE or offspring from thrombosis-prone families benefit from IT screening. Thus, IT testing in children should be individualized. PMID- 28010923 TI - Biomonitoring of gasoline station attendants exposed to benzene: Effect of gender. AB - Women are employed in increasing numbers as gasoline station attendants, a work category with risk of exposure to benzene. We have assessed the effect of gender on biomarkers of occupational benzene exposure. Gasoline station attendants (20 men and 20 women) and 40 control individuals (20 men and 20 women) with no history of occupational benzene exposure were evaluated. Benzene exposure was monitoring by environmental and biological measurements. Urinary trans,trans muconic acid levels, well-known genetic and hematological alterations linked to benzene exposure, and non-cancer effects on the immune, hepatic, and renal systems were investigated. Our results suggest a potential effect of gender on some effects of occupational benzene exposure, particularly the hematological parameters and trans,trans-muconic acid levels. Despite limitations of our study, our findings provide important considerations about occupational exposure of women to benzene and may contribute to the development of occupational protection standards. PMID- 28010924 TI - Upregulation of NRF2 through autophagy/ERK 1/2 ameliorates ionizing radiation induced cell death of human osteosarcoma U-2 OS. AB - The antioxidative response mediated by transcription factor NRF2 is thought to be a pivotal cellular defense system against various extrinsic stresses. It has been reported that activation of the NRF2 pathway confers cells with resistance to ionizing radiation-induced damage. However, the underlying mechanism remains largely unknown. In the current research, it was found that alpha-particle radiation has the ability to stimulate NRF2 expression in human osteosarcoma U-2 OS cells. Knockdown of cellular NRF2 level by shRNA-mediated gene silencing decreased the survival rate, increased the micronucleus formation rate and apoptosis rate in irradiated cells. Consistently, knockdown of NRF2 resulted in decreased expression of p65 and Bcl-2, and increased expression of p53 and Bax. Besides, it was observed that increased expression of NRF2 was partially dependent on radiation induced phosphorylation of ERK 1/2. Further results showed that radiation promoted autophagy flux which leads to the enhanced phosphorylation of ERK 1/2, as evidenced by the resultls that knockdown of ATG5 (Autophagy protein 5) gene by shRNA suppressed both radiation induced ERK 1/2 phosphorylation and NRF2 upregulation. Based on these results, it is proposed that attenuation of NRF2 antioxidative pathway can sensitize U-2 OS cells to radiation, where NRF2 antioxidative response is regulated by autophagy mediated activation of ERK 1/2 kinases. PMID- 28010925 TI - Effects of chronic restraint-induced stress on radiation-induced chromosomal aberrations in mouse splenocytes. AB - Both ionizing radiation (IR) and psychological stress (PS) cause detrimental effects on humans. A recent study showed that chronic restraint-induced PS (CRIPS) diminished the functions of Trp53 and enhanced radiocarcinogenesis in Trp53-heterozygous (Trp53+/-) mice. These findings had a marked impact on the academic field as well as the general public, particularly among residents living in areas radioactively contaminated by nuclear accidents. In an attempt to elucidate the modifying effects of CRIPS on radiation-induced health consequences in Trp53 wild-type (Trp53+/+) animals, investigations involving multidisciplinary analyses were performed. We herein demonstrated that CRIPS induced changes in the frequency of IR-induced chromosomal aberrations (CAs) in splenocytes. Five-week old male Trp53+/+ C57BL/6J mice were restrained for 6h per day for 28 consecutive days, and total body irradiation (TBI) at a dose of 4Gy was performed on the 8th day. Metaphase chromosome spreads prepared from splenocytes at the end of the 28 day restraint regimen were painted with fluorescence in situ hybridization (FISH) probes for chromosomes 1, 2, and 3. The results obtained showed that CRIPS alone did not induce CAs, while TBI caused significant increases in CAs, mostly translocations. Translocations appeared at a lower frequency in mice exposed to TBI plus CRIPS than in those exposed to TBI alone. No significant differences were observed in the frequencies of the other types of CAs (insertions, dicentrics, and fragments) visualized with FISH between these experimental groups (TBI+CRIPS vs. TBI). These results suggest that CRIPS does not appear to synergize with the clastogenicity of IR. PMID- 28010926 TI - Increased methylation of repetitive elements and DNA repair genes is associated with higher DNA oxidation in children in an urbanized, industrial environment. AB - DNA methylation in DNA repair genes participates in the DNA damage regulation. Particulate matter (PM), which has metals and polycyclic aromatic hydrocarbons (PAHs) adsorbed, among others has been linked to adverse health outcomes and may modify DNA methylation. To evaluate PM exposure impact on repetitive elements and gene-specific DNA methylation and DNA damage, we conducted a cross-sectional study in 150 schoolchildren (7-10 years old) from an urbanized, industrial area of the metropolitan area of Mexico City (MAMC), which frequently exhibits PM concentrations above safety standards. Methylation (5mC) of long interspersed nuclear element-1 (LINE1) and DNA repair gene (OGG1, APEX, and PARP1) was assessed by pyrosequencing in peripheral mononuclear cells, DNA damage by comet assay and DNA oxidation by 8-OHdG content. PAH and metal contents in PM10 (<=10MUm aerodynamic diameter) were determined by HPLC-MS and ICP-AES, respectively. Multiple regression analysis between DNA methylation, DNA damage, and PM10 exposure showed that PM10 was significantly associated with oxidative DNA damage; a 1% increase in 5mC at all CpG sites in PARP1 promoter was associated with a 35% increase in 8-OHdG, while a 1% increase at 1, 2, and 3 CpG sites resulted in 38, 9, and 56% increments, respectively. An increase of 10pg/m3 in benzo[b]fluoranthene content of PM10 was associated with a 6% increase in LINE1 methylation. Acenaphthene, indene [1,2,3-cd] pyrene, and pyrene concentrations correlated with higher dinucleotide methylation in OGG1, APEX and PARP1 genes, respectively. Vanadium concentration correlated with increased methylation at selected APEX and PARP1 CpG sites. DNA repair gene methylation was significantly correlated with DNA damage and with specific PM10-associated PAHs and Vanadium. Data suggest that exposure to PM and its components are associated with differences in DNA methylation of repair genes in children, which may contribute to DNA damage. PMID- 28010927 TI - Assessing the genotoxicity of two commonly occurring byproducts of water disinfection: Chloral hydrate and bromal hydrate. AB - Water disinfection treatments result in the formation of disinfection byproducts (DBPs) that have been linked to adverse human health outcomes including higher incidence of bladder and colorectal cancer. However, data about the genotoxicity of DBPs is limited to only a small fraction of compounds. Chloral hydrate (CH) and bromal hydrate (BH) are two trihaloacetaldehydes commonly detected in disinfected waters, but little is known about their genotoxicity, especially BH. We investigated the genotoxicity of CH and BH using a test battery that includes three in vitro genotoxicity assays. We conducted the Ames test using Salmonella bacterial strains TA97a, TA98, TA100 and TA102, and the alkaline comet assay and the micronucleus test both using Chinese hamster ovary cells. We carried out the tests in the absence and presence of the metabolic fraction S9 mix. CH did not exhibit statistically significant genotoxic effects in any of the three assays. In contrast, BH exhibited mutagenic activity in the Salmonella strain TA100 and induced statistically significant DNA lesions in CHO cells as appeared in the comet assay. The genotoxic potential of BH in both assays decreased in the presence of the metabolic fraction S9 mix. BH did not induce chromosomal damage in CHO cells. Our results show that BH exhibited genotoxic activity by causing mutations and primary DNA damage while CH did not induce genotoxic effects. Our findings highlight concerns about the higher genotoxicity of brominated DBPs in comparison to their chlorinated analogues. PMID- 28010928 TI - Ganoderma lucidum total triterpenes induce apoptosis in MCF-7 cells and attenuate DMBA induced mammary and skin carcinomas in experimental animals. AB - Ganoderma lucidum total triterpenes were evaluated for its apoptosis-inducing and anti-cancer activities. Cytotoxicity and pro-apoptotic effect of total triterpenes were evaluated in human breast adenocarcinoma (MCF-7) cell line using MTT assay and DNA fragmentation analysis. Total triterpenes induced apoptosis in MCF-7 cells by down-regulating the levels of cyclin D1, Bcl-2, Bcl-xL and also by up-regulating the levels of Bax and caspase-9. Anti-carcinogenicity of total triterpenes was analysed using dimethyl benz [a] anthracene (DMBA) induced skin papilloma and mammary adenocarcinoma in Swiss albino mice and Wistar rats respectively. Topical application of 5mg, 10mg and 20mg total triterpenes reduced the incidence of skin papilloma by 62.5, 37.5 and 12.5% respectively. Incidence of the mammary tumour was also reduced significantly by 33.33, 66.67 and 16.67% in 10, 50 and 100mg/kg b.wt. total triterpenes treated animals respectively. Total triterpenes were also found to reduce the average number of tumours per animal and extended the tumour latency period in both the models. The results indicate the potential cytotoxicity and anti-cancerous activity of total triterpenes, there by opens up a path to the development of a safe and successive chemo preventive agent of natural origin. PMID- 28010929 TI - Dr. Galen Wagner (1939-2016) as an Academic Writer: An Overview of his Peer reviewed Scientific Publications. PMID- 28010932 TI - Stereotactic precision and conventional radiotherapy evaluation (SPACE)-Trial for medically inoperable Stage I NSCLC: A lost opportunity? PMID- 28010933 TI - Paediatric fingertip composite grafts: Do they all go black? AB - BACKGROUND: Fingertip injuries are amongst the most frequently seen hand injuries in the paediatric population. The present study evaluated the composite graft survival rate in distal digital amputations with respect to injury type, amputation level and time to surgery. METHODS: We performed a retrospective review of patients who underwent composite grafting of fingertip injuries over an 11-year period at a paediatric hospital. All children who underwent non vascularized replantation of amputated fingertips were included. Patients were excluded if they failed to attend at least one follow-up appointment. Demographic information was recorded. The nature and level of injury and time to surgery was also recorded. Graft viability was characterized as no take, partial take, or complete take. The number of secondary procedures and number and duration of follow-up appointments were recorded. RESULTS: A total of 105 patients underwent fingertip composite grafting, of whom 96 were suitable for inclusion in this study. The median age was 2.4 years (0-16 years); there were 48 boys (46%) and 57 girls (54%). Thirty-one patients had no graft take (32%), 50 patients had partial take (52%) and 15 patients had complete take (16%). Only two patients underwent secondary revision (2%). The median number of follow-up appointments was 4, and the mean follow-up time was 68 days. Time to surgery or level of amputation did not have a statistically significant influence on outcome. CONCLUSIONS: Over two thirds of composite grafts in children showed some degree of take, albeit partially in the majority. Morbidity was low, and most children did not require further surgery. PMID- 28010934 TI - Facilitating shared decision-making with breast augmentation patients: Acceptability of the PEGASUS intervention. AB - BACKGROUND: PEGASUS is an intervention to facilitate shared decision-making by helping prospective patients consider their expectations of surgery, so that surgeons have a clear understanding of their individual goals. To date, shared decision-making interventions within aesthetic surgery are lacking. The present mixed methods study therefore explored the acceptability of implementing PEGASUS into routine private practice with breast augmentation patients and aesthetic providers. METHOD: Seventeen women presenting for breast augmentation surgery from three practices received the PEGASUS intervention pre-operatively and completed a process evaluation post-operatively. Semi-structured interviews exploring 3 aesthetic providers' experiences of using PEGASUS were subjected to a thematic analysis, whilst a content analysis was conducted on the 77 goals identified by patients. RESULTS: The majority of patients reported that the PEGASUS intervention was relevant, helpful and useful, and they felt comfortable during it. Qualitatively, patients and aesthetic providers found that PEGASUS enabled them to reflect on and discuss about their expectations from surgery. Aesthetic providers discussed some of the issues and barriers associated with implementing PEGASUS in routine private practice, factors that must be considered prior to further evaluation. CONCLUSION: This study provides preliminary support for the acceptability of PEGASUS to breast augmentation patients and to aesthetic providers working in the private sector. PMID- 28010935 TI - Managing a seroma with wireless mobile ultrasound device. PMID- 28010936 TI - Oscillatory shear stress, flow-mediated dilatation, and circulating microparticles at sea level and high altitude. AB - BACKGROUND AND AIMS: Exposing the endothelium to acute periods of imposed oscillatory shear stress reduces endothelial function and elevates circulating microparticles (MPs). Oscillatory shear stress may be especially pathogenic when superimposed on hypoxia, an environmental stimulus that disrupts the endothelial milieu. We examined the effects of acute manipulation of oscillatory shear stress on endothelial function and circulating MPs at sea level (SL) and high altitude (HA). METHODS: Healthy adults (n = 12) participated, once at SL and once on the second or third day at HA (3800 m). Oscillatory shear stress was provoked using a 30-min distal cuff occlusion intervention (75 mmHg). Endothelial function was assessed before and immediately after the intervention in the brachial artery by reactive hyperaemia flow-mediated dilatation (FMD). Venous blood samples of MPs (flow cytometry) were obtained before and during the last five minutes of the shear intervention. RESULTS: At baseline, circulating MPs were two-fold higher at HA (p = 0.011) and brachial artery diameter was constricted (p = 0.015). Although the intervention at SL increased endothelial-derived MPs by 83 +/- 39% (mean +/- SEM; p = 0.021), FMD was unaltered. Conversely, at HA, the intervention elicited a 26 +/- 11% reduction in FMD (p = 0.020); this reduction was inversely correlated with the change in total circulating MPs (r = -0.737, p = 0.006) and the change in endothelial-derived MPs (r = -0.614, p = 0.034). CONCLUSIONS: The vascular endothelium appears to be susceptible to periods of oscillatory shear stress at HA, where impairments in endothelium-dependent vasodilatation may be amplified by endothelial injury. These findings have important implications for understanding the early impact of clinical situations of hypoxaemia on the vascular endothelium. PMID- 28010937 TI - Clinical Relevance of the Nonvisualized Appendix on Ultrasonography of the Abdomen in Children. AB - OBJECTIVES: To evaluate the clinical relevance of the nonvisualized appendix on ultrasound imaging in children with right lower quadrant pain. STUDY DESIGN: We reviewed 1359 children admitted for abdominal pain between January and December 2013 who had abdominal ultrasound imaging for right lower quadrant pain. Patients who had scans for genitourinary symptoms or intussusception were excluded from the study. When the appendix was not visualized, secondary signs indicating right lower quadrant inflammatory pathology were noted. RESULTS: Of all admissions for abdominal pain, 810 had ultrasound scans. Thirty-eight did not evaluate the appendix and 131 were excluded for suspected intussusception, leaving 641 reports for children with a median age of 10.8 years (range, 1.3-21.3); 297 were boys (46.3%). There were 17 of 160 patients with a nonvisualized appendix (10.6%) who underwent appendectomy. Of these, 14 had secondary signs on ultrasound imaging and 3 (1.9%) had normal ultrasound reports. The 3 patients with normal ultrasound imaging had computed tomography imaging confirming appendicitis. There were 51 patients with a partially visualized appendix. The segment of appendix that could be seen was normal in 34 patients, none of whom had appendectomy. The remaining 17 had appendectomy, in whom the appendix seemed to be inflamed in 13 and equivocal in 4, all with histologically confirmed appendicitis. Overall, 232 children underwent appendectomy; 58 had no ultrasound imaging done, and 5 had a histologically normal appendix (overall negative appendectomy rate, 2.2%). Only 35 of 1359 patients (0.03%) had computed tomography scans. CONCLUSION: In patients with a nonvisualized appendix on ultrasound imaging and no evidence of secondary inflammatory changes, the likelihood of appendicitis is less than 2%. Generous use of ultrasonography as an adjunct to clinical examination can achieve low negative appendectomy rates without underdiagnosis of acute appendicitis. PMID- 28010938 TI - Deep Lamellar Endothelial Keratoplasty Clinical Outcome: The 13- to 18-year Follow-up. PMID- 28010939 TI - Disentangling subgroups of participants recruiting shared as well as different brain regions for the execution of the verb generation task: A data-driven fMRI study. AB - The spatial pattern of task-related brain activity in fMRI studies might be expected to change according to several variables such as handedness and age. However this spatial heterogeneity might also be due to other unmodeled sources of inter-subject variability. Since group-level results reflect patterns of task evoked brain activity common to most of the subjects in the sample, they could conceal the presence of subgroups recruiting other brain regions beyond the common pattern. To deal with these issues, data-driven methods can be used to detect the presence of sources of inter-subject variability that might be hard to identify and therefore model a priori. Here we assess the potential of Independent Component Analysis (ICA) to detect the presence of unexpected subgroups of participants. To this end, we acquired task-evoked fMRI data on 45 healthy adults using the verb generation (VGEN) task, in which participants are visually presented with the noun of an object of everyday use, and asked to covertly generate a verb describing the corresponding action. As expected, the task elicited activity in a temporo-parieto-frontal network typically found in previous VGEN experiments. We then quantified the contribution of every subject to nine task-related spatio-temporal processes identified by ICA. A cluster analysis of this quantity yielded three subgroups of participants. Differences between the three identified subgroups were distributed in left and right prefrontal, posterior parietal and extrastriate occipital regions. These results could not be explained by differences in sex, age or handedness across the participants. Furthermore, some regions where a significant difference was found between subgroups were not present in the group-level pattern of task-related activity. We discuss the potential application of this approach for characterizing brain activity in different subgroups of patients with neuropsychiatric or neurological conditions. PMID- 28010940 TI - [Profile of heart failure according to the department of admission. Implications for multidisciplinary management]. AB - INTRODUCTION: Population aging has led to notable changes in heart failure admissions. The aim of this study was to analyse the characteristics, comorbidity, management, and outcomes of this patient population in three hospital departments. METHODS: An analysis was made of a prospective register that included all patients admitted due to heart failure in Internal Medicine, Cardiology, and Geriatrics over a period of 45 days. RESULTS: Of a total of 235 patients, 124 (52.7%) were admitted to Internal Medicine, 83 (35.3%) to Cardiology, and 28 (11.9%) to Geriatrics. Mean age was 77.0+/-20.2 years (Cardiology 71.5+/-13.5; Internal Medicine 79.2+/-21.1; Geriatrics 89.9+/-5.1; p<.001). Preserved ejection fraction was found in 121 (51.5%) patients, and this rate was higher in Internal Medicine (62.5%) and Geriatrics (70.0%) than in Cardiology (31.3%), p<.001. Comorbidity was frequent, especially atrial fibrillation (126; 53.6%), renal disease (89; 37.8%), and chronic obstructive pulmonary disease (65; 27.6%). Infections were the most common decompensating trigger in Internal Medicine (56; 45.2%), and there was often no trigger in Cardiology (45; 54.2%) and Geriatrics (14; 50.0%), p<.0001. The use of renin angiotensin system inhibitors, beta-blockers, and spironolactone in patients with systolic dysfunction was higher in Cardiology. During the 45 days follow-up, 23 patients (9.9%) were readmitted, which was more frequent in Internal Medicine than in Cardiology (odds ratio 3.0 [95% confidence interval: 1.1 - 8.6], p=.03), with no other significant comparisons. CONCLUSIONS: Patients admitted due to decompensated heart failure are elderly and often have comorbidities. There are major differences between departments as regards age and clinical profile. PMID- 28010941 TI - [French translation of the clinical practice guideline on management of patients with diabetes and chronic kidney disease stage 3B or higher (eGFR<45mL/min/1.73 m2)]. PMID- 28010942 TI - Syndrome of inappropriate antidiuretic hormone secretion in a case of olfactory neuroblastoma without anti-diuretic hormone immunoreactivity: A case report and review of the literature. AB - Olfactory neuroblastoma (ONB) is a relatively rare nasal or paranasal malignant tumor. This tumor is rarely accompanied by paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Here, we report a 31-year-old female with histologically confirmed ONB who had been diagnosed with SIADH three years prior. She was treated with surgery followed by concurrent chemoradiotherapy. SIADH resolved immediately after surgical tumor resection. Immunohistochemically, both biopsy and resected specimens from the nasal cavity had been negative for ADH. Although extremely rare, ONB may be associated with SIADH, and the possibility of this cancer should be taken into account during the follow-up of idiopathic SIADH. PMID- 28010943 TI - Neck dissection with harmonic scalpel and electrocautery? A randomised study. AB - OBJECTIVE: Is the use of harmonic scalpel for neck dissection useful? Literature search did not show a single, prospective, randomised control trial. We intended to study the role of harmonic scalpel in neck dissection and compare it with conventional electrocautery technique for oral cavity carcinoma. METHODS: 40 patients undergoing selective neck dissection for primary oral cavity malignancy were enrolled in this study. The harmonic scalpel (HS) group consisted of 20 patients, and the electrocautery technique (ET) group comprised of 20 patients. The following variables were examined: intraoperative blood loss, operative time, number of ligatures used, postoperative drain, and postoperative hospital stay. RESULTS: Intraoperative blood loss was found to be significantly reduced in harmonic scalpel group as compared to electrocautery group. However, we found no difference in other parameters like operative time, postop drain, postoperative hospital stay and number of ligatures used between both groups. CONCLUSION: Harmonic scalpel for neck dissection is associated with significantly lesser intraoperative blood loss as compared to electrocautery. There is no effect on operative time and postoperative hospital stay in both groups. PMID- 28010944 TI - Reply to "Spontaneous coronary artery dissection was missed but not misdiagnosed as takotsubo syndrome". PMID- 28010945 TI - Impact of material and morphological parameters on the mechanical response of the lumbar spine - A finite element sensitivity study. AB - Finite element models are frequently used to study lumbar spinal biomechanics. Deterministic models are used to reflect a certain configuration, including the means of geometrical and material properties, while probabilistic models account for the inherent variability in the population. Because model parameters are generally uncertain, their predictive power is frequently questioned. In the present study, we determined the sensitivities of spinal forces and motions to material parameters of intervertebral discs, vertebrae, and ligaments and to lumbar morphology. We performed 1200 model simulations using a generic model of the human lumbar spine loaded under pure moments. Coefficients of determination and of variation were determined for all parameter and response combinations. Material properties of the vertebrae displayed the least impact on results, whereas those of the discs and morphology impacted most. The most affected results were the axial compression forces in the vertebral body and in several ligaments during flexion and the facet-joint forces during extension. Intervertebral rotations were considerably affected only when several parameters were varied simultaneously. Results can be used to decide which model parameters require careful consideration in deterministic models and which parameters might be omitted in probabilistic studies. Findings allow quantitative estimation of a model's precision. PMID- 28010946 TI - Response to Letter to the Editor on "Deriving injury risk curves using survival analysis from biomechanical experiments", Journal of Biomechanics (in press). PMID- 28010947 TI - Temporal-spatial reach parameters derived from inertial sensors: Comparison to 3D marker-based motion capture. AB - Reaching is a well-practiced functional task crucial to daily living activities, and temporal-spatial measures of reaching reflect function for both adult and pediatric populations with upper-extremity motor impairments. Inertial sensors offer a mobile and inexpensive tool for clinical assessment of movement. This research outlines a method for measuring temporal-spatial reach parameters using inertial sensors, and validates these measures with traditional marker-based motion capture. 140 reaches from 10 adults, and 30 reaches from nine children aged 18-20 months, were recorded and analyzed using both inertial-sensor and motion-capture methods. Inertial sensors contained three-axis accelerometers, gyroscopes, and magnetometers. Gravitational offset of accelerometer data was measured when the sensor was at rest, and removed using sensor orientation measured at rest and throughout the reach. Velocity was calculated by numeric integration of acceleration, using a null-velocity assumption at reach start. Sensor drift was neglected given the 1-2s required for a reach. Temporal-spatial reach parameters were calculated independently for each data acquisition method. Reach path length and distance, peak velocity magnitude and timing, and acceleration at contact demonstrated consistent agreement between sensor- and motion-capture-based methods, for both adult and toddler reaches, as evaluated by intraclass correlation coefficients from 0.61 to 1.00. Taken together with actual difference between method measures, results indicate that these functional reach parameters may be reliably measured with inertial sensors. PMID- 28010948 TI - Letter to the Editor regarding "Gait recording with inertial sensors - How to determine initial and terminal contact" by Botzel and colleagues. PMID- 28010949 TI - Monocular floaters and flashes. PMID- 28010950 TI - Biomarker validation: Methods and matrix matter. PMID- 28010951 TI - Utility of Ward-Based Retinal Photography in Stroke Patients. AB - BACKGROUND: Improvements in acute care of stroke patients have decreased mortality, but survivors are still at increased risk of future vascular events and mitigation of this risk requires thorough assessment of the underlying factors leading to the stroke. The brain and eye share a common embryological origin and numerous similarities exist between the small vessels of the retina and brain. Recent population-based studies have demonstrated a close link between retinal vascular changes and stroke, suggesting that retinal photography could have utility in assessing underlying stroke risk factors and prognosis after stroke. Modern imaging equipment can facilitate precise measurement and monitoring of vascular features. However, use of this equipment is a challenge in the stroke ward setting as patients are frequently unable to maintain the required seated position, and pupil dilatation is often not feasible as it could potentially obscure important neurological signs of stroke progression. MATERIALS AND METHODS: This small study investigated the utility of a novel handheld, nonmydriatic retinal camera in the stroke ward and explored associations between retinal vascular features and stroke risk factors. This camera circumvented the practical limitations of conducting retinal photography in the stroke ward setting. RESULTS: A positive correlation was found between carotid disease and both mean width of arterioles (r = .40, P = .00571) and venules (r = .30, P = .0381). CONCLUSIONS: The results provide further evidence that retinal vascular features are clinically informative about underlying stroke risk factors and demonstrate the utility of handheld retinal photography in the stroke ward. PMID- 28010952 TI - Erratum. PMID- 28010953 TI - The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study: Rationale and Trial Protocol. AB - OBJECTIVE: The preventive effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study aims to determine the effect of pravastatin on carotid IMT in Japanese patients with hyperlipidemia who developed noncardioembolic ischemic stroke. DESIGN: This is a substudy of the J-STARS, a multicenter, randomized, open-label, blinded-end point, parallel-group trial to examine whether pravastatin reduces stroke recurrence in patients with noncardioembolic stroke. The patients are randomized to receive pravastatin (10 mg daily) or not to receive any statins. Carotid ultrasonography is performed by well-trained certified examiners in each participating institute, and the recorded data are measured centrally. The primary outcome is change in the IMT of the distal wall in a consecutive 2-cm section on the central side of the common carotid artery bifurcation over 5 years of observation. CONCLUSION: The trial may help determine if the usual dose of pravastatin for daily clinical practice in Japan can affect carotid IMT in Japanese patients with noncardioembolic stroke. PMID- 28010954 TI - Reconstructions Following Graft Infection: An Unsolved Challenge. PMID- 28010955 TI - Three-year and five-year outcomes of surgical resection for pancreatic ductal adenocarcinoma: Long-term experiences in one medical center. AB - OBJECTIVE: Pancreatic ductal adenocarcinoma is one of the most malignant types of cancer. This study evaluated the 3-year and 5-year surgical outcomes associated with the cancer and determined whether statistically identified factors can be used to predict survival. METHODS: This retrospective review was conducted from 1995 to 2010. Patients who had resectable pancreatic ductal adenocarcinoma and received surgical treatment were included. Cases of hospital mortality were excluded. The relationships between several clinicopathological factors and the survival rate were analyzed. RESULTS: A total of 223 patients were included in this study. The 3-year and 5-year survival rates were 21.4% and 10.1%, respectively, and the median survival was 16.1 months. Tumor size, N status, and resection margins were independent predictive factors for 3-year survival. Tumor size independently predicted 5-year survival. CONCLUSION: Tumor size is the most important independent prognostic factor for 3-year and 5-year survival. Lymph node status and the resection margins also independently affected the 3-year survival. These patient outcomes might be improved by early diagnosis and radical resection. Future studies should focus on the tumor biology of this aggressive cancer. PMID- 28010956 TI - Central tegmentum tract hyperintensities in pediatric neurological patients: Incidence or coincidence. AB - AIM: The central tegmental tract hyperintensities (CTTH) have been found in many different pediatric neurological conditions. There is only scarce data about the value of this radiological phenomenon. In this study we aimed to show the neurological conditions associated with this radiological finding. MATERIALS AND METHODS: We performed a retrospective analysis of all pediatric brain MRI's between 2013 and 2015. After finding those patients with CTTH, we evaluated them in the pediatric neurology clinic. RESULTS: There were 41 out of 1464 brain MRI's with CTTH with 2.8% prevalence. Thirty four patients (23 male, age range 3months 98months) were available for evaluation. CTTH were present in mainly younger age group. There were many different neurological conditions associated with CTTH. These included brain tumors, epilepsy, developmental delay, metabolic disorders and genetic syndromes. CONCLUSION: CTTH is found in many different pediatric neurological conditions. Further neuropathological and prospective MRI and clinical studies are needed to better understand this interesting radiological finding. PMID- 28010957 TI - Research domain criteria (RDoC) grows up: Strengthening neurodevelopment investigation within the RDoC framework. PMID- 28010958 TI - Comparing video and direct laryngoscope for endotracheal intubation during CPR. PMID- 28010959 TI - Urine culture guided antibiotic interventions: A pharmacist driven antimicrobial stewardship effort in the ED. AB - BACKGROUND: Antibiotics are overprescribed for abnormal urine tests including asymptomatic bacteriuria (AB), contributing to rising antimicrobial resistance rates. Pharmacists reviewed urine cultures daily from emergency department (ED) encounters to assess antibiotic appropriateness. We studied antibiotic prescribing practices and assessed compliance to national guidelines, correlations with urine analysis (UA) components, and opportunities for antimicrobial stewardship in the ED. METHODS: This quality improvement project (QIP) was a prospective cohort study at a community hospital ED, with data collected from finalized urine cultures resulting October 30, 2014 through January 5, 2015. Analyses were conducted using Chi-squared and Fisher Exact tests and stepwise multiple logistic regression. RESULTS: Urine cultures from 457 encounters were reviewed, of which 136 met the inclusion criteria as non-pregnant and asymptomatic for urinary tract infection (UTI). 43% of 136 patients were treated with antibiotics, for a total of 426 antibiotic days. Pharmacist interventions for these patients resulted in 122/426 (29%) of potential antibiotic days saved. Factors found to significantly increase the odds of antibiotic prescribing in asymptomatic patients included presence of leukocyte esterase (OR=4.5, 95% CI: 1.2-17.2; p=0.03) or nitrites (OR=10.8, 95% CI: 1.7 68.1; p=0.01) in the urine and age>=75 (OR=3.5, 95% CI: 1.2-9.6, p=0.02). DISCUSSION: Pharmacist intervention in discontinuing or modifying antibiotics for asymptomatic patients with urine cultures reduced unnecessary antibiotic exposure and was a first step in antimicrobial stewardship efforts in the ED. Future work includes limiting urine tests and subsequent antibiotic therapy for non-pregnant asymptomatic patients. PMID- 28010960 TI - Dispatcher assisted CPR: Is it still important to continue teaching lay bystander CPR? PMID- 28010962 TI - The Initial Case of Laparoscopic Nephrectomy. PMID- 28010961 TI - Synthetic peptide antigens derived from long-chain alpha-neurotoxins: Immunogenicity effect against elapid venoms. AB - Three-finger toxins (3FTXs), especially alpha-neurotoxins, are the most poorly neutralized elapid snake toxins by current antivenoms. In this work, the conserved structural similarity and motif arrangements of long-chain alpha neurotoxins led us to design peptides with consensus sequences. Eight long-chain alpha-neurotoxins (also known as Type II) were used to generate a consensus sequence from which two peptides were chemically synthesized, LCP1 and LCP2. Rabbit sera raised against them were able to generate partially-neutralizing antibodies, which delayed mice mortality in neutralization assays against Naja haje, Dendrospis polylepis and Ophiophagus hannah venoms. PMID- 28010963 TI - Kidney Stones Destroyed by Shock Waves. PMID- 28010964 TI - The Retrograde Idea of Jack Lapides: Clean Intermittent Catheterization. PMID- 28010965 TI - Where it all Began. PMID- 28010966 TI - The Hinman Syndrome. PMID- 28010967 TI - 25 Years of Experience with the AUA Symptom Index: Increasing Recognition that the Bladder is an Unreliable Witness. PMID- 28010968 TI - Effects of Castration on BPH. PMID- 28010969 TI - Percutaneous Access to the Kidney. PMID- 28010970 TI - Outcomes after Radical Nephrectomy for Renal Cell Carcinoma. PMID- 28010971 TI - The Male Factor in Fertility and Infertility. PMID- 28010972 TI - Urological Tissue Cultures. PMID- 28010974 TI - The Camey Procedure. PMID- 28010973 TI - The Gleason Grading System: The Approach that Changed Prostate Cancer Assessment. PMID- 28010975 TI - Comparison of DRE and PSA in the Detection of Prostate Cancer. PMID- 28010976 TI - OnabotulinumtoxinA for Overactive Bladder and Urinary Incontinence. PMID- 28010977 TI - Hypospadias Repair. PMID- 28010978 TI - Surgical Treatment of Prostate Carcinoma. PMID- 28010979 TI - Foreword. PMID- 28010980 TI - Physiological and Pharmacological Studies of the Prostate Gland. PMID- 28010981 TI - Foley Y-Plasty. PMID- 28010982 TI - Surgical Correction of Vesicoureteral Reflux. PMID- 28010983 TI - Intracavitary bacillus Calmette-Guerin for Superficial Bladder Tumors. PMID- 28010984 TI - Impotence after Radical Prostatectomy. PMID- 28010985 TI - Characterization of Renal Masses by Ultrasound. PMID- 28010986 TI - The Rise of Robotic Surgery in the New Millennium. PMID- 28010987 TI - Mesh, graft, or standard repair for prolapse surgery? PMID- 28010988 TI - Synthetic midurethral slings redeemed. PMID- 28010989 TI - Mesh, graft, or standard repair for women having primary transvaginal anterior or posterior compartment prolapse surgery: two parallel-group, multicentre, randomised, controlled trials (PROSPECT). AB - BACKGROUND: The use of transvaginal mesh and biological graft material in prolapse surgery is controversial and has led to a number of enquiries into their safety and efficacy. Existing trials of these augmentations are individually too small to be conclusive. We aimed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women. METHODS: We did two pragmatic, parallel-group, multicentre, randomised controlled trials for our study (PROSPECT [PROlapse Surgery: Pragmatic Evaluation and randomised Controlled Trials]) in 35 centres (a mix of secondary and tertiary referral hospitals) in the UK. We recruited women undergoing primary transvaginal anterior or posterior compartment prolapse surgery by 65 gynaecological surgeons in these centres. We randomly assigned participants by a remote web-based randomisation system to one of the two trials: comparing standard (native tissue) repair alone with standard repair augmented with either synthetic mesh (the mesh trial) or biological graft (the graft trial). We assigned women (1:1:1 or 1:1) within three strata: assigned to one of the three treatment options, comparison of standard repair with mesh, and comparison of standard repair with graft. Participants, ward staff, and outcome assessors were masked to randomisation where possible; masking was obviously not possible for the surgeon. Follow-up was for 2 years after the surgery; the primary outcomes, measured at 1 year and 2 years, were participant-reported prolapse symptoms (i.e. the Pelvic Organ Prolapse Symptom Score [POP-SS]) and condition-specific (ie, prolapse-related) quality-of-life scores, analysed in the modified intention-to treat population. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN60695184. FINDINGS: Between Jan 8, 2010, and Aug 30, 2013, we randomly allocated 1352 women to treatment, of whom 1348 were included in the analysis. 865 women were included in the mesh trial (430 to standard repair alone, 435 to mesh augmentation) and 735 were included in the graft trial (367 to standard repair alone, 368 to graft augmentation). Because the analyses were carried out separately for each trial (mesh trial and graft trial) some women in the standard repair arm assigned to all treatment options were included in the standard repair group of both trials. 23 of these women did not receive any surgery (15 in the mesh trial, 13 in the graft trial; five were included in both trials) and were included in the baseline analyses only. Mean POP-SS at 1 year did not differ substantially between comparisons (standard 5.4 [SD 5.5] vs mesh 5.5 [5.1], mean difference 0.00, 95% CI -0.70 to 0.71; p=0.99; standard 5.5 [SD 5.6] vs graft 5.6 [5.6]; mean difference -0.15, 0.93 to 0.63; p=0.71). Mean prolapse-related quality-of-life scores also did not differ between groups at 1 year (standard 2.0 [SD 2.7] vs mesh 2.2 [2.7], mean difference 0.13, 95% CI -0.25 to 0.51; p=0.50; standard 2.2 [SD 2.8] vs graft 2.4 [2.9]; mean difference 0.13, -0.30 to 0.56; p=0.54). Mean POP-SS at 2 years were: standard 4.9 (SD 5.1) versus mesh 5.3 (5.1), mean difference 0.32, 95% CI -0.39 to 1.03; p=0.37; standard 4.9 (SD 5.1) versus graft 5.5 (5.7); mean difference 0.32, -0.48 to 1.12; p=0.43. Prolapse-related quality-of-life scores at 2 years were: standard 1.9 (SD 2.5) versus mesh 2.2 (2.6), mean difference 0.15, 95% CI 0.23 to 0.54; p=0.44; standard 2.0 (2.5) versus graft 2.2 (2.8); mean difference 0.10, -0.33 to 0.52; p=0.66. Serious adverse events such as infection, urinary retention, or dyspareunia or other pain, excluding mesh complications, occurred with similar frequency in the groups over 1 year (mesh trial: 31/430 [7%] with standard repair vs 34/435 [8%] with mesh, risk ratio [RR] 1.08, 95% CI 0.68 to 1.72; p=0.73; graft trial: 23/367 [6%] with standard repair vs 36/368 [10%] with graft, RR 1.57, 0.95 to 2.59; p=0.08). The cumulative number of women with a mesh complication over 2 years in women actually exposed to synthetic mesh was 51 (12%) of 434. INTERPRETATION: Augmentation of a vaginal repair with mesh or graft material did not improve women's outcomes in terms of effectiveness, quality of life, adverse effects, or any other outcome in the short term, but more than one in ten women had a mesh complication. Therefore, follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery. FUNDING: UK National Institute of Health Research. PMID- 28010990 TI - Pelvic organ prolapse: prevention by training? PMID- 28010992 TI - Department of Error. PMID- 28010991 TI - Malnutrition in Yemen: an invisible crisis. PMID- 28010993 TI - Adverse events after first, single, mesh and non-mesh surgical procedures for stress urinary incontinence and pelvic organ prolapse in Scotland, 1997-2016: a population-based cohort study. AB - BACKGROUND: Concerns have been raised about the safety of surgery for stress urinary incontinence and pelvic organ prolapse using transvaginal mesh. We assessed adverse outcomes after first, single mesh procedures and comparable non mesh procedures. METHODS: We did a cohort study of women in Scotland aged 20 years or older undergoing a first, single incontinence procedure or prolapse procedure during 1997-98 to 2015-16 identified from a national hospital admission database. Primary outcomes were immediate postoperative complications and subsequent (within 5 years) readmissions for later postoperative complications, further incontinence surgery, or further prolapse surgery. Poisson regression models were used to compare outcomes after procedures carried out with and without mesh. FINDINGS: Between April 1, 1997, and March 31, 2016, 16 660 women underwent a first, single incontinence procedure, 13 133 (79%) of which used mesh. Compared with non-mesh open surgery (colposuspension), mesh procedures had a lower risk of immediate complications (adjusted relative risk [aRR] 0.44 [95% CI 0.36-0.55]) and subsequent prolapse surgery (adjusted incidence rate ratio [aIRR] 0.30 [0.24-0.39]), and a similar risk of further incontinence surgery (0.90 [0.73-1.11]) and later complications (1.12 [0.98-1.27]); all ratios are for retropubic mesh. During the same time period, 18 986 women underwent a first, single prolapse procedure, 1279 (7%) of which used mesh. Compared with non-mesh repair, mesh repair of anterior compartment prolapse was associated with a similar risk of immediate complications (aRR 0.93 [95% CI 0.49-1.79]); an increased risk of further incontinence (aIRR 3.20 [2.06-4.96]) and prolapse surgery (1.69 [1.29-2.20]); and a substantially increased risk of later complications (3.15 [2.46-4.04]). Compared with non-mesh repair, mesh repair of posterior compartment prolapse was associated with a similarly increased risk of repeat prolapse surgery and later complications. No difference in any outcome was observed between vaginal and, separately, abdominal mesh repair of vaginal vault prolapse compared with vaginal non-mesh repair. INTERPRETATION: Our results support the use of mesh procedures for incontinence, although further research on longer term outcomes would be beneficial. Mesh procedures for anterior and posterior compartment prolapse cannot be recommended for primary prolapse repair. Both vaginal and abdominal mesh procedures for vaginal vault prolapse repair are associated with similar effectiveness and complication rates to non-mesh vaginal repair. These results therefore do not clearly favour any particular vault repair procedure. FUNDING: None. PMID- 28010994 TI - Pelvic floor muscle training for secondary prevention of pelvic organ prolapse (PREVPROL): a multicentre randomised controlled trial. AB - BACKGROUND: Pelvic floor muscle training can reduce prolapse severity and symptoms in women seeking treatment. We aimed to assess whether this intervention could also be effective in secondary prevention of prolapse and the need for future treatment. METHODS: We did this multicentre, parallel-group, randomised controlled trial at three centres in New Zealand and the UK. Women from a longitudinal study of pelvic floor function after childbirth were potentially eligible for inclusion. Women of any age who had stage 1-3 prolapse, but had not sought treatment, were randomly assigned (1:1), via remote computer allocation, to receive either one-to-one pelvic floor muscle training (five physiotherapy appointments over 16 weeks, and annual review) plus Pilates-based pelvic floor muscle training classes and a DVD for home use (intervention group), or a prolapse lifestyle advice leaflet (control group). Randomisation was minimised by centre, parity (three or less vs more than three deliveries), prolapse stage (above the hymen vs at or beyond the hymen), and delivery method (any vaginal vs all caesarean sections). Women and intervention physiotherapists could not be masked to group allocation, but allocation was masked from data entry researchers and from the trial statistician until after database lock. The primary outcome was self-reported prolapse symptoms (Pelvic Organ Prolapse Symptom Score [POP SS]) at 2 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01171846. FINDINGS: Between Dec 21, 2008, and Feb 24, 2010, in New Zealand, and Oct 27, 2010, and Sept 5, 2011, in the UK, we randomly assigned 414 women to the intervention group (n=207) or the control group (n=207). One participant in each group was excluded after randomisation, leaving 412 women for analysis. At baseline, 399 (97%) women had prolapse above or at the level of the hymen. The mean POP-SS score at 2 years was 3.2 (SD 3.4) in the intervention group versus 4.2 (SD 4.4) in the control group (adjusted mean difference -1.01, 95% CI -1.70 to -0.33; p=0.004). The mean symptom score stayed similar across time points in the control group, but decreased in the intervention group. Three adverse events were reported, all of which were in the intervention group (one women had a fall, one woman had a pain in her tail bone, and one woman had chest pain and shortness of breath). INTERPRETATION: Our study shows that pelvic floor muscle training leads to a small, but probably important, reduction in prolapse symptoms. This finding will be important for women and caregivers considering preventive strategies. FUNDING: Wellbeing of Women charity, the New Zealand Continence Association, and the Dean's Bequest Fund of Dunedin School of Medicine. PMID- 28010995 TI - Profiling subjective symptoms and autonomic changes associated with cybersickness. AB - Our aim was to expand knowledge of cybersickness - a subtype of motion sickness provoked by immersion into a moving computer-generated virtual reality. Fourteen healthy subjects experienced a 15-min rollercoaster ride presented via a head mounted display (Oculus Rift), for 3 consecutive days. Heart rate, respiration, finger and forehead skin conductance were measured during the experiment; this was complemented by a subjective nausea rating during the ride and by Motion Sickness Assessment Questionnaire before, immediately after and then 1, 2 and 3h post-ride. Physiological measurements were analysed in three dimensions: ride time, association with subjective nausea rating and experimental day. Forehead, and to a lesser extent finger phasic skin conductance activity showed a correlation with the reported nausea ratings, while alteration in other measured parameters were mostly related to autonomic arousal during the virtual ride onset. A significant habituation was observed in subjective symptom scores and in the duration of tolerated provocation. The latter increased from 7.0+/-1.3min on the first day to 12.0+/-2.5min on the third day (p<0.05); this was associated with a reduced slope of nausea rise from 1.3+/-0.3units/min on the first to 0.7+/ 0.1units/min on the third day (p<0.01). Furthermore, habituation with repetitive exposure was also determined in the total symptom score post-ride: it fell from 1.6+/-0.1 on the first day to 1.2+/-0.1 on the third (p<0.001). We conclude that phasic changes of skin conductance on the forehead could be used to objectively quantify nausea; and that repetitive exposure to provocative VR content results in habituation. PMID- 28010996 TI - Pharmacological characterization of rat VD-hemopressin(alpha), an alpha hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice. AB - Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. Moreover, hemopressin and its truncated peptides were also reported to produce a slight modulatory effect on opioid system. In the present work, based on the amino acid sequence analyses of hemoglobin subunit alpha, rat VD-hemopressin(alpha) [(r)VD-Hpalpha] was predicted as a cannabinoid peptide derived from rat alpha-hemoglobin. Furthermore, (r)VD Hpalpha was synthesized and characterized in a series of in vitro and in vivo assays. Our results demonstrated that (r)VD-Hpalpha induced neurite outgrowth in Neuro 2A cells via CB1 receptor. In the tail-flick assay, (r)VD-Hpalpha dose dependently exerted central antinociception through CB1 receptor, but not CB2 and opioid receptors. In mice, supraspinal administration of (r)VD-Hpalpha produced dose-dependent hypothermia, which was partially reduced by the CB1 receptor antagonist AM251, but not by the antagonists of CB2 and opioid receptors. In addition, (r)VD-Hpalpha caused hypoactivity after intracerebroventricular injection, and this effect was insensitive to the antagonists of cannabinoid and opioid receptors. Further assessment of the side-effects demonstrated that (r)VD Hpalpha evoked the limited effects on gastrointestinal transit at antinociceptive doses, but repeated i.c.v. injection of (r)VD-Hpalpha induced development of antinociceptive tolerance. Taken together, these data suggest that the predicted peptide (r)VD-Hpalpha produces antinociception, hypothermia and hypoactivity via different pharmacological mechanisms, at least partially, which may offer an attractive strategy for separating cannabinoid analgesia from hypoactivity. Moreover, it implies that (r)VD-Hpalpha has therapeutic potential in pain management with limited side-effects. PMID- 28010997 TI - Patellar tendon mechanical properties change with gender, body mass index and quadriceps femoris muscle strength. AB - OBJECTIVE: The purpose of this study is to assess the effect and correlation of gender, body mass index (BMI) and quadriceps femoris (QF) muscle strength on patellar tendon (PT) thickness and stiffness in healthy sedentary individuals. METHODS: This study was carried out with 67 (36 female, 31 male) healthy sedentary individuals between the ages of 18-44 (28.0 +/- 7.5 years). The individuals included in the study were divided into two groups according to their gender and BMI (18.5=50% referred for endomyocardial biopsy. Seventy-three (28%) had CAm. Multivariable independent predictors of CAm were identified. Over a mean follow-up of 2.6 +/- 3.3 years, CAm patients had worse survival than those without (1.5 y vs 6.3 y; log rank P < .0001). CONCLUSIONS: Clinicians should be suspicious of CAm in patients with EF 50%-75%, >50 years of age, BMI <30 kg/m2, peripheral neuropathy, Sokolow-Lyon index <=15 mm, and septal wall thickness >=1.4 cm. PMID- 28011001 TI - It's About Time: A Critique of Macroecological Inferences Concerning Plant Competition. AB - Several macroecological studies have used static spatial data to evaluate plant competition in natural ecosystems and to investigate its role in plant community dynamics and species assembly. The assumptions on which the inferences are based have not been consistent with ecological knowledge. Inferences about processes, such as competition, from static data are weak. Macroecology will benefit more from dynamic data, even if limited, than from increasingly sophisticated analyses of static spatial patterns. PMID- 28011002 TI - Anthony Sclafani: Consummate scientist. AB - In this article we review the scientific contributions of Anthony Sclafani, with specific emphasis on his early work on the neural substrate of the ventromedial hypothalamic (VMH) hyperphagia-obesity syndrome, and on the development of diet induced obesity (DIO). Over a period of 20 years Sclafani systematically investigated the neuroanatomical basis of the VMH hyperphagia-obesity syndrome, and ultimately identified a longitudinal oxytocin-containing neural tract contributing to its expression. This tract has since been implicated in mediating the effects of at least two gastrointestinal satiety factors. Sclafani was one of the first investigators to demonstrate DIO in rats as a result of exposure to multiple palatable food items (the "supermarket diet"), and concluded that diet palatability was the primary factor responsible for DIO. Sclafani went on to investigate the potency of specific carbohydrate and fat stimuli for inducing hyperphagia, and in so doing discovered that post-ingestive nutrient effects contribute to the elevated intake of palatable food items. To further investigate this effect, he devised an intragastric infusion system which allowed the introduction of nutrients into the gut paired with the oral intake of flavored solutions, an apparatus her termed the "electronic esophagus". Sclafani coined the term "appetition" to describe the effect of intestinal nutrient sensing on post-ingestive appetite stimulation. Sclafani's productivity in the research areas he chose to investigate has been nothing short of extraordinary, and his studies are characterized by inventive hypothesizing and meticulous experimental design. His results and conclusions, to our knowledge, have never been contradicted. PMID- 28011003 TI - Pre-meal screen-time activities increase subjective emotions, but not food intake in young girls. AB - PURPOSE: To determine the effect of pre-meal screen-time activities on subjective emotions, subjective appetite, and food intake (FI) in 9-14 year-old girls. METHODS: In this clinical study, 31 girls completed four 45-min treatment conditions of television viewing (TVV), video game playing (VGP), a challenging computer task (CT), and sitting without screen exposure (control) in a randomized order. Each treatment condition was followed immediately by an ad libitum pizza lunch, and FI was calculated from the weight of the consumed pizza. Subjective appetite was assessed at baseline, 15, 30, and 45 min during the treatment condition, and upon trial completion at 75 min. Subjective emotions were assessed at baseline and at 45 min. RESULTS: FI was not affected by screen type, but was positively correlated with body composition (fat mass [FM, kg], fat free mass [FFM, kg]) in all treatment conditions. Subjective appetite was not affected by screen type, but increased with time in all treatment conditions (p < 0.0001). Subjective emotions were affected by VGP only. Anger, excitement, frustration, and upset feelings were increased at 45 min following VGP. VGP led to increased frustration compared to control (p = 0.0003), CT (p = 0.007) and TVV (p = 0.0002). CONCLUSION: Exposure to TVV or CT before eating did not affect subjective emotions, subjective appetite, or FI, and no difference was found between screen activities and the control condition for average appetite or FI. Despite a change in subjective emotions during the VGP condition, there was no increase in subjective appetite or subsequent FI. These findings suggest that physiologic signals of satiation and satiety are not overridden by environmental stimuli of pre-meal screen-time exposure among young girls. (Clinical trial number NCT01750177). PMID- 28011004 TI - Appetite loss as a potential predictor of suicidal ideation and self-harm in adolescents: A school-based study. AB - Suicide is a leading cause of death in adolescents, but detection of its risk is often challenging. Many mental illnesses share the common symptom of appetite loss and it is also known that people who suffer from these illnesses are at greater risk of suicide. However, the relationship between appetite loss and suicide risk has yet to be examined. For adolescents in particular, questions about appetite loss may be easier to answer than sensitive questions regarding mental health. The present study aims to investigate the association of appetite loss with suicidal ideation and self-harm in adolescents. Rates of adolescents with suicidal ideation or self-harm associated with appetite-loss were examined in 18,250 Japanese junior and senior high school students (aged 12-18) using a self-report questionnaire. Insomnia, a physical symptom which has previously been associated with suicide risk, was also controlled for in the analysis. Results showed that rates of adolescents with suicidal ideation or self-harm significantly increased according to the degree of self-reported appetite loss. Similar results were observed for insomnia. Odds ratios (ORs) for suicidal ideation and self-harm were 5.5 and 4.1 for adolescents with appetite loss compared to those without it, and the ORs were 5.5 and 3.5 for those with insomnia compared to those without it, respectively, adjusting for sex and age (p < 0.001). ORs remained statistically significant after adjusting for depression/anxiety (General Health Questionnaire-12 score). In conclusion, self reported appetite loss was highly associated with suicidal ideation and self-harm in adolescents; adolescents reporting physical symptoms such as loss of appetite or insomnia should be given careful attention. PMID- 28011006 TI - Lung resection is safe and feasible among stage IV cancer patients: An American College of Surgeons National Surgical Quality Improvement Program analysis. AB - BACKGROUND: Operative resection can be associated with improved survival for selected patients with stage IV malignancies but may also be associated with prohibitive acute morbidity and mortality. We sought to evaluate rates of acute morbidity and mortality after lung resection in patients with disseminated malignancy with primary lung cancer and non-lung cancer pulmonary metastatic disease. METHODS: For 2011-2012, 6,360 patients were identified from the American College of Surgeons National Surgical Quality Improvement Program undergoing lung resections, including 603 patients with disseminated malignancy. Logistic regression analyses were used to compare outcomes between patients with and without disseminated malignancy. RESULTS: After controlling for preoperative and intraoperative differences, we observed no statistically significant differences in rates of 30-day overall and serious morbidity or mortality between disseminated malignancy and non-disseminated malignancy patients (P > .05). Disseminated malignancy patients were less likely to have a prolonged duration of stay and be discharged to a facility compared to non-disseminated malignancy patients (P < .05). Subgroup analyses by procedure type and diagnosis showed similar results. CONCLUSION: Disseminated malignancy patients undergoing lung resections experienced low rates of overall morbidity, serious morbidity, and mortality comparable to non-disseminated malignancy patients. These data suggest that lung resections may be performed safely on carefully selected, disseminated malignancy patients with both primary lung cancer and pulmonary metastatic disease, with important implications for multimodality care. PMID- 28011007 TI - Comment on: Potential role for carbon nanoparticles to guide central neck dissection in patients with papillary thyroid cancer. PMID- 28011005 TI - The enduring patency of primary inferior vena cava repair. AB - BACKGROUND: Inferior vena cava repair after planned and unplanned venotomy is performed by either interposition bypass, patch venopasty, or lateral venorrhaphy and primary repair. Primary repair of the inferior vena cava avoids the use of foreign material and allows an all-autologous repair in an expeditious fashion. The purpose of this study was to demonstrate the utility of inferior vena cava repair, determine the degree of inferior vena cava stenosis, and examine clinical outcomes after primary repair. METHODS: We conducted a single-center retrospective review of patients who underwent primary inferior vena cava repairs between January 2002 and January 2014 at a tertiary care center. Primary repair followed lateral venorrhaphy for tumor extraction or for repair of an iatrogenic inferior vena cava injury. Patient demographics, cross-sectional vena cava dimensions, and patient outcomes were tabulated. RESULTS: In total, 47 (30 men and 17 women) patients underwent primary inferior vena cava repair (median age 58 years, range 31-83 years). Twenty-six patients (15 men and 11 women) underwent en bloc radical nephrectomy, inferior vena cava tumor thrombus extraction, and primary lateral venorrhaphy (median age 61 years, range 39-83 years). The majority, 92% of these patients, had renal cell carcinoma on final pathology, with a median follow-up period of 39 months (range 1-108 months). Twenty-one patients (15 men and 6 women) underwent primary repair for iatrogenic inferior vena cava injury (median age 54 years, range 31-82 years). The median follow-up period was 18.5 months (3-110 months). Clinic follow-up with postoperative imaging was obtained in 76.9% of those undergoing tumor thrombus extraction (n = 20) and 76.2% of those undergoing repair of an iatrogenic injury (n = 16). Overall, there was a 13% infrarenal inferior vena cava diameter loss, 17% inferior vena cava diameter loss at the level of the renal veins, and 10% suprarenal inferior vena cava diameter loss when comparing postoperative with preoperative imaging. All patients remained asymptomatic; therefore, inferior vena cava narrowing associated with primary repair was clinically insignificant. CONCLUSION: Primary inferior vena cava repair is associated with less than 20% inferior vena cava diameter loss and does not compromise venous outflow from the extremities. Primary inferior vena cava repair is a safe and expeditious technique that provides excellent clinical outcomes and long-term patency. PMID- 28011008 TI - Outcome analysis of continuous intraoperative renal replacement therapy in the highest acuity liver transplant recipients: A single-center experience. AB - BACKGROUND: Orthotopic liver transplantation is the definitive treatment modality for patients with end-stage liver disease. Pre-orthotopic liver transplantation renal dysfunction has a significant negative influence on outcomes post orthotopic liver transplantation. Intraoperative renal replacement therapy is an adjunctive therapy to address the metabolic challenges during orthotopic liver transplantation in patients with a high acuity of illness. The impact of intraoperative renal replacement therapy on post-orthotopic liver transplantation outcomes, however, is unclear. METHODS: From October of 2012 to April of 2016, 96 adult patients underwent orthotopic liver transplantation for end-stage liver disease. Three groups were identified: (1) Group I: patients with pre-orthotopic liver transplantation renal dysfunction who underwent intraoperative renal replacement therapy, (2) Group II: patients with pre-orthotopic liver transplantation renal dysfunction who did not receive intraoperative renal replacement therapy, and (3) Group III: patients with orthotopic liver transplantation without evidence of pretransplant renal dysfunction. RESULTS: At 17.7 months follow-up, there was no difference in survival among the study groups. Physiologic model for end-stage liver disease at the time of orthotopic liver transplantation was significantly higher in both groups with renal dysfunction (I = 43, II = 39) than in Group III (18). Post-orthotopic liver transplantation, 12-month patient survival in Group II was 100%. While the model for end-stage liver disease score at orthotopic liver transplantation was significantly different between Group I and Group III, the 12-month, post orthotopic liver transplantation patient survival was comparable at 78% vs 88%, respectively. CONCLUSION: Intraoperative renal replacement therapy is a safe adjunctive therapy during liver transplantation of critically ill patients with renal dysfunction. Identifying patients who require intraoperative renal replacement therapy would improve intraoperative and post-liver transplant survival and may facilitate recovery of native kidney function after transplant. PMID- 28011009 TI - Early crisis nontechnical skill teaching in residency leads to long-term skill retention and improved performance during crises: A prospective, nonrandomized controlled study. AB - BACKGROUND: Medical error is common in crises, and the majority of observed errors are nontechnical in nature. The long-term impact of teaching crisis nontechnical skills to residents has not been evaluated. The objective of this study was to determine the effect of simulation-based teaching of crisis nontechnical skills compared to controls one year after initial teaching. METHODS: This was a prospective study using both historical controls and a before and-after methodology to evaluate the effect of a high-fidelity simulation curriculum that used crisis resource management principles to teach nontechnical skills. Postgraduate year 2 and 3 residents were invited to take part in a prospective training course over 2 years. The primary outcome was leader performance evaluated by expert raters using the previously validated 7-point Ottawa Global Rating Scale. RESULTS: Overall, 23 residents performed 30 simulations over the 2 years with the intervention group of 7 residents being assessed in both years. After adjustment, the postgraduate year 3 intervention group who received training the previous year had significantly higher overall performance scores than all postgraduate year 2 scores (1.09 95% confidence interval 0.70-1.47, P < .001) and the historical postgraduate year 3 cohort who received no prior training (1.20, 95% confidence interval 0.37-2.03, P = .005). There was no decay of skills noted over the course of the study. CONCLUSION: Postgraduate year 3 residents who had prior training had significantly improved crisis performance compared to historical postgraduate year 3 controls and untrained postgraduate year 2 residents. There were no significant differences between the crisis performance of postgraduate year 2 residents and the untrained postgraduate year 3 controls. This confirms the beneficial effect and long-term retention after crisis nontechnical skill training. PMID- 28011010 TI - Technique for subcutaneous forearm transplantation of autologous parathyroid tissue. PMID- 28011011 TI - Robotic cholecystectomy versus conventional laparoscopic cholecystectomy: A meta analysis. AB - BACKGROUND: Robotic cholecystectomy is a novel approach that offers the surgeon improved high-definition, 3-dimensional views and enhanced instrument ergonomics, which represent a technical development from previous operative platforms that include conventional and single-incision laparoscopy. This review compares its short-term outcomes with conventional laparoscopic cholecystectomy by a meta analysis. METHODS: A literature search was conducted using the MEDLINE, EMBASE, and PubMed databases (January 1990-October 2015). Studies identified were appraised with standard selection criteria. Data were extracted and a meta analysis performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses. RESULTS: Thirteen studies, 12 retrospective trials and one randomized controlled trial comprising 1,589 patients (laparoscopic cholecystectomy, n = 921; robotic cholecystectomy, n = 668) were examined. There was a trend of a greater median total operative time (115.3 min vs 128.0 min; pooled MD = 31.22, 95% confidence interval = -2.48 to 59.96; Z = 2.13; P = .03) and preoperative time (32.4 min vs 53.4 min; pooled MD = 20.98, 95% confidence interval = 15.74 to 26.23; Z = 7.84; P < .001) in the robotic cholecystectomy group. Intraoperative complications (P = .52), conversion rate (P = .06), estimated blood loss (P = .55), postoperative complications (P = .28), duration of hospital stay (P = .36), and readmission rate (P = .85) were similar between both groups. CONCLUSION: Robotic cholecystectomy is associated with greater operative times related primarily to the preparatory phase of the operation but with similar safety and perioperative outcome as conventional laparoscopic cholecystectomy. For it to gain acceptance, future studies are required to define specific measures to quantify equipment benefits to the surgeon and to evaluate the potential advantage of its use in the acute setting. PMID- 28011012 TI - Intestinal adaptation in proximal and distal segments: Two epithelial responses diverge after intestinal separation. AB - BACKGROUND: In short bowel syndrome, luminal factors influence adaptation in which the truncated intestine increases villus lengths and crypt depths to increase nutrient absorption. No study has evaluated the effect of adaptation within the distal intestine after intestinal separation. We evaluated multiple conditions, including Igf1r inhibition, in proximal and distal segments after intestinal resection to evaluate the epithelial effects of the absence of mechanoluminal stimulation. METHODS: Short bowel syndrome was created in adult male zebrafish by performing a proximal stoma with ligation of the distal intestine. These zebrafish with short bowel syndrome were compared to sham operated zebrafish. Groups were treated with the Igf1r inhibitor NVP-AEW541, DMSO, a vehicle control, or water for 2 weeks. Proximal and distal intestine were analyzed by hematoxylin and eosin for villus epithelial circumference, inner epithelial perimeter, and circumference. We evaluated BrdU+ cells, including costaining for beta-catenin, and the microbiome was evaluated for changes. Reverse transcription quantitative polymerase chain reaction was performed for beta-catenin, CyclinD1, Sox9a, Sox9b, and c-Myc. RESULTS: Proximal intestine demonstrated significantly increased adaptation compared to sham-operated proximal intestine, whereas the distal intestine showed no adaptation in the absence of luminal flow. Addition of the Igf1r inhibitor resulted in decreased adaption in the distal intestine but an increase in distal proliferative cells and proximal beta-catenin expression. While some proximal proliferative cells in short bowel syndrome colocalized beta-catenin and BrdU, the distal proliferative cells did not co-stain for beta-catenin. Sox9a increased in the distal limb after division but not after inhibition with the Igf1r inhibitor. There was no difference in alpha diversity or species richness of the microbiome between all groups. CONCLUSION: Luminal flow in conjunction with short bowel syndrome significantly increases intestinal adaption within the proximal intestine in which proliferative cells contain beta-catenin. Addition of an Igf1r inhibitor decreases adaptation in both proximal and distal limbs while increasing distal proliferative cells that do not colocalize beta-catenin. Igf1r inhibition abrogates the increase in distal Sox9a expression that otherwise occurs in short bowel syndrome. Mechanoluminal flow is an important stimulus for intestinal adaptation. PMID- 28011013 TI - Health-related quality of life after laparoscopic Heller myotomy and Dor fundoplication for achalasia. AB - BACKGROUND: In addition to symptom scores, a person's perception of health and quality of life assessment is an important indicator of quality of treatment and can provide an efficient index to compare different therapeutic modalities in chronic disease states. Only a few studies have investigated quality of life comprehensively in patients with achalasia, and therefore the controversy regarding the best treatment algorithm continues. The primary study outcome was pre- and postoperative quality of life in patients with achalasia undergoing laparoscopic Heller myotomy and Dor fundoplication. METHODS: The study is a retrospective, observational cohort. The hospital registry and the updated research database were reviewed to identify all patients who were treated for achalasia between 2010 and 2015. Patients were eligible for the study if they had a minimum 1-year follow-up and had pre-and postoperative Eckardt, Short Form-36, and Gastro-Esophageal Reflux Disease Health-Related Quality of Life scores. Patients with previous operative and/or endoscopic treatments for achalasia were excluded. RESULTS: One-hundred and eighteen patients were identified. The median follow-up was 40 months (interquartile range 27). The proportion of patients with Eckardt stage II-III decreased from 94.9-13% (P < .001). The mean Eckardt score decreased from 6.9 +/- 1.9 to 1.7 +/- 1.2 (P < .001); the mean Short Form-36 scores significantly increased in all 8 domains; the mean Gastro-Esophageal Reflux Disease Health-Related Quality of Life score decreased from 13.9 +/- 5.7 to 5.5 +/- 5.4 (P < .001). Finally, 88% (confidence interval 81-93) of patients were satisfied regarding their present condition. CONCLUSION: Quality of life assessed with generic and disease-specific validated instruments significantly improved after laparoscopic Heller myotomy combined with Dor fundoplication. PMID- 28011014 TI - Effects of a retention interval and refresher session on intracorporeal suturing and knot tying skill and mental workload. AB - BACKGROUND: The effects of refraining from practice for different intervals on laparoscopic suturing and mental workload was assessed with a secondary task developed by the authors. We expected the inability to practice to produce a decrease in performance on the suturing, knot tying, and secondary task and skills to rebound after a single refresher session. METHODS: In total, 22 surgical assistant and premedical students trained to Fundamentals of Laparoscopic Surgery proficiency in intracorporeal suturing and knot tying were assessed on that task using a secondary task. Participants refrained from practicing any Fundamentals of Laparoscopic Surgery tasks for 1 or 5 months. At the time of their return, they were assessed immediately on suturing and knot tying with the secondary task, practiced suturing and knot tying for 40 minutes, and then were reassessed. RESULTS: The mean suture times from the initial reassessment were greater than the proficiency times but returned to proficiency levels after one practice session, F(2, 40) = 14.5, P < .001, partial eta2 = .420. Secondary task scores mirrored the results of suturing time, F(2, 40) = 6.128, P < .005, partial eta2 = .235, and were moderated by retention interval. CONCLUSION: When participants who reached proficiency in suturing and knot tying were reassessed after either 1or 5 months without practice, their performance times increased by 35% and secondary task scores decreased by 30%. These deficits, however, were nearly reversed after a single refresher session. PMID- 28011015 TI - Decentralised schemes for integrated management of wastewater and domestic organic waste: the case of a small community. AB - This study assesses from an environmental perspective two different configurations for the combined treatment of wastewater and domestic organic waste (DOW) in a small and decentralised community having a population of 2000. The applied schemes consist of an upflow anaerobic blanket (UASB) as core treatment process. Scheme A integrates membranes with the anaerobic treatment; while in Scheme B biological removal of nutrients in a sequencing batch reactor (SBR) is applied as a post treatment to UASB effluent. In energy-related categories, the main contributor is electricity consumption (producing 18-50% of the impacts); whereas in terms of eutrophication-related categories, the discharge of the treated effluent arises as a major hotspot (with 57-99% of the impacts). Scheme B consumes 25% more electricity and produces 40% extra sludge than Scheme A, resulting in worse environmental results for those energy categories. However, the environmental impact due to the discharge of the treated effluent is 75% lower in eutrophication categories due to the removal of nutrients. In addition, the quality of the final effluent in Scheme B would allow its use for irrigation (9.6 mg N/L and 2 mg P/L) if proper tertiary treatment and disinfection are provided, expanding its potential adoption at a wider scale. Direct emissions due to the dissolved methane in the UASB effluent have a significant environmental impact in climate change (23-26%). Additionally, the study shows the environmental feasibility of the use of food waste disposers for DOW collection in different integration rates. PMID- 28011016 TI - Engineering imaginaries: Anticipatory foresight for solar radiation management governance. AB - Since solar radiation management (SRM) technologies do not yet exist and capacities to model their impacts are limited, proposals for its governance are implicitly designed not around realities, but possibilities - baskets of risk and benefit that are often components of future imaginaries. This paper reports on the project Solar Radiation Management: Foresight for Governance (SRM4G), which aimed to encourage an anticipatory mode of thinking about the future of an engineered climate. Leveraging the participation of 15 scholars and practitioners heavily engaged in early conversations on SRM governance, SRM4G applied scenario construction to generate a set of alternative futures leading to 2030, each exercising different influences on the need for - and challenges associated with development of SRM technologies. The scenarios then provided the context for the design of systems of governance with the capacity and legitimacy to respond to those challenges, and for the evaluation of the advantages and drawbacks of different options against a wide range of imaginary but plausible futures. SRM4G sought to initiate a conversation within the SRM research community on the capacity of foresight approaches to highlight the centrality of conceptions of the future to discussions of SRM's threats and opportunities, and in doing so, examined and challenged the assumptions embedded in conceptualizing SRM's aims, development and governance, and discussed the capacity of governance options to adapt to a wide range of possibilities. PMID- 28011018 TI - A ternary classification using machine learning methods of distinct estrogen receptor activities within a large collection of environmental chemicals. AB - Endocrine-disrupting chemicals (EDCs), which can threaten ecological safety and be harmful to human beings, have been cause for wide concern. There is a high demand for efficient methodologies for evaluating potential EDCs in the environment. Herein an evaluation platform was developed using novel and statistically robust ternary models via different machine learning models (i.e., linear discriminant analysis, classification and regression tree, and support vector machines). The platform is aimed at effectively classifying chemicals with agonistic, antagonistic, or no estrogen receptor (ER) activities. A total of 440 chemicals from the literature were selected to derive and optimize the three class model. One hundred and nine new chemicals appeared on the 2014 EPA list for EDC screening, which were used to assess the predictive performances by comparing the E-screen results with the predicted results of the classification models. The best model was obtained using support vector machines (SVM) which recognized agonists and antagonists with accuracies of 76.6% and 75.0%, respectively, on the test set (with an overall predictive accuracy of 75.2%), and achieved a 10-fold cross-validation (CV) of 73.4%. The external predicted accuracy validated by the E-screen assay was 87.5%, which demonstrated the application value for a virtual alert for EDCs with ER agonistic or antagonistic activities. It was demonstrated that the ternary computational model could be used as a faster and less expensive method to identify EDCs that act through nuclear receptors, and to classify these chemicals into different mechanism groups. PMID- 28011017 TI - Investigation of diverse bacteria in cloud water at Mt. Tai, China. AB - Bacteria are abundant in atmospheric water phase with the potential to influence atmospheric processes and human health, yet relatively little information is known about the bacterial characteristics at high altitudes. Here we investigated the bacterial community by high throughput sequencing in 24 cloud water samples collected from September 26 to October 31, at the summit of Mt. Tai (36 degrees 15' N, 117 degrees 06' E, 1534m a.s.l) in China. Diverse bacterial population were identified and the gram-negative bacteria contributed the majority of total bacteria including Proteobacteria (81.6%) and Bacteroidetes (3.9%), followed by gram-positive bacteria Firmicutes (7.1%) and Actinobacteria (2.3%). These gram negative taxa mainly inhabited in leaf-surface and cold environments. Meanwhile bacteria involved in the cloud condensation nuclei and ice nuclei formation were observed such as Sphingomonas (6.7%), Pseudomonas (4.1%), and Bacillus (1.1%). In addition, Sphingmonas was more active than that in daytime and participated in the cloud chemistry process. Meanwhile O3 and SO2 critically contributed to the variation of bacterial community. It is the first report on the bacterial community structure of cloud water over Asian area. Our results can serve as an important reference for environmental scientists, and biologists. PMID- 28011019 TI - Alkaline fermentation of waste sludge causes a significant reduction of antibiotic resistance genes in anaerobic reactors. AB - Alkaline fermentation has been reported to be an effective method to recover valuable products from waste sludge. However, to date, the potential effect of alkaline pH on the fate of antibiotic resistance genes (ARGs) during anaerobic fermentation of sludge has never been documented. In this study, the target ARGs in sludge was observed to be removed effectively and stably when sludge was anaerobically fermented at pH10. Compared with the control (without pH adjustment), the abundances of target ARGs at pH10 were reduced by 0.87 (sulI), 1.36 (sulII), 0.42 (tet(O)), 1.11 (tet(Q)), 0.79 (tet(C)) and 1.04 (tet(X)) log units. Further investigations revealed that alkaline fermentation shifted the community structures of potential ARGs hosts. Moreover, alkaline fermentation remarkably decreased the quantities and the ARGs-possessing ability of genetic vectors (plasmid DNA, extracellular DNA and phage DNA), which might limit the transfer of ARGs via conjugation, transformation and transduction. These results suggest that the shifted compositions of gene hosts and restricted gene transfer potential might be the critical reasons for the attenuation of ARGs at pH10. PMID- 28011020 TI - Environmental photochemical fate of selected pharmaceutical compounds in natural and reconstituted Suwannee River water: Role of reactive species in indirect photolysis. AB - This study reports the impact of two reactive species, hydroxyl radical and singlet oxygen, on the photochemical degradation of three selected pharmaceutical compounds in natural and reconstituted solutions of Suwannee River water. Absolute bimolecular rate constants (M-1s-1) were determined for the reaction of hydroxyl radical and singlet oxygen with danofloxacin ((6.15+/-0.11)*109; (7.50+/ 0.13)*104), fluvastatin ((6.96+/-0.16)*109; (1.64+/-0.18)*108), and paroxetine ((8.65+/-0.12)*109, (1.18+/-0.13)*108), respectively. For all three pharmaceutical compounds, the rate constants for reactions with the hydroxyl radical were similar; however, those for singlet oxygen varied by three orders of magnitude. In the waters studied, the steady-state concentration of the hydroxyl radical was on the order of 10-17-10-18M, and for singlet oxygen, 10-12-10-14M. The percent contribution of each species to the degradation of each pharmaceutical in each water matrix was calculated, and several trends were identified enabling a better understanding of the role of these reactive species. PMID- 28011021 TI - UV-based technologies for marine water disinfection and the application to ballast water: Does salinity interfere with disinfection processes? AB - Water contained on ships is employed in the majority of activities on a vessel; therefore, it is necessary to correctly manage through marine water treatments. Among the main water streams generated on vessels, ballast water appears to be an emerging global challenge (especially on cargo ships) due to the transport of invasive species and the significant impact that the ballast water discharge could have on ecosystems and human activities. To avoid this problem, ballast water treatment must be implemented prior to water discharge in accordance with the upcoming Ballast Water Management Convention. Different UV-based treatments (photolytic: UV-C and UV/H2O2, photocatalytic: UV/TiO2), have been compared for seawater disinfection. E. faecalis is proposed as a biodosimeter organism for UV based treatments and demonstrates good properties for being considered as a Standard Test Organism for seawater. Inactivation rates by means of the UV-based treatments were obtained using a flow-through UV-reactor. Based on the two variables responses that were studied (kinetic rate constant and UV-Dose reductions), both advanced oxidation processes (UV/H2O2 and photocatalysis) were more effective than UV-C treatment. Evaluation of salinity on the processes suggests different responses according to the treatments: major interference on photocatalysis treatment and minimal impact on UV/H2O2. PMID- 28011022 TI - Effects of ambient temperature on stroke hospital admissions: Results from a time series analysis of 104,432 strokes in Guangzhou, China. AB - BACKGROUND: Stroke is a main cause of death and public health burden in China. The evidence on the burden of different strokes attack attribute to ambient temperature in China is limited. This study aimed to show the characteristics of stroke attack and the attributable risk due to temperature based on hospital admission data in Guangzhou, one of the most developed cities in China. MATERIAL AND METHODS: From January 1, 2013 to December 31, 2015, 104,432 stroke hospitalizations in Guangzhou residents from 67 hospitals for stroke sentinel surveillance were registered. Characteristics of hospital admissions by gender, age group, calendar year and stroke subtype were analyzed, and distributed lag non-linear models were applied to evaluate the effects of temperature on stroke attack admissions. RESULTS: Stroke attack admissions increased from 31,851 to 36,755 through 2013 to 2015, increasing by 15.4%. An increasing trend in the risk of stroke attack with age was observed, irrespectively of stroke subtype and calendar year. People with hypertension were more likely to have an associated stroke than people without that. The effects of cold temperature on attack admissions for CBI and ICH strokes were significant. Overall, the percentages of CBI and ICH attack admissions attribute to cold temperature were 9.06% (95% CI: 1.84, 15.00) and 15.09% (95% CI: 5.86, 21.96), respectively. Besides, elderly people were more vulnerable to cold temperature than the young. CONCLUSIONS: Measures should be taken to increase public awareness about the ill effects of cold temperature on stroke attack, and educate the public about self-protection. PMID- 28011023 TI - Perception, culture, and science: A framework to identify in-home heating options to improve indoor air quality in the Navajo Nation. AB - A 2010 study identified higher than average incidence of respiratory disease in Shiprock, NM, the largest city in the Navajo Nation. That study suggested that the potential cause was the combustion of solid fuels in in-home heating stoves and that respiratory disease could be greatly reduced by changing indoor heating behaviors and improving heating stove quality. Since the Navajo people are deeply embedded in culture and traditions that strongly influence their daily lives, a new framework was needed to identify feasible heating alternatives that could reduce the negative environmental and health impacts related to solid fuel use while respecting the culture of the Navajo people. The resulting Navajo framework included perception, cultural, and technical assessments to evaluate seven heating alternatives perceived viable by Navajo stakeholders. Cultural experts at the Dine Policy Institute identified potential cultural limitations and motivating factors for each alternative. A limited technical assessment of the health benefits of these options was conducted and integrated into the process. A parallel convergent mixed-methods approach was employed to integrate qualitative and quantitative results. The results and framework developed and presented here may be useful for decision makers in communities heavily reliant on solid fuels for heat, especially Native Nations, where culture plays an important role in the success of any intervention. PMID- 28011024 TI - The impact of the "Air Pollution Prevention and Control Action Plan" on PM2.5 concentrations in Jing-Jin-Ji region during 2012-2020. AB - In order to cope with heavy haze pollution in China, the Air Pollution Prevention and Control Action Plan including phased goals of the fine particulate matter (PM2.5) was issued in 2013. In this study, China's emission inventories in the baseline 2012 and the future scenarios of 2017 and 2020 have been developed based on this Action Plan. Beijing-Tianjin-Hebei (Jing-Jin-Ji) region, one of the most polluted regions in China, was taken as a case to assess the impact of phased emission control measures on PM2.5 concentration reduction using WRF-CMAQ model system. With the implementation of the Action Plan, the emissions of sulfur dioxide (SO2), nitrogen oxides (NOX), PM2.5, non-methane volatile organic compound (NMVOC), and ammonia (NH3) in 2017 will decrease by36%, 31%, 30%,12%, and -10% from the 2012 levels in Jing-Jin-Ji, respectively. In 2020, the emissions of SO2, NOX, PM2.5, NMVOC, and NH3 will decrease by 40%, 44%, 40%, 22%, and -3% from the 2012 levels in Jing-Jin-Ji, respectively. Consequently, the ambient annual PM2.5 concentration under the scenarios of 2017 and 2020 will be 28.3% and 37.8% lower than those in 2012, respectively. The Action Plan provided an effective approach to alleviate PM2.5 pollution level in Jing-Jin-Ji region. However, emission control of NMVOC and NH3 should be paid more attention and be strengthened in future. Meanwhile, emission control of NOx, SO2, NH3 and NMVOC synergistically are highly needed in the future because multiple pollutants impact on PM2.5 and O3 concentrations nonlinearly. PMID- 28011025 TI - Reproduction capacity of Potamogeton crispus fragments and its role in water purification and algae inhibition in eutrophic lakes. AB - The role of fragments in restoring eutrophic lakes remains unclear despite the importance of re-establishing submerged macrophytes via fragments. This study established a manipulative experiment using different biomass fragments of Potamogeton crispus. This approach was adapted to study the reproductive capacity, nutrient removal efficiency, and algae inhibitory effect of fragments. Results showed that fragments could grow throughout a 49-day experiment by maintaining the stable photosynthesis efficiency of leaves and lengthening the stems. These floating fragments could regenerate by producing turions for the maintenance of their species. Moreover, the increasing removal efficiency of TP, TN, NH4+-N, and NO3--N in water with the increase of fragment biomass indicates that the fragments could effectively purify water quality. Floating fragments competed with algae for nutrients, occupied a favorable ecological niche, and reduced algae biomass. They altered the structure of algae community and shifted the dominated green algae to cyanobacteria, the green algae of phytoplankton, and benthic algae. Findings imply that the postponable regulation of fragments is necessary for the ecological restoration of eutrophic lakes. PMID- 28011026 TI - Experimental modeling of thaw lake water evolution in discontinuous permafrost zone: Role of peat, lichen leaching and ground fire. AB - Thaw of frozen peat in discontinuous permafrost zone produces a significant number of thermokarst lakes, which are known to contribute to Green House Gases (GHG) emission in the atmosphere. In palsa peatland of western Siberia, the thermokarst lake formation includes soil subsidences, lichen submergence and peat abrasion, leading to lateral spreading of the lake border, often intensified by ground fires. Mesocosm experiments were conducted during 3weeks on two thermokarst lake waters interacting in 30-L tanks with surface horizon of peat, the dominant ground vegetation (lichen Cladonia sp.) and the ash produced by lichen burning at 450 degrees C. The obtained results allowed a better understanding of physico-chemical factors controlling the enrichment of thermokarst lake water in organic carbon and metals, and evaluating CO2 sequestration/emission potential. The changes of dissolved organic carbon (DOC) and dissolved inorganic carbon (DIC), major element and divalent metal concentration in response to peat and lichen biomass addition were less than a factor of 2 over full duration of the experiment. Iron (Fe) concentration in the lake water decreased by a factor of 2 to 3 after the addition of peat and lichen biomass. The concentration of low-soluble trivalent and tetravalent hydrolysates decreased by ca. 30 to 50%, presumably due to their co-precipitation with Fe hydroxide. The dissolved carbon dioxide (CO2) in tank with lichen increased by a factor of 5.5+/-0.5, likely due to respiration of algal component in closed environment. Strong enrichment of the lake water in DIC, P, K, Ca, Mg, Si, Al, Ti, Mn, Mo, Rb, As, Sb and U upon the ash addition persisted over full duration of experiments and was significant (p<0.0001) compared to peat and lichen biomass treatments. These elements may serve as indicators of ground fire impact on thermokarst lake water's chemistry. The overall effect of ash leaching on aquatic ecosystems after ground fire of frozen Siberian peatland is predicted to be much stronger than that currently recognized for non-permafrost regions. PMID- 28011027 TI - Treatment of anaerobic digestate supernatant in microbial fuel cell coupled constructed wetlands: Evaluation of nitrogen removal, electricity generation, and bacterial community response. AB - The objective of this study was to assess whether the improved configuration of vertical upflow constructed wetlands (CWs) coupled with aeration in the centre part and effluent recirculation can strengthen the treatment performance of high strength anaerobic digestate supernatant. Moreover, electricity generation and bacterial community characteristics were also examined. The results indicated that intermittent aeration in vertical upflow CWs significantly enhanced organic matter (>69%, 214-401g/m2d) and ammonium (>92%, 62-138g/m2d) removal, regardless of aeration position. However, the removal efficiency of total nitrogen (TN) was limited to 24%-40%. Effluent recirculation was examined to enhance TN removal up to 69% in the central aerated CW, as compared to 44% observed in the bottom aerated CW. Accordingly, significantly higher abundances of denitrifiers (nirK and nirS) and anaerobic ammonium oxidation bacteria (anammox) were found in the bottom layer of the central aerated CW. In addition, the central aerated CW coupled with effluent recirculation generated significantly higher electricity (maximum power density of 112mW/m2) than traditional bottom aerated CWs when integrated with a microbial fuel cell (MFC). Results confirmed the application potential of this new configuration of upflow CW integrated with central aeration and effluent recirculation. PMID- 28011028 TI - Statistical analysis of Seoul air quality to assess the efficacy of emission abatement strategies since 1987. AB - The combined influences of recent mitigation measures on urban air quality have been assessed using hourly observations of the criteria air pollutants (NO, NO2, O3, CO, and SO2) made from the Yongsan district of Seoul, Korea, over 26years (1987 to 2013). A number of data selection criteria are proposed in order to minimize variability associated with temporal changes (at diurnal, weekly, and seasonal timescales) in source strengths, their spatial distribution, and the atmospheric volume into which they mix. The temporal constraints required to better characterize relationships between observed air quality and changes in source strengths in Seoul were identified as: (i) a 5-hour diurnal sampling window (1300-1700h), (b) weekday measurements (Monday to Friday only), and (c) summer measurements (when pollutant fetch is mostly Korea-specific, and mean wind speeds are the lowest). Using these selection criteria, we were able to closely relate long-term trends identified in criteria pollutants to a number of published changes to traffic-related source strengths brought about by mitigation measures adopted over the last 10-15years. PMID- 28011029 TI - Long-term trend of chemical composition of atmospheric precipitation at a regional background station in Northern China. AB - Understanding the trend of chemical composition of precipitation is of great importance for air pollution control strategies in Northern China. A comprehensive study on the long-term chemical compositions of precipitation was carried out from 2003 to 2014 at the Shangdianzi (SDZ) regional background station in northern China. All samples were analyzed for pH, electrical conductivity and major ions (F-, Cl-, NO3-, SO42-, NH4+, Mg2+, Ca2+, K+ and Na+). The average pH during this period was 4.53+/-0.35, which is considerably lower than those reported in other background stations in China (Linan, Waliguan and Longfengshan). NH4+, SO42-, Ca2+ and NO3- were the dominant ions in precipitation, with concentrations (volume-weighted mean) of 212.99MUeqL-1, 200.20MUeqL-1, 116.88MUeqL-1 and 98.56MUeqL-1, respectively. The ion concentrations at SDZ were much higher than those of other background stations and megacities in China. A significantly increasing trend was observed for NO3- (7.26%year-1), and a decreasing trend was observed for SO42-/NO3-, suggesting that the precipitation of SDZ evolved from a sulfuric acid type to a mixed type dominated by both sulfuric and nitric acid. The source identification indicated that SO42-, NO3-, NH4+ and F- were dominated by secondary sources, Mg2+, Ca2+ and Na+ mostly originated from natural sources, and K+ and Cl- probably associated with anthropogenic sources. Long-range transport of air masses could influence the acidity, electrical conductivity and ion concentrations of precipitation at SDZ. The higher acidity and ion concentrations mainly occurred in the southerly and westerly trajectory pathways and partially in northwest pathways. Anthropogenic pollutants and crustal sources along these pathways were significant contributors to the chemical composition of precipitation in SDZ. PMID- 28011030 TI - Translation and cross-cultural adaptation of the Cardiff Wound Impact Schedule to Brazilian Portuguese. AB - AIM: To translate into Brazilian Portuguese and cross-culturally adapt the Cardiff Wound Impact Schedule, a specific measure of health-related quality of life (HRQoL) for patients with chronic wounds. Chronic wounds have a relevant impact on the HRQoL of patients. However, there are few instruments cross culturally adapted and validated in Brazil to assess HRQoL in patients with wounds. METHODS: A descriptive cross-sectional study was conducted following six steps: (1) translation of the original instrument into Brazilian-Portuguese by two independent translators; (2) construction of a consensus version based on both translations; (3) two independent back-translations into English of the consensus version; (4) review by an expert committee and construction of the pre final version; (5) testing of the pre-final version on patients with chronic wounds; and (6) construction of the final version. The psychometric properties of the instrument were tested on 30 patients with chronic wounds of the lower limb; 76.7% were men, 70.0% had traumatic wounds, and 43.3% had the wound for more than 1 year. Participants were recruited from an outpatient wound care clinic in Sao Paulo, Brazil. RESULTS: The final version approved by the expert committee was well understood by all patients who participate in the study and had satisfactory face validity, content validity, and internal consistency, with Cronbach's alpha coefficients ranging from 0.681 to 0.920. CONCLUSION: The cross-culturally adapted Brazilian-Portuguese version of the instrument showed satisfactory face and content validity, good internal consistency, and was named Cardiff Wound Impact Schedule-Federal University of Sao Paulo School of Medicine or CWIS UNIFESP/EPM. PMID- 28011031 TI - Editorial. PMID- 28011032 TI - A Rare Diagnosis: Recognizing and Managing Fungal Tenosynovitis of the Hand and Upper Extremity. AB - PURPOSE: Fungal infections involving the tenosynovium of the upper extremity are uncommon and are often misdiagnosed. This study evaluates the epidemiology, diagnosis, treatment, and outcomes of patients with fungal tenosynovitis of the upper extremity over a 20-year period. METHODS: A retrospective review of all culture-confirmed cases of fungal tenosynovitis of the upper extremity treated between 1990 and 2013 at a single institution was performed. Clinical data included patient and epidemiologic risk factors, causative fungal organism, surgical management, antimicrobial regimen, recurrence rates, and outcomes. RESULTS: There were 10 patients (9 female, 1 male) who met the inclusion criteria. The mean patient age was 60 years (range, 47-76 y). Identified pathogens included Histoplasmacapsulatum (7), Coccidioides posadasii/immitis (2), and Cryptococcus neoformans (1). Eight patients were on immunosuppressant medications at the time of diagnosis. The most common clinical presentation was subacute localized pain, swelling, and erythema consistent with tenosynovitis. The diagnosis was delayed by a median of 6 months (range, 0-48 mo). The most helpful diagnostic imaging studies included magnetic resonance imaging and ultrasound. All patients were treated with extensive surgical synovectomy and debridement. Seven patients were treated by a single surgery, whereas 3 required multiple consecutive debridements (2, 7, and 10 surgeries). The mean course of initial antimicrobial therapy was 8.2 months (range, 3-12 mo). Clinical recurrence was noted in 3 patients (30%) during a median follow-up period of 46 months (range, 7-250 mo). Both patients with Coccidioides infection incurred recurrence. CONCLUSIONS: Although uncommon, surgeons and clinicians should consider a diagnosis of fungal tenosynovitis among immunocompromised patients with signs of mild tenosynovitis and should consider operative debridement and biopsy. Although the majority of patients were successfully treated with surgical debridement and antimicrobial therapy, a recurrence rate of 30% highlights the need for close post-treatment follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 28011033 TI - Cost Savings and Patient Experiences of a Clinic-Based, Wide-Awake Hand Surgery Program at a Military Medical Center: A Critical Analysis of the First 100 Procedures. AB - PURPOSE: Wide-awake, local anesthesia, no tourniquet (WALANT) hand surgery was developed to improve access to hand surgery care while optimizing medical resources. Hand surgery in the clinic setting may result in substantial cost savings for the United States Military Health Care System (MHS) and provide a safe alternative to performing similar procedures in the operating room. METHODS: A prospective cohort study was performed on the first 100 consecutive clinic based WALANT hand surgery procedures performed at a military medical center from January 2014 to September 2015 by a single hand surgeon. Cost savings analysis was performed by using the Medical Expense and Performance Reporting System, the standard cost accounting system for the MHS, to compare procedures performed in the clinic versus the operating room during the study period. A study specific questionnaire was obtained for 66 procedures to evaluate the patient's experience. RESULTS: For carpal tunnel release (n = 34) and A1 pulley release (n = 33), there were 85% and 70% cost savings by having the procedures performed in clinic under WALANT compared with the main operating room, respectively. During the study period, carpal tunnel release, A1 pulley release, and de Quervain release performed in the clinic instead of the operating room amounted to $393,100 in cost savings for the MHS. There were no adverse events during the WALANT procedure. CONCLUSIONS: A clinic-based WALANT hand surgery program at a military medical center results in considerable cost savings for the MHS. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic/Decision Analysis IV. PMID- 28011034 TI - Interosseous Ligament and Transverse Forearm Stability: A Biomechanical Cadaver Study. AB - PURPOSE: The interosseous ligament (IOL) is known to be an important longitudinal stabilizer of the forearm. We hypothesize that it may also contribute to transverse stability, with pronosupination tensioning of the radius relative to the ulna. Therefore, when injured, we predict the interosseous space should widen in the transverse plane, enough to be appreciable on plain radiographs. A measurable difference in interosseous space, comparing an injured with an uninjured forearm, can potentially be of diagnostic and clinical value. METHODS: Ten fresh-frozen cadaver arms (from 5 individuals) were radiographed in 6 different positions of forearm supination, first in an uninjured state and then with the IOL sectioned, both partially (central band only) and completely. The transverse interosseous distance was measured on radiographs using edge detection software and compared using analysis of variance and contrast analysis. The maximum range of pronosupination was also compared before and after injury, using a paired t test. RESULTS: Average maximum supination increased from 84 degrees to 106 degrees , and pronation from 69 degrees to 84 degrees , after the IOL was sectioned completely. Sectioning of the IOL led to a statistically significant increase in the interosseous distance, a minimum of 2 mm, in all but one forearm position. CONCLUSIONS: The IOL of the forearm plays an important role in providing transverse stability to the radius and ulna. When the IOL is sectioned, the forearm exhibits increased pronosupination range of motion. Radiographs of bilateral forearms taken in identical rotational position can reliably differentiate between an intact and torn IOL in cadavers. CLINICAL RELEVANCE: The IOL's stabilizing role during forearm rotation suggests a novel strategy for diagnosing forearm IOL injury using comparative radiographic measurements. PMID- 28011035 TI - Proximalization of the Vascularized Toe Joint in Finger Proximal Interphalangeal Joint Reconstruction: A Technique to Derive Optimal Flexion From a Joint With Expected Limited Motion. AB - When used to reconstruct a finger proximal interphalangeal joint, a free toe interphalangeal joint, without modification, cannot meet the motion demands of the finger to allow palm touchdown. This limitation is the direct result of the toe interphalangeal joint having an intrinsic arc of motion that delivers less flexion than that of a normal functioning finger proximal interphalangeal joint. By modifying the inset of the transferred joint to an extra-anatomical more proximal position, this limitation can be overcome. With a mathematical justification highlighted by a clinical illustration, we demonstrate the feasibility and utility of this "proximalization" technique. PMID- 28011036 TI - A little CFTR can change a lot: slowing cystic fibrosis progression. PMID- 28011038 TI - Msx1-Positive Progenitors in the Retinal Ciliary Margin Give Rise to Both Neural and Non-neural Progenies in Mammals. AB - In lower vertebrates, stem/progenitor cells located in a peripheral domain of the retina, called the ciliary margin zone (CMZ), cooperate with retinal domain progenitors to build the mature neural retina. In mammals, it is believed that the CMZ lacks neurogenic potential and that the retina develops from one pool of multipotent retinal progenitor cells (RPCs). Here we identify a population of Msx1-expressing progenitors in the mouse CMZ that is both molecularly and functionally distinct from RPCs. Using genetic lineage tracing, we report that Msx1 progenitors have unique developmental properties compared with RPCs. Msx1 lineages contain both neural retina and non-neural ciliary epithelial progenies and overall generate fewer photoreceptors than classical RPC lineages. Furthermore, we show that the endocytic adaptor protein Numb regulates the balance between neural and non-neural fates in Msx1 progenitors. These results uncover a population of CMZ progenitors, distinct from classical RPCs, that also contributes to mammalian retinogenesis. PMID- 28011039 TI - The direction of human mesenchymal stem cells into the chondrogenic lineage is influenced by the features of hydrogel carriers. AB - Low back pain is a major public health issue in the Western world, one main cause is believed to be intervertebral disc (IVD) degeneration. To halt/diminish IVD degeneration, cell therapy using different biomaterials e.g. hydrogels as cell carriers has been suggested. In this study, two different hydrogels were examined (in vitro) as potential cell carriers for human mesenchymal stem cells (hMSCs) intended for IVD transplantation. The aim was to investigate cell-survival and chondrogenic differentiation of hMSCs when cultured in hydrogels Puramatrix(r) or Hydromatrix(r) and potential effects of stimulation with growth hormone (GH). hMSCs/hydrogel cultures were investigated for cell-viability, attachment, gene expression of chondrogenic markers SOX9, COL2A1, ACAN and accumulation of extracellular matrix (ECM). In both hydrogel types, hMSCs were viable for 28days, expressed integrin beta1 which indicates adhesion of hMSCs. Differentiation was observed into chondrocyte-like cells, in a higher extent in hMSCs/Hydromatrix(r) cultures when compared to hMSCs/Puramatrix(r) hydrogel cultures. Gene expression analyses of chondrogenic markers verified results. hMSCs/hydrogel cultures stimulated with GH displayed no significant effects on chondrogenesis. In conclusion, both hydrogels, especially Hydromatrix(r) was demonstrated as a promising cell carrier in vitro for hMSCs, when directed into chondrogenesis. This knowledge could be useful in biological approaches for regeneration of degenerated human IVDs. PMID- 28011037 TI - Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. AB - BACKGROUND: The 24-week safety and efficacy of lumacaftor/ivacaftor combination therapy was shown in two randomised controlled trials (RCTs)-TRAFFIC and TRANSPORT-in patients with cystic fibrosis who were aged 12 years or older and homozygous for the F508del-CFTR mutation. We aimed to assess the long-term safety and efficacy of extended lumacaftor/ivacaftor therapy in this group of patients in PROGRESS, the long-term extension of TRAFFIC and TRANSPORT. METHODS: PROGRESS was a phase 3, parallel-group, multicentre, 96-week study of patients who completed TRAFFIC or TRANSPORT in 191 sites in 15 countries. Patients were eligible if they were at least 12 years old with cystic fibrosis and homozygous for the F508del-CFTR mutation. Exclusion criteria included any comorbidity or laboratory abnormality that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering the study drug to the participant, history of drug intolerance, and history of poor compliance with the study drug. Patients who previously received active treatment in TRANSPORT or TRAFFIC remained on the same dose in PROGRESS. Patients who had received placebo in TRANSPORT or TRAFFIC were randomly assigned (1:1) to receive lumacaftor (400 mg every 12 h)/ivacaftor (250 mg every 12 h) or lumacaftor (600 mg once daily)/ivacaftor (250 mg every 12 h). The primary outcome was to assess the long-term safety of combined therapy. The estimated annual rate of decline in percent predicted FEV1 (ppFEV1) in treated patients was compared with that of a matched registry cohort. Efficacy analyses were based on modified intention-to treat, such that data were included for all patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01931839. FINDINGS: Between Oct 24, 2013, and April 7, 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 received at least one dose of study drug. 340 patients continued treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h; 176 patients who had received placebo in the TRANSPORT or TRAFFIC studies initiated treatment with lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h, the commercially available dose, for which data are presented. The most common adverse events were infective pulmonary exacerbations, cough, increased sputum, and haemoptysis. Modest blood pressure increases seen in TRAFFIC and TRANSPORT were also observed in PROGRESS. For patients continuing treatment, the mean change from baseline in ppFEV1 was 0.5 (95% CI -0.4 to 1.5) at extension week 72 and 0.5 (-0.7 to 1.6) at extension week 96; change in BMI was 0.69 (0.56 to 0.81) at extension week 72 and 0.96 (0.81 to 1.11) at extension week 96. The annualised pulmonary exacerbation rate in patients continuing treatment through extension week 96 (0.65, 0.56 to 0.75) remained lower than the placebo rate in TRAFFIC and TRANSPORT. The annualised rate of ppFEV1 decline was reduced in lumacaftor/ivacaftor-treated patients compared with matched controls (-1.33, 1.80 to -0.85 vs -2.29, -2.56 to -2.03). The efficacy and safety profile of the lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 h groups was generally similar to that of the lumacaftor 400 mg every 12 h/ivacaftor 250 mg every 12 h groups. INTERPRETATION: The long-term safety profile of lumacaftor/ivacaftor combination therapy was consistent with previous RCTs. Benefits continued to be observed with longer-term treatment, and lumacaftor/ivacaftor was associated with a 42% slower rate of ppFEV1 decline than in matched registry controls. FUNDING: Vertex Pharmaceuticals Incorporated. PMID- 28011040 TI - Cranial nerves in the Australian lungfish, Neoceratodus forsteri, and in fossil relatives (Osteichthyes: Dipnoi). AB - Three systems, two sensory and one protective, are present in the skin of the living Australian lungfish, Neoceratodus forsteri, and in fossil lungfish, and the arrangement and innervation of the sense organs is peculiar to lungfish. Peripheral branches of nerves that innervate the sense organs are slender and unprotected, and form before any skeletal structures appear. When the olfactory capsule develops, it traps some of the anterior branches of cranial nerve V, which emerged from the chondrocranium from the lateral sphenotic foramen. Cranial nerve I innervates the olfactory organ enclosed within the olfactory capsule and cranial nerve II innervates the eye. Cranial nerve V innervates the sense organs of the snout and upper lip, and, in conjunction with nerve IX and X, the sense organs of the posterior and lateral head. Cranial nerve VII is primarily a motor nerve, and a single branch innervates sense organs in the mandible. There are no connections between nerves V and VII, although both emerge from the brain close to each other. The third associated system consists of lymphatic vessels covered by an extracellular matrix of collagen, mineralised as tubules in fossils. Innervation of the sensory organs is separate from the lymphatic system and from the tubule system of fossil lungfish. PMID- 28011041 TI - Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T Cell Lymphoma, Large Cell Type. AB - The pathogenesis of canine T-cell lymphoma remains incompletely understood, partly because there are no well-established in-vivo models to study these malignancies. For this study, we generated a patient-derived tumour xenograft (PDTX) from a 10-year-old neutered male golden retriever dog with enteropathy associated intestinal T-cell lymphoma, large cell type. One of two female, 15 week-old beige/nude/XID mice developed a visible tumour 7 weeks after sections of tumour material from the spleen were surgically implanted. The histological appearance, immunophenotype and clonal antigen receptor rearrangements of the tumour from the recipient mouse showed that it was derived from the primary canine tumour. Our results indicate that immunodeficient mice are receptive hosts to develop in-vivo PDTX models to study the pathogenesis and management of canine T-cell lymphomas. PMID- 28011043 TI - Prediction of Individual Differences from Neuroimaging Data. PMID- 28011042 TI - Glial Changes and Evidence for Apoptosis in the Brain of Cats Infected by Cytauxzoon felis. AB - Ischaemic neuropathological changes associated with Cytauxzoon felis infection in cats have been reported recently. This paper describes the associated glial changes and the evidence for apoptosis in the brain of cats infected naturally by C. felis. Sections of brain from eight affected cats and eight age- and sex matched control cats were evaluated by immunohistochemistry for expression of glial fibrillary acidic protein, CD18 and cleaved caspase-3. Vascular changes in the leptomeninges and parenchyma, the number of positive astrocytes and phagocytic cells (microglia or macrophages) and the average astrocytic cytoplasmic area and number and length of astrocytic processes were quantified, and a mean value for the grey and white matter in both groups was generated. Astrocytic hyperplasia (astrogliosis) and phagocytic cell hyperplasia were detected in all affected cats. Immunoexpression of cleaved caspase-3 was detected in intravascular and perivascular macrophages in the leptomeninges and, less often, in the grey and white matter in all affected cats. Four cats with encephalomalacia had additional cytoplasmic immunolabelling of phagocytic cells around the necrotic foci and macrophages and cell debris within the areas of necrosis. These results support the role of an extensive reaction of the brain tissue to hypoxia-ischaemia and a potential role of apoptosis in the neuropathogenesis of C. felis infection in cats. PMID- 28011044 TI - Association of Radiomics and Metabolic Tumor Volumes in Radiation Treatment of Glioblastoma Multiforme. AB - PURPOSE: To build a framework for investigation of the associations between imaging, clinical target volumes (CTVs), and metabolic tumor volumes (MTVs) features for better understanding of the underlying information in the CTVs and dependencies between these volumes. High-throughput extraction of imaging and metabolomic quantitative features from magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging of glioblastoma multiforme (GBM) results in tens of variables per patient. In radiation therapy of GBM the relevant metabolic tumor volumes (MTVs) are related to aberrant levels of N-acetyl aspartate (NAA) and choline (Cho). The corresponding clinical target volumes (CTVs) for radiation therapy are based on contrast-enhanced T1-weighted (CE-T1w) and T2-weighted (T2w)/fluid-attenuated inversion recovery MRI. METHODS AND MATERIALS: Necrotic portions, enhancing lesion, and edema were manually contoured on CE-T1w/T2w images for 17 GBM patients. Clinical target volumes and MTVs for NAA (MTVNAA) and Cho (MTVCho) were constructed. Imaging and metabolic features related to size, shape, and signal intensities of the volumes were extracted. Tumors were also scored categorically for 10 semantic imaging traits by a neuroradiologist. All features were investigated for redundancy. Two-way correlations between imaging and CTVs/MTVs features were visualized as heatmaps. Associations between MTVNAA and MTVCho and imaging features were studied using Spearman correlation. RESULTS: Forty-eight imaging features were extracted per patient. Half of the imaging traits were replaced with automatically extracted continuous variables. Twenty features were extracted from CTVs and MTVs. A series of semantic imaging traits were replaced with automatically extracted continuous variables. There were multiple (22) significant correlations of imaging measures with CTVs/MTVNAA, whereas there were only 6 with CTVs/MTVCho. CONCLUSIONS: A framework for investigation of codependencies between MRI and magnetic resonance spectroscopic imaging radiomic features and CTVs/MTVs has been established. The MTV for NAA was found to be closely associated with MRI volumes, whereas very few imaging features were related to MTVCho, indicating that Cho provides additional information to imaging. PMID- 28011045 TI - Diffusion-Weighted Magnetic Resonance Imaging as a Predictor of Outcome in Cervical Cancer After Chemoradiation. AB - PURPOSE: To determine whether apparent diffusion coefficient (ADC) value is predictive of survival after definitive chemoradiation for cervical cancer independent of established imaging and clinical prognostic factors. METHODS AND MATERIALS: Between 2011 and 2013, the pretreatment MRI scans for 69 patients treated with definitive chemoradiation for newly diagnosed cervical cancer were retrieved. Scans were acquired with a 1.5-T magnetic resonance scanner, including diffusion-weighted imaging sequences. Mean ADC value was measured within a region of interest in the primary cervical cancer on the baseline MRI scan. Baseline tumor maximum standardized uptake value on positron emission tomography/computed tomography was determined by the reading radiologist. Treatment included external beam radiation therapy to the pelvis followed by brachytherapy in 97%, and with concurrent weekly cisplatin in 99% of patients. Univariate and multivariate analyses were done to investigate the association of clinical and imaging variables with disease control and survival endpoints using a Cox proportional hazard test. RESULTS: Median follow-up was 16.7 months (range, 3.1-44.2 months). The 1-year overall survival, locoregional recurrence-free survival, and disease free survival rates were 91%, 86%, and 74%, respectively. The median ADC value was 0.941 * 10-3 mm2/s (range, 0.256-1.508 * 10-3 mm2/s). The median standardized uptake value in the primary tumor was 15 (range, 6.2-43.4). In multivariate analysis, higher ADC value (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.15-0.85, P=.02), higher stage (HR 2.4, 95% CI 1.1-5.5, P=.033), and nonsquamous histology (HR 0.23, 95% CI 0.07-0.82, P=.024) were independent predictors of disease-free survival. CONCLUSIONS: The mean ADC value of the primary tumor on pretreatment MRI was the only imaging feature that was an independent predictor of disease-free survival in cervical cancer patients treated with chemoradiation. Further validation will be needed to determine whether ADC values may prove useful in identifying cervical patients at high risk of recurrence. PMID- 28011046 TI - Promoting the Appropriate Use of Advanced Radiation Technologies in Oncology: Summary of a National Cancer Policy Forum Workshop. AB - PURPOSE: Leaders in the oncology community are sounding a clarion call to promote "value" in cancer care decisions. Value in cancer care considers the clinical effectiveness, along with the costs, when selecting a treatment. To discuss possible solutions to the current obstacles to achieving value in the use of advanced technologies in oncology, the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine held a workshop, "Appropriate Use of Advanced Technologies for Radiation Therapy and Surgery in Oncology" in July 2015. The present report summarizes the discussions related to radiation oncology. METHODS AND MATERIALS: The workshop convened stakeholders, including oncologists, researchers, payers, policymakers, and patients. Speakers presented on key themes, including the rationale for a value discussion on advanced technology use in radiation oncology, the generation of scientific evidence for value of advanced radiation technologies, the effect of both scientific evidence and "marketplace" (or economic) factors on the adoption of technologies, and newer approaches to improving value in the practice of radiation oncology. The presentations were followed by a panel discussion with dialogue among the stakeholders. RESULTS: Challenges to generating evidence for the value of advanced technologies include obtaining contemporary, prospective, randomized, and representative comparative effectiveness data. Proposed solutions include the use of prospective registry data; integrating radiation oncology treatment, outcomes, and quality benchmark data; and encouraging insurance coverage with evidence development. Challenges to improving value in practice include the slow adoption of higher value and the de-adoption of lower value treatments. The proposed solutions focused on engaging stakeholders in iterative, collaborative, and evidence-based efforts to define value and promote change in radiation oncology practice. Recent examples of ongoing or successful responses to the discussed challenges were provided. CONCLUSIONS: Discussions of "value" have increased as a priority in the radiation oncology community. Practitioners in the radiation oncology community can play a critical role in promoting a value oriented framework to approach radiation oncology treatment. PMID- 28011047 TI - Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer. AB - PURPOSE: For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population. METHODS AND MATERIALS: The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes. RESULTS: From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor size was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P=.02) and OS (31.4 vs 14.3 months; P=.02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P=.01). Toxicities were uncommon; 5.2% experienced grade >=2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and "elsewhere lung" (20.8%). The median time to each was 5 to 7 months. CONCLUSIONS: From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (>=50 Gy) with chemotherapy should be considered a standard option. PMID- 28011048 TI - Direct Comparison of Respiration-Correlated Four-Dimensional Magnetic Resonance Imaging Reconstructed Using Concurrent Internal Navigator and External Bellows. AB - PURPOSE: To compare the image quality of amplitude-binned 4-dimensional magnetic resonance imaging (4DMRI) reconstructed using 2 concurrent respiratory (navigator and bellows) waveforms. METHODS AND MATERIALS: A prospective, respiratory correlated 4DMRI scanning program was used to acquire T2-weighted single-breath 4DMRI images with internal navigator and external bellows. After a 10-second training waveform of a surrogate signal, 2-dimensional MRI acquisition was triggered at a level (bin) and anatomic location (slice) until the bin-slice table was completed for 4DMRI reconstruction. The bellows signal was always collected, even when the navigator trigger was used, to retrospectively reconstruct a bellows-rebinned 4DMRI. Ten volunteers participated in this institutional review board-approved 4DMRI study. Four scans were acquired for each subject, including coronal and sagittal scans triggered by either navigator or bellows, and 6 4DMRI images (navigator-triggered, bellows-rebinned, and bellows-triggered) were reconstructed. The simultaneously acquired waveforms and resulting 4DMRI quality were compared using signal correlation, bin/phase shift, and binning motion artifacts. The consecutive bellows-triggered 4DMRI scan was used for indirect comparison. RESULTS: Correlation coefficients between the navigator and bellows signals were found to be patient-specific and inhalation /exhalation-dependent, ranging from 0.1 to 0.9 because of breathing irregularities (>50% scans) and commonly observed bin/phase shifts (-1.1 +/- 0.6 bin) in both 1-dimensional waveforms and diaphragm motion extracted from 4D images. Navigator-triggered 4DMRI contained many fewer binning motion artifacts at the diaphragm than did the bellows-rebinned and bellows-triggered 4DMRI scans. Coronal scans were faster than sagittal scans because of the fewer slices and higher achievable acceleration factors. CONCLUSIONS: Navigator-triggered 4DMRI contains substantially fewer binning motion artifacts than bellows-rebinned and bellows-triggered 4DMRI, primarily owing to the deviation of the external from the internal surrogate. The present study compared 2 concurrent surrogates during the same 4DMRI scan and their resulting 4DMRI quality. The navigator-triggered 4DMRI scanning protocol should be preferred to the bellows-based, especially for coronal scans, for clinical respiratory motion simulation. PMID- 28011049 TI - Effect of Anatomic Changes on Pencil Beam Scanned Proton Dose Distributions for Cranial and Extracranial Tumors. AB - PURPOSE: To estimate the frequency and impact of anatomic changes on the delivered dose in pencil beam scanning proton therapy, to assess the need for repeat CT scanning and adaptive replanning. METHODS AND MATERIALS: A total of 730 patients treated at Paul Scherrer Institut between 2007 and 2014 were included in this study, for which the number of patients who had control CT scans and who were replanned as a result of anatomic changes was analyzed. For those that were replanned, the nominal dose distributions (originally optimized on the planning CT scan) were recalculated on the replanning CT scan and differences evaluated using standard dose metrics for planning target volumes and clinical target volumes and organs at risk (OARs). RESULTS: Control CT studies were acquired for 244 patients (33.5%), and replanning was deemed clinically necessary for 40 (16%) of these (5.5% of the total cohort). The OARs and target dose differences between the nominal and recalculated dose distributions were found to be strongly dependent on the subgroup of patients. Nevertheless, dose differences were found to be <= 5% for 88% of all analyzed OARs, and planning target volume/clinical target volume V95% was reduced by <=5% in 87%/90% of cases. CONCLUSIONS: Despite anatomic variations, clinically delivered plans have been found to be robust to anatomic changes, with replanning being deemed necessary in only a small number of cases. However, because the dosimetric effect of such changes can be quite large for some cases, they have to be monitored and evaluated on an individual basis. PMID- 28011050 TI - Could the Addition of Cetuximab to Conventional Radiation Therapy Improve Organ Preservation in Those Patients With Locally Advanced Larynx Cancer Who Respond to Induction Chemotherapy? An Organ Preservation Spanish Head and Neck Cancer Cooperative Group Phase 2 Study. AB - PURPOSE: To evaluate the efficacy and safety of induction chemotherapy (IC) followed by bioradiotherapy (BRT) to achieve functional larynx preservation in the setting of locally advanced head and neck tumors. METHODS AND MATERIALS: This was a phase 2, open-label, multicenter study of patients with stage III and IVA laryngeal carcinoma who were candidates for total laryngectomy. The primary endpoint was the rate of survival with functional larynx (SFL) at 3 years, with a critical value to consider the study positive of SFL >59%. Patients received 3 cycles of IC with TPF (docetaxel, cisplatin, and 5-fluorouracil), and those who responded received conventional BRT with cetuximab. In patients with residual nodal disease after BRT, neck dissection was planned 2 months after BRT. Patients who did not respond to IC underwent total laryngectomy plus neck dissection and radiation therapy. RESULTS: A total of 93 patients started TPF. Responses to IC on larynx target lesion were as follows: 37 patients (40%) showed a complete response; 38 patients (41%) showed a partial response; 8 patients (9%) showed stabilization; 2 patients (2%) showed progressive disease, and 8 patients (9%) were not evaluated (2 deaths, 5 adverse events, and 1 lost to follow-up). Seventy three patients (78%) received BRT: 72 as per protocol, but 1 with only stable disease. Median follow-up was 53.7 months. Three-year actuarial rates were as follows: SFL: 70% (95% confidence interval [CI] 60%-79%); laryngectomy-free survival: 72% (95% CI 61%-81%); overall survival: 78% (95% CI: 63%-82%). The acute toxicity observed during both IC and BRT was as expected, with only 1 toxicity-related death (local bleeding) during BRT. CONCLUSIONS: According to this protocol, the SFL rate was clearly higher than the critical value, with acceptable levels of toxicity. The use of cetuximab added to radiation therapy in patients with stage III and IVA laryngeal cancer who respond to TPF could improve functional larynx preservation. A phase 3 trial is warranted. PMID- 28011051 TI - A Phase 2 Trial of Neoadjuvant Temozolomide Followed by Hypofractionated Accelerated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma. AB - PURPOSE: We performed a phase 2 trial of neoadjuvant temozolomide (TMZ), followed by hypofractionated accelerated radiation therapy (HART) with concurrent TMZ, and adjuvant TMZ in patients with newly diagnosed glioblastoma to determine whether neoadjuvant TMZ would safely improve outcomes in this group of patients prior to subsequent cytotoxic therapy. METHODS AND MATERIALS: Adult patients with newly diagnosed glioblastoma and a Karnofsky Performance Status >60 were eligible. Neoadjuvant TMZ administration started 2 to 3 weeks from surgery at a daily dose of 75 mg/m2 for 2 weeks prior to delivery of HART (60 Gy in 20 daily fractions) with concurrent and adjuvant TMZ. The primary endpoints were feasibility and toxicity. The secondary endpoints included overall survival (OS) and progression free survival. RESULTS: Fifty patients were accrued. The median follow-up period was 44.0 months for patients at risk and 22.3 months for all 50 patients. Except for 1 patient in whom infection developed and another patient with progression during HART, all patients completed protocol therapy as planned. The median OS and progression-free survival were 22.3 months (95% confidence interval, 14.6 42.7 months) and 13.7 months (95% confidence interval, 8.0-33.3 months), respectively. The 4-year OS rates were 30.4% for the entire cohort and 53.3% and 14.0% for patients with methylated (n=21) and unmethylated (n=27) MGMT gene promoter tumors, respectively. One patient had grade 5 pancytopenia during HART, and another patient had transient grade 4 hepatotoxicity. A second surgical procedure was performed in 13 patients: 2 had intracranial infection, 3 had recurrences, 4 had recurrences and radiation-induced damage, and 4 had only radiation-induced damage. CONCLUSIONS: This novel approach of neoadjuvant TMZ is associated with an encouraging favorable long-term survival with acceptable toxicity. A future comparative trial of the efficacy of this regimen is warranted. PMID- 28011052 TI - Characterizing human skin blood flow regulation in response to different local skin temperature perturbations. AB - Small nerve fibers regulate local skin blood flow in response to local thermal perturbations. Small nerve fiber function is difficult to assess with classical neurophysiological tests. In this study, a vasomotor response model in combination with a heating protocol was developed to quantitatively characterize the control mechanism of small nerve fibers in regulating skin blood flow in response to local thermal perturbation. The skin of healthy subjects' hand dorsum (n=8) was heated to 42 degrees C with an infrared lamp, and then naturally cooled down. The distance between the lamp and the hand was set to three different levels in order to change the irradiation intensity on the skin and implement three different skin temperature rise rates (0.03 degrees C/s, 0.02 degrees C/s and 0.01 degrees C/s). A laser Doppler imager (LDI) and a thermographic video camera recorded the temporal profile of the skin blood flow and the skin temperature, respectively. The relationship between the skin blood flow and the skin temperature was characterized by a vasomotor response model. The model fitted the skin blood flow response well with a variance accounted for (VAF) between 78% and 99%. The model parameters suggested a similar mechanism for the skin blood flow regulation with the thermal perturbations at 0.03 degrees C/s and 0.02 degrees C/s. But there was an accelerated skin vasoconstriction after a slow heating (0.01 degrees C/s) (p-value<0.05). An attenuation of the skin vasodilation was also observed in four out of the seven subjects during the slow heating (0.01 degrees C/s). Our method provides a promising way to quantitatively assess the function of small nerve fibers non-invasively and non-contact. PMID- 28011053 TI - Reply - Letter to the Editor - Heart failure and vitamin D receptor gene. PMID- 28011054 TI - Corrigendum to: "The Influence of Baseline Parameters on Changes in IPSS with Dutasteride, Tamsulosin, and Combination Therapy: Two-Year Data from the Combination of Avodart(r) and Tamsulosin (CombAT) Study" [Eur Urol Suppl 2008;7:171 (Abstract no. 403)]. PMID- 28011055 TI - Corrigendum to: "A Critical Analysis of Penile Enhancement Procedures for Patients with Normal Penile Size: Surgical Techniques, Success, and Complications" [Eur Urol 2008;54:1042-50]. PMID- 28011056 TI - An under-recognized cause for syncope. PMID- 28011057 TI - The ischemic/nephrotoxic acute kidney injury and the use of renal biomarkers in clinical practice. AB - The term Acute Renal Failure (ARF) has been replaced by the term Acute Kidney Injury (AKI). AKI indicates an abrupt (within 24-48h) decrease in Glomerular Filtraton Rate, due to renal damage, that causes fluid and metabolic waste retention and alteration of electrolyte and acid-base balance. The renal biomarkers of AKI are substances or processes that are indicators of normal or impaired function of the kidney. The most used renal biomarker is still serum creatinine that is inadequate for several reasons, one of which is its inability to differentiate between hemodynamic changes of renal function ("prerenal azotemia") from intrinsic renal failure or obstructive nephropathy. Cystatin C is no better in this respect. After the description of the pathophysiology of "prerenal azotemia" and of Acute Kidney Injury (AKI) due to ischemia or nephrotoxicity, the renal biomarkers are listed and described: urinary NAG, urinary and serum KIM-1, serum and urinary NGAL, urinary IL-18, urinary L-FABP, serum Midkine, urinary IGFBP7 and TIMP2, urinary alpha-GST and pi-GST, urinary gammaGT and AP, urinary beta2M, urinary RBP, serum and urinary miRNA. All have been shown to appear much earlier than the rise of serum Creatinine. Some of them have been demonstrated to predict the clinical outcomes of AKI, such as the need for initiation of dialysis and mortality. PMID- 28011058 TI - Lived experiences of women with co-existing BMI>=30 and Gestational Diabetes Mellitus. AB - OBJECTIVE: to explore the lived experiences of women with co-existing maternal obesity (BMI >= 30) and Gestational Diabetes Mellitus (GDM) during pregnancy and the post-birth period (<3 months post-birth). DESIGN: A qualitative, sociological design was utilised. Data were collected using a series of sequential in-depth narrative interviews during pregnancy and post-birth and fieldnotes. Cross sectional thematic analysis of the data set was undertaken, alongside the construction/analysis of in-depth biographical longitudinal case profiles of individual participants. SETTING: Participants were recruited from diabetic antenatal clinics at two NHS hospital trusts in the South West of England. PARTICIPANTS: 27 women with co-existing BMI >= 30 and GDM. Participants were predominantly of low socio-economic status (SES). FINDINGS: Women were experiencing a number of social and economic stressors that compromised their ability to manage pregnancies complicated by maternal obesity and GDM, and make lifestyle changes.Women perceived themselves to be stigmatised by healthcare professionals and the general public due to their obese and gestational diabetic status. KEY CONCLUSIONS: Women of low SES with maternal obesity and GDM perceived healthcare professionals' recommendations with respect to lifestyle change as unrealistic given their constrained social/material circumstances. Frequent references to weight/lifestyle change by different HCPs were seen as stigmatising and may be counterproductive. IMPLICATIONS FOR PRACTICE: Women would like more collaborative care which acknowledges/addresses their personal and financial circumstances. Multidisciplinary teams should give consideration to how, by whom, and the frequency with which issues of weight/lifestyle change are being discussed in order to avoid women feeling stigmatised. PMID- 28011059 TI - Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers. AB - BACKGROUND: The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. OBJECTIVE: We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. METHODS: We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1beta levels were measured by means of ELISA. RESULTS: Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1beta, an innate inflammatory mediator. CONCLUSIONS: The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory. PMID- 28011060 TI - Sex differences in cortisol's regulation of affiliative behavior. AB - A contribution to a special issue on Hormones and Human Competition. A stress perspective is used to illuminate how competitive defeat and victory shape biology and behavior. We report a field study examining how change in cortisol following perceived defeat (vs. victory) in a competition-in this case, a dog agility competition-relates to affiliative behavior. Following competition, we measured cortisol change and the extent to which dog handlers directed affiliative behaviors toward their dogs. We found striking sex differences in affiliation. First, men were more affiliative toward their dogs after victory, whereas women were more affiliative after defeat. Second, the greater a female competitor's increase in cortisol, the more time she spent affiliating with her dog, whereas for men, the pattern was the exact opposite: the greater a male competitor's increase in cortisol, the less time he spent affiliating with his dog. This pattern suggests that, in the wake of competition, men and women's affiliative behavior may serve different functions-shared celebration for men; shared consolation for women. These sex differences show not only that men and women react very differently to victory and defeat, but also that equivalent changes in cortisol across the sexes are associated with strikingly different behavioral consequences for men and women. PMID- 28011061 TI - Repair, Reuse, Recycle: The Expanding Role of Autophagy in Genome Maintenance. AB - (Macro)Autophagy is a catabolic pathway that delivers excess, aggregated, or damaged proteins and organelles to lysosomes for degradation. Autophagy is activated in response to numerous cellular stressors such as increased levels of reactive oxygen species (ROS) and low levels of cellular nutrients as well as DNA damage. Although autophagy occurs in the cytoplasm, its inhibition leads to accumulation of DNA damage and genomic instability. In the past few years, our understanding of the interplay between autophagy and genomic stability has greatly increased. In this review we summarize these recent advances in understanding the molecular mechanisms linking autophagy to DNA repair. PMID- 28011062 TI - Factors associated with pain in individuals infected by human T-cell lymphotropic virus type 1 (HTLV-1). AB - INTRODUCTION: Despite the high prevalence of chronic pain in individuals infected with HTLV-1, predictive and protective factors for its development are still unclear. OBJECTIVE: To identify factors associated with chronic pain in individuals with HTLV-1. METHODS: This cross-sectional study was conducted in a reference center for treatment of patients infected with HTLV-1 in Salvador, Bahia, Brazil. The study included individuals infected with HTLV-1, over 18 years, and excluded those with difficulty to respond the pain protocol. Data on sociodemographic, health behavior, and clinical characteristics were collected in a standardized way. The prevalence ratio (PR) of pain is described, as well as the factors independently associated with the presence of pain, which were assessed by multiple logistic regression. RESULTS: A total of 142 individuals were included in the study, mostly female (62.7%), aged 20-64 years (73.2%), married (61.3%), with less than eight years of education (54.2%), and with a steady income (79.6%). Multivariate analysis showed that being symptomatic for HTLV-1 - sensory manifestations, erectile dysfunction, overactive bladder, and/or HAM/TSP (PR=1.21, 95% CI: 1.05 to 1.38), self-medication (PR=1.29, 95% CI: 1.08 1.53), physiotherapy (PR=1.15, 95% CI: 1.02-1.28), and depression (PR=1.14, 95% CI: 1.01-1.29) were associated with an increased likelihood of presenting pain. On the other hand, physical activity (PR=0.79, 95% CI: 0.67-0.93) and religious practice (PR=0.83, 95% CI: 0.72-0.95) were associated with a decreased likelihood of having pain. CONCLUSION: The use of self-medication, physiotherapy and the presence of depression are independently associated with neurological symptoms in HTLV-1 infected patients. Religious practice and physical activity are both protective for the development of pain. PMID- 28011063 TI - The Role of Parental Engagement in the Intergenerational Transmission of Smoking Behavior and Identity. AB - PURPOSE: Prior research has found that the protective effect of parental engagement on adolescent smoking behaviors may be weaker if parents smoke. We examine parental influence on adolescent smoking using a social learning theory framework. We hypothesize that adolescents are more likely to mimic parental smoking behavior if they perceive parents as being more engaged and if the parent is the same gender of the adolescent. METHODS: Hypotheses were tested using a diverse sample of 6,998 adolescents who were followed for seven waves (grades 6 12). Adolescent gender, time-stable and time-varying effects of parental engagement, adolescent perceptions of parental smoking, and interactions among the effects of these variables are tested using multilevel mediation models. We use a traditional measure of past 3-month adolescent smoking and a novel measure of smoking identity. RESULTS: Parental smoking was associated with a developmental increase in adolescent smoking and time-stable and time-varying parental engagement protected against adolescent smoking, whereas maternal engagement and smoking exerted independent and opposite effects with no moderation and time-stable paternal engagement moderated the effects of perceived paternal smoking on adolescent smoking outcomes. Parental smoking was more strongly associated with adolescent smoking outcomes when adolescent gender was congruent with parent gender. CONCLUSIONS: Even when parents smoke, parental engagement confers protection. Protective effects of engagement may be enhanced among parents who smoke through increased antismoking communication, particularly as adolescents reach the legal smoking age. PMID- 28011065 TI - Independent Versus Co-occurring Substance Use in Relation to Gambling Outcomes in Older Adolescents and Young Adults. AB - PURPOSE: Gambling is prevalent among college students and can be associated with significant negative consequences. Students who report gambling also tend to report use of alcohol and cannabis, but little research has explored the associated risks of using these substances in relation to gambling episodes. This study explored associations between the independent and co-occurring use of alcohol and cannabis before/during gambling episodes and gambling outcomes. METHODS: Students (n = 1,834) completed an online survey that included measures of gambling frequency, amount lost, negative gambling consequences, gambling problem severity, and substance use. RESULTS: As hypothesized, individuals who reported using either alcohol or cannabis alone or both substances before/while gambling endorsed greater gambling quantity, frequency, negative consequences, and problem severity than individuals who used alcohol and cannabis in general but denied use of either substance before/while gambling. Use of both substances compared to use of alcohol alone was associated with greater gambling quantity, frequency, and negative consequences, although these groups did not differ on gambling problem severity. Cannabis use alone was no different on any outcome than use of both substances, and alcohol use alone was no different than cannabis use alone on any outcome. CONCLUSIONS: Use of cannabis alone before/while gambling may confer the same level of risk for negative gambling outcomes as use of both cannabis and alcohol. Prevention efforts may, therefore, benefit from targeting cannabis use in relation to gambling. Additional investigation is needed in light of recent and upcoming state legislation on the legalization of cannabis. PMID- 28011066 TI - How concerned should we be over the long-term safety of growth hormone therapy? PMID- 28011064 TI - Research on Clinical Preventive Services for Adolescents and Young Adults: Where Are We and Where Do We Need to Go? AB - We reviewed research regarding system- and visit-level strategies to enhance clinical preventive service delivery and quality for adolescents and young adults. Despite professional consensus on recommended services for adolescents, a strong evidence base for services for young adults, and improved financial access to services with the Affordable Care Act's provisions, receipt of preventive services remains suboptimal. Further research that builds off successful models of linking traditional and community clinics is needed to improve access to care for all youth. To optimize the clinical encounter, promising clinician-focused strategies to improve delivery of preventive services include screening and decision support tools, particularly when integrated into electronic medical record systems and supported by training and feedback. Although results have been mixed, interventions have moved beyond increasing service delivery to demonstrating behavior change. Research on emerging technology-such as gaming platforms, mobile phone applications, and wearable devices-suggests opportunities to expand clinicians' reach; however, existing research is based on limited clinical settings and populations. Improved monitoring systems and further research are needed to examine preventive services facilitators and ensure that interventions are effective across the range of clinical settings where youth receive preventive care, across multiple populations, including young adults, and for more vulnerable populations with less access to quality care. PMID- 28011067 TI - Metabolic health of young adults who were born small for gestational age and treated with growth hormone, after cessation of growth hormone treatment: a 5 year longitudinal study. AB - BACKGROUND: Growth hormone treatment reduces fat mass and insulin sensitivity and increases lean body mass. Data are only available for short-term longitudinal changes after cessation of growth hormone treatment in young adults born small for gestational age. We aimed to assess long-term changes over a 5-year period following cessation of growth hormone treatment. METHODS: We did a longitudinal study of young adults born small for gestational age and previously treated with growth hormone. Individuals were followed up for 5 years after attainment of adult height, when growth hormone treatment was discontinued: assessments were done at cessation of growth hormone treatment and at 6 months, 2 years, and 5 years thereafter. Data 5 years after cessation of growth hormone were compared with untreated age-matched controls. We used dual-energy x-ray absorptiometry to assess body composition, and did frequently sampled intravenous glucose tolerance tests to assess insulin sensitivity, acute insulin response, and the disposition index (a measure of beta-cell function). This study is registered with ISRCTN, numbers ISRCTN96883876 and ISRCTN65230311. FINDINGS: Between April, 2004, and April, 2016, we followed up 199 young adults born small for gestational age and previously treated with growth hormone, during the 5 years after cessation of growth hormone treatment. Data at 5 years for these individuals were compared with those for 51 untreated adults born small for gestational age with short stature, 92 untreated adults born small for gestational age with spontaneous catch-up growth, and 142 adults born appropriate for gestational age and unexposed to growth hormone treatment. In young adults born small for gestational age and previously treated with growth hormone, 5 years after cessation of growth hormone treatment, there were increases in fat mass (estimated marginal mean 10.73 kg [95% CI 9.95-11.50] at cessation of treatment vs 16.12 kg [14.77-17.46] at 5 years; p<0.0001), trunk fat (5.34 kg [4.94-5.73] vs 7.86 kg [7.12-8.60]; p<0.0001), and limb fat (4.87 kg [4.49-5.25] vs 7.41 kg [6.78-8.05]; p<0.0001); furthermore, lean body mass had decreased (42.41 kg [95% CI 41.09-43.73] at cessation of treatment vs 41.42 kg [40.17-42.66] at 5 years; p=0.0013). Insulin sensitivity increased within 6 months of cessation and was sustained 5 years after treatment cessation (estimated marginal mean 4.14 mU/L [95% CI 3.79-4.53] at cessation of treatment vs 6.15 mU/L [5.21-7.24] at 5 years; p<0.0001), and acute insulin response was diminished at 6 months, which persisted at 5 year follow-up (597.63 mU/L [539.62-661.86] vs 393.69 mU/L [337.56-459.15]; p<0.0001). The disposition index was increased 6 months after treatment but values at 5 years were similar to those at cessation of treatment (2483.94 [95% CI 2233.43 2762.54] at cessation of treatment vs 2367.83 [2033.43-2757.22] at 5 years; p=0.49). 5 years after cessation of growth hormone treatment, adults born small for gestational age and previously treated with growth hormone had fat mass, insulin sensitivity, and disposition index similar to those of untreated adults born small for gestational age with short stature, but lean body mass (adjusted for sex and height) was lower (46.47 kg [44.95-48.00] in those born small for gestational age with short stature vs 44.32 kg [43.35-45.30] in those born small for gestational age and treated with growth hormone; p=0.007). In adults previously treated with growth hormone born small for gestational age, at 5 years after cessation of growth hormone treatment, compared with adults born small for gestational age with spontaneous catch-up growth and adults born appropriate for gestational age, lean body mass was lower and results from frequently sampled intravenous glucose tolerance tests were similar. INTERPRETATION: Significant changes in body composition and insulin sensitivity were recorded 5 years after cessation of growth hormone treatment in adults born small for gestational age, reflecting a loss of pharmacological effects of growth hormone. 5 years after cessation of treatment, fat mass, insulin sensitivity, and beta-cell function of previously treated adults were similar to untreated adults born small for gestational age with short stature, indicating that long-term growth hormone treatment in children born small for gestational age has no unfavourable effects on metabolic health in early adulthood. FUNDING: Novo Nordisk Farma BV (Netherlands). PMID- 28011068 TI - Otitis media in children: A proposal for a new nosological classification. PMID- 28011070 TI - Prevention and management of lymphocele formation following kidney transplantation. AB - Despite preventive methods, lymphoceles frequently form following kidney transplantation (KTx), with an incidence of 0.6%-51%. Here, we summarize the current strategies for preventing and managing this complication, and describe the approach used in our department. Rapid diagnosis and early treatment of lymphoceles through a well-defined approach can prevent or reduce the risk of organ loss. Diagnosis can be made by ultrasound, computed tomography, or magnetic resonance imaging and laparoscopic fenestration is the current therapy of choice when non-surgical methods fail. Preventive methods should be performed pre-, intra-, and post-operatively. A peritoneal fenestration at the end of KTx seems to be a reasonable method for preventing lymphocele formation. PMID- 28011069 TI - Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants. AB - BACKGROUND: Germline heterozygous mutations in human signal transducer and activator of transcription 1 (STAT1) can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases, or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis. LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil domain (CCD) and DNA-binding domain (DBD). Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants. OBJECTIVE: We estimated variations in the CCD/DBD of STAT1. METHODS: We mutagenized 342 individual wild-type amino acids in the CCD/DBD (45.6% of full length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity. RESULTS: Of these 342 mutants, 201 were neutral, 30 were LOF, and 111 were GOF mutations in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in the CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the effect of 2 hypomorphic and dominant negative mutations, E157K and G250E, in the CCD of STAT1 that we found in 2 unrelated patients with Mendelian susceptibility to mycobacterial diseases. CONCLUSION: The systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases. PMID- 28011071 TI - Is device-assisted reduction prior to semi-extended intramedullary nailing of distal tibial fractures necessary? AB - INTRODUCTION: Traditional methods of nailing distal tibial fractures have an unacceptable risk of mal-alignment due to difficulty in obtaining and maintaining reduction intra-operatively. Methods to obtain and maintain reduction when nailing these fractures, and therefore reducing the risk of Mal-alignment include modified external fixators, distractors and commercial reduction tools. Semi extended intramedullary nailing of distal tibial fractures via a supra-patellar approach is now being used more commonly. The aim of this study was to assess whether a commercial reduction device (Staffordshire Orthopaedic Reduction Machine - STORM, Intelligent Orthopaedics, Stafffordshire, UK) is necessary to reduce the risk of mal-alignment in patients undergoing semi-extended nailing for distal tibial fractures. METHODOLOGY: A case-control study was conducted in 20 patients who had STORM-assisted reduction of distal tibial fractures prior to intramedullary nailing and 20 controls without STORM. The control group was matched for age, sex, fracture type (AO/OTA), ASA and gender. All patients had an intramedullary nail (IMN) using the semi-extended system. Primary outcome measures were coronal and sagittal mal-alignment. Secondary outcome measure was unplanned return to theatre for complications and problems with fracture healing. RESULTS: There was no difference in post-operative mal-alignment in both groups. There was no significant difference in time to union in both groups Both groups had equal number of patients requiring unplanned return to theatre. The STORM group was associated with a significantly increased operative time [p=0.007, 130.3min (SD 49.4) STORM vs 95.6 mins (SD 22.9) Control]. CONCLUSION: Intraoperative use of STORM significantly increases operative time with no difference in outcome. The superior orthogonal views and manual control obtained during semi-extended nailing via a supra-patellar approach obviate the need for additional methods: of intraoperative reduction for this fracture group. PMID- 28011072 TI - Mortality prediction models in the general trauma population: A systematic review. AB - BACKGROUND: Trauma is the leading cause of death in individuals younger than 40 years. There are many different models for predicting patient outcome following trauma. To our knowledge, no comprehensive review has been performed on prognostic models for the general trauma population. Therefore, this review aimed to describe (1) existing mortality prediction models for the general trauma population, (2) the methodological quality and (3) which variables are most relevant for the model prediction of mortality in the general trauma population. METHODS: An online search was conducted in June 2015 using Embase, Medline, Web of Science, Cinahl, Cochrane, Google Scholar and PubMed. Relevant English peer reviewed articles that developed, validated or updated mortality prediction models in a general trauma population were included. RESULTS: A total of 90 articles were included. The cohort sizes ranged from 100 to 1,115,389 patients, with overall mortality rates that ranged from 0.6% to 35%. The Trauma and Injury Severity Score (TRISS) was the most commonly used model. A total of 258 models were described in the articles, of which only 103 models (40%) were externally validated. Cases with missing values were often excluded and discrimination of the different prediction models ranged widely (AUROC between 0.59 and 0.98). The predictors were often included as dichotomized or categorical variables, while continuous variables showed better performance. CONCLUSION: Researchers are still searching for a better mortality prediction model in the general trauma population. Models should 1) be developed and/or validated using an adequate sample size with sufficient events per predictor variable, 2) use multiple imputation models to address missing values, 3) use the continuous variant of the predictor if available and 4) incorporate all different types of readily available predictors (i.e., physiological variables, anatomical variables, injury cause/mechanism, and demographic variables). Furthermore, while mortality rates are decreasing, it is important to develop models that predict physical, cognitive status, or quality of life to measure quality of care. PMID- 28011073 TI - Behavioral effects and neuroanatomical targets of acute atrazine exposure in the male Sprague-Dawley rat. AB - Atrazine (ATR) is an herbicide broadly used in the world to control weeds in corn and sorghum fields, and it is potentially toxic for the dopaminergic system. Alterations in dopaminergic markers after ATR administration in rats and C57BL/6 mice have been reported. Behaviorally, it has been observed that ATR exposure causes hypoactivity shortly after its administration. To understand how acute ATR administration induces hypoactivity, we set out to map the brain areas responsive to ATR using c-Fos as a marker of neuronal activity, and tyrosine hydroxylase (TH) as a marker of dopaminergic neurons. The levels of glutamate and gamma aminobutyric acid (GABA) were measured using high performance liquid chromatography, and spontaneous locomotor activity was evaluated as well. Male Sprague-Dawley rats received a systemic injection of 1% methyl cellulose (vehicle) or 100mg ATR/kg body weight to evaluate locomotor activity immediately after injection, c-Fos and TH immunohistochemistry in forebrain, midbrain and hindbrain, or glutamate and GABA content in various brain areas 90min after injection. To assess the possible involvement of the GABAergic system on ATR effects we tested the effects of a GABA-B antagonist. We found statistically significant decreases in locomotor activity, which were partially reversed by the GABA-B antagonist, and increases in the number of c-Fos-positive cells in thalamus, central amygdala, subthalamic nucleus, superior colliculus, and substantia nigra, TH positive cells were not selectively activated by ATR. The acute administration of ATR did not affect GABA or glutamate tissue levels but significantly decreased locomotor activity. These results corroborate the hypoactivity-inducing effect of ATR, and show that non-dopaminergic cells respond to the acute administration of ATR. The activation of cell populations in the basal ganglia and their target nuclei may contribute to the acute behavioral effects of ATR. PMID- 28011074 TI - Patient database analysis of fulvestrant 500 mg in the treatment of metastatic breast cancer: A European perspective. AB - INTRODUCTION: Clinical guidelines recommend that patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) should be preferentially treated with endocrine therapy. Fulvestrant (a selective estrogen receptor degrader) is approved for use in these patients following relapse after, or relapse or progression during, antiestrogen therapy. This descriptive study analyzed European treatment patterns for HR-positive MBC in real-world clinical practice. METHODS: The IMS Oncology Analyzer (OA), a retrospective cancer treatment database reporting physician-entered patient case histories, was used to identify records for postmenopausal women with HR-positive MBC from April 1, 2004 to June 30, 2013 in France, Germany, Italy, and Spain. Treatments were allocated to mutually exclusive categories (fulvestrant-containing, aromatase inhibitor [AI] containing, tamoxifen-containing, or chemotherapy-containing regimens) and assessed by line of therapy for MBC. Fulvestrant use was also assessed pre- and post-2010 (when fulvestrant 500 mg dosing was approved). RESULTS: In total, 27,214 eligible patients were included (France: 6801; Germany: 6852; Italy: 7061; Spain: 6500). Chemotherapy-based regimens were the most common first-line treatments for MBC across all countries. Across countries, the proportion of patients initiating on each treatment category ranged from: chemotherapy, 57.5 70.4%; AI, 23.5-30.1%; tamoxifen, 2.7-9.8%; fulvestrant 0.8-2.6%. When administered, fulvestrant was usually given as first- or second-line treatment. Post-2010, more patients received fulvestrant 500 mg than fulvestrant 250 mg in France, Germany, and Spain; in Italy, more patients continued to receive fulvestrant 250 mg. CONCLUSION: Most patients with HR-positive MBC receive chemotherapy over endocrine therapy; fulvestrant constitutes a small proportion of treatments for such patients. PMID- 28011075 TI - Detection of on-target and off-target mutations generated by CRISPR/Cas9 and other sequence-specific nucleases. AB - The development of customizable sequence-specific nucleases such as TALENs, ZFNs and the powerful CRISPR/Cas9 system has revolutionized the field of genome editing. The CRISPR/Cas9 system is particularly versatile and has been applied in numerous species representing all branches of life. Regardless of the target organism, all researchers using sequence-specific nucleases face similar challenges: confirmation of the desired on-target mutation and the detection of off-target events. Here, we evaluate the most widely-used methods for the detection of on-target and off-target mutations in terms of workflow, sensitivity, strengths and weaknesses. PMID- 28011076 TI - Revised set of diagnostic criteria for neurocysticercosis (in reply to Garg and Malhotra). PMID- 28011077 TI - Top-down and bottom-up analysis of commercial enoxaparins. AB - A strategy for the comprehensive analysis of low molecular weight (LMW) heparins is described that relies on using an integrated top-down and bottom-up approach. Liquid chromatography-mass spectrometry, an essential component of this approach, is rapid, robust, and amenable to automated processing and interpretation. Nuclear magnetic resonance spectroscopy provides complementary top-down information on the chirality of the uronic acid residues comprising a low molecular weight heparin. Using our integrated approach four different low molecular weight heparins prepared from porcine heparin through chemical beta eliminative cleavage were comprehensively analyzed. LovenoxTM and ClexaneTM, the innovator versions of enoxaparin marketed in the US and Europe, respectively, and two generic enoxaparins, from Sandoz and Teva, were analyzed. The results which were supported by analysis of variation (ANOVA), while showing remarkable similarities between different versions of the product and good lot-to-lot consistency of each product, also detects subtle differences that may result from differences in their manufacturing processes or differences in the source (or parent) porcine heparin from which each product is prepared. PMID- 28011078 TI - Preparation and characterization of hydrophilic hybrid monoliths via thiol-ene click polymerization and their applications in chromatographic analysis and glycopeptides enrichment. AB - A macroporous hydrophilic organic-silica hybrid monolithic column was synthesized via photoinitiated thiol-ene click polymerization reaction of 1-thioglycerol modified polyhedral oligomeric vinylsilsesquioxane (vinylPOSS) and dithiothreitol (DTT) in a binary porogenic system consisting of tetrahydrofuran (THF) and dodecanol. 1-Thioglycerol was used to modify vinylPOSS in order to form a precursor with good solubility in the binary porogenic system. The influences of both the ratio of 1-thioglycerol/vinylPOSS and the porogenic solvents on the morphology and permeability of hybrid monoliths were studied in detail. The physical properties of hybrid monolith were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and nitrogen adsorption/desorption measurement. The chromatographic performance was evaluated by separation of neutral polar compounds in capillary liquid chromatography (cLC). The resulting column possessed homogeneous macroporous structure and showed hydrophilic interaction liquid chromatography (HILIC) separation mechanism with high efficiency of 65,000Nm-1 for formamide. Ultimately, the hybrid matrix was grafted with hydrazine groups and then exhibited the ability of glycopeptides enrichment. PMID- 28011079 TI - Interprofessional Education to Create and Sustain High-Performance Teams to Support Our Transforming Health Care System and Future Educational Model: How Nutrition and Dietetics Can "Weigh-in". PMID- 28011080 TI - Reaction time norms as measured by ruler drop method in school-going South Asian children: A cross-sectional study. AB - This study aimed to estimate normative range for reaction time using ruler drop method for school-going South Asian children between 6 and 12 years of age. A cross-sectional study was used to evaluate the reaction time for 204 children. Normal values for each age group were obtained. The results of multiple linear regressions showed a decrease in the reaction time values with age, and a significant change occurring between six and eight years of age. No difference in reaction time was obtained between boys and girls. Ruler drop method is an easy to use test and the results of this study provide a normative data for age groups 6-12 years ranging from 214.2ms to 248.8ms. These values can serve as a reference to screen children with delayed reaction time. PMID- 28011081 TI - From Theory to Practice: Measuring end-of-life communication quality using multiple goals theory. AB - OBJECTIVES: To describe how multiple goals theory can be used as a reliable and valid measure (i.e., coding scheme) of the quality of conversations about end-of life issues. METHODS: We analyzed conversations from 17 conversations in which 68 participants (mean age=51years) played a game that prompted discussion in response to open-ended questions about end-of-life issues. Conversations (mean duration=91min) were audio-recorded and transcribed. Communication quality was assessed by three coders who assigned numeric scores rating how well individuals accomplished task, relational, and identity goals in the conversation. RESULTS: The coding measure, which results in a quantifiable outcome, yielded strong reliability (intra-class correlation range=0.73-0.89 and Cronbach's alpha range=0.69-0.89 for each of the coded domains) and validity (using multilevel nonlinear modeling, we detected significant variability in scores between games for each of the coded domains, all p-values <0.02). CONCLUSIONS: Our coding scheme provides a theory-based measure of end-of-life conversation quality that is superior to other methods of measuring communication quality. PRACTICE IMPLICATIONS: Our description of the coding method enables researches to adapt and apply this measure to communication interventions in other clinical contexts. PMID- 28011082 TI - [Neonatal arterial ischemic stroke: Review of the current guidelines]. AB - Neonatal arterial ischemic stroke (NAIS) is a rare event that occurs in approximately one in 5000 term or close-to-term infants. Most affected infants will present with seizures. Although a well-recognized clinical entity, many questions remain regarding diagnosis, risk factors, treatment, and follow-up modalities. In the absence of a known pathophysiological mechanism and lack of evidence-based guidelines, only supportive care is currently provided. To address these issues, a French national committee set up by the French Neonatal Society (Societe francaise de neonatologie) and the national referral center (Centre national de reference) for arterial ischemic stroke in children drew up guidelines based on an HAS (Haute Autorite de sante [HAS]; French national authority for health) methodology. The main findings and recommendations established by the study group are: (1) among the risk factors, male sex, primiparity, caesarean section, perinatal hypoxia, and fetal/neonatal infection (mainly bacterial meningitis) seem to be the most frequent. As for guidelines, the study group recommends the following: (1) the transfer of neonates with suspected NAIS to a neonatal intensive care unit with available equipment to establish a reliable diagnosis with MRI imaging and neurophysiological monitoring, preferably by continuous video EEG; (2) acute treatment of suspected infection or other life-threatening processes should be addressed immediately by the primary medical team. Persistent seizures should be treated with a loading dose of phenobarbital 20mg/kg i.v.; (3) MRI of the brain is considered optimal for the diagnosis of NAIS. Diffusion-weighted imaging with apparent diffusion coefficient is considered the most sensitive measure for identifying infarct in the neonatal brain. The location and extent of the lesions are best assessed between 2 and 4 days after the onset of stroke; (4) routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocysteinemia, the Lp(a) test, the MTHFR thermolabile variant should not be considered in neonates with NAIS. Testing for FV Leiden can be performed only in case of a documented family history of venous thromboembolic disease. Testing neonates for the presence of antiphospholipid antibodies should be considered only in case of clinical events arguing in favor of antiphospholipid syndrome in the mother; (5) unlike childhood arterial ischemic stroke, NAIS has a low 5-year recurrence rate (approximately 1 %), except in those children with congenital heart disease or multiple genetic thrombophilia. Therefore, initiation of anticoagulation or antithrombotic agents, including heparin products, is not recommended in the newborn without identifiable risk factors; (6) the study group recommends that in case of delayed motor milestones or early handedness, multidisciplinary rehabilitation is recommended as early as possible. Newborns should have physical therapy evaluation and ongoing outpatient follow-up. Given the risk of later-onset cognitive, language, and behavioral disabilities, neuropsychological testing in preschool and at school age is highly recommended. PMID- 28011083 TI - Impaired auditory processing and altered structure of the endbulb of Held synapse in mice lacking the GluA3 subunit of AMPA receptors. AB - AMPA glutamate receptor complexes with fast kinetics conferred by subunits like GluA3 and GluA4 are essential for temporal precision of synaptic transmission. The specific role of GluA3 in auditory processing and experience related changes in the auditory brainstem remain unknown. We investigated the role of the GluA3 in auditory processing by using wild type (WT) and GluA3 knockout (GluA3-KO) mice. We recorded auditory brainstem responses (ABR) to assess auditory function and used electron microscopy to evaluate the ultrastructure of the auditory nerve synapse on bushy cells (AN-BC synapse). Since labeling for GluA3 subunit increases on auditory nerve synapses within the cochlear nucleus in response to transient sound reduction, we investigated the role of GluA3 in experience dependent changes in auditory processing. We induced transient sound reduction by plugging one ear and evaluated ABR threshold and peak amplitude recovery for up to 60 days after ear plug removal in WT and GluA3-KO mice. We found that the deletion of GluA3 leads to impaired auditory signaling that is reflected in decreased ABR peak amplitudes, an increased latency of peak 2, early onset hearing loss and reduced numbers and sizes of postsynaptic densities (PSDs) of AN BC synapses. Additionally, the lack of GluA3 hampers ABR threshold recovery after transient ear plugging. We conclude that GluA3 is required for normal auditory signaling, normal ultrastructure of AN-BC synapses in the cochlear nucleus and normal experience-dependent changes in auditory processing after transient sound reduction. PMID- 28011085 TI - Self-excising Cre/mutant lox marker recycling system for multiple gene integrations and consecutive gene deletions in Aspergillus oryzae. AB - In this study, we developed a self-excising Cre/loxP-mediated marker recycling system with mutated lox sequences to introduce a number of biosynthetic genes into Aspergillus oryzae. To construct the self-excising marker cassette, both the selectable marker, the Aspergillus nidulans adeA gene, and the Cre recombinase gene (cre), conditionally expressed by the xylanase-encoding gene promoter, were designed to be located between the mutant lox sequences, lox66 and lox71. However, construction of the plasmid failed, possibly owing to a slight expression of cre downstream of the fungal gene promoter in Escherichia coli. Hence, to avoid the excision of the cassette in E. coli, a 71-bp intron of the A. oryzae xynG2 gene was inserted into the cre gene. The A. oryzae adeA deletion mutant was transformed with the resulting plasmid in the presence of glucose, and the transformants were cultured in medium containing xylose as the sole carbon source. PCR analysis of genomic DNA from resultant colonies revealed the excision of both the marker and Cre expression construct, indicating that the self excising marker cassette was efficient at removing the selectable marker. Using the marker recycling system, hyperproduction of kojic acid could be achieved in A. oryzae by the introduction of two genes that encode oxidoreductase and transporter. Furthermore, we also constructed an alternative marker recycling cassette bearing the A. nidulans pyrithiamine resistant gene (ptrA) as a dominant selectable marker. PMID- 28011086 TI - The application of epidemiology in national veterinary services: Challenges and threats in Brazil. AB - The application of epidemiology in national veterinary services must take place at the interface between science and politics. Animal health policy development and implementation require attention to macro-epidemiology, the study of economic, social and policy inputs that affect the distribution and impact of animal or human disease at the national level. The world has changed fast over the last three decades including the delivery of veterinary services, their remit and the challenges addressed by public and animal health policies. Rethinking the role of public services and how to make public programs more efficient has been at the heart of the political discussion. The WTO through its SPS Agreement has changed the way in which national veterinary services operate and how trade decisions are made. Most low and middle income countries are still struggling to keep up with the new international scene. Some of these countries, such as Brazil, have very important livestock industries and are key to the global food systems. Over the last two decades, Brazil became a leading player in exports of livestock products, including poultry, and this created a strong pressure on the national veterinary services to respond to trade demands, leading to focus animal health policies on the export-driven sector. During the same period, Brazil has gone a long way in the direction of integrating epidemiology with veterinary services. Epidemiology groups grew at main universities and have been working with government to provide support to animal health policy. The scope and quality of the applied epidemiological work improved and focused on complex data analysis and development of technologies and tools to solve specific disease problems. Many public veterinary officers were trained in modern epidemiological methods. However, there are important institutional bottlenecks that limit the impact of epidemiology in evidence-based decision making. More complex challenges require high levels of expertise in veterinary epidemiology, as well as institutional models that provide an appropriate environment for building and sustaining capacity in national veterinary services. Integrating epidemiology with animal health policy is a great opportunity if epidemiologists can understand the real issues, including the socio-economic dimensions of disease management, and focus on innovation and production of knowledge. It may be a trap if epidemiologists are restricted to answering specific decision-making questions and policy makers perceive their role exclusively as data analysts or providers of technological solutions. Fostering solutions for complex issues is key to successful integration with policy making. PMID- 28011084 TI - Multiscale mapping of frequency sweep rate in mouse auditory cortex. AB - Functional organization is a key feature of the neocortex that often guides studies of sensory processing, development, and plasticity. Tonotopy, which arises from the transduction properties of the cochlea, is the most widely studied organizational feature in auditory cortex; however, in order to process complex sounds, cortical regions are likely specialized for higher order features. Here, motivated by the prevalence of frequency modulations in mouse ultrasonic vocalizations and aided by the use of a multiscale imaging approach, we uncover a functional organization across the extent of auditory cortex for the rate of frequency modulated (FM) sweeps. In particular, using two-photon Ca2+ imaging of layer 2/3 neurons, we identify a tone-insensitive region at the border of AI and AAF. This central sweep region behaves fundamentally differently from nearby neurons in AI and AII, responding preferentially to fast FM sweeps but not to tones or bandlimited noise. Together these findings define a second dimension of organization in the mouse auditory cortex for sweep rate complementary to that of tone frequency. PMID- 28011088 TI - Nitration of MOG diminishes its encephalitogenicity depending on MHC haplotype. AB - Post-translational modifications of autoantigens are hypothesized to affect their immunogenicity. We here report that nitration of tyrosine 40 in Myelin Oligodendrocyte Glycoprotein (MOG) abrogates its encephalitogenicity both at protein and peptide levels in the experimental autoimmune encephalomyelitis (EAE) model in H2b C57BL/6 mice. Furthermore, nitrated MOG displays inferior antigen specific proliferation of 2D2 splenocytes in vitro. Conversely, H2q DBA1 mice remain fully susceptible to EAE induction using nitrated MOG as the dominant epitope of H2q mice is unaltered. Molecular modeling analysis of the MOG35-55/H2 IAb complex and bioinformatics peptide binding predictions indicate that the lack of T cell reactivity towards nitrated MOG can be attributed to the inability of murine H2-IAb to efficiently present the altered peptide ligand of MOG35-55 because the nitrated tyrosine 40 cannot be accommodated in the p1 anchor pocket. In conclusion we demonstrate nitration as a relevant determinant affecting T cell recognition of carrier antigen depending on MHC haplotype. Our data have implications for understanding the role of post-translationally modified antigen in autoimmunity. PMID- 28011089 TI - [Hailey-Hailey disease: Efficiency of combined doxycycline and vitamin PP]. PMID- 28011087 TI - Transcription Factor EB Controls Metabolic Flexibility during Exercise. AB - The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC1alpha). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism. PMID- 28011090 TI - [Toxic epidermal necrolysis due to anti-PD1 treatment with fatal outcome]. PMID- 28011091 TI - [Oral care recommendations for patients with oral autoimmune bullous diseases]. AB - BACKGROUND: Autoimmune bullous diseases (AIBD) may cause chronic oral lesions that progress insidiously. AIMS: To provide recommendations for optimal oral dental management of patients presenting AIBD with oral involvement. PATIENTS AND METHODS: In the absence of scientific studies with high levels of proof, these recommendations have been drawn up at two meetings by a committee of experts on AIBD comprising 7 dermatologists, 1 stomatologist, 1 maxillofacial surgeon, 2 odontologists and 4 parodontologists. RESULTS: The oral lesions associated with AIBD may be classified into three grades of severity: severe (generalised erosive gingivitis affecting at least 30% of dental sites), moderate (localised erosive gingivitis affecting less than 30% of dental sites) and controlled (no erosive oral lesions). Good oral-dental hygiene suited to the severity of the oral lesions, must be practised continually by these patients so as to avoid the formation of dental plaque, which aggravates symptoms. Dental and parodontal care must be considered in accordance with the severity grade of the oral lesions: in severe cases, the dental plaque must be eliminated manually with a curette, but several types of care (descaling, treatment for tooth decay, non-urgent extractions, etc.) must be suspended until the grade of severity is moderate or until the disease is stabilised. PMID- 28011092 TI - Study of plasmonic nanoparticles interactions with skin layers by vibrational spectroscopy. AB - The healing effects of silver and gold nanoparticles (AgNPs, AuNPs) are already known from ancient times. In addition considering to their antibacterial and anti inflammatory effects speculations are being lead with respect to these nanoparticles (NPs) also about enhancement of skin penetration properties. In this work the interactions of pig skin (PS) layers and ointments with additions of AgNPs or AuNPs prepared by standard procedures and also by "green" synthesis in a different weight proportion by vibrational spectroscopy were studied. Spectra of untreated skin and skin treated by pure ointment were measured, as well as by ointment modified by vitamins without addition of NPs or with different proportion of NPs. Kinetics of interactions of modified ointments with skin was monitored during two hours with a five-minutes interval between each two consecutive measurements. The obtained series of spectra were analyzed by multivariate statistical methods namely Partial Least Squares (PLS), Principal Component Analysis (PCA) and Soft Independent Modelling of Class Analogy (SIMCA) which revealed observation of spectral changes in time-dependent spectra and variations of the peak intensity ratios. The study showed that the effects of quantity and type of NPs on skin penetration characteristics are evident. PMID- 28011093 TI - Influence of different stabilizers on the encapsulation of desmopressin acetate into PLGA nanoparticles. AB - To address targeting and bioavailability issues of peptidic drugs like desmopressin, the encapsulation into nanoparticles (NP) has become standard in pharmaceutics. This study investigated the encapsulation of desmopressin into PLGA NP by the use of pharmaceutically common stabilizers as a precursor to future, optional targeting and bioavailability experiments. Polymer dry weights were measured by freeze drying and thermo gravimetric analysis (TGA). Particle sizes (ranging between 105 and 130nm, PDI<0.1) and zeta potentials (-35 to -45mV) were analyzed with Dynamic Light Scattering (DLS) and Laser-Doppler-Anemometry (LDA) respectively. Highest loading efficiencies, quantified by RP-HPLC, were achieved with Pluronic F-68 as stabilizer of the inner aqueous phase (1.16+/ 0.07MUg desmopressin/mg PLGA) and were significantly higher than coating approaches and approaches without stabilizer (0.74+/-0.01MUg/mg). Optimized nanoformulations are thus in competition with the concentration of commercial non nanoparticulate desmopressin products. Stability of desmopressin after the process was evaluated by HPLC peak purity analysis (diode array detector) and by mass spectrometry. Desmopressin was shown to remain intact during the whole process; however, despite these very good results the encapsulation efficiency turned out to be a bottle neck and makes the system a challenge for potential applications. PMID- 28011094 TI - Using cost-benefit analysis and social return on investment to evaluate the impact of social enterprise: Promises, implementation, and limitations. AB - Since the early 2000's there has been growing interest in using the Social Return on Investment (SROI) as a measure for assessing the performance of social enterprises. By analogy with its business counterpart, the Return on Investment (ROI), the SROI is a metric that compares the monetized social costs of a program with the monetized social benefits of achieving an outcome (or set of outcomes). For example, calculating the SROI of a nonprofit half-way house for drug addicts might involve estimating the reduced social costs attributable to successful rehabilitation of addicts, and comparing this to the social costs of operating the half-way house. Alternatively, the total return of a for-profit social enterprise providing affordable housing might consist both of the traditional private return on investment along with the economic value of meeting the housing needs of lower income households. Early descriptions of the methodology for calculating the SROI suggest that the approach initially evolved from standard methodologies found in the business finance literature for evaluating investments, with the important twist that nonprofit sector returns/payoffs are defined in broader social terms (Thornley, Anderson, & Dixon, 2016). Yet, someone who is familiar with the economic literature on cost benefit analysis (CBA) as it is applied to the evaluation of public programs cannot help but be struck by the similarity between the outcomes that CBA is intended to measure, and those that are the object of efforts to calculate the SROI. One implication is that the literature on the theory and practice of cost benefit analysis offers useful lessons about how to measure the social return on investment, as well as about potential caveats and limitations that need to be confronted when attempting to undertake an analysis of the SROI. The paper discusses the potential uses and limitations of CBA and SROI as tools that governments, private donor/investors, and foundations can use to help set funding priorities, and evaluate performance. It summarizes: (1) the conceptual foundations of CBA and its application to SROI analysis, (2) issues raised in the implementation of CBA and SROI in practice, and (3) discusses when CBA and/or SROI approaches are a useful lens for setting priorities and/or evaluating performance, as well as important limitations of such methods. PMID- 28011095 TI - [One-and- a-half syndrome after head trauma]. PMID- 28011096 TI - Minimally Invasive Radical Hysterectomy for Cervical Cancer Is Associated With Reduced Morbidity and Similar Survival Outcomes Compared With Laparotomy. AB - STUDY OBJECTIVE: To assess outcomes of women with cervical cancer undergoing upfront radical hysterectomy (RH) via a minimally invasive surgery (MIS) or a traditional laparotomy (XL) approach at 2 large US academic institutions to determine whether the mode of surgery affects patient outcomes. DESIGN: Retrospective cohort study (Canadian Task Force classification II-1). SETTING: Two academic medical institutions in the United States. PATIENTS: Women undergoing upfront RH for cervical cancer between 2000 and 2013. INTERVENTION: Minimally invasive techniques (laparoscopic and robotic) for RH compared with XL. MEASUREMENTS AND MAIN RESULTS: A total of 383 women met the eligibility requirements. Of these, 101 underwent an MIS (i.e., traditional laparoscopy, laparoendoscopic single site, or robotic) approach, and 282 underwent an XL approach. Overall survival (median not reached; p = .29) was not different between the 2 groups. Recurrence was rare and equivalent in the 2 groups, affecting 5.0% of patients in the MIS group and 6.4% of those in the XL group (p = .86). Pelvic lymph nodes were dissected in 98% of patients in the MIS group and 97% of those in the XL group (p > .99) and were found to be positive in 10.9% and 8.5% of those patients, respectively (p = .55). The mean number of pelvic lymph nodes retrieved was higher in the MIS group (19.4 vs 16.0; p < .001). There was no between-group difference in the rate of postoperative chemotherapy (p = .32) or radiation therapy (p = .28). Surgical margins were positive in 5.0% of specimens in the MIS group and in 4.6% of specimens in the XL group (p = .54). Although there was no difference in the overall rate of complications (15.1% and 17.2%, respectively; p = .87), laparotomy was associated with a higher median estimated blood loss (EBL) (50 cm3 vs 500 cm3) and a higher rate of perioperative blood transfusion (3.0% vs 26.2%; p < .001). Length of perioperative hospital stay was significantly shorter in the MIS group (1.9 days vs 4.9 days; p < .001). CONCLUSION: MIS RH does not compromise patient outcomes, including overall survival, rate of recurrence, and the frequency of pelvic lymph node dissection or positivity. Morbidity was decreased in the MIS group, including decreased EBL, fewer blood transfusions, and shorter hospital stay. PMID- 28011097 TI - Hemostasis During Ovarian Cystectomy: Systematic Review of the Impact of Suturing Versus Surgical Energy on Ovarian Function. AB - This systematic review compares the effect of suturing and surgical energy used for hemostasis during ovarian cystectomies on ovarian function. A search of Scopus, Embase, and PubMed databases was conducted through December 1, 2016 for prospective, retrospective, and randomized controlled trials that analyzed ovarian function after ovarian cystectomies where hemostasis was obtained using suturing versus surgical energy. Of the 25 studies identified, 12 with a total of 1133 subjects met the criteria and were included in this review. Analysis of the pooled data strongly supports the use of suturing rather than surgical energy (bipolar or ultrasonic coagulation) for hemostasis, because it provides improved preservation of ovarian function at the time of cystectomy. Four of 8 ovarian reserve markers (anti-Mullerian hormone, antral follicle count, peak systolic velocity, and ovarian volume) demonstrated a positive association using suturing, whereas the remainder of ovarian markers showed a positive trend toward suturing or noninferiority to bipolar energy. In conclusion, suturing for hemostasis after ovarian cystectomy is superior to surgical energy in preserving ovarian function. Further studies are needed to assess whether this difference is clinically relevant in regards to fertility and premature ovarian failure. (USPSTF Level II 1 Evidence). PMID- 28011098 TI - Serum IGF-I, IGFBP-3 and ALS concentrations and physical performance in young swimmers during a training season. AB - INTRODUCTION: The GH/IGF-I axis is a system of growth mediators, receptors, and binding proteins that regulate somatic and tissue growth; and it has been shown that exercise programs are related to the anabolic function of this axis. OBJECTIVE: The aim of this study was to analyse the changes of serum IGF-I concentration and that of its binding proteins IGFBP-3 and ALS in adolescent swimmers at different stages of a training season, and compare them with physical performance parameters and body composition of the athletes. MATERIAL AND METHODS: Nine male athletes, aged 16 to 19years and who trained regularly throughout the season, were included in this study. Serum IGF-I, IGFBP-3, and ALS concentrations were recorded before and after (pre*post) standardized training sessions during the different stages of a training season (extensive*intensive*tapering). Endurance in freestyle, anaerobic fitness in tied swimming (Peak Force and Average Force), body mass, fat percentage, and lean body mass were also analysed at the different stages of training in order to compare the changes of the IGF-I/IGFBP/ALS system with the physical performance and body composition of the athletes. Variations in the IGF-I/IGFBP-3-ALS system before and after a standardized training session, and at the different stages of training were analysed by the Wilcoxon and Friedman non-parametric tests, respectively. Significance was considered at 5%. RESULTS: The results from this study demonstrate that IGF-I is sensitive to the acute and chronic effects of training, exhibiting biphasic behaviour throughout the season. The catabolic phase was characterized by a reduction in serum IGF-I concentrations during the intensive stage (?IGF-I: - 43.33+/-47.32ng/ml; P<0.05) while the anabolic phase was marked by similar basal concentrations at the different stages of training and an increase in post-training serum IGF-I concentrations during the tapering stage (320+/-40; 298+/-36 and 359+/-94ng/ml; P<0.05). IGFBP-3 was only sensitive to the chronic effects of training, with a reduction in post-training serum concentrations during the intensive stage and an increase during the tapering stage (4.7+/-0.7, 4.6+/-0.4 and 5.0+/-0.7mg/l; P<0.05). No significant difference (P>0.05) was observed in pre- or post-training IGFBP-3 concentrations (?IGFBP-3) at the different stages. ALS concentrations remained unchanged throughout the season, demonstrating that in adolescent athletes they are unaffected by the acute or chronic effects of swimming. Peak Force (25.0+/-6.3, 24.2+/-5.7 and 28.5+/-6.5N; P<0.05) and Average Force (10.3+/-3.6, 8.8+/-1.8 and 14.7+/-1.8N; P<0.05) followed IGF-I and IGFBP-3 variations, with a decrease during the intensive stage and a significant (P<0.05) increase during the tapering stage. The body composition and cardiorespiratory condition of the swimmers did not vary significantly throughout the season, exhibiting behaviour independent of IGF-I or IGFBP-3. CONCLUSION: Serum IGF-I and IGFPB-3 concentrations have proven to be sensitive markers of training status and, thus, may be used as guides for coaches and athletes in the challenging task of modulating training intensity in young athletes. PMID- 28011099 TI - A walking program for people with severe knee osteoarthritis did not reduce pain but may have benefits for cardiovascular health: a phase II randomised controlled trial. AB - OBJECTIVE: The primary aim was to evaluate the effect of a dosed walking program on knee pain for patients with severe knee osteoarthritis (OA). Secondary aims evaluated the effects on cardiovascular health, function and quality of life. DESIGN: Participants with severe knee OA and increased cardiovascular risk were randomly assigned to a 12-week walking program of 70 min/week of at least moderate intensity, or to usual care. The primary outcome was knee pain (0-10). Secondary outcomes were of cardiovascular risk including physical activity, blood pressure, blood lipid and glucose levels, body mass index and waist circumference; WOMAC Index scores; physical function; and quality of life. RESULTS: Forty-six participants (23 each group) were recruited. Sixteen participants (70%) adhered to the walking program. Intention to treat analysis showed no between-group difference in knee pain. The walking group had increased odds of achieving a healthy systolic blood pressure (OR = 5.7, 95% CI 1.2-26.9), and a faster walking speed (Mean Difference (MD) = 0.12 m/s, 95% CI 0.02-0.23). Per protocol analysis based on participant adherence showed the walking group had more daily steps (MD = 1345 steps, 95% CI 365-2325); more time walking (MD = 18 min/day, 95% CI 5-31); reduced waist circumference (MD = -5.3 cm, 95% CI -10.5 to -0.03); and increased knee stiffness (MD = 0.9 units, 95% CI 0.07-1.8). CONCLUSIONS: Patients with severe knee OA prescribed a 12-week walking program of 70 min/week may have had cardiovascular benefits without decreasing knee pain. Australian New Zealand Clinical Trials Registry ACTRN12615000015549. PMID- 28011100 TI - Association between smoking and risk of knee osteoarthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the association between smoking and the risk for knee osteoarthritis (OA). DESIGN: Cohort, case-control, and cross-sectional studies were obtained from the Medline, Embase, and Web of Science databases. Estimates were calculated using a random-effects model. Subgroup analyses and meta regression models were performed to investigate potential sources of heterogeneity. We further analyzed the dose-response relationship between cigarette consumption and risk of knee OA. RESULTS: Thirty-eight independent observational studies that included 481,744 participants were analyzed. Those who had ever smoked had a significantly decreased risk of developing knee OA relative to those who had never smoked (RR = 0.80; 95% CI 0.73-0.88). This was unaffected by study design, and the pooled relative risks (RRs) were 0.79 (95% CI, 0.65 0.96), 0.71 (95% CI, 0.61-0.84) and 0.83 (95% CI, 0.73-0.94) for cohort, case control, and cross-sectional studies, respectively. Analysis of subgroups stratified by gender reduced the heterogeneity from moderate to low in both males and females. The lower risk for developing knee OA was more apparent in male smokers (RR = 0.69; 95% CI 0.58-0.80) than female smokers (RR = 0.89; 95% CI 0.77 1.02) and dose-response analysis showed a linear decrease in knee OA with increased cigarette consumption. CONCLUSIONS: We found an inverse association between cigarette smoking and risk of knee OA, irrespective of study design. This association was more apparent in males. However, we have not demonstrated a causal relationship between smoking and OA, and further investigations are needed. PMID- 28011101 TI - Cartilage MRI T2* relaxation time and perfusion changes of the knee in a 5/6 nephrectomy rat model of chronic kidney disease. AB - OBJECTIVE: Chronic kidney disease (CKD) is characterized by metabolic disturbances in calcium and phosphorus homeostasis as kidney function declines. Alterations in blood perfusion in bone resulting from arteriosclerosis of bone vessels may relate to the progression of CKD. Herein, change in dynamic contrast enhanced (DCE) MRI parameters (A: amplitude, kel: elimination constant, and kep: permeability rate constant) and MRI T2* relaxation time of the knee cartilage were measured in a rodent nephrectomy model in order to (1) examine the relationship of peripheral blood perfusion to CKD and (2) demonstrate the feasibility of using DCE-MRI parameters and MRI T2* as imaging biomarkers to monitor disease progression. DESIGN: Two groups of male Sprague-Dawley rats received either (1) no intervention or (2) 5/6 nephrectomy. RESULTS: We found that the CKD group (compared with the control group) had lower A and kel values and similar kep value in the lateral and medial articular cartilages beginning at 12 weeks (P < 0.05); statistically significantly higher T2* values in the lateral and medial articular cartilages beginning at 18 weeks (P < 0.05); statistically significantly decreased inner luminal diameter of the popliteal artery, and altered structure of the lateral and medial articular cartilages (P < 0.05). CONCLUSION: Perfusion deficiency and CKD may be related. DCE parameters and MRI T2* could serve as imaging biomarkers of cartilage degeneration in CKD progression. PMID- 28011102 TI - Variations in pain and function before and after total knee arthroplasty: a comparison between Swedish and Australian cohorts. AB - OBJECTIVE: Preoperative pain and function is viewed as an important predictor of total knee arthroplasty (TKA) outcomes. We examined whether variations in pain and function outcomes existed at 12 months between two centres in Sweden and Australia, and whether this was explained by variations in patient presentation for TKA. METHODS: This was a retrospective analysis of prospectively collected data. Patients from one centre in Australia (St. Vincent's Hospital (SVH), N = 516) and in Sweden (Trelleborg (TBG), N = 899) who underwent primary TKA between 2012 and 2013. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was analysed pre- and 12 months' post TKA from which non-response to surgery was determined using the OMERACT-OARSI criteria. Multiple linear regression analysis was used to examine the relationship between change in pain and function and surgery centre, adjusting for preoperative patient characteristics and surgical technique. RESULTS: Despite worse preoperative outcomes in all subscales of the WOMAC for the SVH cohort, there were no clinically meaningful differences in 12-month WOMAC subscales nor change in WOMAC subscales between SVH and TBG. Almost identical proportions of patients were considered OMERACT-OARSI responders, 85.7% (SVH) and 85.9% (TBG), however for the SVH cohort 25 (4.9%) were moderate and 417 (80.8%) were high responders, compared to the TBG cohort of which 225 (25%) were moderate and 547 (60.9%) were high responders. CONCLUSION: Despite differences in preoperative presentation between 2 countries, improvements in pain and function and the proportion of individual who responded to TKA surgery at 1 year were similar. Factors related to poor response to TKA surgery require further elucidation. PMID- 28011103 TI - Characterization of new exopolysaccharide production by Rhizobium tropici during growth on hydrocarbon substrate. AB - Exopolysaccharide (EPS) are produced by a diverse of rhizobia species and has been demonstrated to be a bioemulsifier with potential applications in the degradation of hydrocarbons. In the present study, attempts were made to obtain the new exopolysaccharide production by Rhizobium tropici (SEMIA 4080 and MUTZC3) strains during growth on hydrocarbon substrate. Under the different cultivation conditions, the high molecular weight exopolysaccharides from Rhizobium tropici strains cultivated for 96h mainly consisted of carbohydrates (79-85%) and a low percentage of protein. The EPSC3-D differed from the others, with only 60% of carbohydrate. However, all strains produced polymers with distinct rheology properties, such as viscosity of each EPS sample, suitable for different applications. In addition, RP-HPLC, FTIR and NMR studies revealed EPS produced by rhizobia strains were similar indicating minimal difference between EPS compositions. PMID- 28011105 TI - A Guide to Transseptal Access. AB - Transseptal access is commonly performed for any procedure that requires access to the left side of the heart such as catheter ablation of atrial fibrillation, left atrial tachycardia, left-sided accessory pathways, ventricular tachycardia, left atrial appendage closure, percutaneous mitral valvuloplasty, and mitral valve repair. To perform this in a safe and effective manner it is important that the operator has a detailed knowledge of the relevant anatomy, the technique required, and the ability to deal with difficult cases and complications. The aim of this article is to provide a detailed description of the anatomy, techniques, potential complications, and difficulties associated with performing this procedure. PMID- 28011104 TI - Microwave ablation of renal tumors: A narrative review of technical considerations and clinical results. AB - PURPOSE: The purpose of this review was to identify the specific technical considerations to adequately perform microwave ablations (MWA) of renal tumors and analyze the currently available clinical results. METHODS: Using Medline, a systematic review was performed including articles published between January 2000 and September 2016. English language original articles, reviews and editorials were selected based on their clinical relevance. RESULTS: MWA has several theoretical advantages over radiofrequency ablation in consistently providing higher intratumoral temperatures. MWA is less dependent of electrical conductivities of tissues and the delivered energy is less limited by desiccation of heated tissues. While there are insufficient data, especially because of a lack of studies with mid- to long-term follow-up, to determine the oncologic effectiveness of MWA, this technique appears safe and effective for the ablation of T1 renal tumors. There is evidence for using mid-level settings based on experimental and clinical data. Power set at 50-65W for 5-15min appears adequate in kidney but close clinical and imaging follow-up have to be performed. CONCLUSION: Renal MWA offers theoretical advantages by comparison with other available techniques to treat renal tumors. However, MWA suffers of less cumulative data compared to radiofrequency ablation or cryoablation. Moreover, microwaves still require further studies to identify the optimal tumor characteristics and device settings leading to predictable ablation. PMID- 28011106 TI - A Novel SCN5A Mutation Found in a Familial Case of Long QT Syndrome Complicated by Severe Left Ventricular Dysfunction. AB - A 16-year-old boy with long QT syndrome type 3 (LQT3) was admitted for decompensated heart failure resulting from dilated cardiomyopathy (DCM). His brother was also diagnosed with LQT3 and DCM. A comprehensive genetic analysis identified a novel SCN5A missense mutation-p.Q371E-in these 2 affected living family members. It might be important to suspect the coexistence of DCM and LQT3 (which is rare according to previous articles) in cases with this novel SCN5A missense mutation. PMID- 28011107 TI - Trainee Perceptions of the Canadian Cardiac Surgery Workforce: A Survey of Canadian Cardiac Surgery Trainees. AB - Management of cardiac surgery health human resources (HHR) has been challenging, with recent graduates struggling to secure employment and a shortage of cardiac surgeons predicted as early as 2020. The length of cardiac surgery training prevents HHR supply from adapting in a timely fashion to changes in demand, resulting in a critical need for active workforce management. This study details the results of the 2015 Canadian Society of Cardiac Surgeons (CSCS) workforce survey undertaken as part of the CSCS strategy for active workforce management. The 38-question survey was administered electronically to all 96 trainees identified as being registered in a Canadian cardiac surgery residency program for the 2015-2016 academic year. Eighty-four of 96 (88%) trainees responded. The majority of participants were satisfied with their training experience. However, 29% stated that their clinical and operative exposure needed improvement, and 57% of graduating trainees did not believe that they would be competent to practice independently at the conclusion of their training. Although 51% of participants believe the job market is improving, 94% of senior trainees found it competitive or extremely difficult to secure an attending staff position. Participants highlighted a need for improved career counselling and formal mentorship. Although the job market is perceived to be improving, a mismatch in the cardiac surgery workforce supply and demand remains because current trainees continue to experience difficulty securing employment after the completion of residency training. Trainees have identified improved career counselling and mentorship as potential strategies to aid graduates in securing employment. PMID- 28011108 TI - Evolving Understanding of Shone Complex Through the Lifespan: What's in an Eponym? PMID- 28011109 TI - Application of Hypertension Guidelines in the Elderly: Revisiting Where the Bridge to Nowhere Might Actually Be Going. PMID- 28011110 TI - Characterization and 10Be content of iron carbonate concretions for genetic aspects - Weathering, desert varnish or burning: Rim effects in iron carbonate concretions. AB - The research investigated three iron carbonate (siderite) sedimentary concretions from Nagykovacsi, Uri and Delegyhaza, Hungary. To identify possible source rocks and effects of the glaze-like exposed surface of the concretions, we carried on comparative petrological, mineralogical, geochemical and isotopic studies. The samples were microbially mediated siderite concretions with embedded metamorphous and igneous mineral clasts, and had specific rim belts characterized by semi concentric outer Fe-oxide layers, fluffy pyrite-rich outer belts and siderite inner parts. We investigated the cross section of the Fe-carbonate concretions by independent methodologies in order to identify their rim effects. Their surficial oxide layers showed evidence of degassing of the exposed surface caused most probably by elevated temperatures. The inner rim pyrite belt in the concretions excluded the possibility of a prolonged wet surface environment. Microtextural and mineralogical features did not support desert varnish formation. 10Be nuclide values of the Nagykovacsi and Uri concretions were far above the level of terrestrial in-situ cosmogenic nuclides, but they were consistent with the lowest levels for meteorites. Though the data were not conclusive to confirm any kind of known origin, they are contradictary, and open possibilities for a scenario of terrestrial meteorite origin. PMID- 28011111 TI - Improving the quantity, quality and transparency of data used to derive radionuclide transfer parameters for animal products. 2. Cow milk. AB - Under the International Atomic Energy Agency (IAEA) MODARIA (Modelling and Data for Radiological Impact Assessments) Programme, there has been an initiative to improve the derivation, provenance and transparency of transfer parameter values for radionuclides from feed to animal products that are for human consumption. A description of the revised MODARIA 2016 cow milk dataset is described in this paper. As previously reported for the MODARIA goat milk dataset, quality control has led to the discounting of some references used in IAEA's Technical Report Series (TRS) report 472 (IAEA, 2010). The number of Concentration Ratio (CR) values has been considerably increased by (i) the inclusion of more literature from agricultural studies which particularly enhanced the stable isotope data of both CR and Fm and (ii) by estimating dry matter intake from assumed liveweight. In TRS 472, the data for cow milk were 714 transfer coefficient (Fm) values and 254 CR values describing 31 elements and 26 elements respectively. In the MODARIA 2016 cow milk dataset, Fm and CR values are now reported for 43 elements based upon 825 data values for Fm and 824 for CR. The MODARIA 2016 cow milk dataset Fm values are within an order of magnitude of those reported in TRS 472. Slightly bigger changes are seen in the CR values, but the increase in size of the dataset creates greater confidence in them. Data gaps that still remain are identified for elements with isotopes relevant to radiation protection. PMID- 28011112 TI - The artificial and natural isotopes distribution in sedge (Carex L.) biomass from the Yenisei River flood-plain: Adaptation of the sequential elution technique. AB - The study of migration pathways of artificial isotopes in the flood-plain biogeocoenoses, impacted by the nuclear fuel cycle plants, requires determination of isotope speciations in the biomass of higher terrestrial plants. The optimal method for their determination is the sequential elution technique (SET). The technique was originally developed to study atmospheric pollution by metals and has been applied to lichens, terrestrial and aquatic bryophytes. Due to morphological and physiological differences, it was necessary to adapt SET for new objects: coastal macrophytes growing on the banks of the Yenisei flood-plain islands in the near impact zone of Krasnoyarsk Mining and Chemical Combine (KMCC). In the first version of SET, 20 mM Na2EDTA was used as a reagent at the first stage; in the second version of SET, it was 1 M CH3COONH4. Four fractions were extracted. Fraction I included elements from the intercellular space and those connected with the outer side of the cell wall. Fraction II contained intracellular elements; fraction III contained elements firmly bound in the cell wall and associated structures; fraction IV contained insoluble residue. Adaptation of SET has shown that the first stage should be performed immediately after sampling. Separation of fractions III and IV can be neglected, since the output of isotopes into the IV fraction is at the level of error detection. The most adequate version of SET for terrestrial vascular plants is the version using 20 mM Na2EDTA at the first stage. Isotope 90Sr is most sensitive to the technique changes. Its distribution depends strongly on both the extractant used at stage 1 and duration of the first stage. Distribution of artificial radionuclides in the biomass of terrestrial vascular plants can vary from year to year and depends significantly on the age of the plant. PMID- 28011113 TI - The refractive index in electron microscopy and the errors of its approximations. AB - In numerical calculations for electron diffraction often a simplified form of the electron-optical refractive index, linear in the electric potential, is used. In recent years improved calculation schemes have been proposed, aiming at higher accuracy by including higher-order terms of the electric potential. These schemes start from the relativistically corrected Schrodinger equation, and use a second simplified form, now for the refractive index squared, being linear in the electric potential. The second and higher-order corrections thus determined have, however, a large error, compared to those derived from the relativistically correct refractive index. The impact of the two simplifications on electron diffraction calculations is assessed through numerical comparison of the refractive index at high-angle Coulomb scattering and of cross-sections for a wide range of scattering angles, kinetic energies, and atomic numbers. PMID- 28011114 TI - In situ investigation of ordering phase transformations in FePt magnetic nanoparticles. AB - In situ high-resolution electron microscopy was used to reveal information at the atomic level for the disordered-to-ordered phase transformation of equiatomic FePt nanoparticles that can exhibit outstanding magnetic properties after transforming from disordered face-centered-cubic into the tetragonal L10 ordered structure. High-angle annular dark-field imaging in the scanning transmission electron microscope provided sufficient contrast between the Fe and Pt atoms to readily monitor the ordering of the atoms during in situ heating experiments. However, during continuous high-magnification imaging the electron beam influenced the kinetics of the transformation so annealing had to be performed with the electron beam blanked. At 500 degrees C where the reaction rate was relatively slow, observation of the transformation mechanisms using this sequential imaging protocol revealed that ordering proceeded from (002) surface facets but was incomplete and multiple-domain particles were formed that contained anti-phase domain boundaries and anti-site defects. At 600 and 700 degrees C, the limitations of sequential imaging were revealed as a consequence of increased transformation kinetics. Annealing for only 5min at 700 degrees C produced complete single-domain L10 order; such single-domain particles were more spherical in shape with (002) facets. The in situ experiments also provided information concerning nanoparticle sintering, coalescence, and consolidation. Although there was resistance to complete sintering due to the crystallography of L10 order, the driving force from the large surface-area-to-volume ratio resulted in considerable nanoparticle coalescence, which would render such FePt nanoparticles unsuitable for use as magnetic recording media. Comparison of the in situ data acquired using the protocol described above with parallel ex situ annealing experiments showed that identical behavior resulted in all cases. PMID- 28011115 TI - A pulmonary index able to predict peripheral muscle function in COPD. PMID- 28011116 TI - Ethylene glycol, but not DMSO, could replace glycerol inclusion in soybean lecithin-based extenders in ram sperm cryopreservation. AB - The aim of this study was to evaluate the effects of glycerol, ethylene glycol or DMSO in a soybean lecithin extender for freezing ram semen. In this study, 20 ejaculates were collected from four Ghezel rams and diluted with soybean lecithin extender with glycerol (7%), ethylene glycol (3%, 5% and 7%) or DMSO (3%, 5% and 7%). Sperm motility (CASA), membrane integrity (HOS test), viability, total abnormality, mitochondrial activity (Rhodamine 123) and apoptotic features (Annexin V/Propidium iodide) were assessed after thawing. There was no significant difference between glycerol and ethylene glycol at different concentrations (3% and 5%) regarding sperm total and progressive motility, viability, and membrane integrity. The least percentages of mitochondrial functionality were observed in samples frozen with all different DMSO concentrations tested (P<0.05). Moreover, the percentage of post-thawed dead sperm was the greatest for all the DMSO concentrations compared with other groups (P<0.05). Thus, DMSO had an adverse effect on the post thaw ram sperm parameters. In contrast, ethylene glycol could be a desirable substitute of glycerol in the freezing extender, in view of similar results obtained in post-thaw quality of ram semen cryopreserved in a soybean lecithin extender. We propose that glycerol in a soybean lecithin based extender could be replaced by ethylene glycol at 3% or 5% concentrations. PMID- 28011117 TI - Association between single nucleotide polymorphisms and sexual precocity in Nellore heifers. AB - The aim of this study was to determine the extent (r2) of linkage disequilibrium (LD) in the genome of Nellore cattle, and to examine associations between single nucleotide polymorphisms (SNP) and age at first calving (AFC) and early pregnancy (EP) using a panel of high-density SNPs and data from 1182 Nellore females. A total of 13 contemporary groups (CG) were used consisting of farm, season, and year of birth. For genome-wide association analysis, SNPs with a minor allele frequency (MAF)<0.05 and animals with a call rate<0.90 were excluded, totaling 431,885 SNPs. For statistical analysis, a linear model was used for AFC and a threshold model for EP. To estimate the significance of the associations for the two traits, the model included the categorical fixed effects of CG, SNPs, and sire. In addition, the polygenic effect was included in the analysis. The additive effects and dominance deviations of Bonferroni-adjusted significant SNPs for AFC and EP were estimated using orthogonal contrasts. The average estimate of r2 for all autosomes was 0.18 at a distance of 4.8kb and the mean MAF was 0.25+/ 0.13. The LD decreased as the distance between markers increased: 0.35 (1kb) to 0.12 (100kb). Eleven significant associations were detected in seven different chromosomes. Seven SNPs were associated with AFC and four were associated with EP. Three SNPs were significant for both traits. The identification of SNPs associated with AFC and EP may contribute for selecting sexually precocious animals. PMID- 28011118 TI - Classification scheme for operative intervention for gastrogastric fistulae. PMID- 28011120 TI - Effect of hearing aids use on speech stimulus decoding through speech-evoked ABR. AB - INTRODUCTION: The electrophysiological responses obtained with the complex auditory brainstem response (cABR) provide objective measures of subcortical processing of speech and other complex stimuli. The cABR has also been used to verify the plasticity in the auditory pathway in the subcortical regions. OBJECTIVE: To compare the results of cABR obtained in children using hearing aids before and after 9 months of adaptation, as well as to compare the results of these children with those obtained in children with normal hearing. METHODS: Fourteen children with normal hearing (Control Group - CG) and 18 children with mild to moderate bilateral sensorineural hearing loss (Study Group - SG), aged 7 12 years, were evaluated. The children were submitted to pure tone and vocal audiometry, acoustic immittance measurements and ABR with speech stimulus, being submitted to the evaluations at three different moments: initial evaluation (M0), 3 months after the initial evaluation (M3) and 9 months after the evaluation (M9); at M0, the children assessed in the study group did not use hearing aids yet. RESULTS: When comparing the CG and the SG, it was observed that the SG had a lower median for the V-A amplitude at M0 and M3, lower median for the latency of the component V at M9 and a higher median for the latency of component O at M3 and M9. A reduction in the latency of component A at M9 was observed in the SG. CONCLUSION: Children with mild to moderate hearing loss showed speech stimulus processing deficits and the main impairment is related to the decoding of the transient portion of this stimulus spectrum. It was demonstrated that the use of hearing aids promoted neuronal plasticity of the Central Auditory Nervous System after an extended time of sensory stimulation. PMID- 28011119 TI - Benefits of bariatric surgery before elective total joint arthroplasty: is there a role for weight loss optimization? AB - BACKGROUND: The association between obesity and osteoarthritis is well established, as is the increased risk of postoperative complications after total knee arthroplasty (TKA) and total hip arthroplasty (THA) among patients with obesity. OBJECTIVE: To evaluate the outcomes after TKA/THA based on whether the surgery was performed before or after bariatric surgery. SETTING: Integrated, multispecialty, community teaching hospital. METHODS: The medical records of all patients who underwent bariatric surgery from 2001 to 2014 were reviewed. Statistical analysis included chi2 test and t tests. A P value<.05 was considered significant. RESULTS: One-hundred and two patients were included; 36 had TKA/THA before their bariatric procedure, 66 underwent TKA/THA after their bariatric procedure. TKAs/THAs were performed at a mean of 4.9+/-3.2 years before and 4.3+/ 3.3 years after bariatric surgery. Body mass index for those undergoing TKA/THA after bariatric surgery was lower than those with TKA/THA before bariatric surgery (37.6+/-7.4 versus 43.7+/-5.7 kg/m2; P<.001). Operative time and length of stay (LOS) were significantly decreased for TKA/THA performed after versus before bariatric surgery: 81.7+/-33.9 min versus 117+/-38.1 min; P<.001 and 2.9+/ 0.7 versus 3.8+/-1.4 d; P<.001, respectively. Early complications and late reinterventions were similar. CONCLUSIONS: Decreased operative time and LOS were observed among patients who underwent TKA/THA after versus before their bariatric surgery. Patients who underwent TKA/THA after bariatric surgery had lower body mass index before and 1 year after TKA/THA. Postoperative complication rates were similar. Benefits of bariatric surgery and subsequent weight loss should be considered among patients with obesity requiring TKA/THA. Optimal timing of TKA/THA and bariatric surgery has yet to be established. PMID- 28011121 TI - Temporal bone paragangliomas: 15 years experience. AB - INTRODUCTION: Temporal bone paragangliomas (TBPs) are benign tumors arising from neural crest cells located along the jugular bulbus and the tympanic plexus. In general surgical excision, radiotherapy and wait-and-scan protocols are the main management modalities for TBPs. OBJECTIVE: In this paper we aim to present our clinical experience with TBPs and to review literature data. METHODS: The patients who were operated for tympanomastoid paraganglioma (TMP) or tympanojugular paraganglioma (TJP) in our clinic in the last 15 years were enrolled in the study. A detailed patient's charts review was performed retrospectively. RESULTS: There were 18 (52.9%) cases with TMPs and 16 (47.1%) cases with TJPs, a total of 34 patients operated for TBPs in this time period. The mean age was 50.3+/- 11.7 (range 25-71 years). The most common presenting symptoms were tinnitus and hearing loss for both TMPs and TJPs. Gross total tumor resection was achieved in 17 (94.4%) and 10 (62.5%) cases for TMPs and TJPs, respectively. Five patients (31.2%) with TJP experienced facial palsy following the operation. For all the patients the mean follow-up period was 25.8 months (range 4-108 months). CONCLUSION: In conclusion, based on our findings and literature review, total surgical excision alone or with preoperative embolization is the main treatment modality for TBPs. However radiotherapy, observation protocol and subtotal resection must be considered in cases of preoperative functioning cranial nerves, large tumors and advanced age. PMID- 28011123 TI - Sinonasal adenocarcinoma: clinical outcomes and predictive factors. AB - A retrospective study of 39 patients treated for sinonasal adenocarcinoma between 1995 and 2010 was performed. Epidemiological, clinical, histological, and therapeutic aspects of this series of patients were analyzed statistically and their impact in terms of overall and disease-free survival established using the Kaplan-Meier method. A search for prognostic factors was made using a log-rank test. The male to female sex ratio was 6.8 to 1. The average age at diagnosis was 65.7 years (range 40.2-85.6 years). An occupational risk factor (wood dust, leather) was found for 19 patients (48.7%). The median patient follow-up was 51.9 months (range 8-180 months). Tumours were classified as T1 in 20.5%, T2 in 25.6%, T3 in 23.1%, and T4 in 30.8% of cases. Disease-free survival rates at 1, 5, and 10 years were 87.9%, 44.8%, and 39.2%, respectively; overall survival rates were 86.1%, 72.2%, and 50.3%, respectively. Overall survival was correlated with tumour status (TNM, American Joint Committee on Cancer) (P=0.004). Surgery followed by radiotherapy improved overall survival (P=0.012) and disease-free survival (P=0.028) when compared to other treatment modalities. When compared to surgery alone, surgery followed by radiotherapy improved disease-free survival regardless of tumour stage (P=0.049). PMID- 28011124 TI - Islanded facial artery musculomucosal flap for tongue reconstruction. AB - Reconstruction of the tongue can be achieved by means of various local, regional, and microvascular free flaps. Local flaps commonly used for tongue reconstruction include the nasolabial flap, submental flap, infrahyoid flap, and pedicled facial artery musculomucosal (FAMM) flap. The purpose of this article is to propose a technical modification to the FAMM flap for the reconstruction of small to medium sized tongue defects post tumour excision: islanding the flap and tunnelling it from the lingual aspect of the mandible in a single-stage procedure. Islanding of the FAMM flap was found to be an extremely useful modification, giving excellent range of movement for the flap and eliminating the need for revision in a second stage procedure. PMID- 28011122 TI - Lithium increases hippocampal SNARE protein abundance after traumatic brain injury. AB - Rodent models of traumatic brain injury (TBI) reproduce secondary injury sequela and cognitive impairments observed in patients afflicted by a TBI. Impaired neurotransmission has been reported in the weeks following experimental TBI, and may be a contributor to behavioral dysfunction. The soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complex, the machinery facilitating vesicular docking and fusion, is a highly-conserved mechanism important for neurotransmission. Following TBI, there is a reduction in both the formation of the SNARE complex and the abundance of multiple SNARE proteins, including the chaperone protein cysteine string protein alpha (CSPalpha). Treatment with lithium in naive rats reportedly increases the expression of CSPalpha. In the context of TBI, brain-injured rats treated with lithium exhibit improved outcome in published reports, but the mechanisms underlying the improvement are poorly understood. The current study evaluated the effect of lithium administration on the abundance of SNARE proteins and SNARE complex formation, hemispheric tissue loss, and neurobehavioral performance following controlled cortical impact (CCI). Sprague Dawley rats were subjected to CCI or sham injury, and treated daily with lithium chloride or vehicle for up to 14days. Administration of lithium after TBI modestly improved spatial memory at 14days post-injury. Semi-quantitative immunoblot analysis of hippocampal lysates revealed that treatment with lithium attenuated reductions in key SNARE proteins and SNARE complex formation at multiple time points post-injury. These findings highlight that treatment with lithium increased the abundance of synaptic proteins that facilitate neurotransmission and may contribute to improved cognitive function after TBI. PMID- 28011125 TI - Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling. AB - The aim of this study was to optimize the in vitro transfer model and to increase its biorelevance to more accurately mimic the in vivo supersaturation and precipitation behaviour of weak basic drugs. Therefore, disintegration of the formulation, volumes of the stomach and intestinal compartments, transfer rate, bile salt concentration, pH range and paddle speed were varied over a physiological relevant range. The supersaturation and precipitation data from these experiments for Ketoconazole (KTZ) were coupled to physiologically based pharmacokinetic (PBPK) model using Stella(r) software, which also incorporated the disposition kinetics of KTZ taken from the literature, in order to simulate the oral absorption and plasma profile in humans. As expected for a poorly soluble weak base, KTZ demonstrated supersaturation followed by precipitation under various in vitro conditions simulating the proximal small intestine with the results influenced by transfer rate, hydrodynamics, volume, bile salt concentration and pH values. When the in vitro data representing the "average" GI conditions was coupled to the PBPK model, the simulated profiles came closest to the observed mean plasma profiles for KTZ. In line with the high permeability of KTZ, the simulated profiles were highly influenced by supersaturation whilst precipitation was not predicted to occur in vivo. A physiological relevant in vitro "standard" transfer model setup to investigate supersaturation and precipitation was established. For translating the in vitro data to the in vivo setting, it is important that permeability is considered which can be achieved by coupling the in vitro data to PBPK modelling. PMID- 28011126 TI - Drug-drug cocrystals of antituberculous 4-aminosalicylic acid: Screening, crystal structures, thermochemical and solubility studies. AB - Experimental multistage cocrystal screening of the antituberculous drug 4 aminosalicylic acid (PASA) has been conducted with a number of coformers (pyrazinamide (PYR), nicotinamide (NAM), isonicotinamide (iNAM), isoniazid (INH), caffeine (CAF) and theophylline (TPH)). The crystal structures of 4 aminosalicylic acid cocrystals with isonicotinamide ([PASA+iNAM] (2:1)) and methanol solvate with caffeine ([PASA+CAF+MeOH] (1:1:1)) have been determined by single X-ray diffraction experiments. For the first time for PASA cocrystals it has been found that the structural unit of the [PASA+iNAM] cocrystal (2:1) is formed by 2 types of heterosynthons: acid-pyridine and acid-amide. The desolvation study of the [PASA+CAF+MeOH] cocrystal solvate (1:1:1) has been conducted. The correlation models linking the melting points of the cocrystals with the melting points of the coformers used in this paper have been developed. The thermochemical and solubility properties for all the obtained cocrystals have been studied. Cocrystallization has been shown to lead not only to PASA solubility improving but also to its higher stability against the chemical decomposition. PMID- 28011127 TI - Anticandidal, antibacterial, cytotoxic and antioxidant activities of Calendula arvensis flowers. AB - Calendula arvensis (CA) is one of the important plants used in traditional medicine in Morocco, due to its interesting chemical composition. The present study aimed to determine the anticandidal, antioxidant and antibacterial activities, and the effects of extracts of CA flowers on the growth of myeloid cancer cells. Also, to characterize the chemical composition of the plant. Flowers of CA were collected based on ethnopharmacological information from the villages around the region Rabat-Khemisset, Moroccco. The hexane and methanol extracts were obtained by soxhlet extraction, while aqueous extracts was obtained by maceration in cold water. CA extracts were assessed for antioxidant activity using four different methods (DPPH, FRAP, TEAC, beta-carotene bleaching test). Furthermore, the phenolic and flavonoid contents were measured, also the antimicrobial activity has been evaluated by the well diffusion method using several bacterial and fungal strains. Finally, extracts cytotoxicity was assessed using MTT test. Phytochemical quantification of the methanolic and aqueous extracts revealed that they were rich with flavonoid and phenolic content and were found to possess considerable antioxidant activities. MIC values of methanolic extracts were 12.5-25MUg/mL. While MIC values of hexanolic extracts were between 6.25-12.5MUg/mL and were bacteriostatic for all bacteria while methanolic and aqueous extracts were bactericidal. In addition, the extracts exhibited no activity on Candida species except the methanolic extract, which showed antifungal activity onCandida tropicalis 1 and Candida famata 1. The methanolic and aqueous extracts also exhibited antimyeloid cancer activity (IC50 of 31MUg/mL). In our study, we conclude that the methanolic and aqueous extracts were a promising source of antioxidant, antimicrobial and cytotoxic agents. PMID- 28011128 TI - Isolation of lactic acid-forming bacteria from biogas plants. AB - Direct molecular approaches provide hints that lactic acid bacteria play an important role in the degradation process of organic material to methanogenetic substrates in biogas plants. However, their diversity in biogas fermenter samples has not been analyzed in detail yet. For that reason, five different biogas fermenters, which were fed mainly with maize silage and manure from cattle or pigs, were examined for the occurrence of lactic acid-forming bacteria. A total of 197 lactic acid-forming bacterial strains were isolated, which we assigned to 21 species, belonging to the genera Bacillus, Clostridium, Lactobacillus, Pediococcus, Streptococcus and Pseudoramibacter-related. A qualitative multiplex system and a real-time quantitative PCR could be developed for most isolates, realized by the selection of specific primers. Their role in biogas plants was discussed on the basis of the quantitative results and on physiological data of the isolates. PMID- 28011129 TI - Fast and sensitive in vivo studies under controlled environmental conditions to substitute long-term field trials with genetically modified plants. AB - We introduce an easy, fast and effective method to analyze the influence of genetically modified (GM) plants on soil and model organisms in the laboratory to substitute laborious and time consuming field trials. For the studies described here we focused on two GM plants of the so-called 3rd generation: GM plants producing pharmaceuticals (PMP) and plant made industrials (PMI). Cyanophycin synthetase (cphA) was chosen as model for PMI and Choleratoxin B (CTB) as model for PMP. The model genes are expressed in transgenic roots of composite Vicia hirsuta plants grown in petri dishes for semi-sterile growth or small containers filled with non-sterile soil. No significant influence of the model gene expression on root induction, growth, biomass, interaction with symbionts such as rhizobia (number, size and functionality of nodules, selection of nodulating strains) or arbuscular mycorrhizal fungi could be detected. In vitro, but not in situ under field conditions, structural diversity of the bulk soil microbial community between transgenic and non-transgenic cultivars was determined by PLFA pattern-derived ratios of bacteria: fungi and of gram+: gram- bacteria. Significant differences in PLFA ratios were associated with dissimilarities in the quantity and molecular composition of rhizodeposits as revealed by Py-FIMS analyses. Contrary to field trials, where small effects based on the transgene expression might be hidden by the immense influence of various environmental factors, our in vitro system can detect even minor effects and correlates them to transgene expression with less space, time and labour. PMID- 28011130 TI - Highly efficient bioreduction of 2-hydroxyacetophenone to (S)- and (R)-1-phenyl 1,2-ethanediol by two substrate tolerance carbonyl reductases with cofactor regeneration. AB - Optically pure 1-phenyl-1,2-ethanediol is a very important chiral building block and intermediate in fine chemical and pharmaceutical industries. Reduction of 2 hydroxyacetophenone provides a straightforward approach to access these important compounds. In this study, two enantiocomplementary carbonyl reductases, BDHA (2,3 butanediol dehydrogenase from Bacillus subtilis) and GoSCR (polyol dehydrogenase from Gluconobacter oxydans) were discovered for the first time to convert 2 hydroxyacetophenone (2-HAP) to (R)-1-phenyl-1,2-ethanediol ((R)-PED) and (S)-1 phenyl-1,2-ethanediol ((S)-PED) with excellent stereochemical selectivity, respectively. The two enzymes were purified and characterized. In vitro bioreduction of 2-HAP catalyzed by BDHA and GoSCR coupled with glucose dehydrogenase (GDH) from Bacillus subtilis for cofactor regeneration were demonstrated, affording both (R)-PED and (S)-PED in>99% ee and 99% conversion. Recombinant Escherichia coli whole cells co-expressing both GDH and BDHA or GoSCR genes were used to asymmetric reduction of 2-HAP to (R)-PED or (S)-PED. Under the optimized conditions, the bioreduction of 400mM (54g/L) substrate was proceeded smoothly without the external addition of cofactor, and the product (R)-PED and (S)-PED were obtained with 99% yield, >99% ee and 18.0g/L/h volumetric productivity. These results offer a practical biocatalytic method for the preparation of both (R)-PED and (S)-PED with high volumetric productivity. PMID- 28011131 TI - Functional brain networks in treatment-resistant schizophrenia. AB - INTRODUCTION: Up to 20% of individuals with schizophrenia show minimal or no response to medication and are considered to have 'treatment-resistant' schizophrenia (TRS). Unlike early and established schizophrenia, few studies have investigated resting-state functional connectivity (rs-FC) in TRS. Here, we test for disruptions in FC and altered efficiency of functional brain networks in a well-characterized cohort of TRS patients. METHODS: Resting-state functional magnetic resonance imaging was used to investigate functional brain networks in 42 TRS participants prescribed clozapine (30 males, mean age=41.3(10)) and 42 healthy controls (24 males, mean age=38.4(10)). Graph analysis was used to characterize between-group differences in local and global efficiency of functional brain network organization as well as the strength of FC. RESULTS: Global brain FC was reduced in TRS patients (p=0.0001). Relative to controls, 3.4% of all functional connections showed reduced strength in TRS (p<0.001), predominantly involving fronto-temporal, fronto-occipital and temporo-occipital connections. Global efficiency was reduced in TRS (p=0.0015), whereas local efficiency was increased (p=0.0042). CONCLUSIONS: TRS is associated with widespread reductions in rs-FC and altered network topology. Increased local functional network efficiency coupled with decreased global efficiency suggests that hub-to-hub connections are preferentially affected in TRS. These findings further our understanding of the neurobiological impairments in TRS. PMID- 28011132 TI - Predominant processing adaptability of Staphylococcus xylosus strains isolated from Chinese traditional low-salt fermented whole fish. AB - This study aimed to determine the predominant processing adaptability of 27 selected isolates of Staphylococcus xylosus in 'Suan yu', a traditional Chinese low-salt fermented whole-fish product. The isolates were screened for proteolytic, lipolytic, and enzymatic profiles; amino-acid decarboxylase content; antimicrobial activities; and tolerance to low temperatures, pH5.0, and salt. Two S. xylosus strains grew at 10 degrees C in the presence of 10% NaCl and at pH5.0. Agar-plate assays and sodium dodecyl sulphate-polyacrylamide gel electrophoresis revealed that 21 and 8 of the strains exhibited appropriate proteolytic activities against myofibrillar and sarcoplasmic proteins, respectively. All S. xylosus strains also displayed different enzymatic profiles, and most strains showed negative decarboxylase activities. The results of this step were used as input data for a Principal Component Analysis; therefore, the most technologically relevant strain 3 and 8 were combined with L. plantarum 120 as MS1 and MS2, respectively, were further selected for the fermented fish surimi, and the fish surimi inoculated with mixed starter cultures (MS1, MS2) scored high for overall acceptability. Free amino acid contents of 1757 and 1765mg/100g sample were found in fish surimi inoculated with MS1 and MS2, respectively, after 72h of fermentation. Therefore, Sx-3 and Sx-8, which presented the best predominant processing adaptability, is an eligible starter culture for fermented fish production. PMID- 28011133 TI - Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations. AB - The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold. 22SHC (8) and 22RHC (1) performed as expected while 22-ketocholesterol (22KC, 10) revealed an attractive in vitro profile for further investigation in terms of anti-atherosclerotic properties as selective upregulation of the ATP-binding cassette transporter ABCA1 was observed. A new synthesized amide derivate, Fernholtz cyclohexylamide (13) was shown to reduce lipogenesis in a dose responsive manner and abolish the effect of the potent LXR agonist T0901317 when administered simultaneously. PMID- 28011134 TI - Active transport and obesity prevention - A transportation sector obesity impact scoping review and assessment for Melbourne, Australia. AB - Given the alarming prevalence of obesity worldwide and the need for interventions to halt the growing epidemic, more evidence on the role and impact of transport interventions for obesity prevention is required. This study conducts a scoping review of the current evidence of association between modes of transport (motor vehicle, walking, cycling and public transport) and obesity-related outcomes. Eleven reviews and thirty-three primary studies exploring associations between transport behaviours and obesity were identified. Cohort simulation Markov modelling was used to estimate the effects of body mass index (BMI) change on health outcomes and health care costs of diseases causally related to obesity in the Melbourne, Australia population. Results suggest that evidence for an obesity effect of transport behaviours is inconclusive (29% of published studies reported expected associations, 33% mixed associations), and any potential BMI effect is likely to be relatively small. Hypothetical scenario analyses suggest that active transport interventions may contribute small but significant obesity-related health benefits across populations (approximately 65 health adjusted life years gained per year). Therefore active transport interventions that are low cost and targeted to those most amenable to modal switch are the most likely to be effective and cost-effective from an obesity prevention perspective. The uncertain but potentially significant opportunity for health benefits warrants the collection of more and better quality evidence to fully understand the potential relationships between transport behaviours and obesity. Such evidence would contribute to the obesity prevention dialogue and inform policy across the transportation, health and environmental sectors. PMID- 28011135 TI - Hypertension, diabetes and lifestyle in the long-term - Results from a Swiss population-based cohort. AB - Healthy lifestyles are integral in preventing and treating common cardiovascular and metabolic diseases. The aim of this study was to observe smoking habits, alcohol intake, physical activity and body mass index over a 10-year period in a population-based cohort, particularly focusing on participants with hypertension and type 2 diabetes mellitus. Included were 4155 participants from the first (2001-2003) and second (2010-2011) follow-ups of the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA). Information was collected via health questionnaire; height and weight were measured. In a healthy lifestyle score one point was attributed per criterion; non-smoking, low risk alcohol consumption, BMI<25kg/m2, and regular physical activity. Overall in 2010 2011, 16.4% were smokers, 7.7% had at risk alcohol consumption, 25.5% were physically inactive and 57.8% were overweight or obese. Both those with hypertension and diabetes had lower mean healthy lifestyle scores than those without disease. Women with incident hypertension from 2001 to 2011 had lower odds of improving their healthy lifestyle score during this time period compared to those without this disease. In contrast, women with incident diabetes had higher odds of lifestyle score improvement. In men, neither hypertension nor diabetes was associated with change in lifestyle score. Our findings suggest that, irrespective of disease status, preventative attention is needed, particularly in regards to physical activity and bodyweight. These needs could be met by population-based interventions, a necessary and suitable option in both preventing and treating the non-communicable disease epidemic which currently faces countries worldwide. PMID- 28011136 TI - Emerging adults without a driver's license engage in more transportation-related physical activity to school/work in certain environmental contexts. AB - The aim was to examine the moderation effect of driving licensure status on the association between different environmental contexts and transportation-related physical activity to and from school and/or work (TPA-SW) among emerging adults. The data were from Wave 4 (n=2026, year 2013) of the NEXT Generation Health Study, an annual assessment of a nationally representative cohort across the nine U.S. Census Divisions. The outcome variable, TPA-SW, was derived from walking or cycling as modes of travel to and from school and/or work. Environmental context variables included residence, college attendance, and work status. Driving licensure status indicated whether or not participants had an independent driver's license. Poisson regression models, adjusted for potential confounders, were used to test interactions between environmental context and driving licensure. There were significant interactions between environmental context and licensure. Interaction contrasts indicated that participants who did not have a driver's license engaged in more TPA-SW than their licensed counterparts if they were living at home (beta=1.10, p<0.001), not attending school (beta=0.73, p<0.001), attending a technical school/community college (beta=1.13, p<0.001), working 1-30 hours/week (beta=0.69, p<0.001), or working 30+hours/week (beta=1.12, p<0.001). Among non-workers, those without a license engaged in less TPA-SW than participants with a license (beta=-0.22, p=0.05). Among emerging adults in certain environmental contexts, delayed driver licensing may result in more physical activity with the possible tradeoff of less transportation mobility. PMID- 28011137 TI - Cumulative risk over the early life course and its relation to academic achievement in childhood and early adolescence. AB - Early-life risk factors, such as family disruption, maltreatment, and poverty, can negatively impact children's scholastic abilities; however, most previous studies have relied on cross-sectional designs and retrospective measurement. This study investigated the relation between cumulative risk factors during the early life course and subsequent academic achievement in a cohort of children and adolescents. Data for this study were based on registry-data material from the LIFECOURSE study of 1151 children from the 2000 birth cohort in Reykjavik, Iceland, assembled in 2014-2016. Multiple lifetime risk factors, including maternal smoking during pregnancy, parent's disability status, being born to a young mother, number of children in the household, family income, number of visits to school nurses, and reports of maltreatment, were assessed. Latent class analysis and Analysis of Covariance (ANCOVA) were used to predict academic achievement in the 4th and 7th grades. Individuals with no risk factors reported the highest average academic achievement in the 4th (M=66 points, SD=17) and 7th grades (M=67 points, SD=15). There was a significant main effect for 4th-grade risk factors and academic achievement (F [7, 1146]=12.06, p<0.001) and a similar relationship between the risk factor profile and achievement scores in 7th grade (F [7, 1146]=15.08, p<0.001). Each additional risk factor was associated with a drop in academic achievement at both grade levels. We conclude that academic achievement declines in proportion to the number of risk factors in early life. PMID- 28011138 TI - Magnetic resonance imaging based functional imaging in paediatric oncology. AB - Imaging is central to management of solid tumours in children. Conventional magnetic resonance imaging (MRI) is the standard imaging modality for tumours of the central nervous system (CNS) and limbs and is increasingly used in the abdomen. It provides excellent structural detail, but imparts limited information about tumour type, aggressiveness, metastatic potential or early treatment response. MRI based functional imaging techniques, such as magnetic resonance spectroscopy, diffusion and perfusion weighted imaging, probe tissue properties to provide clinically important information about metabolites, structure and blood flow. This review describes the role of and evidence behind these functional imaging techniques in paediatric oncology and implications for integrating them into routine clinical practice. PMID- 28011139 TI - Depression and Cerebrovascular Disease: What is to be Done? PMID- 28011140 TI - Learning Their Language: The Importance of Detecting and Managing Pain in Dementia. PMID- 28011142 TI - Cell-matrix mechanical interaction in electrospun polymeric scaffolds for tissue engineering: Implications for scaffold design and performance. AB - : Engineered scaffolds produced by electrospinning of biodegradable polymers offer a 3D, nanofibrous environment with controllable structural, chemical, and mechanical properties that mimic the extracellular matrix of native tissues and have shown promise for a number of tissue engineering applications. The microscale mechanical interactions between cells and electrospun matrices drive cell behaviors including migration and differentiation that are critical to promote tissue regeneration. Recent developments in understanding these mechanical interactions in electrospun environments are reviewed, with emphasis on how fiber geometry and polymer structure impact on the local mechanical properties of scaffolds, how altering the micromechanics cues cell behaviors, and how, in turn, cellular and extrinsic forces exerted on the matrix mechanically remodel an electrospun scaffold throughout tissue development. Techniques used to measure and visualize these mechanical interactions are described. We provide a critical outlook on technological gaps that must be overcome to advance the ability to design, assess, and manipulate the mechanical environment in electrospun scaffolds toward constructs that may be successfully applied in tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE: Tissue engineering requires design of scaffolds that interact with cells to promote tissue development. Electrospinning is a promising technique for fabricating fibrous, biomimetic scaffolds. Effects of electrospun matrix microstructure and biochemical properties on cell behavior have been extensively reviewed previously; here, we consider cell-matrix interaction from a mechanical perspective. Micromechanical properties as a driver of cell behavior has been well established in planar substrates, but more recently, many studies have provided new insights into mechanical interaction in fibrillar, electrospun environments. This review provides readers with an overview of how electrospun scaffold mechanics and cell behavior work in a dynamic feedback loop to drive tissue development, and discusses opportunities for improved design of mechanical environments that are conducive to tissue development. PMID- 28011141 TI - Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models. AB - : Tumor associated macrophages (TAMs) are critical stromal components intimately involved with the progression, invasion, and metastasis of cancer cells. To address the need for an in vitro system that mimics the clinical observations of TAM localizations and subsequent functional performance, a cancer cell/macrophage spheroid model is described. The central component of the model is a triple negative breast cancer spheroid embedded in a three-dimensional collagen gel. Macrophages are incorporated in two different ways. The first is a heterospheroid, a spheroid containing both tumor cells and macrophages. The heterospheroid mimics the population of TAMs infiltrated into the tumor mass, thus being exposed to hypoxia and metabolic gradients. In the second model, macrophages are diffusely seeded in the collagen surrounding the spheroid, thus modeling TAMs in the cancer stroma. The inclusion of macrophages as a heterospheroid changes the metabolic profile, indicative of synergistic growth. In contrast, macrophages diffusely seeded in the collagen bear the same profile regardless of the presence of a tumor cell spheroid. The macrophages in the heterospheroid secrete EGF, a cytokine critical to tumor/macrophage co-migration, and an EGF inhibitor decreases the metabolic activity of the heterospheroid, which is not observed in the other systems. The increased secretion of IL-10 indicates that the heterospheroid macrophages follow an M2/TAM differentiation pathway. Lastly, the heterospheroid exhibits resistance to paclitaxel. In summary, the collagen embedded heterospheroid model promotes TAM-like characteristics, and will be of utility in cancer biology and drug discovery. STATEMENT OF SIGNIFICANCE: Two in vitro collagen-embedded multicellular spheroid models are described that mimic the clinical observations of macrophage localization within a tumor. Incorporation of macrophages within a breast cancer spheroid emphasizes cell-cell interactions with subsequent differentiation toward a tumor-promoting TAM phenotype. In contrast, macrophages seeded around the tumor spheroid display decreased interaction with cancer cells and no indication of a TAM phenotype. Finally, the presence of macrophages in the heterospheroid increases resistance to paclitaxel. This study demonstrates that cell-cell interactions and 3D collagen matrix direct macrophage activity, and, thus, highlights the important role the local environment itself plays in macrophage behavior. PMID- 28011143 TI - Dynamic Changes in Resident and Infiltrating Epidermal Dendritic Cells in Active and Resolved Psoriasis. AB - Epidermal Langerhans cells (LCs) are spatially separated from dermal dendritic cells (DCs) in healthy human skin. In active psoriasis, maintained by local production of IL-23 and IL-17, inflammatory DCs infiltrate both skin compartments. Here we show that CCR2+ epidermal DCs (eDCs) were confined to lesional psoriasis and phenotypically distinct from dermal DCs. The eDCs exceeded the number of LCs and displayed high expression of genes involved in neutrophil recruitment and the activation of keratinocytes and T cells. Resident LCs responded to toll-like receptor 4 and toll-like receptor 7/8 activation with increased IL-23 production, whereas eDCs additionally produced IL-1beta together with IL-23 and tumor necrosis factor. Psoriasis typically recur in fixed skin lesions. eDCs were absent from resolved psoriasis. Instead, LCs from anti-tumor necrosis factor-treated lesions retained high IL23A expression and responded to toll-like receptor stimulation by producing IL-23. Our results reveal phenotypic and functional properties of eDCs and resident LCs in different clinical phases of psoriasis, and the capacity of these cells to amplify the epidermal microenvironment through the secretion of IL-17 polarizing cytokines. PMID- 28011144 TI - ARCI7 Revisited and Repositioned. PMID- 28011145 TI - A Functional Genomic Meta-Analysis of Clinical Trials in Systemic Sclerosis: Toward Precision Medicine and Combination Therapy. AB - Systemic sclerosis is an orphan, systemic autoimmune disease with no FDA-approved treatments. Its heterogeneity and rarity often result in underpowered clinical trials making the analysis and interpretation of associated molecular data challenging. We performed a meta-analysis of gene expression data from skin biopsies of patients with systemic sclerosis treated with five therapies: mycophenolate mofetil, rituximab, abatacept, nilotinib, and fresolimumab. A common clinical improvement criterion of -20% or -5 modified Rodnan skin score was applied to each study. We applied a machine learning approach that captured features beyond differential expression and was better at identifying targets of therapies than the differential expression alone. Regardless of treatment mechanism, abrogation of inflammatory pathways accompanied clinical improvement in multiple studies suggesting that high expression of immune-related genes indicates active and targetable disease. Our framework allowed us to compare different trials and ask if patients who failed one therapy would likely improve on a different therapy, based on changes in gene expression. Genes with high expression at baseline in fresolimumab nonimprovers were downregulated in mycophenolate mofetil improvers, suggesting that immunomodulatory or combination therapy may have benefitted these patients. This approach can be broadly applied to increase tissue specificity and sensitivity of differential expression results. PMID- 28011146 TI - Association of Atopic Dermatitis with Cardiovascular Risk Factors and Diseases. AB - Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease. Therefore, we investigate associations and potential underlying pathways of AD and cardiovascular disease in large cohort studies: the AOK PLUS cohort (n = 1.2 Mio), the GINIplus/LISAplus birth cohorts (n = 2,286), and the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 2,990). In addition, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of patients with AD in AOK PLUS showed slightly increased risk for incident angina pectoris (adjusted risk ratio 1.17 [95% confidence interval 1.12-1.23]), hypertension (1.04 [1.02-1.06]), and peripheral arterial disease (1.15 [1.11-1.19]) but not for myocardial infarction (1.05 [0.99 1.12]) and stroke (1.02 [0.98-1.07]). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and cardiovascular disease. This study indicates only a marginally increased risk for angina pectoris, hypertension, and peripheral arterial disease and no increased risk for myocardial infarction or stroke in patients with AD. Relevant associations of AD with cardiovascular risk factors reported in US populations could not be confirmed. Likewise, patients with AD did not have increased genetic risk factors for cardiovascular disease. PMID- 28011147 TI - Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. AB - Early diagnosis and prognosis monitoring for Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) still remain a challenge. This study aims to explore any cytokine/chemokine with prognostic potential in Stevens-Johnson syndrome/TEN. Through screening a panel of 28 serological factors, IL-6, IL-8, IL-15, tumor necrosis factor-alpha, and granulysin were upregulated in patients with Stevens Johnson syndrome/TEN and selected for the further validation in total 155 patients with Stevens-Johnson syndrome/TEN, including 77 from Taiwan and 78 from the Registry of Severe Cutaneous Adverse Reactions. Among these factors evaluated, the levels of IL-15 (r = 0.401; P < 0.001) and granulysin (r = 0.223; P = 0.026) were significantly correlated with the disease severity in 112 samples after excluding patients with insufficient data to calculate the score of TEN. In addition, IL-15 was also associated with mortality (P = 0.002; odds ratio, 1.09; 95% confidence interval, 1.03-1.14; P = 0.001; adjusted odds ratio, 1.10; 95% confidence interval, 1.04-1.16). Consistent results were obtained after the exclusion of Taiwanese patients with sepsis to rule out possible confounders. Moreover, IL-15 was shown to enhance cytotoxicity of cultured natural killer cells and blister cells from patients with TEN. Our findings highlight a usefulness of IL-15 in prognosis monitoring and therapeutic intervention of this devastating condition. PMID- 28011148 TI - A Genome-Wide Association Study of Basal Transepidermal Water Loss Finds that Variants at 9q34.3 Are Associated with Skin Barrier Function. PMID- 28011149 TI - Chromatin associated mechanisms in base excision repair - nucleosome remodeling and DNA transcription, two key players. AB - Genomic DNA is prone to a large number of insults by a myriad of endogenous and exogenous agents. The base excision repair (BER) is the major mechanism used by cells for the removal of various DNA lesions spontaneously or environmentally induced and the maintenance of genome integrity. The presence of persistent DNA damage is not compatible with life, since abrogation of BER leads to early embryonic lethality in mice. There are several lines of evidences showing existence of a link between deficient BER, cancer proneness and ageing, thus illustrating the importance of this DNA repair pathway in human health. Although the enzymology of BER mechanisms has been largely elucidated using chemically defined DNA damage substrates and purified proteins, the complex interplay of BER with another vital process like transcription or when DNA is in its natural state (i.e. wrapped in nucleosome and assembled in chromatin fiber is largely unexplored. Cells use chromatin remodeling factors to overcome the general repression associated with the nucleosomal organization. It is broadly accepted that energy-dependent nucleosome remodeling factors disrupt histones-DNA interactions at the expense of ATP hydrolysis to favor transcription as well as DNA repair. Importantly, unlike transcription, BER is not part of a regulated developmental process but represents a maintenance system that should be efficient anytime and anywhere in the genome. In this review we will discuss how BER can deal with chromatin organization to maintain genetic information. Emphasis will be placed on the following challenging question: how BER is initiated within chromatin? PMID- 28011150 TI - Piperlongumine attenuates experimental autoimmune encephalomyelitis through inhibition of NF-kappaB activity. AB - Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disease in which demyelination sporadically and repeatedly occurs in the central nervous system (CNS). The activity of nuclear factor kappa B (NF-kappaB), a family of transcription factors, was increased in the cerebrospinal fluid (CSF) and/or the serum and brain and/or spinal cord of MS patients than in a healthy donors. In our study, we investigated whether piperlongumine (PL), which is known to have inhibitory effect on activity of NF-kappaB, can alleviate an experimental autoimmune encephalomyelitis (EAE). The mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), and then we injected PL (1.5mg/kg/day or 3.0mg/kg/day) into the mice intraperitoneally on every second day from days 2 to 28. For in vitro study, we treated PL (0.5, 1 and 2.5MUM) to RAW 264.7 and Jurkat cells with each stimulator. We observed that the paralytic severity and neuropathology of EAE in PL-treated group were decreased compared with the EAE group. PL showed a suppressed effect on demyelination, immune cells infiltration, astrocytes/microglials activation, level of inflammatory cytokines and proteins as well as NF-kappaB activity. Production of inflammatory cytokines and proteins as well as translocation of NF-kappaB into nucleus by treatment stimulators in RAW 264.7 and Jurkat cells were reduced by PL. Moreover, treatment of NF-kappaB inhibitor further inhibited production of inflammatory cytokines and proteins. These results suggest that PL can mitigate MOG-induced EAE symptoms and activation of macrophages and T cells by inhibiting NF-kappaB signaling. Therefore, PL could be useful for the treatment for MS. PMID- 28011151 TI - The cyclopurine deoxynucleosides: DNA repair, biological effects, mechanistic insights, and unanswered questions. AB - Patients with the genetic disease xeroderma pigmentosum (XP) who lack the capacity to carry out nucleotides excision repair (NER) have a dramatically elevated risk of skin cancer on sun exposed areas of the body. NER is the DNA repair mechanism responsible for the removal of DNA lesions resulting from ultraviolet light. In addition, a subset of XP patients develop a progressive neurodegenerative disease, referred to as XP neurologic disease, which is thought to be the result of accumulation of endogenous DNA lesions that are repaired by NER but not other repair pathways. The 8,5-cyclopurine deoxynucleotides (cyPu) have emerged as leading candidates for such lesions, in that they result from the reaction of the hydroxyl radical with DNA, are strong blocks to transcription in human cells, and are repaired by NER but not base excision repair. Here I present a focused perspective on progress into understating the repair and biological effects of these lesions. In doing so, I emphasize the role of Tomas Lindahl and his laboratory in stimulating cyPu research. I also include a critical evaluation of the evidence supporting a role for cyPu lesions in XP neurologic disease, with a focus on outstanding questions, and conceptual and technologic challenges. PMID- 28011152 TI - Adenosine A2a receptor stimulation blocks development of nonalcoholic steatohepatitis in mice by multilevel inhibition of signals that cause immunolipotoxicity. AB - Lipotoxicity and immunoinflammation are associated with the evolution of steatosis toward nonalcoholic steatohepatitis (NASH). This study reports the ability of adenosine A2a receptor (A2aR) activation to inhibit NASH development by modulating the responses of CD4+ T-helper (Th) cells to avoid an immuno mediated potentiation of lipotoxicity. The effect of the A2aR agonist CGS21680 on immunoinflammatory signals, CD4+Th cell infiltration and immunolipotoxicity was analyzed in steatotic C57BL/6 mice fed with a methionine-choline-deficient (MCD) diet and in mouse hepatocytes exposed to palmitic acid (PA). CGS21680 inhibited NASH development in steatotic mice and decreased cytokines and chemokines involved in Th cell recruitment or polarization (namely CXCL10, CCL2, tumor necrosis factor alfa [TNFalpha], tumor growth factor [TGFbeta], and IL-12). CGS21680 also reduced the expansion of Th17, Th22, and Th1 cells and increased the immunosuppressive activity of T regulatory cells. In PA-treated mice hepatocytes, CGS21680 inhibited the production of CXCL10, TNFalpha, TGFbeta, IL 12, and CCL2; CGS21680 also prevented JNK-dependent lipotoxicity and its intensification by IL-17 or IL-17 plus IL-22 through Akt/PI3-kinase stimulation and inhibition of the negative regulator of PI3-kinase, (phosphatase and tensin homologue deleted from chromosome 10 (PTEN), which is upregulated by IL-17. In MCD livers, CGS21680 reduced JNK activation and PTEN expression and increased Akt phosphorylation. In conclusion, A2aR stimulation inhibited NASH development by reducing Th17 cell expansion and inhibiting the exacerbation of the IL-17-induced JNK-dependent lipotoxicity. These data promote the implementation of further studies to evaluate the potential clinical application of A2aR agonists that, by being able to function as both cytoprotective and immunomodulatory agents, could efficiently antagonize the multi-faced pathogenesis of NASH. PMID- 28011154 TI - Persistent organic pollutants alter DNA methylation during human adipocyte differentiation. AB - Ubiquitous persistent organic pollutants (POPs) can accumulate in humans where they might influence differentiation of adipocytes. The aim of this study was to investigate whether DNA methylation is one of the underlying mechanisms by which POPs affect adipocyte differentiation, and to what extent DNA methylation can be related to gene transcription. Adipocyte differentiation was induced in two human cell models with continuous exposure to different POPs throughout differentiation. From the seven tested POPs, perfluorooctanesulfonic acid (PFOS) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decreased lipid accumulation, while tributyltin (TBT) increased lipid accumulation. In human mesenchymal stem cells (hMSCs), TCDD and TBT induced opposite gene expression profiles, whereas after PFOS exposure gene expression remained relatively stable. Genome-wide DNA methylation analysis showed that all three POPs affected DNA methylation patterns in adipogenic and other genes, possibly related to the phenotypic outcome, but without concomitant gene expression changes. Differential methylation was predominantly detected in intergenic regions, where the biological relevance of alterations in DNA methylation is unclear. This study demonstrates that POPs, at environmentally relevant levels, are able to induce differential DNA methylation in human differentiating adipocytes. PMID- 28011153 TI - Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse. AB - Adult mammalian CNS axons generally do not regenerate, creating an obstacle to effective repair and recovery after neuronal injury. The canonical Wnt/beta catenin signaling pathway is an essential signal transduction cascade that regulates axon growth and neurite extension in the developing mammalian embryo. In this study, we investigated whether a Wnt/beta-catenin signaling activator could be repurposed to induce regeneration in the adult CNS after axonal injury. We used a retinal ganglion cell (RGC) axon crush injury model in a transgenic Wnt reporter mouse, and intravitreal injections were used to deliver Wnt3a or saline to the RGC cell bodies within the retina. Our findings demonstrated that Wnt3a induced Wnt signaling in RGCs and resulted in significant axonal regrowth past the lesion site when measured at two and four weeks post-injury. Furthermore, Wnt3a-injected eyes showed increased survival of RGCs and significantly higher pattern electroretinography (PERG) amplitudes compared to the control. Additionally, Wnt3a-induced axonal regeneration and RGC survival were associated with elevated activation of the transcription factor Stat3, and reducing expression of Stat3 using a conditional Stat3 knock-out mouse line led to diminished Wnt3a-dependent axonal regeneration and RGC survival. Therefore, these findings reveal a novel role for retinal Wnt signaling in axonal regrowth and RGC survival following axonal injury, which may lead to the development of novel therapies for axonal regeneration. PMID- 28011155 TI - Soluble vascular endothelial (VE) cadherin and autoantibodies to VE-cadherin in rheumatoid arthritis patients treated with etanercept or adalimumab. AB - OBJECTIVES: The aim of this study was to investigate the clinical value of sVE and anti-vascular endothelial-cadherin antibodies (AAVE) in RA treated with etanercept or adalimumab combined with methotrexate. METHODS: This was an 18 month prospective multicenter study in which patients had active RA, requiring TNF antagonist. sVE rates and AAVE titers were measured respectively by dot blot and ELISA. The relationship of these biomarkers with parameters reflecting articular or systemic disease activity, progression of structural damage, and response or remission to treatment was analyzed. RESULTS: Forty-eight patients received TNF blocking agents. Variation of sVE rates were significantly correlated with that of C-reactive protein (CRP) levels at weeks 6, 12, 26 and 52. A significant decrease in sVE levels was observed in the group of patients exhibiting a decrease in CRP levels as compared to the patient group with unmodified CRP. AAVE at baseline were correlated with rheumatoid factor. Kinetics analysis of sVE levels and AAVE titers showed that their level were not associated with disease activity score and to methotrexate/adalimumab or etanercept response. CONCLUSIONS: sVE is a biomarker associated with systemic RA activity under anti-TNF. AAVE are related to autoantibodies usually associated to RA. PMID- 28011156 TI - Maffucci syndrome with multiple hand calcifications. PMID- 28011157 TI - Increased Identification of Candidates for High-Risk Breast Cancer Screening Through Expanded Genetic Testing. AB - PURPOSE: Breast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone. METHODS: Women were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a >20% lifetime risk for breast cancer (ATM, CHEK2, PALB2, TP53, PTEN, CDH1, and STK11). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at >20% lifetime risk on the basis of family history. RESULTS: In total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM, CHEK2, or PALB2. Only 24.7% of all women with PVs found in any gene reached the >20% lifetime risk threshold using the Claus model. CONCLUSIONS: Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment. PMID- 28011158 TI - Radiology Education in Latin America. PMID- 28011159 TI - The Impact of State Tort Reforms on Imaging Utilization. AB - PURPOSE: Defensive medicine, broadly defined as medical practices that protect physicians from malpractice lawsuits without providing benefits to patients, can lead to wasteful use of health care resources and higher cost. Although physicians cite malpractice liability as an important factor driving their decisions to order imaging tests, little research has been done to examine the systematic impact of liability pressure on overall imaging. The authors examined the extent to which radiography use is influenced by malpractice liability pressure among office-based physicians. METHODS: Using National Ambulatory Medical Care Survey data from 1999 to 2010, the authors used multivariate difference-in-difference logistic regression to examine the effects of different types of state tort reforms on the probability of radiography orders by primary care physicians (PCPs) and specialists. RESULTS: The probability that a PCP ordered radiography decreased when states enacted permanent caps on noneconomic damages (-1.0%, P < .01), periodic payment reforms (-1.6%, P < .05), and the total number of tort reforms (-0.5%, P < .05). Specialist physicians were responsive to two reforms: caps on punitive damages (-6.1%, P < .01) and the total number of medical tort laws (-1.2%, P < .01). The passage of new indirect reforms was found to reduce radiography orders for PCPs (-1.8%, P < .05), and the repeal of indirect reforms was found to increase radiography orders for specialists (+3.4%, P < .01). CONCLUSIONS: State tort reform seems to reduce physicians' ordering of radiography. This analysis also suggests that reforms that make it harder to sue physicians have a stronger impact than reforms that directly reduce physicians' malpractice claim payments. PMID- 28011160 TI - piragua encodes a zinc finger protein required for development in Drosophila. AB - We isolated and characterized embryonic lethal mutations in piragua (prg). The prg locus encodes a protein with an amino terminus Zinc Finger-Associated-Domain (ZAD) and nine C2H2 zinc fingers (ZF). prg mRNA and protein expression during embryogenesis is dynamic with widespread maternal contribution, and subsequent expression in epithelial precursors. About a quarter of prg mutant embryos do not develop cuticle, and from those that do a small fraction have cuticular defects. Roughly half of prg mutants die during embryogenesis. prg mutants have an extended phenocritical period encompassing embryogenesis and first instar larval stage, since the other half of prg mutants die as first or second instar larvae. During dorsal closure, time-lapse high-resolution imaging shows defects arising out of sluggishness in closure, resolving at times in failures of closure. prg is expressed in imaginal discs, and is required for imaginal development. prg was identified in imaginal tissue in a cell super competition screen, together with other genes, like flower. We find that flower mutations are also embryonic lethal with a similar phenocritical period and strong embryonic mutant phenotypes (head involution defects, primarily). The two loci interact genetically in the embryo, as they increase embryonic mortality to close to 90% with the same embryonic phenotypes (dorsal closure and head involution defects, plus lack of cuticle). Mutant prg clones generated in developing dorsal thorax and eye imaginal tissue have strong developmental defects (lack of bristles and ommatidial malformations). prg is required in several developmental morphogenetic processes. PMID- 28011161 TI - Using Failure mode and Effects Analysis to reduce patient safety risks related to the dispensing process in the community pharmacy setting. PMID- 28011162 TI - Effect of St.John's wort (Hypericum perforatum) oily extract for the care and treatment of pressure sores; a case report. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Topical formulations such as oily extracts or ointments prepared with the flowering aerial parts of St. John's wort (Hypericum perforatum L., Hypericaceae) have been used in the management of a wide range dermatological problems including superficial wounds and burns, bruises, contusions and many others in the worldwide traditional medicines. AIM OF THE STUDY: This is the first case study reporting the beneficial effects of an oily extract of St. John's wort in the treatment of pressure sores in a intensive care unit (ICU) patient. MATERIAL AND METHODS: The oily extract of St. John's wort was applied to a volunteer patient at ICU daily for forty successive days for wound care and treatment. Healing status was monitored macroscopically by measuring the wound size and stages at certain intervals as well as histopathological evaluation of the tissue sections taken at the initial and final dates of treatment. RESULTS: Evaluation of the results obtained from the macroscopical and histopathological experimentation have shown that oily extract of St. John's wort provided significant efficacy for the treatment of pressure sore wounds. CONCLUSION: St. John's wort oily extract may be suggested as a cost-effective option for the prevention or treatment of pressure sores in ICU patients. PMID- 28011163 TI - Lactucopicrin potentiates neuritogenesis and neurotrophic effects by regulating Ca2+/CaMKII/ATF1 signaling pathway. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Lactucopicrin is one of constitutes in Cichorium intybus L, which is commonly known as chicory in worldwide. It has been used for traditional usage such as antianalgesics, antidepressants and antihyperglycemics AIM OF STUDY: We investigated the neurotrophin-mediated neuroprotective effect of lactucopicrin in in vitro and examined for the underlying mechanism. MATERIALS AND METHOD: To verify the neuroprotective effect of lactucopicrin, we investigated the inhibitory AChE activity, neurite outgrowth-related downstream signaling in murine neuroblastoma N2a and neurotrophins secretion in rat C6 glioma cells. RESULTS: Lactucopicrin inhibited the AChE activity and increased intracellular Ca2+ levels with a substantial rise in muscarinic acetylcholine receptor M1 (CHRM1) expression in N2a cells. Moreover, lactucopicrin actively promoted neurite outgrowth via Ca2+-mediated activation of Ca2+/calmodulin dependent protein kinase-II (CaMKII). It further activates transcription factor 1 (ATF1) along with modulating the levels of tropomyosin receptor kinase A, extracellular signal-regulated kinase 1 and 2, AKT, and synaptophysin 1 in N2a cells. Additionally, the levels of neurotrophins including NGF, BDNF, and NT3 were increased by treatment of lactucopicrin in C6 cells. The effects of lactucopicrin on NGF secretion and neuritogenesis were maintained even in the presence of phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, indicating that lactucopicrin exerts its effect on neuritogenesis in a PI3K-independent manner. CONCLUSION: Our results suggest that the natural compound lactucopicrin may be a promising neurotrophin-mediated neuroprotective candidate for neurodegenerative diseases. PMID- 28011164 TI - Impact of sleep apnea syndrome on survival in patients with multiple system atrophy. AB - INTRODUCTION: Sleep apnea is very frequent in multiple system atrophy (MSA) and may contribute to the poor prognosis. The aim of the present study was to prospectively assess the relation between sleep apnea and survival in 30 consecutive MSA patients recruited at the French Reference Center for MSA. METHODS: Patients with "probable" MSA according to current consensus diagnosis criteria were enrolled in this prospective cohort study. All patients received full polysomnography at baseline and were then followed for up to 4.5 years. The prognostic role of sleep apnea was assessed by a Cox model in an univariate analysis and then adjusted on other potential factors. RESULTS: Analyzable polysomnographic recordings were available for 28 patients. Sleep apnea was found in 11 patients. During follow-up, 15 patients died, including 9 with baseline sleep apnea. In an univariate analysis, sleep apnea, Unified MSA Rating Scale I + II score at baseline and at year one, and disease duration were associated with mortality. However, when adjusting for disease duration and baseline Unified MSA Rating Scale score, the association between sleep apnea and mortality was no longer significant. CONCLUSIONS: Sleep apnea was not an independent factor associated with mortality in this prospective cohort study. PMID- 28011165 TI - A robust and reproducible human pluripotent stem cell derived model of neurite outgrowth in a three-dimensional culture system and its application to study neurite inhibition. AB - The inability of neurites to grow and restore neural connections is common to many neurological disorders, including trauma to the central nervous system and neurodegenerative diseases. Therefore, there is need for a robust and reproducible model of neurite outgrowth, to provide a tool to study the molecular mechanisms that underpin the process of neurite inhibition and to screen molecules that may be able to overcome such inhibition. In this study a novel in vitro pluripotent stem cell based model of human neuritogenesis was developed. This was achieved by incorporating additional technologies, notably a stable synthetic inducer of neural differentiation, and the application of three dimensional (3D) cell culture techniques. We have evaluated the use of photostable, synthetic retinoid molecules to promote neural differentiation and found that 0.01 MUM EC23 was the optimal concentration to promote differentiation and neurite outgrowth from human pluripotent stem cells within our model. We have also developed a methodology to enable quick and accurate quantification of neurite outgrowth derived from such a model. Furthermore, we have obtained significant neurite outgrowth within a 3D culture system enhancing the level of neuritogenesis observed and providing a more physiological microenvironment to investigate the molecular mechanisms that underpin neurite outgrowth and inhibition within the nervous system. We have demonstrated a potential application of our model in co-culture with glioma cells, to recapitulate aspects of the process of neurite inhibition that may also occur in the injured spinal cord. We propose that such a system that can be utilised to investigate the molecular mechanisms that underpin neurite inhibition mediated via glial and neuron interactions. PMID- 28011166 TI - Hyperglycemia and high nitric oxide level induced oxidative stress in the brain and molecular alteration in the neurons and glial cells of laboratory mouse, Mus musculus. AB - Chronic hyperglycemia (glucotoxicity) is reported to have detrimental effects on various brain functions leading to neurodegenerative changes. However, the effect of hyperglycemia in combination with high nitric oxide (NO) level (reported to be increased during glucotoxicity), on brain functions is not clear yet. The present study was designed to investigate the effects of hyperglycemic drug Streptozotocin (STZ) and NO donor Sodium nitroprusside (SNP) on the brain of laboratory mouse, Mus musculus. Effects of these conditions were studied on the markers of oxidative stress, NF-kappaB signalling and the markers of neuronal and glial cell activation/inflammation. Results indicate increased level of MDA and altered antioxidant enzymes activity in both the treated groups compared to control but high levels of AGEs, AOPP and AR activity (markers of diabetic complications) were observed in STZ group only. On the other hand, while STZ group showed decreased IL-6 level, it was increased in SNP group but IFN-Upsilon level increased in both the treated groups compared to control. Further, in addition to alterations in the expressions of iNOS, IKKbeta, IKBalpha and NF kappaB subunits (RelA-p65/RelB-p50) observed in the neurons and glial cells of different brain regions (hypothalamus, basolateral amygdala and cerebral cortex), enhanced expression of microglial CD11b and astrocytic GFAP was also found in both the treated groups compared to control. Present findings led us to conclude that both hyperglycemia and high NO level causes oxidative stress in addition to molecular alteration in the neurons and glial cells. It is suggested that high blood glucose and NO level induced oxidative stress may lead to neuroinflammation possibly via NF-kappaB signalling. PMID- 28011167 TI - Trypanosoma brucei brucei traverses different biological barriers differently and may modify the host plasma membrane in the process. AB - Trypanosoma brucei are extracellular hemoflagellate protozoan parasites and one of the causative agents of a devastating zoonotic disease called African Trypanosomiasis. In humans, the disease is caused by Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense, which cross the blood brain barrier (BBB) causing neurological disorders which culminate in death if untreated. In some domestic animals and laboratory rodents, Trypanosoma brucei brucei causes a disease similar to that in humans. The mechanism by which Trypanosoma brucei brucei invade biological barriers including the BBB has not been fully elucidated. To further address this issue, Mardin Dardy Canine Kidney II (MDCKII) and Human dermal microvascular endothelial cell (HDMEC) monolayers were grown to confluence on transwell inserts to constitute in vitro biological barriers. MDCKII cells were chosen for their ability to form tight junctions similar to those formed by the BBB endothelial cells. Labeled trypanosomes were placed in the upper chamber of transwell inserts layered with confluent MDCKII/HDMEC monolayers and their ability to cross the monolayer over time evaluated. Our results show that only 0.5-1.25% of Trypanosoma brucei brucei were able to migrate across the monolayers after 3 h. By employing immune-staining and confocal microscopic analysis we observed that trypanosomes were located at the tight junctions and inside the cell in the MDCK II monolayers indicating that they crossed the monolayer using both the paracellular and transcellular routes. Our observations also showed that there seemed to be no obvious degradation of junction proteins Zonula Ocludens-1, Occludin and Ecadherin. In the HDMEC cell monolayer, our scanning electron microscopy data showed that Trypanosoma brucei brucei is able to modulate the plasma membrane to form invaginations similar to cuplike structures formed by Tlymphocytes. However these structures seemed to be independent of vascular adhesion molecules suggesting that they could be more like the membrane ruffles formed by certain intracellular bacteria during invasion. Taken together, our data reveal a mechanism by which Trypanosoma brucei brucei is able to cross different biological barriers including the BBB without causing any obvious damage. PMID- 28011168 TI - Toxoplasma gondii plaque assays revisited: Improvements for ultrastructural and quantitative evaluation of lytic parasite growth. AB - Lytic growth of intracellular Toxoplasma gondii tachyzoite stages over a period of days results in plaques within mononolayers of host cells. Plaque assays are in frequent use to isolate single clones and to investigate invasion, replication and egress over a longer time frame. To allow correlating plaque morphology and/or size with ultrastructural examination of individual parasites we introduce a simple protocol for correlative light and electron microscopy (CLEM) of entire plaques. We also illustrate the advantages of visualizing only the boundaries of plaques by staining for infected cells ('positive staining') rather than the traditional staining of the intact cell monolayer, thus outlining the area of lysed cells ('negative staining'). Tachyzoites expressing beta-galactosidase of Escherichia coli are an easy to visualize histochemical marker for this purpose. Quantitative measurements of plaque area with our compiled user-friendly ImageJ macros are compared to commercial software for ease and shown to be more accurate for some applications. Finally, a chemically defined medium is shown to be superior to the fetal bovine serum-containing medium for plaque assays, resulting in larger plaques. The reported additions and changes of the plaque assay procedure offer improved ways to analyze subtle differences in invasion, pathogen growth and egress. Our chemically defined medium will improve standardization of e.g. drug screening assays. PMID- 28011169 TI - Leishmanicidal activity of the alkaloid-rich fraction from Guatteria latifolia. AB - Leishmaniasis is caused by protozoan parasites belonging to the genus Leishmania and includes cutaneous, mucocutaneous and visceral clinical forms. The drugs currently available for leishmaniasis treatment are pentavalent antimonials, amphotericin B and miltefosine, which present high toxicity, elevated cost and development of parasite resistance. The natural products constitute an important source of substances with leishmanicidal potential. Here we evaluated in vitro the anti-Leishmania amazonensis activity of crude extracts of branches, leaves and fruits of Guatteria latifolia. The branch extract (GCE) exhibited promising leishmanicidal activity against promastigotes (IC50 51.7 MUg/ml), and was submitted to fractionation guided by in vitro assays. Among the seven subfractions obtained, GF1 and GF2 were the most actives against promastigotes with IC50 25.6 and 16 MUg/ml, respectively. Since GCE, GF1 and GF2 were not toxic for macrophages, next, we tested their effect on intracellular amastigotes, and the IC50 values obtained were, respectively 30.5, 10.4 and 7.4 MUg/ml, after 24 h treatment. The selectivity index for GCE, GF1 and GF2 were >6.5, >19.2 and > 27, respectively. Additionally, GCE, GF1 and GF2 affected the division pattern of the promastigotes by increasing 6.7, 9.4 and 7-fold the cells in Sub-G0/G1 phase, and decreasing 1.6, 2.5 and 1.8-fold the cells in G0/G1 phase, respectively. To assess the GCE and GFs capacity to modulate microbicidal mechanisms of macrophages, nitric oxide (NO) and TNF-alpha production were tested. Our results indicated that at the IC50s GCE, GF1 and GF2 decreased NO production of infected macrophages stimulated with IFN-gamma and LPS, besides, only GF1 decreased the production of TNF-alpha. Our data warrant further studies of GCE, GF1 and GF2 to identify active compounds against Leishmania parasites. PMID- 28011170 TI - Antiprotozoal drug nitazoxanide enhances parasitemia, tissue lesions and mortality caused by Trypanosoma cruzi in murine model. AB - Chagas' disease is caused by unicellular parasite Trypanosoma cruzi (T. cruzi). It is endemic throughout Latin America, but nowadays has become a global challenge due to tourism and migration. Non-treated infection may result in health-threatening complications and lead to death. Current medications for this infection are nifurtimox (NFT) and benznidazol. Both drugs may cause side effects and are ineffective in the chronic phase. Therefore, new antichagasic compounds are urgently required. Nitazoxanide (NTZ) is a broad spectrum antiparasitic drug, proposed recently as a potential candidate to be added to the list of essential medicines for integrated neglected tropical disease control and elimination. Although the effect of NTZ against T. cruzi epimastigotes in vitro was reported, the corresponding experiments in animal models of T. cruzi infection have never been undertaken. The present work was designed to fill this gap and evaluate the effect of NTZ on experimental murine trypanosomiasis, in comparison with classical antichagasic agent NFT. Highly sensitive to T. cruzi BALB/c mice were infected using Albarrada T. cruzi strain, recently isolated in Mexico. Experimental groups were either left untreated, or otherwise treated with NFT, NTZ (100 and 1000 mg/kg), or with both drugs simultaneously. The severity of the infection was estimated based on criteria such as parasitemia, lesions in target tissues (heart, muscles and lungs) and mortality. Despite the expected protective effect, NTZ drastically aggravates the course of T. cruzi infection. Namely, parasitemia, tissue lesions and mortality caused by T. cruzi infection were significantly higher in NTZ-treated mice groups, even in comparison with untreated infected animals. NTZ by itself no produced mortality o tissue damage, and NFT showed an expected protective effect. Our results indicate that NTZ cannot be considered for Chagas' disease treatment. Moreover, NTZ should be used with caution in patients positive for T. cruzi infection. PMID- 28011171 TI - Mental rotation task specifically modulates functional connectivity strength of intrinsic brain activity in low frequency domains: A maximum uncertainty linear discriminant analysis. AB - Neuroimaging studies have highlighted that intrinsic brain activity is modified to implement task demands. However, the relation between mental rotation and intrinsic brain activity remains unclear. To answer this question, we collected functional MRI (fMRI) data from 30 healthy participants in two mental rotation task periods (1st-task state, 2nd-task state) and two rest periods before (pre task resting state) and after the task (post-task resting state) respectively. By combining the spatial independent component analysis (ICA) and voxel-wise functional connectivity strength (FCS), we identified FCS maps of 10 brain resting state networks (RSNs) within six different bands (i.e., 0-0.05, 0.05-0.1, 0.1-0.15, 0.15-0.2, 0.2-0.25, and 0.01-0.08Hz) corresponding to the four states for each subject. The maximum uncertainty linear discriminant analysis (MLDA) method showed that the FCS within the low frequency bandwidth of 0.05-0.1Hz could effectively classify the mental rotation task state from pre-/post-task resting states but failed to discriminate the pre- and post-task resting states. Discriminative FCSs were observed in the cognitive executive-control network (central executive and attention) and the imagery-based internal mental manipulation network (default mode, primary sensorimotor, and primary visual). Imagery manipulation is a stable mental element of mental rotation, and the involvement of executive control is dependent on the degree of task familiarity. Together, the present study provides evidence that mental rotation task specifically modifies intrinsic brain activity to complement cognitive demands, which provides further insight into the neural basis of mental rotation manipulation. PMID- 28011172 TI - Wake-sleep and cardiovascular regulatory changes in rats made obese by a high-fat diet. AB - Obesity is known to be associated with alterations in wake-sleep (WS) architecture and cardiovascular parameters. This study was aimed at assessing the possible influence of diet-induced obesity (DIO) on sleep homeostasis and on the WS state-dependent levels of arterial pressure (AP) and heart rate in the rat. Two groups of age-matched Sprague-Dawley rats were fed either a high-fat hypercaloric diet, leading to DIO, or a normocaloric standard diet (lean controls) for 8 weeks. While under general anesthesia, animals were implanted with instrumentation for the recording of electroencephalogram, electromyogram, arterial pressure, and deep brain temperature. The experimental protocol consisted of 48h of baseline, 12h of gentle handling, enhancing wake and depressing sleep, and 36-h post-handling recovery. Compared to lean controls, DIO rats showed: i) the same amount of rapid-eye movement (REM) and non-REM (NREM) sleep in the rest period, although the latter was characterized by more fragmented episodes; ii) an increase in both REM sleep and NREM sleep in the activity period; iii) a comparable post-handling sleep homeostatic response, in terms of either the degree of Delta power increase during NREM sleep or the quantitative compensation of the REM sleep loss at the end of the 36-h recovery period; iv) significantly higher levels of AP, irrespectively of the different WS states and of the changes in their intensity throughout the experimental protocol. Overall, these changes may be the reflection of a modification in the activity of the hypothalamic areas where WS, autonomic, and metabolic regulations are known to interact. PMID- 28011173 TI - Neuronal expression of a thyroid hormone receptor alpha mutation alters mouse behaviour. AB - In humans, alterations in thyroid hormone signalling are associated with mood and anxiety disorders, but the neural mechanisms underlying such association are poorly understood. The present study investigates the involvement of neuronal thyroid hormone receptor alpha (TRalpha) in anxiety, using mouse genetics and Cre/loxP technology to specifically alter TRalpha signalling in neurons. We evaluated the behaviour of mice expressing a dominant negative, neuron-specific mutation of TRalpha (TRalphaAMI/Cre3 mice), using the elevated-plus maze, light dark box and open-field tests. In a first experiment, mice were housed individually, and the behaviour of TRalphaAMI/Cre3 mice differed significantly from that of control littermates in these 3 tests, suggesting heightened anxiety. In a second experiment, designed to evaluate the robustness of the results with the same 3 tests, mice were housed in groups. In these conditions, the behaviour of TRalphaAMI/Cre3 mice differed from that of control littermates only in the light-dark box. Thus, TRalphaAMI/Cre3 mice appear to be more likely to develop anxiety under stressful housing conditions than control mice. These results suggest that in adult mice, thyroid hormone signalling in neurons, via TRalpha, is involved in the control of anxiety behaviour. PMID- 28011174 TI - Predictive but not emotional value of Pavlovian stimuli leads to pavlovian-to instrumental transfer. AB - Reward-predictive stimuli augment instrumental reward-seeking in humans, an effect denoted Pavlovian-to-instrumental transfer (PIT), but the role of differential reward value of these stimuli and of emotional conditioned responses in PIT remains unknown. Fifty one participants experienced a Pavlovian phase that associated two stimuli with either 10p (CS10) or 50p (CS50). Next, participants underwent instrumental training for two responses reinforced with either 10p or 50p. Finally, the transfer phase continued as had instrumental training, now in the presence of the Pavlovian stimuli. Participants were dichotomised as aware/unaware according to their expectancy awareness of the CS->outcome associations. Only aware participants demonstrated PIT (increased choice and number of responses on the 10p and 50p response key in the presence of CS10 and CS50 respectively), yet both aware and unaware groups rated the 50p stimulus as more pleasant than the 10p stimulus. These findings suggest that expectancy of reward is necessary for PIT; however, emotional conditioned responses appear not sufficient to influence PIT. Future research should attempt to manipulate emotional conditioned responses in a PIT context, to test the sufficiency of reward expectancy in PIT. PMID- 28011175 TI - Atypical onset of sciatica in a patient with a filum terminale hemangioblastoma. PMID- 28011176 TI - Alkyl-substituted phenylamino derivatives of 7-nitrobenz-2-oxa-1,3-diazole as uncouplers of oxidative phosphorylation and antibacterial agents: involvement of membrane proteins in the uncoupling action. AB - In search for new effective uncouplers of oxidative phosphorylation, we studied 4 aryl amino derivatives of a fluorescent group 7-nitrobenz-2-oxa-1,3-diazol (NBD). In our recent work (Denisov et al., Bioelectrochemistry, 2014), NBD-conjugated alkyl amines (NBD-Cn) were shown to exhibit uncoupling activity. It was concluded that despite a pKa value being about 10, the expected hindering of the uncoupling activity could be overcome by insertion of an alkyl chain. There is evidence in the literature that the introduction of an aryl substituent in the 4-amino NBD group shifts the pKa to neutral values. Here we report the data on the properties of a number of 4-arylamino derivatives of NBD, namely, alkylphenyl-amino-NBD (Cn phenyl-NBD) with varying alkyl chain Cn. By measuring the electrical current across planar bilayer lipid membrane, the protonophoric activity of Cn-phenyl-NBD at neutral pH grew monotonously from C1- to C6-phenyl-NBD. All of these compounds increased the respiration rate and reduced the membrane potential of isolated rat liver mitochondria. Importantly, the uncoupling action of C6- and C4-phenyl-NBD was partially reversed by glutamate, diethyl pyrocarbonate (DEPC), 6 ketocholestanol, and carboxyatractyloside, thus pointing to the involvement of membrane proteins in the uncoupling activity of Cn-phenyl-NBD in mitochondria. The pronounced recoupling effect of DEPC, an inhibitor of an aspartate-glutamate carrier (AGC), and that of its substrates for the first time highlighted AGC participation in the action of potent uncouplers on mitochondria. C6-phenyl-NBD produced strong antimicrobial effect on Bacillus subtilis, which manifested itself in cell membrane depolarization and suppression of bacterial growth at submicromolar concentrations. PMID- 28011177 TI - Correction of iron-deficiency anaemia in colorectal surgery reduces perioperative transfusion rates: A before and after study. AB - BACKGROUND: Preoperative anaemia is a risk factor for poorer postoperative outcomes and many colorectal cancer patients have iron-deficiency anaemia. The aim of this study was to assess if a preoperative iron-deficiency anaemia management protocol for elective colorectal surgery patients helps improve detection and treatment of iron-deficiency, and improve patient outcomes. MATERIALS AND METHODS: Retrospective data was collected from 95 consecutive patients undergoing colorectal cancer surgery to establish baseline anaemia correction rates and perioperative transfusion rates. A new pathway for early detection of iron-deficiency anaemia, and treatment with intravenous iron replacement, for colorectal cancer patients was then developed and implemented. Data from 81 patients was collected prospectively post-implementation to assess the impact of the pathway. RESULTS: Pre-intervention data showed anaemic patients were seventeen times more likely to require perioperative transfusion than non anaemic patients (95% CI 1.9-151.0, p = 0.011). Post-intervention, fifteen patients with iron-deficiency were treated with either intravenous (n = 8) or oral iron (n = 7). Mean Day 3 postoperative haemoglobin levels were significantly lower in patients with uncorrected anaemia (9.5 g/dL, p = 0.004); those patients whose anaemia was corrected by iron replacement therapy preoperatively had similar postoperative results to non-anaemic patients (10.93 g/dL vs 11.4 g/dL, p = 0.781). Postoperative transfusion rates remained high at 38% in patients with uncorrected anaemia, compared to 0% in corrected anaemia and 3.5% in non-anaemic patients. CONCLUSIONS: Introduction of an iron-deficiency anaemia management pathway has resulted in improved perioperative haemoglobin levels, with a reduction in perioperative transfusion, in elective colorectal patients. Implementation of this pathway could result in similar outcomes across other categories of surgical patients. PMID- 28011178 TI - Recurrence probability for keratocystic odontogenic tumors: An analysis of 6427 cases. AB - PURPOSE: To investigate and compare the probability of recurrence of keratocystic odontogenic tumors (KCOTs) for different variables and treatment protocols. MATERIALS AND METHODS: An electronic search was undertaken in April 2016 that included clinical series of KCOTs reporting recurrences. Untransformed proportions and meta-analyses were performed to estimate the probability/risk of recurrence, according to several variables. RESULTS: A total of 94 publications were included (6427 KCOTs, 1464 recurrences). Probability of recurrence: all lesions, 21.1%; nevoid basal cell carcinoma syndrome, 35.4%; males, 20.3%; females, 19.3%; maxilla, 15.3%; mandible, 21.5%; unilocular, 14.7%; multilocular, 24.4%; marsupialization/decompression, 28.7%; decompression + enucleation +/- additional therapy, 18.6%; enucleation/curettage, 22.5%; enucleation + peripheral ostectomy, 18.6%; enucleation + Carnoy's solution, 5.3%; enucleation + cryotherapy, 20.9%; marginal/segmental resection, 2.2%. The recurrence was not statistically significantly affected by lesion location (maxilla vs. mandible, risk ratio [RR] 0.92, P = 0.32) or patient's sex (male vs. female, RR 0.94, P = 0.44), but by locularity (unilocular vs. multilocular, RR 0.67, P = 0.007). Recurrence risk for surgical managements: marsupialization vs. enucleation (RR 1.65, P = 0.0006), marsupialization vs. resection (RR 3.17, P = 0.009), enucleation alone vs. enucleation + peripheral ostectomy (RR 1.66, P = 0.05), enucleation alone vs. enucleation + Carnoy's solution (RR 1.94, P = 0.03), enucleation alone vs. enucleation + cryotherapy (RR 0.88, P = 0.56). CONCLUSIONS: KCOTs have a considerable rate of recurrence, which varies significantly according to some clinical, radiographic, and histopathological features, as well as surgical management. PMID- 28011179 TI - Therapy of sinonasal malignancies invading the orbit-orbital exenteration versus preservation of the orbit plus radiotherapy. AB - INTRODUCTION: Orbital invasion is a strong independent prognostic factor for sinonasal malignancies. While there is consent about preservation of the orbit for tumors limited to the orbital periosteum there is controversy about the optimal management of sinonasal malignancies transgressing this barrier. Therefore the aim of our study was to compare exenteration versus preservation of the orbit. MATERIAL AND METHODS: 52 patients with sinonasal malignancies invading the orbit beyond the orbital periosteum with involvement of the orbital soft tissues were included in the retrospective study. Prognostic factors were identified through univariate analysis. RESULTS: Univariate analysis revealed a significant impact of N-classification (p = 0.017), and treatment strategy (p = 0.016). Exenteration of the orbit was associated with a significantly better 5 year overall survival rate (65.5%) than preservation of the orbit (14%). CONCLUSIONS: For patients with invasion of the structures beyond the orbital periosteum, exenteration yields better survival results than preservation of the orbital structures in combination with radiotherapy. In cases where both eyes are affected from the tumor or if only one dysfunctional eye would be left over after therapy, we do not recommend orbital exenteration because life quality would be critically deteriorated. PMID- 28011180 TI - Influence of bone invasion on outcomes after marginal mandibulectomy in squamous cell carcinoma of the oral cavity. AB - INTRODUCTION: Marginal mandibulectomy (MM) is indicated for oral cavity squamous cell carcinomas (OCSCC) that abut or minimally erode the mandible without gross invasion. Successful implementation of MM is predicated on accurate patient selection and appropriate adjuvant treatment based on well-known host and tumor characteristics. The incidence of microscopically diagnosed bone involvement in MM specimens and its implications on outcomes have however not been reported in large contemporary series. PURPOSE: To report the incidence of bone involvement and analyze its influence on oncologic outcomes in selected patients who underwent MM in treatment of OCSCC. METHOD: A retrospective cohort study was performed on a consecutive series of previously untreated patients requiring MM, at a tertiary care cancer center, between 1985 and 2012 (n = 326). The median age was 64 years and 59% were male. The majority of patients (67%) had a primary tumor of the floor of the mouth or lower alveolus, 80% were clinically staged T1 2, and 31% were clinically N+. Postoperative radiation (PORT) was used in 27% and chemoradiation (POCTRT) in 8% of patients who had microscopic bone invasion. The median follow up period was 55 months and endpoints of interest were local and regional recurrence free (LRFS and RRFS) and disease specific (DSS) survival. RESULTS: Microscopic bone invasion was present in 15% of patients (n = 49). Among these, cortical invasion was present in 32, medullary in 13, and it was not specified in 4. Eight patients had microscopic positive bone margins. Positive bone margins were associated with medullary bone involvement (p < 0.001), floor of mouth and buccal mucosa primary site (p = 0.03), and positive soft tissue margins (p = 0.06). LRFS and DSS were similar in patients without versus with bone invasion (62.8% vs 79.7% and 76.2% vs 66% respectively, p = NS). LRFS were similar in patients with microscopic positive versus negative bone margins, as long as postoperative adjuvant treatment was administered. CONCLUSION: Microscopic bone involvement does not adversely influence outcomes but medullary bone involvement does confer a higher risk of positive bone margins. MM and appropriate adjuvant treatment is an effective strategy for treatment of OCSCC in selected patients with primary tumors adherent to or in proximity to the mandible. PMID- 28011181 TI - Patient-specific polymethylmethacrylate prostheses for secondary reconstruction of large calvarial defects: A retrospective feasibility study of a new intraoperative moulding device for cranioplasty. AB - PURPOSE: The aim of this study was to review a new template-based technique for intraoperative patient-specific cranioplasty manufacturing (PSCM) with polymethylmethacrylate (PMMA) to cover large calvarial defects. MATERIAL AND METHODS: A polypropylene foil thermoformed on a three-dimensional reprint of the calvarial defect was used as an intraoperative moulding device for PMMA between August 2012 and December 2015. Surgical and radiological data were retrospectively reviewed, and a patient questionnaire was used to assess functional and cosmetic outcome (numeric rating scale, Odom's criteria). RESULTS: Seventeen patients (mean age 42.2 +/- 14.5 years) received PSCM. Operating time averaged 130 +/- 34 min, and the approximate blood loss was 293 +/- 185 ml. Volumetric analysis revealed a lower implant volume compared to index bone (mean 66.5 vs. 72 cm3, p = 0.513), the mean difference in thickness being the lowest in the posterior parietal and pterional (0.4-0.7 mm) and the highest in the anterior superior frontal area (1.8 mm). Cosmetic satisfaction averaged 9 +/- 1.5, with 70.6% of patients judging the overall result as excellent or good and 29.4% as satisfactory. Mean follow-up was 19.5 +/- 13.3 months, with an overall complication rate of 17.6%, including 11.8% surgical site infections (SSIs) and one implant removal. CONCLUSIONS: Intraoperative PSCM using PMMA moulded on a thermoformed polypropylene foil leads to satisfactory outcomes. It is a safe technique with complication rates comparable but not superior to those of other alloplastic techniques, but the device has considerable production costs. PMID- 28011182 TI - Dynamic facial asymmetry in patients with repaired cleft lip using 4D imaging (video stereophotogrammetry). AB - BACKGROUND: Unilateral cleft lip is a profoundly asymmetrical condition affecting all hard and soft tissue layers from the nose to the upper lip. Although the asymmetry is minimized through cleft lip repair, a degree of asymmetry inevitably persists. Studies investigating asymmetry in patients with cleft lip have used facial measurements, and static 2D and 3D photography. The nose/lip/mouth area, however, is rarely static in our day to day social interactions. METHODS: Non syndromic patients with cleft lip and palate, and a control group without orofacial clefts underwent 50 frames per second 4D imaging while generating facial expressions including smiling and pouting. Key landmarks were tracked throughout the expression, corrected for head movement and a motion path of each landmark was generated. Asymmetry was assessed for both extent of displacement, using Euclidean distances between frames, and the shape of the motion path using Procrustes analysis. RESULTS: Twelve patients were compared in each group with an age range from 8 to 18. Comparing the motion path of key landmarks in the upper lip demonstrated statistically significant differences in both the magnitude and shape of motion during smiling and pouting between cleft and non-cleft groups. CONCLUSION: Video stereophotogrammetry of the repaired cleft lip demonstrates asymmetry of both the magnitude of motion as well as asymmetry of the path of the motion itself. This may be due to the effect of the scar tissue from the repair, from the abnormal anatomy involved with cleft lip or a combination of the two. PMID- 28011183 TI - Comparison of skeletal stability after sagittal split ramus osteotomy among mono cortical plate fixation, bi-cortical plate fixation, and hybrid fixation using absorbable plates and screws. AB - PURPOSE: The purpose of this study was to examine skeletal stability and plate breakage after sagittal split ramus osteotomy (SSRO) with the mono-cortical plate fixation, bi-cortical plate fixation, and hybrid fixation techniques using absorbable plates and screws. MATERIALS AND METHODS: A total of 76 Japanese patients diagnosed with mandibular prognathism with and without maxillary deformity were divided into 3 groups randomly. A total of 28 patients underwent SSRO with mono-cortical plate fixation, 23 underwent SSRO with bi-cortical plate fixation, and 25 underwent SSRO with hybrid fixation. Skeletal stability and horizontal condylar angle were analyzed by axial, frontal, and lateral cephalograms from before the operation to 1 year postoperatively. Breakage of the plate and screws was observed by 3-dimensional computed tomography (3DCT) immediately after surgery and after 1 year. RESULTS: Although there was a significant difference between the mono-cortical plate fixation group and hybrid fixation group regarding right MeAg in T1 (P = 0.0488) and occlusal plane in T1 (P = 0.0346), there were no significant differences between the groups for the other measurements in each time interval. In 2 cases, namely, 6 sides in the mono cortical plate fixation group, breakage of the absorbable plate was found by 3DCT. However, there was no breakage in the bi-cortical plate fixation group and hybrid fixation group. CONCLUSION: This study results suggested that there were no significant differences in the postoperative skeletal stability among the 3 groups, and bi-cortical fixation as well as hybrid fixation was a reliable and useful method to prevent plate breakage even if an absorbable material was used. PMID- 28011184 TI - The role of flexible fiberoptic laryngoscopy in Robin Sequence: A systematic review. AB - OBJECTIVE: Systematically search literature for flexible fiberoptic laryngoscopy (FFL) use in Robin Sequence (RS) patients, in diverse clinical scenarios. DATA SOURCES: Pubmed, LILACS and SCIELO. REVIEW METHODS: Systematic review using a sensitive search strategy focused on RS patients and FFL. RESULTS: There were 48 full text articles included in this systematic review. No summary meta-analytic measurement could be calculated due to heterogeneity of interventions and outcomes. FFL approaches were grouped in five topics, as follows: Endoscopic classification: no evidence on superiority of awake over light sedation and correlation of grading scales with symptom severity. Airway abnormalities: high incidence of concomitant lesions besides glossoptosis. Swallowing evaluation: no validation against fluoroscopy (gold standard) yet. Intubation aid for mechanical ventilation: ultra-thin bronchoscopes improve success rates of intubation. Treatment outcome monitoring: no consensus on ideal parameters to be checked. CONCLUSION: Some applications have their roles already well established in the management of RS patients, like the evaluation of glossoptosis and associated lesions and as an intubation assistance tool, while others need to be the subject of further research, like the exact method of evaluation, its association with clinical manifestations, its role in swallowing investigation and as a postoperative success predictor. PMID- 28011185 TI - Novel Rickettsia and emergent tick-borne pathogens: A molecular survey of ticks and tick-borne pathogens in Shimba Hills National Reserve, Kenya. AB - Ticks are important vectors of emerging and re-emerging zoonoses, the majority of which originate from wildlife. In recent times, this has become a global public health concern that necessitates surveillance of both known and unknown tick borne pathogens likely to be future disease threats, as well as their tick vectors. We carried out a survey of the diversity of ticks and tick-borne pathogens in Kenya's Shimba Hills National Reserve (SHNR), an area with intensified human-livestock-wildlife interactions, where we collected 4297 questing ticks (209 adult ticks, 586 nymphs and 3502 larvae). We identified four tick species of two genera (Amblyomma eburneum, Amblyomma tholloni, Rhipicephalus maculatus and a novel Rhipicephalus sp.) based on both morphological characteristics and molecular analysis of 16S rRNA, internal transcribed spacer 2 (ITS 2) and cytochrome oxidase subunit 1 (CO1) genes. We pooled the ticks (3-8 adults, 8-15 nymphs or 30 larvae) depending on species and life-cycle stages, and screened for bacterial, arboviral and protozoal pathogens using PCR with high resolution melting analysis and sequencing of unique melt profiles. We report the first molecular detection of Anaplasma phagocytophilum, a novel Rickettsia-like and Ehrlichia-like species, in Rh. maculatus ticks. We also detected Ehrlichia chaffeensis, Coxiella sp., Rickettsia africae and Theileria velifera in Am. eburneum ticks for the first time. Our findings demonstrate previously unidentified tick-pathogen relationships and a unique tick diversity in the SHNR that may contribute to livestock, and possibly human, morbidity in the region. This study highlights the importance of routine surveillance in similar areas to elucidate disease transmission dynamics, as a critical component to inform the development of better tick-borne disease diagnosis, prevention and control measures. PMID- 28011186 TI - NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients. AB - NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD. PMID- 28011187 TI - Mucosal-associated invariant T cells are depleted and functionally altered in patients with common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is a primary immunoglobulin deficiency characterized by recurrent infections and complications, including autoimmunity, enteropathy, polyclonal lymphocytic infiltration or lymphoid malignancy. Innate T cells can support B cell maturation and antibody production. We investigated the numbers, phenotypes and functions of circulating B cell, gammadelta T cell, invariant natural killer T (iNKT) cell and mucosal-associated invariant T (MAIT) cell subsets in 23 CVID patients and 27 healthy controls. Switched-memory B cells and plasmablasts were depleted in CVID patients (p<0.0001). gammadelta T cells were found at normal numbers, but iNKT and MAIT cells were depleted (p<0.0001 and p<0.002). MAIT cells were especially low in patients with complicated CVID (p<0.05). MAIT cells from patients appeared more activated and more frequently produced interleukin-17A, interleukin-22 and tumor necrosis factor-alpha than MAIT cells from healthy subjects in vitro. Thus, MAIT cell depletion and activation may contribute to immunodeficiency and complications associated with CVID. PMID- 28011188 TI - Mid-range Ejection Fraction Does Not Permit Risk Stratification Among Patients Hospitalized for Heart Failure. AB - INTRODUCTION AND OBJECTIVES: European Society of Cardiology heart failure guidelines include a new patient category with mid-range (40%-49%) left ventricular ejection fraction (HFmrEF). HFmrEF patient characteristics and prognosis are poorly defined. The aim of this study was to analyze the HFmrEF category in a cohort of hospitalized heart failure patients (REDINSCOR II Registry). METHODS: A prospective observational study was conducted with 1420 patients classified according to ejection fraction as follows: HFrEF, < 40%; HFmrEF, 40%-49%; and HFpEF, >= 50%. Baseline patient characteristics were examined, and outcome measures were mortality and readmission for heart failure at 1-, 6-, and 12-month follow-up. Propensity score matching was used to compare the HFmrEF group with the other ejection fraction groups. RESULTS: Among the study participants, 583 (41%) had HFrEF, 227 (16%) HFmrEF, and 610 (43%) HFpEF. HFmrEF patients had a clinical profile similar to that of HFpEF patients in terms of age, blood pressure, and atrial fibrillation prevalence, but shared with HFrEF patients a higher proportion of male participants and ischemic etiology, and use of class I drugs targeting HFrEF. All other features were intermediate, and comorbidities were similar among the 3 groups. There were no significant differences in all-cause mortality, cause of death, or heart failure readmission. The similar outcomes were confirmed in the propensity score matched cohorts. CONCLUSIONS: The HFmrEF patient group has characteristics between the HFrEF and HFpEF groups, with more similarities to the HFpEF group. No between-group differences were observed in total mortality, cause of death, or heart failure readmission. PMID- 28011189 TI - Primary hyperparathyroidism regression associated to cinacalcet therapy proved by 99mTc-MIBI scintigraphy. PMID- 28011191 TI - Determinants to trigger memory reconsolidation: The role of retrieval and updating information. AB - Long-term memories can undergo destabilization/restabilization processes, collectively called reconsolidation. However, the parameters that trigger memory reconsolidation are poorly understood and are a matter of intense investigation. Particularly, memory retrieval is widely held as requisite to initiate reconsolidation. This assumption makes sense since only relevant cues will induce reconsolidation of a specific memory. However, recent studies show that pharmacological inhibition of retrieval does not avoid memory from undergoing reconsolidation, indicating that memory reconsolidation occurs through a process that can be dissociated from retrieval. We propose that retrieval is not a unitary process but has two dissociable components; one leading to the expression of memory and the other to reconsolidation, referred herein as executer and integrator respectively. The executer would lead to the behavioral expression of the memory. This component would be the one disrupted on the studies that show reconsolidation independence from retrieval. The integrator would deal with reconsolidation. This component of retrieval would lead to long-term memory destabilization when specific conditions are met. We think that an important number of reports are consistent with the hypothesis that reconsolidation is only initiated when updating information is acquired. We suggest that the integrator would initiate reconsolidation to integrate updating information into long-term memory. PMID- 28011190 TI - Real-time near-infrared bioimaging of a receptor-targeted cytotoxic dendritic theranostic agent. AB - Efficient and site-specific delivery of anticancer drugs to tumors is important in the development of effective cancer chemotherapy. As an undecapeptide of the tachykinin neuropeptide family, the substance P (SP)/neurokinin-1 receptor (NK1R) system has been identified as a promising ligand-receptor pair in tumor-specific drug delivery. However, the rational design of suitable theranostic agents with high drug loading capacity and tumor targeting for cancer patients remains a great challenge. Herein, we report a dendritic strategy that utilizes the two amine functionalities of lysine to create branch points that allow conjugation of the anticancer drug 5-fluorouracil (5-FU) to the tumor-targeting ligand substance P, along with an additional near-infrared (NIR) squaraine dye, to construct a theranostic dendritic agent, P-FU 4. This cytotoxic theranostic agent, containing four carboxyl-modified 5-FU molecules, has several desirable advantages: i) the ability to self-assemble into nanoparticles; ii) enhanced cytotoxicity with high drug loading capacity (16%) and a specific receptor-targeted interaction with NK1R through the SP moiety; and iii) a high NIR squaraine fluorescence efficiency due to the specific dendron isolation, avoiding aggregation-mediated quenching. As demonstrated in this report, the cytotoxic activity of P-FU 4 is dose dependent against the tested cancer cells. The improved drug loading capacity with dendritic branching distinctly enhanced cytotoxicity to tumor cells but had little effect on the viability of normal cells. P-FU 4 was preferentially taken up by tumor cells through a receptor-mediated interaction, which was monitored by effective NIR fluorescence with high tissue penetration. Studies using a mouse model revealed that P-FU 4 can significantly inhibit tumor progression, with a tumor-inhibition rate of 60.2%. The receptor-targeted cytotoxic dendritic theranostic agent is highly preferable to standard chemotherapeutic treatments and decreases the negative side effects of medications on healthy cells, which establishes its utility in drug delivery and cancer chemotherapy. PMID- 28011192 TI - Naringin alleviates early brain injury after experimental subarachnoid hemorrhage by reducing oxidative stress and inhibiting apoptosis. AB - This study aims to clarify the neuroprotective effect of naringin on early brain injury (EBI) following subarachnoid hemorrhage (SAH) and the possible mechanisms of naringin in the treatment of SAH. The endovascular puncture model was performed to induce SAH model in rats and the efficacy of 40mg/kg and 80mg/kg naringin were tested by intraperitoneally administration. SAH grade, neurological score, brain edema, blood-brain barrier permeability, the changes of oxidative stress related factors, apoptosis-related proteins, mitogen-activated protein kinase (MAPK) signaling pathway and neuronal morphology were detected to analyze the potential effect of naringin against SAH. The results demonstrated that naringin significantly ameliorated EBI, including SAH severity, neurologic deficits, brain edema and blood-brain barrier integrity by attenuating SAH induced oxidative stress and apoptosis, and reduced the oxidant damage and apoptosis by inhibiting the activation of MAPK signaling pathway, which suggested a therapeutic potential of naringin in providing neuroprotection after SAH. PMID- 28011193 TI - Monitoring Ca2+ elevations in individual astrocytes upon local release of amyloid beta in acute brain slices. AB - The pathogenesis of Alzheimer's disease (AD) is thought to involve acute neurotoxic effects exerted by oligomeric forms of amyloid-beta 1-42 (Abeta). Application of Abeta oligomers in physiological concentrations have been shown to transiently elevate internal Ca2+ in cultured astroglia. While the cellular machinery involved has been extensively explored, to what degree this important signalling cascade occurs in organised brain tissue has remained unclear. Here we adapted two-photon excitation microscopy and calibrated time-resolved imaging (FLIM), coupled with patch-clamp electrophysiology, to monitor Ca2+ concentration ([Ca2+]) inside individual astrocytes and principal neurons in acute brain slices. Inside the slice tissue local micro-ejection of Abeta in sub-micromolar concentrations triggered prominent [Ca2+] elevations in an adjacent astrocyte translated as an approximately two-fold increase (averaged over ~5min) in basal [Ca2+]. This elevation did not spread to neighbouring cells and appeared comparable in amplitude with commonly documented spontaneous [Ca2+] rises in astroglia. Principal nerve cells (pyramidal neurons) also showed Ca2+ sensitivity, albeit to a lesser degree. These observations shed light on the extent and dynamics of the acute physiological effects of Abeta on brain cells in situ, in the context of AD. PMID- 28011195 TI - Protective role of klotho protein on epithelial cells upon co-culture with activated or senescent monocytes. AB - Monocytes ensure proper functioning and maintenance of epithelial cells, while good condition of monocytes is a key factor of these interactions. Although, it was shown that in some circumstances, a population of altered monocytes may appear, there is no data regarding their effect on epithelial cells. In this study, using direct co-culture model with LPS-activated and Dox-induced senescent THP-1 monocytes, we reported for the first time ROS-induced DNA damage, reduced metabolic activity, proliferation inhibition and cell cycle arrest followed by p16-, p21- and p27-mediated DNA damage response pathways activation, premature senescence and apoptosis induction in HeLa cells. Also, we show that klotho protein possessing anti-aging and anti-inflammatory characteristics reduced cytotoxic and genotoxic events by inhibition of insulin/IGF-IR and downregulation of TRF1 and TRF2 proteins. Therefore, klotho protein could be considered as a protective factor against changes caused by altered monocytes in epithelial cells. PMID- 28011194 TI - Convergence of eicosanoid and integrin biology: Role of Src in 12-LOX activation. AB - 12-Lipoxygenase (12-LOX) metabolizes arachidonic acid to 12(S) hydroxyeicosatetraenoic acid, or 12(S)-HETE, a proinflammatory bioactive lipid implicated in tumor angiogenesis, growth, and metastasis. The mechanisms underlying 12-LOX-mediated signaling in cancer progression are still ill-defined. In the present study we demonstrate that 12-LOX phosphorylation and subsequent enzymatic activity occurs after integrin beta4 stimulation and Src kinase recruitment to the integrin subunit. Inhibition of Src activity by PP2 or Src dominant-negative mutants reduced 12-LOX tyrosine phosphorylation and 12(S)-HETE production in response to integrin beta4 stimulation in A431 cells. The pertinent Src-targeted residues for 12-LOX activity were mapped to Y19 and Y614, where 12 LOX mutants Y19F and Y614F showed 70% less enzymatic activity. Furthermore, we have shown that the 12-LOX activity modulated by these residues impacts migration. To our knowledge, this is the first report that c-Src kinase activity is required for beta4-integrin-mediated phosphorylation of 12-LOX. PMID- 28011196 TI - Isolating subpopulations of human epidermal basal cells based on polyclonal serum against trypsin-resistant CSPG4 epitopes. AB - Chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed by human epidermal keratinocytes located at the tip of the dermal papilla where keratinocytes show characteristics of stem cells. However, since available antibodies to CSPG4 are directed against trypsin-sensitive epitopes we have been unable to study these keratinocytes isolated directly from skin samples by flow cytometry. By choosing epitopes of CSPG4 relatively close to the cell membrane we were able to generate a polyclonal antibody that successfully detects CSPG4 on keratinocytes after trypsinization. Although CSPG4-positive basal cells express higher levels of Itgbeta1 the colony-forming efficiency is slightly lower than CSPG4-negative basal cells. Sorting the directly isolated keratinocytes based on Itgbeta1 did not reveal differences in colony-forming efficiency between keratinocytes expressing high or low levels of Itgbeta1. However, after the first passage Itgbeta1 could be used to predict colony-forming efficiency whether the culture was established from CSPG4-positive or CSPG4-negative basal cell keratinocytes. Although we were unable to detect differences in the colony-forming assay, global gene expression profiling showed that CSPG4-positive basal cell keratinocytes are distinct from CSPG4-negative basal cell keratinocytes. Our study demonstrates that it is possible to generate antibodies against trypsin-resistant epitopes of CSPG4. Our study also documents a marked change in behaviour upon cell culturing and challenges the way we assess for stemness within the human epidermal basal layer. PMID- 28011197 TI - Septin 7 reduces nonmuscle myosin IIA activity in the SNAP23 complex and hinders GLUT4 storage vesicle docking and fusion. AB - Glomerular epithelial cells, podocytes, are insulin responsive and can develop insulin resistance. Here, we demonstrate that the small GTPase septin 7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA; encoded by MYH9), a component of the nonmuscle myosin IIA (NM-IIA) hexameric complex. We observed that knockdown of NMHC-IIA decreases insulin-stimulated glucose uptake into podocytes. Both septin 7 and NM-IIA associate with SNAP23, a SNARE protein involved in GLUT4 storage vesicle (GSV) docking and fusion with the plasma membrane. We observed that insulin decreases the level of septin 7 and increases the activity of NM-IIA in the SNAP23 complex, as visualized by increased phosphorylation of myosin regulatory light chain. Also knockdown of septin 7 increases the activity of NM-IIA in the complex. The activity of NM-IIA is increased in diabetic rat glomeruli and cultured human podocytes exposed to macroalbuminuric sera from patients with type 1 diabetes. Collectively, the data suggest that the activity of NM-IIA in the SNAP23 complex plays a key role in insulin-stimulated glucose uptake into podocytes. Furthermore, we observed that septin 7 reduces the activity of NM-IIA in the SNAP23 complex and thereby hinders GSV docking and fusion with the plasma membrane. PMID- 28011198 TI - Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts. AB - Our previous studies of Antxr1 knockout mice suggested that fibrotic skin abnormalities in these mice are associated with increased VEGF signaling. Here, based on studies of primary fibroblasts isolated from skin of Antx1+/+ and Antxr1 /- mice at embryonic stage E17.5 and postnatal day P49, we conclude that increased Col1a1 and Fn1 expression in Antxr1-deficient fibroblasts is partly mediated by a cell-autonomous ANTXR1-dependent mechanism. In turn, this may act in parallel with VEGF-dependent regulation of collagen type I and fibronectin production. We demonstrate that shRNA mediated knockdown of VEGF in Antxr1-/- fibroblasts reduces Col1a1 and Fn1 expression to below control levels, and these are restored by exogenous addition of recombinant VEGF. In addition, the increase in protein levels of collagen type I and fibronectin in mutant cells is blocked by VEGF neutralizing antibody. However, expressing the longest isoform of ANTXR1 (sv1) in mutant fibroblasts decreases levels of Ctgf, Col1a1 and Fn1 transcripts, but has no effect on VEGF expression. Taken together, our data suggest that the increased matrix production in Antxr1- deficient fibroblasts primarily occurs via a CTGF-dependent pathway and that other ANTXR1-associated mechanisms contribute to VEGF-dependent increase of collagen type I and fibronectin expression. Our findings provide a basis for further studies of novel ANTXR1-dependent connective tissue homeostatic control mechanisms in healthy individuals, patients with organ fibrosis, and patients with GAPO syndrome. PMID- 28011199 TI - Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products. AB - A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD). PMID- 28011200 TI - Synthesis, X-ray molecular structure, biological evaluation and molecular docking studies of some N4-benzyl substituted 5-nitroisatin-3-thiosemicarbazones. AB - A series of fifteen N4-benzyl substituted 5-nitroisatin-3-thiosemicarbazones 5a-o was synthesized and evaluated for urease inhibitory, phytotoxic and cytotoxic influences. All the compounds proved to be highly potent inhibitors of the enzyme, showing inhibitory activity (IC50=0.87+/-0.25-8.09+/-0.23MUM) much better than the reference inhibitor, thiourea (IC50=22.3+/-1.12MUM) and may thus act as persuasive leads for further studies. In phytotoxicity assay, twelve out of fifteen thiosemicarbazones tested i.e. 5a-e, 5g, 5i and 5k-o appeared to be active, exhibiting weak or non-significant (5-35%) growth inhibition at the highest tested concentrations (1000 or 500MUg/mL). In contrast, only one compound i.e. 5i was active in the brine shrimp (Artemia salina) lethality bioassay, demonstrating cytotoxic activity with LD50 value 2.55*10-5M. Molecular docking studies of compounds 5a-o were also performed to identify their probable binding modes in the active site of the enzyme. PMID- 28011201 TI - Design, synthesis, in vitro characterization and preliminary imaging studies on fluorinated bile acid derivatives as PET tracers to study hepatic transporters. AB - With the aim of identifying a fluorinated bile acid derivative that could be used as [18F]-labeled Positron Emission Tomography (PET) tracer for imaging the in vivo functioning of liver transporter proteins, and particularly of OATP1B1, three fluorinated bile acid triazole derivatives of cholic, deoxycholic and lithocholic acid (CATD, DCATD and LCATD 4a-c, respectively) were synthesized and labeled with tritium. In vitro transport properties were studied with cell-based assays to identify the best substrate for OATP1B1. In addition, the lead compound, LCATD (4c), was tested as a substrate of other liver uptake transporters OATP1B3, NTCP and efflux transporter BSEP to evaluate its specificity of liver transport. The results suggest that 4c is a good substrate of OATP1B1 and NTCP, whereas it is a poor substrate of OATP1B3. The efflux transporter BSEP also appears to be involved in the excretion of 4c from hepatocytes. The automated radiosynthesis of [18F]-4c was accomplished in a multi GBq scale and a pilot imaging experiment in a wild type rat was performed after i.v. administration to assess the biodistribution and clearance of the tracer. PET imaging revealed that radioactivity was primarily located in the liver (tmax=75s) and cleared exclusively through the bile, thus allowing to image the hepatobiliary excretion of bile acids in the animal model. These findings suggest that [18F]-LCATD 4c is a promising PET probe for the evaluation of hepatic transporters OATP1B1, NTCP and BSEP activity with potential for studying drug drug interactions and drug-induced toxicity involving these transporters. PMID- 28011202 TI - Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective c-Met inhibitors. AB - Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC50]=1.1nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC50 values of 0.08, 0.22 and 0.07MUM, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H imidazole-4-carboxamido as a linker was of great importance for the antitumor activity. PMID- 28011203 TI - Small molecule mimics of DFTamP1, a database designed anti-Staphylococcal peptide. AB - Antimicrobial peptides (AMPs) are important templates for developing new antimicrobial agents. Previously, we developed a database filtering technology that enabled us to design a potent anti-Staphylococcal peptide DFTamP1. Using this same design approach, we now report the discovery of a new class of bis indole diimidazolines as AMP small molecule mimics. The best compound killed multiple S. aureus clinical strains in both planktonic and biofilm forms. The compound appeared to target bacterial membranes with antimicrobial activity and membrane permeation ability similar to daptomycin. PMID- 28011204 TI - Structure-guided development of covalent TAK1 inhibitors. AB - TAK1 (transforming growth factor-beta-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol. PMID- 28011205 TI - Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation. AB - Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans. PMID- 28011206 TI - Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease. AB - A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50=4.91MUM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self induced Abeta1-42 aggregation and Cu2+-induced Abeta1-42 aggregation by 89.5% and 79.7% at 25MUM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50=0.29MUM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease. PMID- 28011207 TI - Quantifying Barriers to Improvement of Treatment Satisfaction in Men With Erectile Dysfunction: Use of Person-Item Maps. AB - INTRODUCTION: Patient-reported outcomes are a valuable tool used to gauge treatment satisfaction in different conditions, including erectile dysfunction (ED). AIM: To use person-item maps to quantify barriers to improvement of treatment satisfaction in men with ED. METHODS: Men 18 to 65 years old with documented ED received sildenafil 50 mg, sildenafil 100 mg, or placebo for 8 weeks in a double-blinded manner. Post hoc analyses were conducted on Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) data (11 items rating treatment satisfaction; each item score range = 0-4). MAIN OUTCOME MEASURES: Person-item maps were developed based on Rasch models. To quantify barriers to improvement of treatment satisfaction, responses to the 11 items of the EDITS questionnaire were dichotomized to indicate improvement (responses of 3 or 4 were combined to a score of 1) vs no change or worsening (responses of 0, 1, or 2 were combined to a score of 0). RESULTS: Analyses were conducted using data from 278 men who completed the EDITS questionnaire at the end of double-blinded treatment. The person-item map indicated that EDITS item 4 (ease of use of treatment) was the easiest barrier to overcome, whereas the most difficult barrier to improvement of treatment satisfaction was EDITS item 2 (degree to which treatment met expectations). Most men in the sildenafil 100-mg group endorsed most EDITS items, consistent with substantial improvement. The sildenafil 50-mg group was similar, but with smaller frequencies for endorsing improvement of the more difficult EDITS items. In contrast, men receiving placebo endorsed mainly the easiest EDITS items, with only a small number of men endorsing the difficult items. CONCLUSION: A person-item map is a useful means for quantifying barriers to improvement of treatment satisfaction represented by EDITS items in patients with ED. PMID- 28011208 TI - Profiles of Cyberpornography Use and Sexual Well-Being in Adults. AB - INTRODUCTION: Although findings concerning sexual outcomes associated with cyberpornography use are mixed, viewing explicit sexual content online is becoming a common activity for an increasing number of individuals. AIM: To investigate heterogeneity in cyberpornography-related sexual outcomes by examining a theoretically and clinically based model suggesting that individuals who spend time viewing online pornography form three distinct profiles (recreational, at-risk, and compulsive) and to examine whether these profiles were associated with sexual well-being, sex, and interpersonal context of pornography use. METHODS: The present cluster-analytic study was conducted using a convenience sample of 830 adults who completed online self-reported measurements of cyberpornography use and sexual well-being, which included sexual satisfaction, compulsivity, avoidance, and dysfunction. MAIN OUTCOMES MEASURES: Dimensions of cyberpornography use were assessed using the Cyber Pornography Use Inventory. Sexual well-being measurements included the Global Measure of Sexual Satisfaction, the Sexual Compulsivity Scale, the Sexual Avoidance Subscale, and the Arizona Sexual Experiences Scale. RESULTS: Cluster analyses indicated three distinct profiles: recreational (75.5%), highly distressed non-compulsive (12.7%), and compulsive (11.8%). Recreational users reported higher sexual satisfaction and lower sexual compulsivity, avoidance, and dysfunction, whereas users with a compulsive profile presented lower sexual satisfaction and dysfunction and higher sexual compulsivity and avoidance. Highly distressed less active users were sexually less satisfied and reported less sexual compulsivity and more sexual dysfunction and avoidance. A larger proportion of women and of dyadic users was found among recreational users, whereas solitary users were more likely to be in the highly distressed less active profile and men were more likely to be in the compulsive profile. CONCLUSION: This pattern of results confirms the existence of recreational and compulsive profiles but also demonstrates the existence of an important subgroup of not particularly active, yet highly distressed consumers. Cyberpornography users represent a heterogeneous population, in which each subgroup is associated with specific sexual outcomes. PMID- 28011209 TI - Validation of Clinical Tools for Vaginal and Vulvar Symptom Assessment in Cancer Patients and Survivors. AB - INTRODUCTION: Health care professionals can play a pivotal role in promoting vulvovaginal health through assessment and appropriate intervention. AIM: To develop and validate brief clinical measurements to facilitate the identification of vulvovaginal symptoms in patients with and survivors of cancer. METHODS: One hundred seventy-five women survivors of cancer attending a Female Sexual Medicine and Women's Health Program from September 26, 2012 through October 31, 2014 completed the Vaginal Assessment Scale (VAS) and the Vulvar Assessment Scale (VuAS)-a modified version of the VAS that targets vulvar symptoms. Pelvic examination results were recorded using a clinical examination checklist. MAIN OUTCOME MEASURES: Internal consistency of the two scales was assessed using Cronbach alpha, and the correlation between scales and other outcomes was reported. RESULTS: The internal consistency measurements of the VAS and VuAS at the first visit were 0.70 and 0.68, which decreased to 0.53 and 0.66 at the last visit. The VAS composite and VuAS composite scores were moderately correlated with each other (0.42 and 0.45 at first and last visits, respectively). A strong correlation was observed between VAS pain with intercourse and Female Sexual Function Index (FSFI) pain with intercourse (-0.63 and -0.71 at the first and last visits, respectively). Worse pain with examination, worse functioning on the FSFI pain, lubrication, and total scores, and worse vulvar irritation were correlated with more severe symptoms on the VAS and VuAS. CONCLUSION: The VAS and VuAS are simple tools that can be used by clinicians to assess health concerns in women diagnosed with and treated for cancer. Validation is needed across diverse settings and groups of women. PMID- 28011210 TI - Synergistic antibacterial effect of Bi2S3 nanospheres combined with ineffective antibiotic gentamicin against methicillin-resistant Staphylococcus aureus. AB - In this paper, Bi2S3 nanospheres with size of 212nm were prepared by a simple hydrothermal process. The selectively enhanced antibacterial effects of Bi2S3 nanospheres with three classes of ineffective antibiotics, beta-lactam (cefuroxime, CXM; cefotaxime, CTX and piperacillin, PIP), quinolone (ciprofloxacin, CIP) and aminoglycoside (gentamicin, GEN) against clinical isolated methicillin-resistant Staphylococcus aureus (MRSA) were investigated for the first time. GEN shows significantly synergistic growth inhibition against MRSA when combined with Bi2S3 nanospheres, while CXM, CTX, PIP and CIP do not. Raman spectroscopy and Z potential studies reveal that Bi2S3 could interact with GEN and the combination showed small electronegativity, which probably induced the increase of GEN content in cytoplasm of bacteria. Furthermore, the combination of Bi2S3 nanospheres and GEN can destroy the bacterial membrane function and induce more bactericidal reactive oxygen generation than that of Bi2S3 or GEN alone. The cytotoxicity test indicates that the combination of Bi2S3 and GEN presented low toxicity to human normal hepatocyte L02. This work shows that Bi2S3 nanospheres can be used to enhance the action of ineffective antibiotic GEN against MRSA, thus strengthening the antibiotic capacity for fighting MRSA infections. PMID- 28011211 TI - 2-Guanidino-quinazolines as a novel class of translation inhibitors. AB - A variety of structurally unrelated organic compounds has been reported to have antibacterial activity. Among these, certain small-molecule translation inhibitors have attracted a great deal of attention, due to their relatively high selectivity against prokaryotes, and an appropriate therapeutic index with minor "off target" effects. However, ribosomes are being considered as poorly druggable biological targets, thereby making some routine computational-based approaches to rational drug design and its development rather ineffective. Taking this into account, diversity-oriented biological screening can reasonably be considered as the most advantageous strategy. Thus, using a high-throughput screening (HTS) platform, we applied a unique biological assay for in vitro evaluation of thousands of organic molecules, especially targeted against bacterial ribosomes and translation. As a result, we have identified a series of structurally diverse small-molecule compounds that induce a reporter strain sensitive to translation and DNA biosynthesis inhibitors. In a cell free system, several molecules were found to strongly inhibit protein biosynthesis. Among them, compounds bearing a 2 guanidino-quinazoline core demonstrated the most promising antibacterial activity. With regard to the preliminary structure-activity relationship (SAR) study, we revealed that relatively small substituents at positions 4, 6 and 8 of the quinazoline ring significantly enhance the target activity whereas modification of the guanidine group leads to decrease or loss of antibacterial potency. This novel class of translation inhibitors can properly be regarded as a promising starting point for the development of novel antibacterial therapeutic or screening tools. PMID- 28011212 TI - PPARbeta in macrophages and atherosclerosis. AB - Macrophages are central cells in the genesis and development of atherosclerosis, one of the major causes of cardiovascular diseases. Macrophages take up lipids (mainly cholesterol and triglycerides) from lipoproteins thus transforming into foam cells. Moreover, through the efflux pathway, macrophages are the main actors of the elimination of excessive tissue cholesterol toward extra-cellular acceptors. Macrophages participate in the control of inflammation by displaying different functional phenotypes, from the M1 pro-inflammatory to the M2 anti inflammatory state. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta (also called PPARdelta or PPARbeta/delta) is expressed in macrophages where it plays a different role in the control of lipid metabolism, inflammation and phagocytosis of apoptotic cells. This review will summarize our current understanding of how PPARbeta regulates macrophage biology and its impact on atherosclerosis. Differences between studies and species-specific macrophage gene regulation will be discussed. PMID- 28011213 TI - Design, synthesis, biological evaluation, and molecular docking of chalcone derivatives as anti-inflammatory agents. AB - In this study, two series of 35 new chalcone derivatives containing aryl piperazine or aryl-sulfonyl-piperazine fragment were synthesized and their structures were characterized by 1H, 13C and ESI-MS. The in vivo and in vitro anti-inflammatory activities of target compounds were evaluated by using classical para-xylene-induced mice ear-swelling model and ELISA assays. Furthermore, docking studies were performed in COX-2 (4PH9). The in vivo anti inflammatory assays indicated that most of the target compounds showed significant anti-inflammatory activities. Docking results revealed that the anti inflammatory activities of compounds correlated with their docking results. Especially, compound 6o exhibited the most potent anti-inflammatory activity in vivo with the lowest docking score of -17.4kcal/mol and could significantly inhibit the release of LPS-induced IL-6 and TNF-alpha in a dose-dependent manner in vitro. PMID- 28011214 TI - 1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents. AB - A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ~6-10MUM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10MUM) that was supported by the docking studies (PLP score 87-94) in silico. PMID- 28011216 TI - Amine promiscuity and toxicology analysis. AB - Drug discovery programs often face challenges to obtain sufficient duration of action of the drug (i.e. seek longer half-lives). If the pharmacodynamic response is driven by free plasma concentration of the drug then extending the plasma drug concentration is a valid approach. Half-life is dependent on the volume of distribution, which in turn can be dependent upon the ionization state of the molecule. Basic compounds tend to have a higher volume of distribution leading to longer half-lives. However, it has been shown that bases may also have higher promiscuity. In this work, we describe an analysis of in vitro pharmacological profiling and toxicology data investigating the role of primary, secondary, and tertiary amines in imparting promiscuity and thus off-target toxicity. Primary amines are found to be less promiscuous in in vitro assays and have improved profiles in in vivo toxicology studies compared to secondary and tertiary amines. PMID- 28011215 TI - Triterpene saponins and megastigmane glucosides from Camellia bugiamapensis. AB - Two new triterpene saponins, camelliosides I and J (1 and 2), two new megastigmane glycosides, camellistigosides A and B (3 and 4), and two known megastigmane glycosides, icariside B1 (5) and (6S,9R)-roseoside (6), were isolated from a methanol extract of the Camellia bugiamapensis leaves using various chromatographic separation techniques. Their structures were elucidated based on spectroscopic analyses, including HR ESI MS, CD, 1D and 2D NMR. Their inhibitory effects on LPS-induced NO production in RAW264.7 cells were evaluated. This is the first report of the chemical constituents and biological activity of C. bugiamapensis. PMID- 28011217 TI - Synthesis and biological evaluation of novel hydroxybenzaldehyde-based kojic acid analogues as inhibitors of mushroom tyrosinase. AB - Two series of novel kojic acid analogues (4a-j) and (5a-d) were designed and synthesized, and their mushroom tyrosinase inhibitory activities was evaluated. The result indicated that all the synthesized derivatives exhibited excellent tyrosinase inhibitory properties having IC50 values in the range of 1.35+/-2.15 17.50+/-2.75MUM, whereas standard inhibitor kojic acid have IC50 values 20.00+/ 1.08MUM. Specifically, 5-phenyl-3-[5-hydroxy-4-pyrone-2-yl-methylmercap-to]-4 (2,4-dihydroxyl-benzylamino)-1,2,4-triazole (4f) exhibited the most potent tyrosinase inhibitory activity with IC50 value of 1.35+/-2.15MUM. The kinetic studies of the compound (4f) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed. PMID- 28011218 TI - Recent advances on the encoding and selection methods of DNA-encoded chemical library. AB - DNA-encoded chemical library (DEL) has emerged as a powerful and versatile tool for ligand discovery in chemical biology research and in drug discovery. Encoding and selection methods are two of the most important technological aspects of DEL that can dictate the performance and utilities of DELs. In this digest, we have summarized recent advances on the encoding and selection strategies of DEL and also discussed the latest developments on DNA-encoded dynamic library, a new frontier in DEL research. PMID- 28011219 TI - In silico selection and cell-based characterization of selective and bioactive compounds for androgen-dependent prostate cancer cell. AB - Prostate cancer is one of the most prevalent types of cancer in male population. It is a hormone driven disease, especially in its initial phase. Hence, androgen deprivation therapy (ADT) is the major chemotherapeutic effort and novel AR inhibitors with improved pharmacological profiles are needed. In this report, a novel bioactive compound was selected and investigated using in silico and cell based assays. Neq0502 compound was selective for the testosterone stimulated AR dependent prostate cancer cell (LNCaP, GI50=22.4MUM) when compared with unstimulated LNCaP or AR-insensitive (DU145 and PC-3) cell lines. Cell cycle arrest study provided the same profile for Neq0502 and the reference drug enzalutamide. Moreover, this compound is not cytotoxic for fibroblast Balb/C 3T3 clone A31 cells up to 250MUM, with a good selectivity ratio (SI>11), which could be used in compound optimization effort to a novel therapeutic alternative. PMID- 28011220 TI - Solvent free, catalyst free, microwave or grinding assisted synthesis of bis cyclic imide derivatives and their evaluation for anticancer activity. AB - Cyclic imides are well known to be very important antitumor agents such as mitonafide and amonafide etc. Based on this fact, we have synthesized two series of cyclic imide derivatives containing two cyclic imide moiety in their structures (bis-cyclic imides) and screened them for in vitro anticancer activity against five human cancer cell lines i.e. breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1) and liver (Hep G2). One series of bis-cyclic imide derivatives (3a-h) have been synthesized by condensation of acid anhydrides (1a b) with diamines (2a-d) and another series (9a-f, 10a-f, 11a-f and 12a-f) by condensation of various diamines (4a-f) with diacids (5-8) in good yields. Structures assigned to 3a-h, 9a-f, 10a-f, 11a-f and 12a-f were fully characterized by spectroscopic means and elemental analysis. On screening for in vitro anticancer activity, compounds 3a (breast T47D), 3d (breast T47D, liver Hep G2), 3e (breast T47D, liver Hep G2), 3h (colon HCT-15), 10f (liver Hep G2) and 11a (colon HCT-15, ovary PA-1) exhibited good anticancer activities with IC50 values range from 12.41+/-3.2 to 17.9+/-2.5MUM. PMID- 28011221 TI - Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus. AB - The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided. PMID- 28011223 TI - Identification of a diverse synthetic abietane diterpenoid library for anticancer activity. AB - A diverse natural-product-like synthetic abietane diterpenoid library contains about 56 compounds were obtained, and evaluated for their potential in vitro cytotoxic or antitumor activity against A549, PC-3 and SKOV-3 tumor cell lines by SRB assay. Treatment of A549 cells with the most potent compound ketone 19 showed induction of apoptosis, as revealed by JC-1 mitochondrial membrane potential staining, TUNNEL assay, western blotting analysis and flow cytometry assay. PMID- 28011224 TI - Reply by Authors. PMID- 28011222 TI - Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands. AB - Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands. PMID- 28011225 TI - Editorial Comment. PMID- 28011226 TI - Metabolic profiling of human endothelial cells during autophagy assessed in a biomimetic microfluidic device model. AB - AIMS: Autophagy is critical to endothelial function. We explored the effects of autophagy induced by serum deprivation on Human Umbilical Vascular Endothelial Cells (HUVEC) metabolome profile and its inhibition by the antimalarial drug chloroquine (CLQ) using a microfluidic biomimetic model. MAIN METHODS: The metabolites secreted by HUVEC into the circulating microfluidics were determined by liquid chromatography mass spectrometry (LC-MS) and further analyzed using Metaboanalyst 3.0 multivariate and pathway analysis tools. KEY FINDINGS: Principal component analysis showed the discrimination of metabolites between treated and control groups. The results also identified alterations in metabolites relevant to endothelial function such as arginine, glutamate and energy metabolism pathways. Interestingly, CLQ mostly reversed the changes induced by serum deprivation. SIGNIFICANCE: The knowledge of endothelial metabolic profile during autophagy may contribute to the identification of clinical biomarkers and potential therapeutic approaches based on the regulation of autophagy. PMID- 28011227 TI - Effects of MgSO4 and magnesium transporters on 6-hydroxydopamine-induced SH-SY5Y cells. AB - AIMS: The magnesium ion (Mg2+) fulfils several important functions for living organisms. We investigated whether there is a protective effect of MgSO4 on 6 OHDA-induced neurotoxicity in SH-SY5Y cells, and gained insight into the effects of cellular mRNA and protein expression of the magnesium transporters SLC41A1, NIPA1, MagT1 and CNNM2 on 6-OHDA-induced neurotoxicity. MAIN METHODS: The effect of MgSO4 on cell viability in 6-OHDA-treated SH-SY5Y cells was measured using a CCK-8 kit. The mRNA and protein expression of SLC41A1, NIPA1, MagT1, and CNNM2 were detected using reverse transcription-qPCR and Western blot. KEY FINDINGS: The results showed that SH-SY5Y cells treated with 25-50MUM 6-OHDA for 24h significantly decreased cell viability, while if pre-incubated with 0.125-1mM MgSO4 for 1h before adding 6-OHDA it partially prevented the cell damage. There was a significant decrease in cellular mRNA and protein expression of SLC41A1, NIPA1, MagT1 and CNNM2 in 6-OHDA treated SH-SY5Y cells, and MgSO4 can reverse its decline. SIGNIFICANCE: Our results suggest that MgSO4 may protect SH-SY5Y cells against 6-OHDA-induced cell injury and that gene expression of SLC41A1, NIPA1, MagT1, and CNNM2 might be involved in dopaminergic neurons. PMID- 28011228 TI - The virulence of Streptococcus pneumoniae partially depends on dprA. AB - Streptococcus pneumoniae is one of the most frequent opportunistic pathogens worldwide. DNA processing protein A (DprA) is an important factor involved in bacterial uptake and DNA integration into bacterial genome, but its role in S. pneumoniae virulence remains unclear. The aim of this study was to characterize the effects of the pneumococcal dprA gene on the pathogenesis of S. pneumoniae. To construct a dprA-deficient pneumococcal strain, the dprA gene of the S. pneumoniae strain D39 was inactivated. The virulence of this dprA-deficient strain, designated DeltaD39, was compared with that of the wild-type strain by evaluating their respective capabilities to adhere to human pulmonary epithelial cells (PEC-A549) and by analyzing their choline-binding protein expression levels. In addition, the expression profiles of genes associated with virulence and host survival assays were also conducted with the mutant and the wild-type strain. Our results indicate that the capability of DeltaD39 to adhere to the PEC A549 airway cells was significantly lower (p<0.01) compared with D39. Additionally, the 100-KD choline-binding protein was not detected in DeltaD39. The addition of competence-stimulating peptide (CSP) lead to a significantly reduction of psaA mRNA expression in the dprA-deficient mutant and an increased level of psaA transcripts in the wild-type strain (p<0.01). The median survival time of mice intraperitoneally infected with DeltaD39 was significantly higher (p<0.01) than that of mice infected with D39. The results of this study suggest that DprA has a significant effect on virulence characteristics of S. pneumoniae by influencing the expression of choline-binding protein and PsaA. PMID- 28011229 TI - Differential colony size, cell length, and cellular proteome of Escherichia coli isolated from urine vs. stone nidus of kidney stone patients. AB - BACKGROUND: Escherichia coli is associated with kidney stone disease, as a cause or an effect (secondary or recurrent urinary tract infection, UTI). Defining phenotypic or functional differences between E. coli inside stone nidus (ECS, associated with infection-induced stone) and outside the stone (i.e. from urine) (ECU, represented secondary infection) would be helpful to better understand bacterial involvement in this disease. METHODS: ECS and ECU were isolated from 100 stone formers and subjected to antimicrobial susceptibility test, ERIC-PCR genotyping, determination of biofilm formation, bacterial colony size on agar plate and cell length in broth, 2-DE, nanoLC-MS/MS, protein network analysis, and pyruvate dehydrogenase (PDH) activity assay. RESULTS: From 100 stone formers, 36 had positive bacterial culture, of which 5 pairs had identical antimicrobial susceptibility patterns and comparable ERIC-PCR genotypes. ECS had smaller colony size and longer cell length than ECU. 2-DE proteomic analysis revealed significantly differential levels of proteins involved in carbohydrate metabolism, stress response, and RNA/protein metabolism. Functional validation demonstrated lower PDH activity in ECS. CONCLUSIONS: All these differential phenotypic and cellular proteome findings might be adaptive response of E. coli from remote infection to survive within the stone matrix that subsequently caused recurrent UTI in kidney stone patients. PMID- 28011230 TI - SGLT-2 inhibitors: Their pleiotropic properties. AB - Type 2 diabetes mellitus has become a global pandemic. Nowadays, it is estimated that approximately 415 million people all over the world have diabetes. The sodium glucose co-transporters 2 inhibitors are a new class of glucose-lowering agents, which act through a novel mechanism by producing a decline in glucose re absorption in the kidney, thereby increasing glycosuria and decreasing serum glucose levels. Data suggest that apart from lowering HbA1c, they produce a small but significant weight loss and a small decrease in blood pressure. Also, they possess nephro-protective potential. These drugs are demonstrated to restore intra-glomerular pressure by increasing angiotensin (1-7), which exerts vasodilatory and anti-inflammatory effects. Their profile on cardiovascular events is still under investigation. In this review, the pleiotropic potential of this novel class of glucose-lowering levels will be discussed. Further research is warranted to determine their safety in the long term. PMID- 28011231 TI - Metabolic syndrome and occupation: Any association? Prevalence among auto technicians and school teachers in South West Nigeria. AB - AIMS: To determine occupational association with metabolic syndrome among auto technicians and school teachers. METHODS: One hundred and sixty six subjects were selected for this study. Clinical data was obtained while laboratory investigations including plasma glucose and lipid profile were performed. Statistical analysis was done with SPSS 20.0. P<0.05 was taken as statistically significant. RESULTS: School teachers had significantly higher mean total cholesterol and LDL-cholesterol compared to auto technicians. Mean serum triglycerides was significantly higher among auto-technicians compared to school teachers in this study. The prevalence of some conventional cardiovascular risk factors was significantly higher among auto-technicians compared to school teachers: Impaired blood glucose (9.6% vs. 1.2%, p<0.05), hypertriglyceridaemia (18.1% vs. 7.2%, p<0.05) and low HDL-Cholesterol (47.0% vs. 37.3%, p<0.05) respectively. However elevated LDL-cholesterol (56.6% vs. 32.5%, p<0.05) was significantly more common among school teachers compared to auto-technicians. Based on the WHO and the Harmonized criteria, metabolic syndrome was more frequent among auto-technicians compared to school teachers. (8.4% vs. 1.2% and 19.3% vs. 7.2% respectively, p<0.05) CONCLUSION: The prevalence of metabolic syndrome appears to be significantly higher among auto technicians despite their high level of physical activity, exertion and education compared to teachers. This may be related to the increased occupational exposure to organic and inorganic materials from dust particles, oil and oil related matter and particulate matter among auto technicians. Prompt definitive evaluation of this concept and appropriate health education to encourage safety mechanism can reduce this burden of metabolic syndrome among auto technicians in Nigeria. PMID- 28011232 TI - Cardiac biomarkers in diabetes mellitus: New dawn for risk stratification? AB - Type 2 diabetes mellitus (T2DM) remains a leading cause of cardiovascular (CV) events and diseases worldwide. The aim of the review is to summarize our knowledge regarding clinical implementation of the biomarker-based strategy of the CV risk assessment in T2DM patient population. There is large body of evidence regarding use of the cardiac biomarkers to risk stratification at higher CV risk individuals who belongs to general population and cohort with established CV disease. Although T2DM patients have higher incidence of macrovascular and microvascular CV complications than the general population, whether cardiac biomarkers would be effective to risk stratification of the T2DM is not fully understood. The role of natriuretic peptides, galectin-3, interleukins, growth differentiation factor-15, as well as biomarkers of endothelial dysfunction are widely discussed. In conclusion, future directions, which associate with discovering of novel biomarkers and their best combinations to provide additional predictive information beyond other traditional CV risk factors, are discussed. PMID- 28011233 TI - Septic shock prediction for ICU patients via coupled HMM walking on sequential contrast patterns. AB - BACKGROUND AND OBJECTIVE: Critical care patient events like sepsis or septic shock in intensive care units (ICUs) are dangerous complications which can cause multiple organ failures and eventual death. Preventive prediction of such events will allow clinicians to stage effective interventions for averting these critical complications. METHODS: It is widely understood that physiological conditions of patients on variables such as blood pressure and heart rate are suggestive to gradual changes over a certain period of time, prior to the occurrence of a septic shock. This work investigates the performance of a novel machine learning approach for the early prediction of septic shock. The approach combines highly informative sequential patterns extracted from multiple physiological variables and captures the interactions among these patterns via coupled hidden Markov models (CHMM). In particular, the patterns are extracted from three non-invasive waveform measurements: the mean arterial pressure levels, the heart rates and respiratory rates of septic shock patients from a large clinical ICU dataset called MIMIC-II. EVALUATION AND RESULTS: For baseline estimations, SVM and HMM models on the continuous time series data for the given patients, using MAP (mean arterial pressure), HR (heart rate), and RR (respiratory rate) are employed. Single channel patterns based HMM (SCP-HMM) and multi-channel patterns based coupled HMM (MCP-HMM) are compared against baseline models using 5-fold cross validation accuracies over multiple rounds. Particularly, the results of MCP-HMM are statistically significant having a p value of 0.0014, in comparison to baseline models. Our experiments demonstrate a strong competitive accuracy in the prediction of septic shock, especially when the interactions between the multiple variables are coupled by the learning model. CONCLUSIONS: It can be concluded that the novelty of the approach, stems from the integration of sequence-based physiological pattern markers with the sequential CHMM model to learn dynamic physiological behavior, as well as from the coupling of such patterns to build powerful risk stratification models for septic shock patients. PMID- 28011234 TI - Epidemic arboviral diseases: priorities for research and public health. AB - For decades, arboviral diseases were considered to be only minor contributors to global mortality and disability. As a result, low priority was given to arbovirus research investment and related public health infrastructure. The past five decades, however, have seen an unprecedented emergence of epidemic arboviral diseases (notably dengue, chikungunya, yellow fever, and Zika virus disease) resulting from the triad of the modern world: urbanisation, globalisation, and international mobility. The public health emergency of Zika virus, and the threat of global spread of yellow fever, combined with the resurgence of dengue and chikungunya, constitute a wake-up call for governments, academia, funders, and WHO to strengthen programmes and enhance research in aedes-transmitted diseases. The common features of these diseases should stimulate similar research themes for diagnostics, vaccines, biological targets and immune responses, environmental determinants, and vector control measures. Combining interventions known to be effective against multiple arboviral diseases will offer the most cost-effective and sustainable strategy for disease reduction. New global alliances are needed to enable the combination of efforts and resources for more effective and timely solutions. PMID- 28011235 TI - Early Parturition: Is Young Maternal Age at First Birth Associated with Obesity? AB - STUDY OBJECTIVE: Examine the association of age at first birth with body mass index (BMI), and explore the role of young maternal age and subsequent obesity. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: This study analyzed data from the Panel Study of Income Dynamics, a nationally representative longitudinal study of US families. Analyses were conducted using a mixed effects longitudinal linear regression with a random intercept to examine the effect of aging, age at first birth, and minority status using nested data. Study criteria yielded a final sample of 146 women with 707 observations. MAIN OUTCOME MEASURES: BMI. RESULTS: Age at first birth exhibited a significant association with BMI. The association of age at first birth with BMI was greatest for women age 21 and younger. Overall, women who experienced their first birth at age 21 or younger had a BMI 5 units greater than women who delayed childbearing until at least age 30 (point estimate, 5.02; P = .02; 95% confidence interval, 0.65-9.40). CONCLUSION: Young maternal age at first birth might be associated with increased BMI. Minority women also experience their first birth at younger ages compared with white women, suggesting possible linkages between the timing of reproductive events and obesity disparities. PMID- 28011236 TI - MicroRNAs in thyroid development, function and tumorigenesis. AB - MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that modulate the vast majority of cellular processes. During development, the correct timing and expression of miRNAs in the tissue differentiation is essential for organogenesis and functionality. In thyroid gland, DICER and miRNAs are necessary for accurately establishing thyroid follicles and hormone synthesis. Moreover, DICER1 mutations and miRNA deregulation observed in human goiter influence thyroid tumorigenesis. The thyroid malignant transformation by MAPK oncogenes is accompanied by global miRNA changes, with a marked reduction of "tumor-suppressor" miRNAs and activation of oncogenic miRNAs. Loss of thyroid cell differentiation/function, and consequently iodine trapping impairment, is an important clinical characteristic of radioiodine-refractory thyroid cancer. However, few studies have addressed the direct role of miRNAs in thyroid gland physiology. Here, we focus on what we have learned in the thyroid follicular cell differentiation and function as revealed by cell and animal models and miRNA modulation in thyroid tumorigenesis. PMID- 28011237 TI - Estradiol regulates expression of miRNAs associated with myogenesis in rainbow trout. AB - 17beta-Estradiol (E2) is a steroid hormone that negatively affects muscle growth in rainbow trout, but the mechanism associated with this response is not fully understood. To better characterize the effects of E2 on muscle, we identified differentially regulated microRNAs (miRNAs) and muscle atrophy-related transcripts in juvenile rainbow trout exposed to E2. Small RNA-Seq analysis of E2 treated vs. control muscle identified 36 differentially expressed miRNAs including those known to be involved in myogenesis, cell cycle, apoptosis, and cell death. Some important myogenic miRNAs, such as miR-133 and miR-206, are upregulated while others like miR-145 and miR-499, are downregulated. Gene Ontology analysis of the target genes regulated by the miRNAs involved in atrophy and cell cycle indicates that E2 influence leads to expansion of quiescent myogenic precursor cell population to address atrophying mature muscle in rainbow trout during sexual development. PMID- 28011238 TI - Effect of light-dark cycles on hydrogen and poly-beta-hydroxybutyrate production by a photoheterotrophic culture and Rhodobacter capsulatus using a dark fermentation effluent as substrate. AB - A Rhodobacter capsulatus strain and a photoheterotrophic culture (IZT) were cultivated to produce hydrogen under different light-dark cycles. A dark fermentation effluent (DFE) was used as substrate. It was found that IZT culture had an average cumulative hydrogen production (Paccum H2) of 1300+/-43mLH2L-1 under continuous illumination and light-dark cycles of 30 or 60min. In contrast, R. capsulatus reduced its Paccum H2 by 20% under 30:30min light-dark cycles, but tripled its poly-beta-hydroxybutyrate (PHB) content (308+/-2mgPHB gdw-1) compared to continuous illumination. The highest PHB content by IZT culture was 178+/ 10mgPHB gdw-1 under 15:15min light-dark cycles. PCR-DGGE analysis revealed that the IZT culture was mainly composed of Rhodopseudomonas palustris identified with high nucleotide similarity (99%). The evaluated cultures might be used for hydrogen and PHB production. They might provide energy savings by using light dark cycles and DFE valorization. PMID- 28011239 TI - Catalytic conversion of corncob and corncob pretreatment hydrolysate to furfural in a biphasic system with addition of sodium chloride. AB - Catalytic conversion of corncob pretreatment hydrolysate and raw corncob into furfural in a modified biphasic system by SO42-/SnO2- MMT solid catalyst has been developed. The influence of the organic solvent type, organic to water phase ratio, sodium chloride concentration, reaction temperature and time on the furfural production were comparatively evaluated. The results showed that furfural yields of 81.7% and 66.1% were achieved at 190 degrees C for 15mins and 190 degrees C for 20mins, respectively, for corncob pretreatment hydrolysate and raw corncob by this solid catalyst. The solid catalyst used in this study exhibited good stability and high efficiency applied in the modified biphasic system in addition to excellent recyclability. The proposed catalytic system displayed high performance for catalytic conversion of lignocellulosic biomass into important platform chemicals and has great potential in industrial application. PMID- 28011240 TI - Physician training programs significantly improve diagnosis in cases coded as anaphylaxis over time: A major factor compounding time-trend data? PMID- 28011241 TI - Role of fruits, nuts, and vegetables in maintaining cognitive health. AB - Population aging is leading to an increase in the incidence of age-related cognitive dysfunction and, with it, the health care burden of caring for older adults. Epidemiological studies have shown that consumption of fruits, nuts, and vegetables is positively associated with cognitive ability; however, these foods, which contain a variety of neuroprotective phytochemicals, are widely under consumed. Surprisingly few studies have investigated the effects of individual plant foods on cognitive health but recent clinical trials have shown that dietary supplementation with individual foods, or switching to a diet rich in several of these foods, can improve cognitive ability. While additional research is needed, increasing fruit, nut, and vegetable intake may be an effective strategy to prevent or delay the onset of cognitive dysfunction during aging. PMID- 28011242 TI - More stents, more troubles. PMID- 28011243 TI - Comparison of paclitaxel drug-eluting balloon and paclitaxel-eluting stent in small coronary vessels in diabetic and nondiabetic patients - results from the BELLO (balloon elution and late loss optimization) trial. AB - OBJECTIVES: To evaluate the impact of diabetes on the efficacy of drug-eluting balloon (DEB) as compared to paclitaxel-eluting stent (PES) for the reduction of restenosis in small vessels according to the presence of diabetes in patients enrolled in the BELLO (Balloon Elution and Late Loss Optimization) trial. BACKGROUND: Small vessel disease is common in diabetic patients but currently there are no available data regarding DEB in these patients. METHODS: In the BELLO trial, 182 patients with lesions in small vessels were randomized 1:1 to receive DEB or PES. In the current sub analysis, patients were stratified according to the presence of diabetes. The diabetic group consisted of 74 patients (DEB=39, PES=35) and the nondiabetic group of 108 patients (DEB=51, PES=57). Angiographic endpoints examined were in-stent/in-balloon and in-segment late loss and binary restenosis at 6 months. Clinical endpoints were major adverse cardiac events (MACE; death, myocardial infarction, target vessel revascularization) at 1 year. RESULTS: In-stent/in-balloon late loss was significantly less with DEB as compared to PES in both diabetic (0.05+/-0.41 vs. 0.30+/-0.51mm, p=0.033) and nondiabetic patients (0.10+/-0.36 vs. 0.29+/-0.40mm, p=0.015). In patients with diabetes, angiographic restenosis and in-segment late loss were significantly lower with DEB as compared to PES (respectively, 6.3% vs. 25.0%; p=0.039 and -0.013+/-0.39 vs. 0.25+/-0.53; p=0.023), with no differences noted in nondiabetic patients. The cumulative MACE rate at 1 year was similar between DEB and PES in both the diabetic (13.2% vs. 25%, p=0.194) and nondiabetic groups (11.8% vs. 14.3%, p=0.699). CONCLUSIONS: Diabetes does not appear to have a negative impact on the efficacy of DEB in small vessels, which were associated with better angiographic outcomes at 6 months in this complex subgroup. Larger studies are needed to confirm these findings. PMID- 28011244 TI - Predicting readmission risk following percutaneous coronary intervention at the time of admission. AB - OBJECTIVE: To investigate whether a prediction model based on data available early in percutaneous coronary intervention (PCI) admission can predict the risk of readmission. BACKGROUND: Reducing readmissions following hospitalization is a national priority. Identifying patients at high risk for readmission after PCI early in a hospitalization would enable hospitals to enhance discharge planning. METHODS: We developed 3 different models to predict 30-day inpatient readmission to our institution for patients who underwent PCI between January 2010 and April 2013. These models used data available: 1) at admission, 2) at discharge 3) from CathPCI Registry data. We used logistic regression and assessed the discrimination of each model using the c-index. The models were validated with testing on a different patient cohort who underwent PCI between May 2013 and September 2015. RESULTS: Our cohort included 6717 PCI patients; 3739 in the derivation cohort and 2978 in the validation cohort. The discriminative ability of the admission model was good (C-index of 0.727). The c-indices for the discharge and cath PCI models were slightly better. (C-index of 0.751 and 0.752 respectively). Internal validation of the models showed a reasonable discriminative admission model with slight improvement with adding discharge and registry data (C-index of 0.720, 0.739 and 0.741 respectively). Similarly validation of the models on the validation cohort showed similar results (C-index of 0.703, 0.725 and 0.719 respectively). CONCLUSION: Simple models based on available demographic and clinical data may be sufficient to identify patients at highest risk of readmission following PCI early in their hospitalization. PMID- 28011245 TI - Comment on the article "Investigation of Fluorescence Resonance Energy Transfer between Fluorescein and Rhodamine 6G". AB - In this comment we, report the missing of relevant literature regarding Forster energy transfer (FRET) between fluorescein and rhodamine 6G in a recent paper (Spectrochim. Acta A, 149 (2015) 143-149). In this paper, the authors claim that "a new FRET pair" has been identified, which is absolutely incorrect. In fact, studies on FRET in this dye pair under different conditions have been done earlier. Further, the estimated critical transfer distance may have uncertainty because of donor quantum yield which is not clarified in the paper. PMID- 28011246 TI - Aids for eye drop administration. AB - One aspect to eye drop adherence is successful instillation of the drops; however, it is well known that many patients struggle with this task. Difficulties may include aiming their drops, extending their neck, preventing excess drop leakage, avoiding contamination of the bottle tip, and generating enough force to expel a drop from the bottle. Instillation aids are devices that aim to ameliorate one or more of these barriers. We review the literature on instillation aids to describe the options available to patients and to report evaluations of their efficacy. Most instillation aids studied improved objective or subjective outcomes of eye drop instillation, including improved rates of successful administration and increased patient satisfaction compared with standard eye-drop bottles. Although further research is warranted, instillation aids may be an underutilized resource for the many patients who struggle to administer their own eye drops. PMID- 28011247 TI - Health Status of Patients with Moderate to Severe COPD after Treatment with Nebulized Arformoterol Tartrate or Placebo for 1 Year. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is a progressive disease that impairs both objectively measured lung function and patient-reported health status. In a randomized clinical trial of patients with moderate to severe COPD, we compared changes in health status after adding arformoterol tartrate or placebo to patients' treatment regimens. METHODS: In this multicenter, double blind trial, patients were randomized to receive nebulized arformoterol 15 ug BID (n = 420) or matched placebo (n = 421). Treatment with other COPD medications was permitted, except for long-acting beta2-agonists. Inclusion criteria were a forced expiratory volume in 1 second (FEV1) <=65% of predicted, FEV1 >0.50 L, age >=40 years, smoking history >=15 pack-years, and a baseline breathlessness severity grade >=2. The Clinical COPD Questionnaire (CCQ) was used to measure health status at randomization and at months 3, 6, and 12. CCQ scores range from 0 to 6, with higher scores indicating worse health status, and a decrease from baseline in total score by 0.4 point is considered clinically significant. Outcomes were analyzed by using mixed models for repeated measures. FINDINGS: At baseline, patients' mean age was 63.8 years; 42.9% of patients were female, and 51.4% were current smokers. The mean baseline CCQ total scores were 2.88 and 2.91 for the arformoterol and placebo groups, respectively. A total of 841 patients were randomized to receive either arformoterol (n = 420) or placebo (n = 421); among them, 211 (50.1%) who received placebo and 255 (60.7%) who received arformoterol completed the trial. Arformoterol-treated patients had greater mean improvement from baseline in CCQ total score (-0.18 vs 0.02; P = 0.001), symptoms (-0.21 vs 0.01; P = 0.002), functional state (-0.15 vs 0.02; P = 0.018), and mental state (-0.18 vs 0.02; P = 0.023) than patients receiving placebo. At study end, 38.3% of the arformoterol-treated patients and 30.8% of patients receiving placebo reported clinically significant improvements on the CCQ (P = 0.026). These improvements were only modestly correlated with improvements in FEV1 (r = 0.15; P < 0.01). IMPLICATIONS: In this 52-week trial, arformoterol-treated patients had greater improvements in health status than patients receiving placebo. Assessing health status along with lung function seems to provide additional information regarding the effectiveness of COPD maintenance treatments. ClinicalTrials.gov identifier: NCT00909779. PMID- 28011248 TI - Different Disclosed Probabilities to Receive an Antiemetic Equally Decrease Subjective Symptoms in an Experimental Placebo Study: To Be or Not to Be Sure. AB - PURPOSE: The purpose of this study was to examine whether the disclosed probability of receiving an antiemetic affects nausea. METHODS: Forty-eight healthy participants (mean [SD] age, 26.8 [5.4] years; 50% female) were exposed to 5 * 2 minutes of nauseogenic body rotations on 2 days. On day 2, participants were randomized to 3 experimental groups that were given different instructions concerning the probability of receiving an antiemetic remedy (100%, 50%, or 0% probability), whereas all received an inert substance. Subjective symptoms, behavioral (rotation tolerance) measures, and physiologic (electrogastrogram) measures of nausea were assessed and mediator and moderator analyses performed for effects of expectations and psychological characteristics on outcomes. FINDINGS: Disclosed probabilities of both 100% and 50% significantly reduced subjective symptoms of nausea in an equal manner compared with the 0% probability group from day 1 to day 2. This effect was found for neither rotation tolerance nor myoelectric gastric activity. Expectations and psychological characteristics did not affect the results found. Post hoc analyses revealed that women only seem to be susceptible to this placebo effect. IMPLICATIONS: Nausea is susceptible to placebo effects independent of the disclosed probability of receiving a drug and of explicit expectations. In line with placebo research, this effect is probably attributable to central mechanisms, and it is speculated that it could be related to the reward circuitry and social interactions. PMID- 28011249 TI - Lack of effects of statins on high-density lipoprotein subfractions in HIV-1 infected patients receiving protease inhibitors. AB - BACKGROUND: We evaluated the effect of 45 days of rosuvastatin or pravastatin treatment on the distribution of HDL subfractions in HIV-1-infected individuals receiving boosted protease inhibitors (PIs) with cardiovascular risk. METHODS: The distribution of HDL subclasses by gradient gel electrophoresis was blindly assessed in 74 HIV-1-infected individuals receiving boosted PIs at baseline and at day 45 of statin treatment, and compared with the distribution obtained in 63 healthy normolipidemic individuals taken as controls. RESULTS: No significant modification appeared in HDL distribution between the two arms of statins for the HIV-1-infected individuals. Nevertheless, when compared to controls, HDL subfractions showed a significantly lower HDL2b proportion and significantly higher proportions of HDL2a and HDL3b (P<0.001). CONCLUSION: No difference was observed in HDL distribution between pravastatin and rosuvastatin after 45 days treatment, in HIV-1-infected individuals under PIs. Nevertheless, when compared to healthy normolipidemic subjects, HDL distribution is clearly different, with a distribution in HIV-infected individuals under PIs associated with an increased cardiovascular risk. PMID- 28011251 TI - Prospective motion correction in diffusion-weighted imaging using intermediate pseudo-trace-weighted images. AB - Subject head motion is a major challenge in diffusion-weighted imaging, which requires a precise alignment of images from different time points to allow a reliable quantification of diffusion parameters within each voxel. The technique requires long measurement times, making it highly sensitive to long-term subject motion, even when head restraint is used. Current methods of data analysis rely on retrospective motion correction, but there are potential benefits to using prospective motion correction, in which motion is tracked and compensated for during data acquisition. This technique is regularly used to enhance image quality in blood-oxygen-level dependent (BOLD) imaging, but its application to diffusion-weighted imaging has been limited by the contrast variation between images acquired with different diffusion-gradient directions. This paper describes a novel approach to this topic that exploits the rotational invariance of the trace of the diffusion tensor to reduce the effect of this contrast variation, making it possible to perform a fast image registration using a least squares cost function. This results in an image-based motion detection algorithm that can be applied in real time during data acquisition to adapt the slice position and orientation in response to subject motion. The motion detection capabilities of the technique were evaluated in a study of ten subjects with b values up to 3000s/mm2. The resulting motion-parameter estimates were in close agreement with reference values provided by interleaved low-b-value images with a correlation coefficient of R=0.9634 for the voxel displacements measured across all subjects and b-values. The technique was also used to perform prospective motion correction on a standard clinical MRI system with b-values up to 2000s/mm2. The correction was evaluated in 3 subjects using interleaved low-b value images, retrospective image registration using the AFNI processing package and mean diffusivity histogram analysis. Compared to acquisitions without motion correction, prospective motion correction based on pseudo-trace-weighted images was found to provide a robust method for substantially reducing the level of misregistration between volumes. In most cases, misregistrations were reduced to less than 0.2mm of translation and 0.2 degrees of rotation for an isotropic voxel size of 2mm, yielding high-quality diffusion parameter maps even in the absence of head restraint and post-acquisition image registration. PMID- 28011250 TI - Shared orthographic neuronal representations for spelling and reading. AB - A central question in the study of the neural basis of written language is whether reading and spelling utilize shared orthographic representations. While recent studies employing fMRI to test this question report that the left inferior frontal gyrus (IFG) and ventral occipitotemporal cortex (vOTC) are active during both spelling and reading in the same subjects (Purcell et al., 2011a; Rapp and Lipka, 2011), the spatial resolution of fMRI limits the interpretation of these findings. Specifically, it is unknown if the neurons which encode orthography for reading are also involved in spelling of the same words. Here we address this question by employing an event-related functional magnetic resonance imaging adaptation (fMRI-A) paradigm designed to examine shared orthographic representations across spelling and reading. First, we identified areas that independently showed adaptation to reading, and adaptation to spelling. Then we identified spatial convergence for these two separate maps via a conjunction analysis. Consistent with previous studies (Purcell et al., 2011a; Rapp and Lipka, 2011), this analysis revealed the left dorsal IFG, vOTC and supplementary motor area. To further validate these observations, we then interrogated these regions using an across-task adaptation technique, and found adaptation across reading and spelling in the left dorsal IFG (BA 44/9). Our final analysis focused specifically on the Visual Word Form Area (VWFA) in the vOTC, whose variability in location among subjects requires the use of subject-specific identification mechanisms (Glezer and Riesenhuber, 2013). Using a functional localizer for reading, we defined the VWFA in each subject, and found adaptation effects for both within the spelling and reading conditions, respectively, as well as across spelling and reading. Because none of these effects were observed during a phonological/semantic control condition, we conclude that the left dorsal IFG and VWFA are involved in accessing the same orthography-specific representations for spelling and reading. PMID- 28011252 TI - Construction and modeling of a reconfigurable MRI coil for lowering SAR in patients with deep brain stimulation implants. AB - Post-operative MRI of patients with deep brain simulation (DBS) implants is useful to assess complications and diagnose comorbidities, however more than one third of medical centers do not perform MRIs on this patient population due to stringent safety restrictions and liability risks. A new system of reconfigurable magnetic resonance imaging head coil composed of a rotatable linearly-polarized birdcage transmitter and a close-fitting 32-channel receive array is presented for low-SAR imaging of patients with DBS implants. The novel system works by generating a region with low electric field magnitude and steering it to coincide with the DBS lead trajectory. We demonstrate that the new coil system substantially reduces the SAR amplification around DBS electrodes compared to commercially available circularly polarized coils in a cohort of 9 patient derived realistic DBS lead trajectories. We also show that the optimal coil configuration can be reliably identified from the image artifact on B1+ field maps. Our preliminary results suggest that such a system may provide a viable solution for high-resolution imaging of DBS patients in the future. More data is needed to quantify safety limits and recommend imaging protocols before the novel coil system can be used on patients with DBS implants. PMID- 28011253 TI - A single-scan protocol for absolute D2/3 receptor quantification with [123I]IBZM SPECT. AB - PURPOSE: Molecular imaging of the D2/3 receptor is widely used in neuropsychiatric research. Non-displaceable binding potential (BPND) is a very popular quantitative index, defined as the product of the receptor concentration (Bavail) and the radiotracer affinity for the receptor (1/appKd). As the appKd is influenced by parameters such as the endogenous neurotransmitter dynamics, it often constitutes a confounding factor in research studies. A simplified method for absolute quantification of both these parameters would be of great interest in this context. Here, we describe the use of a partial saturation protocol that permits to produce an in vivo Scatchard plot and thus estimate Bavail and appKd separately, through a single dynamic SPECT session. To validate this approach, a multi-injection protocol is used for the full kinetic modeling of [123I]IBZM using a 3-tissue compartment, 7-parameter model (3T-7k). Finally, more "classic" BPND estimation methods are also validated against the results of the 3T-7k. METHODS: Twenty-nine male rats were used. Binding parameters were estimated using the 3T-7k in a multi-injection protocol. A partial saturation protocol was applied at the region- and voxel-level and results were compared to those obtained with the 3T-7k model. The partial saturation protocol was applied after an adenovirus-mediated D2 receptor striatal overexpression and in an amphetamine induced dopamine release paradigm. The Simplified Reference Tissue Model (SRTM), the Logan's non-invasive graphical analysis (LNIGA) and a simple standardized uptake ratio (SUR) method were equally applied. RESULTS: The partial saturation experiments gave similar values as the 3T-7k both at the regional and voxel level. After adenoviral-mediated D2-receptor overexpression, an increase in Bavail by approximately 18% was observed in the striatum. After amphetamine administration, a 16.93% decrease in Bavail (p<0.05) and a 39.12% increase (p<0.01) in appKd was observed. BPND derived from SRTM, LNIGA and SUR correlated well with the Bavail values from the 3T-7k (r=0.84, r=0.84 and r=0.83, respectively, p<0.0001 for all correlations). CONCLUSION: A partial saturation protocol permits the non-invasive and time-efficient estimation of Bavail and appKd separately. Given the different biological phenomena that underlie these parameters, this method may be applied for the in-depth study of the dopaminergic system in translational molecular imaging studies. It can detect the biological variations in these parameters, dissociating the variations in receptor density (Bavail) from affinity (1/appKd), which reflects the interactions of the receptor with its endogenous ligand. PMID- 28011255 TI - The gamma-parameter of anomalous diffusion quantified in human brain by MRI depends on local magnetic susceptibility differences. AB - Motivated by previous results obtained in vitro, we investigated the dependence of the anomalous diffusion (AD) MRI technique on local magnetic susceptibility differences (Deltachi) driven by magnetic field inhomogeneity in human brains. The AD-imaging contrast investigated here is quantified by the stretched exponential parameter gamma, extracted from diffusion weighted (DW) data collected by varying diffusion gradient strengths. We performed T2* and DW experiments in eight healthy subjects at 3.0T. T2*-weighted images at different TEs=(10,20,35,55)ms and DW-EPI images with fourteen b-values from 0 to 5000s/mm2 were acquired. AD-metrics and Diffusion Tensor Imaging (DTI) parameters were compared and correlated to R2* and to Deltachi values taken from literature for the gray (GM) and the white (WM) matter. Pearson's correlation test and Analysis of Variance with Bonferroni post-hoc test were used. Significant strong linear correlations were found between AD gamma-metrics and R2* in both GM and WM of the human brain, but not between DTI-metrics and R2*. Depending on Deltachi driven magnetic field inhomogeneity, the new contrast provided by AD-gamma imaging reflects Deltachi due to differences in myelin orientation and iron content within selected regions in the WM and GM, respectively. This feature of the AD gamma imaging due to the fact that gamma is quantified by using MRI, may be an alternative strategy to investigate, at high magnetic fields, microstructural changes in myelin, and alterations due to iron accumulation. Possible clinical applications might be in the field of neurodegenerative diseases. PMID- 28011254 TI - State-dependent modulation of functional connectivity in early blind individuals. AB - Resting-state functional connectivity (RSFC) studies have provided strong evidences that visual deprivation influences the brain's functional architecture. In particular, reduced RSFC coupling between occipital (visual) and temporal (auditory) regions has been reliably observed in early blind individuals (EB) at rest. In contrast, task-dependent activation studies have repeatedly demonstrated enhanced co-activation and connectivity of occipital and temporal regions during auditory processing in EB. To investigate this apparent discrepancy, the functional coupling between temporal and occipital networks at rest was directly compared to that of an auditory task in both EB and sighted controls (SC). Functional brain clusters shared across groups and cognitive states (rest and auditory task) were defined. In EBs, we observed higher occipito-temporal correlations in activity during the task than at rest. The reverse pattern was observed in SC. We also observed higher temporal variability of occipito-temporal RSFC in EB suggesting that occipital regions in this population may play the role of a multiple demand system. Our study reveals how the connectivity profile of sighted and early blind people is differentially influenced by their cognitive state, bridging the gap between previous task-dependent and RSFC studies. Our results also highlight how inferring group-differences in functional brain architecture solely based on resting-state acquisition has to be considered with caution. PMID- 28011256 TI - Erratum to "Undifferentiated round cell sarcoma with BCOR-CCNB3 translocation in the jaw of a child" [2016; Vol 122, No 5, Page e174]. PMID- 28011257 TI - Cellular subtype expression and activation of CaMKII regulate the fate of atherosclerotic plaque. AB - BACKGROUND AND AIMS: Atherosclerosis is a degenerative process of the arterial wall implicating activation of macrophages and proliferation of vascular smooth muscle cells. Calcium-calmodulin dependent kinase type II (CaMKII) in vascular smooth muscle cells (VSMCs) regulates proliferation, while in macrophages, this kinase governs diapedesis, infiltration and release of extracellular matrix enzymes. We aimed at understanding the possible role of CaMKII in atherosclerosis plaques to regulate plaque evolution towards stability or instability. METHODS: Clinically defined stable and unstable plaques obtained from patients undergoing carotid end arteriectomy were processed for evaluation of CaMKs protein expression, activity and localization. RESULTS: The larger content of CaMKII was found in CD14+myeloid cells that were more abundant in unstable rather than stable plaques. To test the biological effect of activated CD14+myeloid cells, VSMCs were exposed to the conditioned medium (CM) of macrophages extracted from carotid plaques. CM induced attenuation of CaMKs expression and activity in VSMCs, leading to the reduction of VSMCs proliferation. This appears to be due to the CaMKII dependent release of cytokines. CONCLUSIONS: These results indicate a pivotal role of CaMKs in atherosclerosis by regulating activated myeloid cells on VSMCs activity. CaMKII could represent a possible target for therapeutic strategies based on macrophages specific inhibition for the stabilization of arteriosclerotic lesions. PMID- 28011258 TI - Identification of kinases phosphorylating 13 sites in the nuclear, DNA-binding protein NUCKS. AB - NUCKS is a vertebrate specific, nuclear and DNA-binding phospho protein. The protein is highly expressed in rapidly dividing cells, and is overexpressed in a number of cancer tissues. The phosphorylation of NUCKS is cell cycle and DNA damage regulated, but little is known about the responsible kinases. By utilizing in vitro and in vivo phosphorylation assays using isolated NUCKS as well as synthetic NUCKS-derived peptides in combination with mass spectrometry, phosphopeptide mapping, phosphphoamino acid analyses, phosphospecific antibodies and the use of specific kinase inhibitors, we found that NUCKS is phosphorylated on 11 sites by CK2. At least 7 of the CK2 sites are phosphorylated in vivo. We also found that NUCKS is phosphorylated on two sites by ATM kinase and DNA-PK in vitro, and is phosphorylated in vivo by ATM kinase in gamma-irradiated cells. All together, we identified three kinases phosphorylating 13 out of 39 in vivo phosphorylated sites in mammalian NUCKS. The identification of CK2 and PIKK kinases as kinases phosphorylating NUCKS in vivo provide further evidence for the involvement of NUCKS in cell cycle control and DNA repair. PMID- 28011259 TI - Exploration of Luteinizing hormone in murrah buffalo (Bubalus bubalis) urine: Extended surge window opens door for estrus prediction. AB - Estrus detection in buffaloes has been a major concern for decades, and lack of reliable methods affects their effective reproductive management. Luteinizing hormone (LH) detection in urine is in practice for several mammals for timed insemination, whereas very few reports are available on buffalo urinary LH. The focus of this study is to detect the presence of LH in buffalo urine, quantitate variation in urinary LH during different estrous cycle phases and examine the duration of mid-cycle LH window. Nearly hundred buffaloes were examined, longitudinal urine samples (n=42) were collected from seventeen animals and classified into respective phases based on several estrus detection parameters. The urinary LH was detected using bovine LH ELISA kit validated for serum/plasma/tissue homogenate. Detection of buffalo LH in the neat urine convincingly proved the competence of the bovine LH kit. Variation in the LH range was observed between different phases of estrous cycle and significant fold variation (P<0.05) was noticed during estrus phase (1.01+/-0.23) with average baseline value of 46.73+/-3.36mIU/mL. Interestingly, an extended window (A1-A3) of mid-cycle LH surge was observed due to its lingering excretion in urine. The results, altogether, revealed that LH can be detected in buffalo urine with noticeable fold variation during estrus phase and the extended LH window intensifies the chance of ovulation prediction for timed insemination. PMID- 28011260 TI - Cost Comparison of Fundamentals of Laparoscopic Surgery Training Completed With Standard Fundamentals of Laparoscopic Surgery Equipment versus Low-Cost Equipment. AB - OBJECTIVE: Training for the Fundamentals of Laparoscopic Surgery (FLS) skills test can be expensive. Previous work demonstrated that training on an ergonomically different, low-cost platform does not affect FLS skills test outcomes. This study compares the average training cost with standard FLS equipment and medical-grade consumables versus training on a lower cost platform with non-medical-grade consumables. DESIGN: Subjects were prospectively randomized to either the standard FLS training platform (n = 19) with medical grade consumables (S-FLS), or the low-cost platform (n = 20) with training-grade products (LC-FLS). Both groups trained to proficiency using previously established mastery learning standards on the 5 FLS tasks. The fixed and consumable cost differences were compared. SETTING: Training occurred in a surgical simulation center. PARTICIPANTS: Laparoscopic novice medical student and resident physician health care professionals who had not completed the national FLS proficiency curriculum and who had performed less than 10 laparoscopic cases. RESULTS: The fixed cost of the platform was considerably higher in the S-FLS group (S-FLS, $3360; LC-FLS, $879), and the average consumable training cost was significantly higher for the S-FLS group (S-FLS, $1384.52; LC-FLS, $153.79; p < 0.001). The LC-FLS group had a statistically discernable cost reduction for each consumable (Gauze $9.24 vs. $0.39, p = 0.002; EndoLoop $540.00 vs. $40.60, p < 0.001; extracorporeal suture $216.45 vs. $25.20, p < 0.001; intracorporeal suture $618.83 vs. $87.60, p < 0.001). The annual fixed and consumable cost to train 5 residents is $10,282.60 in the S-FLS group versus $1647.95 in the LC-FLS group. CONCLUSIONS: This study shows that the average cost to train a single trainee to proficiency using a lower fixed-cost platform and non-medical-grade equipment results in significant financial savings. A 5-resident program will save approximately $8500 annually. Residency programs should consider adopting this strategy to reduce the cost of FLS training. PMID- 28011261 TI - Common Femoral Artery Access on YouTube: What Practices are Being Shown and Who is Delivering the Message? AB - OBJECTIVES: Novice learners are increasingly turning to YouTube as a learning resource for surgical procedures. One example of such a procedure is common femoral artery puncture and sheath placement. Practitioners in several specialties perform this procedure to access the arterial system for angiography and intervention. We set forth to compare the techniques demonstrated on YouTube by the various specialists, as well as compare each specialty's prevalence on this website. METHODS: YouTube (www.youtube.com) was accessed in December 2015 at multiple time points with a cleared-cache web browser for the keyword search categories: "femoral artery access," "femoral access," and "angiography access." The top 500 videos from each of these keyword searches were analyzed. Videos were categorized by practitioner specialty, technique, duration of video, age of video, and total views. Videos with clear demonstration of femoral artery access were included in the analysis. All industry videos were excluded from the analysis. Categorical variables were compared using Fisher's exact test, and continuous variables were compared with the Student's t-test. RESULTS: A total of 2460, 4680 and 1800 videos were found for each keyword search, respectively. Of these, 33 videos clearly demonstrated femoral artery access technique. Vascular specialists, compared to interventional cardiology and radiology, had fewer videos (n = 4 vs. 14) and older videos (3.5 +/- 2.1y vs. 2.25 +/- 0.5y, p < 0.05). The vascular specialists demonstrated ultrasound-guided access, while interventional cardiology predominantly demonstrated landmark-guided access (p < 0.05). CONCLUSIONS: Although YouTube and other online resources are being used by novice learners, vascular specialists are underrepresented for femoral artery access, a foundational vascular procedure. Other practitioners demonstrate videos with landmark-guided access and rarely demonstrate ultrasound use. As recognized vascular experts, vascular surgeons should improve their visibility in online learning resources. PMID- 28011262 TI - Training Tools for Nontechnical Skills for Surgeons-A Systematic Review. AB - OBJECTIVE: Development of nontechnical skills for surgeons has been recognized as an important factor in surgical care. Training tools for this specific domain are being created and validated to maximize the surgeon's nontechnical ability. This systematic review aims to outline, address, and recommend these training tools. DESIGN: A full and comprehensive literature search, using a systematic format, was performed on ScienceDirect and PubMed, with data extraction occurring in line with specified inclusion criteria. SETTING: Systematic review was performed fully at King's College London. RESULTS: A total of 84 heterogeneous articles were used in this review. Further, 23 training tools including scoring systems, training programs, and mixtures of the two for a range of specialities were identified in the literature. Most can be applied to surgery overall, although some tools target specific specialities (such as neurosurgery). Interrater reliability, construct, content, and face validation statuses were variable according to the specific tool in question. CONCLUSIONS: Study results pertaining to nontechnical skill training tools have thus far been universally positive, but further studies are required for those more recently developed and less extensively used tools. Recommendations can be made for individual training tools based on their level of validation and for their target audience. Based on the number of studies performed and their status of validity, NOTSS and Oxford NOTECHS II can be considered the gold standard for individual- and team-based nontechnical skills training, respectively, especially when used in conjunction with a training program. PMID- 28011264 TI - Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via beta2-adrenergic activation. AB - Regular exercise is shown to exert anti-inflammatory effects, yet the effects of acute exercise on cellular inflammatory responses and its mechanisms remain unclear. We tested the hypothesis that sympathoadrenergic activation during a single bout of exercise has a suppressive effect on monocytic cytokine production mediated by beta2 adrenergic receptors (AR). We investigated the effects of 20 min moderate (65-70% VO2 peak) exercise-induced catecholamine production on LPS stimulated TNF production by monocytes in 47 healthy volunteers and determined AR subtypes involved. We also examined the effects of beta-agonist isoproterenol and endogenous beta- and alpha-agonists epinephrine and norepinephrine, and receptor subtype-specific beta- and alpha-antagonists on TNF production in a series of in vitro investigations. LPS-stimulated TNF production by peripheral blood monocytes was determined intracellularly by flow cytometry, using an intracellular protein transport inhibitor. Percent TNF-producing monocytes and per-cell TNF production with and without LPS was suppressed by exercise with moderate to large effects, which was reversed by a beta2-AR antagonist in spite that plasma TNF levels did not change. This inhibitory response in TNF production by exercise was mirrored by beta-AR agonists in an agonist-specific and dose-dependent manner in vitro: similar isoproterenol (EC50=2.1-4.7*10-10M) and epinephrine (EC50=4.4-10*10-10M) potency and higher norepinephrine concentrations (EC50=2.6-4.3*10-8M) needed for the effects. Importantly, epinephrine levels observed during acute exercise in vivo significantly inhibited TNF production in vitro. The inhibitory effect of the AR agonists was abolished by beta2-, but not by beta1- or alpha-AR blockers. We conclude that the downregulation of monocytic TNF production during acute exercise is mediated by elevated epinephrine levels through beta2-ARs. Decreased inflammatory responses during acute exercise may protect against chronic conditions with low-grade inflammation. PMID- 28011265 TI - Involvement of Ly6C, 4-1BB, and KLRG1 in the activation of lamina propria lymphocytes in the small intestine of sanroque mice. AB - Roquin is an E3 ligase that regulates mRNA stability. Mice with a mutation in the Rc3h1 gene and Roquin protein, referred to as Roquinsan/san or sanroque mice, develop broad-spectrum chronic inflammatory conditions and autoimmune pathologies. Our laboratory recently reported that sanroque mice also develop extensive inflammation that is localized in the small intestine but is rare in the colon. Here, we demonstrate that small intestinal intraepithelial lymphocytes (IELs) are present in the epithelium of sanroque mice but that cell recoverability is low using standard extraction techniques even though lamina propria lymphocytes (LPLs) can be recovered in normal numbers. In studies aimed at characterizing T cell costimulatory markers and activation molecules on LPLs in sanroque mice, we identified Ly6C and 4-1BB (CD137) as being expressed at elevated levels on sanroque small intestinal LPLs, and we show that both of those subsets, in conjunction with cells expressing the KLRG1 T cell activation molecule, are sources of IL-17A, IFN-gamma, and TNFalpha. TNFalpha was primarily produced by 4-1BB+, KLRG1-cells, but was also made by some 4-1BB-, KLRG1-cells, and 4-1BB-, KLRG1+ cells. These findings collectively suggest that the small intestinal inflammatory response in sanroque mice is driven, at least in part, by LPL activation through Ly6C and 4-1BB signaling, and they provide further evidence in support of using the sanroque mouse as an animal model of chronic small intestinal inflammation. PMID- 28011263 TI - Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels. AB - A growing body of evidence indicates that prenatal alcohol exposure (PAE) may predispose individuals to secondary medical disabilities later in life. Animal models of PAE reveal neuroimmune sequelae such as elevated brain astrocyte and microglial activation with corresponding region-specific changes in immune signaling molecules such as cytokines and chemokines. The aim of this study was to evaluate the effects of moderate PAE on the development and maintenance of allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in adult male rat offspring. Because CCI allodynia requires the actions of glial cytokines, we analyzed lumbar spinal cord glial and immune cell surface markers indicative of their activation levels, as well as sciatic nerve and dorsal root ganglia (DRG) cytokines in PAE offspring in adulthood. While PAE did not alter basal sensory thresholds before or after sham manipulations, PAE significantly potentiated adult onset and maintenance of allodynia. Microscopic analysis revealed exaggerated astrocyte and microglial activation, while flow cytometry data demonstrated increased proportions of immune cells with cell surface major histocompatibility complex II (MHCII) and beta-integrin adhesion molecules, which are indicative of PAE-induced immune cell activation. Sciatic nerves from CCI rats revealed that PAE potentiated the proinflammatory cytokines interleukin (IL) 1beta, IL-6 and tumor necrosis factor-alpha (TNFalpha) protein levels with a simultaneous robust suppression of the anti-inflammatory cytokine, IL-10. A profound reduction in IL-10 expression in the DRG of PAE neuropathic rats was also observed. Taken together, our results provide novel insights into the vulnerability that PAE produces for adult-onset central nervous system (CNS) pathological conditions from peripheral nerve injury. PMID- 28011266 TI - Rebamipide induces the gastric mucosal protective factor, cyclooxygenase-2, via activation of 5'-AMP-activated protein kinase. AB - Rebamipide, an amino acid derivative of 2(1H)-quinolinone, has been used for mucosal protection, healing of gastroduodenal ulcers, and treatment of gastritis. Induction of cyclooxygenase (COX)-2, a gastric mucosal protective factor, by rebamipide has been suggested as the major mechanism of the drug action. However, how rebamipide induces COX-2 at the molecular level needs further investigation. In this study, the molecular mechanism underlying the induction of COX-2 by rebamipide was investigated. In gastric carcinoma cells and macrophage cells, rebamipide induced phosphorylation of AMP-activated protein kinase (AMPK), leading to phosphorylation of acetyl-CoA carboxylase (ACC), a substrate of AMPK. The induction of COX-2 by rebamipide was dependent on AMPK activation because compound C, an AMPK inhibitor, abolished COX-2 induction by rebamipide. In a mouse ulcer model, rebamipide protected against hydrochloric acid/ethanol-induced gastric ulcer, and these protective effects were deterred by co-administration of compound C. In parallel, in the gastric tissues, rebamipide increased the phosphorylation AMPK, whereas compound C reduced the levels of COX-2 and phosphorylated ACC, which were increased by rebamipide. Taken together, the activation of AMPK by rebamipide may be a molecular mechanism that contributes to induction of COX-2, probably resulting in protection against gastric ulcers. PMID- 28011267 TI - Methotrexate-induced germ cell toxicity and the important role of zinc and SOD1: Investigation of molecular mechanisms. AB - Zinc (Zn) was proved to be a germ cell protectant against various disease conditions and toxic insults. Besides other mechanisms, here we have explored the important role of Zn and Zn-dependent SOD1in methotrexate (MTX)-induced germ cell damage. MTX was given 5 mg/kg i.p. once a week for four consecutive weeks, while Zn was supplemented daily at the doses of 3 and 6 mg/kg i.p. for four consecutive weeks. After four weeks of treatment the animals were sacrificed and observed for various end points. There were several histopahtological alterations in the testes like desquamation and altered tubular structures. DNA damage was also increased by MTX as evident by TUNEL assay. Sperm head abnormalities were increased in case of MTX treated animals. Protein expressions of PCNA, BCl-2/Bax, SOD, catalase and GPX5 were found to be altered by the MTX treatment. To further investigate the role of Zn and Zn-dependent SOD1, rats were injected intratesticularly with diethyldithiocarbamate (DEDTC) for three days after MTX 20 mg/kg i.p. was given on the first day. DEDTC in combination with MTX was found to significantly decrease the protein expressions of SOD1, catalase, Nrf2 and GPX4, along with deranged histology. This study adds to the point that Zn might be a better germ cell protectant and deserve further investigation. PMID- 28011268 TI - NIP-SNAP-1 and -2 mitochondrial proteins are maintained by heat shock protein 60. AB - NIP-SNAP-1 and -2 are ubiquitous proteins thought to be associated with maintenance of mitochondrial function, neuronal transmission, and autophagy. However, their physiological functions remain largely unknown. To elucidate their functional importance, we screened for proteins that interact with NIP-SNAP-1 and -2, resulting in identification of HSP60 and P62/SQSTM1 as binding proteins. NIP SNAP-1 and -2 localized in the mitochondrial inner membrane space, whereas HSP60 localized in the matrix. Native gel electrophoresis and filter trap assays revealed that human HSP60 prevented aggregation of newly synthesized NIP-SNAP-2 in an in vitro translation system. Moreover, expression levels of NIP-SNAP-1 and 2 in cells were decreased by knockdown of HSP60, but not HSP10. These findings indicate that HSP60 promotes folding and maintains the stability of NIP-SNAP-1 and -2. PMID- 28011269 TI - Omega-3 fatty acid fish oil dietary supplements contain saturated fats and oxidized lipids that may interfere with their intended biological benefits. AB - Widely available fish oil dietary supplements (DS) may contain fats and oxidized lipids in addition to the beneficial omega-3 fatty acids (OM3FAs) for which they are purchased. Little is known about the potential biological effects of these oxidized lipids. The objective of this study was to assess the fatty acid content, oxidation products, and biological effects of leading fish oil DS available in the United States. Three top-selling fish oil DS in the US were included in this analysis. Fatty acid composition was measured using gas chromatography. Lipid oxidation (primary and secondary products) was measured by spectroscopy in both DS and a prescription OM3FA product. OM3FAs were also isolated and concentrated from DS and were tested for the ability to inhibit copper-induced oxidation of human small dense low-density lipoprotein particles (sdLDL) in vitro. Fish oil DS were found to contain more than 30 different fatty acids, including 10 to 14 different saturated species comprising up to 36% of the total fatty acid content. Levels of OM3FAs also varied widely among DS (33%-79%). Primary (peroxide), secondary (anisidine), and total oxidation products exceeded maximum levels established by international standards of quality in the DS but not the prescription OM3FA product. Oxidation of sdLDL was inhibited by >95% (P < 0.001) with non-oxidized forms of OM3FA but not with OM3FAs isolated from DS, which were a mixture of oxidized and non-oxidized OM3FAs. These data indicate that levels of saturated fat and oxidized OM3FAs found in common DS may interfere with their intended/potential biological benefits. PMID- 28011270 TI - H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4 mediated ROS generation during atrial fibrillation. AB - Our previous study demonstrated that angiotensin II (Ang II) upregulates the expression of Kv1.5, a promising target for atrial fibrillation (AF) therapy, by activating ROS-dependent P-Smad2/3 and P-ERK 1/2. A recent study showed that hydrogen sulfide (H2S) may modulate the effects of angiotensin II (Ang II) by inhibiting the NADPH oxidase 4 (Nox4)-ROS signaling in the heart. The present study aimed to determine whether H2S is involved in the regulation of atrial Kv1.5 via ROS-related mechanisms in AF. Cultured neonatal rat atrial myocytes and a beagle model of AF were used for this study. In the neonatal rat atrial myocytes, quantitative PCR and enzyme immunoassays revealed that the mRNA expression levels of angiotensinogen, angiotensin-converting enzyme, and Ang II type I receptor (AT1R) and the Ang II supernatant concentration were significantly increased by hydrogen peroxide (H2O2) incubation, and these H2O2 induced alterations were reversed by diphenyleneiodonium, apocynin and H2S supplementation. Flow cytometry and Western blotting revealed that blockade of H2S biosynthesis using dl-propargylglycine increased ROS production and the expression of Ang II and Kv1.5. Sodium hydrosulfide (an exogenous H2S donor) and Nox4 siRNA inhibited Ang II-induced ROS production and Ang II-induced expression of Kv1.5, P-Smad2/3, P-ERK 1/2. Sodium hydrosulfide suppressed the Ang II-induced upregulation of Nox4. In our beagle AF model, 24 h of rapid atrial pacing (RAP) increased the atrial Ang II concentration, ROS production and the protein expression of Nox4, Kv1.5, P-Smad2/3 and P-ERK 1/2. These RAP-induced changes were inhibited by H2S supplementation and losartan (an AT1R blocker) pretreatment. In conclusion, our study indicates that H2S downregulates Ang II induced atrial Kv1.5 expression by attenuating Nox4-related ROS-triggered P Smad2/3 and P-ERK 1/2 activation during AF. H2S supplementation would be beneficial for AF treatment via the suppression of atrial Kv1.5 expression. PMID- 28011271 TI - Structural mechanism underlying regulation of human EFhd2/Swiprosin-1 actin bundling activity by Ser183 phosphorylation. AB - EF-hand domain-containing protein D2/Swiprosin-1 (EFhd2) is an actin-binding protein mainly expressed in the central nervous and the immune systems of mammals. Intracellular events linked to EFhd2, such as membrane protrusion formation, cell adhesion, and BCR signaling, are triggered by the association of EFhd2 and F-actin. We previously reported that Ca2+ enhances the F-actin-bundling ability of EFhd2 through maintaining a rigid parallel EFhd2-homodimer structure. It was also reported that the F-actin-bundling ability of EFhd2 is regulated by a phosphorylation-dependent mechanism. EGF-induced phosphorylation at Ser183 of EFhd2 has been shown to inhibit F-actin-bundling, leading to irregular actin dynamics at the leading edges of cells. However, the underlying mechanism of this inhibition has remained elusive. Here, we report the crystal structure of a phospho-mimicking mutant (S183E) of the EFhd2 core domain, where the actin binding sites are located. Although the overall structure of the phospho mimicking mutant is similar to the one of the unphosphorylated form, we observed a conformational transition from ordered to disordered structure in the linker region at the C-terminus of the mutant. Based on our structural and biochemical analyses, we suggest that phosphorylation at Ser183 of EFhd2 causes changes in the local conformational dynamics and the surface charge distribution of the actin-binding site, resulting in a re-coordination of the actin-binding sites in the dimer structure and a reduction of F-actin-bundling activity without affecting the F-actin-binding capacity. PMID- 28011272 TI - Resolution of Hydronephrosis in a Patient With Mucopolysaccharidosis Type II With Enzyme Replacement Therapy. AB - Mucopolysaccharidosis type II (MPS II) is caused by deficiency of lysosomal enzyme iduronate-2-sulfatase. Insufficient activity of the enzyme results in accumulation of glycosaminoglycans leading to progressive multisystem pathologies. MPS II is less likely to be complicated by kidney and urinary tract problems. We report a boy with MPS II, who developed left hydronephrosis. His hydronephrosis improved after starting enzyme replacement therapy. It was suggested that MPS II was closely associated with the pathogenesis of hydronephrosis. PMID- 28011273 TI - Obstructive Nephropathy Without Hydronephrosis: Suspicion Is the Key. AB - Urinary tract obstruction leading to acute kidney injury is usually associated with bilateral hydroureters and hydronephrosis, often accompanied by oliguria. We present an atypical case of obstructive uropathy without these features that presented with severe acute kidney injury. A 64-year-old male with no known medical history has presented with a 2-week history of nausea, decreased appetite, flank pain, and lower extremity edema, and was found to have an elevated creatinine of 10.5 mg/dL. Renal ultrasound showed mild prominence of the bilateral renal collecting systems with no evidence of hydronephrosis. Computed tomography scan showed findings suggestive of retroperitoneal fibrosis involving ureteral region and bilateral ureteral stent placement has led to dramatic improvement of creatinine to 1.3 mg/dL over the next 4 days. PMID- 28011274 TI - Reply by the Authors. PMID- 28011275 TI - Perioperative Transfusion of Leukocyte-depleted Blood Products in Contemporary Radical Cystectomy Cohort Does Not Adversely Impact Short-term Survival. AB - OBJECTIVE: To evaluate the effect of leukoreduced-only perioperative blood transfusion (PBT) and corresponding survival outcomes in a radical cystectomy cohort of patients. MATERIALS AND METHODS: We analyzed data from 1026 patients who underwent radical cystectomy at our institution. PBT was defined as transfusion in the intraoperative or within the postoperative hospitalization period. Multivariable analyses using Cox proportional hazards were performed to measure the association between PBT, patient variables, and 3 primary end points: recurrence-free survival, disease-specific survival, and overall survival. Kaplan Meier curves estimated survival times and were compared with log-rank test. RESULTS: Overall, of a total of 1026 patients, 341 (33.2%) received leukoreduced PBT. The median follow-up was 27.5 months. Transfused patients were more likely to be female, had higher estimated blood loss, lower preoperative hemoglobin, were more likely to have received neoadjuvant chemotherapy, or had undergone a continent urinary diversion. Higher pathologic tumor and nodal stage were observed more frequently in patients who received PBT. On multivariable analysis, PBT was not associated with worse recurrence-free survival, disease-specific survival, and overall survival (all P > .05). Kaplan-Meier curves did not show any significant differences (all P > .05) between the transfused and nontransfused groups. In addition, no differences were found in regard to timing of transfusion, that is, intraoperative vs postoperative, in distinct analysis. CONCLUSION: No significant association was found between leukoreduced PBT and worse survival outcomes at short-term follow-up in a contemporary cohort of cystectomy patients. Prospective long-term follow-up is warranted. PMID- 28011276 TI - Excised Parenchymal Mass During Partial Nephrectomy: Functional Implications. AB - OBJECTIVE: To evaluate whether excised parenchymal mass (EPM) during partial nephrectomy (PN) correlates with functional decline and can serve as a surrogate for functional outcomes. MATERIALS AND METHODS: All 215 patients managed with PN for unifocal renal mass with necessary studies to determine EPM and percent glomerular filtration rate (GFR) and parenchymal mass preserved (both global and specific to the operated kidney) were analyzed. EPM was estimated from the pathologic specimen by subtracting the tumor mass from the specimen mass, with both calculated using the elliptical formula. Vascularized parenchymal mass preserved was measured from computed tomography scans obtained <2 months prior and 3-12 months after surgery. All functional analyses were required to be within the same time frames, and patients with a contralateral kidney were also required to have nuclear renal scans. RESULTS: The median tumor size was 3.5 cm and the median R.E.N.A.L. was 7. Warm and cold ischemia were utilized in 123 and 92 patients, respectively (median ischemia time = 23 minutes). The median global GFR preserved was 89%, the median total parenchymal mass preserved was 93%, and the median estimated EPM was 16 cm3. Whereas percent parenchymal mass preserved correlated strongly with global and ipsilateral GFR preserved (both P < .001), EPM failed to correlate with functional outcomes on both univariable and multivariable analyses. CONCLUSION: Our data suggest that parenchymal mass preserved with standard PN by experienced surgeons associates strongly with function preserved, whereas EPM fails to correlate with functional outcomes. Further study of the functional impact of EPM in other circumstances will be required, such as enucleation or PN performed by less-experienced surgeons. PMID- 28011277 TI - Large Cystic Metanephric Adenoma in a 15-Year-Old Girl. AB - Metanephric adenoma is a rare pediatric renal tumor, generally considered to be benign. It can be difficult to distinguish from Wilms tumor and renal cell carcinoma based on imaging alone, and even may be difficult on histopathologic analysis. We present a case of a large cystic metanephric adenoma managed with surgical resection. This case highlights the difficulty in managing cystic renal lesions in children and adolescents as there is a paucity of data on the radiologic and pathologic correlation in such patients. PMID- 28011278 TI - Molecular characterization of echovirus 13 uncovering high genetic diversity and identification of new genotypes in Pakistan. AB - Echovirus 13 (E-13) is reported worldwide and is mostly related to aseptic meningitis but it is also isolated from cases of acute flaccid paralysis (AFP). Unfortunately, all studies conducted on non polio enterovirus in Pakistan only confirm E-13 isolation based on microneutralization assay but there is lack of molecular epidemiological data on this serotype. In this study, 113 stool samples were collected from AFP patients during 2008-2010. An enterovirus primer mediated real-time reverse transcriptase polymerase chain reaction, a standard microneutralization assay and sequencing of viral protein 1 gene (VP1) identified the predominant serotype E-13. For molecular characterization, genetic relationship between 12 clinical isolates of echovirus 13 was investigated by partial sequencing of viral protein 1 gene. These strains, combined with related sequences from GenBank were divided phylogenetically into two different genogroups A and B (>30% divergence) and were found genetically distinct from the circulating strains in the world. Additionally, phylogenic grouping pattern revealed that the study strains clustered into three distinct subgroups (A3, A7 and B3) having >23% nucleotide divergence representing three new genotypes. The genotype A7 seems to be restricted geographically. In conclusion, the current study provides an overview of the molecular epidemiology and evolution of E-13 in the country. This study strongly suggests that enterovirus surveillance system should be established in the country to determine the temporal and geographical trends and disease pattern of different enterovirus serotypes in the community. PMID- 28011279 TI - Association of prophylactic endotracheal intubation in critically ill patients with upper GI bleeding and cardiopulmonary unplanned events. AB - BACKGROUND AND AIMS: Prophylactic endotracheal intubation (PEI) is often advocated to mitigate the risk of cardiopulmonary adverse events in patients presenting with brisk upper GI bleeding (UGIB). However, the benefit of such a measure remains controversial. Our study aimed to compare the incidence of cardiopulmonary unplanned events between critically ill patients with brisk UGIB who underwent endotracheal intubation versus those who did not. METHODS: Patients aged 18 years or older who presented at Cleveland Clinic between 2011 and 2014 with hematemesis and/or patients with melena with consequential hypovolemic shock were included. The primary outcome was a composite of several cardiopulmonary unplanned events (pneumonia, pulmonary edema, acute respiratory distress syndrome, persistent shock/hypotension after the procedure, arrhythmia, myocardial infarction, and cardiac arrest) occurring within 48 hours of the endoscopic procedure. Propensity score matching was used to match each patient 1:1 in variables that could influence the decision to intubate. These included Glasgow Blatchford Score, Charleston Comorbidity Index, and Acute Physiology and Chronic Health Evaluation scores. RESULTS: Two hundred patients were included in the final analysis. The baseline characteristics, comorbidity scores, and prognostic scores were similar between the 2 groups. The overall cardiopulmonary unplanned event rates were significantly higher in the intubated group compared with the nonintubated group (20% vs 6%, P = .008), which remained significant (P = .012) after adjusting for the presence of esophageal varices. CONCLUSIONS: PEI before an EGD for brisk UGIB in critically ill patients is associated with an increased risk of unplanned cardiopulmonary events. The benefits and risks of intubation should be carefully weighed when considering airway protection before an EGD in this group of patients. PMID- 28011280 TI - Risk of colorectal cancer in chronic liver diseases: a systematic review and meta analysis. AB - BACKGROUND AND AIMS: The risk of colorectal cancer (CRC) in various chronic liver diseases compared with the general population remains unclear. We performed a systematic review and meta-analysis to assess the risk of CRC in patients with chronic liver diseases before and after liver transplantation. METHODS: Electronic databases were searched for studies assessing the risk of CRC in patients with chronic liver diseases. The primary outcome was the pooled risk of CRC among studies that reported the risk as standardized incidence rate (SIR). RESULTS: Fifty studies that included 55,991 patients were identified. Among studies that included hepatitis and cirrhotic patients, the pooled SIR was 2.06 (P < .0001; 95% confidence interval (CI), 1.46-2.90) with moderate heterogeneity (I2 = 49.2%), which appeared to be because of the difference between subgroup of diseases and the power of studies. Three studies reported an increased risk of CRC in primary sclerosing cholangitis patients (pooled SIR 6.70; P < .0001; 95% CI, 3.48-12.91) with moderate heterogeneity (I2 = 36.3%), which appeared to be because of the difference between the power of studies. Among studies that included post-transplant patients, the pooled SIR was 2.16 (P < .0001; 95% CI, 1.59-2.94) with moderate heterogeneity (I2 = 56.4%). Meta-regression showed a correlation between the proportion of autoimmune-related liver diseases and the risk of CRC. CONCLUSIONS: Patients with chronic liver diseases had an increased risk of CRC compared with the general population, which persisted after liver transplantation. A more intensive surveillance for CRC is warranted in this population. PMID- 28011281 TI - A definitive analytical spectroscopic study of Indian yellow, an ancient pigment used for dating purposes. AB - The Raman spectrum of tartrazine has been mistakenly reported as being that of Indian yellow in the literature, which has serious consequences for the identification of this pigment in art works regarding their authentication. Unlike tartrazine, Indian yellow (a natural mixture of the magnesium and calcium salts of euxanthic acid) exhibits in its Raman spectrum a strong fluorescent background when visible excitation is used, however, excitation in the near infrared (1064nm) permitted the observation of the Raman bands from the raw pigment with the main features placed at 1346, 1368, 1425, 1441 and 1626cm-1. Indian yellow identification was assured by 1H and 13C Nuclear Magnetic Resonance characterization and the complete assignment of the proton and carbon resonances was accomplished using heteronuclear single quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), nuclear overhauser effect spectroscopy (NOESY) and 1H-1H correlation spectroscopy (COSY). Scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and X-ray fluorescence (XRF) analyzes were also conducted on a genuine sample of this historical pigment. PMID- 28011282 TI - 1,2-Indanedione - A winning ticket for developing fingermarks: A validation study. AB - 1,2-Indanedione has been extensively researched since the discovery of its fluorogenic reaction with amino acids in 1997 by Joullie et al. [1]. This current study compares the development of fingermarks on used train tickets by the three leading reagents for amino acids-ninhydrin, DFO and 1,2-indanedione. The train tickets are ideal for the task due to their high abundance and frequent use by a diverse population. However, their unique double-layer composition of a cellulose based regular paper on one side and a thermally sensitive layer on the other requires an adjustment of the traditional development procedures. Heat, which is normally applied after dipping the specimens in the reagents solutions, had to be avoided due to darkening of the sensitive thermal layer. Instead, it has been replaced by air-drying in a fume-hood 24h prior to the recording of the results. Three groups, each containing 500 used train tickets had been treated by each of the three reagents. The results were expressed in terms of percentage of both comparable and partial fingermarks. In this study we controlled neither the quality of the fingerprint donors nor the conditions under which the latent fingermarks had been deposited or stored. However, the large number of similar exhibits which are randomly chosen allows tentative conclusions on the potential of each reagent, hence, a new criterion for the potential of fingermark development (PFD) is proposed. The PFD combines all the partial fingermarks and identifiable fingermarks (graded 1 and 2) thus, highlighting the sensitivity of the reagents. In this work, the superiority of 1,2-indanedione is demonstrated using both the traditional comparison tests as well as the suggested "PFD". PMID- 28011283 TI - Integrin-linked kinase regulates cellular mechanics facilitating the motility in 3D extracellular matrices. AB - The motility of cells plays an important role for many processes such as wound healing and malignant progression of cancer. The efficiency of cell motility is affected by the microenvironment. The connection between the cell and its microenvironment is facilitated by cell-matrix adhesion receptors and upon their activation focal adhesion proteins such as integrin-linked kinase (ILK) are recruited to sites of focal adhesion formation. In particular, ILK connects cell matrix receptors to the actomyosin cytoskeleton. However, ILK's role in cell mechanics regulating cellular motility in 3D collagen matrices is still not well understood. We suggest that ILK facilitates 3D motility by regulating cellular mechanical properties such as stiffness and force transmission. Thus, ILK wild type and knock-out cells are analyzed for their ability to migrate on 2D substrates serving as control and in dense 3D extracellular matrices. Indeed, ILK wild-type cells migrated faster on 2D substrates and migrated more numerous and deeper in 3D matrices. Hence, we analyzed cellular deformability, Young's modulus (stiffness) and adhesion forces. We found that ILK wild-type cells are less deformable (stiffer) and produce higher cell-matrix adhesion forces compared to ILK knock-out cells. Finally, ILK is essential for providing cellular mechanical stiffness regulating 3D motility. PMID- 28011284 TI - Phosphorylation of Tudor-SN, a novel substrate of JNK, is involved in the efficient recruitment of Tudor-SN into stress granules. AB - Posttranslational modifications of certain stress granule (SG) proteins are closely related to the assembly of SGs, a type of cytoplasmic foci structure. Our previous studies revealed that the Tudor staphylococcal nuclease (Tudor-SN) protein participates in the formation of SGs. However, the functional significance of potential Tudor-SN modifications during stress has not been reported. In this study, we demonstrated that the Tudor-SN protein was phosphorylated at threonine 103 (T103) upon stimulation with arsenite. In addition, c-Jun N-terminal kinase (JNK) was found to be responsible for Tudor-SN phosphorylation at the T103 site. We further illustrated that either a T103A mutation or the suppression of phosphorylation of T103 by the JNK inhibitor SP600125 inhibited the efficient recruitment of Tudor-SN into SGs. In addition, the T103A mutation could affect the physical binding of Tudor-SN with the G3BP (Ras-GAP SH3 domain-binding protein) protein but not with the HuR (Hu antigen R) protein and AGTR1-3'UTR (3'-untranslated region of angiotensin II receptor, type 1) mRNA cargo. These data suggested that JNK-enhanced Tudor-SN phosphorylation promotes the interaction between Tudor-SN and G3BP and facilitates the efficient recruitment of Tudor-SN into SGs under conditions of sodium arsenite-induced oxidative stress. This finding provides novel insights into the physiological function of Tudor-SN modification. PMID- 28011286 TI - Recycling of rare earth particle by mini-hydrocyclones. AB - Mini-hydrocyclones were applied to separate the fine rare earth particles from the suspensions. The effects of the flow rate, split ratio, and feed concentration on the total separation efficiency and grade separation efficiency were studied. The combined effects of the flow rate (1200-1600L/h), split ratio (20-60%) and concentration (0.6-1.0wt%) on the total separation efficiency in mini-hydrocyclones were investigated using a response surface methodology. The optimum operating parameters for a total separation efficiency of 92.5% were: feed flow rate=1406L/h, split ratio=20%, and feed concentration=1wt%. PMID- 28011287 TI - Green residues from Bangkok green space for renewable energy recovery, phosphorus recycling and greenhouse gases emission reduction. AB - Effective ways to integrate human life quality, environmental pollution mitigation and efficient waste management strategies are becoming a crisis challenge for sustainable urban development. The aims of this study are: (1) to evaluate and recommend an optimum Urban Green Space (UGS) area for the Bangkok Metropolitan Administration (BMA); and (2) to quantify potential renewable resources including electricity generation and potential nutrient recovery from generated ash. Green House Gases (GHGs) emissions from the management of Green Residues (GR) produced in a recommended UGS expansion are estimated and compared with those from the existing BMA waste management practice. Results obtained from this study indicate that an increase in UGS from its current 2.02% to 22.4% of the BMA urban area is recommended. This optimum value is primarily due to the area needed as living space for its population. At this scale, GR produced of about 334kt.y-1 may be used to generate electricity at the rate of 206GWh.y-1 by employing incineration technology. Additionally, instead of going to landfill, phosphorus (P) contained in the ash of 1077 t P.y-1 could be recovered to produce P fertilizer to be recycled for agricultural cultivation. Income earned from selling these products is found to offset all of the operational cost of the proposed GR management methodology itself plus 7% of the cost of BMA's Municipal Solid Waste (MSW) operations. About 70% of the current GHGs emission may be reduced based on incineration simulation. PMID- 28011285 TI - Outside in: The matrix as a modifier of muscular dystrophy. AB - Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein's function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFbeta binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting. PMID- 28011288 TI - Pooled analysis of two randomized, open-label studies comparing the effects of nomegestrol acetate/17beta-estradiol and drospirenone/ethinyl estradiol on bleeding patterns in healthy women. AB - OBJECTIVES: To obtain more precise and detailed information regarding the bleeding patterns of nomegestrol acetate (NOMAC)/17beta-estradiol (E2) and drospirenone/ethinyl estradiol (DRSP/EE) and to identify whether baseline demographic characteristics were associated with unscheduled bleeding, absent scheduled bleeding, or amenorrhea. STUDY DESIGN: This analysis pooled results from two pivotal open-label, randomized trials that compared bleeding patterns of NOMAC/E2 and DRSP/EE. In the two studies 4317 women aged 18-50 years from 24 countries across the Americas, Europe, and Asia underwent treatment. RESULTS: 2835 women taking NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen and 938 women taking DRSP/EE (3 mg/30 MUg) in a 21/7-day regimen had at least 1 evaluable cycle for vaginal bleeding analyses. The frequency of absent scheduled bleeding was higher (p<.0001) for women using NOMAC/E2 than DRSP/EE across all 11 cycles (cycles 2-12), ranging between 17.6% and 31.6% and between 3.4% and 5.8%, respectively. For women who had absent scheduled bleeding in cycles 2, 3, or 4 the incidence of absent scheduled bleeding in subsequent cycles was high and ranged between approximately 50%-60% for NOMAC/E2 and approximately 40%-50% for DRSP/EE. Amenorrhea increased over time with both regimens, being higher with NOMAC/E2. Both absent scheduled bleeding and amenorrhea with NOMAC/E2 were more common in older women, overweight women, switchers, and smokers; unscheduled bleeding was more common in starters, but had no association with age, body mass index, and smoking. CONCLUSIONS: NOMAC/E2 is associated with a higher prevalence of absent scheduled bleeding compared with DRSP/EE. Absent scheduled bleeding and amenorrhea were associated with age, body weight, switching and smoking. Unscheduled bleeding was more common in starters. IMPLICATIONS: Information about the factors associated with bleeding patterns may help clinicians provide guidance to women considering use of the NOMAC/E2 oral contraceptive. PMID- 28011289 TI - Immobilization of laccase of Pycnoporus sanguineus CS43. AB - Laccase from Pycnoporus sanguineus CS43 was successfully immobilized onto Immobead-150 and Eupergit-C by covalent binding and by entrapment in LentiKats. The highest immobilization was onto Immobead-150 (97.1+/-1.2%) compared to the other supports, LentiKats (89+/-1.1%) and Eupergit-C (83.2+/-1.4%). All three immobilized enzyme systems showed increased thermostability and better mechanical properties than free laccase. Moreover, after 5 cycles of reuse of these systems, 90% of initial laccase activity was retained. Immobead-150 and LentiKats systems exhibited the highest efficiencies in removal of m-cresol under the combined actions of biodegradation and adsorption, while laccase entrapped in LentiKats showed a high ability for degradation of m-cresol within 24h. In addition, the typical Michaelis-Menten enzymatic model effectively described the kinetic profile of m-cresol degradation by the enzyme entrapped in LentiKats. Based on the results obtained in the present study, it can be established that the immobilized biocatalysts developed here possess significant potential for wastewater treatment. PMID- 28011290 TI - The effect of a specialized content knowledge workshop on teaching and learning Basic Life Support in elementary school: A cluster randomized controlled trial. AB - BACKGROUND: Research investigating the effect of specialised content knowledge (SCK) on teaching and learning Basic Life Support (BLS) is lacking. PURPOSE: To investigate the effect of a specialised content knowledge workshop on teaching behaviour, lesson context and student learning of BLS. Specialised content knowledge comprises knowledge of content progressions, skill analysis, and how to correct common errors. METHODS: A cluster randomized controlled trial. Ten elementary teachers from three schools were assigned to a common content knowledge (n=4) and specialized content knowledge condition (n=6). Common content knowledge teachers received a 50-min BLS workshop focused on learning BLS. Next to learning BLS, specialised content knowledge teachers also practised the teaching of BLS focussing on skill progressions, skill analysis and how to correct common errors children would likely make. Teachers then taught one BLS lesson and their behaviour together with lesson context was collected through direct observation. BLS performance of 203 children (mean age: 11.3 years) was individually assessed immediately after the lesson. RESULTS: Students taught by specialised content knowledge teachers spent more time practising BLS (57% vs 30%), were less engaged in cognitive activities (29% vs 55%) and achieved a significantly higher BLS performance (62% vs 57%) compared to students taught by common content knowledge teachers, P<.05. Specialised content knowledge teachers on average gave more feedback (31 vs 19). DISCUSSION AND CONCLUSION: This study demonstrates that a 50-min workshop with a focus on specialised content knowledge impacted teachers' in-class behaviour, which in turn significantly improved students' BLS performance. PMID- 28011291 TI - Mean airway pressure and outcome of OHCA. PMID- 28011292 TI - Utilization of palliative care services for cardiac arrest patients undergoing therapeutic hypothermia: A retrospective analysis. AB - BACKGROUND: Palliative care (PC) services are integral to the care of patients with advanced medical illnesses. Given the significant morbidity and mortality associated with cardiac arrest, we sought to measure the use and impact of PC in the care of patients treated with therapeutic hypothermia (TH). METHODS: We conducted a retrospective study of 317 consecutive patients undergoing TH after cardiac arrest. We compared intensive care unit (ICU) characteristics and clinical outcomes of subjects who received PC consultation (n=125) to those who did not (n=192). RESULTS: The proportion of TH patients with PC consultations increased to greater than 60% by 2013, corresponding to our institution's expansion of PC services, development of a dedicated PC unit, and integration of this service into our published TH protocol. In the TH population, time to return of spontaneous circulation (ROSC) was associated with higher inpatient mortality (p<0.001) and placement of a PC consult (p=0.011). TH patients who received PC consultation had longer ICU stays (p=0.034), more ventilator days (p<0.001), and higher inpatient mortality (p<0.001). When these measures were analyzed cohort wide comparing all TH patients pre- and post-2013, at which time the frequency of PC consultation had dramatically increased, there were no statistically significant differences in ICU care or outcomes. CONCLUSION: In our population of cardiac arrest patients undergoing TH, the utilization of PC services has increased over time, particularly for those patients with high morbidity and mortality. Future randomized studies may further delineate optimal patient selection for PC consultation to better facilitate goals of care discussions and timely medical decision-making. PMID- 28011293 TI - Gene regulatory mechanisms underlying the intestinal innate immune response. AB - In the mammalian gastrointestinal tract, distinct types of cells, including epithelial cells and macrophages, collaborate to eliminate ingested pathogens while striving to preserve the commensal microbiota. The underlying innate immune response is driven by significant gene expression changes in each cell, and recent work has provided novel insights into the gene regulatory mechanisms that mediate such transcriptional changes. These mechanisms differ from those underlying the canonical cellular differentiation model in which a sequential deposition of DNA methylation and histone modification marks progressively restricts the chromatin landscape. Instead, inflammatory macrophages and intestinal epithelial cells appear to largely rely on transcription factors that explore an accessible chromatin landscape to generate dynamic stimulus-specific and spatial-specific physiological responses. PMID- 28011294 TI - Sea-ice eukaryotes of the Gulf of Finland, Baltic Sea, and evidence for herbivory on weakly shade-adapted ice algae. AB - To determine community composition and physiological status of early spring sea ice organisms, we collected sea-ice, slush and under-ice water samples from the Baltic Sea. We combined light microscopy, HPLC pigment analysis and pyrosequencing, and related the biomass and physiological status of sea-ice algae with the protistan community composition in a new way in the area. In terms of biomass, centric diatoms including a distinct Melosira arctica bloom in the upper intermediate section of the fast ice, dinoflagellates, euglenoids and the cyanobacterium Aphanizomenon sp. predominated in the sea-ice sections and unidentified flagellates in the slush. Based on pigment analyses, the ice-algal communities showed no adjusted photosynthetic pigment pools throughout the sea ice, and the bottom-ice communities were not shade-adapted. The sea ice included more characteristic phototrophic taxa (49%) than did slush (18%) and under-ice water (37%). Cercozoans and ciliates were the richest taxon groups, and the differences among the communities arose mainly from the various phagotrophic protistan taxa inhabiting the communities. The presence of pheophytin a coincided with an elevated ciliate biomass and read abundance in the drift ice and with a high Eurytemora affinis read abundance in the pack ice, indicating that ciliates and Eurytemora affinis were grazing on algae. PMID- 28011295 TI - Historical trends in the species inventory of tintinnids (ciliates of the microzooplankton) in the Bay of Villefranche (NW Mediterranean Sea): Shifting baselines. AB - In the Bay of Villefranche, tintinnid ciliates have been studied since 1879 yielding a unique time series. The species inventory, excluding likely synonymous records, numbers 108. Temporal increases in the inventory appear linearly related to sampling effort up until the 2000s with a cumulative sampling effort of about 200 dates. Subsequently, with a large increase in sampling to currently over 460 dates, the rate of increases in species numbers declines. Surprisingly, the inventory is not highly inflated by unique occurrences, as species found but once are only 17 out of the 108. However, in recent years many previously recorded taxa have not been seen. Missing from a species list derived solely from intensive sampling from 2013 to 2016 are 38 previously recorded species. Most (26 out of 38) were recorded from a single year and thus may have been temporary residents. However, 12 species were found in multiple years by different investigators suggesting relatively common occurrence in the past. The substantial effort required to adequately sample a locality and possible historical changes in species inventories suggest that claims of a species as 'new' to a locality should be made with caution & caveats. PMID- 28011296 TI - Bridging the gap between morphological species and molecular barcodes - Exemplified by loricate choanoflagellates. AB - Translating the vast amounts of molecular barcodes from global surveys of microbial eukaryotes into ecological insight depends critically on a well-curated reference database with adequate taxonomic coverage. In this respect, the choanoflagellates resemble other eukaryotic lineages: reasonable coverage at higher taxonomic levels, but missing diversity at the species level. The acanthoecid (loricate) choanoflagellates are well-characterized morphologically, with over 115 species described, but less than 10% with any sequence data. Because lorica shape is species-specific, the acanthoecids represent an opportunity to link morphological with molecular data within a lineage of eukaryotes. To match morphospecies to sequences, we sampled the Kattegat and the Isefjord in Denmark in September 2014 and February 2015. We identified 45 morphospecies and sequenced ribosomal DNA of nine previously unsequenced species, roughly doubling the number of acanthoecid species with sequence data, including the first data representing five genera: Bicosta, Calliacantha, Cosmoeca, Crinolina and Pleurasiga. Our phylogenetic analysis is mainly congruent with morphology-based systematics. Five of the newly sequenced species match a previously unidentified barcode from Tara Oceans, providing access to the global distribution of species isolated from Danish waters. One species, Calliacantha natans, is the second most globally abundant choanoflagellate present in Tara Oceans. Our project translating new ribosomal DNA sequences to distributions of described species on a global scale supports the approach linking morphology to molecular barcodes for microbial eukaryote ecology. PMID- 28011297 TI - Effect of Entodinium caudatum on starch intake and glycogen formation by Eudiplodinium maggii in the rumen and reticulum. AB - This study aimed to quantify the engulfed starch and reserve alpha-glucans (glycogen) in the cells of the ciliates Eudiplodinium maggii, as well the alpha glucans in defaunated and selectively faunated sheep. The content of starch inside the cell of ciliates varied from 21 to 183mg/g protozoal DM relative to the rumen fauna composition whereas, the glycogen fluctuated between 17 and 126mg/g dry matter (DM) of this ciliate species. Establishment of the population Entodinium caudatum in the rumen of sheep already faunated with E. maggii caused a drop in both types of quantified carbohydrates. The content of alpha-glucans in the rumen of defaunated sheep varied from 4.4 to 19.9mg/g DM and increased to 7.4 29.9 or 11.8-33.9mg/g DM of rumen contents in the presence of only E. maggii or E. maggii and E. caudatum, respectively. The lowest content of the carbohydrates was always found just before feeding and the highest at 4h thereafter. The alpha glucans in the reticulum varied 7.5-40.1, 14.3-76.8 or 21.9-106.1mg/g DM of reticulum content for defaunated, monofaunated or bifaunated sheep, respectively. The results indicated that both ciliate species engulf starch granules and convert the digestion products to the glycogen, diminishing the pool of starch available for amylolytic bacteria. PMID- 28011298 TI - Morphology and molecular phylogeny of Aegyria foissneri sp. n. and Lynchella minuta sp. n. (Ciliophora, Cyrtophoria) from brackish waters of southern China. AB - The morphology, ciliary pattern and small subunit rDNA (SSU rDNA) sequences of two new cyrtophorian ciliates, Aegyria foissneri sp. n. and Lynchella minuta sp. n., isolated from brackish waters in southern China, were investigated. Aegyria foissneri sp. n. is characterized as follows: cell size 85-170*45-80MUm in vivo; body inverted oval with a protrusion and a dark pigment spot on anterior left part; 42-77 somatic kineties; one preoral and three to six circumoral kineties; five to eight transpodial segments; 31-44 nematodesmal rods; 12-16 contractile vacuoles; and single oval macronucleus. Lynchella minuta sp. n. is distinguished from its congeners by having a cell size of 20-30*15-20MUm in vivo, oval body outline; four preoral and 14 or 15 postoral kineties, three circumoral kineties; ca. 11 nematodesmal rods; one finger-like tentacle on the ventral side; and two diagonally located contractile vacuoles. Molecular phylogenetic analyses support the genus assignment of Aegyria foissneri sp. n. and indicate the monophyly of the genus. While Lynchella minuta sp. n. clusters with Coeloperix species, which indicates that Lynchella is non-monophyletic. PMID- 28011299 TI - Apoptosis inducing factor gene depletion inhibits zearalenone-induced cell death in a goat Leydig cell line. AB - Zearalenone (ZEA) is a contaminant of human food and animal feedstuffs that causes health hazards. However, the signal pathways underlying ZEA toxicity remain elusive. The aims of this study were to determine which pathways are involved in ZEA-induced cell death and investigate the effect of apoptosis inducing factor (AIF) on cell death during ZEA treatment in the immortalized goat Leydig cell line hTERT-GLC. This study showed that ZEA-induced cell death in hTERT-GLCs works via endoplasmic reticulum (ER) stress, the caspase-dependent pathway, the caspase-independent pathway and autophagy. Recombinant lentiviral vectors were constructed to silence AIF expression in hTERT-GLCs. Flow cytometry results showed that knockdown of AIF diminished ZEA-induced cell apoptosis in hTERT-GLCs. Furthermore, we found AIF depletion down-regulated phosphoIRE1alpha, GRP78, CHOP and promoted the switch of LC3-I to LC3-II. Therefore, ZEA induces cytotoxicity in hTERT-GLCs via different pathways, while AIF-mediated signaling plays a critical role in ZEA-induced cell death in hTERT-GLCs. PMID- 28011300 TI - Thermal inactivation and sublethal injury kinetics of Salmonella enterica and Listeria monocytogenes in broth versus agar surface. AB - The objective of the present study was to compare the thermal inactivation and sublethal injury kinetics of Salmonella enterica and Listeria monocytogenes in broth (suspended cells) and on solid surface (agar-seeded cells). A 3-strain cocktail of S. enterica or L. monocytogenes inoculated in broth or on agar was subjected to heating in a water bath at various set temperatures (55.0, 57.5 and 60.0 degrees C for S. enterica and 60.0, 62.5 and 65 degrees C for L. monocytogenes). The occurrence of sublethally injured cells was determined by comparing enumerations on nonselective (TSAYE) and selective (XLD or ALOA) media. Results showed that the inactivation curves obtained from selective media were log-linear, and significant shoulders (p<0.05) were observed on some of the inactivation curves from TSAYE media. The D-values derived from the total population were higher than those from the uninjured cells. Generally, cells on agar surface exhibited higher heat resistance than those in broth. For S. enterica, cell injury increased with the exposure time, no difference was observed when treated at temperatures from 55.0 to 60.0 degrees C, while for L. monocytogenes, cell injury increased significantly with heating time and treatment temperature (from 60.0 to 65 degrees C). Moreover, the degree of sublethal injury affected by thermal treatment in broth or on agar surface depended upon the target microorganism. Higher proportions of injured S. enterica cells were observed for treatment in broth than on agar surface, while the opposite was found for L. monocytogenes. The provided information may be used to assess the efficacy of thermal treatment processes on surfaces for inactivation of S. enterica and L. monocytogenes, and it provides insight into the sublethally injured survival state of S. enterica and L. monocytogenes treated in liquid or on solid food. PMID- 28011301 TI - Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids. AB - BACKGROUND: Exposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed. METHODS: We used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed. RESULTS: We discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure). CONCLUSIONS: These results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure. GENERAL SIGNIFICANCE: Our findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution. PMID- 28011302 TI - Structure-activity relationships in carbohydrates revealed by their hydration. AB - One of the more intriguing aspects of carbohydrate chemistry is that despite having very similar molecular structures, sugars have very different properties. For instance, there is a sensible difference in sweet taste between glucose and trehalose, even though trehalose is a disaccharide that comprised two glucose units, suggesting a different ability of these two carbohydrates to bind to sweet receptors. Here we have looked at the hydration of specific sites and at the three-dimensional configuration of water molecules around three carbohydrates (glucose, cellobiose, and trehalose), combining neutron diffraction data with computer modelling. Results indicate that identical chemical groups can have radically different hydration patterns depending on their location on a given molecule. These differences can be linked with the specific activity of glucose, cellobiose, and trehalose as a sweet substance, as building block of cellulose fiber, and as a bioprotective agent, respectively. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader. PMID- 28011303 TI - The promiscuous ectonucleotidase NPP1: molecular insights into substrate binding and hydrolysis. PMID- 28011304 TI - Contrasting patterns of adaptive sequence convergence among echolocating mammals. AB - Several recent studies have described genes demonstrating adaptive sequence convergence between echolocating bats and dolphin, suggesting that common selective pressures can induce common molecular changes, even in distantly related species. However, in the case of the auditory genes Otoferlin (Otof), Cadherin 23 (Cdh23) and Protocadherin 15 (Pcdh15), the reported sequence convergence was supported only by incongruent gene and species trees and counts of convergent substitutions. Therefore, it remains unclear whether echolocating bats and dolphin really do demonstrate evidence of adaptive sequence convergence, or whether there is simply a high level of random background convergence in these genes. To address this question, we estimated the number of convergent and divergent amino acid substitutions along all independent branches of a sufficiently deep phylogeny containing between 22 and 32 mammals for each gene, and compared convergence between the two proposed suborders of bat, Yangochiroptera and Yinpterochiroptera, and dolphin. We find no support for convergence between bats and dolphin in the gene Pcdh15. For the gene Otof we report minimal evidence for convergent evolution only between the Yinpterochiroptera and dolphin. Cdh23 displayed a high level of convergence between dolphin and the Yinpterochiroptera. In addition, dolphin and certain members of the Yangochiroptera that emit high frequency echolocation calls shared several unique convergent substitutions. These results indicate that the convergent evolution of Cdh23 was likely driven by selection for hearing above a certain frequency threshold. Moreover, the contrasting patterns of convergence between the two bat suborders and dolphin in all auditory genes studied thus far suggest echolocation may have evolved independently in the Yinpterochiroptera and Yangochiroptera. PMID- 28011305 TI - Aerobic and anaerobic biosynthesis of nano-selenium for remediation of mercury contaminated soil. AB - Selenium (Se) nanoparticles are often synthesized by anaerobes. However, anaerobic bacteria cannot be directly applied for bioremediation of contaminated top soil which is generally aerobic. In this study, a selenite-reducing bacterium, Citrobacter freundii Y9, demonstrated high selenite reducing power and produced elemental nano-selenium nanoparticles (nano-Se0) under both aerobic and anaerobic conditions. The biogenic nano-Se0 converted 45.8-57.1% and 39.1-48.6% of elemental mercury (Hg0) in the contaminated soil to insoluble mercuric selenide (HgSe) under anaerobic and aerobic conditions, respectively. Addition of sodium dodecyl sulfonate enhanced Hg0 remediation, probably owing to the release of intracellular nano-Se0 from the bacterial cells for Hg fixation. The reaction product after remediation was identified as non-reactive HgSe that was formed by amalgamation of nano-Se0 and Hg0. Biosynthesis of nano-Se0 both aerobically and anaerobically therefore provides a versatile and cost-effective remediation approach for Hg0-contaminated surface and subsurface soils, where the redox potential often changes dramatically. PMID- 28011306 TI - Heavy metal contamination of freshwater prawn (Macrobrachium rosenbergii) and prawn feed in Bangladesh: A market-based study to highlight probable health risks. AB - An assessment of the dietary risk of heavy metal exposure to humans is important since it is the main source of exposure. This study aimed to estimate the degree of contamination and assess the probable health risk in the prawn food chain. In prawn feed, the concentrations of metals were detected in the following order: Hg > Co > Pb > Cd. The concentrations of heavy metals in prawn were the highest for Co and lowest for Cd. Trace amounts of As and Cr were detected in the analyzed sample. Target hazard quotients for heavy metals for adults were >1 for Pb, Cd, Hg, and Co, and for children, the same were high for Co and Hg, indicating significant health risks upon dietary exposure. All the prawn samples contained nine-fold and fourteen-fold higher concentrations than the maximum acceptable levels for Pb and Hg, respectively (0.5 mg kg-1; WHO/FAO). Human health risk due to the Co exposure is quite alarming as the level of exposure was found to be very high. In the prawn samples intended for human consumption, the hazard index (HI) was highest in the samples obtained from Bagerhat (3.25 in flesh and 3.26 in skin), followed by the samples obtained from Satkhira (2.84 in flesh and 3.10 in skin) and Dhaka City Corporation (2.81 in flesh and 3.42 in Skin); this indicates a potential risk of prawn consumption obtained from Southeast Bangladesh. This is particularly problematic as this area accounts for the majority of prawn production and export of the country. PMID- 28011308 TI - Assessing for Multiple Endocrine Neoplasia Type 1 in Patients Evaluated for Zollinger-Ellison Syndrome-Clues to a Safer Diagnostic Process. AB - BACKGROUND: Zollinger-Ellison syndrome is a rare cause of tumoral hypergastrinemia; 1 of 5 patients with this syndrome also has multiple endocrine neoplasia type 1. The diagnosis of this disease is complicated by the widespread use of proton pump inhibitors that can elevate serum gastrin levels, the cornerstone for biochemical diagnosis. Abrupt discontinuation of proton pump inhibitors could lead to adverse outcomes. Clinician awareness of the relationship between Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 could lead to a safer diagnostic pathway. METHODS: We conducted a retrospective review of a cohort of patients with multiple endocrine neoplasia type 1. RESULTS: There were 287 patients with multiple endocrine neoplasia type 1 (73 with gastrinoma) evaluated between 1997 and 2014. Two patients experienced adverse events after proton pump inhibitor therapy was discontinued to re-measure serum gastrin level during the evaluation of severe peptic ulcer disease. In both cases, the diagnosis of multiple endocrine neoplasia type 1 was made after proton pump therapy was discontinued. CONCLUSION: Abrupt discontinuation of proton pump therapy can lead to adverse outcomes in patients with Zollinger-Ellison syndrome. Clinical assessment for features of multiple endocrine neoplasia type 1 (eg, serum calcium levels, personal and family history of hypercalcemia, pituitary or pancreatic tumors) could identify patients with higher risk for a tumoral source of hypergastrinemia where imaging studies can help support the diagnosis without the potential side effects of abrupt discontinuation of proton pump inhibitor therapy. PMID- 28011309 TI - The Effect of Prolonged Glucosamine Usage on HbA1c Levels and New-Onset Diabetes Mellitus in Overweight and Obese Middle-Aged Women. AB - OBJECTIVE: The aim of the present study was to evaluate the effect of a 2.5-year glucosamine sulfate intervention on hemoglobin A1c (HbA1c) levels and the incidence of new-onset diabetes mellitus over 6.5 years in middle-aged women with a body mass index >=27 kg/m2. METHODS: In total, 407 women were randomized into either oral crystalline glucosamine sulfate or placebo. At baseline, 1 year, 2.5 years, and 6.5 years, a blood sample for the HbA1c level was drawn and questionnaires were taken. After 6.5 years there were missing data for some variables, therefore, multiple imputation was used. With the imputed data, a generalized estimating equation was performed to analyze the effect of glucosamine sulfate usage over 6.5 years. Finally, these analyses were rerun for the 2 subgroups of participants with and without high HbA1c level (>=42 mmol/mol) at baseline. RESULTS: There was no significant effect of a 2.5-year glucosamine sulfate intervention on mean HbA1c level or on obtaining a high HbA1c level or new-onset diabetes mellitus over 6.5 years. The subgroup analyses of participants with and without high HbA1c level at baseline were also not statistically significant. However, participants with a high HbA1c level at baseline had higher odds ratios compared with the participants with a normal HbA1c at baseline. CONCLUSIONS: There was no effect of glucosamine sulfate on mean HbA1c level nor on obtaining a high HbA1c level or new-onset diabetes mellitus over 6.5 years, especially in participants with a normal HbA1c level at baseline. PMID- 28011310 TI - A Rarity in a Common Disease: Thyroid Paraganglioma. PMID- 28011311 TI - On Immigration: Welcome to America! PMID- 28011312 TI - The Case for Medical History in Physicians' Education: A Survey of What Physicians and Physicians-in-Training Think. PMID- 28011313 TI - Prognostic Value of High-Sensitivity Cardiac Troponin T Compared with Risk Scores in Stable Cardiovascular Disease. AB - BACKGROUND: Risk stratification of patients with cardiovascular disease remains challenging despite consideration of risk scores. METHODS: We aimed to evaluate the prognostic performance of high-sensitivity cardiac troponin T in a low-risk outpatient population presenting for nonsecondary and secondary prevention. All cause mortality, a composite of all-cause mortality, acute myocardial infarction, and stroke (end point 2), and a composite of all-cause mortality, acute myocardial infarction, stroke and rehospitalization for acute coronary syndrome, and decompensated heart failure (end point 3) were defined. The prognostic performance of high-sensitivity cardiac troponin T on index visit was compared with the PROCAM score and 3 FRAMINGHAM subscores. RESULTS: In 693 patients with a median follow-up of 796 days, we observed 16 deaths, 32 patients with end point 2, and 83 patients with end point 3. All risk scores performed better in the prediction of all-cause mortality in nonsecondary prevention (area under the curve [AUC]: PROCAM: 0.922 vs 0.523, P = .001, consistent for all other scores). In secondary prevention, high-sensitivity cardiac troponin T outperformed all risk scores in the prediction of all-cause mortality (DeltaAUC: PROCAM: 0.319, P <.001, consistent for all other scores) and performed superiorly in the prediction of end point 2 compared with the PROCAM, FRAMINGHAM-Coronary Heart Disease, and FRAMINGHAM-Hard Coronary Heart Disease scores (DeltaAUC: PROCAM: 0.176, P = .047, consistent for FRAMINGHAM-Coronary Heart Disease and FRAMINGHAM Hard Coronary Heart Disease). In nonsecondary prevention, we observed a comparable prognostic performance of high-sensitivity cardiac troponin T and multivariable risk scores. Our findings on the prediction of all-cause mortality compared with the FRAMINGHAM-Hard Coronary Heart Disease score were confirmed in an independent validation cohort on 2046 patients. CONCLUSIONS: High-sensitivity troponin T provides excellent risk stratification regarding all-cause mortality and all-cause mortality, acute myocardial infarction, and stroke in a secondary prevention cohort in whom risk scores perform poorly. PMID- 28011314 TI - Idarucizumab (Praxbind): The First Reversal Agent for a Direct Oral Anticoagulant. PMID- 28011315 TI - Purpura from a Tick Bite. PMID- 28011307 TI - The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. AB - Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders, olfactory disturbances appear early and are considered as prodromal symptoms of the disease. In addition, pathological protein aggregates affect olfactory regions prior to other regions, suggesting that the olfactory system might be particularly vulnerable to neurodegenerative diseases. Exposed to the external environment, the olfactory epithelium and olfactory bulb allow pathogen and toxin penetration into the brain, a process that has been proposed to play a role in neurodegenerative diseases. Determining whether the olfactory bulb could be a starting point of pathology and of pathology spread is crucial to understanding how neurodegenerative diseases evolve. We argue that pathological changes following environmental insults contribute to the initiation of protein aggregation in the olfactory bulb, which then triggers the spread of the pathology within the brain by a templating mechanism in a prion-like manner. We review the evidence for the early involvement of olfactory structures in neurodegenerative diseases and the relationship between neuropathology and olfactory function. We discuss the vulnerability and putative underlying mechanisms by which pathology could be initiated in the olfactory bulb, from the entry of pathogens (promoted by increased permeability of the olfactory epithelium with aging or inflammation) to the sensitivity of the olfactory system to oxidative stress and inflammation. Finally, we review changes in protein expression and neural excitability triggered by pathogenic proteins that can promote pathogenesis in the olfactory bulb and beyond. PMID- 28011317 TI - Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS): Common, but Currently Nameless. PMID- 28011318 TI - Maturation of conidia on conidiophores of Aspergillus niger. AB - Conidia of Aspergillus niger are produced on conidiophores. Here, maturation of conidia on these asexual reproductive structures was studied. Pigmented conidia that had developed on conidiophores for 2, 5, and 8days were similarly resistant to heat and were metabolically active as shown by CO2 release and conversion of the metabolic probe Tempone. A total number of 645-2421 genes showed a ?2-fold change in expression when 2-day-old conidia were compared to 5- and 8-day-old spores. Melanin was extracted more easily from the cell wall of 2-day-old conidia when compared to the older spores. In addition, mannitol content and germination rate of the 2-day-old conidia were higher. Dispersal efficiency by water was lower in the case of the 8-day-old conidia but no differences were observed in dispersal by wind and a hydrophobic moving object. These data and the fact that only a minor fraction of the conidia on a conidiophore were dispersed in the assays imply that a single colony of A. niger releases a heterogeneous population of conidia. This heterogeneity would provide a selective advantage in environments with rapidly changing conditions such as availability of water. PMID- 28011319 TI - Effect of vacuolar ATPase subunit H (VmaH) on cellular pH, asexual cycle, stress tolerance and virulence in Beauveria bassiana. AB - Vacuolar ATPase (V-ATPase) is a conserved multi-subunit protein complex that mediates intracellular acidification in fungi. Here we show functional diversity of V-ATPase subunit H (BbVmaH) in Beauveria bassiana, a filamentous fungal insect pathogen. Deletion of BbvmaH resulted in elevated vacuolar pH, increased Ca2+ level in cytosol but not in vacuoles, accelerated culture acidification and reduced accumulation of extracellular ammonia. Aerial conidiation and submerged blastospore production were largely delayed and reduced in the deletion mutant, respectively, accompanied with a significant delay in conidial germination, alterations of conidia and blastospores in morphology, size and/or density, and severe growth defects in minimal media with different carbon and nitrogen sources. Despite null responses to osmotic, oxidative and cell wall perturbing stresses, the deletion mutant showed increased sensitivity to Ca2+, Zn2+ and Cu2+ during growth while its conidia were less tolerant to a wet-heat stress at 45 degrees C and UV-B irradiation. Intracellular glycerol and mannitol contents also decreased significantly. Its virulence to Galleria mellonella larvae was significantly attenuated when conidia were topically applied for normal cuticle infection or injected into haemocoel for cuticle-bypassing infection. All phenotypic changes were restored by targeted gene complementation. Our results indicate that BbVmaH plays an important role in sustaining not only vacuolar acidification but also cytosolic calcium accumulation, ambient pH homeostasis, in vitro asexual cycle and virulence in B. bassiana. PMID- 28011316 TI - Treatment of Right Heart Thrombi Associated with Acute Pulmonary Embolism. AB - BACKGROUND: Evidence-based recommendations do not adequately address the treatment of right heart thrombi in patients who present with acute symptomatic pulmonary embolism. METHODS: This study included patients who had acute pulmonary embolism associated with right heart thrombi and participated in the Registro Informatizado de la Enfermedad TromboEmbolica registry. We assessed the effectiveness of anticoagulation versus reperfusion treatment for the outcomes of all-cause mortality, pulmonary embolism-related mortality, recurrent venous thromboembolism, and major bleeding rates through 30 days after initiation of pulmonary embolism treatment. We used propensity score matching to adjust for the likelihood of receiving reperfusion treatment. RESULTS: Of 325 patients with pulmonary embolism and right heart thrombi, 255 (78%; 95% confidence interval, 74 83) received anticoagulation and 70 (22%; 95% confidence interval, 17-26) also received reperfusion treatment. Propensity score-matched pairs analyses did not detect a statistically lower risk of all-cause death (6.2% vs 14%, P = .15) or pulmonary embolism-related mortality (4.7% vs 7.8%; P = .47) for reperfusion compared with anticoagulation. Of the patients who received reperfusion treatment, 6.2% had a recurrence during the study follow-up period, compared with 0% of those who received anticoagulation (P = .049). The incidence of major bleeding events was not statistically different between the 2 treatment groups (3.1% vs 3.1%; P = 1.00). CONCLUSIONS: In patients with pulmonary embolism and right heart thrombi, no significant difference was found between reperfusion therapy and anticoagulant therapy for mortality and bleeding. The risk of recurrences was significantly higher for reperfusion therapy compared with anticoagulation. Right heart thrombi may not warrant riskier interventions than standard anticoagulation. PMID- 28011320 TI - Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF kappaB-IL1alpha/beta-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. AB - As a cellular degradation mechanism, autophagy exerts crucial and complicated effects on HCC development. Liver non-parenchymal cells, including hepatic resident macrophage Kupffer cells, also play important roles in this process. However, most associated studies have focused on the influence of the autophagy level in hepatic cells and HCC cells, but not liver non-parenchymal cells. Based on our previous study, we confirmed that Atg5 silence in the liver during the preneoplastic stage facilitated liver fibrosis, inflammation and, ultimately, tumorigenesis. We further found that autophagy deficiency promotes the production of inflammatory and fibrogenic factors in macrophages. Moreover, Kupffer cell depletion rescued the tumor-promoting effect of autophagy deficiency during the preneoplastic stage. In autophagy-deficient macrophages, mitochondrial ROS mediated inflammation- and fibrosis-promoting effects by increasing IL1alpha/beta production via enhancing NF-kappaB-associated pathways. Both blocking of mitochondrial ROS and blocking the IL1 receptor stopped the promotion of fibrosis, inflammation and tumorigenesis resulting from Atg5 knockdown during the preneoplastic stage. In conclusion, autophagy-deficient Kupffer cells promote liver fibrosis, inflammation and, finally, hepatocarcinogenesis during the preneoplastic stage by enhancing mitochondrial ROS- NF-kappaB-IL1alpha/beta pathways. PMID- 28011322 TI - Erratum. PMID- 28011321 TI - Cuticular body hairs mediate clumping of small Camponotus floridanus larvae. AB - The body surface of insects usually carries cuticular hairs. Commonly, important functions of these structures are to prevent drowning and to defend against predators. Here, we report on our studies on hairs at the surface of larvae of the ant species Camponotus floridanus and Camponotus sericeiventris. First, we present data supporting the hypothesis that anti-drowning properties of the surface might rely on cuticular hairs. Second, we show that especially in young larvae body hairs serve as attachment and interlocking devices mediating clumping of larvae facilitating transport by workers. Based on our observations, we speculate that clumping also enhances larval perceptibility. Taken together, larval cuticular hairs seem to have at least two important functions augmenting chances of larval survival. Obviously, despite their immobility, young Camponotus larvae support childcare in the ant colony providing an arsenal of cuticular hairs on their body surface. PMID- 28011323 TI - Intensive Care Unit Monitoring After Pharyngeal Flap Surgery: Is It Necessary? AB - PURPOSE: To assess the incidence of perioperative complications and the utility of intensive care monitoring in patients undergoing posterior pharyngeal flap surgery for velopharyngeal dysfunction (VPD). MATERIALS AND METHODS: This study was a retrospective evaluation of patients who underwent posterior pharyngeal flap surgery for treatment of VPD and an assessment of the incidence of perioperative complications. Descriptive statistics were computed. RESULTS: Over an 18-year period, 145 patients underwent pharyngeal flap surgery for VPD; 133 (91.7%) had complete data and were included as subjects. Mean patient age was 9.4 +/- 7.4 years; 50.4% were female. One hundred twenty-six patients (94.7%) had a history of cleft palate. Thirty-four patients (25.5%) had asthma or obstructive sleep apnea. Eighty-three patients (62.4%) were admitted to the intensive care unit (ICU) for postoperative monitoring. The average length of hospital stay was 1.9 +/- 0.9 days (range, 1 to 5 days). There were no incidents of serious postoperative complications, including death, bleeding, flap dehiscence or loss, or airway compromise requiring reintubation. Two patients (1.5%) had perioperative complications related to respiratory issues, one of whom required readmission to the ICU (0.8%). There were no differences in complications between those who were routinely admitted to the ICU and those who went directly to the floor (P = 1.00). There was no association between respiratory comorbidities and complications (P = .06). CONCLUSION: The perioperative complication rate for posterior pharyngeal flap surgery is low (<2%). Routine ICU admission for monitoring is not necessary. PMID- 28011324 TI - Temporomandibular Joint Discectomy With Abdominal Fat Graft Versus Temporalis Myofascial Flap: A Comparative Study. AB - PURPOSE: Open temporomandibular joint (TMJ) arthroplasty with discectomy has been described as a primary surgical treatment and as a secondary treatment when minimally invasive procedures have failed. The aim of the present study was to compare TMJ discectomy with a fat graft versus TMJ discectomy with a temporalis graft using the pain score and maximal interincisal opening (MIO). PATIENTS AND METHODS: We performed a retrospective study of patients who had undergone TMJ arthroplasty and discectomy with an abdominal fat graft or an interpositional temporalis flap at the University of Michigan from 1999 to 2014. The predictor variable was the type of surgical intervention. The main outcome variables were the pain score and MIO. Additional outcome variables were diet, medication use, the presence of myofascial pain, and occlusal outcomes. The statistical analysis included the mean +/- standard deviation, a 1-way analysis of variance for continuous data, and Pearson's chi2 test for categorical variables. RESULTS: The study cohort included 50 patients, of whom 30 had undergone discectomy with a fat graft and 20 had undergone discectomy with a temporalis myofascial graft. The mean pain scores were decreased by 78.3% in the myofascial flap group and 52.8% in the fat graft group. Changes in MIO showed a statistically significant increase in the fat graft group but only approached statistical significance in the myofascial flap group. CONCLUSIONS: The patients who had undergone TMJ arthroplasty and discectomy with a temporalis myofascial flap showed significantly greater improvement in pain scores and marginal improvement in the MIO compared with patients who had received an abdominal fat graft. PMID- 28011325 TI - Third Molar Complications in the Elderly-A Matched-Pairs Analysis. AB - PURPOSE: The aim of this study was to evaluate the perioperative morbidity of third molar (3M) removal in elderly patients in an attempt to estimate the long term future burden of 3M-related morbidity resulting from the postponement of 3M surgery to old age. MATERIALS AND METHODS: The study design was a retrospective matched-pair analysis comparing patients at least 65 years old (group A) with a control group of 15- to 20-year-old patients (group B). Age group was the predictor variable in this study. Outcome variables were general health status as defined by the modified Charlson score (MCS) and the American Society of Anesthesiologists (ASA) score, general surgical risks from antithrombotic or antiresorptive medication, and specific local surgical risks and complications. RESULTS: Patients in group A showed substantially more comorbidities as reflected in significantly higher MCS and ASA scores (P < .001). Older patients more frequently used antithrombotic agents (P < .001), had higher rates of ankylosis (P < .001) and nerve proximity (P < .001), and showed significantly more in intra and postoperative complications (P < .001), thus resulting in longer operations and a substantially longer hospital stay (P < .001). CONCLUSION: Within the limits of a non-epidemiologic approach, this study showed a substantially greater burden of morbidity and substantially worse outcome of 3M surgery in older adults compared with young adults. For the medical risks of an aging population, the present data suggest a veritable burst of 3M-associated morbidity when surgery is shifted to late adulthood. PMID- 28011326 TI - Preoperative Neutrophil-to-Lymphocyte Ratio Predicts the Prognosis of Oral Squamous Cell Carcinoma: A Large-Sample Prospective Study. AB - PURPOSE: To assess and determine the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The prospective study involving 1,202 patients with OSCC and surgical resection was carried out in Fujian, China. Two stage analyses were performed by randomly dividing all patients into 800 discovery and 402 replication sets. The optimal NLR cutoff points were identified by the X-tile program with minimum P values. Prognostic factors were evaluated using univariate and multivariate Cox regression models. RESULTS: The discovery set was categorized as low-, middle-, and high-risk groups based on optimal NLR cutoff points (<1.94, 1.94 to 3.66, and >3.66, respectively). A high NLR was meaningfully associated with an increased risk of death on survival (NLR 1.94 to 3.66, hazard ratio [HR] = 1.51; 95% confidence interval [CI], 1.09-2.08; NLR >3.66, HR = 1.76; 95% CI, 1.21-2.55). In the replication phase, patients with a high NLR showed considerably worse overall survival compared with those with a low NLR (NLR 1.94 to 3.66, HR = 1.61; 95% CI, 1.02-2.55; NLR >3.66, HR = 1.94; 95% CI, 1.16-3.27). In addition, better overall survival was observed for patients with a higher NLR who had received postoperative chemoradiotherapy (HR = 0.49; 95% CI, 0.26-0.92). CONCLUSION: The preoperative NLR is an independent factor in predicting the prognosis of OSCC, especially for patients with chemoradiotherapy, which could serve as a potential target for improving patients' prognosis. PMID- 28011327 TI - Simultaneous Impacted Third Molar Extraction and Lateral Ramus Block Graft Harvest for Horizontal Ridge Augmentation: A Case Series. AB - PURPOSE: The purpose of this study was to confirm the efficiency of using a lateral ramus block graft taken at the time of impacted mandibular third molar removal for horizontal ridge augmentation and implant placement. PATIENTS AND METHODS: Ten patients had grafts obtained from the lateral aspect of the mandible during impacted third molar removal and placed in areas of horizontal ridge deficiency. RESULTS: Measurements made on cone-beam computerized tomograms after 4 months showed gains of 2.7 to 3.5 mm and 16 implants were placed successfully. CONCLUSIONS: In patients with impacted third molars requiring dental implants, simultaneous harvest of a lateral block bone graft is an efficient way of obtaining bone for horizontal ridge augmentation. PMID- 28011328 TI - Impact of acute atrial fibrillation termination and prolongation of atrial fibrillation cycle length on the outcome of ablation of persistent atrial fibrillation: A substudy of the STAR AF II trial. AB - BACKGROUND: Controversy exists about the impact of acute atrial fibrillation (AF) termination and prolongation of atrial fibrillation cycle length (AFCL) during ablation on long-term procedural outcome. OBJECTIVE: The purpose of this study was to analyze the influence of AF termination and AFCL prolongation on freedom from AF in patients from the STAR AF II (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial-Part II) trial. METHODS: Acute changes in AFCL and AF termination were collected during the index procedure of the STAR AF II trial and compared to recurrence of AF at 18 months. Recurrence was assessed by ECG, Holter (3, 6, 9, 12, 18 months), and weekly transtelephonic ECG monitoring for 18 months. RESULTS: AF terminated in 8% of the pulmonary vein isolation (PVI) arm, 45% in the PVI+complex electrogram arm, and 22% of the PVI+linear ablation arm (P <.001), but freedom from AF did not differ among the 3 groups (P = .15). Freedom from AF was significantly higher in patients who presented to the laboratory in sinus rhythm (SR) compared to those without AF termination (63% vs 44%, P = .007). Patients with AF termination had an intermediate outcome (53%) that was not significantly different from those in SR (P = .84) or those who did not terminate (P = .08). AF termination was a univariable predictor of success (P = .007), but by multivariable analysis, presence of early SR was the strongest predictor of success (hazard ratio 0.67, P = .004). Prolongation of AFCL was not predictive of 18-month freedom from AF. CONCLUSION: Acute AF termination and prolongation in AFCL did not consistently predict 18-month freedom from AF. Presence of SR before or early during the ablation was the strongest predictor of better outcome. PMID- 28011329 TI - Functional role of CCL5/RANTES for HCC progression during chronic liver disease. AB - BACKGROUND & AIMS: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development. METHODS: CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMODeltahepa/CCL5-/- animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24h or 8weeks. RESULTS: In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2-/- and NEMODeltahepa model. CCL5 deletion in NEMODeltahepa mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45+/Ly6G+ granulocytes, CD45+/CD11b+/Gr1.1+/F4/80+ pro-inflammatory monocytes, CD4+ and CD8+ T cells were decreased. One year old NEMODeltahepa/CCL5-/- mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMODeltahepa hepatocytes towards TNFalpha induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8weeks ameliorated liver disease progression. CONCLUSION: We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD. LAY SUMMARY: Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease. PMID- 28011330 TI - Current progress in immunotherapy of hepatocellular carcinoma. PMID- 28011331 TI - Multi drug resistant female genital tuberculosis: A preliminary report. AB - OBJECTIVE: Evaluation of 6 patients presenting with tubo-ovarian mass or infertility with multi drug resistant (MDR) female genital tuberculosis (FGTB). STUDY DESIGN: It was an observational study in a tertiary referral centre, India on subjects with MDR FGTB on clinical examination and investigations. All patients were given category IV drugs using kanamycin (intramuscular), levofloxacin, pyrazinamide, cycloserine, ethionamide and ethambutol (or para aminosalicylic acid [PAS] for ethambutol resistant cases) for 6 months intensive phase followed by oral levofloxacin, cycloserine, ethionamide and ethambutol (or PAS for ethambutol resistant cases) for 18 months continuation phase. Patients were evaluated for primary end points (complete cure, partial response, no response, treatment completed) and secondary end points (recurrence rate, pregnancy rate) during treatment. RESULTS: There were 2 (33.3%) primary MDR FGTB patients and 4 (66.6%) secondary MDR FGTB (three pulmonary MDR and one MDR lymphadenitis) patients. Mean age was 23.6 years. Presenting features were menstrual dysfunction in all patients (100%) especially oligomenorrhea in 3 (50%) patients, weight loss in all the patients (100%), cough with expectoration in three patients (50%), tubo-ovarian masses in five (83.3%) patients. Endometrial biopsy showed positive culture for AFB with rifampicin and isoniazid (INH) resistance in both primary MDR FGTB patients and in two secondary MDR FGTB patients who were sexually active. In secondary MDR FGTB, three pulmonary MDR patients had positive sputum AFB smear and culture, while the patient with MDR lymphadenitis had lymph node aspirate for AFB smear and culture positive with all showing resistance to rifampicin and isoniazid. Gene Xpert on endometrial biopsy or sputum was positive in 5 (83.3%) patients. Three (50%) patients (one primary and two secondary) have completed therapy while other 3 (50%) are in continuation phase. All patients are asymptomatic with one having 12 weeks ongoing successful pregnancy. CONCLUSION: MDR FGTB should be thought of in women of FGTB with tubo- ovarian masses who are not responding to first line drugs. Gene Xpert can be used in early diagnosis of MDR FGTB. PMID- 28011332 TI - Cardiac complications in cancer treatment - A review. AB - Cardiac dysfunction is often associated with effective cancer treatment. A number of targeted therapies against cancer have been observed to cause cardiac dysfunction. In some instances, a patient may outlive his or her cancer but die due to heart failure. Recent research has been focused on the development of new avenues and technological advancements to monitor clinical cardiotoxicity and cardiac dysfunction due to anticancer treatment. These newer treatment options are also increasingly effective and are focused more on post-cancer life. The present review article expands the current view of cardiac complications involved in cancer treatment along with the recent developments in the area. PMID- 28011333 TI - Effect of simulation training on the development of nurses and nursing students' critical thinking: A systematic literature review. AB - OBJECTIVE: To gain insight into the existing scientific evidence on the effect of simulation on critical thinking in nursing education. DESIGN: A systematic literature review of original research publications. DATA SOURCES: In this systematic review, the papers published in English and Farsi databases of PubMed, Science Direct, ProQuest, ERIC, Google Scholar and Ovid, MagIran and SID, from 1975 to 2015 were reviewed by two independent researchers. REVIEW METHODS: Original research publications were eligible for review when they described simulation program directed on nursing student and nurses; used a control group or a pretest post-test design; and gave information about the effects of simulation on critical thinking. Two reviewers independently assessed the studies for inclusion. Methodological quality of the included studies was also independently assessed by the reviewers, using a checklist developed by Greenhalgh et al. and the checklist of Cochrane Center. Data related to the original publications were extracted by one reviewer and checked by a second reviewer. No statistical pooling of outcomes was performed, due to the large heterogeneity of outcomes. RESULTS: After screening the titles and abstracts of 787 papers, 16 ones were included in the review according to the inclusion criteria. These used experimental or quasi-experimental designs. The studies used a variety of instruments and a wide range of simulation methods with differences in duration and numbers of exposures to simulation. Eight of the studies reported that simulation training positively affected the critical thinking skills. However, eight studies reported ineffectiveness of simulation on critical thinking. CONCLUSION: Studies are conflicting about the effect of simulation on nurses and nursing students' critical thinking. Also, a large heterogeneity exists between the studies in terms of the instruments and the methods used. Thus, more studies with careful designs are needed to produce more credible evidence on the effectiveness of simulation on critical thinking. PMID- 28011334 TI - "The five-minute check-in" intervention to ease the transition into professional education: A descriptive analysis. AB - BACKGROUND: Students can have problems transitioning into nursing education, and nursing instructors can have an impact on this transition by using an active coaching role. OBJECTIVES: The objective of this study was to evaluate how early an academic coaching intervention helped students progress during the beginning of their first nursing semester. Student perceptions of the intervention were also explored. DESIGN: This study followed a descriptive non-experimental design. A nonprobability convenience sample was used. SETTINGS: A four-year Bachelor's nursing program at a private college in central Pennsylvania. PARTICIPANTS: The sample included 22 first semester students enrolled in their first nursing course. METHOD: For the first five weeks of the semester students were asked to meet with their nursing course instructors for "five minute check-ins". Students were coached on time management, study skills, access to resources, stress management, upcoming assignments, and grades. An online survey was also sent to students regarding their check-in experience. RESULTS: The student coaching needs changed throughout the five week intervention. At first students heavily needed time management coaching. Study skill coaching was a steady need through the second through fifth week, and stress management coaching increased during the last week of data collection, which was along the same time as their first exams. Students who attended four to five of the weekly visits had higher first test scores and higher overall course grades. The majority of students reported benefits for attending check-in visits including organization, study skills, and feeling more connected to the instructor. CONCLUSIONS: Students reported an overall benefit to attending check-in visits. Course instructors were able to intervene early with students' academic problems, and help students gain access to resources. Although the check-ins were to be brief visits, there was an impact on instructors time during the check-in weeks. PMID- 28011335 TI - Using simulation to improve the capability of undergraduate nursing students in mental health care. AB - INTRODUCTION: Mental health care is an increasing component of acute patient care and yet mental health care education can be limited in undergraduate nursing programs. The aim of this study was to establish if simulation learning can be an effective method of improving undergraduate nurses' capability in mental health care in an acute care environment. INTERVENTION: Undergraduate nursing students at an Australian university were exposed to several high-fidelity high-technology simulation activities that incorporated elements of acute emergency nursing practice and acute mental health intervention, scaffolded by theories of learning. This approach provided a safe environment for students to experience clinical practice, and develop their skills for dealing with complex clinical challenges. METHODS: Using a mixed method approach, the primary domains of interest in this study were student confidence, knowledge and ability. These were self-reported and assessed before and after the simulation activities (intervention) using a pre-validated survey, to gauge the self-rated capacity of students to initiate and complete effective care episodes. Focus group interviews were subsequently held with students who attended placement in the emergency department to explore the impact of the intervention on student performance in this clinical setting. RESULTS: Students who participated in the simulation activity identified and reported significantly increased confidence, knowledge and ability in mental health care post-intervention. They identified key features of the intervention included the impact of its realism on the quality of learning. There is some evidence to suggest that the intervention had an impact on the performance and reflection of students in the clinical setting. DISCUSSION: This study provides evidence to support the use of simulation to enhance student nurses' clinical capabilities in providing mental health care in acute care environments. Nursing curriculum development should be based on best evidence to ensure that future nursing graduates have the skills and capability to provide high-quality, holistic care. PMID- 28011336 TI - Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication. AB - The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 MUm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 MUg/mL SPION and 20 MUg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics. PMID- 28011337 TI - Risk-taking, locomotor activity and dopamine levels in the nucleus accumbens and medial prefrontal cortex in male rats treated prenatally with alcohol. AB - BACKGROUND: Prenatal alcohol exposure (PA) restricted to days 8-20 of rat gestation reduces the activity of the dopaminergic neurons (DA) in the ventral tegmental area (VTA). Hyperactivity and impulsivity have been observed under this treatment; however, it is unknown whether DA levels are affected. Decision-making in risk situations, meanwhile, has been associated with impulsive behavior, but because studies of this phenomenon in animal models are limited, we do not yet know whether PA has any effect. The present study investigated the effects of PA on risk-taking behavior and locomotor activity in pre-pubertal male rats. In addition, DA levels in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) in response to methylphenidate (MP) were assessed. METHODS: Dams were treated with either two daily 3.0-g/kg doses of alcohol or an isocaloric solution, from days 8-20 of gestation. Locomotor activity and risk-taking in pre pubertal male rats after PA, and DA levels in the NAcc and mPFC after a single dose of MP (5mg/kg), were analyzed. RESULTS: Hyperactivity and increased risk taking behavior were observed in the rats treated prenatally with alcohol compared to controls. Methylphenidate increased DA levels in the NAcc regardless of prenatal treatment, but significantly higher DA levels were found in the PA group regardless of postnatal treatment with saline or MP. CONCLUSION: The presence of hyperactivity and increased risk-taking behavior after prenatal alcohol treatment is supported. Results suggest that higher DA levels in the rats with PA could be due to a down-regulation of postsynaptic receptors, the desensitization of presynaptic receptors, or a compensatory over-activity of DA neurons in the VTA. PMID- 28011338 TI - Phylogenetic relationships of Burmeistera (Campanulaceae: Lobelioideae): Combining whole plastome with targeted loci data in a recent radiation. AB - The field of molecular systematics has benefited greatly with the advent of high throughput sequencing (HTS), making large genomic datasets commonplace. However, a large number of targeted Sanger sequences produced by many studies over the last two decades are publicly available and should not be overlooked. In this study, we elucidate the phylogenetic relationships of the plant genus Burmeistera (Campanulaceae: Lobelioideae), while investigating how to best combine targeted Sanger loci with HTS data. We sequence, annotate, and analyze complete to nearly complete plastomes for a subset of the genus. We then combine these data with a much larger taxonomic dataset for which only Sanger sequences are available, making this the most comprehensively sampled study in the genus to date. We show that using a phylogeny inferred from the species with plastome data as a topological constraint for the larger dataset increases the resolution of our data and produces a more robust evolutionary hypothesis for the group. We then use the resulting phylogeny to study the evolution of morphological traits thought to be important in Burmeistera, and assess their usefulness in the current taxonomic classification of the genus. The main morphological character used to delimit subgeneric sections, the presence or absence of hairs on the apex of the two ventral anthers, shows a complex evolutionary history with many changes in the tree, suggesting that this character should not be used for taxonomic classification. Although it is too soon to propose a new subgeneric classification for Burmeistera, our results highlight some morphological traits shared by whole clades that could potentially be used in future taxonomic work. PMID- 28011339 TI - Assessment of accumulated damage in circular tubes using nonlinear circumferential guided wave approach: A feasibility study. AB - The feasibility of using the nonlinear effect of primary Circumferential Guided Wave (CGW) propagation for assessing accumulated damage in circular tubes has been investigated. For a given circular tube, an appropriate mode pair of fundamental and double frequency CGWs is chosen to enable that the second harmonic of the primary wave mode can accumulate along the circumferential direction. After the given circular tube is subjected to compression-compression repeated loading for different numbers of loading cycles, the corresponding ultrasonic measurements are conducted. It is found that there is a direct correlation between the acoustic nonlinearity parameter measured with CGWs propagating through one full circumference and the level of accumulated damage in the circular tube. The experimental result obtained validates the feasibility for quantitative assessment of the accumulated damage in circular tubes using the effect of second-harmonic generation by CGW propagation. PMID- 28011340 TI - Depth-of-field enhancement in Filtered-Delay Multiply and Sum beamformed images using Synthetic Aperture Focusing. AB - The Synthetic Aperture Focusing (SAF) technique makes it possible to achieve a higher and more uniform quality of ultrasound images throughout depth, as if both transmit and receive dynamic focusing were applied. In this work we combine a particular implementation of SAF, called Synthetic Transmit Aperture (STA) technique, in which a single element in turn transmits and all the array elements receive the ultrasound wave, with the Filtered-Delay Multiply and Sum (F-DMAS) non-linear beamforming algorithm that we presented in a previous paper. We show that using F-DMAS, which is based on a measure of backscattered signal spatial correlation, B-mode images have a higher contrast resolution but suffer from a loss of brightness away from the transmit focus, when a classical scan with receive-only dynamic focusing is performed. On the other hand, when synthetic transmit focusing is achieved by implementing STA, such a loss is compensated for and a higher depth of field is obtained, as signal coherence improves. A drawback of SAF/STA however is the reduced signal-to-noise ratio, due to single-element transmission; in the paper we also analyze how this influences F-DMAS images. Finally, a preliminary investigation on the use of the classical monostatic SAF technique with F-DMAS beamforming is also carried out to evaluate its potential performances. PMID- 28011341 TI - How schistosomes alter the human serum proteome. AB - Schistosomes are intravascular parasitic worms that cause the debilitating disease schistosomiasis. To better understand how these long-lived parasites may subvert host immune and hemostatic capabilities, we examine here the impact of adult Schistosoma mansoni worms on the human serum proteome. Normal human serum (150MUl) was incubated at 37 degrees C for one hour either in the presence or absence of adult worms (~50 pairs). Thereafter parasites were removed, serum samples were labeled and their proteins resolved for comparative analysis by 2D Differential in-Gel Electrophoresis (2D-DIGE). Several differences were noted between the two samples. Twenty protein spots were recovered and identified following trypsin digestion and mass spectroscopy. Strikingly, most of these (11/20) are associated with the complement system and include complement components C3, C4, factor B, complement factor H related protein 1 and clusterin. Western blot analysis confirms the impact of the worms on C3, C4 and factor B in serum. The data suggest that schistosomes engage complement but can rapidly degrade selected complement proteins which may help explain the worm's refractoriness towards complement-mediated attack. Other serum proteins identified as being impinged upon by schistosomes are alpha 2 macroglobulin, alpha 1 anti-chymotrypsin, actin cytoplasmic 2, serum amyloid A-4, protein DDX26B, hemoglobin subunit B and serum albumin. While the molecular nature of the interaction between these proteins and schistosomes is not known, possible roles for some of them in hemostasis, immune evasion and in the host response to serum stress are suggested. PMID- 28011342 TI - Understanding and predicting the impact of critical dissolution variables for nifedipine immediate release capsules by multivariate data analysis. AB - In this study the selection of in vivo predictive in vitro dissolution experimental set-ups using a multivariate analysis approach, in line with the Quality by Design (QbD) principles, is explored. The dissolution variables selected using a design of experiments (DoE) were the dissolution apparatus [USP1 apparatus (basket) and USP2 apparatus (paddle)], the rotational speed of the basket/or paddle, the operator conditions (dissolution apparatus brand and operator), the volume, the pH, and the ethanol content of the dissolution medium. The dissolution profiles of two nifedipine capsules (poorly soluble compound), under conditions mimicking the intake of the capsules with i. water, ii. orange juice and iii. an alcoholic drink (orange juice and ethanol) were analysed using multiple linear regression (MLR). Optimised dissolution set-ups, generated based on the mathematical model obtained via MLR, were used to build predicted in vitro in vivo correlations (IVIVC). IVIVC could be achieved using physiologically relevant in vitro conditions mimicking the intake of the capsules with an alcoholic drink (orange juice and ethanol). The multivariate analysis revealed that the concentration of ethanol used in the in vitro dissolution experiments (47% v/v) can be lowered to less than 20% v/v, reflecting recently found physiological conditions. PMID- 28011343 TI - Design and characterization of a magnetite/PEI multifunctional nanohybrid as non viral vector and cell isolation system. AB - It is described the reproducible formulation and complete physicochemical characterization of nanohybrids based on magnetite (Fe3O4) cores embedded within a polyethylenimine (PEI) matrix. Particle size, surface electrical charge, X-ray diffraction and Fourier transform infrared spectroscopy (FTIR) analyses, and magnetic field-responsive behaviour characterizations defined that the 4:3 (Fe3O4:PEI) weight proportion led to the best production performances of magnetically responsive nanocomposites in which the magnetic nuclei are completely covered by the polymeric shell. Agarose gel electrophoresis assays demonstrated the capacity of the Fe3O4/PEI particles to condense, release, and protect the DNA against enzymatic degradation. In vitro assays were performed to evaluate the transfection efficiency (up to 4.5% of transfected HEK-293 cells at a 10/1 PEI/DNA ratio), iron absorption by D1-mesenchymal stem cells (D1-MSCs, high values after only 15min of magnetic incubation), influence on metabolic activity (negligible effect up to 44MUg nanocomposites/105 cells), and cell isolation capacity of the core/shell particles (significant increase in the retention of D1-MSCs transduced with green fluorescent protein). The Fe3O4/PEI nanohybrids hold promising characteristics suggestive of their capacity for transfection and cell isolation applications. PMID- 28011344 TI - Dermal quercetin lipid nanocapsules: Influence of the formulation on antioxidant activity and cellular protection against hydrogen peroxide. AB - Quercetin is a plant flavonoid with strong antioxidant and antiinflammatory properties interesting for skin protection. However, its poor water solubility limits its penetration and so its efficiency on skin. For this purpose, quercetin lipid nanocapsules were formulated implementing phase inversion technique wherein several modifications were introduced to enhance quercetin loading. Quercetin lipid nanocapsules were formulated with two particle size range, (50nm and 20nm) allowing a drug loading of 18.6 and 32mM respectively. The successful encapsulation of quercetin within lipid nanocapsules increased its apparent water solubility by more than 5000 fold (from 0.5MUg/ml to about 5mg/ml). The physicochemical properties of these formulations such as surface charge, stability and morphology were characterized. Lipid nanocapsules had spherical shape and were stable for 28days at 25 degrees C. Quercetin release from lipid nanocapsules was studied and revealed a prolonged release kinetics during 24h. Using DPPH assay, we demonstrated that the formulation process of lipid nanocapsules did not modify the antioxidant activity of quercetin in vitro (92.3%). With the goal of a future dermal application, quercetin lipid nanocapsules were applied to THP-1 monocytes and proved the cellular safety of the formulation up to 2MUg/ml of quercetin. Finally, formulated quercetin was as efficient as the crude form in the protection of THP-1 cells from oxidative stress by exogenous hydrogen peroxide. With its lipophilic nature and occlusive effect on skin, lipid nanocapsules present a promising strategy to deliver quercetin to skin tissue and can be of value for other poorly water soluble drug candidates. PMID- 28011345 TI - Genotyping of friesian horses to detect a hydrocephalus-associated c.1423C>T mutation in B3GALNT2 using PCR-RFLP and PCR-PIRA methods: Frequency in stallion horses in Mexico. AB - Hydrocephalus in Friesian horses is an autosomal recessive hereditary disease that can result in an abortion, a stillbirth, or euthanization of a newborn foal. Here, the hydrocephalus-associated c.1423C > T mutation in B3GALNT2 gene was detected with PCR-RFLP and PCR-PIRA methods for horse genotyping. A preliminary genotyping survey was performed on 83 randomly selected Friesian stallion horses to determine the current allele frequency in Mexico. The frequency of the mutant T allele was 9.6%. PMID- 28011346 TI - Bucindolol improves right ventricle function in rats with pulmonary arterial hypertension through the reversal of autonomic imbalance. AB - Pulmonary arterial hypertension (PAH) is characterised by an elevation in afterload imposed on the right ventricle (RV), leading to hypertrophy and failure. The autonomic nervous system (ANS) plays a key role in the progression to heart failure, and the use of beta-blockers attenuates this process. The aim of this study was to verify the role of bucindolol, abeta1-, beta2- and alpha1 blocker, on the ANS, and its association with RV function in rats with PAH. Male Wistar rats were divided into four groups: control, monocrotaline, control+bucindolol, and monocrotaline+bucindolol. PAH was induced by a single intraperitoneal injection of monocrotaline (60mg/kg). After two weeks, animals were treated for seven days with bucindolol (2mg/kg/day i.p.) or vehicle. At the end of the treatment, animals underwent echocardiographic assessment, catheterisation of the femoral artery and RV, and tissue collection for morphometric and histological evaluation. In the monocrotaline+bucindolol group, there was a decrease in mean pulmonary artery pressure (33%) and pulmonary congestion (21%), when compared to the monocrotaline. Bucindolol treatment also reduced RV pleomorphism, necrosis, fibrosis and infiltration of inflammatory cells. An improvement in RV systolic function was also observed in the monocrotaline+bucindolol group compared to the monocrotaline. In addition, bucindolol promoted a decrease in the cardiac sympathovagal balance (93%) by reducing sympathetic drive (70%) and increasing parasympathetic drive (142%). Bucindolol also reduced blood pressure variability (75%). Our results show that the beneficial effects from bucindolol treatment appeared to be a consequence of the reversal of monocrotaline-induced autonomic imbalance. PMID- 28011347 TI - EBSD and electron channeling study of anomalous slip in oligocrystals of high chromium ferritic stainless steel. AB - In the present study, electron backscatter diffraction (EBSD) and electron channeling contrast imaging (ECCI) techniques were applied to investigate the deformation pattern of coarse ferrite grains after being subjected to 3%, 6%, and 10% tensile deformation. Oligocrystals of Crofer(r) 22H ferritic steel were obtained as experimental material at 1075 degrees C for 22min annealing. Using kernel average misorientation (KAM) mapping obtained from EBSD, possible slip planes are (110), (101), (12-1) and (32-1) in grain A; (0-11), (-101), (-112), (1 21) in grain B; and (0-11), (1-21) and (11-2) in grain C. Combining ECCI and EBSD techniques enables us to identify two a0[11-1]/2 edge dislocations that occur on the (110)[1-11] and (32-1)[1-11] slip systems for grain A, thereby breaking down Schmid's law. PMID- 28011349 TI - Elevated prevalence of multidrug-resistant Acinetobacter baumannii with extensive genetic diversity in the largest burn centre of northeast Iran. AB - OBJECTIVES: The emergence and spread of multidrug-resistant (MDR) Acinetobacter baumannii isolates is now frequently associated with nosocomial infections. The aim of this study was to evaluate the genetic relatedness and patterns of antimicrobial resistance amongst A. baumannii isolated from a burn centre at a teaching hospital in Iran. METHODS: A total of 54 A. baumannii isolates were collected from burn wound infections of hospitalised patients. Antimicrobial susceptibility of the isolates was determined, and genotyping analysis was performed by repetitive extragenic palindromic PCR (rep-PCR). PCR assay was performed to investigate the distribution of beta-lactamase, aminoglycoside modifying enzyme and efflux pump genes. RESULTS: Etest results revealed that the most active antimicrobial agent was colistin (100% susceptibility), followed by tigecycline (96.3%). The blaOXA-51 and blaADC genes were detected in all of the isolates, but blaOXA-58-like was not detected. The prevalence of blaTEM, blaIMP, blaVIM, blaOXA-23-like and blaOXA-24-like genes was 64.8%, 70.4%, 70.4%, 66.7% and 68.5%, respectively. ISAba1 was detected upstream of blaOXA-23-like and blaADC in 66.7% and 77.8% of isolates, respectively. This study showed a high level of distribution of adeB (72.2%), aphA6 (81.5%), aacC1 (85.2%), aadA1 (59.3%), aadB (31.5%), tetB (70.4%) and aphA1 (29.6%) in A. baumannii strains. Based on rep-PCR analysis, four clusters (I-IV) were defined. CONCLUSIONS: The elevated prevalence of MDR A. baumannii strains in this burn centre suggests that local antibiotic prescription policies should be precisely revised. Moreover, strict infection control procedures to prevent further dissemination need to be prioritised immediately. PMID- 28011348 TI - Multidrug transporters and organic anion transporting polypeptides protect insects against the toxic effects of cardenolides. AB - In the struggle against dietary toxins, insects are known to employ target site insensitivity, metabolic detoxification, and transporters that shunt away toxins. Specialized insects across six taxonomic orders feeding on cardenolide-containing plants have convergently evolved target site insensitivity via specific amino acid substitutions in the Na/K-ATPase. Nonetheless, in vitro pharmacological experiments have suggested a role for multidrug transporters (Mdrs) and organic anion transporting polypeptides (Oatps), which may provide a basal level of protection in both specialized and non-adapted insects. Because the genes coding for these proteins are evolutionarily conserved and in vivo genetic evidence in support of this hypothesis is lacking, here we used wildtype and mutant Drosophila melanogaster (Drosophila) in capillary feeder (CAFE) assays to quantify toxicity of three chemically diverse, medically relevant cardenolides. We examined multiple components of fitness, including mortality, longevity, and LD50, and found that, while the three cardenolides each stimulated feeding (i.e., no deterrence to the toxin), all decreased lifespan, with the most apolar cardenolide having the lowest LD50 value. Flies showed a clear non-monotonic dose response and experienced high levels of toxicity at the cardenolide concentration found in plants. At this concentration, both Mdr and Oatp knockout mutant flies died more rapidly than wildtype flies, and the mutants also experienced more adverse neurological effects on high-cardenolide-level diets. Our study further establishes Drosophila as a model for the study of cardenolide pharmacology and solidifies support for the hypothesis that multidrug and organic anion transporters are key players in insect protection against dietary cardenolides. PMID- 28011350 TI - Clinical effectiveness of daptomycin loading dose in patients infected with Gram positive pathogens. AB - This study was to evaluate the loading does of daptomycin, a novel lipopeptide antibacterial active against Gram-positive pathogens, on clinical efficiency. We divided patients received daptomycin therapy into 2 groups. One of two groups comprised patients received the loading dose of daptomycin on day 1 (group 1) and the other group received normal dosage (4-6 mg/kg/day) (group 2). Inflammatory markers were assessed at least 3 days before daptomycin therapy started as their baseline, and 2 weeks from daptomycin therapy started for the evaluation of clinical efficacy. The bacteriological results were also evaluated. The occurrence of creatinine kinase (CK) elevation was evaluated as side effect. As results, the only group 1 showed significant improvements in body temperature and CRP on 4-7 days after daptomycin therapy started, while 2 groups significantly improved in WBC, body temperature and CRP on 8-14 days, respectively. The group 1 showed early improvement of body temperature (<37.5 degrees C) on 4-7 days, compared with the group 2 (group 1; 3 [2-7], group 2; 6 [2-11], p = 0.01). The bacteriological cure rates in both groups showed high cure rates (group 1; 20/0, group 2; 27/3, p = 0.14). The frequency of CK elevation was 0% (0/22 patients) and 3.0% (1/33 patients) in group 1 and group 2, respectively. In our conclusion, daptomycin loading dose did not prove evident clinical effectiveness, compared with the regimen without loading dose. However, we could not disclaim the potential to improve clinical response early with DAP loading dose for critically ill patients. PMID- 28011351 TI - Intracranial hypertension secondary to high dose cytosine arabinoside - A case study. AB - We report a rare case of intracranial hypertension following high dose cytosine arabinoside (HiDAC) in a 20-year-old man, with precursor B-cell acute lymphoblastic leukemia (ALL). A five drug induction protocol for ALL was initiated; post induction consolidation was with HiDAC (3 g/m2 IV every 12 h on days 1, 3 and 5). Post consolidation, cytogenetic remission was attained and he received an intensification and maintenance regimen for ALL, for a period of approximately 24 months. Four months following the completion of his treatment, the patient relapsed within the central nervous system (CNS). Intravenous salvage chemotherapy was initiated using a combination of fludarabine 30 mg/m2, followed by cytarabine 2 g/m2 4 h later on days 1 through 5 (FA). On day # 23 of FA, he developed a severe headache. A gadolinium-enhanced brain magnetic resonance imaging (MRI) revealed increased intracranial pressure. On day # 25, ophthalmology examination suggested bilateral papilledema. He was started on acetazolamide 250 mg twice daily. He had spontaneous resolution of his symptoms. The patient had no recurrence of papilledema or any other neurological symptoms. Intracranial hypertension secondary to HiDAC, is an exceedingly rare complication and is not regularly associated as a common side effect of cytarabine administration. Prompt action in diagnosing and treating intracranial hypertension will save the patient from consequences, such as loss of vision, that are prevalent in this condition. PMID- 28011352 TI - Clinical characteristics and predictive factors for mortality in coryneform bacteria bloodstream infection in hematological patients. AB - BACKGROUND: We examined the clinical characteristics and predictive factors for mortality in coryneform bacteria bloodstream infection in hematological patients. METHODS: We searched for hematological patients who had positive blood cultures for coryneform bacteria at our center between April 2007 and January 2016. Patients with definite bloodstream infections were included. We started species identification in April 2014. RESULTS: Twenty of twenty-eight cases with a positive blood culture for coryneform bacteria were regarded as definite infections. Sixteen and two patients were allogeneic and autologous hematopoietic stem cell transplantation (HSCT) recipients, respectively. Corynebacterium striatum was identified in all nine of the cases tested and one patient was co infected with Corynebacterium amycolatum. None of the patients died directly due to coryneform bacteria infection. The survival rates at 30, 60 and 180 days were 100%, 73.7% and 51.3%, respectively. Causes of mortality included progression of the underlying disease (n = 6), other infections (n = 4) and HSCT complications (n = 2). Mixed infection (hazard ratio (HR) 5.47, 95% confidence interval (CI) 1.30-23.0), renal impairment (HR 6.31, 95% CI 1.06-37.4) and absence of a central venous (CV) catheter at the onset (HR 6.39, 95% CI 1.04-39.45) were identified as predictive factors for mortality. CONCLUSION: Most of the coryneform bacteria bloodstream infections occurred in HSCT recipients. Contamination seemed to be less common when coryneform bacteria were detected in blood in hematological patients. Although coryneform bacteria bloodstream infection seemed to mostly be manageable, the prognosis was not desirable, particularly in patients with mixed infection, renal impairment and absence of a CV catheter. PMID- 28011353 TI - Erratum to "Genome-wide association study in East Asians suggests UHMK1 as a novel bone mineral density susceptibility" [Bone 91 (2016) 113-121]. PMID- 28011354 TI - Ozone regeneration of granular activated carbon for trihalomethane control. AB - Spatial and temporal variations of trihalomethanes (THMs) in distribution systems have challenged water treatment facilities to comply with disinfection byproduct rules. In this study, granular activated carbon (GAC) and modified GAC (i.e., Ag GAC and TiO2-GAC) were used to treat chlorinated tap water containing CHCl3 (15 21MUg/L), CHBrCl2 (13-16MUg/L), CHBr2Cl (13-14MUg/L), and CHBr3 (3MUg/L). Following breakthrough of dissolved organic carbon (DOC), GAC were regenerated using conventional and novel methods. GAC regeneration efficiency was assessed by measuring adsorptive (DOC, UV absorbance at 254nm, and THMs) and physical (surface area and pore volume) properties. Thermal regeneration resulted in a brief period of additional DOC adsorption (bed volume, BV, ~6000), while ozone regeneration was ineffective regardless of the GAC type. THM adsorption was restored by either method (e.g., BV for >=80% breakthrough, CHBr3 ~44,000>CHBr2Cl ~35,000>CHBrCl2 ~31,000>CHCl3 ~7000). Cellular and attached adenosine triphosphate measurements illustrated the antimicrobial effects of Ag-GAC, which may have allowed for the extended THM adsorption compared to the other GAC types. The results illustrate that ozone regeneration may be a viable in-situ alternative for the adsorption of THMs during localized treatment in drinking water distribution systems. PMID- 28011355 TI - Elimination of representative contaminant candidate list viruses, coxsackievirus, echovirus, hepatitis A virus, and norovirus, from water by coagulation processes. AB - We examined the removal of representative contaminant candidate list (CCL) viruses (coxsackievirus [CV] B5, echovirus type [EV] 11, and hepatitis A virus [HAV] IB), recombinant norovirus virus-like particles (rNV-VLPs), and murine norovirus (MNV) type 1 by coagulation. Water samples were subjected to coagulation with polyaluminum chloride (PACl, basicity 1.5) followed by either settling or settling and filtration. Together with our previously published results, the removal ratio order, as evaluated by a plaque-forming-unit method or an enzyme-linked immunosorbent assay after settling, was HAV>EV=rNV VLPs>=CV=poliovirus type 1=MNV>adenovirus type 40 (range, 0.1-2.7-log10). Infectious HAV was likely inactivated by the PACl and therefore was removed to a greater extent than the other viruses. A nonsulfated high-basicity PACl (basicity 2.1), removed the CCL viruses more efficiently than did two other sulfated PACls (basicity 1.5 or 2.1), alum, or ferric chloride. We also examined the removal ratio of two bacteriophages. The removal ratios for MS2 tended to be larger than those of the CCL viruses, whereas those for phiX174 were comparable with or smaller than those of the CCL viruses. Therefore, phiX174 may be a useful conservative surrogate for CCL viruses during coagulation. PMID- 28011356 TI - Endoscopic Removal of Suprasellar Colloid Cyst with Interpeduncular and Prepontine Cisterns Extension. AB - BACKGROUND: Colloid cysts (CCs) are rarely found in the sellar-suprasellar region. Differential diagnosis of CCs is more challenging in this region because many other cystic lesions may locate or invade sellar or suprasellar structures. We present a large and unusual case of sellar-suprasellar CC with extension into the suprasellar, interpeduncular, and prepontine cisterns. This is the first case of sellar-suprasellar CC treated with an endoscopic transsphenoidal approach. CASE DESCRIPTION: A 33-year-old woman presented with a 1-year history of recurrent headaches. Her headaches had been unresponsive to medical treatment for the last 2 weeks. She had normal neurologic and ophthalmologic examinations. Neuroradiologic studies showed a large cystic sellar lesion with extension into the suprasellar, interpeduncular, and prepontine cisterns. The lesion did not show any enhancement, not even in the cyst wall. Her hormonal status was also normal. The cystic lesion was totally resected via a purely endoscopic endonasal approach. There were no complications, and the patient was recovered completely with improvement of her headache. Pathology was consistent with a CC. At 6-month follow-up, magnetic resonance imaging did not show any evidence of the residual or recurrent lesion. CONCLUSIONS: Although rarely found in this location, CC should be considered in the differential diagnosis in patients who present with a sellar-suprasellar cystic lesion. Additionally, sellar-suprasellar CC would be a good candidate for the endoscopic endonasal approach. PMID- 28011357 TI - Prognostic Differences: Epstein-Barr Virus-Associated Primary Leiomyosarcoma of the Spine Versus Spinal Leiomyosarcoma Metastases. AB - OBJECTIVE: The authors studied 6 cases of osseous leiomyosarcoma of the spine. Two of these cases were of immunocompromised human immunodeficiency virus (HIV) positive patients with Epstein-Barr virus (EBV)-associated primary vertebral leiomyosarcomas. The remaining 4 cases were of patients with leiomyosarcoma metastases to the spine. METHODS: Each patient underwent surgical resection of their vertebral mass; however, the patients with the EBV-associated tumors had the best postoperative prognosis. RESULTS: The HIV-positive patients have had no further local recurrence, while the other 4 patients had rapid local recurrences requiring multiple surgical interventions. Furthermore, the patients living with HIV have lived longer with fewer leiomyosarcoma-related health complications. CONCLUSIONS: These findings suggest that EBV-associated vertebral leiomyosarcoma is of a less aggressive variety than metastatic leiomyosarcoma of the spine. PMID- 28011358 TI - Anticoagulation Therapy in Patients Suffering from Aneurysmal Subarachnoid Hemorrhage: Influence on Functional Outcome-a Single-Center Series and Multivariate Analysis. AB - INTRODUCTION: Favorable outcome in patients presenting with aneurysmal subarachnoid hemorrhage (SAH) is determined by several factors. Nevertheless, data on the influence of prior use of oral anticoagulation drugs on functional outcome in patients suffering from SAH are scarce. We therefore analyzed our institutional data. METHODS: From January 2009 to October 2015, 480 patients suffering from aneurysmal SAH were admitted to our institution. Information including patient characteristics, treatment modality, aneurysm size and location, radiologic features, and functional neurologic outcome was assessed and further analyzed. Outcome was assessed according to the modified Rankin Scale (mRS) at 6 months and stratified into favorable (mRS 0-2) versus unfavorable (mRS 3-6). RESULTS: Overall, 17 of 480 patients suffering from aneurysmal SAH were on anticoagulation therapy before ictus (4%). Patients without anticoagulation therapy were significantly younger compared with patients with anticoagulation therapy before SAH (P = 0.005). Furthermore, patients without anticoagulation therapy presented in a significantly better clinical condition compared with patients with anticoagulation therapy before SAH (P = 0.02). Additionally, patients without anticoagulation therapy achieved significantly more often favorable functional outcome compared with patients with anticoagulation therapy before SAH (P = 0.02). However, anticoagulation therapy was not identified as a significant and independent predictor for unfavorable outcome in the multivariate logistic regression analysis. CONCLUSION: Anticoagulation therapy has not been identified as a significant and independent factor influencing functional outcome in patients suffering from SAH. Therefore treatment should not be omitted. Nevertheless, cautious management is necessary in patients with known anticoagulation therapy before SAH. PMID- 28011359 TI - Detection of a Rare Complication of Endovascular Treatment for Brain Arteriovenous Malformation with Echocardiography. AB - A brain arteriovenous malformation (AVM) is a congenital malformation of the vascular system, in which an abnormal short circuit (vascular malformation) connects cerebral arteries and veins. When the brain AVMs are diagnosed, the majority of them must be closed with surgical or endovascular treatment, because only a small portion of the brain AVMs remain asymptomatic during the patient's life. Endovascular transarterial embolization using Onyx Liquid Embolic System is a suitable method for treating brain AVMs. Previously known complications of Onyx usage are bleeding and neurologic deficits. We report a young man with a rare complication of Onyx injection, clinically silent distal embolization to the heart chamber and pulmonary circulation, discovered incidentally with echocardiography. PMID- 28011360 TI - Effects of peppermint tea consumption on the activities of CYP1A2, CYP2A6, Xanthine Oxidase, N-acetyltranferase-2 and UDP-glucuronosyltransferases-1A1/1A6 in healthy volunteers. AB - Peppermint leaves are widely used for the symptomatic treatment of digestive disorders. Previous studies have shown significant effects of its natural products on human enzyme activity; however, there is no study available concerning the effects of peppermint tea on metabolizing enzymes in humans. Aim of the present study was to investigate the effect of peppermint tea on CYP1A2, CYP2A6, Xanthine Oxidase (XO), N-acetyltranferase-2 (NAT2) and UDP glucuronosyltransferases-1A1/1A6 (UGT1A1/1A6) activities in healthy subjects. Four males and five females consumed peppermint tea (2 g of dry leaves/200 mL water, twice daily) for six days. CYP1A2, CYP2A6, XO, NAT2 and UGT1A1/1A6 activities were determined before and at the end of the study period, using the following caffeine and paracetamol metabolic ratios: CYP1A2: 17MX/137MX (saliva) and (AFMU+1MU+1MX)/17MU (urine); CYP2A6: 17MU/(17MU + 17MX), XO: 1MU/(1MU+1MX), NAT2, AFMU/(AFMU+1MU+1MX) and UGT1A1/1A6 glucuronidated/total paracetamol, all determined in urine. NAT2 metabolic ratio was significantly reduced following peppermint consumption (0.15 +/- 0.13 vs 0.14 +/- 0.13; p < 0.05). CYP1A2 urine and saliva indices were reduced, yet not significantly, following peppermint consumption (urine: 3.17 +/- 1.08 vs 2.91 +/- 0.76, saliva: 0.56 +/- 0.12 vs 0.50 +/- 0.12; p > 0.05). Peppermint had no influence on CYP2A6, XO and UGT1A1/1A6 indices. Daily ingestion of peppermint tea may alter pharmacokinetics of clinically administered drugs and promote cancer chemoprevention through NAT2 inhibition. PMID- 28011361 TI - Unexpected effect of dry olive leaf extract on the level of DNA damage in lymphocytes of lead intoxicated workers, before and after CaNa2EDTA chelation therapy. AB - The CaNa2EDTA chelation therapy is often practiced with antioxidant supplementation. Dry olive leaf extract (DOLE) is natural product with antioxidant and DNA protective properties. The effects of DOLE on the levels of DNA damage were investigated ex vivo in peripheral blood lymphocytes (PBLs) of 19 workers occupationally exposed to lead (Pb), before and after CaNa2EDTA chelation therapy. DOLE demonstrated pronounced radical scavenging activity in concentrations >=1 mg/mL, and showed no genotoxicity per se, in concentrations 0.125-1 mg/mL. The level of DNA damage in PBLs of workers before chelation therapy was elevated (24.21 +/- 14.26) compared to controls (6.0 +/- 3.37). The incubation of PBLs before chelation therapy with selected concentration of DOLE lead to a severe increase of DNA damage (64.03 +/- 20.96), exhibiting prooxidant rather than antioxidant effect. After the five-day CaNa2EDTA chelation regimen, DNA damage in PBLs of workers decreased (8.26 +/- 4.62) significantly compared to baseline. Treatment of PBLs with DOLE after chelation, again produced high level of damage (41.82 +/- 23.17) and the acute prooxidant effects of DOLE remained, but, DNA damage was less severe than before chelation. The DOLE exhibits prooxidant effect in presence of Pb in lymphocytes of exposed workers, and its effect is less pronounced following the removal of Pb after standard chelation therapy. PMID- 28011362 TI - Designing living walls for greywater treatment. AB - Greywater is being increasingly used as an alternative water source to reduce potable water demand and to alleviate pressure on sewerage systems. This paper presents the development of a low energy and low maintenance greywater treatment technology: a living wall system, employing ornamental plants (including vines) grown in a sand filter on a side of a building to treat shower, bath, and washing basin wastewaters. The system can, at the same time, provide critical amenity and micro-climate benefits to our cities. A large scale column study was conducted in Melbourne, Australia, to investigate the following design and operational factors of the proposed system: plant species, saturated zone design, rest period, hydraulic loading rate and pollutant inflow concentration. The results indicate that the use of ornamental species (e.g. Canna lilies, Lonicera japonica, ornamental grape vine) can contribute to pollutant removal. Vegetation selection was found to be particularly important for nutrient removal. While a wider range of tested plant species was effective for nitrogen removal (>80%), phosphorus removal was more variable (-13% to 99%) over the study period, with only a few tested plants being effective - Carex appressa and Canna lilies were the best performers. It was also found that phosphorus removal can be compromised over the longer term as a result of leaching. Excellent suspended solids and organics removal efficiencies can be generally achieved in these systems (>80% for TSS and >90% for BOD) with plants having a relatively small impact. Columns had an acceptable infiltration capacity after one year of operation. When planted with effective species (e.g. Carex appressa and Canna lilies), it is expected that performance will not be significantly affected by longer rest periods and higher pollutant concentrations in the early years of system operation. The results of this study, thus, demonstrate that innovative and aesthetically pleasing living walls can be designed for treatment of greywater at the household scale. PMID- 28011363 TI - Significant changes in the photo-reactivity of TiO2 in the presence of a capped natural dissolved organic matter layer. AB - Natural dissolved organic matter (NDOM) in surface waters has a high sorption affinity for TiO2 during long contact. An attached NDOM layer can act as a conduction band electron and/or valance band hole acceptor, and NDOM can also decrease the concentration of hydroxyl radicals (OH) in the bulk phase. Therefore, the degradation kinetics and mechanism for degradation of acetaminophen on NDOM capped TiO2 (NDOM-TiO2) are significantly different from those on raw TiO2. Quantum calculation results suggest that hydroxylation to the ortho position in relation to the acetamide group is more favorable. Although OH induced hydroxylation is the predominant pathway for degradation of acetaminophen on TiO2, one-electron oxidation of acetaminophen by a valance band hole, excited triplet NDOM or NDOM radical cation is the major degradation pathway on NDOM TiO2. This study is the first to detect and confirm APAP oligomers as intermediates during the degradation of acetaminophen by TiO2 photocatalysis, especially when using NDOM-TiO2 as a catalyst. The results suggest the reactivity of TiO2 could change significantly after long exposure to natural water, which need to be concerned about for removal of micropollutants in surface water by TiO2 photocatalysis. PMID- 28011364 TI - Functionality of microbial communities in constructed wetlands used for pesticide remediation: Influence of system design and sampling strategy. AB - The objective of this study was to compare the microbial community metabolic function from both unsaturated and saturated constructed wetland mesocosms (CWs) when treating the pesticide tebuconazole. The comparison was performed for both interstitial water and substrate biofilm by community level physiological profiling (CLPP) via BIOLOGTM EcoPlates. For each CW design (saturated or unsaturated), six mesocosms were established including one unplanted and five planted individually with either Juncus effusus, Typha latifolia, Berula erecta, Phragmites australis or Iris pseudacorus. Microbial activity and metabolic richness of interstitial water from unsaturated CWs were significantly lower than that from saturated CWs. However, in general, the opposite result was observed for biofilm samples. Wetland plants promoted significantly higher biofilm microbial activity and metabolic richness than unplanted CWs in both CW designs. Differences in the microbial community functional profiles between plant species were only found for saturated CWs. Biofilm microbial metabolic richness was generally statistically higher than that of interstitial water in both unsaturated (1.4-24 times higher) and saturated (1.2-1.7 times higher) CWs. Carbon source (guild) utilization patterns were generally different between interstitial water and biofilm samples. Functionality of the biofilm microbial community was positively correlated to the removal of all pollutants (TN, NH4+-N, TP, TOC and tebuconazole) for both unsaturated and saturated CWs, suggesting the biofilm plays a more important role in pollutant removal than the interstitial water microbial community. Thus, merely observing the interstitial water microbial communities may underestimate the role of the microbial community in CW performance. Interestingly, the ability for the biofilm microbial community to utilize amino acids and amines/amides was positively correlated with tebuconazole removal in all system types. PMID- 28011365 TI - Prescription hypnotics in the news: A study of UK audiences. AB - In 2012 the UK media reported the results of a paper in the British Medical Journal Open, including the finding that hypnotics increase the risk of 'premature death'. Taking this media coverage as a case study, the paper explores UK people's responses and assesses the implications for the debate about the (de)pharmaceuticalisation of sleep. Two hundred and fifty one posts to the websites of 6 UK newspapers were analysed thematically, along with 12 focus group discussions (n = 51) of newspaper coverage from one UK newspaper. Four thematic responses were identified: bad science/journalism, Hobson's choice, risk assessment and challenging pharmaceuticalisation. We found that most people claimed that the story did not worry them, even if they stated that they were using sleeping pills, and that focus group members generally appeared to respond in terms of their pre-existing views of hypnotics. The way in which lay expertise was drawn on in responding to the coverage was one of the most striking findings of the study. People referred to their own or others' experience of taking hypnotics to recognise the legitimacy of taking them or to weigh up the risks and benefits, as reflexive users. Overall, our case study cautions against making strong claims about the power of the media to legitimate de pharmaceuticalisation. While the media may have such a role, this is in the main only for those who are receptive to such a message already. PMID- 28011366 TI - Climate change and epidemics in Chinese history: A multi-scalar analysis. AB - This study seeks to provide further insight regarding the relationship of climate epidemics in Chinese history through a multi-scalar analysis. Based on 5961 epidemic incidents in China during 1370-1909 CE we applied Ordinary Least Square regression and panel data regression to verify the climate-epidemic nexus over a range of spatial scales (country, macro region, and province). Results show that epidemic outbreaks were negatively correlated with the temperature in historical China at various geographic levels, while a stark reduction in the correlational strength was observed at lower geographic levels. Furthermore, cooling drove up epidemic outbreaks in northern and central China, where population pressure reached a clear threshold for amplifying the vulnerability of epidemic outbreaks to climate change. Our findings help to illustrate the modifiable areal unit and the uncertain geographic context problems in climate-epidemics research. Researchers need to consider the scale effect in the course of statistical analyses, which are currently predominantly conducted on a national/single scale; and also the importance of how the study area is delineated, an issue which is rarely discussed in the climate-epidemics literature. Future research may leverage our results and provide a cross-analysis with those derived from spatial analysis. PMID- 28011367 TI - Biomarkers associated with disease severity in allergic and nonallergic asthma. AB - Asthma is a complex, chronic respiratory disease with a wide clinical spectrum. Use of high-throughput technologies has generated a great deal of data that require validation. In this work the objective was to validate molecular biomarkers related to asthmatic disease types in peripheral blood samples and define their relationship with disease severity. With this purpose, ninety-four previously described genes were analyzed by qRT-PCR in 30 healthy control (HC) subjects, 30 patients with nonallergic asthma (NA), 30 with allergic asthma (AA), and 14 patients with allergy (rhinitis) but without asthma (AR). RNA was extracted from peripheral blood mononuclear cells (PBMCs) using the TRIzol method. After data normalization, principal component analysis (PCA) was performed, and multiple approaches were used to test for differential gene expression. Relevance was defined by RQ (relative quantification) and corrected P value (<0.05). Protein levels of IL-8 and MSR1 were determined by ELISA and Western blot, respectively. PCA showed 4 gene expression clusters that correlated with the 4 clinical phenotypes. Analysis of differential gene expression between clinical groups and HCs revealed 26 statistically relevant genes in NA and 69 in AA. Protein interaction analysis revealed IL-8 to be a central protein. Average levels of IL-8 were higher in the asthma patients' sera (NA: 452.28+/-357.72, AA: 327.46+/-377pg/ml) than in HCs (286.09+/-179.10), but without reaching statistical significance. Nine genes, especially MSR1, were strongly associated with severe NA. In conclusion, several molecular biomarkers of asthma have been defined, some of which could be useful for the diagnosis or prognosis of disease severity. PMID- 28011368 TI - Co-metal-organic-frameworks with pure uniform crystal morphology prepared via Co2+ exchange-mediated transformation from Zn-metallogels for luminol catalysed chemiluminescence. AB - Cation exchange-mediated transformation from Zn-metallogels (MOGs), which was a mild facile strategy relative to the demanding hydrothermal method, was employed to develop Co2+ metal-organic frameworks (Co-MOFs) at room temperature. The obtained Co-MOFs was of uniform octahedral morphology and possessed high activity to catalyze luminol chemiluminescence without extra oxidants. By adding cysteine, the CL emission of luminol-Co-MOFs system was further enhanced. Based on this phenomenon, Co-MOFs was utilized to build a practical sensing platform for cysteine determination. Under the optimized conditions, the relative CL intensity (DeltaI) was proportional to the concentration of cysteine in the range of 2 10MUM, and the detection limit was 0.49MUM (3S/N). Moreover, the established method was applied to the determination of cysteine in commercially available pharmaceutical injections. PMID- 28011369 TI - Near infrared spectroscopy combined with multivariate analysis for monitoring the ethanol precipitation process of fraction I+II+III supernatant in human albumin separation. AB - Nowadays, as a powerful process analytical tool, near infrared spectroscopy (NIRS) has been widely applied in process monitoring. In present work, NIRS combined with multivariate analysis was used to monitor the ethanol precipitation process of fraction I+II+III (FI+II+III) supernatant in human albumin (HA) separation to achieve qualitative and quantitative monitoring at the same time and assure the product's quality. First, a qualitative model was established by using principal component analysis (PCA) with 6 of 8 normal batches samples, and evaluated by the remaining 2 normal batches and 3 abnormal batches. The results showed that the first principal component (PC1) score chart could be successfully used for fault detection and diagnosis. Then, two quantitative models were built with 6 of 8 normal batches to determine the content of the total protein (TP) and HA separately by using partial least squares regression (PLS-R) strategy, and the models were validated by 2 remaining normal batches. The determination coefficient of validation (Rp2), root mean square error of cross validation (RMSECV), root mean square error of prediction (RMSEP) and ratio of performance deviation (RPD) were 0.975, 0.501g/L, 0.465g/L and 5.57 for TP, and 0.969, 0.530g/L, 0.341g/L and 5.47 for HA, respectively. The results showed that the established models could give a rapid and accurate measurement of the content of TP and HA. The results of this study indicated that NIRS is an effective tool and could be successfully used for qualitative and quantitative monitoring the ethanol precipitation process of FI+II+III supernatant simultaneously. This research has significant reference value for assuring the quality and improving the recovery ratio of HA in industrialization scale by using NIRS. PMID- 28011370 TI - New anthracene-based Schiff bases: Theoretical and experimental investigations of photophysical and electrochemical properties. AB - The new Schiff bases bearing anthracene unit were synthesized from 2 aminoanthracene and various aldehydes such as: benzaldehyde, 4 (diphenylamino)benzaldehyde, 9-phenanthrenecarboxaldehyde, 9 anthracenecarboxaldehyde, and biphenyl-4-carboxaldehyde, 2-naphthaldehyde. Resulted azomethines were characterized by IR, NMR (1H and 13C), elemental analysis and UV-vis spectroscopy. The imine consists of anthracene and biphenyl moieties exhibited liquid crystal properties and their nematic phase showed Schlieren texture. The photoluminescence measurements carried out in solution and in solid state as blend with PMMA revealed the ability of the imines to emission of the blue light with quantum yield efficiency in the range of 2.18-6.03% in blend. Based on the electrochemical experiment they showed value of energy gap (Eg) in the range of 2.5-2.7eV. Additionally, density functional theory (DFT) was applied for calculations of both electronic structure and spectroscopic properties of synthesized Schiff bases. Moreover, the results obtained from preliminary tests of application of the azomethines in organic photovoltaic (OPV) devices confirmed their electron acceptor character. PMID- 28011371 TI - First report of metronidazole resistant, nimD-positive, Bacteroides stercoris isolated from an abdominal abscess in a 70-year-old woman. AB - We here present the first case of a metronidazole resistant nimD positive Bacteroides stercoris. The isolate originated from a polymicrobial intra abdominal abscess in a 70-year-old woman. The nimD gene was detected by use of whole-genome shotgun sequencing and the subsequent use of the ResFinder 2.1 web service. PMID- 28011372 TI - My life as a pupil: The autobiographical memories of adolescents excluded from school. AB - Narrative psychology is founded on the premise that substantial insight can be gained into individuals' self-understanding and behaviour by studying the content of their autobiographical memories. This article contributes to this field of inquiry by suggesting that our understanding of adolescents' exclusion from mainstream education can be enhanced by examining their recollections of school using a narrative dialogical approach. In a research project the autobiographical memories of fifteen female and twenty male students, aged 15-16 years, who had been excluded from secondary schools in London, England were collected and analysed. The aim was to examine how in their narrated depictions of the past, the adolescents explained and justified their position and behaviour at different times in their lives at school. The findings highlight how adolescents perceive themselves to have become positioned by the voices of significant others, schools as institutions and themselves at earlier or later stages in their lives. PMID- 28011373 TI - Bioremediation of diuron contaminated soils by a novel degrading microbial consortium. AB - Diuron is a biologically active pollutant present in soil, water and sediments. It is persistent in soil, water and groundwater and slightly toxic to mammals and birds as well as moderately toxic to aquatic invertebrates. Its principal product of biodegradation, 3,4-dichloroaniline, exhibits a higher toxicity than diuron and is also persistent in the environment. On this basis, the objective of the study was to determine the potential capacity of a proposed novel diuron degrading microbial consortium (DMC) for achieving not only diuron degradation, but its mineralisation both in solution as well as in soils with different properties. The consortium was tested in a soil solution where diuron was the only carbon source, and more than 98.8% of the diuron initially added was mineralised after only a few days. The consortium was composed of three diuron degrading strains, Arthrobacter sulfonivorans, Variovorax soli and Advenella sp. JRO, the latter had been isolated in our laboratory from a highly contaminated industrial site. This work shows for the first time the potential capacity of a member of the genus Advenella to remediate pesticide-contaminated soils. However, neither of the three strains separately achieved mineralisation (ring-14C) of diuron in a mineral medium (MSM) with a trace nutrient solution (NS); combined in pairs, they mineralised 40% of diuron in solution, but the most relevant result was obtained in the presence of the three-member consortium, where complete diuron mineralisation was achieved after only a few days. In the presence of the investigated soils in suspension, the capacity of the consortium to mineralise diuron was evaluated, achieving mineralisation of a wide range of herbicides from 22.9 to 69.0%. PMID- 28011374 TI - Robust cranial cavity segmentation in CT and CT perfusion images of trauma and suspected stroke patients. AB - A robust and accurate method is presented for the segmentation of the cranial cavity in computed tomography (CT) and CT perfusion (CTP) images. The method consists of multi-atlas registration with label fusion followed by a geodesic active contour levelset refinement of the segmentation. Pre-registration atlas selection based on differences in anterior skull anatomy reduces computation time whilst optimising performance. The method was evaluated on a large clinical dataset of 573 acute stroke and trauma patients that received a CT or CTP in our hospital in the period February 2015-December 2015. The database covers a large spectrum of the anatomical and pathological variations that is typically observed in everyday clinical practice. Three orthogonal slices were randomly selected per patient and manually annotated, resulting in 1659 reference annotations. Segmentations were initially visually inspected for the entire study cohort to assess failures. A total of 20 failures were reported. Quantitative evaluation in comparison to the reference dataset showed a mean Dice coefficient of 98.36 +/- 2.59%. The results demonstrate that the method closely approaches the high performance of expert manual annotation. PMID- 28011375 TI - Acute, 28days sub acute and genotoxic profiling of Quercetin-Magnesium complex in Swiss albino mice. AB - Quercetin-Magnesium complex is one of the youngest alkaline rare earth metal (Magnesium) complexes with flavonoids (Quercetin) in organo-metalic family. Earlier studies describe the details of the complex formation, characterization and antioxidant study of the complex but toxicity profile is still under darkness. The present study was taken up to investigate the oral acute toxicity, 28days repeated oral sub-acute toxicity study and genotoxicity study of Quercetin Magnesium complex in Swiss albino mice. Quercetin-Magnesium complex showed mortality at a dose of 185mg/kg in the Swiss albino mice. In 28days repeated oral toxicity study, Quercetin-Magnesium complex was administered to both sex of Swiss albino mice at dose levels of 150, 130 and 100mg/kg body weight respectively. Where 150mg/kg dose shows increased levels of white blood cells and changes in total protein, serum creatinine and blood urea nitrogen. Histopathological study of Quercetin-Magnesium complex shows minor structural alteration in kidney at 150mg/kg dose. No observed toxic level found in 130mg/kg or below doses. No genotoxic effect found in any doses of the complex. Therefore 130mg/kg or below dose level could be better for further study. PMID- 28011376 TI - Grape seed procyanidin B2 inhibits adipogenesis of 3T3-L1 cells by targeting peroxisome proliferator-activated receptor gamma with miR-483-5p involved mechanism. AB - Procyanidins have lipolysis effect on adipose metabolism, but the underlying mechanism is not fully understood. The aim of present study was to examine the effect of grape seed procyanidin B2 (GSP) on the adipogenic differentiation of 3T3-L1 preadipocyte cell line and investigate the underlying mechanism. The results showed that GSP treatment significantly reduced the intracellular lipid accumulation in induced 3T3-L1 cells by targeting miR-483-5p as well as peroxisome proliferator-activated receptor gamma (PPARgamma). In addition, our results revealed that overexpression of miR-483-5p increased adipogenic differentiation, while inhibition of miR-483-5p reduced the lipid accumulation by suppressing the adipogenic differentiation. Moreover, overexpression of miR-483 5p could reverse GSP's inhibition of adipocyte differentiation as well as increase the level of PPARgamma. These results demonstrate that GSP inhibits adipogenesis by targeting PPARgamma and suggest this effect might be mediated by miR-483-5p. PMID- 28011377 TI - Possible involvement of Nrf2 and PPARgamma up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity. AB - Umbelliferone (UMB) is a coumarin derivative with promising hepatoprotective effects. In this study, we examined the possible protective effects of UMB against cyclophosphamide (CP)-induced hepatotoxicity, addressing the question of the possible role of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator activated receptor gamma (PPARgamma). Wistar rats were orally administered UMB at doses 50 and 100mg/kg two weeks prior to CP injection. Five days after CP administration, the rats were sacrificed and samples were collected for analyses. CP induced a significant increase in circulating liver marker enzymes and pro-inflammatory cytokines. Hepatic lipid peroxidation and nitric oxide levels, and nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression were significantly increased following CP administration. UMB supplementation attenuated CP-induced inflammation and oxidative stress as assessed by restoration of the activity and expression of the antioxidant defenses, and suppression of pro-inflammatory cytokines. Histological examination also showed that UMB could significantly reduce CP-induced alterations. CP-induced rats showed significant down-regulation of Nrf2, HO-1 and PPARgamma, an effect that was markedly reversed by UMB. In conclusion, the hepatoprotective effects of UMB appear to depend on co-activation of PPARgamma and Nrf2, and subsequent suppression of oxidative stress and inflammation. PMID- 28011378 TI - Anti-diabetic effect of the ethyl acetate fraction of Clerodendrum volubile: protocatechuic acid suppresses phagocytic oxidative burst and modulates inflammatory cytokines. AB - The antidiabetic effects of the ethyl acetate (EtOAc) fraction of Clerodendrum volubile leaves was investigated in this study. EtOAc extract was also fractionated to isolate the active compounds. The structure of the isolated compound (Protocatechuic acid) was established using 1H and 13C NMR spectroscopies and mass spectrometry. Protocatechuic acid was investigated for its anti-oxidative burst in polymorphonuclear neutrophils (PMNs) and macrophages. It was also docked with alpha-glucosidase and TNF-alpha. Acute treatment with EtOAc fraction of Clerodendrum volubile leaves significantly (p<0.05) decreased blood glucose level and hepatic biomarkers, and significantly (p<0.05) increased serum insulin level and beta-cell function. It had little or no effect on serum lipid profile and atherogenic indices. Protocatechuic acid significantly (p<0.05) suppressed phagocytic oxidative burst and docked well with alpha-glucosidase and TNF-alpha. These results indicate the therapeutic effect of EtOAc fraction of C. volubile on type 2 diabetes and its complications, which can be attributed to the main bioactive compound, protocatechuic acid. PMID- 28011379 TI - Heart targeted nanoliposomal/nanoparticles drug delivery: An updated review. AB - Nanoliposomes are type of nano-sized vesicles made of bi-layered phospholipid membranes with an aqueous interior. They have been demonstrated to deliver several materials like low molecular weight drugs, imaging agents, peptides, proteins, and nucleic acids. Nanoliposomes have been demonstrated to slowly release an encapsulated drug, thereby leading to sustained exposure to target region and improved efficacy. This ability of nano-liposomes can be harnessed to deliver therapeutic agents precisely to the infarcted heart. Accordingly, this article will review recent developments in the application of nano liposomes and nanoparticles as drug delivery systems to treat cardiovascular related disorders such as atherosclerosis, restenosis and myocardial infarction. PMID- 28011380 TI - Propofol enhances the cisplatin-induced apoptosis on cervical cancer cells via EGFR/JAK2/STAT3 pathway. AB - OBJECTIVE: The main purpose of this study was to evaluate propofol and its combined effect with cisplatin on apoptosis of cervical cancer cells and molecular mechanisms of this phenomenon. METHODS: The effects of propofol and cisplatin on cell viability and apoptosis were detected by cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry assay. Besides, protein expression of EGFR/JAK2/STAT3 pathway was determined by western blot. STAT3 was over-expressed in cervical cancer cells by STAT3 cDNA. Expression of EGFR and STAT3 protein of human tissues was evaluated by immunohistochemistry (IHC) assay. RESULTS: In this study, we found that not only propofol alone could inhibit cervical cancer cells viability but also could increase the inhibitory effect of cisplatin on cervical cancer cells growth. Meanwhile, propofol sensitized cervical cancer cells to cisplatin-induced apoptosis but not affected normal cervical cells. In genetic level, propofol could enhance the anti-tumor effect of cisplatin through EGFR/JAK2/STAT3 pathway. Further studies indicated that overexpression of EGFR and STAT3 is related to poor prognoses in cervical cancer patients, which contributed to confirm the clinical role of combined application of propofol and cisplatin. CONCLUSION: Propofol enhances the cisplatin-induced cell apoptosis cervical cancer cells via EGFR/JAK2/STAT3 pathway and may be developed as a potential therapeutic agent to treat cervical cancer. PMID- 28011381 TI - Induction of G2/M phase arrest and apoptosis by a new tetrahydroingenol diterpenoid from Euphorbia erythradenia Bioss. in melanoma cancer cells. AB - In the current study, a new tetrahydroingenol diterpene isolated from Euphorbia erythradenia, 7,13-diacetyl-5-angeloyl-20-nicotinyl-3-propionyl-1,2,6,7 tetrahydroingenol (DANPT), were tested for the molecular mechanism of its anti cancer activity in two human melanoma cancer cell lines, A375 and HMCB. DANPT was found cytotoxic against A375 and HMCB cells with IC50 value of 15.37+/-2.6MUM and 15.62+/-1.89MUM, respectively. Flow cytometric analysis showed that DANPT halted the A375 and HMCB cells in G2/M phase and induced apoptosis in a dose-dependent manner. Cell cycle arrest was associated with down-regulation of cyclin B and Cdk 1 and subsequent up-regulation of p53 and p21. Moreover, DANPT induced Bax and inhibited Bcl-2 expression, which results in increasing Bax/Bcl-2 ratio and activation of caspase-3. Furthermore, the apoptotic effect of DANPT was also related to ROS production and loss of mitochondrial membrane potential (DeltaYm). Overall, our results suggest that DANPT can inhibit proliferation of human melanoma cancer cells by promoting apoptosis and inducing cell cycle arrest and therefore, it can be a promising natural agent for the treatment of melanoma cancer. PMID- 28011382 TI - Multiple sclerosis: Therapeutic applications of advancing drug delivery systems. AB - Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, which is accompanying with demyelination, neurodegeneration and sensibility to oxidative stress. In MS, auto-reactive lymphocytes cross the blood brain barrier (BBB) and reside in the perivenous demyelinating lesions which create various distinct inflammatory demyelinated plaques situated predominantly in the white matter. The current MS-related therapeutic approaches can be classified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs suppress circulating immune cells, inhibit passing the BBB and decrease the inflammatory responses. Recent advances have remarkably delayed disease development and improved the quality of life for numerous patients. In spite of major improvements in therapeutic options, there are some limitations regarding the routes of administration and the necessity for repeated and long-term dosing in which cause to systemic disadvantageous consequences and patient non compliance. Nanotechnology presents promising approaches to improve autoimmune disease treatment with the capability to overcome many of the limitations common to the current immunosuppressive and biological therapies. Here we emphasis on nanomedicine-based drug delivery approaches of biological immunomodulatory mediators for the treatment of multiple sclerosis. This comprehensive review details the most successful drugs in MS therapy and also focuses on conceptions and clinical potential of novel nanomedicine attitudes for inducing immunosuppression and immunological tolerance in MS to modulate abnormal and pathologic immune responses. PMID- 28011383 TI - The combination of db-cAMP and ChABC with poly(propylene carbonate) microfibers promote axonal regenerative sprouting and functional recovery after spinal cord hemisection injury. AB - This study describes the use of poly(propylene carbonate) (PPC) electrospun microfibres impregnated with a combination of dibutyryl cyclic adenosine monophosphate (db-cAMP) and chondroitinase ABC (ChABC) in the treatment of right side hemisected spinal cord injury (SCI). Release of db-cAMP and/or ChABC from the microfibres was assessed in vitro using high-performance liquid chromatography (HPLC). Drug-impregnated microfibres were implanted into the hemisected thoracic spinal cord of rats, and treatment was evaluated using functional recovery examinations and immunohistochemistry. Our results demonstrated that the microfibres containing db-cAMP and/or ChABC displayed a stable and prolonged release of each agent. Sustained delivery of db-cAMP and/or ChABC was found to promote axonal regenerative sprouting, functional recovery, and reduced glial scar formation when compared to untreated control animals. The combination of both db-cAMP and ChABC was determined to be more effective than using either drug alone in the treatment of SCI. These findings demonstrate the feasibility of using PPC electrospun microfibres for multi-drug combination therapy in SCI. PMID- 28011384 TI - Effect of hydroalcoholic Allium ampeloprasum extract on oxidative stress, diabetes mellitus and dyslipidemia in alloxan-induced diabetic rats. AB - Allium ampeloprasum (AA) is a medicinal plant which is used in Iranian traditional medicine to treat or prevent different diseases. The aim of this study is to investigate the effect of AA extract on oxidative stress and dyslipidemia in diabetic rats induced by alloxan. In this experimental study, 60 male Wistar rats weighing 200-250gr were randomly divided to five groups of 12 each including healthy control (group I), diabetic control (group II), metformin treated diabetic positive control (group III) and two groups treated with doses 400 (group IV) and 800 (groupV) mg/kg/BW of AA extracts. Diabetes mellitus was experimentally induced by injection of two doses of alloxan-120 and 65mg/kg within two consecutive days. Alloxan-induced diabetes caused significant increase in serum glucose, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and high density lipoprotein (HDL) levels in group II (p<0.05). Furthermore, serum malondialdehyde (MDA) levels increased significantly and liver catalase activity decreased significantly in the 2nd group compared to 1st control; respectively p=0.0001 and p=0.009. In the group IV has seen a significant decrease in serum TG (p=0.01), TC (p=0.0001), VLDL (p=0.01), and MDA (p=0.0001) levels and significant increase in the liver and kidney catalase activities of the rats compared to the group II; respectively p=0.0001 and p=0.0001. In Conclusion our results highlight potentially relevant health beneficial effects of AA extract which exerts hypoglycemic, hypolipidemic, and anti-oxidative stress effects in rats with alloxan-induced diabetes. Therefore, it may be considered as useful dietary supplements in diabetic patients. PMID- 28011385 TI - The effect of Searsia chirindensis stem-bark extract on renal and liver function in a rat model of neurotoxicity. AB - Searsia chirindensis (SC) (Baker F.) (Anacardiaceae) has shown potential for the treatment of many neurological diseases however its effect on other bodily systems in neurotoxic models is not well-documented. In this study we investigated the effects of SC on blood glucose homeostasis, as well as its effect on liver and kidney function by assessing lipid peroxidation using the TBARS assay and measuring plasma and urinary electrolyte concentrations in a 6 hydroxydopamine parkinsonian model. The relative levels of phytochemicals were also quantified, along with testing free radical scavenging activity via the DPPH assay. Our results showed that SC decreases blood glucose levels but did not alter the liver and kidney function as reflected by the absence of electrolyte imbalances and lipid peroxidation damage. We also found that SC comprises primarily phenolic acids (945.73+/-154.01mg GA/g SC) and triterpenoids (1997.21+/ 404.04mg OA/g SC) with minimal flavonoid content (12.98+/-2.75mg Q/g SC) and exhibited strong free radical scavenging activity (~80%). In conclusion, these results suggest that SC does not alter the renal and liver function at least in the different parameters studied. PMID- 28011386 TI - Curcumin inhibits growth potential by G1 cell cycle arrest and induces apoptosis in p53-mutated COLO 320DM human colon adenocarcinoma cells. AB - Curcumin, a natural polyphenolic compound and it is isolated from the rhizome of Curcuma longa, have been reported to possess anticancer effect against stage I and II colon cancer. However, the effect of curcumin on colon cancer at Dukes' type C metastatic stage III remains still unclear. In the present study, we have investigated the anticancer effects of curcumin on p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage. The cellular viability and proliferation were assessed by trypan blue exclusion assay and MTT assay, respectively. The cytotoxicity effect was examined by lactate dehydrogenase (LDH) cytotoxicity assay. Apoptosis was analyzed by DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis. Cell cycle distribution was performed by flow cytometry analysis. Here we have observed that curcumin treatment significantly inhibited the cellular viability and proliferation potential of p53 mutated COLO 320DM cells in a dose- and time-dependent manner. In addition, curcumin treatment showed no cytotoxic effects to the COLO 320DM cells. DNA fragmentation analysis, Hoechst and propidium iodide double fluorescent staining and confocal microscopy analysis revealed that curcumin treatment induced apoptosis in COLO 320DM cells. Furthermore, curcumin caused cell cycle arrest at the G1 phase, decreased the cell population in the S phase and induced apoptosis in COLO 320DM colon adenocarcinoma cells. Together, these data suggest that curcumin exerts anticancer effects and induces apoptosis in p53 mutated COLO 320DM human colon adenocarcinoma cells derived from Dukes' type C metastatic stage. PMID- 28011387 TI - The Kidney and Periodontal Disease (KAPD) study: A pilot randomized controlled trial testing the effect of non-surgical periodontal therapy on chronic kidney disease. AB - INTRODUCTION: Chronic kidney disease (CKD) remains a prevalent public health problem that disproportionately affects minorities and the poor, despite intense efforts targeting traditional risk factors. Periodontal diseases are common bacterial plaque-induced inflammatory conditions that can respond to treatment and have been implicated as a CKD risk factor. However there is limited evidence that treatment of periodontal disease slows the progression of CKD. METHODS/DESIGN: We describe the protocol of the Kidney and Periodontal Disease (KAPD) study, a 12-month un-blinded, randomized, controlled pilot trial with two intent-to-treat treatment arms: 1. immediate intensive non-surgical periodontal treatment or 2. rescue treatment with delayed intensive treatment. The goals of this pilot study are to test the feasibility of conducting a larger trial in an ethnically and racially diverse, underserved population (mostly poor and/or low literacy) with both CKD and significant periodontal disease to determine the effect of intensive periodontal treatment on renal and inflammatory biomarkers over a 12-month period. RESULTS: To date, KAPD has identified 634 potentially eligible patients who were invited to in-person screening. Of the 83 (13.1%) of potentially eligible patients who attended in-person screening, 51 (61.4%) were eligible for participation and 46 enrolled in the study. The mean age of participants is 59.2years (range 34 to 73). Twenty of the participants (43.5%) are Black and 22 (47.8%) are Hispanic. DISCUSSION: Results from the KAPD study will provide needed preliminary evidence of the effectiveness of non-surgical periodontal treatment to slow CKD progression and inform the design future clinical research trials. PMID- 28011388 TI - Dietary Intervention for Glucose Tolerance In Teens (DIG IT): Protocol of a randomized controlled trial using health coaching to prevent youth-onset type 2 diabetes. AB - BACKGROUND: Youth-onset type 2 diabetes (T2D) is a disease that is newly emerging and behavioral strategies for its prevention are limited. Interventions that target the lifestyle behaviors of adolescents, to improve poor dietary quality and reduce excessive sedentariness, promise to reduce the risk of developing T2D. Health coaching is effective for promoting healthy behaviors in patients who have chronic disease, but few experimental studies are in adolescents. This randomized controlled trial, in adolescents with prediabetes, will determine the effectiveness of a health coaching intervention to facilitate adoption of healthy diet and activity behaviors that delay or prevent development of T2D. METHODS/DESIGN: The Dietary Intervention for Glucose Tolerance In Teens (DIG IT) trial will involve an evaluation of a health coaching intervention in adolescents with prediabetes. Eligible participants will be randomized to receive 6months of health coaching or a single dietary consultation that is standard-of-care. The primary outcome will be 2-hour oral glucose tolerance test concentration. Secondary outcomes will include measures of glycemia and insulin action as well as dietary, physical activity and sedentary behaviors measured using an electronic food record, and by inclinometer. Data will be collected before and after the intervention (at 6months) and at 12months (to assess sustainability). DISCUSSION: This trial will determine whether a health coaching intervention, a personalized and low-cost approach to modify dietary and activity behaviors, is effective and sustainable for prevention of youth-onset T2D, relative to standard of-care. Health coaching has the potential to be widely implemented in clinical or community settings. PMID- 28011389 TI - Extended-release naltrexone for pre-release prisoners: A randomized trial of medical mobile treatment. AB - BACKGROUND: Extended-release naltrexone (XR-NTX), is an effective treatment for opioid use disorder but is rarely initiated in US prisons or with criminal justice populations. Mobile treatment for chronic diseases has been implemented in a variety of settings. Mobile treatment may provide an opportunity to expand outreach to parolees to surmount barriers to traditional clinic treatment. METHODS: Male and female prisoners (240) with pre-incarceration histories of opioid use disorder who are within one month of release from prison will be enrolled in this randomized clinical trial. Participants are randomized to one of two study arms: 1) [XR-NTX-OTx] One injection of long-acting naltrexone in prison, followed by 6 monthly injections post-release at a community opioid treatment program; or 2) [XR-NTX+ MMTx] One injection of long-acting naltrexone in prison followed by 6 monthly injections post-release at the patient's place of residence utilizing mobile medical treatment. The primary outcomes are: treatment adherence; opioid use; criminal activity; re-arrest; reincarceration; and HIV risk-behaviors. RESULTS: We describe the background and rationale for the study, its aims, hypotheses, and study design. CONCLUSIONS: The use of long-acting injectable naltrexone may be a promising form of treatment for pre-release prisoners. Finally, as many individuals in the criminal justice system drop out of treatment, this study will assess whether treatment at their place of residence will improve adherence and positively affect treatment outcomes. ClinicalTrials.gov: NCT02867124. PMID- 28011390 TI - Reversible MRI findings in a case of acute intermittent porphyria with a novel mutation in the porphobilinogen deaminase gene. AB - Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficiency of porphobilinogen deaminase (PBGD), the third enzyme in the of heme biosynthetic pathway. It can affect the autonomic, peripheral, and central nervous system. Posterior reversible encephalopathy syndrome is a clinicoradiological entity characterized by headache, seizures, altered consciousness, and visual disorder associated with potentially reversible neuroradiological abnormalities predominantly in the parieto-occipital lobes. Establishing accurate diagnoses of the patient and asymptomatic family members with AIP involves identifying the PBGD enzyme mutations directly. In this study, we report a 28-year-old woman with acute intermittent porphyria who presented with radiological manifestations suggestive of posterior reversible encephalopathy syndrome, she had a novel PBGD frame shift mutation, base 875 and 876 have been deleted resulting in glutamine to a stop codon (Gln292fs), in a Chinese family. PMID- 28011391 TI - Pathophysiology of status epilepticus. AB - Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures. Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively. As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA(A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizure-dependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline. PMID- 28011392 TI - Selective induction of P-glycoprotein at the CNS barriers during symptomatic stage of an ALS animal model. AB - P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP) and Multidrug resistance-associated protein 2 (MRP2) residing at the blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are major obstacles for drug delivery to the Central Nervous System (CNS). Disease-induced changes of these xenobiotic transporters at the CNS barriers have been previously documented. Changes in the functional expression of these transporters at the CNS barriers would limit the clinical efficacy of therapeutic agents targeting the CNS. In this study, we characterized the changes in expression and efflux activity of P-gp, BCRP and MRP2 at the BBB and BSCB of an amyotrophic lateral sclerosis (ALS) SOD1-G93A transgenic rat model across the three stages of disease progression: pre-onset, onset and symptomatic. Up-regulation of P-gp and BCRP at the BBB and BSCB during disease progression of ALS would reduce drug entry to the CNS, while any decreases in transport activity would increase drug entry. In SOD rats at the ALS symptomatic stage, we observed increases in both P-gp transport activity and expression compared to age-matched wildtypes. BCRP and MRP2 levels were unchanged in these animals. Immunohistochemical analysis in brain and spinal cord capillaries of SOD rats from all three ALS stages and age-matched wildtypes showed no differences in nuclear localization of a known P-gp regulator, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB). It suggests that NFkappaB may have a limited role during P-gp induction observed in our study and additional signaling pathways could be responsible for this response. Our observations imply that novel pharmacological approaches for treating ALS require selecting drugs that are not P-gp substrates in order to improve therapeutic efficacy in the CNS during ALS progression. PMID- 28011393 TI - Astragaloside IV attenuates cognitive impairments induced by transient cerebral ischemia and reperfusion in mice via anti-inflammatory mechanisms. AB - Astragaloside IV (AS-IV) is the main active component isolated from the traditional Chinese medicinal herb Astragalus membranaceus. Studies have demonstrated that AS-IV has neuroprotective effects in cerebral ischemic models. In this study, we aimed to investigate the effects of AS-IV on memory impairment induced by transient cerebral ischemia and reperfusion in mice, as well as the associated signaling mechanisms. Severe memory deficits were induced by bilateral common carotid artery occlusion (BCCAO) in mice as indicated in the Morris water maze test in this study. Oral administration of AS-IV (10 and 20mg/kg, once per day, started 7days before surgery and continued for 7days after surgery) significantly attenuated memory impairment and neuroinflammation. Moreover, AS-IV treatment significantly reduced the expression of toll-like receptor-4 (TLR4) and its downstream adaptor proteins, including myeloid differentiation primary response gene 88 (MyD88), toll/interleukin-1 receptor-domain containing adaptor inducing interferon-beta (TRIF) and tumour necrosis factor receptor associated factor-6 (TRAF6), and subsequently inhibited NF-kappaB phosphorylation. It is well-known that cerebral ischemia and reperfusion injury enhances the formation of reactive oxygen species (ROS) and further neuroinflammation. Importantly, we found that AS-IV suppressed NLRP3 inflammasome activation by controlling ROS production. In addition, AS-IV markedly reduced overactivation of microglia and the overexpression of inflammatory cytokines in the hippocampus compared with the transient cerebral ischemia and reperfusion group. These results suggest that AS IV might possess neuroprotective effects against transient cerebral ischemia and reperfusion partly through its anti-inflammatory effects by inhibiting TLR4 signaling pathway and NLRP3 inflammasome overactivation. PMID- 28011394 TI - 131I-labeled and DOX-loaded multifunctional nanoliposomes for radiotherapy and chemotherapy in brain gliomas. AB - The codelivery of different therapeutics is a promising option because of its synergetic effects of drugs. In this study, a new combination therapy that used the doxorubicin-loaded and 131I-labeled nanoliposomes (131I-DOX-NL) was proposed to delay tumor growth of gliomas, which are characterized by significant mortality and morbidity. 131I-DOX-NL was constructed based on bovine serum albumin (BSA)-tailor made hydrophobic maleimide-functionalized poly(epsilon caprolactone) (PCL) (Fig. 1) and was evaluated by cellular viability in vitro and by U87 xenograft models in vivo. Compared with using 131I-NL or DOX-NL alone, our experimental results show that 131I-DOX-NL exhibits similar high cellular uptake but enhanced efficacy to cure gliomas because of its codelivery of 131I and DOX. In the U87 mouse tumor models, the combination therapy resulted in higher survival rates of mice and smaller tumor sizes than monotherapy did alone. In conclusion, multifunctional nanoliposome 131I-DOX-NL is a good candidate for the codelivery of 131I-mediated radiotherapy and DOX-mediated chemotherapy due to its ability to inhibit U87 cell proliferation and tumor growth. 131I-DOX-NL can be used as a promising effective therapy for malignant gliomas and deserves further investigation. PMID- 28011396 TI - Left inferior frontal gyrus mediates morphosyntax: ERP evidence from verb processing in left-hemisphere damaged patients. AB - Neurocognitive models of language comprehension have proposed different mechanisms with different neural substrates mediating human language processing. Whether the left inferior frontal gyrus (LIFG) is engaged in morpho-syntactic information processing is currently still controversially debated. The present study addresses this issue by examining the processing of irregular verb inflection in real words (e.g., swim > swum > swam) and pseudowords (e.g., frim > frum > fram) by using event-related brain potentials (ERPs) in neurological patients with lesions in the LIFG involving Broca's area as well as healthy controls. Different ERP patterns in response to the grammatical violations were observed in both groups. Controls showed a biphasic negativity-P600 pattern in response to incorrect verb inflections whereas patients with LIFG lesions displayed a N400. For incorrect pseudoword inflections, a late positivity was found in controls, while no ERP effects were obtained in patients. These findings of different ERP patterns in the two groups strongly indicate an involvement of LIFG in morphosyntactic processing, thereby suggesting brain regions' specialization for different language functions. PMID- 28011395 TI - Salvianolic acid A ameliorates the integrity of blood-spinal cord barrier via miR 101/Cul3/Nrf2/HO-1 signaling pathway. AB - Salvianolic acid A (Sal A), a bioactive compound isolated from the Chinese medicinal herb Danshen, is used for the prevention and treatment of cardiovascular diseases. However, the protective function of Sal A on preserving the role of blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) is unclear. The present study investigated the effects and mechanisms of Sal A (2.5, 5, 10mg/kg, i.p.) on BSCB permeability at different time-points after compressive SCI in rats. Compared to the SCI group, treatment with Sal A decreased the content of the Evans blue in the spinal cord tissue at 24h post-SCI. The expression levels of tight junction proteins and HO-1 were remarkably increased, and that of p-caveolin-1 protein was greatly decreased after SCI Sal A. The effect of Sal A on the expression level of ZO-1, occluding, and p-caveolin-1 after SCI was blocked by the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP). Also, Sal A inhibited the level of apoptosis-related proteins and improved the motor function until 21days after SCI. In addition, Sal A significantly increased the expression of microRNA-101 (miR-101) in the RBMECs under hypoxia. AntagomiR-101 markedly increased the RBMECs permeability and the expression of the Cul3 protein by targeting with 3'-UTR of its mRNA. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 was significantly increased after agomiR-101 treatment. Therefore, Sal A could improve the recovery of neurological function after SCI, which could be correlated with the repair of BSCB integrity by the miR 101/Cul3/Nrf2/HO-1 signaling pathway. PMID- 28011397 TI - 3-Methoxy-catalposide inhibits inflammatory effects in lipopolysaccharide stimulated RAW264.7 macrophages. AB - Pseudolysimachion rotundum var. subintegrum is utilized as a traditional herbal remedy to treat cough, bronchitis, and asthma in Korea, Russia, China, and Europe. Here, we show that 3-methoxy-catalposide, a novel iridoide glycoside isolated from P. rotundum var. subintegrum has the anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated macrophages. The chemical structure of 3 methoxy-catalposide was determined by NMR, optical rotation and HRESIMS. In in vitro experiment, RAW264.7 cells were treated with 3-methoxy-catalposide for 2h before exposure to LPS for different times. Inflammatory gene and protein expressions were assayed using RT-PCR and ELISA. Activities of signal proteins were examined using western analysis. Our results demonstrated that 3-methoxy catalposide significantly inhibits the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in RAW264.7 cells stimulated by LPS, thereby suppressing the release of prostaglandin E2 (PGE2) and nitric oxide (NO). Moreover, 3-methoxy-catalposide markedly reduced the LPS-induced expression of pro-inflammatory genes, such as interleukin (IL)-6, IL-1beta, and TNF-alpha. Further, 3-methoxy-catalposide inhibited both LPS-induced activation of three MAP kinases (ERK 1/2, JNK, and p38) and the nuclear translocation of NF-kappaB and AP 1. These results support that 3-methoxy-catalposide may be a promising candidate for inflammation treatment. PMID- 28011398 TI - Glycosaminoglycans are important mediators of neutrophilic inflammation in vivo. AB - The pro-inflammatory chemokine interleukin-8 (CXCL8) exerts its function by establishing a chemotactic gradient in infected or damaged tissues to guide neutrophil granulocytes to the site of inflammation via its G protein-coupled receptors (GPCRs) CXCR1 and CXCR2 located on neutrophils. Endothelial glycosaminoglycans (GAGs) have been proposed to support the chemotactic gradient formation and thus the inflammatory response by presenting the chemokine to approaching leukocytes. In this study, we show that neutrophil transmigration in vitro can be reduced by adding soluble GAGs and that this process is specific with respect to the nature of the glycan. To further investigate the GAG influence on neutrophil migration, we have used an engineered CXCL8 mutant protein (termed PA401) which exhibits a much higher affinity towards GAGs and an impaired GPCR activity. This dominant-negative mutant chemokine showed anti inflammatory activity in various animal models of neutrophil-driven inflammation, i.e. in urinary tract infection, bleomycin-induced lung fibrosis, and experimental autoimmune uveitis. In all cases, treatment with PA401 resulted in a strong reduction of transmigrated inflammatory cells which became evident from histology sections and bronchoalveolar lavage. Since our CXCL8-based decoy targets GAGs and not GPCRs, our results show for the first time the crucial involvement of this glycan class in CXCL8/neutrophil-mediated inflammation and will thus pave the way to novel approaches of anti-inflammatory treatment. PMID- 28011400 TI - Biofouling prevention using silver nanoparticle impregnated polyethersulfone (PES) membrane: E. coli cell-killing in a continuous cross-flow membrane module. AB - Biofouling significantly decreases membrane performance. So silver nanoparticle (Ag-NP) was impregnated selectively on a sulfonated polyethersulfone (SPES) membrane and its efficacy was tested in a continuous, cross-flow membrane module. The main challenges are: (i) to prevent biofouling on the membrane surface, (ii) achieve zero bacterial cell (E. coli) count in the permeate water, (iii) maintain Ag concentration in the permeate stream within the permissible limit of drinking water and (iv) maintain a high tensile strength of the membrane to prevent mechanical failure. Addressing these factors would ensure a long and productive service-life of the membrane. To this end, 104CFU/ml of E. coli cell-suspension was passed through the Ag-SPES membrane of 150MUm total thickness, which has a narrow (1.74MUm thickness), upper surface of Ag-NPs. We achieved zero E. coli cell-count and a minimum (10MUg/L) Ag concentration in the permeate stream; simultaneously increasing the tensile strength from 2.78MPa to 3.92MPa due to Ag NP impregnation. Thus, for a continuous inlet flow of E. coli contaminated water, the membrane module could deliver an almost constant permeate flow rate of 3.45L per hour, due to complete E. coli cell-killing. Simultaneously, Ag concentration in permeate stream is well-below the WHO's recommended limit of 100MUg/L, for potable quality water. Therefore, the Ag-SPES membrane can be used as an anti biofouling membrane in a continuous operational mode. PMID- 28011399 TI - Graphene oxide/alginate beads as adsorbents: Influence of the load and the drying method on their physicochemical-mechanical properties and adsorptive performance. AB - Graphene oxide/alginate beads were prepared from lab-synthesized graphene oxide, varying its content within the beads (0.05, 0.125, and 0.25wt.%). Ethanol-drying and lyophilization were compared as drying methods to obtain suitable adsorbents which were later tested to the removal of a model organic molecule (methylene blue). The morphological and textural properties of all the beads were characterized by scanning electron microscopy and N2 adsorption/desorption isotherms at -196 degrees C, respectively. Limited porosity was obtained for all cases (SBET<60m2/g). Uniaxial compression tests were performed to assess the mechanical properties of the beads. Ethanol-dried ones exhibited higher Young's elasticity modulus (E=192kPa) than the lyophilized samples (twice at 0.25wt.% graphene oxide loading), which disclosed breakage points at lower deformation percentages. Adsorption experiments were conducted and dye adsorption isotherms were obtained for the beads with the best removal performance. The experimental data were better fitted by the Langmuir model. The highest maximum adsorption capacity (4.25mmol/g) was obtained for the lyophilized beads with the highest graphene oxide content. Mechanical properties were found to be affected also by the dye adsorption. PMID- 28011401 TI - The role of reward circuitry and food addiction in the obesity epidemic: An update. AB - The increasing worldwide prevalence of obesity is partially related to the ready availability of highly palatable foods which increases the incidence of hedonic, non-homeostatic feeding. The "food addiction" hypothesis postulates that exposure to these foods alters the brain's reward circuitry, driving an addiction-like behavioural phenotype of compulsive overeating. This review highlights recent evidence that examines changes in the mesolimbic dopaminergic circuit, the primary component of the reward system, associated with exposure to highly palatable foods and obesity. The majority of obesity studies in animals have not measured addictive-like behaviours, but reports of such behaviours have been restricted to experiments using models of binge eating. Where examined, the prevalence of addiction-like behaviour in overweight and obese subjects indicates that 10-25% of the population meets the Yale Food Addiction Score criteria. There is considerable overlap in the behaviours ascribed to food addiction and binge eating disorder, and food addiction scores correlate highly with measures of binge eating. We feel that more research is required in humans to determine whether food addiction is both behaviourally and neurobiologically distinct from binge eating disorder. While the reward circuitry is clearly affected by both highly palatable foods and diet-induced obesity in a similar manner to short and long exposure to drugs of abuse, the challenge for the future is to show that these neurobiological changes are associated with addiction-like behaviour. PMID- 28011402 TI - The impact of the appetite-regulating, orexigenic peptide ghrelin on alcohol use disorders: A systematic review of preclinical and clinical data. AB - Ghrelin, which is mainly released from the stomach, is the most important orexigenic regulator of food intake, inducing appetite, enhancing adiposity and releasing growth hormone. Besides the hypothalamus, ghrelin receptors (GHS-R1A) are also expressed in the mesolimbic dopaminergic system, which increases the possibility that ghrelin plays an important role in reward regulation for substance use disorders such as alcohol addiction, especially through activating the cholinergic-dopaminergic reward link. In this review we focus on the impact of ghrelin on the development and maintenance of alcohol addiction/dependence, alcohol consumption, alcohol craving and alcohol withdrawal, attempting to integrate preclinical and clinical studies concerning the intriguing relationship between appetite regulation, reward and alcohol addiction. Integrating the existing preclinical and clinical data on ghrelin antagonism, specifically at the GHS-R1A receptor in mesolimbic dopaminergic pathways, may reveal a new and innovative target for the treatment of alcohol dependence in the future. PMID- 28011403 TI - Cyanidin-3-O-glucoside ameliorates palmitate-induced insulin resistance by modulating IRS-1 phosphorylation and release of endothelial derived vasoactive factors. AB - Increased plasma levels of free fatty acids, including palmitic acid (PA), cause insulin resistance in endothelium characterized by a decreased synthesis of insulin-mediated vasodilator nitric oxide (NO), and by an increased production of the vasoconstrictor protein, endothelin-1. Several in vitro and in vivo studies suggest that anthocyanins, natural phenols commonly present in food and vegetables from Mediterranean Diet, exert significant cardiovascular health promoting activities. These effects are possibly mediated by a positive regulation of the transcription factor Nrf2 and activation of cellular antioxidant and cytoprotective genes. The present study examined, at a molecular level, the effects of cyanidin-3-O-glucoside (C3G), a widely distributed anthocyanin, on PA-induced endothelial dysfunction and insulin resistance in human umbilical vein endothelial cells (HUVECs). Our results indicate that C3G pretreatment effectively reverses the effects of PA on PI3K/Akt axis, and restores eNOS expression and NO release, altered by PA. We observed that these effects were exerted by changes on the phosphorylation of IRS-1 on specific serine and tyrosine residues modulated by PA through the modulation of JNK and IKK activity. Furthermore, silencing Nrf2 transcripts demonstrated that the protective effects of C3G are directly related to the activation of Nrf2. PMID- 28011405 TI - Platelet-to-lymphocyte ratio as a novel marker of in-hospital and long-term adverse outcomes among patients with acute pulmonary embolism: A single center large-scale study. AB - BACKGROUND: The interaction of platelets with leukocytes is a well-known process both in progression and prognosis of acute pulmonary embolism (PE). Recently, platelet to lymphocyte ratio (PLR) is emerged as an indirect inflammatory indicator which was shown to be associated with adverse cardiovascular events in various clinical conditions, including acute PE. However, the long-term prognostic value of PLR in acute PE has not been investigated thoroughly. Therefore, we aimed to assess the impact of PLR on both in-hospital and long-term adverse outcomes in acute PE. METHODS: A total of 459 patients with definite diagnosis of acute PE between January 2009 and January 2016 were enrolled. On admission, blood sampling to calculate PLR and detailed clinical data were obtained. Patients were divided into tertiles according to the admission PLR levels. Simplified PE severity index (sPESI) score and computerized tomography (CT) based pulmonary artery obstruction index were calculated for each patient. RESULTS: Mean sPESI score of the study population was 1.6. A total of 34 patients (7.4%) died during index hospitalization. At median 28.8months follow-up, all cause mortality was observed in 81 patients (1.9%). Patients in the highest tertile of PLR revealed a higher rate of in-hospital adverse events including cardiogenic shock, the necessity for thrombolytic therapy and in-hospital mortality as well as long-term all-cause mortality. In multivariate analysis, the PLR was found to be a significant predictor of both in-hospital adverse events (OR: 1.588, 95% CI:1.116-2.154, p=0.004) and long-term all-cause mortality (OR:1.746, 95% CI:1.211-2.865, p=0.001). CONCLUSIONS: The PLR, as a simple, inexpensive and available marker of inflammatory and prothrombotic status, seemed to be a novel predictor of in-hospital and long-term adverse outcomes in patients with acute PE. PMID- 28011404 TI - Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD. AB - Sterol regulatory element-binding protein 2 (SREBP-2), is a well-known transcriptional regulator of cholesterol metabolism. SREBP-2 is activated unconventionally to promote excessive cholesterol accumulation in non-alcoholic fatty liver disease (NAFLD). In addition, recent studies suggested that excessive lipid and cholesterol accumulation can weaken cellular autophagy function and promote endoplasmic reticulum stress (ERS). However, it remains unknown whether regulation of SREBP-2 processing modulates autophagy and ERS. In this study, we demonstrated that inhibition of SREBP-2 intracellular trafficking by site-1 protease (S1P) and site-2 protease (S2P) specific inhibitors, or shRNAs targeting S1P and S2P, upregulated gene and protein expression of autophagy markers, and improved the impaired autophagic flux induced in both cell and mouse models of NAFLD. Furthermore, increased lipid degradation by autophagy could repress PERK-P EIF2alpha signaling. Taken together, these findings suggest that regulating the nuclear transport of SREBP-2 reduces lipid deposition and ERS via an autophagy dependent pathway. PMID- 28011406 TI - Bone as a surrogate tissue to monitor metals in baleen whales. AB - Metals are massively deposited in the marine environment through direct emissions or atmospheric dry and wet depositions, a process since long enhanced by human activities. Metal contamination in the marine organisms has been increasingly investigated, but most research focuses on few tissues, elements and species considered indicative. Baleen whales have been scarcely studied in this respect. Here we contribute to the fragmented knowledge on this field examining the concentrations of zinc, copper, lead, titanium and strontium in the bone of fin whales (Balaenoptera physalus) from NW Spain and W Iceland. Bone was selected because it is a tissue commonly available in archival historic collections, and it is therefore useful to examine long-term trends in metal pollution. We tested differences between populations and we investigated age- and sex-related accumulation trends, as well as the occurrence of placental transfer. Sr concentrations and Pb accumulation rates with age were significantly higher in individuals from NW Spain than in those from W Iceland. Placental transfer occurred, at different levels, for all metals: as a result fetuses showed significantly higher Cu, Pb and Zn concentrations than adults. After birth, only Zn and Pb concentrations significantly increased with age. Through this study we contributed to fill some gaps in the knowledge regarding metal contamination in marine mammals, and we concluded that bone can be a suitable surrogate tissue to monitor a number of trace elements, provided that dissimilarities in tissue specific deposition are taken into account when comparing concentrations from different tissues. PMID- 28011407 TI - Non-steroidal anti-inflammatory drugs in the watercourses of Elbe basin in Czech Republic. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) belong to most used pharmaceuticals in the human and veterinary medicine. The widespread consumption of NSAIDs has led to their ubiquitous occurrence in water environment including large river systems. In the present study, concentrations of the five most frequently used NSAIDs (ibuprofen, diclofenac, naproxen, ketoprofen and indomethacin) were determined in the watercourses of the river Elbe basin in Czech Republic. The presence of the pharmaceuticals was measured at 29 sampling sites including urban and rural areas, small creeks and main tributaries of the Elbe monthly from April to December of 2011. For the NSAIDs quantitation, the comprehensive analytical method combing pentafluorobenzyl bromide (PFBBr) derivatization with highly sensitive two-dimensional gas chromatography time-of flight mass spectrometry (GCxGC-TOFMS) was developed. Although the content of all NSAIDs varied at the particular sampling points significantly, total amount of particular compounds was relatively stable during all monitored periods with only non-significant increase in the spring and autumnal months. Ibuprofen was found to be the most abundant drug with maximum concentration of 3210 ng/L, followed by naproxen, diclofenac and ketoprofen (1423.8 ng/L, 1080 ng/L and 929.8 ng/L, respectively). Indomethacin was found only at several sampling sites (maximum concentration of 69.3 ng/L). Concentrations of all compounds except ibuprofen were significantly higher at sampling sites with low flow rates (creeks), followed by the biggest watercourses. PMID- 28011408 TI - Measurement of fidgeting in patients with anorexia nervosa using a novel shoe based monitor. AB - OBJECTIVE: To objectively assess seated non-exercise physical activity in patients with anorexia nervosa (AN) relative to healthy controls (HCs) and examine the associations between this physical activity, eating disorder pathology, and levels of anxiety and depression. METHOD: Eleven inpatients with AN and 10 HCs wore a shoe-based accelerometer (SmartShoe) at three time points: a) while eating lunch, b) filling out questionnaires, and c) watching television for 1h. RESULTS: Across all three tasks, patients with AN were significantly more active than HCs, thereby engaging in a greater degree of restless or fidgeting behavior. Degree of physical activity was positively correlated with eating disorder psychopathology in the sample with AN, and a trend towards a positive association between physical activity and levels of depression and anxiety was also found in this sample. Among individuals with AN, physical activity was not significantly correlated with BMI, duration of illness, or number of days since hospital admission. DISCUSSION: Use of a minimally invasive, shoe-based monitor revealed patients with AN engaged in a greater degree of fidgeting relative to HCs during quiet, seated tasks and this heightened activity was related to measures of pathology. Non-exercise physical activity, including fidgeting, may warrant further clinical attention in this patient population. PMID- 28011409 TI - Geographic variation and within-individual correlations of physiological stress markers in a widespread reptile, the common garter snake (Thamnophis sirtalis). AB - Characterizing the baseline and stress-induced hormonal, metabolite, and immune profiles of wild animals is important to assess the impacts of variable environments, including human-induced landscape changes, on organismal health. Additionally, the extent to which these profiles are coordinated across physiological systems within individuals remains an important question in understanding how stressors can differentially affect aspects of an individual's physiology. Here, we present data from wild populations of the common garter snake (Thamnophis sirtalis) on both baseline and stress-induced biomarkers: plasma corticosterone (CORT) concentration, plasma glucose concentration, and whole blood heterophil:lymphocyte ratio. Using a standardized restraint protocol with individuals from populations in disparate portions of this species' range - the Sierra Nevada Mountains of California and the plains of Iowa - we collected blood plasma samples at nine time points over three days. Both CORT and glucose response curves differed between georegions, with Iowa snakes attaining higher glucose concentration and maintaining elevated CORT and glucose levels for a longer duration. Additionally, both the total amount and proportional increases of CORT and glucose were lower in larger and therefore older snakes, suggesting ontogenetic shifts in stress perception or response. Within-individual correlation among the three physiological indicators was significant at the time of capture, absent after 3h in captivity, and partially restored after 3days in captivity, demonstrating the effect of stress on the relationships among these physiological systems. Together, these results provide further evidence for the great physiological flexibility of ectothermic tetrapods in maintaining homeostasis across a range of factors. PMID- 28011410 TI - Rates of oxygen uptake increase independently of changes in heart rate in late stages of development and at hatching in the green iguana, Iguana iguana. AB - Oxygen consumption (VO2), heart rate (fH), heart mass (Mh) and body mass (Mb) were measured during embryonic incubation and in hatchlings of green iguana (Iguana iguana). Mean fH and VO2 were unvarying in early stage embryos. VO2 increased exponentially during the later stages of embryonic development, doubling by the end of incubation, while fH was constant, resulting in a 2.7-fold increase in oxygen pulse. Compared to late stage embryos, the mean inactive level of VO2 in hatchlings was 1.7 fold higher, while fH was reduced by half resulting in a further 3.6 fold increase in oxygen pulse. There was an overall negative correlation between mean fH and VO2 when data from hatchlings was included. Thus, predicting metabolic rate as VO2 from measurements of fH is not possible in embryonic reptiles. Convective transport of oxygen to supply metabolism during embryonic incubation was more reliably indicated as an index of cardiac output (COi) derived from the product of fH and Mh. However, a thorough analysis of factors determining rates of oxygen supply during development and eclosion in reptiles will require cannulation of blood vessels that proved impossible in the present study, to determine oxygen carrying capacity by the blood and arteriovenous oxygen content difference (A-V diff), plus patterns of blood flow. PMID- 28011411 TI - Call to action: A new path for improving diabetes care for Indigenous peoples, a global review. AB - Diabetes has reached epidemic proportions in Indigenous populations around the globe, and there is an urgent need to improve the health and health equity of Indigenous peoples with diabetes through timely and appropriate diabetes prevention and management strategies. This review describes the evolution of the diabetes epidemic in Indigenous populations and associated risk factors, highlighting gestational diabetes and intergenerational risk, lifestyle risk factors and social determinants as having particular importance and impact on Indigenous peoples. This review further describes the impact of chronic disease and diabetes on Indigenous peoples and communities, specifically diabetes-related comorbidities and complications. This review provides continued evidence that dramatic changes are necessary to reduce diabetes-related inequities in Indigenous populations, with a call to action to support programmatic primary healthcare transformation capable of empowering Indigenous peoples and communities and improving chronic disease prevention and management. Promising strategies for transforming health services and care for Indigenous peoples include quality improvement initiatives, facilitating diabetes and chronic disease registry and surveillance systems to identify care gaps, and prioritizing evaluation to build the evidence-base necessary to guide future health policy and planning locally and on a global scale. PMID- 28011412 TI - Electromyographic analysis of muscle activation during pull-up variations. AB - This study sought to identify any differences in peak muscle activation (EMGPEAK) or average rectified variable muscle activation (EMGARV) during supinated grip, pronated grip, neutral grip and rope pull-up exercises. Nineteen strength trained males (24.9+/-5y; 1.78+/-0.74m; 81.3+/-11.3kg; 22.7+/-2.5kgm-2) volunteered to participate in the study. Surface electromyography (EMG) was collected from eight shoulder-arm-forearm complex muscles. All muscle activation was expressed as a percentage of maximum voluntary isometric contraction (%MVIC). Over a full repetition, the pronated grip resulted in significantly greater EMGPEAK (60.1+/ 22.5vs. 37.1+/-13.1%MVIC; P=0.004; Effect Size [ES; Cohen's d]=1.19) and EMGARV (48.0+/-21.2vs. 27.4+/-10.7%MVIC; P=0.001; ES=1.29) of the middle trapezius when compared to the neutral grip pull-up. The concentric phases of each pull-up variation resulted in significantly greater EMGARV of the brachioradialis, biceps brachii, and pectoralis major in comparison to the eccentric phases (P=<0.01). Results indicate that EMGPEAK and EMGARV of the shoulder-arm-forearm complex during complete repetitions of pull-up variants are similar despite varying hand orientations; however, differences exist between concentric and eccentric phases of each pull-up. PMID- 28011413 TI - A systematic review and meta-analysis of seroprevalence of varicella zoster virus: A nationwide population-based study. AB - Varicella zoster virus (VZV) causes chicken pox as a primary infection following which it becomes latent in neurons. It may then reactivate to cause shingles (herpes zoster). Severity of lesions and VZV pathogenicity are depended on the host's immune response and variant in VZV Dr Athina Myrto ChioniIdentification of VZV seroprevalance rate in general population may lead to develop new health strategic managements such as vaccination. Therefore, we aimed to provide a systematic review of the seroprevalence of VZV infection among Iranian population and estimate age- and gender- specific prevalence of VZV. Keywords "seroprevalence"; "varicella zoster virus" and "Iran"; were searched in international electronic databases and also in national Persian databases. Twenty two pooled studies among 262 total studies containing (240 published articles; 18 dissertations; and 4 proceedings abstracts) from 1992 to 2014 with total sample size of 7867 individuals were included in the final review. Data was analyzed using random effect method. The heterogeneity was calculated using I-square statistics The overall IgG seroprevalence rate of VZV infection in general population of Iran was 78.50% (95% CI; 77.74%-79.25%). There was significant heterogeneity among the studies (P<0.0001; I2=99.4%). Furthermore, the relative risk of VZV infection is high in females (80.47%, 95% CI; 79.40%-81.54%) and older adults (95.30%, 95% CI; 94.11% -96.48%). Our results may represent a true background and estimation of VZV infection in Iran and generate the cost-benefits immunization program. Moreover, the ensuing data suggests further attention on disease seroprevalence in order to obtain efficient data for therapeutic intervention targeted against VZV. PMID- 28011414 TI - An electrochemical DNA sensor without electrode pre-modification. AB - We present a non-modification electrochemical DNA sensing strategy, which used Potential-Assisted Au-S Deposition and a clamp-like DNA probe. The dual-hairpin probe DNA was tagged with a methylene blue (MB) at the 3' terminal and a thiol at the 5' terminal., Without being hybridized with target DNA, the loop of probe prevented the thiol from reaching the bare gold electrode surface with an applied potential., After hybridization with the target DNA, the probe' s loop-stem structure opened through two distinct and sequential events, which led to the formation of a triplex DNA structure. Then the thiol easily contacted with electrode and resulted in potential-assisted Au-S self-assembly. Electrochemical signals of MB were measured by differential pulse voltammetry (DPV) and used for target quantitative detection. This strategy offered a detection limit down to 2.3pM. and an inherently high specificity for detecting even single mismatch. PMID- 28011415 TI - A highly sensitive signal-amplified gold nanoparticle-based electrochemical immunosensor for dibutyl phthalate detection. AB - A simple and signal-amplified, label-free electrochemical impedimetric immunosensor for dibutyl phthalate (DBP), a type of phthalate ester, was developed using gold nanoparticles (AuNPs) induced signal amplification. The approach was based on an indirectly competitive binding system of coating antigen that coated on antigen/chitosan/MWCNTs@GONRs/GCE (modified electrodes), target (DBP) and anti-DBP antibody. Signal amplification was performed via the enlargement of AuNPs through NADH-promoted catalytic precipitation, which caused a marked increase in the electron-transfer resistance and electrostatic repulsion after an AuNP-labeled second antibody conjugated to anti-DBP. Under the optimized conditions, this method displayed: (i) low detection limits (7ng/mL, 10 times lower than the traditional ELISA method using the same antibody); (ii) satisfactory accuracy (recoveries, 86.0-120.4%) and agreement with corresponding ELISA method; (iii) high tolerance to some environmental interferents; and (iv) low cost and low sample consumption (6uL). Our results demonstrate the great potential and high efficiency of this immunosensor in practical applications for the cost-effective and sensitive monitoring of DBP in aquatic environments. PMID- 28011416 TI - Lab-in-a-syringe using gold nanoparticles for rapid colorimetric chiral discrimination of enantiomers. AB - Nanomaterials with different characteristics are offering many ingenious sensing approaches with interest for simple and disposable paper-based (bio)sensing applications. In this study, the colorimetric discrimination of alanine enantiomers is examined and, more importantly, AuNPs-embedded paper-based lab-in a-syringe (LIS) device is developed as a sensing strategy. The LIS consists of two cellulose acetate membranes: the conjugate pad capturing the analyte and the detection pad signaling the presence of the captured analyte, both are sandwiched between reusable plastic filter holders connected to a disposable syringe. The principle of LIS assay is based on the enantioselective interaction occurring between the inherently chiral AuNPs and enantiomers in the first filter holder, which results in aggregation of AuNPs to give a distinct colour change from red to purple in solution and finally the aggregated AuNPs is kept on the detection pad through vertical-flow operation. AuNPs show an enantioselective recognition response toward L-Alanine and limit of detection (LOD) value is determined as 0.77mM. In addition, we demonstrate the efficiency of the LIS device for detecting L-Alanine in human serum. The proposed LIS assay has some advantages such as useful for naked-eye observation, disposable, not time-consuming, inexpensive, no need of advanced instruments, easy to prepare and easy to handle. In the field, the approach which is the first demonstration of applicability of LIS device to show simple colorimetric enantioselective sensing of chiral species with a fast readout in less than 5min is truly new and may have broad interest in enantiosensing of various chiral molecules. PMID- 28011417 TI - Ratiometric fluorescent response of electrospun fibrous strips for real-time sensing of alkaline phosphatase in serum. AB - The development of rapid, convenient and reliable assays for monitoring alkaline phosphatase (ALP) levels is valuable for clinical diagnoses and biomedical research. In the current study, a ratiometric assay of ALP activity has been realized by covalent immobilization of fluorescein onto polyethylene terephthalate (PET) fibers, followed by electrostatic adsorption of bisquaternary ammonium salt of tetraphenylethene (TPE-2N+). In the absence of ALP, the complex formation between phosphorylated fluorescein and TPE-2N+ results in the aggregation-induced emission (AIE) of TPE at 471nm. While in the presence of ALP, the hydrolysis of phosphoesters leads to a gradual removal of TPE-2N+ and the restoration of fluorescein emission at 514nm. Fibers with surface amine densities of 30 nmol/mg show the most significant and almost linear increases in I514/I471 ratios from 0.73 to 3.05 with increasing ALP concentrations from 0 to 100 mU/mL. The ratiometric fluorescence responses result in color changes of fibrous strips from blue (TPE-2N+) to green (fluorescein) under an ultraviolet lamp in a matter of minutes. The color changes are more suitable for an eyeball detection of ALP levels ranging from 0 to 80 mU/mL, which is included in the concentration range of ALP in human serum considering the dilution factor if necessary. The ALP detection indicates no apparent interference by serum components and good agreement with enzyme-linked immunosorbent assay (ELISA). Thus, this is the first study on ratiometric fluorescent assay of serum ALP levels by fibrous strips, which offers a capacity to exploit electrospun fibrous mats and ratiometric responses for real-time assays of bioactive substances as self-test devices. PMID- 28011418 TI - COMPOSE: Using temporal patterns for interpreting wearable sensor data with computer interpretable guidelines. AB - This paper describes a novel temporal logic-based framework for reasoning with continuous data collected from wearable sensors. The work is motivated by the Metabolic Syndrome, a cluster of conditions which are linked to obesity and unhealthy lifestyle. We assume that, by interpreting the physiological parameters of continuous monitoring, we can identify which patients have a higher risk of Metabolic Syndrome. We define temporal patterns for reasoning with continuous data and specify the coordination mechanisms for combining different sets of clinical guidelines that relate to this condition. The proposed solution is tested with data provided by twenty subjects, which used sensors for four days of continuous monitoring. The results are compared to the gold standard. The novelty of the framework stands in extending a temporal logic formalism, namely the Event Calculus, with temporal patterns. These patterns are helpful to specify the rules for reasoning with continuous data and in combining new knowledge into one consistent outcome that is tailored to the patient's profile. The overall approach opens new possibilities for delivering patient-tailored interventions and educational material before the patients present the symptoms of the disease. PMID- 28011419 TI - Implications of the new sepsis definition on research and practice. AB - INTRODUCTION: The Society of Critical-Care Medicine and the European Society of Intensive Care Medicine recently announced a marked change in the sepsis definition. A task force of 19 sepsis clinicians and researchers made the change based on advances in the pathobiological understanding of the septic process. SUMMARY OF CHANGE: The task force determined that there were numerous justifications for a revision of the sepsis definition, which are outlined in this article. The systemic inflammatory response criteria have been replaced by the Sequential Organ Failure Assessment (SOFA) score in the newly operationalized definition (Singer et al., 2016). In addition to the definition change, the task force recommended using the new quick SOFA (qSOFA) score in non-ICU settings, as a risk stratification tool to identify patients who may be septic or be at risk of developing sepsis. IMPLICATIONS ON RESEARCH & PRACTICE: The change in definition will likely have a negative impact on sepsis research in the short term as hospitals adjust their coding for the new definition, but may result in less misclassification bias and improved research data in the long-term. While the intent of the SCCM/ESICM task force was to better define sepsis for coding and epidemiological research purposes, there is the potential for improved patient outcomes if clinicians are better able to differentiate between sepsis and inflammatory events. The qSOFA tool may also aid clinicians in recognizing sepsis in a quicker manner, leading to more timely treatment, and potentially better outcomes. CONCLUSIONS: While the new operationalized Sepsis-3 definition appears on the surface to be an improvement over the previous iterations, it remains to be seen if research data will be more robust using the new criteria. There is the potential for better patient outcomes if clinicians are better able to differentiate sepsis from inflammatory events with the new definition, and if sepsis cases are recognized sooner with qSOFA. Future research on the impact of this definition change on research and practice will be essential, to determine if the Sepsis 3 definition, its associated clinical criteria, and the qSOFA need further revision. PMID- 28011420 TI - Perspectives of patients and family members regarding psychological support using intensive care diaries: An exploratory mixed methods study. AB - PURPOSE: Diaries summarizing intensive care are routine practice in some countries, although evidence to support diary use is limited. The purpose of this study was to identify whether distress post-intensive care influences patients' and relatives' choice as to whether they would like to receive a diary and what information delivery method is preferred. MATERIALS AND METHODS: Intensive care patients admitted for at least 3 days and their relatives participated in an exploratory mixed methods study. Interviews were conducted 3 to 5 months after discharge. Psychological distress was assessed using Kessler-10 and Posttraumatic Stress Disorder Symptom Checklist - 5. Perceptions of benefit of diaries were assessed using a 4-point Likert scale. Differences were examined using Fisher exact test (P<.05). RESULTS: Fifty-seven patients and 22 relatives consented to participation, with 22 patients and 22 relatives interviewed before data saturation. Psychological distress was evident in 25 (47%) patients and 5 (23%) relatives. Participants' psychological health was similar for those who perceived diaries as beneficial, and those who did not. Themes included memory, process, and impact, although opinions were diverse. CONCLUSIONS: Patient and relative preferences of receiving a diary are not related to psychological distress. Diverse opinions around common themes suggest the need for a range of interventions to aid psychological recovery. PMID- 28011421 TI - Cd immobilization and reduced tissue Cd accumulation of rice (Oryza sativa wuyun 23) in the presence of heavy metal-resistant bacteria. AB - Two metal-resistant Bacillus megaterium H3 and Neorhizobium huautlense T1-17 were investigated for their immobilization of Cd in solution and tissue Cd accumulation of rice (Oryza sativa wuyun-23) in the Cd-contaminated soil. Strains H3 and T1-17 decreased 79-96% of water-soluble Cd in solution and increased grain biomass in the high Cd-contaminated soil. Inoculation with H3 and T1-17 significantly decreased the root (ranging from 25% to 58%), above-ground tissue (ranging from 13% to 34%), and polished rice (ranging from 45% to 72%) Cd contents as well as Cd bioconcentration factor of the rice compared to the controls. Furthermore, H3 and T1-17 significantly reduced the exchangeable Cd content of the rhizosphere soils compared with the controls. Notably, strain T1 17 had significantly higher ability to reduce Cd bioconcentration factor and polished rice Cd uptake than strain H3. The results demonstrated that H3 and T1 17 decreased the tissue (especially polished rice) Cd uptake by decreasing Cd availability in soil and Cd bioconcentration factor and the effect on the reduced polished rice Cd uptake was dependent on the strains. The results may provide an effective synergistic bioremediation of Cd-contaminated soils in the bacteria and rice plants and bacterial-assisted safe production of rice in Cd-contaminated soils. PMID- 28011422 TI - A hepatic metabolomics-based diagnostic approach to assess lethal toxicity of dithiocarbamate fungicide polycarbamate in three marine fish species. AB - The present study was performed to evaluate the toxic effect of the dithiocarbamate fungicide polycarbamate (PC) on the hepatic metabolic profiles of three marine fish species, red sea bream (Pagrus major), spotted halibut (Verasper variegatus), and marbled flounder (Pleuronectes yokohamae). First, juvenile fish were exposed to graded concentrations of PC for 96h; the 96-h LC50 values obtained were 22-29, 239-553, and 301-364ugL-1 for red sea bream, spotted halibut, and marbled flounder, respectively, indicating that red sea bream possessed higher sensitivity to PC than the two benthic species. Second, the fish were exposed to lethal-equivalent concentration (H group) or sub-lethal (one tenth of the H group concentrations; L group) for 24 and 96h and gas chromatography based metabolomics approach was employed to explore the crucial biomarker metabolite associated with lethal toxicity. Of the 53 metabolites identified, only reduced glutathione (GSH) was consistently elevated in the H group for the three fish species at 96h. The calculated cut-off value of GSH (mM) based on receiver operating curve analysis between H group and the other treatment groups (control, solvent control, and L group) was obtained at 0.56mM, which allowed to distinguish between the groups with high confidence for the three fish species. These results are the first to demonstrate the potential of using GSH as a possible biomarker metabolite and its usefulness of threshold cut off value for diagnosing life-threatening health conditions of fish. PMID- 28011423 TI - mRNA decay in plants: both quantity and quality matter. AB - In eukaryotes, degradation of messenger RNAs (mRNAs) is required for both mRNA quantity and quality control. Fine-tuning of the abundance of mRNAs that are to be translated can be achieved through a deadenylation-mediated RNA decay pathway involving progressive removal of poly(A) tails, decapping and exoribonuclease digestion. While the classical view assumes that mRNAs are degraded only after their exit from protein translation, recent studies have revealed mRNA decay can occur during translation in plants. Those mRNAs that have structural or functional defects can be filtered by translation-dependent RNA quality control pathways and rapidly degraded, so that translation fidelity is preserved. In addition, aberrant transcripts can also be efficiently eliminated through bidirectional RNA decay pathways. In the absence of those pathways, accumulation of those aberrant transcripts evokes the activation of RNA silencing, with detrimental consequences. PMID- 28011424 TI - Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles. AB - A series of chalcone linked-1,2,3-triazoles was synthesized via cellulose supported copper nanoparticle catalyzed click reaction in water. The structures of all the compounds were analyzed by IR, NMR and Mass spectral techniques. All the synthesized products were subjected to 3-(4,5-dimethylthiazole-2-yl)-2,5 diphenyltetrazolium bromide (MTT) cytotoxicity assay against a panel of four human cancer cell lines (MCF-7, MIA-Pa-Ca-2, A549, HepG2) to check their anticancer potential. Compound 6h was found to be most active against all the tested cancer cell lines with IC50 values in the range of 4-11 MUM and showed better or comparable activity to the reference drug against all the tested cell lines. Cell cycle analysis revealed that compound 6h induces apoptosis and G2/S arrest in MIA-Pa-Ca-2 cells. Compound 6h triggers mitochondrial potential loss in pancreatic cancer MIA-Pa-Ca-2 cells. Further, Compound 6h also triggers caspase-3 and PARP-1 cleavage, which increases in dose dependent manner. PMID- 28011425 TI - Discovery and evaluation of inhibitors to the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1): Probing the active site-inhibitor interactions. AB - High expression of the immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) for a broad range of malignancies is associated with poor patient prognosis, and the enzyme is a validated target for cancer intervention. To identify novel IDO1 inhibitors suitable for drug development, 1597 compounds in the National Cancer Institute Diversity Set III library were tested for inhibitory activity against recombinant human IDO1. We retrieved 35 hits that inhibited IDO1 activity >50% at 20 MUM. Five structural filters and the PubChem Bioassay database were used to guide the selection of five inhibitors with IC50 between 3 and 12 MUM for subsequent experimental evaluation. A pyrimidinone scaffold emerged as being the most promising. It showed excellent cell penetration, negligible cytotoxicity and passed four out of the five structural filters applied. To evaluate the importance of Ser167 and Cys129 residues in the IDO1 active site for inhibitor binding, the entire NCI library was subsequently screened against alanine-replacement mutant enzymes of these two residues. The results established that Ser167 but not Cys129 is important for inhibitory activity of a broad range of IDO1 inhibitors. Structure-activity-relationship studies proposed substituents interacting with Ser167 on four investigated IDO1 inhibitors. Three of these four Ser167 interactions associated with an increased IDO1 inhibition and were correctly predicted by molecular docking supporting Ser167 as an important mediator of potency for IDO1 inhibitors. PMID- 28011426 TI - Improving potency and metabolic stability by introducing an alkenyl linker to pyridine-based histone deacetylase inhibitors for orally available RUNX3 modulators. AB - RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (E)-3-(1-cinnamyl-2-oxo-1,2 dihydropyridin-3-yl)-N-hydroxyacrylamide (7k), showed excellent properties in a microsomal stability study, in a xenograft study, and in an in vivo pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents. PMID- 28011427 TI - Heavy metals in sludge during anaerobic sanitary landfill: Speciation transformation and phytotoxicity. AB - Sanitary landfill persists as a predominant sludge disposal method in particular in China. In this study, successive subsurface sludge samples (0.3 m deep) were collected from a bioreactor landfill unit where an anaerobic process took place during a 500 d period. The sludge samples were analyzed for total concentrations of cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) and their species distributions, together with selected sludge chemical properties. In addition, the sludge samples were subjected to phytotoxicity testing. The results showed that the mobilities of Cd and Ni were decreased with landfill time, while the mobilities of Cr, Cu, Pb and Zn remained consistently low over the landfill period. The residual amounts of all these heavy metals were increased with landfill time, suggesting that the anaerobic sanitary landfill is an effective sludge stabilization method to reduce the ecological risk of these heavy metals. The increase in the sludge pH value with landfill time tended to promote the precipitation of heavy metals. Moreover, the sludge stabilization was found to be indicated by the formation of humic substance (HS) and volatilization of volatile matter (VM). The germination index (GI) values of barley (Hordeum vulgare L.) and Chinese cabbage (Brassica rapa chinensis) seeds grown in the 500 d anaerobically stabilized sludge were approximately 5.2- and 4.1-times higher than the values of those grown in the fresh sludge. The final sludge extract did not cause any significant inhibitory effect on the germination of the two types of seeds. PMID- 28011428 TI - Characterization of fly ash ceramic pellet for phosphorus removal. AB - Phosphorus has been recognized as a leading pollutant for surface water quality deterioration. In the Midwestern USA, subsurface drainage not only provides a pathway for excess water to leave the field but it also drains out nutrients like nitrogen (N) and phosphorus (P). Fly ash has been identified as one of the viable materials for phosphorus removal from contaminated waters. In this study, a ceramic pellet was manufactured using fly ash for P absorption. Three types of pellet with varying lime and clay proportions by weight (type 1: 10% lime + 30% clay, type 2: 20% lime + 20% clay, and type 3: 30% lime + 10% clay) were characterized and evaluated for absorption efficiency. The result showed that type 3 pellet (60% fly ash with 30% lime and 10% clay) had the highest porosity (14%) and absorption efficiency and saturated absorption capacity (1.98 mg P/g pellet) compared to type 1 and 2 pellets. The heavy metal leaching was the least (30 MUg/L of chromium after 5 h) for type 3 pellet compared to other two. The microcosmic structure of pellet from scanning electron microscope showed the type 3 pellet had the better distribution of aluminum and iron oxide on the surface compared other two pellets. This result indicates that addition of lime and clay can improve P absorption capacity of fly ash while reducing the potential to reduce chromium leaching. PMID- 28011429 TI - Phytostabilization of Zn-Pb ore flotation tailings with Dianthus carthusianorum and Biscutella laevigata after amending with mineral fertilizers or sewage sludge. AB - Zinc-lead mining wastes remain largely unvegetated and prone to erosion for many years because of phytotoxic levels of residual heavy metals, low nutrient status and poor physical structure. The optimal solution for these areas is to restore plant cover using species which spontaneously appear on the spoils. These species are adapted to the conditions of tailings, and their establishment will promote further vegetation by increasing soil organic matter and development of a soil system capable of supporting the nutrient and water requirements of plants and microoorganisms. The potential of Dianthus carthusianorum and Biscutella laevigata to stabilize mine spoils was analysed in a three-year pot experiment. Post-flotation wastes accumulated after Zn and Pb recovery from ores, were collected from tailings and used as a substrate for plant growth. Seeds for seedling production were collected from plants growing spontaneously on mine tailings. Prior to the establishment of the three-year pot experiment, the substrate was amended with fertilizer NPK or municipal sewage sludge, supplemented with K2O (SS). Substrate samples were collected for chemical analyses, dehydrogenase and urease activities measurements each year at the end of the growing season. The plants were harvested three years after the amendments. Both tested plant species were equally suitable for revegetation of the tailings. The amendment including both SS and NPK resulted in an increase of Corg, Nt, available P, K, Mg contents, an increase of dehydrogenase (DHA) and urease activities and a decrease in the concentrations of the soluble forms of Zn, Pb and Cd. However, nutrient content, DHA activity and plant biomass were higher with SS than NPK addition. NPK application enhanced the substrate properties after the first growing season, while positive effects of SS use were still observed after three years. A longer-lasting positive effect of SS than NPK application was probably due to the high organic matter content in SS, which was gradually decomposing and releasing nutrients. PMID- 28011430 TI - Carbon dioxide sequestration using NaHSO4 and NaOH: A dissolution and carbonation optimisation study. AB - The use of NaHSO4 to leach out Mg fromlizardite-rich serpentinite (in form of MgSO4) and the carbonation of CO2 (captured in form of Na2CO3 using NaOH) to form MgCO3 and Na2SO4 was investigated. Unlike ammonium sulphate, sodium sulphate can be separated via precipitation during the recycling step avoiding energy intensive evaporation process required in NH4-based processes. To determine the effectiveness of the NaHSO4/NaOH process when applied to lizardite, the optimisation of the dissolution and carbonation steps were performed using a UK lizardite-rich serpentine. Temperature, solid/liquid ratio, particle size, concentration and molar ratio were evaluated. An optimal dissolution efficiency of 69.6% was achieved over 3 h at 100 degrees C using 1.4 M sodium bisulphate and 50 g/l serpentine with particle size 75-150 MUm. An optimal carbonation efficiency of 95.4% was achieved over 30 min at 90 degrees C and 1:1 magnesium:sodium carbonate molar ratio using non-synthesised solution. The CO2 sequestration capacity was 223.6 g carbon dioxide/kg serpentine (66.4% in terms of Mg bonded to hydromagnesite), which is comparable with those obtained using ammonium based processes. Therefore, lizardite-rich serpentinites represent a valuable resource for the NaHSO4/NaOH based pH swing mineralisation process. PMID- 28011431 TI - Iron removal, energy consumption and operating cost of electrocoagulation of drinking water using a new flow column reactor. AB - The goal of this project was to remove iron from drinking water using a new electrocoagulation (EC) cell. In this research, a flow column has been employed in the designing of a new electrocoagulation reactor (FCER) to achieve the planned target. Where, the water being treated flows through the perforated disc electrodes, thereby effectively mixing and aerating the water being treated. As a result, the stirring and aerating devices that until now have been widely used in the electrocoagulation reactors are unnecessary. The obtained results indicated that FCER reduced the iron concentration from 20 to 0.3 mg/L within 20 min of electrolysis at initial pH of 6, inter-electrode distance (ID) of 5 mm, current density (CD) of 1.5 mA/cm2, and minimum operating cost of 0.22 US $/m3. Additionally, it was found that FCER produces H2 gas enough to generate energy of 10.14 kW/m3. Statistically, it was found that the relationship between iron removal and operating parameters could be modelled with R2 of 0.86, and the influence of operating parameters on iron removal followed the order: C0>t>CD>pH. Finally, the SEM (scanning electron microscopy) images showed a large number of irregularities on the surface of anode due to the generation of aluminium hydroxides. PMID- 28011432 TI - Challenges in quantitative crystallographic characterization of 3D thin films by ACOM-TEM. AB - Automated crystal orientation mapping for transmission electron microscopy (ACOM TEM) has become an easy to use method for the investigation of crystalline materials and complements other TEM methods by adding local crystallographic information over large areas. It fills the gap between high resolution electron microscopy and electron back scatter diffraction in terms of spatial resolution. Recent investigations showed that spot diffraction ACOM-TEM is a quantitative method with respect to sample parameters like grain size, twin density, orientation density and others. It can even be used in combination with in-situ tensile or thermal testing. However, there are limitations of the current method. In this paper we discuss some of the challenges and discuss solutions, e.g. we present an ambiguity filter that reduces the number of pixels with a '180 degrees ambiguity problem'. For that an ACOM-TEM tilt series of nanocrystalline Pd thin films with overlapping crystallites was acquired and analyzed. PMID- 28011433 TI - Assessing local capacity to expand rural breast cancer screening and patient navigation: An iterative mixed-method tool. AB - BACKGROUND: Despite federal funding for breast cancer screening, fragmented infrastructure and limited organizational capacity hinder access to the full continuum of breast cancer screening and clinical follow-up procedures among rural-residing women. We proposed a regional hub-and-spoke model, partnering with local providers to expand access across North Texas. We describe development and application of an iterative, mixed-method tool to assess county capacity to conduct community outreach and/or patient navigation in a partnership model. METHODS: Our tool combined publicly-available quantitative data with qualitative assessments during site visits and semi-structured interviews. RESULTS: Application of our tool resulted in shifts in capacity designation in 10 of 17 county partners: 8 implemented local outreach with hub navigation; 9 relied on the hub for both outreach and navigation. Key factors influencing capacity: (1) formal linkages between partner organizations; (2) inter-organizational relationships; (3) existing clinical service protocols; (4) underserved populations. Qualitative data elucidate how our tool captured these capacity changes. CONCLUSIONS: Our capacity assessment tool enabled the hub to establish partnerships with county organizations by tailoring support to local capacity and needs. Absent a vertically integrated provider network for preventive services in these rural counties, our tool facilitated a virtually integrated regional network to extend access to breast cancer screening to underserved women. PMID- 28011434 TI - Facile and green synthesis of phytochemicals capped platinum nanoparticles and in vitro their superior antibacterial activity. AB - The increase in the severe infectious diseases and resistance of the majority of the bacterial pathogens to the available drug is a serious problem now a day. In order to overcome this problem it is necessary to develop new therapeutic agents which are non-toxic and more effective to inhibit these microbial pathogens. For this purpose the plant extract of highly active medicinal plant, Taraxacum laevigatum was used for the synthesis of platinum nanoparticles (PtNPs) to enhance its bio-activities. The surface plasmon resonance peak appeared at 283nm clearly represent the formation of PtNPs. The results illustrate that the bio synthesized PtNPs were uniformly dispersed, small sized (2-7nm) and spherical in shape. The green synthesized PtNPs were characterized by UV-vis spectroscopy, XRD, TEM, SEM, EDX, DLS and FTIR. These nanoparticles were tested against gram positive bacteria (Bacillus subtilis) and gram negative bacteria (Pseudomonas aeruginosa). The bio-synthesized PtNPs were examined to be more effective against both of the bacteria. The results showed, that the zone of inhibition of PtNPs against P. aeruginosa was 15 (+/-0.5) mm and B. subtilis was 18 (+/-0.8) mm. The most significant outcome of this examination is that PtNPs exhibited strong antibacterial activity against P. aeruginosa and B. subtilis which have strong defensive system against several antibiotics. PMID- 28011435 TI - Diastase induced green synthesis of bilayered reduced graphene oxide and its decoration with gold nanoparticles. AB - In this paper, we report an enzyme dependent, green one-pot deoxygenation cum decoration method to synthesize diastase-conjugated reduced graphene oxide (DRG) nanosheets, DRG/gold nanoparticles (DRG/Au) composite. The DRG synthesis was completed in 7h under heating at 90 degrees C on water bath. Selected area electron diffraction (SAED) and Atomic force microscopy (AFM) study has revealed the formation of bilayered reduced graphene oxide sheets. Transmission electron microscopy (TEM) images of DRG/Au composite have shown the uniform decoration of gold nanoparticles (AuNPs) onto the DRG nanosheet surface. Fourier transform infrared spectroscopy (FTIR) and Raman results additionally have shown the functionalization of enzyme molecules onto the DRG nanosheet surface after reduction making it as an effective platform towards the efficient binding of gold nanoparticles. In vitro cytotoxicity studies by MTT assay on A549 and HCT116 cell lines exhibited that the cytotoxicity of the prepared graphene oxide (GO), DRG and DRG/Au is dose dependant. These results have shown that this synthetic method is effective for the production of large scale graphene in a low cost, simple and green method. Since this process avoids the use of hazardous and toxic substances, the produced DRG/Au composites are likely to offer various potential applications in biology and medicine. PMID- 28011436 TI - Phonological abilities in literacy-impaired children: Brain potentials reveal deficient phoneme discrimination, but intact prosodic processing. AB - Intact phonological processing is crucial for successful literacy acquisition. While individuals with difficulties in reading and spelling (i.e., developmental dyslexia) are known to experience deficient phoneme discrimination (i.e., segmental phonology), findings concerning their prosodic processing (i.e., suprasegmental phonology) are controversial. Because there are no behavior independent studies on the underlying neural correlates of prosodic processing in dyslexia, these controversial findings might be explained by different task demands. To provide an objective behavior-independent picture of segmental and suprasegmental phonological processing in impaired literacy acquisition, we investigated event-related brain potentials during passive listening in typically and poor-spelling German school children. For segmental phonology, we analyzed the Mismatch Negativity (MMN) during vowel length discrimination, capturing automatic auditory deviancy detection in repetitive contexts. For suprasegmental phonology, we analyzed the Closure Positive Shift (CPS) that automatically occurs in response to prosodic boundaries. Our results revealed spelling group differences for the MMN, but not for the CPS, indicating deficient segmental, but intact suprasegmental phonological processing in poor spellers. The present findings point towards a differential role of segmental and suprasegmental phonology in literacy disorders and call for interventions that invigorate impaired literacy by utilizing intact prosody in addition to training deficient phonemic awareness. PMID- 28011438 TI - Photoswitchable carbohydrate-based fluorosurfactants as tuneable ice recrystallization inhibitors. AB - Cryopreservation is an important technique employed for the storage and preservation of biological tissues and cells. The limited effectiveness and significant toxicity of conventionally-used cryoprotectants, such as DMSO, have prompted efforts toward the rational design of less toxic alternatives, including carbohydrate-based surfactants. In this paper, we report the modular synthesis and ice recrystallization inhibition (IRI) activity of a library of variably substituted, carbohydrate-based fluorosurfactants. Carbohydrate-based fluorosurfactants possessed a variable mono- or disaccharide head group appended to a hydrophobic fluoroalkyl-substituted azobenzene tail group. Light-addressable fluorosurfactants displayed weak-to-moderate IRI activity that could be tuned through selection of carbohydrate head group, position of the trifluoroalkyl group on the azobenzene ring, and isomeric state of the azobenzene tail fragment. PMID- 28011439 TI - Construction of poly (vinyl alcohol)/poly (lactide-glycolide acid)/vancomycin nanoparticles on titanium for enhancing the surface self-antibacterial activity and cytocompatibility. AB - Comparing with traditional drug dosage form, controlled release systems offer more effective and favorable route to deliver drugs in optimum dose to specific sites with long term release duration. In this work, an effective drug delivery system composed of poly (vinyl alcohol) (PVA)/poly (lactide-glycolide acid) (PLGA) nanoparticles (NPs) with encapsulated vancomycin (Van), is constructed on the surface of biomedical titanium. The PVA/PLGA/Van NPs synthesized via double emulsion route are grafted onto the surface of titanium plates modified by alkaline-heat treatment and subsequent aminopropyltriethoxysilane (APTES) deposition. In vitro tests disclose that NPs can release a small amount of drugs continuously due to the slow swelling or hydrolysis of polymer chain segments as the immersion time increases. As the pH value reduces, the ester bonds rupture with releasing more drugs, which is why this drug delivery system exhibits the highest antibacterial efficiency at the lowest pH value of 4.5 in this work. Cell culture results reveal that this smart surface system on titanium facilitates the cell attachment and proliferation on implants. Hence, this pH controlled drug delivery system can be successfully applied as a bio-platform for improving both the osteoblasts adhesion and antibacterial activity of metallic implants. PMID- 28011437 TI - Childhood poverty is associated with altered hippocampal function and visuospatial memory in adulthood. AB - Childhood poverty is a risk factor for poorer cognitive performance during childhood and adulthood. While evidence linking childhood poverty and memory deficits in adulthood has been accumulating, underlying neural mechanisms are unknown. To investigate neurobiological links between childhood poverty and adult memory performance, we used functional magnetic resonance imaging (fMRI) during a visuospatial memory task in healthy young adults with varying income levels during childhood. Participants were assessed at age 9 and followed through young adulthood to assess income and related factors. During adulthood, participants completed a visuospatial memory task while undergoing MRI scanning. Patterns of neural activation, as well as memory recognition for items, were assessed to examine links between brain function and memory performance as it relates to childhood income. Our findings revealed associations between item recognition, childhood income level, and hippocampal activation. Specifically, the association between hippocampal activation and recognition accuracy varied as a function of childhood poverty, with positive associations at higher income levels, and negative associations at lower income levels. These prospective findings confirm previous retrospective results detailing deleterious effects of childhood poverty on adult memory performance. In addition, for the first time, we identify novel neurophysiological correlates of these deficits localized to hippocampus activation. PMID- 28011440 TI - Adaptation to nursing home: The role of leisure activities in light of motivation and relatedness. AB - Based on the motivational sequence described in Self-Determination Theory, this study explored the relationship between relatedness, motivation, adaptation and leisure in nursing homes. We formulated the hypothesis that the variables of the study would be found in an integrative mediational sequence: Participation in leisure activities->Relatedness->Self-determined motivation->Adaptation to nursing homes. Participants (N=112, mean age=84.17) were invited to complete questionnaires assessing these variables. Results of the path analysis found an unsatisfactory fit for this model but revealed another model (Model 2) with a good fit index: Relatedness->Participation in leisure activities->Self-determined motivation->Adaptation to nursing homes->Relatedness. Model 2 fitted better than model 1: the Chi-square values were not significant, Chi2 (df=2)=5.1, p=0.078 and other indices were satisfactory (CFI=0.930, RMSEA=0.049 and NFI=0.918). These results suggest that feeling connected and secure in the relationships with others, and integrated as an individual to the group contribute to enhance leisure practice, self-determined motivation, and finally adaptation to life environment. Consequently, the relatedness promotes leisure activities practice which represents a central adaptive behavior in nursing homes. PMID- 28011441 TI - Cannabinoid receptors on peripheral leukocytes from patients with schizophrenia: Evidence for defective immunomodulatory mechanisms. AB - OBJECTIVES: to evaluate cannabinoid receptors (CBRs) expression on peripheral immune cells, i.e., blood monocytes, neutrophils, lymphocytes, and NK cells, and their relationship to a wide range of serum cytokine levels in subjects with schizophrenia and controls. METHODS: A sample of 55 people with chronic schizophrenia and 48 controls were enrolled in the study. The expression of the cannabinoid receptors CB1R and CB2R was evaluated in peripheral blood leukocytes by flow cytometry. Serum levels of cytokines/chemokines were simultaneously analyzed by cytometric bead array. RESULTS: We found higher expression of cannabinoid receptors on cells of the innate immune system in subjects with schizophrenia when compared with controls. Serum levels of interleukin-4 (IL-4), IL-6, IL-10, IL-17, interferon (IFN-gamma), and (C-X-C motif) ligand 10/interferon gamma-induced protein 10 (CXCL10/IP10) were decreased, while levels of the chemokine (C-C motif) ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were increased in the schizophrenia group in comparison with controls. Patients with schizophrenia showed simpler correlation network between cytokines and CBRs expression than controls. CONCLUSION: Patients with schizophrenia showed increased CBRs expression in cells of the innate immune system and simpler correlation network between cytokines and CBRs expression when compared with controls. These results suggest a defective endocannabinoid system mediated immunomodulation in patients with schizophrenia. PMID- 28011442 TI - Mental health of adolescents with currently and formerly incarcerated parents. AB - Reliable information about children of incarcerated people is difficult to obtain, and major gaps exist in our understanding of their well-being. This study aims to determine whether adolescents with incarcerated parents report higher levels of mental health problems than those without an incarcerated parent, and whether the relationship between parental incarceration and adolescent mental health is moderated by parent-child relationships. Using a statewide survey from one US state, we compared adolescents with a currently incarcerated parent to those with a formerly incarcerated parent and those with no history of parental incarceration on self-reported indicators of mental health, and examined whether strong parent-child relationships were protective against mental health concerns. Results indicate that adolescents with incarcerated parents are at elevated risk for mental health problems, and strong parent-child relationships partially buffer children from risk. Findings underscore the need for more investment in effective early interventions for adolescents in highly adverse contexts. PMID- 28011443 TI - Co-evolution of methods and thoughts in cereal domestication studies: a tale of barley (Hordeum vulgare). AB - Five major cereals such as wheat, rice, maize, barley and sorghum were among the first Neolithic crops that facilitated the establishment of the early agricultural societies. Since then they have remained the staple source of calories for the majority of the human population. Ample archaeological and molecular evidence has provided important insights into the domestication history of cereals but the debates on the origin of cereal crops are still far from resolved. Here, we review the recent advances in applying genome sequencing technologies for deciphering the history of cereal domestication. As a model example, we demonstrate that the evolution of thoughts on barley domestication closely followed the development of views on the rise of agriculture in the Near East in general and greatly accelerated with the advent of the genomic technologies and resources available for barley research. PMID- 28011444 TI - Rapid determination of alkaloids in Macleaya cordata using ionic liquid extraction followed by multiple reaction monitoring UPLC-MS/MS analysis. AB - The ultrasonic-assisted extraction (UAE) and ionic liquid based dispersive liquid liquid microextraction (IL-DLLME) have been successfully applied in extracting of six alkaloids from M. cordata. 1-hexyl-3-methylimidazolium tetrafluoroborate ([C6MIM][BF4]) aqueous solution was used as extraction solvent. The target analytes in raw material were deposited into a single drop of 1-hexyl-3 methylimidazolium hexafluorophosphate ([C6MIM][PF6]), which was in situ formed by mixing [C6MIM][BF4] and potassium hexafluorophosphate ([K][PF6]. Afterwards, the extract was analyzed by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) in multiple-reaction monitoring (MRM) mode. The proposed method was fully validated in terms of linearity (0.9983-0.9992), LOD (0.080ngmL-1), LOQ (0.25ngmL-1), intra-day precision (<5.46%), inter-day precision (<6.36%), and recovery (86.42-112.48%). The results indicate that the approach of combining IL-DLLME with UPLC-MS/MS is powerful and practical for analyzing alkaloids in M. cordata., and it also has great potential for comprehensive quality control of other herbal medicines. PMID- 28011447 TI - Young children risk choking on whole grapes, doctors warn. PMID- 28011446 TI - Transdiagnostic Cognitive Behavioral Therapy Versus Treatment as Usual in Adult Patients With Emotional Disorders in the Primary Care Setting (PsicAP Study): Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Demand for primary care (PC) services in Spain exceeds available resources. Part of this strong demand is due to the high prevalence of emotional disorders (EDs)-anxiety, depression, and somatic symptom disorders-and related comorbidities such as pain or chronic illnesses. EDs are often under- or misdiagnosed by general practitioners (GPs) and, consequently, treatment is frequently inadequate. OBJECTIVE: We aim to compare the short- and long-term effectiveness of group-delivered transdiagnostic cognitive behavioral therapy (TD CBT) versus treatment as usual (TAU) in the treatment of EDs in the PC setting in Spain. We also aim to compare the effect of these treatments on disability, quality of life, cognitive-emotional factors, and treatment satisfaction. METHODS: Here we present the study design of a two-arm, single-blind, randomized controlled trial (N=1126) to compare TAU to TD-CBT for EDs. TAU will consist primarily of pharmacological treatment and practical advice from the GP while TD CBT will be administered in seven 90-minute group sessions held over a period ranging from 12 to 14 weeks. Psychological assessments are carried out at baseline (ie, pretreatment); posttreatment; and at 3-, 6-, and 12-month follow up. The study is conducted in approximately 26 PC centers from the National Health System in Spain. RESULTS: This study was initiated in December 2013 and will remain open to new participants until recruitment and follow-up has been completed. We expect all posttreatment evaluations to be completed by December 2017, and follow-up will end in December 2018. CONCLUSIONS: We expect the TD-CBT group to have better results compared to TAU on all posttreatment measures and that this improvement will be maintained during follow-up. This project could serve as a model for use in other areas or services of the National Health System in Spain and even in other countries. CLINICALTRIAL: International Standard Randomized Controlled Trial Number (ISRCTN): 58437086; http://www.isrctn.com/ISRCTN58437086 (Archived by WebCite at http://www.webcitation.org/6mbYjQSn3). PMID- 28011448 TI - Statistical controversies in clinical research: comparison of primary outcomes in protocols, public clinical-trial registries and publications: the example of oncology trials. AB - Background: Protocols are often unavailable to peer-reviewers and readers. To detect outcome reporting bias (ORB), readers usually have to resort to publicly available descriptions of study design such as public clinical trial registries. We compared primary outcomes in protocols, ClinicalTrials.gov and publications of oncology trials and evaluated the use of ClinicalTrials.gov as compared with protocols in detecting discrepancies between planned and published outcomes. Method: We searched for phase III oncology trials registered in ClinicalTrials.gov and published in the Journal of Clinical Oncology and New England Journal of Medicine between January 2014 and June 2015. We extracted primary outcomes reported in the protocol, ClinicalTrials.gov and the publication. First, we assessed the quality of primary outcome descriptions by using a published framework. Second, we evaluated modifications of primary outcomes between each source. Finally, we evaluated the agreement, specificity and sensitivity of detecting modifications between planned and published outcomes by using protocols or ClinicalTrials.gov. Results: We included 65 trials, with 81 primary outcomes common among the 3 sources. The proportion of primary outcomes reporting all items from the framework was 73%, 22%, and 75% for protocols, ClinicalTrials.gov and publications, respectively. Eight (12%) trials presented a discrepancy between primary outcomes reported in the protocol and in the publication. Twelve (18.5%) trials presented a discrepancy between primary outcomes registered at ClinicalTrials.gov and in publications. We found a moderate agreement in detecting discrepant reporting of outcomes by using protocols or ClinicalTrials.gov [kappa = 0.53, 95% confidence interval (0.25 0.81)]. Using ClinicalTrials.gov to detect discrepant reporting of outcomes showed high specificity (89.5%) but lacked sensitivity (75%) as compared with use of protocols. Conclusion: In oncology trials, primary outcome descriptions in ClinicalTrials.gov are often of low quality and may not reflect what is in the protocol, thus limiting the detection of modifications between planned and published outcomes. PMID- 28011445 TI - Drivers and Barriers to Acceptance of Web-Based Aftercare of Patients in Inpatient Routine Care: A Cross-Sectional Survey. AB - BACKGROUND: Web-based aftercare can help to stabilize treatment effects and support transition after inpatient treatment, yet uptake by patients seems limited in routine care and little is known about the mechanisms of adoption and implementation. OBJECTIVE: The aim of this study was to (1) determine acceptance of Web-based aftercare and (2) explore its drivers and barriers in different subgroups of a mixed inpatient sample. METHOD: In a cross-sectional design, 38.3% (374/977) of the inpatients from a broad spectrum of diagnostic groups (psychosomatic, cardiologic, orthopedic, pediatric, and substance-related disorders) filled out a self-administered questionnaire prior to discharge. Drivers and barriers to patients' acceptance of Web-based aftercare were examined based on an extension to the "unified theory of acceptance and use of technology" (UTAUT). In total, 16.7% (59/353) of the participants indicated prior use of eHealth interventions. RESULTS: Acceptance (min 1, max 5) was low (mean 2.56, SD 1.22) and differed between diagnostic groups (Welch F4,133.10 =7.77, P<.001), with highest acceptance in adolescent patients (mean 3.46, SD 1.42). Acceptance was significantly predicted by 3 UTAUT predictors: social influence (beta=.39, P<.001), performance expectancy (beta=.31, P<.001), and effort expectancy (beta=.22, P<.001). Furthermore, stress due to permanent availability (beta=-.09, P=.01) was negatively associated with acceptance. CONCLUSION: This study demonstrated a limited acceptance of Web-based aftercare in inpatients. Expectations, social environment's attitude, and negative experience with permanent availability influence eHealth acceptance. Improving implementation, therefore, means increasing eHealth experience and literacy and facilitating positive attitudes in patients and health professionals through education and reduction of misconceptions about effectiveness or usability. PMID- 28011449 TI - Association of plasma concentrations of branched-chain amino acids with risk of colorectal adenoma in a large Japanese population. AB - Background: Available evidence from animal studies suggests that branched-chain amino acids (BCAAs) may have a protective effect against colorectal carcinogenesis. However, a possible effect of BCAAs against colorectal neoplasia has not been evaluated in humans. Here, we aimed to evaluate whether plasma concentrations of BCAA are associated with the risk of colorectal adenoma (CRA), a precursor lesion of colorectal cancer. Patients and methods: CRA cases and controls were identified from examinees who underwent total colonoscopy as part of a cancer screening program between 2004 and 2005 and responded to self administered dietary and lifestyle questionnaires. We measured plasma concentrations of leucine, isoleucine and valine in 629 patients with adenoma and 584 controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between BCAA and CRA risk after adjustment for potential confounders. Results: High plasma concentrations of leucine, valine and total BCAA were inversely associated with CRA risk after adjustment of potential confounders. The multivariate-adjusted ORs for the highest versus lowest quartiles were 0.60 (95% CI 0.42-0.87, Ptrend = 0.006) for leucine, 0.68 (95% CI 0.48-0.97, Ptrend = 0.09) for valine and 0.68 (95% CI 0.48-0.98, Ptrend = 0.10) for total BCAA. Further analysis by gender revealed that this inverse association was clearly evident in men, but not in women: the corresponding OR for leucine, valine and total BCAA was 0.50 (95% CI 0.32-0.80, Ptrend = 0.003), 0.60 (95% CI 0.38-0.95, Ptrend = 0.01) and 0.58 (95% CI 0.37-0.93, Ptrend = 0.04), respectively, in men and 0.78 (95% CI 0.42-1.45, Ptrend = 0.44), 0.77 (95% CI 0.41-1.43, Ptrend = 0.85) and 0.84 (95% CI 0.45 1.57, Ptrend = 0.81), respectively, in women. Conclusion: Our finding suggests that BCAAs may have a beneficial influence against the process of colorectal carcinogenesis, at least in the early stage. The mechanisms underlying this potential association between BCAA and colorectal carcinogenesis warrant further investigation. PMID- 28011450 TI - Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies. AB - Background: In recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies. Design: We describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations. Results: Operating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes. Conclusions: The proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma. PMID- 28011451 TI - Disease-modifying treatment in rheumatoid arthritis: treat early and do not forget to try to taper and stop. PMID- 28011452 TI - Testing for antineutrophil cytoplasmic antibodies (ANCAs) in patients with systemic vasculitides and other diseases. PMID- 28011453 TI - Autoinflammatory Disease Damage Index (ADDI): a possible newborn also in hidradenitis suppurativa daily practice. PMID- 28011454 TI - Predicting neurosurgical outcomes in focal epilepsy patients using computational modelling. AB - SEE EISSA AND SCHEVON DOI101093/AWW332 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Surgery can be a last resort for patients with intractable, medically refractory epilepsy. For many of these patients, however, there is substantial risk that the surgery will be ineffective. The prediction of who is likely to benefit from a surgical approach is crucial for being able to inform patients better, conduct principled prospective clinical trials, and ultimately tailor therapeutic approaches to these patients more effectively. Dynamical computational models, informed with patient data, can be used to make predictions and give mechanistic insight. In this study, we develop patient-specific dynamical network models of epileptogenic cortex. We infer the network connectivity matrix from non-seizure electrographic recordings of patients and use these connectivity matrices as the network structure in our model. The model simulates the dynamics of a bi-stable switch at every node in this network, meaning that every node starts in a background state, but has the ability to transit to a co-existing seizure state. Whether a transition happens in a node is partly determined by the stochastic nature of the input to the node, but also by the input the node receives from other connected nodes in the network. By conducting simulations with such a model, we can detect the average transition time for nodes in a given network, and therefore define nodes with a short transition time as highly epileptogenic. In a retrospective study, we found that in some patients the regions with high epileptogenicity in the model overlap with those identified clinically as the seizure onset zone. Moreover, it was found that the resection of these regions in the model reduces the overall likelihood of a seizure. Following removal of these regions in the model, we predicted surgical outcomes and compared these to actual patient outcomes. Our predictions were found to be 81.3% accurate on a dataset of 16 patients with intractable epilepsy. Intriguingly, in patients with unsuccessful outcomes, the proposed computational approach is able to suggest alternative resection sites. The model presented here gives mechanistic insight as to why surgery may be unsuccessful in some patients. This may aid clinicians in presurgical evaluation by providing a tool to explore various surgical options, offering complementary information to existing clinical techniques. PMID- 28011455 TI - Individual and interactive effects of drought and heat on leaf physiology of seedlings in an economically important crop. AB - Heat waves in combination with drought are predicted to occur more frequently with climate warming, yet their interactive effects on crop carbon and water balance are still poorly understood. Hence, research on the capacity of crops to withstand and recover from the combined stress is urgently needed. This study investigated the effects of drought and heat wave on a crop species as well as the recovery from the combined stress. Seedlings were grown in growth chambers under two soil water conditions (i.e. well watered and drought stress) at ambient temperature (26 degrees C) for 10 days. Afterwards, half of the seedlings were exposed to a 7-day 42 degrees C heat wave. All the drought-stressed seedlings were then rehydrated upon relief of the heat wave. Leaf gas exchange, the maximum carboxylation capacity (V cmax), plant growth, relative chlorophyll content and leaf water potential were examined during the experimental period. The heat wave reduced leaf gas exchange rates, V cmax and relative chlorophyll content, while it had no impacts on leaf water potential. In contrast, drought stress led to greater reductions in leaf gas exchange rates, growth and water potential than heat wave alone. Seedlings underwent a greater degree of stress in the combination of drought and heat wave than under the single drought treatment. The recovery of leaf gas exchange from drought stress lagged behind the water potential recovery and was delayed by heat wave. Our results show that drought stress had a predominant role in determining plant physiological responses and the negative impacts of drought stress were exacerbated by heat wave. The greater stress in the combination of drought and heat wave translated into the slower recovery of leaf gas exchange. Therefore, drought combined with heat wave may induce greater risks on crops under future climates. PMID- 28011456 TI - Herbivory as an important selective force in the evolution of floral traits and pollinator shifts. AB - Floral trait evolution is frequently attributed to pollinator-mediated selection but herbivores can play a key role in shaping plant reproductive biology. Here we examine the role of florivores in driving floral trait evolution and pollinator shifts in a recently radiated clade of flowering plants, Oenothera sect. Calylophus We compare florivory by a specialist, internal feeder, Mompha, on closely related hawkmoth- and bee-pollinated species and document variation in damage based on floral traits within sites, species and among species. Our results show that flowers with longer floral tubes and decreased floral flare have increased Mompha damage. Bee-pollinated flowers, which have substantially smaller floral tubes, experience on average 13% less Mompha florivory than do hawkmoth-pollinated flowers. The positive association between tube length and Mompha damage is evident even within sites of some species, suggesting that Mompha can drive trait differentiation at microevolutionary scales. Given that there are at least two independent shifts from hawkmoth to bee pollination in this clade, florivore-mediated selection on floral traits may have played an important role in facilitating morphological changes associated with transitions from hawkmoth to bee pollination. PMID- 28011457 TI - Citalopram-induced dyskinesia of the tongue: a video presentation. AB - We describe a 51-year-old man with sudden onset involuntary movements of the tongue 2 weeks after initiation of citalopram. The movements were continuous and isolated to the tongue. Speech was minimally dysarthric. Further examination revealed no abnormalities. Citalopram was continued and spontaneous improvement was noticed in the following weeks. There was complete recovery 5 weeks after symptoms had started. We argue that the involuntary tongue movements were a side effect of citalopram. Furthermore, our patient used concomitant citalopram and methylphenidate, a combination which potentially elicits side effects. We include a video of the tongue movements in this patient. PMID- 28011458 TI - Insulin and Glucose Alter Death-Associated Protein Kinase 3 (DAPK3) DNA Methylation in Human Skeletal Muscle. AB - DNA methylation is altered by environmental factors. We hypothesized that DNA methylation is altered in skeletal muscle in response to either insulin or glucose exposure. We performed a genome-wide DNA methylation analysis in muscle from healthy men before and after insulin exposure. DNA methylation of selected genes was determined in muscle from healthy men and men with type 2 diabetes before and after a glucose tolerance test. Insulin altered DNA methylation in the 3' untranslated region of the calcium pump ATP2A3 gene. Insulin increased DNA methylation in the gene body of DAPK3, a gene involved in cell proliferation, apoptosis, and autophagy. DAPK3 methylation was reduced in patients with type 2 diabetes. Carbohydrate ingestion reduced DAPK3 DNA methylation in healthy men and men with type 2 diabetes, suggesting glucose may play a role. Supporting this, DAPK3 DNA methylation was inversely correlated with the 2-h glucose concentration. Whereas glucose incorporation to glycogen was unaltered by small interfering RNA against DAPK3, palmitate oxidation was increased. In conclusion, insulin and glucose exposure acutely alter the DNA methylation profile of skeletal muscle, indicating that DNA methylation constitutes a rapidly adaptive epigenetic mark. Furthermore, insulin and glucose modulate DAPK3 DNA methylation in a reciprocal manner, suggesting a feedback loop in the control of the epigenome. PMID- 28011462 TI - Making patient relevant clinical research a reality. PMID- 28011460 TI - 18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials. AB - Purpose: Evaluate 18F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.Experimental Design: In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as >=90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.Results: Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved >=90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.Conclusions: FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. Clin Cancer Res; 23(12); 3053-60. (c)2016 AACR. PMID- 28011461 TI - Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or Mutations. AB - Purpose: While multikinase inhibitors with RET activity are active in RET rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations.Experimental design: The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by in vivo tumor growth inhibition studies in cell line- and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).Results: Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCgamma. Additionally, a patient with advanced RET-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.Conclusions: These data support the inclusion of patients bearing RET alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types. Clin Cancer Res; 23(12); 2981-90. (c)2016 AACR. PMID- 28011463 TI - Functional Response of the Predators Alloeocranum biannulipes (Hemiptera: Reduviidae) and Teretrius nigrescens (Coleoptera: Histeridae) Feeding on Dinoderus porcellus (Coleoptera: Bostrichidae) Infesting Yam Chips. AB - The functional response and some predation parameters of the predators Alloeocranum biannulipes Montrouzier & Signoret (Hemiptera: Reduviidea) and Teretrius nigrescens Lewis (Coleoptera: Histeridae) were evaluated at five different densities of larvae and pupae of Dinoderus porcellus Lesne (Coleoptera: Bostrichidae) with the aim to understand their roles in the biological control of this major pest of stored yam chips. Experiments were performed in petri dishes at 25 +/- 1 degrees C, 60 +/- 10% RH, and a photoperiod of 12:12 (L:D) h in a controlled temperature room. Both predators showed Type II of functional response with respect to larvae, determined by a logistic regression model. However, T. nigrescens significantly killed more larvae of D. porcellus compared with A. biannulipes. This behavior, however, changed to a linear functional response (Type I), when pupae of D. porcellus were offered to both predators, possibly because of their immobility. In addition, there was no significant difference between T. nigrescens and A. biannulipes in terms of the killed pupae. Parameters of the Holling disc equation for both predators were estimated. Estimated handling time on larvae of D. porcellus for T. nigrescens and A. biannulipes was 0.254 and 0.677 h and the rate of searching efficiency was 0.289 and 0.348 h-1, respectively. Results indicated that T. nigrescens was a more suitable candidate for augmentative release for D. porcellus control than A. biannulipes. However, semifield studies are required to draw firm conclusions. PMID- 28011464 TI - Contour Symmetry of the Upper Eyelid Following Bilateral Conjunctival-Muller's Muscle Resection. AB - Background: Conjunctiva-Muller muscle resection (CMMR) is a simple, effective, and predictable procedure for internal treatment of ptosis. Objectives: The authors determined contour symmetry of the upper eyelid following bilateral CMMR. Methods: Thirty control participants (ie, without ptosis) and 44 patients with acquired bilateral blepharoptosis who underwent CMMR were evaluated in a prospective study. To assess symmetry of lid contour, distances from midpupil to the upper eyelid (ie, MPLDs) were determined radially at intervals of 15 degrees (total, 180 degrees ) along the palpebral fissure, and MPLDs at each angle were compared for right and left eyes. Results: For control participants, the mean marginal reflex distance (MRD1; ie, MPLD at 90 degrees ) +/- standard error (SE) was 4.05 mm +/- 0.75 mm, and small contour asymmetries (<10%) were measured for all angles. Medial (9.4% +/- 4.7%) and lateral (8.1% +/- 4.9 %) asymmetries were not significantly different for these participants. For patients with ptosis, the mean preoperative MRD1 was 2.56 +/- 0.1 mm, and mean medial and lateral lid asymmetries (14.3% +/- 8.4% and 16.7% +/- 9.7%, respectively) were significantly higher than those of controls. Medial and lateral asymmetries correlated significantly with the extent of ptosis and were more pronounced laterally than medially. One month after CMMR, the lateral-medial discrepancy in lid asymmetry was resolved, and mean medial and lateral MPLDs (9.9% +/- 7.5% and 8.5% +/- 5.3%, respectively) were similar to those of controls. Conclusions: For patients with involutional ptosis, CMMR enables elevation of the lid margin and correction of contour anomalies. PMID- 28011465 TI - Donald Emslie-Smith. PMID- 28011466 TI - Tony R Bull. PMID- 28011467 TI - Clinical Implications of High-mobility Group Box-1 (HMGB1) and the Receptor for Advanced Glycation End-products (RAGE) in Cutaneous Malignancy: A Systematic Review. AB - Inflammation and the immune system play a role in the development and progression of melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). The pro-inflammatory and tumor-promoting effects of the high-mobility group box-1 (HMGB1) protein and the receptor for advanced glycation end products (RAGE) have been investigated in these cutaneous malignancies. The clinical implication of these molecules is not fully described. The National Library of Medicine database was searched for articles addressing the clinical relevance of HMGB1 and RAGE in melanoma, BCC, and SCC. This systematic review includes nine articles, with six summarizing RAGE in cutaneous malignancies and three involving HMGB1. RAGE has been found to be up-regulated in SCC lesions, as well as melanoma. Levels of RAGE were highest in stage IV melanomas. Lower levels of soluble RAGE have been associated with poor overall survival in melanoma. Sporadic extracellular expression of HMGB1 was evident in BCC and SCC lesions, which could be released by necrotic tumor cells. HMGB1 was found to be a prognostic marker in melanoma, and HMGB1 levels were elevated in patients who were non-responders to ipilimumab treatment. HMGB1 and RAGE could serve as potential prognostic markers or therapeutic targets in treating melanoma, BCC, and SCC, but further research regarding the clinical utility of the HMGB1-RAGE axis in cutaneous malignancies is warranted. PMID- 28011468 TI - Parenchymal-sparing Hepatectomy as the New Doctrine in the Treatment of Liver metastatic Colorectal Disease: Beyond Oncological Outcomes. AB - Colorectal cancer is one of the leading causes of mortality in the Western world. Half of patients with colorectal cancer will develop liver-metastatic (CLM) disease, with fewer than 30% having surgically resectable disease at diagnosis. It is well established in the literature that major hepatectomy offers a high rate of R0 resection, however, with concommitant increased rates of mortality and morbidity. Emerging literature during the past two decades has demonstrated the potential superiority of parenchymal-sparing hepatectomy (PSH) in treating CLM disease in terms of oncological outcomes, survival and re-operation in cases of recurrence (salvageability). To date, no data regarding the evaluation of quality of life and cost after PSH have been published. PSH seems to be correlated with less mortality and morbidity, which can be translated in lower re-admission rates, better quality of life and, therefore, reduced relevant cost. Prospective studies and clinical trials evaluating the multiple beneficial role of a PSH surgical strategy in CLM disease are mandatory to support or reject the emerging belief that PSH could be the gold standard of treatment of CLM disease. PMID- 28011469 TI - Three Pathways of Colonic Carcinogenesis in Rats. AB - BACKGROUND: Colorectal cancer (CRC) is one of the more intensively studied human malignancies. For many years, the general view has been that the vast majority of CRCs in humans evolve from conventional (tubular or villous) adenomas via the adenoma-carcinoma pathway. More recently, serrated colorectal polyps (hyperplastic polyps, sessile serrated polyps and traditional serrated adenomas) have emerged as an alternative pathway of colorectal carcinogenesis in humans. Archival sections from early experiments in Sprague-Dawley (SD) rats injected with dimethylhydrazine (DMH) were reviewed and the histology of colonic neoplasias was re-evaluated. Out of 215 colonic neoplasias, 9% were serrated adenomas and 6% serrated carcinomas, 11% conventional adenomas, 39% highly differentiated carcinomas, 21% gut-associated lymphoid tissue (GALT) carcinomas, 13% signet-ring cell carcinomas, and 1% villous carcinomas. In a more recent review of archived sections from DMH-treated rats with colonic GALT follicles, dysplastic crypts exhibiting asymmetrical bifurcations in GALT mucosa were found in 49% and colonic GALT carcinomas in 53% of 276 DMH-treated rats. Histology of the 146 colonic GALT-carcinomas revealed highly differentiated carcinoma in 75%, signet-ring cell carcinoma in 20%, mucinous carcinomas in 3% and mixed in the remaining 2%. Highly differentiated carcinomas were seen to evolve from dysplastic crypts with asymmetric bifurcations and from adenomas and signet-ring cell carcinomas, and from non-dysplastic crypts having goblet cells with marked anisocytosis. It is apparent that DMH treatment in SD rats induced conventional adenomas, conventional carcinomas, serrated adenomas, serrated carcinomas and GALT carcinomas. The paradigm permits to monitor in detail the early histological steps that epitomize the three alternative pathways of colonic carcinogenesis in SD rats. This model might be useful for analyzing different molecular aberrations evolving during the conventional adenoma-carcinoma pathway, the serrated carcinoma pathway, and the GALT carcinoma pathway of colonic carcinogenesis, under standard laboratory conditions. PMID- 28011470 TI - Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single anti-angiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed. PMID- 28011471 TI - Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer. AB - : With a lifetime risk estimated to be one in eight in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide. Patients are often treated with anti-estrogens, but it is common that some tumors develop resistance to therapy. The causation and progression of cancer is controlled by epigenetic processes, so there is an ongoing interest in research into mechanisms, genes and signaling pathways associating carcinogenesis with epigenetic modulation of gene expression. Given the fact that histone deacetylases (HDACs) have a great impact on chromatin remodeling and epigenetics, their inhibitors have become a very interesting field of research. AIM: This review focused on the use of HDAC inhibitors as anticancer treatment and explains the mechanisms of therapeutic effects on breast cancer. We anticipate further clinical benefits of this new class of drugs, both as single agents and in combination therapy. Molecules such as suberoylanilide hydroxamic acid, trichostatin A, suberoylbis-hydroxamic acid, panobinostat, entinostat, valproic acid, sodium butyrate, SK7041, FTY720, N-(2-hydroxyphenyl)-2-propylpentanamide, Scriptaid, YCW1, santacruzamate A and ferrocenyl have shown promising antitumor effects against breast cancer. HDAC inhibitors consists an attractive field for targeted therapy against breast cancer. Future therapeutic strategies will include combination of HDAC inhibitors and chemotherapy or other inhibitors, in order to target multiple oncogenic signaling pathways. More trials are needed. PMID- 28011472 TI - KIF11 Is Required for Spheroid Formation by Oesophageal and Colorectal Cancer Cells. AB - BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) are common types of human cancer. Spheroid colony formation is used to characterize cancer stem cell (CSCs). In the present study, we analyzed the significance of kinesin family 11 (KIF11 in human ESCC and CRC. MATERIALS AND METHODS: Expression of KIF11 in 105 ESCC and 100 CRC cases was determined using immunohistochemistry. RNA interference was used to inhibit KIF11 expression in ESCC and CRC cell lines. RESULTS: In total, 61 out of 105 (58%) ESCC and 62 out of 100 (62%) CRC cases were positive for KIF11. Expression of KIF11 was not associated with any clinicopathological characteristics. Both the number and size of spheres produced by from TE-5 ESCC cells and DLD-1 CRC cells were significantly reduced upon KIF11 siRNA transfection compared to negative control siRNA transfection. CONCLUSION: These results indicate that KIF11 plays an important role in CSCs of ESCC and CRC. PMID- 28011473 TI - Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models. AB - BACKGROUND: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. MATERIALS AND METHODS: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. RESULTS: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDA-MB-231 tumors were resected. CONCLUSION: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly metastatic MDA-MB-231 TNBC. PMID- 28011474 TI - Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel. AB - BACKGROUND: Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective. MATERIALS AND METHODS: Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX. RESULTS: H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42+/-0.36) than the control group (tumor volume ratio: 3.47+/-1.66) (p<0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85+/-1.45) (p=0.47). CDDP-treated tumor weight (50+/-50 mg) was significantly less than control (238+/-114 mg) (p<0.01). NAB-PTX-treated tumors were not reduced in weight (246+/-136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX treated tumors. CONCLUSION: The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease. PMID- 28011475 TI - A Novel NHERF1 Mutation in Human Breast Cancer and Effects on Malignant Progression. AB - Na+/H+ exchanger regulatory factor 1 (NHERF1) has been reported to interact with post-synaptic density protein/Drosophila disc large tumour suppressor/zonula occludens 1 protein (PDZ) binding proteins by its two PDZ domains. These associations have effects on cellular signal transductions. NHERF1 has also been indicated as a cancer-related gene in several solid tumour types. We identified a novel mutation (A190D), of the PDZ2 domain of NHERF1 in breast cancer tissues. NHERF1 A190D mutation abolished NHERF1 modulation of proliferation and migration. In this study, we found that NHERF1 A190D mutation increased nuclear localisation of the protein compared to wild-type NHERF1. It has been reported that YES associated protein (YAP) interacts with NHERF1. Here we found that NHERF1 A190D mutation increased the binding affinity between NHERF1 and YAP, which inhibited the phosphorylation of YAP. These data suggest that wild-type NHERF1 acts as a tumour suppressor, while NHERF1 A190D mutation abolishes the tumour-suppressive effect in cancer cells, due to A190D mutation-mediated nuclear NHERF1 translocation and induction of YAP phosphorylation. PMID- 28011476 TI - YM155 Reverses Statin Resistance in Renal Cancer by Reducing Expression of Survivin. AB - AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reverses statin resistance in statin-resistant renal cell cancer (RCC). MATERIALS AND METHODS: We induced simvastatin resistance in a renal clear cell carcinoma cell line (Caki-1-staR). In vitro and in vivo models were used to test the efficacy of YM155 and simvastatin. RESULTS: Survivin gene expression was significantly stronger in Caki 1-staR cells than in its parent cells (Caki-1). In Caki-1-staR cells, YM155 significantly reduced expression of survivin gene and cell proliferation in a dose-dependent manner. Treatment with YM155 significantly reversed simvastatin resistance in Caki-1-staR cells. YM155 significantly inhibited the growth of Caki 1-staR tumors in a nude mouse tumor xenograft model. Furthermore, YM155 significantly enhanced the antitumor effects of simvastatin on Caki-1-staR tumors. CONCLUSION: Our results indicate that inhibition of survivin by YM155 overcomes statin resistance in RCC cells. PMID- 28011477 TI - Long Noncoding RNA PANDA Positively Regulates Proliferation of Osteosarcoma Cells. AB - BACKGROUND: A long noncoding RNA, p21-associated ncRNA DNA damage-activated (PANDA), associates with nuclear transcription factor Y subunit alpha (NF-YA) and inhibits its binding to promoters of apoptosis-related genes, thereby repressing apoptosis in normal human fibroblasts. Here, we show that PANDA is involved in regulating proliferation in the U2OS human osteosarcoma cell line. MATERIALS AND METHODS: U2OS cells were transfected with siRNAs against PANDA 72 h later and they were subjected to reverse transcription-polymerase chain reaction (RT-PCR), quantitative RT-PCR and cell-cycle analysis. RESULTS: PANDA was highly expressed in U2OS cells, and its expression was induced by DNA damage. Silencing PANDA caused arrest at the G1 phase of the cell cycle, leading to inhibition of cell proliferation. Quantitative RT-PCR showed that silencing PANDA increased mRNA levels of the cyclin-dependent kinase inhibitor p18, which caused G1 phase arrest. CONCLUSION: These results suggest that PANDA promotes G1-S transition by repressing p18 transcription, and thus promotes U2OS cell proliferation. PMID- 28011478 TI - Validation of VX2 as a Hepatocellular Carcinoma Model: Comparison of the Molecular Reaction of VX2 and HepG2 Tumor Cells to Sorafenib In Vitro. AB - As there is currently no superior hepatocellular carcinoma (HCC) model with percutaneous vascular access for transarterial treatments available, the VX2 rabbit model is frequently used for in vivo investigations on liver carcinoma. However, the VX2 cell line was derived from a virus-induced skin papilloma that can form carcinosarcoma in liver of rabbits and the transferability of obtained results to HCC treatment remains open. Here we compared the most frequently investigated human HCC model cell line, HepG2, with VX2 cells in vitro in terms of sensitivity towards the broad specificity kinase inhibitor sorafenib and responsiveness to the addition of platelet-derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF), as well as insulin and interleukin-1beta (IL1beta). Phosphorylation of protein kinase B (AKT) the mitogen-activated protein kinases (MAPKs) p38 and p42/44 (extracellular signal-regulated kinase, ERK1/2) and inhibitor of kappa light chain gene enhancer alpha (IKBalpha) was determined by western blotting as these events are associated with early signaling cascades. Additionally, the inhibition of phosphorylation under sorafenib treatment was investigated. Sorafenib was equally toxic to both cell lines, but only in HepG2 was activation of caspase 3/7 activity, as a sign of apoptosis, observed. VX2 cells exhibited generally more intense phosphorylation signals in response to the growth factors and also serum. In contrast to VX2, HepG2 cells showed no response to PDGF-AB or VEGF as determined by kinase phosphorylation. In both cell lines, sorafenib inhibited growth factor-induced phosphorylation of ERK and p38-MAPK. AKT phosphorylation was only inhibited in VX2 cells and IKBalpha phosphorylation was not influenced by this kinase inhibitor in either cell type. Taken together, the two cellular models for HCC share several features related to sorafenib application, but differed in their responsiveness towards growth factors. Therefore, results obtained with the VX2 model cannot be extended to human HCC without appropriate caution. PMID- 28011479 TI - The Effects of Petroselinum Crispum on Estrogen Receptor-positive Benign and Malignant Mammary Cells (MCF12A/MCF7). AB - BACKGROUND: Phytoestrogens have controversial effects on hormone-dependent tumors. Herein we investigated the effects of parsley root extract (PCE) on DNA synthesis performance, metabolic activity and cytotoxicity in malignant and benign breast cells. MATERIALS AND METHODS: The PCE was prepared and analyzed by mass spectrometry. MCF7 and MCF12A cells were incubated with various concentrations of PCE and analyzed for DNA synthesis performance, metabolic activity and cytotoxicity by BrdU proliferation, MTT and LDH assays, respectively. RESULTS: PCE was found to contain a substantial ratio of lignans. At a concentration range of 0.01 MUg/ml-100 MUg/ml the LDH assay analysis showed no significant cytotoxicity of PCE in both cell lines. However, at 500 MUg/ml PCE's cytotoxicity was well over 70% of total cell population in both cell lines. According to the BrdU proliferation assay analysis, PCE demonstrated significant DNA synthesis inhibition of up to 80% at concentrations of 10, 50, 100 and 500 MUg/ml in both cell lines. Based on the MTT assay analysis, only at a concentration of 500 MUg/ml, PCE demonstrated a statistically significant inhibition of cellular metabolic activity of 63% in MCF7 and 75% in MCF12A of their respective normal capacity. CONCLUSION: PCE showed antiproliferative effects in MCF7 and MCF12A cells. Further investigation is required to determine whether this effect can be solely attributed to its phytoestrogens. PMID- 28011480 TI - Synergistically Anti-metastatic Effect of 5-Flourouracil on Colorectal Cancer Cells via Calcium-mediated Focal Adhesion Kinase Proteolysis. AB - AIM: To investigate the possibility of enhancing an anti-metastatic effect of 5 fluorouracil (5-FU) on colorectal cancer (CRC) cells by combining it with continuous calcium supplementation. MATERIALS AND METHODS: Optimal doses of 5-FU with/without lactate salt (CaLa) were determined via clonogenicity and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays using human CRC cells cultured on normal or low-attachment plates. Invasion and migration assays confirmed the enhanced anti-metastatic effect of combining 5-FU and CaLa. Western blot analysis for elements of the focal adhesion kinase (FAK) signaling cascade and epithelial-mesenchymal transition (EMT) markers was used to investigate the underlying mechanism. RESULTS: 5-FU (2.5 MUM) had no antitumor activity against unanchored CRC cells, while it significantly suppressed anchorage-dependent cell proliferation. In contrast, treatment with CaLa (2.5 mM), alone and in combination with 5-FU, exerted antitumor activity against both anchored and unanchored CRC cells via calcium-mediated FAK proteolysis and inhibition of EMT markers, such as vimentin and SNAIL. CONCLUSION: Calcium supplementation represents a method of enhancing the potency of existing antitumor agents such as 5-FU, augmenting their clinical effectiveness. PMID- 28011481 TI - Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-KB. AB - BACKGROUND/AIM: Cholangiocarcinoma (CCA) is an aggressive cancer for which standard treatments are still ineffective. This study demonstrated the antiproliferative and anti-metastatic activity of metformin, an anti-diabetic drug, in CCA cells. MATERIALS AND METHODS: Cell proliferation, migration/invasion and anoikis resistance were determined. The underlying mechanisms were identified using western blotting and immunocytofluorescence. RESULTS: Metformin significantly suppressed proliferation of CCA cells in a dose- and time-dependent manner, regardless of glucose present in the medium. A low dose of metformin significantly increased anoikis and inhibited migration/ invasion of CCA cells that was in concert with the decrease of vimentin, matrix metalloproteinase (MMP) 2 and -7. Activation of 5' adenosine monophosphate-activated protein kinase (AMPK) by phosphorylation together with suppression of nuclear translocation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-KB) were the underlying mechanisms for these effects. CONCLUSION: Metformin is a potent antiproliferative and anti-metastatic agent against human CCA cells. These findings encourage the repurposing of metformin in clinical trials to improve CCA treatment. PMID- 28011482 TI - Galectin-3 Is Implicated in Tumor Progression and Resistance to Anti-androgen Drug Through Regulation of Androgen Receptor Signaling in Prostate Cancer. AB - BACKGROUND: Castration-resistant prostate cancer (CRPC)-related deaths are increasing worldwide. Therefore, clarification of the mechanisms of hormone related tumor progression and resistance to anti-androgen drugs is useful in order to develop strategies for appropriate treatment of CRPC. Galectin-3 has been shown to be correlated with tumor progression in a variety of cancer types through the regulation of tumor proliferation, angiogenesis, and apoptosis. MATERIALS AND METHODS: We examined tumor cell invasion and migration using the xCELLigence system. Control LNCaP and galectin-3-expressing LNCaP (LNCaP-Gal-3) cells were cultured with androgen-depleted medium with 5% charcoal-stripped serum. Cells were treated for 24 h with or without dihydrotestosterone alone or combined with MDV3100 and bicalutamide; gene profile was then analyzed by microarray analysis and mRNA expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). We evaluated tumor growth using spheroids and xenograft tumor growth in a mouse model. RESULTS: In vitro, LNCaP-Gal-3 cells promoted both cell migration and invasion in an androgen-independent manner compared to control LNCaP cells. Galectin-3 also enhanced anchorage-independent growth and xenograft tumor growth even after castration. Importantly, galectin-3 greatly enhanced transcriptional activity of the androgen receptor (AR), especially on treatment with dihydrotestosterone. In microarray and qRT-PCR analyses, galectin-3 increased the expression of several AR-target genes, such as kallikrein-related peptidase 3 (KLK3), and transmembrane protease, serine 2 (TMPRSS2). These AR-target genes were not fully suppressed by anti-androgen drugs such as bicalutamide or MDV3100. Galectin-3 significantly inhibited the effect induced by anti-androgen drugs MDV3100 and bicalutamide, suggesting that galectin 3 may be involved in resistance to anti-androgen drug through enhancement of transcriptional activity of AR and expression of AR-related genes. CONCLUSION: These results suggest that galectin-3 is a potential target molecule for future treatment of anti-androgen drug-resistant prostate cancer. PMID- 28011483 TI - Clinicopathological Implication of Insulin-like Growth Factor-II mRNA-Binding Protein 3 (IMP3) Expression in Gastric Cancer. AB - BACKGROUND: The clinicopathological significance of oncofetal mRNA-binding protein, human insulin-like growth factor II mRNA-binding protein 3 (IMP3), in gastric carcinoma (GC) is not fully understood. MATERIALS AND METHODS: Tissue microarray blocks with specimens from 346 patients with GC were constructed to evaluate the clinicopathological role of IMP3 expression in GC. These results were validated with an online dataset of 876 patients from the Kaplan-Meier Plotter. Sera from 15 controls and 57 patients with GC were collected in order to compare the levels of serum IMP3 between groups. RESULTS: High expression of IMP3 was significantly associated with poor prognosis. Survival curves from the Kaplan Meier Plotter showed that high IMP3 expression was significantly related to worse disease-free survival and overall survival. CONCLUSION: Tissue overexpression of IMP3 might be used as a predictor of advanced disease or lymph node metastasis, and is associated with poorer prognosis in GCs. PMID- 28011485 TI - Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes But Not Normal Lymphocytes. AB - The present study demonstrates specific sensitization of leukemia lymphocytes towards anticancer drugs using melatonin and clarifies the role of reactive oxygen species (ROS) for induction of apoptosis. The study covers four conventional and 11 new-generation anticancer drugs. Four parameters were analyzed simultaneously in leukemia and normal lymphocytes treated with drug, melatonin, or their combination: cell viability, induction of apoptosis, level of reactive oxygen species (ROS), and level of protein-carbonyl products. Almost all investigated combinations of melatonin with new-generation anticancer drugs were characterized by synergistic cytotoxicity towards leukemia lymphocytes, while the combinations with conventional drugs exhibited additive or antagonistic effects on cell viability. In leukemia lymphocytes, the additive cytotoxicity of doxorubicin plus melatonin was accompanied by low levels of ROS and protein carbonyl products, as well as by suppression of apoptosis. In normal lymphocytes, none of the studied parameters changed significantly compared to cells treated with doxorubicin only. The combinations of everolimus plus melatonin and barasertib plus melatonin exhibited impressive synergistic cytotoxic effects on leukemia lymphocytes but did not affect the viability of normal lymphocytes. In leukemia cells, the synergistic cytotoxicity was accompanied by strong induction of apoptosis but a decrease of ROS to a level below that of the control. In normal lymphocytes, these combinations did not affect the level of ROS nor of protein-carbonyl products, and did not induce apoptosis. The data suggest that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side effects. PMID- 28011484 TI - Potential Prognostic Molecular Signatures in a Preclinical Model of Melanoma. AB - Numerous studies have revealed a variety of pathways involved in the development of melanoma, however, the molecular and genetic divergence of underlying mechanisms remain vague. In a mouse model, we studied the expression pattern of insulin-like growth factor 2 mRNA-binding protein 1 (Igf2bp1) and target genes microphthalmia-associated transcription factor (Mitf), v-myc avian myelocytomatosis viral oncogene homolog (Myc), B-cell lymphoma 2 (Bcl2), prothymosin alpha (Ptma) and melan-A (Mlana) in relation to tumor-growth characteristics. The in vivo expression of the aforementioned genes was assessed by quantitative Real Time-Polymerase Chain Reaction (RT-PCR) in tumors established by B16-F1-derived clones. Gene expression was correlated with tumor growth characteristics. Simultaneous expression of elevated levels of Myc, Igf2bp1, Ptma and Mitf characterizes tumors with a more aggressive phenotype. Our findings introduce a tumor-specific molecular signature possibly associated with melanoma heterogeneity. The concomitant overexpression of key molecules such as IGF2BP1, PTMA, MYC and MITF could serve as prognostic or predictive marker. PMID- 28011486 TI - Hyperforin Inhibits Cell Growth by Inducing Intrinsic and Extrinsic Apoptotic Pathways in Hepatocellular Carcinoma Cells. AB - The aim of the present study was to investigate the antitumor effect and mechanism of action of hyperforin in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro. Cells were treated with different concentrations of hyperforin for different periods of time. Effects of hyperforin on cell viability, apoptosis signaling, and expression of anti-apoptotic and proliferative proteins [cellular FLICE-like inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), myeloid cell leukemia 1(MCL1), and cyclin-D1] were investigated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and western blotting. Hyperforin significantly inhibited cell viability and expression of anti-apoptotic and proliferative proteins. We also found that hyperforin significantly induced accumulation of cells in sub-G1 phase, loss of mitochondrial membrane potential, and increased levels of active caspase-3, and caspase-8. Taken together, our findings indicate that hyperforin triggers inhibition of tumor cell growth by inducing intrinsic and extrinsic apoptotic pathways in HCC SK-Hep1 cells. PMID- 28011487 TI - Detection of Circulating Tumour Cells and Survival of Patients with Non-small Cell Lung Cancer. AB - BACKGROUND: Detection of circulating tumour cells (CTCs) in the peripheral blood of lung cancer patients may predict survival. Various platforms exist that allow capture of these cells for further analysis; little work however, has been done with the ScreenCell device, an antibody-independent CTC platform. The aim of our study was to evaluate the ScreenCell device for detection of CTCs in lung cancer patients and to establish correlations of these findings with survival. MATERIALS AND METHODS: Twenty-three patients, nine males, and fourteen females, underwent surgical treatment from February to May 2014 for non-small cell lung cancer. Thirteen patients had adenocarcinoma and ten squamous cell carcinoma, while eight were at an early stage (I-II) and five at a later stage (III-IV). Blood samples were obtained prior to surgery and following filtration through the ScreenCell device, were independently reviewed by 2 consultant pathologists. RESULTS: The pathologists were able to independently identify CTCs in 78.3% (N=18) and 73.9% (N=17) of the cases examined, with overall 80.6% in early stages compared to 60.0% in late stages. The median survival times of positive vs. negative for CTC patients were 1011 and 711 days respectively, with a survival percentage rate of 77.8% and 60% in positive and negative CTC cohorts respectively. CONCLUSION: The results of this study suggest that the presence of CTCs analyzed by ScreenCell did not necessarily lead to a poorer prognosis in patients with lung cancer after curative surgery. PMID- 28011488 TI - Different Expression Patterns of CXCR4, CCR7, Maspin and FOXP3 in Luminal Breast Cancers and Their Sentinel Node Metastases. AB - AIM: Luminal A breast cancers (BC) represent low-risk tumors conferring better outcome than luminal B and human epidermal growth factor 2 (HER2)-positive or triple-negative tumors. One reason for the heterogeneous outcome among patients with luminal BC is the variation in cell proliferation. As chemokine receptors and tumor suppressors show potential for estimation of infiltration to regional lymph nodes, we aimed to compare differently sized sentinel node metastases with their primary tumors (PT). MATERIALS AND METHODS: We compared 29 BCs of luminal subtype A and 23 of subtype B (Ki-67 cut off at 14%) by immunohistochemistry for the chemokine receptors C-X-C chemokine receptor 4 (CXCR4), C-C-chemokine receptor 7 (CCR7), the tumor suppressor Maspin and the regulatory T-cell immunosuppressor forkhead box protein 3 (FOXP3) between PTs and their metastases of different size. RESULTS: Expression of CXCR4 was low in luminal A type tumors, and CCR7 and FOXP3 expression were high in luminal B type cancer. CXCR4 expression significantly positively correlated with CCR7 both in PTs and metastases. Most Maspin-positive PTs became negative in the metastases. The PTs for all Maspin-positive metastases were luminal B type. CONCLUSION: High CXCR4 expression in PTs was found to be associated with luminal A type tumor, suggesting more favorable outcome. In contrast, CCR7 and FOXP3 expressions in PTs represented luminal B tumors, pointing to more aggressive tumor behavior. Maspin expression did not differ between luminal types. PMID- 28011489 TI - Prognostic Impact of CD163+ Macrophages in Tumor Stroma and CD8+ T-Cells in Cancer Cell Nests in Invasive Extrahepatic Bile Duct Cancer. AB - AIM: The aim of this study was to examine the clinicopathological influence of tumor-infiltrating cluster of differentiation (CD) 163+ macrophages and CD8+ T cells, and to clarify the prognostic effects of these cells in patients with invasive extrahepatic bile duct cancer (EHBC). MATERIALS AND METHODS: The numbers of CD8+ T-cells in cancer cell nests and CD163+ macrophages in tumor stroma were evaluated using immunohistochemistry in 101 resected EHBC specimens. Correlations with clinicopathological variables and overall survival were analyzed. RESULTS: Perihilar EHBC and perineural invasion were significantly associated with a low number of tumor-infiltrating CD8+ T-cells. Poorly- differentiated histology and nodal metastasis were significantly associated with a high number of tumor infiltrating CD163+ macrophages. A combination of high number of CD8+ T-cells and low number of CD163+ macrophages was independently related to better overall survival in the whole patient cohort (hazard ratio=0.127, p<0.001) and in patients treated with adjuvant chemotherapy (hazard ratio=0.139, p=0.021). CONCLUSION: Infiltrating CD163+ macrophages in tumor stroma and CD8+ T-cells in cancer cell nests have a prognostic impact in patients with EHBC following resection and also after adjuvant chemotherapy. PMID- 28011490 TI - Low Expression of FBXO45 Is Associated with Gastric Cancer Progression and Poor Prognosis. AB - BACKGROUND: F-Box protein 45 (FBXO45) is reported to be associated with cancer aggressiveness. We investigated the relationship between FBXO45 and clinicopathological factors in gastric cancer (GC). MATERIALS AND METHODS: We used immunohistochemistry to investigate FBXO45 expression in 104 GC samples; the prognostic value of FBXO45 was also calculated. RESULTS: FBXO45 levels in GC were higher than in normal tissues. Patients with relatively low FBXO45 expression (n=58) had increased cancer progression and poorer prognosis than those with high expression (n=46). Low FBXO45 expression was an independent negative prognostic factor in patients with GC. Using the public Kaplan-Meier plotter database, we showed that survival in patients with low expression of FBXO45 in GC was shorter than that in those with high FBXO45 expression, regardless of lymph node metastasis. CONCLUSION: A low FBXO45 expression level in GC tissues may be a powerful predictor of poor prognosis. FBXO45 might, therefore, be a promising candidate for a molecular targeted therapy in GC. PMID- 28011491 TI - Gender Difference in Distribution of Estrogen and Androgen Receptors in Intestinal-type Gastric Cancer. AB - BACKGROUND: Gender difference in survival of patients with gastric cancer is not well investigated. The aim of this study was to analyze the gender-related distribution of estrogen receptor alpha (ERalpha) and androgen receptor (AR) in the epithelium and stroma of intestinal-type gastric cancer. MATERIALS AND METHODS: Immunohistochemical analysis was performed in 60 patients (42% females). RESULTS: In gastric cancer patients, frequency of ERalpha-positive cells was lower in epithelium than in healthy individuals, but not significantly. In stroma and epithelium, AR-positive cells were absent from samples of women with T1 and T2 stage disease, while in men, their frequency was significantly increased in stroma of those with T3 and T4 stages and was significantly higher compared to women. AR-positive cells in stroma were fibroblasts, myofibroblasts and mast cells. CONCLUSION: To our knowledge, this study is the first to show gender differences in the distribution and frequency of AR-positive cells in neoplastic stroma of gastric cancer. PMID- 28011492 TI - Survival Following Palliative External-beam Radiotherapy of Locally Advanced and Metastatic Liver Cancer. AB - AIM: The goal of this study was to identify prognostic factors of survival in patients receiving palliative external-beam radiotherapy (EBRT) for advanced liver cancer. PATIENTS AND METHODS: Seventeen patients irradiated for advanced liver cancer were retrospectively evaluated. Fourteen patients had metastatic disease, three had locally advanced disease. Six variables were investigated for survival: age at EBRT, time from liver cancer diagnosis to EBRT, number of involved metastatic sites, gender, Eastern Cooperative Oncology Group (ECOG) performance score, radiation dose. RESULTS: On univariate analyses, time from liver cancer diagnosis to EBRT >12 months (p=0.040), only 0-1 metastatic sites (p=0.003) and ECOG performance score 1-2 (p<0.001) were positively correlated with survival. On Cox regression analysis, the number of metastatic sites (risk ratio=4.68, p=0.053) and ECOG performance score (risk ratio=4.68, p=0.056) showed a strong trend for association with survival. CONCLUSION: Predictors of survival were found that can facilitate choosing the optimal treatment for individual patients with liver cancer assigned to palliative EBRT. PMID- 28011493 TI - Podoplanin Expression in Cancer-associated Fibroblasts Predicts Poor Prognosis in Patients with Squamous Cell Carcinoma of the Lung. AB - BACKGROUND/AIM: Podoplanin is a candidate cancer stem cell marker in squamous cell carcinoma (SCC). Several studies have reported the prognostic value of podoplanin expression in tumor cells in lung SCC but few have focused on its expression in cancer-associated fibroblasts (CAFs). The aim of this study was to analyze the prognostic significance of podoplanin expression, with special reference to the expression pattern in both tumor cells and CAFs. PATIENTS AND METHODS: Immunohistochemical analyses using anti-podoplanin antibody were performed on 126 resected specimens of lung SCC. When more than 10% of tumor cells or CAFs showed immunoreactivity with podoplanin levels as strong as those of the positive controls, the specimens were classified as a podoplanin-positive. RESULTS: Podoplanin-positive status in tumor cells (n=54) was correlated with a lower incidence of lymphatic invasion (p=0.031) but there were no significant differences in disease-free survival (DFS) and disease-specific survival (DSS) by the log-rank test. Podoplanin-positive status in CAFs (n=41) was correlated with more advanced stage (p=0.008), higher frequency of pleural invasion (p=0.002) and both shorter DFS (p=0.006) and DSS (p=0.006). In Cox's multivariate analysis, podoplanin-positive status in CAFs was an independent negative prognostic factor for DFS (p=0.027) and DSS (p=0.027). CONCLUSION: Podoplanin expression in CAFs might be an independent unfavorable prognostic indicator in patients with lung SCC, irrespective of the expression status of tumor cells. PMID- 28011494 TI - mMRI at 3.0 T as an Evaluation Tool of Therapeutic Response to Neoadjuvant CRT in Patients with Advanced-stage Rectal Cancer. AB - AIM: To assess whether multiparametric MRI (mMRI) can serve as a tool for evaluating response to chemoradiation therapy (CRT) in advanced-stage rectal cancer. PATIENTS AND METHODS: Twenty-one patients underwent a mMRI protocol at 3T before and after CRT. Two experienced radiologists evaluated the MRI measurements and inter-reader correlation was assessed. Changes in functional parameters in relation to regression, as well as pT stage were analyzed. The perfusion parameters plasma flow (PF) and mean transit time (MTT) were calculated offline using the established UMM Perfusion tool. RESULTS: Apparent diffusion coefficient values were significantly different among the different tumor RGs before CRT (p=0.041). Changes of dynamic contrast enhanced (DCE) MRI values did not reflect treatment response (PF: p=0.5; MTT: p=0.74). CONCLUSION: The results of our study population indicate that a high initial apparent diffusion coefficient value may be predictive of response to therapy following CRT. PMID- 28011495 TI - Granulocyte Colony-stimulating Factor Producing Anaplastic Carcinoma of the Pancreas: Case Report and Review of the Literature. AB - We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34. PMID- 28011496 TI - Identification and Management of Head and Neck Cancer Recurrences Detected on Adjuvant Radiation Oncology Simulation Scans. AB - BACKGROUND/AIM: Computerized tomographic (CT) simulation is used to design precise radiation therapy treatment plans. These scans are not routinely read by radiology and are only used for planning purposes. As radiation oncology departments adopt the addition of intravenous contrast to their CT simulations, there is the potential for identification of post-surgical recurrences. PATIENTS AND METHODS: We identified all biopsy-proven local recurrences of head and neck cancer detected during CT simulation and followed their outcomes. RESULTS: A total of 218 patients with head and neck cancer underwent CT simulation with intravenous contrast since our Department adopted the new technique. There were a total of four recurrences detected during simulation: two of the right tongue, one oral cavity and one laryngeal. Intensified salvage chemoradiotherapy was used for these cases. Two out of the four were successfully salvaged and remain disease-free. CONCLUSION: Recurrences of head and neck cancer following surgical resection can be detected on simulation scans, with the potential for survival after appropriate salvage therapy. PMID- 28011497 TI - Gemcitabine and S-1 Induction Chemotherapy Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancers. AB - BACKGROUND: Gemcitabine and S-1 are drugs commonly used for treating locally advanced pancreatic cancer (LAPC). However, the safety and efficacy of combination of these agents for induction chemotherapy (IC) followed by chemoradiotherapy are not well-defined. PATIENTS AND METHODS: Fifteen patients with LAPC (IC-CRT group) were treated with gemcitabine and S-1 IC, followed by S 1 chemoradiotherapy. The clinical outcomes were compared to a cohort of 38 patients who received chemoradiotherapy alone (CRT group). RESULTS: Disease control rates in the CRT and IC-CRT groups were 84% and 93%, respectively (p=0.024). The median time of disease progression was 10.8 and 15.4 months in the CRT and IC-CRT group, respectively (p=0.043). The median overall survival time was longer in the IC-CRT group compared to CRT (23.4 vs. 17.3 months), but this increase was not statistically significant. CONCLUSION: Gemcitabine and S-1 combination chemotherapy, followed by CRT, is a promising IC regimen for treating LAPC. PMID- 28011499 TI - Development of a Survival Score for Patients with Cerebral Metastases from Melanoma. AB - BACKGROUND/AIM: To develop a survival score for patients receiving whole-brain irradiation (WBI) alone for cerebral metastases from melanoma. PATIENTS AND METHODS: Forty-five patients who met the required criteria were included. WBI doses had to be >30 Gy. Six variables were analyzed: age, gender, Karnofsky performance score (KPS), number of cerebral metastases, extracranial metastatic spread and interval from diagnosis of melanoma until WBI. In order to estimate patients' survival scores, variables showing at least a trend (p<0.06) on multivariate analysis were considered. One point was assigned to each variable correlating with better survival rates and zero points to those correlating with worse survival rates. RESULTS: By multivariate analysis, age (p=0.002) achieved significance and KPS (p=0.056) showed a trend. Patients' survival scores were obtained by adding zero or one point from each variable and resulted in three groups of 0, 1 or 2 points. The median survival times of these groups were one, four and ten months (p<0.0001). CONCLUSION: A survival score was developed for patients assigned to WBI alone for cerebral metastases from melanoma. This new instrument may facilitate the decision for the appropriate WBI-program. PMID- 28011498 TI - Metastatic Pattern of Stage IV Colorectal Cancer with High-Frequency Microsatellite Instability as a Prognostic Factor. AB - BACKGROUND: A recent clinical trial on the immune check-point inhibitor pembrolizumab demonstrated that microsatellite instability (MSI) is a good biomarker for response to this inhibitor. However, clinicopathological features of advanced colorectal cancer (CRC) with high-frequency MSI (MSI-H) are unclear. PATIENTS AND METHODS: A total of 2,439 surgically resected CRC tissues were analyzed for MSI status, and mutational status of V-Ki-Ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf murine sarcoma viral oncogene homolog B (BRAF). Stage IV cases were selected, and clinical and molecular features were evaluated. RESULTS: There was no significant survival difference observed between MSI-H CRC and microsatellite stable (MSS) CRC in patients with stage IV disease (3.92 vs. 2.50 years; p=0.766). However, hematogenous and lymphogenous metastasis-dominant CRC with MSI H demonstrated poor prognosis, whereas peritoneal metastasis-dominant CRC with MSI-H demonstrated good prognosis, (1.33 vs. 5.2 years; p=0.006). CONCLUSION: Prognosis of stage IV CRC with MSI-H depended on the metastatic pattern. These findings provide useful information for the adaptation of CRC immunotherapy. PMID- 28011500 TI - A Study of Angiogenesis Markers in Patients with Renal Cell Carcinoma Undergoing Therapy with Sunitinib. AB - BACKGROUND: Sunitinib is a tyrosine kinase inhibitor (TKI) targeting tumour angiogenesis in patients with advanced renal cell carcinoma (RCC). Currently no universally agreed model exists correlating the expression of angiogenesis markers with the success of treatment. PATIENTS AND METHODS: We retrospectively analysed archival tissue for 59 RCC patients treated with sunitinib. The expression of angiogenesis markers VEGF-A, VEGFR, PDGFbetabeta, PDGFR, CCND1 and CA9 was assessed by immunohistochemistry (IHC) and correlated with overall survival (OS) and progression-free survival (PFS). RESULTS: The median OS and median PFS of the whole group of patients was 24.6 months (17.3-34.2) and 19.5 months (11-27) respectively. VEGFA was positive in 29% of tumors, whereas VEGFR was expressed in only 12% of tumours. PDGFbetabeta and its receptor were detected in a minority of cases. CCND1 and CA9 were positive in 44% and 60% of cases. CONCLUSION: The OS and PFS achieved by our patients reflected previous observations seen with sunitinib, but no correlation was found between expression of angiogenesis markers and clinical outcome. PMID- 28011501 TI - Laparoscopic versus Open Partial Nephrectomy: Comparison of Overall and Subgroup Outcomes. AB - BACKGROUND: At experienced centers, laparoscopic partial nephrectomy (LPN) can achieve similar results to those of open surgery (OPN). However, the role of LPN for complex tumors and imperative indications is under debate. PATIENTS AND METHODS: A total of 356 cases (186 LPN and 170 OPN) between 2005-2012 were reviewed. Clinical, surgical, pathological and radiological data, including PADUA classification were analyzed. RESULTS: In overall analysis, OPN was associated with higher tumor complexity (p<=0.03). Subgroup analysis of PADUA >8 tumors (n=85) showed no significant difference between LPN and OPN. In patients with unfavorable treatment characteristics (imperative indication/multifocal tumors, n=71) LPN was beneficial. In this subgroup, LPN led to better perioperative (p<=0.02) and postoperative (p<=0.04) outcome. CONCLUSION: Use of LPN is associated with favorable tumor characteristics. Although no advantage was shown for LPN for tumors with higher complexity (PADUA>8), this large series confirmed the superiority of LPN for imperative indication or multifocal tumors. PMID- 28011502 TI - Objective Predictive Score as a Feasible Biomarker for Short-term Survival in TerminalIy Ill Patients with Cancer. AB - BACKGROUND: In palliative care, prediction of life expectancy is one of the most crucial issues for patients, family and medical staff, in order to provide appropriate end-of-life care. The aim of this study was to formulate a new objective score to predict life expectancy within 1 week for terminally ill patients with cancer. PATIENTS AND METHODS: Medical records were obtained from 187 terminally-ill patients with cancer who were admitted for palliative care. The biomarkers for a potential 'Objective Predictive Score' were assessed. RESULTS: Profiling of blood parameters demonstrated that elevated levels of alanine aminotransferase (ALT), total bilirubin (T-bil), blood urea nitrogen (BUN), creatinine (Cr) and a decreased platelet count were significantly correlated with death within 1 week in a training cohort. Our formulated Objective Predictive Score was able to predict death within 1 week with high accuracy in a training and a validation cohort. CONCLUSION: Our scoring system might enable the assessment of prognostication with higher accuracy in a terminal care setting. PMID- 28011503 TI - Surgical Resection of Giant Pheochromocytomas Arising Behind the Retrohepatic Inferior Vena Cava. AB - BACKGROUND: Surgical resection of retrocaval giant pheochromocytomas (PCs) and of extra-adrenal paragangliomas (EAPs) is a technically challenging procedure but data on these procedures are scarce. The purpose of this study was to present and evaluate our surgical results for such tumors. PATIENTS AND METHODS: We retrospectively analyzed four consecutive patients who had surgery for giant retro-caval PCs and EAPs in terms of surgical technique, resectability of the tumor, requirement for bypass, and postoperative complications. A laparoscopic approach was not feasible in all cases because of the undesirable location of the tumors. RESULTS: In all cases, the liver was completely mobilized from the right side to expose and control the supra- and infra-hepatic inferior vena cava. Resection of the tumors was feasible for all patients with a minimum titration of blood pressure during surgery. None of the cases required venous bypass. In the patient who had the largest tumor, the infra-hepatic inferior vena cava was transected temporally to obtain direct and maximum exposure of the tumor. None of the patients have had any postoperative complications and all are currently alive without recurrence and use of antihypertensive drugs. CONCLUSION: Resection of retrocaval giant PCs and EAPs is a safe procedure. Temporal transection of the infra-hepatic inferior vena cava can offer excellent exposure, especially for an extremely large tumor, without compromising hepatic and systemic hemodynamics. PMID- 28011504 TI - Prognostic and Therapeutic Potential Implications of Genetic Variability in Prostaglandin E2 Pathway Genes in Rectal Cancer. AB - AIM: To evaluate the prognostic significance and potential therapeutic implication of genetic variability in prostaglandin E2 pathway genes in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery. MATERIALS AND METHODS: This cohort study included 167 patients with LARC, treated with nCRT followed by surgery. A total of 61 single nucleotide polymorphisms (SNPs) were characterized using the Sequenom platform through multiplex amplification followed by mass-spectometric product separation. Surgical specimens were classified according to Mandard tumor regression grade (TRG). The patients were divided as 'good responders' (Mandard TGR1-2) and 'poor responders' (Mandard TRG3-5). We examined prognostic value of polymorphisms studied to determine if they are related to Mandard response. RESULTS: Mandard tumor response and rs17268122 in ATP binding cassette subfamily C member (ABCC4) gene were the only two parameters with independent prognostic significance for disease-free survival. CONCLUSION: tagSNP ABCC4 rs17268122 appears to be a prognostic factor in LARC treated with nCRT and surgery, independently of response to nCRT. The screening of ABCC4 rs17268122 tagSNP and the Mandard tumor response in clinical practice may help to identify patients with different rectal cancer prognosis and contribute to an individualized therapeutic decision tree. PMID- 28011505 TI - Association of Inflammasome Components in Background Liver with Poor Prognosis After Curatively-resected Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Inflammasomes are multiprotein complexes that evoke key inflammatory cascades. The present study evaluated the influence of inflammasome component expression in non-tumorous tissue on postsurgical hepatocellular carcinoma (HCC) prognosis. MATERIALS AND METHODS: The expressions of candidate genes were investigated using real-time quantitative reverse-transcription polymerase chain reaction in resected HCC cases. In order to identify potential prognostic factors, statistical analyses were performed for each gene. RESULTS: The expression of nod-like receptor family, pyrin domain containing 3 (NLRP3), nod-like receptor family, CARD domain containing 4 (NLRC4), and absent in melanoma 2 (AIM2) was significantly higher in corresponding normal tissue (CN) compared to those in HCC. High expression of NLRP3, NLRC4, and caspase 1 (CASP1) in CN was significantly correlated with worse overall survival. Furthermore, multivariate analysis revealed that NLRP3 expression in CN greater than the median was an independent prognostic factor for poorer overall survival. CONCLUSION: High expression of NLRP3, NLRC4, and CASP1 in background non-tumorous liver is significantly correlated with poor prognosis of patients after resection of HCC. PMID- 28011506 TI - Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. AB - BACKGROUND: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. MATERIALS AND METHODS: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. RESULTS: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. CONCLUSION: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system. PMID- 28011507 TI - Platinum-based Doublet Chemotherapy for Advanced Gastric Cancer with Disseminated Intravascular Coagulation. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) is a rare complication of advanced gastric cancer (AGC). Despite reports of the efficacy of chemotherapy for AGC with DIC, little is known of platinum-based doublet therapy. PATIENTS AND METHODS: We conducted a single-institute, retrospective chart review of 500 consecutive chemotherapy-naive patients with advanced gastric adenocarcinoma (recurrent or metastatic) from November 2010 to November 2015. RESULTS: Six patients were diagnosed with AGC with DIC (1.2%); five (1.0%; 3 men, 2 women) received platinum-based doublet chemotherapy. All patients exhibited improved DIC and thrombocytopenia and survived for >100 days (range=114-313) with no therapy related mortality. Grade >=3 adverse effects included neutropenia, anemia, hyponatremia, catheter-related infection and diarrhea (maximum: 2 patients each). CONCLUSION: Fluoropyrimidine plus platinum combination therapy was effective against DIC and yielded acceptable survival outcomes. Combination chemotherapy should be considered as a primary therapy for AGC with DIC. PMID- 28011508 TI - Stereotactic Body Radiotherapy in Patients with Lung Oligometastases from Colorectal Cancer. AB - AIM: To assess the role of stereotactic body radiotherapy (SBRT) in pulmonary metastases from colorectal cancer (CRC). PATIENTS AND METHODS: Thirty-three consecutive patients with pulmonary metastases from CRC who received SBRT were included in the analysis. The primary endpoints were local and systemic progression-free survival, a secondary endpoint was the safety profile of SBRT. RESULTS: A total of 56 lesions were treated with SBRT. A single nodule was treated in 15 patients, two in 13 and three in five. The radiotherapy dose and the adopted fractionations were 24-27 Gy as a single fraction for 40 lesions and 27-42 Gy in three fractions (2-3 times a week) for the other 16 lesions. After a median follow-up of 22.8 months (range=1.3-45.7 months), the median progression free survival of the irradiated sites was 13.4 months. CONCLUSION: SBRT can be considered as local therapy in patients with lung metastases from CRC. PMID- 28011509 TI - Technical Feasibility and Oncological Legitimacy of Enucleation of Intraductal Papillary Mucinous Neoplasm Located at the Pancreatic Head or Uncinate Process. AB - BACKGROUND: Surgical indications and strategies for branch duct (BD)-intraductal papillary mucinous neoplasm (IPMN) at the pancreatic head (PH) are controversial issues. We investigated the technical feasibility and oncological legitimacy of enucleation for IPMN of the PH. PATIENTS AND METHODS: The clinicopathological parameters of 11 patients with IPMN who underwent conventional pancreaticoduodenectomy (PD, n=7) or enucleation (n=4) during the same period were evaluated. RESULTS: The mean operative time (442 vs. 280 min, p<0.05) and blood loss (864 vs. 93 ml, p<0.05) were significantly better in the enucleation group. The final pathological diagnosis (low-/intermediate-/high-grade dysplasia) in the PD and enucleation groups was 4/2/1 and 3/1/0, respectively. The incidence of grade B pancreatic fistula and Clavien III complications was 14% vs. 0% and 43% vs. 25%, respectively. No recurrent pancreatitis or exocrine or endocrine dysfunction was noted in the enucleation group; however, de novo or exacerbated diabetes mellitus developed in three patients in the PD group. All patients were alive and no disease recurrence was noted at a mean follow-up of 1,059 days. CONCLUSION: Enucleation of BD-IPMN at the PH is a technically feasible and oncologically acceptable procedure which should be justified in patients with IPMNs with a low risk of malignancy. PMID- 28011510 TI - Clinical Impact of Escalating Relative High-dose-rate Intracavitary Brachytherapy Dose in Stage IIB Cervical Cancer. AB - BACKGROUND/AIM: To investigate whether high-dose-rate (HDR) intracavitary brachytherapy (IBT) dose ratios can predict treatment outcomes in patients with stage IIB cervical cancer. PATIENTS AND METHODS: Ninety-three patients treated with weekly cisplatin-based concurrent chemoradiotherapy and HDR IBT were analyzed. Potential prognostic factors and treatment outcomes were compared between low-HDR-IBT-ratio (<=0.43) and high-HDR-IBT-ratio (>0.43) groups, and univariate and multivariate analyses were performed. RESULTS: Five-year disease specific survival (DSS) and progression-free survival (PFS) rates were significantly shorter in the low-compared to the high-HDR-IBT-ratio group. A high HDR IBT ratio was confirmed as an independent prognostic factor for DSS and PFS. CONCLUSION: A high HDR IBT dose ratio improves DSS and PFS in patients with stage IIB cervical cancer. Therefore, active administration of HDR IBT beyond previously accepted levels may be necessary for the treatment of locally advanced cervical cancer. PMID- 28011511 TI - Minimally Invasive Lymphadenectomy in Uterine Cervical Cancer: A Systematic Review. AB - BACKGROUND/AIM: The aim of this study was to review the current literature on the role of minimally invasive lymphadenectomy in the treatment of cervical cancer. MATERIALS AND METHODS: Non-randomized control trials published between January 2007 to May 2016 were identified by searching the Pubmed, EMBASE and Cochrane Library databases. Primary endpoints included operative outcomes (operative time, intraoperative blood loss, number of transfused patients and conversion rates), postoperative outcomes (length of postoperative hospital stay, postoperative morbidity and postoperative in-hospital mortality), and oncological outcomes (number of harvested lymph nodes, tumor recurrence, disease-free rates and overall survival rates). RESULTS: A total of 17 studies with a total of 1,676 patients were included in the review. Compared to the open approach, minimally invasive lymphadenectomy demonstrated a significantly larger number of harvested lymph nodes, longer operative time, lower intraoperative blood loss and shorter postoperative hospital stay. No significant differences were observed between groups treated with an open, laparoscopic or robotic approach for the following criteria: lymph node metastasis, postoperative morbidity, tumor recurrence and postoperative mortality. CONCLUSION: Although a technically demanding and time consuming procedure, minimally invasive lymphadenectomy appears to be safe and feasible and may offer an alternative approach in staging and treatment of cervical cancer. Multicentre randomized controlled trials investigating its long term oncological outcomes and its cost-effectiveness are required to determine the advantages of this procedure over the open approach in cervical cancer. PMID- 28011512 TI - Double Endoscopic Intraluminal Operation (DEILO) for Early Gastric Cancer: Outcome of Novel Procedure for Endoscopic Submucosal Dissection. AB - Endoscopic submucosal dissection (ESD) has been used to treat patients with early gastric cancer (EGC). Although several endoscopic devices have been developed to ensure easy and safe ESD, this technique still requires an experienced, highly skilled endoscopist, as it is performed through a single gastroscope, thus requiring one-handed surgical techniques. To overcome these limitations, many ESD procedures with counter-traction have been developed, such as the double scope, double channel scope, clip with line, magnetic anchor, percutaneous traction and external grasping forceps methods. We devised a double endoscopic intraluminal operation (DEILO). Two endoscopes were simultaneously inserted into the stomach. One endoscope was used to lift the lesion, and the other was used to excise the lesion. The DEILO procedure was performed on 122 cases of EGC. In this article, we report the efficacy and safety of DEILO in patients with EGC. PMID- 28011513 TI - Tumescent Anesthesia in Skin- and Nipple-sparing Mastectomy: Results of a Prospective Clinical Study. AB - BACKGROUND: The tumescent mastectomy technique has been used to facilitate dissection of subcutaneous tissue and mammary gland in order to reduce intraoperative bleeding and speed the operation. PATIENTS AND METHODS: A prospective clinical study was performed on 30 female patients undergoing immediate breast reconstructions after skin-sparing mastectomy (SSM) or nipple sparing mastectomy (NSM) in order to assess early postoperative complications, pain, and final esthetic outcome of skin flaps related to tumescent anesthesia (TA). RESULTS: TA significantly speeded-up the operative procedure (131+/-49.99 vs. 180.5+/-67.15 min; p=0.03) achieving less skin damage compared to patients who did not have TA (p=0.045); moreover, no significant difference occurred with regard to the length of in-hospital stay and overall lymphatic drainage. CONCLUSION: The length of the operation as well as the final cosmetic outcome of skin flaps was significantly improved due to TA, with no appreciable side effects. PMID- 28011514 TI - Clinical Performance of CEA, CA19-9, CA15-3, CA125 and AFP in Gastrointestinal Cancer Using LOCITM-based Assays. AB - BACKGROUND/AIM: Few data are available regarding the clinical performance of LOCITM-based tumor marker assays. We investigated the diagnostic power of carcinogenic antigen, carbohydrate antigen 19-9, carbohydrate antigen 15-3, carbohydrate antigen 125 and alpha-fetoprotein for detection of gastrointestinal (GI) cancer. PATIENTS AND METHODS: We analyzed sera from 204 patients (107 with GI cancer, 73 with benign GI diseases and 24 healthy controls) using the DimensionTM Vista1500 analyzer. RESULTS: Levels of biomarkers in healthy controls were in the expected ranges and were only slightly higher in benign GI controls. Established tumor-type-associated markers were elevated in specific cancer types and discriminated well between cancer and benign controls. Best performance was found for CEA in colorectal cancer (area under the curve=0.84, sensitivity=51.7% at 95% specificity vs. benign), CA19-9 in gallbladder/pancreatic cancer (AUC=0.85, sensitivity=60.6%) and AFP in liver cancer (AUC=0.87, sensitivity=68.4%). CONCLUSION: Our study demonstrated the high diagnostic power of well-known biomarkers. LOCITM-based tumor marker assays give reliable results in routine diagnostics. PMID- 28011577 TI - Examining the potential use and long-term stability of guaiac faecal occult blood test cards for microbial DNA 16S rRNA sequencing. AB - AIMS: With a growing interest in the influence the gut microbiome has on the development of colorectal cancer (CRC), we investigated the feasibility and stability of isolating and typing microbial DNA from guaiac faecal occult blood test (gFOBt) cards. This has the future potential to screen the microbial populations present in confirmed colorectal neoplasia cases with aims to predict the presence and development of CRC. METHODS: Fresh stool samples from three healthy volunteers were applied to gFOBt cards. DNA was extracted from both the cards and fresh stool samples. A series of additional cards were prepared from one volunteer, and extracted at time points between 2 weeks and 3 years. The V4 region of the 16S rRNA gene was amplified and sequenced on an Illumina MiSeq at 2*250 bp read lengths. Data were analysed using QIIME software. RESULTS: Samples were grouped both by volunteer and by type (fresh or gFOBt), and compared a variety of ways: visual inspection of taxa, alpha and beta diversity, intraclass correlation. In all comparisons, samples grouped by volunteer, and not by sample type. The different time points showed no appreciable differences with increased storage time. CONCLUSIONS: This study has demonstrated that there is good concordance between microbial DNA isolated from fresh stool sample, and from the matched gFOBt card. Samples stored for up to 3 years showed no detrimental effect on measureable microbial DNA. This study has important future implications for investigating microbial influence on CRC development and other pathologies. PMID- 28011578 TI - Prognostic implications of RASAL1 expression in oesophagogastric adenocarcinoma. PMID- 28011579 TI - 10-Minute Consultation: A painful tingling hand. PMID- 28011580 TI - Replication fork passage drives asymmetric dynamics of a critical nucleoid associated protein in Caulobacter. AB - In bacteria, chromosome dynamics and gene expression are modulated by nucleoid associated proteins (NAPs), but little is known about how NAP activity is coupled to cell cycle progression. Using genomic techniques, quantitative cell imaging, and mathematical modeling, our study in Caulobacter crescentus identifies a novel NAP (GapR) whose activity over the cell cycle is shaped by DNA replication. GapR activity is critical for cellular function, as loss of GapR causes severe, pleiotropic defects in growth, cell division, DNA replication, and chromosome segregation. GapR also affects global gene expression with a chromosomal bias from origin to terminus, which is associated with a similar general bias in GapR binding activity along the chromosome. Strikingly, this asymmetric localization cannot be explained by the distribution of GapR binding sites on the chromosome. Instead, we present a mechanistic model in which the spatiotemporal dynamics of GapR are primarily driven by the progression of the replication forks. This model represents a simple mechanism of cell cycle regulation, in which DNA-binding activity is intimately linked to the action of DNA replication. PMID- 28011581 TI - Hippo kinases maintain polarity during directional cell migration in Caenorhabditis elegans. AB - Precise positioning of cells is crucial for metazoan development. Despite immense progress in the elucidation of the attractive cues of cell migration, the repulsive mechanisms that prevent the formation of secondary leading edges remain less investigated. Here, we demonstrate that Caenorhabditis elegans Hippo kinases promote cell migration along the anterior-posterior body axis via the inhibition of dorsal-ventral (DV) migration. Ectopic DV polarization was also demonstrated in gain-of-function mutant animals for C. elegans RhoG MIG-2. We identified serine 139 of MIG-2 as a novel conserved Hippo kinase phosphorylation site and demonstrated that purified Hippo kinases directly phosphorylate MIG-2S139 Live imaging analysis of genome-edited animals indicates that MIG-2S139 phosphorylation impedes actin assembly in migrating cells. Intriguingly, Hippo kinases are excluded from the leading edge in wild-type cells, while MIG-2 loss induces uniform distribution of Hippo kinases. We provide evidence that Hippo kinases inhibit RhoG activity locally and are in turn restricted to the cell body by RhoG-mediated polarization. Therefore, we propose that the Hippo-RhoG feedback regulation maintains cell polarity during directional cell motility. PMID- 28011582 TI - Fluid shear stress induces upregulation of COX-2 and PGI2 release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38. AB - Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I2 (PGI2) is an important antiatherogenic prostanoid and vasodilator produced in endothelial cells through the action of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2. However, the mechanisms involved in sustained, shear-induced production of COX-2 and PGI2 have not been elucidated but are determined in the present study. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm2 for 5 h to examine shear stress-induced induction of COX-2/PGI2 Our results demonstrate the relationship between the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1) and the intracellular mechanoresponsive molecules phosphatidylinositol 3-kinase (PI3K), focal adhesion kinase (FAK), and mitogen-activated protein kinase p38 in the FSS induction of COX-2 expression and PGI2 release. Knockdown of PECAM-1 (small interference RNA) expression inhibited FSS-induced activation of alpha5beta1-integrin, upregulation of COX-2, and release of PGI2 in both bovine aortic endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway (LY294002) substantially inhibited FSS activation of alpha5beta1-integrin, upregulation of COX-2 gene and protein expression, and release of PGI2 in BAECs. Inhibition of integrin associated FAK (PF573228) and MAPK p38 (SB203580) also inhibited the shear induced upregulation of COX-2. Finally, a PECAM-1-/- mouse model was characterized by reduced COX-2 immunostaining in the aorta and reduced plasma PGI2 levels compared with wild-type mice, as well as complete inhibition of acute flow-induced PGI2 release compared with wild-type animals.NEW & NOTEWORTHY In this study we determined the major mechanotransduction pathway by which blood flow-driven shear stress activates cyclooxygenase-2 (COX-2) and prostaglandin I2 (PGI2) release in endothelial cells. Our work has demonstrated for the first time that COX-2/PGI2 mechanotransduction is mediated by the mechanosensor platelet endothelial cell adhesion molecule-1 (PECAM-1). PMID- 28011583 TI - Association of serum HMGB2 level with MACE at 1 mo of myocardial infarction: Aggravation of myocardial ischemic injury in rats by HMGB2 via ROS. AB - High-mobility group box (HMGB) family is related to inflammatory diseases. We investigated whether serum HMGB2 levels are related to myocardial infarction (MI) severity and major adverse cardiac events (MACE) during MI. We included 432 consecutive patients with ST-segment elevation myocardial infarction and 312 controls. Serum HMGB2 levels were significantly higher in MI patients than in controls. Increased HMGB2 levels were associated with MACE and negatively with ejection fraction in MI patients. HMGB2 was an independent determinant of MACE in logistic regression analysis. HMGB2 protein (10 MUg) or saline was injected intramyocardially in MI rats, with or without coadministration of the NADPH oxidase inhibitor apocynin. After 72 h, pathological, echocardiographic, and hemodynamic examinations showed that HMGB2 increased infarct size and worsened cardiac function in MI rats. Moreover, HMGB2 administration enhanced reactive oxygen species (ROS) production, cell apoptosis, inflammation, and autophagosome clearance impairment, which were attenuated by coadministration of apocynin or knock down of receptor for advanced glycation end products (RAGE). In conclusion, increased serum HMGB2 levels are associated with MI severity and MACE at 1 mo. HMGB2 promotes myocardial ischemic injury in rats and hypoxic H9C2 cell damage via ROS provoked by RAGE.NEW & NOTEWORTHY We demonstrate that serum high-mobility group box 2 is associated with major adverse cardiac events at 1 mo in myocardial infarction patients. Mechanistically, high-mobility group box 2 promotes reactive oxygen species production via receptor for advanced glycation end products signaling in ischemic myocardium, thereby aggravating cell apoptosis, inflammation, and autophagosome clearance impairment. This study reveals that high-mobility group box 2 is a novel factor enhancing ischemic injury in myocardial infarction. PMID- 28011584 TI - Effect of anisotropy on ventricular vulnerability to unidirectional block and reentry by single premature stimulation during normal sinus rhythm in rat heart. AB - Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's "pinwheel experiment," usually induce reentry arrhythmias in the normal heart, while single low intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites (n = 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows: 1) along fiber direction, on right and left ventricular free walls (n = 23), initiating figure-eight reentry (n = 17) and tachycardia (n = 12), and 2) across fiber direction, on lower interventricular septum (n = 3), initiating spiral wave reentry (n = 2) and tachycardia (n = 1). Critical time window (55.1 +/- 4.7 ms, 68.2 +/- 6.0 ms) and stimulus strength lower limit (4.9 +/- 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low intensity premature stimuli can induce repetitive ventricular response (n = 13) characterized by focal activations.NEW & NOTEWORTHY We performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations. PMID- 28011585 TI - The role of sympathetic and vagal cardiac control on complexity of heart rate dynamics. AB - Analysis of heart rate variability (HRV) by nonlinear approaches has been gaining interest due to their ability to extract additional information from heart rate (HR) dynamics that are not detectable by traditional approaches. Nevertheless, the physiological interpretation of nonlinear approaches remains unclear. Therefore, we propose long-term (60 min) protocols involving selective blockade of cardiac autonomic receptors to investigate the contribution of sympathetic and parasympathetic function upon nonlinear dynamics of HRV. Conscious male Wistar rats had their electrocardiogram (ECG) recorded under three distinct conditions: basal, selective (atenolol or atropine), or combined (atenolol plus atropine) pharmacological blockade of autonomic muscarinic or beta1-adrenergic receptors. Time series of RR interval were assessed by multiscale entropy (MSE) and detrended fluctuation analysis (DFA). Entropy over short (1 to 5, MSE1-5) and long (6 to 30, MSE6-30) time scales was computed, as well as DFA scaling exponents at short (alphashort, 5 <= n <= 15), mid (alphamid, 30 <= n <= 200), and long (alphalong, 200 <= n <= 1,700) window sizes. The results show that MSE1 5 is reduced under atropine blockade and MSE6-30 is reduced under atropine, atenolol, or combined blockade. In addition, while atropine expressed its maximal effect at scale six, the effect of atenolol on MSE increased with scale. For DFA, alphashort decreased during atenolol blockade, while the alphamid increased under atropine blockade. Double blockade decreased alphashort and increased alphalong Results with surrogate data show that the dynamics during combined blockade is not random. In summary, sympathetic and vagal control differently affect entropy (MSE) and fractal properties (DFA) of HRV. These findings are important to guide future studies.NEW & NOTEWORTHY Although multiscale entropy (MSE) and detrended fluctuation analysis (DFA) are recognizably useful prognostic/diagnostic methods, their physiological interpretation remains unclear. The present study clarifies the effect of the cardiac autonomic control on MSE and DFA, assessed during long periods (1 h). These findings are important to help the interpretation of future studies. PMID- 28011586 TI - Activation of PPAR-alpha in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. AB - Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-alpha transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-alpha knockout mice in response to chronic pressure overload. We created a pressure overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-alpha during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-alpha expression in wild-type mice. We examined the effect of PPAR-alpha induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR alpha induction with an increase in PPAR-alpha-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-alpha induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-alpha. Myocardial high-energy phosphates were significantly preserved by PPAR-alpha induction. These results suggest that PPAR-alpha activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-alpha and modulation of FAO could be a promising therapeutic strategy for heart failure.NEW & NOTEWORTHY The present study demonstrates the role of PPAR-alpha activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-alpha preserved heart function, and myocardial energetics. Activating PPAR-alpha and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure. PMID- 28011588 TI - Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis. AB - Advancing age is an independent risk factor for cardiovascular disease. Matrix metalloproteinase-9 (MMP-9) is secreted by macrophages and robustly increases in the left ventricle (LV) with age. The present study investigated the effect of MMP-9 overexpression in macrophages on cardiac aging. We compared 16- to 21-mo old C57BL/6J wild-type (WT) and transgenic (TG) male and female mice (n = 15 20/group). MMP-9 overexpression amplified the hypertrophic response to aging, as evidenced by increased LV wall thickness and myocyte cross-sectional areas (P < 0.05 for both). MMP-9 overexpression reduced LV expression of the angiogenesis related factors ICAM-1, integrins alpha3 and beta3, platelet/endothelial cell adhesion molecule-1, thrombospondin-1, tenascin-c, and versican (all P < 0.05). Concomitantly, the number of vessels in the TG was lower than WT LV (P < 0.05). This led to a mismatch in the muscle-to-vessel ratio and resulted in increased cardiac inflammation. Out of 84 inflammatory genes analyzed, 16 genes increased in the TG compared with WT (all P < 0.05). Of the elevated genes, 14 were proinflammatory genes. The increase in cardiac inflammation resulted in greater accumulation of interstitial collagen in TG (P < 0.05). Fractional shortening was similar between groups, indicating that global cardiac function was still preserved at this age. In conclusion, overexpression of MMP-9 in macrophages resulted in exacerbated cardiac hypertrophy in the setting of vessel rarefaction, which resulted in enhanced inflammation and fibrosis to augment the cardiac-aging phenotype. Our results provide evidence that macrophage-derived MMP-9 may be a therapeutic target in elderly subjects.NEW & NOTEWORTHY The present study was the first to use mice with transgenic overexpression of matrix metalloproteinase-9 (MMP-9) in macrophages to examine the effects of macrophage-derived MMP-9 on cardiac aging. We found that an elevation in macrophage-derived MMP-9 induced a greater age-dependent cardiac hypertrophy and vessel rarefaction phenotype, which enhanced cardiac inflammation and fibrosis. PMID- 28011587 TI - Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction. AB - Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of MetS (JCR) completely restored and neutrophil depletion significantly improved CCG. We determined whether low endogenous levels of miR-145 in MetS allowed for elevated production of 20-hydroxyeicosatetraenoic acid (20-HETE), which, in turn, resulted in excessive neutrophil accumulation and endothelial dysfunction leading to impaired CCG. Rats underwent 0-9 days of repetitive ischemia (RI). RI-induced cardiac CYP4F (neutrophil-specific 20-HETE synthase) expression and 20-HETE levels were increased (4-fold) in JCR vs. normal rats. miR-145-Adv and 20-HETE antagonists abolished and neutrophil depletion (blocking antibodies) reduced (~60%) RI induced increases in CYP4F expression and 20-HETE production in JCR rats. Impaired CCG in JCR rats (collateral-dependent blood flow using microspheres) was completely restored by 20-HETE antagonists [collateral-dependent zone (CZ)/normal zone (NZ) flow ratio was 0.76 +/- 0.07 in JCR + 20-SOLA, 0.84 +/- 0.05 in JCR + 20-HEDGE vs. 0.11 +/- 0.02 in JCR vs. 0.84 +/- 0.03 in normal rats]. In JCR rats, elevated 20-HETE was associated with excessive expression of endothelial adhesion molecules and neutrophil infiltration, which were reversed by miR-145-Adv. Endothelium-dependent vasodilation of coronary arteries, endothelial nitric oxide synthase (eNOS) Ser1179 phosphorylation, eNOS-dependent NO.- production and endothelial cell survival were compromised in JCR rats. These parameters of endothelial dysfunction were completely reversed by 20-HETE antagonism or miR-145 Adv delivery, whereas neutrophil depletion resulted in partial reversal (~70%). We conclude that low miR-145 in MetS allows for increased 20-HETE, mainly from neutrophils, which compromises endothelial cell survival and function leading to impaired CCG. 20-HETE antagonists could provide viable therapy for restoration of CCG in MetS.NEW & NOTEWORTHY Elevated 20-hydroxyeicosatetraenoic acid (20-HETE) impairs coronary collateral growth (CCG) in metabolic syndrome by eliciting endothelial dysfunction and apoptosis via excessive neutrophil infiltration. 20 HETE antagonists completely restore coronary collateral growth in metabolic syndrome. microRNA-145 (miR-145) is an upstream regulator of 20-HETE production in metabolic syndrome; low expression of miR-145 in metabolic syndrome promotes elevated production of 20-HETE. PMID- 28011589 TI - Maternal-engineered nanomaterial exposure disrupts progeny cardiac function and bioenergetics. AB - Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The present study was designed to determine whether gestational nano-sized titanium dioxide exposure impacts cardiac and metabolic function of developing progeny. Pregnant Sprague-Dawley rats were exposed to nano-aerosols (~10 mg/m3, 130- to 150-nm count median aerodynamic diameter) for 7-8 nonconsecutive days, beginning at gestational day 5-6 Physiological and bioenergetic effects on heart function and cardiomyocytes across three time points, fetal (gestational day 20), neonatal (4-10 days), and young adult (6-12 wk), were evaluated. Functional analysis utilizing echocardiography, speckle tracking based strain, and cardiomyocyte contractility, coupled with mitochondrial energetics, revealed effects of nano-exposure. Maternal exposed progeny demonstrated a decrease in E- and A-wave velocities, with a 15% higher E to-A ratio than controls. Myocytes isolated from exposed animals exhibited ~30% decrease in total contractility, departure velocity, and area of contraction. Bioenergetic analysis revealed a significant increase in proton leak across all ages, accompanied by decreases in metabolic function, including basal respiration, maximal respiration, and spare capacity. Finally, electron transport chain complex I and IV activities were negatively impacted in the exposed group, which may be linked to a metabolic shift. Molecular data suggest that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano exposure significantly impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction.NEW & NOTEWORTHY Cardiac function is evaluated, for the first time, in progeny following maternal nanomaterial inhalation. The findings indicate that exposure to nano-sized titanium dioxide (nano-TiO2) during gestation negatively impacts cardiac function and mitochondrial respiration and bioenergetics. We conclude that maternal nano-TiO2 inhalation contributes to adverse cardiovascular health effects, lasting into adulthood. PMID- 28011590 TI - Cardiac sympathetic innervation via middle cervical and stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy. AB - Cardiac sympathetic denervation (CSD) is reported to reduce the burden of ventricular tachyarrhythmias [ventricular tachycardia (VT)/ventricular fibrillation (VF)] in cardiomyopathy patients, but the mechanisms behind this benefit are unknown. In addition, the relative contribution to cardiac innervation of the middle cervical ganglion (MCG), which may contain cardiac neurons and is not removed during this procedure, is unclear. The purpose of this study was to compare sympathetic innervation of the heart via the MCG vs. stellate ganglia, assess effects of bilateral CSD on cardiac function and VT/VF, and determine changes in cardiac sympathetic innervation after CSD to elucidate mechanisms of benefit in 6 normal and 18 infarcted pigs. Electrophysiological and hemodynamic parameters were evaluated at baseline, during bilateral stellate stimulation, and during bilateral MCG stimulation in 6 normal and 12 infarcted animals. Bilateral CSD (removal of bilateral stellates and T2 ganglia) was then performed and MCG stimulation repeated. In addition, in 18 infarcted animals VT/VF inducibility was assessed before and after CSD. In infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response than stellate ganglion stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in infarcted hearts and prolonged global activation recovery interval. CSD mitigated effects of MCG stimulation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts, without causing hemodynamic compromise. These data demonstrate that the MCG provides significant cardiac sympathetic innervation before CSD and adequate sympathetic innervation after CSD, maintaining hemodynamic stability. Bilateral CSD reduces VT/VF inducibility by improving electrical stability in infarcted hearts in the setting of sympathetic activation.NEW & NOTEWORTHY Sympathetic activation in myocardial infarction leads to arrhythmias and worsens heart failure. Bilateral cardiac sympathetic denervation reduces ventricular tachycardia/ventricular fibrillation inducibility and mitigates effects of sympathetic activation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts. Hemodynamic stability is maintained, as innervation via the middle cervical ganglion is not interrupted. PMID- 28011591 TI - Impact of Fall Prevention on Nurses and Care of Fall Risk Patients. AB - Purpose of the Study: Falls are common events for hospitalized older adults, resulting in negative outcomes both for patients and hospitals. The Center for Medicare and Medicaid (CMS) has placed pressure on hospital administrators by identifying falls as a "never event", resulting in a zero falls goal for many hospitals. Staff nurses are responsible for providing direct care to patients and for meeting the hospital no falls goal. Little is known about the impact of "zero falls" on nurses, patients and the organization. Design and Methods: A qualitative study, using Grounded Dimensional Analysis (GDA) was conducted to explore nurses' experiences with fall prevention in hospital settings and the impact of those experiences on how nurses provide care to fall risk patients. Twenty-seven registered nurses and certified nursing assistants participated in in-depth interviews. Open, axial and selective coding was used to analyze data. A conceptual model which illustrates the impact of intense messaging from nursing administration to prevent patient falls on nurses, actions nurses take to address the message and the consequences to nurses, older adult patients and to the organization was developed. Results: Intense messaging from hospital administration to achieve zero falls resulted in nurses developing a fear of falls, protecting self and unit, and restricting fall risk patients as a way to stop messages and meet the hospital goal. Implications: Results of this study identify unintended consequences of fall prevention message on nurses and older adult patients. Further research is needed understand how nurse care for fall risk patients. PMID- 28011592 TI - Personal health records in the Netherlands: potential user preferences quantified by a discrete choice experiment. AB - Objective: To identify groups of potential users based on their preferences for characteristics of personal health records (PHRs) and to estimate potential PHR uptake. Methods: We performed a discrete choice experiment, which consisted of 12 choice scenarios, each comprising 2 hypothetical PHR alternatives and an opt-out. The alternatives differed based on 5 characteristics. The survey was administered to Internet panel members of the Dutch Federation of Patients and Consumer Organizations. We used latent class models to analyze the data. Results: A total of 1,443 potential PHR users completed the discrete choice experiment. We identified 3 latent classes: "refusers" (class probability 43%), "eager adopters" (37%), and "reluctant adopters" (20%). The predicted uptake for the reluctant adopters ranged from 4% in the case of a PHR with the worst attribute levels to 68% in the best case. Those with 1 or more chronic diseases were significantly more likely to belong to the eager adopter class. The data storage provider was the most decisive aspect for the eager and reluctant adopters, while cost was most decisive for the refusers. Across all classes, health care providers and independent organizations were the most preferred data storage providers. Conclusion: We identified 3 groups, of which 1 group (more than one-third of potential PHR users) indicated great interest in a PHR irrespective of PHR characteristics. Policymakers who aim to expand the use of PHRs will be most successful when health care providers and health facilities or independent organizations store PHR data while refraining from including market parties. PMID- 28011593 TI - An informatics-based approach to reducing heart failure all-cause readmissions: the Stanford heart failure dashboard. AB - Background: Reduction of 30-day all-cause readmissions for heart failure (HF) has become an important quality-of-care metric for health care systems. Many hospitals have implemented quality improvement programs designed to reduce 30-day all-cause readmissions for HF. Electronic medical record (EMR)-based measures have been employed to aid in these efforts, but their use has been largely adjunctive to, rather than integrated with, the overall effort. Objectives: We hypothesized that a comprehensive EMR-based approach utilizing an HF dashboard in addition to an established HF readmission reduction program would further reduce 30-day all-cause index hospital readmission rates for HF. Methods: After establishing a quality improvement program to reduce 30-day HF readmission rates, we instituted EMR-based measures designed to improve cohort identification, intervention tracking, and readmission analysis, the latter 2 supported by an electronic HF dashboard. Our primary outcome measure was the 30-day index hospital readmission rate for HF, with secondary measures including the accuracy of identification of patients with HF and the percentage of patients receiving interventions designed to reduce all-cause readmissions for HF. Results: The HF dashboard facilitated improved penetration of our interventions and reduced readmission rates by allowing the clinical team to easily identify cohorts with high readmission rates and/or low intervention rates. We significantly reduced 30 day index hospital all-cause HF readmission rates from 18.2% at baseline to 14% after implementation of our quality improvement program ( P = .045). Implementation of our EMR-based approach further significantly reduced 30-day index hospital readmission rates for HF to 10.1% ( P for trend = .0001). Daily time to screen patients decreased from 1 hour to 15 minutes, accuracy of cohort identification improved from 83% to 94.6% ( P = .0001), and the percentage of patients receiving our interventions, such as patient education, also improved significantly from 22% to 100% over time ( P < .0001). Conclusions: In an institution with a quality improvement program already in place to reduce 30-day readmission rates for HF, an EMR-based approach further significantly reduced 30 day index hospital readmission rates. PMID- 28011594 TI - Anonymization for outputs of population health and health services research conducted via an online data center. AB - Objective: Online data centers (ODCs) are becoming increasingly popular for making health-related data available for research. Such centers provide good privacy protection during analysis by trusted researchers, but privacy concerns may still remain if the system outputs are not sufficiently anonymized. In this article, we propose a method for anonymizing analysis outputs from ODCs for publication in academic literature. Methods: We use as a model system the Secure Unified Research Environment, an online computing system that allows researchers to access and analyze linked health-related data for approved studies in Australia. This model system suggests realistic assumptions for an ODC that, together with literature and practice reviews, inform our solution design. Results: We propose a two-step approach to anonymizing analysis outputs from an ODC. A data preparation stage requires data custodians to apply some basic treatments to the dataset before making it available. A subsequent output anonymization stage requires researchers to use a checklist at the point of downloading analysis output. The checklist assists researchers with highlighting potential privacy concerns, then applying appropriate anonymization treatments. Conclusion: The checklist can be used more broadly in health care research, not just in ODCs. Ease of online publication as well as encouragement from journals to submit supplementary material are likely to increase both the volume and detail of analysis results publicly available, which in turn will increase the need for approaches such as the one suggested in this paper. PMID- 28011595 TI - Problems with health information technology and their effects on care delivery and patient outcomes: a systematic review. AB - Objective: To systematically review studies reporting problems with information technology (IT) in health care and their effects on care delivery and patient outcomes. Materials and methods: We searched bibliographic databases including Scopus, PubMed, and Science Citation Index Expanded from January 2004 to December 2015 for studies reporting problems with IT and their effects. A framework called the information value chain, which connects technology use to final outcome, was used to assess how IT problems affect user interaction, information receipt, decision-making, care processes, and patient outcomes. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. Results: Of the 34 studies identified, the majority ( n = 14, 41%) were analyses of incidents reported from 6 countries. There were 7 descriptive studies, 9 ethnographic studies, and 4 case reports. The types of IT problems were similar to those described in earlier classifications of safety problems associated with health IT. The frequency, scale, and severity of IT problems were not adequately captured within these studies. Use errors and poor user interfaces interfered with the receipt of information and led to errors of commission when making decisions. Clinical errors involving medications were well characterized. Issues with system functionality, including poor user interfaces and fragmented displays, delayed care delivery. Issues with system access, system configuration, and software updates also delayed care. In 18 studies (53%), IT problems were linked to patient harm and death. Near-miss events were reported in 10 studies (29%). Discussion and conclusion: The research evidence describing problems with health IT remains largely qualitative, and many opportunities remain to systematically study and quantify risks and benefits with regard to patient safety. The information value chain, when used in conjunction with existing classifications for health IT safety problems, can enhance measurement and should facilitate identification of the most significant risks to patient safety. PMID- 28011596 TI - Comparative analysis of stakeholder experiences with an online approach to prioritizing patient-centered research topics. AB - Objective: Little evidence exists about effective and scalable methods for meaningful stakeholder engagement in research. We explored patient/caregiver experiences with a high-tech online engagement approach for patient-centered research prioritization, compared their experiences with those of professional stakeholders, and identified factors associated with favorable participant experiences. Methods: We conducted 8 online modified-Delphi (OMD) panels. Panelists participated in 2 rating rounds with a statistical feedback/online discussion round in between. Panels focused on weight management/obesity, heart failure, and Kawasaki disease. We recruited a convenience sample of adults with any of the 3 conditions (or parents/guardians of Kawasaki disease patients), clinicians, and researchers. Measures included self-reported willingness to use OMD again, the panelists' study participation and online discussion experiences, the system's perceived ease of use, and active engagement metrics. Results: Out of 349 panelists, 292 (84%) completed the study. Of those, 46% were patients, 36% were clinicians, and 19% were researchers. In multivariate models, patients were not significantly more actively engaged (Odds ratio (OR) = 1.69, 95% confidence interval (CI), 0.94-3.05) but had more favorable study participation (beta = 0.49; P <= .05) and online discussion (beta = 0.18; P <= .05) experiences and were more willing to use OMD again (beta = 0.36; P <= .05), compared to professional stakeholders. Positive perceptions of the OMD system's ease of use (beta = 0.16; P <= .05) and favorable study participation (beta = 0.26; P <= .05) and online discussion (beta = 0.57; P <= .05) experiences were also associated with increased willingness to use OMD in the future. Active engagement was not associated with online experience indices or willingness to use OMD again. Conclusion: Online approaches to engaging large numbers of stakeholders are a promising and efficient adjunct to in-person meetings. PMID- 28011597 TI - Exploring the methanogen and bacterial communities of rumen environments: solid adherent, fluid and epimural. AB - The rumen microbiome occupies a central role in animal health and productivity. A better understanding of the rumen ecosystem is essential to increase productivity or decrease methane production. Samples were collected from the three main rumen environments: the solid-adherent fraction, the liquid fraction and the epithelium. For the liquid and solid fraction, two alternative sample processing protocols were compared, resulting in a total of five sample types: crude solids (S), the eluted solid-adherent fraction (Ad), free-living species in the crude rumen liquid (CRL), strained liquid samples (Lq) and epimural scrapings (Ep). The bacterial and methanogen communities of these sample types were analysed using 16S metabarcoding and qPCR. The results indicate that the liquid and solid adherent environments are distinguished mainly by the differential abundance of specific taxonomic groups. Cellulolytic bacteria that pioneer biofilm formation, together with secondary colonisers are prevalent in solid-adherent samples, while dominant species in the fluid samples are primarily identified as consumers of soluble nutrients. Also, methanogen species are found to have a preference for either a solid-adherent or free-living occurrence. The epimural environment is characterised by a different microbial profile. Ten bacterial families and two methanogen genera are almost exclusively found in this environment. PMID- 28011598 TI - Reconstructing metabolic pathways of a member of the genus Pelotomaculum suggesting its potential to oxidize benzene to carbon dioxide with direct reduction of sulfate. AB - The enrichment culture BPL is able to degrade benzene with sulfate as electron acceptor and is dominated by an organism of the genus Pelotomaculum. Members of Pelotomaculum are usually known to be fermenters, undergoing syntrophy with anaerobic respiring microorganisms or methanogens. By using a metagenomic approach, we reconstructed a high-quality genome (~2.97 Mbp, 99% completeness) for Pelotomaculum candidate BPL. The proteogenomic data suggested that (1) anaerobic benzene degradation was activated by a yet unknown mechanism for conversion of benzene to benzoyl-CoA; (2) the central benzoyl-CoA degradation pathway involved reductive dearomatization by a class II benzoyl-CoA reductase followed by hydrolytic ring cleavage and modified beta-oxidation; (3) the oxidative acetyl-CoA pathway was utilized for complete oxidation to CO2. Interestingly, the genome of Pelotomaculum candidate BPL has all the genes for a complete sulfate reduction pathway including a similar electron transfer mechanism for dissimilatory sulfate reduction as in other Gram-positive sulfate reducing bacteria. The proteome analysis revealed that the essential enzymes for sulfate reduction were all formed during growth with benzene. Thus, our data indicated that, besides its potential to anaerobically degrade benzene, Pelotomaculum candidate BPL is the first member of the genus that can perform sulfate reduction. PMID- 28011599 TI - Long-term effects of aided phytostabilisation on microbial communities of metal contaminated mine soil. AB - Aided phytostabilisation uses metal-tolerant plants, together with organic or inorganic amendments, to reduce metal bioavailability in soil while improving soil quality. The long-term effects of the following organic amendments were examined as part of an aided phytostabilisation field study in an abandoned Pb/Zn mining area: cow slurry, sheep manure and paper mill sludge mixed with poultry manure. In the mining area, two heavily contaminated vegetated sites, showing different levels of soil metal contamination (LESS and MORE contaminated site), were selected for this study. Five years after amendment application, metal bioavailability (CaCl2 extractability) along with a variety of indicators of soil microbial activity, biomass and diversity were analysed. Paper mill sludge mixed with poultry manure treatment resulted in the highest reduction of Cd, Pb and Zn bioavailability, as well as in stimulation of soil microbial activity and diversity, especially at the LESS contaminated site. In contrast, cow slurry was the least successful treatment. Our results emphasise the importance of the (i) long-term monitoring of soil quality at sites subjected to aided phytostabilisation and (ii) selection of the most efficient amendments and plants in terms of both reduction of metal bioavailability and improvement of soil quality. PMID- 28011600 TI - Aspect has a greater impact on alpine soil bacterial community structure than elevation. AB - Gradients in environmental conditions, including climate factors and resource availability, occur along mountain inclines, providing a 'natural laboratory' to explore their combined impacts on microbial distributions. Conflicting spatial patterns observed across elevation gradients in soil bacterial community structure suggest that they are driven by various interacting factors at different spatial scales. Here, we investigated the relative impacts of non resource (e.g. soil temperature, pH) and resource conditions (e.g. soil carbon and nitrogen) on the biogeography of soil bacterial communities across broad (i.e. along a 1500 m mountain elevation gradient) and fine sampling scales (i.e. along sunny and shady aspects of a mountain ridge). Our analysis of 16S rRNA gene data confirmed that when sampling across distances of < 1000 m, bacterial community composition was more closely related to the aspect of a site than its elevation. However, despite large differences in climate and resource availability factors across elevation- and aspect-related gradients, bacterial community composition and richness were most strongly correlated with soil pH. These findings highlight the need to incorporate knowledge of multiple factors, including site aspect and soil pH for the appropriate use of elevation gradients as a proxy to explore the impacts of climate change on microbial community composition. PMID- 28011601 TI - CSDB_GT: a new curated database on glycosyltransferases. AB - Glycosyltransferases (GTs) are carbohydrate-active enzymes (CAZy) involved in the synthesis of natural glycan structures. The application of CAZy is highly demanded in biotechnology and pharmaceutics. However, it is being hindered by the lack of high-quality and comprehensive repositories of the research data accumulated so far. In this paper, we describe a new curated Carbohydrate Structure Glycosyltransferase Database (CSDB_GT). Currently, CSDB_GT provides ca. 780 activities exhibited by GTs, as well as several other CAZy, found in Arabidopsis thaliana and described in ca. 180 publications. It covers most published data on A. thaliana GTs with evidenced functions. CSDB_GT is linked to the Carbohydrate Structure Database (CSDB), which stores data on archaeal, bacterial, fungal and plant glycans. The CSDB_GT data are supported by experimental evidences and can be traced to original publications. CSDB_GT is freely available at http://csdb.glycoscience.ru/gt.html. PMID- 28011602 TI - Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients. AB - Background: Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are associated with significant mortality. Daptomycin exhibits concentration dependent activity vs VRE in vitro, yet the clinical impact of higher-dose strategies remains unclear. Methods: We performed a national retrospective cohort study of hospitalized Veterans Affairs patients treated with standard-dose (6 mg/kg total body weight), medium-dose (8 mg/kg total body weight), or high-dose (>=10 mg/kg total body weight) daptomycin for VRE-BSI. Patient-related, microbiological, and outcomes data were abstracted from clinical databases. The primary outcome was overall survival, evaluated by Cox regression. Secondary outcomes included 30-day mortality, time to microbiological clearance, and creatine phosphokinase (CPK) elevation. Results: A total of 911 patients were included (standard dose, n = 709; medium dose, n = 142; high dose, n = 60). Compared to high-dose daptomycin, both standard-dose (hazard ratio [HR], 2.68; 95% confidence interval; [CI], 1.33-3.06; P = .002) and medium-dose (HR, 2.66; 95% CI, 1.33-3.92; P = .003) daptomycin were associated with poorer survival. After adjusting for confounders, the relationship between poorer survival and standard-dose (adjusted HR [aHR], 2.58; 95% CI, 1.27-4.88; P = .004) and medium dose (aHR, 2.52; 95% CI, 1.27-5.00; P = .008) daptomycin persisted. Thirty-day mortality was significantly lower among high-dose daptomycin-treated patients compared with other dosing strategies (risk ratio, 0.83; 95% CI, .74-.94; P = .015). Compared with standard-dose daptomycin, both medium-dose (HR, 0.78; 95% CI, .55-.90; P = .012) and high-dose daptomycin (HR, 0.70; 95% CI, .41-.84; P = .006) were associated with significantly improved microbiological clearance. No difference in the risk of CPK elevation was observed between the treatment groups (P = .504). Conclusions: High-dose daptomycin was associated with improved survival and microbiological clearance in VRE-BSI. PMID- 28011603 TI - Viral Shedding and Transmission Potential of Asymptomatic and Paucisymptomatic Influenza Virus Infections in the Community. AB - Background: Influenza virus infections are associated with a wide spectrum of disease. However, few studies have investigated in detail the epidemiological and virological characteristics of asymptomatic and mild illness with influenza virus infections. Methods: In a community-based study in Hong Kong from 2008 to 2014, we followed up initially healthy individuals who were household contacts of symptomatic persons with laboratory-confirmed influenza, to identify secondary infections. Information from daily symptom diaries was used to classify infections as symptomatic (>=2 signs/symptoms, including fever >=37.8 degrees C, headache, myalgia, cough, sore throat, runny nose and sputum), paucisymptomatic (1 symptom only), or asymptomatic (none of these symptoms). We compared the patterns of influenza viral shedding between these groups. Results: We identified 235 virologically confirmed secondary cases of influenza virus infection in the household setting, including 31 (13%) paucisymptomatic and 25 (11%) asymptomatic cases. The duration of viral RNA shedding was shorter and declined more rapidly in paucisymptomatic and asymptomatic than in symptomatic cases. The mean levels of influenza viral RNA shedding in asymptomatic and paucisymptomatic cases were approximately 1-2 log10 copies lower than in symptomatic cases. Conclusions: The presence of influenza viral shedding in patients with influenza who have very few or no symptoms reflects their potential for transmitting the virus to close contacts. These findings suggest that further research is needed to investigate the contribution of persons with asymptomatic or clinically mild influenza virus infections to influenza virus transmission in household, institutional, and community settings. PMID- 28011604 TI - Elimination of Screening Urine Cultures Prior to Elective Joint Arthroplasty. AB - Discontinuing routine processing of screening urine cultures prior to elective joint arthroplasty resulted in substantial reduction in urine cultures ordered and antimicrobial prescriptions for asymptomatic bacteriuria, without any significant impact on incidence of prosthetic joint infection. This simple change would be scalable across institutions with potential for significant healthcare savings. PMID- 28011605 TI - Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir Combination Treatment in Patients with HIV/HCV Co-Infection: Results of an Italian Compassionate Use Program. AB - Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are at high risk of liver disease progression. We report a favorable safety profile and SVR12 rates of 96.7% among HIV/HCV co-infected patients participating in an Italian compassionate-use program of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) +/- ribavirin (RBV). PMID- 28011606 TI - Penile Immune Activation and Risk of HIV Shedding: A Prospective Cohort Study. AB - Background: Genital immune activation is suspected to modulate local human immunodeficiency virus (HIV) RNA levels and the risk of sexual HIV transmission. Methods: A prospective, observational cohort study of 221 HIV-infected men undergoing male circumcision (MC) was conducted in Rakai, Uganda. Penile lavage samples collected from the coronal sulcus at baseline and 4 weekly visits after MC were assayed for pro-inflammatory cytokines and HIV RNA. The main analysis was limited to 175 men with detectable HIV plasma viral load (VL > 400 copies/mL; n = 808 visits). The primary exposures of interest were individual and total cytokine detection at the previous postoperative visit. Adjusted prevalence risk ratios (adjPRR) of detectable HIV shedding (VL > 40 copies/mL) were estimated by Poisson regression models with generalized estimating equations and robust variance estimators and included adjustment for plasma HIV VL. Findings: Among men with a detectable plasma VL, penile HIV shedding was detected at 136 visits (16.8%). Detectable interleukin (IL)-1beta (adjPRR = 2.14; 95% confidence interval (CI) = 1.02-4.48), IL-6 (adjPRR = 2.24; 95% CI = 1.28-3.90), IL-8 (adjPRR = 2.42; 95% CI = 1.15-5.08), IL-10 (adjPRR = 2.51; 95% CI = 1.67-3.80), and IL-13 (adjPRR = 1.87; 95% CI = 1.15-3.03) were associated with penile HIV shedding at the subsequent visit. Men with 2-4 (adjPRR = 2.36; 95% CI = 1.08-5.14) and 5-7 (adjPRR = 3.00; 95% CI = 1.28-7.01) detectable cytokines had a greater likelihood of detectable penile HIV shedding at the subsequent visit, compared to men with <= 1 detectable cytokine. The total number of detectable cytokines was also associated with a higher penile log10 HIV VL at the subsequent visit among HIV shedders. Interpretation: Pro-inflammatory cytokine production had a dose dependent and temporal association with penile HIV shedding, suggesting that genital immune activation may increase the risk of sexual HIV transmission by driving local HIV replication. PMID- 28011607 TI - Azithromycin 1.5g Over 5 Days Compared to 1g Single Dose in Urethral Mycoplasma genitalium: Impact on Treatment Outcome and Resistance. AB - BACKGROUND: We evaluated the impact of extended azithromycin (1.5g over 5 days) on selection of macrolide resistance and microbiological cure in men with Mycoplasma genitalium urethritis during 2013-2015 and compared this to cases treated with azithromycin 1g in 2012-2013. METHODS: Microbiological cure was determined for men with M. genitalium urethritis treated with azithromycin 1.5g using quantitative polymerase chain reaction specific for M. genitalium DNA on samples 14-100 days post-treatment. Pre- and post-treatment macrolide resistance mutations were detected by sequencing the 23 S gene. RESULTS: There was no difference in proportions with microbiological cure between azithromycin 1.5g and 1g: 62/106 (58%; 95% confidence interval [CI], 49%, 68%) and 56/107 (52%; 95%CI 42-62%), P = .34, respectively. Also, there was no difference in the proportion of wild-type 23 S rRNA (presumed macrolide sensitive) infections cured after 1.5g and azithromycin 1g: 28/34 (82%; 95%CI 65-92%) and 49/60 (82%; 95%CI 70-90%), P=1.0, respectively. There was no difference between 1.5g and 1g in the proportions of wild-type infections with post-treatment resistance mutations: 4/34 (12%; 95%CI 3-27%) and 11/60 (18%; 95%CI 10-30%), respectively, P = .40. Pre treatment resistance was present in 51/98 (52%; 95%CI 42-62%) cases in 2013-2015 compared to 47/107 (44%; 95%CI 34-54%) in 2012-2013, P = .25. CONCLUSIONS: Extended azithromycin 1.5g was no more effective than a single 1g dose at achieving cure of M. genitalium urethritis and importantly did not reduce the selection of macrolide resistance. Nonmacrolide and new approaches for the treatment of M. genitalium urethritis are required. PMID- 28011608 TI - Mycobacterial Characteristics and Treatment Outcomes in Mycobacterium abscessus Lung Disease. AB - BACKGROUND: Treatment outcomes of patients with Mycobacterium abscessus subspecies abscessus lung disease are poor, and the microbial characteristics associated with treatment outcomes have not been studied systematically. The purpose of this study was to identify associations between microbial characteristics and treatment outcomes in patients with M. abscessus lung disease. METHODS: Sixty-seven consecutive patients with M. abscessus lung disease undergoing antibiotic treatment for >=12 months between January 2002 and December 2012 were included. Morphotypic and genetic analyses were performed on isolates from 44 patients. RESULTS: Final sputum conversion to culture negative occurred in 34 (51%) patients. Compared to isolates from 24 patients with persistently positive cultures, pretreatment isolates from 20 patients with final negative conversion were more likely to exhibit smooth colonies (9/20, 45% vs 2/24, 8%; P = .020), susceptibility to clarithromycin (7/20, 35% vs 1/24, 4%; P = .015), and be of the C28 sequevar with regard to the erm(41) gene (6/20, 30% vs 1/24, 4%; P = .035). Mycobacterium abscessus lung disease recurred in 5 (15%) patients after successful completion of antibiotic therapy. Genotypic analysis revealed that most episodes (22/24, 92%) of persistently positive cultures during antibiotic treatment and all cases of microbiologic recurrence after treatment completion were caused by different M. abscessus genotypes within a patient. CONCLUSIONS: Precise identification to the subspecies level and analysis of mycobacterial characteristics could help predict treatment outcomes in patients with M. abscessus lung disease. Treatment failures and recurrences are frequently associated with multiple genotypes, suggesting reinfection. CLINICAL TRIALS REGISTRATION: NCT00970801. PMID- 28011609 TI - Progression and Treatment Outcomes of Lung Disease Caused by Mycobacterium abscessus and Mycobacterium massiliense. AB - BACKGROUND: Mycobacterium abscessus and Mycobacterium massiliense are grouped as the Mycobacterium abscessus complex. The aim of this study was to elucidate the differences between M. abscessus and M. massiliense lung diseases in terms of progression rate, treatment outcome, and the predictors thereof. METHODS: Between 1 January 2006 and 30 June 2015, 56 patients and 54 patients were diagnosed with M. abscessus and M. massiliense lung diseases, respectively. The time to progression requiring treatment and treatment outcomes were compared between the 2 groups of patients, and predictors of progression and sustained culture conversion with treatment were analyzed. In addition, mediation analysis was performed to evaluate the effect of susceptibility to clarithromycin on treatment outcomes. RESULTS: During follow-up, 21 of 56 patients with M. abscessus lung diseases and 21 of 54 patients with M. massiliense lung diseases progressed, requiring treatment. No difference was detected in the time to progression between the 2 patient groups. Lower body mass index, bilateral lung involvement, and fibrocavitary-type disease were identified as predictors of disease progression. Among the patients who began treatment, infection with M. massiliense rather than M. abscessus and the use of azithromycin rather than clarithromycin were associated with sustained culture conversion. The difference in treatment outcomes was partly mediated by the organism's susceptibility to clarithromycin. CONCLUSIONS: Progression rates were similar but treatment outcomes differed significantly between patients with lung disease caused by M. abscessus and M. massiliense. This difference in treatment outcomes was partly explained by the susceptibility of these organisms to clarithromycin. PMID- 28011610 TI - Characteristics and Outcomes of Pediatric Patients With Ebola Virus Disease Admitted to Treatment Units in Liberia and Sierra Leone: A Retrospective Cohort Study. AB - BACKGROUND: The clinical and virologic characteristics of Ebola virus disease (EVD) in children have not been thoroughly documented. METHODS: Consecutive children aged <18 years with real-time polymerase chain reaction (RT-PCR) confirmed EVD were enrolled retrospectively in 5 Ebola treatment units in Liberia and Sierra Leone in 2014/2015. Data collection and medical management were based on standardized International Medical Corps protocols. We performed descriptive statistics, multivariate logistic regression, and Kaplan-Meier survival analyses. RESULTS: Of 122 children enrolled, the median age was 7 years and one-third were aged <5 years. The female-to-male ratio was 1.3. The most common clinical features at triage and during hospitalization were fever, weakness, anorexia, and diarrhea, although 21% of patients were initially afebrile and 6 patients remained afebrile. Bleeding was rare at presentation (5%) and manifested subsequently in fewer than 50%. The overall case fatality rate was 57%. Factors associated with death in bivariate analyses were age <5 years, bleeding at any time during hospitalization, and high viral load. After adjustment with logistic regression modeling, the odds of death were 14.8-fold higher if patients were aged <5 years, 5-fold higher if the patient had any evidence of bleeding, and 5.2 fold higher if EVD RT-PCR cycle threshold value was <=20. Plasmodium parasitemia had no impact on EVD outcomes. CONCLUSIONS: Age <5 years, bleeding, and high viral loads were poor prognostic indicators of children with EVD. Research to understand mechanisms of these risk factors and the impact of dehydration and electrolyte imbalance will improve health outcomes. PMID- 28011611 TI - Fecal Fixation: Fecal Microbiota Transplantation for Clostridium difficile Infection. PMID- 28011612 TI - Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial. AB - BACKGROUND: Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. METHODS: In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. RESULTS: The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. CONCLUSIONS: In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. CLINICAL TRIALS REGISTRATION: NCT01226992. PMID- 28011613 TI - Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non HIV Previously Healthy Adults. AB - BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics. PMID- 28011614 TI - Dosing guidance for intravenous colistin in critically-ill patients. AB - Background: Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2mg/L. Methods: Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/min; 29 receiving renal replacement therapy (RRT)) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based upon the relationship between the dose of colistimethate that would be needed to achieve a desired Css,avg and creatinine clearance. The increase in colistin clearance when patients were on RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg >=2 and <30% for Css,avg >=4mg/L. Results: When algorithm doses were applied back to individual patients not on RRT (including patients prescribed intermittent dialysis on a non-dialysis day), >80% of patients with creatinine clearance <80mL/min achieved Css,avg >=2mg/L; but for patients with creatinine clearance >=80mL/min target attainment was <40%, even with the maximum allowed daily dose of 360mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg >=4mg/L. Conclusions: The project has generated clinician-friendly dosing algorithms and pointed to circumstances where intravenous monotherapy may be inadequate. PMID- 28011615 TI - Impact and Cost-effectiveness of Selective Human Papillomavirus Vaccination of Men Who Have Sex With Men. AB - Background: Men who have sex with men (MSM) have a high lifetime risk of anogenital warts and cancers related to infection with human papillomavirus (HPV). They also benefit less from herd protection than heterosexual males in settings with female-only HPV vaccination. Methods: We evaluated the potential health impact and cost-effectiveness of offering vaccination to MSM who visit genitourinary medicine (GUM) clinics. We used a mathematical model of HPV 6/11/16/18 sexual transmission within an MSM population in England, parameterized with sexual behaviour, GUM attendance, HPV prevalence, HIV prevalence, warts, and cancer incidence data. Interventions considered were offering HPV vaccination to either HIV-positive MSM or MSM regardless of HIV status, for age bands 16-25, 16 30, 16-35, and 16-40 years. Results: Substantial declines in anogenital warts and male HPV-related cancer incidence are projected to occur following an offer of vaccination to MSM. MSM not attending GUM clinics will partially benefit from herd protection. Offering vaccination to HIV-positive MSM up to age 40 is likely to be cost-effective if vaccine procurement and administration costs are below L96.50 a dose. At L48 a dose, offering vaccination to all MSM up to age 40 is likely to be cost-effective. Conclusions: Quadrivalent HPV vaccination of MSM via GUM clinics is likely to be an effective and cost-effective way of reducing the burden of HPV-related disease in MSM. PMID- 28011616 TI - Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells. AB - Airway mucus hypersecretion contributes to the morbidity and mortality in patients with chronic inflammatory lung diseases. Reducing mucus production is crucial for improving patients' quality of life. The transcription factor SAM pointed domain-containing Ets-like factor (SPDEF) plays a critical role in the regulation of mucus production and, therefore, represents a potential therapeutic target. This study aims to reduce lung epithelial mucus production by targeted silencing SPDEF using the novel strategy, epigenetic editing. Zinc fingers and CRISPR/dCas platforms were engineered to target repressors (KRAB, DNA methyltransferases, histone methyltransferases) to the SPDEF promoter. All constructs were able to effectively suppress both SPDEF mRNA and protein expression, which was accompanied by inhibition of downstream mucus-related genes [anterior gradient 2 (AGR2), mucin 5AC (MUC5AC)]. For the histone methyltransferase G9A, and not its mutant or other effectors, the obtained silencing was mitotically stable. These results indicate efficient SPDEF silencing and downregulation of mucus-related gene expression by epigenetic editing, in human lung epithelial cells. This opens avenues for epigenetic editing as a novel therapeutic strategy to induce long-lasting mucus inhibition. PMID- 28011617 TI - A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models. AB - Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), a progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one of the major glycosaminoglycans produced in the small airway, decreased in lungs of cigarette smoke-exposed mice. To confirm the protective effect of KS in the small airway, a disaccharide repeating unit of KS designated L4 ([SO3--6]Galbeta1-4[SO3- 6]GlcNAc) was administered to two murine models: elastase-induced-emphysema and LPS-induced exacerbation of a cigarette smoke-induced emphysema. Histological and microcomputed tomography analyses revealed that, in the mouse elastase-induced emphysema model, administration of L4 attenuated alveolar destruction. Treatment with L4 significantly reduced neutrophil influx, as well as the levels of inflammatory cytokines, tissue-degrading enzymes (matrix metalloproteinases), and myeloperoxidase in bronchoalveolar lavage fluid, suggesting that L4 suppressed inflammation in the lung. L4 consistently blocked the chemotactic migration of neutrophils in vitro. Moreover, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone. Taken together, L4 represents one of the potential glycan-based drugs for the treatment of COPD through its inhibitory action against inflammation. PMID- 28011618 TI - Novel applications for a noninvasive sampling method of the nasal mucosa. AB - Reliable methods for sampling the nasal mucosa provide clinical researchers with key information regarding respiratory biomarkers of exposure and disease. For quick and noninvasive sampling of the nasal mucosa, nasal lavage (NL) collection has been widely used as a clinical tool; however, limitations including volume variability, sample dilution, and storage prevent NL collection from being used in nonlaboratory settings and analysis of low abundance biomarkers. In this study, we optimize and validate a novel methodology using absorbent Leukosorb paper cut to fit the nasal passage to extract epithelial lining fluid (ELF) from the nasal mucosa. The ELF sampling method limits the dilution of soluble mediators, allowing quantification of both high- and low-abundance soluble biomarkers such as IL-1beta, IL-8, IL-6, interferon gamma-induced protein 10 (IP 10), and neutrophil elastase. Additionally, we demonstrate that this method can successfully detect the presence of respiratory pathogens such as influenza virus and markers of antibiotic-resistant bacteria in the nasal mucosa. Efficacy of ELF collection by this method is not diminished in consecutive-day sampling, and percent recovery of both recombinant IL-8 and soluble mediators are not changed despite freezing or room temperature storage for 24 h. Our results indicate that ELF collection using Leukosorb paper sampling of ELF provides a sensitive, easy to-use, and reproducible methodology to collect concentrated amounts of soluble biomarkers from the nasal mucosa. Moreover, the methodology described herein improves upon the standard NL collection method and provides researchers with a novel tool to assess changes in nasal mucosal host defense status. PMID- 28011619 TI - The Natural Diterpenoid Isoforretin A Inhibits Thioredoxin-1 and Triggers Potent ROS-Mediated Antitumor Effects. AB - Aberrant expression of thioredoxin 1 (Trx1) plays an important role in cancer initiation and progression and has gained attention as an anticancer drug target. Here we report that the recently discovered natural diterpenoid isoforretin A (IsoA) significantly inhibits Trx1 activity and mediates anticancer effects in multiple preclinical settings. The inhibitory effect of IsoA was antagonized by free radical scavengers polyethylene glycol-catalase, polyethylene glycol superoxide dismutase, thiol-based antioxidants N-acetylcysteine and glutathione. Mass spectrometry analysis revealed that the mechanism of action was based on direct conjugation of IsoA to the Cys32/Cys35 residues of Trx1. This conjugation event attenuated reversible thiol reduction of Trx1, leading to ROS accumulation and a broader degradation of thiol redox homeostasis in cancer cells. Extending these in vitro findings, we documented that IsoA administration inhibited the growth of HepG2 tumors in a murine xenograft model of hepatocellular carcinoma. Taken together, our findings highlight IsoA as a potent bioactive inhibitor of Trx1 and a candidate anticancer natural product. Cancer Res; 77(4); 926-36. (c)2016 AACR. PMID- 28011620 TI - Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells. AB - Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996-1007. (c)2016 AACR. PMID- 28011621 TI - A Novel Mouse Model to Study Image-Guided, Radiation-Induced Intestinal Injury and Preclinical Screening of Radioprotectors. AB - Radiation is an important treatment modality for gastrointestinal tumors, but intestinal injury is a common side effect. Here we describe a physiologically relevant model for studying the molecular determinants of radiation-induced intestinal damage and testing novel radioprotectors. The model employs a radiopaque marker implanted into the surface of the mouse jejunum, serving as a fiducial marker for precise radiation targeting. Mice were imaged with Cone-Beam CT (CBCT) and irradiated (IR) to the marked area using the Small Animal Radiation Research Platform (SARRP). IR-induced damage was acute but reversible and largely restricted to the area of the marker, leaving the surrounding tissues intact. Although whole gut irradiation with these doses caused lethal GI syndrome, focal (5 mm) radiation of the intestine did not cause any weight loss or lethality. However, fibrosis and collagen deposition 4 months post-IR indicated chronic intestinal damage. A separate cohort of mice was treated daily with curcumin, a clinically tested radioprotector, prior to and post-IR. Curcumin-treated mice showed significant decreases in both local and systemic inflammatory cytokine levels and in fibrosis, suggesting it is an effective radioprotector of the intestine. Our results indicate that this model, which emulates clinically relevant intestinal radiation-induced injury, can be used to assess radioprotectors prior to testing in the clinic. Cancer Res; 77(4); 908-17. (c)2016 AACR. PMID- 28011622 TI - MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2. AB - Serum levels of miR-194 have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion, and epithelial-mesenchymal transition in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts. Conversely, inhibition of miR 194 activity suppressed the invasive capacity of prostate cancer cell lines in vitro and in vivo Mechanistic investigations identified the ubiquitin ligase suppressor of cytokine signaling 2 (SOCS2) as a direct, biologically relevant target of miR-194 in prostate cancer. Low levels of SOCS2 correlated strongly with disease recurrence and metastasis in clinical specimens. SOCS2 downregulation recapitulated miR-194-driven metastatic phenotypes, whereas overexpression of a nontargetable SOCS2 reduced miR-194-stimulated invasion. Targeting of SOCS2 by miR-194 resulted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signaling. Pharmacologic inhibition of ERK and JAK/STAT pathways reversed miR-194-driven phenotypes. The GATA2 transcription factor was identified as an upstream regulator of miR-194, consistent with a strong concordance between GATA2 and miR-194 levels in clinical specimens. Overall, these results offer new insights into the molecular mechanisms of metastatic progression in prostate cancer. Cancer Res; 77(4); 1021 34. (c)2016 AACR. PMID- 28011623 TI - Sunitinib Treatment Enhances Metastasis of Innately Drug-Resistant Breast Tumors. AB - Antiangiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date, there has not been an inquiry into the roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the antiangiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs, and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. Cancer Res; 77(4); 1008-20. (c)2016 AACR. PMID- 28011624 TI - Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women. AB - Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918-25. (c)2017 AACR. PMID- 28011625 TI - Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop. AB - Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/STAT3 pathway activated by IL6 and other proinflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and upregulation of its downstream target cyclophilin B (CypB) regulate the growth and survival of gastric cancer cells. In clinical specimens of gastric cancer, we documented increased expression of CypB and activation of STAT3. Mechanistic investigations identified miR-520d-5p as a regulator of CypB mRNA levels. This signaling axis regulated gastric cancer growth by modulating phosphorylation of STAT3. Furthermore, miR-520d-5p was identified as a direct STAT3 target and IL6-mediated inhibition of miR-520d-5p relied upon STAT3 activity. Our findings define a positive feedback loop that drives gastric carcinogenesis as influenced by H. pylori infections that involve proinflammatory IL6 stimulation. Cancer Res; 77(5); 1227-40. (c)2016 AACR. PMID- 28011626 TI - Meningeal retinoic acid contributes to neocortical lamination and radial migration during mouse brain development. AB - Retinoic acid (RA) is a diffusible molecule involved in early forebrain patterning. Its later production in the meninges by the retinaldehyde dehydrogenase RALDH2 coincides with the time of cortical neuron generation. A function of RA in this process has not been adressed directly as Raldh2-/- mouse mutants are embryonic lethal. Here, we used a conditional genetic strategy to inactivate Raldh2 just prior to onset of its expression in the developing meninges. This inactivation does not affect the formation of the cortical progenitor populations, their rate of division, or timing of differentiation. However, migration of late-born cortical neurons is delayed, with neurons stalling in the intermediate zone and exhibiting an abnormal multipolar morphology. This suggests that RA controls the multipolar-to-bipolar transition that occurs in the intermediate zone and allows neurons to start locomotion in the cortical plate. Our work also shows a role for RA in cortical lamination, as deep layers are expanded and a subset of layer IV neurons are not formed in the Raldh2-ablated mutants. These data demonstrate that meninges are a source of extrinsic signals important for cortical development. PMID- 28011627 TI - Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. AB - Familial forms of Parkinson's disease (PD) caused by mutations in PINK1 are linked to mitochondrial impairment. Defective mitochondria are also found in Drosophila models of PD with pink1 mutations. The co-enzyme nicotinamide adenine dinucleotide (NAD+) is essential for both generating energy in mitochondria and nuclear DNA repair through NAD+-consuming poly(ADP-ribose) polymerases (PARPs). We found alterations in NAD+ salvage metabolism in Drosophila pink1 mutants and showed that a diet supplemented with the NAD+ precursor nicotinamide rescued mitochondrial defects and protected neurons from degeneration. Additionally, a mutation of Parp improved mitochondrial function and was neuroprotective in the pink1 mutants. We conclude that enhancing the availability of NAD+ by either the use of a diet supplemented with NAD+ precursors or the inhibition of NAD+ dependent enzymes, such as PARPs, which compete with mitochondria for NAD+, is a viable approach to preventing neurotoxicity associated with mitochondrial defects. PMID- 28011628 TI - A genetically encoded biosensor for visualising hypoxia responses in vivo. AB - Cells experience different oxygen concentrations depending on location, organismal developmental stage, and physiological or pathological conditions. Responses to reduced oxygen levels (hypoxia) rely on the conserved hypoxia inducible factor 1 (HIF-1). Understanding the developmental and tissue-specific responses to changing oxygen levels has been limited by the lack of adequate tools for monitoring HIF-1 in vivo. To visualise and analyse HIF-1 dynamics in Drosophila, we used a hypoxia biosensor consisting of GFP fused to the oxygen dependent degradation domain (ODD) of the HIF-1 homologue Sima. GFP-ODD responds to changing oxygen levels and to genetic manipulations of the hypoxia pathway, reflecting oxygen-dependent regulation of HIF-1 at the single-cell level. Ratiometric imaging of GFP-ODD and a red-fluorescent reference protein reveals tissue-specific differences in the cellular hypoxic status at ambient normoxia. Strikingly, cells in the larval brain show distinct hypoxic states that correlate with the distribution and relative densities of respiratory tubes. We present a set of genetic and image analysis tools that enable new approaches to map hypoxic microenvironments, to probe effects of perturbations on hypoxic signalling, and to identify new regulators of the hypoxia response. PMID- 28011629 TI - A feedback mechanism between PLD and deadenylase PARN for the shortening of eukaryotic poly(A) mRNA tails that is deregulated in cancer cells. AB - The removal of mRNA transcript poly(A) tails by 3'->5' exonucleases is the rate limiting step in mRNA decay in eukaryotes. Known cellular deadenylases are the CCR4-NOT and PAN complexes, and poly(A)-specific ribonuclease (PARN). The physiological roles and regulation for PARN is beginning to be elucidated. Since phospholipase D (PLD2 isoform) gene expression is upregulated in breast cancer cells and PARN is downregulated, we examined whether a signaling connection existed between these two enzymes. Silencing PARN with siRNA led to an increase in PLD2 protein, whereas overexpression of PARN had the opposite effect. Overexpression of PLD2, however, led to an increase in PARN expression. Thus, PARN downregulates PLD2 whereas PLD2 upregulates PARN. Co-expression of both PARN and PLD2 mimicked this pattern in non-cancerous cells (COS-7 fibroblasts) but, surprisingly, not in breast cancer MCF-7 cells, where PARN switches from inhibition to activation of PLD2 gene and protein expression. Between 30 and 300 nM phosphatidic acid (PA), the product of PLD enzymatic reaction, added exogenously to culture cells had a stabilizing role of both PARN and PLD2 mRNA decay. Lastly, by immunofluorescence microscopy, we observed an intracellular co localization of PA-loaded vesicles (0.1-1 nm) and PARN. In summary, we report for the first time the involvement of a phospholipase (PLD2) and PA in mediating PARN induced eukaryotic mRNA decay and the crosstalk between the two enzymes that is deregulated in breast cancer cells. PMID- 28011630 TI - A polycystin-type transient receptor potential (Trp) channel that is activated by ATP. AB - ATP and ADP are ancient extra-cellular signalling molecules that in Dictyostelium amoebae cause rapid, transient increases in cytosolic calcium due to an influx through the plasma membrane. This response is independent of hetero-trimeric G proteins, the putative IP3 receptor IplA and all P2X channels. We show, unexpectedly, that it is abolished in mutants of the polycystin-type transient receptor potential channel, TrpP. Responses to the chemoattractants cyclic-AMP and folic acid are unaffected in TrpP mutants. We report that the DIF morphogens, cyclic-di-GMP, GABA, glutamate and adenosine all induce strong cytoplasmic calcium responses, likewise independently of TrpP. Thus, TrpP is dedicated to purinergic signalling. ATP treatment causes cell blebbing within seconds but this does not require TrpP, implicating a separate purinergic receptor. We could detect no effect of ATP on chemotaxis and TrpP mutants grow, chemotax and develop almost normally in standard conditions. No gating ligand is known for the human homologue of TrpP, polycystin-2, which causes polycystic kidney disease. Our results now show that TrpP mediates purinergic signalling in Dictyostelium and is directly or indirectly gated by ATP. PMID- 28011631 TI - Lipid droplet dynamics during Schizosaccharomyces pombe sporulation and their role in spore survival. AB - Upon nitrogen starvation, the fission yeast Schizosaccharomyces pombe forms dormant spores; however, the mechanisms by which a spore sustains life without access to exogenous nutrients remain unclear. Lipid droplets are reservoirs of neutral lipids that act as important cellular energy resources. Using live-cell imaging analysis, we found that the lipid droplets of mother cells redistribute to their nascent spores. Notably, this process was actin polymerization-dependent and facilitated by the leading edge proteins of the forespore membrane. Spores lacking triacylglycerol synthesis, which is essential for lipid droplet formation, failed to germinate. Our results suggest that the lipid droplets are important for the sustenance of life in spores. PMID- 28011632 TI - A developmental transcriptomic analysis of Pax1 and Pax9 in embryonic intervertebral disc development. AB - Pax1 and Pax9 play redundant, synergistic functions in the patterning and differentiation of the sclerotomal cells that give rise to the vertebral bodies and intervertebral discs (IVD) of the axial skeleton. They are conserved in mice and humans, whereby mutation/deficiency of human PAX1/PAX9 has been associated with kyphoscoliosis. By combining cell-type-specific transcriptome and ChIP sequencing data, we identified the roles of Pax1/Pax9 in cell proliferation, cartilage development and collagen fibrillogenesis, which are vital in early IVD morphogenesis. Pax1 is up-regulated in the absence of Pax9, while Pax9 is unaffected by the loss of Pax1/Pax9 We identified the targets compensated by a single- or double-copy of Pax9 They positively regulate many of the cartilage genes known to be regulated by Sox5/Sox6/Sox9 and are connected to Sox5/Sox6 by a negative feedback loop. Pax1/Pax9 are intertwined with BMP and TGF-B pathways and we propose they initiate expression of chondrogenic genes during early IVD differentiation and subsequently become restricted to the outer annulus by the negative feedback mechanism. Our findings highlight how early IVD development is regulated spatio-temporally and have implications for understanding kyphoscoliosis. PMID- 28011633 TI - The Pentatricopeptide Repeat Protein EMB2654 Is Essential for Trans-Splicing of a Chloroplast Small Ribosomal Subunit Transcript. AB - We report the partial complementation and subsequent comparative molecular analysis of two nonviable mutants impaired in chloroplast translation, one (emb2394) lacking the RPL6 protein, and the other (emb2654) carrying a mutation in a gene encoding a P-class pentatricopeptide repeat protein. We show that EMB2654 is required for the trans-splicing of the plastid rps12 transcript and that therefore the emb2654 mutant lacks Rps12 protein and fails to assemble the small subunit of the plastid ribosome, explaining the loss of plastid translation and consequent embryo-lethal phenotype. Predictions of the EMB2654 binding site match a small RNA "footprint" located on the 5' half of the trans-spliced intron that is almost absent in the partially complemented mutant. EMB2654 binds sequence specifically to this target sequence in vitro. Altered patterns in nuclease-protected small RNA fragments in emb2654 show that EMB2654 binding must be an early step in, or prior to, the formation of a large protein-RNA complex covering the free ends of the two rps12 intron halves. PMID- 28011634 TI - Structure of the Branched-chain Amino Acid and GTP-sensing Global Regulator, CodY, from Bacillus subtilis. AB - CodY is a branched-chain amino acid (BCAA) and GTP sensor and a global regulator of transcription in low G + C Gram-positive bacteria. It controls the expression of over 100 genes and operons, principally by repressing during growth genes whose products are required for adaptations to nutrient limitation. However, the mechanism by which BCAA binding regulates transcriptional changes is not clear. It is known that CodY consists of a GAF (cGMP-stimulated phosphodiesterases, adenylate cyclases, FhlA) domain that binds BCAAs and a winged helix-turn-helix (wHTH) domain that binds to DNA, but the way in which these domains interact and the structural basis of the BCAA dependence of this interaction are unknown. To gain new insights, we determined the crystal structure of unliganded CodY from Bacillus subtilis revealing a 10-turn alpha-helix linking otherwise discrete GAF and wHTH domains. The structure of CodY in complex with isoleucine revealed a reorganized GAF domain. In both complexes CodY was tetrameric. Size exclusion chromatography with multiangle laser light scattering (SEC-MALLS) experiments showed that CodY is a dimer at concentrations found in bacterial cells. Comparison of structures of dimers of unliganded CodY and CodY-Ile derived from the tetramers showed a splaying of the wHTH domains when Ile was bound; splaying is likely to account for the increased affinity of Ile-bound CodY for DNA. Electrophoretic mobility shift and SEC-MALLS analyses of CodY binding to 19-36-bp operator fragments are consistent with isoleucine-dependent binding of two CodY dimers per duplex. The implications of these observations for effector control of CodY activity are discussed. PMID- 28011635 TI - Hemoglobin Kirklareli (alpha H58L), a New Variant Associated with Iron Deficiency and Increased CO Binding. AB - Mutations in hemoglobin can cause a wide range of phenotypic outcomes, including anemia due to protein instability and red cell lysis. Uncovering the biochemical basis for these phenotypes can provide new insights into hemoglobin structure and function as well as identify new therapeutic opportunities. We report here a new hemoglobin alpha chain variant in a female patient with mild anemia, whose father also carries the trait and is from the Turkish city of Kirklareli. Both the patient and her father had a His-58(E7) -> Leu mutation in alpha1. Surprisingly, the patient's father is not anemic, but he is a smoker with high levels of HbCO (~16%). To understand these phenotypes, we examined recombinant human Hb (rHb) Kirklareli containing the alpha H58L replacement. Mutant alpha subunits containing Leu-58(E7) autoxidize ~8 times and lose hemin ~200 times more rapidly than native alpha subunits, causing the oxygenated form of rHb Kirklareli to denature very rapidly under physiological conditions. The crystal structure of rHb Kirklareli shows that the alpha H58L replacement creates a completely apolar active site, which prevents electrostatic stabilization of bound O2, promotes autoxidation, and enhances hemin dissociation by inhibiting water coordination to the Fe(III) atom. At the same time, the mutant alpha subunit has an ~80,000-fold higher affinity for CO than O2, causing it to rapidly take up and retain carbon monoxide, which prevents denaturation both in vitro and in vivo and explains the phenotypic differences between the father, who is a smoker, and his daughter. PMID- 28011636 TI - Chemical-controlled Activation of Antiviral Myxovirus Resistance Protein 1. AB - The antiviral myxovirus resistance protein 1 (MX1) is an interferon-induced GTPase that plays an important role in the defense of mammalian cells against influenza A viruses. Mouse MX1 interacts with the influenza ribonucleoprotein complexes (vRNPs) and can prevent the interaction between polymerase basic 2 (PB2) and the nucleoprotein (NP) of influenza A viruses. However, it is unclear whether mouse MX1 disrupts the PB2-NP interaction in the context of pre-existing vRNPs or prevents the assembly of new vRNP components. Here, we describe a conditionally active mouse MX1 variant that only exerts antiviral activity in the presence of a small molecule drug. Once activated, this MX1 construct phenocopies the antiviral and NP binding activity of wild type MX1. The interaction between PB2 and NP is disrupted within minutes after the addition of the small molecule activator. These findings support a model in which mouse MX1 interacts with the incoming influenza A vRNPs and inhibits their activity by disrupting the PB2-NP interaction. PMID- 28011637 TI - Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-beta induced Neuronal Death. AB - Amyloid-beta (Abeta)-induced neuron death is considered central to the pathogenesis of Alzheimer's disease (AD). Among several death modalities, autophagy and apoptosis play important roles in Abeta-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon Abeta treatment, tribbles pseudokinase 3 (Trib3, an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it. As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro-apoptotic gene BCL2-like 11 (Bim). Conversely, FoxO1 responded to Abeta insult by binding to the Trib3 gene promoter, enhancing its expression. Our investigations further revealed that Trib3 also induces autophagy. We found that Trib3 indirectly activates unc-51-like autophagy activating kinase1 (Ulk1) by impeding phosphorylation of, and thus inactivating, a negative regulator of Ulk1, mechanistic target of rapamycin. Ulk1 activation augmented autophagosome formation and reduced autophagy flux. Thus, Trib3 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous Trib3 strongly protected neurons from Abeta insult. Our results suggest that a self amplifying feed-forward loop among Trib3, Akt, and FoxO1 in Abeta-treated neurons induces both apoptosis and autophagy, culminating in neuron death. Thus, Trib3 may serve as a potential therapeutic target for AD. PMID- 28011638 TI - A Critical Role for Ubiquitination in the Endocytosis of Glutamate Receptors. AB - Group I metabotropic glutamate receptors (mGluRs) play important roles in various neuronal processes and elicit changes in synaptic efficacy through AMPA receptor (AMPAR) endocytosis. Trafficking of mGluRs plays an important role in controlling the precise localization of these receptors at specific region of the cell; it also regulates the activity of these receptors. Despite this obvious significance, we know very little about the cellular mechanisms that control the trafficking of group I mGluRs. We show here that ligand-mediated internalization of group I mGluRs is ubiquitination-dependent. A lysine residue (Lys1112) at the C-terminal tail of mGluR1 (a member of the group I mGluR family) plays crucial role in this process. Our data suggest that Lys63-linked polyubiquitination is involved in the ligand-mediated endocytosis of mGluR1. We also show here that the mGluR1 internalization is dependent on a specific E3 ubiquitin ligase, Siah-1A. Furthermore, acute knockdown of Siah-1A enhances the mGluR-mediated AMPAR endocytosis. These studies reveal a novel function of ubiquitination in the regulation of group I mGluRs, as well as its role in mGluR-dependent AMPAR endocytosis. PMID- 28011639 TI - Loss of Functionally Redundant p38 Isoforms in T Cells Enhances Regulatory T Cell Induction. AB - The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38alpha, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38beta. Mice with T cells simultaneously lacking p38alpha and p38beta displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38alpha and p38beta in naive CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications. PMID- 28011640 TI - Regulation of ULK1 Expression and Autophagy by STAT1. AB - Autophagy involves the lysosomal degradation of cytoplasmic contents for regeneration of anabolic substrates during nutritional or inflammatory stress. Its initiation occurs rapidly after inactivation of the protein kinase mammalian target of rapamycin (mTOR) (or mechanistic target of rapamycin), leading to dephosphorylation of Unc-51-like kinase 1 (ULK1) and autophagosome formation. Recent studies indicate that mTOR can, in parallel, regulate the activity of stress transcription factors, including signal transducer and activator of transcription-1 (STAT1). The current study addresses the role of STAT1 as a transcriptional suppressor of autophagy genes and autophagic activity. We show that STAT1-deficient human fibrosarcoma cells exhibited enhanced autophagic flux as well as its induction by pharmacological inhibition of mTOR. Consistent with enhanced autophagy initiation, ULK1 mRNA and protein levels were increased in STAT1-deficient cells. By chromatin immunoprecipitation, STAT1 bound a putative regulatory sequence in the ULK1 5'-flanking region, the mutation of which increased ULK1 promoter activity, and rendered it unresponsive to mTOR inhibition. Consistent with an anti-apoptotic effect of autophagy, rapamycin induced apoptosis and cytotoxicity were blocked in STAT1-deficient cells but restored in cells simultaneously exposed to the autophagy inhibitor ammonium chloride. In vivo, skeletal muscle ULK1 mRNA and protein levels as well as autophagic flux were significantly enhanced in STAT1-deficient mice. These results demonstrate a novel mechanism by which STAT1 negatively regulates ULK1 expression and autophagy. PMID- 28011641 TI - Glycan Bound to the Selectin Low Affinity State Engages Glu-88 to Stabilize the High Affinity State under Force. AB - Selectin interactions with fucosylated glycan ligands mediate leukocyte rolling in the vasculature under shear forces. Crystal structures of P- and E-selectin suggest a two-state model in which ligand binding to the lectin domain closes loop 83-89 around the Ca2+ coordination site, enabling Glu-88 to engage Ca2+ and fucose. This triggers further allostery that opens the lectin/EGF domain hinge. The model posits that force accelerates transition from the bent (low affinity) to the extended (high affinity) state. However, transition intermediates have not been described, and the role of Glu-88 in force-assisted allostery has not been examined. Here we report the structure of the lectin and EGF domains of L selectin bound to a fucose mimetic; that is, a terminal mannose on an N-glycan attached to a symmetry-related molecule. The structure is a transition intermediate where loop 83-89 closes to engage Ca2+ and mannose without triggering allostery that opens the lectin/EGF domain hinge. We used three complementary assays to compare ligand binding to WT selectins and to E88D selectins that replaced Glu-88 with Asp. Soluble P-selectinE88D bound with an ~9 fold lower affinity to PSGL-1, a physiological ligand, due to faster dissociation. Adhesion frequency experiments with a biomembrane force probe could not detect interactions of P-selectinE88D with PSGL-1. Cells expressing transmembrane P-selectinE88D or L-selectinE88D detached from immobilized ligands immediately after initiating flow. Cells expressing E-selectinE88D rolled but detached faster. Our data support a two-state model for selectins in which Glu-88 must engage ligand to trigger allostery that stabilizes the high affinity state under force. PMID- 28011642 TI - Structure and Polymannuronate Specificity of a Eukaryotic Member of Polysaccharide Lyase Family 14. AB - Alginate is an abundant algal polysaccharide, composed of beta-d-mannuronate and its C5 epimer alpha-l-guluronate, that is a useful biomaterial in cell biology and tissue engineering, with applications in cancer and aging research. The alginate lyase (EC 4.2.2.3) from Aplysia kurodai, AkAly30, is a eukaryotic member of the polysaccharide lyase 14 (PL-14) family and degrades alginate by cleaving the glycosidic bond through a beta-elimination reaction. Here, we present the structural basis for the substrate specificity, with a preference for polymannuronate, of AkAly30. The crystal structure of AkAly30 at a 1.77 A resolution and the putative substrate-binding model show that the enzyme adopts a beta-jelly roll fold at the core of the structure and that Lys-99, Tyr-140, and Tyr-142 form catalytic residues in the active site. Their arrangements allow the carboxyl group of mannuronate residues at subsite +1 to form ionic bonds with Lys 99. The coupled tyrosine forms a hydrogen bond network with the glycosidic bond, and the hydroxy group of Tyr-140 is located near the C5 atom of the mannuronate residue. These interactions could promote the beta-elimination of the mannuronate residue at subsite +1. More interestingly, Gly-118 and the disulfide bond formed by Cys-115 and Cys-124 control the conformation of an active-site loop, which makes the space suitable for substrate entry into subsite -1. The cleavage efficiency of AkAly30 is enhanced relative to that of mutants lacking either Gly 118 or the Cys-115-Cys-124 disulfide bond. The putative binding model and mutagenesis studies provide a novel substrate recognition mode explaining the polymannuronate specificity of PL-14 alginate lyases. PMID- 28011643 TI - Deciphering Key Residues Involved in the Virulence-promoting Interactions between Streptococcus pneumoniae and Human Plasminogen. AB - Bacterial pathogens recruit circulating proteins to their own surfaces, co-opting the host protein functions as a mechanism of virulence. Particular attention has focused on the binding of plasminogen (Plg) to bacterial surfaces, as it has been shown that this interaction contributes to bacterial adhesion to host cells, invasion of host tissues, and evasion of the immune system. Several bacterial proteins are known to serve as receptors for Plg including glyceraldehyde-3 phosphate dehydrogenase (GAPDH), a cytoplasmic enzyme that appears on the cell surface in this moonlighting role. Although Plg typically binds to these receptors via several lysine-binding domains, the specific interactions that occur have not been documented in all cases. However, identification of the relevant residues could help define strategies for mitigating the virulence of important human pathogens, such as Streptococcus pneumoniae (Sp). To shed light on this question, we have described a combination of peptide-spot array screening, competition and SPR assays, high-resolution crystallography, and mutational analyses to characterize the interaction between SpGAPDH and Plg. We identified three SpGAPDH lysine residues that were instrumental in defining the kinetic and thermodynamic parameters of the interaction. Altogether, the integration of the data presented in this work allows us to propose a structural model for the molecular interaction of the SpGAPDH-Plg complex. PMID- 28011646 TI - Infection-related hospitalization and risk of end-stage renal disease in patients with systemic lupus erythematosus: a nationwide population-based study. AB - Background: Infections are a major cause of morbidity in patients with systemic lupus erythematosus (SLE), and may lead to death. No nationally representative study of patients with SLE has examined the rates of infection-related hospitalization and the risk of end-stage renal disease (ESRD). Methods: We conducted a nationwide cohort study of 7326 patients with newly diagnosed SLE and no history of ESRD. All data were from Taiwan's National Health Insurance claims database for the period 2000-11. Results: Among all SLE patients, 316 (4.3%) developed ESRD (mean follow-up time: 8.1 years). Multivariate Cox regression analysis indicated that the risk of ESRD increased with the number of infection related hospitalizations. For patients with three or more infection-related admissions, the hazard ratio (HR) for ESRD was 5.08 [95% confidence interval (CI): 3.74-6.90] relative to those with no infection-related admission. Analysis by type of infection indicated that bacteremia patients had the greatest risk for ESRD (HR: 4.82; 95% CI: 3.40-6.85). Analysis of age of SLE onset indicated that patients with juvenile-onset (<18 years) and three or more infection-related hospitalizations had a greatly increased risk for ESRD (HR: 14.49; 95% CI: 5.34 39.33). Conclusions: Infection-related hospitalizations are associated with a significantly increased risk of ESRD in patients with SLE, especially those with juvenile-onset SLE. Among patients with different types of infectious diseases, those with bacteremia were more likely to develop ESRD. PMID- 28011644 TI - Phosphatidylserine Stimulates Ceramide 1-Phosphate (C1P) Intermembrane Transfer by C1P Transfer Proteins. AB - Genetic models for studying localized cell suicide that halt the spread of pathogen infection and immune response activation in plants include Arabidopsis accelerated-cell-death 11 mutant (acd11). In this mutant, sphingolipid homeostasis is disrupted via depletion of ACD11, a lipid transfer protein that is specific for ceramide 1-phosphate (C1P) and phyto-C1P. The C1P binding site in ACD11 and in human ceramide-1-phosphate transfer protein (CPTP) is surrounded by cationic residues. Here, we investigated the functional regulation of ACD11 and CPTP by anionic phosphoglycerides and found that 1-palmitoyl-2-oleoyl phosphatidic acid or 1-palmitoyl-2-oleoyl-phosphatidylglycerol (<=15 mol %) in C1P source vesicles depressed C1P intermembrane transfer. By contrast, replacement with 1-palmitoyl-2-oleoyl-phosphatidylserine stimulated C1P transfer by ACD11 and CPTP. Notably, "soluble" phosphatidylserine (dihexanoyl phosphatidylserine) failed to stimulate C1P transfer. Also, none of the anionic phosphoglycerides affected transfer action by human glycolipid lipid transfer protein (GLTP), which is glycolipid-specific and has few cationic residues near its glycolipid binding site. These findings provide the first evidence for a potential phosphoglyceride headgroup-specific regulatory interaction site(s) existing on the surface of any GLTP-fold and delineate new differences between GLTP superfamily members that are specific for C1P versus glycolipid. PMID- 28011647 TI - Elizabeth Clare Abernethy. PMID- 28011645 TI - In Vitro and in Vivo Analyses Reveal Profound Effects of Fibroblast Growth Factor 16 as a Metabolic Regulator. AB - The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell based screen, we identified fibroblast growth factor 16 (FGF16) as a potent inducer of several physical and transcriptional characteristics analogous to those of both "classical" BAT and iBAT. Overexpression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically the significant induction of the Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 overexpression in vivo were not the result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake, combined with feces replete with lipid and bile acid, indicated a phenotype more akin to that of starvation and intestinal malabsorption. Gene expression analysis of the liver and ileum indicated alterations in several steps of bile acid metabolism, including hepatic synthesis and reabsorption. Histological analysis of intestinal tissue revealed profound abnormalities in support of this conclusion. The in vivo data, together with FGF receptor binding analysis, indicate that the in vivo outcome observed is the likely result of both direct and indirect mechanisms and probably involves multiple receptors. These results highlight the complexity of FGF signaling in the regulation of various metabolic processes. PMID- 28011650 TI - Social inequalities in health information seeking among young adults in Montreal. AB - Over their lifecourse, young adults develop different skills and preferences in relationship to the information sources they seek when having questions about health. Health information seeking behaviour (HISB) includes multiple, unequally accessed sources; yet most studies have focused on single sources and did not examine HISB's association with social inequalities. This study explores 'multiple-source' profiles and their association with socioeconomic characteristics. We analyzed cross-sectional data from the Interdisciplinary Study of Inequalities in Smoking involving 2093 young adults recruited in Montreal, Canada, in 2011-2012. We used latent class analysis to create profiles based on responses to questions regarding whether participants sought health professionals, family, friends or the Internet when having questions about health. Using multinomial logistic regression, we examined the associations between profiles and economic, social and cultural capital indicators: financial difficulties and transportation means, friend satisfaction and network size, and individual, mother's, and father's education. Five profiles were found: 'all sources' (42%), 'health professional centred' (29%), 'family only' (14%), 'Internet centred' (14%) and 'no sources' (2%). Participants with a larger social network and higher friend satisfaction were more likely to be in the 'all sources' group. Participants who experienced financial difficulties and completed college/university were less likely to be in the 'family only' group; those whose mother had completed college/university were more likely to be in this group. Our findings point to the importance of considering multiple sources to study HISB, especially when the capacity to seek multiple sources is unequally distributed. Scholars should acknowledge HISB's implications for health inequalities. PMID- 28011648 TI - Foxo4- and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. AB - Progranulin (PGRN) restrains inflammation and is therapeutic against inflammatory arthritis; however, the underlying immunological mechanism remains unknown. In this study, we demonstrated that anti-inflammatory cytokine IL-10 was a critical mediator for PGRN-mediated anti-inflammation in collagen-induced arthritis by using PGRN and IL-10 genetically modified mouse models. IL-10 green fluorescent protein reporter mice revealed that regulatory T (Treg) cells were the predominant source of IL-10 in response to PGRN. In addition, PGRN-mediated expansion and activation of Treg cells, as well as IL-10 production, depends on JNK signaling, but not on known PGRN-activated ERK and PI3K pathways. Furthermore, microarray and chromatin immunoprecipitation sequencing screens led to the discovery of forkhead box protein O4 and signal transducer and activator of transcription 3 as the transcription factors required for PGRN induction of IL 10 in Treg cells. These findings define a previously unrecognized signaling pathway that underlies IL-10 production by PGRN in Treg cells and present new insights into the mechanisms by which PGRN resolves inflammation in inflammatory conditions and autoimmune diseases, particularly inflammatory arthritis.-Fu, W., Hu, W., Shi, L., Mundra, J. J. Xiao, G., Dustin, M. L., Liu, C. Foxo4- and Stat3 dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis. PMID- 28011649 TI - Newcastle disease virus induces stable formation of bona fide stress granules to facilitate viral replication through manipulating host protein translation. AB - Mammalian cells respond to various environmental stressors to form stress granules (SGs) by arresting cytoplasmic mRNA, protein translation element, and RNA binding proteins. Virus-induced SGs function in different ways, depending on the species of virus; however, the mechanism of SG regulation of virus replication is not well understood. In this study, Newcastle disease virus (NDV) triggered stable formation of bona fide SGs on HeLa cells through activating the protein kinase R (PKR)/eIF2alpha pathway. NDV-induced SGs contained classic SG markers T-cell internal antigen (TIA)-1, Ras GTPase-activating protein-binding protein (G3BP)-1, eukaryotic initiation factors, and small ribosomal subunit, which could be disassembled in the presence of cycloheximide. Treatment with nocodazole, a microtubule disruption drug, led to the formation of relatively small and circular granules, indicating that NDV infection induces canonical SGs. Furthermore, the role of SGs on NDV replication was investigated by knockdown of TIA-1 and TIA-1-related (TIAR) protein, the 2 critical components involved in SG formation from the HeLa cells, followed by NDV infection. Results showed that depletion of TIA-1 or TIAR inhibited viral protein synthesis, reduced extracellular virus yields, but increased global protein translation. FISH revealed that NDV-induced SGs contained predominantly cellular mRNA rather than viral mRNA. Deletion of TIA-1 or TIAR reduced NP mRNA levels in polysomes. These results demonstrate that NDV triggers stable formation of bona fide SGs, which benefit viral protein translation and virus replication by arresting cellular mRNA.-Sun, Y., Dong, L., Yu, S., Wang, X., Zheng, H., Zhang, P., Meng, C., Zhan, Y., Tan, L., Song, C., Qiu, X., Wang, G., Liao, Y., Ding, C. Newcastle disease virus induces stable formation of bona fide stress granules to facilitate viral replication through manipulating host protein translation. PMID- 28011651 TI - Attitudes and beliefs towards alcohol minimum pricing in Western Australia. AB - Modelling data have provided good evidence to support the efficacy of a minimum pricing policy for alcoholic beverages as a means to reduce alcohol consumption and risky and harmful drinking. The aim of the present study was to investigate attitudes and beliefs towards a minimum price policy for alcohol among members of the general public in Western Australia (WA). The study also explored what factors might promote acceptance of the policy. Eleven focus groups, comprising participants from a broad range of backgrounds in WA, were conducted. Using a facilitator-administered semi-structured interview schedule participants discussed their beliefs about the policy and how its acceptability might be promoted. Transcriptions of discussions were analysed using qualitative inductive content analysis for emergent themes. Three major themes emerged: attitudes towards the policy, beliefs about effectiveness and strategies to increase acceptability. Participants expressed negative attitudes towards the policy and thought that it would lead to increased crime, drug use and financial strain. Participants identified the policy as unfair on disadvantaged groups, and suggested that individuals would find a way to procure alcohol regardless of minimum pricing policies. Suggestions to make the policy more acceptable included increasing alcohol education and directing the revenue towards alcohol reduction initiatives. Participants' negative views and perceived lack of effectiveness corroborate research conducted in the UK. Information and education campaigns aimed at reducing misunderstanding of the policy and highlighting its effectiveness may help to promote greater acceptability. PMID- 28011652 TI - Evaluating a community-led project for improving fathers' and children's wellbeing in England. AB - Although under-researched and under-theorized compared to other settings, there is potential for the family setting to be harnessed to support the development of healthy children and societies and to reduce health inequalities. Within this setting, the role of fathers as health facilitators has yet to be fully understood and considered within health promotion. This paper draws on a two year evaluation of a community embedded intervention for fathers and children in an area of multiple deprivation in North West England. The evaluation integrated a variety of qualitative methods within a participatory evaluation framework to help understand the development and impact of a programme of work co-created by a social enterprise and fathers from within the community. Findings suggest that allowing fathers to define their own concerns, discover solutions to these and design locally appropriate ways to share these solutions can result in significant change for them, their children and the wider community. The key to this process is the provision of alternative spaces where fathers feel safe to share the substantial difficulties they are experiencing. This improved their confidence and had a positive impact on their relationships with their children and with significant others around them. However, this process required patience, and a commitment to trusting that communities of men can co-create their own solutions and generate sustainable success. We suggest that commissioning of services delivered 'to' people could be replaced, or supplemented, by commissioning appropriate organisations to work with communities to co-create solutions to the needs they themselves have recognized. PMID- 28011653 TI - Framing the policy debate over spirits excise tax in Poland. AB - Industry lobbying remains an obstacle to effective health-oriented alcohol policy. In 2013, an increase in excise tax on spirits was announced by the Polish government. This article presents a qualitative analysis of the public debate that ensued on the potential economic, health and social effects of the policy. It focuses on how competing groups, including industry actors, framed their position and sought to dominate the debate. Online archives of five Polish national newspapers, two spirits trade associations, and parliamentary and ministerial archives were searched. A thematic content analysis of the identified sources was conducted. The overall findings were compared with existing research on the framing of the Minimum Unit Pricing (MUP) debate in the UK. A total of 155 sources were analysed. Two main frames were identified: health, and economic. The spirits industry successfully promoted the economic frame in their own publications and in the media. The debate was dominated by arguments about potential growth of the grey market and losses in tax revenue that might result from the excise tax increase. The framing of the debate in Poland differed from the framing of the MUP debate in the United Kingdom. The Polish public health community was unsuccessful in making health considerations a significant element of the alcohol policy debate. The strategies pursued by UK health advocates offer lessons for how to make a more substantial impact on media coverage and promote health-oriented legislation. PMID- 28011654 TI - School-based primary NCD risk reduction: education and public health perspectives. AB - The rising global burden of noncommunicable diseases (NCDs) has heightened awareness of the necessity for primary risk prevention programmes. These aim to facilitate long-term behaviour changes in children and adolescents that can reduce NCD risk factors and disease onset in later-life. School-based programmes designed to improve childhood and adolescent health behaviours and wellbeing contribute to this; however, design and impact assessment of these is complex. These programmes should be multidisciplinary, utilizing both educational and health expertise. Health outcomes may not be evident in the short term, but may occur with learning-related behaviour modifications, highly effective when sustained over a lifetime. Thus assessment must analyse short-term learning and behaviour impacts as well as long-term capability, behaviour and health outcomes.The focus of assessment measures in the health and education sectors differs and often lacks depth in one or other area. Educators generally focus on identifying evidence of learning related to capability, attitude and/or behaviour changes, while public health practitioners typically focus on health measures (e.g. body mass index (BMI), mental health, or risk behaviours).We argue that multidisciplinary approaches incorporating education and health viewpoints clarify issues relating to the potential value of schools as a setting to facilitate primary NCD risk reduction. To demonstrate this, we need to: 1) build stronger understandings of the features of effective learning for behavioural change and the best way to evaluate these, and 2) convincingly correlate these measures with long-term metabolic health indicators by tracking learner behaviour and health over time. PMID- 28011655 TI - Cross-national differences in the holistic use of traditional East Asian medicine in East Asia. AB - Complementary and alternative medicine (CAM) has been one of the popular strategies for health promotion. Traditional East Asian medicine (TEAM) is one of the most popular CAM practices in the world and there are suggestions that its holistic utilization is important for users to gain its effects for health promotion. In this context, this study investigates the extent to which TEAM users in East Asian countries utilize various modalities of TEAM holistically. It provides a model that explains cross-national differences in the extent of the holistic use of TEAM between China, Japan, Korea and Taiwan. Using the 2010 East Asian Social Survey, regression models specify the relationship between the holistic use of TEAM and the geographical location (country). The presence of TEAM doctors who hold the comprehensive and exclusive practice rights over TEAM is found to be conducive to the holistic utilization of various TEAM modalities. Thus, Taiwanese and Koreans use TEAM more holistically than Chinese and even more so than Japanese. The result suggests that the manner in which TEAM is institutionalized affect the extent to which TEAM users utilize various TEAM modalities together and potentially the health promotion effects of TEAM. PMID- 28011656 TI - The role of the care sport connector in the Netherlands. AB - Introduction: To stimulate physical activity and guide primary care patients towards local sport facilities, Care Sport Connectors (CSC), to whom a broker role has been ascribed, were introduced in 2012 in the Netherlands. The aim of this study was to explore CSCs' role in connecting the primary care sector and the PA sector. Method: Fifteen CSCs were selected to participate in this study and were followed in their work of connecting both sectors. Over the course of one year, three rounds of interviews were held with these CSCs on the topics of their role and the connection between the primary care and the PA sector. Both top-down and bottom-up codes were used to analyse the interviews. Results: CSCs fulfilled three roles: 1) broker, 2) referral, 3) organiser. The extent to which CSCs fulfilled these roles was influenced by the way municipalities implemented the CSC funding. CSCs set up two forms of collaboration structures: 1) project basis and 2) referral scheme. CSCs perceived the following barriers to connecting the primary care and the PA sector: lack of knowledge and time, primary care professionals' own interests, and lack of suitable sport activities for the target group. Conclusion: The CSC role seems to hold the promise of improving collaboration between the primary care and the PA sector, especially, because the roles that CSCs perceive themselves as having seem to be directed at eliminating barriers in this connection. Future research is needed to study whether CSCs are capable of establishing a connection over time. PMID- 28011657 TI - Citizen Science for public health. AB - Community engagement in public health policy is easier said than done. One reason is that public health policy is produced in a complex process resulting in policies that may appear not to link up to citizen perspectives. We therefore address the central question as to whether citizen engagement in knowledge production could enable inclusive health policy making. Building on non-health work fields, we describe different types of citizen engagement in scientific research, or 'Citizen Science'. We describe the challenges that Citizen Science poses for public health, and how these could be addressed. Despite these challenges, we expect that Citizen Science or similar approaches such as participatory action research and 'popular epidemiology' may yield better knowledge, empowered communities, and improved community health. We provide a draft framework to enable evaluation of Citizen Science in practice, consisting of a descriptive typology of different kinds of Citizen Science and a causal framework that shows how Citizen Science in public health might benefit both the knowledge produced as well as the 'Citizen Scientists' as active participants. PMID- 28011659 TI - Measuring health literacy in university students in Vientiane, Lao PDR. AB - Health literacy includes the knowledge, motivation and competence of a person to make judgments and decisions on health information in order to promote and maintain their health in relation to health care, disease prevention and health promotion. The role health literacy plays in determining health outcomes makes it an important focus of public health research. In line with a larger Asia wide initiative (HLS-Asia), this study set out to measure health literacy in the Lao People's Democratic Republic (Lao-PDR). A mixed-methods study design was employed. The HLS-Asia questionnaire was conducted as a self-administered survey with first year students at the National University of Lao PDR in Vientiane. The survey was complimented with in-depth, vignette style interviews. Student's scores on the questionnaire showed problematic health literacy levels, with clear patterns to the type of questions students struggled with. However, responses in the interviews suggested a higher level of health literacy. These findings highlight the importance of health systems and social context in health literacy. The results question the appropriateness of the HLS measurement tool, but more broadly suggest that health literacy may be a concept only comparable between populations when social, economic and health systems are measured concurrently. PMID- 28011658 TI - Which types of anti-smoking television advertisements work better in Taiwan? AB - Research in high income countries suggests that anti-smoking television advertisements with emotionally evocative graphic messages or personal testimonials that depict serious consequences from smoking are the most effective. Research to determine the most effective smoking cessation messages for low- and middle-income countries is needed to inform campaign development in these countries. Fifty-four male Taiwanese smokers, aged 18-34, rated advertisements and participated in a focus group to evaluate eight antismoking television advertisements with contrasting messaging strategies. Participants individually evaluated advertisements, after which they participated in a semi structured focus group discussion (10 groups, 2-9 smokers per group). One week after this session, participants were called to assess advertisement recall. Both quantitative and qualitative data indicated that highly emotional testimonial ads that featured a graphic portrayal of personal suffering from the consequences of smoking and visceral graphic ads were more effective. The ad on tobacco industry denormalization that focuses on the responsibility of the industry for smoking related harms was considered ineffective because smokers perceived it as having little personal relevance. Humorous advertisements were evaluated as the least effective because they lacked strong emotional content linked to smoking consequences. Qualitative results suggest that advertisement characteristics are more important than the demographic characteristics of people featured in advertisements. Study findings provide preliminary evidence that testimonial ads that involve graphic and emotionally evocative portrayals of smoking-attributed diseases and visceral graphic ads may have the greater potential to motivate Taiwanese smokers to quit smoking. PMID- 28011660 TI - Time and participation in workplace health promotion: Australian qualitative study. AB - Workplaces are considered promising settings for protecting and promoting the health and wellbeing of employees. To date, few workplaces, particularly small and medium sized enterprises (SME), or their workers, have adopted Workplace Health Promotion (WHP), raising questions as to why. We conducted interviews in 10 SME in the Australian Capital Territory (ACT) asking managers and workers to reflect on the reasons for their participation (or not) in WHP activities. We qualitatively explored factors that managers consider important when deciding whether to offer WHP and compared these to worker considerations regarding participation. Both workers and managers identified time constraints as a major barrier for participation in WHP activities. If WHP was implemented, time constraints arose mainly from: difficulties scheduling and synchronising activities to include most staff, even then casual staff were mostly excluded; and the duration of time required by employees to participate in the offered activities, and whether this was in paid (work) or unpaid (worker) time. Workers struggled to participate in WHP in their scheduled breaks and were reluctant to use time outside of work hours. We have developed a model illustrating the emerging tension between managers' and workers' needs for WHP participation. WHP participation will likely remain low until this tension, and associated financial implications, are widely acknowledged and addressed. Our research indicates that time should be considered more explicitly and thoughtfully in the workplace engagement and WHP design, to actively respond to constraints from activity duration, scheduling and synchronisation. PMID- 28011661 TI - The UK Healthy Universities Self-Review Tool: Whole System Impact. AB - Over recent years, there has been growing interest in Healthy Universities, evidenced by an increased number of national networks and the participation of 375 participants from over 30 countries in the 2015 International Conference on Health Promoting Universities and Colleges, which also saw the launch of the Okanagan Charter. This paper reports on research exploring the use and impact of the UK Healthy Universities Network's self review tool, specifically examining whether this has supported universities to understand and embed a whole system approach. The research study comprised two stages, the first using an online questionnaire and the second using focus groups. The findings revealed a wide range of perspectives under five overarching themes: motivations; process; outcomes/benefits; challenges/suggested improvements; and future use. In summary, the self review tool was extremely valuable and, when engaged with fully, offered significant benefits to universities seeking to improve the health and wellbeing of their communities. These benefits were felt by institutions at different stages in the journey and spanned outcome and process dimensions: not only did the tool offer an engaging and user-friendly means of undertaking internal benchmarking, generating an easy-to-understand report summarizing strengths and weaknesses; it also proved useful in building understanding of the whole system Healthy Universities approach and served as a catalyst to effective cross university and cross-sectoral partnership working. Additionally, areas for potential enhancement were identified, offering opportunities to increase the tool's utility further whilst engaging actively in the development of a global movement for Healthy Universities. PMID- 28011662 TI - Placing preterm infants on their side at birth does not increase 5 min SpO2. PMID- 28011666 TI - Incremental value of 3D over 2D echocardiography in a patient with multiple ICD leads in the right ventricle. PMID- 28011667 TI - Echocardiographic assessment of pulmonary artery systolic pressure following treadmill stress testing. AB - Aims: The use of treadmill stress echocardiography (SE) for the diagnosis of nascent pulmonary hypertension (PH) has been hampered by a lack of well-defined, post-exercise pulmonary artery systolic pressure (PASP) values across representative age groups in a normal cohort. Methods and results: Five hundred and eleven subjects (mean age: 53 +/-14, 68% female) with normal resting PASP were included in the study. All participants performed treadmill exercise using the Bruce protocol to a high level of perceived exertion. PASP was calculated before and immediately after exercise using Doppler assessment of tricuspid regurgitation. For the cohort, post-exercise PASP was 39 +/- 7 mmHg (range: 23-64 mmHg) representing an increase of 11 +/- 6 mmHg (44%) from resting values (P < 0.001). The 95th centile values for post-exercise PASP were calculated for the following age cohorts: <30 years; 46 mmHg, 31-50 years; 50 mmHg, 51-70 years; 52 mmHg, >70 years; 53 mmHg. There was a modest independent correlation between post exercise PASP and (i) increasing age and (ii) resting PASP (r2 = 0.35 and 0.49, respectively, P = 0.01). Conclusion: An increase of post-exercise PASP was seen in all patients undergoing SE in this study. Age was directly correlated with post-exercise PASP. Using normative data from healthy controls, treadmill SE derived post-exercise PASP may be a useful adjunct in the diagnosis of PH. PMID- 28011668 TI - Cardiac remodelling amongst adults with various aetiologies of pulmonary arterial hypertension including Eisenmenger syndrome-implications on survival and the role of right ventricular transverse strain. AB - Aims: Survival in pulmonary arterial hypertension (PAH) and Eisenmenger syndrome (ES) relates to right ventricular (RV) function. Little is known about differences of ventricular function between ES patients and those suffering from other PAH aetiologies. In this study, we compared global ventricular function assessed by speckle-tracking in adult patients with ES, other PAH aetiologies, or healthy controls; and assessed the relationship between ventricular function and survival. Methods and results: We performed a prospective cohort study recruiting 83 adult PAH patients (43 ES and 40 other PAH aetiologies patients) and 37 controls between March 2011 and June 2015. Patients with complex congenital heart disease were excluded. Fifty-three patients (63.9%) were in NYHA functional class >=III at baseline and 60 (72.3%) were on advanced therapies. Mean RV peak longitudinal strain was -16.3 +/- 7% in ES, lower compared with healthy controls (P < 0.001) but similar to other PAH aetiologies (P = 0.6). Mean RV peak transverse strain was +26.1 +/- 17% in ES, lower than in controls (P < 0.001) but higher than in other PAH aetiologies (P < 0.001). No difference was observed between ES and other PAH in LV circumferential and longitudinal strain. Over a median follow-up of 22.6 months (3.3-32.2), 22 (26.5%) patients died all from cardio-pulmonary causes. ES and RV peak transverse strain were independent predictors of survival. RV peak transverse strain <=22% identified patients with a 14-fold increased risk of death. Conclusion: Right ventricular remodelling differs between adults with ES and other PAH aetiologies. ES and increased RV free wall transverse strain are associated with better survival. PMID- 28011669 TI - Rapidly growing intraventricular mass in a patient with hereditary haemorrhagic telangiectasia. PMID- 28011670 TI - Ventricular interdependence diagnosed by respirophasic mid-diastolic ventricular wall excursion: M-mode redux. PMID- 28011671 TI - When exploring patients during exercise makes sense? PMID- 28011672 TI - Inflamed human carotid plaques evaluated by PET/CT exhibit increased temperature: insights from an in vivo study. AB - Aims: To explore the relationship between temperature measurements derived by microwave radiometry (MWR) and carotid flurodeoxyglucose (FDG) uptake and assess their association with histological and immunohistochemistry findings in patients with high-grade carotid stenosis. Methods and results: In 21 patients undergoing carotid endarterectomy, carotid inflammation was evaluated by both FDG positron emission/computed tomography (FDG-PET/CT) imaging and MWR measurements. Carotid inflammation was assessed by PET/CT as target-to-background ratio (TBR) by obtaining measurements in consecutive axial slices 2 cm below to 2 cm above the carotid bifurcation. Temperature difference (DeltaT) by MWR was assigned as the maximum-minimum temperature measurements over the corresponding carotid segments. The extent of lipid core, calcification as well as CD68 and CD31 levels were also assessed. There was a significant correlation between DeltaT values and FDG uptake (R = 0.40, P = 0.01), but no correlation between the degree of angiographic stenosis and DeltaT values (R = -0.02, P = 0.91) or PET/CT measurements (R = -0.28, P = 0.86). Patients with plaques containing high lipid core extension or low calcification exhibited higher DeltaT (P = 0.001 and P < 0.001, respectively) and FDG uptake values (P = 0.02 and P = 0.02, respectively). Patients with plaques containing increased CD68 expression exhibited higher DeltaT and FDG uptake measurements. Conclusion: Carotid plaque inflammation was evaluated by temperature measurements, which were correlated with FDG-PET/CT indices, confirmed by histopathology and immunohistochemistry findings. Structural changes did not predict inflammatory process. The implications of these findings in risk stratification and management of patients with carotid atherosclerosis and the precise algorithm for potential clinical utilization of MWR and PET/CT remain to be determined. PMID- 28011674 TI - Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism. AB - Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations (P < 10-5). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (SMAP1), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and beta-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of P = 1.42 * 10-6/2.0 * 10-6 and P = 6.11 * 10-6/1.8 * 10-5, respectively. Rs2748331 was replicated (P = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined P = 7.88 * 10-7). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in SMAP1 and 3 in RIMS1, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: P = .08326, SMAP1; rs767118962: P = .08326, RIMS1; and rs41265501: P = .05778, RIMS1). In conjunction, our data provide compelling evidence for SMAP1, B3GAT2, and RIMS1 as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE. PMID- 28011675 TI - CX3CR1-dependent endothelial margination modulates Ly6Chigh monocyte systemic deployment upon inflammation in mice. AB - Two subsets of blood monocytes are commonly described in mice and humans: the classical inflammatory monocytes, which are rapidly mobilized upon inflammation in a CC-chemokine receptor 2-dependent manner, and the nonclassical blood resident monocyte subset that patrols the intraluminal side of the endothelium. Old reports suggest that blood monocytes are distributed into circulating and marginating pools, but no direct evidence of the latter has been obtained so far. Using a combination of in vivo real-time imaging and blood/tissue partitioning by intravascular staining of leukocytes, we showed that both inflammatory and resident monocytes are retained in the bone marrow vasculature, representing an important reservoir of marginated monocytes. Upon lipopolysaccharide or cecal ligation and puncture-induced peritonitis, these marginated cells are rapidly released and recruited to the peritoneum membrane lumen vasculature where they reside through CX3C-chemokine receptor 1 (CX3CR1)-dependent adherence. At a later time point, inflammatory monocytes infiltrate the spleen parenchyma but remain mainly intravascular in the vicinity of the lungs and the peritoneum. Our results show that this monocyte deployment is controlled by a CX3CR1-dependent balance between marginating and circulating monocytes and highlight that tissue infiltration is not a mandatory fate for inflammatory monocytes. PMID- 28011673 TI - Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. AB - Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cgamma), but had low alpha-BCR-induced signaling. This contrasted MCL tumors, where alpha-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, alpha-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors. PMID- 28011676 TI - Reduction of aGVHD using chicken antibodies directed against intestinal pathogens in a murine model. PMID- 28011677 TI - N-acetylcysteine in preclinical mouse and baboon models of thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic disorder diagnosed by thrombocytopenia and hemolytic anemia, associated with a deficiency in von Willebrand factor (VWF)-cleaving protease ADAMTS13. Current treatment is based on plasma infusion for congenital TTP, or plasma exchange, often in combination with immunosuppressive agents, for acquired TTP. These treatment methods are not always effective; therefore, new treatment methods are highly necessary. N-acetylcysteine (NAC), an FDA-approved anti-mucolytic agent, is a possible new treatment strategy for TTP, as it was demonstrated to reduce disulfide bonds in VWF, thereby decreasing VWF multimers size and hence their prothrombotic potential. We investigated whether NAC, without concurrent plasma exchange and immunosuppressive therapy, is effective in preventing and resolving TTP signs, using well-established murine and baboon models for TTP. In mice, prophylactic administration of NAC was effective in preventing severe TTP signs. This in vivo finding was supported by in vitro data demonstrating the VWF multimer-reducing properties of NAC in solution. Nonetheless, in both mice and baboons, administration of NAC was not effective in resolving preexisting TTP signs; thrombocytopenia, hemolytic anemia, and organ damage could not be reversed, as thrombus resolution was not achieved. Failure to improve clinical outcome occurred even though a reduction in VWF multimers was observed, demonstrating that NAC was efficient in reducing disulfide bonds in circulating VWF multimers. In conclusion, prophylactic administration of NAC, without concurrent plasma exchange, was effective in preventing severe TTP signs in mice, but NAC was not effective in resolving preexistent acute TTP signs in mice and baboons. PMID- 28011679 TI - Seasonal Population Dynamics of Thrips (Thysanoptera) in Wisconsin and Iowa Soybean Fields. AB - With the discovery of Neohydatothrips variabilis (Beach) as a vector of Soybean vein necrosis virus (Family Bunyaviridae Genus Tospovirus), a relatively new pathogen of soybean, a multiyear study was initiated in Wisconsin (2013 and 2014) and Iowa (2014 and 2015) to determine the phenology and species composition of thrips in soybean fields. Yellow sticky card traps were used to sample thrips at regular intervals in five counties within each state's primary soybean-growing region. The assemblage of species present in Wisconsin was determined in all site years, revealing that N. variabilis and other known vectors of tospoviruses were a relatively small percentage of the total thrips captures in 2013 (1.6%) and 2014 (3.6%). A repeated measures analysis was conducted on cumulative proportion thrips capture data within each state's sampling year to investigate differences in phenology, and standardized cumulative insect days were analyzed between sampling years within each state to determine differences in the relative magnitude of populations. Distinct seasonal trends were not detected based on location, as originally hypothesized, and thrips populations varied significantly among locations and between years. These results suggest that thrips populations may be overwintering in northern climates instead of relying solely on migrations to colonize northern soybean fields. PMID- 28011678 TI - Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI. AB - Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the O-acyl transferase Porcupine (PORCN). Here we investigated the activity of a potent and selective PORCN inhibitor, WNT974, against CML stem and progenitor cells. WNT974 efficiently antagonized Wnt signaling in human CML CD34+ cells, and in combination with the TKI nilotinib (NIL) significantly enhanced inhibition of proliferation and colony-forming potential of CML stem and progenitor cells and reduced their growth in immunodeficient mice in vivo, in comparison with NIL alone. Treatment of transgenic CML mice in vivo with NIL in combination with WNT974 significantly reduced leukemic stem and progenitor cell numbers, reduced regeneration of leukemic long-term hematopoietic stem cells in secondary transplant recipients, and enhanced survival of mice after discontinuation of treatment, in comparison with NIL alone. CML progenitors demonstrated enhanced sensitivity to Wnt stimulation, associated with increased expression of the FZD4 receptor. FZD4 knockdown inhibited CML progenitor growth. These results support further investigation of PORCN targeting to inhibit Wnt secretion and signaling and enhance targeting of CML stem cells while sparing their normal counterparts. PMID- 28011680 TI - Impact of Temperature on the Growth and Development of Athetis dissimilis (Lepidoptera: Noctuidae). AB - Athetis dissimilis (Hampson) has emerged as a serious pest on corn in recent years in China. Understanding the population response of A. dissimilis to temperature will be beneficial for adopting control strategies for this pest. The impact of five constant temperatures (17, 21, 25, 29, and 33 degrees C) on the life table of A. dissimilis was studied using age-stage, two-sex life table method in the laboratory. The results showed that the developmental time of egg, larva, pupa, and adult decreased when temperature increased from 17 degrees C to 33 degrees C. The TPOP (total preoviposition period) decreased with temperature increasing from 17 degrees C to 29 degrees C, while the longest APOP (adult preoviposition period) occurred at 21 degrees C (3.57 d) and the shortest at 33 degrees C (2.15 d). The fecundity increased from 407.52 to 763.94 eggs as temperatures were raised from 17 to 25 degrees C, but decreased at temperatures from 25 degrees C to 33 degrees C. The intrinsic rate of increase (r), finite rate of increase (lambda), and net reproductive rate (R0) increased as temperatures increased from 17 to 25 degrees C, then decreased when temperatures exceeded 25 degrees C. In contrast, the mean generation time (T) decreased as temperatures increased from 17 to 33 degrees C. Based on the estimated data, the highest female age-stage-specific fecundity (fx) and age-specific fecundity (mx) were 81.91 and 45.04 eggs, respectively, at 25 degrees C. The age-stage life expectancy (exj) of all stages decreased as the temperature increased. The reproductive value (vxj) increased gradually with age and stage. The developmental rates of A. dissimilis between 17 to 29 degrees C fit the linear equation y = -0.01315 + 0.001303x, with a coefficient of determination (R2) of 0.9314. In conclusion, our finding clearly states that A. dissimilis has the greatest population increase at 25 degrees C, and this may help develop appropriate pest management strategies. PMID- 28011681 TI - Effects of Size and Age of the Host Musca domestica (Diptera: Muscidae) on Production of the Parasitoid Wasp Spalangia endius (Hymenoptera: Pteromalidae). AB - One method of control of house flies, Musca domestica L. (Diptera: Muscidae), and other filth flies is by repeated release of large numbers of pupal parasitoids such as Spalangia endius Walker. Rearing these parasitoids may be facilitated by understanding how host factors affect their production. Previous studies have examined the effects of host size and host age on parasitoid production, but have not examined the interaction between host size and host age or the effects with older females, which may be less capable of drilling tough hosts. Females were given hosts of a single size-age category (small young, small old, large young, or large old) for 2 wk. The effect of host size and of host age on parasitoid production depended on female age. On their first day of oviposition, females produced more offspring from large than from small hosts, but host age had no significant effect. The cumulative number of parasitoids produced in the first week was not significantly affected by host size or host age. However, the cumulative number of parasitoids produced over 2 wk was affected by both host size and host age, with the greatest number of parasitoids produced from small young hosts. Thus, not only are smaller hosts cheaper to produce, but these results suggest that their use may have no effect or a positive effect on the number of parasitoids that can be produced when females are ovipositing for a week or two. PMID- 28011682 TI - Resistance to Melanaphis sacchari (Hemiptera: Aphididae) in Forage and Grain Sorghums. AB - The sugarcane aphid, Melanaphis sacchari (Zehntner), has established itself as a perennial pest of grain and forage sorghums in the United States since the summer of 2013. We conducted traditional plant resistance studies that determine tolerance, antibiosis, and antixenosis in 32 sorghum genotypes when challenged with sugarcane aphids. The genotypes included one exotic plant introduction and 31 seed and pollinator parental lines that are used to produce grain, sudangrass, and forage sorghum hybrids. One seed parent (B11055) and one grain pollinator parent (R13219) expressed significant degrees of tolerance, antibiosis, and antixenosis and were top performers in all three resistance type experiments. An additional group of seed parents (B13045 and B1057) and grain pollinator parents (R11159, R13422, and RTx2908) and the plant introduction (PI 550610) resulted in an intermediate range of phenotypic resistance (i.e., 4.0 < 6.0) indicative of antibiosis from reduced fecundity, increased intrinsic rate of increase, and increased generation times. The forms of resistance expressed in these lines, especially B11055 and R13219, have great potential in breeding programs that can be integrated into useable forms of resistant sorghums. PMID- 28011683 TI - Larval Performance and Adult Attraction of Delia platura (Diptera: Anthomyiidae) in a Native and an Introduced Crop. AB - Delia platura Meigen is an important pest in crops around the world. Its host range includes almost 50 species, and it can develop in soil organic matter. In Ecuador, D. platura is a serious problem for the crop, Lupinus mutabilis Sweet (Chocho), and it also attacks broccoli (Brassica oleracea L.). After broccoli is harvested, crop residue is mixed with soil or collected and stored close to Chocho fields. The objectives of this study were to determine the adaptive responses of larvae reared on different hosts and whether D. platura females are preferentially attracted to germinating L. mutabilis seeds or broccoli residue. Accordingly, larval performance and attraction of female D. platura reared on broccoli residue and L. mutabilis seeds were evaluated. The number of larvae, pupae, and adults were higher when reared on broccoli. Conversely, pupal weight was higher and time from larva to pupa, pupa to adult, and total life cycle were longer in flies reared on L. mutabilis. Although D. platura developed more quickly on broccoli, L. mutabilis was also a good host since pupae were heavier compared with flies reared on broccoli. Delia platura females reared on broccoli preferred broccoli residue to L. mutabilis in an olfactometer. Volatiles from broccoli residue in soil may attract D. platura females and stimulate oviposition on L. mutabilis seeds. Environmentally benign production of L. mutabilis crops with minimal insecticide applications may require the elimination of fresh broccoli residue as fertilizer in soils where L. mutabilis is cultivated. PMID- 28011684 TI - Effects of Food Quality on Biology and Physiological Traits of Sitotroga cerealella (Lepidoptera: Gelechiidae). AB - Biology and physiological traits of Sitotroga cerealella Olivier, a world-wide insect pest of cereals, were investigated on different grains (barley, maize, rye, sorghum, triticale, and wheat). Larval and pupal duration was the shortest on wheat and triticale, and the longest on sorghum. There were significant differences in survival rate of immature stages on grains with different seed hardness. The highest realized fecundity and egg fertility was observed on triticale and the lowest was seen on sorghum. Larvae fed on triticale and wheat showed higher amount of alpha-amylase activity than larvae fed on other grains. Maximum Vmax/KM ratio was determined for the midgut alpha-amylase of S. cerealella larvae fed on wheat. Whole-body protein, lipid, and glycogen contents of pupae reared on sorghum and rye were significantly lower than those reared on other grains. The statistical analysis showed that the clear correlation could be drawn between the biological characteristics and energy contents of S. cerealella on one side and seed hardness, amylolytic activity, and food consumed on the other. According to the findings of this study, the variable responses of S. cerealella to feeding on different host grains could be attributed to the quality of diets tested. PMID- 28011685 TI - Activity of Selected Formulated Biorational and Synthetic Insecticides Against Larvae of Helicoverpa armigera (Lepidoptera: Noctuidae). AB - This work studied 17 insecticides belonging to nucleopolyhedrovirus (NPV), Bacillus thuringiensis (Bt kurstaki and Bt aizawai), benzoylureas (insect growth regulators [IGRs]), carbamates, organophosphates, spinosyns, and diamides against larvae of Helicoverpa armigera (Hubner), invasive species in the South American continent. Larvae of different instars were fed for 7 d with untreated or insecticide-treated diets. Mortality was recorded daily for 7 d, and surviving larvae were individually weighed on the seventh day. The NPV and Bt insecticides caused 100% mortality of first-instar larvae and first-instar and second-instar larvae, respectively. However, both NPV and Bt-based products caused low mortality of third-instar larvae and did not kill older larvae. The IGR lufenuron was highly effective against all three ages of larvae tested, whereas teflubenzuron and triflumuron produced maximum 60% mortality of second-instar larvae and lower than 50% to older larvae. Thiodicarb, chlorantraniliprole, indoxacarb, chlorpyrifos, and chlorfenapyr, irrespective of tested age, caused 100% mortality of larvae, with the last two insecticides reaching 100% mortality within 2 d of feeding on the treated diet. Flubendiamide caused lower mortality but significantly affected the weight of surviving larvae, whereas neither spinosad nor methomyl produced significant mortality or affected the weight of larvae. Based on the results, the age of H. armigera larvae plays an important role in the recommendation of NPV and Bt insecticides. Furthermore, there are potential options between biological and synthetic insecticides tested against H. armigera, and recording larval size during monitoring, in addition to the infestation level, should be considered when recommending biological-based insecticides to control this pest. PMID- 28011686 TI - A Survey of Insecticide Resistance in Aedes albopictus (Diptera: Culicidae) During a 2014 Dengue Fever Outbreak in Guangzhou, China. AB - A dengue fever outbreak in Guangzhou, Guangdong Province, China, in 2014 resulted in ~37,000 cases and five deaths. Insecticides were sprayed to control the vector of this outbreak, Aedes albopictus (Skuse), a species of mosquito. Aedes albopictus specimens collected from Huadu District (HD), Huangpu District (HP), Luogang District (LG), and Nansha District (NS) in Guangzhou were evaluated using WHO-recommended bioassays for both larvae and adult mosquitoes to determine population resistance to deltamethrin, beta-cypermethrin, cypermethrin, permethrin, dichlorvos, temephos, propoxur, and DDT. Compared with a susceptible laboratory strain of Ae. albopictus (S-lab), all populations showed decreased sensitivities to the eight insecticides, with resistance ratios (RRs) ranging from 2.2 to 275. The RRs were 6.8-275 for pyrethroids, 2.2-4.4 for organophosphates, 5.7-9.0 for carbamates, and 5.3-94.3 for organochlorines. For adult mosquitoes, all populations were sensitive to dichlorvos with 100% mortalities. Mosquitoes from HP, LG, and NS were also sensitive to propoxur. But for other tested insecticides, different degrees of resistance (mortality rate ranging from 11.7% to 94.7%) were observed. Among the four field populations, the resistance levels are presented as follows in descending order: HP > HD > NS > LG. The levels among insecticides classes were pyrethroids > organochlorines > carbamates > organophosphates. PMID- 28011687 TI - Screening of Potential Sources of Resistance to Spodoptera exigua (Lepidoptera: Noctuidae) in 24 Sugar Beet Genotypes. AB - Spodoptera exigua (Hubner) is one of the polyphagous pests destroying crops such as sugar beet worldwide. The aim of this experiment was to evaluate the resistance of 24 sugar beet genotypes to S. exigua. In this study, nine sugar beet cultivars (Dorotea, Tous, Persia, Silenta, Jaam, HM1339RZ, Jolgeh, Ekbatan, and SBSI006), three hybrids ((7112*SB36)*Sh-1-HSF-5, (7112*SB36)*Sh-1-HSF-15, and (7112*SB36)*Sh-1-HSF-16), four lines (FC201, FC301, FC220, and FC221), and eight populations (SB26, SB27, SB28, SB29, SB30, SB33, SB34, and SB35) were assessed. The experiments were performed under laboratory conditions at 25 +/- 1 degrees C, 60 +/- 5% RH, and a photoperiod of 16:8 (L:D) h using age-stage, two-sex life table procedure. The larval period ranged from 17.09 d on FC301 to 14.47 d on SB30. The total fecundity (F) was highest on (7112*SB36)*Sh-1-HSF-5 (905.13 eggs) and lowest on FC301 (312.46 eggs). (7112*SB36)*Sh-1-HSF-5 and FC220 with 318.02 and 26.76 eggs per individual had the highest and lowest net reproductive rates (R0), respectively. The highest values of the intrinsic rate of increase (r) and finite rate of increase (lambda) were on (7112*SB36)*Sh-1-HSF-5 (r: 0.187 d - 1, lambda: 1.205 d - 1) and the lowest were on FC301 (r: 0.104 d - 1, lambda: 1.11 d - 1). SB26 (r: 0.185 d - 1, lambda: 1.203 d - 1) and FC220 (r: 0.114 d - 1, lambda: 1.12 d - 1) had no significant difference with (7112*SB36)*Sh-1-HSF-5 and FC301, respectively. The comparison of demographic parameters of S. exigua on 24 sugar beet genotypes suggested that FC220 and FC301 were the most resistant and (7112*SB36)*Sh-1-HSF-5 and SB26 were the most susceptible genotypes to this pest. PMID- 28011688 TI - Cyantraniliprole at Sublethal Dosages Negatively Affects the Development, Reproduction, and Nutrient Utilization of Ostrinia furnacalis (Lepidoptera: Crambidae). AB - To better understand the application prospect of cyantraniliprole against the Asian corn borer, Ostrinia furnacalis, a diet-incorporation bioassay was adopted to determine the toxicity of cyantraniliprole against the fourth instar of O. furnacalis. Moreover, other experiments were conducted to examine effects of sublethal levels of cyantraniliprole on larval development, nutrient utilization, and reproduction. In this study, cyantraniliprole showed a high toxicity to fourth-instar larvae of O. furnacalis at dosages of 0.05 MUg/g (LC5), 0.11 MUg/g (LC20), 0.20 MUg/g (LC40), and 0.26 MUg/g (LC50) administered through artificial diet. At three sublethal dosages, cyantraniliprole inhibited larval feeding processes, decreased the relative growth rate, the relative consumption rate, the efficiency of food ingestion, and the efficiency of food digestion, as well as decreased the contents of nutrients such as proteins, lipids, and carbohydrates. All these effects go against to the normal growth of O. furnacalis, including reductions in larval and pupal weight, the extension of the larval and pupal period, the prolongation of the adult preoviposition period, total preoviposition period, and mean generation time, and the reduction of adult longevity, oviposition period, and eggs laid by female adults. Together, these changes resulted in the reduction of the intrinsic rate of increase. Hence, even at sublethal concentrations, cyantraniliprole can affect population dynamics by reducing the survival rate, fecundity, and population parameters. This result provides useful information for developing control strategies for O. furnacalis. PMID- 28011689 TI - Performance of a Genetically Modified Strain of the Mediterranean Fruit Fly (Diptera: Tephritidae) for Area-Wide Integrated Pest Management With the Sterile Insect Technique. AB - The genetically modified strain of Ceratitis capitata (Wiedemann) VIENNA 8 1260 has two morphological markers that exhibit fluorescence in body and sperm. To assess the feasibility of its use in area-wide integrated pest management (AW IPM) programs using the sterile insect technique, its rearing performance and quality control profile under small, medium, and large scales was evaluated, as well as in field cages. The VIENNA 8 1260 strain had a lower yield than the control strains, VIENNA 8 with D53 inversion (VIENNA 8) and without D53 inversion (VIENNA 8 D53-). At mass-rearing scale, yield gradually increased in three generations without reaching the control strain values. The VIENNA 8 1260 strain was stable in the genetic sexing mechanism (>99.9%) and expression of fluorescence (100%). In field cages, the VIENNA 8 1260 males reduced the mating potential of wild males in the same magnitude as the VIENNA 8, when evaluated in independent cage tests. However, the relative sterility index and the strain male relative performance index of VIENNA 8 1260 males were significantly lower than those of the VIENNA 8. There were no significant differences in longevity of these strains. The potential application of the VIENNA 8 1260 in AW-IPM programs is further discussed. PMID- 28011691 TI - CORRECTION. PMID- 28011690 TI - Induced Genome-Wide Binding of Three Arabidopsis WRKY Transcription Factors during Early MAMP-Triggered Immunity. AB - During microbial-associated molecular pattern-triggered immunity (MTI), molecules derived from microbes are perceived by cell surface receptors and upon signaling to the nucleus initiate a massive transcriptional reprogramming critical to mount an appropriate host defense response. WRKY transcription factors play an important role in regulating these transcriptional processes. Here, we determined on a genome-wide scale the flg22-induced in vivo DNA binding dynamics of three of the most prominent WRKY factors, WRKY18, WRKY40, and WRKY33. The three WRKY factors each bound to more than 1000 gene loci predominantly at W-box elements, the known WRKY binding motif. Binding occurred mainly in the 500-bp promoter regions of these genes. Many of the targeted genes are involved in signal perception and transduction not only during MTI but also upon damage-associated molecular pattern-triggered immunity, providing a mechanistic link between these functionally interconnected basal defense pathways. Among the additional targets were genes involved in the production of indolic secondary metabolites and in modulating distinct plant hormone pathways. Importantly, among the targeted genes were numerous transcription factors, encoding predominantly ethylene response factors, active during early MTI, and WRKY factors, supporting the previously hypothesized existence of a WRKY subregulatory network. Transcriptional analysis revealed that WRKY18 and WRKY40 function redundantly as negative regulators of flg22-induced genes often to prevent exaggerated defense responses. PMID- 28011692 TI - Different Endomembrane Trafficking Pathways Establish Apical and Basal Polarities. AB - The endomembrane system is an interconnected network required to establish signal transduction, cell polarity, and cell shape in response to developmental or environmental stimuli. In the model plant Arabidopsis thaliana, there are numerous markers to visualize polarly localized plasma membrane proteins utilizing endomembrane trafficking. Previous studies have shown that the large ARF-GEF GNOM plays a key role in the establishment of basal (rootward) polarity, whereas the apically (shootward) polarized membrane proteins undergo sorting via different routes. However, the mechanism that maintains apical polarity is largely unknown. Here, we used a chemical genomic approach and identified the compound endosidin 16 (ES16), which perturbed apically localized plasma membrane proteins without affecting basal polarity. We demonstrated that ES16 is an inhibitor for recycling of apical, lateral, and nonpolar plasma membrane proteins as well as biosynthetic secretion, leaving the basal proteins as the only exceptions not subject to ES16 inhibition. Further evidence from pharmaceutical and genetic data revealed that ES16 effects are mediated through the regulation of small GTPase RabA proteins and that RabA GTPases work in concert with the BIG clade ARF-GEF to modulate the nonbasal trafficking. Our results reveal that ES16 defines a distinct pathway for endomembrane sorting routes and is essential for the establishment of cell polarity. PMID- 28011693 TI - Protein Phosphatase 2Cs and Microtubule-Associated Stress Protein 1 Control Microtubule Stability, Plant Growth, and Drought Response. AB - Plant growth is coordinated with environmental factors, including water availability during times of drought. Microtubules influence cell expansion; however, the mechanisms by which environmental signals impinge upon microtubule organization and whether microtubule-related factors limit growth during drought remains unclear. We found that three Clade E Growth-Regulating (EGR) Type 2C protein phosphatases act as negative growth regulators to restrain growth during drought. Quantitative phosphoproteomics indicated that EGRs target cytoskeleton and plasma membrane-associated proteins. Of these, Microtubule-Associated Stress Protein 1 (MASP1), an uncharacterized protein, increased in abundance during stress treatment and could bind, bundle, and stabilize microtubules in vitro. MASP1 overexpression enhanced growth, in vivo microtubule stability, and recovery of microtubule organization during drought acclimation. These MASP1 functions in vivo were dependent on phosphorylation of a single serine. For all EGR and MASP1 mutants and transgenic lines examined, enhanced microtubule recovery and stability were associated with increased growth during drought stress. The EGR MASP1 system selectively regulates microtubule recovery and stability to adjust plant growth and cell expansion in response to changing environmental conditions. Modification of EGR-MASP1 signaling may be useful to circumvent negative growth regulation limiting plant productivity. EGRs are likely to regulate additional proteins involved in microtubule stability and stress signaling. PMID- 28011696 TI - Genotypic characterization and biofilm formation of Shiga toxin-producing Escherichia coli. AB - Shiga toxin-producing Escherichia coli (STEC) are recognized as one of the most dangerous foodborne pathogens. The production of Shiga toxins together with intimin protein is among the main virulence factors. However, the ability to form biofilm can protect bacteria against environmental factors (i.e. desiccation, exposure to UV rays, predation, etc.) and sanitization procedures (cleaning, rinsing, chlorination), increasing their survival on food products and in manufacturing plants. Forty-five isolates collected from food and fecal samples were genotyped by pulsed field gel electrophoresis analysis with XbaI restriction enzyme and investigated by searching for toxins (stx1, stx2) and intimin (eae) genes and serogroup (O157, O26, O145, O111, O103 and O104). Afterward, the ability to develop biofilm in microtiter assay and the production of adhesive curli fimbriae and cellulose on agar plates were tested. Our study demonstrated that biofilm formation has a great variability among STEC strains and cannot be related to a specific pulsotype nor even to serogroup or presence of virulence genes. PMID- 28011695 TI - Chaetomium globosum CDW7, a potential biological control strain and its antifungal metabolites. AB - Screening for endophytic fungi with antifungal activity is an effective strategy for the discovery of novel biopesticides. Our previous work indicated that Chaetomium globosum CDW7, an endophyte from Ginkgo biloba, exhibited strong inhibitory activity against plant pathogenic fungi in vitro. In this study, we evaluated the CDW7 strain for its antifungal activities against nine phytopathogenic fungi and its biocontrol potential against rape sclerotinia rot caused by Sclerotinia sclerotiorum. The fermentation broth of CDW7 could successfully inhibit disease development in S. sclerotiorum-infected rape in vivo with 57.8% protective efficiency, which is comparable to that of carbendazim (59.8%) at 250 MUg mL-1. The fermentation broth also expressed significant activity stability when exposed to 60 degrees C and UV illumination, or when stored at 4 degrees C. Furthermore, we found that 10% fermentation broth can promote the germination and growth of rape seedlings. Followed by the bioassay guided approach, seven known metabolites were isolated and identified by spectroscopic analyses. Among them, chaetoglobosin A and D exhibited inhibitory activity against S. sclerotiorum with IC50 values of 0.35 and 0.62 MUg mL-1, respectively, compared with carbendazim (0.17 MUg mL-1). Therefore, our study demonstrated that CDW7 is a promising biocontrol fungus against S. sclerotiorum in agriculture. PMID- 28011694 TI - WIND1 Promotes Shoot Regeneration through Transcriptional Activation of ENHANCER OF SHOOT REGENERATION1 in Arabidopsis. AB - Many plant species display remarkable developmental plasticity and regenerate new organs after injury. Local signals produced by wounding are thought to trigger organ regeneration but molecular mechanisms underlying this control remain largely unknown. We previously identified an AP2/ERF transcription factor WOUND INDUCED DEDIFFERENTIATION1 (WIND1) as a central regulator of wound-induced cellular reprogramming in plants. In this study, we demonstrate that WIND1 promotes callus formation and shoot regeneration by upregulating the expression of the ENHANCER OF SHOOT REGENERATION1 (ESR1) gene, which encodes another AP2/ERF transcription factor in Arabidopsis thaliana The esr1 mutants are defective in callus formation and shoot regeneration; conversely, its overexpression promotes both of these processes, indicating that ESR1 functions as a critical driver of cellular reprogramming. Our data show that WIND1 directly binds the vascular system-specific and wound-responsive cis-element-like motifs within the ESR1 promoter and activates its expression. The expression of ESR1 is strongly reduced in WIND1-SRDX dominant repressors, and ectopic overexpression of ESR1 bypasses defects in callus formation and shoot regeneration in WIND1-SRDX plants, supporting the notion that ESR1 acts downstream of WIND1. Together, our findings uncover a key molecular pathway that links wound signaling to shoot regeneration in plants. PMID- 28011697 TI - Incidental mutations occur frequently during transposon mutagenesis. AB - Transposon mutagenesis and subsequent phenotype-driven screening have been extensively used to annotate gene function and uncover the mechanisms of biological phenomena. During this process, the resulting phenotypic differences are specifically attributable to the disrupted genes. In this study, the complementation of the mini-Tn10 transposon-disrupted gene gntP did not restore the germination ability of the Bacillus thuringiensis MT1518-1 mutant to the wild type level. Genome sequencing identified 186 unlinked mutations on the chromosome of the mutant MT1518-1, including one frameshift mutation in the germination related gene exsA. We randomly selected 19 mini-Tn10 mutants for high throughput genome sequencing. The sequencing data revealed that incidental mutations occurred frequently on their chromosomes, including 2343 single-nucleotide polymorphisms, three insertions and one deletion. We also found that stressful conditions are the underlying cause for the appearance of incidental mutations. Caution is warranted when attributing the observed phenotypic changes to the transposon-disrupted genes. PMID- 28011698 TI - Pseudomonas baetica: pathogenicity for marine fish and development of protocols for rapid diagnosis. AB - Pseudomonas baetica is a pathogen isolated in 2012 from wedge sole (Dicologoglossa cuneata). The aims of this study were (i) to determine the influence of temperature on its virulence, and (ii) to develop specific protocols for rapid diagnosis. Virulence assays carried out by bath using Senegalese sole fry showed that virulence is strongly influenced by temperature: LD50 at 14 degrees C was 8.5 * 105 cfu ml-1 while at 20 degrees C no mortalities were recorded. On the other hand, the high mortality rates observed in virulence assays involving intraperitoneal injection of 2.5 * 105 cfu g-1 suggest that P. baetica may be pathogenic for the five fish species tested (wedge sole, Senegalese sole, sea bream, European sea bass and meagre). Two PCR protocols, using specific primers targeting the gyrB and rpoD genes, were developed for rapid diagnosis from pure cultures. An additional protocol, using both primer sets, was also optimized for detection from fish tissue samples. Specificity was tested using 81 strains from 66 bacterial species, taxonomically and/or ecologically related; only the P. baetica strains showed the expected DNA amplicons. A specific dot-blot assay using polyclonal antibodies was also developed for differentiation of P. baetica from related species. Altogether, the protocols described here will constitute useful tools for diagnosis and clarify the relevance of this pathogen. PMID- 28011699 TI - Analysis of evolving lysogenised products of spontaneous zygogenesis in Escherichia coli. AB - Subclonal analysis of spontaneous zygogenesis (Z-mating) products of Escherichia coli K12 was undertaken to grasp the extent of vertical and horizontal evolution in unstable strains expressing one parental or recombinant genome. Isolates were obtained following serial cultures or serial intercrosses. A high diversity of strains was obtained, among which some resumed the phenotype of the partners of the initial or subsequent Z-matings. When non-complementing diploids are infected with a mixture of distinct temperate bacteriophages, lysogenisation occurs at the expenses of the active chromosome only. This event is associated with an alternate expression of prophage and chromosomal genes. Present work provides further evidence for the existence of non-complementing diploidy and opens a novel route for virus research in general. PMID- 28011700 TI - Role of the Talaromyces marneffei (Penicillium marneffei) sakA gene in nitrosative stress response, conidiation and red pigment production. AB - Stress-activated MAPK pathways are systems used to regulate the stress adaptation of most fungi. It has been shown that in Talaromyces marneffei (Penicillium marneffei), a pathogenic dimorphic fungus, the sakA gene is involved, not only in tolerance against oxidative and heat stresses, but also in playing a role in asexual development, yeast cell generation in vitro and survival inside macrophage cell lines. In this study, the role of the T. marneffei sakA gene on the nitrosative stress response and the regulation of gene expression were investigated. The susceptibility of the sakA mutant to NaNO2 was investigated using drop dilution assay and the expression of genes of interest were determined by RT-PCR, comparing them to the wild-type and complemented strains. The results demonstrated that the T. marneffei sakA gene played a role in the stress response to NaNO2, the expression of genes functioning in conidial development (brlA, abaA and wetA) and red pigment biosynthesis (pks3, rp1, rp2 and rp3). These findings suggest that T. marneffei sakA is broadly involved in a wide variety of cell activities, including stress response, cell morphogenesis, asexual development and pigmentation. PMID- 28011701 TI - Use of pan-genome analysis for the identification of lineage-specific genes of Helicobacter pylori. AB - The human bacterial pathogen Helicobacter pylori has a highly variable genome, with significant allelic and sequence diversity between isolates and even within well-characterised strains, hampering comparative genomics of H. pylori In this study, pan-genome analysis has been used to identify lineage-specific genes of H. pylori A total of 346 H. pylori genomes spanning the hpAfrica1, hpAfrica2, hpAsia2, hpEurope, hspAmerind and hspEAsia multilocus sequence typing (MLST) lineages were searched for genes specifically overrepresented or underrepresented in MLST lineages or associated with the cag pathogenicity island. The only genes overrepresented in cag-positive genomes were the cag pathogenicity island genes themselves. In contrast, a total of 125 genes were either overrepresented or underrepresented in one or more MLST lineages. Of these 125 genes, alcohol/aldehyde-reducing enzymes linked with acid resistance and production of toxic aldehydes were found to be overrepresented in African lineages. Conversely, the FecA2 ferric citrate receptor was missing from hspAmerind genomes, but present in all other lineages. This work shows the applicability of pan-genome analysis for identification of lineage-specific genes of H. pylori, facilitating further investigation to allow linkage of differential distribution of genes with disease outcome or virulence of H. pylori. PMID- 28011702 TI - Branding yourself effective communication skills. PMID- 28011703 TI - Optogenetic termination of ventricular arrhythmias in the whole heart: towards biological cardiac rhythm management. AB - Aims: Current treatments of ventricular arrhythmias rely on modulation of cardiac electrical function through drugs, ablation or electroshocks, which are all non biological and rather unspecific, irreversible or traumatizing interventions. Optogenetics, however, is a novel, biological technique allowing electrical modulation in a specific, reversible and trauma-free manner using light-gated ion channels. The aim of our study was to investigate optogenetic termination of ventricular arrhythmias in the whole heart. Methods and results: Systemic delivery of cardiotropic adeno-associated virus vectors, encoding the light-gated depolarizing ion channel red-activatable channelrhodopsin (ReaChR), resulted in global cardiomyocyte-restricted transgene expression in adult Wistar rat hearts allowing ReaChR-mediated depolarization and pacing. Next, ventricular tachyarrhythmias (VTs) were induced in the optogenetically modified hearts by burst pacing in a Langendorff setup, followed by programmed, local epicardial illumination. A single 470-nm light pulse (1000 ms, 2.97 mW/mm2) terminated 97% of monomorphic and 57% of polymorphic VTs vs. 0% without illumination, as assessed by electrocardiogram recordings. Optical mapping showed significant prolongation of voltage signals just before arrhythmia termination. Pharmacological action potential duration (APD) shortening almost fully inhibited light-induced arrhythmia termination indicating an important role for APD in this process. Conclusion: Brief local epicardial illumination of the optogenetically modified adult rat heart allows contact- and shock-free termination of ventricular arrhythmias in an effective and repetitive manner after optogenetic modification. These findings could lay the basis for the development of fundamentally new and biological options for cardiac arrhythmia management. PMID- 28011704 TI - Adult congenital heart disease: the challenges of a lifetime. AB - The growing population of adults with congenital heart disease (CHD) poses challenges for cardiac surgeons, general cardiologists and CHD sub specialists. The patients themselves, often believing themselves to be 'totally corrected' following operative repair, also face challenges with re-operations and lifelong cardiac problems. This review examines the challenges of the past, present and future for both medical providers and patients. PMID- 28011705 TI - Pulmonary hypertension in heart failure with preserved ejection fraction: a plea for proper phenotyping and further research. PMID- 28011706 TI - Profiling and validation of circulating microRNAs for cardiovascular events in patients presenting with ST-segment elevation myocardial infarction. AB - Aims: MicroRNAs (miRNA) are important non-coding modulators controlling patterns of gene expression. However, profiling and validation of circulating miRNA levels related to adverse cardiovascular outcome has not been performed in patients with an acute coronary syndrome (ACS). Methods and results: In a multicentre, prospective ACS cohort, 1002 out of 2168 patients presented with ST-segment elevation myocardial infarction (STEMI). Sixty-three STEMI patients experienced an adjudicated major cardiovascular event (MACE, defined as cardiac death or recurrent myocardial infarction) within 1 year of follow-up. From a miRNA profiling in a matched derivation case-control cohort, 14 miRNAs were selected for validation. Comparing 63 cases vs. 126 controls, 3 miRNAs were significantly differentially abundant. In patients with MACE, miR-26b-5p levels (P = 0.038) were decreased, whereas miR-320a (P = 0.047) and miR-660-5p (P = 0.01) levels were increased. MiR-26b-5p has been suggested to prevent adverse cardiomyocyte hypertrophy, whereas miR-320a promotes cardiomyocyte death and apoptosis, and miR 660-5p has been related to active platelet production. This suggests that miR-26b 5p, miR-320a, and miR-660-5p may reflect alterations of different pathophysiological pathways involved in clinical outcome after ACS. Consistently, these three miRNAs reliably discriminated cases from controls [area under the receiver-operating characteristic curve (AUC) in age- and sex-adjusted Cox regression for miR-26b-5p = 0.707, miR-660-5p = 0.683, and miR-320a =0.672]. Combination of the three miRNAs further increased AUC to 0.718. Importantly, addition of the three miRNAs to both, the Global Registry of Acute Coronary Events (GRACE) score and a clinical model increased AUC from 0.679 to 0.720 and 0.722 to 0.732, respectively, with a net reclassification improvement of 0.20 in both cases. Conclusion: This is the first study performing profiling and validation of miRNAs that are associated with adverse cardiovascular outcome in patients with STEMI. MiR-26b-5p, miR-320a, and miR-660-5p discriminated for MACE and increased risk prediction when added to the GRACE score and a clinical model. These findings suggest that the release of specific miRNAs into circulation may reflect the activation of molecular pathways that impact on clinical outcome after STEMI. PMID- 28011707 TI - Fatty acid binding profile of the liver X receptor alpha. AB - Liver X receptor (LXR)alpha is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRalpha binds to and is regulated by synthetic (T 0901317, GW3695) and endogenous (oxysterols) ligands. LXRalpha activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXRalpha remains unknown. We investigated whether LXRalpha binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated whether FAs regulate LXRalpha activation. Saturated medium-chain FA (MCFA) displayed binding affinities in the low nanomolar concentration range, while long-chain fatty acyl-CoA did not bind or bound weakly to LXRalpha. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXRalpha ligand binding pocket similar to the known synthetic agonist of LXRalpha (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXRalpha, whereas long-chain FA caused no effect. Our results suggest that LXRalpha functions as a receptor for saturated FA or acyl-CoA of C10 and C12 in length. PMID- 28011708 TI - More ACTIONS needed to reach a consensus on adjunctive antidepressant therapy for negative symptoms of schizophrenia. PMID- 28011709 TI - Cognitive-behavioural group therapy for youth with high-functioning autism spectrum disorders demonstrates modest effects on social responsiveness. PMID- 28011710 TI - Identification of novel loci affecting circulating chromogranins and related peptides. AB - Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 * 10-30 for rs4253311 and 1.85 * 10-19 for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro. PMID- 28011711 TI - Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration?. AB - Although numerous common age-related macular degeneration (AMD) alleles have been discovered using genome-wide association studies, substantial disease heritability remains unexplained. We sought to identify additional common and rare variants associated with advanced AMD. A total of 4,332 cases and 25,268 controls of European ancestry from three different populations were genotyped using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants, and single variant and gene-based burden tests to identify rare variants. Two protective, low-frequency, non synonymous variants were significantly associated with a decrease in AMD risk: A307V in PELI3 (odds ratio [OR] = 0.14, P = 4.3 * 10-10) and N1050Y in CFH (OR = 0.76, P = 6.2 * 10-12). The new variants have a large effect size, similar to some rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR = 18.82, P = 3.5 * 10-07), C3 K155Q (OR = 3.27, P = 1.5 * 10-10) and C9 P167S (OR = 2.04, P = 2.8 * 10-07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR = 0.71, P = 1.8 * 10-07). Suggestive protective loci were identified in the COL4A3 and APOH genes. Our results support the involvement of common and low-frequency protective variants in this vision-threatening condition. This study expands the roles of the innate immune pathway as well as the extracellular matrix and high-density lipoprotein pathways in the aetiology of AMD. PMID- 28011712 TI - Genome-wide association study of Parkinson's disease in East Asians. AB - Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci. PMID- 28011713 TI - Germline compound heterozygous poly-glutamine deletion in USF3 may be involved in predisposition to heritable and sporadic epithelial thyroid carcinoma. AB - Cowden syndrome (CS) is an autosomal dominant disorder that predisposes to breast, thyroid, and other epithelial cancers. Differentiated thyroid carcinoma (DTC), as one of the major component cancers of CS, is the fastest rising incident cancer in the USA, and the most familial of all solid tumours. To identify additional candidate genes of CS and potentially DTC, we analysed a multi-generation CS-like family with papillary thyroid cancer (PTC), applying a combined linkage-based and whole-genome sequencing strategy and identified an in frame germline compound heterozygous deletion, p.[Gln1478del];[Gln1476 Gln1478del] in USF3 (previously known as KIAA2018). Among 90 unrelated CS/CS-like individuals, 29% were found to have p.[Gln1478del];[Gln1476-Gln1478del]. Of 497 TCGA PTC individuals, 138 (27%) were found to carry this germline compound deletion, with somatically decreased tumour USF3 expression. We demonstrate an increased migration phenotype along with enhanced epithelial-to-mesenchymal transition (EMT) signature after USF3 knockdown or USF3 p.[Gln1478del];[Gln1476 Gln1478del] overexpression, which sensitizes cells to the endoplasmic reticulum (ER) stress. Loss of USF3 function induced cell necrosis-like features and impaired respiratory capacity while providing a glutamine-dependent cell survival advantage, strongly suggests a metabolic survival and migration-favouring microenvironment for carcinogenesis. Therefore, USF3 may be involved in the predisposition of thyroid cancer. Importantly, the results that glutamine dependent survival and sensitivity to ER stress in USF3-deficient cells provide avenues for therapeutic and adjunct preventive interventions for both sporadic cancer as well as cancer predisposition syndromes with similar mechanisms. PMID- 28011715 TI - Generation of Hoxc13 knockout pigs recapitulates human ectodermal dysplasia-9. AB - Atrichia and sparse hair phenotype cause distress to many patients. Ectodermal dysplasia-9 (ED-9) is a congenital condition characterized by hypotrichosis and nail dystrophy without other disorders, and Hoxc13 is a pathogenic gene for ED-9. However, mice carrying Hoxc13 mutation present several other serious disorders, such as skeletal defects, progressive weight loss and low viability. Mouse models cannot faithfully mimic human ED-9. In this study, we generated an ED-9 pig model via Hoxc13 gene knockout through single-stranded oligonucleotides (c.396C > A) combined with CRISPR/Cas9 and somatic cell nuclear transfer. Eight cloned piglets with three types of biallelic mutations (five piglets with Hoxc13c.396C > A/c.396C > A, two piglets with Hoxc13c.396C > A/c.396C > A + 1 and one piglet with Hoxc13Delta40/Delta40) were obtained. Hoxc13 was not expressed in pigs with all three mutation types, and the expression levels of Hoxc13-regulated genes, namely, Foxn1, Krt85 and Krt35, were decreased. The hair follicles displayed various abnormal phenotypes, such as reduced number of follicles and disarrayed hair follicle cable without normal hair all over the body. By contrast, the skin structure, skeleton phenotype, body weight gain and growth of Hoxc13 knockout pigs were apparently normal. The phenotypes of Hoxc13 mutation in pigs were similar to those in ED-9 patients. Therefore, Hoxc13 knockout pigs could be utilized as a model for ED-9 pathogenesis and as a hairless model for hair regeneration research. Moreover, the hairless pigs without other major abnormal phenotypes generated in this study could be effective models for other dermatological research because of the similarity between pig and human skins. PMID- 28011716 TI - Inorganic nitrogen form: a major player in wheat and Arabidopsis responses to elevated CO2. AB - Critical for predicting the future of primary productivity is a better understanding of plant responses to rising atmospheric carbon dioxide (CO2) concentration. This review considers recent results on the role of the inorganic nitrogen (N) forms nitrate (NO3-) and ammonium (NH4+) in determining the responses of wheat and Arabidopsis to elevated atmospheric CO2 concentration. Here, we identify four key issues: (i) the possibility that different plant species respond similarly to elevated CO2 if one accounts for the N form that they are using; (ii) the major influence that plant-soil N interactions have on plant responses to elevated CO2; (iii) the observation that elevated CO2 may favor the uptake of one N form over others; and (iv) the finding that plants receiving NH4+ nutrition respond more positively to elevated CO2 than those receiving NO3- nutrition because elevated CO2 inhibits the assimilation of NO3- in shoots of C3 plants. We conclude that the form and amount of N available to plants from the rhizosphere and plant preferences for the different N forms are essential for predicting plant responses to elevated CO2. PMID- 28011714 TI - Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions. AB - Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease. PMID- 28011717 TI - Hormonal regulation of reproductive growth under normal and heat-stress conditions in legume and other model crop species. AB - Legume crops are grown throughout the world and provide an excellent food source of digestible protein and starch, as well as dietary fibre, vitamins, minerals, and flavonoids. Fruit and seeds from legumes are also an important source of vegetables for a well-balanced diet. A trend in elevated temperature as a result of climate change increases the risk of a heat stress-induced reduction in legume crop yield. High temperatures during the crop reproductive development phase are particularly detrimental to fruit/seed production because the growth and development of the reproductive tissues are sensitive to small changes in temperature. Hormones are signalling molecules that play important roles in a plant's ability to integrate different environmental inputs and modify their developmental processes to optimize growth, survival, and reproduction. This review focuses on the hormonal regulation of reproductive development and heat stress-induced alteration of this regulation during (i) pollination, (ii) early fruit set, and (iii) seed development that affects fruit/seed yield in legume and other model crops. Further understanding of hormone-regulated reproductive growth under non-stress and heat-stress conditions can aid in trait selection and the development of gene modification strategies and cultural practices to improve heat tolerance in legume crops contributing to improved food security. PMID- 28011718 TI - High serine:glyoxylate aminotransferase activity lowers leaf daytime serine levels, inducing the phosphoserine pathway in Arabidopsis. AB - Serine:glyoxylate aminotransferase (SGAT) converts glyoxylate and serine to glycine and hydroxypyruvate during photorespiration. Besides this, SGAT operates with several other substrates including asparagine. The impact of this enzymatic promiscuity on plant metabolism, particularly photorespiration and serine biosynthesis, is poorly understood. We found that elevated SGAT activity causes surprisingly clear changes in metabolism and interferes with photosynthetic CO2 uptake and biomass accumulation of Arabidopsis. The faster serine turnover during photorespiration progressively lowers day-time leaf serine contents and in turn induces the phosphoserine pathway. Transcriptional upregulation of this additional route of serine biosynthesis occurs already during the day but particularly at night, efficiently counteracting night-time serine depletion. Additionally, higher SGAT activity results in an increased use of asparagine as the external donor of amino groups to the photorespiratory pathway but does not alter leaf asparagine content at night. These results suggest leaf SGAT activity needs to be dynamically adjusted to ensure (i) variable flux through the photorespiratory pathway at a minimal consumption of asparagine and (ii) adequate serine levels for other cellular metabolism. PMID- 28011719 TI - Coordinated regulation of photosynthetic and respiratory components is necessary to maintain chloroplast energy balance in varied growth conditions. AB - Mitochondria have a non-energy-conserving alternative oxidase (AOX) proposed to support photosynthesis, perhaps by promoting energy balance under varying growth conditions. To investigate this, wild-type (WT) Nicotiana tabacum were compared with AOX knockdown and overexpression lines. In addition, the amount of AOX protein in WT plants was compared with that of chloroplast light-harvesting complex II (LHCB2), whose amount is known to respond to chloroplast energy status. With increased growth irradiance, WT leaves maintained higher rates of respiration in the light (RL), but no differences in RL or photosynthesis were seen between the WT and transgenic lines, suggesting that, under non-stress conditions, AOX was not critical for leaf metabolism, regardless of growth irradiance. However, under drought, the AOX amount became an important determinant of RL, which in turn was an important determinant of chloroplast energy balance (measured as photosystem II excitation pressure, EP), and photosynthetic performance. In the WT, the AOX amount increased and the LHCB2 amount decreased with increased growth irradiance or drought severity. These changes in protein amounts correlated strongly, in opposing ways, with growth EP. This suggests that a signal deriving from the photosynthetic electron transport chain status coordinately controls the amounts of AOX and LHCB2, which then both contribute to maintaining chloroplast energy balance, particularly under stress conditions. PMID- 28011720 TI - Exploiting the great potential of Sequence Capture data by a new tool, SUPER-CAP. AB - The recent development of Sequence Capture methodology represents a powerful strategy for enhancing data generation to assess genetic variation of targeted genomic regions. Here, we present SUPER-CAP, a bioinformatics web tool aimed at handling Sequence Capture data, fine calculating the allele frequency of variations and building genotype-specific sequence of captured genes. The dataset used to develop this in silico strategy consists of 378 loci and related regulative regions in a collection of 44 tomato landraces. About 14,000 high quality variants were identified. The high depth (>40*) of coverage and adopting the correct filtering criteria allowed identification of about 4,000 rare variants and 10 genes with a different copy number variation. We also show that the tool is capable to reconstruct genotype-specific sequences for each genotype by using the detected variants. This allows evaluating the combined effect of multiple variants in the same protein. The architecture and functionality of SUPER-CAP makes the software appropriate for a broad set of analyses including SNP discovery and mining. Its functionality, together with the capability to process large data sets and efficient detection of sequence variation, makes SUPER-CAP a valuable bioinformatics tool for genomics and breeding purposes. PMID- 28011721 TI - Genome analysis of Hibiscus syriacus provides insights of polyploidization and indeterminate flowering in woody plants. AB - Hibiscus syriacus (L.) (rose of Sharon) is one of the most widespread garden shrubs in the world. We report a draft of the H. syriacus genome comprised of a 1.75 Gb assembly that covers 92% of the genome with only 1.7% (33 Mb) gap sequences. Predicted gene modeling detected 87,603 genes, mostly supported by deep RNA sequencing data. To define gene family distribution among relatives of H. syriacus, orthologous gene sets containing 164,660 genes in 21,472 clusters were identified by OrthoMCL analysis of five plant species, including H. syriacus, Arabidopsis thaliana, Gossypium raimondii, Theobroma cacao and Amborella trichopoda. We inferred their evolutionary relationships based on divergence times among Malvaceae plant genes and found that gene families involved in flowering regulation and disease resistance were more highly divergent and expanded in H. syriacus than in its close relatives, G. raimondii (DD) and T. cacao. Clustered gene families and gene collinearity analysis revealed that two recent rounds of whole-genome duplication were followed by diploidization of the H. syriacus genome after speciation. Copy number variation and phylogenetic divergence indicates that WGDs and subsequent diploidization led to unequal duplication and deletion of flowering-related genes in H. syriacus and may affect its unique floral morphology. PMID- 28011722 TI - Evaluation of Doxycycline-Laden Oral Bait and Topical Fipronil Delivered in a Single Bait Box to Control Ixodes scapularis (Acari: Ixodidae) and Reduce Borrelia burgdorferi and Anaplasma phagocytophilum Infection in Small Mammal Reservoirs and Host-Seeking Ticks. AB - A field trial was conducted on residential properties in a Lyme disease endemic area of New Jersey to determine the efficacy of Maxforce Tick Management System (TMS) bait boxes modified with doxycycline hyclate-laden bait to reduce the acarological risk of Lyme disease and the utility of galvanized steel shrouds to protect the bait boxes from squirrel depredation and ability to routinely service these devices. The strategy began with a 9-wk deployment against larvae followed by a 17-wk deployment against nymphs and larvae the second year. Passive application of fipronil reduced nymphal and larval tick burdens on small mammals by 76 and 77%, respectively, and nymphal tick abundance by 81% on treated properties. In addition, the percentage of infected small mammals recovered from intervention areas following treatment was reduced by 96% for Borrelia burgdorferi and 93% for Anaplasma phagocytophilum. Infection prevalence in host seeking nymphal ticks for both B. burgdorferi and A. phagocytophilum were reduced by 93 and 61%, respectively. Results indicate that Maxforce TMS bait boxes fitted with doxycycline-impregnated bait is an effective means of reducing ticks and infection prevalence for B. burgdorferi and A. phagocytophilum in both rodent reservoirs and questing Ixodes scapularis Say ticks. The protective shroud allows the device to be routinely serviced and protect against squirrel depredation. PMID- 28011723 TI - Low Temperature Tolerance of Culicoides sonorensis (Diptera: Ceratopogonidae) Eggs, Larvae, and Pupae From Temperate and Subtropical Climates. AB - Culicoides sonorensis Wirth and Jones biting midges are the primary North American vectors of bluetongue virus (BTV), which infects domestic ruminant livestock and can cause high morbidity and mortality. Both virus and vector exhibit highly seasonal activity patterns, even in subtropical climates like southern California. However, the exact mechanism of BTV and Culicoides overwintering has been debated. In this study, we examined the supercooling point (SCP) and lower lethal temperature of a laboratory colony of C. sonorensis eggs, larvae, and pupae, as well as of field-collected larvae and pupae from subtropical (California) and temperate (Colorado) climates. Larvae and pupae succumbed to temperatures higher than their respective SCPs, indicating death from prefreezing cold injury. Eggs were the most cold-tolerant life stage, and were able to tolerate 1-h exposures to temperatures as low as -20 degrees C without suffering complete mortality. Larvae were the least cold-tolerant life stage and suffered complete mortality at < -4 degrees C, while temperatures of 9 to -10 degrees C were required to kill all pupae. Larvae and embryos suffered chronic cold injury after exposure to subzero temperatures, which increased mortality. Field-collected larvae succumbed to slightly higher temperatures ( > 3 degrees C) than colony larvae, but did not differ significantly in their survival. Culicoides sonorensis immatures did not cold harden when exposed to 4 degrees C for 24 h before freezing. Results of this study indicate that C. sonorensis eggs are more tolerant of environmental stress than previously thought. Further work is needed on C. sonorensis winter survival in the field to corroborate laboratory studies. PMID- 28011724 TI - Toxicity and Synergistic Activities of Chalcones Against Aedes aegypti (Diptera: Culicidae) and Drosophila melanogaster (Diptera: Drosophilidae). AB - Mosquito-borne illnesses are of great concern throughout the world, and chemical insecticides are commonly employed to decrease mosquito populations. However, the developmental insecticide pipeline for vector control has primarily been filled by repurposed agricultural products, and is hampered by their widespread use and insecticide resistance. The present study was performed in the search for new chemical insecticides or insecticide synergists. Screening of 31 chalcone analogs was performed using Aedes aegypti (Linnaeus) first-instar larval toxicity assay, and oral feeding to Drosophila melanogaster's proper authority should be (Meigen). Synergism studies were performed by topically applying chalcones to adult female Ae. aegypti mosquitoes to examine its impact on activity of carbaryl, which was compared to piperonyl butoxide alone. Fourteen chalcone analogs had LC50 values in the range of 0.4-38 ppm against first-instar Ae. aegypti larvae, and three chalcones displayed toxicity against D. melanogaster via feeding (LC50 values ranged from 146-214 MUg/ml). Two chalcones synergized carbaryl toxicity against adult Ae. aegypti with efficacy similar to piperonyl butoxide. As a result, it is concluded that chalcones may serve as novel insecticides and synergists after further structural optimization. PMID- 28011725 TI - Indoor Resting Behavior of Aedes aegypti (Diptera: Culicidae) in Acapulco, Mexico. AB - The markedly anthropophilic and endophilic behaviors of Aedes aegypti (L.) make it a very efficient vector of dengue, chikungunya, and Zika viruses. Although a large body of research has investigated the immature habitats and conditions for adult emergence, relatively few studies have focused on the indoor resting behavior and distribution of vectors within houses. We investigated the resting behavior of Ae. aegypti indoors in 979 houses of the city of Acapulco, Mexico, by performing exhaustive indoor mosquito collections to describe the rooms and height at which mosquitoes were found resting. In total, 1,403 adult and 747 female Ae. aegypti were collected, primarily indoors (98% adults and 99% females). Primary resting locations included bedrooms (44%), living rooms (25%), and bathrooms (20%), followed by kitchens (9%). Aedes aegypti significantly rested below 1.5 m of height (82% adults, 83% females, and 87% bloodfed females); the odds of finding adult Ae. aegypti mosquitoes below 1.5 m was 17 times higher than above 1.5 m. Our findings provide relevant information for the design of insecticide-based interventions selectively targeting the adult resting population, such as indoor residual spraying. PMID- 28011726 TI - Development of the Forensically Important Beetle Creophilus maxillosus (Coleoptera: Staphylinidae) at Constant Temperatures. AB - Creophilus maxillosus (L., 1758) is a common and widely distributed beetle species found on corpses, and its development duration is far longer than species belonging to the genus Calliphoridae and Sarcophagidae. Therefore, C. maxillosus can be used as a supplementary indicator to estimate minimum postmortem interval (PMImin), and could greatly extend the range of PMImin when the primary colonizers are no longer associated with the corpse or have emerged from pupae. Better descriptions of C. maxillosus development are needed to apply this species for forensic investigations. In this study, the development of C. maxillosus at seven constant temperatures ranging from 17.5-32.5 degrees C was studied. Through regression analyses, the simulation equations of larval body length variation with time after hatching were obtained. Isomegalen diagrams of the changes of larval body length over time at specific temperatures, and the isomorphen diagrams on the duration of different developmental milestones at specific temperatures were generated. In addition, thermal summation models of different developmental stages and the overall development process of C. maxillosus were generated through regression analysis, by estimating the development threshold temperatures (D0) and the thermal summation constants (K). These results provide important tools for forensic investigations to generate a long-range of PMImin estimation based on the development of C. maxillosus. PMID- 28011728 TI - Contribution to the Biodiversity Assessment of Mosquitoes (Diptera: Culicidae) in the Atlantic Forest in Santa Catarina, Brazil. AB - The mosquito fauna of a coastal area of Santa Catarina state, Brazil (Baixada do Maciambu), was assessed, and possible mosquito larval habitats were mapped. Five new species records for the state are presented, two of which also are new genera records. From the 24 recognized species present in the area, 28% were from the subfamily Anophelinae and 72% from the Culicinae. The community structure throughout a year, the relevance of the new findings, and the medical importance of some species are discussed. PMID- 28011727 TI - Evaluating the Adaptation Process of Sandfly Fauna to Anthropized Environments in a Leishmaniasis Transmission Area in the Brazilian Amazon. AB - Phlebotomines (Diptera: Psychodidae) are vectors of several etiological agents of human and animal diseases, including protozoans of the gender Leishmania. Precarious socioeconomic conditions and uncontrolled population growth directly influence the transmission risk of parasites and the urbanization of vector species, previously restricted to wild environments. The Marajo Archipelago is considered a high incidence area of leishmaniasis in the Brazilian Amazon. However, it is poorly studied. The aim of this study was to assess the adaptation processes of phlebotomine species to anthropized environments in this region. For this purpose, the phlebotomine fauna was compared between three municipalities of the Marajo Archipelago: Anajas, Portel, and Sao Sebastiao da Boa Vista. To survey the phlebotomine fauna, CDC (Center for Disease Control) light traps were installed in the wild areas and in the intra and peridomiciliary areas of rural and urban environments. The environments studied presented a diversified phlebotomine fauna, with higher richness in the wild environment (15 species), followed by the rural (seven species), and finally, the urban environment (three species). A migration of wild fauna to the adjacent anthropized areas (rural environment) and to urban areas was observed, evidencing the adaptation process of this vector to anthropized environments in the studied region. Thus, our study evidenced that the disorganized human occupation and utilization of the landscape might cause the invasion of urban areas by wild populations of phlebotomines, in this way enabling the settlement of urban leishmaniasis transmission cycles. PMID- 28011729 TI - Variation in Mitochondrial Cytochrome c Oxidase I DNA Can Successfully Identify Culex (Melanoconion) pedroi (Diptera: Culicidae) and Culex (Melanoconion) ribeirensis (Diptera: Culicidae). AB - Culex (Melanoconion) pedroiSirivanakarn & Belkin 1980 and Culex (Melanoconion) ribeirensisForattini & Sallum 1985 are two morphologically very similar species of the Pedroi subgroup of mosquitoes in the Spissipes section of the subgenus Melanoconion of the genus Culex L. 1758. We carried out an analysis of the mitochondrial cytochrome c oxidase I (COI) DNA variation between these two species. The recent observation of sympatric coexistence in a forested area of Rio de Janeiro State (Brazil) triggered the need to validate these two species previously identified based on morphology. We concluded that the COI is a useful tool for identification of Cx. pedroi and Cx. ribeirensis. PMID- 28011730 TI - Arrestant Effect of Human Scalp Components on Head Louse (Phthiraptera: Pediculidae) Behavior. AB - Relevant evidence has shown that parasites process host-related information using chemical, visual, tactile, or auditory cues. However, the cues that are involved in the host-parasite interaction between Pediculus humanus capitis (De Geer 1767) and humans have not been identified yet. In this work, we studied the effect of human scalp components on the behavior of adult head lice. Filter paper segments were rubbed on volunteers' scalps and then placed in the experimental arena, where adult head lice were individually tested. The movement of the insects was recorded for each arena using the software EthoVision. Average movement parameters were calculated for the treatments in the bioassays such as total distance, velocity, number of times a head louse crossed between zones of the arena, and time in each zone of the arena. We found that scalp components induced head lice to decrease average locomotor activity and to remain arrested on the treated paper. The effect of the ageing of human scalp samples in the response of head lice was not statistically significant (i.e., human scalp samples of 4, 18, 40, and 60 h of ageing did not elicit a significant change in head louse behavior). When we analyzed the effect of the sex in the response of head lice to human scalp samples, males demonstrated significant differences. Our results showed for the first time the effect of host components conditioning head lice behavior. We discuss the role of these components in the dynamic of head lice infestation. PMID- 28011731 TI - Distribution of the Habitat Suitability of the Main Malaria Vector in French Guiana Using Maximum Entropy Modeling. AB - Malaria is an important health issue in French Guiana. Its principal mosquito vector in this region is Anopheles darlingi Root. Knowledge of the spatial distribution of this species is still very incomplete due to the extent of French Guiana and the difficulty to access most of the territory. Species distribution modeling based on the maximal entropy procedure was used to predict the spatial distribution of An. darlingi using 39 presence sites. The resulting model provided significantly high prediction performances (mean 10-fold cross-validated partial area under the curve and continuous Boyce index equal to, respectively, 1.11-with a level of omission error of 20%-and 0.42). The model also provided a habitat suitability map and environmental response curves in accordance with the known entomological situation. Several environmental characteristics that had a positive correlation with the presence of An. darlingi were highlighted: nonpermanent anthropogenic changes of the natural environment, the presence of roads and tracks, and opening of the forest. Some geomorphological landforms and high altitude landscapes appear to be unsuitable for An. darlingi. The species distribution modeling was able to reliably predict the distribution of suitable habitats for An. darlingi in French Guiana. Results allowed completion of the knowledge of the spatial distribution of the principal malaria vector in this Amazonian region, and identification of the main factors that favor its presence. They should contribute to the definition of a necessary targeted vector control strategy in a malaria pre-elimination stage, and allow extrapolation of the acquired knowledge to other Amazonian or malaria-endemic contexts. PMID- 28011732 TI - Effects of Irrigation and Rainfall on the Population Dynamics of Rift Valley Fever and Other Arbovirus Mosquito Vectors in the Epidemic-Prone Tana River County, Kenya. AB - Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that is found in most regions of sub-Saharan Africa, and it affects humans, livestock, and some wild ungulates. Outbreaks are precipitated by an abundance of mosquito vectors associated with heavy persistent rainfall with flooding. We determined the impact of flood-irrigation farming and the effect of environmental parameters on the ecology and densities of primary and secondary vectors of the RVF virus (RVFV) in an RVF-epidemic hotspot in the Tana River Basin, Kenya. Mosquito sampling was conducted in farms and villages (settlements) in an irrigated and a neighboring nonirrigated site (Murukani). Overall, a significantly higher number of mosquitoes were collected in farms in the irrigation scheme compared with villages in the same area (P < 0.001), or farms (P < 0.001), and villages (P = 0.03) in Murukani. In particular, key primary vectors of RVFV, Aedes mcintoshi Marks and Aedes ochraceous Theobald, were more prevalent in the farms compared with villages in the irrigation scheme (P = 0.001) both during the dry and the wet seasons. Similarly, there was a greater abundance of secondary vectors, particularly Culex univittatus Theobald and Culex pipiens (L.) in the irrigation scheme than in the Murukani area. Rainfall and humidity were positively correlated with mosquito densities, particularly the primary vectors. Adult floodwater mosquitoes and Mansonia spp. were collected indoors; immatures of Ae. mcintoshi and secondary vectors were collected in the irrigation drainage canals, whereas those of Ae. ochraceous and Aedes sudanensis Theobald were missing from these water bodies. In conclusion, irrigation in RVF endemic areas provides conducive resting and breeding conditions for vectors of RVFV and other endemic arboviruses. PMID- 28011733 TI - Intrinsic Activity of IGRs Against Larval Cat Fleas. AB - Insect growth regulators (IGRs) such as lufenuron, methoprene, and pyriproxyfen have been important tools in the integrated pest management of cat fleas, Ctenocephalides felis (Bouche), for the past two decades. Other IGRs have been registered for the control of termite, dipteran, and lepidopterous pests including chlorfluazuron, cyromazine, dicyclanil, and precocene I, but have been not tested against C. felis. The intrinsic activity of IGRs was determined by exposing larvae to treated larval rearing media. The LC50s of chlorfluazuron, cyromazine, dicyclanil, lufenuron, and precocene I against cat fleas were 0.19, 2.66, 0.04, 0.20, and 10.97 ppm, respectively. The LC95s of chlorfluazuron, cyromazine, dicyclanil, lufenuron, and precocene I were 0.78, 51.24, 0.30, 0.62, and 175.05, respectively. The regression slopes of chlorfluazuron and lufenuron were 2.65 +/- 0.24 and 3.40 +/- 0.45 (SEM), respectively, and considerably steeper than the other IGRs tested (1.51 to 1.74). The intrinsic activity of IGRs tested is summarized as dicyclanil > chlorfluazuron = lufenuron > cyromazine > precocene I. The responses of the laboratory UCR strain to these IGRs can serve as a baseline of susceptibility until a more susceptible cat flea strain is found. Chlorfluazuron and dicyclanil look like promising candidates against cat fleas. PMID- 28011734 TI - Erratum. PMID- 28011735 TI - Occurrence of Amblyomma americanum (Acari: Ixodidae) and Human Infection With Ehrlichia chaffeensis in Wisconsin, 2008-2015. AB - Because of the increasing incidence of human ehrlichiosis in Wisconsin, we assessed reports of human infections by Ehrlichia chaffeensis and the distribution of its vector, the lone star tick (Amblyomma americanum (L.)). From 2008 through 2015, 158 probable and confirmed human cases of E. chaffeensis infections were reported to the Wisconsin Department of Health Services. Five cases without travel history outside of Wisconsin were confirmed as E. chaffeensis by polymerase chain reaction. Surveillance for the vector occurred from 2008 through 2015 and was based on active and passive methods, including examination of white-tailed deer, collections from live-trapped small mammals, submissions of ticks removed from wild and domestic animals through the Wisconsin Surveillance of Animals for Ticks (SWAT) program, digital or physical submissions by the public to the University of Wisconsin Insect Diagnostic or Medical Entomology laboratories, and active tick dragging. More than 50 lone star ticks (46 adults, 6 nymphs, and 1 larva) were identified. Lone star ticks were more commonly found in south central Wisconsin, particularly in Dane County, where discovery of more than one life stage in a single year indicates possible establishment. PMID- 28011737 TI - Influence of the Length of Storage on Aedes aegypti (Diptera: Culicidae) Egg Viability. AB - Aedes aegypti (L.) is one of the most important arboviral vectors worldwide. Vector control is targeted at immature and adult stages; however, eggs are resistant to desiccation and may repopulate treated areas long after treatment ceases. We investigated the effect of age on Ae. aegypti egg hatching rates using newly colonized populations (F2) from an arid region. We found a strongly negative association where older eggs had lower hatch rates. The capacity of eggs to survive for long periods of time has implications on mosquito control. In addition, the accumulation of eggs in containers should be accounted for in abundance modeling efforts where populations may grow rapidly early in the season. PMID- 28011736 TI - Toxicological, Enzymatic, and Molecular Assessment of the Insecticide Susceptibility Profile of Triatoma infestans (Hemiptera: Reduviidae, Triatominae) Populations From Rural Communities of Santa Cruz, Bolivia. AB - A wide range of insecticide resistance profiles has been reported across Bolivian domestic and sylvatic populations of Triatoma infestans (Klug, 1834) (Hemiptera, Reduviidae), including some with levels proven to be a threat for vector control. In this work, the insecticide profile of domestic T. infestans was studied with standardized toxicological bioassays, in an area that has not undergone consistent vector control. F1 first-instar nymphs hatched in laboratory from bugs captured in three communities from the Santa Cruz Department were evaluated with different insecticides. Moreover, the enzymatic activity of esterases and cytochrome P450 monooxygenases was measured in individual insects to evaluate the possible mechanism of metabolic resistance to pyrethroids. In addition, the DNA sequence of sodium channel gene (kdr) was screened for two point mutations associated with pyrethroid resistance previously reported in T. infestans.All populations showed reduced susceptibility to deltamethrin and alpha-cypermethrin, albeit the RR50 values varied significantly among them. Increased P450 monooxygenases and permethrate esterases suggest the contribution, as detoxifying mechanisms, to the observed resistance to deltamethrin in all studied populations. No individuals presented either mutation associated to resistance in the kdr gene. The level of susceptibility to alpha-cypermethrin, the insecticide used by the local vector control program, falls within an acceptable range to continue its use in these populations. However, the observed RR50 values evidence the possibility of selection for resistance to pyrethroids, especially to deltamethrin. Consequently, the use of pyrethroid insecticides should be closely monitored in these communities, which should be kept under entomological surveillance and sustained interventions. PMID- 28011738 TI - Coronary artery and supra-aortic vessel revascularization without aortic clamping for Takayasu arteritis. AB - Takayasu arteritis (TA) is a rare idiopathic large-vessel vasculitis involving the aorta and its major branches. Coronary artery disease and its surgical management in patients with TA is also a rare clinical entity. We report the case of a 73-year-old woman with TA and 3-vessel coronary artery disease in whom we performed off-pump coronary artery bypass graft concomitant with supra-aortic vessel revascularization. PMID- 28011739 TI - Surgical management of aortic coarctation in adolescents and adults. AB - Objectives: Coarctation of the aorta (CoA) in adolescents and adults is often complicated by other cardiac or aortic problems and may carry additional surgical difficulties. Limited studies have reported the surgical outcomes of CoA repair in this particular patient population. We reviewed our contemporary experience of open surgical management of CoA in adolescents and adults. Methods: From 2008 to 2016, a total of 60 adolescents and adults (mean age, 32 years) underwent CoA repair at our centre. Of this cohort, 43 patients only underwent CoA repair (isolated group), while the remaining 17 underwent other concomitant cardiac procedures (concomitant group). Ascending-to-descending aortic bypass was the preferred repair technique in the concomitant group. Aortic valve replacement and a Bentall/David procedure were the two most frequently combined procedures. Results: There were no in-hospital deaths in the isolated group compared with three in the concomitant group (0% vs 17.6%, P = 0.029). The median intensive care unit stay (1 vs 2 days, P <0.01) and postoperative hospital stay (6 vs 9 days, P <0.01) were significantly longer in the concomitant group. Postoperative respiratory failure occurred more frequently in the concomitant group (0% vs 17.6%, P = 0.029). The isolated group had better overall survival during follow up ( P = 0.037). The 5-year overall survival rate was 98% in the isolated group and 82% in the concomitant group. Conclusions: Surgical management of coarctation in adolescents and adults can achieve similar satisfactory outcomes as their neonatal counterparts, but the complexity of the concomitant procedures is a risk factor for this particular patient population. PMID- 28011740 TI - Effects of glutaraldehyde concentration and fixation time on material characteristics and calcification of bovine pericardium: implications for the optimal method of fixation of autologous pericardium used for cardiovascular surgery. AB - Objectives: Autologous pericardium, which is widely used in the field of cardiovascular surgery, is usually fixed with glutaraldehyde (GA) to improve handling and provide biomechanical stability. However, an optimal method of GA fixation of autologous pericardium is not known. The objective of this study was to evaluate the effects of GA concentration and fixation time on material characteristics and calcification of bovine pericardium. Methods: Bovine pericardial tissues were fixed with different concentrations of GA (0.3, 0.4, 0.5 and 0.6%) for different exposure times (10 and 20 min). Material characteristics of the fixed tissues were assessed by mechanical test, thermal stability test and pronase test. The tissues were subcutaneously implanted into 3-week-old rats for 2 months, and the calcium contents of the explanted tissues were measured. Differences between the groups were evaluated by two-way analysis of variance. Results: Differently treated tissues showed no significant differences in tensile strength. The mean elongation at break of the pericardial tissues fixed with 0.5 and 0.6% was significantly higher compared with 0.3 and 0.4% when fixed for 20 min. The mean elongation at break of the pericardial tissues fixed for 20 min was significantly higher compared with 10 min when fixed with 0.5 and 0.6%. Thermal stability test revealed significantly higher mean shrinkage temperature of the pericardial tissues fixed with 0.6% compared with lower concentrations irrespective of fixation time. The mean shrinkage temperature of the pericardial tissues fixed for 20 min was significantly higher compared with 10 min irrespective of GA concentration. Pronase test revealed significantly lower mean percent remaining weight of the pericardial tissues fixed with 0.3% compared with higher concentrations irrespective of fixation time. The mean percent remaining weight of the pericardial tissues fixed for 20 min was significantly higher compared with 10 min irrespective of GA concentration. The mean calcium content of the pericardial tissues fixed with 0.6% was significantly lower than that of the pericardial tissues fixed with 0.4% irrespective of fixation time. Conclusions: Fixation of bovine pericardium with 0.5 and 0.6% GA for 20 min produced superior results with regard to material characteristics (mechanical properties, degree of fixation and resistance to enzymatic degradation) and postimplantation calcification. These results may have implications for optimal fixation of autologous pericardium used for cardiovascular surgery. PMID- 28011741 TI - A novel solution to prosthetic valve dehiscence after aortic valve surgery in Behcet's disease. AB - Objectives: Prosthetic valve dehiscence after aortic valve surgery in Behcet's disease patients is common. We aimed to validate the usefulness of our new technique 'subannular endomyocardial implantation of valve prosthesis' designed to prevent prosthetic valve dehiscence. Methods: Subannular endomyocardial implantation of valve prosthesis involves suturing the sewing cuff of the valve prosthesis in the endomyocardium below the aortic annulus, which is based on the idea that annular tissue should be excluded from the suture line in Behcet's disease patients. Medical records of 7 patients in whom the new technique was performed between 2002 and 2014 were reviewed. Results: Five men and two women were included (median age, 44 years). Aortic root replacement was performed in 6 cases, and aortic valve replacement in 1. No operative mortality occurred. Postoperatively, complete atrioventricular block developed in 3 cases, and permanent pacemakers were implanted in 2. No reoperation was performed for prosthetic valve dehiscence during the median 7.8-year follow-up. One late death occurred due to sudden cardiac arrest 8.4 years after surgery. One additional permanent pacemaker was implanted for complete atrioventricular block, which developed at 4.2 years postoperatively. The last echocardiography (median, 6.7 years after surgery) revealed no paravalvular leakages. Conclusions: Subannular endomyocardial implantation of valve prosthesis seems useful for preventing prosthetic valve dehiscence after aortic valve surgery for Behcet's disease. It poses a risk of complete atrioventricular block, but considering the high reoperation rate and mortality due to prosthetic valve dehiscence after conventional aortic valve surgery, this risk seems reasonable. PMID- 28011742 TI - The Superior Temporal Sulcus Is Causally Connected to the Amygdala: A Combined TBS-fMRI Study. AB - : Nonhuman primate neuroanatomical studies have identified a cortical pathway from the superior temporal sulcus (STS) projecting into dorsal subregions of the amygdala, but whether this same pathway exists in humans is unknown. Here, we addressed this question by combining theta burst transcranial magnetic stimulation (TBS) with fMRI to test the prediction that the STS and amygdala are functionally connected during face perception. Human participants (N = 17) were scanned, over two sessions, while viewing 3 s video clips of moving faces, bodies, and objects. During these sessions, TBS was delivered over the face selective right posterior STS (rpSTS) or over the vertex control site. A region of-interest analysis revealed results consistent with our hypothesis. Namely, TBS delivered over the rpSTS reduced the neural response to faces (but not to bodies or objects) in the rpSTS, right anterior STS (raSTS), and right amygdala, compared with TBS delivered over the vertex. By contrast, TBS delivered over the rpSTS did not significantly reduce the neural response to faces in the right fusiform face area or right occipital face area. This pattern of results is consistent with the existence of a cortico-amygdala pathway in humans for processing face information projecting from the rpSTS, via the raSTS, into the amygdala. This conclusion is consistent with nonhuman primate neuroanatomy and with existing face perception models. SIGNIFICANCE STATEMENT: Neuroimaging studies have identified multiple face-selective regions in the brain, but the functional connections between these regions are unknown. In the present study, participants were scanned with fMRI while viewing movie clips of faces, bodies, and objects before and after transient disruption of the face-selective right posterior superior temporal sulcus (rpSTS). Results showed that TBS disruption reduced the neural response to faces, but not to bodies or objects, in the rpSTS, right anterior STS (raSTS), and right amygdala. These results are consistent with the existence of a cortico-amygdala pathway in humans for processing face information projecting from the rpSTS, via the raSTS, into the amygdala. This conclusion is consistent with nonhuman primate neuroanatomy and with existing face perception models. PMID- 28011744 TI - Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF kappaB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.SIGNIFICANCE STATEMENT We provide evidence that extracellular cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), is a mediator of the neuroinflammatory reaction in amyotrophic lateral sclerosis (ALS) and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons, and extended survival in the SOD1G93A mouse model of familial ALS. Our findings suggest selective pharmacological inhibition of extracellular PPIA as a novel therapeutic strategy, not only for SOD1-linked ALS, but possibly also for sporadic ALS. This approach aims to address the neuroinflammatory reaction that is a major hallmark of ALS. However, given the complexity of the disease, a combination of therapeutic approaches may be necessary. PMID- 28011745 TI - Neural and Behavioral Evidence for an Online Resetting Process in Visual Working Memory. AB - : Visual working memory (VWM) guides behavior by holding a set of active representations and modifying them according to changes in the environment. This updating process relies on a unique mapping between each VWM representation and an actual object in the environment. Here, we destroyed this mapping by either presenting a coherent object but then breaking it into independent parts or presenting an object but then abruptly replacing it with a different object. This allowed us to introduce the neural marker and behavioral consequence of an online resetting process in humans' VWM. Across seven experiments, we demonstrate that this resetting process involves abandoning the old VWM contents because they no longer correspond to the objects in the environment. Then, VWM encodes the novel information and reestablishes the correspondence between the new representations and the objects. The resetting process was marked by a unique neural signature: a sharp drop in the amplitude of the electrophysiological index of VWM contents (the contralateral delay activity), presumably indicating the loss of the existent object-to-representation mappings. This marker was missing when an updating process occurred. Moreover, when tracking moving items, VWM failed to detect salient changes in the object's shape when these changes occurred during the resetting process. This happened despite the object being fully visible, presumably because the mapping between the object and a VWM representation was lost. Importantly, we show that resetting, its neural marker, and the behavioral cost it entails, are specific to situations that involve a destruction of the objects-to-representations correspondence. SIGNIFICANCE STATEMENT: Visual working memory (VWM) maintains task-relevant information in an online state. Previous studies showed that VWM representations are accessed and modified after changes in the environment. Here, we show that this updating process critically depends on an ongoing mapping between the representations and the objects in the environment. When this mapping breaks, VWM cannot access the old representations and instead resets. The novel resetting process that we introduce removes the existing representations instead of modifying them and this process is accompanied by a unique neural marker. During the resetting process, VWM was blind to salient changes in the object's shape. The resetting process highlights the flexibility of our cognitive system in handling the dynamic environment by abruptly abandoning irrelevant schemas. PMID- 28011743 TI - 5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors. AB - Neuroplasticity in the amygdala drives pain-related behaviors. The central nucleus (CeA) serves major amygdala output functions and can generate emotional affective behaviors and modulate nocifensive responses. The CeA receives excitatory and inhibitory inputs from the basolateral nucleus (BLA) and serotonin receptor subtype 5-HT2CR in the BLA, but not CeA, has been implicated anxiogenic behaviors and anxiety disorders. Here, we tested the hypothesis that 5-HT2CR in the BLA plays a critical role in CeA plasticity and neuropathic pain behaviors in the rat spinal nerve ligation (SNL) model. Local 5-HT2CR knockdown in the BLA with stereotaxic injection of 5-HT2CR shRNA AAV vector decreased vocalizations and anxiety- and depression-like behaviors and increased sensory thresholds of SNL rats, but had no effect in sham controls. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that 5-HT2CR knockdown blocked the increase in neuronal activity (increased responsiveness, irregular spike firing, and increased burst activity) in SNL rats. At the synaptic level, 5 HT2CR knockdown blocked the increase in excitatory transmission from BLA to CeA recorded in brain slices from SNL rats using whole-cell patch-clamp conditions. Inhibitory transmission was decreased by 5-HT2CR knockdown in control and SNL conditions to a similar degree. The findings can be explained by immunohistochemical data showing increased expression of 5-HT2CR in non-GABAergic BLA cells in SNL rats. The results suggest that increased 5-HT2CR in the BLA contributes to neuropathic-pain-related amygdala plasticity by driving synaptic excitation of CeA neurons. As a rescue strategy, 5-HT2CR knockdown in the BLA inhibits neuropathic-pain-related behaviors.SIGNIFICANCE STATEMENT Neuroplasticity in the amygdala has emerged as an important pain mechanism. This study identifies a novel target and rescue strategy to control abnormally enhanced amygdala activity in an animal model of neuropathic pain. Specifically, an integrative approach of gene transfer, systems and brain slice electrophysiology, behavior, and immunohistochemistry was used to advance the novel concept that serotonin receptor subtype 5-HT2C contributes critically to the imbalance between excitatory and inhibitory drive of amygdala output neurons. Local viral vector-mediated 5-HT2CR knockdown in the amygdala normalizes the imbalance, decreases neuronal activity, and inhibits neuropathic-pain-related behaviors. The study provides valuable insight into serotonin receptor (dys)function in a limbic brain area. PMID- 28011747 TI - NanoGenotoxicology: present and the future. AB - This Mutagenesis special issue is on the topic of nanogenotoxicology. It unites a collection of reports that provide insight into: (i) the properties of engineered nanomaterials (ENMs) that contribute to genotoxicity, (ii) the genotoxic mechanisms associated with DNA damage observed in both in vitro and in vivo tests and (iii) the future test systems that will provide more accurate prediction of ENM genotoxicity to support regulatory hazard assessment frameworks. The contributions within therefore provide collective oversight of our current understanding, coupled to future perspectives aimed at overcoming technical hurdles and describing novel analytical methods to further advance the field. PMID- 28011746 TI - The Pharmacology of Autonomic Failure: From Hypotension to Hypertension. AB - Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic fibers (pure autonomic failure, Parkinson's disease). Pharmacologic probes such as the ganglionic blocker trimethaphan can help us in the understanding of the underlying pathophysiology and diagnosis of these disorders. Conversely, understanding the pathophysiology is crucial in the development of effective pharmacotherapy for these patients. Autonomic failure patients provide us with an unfortunate but unique research model characterized by loss of baroreflex buffering. This greatly magnifies the effect of stimuli that would not be apparent in normal subjects. An example of this is the discovery of the osmopressor reflex: ingestion of water increases blood pressure by 30-40 mm Hg in autonomic failure patients. Animal studies indicate that the trigger of this reflex is related to hypo-osmolality in the portal circulation involving transient receptor potential vanilloid 4 receptors. Studies in autonomic failure patients have also revealed that angiotensin II can be generated through noncanonical pathways independent of plasma renin activity to contribute to hypertension. Similarly, the mineralocorticoid receptor antagonist eplerenone produces acute hypotensive effects, highlighting the presence of non nuclear mineralocorticoid receptor pathways. These are examples of careful clinical research that integrates pathophysiology and pharmacology to advance our knowledge of human disease. PMID- 28011748 TI - Genotoxicity and gene expression analyses of liver and lung tissues of mice treated with titanium dioxide nanoparticles. AB - Titanium dioxide nanoparticles (TiO2 NPs) are used in paints, plastics, papers, inks, foods, toothpaste, pharmaceuticals and cosmetics. However, TiO2 NPs cause inflammation, pulmonary damage, fibrosis and lung tumours in animals and are possibly carcinogenic to humans. Although there are a large number of studies on the toxicities of TiO2 NPs, the data are inconclusive and the mechanisms underlying the toxicity are not clear. In this study, we used the Comet assay to evaluate genotoxicity and whole-genome microarray technology to analyse gene expression pattern in vivo to explore the possible mechanisms for toxicity and genotoxicity of TiO2 NPs. Mice were treated with three daily i.p. injections of 50 mg/kg 10 nm anatase TiO2 NPs and sacrificed 4 h after the last treatment. The livers and lungs were then isolated for the Comet assay and whole genome microarray analysis of gene expression. The NPs were heavily accumulated in liver and lung tissues. However, the treatment was positive for DNA strand breaks only in liver measured with the standard Comet assay, but positive for oxidative DNA adducts in both liver and lung as determined with the enzyme-modified Comet assay. The genotoxicity results suggest that DNA damage mainly resulted from oxidised nucleotides. Gene expression profiles and functional analyses revealed that exposure to TiO2 NPs triggered distinct gene expression patterns in both liver and lung tissues. The gene expression results suggest that TiO2 NPs impair DNA and cells by interrupting metabolic homeostasis in liver and by inducing oxidative stress, inflammatory responses and apoptosis in lung. These findings have broad implications when evaluating the safety of TiO2 NPs used in numerous consumer products. PMID- 28011749 TI - Integrated biological responses and tissue-specific expression of p53 and ras genes in marine mussels following exposure to benzo(alpha)pyrene and C60 fullerenes, either alone or in combination. AB - We used the marine bivalve (Mytilus galloprovincialis) to assess a range of biological or biomarker responses following exposure to a model-engineered nanoparticle, C60 fullerene, either alone or in combination with a model polycyclic aromatic hydrocarbon, benzo(alpha)pyrene [B(alpha)P]. An integrated biomarker approach was used that included: (i) determination of 'clearance rates' (a physiological indicator at individual level), (ii) histopathological alterations (at tissue level), (iii) DNA strand breaks using the comet assay (at cellular level) and (iv) transcriptional alterations of p53 (anti-oncogene) and ras (oncogene) determined by real-time quantitative polymerase chain reaction (at the molecular/genetic level). In addition, total glutathione in the digestive gland was measured as a proxy for oxidative stress. Here, we report that mussels showed no significant changes in 'clearance rates' after 1 day exposure, however significant increases in 'clearance rates' were found following exposure for 3 days. Histopathology on selected organs (i.e. gills, digestive glands, adductor muscles and mantles) showed increased occurrence of abnormalities in all tissues types, although not all the exposed organisms showed these abnormalities. Significantly, increased levels of DNA strand breaks were found after exposure for 3-days in most individuals tested. In addition, a significant induction for p53 and ras expression was observed in a tissue and chemical-specific pattern, although large amounts of inter-individual variability, compared with other biomarkers, were clearly apparent. Overall, biological responses at different levels showed variable sensitivity, with DNA strand breaks and gene expression alterations exhibiting higher sensitivities. Furthermore, the observed genotoxic responses were reversible after a recovery period, suggesting the ability of mussels to cope with the toxicants C60 and/or B(alpha)P under our experimental conditions. Overall, in this comprehensive study, we have demonstrated mussels as a suitable model marine invertebrate species to study the potential detrimental effects induced by possible genotoxicants and toxicants, either alone or in combinations at different levels of biological organisation (i.e. molecular to individual levels). PMID- 28011752 TI - Visualizing and comparing results of different peptide identification methods. AB - In mass spectrometry-based proteomics, peptides are typically identified from tandem mass spectra using spectrum comparison. A sequence search engine compares experimentally obtained spectra with those predicted from protein sequences, applying enzyme cleavage and fragmentation rules. To this, there are two main alternatives: spectral libraries and de novo sequencing. The former compares measured spectra with a collection of previously acquired and identified spectra in a library. De novo attempts to sequence peptides from the tandem mass spectra alone. We here present a theoretical framework and a data processing workflow for visualizing and comparing the results of these different types of algorithms. The method considers the three search strategies as different dimensions, identifies distinct agreement classes and visualizes the complementarity of the search strategies. We have included X! Tandem, SpectraST and PepNovo, as they are in common use and representative for algorithms of each type. Our method allows advanced investigation of how the three search methods perform relatively to each other and shows the impact of the currently used decoy sequences for evaluating the false discovery rates. PMID- 28011750 TI - Epigenetic effects of carbon nanotubes in human monocytic cells. AB - Carbon nanotubes (CNTs) are fibrous carbon-based nanomaterials with a potential to cause carcinogenesis in humans. Alterations in DNA methylation on cytosine phosphate-guanidine (CpG) sites are potential markers of exposure-induced carcinogenesis. This study examined cytotoxicity, genotoxicity and DNA methylation alterations on human monocytic cells (THP-1) after incubation with single-walled CNTs (SWCNTs) and multi-walled CNTs (MWCNTs). Higher cytotoxicity and genotoxicity were observed after incubation with SWCNTs than incubation with MWCNTs. At the selected concentrations (25 and 100 ug/ml), DNA methylation alterations were studied. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to assess global DNA methylation, and Illumina 450K microarrays were used to assess methylation of single CpG sites. Next, we assessed gene promoter-specific methylation levels. We observed no global methylation or hydroxymethylation alterations, but on gene-specific level, distinct clustering of CNT-treated samples were noted. Collectively, CNTs induced gene promoter-specific altered methylation and those 1127 different genes were identified to be hypomethylated. Differentially methylated genes were involved in several signalling cascade pathways, vascular endothelial growth factor and platelet activation pathways. Moreover, possible contribution of the epigenetic alterations to monocyte differentiation and mixed M1/M2 macrophage polarisation were discussed. PMID- 28011753 TI - A review on machine learning principles for multi-view biological data integration. AB - Driven by high-throughput sequencing techniques, modern genomic and clinical studies are in a strong need of integrative machine learning models for better use of vast volumes of heterogeneous information in the deep understanding of biological systems and the development of predictive models. How data from multiple sources (called multi-view data) are incorporated in a learning system is a key step for successful analysis. In this article, we provide a comprehensive review on omics and clinical data integration techniques, from a machine learning perspective, for various analyses such as prediction, clustering, dimension reduction and association. We shall show that Bayesian models are able to use prior information and model measurements with various distributions; tree-based methods can either build a tree with all features or collectively make a final decision based on trees learned from each view; kernel methods fuse the similarity matrices learned from individual views together for a final similarity matrix or learning model; network-based fusion methods are capable of inferring direct and indirect associations in a heterogeneous network; matrix factorization models have potential to learn interactions among features from different views; and a range of deep neural networks can be integrated in multi-modal learning for capturing the complex mechanism of biological systems. PMID- 28011754 TI - Logic programming to infer complex RNA expression patterns from RNA-seq data. AB - To meet the increasing demand in the field, numerous long noncoding RNA (lncRNA) databases are available. Given many lncRNAs are specifically expressed in certain cell types and/or time-dependent manners, most lncRNA databases fall short of providing such profiles. We developed a strategy using logic programming to handle the complex organization of organs, their tissues and cell types as well as gender and developmental time points. To showcase this strategy, we introduce 'RenalDB' (http://renaldb.uni-frankfurt.de), a database providing expression profiles of RNAs in major organs focusing on kidney tissues and cells. RenalDB uses logic programming to describe complex anatomy, sample metadata and logical relationships defining expression, enrichment or specificity. We validated the content of RenalDB with biological experiments and functionally characterized two long intergenic noncoding RNAs: LOC440173 is important for cell growth or cell survival, whereas PAXIP1-AS1 is a regulator of cell death. We anticipate RenalDB will be used as a first step toward functional studies of lncRNAs in the kidney. PMID- 28011755 TI - Computational modeling of brain pathologies: the case of multiple sclerosis. AB - The central nervous system is the most complex network of the human body. The existence and functionality of a large number of molecular species in human brain are still ambiguous and mostly unknown, thus posing a challenge to Science and Medicine. Neurological diseases inherit the same level of complexity, making effective treatments difficult to be found. Multiple sclerosis (MS) is a major neurological disease that causes severe inabilities and also a significant social burden on health care system: between 2 and 2.5 million people are affected by it, and the cost associated with it is significantly higher as compared with other neurological diseases because of the chronic nature of the disease and to the partial efficacy of current therapies. Despite difficulties in understanding and treating MS, many computational models have been developed to help neurologists. In the present work, we briefly review the main characteristics of MS and present a selection criteria of modeling approaches. PMID- 28011756 TI - MicroRNAs and their variants in an RNA world: implications for complex interactions and diverse roles in an RNA regulatory network. AB - Multiple microRNA (miRNA) variant (isomiR) sequences have been identified at miRNA loci, suggesting that the miRNA sequence is not a single sequence but a series of isomiR sequences with sequence and expression heterogeneities. These isomiRs may be considered a large gene family with diverse expression patterns or a mini-gene cluster with high levels of sequence similarity. Although the isomiRs are diverse and have potentially coordinated relationships in regulatory networks via isomiR-isomiR interactions, they are largely unstudied. External interactions with other RNAs also enrich the cross-talk across different RNA molecules. In the present study, we describe miRNAs/isomiRs and their interactions, and methods and platforms. Interactions with small RNAs may be an internal regulatory pattern and an effective means of achieving synergistic regulation, which provides a new angle to explore the small RNA world. PMID- 28011758 TI - Ambulance telephone triage using 'NHS Pathways' to identify adult cardiac arrest. AB - BACKGROUND: UK ambulance services are called to 30 000 cardiac arrests (CAs) annually where resuscitation is attempted. Correct identification by the ambulance service trebles survival by facilitating bystander-cardiopulmonary resuscitation (CPR) and immediate ambulance dispatch. Identification of CA by telephone is challenging and involves algorithms to identify key features. 'NHS Pathways' is now used for triage by six of 12 UK ambulance services, covering a population of 20 million. With the significant improvements in survival when CA is accurately identified, it is vital that 'NHS Pathways' is able to identify CA correctly. METHODS: All '999' emergency calls to South Central Ambulance Service (SCAS) over a 12-month period screened by NHS Pathways v9.04 were identified. All actual or presumed CAs identified by the emergency call taker were cross referenced with the ambulance crew's Patient Report Form to identify all confirmed CAs. RESULTS: A total of 469 400 emergency (999) calls were received by SCAS. Of the 3119 CA identified by ambulance crew, 753 were not initially classified as CA by NHS Pathways (24.1%). Overall, sensitivity=0.759 (95% CI 0.743 to 0.773); specificity=0.986 (95% CI 0.9858 to 0.98647); and positive predictive value=26.80% (95% CI 25.88 to 27.73%). CONCLUSIONS: NHS Pathways accurately identifies 75.9% of adult CAs. The remainder represents approximately 7500 treatable CAs in the UK annually where the diagnosis is missed, with significant implications for patient outcome. Further work is required to improve this first link in the chain of survival. PMID- 28011757 TI - Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension. AB - OBJECTIVE: We compared the haemodynamic effects of riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy in the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 study. METHODS: Patients with inoperable or persistent/recurrent CTEPH (n=261; mean+/- SD age 59+/-14 years; 66% women) were randomised to riociguat (up to 2.5 mg three times daily) or placebo. Haemodynamic parameters were assessed at baseline and week 16. RESULTS: Riociguat decreased pulmonary vascular resistance (PVR) in inoperable (n=189; least-squares mean difference: -285 dyn s/cm5 (95% CI -357 to -213); p<0.0001) and persistent/recurrent (n=72; -131 dyn s/cm5 (95% CI 214 to -48); p=0.0025) patients. Cardiac index improved in inoperable patients by a least-squares mean difference of +0.6 L/min/m2 (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2 L/min/m2 (95% CI -0.1 to 0.5; p=0.17). Mean pulmonary artery pressure decreased in inoperable and persistent/recurrent patients(-4.7 mm Hg (95% CI -6.9 to -2.6; p<0.0001 and -4.8 mm Hg (-8.2 to -1.5; p=0.0055), respectively). For all patients, changes in 6 min walk distance correlated with changes in PVR (r=-0.29 (95% CI -0.41 to -0.17); p<0.0001) and cardiac index (r=0.23 (95% CI 0.10 to 0.35); p=0.0004). CONCLUSIONS: Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH. TRIAL REGISTRATION NUMBER: NCT00855465. PMID- 28011760 TI - We need clear health messages about exercise. PMID- 28011759 TI - 'End-stage' heart failure therapy: potential lessons from congenital heart disease: from pulmonary artery banding and interatrial communication to parallel circulation. AB - The final therapy of 'end-stage heart failure' is orthotopic heart, lung or heart lung transplantation. However, these options are not available for many patients worldwide. Therefore, novel therapeutical strategies are needed. Based on pathophysiological insights regarding (1) the long-term impact of an obstructive pulmonary outflow tract in neonates with congenitally corrected transposition of the great arteries, (2) the importance of a restrictive versus a non-restrictive atrial septum in neonates born with a borderline left ventricle and (3) the significance of both, a patent foramen ovale and/or open ductus arteriosus for survival of newborns with persistent pulmonary hypertension, the current review introduces some therapeutical strategies that may be applicable to selected patients with heart failure. These strategies include (1) reversible pulmonary artery banding in left ventricular-dilated cardiomyopathy with preserved right ventricular function, (2) the creation of restrictive interatrial communication to treat diastolic (systolic) heart failure, (3) atrioseptostomy or reverse Potts shunt in pulmonary arterial hypertension and (4) return to a fetal, parallel circulation by combining atrioseptostomy and reversed Potts shunt with or without placement of a bilateral pulmonary artery banding. While still being experimental, it is hoped that the procedures presented in the current overview will inspire future novel therapeutic strategies that may be applicable to selected patients with heart failure. PMID- 28011761 TI - Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and ultimately fatal disorder for which there is no cure. While the disease is by definition idiopathic, accumulating evidence, including familial aggregation of cases and the occurrence of pulmonary fibrosis in the context of a number of rare genetic disorders, indicates that genetic factors contribute significantly to the pathogenesis of IPF. Several disease-associated genetic variants, both rare and common, have been identified in familial and sporadic IPF. While the full clinical implications of these genetic associations remain to be elucidated, observational studies suggest that genotype influences the development of the disease and its outcome. Available data indicate that genetics has the potential to identify individuals at risk of IPF, classify patients more precisely, clarify the key pathways involved in disease pathogenesis and eventually develop more effective targeted therapies. Considerable research is required before a comprehensive disease fingerprint of IPF can be delivered. Nevertheless, the application of rapidly evolving molecular biology and genomic technologies combined with appropriate bioinformatic methodology offers an unprecedented and realistic opportunity to achieve this goal. PMID- 28011762 TI - IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization. AB - Although the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to alpha-ketoglutarate (alpha-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wild-type (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular alpha-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing alpha-KG-dependent transamination of glucogenic AAs such as alanine. PMID- 28011763 TI - Systematic development of small molecules to inhibit specific microscopic steps of Abeta42 aggregation in Alzheimer's disease. AB - The aggregation of the 42-residue form of the amyloid-beta peptide (Abeta42) is a pivotal event in Alzheimer's disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Abeta42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Abeta42 aggregation that uses as a read-out the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Abeta42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery. PMID- 28011765 TI - RADER: a RApid DEcoy Retriever to facilitate decoy based assessment of virtual screening. AB - Summary: Evaluation of the capacity for separating actives from challenging decoys is a crucial metric of performance related to molecular docking or a virtual screening workflow. The Directory of Useful Decoys (DUD) and its enhanced version (DUD-E) provide a benchmark for molecular docking, although they only contain a limited set of decoys for limited targets. DecoyFinder was released to compensate the limitations of DUD or DUD-E for building target-specific decoy sets. However, desirable query template design, generation of multiple decoy sets of similar quality, and computational speed remain bottlenecks, particularly when the numbers of queried actives and retrieved decoys increases to hundreds or more. Here, we developed a program suite called RApid DEcoy Retriever (RADER) to facilitate the decoy-based assessment of virtual screening. This program adopts a novel database-management regime that supports rapid and large-scale retrieval of decoys, enables high portability of databases, and provides multifaceted options for designing initial query templates from a large number of active ligands and generating subtle decoy sets. RADER provides two operational modes: as a command line tool and on a web server. Validation of the performance and efficiency of RADER was also conducted and is described. Availability and Implementation: RADER web server and a local version are freely available at http://rcidm.org/rader/ . Contact: lingwang@scut.edu.cn or went@scut.edu.cn . Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011764 TI - Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin. AB - Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA 9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy. PMID- 28011767 TI - Analyzing user-generated online content for drug discovery: development and use of MedCrawler. AB - Motivation: Ethnopharmacology, or the scientific validation of traditional medicine, is a respected starting point in drug discovery. Home remedies and traditional use of plants are still widespread, also in Western societies. Instead of perusing ancient pharmacopeias, we developed MedCrawler, which we used to analyze blog posts for mentions of home remedies and their applications. This method is free and accessible from the office computer. Results: We developed MedCrawler, a data mining tool for analyzing user-generated blog posts aiming to find modern 'traditional' medicine or home remedies. It searches user-generated blog posts and analyzes them for correlations between medically relevant terms. We also present examples and show that this method is capable of delivering both scientifically validated uses as well as not so well documented applications, which might serve as a starting point for follow-up research. Availability and Implementation: Source code is available on GitHub at {{ https://github.com/a hel/medcrawler }}. Contact: paivi.tammela@helsinki.fi. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011766 TI - Structural insight to mutation effects uncover a common allosteric site in class C GPCRs. AB - Motivation: Class C G protein-coupled receptors (GPCRs) regulate important physiological functions and allosteric modulators binding to the transmembrane domain constitute an attractive and, due to a lack of structural insight, a virtually unexplored potential for therapeutics and the food industry. Combining pharmacological site-directed mutagenesis data with the recent class C GPCR experimental structures will provide a foundation for rational design of new therapeutics. Results: We uncover one common site for both positive and negative modulators with different amino acid layouts that can be utilized to obtain selectivity. Additionally, we show a large potential for structure-based modulator design, especially for four orphan receptors with high similarity to the crystal structures. Availability and Implementation: All collated mutagenesis data is available in the GPCRdb mutation browser at http://gpcrdb.org/mutations/ and can be analyzed online or downloaded in excel format. Contact: david.gloriam@sund.ku.dk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011768 TI - SeqLib: a C ++ API for rapid BAM manipulation, sequence alignment and sequence assembly. AB - : We present SeqLib, a C ++ API and command line tool that provides a rapid and user-friendly interface to BAM/SAM/CRAM files, global sequence alignment operations and sequence assembly. Four C libraries perform core operations in SeqLib: HTSlib for BAM access, BWA-MEM and BLAT for sequence alignment and Fermi for error correction and sequence assembly. Benchmarking indicates that SeqLib has lower CPU and memory requirements than leading C ++ sequence analysis APIs. We demonstrate an example of how minimal SeqLib code can extract, error-correct and assemble reads from a CRAM file and then align with BWA-MEM. SeqLib also provides additional capabilities, including chromosome-aware interval queries and read plotting. Command line tools are available for performing integrated error correction, micro-assemblies and alignment. Availability and Implementation: SeqLib is available on Linux and OSX for the C ++98 standard and later at github.com/walaj/SeqLib. SeqLib is released under the Apache2 license. Additional capabilities for BLAT alignment are available under the BLAT license. Contact: jwala@broadinstitue.org ; rameen@broadinstitute.org. PMID- 28011769 TI - The PPI3D web server for searching, analyzing and modeling protein-protein interactions in the context of 3D structures. AB - Summary: The PPI3D web server is focused on searching and analyzing the structural data on protein-protein interactions. Reducing the data redundancy by clustering and analyzing the properties of interaction interfaces using Voronoi tessellation makes this software a highly effective tool for addressing different questions related to protein interactions. Availability and Implementation: The server is freely accessible at http://bioinformatics.lt/software/ppi3d/ . Contact: ceslovas.venclovas@bti.vu.lt. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011770 TI - Simulation-based estimation of branching models for LTR retrotransposons. AB - Motivation: LTR retrotransposons are mobile elements that are able, like retroviruses, to copy and move inside eukaryotic genomes. In the present work, we propose a branching model for studying the propagation of LTR retrotransposons in these genomes. This model allows us to take into account both the positions and the degradation level of LTR retrotransposons copies. In our model, the duplication rate is also allowed to vary with the degradation level. Results: Various functions have been implemented in order to simulate their spread and visualization tools are proposed. Based on these simulation tools, we have developed a first method to evaluate the parameters of this propagation model. We applied this method to the study of the spread of the transposable elements ROO, GYPSY and DM412 on a chromosome of Drosophila melanogaster . Availability and Implementation: Our proposal has been implemented using Python software. Source code is freely available on the web at https://github.com/SergeMOULIN/retrotransposons-spread . Contact: serge.moulin@univ-fcomte.fr. Supplementary information: are available at Bioinformatics online. PMID- 28011771 TI - Improving protein disorder prediction by deep bidirectional long short-term memory recurrent neural networks. AB - Motivation: Capturing long-range interactions between structural but not sequence neighbors of proteins is a long-standing challenging problem in bioinformatics. Recently, long short-term memory (LSTM) networks have significantly improved the accuracy of speech and image classification problems by remembering useful past information in long sequential events. Here, we have implemented deep bidirectional LSTM recurrent neural networks in the problem of protein intrinsic disorder prediction. Results: The new method, named SPOT-Disorder, has steadily improved over a similar method using a traditional, window-based neural network (SPINE-D) in all datasets tested without separate training on short and long disordered regions. Independent tests on four other datasets including the datasets from critical assessment of structure prediction (CASP) techniques and >10 000 annotated proteins from MobiDB, confirmed SPOT-Disorder as one of the best methods in disorder prediction. Moreover, initial studies indicate that the method is more accurate in predicting functional sites in disordered regions. These results highlight the usefulness combining LSTM with deep bidirectional recurrent neural networks in capturing non-local, long-range interactions for bioinformatics applications. Availability and Implementation: SPOT-disorder is available as a web server and as a standalone program at: http://sparks lab.org/server/SPOT-disorder/index.php . Contact: j.hanson@griffith.edu.au or yuedong.yang@griffith.edu.au or yaoqi.zhou@griffith.edu.au. Supplementary information: Supplementary data is available at Bioinformatics online. PMID- 28011772 TI - Controlling the joint local false discovery rate is more powerful than meta analysis methods in joint analysis of summary statistics from multiple genome wide association studies. AB - Motivation: In genome-wide association studies (GWASs) of common diseases/traits, we often analyze multiple GWASs with the same phenotype together to discover associated genetic variants with higher power. Since it is difficult to access data with detailed individual measurements, summary-statistics-based meta analysis methods have become popular to jointly analyze datasets from multiple GWASs. Results: In this paper, we propose a novel summary-statistics-based joint analysis method based on controlling the joint local false discovery rate (Jlfdr). We prove that our method is the most powerful summary-statistics-based joint analysis method when controlling the false discovery rate at a certain level. In particular, the Jlfdr-based method achieves higher power than commonly used meta-analysis methods when analyzing heterogeneous datasets from multiple GWASs. Simulation experiments demonstrate the superior power of our method over meta-analysis methods. Also, our method discovers more associations than meta analysis methods from empirical datasets of four phenotypes. Availability and Implementation: The R-package is available at: http://bioinformatics.ust.hk/Jlfdr.html . Contact: eeyu@ust.hk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011773 TI - ALTRE: workflow for defining ALTered Regulatory Elements using chromatin accessibility data. AB - Summary: Regulatory elements regulate gene transcription, and their location and accessibility is cell-type specific, particularly for enhancers. Mapping and comparing chromatin accessibility between different cell types may identify mechanisms involved in cellular development and disease progression. To streamline and simplify differential analysis of regulatory elements genome-wide using chromatin accessibility data, such as DNase-seq, ATAC-seq, we developed ALTRE ( ALT ered R egulatory E lements), an R package and associated R Shiny web app. ALTRE makes such analysis accessible to a wide range of users-from novice to practiced computational biologists. Availability and Implementation: https://github.com/Mathelab/ALTRE. Contact: ewy.mathe@osumc.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011774 TI - Fast motif matching revisited: high-order PWMs, SNPs and indels. AB - Motivation: While the position weight matrix (PWM) is the most popular model for sequence motifs, there is growing evidence of the usefulness of more advanced models such as first-order Markov representations, and such models are also becoming available in well-known motif databases. There has been lots of research of how to learn these models from training data but the problem of predicting putative sites of the learned motifs by matching the model against new sequences has been given less attention. Moreover, motif site analysis is often concerned about how different variants in the sequence affect the sites. So far, though, the corresponding efficient software tools for motif matching have been lacking. Results: We develop fast motif matching algorithms for the aforementioned tasks. First, we formalize a framework based on high-order position weight matrices for generic representation of motif models with dinucleotide or general q -mer dependencies, and adapt fast PWM matching algorithms to the high-order PWM framework. Second, we show how to incorporate different types of sequence variants , such as SNPs and indels, and their combined effects into efficient PWM matching workflows. Benchmark results show that our algorithms perform well in practice on genome-sized sequence sets and are for multiple motif search much faster than the basic sliding window algorithm. Availability and Implementation: Implementations are available as a part of the MOODS software package under the GNU General Public License v3.0 and the Biopython license ( http://www.cs.helsinki.fi/group/pssmfind ). Contact: janne.h.korhonen@gmail.com. PMID- 28011775 TI - MetaboSignal: a network-based approach for topological analysis of metabotype regulation via metabolic and signaling pathways. AB - Summary: MetaboSignal is an R package that allows merging metabolic and signaling pathways reported in the Kyoto Encyclopaedia of Genes and Genomes (KEGG). It is a network-based approach designed to navigate through topological relationships between genes (signaling- or metabolic-genes) and metabolites, representing a powerful tool to investigate the genetic landscape of metabolic phenotypes. Availability and Implementation: MetaboSignal is available from Bioconductor: https://bioconductor.org/packages/MetaboSignal/. Contact: m.dumas@imperial.ac.uk . Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011776 TI - SarConfoCal: simultaneous sarcomere length and cytoplasmic calcium measurements for laser scanning confocal microscopy images. AB - Summary: Simultaneous recordings of myocytes contractility and their cytoplasmic calcium concentration allow powerful studies, particularly on heart failure and other cardiac dysfunctions. Such studies require dedicated and expensive experimental devices that are difficult to use. Thus we propose SarConfoCal, the first and only software to simultaneously analyse both cytoplasmic calcium variations (from fluorescence signal) and myocytes contractility (from sarcomere length measurement) on laser scanning confocal microscopy images. SarConfoCal is easy to set up and use, especially by people without programming skills. Availability and implementation: The software is freely distributed under the GNU General Public License. Download and setup instructions are available at http://pccv.univ-tours.fr/ImageJ/SarConfoCal . It is provided as a toolset for ImageJ (the open-source program for image analysis provided by the National Institutes of Health). SarConfoCal has been tested under Windows, Mac and Linux operating systems. Contact: come.pasqualin@univ-tours.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011777 TI - Expanding the toolkit for membrane protein modeling in Rosetta. AB - Motivation: A range of membrane protein modeling tools has been developed in the past 5-10 years, yet few of these tools are integrated and make use of existing functionality for soluble proteins. To extend existing methods in the Rosetta biomolecular modeling suite for membrane proteins, we recently implemented RosettaMP, a general framework for membrane protein modeling. While RosettaMP facilitates implementation of new methods, addressing real-world biological problems also requires a set of accessory tools that are used to carry out standard modeling tasks. Results: Here, we present six modeling tools, including de novo prediction of single trans-membrane helices, making mutations and refining the structure with different amounts of flexibility, transforming a protein into membrane coordinates and optimizing its embedding, computing a Rosetta energy score, and visualizing the protein in the membrane bilayer. We present these methods with complete protocol captures that allow non-expert modelers to carry out the computations. Availability and Implementation: The presented tools are part of the Rosetta software suite, available at www.rosettacommons.org . Contact: julia.koehler.leman@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011778 TI - Mutual enrichment in aggregated ranked lists with applications to gene expression regulation. PMID- 28011779 TI - cerebroViz: an R package for anatomical visualization of spatiotemporal brain data. AB - Summary: Spatiotemporal transcriptomic profiling has provided valuable insight into the patterning of gene expression throughout the human brain from early fetal development to adulthood. When combined with prior knowledge of a disease's age at onset and region-specificity, these expression profiles have provided the necessary context to both strengthen putative gene-disease associations and infer new associations. While a wealth of spatiotemporal expression data exists, there are currently no tools available to visualize this data within the anatomical context of the brain, thus limiting the intuitive interpretation of many such findings. We present cerebroViz, an R package to map spatiotemporal brain data to vector graphic diagrams of the human brain. Our tool allows rapid generation of publication-quality figures that highlight spatiotemporal trends in the input data, while striking a balance between usability and customization. cerebroViz is generalizable to any data quantifiable at a brain-regional resolution and currently supports visualization of up to thirty regions of the brain found in databases such as BrainSpan, GTEx and Roadmap Epigenomics. Availability and Implementation: cerebroViz is freely available through GitHub ( https://github.com/ethanbahl/cerebroViz ). The tutorial is available at http://ethanbahl.github.io/cerebroViz/. Contacts: ethan-bahl@uiowa.edu or jacob michaelson@uiowa.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011780 TI - FUEL-mLoc: feature-unified prediction and explanation of multi-localization of cellular proteins in multiple organisms. AB - : Although many web-servers for predicting protein subcellular localization have been developed, they often have the following drawbacks: (i) lack of interpretability or interpreting results with heterogenous information which may confuse users; (ii) ignoring multi-location proteins and (iii) only focusing on specific organism. To tackle these problems, we present an interpretable and efficient web-server, namely FUEL-mLoc, using eature- nified prediction and xplanation of m ulti- oc alization of cellular proteins in multiple organisms. Compared to conventional localization predictors, FUEL-mLoc has the following advantages: (i) using unified features (i.e. essential GO terms) to interpret why a prediction is made; (ii) being capable of predicting both single- and multi location proteins and (iii) being able to handle proteins of multiple organisms, including Eukaryota, Homo sapiens, Viridiplantae, Gram-positive Bacteria, Gram negative Bacteria and Virus . Experimental results demonstrate that FUEL-mLoc outperforms state-of-the-art subcellular-localization predictors. Availability and Implementation: http://bioinfo.eie.polyu.edu.hk/FUEL-mLoc/. Contacts: shibiao.wan@princeton.edu or enmwmak@polyu.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011781 TI - cBinderDB: a covalent binding agent database. AB - Motivation: Small molecule drug candidates with attractive toxicity profiles that modulate target proteins through non-covalent interactions are usually favored by scientists and pharmaceutical industry. In the past decades, many non-covalent binding agents have been developed for different diseases. However, an increasing attention has been paid to covalent binding agents in pharmaceutical fields during recent years. Many covalent binding agents entered clinical trials and exerted significant advantages for diseases such as infection, cancers, gastrointestinal disorders, central nervous system or cardiovascular diseases. It has been recognized that covalent binding ligands can be attractive drug candidates. But, there is lack of resource to support covalent ligand discovery. Results: Hence, we initiated a covalent binder database (cBinderDB). To our best knowledge, it is the first online database that provides information on covalent binding compound structures, chemotypes, targets, covalent binding types and other biological properties. The covalent binding targets are annotated with biological functions, protein family and domains, gene information, modulators and receptor-ligand complex structure. The data in the database were collected from scientific publications by combining a text mining method and manual inspection processes. cBinderDB covers covalent binder's data up to September 2016. Availability and Implementation: cBinderDB is freely available at www.rcdd.org.cn/cbinderdb/. Contact: guqiong@mail.sysu.edu.cn or junxu@biochemomes.com . Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011782 TI - Inference of cellular level signaling networks using single-cell gene expression data in Caenorhabditis elegans reveals mechanisms of cell fate specification. AB - Motivation: Cell fate specification plays a key role to generate distinct cell types during metazoan development. However, most of the underlying signaling networks at cellular level are not well understood. Availability of time lapse single-cell gene expression data collected throughout Caenorhabditis elegans embryogenesis provides an excellent opportunity for investigating signaling networks underlying cell fate specification at systems, cellular and molecular levels. Results: We propose a framework to infer signaling networks at cellular level by exploring the single-cell gene expression data. Through analyzing the expression data of nhr-25 , a hypodermis-specific transcription factor, in every cells of both wild-type and mutant C.elegans embryos through RNAi against 55 genes, we have inferred a total of 23 genes that regulate (activate or inhibit) nhr-25 expression in cell-specific fashion. We also infer the signaling pathways consisting of each of these genes and nhr-25 based on a probabilistic graphical model for the selected five founder cells, 'ABarp', 'ABpla', 'ABpra', 'Caa' and 'Cpa', which express nhr-25 and mostly develop into hypodermis. By integrating the inferred pathways, we reconstruct five signaling networks with one each for the five founder cells. Using RNAi gene knockdown as a validation method, the inferred networks are able to predict the effects of the knockdown genes. These signaling networks in the five founder cells are likely to ensure faithful hypodermis cell fate specification in C.elegans at cellular level. Availability and Implementation: All source codes and data are available at the github repository https://github.com/xthuang226/Worm_Single_Cell_Data_and_Codes.git . Contact: zhuyuan@cug.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011783 TI - A new method for decontamination of de novo transcriptomes using a hierarchical clustering algorithm. AB - Motivation: The identification of contaminating sequences in a de novo assembly is challenging because of the absence of information on the target species. For sample types where the target organism is impossible to isolate from its matrix, such as endoparasites, endosymbionts and soil-harvested samples, contamination is unavoidable. A few post-assembly decontamination methods are currently available but are based only on alignments to databases, which can lead to poor decontamination. Results: We present a new decontamination method based on a hierarchical clustering algorithm called MCSC. This method uses frequent patterns found in sequences to create clusters. These clusters are then linked to the target species or tagged as contaminants using classic alignment tools. The main advantage of this decontamination method is that it allows sequences to be tagged correctly even if they are unknown or misaligned to a database. Availability and Implementation: Scripts and documentation about the MCSC decontamination method are available at https://github.com/Lafond-LapalmeJ/MCSC_Decontamination . Contact: : benjamin.mimee@agr.gc.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011786 TI - VarMatch: robust matching of small variant datasets using flexible scoring schemes. AB - Motivation: Small variant calling is an important component of many analyses, and, in many instances, it is important to determine the set of variants which appear in multiple callsets. Variant matching is complicated by variants that have multiple equivalent representations. Normalization and decomposition algorithms have been proposed, but are not robust to different representation of complex variants. Variant matching is also usually done to maximize the number of matches, as opposed to other optimization criteria. Results: We present the VarMatch algorithm for the variant matching problem. Our algorithm is based on a theoretical result which allows us to partition the input into smaller subproblems without sacrificing accuracy. VarMatch is robust to different representation of complex variants and is particularly effective in low complexity regions or those dense in variants. VarMatch is able to detect more matches than either the normalization or decomposition algorithms on tested datasets. It also implements different optimization criteria, such as edit distance, that can improve robustness to different variant representations. Finally, the VarMatch software provides summary statistics, annotations and visualizations that are useful for understanding callers' performance. Availability and Implementation: VarMatch is freely available at: https://github.com/medvedevgroup/varmatch. Contact: chensun@cse.psu.edu or pashadag@cse.psu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011787 TI - switchde: inference of switch-like differential expression along single-cell trajectories. AB - Motivation: Pseudotime analyses of single-cell RNA-seq data have become increasingly common. Typically, a latent trajectory corresponding to a biological process of interest-such as differentiation or cell cycle-is discovered. However, relatively little attention has been paid to modelling the differential expression of genes along such trajectories. Results: We present switchde , a statistical framework and accompanying R package for identifying switch-like differential expression of genes along pseudotemporal trajectories. Our method includes fast model fitting that provides interpretable parameter estimates corresponding to how quickly a gene is up or down regulated as well as where in the trajectory such regulation occurs. It also reports a P -value in favour of rejecting a constant-expression model for switch-like differential expression and optionally models the zero-inflation prevalent in single-cell data. Availability and Implementation: The R package switchde is available through the Bioconductor project at https://bioconductor.org/packages/switchde . Contact: kieran.campbell@sjc.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28011789 TI - myGenomeBrowser: building and sharing your own genome browser. AB - : myGenomeBrowser is a web-based environment that provides biologists with a way to build, query and share their genome browsers. This tool, that builds on JBrowse, is designed to give users more autonomy while simplifying and minimizing intervention from system administrators. We have extended genome browser basic features to allow users to query, analyze and share their data. Availability and implementation: myGenomeBrowser is freely available at https://bbric pipelines.toulouse.inra.fr/myGenomeBrowser and includes tutorial screencasts. Source code and installation instructions can be found at https://framagit.org/BBRIC/myGenomeBrowser . myGenomeBrowser is open-source and mainly implemented in Perl, JavaScript, Apache and Docker. Contact: sebastien.carrere@inra.fr. PMID- 28011790 TI - High-throughput interpretation of gene structure changes in human and nonhuman resequencing data, using ACE. AB - Motivation: The accurate interpretation of genetic variants is critical for characterizing genotype-phenotype associations. Because the effects of genetic variants can depend strongly on their local genomic context, accurate genome annotations are essential. Furthermore, as some variants have the potential to disrupt or alter gene structure, variant interpretation efforts stand to gain from the use of individualized annotations that account for differences in gene structure between individuals or strains. Results: We describe a suite of software tools for identifying possible functional changes in gene structure that may result from sequence variants. ACE ('Assessing Changes to Exons') converts phased genotype calls to a collection of explicit haplotype sequences, maps transcript annotations onto them, detects gene-structure changes and their possible repercussions, and identifies several classes of possible loss of function. Novel transcripts predicted by ACE are commonly supported by spliced RNA-seq reads, and can be used to improve read alignment and transcript quantification when an individual-specific genome sequence is available. Using publicly available RNA-seq data, we show that ACE predictions confirm earlier results regarding the quantitative effects of nonsense-mediated decay, and we show that predicted loss-of-function events are highly concordant with patterns of intolerance to mutations across the human population. ACE can be readily applied to diverse species including animals and plants, making it a broadly useful tool for use in eukaryotic population-based resequencing projects, particularly for assessing the joint impact of all variants at a locus. Availability and Implementation: ACE is written in open-source C ++ and Perl and is available from geneprediction.org/ACE. Contact: myandell@genetics.utah.edu or tim.reddy@duke.edu. Supplementary information: Supplementary information is available at Bioinformatics online. PMID- 28011792 TI - High flow nasal cannula versus NCPAP, duration to full oral feeds in preterm infants: a randomised controlled trial. AB - OBJECTIVE: To compare the time taken by preterm infants with evolving chronic lung disease to achieve full oral feeding when supported with humidified high flow nasal cannula (HFNC) or nasal continuous positive airway pressure (NCPAP). DESIGN: Single centre randomised controlled trial. SETTING: Level III neonatal intensive care unit at the Coombe Women and Infants University Hospital, Dublin, Ireland. PATIENTS: Very low birthweight (birth weight <1500 g) infants born before 30 weeks' gestation who were NCPAP-dependent at 32 weeks corrected gestational age were eligible to participate. INTERVENTIONS: Enrolled infants were randomised in a 1:1 ratio to receive HFNC or NCPAP. Participants were monitored daily until full oral feeding was established and the baby was off respiratory support. MAIN OUTCOME MEASURES: Our primary outcome was the number of days taken to establish full oral feeds (defined as oral intake >=120 mL/kg/day) from the time of randomisation. We estimated that enrolling 44 subjects (22 in each group) would allow us demonstrate a 7-day difference in our primary outcome with 80% power and alpha of 5%. RESULTS: Forty-four infants were randomised (22 to HFNC vs 22 to NCPAP). The mean time to achieve full oral feeding was not different between the groups (HFNC 36.5 (+/-18.2) days vs NCPAP 34.1 (+/-11.2) days, p=0.61). CONCLUSIONS: Preterm infants treated with HFNC did not achieve full oral feeding more quickly than infants treated with NCPAP. TRIAL REGISTRATION NUMBER: ISRCTN66716753. PMID- 28011791 TI - Maternal Smoking and Newborn Cytokine and Immunoglobulin Levels. AB - Introduction: Prenatal smoking exposure may lead to permanent changes in neonatal inflammation and immune response that have lifelong implications, including increased risks for atopy and respiratory disorders. Methods: The effect of maternal smoking on neonatal biomarkers of inflammation and immune response was assessed among 3459 singletons and twins in the Upstate KIDS Study. The following inflammatory biomarkers were measured using newborn dried blood spots (DBSs): interleukin (IL)-1alpha, IL-1 receptor antagonist, IL-6, IL-8, C-reactive protein, and tumor necrosis factor alpha. Immunoglobulins (IgE, IgA, IgM, and IgG subclasses) were also assessed. We used generalized estimating equations to calculate mean differences (beta) in biomarker levels by timing of pregnancy smoking, cigarette load, and secondhand smoke exposure after adjusting for sociodemographic and lifestyle factors including maternal body mass index. Results: Of the 344 (12%) women reporting smoking during pregnancy, about 40% continued throughout pregnancy and 13% reported smoking more than 1 pack per day. After covariate adjustment and Bonferroni correction for multiple comparisons, maternal smoking throughout pregnancy remained significantly associated with increased levels of IL-8 (beta = 0.20, 95% confidence interval: 0.07, 0.32; p < .003). No significant associations were found with cigarette load or secondhand smoke exposure. Higher IgG3 levels were also associated with maternal smoking throughout pregnancy, although the association became nominally significant after adjustment for covariates (beta = 0.09; 95% confidence interval: 0.0007, 0.17; p < .05). Conclusions: Maternal smoking throughout pregnancy was independently associated with increased IL-8 levels in newborns. Importantly, neonates of women who stopped smoking anytime in pregnancy did not have increased IL-8 levels. Implications: This study evaluated a range of inflammatory biomarkers and immunoglobulins in association with maternal smoking and timing/duration of smoking along with secondhand smoke exposure. By using DBSs, we present data from a large cohort of children born in Upstate New York. Our findings suggest that early differences in immunoregulation of neonates exposed to maternal smoking for full duration in utero may already be detected at birth. PMID- 28011793 TI - Protecting the premature brain: current evidence-based strategies for minimising perinatal brain injury in preterm infants. AB - Improving neurodevelopmental outcome for preterm infants is an important challenge for neonatal medicine. The disruption of normal brain growth and neurological development is a significant consequence of preterm birth and can result in physical and cognitive impairments. While advances in neonatal medicine have led to progressively better survival rates for preterm infants, there has only been a modest improvement in the proportion of surviving infants without neurological impairment, and no change in the proportion with severe disability. The overall number of children with neurodisability due to prematurity is increasing. Trials investigating novel therapies are underway and many have promising early results; however, in the interim, current treatments and management strategies that have proven benefit for neurodevelopment or reduction in neonatal brain injury are often underutilised. We collate the evidence for the efficacy of such interventions, recommended by guidelines or supported by large meta-analysis or randomised control trials. We address controversies that have hindered uptake and problems with translating research into practice. We then look to the future of preterm neuroprotective care. PMID- 28011794 TI - Can Ambu self-inflating bag and Neopuff infant resuscitator provide adequate and safe manual inflations for infants up to 10 kg weight? AB - BACKGROUND: Manual resuscitation devices for infants and newborns must be able to provide adequate ventilation in a safe and consistent manner across a wide range of patient sizes (0.5-10 kg) and differing clinical states. There are little comparative data assessing biomechanical performance of common infant manual resuscitation devices across the manufacturers' recommended operating weight ranges. We aimed to compare performance of the Ambu self-inflating bag (SIB) with the Neopuff T-piece resuscitator in three resuscitation models. METHODS: Five experienced clinicians delivered targeted ventilation to three lung models differing in compliance, delivery pressures and inflation rates; Preterm (0.5 mL/cmH2O, 25/5 cmH2O, 60 per minute), Term (3 mL/cmH2O, 30/5 cmH2O, 40 per minute) and Infant (9 mL/cmH2O, 35/5 cmH2O, 30 per minute). The Neopuff was examined with three gas inflow rates (5 litres per minute (LPM), 10 LPM and 15 LPM) and the Ambu with no gas inflow. RESULTS: 3309 inflations were collected and analysed with analysis of variance for repeated measures. The Neopuff was unable to reach set peak inflation pressures and exhibited seriously elevated positive end expiratory pressure (PEEP) with all inflow gas rates (p<0.001) in this infant model. The Ambu SIB accurately delivered targeted pressures in all three models. CONCLUSIONS: The Ambu SIB was able to accurately deliver targeted pressures across all three models from preterm to infant. The Neopuff infant resuscitator was unable to deliver the targeted pressures in the infant model developing clinically significant levels of inadvertent PEEP which may pose risk during infant resuscitation. PMID- 28011795 TI - Cardiac resynchronization therapy (CRT) device replacement considerations: upgrade or downgrade? A complex decision in the current clinical setting. AB - There are limited data about the management of patients presenting for elective generator replacements in the setting of previously implanted cardiac resynchronization therapy (CRT) devices that are nearing end-of-life. The individual patient's clinical status and concomitant morbidities may evolve so that considerations may include not only replacement of the pulse generator, but also potentially changing the type of device [e.g. downgrading CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P) or ICD or upgrading of CRT-P to CRT-D]. Moreover, the clinical evidence for CRT-D/CRT-P implantation may change over time, with ongoing research and availability of new trial data. In this review we discuss the ethical, clinical and financial implications related to CRT generator replacements and the need for additional clinical trials to better understand which patients should undergo CRT device downgrading or upgrading at the time of battery depletion. PMID- 28011797 TI - Reappraisal and new observations on atrial tachycardia ablated from the non coronary aortic sinus of Valsalva. AB - Aims: The clinical characteristics of atrial tachycardias (AT) ablated from the non-coronary aortic sinus (NCS) are thus far described only in small series. We aimed to outline, in a large cohort of patients, the clinical, electrocardiographic, electrophysiological characteristics of this tachycardia. Methods and results: We analysed data pertaining to clinical, electrocardiographic, and electrophysiological characteristics of 43 consecutive patients from an overall cohort of 441 with AT who were successfully ablated from the NCS. The tachycardias ablated from the NCS were paroxysmal (98%) and adenosine sensitive (35/35). The patients were aged 54.6 +/- 12.4 years, showing female preponderance (74%). No P wave pattern was predictive of the location of ablation. Electrophysiological findings suggested a possible micro-reentrant mechanism. During tachycardia, atrial electrograms recorded in the NCS preceded the A in the His region by 10.9 +/- 7.4 ms. Fractionated atrial electrograms were noted at the site of ablation in 42 patients during the tachycardia. Radiofrequency ablation terminated the tachycardia within 5 s in 88%, with thermal automaticity seen only in 3 patients. The site of ablation at the base of the NCS was adjacent to the presumed site of the retroaortic node, a remnant of the initial atrio-ventricular canal musculature. Conclusions: AT ablated from the NCS is a paroxysmal arrhythmia in middle-aged women, with distinct electrocardiographic and electrophysiological characteristics. We suspect the retroaortic node to be involved in the tachycardia circuit. PMID- 28011798 TI - Stepwise mass screening for atrial fibrillation using N-terminal pro b-type natriuretic peptide: the STROKESTOP II study design. AB - Aim: Atrial fibrillation (AF) is the most prevalent clinical arrhythmia and a major risk factor for ischaemic stroke. Treatment with oral anticoagulants (OACs) reduces the risk of stroke by two thirds in AF patients with risk factors. Due to its often paroxysmal and asymptomatic presentation, AF is sometimes challenging to diagnose. So far, AF screening studies have applied opportunistic or systematic screening, most often using a single 12-lead electrocardiogram (ECG) recording or ambulatory ECG. We hypothesise that the biomarker N-terminal pro b type natriuretic peptide (NT-proBNP) is a valuable adjunct in population based AF screening. Methods: We are conducting a randomized population-based study on AF screening using ambulatory ECG recording where the decision to use prolonged intermittent ECG recording is directed by NT-proBNP levels, the STROKESTOP II trial. The entire population of inhabitants 75 or 76 years of age (n = 28 712) in the capital region of Sweden will be randomized 1:1 to intervention or control group. In the intervention group NT-proBNP will be analysed in all without previously known AF. Those with NT-proBNP <= 125 pg/L will make a single one lead ECG recording, participants with NTproBNP >= 125 np/L will be instructed to record ECG for 30 s at least twice daily for 2 weeks with a handheld ambulatory ECG recorder. Participants with newly diagnosed or undertreated AF will be referred to a cardiologist and offered OAC treatment. Primary endpoint is incidence of stroke or systemic embolus, during a 5 year follow-up period in the control group vs the group invited to screening. PMID- 28011799 TI - Higher burden of supraventricular ectopic complexes early after catheter ablation for atrial fibrillation is associated with increased risk of recurrent atrial fibrillation. AB - Aims: Early identification of patients who could benefit from early re intervention after catheter ablation is highly warranted. Our aim was to investigate the association between post-procedural burden of supraventricular ectopic complexes (SVEC) and the risk of long-term atrial fibrillation (AF) recurrence. Methods and results: A total of 125 patients undergoing catheter ablation for AF were included. Patients underwent 7-day Holter recordings immediately post-procedural. The number of SVEC in post-procedural Holter recordings was categorized into quartiles: 0-72, 73-212, 213-782 and >= 783 SVEC/day. Long-term AF recurrence was defined as a combined endpoint of AF >= 1 min during follow-up Holter recordings, cardioversion or hospitalization for AF after a 3-month blanking period and within 24 months of follow-up. High post procedural supraventricular ectopy burden was associated with an increased risk of long-term AF recurrence in a dose-dependent manner (>= 783 SVEC: HR 4.6 [1.9 11.5], P < 0.001) irrespective of AF recurrence during the blanking period or other risk factors. In patients with early AF recurrence < 90 days after catheter ablation ectopy burden was also highly predictive of long-term AF recurrence (SVEC >= 213: HR 3.0 [1.3-6.7], P = 0.007). Correspondingly, patients with early AF recurrence but low ectopy burden remained at low risk of long-term AF recurrence after the blanking period. Conclusion: Our results indicate that post procedural ectopy burden is highly associated with long-term AF recurrence and could be a potent risk marker for selection of patients for early re-ablation. Development of future ablation risk stratification and strategies should include focus on post-procedural ectopy burden. PMID- 28011800 TI - Important reduction of the radiation dose for pulmonary vein isolation using a multimodal approach. AB - Aims: The number of pulmonary vein isolation (PVI) ablation procedures is steadily increasing worldwide resulting in a substantial radiation exposure to patients and operators. The aim of our study was to reduce radiation exposure during these procedures to a critical amount without compromising patient safety. Methods and results: First, we assessed radiation exposure for primary PVI procedures over time (2005-2015) at the University Heart Center Freiburg-Bad Krozingen. Second, we prospectively evaluated in 52 patients, the efficacy and safety of a novel radiation reduction program (particularly applying an enhanced fluoroscopy pulse dose-reduction and optimized 3D-mapping system use). In 2035 primary PVI procedures, radiation exposure, assessed as estimated effective dose (eED in mSv, dose area product * 0.002 * conversion factor for females), fluoroscopy-time, and procedure-time decreased significantly from 2005 to 2015 (e.g. eED decreased from 9.3 (interquartile range (IQR) 6.4-13.4) mSv to 0.9 (IQR 0.5-1.6) mSv, p for trend <0.001). Importantly, application of the enhanced radiation reduction program further reduced eED to 0.4 mSv (IQR 0.3-0.6, P < 0.001 vs. control), a value not significantly different from slow-pathway ablation procedures (P = 0.41). Multiple linear regression analysis identified the radiation reduction program as the only independent variable associated with a decrease in radiation exposure. Conclusion: Radiation exposure during PVI decreased over the last decade and can further be reduced significantly by the implementation of an enhanced radiation reduction program. PMID- 28011801 TI - Impact of haemodynamic SonR sensor on monitoring of left ventricular function in patients undergoing cardiac resynchronization therapy. AB - Aims: The haemodynamic SonR sensor is able to measure myocardial contractility. The isometric effort is useful in quantifying left ventricular (LV) performance. We investigated the amplitude changes in SonR signal over time and during static exercise according to the recovery of the left ventricle. Methods and results: Twenty five patients [18 male, 70 +/- 8 years, LV ejection fraction (LVEF) 29 +/- 5%, in sinus rhythm] underwent biventricular SonR implantable cardioverter defibrillator implant. After procedure and at 6 months, each patient underwent detection of SonR signal and continuous measurement of blood pressure, at rest and during isometric effort. During evaluation at baseline device was programmed in VVI at 40 bpm while in DDD at 60 bpm at follow-up. At 6 months, LV reverse remodelling was investigated. Cardiac resynchronization therapy patients were considered responders when an absolute improvement in LV ejection fraction >= 5% occurred. At 6 months, 14 (56%) patients were responders and 11 (44%) non responders (mean LVEF 40 +/- 10% vs. 27 +/- 6%, respectively). In responders, SonR value did not significantly change at follow-up compared to baseline (P = 0.894). At follow-up, SonR value was not significantly different between two groups (P = 0.651). SonR signal significantly increased during isometric effort in responders (P = 0.002) while it slightly decreased in non-responders at follow up (P = 0.572). No differences were observed in response to isometric effort between two groups at baseline (P = 0.182, P = 0.069, respectively). Conclusions: The absolute SonR amplitude provides limited information on the status of LV performance. The variation in SonR signal during static exercise is more likely to identify responders at follow-up. PMID- 28011802 TI - Novel electrocardiographic dyssynchrony criteria improve patient selection for cardiac resynchronization therapy. AB - Aims: We hypothesized that the greater the intra- or interventricular dyssynchrony (intraD, interD), the more effective cardiac resynchronization therapy (CRT) is. We sought to improve patient selection for CRT by using novel ECG dyssynchrony criteria. Methods and results: Left ventricular (LV) intraD was estimated by the absolute time difference between the intrinsicoid deflections (ID) in leads aVL and aVF divided by the QRS duration (QRSd): [aVLID - aVFID]/QRSd (%). InterD was estimated from the formula: [V5ID - V1ID]/QRSd (%). Their >25% value indicated electrical dyssynchrony present (ED+) and <=25% value electrical dyssynchrony absent (ED-) diagnoses. Using the intraD + interD criteria (intra + interDC) together, if at least one of them indicated ED+ diagnosis, a final ED+ diagnosis, if both indicated ED- diagnosis, a final ED- diagnosis was made. Two authors, blinded to CRT response, retrospectively analysed pre-CRT ECGs of 124 patients with known CRT outcome. CRT response was defined as improvement of >= 1 NYHA class, being alive and having no hospitalizations for heart failure during 6 months of follow-up. 35/124 (28%) patients were non-responders (NRs), using the traditional criteria (TC) correct diagnosis was made in the remaining 89/124 (72%) responder (R) cases. The test accuracy (TA) of intra + interDC + TC [100/124 (81%), P < 0.001] was superior to that of TC [89/124 (72%)] due to its superior TA [36/43 (84%) vs. 29/43 (67%), respectively, P = 0.0156] in the non-specific intra-ventricular conduction disturbance (NICD) subgroup [43/124 (35%)]. In the left bundle branch block subgroup [70/124 (56%)] there was no between-criteria difference in TA. Conclusion: The intra + interDC + TC predicts clinical response after CRT more accurately than TC alone, due to greater TA in the NICD subgroup. PMID- 28011803 TI - The Italian subcutaneous implantable cardioverter-defibrillator survey: S-ICD, why not? AB - Aims: A recommendation for a subcutaneous-implantable cardioverter-defibrillator (S-ICD) has been added to recent European Society of Cardiology Guidelines. However, the S-ICD is not ideally suitable for patients who need pacing. The aim of this survey was to analyse the current practice of ICD implantation and to evaluate the actual suitability of S-ICD. Methods and results: The survey 'S-ICD Why Not?' was an independent initiative taken by the Italian Heart Rhythm Society (AIAC). Clinical characteristics, selection criteria, and factors guiding the choice of ICD type were collected in consecutive patients who underwent ICD implantation in 33 Italian centres from September to December 2015. A cardiac resynchronization therapy (CRT) device was implanted in 39% (369 of 947) of patients undergoing de novo ICD implantation. An S-ICD was implanted in 12% of patients with no CRT indication (62 of 510 with available data). S-ICD patients were younger than patients who received transvenous ICD, more often had channelopathies, and more frequently received their device for secondary prevention of sudden death. More frequently, the clinical reason for preferring a transvenous ICD over an S-ICD was the need for pacing (45%) or for antitachycardia pacing (36%). Nonetheless, only 7% of patients fulfilled conditions for recommending permanent pacing, and 4% of patients had a history of monomorphic ventricular tachycardia that might have been treatable with antitachycardia pacing. Conclusion: The vast majority of patients needing ICD therapy are suitable candidates for S-ICD implantation. Nevertheless, it currently seems to be preferentially adopted for secondary prevention of sudden death in young patients with channelopathies. PMID- 28011804 TI - Shape of the association between income and mortality: a cohort study of Denmark, Finland, Norway and Sweden in 1995 and 2003. AB - OBJECTIVES: Prior work has examined the shape of the income-mortality association, but work has not compared gradients between countries. In this study, we focus on changes over time in the shape of income-mortality gradients for 4 Nordic countries during a period of rising income inequality. Context and time differentials in shape imply that the relationship between income and mortality is not fixed. SETTING: Population-based cohort study of Denmark, Finland, Norway and Sweden. PARTICIPANTS: We collected data on individuals aged 25 or more in 1995 (n=12.98 million individuals, 0.84 million deaths) and 2003 (n=13.08 million individuals, 0.90 million deaths). We then examined the household size equivalised disposable income at the baseline year in relation to the rate of mortality in the following 5 years. RESULTS: A steep income gradient in mortality in men and women across all age groups except the oldest old in Denmark, Finland, Norway and Sweden. From the 1990s to 2000s mortality dropped, but generally more so in the upper part of the income distribution than in the lower part. As a consequence, the shape of the income gradient in mortality changed. The shift in the shape of the association was similar in all 4 countries. CONCLUSIONS: A non-linear gradient exists between income and mortality in most cases and because of a more rapid mortality decline among those with high income the income gradient has become steeper over time. PMID- 28011805 TI - Climate change and human health: what are the research trends? A scoping review protocol. AB - INTRODUCTION: For 28 years, the Intergovernmental Panel on Climate Change (IPCC) has been assessing the potential risks associated with anthropogenic climate change. Although interest in climate change and health is growing, the implications arising from their interaction remain understudied. Generating a greater understanding of the health impacts of climate change could be key step in inciting some of the changes necessary to decelerate global warming. A long term and broad overview of the existing scientific literature in the field of climate change and health is currently missing in order to ensure that all priority areas are being adequately addressed. In this paper we outline our methods to conduct a scoping review of the published peer-reviewed literature on climate change and health between 1990 and 2015. METHODS AND ANALYSIS: A detailed search strategy will be used to search the PubMed and Web of Science databases. Specific inclusion and exclusion criteria will be applied in order to capture the most relevant literature in the time frame chosen. Data will be extracted, categorised and coded to allow for statistical analysis of the results. ETHICS AND DISSEMINATION: No ethical approval was required for this study. A searchable database of climate change and health publications will be developed and a manuscript will be complied for publication and dissemination of the findings. We anticipate that this study will allow us to map the trends observed in publications over the 25-year time period in climate change and health research. It will also identify the research areas with the highest volume of publications as well as highlight the research trends in climate change and health. PMID- 28011806 TI - Nationwide cross-sectional study of the impact of chronic pain on an individual's employment: relationship with the family and the social support. AB - OBJECTIVES: To determine the prevalence and the factors related to sick leave and job loss among individuals suffering from chronic pain (CP), and to analyse specifically the effect of family and social support on the individual's employment. DESIGN: Observational cross-sectional study. SETTING: Data were collected using structured computer-assisted telephone interviews between February and June 2011. PARTICIPANTS: A nationwide study of 1543 Spanish adults of working age (<65), 213 of whom suffered from CP (pain suffered at least 4 or 5 days a week during the past 3 months, according to the criteria of the International Association for the Study of Pain (IASP)). MAIN OUTCOME MEASURE: Information was collected regarding the individual's sociodemographic status, pain characteristics, healthcare use and satisfaction, limitations in daily activities, mood status, perception of the impact of pain on their families, and their satisfaction with the family and social support. To identify factors associated with sick leave and job loss among those suffering CP, 2 logistic regression models were generated. RESULTS: The prevalence of sick leave due to CP in the general Spanish population was 4.21% (95% CI 3.2% to 5.2%). Sick leave were more likely for individuals who considered their family were affected by their pain (OR=2.18), needed help to dressing and grooming (OR=2.98), taking medication (OR=2.18), had a shorter pain duration (OR=0.99) and higher educational level. The prevalence of job loss due to CP was 1.8% (95% CI 1.1% to 2.5%). It was related to feelings of sadness (OR=4.25), being unsatisfied with the care provided by health professionals (OR=2.60) and consulting a doctor more often due to CP (OR=1.09). CONCLUSIONS: CP is negatively associated with an individual's employment. This detrimental effect could be ameliorated if the factors related to sick leave and job loss provoked by CP are identified, especially those related to the effect of CP on the family and social environment. PMID- 28011807 TI - Multicentre individual randomised controlled trial of screening and brief alcohol intervention to prevent risky drinking in young people aged 14-15 in a high school setting (SIPS JR-HIGH): study protocol. AB - INTRODUCTION: Drinking has adverse impacts on health, well-being, education and social outcomes for adolescents. Adolescents in England are among the heaviest drinkers in Europe. Recently, the proportion of adolescents who drink alcohol has fallen, although consumption among those who do drink has actually increased. This trial seeks to investigate how effective and efficient an alcohol brief intervention is with 11-15 years olds to encourage lower alcohol consumption. METHODS AND ANALYSIS: This is an individually randomised two-armed trial incorporating a control arm of usual school-based practice and a leaflet on a healthy lifestyle (excl. alcohol), and an intervention arm that combines usual practice with a 30 min brief intervention delivered by school learning mentors and a leaflet on alcohol. At least 30 schools will be recruited from four regions in England (North East, North West, London, Kent and Medway) to follow-up 235 per arm. The primary outcome is total alcohol consumed in the last 28 days, using the 28 day Timeline Follow Back questionnaire measured at the 12-month follow-up. The analysis of the intervention will consider effectiveness and cost-effectiveness. A qualitative study will explore, via 1:1 in-depth interviews with (n=80) parents, young people and school staff, intervention experience, intervention fidelity and acceptability issues, using thematic narrative synthesis to report qualitative data. ETHICS AND DISSEMINATION: Ethical approval was granted by Teesside University. Dissemination plans include academic publications, conference presentations, disseminating to local and national education departments and the wider public health community, including via Fuse, and engaging with school staff and young people to comment on whether and how the project can be improved. TRIAL REGISTRATION TRIAL: ISRCTN45691494; Pre-results. PMID- 28011808 TI - Cancer Data and Aboriginal Disparities (CanDAD)-developing an Advanced Cancer Data System for Aboriginal people in South Australia: a mixed methods research protocol. AB - INTRODUCTION: In Australia, Aboriginal and Torres Strait Islander People carry a greater burden of cancer-related mortality than non-Aboriginal Australians. The Cancer Data and Aboriginal Disparities Project aims to develop and test an integrated, comprehensive cancer monitoring and surveillance system capable of incorporating epidemiological and narrative data to address disparities and advocate for clinical system change. METHODS AND ANALYSIS: The Advanced Cancer Data System will integrate routinely collected unit record data from the South Australian Population Cancer Registry and a range of other data sources for a retrospective cohort of indigenous people with cancers diagnosed from 1990 to 2010. A randomly drawn non-Aboriginal cohort will be matched by primary cancer site, sex, age and year at diagnosis. Cross-tabulations and regression analyses will examine the extent to which demographic attributes, cancer stage and survival vary between the cohorts. Narratives from Aboriginal people with cancer, their families, carers and service providers will be collected and analysed using patient pathway mapping and thematic analysis. Statements from the narratives will structure both a concept mapping process of rating, sorting and prioritising issues, focusing on issues of importance and feasibility, and the development of a real-time Aboriginal Cancer Measure of Experience for ongoing linkage with epidemiological data in the Advanced Cancer Data System. Aboriginal Community engagement underpins this Project. ETHICS AND DISSEMINATION: The research has been approved by relevant local and national ethics committees. Findings will be disseminated in local and international peer-reviewed journals and conference presentations. In addition, the research will provide data for knowledge translation activities across the partner organisations and feed directly into the Statewide Cancer Control Plan. It will provide a mechanism for monitoring and evaluating the implementation of the recommendations in these documents. PMID- 28011809 TI - Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo controlled randomised trial. AB - INTRODUCTION: Osteoporosis is a major health concern in postmenopausal women, and oxidative stress contributes to the development of bone loss. Cellular studies and ovariectomised rat model mimicking bone loss in postmenopausal women show the bone-protective effect of tocotrienols (TTs) with antioxidant capability. We aim to access the safety and efficacy of TT consumption for bone health in postmenopausal women. METHODS AND ANALYSIS: In this 12-week randomised double blinded placebo-controlled trial for the effects of dietary TT supplementation in postmenopausal women, postmenopausal women aged 45 years and older with at least 1 year after menopause and bone mineral density T-score at the spine and/or hip 2.5 or more below the reference values will be randomly assigned to 3 daily supplements: (1) placebo group receiving 860 mg olive oil, (2) low TT group receiving 430 mg of 70% pure TTs (containing 300 mg TT) and (3) high TT group receiving 860 mg of 70% pure TTs (600 mg TT). The primary outcome measure will be urinary N-terminal telopeptide. The secondary outcome measures will be serum bone specific alkaline phosphatase, receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, urinary 8-hydroxy-2'-deoxyguanosine and quality of life. At 0, 6 and 12 weeks, the following will be assessed: (1) primary and secondary outcome measures; (2) serum TT and tocopherol concentrations; (3) physical activity and food frequency questionnaires. Liver function will be monitored every 6 weeks for safety. 'Intent-to-treat' principle will be employed for data analysis. A model of repeated measurements with random effect error terms will be applied. Analysis of covariance, chi2 analysis and regression will be used for comparisons. ETHICS AND DISSEMINATION: This study was approved by the Bioethics Committee of the Texas Tech University Health Sciences Center. The findings of this trial will be submitted to a peer-reviewed journal in the areas of bone or nutrition and international conferences. TRIAL REGISTRATION NUMBER: NCT02058420; results. PMID- 28011811 TI - Safetxt: a pilot randomised controlled trial of an intervention delivered by mobile phone to increase safer sex behaviours in young people. AB - OBJECTIVE: To test the procedures proposed for a main trial of a safer sex intervention for young people delivered by mobile phone text message ('safetxt'). DESIGN AND SETTING: Pilot randomised controlled trial. Participants were recruited through sexual health services in the UK. An independent online randomisation system allocated participants to receive the safetxt intervention or to receive the control text messages (monthly messages about participation in the study). Texting software delivered the messages in accordance with a predetermined schedule. PARTICIPANTS: Residents of England aged 16-24 who had received either a positive chlamydia test result or reported unsafe sex in the last year (defined as more than 1 partner and at least 1 occasion of sex without a condom). INTERVENTION: The safetxt intervention is designed to reduce sexually transmitted infection in young people by supporting them in using condoms, telling a partner about an infection and testing before unprotected sex with a new partner. Safetxt was developed drawing on: behavioural science; face-to-face interventions; the factors known to influence safer sex behaviours and the views of young people. OUTCOMES: The coprimary outcomes of the pilot trial were the recruitment rate and completeness of follow-up. RESULTS: We recruited 200 participants within our target of 3 months and we achieved 81% (162/200) follow up response for the proposed primary outcome of the main trial, cumulative incidence of chlamydia at 12 months. CONCLUSIONS: Recruitment, randomisation, intervention delivery and follow-up were successful and a randomised controlled trial of the safetxt intervention is feasible. TRIAL REGISTRATION NUMBER: ISRCTN02304709; Results. PMID- 28011810 TI - Cohort profile of BIOMArCS: the BIOMarker study to identify the Acute risk of a Coronary Syndrome-a prospective multicentre biomarker study conducted in the Netherlands. AB - PURPOSE: Progression of stable coronary artery disease (CAD) towards acute coronary syndrome (ACS) is a dynamic and heterogeneous process with many intertwined constituents, in which a plaque destabilising sequence could lead to ACS within short time frames. Current CAD risk assessment models, however, are not designed to identify increased vulnerability for the occurrence of coronary events within a precise, short time frame at the individual patient level. The BIOMarker study to identify the Acute risk of a Coronary Syndrome (BIOMArCS) was designed to evaluate whether repeated measurements of multiple biomarkers can predict such 'vulnerable periods'. PARTICIPANTS: BIOMArCS is a multicentre, prospective, observational study of 844 patients presenting with ACS, either with or without ST-elevation and at least one additional cardiovascular risk factor. METHODS AND ANALYSIS: We hypothesised that patterns of circulating biomarkers that reflect the various pathophysiological components of CAD, such as distorted lipid metabolism, vascular inflammation, endothelial dysfunction, increased thrombogenicity and ischaemia, diverge in the days to weeks before a coronary event. Divergent biomarker patterns, identified by serial biomarker measurements during 1-year follow-up might then indicate 'vulnerable periods' during which patients with CAD are at high short-term risk of developing an ACS. Venepuncture was performed every fortnight during the first half-year and monthly thereafter. As prespecified, patient enrolment was terminated after the primary end point of cardiovascular death or hospital admission for non-fatal ACS had occurred in 50 patients. A case-cohort design will explore differences in temporal patterns of circulating biomarkers prior to the repeat ACS. FUTURE PLANS AND DISSEMINATION: Follow-up and event adjudication have been completed. Prespecified biomarker analyses are currently being performed and dissemination through peer-reviewed publications and conference presentations is expected from the third quarter of 2016. Should identification of a 'vulnerable period' prove to be feasible, then future research could focus on event reduction through pharmacological or mechanical intervention during such periods of high risk for ACS. TRIAL REGISTRATION NUMBER: NTR1698 and NTR1106. PMID- 28011812 TI - Impact of self-funding on patient experience of oral anticoagulation self monitoring: a qualitative study. AB - OBJECTIVE: To explore the impact self-funding has on patient experience of oral anticoagulation therapy self-monitoring. DESIGN: Semistructured, qualitative interviews were conducted. Transcripts were analysed thematically using constant comparison. SETTING: England. PARTICIPANTS: Interviewees were participants of the Cohort Study of Anticoagulation Self-Monitoring (CASM). Cohort members were recruited as they bought a monitor from the major manufacturer in the UK. A purposive sample was invited to be interviewed on completion of the 12-month cohort follow-up. DATA: Patient narratives on their experiences of self monitoring their oral anticoagulation therapy in non-trial conditions. RESULTS: 26 interviews were completed. Interviewees viewed purchasing the monitoring device as a long-term commitment balancing the limitations of clinic-based monitoring against the cost. They were unable to try out the monitor prior to purchase and therefore had to be confident in their own ability to use it. The variable provision of self-monitoring equipment caused resentment, and interviewees were uncomfortable negotiating with healthcare professionals. High test strip usage while learning how to use the monitor caused anxiety that was exacerbated by worries about their cost. However, self-funding did mean that interviewees felt a sense of ownership and were determined to persevere to overcome problems. CONCLUSIONS: Self-funding has negative implications in terms of equity of access; however, the money invested acts as a barrier to discontinuation. If oral anticoagulation therapy self-monitoring devices and consumables were provided free of charge in routine care, the training and support available in England may need to be reviewed to prevent discontinuation rates rising to those observed in clinical trials. PMID- 28011813 TI - Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine. AB - BACKGROUND: BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV). METHODS: During an RCT of 2 doses of MV at 4.5 and 9 months versus 1 dose of MV at 9 months of age, we experienced 2 natural experiments with OPV. We assessed whether these OPV experiments modified the effect of 2-dose MV in the MV trial. SETTING: MV RCT conducted in urban Guinea-Bissau 2003-2009. INTERVENTIONS: Natural experiments with OPV due to missing vaccine and the implementation of OPV campaigns. MAIN OUTCOME MEASURE: Changes in the mortality rate ratio (MRR) for 2 dose MV versus 1-dose MV. RESULTS: First, the MRR (2-dose/1-dose MV) overall was 0.70 (0.52 to 0.94), but the MRR was 1.04 (0.53 to 2.04) when OPV at birth (OPV0) was not given, suggesting that early priming with OPV was important for the effect of 2-dose MV. The effect of OPV0 depended on age of administration; the MRR (2-dose/1-dose MV) was 0.45 (0.29 to 0.71) for children receiving OPV0 in the first week of life, but 3.63 (0.87 to 15.2) for those receiving OPV0 after the first month of life (p=0.007, test of no interaction). Second, campaign-OPV may have reduced the difference between the randomisation groups since the MRR (2 dose/1-dose MV) was 0.60 (0.42 to 0.85) for children who had not received campaign-OPV before RCT-enrolment versus 0.72 (0.23 to 2.31) and 1.42 (0.70 to 2.90) for children who had received 1 or 2 doses of campaign-OPV-before enrolment, respectively. CONCLUSIONS: Bissau had no polio infection during this trial, so OPV0 and campaign-OPV may have NSEs since they modified the effect of 2 dose MV in an RCT. Different interventions may interact to a much larger effect than usually assumed. PMID- 28011814 TI - Associations of lipid levels during gestation with hypertensive disorders of pregnancy and gestational diabetes mellitus: a prospective longitudinal cohort study. AB - OBJECTIVE: To assess associations of elevated lipid levels during gestation with hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM). METHODS: This prospective cohort study was conducted in a tertiary maternal hospital in Shanghai, China from February to November 2014. Lipid constituents, including triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) of 1310 eligible women were assessed in the first (10-13+ weeks), second (22-28 weeks) and third (30-35 weeks) trimesters consecutively. Associations of lipid profiles with HDP and/or GDM outcomes were assessed. RESULTS: Compared with the normal group, maternal TG concentrations were higher in the HDP/GDM groups across the three trimesters (p<0.001); TC and LDL-c amounts were only higher in the first trimester for the HDP and GDM groups (p<0.05). HDL-c levels were similar in the three groups. Compared with intermediate TG levels (25-75th centile), higher TG amounts (>75th centile) were associated with increased risk of HDP/GDM in each trimester with aORs (95% CI) of 2.04 (1.41 to 2.95), 1.81 (1.25 to 2.63) and 1.78 (1.24 to 2.54), respectively. High TG elevation from the first to third trimesters (>75th centile) was associated with increased risk of HDP, with an aOR of 2.09 (1.16 to 3.78). High TG elevation before 28 weeks was associated with increased risk of GDM, with an aOR of 1.67 (1.10 to 2.54). TG elevation was positively correlated with weight gain during gestation (R=0.089, p=0.005). CONCLUSIONS: Controlling weight gain during pregnancy could decrease TG elevation and reduce the risk of HDP/GDM. TGs could be used as follow-up parameters during complicated pregnancy, while other lipids are meaningful only in the first trimester. PMID- 28011815 TI - Barriers, facilitators, strategies and outcomes to engaging policymakers, healthcare managers and policy analysts in knowledge synthesis: a scoping review protocol. AB - INTRODUCTION: Engaging policymakers, healthcare managers and policy analysts in the conduct of knowledge synthesis can help increase its impact. This is particularly important for knowledge synthesis studies commissioned by decision makers with limited timelines, as well as reviews of health policy and systems research. A scoping review will be conducted to assess barriers, facilitators, strategies and outcomes of engaging these individuals in the knowledge synthesis process. METHODS AND ANALYSIS: We will follow the Joanna Briggs Institute guidance for scoping reviews. Literature searches of electronic databases (eg, MEDLINE, EMBASE, Cochrane Library, ERIC, PsycINFO) will be conducted from inception onwards. The electronic search will be supplemented by searching for sources that index unpublished/difficult to locate studies (eg, GreyNet International database), as well as through scanning of reference lists of reviews on related topics. All study designs using either qualitative or quantitative methodologies will be eligible if there is a description of the strategies, barriers or facilitators, and outcomes of engaging policymakers, healthcare managers and policy analysts in the knowledge synthesis process. Screening and data abstraction will be conducted by 2 team members independently after a calibration exercise across the team. A third team member will resolve all discrepancies. We will conduct frequency analysis and thematic analysis to chart and characterise the literature, identifying data gaps and opportunities for future research, as well as implications for policy. ETHICS AND DISSEMINATION: This project was commissioned by the Alliance for Health Policy and Systems Research, WHO. The results will be used by Alliance Review Centers of health policy and systems research in low-income and middle-income countries that are conducting knowledge synthesis to inform health policymaking and decision making. Our results will also be disseminated through conference presentations, train-the-trainer events, peer-reviewed publication and a 1-page policy brief that will be posted on the authors' websites. PMID- 28011816 TI - Psychological Impact of Primary Screening (PIPS) for HPV: a protocol for a cross sectional evaluation within the NHS cervical screening programme. AB - INTRODUCTION: The NHS Cervical Screening Programme is now using human papillomavirus (HPV) testing as the primary test in six sentinel sites in England, with the intention of rolling this out across the whole of England. Previous research evaluating HPV testing in the cervical screening context suggests that an HPV-positive result may increase anxiety beyond that associated with abnormal cytology, but this has not been explored in the context of primary HPV testing. The main aim of this study is to explore the impact of the HPV primary screening programme on anxiety and distress. METHODS AND ANALYSIS: A cross-sectional between-groups design (total N ~ 673) will be employed to assess the psychological impact of different HPV and cytology results at three time points: shortly after receiving the results, and 6 and 12 months later. Women will fall into one of six groups based on their screening results. The primary outcomes will be anxiety and general distress. Secondary outcomes will include understanding of screening results, perceived risk of cervical cancer, psychosexual functioning, intention to attend future screening and knowledge of HPV. General linear modelling will be used to test for differences between groups and changes over the three time points. ETHICS AND DISSEMINATION: Health Research Authority approval was received on 26 September 2016. Ethical approval was received from London- Surrey Borders NHS Research Ethics Committee on 30 August 2016. Section 251 approval was received from the Confidentiality Advisory Group on 24 August 2016. Results will be disseminated via peer-reviewed publication and presentation at national and international conferences. PMID- 28011817 TI - A mechanism for evasion of CTL immunity by altered O-glycosylation of HLA class I. AB - Anti-tumour immunity by cytotoxic T-lymphocytes (CTLs) is essential to suppress tumour progression. Cancer cells that evade CTL immunity proliferate in the host, promoting metastasis, but mechanisms underlying this capacity remain unknown. Here we report that bladder cancer cells metastasized to lymph nodes evade CTL immunity by a new mechanism via altered glycosylation. CTLs normally recognize and kill cancer cells presenting antigenic peptides on human leukocyte antigen (HLA) class I. We show bladder cancer cells expressing the O-glycan processing enzyme, core2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) exhibit HLA class I O-glycan modified with poly-N-acetyllactosamine and are highly susceptible to CTL. In those cells, poly-N-acetyllactosamine on HLA class I O-glycan binds galectin-3 to form a cell-surface molecular lattice, enabling efficient cell surface retention of HLA class I. In contrast, bladder cancer cells in which C2GnT is downregulated show decreased levels of poly-N-acetyllactosamine on HLA class I O-glycans, attenuating lattice formation and reducing the cell-surface half-life of HLA class I. These tumour cells present antigenic peptides less efficiently, thereby evading CTL lysis and facilitating metastasis. PMID- 28011818 TI - The emerging complexity of ubiquitin architecture. AB - Ubiquitylation is an essential post-translational modification (PTM) of proteins with diverse cellular functions. Polyubiquitin chains with different topologies have different cellular roles, and are referred to as a 'ubiquitin code'. Recent studies have begun to reveal that more complex ubiquitin architectures function as important signals in several biological pathways. These include PTMs of ubiquitin itself, such as acetylated ubiquitin and phospho-ubiquitin. Moreover, important roles for heterogeneous polyubiquitin chains, such as mixed or branched chains, have been reported, which significantly increase the diversity of the ubiquitin code. In this review, we describe mass spectrometry-based methods to characterize the ubiquitin signal. We also describe recent advances in our understanding of complex ubiquitin architectures, including our own findings concerning ubiquitin acetylation and branching within polyubiquitin chains. PMID- 28011819 TI - Evolution of vocal patterns: tuning hindbrain circuits during species divergence. AB - The neural circuits underlying divergent courtship behaviors of closely related species provide a framework for insight into the evolution of motor patterns. In frogs, male advertisement calls serve as unique species identifiers and females prefer conspecific to heterospecific calls. Advertisement calls of three relatively recently (~8.5 Mya) diverged species - Xenopus laevis, X. petersii and X. victorianus - include rapid trains of sound pulses (fast trills). We show that while fast trills are similar in pulse rate (~60 pulses s-1) across the three species, they differ in call duration and period (time from the onset of one call to the onset of the following call). Previous studies of call production in X. laevis used an isolated brain preparation in which the laryngeal nerve produces compound action potentials that correspond to the advertisement call pattern (fictive calling). Here, we show that serotonin evokes fictive calling in X. petersii and X. victorianus as it does in X. laevis As in X. laevis, fictive fast trill in X. petersii and X. victorianus is accompanied by an N-methyl-d-aspartate receptor-dependent local field potential wave in a rostral hindbrain nucleus, DTAM. Across the three species, wave duration and period are strongly correlated with species-specific fast trill duration and period, respectively. When DTAM is isolated from the more rostral forebrain and midbrain and/or more caudal laryngeal motor nucleus, the wave persists at species-typical durations and periods. Thus, intrinsic differences within DTAM could be responsible for the evolutionary divergence of call patterns across these related species. PMID- 28011820 TI - Importance of the antenniform legs, but not vision, for homing by the neotropical whip spider Paraphrynus laevifrons. AB - Amblypygids, or whip spiders, are nocturnal, predatory arthropods that display a robust ability to navigate to their home refuge. Prior field observations and displacement studies in amblypygids demonstrated an ability to home from distances as far away as 10 m. In the current study, micro-transmitters were used to take morning position fixes of individual Paraphrynus laevifrons following an experimental displacement of 10 m from their home refuge. The intention was to assess the relative importance of vision compared with sensory input acquired from the antenniform legs for navigation as well as other aspects of their spatial behavior. Displaced individuals were randomly assigned to three treatment groups: (i) control individuals; (ii) vision-deprived individuals, VD; and (iii) individuals with sensory input from the tips of their antenniform legs compromised, AD. Control and VD subjects were generally successful in returning home, and the direction of their movement on the first night following displacement was homeward oriented. By contrast, AD subjects experienced a complete loss of navigational ability, and movement on the first night indicated no hint of homeward orientation. The data strongly support the hypothesis that sensory input from the tips of the antenniform legs is necessary for successful homing in amblypygids following displacement to an unfamiliar location, and we hypothesize an essential role of olfaction for this navigational ability. PMID- 28011821 TI - Diet-induced co-variation between architectural and physicochemical plasticity in an extended phenotype. AB - The adaptive benefits of extended phenotypic plasticity are imprecisely defined due to a paucity of experiments examining traits that are manipulable and measurable across environments. Spider webs are often used as models to explore the adaptive benefits of variations in extended phenotypes across environments. Nonetheless, our understanding of the adaptive nature of the plastic responses of spider webs is impeded when web architectures and silk physicochemical properties appear to co-vary. An opportunity to examine this co-variation is presented by modifying prey items while measuring web architectures and silk physiochemical properties. Here, we performed two experiments to assess the nature of the association between web architectures and gluey silk properties when the orb web spider Argiope keyserlingi was fed a diet that varied in either mass and energy or prey size and feeding frequency. We found web architectures and gluey silk physicochemical properties to co-vary across treatments in both experiments. Specifically, web capture area co-varied with gluey droplet morphometrics, thread stickiness and salt concentrations when prey mass and energy were manipulated, and spiral spacing co-varied with gluey silk salt concentrations when prey size and feeding frequency were manipulated. We explained our results as A. keyserlingi plastically shifting its foraging strategy as multiple prey parameters simultaneously varied. We confirmed and extended previous work by showing that spiders use a variety of prey cues to concurrently adjust web and silk traits across different feeding regimes. PMID- 28011822 TI - The energetic cost of filtration by demosponges and their behavioural response to ambient currents. AB - Sponges (Porifera) are abundant in most marine and freshwater ecosystems, and as suspension feeders they play a crucial role in filtering the water column. Their active pumping enables them to filter up to 900 times their body volume of water per hour, recycling nutrients and coupling a pelagic food supply with benthic communities. Despite the ecological importance of sponge filter feeding, little is known about how sponges control the water flow through their canal system or how much energy it costs to filter the water. Sponges have long been considered textbook examples of animals that use current-induced flow. We provide evidence that suggests that some species of demosponge do not use current-induced flow; rather, they respond behaviourally to increased ambient currents by reducing the volume of water filtered. Using a morphometric model of the canal system, we also show that filter feeding may be more energetically costly than previously thought. Measurements of volumetric flow rates and oxygen removal in five species of demosponge show that pumping rates are variable within and between species, with the more oxygen consumed the greater the volume filtered. Together, these data suggest that sponges have active control over the volume of water they process, which may be an adaptation to reduce the energetic cost of filtration in times of high stress. PMID- 28011823 TI - Predator exposure-induced immunosuppression: trade-off, immune redistribution or immune reconfiguration? AB - Although predator exposure increases the risk of wound infections, it typically induces immunosuppression. A number of non-mutually exclusive hypotheses have been put forward to explain this immunosuppression, including: trade-offs between the immune system and other systems required for anti-predator behaviour, redistribution of immune resources towards mechanisms needed to defend against wound infections, and reconfiguration of the immune system to optimize defence under the physiological state of fight-or-flight readiness. We tested the ability of each hypothesis to explain the effects of chronic predator stress on the immune system of the caterpillar Manduca sexta Predator exposure induced defensive behaviours, reduced mass gain, increased development time and increased the concentration of the stress neurohormone octopamine. It had no significant effect on haemocyte number, melanization rate, phenoloxidase activity, lysozyme like activity or nodule production. Predator stress reduced haemolymph glutathione concentrations. It also increased constitutive expression of the antimicrobial peptide attacin-1 but reduced attacin-1 expression in response to an immune challenge. These results best fit the immune reconfiguration hypothesis, although the other hypotheses are also consistent with some results. Interpreting stress-related changes in immune function may require an examination at the level of the whole organism. PMID- 28011824 TI - The Lombard effect emerges early in young bats: implications for the development of audio-vocal integration. AB - Auditory feedback plays an important role in vocal learning and, more generally, in fine-tuning the acoustic features of communication signals. So far, only a few studies have assessed the developmental onset of auditory feedback. The Lombard effect, a well-studied audio-vocal phenomenon, refers to an increase in vocal loudness of a subject in response to an increase in background noise. Here, we studied the time course of the Lombard effect in developing bats, Phyllostomus discolor We show that infant bats produced louder vocalizations in noise than in silence at an age of only 2 weeks. In contrast, the infant bats' morphology and vocalizations changed gradually until 2 months of age. Furthermore, we found that the Lombard magnitude, i.e. how much the bats increased their vocal loudness in noise relative to silence, correlated positively with the age of the infant bats. We conclude that the Lombard effect features an early developmental origin, indicating a fast maturation of the underlying neural circuits for audio-vocal feedback. PMID- 28011825 TI - Eighth TRM Forum on Computer Simulation and Experimental Assessment of Cardiac Function: Towards Integration of Cardiac Functions. PMID- 28011826 TI - Human ventricular activation sequence and the simulation of the electrocardiographic QRS complex and its variability in healthy and intraventricular block conditions. AB - AIMS: To investigate how variability in activation sequence and passive conduction properties translates into clinical variability in QRS biomarkers, and gain novel physiological knowledge on the information contained in the human QRS complex. METHODS AND RESULTS: Multiscale bidomain simulations using a detailed heart-torso human anatomical model are performed to investigate the impact of activation sequence characteristics on clinical QRS biomarkers. Activation sequences are built and validated against experimentally-derived ex vivo and in vivo human activation data. R-peak amplitude exhibits the largest variability in terms of QRS morphology, due to its simultaneous modulation by activation sequence speed, myocardial intracellular and extracellular conductivities, and propagation through the human torso. QRS width, however, is regulated by endocardial activation speed and intracellular myocardial conductivities, whereas QR intervals are only affected by the endocardial activation profile. Variability in the apico-basal location of activation sites on the anterior and posterior left ventricular wall is associated with S-wave progression in limb and precordial leads, respectively, and occasional notched QRS complexes in precordial derivations. Variability in the number of early activation sites successfully reproduces pathological abnormalities of the human conduction system in the QRS complex. CONCLUSION: Variability in activation sequence and passive conduction properties captures and explains a large part of the clinical variability observed in the human QRS complex. Our physiological insights allow for a deeper interpretation of human QRS biomarkers in terms of QRS morphology and location of early endocardial activation sites. This might be used to attain a better patient-specific knowledge of activation sequence from routine body surface electrocardiograms. PMID- 28011827 TI - Localization of premature ventricular contractions from the papillary muscles using the standard 12-lead electrocardiogram: a feasibility study using a novel cardiac isochrone positioning system. AB - AIMS: The precise localization of the site of origin of a premature ventricular contraction (PVC) prior to ablation can facilitate the planning and execution of the electrophysiological procedure. In clinical practice, the targeted ablation site is estimated from the standard 12-lead ECG. The accuracy of this qualitative estimation has limitations, particularly in the localization of PVCs originating from the papillary muscles. Clinical available electrocardiographic imaging (ECGi) techniques that incorporate patient-specific anatomy may improve the localization of these PVCs, but require body surface maps with greater specificity for the epicardium. The purpose of this report is to demonstrate that a novel cardiac isochrone positioning system (CIPS) program can accurately detect the specific location of the PVC on the papillary muscle using only a 12-lead ECG. METHODS AND RESULTS: Cardiac isochrone positioning system uses three components: (i) endocardial and epicardial cardiac anatomy and torso geometry derived from MRI, (ii) the patient-specific electrode positions derived from an MRI model registered 3D image, and (iii) the 12-lead ECG. CIPS localizes the PVC origin by matching the anatomical isochrone vector with the ECG vector. The predicted PVC origin was compared with the site of successful ablation or stimulation. Three patients who underwent electrophysiological mapping and ablation of PVCs originating from the papillary muscles were studied. CIPS localized the PVC origin for all three patients to the correct papillary muscle and specifically to the base, mid, or apical region. CONCLUSION: A simplified form of ECGi utilizing only 12 standard electrocardiographic leads may facilitate accurate localization of the origin of papillary muscle PVCs. PMID- 28011828 TI - Changes in P-wave morphology after pulmonary vein isolation: insights from computer simulations. AB - AIMS: Apparently conflicting clinical measurements of P-wave duration (PWD) pre- vs. post-ablation have been reported. To assist the interpretation of these clinical data, we used a computer model of the atria and torso to simulate P waves before and after pulmonary vein (PV) isolation. METHODS AND RESULTS: Twenty ablation patterns were designed (segmental or ipsilateral ablation; five distances to PV sleeves; addition of a roof line or not). Possible PV reconnections were introduced as gaps in the ablation lines. PWD and area were measured during sinus rhythm in vectorcardiogram (VCG) magnitude signals and on the 16-lead ECG before and after ablation, and after PV reconnection. After PV isolation, biatrial activation time was prolonged by 0-5 ms without and by 48+/-5 ms with roof line. Yet PWD was shortened in lead V3 and V4 by up to 15 ms. The effect of ablation on P-wave morphology was stronger when larger PV areas were isolated. Segmental and ipsilateral PV isolation led to concordant results. P wave area increased in V1 and decreased in V6. Changes in PWD and area on the VCG were sensitive to the threshold used for detecting the end of the P wave. The occurrence of PV reconnection was best identified on leads V3, V4, and V9. CONCLUSION: PV isolation and reconnection induced measurable changes on the 16 lead ECG that might be used to improve patient follow-up after ablation. PMID- 28011829 TI - Influence of the earliest right atrial activation site and its proximity to interatrial connections on P-wave morphology. AB - AIMS: P-wave morphology correlates with the risk for atrial fibrillation (AF). Left atrial (LA) enlargement could explain both the higher risk for AF and higher P-wave terminal force (PTF) in lead V1. However, PTF-V1 has been shown to correlate poorly with LA size. We hypothesize that PTF-V1 is also affected by the earliest activated site (EAS) in the right atrium and its proximity to inter atrial connections (IAC), which both show tremendous variability. METHODS AND RESULTS: Atrial excitation was triggered from seven different EAS in a cohort of eight anatomically personalized computational models. The posterior IACs were non conductive in a second set of simulations. Body surface ECGs were computed and separated by left and right atrial contributions. Mid-septal EAS yielded the highest PTF-V1. More anterior/superior and more inferior EAS yielded lower absolute PTF-V1 values deviating by a factor of up to 2.0 for adjacent EAS. Earliest right-to-left activation was conducted via Bachmann's Bundle (BB) for anterior/superior EAS and shifted towards posterior IACs for more inferior EAS. Non-conducting posterior IACs increased PTF-V1 by up to 150% compared to intact posterior IACs for inferior EAS. LA contribution to the P-wave integral was 24% on average. CONCLUSION: The electrical contributor's site of earliest activation and intactness of posterior IACs affect PTF-V1 significantly by changing LA breakthrough sites independent from LA size. This should be considered for interpretation of electrocardiographical signs of LA abnormality and LA enlargement. PMID- 28011830 TI - Electrical remodelling in patients with iatrogenic left bundle branch block. AB - AIMS: Left bundle branch block (LBBB) is induced in approximately one-third of all transcatheter aortic valve implantation (TAVI) procedures. We investigated electrophysiological remodelling in patients with TAVI-induced LBBB. METHODS AND RESULTS: This retrospective study comprises 107 patients with initially narrow QRS complex of whom 40 did not and 67 did develop persistent LBBB after TAVI. 12 lead electrocardiograms (ECGs) taken before TAVI, within 24 hours ('acute'), and 1-12 months after TAVI ('chronic') were used to reconstruct vectorcardiograms. From these vectorcardiograms, QRS and T-wave area were calculated as comprehensive indices of depolarization and repolarization abnormalities, respectively. TAVI-induced LBBB resulted in significant acute depolarization and repolarization changes while further repolarization changes were observed with longer lasting LBBB. The amount of long-term repolarization changes (remodelling) was highly variable between patients. The change in T-wave area between acute and chronic LBBB ranged from +57% to - 77%. After dividing the LBBB cohort into tertiles based on the change in T-wave area, only baseline QRS area was larger in the tertile with no significant change in T-wave area. During longer lasting LBBB, the spatial vector gradient (SVG) changed orientation towards the direction of the QRS-vector, indicating that later-activated regions developed shorter action potential duration. CONCLUSION: This study in patients with TAVI-induced LBBB shows that repolarization changes develop within months after onset of LBBB, and that these changes are highly variable between individual patients. PMID- 28011831 TI - Atrial fibrillation septal pacing: translation of modelling results. AB - AIMS: Atrial fibrillation (AF) septal pacing consists of rapid pacing from a ring of electrodes around the atrial septum, leading to local capture of both atria during AF. The present model-based study evaluated the impact of the number of stimulation electrodes in the septal ring on AF capture for different types of sustained AF dynamics. METHODS AND RESULTS: Using a biophysical model of AF based on CT scans from an AF patient, models with different AF substrates (Cholinergic AF and Meandering Wavelets) were created by varying the atrial membrane kinetics. Rapid pacing was applied from the septum area with a ring of 1, 2, 3, 4, 6, 8, or 12 electrodes during 20 seconds at a pacing cycle lengths (PCLs) in the range 60 100% of AF cycle length (AFCL), in 4% steps. Percentage of captured tissue during rapid pacing was determined using 24 sensing electrode pairs evenly distributed on the atrial surface. Results were averaged over 10 AF simulations. For Cholinergic AF, the number of stimulation electrodes on the septal ring had no significant impact on AF capture independently of AF dynamics. For Meandering Wavelets, more electrodes were needed to achieve AF capture in the presence of complex AF. CONCLUSION: Changes in AF substrate significantly impacted septal pacing outcomes and response to rapid AF pacing may similarly vary patient-to patient. The number of stimulation electrodes had a lesser impact, suggesting that the design of a ring with 3-4 electrodes around the septum would be sufficient for most AF dynamics. PMID- 28011832 TI - A feasibility study of arrhythmia risk prediction in patients with myocardial infarction and preserved ejection fraction. AB - AIM: To predict arrhythmia susceptibility in myocardial infarction (MI) patients with left ventricular ejection fraction (LVEF) >35% using a personalized virtual heart simulation approach. METHODS AND RESULTS: A total of four contrast enhanced magnetic resonance imaging (MRI) datasets of patient hearts with MI and average LVEF of 44.0 +/- 2.6% were used in this study. Because of the preserved LVEF, the patients were not indicated for implantable cardioverter defibrillator (ICD) insertion. One patient had spontaneous ventricular tachycardia (VT) prior to the MRI scan; the others had no arrhythmic events. Simulations of arrhythmia susceptibility were blind to clinical outcome. Models were constructed from patient MRI images segmented to identify myocardium, grey zone, and scar based on pixel intensity. Grey zone was modelled as having altered electrophysiology. Programmed electrical stimulation (PES) was performed to assess VT inducibility from 19 bi-ventricular sites in each heart model. Simulations successfully predicted arrhythmia risk in all four patients. For the patient with arrhythmic event, in-silico PES resulted in VT induction. Simulations correctly predicted that VT was non-inducible for the three patients with no recorded VT events. CONCLUSIONS: Results demonstrate that the personalized virtual heart simulation approach may provide a novel risk stratification modality to non-invasively and effectively identify patients with LVEF >35% who could benefit from ICD implantation. PMID- 28011833 TI - Human-induced pluripotent stem cell-derived cardiomyocytes from cardiac progenitor cells: effects of selective ion channel blockade. AB - AIM: Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are likely to revolutionize electrophysiological approaches to arrhythmias. Recent evidence suggests the somatic cell origin of hiPSCs may influence their differentiation potential. Owing to their cardiomyogenic potential, cardiac stromal progenitor cells (CPCs) are an interesting cellular source for generation of hiPSC-derived cardiomyocytes. The effect of ionic current blockade in hiPSC derived cardiomyocytes generated from CPCs has not been characterized yet. METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes were generated from adult CPCs and skin fibroblasts from the same individuals. The effect of selective ionic current blockade on spontaneously beating hiPSC derived cardiomyocytes was assessed using multi-electrode arrays. Cardiac-stromal progenitor cells could be reprogrammed into hiPSCs, then differentiated into hiPSC-derived cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin showed higher upregulation of cardiac-specific genes compared with those of fibroblastic origin. Human-induced pluripotent stem cell-derived cardiomyocytes of both somatic cell origins exhibited sensitivity to tetrodotoxin, a blocker of Na+ current (INa), nifedipine, a blocker of L-type Ca2+ current (ICaL), and E4031, a blocker of the rapid component of delayed rectifier K+ current (IKr). Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin exhibited sensitivity to JNJ303, a blocker of the slow component of delayed rectifier K+ current (IKs). CONCLUSION: In hiPSC derived cardiomyocytes of cardiac origin, INa, ICaL, IKr, and IKs were present as tetrodotoxin-, nifedipine-, E4031-, and JNJ303-sensitive currents, respectively. Although cardiac differentiation efficiency was improved in hiPSCs of cardiac vs. non-cardiac origin, no major functional differences were observed between hiPSC derived cardiomyocytes of different somatic cell origins. Further studies are warranted to characterize electrophysiological properties of hiPSC-derived cardiomyocytes generated from CPCs. PMID- 28011834 TI - Impact of mechanical deformation on pseudo-ECG: a simulation study. AB - AIMS: Electrophysiological simulations may help to investigate causes and possible treatments of ventricular conduction disturbances. Most electrophysiological models do not take into account that the heart moves during the cardiac cycle. We used an electro-mechanical model to study the effect of mechanical deformation on the results of electrophysiological simulations. METHODS AND RESULTS: Pseudo-electrocardiogram (ECG) were generated from the propagation of electrical signals in tissue slabs undergoing active mechanical deformation. We used the mono-domain equation for electrophysiology with the Bueno-Orovio ionic model and a fully incompressible Guccione-Costa hyperelastic law for the mechanics with the Nash-Panfilov model for the active force. We compared a purely electrophysiological approach (PE) with mono-directional (MD) and bi-directional (BD) electromechanical coupling strategies. The numerical experiments showed that BD and PE simulations led to different S- and T-waves. Mono-directional simulations generally approximated the BD ones, unless fibres were oriented along one short axis of the slab. When present, notching in the QRS complex was larger in MD than in BD simulations. CONCLUSIONS: Tissue deformation has to be taken into account when estimating the S- and T-wave of the ECG in electrophysiological simulations. PMID- 28011835 TI - Comparing maximum rate and sustainability of pacing by mechanical vs. electrical stimulation in the Langendorff-perfused rabbit heart. AB - AIMS: Mechanical stimulation (MS) represents a readily available, non-invasive means of pacing the asystolic or bradycardic heart in patients, but benefits of MS at higher heart rates are unclear. Our aim was to assess the maximum rate and sustainability of excitation by MS vs. electrical stimulation (ES) in the isolated heart under normal physiological conditions. METHODS AND RESULTS: Trains of local MS or ES at rates exceeding intrinsic sinus rhythm (overdrive pacing; lowest pacing rates 2.5+/-0.5 Hz) were applied to the same mid-left ventricular free-wall site on the epicardium of Langendorff-perfused rabbit hearts. Stimulation rates were progressively increased, with a recovery period of normal sinus rhythm between each stimulation period. Trains of MS caused repeated focal ventricular excitation from the site of stimulation. The maximum rate at which MS achieved 1:1 capture was lower than during ES (4.2+/-0.2 vs. 5.9+/-0.2 Hz, respectively). At all overdrive pacing rates for which repetitive MS was possible, 1:1 capture was reversibly lost after a finite number of cycles, even though same-site capture by ES remained possible. The number of MS cycles until loss of capture decreased with rising stimulation rate. If interspersed with ES, the number of MS to failure of capture was lower than for MS only. CONCLUSION: In this study, we demonstrate that the maximum pacing rate at which MS can be sustained is lower than that for same-site ES in isolated heart, and that, in contrast to ES, the sustainability of successful 1:1 capture by MS is limited. The mechanism(s) of differences in MS vs. ES pacing ability, potentially important for emergency heart rhythm management, are currently unknown, thus warranting further investigation. PMID- 28011836 TI - New insights from a computational model on the relation between pacing site and CRT response. AB - AIMS: Cardiac resynchronization therapy (CRT) produces clinical benefits in chronic heart failure patients with left bundle-branch block (LBBB). The position of the pacing site on the left ventricle (LV) is considered an important determinant of CRT response, but the mechanism how the LV pacing site determines CRT response is not completely understood. The objective of this study is to investigate the relation between LV pacing site during biventricular (BiV) pacing and cardiac function. METHODS AND RESULTS: We used a finite element model of BiV electromechanics. Cardiac function, assessed as LV dp/dtmax and stroke work, was evaluated during normal electrical activation, typical LBBB, fascicular blocks and BiV pacing with different LV pacing sites. The model replicated clinical observations such as increase of LV dp/dtmax and stroke work, and the disappearance of a septal flash during BiV pacing. The largest hemodynamic response was achieved when BiV pacing led to best resynchronization of LV electrical activation but this did not coincide with reduction in total BiV activation time (~ QRS duration). Maximum response was achieved when pacing the mid-basal lateral wall and this was close to the latest activated region during intrinsic activation in the typical LBBB, but not in the fascicular block simulations. CONCLUSIONS: In these model simulations, the best cardiac function was obtained when pacing the mid-basal LV lateral wall, because of fastest recruitment of LV activation. This study illustrates how computer modeling can shed new light on optimizing pacing therapies for CRT. The results from this study may help to design new clinical studies to further investigate the importance of the pacing site for CRT response. PMID- 28011837 TI - Non-invasive, model-based measures of ventricular electrical dyssynchrony for predicting CRT outcomes. AB - AIMS: Left ventricular activation delay due to left bundle branch block (LBBB) is an important determinant of the severity of dyssynchronous heart failure (DHF). We investigated whether patient-specific computational models constructed from non-invasive measurements can provide measures of baseline dyssynchrony and its reduction after CRT that may explain the degree of long-term reverse ventricular remodelling. METHODS AND RESULTS: LV end-systolic volume reduction (DeltaESVLV) measured by 2D trans-thoracic echocardiography in eight patients following 6 months of CRT was significantly (P < 0.05) greater in responders (26 +/- 20%, n = 4) than non-responders (11 +/- 16%, n = 4). LV reverse remodelling did not correlate with baseline QRS duration or its change after biventricular pacing, but did correlate with baseline LV endocardial activation measured by electroanatomic mapping (R2 = 0.71, P < 0.01). Patient-specific models of LBBB ventricular activation with parameters obtained by matching model-computed vectorcardiograms (VCG) to those derived from standard patient ECGs yielded LV endocardial activation times that correlated well with those measured from endocardial maps (R2 = 0.90). Model-computed 3D LV activation times correlated strongly with the reduction in LVESV (R2 = 0.93, P < 0.001). Computed decreases due to simulated CRT in the time delay between LV septal and lateral activation correlated strongly with DeltaESVLV (R2 = 0.92, P < 0.001). Models also suggested that optimizing VV delays may improve resynchronization by this measure of activation delay. CONCLUSIONS: Patient-specific computational models constructed from non-invasive measurements can compute estimates of LV dyssynchrony and their changes after CRT that may be as good as or better than electroanatomic mapping for predicting long-term reverse remodelling. PMID- 28011838 TI - Analysis of lead placement optimization metrics in cardiac resynchronization therapy with computational modelling. AB - AIMS: The efficacy of cardiac resynchronization therapy (CRT) is known to vary considerably with pacing location, however the most effective set of metrics by which to select the optimal pacing site is not yet well understood. Computational modelling offers a powerful methodology to comprehensively test the effect of pacing location in silico and investigate how to best optimize therapy using clinically available metrics for the individual patient. METHODS AND RESULTS: Personalized computational models of cardiac electromechanics were used to perform an in silico left ventricle (LV) pacing site optimization study as part of biventricular CRT in three patient cases. Maps of response to therapy according to changes in total activation time (DeltaTAT) and acute haemodynamic response (AHR) were generated and compared with preclinical metrics of electrical function, strain, stress, and mechanical work to assess their suitability for selecting the optimal pacing site. In all three patients, response to therapy was highly sensitive to pacing location, with laterobasal locations being optimal. DeltaTAT and AHR were found to be correlated (rho < -0.80), as were AHR and the preclinical activation time at the pacing site (rho >= 0.73), however pacing in the last activated site did not result in the optimal response to therapy in all cases. CONCLUSION: This computational modelling study supports pacing in laterobasal locations, optimizing pacing site by minimizing paced QRS duration and pacing in regions activated late at sinus rhythm. Results demonstrate information content is redundant using multiple preclinical metrics. Of significance, the correlation of AHR with DeltaTAT indicates that minimization of QRSd is a promising metric for optimization of lead placement. PMID- 28011839 TI - Patient-specific modeling of left ventricular electromechanics as a driver for haemodynamic analysis. AB - AIMS: Models of blood flow in the left ventricle (LV) and aorta are an important tool for analysing the interplay between LV deformation and flow patterns. Typically, image-based kinematic models describing endocardial motion are used as an input to blood flow simulations. While such models are suitable for analysing the hemodynamic status quo, they are limited in predicting the response to interventions that alter afterload conditions. Mechano-fluidic models using biophysically detailed electromechanical (EM) models have the potential to overcome this limitation, but are more costly to build and compute. We report our recent advancements in developing an automated workflow for the creation of such CFD ready kinematic models to serve as drivers of blood flow simulations. METHODS AND RESULTS: EM models of the LV and aortic root were created for four pediatric patients treated for either aortic coarctation or aortic valve disease. Using MRI, ECG and invasive pressure recordings, anatomy as well as electrophysiological, mechanical and circulatory model components were personalized. RESULTS: The implemented modeling pipeline was highly automated and allowed model construction and execution of simulations of a patient's heartbeat within 1 day. All models reproduced clinical data with acceptable accuracy. CONCLUSION: Using the developed modeling workflow, the use of EM LV models as driver of fluid flow simulations is becoming feasible. While EM models are costly to construct, they constitute an important and nontrivial step towards fully coupled electro-mechano-fluidic (EMF) models and show promise as a tool for predicting the response to interventions which affect afterload conditions. PMID- 28011840 TI - Cardiac MRI Anatomy and Function as a Substrate for Arrhythmias. AB - The use of cardiovascular magnetic resonance (CMR) has been implemented in the diagnostic work-up of patients with cardiomyopathies by providing an accurate assessment of biventricular volumes and function and a detailed myocardial tissue characterization in a one-stop-shop multi-parametric imaging technique. Its unique capability to perform an accurate tissue characterization of the myocardium, which is superior to other imaging modalities, has prompt its use in the analysis of myocardial arrhythmic substrates and in the prognostic risk stratification of patients. Although left ventricular ejection fraction (LVEF) has always been the best-known predictor of arrhythmic risk, the quantification of myocardial scar by CMR has been recognised as a powerful risk stratification tool, independent of LVEF. Moreover, due to its ability to identify myocardial arrhythmic substrate, both ventricular but more recently also atrial, CMR is increasingly offered as a guide to ablation procedures. PMID- 28011841 TI - Towards personalized computational modelling of the fibrotic substrate for atrial arrhythmia. AB - : Atrial arrhythmias involving a fibrotic substrate are an important cause of morbidity and mortality. In many cases, effective treatment of such rhythm disorders is severely hindered by a lack of mechanistic understanding relating features of fibrotic remodelling to dynamics of re-entrant arrhythmia. With the advent of clinical imaging modalities capable of resolving the unique fibrosis spatial pattern present in the atria of each individual patient, a promising new research trajectory has emerged in which personalized computational models are used to analyse mechanistic underpinnings of arrhythmia dynamics based on the distribution of fibrotic tissue. In this review, we first present findings that have yielded a robust and detailed biophysical representation of fibrotic substrate electrophysiological properties. Then, we summarize the results of several recent investigations seeking to use organ-scale models of the fibrotic human atria to derive new insights on mechanisms of arrhythmia perpetuation and to develop novel strategies for model-assisted individualized planning of catheter ablation procedures for atrial arrhythmias. PMID- 28011842 TI - Modelling methodology of atrial fibrosis affects rotor dynamics and electrograms. AB - AIMS: Catheter ablation is an effective technique for terminating atrial arrhythmia. However, given a high atrial fibrillation (AF) recurrence rate, optimal ablation strategies have yet to be defined. Computer modelling can be a powerful aid but modelling of fibrosis, a major factor associated with AF, is an open question. Several groups have proposed methodologies based on imaging data, but no comparison to determine which methodology best corroborates clinically observed reentrant behaviour has been performed. We examined several methodologies to determine the best method for capturing fibrillation dynamics. METHODS AND RESULTS: Patient late gadolinium-enhanced magnetic resonance imaging data were transferred onto a bilayer atrial computer model and used to assign fibrosis distributions. Fibrosis was modelled as conduction disturbances (lower conductivity, edge splitting, or percolation), transforming growth factor-beta1 ionic channel effects, myocyte-fibroblast coupling, and combinations of the preceding. Reentry was induced through pulmonary vein ectopy and the ensuing rotor dynamics characterized. Non-invasive electrocardiographic imaging data of the patients in AF was used for comparison. Electrograms were computed and the fractionation durations measured over the surface. Edge splitting produced more phase singularities from wavebreaks than the other representations. The number of phase singularities seen with percolation was closer to the clinical values. Addition of fibroblast coupling had an organizing effect on rotor dynamics. Simple tissue conductivity changes with ionic changes localized rotors over fibrosis which was not observed with clinical data. CONCLUSION: The specific representation of fibrosis has a large effect on rotor dynamics and needs to be carefully considered for patient specific modelling. PMID- 28011843 TI - Histological evidence of inflammatory reaction associated with fibrosis in the atrial and ventricular walls in a case-control study of patients with history of atrial fibrillation. AB - AIMS: Chronic inflammation in the atrial myocardium was shown to play an important role in the development of atrial fibrosis in patients with atrial fibrillation (AF). However, it is not clear to what extent atrial inflammatory reaction associated with AF extends on the ventricular myocardium. Our aim was to assess the extent of fibrosis and lymphomononuclear infiltration in human ventricular myocardium and explore its association with AF. METHODS AND RESULTS: Medical records from consecutive autopsies were checked for presence of AF. Heart specimens from 30 patients died from cardiovascular causes (64 +/- 12 years, 17 men) were collected in three equal groups: no AF, paroxysmal AF, and permanent AF. Tissue samples were taken from the Bachmann's bundle, crista terminalis, posterior left atrium, left ventricle and right ventricle free walls and stained with Masson's trichrome for analysis of fibrosis extent. Immunohistochemistry was performed using antibodies against CD3- and CD45-antigens and quantified as number of antigen-positive cells per 1 mm2. Fibrosis extent, CD3+ and CD45+ cell counts were elevated in AF patients at all sites (P < 0.001 for all). Fibrosis extent demonstrated correlation with both CD3+ and CD45+ cell counts in the right (r = 0.781, P < 0.001 for CD45+ and r = 0.720, P < 0.001 for CD3+) and the left (r = 0.515, P = 0.004 for CD45+ and r = 0.573, P = 0.001 for CD3+) ventricles. Neither fibrosis nor inflammatory cell count showed association with either age or comorbidities. CONCLUSION: Histological signs of chronic inflammation affecting ventricular myocardium are strongly associated with AF and demonstrate significant correlation with fibrosis extent that cannot be explained by cardiovascular comorbidities otherwise. PMID- 28011844 TI - The Visible Heart(r) project and free-access website 'Atlas of Human Cardiac Anatomy'. AB - AIMS: Pre- and post-evaluations of implantable cardiac devices require innovative and critical testing in all phases of the design process. The Visible Heart(r) Project was successfully launched in 1997 and 3 years later the Atlas of Human Cardiac Anatomy website was online. The Visible Heart(r) methodologies and Atlas website can be used to better understand human cardiac anatomy, disease states and/or to improve cardiac device design throughout the development process. METHODS AND RESULTS: To date, Visible(r) Heart methodologies have been used to reanimate 75 human hearts, all considered non-viable for transplantation. The Atlas is a unique free-access website featuring novel images of functional and fixed human cardiac anatomies from >400 human heart specimens. Furthermore, this website includes education tutorials on anatomy, physiology, congenital heart disease and various imaging modalities. For instance, the Device Tutorial provides examples of commonly deployed devices that were present at the time of in vitro reanimation or were subsequently delivered, including: leads, catheters, valves, annuloplasty rings, leadless pacemakers and stents. Another section of the website displays 3D models of vasculature, blood volumes, and/or tissue volumes reconstructed from computed tomography (CT) and magnetic resonance images (MRI) of various heart specimens. A new section allows the user to interact with various heart models. CONCLUSION: Visible Heart(r) methodologies have enabled our laboratory to reanimate 75 human hearts and visualize functional cardiac anatomies and device/tissue interfaces. The website freely shares all images, video clips and CT/MRI DICOM files in honour of the generous gifts received from donors and their families. PMID- 28011845 TI - An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity. AB - Ceramides are key intermediates in sphingolipid biosynthesis and potent signaling molecules. However, excess ceramide is toxic, causing growth arrest and apoptosis. In this study, we identify a novel mechanism by which cells prevent the toxic accumulation of ceramides; they facilitate nonvesicular ceramide transfer from the endoplasmic reticulum (ER) to the Golgi complex, where ceramides are converted to complex sphingolipids. We find that the yeast protein Nvj2p promotes the nonvesicular transfer of ceramides from the ER to the Golgi complex. The protein is a tether that generates close contacts between these compartments and may directly transport ceramide. Nvj2p normally resides at contacts between the ER and other organelles, but during ER stress, it relocalizes to and increases ER-Golgi contacts. ER-Golgi contacts fail to form during ER stress in cells lacking Nvj2p. Our findings demonstrate that cells regulate ER-Golgi contacts in response to stress and reveal that nonvesicular ceramide transfer out of the ER prevents the buildup of toxic amounts of ceramides. PMID- 28011847 TI - Spot sign, prognosis and intracerebral haemorrhage. PMID- 28011848 TI - Heisenberg's uncertainty principle. PMID- 28011846 TI - Two distinct membrane potential-dependent steps drive mitochondrial matrix protein translocation. AB - Two driving forces energize precursor translocation across the inner mitochondrial membrane. Although the membrane potential (Deltapsi) is considered to drive translocation of positively charged presequences through the TIM23 complex (presequence translocase), the activity of the Hsp70-powered import motor is crucial for the translocation of the mature protein portion into the matrix. In this study, we show that mitochondrial matrix proteins display surprisingly different dependencies on the Deltapsi. However, a precursor's hypersensitivity to a reduction of the Deltapsi is not linked to the respective presequence, but rather to the mature portion of the polypeptide chain. The presequence translocase constituent Pam17 is specifically recruited by the receptor Tim50 to promote the transport of hypersensitive precursors into the matrix. Our analyses show that two distinct Deltapsi-driven translocation steps energize precursor passage across the inner mitochondrial membrane. The Deltapsi- and Pam17 dependent import step identified in this study is positioned between the two known energy-dependent steps: Deltapsi-driven presequence translocation and adenosine triphosphate-driven import motor activity. PMID- 28011849 TI - Leprosy and bone marrow involvement. PMID- 28011850 TI - Sarcoidosis, neurotoxoplasmosis and golimumab therapy. PMID- 28011851 TI - Moyamoya disease. PMID- 28011852 TI - Choriocarcinoma as a cause of hyperthyroidism. PMID- 28011853 TI - Whole-genome sequencing identifies nosocomial transmission of extra-pulmonary M. tuberculosis. PMID- 28011854 TI - Denosumab as a long-term palliative therapy in parathyroid carcinoma. PMID- 28011855 TI - Lion face in a uremia patient. PMID- 28011856 TI - Denosumab is a long-term option for the management of parathyroid carcinoma related refractory hypercalcemia. PMID- 28011857 TI - An oesophageal and pulmonary association not to forget. PMID- 28011858 TI - COPD+OSA: can two bad things be good for you? PMID- 28011859 TI - Robert Desmond Abernethy. PMID- 28011861 TI - An unusual case of gastric outlet obstruction caused by multiple giant persimmon phytobezoars. AB - A phytobezoar is a bezoar or trapped mass in the gastrointestinal system that consists of indigestible plant material such as fibers, skins and seeds. A persimmon phytobezoar (considered to be harder than other types of phytobezoars) is formed after frequent consumption of persimmons. The complication of gastrointestinal tract obstruction from bezoars was found to exist in the intestines but was rarely reported in the gastric tract because of its flexible volume. Here we present a 57-year-old man with persimmon phytobezoars, which ultimately led to gastric outlet obstruction. PMID- 28011860 TI - Reprogramming-derived gene cocktail increases cardiomyocyte proliferation for heart regeneration. AB - Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis in vitro More importantly, this gene cocktail increased CM proliferation in vivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction. Collectively, our findings present a cocktail FIJs that may be useful in cardiac regeneration and also provide a practical strategy for probing reprogramming assays for regeneration of other tissues. PMID- 28011862 TI - Esophageal food impaction during cultural holidays and national athletic events. AB - BACKGROUND: Although intrinsic risk factors contributing to esophageal food impaction are well established, whether social behavior affects its occurrence has not yet been examined. METHODS: We conducted a retrospective review of the gastroenterology endoscopy procedural documentation software for the period of 2001-2012 to identify all patients who presented to our emergency department for esophageal foreign-body removal at the time of national athletic events and holidays associated with dietary indiscretions. RESULTS: We found that adults undergoing emergent esophagogastroduodenoscopy during periods celebrating cultural holidays and national athletic events were more likely to experience esophageal food impaction compared with those undergoing emergent endoscopy during periods not associated with these events (36.8% vs 3.6%; P < 0.001): a 10 fold increase. During a national holiday/athletic event period, the most common impacted food item was turkey (50%) followed by chicken (29%) and beef (21%). CONCLUSIONS: Esophageal food impaction is more likely to occur on American holidays and national athletic events and is associated with large meals. Patients with intrinsic risk factors should be advised to modify their diet during cultural events associated with tachyphagia and large meals to prevent esophageal food impaction. PMID- 28011863 TI - Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. AB - Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV induced B cell proliferations including Hodgkin's lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70-CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies. PMID- 28011864 TI - Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. AB - In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell mediated immunity, especially for protection against EBV and humoral immunity. PMID- 28011865 TI - Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. AB - Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor kappaB (NF-kappaB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-kappaB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease. PMID- 28011866 TI - The aryl hydrocarbon receptor controls cell-fate decisions in B cells. AB - Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool. In this study, we show that an environmental sensor, the aryl hydrocarbon receptor (AhR) is highly induced upon B cell activation and serves a critical role in regulating activation-induced cell fate outcomes. We find that AhR negatively regulates class-switch recombination ex vivo by altering activation-induced cytidine deaminase expression. We further demonstrate that AhR suppresses class switching in vivo after influenza virus infection and immunization with model antigens. In addition, by regulating Blimp-1 expression via Bach2, AhR represses differentiation of B cells into plasmablasts ex vivo and antibody-secreting plasma cells in vivo. These experiments suggest that AhR serves as a molecular rheostat in B cells to brake the effector response, possibly to facilitate optimal recall responses. Thus, AhR might represent a novel molecular target for manipulation of B cell responses during vaccination. PMID- 28011867 TI - Cytosol-Localized UDP-Xylose Synthases Provide the Major Source of UDP-Xylose for the Biosynthesis of Xylan and Xyloglucan. AB - Xylan and xyloglucan are the two major cell wall hemicelluloses in plants, and their biosynthesis requires a steady supply of the sugar donor, UDP-xylose. UDP xylose is synthesized through conversion of UDP-glucuronic acid (UDP-GlcA) by the activities of UDP-xylose synthase (UXS). There exist six UXS genes in the Arabidopsis thaliana genome; three of them (UXS1, UXS2 and UXS4) encode Golgi localized enzymes and the other three (UXS3, UXS5 and UXS6) encode cytosol localized enzymes. In this report, we investigated the contributions of these UXS genes in supplying UDP-xylose for the biosynthesis of xylan and xyloglucan. Expression analyses revealed that the six UXS genes exhibited distinct and overlapping expression patterns in different cell types of stems, root-hypocotyls and young seedlings, and that the relative enzymatic activity of UXS in the cytosol was 17 times higher than that in the Golgi. Among the six UXS genes, UXS3, UXS5 and UXS6 showed the highest expression in stems and were expressed predominantly in xylem cells and interfascicular fibers. Their predominant expression in secondary wall-forming cells was consistent with the finding that the expression of UXS3, UXS5 and UXS6 was directly activated by the secondary wall NAC master switches. Although simultaneous mutations of UXS1, UXS2 and UXS4 did not cause any apparent effects on plant growth and xylan biosynthesis, simultaneous down-regulation/mutations of UXS3, UXS5 and UXS6 led to a drastic reduction in secondary wall thickening, a severe deformation of xylem vessels, a significant decrease in xylan content without an apparent reduction in its chain length and an absence of GlcA side chains in xylan, which are reminiscent of the phenotypes of some known xylan-deficient mutants. Moreover, Immunolocalization with two xyloglucan monoclonal antibodies, LM15 and LM25, revealed a significant reduction in the amount of xylogulcan in the primary walls. These results demonstrate that the cytosol-localized UXS3, UXS5 and UXS6 play a predominant role in the supply of UDP-xylose for the biosynthesis of xylan and xyloglucan. PMID- 28011868 TI - Chemical-Induced Inhibition of Blue Light-Mediated Seedling Development Caused by Disruption of Upstream Signal Transduction Involving Cryptochromes in Arabidopsis thaliana. AB - Plants have a remarkable ability to perceive and respond to various wavelengths of light and initiate regulation of different cascades of light signaling and molecular components. While the perception of red light and the mechanisms of its signaling involving phytochromes are largely known, knowledge of the mechanisms of blue light signaling is still limited. Chemical genetics involves the use of diverse small active or synthetic molecules to evaluate biological processes. By combining chemicals and analyzing the effects they have on plant morphology, we identified a chemical, 3-bromo-7-nitroindazole (3B7N), that promotes hypocotyl elongation of wild-type Arabidopsis only under continuous blue light. Further evaluation with loss-of-function mutants confirmed that 3B7N inhibits photomorphogenesis through cryptochrome-mediated light signaling. Microarray analysis demonstrated that the effect of 3B7N treatment on gene expression in cry1cry2 is considerably smaller than that in the wild type, indicating that 3B7N specifically interrupts cryptochrome function in the control of seedling development in a light-dependent manner. We demonstrated that 3B7N directly binds to CRY1 protein using an in vitro binding assay. These results suggest that 3B7N is a novel chemical that directly inhibits plant cryptochrome function by physical binding. The application of 3B7N can be used on other plants to study further the blue light mechanism and the genetic control of cryptochromes in the growth and development of plant species. PMID- 28011869 TI - PCoM-DB Update: A Protein Co-Migration Database for Photosynthetic Organisms. AB - The identification of protein complexes is important for the understanding of protein structure and function and the regulation of cellular processes. We used blue-native PAGE and tandem mass spectrometry to identify protein complexes systematically, and built a web database, the protein co-migration database (PCoM DB, http://pcomdb.lowtem.hokudai.ac.jp/proteins/top), to provide prediction tools for protein complexes. PCoM-DB provides migration profiles for any given protein of interest, and allows users to compare them with migration profiles of other proteins, showing the oligomeric states of proteins and thus identifying potential interaction partners. The initial version of PCoM-DB (launched in January 2013) included protein complex data for Synechocystis whole cells and Arabidopsis thaliana thylakoid membranes. Here we report PCoM-DB version 2.0, which includes new data sets and analytical tools. Additional data are included from whole cells of the pelagic marine picocyanobacterium Prochlorococcus marinus, the thermophilic cyanobacterium Thermosynechococcus elongatus, the unicellular green alga Chlamydomonas reinhardtii and the bryophyte Physcomitrella patens. The Arabidopsis protein data now include data for intact mitochondria, intact chloroplasts, chloroplast stroma and chloroplast envelopes. The new tools comprise a multiple-protein search form and a heat map viewer for protein migration profiles. Users can compare migration profiles of a protein of interest among different organelles or compare migration profiles among different proteins within the same sample. For Arabidopsis proteins, users can compare migration profiles of a protein of interest with putative homologous proteins from non Arabidopsis organisms. The updated PCoM-DB will help researchers find novel protein complexes and estimate their evolutionary changes in the green lineage. PMID- 28011870 TI - Inhibition of Recombinant Aldose-6-Phosphate Reductase from Peach Leaves by Hexose-Phosphates, Inorganic Phosphate and Oxidants. AB - Glucitol, also known as sorbitol, is a major photosynthetic product in plants from the Rosaceae family. This sugar alcohol is synthesized from glucose-6 phosphate by the combined activities of aldose-6-phosphate reductase (Ald6PRase) and glucitol-6-phosphatase. In this work we show the purification and characterization of recombinant Ald6PRase from peach leaves. The recombinant enzyme was inhibited by glucose-1-phosphate, fructose-6-phosphate, fructose-1,6 bisphosphate and orthophosphate. Oxidizing agents irreversibly inhibited the enzyme and produced protein precipitation. Enzyme thiolation with oxidized glutathione protected the enzyme from insolubilization caused by diamide, while incubation with NADP+ (one of the substrates) completely prevented enzyme precipitation. Our results suggest that Ald6PRase is finely regulated to control carbon partitioning in peach leaves. PMID- 28011871 TI - Cell Death and Cell Cycle Arrest of Silene latifolia Stamens and Pistils After Microbotryum lychnidis-dioicae Infection. AB - Mechanisms of suppression of pistil primordia in male flowers and of stamen primordia in female flowers differ in diclinous plants. In this study, we investigated how cell death and cell cycle arrest are related to flower organ formation in Silene latifolia. Using in situ hybridization and a TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, we detected both cell cycle arrest and cell death in suppressed stamens of female flowers and suppressed pistils of male flowers in S. latifolia. In female flowers infected with Microbotryum lychnidis-dioicae, developmental suppression of stamens is released, and cell cycle arrest and cell death do not occur. Smut spores are formed in S. latifolia anthers infected with M. lychnidis-dioicae, followed by cell death in the endothelium, middle layer, tapetal cells and pollen mother cells. Cell death is difficult to detect using a fluorescein isothiocyanate labeled TUNEL assay due to strong autofluorescence in the anther. We therefore combined a TUNEL assay in an infrared region with transmission electron microscopy to detect cell death in anthers. We show that following infection by M. lychnidis-dioicae, a TUNEL signal was not detected in the endothelium, middle layer or pollen mother cells, and cell death with outflow of cell contents, including the nucleoplast, was observed in tapetal cells. PMID- 28011872 TI - Functional Significance of NADPH-Thioredoxin Reductase C in the Antioxidant Defense System of Cyanobacterium Anabaena sp. PCC 7120. AB - The redox regulation system is widely accepted as a crucial mechanism for controlling the activities of various metabolic enzymes. In addition to thioredoxin reductase/thioredoxin cascades, NADPH-thioredoxin reductase C (NTRC), a hybrid protein formed by an NADPH-thioredoxin reductase domain and a thioredoxin (Trx) domain, is present in chloroplasts and in most cyanobacteria species. Although several target proteins and physiological functions of NTRC in chloroplasts have been characterized, little is known about NTRC functions in cyanobacteria. Therefore, we investigated the molecular basis and physiological significance of NTRC-dependent redox regulation in the filamentous heterocyst forming nitrogen-fixing cyanobacterium Anabaena sp. PCC 7120 (Anabaena 7120). Initially, we identified six candidate NTRC targets in Anabaena 7120 using NTRC affinity chromatography. Subsequently, we compared the efficiency of reducing equivalent transfer from NTRC and Trx-m1 to the NTRC target protein 2-Cys peroxiredoxin. Biochemical analyses revealed that compared with Trx-m1, NTRC more efficiently transfers reducing equivalents to 2-Cys peroxiredoxin. Subsequently, we constructed and analyzed an ntrC knockout strain in Anabaena 7120. The mutant showed impaired growth under oxidative stress conditions and lower concentrations of reduced 2-Cys peroxiredoxin in cells. Taken together, the present in vitro and in vivo results indicate that NTRC is a significant electron donor for 2-Cys peroxiredoxin and plays a pivotal role in antioxidant defense systems in Anabaena 7120 cells. PMID- 28011873 TI - Exogenous Cellulase Switches Cell Interdigitation to Cell Elongation in an RIC1 dependent Manner in Arabidopsis thaliana Cotyledon Pavement Cells. AB - Pavement cells in cotyledons and true leaves exhibit a jigsaw puzzle-like morphology in most dicotyledonous plants. Among the molecular mechanisms mediating cell morphogenesis, two antagonistic Rho-like GTPases regulate local cell outgrowth via cytoskeletal rearrangements. Analyses of several cell wall related mutants suggest the importance of cell wall mechanics in the formation of interdigitated patterns. However, how these factors are integrated is unknown. In this study, we observed that the application of exogenous cellulase to hydroponically grown Arabidopsis thaliana cotyledons switched the interdigitation of pavement cells to the production of smoothly elongated cells. The cellulase induced inhibition of cell interdigitation was not observed in a RIC1 knockout mutant. This gene encodes a Rho-like GTPase-interacting protein important for localized cell growth suppression via microtubule bundling on concave cell interfaces. Additionally, to characterize pavement cell morphologies, we developed a mathematical model that considers the balance between cell and cell wall growth, restricted global cell growth orientation, and regulation of local cell outgrowth mediated by a Rho-like GTPase-cytoskeleton system. Our computational simulations fully support our experimental observations, and suggest that interdigitated patterns form because of mechanical buckling in the absence of Rho-like GTPase-dependent regulation of local cell outgrowth. Our model clarifies the cell wall mechanics influencing pavement cell morphogenesis. PMID- 28011876 TI - Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet induced obesity by means of increased thermogenesis. PMID- 28011874 TI - Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin. AB - UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates. PMID- 28011877 TI - Inflammation of the hypothalamus leads to defective pancreatic islet function. PMID- 28011878 TI - Chaperone insufficiency links TLR4 signaling to endoplasmic reticulum stress. PMID- 28011879 TI - Ebola vaccine is highly protective, show latest study results. PMID- 28011880 TI - Roles of estrogen receptor-alpha in mediating life span: the hypothalamic deregulation hypothesis. AB - In several species caloric restriction (CR) extends life span. In this paper we integrate data from studies on CR and other sources to articulate the hypothalamic deregulation hypothesis by which estrogen receptor-alpha (ER-alpha) signaling in the hypothalamus and limbic system affects life span under the stress of CR in mammals. ER-alpha is one of two principal estrogen-binding receptors differentially expressed in the amygdala, hippocampus, and several key hypothalamic nuclei: the arcuate nucleus (ARN), preoptic area (POA), ventromedial nucleus (VMN), antero ventral periventricular nucleus (AVPV), paraventricular nucleus (PVN), supraoptic nucleus (SON), and suprachiasmatic nucleus (SCN). Estradiol signaling via ER-alpha is essential in basal level functioning of reproductive cycle, sexually receptive behaviors, physiological stress responses, as well as sleep cycle, and other nonsexual behaviors. When an organism is placed under long-term CR, which introduces an external stress to this ER-alpha signaling, the reduction of ER-alpha expression is attenuated over time in the hypothalamus. This review paper seeks to characterize the downstream effects of ER-alpha in the hypothalamus and limbic system that affect normal endocrine functioning. PMID- 28011881 TI - Alterations in the gut microbiota can elicit hypertension in rats. AB - Gut dysbiosis has been linked to cardiovascular diseases including hypertension. We tested the hypothesis that hypertension could be induced in a normotensive strain of rats or attenuated in a hypertensive strain of rats by exchanging the gut microbiota between the two strains. Cecal contents from spontaneously hypertensive stroke prone rats (SHRSP) were pooled. Similarly, cecal contents from normotensive WKY rats were pooled. Four-week-old recipient WKY and SHR rats, previously treated with antibiotics to reduce the native microbiota, were gavaged with WKY or SHRSP microbiota, resulting in four groups; WKY with WKY microbiota (WKY g-WKY), WKY with SHRSP microbiota (WKY g-SHRSP), SHR with SHRSP microbiota (SHR g-SHRSP), and SHR with WKY microbiota (SHR g-WKY). Systolic blood pressure (SBP) was measured weekly using tail-cuff plethysmography. At 11.5 wk of age systolic blood pressure increased 26 mmHg in WKY g-SHRSP compared with that in WKY g-WKY (182 +/- 8 vs. 156 +/- 8 mmHg, P = 0.02). Although the SBP in SHR g-WKY tended to decrease compared with SHR g-SHRSP, the differences were not statistically significant. Fecal pellets were collected at 11.5 wk of age for identification of the microbiota by sequencing the 16S ribosomal RNA gene. We observed a significant increase in the Firmicutes:Bacteroidetes ratio in the hypertensive WKY g-SHRSP, as compared with the normotensive WKY g-WKY (P = 0.042). Relative abundance of multiple taxa correlated with SBP. We conclude that gut dysbiosis can directly affect SBP. Manipulation of the gut microbiota may represent an innovative treatment for hypertension. PMID- 28011884 TI - Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia. AB - A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace. PMID- 28011882 TI - Mycophenolate mofetil prevents cerebrovascular injury in stroke-prone spontaneously hypertensive rats. AB - Stroke-prone spontaneously hypertensive rats (SHR-A3) develop strokes and progressive kidney disease as a result of naturally occurring genetic variations. We recently identified genetic variants in immune signaling pathways that contribute to end-organ injury. The present study was designed to test the hypothesis that a dysregulated immune response promotes stroke susceptibility. We salt-loaded 20 wk old male SHR-A3 rats and treated them with the immunosuppressant mycophenolate mofetil (MMF, 25 mg/kg/day po) (n = 8) or vehicle (saline) (n = 9) for 8 wk. Blood pressure (BP) was measured weekly by telemetry. Compared with vehicle-treated controls, MMF-treated SHR-A3 rats had improved survival and lower neurological deficit scores (1.44 vs. 0.125; P < 0.02). Gross morphology of the brain revealed cerebral edema in 8 of 9, and microbleeds and hemorrhages in 5 of 9 vehicle-treated rats. These lesions were absent in MMF treated rats. Brain CD68 expression, indicating macrophage/microglial activation, was upregulated in vehicle-treated rats with microbleeds and hemorrhages but was undetectable in the brains of MMF-treated rats. MMF also prevented renal injury in SHR-A3 rats, evidenced by reduced proteinuria (albumin:creatinine) from 7.52 to 1.05 mg/mg (P < 0.03) and lower tubulointerstitial injury scores (2.46 vs. 1.43; P < 0.01). Salt loading resulted in a progressive increase in BP, which was blunted in rats receiving MMF. Our findings provide evidence that abnormal immune activation predisposes to cerebrovascular and renal injury in stroke-prone SHR-A3 rats. PMID- 28011883 TI - Single cell transcriptomic profiling of mouse pancreatic progenitors. AB - The heterogeneity of the developing pancreatic epithelium and low abundance of endocrine progenitors limit the information derived from traditional expression studies. To identify genes that characterize early developmental tissues composed of multiple progenitor lineages, we applied single-cell RNA-Seq to embryonic day (e)13.5 mouse pancreata and performed integrative analysis with single cell data from mature pancreas. We identified subpopulations expressing macrophage or endothelial markers and new pancreatic progenitor markers. We also identified potential alpha-cell precursors expressing glucagon (Gcg) among the e13.5 pancreatic cells. Despite their high Gcg expression levels, these cells shared greater transcriptomic similarity with other e13.5 cells than with adult alpha cells, indicating their immaturity. Comparative analysis identified the sodium dependent neutral amino acid transporter, Slc38a5, as a characteristic gene expressed in alpha-cell precursors but not mature cells. By immunofluorescence analysis, we observed SLC38A5 expression in pancreatic progenitors, including in a subset of NEUROG3+ endocrine progenitors and MAFB+ cells and in all GCG+ cells. Expression declined in alpha-cells during late gestation and was absent in the adult islet. Our results suggest SLC38A5 as an early marker of alpha-cell lineage commitment. PMID- 28011885 TI - LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. AB - PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell-like properties to leukemia cells that is important for leukemogenesis.Implications: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294-303. (c)2016 AACR. PMID- 28011886 TI - Regression of a glioblastoma multiforme: spontaneous versus a potential antineoplastic effect of dexamethasone and levetiracetam. AB - Patients with grade IV astrocytoma or glioblastoma multiforme (GBM) have a median survival of <12 months, increased to 14.6 months by maximal safe resection with radiation and temozolamide. In the absence of chemotherapy, radiotherapy or chemoradiotherapy, spontaneous regression of GBM or regression while only being on dexamethasone (DEX) and levetiracetam (LEV) have seldom been reported. Here, we present a case of a patient who had significant regression of the GBM with DEX and LEV alone. In this study, we hypothesise a plausible antineoplastic role of DEX and or LEV in GBM and highlight molecular, preclinical and clinical studies supporting this role. PMID- 28011887 TI - Sweet syndrome: a painful reality. AB - Sweet syndrome is a rare disorder that is manifested by constellation of clinical features, including fever, neutrophilic leucocytosis, raised painful plaques on skin and dermal infiltration by neutrophils. Numerous aetiological associations have been reported in the literature, including various haematological malignancies and drugs. Our case was peculiar because of association of capecitabine and Sweet syndrome in rectal cancer. We describe a case of a woman aged 57 years, with recently diagnosed stage III rectal cancer, developed painful erythematous rash over her face along with fever and headache. Skin biopsy was performed which revealed typical findings of Sweet syndrome. She was successfully treated with systemic steroids. Our case was an unusual presentation of Sweet syndrome in a patient with rectal adenocarcinoma treated with neoadjuvant capecitabine. PMID- 28011888 TI - Massive non-traumatic calcification of the medial collateral ligament of the knee. PMID- 28011889 TI - Rare case of losartan-induced cough complicated by rectus sheath haematoma: in a patient on rivaroxaban therapy. AB - Spontaneous rectus sheath haematomas and cough secondary to losartan are individually rare conditions. Abdominal wall haematomas present with abdominal pain and abdominal mass. Most patients are managed conservatively; Surgery or embolisation is indicated for shock, infection, rupture into the peritoneum or intractable pain. This is a man aged 65 years presented with dry cough and right sided abdominal pain. He started losartan a few weeks prior to the onset of cough and had been on rivaroxaban for prior deep venous thrombosis. The right side of his abdomen was distended, bruised and tender. His haemoglobin dropped from 13.3to 9.5 g/dL. CT abdomen/pelvis showed a large 14.5*9.1*4.5 cm haematoma within the right lateral rectus muscle. His only risk factor for developing rectus sheath haematoma was cough in the setting of anticoagulation. Dry cough due to angiotensin receptor blockers is rare, but can have very serious consequences. PMID- 28011890 TI - Idiopathic myelofibrosis with disseminated hepatosplenic, mesenteric, renal and pulmonary extramedullary haematopoeisis, portal hypertension and tuberculosis: initial presentation and 2 years follow-up. AB - A 35-year-old man with a 12-year history of idiopathic myelofibrosis (IMF) presented in 2014 with fatigue and abdominal distension. CT scan revealed massive hepatosplenomegaly with focal splenic lesions, soft tissue around renal pelvis, mesenteric masses compressing bowel loops and perilymphatic nodules in lungs. There was portal hypertension, ascites, pleural effusion, bilateral psoas abscesses and necrotic retroperitoneal lymphadenopathy. MRI additionally revealed hypointense periportal infiltrative lesions in liver, not seen on CT scan. None of these lesions showed diffusion restriction. Biopsy from mesenteric masses revealed extramedullary haematopoeisis. Aspiration from psoas abscess confirmed tuberculosis. Follow-up after 6 weeks of ruxolitinib (JAK2 tyrosine kinase inhibitor) and 9 months of antitubercular therapy revealed resolution of psoas abscesses and lymph nodes. Mild reduction was noted in mesenteric masses and ascites while perirenal soft tissue had increased. Follow-up imaging after another 1 year of ruloxitinib showed new-onset bilateral paravertebral and presacral foci of extramedullary haematopoeisis. PMID- 28011891 TI - Expectoration of an inferior vena cava filter strut. AB - Inferior vena cava (IVC) filter use is widespread in patients with venous thromboembolism (VTE) and temporary contraindication to anticoagulation, though timely removal is often not performed. We report the case of an expectoration of an IVC filter strut. Review of the patient's prior imaging confirmed an infrarenal Bard G2 filter with an absent strut, which was visualised in the left lung base. The strut was presumed to have embolised to a pulmonary artery branch and eroded into an adjacent bronchus. Subsequent fluoroscopically guided filter retrieval was successful. The incidence of IVC filter fractures increases with longer dwell times. Filter fragment embolisation has resulted in major adverse events, including sudden death and cardiac tamponade. Recent evidence has suggested that retrieval of IVC filters with prolonged dwell times is feasible and safe. This report brings awareness to the range of complications with indwelling IVC filters, and highlights the importance of timely removal. PMID- 28011892 TI - Adipose type I interferon signalling protects against metabolic dysfunction. AB - OBJECTIVE: Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD. DESIGN: We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (alpha and beta) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Deltahep ), adipocytes (Ifnar1Deltaat ), intestinal epithelial cells (Ifnar1DeltaIEC ) or myelocytes (Ifnar1Deltamyel ) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB). RESULTS: Long chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver. CONCLUSIONS: Our study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted. PMID- 28011893 TI - Misfolding cationic trypsinogen variant p.L104P causes hereditary pancreatitis. PMID- 28011894 TI - Palatal tremor with audible click. PMID- 28011895 TI - Emergency department interpretation of CT of the brain: a systematic review. AB - BACKGROUND AND OBJECTIVES: CT of the brain (CTB) is one of the most common radiological investigations performed in the emergency department (ED). Emergency clinicians rely upon this imaging modality to aid diagnosis and guide management. However, their capacity to accurately interpret CTB is unclear. This systematic review aims to determine this capacity and identify the potential need for interventions directed towards improving the ability of emergency clinicians in this important area. METHODS: A systematic review of the literature was conducted without date restrictions. We searched MEDLINE, EMBASE and Cochrane databases and studies reporting the primary outcome of concordance of CTB interpretation between a non-radiologist and a radiology specialist were identified. Studies were assessed for heterogeneity and a subgroup analysis of pooled data based on medical specialty was carried out to specifically identify the concordance of ED clinicians. The quality of evidence was assessed using the GRADE criteria. RESULTS: There were 21 studies included in this review. Among the included studies, 12 reported on the concordance of emergency clinicians, 5 reported on radiology trainees and 4 on surgeons. Clinical and statistical heterogeneity between studies was high (I2=97.8%, p<0.01). The concordance in the emergency subgroup was the lowest among all subgroups with a range of 0.63-0.95 and a clinically significant error rate ranging from 0.02 to 0.24. CONCLUSIONS: Heterogeneity and the presence of bias limit our confidence in these findings. However, the variance in the interpretation of CTB between emergency clinicians and radiologists suggests that interventions towards improving accuracy may be useful. PMID- 28011896 TI - Palliative care series: an overview. PMID- 28011898 TI - Cellular and molecular mechanisms of the brain-derived neurotrophic factor in physiological and pathological conditions. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in the central nervous system, promoting synaptic plasticity, neurogenesis and neuroprotection. The BDNF gene structure is very complex and consists of multiple 5'-non-coding exons, which give rise to differently spliced transcripts, and one coding exon at the 3'-end. These multiple transcripts, together with the complex transcriptional regulatory machinery, lead to a complex and fine regulation of BDNF expression that can be tissue and stimulus specific. BDNF effects are mainly mediated by the high-affinity, tropomyosin-related, kinase B receptor and involve the activation of several downstream cascades, including the mitogen-activated protein kinase, phospholipase C-gamma and phosphoinositide-3-kinase pathways. BDNF exerts a wide range of effects on neuronal function, including the modulation of activity-dependent synaptic plasticity and neurogenesis. Importantly, alterations in BDNF expression and function are involved in different brain disorders and represent a major downstream mechanism for stress response, which has important implications in psychiatric diseases, such as major depressive disorders and schizophrenia. In the present review, we have summarized the main features of BDNF in relation to neuronal plasticity, stress response and pathological conditions, and discussed the role of BDNF as a possible target for pharmacological and non-pharmacological treatments in the context of psychiatric illnesses. PMID- 28011897 TI - Association between polymorphisms of thymidylate synthase gene 5'- and 3'-UTR and gastric cancer risk: meta-analysis. AB - Gastric cancer is the most common cancer and the most frequent cause of cancer death worldwide. Several studies have identified the role of thymidylate synthase (TS) 5'- and 3'-UTR and gastric cancer susceptibility; however, the results still remain inconclusive. The purpose of this meta-analysis was to reinvestigate this correlation. In the present study, online databases were searched to retrieve relevant articles published between January 2000 and 2016. The odds ratio (OR) and 95% confidence interval (CI) were employed to calculate the strength of association. Overall, a total of 13 articles were screened out, including 2382 gastric cancer patients and 3171 healthy controls. We found that polymorphisms of TS 5'-UTR 2R (double repeats)/3R (triple repeats) of a 28-bp sequence (11 articles) and 3'-UTR del6/ins6 (seven articles) were not significantly associated with increased risk of gastric cancer. Subgroup analysis by ethnicity showed that 2R allele and 2R/2R genotype in TS 5'-UTR were associated with gastric cancer susceptibility in Caucasian and African populations; del6 allele, del6/del6 and del6/ins6 genotypes were correlated with gastric cancer in Caucasian population. In conclusion, our result suggested that TS polymorphisms might be the risk factors for gastric cancer risk in Caucasian population, although this association needs further study, and future large-scale researches are still required. PMID- 28011899 TI - Oxidative stress-call for papers. PMID- 28011900 TI - DUSPs as critical regulators of cardiac hypertrophy. AB - This commentary highlights the research presented by Li et al. [15]. In this issue of Clinical Science, which demonstrates that dual specific phosphatase 12 (DUSP12), through JNK1/2 inhibition, alleviates cardiac hypertrophy in response to pressure overload, making it a potential therapeutic target. PMID- 28011901 TI - Efferocytosis is impaired in Gaucher macrophages. AB - Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylceramide-laden macrophages resulting from impaired digestion of aged erythrocytes or apoptotic leukocytes. Studies of macrophages from patients with type 1 Gaucher disease with genotypes N370S/N370S, N370S/L444P or N370S/c.84dupG revealed that Gaucher macrophages have impaired efferocytosis resulting from reduced levels of p67phox and Rab7. The decreased Rab7 expression leads to impaired fusion of phagosomes with lysosomes. Moreover, there is defective translocation of p67phox to phagosomes, resulting in reduced intracellular production of reactive oxygen species. These factors contribute to defective deposition and clearance of apoptotic cells in phagolysosomes, which may have an impact on the inflammatory response and contribute to the organomegaly and inflammation seen in patients with Gaucher disease. PMID- 28011902 TI - ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. AB - The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies for various types of infection in patients with hematologic malignancies or hematopoietic stem cell transplantation recipients. Meetings are held every two years since 2005 and evidence-based recommendations are elaborated after evaluation of the literature and discussion among specialists of nearly all European countries. In this manuscript, the ECIL group presents the 2015-update of the recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis. Current data now allow a very strong recommendation in favor of echinocandins for first-line therapy of candidemia irrespective of the underlying predisposing factors. Anidulafungin has been given the same grading as the other echinocandins for hemato-oncological patients. The beneficial role of catheter removal in candidemia is strengthened. Aspergillus guidelines now recommend the use of either voriconazole or isavuconazole for first-line treatment of invasive aspergillosis, while first-line combination antifungal therapy is not routinely recommended. As only few new data were published since the last ECIL guidelines, no major changes were made to mucormycosis recommendations. PMID- 28011903 TI - Safety and efficacy of obinutuzumab with CHOP or bendamustine in previously untreated follicular lymphoma. AB - The GAUDI study assessed safety and preliminary efficacy of induction therapy with obinutuzumab plus chemotherapy, followed by maintenance therapy with obinutuzumab alone, in previously untreated patients with follicular lymphoma. Assignment to chemotherapy was decided on a per-center basis before the patients' enrollment. Patients (n=81) received four to six cycles of obinutuzumab plus bendamustine every 4 weeks or six to eight cycles of obinutuzumab plus CHOP every 3 weeks. Patients with an end-of-treatment response were eligible for obinutuzumab maintenance therapy every 3 months for 2 years or until disease progression. Induction treatment was completed by 90% of patients in the obinutuzumab plus bendamustine group and 95% in the obinutuzumab plus CHOP group, while maintenance was completed by 81% and 72% of patients, respectively. All patients experienced at least one adverse event during induction, most commonly infusion-related reactions (58%), the majority of which were grade 1/2. The most common hematologic adverse event was grade 3/4 neutropenia (36% during induction and 7% during maintenance). One treatment-related death occurred during the maintenance phase. At the end of induction, 94% of patients had achieved an overall response, with complete response based on computed tomography in 36%. The progression-free survival rate at 36 months was 90% in the obinutuzumab plus bendamustine group and 84% in the obinutuzumab plus CHOP group. These results demonstrate that induction therapy with obinutuzumab plus bendamustine or obinutuzumab plus CHOP, followed by obinutuzumab maintenance, is associated with tolerable safety and promising efficacy. This study is registered at ClinicalTrials.gov as NCT00825149. PMID- 28011904 TI - Multifunctional roles of Saccharomyces cerevisiae Srs2 protein in replication, recombination and repair. AB - The Saccharomyces cerevisiae Srs2 DNA helicase has important roles in DNA replication, recombination and repair. In replication, Srs2 aids in repair of gaps by repair synthesis by preventing gaps from being used to initiate recombination. This is considered to be an anti-recombination role. In recombination, Srs2 plays both prorecombination and anti-recombination roles to promote the synthesis-dependent strand annealing recombination pathway and to inhibit gaps from initiating homologous recombination. In repair, the Srs2 helicase actively promotes gap repair through an interaction with the Exo1 nuclease to enlarge a gap for repair and to prevent Rad51 protein from accumulating on single-stranded DNA. Finally, Srs2 helicase can unwind hairpin forming repeat sequences to promote replication and prevent repeat instability. The Srs2 activities can be controlled by phosphorylation, SUMO modification and interaction with key partners at DNA damage or lesions sites, which include PCNA and Rad51. These interactions can also limit DNA polymerase function during recombinational repair independent of the Srs2 translocase or helicase activity, further highlighting the importance of the Srs2 protein in regulating recombination. Here we review the myriad roles of Srs2 that have been documented in genome maintenance and distinguish between the translocase, helicase and additional functions of the Srs2 protein. PMID- 28011905 TI - Replication fork regression and its regulation. AB - One major challenge during genome duplication is the stalling of DNA replication forks by various forms of template blockages. As these barriers can lead to incomplete replication, multiple mechanisms have to act concertedly to correct and rescue stalled replication forks. Among these mechanisms, replication fork regression entails simultaneous annealing of nascent and template strands, which leads to regression of replication forks and formation of four-way DNA junctions. In principle, this process can lead to either positive outcomes, such as DNA repair and replication resumption, or less desirable outcomes, such as misalignment between nascent and template DNA and DNA cleavage. While our understanding of replication fork regression and its various possible outcomes is still at an early stage, recent studies using combinational approaches in multiple organisms have begun to identify the enzymes that catalyze this DNA transaction and how these enzymes are regulated, as well as the specific manners by which fork regression can influence replication. This review summarizes these recent progresses. In keeping with the theme of this series of reviews, we focus on studies in yeast and compare to findings in higher eukaryotes. It is anticipated that these findings will form the basis for future endeavors to further elucidate replication fork remodeling and its implications for genome maintenance. PMID- 28011906 TI - Saccharomyces uvarum is responsible for the traditional fermentation of apple chicha in Patagonia. AB - Apple chicha is a fresh low alcoholic beverage elaborated by aboriginal communities of Andean Patagonia (Argentina and Chile). In the present work, we identified the yeast microbiota associated with this fermentation, and characterized genetically those belonging to the genus Saccharomyces. Both Saccharomyces cerevisiae and S. uvarum were found in the analyzed fermentations. Phylogenetic and population structure analyses based on genes sequence analysis were carried out for both S. cerevisiae and S. uvarum strains obtained in this study and a set of additional strains from diverse origins. The results demonstrate that S. cerevisiae strains from apple chicha belong to the big group of wine/European strains of this species, while S. uvarum strains were included in the Holartic population of this species. Additionally, some S. uvarum strains from chichas evidenced as an admixture of both pure Holartic and pure South American populations. Our results suggest that Holartic strains could have been introduced in South America together with the domestication of apple trees by Mapuche communities. This Holartic population suffered admixis with the naturally present South American population of this species, originating strains bearing genetic features from the two populations, detectable in both chichas and natural habitats. PMID- 28011907 TI - Development of a Global Respiratory Severity Score for Respiratory Syncytial Virus Infection in Infants. AB - Background: Respiratory syncytial virus (RSV) infection in infants has recognizable clinical signs and symptoms. However, quantification of disease severity is difficult, and published scores remain problematic. Thus, as part of a RSV pathogenesis study, we developed a global respiratory severity score (GRSS) as a research tool for evaluating infants with primary RSV infection. Methods: Previously healthy infants <10 months of age with RSV infections representing the spectrum of disease severity were prospectively evaluated. Clinical signs and symptoms were collected at 3 time points from hospitalized infants and those seen in ambulatory settings. Data were also extracted from office, emergency department, and hospital records. An unbiased data-driven approach using factor analysis was used to develop a GRSS. Results: A total of 139 infants (84 hospitalized and 55 nonhospitalized) were enrolled. Using hospitalization status as the output variable, 9 clinical variables were identified and weighted to produce a composite GRSS. The GRSS had an area under the receiver operator curve of 0.961. Construct validity was demonstrated via a significant correlation with length of stay (r = 0.586, P < .0001). Conclusions: Using routine clinical variables, we developed a severity score for infants with RSV infection that should be useful as an end point for investigation of disease pathogenesis and as an outcome measure for therapeutic interventions. PMID- 28011909 TI - Management of Ebola Virus Disease: Is Environmental Decontamination Effective? PMID- 28011908 TI - Genital Injury Signatures and Microbiome Alterations Associated With Depot Medroxyprogesterone Acetate Usage and Intravaginal Drying Practices. AB - Background: Increasing evidence suggests depot medroxyprogesterone acetate (DMPA) and intravaginal practices may be associated with human immunodeficiency virus (HIV-1) infection risk; however, the mechanisms are not fully understood. This study evaluated the effect of DMPA and intravaginal practices on the genital proteome and microbiome to gain mechanistic insights. Methods: Cervicovaginal secretions from 86 Kenyan women, including self-reported DMPA users (n = 23), nonhormonal contraceptive users (n = 63), and women who practice vaginal drying (n = 46), were analyzed using tandem-mass spectrometry. Results: We identified 473 human and 486 bacterial proteins from 18 different genera. Depot medroxyprogesterone acetate use associated with increased hemoglobin and immune activation (HBD, HBB, IL36G), and decreased epithelial repair proteins (TFF3, F11R). Vaginal drying associated with increased hemoglobin and decreased phagocytosis factors (AZU1, MYH9, PLAUR). Injury signatures were exacerbated in DMPA users who also practiced vaginal drying. More diverse (H index: 0.71 vs 0.45; P = .009) bacterial communities containing Gardnerella vaginalis associated with vaginal drying, whereas DMPA showed no significant association with community composition or diversity. Conclusions: These findings provide new insights into the impact of DMPA and vaginal drying on mucosal barriers. Future investigations are needed to confirm their relationship with HIV risk in women. PMID- 28011910 TI - Induction of H7N9-Cross-Reactive Antibody-Dependent Cellular Cytotoxicity Antibodies by Human Seasonal Influenza A Viruses that are Directed Toward the Nucleoprotein. AB - Antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) against avian influenza virus subtypes, including H7N9 and H5N1, have been detected in human sera. Using NK cell activation and NK cytotoxicity assays, we compared ADCC mediating antibodies (ADCC-Abs) in sera collected from healthy infants, children and adults against H7N9 virus-infected cells and recombinant hemagglutinin (HA), neuraminidase (NA), and nucleoprotein (NP) proteins. High titers of ADCC-Abs against H7N9 virus-infected cells were detected in sera from adults and children but not infants. ADCC-Abs titers directed against H7N9 HA or NA proteins. Further analysis showed that ADCC-Abs titers were significantly higher toward H7N9 NP, as compared with H7N9 HA or NA proteins, and correlated strongly with ADCC-Abs titers against H7N9 virus-infected cells. Indeed, ADCC-Abs to NPs of seasonal H1N1 and H3N2 viruses correlated strongly with ADCC-Abs to H7N9 NP, suggesting that seasonal influenza infections and vaccinations may induce these cross reactive antibodies. Targeting ADCC-Abs to internal proteins may be a potential mechanism of universal vaccine design. PMID- 28011911 TI - Effectiveness of Human Papillomavirus Vaccination on Prevalence of Vaccine Genotypes in Young Sexually Active Women in France. AB - Background: Effectiveness of human papillomavirus (HPV) vaccines in the context of both guidelines, which recommend vaccination at 14 years and modest vaccine coverage, is poorly documented. Methods: Residual specimens from females aged <25 years undergoing chlamydia testing were collected, together with demographic, sexual behavior, and vaccine status data. Human pappilomavirus genotypes were determined using the PapilloCheck test system. We compared vaccine type (VT; types 6, 11, 16, 18) prevalence according to vaccination status and identified factors associated with VT prevalence. Results: Of 3736 eligible samples, 822 were from vaccinated women according to immunization record, 1021 from women self reporting vaccination, and 1893 from unvaccinated women. Adjusted vaccine effectiveness for confirmed vaccinated compared with unvaccinated women was 95.93% (95% confidence interval [CI] = 90.22-98.32) against VT HPV and 38.37% (95% CI = 12.68-56.51) against cross-reactive genotypes (HPV 31, 33, 45), respectively. Vaccine type HPV prevalence was significantly lower (0.61%) among confirmed-vaccinated women than among those who self-reported vaccination or unvaccinated women (1.76% and 15.0%, respectively). Factors associated with prevalent VT in multivariable analysis were vaccine status, positive Chlamydia trachomatis and >=4 partners in the preceding year. Conclusion: Our study demonstrates evidence of high effectiveness of HPV prophylactic vaccines at an individual level, supporting that wider implementation will help to reduce cervical cancer and precursors incidence. PMID- 28011912 TI - Cytomegalovirus Acquisition and Inflammation in Human Immunodeficiency Virus Exposed Uninfected Zimbabwean Infants. AB - Cytomegalovirus (CMV) acquisition and inflammation were evaluated in 231 human immunodeficiency virus (HIV)-exposed uninfected (HEU) and 100 HIV-unexposed Zimbabwean infants aged 6 weeks. The HEU and HIV-unexposed infants had a similarly high prevalence of CMV (81.4% vs 74.0%, respectively; P = .14), but HEU infants had higher CMV loads (P = .005) and >2-fold higher C-reactive protein (CRP) concentrations (P < .0001). The CMV-positive HEU infants had higher CRP than the CMV-negative HEU infants; this association disappeared after adjusting for maternal HIV load. Overall, CMV acquisition is high in early life, but HEU infants have higher CMV loads and a proinflammatory milieu, which may be driven partly by maternal HIV viremia. PMID- 28011913 TI - Trends and Determinants of Human Papillomavirus Concordance Among Human Immunodeficiency Virus-Positive and -Negative Heterosexual Couples in Rakai, Uganda. AB - Background: Limited data are available on human papillomavirus (HPV) infection among human immunodeficiency virus (HIV)-negative or HIV-positive couples followed longitudinally. Methods: Genital HPV was assessed in 725 concordant HIV negative couples and 209 HIV-positive couples enrolled in a male circumcision trial in Rakai, Uganda, using the Roche Linear Array assay, which detects 37 HPV genotypes. Human papillomavirus prevalence and determinants of genotype-specific concordance were assessed at annual visits. Cumulative detection of HPV genotypes over 2 years was also assessed. Results: At enrollment, HPV infection was detected in 54% of HIV-negative women, 56% of HIV-negative men, and 93% of HIV positive men and women. For HIV-negative couples, genotypic concordance was 30% at baseline (n = 219/725) and declined significantly with age (adjusted prevelance risk ratio [adjPRR] = 0.53; 95% confidence interval [CI] = 0.28-0.93 comparing women aged >40 years to those aged 15-19 years) and male circumcision (adjPRR = 0.60; 95% CI = 0.47-0.77) and increased among couples with recent intercourse (adjPRR = 1.26; 95% CI = 1.04-1.53). These associations were not seen in HIV-positive couples. Among couples with HPV results at all visits, >=1 of the same genotypes were detected in both partners in 60% of HIV-negative couples and 96% of HIV-positive couples over 2 years. Conclusion: Human papillomavirus genotype-specific concordance is more common in HIV-positive couples, and irrespective of HIV status, the majority of couples exhibit HPV concordance over 2 years. PMID- 28011914 TI - Effect of the Streptococcus agalactiae Virulence Regulator CovR on the Pathogenesis of Urinary Tract Infection. AB - Background: Streptococcus agalactiae can cause urinary tract infection (UTI). The role of the S. agalactiae global virulence regulator, CovR, in UTI pathogenesis is unknown. Methods: We used murine and human bladder uroepithelial cell models of UTI and S. agalactiae mutants in covR and related factors, including beta hemolysin/cytolysin (beta-h/c), surface-anchored adhesin HvgA, and capsule to study the role of CovR in UTI. Results: We found that covR-deficient serotype III S. agalactiae 874391 was significantly attenuated for colonization in mice and adhesion to uroepithelial cells. Mice infected with covR-deficient S. agalactiae produced less proinflammatory cytokines than those infected with wild-type 874391. Acute cytotoxicity in uroepithelial cells triggered by covR-deficient but not wild-type 874391 was associated with significant caspase 3 activation. Mechanistically, covR mutation significantly altered the expression of several genes in S. agalactiae 874391 that encode key virulence factors, including beta h/c and HvgA, but not capsule. Subsequent mutational analyses revealed that HvgA and capsule, but not the beta-h/c, exerted significant effects on colonization of the murine urinary tract in vivo. Conclusions: S. agalactiae CovR promotes bladder infection and inflammation, as well as adhesion to and viability of uroepithelial cells. The pathogenesis of S. agalactiae UTI is complex, multifactorial, and influenced by virulence effects of CovR, HvgA, and capsule. PMID- 28011915 TI - Genome-Wide Association Mapping of the Antibody Response to Diphtheria, Tetanus and Acellular Pertussis Vaccine in Mice. AB - The objective of the current study was to investigate the genetics of antibody responses to an acellular pertussis vaccine by a genome-wide association study in mice. Female mice of 28 inbred strains received this vaccine at 6, 8, and 12 weeks of age. The antibody titer and avidity of immunoglobulin (Ig) G specific for diphtheria toxin, pertussis toxin, filamentous hemagglutinin and pertactin were measured at 14 and 24 weeks of age. The magnitude, longevity and avidity of IgG differed significantly among mouse strains. There was significant correlation between antigen-specific IgGs for longevity but not for magnitude and avidity. Association mapping and analysis with PolyPhen software identified 6 genetic markers associated with longevity for all 4 antigens, although the expression levels of these genes did not correlate with longevity phenotype. This study provides novel insights into the genetic basis and potential candidate genes for differences in the IgG responses to vaccination. PMID- 28011916 TI - Immune Responses After 2 Versus 3 Doses of HPV Vaccination up to 41/2 Years After Vaccination: An Observational Study Among Dutch Routinely Vaccinated Girls. AB - Background: In 2014 the Netherlands switched from 3 to 2 doses for routine vaccination with the prophylactic bivalent human papillomavirus (HPV) vaccine. The current study explored whether antibody responses are noninferior after 2 versus 3 doses in girls. Methods: Girls vaccinated at 12 years of age with 2 (at 0 and 6 months) or 3 doses (at 0, 1, and 6 months) of the bivalent HPV vaccine were identified in the vaccination registration system. Type-specific antibody concentrations and avidity against HPV-16/18/31/33/45/52/58 were assessed. Analyses were stratified for time since the first dose (0-2, 2-3, 3-4, or 4-41/2 years). Noninferiority (margin, 0.5) of the 2- versus the 3-dose schedule in girls was examined. Results: Geometric mean concentrations (GMCs) for vaccine types were only noninferior for 2 versus 3 doses for HPV-18 (at 2-3 years after the first dose; GMC ratio, 0.89; 95% confidence interval, .57-1.38) For vaccine types and cross-protective types (HPV-16/18/31/33/45), the avidity index was noninferior for the 2-dose compared with the 3-dose schedule, except for HPV-31 at 4-41/2 years after the first dose and HPV-33 at 3-4 and 4-41/2 years. Conclusions: GMCs for HPV-16/18 were not noninferior for 2 versus 3 doses, except for HPV-18 (at 2-3 years after first dose). However, antibody avidity for these types showed noninferiority, independent of concentrations. PMID- 28011917 TI - Toll-like Receptors 2 and 4-Mediated Reciprocal Th17 and Antibody Responses to Group A Streptococcus Infection. AB - Background: The role of Toll-like receptors (TLRs) in adaptive immunity is incompletely understood. Recurrent human infections by group A streptococcus (GAS) and associated autoimmune conditions suggest that the immunity to GAS is intricately regulated and that TLRs may be involved in the regulation. Methods: This study investigated adaptive mucosal immune responses to GAS in TLR2-/- and TLR4-/- mice with an intranasal infection model. Results: Flow cytometric analyses of nasal-associated lymphoid tissue (NALT) cells showed that robust T helper 17 (Th17) cell responses to GAS in wild-type (WT) mice were reduced in TLR2-/- mice by 50%. Conversely, antibody levels and follicular T and B cells in the germinal center of NALT were significantly higher in TLR2-/- than in WT mice. However, antibody response to soluble antigens coimmunized with GAS was similar in WT and TLR2-/- mice. Moreover, the adaptive clearance of GAS in TLR2-/- mice was as efficient as in WT mice, whereas it was significantly impaired in TLR4-/- mice in which antibody responses were significantly lower than in WT mice. Conclusions: Activation of TLR2 by GAS is responsible for massive Th17 activation and deficient antibody response, which may increase predisposition to GAS-related autoimmunity and reduce protection efficiency. PMID- 28011918 TI - Hepatitis B Virus Reactivation in Rheumatoid Arthritis Patients Undergoing Biologics Treatment. AB - Background: Immunosuppressants can induce hepatitis B virus (HBV) reactivation; however, informative data about the risk of different immunosuppressive regimens, including biologics, on HBV reactivation (HBVr) among patients with rheumatoid arthritis (RA) are incomplete. Methods: Among 2334 RA patients who had available hepatitis B surface antigen (HBsAg) data, 123 patients positive for HBsAg who were not receiving anti-HBV prophylaxis were enrolled. These patients were undergoing varied mono or combination immunosuppressive therapy, including 36 who were receiving biological disease-modifying antirheumatic drugs (bDMARDs). Results: During 3459 person-months of follow-up, 30 (24.4%) patients developed HBVr. The multivariate Cox proportional hazard models showed that glucocorticoid significantly increased the risk of HBVr. Among all kinds of immunosuppressive treatments, glucocorticoid in combination with bDMARDs and synthetic disease modifying antirheumatic drugs (sDMARDs) had the highest risk of HBVr (adjusted hazard ratio [HR] = 5.14; 95% confidence interval [CI] = 1.77-14.92; P = .003). Rituximab had the greatest risk for HBVr (adjusted HR = 16.51; 95% CI = 1.82 149.67; P = .01) among the patients who received bDMARDs. Conclusions: Glucocorticoid has a detrimental effect on HBVr in RA patients. Antiviral prophylactic strategies should be justified according to the risk of HBVr under different combinations of immunosuppressive therapy in rheumatic patients. PMID- 28011919 TI - HPV-6 Molecular Variants Association With the Development of Genital Warts in Men: The HIM Study. AB - Background: Human papillomavirus type 6 (HPV-6) and HPV-11 are the etiological agents of approximately 90% of genital warts (GWs). The impact of HPV-6 genetic heterogeneity on persistence and progression to GWs remains undetermined. Methods: HPV Infection in Men (HIM) Study participants who had HPV-6 genital swabs and/or GWs preceded by a viable normal genital swab were analyzed. Variants characterization was performed by polymerase chain reaction sequencing and samples classified within lineages (A, B) and sublineages (B1, B2, B3, B4, B5). Country- and age-specific analyses were conducted for individual variants; odds ratios and 95% confidence intervals for the risk of GWs according to HPV-6 variants were calculated. Results: B3 variants were most prevalent. HPV-6 variants distribution differed between countries and case status. HPV-6 B1 variants prevalence was increased in GWs and genital swabs of cases compared to controls. There was difference in B1 and B3 variants detection in GW and the preceding genital swab. We observed significant association of HPV-6 B1 variants detection with GW development. Conclusions: HPV-6 B1 variants are more prevalent in genital swabs that precede GW development, and confer an increased risk for GW. Further research is warranted to understand the possible involvement of B1 variants in the progression to clinically relevant lesions. PMID- 28011920 TI - Nasopharyngeal Pneumococcal Carriage During Childhood Community-Acquired Alveolar Pneumonia: Relationship Between Specific Serotypes and Coinfecting Viruses. AB - Background: Respiratory viruses and Streptococcus pneumoniae are known to be copathogens in childhood pneumonia. However, it is unclear whether all pneumococcal serotypes are equally prone to such interaction. We attempted to determine association between carried pneumococcal serotypes and respiratory viruses during childhood community-acquired alveolar pneumonia (CAAP). Methods: The study was conducted during respiratory syncytial virus (RSV) seasons, before pneumococcal vaccine introduction. Children aged <5 years diagnosed with CAAP with positive pneumococcal nasopharyngeal cultures from whom viral diagnostic tests were obtained were enrolled. Viral detection was done by culture, direct immunofluorescence assay (DFA) or polymerase chain reaction. Adjusted odd ratios (ORs) for serotype-specific carriage rates by presence of specific viruses were calculated: single RSV-positive (RSV[+]); other respiratory viruses (ORspVs[+]); and no respiratory virus (RspVs[-]). We compared invasive and noninvasive pneumococcal serotypes according to previous publications. Results: Invasive serotype colonization was significantly lower in RSV(+) versus RspVs(-) CAAP (OR = 0.18; 95% confidence interval [CI] = .05-.60), whereas colonization with noninvasive serotypes tended to be higher in RSV(+) (OR = 2.39; 95% CI = .98 5.79). Conclusions: We found an inverse relationship between pneumonia-associated invasive pneumococcal serotypes and RSV detection during CAAP. This finding may lead to better understanding of the interaction between respiratory viruses and S. pneumoniae in CAAP pathogenesis. PMID- 28011921 TI - Long-term Durability of Responses to 2 or 3 Doses of Hepatitis A Vaccination in Human Immunodeficiency Virus-Positive Adults on Antiretroviral Therapy. AB - Background: Previous studies have shown that the durability of serological response is impaired in successfully vaccinated human immunodeficiency virus-1 (HIV-1) positive subjects after receiving 2 doses of inactivated hepatitis A virus (HAV) vaccine. We evaluated whether 3 doses compared with 2 doses of HAV vaccine could improve the long-term seroprotection for this susceptible group. Methods: Antibody persistence among HIV-positive men who have sex with men aged 18-40 years who had received 2 or 3 doses of HAV vaccine according to a 0-6- or a 0-1-6-month schedule was evaluated biannually for 5 consecutive years in this prospective, nonrandomized cohort study. Results: At the end of 5 years, seroprotection persisted in 79% (146/185) versus 76% (85/110) and 94% (146/155) versus 88% (84/95) of the 3- versus 2-dose primary responders by intention-to treat and per-protocol analyses, respectively (P > .05). Throughout the 5 years, the geometric mean concentrations of anti-HAV immunoglobulin G (IgG) were significantly higher for the 3-dose than the 2-dose group. In the multivariable analysis, a 3-dose regimen compared with a 2-dose regimen (odds ratio = 3.36; 95% confidence interval = 1.14-9.93) was independently associated with sustained seroprotection. Conclusions: Three doses versus 2 doses of HAV vaccine improve the durability of immune responses in terms of higher concentrations of specific IgG, which take longer to decay to subthreshold levels. PMID- 28011922 TI - Detection of Ebola Virus RNA Through Aerosol Sampling of Animal Biosafety Level 4 Rooms Housing Challenged Nonhuman Primates. AB - Ebola virus disease is a serious illness of humans and nonhuman primates (NHPs). Direct contact has been shown to be the primary source of Ebola (EBOV) transmission. We used a high-volume air sampler to determine whether EBOV could be detected during 3 independent studies with EBOV-challenged NHPs. Viral RNA was recovered during days 9 and 10 of Study I and days 7 and 8 of Study III. Viral RNA levels were below limits of detection during all other collections. The results demonstrate that the biosafety level 4 (BSL-4) suit protects workers from aerosols in a BSL-4 environment using proper engineering and administrative controls. PMID- 28011924 TI - Childhood secondhand smoke exposure and pregnancy loss in never smokers: the Guangzhou Biobank Cohort Study. AB - OBJECTIVE: Studies of secondhand smoke (SHS) exposure especially childhood SHS exposure and pregnancy loss are limited. We used baseline data of the Guangzhou Biobank Cohort Study (GBCS) to examine the association of childhood SHS exposure with a history of pregnancy loss. METHODS: Never smoking women aged 50 years or above in GBCS from 2003 to 2008 were included. Propensity score matching (PSM) was used to control for confounding. Negative binomial regression and logistic regression were used to examine the association of childhood SHS, assessed by number of smokers in childhood household and frequency of exposure, with past pregnancy loss. RESULTS: Of 19 562 women, 56.7% (11 096) had SHS exposure during childhood. In negative binomial regression, after adjusting for age, education, past occupational dust exposure, past home fuel exposure, oral contraceptive, adulthood SHS exposure, age at first pregnancy and age at first menarche, compared to non-exposure, the incidence rate ratio of one more pregnancy loss was 1.20 (95% CI1.05 to 1.37) in those who lived with >=2 smokers in the same household, and 1.14 (95% CI 1.04 to 1.25) in those exposed >=5 times/week. After similar adjustment, logistic regression showed that the OR of pregnancy loss >=2 times (versus 0 to 1 time) was 1.25 (95% CI 1.00 to 1.57) and 1.20 (95% CI 1.03 to 1.40) for high density (>=2 smokers in the same household) and frequency (>=5 times/week) of childhood exposure, respectively. CONCLUSIONS: Childhood SHS exposure was associated with higher risks of pregnancy loss in middle-aged and older Chinese women. PMID- 28011925 TI - Primary intramedullary spinal cord lymphoma: a population-based study. AB - Background: Primary intramedullary spinal cord lymphoma (PISCL) is a rare diagnosis with poorly understood disease progression. Clarification of the factors associated with survival in PISCL patients is warranted. Methods: We conducted a population-based cohort study utilizing prospectively collected data from the Surveillance, Epidemiology, and End Results (SEER) database. Patients with histological diagnosis of primary lymphoma in spinal cord (C72.0) from 1973 to 2012 in the SEER database were included. Multivariable survival analysis between patient, lesion characteristics, and PISCL-related death was performed to adjust for confounding factors. Results: We included 346 PISCL patients in our study. Average age was 56.5 +/- 17.8 years, with 62.7% being male. Racial distribution of these patients was white (87.6%), black (8.0%), and other (4.3%). More than half (55.8%) of patients were married. The most prevalent histology of PISCL was diffuse B-cell (46.2%), and the majority (55.2%) were low stage (Ann Arbor stage I/II). Most patients (67.9%) received radiation therapy. Average survival interval of patients with PISCL-related death (n=135, 39.0%) was 27.8 months. General cumulative survival probability at 1 year, 2 years, and 5 years was 73.8%, 67.9%, and 63.1%, respectively. Multivariable accelerated failure time (AFT) regression showed follicular lymphoma (HR:0.25, P=.008) and more recent diagnosis (HR:0.96, P<.001) was positively associated with PISCL-related survival. Conversely, nonwhite race (HR:1.69, P=.046), older age (HR:1.02, P<.001), unmarried status (HR:2.14, P<.001), and higher stage (HR:1.54, P=.022) were negatively associated with survival. Conclusions: Age, race, marital status, tumor histology, tumor stage, and year of diagnosis were associated with survival of PISCL. While most PISCL-related deaths occur within a 1-year period, subsequent slow progression was observed after the first year of survival. PMID- 28011929 TI - Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy. AB - OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1. METHODS: We explored 354 unrelated index cases recruited between 1999 and 2014 in several neuromuscular centers in France. RESULTS: This cohort allowed us to characterize the frequency of mutated alleles in the French population and to demonstrate a statistical correlation between the size of the expansion and the mean age at diagnosis. We also confirmed that homozygous patients present with a more severe disease. CONCLUSIONS: It has been difficult to establish phenotype-genotype correlations because of the rare nature of this disease. Our work demonstrates that patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion, confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression. PMID- 28011926 TI - Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data. AB - Background: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age >=4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients <4 years old, 5-year PFS/overall survival (OS) were 11 +/- 4%/12 +/- 4%. Two patients survived after chemotherapy only, while 3 of 16 treated with craniospinal irradiation (CSI) with boost, and 3 of 5 treated with high-dose chemotherapy (HDCT) and local radiotherapy survived. In 78 patients aged >=4 years, PFS/OS were 72 +/- 7%/73 +/ 7% for patients without metastases, and 50 +/- 10%/55 +/- 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients. PMID- 28011930 TI - Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. AB - OBJECTIVE: To compare refractory convulsive status epilepticus (rSE) management and outcome in children with and without a prior diagnosis of epilepsy and with and without a history of status epilepticus (SE). METHODS: This was a prospective observational descriptive study performed from June 2011 to May 2016 on pediatric patients (1 month-21 years of age) with rSE. RESULTS: We enrolled 189 participants (53% male) with a median (25th-75th percentile) age of 4.2 (1.3-9.6) years. Eighty-nine (47%) patients had a prior diagnosis of epilepsy. Thirty-four (18%) patients had a history of SE. The time to the first benzodiazepine was similar in participants with and without a diagnosis of epilepsy (15 [5-60] vs 16.5 [5-42.75] minutes, p = 0.858). Patients with a diagnosis of epilepsy received their first non-benzodiazepine (BZD) antiepileptic drug (AED) later (93 [46-190] vs 50.5 [28-116] minutes, p = 0.002) and were less likely to receive at least one continuous infusion (35/89 [39.3%] vs 57/100 [57%], p = 0.03). Compared to patients with no history of SE, patients with a history of SE received their first BZD earlier (8 [3.5-22.3] vs 20 [5-60] minutes, p = 0.0073), although they had a similar time to first non-BZD AED (76.5 [45.3-124] vs 65 [32.5-156] minutes, p = 0.749). Differences were mostly driven by the patients with an out of-hospital rSE onset. CONCLUSIONS: Our study establishes that children with rSE do not receive more timely treatment if they have a prior diagnosis of epilepsy; however, a history of SE is associated with more timely administration of abortive medication. PMID- 28011931 TI - HTLV-1 Tax-Specific CTL Epitope-Pulsed Dendritic Cell Therapy Reduces Proviral Load in Infected Rats with Immune Tolerance against Tax. AB - Adult T cell leukemia/lymphoma (ATL), a CD4+ T cell malignancy with a poor prognosis, is caused by human T cell leukemia virus type 1 (HTLV-1) infection. High proviral load (PVL) is a risk factor for the progression to ATL. We previously reported that some asymptomatic carriers had severely reduced functions of CTLs against HTLV-1 Tax, the major target Ag. Furthermore, the CTL responses tended to be inversely correlated with PVL, suggesting that weak HTLV-1 specific CTL responses may be involved in the elevation of PVL. Our previous animal studies indicated that oral HTLV-1 infection, the major route of infection, caused persistent infection with higher PVL in rats compared with other routes. In this study, we found that Tax-specific CD8+ T cells were present, but not functional, in orally infected rats as observed in some human asymptomatic carriers. Even in the infected rats with immune unresponsiveness against Tax, Tax-specific CTL epitope-pulsed dendritic cell (DC) therapy reduced the PVL and induced Tax-specific CD8+ T cells capable of proliferating and producing IFN-gamma. Furthermore, we found that monocyte-derived DCs from most infected individuals still had the capacity to stimulate CMV-specific autologous CTLs in vitro, indicating that DC therapy may be applicable to most infected individuals. These data suggest that peptide-pulsed DC immunotherapy will be useful to induce functional HTLV-1-specific CTLs and decrease PVL in infected individuals with high PVL and impaired HTLV-1-specific CTL responses, thereby reducing the risk of the development of ATL. PMID- 28011932 TI - Immunodominance of Antibody Recognition of the HIV Envelope V2 Region in Ig Humanized Mice. AB - In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with Abs that reacted with a linear epitope at a lysine residue at position 169 (K169) in the HIV-1 envelope (Env) V2 region. The K169 V2 response was restricted to Abs bearing Vlambda rearrangements that expressed aspartic acid/glutamic acid in CDR L2. The AE.A244 gp120 in AIDSVAX B/E also bound to the unmutated ancestor of a V2-glycan broadly neutralizing Ab, but this Ab type was not induced in the RV144 trial. In this study, we sought to determine whether immunodominance of the V2 linear epitope could be overcome in the absence of human Vlambda rearrangements. We immunized IgH- and Igkappa-humanized mice with the AE.A244 gp120 Env. In these mice, the V2 Ab response was focused on a linear epitope that did not include K169. V2 Abs were isolated that used the same human VH gene segment as an RV144 V2 Ab but paired with a mouse lambda L chain. Structural characterization of one of these V2 Abs revealed how the linear V2 epitope could be engaged, despite the lack of aspartic acid/glutamic acid encoded in the mouse repertoire. Thus, despite the absence of the human Vlambda locus in these humanized mice, the dominance of Vlambda pairing with human VH for HIV-1 Env V2 recognition resulted in human VH pairing with mouse lambda L chains instead of allowing otherwise subdominant V2-glycan broadly neutralizing Abs to develop. PMID- 28011933 TI - Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages. AB - During macrophage activation, expression of IL-1R-associated kinase (IRAK)-M is induced to suppress TLR-mediated responses and is a hallmark of endotoxin tolerance. Endotoxin tolerance requires tight regulation of genes occurring at the transcriptional and epigenetic levels. To identify novel regulators of IRAK M, we used RAW 264.7 macrophages and performed a targeted RNA interference screen of genes encoding chromatin-modifying enzymes, signaling molecules, and transcription factors involved in macrophage activation. Among these, the transcription factor CCAAT/enhancer binding protein (C/EBP)beta, known to be involved in macrophage inactivation, was necessary for the induction of IRAK-M expression. Chromatin immunoprecipitation showed that C/EBPbeta was recruited to the IRAK-M promoter following LPS stimulation and was indispensable for IRAK-M transcriptional activation. Among histone 3-modifying enzymes, our screen showed that knockdown of the histone 3 lysine 27 (H3K27) methyltransferase and part of the polycomb recessive complex 2, enhancer of Zeste 2, resulted in IRAK-M overexpression. In contrast, knockdown of the H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat X chromosome suppressed the induction of IRAK-M in response to LPS stimulation. Accordingly, we demonstrated that H3K27 on the IRAK-M promoter is trimethylated in unstimulated cells and that this silencing epigenetic mark is removed upon LPS stimulation. Our data propose a mechanism for IRAK-M transcriptional regulation according to which, in the naive state, polycomb recessive complex 2 repressed the IRAK-M promoter, allowing low levels of expression; following LPS stimulation, the IRAK-M promoter is derepressed, and transcription is induced to allow its expression. PMID- 28011934 TI - Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer. AB - The role of IL-33, particularly in tumor growth and tumor immunity, remains ill defined. We show that exogenous IL-33 can induce robust antitumor effect through a CD8+ T cell-dependent mechanism. Systemic administration of rIL-33 alone was sufficient to inhibit growth of established tumors in transplant and de novo melanoma tumorigenesis models. Notably, in addition to a direct action on CD8+ T cell expansion and IFN-gamma production, rIL-33 therapy activated myeloid dendritic cells (mDCs) in tumor-bearing mice, restored antitumor T cell activity, and increased Ag cross-presentation within the tumor microenvironment. Furthermore, combination therapy consisting of rIL-33 and agonistic anti-CD40 Abs demonstrated synergistic antitumor activity. Specifically, MyD88, an essential component of the IL-33 signaling pathway, was required for the IL-33-mediated increase in mDC number and upregulation in expression of costimulatory molecules. Importantly, we identified that the IL-33 receptor ST2, MyD88, and STAT1 cooperate to induce costimulatory molecule expression on mDCs in response to rIL 33. Thus, our study revealed a novel IL-33-ST2-MyD88-STAT1 axis that restores mDC activation and maturation in established cancer and, thereby, the magnitude of antitumor immune responses, suggesting a potential use of rIL-33 as a new immunotherapy option to treat established cancer. PMID- 28011935 TI - TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS. AB - Upon virus infection, host cells use retinoic-acid-inducible geneI I (RIG-I)-like receptors to recognize viral RNA and activate type I IFN expression. To investigate the role of protein methylation in the antiviral signaling pathway, we screened all the SET domain-containing proteins and identified TTLL12 as a negative regulator of RIG-I signaling. TTLL12 contains SET and TTL domains, which are predicted to have lysine methyltransferase and tubulin tyrosine ligase activities, respectively. Exogenous expression of TTLL12 represses IFN-beta expression induced by Sendai virus. TTLL12 deficiency by RNA interference and CRISPR-gRNA techniques increases the induced IFN-beta expression and inhibits virus replication in the cell. The global gene expression profiling indicated that TTLL12 specifically inhibits the expression of the downstream genes of innate immunity pathways. Cell fractionation and fluorescent staining indicated that TTLL12 is localized in the cytosol. The mutagenesis study suggested that TTLL12's ability to repress the RIG-I pathway is probably not dependent on protein modifications. Instead, TTLL12 directly interacts with virus-induced signaling adaptor (VISA), TBK1, and IKKepsilon, and inhibits the interactions of VISA with other signaling molecules. Taken together, our findings demonstrate TTLL12 as a negative regulator of RNA-virus-induced type I IFN expression by inhibiting the interaction of VISA with other proteins. PMID- 28011940 TI - Introduction to the special issue of Radiation Protection Dosimetry. PMID- 28011936 TI - The MHC Class II Immunopeptidome of Lymph Nodes in Health and in Chemically Induced Colitis. AB - We recently described a mass spectrometry-based methodology that enables the confident identification of hundreds of peptides bound to murine MHC class II (MHCII) molecules. In this article, we describe its application to the characterization of MHCII-bound peptides isolated from lymph nodes (LNs) of C57BL/6 mice. More than 1000 peptides could be identified in individual analyses, allowing a direct comparison of the MHCII peptidome in different types of normal LNs or in animals with colitis. The peptide length distribution and consensus sequences in axillary, brachial, inguinal, and mesenteric LNs were virtually identical, and a substantial portion of identified peptides corresponded to proteins found in all LNs. However, skin-specific proteins Sbsn and Dmkn and intestine-specific proteins Dmbt1, Krt19, and Maoa, among others, were exclusively identified in skin-draining and mesenteric LNs, respectively. Differences in peptide-presentation patterns were also observed when comparing healthy mice and mice with dextran sodium sulfate-induced colitis. Peptides derived from a subset of proteins (including IgE, Bank1, chondroitin sulfate synthase 2, Cmip, and Fth1) were exclusively identified in mice with colitis, revealing changes in the peptidome associated with the inflammatory process, as well as activation and clonal expansion of B cells. PMID- 28011942 TI - Child Health Care Delivery Is Improving and So Is Pediatrics. PMID- 28011943 TI - Pediatric Residency Education and the Behavioral and Mental Health Crisis: A Call to Action. AB - For at least 4 decades, the need for improved pediatric residency training in behavioral and mental health has been recognized. The prevalence of behavioral and mental health conditions in children, adolescents, and young adults has increased during that period. However, as recently as 2013, 65% of pediatricians surveyed by the American Academy of Pediatrics indicated that they lacked training in recognizing and treating mental health problems. Current pediatric residency training requirements do not stipulate curricular elements or assessment requirements in behavioral and mental health, and fewer than half of pediatric residents surveyed felt that their competence in dealing with mental health problems was good to excellent. It is time that pediatric residency programs develop the capacity to prepare their residents to meet the behavioral and mental health needs of their patients. Meeting this challenge will require a robust curriculum and effective assessment tools. Ideal training environments will include primary care ambulatory sites that encourage residents to work longitudinally in partnership with general pediatricians and behavioral and mental health trainees and providers; behavioral and mental health training must be integrated into both ambulatory and inpatient experiences. Faculty development will be needed, and in most programs it will be necessary to include nonpediatrician mental health providers to enhance pediatrician faculty expertise. The American Board of Pediatrics intends to partner with other organizations to ensure that pediatric trainees develop the competence needed to meet the behavioral and mental health needs of their patients. PMID- 28011944 TI - Bioavailability of aspirin in rats comparing the drug's uptake into gastrointestinal tissue and vascular and lymphatic systems: implications on aspirin's chemopreventive action. AB - Aspirin is an effective analgesic and antiplatelet drug that in addition to its ability to reduce pain, inflammation and fever, appears to have efficacy in the prevention/treatment of a range of diseases including heart disease, numerous cancers and Alzheimer's. It is important to understand the bioavailability of aspirin and its major metabolite, salicylic acid, since dosage and route of administration can vary for treating differing diseases, and the major side effects of aspirin, upper gastrointestinal ulceration and bleeding, are dose dependent. We examined the time course for gastroduodenal uptake of aspirin and the appearance of its major metabolite salicylic acid in blood and lymph after intragastric (to simulate oral) and intraduodenal (to simulate enteric-coating) dosing in rats. Results show that after intragastric dosing, intact aspirin is absorbed primarily by the gastric mucosa and to a lesser extent by the duodenal mucosa. When aspirin is dosed intragastrically or intraduodenally, a much greater concentration of aspirin enters the lymph than the blood. In contrast, the concentration of salicylic acid was higher in blood than in lymph. Lymph levels of both aspirin and salicylic acid were sufficiently high so as to perform a pharmacologic function there, possibly as a chemopreventive agent against colon cancer and potentially the metastatic spread of non-gastrointestinal cancers. PMID- 28011945 TI - Orexin A modulates INS-1E cell proliferation and insulin secretion via extracellular signal-regulated kinase and transient receptor potential channels. AB - Orexins A (OXA) and B (OXB) control energy homeostasis by regulating food intake, energy expenditure and sleep-wake cycle. Several studies showed that OXA stimulates insulin secretion and proliferation of beta cells. However, mechanisms of action are still not well understood. Here, we investigated whether ERK and transient receptor potential channels (TRPs) play a role in mediating the effect of OXA on cell growth, insulin production, and secretion using the established INS-1E cell line. Cell proliferation was measured using BrdU assay. Insulin mRNA expression was detected by real-time PCR. Insulin secretion was assessed using ELISA. Intracellular calcium levels were measured using fluorescence calcium imaging (fura-2/AM). Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was detected by Western blot. TRP channel activity was blocked by lanthanum (III) chloride (La3+; 100 - 300 MUM) or ruthenium red (RuR; 10 MUM). OXA (100 nM) stimulated INS-1E cell proliferation, insulin secretion, intracellular Ca2+ concentration and ERK1/2 phosphorylation, without changing insulin mRNA expression. Inhibition of ERK1/2 by 10 MUM U0126 attenuated OXA stimulated INS-1E cell proliferation. Blockade of TRP channel activity by La3+ or RuR rendered OXA ineffective at modulating Ca2+ regulation and insulin release. In contrast, the L-type channel blocker nifedipine (10 MUM) failed to affect OXA stimulated insulin release. Taken together, OXA increases INS-1E cell proliferation via ERK1/2-dependent mechanism. Furthermore, OXA stimulates insulin secretion from INS-1E cells. TRPs are relevant for OXA-stimulated insulin secretion and intracellular calcium regulation. PMID- 28011946 TI - High-fat diet with stress impaired islets' insulin secretion by reducing plasma estradiol and pancreatic GLUT2 protein levels in rats' proestrus phase. AB - This study was conducted to determine whether two estrus phases (proestrus and diestrus) in female rats may influence the metabolic response to a high-fat diet and/or stress, focusing on pancreatic insulin secretion and content. Animals were divided into high-fat and normal diet groups, then each group was subdivided into stress and non-stress groups, and finally, each one of these was divided into proestrus and diestrus subgroups. At the end of high-fat diet treatment, foot shock stress was applied to the animals. Then, blood samples were taken to measure plasma factors. Finally, the pancreas was removed for determination of glucose transporter 2 (GLUT2) protein levels and assessment of insulin content and secretion of the isolated islets. In the normal and high-fat diet groups, stress increased plasma corticosterone concentration in both phases. In both study phases, high-fat diet consumption decreased estradiol and increased leptin plasma levels. In the high-fat diet group in response to high glucose concentration, a reduction in insulin secretion was observed in the proestrus phase compared with the same phase in the normal diet group in the presence and absence of stress. Also, high-fat diet decreased the insulin content of islets in the proestrus phase compared with the normal diet. High-fat diet and/or stress caused a reduction in islet GLUT2 protein levels in both phases. In conclusion, it seems possible that high-fat diet alone or combined with foot-shock, predispose female rats to impaired insulin secretion, at least in part, by interfering with estradiol levels in the proestrus phase and decreasing pancreatic GLUT2 protein levels. PMID- 28011947 TI - Effects of time of day and the wingate test on appetite perceptions, food intake and plasma levels of adipokines. AB - It has been demonstrated that several aspects of adipose-related physiology including adipokine release, exhibit daily oscillations. Physical exercise exerts a strong influence on adipokine release and a possible reverse disruption of peripheral circadian clocks. The aim of this study was to establish the effects of time of day and the Wingate test on appetite perception, food intake and plasma levels of adipokines. Twenty-four moderately active non-smoking males (mean +/- S.D. age: 27.1 +/- 3.1 years; height: 1.79 +/- 0.1 m; weight: 76.1 +/- 11.7 kg) were recruited for this study and divided in two groups; one fed with an ad libitum test meal and another one without an ad libitum test meal. Each subject participated in the following studies performed at 11:00 and 23:00 hours on separate days: 1) Exercise study (ES): a 30-second Wingate Anaerobic Test (WAnT), and 2) sedentary study (SS). Subjects rated their appetite perceptions (hunger and prospective food consumption) on a 100-milimeter visual analogue scale (VAS) at baseline, after exercise, after test meal and during the postprandial/control period. At those time points blood samples were obtained for the measurement of plasma leptin, visfatin and apelin concentrations. Appetite perception and energy intake results at test meal decreased in response to WAnT in comparison with sedentary subjects. Time of day had no statistically significant effect on energy intake but the appetite perception score after test meal at 24:00 hours was statistically higher than that after test meal at 12:00 hours. No significant differences in the tested plasma adipokine concentrations between the trials existed at baseline, however, all plasma adipokine levels at 24:00 hours were higher than those at 12:00 hours. Plasma apelin concentrations after WAnT were significantly higher than its pre-exercise value at 12:00 hours, unlike those at 24:00 hours. Sedentary experiments showed a modest, yet significant, rise in plasma apelin levels after the test meal at 12:00 hours but not after the one at 24:00 hours. There were no significant changes in plasma leptin concentrations after exercise or test meal but a significant decrease in plasma visfatin concentrations after exercise intervention both at the 12:00 hours test and the 24:00 hours test has been observed. Test meals caused a significant rise in visfatin concentrations in sedentary, but not exercise series, in the daytime and nighttime tests. We conclude that time of day is an important aspect to consider in the relationships between exercise, metabolism and appetite. Further studies are needed to explain the specific mechanisms underlying the effects of acute exercise on postprandial physiology at different times of the day. PMID- 28011948 TI - Molecular hydrogen affords neuroprotection in a translational piglet model of hypoxic-ischemic encephalopathy. AB - Hypoxic-ischemic encephalopathy (HIE) is the major consequence of perinatal asphyxia (PA) in term neonates. Although the newborn piglet is an accepted large animal PA/HIE model, there is no consensus on PA-induction methodology to produce clinically relevant HIE. We aimed to create and to characterize a novel PA model faithfully reproducing all features of asphyxiation including severe hypercapnia resulting in HIE, and to test whether H2 is neuroprotective in this model. Piglets were anaesthetised, artificially ventilated, and intensively monitored (electroencephalography, core temperature, O2 saturation, arterial blood pressure and blood gases). Asphyxia (20 min) was induced by ventilation with a hypoxic hypercapnic (6%O2 - 20%CO2) gas mixture. Asphyxia-induced changes in the cortical microcirculation were assessed with laser-speckle contrast imaging and analysis. Asphyxia was followed by reventilation with air or air containing hydrogen (2.1%H2, 4 hours). After 24 hours survival, the brains were harvested for neuropathology. Our PA model was characterized by the development of severe hypoxia (pO2 = 27 +/- 4 mmHg), and combined acidosis (pH = 6.76 +/- 0.04; pCO2 = 114 +/- 11 mmHg; lactate = 12.12 +/- 0.83 mmol/L), however, cortical ischemia did not develop during the stress. Severely depressed electroencephalography (EEG), and marked neuronal injury indicated the development of HIE. H2 was neuroprotective shown both by the enhanced recovery of EEG and by the significant preservation of neurons in the cerebral cortex, hippocampus, basal ganglia, and the thalamus. H2 appeared to reduce oxidative stress shown by attenuation of 8 hydroxy-2'-deoxyguanosine immunostaining. In summary, this new PA piglet model is able to induce moderate/severe HIE, and the efficacy of hydrogen post-treatment to preserve neuronal activity/function in this PA/HIE model suggests the feasibility of this safe and inexpensive approach in the treatment of asphyxiated babies. PMID- 28011949 TI - The presence of Tau protein in blood as a potential prognostic factor in stroke patients. AB - Tau protein is found in the blood of 40 - 50% of patients in the acute phase of a stroke, as a result of the degradation of neurons and damage to the blood-brain barrier. The aim of the study was to assess the incidence of tau protein in the blood of stroke patients, as well as to evaluate the potential impact of tau protein presence in the blood of patients on their neurological state during the first 24 hours, and their functional condition three months after the stroke. Eighty-seven patients aged 39 - 99 (42 females and 45 males) diagnosed with stroke were enrolled in the prospective study (August 2014 - April 2015). The following parameters were analyzed in enrolled participants: the age at which first ischemic stroke occurred, neurological state during the first 24 hours (National Institutes of Health Stroke Scale - NIHSS), blood tau protein and brain derived neurotrophic factor (BDNF) concentrations on day 2 of stroke, the functional condition on day 90 after stroke onset (mRankin). A multifactorial analysis was carried out to establish independent factors for the presence of serum tau protein and to identify independent factors for poor prognosis. Eighty seven patients of the mean age of 71.7 +/- 11.8 years (median 74; min. 39 max. 99 years) took part in the study. The tau protein was found in the serum of 42 (48.27%) patients in the concentrations between 29.56 and 19 023.50 ng/ml. The female sex was the only independent factor for the presence of tau protein in blood (RR 4.49 (1.68 - 11.97), P = 0.003). The mean BDNF concentration in the evaluated group was: 9.96 +/- 5.21; median 10.39. Three independent factors for poor functional condition of patients on day 90 after the stroke were identified: the presence of tau protein in blood (RR 3.90 (1.45 - 10.49), P = 0.007), BDNF concentration below the mean value for the study (RR 14.49 (4.60 - 45.45); P = 0.000) and NIHSS score > 4 during the first 24 hours of stroke (RR 1.14; 95% CI: 1.00 - 1.31; P = 0.027). The presence of the tau protein, low BDNF concentrations, and moderate/serious neurological state during the first 24 hours of stroke can be considered as negative prognosis for the patient's functional condition. The coincidence of high BDNF concentrations and absence of tau in blood during the acute phase of an ischemic stroke is a predictor of patient's good state in 3 months after stroke. PMID- 28011950 TI - Involvement of corticotropin-releasing factor and corticotropin-releasing factor 2 receptors in pathogenesis of ischemia/reperfusion-induced enteritis in rats. AB - We herein investigated, using a corticotropin-releasing factor (CRF) agonist and antagonists, whether CRF plays a role in the pathogenesis of ischemia/reperfusion induced small intestinal lesions in rats. Under pentobarbital anesthesia, the superior mesenteric artery was clamped (ischemia) for 75 min, followed by reperfusion with removal of the clamp. After a 24-h reperfusion, the area of hemorrhagic lesions that developed in the small intestine was measured. Urocortin I (CRF receptor 1/2 agonist), astressin (CRF receptor 1/2 antagonist), NBI27914 (CRF receptor 1 antagonist), or astressin 2B (CRF receptor 2 antagonist) was administered i.v. twice: 5 min before ischemia and 6 hours after reperfusion. Ischemia/reperfusion caused hemorrhagic lesions in the small intestine in ampicillin- and aminoguanidine-inhibitable manners, accompanied by enterobacterial invasion and the up-regulation of inducible nitric oxide synthase expression and myeloperoxidase activity. The severity of ischemia/reperfusion induced lesions was significantly reduced by astressin and astressin 2B, but not by NBI27914, with the suppression of bacterial invasion, myeloperoxidase activity, and inducible nitric oxide synthase expression. In contrast, urocortin I markedly aggravated these lesions, and this response was completely abrogated by the co-administration of astressin 2B, but not NBI27914. The gene expression of CRF, CRF receptor 1, and CRF receptor 2 was observed in the small intestine, and remained unchanged following ischemia/reperfusion. These results suggest that ischemia/reperfusion caused hemorrhagic lesions in the small intestine, the pathogenesis of which involved enterobacteria and inducible nitric oxide synthase/nitric oxide. These lesions were aggravated by urocortin I in an astressin 2B-inhibitable manner, but suppressed by astressin in a CRF receptor 2 dependent manner. Endogenous CRF may be involved in the pathogenesis of ischemia/reperfusion-induced enteritis, possibly via the activation of peripheral CRF receptor 2. PMID- 28011951 TI - Alterations in glutathione peroxidase and superoxide dismutase activities in plasma and saliva in relation to disease activity in patients with Crohn's disease. AB - Crohn's disease (CD) is a chronic inflammatory condition with uncertain aetiology. Dysfunction of immunoregulatory factors and overproduction of reactive oxygen species (ROS) may contribute to the damage of the gastrointestinal tract. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) are involved in protection of cells from the damaging effects of ROS. The aim of the study was to assess activity of antioxidative stress enzymes, GPx and SOD, in plasma and saliva of patients with active and inactive forms of CD. Forty-seven patients with CD were prospectively enrolled in the study. The control group comprised 25 healthy volunteers. Patients' demographics, clinical features, localization of inflammatory changes, CD history, and treatment were recorded. SOD and GPx were assayed in plasma and saliva samples by ELISA method. CD activity index (CDAI) scores correlated inversely with SOD in plasma (r = - 0.46; P = 0.0012), but not in saliva. No correlations were observed in respect to GPx activities in both plasma and saliva and CDAI. Higher activity of plasma SOD was observed in patients with inactive CD in comparison with active CD (P = 0.004). No significant differences in SOD and GPx activity both in plasma and saliva were found between CD remission group and the control group. We concluded that in active CD the antioxidant defence system was diminished and returned to normal values in remission. Results of SOD and GPx assays in saliva are not conclusive, suggesting that saliva seems to be not an appropriate material for further similar studies. PMID- 28011952 TI - Role of sensory afferent nerves, lipid peroxidation and antioxidative enzymes in the carbon monoxide-induced gastroprotection against stress ulcerogenesis. AB - Carbon monoxide (CO) is a physiological gaseous mediator recently implicated in the mechanism of gastric mucosal defense due to its vasodilatory and antioxidative properties. Small quantities of endogenous CO are produced during heme degradation by heme oxygenase (HO-1), however, the involvement of the capsaicin-sensitive afferent neurons releasing calcitonin gene related peptide (CGRP) and anti-oxidative factors and mechanisms in the CO-induced gastroprotection against stress ulcerogenesis has been little studied. We investigated the possible role of CO released from the CO donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) in the protection against water immersion and restraint stress (WRS)-induced lesions in rats with intact sensory nerves and those with capsaicin denervation and the accompanying changes in malondialdehyde (MDA) content considered as an index of lipid peroxidation, the activity of GSH and SOD-2 and gastric mucosal expression of antioxidative enzymes glutathione peroxidase (GPx) and SOD-2. Wistar rats with intact sensory nerves or those with capsaicin administered in total dose of 125 mg/kg s.c. within 3 days (capsaicin denervation) were pretreated either with 1) vehicle (saline) or 2) CORM-2 (0.1 - 0 mg/kg i.g.) with or without exogenous CGRP (10 MUg/kg i.p.) and 30 min later exposed to 3.5 h of WRS. At the termination of WRS, the number of gastric lesions was counted and gastric blood flow (GBF) was assessed by H2-gas clearance technique. The mucosal content of MDA and reduced glutathione (GSH) and the activity of SOD-2 were determined and the expression of GPx-1 and SOD-2 mRNA in the gastric mucosa was analyzed by real-time PCR. The exposure of rats to 3.5 h of WRS resulted in numerous hemorrhagic gastric lesions and significantly decreased the GBF, raised MDA content and significantly decreased the mucosal SOD and GSH contents compared with intact gastric mucosa and these changes were exacerbated in rats with capsaicin denervation. Pretreatment with CORM-2 (1 mg/kg i.g.) which in our previous studies significantly reduced the ethanol and aspirin induced gastric damage, significantly decreased the number of WRS-induced gastric lesions while raising the GBF and significantly increasing the activity of SOD and GSH (P < 0.05). The pretreatment with CORM-2 significantly decreased MDA content as compared with vehicle-pretreated rats exposed to WRS (P < 0.05). The reduction of WRS damage and the accompanying increase in the GBF as well as the significant decrease in MDA content and the increase in GSH content and SOD activity induced by CORM-2 (1 MUg/kg i.g.) were all significantly altered in rats with capsaicin denervation (P < 0.05). The concurrent treatment of CORM-2 with exogenous CGRP in rats with or without sensory nerves tended to decrease the number of WRS lesions as compared with CORM-2 alone pretreated animals and significantly increased the GBF over the values measured in gastric mucosa of CORM-2 alone pretreated rats with or without capsaicin denervation. Such combined administration of CORM-2 and CGRP in rats with capsaicin denervation significantly inhibited an increase in MDA and 4-HNE content and evoked a significant increase in the GSH concentration (P < 0.05) remaining without significant effect on the increase in SOD activity observed with CORM-2 alone. The gastric mucosal expression of SOD-2- and GPx-1 mRNA was significantly increased as compared with those in intact gastric mucosa (P < 0.05). The pretreatment with CORM-2 applied with or without CGRP failed to significantly alter the mRNA expression for SOD-2 and GPx in the gastric mucosa of rats exposed to WRS. Both, the expression of SOD-2- and GPx-1 mRNA was significantly increased in capsaicin denervated rats exposed to WRS rats (P < 0.05) and this effect was abolished by the pretreatment with CORM-2. The expression of SOD-2 tended to decrease, though insignificantly, in rats pretreated with the combination of CORM 2 and CGRP as compared with that detected in CORM-2 alone in rats with capsaicin denervation. In contrast, the mRNA expression of GPx-1 was significantly decreased in gastric mucosa of capsaicin-denervated rats treated with the combination of CORM-2 and CGRP as compared with CORM-2 alone pretreated animals. We conclude that 1) CORM-2 releasing CO exerts gastroprotective activity against stress ulcerogenesis and this effect depends upon an increase in the gastric microcirculation and the vasodilatory activity of this gaseous mediator, and 2) the sensory nerve endings releasing CGRP can contribute, at least in part, to the CO-induced gastric hyperemia, the attenuation of gastric mucosal lipid peroxidation and prevention of oxidative stress as indicated by the CORM-2 induced normalization of the antioxidative enzyme expression enhanced in gastric mucosa of capsaicin-denervated rats. PMID- 28011953 TI - Hyperventilation assists proarrhythmia development during delayed repolarization in clofilium-treated, anaesthetized, mechanically ventilated rabbits. AB - Hyperventilation reduces partial pressure of CO2 (PCO2) in the blood, which results in hypokalaemia. Hypokalaemia helps the development of the life threatening torsades de pointes type ventricular arrhythmia (TdP) evoked by repolarization delaying drugs. This implies that hyperventilation may assist the development of proarrhythmic events. Therefore, this study experimentally investigated the effect of hyperventilation on proarrhythmia development during delayed repolarization. Phenylephrine (an alpha1-adrenoceptor agonist) and clofilium (as a representative repolarization delaying agent inhibiting the rapid component of the delayed rectifier potassium current, IKr) were administered intravenously to pentobarbital-anaesthetized, mechanically ventilated, open chest rabbits. ECG was recorded, and the onset times and incidences of the arrhythmias were determined. Serum K+, pH and PCO2 were measured in arterial blood samples. Clofilium prolonged the rate corrected QT interval. TdP occurred in 15 animals (TdP+ group), and did not occur in 14 animals (TdP- group). We found a strong, positive, linear correlation between serum K+ and PCO2. There was no relationship between the occurrence of TdP and the baseline K+ and PCO2 values. However, a positive, linear correlation was found between the onset time of the first arrhythmias and the K+ and PCO2 values. The regression lines describing the relationship between PCO2 and onset time of first arrhythmias were parallel in the TdP+ and TdP- groups, but the same PCO2 resulted in earlier arrhythmia onset in the TdP+ group than in the TdP- group. We conclude that hyperventilation and hypocapnia with the resultant hypokalaemia assist the multifactorial process of proarrhythmia development during delayed repolarization. This implies that PCO2 and serum K+ should be controlled tightly during mechanical ventilation in experimental investigations and clinical settings when repolarization-delaying drugs are applied. PMID- 28011954 TI - New cationically modified pullulan attenuates atherogenesis and influences lipid metabolism in apoE-knockout mice. AB - Pullulan is a biocompatible polysaccharide obtained from black, yeast-like fungus Aureobasidium pullulans. This polymer is used to deliver various substances to the liver because of its specificity for this organ. Pullulan is internalized into hepatocytes in the process of asialoglycoprotein receptor mediated endocytosis. Recently, by reaction with glycidyltrimethylammonium chloride (GTMAC) we have successfully synthesized a cationically-modified pullulan (Pull GTMAC). Pull-GTMAC exhibits some unique beneficial effects not found for its native counterpart. In this article we have reported for the first time that Pull GTMAC administered orally to apoE-knockout mice (murine model of atherosclerosis) at a dose of 300 mg/kg b.w./day for 18 weeks showed anti-atherosclerotic activity reducing the area of atherosclerotic plaque. We have also found that Pull-GTMAC at a dose of 300 mg/kg b.w./day increases both the average daily mass of feces and the average number of droppings excreted by apoE(-/-) mouse in relation to the control sample derived from the mice fed with feed without the tested compound. However, the raw fat content in the feces of apoE-knockout mice was decreased in the group fed with the diet containing Pull-GTMAC towards control group of animals. Pull-GTMAC caused also statistically significant increase of mRNA level for LDL receptor in the apoE(-/-) mice liver after administration at a dose of 300 mg/kg/b.w./day for 18 weeks. However, the compound had no impact on lipid profile in serum of the tested mice. What is more, the studies on HepG2 cell line indicated an antiproliferative potential of cationically modified pullulan after 24 hour and 48 hour of incubation with the polysaccharide. In this paper we have shown for first time that cationically modified pullulan has antiatherogenic potential and influences on lipid metabolism. PMID- 28011955 TI - The protective effects of zinc in experimental gentamicin induced acute renal failure in rats. AB - This study investigates the effects of zinc in acute kidney injury induced by gentamicin (Ge). We used Wistar male rats distributed in 4 groups of 12 animals each, treated intraperitoneally as follows: Group I (Control) treated with distilled water; Group II (Ge) with experimental induced acute renal failure with Ge; Group III (Ge + Zn) administration of ZnCl2 in animals with experimental induced renal failure with Ge, Group IV (Zn) treated with ZnCl2 as positive control. We measured serum levels of urea, creatinine, total antioxidant status, superoxide dismutase, glutathione peroxidase and urinary proteins before the nephrotoxicity induction (baseline) and 3, 7 and 10 days after Ge administration. The renal histopathological analysis was also done. The results showed an increase of urea and creatinine values in Ge + Zn group after 7 days compared to baseline, but less accentuated than those in Ge group. Zn supplementation was associated with an increase of the total antioxidant status in Ge + Zn group compared to Ge group (P < 0.01). It was also revealed a significant reduction of proteinuria in Ge + Zn group compared to Ge group (P < 0.001). The histopathological investigation highlighted the tubular necrosis affecting more than 90% of proximal tubules in Ge group. In Ge + Zn group it was observed a milder degree of tubular necrosis (influencing less than 25% of proximal tubules), a moderate inflammation and the presence of tubular regeneration. In conclusion, Zn administration proved a to have a protective role in experimental gentamicin-induced acute renal failure. PMID- 28011956 TI - Repeated cures with paracetamol worsen sarcopenia in old rats with suboptimal food intake. AB - The availability of all amino acids is of prime importance to prevent the ageing associated decrease in skeletal muscle mass i.e. sarcopenia. Cysteine is the precursor of sulfate and glutathione that are both utilized in the liver to detoxify paracetamol (APAP). Cysteine availability could become limiting under repeated cures with APAP, especially when food intake is suboptimal. The aim of the study was to determine whether repeated cures with APAP could worsen sarcopenia. Twenty-two-month-old male Wistar rats received 3 two-week-long cures of APAP (1% of the diet) intercalated with washout periods of two weeks (APAP group). They were compared to untreated control rats euthanatized prior to the experiment (CT group) and rats pair-fed to the APAP group (PF group). Skeletal muscle mass and protein metabolism, as well as plasma amino acids and glutathione were assessed at the end of the third cure. APAP cures reduced food intake by 33, 23 and 33 % during the successive cures leading to an overall body weight loss of 8%. APAP rats lost lean mass during the experiment (-11%). This loss tended (P = 0.09) to be higher than in the PF group (-9%). The mass of hind limb muscles and the absolute synthesis rate of muscle proteins were 13 and 17% lower in the APAP group than the PF group, respectively. Plasma free cyst(e)ine (i.e. all free forms of cysteine not bound to proteins) and glutathione were 25% lower in the APAP group than the PF group. Repeated cures with APAP worsened sarcopenia in old rats with suboptimal food intake likely as a consequence of the APAP-induced shortage in cysteine/glutathione. Clinical studies are needed to clarify the effect of repeated treatments with paracetamol on skeletal muscle mass in older persons having suboptimal or insufficient dietary intakes. PMID- 28011957 TI - Effect of pulsed electromagnetic fields on endoplasmic reticulum stress. AB - The maintenance of protein homeostasis in the endoplasmic reticulum (ER) is crucial in cell life. Disruption of proteostasis results in ER stress that activates the unfolded protein response (UPR); a signalling network assigned to manage the accumulated misfolded or unfolded proteins. Prolonged or unresolved ER stress leads to apoptotic cell death that can be the basis of many serious diseases. Our aim was to study the effect of pulsed electromagnetic fields (PEMF), an alternative, non-invasive therapeutic method on ER stressed cell lines. First, the effect of PEMF treatment on the expression of ER stress markers was tested in three different cell lines. PEMF had no remarkable effect on ER stress protein levels in human embryonic kidney (HEK293T) and human liver carcinoma (HepG2) cell lines. However, the expression of BiP, Grp94 and CHOP were increased in HeLa cells upon PEMF exposure. Therefore, HepG2 cell line was selected for further experiments. Cells were stressed by tunicamycin and exposed to PEMF. Grp94, PDI, CHOP and PARP expression as markers of stress were monitored by Western blot and cell viability was also investigated. Tunicamycin treatment, as expected, increased the expression of Grp94, PDI, CHOP and inactivated PARP. Analysis of protein expression showed that PEMF was able to decrease the elevated level of ER chaperons Grp94, PDI and the apoptosis marker CHOP. The truncated, inactive form of PARP was also decreased. Accordingly, cell viability was also improved by PEMF exposure. These results indicate that PEMF is able to moderate ER stress induced by tunicamycin in HepG2 cells. However, our results clearly draw attention to that different cell lines may vary in the response to PEMF treatment. PMID- 28011958 TI - Cationic porphyrin-mediated photodynamic inactivation of Candida biofilms and the effect of miconazole. AB - The formation of biofilms by Candida and the increasing resistance of Candida species to antifungals contribute to the high recurrence rates of denture stomatitis. This increase has stimulated an interest in antimicrobial photodynamic therapy (aPDT) as an alternative treatment. We examined the photoactivity of the porphyrin-based photosensitizer, TMP-1363, against biofilms of C. albicans, C. glabrata, C. tropicalis and C. parapsilosis, and the effect of the combined use of miconazole and aPDT. Biofilms of three American Type Culture Collection (ATCC) strains and four clinical isolates developed on poly(methyl methacrylate) (PMMA) disks, were incubated with miconazole, followed by treatment with TMP-1363 for 30 min at 37 degrees C. The plates were exposed to broadband visible light at a distance of 10 cm to the plate, for 30 min (irradiance at the surface of the plate: 32.5 mW/cm2). The metabolic activity of the biofilms was measured by the XTT assay. ATCC strains and C. glabrata 7531/06 were not sensitive to TMP-aPDT, whereas the metabolic activities of the remaining three clinical isolates were reduced to 64.2 +/- 5.5% of controls. Miconazole at 25 MUg/ml decreased the viability of all strains except the ATTCC strain C. albicans MYA274; however its combination with aPDT was effective against this strain, suggesting a synergistic interaction. Effects of miconazole and aPDT on C. albicans MYA 2732, C. albicans 6122/06 were additive. With C. tropicalis and C. parapsilosis, the combined treatment had a higher, but not entirely additive, cytotoxic effect. The combined use of miconazole and TMP-aPDT is advantageous in the treatment of biofilms of a number of Candida species and strains, but not all. The molecular basis of this differential response is not known. PMID- 28011959 TI - The 2009 influenza A virus subtype H1N1 pandemic, a glance from Greece. AB - The 2009 influenza A - subtype H1N1 pandemic tested the public health care systems all around the globe, infecting millions and leading to thousands of deaths. Greece became the epidemic centre of the 2009 flu pandemic due to the low compliance of the general population towards the vaccination programme, the resistance acquired against antiviral drugs and the economic scenario at the time. Our study, after a thorough research in the "Medline/PubMed, Scopus, Google Scholars" medical databases, accompanied by a wide range search of medical literature from Greece, sought to have a closer look at the pandemic from a Greek perspective. Finally, we used as key words the terms: "2009, flu, influenza A - H1N1 virus, vaccine, pandemic, Greece". PMID- 28011960 TI - Visceral leishmaniasis in immunocompromised: diagnostic and therapeutic approach and evaluation of the recently released IDSA guidelines. AB - Visceral Leishmaniasis (VL) is a chronic infectious disease endemic in tropical and sub-tropical areas including the Mediterranean basin, caused by a group of protozoan parasites of the genus Leishmania and transmitted by phlebotomine sandflies. Typically, VL is classified as a zoonotic infection when Leishmania infantum is the causative agent and as an anthroponotic one when L. donovani is the causative agent. Immunocompromised patients, in particular HIV positive, are considered at risk of VL. They may present atypical signs and poor response to the treatment due to a compromission of T-helper and regulatory cells activity. Also pregnancy can be considered a condition predisposing to Leishmania reactivation and to the changes in immune response, due to a switch toward a Th2 response reported in this condition of the life. Laboratory diagnosis is based on microscopy for parasites detection on bone-marrow or spleen aspirates. Value of serology remains high in term of sensibility, but a positive test has to be confirmed by microscopy or molecular tests. Hypergammaglobulinemia and pancytopenia are the main alteration identified by blood examination. Treatment is based on use of liposomal amphotericin B (L-AmB) whose administration is associated to lower incidence of side effects, in respect to antimonials and other formulations of AmB. Use of Miltefosine needs further investigation when L. infantum is the causative agent. Relapses to treatment are observed in coinfected HIV patients. They can benefit of a second cycle, but cumulative efficacy of the treatment can be low. PMID- 28011961 TI - Genotypic analysis of HCV 1a by sequencing of the NS3 proteasic region in simeprevir therapy candidates. AB - Each phase of the HCV replication cycle can represent a therapy target. In fact, SIMEPREVIR (SMV) acts as NS3/4A protease inhibitor (PI); its efficacy is, however, reduced in HCV1a patients characterized by NS3Q80K polymorphism. The aim of this work was to design a genotypic analysis of NS3 protease in order to characterize viral quasispecies in HCV 1a patients before starting the SMV therapy. In all, 38 peripheral blood-EDTA samples were collected from patients infected with HCV 1a (RNA > 10,000 cp/ml). The samples were sequenced in a region of 543 nucleotides, codifying for 181 amino acids of the NS3 protease with ABI PRISM 3130xl Genetic Analyzer (Applied Biosystems). Of the 38 samples, two showed the Q80K mutation associated with resistance to SMV. In 16 samples mutations associated with a possible resistance to protease inhibitor, TELAPREVIR, were observed. Only one sample showed the T54S mutation, which is responsible for resistance to BOCEPREVIR, a protease inhibitor too. The data reported in this paper show a 5% prevalence of the Q80K mutation in HCV 1a patients. So far, some differences in the percentage of the Q80K mutations were observed within the European population, when compared with its US counterpart. The prevalence study described herein, albeit observed on a low number of samples, could challenge the recommendations reported in the technical data sheet of SMV. PMID- 28011962 TI - Tenofovir disoproxil fumarate monotherapy maintains HBV suppression achieved by a "de novo" combination of lamivudine-adefovir: a pilot study. AB - Chronic hepatitis B (CHB) treatment aims at long-term suppression of HBV replication and improvement in clinical outcomes. We describe the data of a pilot, non-profit study in which patients with CHB were treated with de novo combination lamivudine-adefovir (LAM-ADV) for at least four years with a view to HBV suppression and resistance prevention, and shifted to tenofovir (TDF) when new antiviral agents were available. Fifty-one HBeAg negative patients were enrolled. Histology was available for 39 patients and data of liver stiffness (LS) for 24 patients at baseline. Serum quantification of HBsAg and HBVDNA was obtained regularly during the follow-up. In 10 and 7 patients, a paired histology and LS were available at the end of LAM-ADV treatment, respectively. The de novo LAM-ADV combination was able to obtain HBVDNA suppression and ALT normalization in one year in most of the patients and in the second year in the remaining. Histology improved in patients with paired biopsy, but tissue HBsAg was present in all but one patient after 48 months of therapy. TDF maintained biochemical and virological response throughout the follow-up. Renal impairment during LAM-ADV therapy improved on shifting to TDF; only in 4 cases was a second shift to entecavir needed. TDF was safe and effective in maintaining HBV DNA suppression achieved by a long-term course of LAM-ADV de novo combination for the treatment of HBeAg-negative CHB. PMID- 28011963 TI - Comparison of the Elecsys HBsAg II Assay and the Architect Assay for Quantification of hepatitis B surface antigen in patients with chronic hepatitis B. AB - Quantitative hepatitis B surface antigen (HBsAg) is a valuable tool in hepatitis B virus (HBV) disease diagnosis and management for evaluating the effectiveness of antiviral therapy. The aim of the current research was to compare the performances of the Elecsys HBsAg II and Abbott Architect HBsAg assays in chronic hepatitis B (CHB) patients. Between May 2014 and December 2014, 72 CHBs were tested using Abbott Architect HBsAg QT and Roche Elecsys HBsAg II assay. After transformation to log (10) IU/mL, the results of the two assays were compared using the interclass correlation test, the Pearson correlation test and Bland Altman analyses. We also analyzed all the parameters in on-treatment patients and naive patients with Pearson correlation test. There was a significant overall correlation between the Elecsys and Architect assays. We also analyzed all the parameters in naive and on-treatment patients. There was a significantly good correlation between the two assays in untreated patients and on-treatment patients. In this study, there was a significant correlation between the results of the Elecsys HBsAg II and Abbott Architect HBsAg assays in the overall and naive/on-treatment CHB patients. Additionally, we found that mean HBsAg levels resulting from the Architect assay were higher than those obtained by Elecsys assay. PMID- 28011964 TI - Does antimicrobial usage before meningitis lead to a higher risk of adult postsurgical Acinetobacter baumannii meningitis than that of Enterobacteriaceae meningitis? AB - Acinetobacter baumannii and Enterobacteriaceae are two pathogens responsible for postneurosurgical meningitis. The aim of this retrospective study was to evaluate the factors that influenced the outcomes in patients with postneurosurgical meningitis caused by A. baumannii and Enterobacteriaceae. Patients with post surgical meningitis were identified from infection control committee charts between 2007 and 2015. Subjects over 16 years old who had positive cerebral spinal fluid cultures for A. baumannii or Enterobacteriaceae were enrolled in the study. Clinical and laboratory data for 30 patients with A. baumannii meningitis were compared with those of 12 patients with Enterobacteriaceae meningitis. The mean age of patients was 51.9 years and 57.1% were male. Eleven patients had comorbidities, the most common being diabetes mellitus. Most patients were due to intracranial haemorrhage (78.6%). The rate of the patients who received an appropriate antimicrobial therapy was 35.7%, and the crude mortality rate was 64.3%. In univariate analysis, previous antibiotic use, an infection before meningitis and mechanical ventilation had an increased risk of A. baumannii meningitis. Moreover, intrathecal antimicrobial use, inappropriate empirical antimicrobial use, antimicrobial resistance and alanine aminotransferase elevation were significantly higher in patients with A. baumannii meningitis than in those with Enterobacteriaceae meningitis. Antimicrobial use before meningitis (8.84 times) and mechanical ventilation (7.28 times) resulted in an increased risk of A. baumannii meningitis. None of the results affected 30-day mortality. Avoidance of unnecessarily prolonged antimicrobial usage may help to prevent a selection of A. baumannii. PMID- 28011965 TI - Are municipal solid waste collectors at increased risk of Hepatitis A Virus infection? A Greek cross-sectional study. AB - Municipal solid waste collectors are reportedly at risk for Hepatitis A virus infection (HAV) as an occupational hazard. We aimed to investigate the prevalence and possible risk factors of HAV infection among solid waste collectors in a municipality of the broader region of Attica, Greece. A cross-sectional sero prevalence study was conducted. Fifty (n=50) waste collectors participated in the study (response rate: 95%). The group of municipal waste collectors was compared to a convenient sample of workers not exposed to solid waste (n=83). Municipal solid waste collectors recorded a higher, but not statistically significant, prevalence of anti-HAV(+) in comparison to subjects without occupational exposure to waste (40% vs 34% respectively p=0,4). No significant associations were found between inappropriate work practices and anti- HAV (+). Education was the only factor independently associated with the risk of HAV infection. This study did not corroborate previous reports of an increased prevalence of Hepatitis A Virus infection among municipal solid waste collectors. PMID- 28011966 TI - Performance of real-time PCR Xpert (r)MTB/RIF in diagnosing extrapulmonary tuberculosis. AB - The real time PCR Xpert (r) MTB/RIF is fundamental for rapid diagnosis in paucibacillary respiratory samples and for the detection of multidrug-resistant TB cases. This paper aimed to determine its performance on different extrapulmonary samples. We determined sensitivity, specificity, positive and negative predictive value on respiratory and non-respiratory samples collected from January 2010 to June 2014. The protocol for the Xpert (r) MTB/RIF PCR suggested by Cepheid was strictly followed for all specimens. In 12257 respiratory samples we observed a sensitivity of 87.1% and a specificity of 99.9%. There were 2818 extrapulmonary specimens, of which 250 were followed by a positive culture for Mycobacterium tuberculosis complex, whereas 72 samples were culture-negative: tuberculosis was clinically confirmed in 71 of them and was excluded for one sample. The sensitivity of the test on urine, pus and CSF samples was 88.2%, 95.6% and 100% respectively. In contrast, the sensitivity of gastric aspirates and biopsies was 81.8% and 83.6% respectively, whereas results of total cavitary fluids were significantly worse than expected (53.7% sensitivity). Our experience shows that Xpert MTB/RIF assay is an accurate, sensitive, and specific test for the rapid detection of pulmonary and extra pulmonary TB with the only exception of cavitary fluids. PMID- 28011967 TI - Reduced wound infection in colorectal resection by using a wound auto-retractor. AB - Surgical site infection (SSI) remains an important problem in colorectal surgery. The aim of this study is to determine whether the use of a wound protection system can be effective in reducing the incidence of wound infection after colorectal resection. Ninety-five consecutive patients underwent colorectal resection, carried out by one single surgeon during a six-year period (2009 2015). A laparotomy auto-retractor was used in all cases (Alexis Wound Retractor; Applied Medical, Rancho Santa Margarita, CA). Forty-two resections (44%) were made by laparoscopy. Anastomoses for laparoscopic right colectomies, section of left colon and insertion of the anvil of CEEA for laparoscopic left colectomies were made extracorporeally. No colon cleansing was used in 67 patients (72%). The median age for those undergoing colectomy was 67 (range 41-90). The median Body Mass Index was 25.04 (range 18- 36.76). Three patients (3%) were operated on an emergency basis because of bowel obstruction or perforation. Fifty-three patients were classified ASA I-II (56%). There were six re-operations, for anastomotic dehiscence, peri-ostomal cellulitis and postoperative bleeding. The median postoperative stay was eight days (range 3-28). Only one patient (1%) developed wound infection. Due to the significantly reduced incidence of postoperative wound infection, this study suggests that the Alexis retractor be considered for routine use. PMID- 28011968 TI - Extended-Spectrum Beta Lactamase-producing Enterobacteriaceae among the pediatric population: who is at risk and why? Results from a single-centre prospective study. AB - A prospective 18-month case-control study was performed in a tertiary Paediatric Centre in Turin (Italy) to analyse the disease burden and identify risk factors for acquisition of Extended Spectrum Beta Lactamase-producing Enterobacteriaceae (ESBL-pE). Children with ESBL-pE isolation were enrolled as cases, with controls matched according to age, type of pathogen isolated and sample of isolation. Out of 83 children (37 males, mean age 4.7 +/- 5.46 years), 45 were identified as infected (54.2%) and 38 as colonised (45.8%) by ESBL-pE. Twenty-nine (64.4%) infectious disease episodes were categorised as community-acquired, 16 (35.6%) as healthcare-associated. Escherichia coli was the most frequently isolated pathogen (52, 62.7%) and the urinary tract the most frequent site involved (26, 57.9%). No deaths occurred, even in bloodstream infection cases. Hospitalisation and exposure to broad-spectrum penicillins and III/IV generation cephalosporins in the 90-day period before bacteria isolation were found to be independent risk factors at multivariate analysis. Immunodepression, prolonged central venous catheter (CVC) and urine catheter stay, and receiving a total parenteral nutrition (TPN) in the previous 30 days were otherwise recognized as potential risk factors at univariated analysis. ESBL-producing Enterobacteriaceae infections are a growing threat even in children. Careful recognition of patients at risk should promote targeted interventions in order to reduce the ESBL burden. PMID- 28011969 TI - Comparison of quinolone and beta-lactam resistance among Escherichia coli strains isolated from urinary tract infections. AB - The growing frequency of antibiotic resistances is now a universal problem. Increasing resistance to new generations of beta-lactam and quinolone antibiotics in multidrug-resistant Enterobacteriaceae isolates is considered an emergency health issue worldwide. The aim of this study was to evaluate plasmid-mediated quinolone resistance genes in ESBL-producing Escherichia coli isolated from urinary tract infections (UTIs). In our study ESBL-producing isolates were assessed by screening methods. After determination of antimicrobial susceptibility testing, detection of ESBLs and quinolone resistance genes was performed. A total of 97 ESBL-producing E. coli were determined. The bla-TEM, bla SHV and bla-CTX-M genes were detected in 90 isolates. The bla-TEM was the most frequently detected gene (46.4%), followed by bla-SHV (31.9%) and bla-CTX-M (14.4%). The most prevalent quinolone resistance gene among ESBL-producing isolates was oqxAB which was found in 67 isolates (69.1%). The frequencies of the aac(6')-Ib-cr, qnr and qepA were 65 (67%), 8 (8.2%) and 6 (6.2%), respectively. Our data indicate that the prevalence of plasmid-mediated quinolone resistance genes in ESBL-positive isolates is increasing. The co-dissemination of PMQR and ESBL genes among E. coli isolates can be considered a threat to public health. Therefore, prescription of antibiotics against infectious disease should be managed carefully. PMID- 28011970 TI - Zinc sulphate for acute bronchiolitis: A double-blind placebo-controlled trial. AB - The use of adjunctive therapies to achieve rapid recovery from clinical symptoms of acute bronchiolitis would appear necessary. This study was performed to determine the effect of zinc sulphate on treating acute bronchiolitis. In this study, 100 children affected with acute bronchiolitis were investigated. Fifty patients received oral zinc sulphate and 50 patients placebo. Signs and symptoms of the disease were compared between two groups at the time of admission and then 24, 48, 72, 96 and 120 hours after the beginning of treatment. The trend of recovery of clinical signs and symptoms was more favourable in the case group than in the control group in 24, 48, 72, 96 and 120 hours after beginning of the treatment. The significant differences were observed between the two groups in terms of improvements in coughing and wheezing 48 and 72 hours after the beginning of the treatment (P<0.05). Full recovery was observed in 49 (98%) patients receiving zinc sulphate within 72 hours of the beginning of treatment (P=0.0001). The present study showed that administration of zinc sulphate accelerates improvement from clinical signs and symptoms of acute bronchiolitis. Thus we recommend the use of zinc sulphate for the treatment of acute bronchiolitis. PMID- 28011971 TI - Tuberculous pericarditis: a case report. AB - Pericardial effusion is common disease and difficult to diagnose. Tuberculosis accounts for up to 4% of acute pericarditis and 7% of cardiac tamponade cases. Quick treatment can be lifesaving but requires accurate diagnosis. We report a case of a 65-year-old man who presented with a 3-week history of fever with chills, non-productive cough and dyspnea. The case was diagnosed by positivity of acid-fast staining, culture and polymerase chain reaction (PCR) of the aspirated pericardial fluid and treated promptly with antituberculosis drugs. The patient showed complete recovery. PMID- 28011972 TI - Four cases with Kawasaki disease and viral infection: aetiology or association. AB - The aetiology of Kawasaki disease has not yet been precisely determined. It has been associated with a variety of bacterial and viral agents. Some viruses including human adenovirus, coronavirus, and parainfluenza virus type 3 have been isolated from patients with Kawasaki disease. Clinical presentation of patients with human coronavirus and adenovirus infections mimics Kawasaki disease. In addition, these viruses may also be detected in Kawasaki disease as a coinfection. In this report, we present four Kawasaki disease patients infected with adenovirus, coronavirus OC43/HKU1 and parainfluenza virus type 3. PMID- 28011973 TI - Pulmonary and Vertebral Mycobacterium avium Disease in a HIV-negative 71-year-old Man - A Case Report. AB - Nontuberculous mycobacteria (NTM) caused pulmonary disease is on increase worldwide, especially in countries with decreasing time trend of tuberculosis incidence. NTM skeletal affection is rare. Mycobacterium avium related disease, with still unclear clinical and radiologic features, is in current focus of both clinicians and researchers. An exhausted severely ill 71-year-old man was admitted on emergency due to cough, dyspnea and lumbar back pain to be diagnosed with terminal phase M. avium disease. Three sputum smears were positive for acid fast bacilli and M. avium was identified with hybridization reaction by means of GenoType (r) MTBC (Hain). Apart from pulmonary disease, compressive fractures of the 12th thoracic and 1-4th lumbar vertebrae were detected. We found age, chronic alcoholism, previous professional exposure, tobacco smoking, chronic obstructive pulmonary disease and previous tuberculosis as risk factors for NTM disease in the HIV-negative patient. Despite combined antibiotic treatment, disease had lethal outcome. This case report might contribute to clinicians' awareness and improved knowledge on this sort of pathology, and lead to earlier diagnosis with possibly better disease outcome. PMID- 28011974 TI - Hospital management in patients with Dengue: what challenges do we face in Latin America? AB - Not available. PMID- 28011975 TI - Dental worm disease. AB - During human evolution, the period in which groups of humans stopped harvesting fruits and seeds growing wild and introduced the cultivation of cereals as well as the domestication of animals represents a very important event. This circumstance had a considerable impact on human pathocenosis, increasing the risk of infectious diseases of animal origin. The aim of this review was to summarise the archaeological and palaeo-pathological evidence in the literature concerning this topic. Starting from early prehistory (about 1.5 million years ago) up to the historical period, several authors have described the changes in human habits and the consequent changes in food supply, leading to the transition from a protein- to a carbohydrate-rich diet across a broad interval of time. This led to additional problems for human health. The increased accumulation of carbohydrate debris in the odonto-stomatological apparatus, without the appropriate use of hygiene in the oral cavity, increased the risk of infectious disease involving the mouth. Therefore, since the Neolithic period there has been a higher risk of tooth caries, abscesses, deep infection of the teeth roots, reaching also the mandibular and maxillary bone. Several hypotheses have been proposed by the distinct civilizations, which have alternated in the different ages, to explain the cause of these human health problems, including the idea that a "dental worm" could be involved in this process, such as in the Sumerian period. We describe and discuss further modifications of this theory, developed in Egypt, Assyria, Babylon, China, Greece, in Etruscan cities and in Rome in ancient times as well as in the Middle Ages, and the evolution of scientific thought on this topic in the past 300 years. In addition, the results of some palaeo-pathological studies, which were performed on human remains, such as the maxillary bone and teeth, mainly in different geographical areas in Italy, are examined and reported. PMID- 28011977 TI - Multivariate time series analysis on the dynamic relationship between Class B notifiable diseases and gross domestic product (GDP) in China. AB - The surveillance of infectious diseases is of great importance for disease control and prevention, and more attention should be paid to the Class B notifiable diseases in China. Meanwhile, according to the International Monetary Fund (IMF), the annual growth of Chinese gross domestic product (GDP) would decelerate below 7% after many years of soaring. Under such circumstances, this study aimed to answer what will happen to the incidence rates of infectious diseases in China if Chinese GDP growth remained below 7% in the next five years. Firstly, time plots and cross-correlation matrices were presented to illustrate the characteristics of data. Then, the multivariate time series (MTS) models were proposed to explore the dynamic relationship between incidence rates and GDP. Three kinds of MTS models, i.e., vector auto-regressive (VAR) model for original series, VAR model for differenced series and error-correction model (ECM), were considered in this study. The rank of error-correction term was taken as an indicator for model selection. Finally, our results suggested that four kinds of infectious diseases (epidemic hemorrhagic fever, pertussis, scarlet fever and syphilis) might need attention in China because their incidence rates have increased since the year 2010. PMID- 28011976 TI - Genetic Polymorphisms of SP-A, SP-B, and SP-D and Risk of Respiratory Distress Syndrome in Preterm Neonates. AB - BACKGROUND We examined selected polymorphisms in 3 pulmonary surfactant associated proteins (SP) for their influence on serum SP levels and risk of respiratory distress syndrome (RDS) in preterm neonates. MATERIAL AND METHODS Premature infants from a Han population were enrolled, including 100 premature infants with RDS (case group) and 120 premature infants without RDS (control group). SNP genotyping for SP-A (+186A/G and +655C/T), SP-B (-18A/C and 1580C/T), and SP-D (Met11ThrT/C and Ala160ThrG/A) used polymerase chain reaction restriction fragment length polymorphism. Haplotypes were calculated with Shesis software and serum SP-A/B/D levels were quantified by ELISA. RESULTS Case and control groups exhibited significant differences in genotype and allele frequencies of SP-A (+186A/G, +655C/T) and SP-B (1580C/T). However, no statistically significant differences were observed in the allele and genotype frequencies of SP-B -18A/C, SP-D Met11ThrT/C, and SP-D Ala160ThrG/A. Importantly, serum SP-A and SP-B levels were reduced in RDS patients carrying SP-A (+186A/G, +655C/T) and SP-B (1580C/T) polymorphisms. AA genotype of +186A/G, SP-A level, and CC genotype of 1580C/T were independently correlated with increased RDS risk. CONCLUSIONS SP-A (+186A/G) and SP-B (1580C/T) polymorphisms are strongly associated with the risk of RDS in preterm infants. Notably, reduced serum SP-A levels were correlated with a high risk of RDS and may serve as novel biomarkers for RDS detection and monitoring. PMID- 28011978 TI - What is the best tool for transanal endoscopic microsurgery (TEM)? A case-matched study in 74 patients comparing a standard platform and a disposable material. AB - PURPOSE: Transanal endoscopic microsurgery (TEM) is the gold standard for local excision of rectal lesions, but no study exists concerning the best material. The objective was to compare TEM using a disposable material vs a standard platform through a case-matched study. METHODS: Patients who underwent TEM for rectal neoplasms were identified from prospective databases in two tertiary referral centers and matched according to four criteria (sex, tumor location, size, distance from the anal verge): TEM using a disposable material (GelPoint Applied(r); group A) and TEM using a standard TEO(r) platform (Karl Storz, Tuttlingen, Germany; group B). RESULTS: A total of 74 patients were included and divided into group A (n = 33) and group B (n = 41). Full-thickness resection was less frequent in group A (85%) than B (100%; p = 0.01). Adenocarcinoma was less frequent in group A than B: 27 vs 42% (p = 0.03). No difference was noted regarding median operative time (53 vs 53 min; p = 0.6) and a peritoneal perforation rate (6 vs 20%; p = 0.17). Median length of stay was shorter in group A than B (4 vs 5 days; p < 0.008). No significant difference was noted for major morbidity (12 vs 10%; p = 0.66), R1 resection (21 vs 10%; p = 0.2), and recurrence rates (8 vs 7%; p = 0.62). No difference was noted for rectal stenosis (3 vs 12%; p = 0.22) and transit disorder rates (12 vs 17%; p = 0.74). CONCLUSIONS: Our study suggested that TEM can be performed using either a TEO(r) platform or a disposable material, with similar surgical results. The TEO(r) platform seems to be superior to obtain full-thickness and R0 resection. PMID- 28011979 TI - Clinical outcome of high-dose bolus intravenous interleukin-2 with a modified administration schedule for Asian patients with metastatic renal cell carcinoma. AB - PURPOSE: The standard regimen of high-dose interleukin-2 (HDIL-2) for metastatic renal cell carcinoma (RCC) is two cycles separated by 9 days, which constitutes one course. Each course is separated by an 8-12 weeks. However, the 9-day interval between each HDIL-2 cycle is often not long enough to allow recovery from adverse effects. Therefore, we modified HDIL-2 schedules by increasing the interval between each cycle without changing the total cumulative doses of IL-2. METHODS: Clinical data from 37 patients who were treated with modified HDIL-2 schedule were reviewed. Patients received the first dose of IL-2 on day 1 and took subsequent doses every 8 h for a maximum of 14 doses each cycle. Treatment was repeated every 4 weeks, and a maximum of six cycles were planned. RESULTS: The overall response rate was 35% including two patients with complete response. With a median follow-up duration of 46.9 months, median progression-free survival was 16.0 months (95% CI 10.2-21.7 months) and median overall survival was 58.9 months (95% CI 49.6-68.3 months) with a 3-year overall survival rate of 77.8%. Toxicity profile was acceptable and comparable to standard HDIL-2 schedule. There were no treatment-related mortalities. The incidence of >=grade 3 adverse events did not differ between patients who had prior exposure to vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) and VEGFR TKI-naive patients. CONCLUSION: Modified HDIL-2 schedule seems to be a safe and effective option for selected Asian patients with metastatic RCC, even in patients with prior VEGFR TKI treatment. PMID- 28011980 TI - Potential safety concerns of TLR4 antagonism with irinotecan: a preclinical observational report. AB - PURPOSE: Irinotecan-induced gut toxicity is mediated in part by Toll-Like receptor 4 (TLR4) signalling. The primary purpose of this preclinical study was to determine whether blocking TLR4 signalling by administering (-)-naloxone, a TLR4 antagonist, would improve irinotecan-induced gut toxicity. Our secondary aim was to determine the impact of (-)-naloxone on tumour growth. METHODS: Female Dark Agouti (DA) tumour-bearing rats were randomly assigned to four treatments (n = 6 in each); control, (-)-naloxone (100 mg/kg oral gavage at -2, 24, 48, and 72 h), irinotecan (175 mg/kg intraperitoneal at 0 h), and (-)-naloxone and irinotecan. Body weight and tumour growth were measured daily, and diarrhoea incidence and severity were recorded 4* per day up to 72 h post-treatment. RESULTS: At 72 h, all rats that received irinotecan lost weight compared to controls (p = 0.03). In addition, rats that received (-)-naloxone and irinotecan lost significantly more weight compared to controls (p < 0.005) than irinotecan only compared to controls (p = 0.001). (-)-Naloxone did not attenuate irinotecan induced severe diarrhoea at 48 and 72 h. Finally, (-)-naloxone caused increased tumour growth compared to control at 72 h (p < 0.05) and significantly reduced the efficacy of irinotecan (p = 0.001). CONCLUSIONS: (-)-Naloxone in our preclinical model was unable to block irinotecan-induced gut toxicity and decreased the efficacy of irinotecan. As (-)-naloxone-oxycodone combination is used for cancer pain, this may present a potential safety concern for patients receiving (-)-naloxone-oxycodone and irinotecan concurrently and requires further investigation. PMID- 28011982 TI - Histoplasma capsulatum in a peripheral blood smear in a non-HIV patient. PMID- 28011981 TI - Nicotine-induced enhancement of Pavlovian alcohol-seeking behavior in rats. AB - RATIONALE: Nicotine enhances responding elicited by Pavlovian cues that predict positive outcomes. OBJECTIVES: We tested the hypothesis that nicotine acting at nicotinic acetylcholine receptors (nAChRs) would augment Pavlovian alcohol seeking. METHODS: Male, Long-Evans rats with unrestricted access to food and water were acclimated to drinking 15% ethanol in their home cages and then given Pavlovian conditioning sessions in which each trial of a 15-s conditioned stimulus (CS, 12 trials/session) was paired with 0.2 ml of ethanol (unconditioned stimulus, US, 2.4 ml/session). Entries into a port where ethanol was delivered were used to assess conditioning. Control groups received explicitly unpaired trials of the CS and US. In experiment 1, systemic injections of saline (1 ml/kg) or nicotine (0.4 mg/kg, freebase) were administered before each session. In experiments 2 and 3, an identical regimen of saline or nicotine injections was administered before the start of Pavlovian conditioning sessions. RESULTS: All paired groups acquired conditioned port-entry responding to the CS, indicative of Pavlovian alcohol-seeking, whereas unpaired control group did not. Pre-session nicotine injections increased CS port-entries relative to saline, only in the paired group. This nicotine-induced enhancement of Pavlovian alcohol-seeking was blocked by pre-treatment with the nAChR antagonist mecamylamine. Prior exposure to nicotine did not influence the subsequent acquisition of Pavlovian alcohol seeking. CONCLUSIONS: These findings highlight for the first time that nicotine acting at nAChRs augments Pavlovian alcohol-seeking, specifically in non restricted rats. Individuals who smoke and drink may thus be particularly susceptible to alcohol cues that could trigger further drinking. PMID- 28011983 TI - Refractory plasmablastic lymphoma-a review of treatment options beyond standard therapy. AB - Plasmablastic lymphoma (PBL) is a rare distinct subtype of aggressive diffuse large B-cell lymphoma and a notoriously hard to treat entity with a dismal prognosis in both HIV-negative and HIV-positive patients. Clinicians often face the question of second or third line treatment. As the treatment options with novel agents in lymphomas are rapidly evolving, more and more options beyond standard chemotherapy are available. In connection with a review of treatment options with novel lymphoma agents, we present a case report of a patient with a complete remission after the administration of brentuximab vedotin and lenalidomide. PMID- 28011984 TI - Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: a bridge to reduced intensity conditioning transplant? AB - Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant. PMID- 28011985 TI - BeEAM conditioning with bendamustine-replacing BCNU before autologous transplantation is safe and effective in lymphoma patients. AB - BEAM with BCNU is commonly used for conditioning treatment followed by autologous stem cell transplantation (ASCT). However, pulmonary toxicity and availability issues associated with BCNU prompted us to evaluate bendamustine-replacing BCNU (BeEAM). We analyzed 39 lymphoma patients receiving BeEAM conditioning with 200 mg/m2 bendamustine at days -7 and -6. The median duration until neutrophil recovery was 11 days, and 15 days for platelet recovery (>20 g/L). The most common grade 3/4 non-hematologic toxicities comprised mucosal side effects (27 pts.). Pulmonary toxicity was observed in one patient (2.5%), and one patient died of septic complications. The CR rate increased from 33% to 74% 100 days after ASCT. After a median follow-up of 18.5 months, progression and death each occurred in 11 patients (28%). Median progression-free and overall survival at 2 years were 69% and 72%. Our data suggest that BeEAM conditioning using bendamustine is safe and results in promising survival rates. PMID- 28011987 TI - [Interprofessional collaboration of physicians and respiratory therapists : It is easier as a team]. PMID- 28011986 TI - Carotenoid intake and risk of non-Hodgkin lymphoma: a systematic review and dose response meta-analysis of observational studies. AB - Carotenoids may play a protective role in the development of non-Hodgkin lymphoma (NHL), but findings from epidemiological studies on the associations between carotenoid intake and NHL risk are inconsistent. We therefore performed a meta analysis to systemically evaluate the associations. Eligible studies were identified by a search of PubMed, Web of Science, Embase, and article reference lists. We pooled risk estimates from individual studies using a random-effect model to quantify the associations between intakes of specific carotenoids and NHL risk. A total of 10 (7 case-control and 3 cohort) studies met our inclusion criteria. In the highest versus lowest analyses, intakes of alpha-carotene, beta carotene, and lutein/zeaxanthin, but not lycopene or beta-cryptoxanthin, were associated with a significant reduced risk of NHL. The estimated summary relative risks (95% confidence intervals) for alpha-carotene, beta-carotene, and lutein/zeaxanthin were 0.87 (0.78-0.97), 0.80 (0.68-0.94), and 0.82 (0.69-0.97), respectively. Subgroup analyses showed that evidence supporting these protective associations was mostly based on studies with a case-control design. In addition, intakes of alpha-carotene and beta-carotene were associated with a significant decreased risk of diffuse large B-cell lymphoma, but not follicular lymphoma or small lymphocytic lymphoma/chronic lymphocytic leukemia. There was a significant inverse dose-response relationship between alpha-carotene intake and NHL risk (13% lower risk per 1000 MUg/day increment of intake). In conclusion, our findings suggest that higher intakes of alpha-carotene, beta-carotene, and lutein/zeaxanthin might protect against NHL development. Further cohort studies with a control of plausible confounding are needed to confirm these associations. PMID- 28011988 TI - Role of D-Dimer testing in venous thromboembolism with concomitant renal insufficiency in critical care. PMID- 28011989 TI - Right-left ventricular interdependence: a promising predictor of successful extracorporeal membrane oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock. PMID- 28011990 TI - The unmet need of information access for family members of ICU patients. PMID- 28011991 TI - Hair analysis for the biomonitoring of pesticide exposure: comparison with blood and urine in a rat model. AB - Urine and plasma have been used to date for the biomonitoring of exposure to pollutants and are still the preferred fluids for this purpose; however, these fluids mainly provide information on the short term and may present a high level of variability regarding pesticide concentrations, especially for nonpersistent compounds. Hair analysis may provide information about chronic exposure that is averaged over several months; therefore, this method has been proposed as an alternative to solely relying on these fluids. Although the possibility of detecting pesticides in hair has been demonstrated over the past few years, the unknown linkage between exposure and pesticides concentration in hair has limited the recognition of this matrix as a relevant tool for assessing human exposure. Based on a rat model in which there was controlled exposure to a mixture of pesticides composed of lindane, beta-hexachlorocyclohexane, beta-endosulfan, p,p' DDT, p,p'-DDE, dieldrin, pentachlorophenol, diazinon, chlorpyrifos, cyhalothrin, permethrin, cypermethrin, propiconazole, fipronil, oxadiazon, diflufenican, trifluralin, carbofuran, and propoxur, the current work demonstrates the association between exposure intensity and resulting pesticide concentration in hair. We also compared the results obtained from a hair analysis to urine and plasma collected from the same rats. Hair, blood, and urine were collected from rats submitted to 90-day exposure by gavage to the aforementioned mixture of common pesticides at different levels. We observed a linear relationship between exposure intensity and the concentration of pesticides in the rats' hair (R Pearson 0.453-0.978, p < 0.01). A comparison with results from urine and plasma samples demonstrated the relevance of hair analysis and, for many chemicals, its superiority over using fluids for differentiating animals from different groups and for re-attributing animals to their correct groups of exposure based on pesticide concentrations in the matrix. Therefore, this study strongly supports hair analysis as a reliable tool to be used during epidemiological studies to investigate exposure-associated adverse health effects. PMID- 28011993 TI - Putative orotate transporter of Cryptococcus neoformans, Oat1, is a member of the NCS1/PRT transporter super family and its loss causes attenuation of virulence. AB - It is well known that 5-fluoroorotic acid (5-FOA)-resistant mutants isolated from wild-type Cryptococcus neoformans are exclusively either ura3 or ura5 mutants. Unexpectedly, many of the 5-FOA-resistant mutants isolated in our selective regime were Ura+. We identified CNM00460 as the gene responsible for these mutations. Cnm00460 belongs to the nucleobase cation symporter 1/purine-related transporter (NCS1/PRT) super family of fungal transporters, representative members of which are uracil transporter, uridine transporter and allantoin transporter of Saccharomyces cerevisiae. Since the CNM00460 gene turned out to be involved in utilization of orotic acid, most probably as transporter, we designated this gene Orotic Acid Transporter 1 (OAT1). This is the first report of orotic acid transporter in this family. C. neoformans has four members of the NCS1/PRT family, including Cnm00460, Cnm02550, Cnj00690, and Cnn02280. Since the cnm02550? strain showed resistance to 5-fluorouridine, we concluded that CNM02550 encodes uridine permease and designated it URidine Permease 1 (URP1). We found that oat1 mutants were sensitive to 5-FOA in the medium containing proline as nitrogen source. A mutation in the GAT1 gene, a positive transcriptional regulator of genes under the control of nitrogen metabolite repression, in the genetic background of oat1 conferred the phenotype of weak resistance to 5-FOA even in the medium using proline as nitrogen source. Thus, we proposed the existence of another orotic acid utilization system (tentatively designated OAT2) whose expression is under the control of nitrogen metabolite repression at least in part. We found that the OAT1 gene is necessary for full pathogenic activity of C. neoformans var. neoformans. PMID- 28011992 TI - APPL1 prevents pancreatic beta cell death and inflammation by dampening NFkappaB activation in a mouse model of type 1 diabetes. AB - AIMS/HYPOTHESIS: Beta cell inflammation and demise is a feature of type 1 diabetes. The insulin-sensitising molecule 'adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1' (APPL1), which contains an NH2 terminal Bin/Amphiphysin/Rvs domain, a central pleckstrin homology domain and a COOH-terminal phosphotyrosine-binding domain, has been shown to modulate inflammatory response in various cell types but its role in regulating beta cell mass and inflammation in type 1 diabetes remains unknown. Thus, we investigated whether APPL1 prevents beta cell apoptosis and inflammation in diabetes. METHODS: Appl1-knockout mice and their wild-type littermates, as well as C57BL/6N mice injected with adeno-associated virus encoding APPL1 or green fluorescent protein, were treated with multiple-low-dose streptozotocin (MLDS) to induce experimental type 1 diabetes. Their glucose metabolism and beta cell function were assessed. The effect of APPL1 deficiency on beta cell function upon exposure to a diabetogenic cytokine cocktail (CKS; consisting of TNF-alpha, IL-1beta and IFN gamma) was assessed ex vivo. RESULTS: Expression of APPL1 was significantly reduced in pancreatic islets from mouse models of type 1 diabetes or islets treated with CKS. Hyperglycaemia, beta cell loss and insulitis induced by MLDS were exacerbated by genetic deletion of Appl1 but were alleviated by beta cell specific overexpression of APPL1. APPL1 preserved beta cell mass by reducing beta cell apoptosis upon treatment with MLDS. Mechanistically, APPL1 deficiency potentiate CKS-induced phosphorylation of NFkappaB inhibitor, alpha (IkappaBalpha) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFkappaB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFkappaB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. CONCLUSIONS/INTERPRETATION: APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFkappaB-iNOS-NO axis, representing a promising target for treating type 1 diabetes. PMID- 28011994 TI - Ecophysiological Response on Dehydration and Temperature in Terrestrial Klebsormidium (Streptophyta) Isolated from Biological Soil Crusts in Central European Grasslands and Forests. AB - The green algal genus Klebsormidium (Klebsormidiophyceae, Streptophyta) is a typical member of biological soil crusts (BSCs) worldwide. Ecophysiological studies focused so far on individual strains and thus gave only limited insight on the plasticity of this genus. In the present study, 21 Klebsormidium strains (K. dissectum, K. flaccidum, K. nitens, K. subtile) from temperate BSCs in Central European grassland and forest sites were investigated. Photosynthetic performance under desiccation and temperature stress was measured under identical controlled conditions. Photosynthesis decreased during desiccation within 335-505 min. After controlled rehydration, most isolates recovered, but with large variances between single strains and species. However, all K. dissectum strains had high recovery rates (>69%). All 21 Klebsormidium isolates exhibited the capability to grow under a wide temperature range. Except one strain, all others grew at 8.5 degrees C and four strains were even able to grow at 6.2 degrees C. Twenty out of 21 Klebsormidium isolates revealed an optimum growth temperature >17 degrees C, indicating psychrotrophic features. Growth rates at optimal temperatures varied between strains from 0.26 to 0.77 MU day-1. Integrating phylogeny and ecophysiological traits, we found no phylogenetic signal in the traits investigated. However, multivariate statistical analysis indicated an influence of the recovery rate and growth rate. The results demonstrate a high infraspecific and interspecific physiological plasticity, and thus wide ecophysiological ability to cope with strong environmental gradients. This might be the reason why members of the genus Klebsormidium successfully colonize terrestrial habitats worldwide. PMID- 28011995 TI - Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice. AB - Cytotoxic T lymphocyte (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL-based anticancer therapy has met with many challenges. Within tumor cells, there exist subpopulations with low or no expression of the targeted antigen (termed as antigen-loss variants). In addition, tumor cells can downregulate the levels of major histocompatibility complex class I (MHC-I) molecules on cell surface due to immune pressure. As a result, some tumor cells can escape the immune pressure bestowed by CTLs, resulting in treatment failure. To address these difficulties, a new approach is developed to deliver foreign high-affinity CTL epitopes to tumor tissues utilizing pH-responsive "smart" microparticles (MPs). These MPs could encapsulate CTL peptide epitope, release the peptide under acidic condition encountered in tumor tissues and enhance CTL activation. Mice bearing pre-established tumor as "antigen-loss variant" solid tumor models were administered intratumorally with MPs containing the CTL peptide, which showed 100% survival following the treatment. In contrast, all control mice died from tumor. Significant protection from tumor-induced death was also observed with systemic administration of CTL peptide-MPs. The therapeutic efficacy can be attributed to enhanced delivery of the epitope to tumor tissues, presentation of the epitope by tumor cells as well as tumor stromal cells and/or generation of epitope-specific CTLs by the peptide containing MPs. These findings offer a promising new direction for treating established solid tumor using CTL therapy. PMID- 28011996 TI - The kinase inhibitors R406 and GS-9973 impair T cell functions and macrophage mediated anti-tumor activity of rituximab in chronic lymphocytic leukemia patients. AB - Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients. This effect could not be ascribed to Syk-inhibition given that we show that T cells from CLL patients do not express Syk protein. Interestingly, zeta-chain-associated protein kinase (ZAP)-70 phosphorylation was diminished by both inhibitors upon TCR stimulation on T cells. In addition, we found that both agents reduced macrophage-mediated phagocytosis of rituximab-coated CLL cells. Overall, these results suggest that in CLL patients treated with R406 or GS-9973 T cell functions, as well as macrophage-mediated anti-tumor activity of rituximab, might be impaired. The potential consequences for CLL-treated patients are discussed. PMID- 28011998 TI - Can balneotherapy improve the bowel motility in chronically constipated middle aged and elderly patients? AB - Balneotherapy or spa therapy is usually known for different application forms of medicinal waters and its effects on the human body. Our purpose is to demonstrate the effect of balneotherapy on gastrointestinal motility. A total of 35 patients who were treated for osteoarthritis with balneotherapy from November 2013 through March 2015 at our hospital had a consultation at the general surgery for constipation and defecation disorders. Patients followed by constipation scores, short-form health survey (SF-12), and a colonic transit time (CTT) study before and after balneotherapy were included in this study, and the data of the patients were analyzed retrospectively. The constipation score, SF-12 score, and CTT were found statistically significant after balneotherapy (p < 0.05). The results of our study confirm the clinical finding that a 15-day course of balneotherapy with mineral water from a thermal spring (Bursa, Turkey) improves gastrointestinal motility and reduces laxative consumption in the management of constipation in middle-aged and elderly patients, and it is our belief that treatment with thermal mineral water could considerably improve the quality of life of these patients. PMID- 28011997 TI - Do salivary bypass tubes lower the incidence of pharyngocutaneous fistula following total laryngectomy? A retrospective analysis of predictive factors using multivariate analysis. AB - Salivary bypass tubes (SBT) are increasingly used to prevent pharyngocutaneous fistula (PCF) following laryngectomy and pharyngolaryngectomy. There is minimal evidence as to their efficacy and literature is limited. The aim of the study was to determine if SBT prevent PCF. The study was a multicentre retrospective case control series (level of evidence 3b). Patients who underwent laryngectomy or pharyngolaryngectomy for cancer or following cancer treatment between 2011 and 2014 were included in the study. The primary outcome was development of a PCF. Other variables recorded were age, sex, prior radiotherapy or chemoradiotherapy, prior tracheostomy, type of procedure, concurrent neck dissection, use of flap reconstruction, use of prophylactic antibiotics, the suture material used for the anastomosis, tumour T stage, histological margins, day one post-operative haemoglobin and whether a salivary bypass tube was used. Univariate and multivariate analysis were performed. A total of 199 patients were included and 24 received salivary bypass tubes. Fistula rates were 8.3% in the SBT group (2/24) and 24.6% in the control group (43/175). This was not statistically significant on univariate (p value 0.115) or multivariate analysis (p value 0.076). In addition, no other co-variables were found to be significant. No group has proven a benefit of salivary bypass tubes on multivariate analysis. The study was limited by a small case group, variations in tube duration and subjects given a tube may have been identified as high risk of fistula. Further prospective studies are warranted prior to recommendation of salivary bypass tubes following laryngectomy. PMID- 28011999 TI - Transcriptome response and developmental implications of RNAi-mediated ODC knockdown in tobacco. AB - Polyamines (PAs) are ubiquitously present polycationic compounds that play a critical role in various growth and developmental processes including stress responses in plants. Yet, their specific functions and mode of action remain largely unknown. In the present study, we have targeted tobacco ornithine decarboxylase gene (ODC) by RNA interference to modulate cellular PA levels and study the effects at different developmental time points. Down-regulation of ODC resulted in significant physiological and morphological anomalies including reduced leaf size, reduced chlorophyll and carotene content, decreased abiotic stress tolerance, early onset of senescence, delayed flowering, partial male and female sterility, reduced seed setting, delayed seed germination, reduced seed viability, and poor in vitro regeneration response from leaf explants. Also, for the first time, microarray analysis has been attempted to study genome-wide gene expression changes in response to lowered PA titers in an ODC knockdown line. A number of transcription factors, auxin- and ethylene-responsive genes, stress induced genes, lignin-biosynthesis genes, photosynthesis-related genes, senescence-associated genes, membrane proteins, and protein kinases were found to be affected, suggesting a probable list of PA-responsive genes. Transcriptome analysis has also indicated many genes, which could directly or indirectly be responsible for regulating the PA metabolic pathway. Various phenotypic changes observed upon ODC knockdown along with the identification of a number of gene targets means it is a step forward in envisaging possible mechanisms of PA action and for assigning them with specific roles in various developmental processes they are known to be a part of. PMID- 28012001 TI - Cell wall swelling, fracture mode, and the mechanical properties of cherry fruit skins are closely related. AB - MAIN CONCLUSION: Cell wall swelling, fracture mode (along the middle lamellae vs. across cell walls), stiffness, and pressure at fracture of the sweet cherry fruit skin are closely related. Skin cracking is a common phenomenon in many crops bearing fleshy fruit. The objectives were to investigate relationships between the mode of fracture, the extent of cell wall swelling, and the mechanical properties of the fruit skin using sweet cherry (Prunus avium) as a model. Cracking was induced by incubating whole fruit in deionised water or by fracturing exocarp segments (ESs) in biaxial tensile tests. The fracture mode of epidermal cells was investigated by light microscopy. In biaxial tensile tests, the anticlinal cell walls of the ES fractured predominantly across the cell walls (rather than along) and showed no cell wall swelling. In contrast, fruit incubated in water fractured predominantly along the anticlinal epidermal cell walls and the cell walls were swollen. Swelling of cell walls also occurred when ESs were incubated in malic acid, in hypertonic solutions of sucrose, or in water. Compared to the untreated controls, these treatments resulted in more frequent fractures along the cell walls, lower pressures at fracture (p fracture), and lower moduli of elasticity (E, i.e., less stiff). Conversely, compared to the untreated controls, incubating the ES in CaCl2 and in high concentrations of ethanol resulted in thinner cell walls, in less frequent fractures along the cell walls, higher E and p fracture. Our study demonstrates that fracture mode, stiffness, and pressure at fracture are closely related to cell wall swelling. A number of other factors, including cultivar, ripening stage, turgor, CaCl2, and malic acid, exert their effects only indirectly, i.e., by affecting cell wall swelling. PMID- 28012000 TI - Differential distribution and functional impact of BK channel beta1 subunits across mesenteric, coronary, and different cerebral arteries of the rat. AB - Large conductance, Ca2+i- and voltage-gated K+ (BK) channels regulate myogenic tone and, thus, arterial diameter. In smooth muscle (SM), BK channels include channel-forming alpha and auxiliary beta1 subunits. BK beta1 increases the channel's Ca2+ sensitivity, allowing BK channels to negatively feedback on depolarization-induced Ca2+ entry, oppose SM contraction and favor vasodilation. Thus, endothelial-independent vasodilation can be evoked though targeting of SM BK beta1 by endogenous ligands, including lithocholate (LCA). Here, we investigated the expression of BK beta1 across arteries of the cerebral and peripheral circulations, and the contribution of such expression to channel function and BK beta1-mediated vasodilation. Data demonstrate that endothelium independent, BK beta1-mediated vasodilation by LCA is larger in coronary (CA) and basilar (BA) arteries than in anterior cerebral (ACA), middle cerebral (MCA), posterior cerebral (PCA), and mesenteric (MA) arteries, all arterial segments having a similar diameter. Thus, differential dilation occurs in extracranial arteries which are subjected to similar vascular pressure (CA vs. MA) and in arteries that irrigate different brain regions (BA vs. ACA, MCA, and PCA). SM BK channels from BA and CA displayed increased basal activity and LCA responses, indicating increased BK beta1 functional presence. Indeed, in the absence of detectable changes in BK alpha, BA and CA myocytes showed an increased location of BK beta1 in the plasmalemma/subplasmalemma. Moreover, these myocytes distinctly showed increased BK beta1 messenger RNA (mRNA) levels. Supporting a major role of enhanced BK beta1 transcripts in artery dilation, LCA-induced dilation of MCA transfected with BK beta1 complementary DNA (cDNA) was as high as LCA-induced dilation of untransfected BA or CA. PMID- 28012002 TI - Diagnostic performance and factors influencing the accuracy of EUS-FNA of pancreatic neuroendocrine neoplasms. PMID- 28012003 TI - Effect of radial meniscal tear on in situ forces of meniscus and tibiofemoral relationship. AB - PURPOSE: To clarify the effect of the radial tear of the lateral meniscus on the in situ meniscus force and the tibiofemoral relationship under axial loads and valgus torques. METHODS: Ten intact porcine knees were settled to a 6-degree of freedom robotic system, while the force and 3-dimensional path of the knees were recorded via Universal Force Sensor (UFS) during 3 cycles of 250-N axial load and 5-Nm valgus torque at 15 degrees , 30 degrees , 45 degrees , and 60 degrees of knee flexion. The same examination was performed on the following 3 meniscal states sequentially; 33, 66, and 100% width of radial tears at the middle segment of the lateral meniscus, while recording the force and path of the knees via UFS. Finally, all paths were reproduced after total lateral meniscectomy and the in situ force of the lateral meniscus were calculated with the principle of superposition. RESULTS: The radial tear of 100% width significantly decreased the in situ force of the lateral meniscus and caused tibial medial shift and valgus rotation at 30 degrees -60 degrees of knee flexion in both testing protocols. Under a 250-N axial load at 60 degrees of knee flexion, the in situ force decreased to 36 +/- 29 N with 100% width of radial tear, which was 122 +/- 38 N in the intact state. Additionally, the tibia shifted medially by 2.1 +/- 0.9 mm and valgusrotated by 2.5 +/- 1.9 degrees with the complete radial tear. However, the radial tear of 33 or 66% width had little effect on either the in situ force or the tibial position. CONCLUSION: A radial tear of 100% width involving the rim significantly decreased the in situ force of the lateral meniscus and caused medial shift and valgus rotation of the tibia, whereas a radial tear of up to 66% width produced only little change. The clinical relevance is that loss of meniscal functions due to complete radial tear can lead to abnormal stress concentration in a focal area of cartilage and can increase the risk of osteoarthritis in the future. PMID- 28012004 TI - Post-operative deformation and extrusion of the discoid lateral meniscus following a partial meniscectomy with repair. AB - PURPOSE: The purpose of this study was to investigate the morphology of the discoid lateral meniscus sequentially following a partial meniscectomy with repair using magnetic resonance imaging (MRI). METHODS: Nine patients with a symptomatic discoid lateral meniscus with a peripheral tear were enrolled in this study, and a partial meniscectomy with repair was performed arthroscopically. An MRI examination was performed 2 weeks after surgery (before weight bearing was permitted) and again 6 months after surgery (when sporting activities could resume). The width, height and distance of the discoid lateral meniscus were measured. The distance was defined as the distance between the edges of the discoid lateral meniscus and the tibia. RESULTS: The width of the anterior, middle and posterior segments significantly decreased from 2 weeks to 6 months after surgery. The height of the middle and posterior segments significantly increased from 2 weeks to 6 months after surgery, whereas the height of the anterior segment did not significantly change. The distance of the anterior, middle and posterior segments significantly decreased from 2 weeks to 6 months after surgery. CONCLUSION: The discoid lateral meniscus exhibited deformation and extrusion from 2 weeks to 6 months after a partial meniscectomy with repair. Therefore, the function of load transmission might not be maintained appropriately after surgery. LEVEL OF EVIDENCE: IV. PMID- 28012006 TI - Diabetes and nephrotic syndrome: Answers. PMID- 28012005 TI - Primary non-surgical management of unilateral ureteropelvic junction obstruction in children: a systematic review. AB - Ureteropelvic junction obstruction (UPJO) is the most common obstructive uropathy and its optimal management remains controversial. However, there is a current trend towards non-surgical management. We aimed to determine the effects of the non-surgical management in children with unilateral UPJO. For a systematic review, we searched MEDLINE, EMBASE, CENTRAL, clinical trials registries, and selected conference proceedings for eligible studies. Any type of study reporting the outcomes renal function, secondary surgical intervention, drainage pattern or hydronephrosis of non-surgical management in children with unilateral UPJO was included. Data from 20 studies were extracted and evaluated by two independent authors. The pooled prevalence was 21% for split renal function deterioration, 27.9% for secondary surgical intervention, 3.2% for progressive hydronephrosis, and 82.2% for improved drainage pattern. Not all patients with surgical intervention regained split renal function from enrolment. Renal imaging methods did not strongly correlate with each other. Many studies had to be excluded because of a lack of detection of an obstruction or mixed populations with bilateral UPJO or other uropathies. The variable definitions of UPJO, different criteria for surgical intervention, incongruity of management protocols, and the imprecise reporting of outcomes were limiting factors in the comparability of the results, leading to heterogeneity in meta-analyses. Although the available evidence cannot recommend or refute the current non-surgical management, the systematic review clarifies aspects of the ongoing controversy by providing realistic estimates for non-surgical management in children with unilateral UPJO. Additionally, it reveals unclear potential risks, particularly for long-term outcomes, which were rarely reported. PMID- 28012007 TI - Long-term health-related quality of life and psychological adjustment in children after haemolytic-uraemic syndrome. AB - BACKGROUND: In children after haemolytic-uraemic syndrome (HUS), little is known about long-term health-related quality of life (HRQoL) and psychological adjustment as defined by behavioural problems, depressive symptoms and post traumatic stress symptoms. METHODS: Sixty-two paediatric patients with a history of HUS were included in this study. Medical data of the acute HUS episode were retrieved retrospectively from hospital records. Data on the clinical course at study investigation were assessed by clinical examination and laboratory evaluation. HRQoL and psychological adjustment data were measured by standardised, parent- and self-reported questionnaires. RESULTS: Haemolytic uraemic syndrome was diagnosed at a mean of 6.5 years before the initiation of the study (standard deviation 2.9, range 0.1-15.7) years. Among the preschool children, parents reported that their child was less lively and energetic (HRQoL emotional dimension), while no increased behavioural problems were reported. In the school-age children, self- and proxy-reported HRQoL was well within or even above the norms, while increased total behavioural problems were found. The school-age children reported no increased depression scores. Also none of the children met the criteria for full or partial HUS-associated posttraumatic stress disorder. CONCLUSIONS: Healthcare providers should be particularly alert to behavioural problems in school-age children with a history of HUS and to lower HRQoL in preschool children. PMID- 28012008 TI - Bivariate genome-wide association analyses identified genetic pleiotropic effects for bone mineral density and alcohol drinking in Caucasians. AB - Several studies indicated bone mineral density (BMD) and alcohol intake might share common genetic factors. The study aimed to explore potential SNPs/genes related to both phenotypes in US Caucasians at the genome-wide level. A bivariate genome-wide association study (GWAS) was performed in 2069 unrelated participants. Regular drinking was graded as 1, 2, 3, 4, 5, or 6, representing drinking alcohol never, less than once, once or twice, three to six times, seven to ten times, or more than ten times per week respectively. Hip, spine, and whole body BMDs were measured. The bivariate GWAS was conducted on the basis of a bivariate linear regression model. Sex-stratified association analyses were performed in the male and female subgroups. In males, the most significant association signal was detected in SNP rs685395 in DYNC2H1 with bivariate spine BMD and alcohol drinking (P = 1.94 * 10-8). SNP rs685395 and five other SNPs, rs657752, rs614902, rs682851, rs626330, and rs689295, located in the same haplotype block in DYNC2H1 were the top ten most significant SNPs in the bivariate GWAS in males. Additionally, two SNPs in GRIK4 in males and three SNPs in OPRM1 in females were suggestively associated with BMDs (of the hip, spine, and whole body) and alcohol drinking. Nine SNPs in IL1RN were only suggestively associated with female whole body BMD and alcohol drinking. Our study indicated that DYNC2H1 may contribute to the genetic mechanisms of both spine BMD and alcohol drinking in male Caucasians. Moreover, our study suggested potential pleiotropic roles of OPRM1 and IL1RN in females and GRIK4 in males underlying variation of both BMD and alcohol drinking. PMID- 28012009 TI - Hydrolase BioH knockout in E. coli enables efficient fatty acid methyl ester bioprocessing. AB - Fatty acid methyl esters (FAMEs) originating from plant oils are most interesting renewable feedstocks for biofuels and bio-based materials. FAMEs can also be produced and/or functionalized by engineered microbes to give access to, e.g., polymer building blocks. Yet, they are often subject to hydrolysis yielding free fatty acids, which typically are degraded by microbes. We identified BioH as the key enzyme responsible for the hydrolysis of medium-chain length FAME derivatives in different E. coli K-12 strains. E. coli DeltabioH strains showed up to 22-fold reduced FAME hydrolysis rates in comparison with respective wild-type strains. Knockout strains showed, beside the expected biotin auxotrophy, unchanged growth behavior and biocatalytic activity. Thus, high specific rates (~80 U g CDW-1 ) for terminal FAME oxyfunctionalization catalyzed by a recombinant alkane monooxygenase could be combined with reduced hydrolysis. Biotransformations in process-relevant two-liquid phase systems profited from reduced fatty acid accumulation and/or reduced substrate loss via free fatty acid metabolization. The BioH knockout strategy was beneficial in all tested strains, although its effect was found to differ according to specific strain properties, such as FAME hydrolysis and FFA degradation activities. BioH or functional analogs can be found in virtually all microorganisms, making bioH deletion a broadly applicable strategy for efficient microbial bioprocessing involving FAMEs. PMID- 28012010 TI - Assessment of HCV genotypes in Yunnan Province of Southwest China. AB - Recently, we reported that the frequency of hepatitis C virus (HCV) genotypes and subtypes has rapidly changed among intravenous drug users (IDUs) in Yunnan Province over the last 5 years; this is especially true for subtype 6a which has increased in frequency from 5 to 15%. Here, we assessed 120 HCV-positive plasma samples from the general population (GP). HCV NS5B fragments were amplified and sequenced by PCR. We identified four HCV genotypes (1, 2, 3 and 6) and seven HCV subtypes (1b, 2a, 3a, 3b, 6a, 6n, and 6k) in this population. Genotype 3 was predominant, with a distribution frequency of 0.484, followed by genotype 1 (0.283), genotype 6 (0.133) and genotype 2 (0.100). HCV subtypes 3b (frequency 0.292) and 1b (frequency 0.283) were the most common subtypes. A comparison of the current data with previous results reported for IDUs showed that the distribution frequencies of genotypes 1, 2 and 6 were significantly different between patients in the GP and IDUs (P < 0.05). Among the HCV subtypes, the distribution frequencies of 1b, 2a, 6a, and 6n were significantly different between patients in the GP and IDU groups (P < 0.05). Moreover, Phylogenetic analyses showed that HCV subtype 6a strains isolated from IDUs and the GP were intermixed and not separately clustered. HCV subtype 6a was predominant not only among IDUs but also among those in the GP in the Guangdong Province and Vietnam. However, HCV subtype 6a was predominant only among IDUs and not among those in the GP in the Yunnan and Guangxi Provinces. Our results indicate that the HCV subtype 6a could rapidly spread across China. PMID- 28012011 TI - Molecular characterization of a distinct monopartite begomovirus associated with betasatellites and alphasatellites infecting Pisum sativum in Nepal. AB - Pea (Pisum sativum) plants exhibiting leaf distortion, yellowing, stunted growth and reduction in leaf size from Rampur, Nepal were shown to be infected by a begomovirus in association with betasatellites and alphasatellites. The begomovirus associated with the disease showed only low levels of nucleotide sequence identity (<91%) to previously characterized begomoviruses. This finding indicates that the pea samples were infected with an as yet undescribed begomovirus for which the name Pea leaf distortion virus (PLDV) is proposed. Two species of betasatellite were identified in association with PLDV. One group of sequences had high (>78%) nucleotide sequence identity to isolates of Ludwigia leaf distortion betasatellite (LuLDB), and the second group had less than 78% to all other betasatellite sequences. This showed PLDV to be associated with either LuLDB or a previously undescribed betasatellite for which the name Pea leaf distortion betasatellite is proposed. Two types of alphasatellites were identified in the PLDV-infected pea plants. The first type showed high levels of sequence identity to Ageratum yellow vein alphasatellite, and the second type showed high levels of identity to isolates of Sida yellow vein China alphasatellite. These are the first begomovirus, betasatellites and alphasatellites isolated from pea. PMID- 28012012 TI - The influence of PEEP and positioning on central venous pressure and venous hepatic hemodynamics in patients undergoing liver resection. AB - PURPOSE: In order to assess the occurrence of blood congestion in the liver during liver resection, we aimed to evaluate the influence of a positive-end expiratory-pressure (PEEP) and positioning of patients on central venous pressure (CVP) and venous hepatic blood flow parameters. We further analyzed correlations between CVP and venous hepatic blood flow parameters. METHODS: In 20 patients scheduled for elective liver resection we measured CVP and quantified venous hepatic hemodynamics by ultrasound assessment of flow-velocity and diameter of the right hepatic vein and the portal vein after equilibration following these maneuvers: M1: 0 degrees supine position, PEEP 0 cmH2O; M2: 0 degrees supine position, PEEP 10 cmH2O; M3: 20 degrees reverse-trendelenburg position; PEEP 10 cmH2O; M4: 20 degrees reverse-trendelenburg position, PEEP 0cmH2O. RESULTS: Changing from supine to reverse-trendelenburg position led to a significant decrease in CVP (M3 5.95 +/- 2.06 vs. M1 7.35 +/- 2.18 mmHg and M2 8.55 +/- 1.79 mmHg). A PEEP of 10 cmH2O and reverse-trendelenburg position led to significant reduction of systolic (VsHV) and diastolic (VdHV) flow-velocities of the right hepatic vein (VsHV M3 19.96 +/- 6.47 vs. M1 27.81 +/- 11.03 cm s-1;VdHV M3 14.94 +/- 6.22 vs. M1 20.15 +/- 10.34 cm s-1 and M2 20.19 +/- 13.19 cm s-1) whereas no significant changes of flow-velocity occurred in the portal vein. No correlations between CVP and diameters or flow-velocities of the right hepatic and the portal vein were found. CONCLUSIONS: Changes of central venous pressure due to changes of PEEP and positioning were not correlated with changes of venous hepatic blood flow parameters as measured after equilibration. Strategies aiming for low central venous pressure cannot be supported by these results. However, before ruling out low-CVP-strategies during liver resections these results should be confirmed by further studies. PMID- 28012013 TI - Ventilation/perfusion ratio and right to left shunt in healthy newborn infants. AB - Oxygenation impairment can be assessed non-invasively by determining the degree of right-to-left shunt and ventilation/perfusion (VA/Q) inequality. These indices have been used in sick newborn infants, but normative values have not been reported which are essential to determine the magnitude of the abnormality. We, therefore, aimed to measure the shunt and VA/Q in infants with no history of respiratory conditions and determine if there was any effect of supine or prone position and the reproducibility of the data. Data were analysed from infants who had undergone a hypoxic challenge and in a subset who had been assessed in the supine or prone position. Transcutaneous oxygen saturations (SpO2) were recorded at fractions of inspired oxygen (FIO2) of 0.21 and 0.15. Two independent raters used a computer software algorithm which analysed and fitted paired data for FIO2 and SpO2 and derived a curve which represented the best fit for each infant's data and calculated the shunt and VA/Q. The raters ability to interpret the SpO2 value which corresponded to a given FIO2 was compared. The downwards displacement of the FIO2 versus SpO2 curve was used to estimate the degree of right-to-left shunt and the rightwards shift of the curve was used to calculate the VA/Q ratio. The mean (SD) gestational age of the 145 infants was 39 (1.6) weeks, their birth weight was 2990 (578) gms and median (range) postnatal age at measurement 3 (1-8) days. The mean (SD) VA/Q ratio was 0.95 (0.21). None of the infants had a right to-left shunt. No significant differences were found in VA/Q in the supine compared to the prone position. The intraclass correlation coefficient of VA/Q between two independent raters was 0.968 (95% CI 0.947-0.980), p < 0.001. Right to-left shunt and VA/Q ratio in healthy newborn infants were similar in the prone compared to the supine position. PMID- 28012014 TI - Analysis of the expression of human bitter taste receptors in extraoral tissues. AB - The 25 bitter taste receptors (T2Rs) in humans perform a chemosensory function. However, very little is known about the level of expression of these receptors in different tissues. In this study, using nCounter gene expression we analyzed the expression patterns of human TAS2R transcripts in cystic fibrosis bronchial epithelial (CuFi-1), normal bronchial epithelial (NuLi-1), airway smooth muscle (ASM), pulmonary artery smooth muscle (PASM), mammary epithelial, and breast cancer cells. Our results suggest a specific pattern of TAS2R expression with TAS2R3, 4, 5, 10, 13, 19, and 50 transcripts expressed at moderate levels and TAS2R14 and TAS2R20 (or TASR49) at high levels in the various tissues analyzed. This pattern of expression is mostly independent of tissue origin and the pathological state, except in cancer cells. To elucidate the expression at the protein level, we pursued flow cytometry analysis of select T2Rs from CuFi-1 and NuLi-1 cells. The expression levels observed at the gene level by nCounter analysis correlate with the protein levels for the T2Rs analyzed. Next, to assess the functionality of the expressed T2Rs in these cells, we pursued functional assays measuring intracellular calcium mobilization after stimulation with the bitter compound quinine. Using PLC inhibitor, U-73122, we show that the calcium mobilized in these cells predominantly takes place through the Quinine-T2R Galphabetagamma-PLC pathway. This report will accelerate studies aimed at analyzing the pathophysiological function of T2Rs in different extraoral tissues. PMID- 28012015 TI - Modulation of cell death in human colorectal and breast cancer cells through a manganese chelate by involving GSH with intracellular p53 status. AB - Chemotherapy is central to current treatment modality especially for advanced and metastatic colorectal and breast cancers. Targeting the key molecular events of the neoplastic cells may open a possibility to treat cancer. Although some improvements in understanding of colorectal and breast cancer treatment have been recorded, the involvement of glutathione (GSH) and dependency of p53 status on the modulation of GSH-mediated treatment efficacy have been largely overlooked. Herein, we tried to decipher the underlying mechanism of the action of Mn-N-(2 hydroxyacetophenone) glycinate (MnNG) against differential p53 status bearing Hct116, MCF-7, and MDA-MB-468 cells on the backdrop of intracellular GSH level and reveal the role of p53 status in modulating GSH-dependant abrogation of MnNG induced apoptosis in these cancer cells. Present study discloses that MnNG targets specifically wild-type-p53 expressing Hct116 and MCF-7 cells by significantly depleting both cytosolic, mitochondrial GSH, and modulating nuclear GSH through Glutathione reductase and Glutamate-cysteine ligase depletion that may in turn induce p53-mediated intrinsic apoptosis in them. Thus GSH addition abrogates p53-mediated apoptosis in wild-type-p53 expressing cells. GSH addition also overrides MnNG-induced modulation of phase II detoxifying parameters in them. However, GSH addition partially replenishes the down-regulated or modulated GSH pool in cytosol, mitochondria, and nucleus, and relatively abrogates MnNG induced intrinsic apoptosis in p53-mutated MDA-MB-468 cells. On the contrary, although MnNG induces significant cell death in p53-null Hct116 cells, GSH addition fails to negate MnNG-induced cell death. Thus p53 status with intracellular GSH is critical for the modulation of MnNG-induced apoptosis. PMID- 28012016 TI - The ferredoxin-dependent glutamate synthase (OsFd-GOGAT) participates in leaf senescence and the nitrogen remobilization in rice. AB - Ferredoxin-dependent glutamate synthase (Fd-GOGAT, EC 1.4.7.1) plays major roles in photorespiration and primary nitrogen assimilation. However, due to no mutant or knockdown lines of OsFd-GOGAT have been reported in rice (Oryza sativa L.), the contribution of OsFd-GOGAT to rice foliar nitrogen metabolism remains little up-to-date. Here, we isolated a rice premature leaf senescence mutant named gogat1, which was reduced in 67% of the total GOGAT enzyme activity in leaves. The gogat1 mutant exhibited chlorosis under natural condition, while showed less extent premature leaf senescence under low light treatment. The gogat1 locus was mapped to a 54.1 kb region on chromosome 7, and the sequencing of OsFd-GOGAT showed one substitution (A to T) at the 3017th nucleotide of the open reading frame, leading to the amino-acid substitution of leucine changed to histidine. The gogat1 mutant showed reduced seed setting rate, while the grain protein content in gogat1 mutant was significantly higher than that in wild type. Meanwhile, during the grain-filling stage, total amino acids in the up three leaves and the upmost internode were increased dramatically. The results in this study suggested that OsFd-GOGAT might participate in nitrogen remobilization during leaf senescence, which provides a potential way to improve nitrogen use efficiency in rice. PMID- 28012017 TI - Surgical exploration in persistent inferior oblique overactions. AB - PURPOSE: To report the causes of persistent inferior oblique (IO) overactions after disinsertion procedure. METHODS: Surgical findings of nine eyes of eight patients who needed secondary surgery to the IO muscles because of persistent overaction after IO disinsertion were evaluated retrospectively. Inferior obliques were found partially retracted into their sheath, and some parts of the proximal muscle stumps were found to have established attachments through scar tissues to the sclera in five eyes. They were totally in the subtenon space, reattached to the sclera in the three eyes and were found untouched; inferior rectus was disinserted instead of IO muscle, in the last eye. Proximal terminals of the IOs were isolated, dissected from its sheath and from other fascial attachments. The muscle stump pushed out of subtenon's space through its Tenon's sheath after 5-8 mm myectomy and cauterization to prevent any direct or indirect contact between the muscle and sclera. RESULTS: Persistent overactions of IO muscles were resolved in all cases and did not return in any case in the follow up period of 4 months to 6 years. CONCLUSIONS: Persistent overaction of IO muscle after disinsertion usually results from insufficient retraction of the muscle from the subtenon's space. It can be both prevented and managed by complete dissection of the IO muscle from its all fascial attachments and pushing the proximal terminal of the muscle completely out of subtenon's space through its sheath traversing Tenon's capsule after a segment myectomy and cauterization. PMID- 28012018 TI - Bilateral insufficiency hip fractures after bariatric surgery. AB - Bariatric surgery is one of the most common surgeries within developed countries due to the increase in morbid obesity that has been observed in the past decades. The short-term alterations in the metabolism of calcium and vitamin D are well known after these procedures; however, the clinical and biochemical consequences may not be detected for years or even remain undiagnosed. We present the first case of bilateral insufficiency hip fracture after years of bariatric surgery. Although this is a long-term and rare complication, with the high number of gastric bypass performed in the past years, the number of these cases could increase with time. Moreover, it is important as an undiagnosed hip fracture can cause a displacement that could need an arthroplasty, with all the complications that entails. For that reason, this long-term complication highlights the need to reevaluate the optimal follow-up of these patients and the importance to continue monitoring metabolic bone diseases in the prevention of insufficiency fractures. PMID- 28012020 TI - Product safety spillovers and market viability for biologic drugs. AB - When a pharmaceutical manufacturer experiences a safety problem, negative impacts on profitability can spread to its competitors. Reduced consumer confidence, product recalls, and litigation are limited to the responsible manufacturer only if that manufacturer can be clearly linked to the safety problem. We analyze the impact of "accountability" for safety problems on manufacturer entry decisions and investments to mitigate risk. Consistent with prior research, we find investment levels increase with accountability in a duopoly market, and that accountability can thus enhance market viability and improve consumer welfare. However, we also analyze the impact of accountability on entry of a competitor, after the originator's exclusivity has expired. Accountability promotes the development of a robust market by raising expected profits, particularly for an entrant with a relatively low likelihood of a safety problem. Yet entry need not improve consumer welfare, and may benefit the incumbent in our model. In contrast to the traditional entry deterrence mechanism, when accountability is sufficiently low, increased incumbent investment encourages entry. Our analysis has important implications for biologic drugs, insofar as pathways for entry by "biosimilars" have been established in Europe and the United States, and informs pharmacovigilance and other accountability policies for biologics. PMID- 28012019 TI - Birmingham epidermolysis severity score and vitamin D status are associated with low BMD in children with epidermolysis bullosa. AB - : Bone status impairment represents a complication of generalized forms of epidermolysis bullosa (EB); however, the prevalence and the main determinants of this event in localized forms remain poorly defined. Birmingham epidermolysis bullosa severity (BEBS) score and 25-hydroxyvitamin D levels are strongly associated with low bone mass, suggesting that vitamin D may play a potential beneficial role in bone health. Further longitudinal studies are needed in order to confirm this hypothesis. INTRODUCTION: Bone status impairment represents a complication of generalized forms of EB; thus, we aimed to estimate the prevalence of low bone mass, to examine mineralization differences in various EB subtypes and to identify the most important determinants of bone impairment in children with either generalized or localized EB. METHODS: An observational study of 20 children (11 males; mean age +/- standard deviation, 11.7 +/- 3.9 years) with EB was performed. Clinical history, physical examination, laboratory studies, X-ray of the left hand and wrist for bone age, and dual energy X-ray absorptiometry scans of the lumbar spine were obtained. Areal bone mineral density (aBMD Z-scores) and bone mineral apparent density were related to the BEBS score. RESULTS: Areal BMD Z-score (mean -1.82 +/- 2.33, range, -7.6-1.7) was reduced (<-2 SD) in 8 patients (40%), whereas aBMD Z-score adjusted for bone age was low in 7 patients (35%). BEBS score and 25-hydroxyvitamin D serum levels were the most important elements associated with aBMD (P = 0.0001 and P = 0.016, respectively). A significant correlation between the aBMD Z-score and area of skin damage, insulin-like growth factor-1, C-reactive protein, and sodium serum levels was also found. CONCLUSIONS: Low aBMD can be considered a systemic complication of EB, primarily associated with BEBS score and 25-hydroxyvitamin D levels. Therefore, longitudinal evaluation of bone status is ongoing in these patients to define whether vitamin D supplementation would prevent, or at least reduce, bone status impairment. PMID- 28012021 TI - Lentiviral Modulation of Wnt/beta-Catenin Signaling Affects In Vivo LTP. AB - Wnt signaling is involved in hippocampal development and synaptogenesis. Numerous recent studies have been focused on the role of Wnt ligands in the regulation of synaptic plasticity. Inhibitors and activators of canonical Wnt signaling were demonstrated to decrease or increase, respectively, in vitro long-term potentiation (LTP) maintenance in hippocampal slices (Chen et al. in J Biol Chem 281:11910-11916, 2006; Vargas et al. in J Neurosci 34:2191-2202, 2014, Vargas et al. in Exp Neurol 264:14-25, 2015). Using lentiviral approach to down- and up regulate the canonical Wnt signaling, we explored whether Wnt/beta-catenin signaling is critical for the in vivo LTP. Chronic suppression of Wnt signaling induced an impairment of in vivo LTP expression 14 days after lentiviral suspension injection, while overexpression of Wnt3 was associated with a transient enhancement of in vivo LTP magnitude. Both effects were related to the early phase LTP and did not affect LTP maintenance. A loss-of-function study demonstrated decreased initial paired pulse facilitation ratio, beta-catenin, and phGSK-3beta levels. A gain-of-function study revealed not only an increase in PSD 95, beta-catenin, and Cyclin D1 protein levels, but also a reduced phGSK-3beta level and enhanced GSK-3beta kinase activity. These results suggest a presynaptic dysfunction predominantly underlying LTP impairment while postsynaptic modifications are primarily involved in transient LTP amplification. This study is the first demonstration of the involvement of Wnt/beta-catenin signaling in synaptic plasticity regulation in an in vivo LTP model. PMID- 28012023 TI - Oral to subcutaneous methotrexate dose-conversion strategy in the treatment of rheumatoid arthritis. AB - Both the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) guidelines recommend the use of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) when there is no contraindication. While MTX is the foundation of RA therapy (Singh et al. in Arthritis Care Res 64:625 639,2012), absorption saturation compromises its oral bioavailability (BA). Differences in the relative BA of oral versus subcutaneous (SC) MTX demonstrate the need for guidance on successful dose-conversion strategies. This study was designed to compare MTX PK profiles as a result of MTX administration via three different treatment administrations: oral, SC MTX administered via an auto injector (MTXAI) into the abdomen (MTXAIab) and into the thigh (MTXAIth). In this paper, we establish a dose-conversion method based on the BA of MTX from oral and SC administration. SC administration provided higher exposure of MTX than the same dose given orally. Unlike the exposure limitations of oral MTX, dose proportional exposure was seen with SC MTX. PMID- 28012022 TI - RUNX1 Regulates Migration, Invasion, and Angiogenesis via p38 MAPK Pathway in Human Glioblastoma. AB - Runt-related transcription factor 1 (RUNX1) is essential for the establishment of fetal and adult hematopoiesis and neuronal development. Aberrant expression of RUNX1 led to proliferation and metastasis of several cancers. The aim of the present study was to investigate the role of RUNX1 in migration, invasion, and angiogenesis of human glioblastoma using IL-1beta-treated U-87 MG human glioblastoma cells as a model. IL-1beta at 10 ng/ml stimulated translocation of RUNX1 into the nucleus with increased expressions of RUNX1, MMP-1, MMP-2, MMP-9, MMP-19, and VEGFA in U-87 MG cells. In addition, silencing of RUNX1 gene significantly suppressed U-87 MG cell migration and invasion abilities. Moreover, knockdown of RUNX1 mRNA in U-87 MG cells reduced the tube formation of human umbilical vein endothelial cells. Further investigation revealed that IL-1beta induced RUNX1 expression might be mediated via the p38 mitogen-activated protein kinase (MAPK) signaling molecule for the expression of these invasion- and angiogenic-related molecules. Together with an inhibitor of p38 MAPK (SB203580) could decrease RUNX1 mRNA expression. Thus, RUNX1 may be one of the putative molecular targeted therapies against glioma metastasis and angiogenesis through the activation of p38 MAPK signaling pathway. PMID- 28012024 TI - Targeted disruption of Noc4l leads to preimplantation embryonic lethality in mice. PMID- 28012025 TI - Antifibrotic Effects of Carvedilol and Impact of Liver Fibrosis on Carvedilol Pharmacokinetics in a Rat model. AB - BACKGROUND AND OBJECTIVES: Carvedilol is a drug of choice in treatment of portal hypertension. The present study was designed to elucidate the potential role of antifibrotic effects of carvedilol in improving hepatic efficiency and the carvedilol oral pharmacokinetic changes during induction of liver fibrosis. METHODS: Rats were given CCl4 (1 ml/kg, intraperitoneal) twice weekly for 6 weeks and/or co-treated with carvedilol (10 mg/kg, orally) three times weekly on alternating days. Indocyanine green (ICG) clearance test was used as a modality for the measurement of hepatic blood flow. In addition, assessment of serum albumin as a marker of synthetic capacity and immunohistochemical staining of P glycoprotein (P-gp) expression as a marker of metabolic capacity were done. Furthermore, hydroxyproline and TGF-beta1 were detected as markers of liver fibrosis. RESULTS: The area under plasma concentration-time curve of a single dose of carvedilol was significantly increased, associated with decreased the clearance in rats intoxicated with CCl4 compared to control group. Carvedilol co treatment in CCl4-intoxicated rats for 6 weeks significantly counteracted the changes in hepatotoxicity markers and histopathological lesions induced by CCl4. In addition, there were no significant alterations in carvedilol pharmacokinetics between control and CCl4-intoxicated rats. Furthermore, carvedilol treatment restored liver efficiency, including synthetic and metabolic capacity as well as hepatic blood flow. CONCLUSION: The present study provides evidence underlying the antifibrotic effects of carvedilol and enhancement of hepatic efficiency. In addition, the pharmacokinetic parameters of a single dose of carvedilol are altered in liver fibrosis, manifested as delayed clearance. This was attributed to the reduction of both hepatic blood flow and CYP2D6 expression in the liver. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks recovered its pharmacokinetic profile, which is mainly attributed to the impact of pharmacodynamic antifibrotic effects of carvedilol on its own kinetics. PMID- 28012026 TI - Role of cyclooxygenase-mediated metabolites in lipid metabolism and expression of some immune-related genes in juvenile grass carp (Ctenopharyngodon idellus) fed arachidonic acid. AB - Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid (ARA) to prostaglandins, and COX-mediated metabolites play important roles in the regulation of lipid metabolism and immunity in mammals. However, such roles of COX in fish remain largely unknown. In this study, we designed three semi purified diets, namely ARA-free (control), ARA, and ARA + acetylsalicylic acid (ASA; a COX inhibitor), and used them to feed grass carp (27.65 +/- 3.05 g) for 8 weeks. The results showed that dietary ARA significantly increased the amount of ARA in the hepatopancreas, muscle, and kidney (P < 0.05), whereas this increase was reduced by dietary ASA. The hepatopancreatic prostaglandin E2 content increased in the ARA group, and this increase was inhibited by ASA (P < 0.05). ARA decreased the lipid content in the hepatopancreas, whereas ASA recovered lipid content to a significant level (P < 0.05). ARA significantly decreased the messenger RNA (mRNA) expression levels of fatty acid synthase and stearoyl-CoA desaturase in the hepatopancreas (P < 0.05). However, ASA did not rescue the mRNA expression of these genes (P > 0.05). Interestingly, ARA significantly enhanced the level of peroxisome proliferator-activated receptor alpha gene expression, and this increase was attenuated by ASA (P < 0.05). Finally, ARA significantly enhanced the mRNA expression of myeloid differentiation factor 88 (MyD88) in the kidney, and ASA attenuated the expression of toll-like receptor 22 and MyD88 (P < 0.05). In conclusion, our findings suggest that COX metabolites play important roles in the inhibition of lipid accumulation in the hepatopancreas of grass carp fed with ARA and that regulation of gene expression promotes lipid catabolism rather than lipogenic activities. Additionally, these eicosanoids might participate in the upregulation of immunity-related genes in the kidney. PMID- 28012027 TI - Having bird schistosomes in mind-the first detection of Bilharziella polonica (Kowalewski 1895) in the bird neural system. AB - Nasal bird schistosomes can cause bilharziosis in birds and have the potential to cause swimmer's itch in humans. We determined the prevalence of bird schistosomes in 106 mallards (Anas plathyrhynchos) from 11 water sources in Germany from 2014. Dissections were performed focusing on parasitic infections of the neural system. Infections with Trichobilharzia regenti (Horak et al. 1998) were found in 21% of the birds (n = 22), whereas Bilharziella polonica (Kowalewski 1895) were found between the brain membranes (meninges) and the brain, in the spinal cord or in the intestine of 12% of the mallards (n = 13). No significant influence of sex, age, and body condition between infected and non-infected animals was observed. Our study provides the first description of B. polonica from the neural system of birds and provides an epidemiological understanding of a parasite of human health concern. PMID- 28012028 TI - Development of PCR method for detecting Kudoa iwatai (Myxozoa: Multivalvulida) from rock bream Oplegnathus fasciatus. AB - We developed a PCR assay targeting the 28S rDNA of Kudoa iwatai (Multivalvulida: Myxozoa) and investigated the prevalence of infection in rock bream Oplegnathus fasciatus, which is commercially an important aquaculture species in Korea, with this assay. Detection limit of the PCR assay was 2.5 fg/MUl with plasmid DNA and 8.6 * 103 spores/ml with purified spores, respectively. This PCR assay did not amplify DNA of other Kudoa species (Kudoa septempunctata, Kudoa lateolabracis, Kudoa thyrsites) tested. Sliced muscles of whole body from 318 rock bream (wild and cultured) were examined by this PCR assay and also with the naked eyes. All of the wild fish did not produce amplicons nor did harbor visible Kudoa cysts (0/70). Three of the cultured fish were PCR-positive and also harbored visible Kudoa cysts (3/248, 1.2%). The sequences of amplicons (574 bp) were 100% identical with those of the K. iwatai already registered in Genbank. When the visceral organs of these three fish were examined, visible cysts were not found, but one stomach sample was found to be PCR-positive. There was no difference in the prevalence of infection estimated by PCR assay and the presence of visible Kudoa cysts in our samples. This is thought to be because the development of K. iwatai is already completed and only mature Kudoa cysts existed in our samples. PMID- 28012029 TI - Impact of Bacillus sphaericus exposure on Anopheles dirus's fecundity and resistance development. AB - Mosquitoes are important vectors of many infectious diseases. Bacillus sphaericus (Bs) is an ideal larvicide and has attracted more and more attention, recently. However, the fundamental research of its application is very limited, especially on the subsequent impact of Bs exposure on mosquito's fecundity and resistance emergence. Through bioassay, LC50 and LC95 of Bs in killing Anopheles dirus larvae were determined as 9.793 +/- 1.878 IU/L and 62.4 +/- 6.438 IU/L at 48 h posttreatment, 7.128 +/- 0.913 IU/L and 34.385 +/- 12.547 IU/L at 72 h post treatment, respectively. After being treated with a sub-lethal dose of Bs, gravidity, oviposition, hatch, pupation, and eclosion of the surviving mosquitoes were counted and analyzed to elucidate the subsequent effects of Bs exposure on the reproductive capacity of A. dirus. The result interestingly showed that the exposure of Bs significantly reduced the oviposition ability of the surviving A. dirus, without effect on egg formation/gravidity, hatch, pupation, and eclosion. The surviving mosquitoes were also maintained routinely for generations to test the sustained effect of Bs exposure on the fecundity of the offsprings. After conventional breeding for generations, the capacity of egg laying totally recovered. To explore the rules of resistance development, bioassays were performed after treatment twice with a sub-lethal dose of Bs on two continuous generations of A. dirus larvae. The killing efficacies between the Bs treated group and control group were compared. The results showed that LC50 and LC95 increased by 4.35- and 7.37-folds after treatment with the sub-lethal dose of Bs on two consecutive generations, respectively. The results indicated that A. dirus was sensitive to Bs, which could reduce oviposition of the surviving A. dirus. The subsequent effect might help to further decrease the mosquito population. However, a sub-lethal dose of Bs exposure could easily cause resistance development. Our study provides a dose standard and reference for the rational use of Bs, which will be helpful for mosquito control. PMID- 28012030 TI - Left ventricular intracavitary and intramyocardial metastases from renal cell carcinoma. PMID- 28012031 TI - First 200 consecutive transumbilical single-incision laparoscopic TEPs. AB - BACKGROUND: Endoscopic pre-peritoneal mesh repair (TEP) through single-incision laparoscopy (SIL) permits placement of a large mesh through a final millimetric umbilical scar. This prospective study evaluates the first 200 consecutive SILTEPs performed by a single surgeon. PATIENTS AND METHODS: Between November 2011 and September 2015, 200 consecutive SILTEPs were performed in 161 patients. The mean age was 49.8 +/- 16.3 years and the mean BMI was 24.5 +/- 3.4 kg/m2. The technique involved one 11-mm trocar, one 10-mm 0 degrees scope and curved reusable instruments. A supplementary 1.8-mm straight trocarless grasping forceps was percutaneously inserted for perioperative complications or difficulties. RESULTS: A unilateral hernia repair was performed in 122 patients, and a bilateral repair in 39 patients. The total operative time was 57.4 +/- 22.3 min, and pure laparoscopic time was 46.6 +/- 21.6 min. There was no need for insertion of a supplementary 5-mm trocar, and the need for insertion of 1.8-mm trocarless grasper was 32.9%. Perioperative complications occurred in 73 patients. The mean final scar length was 15.3 +/- 2.6 mm. The mean hospital stay was 1.0 +/- 0.3 days. Postoperative complications at the access site affected 15 patients and at the hernia site 31 patients. After a mean follow-up of 25.4 +/- 12.3 months, there was one asymptomatic, small incisional hernia at the access site as well as one reoperation for recurrent inguinal hernia at 16 months. No other late complications were registered. CONCLUSION: Transumbilical SILTEP permits placement of a large mesh through a final millimetric scar. Getting over the learning curve in conventional multitrocar TEP is mandatory. As per our institute's algorithm, the contraindications continue to be giant inguino scrotal, incarcerated and recurrent inguinal hernias. PMID- 28012032 TI - Abdominal wall reinforcement: biologic vs. degradable synthetic devices. AB - BACKGROUND: New biodegradable synthetic and biologic hernia implants have been promoted for rapid integration and tissue reinforcement in challenging repairs, e.g. at the hiatus or in contaminated wound fields. Interestingly, experimental data to support or falsify this assumption is scarce. METHODS: Synthetic (BioA(r)) and biologic implants (porcine and bovine collagen matrices Strattice(r) and Veritas(r)) have been tested in experimental onlay hernia repair in rats in observation periods of 30 and 60 days. The key outcome parameters were mesh integration and reinforcement of the tissue at the implant site over sutured and sealed defects as well as comparison to native abdominal wall. Macroscopic assessment, biomechanical analysis and histology with haematoxylin/eosin staining, collagen staining and van Willebrand factor staining for detection of neovascularization were performed. RESULTS: BioA(r) was well integrated. Although the matrices were already fragmented at 60 days follow-up, hernia sites treated with synthetic scaffolds showed a significantly enhanced tissue deflection and resistance to burst force when compared to the native abdominal wall. In porcine and bovine matrices, tissue integration and shrinkage were significantly inferior to BioA(r). Histology revealed a lack of fibroblast ingrowth through mesh interstices in biologic samples, whereas BioA(r) was tightly connected to the underlying tissue by reticular collagen fibres. CONCLUSIONS: Strattice(r) and Veritas(r) yielded reduced tissue integration and significant shrinkage, prohibiting further biomechanical tests. The synthetic BioA(r) provides little inherent strength but reticular collagen remodelling led to an augmentation of the scar due to significantly higher burst force resistance in comparison to native tissue. PMID- 28012033 TI - Early maladaptive schemas in adult patients with attention deficit hyperactivity disorder. AB - The main purpose of this study was to examine whether adult patients with attention deficit hyperactivity disorder (ADHD) demonstrate sets of dysfunctional cognitive beliefs and behavioural tendencies according to Jeffrey Young's schema focused therapy model. Sets of dysfunctional beliefs (maladaptive schemas) were assessed with the Young Schema Questionnaire (YSQ-S2) in 78 adult ADHD patients and 80 control subjects. Patients with ADHD scored significantly higher than the control group on almost all maladaptive schemas. The 'Failure', 'Defectiveness/Shame', 'Subjugation' and 'Emotional Deprivation' schemas were most pronounced in adult ADHD patients, while only 'Vulnerability to Harm or Illness' did not differ between the two groups. The schemas which were most pronounced in adult patients with ADHD correspond well with their learning histories and core symptoms. By demonstrating the existence of early maladaptive schemas in adults suffering from ADHD, this study suggests that schema theory may usefully be applied to adult ADHD therapy. PMID- 28012034 TI - Surgical treatment of perihilar cholangiocarcinoma: early results of en bloc portal vein resection. AB - OBJECTIVE: The objective of this study was to analyse the safety, feasibility and survival outcomes of our treatment of perihilar cholangiocarcinoma (PHC) since the introduction of more aggressive approaches (en bloc, vascular and extended liver resections) in 2007. PATIENTS AND METHODS: From July 2007 to December 2014, 32 consecutive patients with PHC underwent surgery with curative intent. Surgery with resection and reconstruction of the portal vein bifurcation and right hepatic artery was performed if necessary for a complete removal of the tumour. Perioperative data and postoperative histological findings, tumour recurrence rates and survival rates were recorded. Seventeen (53%) of the patients presented with stage IIIb or IV according to the UICC classification system. RESULTS: The 5 year survival rate in our series was 45%, and this percentage increased to 65% when patients with advanced stage cancer (stage IIIb or higher) were excluded. We performed 3 arterials and 23 portal vein reconstruction. Twelve patients underwent extended hemihepatectomy. We achieved cancer-free margins in 19 patients (60%). Tumour stage and nodal involvement were the most important prognostic factors. The perioperative morbidity and mortality rates of this cohort were 72% (23) and 15.6% (5), respectively; these results were similar to data published by other groups. CONCLUSIONS: An aggressive approach involving en bloc or extended liver resection combined with vascular reconstruction provides acceptable morbidity and mortality and increases the 5-year survival rate of PHC. PMID- 28012035 TI - Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma. AB - OBJECTIVES: To evaluate the safety and feasibility of sorafenib prior to surgery for downsizing tumors in patients with non-metastatic cT1-3 renal tumors together with a characterization of functional intratumoral heterogeneity (ITH). MATERIALS AND METHODS: The effects of 4-week sorafenib prior to curative surgery were assessed in a prospective, single-center, randomized, placebo-controlled, double blinded, pilot trial in patients with T1-3N0M0 renal cell carcinoma (RCC). Patients received sorafenib or placebo for 28 days prior to surgery. MRI was performed at baseline and prior to surgery to calculate tumor volume. The clinical responses were further characterized on the molecular level by immunohistochemical stainings for Ki-67, cleaved caspase-3, and CD31. RESULTS: After enrolling 20 patients into the study, 14 patients were randomized, of which 12 patients were available for analysis. While no significant change in tumor volume was seen for placebo (range = -24.2-0.2%) a reduction of 29.0% (range = 4.9-61.1%) was detected for sorafenib (p < 0.05). Primary renal tumor diameter changed from 10.6 cm (range = 6.5-10.8) to 10.7 cm (range = 6.7-11.1) in the placebo group, and from 5.4 cm (range = 4.3-7.3) to 4.4 cm (range = 3.5-6.8) for the sorafenib group, at baseline vs. 28 days of treatment. Correlative assessment of proliferation, apoptosis, and microvessel density revealed an enhanced degree of functional ITH in treated patients suggesting adaptive and/or regenerative processes with potential relevance for the development of drug resistance. CONCLUSIONS: Sorafenib in standard dosage, given preoperatively for 28 days, was clinically active in downsizing tumors in patients with locally confined, non metastatic RCC together but led to an enhanced functional ITH in the residual tumor tissue. PMID- 28012037 TI - Differentiating swelling and hypertrophy through indirect assessment of muscle damage in untrained men following repeated bouts of resistance exercise. AB - PURPOSE: To examine the swelling response and other markers of muscle damage throughout the early portions of a training program (Experiment 1). We also determined if a "swollen" muscle could swell further following additional exercise (Experiment 2). METHODS: Nine males performed four sets of biceps curls (or time-matched rest on control arm) at 70% of their one-repetition maximum three times over 8 days. Muscle thickness and torque were measured before and after exercise as well as on the days in between. Soreness was measured at the beginning of each day (Experiment 1). On the final day (Experiment 2), participants performed two bouts of exercise, followed by additional measures of muscle thickness. RESULTS: Following three bouts of exercise, muscle thickness was elevated over baseline (mean of visit 9 pre to visit 2 pre, 95% CI) at the 50% [0.21 (0.07, 0.34) cm], 60% [0.21 (0.02, 0.39) cm], and 70% [0.21 (0.06, 0.36) cm] sites. However, differences from a non-exercise control were only observed immediately following bouts of exercise (indicative of acute swelling). Torque was lower at every time point following the first bout of exercise and remained suppressed relative to pre at visit 9 [-6.1 (-11.7, -0.47 Nm] in the experimental arm. Experiment 2 found that a swollen muscle could not appreciably swell more. CONCLUSION: Resting levels of muscle thickness do not appear to change beyond what occurs following the first naive bout of exercise. Also, the acute swelling response may be used to differentiate swelling from muscle growth. PMID- 28012036 TI - No influence of ischemic preconditioning on running economy. AB - PURPOSE: Many of the potential performance-enhancing properties of ischemic preconditioning suggest that the oxygen cost for a given endurance exercise workload will be reduced, thereby improving the economy of locomotion. The aim of this study was to identify whether ischemic preconditioning improves exercise economy in recreational runners. METHODS: A randomized sham-controlled crossover study was employed in which 18 adults (age 27 +/- 7 years; BMI 24.6 +/- 3 kg/m2) completed two, incremental submaximal (65-85% VO2max) treadmill running protocols (3 * 5 min stages from 7.2-14.5 km/h) coupled with indirect calorimetry to assess running economy following ischemic preconditioning (3 * 5 min bilateral upper thigh ischemia) and sham control. Running economy was expressed as mlO2/kg/km and as the energy in kilocalories required to cover 1 km of horizontal distance (kcal/kg/km). RESULTS: Ischemic preconditioning did not influence steady-state heart rate, oxygen consumption, minute ventilation, respiratory exchange ratio, energy expenditure, and blood lactate. Likewise, running economy was similar (P = 0.647) between the sham (from 201.6 +/- 17.7 to 204.0 +/- 16.1 mlO2/kg/km) and ischemic preconditioning trials (from 202.8 +/- 16.2 to 203.1 +/- 15.6 mlO2/kg/km). There was no influence (P = 0.21) of ischemic preconditioning on running economy expressed as the caloric unit cost (from 0.96 +/- 0.12 to 1.01 +/ 0.11 kcal/kg/km) compared with sham (from 1.00 +/- 0.10 to 1.00 +/- 0.08 kcal/kg/km). CONCLUSIONS: The properties of ischemic preconditioning thought to affect exercise performance at vigorous to severe exercise intensities, which generate more extensive physiological challenge, are ineffective at submaximal workloads and, therefore, do not change running economy. PMID- 28012038 TI - Study of the union method of microelectrode array and AFM for the recording of electromechanical activities in living cardiomyocytes. AB - Electrophysiology and mechanics are two essential components in the functions of cardiomyocytes and skeletal muscle cells. The simultaneous recording of electrophysiological and mechanical activities is important for the understanding of mechanisms underlying cell functions. For example, on the one hand, mechanisms under cardiovascular drug effects will be investigated in a comprehensive way by the simultaneous recording of electrophysiological and mechanical activities. On the other hand, computational models of electromechanics provide a powerful tool for the research of cardiomyocytes. The electrical and mechanical activities are important in cardiomyocyte models. The simultaneous recording of electrophysiological and mechanical activities can provide much experimental data for the models. Therefore, an efficient method for the simultaneous recording of the electrical and mechanical data from cardiomyocytes is required for the improvement of cardiac modeling. However, as far as we know, most of the previous methods were not easy to be implemented in the electromechanical recording. For this reason, in this study, a union method of microelectrode array and atomic force microscope was proposed. With this method, the extracellular field potential and beating force of cardiomyocytes were recorded simultaneously with a low root-mean-square noise level of 11.67 MUV and 60 pN. Drug tests were conducted to verify the feasibility of the experimental platform. The experimental results suggested the method would be useful for the cardiovascular drug screening and refinement of the computational cardiomyocyte models. It may be valuable for exploring the functional mechanisms of cardiomyocytes and skeletal muscle cells under physiological or pathological conditions. PMID- 28012039 TI - Characterization of specific allosteric effects of the Na+ channel beta1 subunit on the Nav1.4 isoform. AB - The mechanism of inactivation of mammalian voltage-gated Na+ channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the beta1 subunit. Navbeta1 subunits constitute single-pass transmembrane proteins that form protein-protein associations with pore-forming alpha subunits to allosterically modulate the Na+ influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNav1.4 (skeletal muscle isoform of the rat Na+ channel) on the alpha-beta1 functional interaction and showed for the first time that the modulation of beta1 is independent of the IFM motif. We found that: (1) Nav1.4 channels that lack the IFM inactivation particle can undergo a "C-type like inactivation" albeit in an ultraslow gating mode; (2) beta1 can significantly accelerate the inactivation of Nav1.4 channels in the absence of the IFM motif. Previously, we identified two residues (T109 and N110) on the beta1 subunit that disrupt the alpha-beta1 allosteric modulation. We further characterized the electrophysiological effects of the double alanine substitution of these residues demonstrating that it decelerates inactivation and recovery from inactivation, abolishes the modulation of steady-state inactivation and induces a current rundown upon repetitive stimulation, thus causing a general loss of function. Our results contribute to delineating the process of the mammalian Na+ channel inactivation. These findings may be relevant to the design of pharmacological strategies, targeting beta subunits to treat pathologies associated to Na+ current dysfunction. PMID- 28012040 TI - "Missed Band Under the Band": Don't Miss it ! PMID- 28012041 TI - Brain-to-stomach transfer of alpha-synuclein via vagal preganglionic projections. AB - Detection of alpha-synuclein lesions in peripheral tissues is a feature of human synucleinopathies of likely pathogenetic relevance and bearing important clinical implications. Experiments were carried out to elucidate the relationship between alpha-synuclein accumulation in the brain and in peripheral organs, and to identify potential pathways involved in long-distance protein transfer. Results of this in vivo study revealed a route-specific transmission of alpha-synuclein from the rat brain to the stomach. Following targeted midbrain overexpression of human alpha-synuclein, the exogenous protein was capable of reaching the gastric wall where it was accumulated into preganglionic vagal terminals. This brain-to stomach connection likely involved intra- and inter-neuronal transfer of non fibrillar alpha-synuclein that first reached the medulla oblongata, then gained access into cholinergic neurons of the dorsal motor nucleus of the vagus nerve and finally traveled via efferent fibers of these neurons contained within the vagus nerve. Data also showed a particular propensity of vagal motor neurons and efferents to accrue alpha-synuclein and deliver it to peripheral tissues; indeed, following its midbrain overexpression, human alpha-synuclein was detected within gastric nerve endings of visceromotor but not viscerosensory vagal projections. Thus, the dorsal motor nucleus of the vagus nerve represents a key relay center for central-to-peripheral alpha-synuclein transmission, and efferent vagal fibers may act as unique conduits for protein transfer. The presence of alpha-synuclein in peripheral tissues could reflect, at least in some synucleinopathy patients, an ongoing pathological process that originates within the brain and, from there, reaches distant organs innervated by motor vagal projections. PMID- 28012043 TI - Prospective evaluation of health-related quality of life after radical cystectomy: focus on peri- and postoperative complications. AB - OBJECTIVES: To analyse the impact of perioperative complications and complex treatment courses on postoperative health-related quality of life (HRQOL) after radical cystectomy (RC) and continent (ONB) or incontinent (IC) urinary diversion at multiple prospective time points. METHODS: A total of 121 consecutive patients underwent RC with curative intent between 2013 and 2014. HRQOL was prospectively assessed preoperatively, after 3 and 12 months, using the QLQ-C30 questionnaire. The impact of complex perioperative treatment courses including cases requiring surgical re-interventions was retrospectively assessed using Martin criteria and the Clavien-Dindo scale. Urinary continence was determined using the validated ICIQ-SF questionnaire. Statistical analysis included Kruskal-Wallis ANOVA, Spearman's rank correlation, and ordinal regression models (p < 0.05). RESULTS: A total of 100 patients underwent further analysis. Physical functioning (PF), role functioning (RF), and global health status (GHS) scores were higher in the ONB subgroup both preoperatively (p < 0.001, 0.010, 0.048) and 3 months after RC (p = 0.003, 0.048, 0.019). Clavien complications >=III led to reduced PF levels after 3 months (p = 0.050) without effect on GHS (p = 0.825). Operating time and length of critical care monitoring correlated with 3 months pain scores in the ONB subgroup (p = 0.003, 0.009) without affecting GHS (p = 0.603, 0.653). Continent urinary diversion was an independent predictor of increased HRQOL after 3 months (p = 0.021), however, not after 12 months (p = 0.803). CONCLUSIONS: Patients receiving an IC have lower PF, RF, and GHS scores than those receiving ONB. Perioperative complications and complicated treatment courses can affect HRQOL subdomains but do not significantly impact the GHS. ONB is an independent predictor for better overall HRQOL 3 months, but not 12 months after RC. PMID- 28012042 TI - Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. AB - Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR. PMID- 28012044 TI - A survey of yeast from the Yarrowia clade for lipid production in dilute acid pretreated lignocellulosic biomass hydrolysate. AB - Yarrowia lipolytica is an oleaginous yeast species that has attracted attention as a model organism for synthesis of single cell oil. Among over 50 isolates of Y. lipolytica identified, only a few of the strains have been studied extensively. Furthermore, 12 other yeast species were recently assigned to the Yarrowia clade, and most are not well characterized in terms of cell growth and lipid accumulation, especially in industrially relevant conditions. In the present study, we investigated biomass and lipid production by 57 yeast isolates, representing all 13 species in the Yarrowia clade, on a non-detoxified dilute acid-pretreated switchgrass hydrolysate under highly aerobic conditions. The objective was to compare yeast physiology during growth in an abundant, low-cost biomass feedstock and to expand diversity of genetically tractable, oleaginous yeasts available for lipid research. Screening of 45 Y. lipolytica isolates demonstrated considerable variation within the species in terms of lipid accumulation (min = 0.1 g/L; max = 5.1 g/L; mean = 2.3 g/L); three strains (NRRL YB-420, YB-419, and YB-392) were especially promising for cellulosic biomass conversion with average improvements of 43, 57, and 64%, respectively, in final lipid titer as compared to control strain W29. Subsequently, evaluation of strains from 13 distinct species in the Yarrowia clade identified Candida phangngensis PT1-17 as the top lipid producer with a maximum titer of 9.8 g/L lipid, which was over twofold higher than the second-best species in the clade (Candida hollandica NRRL Y-48254). A small set of the most promising strains from the screenings was further characterized to evaluate inhibitor tolerance, lipid production kinetics, and fatty acid distribution. We expect that the results of this study will pave the way for new biotechnological applications involving previously overlooked and under-characterized strains within the Yarrowia clade. PMID- 28012045 TI - Hydrophobic features of EPS extracted from anaerobic granular sludge: an investigation based on DAX-8 resin fractionation and size exclusion chromatography. AB - The hydrophobic fractionation of extracellular polymeric substances (EPS) extracted from anaerobic granular sludge was performed on the DAX-8 resin (two elution pH conditions, i.e., pH 2 and pH 5 were tested). The impact of seven different EPS extraction methods on EPS hydrophobicity features was assessed. The results showed that the extraction methods and bulk solution pH influenced dramatically the biochemical composition of the EPS, and in turn, the hydrophobicity determined. Besides, EPS extracting reagents i.e., formaldehyde, ethanol, sodium dodecyl sulfate (SDS), and Tween 20 not only introduced extra carbon content in the total organic carbon (TOC) measurement but also interacted with the DAX-8 resin. By comparing the apparent molecular weight (aMW) distribution of untreated and pH-adjusted EPS samples, more complete EPS aMW information was preserved at pH 5. Thus, elution at pH 5 was preferred in this study for the qualitative analysis of EPS hydrophobic features. The hydrophobic fraction of EPS retained by the resin at pH 5 was ascribed to a wide aMW range, ranging from >440 to 0.3 kDa. Within this range, EPS molecules ranging from 175 to 31 kDa were mostly retained by the DAX-8 resin, which indicates that these EPS molecules are highly hydrophobic. PMID- 28012046 TI - Imidazolium-based ionic liquids for cellulose pretreatment: recent progresses and future perspectives. AB - As the most abundant biomass in nature, cellulose is considered to be an excellent feedstock to produce renewable fuels and fine chemicals. Due to its hydrogen-bonded supramolecular structure, cellulose is hardly soluble in water and most conventional organic solvents, limiting its further applications. The emergence of ionic liquids (ILs) provides an environmentally friendly, biodegradable solvent system to dissolve cellulose. This review summarizes recent advances concerning imidazolium-based ILs for cellulose pretreatment. The structure of cations and anions which has an influence on the solubility is emphasized. Methods to assist cellulose pretreatment with ILs are discussed. The state of art of the recovery, regeneration, and reuse aspects of ILs is also presented in this work. The current challenges and development directions of cellulose dissolution in ILs are put forward. Although further studies are still much required, commercialization of IL-based processes has made great progress in recent years. PMID- 28012047 TI - The protective mechanism of QGC in feline esophageal epithelial cells by interleukin-1beta treatment. AB - In a previous study, Quercetin-3-O-beta-D-glucuronopyranoside (QGC) has anti oxidative and anti-inflammatory effects in vivo. QGC is a flavonoid glucoside extracted from Rumex Aquaticus. We investigated the downstream target proteins involved in IL-1beta-stimulated ROS production and the ability of QGC to inhibit ROS production. Cell viability was determined using the MTT reduction assay. Western blot analysis was performed with antibodies to investigate the activation of three MAPKs, NF-kappaB, and phosphorylated IkappaB-alpha (pIB), and the expression of COX-2. 2',7'-dichlorofluorescin diacetate was used to detect the generation of intracellular ROS species. When the cells were exposed to media containing IL-1beta for 18 h, cell viability was not affected. QGC did not reduce the COX-2 expression induced by IL-1beta. However; QGC attenuated the production of intracellular ROS induced by IL-1beta. IL-1beta increased the expression of ERK, p38 MAPK, and pIB, and nuclear translocation of NF-kappaB were recovered by the ROS scavenger N-acetyl-L-cysteine (NAC) and QGC, but not by the NADPH oxidase inhibitor diphenylene iodonium. Pretreatment of cells with the ERK inhibitor PD98059, the p38 MAPK inhibitor SB202190, NAC, and QGC attenuated nuclear translocation of NF-kappaB and activation of pIB. QGC has a scavenging effect on cytokine-induced ROS production, thereby preventing its downstream effects, nuclear translocation of NF-kappaB, and activation of pIB is mediated by activation of ERK and p38 MAPK, although QGC does not inhibit IL-1beta-stimulated COX-2 expression in feline esophageal epithelial cells. The data suggest that QGC exerts anti-oxidative effects and inhibitory effects against esophageal epithelial cells signals by the action of IL-1beta treatment. PMID- 28012048 TI - Segmental acetabular rim defects, bone loss, oversizing, and press fit cup in total hip arthroplasty evaluated with a probabilistic finite element analysis. AB - PURPOSE: Management of segmental rim defects and bone mineral density (BMD) loss in the elderly prior to total hip replacement is unclear within classification systems for acetabular bone loss. In this study, our objectives were (1) to understand how a reduction in BMD in the elderly affects the oversizing of a press-fit cup for primary fixation and (2) to evaluate whether the location of the segmental defect affected cup fixation. METHODS: A finite element (FE) model was used to simulate and evaluate cup insertion and fixation in the context of segmental rim defects. We focused on the distribution of patients over age 70 and used BMD (estimated from CT) as a proxy for aging's implications on THR and used probabilistic FE analysis to understand how BMD loss affects oversizing of a press-fit cup. RESULTS: A cup oversized by 1.10 +/- 0.28 mm provides sufficient fixation and lower stresses at the cup-bone interface for elderly patients. Defects in the anterior column and posterior column both required the same mean insertion force for cup seating of 84% (taken as an average of 2 anterior column and 2 posterior column defects) compared to the control configuration, which was 5% greater than the insertion force for a superior rim defect and 12% greater than the insertion force for an inferior rim defect. CONCLUSIONS: A defect along the superior or inferior rim had a minimal effect on cup fixation, while a defect in the columns created cup instability and increased stress at the defect location. PMID- 28012049 TI - Complications during removal of conventional versus locked compression plates: is there a difference? AB - BACKGROUND: Osteosynthesis plate removal is one of the most commonly performed procedures in orthopaedic surgery. Due to technological advances and the quality of increasing osteosynthesis material, more and more locked plates have been implanted over the last 20 years. The aim of this study was to determine whether the complication rate during plate removal differs between conventional and locked plates. MATERIAL AND METHODS: In this retrospective cohort study, 620 patients were included and divided into two groups based on the type of plate (locked and conventional). Technical complications during implant removal included screw breakage, destroyed screw head, implant breakage, remaining implant material, refracture, bony or soft tissue overgrowth. The following plate associated complications were identified: osteosynthesis plate not detachable, plate bent or broken, necessity of special tools or plate loosened. Three types of screw-related complications were observed: screw not detachable, screw broken or screw dislocated. RESULTS: Overall, complications related to the plate or screws were documented in 110 of the 620 cases. These complications occurred in 48 of the 382 cases involving conventional osteosynthesis (7.7% of all removals, 12.6% of all conventional removals) and in 62 of the 238 cases involving locked plate osteosynthesis (10.0% of all removals, 26.1% of all locked plate removals). The statistical analysis showed a significantly higher implant-related complication rate with locked plates compared to the conventional plates (p < 0.01). CONCLUSIONS: Hardware removal can be a complication-afflicted operation, especially cases involving locked-plate removal should only be performed if a strong indication is evident. Possible benefits of the procedure should be considered carefully, taking the cost-benefit ratio into account. PMID- 28012050 TI - Comparative assessment of "plaque/media" change on three modalities of IVUS immediately after implantation of either everolimus-eluting bioresorbable vascular scaffold or everolimus-eluting metallic stent in Absorb II study. AB - The purpose of the study to assess the comparability of immediate changes in plaque/media volume (PV) on three modalities of intravascular ultrasound (IVUS) after implantation of either bioresorbable vascular scaffold (BVS) or everolimus eluting metallic stent (EES) in Absorb II Study. The two devices have different device volume and ultrasound backscattering that may interfere with the "plaque/media" assessed by three modalities on IVUS: grayscale, backscattering of radiofrequency and brightness function. In a multicenter randomized controlled trial, 501 patients with stable or unstable angina underwent documentary IVUS pre and post- implantation. The change in plaque/media volume (PV) was categorized into three groups according to the relative PV change in device segment: PV "increased" >+5% (PVI), PV unchanged +/-5% (PVU), and PV decreased <-5% (PVD). The change in PV was re-evaluated three times: after subtraction of theoretical device volume, after analysis of echogenicity based on brightness function. In 449 patients, 483 lesions were analyzed pre- and post-implantation. "PVI" was more frequently observed in BVS (53.8%) than EES group (39.4%), p = 0.006. After subtraction of the theoretical device volume, the frequency of "PVI" decreased in both BVS (36.2%) and EES (32.1%) groups and became comparable (p = 0.581). In addition, the percentage of "PVI" was further reduced in both device groups after correction for either radiofrequency backscattering (BVS 34.4% vs. EES 22.6%) or echogenicity (BVS 25.2% vs. EES 9.7%). PV change in device segment was differently affected by BVS and EES devices implantation due to their differences in device volume and ultrasound backscattering. It implies that the lumen volume was also artifactually affected by the type of device implanted. Comparative IVUS assessment of lumen and plaque/media volume changes following implantation of BVS and EES requires specific methodological adjustment. PMID- 28012051 TI - Assessment of the left atrial appendage structure and morphology: comparison of real-time three-dimensional transesophageal echocardiography and computed tomography. AB - In this study, the left atrial appendage (LAA) structure and morphology were assessed using real-time three-dimensional transesophageal echocardiography (RT3D TEE) and enhanced cardiac computed tomography (CT) scanning, and the two measurements obtained using these different techniques were compared. Two hundred nonvalvular atrial fibrillation (NVAF) patients who were prepared to undergo radiofrequency ablation were enrolled, and 62 controls were enrolled prospectively. RT3D-TEE and CT were performed, and the following parameters were measured: LAA orifice diameter, area, depth, maximum volume, and emptying velocity. The differences between the NVAF patients and controls were compared, and the differences and correlations in the LAA parameters between the two imaging techniques were assessed. The NVAF patients had significantly bigger orifice sizes, orifice areas, and maximum volumes, and lower emptying rates. The AF cohort had roughly equal proportions of the four morphological types, whereas the controls predominantly had the windsock type. A Bland-Altman analysis demonstrated that the LAA measurements obtained using RT3D-TEE were lower than those obtained with the CT. However, linear regression analysis showed the good correlations between the RT3D-TEE and CT measurements of the LAA orifice area, depth and volume (r = 0.86, 0.63, and 0.75, respectively). The use of RT3D-TEE for the visualization and quantitative analysis of LAA parameters is feasible, and the obtained measurements correlate well with those obtained with cardiac CT. This technique may be an ideal tool for guiding LAA occlusion procedures, and combining these two methods may enhance the accuracy of LAA measurements. PMID- 28012052 TI - Inadvertent misplacement of the inferior vena cava. PMID- 28012053 TI - Transcriptomic analysis reveals the flooding tolerant mechanism in flooding tolerant line and abscisic acid treated soybean. AB - Soybean is highly sensitive to flooding stress and exhibits markedly reduced plant growth and grain yield under flooding conditions. To explore the mechanisms underlying initial flooding tolerance in soybean, RNA sequencing-based transcriptomic analysis was performed using a flooding-tolerant line and ABA treated soybean. A total of 31 genes included 12 genes that exhibited similar temporal patterns were commonly changed in these plant groups in response to flooding and they were mainly involved in RNA regulation and protein metabolism. The mRNA expression of matrix metalloproteinase, glucose-6-phosphate isomerase, ATPase family AAA domain-containing protein 1, and cytochrome P450 77A1 was up regulated in wild-type soybean under flooding conditions; however, no changes were detected in the flooding-tolerant line or ABA-treated soybean. The mRNA expression of cytochrome P450 77A1 was specifically up-regulated in root tips by flooding stress, but returned to the level found in control plants following treatment with the P450 inhibitor uniconazole. The survival ratio and root fresh weight of plants were markedly improved by 3-h uniconazole treatment under flooding stress. Taken together, these results suggest that cytochrome P450 77A1 is suppressed by uniconazole treatment and that this inhibition may enhance soybean tolerance to flooding stress. PMID- 28012054 TI - Licensing Surrogate Decision-Makers. AB - As medical technology continues to improve, more people will live longer lives with multiple chronic illnesses with increasing cumulative debilitation, including cognitive dysfunction. Combined with the aging of society in most developed countries, an ever-growing number of patients will require surrogate decision-makers. While advance care planning by patients still capable of expressing their preferences about medical interventions and end-of-life care can improve the quality and accuracy of surrogate decisions, this is often not the case, not infrequently leading to demands for ineffective, inappropriate and prolonged interventions. In 1980 LaFollette called for the licensing of prospective parents, basing his argument on the harm they can do to vulnerable people (children). In this paper, I apply his arguments to surrogate decision makers for cognitively incapacitated patients, rhetorically suggesting that we require potential surrogates to qualify for this position by demonstrating their ability to make reasonable and rational decisions for others. I employ this theoretical approach to argue that the loose criteria by which we authorize surrogates' generally unchallenged power should be reconsidered. PMID- 28012055 TI - Childhood versus adult-onset systemic lupus erythematosus: long-term outcome and predictors of mortality. AB - The aim of this study was to compare survival of childhood-onset systemic lupus erythematosus (c-SLE) and adult-onset SLE (a-SLE) according to initial manifestations. This was a retrospective cohort study. All patients were categorized into c-SLE (<=18 years) and a-SLE (>18 years). The clinical and serological data at the time of diagnosis were recorded and compared. Kaplan Meier curves were used to compare survival rates between the two groups. Predictors of mortality were obtained by a backward Cox regression. One hundred eighty patients with c-SLE and 394 patients with a-SLE were enrolled. The female/male ratio was higher in c-SLE (P = 0.0001). Lupus nephritis (P = 0.002) and valvular heart disease (P = 0.025) were more common in c-SLE and a-SLE, respectively. In a 23-year follow-up, 20 patients (11.1%) with c-SLE and 35 patients (8.9%) with a-SLE died. Mortality was not significantly different between them (P = 0.4). The main causes of death were nephritis (50% in c-SLE vs. 29% in a-SLE), infections (40% in c-SLE vs. 29% in a-SLE), and circulatory disease (10% in c-SLE vs. 37% in a-SLE). The difference was not significant (P = 0.08). Cumulative survival rates after 5, 10, 15, and 20 years were 91, 87, 85, and 78% in c-SLE and 93, 90, 90, and 83% in a-SLE, respectively. By multivariate analysis, seizure, proteinuria, and nephritis in c-SLE and seizure, hematuria, and pericarditis in a-SLE had negative prognostic effect on survival. Both c-SLE and a-SLE patients with seizure or renal involvement should be monitored more carefully to prevent ominous outcomes. PMID- 28012056 TI - Pachymeningitis in granulomatosis with polyangiitis: case series with earlier onset in younger patients and literature review. AB - The objective of this study is to describe the characteristics of patients with pachymeningitis (PM) in granulomatosis with polyangiitis (GPA) from Latin America, including three young patients. This is a retrospective case series. Patients were classified according to the ACR criteria, the 2012 Chapel Hill Consensus Conference Nomenclature and the EMA algorithm. Demographic, clinical, serological, and neuroimaging characteristics are described. Thirteen patients (nine females, four males) were identified. Mean age +/- SD of PM diagnosis was 35.5 +/- 20.4 years (median 48, range 8-71 years). Mean time +/- SD between GPA first symptom and PM diagnosis was 59.8 +/- 70.1 months (median 48, range 2-252 months). An important difference between children and adults was the median time elapsed between first GPA symptoms and PM diagnosis (range 2-4 months vs 5-252 months, respectively). Chronic headache was present in all, followed by intracranial hypertension (n = 5), single cranial nerve palsy and orbital mass (n = 4), seizures (n = 3), cavernous sinus syndrome and multiple cranial nerve palsies (n = 2), and meningism and cerebellar syndrome (n = 1 each). At time of PM diagnosis, mean BVAS/WG (Birmingham Vasculitis Activity Score for Wegener's granulomatosis) was 4 +/- 2.4 and mean VDI of 2 +/- 1.6, mostly due to ENT damage. Gadolinium-enhanced brain MRI showed dural thickening in 12 patients and leptomeningeal enhancement in one. All received a combination of glucocorticoids plus immunosuppressants, rituximab being used favourably in one refractory case. Improvement was observed in 12 patients. Chronic headache should lead to suspect PM. PM predominates in localised GPA. Children may present it earlier in the disease course than adults. Treatment is non-standardised and remains difficult. PMID- 28012057 TI - Chronic kidney disease and fragility fracture. AB - Osteoporosis is defined simply as "a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Thus, any bone lesion that causes fragility fracture is osteoporosis, which has quite heterogeneous backgrounds. Chronic kidney disease-related bone and mineral disease (CKD-MBD) is defined as "a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism and/or extra-skeletal calcification". Although CKD-MBD is one of the possible causes of osteoporosis, we do not have evidences that CKD-MBD is the only or crucial determinant of bone mechanical strength in CKD patients. The risk of hip fracture is considerably high in CKD patients. Drugs that intervene in systemic mineral metabolism, indeed, lead to the improvement on bone histology in CKD patients. However, it remains unclear whether the intervention in systemic mineral metabolism also improves bone strength, today. Thus, the use of drugs that directly act on bone and the introduction of fracture liaison concept are promising strategies for fragility fracture prevention among CKD patients, as well as treatment for CKD-MBD. PMID- 28012059 TI - Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae. AB - Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis. PMID- 28012058 TI - Glutamate and Brain Glutaminases in Drug Addiction. AB - Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear. PMID- 28012060 TI - Adipocyte microenvironment promotes Bclxl expression and confers chemoresistance in ovarian cancer cells. AB - Resistance to mitochondria-initiated apoptosis is a hallmark of chemoresistant cancer stem cells including CD44+/MyD88+ epithelial ovarian cancer (EOC) stem cells. This is controlled by members of the Bcl2 family of proteins, which function as rheostats of mitochondrial stability. We observed a differential expression profile of Bcl2 family members comparing the chemoresistant EOC stem cells and the chemosensitive CD44-/MyD88- EOC cells. Chemoresistant EOC stem cells surprisingly express higher levels of the pro-apoptotic members Bak and Bax compared to the chemosensitive EOC cells. In addition, whereas chemosensitive EOC cells preferentially express Bcl2, chemoresistant EOC stem cells preferentially express Bclxl. In the EOC stem cells, 40% knock-down of Bclxl expression was sufficient to induce the full activation of caspases and this can be reversed by concurrent knock-down of Puma. More importantly, we demonstrate that Bclxl expression levels in EOC cells is dynamic and can be regulated by microenvironments that are enriched with the pro-inflammatory cytokine IL-6 such as the cancer stem cell and adipocyte niches. Adipocyte-induced upregulation of Bclxl correlated with acquisition of chemoresistance and thus demonstrates how a specific microenvironment can regulate the expression of apoptotic proteins and confer chemoresistance. PMID- 28012061 TI - [Treatment of acetabular bone defects in revision hip arthroplasty using the Revisio-System]. AB - BACKGROUND: Many different systems for the management of primary and secondary acetabular defects are available, each with its inherent advantages and disadvantages. The Revisio-System is a press-fit oval mono-block implant that makes a defect-oriented reconstruction and restoration of the center of rotation possible. MATERIAL AND METHODS: In this study, we retrospectively reviewed the outcome of 92 consecutive patients treated with this oval press-fit cup due to periacetabular bone loss. The average follow-up was 58.2 months. Defects were classified according to D'Antonio. There were 39 type II, 38 Type III, and 15 type IV defects. After an average of 4.9 years, the implant survival rate was 94.6% with cup revision as the end point and 89.1% with revision for any reason as the end point. The Harris Hip Score increased from 41.1 preoperatively to 62.3 postoperatively. The mean level of pain measured with the Visual Analogue Scale (VSA) was reduced from 6.9 preoperatively to 3.8 postoperatively. RESULTS: The Revisio-System represents a promising toolbox for defect-orientated reconstruction of acetabular bone loss in revision hip arthroplasty. Our results demonstrate that the implantation of the Revisio-System can result in a good mid term clinical outcome. PMID- 28012062 TI - A Synthetic Hybrid Promoter for Xylose-Regulated Control of Gene Expression in Saccharomyces Yeasts. AB - Metabolism of non-glucose carbon sources is often highly regulated at the transcriptional and post-translational levels. This level of regulation is lacking in Saccharomyces cerevisiae strains engineered to metabolize xylose. To better control transcription in S. cerevisiae, the xylose-dependent, DNA-binding repressor (XylR) from Caulobacter crescentus was used to block transcription from synthetic promoters based on the constitutive Ashbya gossypii TEF promoter. The new hybrid promoters were repressed in the absence of xylose and showed up to a 25-fold increase in the presence of xylose. Activation of the promoter was highly sensitive to xylose with activity seen at concentrations below 2 MUM xylose. These new xylose-inducible promoters allow improved control of gene expression for engineered strains of Saccharomyces yeasts. PMID- 28012063 TI - The influence of implantoplasty on the diameter, chemical surface composition, and biocompatibility of titanium implants. AB - OBJECTIVES: The objective of the study was to assess the influence of implantoplasty (IP) on the diameter, chemical surface composition, and biocompatibility of titanium implants in vitro. MATERIAL AND METHODS: Twenty soft tissue-level (TL; machined transmucosal-M and rough endosseous part-SLA) and 20 bone-level (BL; SLA) implants were allocated to IP covering 3 or 6 mm of the structured surface (SLA) area. The samples were subjected to diameter, energy dispersive X-ray spectroscopy (EDX), and cell viability (ginigval fibroblasts, 6 days) assessments. RESULTS: Median diameter reductions varied between 0.1 (TL 3 mm) and 0.2 mm (TL 6 mm). EDX analysis revealed that IP and M surfaces were characterized by a comparable quantity (Wt%) of elements C, O, Na, Cl, K, and Si, but a significantly different quantity of elements Ti and Al. When compared to SLA surfaces, significant differences were noted for elements C, O, Na, Ti, and Al. At BL implants, the extension of IP (i.e., 3 to 6 mm) was associated with a significant increase in cell viability. CONCLUSIONS: IP applied to SLA implants was associated with (i) a minimal diameter reduction, (ii) an undisturbed cell viability, and (iii) a chemical elemental composition comparable to M surfaces. CLINICAL RELEVANCE: This specific IP procedure appears to be suitable for the management of exposed SLA implant surfaces. PMID- 28012064 TI - Patterns of care and treatment outcomes of patients with Craniopharyngioma in the national cancer database. AB - To investigate the patterns of care and outcomes in patients with craniopharyngioma in the National Cancer Data Base (NCDB). This study included 697 patients (166 pediatric and 531 adult cases) treated for craniopharyngioma between 2004 and 2012 in the NCDB. Adjuvant radiotherapy (RT) was defined if within 6 months of surgery. Limited surgery (LS) was defined as biopsy or subtotal resection. Proportional-hazards models were used to evaluate associations between covariates and overall survival (OS). A time-dependent analysis of RT was performed to account for early deaths after surgery. Median follow-up was 46 months. Overall, 21% of patients received adjuvant RT. Of patients with known surgical extent (n = 195), 71% had LS. Utilization of adjuvant RT increased from 18% in 2004-2007 to 24% in 2008-2012. Patterns of care regarding adjuvant RT or LS were not significantly different between adult and pediatric patients. Tumor size, low comorbidity, and LS were associated with increased utilization of adjuvant RT. The 5-year OS among patients treated with LS, LS+RT, and gross total resection were 75, 85, and 82% (p = 0.02). On multivariate analysis of the 195 patients with known surgical extent, LS+RT was associated with improved OS compared to LS (HR 0.22, 95% CI 0.05-0.99, p = 0.04), but was not significant when early deaths (<2 months from surgery) were removed to adjust for immortal-time bias. Medical practice regarding surgical approach and adjuvant RT are similar for pediatric and adult craniopharyngiomas. Immortal time bias may confound assessment of OS for adjuvant RT. Prospective studies comparing adjuvant RT versus observation after LS are warranted. PMID- 28012065 TI - A Return-to-Work Prognostic Model for Orthopaedic Trauma Patients (WORRK) Updated for Use at 3, 12 and 24 Months. AB - Purpose Updating the Wallis Occupational Rehabilitation Risk (WORRK) model formula, predicting non-return to work (nRTW) at different time points (3 and 12 months) than in the validation study (2 years). Methods Secondary analysis of two samples was carried out (following orthopaedic trauma), including work status, the first at 3 months (428 patients) and the second at 12 months (431 patients) after discharge from rehabilitation. We used calibration (agreement between predicted probabilities and observed frequencies) and discrimination (area under the receiver operating characteristics curve) to assess performance of the model after fitting it in the new sample, then calculated the probabilities of nRTW based on the coefficients from the 2-year prediction. Finally, the intercepts were updated for both 3- and 12-month prediction models (re-calibration was necessary for the adjustment of these probabilities) and performance re evaluated. Results Patient characteristics were similar in all samples (mean age 43 in both groups; 86% male at 3 months, 84% male at 12 months). The proportion of nRTW at 3 months was 63.8% and 53.4% at 12 months (50.36% at 2 years). Performance of the original WORRK for both 3- and 12-month prediction showed an AUC of 0.73, while statistically significant miscalibration was found for both time points (p < 0.001). After the updating of the intercept, calibration was improved and did not show significant miscalibration (p = 0.458 and 0.341). The AUC stayed at 0.73. Conclusion The WORRK model was successfully adapted by changing the intercept for 3- and 12-month prediction of nRTW, now available for use in clinical practice. PMID- 28012066 TI - Effects of pre-germinated fenugreek seeds inclusion in low-fiber diets on post weaned rabbits' health status, growth performances, carcass characteristics, and meat chemical composition. AB - Newly weaned rabbits frequently suffer from digestive disorders particularly when fed low-fiber diets. Fenugreek seeds are rich in dietary fiber and would be suited to moderate such disorders. This study investigated the effect of pre germinated fenugreek seeds (PGFS) on rabbits' health, digestibility, growth performance, and carcass parameters. Fourteen weaned rabbits were fed one of the following diets: (1) low fiber as negative control (NC), (2) low fiber containing 5% PGFS (F5), (3) low fiber containing 10% PGFS (F10), and (4) adequate fiber as positive control (PC). Each rabbit was reared in an individual cage for 7 weeks. Morbidity and sanitary risk indexes were not different (P > 0.05) between the four diets. Only 20% of the rabbits had a detectable caecal Escherichia Coli (E. coli) count (<105 cfu/g), and all rabbits did not show Eimeria oocysts in their feces. Compared to NC, PC gave a lower (P < 0.05) weight gain and a higher (P < 0.05) feed conversion ratio (FCR). It was associated with a lighter (P < 0.05) chilled carcass weight, and its meat had slightly more moisture and ether extract with less protein. Inclusion of PGFS decreased (P < 0.05) feed intake at the 10% level and, consequently, tended to improve FCR, while no effect was detected on carcass characteristics and meat composition. This study suggested that (1) the low-fiber diet was adequate for both health and growth aspects of post-weaned rabbits, and (2) the inclusion of PGFS was without consequence on rabbits' health status and growth performance. PMID- 28012067 TI - The gender difference of snore distribution and increased tendency to snore in women with menopausal syndrome: a general population study. AB - PURPOSE: Sleep-disordered breathing (SDB) is a prevalent disorder with a major impact in women, especially postmenopausal women. However, few studies have investigated the prevalence of a specific SDB, snoring, among women especially those with menopausal syndrome. METHODS: Computer-assisted telephone interviews were conducted in Taiwan. Adults over 20 years of age were interviewed. The number of successful interviews was calculated based on the population prior to the study. Demographic data and information about snoring, menopausal syndrome, and medical conditions were obtained. RESULTS: In total, 3624 adults, 1473 males and 2151 females, completed the interviews. Both men and women shows an increase in snoring until age 50 to 59 years, followed by a decline in snoring that is less steep among women. The prevalence of snoring increased significantly in females after age 50 years, which is the mean menopausal age in our country (p < 0.05). After adjusting for age, body mass index, and other major diseases, the percentage of women with snoring was significantly higher among those with menopausal syndrome than those without menopausal syndrome (p = 0.021, odds ratio = 1.629). CONCLUSIONS: This population-based study revealed different snoring percentages among men and women and diminishing differences in the older population. Additionally, the percentage of women with snoring was increased among those women who were older than 50 years and those with menopausal syndrome. PMID- 28012069 TI - Virchows Archiv-an update, and plans for the future. PMID- 28012070 TI - Remission of acromegaly after treatment withdrawal in patients controlled by cabergoline alone or in combination with octreotide: results from a multicenter study. AB - PURPOSE: Remission of acromegaly has been reported after somatostatin analogs withdrawal, but not after withdrawal of combination therapy with cabergoline, and only in case reports of patients controlled by cabergoline alone. METHODS: To establish the remission rates (normal IGF-1 for age/sex: IGF-1 <= 1.00 xULN) after withdrawal of combined treatment with octreotide LAR and cabergoline and of cabergoline alone, we prospectively studied 16 patients with acromegaly controlled by those treatments in the preceding 2 years as part of a larger study on remission of acromegaly after withdrawal of different medical treatments. RESULTS: Among 97 patients with controlled acromegaly included in the entire study, only 16 patients had been on combination therapy (n = 12) or cabergoline alone (n = 4). At 8 weeks after treatment withdrawal, three patients (19%) were in remission (short-term remission). At 60 weeks (long-term remission), IGF-1 levels were still in the normal range in two patients (12.5%) and remained normal up to 108 weeks after treatment withdrawal (last visit). One patient had been treated with cabergoline alone and another one with combination of octreotide and cabergoline before treatment withdrawal. CONCLUSION: Remission of acromegaly after treatment withdrawal seems to be uncommon in patients controlled by cabergoline, either as monotherapy or in combination with octreotide. In the future, larger studies and/or meta-analysis will be necessary to accurately establish the remission rates of acromegaly after withdrawal of cabergoline with or without somatostatin analogs. PMID- 28012068 TI - Ammonia toxicity: from head to toe? AB - Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction. PMID- 28012071 TI - Depression contributing to dyslipidemic cardiovascular risk in the metabolic syndrome. AB - PURPOSE: Triglycerides are considered an emerging risk factor for cardiovascular mortality. Recent evidence relating depression and metabolic syndrome (MetS) implicated triglyceride levels. We thus investigated interrelations of self reported depression severity (Zung) and MetS-related biological measures with CVD risk estimates in MetS patients. METHODS: N = 101 patients fulfilling International Diabetes Federation criteria for MetS from a nationwide sampled treatment cohort for MetS with familial T2DM risk or manifest T2DM in a Ukrainian governmental health care system were participants. Both laboratory and non laboratory measures were included. Recent European cardiological SCORE system CVD risk estimates were used as outcome variables. RESULTS: Following correlation matrix, we entered all variables into principal component analysis (PCA; 76.7% explained variance), followed by hierarchical regression and structural equation modeling (SEM). The PCA suggested a one-factor solution, where the latent variable showed highest loadings of SCORE risk estimates, triglycerides, depression severity, and pulse pressure. A comprehensive SEM was adjusted with 92.7% explained variance: overall CVD risk related to depression, pulse pressure, triglycerides, and fasting glucose. CONCLUSION: The findings in this MetS sample suggest that triglycerides and depression severity are the key variables among MetS biomarkers in cross-sectionally associating with the fatal and total SCORE risk estimates in MetS. PMID- 28012072 TI - A woman by Breu Jorg the Elder, Augsburg ca. 1515 Detroit Institute of Art. PMID- 28012073 TI - 131I age-dependent inhalation dose in Southern Poland from Fukushima accident. AB - A general method for calculating doses absorbed from isotopes released in nuclear accidents is presented. As an example, this method was used to calculate doses for inhabitants of Southern Poland due to inhalation of 131I released due to the Fukushima nuclear plant accident. 131I activity measurements in the air of that region provided the basis for the study. The proposed model is based on a complex biokinetic model for iodine merging the Leggett model developed in 2010 with the human respiratory tract and gastrointestinal tract models recommended by the International Commission on Radiological Protection (ICRP). This model is described here, and it is demonstrated that resulting dose estimates are consistent with those obtained using the ICRP methodology. Using the developed model, total doses were calculated for six age groups of both genders, for gaseous and aerosol fractions alike. The committed effective dose, H 50, for an adult man reached 16 nSv, which is lower than 0.001% of the background dose. The dose for the thyroid of an adult reached 0.33 MUSv, which corresponds to circa 0.0007% of the dose to the population of Southern Poland after the Chernobyl nuclear plant accident. PMID- 28012074 TI - Results of mitral valve repair with an adjustable annuloplasty ring 2 years after implantation. AB - : We aimed to investigate the safety and medium-term durability of an adjustable mitral annuloplasty ring in patients undergoing surgery for mitral valve regurgitation. Forty-five patients requiring mitral valve repair were enrolled into this prospective, multicentre study between May 2012 and May 2013 in six hospitals in Europe and Israel. Study endpoints evaluated the performance and safety of the device assessed using inter-individual comparisons. Implantation was performed through a sternotomy in ten patients and mini-thoracotomy in 35 patients. The ring was adjusted after declamping and weaning from cardio pulmonary bypass under echocardiographic guidance if the coaptation surface was not optimal, or in cases of residual mitral regurgitation. Follow-up was performed up to 2 years post-procedure. Mean age was 61 +/- 12 years. Ring adjustment was performed in 71% of patients to optimise the results of mitral valve repair. Following the procedure, 11/45 patients (24%) who had had mild residual mitral regurgitation had no mitral regurgitation following ring adjustment. Two patients with severe mitral regurgitation post-procedure had mild regurgitation following ring adjustment. Coaptation length increased significantly after adjustment. One patient died before hospital discharge due to complications unrelated to the adjustable ring. One patient had to undergo re operation at 39 days post-procedure due to endocarditis. At 2 years of follow-up, 78% of patients had no residual mitral regurgitation and 22% had mild residual mitral regurgitation. Adjustable mitral annuloplasty ring implantation was safe in all patients. Mitral valve repair with the adjustable ring was durable in all patients who reached 2 years follow-up. CLINICAL TRIAL REGISTRATION: NCT01617720. PMID- 28012075 TI - Editorial. PMID- 28012076 TI - Erratum to: Orally administered multispecies probiotic formulations to prevent uro-genital infections: a randomized placebo-controlled pilot study. PMID- 28012077 TI - Retrospective cohort study: AMH is the best ovarian reserve markers in predicting ovarian response but has unfavorable value in predicting clinical pregnancy in GnRH antagonist protocol. AB - BACKGROUND: Various ovarian reserve markers have been used to predict ovarian response and pregnancy. However, concerning Chinese population, fewer trials have been performed using the combined ovarian reserve markers to predict ovarian response and pregnancy in GnRH antagonist protocols. METHODS: Data from a total of 373 patients' in vitro fertilization cycles using GnRH antagonist protocol was retrospectively included. According to our center's daily practice, circulating follicle-stimulating hormone, luteinizing hormone, and estradiol (E2) were tested on menstrual cycle day 2-4 or hCG trigger day, and the concentration of AMH was determined despite of menstrual cycle. The antral follicle count (AFC) was assessed by transvaginal ultrasound on day 2-4 of menstrual cycle. Different ovarian response was defined as 0-4 and 5-15 and >15 oocyte retrieved for low and normal and high ovarian response, respectively. Gestational sac with fetal heartbeat detected by ultrasound was considered as clinical pregnancy. RESULTS: Serum AMH levels was the most accurate marker in predicting ovarian response [area under the receiver operating characteristic (ROC) curve = 0.767]. Significant difference was found in age between non-clinical pregnancy and clinical pregnancy groups (p < 0.001). CONCLUSIONS: Our data demonstrated that the circulating AMH despite of menstrual cycle was preferable in prediction of oocyte retrieved outcome during GnRH antagonist protocol than age, AFC and the other currently used hormone markers. Furthermore, age is the only marker in predicting clinical pregnancy. PMID- 28012078 TI - Odontoid osteomyelitis with atlantoaxial subluxation in an infant. AB - PURPOSE: To report a rare case of odontoid osteomyelitis with atlantoaxial subluxation in a 6-month-old infant. BACKGROUND: Odontoid osteomyelitis with atlantoaxial subluxation is extremely rare in children. Although several cases have been reported, there have been no studies concerning proper surgical drainage and immobilization in this disease. METHODS: A 6-month-old infant with odontoid osteomyelitis with atlantoaxial subluxation was surgically treated. The patient underwent a 3-month intravenous and oral antibiotic course and the Minerva body jacket cast was used for 3 months. Follow-up was carried out with computed tomographic scans and a cervical spine dynamogram. RESULTS: At 18 months post-surgery, the patient had completely recovered with no cervical instability. Computed tomographic scans revealed complete fusion of odontoid synchondrosis. The infant remained asymptomatic with a full range of head movement. CONCLUSION: Surgical drainage and proper immobilization appears to be a satisfactory treatment for pyogenic osteomyelitis of odontoid synchondrosis secondary to retropharyngeal abscess and atlantoaxial subluxation. LEVEL OF EVIDENCE: N/A. PMID- 28012079 TI - The revised Tokuhashi score; analysis of parameters and assessment of its accuracy in determining survival in patients afflicted with spinal metastasis. AB - PURPOSE: To determine the significance of each parameter of the revised Tokuhashi score and identify which is associated with survival. BACKGROUND: Spinal metastases are common and can be a challenging medical issue. Treatment options depend on patients' prognosis. Many scoring systems in the literature help estimate prognosis, such as the Tokuhashi, revised Tokuhashi, and Tomita scoring systems. METHODS: A retrospective review of all patients from 2003 to 2012 treated for spinal metastases in one center was conducted. Imaging, pathology, and charts were reviewed to determine the modified Tokuhashi scores. Scores were then compared to the actual documented survival. Univariate and multiple regression analyses were used to assess the importance of each individual parameter and survival time. Linear regression was used to determine the relationship between the Tokuhashi score and weighted Tokuhashi score with survival time. RESULTS: A total of 126 patients were reviewed. All parameters in the revised Tokuhashi score were significantly associated with survival time except for primary site using univariate analysis. Only the number of spinal metastases and metastasis to major organs showed statistical significance when multiple variable analysis was used. CONCLUSION: A number of spinal metastases and metastasis to major organs were the most important predictors of actual survival. Modification to the score based on population characteristics would help better identify patients with spinal metastases that can benefit from surgery. PMID- 28012080 TI - Three-dimensional micro-computed tomography analysis for spinal instability after lumbar facetectomy in the rat. AB - PURPOSE: Intervertebral disc degeneration is thought to contribute to low back pain. However, the pathophysiological mechanisms remain controversial. In a previous study, we developed an animal model that showed delayed gait disturbance after lumbar facetectomy in the rat. We believe that this gait disturbance was caused by low back pain, although the mechanisms of this gait abnormality remain unknown. The purpose of this study was to evaluate structural changes of the lumbar spine after facetectomy in the rat utilizing three-dimensional micro computed tomography (3DMUCT) compared to histology. METHODS: Thirty male SD rats were divided into three groups. In the Sham group (n = 13), only exposure of bilateral facet joints at the L4-5 level was performed. In the Experimental group (n = 13), complete resection of bilateral L4-5 facet joints was achieved. Naive rats (n = 4) were used for controls. At 7-week postoperative, 3DuCT and histological analyses were performed. RESULTS: On 3DuCT images, increased disc height and endplate irregularities at the L4-5 segment and decreased disc height at adjacent segments were observed in the Experimental group. Histological scores were also higher in the Experimental group than the Sham Group. CONCLUSIONS: Degenerative changes were observed at the facetectomy level. These may correspond with the previously reported delayed gait disturbance after facetectomy. This animal model may be useful to create mechanically induced disc degeneration without direct tissue damage to the disc. PMID- 28012081 TI - The Norwegian Cervical Arthroplasty Trial (NORCAT): 2-year clinical outcome after single-level cervical arthroplasty versus fusion-a prospective, single-blinded, randomized, controlled multicenter study. AB - PURPOSE: Standard surgical treatment for symptomatic cervical disc disease has been discectomy and fusion, but the use of arthroplasty, designed to preserve motion, has increased, and most studies report clinical outcome in its favor. Few of these trials, however, blinded the patients. We, therefore, conducted the Norwegian Cervical Arthroplasty Trial, and present 2-year clinical outcome after arthroplasty or fusion. METHODS: This multicenter trial included 136 patients with single-level cervical disc disease. The patients were randomized to arthroplasty or fusion, and blinded to the treatment modality. The surgical team was blinded to randomization until nerve root decompression was completed. Primary outcome was the self-rated Neck Disability Index. Secondary outcomes were the numeric rating scale for pain and quality of life questionnaires Short Form 36 and EuroQol-5Dimension-3 Level. RESULTS: There was a significant improvement in the primary and all secondary outcomes from baseline to 2-year follow-up for both arthroplasty and fusion (P < 0.001), and no observed significant between group differences at any follow-up times. However, linear mixed model analyses, correcting for baseline values, dropouts and missing data, revealed a difference in Neck Disability Index (P = 0.049), and arm pain (P = 0.027) in favor of fusion at 2 years. The duration of surgery was longer (P < 0.001), and the frequency of reoperations higher (P = 0.029) with arthroplasty. CONCLUSION: The present study showed excellent clinical results and no significant difference between treatments at any scheduled follow-up. However, the rate of index level reoperations was higher and the duration of surgery longer with arthroplasty. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT 00735176.19. PMID- 28012082 TI - Assessment of multi-contaminant exposure in a cancer treatment center: a 2-year monitoring of molds, mycotoxins, endotoxins, and glucans in bioaerosols. AB - Indoor air quality in health care facilities is a major public health concern, particularly for immunocompromised patients who may be exposed to microbiological contaminants such as molds, mycotoxins, endotoxins, and (1,3)-beta-D-glucans. Over 2 years, bioaerosols were collected on a monthly basis in a cancer treatment center (Centre F. Baclesse, Normandy, France), characterized from areas where there was no any particular air treatment. Results showed the complexity of mycoflora in bioaerosols with more than 100 fungal species identified. A list of major strains in hospital environments could be put forward due to the frequency, the concentration level, and/or the capacity to produce mycotoxins in vitro: Aspergillus fumigatus, Aspergillus melleus, Aspergillus niger, Aspergillus versicolor, Cladosporium herbarum, Purpureocillium lilacinum, and Penicillium brevicompactum. The mean levels of viable airborne fungal particles were less than 30.530 CFU per m3 of air and were correlated to the total number of 0.30 to 20 MUm particles. Seasonal variations were observed with fungal particle peaks during the summer and autumn. Statistical analysis showed that airborne fungal particle levels depended on the relative humidity level which could be a useful indicator of fungal contamination. Finally, the exposure to airborne mycotoxins was very low (only 3 positive samples), and no mutagenic activity was found in bioaerosols. Nevertheless, some fungal strains such as Aspergillus versicolor or Penicillium brevicompactum showed toxigenic potential in vitro. PMID- 28012083 TI - Do the pollution related to high-traffic roads in urbanised areas pose a significant threat to the local population? AB - Many large neighbourhoods are located near heavy-traffic roads; therefore, it is necessary to control the levels of air pollution near road exposure. The primary air pollutants emitted by motor vehicles are CO, NO2 and PM. Various investigations identify key health outcomes to be consistently associated with NO2 and CO. The objective of this study was the measurement-based assessment for determining whether by high-traffic roads, such as motorways and express ways, and the concentrations of CO and NO2 are within normal limits and do not pose threat to the local population. Average daily values (arithmetic values calculated for 1-h values within 24 h or less, depending on result availability) were measured for concentrations of NO2 and CO by automatic stations belonging to the Voivodship Environmental Protection Inspectorate in Katowice, in areas with similar dominant source of pollutant emission. The measurements were made in three sites: near the motorway and expressway, where the average daily traffic intensity is 100983 and 35414 of vehicles relatively. No evidence was found of exceeding average daily values equal to the maximum allowable NO2 concentration due to the protection of human health in the measurement area of the stations. No daily average values exceeding the admissible CO concentration (8-h moving average) were noted in the examined period. The results clearly show lack of hazards for general population health in terms of increased concentrations of CO and NO2 compounds that are closely related to high intensity car traffic found on selected motorways and speedways located near the city centres. PMID- 28012084 TI - Trophic state assessment of Bhindawas Lake, Haryana, India. AB - Trophic state allows for identification of problems and pressures that an ecosystem faces as well as demarcation of remedial measures. This study focuses on spatial and temporal variations in the trophic state and detection of possible causes of its divergence in Bhindawas Lake, India. The trophic state of the lake undulated between eutrophic and hyper-eutrophic state throughout the study period. Higher phosphorus concentration within the lake ecosystem is the dominant causal factor for its eutrophic state. The influence of other water quality parameters has also been analyzed using Spearman's coefficient of correlation. Deviations between trophic state index (TSI)-chlorophyll-a (Chl-a), TSI-total phosphorus (TP), and TSI-Secchi depth (SD) pointed out that the lake is principally phosphorus limited, and its trophic status is influenced by non-algal turbidity to a large extent. Spatial analysis of trophic levels in geographic information system (GIS) helped in identification of pollution sources and chemical attributes affecting the trophic state of the lake. This study provides a rationale for further investigation of nutrient and sediment loading into the lake system and development of sustainable management and conservation strategy identifying suitable measures ascertaining the ecosystem integrity. PMID- 28012085 TI - The influence of 21-gene recurrence score assay on chemotherapy use in a population-based sample of breast cancer patients. AB - PURPOSE: To quantify the influence of RS assay on changing chemotherapy plans in a general practice setting using causal inference methods. METHODS: We surveyed 3880 newly diagnosed breast cancer patients in Los Angeles and Georgia in 2013 14. We used inverse propensity weighting and multiple imputations to derive complete information for each patient about treatment status with and without testing. RESULTS: A half of the 1545 women eligible for testing (ER+ or PR+, HER2 , and stage I-II) received RS. We estimate that 30% (95% confidence interval (CI) 10-49%) of patients would have changed their treatment selections after RS assay, with 10% (CI 0-20%) being encouraged to undergo chemotherapy and 20% (CI 10-30%) being discouraged from chemotherapy. The subgroups whose treatment selections would be changed the most by RS were patients with positive nodes (44%; CI 24 64%), larger tumor (43% for tumor size >2 cm; CI 23-62%), or younger age (41% for <50 years, CI 23-58%). The assay was associated with a net reduction in chemotherapy use by 10% (CI 4-16%). The reduction was much greater for women with positive nodes (31%; CI 21-41%), larger tumor (30% for tumor size >2 cm; CI 22 38%), or younger age (22% for <50 years; CI 9-35%). CONCLUSION: RS substantially changed chemotherapy treatment selections with the largest influence among patients with less favorable pre-test prognosis. Whether this is optimal awaits the results of clinical trials addressing the utility of RS testing in selected subgroups. PMID- 28012086 TI - Radiation therapy targets and the risk of breast cancer-related lymphedema: a systematic review and network meta-analysis. AB - PURPOSE: New indications have been found for regional nodal irradiation (RNI) in breast cancer treatment, yet the relationship of RNI and lymphedema risk is uncertain. We sought to determine the association of RNI and lymphedema. METHODS: We searched MEDLINE, EMBASE, and Scopus for articles in English on humans published from 1995 to 2015, using search terms breast neoplasm, treatment, and morbidity. Two investigators independently selected articles and extracted information, including manuscripts reporting incidence of lymphedema by radiation targets. Meta-analyses, review papers, case-control studies, matched-pair studies, repetitive datasets, and retrospective studies were excluded. A total of 2399 abstracts were identified and 323 corresponding articles reviewed. Twenty one studies met inclusion criteria. Data were pooled using a random effects mixed model. Network meta-analyses were performed to determine the association of radiation targets alone and radiation targets plus extent of axillary surgery on incidence of lymphedema. RESULTS: The addition of RNI to breast/CW irradiation was associated with an increased incidence of lymphedema (OR 2.85; 95% CI 1.24 6.55). In patients treated with sentinel lymph node biopsy or axillary sampling, there was no association of lymphedema with the addition of RNI to breast/CW irradiation (OR 1.58; 95% CI 0.54-4.66; pooled incidence 5.7 and 4.1%, respectively). Among patients treated with axillary lymph node dissection (ALND), treatment with RNI in addition to breast/CW radiation was associated with a significantly higher risk of lymphedema (OR 2.74; 95% CI 1.38-5.44; pooled incidence 18.2 and 9.4%, respectively). CONCLUSIONS: RNI is associated with a significantly higher risk of lymphedema than irradiation of the breast/CW, particularly after ALND. PMID- 28012088 TI - Ultrasound speckle reduction based on fractional order differentiation. AB - PURPOSE: Ultrasound images show a granular pattern of noise known as speckle that diminishes their quality and results in difficulties in diagnosis. To preserve edges and features, this paper proposes a fractional differentiation-based image operator to reduce speckle in ultrasound. METHODS: An image de-noising model based on fractional partial differential equations with balance relation between k (gradient modulus threshold that controls the conduction) and v (the order of fractional differentiation) was constructed by the effective combination of fractional calculus theory and a partial differential equation, and the numerical algorithm of it was achieved using a fractional differential mask operator. RESULTS: The proposed algorithm has better speckle reduction and structure preservation than the three existing methods [P-M model, the speckle reducing anisotropic diffusion (SRAD) technique, and the detail preserving anisotropic diffusion (DPAD) technique]. And it is significantly faster than bilateral filtering (BF) in producing virtually the same experimental results. CONCLUSIONS: Ultrasound phantom testing and in vivo imaging show that the proposed method can improve the quality of an ultrasound image in terms of tissue SNR, CNR, and FOM values. PMID- 28012087 TI - Volumetric breast density affects performance of digital screening mammography. AB - PURPOSE: To determine to what extent automatically measured volumetric mammographic density influences screening performance when using digital mammography (DM). METHODS: We collected a consecutive series of 111,898 DM examinations (2003-2011) from one screening unit of the Dutch biennial screening program (age 50-75 years). Volumetric mammographic density was automatically assessed using Volpara. We determined screening performance measures for four density categories comparable to the American College of Radiology (ACR) breast density categories. RESULTS: Of all the examinations, 21.6% were categorized as density category 1 ('almost entirely fatty') and 41.5, 28.9, and 8.0% as category 2-4 ('extremely dense'), respectively. We identified 667 screen-detected and 234 interval cancers. Interval cancer rates were 0.7, 1.9, 2.9, and 4.40/00 and false positive rates were 11.2, 15.1, 18.2, and 23.80/00 for categories 1-4, respectively (both p-trend < 0.001). The screening sensitivity, calculated as the proportion of screen-detected among the total of screen-detected and interval tumors, was lower in higher density categories: 85.7, 77.6, 69.5, and 61.0% for categories 1-4, respectively (p-trend < 0.001). CONCLUSIONS: Volumetric mammographic density, automatically measured on digital mammograms, impacts screening performance measures along the same patterns as established with ACR breast density categories. Since measuring breast density fully automatically has much higher reproducibility than visual assessment, this automatic method could help with implementing density-based supplemental screening. PMID- 28012089 TI - Orexin and Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most frequent age-related dementia. It prevalently causes cognitive decline, although it is frequently associated with secondary behavioral disturbances. AD neurodegeneration characteristically produces a remarkable destruction of the sleep-wake cycle, with diurnal napping, nighttime arousals, sleep fragmentation, and REM sleep impairment. It was recently hypothesized that the orexinergic system was involved in AD pathology. Accordingly, recent papers showed the association between orexinergic neurotransmission dysfunction, sleep impairment, and cognitive decline in AD. Orexin is a hypothalamic neurotransmitter which physiologically produces wakefulness and reduces REM sleep and may alter the sleep-wake cycle in AD patients. Furthermore, the orexinergic system seems to interact with CSF AD biomarkers, such as beta-amyloid and tau proteins. Beta-amyloid accumulation is the main hallmark of AD pathology, while tau proteins mark brain neuronal injury due to AD pathology. Investigations so far suggest that orexinergic signaling overexpression alters the sleep-wake cycle and secondarily induces beta-amyloid accumulation and tau-mediated neurodegeneration. Therefore, considering that orexinergic system dysregulation impairs sleep-wake rhythms and may influence AD pathology, it is hypothesized that orexin receptor antagonists are likely potential preventive/therapeutic options in AD patients. PMID- 28012091 TI - Hypocretins and Arousal. AB - How the brain controls vigilance state transitions remains to be fully understood. The discovery of hypocretins, also known as orexins, and their link to narcolepsy has undoubtedly allowed us to advance our knowledge on key mechanisms controlling the boundaries and transitions between sleep and wakefulness. Lack of function of hypocretin neurons (a relatively simple and non redundant neuronal system) results in inappropriate control of sleep states without affecting the total amount of sleep or homeostatic mechanisms. Anatomical and functional evidence shows that the hypothalamic neurons that produce hypocretins/orexins project widely throughout the entire brain and interact with major neuromodulator systems in order to regulate physiological processes underlying wakefulness, attention, and emotions. Here, we review the role of hypocretins/orexins in arousal state transitions, and discuss possible mechanisms by which such a relatively small population of neurons controls fundamental brain state dynamics. PMID- 28012092 TI - The Hypocretin/Orexin Neuronal Networks in Zebrafish. AB - The hypothalamic Hypocretin/Orexin (Hcrt) neurons secrete two Hcrt neuropeptides. These neurons and peptides play a major role in the regulation of feeding, sleep wake cycle, reward-seeking, addiction, and stress. Loss of Hcrt neurons causes the sleep disorder narcolepsy. The zebrafish has become an attractive model to study the Hcrt neuronal network because it is a transparent vertebrate that enables simple genetic manipulation, imaging of the structure and function of neuronal circuits in live animals, and high-throughput monitoring of behavioral performance during both day and night. The zebrafish Hcrt network comprises ~16 60 neurons, which similar to mammals, are located in the hypothalamus and widely innervate the brain and spinal cord, and regulate various fundamental behaviors such as feeding, sleep, and wakefulness. Here we review how the zebrafish contributes to the study of the Hcrt neuronal system molecularly, anatomically, physiologically, and pathologically. PMID- 28012090 TI - A Decade of Orexin/Hypocretin and Addiction: Where Are We Now? AB - One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating "motivational activation" under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra(r)) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction. PMID- 28012094 TI - Clinical Pharmacology of the Synthetic Cathinone Mephedrone. AB - 4-Methyl-N-methylcathinone (mephedrone) is a popular new psychoactive substance (NPS) that is structurally related to the parent compound cathinone, the beta keto analogue of amphetamine. Mephedrone appeared on the street drug market as a substitute for 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy) and was subsequently banned due to the potential health risks associated with its use. Nevertheless, mephedrone continues to be widely consumed among specific populations, with unique patterns of misuse. To date, most information about the biological effects of mephedrone comes from user experiences, epidemiological data, clinical cases, toxicological findings, and animal studies, whilst there are very few data regarding its human pharmacodynamics and pharmacokinetics. This chapter reviews the available published data on patterns of mephedrone use, its acute and chronic effects, and its pharmacokinetic properties. More human research is needed to elucidate the safety, toxicity, and addiction potential of mephedrone and related NPS. PMID- 28012093 TI - Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites. AB - Commercial preparations containing synthetic cannabinoids (SCBs) are rapidly emerging as drugs of abuse. Although often assumed to be "safe" and "legal" alternatives to cannabis, reports indicate that SCBs induce toxicity not often associated with the primary psychoactive component of marijuana, Delta9 tetrahydrocannabinol (Delta9-THC). This chapter will summarize the evidence that use of SCBs poses greater health risks relative to marijuana and suggest that distinct pharmacological properties and metabolism of SCBs relative to Delta9-THC may contribute to this increased toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Delta9-THC typically observed in vitro, SCBs act as full CB1 and CB2 receptor agonists both in cellular assays and animal studies. Furthermore, unlike Delta9-THC metabolism, several SCB metabolites retain high affinity for and exhibit a range of intrinsic activities at CB1 and CB2 receptors. Finally, the potential for SCBs to cause adverse drug-drug interactions with other drugs of abuse, as well as with common therapeutic agents, will be discussed. Collectively, the evidence provided in this chapter indicates that SCBs should not be considered safe and legal alternatives to marijuana. Instead, the enhanced toxicity of SCBs relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2 receptors, highlights the inherent danger that may accompany use of these substances. PMID- 28012095 TI - Anatomical variability and histological structure of the ulnar nerve in the Guyon's canal. AB - OBJECTIVES: The goal of our study was to analyze the prevalence of variations, branching patterns, and histology of the ulnar nerve (UN) in Guyon's canal to address its importance in hand surgery, particularly decompression of the UN. METHODS: Fifty fresh cadavers were dissected bilaterally, and the nerve in the area of Guyon's canal was visualized. Samples for histology were also taken and prepared. The collected data were then analyzed. RESULTS: Morphometric measurements of the hands and histological studies were not found to have significant differences when compared by left or right side or by sex. Three major branching patterns were found, with division into deep and superficial UN being the most common (85%). Additional findings included a majority (70%) presenting with a cutaneous branch within the canal and/or with an anastomosis of its distant branches with those of the median nerve (57%). CONCLUSION: The UN is most commonly found to divide into a superficial and deep ulnar branch within Guyon's canal. However, additional branches and anastomoses are common and should be taken into careful consideration when approached during surgery in the area, particularly during decompression procedures of Guyon's canal. PMID- 28012098 TI - Author's reply. PMID- 28012096 TI - A Sodium Channel Myotonia Presenting with Intermittent Dysphagia as a Manifestation of a Rare SCN4A Variant. AB - The voltage gated sodium channel SCN4A mutations account for non-dystrophic myotonia and include a heterogeneous group of conditions that include hyperkalemic periodic paralysis, paramyotonica congenita, potassium-aggravated myotonia, and hypokalemic periodic paralysis type 2. This case report proposes that a rare variant p.Pro1629Leu in SCN4A can cause a skeletal muscle deficit with intermittent dysphagia. PMID- 28012097 TI - miRNA Expression Change in Dorsal Root Ganglia After Peripheral Nerve Injury. AB - The role of microRNAs (miRNAs) in the regulation of nerve injury-induced neuropathic pain is unclear. The aims of this study were to assess and compare miRNA expression profiles in dorsal root ganglia (DRG) following three different kinds of peripheral nerve injury, including spinal nerve ligation (SNL), dorsal root transection (DRT), and ventral root transection (VRT), in Sprague-Dawley rats. Responses to thermal and mechanical stimuli were measured preoperatively and on postoperative days (PODs) 1, 4, and 7. A miRNA microarray analysis was used to detect the miRNA expression profiles in injured L5 DRG from SNL, DRT, and VRT on POD 7. Validation of miRNA expression was performed by qPCR and in situ hybridization. Rats receiving SNL displayed significantly higher mechanical hypersensitivity, but those receiving DRT developed higher thermal hypersensitivity. The number of miRNAs that were significantly upregulated in L5 DRG was 49 (7.2%), 25 (3.7%), and 146 (21.5%) following SNL, DRT, and VRT, respectively. On the other hand, 35 (5.1%) miRNAs were significantly downregulated in the SNL group, 21 (3.1%) miRNAs in the DRT group, and 41 (6.0%) miRNAs in the VRT group. Of the four miRNAs that were mutually aberrant in all three models, two were significantly upregulated (twofold), miR-21 and miR-31, and two were significantly downregulated, miR-668 and miR-672. Using in situ hybridization, miRNA-21, miRNA-31, miRNA-668, and miRNA-672 were found to localize to neurons in the DRG. Collectively, the mutual abnormal miRNA expression of miR-21, miR-31, miR-668, and miR-677 implied that these miRNAs may be therapeutic targets for alleviating multiple forms of neuropathic pain. PMID- 28012099 TI - Thrombocytopaenia during methicillin-sensitive Staphylococcus aureus bacteraemia. AB - The prognostic impact of thrombocytopaenia in Staphylococcus aureus bacteraemia (SAB) has previously been determined at bacteraemia onset only and relevant pre bacteraemic thrombocytopaenia predisposing parameters have not been accounted for. We evaluated the prognostic impact of low thrombocyte count in SAB excluding pre-bacteraemic factors potentially causing thrombocytopaenia. This was a multicentre retrospective analysis of methicillin-sensitive SAB (MS-SAB) patients. Thrombocyte count was determined at blood culture collection and at days 3 and 7. Thrombocytopaenia was defined as a thrombocyte count less than 150 *109/L. Patients with chronic alcoholism, liver diseases and haematologic malignancies were excluded. Altogether, 495 patients were identified. Thrombocytopaenia at blood culture and at day 3 associated to endocarditis (p < 0.05 and p < 0.01) and defervescence (p < 0.001 and p < 0.01). Mortality at 90 days was higher for patients with thrombocytopaenia at blood culture collection (26 vs. 16%, p < 0.05), at day 3 (32 vs. 13%, p < 0.01) and at day 7 (50 vs. 14%, p < 0.001). In receiver operating characteristic analyses, thrombocytopaenia predicted a poor outcome at blood culture collection (p < 0.05), at day 3 (p < 0.001) and at day 7 (p < 0.001). When accounting for all prognostic parameters, thrombocytopaenia at day 3 [hazard ratio (HR), 1.83; p = 0.05] demonstrated a trend towards poor outcome, whereas thrombocytopaenia at day 7 (HR, 3.64; p < 0.001) associated to poor outcome. Thrombocytopaenia at blood culture collection was not a prognostic parameter when all prognostic factors were taken into account. However, thrombocytopaenia at day 3 indicated a poor outcome and thrombocytopaenia at day 7 was a significant independent negative prognostic marker that has not been previously reported in SAB. PMID- 28012100 TI - The peritoneal sieving of sodium: a simple and powerful test to rule out the onset of encapsulating peritoneal sclerosis in patients undergoing peritoneal dialysis. AB - BACKGROUND AND AIMS: Encapsulating peritoneal sclerosis (EPS) is an uncommon but severe complication of peritoneal dialysis (PD). A reliable screening tool to identify patients at risk of developing or not EPS is currently not available. We aimed to evaluate whether the reduction in dialysate sodium concentration (sodium sieving) at 60 min (DeltaDNa60), during a peritoneal equilibration test with 3.86% glucose concentration (3.86%-PET) was able to early rule out patients who will not develop EPS. METHODS: Prospective controlled longitudinal (20-year) cohort study. All eligible incident PD patients attending the hospital underwent a 3.86%-PET during the first 3 months following start of PD and then once a year. The dip in DeltaDNa60 and other factors were correlated with eventual EPS onset. RESULTS: Of 161 incident PD patients, with a median PD duration of 37.8 (24.7 58.3) months and 64.1 (34.5-108.3) months of follow-up, 13 patients (8%) developed EPS at a median PD duration of 72.7 (56.6-109.4) months and 105.0 (76.4 143.2) months of follow-up. DeltaDNa60 demonstrated the best sensitivity and specificity values, estimated by conventional receiver operating characteristic (ROC) curve analysis with an area under the curve (AUC) of 0.90, 0.83 and 0.85 at 1, 2 and 3 years before the onset of EPS, respectively. Multifactorial analysis showed that the most useful factors for predicting EPS were age at start of PD, duration of PD, small solutes transport (D/PCreat) and DeltaDNa60; the AUC at 1, 2 and 3 years before the onset of EPS was, respectively, 0.97, 0.96 and 0.94, the positive predictive value being 0.48, 0.57 and 0.42, and the negative predictive value 1.0, 1.0 and 1.0. CONCLUSIONS: It is possible to predict the occurrence and, better, the non-occurrence of EPS using simple parameters such as age at PD start, duration of PD, and parameters obtained by 3.86%-PET such as D/PCreat and DeltaDNa60. PMID- 28012101 TI - Endoscopic Management of Esophagorespiratory Fistulas: A Multicenter Retrospective Study of Techniques and Outcomes. AB - BACKGROUND AND AIMS: Esophagorespiratory fistulas (ERF) are a devastating complication of benign and malignant etiologies. ERF are associated with high mortality, short survival, and poor quality of life. We performed a multicenter analysis of patients with ERF undergoing endoscopic treatment. METHODS: Multicentre retrospective study. RESULTS: We analyzed 25 patients undergoing 35 procedures over an 8-year period. Our data showed high technical success rates (97.1% of procedures) and with good, but not ideal, clinical success rates (60% of procedures, 80% of patients), which were defined as fistula closure confirmed by radiographic or repeat endoscopic evaluation and/or a lack of recurrent episodes of clinical aspiration to focus on durable ERF closure as opposed to only initial success. Proximal ERF were the most difficult to manage with the lowest overall clinical success rates, highest rates of recurrent aspiration despite endoscopic therapy, highest adverse events, and shortest survival times. Adverse events occurred in 40.0% of our patients and were all minor. Treatment allowed for diet advancement in 75% of patients. CONCLUSION: This represents the largest recent collection of US data and the first multicenter study evaluating the clinical success of multiple treatment modalities while stratifying data by fistula etiology and esophageal location. The endoscopic approaches detailed in this study offer a minimally invasive and safe choice for intervention with the potential to improve quality of life despite overall suboptimal clinical success and survivorship rates for in with ERF. PMID- 28012102 TI - De Novo Inflammatory Bowel Disease After Bariatric Surgery: A Case Series and Literature Review. PMID- 28012103 TI - Determinants of Healthcare Utilization Among Veterans with Inflammatory Bowel Disease. AB - BACKGROUND: Identifying patient-level and disease-specific predictors of healthcare utilization in inflammatory bowel disease (IBD) may allow targeted interventions to reduce costs and improve outcomes. AIM: To identify demographic and clinical predictors of healthcare utilization among veterans with IBD. METHODS: We conducted a single-center cross-sectional study of veterans with IBD from 1998 to 2010. Demographics and disease characteristics were abstracted by manual chart review. Annual number of IBD-related visits was estimated by dividing total number of IBD-related inpatient and outpatient encounters by duration of IBD care. Associations between predictors of utilization were determined using stepwise multivariable linear regression. RESULTS: Overall, 676 patients (56% ulcerative colitis (UC), 42% Crohn's disease (CD), and 2% IBD unclassified (IBDU)) had mean 3.08 IBD-related encounters annually. CD patients had 3.59 encounters compared to 2.73 in UC (p < 0.01). In the multivariable model, Hispanics had less visits compared to Caucasians and African-Americans (2.09 vs. 3.09 vs. 3.42), current smokers had more visits than never smokers (3.54 vs. 2.43, p = 0.05), and first IBD visit at age <40 had more visits than age >65 (3.84 vs. 1.75, p = 0.04). UC pancolitis was associated with more visits than proctitis (3.47 vs. 2.15, p = 0.04). CD penetrating phenotype was associated with more encounters than inflammatory type (4.68 vs. 4.15, p = 0.04). CONCLUSIONS: We found that current tobacco use, age <40 at first IBD visit, UC pancolitis, and CD fistuilizing phenotype in addition to Caucasian and African American race were independent predictors of increased healthcare utilization. Interventions should be targeted at these groups to decrease healthcare utilization and costs. PMID- 28012104 TI - Intravitreal dexamethasone implant for the treatment of cystoid macular oedema associated with acute retinal necrosis. AB - BACKGROUND: Acute retinal necrosis is a rare but devastating ocular condition. We report two cases of acute retinal necrosis in immunocompetent patients, complicated by cystoid macular oedema and treated with intravitreal dexamethasone (OZURDEX(r)) implant. RESULTS: Two patients diagnosed with acute retinal necrosis were treated with intravenous acyclovir. Both of them developed cystoid macular oedema following resolution of viral retinitis. Ocular condition of the first patient was further complicated by central serous chorioretinopathy. Under unavoidable circumstances, cystoid macular oedema in both the patients was treated with intravitreal dexamethasone implant with great caution. Resolution of cystoid macular oedema without recurrence of viral retinitis was noted in the long-term follow-up. CONCLUSIONS: Findings of the case report should be interpreted cautiously, and extreme caution should be exercised prior deciding the management with a corticosteroid implant in patients with viral retinitis. However, intravitreal dexamethasone implant can be a useful option in selected patients with cystoid macular oedema in acute retinal necrosis. PMID- 28012105 TI - The Epidemiology of Hypoparathyroidism in Italy: An 8-Year Register-Based Study. AB - Hypoparathyroidism is a rare endocrine disorder, but few studies have focused on the epidemiology and hospital management of the disease and none has been performed in Italy. We investigated the prevalence of different forms of hypoparathyroidism among hospitalized patients in Italy during an 8-year period. This study is designed as a retrospective register-based study. We retrieved data from the "Record of Hospital Discharge" (SDO) of the Italian Health Ministry, from the year 2006 to 2013 and analyzed the codes corresponding to hypoparathyroidism-related diagnoses. The inpatient prevalence of the disease was also calculated after excluding repeated hospitalizations. Overall, 27,692 hospitalization episodes for hypoparathyroidism were identified during the entire period (72.2% in women and 27.8% in men; mean age 49.5 +/- 22.9 years). The mean length of stay was 7.4 +/- 9.8 days (25.9% of the episodes requiring less than 3 days of stay). The mean hospitalization rate for hypoparathyroidism was 5.9/100,000 inhabitants per year and there was a significant decrease during the period of 2006-2013 (p < 0.0001). The mean hospitalization rate for postsurgical hypoparathyroidism was 1.4/100,000 inhabitants per year and the trend showed a significant reduction during the years (p < 0.0001). The mean prevalence of hypoparathyroidism among inpatients was 5.3/100,000 inhabitants per year, and there was a significant decrease over the years (p < 0.0001). Hypoparathyroidism, particularly the postsurgical form of the disease, is not an uncommon condition among hospitalized patients in Italy. We observed a tendency to a decrease in the frequency of hospitalization during the period 2006-2013. PMID- 28012106 TI - Osteogenic Potential of the Transcription Factor c-MYB. AB - The transcription factor c-MYB is a well-known marker of undifferentiated cells such as haematopoietic cell precursors, but recently it has also been observed in differentiated cells that produce hard tissues. Our previous findings showed the presence of c-MYB in intramembranous bones and its involvement in the chondrogenic steps of endochondral ossification, where the up-regulation of early chondrogenic markers after c-myb overexpression was observed. Since we previously detected c-MYB in osteoblasts, we aimed to analyse the localisation of c-MYB during later stages of endochondral bone formation and address its function during bone matrix production. c-MYB-positive cells were found in the chondro osseous junction zone in osteoblasts of trabecular bone as well as deeper in the zone of ossification in cells of spongy bone. To experimentally evaluate the osteogenic potential of c-MYB during endochondral bone formation, micromasses derived from embryonic mouse limb buds were established. Nuclear c-MYB protein expression was observed in long-term micromasses, especially in the areas around nodules. c-myb overexpression induced the expression of osteogenic-related genes such as Bmp2, Comp, Csf2 and Itgb1. Moreover, alizarin red staining and osteocalcin labelling promoted mineralised matrix production in c-myb overexpressing cultures, whereas downregulation of c-myb by siRNA reduced mineralised matrix production. In conclusion, c-Myb plays a role in the osteogenesis of long bones by inducing osteogenic genes and causing the enhancement of mineral matrix production. This action of the transcription factor c-Myb might be of interest in the future for the establishment of novel approaches to tissue regeneration. PMID- 28012107 TI - The Future Prevalence of Sarcopenia in Europe: A Claim for Public Health Action. AB - Sarcopenia is a major public health issue. To convince health policy makers of the emergency to invest in the sarcopenia field, it is of critical importance to produce reliable figures of the expected burden of sarcopenia in the coming years. Age- and gender-specific population projections were retrieved until 2045 from the Eurostat online database (28 European countries). Age- and gender specific prevalences of sarcopenia were interpolated from a study that compared prevalence estimates according to the different diagnostic cutoffs of the EWGSOP proposed definition. The reported prevalence estimates were interpolated between 65 and 100 years. Interpolated age- and gender-specific estimates of sarcopenia prevalence were then applied to population projections until 2045. Using the definition providing the lowest prevalence estimates, the number of individuals with sarcopenia would rise in Europe from 10,869,527 in 2016 to 18,735,173 in 2045 (a 72.4% increase). This corresponds to an overall prevalence of sarcopenia in the elderly rising from 11.1% in 2016 to 12.9% in 2045. With the definition providing the highest prevalence estimates, the number of individuals with sarcopenia would rise from 19,740,527 in 2016 to 32,338,990 in 2045 (a 63.8% increase), corresponding to overall prevalence rates in the elderly of 20.2% and 22.3% for 2016 and 2045, respectively. We showed that the number of sarcopenic patients will dramatically increase in the next 30 years, making consequences of muscle wasting a major public health issue. PMID- 28012108 TI - Differentiation of frogs from two populations belonging to the Pelophylax esculentus complex by LC-MS/MS comparison of their skin peptidomes. AB - LC-MS/MS was applied to establish the composition of the skin peptidome of a Slovenian green frog belonging to the Pelophylax esculentus complex. As this was similar to the peptidome of the Moscow population of Pelophylax ridibundus, it allowed us to identify the Slovenian frog from the Pelophylax esculentus complex as Pelophylax ridibundus. The sequences of six new peptides from the brevinin 2 family are reported for the first time on the basis of manual interpretation of their tandem mass spectra. The structural similarity of the brevinin 2 peptides from the Moscow and Slovenian populations of Pelophylax ridibundus enables peptides from this family to be utilized as biomarkers for Pelophylax ridibundus inter- and intraspecies differentiation, and the proposed approach can be used as an analytical tool for differentiating the corresponding species and populations. The potential biological activities of the novel peptides were estimated by 2D mass mapping. The results allowed us to classify all of the available peptides belonging to the brevinin 2 family. Graphical Abstract Intraspecies identification within the green frog complex. PMID- 28012109 TI - Development of a lateral flow immunoassay for rapid diagnosis of potato blackleg caused by Dickeya species. AB - Early detection of potato infections is essential for effective disease management. The aim of this study was to develop a lateral flow immunoassay (LFIA) for rapid detection of a serious potato disease, potato blackleg, caused by Dickeya dianthicola and Dickeya solani. Polyclonal antibodies specific to different strains of Dickeya were obtained from rabbits after immunization with bacterial cells of D. dianthicola and D. solani. Enzyme-linked immunosorbent assay testing with use of a wide range of bacterial species showed that the polyclonal antibodies detect closely related strains of D. dianthicola and D. solani. Cross-reactivity with widespread pathogenic bacteria (nine species) and saprophytes of healthy potato plants was not detected. The LFIA based on the obtained antibodies and gold nanoparticles with average diameter of 20 nm was developed. Under optimized conditions, the LFIA method enabled the analysis of potato extracts within 10 min, with a visual limit of detection of 1 * 105 CFU/ml for leaves and 4 * 105 CFU/ml for tubers. The assay was tested on potato stem and tuber extracts, and the results of the LFIA were confirmed in 92.1% of samples using the real-time polymerase chain reaction. The findings confirmed that the developed LFIA could be used for monitoring blackleg infection without the need for special equipment or skills. Graphical Abstract The developed lateral flow immunoassay is an efficient tool for rapid detection of a serious potato disease, potato blackleg, caused by Dickeya dianthicola and Dickeya solani. PMID- 28012110 TI - Enrichment of serum biomarkers by magnetic metal-organic framework composites. AB - Highly efficient extraction of peptides from serum is critical for finding serum biomarkers using mass spectrometry, which still remains a great challenge. Currently, a bottom-up proteomics approach has been applied to discover serum biomarkers. However, the approach was labor intensive, time and cost consuming, and cannot meet the requirements for clinical application. In this work, Fe3O4/C@MIL-100 composites were synthesized to efficiently capture peptides from microwave-assisted formic acid digests of BSA and human serum prior to MALDI-TOF MS analysis. Fe3O4/C@MIL-100 composites exhibited size-selective adsorption performance, thus providing a rapid and convenient approach to enrich low abundance peptides. Notably, the peptides' mass fingerprinting of serum digestions between type 2 diabetes mellitus (T2DM) and healthy persons were distinguishable, which indicated the potential ability of this technique for T2DM diagnosis and rapid biomarker discovery. Graphical Abstract Efficient extraction and identification of serum biomarkers using Fe3O4/C@MIL-100 composites from acid hydrolysate. PMID- 28012111 TI - Automated thin-film microextraction coupled to a flow-through cell: somewhere in between passive and active sampling. AB - A prototype for the automated thin-film microextraction of pharmaceuticals from aqueous solutions has been developed and is presented here for the first time. With a software-controlled setup, extraction methods for ivermectin and iohexol have been developed. The widely used antiparasitic agent ivermectin is non-polar and has a high tendency to sorb to surfaces. In contrast to this, the nonionic but polar iodinated X-ray contrast agent iohexol is freely water soluble. With these two substances, a wide range of polarity is covered. Sorption kinetics and thermodynamics of ivermectin and iohexol were studied. With the presented passive sampling approach, it was possible to extract up to 96.2% ivermectin with a C18 phase within 1 h and up to 74.6% of iohexol with a PS-DVB phase within 36 h out of water. Using abamectin as internal standard, it was possible to quantitatively follow dissipation of ivermectin in a simulated surface water experiment. Predominantly, the newly developed prototype can be used for automated and time resolved extraction of xenobiotics from waterbodies under field conditions, for the extraction of substances under laboratory conditions as an alternative to the elaborate solid-phase extraction, and for the automated control of chemical reaction kinetics. PMID- 28012112 TI - Rapid analysis of cocaine and metabolites in urine using microextraction in packed sorbent and GC/MS. AB - Cocaine is still one of the most abused drugs worldwide and, as such, it is often screened for in driving-under-the-influence or workplace drug - testing scenarios. A large number of samples have usually to be processed in those situations, and this requires fast and simple extraction procedures for the detection and quantification of the drugs. The present work describes an ultrafast and fully validated procedure for the simultaneous detection and quantification of cocaine and its two main metabolites, ecgonine methyl ester and benzoylecgonine, in urine using microextraction by packed sorbent and GC-MS. A small sample volume (200 MUL) was used, and a fast extraction procedure together with a microwave-assisted derivatization (800 W, 2 min) allowed the quantification of all analytes in a range of 25 to 1000 ng/mL (r 2 > 0.99). Inter day precision revealed coefficients of variation (CVs) lower than 10% for all analytes at the tested concentration levels, with an accuracy within a +/-7% interval, with the exception of EME's lowest calibrator (+/-17%). Intra-day CVs were lower than 15% at the studied concentration levels, with a mean relative error within a +/-13% interval. Recoveries ranged from 14.5 to 37.2% (EME), 67.0 to 83.3% (cocaine), and 24.6 to 43.5% (BEG), allowing the limits of detection and quantification to be set at 25 ng/mL for all compounds. Graphical Abstract Schematized analysis of cocaine and metabolites in urine by MEPS- GC/MS. PMID- 28012113 TI - Suicidal Behavior in Iran: What Should Be Done? PMID- 28012114 TI - Differential Effects of Family Structure on Religion and Spirituality of Emerging Adult Males and Females. AB - This study examined measures of religion and spirituality in a sample of male and female emerging adult college students whose parents were either divorced or intact using the Personal Religious Inventory, the Duke University Religion Index, the Daily Spiritual Experiences Scale, the Spiritual Transcendence Scale, and the Spiritual Involvement and Beliefs Scale. Data were collected online, and 66% of participants received extra credit for participating. A main effect of sex was found, as females reported significantly higher scores than men on all but one measure of religion and spirituality, and the dataset was separated by sex. No differences were found between males from divorced and intact families. However, females from intact families scored significantly higher on all religion and spirituality measures than females from divorced families. This study suggests that females may respond differently than males to their parents' divorce in the context of religion and spirituality, and discusses possible reasons. PMID- 28012115 TI - WRN, the Werner Syndrome Gene, Exhibits Frameshift Mutations in Gastric and Colorectal Cancers. PMID- 28012116 TI - Serum Chromogranin A as a Complementary Marker for the Prediction of Prostate Cancer-Specific Survival. AB - Better prognostication of clinically localized prostate cancer (PCA) is urgently needed. Former studies using different study end-points provided controversial results regarding the prognostic value of serum chromogranin A (CGA) in clinically localized PCA. However, serum CGA was not tested for correlation with the most significant study end-point of long-term disease-specific survival (DSS). CGA and matrix metalloproteinase-7 (MMP7) levels were measured by the BRAHMS KRYPTOR in two independent patient groups with 127 serum and 110 plasma samples. CGA and MMP7 concentrations were correlated with clinicopathological and survival data. In addition, we tested the combinations of CGA with PSA and with a currently identified prognostic factor, MMP7, for their prognostic value. CGA concentrations were significantly elevated in advanced compared to clinically localized cases both in serum and plasma samples (45 vs. 23 ng/ml, p < 0.001 and; 41 vs. 22 ng/ml; p = 0.002 respectively). In accordance, high CGA levels were correlated with poor DSS. In clinically localized cases, CGA levels alone were not prognostic, but its dichotomized combinations with PSA or MMP7 were independently associated with DSS (HR: 4.88, 95% CI: 1.35-17.71, p = 0.016, HR: 7.46, 1.65-33.63, p = 0.009, respectively). Elevated serum CGA levels in progressed PCA and its prognostic value suggest a potential for CGA in disease monitoring. Our results revealed no independent prognostic value for CGA as a single serum marker in clinically localized cases. However, when combining with PSA or MMP7, CGA may improve both marker's performance in distinguishing between clinically significant and indolent PCAs. PMID- 28012117 TI - Complete genome sequence analysis of chicken astrovirus isolate from India. AB - OBJECTIVE: Chicken astroviruses have been known to cause severe disease in chickens leading to increased mortality and "white chicks" condition. Here we aim to characterize the causative agent of visceral gout suspected for astrovirus infection in broiler breeder chickens. METHODS: Total RNA isolated from allantoic fluid of SPF embryo passaged with infected chicken sample was sequenced by whole genome shotgun sequencing using ion-torrent PGM platform. The sequence was analysed for the presence of coding and non-coding features, its similarity with reported isolates and epitope analysis of capsid structural protein. RESULTS: The consensus length of 7513 bp genome sequence of Indian isolate of chicken astrovirus was obtained after assembly of 14,121 high quality reads. The genome was comprised of 13 bp 5'-UTR, three open reading frames (ORFs) including ORF1a encoding serine protease, ORF1b encoding RNA dependent RNA polymerase (RdRp) and ORF2 encoding capsid protein, and 298 bp of 3'-UTR which harboured two corona virus stem loop II like "s2m" motifs and a poly A stretch of 19 nucleotides. The genetic analysis of CAstV/INDIA/ANAND/2016 suggested highest sequence similarity of 86.94% with the chicken astrovirus isolate CAstV/GA2011 followed by 84.76% with CAstV/4175 and 74.48%% with CAstV/Poland/G059/2014 isolates. The capsid structural protein of CAstV/INDIA/ANAND/2016 showed 84.67% similarity with chicken astrovirus isolate CAstV/GA2011, 81.06% with CAstV/4175 and 41.18% with CAstV/Poland/G059/2014 isolates. However, the capsid protein sequence showed high degree of sequence identity at nucleotide level (98.64-99.32%) and at amino acids level (97.74-98.69%) with reported sequences of Indian isolates suggesting their common origin and limited sequence divergence. The epitope analysis by SVMTriP identified two unique epitopes in our isolate, seven shared epitopes among Indian isolates and two shared epitopes among all isolates except Poland isolate which carried all distinct epitopes. PMID- 28012118 TI - Risk factors for QTc-prolongation: systematic review of the evidence. AB - Background QTc-interval prolongation has been associated with serious adverse events, such as Torsade de Pointes and sudden cardiac death. In the prevention of QTc-prolongation, special attention should go to high-risk patients. Aim of the review The aim of this review is to summarize and assess the evidence for different risk factors for QTc-prolongation (demographic factors, comorbidities, electrolytes, QTc-prolonging medication). Methods Potential studies were retrieved based on a systematic search of articles published until June 2015 in the databases Medline and Embase. Both terms about QTc-prolongation/Torsade de Pointes and risk factors were added in the search strategy. The following inclusion criteria were applied: randomized controlled trials and observational studies; inclusion of >=500 patients from a general population (not limited to specific disease states); assessment of association between QTc-interval and risk factors. For the articles that met the inclusion criteria, the following data were extracted: study design, setting and study population, number of patients and cases of QTc-prolongation, method of electrocardiogram-monitoring, QTc correction formula, definition of QTc-prolongation, statistical methods and results. Quality assessment was performed using the GRADE approach (for randomized controlled trials) and the STROBE-recommendations (for observational studies). Based on the number of significant results and the level of significance, a quotation of the evidence was allocated. Results Ten observational studies could be included, with a total of 89,532 patients [prospective cohort design: N = 6; multiple regression analyses: N = 5; median STROBE score = 17/22 (range 15-18)]. Very strong evidence was found for hypokalemia, use of diuretics, antiarrhythmic drugs and QTc-prolonging drugs of list 1 of CredibleMeds. Little or no evidence was found for hyperlipidemia, the use of digoxin or statins, neurological disorders, diabetes, renal failure, depression, alcohol abuse, heart rate, pulmonary disorders, hormone replacement therapy, hypomagnesemia, history of a prolonged QTc-interval/Torsade de Pointes, familial history of cardiovascular disease, and the use of only QTc-prolonging drugs of list 2 or 3 of CredibleMeds. Conclusion This systematic review gives a clear overview of the available evidence for a broad range of risk factors for QTc-prolongation. PMID- 28012119 TI - Antibiotic treatment of women with uncomplicated cystitis before and after allowing pharmacist-supply of trimethoprim. AB - Background In 2012, New Zealand reclassified trimethoprim to allow specially trained pharmacists to supply it without a prescription to women with symptoms suggesting uncomplicated cystitis, under strict criteria for supply. Objective To assess how this policy change allowing pharmacist supply of trimethoprim affected overall antibiotic supply. Setting Randomly selected community pharmacies throughout New Zealand. Methods Data were collected in pharmacies before the implementation ('baseline') and 1 year later ('post-implementation'). Pharmacy staff recorded prescription and nonprescription supplies for treatment or prevention of suspected urinary tract infections. Women with a prescription for treatment or prevention of presumed urinary tract infection or purchasing a non prescription medicine for this purpose were invited to self-complete a questionnaire. National prescribing data were extracted for trimethoprim, nitrofurantoin and norfloxacin. Main outcome measure Antibiotic use in women with UTIs from dispensed prescriptions (baseline and post-implementation) and pharmacist-supplied trimethoprim (post-implementation), particularly focusing on women aged 16-65 years with an antibiotic for presumed cystitis without complicating features. Results Baseline data were provided by 139 pharmacies, 120 of which provided post-implementation data. In women with presumed cystitis without complicating features, prescriptions before and after the implementation were primarily for trimethoprim. Overall antibiotic use, and use of second-line agents did not increase post-implementation. Pharmacist-supplies of trimethoprim were modest nearly 1 year after the service started. Conclusion Supply of trimethoprim by specially trained pharmacists working within strict criteria for supply appeared to have little overall effect on antibiotic use. Further research on patient outcomes, resistance and changes over time is recommended. PMID- 28012120 TI - Improvement in automated quantitation of myocardial perfusion abnormality by using iterative reconstruction image in combination with resolution recovery, attenuation and scatter corrections for the detection of coronary artery disease. AB - OBJECTIVE: An iterative reconstruction method in combination with resolution recovery, attenuation and scatter corrections (IR-RASC) can improve image quality. It, however, is undetermined whether this technique can improve the detection of coronary artery disease (CAD) when automated quantitative analysis is used. This study evaluated diagnostic values of IR-RASC in combination with automated quantitative analysis in stress myocardial perfusion imaging (MPI) in the CAD detection. METHODS: This study enrolled consecutive 64 patients (mean age 66.2 +/- 17.3 years, 39 males) who had undergone both 99mTc-labeled tetrofosmin stress MPI and coronary angiography within 3 months. Stress MPI abnormalities quantified as summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS) by Heart Risk View-S (HRV-S) and Quantitative Perfusion SPECT (QPS) softwares using IR-RASC images were compared with those by using conventional filtered back-projection method (FBP) images and angiographic findings. RESULTS: Based on expert visual assessment, SSS and SRS by HRV-S/QPS softwares with IR-RASC were significantly lower than those by HRV-S/QPS softwares with FBP at mid- and basal left ventricular segments. Receiver-operating characteristics analysis showed that areas under the curve assessed by HRV-S (0.687) and QPS (0.678) with IR-RASC were nearly identical to those (0.717-0.724) by expert assessment with FBP, and were significantly (P < 0.05) greater than those by HRV-S (0.505) and QPS (0.522) with FBP. When HRV-S was used, the specificity and diagnostic accuracy of IR-RASC in the CAD detection were significantly greater than those of FBP: 90.3 versus 51.6%, P < 0.0001 and 79.7 versus 54.7%, P = 0.0027, respectively. Likewise, when QPS was used, the specificity and diagnostic accuracy of IR-RASC in the CAD detection were significantly greater than those of FBP: 80.6 versus 41.9%, P < 0.0001, and 78.1 versus 51.6%, P = 0.0018, respectively. There, however, were no significant differences in sensitivity between IR-RASC and FBP images. CONCLUSIONS: IR-RASC can improve diagnostic accuracy of the CAD detection using an automated scoring system compared to FBP, by reducing false positivity due to artefactual appearance. PMID- 28012121 TI - Triathlon training for women breast cancer survivors: feasibility and initial efficacy. AB - : ?: Exercise can improve quality of life (QOL) in breast cancer survivors. In contrast to many group or home-based exercise programs, little is known about the effectiveness of goal-oriented recreational activities. PURPOSE: The purpose of this study was to evaluate a clinically overseen team triathlon training program on improving physiological and psychosocial health-related measures in female breast cancer survivors. METHODS: Twenty-three participants (age = 48 (8), BMI = 25 (1), mean (SE)) were recruited from a 14-week sprint triathlon (800-m swim, 20 km bike, 5-km run) team training program for women breast cancer survivors (4 (3) years post-surgery, chemo-, or radiation-therapy). Training included two supervised group and three home-based individual sessions per week. Pre- and post training outcomes included isokinetic knee extensor strength (60, 180, and 300 degrees s-1), 6-min walk test (6MWT), maximal oxygen uptake (VO2 max), QOL (Functional Assessment of Cancer Therapy -Breast (FACT-B)), and barriers to exercise. Outcomes were also obtained 6 months post except for VO2 max. Significance was set at p < 0.05. RESULTS: Data are mean (SD) from 21 complete data sets. Knee extensor peak torque significantly improved only at 300 degrees s-1 (pre 40.3(8.5) ftlb; post 45.2(8.4); p = 0.001). 6MWT significantly improved (pre 632.8(62.1) m; post 657.4(53.2); p = 0.014) as did VO2 max (pre 31.3(5.8) ml kg-1 min-1; post 35.9(5.8); p < 0.001). FACT-B also improved (pre 114(12); post 122(13); p = 0.004), including the FACT-G total score, social well-being, and breast cancer subscales while barriers to exercise decreased (pre 54(12); post 36(9); p < 0.001). Strength, 6MWT, and barriers to exercise remained improved after 6 months. CONCLUSIONS: Team triathlon training in breast cancer survivors can increase aerobic capacity and improve QOL which may contribute to healthier lifestyles in breast cancer survivors. PMID- 28012122 TI - Skeletal Radiology: the year in review 2016. AB - A look back at Skeletal Radiology in 2016 reveals a sizable number of publications that significantly advanced the state of knowledge about diseases of the musculoskeletal system. This review summarizes the content of some of the most intriguing papers of the year. PMID- 28012123 TI - Not only in the temperate zone: independent gametophytes of two vittarioid ferns (Pteridaceae, Polypodiales) in East Asian subtropics. AB - Independent gametophyte ferns are unique among vascular plants because they are sporophyteless and reproduce asexually to maintain their populations in the gametophyte generation. Such ferns had been primarily discovered in temperate zone, and usually hypothesized with (sub)tropical origins and subsequent extinction of sporophyte due to climate change during glaciations. Presumably, independent fern gametophytes are unlikely to be distributed in tropics and subtropics because of relatively stable climates which are less affected by glaciations. Nonetheless, the current study presents cases of two independent gametophyte fern species in subtropic East Asia. In this study, we applied plastid DNA sequences (trnL-L-F and matK + ndhF + chlL datasets) and comprehensive sampling (~80%) of congeneric species for molecular identification and divergence time estimation of these independent fern gametophytes. The two independent gametophyte ferns were found belonging to genus Haplopteris (vittarioids, Pteridaceae) and no genetic identical sporophyte species in East Asia. For one species, divergence times between its populations imply recent oversea dispersal(s) by spores occurred during Pleistocene. By examining their ex situ and in situ fertility, prezygotic sterility was found in these two Haplopteris, in which gametangia were not or very seldom observed, and this prezygotic sterility might attribute to their lacks of functional sporophytes. Our field observation and survey on their habitats suggest microhabitat conditions might attribute to this prezygotic sterility. These findings point to consideration of whether recent climate change during the Pleistocene glaciation resulted in ecophysiological maladaptation of non-temperate independent gametophyte ferns. In addition, we provided a new definition to classify fern gametophyte independences at the population level. We expect that continued investigations into tropical and subtropical fern gametophyte floras will further illustrate the biogeographic significance of non-temperate fern gametophyte independence. PMID- 28012124 TI - Studies on ontogeny and reproductive behaviour of Lepisorus nudus (Hook.) Ching (Polypodiaceae). AB - In-vitro studies of the ontogeny and mating system of the gametophytes of Lepisorus nudus were carried out through multispore and isolate cultures lasting 23 weeks. Spore germination begins early, on day 5-6. Spore germination pattern was Vittaria type and the germination percentage reached 82.69% (+/- 3.20%). Filamentous gametophyte did not branch and never produce separate prothalli. Occasionally the branching and separate prothalli were produced from mature and cordate gametophytes. Prothallial development was Drynaria type (cordate gametophytes with notched apex) contrary to other known species of Lepisorus, where gametophyte development was Kaulinia type (strap gametophytes without apical notch). Gametophyte production in multispore cultures reached up-to 75.6% (+/- 18.85%). All isolates initially produced archegonia and antheridia only after a prolonged cessation of production in archegonia. In contrast, only 37.2% (+/-12.63%) of individuals in multispore culture exhibited the same pattern with 29.8% (+/-7.56%) developing as males that did not produce archegonia by the end of the study. Only 37.2% (+/-12.63%) of archegoniate gametophytes developed antheridia by the end of the study and only once archegonia had degenerated; i.e., a temporal gap existed in expression of female and male gametangia. In multispore culture, only 26.21% (+/-5.70%) sporophytes developed on 160th day by fusion of female and male gametes that were derived from matings between sib gametophytes. In contrast, isolated gametophytes did not produce sporophytes. In isolate gametophytes, mature archegonia could not take delivery of male gametangia because antheridia were produced sequentially. This study suggests that the sequential expression of gametangia and absence of the intragametophytic selfing may also be a possible cause of reproductive barriers. Lepisorus nudus promotes inter-gametophytic selfing as an adaptive mechanism for reproductive success in multispore culture. This study presents a detailed account on reproductive biology of the taxa whose population is decreasing at distressing rate. PMID- 28012125 TI - High pressure 31P NMR spectroscopy on guanine nucleotides. AB - The 31P NMR pressure response of guanine nucleotides bound to proteins has been studied in the past for characterizing the pressure perturbation of conformational equilibria. The pressure response of the 31P NMR chemical shifts of the phosphate groups of GMP, GDP, and GTP as well as the commonly used GTP analogs GppNHp, GppCH2p and GTPgammaS was measured in the absence and presence of Mg2+-ions within a pressure range up to 200 MPa. The pressure dependence of chemical shifts is clearly non-linear. For all nucleotides a negative first order pressure coefficient B 1 was determined indicating an upfield shift of the resonances with pressure. With exception of the alpha-phosphate group of Mg2+.GMP and Mg2+.GppNHp the second order pressure coefficients are positive. To describe the data of Mg2+.GppCH2p and GTPgammaS a Taylor expansion of 3rd order is required. For distinguishing pH effects from pressure effects a complete pH titration set is presented for GMP, as well as GDP and GTP in absence and presence of Mg2+ ions using indirect referencing to DSS under identical experimental conditions. By a comparison between high pressure 31P NMR data on free Mg2+-GDP and Mg2+-GDP in complex with the proto-oncogene Ras we demonstrate that pressure induced changes in chemical shift are clearly different between both forms. PMID- 28012126 TI - Intra-operative tissue diagnosis: isn't it time for some reporting guidelines? PMID- 28012127 TI - Fluorescein sodium-guided resection of cerebral metastases-an update. AB - BACKGROUND: Cerebral metastasis (CM) is the most common malignancy affecting the brain. In patients eligible for surgery, complete tumor removal is the most important predictor of overall survival and neurological outcome. The emergence of surgical microscopes fitted with a fluorescein-specific filter have facilitated fluorescein-guided microsurgery and identification of tumor tissue. In 2012, we started evaluating fluorescein (FL) with the dedicated microscope filter in cerebral metastases (CM). After describing the treatment results of our first 30 patients, we now retrospectively report on 95 patients. METHODS: Ninety five patients with CM of different primary cancers were included (47 women, 48 men, mean age, 60 years, range, 25-85 years); 5 mg/kg bodyweight of FL was intravenously injected at induction of anesthesia. A YELLOW 560-nm filter (Pentero 900, ZEISS Meditec, Germany) was used for microsurgical tumor resection and resection control. The extent of resection (EOR) was assessed by means of early postoperative contrast-enhanced MRI and the grade of fluorescent staining as described in the surgical reports. Furthermore, we evaluated information on neurological outcome and surgical complications as well as any adverse events. RESULTS: Ninety patients (95%) showed bright fluorescent staining that markedly enhanced tumor visibility. Five patients (5%); three with adenocarcinoma of the lung, one with melanoma of the skin, and one with renal cell carcinoma) showed insufficient FL staining. Thirteen patients (14%) showed residual tumor tissue on the postoperative MRI. Additionally, the MRI of three patients did not confirm complete resection beyond doubt. Thus, gross-total resection had been achieved in 83% (n = 79) of patients. No adverse events were registered during the postoperative course. CONCLUSIONS: FL and the YELLOW 560-nm filter are safe and feasible tools for increasing the EOR in patients with CM. Further prospective evaluation of the FL-guided technique in CM-surgery is in planning. PMID- 28012128 TI - Death of a seven-month-old child in a washing machine: a case report. AB - The authors present a case which brings out a unique modality of child homicide by placing the baby in a washing machine and turning it on. The murder was perpetrated by the baby's mother, who suffered from a serious depressive disorder. A postmortem RX and then a forensic autopsy were performed, followed by histologic examinations and toxicology. On the basis of the results of the autopsy, as well as the histology and the negative toxicological data, the cause of death was identified as acute asphyxia. This diagnosis was rendered in light of the absence of other causes of death, as well as the presence of typical signs of asphyxia, such as epicardial and pleural petechiae and, above all, the microscopic examinations, which pointed out a massive acute pulmonary emphysema. Regarding the cause of the asphyxia, at least two mechanisms can be identified: drowning and smothering. In addition, the histology of the brain revealed some findings that can be regarded as a consequence of the barotrauma due to the centrifugal force applied by the rotating drum of the washing machine. Another remarkable aspect is that we are dealing with a mentally-ill assailant. In fact, the baby's mother, after a psychiatric examination, was confirmed to be suffering from a mental illness-a severe depressive disorder-and so she was adjudicated not guilty-by-reason-of-insanity. This case warrants attention because of its uniqueness and complexity and, above all, its usefulness in the understanding of the pathophysiology of this particular manner of death. PMID- 28012129 TI - Expression of CD24 and Siglec-10 in first trimester placenta: implications for immune tolerance at the fetal-maternal interface. AB - During pregnancy, the fetal-maternal interface establishes immune tolerance between the fetus and the mother. CD24, a mucin-like glycoprotein expressed at the surface of hematopoietic cells and diverse tumor cells, is known to interact with the sialic acid-binding immunoglobulin-type lectins (Siglecs). This interaction was assessed as a candidate complex for the immune suppression response in the placenta. CD24 was affinity purified from term placenta and characterized by SDS-PAGE, Western blot and ELISA. Binding of recombinant Siglecs to placental CD24 was evaluated by ELISA. The expression of CD24 and Siglec-10 in first trimester placental tissues was investigated by immunohistochemistry and immunofluorescence. Placental CD24 had an apparent molecular weight of 30-70 kDa consistent with its high degree of N- and O-linked glycosylation. EDTA-sensitive CD24-Siglec-10 interaction via the terminal sialic acid glycan residues of CD24 was observed. CD24 did not interact with Siglec-3 or Siglec-5. During the first trimester, and already in gestational week (GA) 8, CD24 showed high expression in villous and extravillous cytotrophoblasts. There was also a mild expression in stromal cells, while syncytiotrophoblasts were negative. Co-localization of CD24 with Siglec-10 was observed in endometrial glands and in first trimester decidual cells in close vicinity to extracellular trophoblasts. This study is the first to demonstrate the early presence of CD24 in the placenta cytotrophoblast layers, placental bed and maternal uterine glands. The presence of the CD24-Siglec-10 in these regions of fetal-maternal interactions suggests a possible role in mediating immune tolerance at the fetal-maternal interface. PMID- 28012130 TI - Accumulation of the advanced glycation end product carboxymethyl lysine in breast cancer is positively associated with estrogen receptor expression and unfavorable prognosis in estrogen receptor-negative cases. AB - Advanced glycation end products (AGEs) accumulate as a result of high concentrations of reactive aldehydes, oxidative stress, and insufficient degradation of glycated proteins. AGEs are therefore accepted biomarkers for aging, diabetes, and several degenerative diseases. Due to the Warburg effect and increased oxidative stress, cancer cells frequently accumulate significant amounts of AGEs. As the accumulation of AGEs may reflect the metabolic state and receptor signaling, we evaluated the potential prognostic and predictive value of this biomarker. We used immunohistochemistry to determine the AGE Nepsilon carboxymethyl lysine (CML) in 213 mammary carcinoma samples and Western blotting to detect AGEs in cell cultures. Whereas no significant correlation between hormone receptor status and CML was observed in cell lines, CML accumulation in tumors was positively correlated with the presence of estrogen receptor alpha, the postmenopausal state, and age. A negative correlation was found for grade III carcinomas and triple-negative cases. In a retrospective Kaplan-Meier survival analysis, there was a statistical trend that high CML accumulation correlated with a more favorable prognosis (relapse-free survival, RFS) under tamoxifen treatment (p = 0.1). In estrogen receptor-negative cases, the high CML content was significantly correlated with an unfavorable outcome (RFS) of chemotherapy (p = 0.046). CML is a therefore a potentially predictive marker for the treatment of breast cancer patients with tamoxifen or chemotherapy. PMID- 28012133 TI - CTC clusters in cancer progression and metastasis. AB - Circulating tumor cells (CTC) in the blood of cancer patients are regarded as potential metastatic seeds, and their detailed characterization holds great promises for more exact prognosis, better diagnosis and therapy of the metastatic cancer. Circulating tumor cell clusters represent different class of CTCs, with specific properties, including high metastatic potential. In this review, we present current opinions on differences between single CTCs and CTC clusters, their mode of dissemination, methods of detection and clinical importance in various types of cancer. PMID- 28012132 TI - Galectins: their network and roles in immunity/tumor growth control. AB - One route of realizing the information of glycans involves endogenous receptors (lectins). Occurrence at branch ends renders galactosides particularly accessible. Thus, they are suited for such a recognition process. Fittingly, these epitopes serve as physiological ligands. The ga(lactoside-binding) lectins share the beta-sandwich fold with a sequence signature around a central tryptophan residue besides this specificity. Three modes of presentation of the carbohydrate recognition domain are known for galectins, and genome monitoring from fungi to mammals discloses that galectins form a network. The extent of its complexity varies considerably between organisms, for chicken reaching seven proteins, more for mammals. The current status of network analysis reveals overlapping and distinct expression profiles. Matching intra- and extracellular galectin presence, they have a broad range of functions at each site depending on their specific counterreceptor(s), with the possibility even for functional antagonism between family members. Orchestration of expression of galectin, the cognate glycan, its scaffold (protein or sphingolipid) and spatial aspects of glycoconjugate presentation has been detected to lead to growth regulation of immune and tumor cells. To delineate the factors that underlie the specificity of a galectin for its counterreceptor(s) in the cellular context and the details of structure-activity relationships by comparatively analyzing natural and rationally engineered proteins is the main challenge for ongoing research. PMID- 28012134 TI - Elevated levels of epithelial cell transforming sequence 2 predicts poor prognosis for prostate cancer. AB - Epithelial cell transforming sequence 2 (Ect2) was originally reported as an oncogene that is involved in several types of human cancers. However, little is known about its expression and function in prostate cancer. Immunohistochemical staining for Ect2 was performed on a human tissue microarray. The staining intensity was analyzed in association with clinical pathological parameters such as Gleason score, pathological grade, clinical stage, tumor invasion, lymph node and distant metastasis. Furthermore, we repeated such analysis and investigated the prognostic value of Ect2 using the TCGA (The Cancer Genome Atlas) Dataset. Our immunohistochemical results showed that the expression levels of Ect2 protein were enhanced in human prostate cancer tissues. There existed positive correlations between the expression levels of Ect2 and several clinicopathological parameters, including advanced clinical stage, enhanced tumor invasion and lymph node metastasis. Similarly, we found that the expression levels of Ect2 were positively related to Gleason score, tumor invasion, lymph node metastasis and high distant metastasis in the TCGA Dataset. Kaplan-Meier analysis revealed that lower levels of Ect2 mRNA predicted higher overall survivals and biochemical recurrence (BCR)-free survivals in all patients or non metastatic patients. Multivariate analysis by Cox regression showed that the expression of Ect2 could be an independent prognostic marker of poor BCR-free survivals. Therefore, levels of Ect2 may serve as a novel marker for the diagnosis or prognosis of prostate cancer. PMID- 28012136 TI - Understanding the Therapist Contribution to Psychotherapy Outcome: A Meta Analytic Approach. AB - Understanding the role that therapists play in psychotherapy outcome, and the contribution to outcome made by individual therapist differences has implications for service delivery and training of therapists. In this study we used a novel approach to estimate the magnitude of the therapist contribution overall and the effect of individual therapist differences. We conducted a meta-analysis of studies in which participants were randomised to receive the same treatment either through self-help or through a therapist. We identified a total of 15 studies (commencement N = 910; completion N = 723) meeting inclusion criteria. We found no difference in treatment completion rate and broad equivalence of treatment outcomes for participants treated through self-help and participants treated through a therapist. Also, contrary to our expectations, we found that the variability of outcomes was broadly equivalent, suggesting that differences in efficacy of individual therapists were not sufficient to make therapy outcomes more variable when a therapist was involved. Overall, the findings suggest that self-help, with minimal therapist input, has considerable potential as a first line intervention. The findings did not suggest that individual differences between therapists play a major role in psychotherapy outcome. PMID- 28012135 TI - Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid. To determine the possible cholesterol metabolism promoting mechanism of EPA-PC, we analyzed the transcription of key genes and transcriptional factors involved in hepatic cholesterol metabolism. EPA-PC dramatically alleviated hepatic lipid accumulation, reduced the serum TC concentration, and elevated HDLC levels in NAFLD rats. Fecal neutral cholesterol excretion was also promoted by EPA-PC administration. Additionally, EPA-PC decreased the mRNA expression of hydroxymethyl glutaric acid acyl (HMGR) and cholesterol 7alpha-hydroxylase (CYP7A), and increased the transcription of sterol carrying protein 2 (SCP2). Moreover, EPA-PC stimulated the transcription of peroxisome proliferators-activated receptor alpha (PPARalpha) and adenosine monophosphate activated protein kinase (AMPK) as well as its modulators, liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent kinase kinase (CAMKK). Based on the results, the promoting effects of EPA-PC on NAFLD may be partly associated with the suppression of cholesterol synthesis via HMGR inhibition and the enhancement of fecal cholesterol excretion through increased SCP2 transcription. The underlying mechanism may involve stimulation of PPARalpha and AMPK. PMID- 28012131 TI - Eukaryotic protein glycosylation: a primer for histochemists and cell biologists. AB - Proteins undergo co- and posttranslational modifications, and their glycosylation is the most frequent and structurally variegated type. Histochemically, the detection of glycan presence has first been performed by stains. The availability of carbohydrate-specific tools (lectins, monoclonal antibodies) has revolutionized glycophenotyping, allowing monitoring of distinct structures. The different types of protein glycosylation in Eukaryotes are described. Following this educational survey, examples where known biological function is related to the glycan structures carried by proteins are given. In particular, mucins and their glycosylation patterns are considered as instructive proof-of-principle case. The tissue and cellular location of glycoprotein biosynthesis and metabolism is reviewed, with attention to new findings in goblet cells. Finally, protein glycosylation in disease is documented, with selected examples, where aberrant glycan expression impacts on normal function to let disease pathology become manifest. The histological applications adopted in these studies are emphasized throughout the text. PMID- 28012137 TI - VaProS: a database-integration approach for protein/genome information retrieval. AB - Life science research now heavily relies on all sorts of databases for genome sequences, transcription, protein three-dimensional (3D) structures, protein protein interactions, phenotypes and so forth. The knowledge accumulated by all the omics research is so vast that a computer-aided search of data is now a prerequisite for starting a new study. In addition, a combinatory search throughout these databases has a chance to extract new ideas and new hypotheses that can be examined by wet-lab experiments. By virtually integrating the related databases on the Internet, we have built a new web application that facilitates life science researchers for retrieving experts' knowledge stored in the databases and for building a new hypothesis of the research target. This web application, named VaProS, puts stress on the interconnection between the functional information of genome sequences and protein 3D structures, such as structural effect of the gene mutation. In this manuscript, we present the notion of VaProS, the databases and tools that can be accessed without any knowledge of database locations and data formats, and the power of search exemplified in quest of the molecular mechanisms of lysosomal storage disease. VaProS can be freely accessed at http://p4d-info.nig.ac.jp/vapros/ . PMID- 28012138 TI - Classification of ligand molecules in PDB with graph match-based structural superposition. AB - The fast heuristic graph match algorithm for small molecules, COMPLIG, was improved by adding a structural superposition process to verify the atom-atom matching. The modified method was used to classify the small molecule ligands in the Protein Data Bank (PDB) by their three-dimensional structures, and 16,660 types of ligands in the PDB were classified into 7561 clusters. In contrast, a classification by a previous method (without structure superposition) generated 3371 clusters from the same ligand set. The characteristic feature in the current classification system is the increased number of singleton clusters, which contained only one ligand molecule in a cluster. Inspections of the singletons in the current classification system but not in the previous one implied that the major factors for the isolation were differences in chirality, cyclic conformations, separation of substructures, and bond length. Comparisons between current and previous classification systems revealed that the superposition-based classification was effective in clustering functionally related ligands, such as drugs targeted to specific biological processes, owing to the strictness of the atom-atom matching. PMID- 28012139 TI - Vibrio injenensis sp. nov., isolated from human clinical specimens. AB - Vibrio species are well known as motile, mostly oxidase-positive, facultative anaerobic Gram-negative bacteria. They are abundant in aquatic environments and are a common cause of human infections including diarrhea, soft tissue diseases, and bacteremia. Here, two Gram-negative bacteria, designated M12-1144T and M12 1181, were isolated from human clinical specimens and identified using a polyphasic taxonomic approach. Phylogenetic study based on 16S rRNA gene sequence analysis revealed that the isolates belong to the genus Vibrio, and are closely related to Vibrio metschnikovii KCTC 32284T (98.3%) and Vibrio cincinnatiensis KCTC 2733T (97.8%). The major fatty acids were summed feature 3 (C16:1 omega7c/C16:1 omega6c, 38.0%), C16:0 (23.0%), and summed feature 8 (C18:1 omega7c or C18:1 omega6c, 19.3%) and major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. The G + C content of the genomic DNA was determined to be 44.1 mol%. DNA-DNA relatedness between the two newly isolated strains and V. metschnikovii KCTC 32284T and V. cincinnatiensis KCTC 2733T was between 42.6 to 47.5%. The similarities of genome-to-genome distance between M12-1144T and related species ranged from 18.4-54.8%. Based on these results, a new species of the genus Vibrio, Vibrio injenensis is proposed. The type strain is M12-1144 T(=KCTC 32233T =JCM 30011T). PMID- 28012140 TI - [Imported dengue in two tertiary Italian hospitals: Use of rapid diagnostic tests]. AB - Dengue fever is growing at a global level both as number of cases and as geographic area of endemicity. Italy is not in endemic area, but the competent vector Aedes albopictus is widespread in this country, so that the possibility of introduction of the infection cannot be ruled out. We retrospectively collected demographic, clinical, and laboratory data about consecutive cases diagnosed in Torino and Negrar-Verona in the period 2010-2015. One hundred thirteen cases of dengue were observed, with an increasing trend during years. The infection was imported mostly from south-east Asia, but the risk appears to be higher in Latin America. More than half of the patients were admitted to the hospital but only one case of severe dengue was observed. Many patients presented after the resolution of symptoms. Rapid diagnostic tests were done in the majority of patients and allowed a diagnosis both in the acute (NS1 antigen) and convalescent (IgMantibodies) phases of the disease. An early diagnosis is paramount to avoid the spreading of the infection. PMID- 28012141 TI - Hedgehogs in the dowser state. AB - We show how to easily generate point defects called hedgehogs, in the so-called quasi-planar texture --the dowser state-- of a nematic layer confined between surfaces with homeotropic anchoring conditions. We point out that the dowser texture can be preserved infinitely in spite of its higher energy with respect to the homogeneous homeotropic texture. For topological reasons the dowser state in a squeezed droplet must contain at least one hedgehog. We submitted this hedgehog to a rotating magnetic field and controlled the continuous evolution, transitioning continuously between radial, hyperbolic and circular hedgehogs, which, just as in previous experiments by Lavrentovich et al., are topologically equivalent states. The dynamics of this transformation is shown to be directly sensitive to energy costs of different geometric configurations of the hedgehog defect and therefore can be used as a rough probe for elastic constants; knowing the principal elastic constants K1,2,3, one can retrieve information about the K24 constant. We propose also a method of generation of hedgehog pairs by application of a Poiseuille flow to a dowser state wound by a rotating magnetic field. PMID- 28012142 TI - Confinement effect on the dynamics of non-equilibrium concentration fluctuations far from the onset of convection. AB - In a recent letter (C. Giraudet et al., EPL 111, 60013 (2015)) we reported preliminary data showing evidence of a slowing-down of non-equilibrium fluctuations of the concentration in thermodiffusion experiments on a binary mixture of miscible fluids. The reason for this slowing-down was attributed to the effect of confinement. Such tentative explanation is here experimentally corroborated by new measurements and theoretically substantiated by studying analytically and numerically the relevant fluctuating hydrodynamics equations. In the new experiments presented here, the magnitude of the temperature gradient is changed, confirming that the system is controlled solely by the solutal Rayleigh number, and that the slowing-down is dominated by a combined effect of the driving force of buoyancy, the dissipating force of diffusion and the confinement provided by the vertical extension of the sample cell. Moreover, a compact phenomenological interpolating formula is proposed for easy analysis of experimental results. PMID- 28012143 TI - The NEUF-DIX space project - Non-EquilibriUm Fluctuations during DIffusion in compleX liquids. AB - Diffusion and thermal diffusion processes in a liquid mixture are accompanied by long-range non-equilibrium fluctuations, whose amplitude is orders of magnitude larger than that of equilibrium fluctuations. The mean-square amplitude of the non-equilibrium fluctuations presents a scale-free power law behavior q-4 as a function of the wave vector q, but the divergence of the amplitude of the fluctuations at small wave vectors is prevented by the presence of gravity. In microgravity conditions the non-equilibrium fluctuations are fully developed and span all the available length scales up to the macroscopic size of the systems in the direction parallel to the applied gradient. Available theoretical models are based on linearized hydrodynamics and provide an adequate description of the statics and dynamics of the fluctuations in the presence of small temperature/concentration gradients and under stationary or quasi-stationary conditions. We describe a project aimed at the investigation of Non-EquilibriUm Fluctuations during DIffusion in compleX liquids (NEUF-DIX). The focus of the project is on the investigation in micro-gravity conditions of the non equilibrium fluctuations in complex liquids, trying to tackle several challenging problems that emerged during the latest years, such as the theoretical predictions of Casimir-like forces induced by non-equilibrium fluctuations; the understanding of the non-equilibrium fluctuations in multi-component mixtures including a polymer, both in relation to the transport coefficients and to their behavior close to a glass transition; the understanding of the non-equilibrium fluctuations in concentrated colloidal suspensions, a problem closely related with the detection of Casimir forces; and the investigation of the development of fluctuations during transient diffusion. We envision to parallel these experiments with state-of-the-art multi-scale simulations. PMID- 28012144 TI - Toward the observation of a liquid-liquid phase transition in patchy origami tetrahedra: a numerical study. AB - We evaluate the phase diagram of a model of tetrameric particles where the arms of the tetrahedra are made by six hard cylinders. An interacting site is present on each one of the four vertices allowing the particles to form a bonded network. These model particles provide a coarse-grained but realistic representation of recently synthesised DNA origami tetrahedra. We show that the resulting network is sufficiently empty to allow for partial interpenetration and it is sufficiently flexible to avoid crystallisation (at least on the numerical time scale), satisfying both criteria requested for the observation of a liquid-liquid critical point in tetrahedrally coordinated particles. Grand-canonical simulations provide evidence that, in silico, the model is indeed characterised, in addition to the gas-liquid transition, by a transition between two distinct liquid phases. Our results suggest that an experimental observation of a liquid liquid transition in a colloidal system can be achieved in the near future. PMID- 28012145 TI - Microgravity in a thin film: How confinement kills gravity. AB - Fluctuations in the presence of concentration gradients are long-ranged and decay diffusively for small spatial scales. At larger scales fluctuations are influenced by gravity and confinement. The confinement in the direction of the concentration gradient couples to gravity generating a slowing down that ends up in a diffusion-like behavior of fluctuations of size comparable to the vertical extension of the sample. The resulting enhanced diffusion coefficient depends on the solutal Rayleigh number of the system. For small (in modulus) values of the solutal Rayleigh number the apparent diffusion coefficient tends towards the normal one and a simple diffusive behavior is obtained. This is quite similar to what happens in microgravity conditions when the solutal Rayleigh number is drastically reduced because of the reduction of g by about 6 orders of magnitude. Experiments are shown for positive and negative solutal Rayleigh numbers smaller (in modulus) than 1000. The effect of the confinement on the statics is also investigated. Comparison with microgravity data obtained through the GRADFLEX project is performed. PMID- 28012146 TI - Electrophoretic mobility of a monotopic membrane protein inserted into the top of supported lipid bilayers. AB - We have studied the translational migration of a monotopic membrane protein, the bacterial sulfide quinone reductase (SQR) in supported n-bilayers ([Formula: see text]) under the influence of an electric field parallel to the membrane plane. The direction of the migration changes when the charge of the protein changes its sign. Measuring mobilities at different pH enables us to gain experimental physico-chemical data on SQR as its isoelectric point and its estimated oligomeric state (at least trimeric) when inserted in a lipid membrane. Consequently, in addition to the migration study of membrane proteins in a lipid environment, this experimental system, previously used with a transmembrane protein, is thus suitable to define membrane protein properties in conditions approaching the native ones (in the absence of detergent). PMID- 28012147 TI - Spatial distribution and nematic ordering of anisotropic nanoparticles in lamellae and hexagonal phases of block copolymers. AB - Orientational and translational ordering of anisotropic nanoparticles in the lamellae and hexagonal phases of diblock copolymers have been considered theoretically in the case of strong segregation taking into account the anisotropic interaction between the nanoparticles and the monomers in different blocks. It has been shown that anisotropic nanoparticles are orientationally ordered in the boundary region between the blocks and the nematic order parameter possesses opposite signs in different blocks: the nanoparticles align parallel to the boundary in one block and perpendicular to it in the other. In the hexagonal phase, a weak biaxial ordering of nanoparticles is also induced in the boundary region. Explicit analytical results have been obtained for the distribution of nanoparticles in the lamellae phase. The results are compared with the existing experimental data. PMID- 28012148 TI - Ultrasonic energy device versus monopolar energy device in laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair. AB - Laparoscopic transabdominal preperitoneal (TAPP) is gaining popularity as an approach to repairing of inguinal hernia. In many institutions, a disposable ultrasonic energy device is used in the TAPP repair procedure. However, the benefit and necessity of an ultrasonic device are unclear. We have switched to use of a reusable monopolar energy device, and we conducted a retrospective study comparing the surgical results obtained with each of the energy devices. Our study group comprised 241 adults who underwent TAPP repair for inguinal hernia between November 2012 and December 2014. We compared clinical characteristics, and surgical outcomes between patients in whom a disposable ultrasonic energy device was used (n = 116, U group) and those in whom a reusable monopolar energy device (n = 125, M group) was used. There was no statistically significant difference between the 2 groups in age, sex, body mass index, or hernia type. In cases of unilateral hernia, operation time was significantly longer in the U group than in the M group (71.4 vs. 59.4 min, respectively, p < 0.001). No significant difference was found in intraoperative blood loss (2.3 vs 3.9 ml, p = 0.329), postoperative morbidity (5.2 vs 4.0%, p = 0.663), or postoperative hospital stay (2.1 vs 2.2 days, p = 0.336). Our experience and increased competence with the monopolar energy device lead us to conclude that the ultrasonic energy device is unnecessary for simple TAPP repair. PMID- 28012149 TI - Endoplasmic Reticulum Stress and Apoptosis Triggered by Sub-Chronic Lead Exposure in Mice Spleen: a Histopathological Study. AB - Lead (Pb) is an environmental oncogenic metal that induces immunotoxicity and anaemia. Emerging evidence has linked Pb toxicity with endoplasmic reticulum driven apoptosis and autophagy. Glucose-regulated protein of 78 kDa (Grp78 or binding immunoglobulin protein (BiP)), a master endoplasmic reticulum chaperone, drives macrophage activation and regulates protein folding and calcium flux in response to heavy metals. The spleen may be involved in Pb poisoning due to its crucial role in erythrocatheresis and immune response, although there are no data to support this theory. Here, we found haematic and histopathological changes in the spleen of mice exposed to medium doses of Pb acetate (200 ppm-1 mM) in drinking water for 45 days. Pb deposition was also detected in organs such as the liver, kidney, brain, bone, blood and faeces, indicating an accumulation of this metal despite relatively short exposure time. Blood Pb content (BBL) reached 21.6 MUg/dL; echinocytes and poikilocytes were found in Pb smears of treated group. Inside the spleen, higher Fe(II) and Fe(III) deposits inside macrophages were observed. Grp78 immunostaining, weakly expressed in spleen cells of control mice, after Pb exposure was specifically restricted to macrophages and megakaryocytes of the marginal zone of red pulp. Furthermore, Pb exposure induced superoxide dismutase 1 (SOD1) expression, cleaved caspase-3 and p62/SQSTM1, consistent with oxidative stress, apoptosis and dysregulated autophagy in spleen compartments. We suggest that even at a middle dose, oral Pb intake induces oxidant iron deposition in the spleen and that this may trigger sustained Grp78 redistribution to cells, thus leading to oxidative and autophagy dysfunction as early local reactions to this dangerous metal. PMID- 28012150 TI - AT1 receptor antagonist induces thermogenic beige adipocytes in the inguinal white adipose tissue of obese mice. AB - PURPOSE: To evaluate whether losartan is able to induce beige adipocytes formation, focusing on the thermogenic gene expression and adipocyte remodeling in the subcutaneous white adipose tissue of diet-induced obese mice. METHODS: Male C57BL/6 mice received a control diet (10% energy as lipids) or a high-fat diet (50% energy as lipids) for 10 weeks, followed by a 5-week treatment with losartan: control group, control-losartan group (10 mg/Kg/day), high-fat group and high-fat-losartan group (10 mg/Kg/day). Biochemical, morphometrical, stereological and molecular approaches were used to evaluate the outcomes. RESULTS: The high-fat diet elicited overweight, insulin resistance and adipocyte hypertrophy in the high-fat group, all of which losartan rescued in the high-fat losartan group. These effects comply with the induction of beige adipocytes within the inguinal fat pads in high-fat-losartan group as they exhibited the greatest energy expenditure among the groups along with the presence uncoupling protein 1 positive multilocular adipocytes with enhanced peroxisome proliferator activated receptor gamma coactivator 1-alpha and PR domain containing 16 mRNA levels, indicating a significant potential for mitochondrial biogenesis and adaptive thermogenesis. CONCLUSIONS: Our results show compelling evidence that losartan countered diet-induced obesity in mice by enhancing energy expenditure through beige adipocytes induction. Reduced body mass, increased insulin sensitivity, decreased adipocyte size and marked expression of uncoupling protein 1 by ectopic multilocular adipocytes support these findings. The use of losartan as a coadjutant medicine to tackle obesity and its related disorders merits further investigation. PMID- 28012151 TI - Accuracy of Self-Reported Weight Among Adolescent and Young Adults Following Bariatric Surgery. AB - PURPOSE: This study evaluates accuracy of self-reported weight in adolescent bariatric surgery patients. MATERIALS AND METHODS: During follow-up visits, participants self-reported weight and had weight measured. The differences between self-reported and measured weights were analyzed from 60 participants. RESULTS: Participants were 70% (n = 42) female, 72% (n = 43) white, mean age of 20.8 years and a median body mass index of 36.6 kg/m2. At an average of 3.5 years following surgery, females underestimated weight (0.5 kg, range: -18.7 to 5.6 kg), while males overestimated (1.1 kg, range: -7.8 to 15.2 kg). Most (80%, n = 48) reported within 5 kg of measured weight. The majority of adolescents who previously underwent bariatric surgery reported reasonably accurate weights, but direction of misreporting varied by gender. CONCLUSION: Self-reported weights could be utilized when measured values are unavailable without markedly biasing the interpretation of outcomes. PMID- 28012152 TI - Erratum to: Bone marrow aspirate concentrate for the treatment of osteochondral lesions of the talus: a systematic review of outcomes. PMID- 28012153 TI - Zero valent zinc nanoparticles promote neuroglial cell proliferation: A biodegradable and conductive filler candidate for nerve regeneration. AB - Regeneration of nerve, which has limited ability to undergo self-healing, is one of the most challenging areas in the field of tissue engineering. Regarding materials used in neuroregeneration, there is a recent trend toward electrically conductive materials. It has been emphasized that the capacity of conductive materials to regenerate such tissue having limited self-healing ability improves their clinical utility. However, there have been concerns about the safety of materials or fillers used for conductance due to their lack of degradability. Here, we attempt to use poly(E-caprolactone) (PCL) matrix consisting of varying proportions of zero valent zinc nanoparticles (Zn NPs) via electrospinning. These conductive, biodegradable, and bioactive materials efficiently promoted neuroglial cell proliferation depending on the amount of Zn NPs present in the PCL matrix. Chemical characterizations indicated that the incorporated Zn NPs do not interact with the PCL matrix chemically and that the Zn NPs improved the tensile properties of the PCL matrix. All composites exhibited linear conductivity under in vitro conditions. In vitro cell culture studies were performed to determine the cytotoxicity and proliferative efficiency of materials containing different proportions of Zn NPs. The results were obtained to explore new conductive fillers that can promote tissue regeneration. PMID- 28012154 TI - Mass spectrometry comparison of nerve allograft decellularization processes. AB - Peripheral nerve repair using nerve grafts has been investigated for several decades using traditional techniques such as histology, immunohistochemistry, and electron microscopy. Recent advances in mass spectrometry techniques have made it possible to study the proteomes of complex tissues, including extracellular matrix rich tissues similar to peripheral nerves. The present study comparatively assessed three previously described processing methods for generating acellular nerve grafts by mass spectrometry. Acellular nerve grafts were additionally examined by F-actin staining and nuclear staining for debris clearance. Application of newer techniques allowed us to detect and highlight differences among the 3 treatments. Isolated proteins were separated by mass on polyacrylamide gels serving 2 purposes. This further illustrated that these treatments differ from one another and it allowed for selective protein extractions within specific bands/molecular weights. This approach resulted in small pools of proteins that could then be analyzed by mass spectrometry for content. In total, 543 proteins were identified, many of which corroborate previous findings for these processing methods. The remaining proteins are novel discoveries that expand the field. With this pilot study, we have proven that mass spectrometry techniques complement and add value to peripheral nerve repair studies. PMID- 28012155 TI - Influence of chitosan-chitin nanofiber composites on cytoskeleton structure and the proliferation of rat bone marrow stromal cells. AB - Chitosan scaffolds have gained much attention in various tissue engineering applications, but the effect of their microstructure on cell-material spatial interactions remains unclear. Our objective was to evaluate the effect of chitosan-based matrices doping with chitin nano-whiskers (CNW) on adhesion, spreading, cytoskeleton structure, and proliferation of rat bone marrow stromal cells (BMSCs). The behavior of BMSCs during culture on chitosan-CNW films was determined by the molecular mass, hydrophobicity, porosity, crosslinking degree, protonation degree and molecular structure of the composite chitosan-CNW films. The shape, spreading area, cytoskeleton structure, and proliferation of BMSCs on chitosan matrices with a crystalline structure and high porosity were similar to that observed for BMSCs cultured on polystyrene tissue culture plates. The amorphous polymer structure and high swelling led to a decrease in the spreading area and cell proliferation. Thus, we can control the behavior of cells in culture (adhesion, spreading, and proliferation) by changing the physico-chemical properties of the chitosan-CNW films. PMID- 28012156 TI - Sexual dimorphism in obesity-related genes in the epicardial fat during aging. AB - Aging increases the risk of cardiovascular disease and metabolic syndrome. Alterations in epicardial fat play an important pathophysiological role in coronary artery disease and hypertension. We investigated the impact of normal aging on obesity-related genes in epicardial fat. Sex-specific changes in obesity related genes with aging in epicardial fat (EF) were determined in young (6 months) and old (30/36 months) female and male, Fischer 344 * Brown Norway hybrid (FBN) rats, using a rat obesity RT2 PCR Array. Circulating sex hormone levels, body and heart weights were determined. Statistical significance was determined using two-tailed Student's t test and Pearson's correlation. Our results revealed sex-specific differences in obesity-related genes with aging. Dramatic changes in the expression profile of obesity-related genes in EF with aging in female, but not in male, FBN rats were observed. The older (30 months) female rats had more significant variations in the abundance of obesity-related genes in the EF compared to that seen in younger female rats or both age groups in male rats. A correlation of changes in obesity-related genes in EF to heart weights was observed in female rats, but not in male rats with aging. No correlation was observed to circulating sex hormone levels. Our findings indicate a dysfunctional EF in female rats with aging compared to male rats. These findings, with further functional validation, might help explain the sex differences in cardiovascular risk and mortality associated with aging observed in humans. PMID- 28012157 TI - Biopsy correlation of surface area vs. single-axis measurements on computed tomography scan of lymph nodes in patients with erythrodermic mycosis fungoides and Sezary syndrome. PMID- 28012158 TI - Treatment patterns and outcomes among adults admitted to hospital in the U.K. due to plaque or erythrodermic psoriasis. PMID- 28012159 TI - Does ecological specialization transcend scale? Habitat partitioning among individuals and species of Anolis lizards. AB - Ecological specialization is common across all levels of biological organization, raising the question of whether the evolution of specialization at one scale in a taxon is linked to specialization at other scales. Anolis lizards have diversified repeatedly along axes of habitat use, but it remains unknown if this diversification into habitat use specialists is underlain by individual specialization. From repeated observations of individuals in a population of Anolis sagrei in Florida, we show that the extent of habitat use specialization among individuals is comparable to the extent of specialization in the same traits among ten sympatric Anolis habitat specialist species in Cuba. However, the adaptive correlations between habitat use and morphology commonly seen across species of Anolis were not observed across individuals in the sampled population. Our results therefore suggest that while patterns of ecological specialization can transcend scale, these parallels are the consequence of distinct ecological processes acting at microevolutionary and macroevolutionary scales. PMID- 28012160 TI - Digest: Why are there no ring species? PMID- 28012161 TI - Preferentially expanding Vgamma1+ gammadelta T cells are associated with protective immunity against Plasmodium infection in mice. AB - gammadelta T cells play a crucial role in controlling malaria parasites. Dendritic cell (DC) activation via CD40 ligand (CD40L)-CD40 signaling by gammadelta T cells induces protective immunity against the blood-stage Plasmodium berghei XAT (PbXAT) parasites in mice. However, it is unknown which gammadelta T cell subset has an effector role and is required to control the Plasmodium infection. Here, using antibodies to deplete TCR Vgamma1+ cells, we saw that Vgamma1+ gammadelta T cells were important for the control of PbXAT infection. Splenic Vgamma1+ gammadelta T cells preferentially expand and express CD40L, and both Vgamma1+ and Vgamma4+ gammadelta T cells produce IFN-gamma during infection. Although expression of CD40L on Vgamma1+ gammadelta T cells is maintained during infection, the IFN-gamma positivity of Vgamma1+ gammadelta T cells is reduced in late-phase infection due to gammadelta T-cell dysfunction. In Plasmodium-infected IFN-gamma signaling-deficient mice, DC activation is reduced, resulting in the suppression of gammadelta T-cell dysfunction and the dampening of gammadelta T cell expansion in the late phase of infection. Our data suggest that Vgamma1+ gammadelta T cells represent a major subset responding to PbXAT infection and that the Vgamma1+ gammadelta T-cell response is dependent on IFN-gamma-activated DCs. PMID- 28012162 TI - Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. AB - OBJECTIVE: Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV. METHODS: Radioligand binding studies were carried out using [3 H]BRV and [3 H]LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue. RESULTS: The modulator increased the binding of both radioligands but by different mechanisms. For [3 H]BRV, the increase was driven mainly by an increase in affinity, whereas for [3 H]LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect. SIGNIFICANCE: These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein. PMID- 28012163 TI - IL-10 production in murine IgM+ CD138hi cells is driven by Blimp-1 and downregulated in class-switched cells. AB - In contrast to antibody-induced inflammatory responses, some B-cell subpopulations suppress inflammation through the production of interleukin (IL) 10. However, the mechanisms underlying Il10 gene expression during B-cell development is elusive. Here, we identify IgM+ B220lo CD138hi cells responsible for marked IL-10 production in the bone marrow and spleen of mice. These murine IL-10-producing cells predominantly secrete IgM and have unique characteristics of long-lived plasma cells in spite of high expression of surface IgM. We found that IL-10 production is strongly correlated with the expression level of Prdm1 (encoding the Blimp-1 protein), an essential regulator of plasma cell development. Furthermore, overexpression of Prdm1 induces Il10 expression in naive B cells. Immunoglobulin class-switching recombination events resulted in the downregulation of both Il10 and Prdm1 expression in differentiating B cells. Thus, the prolonged elevation of Blimp-1 expression during the formation of IgM+ CD138hi cells without class-switching elicits IL-10 production. Adoptive transfer of Il10-deficient B cells into B-cell-deficient mice demonstrated that IgM+ CD138hi cell-derived IL-10 supports the survival of class-switched plasma cells and their antibody production in response to antigen challenge. These findings reveal an important role for IL-10 secretion by IgM+ CD138hi cells in the complete and efficient humoral response. PMID- 28012164 TI - Verbal memory after temporal lobe epilepsy surgery in children: Do only mesial structures matter? AB - OBJECTIVE: Previous findings have been mixed regarding verbal memory outcome after left temporal lobectomy in children, and there are few studies comparing verbal memory change after lateral versus mesial temporal lobe resections. We compared verbal memory outcome associated with sparing or including the mesial structures in children who underwent left or right temporal lobe resection. We also investigated predictors of postsurgical verbal memory change. METHODS: We retrospectively assessed verbal memory change approximately 1 year after unilateral temporal lobe epilepsy surgery using a list learning task. Participants included 23 children who underwent temporal lobe surgery with sparing of the mesial structures (13 left), and 40 children who had a temporal lobectomy that included resection of mesial structures (22 left). RESULTS: Children who underwent resection from the left lateral and mesial temporal lobe were the only group to show decline in verbal memory. Furthermore, when we considered language representation in the left temporal resection group, patients with left language representation and spared mesial structures showed essentially no change in verbal memory from preoperative to follow-up, whereas those with left language representation and excised mesial structures showed a decline. Postoperative seizure status had no effect on verbal memory change in children after left temporal lobe surgery. Finally, we found that patients with intact preoperative verbal memory experienced a significant decline compared to those with below average preoperative verbal memory. SIGNIFICANCE: Our findings provide evidence of significant risk factors for verbal memory decline in children, specific to left mesial temporal lobe epilepsy. Children who undergo left temporal lobe surgery that includes mesial structures may be most vulnerable for verbal memory decline, especially when language representation is localized to the left hemisphere and when preoperative verbal memory is intact. PMID- 28012165 TI - Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. AB - BACKGROUND: A promising approach to the treatment of chronic ischaemic heart disease and congestive heart failure is the use of stem cells. The last decade has seen a plethora of randomised controlled trials developed worldwide, which have generated conflicting results. OBJECTIVES: The critical evaluation of clinical evidence on the safety and efficacy of autologous adult bone marrow derived stem/progenitor cells as a treatment for chronic ischaemic heart disease and congestive heart failure. SEARCH METHODS: We searched CENTRAL in the Cochrane Library, MEDLINE, Embase, CINAHL, LILACS, and four ongoing trial databases for relevant trials up to 14 December 2015. SELECTION CRITERIA: Eligible studies were randomised controlled trials comparing autologous adult stem/progenitor cells with no cells in people with chronic ischaemic heart disease and congestive heart failure. We included co-interventions, such as primary angioplasty, surgery, or administration of stem cell mobilising agents, when administered to treatment and control arms equally. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references for eligibility, assessed trial quality, and extracted data. We undertook a quantitative evaluation of data using random effects meta-analyses. We evaluated heterogeneity using the I2 statistic and explored substantial heterogeneity (I2 greater than 50%) through subgroup analyses. We assessed the quality of the evidence using the GRADE approach. We created a 'Summary of findings' table using GRADEprofiler (GRADEpro), excluding studies with a high or unclear risk of selection bias. We focused our summary of findings on long-term follow-up of mortality, morbidity outcomes, and left ventricular ejection fraction measured by magnetic resonance imaging. MAIN RESULTS: We included 38 randomised controlled trials involving 1907 participants (1114 cell therapy, 793 controls) in this review update. Twenty-three trials were at high or unclear risk of selection bias. Other sources of potential bias included lack of blinding of participants (12 trials) and full or partial commercial sponsorship (13 trials).Cell therapy reduced the incidence of long term mortality (>= 12 months) (risk ratio (RR) 0.42, 95% confidence interval (CI) 0.21 to 0.87; participants = 491; studies = 9; I2 = 0%; low-quality evidence). Periprocedural adverse events associated with the mapping or cell/placebo injection procedure were infrequent. Cell therapy was also associated with a long term reduction in the incidence of non-fatal myocardial infarction (RR 0.38, 95% CI 0.15 to 0.97; participants = 345; studies = 5; I2 = 0%; low-quality evidence) and incidence of arrhythmias (RR 0.42, 95% CI 0.18 to 0.99; participants = 82; studies = 1; low-quality evidence). However, we found no evidence that cell therapy affects the risk of rehospitalisation for heart failure (RR 0.63, 95% CI 0.36 to 1.09; participants = 375; studies = 6; I2 = 0%; low-quality evidence) or composite incidence of mortality, non-fatal myocardial infarction, and/or rehospitalisation for heart failure (RR 0.64, 95% CI 0.38 to 1.08; participants = 141; studies = 3; I2 = 0%; low-quality evidence), or long-term left ventricular ejection fraction when measured by magnetic resonance imaging (mean difference 1.60, 95% CI -8.70 to 5.50; participants = 25; studies = 1; low-quality evidence). AUTHORS' CONCLUSIONS: This systematic review and meta-analysis found low-quality evidence that treatment with bone marrow-derived stem/progenitor cells reduces mortality and improves left ventricular ejection fraction over short- and long-term follow-up and may reduce the incidence of non-fatal myocardial infarction and improve New York Heart Association (NYHA) Functional Classification in people with chronic ischaemic heart disease and congestive heart failure. These findings should be interpreted with caution, as event rates were generally low, leading to a lack of precision. PMID- 28012166 TI - Hyperspectral imaging in detecting dermal invasion in lentigo maligna melanoma. PMID- 28012167 TI - Digest: Evolve wisely-some ant defense strategies paved way to diversification, and others to a dead end. PMID- 28012168 TI - Can Housing and Service Interventions Reduce Family Separations for Families Who Experience Homelessness? AB - Family break-up is common in families experiencing homelessness. This paper examines the extent of separations of children from parents and of partners from each other and whether housing and service interventions reduced separations and their precursors among 1,857 families across 12 sites who participated in the Family Options Study. Families in shelters were randomized to offers of one of three interventions: permanent housing subsidies that reduce expenditures for rent to 30% of families' income, temporary rapid re-housing subsidies with some services directed at housing and employment, and transitional housing in supervised facilities with extensive psychosocial services. Each group was compared to usual care families who were eligible for that intervention but received no special offer. Twenty months later, permanent housing subsidies almost halved rates of child separation and more than halved rates of foster care placements; the other interventions did not affect separations significantly. Predictors of separation were primarily homelessness and drug abuse (all comparisons), and alcohol dependence (one comparison). Although housing subsidies reduced homelessness, alcohol dependence, intimate partner violence, and economic stressors, the last three variables had no association with child separations in the subsidy comparison; thus subsidies had indirect effects via reductions in homelessness. No intervention reduced partner separations. PMID- 28012169 TI - Curcumin as a potential candidate for treating hyperlipidemia: A review of cellular and metabolic mechanisms. AB - Curcumin is an herbal polyphenol extensively investigated for antioxidant, anti inflammatory, and hypolipidaemic properties. In the present review, the efficacy of curcumin for improving a plasma lipid profile has been evaluated and compared with statins, a well-known class of medicines for treating hypercholesterolemia and hyperlipidaemia. Curcumin is presumably most effective in reducing triglyceride (TG), while statins are most efficient in lowering low-density lipoproteins-cholesterol (LDL-C). Additionally, various molecular and metabolic mediators of cholesterol and plasma lipid homeostasis are discussed in relation to how they are modulated by curcumin or statins. Overall, curcumin influences the same mediators of plasma lipid alteration as statins do. Almost all the pathways through which cholesterol trafficking takes place are affected by these agents. These include gastrointestinal absorption of dietary cholesterol, hepatocellular removal of plasma cholesterol, the mediators of reverse cholesterol transport, and removal of cholesterol from peripheral tissues. Moreover, the reactive oxygen species (ROS) scavenging potential of curcumin limits the risk of lipid peroxidation that triggers inflammatory responses causing cardiovascular diseases (CVD) and atherosclerosis. Taken together, curcumin could be used as a safe and well-tolerated adjunct to statins to control hyperlipidaemia more effectively than statins alone. PMID- 28012170 TI - Methodological aspects of assessing hand eczema: comparison of two tools and three different categories of evaluators. PMID- 28012171 TI - miR-15b mediates oxaliplatin-induced chronic neuropathic pain through BACE1 down regulation. AB - BACKGROUND AND PURPOSE: Although oxaliplatin is an effective anti-cancer platinum compound, it can cause painful chronic neuropathy, and its molecular mechanisms are poorly understood. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression in a sequence-specific manner. Although miRNAs have been increasingly recognized as important modulators in a variety of pain conditions, their involvement in chemotherapy-induced neuropathic pain is unknown. EXPERIMENTAL APPROACH: Oxaliplatin-induced chronic neuropathic pain was induced in rats by i.p. injections of oxaliplatin (2 mg.kg-1 ) for five consecutive days. The expression levels of miR-15b and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1 also known as beta-secretase 1) were examined in the dorsal root ganglion (DRG). To examine the function of miR-15b, an adeno-associated viral vector encoding miR-15b was injected into the DRG in vivo. KEY RESULTS: Among the miRNAs examined in the DRG in the late phase of oxaliplatin-induced neuropathic pain, miR-15b was most robustly increased. Our in vitro assay results determined that BACE1 was a target of miR-15b. BACE1 and miR 15b were co-expressed in putative myelinated and unmyelinated DRG neurons. Overexpression of miR-15b in DRG neurons caused mechanical allodynia in association with reduced expression of BACE1. Consistent with these results, a BACE1 inhibitor dose-dependently induced significant mechanical allodynia. CONCLUSIONS AND IMPLICATIONS: These findings suggest that miR-15b contributes to oxaliplatin-induced chronic neuropathic pain at least in part through the down regulation of BACE1. PMID- 28012172 TI - MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis. AB - Polymorphisms in the MHC class II (MHCII) genes are strongly associated with rheumatoid arthritis, supporting the importance of autoreactive T helper (Th) cells for the development of this disease. Here, we used pristane-induced arthritis (PIA), induced by the non-antigenic hydrocarbon pristane, to study the impact of different MHCII alleles on T-cell activation and differentiation. In MHCII-congenic rats with disease-promoting MHCII alleles, pristane primarily induced activation of Th1 cells, whereas activated T cells were Th17 biased in rats with protective MHCII alleles. Neutralization of IFN-gamma during T-cell activation abrogated the development of disease, suggesting that Th1 immunity is important for disease induction. Neutralization of IL-17, by contrast, suppressed arthritis only when performed in rats with established disease. Adoptive T-cell transfers showed that T cells acquired arthritogenic capacity earlier in strains with a prevailing Th1 response. Moreover, upon pristane injection, these strains exhibited more Ag-primed OX40+ and proliferating T cells of polyclonal origin. These data show that T cells are polarized upon the first encounter with peptide MHCII complexes in an allele-dependent fashion. In PIA, the polyclonal expansion of autoreactive Th1 cells was necessary for the onset of arthritis, while IL-17 mediated immunity contributed to the progression to chronic disease. PMID- 28012173 TI - TRPC3 channels play a critical role in the theta component of pilocarpine-induced status epilepticus in mice. AB - OBJECTIVE: Canonical transient receptor potential (TRPC) channels constitute a family of cation channels that exhibit a regional and cell-specific expression pattern throughout the brain. It has been reported previously that TRPC3 channels are effectors of the brain-derived neurotrophic factor (BDNF)/trkB signaling pathway. Given the long postulated role of BDNF in epileptogenesis, TRPC3 channels may be a critical component in the underlying pathophysiology of seizure and epilepsy. In this study, we investigated the precise role of TRPC3 channels in pilocarpine-induced status epilepticus (SE). METHODS: The role of TRPC3 channels was investigated using TRPC3 knockout (KO) mice and TRPC3-selective inhibitor Pyr3. Video and electroencephalography (EEG) recording of pilocarpine induced seizures were performed. RESULTS: We found that genetic ablation of TRPC3 channels reduces behavioral manifestations of seizures and the root-mean-square (RMS) power of SE, indicating a significant contribution of TRPC3 channels to pilocarpine-induced SE. Furthermore, the reduction in SE in TRPC3KO mice is caused by a selective attenuation of pilocarpine-induced theta activity, which dominates both the preictal phase and SE phase. Pyr3 also caused a reduction in the overall RMS power of pilocarpine-induced SE and a selective reduction in the theta activity during SE. SIGNIFICANCE: Our results demonstrate that TRPC3 channels unequivocally contribute to pilocarpine-induced SE and could be a novel molecular target for new anticonvulsive drugs. PMID- 28012174 TI - Song evolution, speciation, and vocal learning in passerine birds. AB - Phenotypic divergence can promote reproductive isolation and speciation, suggesting a possible link between rates of phenotypic evolution and the tempo of speciation at multiple evolutionary scales. To date, most macroevolutionary studies of diversification have focused on morphological traits, whereas behavioral traits?including vocal signals?are rarely considered. Thus, although behavioral traits often mediate mate choice and gene flow, we have a limited understanding of how behavioral evolution contributes to diversification. Furthermore, the developmental mode by which behavioral traits are acquired may affect rates of behavioral evolution, although this hypothesis is seldom tested in a phylogenetic framework. Here, we examine evidence for rate shifts in vocal evolution and speciation across two major radiations of codistributed passerines: one oscine clade with learned songs (Thraupidae) and one suboscine clade with innate songs (Furnariidae). We find that evolutionary bursts in rates of speciation and song evolution are coincident in both thraupids and furnariids. Further, overall rates of vocal evolution are higher among taxa with learned rather than innate songs. Taken together, these findings suggest an association between macroevolutionary bursts in speciation and vocal evolution, and that the tempo of behavioral evolution can be influenced by variation in developmental modes among lineages. PMID- 28012175 TI - Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome. AB - OBJECTIVE: Two major classes of SCN1A variants are associated with Dravet syndrome (DS): those that result in haploinsufficiency (truncating) and those that result in an amino acid substitution (missense). The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation-positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment. METHODS: We sequenced all exons and intron-exon boundaries of SCN1A in our cohort, investigated differences in the distribution of truncating and missense variants, tested for associations between variant type and phenotype, and compared these patterns with those of cohorts with milder epilepsy and healthy individuals. RESULTS: Unlike truncation variants, missense variants are found at higher density in the S4 voltage sensor and pore loops and at lower density in the domain I-II and II-III linkers and the first three segments of domain II. Relative to healthy individuals, there is an increased frequency of truncating (but not missense) variants in the noncoding C-terminus. The rate of cognitive decline is more rapid for patients with truncation variants regardless of age at seizure onset, whereas age at onset is a predictor of the rate of cognitive decline for patients with missense variants. SIGNIFICANCE: We found significant differences in the distribution of truncating and missense variants across the SCN1A sequence among healthy individuals, patients with DS, and those with milder forms of SCN1A-variant positive epilepsy. Testing for associations with phenotype revealed that variant type can be predictive of rate of cognitive decline. Analysis of descriptive medication data suggests that in addition to conventional drug therapy in DS, bromide, clonazepam and topiramate may reduce seizure frequency. PMID- 28012177 TI - How reversible is development? Contrast between developmentally plastic gain and loss of segments in barnacle feeding legs. AB - Segmented organisms and structures have fascinated biologists since William Bateson first described homeotic transformation and recognized the fundamental evolutionary significance of segmental organization. On evolutionary time scales, segments may be lost or gained during major morphological transitions. But how segment loss compares to gain on developmental time scales remains mysterious. Here, we examine the ease of reverse development (opposite to normal growth) by comparing developmentally plastic leg segment loss versus gain in individual barnacles transplanted between different water flow conditions. Plastic segment addition occurred rapidly (one to two molts) and exclusively near the limb base. In contrast, developmentally plastic segment loss-the first observation in any arthropod-took much longer (>10 molts) and, remarkably, occurred throughout the leg (23% of losses occurred mid-limb). Segment loss was not a simple reversal of segment addition. Intersegmental membranes fused first, followed by elimination of duplicate tendons and gradual shortening (but not loss) of duplicate setae. Setal loss, in particular, may impose a severe developmental constraint on arthropod segment fusion. This asymmetric developmental potential (time lag of phenotypic response)-plastic segment addition (amplified normal development) is faster and more orderly than segment loss (reverse development)-adds a new dimension to models of developmental plasticity because the cost of making a developmental mistake in one direction will be greater than in the other. PMID- 28012176 TI - Selection and early clinical evaluation of the brain-penetrant 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor UE2343 (XanamemTM). AB - BACKGROUND AND PURPOSE: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11beta-HSD1 inhibitors as potential medicines for the treatment of AD. EXPERIMENTAL APPROACH: Medicinal chemistry optimization of a series of amido-thiophene analogues was performed to identify potent and selective 11beta-HSD1 inhibitors with optimized oral pharmacokinetics able to access the brain. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound. RESULTS: UE2343 was identified as a potent, orally bioavailable, brain-penetrant 11beta-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone was elevated (a marker of systemic enzyme inhibition) at doses of 10 mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal t1/2 ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11beta-HSD1 inhibition in the liver. Concentrations of UE2343 in the CSF were 33% of free plasma levels, and the peak concentration in CSF was ninefold greater than the UE2343 IC50 . CONCLUSIONS AND IMPLICATIONS: UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11beta-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11beta-HSD1 inhibition in brain improves memory in patients with AD. PMID- 28012179 TI - Digest: Songs of the sea: Mammalian vocalizations in aquatic and terrestrial environments. PMID- 28012178 TI - Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: a cohort study. AB - BACKGROUND: Organ transplant recipients (OTRs) have a highly increased risk of cutaneous squamous cell carcinomas (SCCs). Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive SCCs in OTRs. OBJECTIVES: To investigate the impact of painful vs. painless skin lesions and SCC vs. other skin lesions on the overall mortality risk in OTRs. METHODS: We followed 410 OTRs from 10 different centres across Europe and North America between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC, and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis, and risk factors were analysed with Cox proportional hazard analysis. RESULTS: There was an increased overall mortality risk in OTRs who reported painful vs. painless skin lesions, with a hazard ratio (HR) of 1.6 [95% confidence interval (CI) 0.97-2.7], adjusted for age, sex and other relevant factors. There was also an increased overall mortality risk in OTRs diagnosed with SCC compared with other skin lesions, with an adjusted HR of 1.7 (95% CI 1.0-2.8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTRs with SCC. CONCLUSIONS: We suggest that OTRs have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC. PMID- 28012180 TI - Dermoscopic features of squamous cell carcinoma on the lips. PMID- 28012181 TI - Randomized controlled trial comparing 35% trichloroacetic acid peel and 5 aminolaevulinic acid photodynamic therapy for treating multiple actinic keratosis. AB - BACKGROUND: Photodynamic therapy (PDT) and chemical peels with trichloroacetic acid (TCA) can be applied to large skin areas and thus are suitable treatment options for patients with multiple actinic keratosis (AK). However, despite its long use, TCA has been investigated only rarely in this indication. OBJECTIVES: This randomized, observer-blinded, intrapatient comparative study sought to investigate the efficacy and safety of 35% TCA vs. aminolaevulinic acid 20% (ALA) PDT in patients with extensive field cancerization and multiple AKs in the face or on the scalp. METHODS: Twenty-eight patients with at least five AKs in two comparable anatomical areas on the head were treated with 35% TCA and ALA PDT randomly assigned to each area. Their therapeutic efficacy, adverse events and cosmetic outcome were assessed by a blinded investigator at 1, 3, 6 and 12 months after treatment. RESULTS: After 12-months' follow-up TCA and ALA PDT reduced the total lesion count, the primary outcome, by 31% and 58%, respectively (P = 0.006). Complete clearance of pre-existing AKs were 49% for TCA and 74% for ALA PDT (P = 0.011). Treatment failure (number of AKs greater than 50% of the baseline count) was observed in seven patients (25%) after TCA and in two patients (7%) after PDT treatment. Treatment-related pain was significantly higher for ALA PDT (visual analogue scale 7.5 +/- 2.3 vs. TCA: 5.1 +/- 2.6; P = 0.04), whereas scarring (n = 6, 21%) was seen only in TCA treated patients. CONCLUSIONS: ALA PDT provided better clinical results than TCA in the treatment of patients with extensive field cancerization and multiple AKs. PMID- 28012182 TI - Development of a multidimensional assessment tool for uraemic pruritus: Uraemic Pruritus in Dialysis Patients (UP-Dial). AB - BACKGROUND: Dialysis patients with uraemic pruritus (UP) have significantly impaired quality of life. To assess the therapeutic effect of UP treatments, a well-validated comprehensive and multidimensional instrument needed to be established. OBJECTIVES: To develop and validate a multidimensional scale assessing UP in patients on dialysis: the Uraemic Pruritus in Dialysis Patients (UP-Dial). METHODS: The development and validation of the UP-Dial instrument were conducted in four phases: (i) item generation, (ii) development of a pilot questionnaire, (iii) refinement of the questionnaire with patient recruitment and (iv) psychometric validation. Participants completed the UP-Dial, the visual analogue scale (VAS) of UP, the Dermatology Life Quality Index (DLQI), the Kidney Disease Quality of Life-36 (KDQOL-36), the Pittsburgh Sleep Quality Index (PSQI) and the Beck Depression Inventory (BDI) between 15 May 2012 and 30 November 2015. RESULTS: The 27-item pilot UP-Dial was generated, with 168 participants completing the pilot scale. After factor analysis was performed, the final 14 item UP-Dial encompassed three domains: signs and symptoms, psychosocial, and sleep. Face and content validity were satisfied through the item generation process and expert review. Psychometric analysis demonstrated that the UP-Dial had good convergent and discriminant validity. The UP-Dial was significantly correlated [Spearman rank coefficient, 95% confidence interval (CI)] with the VAS UP (0.76, 0.69-0.83), DLQI (0.78, 0.71-0.85), KDQOL-36 (-0.86, -0.91 to -0.81), PSQI (0.85, 0.80-0.89) and BDI (0.70, 0.61-0.79). The UP-Dial revealed excellent internal consistency (Cronbach's alpha 0.90, 95% CI 0.87-0.92) and reproducibility (intraclass correlation 0.95, 95% CI 0.90-0.98). CONCLUSIONS: The UP-Dial is valid and reliable for assessing UP among patients on dialysis. Future research should focus on the cross-cultural adaptation and translation of the scale to other languages. PMID- 28012183 TI - A comparison study of clinician-rated atopic dermatitis outcome measures for intermediate- to dark-skinned patients. AB - BACKGROUND: Atopic dermatitis (AD) assessment is more difficult in patients with skin of colour (SOC). OBJECTIVES: To compare the reliability of commonly used outcome measures for assessing AD in patients with SOC and to evaluate a novel greyscale in this population. METHODS: Twenty-five patients with AD each attended a 1-day scoring exercise based in either Sydney or Melbourne, Australia. Each patient was scored by the same five physicians using the Eczema Area and Severity Index (EASI), objective Scoring Atopic Dermatitis (oSCORAD), Investigator's Global Assessment (IGA) and a novel greyscale. Patients also completed the Patient-Oriented Eczema Measure and quality-of-life measures. A Mexameter was used to measure baseline melanin indices. Ten random patients were rescored to test intrarater reliability. RESULTS: We included 11 light-skinned patients (melanin index <= 200) and 14 patients with SOC (melanin index > 200) in the cohort. The inter-rater intraclass correlation coefficients (ICCs) were EASI 0.83 [95% confidence interval (CI) 0.66-0.94] for light skin and 0.77 (95% CI 0.60 0.91) for SOC; oSCORAD 0.68 (95% CI 0.44-0.88) for light skin and 0.74 (95% CI 0.54-0.89) for SOC; and IGA 0.80 (95% CI 0.62-0.93) for light skin and 0.70 (95% CI 0.49-0.87) for SOC. The greyscale had an ICC of 0.78 (95% CI 0.60-0.91) when replacing the EASI's erythema scale for patients with SOC. All scores showed excellent intrarater reliability for all skin types. Erythema component analysis showed that erythema did not contribute to variability. CONCLUSIONS: EASI showed excellent reliability for patients of all skin colours, and is recommended as the optimal core measure for patients with all skin colours. PMID- 28012184 TI - Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. AB - KEY POINTS: Three weeks of intensified training and mild energy deficit in elite race walkers increases peak aerobic capacity independent of dietary support. Adaptation to a ketogenic low carbohydrate, high fat (LCHF) diet markedly increases rates of whole-body fat oxidation during exercise in race walkers over a range of exercise intensities. The increased rates of fat oxidation result in reduced economy (increased oxygen demand for a given speed) at velocities that translate to real-life race performance in elite race walkers. In contrast to training with diets providing chronic or periodised high carbohydrate availability, adaptation to an LCHF diet impairs performance in elite endurance athletes despite a significant improvement in peak aerobic capacity. ABSTRACT: We investigated the effects of adaptation to a ketogenic low carbohydrate (CHO), high fat diet (LCHF) during 3 weeks of intensified training on metabolism and performance of world-class endurance athletes. We controlled three isoenergetic diets in elite race walkers: high CHO availability (g kg-1 day-1 : 8.6 CHO, 2.1 protein, 1.2 fat) consumed before, during and after training (HCHO, n = 9); identical macronutrient intake, periodised within or between days to alternate between low and high CHO availability (PCHO, n = 10); LCHF (< 50 g day-1 CHO; 78% energy as fat; 2.1 g kg-1 day-1 protein; LCHF, n = 10). Post-intervention, VO2 peak during race walking increased in all groups (P < 0.001, 90% CI: 2.55, 5.20%). LCHF was associated with markedly increased rates of whole-body fat oxidation, attaining peak rates of 1.57 +/- 0.32 g min-1 during 2 h of walking at ~80% VO2 peak . However, LCHF also increased the oxygen (O2 ) cost of race walking at velocities relevant to real-life race performance: O2 uptake (expressed as a percentage of new VO2 peak ) at a speed approximating 20 km race pace was reduced in HCHO and PCHO (90% CI: -7.047, -2.55 and -5.18, -0.86, respectively), but was maintained at pre-intervention levels in LCHF. HCHO and PCHO groups improved times for 10 km race walk: 6.6% (90% CI: 4.1, 9.1%) and 5.3% (3.4, 7.2%), with no improvement (-1.6% (-8.5, 5.3%)) for the LCHF group. In contrast to training with diets providing chronic or periodised high-CHO availability, and despite a significant improvement in VO2 peak , adaptation to the topical LCHF diet negated performance benefits in elite endurance athletes, in part due to reduced exercise economy. PMID- 28012185 TI - Inclusive fitness in finite populations-effects of heterogeneity and synergy. AB - I review recent results concerning the relationship between the inclusive fitness (IF) effect and standard measures of allele fitness in a finite-population, with attention to the effect of heterogeneity in population structure and nonadditive fitness effects. In both cases, existing theoretical work is somewhat technical and I try to provide a more transparent account. In a heterogeneous population it is known that inclusive fitness will generally fail to incorporate the effects of selection on the distribution of alleles among states unless a reproductive-value weighting is used. But even given that, recent work shows that under certain updating rules, the IF effect can fail to be equivalent to standard measures such as fixation probability. In terms of synergistic fitness effects, I review the result that in the finite population model, the IF effect can be calculated using only "additive" relatedness coefficients so that computational difficulties found in the infinite-population model do not arise. In my own work, there is an interaction here in that my 2012 work on synergy with Maciejewski made an assumption about inclusive fitness that my 2014 work on heterogeneity with Tarnita showed to be wrong. I include (Appendix C) a corrected argument for the 2012 result. PMID- 28012186 TI - A critical review of polycyclic aromatic hydrocarbon phototoxicity models. AB - Polycyclic aromatic hydrocarbons (PAHs) are known to exhibit photo-induced toxicity. Hundreds to thousands of PAH parent and substituted compounds are found in the environment, and developing a predictive model applicable to a wide variety of PAHs and organisms is a necessary precursor to environmental risk assessments. There has been evolutionary progress in phototoxicity modeling since 1977. In the present study, a comprehensive review of the models developed to predict phototoxicity of PAHs is presented. The contributions of each of the models to the state of the art are discussed. The models are compared in terms of their scope of applicability to different organisms, PAHs, endpoints (median lethal time and median lethal concentration), and light conditions. The current state of the science that accounts for the key elements of phototoxicity modeling, including the differences in species sensitivity, the partitioning of PAHs into the target lipid of the organisms, and light absorption by the chemicals, as well as light exposure time and conditions, is discussed. In addition, the remaining issues that need to be addressed are explored: the effect of time-varying exposures to light and PAH concentrations, and the lack of a mechanistic understanding that can explain the failure of the Bunsen-Roscoe law of reciprocity. Environ Toxicol Chem 2017;36:1138-1148. (c) 2016 SETAC. PMID- 28012187 TI - Two female cases of focal dermal hypoplasia: One new case with a novel variant in PORCN (c.808_811delGGGG). PMID- 28012188 TI - Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Patients with Hereditary Ventricular Arrhythmias. AB - BACKGROUND: Left cardiac sympathetic denervation (LCSD) has been underutilized in patients with hereditary ventricular arrhythmia syndromes such as congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The purpose of this study was to investigate the safety and efficacy of video-assisted thoracoscopic (VATS) LCSD in such patients. METHODS: Fifteen patients (four men, 24.6 +/- 10.5 years old) who underwent VATS-LCSD between November 2010 and January 2015 for hereditary ventricular arrhythmia syndromes at Kyungpook National University Hospital were enrolled in this study. The safety and efficacy of VATS-LCSD were evaluated by periprocedural epinephrine tests and assessing the development of complications and cardiac events during follow-up. RESULTS: Fourteen patients with LQTS and one patient with CPVT underwent VATS LCSD. Six and one patients developed ventricular tachyarrhythmia during preprocedural and postprocedural epinephrine test, respectively (P = 0.063). No serious complications such as Horner syndrome, pneumothorax, or bleeding developed after LCSD. Mean hospital stay after VATS-LCSD was 3.7 +/- 1.5 days. During a mean follow-up of 927 +/- 350 days, one LQTS patient and one CPVT patient, neither of whom manifested tachyarrhythmia during post-LCSD epinephrine test, developed torsades de pointes and syncope, respectively. The annual event rates of six patients who were symptomatic during the period preceding LCSD decreased from 0.97 to 0.19 events/year (P = 0.045). CONCLUSIONS: VATS-LCSD was a safe, and effective procedure for patients with hereditary ventricular tachycardia syndrome, with no serious adverse events and with short hospital stay. PMID- 28012189 TI - Vitamin D3 derivatives, alone or in combination with glucocorticoids, suppress streptococcal pyrogenic enterotoxin A-stimulated proliferation of peripheral blood mononuclear cells in patients with psoriasis. AB - Bacterial colonization on skin or tonsil may influence the clinical response of patients with psoriasis to immunosuppressive drugs. However, few studies have investigated the effects of bacterial superantigens on therapy in these patients. Recently, combination therapy with topical glucocorticoids (GC) and vitamin D3 (VD3) appears to be more effective than GC or VD3 monotherapy for psoriasis. We evaluated the suppressive effects of betamethasone butyrate propionate (BBP), three VD3 derivatives (calcipotriol, maxacalcitol and tacalcitol), cyclosporin and BBP plus VD3, on concanavalin A (ConA)- or streptococcal pyrogenic enterotoxin A (SPEA)-stimulated proliferation of peripheral blood mononuclear cells (PBMC) obtained from 35 psoriasis patients. Drug concentrations effecting 50% inhibition concentration of ConA- or SPEA-stimulated PBMC proliferation were estimated. Cytokine levels of tumor necrosis factor-alpha, gamma-interferon, interleukin-1b, -2, -4, -5, -6, -8 -10 and -12p70 in PBMC culture supernatants were measured with bead-array procedures. Suppression of PBMC proliferation by BBP was significantly lower when PBMC were stimulated by SPEA than when stimulated by ConA. In contrast, the suppressive effects of calcipotriol and tacalcitol increased significantly when PBMC were stimulated by SPEA than when stimulated by ConA. The suppressive effect of BBP on SPEA-stimulated PBMC proliferation was improved significantly by adding 1-1000 ng/mL calcipotriol, compared with BBP alone. Cytokine levels in PBMC culture supernatants were not significantly different between ConA- and SPEA-stimulated PBMC. Calcipotriol and BBP in combination markedly suppressed SPEA-stimulated PBMC proliferation. SPEA produced by colonization of hemolytic streptococci may reduce the efficacy of BBP but not VD3 derivatives in the treatment of psoriasis. PMID- 28012190 TI - Short-term effect of scalpel debridement of plantar callosities versus treatment with salicylic acid patches: The EMEDESCA randomized controlled trial. AB - This study compares scalpel debridement versus salicylic acid patches in the treatment of plantar callosities. A randomized clinical trial (ACTRN12614000591651) was performed with 62 patients, divided into two intervention groups. Group A received treatment with salicylic acid patches (Callivoro Marthand(r) ) and group B underwent scalpel debridement of plantar callosities. Pain was measured on a visual analog scale, and foot pain and disability were evaluated using the Manchester Foot Pain Disability Index (MFPDI) questionnaire (Spanish version). Significant differences were observed in pain measured immediately after treatment (P < 0.001) and at 15 days and 6 weeks after treatment. For some components, the MFPDI questionnaire revealed significantly better outcomes by scalpel debridement at 15 days after treatment. The scalpel debridement of plantar callosities relieves pain more effectively than salicylic acid patches, and patients achieve greater functionality in the initial weeks after debridement. PMID- 28012191 TI - Neither 'foolish' nor 'finished': identity control among older adults with HIV in rural Malawi. AB - Prevalence of HIV after age 50 is considerable, especially in southern Africa. Negative social constructions of HIV in older age, and the health consequences of ageing with the virus, mean that having HIV presents a challenge for many people's roles and social memberships, threatening to disrupt their sense of self. Using constructivist grounded theory and qualitative data from rural Malawi, this paper describes how older men and women deal with these identity challenges. Drawing on a symbolic interactionist framework, it uses identity control theory to explore how the study's participants presented their post diagnosis behaviours in ways that maintained their most significant pre-diagnosis identities as 'adults', a label they gave to the core identity of being a person who belongs in the social world. Considering the processes through which older people with HIV navigated challenges to their identities in light of the intersectional influences of HIV and age-related stigma and illness, provides insight into how older people might experience HIV, as well as informing theoretical understandings of identity formation and maintenance in light of chronic and/or stigmatising illness more broadly. PMID- 28012192 TI - Extracellular vesicles as therapeutic carriers of microRNAs for cholangiocarcinoma. PMID- 28012193 TI - Theoretical evidence of maximum intracellular currents versus frequency in an Escherichia coli cell submitted to AC voltage. AB - In this work, the problem of intracellular currents in longilinear bacteria, such as Escherichia coli, suspended in a physiological medium and submitted to a harmonic voltage (AC), is analyzed using the Finite-Element-based software COMSOL Multiphysics. Bacterium was modeled as a cylindrical capsule, ended by semi spheres and surrounded by a dielectric cell wall. An equivalent single-layer cell wall was defined, starting from the well-recognized three-shell modeling approach. The bacterium was considered immersed in a physiological medium, which was also taken into account in the modeling. A new complex transconductance was thus introduced, relating the complex ratio between current inside the bacterium and voltage applied between two parallel equipotential planes, separated by a realistic distance. When voltage was applied longitudinally relative to the bacterium main axis, numerical results in terms of frequency response in the 1-20 MHz range for E. coli cells revealed that transconductance magnitude exhibited a maximum at a frequency depending on the cell wall capacitance. This occurred in spite of the purely passive character of the model and could be explained by an equivalent electrical network giving very similar results and showing special conditions for lateral paths of the currents through the cell wall. It is shown that the main contribution to this behavior is due to the conductive part of the current. Bioelectromagnetics. 38:213-219, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28012194 TI - Association of antenatal antithrombin activity with perinatal liver dysfunction: A prospective multicenter study. AB - BACKGROUND AND AIM: Liver dysfunction with decreased antithrombin (AT) activity and/or thrombocytopenia is life threatening in pregnant women. Whether AT is clinically useful for prediction of liver dysfunction remains unclear. METHODS: A total of 541 women were registered prospectively at gestational week 34.7 (20.0 41.4) with available data on antenatal AT and platelet count (PLC). RESULTS: Liver dysfunction defined as serum aspartate aminotransferase > 45 IU/L concomitant with lactate dehydrogenase > 400 IU/L occurred in five women antenatally (<= 2 weeks before delivery) and in 17 women post-partum (within 1 week post-partum). Median (5th-95th) antenatal value was 85 (62-110)% for AT and 202 (118-315) * 109 /L for PLC in the 541 women and was significantly lower in women with than without perinatal liver dysfunction; 75 (51-108) versus 86 (62 110)% and 179 (56-244) versus 203 (121-316) * 109 /L, respectively. Nineteen (86%) women with liver dysfunction showed AT <= 62% or thrombocytopenia (PLC <= 118 * 109 /L) perinatally, but five lacked thrombocytopenia throughout the perinatal period. The best cut-off (AT, 77%; PLC, 139 * 109 /L) suggested by receiver operating characteristic curve gave antenatal AT and PLC sensitivity of 59% and 41% with positive predictive value of 8.6% and 14%, respectively, and combined use of AT and PLC improved sensitivity to 73% (16/22) with positive predictive value of 9.2% for prediction of perinatal liver dysfunction. CONCLUSIONS: Reduced AT not accompanied by thrombocytopenia can precede liver dysfunction. Clinical introduction of AT may enhance the safety of pregnant women. PMID- 28012195 TI - Angels. PMID- 28012196 TI - MicroRNA-184 Modulates Human Central Nervous System Lymphoma Cells Growth and Invasion by Targeting iASPP. AB - Central nervous system lymphoma (CNSL) remains a diagnostical and therapeutical challenge. MiRNAs post-transcriptionally regulate expression of targeted mRNAs through binding to their 3' UTR to inhibit their translation or promote their degradation. Oncoprotein inhibitory member of the ASPP family (iASPP), a key inhibitor of tumor suppressor p53, has been reported to play oncogenic role in cancers. Our present study was aimed to determine whether the miR-184/iASPP axis is involved in the proliferation and invasion of CNSL. A reduced level of miR-184 was observed in CNSL tissues. Exogenous miR-184 inhibited cell survival and invasion, as well as the tumor volumes, while miR-184 inhibition could reverse this process. The RNA and protein levels of iASPP were significantly inhibited by miR-184, and the 3' UTR of iASPP was shown to be a target of miR-184. The expression of iASPP was up-regulated in CNSL tissues, compared to that of the normal brain tissues. The inhibition of iASPP by shRNA iASPP significantly repressed CNSL cells' proliferation and invasion, and reduced the volume of the tumor. Besides, iASPP overexpression could partly restore the suppressive effect of miR-184 on CNSL cell proliferation and invasive capability. We also revealed that miR-184/iASPP axis regulated the proliferation and invasion via PI3K/Akt signaling pathway, which presents a novel potential therapy for intervention of CNSL. Taken together, our findings revealed the detailed role of the miR 184/iASPP axis in CNSL and this axis might modulate the proliferation and invasion of CNSL via regulating the PI3K/Akt signaling pathway. J. Cell. Biochem. 118: 2645-2653, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28012197 TI - Interstitial photodynamic therapy and glioblastoma: Light fractionation in a preclinical model. AB - BACKGROUND: Glioblastoma is a high-grade cerebral tumor with local recurrence and poor outcome. Photodynamic therapy (PDT) is a localized treatment based on the light activation of a photosensitizer (PS) in the presence of oxygen, which results in the formation of cytotoxic species. The delivery of fractionated light may enhance treatment efficacy by reoxygenating tissues. OBJECTIVE: To evaluate the efficiency of two light-fractionation schemes using immunohistological data. MATERIALS AND METHODS: Human U87 cells were grafted into the right putamen of 39 nude rats. After PS precursor intake (5-ALA), an optic fiber was introduced into the tumor. The rats were randomly divided into three groups: without light, with light split into 2 fractions and with light split into 5 fractions. Treatment effects were assessed using brain immunohistology. RESULTS: Fractionated treatments induced intratumoral necrosis (P < 0.001) and peritumoral edema (P = 0.009) associated with a macrophagic infiltration (P = 0.006). The ratio of apoptotic cells was higher in the 5-fraction group than in either the sham (P = 0.024) or 2-fraction group (P = 0.01). Peripheral vascularization increased after treatment (P = 0.017), and these likely new vessels were more frequently observed in the 5-fraction group (P = 0.028). CONCLUSION: Interstitial PDT with fractionated light resulted in specific tumoral lesions. The 5-fraction scheme induced more apoptosis but led to greater peripheral neovascularization. Lasers Surg. Med. 49:506-515, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28012198 TI - The Mechanism under Common TCL-Age Relationship-More to Consider. PMID- 28012199 TI - Who or what controls tendon? PMID- 28012201 TI - How to Achieve Good Atrial Sensing in DX ICDs? PMID- 28012200 TI - Obesity, bodily change and health identities: a qualitative study of Canadian women. AB - Medicalised concerns about an obesity crisis persist yet more needs to be learnt about everyday orientations to weight (loss). This article reports and analyses data generated using qualitative methods, including repeated interviews and fieldwork conducted over one year in Canada with women (n = 13) identifying as (formerly) obese. Three ideal types are explored using empirical data: (1) hopeful narratives; (2) disordered eating distress; and (3) weight-cycling or stagnation. Core themes include women's desire to embody a thin(ner) future and the good life, the harms of intentional weight-loss, and resignation to living as a fat woman whilst nonetheless challenging stigma. The article contributes to critical studies of weight/fatness, the sociology of bodily change and the embodiment of health identities. In concluding, we call for reflexive change in bodies of health knowledge, policy and practice. PMID- 28012202 TI - Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis. AB - OBJECTIVES: To determine association, and predictive ability, of first trimester maternal serum pregnancy associated plasma protein A (PAPP-A) with adverse pregnancy outcomes. METHOD: Searches of Medline, Embase and CINAHL (inception September 2015) for studies including pregnant women with first trimester PAPP-A and assessment of pregnancy outcomes. Study characteristics, quality and results extracted. Meta-analysis of odds ratios (ORs), and likelihood ratios (LRs) and 95% confidence intervals (CI). RESULTS: Thirty-two studies including 175 240 pregnancies. PAPP-A <5th centile had a moderate association with: birth weight <10th centile OR 2.08 (95% CI 1.89-2.29), <5th centile OR 2.83 (95% CI 2.52 3.18); pre-eclampsia OR 1.94 (95% CI 1.63-2.30), preterm birth <37 weeks OR 2.09 (95% CI 1.87-2.33), and composite adverse outcome OR 3.31 (95% CI 1.80-5.11). The predictive ability was poor: Birth weight <10th centile LR + ve 1.96 (95% CI 1.58 2.43), LR-ve 0.93 (95% CI 0.89-0.98); birth weight <5th centile LR + ve 2.65 (95% CI 2.35-2.99), LR-ve 0.85 (95% CI 0.74-0.98); PTB <37 weeks LR + ve 1.84 (95% CI 1.41-2.39), LR-ve 0.92 (95% CI 0.87-0.98). CONCLUSIONS: First trimester low maternal serum PAPP-A is associated with adverse pregnancy outcome, but predictive values are poor. Further work should address PAPP-A as a continuous variable in combination with other prognostic markers as a prediction model. (c) 2016 John Wiley & Sons, Ltd. PMID- 28012203 TI - A Unique Ectopic Atrial Rhythm: Where Is the Origin? AB - In predicting the origin of focal atrial arrhythmias, a precise analysis of the P wave morphology in the 12-lead electrocardiogram is essential. In this report, we demonstrate a unique ectopic atrial rhythm and discuss its origin by analyzing the P-wave morphology. PMID- 28012204 TI - Thorax Percutaneous Approach for Epicardial Ventricular Ablation in a Patient with Electrical Storm. AB - Subxiphoid puncture is considered the standard approach for epicardial ablation of ventricular arrhythmia, but in some cases this access is impracticable due to the patient's anatomy. We describe the case of a patient with electrical storm and abnormal subdiaphragmatic anatomy that precluded the usual subxiphoid approach. In this patient the pericardial space was gained through a direct thorax puncture at the fifth intercostals space close to the mammary line. The tools and technique utilized in this case were similar to what is usually used for traditional subxiphoid puncture. The thorax percutaneous puncture was successfully carried out without complication. PMID- 28012205 TI - Activated alpha2 -Macroglobulin Induces Mesenchymal Cellular Migration Of Raw264.7 Cells Through Low-Density Lipoprotein Receptor-Related Protein 1. AB - Distinct modes of cell migration contribute to diverse types of cell movements. The mesenchymal mode is characterized by a multistep cycle of membrane protrusion, the formation of focal adhesion, and the stabilization at the leading edge associated with the degradation of extracellular matrix (ECM) components and with regulated extracellular proteolysis. Both alpha2 -Macroglobulin (alpha2 M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), play important roles in inflammatory processes, by controlling the extracellular activity of several proteases. The binding of the active form of alpha2 M (alpha2 M*) to LRP1 can also activate different signaling pathways in macrophages, thus inducing extracellular matrix metalloproteinase-9 (MMP-9) activation and cellular proliferation. In the present study, we investigated whether the alpha2 M*/LRP1 interaction induces cellular migration of the macrophage-derived cell line, Raw264.7. By using the wound-scratch migration assay and confocal microscopy, we demonstrate that alpha2 M* induces LRP1-mediated mesenchymal cellular migration. This migration exhibits the production of enlarged cellular protrusions, MT1-MMP distribution to these leading edge protrusions, actin polymerization, focal adhesion formation, and increased intracellular LRP1/beta1-integrin colocalization. Moreover, the presence of calphostin-C blocked the alpha2 M* stimulated cellular protrusions, suggesting that the PKC activation is involved in the cellular motility of Raw264.7 cells. These findings could constitute a therapeutic target for inflammatory processes with deleterious consequences for human health, such as rheumatoid arthritis, atherosclerosis and cancer. J. Cell. Biochem. 118: 1810-1818, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28012206 TI - Uptake and efflux kinetics, and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis. AB - Invasive pulmonary aspergillosis (IPA), most caused by Aspergillus fumigatus, is a serious life-threatening infection in immunocompromised patients. Voriconazole is used to prevent and treat IPA. However, little is known about the pharmacological characteristics of voriconazole in pulmonary epithelial cells, which are the target site for the prophylaxis and early treatment of IPA. The aim of the study was to evaluate the kinetics and activity of voriconazole against A. fumigatus in A549 cells. High-performance liquid chromatography/tandem mass spectrometry and time-kill method were used to study the cellular pharmacokinetic and pharmacodynamics of voriconazole. Voriconazole exerted a concentration dependent toxic effect on A549 cells and could penetrate into cells, reaching plateau concentrations of 1.14 +/- 0.64, 3.72 +/- 1.38 and 6.36 +/- 0.95 ng/mg protein after A549 cells were exposed to voriconazole at extracellular concentrations of 2, 8 and 16 mg/L for 2 h, respectively. The efflux of voriconazole was rapid, with a half-life of 10.2 min. Voriconazole can decrease the A. fumigatus conidia invade cells, and the number of viable A. fumigatus conidia in cells can be decreased 2.1- to 20.6-fold when A549 cells were cultured in medium containing voriconazole. After 24-h incubation, 75.6% and 80.5% of intracellular A. fumigatus were killed when extracellular voriconazole concentration was 8 and 16 mg/L, respectively. This study illustrated a new application for the prophylaxis and early treatment of IPA from the cellular pharmacokinetics and pharmacodynamics and emphasized the importance of monitoring concentrations of voriconazole in epithelial lining fluid in immunocompromised patients receiving voriconazole therapy. PMID- 28012207 TI - Langerhans cell histiocytosis with molluscum contagiosum: A correlation? PMID- 28012208 TI - Anal verrucous carcinoma is not related to infection with human papillomaviruses and should be distinguished from giant condyloma (Buschke-Lowenstein tumour). AB - AIMS: Verrucous carcinoma (VC) is a variant of well-differentiated squamous cell carcinoma and in the anal region is regarded as synonymous with giant condyloma (Buschke-Lowenstein tumour) (BLT). Aetiology, diagnostic criteria and clinical behaviour of both lesions are controversial. Recent studies suggest that VC at other sites is not associated with human papillomaviruses (HPV). We hypothesized that anal VC is also not related to HPV, while BLT is a HPV-induced lesion. METHODS AND RESULTS: Ten cases of VC and four cases of BLT were included. Several techniques were used for HPV detection: in-situ hybridization for HPV6, 11, 16 and 18, six different polymerase chain reaction (PCR) protocols for detection of at least 89 HPV types from alpha-, beta-, gamma- and mu-PV genera and in-situ hybridization for high-risk HPV E6/E7 mRNA; p16 immunohistochemistry and morphometric analysis were also performed. Alpha-, gamma- and mu-PVs were not found in any case of VC, while HPV6 was detected in all cases of BLT. p16 overexpression was not present in any of the lesions. Among microscopic features, only the absence of koilocytosis and enlarged spinous cells seem to be useful to distinguish VC from BLT. CONCLUSIONS: Our results suggest that anal VC, similarly to VC at other sites, is not associated with HPV infection, and must be distinguished from BLT, which is associated with low-risk HPV. Only with well-set diagnostic criteria will it be possible to ascertain clinical behaviour and optimal treatment for both lesions. PMID- 28012209 TI - Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells. AB - Activating transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) may increase apoA-I transcription. Furthermore, Bromodomain and Extra Terminal domain (BET) protein inhibitors increase, whereas Endoplasmic Reticulum (ER) stress decreases apoA-I transcription. We examined possible links between these processes as related to apoA-I transcription in HepG2 cells. JQ1(+), thapsigargin, and GW7647 were used to induce, respectively BET inhibition, ER stress, and PPARalpha activation. Expression of ER-stress markers (CHOP, XBP1s) was analyzed by western blotting. PPARalpha, KEAP1 (marker for BET inhibition), and apoA-I mRNAs were measured using qPCR. ER-stress and BET inhibition both decreased PPARalpha mRNA expression and activity, but did not interfere with each other, as ER-stress did not change KEAP1 and JQ1(+) did not influence ER-stress marker production. Interestingly, PPARalpha activation and BET-inhibition diminished ER-stress marker production and rescued apoA-I transcription during existing ER-stress. We conclude that the ER-stress mediated reduction in apoA-I transcription could be partly mediated via the inhibition of PPARalpha mRNA expression and activity. In addition, BET inhibition increased apoA-I transcription, even if PPARalpha production and activity were decreased. Finally, both BET inhibition and PPARalpha activation ameliorate the apoA-I lowering effect of ER-stress and are therefore interesting targets to elevate apoA-I transcription. J. Cell. Biochem. 118:2161-2167, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28012211 TI - Derivation and validation of a risk scoring model to predict advanced colorectal neoplasm in adults of all ages. AB - BACKGROUND AND AIMS: Little is known about how to include adults < 50 years in colonoscopy screening. This study aimed to derive a risk-scoring model incorporating laboratory indicators for metabolic risks to predict advanced colorectal neoplasia (ACN) in asymptomatic Korean adults both younger and older than 50 years. METHODS: In this cross-sectional study, 70 812 consecutive adult recipients of a screening colonoscopy in a single health check-up center in Korea between 2003 and 2012 were enrolled. A risk score model was developed using multiple logistic regression model and internally validated. RESULTS: Overall prevalence of ACN was 1.4% (956/70 812). A 15-point score model was developed to comprise age, sex, family history of colorectal cancer, smoking, body mass index, serum levels of fasting glucose, low-density lipoprotein cholesterol, and carcinoembryonic antigen. Based on the score, the validation cohort could be categorized into five risk groups (low, borderline, moderate, high, and very high) with an ACN prevalence of 0.7%, 1.3%, 2.7%, 6.6%, and 13.2%, respectively. Compared with the borderline risk group, the low-risk group showed a 50.3% reduced risk of ACN. Meanwhile, the moderate, high, and very high risk groups showed 2, 5, and 10-fold increased risk of ACN. The score showed significantly superior discriminative power than the Asian-Pacific colorectal screening score (P = 0.003). CONCLUSIONS: Our scoring model based on both clinical and laboratory risk factors is useful for the prediction of ACN. This score may be used to include adults < 50 years in colonoscopy screening. PMID- 28012210 TI - Elimination of Ventricular Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia by Targeting "Catecholamine-Sensitive Area": A Dominant Subordinate Relationship between Origin Sites of Bidirectional Ventricular Premature Contractions. AB - We report on a patient diagnosed with catechoaminergic polymorphic ventricular tachycardia (CPVT) who underwent catheter ablation of ventricular premature contractions (VPCs) induced by epinephrine. VPCs were classified roughly into three types. Type 1 and Type 2 VPCs (right bundle branch block [RBBB] configuration and inferior axis) were eliminated by radiofrequency applications at the left aortic sinus of Valsalva and the anterolateral papillary muscle (APM), respectively. Although no spontaneous VPCs were seen after the elimination of Type 1 and 2 VPCs, pacing resulting in capture at the APM induced Type 3 VPC (RBBB configuration and superior axis) reproducibly. The electrophysiological findings observed in our representative case have important implications both for understanding the pathophysiology of CPVT and for considering therapeutic strategies. PMID- 28012212 TI - Incidence of serum antibody titers against varicella zoster virus in Japanese patients with herpes zoster. AB - Herpes zoster is an internal reactivation of varicella zoster virus following establishment of latent infection in the dorsal root ganglia during primary infection, which presents as chickenpox. Therefore, serologically, herpes zoster patients already have anti-varicella zoster virus immunoglobulin G at the onset of disease. Hence, positive serum antibody does not confirm the diagnosis of herpes zoster. We retrospectively investigated the incidence of varicella zoster virus-specific complement fixation in 865 zoster patients at initial presentation to a dermatology clinic. As a result, 66% of patients showed negative complement fixation, with patient numbers decreasing as titer increased. Paired complement fixation tests conducted within a short period showed a marked elevation in titer, and complement fixation titer gradually decreased after a year. Furthermore, incidence showed no correlation with patient age. These observations indicate that the complement fixation titer at first visit is mainly influenced by the duration from onset to presentation at clinic. Our findings indicate that a positive complement fixation result by single-point testing confirms at least recent onset of herpes zoster, while paired tests can confirm disease when primary tests are negative. PMID- 28012213 TI - Antibody-dependent and antibody-independent uptake of HBsAg across human leucocyte subsets is similar between individuals with chronic hepatitis B virus infection and healthy donors. AB - Maintaining detectable levels of antibodies to hepatitis B surface antigen (HBsAg) in serum after HBsAg sero-conversion is the key clinical endpoint indicative of recovery from infection with hepatitis B virus (HBV). As HBV infected hepatocytes secrete HBsAg subviral particles in vast excess over HBV virions, detectable hepatitis B surface antibody (anti-HBs) titres imply complete elimination of HBV virions as well as HBsAg particles. Although intrahepatic phagocytes, for example Kupffer cells, are thought to mediate clearance of HBsAg via antibody (Ab)-dependent and Ab-independent mechanisms, the relative contributions of circulating phagocytic cell types to HBsAg elimination are poorly characterized. Understanding the role of various immune cell subsets in the clearance of HBsAg is important because Ab-dependent or Ab-independent phagocytic HBsAg uptake may modulate presentation of HBsAg-derived epitopes to antigen-specific T cells and hence plays a critical role in adaptive immunity against HBV. This study aims to characterize phagocytic leucocyte subsets capable of internalizing HBsAg immune complexes (HBsAg:IC) or un-complexed HBsAg particles in whole blood directly ex vivo. The data show that uptake of HBsAg:IC occurs most prominently in monocytes, B cells, dendritic cells and in neutrophils. In contrast, B cells, and to a lesser degree also monocytes, seem to be effective phagocytes for un-complexed HBsAg. Importantly, a similar pattern of phagocytic HBsAg uptake was observed in blood from chronic hepatitis B (CHB) patients compared to healthy controls, suggesting that phagocytosis-related cellular functions are not altered in the context of CHB. PMID- 28012214 TI - Long-term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma. AB - Long-term efficacy of proton beam therapy (PBT) remains unclear for patients with previously untreated hepatocellular carcinoma (HCC). We aimed to study the long term outcomes of PBT according to Barcelona Clinic Liver Cancer (BCLC) staging classifications in patients with previously untreated HCC. The major eligibility criteria of this observational study were an Eastern Cooperative Oncology Group performance status (PS) 0-2, Child-Pugh grade A or B, previously untreated HCC covered within an irradiation field, and no massive ascites. A total of 66.0-77.0 GyE was administered in 10-35 fractions. Local tumor control (LTC), defined as no progression in the irradiated field, progression-free survival (PFS), and overall survival (OS) were assessed according to BCLC staging. From 2002 to 2009 at our institution, 129 patients were eligible. The 5-year LTC, PFS, and OS rates were 94%, 28%, and 69% for patients with 0/A stage disease (n = 9/21), 87%, 23%, and 66% for patients with B stage disease (n = 34), and 75%, 9%, and 25% for patients with C stage disease (n = 65), respectively. The 5-year LTC and OS rates of 15 patients with tumor thrombi in major vessels were 90% and 34%, respectively. Multivariate analyses revealed that PS (0 versus 1-2) was a significant prognostic factor for OS. No grade 3 or higher adverse effects were observed. PBT showed favorable long-term efficacies with mild adverse effects in BCLC stage 0 to C, and can be an alternative treatment for localized HCC especially when accompanied with tumor thrombi. This study was registered with UMIN Clinical Trials Registry (UMIN000025342). PMID- 28012215 TI - Real-world experience with daclatasvir plus sofosbuvir +/- ribavirin for post liver transplant HCV recurrence and severe liver disease. AB - Optimizing therapy of post-transplant HCV recurrence remains important, especially in advanced liver disease. We evaluated daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in patients with post-liver transplant recurrence in a real-world European cohort at high risk of decompensation or death within 12 months. Recommended treatment was DCV 60 mg plus SOF 400 mg once daily for 24 weeks; RBV use/shorter treatment duration was at physicians' discretion. Patients (N = 87) were 70% male, 93% white, and mostly infected with HCV genotypes 1b (48%), 1a (32%), or 3 (9%); 37 (43%) had cirrhosis (16 decompensated), five had fibrosing cholestatic hepatitis. Sustained virologic response at post-treatment week 12 (SVR12) was 94% (80/85) in a modified intention-to-treat analysis: 95% (58/61) without RBV and 92% (22/24) with RBV, with no virologic failures. SVR12 was 100% (80/80) in an as-observed analysis excluding five nonvirologic failures. Four patients (5%) discontinued therapy for adverse events (AEs); 16 (18%) experienced serious AEs. One patient died on treatment and five during follow-up. Most AEs were associated with advanced liver disease and unrelated to therapy. No clinically significant drug-drug interactions were observed. DCV + SOF +/- RBV was well tolerated and achieved high SVR12 (94%) in patients with post-transplant HCV recurrence, including patients with severe liver disease. PMID- 28012216 TI - Clones or clans: the genetic structure of a deep-sea sponge, Aphrocallistes vastus, in unique sponge reefs of British Columbia, Canada. AB - Understanding patterns of reproduction, dispersal and recruitment in deep-sea communities is increasingly important with the need to manage resource extraction and conserve species diversity. Glass sponges are usually found in deep water (>1000 m) worldwide but form kilometre-long reefs on the continental shelf of British Columbia and Alaska that are under threat from trawling and resource exploration. Due to their deep-water habitat, larvae have not yet been found and the level of genetic connectivity between reefs and nonreef communities is unknown. The genetic structure of Aphrocallistes vastus, the primary reef building species in the Strait of Georgia (SoG) British Columbia, was studied using single nucleotide polymorphisms (SNPs). Pairwise comparisons of multilocus genotypes were used to assess whether sexual reproduction is common. Structure was examined 1) between individuals in reefs, 2) between reefs and 3) between sites in and outside the SoG. Sixty-seven SNPs were genotyped in 91 samples from areas in and around the SoG, including four sponge reefs and nearby nonreef sites. The results show that sponge reefs are formed through sexual reproduction. Within a reef and across the SoG basin, the genetic distance between individuals does not vary with geographic distance (r = -0.005 to 0.014), but populations within the SoG basin are genetically distinct from populations in Barkley Sound, on the west coast of Vancouver Island. Population structure was seen across all sample sites (global FST = 0.248), especially between SoG and non-SoG locations (average pairwise FST = 0.251). Our results suggest that genetic mixing occurs across sponge reefs via larvae that disperse widely. PMID- 28012217 TI - Association of Increased Urinary Albumin With Risk of Incident Clinical Fracture and Rate of Hip Bone Loss: the Osteoporotic Fractures in Men Study. AB - Prior studies suggest that increased urine albumin is associated with a heightened fracture risk in women, but results in men are unclear. We used data from Osteoporotic Fractures in Men (MrOS), a prospective cohort study of community-dwelling men aged >=65 years, to evaluate the association of increased urine albumin with subsequent fractures and annualized rate of hip bone loss. We calculated albumin/creatinine ratio (ACR) from urine collected at the 2003-2005 visit. Subsequent clinical fractures were ascertained from triannual questionnaires and centrally adjudicated by review of radiographic reports. Total hip BMD was measured by DXA at the 2003-2005 visit and again an average of 3.5 years later. We estimated risk of incident clinical fracture using Cox proportional hazards models, and annualized BMD change using ANCOVA. Of 2982 men with calculable ACR, 9.4% had ACR >=30 mg/g (albuminuria) and 1.0% had ACR >=300 mg/g (macroalbuminuria). During a mean of 8.7 years of follow-up, 20.0% of men had an incident clinical fracture. In multivariate-adjusted models, neither higher ACR quintile (p for trend 0.75) nor albuminuria (HR versus no albuminuria, 0.89; 95% CI, 0.65 to 1.20) was associated with increased risk of incident clinical fracture. Increased urine albumin had a borderline significant, multivariate-adjusted, positive association with rate of total hip bone loss when modeled in ACR quintiles (p = 0.06), but not when modeled as albuminuria versus no albuminuria. Macroalbuminuria was associated with a higher rate of annualized hip bone loss compared to no albuminuria (-1.8% more annualized loss than in men with ACR <30 mg/g; p < 0.001), but the limited prevalence of macroalbuminuria precluded reliable estimates of its fracture associations. In these community dwelling older men, we found no association between urine albumin levels and risk of incident clinical fracture, but found a borderline significant, positive association with rate of hip bone loss. (c) 2016 American Society for Bone and Mineral Research. PMID- 28012218 TI - MET4 expression predicts poor prognosis of gastric cancers with Helicobacter pylori infection. AB - The role of HGF/SF-MET signaling is important in cancer progression, but its relation with Helicobacter pylori-positive gastric cancers remains to be elucidated. In total, 201 patients with primary gastric carcinoma who underwent curative or debulking resection without preoperative chemotherapy were studied. MET4 and anti-HGF/SF mAbs were used for immunohistochemical analysis. Survival of gastric cancer patients was estimated by Kaplan-Meier method and compared with log-rank. Cox proportional hazards models were fit to determine the independent association of MET-staining status with outcome. The effect of live H. pylori bacteria on cell signaling and biological behaviors was evaluated using gastric cancer cell lines. MET4-positive gastric cancers showed poorer prognosis than MET4-negative cases (overall survival, P = 0.02; relapse-free survival, P = 0.06). Positive staining for MET4 was also a statistically significant factor to predict poor prognosis in H. pylori-positive cases (overall survival, P < 0.01; relapse-free survival, P = 0.01) but not in H. pylori-negative cases. Gastric cancers positively stained with both HGF/SF and MET4 showed a tendency of the worst prognosis. Stimulation of MET-positive gastric cancer cells with live H. pylori bacteria directly upregulated MET phosphorylation and activated MET downstream signals such as p44/42MAPK and Akt, conferring cell proliferation and anti-apoptotic activity. In conclusion, positive staining for MET4 was useful for predicting poor prognosis of gastric cancers with H. pylori infection. Helicobacter pylori stimulated MET-positive gastric cancers and activated downstream signaling, thereby promoting cancer proliferation and anti-apoptotic activity. These results support the importance of H. pylori elimination from gastric epithelial surface in clinical therapy. PMID- 28012220 TI - Heart rate variability analysis during immediate recovery from exercise in overweight/obese healthy young adult females. AB - BACKGROUND: Data on heart rate variability (HRV) changes during immediate recovery period after exercise in overweight/obese healthy young adult females are still inconclusive. The aim of this study was to evaluate the heart rate variability (HRV), heart rate recovery (HRR), and arterial blood pressure immediately after cessation of exercise in overweight/obese healthy young adult females. METHODS: This study was carried out in the laboratory of the Physiology Department, Faculty of Medicine, King Abdulaziz University. Fifty-five female students were classified into normal weight group and overweight/obese group. HRV, HRR, and systolic and diastolic blood pressures (SBP, DBP) were estimated at resting condition and immediately after cessation of exercise. RESULTS: During recovery, heart rate was significantly increased in overweight/obese group along with significant decrease in rMSSD (square root of the mean of the sum of the squares of differences between adjacent NN intervals) and HF (high-frequency power) compared with normal group. The recovery of heart rate, normalized HF, and normalized sympathovagal balance to their baseline values were significantly lowered in overweight/obese group. Both SBP and DBP were significantly lowered from their baseline values during recovery in normal group but unchanged in overweight/obese group. CONCLUSIONS: This study provides evidence that overweight/obesity are associated with decreased HRR and delayed vagal reactivation, in addition to impaired postexercise hypotension early in the recovery period after exercise in healthy young adult females. PMID- 28012219 TI - Incorporation of high-dose 131 I-metaiodobenzylguanidine treatment into killer immunoglobulin-like receptor/HLA-ligand mismatched haploidentical stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation. AB - BACKGROUND: We performed a pilot study (NCT 00793351) to evaluate the effectiveness and feasibility of a strategy incorporating high-dose 131 I metaiodobenzylguanidine (HD-MIBG) treatment into killer immunoglobulin-like receptor (KIR)/HLA-ligand mismatched haploidentical stem cell transplantation (haplo-SCT) in improving the survival of children with neuroblastoma who failed previous tandem autologous SCT. PROCEDURE: If the patient remained progression free with salvage treatment, HD-MIBG treatment (18 mCi/kg) was given prior to reduced-intensity conditioning (cyclophosphamide + fludarabine + antithymocyte globulin). Grafts from KIR/HLA-ligand mismatched, preferably BX haplotype, haploidentical donors were transplanted to enhance the graft-versus-tumor (GVT) effect. RESULTS: A total of seven patients were enrolled and three donors had a BX haplotype. Toxicities during HD-MIBG treatment and reduced-intensity conditioning were mild. Neutrophil recovery and complete or near complete donor chimerism were rapidly achieved. Six patients experienced acute graft-versus-host disease (GVHD; grade I in five and grade III in one), and four of six evaluable patients experienced chronic GVHD (two mild and two severe). Four patients died from tumor progression, one died from sepsis without progression, and the other two remained alive in complete response during 34 and 48 months posttransplant. All three patients remained progression free after BX haplotype SCT, whereas the other four experienced progression after AA haplotype SCT. CONCLUSIONS: Our results suggest that the incorporation of HD-MIBG treatment in haplo-SCT and the use of BX haplotype donors might improve outcome, but this approach is currently limited by unacceptable GVHD. Further work focused on enhancement of GVT effects in relapsed neuroblastoma should be coupled with efforts to reduce GVHD. PMID- 28012221 TI - Transcriptomic imprints of adaptation to fresh water: parallel evolution of osmoregulatory gene expression in the Alewife. AB - Comparative approaches in physiological genomics offer an opportunity to understand the functional importance of genes involved in niche exploitation. We used populations of Alewife (Alosa pseudoharengus) to explore the transcriptional mechanisms that underlie adaptation to fresh water. Ancestrally anadromous Alewives have recently formed multiple, independently derived, landlocked populations, which exhibit reduced tolerance of saltwater and enhanced tolerance of fresh water. Using RNA-seq, we compared transcriptional responses of an anadromous Alewife population to two landlocked populations after acclimation to fresh (0 ppt) and saltwater (35 ppt). Our results suggest that the gill transcriptome has evolved in primarily discordant ways between independent landlocked populations and their anadromous ancestor. By contrast, evolved shifts in the transcription of a small suite of well-characterized osmoregulatory genes exhibited a strong degree of parallelism. In particular, transcription of genes that regulate gill ion exchange has diverged in accordance with functional predictions: freshwater ion-uptake genes (most notably, the 'freshwater paralog' of Na+ /K+ -ATPase alpha-subunit) were more highly expressed in landlocked forms, whereas genes that regulate saltwater ion secretion (e.g. the 'saltwater paralog' of NKAalpha) exhibited a blunted response to saltwater. Parallel divergence of ion transport gene expression is associated with shifts in salinity tolerance limits among landlocked forms, suggesting that changes to the gill's transcriptional response to salinity facilitate freshwater adaptation. PMID- 28012222 TI - Temporal dynamics of microbial communities in microcosms in response to pollutants. AB - Elucidating the mechanisms underlying microbial succession is a major goal of microbial ecology research. Given the increasing human pressure on the environment and natural resources, responses to the repeated introduction of organic and inorganic pollutants are of particular interest. To investigate the temporal dynamics of microbial communities in response to pollutants, we analysed the microbial community structure in batch microcosms that were inoculated with soil bacteria following exposure to individual or combined pollutants (phenanthrene, n-octadecane, phenanthrene + n-octadecane and phenanthrene + n octadecane + CdCl2 ). Subculturing was performed at 10-day intervals, followed by high-throughput sequencing of 16S rRNA genes. The dynamics of microbial communities in response to different pollutants alone and in combination displayed similar patterns during enrichment. Specifically, the repression and induction of microbial taxa were dominant, and the fluctuation was not significant. The rate of appearance for new taxa and the temporal turnover within microbial communities were higher than the rates reported in other studies of microbial communities in air, water and soil samples. In addition, conditionally rare taxa that were specific to the treatments exhibited higher betweenness centrality values in the co-occurrence network, indicating a strong influence on other interactions in the community. These results suggest that the repeated introduction of pollutants could accelerate microbial succession in microcosms, resulting in the rapid re-equilibration of microbial communities. PMID- 28012223 TI - Transplant center volume and outcomes in lung transplantation for cystic fibrosis. AB - Transplant volume represents lung transplant (LTx) expertise and predicts outcomes, so we sought to determine outcomes related to center volumes in cystic fibrosis (CF). United Network for Organ Sharing data were queried for patients with CF in the United States (US) receiving bilateral LTx from 2005 to 2015. Multivariable Cox regression was used to model survival to 1 year and long-term (>1 year) survival, conditional on surviving at least 1 year. A total of 2025 patients and 67 centers were included in the analysis. The median annual LTx volumes were three in CF [interquartile range (IQR): 2, 6] and 17 in non-CF (IQR: 8, 33). Multivariable Cox regression in cases with complete data and surviving at least 1 year (n = 1510) demonstrated that greater annual CF LTx volume (HR per 10 LTx = 0.66; 95% CI: 0.49, 0.89; P = 0.006) but not greater non-CF LTx volume (HR = 1.00; 95% CI: 0.96, 1.05; P = 0.844) was associated with improved long-term survival in LTx recipients with CF. A Wald interaction test confirmed that CF LTx volume was more strongly associated with long-term outcomes than non-CF LTx volume (P = 0.012). In a US cohort, center volume was not associated with 1-year survival. CF-specific expertise predicted improved long-term outcomes of LTx for CF, whereas general LTx expertise was unassociated with CF patients' survival. PMID- 28012224 TI - Continuation of low-molecular-weight heparin treatment for cancer-related venous thromboembolism: a prospective cohort study in daily clinical practice. AB - : Essentials Low-molecular-weight heparin (LMWH) injections for venous thromboembolism (VTE) may be burdensome. Patients with active cancer and confirmed VTE were included to evaluate LMWH continuation. The cumulative incidence of discontinuation was 21% after a median period of 90 days. One out of five patients discontinued LMWH injections because of side effects. SUMMARY: Background Current guidelines recommend low-molecular-weight heparin (LMWH) monotherapy for 3-6 months as the first-line treatment for cancer-associated venous thromboembolism (VTE). However, although daily administration of LMWH injections over a course of several months may be burdensome, the number of patients who stop treatment because of LMWH side-effects is unknown. Objectives To evaluate the continuation rate and complications of daily LMWH injections in patients with cancer-associated VTE. Methods Consecutive patients with active cancer and objectively confirmed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, treated at three Dutch hospitals and one Spanish hospital, were included to evaluate continuation LMWH therapy during LMWH treatment. Patients were excluded when they received other anticoagulants, were lost to follow-up, or experienced a venous catheter-associated thrombosis. Results A total of 372 patients were analyzed during LMWH treatment for a maximum of 180 days. The cumulative incidence of discontinuation was 21% (95% confidence interval [CI] 17-25) after a median period of 90 days (interquartile range 60-120 days). Only female sex was found to be significantly associated with premature LMWH discontinuation (odds ratio 1.6; 95% CI 1.03-2.5). Thirty patients (8.1%) developed recurrent VTE, 30 patients (8.3%) suffered a major bleed, and 106 patients (28%) died. Conclusion Our study reveals that one of five patients with cancer-associated VTE stopped LMWH injections because of side-effects. This finding provides relevant background information for current clinical trials investigating the efficacy and safety of direct oral anticoagulants as compared with LMWH. PMID- 28012225 TI - Drivers of genetic differentiation in a generalist insect-pollinated herb across spatial scales. AB - The isolation-by-distance model (IBD) predicts that genetic differentiation among populations increases with geographic distance. Yet, empirical studies show that a variety of ecological, topographic and historical factors may override the effect of geographic distance on genetic variation. This may particularly apply to species with narrow but highly heterogeneous distribution ranges, such as those occurring along elevational gradients. Using nine SSR markers, we study the genetic differentiation of the montane pollination-generalist herb, Erysimum mediohispanicum. Because the effects of any given factor may depend on the geographic scale considered, we investigate the contribution of different environmental and historical factors at three different spatial scales. We evaluate five competing models that put forward the role of geographic distance, local environmental factors [biotic interactions (IBEb) and climatic variables (IBEa)], landscape resistance (IBR) and phylogeographic patterns (IBP), respectively. We find significant IBD regardless of the spatial scale and the genetic distance estimator considered. However, IBEa and IBP also play a prominent role in shaping genetic differentiation patterns at the larger spatial scales, and IBR is significant at the fine spatial scale. Overall, our results highlight the importance of combining different estimators, statistical approaches and spatial scales to disentangle the relative importance of the various ecological factors contributing to the shaping of genetic divergence patterns in natural populations. PMID- 28012226 TI - Treg therapy in transplantation: a general overview. AB - Solid organ transplantation remains the treatment of choice for end-stage organ failure. Whilst the short-term outcomes post-transplant have improved in the last decades, chronic rejection and immunosuppressant side effects remain an ongoing concern. Hematopoietic stem cell transplantation is a well-established procedure for the treatment of patients with haematological disorders. However, donor T cells are continually primed and activated to react against the host causing graft-versus-host disease (GvHD) that leads to tissue damages and death. Regulatory T cells (Tregs) play an essential role in maintaining tolerance to self-antigens, preventing excessive immune responses and abrogating autoimmunity. Due to their suppressive properties, Tregs have been extensively studied for their use as a cellular therapy aiming to treat GvHD and limit immune responses responsible for graft rejection. Several clinical trials have been conducted or are currently ongoing to investigate safety and feasibility of Treg-based therapy. This review summarizes the general understanding of Treg biology and presents the methods used to isolate and expand Tregs. Furthermore, we describe data from the first clinical trials using Tregs, explaining the limitations and future application of these cells. PMID- 28012227 TI - Widespread selective sweeps throughout the genome of model plant pathogenic fungi and identification of effector candidates. AB - Identifying the genes underlying adaptation, their distribution in genomes and the evolutionary forces shaping genomic diversity are key challenges in evolutionary biology. Very few studies have investigated the abundance and distribution of selective sweeps in species with high-quality reference genomes, outside a handful of model species. Pathogenic fungi are tractable eukaryote models for investigating the genomics of adaptation. By sequencing 53 genomes of two species of anther-smut fungi and mapping them against a high-quality reference genome, we showed that selective sweeps were abundant and scattered throughout the genome in one species, affecting near 17% of the genome, but much less numerous and in different genomic regions in its sister species, where they left footprints in only 1% of the genome. Polymorphism was negatively correlated with linkage disequilibrium levels in the genomes, consistent with recurrent positive and/or background selection. Differential expression in planta and in vitro, and functional annotation, suggested that many of the selective sweeps were probably involved in adaptation to the host plant. Examples include glycoside hydrolases, pectin lyases and an extracellular membrane protein with CFEM domain. This study thus provides candidate genes for being involved in plant pathogen interaction (effectors), which have remained elusive for long in this otherwise well-studied system. Their identification will foster future functional and evolutionary studies, in the plant and in the anther-smut pathogens, being model species of natural plant-pathogen associations. In addition, our results suggest that positive selection can have a pervasive impact in shaping genomic variability in pathogens and selfing species, broadening our knowledge of the occurrence and frequency of selective events in natural populations. PMID- 28012228 TI - The escalatory Red Queen: Population extinction and replacement following arms race dynamics in poplar rust. AB - Host-parasite systems provide convincing examples of Red Queen co-evolutionary dynamics. Yet, a key process underscored in Van Valen's theory - that arms race dynamics can result in extinction - has never been documented. One reason for this may be that most sampling designs lack the breadth needed to illuminate the rapid pace of adaptation by pathogen populations. In this study, we used a 25 year temporal sampling to decipher the demographic history of a plant pathogen: the poplar rust fungus, Melampsora larici-populina. A major adaptive event occurred in 1994 with the breakdown of R7 resistance carried by several poplar cultivars widely planted in Western Europe since 1982. The corresponding virulence rapidly spread in M. larici-populina populations and nearly reached fixation in northern France, even on susceptible hosts. Using both temporal records of virulence profiles and temporal population genetic data, our analyses revealed that (i) R7 resistance breakdown resulted in the emergence of a unique and homogeneous genetic group, the so-called cultivated population, which predominated in northern France for about 20 years, (ii) selection for Vir7 individuals brought with it multiple other virulence types via hitchhiking, resulting in an overall increase in the population-wide number of virulence types and (iii) - above all - the emergence of the cultivated population superseded the initial population which predominated at the same place before R7 resistance breakdown. Our temporal analysis illustrates how antagonistic co-evolution can lead to population extinction and replacement, hence providing direct evidence for the escalation process which is at the core of Red Queen dynamics. PMID- 28012229 TI - miR-3941: A novel microRNA that controls IGBP1 expression and is associated with malignant progression of lung adenocarcinoma. AB - Immunoglobulin (CD79a) binding protein 1 (IGBP1) is universally overexpressed in lung adenocarcinoma and exerts an anti-apoptotic effect by binding to PP2Ac. However, the molecular mechanism of IGBP1 overexpression is still unclear. In the present study, we used a microRNA (miRNA) array and TargetScan Human software to detect IGBP1-related miRNAs that regulate IGBP1 expression. The miRNA array analysis revealed more than 100 miRNAs that are dysregulated in early invasive adenocarcinoma. On the other hand, in silico analysis using TargetScan Human revealed 79 miRNAs that are associated with IGBP1 protein expression. Among the miRNAs selected by miRNA array analysis, six (miR-34b, miR-138, miR-374a, miR 374b, miR-1909, miR-3941) were also included among those selected by TargetScan analysis. Real-time reverse transcription PCR (real-time RT-PCR) showed that the six microRNAs were downregulated in invasive adenocarcinoma (IGBP1+) relative to adjacent normal lung tissue (IGBP1-). Among these microRNAs, only miR-34b and miR 3941 depressed luciferase activity by targeting 3'UTR-IGBP1 in the luciferase vector. We transfected miR-34b and miR-3941 into lung adenocarcinoma cell lines (A549, PC-9), and both of them suppressed IGBP1 expression and cell proliferation. Moreover, the transfected miR-34b and miR-3941 induced apoptosis of a lung adenocarcinoma cell line, similarly to the effect of siIGBP1 RNA. As well as miR-34b, we found that miR-3941 targeted IGBP1 specifically and was able to exclusively downregulate IGBP1 expression. These findings indicate that suppression of miR-3941 has an important role in the progression of lung adenocarcinoma at an early stage. PMID- 28012231 TI - Electrochemical Formation of FeV (O) and Mechanism of Its Reaction with Water During O-O Bond Formation. AB - A detailed electrochemical investigation of a series of iron complexes (biuret modified tetraamido iron macrocycles FeIII -bTAML), including the first electrochemical generation of FeV (O), and demonstration of their efficacy as homogeneous catalysts for electrochemical water oxidation (WO) in aqueous medium are reported. Spectroelectrochemical and mass spectral studies indicated FeV (O) as the active oxidant, formed due to two redox transitions, which were assigned as FeIV (O)/FeIII (OH2 ) and FeV (O)/FeIV (O). The spectral properties of both of these high-valent iron oxo species perfectly match those of their chemically synthesised versions, which were thoroughly characterised by several spectroscopic techniques. The O-O bond-formation step occurs by nucleophilic attack of H2 O on FeV (O). A kinetic isotope effect of 3.2 indicates an atom proton transfer (APT) mechanism. The reaction of chemically synthesised FeV (O) in CH3 CN and water was directly probed by electrochemistry and was found to be first-order in water. The pKa value of the buffer base plays a critical role in the rate-determining step by increasing the reaction rate several-fold. The electronic effect on redox potential, WO rates, and onset overpotential was studied by employing a series of iron complexes. The catalytic activity was enhanced by the presence of electron-withdrawing groups on the bTAML framework. Changing the substituents from OMe to NO2 resulted in an eightfold increase in reaction rate, while the overpotential increased threefold. PMID- 28012230 TI - Targeting MUC1 and JNK by RNA interference and inhibitor inhibit the development of hepatocellular carcinoma. AB - Mucin 1 (MUC1), as an oncogene, is overexpressed in hepatocellular carcinoma (HCC) cells and promotes the progression and tumorigenesis of HCC through JNK/TGF beta signaling pathway. In the present study, RNA interference (RNAi) and JNK inhibitor SP600125, which target MUC1 and/or JNK, were used to treat HCC cells in vitro, and the results showed that both silencing the expression of MUC1 and blocking the activity of JNK inhibited the proliferation of HCC cells. In addition, MUC1-stable-knockdown and SP600125 significantly inhibited the growth of tumors in the subcutaneous transplant tumor models that established in BALB/c nude mice rather than MUC1 or JNK siRNAs transiently transfection. Furthermore, the results from immunohistochemical staining assays showed that the inhibitory effects of MUC1 gene silencing and SP600125 on the proliferation of HCC cells in vivo were through the JNK/TGF-beta signaling pathway. These results indicate that MUC1 and JNK are attractive targets for HCC therapy and may provide new therapeutic strategies for the treatment of HCC. PMID- 28012232 TI - Sustained ventricular tachycardia as a first manifestation of hypertrophic cardiomyopathy with mid-ventricular obstruction and apical aneurysm in an elderly female patient. AB - Sustained ventricular tachycardia complicating left ventricular apical aneurysms has been reported previously solely in middle-aged patients with hypertrophic cardiomyopathy and mid-cavity obstruction. We report a case of an elderly female patient who presented with incessant ventricular tachycardia as the first clinical manifestation of hypertrophic cardiomyopathy with mid-ventricular obstruction and apical aneurysm. PMID- 28012233 TI - Angiomatoid fibrous histiocytoma: A case of local recurrence and metastases to loco-regional lymph nodes that responded to chemotherapy. AB - Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumour with intermediate malignant potential. We report the case of a patient with local recurrence of AFH in two locations and lymph node metastases 18 months after primary surgical excision. The patient was treated with six cycles of ifosfamide and doxorubicin chemotherapy and a further three courses of ifosfamide monotherapy. Reassessment imaging showed a good response to chemotherapy with reduction in size of the two tumours of local recurrence and the lymph node metastases. This case demonstrates that AFH can respond to chemotherapy, even though it is rarely used. PMID- 28012234 TI - Hypoxia promotes the phenotypic change of aldehyde dehydrogenase activity of breast cancer stem cells. AB - Stable breast cancer cell (BCC) lines are valuable tools for the identification of breast cancer stem cell (BCSC) phenotypes that develop in response to several stimuli as well as for studying the basic mechanisms associated with the initiation and maintenance of BCSCs. However, the characteristics of individual, BCC-derived BCSCs varies and these cells show distinct phenotypes depending on the different BCSC markers used for their isolation. Aldehyde dehydrogenase (ALDH) activity is just such a recognized biomarker of BCSCs with a CD44+ /CD24- phenotype. We isolated BCSCs with high ALDH activity (CD44+ /CD24- /Aldefluorpos ) from a primary culture of human breast cancer tissue and observed that the cells had stem cell properties compared to BCSCs with no ALDH activity (CD44+ /CD24- /Aldefluorneg ). Moreover, we found Aldefluorpos BCSCs had a greater hypoxic response and subsequent induction of HIF-1alpha expression compared to the Aldefluorneg BCSCs. We also found that knocking down HIF-1alpha, but not HIF 2alpha, in Aldefluorpos BCSCs led to a significant reduction of the stem cell properties through a decrease in the mRNA levels of genes associated with the epithelial-mesenchymal transition. Indeed, HIF-1alpha overexpression in Aldefluorneg BCSCs led to Slug and Snail mRNA increase and the associated repression of E-cadherin and increase in Vimentin. Of note, prolonged hypoxic stimulation promoted the phenotypic changes of Aldefluorneg BCSCs including ALDH activity, tumorigenesis and metastasis, suggesting that hypoxia in the tumor environment may influence BCSC fate and breast cancer clinical outcomes. PMID- 28012235 TI - A safflower oil based high-fat/high-sucrose diet modulates the gut microbiota and liver phospholipid profiles associated with early glucose intolerance in the absence of tissue inflammation. AB - SCOPE: Omega-6 (n-6) PUFA-rich diets are generally considered obesogenic in rodents. Here, we examined how long-term intake of a high-fat/high-sucrose (HF/HS) diet based on safflower oil affected metabolism, inflammation, and gut microbiota composition. METHODS AND RESULTS: We fed male C57BL/6J mice a HF/HS diet based on safflower oil-rich in n-6 PUFAs-or a low-fat/low-sucrose diet for 40 wk. Compared to the low-fat/low-sucrose diet, intake of the safflower-based HF/HS diet only led to moderate weight gain, while glucose intolerance developed at week 5 prior to signs of inflammation, but concurrent with increased levels of linoleic acid and arachidonic acid in hepatic phospholipids. Intake of the HF/HS diet resulted in early changes in the gut microbiota, including an increased abundance of Blautia, while late changes coincided with altered inflammatory profiles and increased fasting plasma insulin. Analysis of immune cells in visceral fat and liver revealed no differences between diets before week 40, where the number of immune cells decreased in the liver of HF/HS-fed mice. CONCLUSION: We suggest that a diet-dependent increase in the n-6 to omega-3 (n-3) PUFA ratio in hepatic phospholipids together with gut microbiota changes contributed to early development of glucose intolerance without signs of inflammation. PMID- 28012236 TI - Effects of Lysine deficiency and Lys-Lys dipeptide on cellular apoptosis and amino acids metabolism. AB - SCOPE: Lysine (Lys) is a common limiting amino acids (AA) for humans and animals and plays an important role in cell proliferation and metabolism, while metabolism of Lys deficiency and its dipeptide is still obscure. Thus, this study mainly investigated the effects of Lys deficiency and Lys-Lys dipeptide on apoptosis and AA metabolism in vitro and in vivo models. METHODS AND RESULTS: Lys deficiency induced cell-cycle arrest and apoptosis and upregulated Lys transporters in vitro and in vivo. SLC7A11, a cystine-glutamate antiporter, was markedly upregulated by Lys deficiency and then further mediated cystine uptake and glutamate release, which was negatively regulated by cystine and glutamate transporters. Meanwhile, Lys deprivation upregulated pept1 expression, which might improve Lys-Lys dipeptide absorption to compensate for the reduced Lys availability. Lys-Lys dipeptide alleviated Lys deficiency induced cell-cycle arrest and apoptosis and influenced AA metabolism. Furthermore, the mammalian target of rapamycin signal might be involved in sensing cellular Lys starvation and Lys-Lys dipeptide. CONCLUSIONS: Altogether, these studies suggest that Lys deficiency impairs AA metabolism and causes apoptosis. Lys-Lys dipeptide serves as a Lys source and alleviates Lys deficiency induced cellular imbalance. PMID- 28012237 TI - Sporadic melanotic schwannoma with overlapping features of melanocytoma bearing a GNA11 mutation in an adolescent girl. AB - Melanotic schwannoma (MS) is a soft tissue neoplasm that shares histologic features with melanocytic tumors and schwannomas. A type of MS, called psammomatous MS (PMS), is associated with Carney complex (CNC), which is caused by PRKAR1A mutations. Other pigmented neoplasms, such as uveal melanomas and melanocytomas (MCs), are associated with genetic defects in other genes including GNA11. We report an adolescent female with a large sporadic mesenteric MS with complex histologic findings reminiscent of both PMS and MC. The lesion carried a mutation of the GNA11 gene. We conclude that sporadic MSs may occur rarely in adolescents without CNC; MSs may also be associated with somatic GNA11 mutations. PMID- 28012238 TI - Solution Growth of Modified Ultrathin W18 O49 Nanobelts with Enhanced Chemical Activity against Alkylamine Radicals. AB - Group IVB ions (Ti4+ and Zr4+ ) are employed to modify solution growth of W18 O49 nanocrystals. In the presence of group IVB ions, the morphology of the produced monoclinic W18 O49 nanocrystals can be modulated from inhomogeneous shapes to uniform an ultrathin nanobelt with the (1? 01) lattice plane being the main exposure surface. Interestingly, the ultrathin W18 O49 nanobelts exhibit a unique chemical activity against alkylamine radicals, probably originated from the highly increased exposure of the (1? 01) plane with extra tungsten and oxygen atoms inserted in the regular lattice, which makes this nanomaterial an active photocatalyst for the N-de-ethylation reaction of the rhodamine B molecules, as well as a promising gas sensor matrix with selective responses to alkylamine molecules, including diethylamine, dimethylamine, triethylamine and trimethylamine. These results could provide useful inspiration for developing other functional nanomaterials with technical significance via modification of their morphologies and chemical properties. PMID- 28012239 TI - Secretion of pro-inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast-like synoviocytes in juvenile idiopathic arthritis. AB - PURPOSE: The goal is to investigate the specific contribution of fibroblast-like synoviocytes (FLS) to the inflammatory milieu of the synovium in juvenile idiopathic arthritis (JIA) through detection of secreted proteins. EXPERIMENTAL DESIGN: Expression of 89 cytokines and chemokines is determined on unprocessed synovial fluid from controls and JIA patients using antibody arrays. Supernatants from pure cell cultures of FLS grown from synovial fluids or tissues from JIA and controls are also examined for protein expression. Ingenuity Pathway Analysis (IPA) is revealed top pathways and upstream regulators of significant proteins. RESULTS: Protein studies is revealed that JIA FLS release pro-inflammatory cytokines and chemokines, including IL-4, IL-6, IL-17, CXCL1, and CXCL6, and lose expression of important regulator signals, such as IL-10 and TIMP2. Of the 84 proteins differentially expressed between controls and JIA in the synovial fluid, 1/3 (29 proteins) are differentially expressed in the cell culture supernatants of JIA and control FLS. ELISA of cell culture supernatants and synovial fluid confirmed seven key proteins. CONCLUSION AND CLINICAL RELEVANCE: JIA FLS are central to perpetuation of inflammation in JIA, including trafficking of inflammatory cells and effects on the extracellular matrix. These cells express key disease-specific chemokines that, with further refinement, may allow us to tailor therapy appropriately. PMID- 28012240 TI - Liquid chromatography with tandem mass spectrometry method for the determination of nicotine and minor tobacco alkaloids in electronic cigarette refill liquids and second-hand generated aerosol. AB - A liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of nicotine and seven minor tobacco alkaloids in both refill liquids for electronic cigarettes and their generated aerosol was developed and validated. The limit of detection and limit of quantification values were 0.3 20.0 and 1.0-31.8 ng/mL, respectively. Within-laboratory reproducibility was 8.2 14.2% at limit of quantification values and 4.8-12.7% at other concentration levels. Interday recovery was 75.8-116.4%. The method was applied to evaluate the compliance of commercial liquids (n = 95) with their labels and to assess levels of minor alkaloids. Levels of nicotine and its corresponding compounds were also evaluated in generated aerosol. About 47% of samples showed differences above +/ 10 % of the stated nicotine concentration. About 78% of the "zero nicotine" liquids showed traces in the range of 1.3 +/- 0.1-254.0 +/- 14.6 MUg/mL. Nicotine N'-oxides, myosmine, and anatabine were the most common minor alkaloids in liquids containing nicotine. Nicotine and N'-oxides were detected in all air samples when aerosol was generated from liquids containing nicotine. Nicotine average emissions from electronic cigarette (2.7 +/- 0.9 MUg/m3 ) were significantly lower (p < 0.01, t-test) with respect to conventional cigarette (30.2 +/- 1.5 MUg/m3 ). PMID- 28012241 TI - A rapid differential display analysis of nasal swab fingerprints to distinguish allergic from non-allergic rhinitis subjects by mesoporous silica particles and MALDI-TOF mass spectrometry. AB - Discriminating different rhinitis cases can sometimes be difficult as the diagnostic criteria used to identify the various subgroups are not always unambiguous. The nasal fluid (NF) highly reflects the pathophysiology of these inflammatory diseases. However, its collection, as nasal lavage fluid, may cause discomfort. Due to the non-invasiveness and rapidity of collection, nasal swab might represent an alternative to overcome these problems and also an ideal source of biomarkers. In this study, we demonstrate that the combined use of mesoporous silica (MPS) with MALDI-TOF MS allows the rapid detection of differential nasal peptide profiles from nasal swabs of healthy (H), allergic rhinitis (AR) and non-allergic rhinitis (NAR) subjects. NF peptides from nasal swabs were captured by the mean of MPS then profiled by MALDI-TOF MS. As a proof of-principle, we also explored the ability of our platform to discriminate between nasal swabs of patients with AR and NAR, and between these groups and H controls. Four peaks resulted differentially expressed between NAR and AR, two peaks discriminated AR from H while one peak segregated NAR from H group. Therefore, peptides selected and enriched by our platform could form a part of a diagnostic ''rhinomic'' profile of the allergic and non-allergic patients. PMID- 28012242 TI - A 12-week intervention with nonivamide, a TRPV1 agonist, prevents a dietary induced body fat gain and increases peripheral serotonin in moderately overweight subjects. AB - SCOPE: A bolus administration of 0.15 mg nonivamide has previously been demonstrated to reduce energy intake in moderately overweight men. This 12-week intervention investigated whether a daily consumption of nonivamide in a protein based product formulation promotes a reduction in body weight in healthy overweight subjects and affects outcome measures associated with mechanisms regulating food intake, e.g. plasma concentrations of (an)orexigenic hormones, energy substrates as well as changes in fecal microbiota. METHODS AND RESULTS: Nineteen overweight subjects were randomly assigned to either a control (C) or a nonivamide (NV) group. Changes in the body composition and plasma concentrations of satiating hormones were determined at fasting and 15, 30, 60, 90, and 120 min after a glucose load. Participants were instructed to consume 0.15 mg nonivamide per day in 450 mL of a milk shake additionally to their habitual diet. After treatment, a group difference in body fat mass change (-0.61 +/- 0.36% in NV and +1.36 +/- 0.38% in C) and an increase in postprandial plasma serotonin were demonstrated. Plasma metabolome and fecal microbiome read outs were not affected. CONCLUSIONS: A daily intake of 0.15 mg nonivamide helps to support to maintain a healthy body composition. PMID- 28012243 TI - Ordered macroporous quercetin molecularly imprinted polymers: Preparation, characterization, and separation performance. AB - Ordered macroporous molecularly imprinted polymers were prepared by a combination of the colloidal crystal templating method and the molecular imprinting technique by using SiO2 colloidal crystal as the macroporogen, quercetin as the imprinting template, acrylamide as the functional monomer, ethylene glycol dimethacrylate as the cross-linker and tetrahydrofuran as the solvent. Scanning electron microscopy and Brunauer-Emmett-Teller measurements show that the ordered macroporous molecularly imprinted polymers have a more regular macroporous structure, a narrower pore distribution and a greater porosity compared with the traditional bulk molecularly imprinted polymers. The kinetic and isothermal adsorption behaviors of the polymers were investigated. The results indicate that the ordered macroporous molecularly imprinted polymers have a faster intraparticle mass transfer process and a higher adsorption capacity than the traditional bulk molecularly imprinted polymers. The ordered macroporous molecularly imprinted polymers were further employed as a sorbent for a solid-phase extraction. The results show that the ordered macroporous molecularly imprinted polymers can effectively separate quercetin from the Gingko hydrolysate. PMID- 28012244 TI - Narrow-leafed lupin (Lupinus angustifolius L.) beta-conglutin proteins modulate the insulin signaling pathway as potential type 2 diabetes treatment and inflammatory-related disease amelioration. AB - SCOPE: We have investigated the potential use of beta-conglutin protein isoforms from narrow-leafed lupin (Lupinus angustifolius L.) as a diabetes treatment. METHODS AND RESULTS: We produced purified recombinant beta1-, beta2-, beta3-, beta4-, and beta6-conglutin proteins and showed that beta1, beta3, and beta6 could bind to insulin. To assess beta-conglutin proteins modulatory effect on insulin activation meditated kinases, whole blood and peripheral blood mononuclear cell cultures from type 2 diabetes (T2D) and healthy control subjects (C) were incubated with conglutin proteins. The treatment of peripheral blood mononuclear cells from T2D patients with beta1, beta3, and beta6 proteins increased up to threefold mRNA and protein levels of genes important in insulin signaling pathways, namely insulin receptor substrate 1/p85/AKT/glucose transporter type 4. This was accompanied by a comparable fold-change decrease in the mRNA expression level of pro-inflammatory genes (iNOS and IL-1beta) and proteins compared to healthy controls. The beta2 and beta4 isoforms had no effect on the insulin signaling pathway. However, these beta-conglutin proteins elicited pro-inflammatory effects since levels of mRNA and proteins of inducible nitric oxide synthase and IL 1 beta were increased. CONCLUSION: Our results raise the possibility of using these particular beta-conglutin proteins in the prevention and treatment of diabetes, as well as their potential as anti-inflammatory molecules. PMID- 28012245 TI - Acute lymphoblastic leukemia in patients with Down syndrome with a previous history of acute myeloid leukemia. AB - Patients with Down syndrome (DS) are predisposed to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in early and later childhood, respectively, but rarely experience both. We herein discuss four patients with DS with ALL and a history of AML who were treated with various chemotherapies, one of whom later received a bone marrow transplantation. Three patients survived and remain in remission. One patient died of fulminant hepatitis during therapy. No common cytogenetic abnormalities in AML and ALL besides constitutional +21 were identified, indicating that the two leukemia types were independent events. However, the underlying pathomechanism of these conditions awaits clarification. PMID- 28012246 TI - Periodic imidazolium-bridged hybrid monolith for high-efficiency capillary liquid chromatography with enhanced selectivity. AB - A novel periodic imidazolium-bridged hybrid monolithic column was developed. With diene imidazolium ionic liquid 1-allyl-3-vinylimidazolium bromide as both cross linker and organic functionalized reagent, a new periodic imidazolium-bridged hybrid monolithic column was facilely prepared in capillary with homogeneously distributed cationic imidazolium by a one-step free-radical polymerization with polyhedral oligomeric silsesquioxane methacryl substituted. The successful preparation of the new column was verified by Fourier transform infrared spectroscopy, scanning electron microscopy, elemental analysis, and surface area analysis. Most interestingly, the bonded amount of 1-allyl-3-vinylimidazolium bromide of the new column is three times higher than that of the conventional imidazolium-embedded hybrid monolithic column and the specific surface area of the column reached 478 m2 /g. The new column exhibited high stability, excellent separation efficiency, and enhanced separation selectivity. The column efficiency reached 151 000 plates/m for alkylbenzenes. Furthermore, the new column was successfully used for separation of highly polar nucleosides and nucleic acid bases with pure water as mobile phase and even bovine serum albumin tryptic digest. All these results demonstrate the periodic imidazolium-bridged hybrid monolithic column is a good separation media and can be used for chromatographic separation of small molecules and complex biological samples with high efficiency. PMID- 28012247 TI - Previous dropout from diabetic care as a predictor of patients' willingness to use mobile applications for self-management: A cross-sectional study. AB - AIMS/INTRODUCTION: Preventing dropout is crucial in managing diabetes. Accordingly, we investigated whether patients who had dropped out of diabetic care are suitable candidates for the use of mobile technologies - such as smartphone applications - to support self-management (mHealth), which might help prevent dropout. MATERIALS AND METHODS: We carried out a cross-sectional study in Tokyo, Japan. Patients aged 20 years or older who were clinically diagnosed as diabetic and who regularly visited the outpatient unit at the University of Tokyo Hospital were recruited between August 2014 and March 2015. Data were collected through face-to-face structured interviews, physical measurements and medical records. Participants were asked whether they were willing to use mHealth after being shown DialBetics - an mHealth application for diabetics - as an example, and about their history of dropout and previous mHealth experience. Data were analyzed by multivariate logistic regression models. RESULTS: Of 307 patients with type 1 and type 2 diabetes, 34 (11.1%) had previously dropped out from diabetic care. Multivariate analysis identified previous mHealth experience as a negative predictor of dropout (odds ratio 0.211, P = 0.023). Of those 34 patients, 27 (79.4%) expressed willingness to use mHealth, a significantly higher percentage than for those who had never dropped out (51.5%, P = 0.002). After adjusting for confounders, history of dropout remained a strong predictor of willingness (odds ratio 3.870, P = 0.004). CONCLUSIONS: Patients who previously dropped out of diabetic care are suitable candidates for mHealth. Future studies must evaluate whether mHealth is effective for preventing repeated dropout and improving glycemic control among this population. PMID- 28012248 TI - Sesamol ameliorates diet-induced obesity in C57BL/6J mice and suppresses adipogenesis in 3T3-L1 cells via regulating mitochondria-lipid metabolism. AB - SCOPE: The aim of the current study was to investigate the effect of sesamol, a natural powerful antioxidant and anti-inflammatory phenol derivative of sesame oil, on adiposity and adiposity-related metabolic disturbances in mice fed with western diet, and the potential underlying mechanisms focusing on the mitochondria-lipid metabolism. METHODS AND RESULTS: In the experimental model that consisted of 3-month-old C57BL/6J mice divided into three groups with/without sesamol in the drinking water including standard diet, high fat and high fructose diet (HFFD), and HFFD with sesamol. Results demonstrated that sesamol mitigated bodyweight gain, development of insulin resistance induced by HFFD. Sesamol was found partially normalized serum and hepatic lipid contents, as well as suppressed HFFD-induced lipogenesis in liver via regulating mitochondria related triglyceride/cholesterol metabolism genes expressions. Importantly, sesamol decreased mass and adipocyte sizes of white adipose tissues and brown adipose tissues by improving mitochondria-related genes expressions including Pgc1a and Ucp1. Moreover, sesamol was also found to reduce differentiation and mitochondrial metabolic inhibitors (oligomycin and antimycin A) stimulated lipid accumulation in 3T3-L1 adipocytes. CONCLUSION: Taken together, this study provides compelling evidence that sesamol supplementation reduced adipocyte size and adipogenesis of diet-induced obesity by regulating mitochondria lipid metabolism. PMID- 28012249 TI - Inappropriate documentation of heparin allergy in the medical record because of misdiagnosis of heparin-induced thrombocytopenia: frequency and consequences. AB - : Essentials Misdiagnosis of heparin-induced thrombocytopenia (HIT) may be associated with adverse outcomes. We conducted a study of patients with a heparin allergy in the chart due to misdiagnosis of HIT. 42% of patients with a heparin allergy due to suspected HIT were clearly HIT-negative. 68% were unnecessarily treated with an alternative anticoagulant, 66% of whom had major bleeding. SUMMARY: Background It is recommended that heparin be added to the allergy list of patients with heparin-induced thrombocytopenia (HIT). Misdiagnosis of HIT could lead to inappropriate documentation of a heparin allergy and adverse outcomes. Objectives To determine the frequency and consequences of inappropriate documentation of a heparin allergy because of misdiagnosis of HIT. Methods We conducted a cohort study of patients with an inappropriate heparin allergy listed in the electronic medical record (EMR) because of misdiagnosis of HIT. We searched the EMR for patients with a new heparin allergy. Patients were eligible if the reason for allergy listing was suspected acute HIT and laboratory testing for HIT was performed within 60 days. Subjects were defined as 'HIT-negative' if they had a 4Ts score of <= 3 or negative laboratory test results. Results Of 239 subjects with a new heparin allergy documented because of concern regarding HIT, 100 (42%) met the prespecified definition of HIT-negative. Sixty-eight (68%) HIT negative subjects unnecessarily received an alternative parenteral anticoagulant for a median duration of 10.5 days. Among these 68 patients, 45 (66%) met criteria for major bleeding. Sixty-eight (68%) of the 100 HIT-negative subjects had an inappropriate allergy to heparin documented that persisted in the EMR for > 3 years beyond the index hospitalization. Conclusions Inappropriate listing of heparin as an allergy in the EMR because of misdiagnosis of HIT is common, is associated with substantial rates of unnecessary alternative anticoagulant use and major bleeding, and tends to persist beyond the index admission. PMID- 28012250 TI - The effect of Ureaplasma urealyticum on the level of P34H expression, the activity of hyaluronidase, and DNA fragmentation in human spermatozoa. AB - BACKGROUND: To study the effect of Ureaplasma urealyticum on the level of P34H expression, the activity of hyaluronidase, and the DNA fragmentation in human spermatozoa. METHOD: Western blot was used to detect the level of P34H expression on spermatozoa.The localization of this protein on human spermatozoa was determined by indirect immunofluorescent and observed by laser scanning confocal microscope. The activity of hyaluronidase was examined by improved fixed substrate film method. The DNA fragmentation was assayed with the use of TUNEL. RESULTS: There were significant differences in the level of P34H protein expression, the percentage of the P34H-positive rate, the activity of HYD, and the percentage of DNA fragmentation between each infertile group and the control (P<.05). The relation among the P34H protein expression, the percentage of P34H positive rate and HYD-positive rate, HYD-activity intensity had a significant positive correlation; Both the P34H protein expression and the percentage of P34H positive rate were inversely correlated with the percentages of sperm DNA fragmentation. CONCLUSION: Ureaplasma urealyticum infection may affect the level of P34H protein expression, the percentage of the P34H-positive rate, the activity of HYD, and DNA fragmentation that influence fertility. PMID- 28012251 TI - Public Health Follow-up of Suspected Exposure to Echinococcus multilocularis in Southwestern Ontario. AB - In the 3 years since the first report of canine alveolar echinococcosis (AE) in Ontario, three additional cases have been diagnosed in the province. Of the four cases reported to date, three have had no known history of travel outside the province. It is possible that this development is an indication of previously unrecognized environmental contamination with Echinococcus multilocularis eggs in some areas of the province. If so, there is the potential for an emerging threat to human health. This article describes a local public health department's investigation of the possible exposure to E. multilocularis of a number of individuals who had had contact with the latest of the four cases of canine AE, and summarizes a comprehensive decision process that can be used by public health departments to assist in the follow-up of such exposures. PMID- 28012252 TI - Breaking the cycle of intergenerational obesity. PMID- 28012253 TI - Probing the Peroxycarbenium [3+2] Cycloaddition Reactions with 1,2-Disubstituted Ethylenes: Results and Insights. AB - The causes for the title reaction to be limited to only the alkenes with an unsubstituted terminal alkenic carbon were explored. In some "failed" cases the cycloaddition products actually formed but rearranged concurrently. An oxygen atom or a N-Boc (Boc=tert-butyloxycarbonyl) group at the double bond was proven essential for acquisition of intact [3+2] cycloaddition products from 1,2 disubstituted ethylenes. PMID- 28012254 TI - Enantioselective Tandem Oxidation/Michael-Aldol Approaches to Tetrasubstituted Cyclohexanes. AB - Enantioselective tandem Michael-aldol and oxidative Michael-aldol approaches have been achieved for the formation of diversely substituted cyclohexanes in total regio-, diastereo- and enantioselective fashion. The presence of nitro, hydroxy and keto groups in the product provides a wide scope for further structural transformations. Furthermore, the utility of the catalytic process is demonstrated in the context of enantioselective formal synthesis of ABT-341, a DPP4 inhibitor. PMID- 28012255 TI - The cirrhotic platelet: Shedding light on an enigma. PMID- 28012256 TI - From NAFLD to HCC: Is IL-17 the crucial link? PMID- 28012257 TI - Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment. AB - : The long-term clinical impact of low-level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change in therapy. A retrospective cohort of 875 treatment-naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 [65.5%], cirrhosis = 443 [50.6%]) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow-up (range 1.0-8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28-3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34-3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. CONCLUSION: LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335-343). PMID- 28012258 TI - Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). AB - : ABCB4 (MDR3) is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding. Five disease-causing variations in these motifs have been identified in ABCB4 (G535D, G536R, S1076C, S1176L, and G1178S), three of which are homologous to the gating mutations of cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7; i.e., G551D, S1251N, and G1349D), that were previously shown to be function defective and corrected by ivacaftor (VX-770; Kalydeco), a clinically approved CFTR potentiator. Three-dimensional structural modeling predicted that all five ABCB4 variants would disrupt critical interactions in the binding of ATP and thereby impair ATP-induced nucleotide-binding domain dimerization and ABCB4 function. This prediction was confirmed by expression in cell models, which showed that the ABCB4 mutants were normally processed and targeted to the plasma membrane, whereas their PC secretion activity was dramatically decreased. As also hypothesized on the basis of molecular modeling, PC secretion activity of the mutants was rescued by the CFTR potentiator, ivacaftor (VX-770). CONCLUSION: Disease-causing variations in the ATP-binding sites of ABCB4 cause defects in PC secretion, which can be rescued by ivacaftor. These results provide the first experimental evidence that ivacaftor is a potential therapy for selected patients who harbor mutations in the ATP-binding sites of ABCB4. (Hepatology 2017;65:560 570). PMID- 28012259 TI - Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. AB - : Direct-acting antiviral (DAA) therapy, recently approved for patients with decompensated cirrhosis (DC) secondary to hepatitis C virus (HCV), is associated with improved hepatic function. We analyzed trends in liver transplant (LT) wait listing (WL) to explore potential impact of effective medical therapy on WL registration. This is a cohort study using the Scientific Registry of Transplant Recipients database from 2003 to 2015. A total of 47,591 adults wait-listed for LT from HCV, hepatitis B virus (HBV), and nonalcoholic steatohepatitis (NASH) were identified. LT indication was defined as DC if the Model for End-Stage Liver Disease (MELD) at WL was >=15 or hepatocellular carcinoma (HCC). Era of listing was divided into interferon (IFN; 2003-2010), protease inhibitor (PI; 2011-2013), and direct-acting antiviral (DAA; 2014-2015). Annual standardized incidence rates of WL were analyzed using Poisson regression. Adjusted incidences of LT WL for DC in HCV patients decreased by 5% in the PI era (P = 0.004) and 32% in the DAA era (P < 0.001) compared to the IFN era. Listing for DC in HBV also decreased in the PI (-17%; P = 0.002) and DAA eras (-24%; P < 0.001). Conversely, WL for DC in NASH increased by 41% in the PI era (P < 0.001) and 81% in the DAA era (P < 0.001). WL for HCC in both the HCV and NASH populations increased in both the PI and DAA eras (P < 0.001 for all) whereas HCC WL in HBV remained stable (P > 0.05 for all). CONCLUSION: The rate of LT WL for HCV complicated by DC has decreased by over 30% in the era of DAA therapy. Further reductions in WL are anticipated with increased testing, linkage to care, and access to DAA therapy. (Hepatology 2017;65:804-812). PMID- 28012260 TI - Synchrotron X-Ray Fluorescence Nanoprobe Reveals Target Sites for Organo-Osmium Complex in Human Ovarian Cancer Cells. AB - A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub-cellular distribution of [Os(eta6 -p-cym)(Azpy NMe2 )I]+ (p-cym=p-cymene, Azpy-NMe2 =2-(p-[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X-ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death. These data are consistent with the ability of 1 to induce rapid bursts of reactive oxygen species and especially superoxide formed in the first step of O2 reduction in mitochondria. Such metabolic targeting differs from the action of Pt drugs, offering promise for combatting Pt resistance, which is a current clinical problem. PMID- 28012261 TI - Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition. AB - The ever-growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as-yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba alpha-d-glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN-mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self-cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism. PMID- 28012263 TI - Robotic gynaecologic surgery: a tool or a toy? PMID- 28012262 TI - Noninvasive experimental bladder pain assessment in painful bladder syndrome. AB - OBJECTIVE: To compare bladder sensitivity between patients with pelvic pain and patients who were pain free, undergoing noninvasive, controlled bladder distension via diuresis. We also sought to measure potential mechanisms underlying bladder sensitivity. DESIGN: Prospective observational study. SETTING: Community teaching hospital. POPULATION: Reproductive-age women with non-bladder chronic pelvic pain (CPP, n = 23), painful bladder syndrome (PBS, n = 23), and pelvic pain-free controls (n = 42) METHODS: Participants were compared on cystometric capacity, pelvic floor pressure-pain thresholds (PPTs), pelvic muscle function, O'Leary-Sant bladder questionnaire, and psychosocial instruments using Wilcoxon rank-sum tests. Multivariate regression was used to identify factors underlying bladder pain phenotypes. MAIN OUTCOME MEASURES: Pelvic floor pain thresholds; self-reported bladder distension pain. RESULTS: Participants with PBS exhibited higher bladder distension pain than those with CPP, with both groups reporting higher pain levels than controls (P < 0.05). No significant associations were found between bladder distension pain and pelvic muscle structure or pain sensitivity measures; however, bladder distension pain positively correlates with both vaginal PPTs adjacent to the bladder (r = 0.46) and pain with transvaginal bladder palpation (r = 0.56). Pain at maximal distension was less influenced by somatic sensitivity than bladder symptoms (r = 0.35 versus r = 0.59; P < 0.05). Multivariate regression identified three independent components of bladder symptoms in PBS: bladder distension pain, bladder sensation, and somatic symptoms. CONCLUSIONS: Diuresis-induced bladder pain differentiates CPP from PBS. Experimental bladder pain is not predicted by pelvic floor sensitivity. Compared with patient-reported outcomes it appears less influenced by psychological factors. Further study is needed to determine whether screening for experimental bladder pain sensitivity could predict future risk of PBS. TWEETABLE ABSTRACT: Controlled, water ingestion-provoked bladder pain can objectively identify visceral pain sensitivity. PMID- 28012264 TI - From culdoscopy to peritoneoscopy: a century of advancement in laparoscopy for minimal-access surgery in gynaecology. PMID- 28012265 TI - Teratoma-associated NMDAr encephalitis: management considerations. PMID- 28012266 TI - Spontaneous haemoperitoneum in pregnancy (SHiP): take-home messages. PMID- 28012267 TI - Local anaesthesia during endometrial ablation: a systematic review. AB - BACKGROUND: Endometrial ablation has been widely implemented in the outpatient setting. Many different protocols of local anaesthesia during endometrial ablation are used and described. However, prospective studies to assess and evaluate these protocols appear to be scarce. OBJECTIVES: To evaluate systematically the different local anaesthesia techniques in relation to pain perception during endometrial ablation. SEARCH STRATEGY: Medline and Embase were systematically searched and reference lists of selected articles were checked for missed publications. SELECTION CRITERIA: All types of studies reporting the performance of endometrial ablation under local anaesthesia in ten or more women were included. DATA COLLECTION AND ANALYSIS: Data about the procedure, the protocol of local anaesthesia, the acceptability and side-effects were extracted. MAIN RESULTS: Twenty-five studies, involving 2013 women, were included. Applied anaesthesia techniques included intracervical, paracervical and intrauterine anaesthesia or a combination of these techniques. Women who received a combination of either intra- or paracervical anaesthesia and intrauterine injections reported significantly lower pain scores than those who received no local anaesthesia or intra- or paracervical anaesthesia alone (P = 0.000), but the quality of evidence is low. The acceptability of endometrial ablation under local anaesthesia was high (77-94%). CONCLUSION: Endometrial ablation under local anaesthesia is a safe, feasible and acceptable procedure. The combination of either intra- or paracervical anaesthesia with intrauterine injections seems to be promising, but has to be investigated more thoroughly. TWEETABLE ABSTRACT: Systematic review of local anaesthesia techniques during endometrial ablation. PMID- 28012268 TI - Visual endometriosis diagnosis is reliable but outpatient tests needed. PMID- 28012269 TI - Research and clinical management for women with abnormal uterine bleeding in the reproductive years: More than PALM-COEIN. PMID- 28012270 TI - Y-plasty vaginoplasty needs proof of superior effectiveness. PMID- 28012271 TI - BJOG Editor's Choice: Demystifying pelvic pain and haemostatic methods for myomectomy. PMID- 28012272 TI - Is the Pictorial Blood Loss Assessment Chart (PBAC) score associated with treatment outcome after endometrial ablation for heavy menstrual bleeding? A cohort study. AB - OBJECTIVE: The Pictorial Blood Loss Assessment Chart (PBAC) is a validated tool that is used to diagnose heavy menstrual bleeding (HMB). Knowledge of the effect of its score and its relationship with outcome could have implications for using the PBAC as an outcome measurement in future HMB studies, and as a tool to evaluate the treatment effect in research and clinical practice. Our aim was to relate PBAC scores to other measures of success after endometrial ablation for HMB. DESIGN: Analysis of individual patient data (IPD) of randomised controlled trials studying women with HMB. SETTING: Women with HMB consulting their gynecologists. POPULATION OR SAMPLE: Individual patient data (IPD) of randomised controlled trials studying women with HMB. METHODS: We included studies if they had studied second-generation endometrial ablation techniques and had collected PBAC scores for both baseline and follow-up. The effectiveness of treatment was scored as satisfaction or re-intervention (yes/no) 12 months after treatment. We related these outcomes to the PBAC score at 12 months after treatment, and to PBAC decrease between baseline and 12 months of follow-up. RESULTS: We studied data for 900 patients included in nine studies. The median PBAC score at 12 months was 7 (0-2500). The overall satisfaction rate was 89% and the overall re intervention rate was 7.2%. A clear association was found between absolute PBAC score at the 12-month follow-up and satisfaction (odds ratio, OR 0.16; 95% confidence interval, 95% CI 0.11-0.24) and surgical re-intervention (OR 2.3, 95% CI 1.8-2.8). A change in PBAC score was also associated with satisfaction (OR 2.0, 95% CI 1.7-2.3) and surgical re-intervention (OR 0.69, 95% CI 0.63-0.75). Both the absolute PBAC scores and the changes in score show high accuracy for both treatment outcomes. CONCLUSIONS: PBAC scores at 12 months after treatment are significantly associated with satisfaction and re-intervention rates. We propose to use the PBAC in research as a primary end point in studies on HMB, and in clinical practice as a measure to assess the effectiveness of treatment. TWEETABLE ABSTRACT: PBAC scores 12 months after treatment are significantly associated with satisfaction and reintervention rates. PMID- 28012273 TI - Timing of insertion of levonorgestrel-releasing intrauterine system: a randomised controlled trial. AB - OBJECTIVE: The objective was to assess whether patient-perceived pain during the insertion of the levonorgestrel-releasing intrauterine system (LNG-IUS) depends on the timing during the menstrual cycle. DESIGN: A stratified two-armed non inferiority randomised controlled trial. SETTING: Large teaching hospital in Veldhoven, the Netherlands. SAMPLE: From October 2013 to May 2014, 60 nulliparous and 60 multiparous women were randomised. Eight women withdrew after randomisation and before insertion took place: therefore, data from 112 women were collected and analysed. METHODS: Women were randomised to the groups 'during menstruation' (i.e. days 1-7 of menstruation) or 'outside menstruation' (i.e. any day of the cycle after menstruation without the presence of vaginal blood loss) in a ratio of 1 : 1. MAIN OUTCOME MEASURES: The primary outcome was pain during insertion, measured by the visual analogue scale (VAS, 0-100 mm). Second, we analysed ease of insertion, bleeding pattern, satisfaction, pregnancy, and expulsion rate. The follow-up time was 3 months. RESULTS: The mean VAS score for nulliparous women was 74 mm (95% confidence interval, 95% CI 67-81) in the 'during menstruation' group, compared with 66 mm (95% CI 59-74) in the 'outside menstruation' group (P = 0.14). The mean VAS score for multiparous women was 30 mm (95% CI 20-40) in the 'during menstruation group', compared with 43 mm (95% CI 32-53) in the 'outside menstruation' group (P = 0.08). There was no difference between the stratified 'during menstruation' group and the 'outside menstruation' group with regards to ease of insertion, satisfaction, bleeding pattern, and median spotting and bleeding days for the use of the LNG-IUS 3 months after insertion. CONCLUSIONS: As we did not find that the level of pain perceived during insertion was higher during menstruation, compared with outside menstruation, we conclude that the LNG-IUS can be inserted at any time during the menstrual cycle, especially in the case of nulliparous women. TWEETABLE ABSTRACT: We conducted an RCT on time of insertion of LNG-IUS. We conclude that the LNG-IUS can be inserted at any time. PMID- 28012274 TI - Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. AB - Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay. PMID- 28012275 TI - EMC1-dependent stabilization drives membrane penetration of a partially destabilized non-enveloped virus. AB - Destabilization of a non-enveloped virus generates a membrane transport-competent viral particle. Here we probe polyomavirus SV40 endoplasmic reticulum (ER)-to cytosol membrane transport, a decisive infection step where destabilization initiates this non-enveloped virus for membrane penetration. We find that a member of the ER membrane protein complex (EMC) called EMC1 promotes SV40 ER membrane transport and infection. Surprisingly, EMC1 does so by using its predicted transmembrane residue D961 to bind to and stabilize the membrane embedded partially destabilized SV40, thereby preventing premature viral disassembly. EMC1-dependent stabilization enables SV40 to engage a cytosolic extraction complex that ejects the virus into the cytosol. Thus EMC1 acts as a molecular chaperone, bracing the destabilized SV40 in a transport-competent state. Our findings reveal the novel principle that coordinated destabilization stabilization drives membrane transport of a non-enveloped virus. PMID- 28012276 TI - Molecular basis of outer kinetochore assembly on CENP-T. AB - Stable kinetochore-microtubule attachment is essential for cell division. It requires recruitment of outer kinetochore microtubule binders by centromere proteins C and T (CENP-C and CENP-T). To study the molecular requirements of kinetochore formation, we reconstituted the binding of the MIS12 and NDC80 outer kinetochore subcomplexes to CENP-C and CENP-T. Whereas CENP-C recruits a single MIS12:NDC80 complex, we show here that CENP-T binds one MIS12:NDC80 and two NDC80 complexes upon phosphorylation by the mitotic CDK1:Cyclin B complex at three distinct CENP-T sites. Visualization of reconstituted complexes by electron microscopy supports this model. Binding of CENP-C and CENP-T to MIS12 is competitive, and therefore CENP-C and CENP-T act in parallel to recruit two MIS12 and up to four NDC80 complexes. Our observations provide a molecular explanation for the stoichiometry of kinetochore components and its cell cycle regulation, and highlight how outer kinetochore modules bridge distances of well over 100 nm. PMID- 28012277 TI - Chemical and Biological Aspects of Extracts from Medicinal Plants with Antidiabetic Effects. AB - Diabetes mellitus is a chronic disease and a leading cause of death in western countries. Despite advancements in the clinical management of the disease, it is not possible to control the late complications of diabetes. The main characteristic feature of diabetes is hyperglycemia, which reflects the deterioration in the use of glucose due to a faulty or poor response to insulin secretion. Alloxan and streptozotocin (STZ) are the chemical tools that are most commonly used to study the disease in rodents. Many plant species have been used in ethnopharmacology or to treat experimentally symptoms of this disease. When evaluated pharmacologically, most of the plants employed as antidiabetic substances have been shown to exhibit hypoglycemic and antihyperglycemic activities, and to contain chemical constituents that may be used as new antidiabetic agents. There are many substances extracted from plants that offer antidiabetic potential, whereas others may result in hypoglycemia as a side effect due to their toxicity, particularly their hepatotoxicity. In this article we present an updated overview of the studies on extracts from medicinal plants, relating the mechanisms of action by which these substances act and the natural principles of antidiabetic activity. PMID- 28012278 TI - The Physiological Effects of Dandelion (Taraxacum Officinale) in Type 2 Diabetes. AB - The tremendous rise in the economic burden of type 2 diabetes (T2D) has prompted a search for alternative and less expensive medicines. Dandelion offers a compelling profile of bioactive components with potential anti-diabetic properties. The Taraxacum genus from the Asteraceae family is found in the temperate zone of the Northern hemisphere. It is available in several areas around the world. In many countries, it is used as food and in some countries as therapeutics for the control and treatment of T2D. The anti-diabetic properties of dandelion are attributed to bioactive chemical components; these include chicoric acid, taraxasterol (TS), chlorogenic acid, and sesquiterpene lactones. Studies have outlined the useful pharmacological profile of dandelion for the treatment of an array of diseases, although little attention has been paid to the effects of its bioactive components on T2D to date. This review recapitulates previous work on dandelion and its potential for the treatment and prevention of T2D, highlighting its anti-diabetic properties, the structures of its chemical components, and their potential mechanisms of action in T2D. Although initial research appears promising, data on the cellular impact of dandelion are limited, necessitating further work on clonal beta-cell lines (INS-1E), alpha-cell lines, and human skeletal cell lines for better identification of the active components that could be of use in the control and treatment of T2D. In fact, extensive in vitro, in-vivo, and clinical research is required to investigate further the pharmacological, physiological, and biochemical mechanisms underlying the effects of dandelion-derived compounds on T2D. PMID- 28012279 TI - Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas. AB - The pancreas is comprised of exocrine and endocrine components. Despite the fact that they are derived from a common origin in utero, these two compartments are often studied individually because of the different roles and functions of the exocrine and endocrine pancreas. Recent studies have shown that not only type 1 diabetes (T1D), but also type 2 diabetes (T2D), is characterized by a deficit in beta-cell mass, suggesting that pathological changes in the pancreas are critical events in the natural history of diabetes. In both patients with T1D and those with T2D, pancreas mass and exocrine function have been reported to be reduced. On the other hand, pancreas volume and pancreatic fat increase with obesity. Increased beta-cell mass with increasing obesity has also been observed in humans, and ectopic fat deposits in the pancreas have been reported to cause beta cell dysfunction. Moreover, neogenesis and transdifferentiation from the exocrine to the endocrine compartment in the postnatal period are regarded as a source of newly formed beta-cells. These findings suggest that there is important interplay between the endocrine and exocrine pancreas throughout life. This review summarizes the current knowledge on physiological and pathological changes in the exocrine and endocrine pancreas (i.e., beta-cell mass), and discusses the potential mechanisms of the interplay between the two compartments in humans to understand the pathophysiology of diabetes better. PMID- 28012280 TI - Whey and Casein Proteins and Medium-Chain Saturated Fatty Acids from Milk Do Not Increase Low-Grade Inflammation in Abdominally Obese Adults. AB - BACKGROUND: Low-grade inflammation is involved in the development of diabetes and cardiovascular disease (CVD). Inflammation can be modulated by dietary factors. Dairy products are rich in saturated fatty acids (SFA), which are known to possess pro-inflammatory properties. However, different fatty acid compositions may exert different effects. Other components such as milk proteins may exert anti-inflammatory properties which may compensate for the potential negative effects of SFAs. Generally, the available data suggest a neutral role of dairy product consumption on inflammation. AIM: To investigate the effects of, and potential interaction between, a dietary supplementation with whey protein and milk fat, naturally enriched in medium-chain SFA (MC-SFA), on inflammatory markers in abdominal obese adults. METHODS: The study was a 12-week, randomized, double-blinded, intervention study. Sixty-three adults were equally allocated to one of four groups which received a supplement of either 60 g/day whey or 60 g/day casein plus 63 g/day milk fat either high or low in MC-SFA content. Fifty two subjects completed the study. Before and after the intervention, changes in plasma interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), high sensitive C-reactive protein (hsCRP), adiponectin, and monocyte chemoattractant protein-1 (MCP-1) were measured. Changes in inflammatory genes in the subcutaneous adipose tissue were also documented. RESULTS: There were no differences in circulating inflammatory markers between protein types or fatty acid compositions in abdominally obese subjects, with the exception of an increase in adiponectin in response to high compared to low MC-SFA consumption in women. We found that combined dairy proteins and MC-SFAs influenced inflammatory gene expression in adipose tissue, while no effect was detected by dairy proteins or MC-SFA per se. CONCLUSION: Whey protein compared with casein and MC-SFA enriched milk fat did not alter circulating markers of low-grade inflammation in abdominally obese subjects, except for an increase in circulating adiponectin in response to high MC-SFA in abdominally obese women. PMID- 28012282 TI - Low Levels of High-Density Lipoprotein Cholesterol Do Not Predict the Incidence of Type 2 Diabetes in an Iranian High-Risk Population: The Isfahan Diabetes Prevention Study. AB - OBJECTIVES: To evaluate the ability of low-level fasting high-density lipoprotein cholesterol (HDLC) to predict the incidence of type 2 diabetes (T2D) in an Iranian high-risk population. METHODS: Seven-year follow-up data (n = 1,775) in non-diabetic first-degree relatives (FDR) of consecutive patients with T2D aged 30-70 years were analyzed. The primary outcome was the diagnosis of T2D based on repeated oral glucose tolerance test (OGTT). We used Cox proportional hazard models to estimate the hazard ratio (HR) for the incidence of T2D across quartiles of HDLC, and plotted a receiver operating characteristic (ROC) curve to assess discrimination. RESULTS: The highest quartile compared with the lowest quartile of HDLC was associated with T2D in age- and gender-adjusted models (HR: 0.83, 95% CI: 0.73-0.95). Further adjustment for fasting plasma glucose and cholesterol attenuated the association for T2D incidence (HR: 0.93, 95% CI: 0.80 1.08). The area under the ROC curve for HDLC was 54.1% (95% CI: 50.2-58.0). CONCLUSIONS: HDLC level was a weak predictor of T2D in an Iranian high-risk population, independent of age and gender. PMID- 28012281 TI - A Critical Evaluation of Existing Diabetic Foot Screening Guidelines. AB - AIM: To evaluate critically the current guidelines for foot screening in patients with diabetes, and to examine their relevance in terms of advancement in clinical practice, improvement in technology, and change in socio-cultural structure. METHODS: A structured literature search was conducted in Pubmed/Medline, CINAHL, Cochrane Register of Controlled Trials, and Google between January 2011 and January 2015 using the keywords '(Diabetes) AND (Foot Screening) AND (Guidelines)'. RESULTS: Ten complete diabetes foot screening guidelines were identified and selected for analysis. Six of them included the full-process guidelines recommended by the International Diabetes Federation. Evaluation of the existing diabetes foot screening guidelines showed substantial variability in terms of different evidence-based methods and grading systems to achieve targets, making it difficult to compare the guidelines. In some of the guidelines, it is unclear how the authors have derived the recommendations, i.e. on which study results they are based, making it difficult for the users to understand them. CONCLUSIONS: Limitations of currently available guidelines and lack of evidence on which the guidelines are based are responsible for the current gaps between guidelines, standard clinical practice, and development of complications. For the development of standard recommendations and everyday clinical practice, it will be necessary to pay more attention to both the limitations of guidelines and the underlying evidence. PMID- 28012283 TI - Effect of Exercise Training on Signaling of Interleukin-6 in Skeletal Muscles of Type 2 Diabetic Rats. AB - OBJECTIVES: Diabetes and exercise training have been shown to involve interleukin 6 (IL-6) signaling in muscle. However, the relationship between the actions of these two stimuli on muscle IL-6 and their downstream components is still unknown. Thus, the effect of endurance training on the key components of muscle IL-6 signaling transduction was investigated in a rat model of type 2 diabetes. METHODS: Diabetes was induced by streptozotocin (STZ) in male Wistar rats fed a high-fat diet, with normal rats acting as controls. The animals were left to conduct their normal activities or assigned to endurance training in a treadmill. At the end of 8 weeks, blood biochemical profiles, exercise performance, muscle oxidative capacity, glucose transporter 4 (GLUT4) protein distribution, and expressions of IL-6 and its downstream proteins were determined. RESULTS: Blood biochemical profiles of the diabetic rats were altered compared to normal rats, whereas endurance training improved blood chemistry and exercise performance. It also increased muscle oxidative capacity, and promoted GLUT4 subcellular localization to the membrane in muscles. Furthermore, protein expression of IL-6 receptor (IL-6Ralpha) was increased in both normal and diabetic rats after endurance training, but no significant changes in IL-6, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), or suppressor of cytokine signaling 3 (SOC3) were observed in muscles of normal and diabetic rats. CONCLUSIONS: IL-6 signaling pathway mediating muscle response to endurance training was conserved in type 2 diabetes. There was no link between training induced IL-6 downstream targets in skeletal muscles and IL-6-induced type 2 diabetes. PMID- 28012284 TI - Validity of the Barcelona Clinic Liver Cancer and Hong Kong Liver Cancer staging systems for hepatocellular carcinoma in Singapore. AB - BACKGROUND: Staging is vital in guiding therapeutic approach in patients diagnosed with hepatocellular carcinoma (HCC). Our study's goal is to compare paradigms in the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) systems, and evaluate the use of both in a local context, comparing their prognostic ability and therapeutic efficacy in the management of HCC. METHODS: Seven hundred and sixty-six patients diagnosed between 2010 and 2015 were identified and staged according to BCLC and HKLC. Both system's performances were compared using Akaike information criterion (AIC), bootstrap concordance-index (c index), and through Kaplan-Meier survival curves of patients who came under HKLC stages 1, 2, and 3 and the individual BCLC stages. Independent prognostic factors of survival were identified using univariate and multivariate analyses. RESULTS: According to AIC and c-index, HKLC (AIC = 5,711, c-index = 0.74) has equivalent prognosticating value as BCLC (AIC = 5,764, c-index = 0.72). Through Kaplan-Meier curves, we determined that more aggressive treatments resulted in better outcomes. Particularly for patients under BCLC stage C, patients who followed the HKLC system's recommended treatments performed markedly better. CONCLUSIONS: In our patient population, the HKLC system is comparable to the BCLC system in prognosticating patients, but is suggested to have better performance in guiding treatment. PMID- 28012285 TI - Randomized clinical trial of BiClamp forceps versus clamp-crushing technique in open liver resection. AB - BACKGROUND: The aim of this trial was to compare the efficacy and safety of BiClamp forceps with the "gold-standard" clamp-crushing technique for open liver resection. METHODS: From October 2014 to May 2016, 86 consecutive patients scheduled to undergo hepatic resection were randomized to a BiClamp forceps group (n = 43) or to a clamp-crushing technique group (n = 43). RESULTS: Background characteristics of the two groups were closely matched. There were no significant differences between the BiClamp forceps group and clamp-crushing group in total intraoperative blood loss (339.81 +/- 257.20 ml vs. 376.73 +/- 303.67 ml, respectively; P = 0.545) or blood loss per transection area (5.35 +/- 3.27 ml/cm2 vs. 5.44 +/- 3.02 ml/cm2 , respectively; P = 0.609). Liver transection speed, the need of blood transfusion, morbidity, length of postoperative hospital stay, total hospitalization cost and liver function recovery were similar in the two groups. Multivariate logistic regression analysis identified major hepatectomy, multiple resections and liver transection time >=30 min as significantly unfavorable factors for decreased intraoperative blood loss. CONCLUSIONS: Liver parenchymal transection with BiClamp forceps is as safe and feasible as the gold standard clamp-crushing technique. PMID- 28012286 TI - Expression and Clinical Significance of miR-26a and Pleomorphic Adenoma Gene 1 (PLAG1) in Invasive Pituitary Adenoma. AB - BACKGROUND Although pituitary adenoma is a malignant tumor, it can present as invasive growth in some cases. MicroRNA (miR)-26a has been found to be abnormally highly expressed in pituitary adenoma, indicating possible involvement in pathogenesis. As a known target gene of miR-26a, PLAG1 has abnormally low expression in pituitary adenoma. The correlation between miR-26a or PLAG1 expressional abnormality and occurrence of pituitary adenoma is still unknown, as is its association with invasiveness of pituitary adenoma. MATERIAL AND METHODS Pituitary adenoma tissues, including both invasive and non-invasive subtypes, were collected from our Neurosurgery Department, in parallel with normal pituitary tissues from postmortem autopsy. qRT-PCR was used to detect mRNA expression of miR-26a and PLAG1, while Western blotting was used to test PLAG1 protein expression. The correlation between miR-26a and PLAG1, and with pathological features, were analyzed. ROC analysis revealed the utility of miR 26a and PLAG1 in differential diagnosis of invasive/non-invasive pituitary tumors and in analyzing their effects on patient prognosis. RESULTS MiR-26a was remarkably upregulated in pituitary tumors, while PLAG1 was downregulated, especially in invasive pituitary tumors. miR-26a and PLAG1 had higher diagnostic values for differentiating between invasive and non-invasive pituitary tumors (AUC=0.889 and 0.818, respectively). Those patients with miR-26 overexpression and PLAG1 downregulation had unfavorable prognosis. miR-26 and PLAG1 are independent factors affecting patient diagnosis. CONCLUSIONS MiR-26a can facilitate occurrence of pituitary tumor and invasiveness, probably via inhibiting PLAG1 expression. PMID- 28012287 TI - Effects of Fe-deficient conditions on Fe uptake and utilization in P-efficient soybean. AB - Phosphorus (P)-efficient soybean (Glycine max) plants absorb and utilize P with high efficiency. To investigate the effects of iron (Fe)-deficient conditions on the absorption and utilization of Fe in P-efficient soybean plants, two soybean cultivars with different P efficiency, the 03-3 (P-efficient variety) and Bd-2 (P inefficient variety), were used in this study. The two soybean cultivars were grown in nutrient solution containing Fe concentrations of 0 (Fe0), 20 (Fe20), 40 (Fe40), or 80 (Fe80) MUM for 7 days. The Fe reductase activity of roots was higher in 03-3 plants grown under the Fe0, Fe20, and Fe40 treatments than in Bd-2 plants and the total Fe uptake was greater in 03-3 plants under the Fe40 treatment. GmFRD3a was much more highly expressed in the stem of 03-3 than in that of Bd-2, and significantly more iron was transported to 03-3 plant shoots during Fe0 treatment. Chlorosis in young leaves caused by Fe deficiency under the Fe0 and Fe20 treatments was alleviated by increased Fe concentration in shoots. Increased levels of active Fe in young 03-3 leaves under Fe-deprivation conditions (Fe0) and maintenance of stable Fe concentrations in 03-3 shoots subjected to Fe20, Fe40, and Fe80 treatments suggested that the P-efficient 03-3 cultivar is also Fe-efficient. It is suggested that 03-3 soybean cultivar should be a good resource for application to farm field. PMID- 28012288 TI - Peach leaf curl disease shifts sugar metabolism in severely infected leaves from source to sink. AB - Peach leaf curl is a disease that affects the leaves of peach trees, and in severe cases all of the leaf can be similarly affected. This study investigated some effects of this disease on the metabolism of peach leaves in which all parts of the leaf were infected. These diseased leaves contained very little chlorophyll and performed little or no photosynthesis. Compared to uninfected leaves, diseased leaves possessed higher contents of fructose and especially glucose, but lowered contents of sucrose, sorbitol and especially starch. The activities of soluble acid invertase, neutral invertase, sorbitol dehydrogenase and sucrose synthase were all higher in diseased leaves, whereas, those of aldose 6-phosphate reductase and sucrose phosphate synthase were lower. The activities of hexokinase and fructokinase were little changed. In addition, immunblots showed that the contents of Rubisco and ADP-glucose phosphorylase were reduced in diseased leaves, whereas, the content of phosphoenolpyruvate carboxylase was increased. The results show that certain aspects of the metabolism of diseased leaves are similar to immature sink leaves. That is photosynthetic function is reduced, the leaf imports rather than exports sugars, and the contents of non structural carbohydrates and enzymes involved in their metabolism are similar to sink leaves. Further, the effects of peach leaf curl on the metabolism of peach leaves are comparable to the effects of some other diseases on the metabolism of photosynthetic organs of other plant species. PMID- 28012289 TI - Synthesis of iron(II,III) oxide/zinc oxide/copper(II) oxide (Fe3O4/ZnO/CuO) nanocomposites and their photosonocatalytic property for organic dye removal. AB - A facile sol-gel method was adopted to synthesize iron(II,III) oxide/zinc oxide/copper(II) oxide (Fe3O4/ZnO/CuO) nanocomposites with various CuO loadings at a low temperature. The prepared nanocomposites were characterized by X-ray diffraction, field-emission scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, UV-Vis spectroscopy, vibrating sample magnetometry, and Brunauer-Emmett-Teller (BET) surface area analyses. The photosonocatalytic properties of the nanocomposites were tested by methylene blue removal in aqueous solutions under the combination of UV or visible light and ultrasound. The catalyst with the lowest CuO loading exhibited the highest photosonocatalytic performance under UV light, while the fastest degradation under visible light was achieved at the highest CuO loading. Overall, the photosonocatalytic process with light and ultrasound irradiation led to more complete degradation compared to using light alone. According to the experiments performed with radical scavengers, the holes and OH radicals are the dominant oxidative species. The nanocomposites can be easily separated from the treated solution using an external magnetic field, and the samples remain very stable after 4 cycles. These results indicate that these materials have great potential for treating organic pollutants in wastewaters. PMID- 28012290 TI - Enhancing reducing ability of alpha-zein by fibrillation for synthesis of Au nanocrystals with continuous flow catalysis. AB - Green low-cost synthesis and efficient recyclability are two major hindrances for Au nanocrystals as catalysts applying in diverse industrial reaction processes. By the use of low-cost alpha-zein (i.e. a major storage protein of corn) as the reductant, capping agent and stabilizer, Au nanocrystals with tunable catalytic activity were synthesized in a wet-chemical approach. Fibrillation of alpha-zein further enhanced its reducing ability due to larger specific surface area and more hydrophilic groups exposed on the surfaces. The obtained Au nanocrystals had biocompatibility, high stability in various solvents, unique solubility in aqueous alcohol and high catalytic ability, being able to detect ethanol composition in aqueous ethanol as well as H2O2 for diagnosis of diabetes mellitus. These advantages also enable efficient recyclability of Au nanocrystals with continuous flow catalysis in different solvents and environments. Thus, the use of alpha-zein offered Au nanocrystals not only with green low-cost synthesis, but also with tunable catalytic activities, ethanol-responsiveness and efficient recyclability, which may be applicable in diverse fields. PMID- 28012291 TI - Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis. AB - The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol are essential for an adequate response to stress. Considering the role of stress as a risk factor for psychiatric disorders, it is not surprising that cortisol stress reactivity has frequently been investigated in patients versus healthy individuals. However, the large heterogeneity in measures of the cortisol stress response has hampered a systematic evaluation of the evidence. We here report of a systematic literature review and meta-analysis on cortisol reactivity to psychosocial stress across psychiatric disorders. Original data from authors were obtained to construct standardized cortisol outcomes (the areas under the curve with respect to increase (AUCi) and ground (AUCg)) and to examine the influence of sex and symptomatic state on cortisol stress reactivity. Fourteen studies on major depressive disorder (MDD) (n=1129), 9 on anxiety disorders (n=732, including social anxiety disorder (SAD), posttraumatic stress disorder, panic disorder and mixed samples of anxiety disorders) and 4 on schizophrenia (n=180) were included that used the Trier Social Stress Test or an equivalent psychosocial stress task. Sex-dependent changes in stress reactivity were apparent in MDD and anxiety disorders. Specifically, women with current MDD or an anxiety disorder exhibited a blunted cortisol stress response, whereas men with current MDD or SAD showed an increased cortisol response to psychosocial stress. In individuals with remitted MDD, altered cortisol stress reactivity was less pronounced in women and absent in men. For schizophrenia, cortisol stress reactivity was blunted in both men and women, but the number of studies was limited and showed evidence for publication bias. These findings illustrate that sharing individual data to disentangle the effects of sex, symptom levels and other factors is essential for further understanding of the alterations in cortisol stress reactivity across psychiatric disorders. PMID- 28012293 TI - Female nurses' burnout symptoms: No association with the Hypothalamic-pituitary thyroid (HPT) axis. AB - Across the world, hospital nurses experience a high level of burnout. Exploring biochemical markers of burnout could help to understand physiological changes and may provide useful evidence for preventing burnout symptoms. The current study included 94 female nurses from one Chinese third-level hospital. The Maslach Burnout Inventory-General Survey (MBI-GS) was used to investigate burnout symptoms: emotional exhaustion, cynicism, reduced professional efficacy, as well as the burnout average. The HPT axis was tested by checking blood levels of thyroid-stimulating hormone (TSH), thyroxin (T4) and triiodothyronine (T3). Nonparametric tests showed that no significant difference in biochemical markers was found between the burnout and non-burnout groups. Spearman correlation analysis found that biochemical markers had no significant association with burnout symptoms, except weakly negative associations between reduced professional efficacy and blood pressure and heart rate. These findings show a rather poor correlation of the HPT axis on burnout symptoms. Expanding the biochemical index of the HPT axis, comparing well-defined samples and using longitudinal studies are recommended for further studies. PMID- 28012292 TI - Behavioral and physiological consequences of enrichment loss in rats. AB - Significant loss produces the highest degree of stress and compromised well-being in humans. Current rodent models of stress involve the application of physically or psychologically aversive stimuli, but do not address the concept of loss. We developed a rodent model for significant loss, involving removal of long-term access to a rewarding enriched environment. Our results indicate that removal from environmental enrichment produces a profound behavioral and physiological phenotype with depression-like qualities, including helplessness behavior, hypothalamo-pituitary-adrenocortical axis dysregulation and overeating. Importantly, this enrichment removal phenotype was prevented by antidepressant treatment. Furthermore, the effects of enrichment removal do not occur following relief from chronic stress and are not duplicated by loss of exercise or social contact. PMID- 28012294 TI - Derivation of respiration rate from ambulatory ECG and PPG using Ensemble Empirical Mode Decomposition: Comparison and fusion. AB - A new method for extracting the respiratory rate from ECG and PPG obtained via wearable sensors is presented. The proposed technique employs Ensemble Empirical Mode Decomposition in order to identify the respiration "mode" from the noise corrupted Heart Rate Variability/Pulse Rate Variability and Amplitude Modulation signals extracted from ECG and PPG signals. The technique was validated with respect to a Respiratory Impedance Pneumography (RIP) signal using the mean absolute and the average relative errors for a group ambulatory hospital patients. We compared approaches using single respiration-induced modulations on the ECG and PPG signals with approaches fusing the different modulations. Additionally, we investigated whether the presence of both the simultaneously recorded ECG and PPG signals provided a benefit in the overall system performance. Our method outperformed state-of-the-art ECG- and PPG-based algorithms and gave the best results over the whole database with a mean error of 1.8bpm for 1min estimates when using the fused ECG modulations, which was a relative error of 10.3%. No statistically significant differences were found when comparing the ECG-, PPG- and ECG/PPG-based approaches, indicating that the PPG can be used as a valid alternative to the ECG for applications using wearable sensors. While the presence of both the ECG and PPG signals did not provide an improvement in the estimation error, it increased the proportion of windows for which an estimate was obtained by at least 9%, indicating that the use of two simultaneously recorded signals might be desirable in high-acuity cases where an RR estimate is required more frequently. PMID- 28012295 TI - Fitting local repolarization parameters in cardiac reaction-diffusion models in the presence of electrotonic coupling. AB - BACKGROUND: Repolarization gradients contribute to arrhythmogenicity. In reaction diffusion models of cardiac tissue, heterogeneities in action potential duration (APD) can be created by locally modifying an intrinsic membrane kinetics parameter. Electrotonic coupling, however, acts as a confounding factor that modulates APD dispersion. METHOD: We developed an algorithm based on a quasi Newton method that iteratively adjusts the spatial distribution of a membrane parameter to reproduce a pre-defined target APD map in a coupled tissue. The method assumes that the relation between the adjustable parameter and APD is bijective in an isolated cell. Each iteration of the algorithm involved simulating the cardiac reaction-diffusion system with the updated parameter profile for one beat and extracting the APD map. The algorithm was extended to simultaneous estimation of two parameter profiles based on two APD maps at different repolarization thresholds. RESULTS: The method was validated in 1D, 2D and 3D atrial tissues using synthetic target APD maps with controllable total variation and maximum APD gradient. The adjustable parameter was local acetylcholine concentration. The iterations converged provided that APD gradients were not too steep. Convergence was found to be faster 2-5 iterations) when the maximal gradient was less steep, when APD range was smaller and when tissue conductivity was reduced. CONCLUSION: This algorithm provides a tool to automatically generate arrhythmogenic substrates with controllable repolarization gradients and possibly incorporate experimental APD maps into computer models. PMID- 28012296 TI - Effects of aging on mechanical properties of sternocleidomastoid and trapezius muscles during transition from lying to sitting position-A cross-sectional study. AB - AIM: The aim of this study was to analyze the effects of aging on the viscoelastic properties of the upper trapezius (UT) and the sternocleidomastoid (SCM) muscle during transition from lying to sitting position. MATERIALS AND METHODS: The study included 39 older (mean age 67+/-5.9years) and 36 younger (21.1+/-1.8years) women. Tone, stiffness and elasticity of the UT and the SCM were measured by means of myotonometry (MyotonPRO) in lying and then, in sitting position. The results were compared using two-way analysis of variance. RESULTS: Irrespective of the position, older women presented with significantly higher muscle tone, stiffness and elasticity than younger subjects (P<0.05). In both groups, the transition from lying to sitting position resulted in a decrease (P<0.05) in the tone and stiffness, but not the elasticity (P>0.05) of the SCM, and stimulated an increase in the tone, stiffness and elasticity of the UT (P<0.05). The degree of changes in both study groups was similar, except from the absolute value of the UT elasticity, significantly higher increase in older women than in younger subjects (P<0.05). CONCLUSION: Age contributes to an increase in the stiffness and tone of the UT and the SCM, as well as to a decrease in the elasticity of these muscles in female subjects. In contrast, age exerts only a slight effect on the mechanical properties of both muscles during transition from lying to sitting position. PMID- 28012298 TI - S3 HMBC hetero: Spin-State-Selective HMBC for accurate measurement of long-range heteronuclear coupling constants. AB - A novel method, Spin-State-Selective (S3) HMBC hetero, for accurate measurement of heteronuclear coupling constants is introduced. The method extends the S3 HMBC technique for measurement of homonuclear coupling constants by appending a pulse sequence element that interchanges the polarization in 13C-1H methine pairs. This amounts to converting the spin-state selectivity from 1H spin states to 13C spin states in the spectra of long-range coupled 1H spins, allowing convenient measurement of heteronuclear coupling constants similar to other S3 or E.COSY type methods. As usual in this type of techniques, the accuracy of coupling constant measurement is independent of the size of the coupling constant of interest. The merits of the new method are demonstrated by application to vinyl acetate, the alkaloid strychnine, and the carbohydrate methyl beta-maltoside. PMID- 28012297 TI - Balanced Steady-State Free Precession (bSSFP) from an effective field perspective: Application to the detection of chemical exchange (bSSFPX). AB - Chemical exchange saturation transfer (CEST) is a novel contrast mechanism and it is gaining increasing popularity as many promising applications have been proposed and investigated. Fast and quantitative CEST imaging techniques are further needed in order to increase the applicability of CEST for clinical use as well as to derive quantitative physiological and biological information. Steady state methods for fast CEST imaging have been reported recently. Here, we observe that an extreme case of these methods is a balanced steady-state free precession (bSSFP) sequence. The bSSFP in itself is sensitive to the exchange processes; hence, no additional saturation or preparation is needed for CEST-like data acquisition. The bSSFP experiment can be regarded as observation during saturation, without separate saturation and acquisition modules as used in standard CEST and similar experiments. One of the differences from standard CEST methods is that the bSSFP spectrum is an XY-spectrum not a Z-spectrum. As the first proof-of-principle step, we have implemented the steady-state bSSFP sequence for chemical exchange detection (bSSFPX) and verified its feasibility in phantom studies. These studies have shown that bSSFPX can achieve exchange mediated contrast comparable to the standard CEST experiment. Therefore, the bSSFPX method has a potential for fast and quantitative CEST data acquisition. PMID- 28012299 TI - Claims-shifting: The problem of parallel reimbursement regimes. AB - Parallel reimbursement regimes, under which providers have some discretion over which payer gets billed for patient treatment, are a common feature of health care markets. In the U.S., the largest such system is under Workers' Compensation (WC), where the treatment workers with injuries that are not definitively tied to a work accident may be billed either under group health insurance plans or under WC. We document that there is significant reclassification of injuries from group health plans into WC, or "claims shifting", when the financial incentives to do so are strongest. In particular, we find that injuries to workers enrolled in capitated group health plans (such as HMOs) see a higher incidence of their claims for soft-tissue injuries (which are hard to classify specifically as work related) under WC than under group health, relative to those in non-capitated plans. Such a pattern is not evident for workers with traumatic injuries. Moreover, we find that such reclassification is more common in states with higher WC fees, once again for soft tissue but not traumatic injuries. Our results imply that a significant shift towards capitated reimbursement, or reimbursement reductions, under GH could lead to a large rise in the cost of WC plans. PMID- 28012300 TI - Long-term outcomes and predictors of internet-delivered cognitive behavioral therapy for childhood anxiety disorders. AB - OBJECTIVE: This study investigated the long-term outcomes of internet-delivered cognitive behavior therapy (ICBT) for children with anxiety disorders, and potential pre-treatment predictors of treatment outcome. METHOD: The sample included eighty-four children (8-12 years old) with anxiety disorders, from both a treatment group and a waitlist control (after participants had crossed over to treatment) of a previous randomized controlled study. Participants were assessed at post-treatment and three- and twelve-months after treatment using a semi structured interview and parent ratings. Pre-treatment data were used to investigate predictors of treatment outcome at three-month follow-up. RESULTS: Intention-to-treat analysis showed that treatment gains were maintained at twelve month follow-up, including clinician rated severity of the principal anxiety disorder, parent rated anxiety symptoms and global functioning, with mainly large effect sizes (Cohen's d = 0.63-2.35). Completer analyses showed that suspected autism spectrum disorder was associated with less change in symptom severity. No other pre-treatment measures significantly predicted treatment outcome. CONCLUSION: This study suggests that internet-delivered CBT can have long-term beneficial effects for children with anxiety disorders. Predictors of treatment outcome need to be evaluated further. TRIAL REGISTRATION: Clinicaltrials.gov; NCT01533402. PMID- 28012301 TI - Psychophysiological reactivity of currently dental phobic-, remitted dental phobic- and never-dental phobic individuals during exposure to dental-related and other affect-inducing materials. AB - Psychophysiological responses indicating the preparation of defensive behaviour, such as heart rate (HR)-increase and startle-response (SR) potentiation, have often been reported amongst individuals suffering from phobic disorders when exposed to phobia-related information. Although exposure is widely considered the 'gold standard' for treatment of Specific Phobia, it is unclear to what extent psychophysiological defensive response patterns change following treatment, and whether any changes are maintained. We assessed the acoustic SR- and HR-response to neutral, positive, negative and phobia-related pictures and sounds in 41 individuals currently suffering from dental phobia, 22 formerly dental phobic individuals who had remitted following an exposure-based treatment eight months prior to assessment, and 29 control individuals with no history of dental phobia. We observed SR-potentiation to dental-related stimuli in controls combined with HR-deceleration. In contrast, amongst phobic individuals SR-potentiation was accompanied by HR-acceleration to dental pictures. Successfully treated individuals showed inhibited startle reactivity in combination with HR deceleration to dental related materials of both modalities. Our findings suggest inappropriate fight-flight preparation amongst individuals with dental phobia, reflecting overactivation of the defensive system. However, successful treatment results in inhibited physiological defence preparation, with remitted individuals displaying a response pattern that differed from that of phobic individuals and controls. PMID- 28012302 TI - Is the "Yoga Bod" the new skinny?: A comparative content analysis of mainstream yoga lifestyle magazine covers. AB - As yoga has gained popularity in Western culture, concerns have been raised about its increased commercialization and assimilation into the predominantly appearance-focused exercise and fitness culture. In this context, the present study examined the physical appearance-related characteristics (e.g., race/ethnicity, body size, shape, objectifying apparel) of 142 female models and the media frames of 567 captions (e.g., commercialism, body competence, health, weight/physical appearance) featured on the covers of three Westernized yoga lifestyle magazines published between 2010-2015. Results indicated that most models were White, embodying the contemporary "thin-and-lean" media fitness aesthetic. Models were actively posed with high body visibility; an appreciable minority was partially-clad in skin-revealing or form-fitting upper-body attire. Media frames conveying commercialism and body competence were equally present. The pattern of effects tended to reflect the strength of the magazine title's endorsement of exercise and fitness cultural values. Clinical and public health implications along with future research directions are discussed. PMID- 28012303 TI - Relationship between body composition and vertical ground reaction forces in obese children when walking. AB - BACKGROUND: Obesity is now a serious worldwide challenge, especially in children. This condition can cause a number of different health problems, including musculoskeletal disorders, some of which are due to mechanical stress caused by excess body weight. The aim of this study was to determine the association between body composition and the vertical ground reaction force produced during walking in obese children. METHODS: Sixteen children participated in the study, six females and ten males [11.5 (1.2) years old, 69.8 (15.5) kg, 1.56 (0.09) m, and 28.36 (3.74) kg/m2 of body mass index (BMI)]. Total weight, lean mass and fat mass were measured by dual-energy X-ray absorptiometry and vertical forces while walking were obtained by a force platform. The vertical force variables analysed were impact and propulsive forces, and the rate of development of both. Multiple regression models for each vertical force parameter were calculated using the body composition variables as input. FINDINGS: The impact force regression model was found to be positively related to the weight of obese children and negatively related to lean mass. The regression model showed lean mass was positively related to the propulsive rate. Finally, regression models for impact and propulsive force showed a direct relationship with body weight. INTERPRETATION: Impact force is positively related to the weight of obese children, but lean mass helps to reduce the impact force in this population. Exercise could help obese persons to reduce their total body weight and increase their lean mass, thus reducing impact forces during sports and other activities. PMID- 28012304 TI - Work of separation - A method to assess intraperitoneal adhesion and healing of parietal peritoneum in an animal model. AB - BACKGROUND: Adhesion grades and adhesion breaking strength are widely used to assess severity of intraperitoneal adhesion in animal models. However, the results of adhesion grades have the large deviations due to vary personal experience. Adhesion breaking strength ignores the details of adhesion. This study introduced work of separation, the energy consumption during breakage of adhesion, to better evaluate intraperitoneal adhesion. METHODS: The intraperitoneal adhesion was induced by traumas created at rat cecum and adjacent abdominal wall. The wounds were coated with or without sodium hyaluronate. On day 14 after surgery, the intraperitoneal adhesion was assessed by adhesion density grade, adhesion area grade, adhesion breaking strength and work of separation. The healing of parietal peritoneum was evaluated with histology, adhesion breaking strength and work of separation. FINDINGS: The severity of adhesion evaluated with work of separation was consistent with those obtained from the grades of adhesion density, adhesion area and adhesion breaking strength. Work of separation had a linear correlation with adhesion breaking strength. Furthermore, the results of histological examination and work of separation demonstrated that adhesion significantly delayed healing process of abdominal wall muscles. INTERPRETATION: Work of separation can quantify all intraperitoneal adhesions rather than the major one by other methods. It is a more precise method to evaluate postoperative adhesions, especially those including adipose tissue. This study proved that work of separation could be a reliable method to assess intraperitoneal adhesion and tissue healing. PMID- 28012306 TI - Interaction of anticancer drug clofarabine with human serum albumin and human alpha-1 acid glycoprotein. Spectroscopic and molecular docking approach. AB - The binding interaction between clofarabine, an important anticancer drug and two important carrier proteins found abundantly in human plasma, Human Serum Albumin (HSA) and alpha-1 acid glycoprotein (AAG) was investigated by spectroscopic and molecular modeling methods. The results obtained from fluorescence quenching experiments demonstrated that the fluorescence intensity of HSA and AAG is quenched by clofarabine and the static mode of fluorescence quenching is operative. UV-vis spectroscopy deciphered the formation of ground state complex between anticancer drug and the two studied proteins. Clofarabine was found to bind at 298K with both AAG and HSA with the binding constant of 8.128*103 and 4.120*103 for AAG and HSA, respectively. There is stronger interaction of clofarabine with AAG as compared to HSA. The Gibbs free energy change was found to be negative for the interaction of clofarabine with AAG and HSA indicating that the binding process is spontaneous. Binding of clofarabine with HSA and AAG induced ordered structures in both proteins and lead to molecular compaction. Clofarabine binds to HSA near to drug site II. Hydrogen bonding and hydrophobic interactions were the main bonding forces between HSA-clofarabine and AAG clofarabine as revealed by docking results. This study suggests the importance of binding of anticancer drug to AAG spatially in the diseases like cancers where the plasma concentration of AAG increases many folds. Design of drug dosage can be adjusted accordingly to achieve optimal treatment outcome. PMID- 28012305 TI - Social emotional information processing in adults: Development and psychometrics of a computerized video assessment in healthy controls and aggressive individuals. AB - A computerized version of an assessment of Social-Emotional Information Processing (SEIP) using audio-video film stimuli instead of written narrative vignettes was developed for use in adult participants. This task allows for an assessment of encoding or relevant/irrelevant social-emotional information, attribution bias, and endorsement of appropriate, physically aggressive, and relationally aggressive responses to aversive social-emotional stimuli. The psychometric properties of this Video-SEIP (V-SEIP) assessment were examined in 75 healthy controls (HC) and in 75 individuals with DSM-5 Intermittent Explosive Disorder (IED) and were also compared with the original questionnaire (SEIP-Q) version of the task (HC=26; IED=26). Internal consistency, inter-rater reliability, and test-retest properties of the V-SEIP were good to excellent. In addition, IED participants displayed reduced encoding of relevant information from the film clips, elevated hostile attribution bias, elevated negative emotional response, and elevated endorsement of physically aggressive and relationally aggressive responses to the ambiguous social-emotional stimuli presented in the V-SEIP. These data indicate that the V-SEIP represents a valid and comprehensive alternative to the paper-and-pencil assessment of social emotional information processing biases in adults. PMID- 28012307 TI - A sensitive LC-MS/MS method for analysis of pericyazine in presence of 7 hydroxypericyazine and pericyazine sulphoxide in human plasma and its application to a comparative bioequivalence study in Chinese healthy volunteers. AB - A robust and highly sensitive liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for the determination of pericyazine in human plasma. The plasma sample was alkalized with sodium hydroxide solution and handled by liquid-liquid extraction with ethyl acetate after adding perphenazine as an internal standard (IS). The analytes were separated on an UltimateTM AQ-C18 analytical column at 40 degrees C, with a gradient elution consisting of A (aqueous phase: 5mM ammonium acetate buffer solution containing 0.1% formic acid) and B (organic phase: acetonitrile) at a flow rate of 0.350mL/min. The detection was conducted on an API 4000 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) transitions, m/z 366.5>142.4 for pericyazine, m/z 382.5>142.4 for its 7 hydroxy and sulphoxide metabolites and m/z 404.3>171.3 for IS were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity (LLOQ of 0.021ng/mL) and good linearity over the concentration range of 0.021-9.90ng/mL. The intra- and inter-day precision, accuracy, and stability results were within the acceptable limits and no matrix effect was observed. This method was successfully applied in a bioequivalence study to evaluate the pharmacokinetics in 20 healthy male Chinese volunteers. Additional exploratory analyses of 7-hydroxy and sulphoxide metabolites of pericyazine in the same samples suggest that the unchanged drug is predominant in the plasma and suitable for the bioequivalence comparison after a single oral administration of 10mg pericyazine. PMID- 28012308 TI - Development of a multi-residue method for the determination of human and veterinary pharmaceuticals and some of their metabolites in aqueous environmental matrices by SPE-UHPLC-MS/MS. AB - The aim of the present work was to develop and validate a multi-residue method for the analysis of 33 human and veterinary pharmaceuticals (non-steroidal anti inflammatory drugs (NSAIDs)/analgesics, antibiotics and psychiatric drugs), including some of their metabolites, in several aqueous environmental matrices: drinking water, surface water and wastewaters. The method is based on solid phase extraction (SPE) followed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and it was validated for different aqueous matrices, namely bottled water, tap water, seawater, river water and wastewaters, showing recoveries between 50% and 112% for the majority of the target analytes. The developed analytical methodology allowed method detection limits in the low nanograms per liter level. Method intra- and inter-day precision was under 8% and 11%, respectively, expressed as relative standard deviation. The developed method was applied to the analysis of drinking water (bottled and tap water), surface waters (seawater and river water) and wastewaters (wastewater treatment plant (WWTP) influent and effluent). Due to the selectivity and sensitivity of the optimized method, it was possible to detect pharmaceuticals in all the aqueous environmental matrices considered, including in bottled water at concentrations up to 31ngL-1 (salicylic acid). In general, non-steroidal anti-inflammatory drugs/analgesics was the therapeutic group most frequently detected, with the highest concentrations found in wastewaters (acetaminophen and the metabolite carboxyibuprofen at levels up to 615 and 120MUgL-1, respectively). PMID- 28012309 TI - Development of new efficient method for isolation of phenolics from sea algae prior to their rapid resolution liquid chromatographic-tandem mass spectrometric determination. AB - The extraction of phenolic compounds from 4 different sea algae samples, three brown algae (Cystoseira abies-marina, C. abies-marina grinded under cryogenic conditions with liquid nitrogen, Undaria pinnatifida and Sargassum muticum) and one red algae (Chondrus crispus) via solid phase extraction using micro-elution solid-phase extraction (MU-SPE) plate method was studied. Prior to MU-SPE, 50mg of algae with 80% methanol mixture was extracted in hyphenated series by various extraction techniques, such as pressurized liquid extraction and Ika Ultra Turrax(r) Tube Drive, in combination with ultrasound assisted extraction. The MU SPE plate technique reduced the time of sample pre-treatment thanks to higher sensitivity and pre-concentration effect. Selected groups of benzoic acid derivatives (p-hydroxybenzoic, protocatechuic, gallic, vanillic, and syringic acids), hydroxybenzaldehydes (4-hydroxybenzaldehyde, and 3,4 dihydroxybenzaldehyde), and cinnamic acid derivatives (p-coumaric, caffeic, ferulic, sinapic, and chlorogenic acids) were determined using rapid resolution liquid chromatography coupled to mass spectrometry detection with negative ion electrospray ionization (RRLC-ESI-MS) using multiple reactions monitoring. LOQs of measured samples varied in the range 0.23-1.68ng/mL and LODs in the range 0.07 0.52ng/mL. The applied method allowed a simultaneous determination of phenolics (i.e. free, esters soluble in methanol, glycosides, and esters insoluble in methanol) in less than 5min (including alkaline or acidic hydrolysis of raw extracts) from sea algae extracts. PMID- 28012310 TI - Physico-chemical profiling of semisynthetic opioids. AB - Species-specific acid-base and partition equilibrium constants were experimentally determined for the therapeutically important semisynthetic opioid receptor agonist hydromorphone, dihydromorphine, and mixed agonist-antagonist nalorphine and nalbuphine. The acid-base microequilibria were characterized by combining pH-potentiometry and deductive methods using synthesized auxiliary compounds. Independent of the pH, there are approximately 4.8 times as many zwitterionic microspecies than non-charged ones in nalbuphine solutions, while for nalorphine it is the non-charged form that predominates by the same ratio. The non-charged microspecies is the dominant one also in the case of hydromorphone, although its concentration exceeds only 1.3 times that of its zwitterionic protonation isomer. The pH-independent partition coefficients of the individual microspecies were determined by a combination of experimentally measured, pH-dependent, conditional distribution constants and a custom-tailored evaluation method, using highly similar auxiliary compounds. The pH-independent contribution of the zwitterionic microspecies to the distribution constant is 1380, 1070, 3160 and 72,440 times smaller than that of the inherently more lipophilic non-charged one for hydromorphone, dihydromorphine, nalbuphine and nalorphine, respectively. PMID- 28012311 TI - Supportive care for older people with frailty in hospital: An integrative review. AB - BACKGROUND: Growing numbers of older people living with frailty and chronic health conditions are being referred to hospitals with acute care needs. Supportive care is a potentially highly relevant and clinically important approach which could bridge the practice gap between curative models of care and palliative care. However, future interventions need to be informed and underpinned by existing knowledge of supportive care. AIM: To identify and build upon existing theories and evidence about supportive care, specifically in relation to the hospital care of older people with frailty, to inform future interventions and their evaluation. DESIGN: An integrative review was used to identify and integrate theory and evidence. Electronic databases (Cochrane Medline, EMBASE and CIHAHL) were searched using the key term 'supportive care'. Screening identified studies employing qualitative and/or quantitative methods published between January 1990 and December 2015. Citation searches, reference checking and searches of the grey literature were also undertaken. DATA SOURCES: Literature searches identified 2733 articles. After screening, and applying eligibility criteria based on relevance to the research question, studies were subject to methodological quality appraisal. Findings from included articles (n=52) were integrated using synthesis of themes. RESULTS: Relevant evidence was identified across different research literatures, on clinical conditions and contexts. Seven distinct themes of the synthesis were identified, these were: Ensuring fundamental aspects of care are met, Communicating and connecting with the patient, Carer and family engagement, Building up a picture of the person and their circumstances, Decisions and advice about best care for the person, Enabling self-help and connection to wider support, and Supporting patients through transitions in care. A tentative integrative model of supportive care for frail older people is developed from the findings. CONCLUSION: The findings and model developed here will inform future interventions and can help staff and hospital managers to develop appropriate strategies, staff training and resource allocation models to improve the quality of health care for older people. PMID- 28012312 TI - Racial and ethnic residential segregation and access to health care in rural areas. AB - This study examined the relationship between racial/ethnic residential segregation and access to health care in rural areas. Data from the Medical Expenditure Panel Survey were merged with the American Community Survey and the Area Health Resources Files. Segregation was operationalized using the isolation index separately for African Americans and Hispanics. Multi-level logistic regression with random intercepts estimated four outcomes. In rural areas, segregation contributed to worse access to a usual source of health care but higher reports of health care needs being met among African Americans (Adjusted Odds Ratio [AOR]: 1.42, CI: 0.96-2.10) and Hispanics (AOR: 1.25, CI: 1.05-1.49). By broadening the spatial scale of segregation beyond urban areas, findings showed the complex interaction between social and spatial factors in rural areas. PMID- 28012313 TI - Typologies of neighbourhood environments and children's physical activity, sedentary time and television viewing. AB - This study examined cross-sectional and prospective associations between clusters of neighbourhood attributes (typologies) and non-school moderate-to-vigorous physical activity, sedentary time (objectively measured) and proxy-reported television viewing among children aged 5-6 and 10-12 years. Four distinct clusters were identified from seven objectively-measured neighbourhood attributes (land use mix, traffic exposure, playgrounds, sports venues, intersections and cul-de-sacs within 800m, crime/postcode). Some cross-sectional associations with behavior were found. Longitudinally, the cluster characterised by mixed land use and many playgrounds and sport venues was associated with less television viewing on weekends three years later. Considering the aggregate effects of urban form elements may help understand how combinations of neighbourhood attributes influence behavior. PMID- 28012314 TI - Do air quality targets really represent safe limits for lung cancer risk? AB - In order to estimate the lung cancer risk associated to airborne particles, exposure and risk-assessment studies ordinarily use particle mass concentration as dosimetry parameter. Consequently, the corresponding air quality targets are based on this metrics, neglecting the potential impact of ultrafine particles (UFPs) due to their negligible mass. The main purpose of this study was to evaluate the reliability of air quality targets in protecting Italian non-smoking people from lung cancer risk due to exposure to polycyclic aromatic hydrocarbons and some heavy metals associated with particle inhalation. A modified risk assessment scheme was applied to estimate the cancer risk contribution from both sub-micron (mainly UFPs) and super-micron particles. We found a very high lung cancer risk related to the actual target levels due to the contribution of UFPs, in particular from indoor microenvironments. Therefore, as possible actions to reduce the lung cancer risk, we have hypothesized and tested three different scenarios: a) a reduction of the concentration of carcinogenic chemicals condensed onto particles in agreement with the current EU air pollution policy; b) the use of local ventilation systems to mitigate the exposure to cooking generated particles; c) the improvement of the overall indoor air quality by considering a mechanical ventilation system instead of the widespread natural ventilation in order to increase the air exchange rates. Even with the simultaneous application of specific actions, performed with the best technologies available, the corresponding estimated lifetime lung cancer risk (ELCR) values for the Italian population for the entire life were equal to 1.25*10-4 and 1.23*10-4 for males and females, respectively, well higher with respect to the maximum tolerable lifetime cancer risk, 1*10-5. PMID- 28012315 TI - Comparison of biomass from integrated fixed-film activated sludge (IFAS), moving bed biofilm reactor (MBBR) and membrane bioreactor (MBR) treating recalcitrant organics: Importance of attached biomass. AB - This study compared microbial characteristics and oil sands process-affected water (OSPW) treatment performance of five types of microbial biomass (MBBR biofilm, IFAS-biofilm, IFAS-floc, MBR-aerobic-floc, and MBR-anoxic-floc) cultivated from three types of bioreactors (MBBR, IFAS, and MBR) in batch experiments. Chemical oxygen demand (COD), ammonium, acid extractable fraction (AEF), and naphthenic acids (NAs) removals efficiencies were distinctly different between suspended and attached bacterial aggregates and between aerobic and anoxic suspended flocs. MBR-aerobic-floc and MBR-anoxic-floc demonstrated COD removal efficiencies higher than microbial aggregates obtained from MBBR and IFAS, MBBR and IFAS biofilm had higher AEF removal efficiencies than those obtained using flocs. MBBR-biofilm demonstrated the most efficient NAs removal from OSPW. NAs degradation efficiency was highly dependent on the carbon number and NA cyclization number according to UPLC/HRMS analysis. Mono- and di-oxidized NAs were the dominant oxy-NA species in OSPW samples. Microbial analysis with quantitative polymerase chain reaction (q-PCR) indicated that the bacterial 16S rRNA gene abundance was significantly higher in the batch bioreactors with suspended flocs than in those with biofilm, the NSR gene abundance in the MBR anoxic bioreactor was significantly lower than that in aerobic batch bioreactors, and denitrifiers were more abundant in the suspended phase of the activated sludge flocs. PMID- 28012316 TI - The effect of trimethylamine N-oxide on Helicobacter pylori-induced changes of immunoinflammatory genes expression in gastric epithelial cells. AB - Colonization of Helicobacter pylori (H. pylori) induces immune and inflammatory response in gastric mucosa. Trimethylamine N-oxide (TMAO), from diet and metabolite through the action of gut microbiota, has been linked to inflammatory diseases. To investigate the effects of TMAO and H. pylori infection on gene expression in gastric epithelial cells, Human gene chip Affymetrix HTA 2.0 was used in this study. 1312 genes were identified as differentially expressed genes in GES-1 cells with H. pylori and TMAO co-treatment compared to the control. GO and KEGG analyses indicated that the functions of these differentially expressed genes were related closely with immune inflammation. GO-network showed that Toll like receptor signaling pathway was the most important biological processes and 49 up-regulated genes related to immune inflammation were obtained. The synergistic effects of H. pylori and TMAO enhanced the genes expression of IL-6, CXCL1, CXCL2, FOS and C3 related to immune inflammation in comparison with those of non-infected control cells, H. pylori-infected cells, and TMAO-stimulated cells. RT-PCR verified the expression levels of IL-6, CXCL1. Additionally, expression levels of 2053 genes were altered and 52 immunoinflammatory genes were upregulated in comparison with H. pylori-infected cells. This study suggested that TMAO altered the expression levels of immunoinflammatory genes induced by H. pylori infection, and the synergistic effects of H. pylori and TMAO provided novel insights into the development of chronic gastritis, gastric ulcer and gastric cancer. PMID- 28012317 TI - A mass spectrometry-based multiplex SNP genotyping by utilizing allele-specific ligation and strand displacement amplification. AB - We herein describe a new mass spectrometry-based method for multiplex SNP genotyping by utilizing allele-specific ligation and strand displacement amplification (SDA) reaction. In this method, allele-specific ligation is first performed to discriminate base sequence variations at the SNP site within the PCR amplified target DNA. The primary ligation probe is extended by a universal primer annealing site while the secondary ligation probe has base sequences as an overhang with a nicking enzyme recognition site and complementary mass marker sequence. The ligation probe pairs are ligated by DNA ligase only at specific allele in the target DNA and the resulting ligated product serves as a template to promote the SDA reaction using a universal primer. This process isothermally amplifies short DNA fragments, called mass markers, to be analyzed by mass spectrometry. By varying the sizes of the mass markers, we successfully demonstrated the multiplex SNP genotyping capability of this method by reliably identifying several BRCA mutations in a multiplex manner with mass spectrometry. PMID- 28012318 TI - Graphene-interfaced electrical biosensor for label-free and sensitive detection of foodborne pathogenic E. coli O157:H7. AB - E. coli O157:H7 is an enterohemorrhagic bacteria responsible for serious foodborne outbreaks that causes diarrhoea, fever and vomiting in humans. Recent foodborne E. coli outbreaks has left a serious concern to public health. Therefore, there is an increasing demand for a simple, rapid and sensitive method for pathogen detection in contaminated foods. In this study, we developed a label free electrical biosensor interfaced with graphene for sensitive detection of pathogenic bacteria. This biosensor was fabricated by interfacing graphene with interdigitated microelectrodes of capacitors that were biofunctionalized with E. coli O157:H7 specific antibodies for sensitive pathogenic bacteria detection. Here, graphene nanostructures on the sensor surface provided superior chemical properties such as high carrier mobility and biocompatibility with antibodies and bacteria. The sensors transduced the signal based on changes in dielectric properties (capacitance) through (i) polarization of captured cell-surface charges, (ii) cells' internal bioactivity, (iii) cell-wall's electronegativity or dipole moment and their relaxation and (iv) charge carrier mobility of graphene that modulated the electrical properties once the pathogenic E. coli O157:H7 captured on the sensor surface. Sensitive capacitance changes thus observed with graphene based capacitors were specific to E. coli O157:H7 strain with a sensitivity as low as 10-100 cells/ml. The proposed graphene based electrical biosensor provided advantages of speed, sensitivity, specificity and in-situ bacterial detection with no chemical mediators, represents a versatile approach for detection of a wide variety of other pathogens. PMID- 28012319 TI - A novel fluorimetric sensing platform for highly sensitive detection of organophosphorus pesticides by using egg white-encapsulated gold nanoclusters. AB - Assays for organophosphorus pesticides (OPs) with high sensitivity as well as on site screening have been urgently required to protect ecosystem and prevent disease. Herein, a novel fluorimetric sensing platform was constructed for quantitative detection of OPs via tyrosinase (TYR) enzyme-controlled quenching of gold nanoclusters (AuNCs). One-step green synthetic approach was developed for the synthesis of AuNCs by using chicken egg white (CEW) as template and stabilizer. Initially, TYR can catalyze the oxidation of dopamine to dopaminechrome, which can efficiently quench the fluorescence intensity of AuNCs at 630nm based on dynamic quenching process. However, with the presence of OPs, the activity of TYR was inhibited, resulting in the fluorescence recovery of AuNCs. This proposed fluorescence platform was demonstrated to enable rapid detection for OPs (paraoxon as model) and to provide excellent sensitivity with a detection limit of 0.1ngmL-1. Significantly, the fluorescence probe was used to prepare paper-based test strips for visual detection of OPs, which validated the excellent potential for real-time and on-site application. PMID- 28012320 TI - Ratiometric detection of copper ions and alkaline phosphatase activity based on semiconducting polymer dots assembled with rhodamine B hydrazide. AB - The rational surface functionalization of semiconducting polymer dots (Pdots) has attracted much attention to extend their applications in fabricating chemo/biosensing platform. In this study, a novel ratiometric fluorescent sensing platform using functionalized Pdots as probes for fluorescence signal transmission has been designed for sensing Cu(II) and activity of alkaline phosphatase (ALP) with high selectivity and enhanced sensitivity. The highly fluorescent Pdots were firstly prepared with Poly[(9,9-dioctylfluorenyl-2,7-diyl) co-(1,4-benzo-{2,1',3}-thiadiazole)] (PFBT) via nanoprecipitation method, and then assembled with non-fluorescent rhodamine B hydrazide (RB-hy), which shows special binding activity to Cu(II), through adsorption process to obtain functionalized nanohybrids, Pdots@RB-hy. As thus, a FRET donors/acceptors pair, in which PFBT Pdots act as energy donors while RB-hy-Cu(II) complexes act as energy acceptors were constructed. On the basis of the varies in fluorescence intensities of donors/acceptors in the presence of different amounts of Cu(II), a ratiometric method for sensing Cu(II) has been proposed. The proposed ratiometric Cu(II) sensor shows a good linear detection range from 0.05 to 5MUM with a detection limit of 15nM. Furthermore, using the Pdots@RB-hy-Cu(II) system as signal transducer, a ratiometric sensing for alkaline phosphatase (ALP) activity has also been established with pyrophosphate (PPi) as substrates. The constructed ratiometric sensor of ALP activity displays a linear detection range from 0.005 to 15UL-1 with a detection limit of 0.0018UL-1. The sensor was further successfully used for ALP activity detection in human serum with satisfactory results. PMID- 28012321 TI - Recurrent spontaneous pneumoperitoneum: A surgical dilemma. AB - INTRODUCTION: Spontaneous pneumoperitoneum describes free air within the peritoneal cavity in the absence of iatrogenic causes or a perforated viscus. This report describes a rare case in which despite raised inflammatory markers, a trial of conservative management proved adequate. CASE REPORT: AM is a 36-year old woman who presented multiple times with abdominal pain and radiologically proven pneumoperitoneum. Her medical history included self catheterisation and cerebrovascular stenosis (Moyamoya disease), asymptomatic gallstones, livedo reticularis and peptic ulceration. On her index admission she exhibited raised inflammatory markers and fever. Despite these findings, emboldened by similar presentations in the past with no cause found, she declined surgical intervention with no untoward consequences. DISCUSSION: Most patients presenting with non surgically induced pneumpoeritoneum display signs of peritonism including pyrexia and raised inflammatory markers. For such patients, surgical intervention is usually required to find and rectify the cause. CONCLUSION: A trial of conservative management may be appropriate in patients with spontaneous pneumoperitoneum but it must always be borne in mind that clinical deterioration represents an indication for surgical intervention. PMID- 28012322 TI - RANK/RANKL expression in prostate cancer. PMID- 28012323 TI - Sclerosing angiomatoid nodular transformation of the spleen presenting rapid growth after adrenalectomy: Report of a case. AB - INTRODUCTION: Sclerosing angiomatoid nodular transformation (SANT) is a rare benign lesion with an unknown natural history and pathogenesis. So far fewer than 100 cases were documented, but detailed incidence and prevalence are unknown. PRESENTATION OF CASE: We report a case of SANT of the spleen in a 37-year-old man that showed rapid growth after adrenalectomy for primary aldosteronism. Computed tomography showed a nodule in the spleen that increased in size from 2.0cm to 7.0cm during 3 years of observation. DISCUSSION: This case is reported because data regarding growth rates and natural history of these lesions are limited and few cases have been reported to show the rapid growth progression seen in this case. CONCLUSION: Decreases in glucocorticoid concentrations following adrenalectomy may have contributed to the rapid growth of SANT of the spleen, because SANT is considered to be related to immunoglobulin G4-associated disease. PMID- 28012324 TI - Image-guided implantation of the BonebridgeTM with a surgical navigation: A feasibility study. AB - OBJECTIVE: To access a method of fitting a designated location on the patient's temporal bone by surgically navigating to the Bonebridge implantation. STUDY DESIGN: A patient with unilateral profound hearing loss received early intervention with the Bonebridge implant for binaural hearing. The optimal implant site was determined from computed tomography (CT) images using a three dimensional (3D) simulation software program before the surgery. The pre calculated coordinates from the 3D simulation software program were moved to the Scopis Hybrid Navigation System. After using the surgical navigation system for the surgery, we evaluated the degree of mismatch of the center of the bone conduction-floating mass transducer (BC-FMT) between the computer simulation and the actual drilling. RESULTS: The time required to determine the implant location on the surface of the patient's temporal bone was shortened, and the accuracy of the implantation was high. The coordinates on the 3D simulation system were comparable to the surgical navigation system. The predicted coordinates were replicated exactly upon actual drilling during the surgery, and we could confirm this in preoperative and postoperative images. CONCLUSIONS: Using an image-guided surgical navigation system to aid in the placement of the BC-FMT on the simulated location is a simple procedure and is more effective that finding the exact coordinates. It also shortens the decision time for applying the implant. PMID- 28012325 TI - Short- and long-term outcomes after pancreaticoduodenectomy following total gastorectomy: Report of case series and literature review. AB - PURPOSE: Pancreaticoduodenectomy (PD) following gastrectomy (TG) should be considered challenging even currently although its procedure and clinical value have been being standardized. Short- and long-term outcomes as well as standard reconstruction method following these procedures remain unclear. In order to clarify these issues, we reviewed worldwide English literature and 4 of our own cases of PD for patients with previous TG. METHODS: Clinicopathological variables of 11 cases of PD for patients with previous TG were evaluated. Seven of these 11 were abstracted from a review of worldwide English literature and 4 of 11 were our own cases. RESULTS: 3 cases was reconstructed using Y-limb made in previous TG and afferent loop syndrome (ALS) was observed in 2 of 3, in these cases whereas no cases of ALS were found in cases reconstructed using newly-made Y limb. In cases where PD was indicated for cancer, early cancer death, defined as death related to cancer recurrence observed within 2 years after PD, was observed in 6 of 9 cases. Notably in cases of pancreatic cancer recurrent cancer was diagnosed within 1year after PD in 5 of 7 cases and 4 of these patients died of pancreatic cancer soon after recurrence. CONCLUSION: In cases of PD following TG, previously-made Y-limb should not be used for reconstruction following PD because of probable cause of previously-made Y-limb for ALS. Long-term outcomes of PD after TG seemed unsatisfactory notably in cases of pancreatic cancer and thus application of PD for patients with previous TG should be carefully decided until reasonable explanation for this dismal outcome is obtained. PMID- 28012326 TI - A case report of desmoid tumour-a forgotten aspect of FAP? AB - INTRODUCTION: Desmoid tumours are locally aggressive tumours which are common in Familial Adenomatous Polyposis (FAP). PRESENTATION OF CASE: A 20-year old Familial Adenomatous Polyposis (FAP) patient presented with abdominal pain and distention. Abdominal imaging showed small bowel obstruction and hydronephrosis due to a pelvic mass. This mass showed significant enlargement on repeat imaging, and a diagnostic biopsy confirmed desmoid tumour. The mass was deemed unresectable and he was initially started on sulindac and raloxifene. Repeat imaging however showed further enlargement of the tumour, and therefore vinblastine+methotrexate chemotherapy was commenced, with a good response. DISCUSSION: FAP is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. Gardner's syndrome is also caused by a mutation in the APC gene, and is now considered a different phenotypic presentation of FAP. Desmoid tumours are initially kept under observation while their size remains stable. Treatment options for enlarging desmoids tumours include surgery (first-line), radiotherapy, and systemic therapy with non cytotoxic and cytotoxic therapy. CONCLUSION: FAP patients should be examined regularly post-panprocotocolectomy, since desmoid tumours may arise. The presence of epidermal cysts in this FAP patient suggests a diagnosis of Gardner's syndrome. PMID- 28012327 TI - Incarcerated and eventrated abdominal wall hernia reconstruction with autologous double-layer dermal graft in the field of purulent peritonitis-A case report. AB - INTRODUCTION: Double-layer dermal grafts are used for the management of complicated abdominal wall hernias in obese, high risk patients. The method has not yet been used in case of emergency in septic/dirty environment. CASE REPORT: A 76-year old female patient (BMI 36.7kg/m2) was admitted with mechanical bowel obstruction and sepsis caused by a third time recurred, incarcerated and eventrated abdominal wall hernia. During the emergency surgery perforation of the terminal ileum and the ascending colon was detected, along with a feculent peritonitis and extended abdominal wall necrosis. Extended right hemicolectomy and necrectomy of the abdominal wall were performed. The surgery resulted in an abdominal wall defect measuring 223cm2, for the management of which direct closure was not possible. Using a specific method, an autologous dermal graft was prepared from the redundant skin. The first dermal graft was placed under the abdominal wall with 5cm overlap, and the second layer was placed onto the first layer with 3cm overlap in a perforated fashion. The operating time was 250min. No significant intra-abdominal pressure elevation was measured. No reoperation was performed. On the fifth postoperative day, the patient was mobilised. She was discharged in satisfactory general condition on the 18th postoperative day. There is no recurrent hernia 8 months after the surgery. DISCUSSION: Abdominal wall reconstruction was possible in a necrotic, purulent environment by using a de epithelised autologous double layer dermal graft, without synthetic or biological graft implantation. The advantage of the procedure was cost-effectivity, and the disadvantage was that only in an obese patient is the sufficient quantity of dermal graft available. CONCLUSION: A homogeneous internal and perforated outer dermal graft was suitable for bridging the abdominal gap in the case of an obese, high risk patient. Autologous dermal grafts can be a safe and feasible alternative to biological meshes in emergency abdominal wall surgeries. Evaluation of a case series can be the next cornerstone of the method described above. PMID- 28012328 TI - Oncogenic hypophosphatemic osteomalacia: From the first signal of disease to the first signal of healthy. AB - INTRODUCTION: The physical incapacitation of the oncogenic hypophosphatemic osteomalacia (OHO) can be catastrophic and can lead to deformities, metabolic and organic instability and death. The only positive outcome is through early diagnosis by the clinical suspicion. At this moment, medical center infrastructure is also a keypoint. PRESENTATION OF CASE: This case report is about a 60-year old woman with multiple fractures, gradual loss of strength and muscle mass and limiting deformities in two years of evolution until the diagnostic. DISCUSSION: The lack of knowledge of this disease causes a delay in diagnosis that can bring deformities to the patient, as well as death. Is crucial that is hypothesized to carry out the necessary tests, since they are expensive and not always available. CONCLUSION: This case reinforces the importance to understand the OHO and tumoral search, once this lesion is, in most cases, imperceptible to physical examination or several imaging studies. PMID- 28012329 TI - Total hip arthroplasty for femoral neck fracture with pyoderma gangrenosum patient: A case report. AB - INTRODUCTION: Pyoderma gangrenosum is a rare inflammatory aseptic, ulcerative neutrophilic dermatosis which manifest as skin recurrent, painful ulcers. PRESENTATION OF CASE: A 65-year-old man with pyoderma gangrenosum underwent left total hip arthroplasty because of femoral neck fractures. Glucocorticoid, antibiotic, anticoagulant drug, etc. were given in perioperative period. Complication of pyoderma gangrenosum was prevented successfully in perioperative period. DISCUSSION: No consensus has been reached about whether to use glucocorticoid, as well as the dosage and administration, in perioperative periods for pyoderma gangrenosum patients as prophylactic means of wound complication. CONCLUSION: We herein report a case of pyoderma gangrenosum patient underwent total hip arthroplasty, meanwhile raise the issue of management in perioperative period for pyoderma gangrenosum patient, especially explore series of standardized therapies for this disease during arthroplasty. PMID- 28012330 TI - Synchronous hepatic metastasis and metachronous Krukenberg tumor from advanced colon cancer. A case report with an unexpected disease-free survival. AB - BACKGROUND: In the international literature we have never found a long survival in patients treated for a colon cancer with synchronous hepatic metastases and for a metachronous Krukenberg tumor. PRESENTATION OF CASE: A 46-year old woman for an advanced colon cancer with a synchronous hepatic metastases was subjected to a left hemicolectomy and a resection of liver segment V (R0 resection; T4N2bM1; stage IVa according AJCC 2010). After one year a CT of the abdomen revealed an expansive formation of the left ovary. The patient was subjected to a bilateral ovariectomy, hysterectomy and hiperthermic intraperitoneal chemotherapy (HIPEC). The patient, after several cycles of adjuvant chemotherapy, is disease free 13 years after surgery. DISCUSSION: To our knowledge, in the literature there do not appear to be cases of such disease-free survival. The survival of patient despite the prognostic indexes is discussed. The authors discus the importance of an adequate surgical treatment especially for liver metastases simultaneously treated to colon cancer. The authors also focus on chemotherapy (FOLFOX and then FOLFIRI) performed in a pre-biological era. Furthermore, the degree to which the HIPEC may have had an impact is still unknown, although it seems to be the gold standard for the treatment of the microscopic peritoneal neoplastic remnant. CONCLUSION: The authors emphasize that the long term survival in colon cancer with hepatic and ovarian metastases is possible as long as it has an adequate surgical approach, a tailored chemotherapy and an intensive follow up. Most likely new prognostic markers will have to be identified. PMID- 28012331 TI - Multidisciplinary management of a patient with van der Woude syndrome: A case report. AB - INTRODUCTION: Van der Woude syndrome (VWS) is the most frequent form of syndromic cleft lip and palate (SCLP) accounting for 2% of all patients with CLP. CASE PRESENTATION: We describe the orthodontic treatment of a girl diagnosed with VWS referred by her family dentist for her cosmetic concerns. DISCUSSION: Comprehensive orthodontic treatment, secondary bone graft, distraction osteogenesis (for a deficient maxilla), secondary palatoplasty and excision of lower lip pits, as well as orthodontic and prosthetic procedures may provide a satisfactory outcome. Genetic testing showed a known putative splice site mutation (c.174+1G/A) as the prime cause of VWS in our patient and her family. CONCLUSION: SCLP has significant effects on facial aesthetics and the psychosocial status. Parents should be assessed and counseled appropriately. This condition is treatable in the absence of life threatening systemic anomalies. An interdisciplinary team approach is advocated. PMID- 28012333 TI - A case report of small bowel obstruction from previously undiagnosed lobular breast carcinoma: First in Australian literature. AB - INTRODUCTION: This case report is the first in the Australian literature of a patient, without prior diagnosis, presenting with a bowel obstruction secondary to lobular breast cancer. This highlights a relatively rare cause of bowel obstruction, but also the importance of breast self-examination as a compliment to the current BreastScreen Australia program. PRESENTATION OF CASE: A 67-year old female presented to the Emergency Department with a 48-h history of sharp, constant epigastric pain, vomiting and constipation. The patient proceeded to emergency laparotomy for presumed large bowel obstruction, which revealed a stricture in the distal terminal ileum causing a distal small bowel obstruction. A right hemicolectomy was performed. Histopathology revealed the terminal ileum stricture to be metastatic lobular breast carcinoma. Clinical examination of the patient's right breast revealed a lesion suggestive of the primary malignancy despite a normal ultrasound and mammogram in 2014. After failing to progress, a CT scan was performed which revealed progressive small and large bowel distension. A repeat laparotomy was performed revealing dilated large bowel without obstructing pathology and an intact anastomosis. A loop ileostomy was performed. Following a further febrile episode, the patient decided to withdraw care and the patient passed away three weeks into her admission from suspected intra-abdominal sepsis. DISCUSSION: Breast cancer is becoming the third most common cancer amongst Australian women with a significant burden of disease and mortality. CONCLUSION: Despite the rare presentation, this case reminds the medical community and general population of the importance of breast self examination and the BreastScreen Australia program. PMID- 28012332 TI - Laparoscopic management of severe reflux after sleeve gastrectomy using the LINX(r) system: Technique and one year follow up case report. AB - INTRODUCTION: Management of severe reflux after sleeve gastrectomy (SG) usually requires converting to Roux-en-y gastric bypass (RYGB). We present a case of managing this problem using the LINX(r) system. PRESENTATION OF CASE: In February 2015, we performed a laparoscopic placement of LINX(r) system to treat severe reflux after sleeve gastrectomy on a 25-year-old female. The operative time was 47min. There were no intra or postoperative complications. The hospital stay was one day. The postoperative UGI showed no reflux. Ten days after surgery her Quality of life score (QOL) changed from 64/75 to 7/75 after the LINX(r) placement. One year later the patient continued to enjoy no reflux and stayed off medication. DISCUSSION: Reflux after sleeve gastrectomy is usually managed by conversion to RYGB by most surgeons. This case report opens the door for an alternative management of this problem while maintaining the original sleeve gastrectomy. This technique is reasonably easy to perform in comparison to the conversion to RYGB with less potential post-operative complications. A one year follow up showed good control of reflux without medication. CONCLUSION: Laparoscopic placement of the LINX(r) system to correct severe reflux after sleeve gastrectomy is a safe alternative procedure to conversion to a RYGB. PMID- 28012334 TI - Infarcted mesothelial cyst: A case report. AB - INTRODUCTION: Mesenteric and omental mesothelial cysts are rare, accounting for only 1 in 100,000 hospital admissions for abdominal pain (Tan Jane et al., 2009) [1]. They are often discovered only on CT imaging, which is frequently non definitive in identifying an exact tissue source owing to overlapping radiographic features with other masses (Stoupis et al., 1994) [2]. The symptoms manifested by such masses are also nonspecific, favoring consideration of more frequently encountered problems in the scope of general surgery over cystic masses in the differential diagnosis. Definitive diagnosis of a mesothelial cyst in this case was made on histopathologic examination of a surgically resected specimen. This case is reported in line with SCARE criteria (Dragoslav et al., 2007) [6]. PRESENTATION OF CASE: A 41 year-old male patient presented to an academic teaching hospital with several days of abdominal pain with nausea and vomiting. Initial workup was unremarkable, save for abdominal CT revealing a central mesenteric focus of inflammation. Neuroendocrine tumor was excluded by normal serum octreotide, 5-HIAA, and chromogranin A. A 4*2cm mass was identified and resected on laparoscopy. Histopathologic diagnosis of the specimen was infarcted mesothelial cyst. The patient reported resolution of symptoms and remains well on most recent follow-up. DISCUSSION: The rapid diagnosis of intra abdominal cystic masses is obscured by their rarity, nonspecific symptomatology, and radiographic features that overlap among such masses (Stoupis et al., 1994) [2]. The etiology of symptoms is likely owed to local mass effect exerted by the cyst on surrounding tissues. Continued resolution of symptoms on resection of such a cyst supports this conclusion. CONCLUSION: imaging following an overall unremarkable physical and laboratory workup for this patient's abdominal pain directed our further workup and management efforts towards surgical excision of an intra-abdominal cystic mass. Histopathologic examination of the cyst was ultimately diagnostic of an infarcted mesothelial cyst. PMID- 28012335 TI - Is the absence of Right Hepatic Vein opening into Inferior Vena Cava a contraindication for right lobe liver donation in Living Donor Liver Transplantation? Common hepatic venous trunk-A rare hepatic vein anomaly: A case report and review. AB - INTRODUCTION: In majority of the living liver donors, the left and the middle hepatic veins form a common trunk and the right hepatic vein drains by a separate trunk into the IVC forming two ostial openings. PRESENTATION OF CASE: This report presents a rare challenge to the operating surgeon in which the three major hepatic veins form a common trunk and drain into the IVC through a single ostial opening. It was detected preoperatively by the routine donor imaging studies. DISCUSSION: To our knowledge, this type of rare venous anatomy in the setting of living donor liver transplantation has not been described in the literature before. A few studies have described similar anatomy in the cadaveric liver specimen of some particular ethnicity. CONCLUSION: This type of a rare anomaly poses challenge to the donor operation and requires a sound expertise on the knowledge of hepatic venous anatomy to perform the donor hepatectomy with the appropriate maneuvering. PMID- 28012336 TI - Forgotten CBD stent (102 months) with stone-stent complex: A case report. AB - INTRODUCTION: Choledocholithiasis is presence of stone in Common bile duct (CBD) which can be treated by endoscopy or surgery [1]. Retained foreign bodies like stents forms a nidus for stone formation resulting in pain, fever, jaundice. CASE PRESENTATION: 60 years female patient admitted in surgery ward with features of cholangitis with computed tomography showing cholangitic abscess with dilated common bile duct and sludge around stent in situ. Stone was found at proximal end of stent during surgery. DISCUSSION: Stents may remain without complications or may migrate, and rarely form nidus for stone formation. If kept for long time they lead to bacterial proliferation, biofilm formation and precipitation of calcium bilirubinate presenting as fever, pain, jaundice. Stent-stone complex can be treated endoscopically and surgically [6,7]. As stent can cause stone formation, infection and other complications, timely removal of stent should advised. CONCLUSION: III-effects of stent in-situ should be explained, record should be maintained [8] and patient should be advised regular follow up and stent removal after 6 weeks. PMID- 28012337 TI - Phytobezoar impaction in a Meckel's diverticulum; a rare cause of bowel obstruction: Case report and review of literature. AB - INTRODUCTION: Meckel's diverticulum is the most common anomaly of the gastrointestinal tract, occurring in 1-3% of the general population. The most common complication of Meckel's diverticulum is intestinal obstruction. In this report, we describe a rare cause of intestinal obstruction due to Meckel's; the phytobezoar. After thorough literature review, the authors found about ten individual reports of the same topic. In all these cases, diagnosis was established intra-operatively. CASE PRESENTATION: A forty-seven-year old male presented to the emergency department with a one-day history of abdominal pain associated with vomiting and constipation. Physical examination diagnostic tests revealed features of intestinal obstruction. DISCUSSION: The lifetime risk of complications in patients with a Meckel'sdiverticulum is usually small and occurs only in up to 4%. In adults' intestinal obstruction is the most common complication (40%). CONCLUSION: Complicated Meckel's diverticulum can have different clinical presentations and can cause bowel obstruction. An association with bezoars impaction is possible and it should be suspected in adult patients presenting with bowel obstruction of unknown causes especially those with high vegetarian diet. PMID- 28012338 TI - An unusual case of left hepatectomy for Focal Nodular Hyperplasia (FNH) linked to the use of Anabolic Androgenic Steroids (AASs). AB - INTRODUCTION: Focal Nodular Hyperplasia (FNH) is the second most common benign tumor of the liver. Clinically FNH is asymptomatic and discovered incidentally . The pathogenesis is unclear; FNH is usually asymptomatic. When the tumor is large, it may be painful. Surgery is recommended only in the case of complications such as compression of adjacent organs, lesion progression with tumor size >5cm and presence of symptoms. PRESENTATION OF CASE: A 30 years old man, was evaluated during a routine visit, for diffuse abdominal pain and weight loss; Abdominal ultrasound showed no evidence of biliary obstruction but the US shows a hypoechoic, well defined focal lesion in the left liver. For a more accurate diagnosis a Magnetic Resonance detected a focal area about 14*9 cm in diameter, hypointense. Liver biopsy was not done.We could not diagnose it definitively as FNH from the results of imaging studies; so for the size of symptomatic lesion, the undefined diagnosis of FNH ,and due to the great increase in the size of the mass located in the left lobe, during such a short period , the surgery was been recommended. DISCUSSION: FNH is the second most common hepatic lesion, but clinically relevant cases of FNH are rare with a reported prevalence in US studies of 0,03%. In our case the young patient was taking dietary supplements including anabolic androgenic steroids (AASs), carnitine and l-arginine. CONCLUSION: The particularity of our case is the increasing of the lesion in two years in which the patient made use of anabolic steroids. under use of . This could be the explanation for increasing of nodule. PMID- 28012339 TI - Rare nodular malignant melanoma of the heel in the Caribbean: A case report. AB - INTRODUCTION: Malignant melanoma of the heel is a rare melanoma subtype with incidence rates that reflect the complex relationship between sun exposure at certain geographic locations, individual melanin levels and overall melanoma risk. It is oftentimes characterized by poor prognosis because of delays in presentation resulting in longitudinal tumor invasion, lymph node involvement and metastasis. PRESENTATION OF CASE: A 59-year-old woman was admitted to the Eric Williams Medical Sciences Complex, Trinidad and Tobago with a 5mm pruritic lesion on her left heel. At presentation, the lesion was asymmetric with border irregularities, color heterogeneity, with dynamics in elevation and overall size. She was subsequently diagnosed with malignant melanoma with left inguinal lymphadenopathy. A single stage wide local excision (WLE) of the left heel lesion with a split-thickness skin graft (STSG) and a left inguinal lymphadenectomy were performed. Dacarbazine (Bayer) was administered post operatively. DISCUSSION: Globally, the incidence of malignant melanoma is rapidly increasing, particularly, in countries like Trinidad and Tobago with a significant population of non-fair skinned individuals. There is need for strategic initiatives to increase patient adherence in these populations. CONCLUSION: The rarity of malignant heel melanomas heightens the need for increased patient awareness and greater clinical surveillance to ensure early diagnosis and treatment. PMID- 28012340 TI - Role of Computed tomography in predicting prognosis of Hepatic portal venous gas. AB - BACKGROUND: The aim of this study was to report through 13 cases the particularities of abdominal computed tomography (CT) aspects of hepatic portal venous gas (HPVG) and its correlation with patient prognosis. METHODS: We analyzed abundance of HPVG and its association with pneumatosis intestinalis (PI) in correlation with fatal outcome using chi-square tests. RESULTS: Etiologies were mesenteric infarction (n=5), sigmoid diverticulitis (n= 1), septic shock (n=1), postoperative peritonitis (n=1), acute pancreatitis (n=1), iatrogenic cause (n=3) and idiopathic after a laparotomy (n=1). The outcome was fatal in for 6 patients. Abundance of HPV was expressed in total number of hepatic segments involved. The involvement of 3 or more segments was a sensitive sign for lethal outcome with high sensitivity (100%) but it was not specific (50%). Negative predictive value of this sign was 100% (p<=0.005). Positive predictive value of PI for death was 100% (p<=0.001). DISCUSSION: Abundance of HPVG is correlated with prognosis. The presence of PI announces poor outcome Negative predictive value of presence of HPVG in 3 or more segments is interesting. Predicting prognosis with CT can help surgeons to assess the most adequate treatment. Iatrogenic causes are increasingly described after interventional radiology procedures with favorable course. CONCLUSION: The first etiology radiologists should look for in front of HPVG involving more than 3 hepatic segments and associated with PI is intestinal necrosis which announces a poor prognosis. This study shows that outside of shock situations, HPVG involving 2 or less hepatic segments without PI predicts a good outcome. PMID- 28012341 TI - Walking cadence affects rate of plantar foot temperature change but not final temperature in younger and older adults. AB - This study examined the relationship between (1) foot temperature in healthy individuals and walking cadence, (2) temperature change at different locations of the foot, and (3) temperature change and its relationship with vertical pressures exerted on the foot. Eighteen healthy adult volunteers (10 between 30 and 40 years - Age: 33.4+/-2.4years; 8 above 40 years - Age: 54.1+/-7.7years) were recruited. A custom-made insole with temperature sensors was placed directly onto the plantar surface of the foot and held in position using a sock. The foot was placed on a pressure sensor and the whole system placed in a canvas shoe. Participants visited the lab on three separate occasions when foot temperature and pressure data were recorded during walking on a treadmill at one of three cadences (80, 100, 120steps/min). The plantar foot temperature increased during walking in both age groups 30-40 years: 4.62+/-2.00 degrees C, >40years: 5.49+/ 2.30 degrees C, with the rise inversely proportional to initial foot temperature (30-40 years: R2=-0.669, >40years: R2=-0.816). Foot temperature changes were not different between the two age groups or the different foot locations and did not depend on vertical pressures. Walking cadence affected the rate of change of plantar foot temperature but not the final measured value and no association between temperature change and vertical pressure was found. These results provide baseline values for comparing foot temperature changes in pathological conditions which could inform understanding of pathophysiology and support development of evidence based healthcare guidelines for managing conditions such as diabetic foot ulceration (DFU). PMID- 28012342 TI - Synthesis and molecular modelling studies of phenyl linked oxadiazole phenylhydrazone hybrids as potent antileishmanial agents. AB - Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6-35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4 dihydroxy analog with IC50 value of 0.95 +/- 0.01 MUM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC50 = 7.02 +/- 0.09 MUM). The current series 6-35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC50 values ranging between 0.95 +/- 0.01-78.6 +/- 1.78 MUM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations. PMID- 28012343 TI - Hydroxylated biphenyls as tyrosinase inhibitor: A spectrophotometric and electrochemical study. AB - A small collection of C2-symmetry hydroxylated biphenyls was prepared by straightforward methods and the capability to act as inhibitors of tyrosinase has been evaluated by both spectrophotometric and electrochemical assays. Our attention was focused on the diphenolase activity of this enzyme characterized by the absence of the characteristic lag time of enzymatic reaction of its monophenolase activity. To this purpose, we evaluated the capability of tyrosinase to oxidize a natural o-diphenol substrate to o-quinone analyzing the changes in the UV-Vis spectrum of a solution of caffeic acid and the reduction of the cathodic current in a tyrosinase-biosensor, respectively. Results of both the methods were comparable. Most of the compounds possessed higher inhibitory activity compared to compound 1, a known hydroxylated biphenyl inhibitor of tyrosinase. PMID- 28012344 TI - An efficient anticoagulant candidate: Characterization, synthesis and in vivo study of a fondaparinux analogue Rrt1.17. AB - Fondaparinux, a synthetic pentasaccharide anticoagulant based on heparin antithrombin-binding domain, is derived from a chemical synthesis with more than 50 steps. Herein, we identified nine analogues separated from commercially available crude fondaparinux sodium, and tested their anticoagulant activity in vitro. Based on the activity results, the most active derivative Rrt1.17 was chemically synthesized. Biological properties in vitro and in vivo indicated that the well-defined derivative Rrt1.17 was a more efficient anticoagulant candidate compared with fondaparinux. PMID- 28012345 TI - Exploring the resistance mechanism of imipenem in carbapenem hydrolysing class D beta-lactamases OXA-143 and its variant OXA-231 (D224A) expressing Acinetobacter baumannii: An in-silico approach. AB - Acinetobacter baumannii (A. baumannii), is a Gram negative, coccobacilli and is associated with nosocomial infections. The bacterium has developed resistance to all known classes of antibiotics. Multi-drug resistant A. baumannii infections have been treated with the carbapenem group of antibiotics like imipenem and meropenem. Recent reports indicate that A. baumannii has acquired resistance to imipenem due to the secretion of carbapenem hydrolysing class D beta-lactamases (CHDLs). Such CHDLs found in carbapenem resistant A. baumannii belongs to OXA-143 and its variant OXA-231, which has Alanine (A) in place of Aspartic acid (D) at sequence position 224. The mutation of the OXA-231 CHDL alters the catalytic activity of the enzyme. Hence, the present study was carried out to find the probable mechanism of imipenem resistance in OXA-143 and OXA-231 (D224A) CHDLs expressing A. baumannii by employing molecular docking and dynamics. Methods Our study reveals that OXA-143 CHDL-imipenem complex has more binding affinity than OXA-231 (D224A) CHDL-imipenem complex. Our results indicate that there is a strong binding affinity of OXA-143 with imipenem when compared with OXA-243 and this mechanism might be the probable reason for imipenem resistance in OXA-143 expressing A. baumannii strains. PMID- 28012346 TI - PET studies in non-human primates: Choosing drug doses. PMID- 28012347 TI - Enhanced dendritic morphogenesis of adult hippocampal newborn neurons in central 5-HT-deficient mice. AB - Serotonin (5-HT) plays an important role in regulating adult hippocampal neurogenesis. Chronic administration of selective 5-HT reuptake inhibitors (SSRIs), which up-regulates extracellular 5-HT concentration, accelerates the maturation of adult-born hippocampal neurons. It is unknown, however, about effects of central 5-HT-deficiency on the dendritic morphogenesis of these newborn neurons. Here, we address this question using two central 5-HT-deficient mouse models, Tph2 conditional knockout mice (CKO) losing central 5-HT from embryonic stage, and Pet1-Cre;Rosa26-DTR (diphtheria toxin receptor) mice lacking central 5-HT neurons exclusively in adulthood. The dendritic length of hippocampal newborn neurons is dramatically increased in these mice. Our findings indicate that reducing central 5-HT can accelerate the dendritic maturation of adult-born neurons, thus revealing a new role of central 5-HT in regulating adult hippocampal neurogenesis. PMID- 28012348 TI - Utility of post-therapy brain surveillance imaging in the detection of primary central nervous system lymphoma relapse. AB - BACKGROUND: The optimal follow-up strategy for primary central nervous system lymphoma (PCNSL) patients after first-line therapy is unclear. The goal of this study is to determine the utility of planned brain surveillance imaging in the detection of relapse in a retrospective cohort of PCNSL patients. METHODS: Patients were consecutive PCNSL cases treated in Leon Berard Cancer Centre, Lyon, France, from 1985 to 2011. Histology was diffuse large B-cell lymphoma in 94%. Patients were treated by methotrexate (92%) and cytarabine (63%) based chemotherapy followed by radiotherapy for 108 patients (51%). Clinical records were reviewed for details at relapse and relationship to planned imaging. The imaging follow-up strategy was performed according to each treating physicians. RESULTS: Among 209 PCNSL patients, 127 complete response patients entered in post treatment observation and 63 (50%) subsequently relapsed. Among the 125 evaluable patients, the majority of relapses (N = 49, 80%) was asymptomatic and identified before the planned brain imaging. Surveillance imaging detected relapses before symptoms in 12 patients who entered in post-therapy observation (10%). The median number of brain imaging during the follow-up was 7 (0-13). A total of 819 MRI/CT scan were performed leading to the detection of 12 asymptomatic relapses. The one year OS rates were 41% and 58% for symptomatic and non-symptomatic relapses, respectively (P = 0.21). CONCLUSION: The majority of PCNSL relapses occurred outside planned follow-up with no difference in patient outcome between symptomatic and asymptomatic relapses. The role of brain imaging for the detection of relapses in the follow-up of PCNSL patients remains to be clarified. PMID- 28012349 TI - Is the prevalence of major depression increasing in the Canadian adolescent population? Assessing trends from 2000 to 2014. AB - BACKGROUND: Major depressive disorder is a relatively common diagnosis with onset across the lifespan. There is a recent belief that major depressive episodes (MDE) are increasing in adolescence; however, it is not clear if this is truly an increase in prevalence or reflective of other causes such as change in diagnostic patterns. This study aimed to determine whether evidence supports an epidemic of MDE in Canadian adolescents. METHODS: Past year MDE prevalence estimates were derived from a series of nationally representative surveys. Random effects meta regression and graphical analyses were used to evaluate trends. A post hoc analysis compared trends in MDE prevalence to trends in self-reported mood disorder diagnosis (made by a health professional). The sample was split into 9 birth cohorts to examine whether MDE prevalence increased in more recent cohorts. RESULTS: Prevalence of MDE did not significantly change between 2000 and 2014 (beta=0.001; p=0.532), and there was no modification of trends by sex or age. However, prevalence of self-reported mood disorder diagnosis by a health professional increased from 2003 to 2014 (beta=0.001; p=0.024). There was no indication that MDE prevalence differed by birth cohort. LIMITATIONS: Limitations include reduced precision in subgroup analyses, lack of clinical judgement in the structured diagnostic interview, and inability to differentiate mild, moderate and severe episodes of depression. CONCLUSION: These findings do not support an epidemic of MDE in adolescents, however as more individuals report diagnoses by a health professional, future policy may need to incorporate an increase in need of mental health services. PMID- 28012351 TI - The association between mental health problems and menstrual cycle irregularity among adolescent Korean girls. AB - BACKGROUND: Menstrual cycle irregularity is common among adolescents and can induce mental health problems such as stress, depression, and suicidal ideation. We examined the association between mental health problems and menstrual cycle irregularity among adolescent Korean girls. METHODS: This population-based cross sectional study was on 808 female adolescents (12-18 years of age) participating in the 2010-2012 Korean National Health and Nutrition Examination Survey. Psychological stress, depressive mood, suicidal ideations, suicide attempts, and psychological counseling were assessed through questionnaires and surveys, and hierarchical multivariable logistic regression analysis was performed. RESULTS: The risk of menstrual cycle irregularity tended to increase, as the number of mental health problems increased (P for trend=0.016). High stress levels, depressive mood, and psychological counseling were associated with increased risks of menstrual cycle irregularity (odd ratio [95% confidence interval]=1.88 [1.1-3.21], 2.01 [1.01-4.03], and 2.92 [1.16-7.34], respectively) even after adjusting for age, body mass index, alcohol consumption, smoking status, physical activity, hemoglobin level, monthly household income, weight loss attempts, age at menarche, and sleep duration. Suicidal ideation was not significantly associated with menstrual cycle irregularity. LIMITATIONS: Menstrual irregularity was evaluated based solely on subjects' self-reports, which are subject to their subjective perceptions and appraisal. Cross-sectional design and retrospective data could not draw causal relationship. CONCLUSIONS: Positive associations were observed between mental health problems and menstrual cycle irregularity among adolescent Korean girls. More attention should be paid towards mental health, to improve menstrual cycle regularity and help prevent related chronic diseases later in life. PMID- 28012350 TI - Parents' behavioral inhibition moderates association of preschoolers' BI with risk for age 9 anxiety disorders. AB - BACKGROUND: Temperamental behavioral inhibition (BI) in children predicts later anxiety disorders. However, many children with BI do not develop anxiety disorders, suggesting the importance of identifying moderating factors. The current study examined whether parents' history of BI moderates the associations between preschoolers' BI and anxiety disorders at age 9. METHODS: The sample was 392 children and their parents from the community. Child BI was measured at age 3 using observational (Laboratory Temperament Assessment Battery; Lab-TAB) and parent report (Behavior Inhibition Questionnaire; BIQ) measures. In addition, both parents reported on their own history of childhood BI using the Retrospective Measure of Behavioral Inhibition (RMBI). When the children were 9 years old, a parent and the child were interviewed using the Kiddie Schedule for the Affective Disorders and Schizophrenia - Present and Lifetime version (K-SADS PL). RESULTS: Parents' reports of their own BI moderated the associations of both observed and parent-reported child BI at age 3 with children's anxiety disorders at age 9. Among children whose parents reported having had higher childhood BI, those who exhibited high BI at age 3 were more likely to meet criteria for anxiety disorders at age 9. LIMITATIONS: The major limitation is the use of a retrospective measure of parental BI. CONCLUSIONS: These findings demonstrate that parents' histories of childhood BI moderate the association between their young children's BI and subsequent anxiety disorders. Thus, parental BI appears to identify a subgroup of BI children at particularly high risk for developing anxiety disorders by late childhood. PMID- 28012352 TI - Attention bias in older women with remitted depression is associated with enhanced amygdala activity and functional connectivity. AB - BACKGROUND: Cognitive bias is a common characteristic of major depressive disorder (MDD) and is posited to remain during remission and contribute to recurrence risk. Attention bias may be related to enhanced amygdala activity or altered amygdala functional connectivity in depression. The current study examined attention bias, brain activity for emotional images, and functional connectivity in post-menopausal women with and without a history of major depression. METHODS: Attention bias for emotionally valenced images was examined in 33 postmenopausal women with (n=12) and without (n=21) a history of major depression using an emotion dot probe task during fMRI. Group differences in amygdala activity and functional connectivity were assessed using fMRI and examined for correlations to attention performance. RESULTS: Women with a history of MDD showed greater attentional bias for negative images and greater activity in brain areas including the amygdala for both positive and negative images (pcorr <0.001) than women without a history of MDD. In all participants, amygdala activity for negative images was correlated with attention facilitation for emotional images. Women with a history of MDD had significantly greater functional connectivity between the amygdala and hippocampal complex. In all participants amygdala-hippocampal connectivity was positively correlated with attention facilitation for negative images. LIMITATIONS: Small sample with unbalanced groups. CONCLUSIONS: These findings provide evidence for negative attentional bias in euthymic, remitted depressed individuals. Activity and functional connectivity in limbic and attention networks may provide a neurobiological basis for continued cognitive bias in remitted depression. PMID- 28012353 TI - Impact of timing of cranioplasty on hydrocephalus after decompressive hemicraniectomy in malignant middle cerebral artery infarction. AB - OBJECTIVE: Patients with malignant middle cerebral artery infarction frequently develop hydrocephalus after decompressive hemicraniectomy. Hydrocephalus itself and known shunt related complications after ventriculo-peritoneal shunt implantation may negatively impact patients outcome. Here, we aimed to identify factors associated with the development of hydrocephalus after decompressive hemicraniectomy in malignant middle cerebral artery infarction. PATIENTS AND METHODS: A total of 99 consecutive patients with the diagnosis of large hemispheric infarctions and the indication for decompressive hemicraniectomy were included. We retrospectively evaluated patient characteristics (gender, age and selected preoperative risk factors), stroke characteristics (side, stroke volume and existing mass effect) and surgical characteristics (size of the bone flap, initial complication rate, time to cranioplasty, complication rate following cranioplasty, type of implant, number of revision surgeries and mortality). RESULTS: Frequency of hydrocephalus development was 10% in our cohort. Patients who developed a hydrocephalus had an earlier time point of bone flap reimplantation compared to the control group (no hydrocephalus=164+/-104days, hydrocephalus=108+/-52days, p<0.05). Additionally, numbers of revision surgeries after cranioplasty was associated with hydrocephalus with a trend towards significance (p=0.08). CONCLUSION: Communicating hydrocephalus is frequent in patients with malignant middle cerebral artery infarction after decompressive hemicraniectomy. A later time point of cranioplasty might lead to a lower incidence of required shunting procedures in general as we could show in our patient cohort. PMID- 28012354 TI - Microsurgical resection of juxtafacet cysts without concomitant fusion-Long-term follow-up of 74 patients. AB - OBJECT: We report on our experience with treating juxtafacet cysts focusing on clinical outcome, rate of recurrence and secondary surgery, especially fusion. METHODS: This retrospective study evaluates patients who underwent surgical resection of juxtafacet cysts without concomitant fusion from 2002 to 2013 with a minimum follow-up of one year. RESULTS: Complete follow-up is available in 74 patients. Mean follow-up in all 74 patients was 69+/-34months (range, 14-140 months). Mean ODI was 14.9%. 68 patients (91.9%) were pleased with the results and would undergo surgery again. Three patients (4.1%) underwent secondary resection because of cyst recurrence at the same site. Four patients (5.4%) needed secondary fusion. CONCLUSIONS: In patients without evident clinical and radiological criteria of instability we regard surgical resection of juxtafacet cysts without concomitant fusion as adequate primary treatment due to good outcome and low incidence of secondary symptomatic instability. PMID- 28012355 TI - A hero in the strife. PMID- 28012356 TI - Radiogenomic evaluation of lung cancer - Are there imaging characteristics associated with lung adenocarcinomas harboring BRAF mutations? AB - INTRODUCTION: We studied computed tomography (CT) features associated with BRAF mutated lung cancer. MATERIALS AND METHODS: CT features of BRAF mutated lung cancers were compared to stage matched lesions without BRAF mutation. RESULTS: 47 (25%) patients with BRAF mutation and 141 (75%) without BRAF mutation were included. BRAF lesions were most frequently solid 37 (84%), spiculated 22 (50%), and peripheral 37 (84%). No feature of the primary tumor was significantly different between BRAF and non-BRAF groups. BRAF patients were more likely than KRAS patients to have pleural metastases [5 (11%) vs 0 (0%), p=0.045]. CONCLUSION: No feature of the primary tumor differentiates BRAF lesions from non BRAF lesions. PMID- 28012357 TI - Comparison of 2D single-shot turbo-spin-echo and spin-echo echo-planar diffusion weighted brain MRI at 3.0 Tesla: preliminary experience in children. AB - PURPOSE: To qualitatively compare a 2D single-shot turbo-spin-echo (ssTSE) diffusion-weighted imaging MRI technique with a spin-echo echo-planar imaging (SE EPI) approach in pediatric neuroimaging. METHODS: Images were acquired at 3T in 15 patients (10.6+/-6.0years). A neuroradiologist rated the data based on the severity of image artifacts from air-tissue interfaces and devices such as ventriculoperitoneal shunts and orthodontia, and whether their presence affected diagnostic image quality. RESULTS: ssTSE was preferred over SE-EPI in diagnostic image quality and exhibited fewer clinically relevant artifacts (p<0.01). CONCLUSION: ssTSE provides superior diffusion-weighted brain images at 3T, particularly in the presence of orthodontia and shunts. PMID- 28012358 TI - Cystic metastatic lymph nodes in malignant melanoma: a case report. AB - Melanoma is a rare type of skin cancer with a high mortality rate. Local invasion and metastatic spread are primarily responsible for the morbidity and mortality of melanoma. While metastatic lesions vary from cystic to solid, cystic metastases can be challenging to diagnose. Up to date, there are only a few published studies that describe cystic metastases in melanoma and other conditions such as lymphoma, squamous cell carcinoma and thyroid papillary carcinoma. We describe a case of cystic metastatic axillary lymph nodes in a patient with subungual acral lentiginous melanoma and the challenges to reaching an accurate diagnosis. PMID- 28012359 TI - Changes of in vitro potency of anticoagulant drugs are similar between patients with cirrhosis due to alcohol or non-alcoholic fatty liver disease. PMID- 28012360 TI - Nursing students' attendance at learning activities in relation to attainment and passing courses: A prospective quantitative study. AB - BACKGROUND: Students' motivation and ways of engaging in their schoolwork are important for their performance, including passing exams. Attendance at learning activities has also been argued to be of major importance, although no causal relationship with passing exams has been established in nursing education. OBJECTIVES: The aim of this study was to describe the impact of attendance at nonmandatory learning activities on attainment, in terms of passing or failing of exams, in nursing education courses including both mandatory and non-mandatory activities. DESIGN: A prospective quantitative design. SETTING: The nursing education programme at a Swedish university. PARTICIPANTS: Nursing students (n=361) from two courses and four classes within the nursing programme. METHODS: Attendance was registered at every non-mandatory teaching activity by asking the students to note their attendance on a list. Data such as sex, age, and whether the students had passed the exam were also collected for each course and each semester separately. RESULTS: Increased participation was associated with an increasing proportion of students passing the exam. The chance of passing the exam increased by 13% for every additional learning occasion attended. Logistic regression showed an OR of 5.4 for an attendance of 100%. CONCLUSIONS: An increase in attendance gave a higher proportion of exam passes. Encouraging students to attend non-mandatory learning activities could be of value, and potentially contribute to an increased graduation rate for nursing students. PMID- 28012361 TI - How are we assessing near-peer teaching in undergraduate health professional education? A systematic review. AB - BACKGROUND: Near Peer teaching (NPT) is reported as an effective pedagogical approach to student learning and performance. Studies in medicine, nursing and health sciences have relied mainly on self-reports to describe its benefits, focusing on psychomotor and cognitive aspects of learning. Despite increasing research reports on peer teaching internationally, little is known about the various domains of learning used in assessment of performance and objective learning outcomes of NPT. OBJECTIVE: To determine the domains of learning and assessment outcomes used in NPT in undergraduate health professional education. METHODS: Quantitative systematic review was conducted in accord with the PRISMA protocol and the Joanna Briggs Institute processes. A wide literature search was conducted for the period 1990-November 2015 of fourteen databases. Grey literature was undertaken from all key research articles. Studies meeting the inclusion criteria were eligible for consideration, including measured learning outcomes of near-peer teaching in undergraduate education in nursing, medicine and health sciences. Set limitations included publications after 1990 (2015 inclusive), English language and objective learning outcomes. A quality appraisal process involving two independent reviewers was used to analyse the data. RESULTS: Of 212 selected articles, 26 were included in the review. Terminology was confusing and found to be a barrier to the review process. Although some studies demonstrated effective learning outcomes resulting from near-peer teaching, others were inconclusive. Studies focused on cognitive and psychomotor abilities of learners with none assessing metacognition, affective behaviours or learning outcomes from quality of understanding. CONCLUSION: The studies reviewed focused on cognitive and psychomotor abilities of learners. Even though evidence clearly indicates that metacognition and affective behaviours have direct influence on learning and performance, indicating more research around this topic is warranted. Methodological quality of the studies and lack of theoretical frameworks underpinned by educational psychology may have contributed to inconsistencies in learning outcomes reported. PMID- 28012362 TI - Quantification and simultaneous evaluation of the bioactivity of antibody produced in CHO cell culture-The use of the ectodomain of FcgammaRI and surface plasmon resonance-based biosensor. AB - A surface plasmon resonance (SPR)-based assay has been developed in order to quantify the monoclonal antibody (Mab) Trastuzumab within the supernatant of a mammalian cell culture using the ectodomain of FcgammaRI (CD64) and confirm Mab bioactivity, i.e. binding to its antigen Her2, in a single biosensing experiment. Under partial mass transport limitation, we were able to quantify Mab present in unpurified samples taken throughout the cell culture. While Mab capture on the biosensor surface confirmed the ability of its Fc region to bind to FcgammaRI, the binding activity of its Fab region was also tested by injecting increasing concentrations of the Mab antigen (Her2). The kinetics of the interactions we recorded from 48h post transfection until the end of the culture, were superimposable, which highly suggested that the quality attributes of the antibody were conserved throughout the process. This SPR methodology is thus of great interest for atline quality control analysis during Mab production campaign. PMID- 28012363 TI - Quantitative limitations to photosynthesis in K deficient sunflower and their implications on water-use efficiency. AB - Potassium (K) is crucial for crop growth and is strongly related to stress tolerance and water-use efficiency (WUE). A major physiological effect of K deficiency is the inhibition of net CO2 assimilation (AN) during photosynthesis. Whether this reduction originates from limitations either to photochemical energy conversion or biochemical CO2 fixation or from a limitation to CO2 diffusion through stomata and the leaf mesophyll is debated. In this study, limitations to photosynthetic carbon gain of sunflower (Helianthus annuus L.) under K deficiency and PEG- induced water deficit were quantified and their implications on plant- and leaf-scale WUE (WUEP, WUEL) were evaluated. Results show that neither maximum quantum use efficiency (Fv/Fm) nor in-vivo RubisCo activity were directly affected by K deficiency and that the observed impairment of AN was primarily due to decreased CO2 mesophyll conductance (gm). K deficiency additionally impaired leaf area development which, together with reduced AN, resulted in inhibition of plant growth and a reduction of WUEP. Contrastingly, WUEL was not affected by K supply which indicated no inhibition of stomatal control. PEG-stress further impeded AN by stomatal closure and resulted in enhanced WUEL and high oxidative stress. It can be concluded from this study that reduction of gm is a major response of leaves to K deficiency, possibly due to changes in leaf anatomy, which negatively affects AN and contributes to the typical symptoms like oxidative stress, growth inhibition and reduced WUEP. PMID- 28012364 TI - Overexpression of tomato SlGGP-LIKE gene improves tobacco tolerance to methyl viologen-mediated oxidative stress. AB - Ascorbate (AsA) is very important in scavenging reactive oxygen species in plants. AsA can reduce photoinhibition by xanthophyll cycle to dissipate excess excitation energy. GGP is an important enzyme in AsA biosynthesis pathway in higher plants. In this study, we cloned a gene, SlGGP-LIKE, that has the same function but different sequence compared with SlGGP. The function of SlGGP-LIKE gene in response to oxidative stress was investigated using transgenic tobacco plants overexpressed SlGGP-LIKE under methyl viologen treatment. After oxidative stress treatment, transgenic tobacco lines exhibited higher levels of reduced AsA content and APX activity than WT plants. Under oxidative stress, transgenic tobacco plants accumulated less ROS and exhibited lower degrees of REC and MDA. Consequently, relatively higher levels of Pn, Fv/Fm, de-epoxidation status of xanthophyll cycle and D1 protein were maintained in transgenic tobacco plants. Hence, overexpression of SlGGP-LIKE gene enhances AsA biosynthesis and can alleviate the photoinhibition of PSII under oxidative stress. PMID- 28012365 TI - New approaches towards discrimination of fresh/chilled and frozen/thawed chicken breasts by HADH activity determination: Customized slope fitting and chemometrics. AB - Fresh/chilled chicken breasts retail at a higher price than their frozen/thawed counterparts. Verification of the fresh/thawed status of chicken meat is determined by measuring beta-hydroxyacyl-Coenzyme A-hydrogenase (HADH) activity present in meat intra-cellular liquids spectrophotometrically. However, considerable numbers of reference samples are required for the current arithmetic method, adding to laboratory costs. Therefore, two alternative mathematical approaches which do not require such reference samples were developed and evaluated: curve fitting and multivariate classification. The approaches were developed using 55 fresh/thawed fillet samples. The performance of the methods was examined by an independent validation set which consisted of 16 samples. Finally, the approach was tested in practice in a market study. With the exception of two minor false classifications, both newly proposed methods performed equally well as the classical method. All three methods were able to identify two apparent fraudulent cases in the market study. Therefore, the experiments showed that the costs of HADH measurements can be reduced by adapting alternative mathematics. PMID- 28012366 TI - Influence of low-level laser therapy on the healing process of autogenous bone block grafts in the jaws of systemically nicotine-modified rats: A histomorphometric study. AB - OBJECTIVE: To analyze the influence of low-level laser therapy (LLLT) on the bone healing process of autogenous bone block grafts installed in nicotine systemically modified rats. METHODS: Seventy-two rats (Wistar) were randomly assigned into 4 groups (n=18). SS-BG: saline application+bone graft. SS-BG/LLLT: saline application+bone graft+LLLT. NIC-BG: nicotine application+bone graft. NIC BG/LLLT: nicotine application+bone graft+LLLT. After 30days of application of solutions, all animals received autogenous bone block graft in the jaw, with the donation from the parietal bone's calvarial area. Treatment with LLLT was in bed graft interface, after accommodation of the graft. The animals in each group were sacrificed at 7, 14, and 28days after graft surgery. RESULTS: The histologic analyses of NIC-BG group depicted a delay of osteogenic activity in the recipient bed-graft interface and the irradiation of tissue with LLLT provided better bone healing. The histometric analysis revealed that SS-BG/LLLT and NIC-BG/LLLT groups showed increased bone formation compared to BG-SS and NIC-BG groups, after 14days (SS-BG 24.94%+/-13.06% versus SS-BG/LLLT 27.53%+/-19.07% and NIC-BG 14.27%+/ 2.22% versus NIC-BG/LLLT 24.37%+/-11.93%) and 28days (SS-BG 50.31%+/-2.69% versus SS-BG/LLLT 58 19%+/-12.32% and NIC-BG 36.89%+/-8.40% versus NIC-BG/LLLT 45.81%+/ 6.03%). CONCLUSION: Nicotine harms bone formation in the bed-graft interface and LLLT action can mitigate this. PMID- 28012368 TI - Selectivity of plant extracts for Trichogramma pretiosum Riley (Hym.: Trichogrammatidae). AB - We evaluated the selectivity of three plant extracts with potential insecticidal effects for the parasitoid Trichogramma pretiosum Riley, which is commonly used in biological pest control. The plant extracts assayed were an acetone extract of Toona ciliata M. Roem., commercial neem oil, and a nanoencapsulated formulation of neem oil (NC40). The toxicity of the plant extracts to T. pretiosum was evaluated according to the recommendations of the International Organization for Biological Control- IOBC Working Group. We assessed the susceptibility of adults of the maternal and F1 generations and immature stages of T. pretiosum to the extracts. Females exposed to egg cards treated with commercial neem oil parasitized almost 70% fewer eggs than control eggs treated with water; and this extract was therefore classified as slightly harmful. When the eggs were offered to females 24h after treatment with neem oil and aqueous NC40, the parasitism rate also decreased, and the two extracts were classified as slightly harmful. Adult emergence was lower for parasitoids that fed on host eggs offered 24h after the treatment with the T. ciliata extract, which was considered slightly harmful. The emergence of T. pretiosum from eggs, larvae and pupae treated with the different plant extracts, did not decrease compared to development stages treated with the water control. The use of T. pretiosum, combined with the application of an ethanol extract of T. ciliata and a nanoencapsulated formulation of neem, appears to be feasible in view of these low toxicity indices. PMID- 28012367 TI - Effect of lead (Pb) on antioxidation system and accumulation ability of Moso bamboo (Phyllostachys pubescens). AB - The antioxidation system and accumulation ability of Moso bamboo (Phyllostachys pubescens), which is a valuable remediation material with large biomass and rapid growth rate were studied in hydroponics and pot experiments. In hydroponics experiment, TBARS concentrations and SOD activities decreased with increase of Pb treatments. The activities of POD boost up with elevated Pb treatments, and reached peak level with application of 400MUM Pb. Proline concentrations reduced with application of 20MUM Pb and then enhanced consistently with application of 100 and 400MUM Pb. The biomass of Moso bamboo improved with increase of Pb treatments upto 400mgkg-1, and then decreased with application of each additional increment of Pb in pot experiment. Application of 800mgkg-1 Pb showed significant increase of photosynthetic pigments, however, non significant variation was observed for other treatments. The Pb concentration in roots, stems and leaves attained 523mgkg-1, 303mgkg-1 and 222mgkg-1 respectively with application of 1600mgkg-1 Pb compared with control. Analysis of TEM-EDX revealed that Pb in cell was mostly concentrated in cytoplasm then in cell wall and followed by vacuole. It is concluded that Moso bamboo may be potential remediation species for phytoremediation in low Pb contaminated soils. PMID- 28012369 TI - Contamination and health risks of heavy metals in street dust from a coal-mining city in eastern China. AB - We collected street dust from Huainan, a typical coal-mining city in China, to investigate the contamination features and health risks of heavy metals. Concentrations of Co, Cr, Cu, Pb, As, and Sb were generally low to moderate, while pollution levels of Cd and Hg were moderate to high. Concentrations of Cd and Hg were associated with considerable health risks at 64.3% and 58.6% of sites, respectively. In particular, about a fifth of samples had associated high risks as a result of Hg contamination levels. Relative to other urban areas, the street dust from the mining area had no more severe metal pollution, which might be partly attributed to the deposition of coal dust onto street dusts. A source assessment indicated that metals in dust form Huainan were mainly derived from vehicular-related activities, industrial emissions, weathering of coal dust and natural soils, and coal combustion. Although the health risk levels from exposure to individual metals in dusts were low, the non-carcinogenic risks from multiple metals to local children exceeded the acceptable level (1.0), suggesting that the overall risk from exposure to multiple metals in dust is concerning. PMID- 28012370 TI - Determinants of theory of mind performance in Alzheimer's disease: A data-mining study. AB - Whether theory of mind (ToM) is preserved in Alzheimer's disease (AD) remains a controversial subject. Recent studies have showed that performance on some ToM tests might be altered in AD, though to a lesser extent than in behavioural variant Frontotemporal Dementia (bvFTD). It is however, unclear if this reflects a genuine impairment of ToM or a deficit secondary to the general cognitive decline observed in AD. Aiming to investigate the cognitive determinants of ToM performance in AD, a data-mining study was conducted in 29 AD patients then replicated in an independent age-matched group of 19 AD patients to perform an independent replication of the results. 44 bvFTD patients were included as a comparison group. All patients had an extensive neuropsychological examination. Hierarchical clustering analyses showed that ToM performance clustered with measures of executive functioning (EF) in AD. ToM performance was also specifically correlated with the executive component extracted from a principal component analysis. In a final step, automated linear modelling conducted to determine the predictors of ToM performance showed that 48.8% of ToM performance was significantly predicted by executive measures. Similar findings across analyses were observed in the independent group of AD patients, thereby replicating our results. Conversely, ToM impairments in bvFTD appeared independent of other cognitive impairments. These results suggest that difficulties of AD patients on ToM tests do not reflect a genuine ToM deficit, rather mediated by general (and particularly executive) cognitive decline. They also suggest that EF has a key role in mental state attribution, which support interacting models of ToM functioning. Finally, our study highlights the relevancy of data-mining statistical approaches in clinical and cognitive neurosciences. PMID- 28012371 TI - Analysis of electron energy loss spectroscopy data using geometric extraction methods. AB - A set of geometric data decomposition methods is discussed. In particular, randomized vertex component analysis (RVCA), an extension of vertex component analysis (VCA) for the application to noisy data, is established. Minimum volume simplex analysis (MVSA), a recent technique for the extraction of endmembers in the absence of pure pixels, is presented. A comparison between MVSA and the previously presented technique of Bayesian Linear Unmixing (BLU) is drawn. Lastly, the efficiency of these methods for high-dimensional data is examined. Improvement on the extracted source components spectral signatures are achieved by establishing Gaussian mixture modeling as extraction technique. PMID- 28012372 TI - 3D elemental mapping with nanometer scale depth resolution via electron optical sectioning. AB - Electron energy loss spectroscopy in the scanning transmission electron microscope has long been used to perform elemental mapping but has not previously exhibited depth sensitivity. The key to depth resolution with optical sectioning is the transfer of sufficiently high lateral spatial frequencies. By performing spectrum imaging with atomic resolution we achieve nanometer scale depth resolution, enabling us to optically section an oxide heterostructure spectroscopically. Such 3D elemental mapping is sensitive to atomic scale changes in structure and composition and is more interpretable than Z-contrast imaging alone. PMID- 28012373 TI - Adding nickel formate in alkali lignin to increase contents of alkylphenols and aromatics during fast pyrolysis. AB - The composition of pyrolysis vapors obtained from alkali lignin pyrolysis with the additive of nickel formate was examined using the pyrolysis gas chromatography-mass spectrometry (Py-GC/MS). Characterization of bio-chars was performed using X-ray diffraction (XRD). Results showed that the nickel formate significantly increased liquid yield, simplified the types of alkali lignin pyrolysis products and increased individual component contents. The additive of nickel formate increased contents of alkylphenols and aromatics from alkali lignin pyrolysis. With an increase in temperature, a greater amount of the relative contents can be achieved. The nickel formate was thermally decomposed to form hydrogen, resulting in hydrodeoxygenation of alkali lignin during pyrolysis. It was also found that Ni is in favor of producing alkylphenols. The analysis based on the experimental result provided evidences used to propose reaction mechanism for pyrolysis of nickel formate-assisted alkali lignin. PMID- 28012374 TI - Macroalgae culture to treat anaerobic digestion piggery effluent (ADPE). AB - Environmental consequences of high productivity piggeries are significant and can result in negative environmental impacts, hence bioremediation techniques (in particular using macroalgae) are therefore of great interest. Here, the growth potential of several freshwater macroalgae in anaerobic digestion piggery effluent (ADPE), their nutrient removal rates and biochemical composition of the biomass were investigated under outdoor climatic conditions. A consortium of two macroalgae, Rhizoclonium sp. and Ulothrix sp. was isolated and could efficiently grow in the ADPE. Maximum ammonium removal rate (30.6+/-6.50mg NH4+-NL-1d-1) was achieved at ADPE concentration equivalent to 248mgNH4+-NL-1. Mean biomass productivity of 31.1+/-1.14g ash-free dry weight (AFDW) m-2d-1 was achieved. Total carbohydrate and protein contents ranged between 42.8-54.8 and 43.4-45.0% AFDW, respectively, while total lipid content was very low. The study indicates the potential use of this macroalgal consortium for treating ADPE as well as source of animal feed production. PMID- 28012375 TI - High efficiency of inorganic nitrogen removal by integrating biofilm-electrode with constructed wetland: Autotrophic denitrifying bacteria analysis. AB - The constructed wetland coupled with biofilm-electrode reactor (CW-BER) is a novel technology to treat wastewater with a relatively high level of total inorganic nitrogen (TIN) concentration. The main objective of this study is to investigate the effects of C/Ns, TIN concentrations, current intensities, and pH on the removal of nitrogen in CW-BER; a control system (CW) was also constructed and operated with similar influent conditions. Results indicated that the current, inorganic carbon source and hydrogen generated by the micro-electric field could significantly improve the inorganic nitrogen removal with in CW-BER, and the enhancement of average removal rate on NH3-N, NO3-N, and TIN was approximately maintained at 5-28%, 5-26%, and 3-24%, respectively. The appropriate operation conditions were I=10mA and pH=7.5 in CW-BER. In addition, high-throughput sequencing analysis implied that the CW-BER reactor has been improved with the relative abundance of autotrophic denitrifying bacteria (Thiobacillus sp.). PMID- 28012376 TI - Importance sampling allows Hd true tests of highly discriminating DNA profiles. AB - Hd true testing is a way of assessing the performance of a model, or DNA profile interpretation system. These tests involve simulating DNA profiles of non-donors to a DNA mixture and calculating a likelihood ratio (LR) with one proposition postulating their contribution and the alternative postulating their non contribution. Following Turing it is possible to predict that "The average LR for the Hd true tests should be one"[1]. This suggests a way of validating softwares. During discussions on the ISFG software validation guidelines [2] it was argued by some that this prediction had not been sufficiently examined experimentally to serve as a criterion for validation. More recently a high profile report [3] has emphasised large scale empirical examination. A limitation with Hd true tests, when non-donor profiles are generated at random (or in accordance with expectation from allele frequencies), is that the number of tests required depends on the discrimination power of the evidence profile. If the Hd true tests are to fully explore the genotype space that yields non-zero LRs then the number of simulations required could be in the 10s of orders of magnitude (well outside practical computing limits). We describe here the use of importance sampling, which allows the simulation of rare events to occur more commonly than they would at random, and then adjusting for this bias at the end of the simulation in order to recover all diagnostic values of interest. Importance sampling, whilst having been employed by others for Hd true tests, is largely unknown in forensic genetics. We take time in this paper to explain how importance sampling works, the advantages of using it and its application to Hd true tests. We conclude by showing that employing an importance sampling scheme brings Hd true testing ability to all profiles, regardless of discrimination power. PMID- 28012377 TI - Autosomal STR variations reveal genetic heterogeneity in the Mon-Khmer speaking group of Northern Thailand. AB - Since prehistoric times, Mon-Khmer speaking people have been recognized as indigenous ethnic groups living in northern Thailand. After the period of Tai colonization in the thirteenth century CE, the Mon-Khmer inhabitants were fragmented; some were expelled to rural areas while some were integrated into the mainstream of Tai society. Autosomal STR variations revealed that the present-day Mon-Khmer people could be genetically divided into two clusters. This finding appears to be consistent with the level of historical contact with the Tai majority ethnic groups. The cluster consisting of the Khamu, Lua, Paluang and Htin people, indicate that they have lived in remote areas and have had little historical contact with the Tai people. In this way, they appeared to have maintained aspects of their Mon-Khmer ancestral genetic bloodline but have genetically diverged from the Tai people. The cluster comprised of the Mon and Lawa people had an exclusively close relationship with the Tai people during the establishment of the prosperous Lan Na Kingdom. A fraction of the Tai genetic component investigated among the Mon people and some Lawa populations reflected the evidence of genetic admixture. However, some Lawa people, who have lived in the mountainous area of Mae Hong Son Province have exhibited a unique gene pool, which might have been shaped by the founder effect that occurred during their historical fragmentation. The rise of the genetic assimilation of the hill-tribe Karen people into the Mon-Khmer and the Tai gene pools indicated that different languages, cultures, and geographical distances have lost their power as barriers of inter-ethnic marriages in the present day. PMID- 28012378 TI - Systemic inflammation before and after antiretroviral therapy initiation as a predictor of immune response among HIV-infected individuals in Manitoba. AB - INTRODUCTION: Despite the life-prolonging effects of Highly Active Antiretroviral Therapy (HAART), persons with HIV are still prone to higher rates of non-AIDS related morbidity (such as heart, kidney, and liver disease) than the general public. This is likely due to chronic immune activation and inflammation that persists in HIV-positive persons despite virological suppression. What remains undetermined, however, is whether a link exists between chronic inflammation/immune activation and suboptimal immune recovery on HAART. The hypothesis of the present study is that higher levels of systemic subclinical inflammation and immune activation are linked with suboptimal immune recovery on HAART. METHODS: Fifteen eligible patients from the Manitoba HIV program were enrolled and followed for up to two years; blood samples were drawn at 4 timepoints each, and concentrations of 21 proinflammatory markers were measured. Patients were grouped according to CD4:CD8 recovery at viral suppression, and the inflammatory profiles of the two groups were compared. RESULTS AND CONCLUSIONS: APRIL and BAFF are higher in those with poor recovery at the point of viral suppression, but were also higher in this group at the onset of therapy and through the three additional follow-up visits. TNF-R1, CD163, and Osteopontin, were also in higher concentrations at the outset of therapy and beyond. These five molecules could thus see potential use in the future as biomarkers of likely poor immune recovery. Future work should focus on replicating these findings with larger cohorts. PMID- 28012379 TI - The LC-MS-based metabolomics of hydroxytyrosol administration in rats reveals amelioration of the metabolic syndrome. AB - Hydroxytyrosol (HT), an important component of olive fruit and olive oil, improves the signs of metabolic syndrome in rats following chronic treatment. At a dose of 20mg/kg/day, HT decreased adiposity and improved cardiovascular and liver structure and function in rats fed with a high-carbohydrate, high-fat diet. An untargeted metabolomics approach has been employed using both UPLC-Orbitrap and -QqTOF methods to identify the changes induced by chronic HT administration on the plasma metabolome. 31 metabolites have been found to be differentially expressed between the examined groups. HT was shown to decrease biosynthesis of unsaturated fatty acids, fatty acid biosynthesis, and the metabolism of linoleic acid, retinol, sphingolipids and arachidonic acid, whereas glycerolipid metabolism is up-regulated. These are plausible mechanisms for the attenuation by HT of cardiovascular, liver and metabolic changes in high-carbohydrate, high-fat diet fed rats. PMID- 28012380 TI - Comparison and evaluation of antimuscarinic and anti-inflammatory effects of five Bulbus fritillariae species based on UPLC-Q/TOF integrated dual-luciferase reporter assay, PCA and ANN analysis. AB - Many species of Bulbus fritillariae are used as traditional medicines for thousands of years; however, their application is not standardized. To clarify the differences and homologies, the antimuscarinic and anti-inflammatory effects of five BM species were firstly tested and compared at cellular level. With an integrated strategy combining UPLC-Q/TOF MS, PCA and ANN analysis, the active ingredients among 28 different chemical markers were predicted and identified. SB and QB extracts showed the best antimuscarinic effects and several steroidal alkaloids, such as solanidine, contributed to this effects. However, ZB was superior to reduce the inflammatory response. Another five components were responsible by decreasing the expression of NF-kappaB, including puqiedine, zhepeiresinol, 2-monopalmitin, N-demethylpuqietinone, and isoverticine. More novelty, a new cluster of five BM species based on active ingredients as potential quality markers was depicted to illustrate their functions. These results of the study could make a reference for the medicinal application of BM species in clinic; and the integrated strategy provided an effective method to obtain the quality markers from medical herbs, which was helpful for the quality control of traditional medicinal products. PMID- 28012381 TI - Automated milk fat extraction for the analyses of persistent organic pollutants. AB - We have utilized an automated acid hydrolysis technology, followed by an abbreviated Soxhlet extraction technique to obtain fat from whole milk for the determination of persistent organic pollutants, namely polychlorinated dibenzo-p dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls. The process simply involves (1) pouring the liquid milk into the hydrolysis beaker with reagents and standards, (2) drying the obtained fat on a filter paper and (3) obtaining pure fat via the modified Soxhlet extraction using 100mL of hexane per sample. This technique is in contrast to traditional manually intense liquid liquid extractions and avoids the preparatory step of freeze-drying the samples for pressurized liquid extractions. Along with these extraction improvements, analytical results closely agree between the methods, thus no quality has been compromised. The native spike (n=12) and internal standard (n=24) precision and accuracy results are within EPA Methods 1613 and 1668 limits. While the median (n=6) Toxic Equivalency Quotient (TEQ) for polychlorinated dibenzo-p dioxins/polychlorinated dibenzofurans and the concentration of the marker polychlorinated biphenyls show a percent difference of 1% and 12%, respectively, compared to 315 previously analyzed milk samples at the same laboratory using liquid-liquid extraction. During our feasibility studies, both egg and fish tissue show substantial promise using this technique as well. PMID- 28012382 TI - A validated LC-MS/MS method for thyroid hormone determination in sea lamprey (Petromyzon marinus) plasma, gill, kidney and liver. AB - A UPLC-MS/MS method was developed to provide a reproducible, sensitive and quantitative assay to determine thyroid hormones in sea lamprey tissues and plasma. l-Thyroxine (T4) and its two triiodo-thyronine isomers have been simultaneously quantified and validated for plasma, gill, liver, and kidney matrices. Multiple sample preparation techniques were investigated to achieve optimal sample matrix digestion and clean-up. Enzymatic digestion followed by protein precipitation was selected to process the samples. The developed method exhibited excellent linearity for all analytes with regression coefficients higher than 0.99 for concentrations ranged from 10 to 50,000pg/mL. The limit of detection (LOD) was under 1pg/mL while the limit of quantification (LOQ) was estimated as 10pg/mL. This method was validated according to the FDA guidance and applied to determine thyroid hormone levels in plasma, gill and kidney of sea lamprey exposed to a sex pheromone. With appropriate implementation and further validation, this method could be applied to tissues in other species including humans. PMID- 28012383 TI - Effects of multiple antibiotics exposure on denitrification process in the Yangtze Estuary sediments. AB - Denitrification is a dominant reactive nitrogen removal pathway in most estuarine and coastal ecosystems, and plays a significant role in regulating N2O release. Although multiple antibiotics residues are widely detected in aquatic environment, combined effects of antibiotics on denitrification remain indistinct. In this work, 5 classes of antibiotics (sulfonamides, chloramphenicols, tetracyclines, macrolides, and fluoroquinolones) were selected to conduct orthogonal experiments in order to explore their combined effects on denitrification. 15N-based denitrification and N2O release rates were determined in the orthogonal experiments, while denitrifying functional genes were examined to illustrate the microbial mechanism of the combined antibiotics effect. Denitrification rates were inhibited by antibiotics treatments, and synergistic inhibition effect was observed for multiple antibiotics exposure. Different classes of antibiotics had different influence on N2O release rates, but multiple antibiotics exposure mostly led to stimulatory effect. Abundances of denitrifying functional genes were inhibited by multiple antibiotics exposure due to the antimicrobial properties, and different inhibition on denitrifiers may be the major mechanism for the variations of N2O release rates. Combined effects of antibiotics on denitrification may lead to nitrate retention and N2O release in estuarine and coastal ecosystems, and consequently cause cascading environmental problems, such as greenhouse effects and hyper-eutrophication. PMID- 28012384 TI - Simultaneous removal of As(V) and Cr(VI) from water by macroporous anion exchanger supported nanoscale hydrous ferric oxide composite. AB - As(V) and Cr(VI) are both highly toxic anionic pollutants and commonly co-exist in some industrial effluents and contaminated waters. In this study, simultaneous removal of them was efficiently achieved by employing a composite adsorbent (HFO 201) fabricated by immobilizing nanoscale hydrous ferric oxide (HFO) within a macroporous anion exchanger D201. The HFO-201 composite possesses two types of adsorption sites, i.e. the quaternary ammonium groups fixed on the D201 matrix and the embedded HFO nanoparticles. In the binary solution, the adsorption kinetic processes of both As(V) and Cr(VI) by HFO-201 were well fitted with the pseudo-first order kinetic model. Furthermore, HFO-201 exhibited a significantly higher adsorption capacity toward As(V) than D201 and an identical adsorption capacity toward Cr(VI) to D201. During the removal process, As(V) was captured by both the electrostatic attraction from the fixed quaternary ammonium groups and the formation of inner-sphere complex with the embedded HFO nanoparticles. Whereas, Cr(VI) was primarily adsorbed by the fixed ammonium groups. Fixed-bed treatment of As(V)/Cr(VI) binary synthetic water by HFO-201 resulted in elimination of As (from 1.0 to below 0.01 mg/L) and Cr (from 5.0 to below 0.05 mg/L), with the treatment capacity of 1700 bed volume (BV). Moreover, the exhausted HFO-201 was amenable to efficient in situ regeneration with a binary NaOH-NaCl solution for repeated use without any significant capacity loss. PMID- 28012386 TI - Performance evaluation of restaurant food waste and biowaste to biogas pilot projects in China and implications for national policy. AB - The objective of this research was to conduct a performance evaluation of three food waste/biowaste-to-biogas pilot projects across 7 scenarios in China based on multi-criteria decision analysis (MCDA) methodology. The projects ranked included a food waste-biogas project in Beijing, a food waste-biogas project in Suzhou and a co-digestion project producing biomethane in Hainan. The projects were ranked from best to worst based on technical, economic and environmental criteria under the MCDA framework. The results demonstrated that some projects are encountering operational problems. Based on these findings, six national policy recommendations were provided: (1) shift away from capital investment subsidies to performance-based subsidies; (2) re-design feed in tariffs; (3) promote bio methane and project clustering; (4) improve collection efficiency by incentivizing FW producers to direct waste to biogas projects; (5) incentivize biogas projects to produce multiple outputs; (6) incentivize food waste-based projects to co-digest food waste with other substrates for higher gas output. PMID- 28012385 TI - Separation of rotational and translational segmental momentum to assess movement coordination during walking. AB - This investigation presents an analysis of segmental angular momentum to describe segmental coordination during walking. Generating and arresting momentum is an intuitive concept, and also forms the foundation of Newton-Euler dynamics. Total segmental angular momentum is separated into separate components, translational angular momentum (TAM) and rotational angular momentum (RAM), which provide different but complementary perspectives of the segmental dynamics needed to achieve forward progression during walking. TAM was referenced to the stance foot, which provides insight into the mechanisms behind how forward progression is achieved through coordinated segmental motion relative to the foot. Translational and rotational segmental moments were calculated directly from TAM and RAM, via Euler's 1st and 2nd laws in angular momentum form, respectively, and are composed of the effects of intersegmental forces and joint moments. Using data from 14 healthy participants, the effort required to generate and arrest momentum were assessed by linking the features of segmental angular momentum and the associated segmental moments to well-known spatiotemporal and kinetic features of the gait cycle. Segmental momentum provides an opportunity to explore and understand system-wide dynamics of coordination from an alternative perspective that is rooted in fundamentals of dynamics, and can be estimated using only segmental kinematic measurements. PMID- 28012387 TI - Optimal location selection for the installation of urban green roofs considering honeybee habitats along with socio-economic and environmental effects. AB - This study proposes a new framework for the selection of optimal locations for green roofs to achieve a sustainable urban ecosystem. The proposed framework selects building sites that can maximize the benefits of green roofs, based not only on the socio-economic and environmental benefits to urban residents, but also on the provision of urban foraging sites for honeybees. The framework comprises three steps. First, building candidates for green roofs are selected considering the building type. Second, the selected building candidates are ranked in terms of their expected socio-economic and environmental effects. The benefits of green roofs are improved energy efficiency and air quality, reduction of urban flood risk and infrastructure improvement costs, reuse of storm water, and creation of space for education and leisure. Furthermore, the estimated cost of installing green roofs is also considered. We employ spatial data to determine the expected effects of green roofs on each building unit, because the benefits and costs may vary depending on the location of the building. This is due to the heterogeneous spatial conditions. In the third step, the final building sites are proposed by solving the maximal covering location problem (MCLP) to determine the optimal locations for green roofs as urban honeybee foraging sites. As an illustrative example, we apply the proposed framework in Seoul, Korea. This new framework is expected to contribute to sustainable urban ecosystems. PMID- 28012388 TI - Determinants of field edge habitat restoration on farms in California's Sacramento Valley. AB - Degradation and loss of biodiversity and ecosystem services pose major challenges in simplified agricultural landscapes. Consequently, best management practices to create or restore habitat areas on field edges and other marginal areas have received a great deal of recent attention and policy support. Despite this, remarkably little is known about how landholders (farmers and landowners) learn about field edge management practices and which factors facilitate, or hinder, adoption of field edge plantings. We surveyed 109 landholders in California's Sacramento Valley to determine drivers of adoption of field edge plantings. The results show the important influence of landholders' communication networks, which included two key roles: agencies that provide technical support and fellow landholders. The networks of landholders that adopted field edge plantings included both fellow landholders and agencies, whereas networks of non-adopters included either landholders or agencies. This pattern documents that social learning through peer-to-peer information exchange can serve as a complementary and reinforcing pathway with technical learning that is stimulated by traditional outreach and extension programs. Landholder experience with benefits and concerns associated with field edge plantings were also significant predictors of adoption. Our results suggest that technical learning, stimulated by outreach and extension, may provide critical and necessary support for broad-scale adoption of field-edge plantings, but that this alone may not be sufficient. Instead, outreach and extension efforts may need to be strategically expanded to incorporate peer-to-peer communication, which can provide critical information on benefits and concerns. PMID- 28012389 TI - Valuing conservation benefits of disease control in wildlife: A choice experiment approach to bovine tuberculosis management in New Zealand's native forests. AB - We assess the non-monetary environmental benefits that accrue incidentally in New Zealand (NZ) from pest management conducted primarily to control an animal disease, bovine tuberculosis (TB). TB is an infectious disease that is one of the world's most serious animal health problems and, in many parts of the developing world, still a major mortality risk for humans. The incidence of TB in New Zealand (NZ) farmed livestock has been reduced progressively over the last 20 years, largely due to extensive and sustained population control of the main wildlife reservoir of disease, the introduced brushtail possum. Possums are also major pests that threaten indigenous forest biodiversity, and so extensive possum control for TB mitigation also incidental benefits conservation, but the extent and public value of this benefit has yet to be quantified. We conducted a choice experiment survey of the NZ public in an effort to value the native forest biodiversity benefits of TB-related possum control. We find strong public support for conservation outcomes consequent to TB-possum control in public native forests. The public place substantial value on the most observable biodiversity benefits of TB possum control, such as improved forest canopies and presence of native birds. The benefits, costs and values of TB-possum control are discussed in relation to the future directives of NZ's TB control programme, which is headed toward first regional and then national level disease eradication. PMID- 28012390 TI - Theoretical insight into the excited-state intramolecular proton transfer mechanisms of three amino-type hydrogen-bonding molecules. AB - Excited-state intramolecular proton transfer (ESIPT) dynamics of the amino-type hydrogen-bonding compound 2-(2'-aminophenyl)benzothiazole (PBT-NH2) as well as its two derivatives 2-(5'-cyano-2'-aminophenyl)benzothiazole (CN-PBT-NH2) and 2 (5'-cyano-2'-tosylaminophenyl)benzothiazole (CN-PBT-NHTs) were studied by the time-dependent density functional theory (TD-DFT) approach with the B3LYP density functional, and their absorption and emission spectra were also explored at the same level of theory. A good agreement is observed between the theoretical simulations and experimental spectra, indicating that the present calculations are reasonably reliable. In addition, it is also found that the energy barriers of the first excited singlet state of the three targeted molecules along the ESIPT reaction are computed to be 0.38, 0.34 and 0.12eV, respectively, showing the trend of gradual decrease, which implies that the introduction of the electron-withdrawing cyano or tosyl group can facilitate the occurrence of the ESIPT reaction of these amino-type H-bonding systems. Following the ESIPT, both CN-PBT-NH2 and CN-PBT-NHTs dye molecules can undergo the cis-trans isomerization reactions in the ground-state and excited-state potential energy curves along the C2-C3 bond between benzothiazole and phenyl moieties, where the energy barriers of the trans-tautomer->cis-tautomer isomerizations in the ground states are calculated to be 0.83 and 0.34eV, respectively. According to our calculations, it is plausible that there may exist the long-lived trans-tautomer species in the ground states of CN-PBT-NH2 and CN-PBT-NHTs. PMID- 28012391 TI - Energy transfer and colour tunability in UV light induced Tm3+/Tb3+/Eu3+: ZnB glasses generating white light emission. AB - A promising energy transfer (Tm3+->Tb3+->Eu3+) approach is brought forward to generate white light emission under ultraviolet (UV) light excitation for solid state lightening. Tm3+/Tb3+/Eu3+ ions are combinedly doped in zinc borate glass system in view of understanding energy transfer process resulting in white light emission. Zinc borate (host) glass displayed optical and luminescence properties due to formation of Zn(II)x-[O(-II)]y centres in the ZnB glass matrix. At 360nm (UV) excitation, triply doped Tm3+/Tb3+/Eu3+: ZnB glasses simultaneously shown their characteristic emission bands in blue (454nm: 1D2->3F4), green (547nm: 5D4 >7F5) and red (616nm: 5D0->7F2) regions. In triple ions doped glasses, energy transfer dynamics is discussed in terms of Forster-Dexter theory, excitation & emission profiles, lifetime curves and from partial energy level diagram of three ions. The role of Tb3+ in ET from Tm3+->Eu3+ was discussed using branch model. From emission decay analysis, energy transfer probability (P) and efficiency (eta) were evaluated. Colour tunability from blue to white on varying (Tb3+, Eu3+) content is demonstrated from Commission Internationale de L'Eclairage (CIE) chromaticity coordinates. Based on chromaticity coordinates, other colour related parameters like correlated colour temperature (CCT) and colour purity are also computed for the studied glass samples. An appropriate blending of such combination of rare earth ions could show better suitability as potential candidates in achieving multi-colour and warm/cold white light emission for white LEDs application in the field of solid state lightening. PMID- 28012392 TI - Structural, spectroscopic and molecular docking studies on 2-amino-3-chloro-5 trifluoromethyl pyridine: A potential bioactive agent. AB - The most stable, optimized structure of the 2-amino-3-chloro-5-trifluoromethyl pyridine (ACTP) molecule was predicted by the density functional theory calculations using the B3LYP method with cc-pVQZ basis set. Antitumor activity of the ACTP molecule was evaluated by molecular docking analysis. The structural parameters and vibrational wavenumbers were calculated for the optimized molecular structure. The experimental and theoretical vibrational wavenumbers were assigned and compared. Ultraviolet-visible spectrum was simulated and validated experimentally. The molecular electrostatic potential surface was simulated. Frontier molecular orbitals and related molecular properties were computed and further density of states spectrum was simulated. The natural bond orbital analysis was also performed to confirm the bioactivity of the ACTP molecule. The molecular docking analysis reveals the better inhibitory nature of the ACTP molecule against the colony-stimulating factor 1 (CSF1) gene which causes tenosynovial giant-cell tumor. Hence, the ACTP molecule can act as a potential inhibitor against tenosynovial giant-cell tumor. PMID- 28012393 TI - Modulatory effect of standardised amentoflavone isolated from Juniperus communis L. agianst Freund's adjuvant induced arthritis in rats (histopathological and X Ray anaysis). AB - ETHOPHARMACOLOGIC RELEVANCE: Juniperus communis. L. is a shrub or small evergreen tree, native to Europe, South Asia, and North America, and belongs to family Cupressaceae. It has been used traditionally in unani system and in Swedish medicine as a decoction in inflammatory diseases. The main chemical constituents, which were reported in J. communis L. was alpha-pinene,, apigenin, sabinene, beta sitosterol, campesterol, limonene, Amentoflavone (AF), cupressuflavone, and many others. AIM: The aim of present study was to isolate the amentoflavone from the plant juniperus communis L. extracts and its protective effects against Freund's adjuvant induced arthritis in rats. MATERIAL METHODS: Adjuvant arthritis was induced by an injection of 1mg heat killed Mycobacterium tuberculosis (CFA) into the left hind paw of rat by sub planter route (at day 0). The experiment was designed and modified as per method available in literature. RESULTS: The study showed that at a dose of 40mg/kg of amentoflavone (AF) from methanolic extract of Juniperus Communis L. possessed potentially useful anti-arthritic activity as it gave a positive result in controlling inflammation in the adjuvant induced experimental model. CONCLUSION: From the present experimental findings of both pharmacological and biochemical parameters observed, it had been concluded that at the doses of 20mg/kg and 40mg/kg of AF fraction from methanolic extract of Juniperus communis L. It possesses useful anti-arthritic activity since it gives a positive result in controlling inflammation in the adjuvant induced arthritic model in rats. The drug is a promising anti-arthritic agent of plant origin in the treatment of inflammatory disorders. PMID- 28012394 TI - Phytochemical, ethnomedicinal uses and pharmacological profile of genus Pistacia. AB - Pistacia genus belong to family Anacardiaceae and it is versatile in that its member species have food (P. vera), medicinal (P. lentiscus) and ornamental (P. chinensis) values. Various species of this genus have folkloric uses with credible mention in diverse pharmacopeia. As a trove of phenolic compounds, terpenoids, monoterpenes, flavonoids, alkaloids, saponins, fatty acids, and sterols, this genus has garnered pharmaceutical attention in recent times. With adequate clinical studies, this genus might be exploited for therapy of a multitude of inflammatory diseases, as promised by preliminary studies. In this regard, the ethnomedicinal, phytochemistry, biological potencies, risks, and scopes of Pistacia genus have been reviewed here. PMID- 28012395 TI - Regulatory mechanism of mineral-balanced deep sea water on hypocholesterolemic effects in HepG2 hepatic cells. AB - Several previous studies have shown the benefits of deep sea water (DSW) in lipid metabolism. However, the effects of DSW on cellular cholesterol accumulation and synthesis induced by high glucose or free fatty acid plus high glucose [4.5g/L] (FFA/glucose) have not been fully elucidated to date. Herein, we showed the effects of mineral-balanced DSW [magnesium (Mg):calcium (Ca)=3:1] (MB-DSW) on cholesterol metabolism induced by high glucose or FFA/glucose in HepG2 hepatic cells. Moreover, the effects of high ratio Mg DSW [Mg:Ca=40:1] (Mg40) were also investigated. MB-DSW and Mg40 prevented the increase of cellular total cholesterol content in high glucose- or FFA/glucose-treated HepG2 hepatic cells. Furthermore, the inhibition by MB-DSW was closely related to the down-regulation of 3-hydroxy-3-methylglutatryl-CoA reductase (HMGCR) expression and an increase in the AMP-activated protein kinase (AMPK) phosphorylation, leading to decreased cholesterol synthesis in both high glucose- and FFA/glucose-treated conditions. However, this effect was not seen in case of Mg40. In addition, both MB-DSW and Mg40 induced the low-density lipoprotein receptor (LDLR) and diminished the proprotein convertase subtilisin/kexin type 9 (PCSK9) transcriptions in high glucose-treated HepG2 hepatic cells. This result demonstrates that the hypocholesterolemic effects of MB-DSW and Mg40 are mediated with LDL-c clearance through increases of LDLR and its transcription factors, such as peroxisome proliferator-activated receptor-alpha (PPAR-alpha), sterol regulatory element binding protein (SREBP)-1a, and SREBP-2, mRNA synthesis and suppression of PCSK9 transcription. Moreover, apolipoprotein (Apo) A1 transcription was enhanced by MB DSW and Mg40 without decreasing the expression of Apo B in high glucose-treated HepG2 hepatic cells. However, ApoA1 protein expression was not changed. Taken together, the present investigation suggests that DSW may prevent the high glucose- or FFA/glucose-induced increase of cellular cholesterol levels by inducing LDLR and ApoA1 transcriptions and inhibiting PCSK9 mRNA expression in HepG2 hepatic cells. Additionally, the ratio of Mg in DSW is an important factor that determines whether HMGCR expression and/or AMPK phosphorylation participate in the hypocholesterolemic effects of DSW. PMID- 28012396 TI - Antidepressant like effects of hydrolysable tannins of Terminalia catappa leaf extract via modulation of hippocampal plasticity and regulation of monoamine neurotransmitters subjected to chronic mild stress (CMS). AB - Terminalia catappa L. belonging to Combretaceae family is a folk medicine, known for its multiple pharmacological properties, but the neuro-modulatory effect of TC against chronic mild stress was seldom explored. The present study was designed to elucidate potential antidepressant-like effect of Terminalia cattapa (leaf) hydro-alcoholic extract (TC) by using CMS model for a period of 7 weeks. Identification of hydrolysable tannins was done by using LC-MS. After the CMS exposure, mice groups were administered with imipramine (IMP, 10mg/kg, i.p.) and TC (25, 50 and 100mg/kg of TC, p.o.). Behavioural paradigms used for the study included forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT). After behavioural tests, monoamine neurotransmitter, cortisol, AchE, oxidative stress levels and mRNA expression studies relevant to depression were assessed. TC supplementation significantly reversed CMS induced immobility time in FST and other behavioural paradigms. Moreover, TC administration significantly restored CMS induced changes in concentrations of hippocampal neurotransmitters (5-HT, DA and NE) as well as levels of acetyl cholinesterase, cortisol, monoamine oxidases (MAO-A, MAO-B), BDNF, CREB, and p CREB. It suggests that TC supplementation could supress stress induced depression by regulating monoamine neurotransmitters, CREB, BDNF, cortisol, AchE level as well as by amelioration of oxidative stress. Hence TC can be used as a complementary medicine against depression-like disorder. PMID- 28012397 TI - miR-381 inhibited breast cancer cells proliferation, epithelial-to-mesenchymal transition and metastasis by targeting CXCR4. AB - BACKGROUND: MicroRNAs act as posttranscriptional regulators of gene expression in many biological processes, which played a vital role in regulation cancer cells epithelial-to-mesenchymal transition and metastasis. The deregulation of miR-381 has been identified in breast cancer. However, the role and mechanism of miR-381 in breast cancer have not been completely unexplored. METHODS: Total RNA was extracted from the tissues of 27 patients with breast cancer and two breast cancer cell lines, respectively. The expression levels of miR-381 were examined by quantitative real-time PCR. The stable overexpress or silence miR-381 expression cells lines and control cells line were constructed by lentivirus infection. Subsequently, cell proliferation, cell migration, invasion assay and western blot assay were performed to detect the biological functions of miR-381 in vitro. Moreover, a luciferase reporter assay was conducted to confirm target associations. RESULTS: In this study, we validated the lower expression of miR 381 in breast cancer tissues than their adjacent non-neoplastic tissues in 27 breast cancer patients. The result also showed that miR-381 was lowly expressed in breast cancer cell lines MCF-7 and MDA-MB-231 than human epithelial cell line MCF-10A. The miR-381 expression was significantly up-regulated under exogenous miRNA-381 treatment in MCF-7 and MDA-MB-231 cells analyzed by quantitative real time PCR. The results also indicated that an inverse correlation existed between miR-381 expression level and breast cancer cell proliferation, epithelial-to mesenchymal transition and metastasis. Furthermore, miR-381 was predicted as a regulatory miRNA of CXCR4 in breast cancer, and the data analysis revealed that there was a negatively relationship between miR-381 and CXCR4 expression in breast cancer tissues from the patients. miR-381 played an important role in breast cancer cells proliferation, epithelial-to-mesenchymal transition and metastasis by targeting CXCR4. CONCLUSIONS: This present study revealed that miR 381 might be considered as a novel therapeutic target for breast cancer treatment. PMID- 28012398 TI - Traditional Chinese medicine Jianpi Bushen therapy suppresses the onset of pre metastatic niche in a murine model of spontaneous lung metastasis. AB - BACKGROUND & AIM: Distinct metastasis accounts for the leading cause of mortality among patients with gastric cancer. The formation of pre-metastatic niche in the target organs provides permissive environments for the adhesion and subsequent growth of metastasized cancer cells. Targeting the pre-metastatic niche is a potential approach to prevent metastasis. Traditional Chinese medicine regimen called Jianpi Bushen therapy (JPBS) has been widely used in clinics to strengthen patients' abilities to fight cancer. The present work is aimed to study the modulating effect of JPBS on the lungs expressions of Rac1, Cdc42, SDF-1, and FN in a murine gastric cancer model showing spontaneous lung metastasis. METHODS: Mice of strain 615 were inoculated with tumor cells derived from mouse forestomach carcinoma (MFC) to induce spontaneous lung metastasis, and were then treated with JPBS, JPBS combined with fluorouracil (5-FU), or 5-FU. Gene and protein expressions of Rac1, Cdc42, SDF-1, and FN in lungs were determined using real-time PCR and immunohistochemistry, respectively. Serum levels of SDF-1 and FN were also measured using ELISA. RESULTS: Gene and protein expressions of Rac1, Cdc42, SDF-1, and FN were significantly elevated in the lungs of model mice comparing to the counterpart mice received no tumor cell inoculation. JPBS treatment reduced protein expressions of Rac1, Cdc42, SDF-1 and FN in the lungs of model mice. The treatment could also suppress SDF-1 and FN in blood. For serum SDF-1 the level was further lower in model mice treated with combination therapy of JPBS and 5-FU. CONCLUSION: The present work identified the potential roles of Rac1, Cdc42, SDF-1 and FN in the early onset of pre-metastatic niche of gastric cancer, and provided insights into the molecular mechanism by which Jianpi Bushen therapy prevent and suppress cancer metastasis. PMID- 28012399 TI - Chinese adolescents' reports of covert parental monitoring: Comparisons with overt monitoring and links with information management. AB - This study compared Chinese adolescents' reports of covert parental monitoring with the overt strategies of solicitation and control. We investigated these behaviors in terms of unique associations with adolescents' perceived privacy invasion and the information management behaviors of disclosure and secrecy. High school students (N = 455, 61.5% female; Mage = 17.39, SD = 0.83) from a predominantly rural province of Mainland China reported a high incidence of covert monitoring (60.40%). Covert monitoring predicted privacy invasion more strongly than solicitation or control. Solicitation positively predicted disclosure, while covert monitoring negatively predicted disclosure and positively predicted secrecy. Privacy invasion fully mediated links between covert monitoring and information management. These latter effects were significantly stronger for girls than for boys. Similar to Western adolescents, Chinese youth might apply selective resistance when parents violate their personal domain. The findings suggest linkage between some parental monitoring behaviors and disruptions in Chinese family communication. PMID- 28012400 TI - Blood cadmium concentrations and environmental exposure sources in newcomer South and East Asian women in the Greater Toronto Area, Canada. AB - BACKGROUND: Immigrant women are often identified as being particularly vulnerable to environmental exposures and health effects. The availability of biomonitoring data on newcomers is limited, thus, presenting a challenge to public health practitioners in the identification of priorities for intervention. OBJECTIVES: In fulfillment of data needs, the purpose of this study was to characterize blood concentrations of cadmium (Cd) among newcomer women of reproductive age (19-45 years of age) living in the Greater Toronto Area (GTA), Canada and to assess potential sources of environmental exposures. METHODS: A community-based model, engaging peer researchers from the communities of interest, was used for recruitment and follow-up purposes. Blood samples were taken from a total of 211 newcomer women from South and East Asia, representing primary, regional origins of immigrants to the GTA, and environmental exposure sources were assessed via telephone survey. Metal concentrations were measured in blood samples (diluted with 0.5% (v/v) ammonium hydroxide and 0.1% (v/v) octylphenol ethoxylate) using a quadrupole ICP-MS. Survey questions addressed a wide range of environmental exposure sources, including dietary and smoking patterns and use of nutritional supplements, herbal products and cosmetics. RESULTS: A geometric mean (GM) blood Cd concentration of 0.39ug/L (SD:+/-2.07ug/L) was determined for study participants (min/max: <0.045ug/L (LOD)/2.36ug/L). Several variables including low educational attainment (Relative Ratio (RR) (adjusted)=1.50; 95% CI 1.17 1.91), milk consumption (RR (adjusted)=0.86; 95% CI 0.76-0.97), and use of zinc supplements (RR (adjusted)=0.76; 95% CI 0.64-0.95) were observed to be significantly associated with blood Cd concentrations in the adjusted regression model. The variable domains socioeconomic status (R2adj=0.11) and country of origin (R2adj=0.236) were the strongest predictors of blood Cd. CONCLUSION: Blood Cd concentrations fell below those generally considered to be of human health concern. However, negative health effects cannot be entirely excluded, especially for those that fall in the upper percentile range of the distribution, given the mounting evidence for negative health outcomes at low environmental exposure concentrations. PMID- 28012401 TI - Using fNIRS to examine occipital and temporal responses to stimulus repetition in young infants: Evidence of selective frontal cortex involvement. AB - How does the developing brain respond to recent experience? Repetition suppression (RS) is a robust and well-characterized response of to recent experience found, predominantly, in the perceptual cortices of the adult brain. We use functional near-infrared spectroscopy (fNIRS) to investigate how perceptual (temporal and occipital) and frontal cortices in the infant brain respond to auditory and visual stimulus repetitions (spoken words and faces). In Experiment 1, we find strong evidence of repetition suppression in the frontal cortex but only for auditory stimuli. In perceptual cortices, we find only suggestive evidence of auditory RS in the temporal cortex and no evidence of visual RS in any ROI. In Experiments 2 and 3, we replicate and extend these findings. Overall, we provide the first evidence that infant and adult brains respond differently to stimulus repetition. We suggest that the frontal lobe may support the development of RS in perceptual cortices. PMID- 28012402 TI - Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data. AB - AIMS: Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic forms of diabetes caused by mutations in at least 14 genes, but mostly by mutations in Glucokinase (GCK) and hepatocyte nuclear factor-1 homeobox A (HNF1A). This study aims to establish a national registry of MODY cases in Brazilian patients, assessing published and unpublished data. METHODS: 311 patients with clinical characteristics of MODY were analyzed, with unpublished data on 298 individuals described in 12 previous publications and 13 newly described cases in this report. RESULTS: 72 individuals had GCK mutations, 9 described in Brazilian individuals for the first time. One previously unpublished novel GCK mutation, Gly178Ala, was found in one family. 31 individuals had HNF1A mutations, 2 described for the first time in Brazilian individuals. Comparisons of GCK probands vs HNF1A: age 16+/-11 vs 35+/-20years; age at diagnosis 11+/-8 vs 21+/-7years; BMI 19+/-6 vs 25+/-6kg/m2; sulfonylurea users 5 vs 83%; insulin users 5 vs 17%; presence of arterial hypertension 0 vs. 33%, all p<0.05. No differences were observed in lipids and C-peptide. CONCLUSIONS: Most MODY cases in Brazil are due to GCK mutations. In agreement with other studied populations, novel mutations are common. Only 14% of patients with familial diabetes carry a HNF1A mutation. Diagnosis of other rare forms of MODY is still a challenge in Brazilian population, as well as adequate strategies to screen individuals for molecular diagnosis. PMID- 28012403 TI - The potential for improvement of outcomes by personalized insulin treatment of type 1 diabetes as assessed by analysis of single-patient data from a randomized controlled cross-over insulin trial. AB - AIMS: The evidence for optimal insulin treatment in type 1 diabetes is mainly based on randomised controlled trials applying a parallel-group design. Such trials yield robust general results but crucial individual treatment effects cannot be extracted. We aimed to assess the potential for further improvement of outcomes by personalized insulin therapy by analyzing data from a cross-over trial at individual level. METHODS: Post hoc analysis of data from a two-year multicentre, prospective, randomised, open, blinded endpoint (PROBE) trial (the HypoAna trial). In a cross-over design 114 patients with type 1 diabetes and recurrent severe hypoglycemia were treated with basal-bolus therapy based on analog (detemir/aspart) or human (NPH/regular) insulin aiming at maintenance of baseline HbA1c levels. For each patient a superior outcome was defined as fewer events of severe hypoglycemia defined by need for third party treatment assistance or a more than 0.4% (4.4mmol/mol) lower HbA1c. RESULTS: Only one quarter had comparable outcome of the two treatments in terms of rate of severe hypoglycemia or HbA1c. Twice as many patients had superior outcome of analog based as compared to human insulin-based insulin treatment. The rate of severe hypoglycemia with the superior treatment was lower compared to the rates obtained with analog insulin and with human insulin (0.67, 1.09, and 1.57 episode per patient-year, respectively (p<0.0001)). CONCLUSIONS: Personalized insulin treatment of type 1 diabetes based on single-patient evidence may improve outcomes significantly compared to a general treatment approach. PMID- 28012404 TI - Influence of air quality on the results of in vitro fertilization attempts: A retrospective study. AB - OBJECTIVE: To assess the influence of air quality on the results of IVF. STUDY DESIGN: We performed a retrospective study on 292 patients who have undergone an IVF attempt from April 2012 to December 2015 in our French university hospital. Patients were included in the study if data on the air quality at home and at work were available and if they haven't been gone for more than 4days in a month. Data were recorded during the 3 months before oocyte collection and 1 month after embryo transfer. Air quality measurements were obtained from the Observatoire Regional de l'Air en Midi-Pyrenees (ORAMIP) and concerned the levels of nitrogen dioxide (NO2), ozone (O3), particulate matter PM10 and SO2 measured every day. RESULTS: Acute exposures to high levels NO2 or PM10 were associated with lower results of IVF (ovarian response to stimulation, number of top embryos) while these parameters were enhanced when patients were exposed to high levels of O3 during the first 2 months of folliculogenesis. These effects were found even for a short exposure (1day). CONCLUSIONS: Air quality has an impact on global health and also on the reproductive function and public and authorities must be aware of environmental protection. PMID- 28012405 TI - An assessment of mode of delivery in history indicated versus ultrasound indicated vaginally placed cervical cerclage. AB - OBJECTIVE: Treatment modalities to reduce the incidence of preterm birth are currently limited. Cerclage, is a common and established intervention in most obstetrics units worldwide, however, many questions regarding its efficacy, with respect to pregnancy outcomes remain unanswered. This study aims to investigate whether an antenatal placed cerclage affects the subsequent mode of delivery in women at high risk of preterm birth who labour. STUDY DESIGN: A retrospective case controlled study was performed at St Thomas's Hospital London. Women who had undergone cervical cerclage were identified using a pre-existing database (n=152). Cases were excluded where a C-section had been performed prior to labour (n=26), datasets were incomplete (n=5) or a rescue cerclage was performed (n=2). Remaining cases were categorised into those who had: history indicated (n=68) or ultrasound indicated (n=51) cerclage. Control cases were obtained from the same database who also laboured but had not undergone cerclage, matched according to gestational age at delivery and parity (n=114). Demographic details and outcome data were recorded. Groups were compared using Chi Squared analysis for discrete variables and t-test for continuous variables using IBM SPSS Statistics version 22. RESULTS: There was no statistical difference in the emergency C-section rate between history indicated and ultrasound indicated cerclage, or between patients who received cerclage and those who had not (p=0.592). The emergency C-section rate for each group was: history indicated, 25%, ultrasound indicated 18% and no cerclage 18%. CONCLUSIONS: Women at risk of preterm birth have high rates of emergency C-section despite the fact that the majority were multiparous. However, they can be reassured that cervical cerclage does not increase this risk. PMID- 28012406 TI - Keratin mediated attachment of stem cells to augment cardiomyogenic lineage commitment. AB - The objective of this work was to develop a simple surface modification technique using keratin derived from human hair for efficient cardiomyogenic lineage commitment of human mesenchymal stem cells (hMSCs). Keratin was extracted from discarded human hair containing both the acidic and basic components along with the heterodimers. The extracted keratin was adsorbed to conventional tissue culture polystyrene surfaces at different concentration. Keratin solution of 500MUg/ml yielded a well coated layer of 12+/-1nm thickness with minimal agglomeration. The keratin coated surfaces promoted cell attachment and proliferation. Large increases in the mRNA expression of known cardiomyocyte genes such as cardiac actinin, cardiac troponin and beta-myosin heavy chain were observed. Immunostaining revealed increased expression of sarcomeric alpha actinin and tropomyosin whereas Western blots confirmed higher expression of tropomyosin and myocyte enhancer factor 2C in cells on the keratin coated surface than on the non-coated surface. Keratin promoted DNA demethylation of the Atp2a2 and Nkx2.5 genes thereby elucidating the importance of epigenetic changes as a possible molecular mechanism underlying the increased differentiation. A global gene expression analysis revealed a significant alteration in the expression of genes involved in pathways associated in cardiomyogenic commitment including cytokine and chemokine signaling, cell-cell and cell-matrix interactions, Wnt signaling, MAPK signaling, TGF-beta signaling and FGF signaling pathways among others. Thus, adsorption of keratin offers a facile and affordable yet potent route for inducing cardiomyogenic lineage commitment of stem cells with important implications in developing xeno-free strategies in cardiovascular regenerative medicine. PMID- 28012407 TI - Sequential delivery of chlorhexidine acetate and bFGF from PLGA-glycol chitosan core-shell microspheres. AB - Wound treatment should meet the challenge both of preventing infection and promoting wound healing. To design a sequential delivery system for wound healing, PLGA-glycol chitosan (GC) core-shell microspheres containing chlorhexidine acetate (CHA) at the GC shell and bFGF in the core of PLGA microspheres were fabricated using emulsion-solvent evaporation method. SEM showed that the microspheres were all spherical in shape with a smooth surface. The average size of PLGA-GC microspheres increased due to the GC coating on the surface. The results of release profiles and fluorescence images indicated that PLGA-GC microspheres had an ability to deliver drugs in sequence. The CHA was rapidly released, whereas the proteins presented a sustained release. The release behavior could be modulated by changing the GC amount. Antibacterial assay and cell proliferation tests suggested that the released CHA and bFGF retained their antimicrobial activity and bioactivity during preparation. The microspheres exhibited non-cytotoxicity against 3T3 cells and had a good biocompatibility. These results demonstrated that PLGA-GC core-shell microspheres could be a promising controlled release system of delivering drugs and proteins in sequence for wound healing. PMID- 28012408 TI - Corrigendum to 'A water-soluble and biocompatible polymeric nanolabel based on naphthalimide grafted poly(acrylic acid) for the two-photon fluorescence imaging of living cells and C. elegans' [Colloids Surf. B: Biointerfaces 148 (2016) 293 298]. PMID- 28012409 TI - Conformational analysis of 9-crown-3, 9-thiacrown-3 and 9-azacrown-3. AB - Crown ethers are an important class of molecules with wide applications. Crown ethers are large ring flexible molecules with a large number of possible conformations. In the current manuscript, we report the conformational analysis results of one of the smallest crown ether systems, namely, 9-crown-3, 9c3, 9 thiacrown-3, 9t3, and 9-azacrown-3, 9a3. The conformational search is performed using the CONFLEX conformational search method utilizing the MMFF94s force field. 8, 11 and 62 conformations were predicted for 9c3, 9t3 and 9a3, respectively. The ab initio computations were performed at B3LYP and MP2 levels using the 6-311G** basis set. For the accurate prediction of the ground state conformation and the energy order of the low-lying energy conformations, the computations were performed at the G4 level for some selected conformations. Factors affecting the stability of different conformations of 9c3, 9t3 and 9a3 are discussed. These factors are also discussed with respect to larger crown ether systems. The ab initio computations were performed also for water and chloroform as solution phases. The same ground state predicted in the gas phase was also predicted in the solution water and chloroform phases. PMID- 28012410 TI - The effect of marital status on breast cancer-related outcomes in women under 65: A SEER database analysis. AB - BACKGROUND: Marital status is strongly associated with improved health and longevity. Being married has been shown to be positively associated with survival in patients with multiple different types of malignancy; however, little is known about the relationship between marital status and breast cancer in younger women. The purpose of this study is to investigate the effect of marital status on diagnosis, and survival of women under the age of 65 with breast cancer. METHODS: The SEER 18 regions database was used to identify women between the ages of 25-64 diagnosed with invasive breast cancer in the years 2004-2009. Logistic regression was used to predict later stage diagnosis by marital status and Cox proportional hazards models were used to compare breast cancer-related and all-cause survival by marital status classification. Models were stratified by AJCC stage. RESULTS: After adjusting for age, race, and ER status, unmarried women were 1.18 times more likely to be diagnosed at a later stage than married women (95% CI 1.15, 1.20). In adjusted analysis unmarried women were more likely to die of breast cancer and more likely to die of all causes than married women across all AJCC stages. CONCLUSIONS: Younger unmarried women with breast cancer may benefit from additional counseling, psychosocial support and case management at the time of diagnosis to ensure their overall outcomes are optimized. PMID- 28012411 TI - Omitting radiation therapy in women with triple-negative breast cancer leads to worse breast cancer-specific survival. AB - PURPOSE: To examine locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) after breast-conserving therapy (BCT) or mastectomy (ME) with or without radiation therapy (RT) in triple-negative breast cancer (TNBC). MATERIAL & METHODS: We identified non-metastatic TNBC cases from a single institution database. BCT, ME with RT (ME + RT) and ME only were compared with respect to LRR and BCSS. Cox regression models were used to analyze the association between prognostic factors and outcome. RESULTS: 439 patients fulfilled the inclusion criteria. Median follow-up was 10.2 years (interquartile range 7.9; 12.4 years). Patients in the BCT (n = 239), ME + RT (n = 116) and ME only (n = 84) group differed with respect to age, pT, pN, lymphovascular invasion, lymph node dissection and chemotherapy administration. Ten-year LRR rates were seven percent, three percent and eight percent for the BCT, ME + RT and ME only group, respectively. pN was associated with LRR. In multivariable analysis LRR were significantly lower in the ME + RT group compared to the BCT and the ME only group (p 0.037 and 0.020, respectively). Ten year BCSS was 87%, 84% and 75% for the BCT, ME + RT and ME only group, respectively. pT, pN, lymph node dissection, lymphovascular invasion and the administration of chemotherapy were associated with BCSS. In multivariable analysis BCSS was significantly lower in the ME only group compared to the BCT group and the ME + RT group (p 0.047 and 0.003, respectively). CONCLUSION: TNBC patients treated with ME without adjuvant RT showed significant lower BCSS compared to patients treated with BCT or ME + RT and significant more LRR compared to ME + RT when corrected for known clinicopathological prognostic factors. PMID- 28012413 TI - Long thickness-extensional waves in thin film bulk acoustic wave filters affected by interdigital electrodes. AB - We studied free vibrations of thin-film bulk acoustic wave filters with interdigital electrodes theoretically using the scalar differential equations by Tiersten and Stevens. The filters are made from AlN or ZnO films on Si substrates with ground and driving electrodes. They operate with thickness-extensional modes. The basic vibration characteristics including resonant frequencies and mode shapes were obtained. Their dependence on various geometric parameters was examined. It was found that for properly design filters there exist trapped modes whose vibrations are strong in regions with a driving electrode and decay away from the electrode edges. These trapped modes are essentially long plate thickness-extensional modes modulated by the electrode fingers. The number of trapped modes is sensitive to the geometric parameters. PMID- 28012412 TI - Human transmission of Ebola virus. AB - Ever since the first recognised outbreak of Ebolavirus in 1976, retrospective epidemiological analyses and extensive studies with animal models have given us insight into the nature of the pathology and transmission mechanisms of this virus. In this review focusing on Ebolavirus, we present an outline of our current understanding of filovirus human-to-human transmission and of our knowledge concerning the molecular basis of viral transmission and potential for adaptation, with particular focus on what we have learnt from the 2014 outbreak in West Africa. We identify knowledge gaps relating to transmission and pathogenicity mechanisms, molecular adaptation and filovirus ecology. PMID- 28012414 TI - The effect of sertraline and 8-OH-DPAT on the PTZ_induced seizure threshold: Role of the nitrergic system. AB - PURPOSE: Serotonin is a key regulatory neurotransmitter in the CNS which plays an important role in seizure through different receptors, especially the 5HT1A subtype. The role of sertraline through the 5HT1A receptor and nitric oxide interaction on the PTZ-induced seizure threshold was investigated in this study. METHOD: In this study, 70 white male mice were randomly divided into 10 groups including intact control, sham-control and eight experimental groups which received sertraline, 8-OH-DPAT, WAY100635, WAY100635+sertraline, WAY100635+8-OH DPAT, L-NAME, L-NAME+sertraline and L-NAME+8-OH-DPAT. After 14days of treatment in different groups, the PTZ-induced seizure threshold was assessed and the measurement of nitric oxide metabolites in the brain tissue was done with the Greiss method. RESULTS: The seizure threshold was significantly increased in the sertraline and 8OH-DPAT receiving groups compared to the sham group (P<0.001). In the presence of WAY100635, the effect of both sertraline and 8-OH-DPAT in raising the seizure threshold was more prominent (P<0.001) but on the other hand, in the presence of L-NAME, an increase in the anticonvulsant effect of 8-OH-DPAT was observed, while L-NAME alone had no effect on the seizure threshold (P<0.001). The NOX concentration was significantly decreased in the 8-OH-DPAT_treated group (P<0.01), while the WAY100657 reversed it and the combination of 8-OH-DPAT with L NAME reduced the NOX levels (P<0.001). CONCLUSIONS: These findings support the anticonvulsant effect of SSRIs and selective 5HT1A receptors, although serotonin receptors other than 5HT1A subtype may be involved and also it is probable that some anticonvulsant effects of the sertraline and 8-OH-DPAT are through the modulation of nitrergic system. PMID- 28012415 TI - Comparing sleep profiles between patients with juvenile myoclonic epilepsy and symptomatic partial epilepsy: Sleep questionnaire-based study. AB - OBJECTIVES: Patients with epilepsy commonly report excessive daytime sleepiness and daytime fatigue, which may be attributed to the direct effect of seizures, a side effect of antiepileptic drugs or a combination of the two. The aim of the study was to compare sleep profiles in patients with juvenile myoclonic epilepsy (JME) and symptomatic partial epilepsy (PE) in drug naive and treated patients using standardized sleep questionnaires. METHODS: Three study groups: - 1) juvenile myoclonic epilepsy (N=40) [drug naive (N=20); On sodium valproate (SVA) (N=20)]; 2) symptomatic partial epilepsy (N=40) [drug naive (N=20); On carbamazepine (CBZ) (N=20)]; 3) healthy controls (N=40) completed 3 standardized sleep questionnaires - Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and NIMHANS Comprehensive Sleep Disorders Questionnaire. Scores were compared using t-test and Chi-squared tests (P<=0.005). RESULTS: The mean PSQI scores as well as the proportion of subjects with abnormal PSQI scores were higher in patients with JME and PE compared to controls. Although the mean ESS scores were comparable between patients with epilepsy and controls, the percentage of patients with partial epilepsy having abnormal ESS scores was higher. No significant differences were present between drug naive and treatment monotherapy groups. Excessive daytime somnolence was reported more often by patients with JME compared to patients with partial epilepsy and controls. CONCLUSION: This study found that patients with epilepsy have a higher prevalence of poor sleep quality compared to controls. Moreover, a significantly higher percentage of patients with partial epilepsy had higher ESS scores compared to healthy controls. However, there was no difference between ESS and PSQI scores between drug naive and treated patients with JME or PE. SIGNIFICANCE: Poor sleep quality is more prevalent in patients with epilepsy irrespective of the use of antiepileptic medications. Excessive daytime somnolence is more commonly seen in patients with partial epilepsy when compared to the general population. PMID- 28012416 TI - Agarose encapsulated mesoporous carbonated hydroxyapatite nanocomposites powder for drug delivery. AB - The powder composites are predominantly used for filling of voids in bone and as drug delivery carrier to prevent the infection or inflammatory reaction in the damaged tissues. The objective of this work was to study the synthesis of agarose encapsulation on carbonated hydroxyapatite powder and their biological and drug delivery properties. Mesoporous, nanosized carbonated hydroxyapatite/agarose (CHAp/agarose) powder composites were prepared by solvothermal method and subsequently calcined to study the physico-chemical changes, if it subjected to thermal exposure. The phase of the as-synthesized powder was CHAp/agarose whereas the calcinated samples were non-stoichiometric HAp. The CHAp/agarose nanorods were of length 10-80nm and width 40-190nm for the samples synthesized at temperatures 120 degrees C (ST120) and 150 degrees C (ST150). The calcination process produced spheres (10-50nm) and rods with reduced size (40-120nm length and 20-30nm width). Composites were partially dissolved in SBF solution followed by exhibited better bioactivity than non-stoichiometric HAp confirmed by gravimetric method. Hemo and biocompatibility remained unaffected by presence of agarose or carbonate in the HAp. Specific surface area of the composites was high and exhibited an enhanced amoxicillin and 5-fluorouracil release than the calcined samples. The composites demonstrated a strong antimicrobial activity against E. coli, S. aureus and S. epidermidis. The ST120 showed prolonged drug (AMX and 5-Fcil) release and antimicrobial efficacy than ST150 and calcined samples. This technique would be simple and rapid for composites preparation, to produce high quality crystalline, resorbable, mesoporous and bioactive nanocomposite (CHAp/agarose) powders. This work provides new insight into the role of agarose coated on bioceramics by solvothermal technique and suggests that CHAp/agarose composites powders are promising materials for filling of void in bone and drug delivery applications. PMID- 28012417 TI - Synthesis and characterization of MnS2/reduced graphene oxide nanohybrids for with photocatalytic and antibacterial activity. AB - A facile one-step hydrothermal route was developed here to prepare MnS2/reduced graphene oxide nanohybrids. The crystal morphologies could be controlled by adjusting the solvent, surfactant, and pH of the precursor solution. X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), UV-Vis absorption spectra, and photoluminescence spectra (PL), were used to characterize the structures of the samples were used to characterize the structures of the samples, and the specific surface area was determined using the Brunauer-Emmett-Teller (BET) method. The thickness of the MnS2 nanoparticles and MnS2/reduced graphene oxide nanohybrids were measured to be about 20 and 5nm, respectively. The total pore volume and specific surface area were 0.540 and 1.173cm3g-1 and 45.91 and 98.23m2g-1 for pure MnS2 and MnS2/r-GO hybrids, respectively. Carbophenothion as an insecticide photodegradation was used to estimate the photocatalytic activity of the MnS2/reduced graphene oxide nanohybrids morphologies under UV light. The Carbophenothion hardly decomposed during photolysis over a period of 45min. The rate constant, k value, for the photocatalysis of Carbophenothion by MnS2/reduced graphene oxide nanohybrids under UV light radiation is 0.134min-1. The antibacterial properties of the nanohybrids were evaluated by determining their minimum inhibitory and bactericidal concentrations (MIC and MBC), using a broth microdilution assay for Escherichia coli (E. coli) bacteria. The MIC and MBC values are 4.0 and 32.0MUg/mL. PMID- 28012418 TI - Characterization of a near-infrared fluorescent DCPO-tagged glucose analogue for cancer cell imaging. AB - Cancer cells are usually characterized with an increase in glucose uptake when compared with normal cells, which is known as Warburg effect. Near-infrared (NIR) fluorescent glucose analogues have been previously synthesized and been applied in cancer cell imaging. However, most NIR dyes usually have one or more charge in their structures, which may cause low cell membrane permeability and hamper their application in cell imaging. Here we reported a novel glucose analogue N2, which was designed and synthesized based on a new type of NIR dye, DCPO. As expected, higher level of N2 uptake was observed in hepatic carcinoma cells (HepG2) and gastric cancer cells (NCI-N87) than their equivalent cells from normal tissues of the same origin, respectively. The accumulation of N2 in cancer cells was in consistent with the overexpression of glucose transporter GLUT-1 in these cells. The cellular uptake of N2 was then confirmed to be dependent on GLUT-1, which was evidenced by the decreased uptake of N2 in the presence of d-glucose or GLUT-1 inhibitor phloretin. Moreover, uptake of N2 in cancer cells was found to be in a concentration- and time-dependent manner. In all, our study demonstrated that N2, as a novel DCPO-conjugated bioprobe, could be used to monitor cellular glucose consumption, and therefore might be applied in cancer cell bioimaging and bioassay in cancer studies. PMID- 28012419 TI - Formulation and purification of therapeutic dose of 90Y-labeled peptides: Some interesting radiochemistry aspects. AB - Yttrium-90 obtained from most of the 90Sr/90Y generators contains 90Sr impurity above permissible limit for human administration. A protocol has been optimized for formulation of therapeutic dose of 90Y-DOTA-Tyr3-octreotate (90Y-DOTA-TATE) and removal of 90Sr impurity from it. The radiochemical purity of 90Y-DOTA-TATE was found to be >98% and it met the requirements for clinical use. The radiopharmaceutical was used in preliminary clinical investigation in patients with neuroendocrine tumors. This promising strategy would aid toward widespread clinical utilization of 90Sr/90Y generators. PMID- 28012420 TI - Measuring social skills of children and adolescents in a Chinese population: Preliminary evidence on the reliability and validity of the translated Chinese version of the Social Skills Improvement System-Rating Scales (SSIS-RS-C). AB - The Social Skills Improvement System-Rating Scales (SSIS-RS; Gresham & Elliott, 2008) are designed to assist in the screening and classification of students (aged 5-18 years) who are suspected of presenting with social skills deficits and to offer guidelines in the development of interventions to remediate those types of problems. The objective of this study is to examine the preliminary reliability and validity of the translated Chinese version of the SSIS-RS, referred to as the SSIS-RS-C. In this study, parent-reported social skills and problem behaviors among students with typical development (n=79) were compared with those of age- and gender-matched students with a known developmental disability (n=79) using the SSIS-RS-C. The results indicated that the SSIS-RS-C subscale scores in all the disability groups were significantly different except for those in the Assertion scale for one disability group. Furthermore, the normative sample of typically developing children and adolescents (aged 5-12 and 13-18 years, n=567) from Hong Kong was established to improve the psychometric properties of the SSIS-RS-C. There were moderate to strong relationships between the common subscales across all forms of the SSIS-RS-C. Acceptable to excellent levels of internal consistency across all common subscales was also obtained. The scores for the Hong Kong sample (n=567) derived from the use of the SSIS-RS-C were then compared to the normative sample scores from the American version of the SSIS-RS. It was found that there were statistically significant differences on five out of the seven SSIS-RS-C Social Skill subscales for children aged 5-12 years and on four out of the seven SSIS-RS-C Social Skills subscales for the adolescent group (aged 13-18 years). Also, there were statistically significant differences between the American and Hong Kong samples on all of the SSIS-RS-C Problem Behavior scale scores. It was concluded that the SSIS-RS-C is a promising instrument for clinicians to be able to differentiate social skills and problem behaviors among students presenting with and without developmental disabilities in Hong Kong contexts. PMID- 28012421 TI - Distribution of tetracycline resistance genes and AmpC beta-lactamase genes in representative non-urban sewage plants and correlations with treatment processes and heavy metals. AB - The mixed development of livestock breeding and industry in non-urban zones is a very general phenomenon in China. Distribution of antibiotic resistance genes (ARGs) in non-urban sewage treatment systems has not been paid enough attentions. In this study, eleven tetracycline resistance genes (tetA, tetB, tetC, tetE, tetG, tetL, tetM, tetO, tetQ, tetS and tetX), four AmpC beta-lactamase genes (EBC, MOX, FOX and CIT) and four heavy metals (Cu, Zn, Cd and Pb) were detected and analyzed in four non-urban sewage plants with different sewage sources and different treatment processes in Guangzhou. The results showed that tetA and tetC were the most prevalent tetracycline resistance genes with the same detection frequency of 85% and EBC was the most prevalent AmpC beta-lactamase gene with a detection frequency of 75%. The relative abundance of tetracycline resistance genes was approximately 1.6 orders of magnitudes higher than that of AmpC beta lactamase genes in all samples. A/O was the most effective process for the non urban sewage plant receiving industrial or agricultural wastewater. Sedimentation was the most key process to eliminate ARGs from liquid phase. Most ARGs were carried in excess sludge rather than effluent. Significant correlation was found between the tet gene and Zn (r = 0.881, p < 0.01), followed by the AmpC gene and Cu (r = 0.847, p < 0.01), the tet gene and Cu (r = 0.714, p < 0.05). Therefore, the pollution of ARGs in the sewage treatment systems of non-urban zones co polluted by heavy metals should be paid more attentions. PMID- 28012422 TI - Altered patterns of association between cortical thickness and subcortical volume in patients with first episode major depressive disorder: A structural MRI study. AB - Depressed individuals may exhibit changes in cortical thickness and subcortical volume. However, we know little about their associated connection patterns in the brain's neural circuits. This study explored correlations between overall cortical thickness and the volume of several subcortical structures in first episode major depressive disorder (MDD) patients. Thirty-six untreated individuals experiencing their first episode of MDD were compared with healthy controls (n=41). Their brains were imaged by T1-weighted MRI, allowing the measurement of cortical thickness and the volume of subcortical structures. We found that in MDD patients, the cortex was thinner in four of the measured regions (frontal, temporal, parietal and insula) and the volume of the putamen and amygdala tended to be smaller compared with controls. Furthermore, the ratio of the volume of the four measured subcortical structures (left pallidum, left putamen, left amygdala and right caudate) to cortical thickness (measured in 11 regions)was significantly larger in the MDD group compared with controls. These results show that there are different relationships between subcortical volume and cortical thickness inearly-stage MDD and control subjects. PMID- 28012423 TI - Lateralization of intrinsic frontoparietal network connectivity and symptoms in schizophrenia. AB - It has been frequently reported that schizophrenia patients have reduced functional lateralization in the areas related to language processing. Furthermore, there is evidence supporting that schizophrenia patients have disrupted functional connectivity in the bilateral frontoparietal networks (FPNs), of which the left is strongly associated with a cognition-language paradigm, using resting-state functional magnetic resonance imaging (rsfMRI). To examine the laterality of resting-state functional connectivity in schizophrenia, we investigated the bilateral FPNs. We investigated 41 schizophrenia and 35 healthy participants using independent component analysis for rsfMRI. We extracted mean connectivity values of both left and right FPNs and calculated their laterality index by (left - right)/(left + right). Subsequently, we investigated group differences of these values and the correlation between these values and symptoms. In schizophrenia, mean connectivity values of both left and right FPNs were significantly lower than in healthy controls, whereas their laterality indices were not significantly different. However, correlation analyses revealed that the laterality index was negatively correlated with positive symptoms, and that mean connectivity of left FPN was negatively correlated with depressive symptoms in schizophrenia. Our results suggest that language-related networks and their laterality might be one of the neural correlates of schizophrenia symptoms. PMID- 28012424 TI - White matter microstructure and volitional motor activity in schizophrenia: A diffusion kurtosis imaging study. AB - Avolition is a core feature of schizophrenia and may arise from altered brain connectivity. Here we used diffusion kurtosis imaging (DKI) to investigate the association between white matter (WM) microstructure and volitional motor activity. Multi-shell diffusion MRI and 24-h actigraphy data were obtained from 20 right-handed patients with schizophrenia and 16 right-handed age and gender matched healthy controls. We examined correlations between fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), and motor activity level, as well as group differences in these measures. In the patient group, increasing motor activity level was positively correlated with MK in the inferior, medial and superior longitudinal fasciculus, the corpus callosum, the posterior fronto occipital fasciculus and the posterior cingulum. This association was not found in control subjects or in DTI measures. These results show that a lack of volitional motor activity in schizophrenia is associated with potentially altered WM microstructure in posterior brain regions associated with cognitive function and motivation. This could reflect both illness related dysconnectivity which through altered cognition, manifests as reduced volitional motor activity, and/or the effects of reduced physical activity on brain WM. PMID- 28012425 TI - Circadian disruption of ICU patients: A review of pathways, expression, and interventions. AB - Intensive care unit patients typically exhibit pathologic wakefulness, poor quality of daytime sleep, nocturnal sleep fragmentation, and sleep patterns that feature the absence of slow wave sleep and rapid eye movement. This article offers a review of the existing literature examining circadian desynchronization in critically ill patients, highlighting contributing factors identified by scholars, and circadian abnormalities observed in these patients. It discusses potential implications for clinical practice and suggests avenues of future research. Elucidating the role of circadian rhythms in the management of critical illness can guide future chronotherapeutic approaches and optimize patient outcomes. PMID- 28012426 TI - Perceived safety and efficacy of neuromuscular blockers for acute respiratory distress syndrome among medical intensive care unit practitioners: A multicenter survey. AB - PURPOSE: Neuromuscular blocking agents (NMBAs) are frequently used in patients with acute respiratory distress syndrome (ARDS). The purpose of this survey is to describe providers' knowledge and perceived efficacy and safety of NMBAs in patients with ARDS. MATERIALS AND METHODS: We performed a prospective, multicenter survey of medical intensive care unit intensivists, fellows, nurse practitioners (NPs), physician's assistants (PAs), and pharmacists at 5 tertiary care centers between July 2012 and May 2013. RESULTS: A total of 335 surveys were sent to providers, with a 47% response rate. Ninety-eight percent of providers correctly identified that NMBAs lack anxiolytic and analgesic properties. The effect of end-organ damage on NMBA clearance was less commonly identified by NPs/PAs for both hepatic (P=.0077) and renal (P=.0272) dysfunction compared with physicians. More NP/PAs identified the association of consciousness with the use of NMBAs than physicians (P=.047). Forty-two percent of prescribers reported always or frequently using continuous-infusion NMBAs in patients with severe ARDS, with 89% initiating NMBAs because of ventilator dyssynchrony. Prescribers perceived continuous NMBAs to be more effective than inhaled prostaglandins (74% vs 56%) in severe ARDS but less safe (45% vs 84%). Train of 4 was identified by 54% of prescribers as their primary method for titration. CONCLUSION: Providers are knowledgeable about NMBAs, but educational opportunities exist. Perceptions about the efficacy and safety of NMBAs varied among prescribers, and inconsistencies existed in the prioritization of management strategies for ARDS. PMID- 28012427 TI - Spousal concordance in the use of alternative tobacco products: A multi-country investigation. AB - BACKGROUND: Married couples often share similar health-related characteristics and behaviors, including cigarette smoking status. Despite their rising popularity in the U.S., little research has examined the patterns of spousal concordance (SC) for alternative tobacco products (ATPs), such as e-cigarettes, cigars, and hookah. METHODS: The purpose of this project was to examine the roles of age, gender, and culture in the strength of SC for these ATPs. Analyses focused on a diverse community sample of married individuals in Ohio, U.S. (N=278), but also examined patterns in Austria, Greece, Israel, the Netherlands, and Slovakia. All participants completed a survey in which they indicated both their own, and their spouse's ever-use of various tobacco products. RESULTS: For the U.S. sample, SC was highest for e-cigarettes, flavored e-cigarettes, flavored cigarettes, and hookah (phis=0.48- 0.61); SC appeared to be stronger among younger couples, and when there was only a small female vs. male differences in use. Similar patterns were found in the other countries, with a few key exceptions. In particular, there was low SC for e-cigarettes and flavored e cigarettes in the other countries, where e-cigarettes had been federally regulated by the time of data collection. CONCLUSION: Overall, these findings have implications for the continued spreading popularity of these tobacco use behaviors. PMID- 28012428 TI - Error detection and behavioural inhibition in young heavy drinkers. AB - BACKGROUND: Increases in inhibitory errors in heavy drinkers are established; less well-studied is whether heavy drinkers are aware of these errors in performance. Reductions in error detection and awareness limit the possibility for remedial action to be taken, and have implications for substance abusers seeking to control use: failure to monitor and/or adjust ongoing behaviour may be linked to using more or more often than intended, and failing to adjust behaviour after a slip. Here we report the first study of both inhibitory control and error awareness in young heavy drinkers, using behavioural and psychophysiological measures. METHODS: Heavy drinkers (n=25) and light- or non-drinking controls (n=35) completed a difficult inhibitory task which required signaling the awareness of inhibitory errors on the subsequent trial, while brain electrical activity was recorded. RESULTS: Heavy drinkers made more inhibitory errors than controls, but we observed no difference in error awareness, both via overt signaling and with equivalent amplitude of the error positivity (Pe), indexing conscious error detection. Similarly, controls and heavy drinkers showed no difference in amplitude or latency of the error-related negativity (ERN), indexing early pre-conscious error detection. CONCLUSIONS: This research suggests no significant difference in detection of errors in heavy drinkers, even as they are more prone to make these errors, a result seen in dependent drinkers reported elsewhere. Future research with larger sample sizes, and a more difficult task producing sufficient errors, should determine whether heavy drinkers employ sufficient post-error remedial action. PMID- 28012429 TI - Excess mortality among people who report lifetime use of illegal drugs in the United States: A 20-year follow-up of a nationally representative survey. AB - OBJECTIVE: The purpose of this study was to determine the mortality risks, over 20 years of follow-up in a nationally representative sample, associated with illegal drug use and to describe risk factors for mortality. METHODS: We analyzed data from the 1991 National Health Interview Survey, which is a nationally representative household survey in the United States, linked to the National Death Index through 2011. This study included 20,498 adults, aged 18-44 years in 1991, with 1047 subsequent deaths. A composite variable of self-reported lifetime illegal drug use was created (hierarchical categories of heroin, cocaine, hallucinogens/inhalants, and marijuana use). RESULTS: Mortality risk was significantly elevated among individuals who reported lifetime use of heroin (HR=2.40, 95% CI: 1.65-3.48) and cocaine (HR=1.27, 95% CI: 1.04-1.55), but not for those who used hallucinogens/inhalants or marijuana, when adjusting for demographic characteristics. Baseline health risk factors (smoking, alcohol use, physical activity, and BMI) explained the greatest amount of this mortality risk. After adjusting for all baseline covariates, the association between heroin or cocaine use and mortality approached significance. In models adjusted for demographics, people who reported lifetime use of heroin or cocaine had an elevated mortality risk due to external causes (poisoning, suicide, homicide, and unintentional injury). People who had used heroin, cocaine, or hallucinogens/inhalants had an elevated mortality risk due to infectious diseases. CONCLUSIONS: Heroin and cocaine are associated with considerable excess mortality, particularly due to external causes and infectious diseases. This association can be explained mainly by health risk behaviors. PMID- 28012430 TI - Factors associated with alcohol drinking behavior of cancer survivors: The Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: This study aimed to evaluate the factors associated with drinking behavior of cancer survivors after cancer diagnosis. METHODS: The study subjects were 906 adult cancer survivors who had reportedly drunk alcohol before cancer diagnosis and participated in the Korean National Health and Nutrition Examination Surveys conducted from 2007 to 2013. Among them, 360 abstained from alcohol drinking after cancer diagnosis. We categorized remaining 546 persistent drinkers into high-risk drinker (consuming>=7 glasses of alcohol for men and>=5 glasses of alcohol for women at one sitting at the frequency of at least once a month) or moderate drinker. We used multiple logistic regression analysis to evaluate risk factors associated with drinking behavior. RESULTS: The high-risk drinkers occupied 27.1% (148 survivors) of the persistent alcohol drinking survivors. Age increase (OR=0.96; 95% CI 0.93-0.99), female sex (OR=0.15; 95% CI 0.08-0.28), and increase of time lapse (by 1-year) after cancer diagnosis (OR=0.94; 95% CI 0.92-0.97) were associated with a lower risk of high-risk drinking as compared with moderate drinking. Meanwhile,<=9years of education (OR=1.99; 95% CI 1.10-3.60), alcohol-related cancer (OR=2.09; 95% CI 1.23-3.56), and current smoking (OR=1.92; 95% CI 1.03-3.59) were associated with increased risk of high-risk drinking of cancer survivors. CONCLUSIONS: These findings suggest that greater efforts for preventing high-risk drinking should be laid on the cancer survivors, with consideration of individual sociodemographic characteristics, especially when the survivors had been diagnosed with alcohol related cancer. PMID- 28012431 TI - Outsourcing cleaning services increases MRSA incidence: Evidence from 126 english acute trusts. AB - There has been extensive outsourcing of hospital cleaning services in the NHS in England, in part because of the potential to reduce costs. Yet some argue that this leads to lower hygiene standards and more infections, such as MRSA and, perhaps because of this, the Scottish, Welsh, and Northern Irish health services have rejected outsourcing. This study evaluates whether contracting out cleaning services in English acute hospital Trusts (legal authorities that run one or more hospitals) is associated with risks of hospital-borne MRSA infection and lower economic costs. By linking data on MRSA incidence per 100,000 hospital bed-days with surveys of cleanliness among patient and staff in 126 English acute hospital Trusts during 2010-2014, we find that outsourcing cleaning services was associated with greater incidence of MRSA, fewer cleaning staff per hospital bed, worse patient perceptions of cleanliness and staff perceptions of availability of handwashing facilities. However, outsourcing was also associated with lower economic costs (without accounting for additional costs associated with treatment of hospital acquired infections). PMID- 28012432 TI - Promissory identities: Sociotechnical representations & innovation in regenerative medicine. AB - The field of regenerative medicine (RM) is championed as a potential source of curative treatments and economic wealth, and initiatives have been launched in several countries to facilitate innovation within the field. As a way of examining the social dimensions of innovation within regenerative medicine, this paper explores the sociotechnical representations of RM technologies in the UK, and the tensions, affordances and complexities these representations present for actors within the field. Specifically, the paper uses the Science and Technology Studies-inspired notions of 'technology identity' and 'development space' to examine how particular technologies are framed and positioned by actors, and how these positionings subsequently shape innovation pathways. Four developing RM technologies are used as case studies: bioengineered tracheas; autologous chondrocyte implantation; T-cell therapies; and a 'point-of-care' cell preparation device. Using these case studies we argue that there are particular identity aspects that have powerful performative effects and provide momentum to innovation projects, and we argue that there are particular stakeholders in the UK RM landscape who appear to have considerable power in shaping these technology identities and thus innovation pathways. PMID- 28012433 TI - Breastfeeding attitude, health-related quality of life and maternal obesity among multi-ethnic pregnant women: A multi-group structural equation approach. AB - BACKGROUND: Identifying the factors influencing breastfeeding attitude is significant for the implementation of effective promotion policies and counselling activities. To our best knowledge, no previous studies have modelled the relationships among breastfeeding attitude, health-related quality of life and maternal obesity among multi-ethnic pregnant women; the current study attempts to fill this research gap. OBJECTIVES: This study investigated the relationships among maternal characteristics, health-related quality of life and breastfeeding attitude amidst normal weight and overweight/obese pregnant women using a multi-group structural equation modelling approach. DESIGN: Exploratory cross-sectional design was used. SETTING: Antenatal clinics of a university affiliated hospital PARTICIPANTS: Pregnant women were invited to participate; 708 (78.8%) agreed to participate in the study. METHODS: We examined a hypothetical model on the basis of integrating the concepts of a breastfeeding decision-making model, theory of planned behaviour-based model for breastfeeding and health related quality of life model among 708 multi-ethnic pregnant women in Singapore. The Iowa Infant Feeding Attitude Scale and Medical Outcomes Study Short Form Health Survey were used to measure breastfeeding attitude and health-related quality of life, respectively. RESULTS: Two structural equation models demonstrated that better health-related quality of life, higher monthly household income, planned pregnancy and previous exclusive breastfeeding experience were significantly associated with positive breastfeeding attitude among normal and overweight/obese pregnant women. Among normal weight pregnant women, those who were older with higher educational level were more likely to have positive breastfeeding attitude. Among overweight/obese pregnant women, Chinese women with confinement nanny plan were less likely to have positive breastfeeding attitude. No significant difference existed between normal weight and overweight/obese pregnant women concerning estimates of health-related quality of life on breastfeeding attitude (Critical Ratio=-0.193). The model satisfactorily fitted the data (Incremental Fit Index=0.924, Tucker-Lewis Index=0.905, Comparative Fit Index=0.921 and Root Means Square Error of Approximation=0.025). Health-related quality of life was found to affect breastfeeding attitude in multi-ethnic pregnant women. CONCLUSIONS: This relationship implied the importance of early culturally specific interventions to enhance health-related quality of life for improving positive breastfeeding attitude among pregnant women across different ethnic groups. PMID- 28012434 TI - Fixations to the eyes aids in facial encoding; covertly attending to the eyes does not. AB - When looking at images of faces, people will often focus their fixations on the eyes. It has previously been demonstrated that the eyes convey important information that may improve later facial recognition. Whether this advantage requires that the eyes be fixated, or merely attended to covertly (i.e. while looking elsewhere), is unclear from previous work. While attending to the eyes covertly without fixating them may be sufficient, the act of using overt attention to fixate the eyes may improve the processing of important details used for later recognition. In the present study, participants were shown a series of faces and, in Experiment 1, asked to attend to them normally while avoiding looking at either the eyes or, as a control, the mouth (overt attentional avoidance condition); or in Experiment 2 fixate the center of the face while covertly attending to either the eyes or the mouth (covert attention condition). After the first phase, participants were asked to perform an old/new face recognition task. We demonstrate that a) when fixations to the eyes are avoided during initial viewing then subsequent face discrimination suffers, and b) covert attention to the eyes alone is insufficient to improve face discrimination performance. Together, these findings demonstrate that fixating the eyes provides an encoding advantage that is not availed by covert attention alone. PMID- 28012435 TI - Estimation of radiation dosimetry for 68Ga-HBED-CC (PSMA-11) in patients with suspected recurrence of prostate cancer. AB - INTRODUCTION: This study was performed to estimate the human radiation dosimetry for [68Ga]Ga-HBED-CC (PSMA-11) (68Ga PSMA-11). METHODS: Under an RDRC-approved research protocol, we evaluated the biodistribution and pharmacokinetics of 68Ga PSMA-11 with serial PET imaging following intravenous administration to nine prostate cancer patients in whom clinical [11C]acetate PET/CT exams had been independently performed under Expanded Access IND 118,204. List-mode imaging was performed over the initial 0-10min post-injection with the pelvis in the field-of view. Whole-body images were acquired, pelvis-to-head, at 15, 60, and 90-min post injection. Additional images of the pelvis were acquired at 40-min and 115-min, and voided urine collected from each subject at 48-min and 120-min post injection. Radiation dosimetry estimates were calculated from these data using the OLINDA software package. RESULTS: Renal uptake was high and relatively invariant, ranging from 11% to 14% of the injected dose between 15 and 90-min post-injection. Radioactivity collected in the voided urine accounted for 14% of the injected dose over a period of 120-min. Lymph nodes and skeletal metastases suspicious for prostate cancer recurrence were detected in a greater number of patients using 68Ga PSMA-11 than using 11C-acetate. CONCLUSION: Kidneys are the critical organ following 68Ga PSMA-11 administration, receiving an estimated dose of 0.413mGy/MBq. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This study confirms that the kidneys will be the critical organ following intravenous administration of 68Ga PSMA-11, and provided data consistent with the expectation that 68Ga PSMA-11 will be superior to [11C]acetate for defining sites of recurrence in prostate cancer patients presenting with biochemical relapse. PMID- 28012436 TI - Reactive oxygen species signaling and stomatal movement: Current updates and future perspectives. AB - Reactive oxygen species (ROS), a by-product of aerobic metabolism were initially studied in context to their damaging effect but recent decades witnessed significant advancements in understanding the role of ROS as signaling molecules. Contrary to earlier views, it is becoming evident that ROS production is not necessarily a symptom of cellular dysfunction but it might represent a necessary signal in adjusting the cellular machinery according to the altered conditions. Stomatal movement is controlled by multifaceted signaling network in response to endogenous and environmental signals. Furthermore, the stomatal aperture is regulated by a coordinated action of signaling proteins, ROS-generating enzymes, and downstream executors like transporters, ion pumps, plasma membrane channels, which control the turgor pressure of the guard cell. The earliest hallmarks of stomatal closure are ROS accumulation in the apoplast and chloroplasts and thereafter, there is a successive increase in cytoplasmic Ca2+ level which rules the multiple kinases activity that in turn regulates the activity of ROS generating enzymes and various ion channels. In addition, ROS also regulate the action of multiple proteins directly by oxidative post translational modifications to adjust guard cell signaling. Notwithstanding, an active progress has been made with ROS signaling mechanism but the regulatory action for ROS signaling processes in stomatal movement is still fragmentary. Therefore, keeping in view the above facts, in this mini review the basic concepts and role of ROS signaling in the stomatal movement have been presented comprehensively along with recent highlights. PMID- 28012437 TI - Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo. AB - Autophagy allows cells fundamental adaptations to metabolic needs and to stress. Using autophagic bulk degradation cells can clear crosslinked macromolecules and damaged organelles that arise under redox stress. Accumulation of such debris results in cellular dysfunction and is observed in aged tissue and senescent cells. Conversely, promising anti-aging strategies aim at inhibiting the mTOR pathway and thereby activating autophagy, to counteract aging associated damage. We have inactivated autophagy related 7 (Atg7), an essential autophagy gene, in murine keratinocytes (KC) and have found in an earlier study that this resulted in increased baseline oxidative stress and reduced capacity to degrade crosslinked proteins after oxidative ultraviolet stress. To investigate whether autophagy deficiency would promote cellular aging, we studied how Atg7 deficient (KO) and Atg7 bearing cells (WT) would respond to stress induced by paraquat (PQ), an oxidant drug commonly used to induce cellular senescence. Atg7 deficient KC displayed increased prostanoid signaling and a pro- mitotic gene expression signature as compared to the WT. After exposure to PQ, both WT and KO cells showed an inflammatory and stress-related transcriptomic response. However, the Atg7 deficient cells additionally showed drastic DNA damage- and cell cycle arrest signaling. Indeed, DNA fragmentation and -oxidation were strongly increased in the stressed Atg7 deficient cells upon PQ stress but also after oxidizing ultraviolet A irradiation. Damage associated phosphorylated histone H2AX (gammaH2AX) foci were increased in the nuclei, whereas expression of the nuclear lamina protein lamin B1 was strongly decreased. Similarly, in both, PQ treated mouse tail skin explants and in UVA irradiated mouse tail skin, we found a strong increase in gammaH2AX positive nuclei within the basal layer of Atg7 deficient epidermis. Atg7 deficiency significantly affected expression of lipid metabolic genes. Therefore we performed lipid profiling of keratinocytes which demonstrated a major dysregulation of cellular lipid metabolism. We found accumulation of autophagy agonisitic free fatty acids, whereas triglyceride levels were strongly decreased. Together, our data show that in absence of Atg7/autophagy the resistance of keratinocytes to intrinsic and environmental oxidative stress was severely impaired and resulted in DNA damage, cell cycle arrest and a disturbed lipid phenotype, all typical for premature cell aging. PMID- 28012438 TI - On the nature of the Cu-rich aggregates in brain astrocytes. AB - Fulfilling a bevy of biological roles, copper is an essential metal for healthy brain function. Cu dyshomeostasis has been demonstrated to be involved in some neurological conditions including Menkes and Alzheimer's diseases. We have previously reported localized Cu-rich aggregates in astrocytes of the subventricular zone (SVZ) in rodent brains with Cu concentrations in the hundreds of millimolar. Metallothionein, a cysteine-rich protein critical to metal homeostasis and known to participate in a variety of neuroprotective and neuroregenerative processes, was proposed as a binding protein. Here, we present an analysis of metallothionein(1,2) knockout (MTKO) mice and age-matched controls using X-ray fluorescence microscopy. In large structures such as the corpus callosum, cortex, and striatum, there is no significant difference in Cu, Fe, or Zn concentrations in MTKO mice compared to age-matched controls. In the astrocyte rich subventricular zone where Cu-rich aggregates reside, approximately 1/3 as many Cu-rich aggregates persist in MTKO mice resulting in a decrease in periventricular Cu concentration. Aggregates in both wild-type and MTKO mice show XANES spectra characteristic of CuxSy multimetallic clusters and have similar [S]/[Cu] ratios. Consistent with assignment as a CuxSy multimetallic cluster, the astrocyte-rich SVZ of both MTKO and wild-type mice exhibit autofluorescent bodies, though MTKO mice exhibit fewer. Furthermore, XRF imaging of Au-labeled lysosomes and ubiquitin demonstrates a lack of co-localization with Cu-rich aggregates suggesting they are not involved in a degradation pathway. Overall, these data suggest that Cu in aggregates is bound by either metallothionein-3 or a yet unknown protein similar to metallothionein. PMID- 28012440 TI - Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. AB - : Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2-antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2-ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC. CONDENSED ABSTRACT: Our results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2-antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2-ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells. PMID- 28012442 TI - Lower use of prostate specific antigen testing by cigarette smokers-Another possible explanation for the unfavorable prostate cancer (PCA) specific prognosis in smokers? PMID- 28012439 TI - Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles. AB - Oxidative stress, mainly contributed by reactive oxygen species (ROS), has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-beta pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS generating NADPH oxidases (NOX) is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents. PMID- 28012441 TI - Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome mediated pathogen clearance. AB - The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1beta processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1beta and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1beta release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases. PMID- 28012443 TI - Evaluation of maternal health and labor and delivery conditions as risk factors for childhood leukemias in children with Down syndrome. AB - Children with Down syndrome (DS) have a remarkably high risk of developing leukemia during childhood; the mechanisms driving that risk are not well understood, and no clear prevention strategies exist. We conducted a nested case control study in a Texas DS birth cohort to investigate possible links between maternal health, labor/delivery conditions, and leukemia risk. For most of the factors studied there was no evidence of an increased risk of total leukemias, or the subtypes acute lymphoid or acute myeloid leukemia. Ultrasound use showed an almost 2-fold increased odds of leukemia, but this result is likely an example of confounding by indication. There was a pattern of increased risk seen for presence of co-occurring heart anomalies, including tetralogy of Fallot, ventricular septal defects, atrial septal defects, and patent ductus arteriosus. Further investigation of the links between co-occurring heart defects in children with DS and development of leukemia may provide new understanding of cancer mechanisms, and ultimately lead to prevention opportunities for this high-risk population. PMID- 28012445 TI - Editorial Comment to Antegrade ultrasound contrast injection facilitates accurate nephrostomy tube positioning during percutaneous nephrolithotomy. PMID- 28012444 TI - Carotid artery plaques and intima medial thickness in familial hypercholesteraemic patients on long-term statin therapy: A case control study. AB - BACKGROUND AND AIMS: Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). However, some FH patients still develop ASCVD despite statin therapy. We compared subclinical atherosclerosis assessed by carotid plaque presence and intima media thickness (C-IMT), in long-term statin-treated FH patients and healthy controls. Furthermore, we analysed whether carotid ultrasonography findings associated with subclinical coronary atherosclerosis. METHODS: We assessed the presence of carotid plaques and C-IMT in 221 asymptomatic heterozygous FH patients (48% men; 46 +/- 15 years) on long-term (10.0 +/- 7.8 years) statin treatment and 103 controls (32% men, 47 +/- 16 years). RESULTS: The frequency of carotid plaques and C-IMT did not differ significantly between the FH patients and controls (69 (31%) versus 24 (23%), p = 0.1 and 0.58 +/- 0.13 versus 0.58 +/- 0.12 mm, p = 0.9, respectively). In a subgroup of 49 FH patients who underwent cardiac computed tomography, coronary artery calcification correlated with carotid plaque presence (R = 0.47; p = 0.001), but not with C-IMT (R = 0.20; p = 0.2). CONCLUSIONS: Carotid plaques and C-IMT did not differ between long-term statin-treated heterozygous FH patients and healthy controls. This shows that long-term statin treatment in these FH patients reduces carotid atherosclerosis to a degree of a healthy population. These findings strongly suggests that sonography of the carotid arteries during follow-up of statin-treated FH patients has limited value. PMID- 28012446 TI - Retroperitoneal liposarcoma excreting insulin-like growth factor 2 that induced severe hypoglycemia. AB - Insulin-like growth factor 2 is overexpressed in various cancers, and is associated with a poor prognosis. Also, it is known that insulin-like growth factor 2 is an etiology of non-islet cell tumor hypoglycemia. In this report, we describe a case of unexpected hypoglycemia caused by a dedifferentiated liposarcoma producing insulin-like growth factor 2. A large mass in the retroperitoneum was detected in a 61-year-old man who complained of appetite loss. Despite having no history of diabetes mellitus, hypoglycemia suddenly occurred after admission, but oral glucose therapy was ineffective. After total parenteral nutrition, tumor resection was attempted, but failed as a result of rigid adhesion to the surrounding organs. The patient died of the disease 21 days after surgery. Pathological diagnosis at autopsy revealed dedifferentiated liposarcoma, and immunohistochemical staining showed that the tumor excreted insulin-like growth factor 2. The possibility of an insulin-like growth factor 2 producing tumor should be taken into consideration when we encounter a patient with spontaneous hypoglycemia resistant to glucose substitution therapy. PMID- 28012447 TI - Health promotion and empowerment in Henganofi District, Papua New Guinea. AB - Evidence shows that the government of Papua New Guinea is failing to provide basic services in health to the majority of its people. Local non-government organisations (NGOs), partnered with international NGOs, are attempting to fill this gap. With limited resources, these small Indigenous organisations must focus much of their effort on training that supports self-reliance as the main strategy for communities to improve their quality of life. This project explored the training content and methodology of Touching The Untouchables (TTU), a small Indigenous NGO based in Goroka, Eastern Highlands Province, that has trained a network of village volunteers in health promotion and safe motherhood.
Village life imposes multiple demands, from self-sufficiency in food to maintaining law and order. There are established attitudes about power and dependence, referred to as 'cargo thinking'. Cargo thinking stands as a barrier to the necessity of self-reliance, and requires training strategies that seek to empower participants to create change from their own initiative. Empowerment is understood as oriented towards individual people taking collective action to improve their circumstances by rectifying disparities in social power and control. To achieve self-reliance, empowerment is necessarily operational on the levels of person, community and society.
In addition to being operational on all three levels of empowerment, the training content and methodology adopted and developed by TTU demonstrate that empowering practice in training employs approaches to knowledge that are evidence-based, reflexive, contextual and skill based. Creating knowledge that is reflexive and exploring knowledge about the broader context uses special kinds of communicative tools that facilitate discussion on history, society and political economy. Furthermore, training methodologies that are oriented to empowerment create settings that require the use of all three types of communication required for cooperative action: dramaturgical, normative and teleological communication.
The success of TTU's training content and methodology demonstrates that creating the conditions for achieving collective self-reliance through empowerment is a necessary part of primary health promotion in Papua New Guinea, and that underlying the success of empowerment oriented training are definable types of knowledge and communication. PMID- 28012448 TI - Expression patterns of the chromosome 21 MicroRNA cluster (miR-99a, miR-125b and let-7c) in chorioamniotic membranes. AB - Trisomy 21 (T21) is the most common chromosome abnormality in humans and is associated with a spectrum of phenotypes, including cognitive impairment, congenital heart defects and immune system defects. In addition, T21 is also associated with abnormalities of fetal membranes including chorioamniotic separation, delayed fusion of the chorioamniotic membranes, defects in syncytiotrophoblast formation, as well as amniocyte senescence. There is evidence indicating miRNAs encoded by sequences on chromosome 21 (Chr-21) are involved in several of the cognitive and neurological phenotypes of T21, but the role of Chr 21 derived miRNAs in fetal membrane abnormalities associated with T21 has not been investigated. In the current study, we determined the expression patterns of three miRNAs derived from a cluster on Chr-21 - hsa-miR-99a, hsa-miR-125b and hsa let-7c in chorioamniotic membranes obtained from term pregnancies with spontaneous rupture (n = 20). Tissue and location specific expression patterns within the chorioamniotic membranes were identified. The rupture zone in the choriodecidua had distinct expression patterns compared to other fetal membrane locations. Despite the increased gene dosage associated with T21, the expression of all three miRNAs was reduced in cultured T21 amniocytes as compared to cultured euploid amniocytes. In silico analysis of experimentally validated targets of the three miRNAs suggest these Chr-21 derived miRNAs play a potential role in fetal membrane rupture and the fetal membrane defects associated with T21. PMID- 28012449 TI - Placental maternal vascular malperfusion and adverse pregnancy outcomes in gestational diabetes mellitus. AB - INTRODUCTION: Maternal vascular malperfusion (MVM) lesions represent hypoxic ischemic damage to the placenta, and they are associated with adverse pregnancy outcomes. Women with gestational diabetes (GDM) are at increased risk for pregnancy complications, so we set out to characterize the prevalence and clinical correlates of MVM lesions in this cohort. METHODS: This was a retrospective cohort study of 1187/1374 (86.4%) women with GDM delivered between 2009 and 2012 who had placental pathology available. Placental lesions of all types were tabulated and grouped into constructs of related entities. MVM lesions specifically included villous infarcts, decidual vasculopathy, increased syncytial knots, perivillous fibrin, and fibrin deposition. We compared maternal characteristics between women with and without MVM lesions, and we also assessed the impact of these lesions on birth weight, preterm birth, and pre-eclampsia using multivariable logistic regression analysis. RESULTS: MVM lesions were the most common placental lesion type in women with GDM (n = 362, 30.5%). Excess gestational weight gain was independently associated with MVM lesions (aOR 1.42, 95% CI 1.06-1.91, p = 0.02) after adjusting for maternal characteristics. MVM lesions were associated with lower birth weight (-90.3 g, 95% CI -148.0 to -32.7, p = 0.002), as well as a 2-fold increased risk for delivery of a small for gestational age infant (10.8 vs 5.9%, p = 0.01) in overweight and obese women. MVM lesions were also associated with increased risk for preterm birth <34 weeks (adjusted OR 2.36, 95% CI 1.31-4.23, p = 0.004) and hypertensive disorders of pregnancy (HDP; adjusted OR 1.58, 95% CI 1.13-2.22, p = 0.02). DISCUSSION: Placental maternal vascular malperfusion lesions may be one pathway linking excess gestational weight gain to adverse pregnancy outcomes in women with GDM, and future studies are needed to identify metabolic factors that may explain this association. PMID- 28012450 TI - Exploring sexual dimorphism in placental circulation at 22-24 weeks of gestation: A cross-sectional observational study. AB - INTRODUCTION: Placental blood flow is closely associated with fetal growth and wellbeing. Recent studies suggest that there are differences in blood flow between male and female fetuses. We hypothesized that sexual dimorphism exists in fetal and placental blood flow at 22-24 weeks of gestation. METHODS: This was a prospective cross-sectional study of 520 healthy pregnant women. Blood flow velocities of the middle cerebral artery (MCA), umbilical artery (UA), umbilical vein (UV) and the uterine arteries (UtA) were measured using Doppler ultrasonography. UV and UtA diameters were measured using two-dimensional ultrasonography and power Doppler angiography. Volume blood flows (Q) of the UV and UtA were calculated. Maternal haemodynamics was assessed with impedance cardiography. UtA resistance (Ruta) was computed as MAP/Quta. RESULTS: UA PI was significantly (p = 0.008) higher in female fetuses (1.19 +/- 0.15) compared with male fetuses (1.15 +/- 0.14). MCA PI, cerebro-placental ratio (MCA PI/UA PI), Quv, UtA PI, Quta and Ruta were not significantly different between groups. At delivery, the mean birth weight and placental weight of female infants (3504 g and 610 g) were significantly (p = 0.0005 and p = 0.039) lower than that of the male infants (3642 g and 634 g). DISCUSSION: We have demonstrated sexual dimorphism in UA PI, a surrogate for placental vascular resistance, at 22-24 weeks of gestation. Therefore, it would be useful to know when this difference emerges and whether it translates into blood flow differences that may impact upon the fetal growth trajectory. PMID- 28012451 TI - Activation of the cholinergic anti-inflammatory pathway by nicotine ameliorates lipopolysaccharide-induced preeclampsia-like symptoms in pregnant rats. AB - INTRODUCTION: Preeclampsia (PE) exerts a more intense systemic inflammatory response than normal pregnancy. Recently, the role of the cholinergic anti inflammatory pathway (CAP) in regulating inflammation has been extensively studied. The aim of this study was to investigate the effect of nicotine, a selective cholinergic agonist, on lipopolysaccharide (LPS)-induced preeclampsia like symptoms in pregnant rats and to determine the molecular mechanism underlying it. METHODS: Rats were administered LPS (1.0 MUg/kg) via tail vein injection on gestational day 14 to induce preeclampsia-like symptoms. Nicotine (1.0 mg/kg/d) and alpha-bungarotoxin (1.0 MUg/kg/d) were injected subcutaneously into the rats from gestational day 14-19. Clinical symptoms were recorded. Serum and placentas were collected to determine cytokine levels using Luminex. The mRNA and protein expression levels of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) were determined using Real time-PCR and Western blot analysis. Immunohistochemistry was performed to determine the level of activation of nuclear factor-kappaB (NF-kappaB) in placentas. RESULTS: Nicotine significantly ameliorated LPS-induced preeclampsia-like symptoms in pregnant rats (P < 0.05). Nicotine treatment decreased the levels of LPS-induced pro-inflammatory cytokines in the serum (P < 0.05) and placenta (P < 0.05). Nicotine significantly increased the expression of alpha7nAChR (P < 0.01) and attenuated the activation of NF kappaB p65 in the placenta in LPS-induced preeclampsia (P < 0.01). Meanwhile, these protective effects of nicotine were abolished by the administration of the cholinergic antagonist alpha-bungarotoxin in preeclampsia rats. DISCUSSION: Our findings suggest that the activation of alpha7nAChR by nicotine attenuates preeclampsia-like symptoms, and this protective effect is likely the result of the inhibition of inflammation via the NF-kappaB p65 pathway. PMID- 28012452 TI - Expression of HLA-E molecules in the placental tissue of women infected with HIV 1 and uninfected women. AB - INTRODUCTION: Expression of HLA-E molecule in the placental extravillous trophoblast is associated with immune system cell inhibition, resulting in immune tolerance to fetus during pregnancy. HIV-1 can infect trophoblast cells and modify the expression of HLA-E, which may inhibit the cytotoxic activity of the immune system. AIM: The aim of this study was to evaluate HLA-E expression in third trimester placental tissue of women infected with HIV-1 and uninfected women. METHODS: We performed an immunohistochemistry assay to evaluate HLA-E staining in the placental tissue of 99 HIV-1 infected and 85 uninfected women. A pathologist analyzed and classified the HLA-E expression in the placental cells. RESULTS: Irrespective of the HIV status, HLA-E staining was observed in the extravillous trophoblast cells, endothelial cells and Hofbauer cells, but not in the syncytiotrophoblast. HLA-E staining showed no significant difference between the placental tissue of women infected with HIV-1 and uninfected women (P = 0.76). Considering HIV-1 infected women, HLA-E staining was not influenced by HIV 1 viral load (P = 0.48), CD4+ T-cell count (P = 0.10) and antiretroviral therapy used during pregnancy (P = 0.54). DISCUSSION: Despite the presence of HIV-1 infection, the expression of HLA-E molecules in the placental tissue was not modified when the infection was under antiretroviral therapy control. PMID- 28012453 TI - The effect of histone deacetylase inhibition on the expression of P-glycoprotein in human placental trophoblast cell lines. AB - INTRODUCTIONS: Placental P-glycoprotein (P-gp), encoded by ABCB1 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Investigations on placental P-gp regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the epigenetic control of placental P-gp is rare. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on P-gp expression in placental trophoblast cell lines and to explore whether HDAC1/2/3 was involved in this process preliminarily. METHODS: Human placental trophoblast cell lines (Bewo and JAR) were treated with two different HDAC inhibitors-suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0 and 5.0 MUM. Cells were harvested after 24, 48, and 72 h treatment. Total HDAC activity was detected by colorimetric assay Kits. HDAC1/2/3/ABCB1 mRNA and protein expressions were determined by real-time quantitative PCR and western-blot, respectively. Pearson correlation analysis test was performed to explore the relationship between HDAC1/2/3 mRNA and ABCB1 mRNA expression. RESULTS: SAHA and TSA could inhibit total HDAC activity and placental HDAC1/2/3 expression both in Bewo and JAR, but displayed a transient induction of HDAC mRNA or protein level after being treated at low dosage or prolonged exposure to drugs. Discordance in HDAC mRNA and protein expression was also observed. Placental P-gp expression was significantly induced in company with HDACs inhibition. There was a significant negative linear relationship between HDAC1/2 mRNA and ABCB1 mRNA expression. CONCLUSIONS: HDACs inhibition could up-regulate placental P-gp expression in trophoblast cells, and HDAC1/2 was most likely to be involved in this process. PMID- 28012454 TI - Prediction of low birth weight: Comparison of placental T2* estimated by MRI and uterine artery pulsatility index. AB - OBJECTIVE: Neonates at low birth weight due to placental dysfunction are at high risk of adverse outcomes. These outcomes can be substantially improved by prenatal identification. The Magnetic Resonance Imaging (MRI) constant, placental T2* reflects placental structure and oxygenation and thereby placental function. Therefore, we aimed to evaluate the performance of placental T2* in the prediction of low birth weight using the uterine artery (UtA) pulsatility index (PI) as gold standard. METHODS: This was a prospective observational study of 100 singleton pregnancies included at 20-40 weeks' gestation. Placental T2* was obtained using a gradient recalled multi-echo MRI sequence and UtA PI was measured using Doppler ultrasound. Placental pathological examination was performed in 57 of the pregnancies. Low birth weight was defined by a Z-score <= 2.0. RESULTS: The incidence of low birth weight was 15%. The median time interval between measurements and birth was 7.3 weeks (interquartile range 3.0, 13.7 weeks). Linear regression revealed significant associations between birth weight Z-score and both placental T2* Z-score (r = 0.68, p < 0.0001) and UtA PI Z-score (r = -0.43, p < 0.0001). Receiver operating characteristic curves demonstrated a significantly higher performance of T2* (AUC of 0.92; 95% CI, 0.85-0.98) than UtA PI (AUC of 0.74; 95% CI, 0.60-0.89) in the prediction of low birth weight (p = 0.010). Placental pathological findings were closely related to the T2* values. CONCLUSIONS: In this population, placental T2* was a strong predictor of low birth weight and it performed significantly better than the UtA PI. Thus, placental T2* is a promising marker of placental dysfunction which deserves further investigation. PMID- 28012455 TI - Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner. AB - INTRODUCTION: Obesity is a major clinical problem in obstetrics being associated with adverse pregnancy outcomes and fetal programming. Brain derived neurotrophic factor (BDNF), a validated miR-210 target, is necessary for placental development, fetal growth, glucose metabolism, and energy homeostasis. Plasma BDNF levels are reduced in obese individuals; however, placental BDNF has yet to be studied in the context of maternal obesity. In this study, we investigated the effect of maternal obesity and sexual dimorphism on placental BDNF signaling. METHODS: BDNF signaling was measured in placentas from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI>30) women at term without medical complications that delivered via cesarean section without labor. MiRNA-210, BDNF mRNA, proBDNF, and mature BDNF were measured by RT - PCR, ELISA, and Western blot. Downstream signaling via TRKB (BDNF receptor) was measured using Western blot. RESULTS: Maternal obesity was associated with increased miRNA-210 and decreased BDNF mRNA in placentas from female fetuses, and decreased proBDNF in placentas from male fetuses. We also identified decreased mature BDNF in placentas from male fetuses when compared to female fetuses. Mir-210 expression was negatively correlated with mature BDNF protein. TRKB phosphorylated at tyrosine 817, not tyrosine 515, was increased in placentas from obese women. Maternal obesity was associated with increased phosphorylation of MAPK p38 in placentas from male fetuses, but not phosphorylation of ERK p42/44. DISCUSSION: BDNF regulation is complex and highly regulated. Pre-pregnancy/early maternal obesity adversely affects BDNF/TRKB signaling in the placenta in a sexually dimorphic manner. These data collectively suggest that induction of placental TRKB signaling could ameliorate the placental OB phenotype, thus improving perinatal outcome. PMID- 28012456 TI - Comparative phenotypic transcriptional characterization of human full-term placenta-derived mesenchymal stromal cells compared to bone marrow-derived mesenchymal stromal cells after differentiation in myogenic medium. AB - Placenta-derived mesenchymal stromal cells (pMSCs) are a very attractive source of MSCs. In this short report we evaluated the expression of phenotypic markers from fetal and maternal pMSCs after exposure to myogenic medium commonly used to differentiate bone marrow MSCs (bmMSCs) to smooth muscle-like cells (SMCs). In order to reveal differences between these different MSC sources, cells were expanded and differentiated to elucidate whether this differentiation protocol facilitated efficient differentiation of SMCs from human pMSCs. We report that TGF-beta1, PDGF and ascorbic acid is not sufficient to produce SMCs from pMSCs. PMID- 28012457 TI - Identification of novel genetic markers for mouse yolk sac cells by using microarray analyses. AB - The mouse embryonic yolk sac consists of a visceral yolk sac (VYS) and parietal yolk sac (PYS), and may function as a materno-fetal exchange system for nutrients and wastes, and physical protector for the embryo/fetus. The present study was undertaken to characterize gene expression of the VYS and PYS endodermal cells, and to identify their novel genetic markers from microarray data. Apoa4, Lrp2, Fxyd2, Slc34a3 and Entpd2 were predominantly expressed in VYS epithelial cells. Gkn2 and Pga5 were selected as markers for PYS cells. These genetic markers may be useful for characterization of murine yolk sacs during development. PMID- 28012458 TI - Impact of early- and late-onset preeclampsia on features of placental and newborn vascular health. AB - INTRODUCTION: Offspring exposed to preeclampsia (PE) show an increased risk of cardiovascular disease in adulthood. We hypothesize that this is mediated by a disturbed vascular development of the placenta, umbilical cord and fetus. Therefore, we investigated associations between early-onset PE (EOPE), late-onset PE (LOPE) and features of placental and newborn vascular health. METHODS: We performed a nested case-control study in The Rotterdam Periconceptional Cohort, including 30 PE pregnancies (15 EOPE, 15 LOPE) and 218 control pregnancies (164 uncomplicated controls, 54 complicated controls including 28 fetal growth restriction, 26 preterm birth) and assessed macroscopic and histomorphometric outcomes of the placenta and umbilical cord. RESULTS: A significant association was observed between PE and a smaller umbilical vein area and wall thickness, independent of gestational age and birth weight. In EOPE we observed significant associations with a lower weight, length and width of the placenta, length of the umbilical cord, and thickness and wall area of the umbilical vein and artery. These associations attenuated after gestational age and birth weight adjustment. In LOPE a significant association with a larger placental width and smaller umbilical vein wall thickness was shown, independent of gestational age and birth weight. DISCUSSION: Our study suggests that PE is associated with a smaller umbilical cord vein area and wall thickness, independent of gestational age and birth weight, which may serve as a proxy of disturbed cardiovascular development in the newborn. Follow-up studies are needed to ultimately predict and lower the risk of cardiovascular disease in offspring exposed to PE. PMID- 28012459 TI - Down-regulated long non-coding RNA-ATB in preeclampsia and its effect on suppressing migration, proliferation, and tube formation of trophoblast cells. AB - Preeclampsia is a pregnancy-specific syndrome and is one of the main causes of maternal, fetal, and neonatal morbidity and mortality. Inadequate trophoblast invasion and failure of uterine spiral artery remodeling exert a major role in the development of preeclampsia, especially the early-onset one. LncRNA-ATB is verified to be aberrantly expressed in many cancers and promote the invasion metastasis and proliferation cascades. But little is known of lncRNA-ATB's role in preeclampsia. The aim of current study is to identify the changes of lncRNA ATB in preeclampsia and its effects on trophoblast. The lncRNA-ATB levels were decreased in placental samples collected from preeclampsia women (n = 51) compared to those of healthy pregnant women (n = 40) by qRT-PCR analysis. Besides, it is demonstrated that lncRNA-ATB was intense stained in the trophoblast of the placenta by performing in-situ hybridization. By designing RNA interference species to suppress lncRNA-ATB and specific plasmids designed to overexpress lncRNA-ATB, we identify the role of lncRNA-ATB on the functions of trophoblast cell-line, HTR-8/SVneo. Inhibition of endogenous lncRNA-ATB decreased migration, proliferation, tube-formation of HTR-8/SVneo cells. In addition, overexpression of lncRNA-ATB promoted migration, proliferation, and tube formation of HTR-8/SVneo cells. Therefore, lncRNA-ATB might be involved in the pathogenesis of preeclampsia by regulating the process of trophoblast invasion and endovascular formation. PMID- 28012460 TI - A new high-resolution 3-D quantitative method for identifying bone surface modifications with implications for the Early Stone Age archaeological record. AB - Bone surface modifications have become important indicators of hominin behavior and ecology at prehistoric archaeological sites. However, the method by which we identify and interpret these marks remains largely unchanged despite decades of research, relying on qualitative criteria and lacking standardization between analysts. Recently, zooarchaeologists have begun using new technologies capable of capturing 3-D data from bone surface modifications to advance our knowledge of these informative traces. However, an important step in this research has been overlooked and after years of work, we lack both a universal and replicable protocol and an understanding of the precision of these techniques. Here we propose a new standard for identifying bone surface modifications using high resolution 3-D data and offer a systematic and replicable approach for researchers to follow. Data were collected with a white-light non-contact confocal profilometer and analyzed with Digital Surf's Mountains(r) software. Our data show that when methods are standardized, results between researchers are statistically indistinguishable. Multivariate analyses using the measured parameters allow discrimination between stone tool cut marks and mammalian carnivore tooth marks with 97.5% accuracy. Application of this method to fossil specimens resulted in 100% correspondence with identifications made by an experienced analyst using macroscopic observations of qualitative features of bone surface modifications. High-resolution 3-D analyses of bone surface modifications have great potential to improve the reliability and accuracy of taphonomic research, but only if our methods are replicable and precise. PMID- 28012461 TI - Ten years in the dump: An updated review of the Miocene primate-bearing localities from Abocador de Can Mata (NE Iberian Peninsula). AB - More than ten years of paleontological fieldwork during the enlargement of the Can Mata Landfill (Abocador de Can Mata [ACM]), in els Hostalets de Pierola (Valles-Penedes Basin, NE Iberian Peninsula) led to the recovery of >60,000 Miocene vertebrate remains. The huge sampling effort (due to continuous surveillance of heavy machinery digging activity, coupled with manual excavation and screen-washing of sediments) enabled generally rare faunal elements such as pliopithecoid and hominoid primates to be found. Thanks to detailed litho-, bio- and magnetostratigraphic controls, accurate dating is possible for all the recovered primate remains from 19 of the 235 localities defined along the 234 m thick composite stratigraphic sequence of the ACM. Here we report updated estimated (interpolated) ages for these paleontological localities and review the timing of the primate succession in this area. Our results indicate that the whole ACM sequence is late Aragonian in age (MN6 and MN7+8) and includes seven magnetozones that are correlated to subchrons C5Ar.1r to C5r.2r (ca. 12.6 to 11.4 Ma). Great apes (dryopithecines) are first recorded at 12.4-12.3 Ma, but most of the finds (Anoiapithecus, Pierolapithecus and Dryopithecus) cluster between 12.0 and 11.9 Ma, followed by some indeterminate dryopithecine remains between 11.7 and 11.6 Ma. Pliopithecoids first appear at 12.1 Ma, being subsequently represented by Pliopithecus between 11.9 and 11.7 Ma. The small-bodied hominoid Pliobates is the youngest ACM primate, with an estimated age of 11.6 Ma. Although these primates probably overlapped in time, their co-occurrence is recorded only twice, at 11.9 Ma (a dryopithecine with Pliopithecus) and at 11.6 Ma (a dryopithecine with Pliobates). The rare co-occurrence between great apes and small-bodied catarrhines might be attributable to sampling biases and/or to presumed diverging ecological preferences of these groups. In the future, more detailed analyses of the fauna recovered from the long and densely-sampled ACM sequence will hopefully throw new light on this long-standing, unresolved question. PMID- 28012462 TI - New sivaladapid primate from Lower Siwalik deposits surrounding Ramnagar (Jammu and Kashmir State), India. AB - Over the past century, numerous vertebrate fossils collected near the town of Ramnagar, India, have proven to be important for understanding the evolution and biogeography of many mammalian groups. Primates from Ramnagar, though rare, include a number of hominoid specimens attributable to Sivapithecus, as well as a single published mandibular fragment preserving the P4-M1 of the Miocene adapoid Sivaladapis palaeindicus. Since 2010, we have renewed fossil prospecting in the Lower Siwalik deposits near Ramnagar in an attempt to better understand the evolution, biogeographic timing, and paleoclimatic context of mammalian radiations in Asia, with a particular focus on primates. Our explorations have resulted in the identification of new fossil localities, including the site of Sunetar. The age of Sunetar and the Ramnagar region, in general, is tentatively dated between 14 and 11 Ma. In 2014, a partial right mandible of a sivaladapid primate was recovered at Sunetar, preserving the corpus with P4 roots and worn M1 M3 dentition. Although sivaladapids are known by numerous specimens of two genera (Sivaladapis and Indraloris) at Lower Siwalik sites on the Potwar Plateau (Pakistan) and at the Middle Siwalik locality of Haritalyangar (India), this new specimen is just the second sivaladapid recovered from the Ramnagar region. Our analyses suggest that the new specimen is distinct from all other sivaladapids, and we therefore describe it as a new genus and species close to the base of the Sivaladapinae. PMID- 28012463 TI - Microchoerus hookeri nov. sp., a new late Eocene European microchoerine (Omomyidae, Primates): New insights on the evolution of the genus Microchoerus. AB - The study of Eocene primates is crucial for understanding the evolutionary steps undergone by the earliest members of our lineage and the relationships between extinct and extant taxa. Recently, the description of new material from Spain has improved knowledge of European Paleogene primates considerably, particularly regarding microchoerines. Here we describe the remains of Microchoerus from Sossis (late Eocene, Northern Spain), consisting of more than 120 specimens and representing the richest sample of Microchoerus from Spain. This primate was first documented in Sossis during the 1960s, on the basis of scarce specimens that were ascribed to Microchoerus erinaceus. However, the studied material clearly differs from M. erinaceus at its type locality, Hordle Cliff, and shows some characters that allow the erection of a new species, Microchoerus hookeri. This new species is characterized by its medium size, moderate enamel wrinkling, generally absent mesoconid and small hypoconulid in the M1 and M2, single paracone in the upper molars and premolars and, particularly, by the lack of mesostyle in most M1 and M2, a trait not observed in any other species of Microchoerus. Some specimens from Eclepens B (late Eocene, Switzerland), determined previously to be Microcherus aff. erinaceus, are also ascribed to M. hookeri. M. hookeri represents the first step of a lineage that differentiated from Necrolemur antiquus and, later, gave rise to several unnamed forms of Microchoerus, such as those from Euzet and Perriere, finally leading to M. erinaceus. This discovery sheds new light on the complex evolutionary scheme of Microchoerus, indicating that it is most probably a paraphyletic group. A detailed revision of the age of the localities containing remains of Microchoerus and the description of the still unpublished material from some European localities, are necessary to clarify the phylogenetic relationships among the members of this microchoerine group. PMID- 28012464 TI - Corrigendum to "New polyhydroxylated sterols from Palythoa tuberculosa and their apoptotic activity in cancer cells" [Steroids 101 (2015) 110-115]. PMID- 28012465 TI - Corrigendum to "Stereocontrolled synthesis of the four 16-hydroxymethyl-19 nortestosterone isomers and their antiproliferative activities" [Steroids 105 (2016) 113-120]. PMID- 28012466 TI - Like a prayer. PMID- 28012467 TI - Changing the bipolar illness trajectory. PMID- 28012468 TI - Monoclonal antibody immunotherapy in psychiatric disorders. PMID- 28012469 TI - Shortage of psychiatric medications in South Africa. PMID- 28012471 TI - Psychiatry's response to mass traumatisation and the global refugee crisis. PMID- 28012470 TI - Trends in new psychoactive substances from surface and "dark" net monitoring. PMID- 28012472 TI - Sobering news about post-stroke depression. PMID- 28012474 TI - Corrections. PMID- 28012475 TI - Misdiagnosis of Huntington's disease - Authors' reply. PMID- 28012476 TI - DSM-III-R change in definition might have affected placebo response to antidepressants. PMID- 28012477 TI - Misdiagnosis of Huntington's disease. PMID- 28012478 TI - DSM-III-R change in definition might have affected placebo response to antidepressants - Authors' reply. PMID- 28012479 TI - First-episode psychosis and abnormal glycaemic control. PMID- 28012480 TI - First-episode psychosis and abnormal glycaemic control - Authors' reply. PMID- 28012482 TI - David Coghill: the right place at the right time. PMID- 28012483 TI - A case for the religious history. PMID- 28012484 TI - Blue. PMID- 28012485 TI - Efficacy of early administration of escitalopram on depressive and emotional symptoms and neurological dysfunction after stroke: a multicentre, double-blind, randomised, placebo-controlled study. AB - BACKGROUND: Mood and emotional disturbances are common in patients with stroke, and adversely affect the clinical outcome. We aimed to evaluate the efficacy of early administration of escitalopram to reduce moderate or severe depressive symptoms and improve emotional and neurological dysfunction in patients with stroke. METHODS: This was a placebo controlled, double-blind trial done at 17 centres in South Korea. Patients who had had an acute stroke within the past 21 days were randomly assigned in a 1:1 ratio to receive oral escitalopram (10 mg/day) or placebo for 3 months. Randomisation was done with permuted blocks stratified by centre, via a web-based system. The primary endpoint was the frequency of moderate or severe depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS] >=16). Endpoints were assessed at 3 months after randomisation in the full analysis set (patients who took study medication and underwent assessment of primary endpoint after randomisation), in all patients who were enrolled and randomly assigned (intention to treat), and in all patients who completed the trial (per-protocol analysis). This trial is registered with ClinicalTrials.gov, number NCT01278498. FINDINGS: Between Jan 27, 2011, and June 30, 2014, 478 patients were assigned to placebo (n=237) or escitalopram (n=241); 405 were included in the full analysis set (195 in the placebo group, 210 in the escitalopram group). The primary outcome did not differ by study group in the full analysis set (25 [13%] patients in the placebo group vs 27 [13%] in the escitalopram group; odds ratio [OR] 1.00, 95% CI 0.56-1.80; p>0.99) or in the intention-to-treat analysis (34 [14%] vs 35 [15%]; OR 1.01, 95% CI 0.61-1.69, p=0.96). The study medication was generally well tolerated; the most common adverse events were constipation (14 [6%] patients who received placebo vs 14 [6%] who received escitalopram), muscle pain (16 [7%] vs ten [4%]), and insomnia (12 [5%] vs 12 [5%]). Diarrhoea was more common in the escitalopram group (nine [4%] patients) than in the placebo group (two [1%] patients). INTERPRETATION: Escitalopram did not significantly reduce moderate or severe depressive symptoms in patients with acute stroke. FUNDING: Dong-A Pharmaceutical and Ministry for Health, Welfare, and Family Affairs, South Korea. PMID- 28012486 TI - Safety management of treatment with nintedanib in clinical practice of IPF. PMID- 28012487 TI - Factors associated with the relapse of cryptogenic and secondary organizing pneumonia. AB - BACKGROUND: Organizing pneumonia (OP) is a histopathological response pattern to lung inflammation. It is clinically classified into cryptogenic OP and secondary OP, which is associated with various clinical conditions. Rapid resolution with corticosteroids and frequent relapses are common in OP. However, few studies have investigated the factors associated with OP relapse. METHODS: The medical records of 75 patients with biopsy-proven OP, diagnosed between January 2010 and August 2015, who underwent corticosteroid therapy were retrospectively reviewed. Initially, the patients were all treated successfully; however, 31 patients experienced relapse thereafter (R group), whereas the others did not (NR group; 44 patients). The clinical, radiological, and pathological characteristics and administered corticosteroid doses were compared between the two groups. RESULTS: The neutrophil percentage in the bronchoalveolar lavage (BAL) fluid and the level of fibrin deposition in lung biopsy specimens were higher in the R group than in the NR group (P=0.01 and P=0.002, respectively). The multivariate analysis demonstrated that both factors were statistically significant predictors of OP relapse. CONCLUSIONS: A high neutrophil percentage in the BAL and the level of fibrin deposition in lung biopsy specimens are considered predictive factors of OP relapse during the tapering or after the cessation of steroid therapy. Patients without these findings may be treated with low-dose corticosteroids. PMID- 28012488 TI - Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study. METHODS: Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (DeltaFVC), and the rate of decline (%DeltaFVC). RESULTS: Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in DeltaFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 >=1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-6 <1000ml and no serial increases in KL-6 had the least decline in DeltaFVC and %DeltaFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values <1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values >=1000U/ml (p<0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes >51.8U/ml/year than in those with serial KL-6 changes <51.8U/ml/year (p=0.0009). CONCLUSION: Thus, serial serum KL 6 measurements can be useful for assessing prognosis in patients with IPF. PMID- 28012489 TI - Pathognomonic remodeling of blood and lymphatic capillaries in idiopathic pulmonary fibrosis. AB - Numerous studies have been published investigating the pathologic alterations in various interstitial pneumonias, particularly in idiopathic pulmonary fibrosis (IPF). However, the few existing studies on capillary remodeling, which does not seem to have priority for pathologic diagnosis, are contradictory, with some reporting increased and others reduced vascularization. We hypothesized that these discrepancies were due to the temporal heterogeneity of the lesions in IPF. We subsequently developed original techniques for evaluating vascular density within the alveolar septa and discovered, for the first time, a heterogeneous increase in alveolar capillaries in the lungs of IPF patients. Notably, we consistently found that the fibrotic lesions in IPF lungs, which are composed mainly of dense collagen with myofibroblasts, featured a reduction in capillaries. This finding provides a plausible explanation for the intractability of IPF, as this reduced vascularization would result in poor delivery of anti fibrotic agents to these lesions. We also reported the disappearance of subpleural and interlobular lymphatics in IPF lungs, which likely results in poor alveolar clearance in the diseased lungs. Finally, we assessed the autopsied lungs of patients with IPF who died because of acute exacerbation and observed increased and dilated alveolar capillaries. These capillaries are likely to be "leaky" owing to exposure to VEGF produced by regenerated alveolar type II epithelial cells. Furthermore, poor alveolar clearance may prolong the high mobility group box 1 (HMGB1)-induced lung injury in acute exacerbation of IPF. Our data obtained from the assessment of blood and lymphatic capillary alterations in IPF provide novel pathogenetic insights and may provide the basis for new therapeutic strategies targeting IPF. PMID- 28012490 TI - Association of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease. AB - BACKGROUND: We attempted to clarify whether the presence of anti-aminoacyl transfer RNA synthetase antibody (anti-ARS Ab) or anti-melanoma differentiation associated gene 5 antibody (anti-MDA5 Ab) is associated with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). METHODS: We retrospectively investigated 22 patients with PM/DM-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab) for whom antibody analysis of conserved serum was possible. We assessed mortality in the first three months as the therapeutic response in the acute phase and compared changes in clinical data for up to one year considered as the chronic phase. We classified the clinical changes over the year into three groups: Improvement (increased % vital capacity [%VC] or diffusing capacity of the lung for carbon monoxide [%DLCO]>=10 or 15%), deterioration (decreased %VC or %DLCO>=10 or 15%), and no change (remainder of the changes). The extent of abnormality demonstrated by high-resolution computed tomography (HRCT) was scored. RESULTS: Positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %DLCO and a decline in the serum KL-6 levels. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by HRCT. CONCLUSIONS: Anti-ARS and anti MDA5 Abs are associated with the therapeutic response of PM/DM-ILD. PMID- 28012491 TI - Associations between the distance covered in the incremental shuttle walk test and lung function and health status in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Field walk tests such as the incremental shuttle walk test (ISWT) are simple tests for assessing the degree of disability in individuals with chronic obstructive pulmonary disease (COPD). In the present study, the correlations between exercise performance in the ISWT, lung function, and health status were examined in patients with COPD of varying severities. METHODS: A retrospective examination of 277 COPD patients was performed using the ISWT and lung function tests along with assessment of health status using St. George's Respiratory Questionnaire (SGRQ). In addition, we assessed the correlations between the walking distance, lung function parameters, and SGRQ scores. RESULTS: ISWT distances were poorly correlated with lung function parameters and SGRQ scores in mild COPD patients. In contrast, ISWT distances were significantly correlated with pulmonary function parameters, such as vital capacity (%predicted) and forced expiratory volume in one second, and SGRQ scores in moderate and severe COPD patients. CONCLUSIONS: The ISWT is more independent of health status and pulmonary function in patients with mild COPD compared to moderate or severe cases. Therefore, the exercise capacity of patients with mild COPD should be estimated by the ISWT. PMID- 28012492 TI - Guidelines-concordant empiric antimicrobial therapy and mortality in patients with severe community-acquired pneumonia requiring mechanical ventilation. AB - BACKGROUND: Community-acquired pneumonia (CAP) has high morbidity and mortality among adults. Several clinical guidelines recommend prompt administration of combined antimicrobial therapy. However, the association between guidelines concordance and mortality in patients with severe pneumonia remains unclear. The present study aimed to examine the impact of guidelines-concordant empiric antimicrobial therapy on 7-day mortality in patients with extremely severe pneumonia who required mechanical ventilation at admission, using a nationwide inpatient database in Japan. METHODS: Data of CAP patients aged over 20 years who required mechanical ventilation at admission between April 2012 and March 2014 were retrospectively analyzed. Multivariable logistic regression analysis was performed to examine the association between guidelines-concordant empiric antimicrobial therapy and all-cause 7-day mortality, with adjustment for patient backgrounds and pneumonia severity. RESULTS: There were a total of 3719 eligible patients, 836 (22.5%) of whom received guidelines-concordant combination therapy. Overall, 7-day mortality was 29.5%. Higher 7-day mortality was associated with advanced age, confusion, lower systolic blood pressure, malignant tumor or immunocompromised state, and C-reactive protein >=20mg/dl or infiltration occupying two-thirds of one lung on chest radiography. After adjustment for these variables, guidelines-concordant combined antimicrobial therapy was associated with significantly lower 7-day mortality (odds ratio: 0.78; 95% confidence interval: 0.65-0.95; P=0.013). CONCLUSIONS: Adherence to initial empiric treatment as recommended by the guidelines was associated with better short-term prognosis in patients with extremely severe pneumonia who required mechanical ventilation on hospital admission. PMID- 28012493 TI - Analysis of the impact of lung cancer treatment on nontuberculous mycobacterial lung diseases. AB - BACKGROUND: Although nontuberculous mycobacteria (NTM) lung diseases can occur in association with lung cancer, no study has evaluated the effect of lung cancer treatment on NTM lung diseases. Therefore, the present study aimed to retrospectively examine the effect of lung cancer treatment on NTM lung diseases. METHODS: Patients diagnosed with NTM lung diseases in combination with cytologically or histologically proven lung cancer between January 1, 2010 and October 31, 2014 were enroled. The clinical history of eligible patients was retrospectively reviewed. RESULTS: Seven hundred twenty-eight patients were diagnosed with NTM lung diseases. Among these patients, 29 (3.9%) also had lung cancer. Of the 29 patients with NTM and lung cancer, 62% had Mycobacterium avium complex as the pathogenic organism. The most common lung cancer histology was adenocarcinoma (62.1%). Anti-cancer cytotoxic chemotherapy was administered to seven patients, and the two patients who did not receive NTM treatment showed worsening of their NTM lung disease. CONCLUSION: Whether NTM lung disease should be treated during anti-cancer chemotherapy has not been not clarified by this study. Induction of anti-NTM therapy should be made after careful consideration, because the duration of anti-NTM treatment is long and anti-mycobacterial drugs have extensive effects on anti-cancer drugs. However, we think that anti-NTM therapy should be introduced after consideration of the worsening of symptoms and radiological findings associated with NTM lung disease. PMID- 28012494 TI - Hepatotoxicity of nintedanib in patients with idiopathic pulmonary fibrosis: A single-center experience. PMID- 28012495 TI - Does normal spirometry rule out an obstructive or restrictive ventilatory defect? PMID- 28012496 TI - An autopsy case of bronchiolitis obliterans as a previously unrecognized adverse event of afatinib treatment. AB - Interstitial lung disease is a well-known pulmonary adverse event that occurs during epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and results in restrictive ventilatory dysfunction. However, obstructive changes such as those associated with bronchiolitis obliterans (BO) have never been reported as adverse events resulting from the use of any approved EGFR-TKI. This report documents an autopsy case of BO that developed during afatinib treatment for adenocarcinoma of the lung. Knowledge of the possibility of this fatal adverse event is important for adequate follow-up of patients with lung cancer undergoing afatinib treatment. PMID- 28012498 TI - Three-dimensional imaging forced oscillation technique to assess position dependent airway obstruction in relapsing polychondritis: A case report. AB - Relapsing polychondritis (RP) is characterized by recurrent systemic inflammation of the cartilages and is accompanied by central airway collapse. We report a case wherein three-dimensional imaging of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) by using MostGraph (CHEST M.I., Tokyo, Japan), a forced oscillation system, revealed that Rrs and Xrs in the inspiratory and expiratory phases correlated with proximal airway collapse. The degree of difference in Rrs and Xrs between the supine and sitting positions reflected airway collapse more closely than did the pulmonary function test. MostGraph could be a useful tool for assessing airway collapse in RP. PMID- 28012497 TI - Giant bulla formation in the lung because of a check-valve mechanism. AB - The pathogenesis of bulla formation has not yet been demonstrated in pathologic examinations or through direct visualization during thoracotomy or thoracoscopic surgery. We present two cases of giant bulla formation after pneumothorax because of cryptogenic organizing pneumonia and lung abscess. The case findings suggested that the pathogenesis was attributable to a check-valve mechanism, secondary to bronchiolitis obliterans, or the presence of an obstructing air leakage due to a lung fistula. The lung fistula had been covered by inflammatory membranes consisting of blood and/or fibrous precipitates with detached visceral pleura. PMID- 28012499 TI - Possible relationship between organizing pneumonia and chronic pulmonary aspergillosis: A case report and literature review. AB - Organizing pneumonia (OP) is a nonspecific response to various forms of lung injury and has been reported in association with several infectious agents. However, little is known about the relationship between OP and chronic pulmonary aspergillosis, and the mechanism of this linkage has not been elucidated. Here, we present a case of chronic pulmonary aspergillosis that led to the development of OP, which was successfully treated with corticosteroid and surgical intervention. In a review of the literature, we aim to highlight the possible relationship between OP and chronic pulmonary aspergillosis. PMID- 28012500 TI - Familial diffuse pulmonary ossification: A possible genetic disorder. AB - Diffuse pulmonary ossification (DPO) is an uncommon disease that is characterized by the widespread formation of ectopic bone in the lungs. Herein, we describe two familial cases of DPO. The patients were a 47-year-old woman and her 76-year-old father. Both patients had a history of recurrent cough, and their chest images showed multiple nodules with ossification. No underlying diseases that might have caused DPO were evident; however, the female patient also had congenital finger hypoplasia and deformity. The present cases indicate the possibility that DPO might be partly associated with genetic disorders. PMID- 28012502 TI - The Future of Long-Term Care. PMID- 28012501 TI - The Japanese Respiratory Society Noninvasive Positive Pressure Ventilation (NPPV) Guidelines (second revised edition). PMID- 28012503 TI - Green Care Farms as Innovative Nursing Homes, Promoting Activities and Social Interaction for People With Dementia. AB - OBJECTIVES: Innovative care environments are developed for people with dementia to encourage person-centered care. This study aims to investigate whether residents of green care farms that provide 24-hour nursing care participate more in (physical) activities and social interaction compared with residents of other nursing homes. DESIGN: Longitudinal observation study. SETTING: Nursing homes in the Netherlands (green care farms, traditional nursing homes, and regular small scale living facilities). PARTICIPANTS: A total of 115 nursing home residents at baseline, 100 at follow-up. MEASUREMENTS: Ecological momentary assessments (n = 16,860) were conducted using the Maastricht Electronic Daily Life Observation Tool. Residents living at green care farms were compared with residents living in traditional nursing homes and regular small-scale living facilities. The following aspects were collected for this study: the activity performed by the participant or occurring in his or her vicinity, the engagement in the activity, the level of physical activity during the activity, the physical environment (location where the activity occurred), and the level of social interaction during the activity. RESULTS: In total, 9660 baseline observations and 7200 follow-up observations were conducted. Analyses showed that residents of green care farms significantly more often participated in domestic activities (P = .004, SE = 1.6) and outdoor/nature-related activities (P = .003, SE = 0.9), and significantly less often engaged in passive/purposeless activities (P < .001, SE = 1.7) compared with residents of traditional nursing homes. Furthermore, residents of green care farms had significantly more active engagement (P = .014, SE = 0.9), more social interaction (P = .006, SE = 1.1), and came outside significantly more (P = .010, SE = 1.1) than residents of traditional nursing homes. Residents of green care farms were significantly more physically active (P = .013, SE = 0.8) than were residents of regular small-scale living facilities. No other significant differences were found. CONCLUSION: Green care farms can be a valuable alternative to traditional nursing homes. They provide an attractive, homelike environment and activities that positively influence engagement and social interaction. Research is needed to study how successful elements of green care farms can be implemented in existing nursing homes. PMID- 28012504 TI - Response to the Letter From Abid Iraqi, MD, CMD and Terry Hughes, RN, CS. PMID- 28012506 TI - Erratum to 'Generation and validation of new quantitative real time PCR assays to detect Elephant Endotheliotropic herpesviruses 1A, 1B, and 4' [J. Virol. Methods 237 (2016) 138-142]. PMID- 28012505 TI - Reversible Cognitive Frailty, Dementia, and All-Cause Mortality. The Italian Longitudinal Study on Aging. AB - OBJECTIVES: Cognitive frailty, a condition describing the simultaneous presence of physical frailty and mild cognitive impairment, has been recently defined by an international consensus group. We estimated the predictive role of a "reversible" cognitive frailty model on incident dementia, its subtypes, and all cause mortality in nondemented older individuals. We verified if vascular risk factors or depressive symptoms could modify this predictive role. DESIGN: Longitudinal population-based study with 3.5- and 7-year of median follow-up. SETTING: Eight Italian municipalities included in the Italian Longitudinal Study on Aging. PARTICIPANTS: In 2150 older individuals from the Italian Longitudinal Study on Aging, we operationalized reversible cognitive frailty with the presence of physical frailty and pre-mild cognitive impairment subjective cognitive decline, diagnosed with a self-report measure based on item 14 of the Geriatric Depression Scale. MEASUREMENTS: Incidence of dementia, its subtypes, and all cause mortality. RESULTS: Over a 3.5-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia [hazard ratio (HR) 2.30, 95% confidence interval (CI) 1.02-5.18], particularly vascular dementia (VaD), and all-cause mortality (HR 1.74, 95% CI 1.07-2.83). Over a 7-year follow up, participants with reversible cognitive frailty showed an increased risk of overall dementia (HR 2.12, 95% CI 1.12-4.03), particularly VaD, and all-cause mortality (HR 1.39, 95% CI 1.03-2.00). Vascular risk factors and depressive symptoms did not have any effect modifier on the relationship between reversible cognitive frailty and incident dementia and all-cause mortality. CONCLUSIONS: A model of reversible cognitive frailty was a short- and long-term predictor of all cause mortality and overall dementia, particularly VaD. The absence of vascular risk factors and depressive symptoms did not modify the predictive role of reversible cognitive frailty on these outcomes. PMID- 28012507 TI - The utility of a handheld metal detector in detection and localization of pediatric metallic foreign body ingestion. AB - OBJECTIVE: To test the ability of a handheld metal detector (HHMD) to identify the presence and location of ingested metallic foreign bodies (MFBs) in children. METHODS: Prospective case series enrolling children suspected of metallic foreign body ingestion presenting to the Emergency Department. Thirty-eight children were enrolled and the HHMD was used to detect the presence and location of a MFB. Results were compared to standard radiographic studies. RESULTS: Thirty-seven of the 38 ingested foreign bodies were MFBs. Of the 37 MFBs, the HHMD positively identified 33, and 4 were missed by HHMD but identified on radiography. When positive, the location indicated by HHMD correlated 100% with radiograph. There were 33 true positives, 0 false positives, 4 false negatives, and 1 true negative. This resulted in a sensitivity of 89% (95% CI of 75%-96%) and specificity of 100% (95% CI of 2.5%-100%). CONCLUSION: Our study demonstrates the accuracy of HHMD in the identification and localization of metallic foreign bodies. We propose an emergency room foreign body protocol that uses HHMD as an early screening tool in triage in order to expedite the process of obtaining Otolaryngology consultation and potentially shorten the wait time to the operating room or discharge. In instances were outside films are previously performed, HHMD use may be able to minimize the overall radiation exposure to children by obviating the need for repeat radiographs. As the sensitivity is not 100%, a negative HHMD screening does not negate the need for a standard radiograph in order to avoid missed MFBs. HHMD is best suited for detection of coins, which accounts for the majority of the MFB ingestions, and may not be suitable for all metallic objects since the amount of metal may decrease its sensitivity. PMID- 28012508 TI - Psychological status in children with ear and nose foreign body insertion. AB - OBJECTIVE: Children with psychological disorders are prone to various unintentional injuries, one of the most common of which is foreign body inserting. In spite of the high incidence, the association is not studied yet. METHODS: This is a case control study in otorhinolaryngology and psychology departments, at a tertiary referral teaching hospital. One hundred five children (2-12 years old) who were referred for removal of foreign bodies in their ear or nose over a period of one year were selected for the study. Also, 155 children were selected and matched from the same community as the controls. Parents were given the standard strengths and difficulty questionnaire (SDQ) for psychological evaluation of their child. The total score and also the subscales for emotional symptoms, hyperactivity disorders, conduct problems, peer-relationship problemsand prosocialbehaviors were recorded and statistical analysis was performed. RESULTS: In the case group, 34 cases (%32.4) were suffering from foreign bodies in their ear, 70 cases (%66.7) in their nose, and just one case (%1) in both. Age and sex distributionin the two groups were comparable. There were significant differences of SDQ scores between the two groups in total score (p < 0.001), emotional symptoms (p < 0.001), hyperactivity disorders (p < 0.001), conduct problems (p < 0.001), and prosocial behaviors (p < 0.001). However peer relationship problems showed no significant difference between the two groups (p = 0.161). CONCLUSION: Psychological problems are more common in children with foreign bodies than the controls. Thus physicians are recommended to consider referring these patients to the pediatric psychologist. PMID- 28012509 TI - Changes in the inner ear structures in cystic fibrosis patients. AB - OBJECTIVE: Although prolonged use of antibiotics is very common in cystic fibrosis (CF) patients, no studies have assessed the changes in both cochlear and peripheral vestibular systems in this population. METHODS: We used human temporal bones to analyze the density of vestibular dark, transitional, and hair cells in specimens from CF patients who were exposed to several types of antibiotics, as compared with specimens from an age-matched control group with no history of ear disease or antibiotic use. Additionally, we analyzed the changes in the elements of the cochlea (hair cells, spiral ganglion neurons, and the area of the stria vascularis). Data was gathered using differential interference contrast microscopy and light microscopy. RESULTS: In the CF group, 83% of patients were exposed to some ototoxic drugs, such as aminoglycosides. As compared with the control group, the density of both type I and type II vestibular hair cells was significantly lower in all structures analyzed; the number of dark cells was significantly lower in the lateral and posterior semicircular canals. We noted a trend toward a lower number of both inner and outer cochlear hair cells at all turns of the cochlea. The number of spiral ganglion neurons in Rosenthal's canal at the apical turn of the cochlea was significantly lower; furthermore, the area of the stria vascularis at the apical turn of the cochlea was significantly smaller. CONCLUSIONS: Deterioration of cochlear and vestibular structures in CF patients might be related to their exposure to ototoxic antibiotics. Well designed case-control studies are necessary to rule out the effect of CF itself. PMID- 28012510 TI - Pediatric rhinoplasty: A discussion of perioperative considerations and systematic review. AB - OBJECTIVES: Pediatric rhinoplasty has traditionally raised numerous concerns, including its impact on growth as well as the psychological sequelae of undergoing a potentially appearance-altering procedure. Our objective was to critically evaluate available individual patient data relevant to pediatric rhinoplasty, and further discuss perioperative considerations. METHODS: A systematic review was conducted using PubMed/MEDLINE databases. Data extracted and analyzed from included studies included patient demographics, surgical indications, operative approaches, outcomes, complications, revision rates, and other clinical considerations. RESULTS: Seven studies encompassing 253 patients were included, with age ranging from 7 months to 19 years. Two-thirds of patients were male. 41.7% reported antecedent trauma, and common overall surgical indications included "functional aesthetic" (24.5%) followed by cleft lip nasal deformity (15.8%). The majority (79.1%) underwent open approaches, and 71.1% of patients underwent concomitant septal intervention. The most frequently used grafting materials were septal cartilage (52.8%) and conchal cartilage (16.5%). Surgical outcomes were heterogeneous among these studies. Complication rates were only specified in 5 of the 7 studies and totaled 57 patients (39.6%). Aesthetic dissatisfaction (11.8%) and postoperative nasal obstruction (5.6%) were the most commonly reported complications. Revisions were performed in 13.5%. CONCLUSION: Rhinoplasty is safe in the pediatric population, although revisions rates appear greater than those reported in adults. This study of 253 represents the largest pooled sample size to date; nonetheless, non-standardized outcome measures, minimal long-term followup data, and lack of discussion regarding psychological sequelae all contribute to the need for further high-quality studies evaluating this topic. PMID- 28012511 TI - The use of the FLACC pain scale in pediatric patients undergoing adenotonsillectomy. AB - OBJECTIVES: 1) Determine the usage rate of opioid pain medication after adenotonsillectomy (T&A). 2) Review the use of the Face, Legs, Activity, Cry, Consolability (FLACC) pain scale for T&A patients 3) Determine the rate of postoperative physician contacts for pain related complaints. METHODS: A retrospective case series review was performed on 125 pediatric patients undergoing T&A and subsequent 23-hour postoperative observation at an academic tertiary care center from June-August of 2015. Postoperative pain scores using the FLACC pain scale, the utilization of opioid pain medications, and the number of postoperative contacts for pain were recorded. RESULTS: Average age of patients was 5.7 years and 50% were female. 90% of T&A's were performed for adenotonsillar hypertrophy. The post-tonsillectomy hemorrhage rate was 4%. 70 (56%) patients required postoperative opioid pain medication, with (30) 43% of these patients requiring more than one dose. The mean number of opioid doses was 1.64 +/- 0.9 and was not related to age, weight or gender. FLACC scores were highly associated (spearman correlation 0.77) with the amount of opioid medication given. Mean FLACC scores decreased over time after T&A. 20% of patients contacted a physician for unsatisfactory pain control postoperatively with 6% requiring emergency department visits and 14% contacting the office via phone call. CONCLUSIONS: A significant portion of pediatric patients undergoing T&A require postoperative opioids for pain control. The FLACC scale is a valuable way of quantifying post-operative T&A pain in pediatric patients. Despite routine pain management postoperatively, a significant proportion of patients require contact with a physician postoperatively for pain management. PMID- 28012512 TI - No evidence for impaired humoral immunity to pneumococcal proteins in Australian Aboriginal children with otitis media. AB - BACKGROUND: The Australian Aboriginal population experiences disproportionately high rates of otitis media (OM). Streptococcus pneumoniae is one of the main pathogens responsible for OM and currently no vaccine offering cross strain protection exists. Vaccines consisting of conserved antigens to S. pneumoniae may reduce the burden of OM in high-risk populations; however no data exists examining naturally acquired antibody in Aboriginal children with OM. METHODS: Serum and salivary IgA and IgG were measured against the S. pneumoniae antigens PspA1 and 2, CbpA and Ply in a cross sectional study of 183 children, including 36 non-Aboriginal healthy control children and 70 Aboriginal children and 77 non Aboriginal children undergoing surgery for OM using a multiplex bead assay. RESULTS: Significant differences were observed between the 3 groups for serum anti-PspA1 IgA, anti-CbpA and anti-Ply IgG and for all salivary antibodies assessed. Aboriginal children with a history of OM had significantly higher antibody titres than non-Aboriginal healthy children with no history of OM and non-Aboriginal children with a history of OM for several proteins in serum and saliva. Non-Aboriginal children with a history of OM had significantly higher salivary anti-PspA1 IgG than healthy children, while all other titres were comparable between the groups. CONCLUSIONS: Conserved vaccine candidate proteins from S. pneumoniae induce serum and salivary antibody responses in Aboriginal and non-Aboriginal children with a history of OM. Aboriginal children do not have an impaired antibody response to the antigens measured from S. pneumoniae and they may represent vaccine candidates in Indigenous populations. PMID- 28012513 TI - Minimally invasive endoscopic treatment for pediatric combined high grade stenosis as a laryngeal manifestation of epidermolysis bullosa. AB - Epidermolysis bullosa refers to a clinically and genetically heterogeneous group of inherited mucocutaneous diseases. Laryngotracheal lesions are momentous regarding the risk of sudden airway obstruction. The traditional treatment is tracheostomy. This case report highlights the advantages of minimally invasive interventions. A successful combined endoscopic management of a life-threatening respiratory crisis is presented in a 4-year-old child. Combined commissure stenosis with supraglottic spread was treated by CO2 laser dissection and bilateral endoscopic arytenoid abduction lateropexy, supplemented with mitomycin C application. Due to expectable less scarring, the combination of these modern methods may be an efficient solution in these vulnerable respiratory tracts. PMID- 28012514 TI - School entry level tele-hearing screening in a town in South India - Lessons learnt. AB - INTRODUCTION: School screening is warranted in developing countries that do not have newborn hearing screening as schools provide access to a large number of young children between 3 and 5 years of age. Due to scarcity of technical manpower and equipment, hearing screening programs are not often conducted in developing countries. In these circumstances, telehealth services appear to be a reasonable solution. Consequently, the purpose of this study was to assess the feasibility of school hearing screening using telehealth technology operated by a practitioner located 400 kms away at a distant hospital. METHOD: Thirty one children received hearing screening procedures in their school. Each child was screened for both in-person and telehealth conditions to assess screening results. Remote computing software was employed for the telehealth condition in order for the practitioner to remotely operate an audiometer, DPOAE system and a video otoscope interfaced to a personal computer at the school site.Teamviewer version 10 was used to provide encrypted videoconferencing and synchronous hearing screening services between the hospital and school sites. All screening was conducted using a mobile phone hotspot or dongle device based internet connection to insure reliable connectivity. RESULTS: The outcome revealed no significant difference between PTA and DPOAE performed in-person and tele-hearing screening methods. Concurrence of greater than 87% was achieved between in-person and tele-video-otoscopy. Strengths and challenges were documented for tele hearing screening in three different dimensions: technical issues, child related and school related. Understanding these challenges may provide more effective tele-audiology services. DISCUSSION: The results of the study indicate synchronous hearing screening services can be provided in a school setting using mobile hotspot or dongle connectivity in locations where Internet bandwidth is otherwise restricted. PMID- 28012515 TI - The utility of early developmental assessments on understanding later nonverbal IQ in children who are deaf or hard of hearing. AB - OBJECTIVE: In children who are deaf or hard of hearing (DHH), it is helpful to have meaningful early measures of development in order to provide effective interventions and offer benchmarks that help recognize varied developmental trajectories. The main objective of this study was to compare results of an early developmental assessment prior to 3 years of age to later nonverbal IQ assessed between 3 and 6 years of age in children who are DHH. METHODS: This study included children 3-6 years of age with bilateral permanent hearing who were enrolled in a prospective cohort study on developmental outcomes. As part of the study, children received the Leiter International Performance Scale-Revised, which provided a nonverbal Brief IQ, as well as standardized language assessment and behavioral checklists. Children were included in this analysis if they had received an early developmental assessment with the Gesell Developmental Schedules-Revised as part of a clinical visit with a developmental pediatrician. Correlation coefficients and multiple regression analysis were used to associate the scores on the Gesell (using a developmental quotient) with scores on the Leiter-R Brief IQ. RESULTS: Forty-five participants who enrolled in the observational study had available evaluation results from the Gesell and complete Brief IQ results from the Leiter-R. The adaptive domain of the Gesell had good correlation (r = 0.61, p < 0.0001) with the Brief IQ on the Leiter-R. Children who had stable developmental or intelligence classifications based on scores (<70, 70 to <85, 85 to <100, >=100) over time were older (>24 months) at the early Gesell assessment. Degree of hearing loss or maternal education did not appear to confound the relationship between the Gesell and the Leiter-R. CONCLUSIONS: The adaptive domain of the Gesell Developmental Schedules - Revised administered in early childhood (under 3 years of age) has good correlation with the nonverbal Brief IQ on the Leiter International Performance Scale-R. Because children who are DHH have a higher likelihood of having a developmental disability compared to the general population, early developmental assessments are often important. Although early developmental assessments have their limitations, our results indicate that they are fairly robust indicators of later development. Such early indicators can be extremely useful in the clinical and educational management of children who are DHH. PMID- 28012516 TI - Utilization of a submental island flap and 3D printed model for skull base reconstruction: Infantile giant cranio-cervicofacial teratoma. AB - Transcranial masses in the infant population can leave considerable skull base defects following resection. Traditional reconstructive techniques can result in significant morbidity or poor cosmetic results. We present a case of a large skull base defect in a six week-old infant, after removal of a giant cranio cervicofacial teratoma, which was reconstructed using a versatile submental island flap. Additionally, preoperative planning and intraoperative navigation was advanced with the use of a 3D constructed model of the patient's mass. PMID- 28012517 TI - Audio-visual speech perception in noise: Implanted children and young adults versus normal hearing peers. AB - OBJECTIVE: The purpose of the current study was to evaluate auditory, visual and audiovisual speech perception abilities among two groups of cochlear implant (CI) users: prelingual children and long-term young adults, as compared to their normal hearing (NH) peers. METHODS: Prospective cohort study that included 50 participants, divided into two groups of CI (10 children and 10 adults), and two groups of normal hearing peers (15 participants each). Speech stimuli included monosyllabic meaningful and nonsense words in a signal to noise ratio of 0 dB. Speech stimuli were introduced via auditory, visual and audiovisual modalities. RESULTS: (1) CI children and adults show lower speech perception accuracy with background noise in audiovisual and auditory modalities, as compared to NH peers, but significantly higher visual speech perception scores. (2) CI children are superior to CI adults in speech perception in noise via auditory modality, but inferior in the visual one. Both CI children and CI adults had similar audiovisual integration. CONCLUSIONS: The findings of the current study show that in spite of the fact that the CI children were implanted bilaterally, at a very young age, and using advanced technology, they still have difficulties in perceiving speech in adverse listening conditions even when adding the visual modality. This suggests that adding audiovisual training might be beneficial for this group by improving their audiovisual integration in difficult listening situations. PMID- 28012518 TI - The impact of adenotonsillectomy on pulmonary arterial pressure in West African children with adenotonsillar hypertrophy. AB - OBJECTIVES: To assess the improvement or otherwise, in the mean pulmonary arterial pressure (mPAP) among children with adenotonsillar hypertrophy (ATH) after adenotonsillectomy (AT), and to examine the impact of timing of surgery as well as the patients' characteristics on the mPAP changes. METHODS: We included 39 children with ATH in this study. The adenoidal enlargement was evaluated radiologically with adenoid nasopharyngeal ratio (ANR) parameter from lateral neck radiograph, whereas the clinical assessment of adeno-tonsillar obstruction was conducted with the 'symptom score'. Pulmonary arterial pressure (PAP) measurement was performed noninvasively by Doppler echocardiography. All patients underwent adenotonsillectomy (AT). After 6 weeks, they were subjected again to clinical and echocardiographic assessments, and the mean pulmonary arterial pressures (mPAP) were then compared. The mPAP changes after AT were further related to the grades of ANR, symptom scores, tonsillar size, and timing of AT. RESULTS: The preoperative mPAP was 23.46 mmHg and was 18.98 mmHg post-operatively (P = 0.003). Seventeen of subjects (43.6%) had pulmonary hypertension (PH) (mPAP >= 25 mmHg) preoperatively, out of which 14 (82%) decreased to normal range 6 weeks after AT. Non-reversal of pulmonary hypertension was associated with ANR > 0.75 (P = 0.043), but was not related to the timing of surgery, tonsillar size, and symptom score. Significant reduction in mPAP was more likely with ANR <= 0.75 and pre-operative mPAP >= 25 mmHg. All the symptoms also improved significantly after AT. CONCLUSION: Elevated PAP due to ATH in children was mostly reversible by AT irrespective of the timing of surgery, symptom severity, and tonsillar size, but gross enlargement of adenoids seem to be associated with non-reversal of PH. PMID- 28012519 TI - Surgical scheduling categorization system (SSCS): A novel classification system to improve coordination and scheduling of operative cases in a tertiary pediatric medical system. AB - OBJECTIVE: To describe a surgical categorization system to create a universal nomenclature, delineating patient complexity as a first step toward developing a true risk stratification system. METHODS: Retrospective database review of all otolaryngology surgical procedures performed in a tertiary pediatric hospital system over one academic year (July 2012-June 2013). All otolaryngology surgical procedures were reviewed, encompassing 8478 procedures on 5711 patients. The attending otolaryngologist assigned surgical scheduling category (SSCS) at the time of case booking based on an institution specific guidelines. The guidelines are as follow: Category I was assigned to American Society of Anesthesiologists physical status classification (ASA) I/II patients, designating them appropriate for institution's suburban ambulatory surgery centers; Category II was ASA I/II patients with social or transportation issues; Category III was ASA I/II patients who required case coordination with other medical or surgical departments; Category IV was reserved for patients of any ASA class whom the surgeon designated to be of a higher complexity. RESULTS: 8478 total procedures analyzed with 7198 having complete records. 48% were Category I, 13.6% were Category II, 1.9% were Category III and 36.5% were Category IV. The ASA were 34.7% ASA I, 50% ASA II, 13.39% ASA III, and 1.9% ASA IV. Although the largest proportion of patients were ASA II (50%), 39.6% of all ASA II were Category IV. Category IV was split into 54.2% ASA II and 34% ASA III and shows that peri-operative surgical concerns were not encompassed by the ASA system. CONCLUSION: This surgical categorization system streamlines surgical scheduling in a tertiary pediatric hospital system, particularly with respect to the designation of cases as ambulatory surgery center or main operating room appropriate. The case mix complexity is also readily apparent, enhancing recognition of the coordination and attention required for the perioperative management of high complexity patients. The SSCS helps convey concerns not addressed by ASA physical status alone. PMID- 28012520 TI - Neonatal airway obstruction in bilateral congenital dacryocystocoele: Case report and review of the literature. AB - Bilateral nasal obstruction due to simultaneous bilateral dacrocystocoeles is a rare and potentially life threatening condition. We present a five day old girl with this condition who presented with respiratory distress without any eye signs or symptoms associated with dacryocystocoeles. She was successfully managed with surgery and the clinical and radiological features of this condition are presented here with a review of the literature. PMID- 28012521 TI - Subspecialist training program in pediatric otorhinolaryngology of UEMS ORL-HNS section. AB - The ORL Section and Board of Otorhinolaryngology-Head and Neck Surgery of the European Union of Medical Specialists (UEMS) developed pediatric ORL subspecialty program. The program was created with support and consultation of the European Society of Pediatric Otorhinolaryngology. It is divided into four sections: Pediatric Otology, Pediatric Rhinology and Facial Plastic Surgery, Pediatric Laryngology and Phoniatrics and Pediatric Head and Neck Surgery. After completion of the program, the trainee is supposed to achieve an advanced level of competency. The aim of the program is to serve as a guideline for training centers, enabling them to meet the European Standard as set out by the European Board of UEMS through competency based assessments. PMID- 28012522 TI - Comparison of intelligence quotients of first- and second-generation deaf children with cochlear implants. AB - Hearing impairment is a common type of sensory loss in children. Studies indicate that children with hearing impairment are deficient in social, cognitive and communication skills. This study compared the intelligence quotients of first- and second-generation deaf children with cochlear implants. This research is causal-comparative. All 15 deaf children investigated had deaf parents and were selected from Baqiyatallah Cochlear Implant Center. The 15 children with cochlear implants were paired with similar children with hearing parents using purposive sampling. The findings show that the Hotelling trace of multivariate analysis of variance (F = 6.78, p < 0.01, etaP2 = 0.73) was significant. The tests of between subjects effects for second-generation children was significantly higher than for first-generation children for all intelligence scales except knowledge. It can be assumed that second-generation children joined their family in the use of sign language as the primary experience before a cochlear implant. The use of sign language before cochlear implants is recommended. PMID- 28012523 TI - Digenic mutations involving both the BSND and GJB2 genes detected in Bartter syndrome type IV. AB - Bartter syndrome type IV, characterized by salt-losing nephropathies and sensorineural deafness, is caused by mutations of BSND or simultaneous mutations of both CLCNKA and CLCNKB. GJB2 is the primary causative gene for non-syndromic sensorineural deafness and associated with several syndromic sensorineural deafness. Owing to the rarity of Bartter syndrome, only a few mutations have been reported in the abovementioned causative genes. To investigate the underlying mutations in a Chinese patient with Bartter syndrome type IV, genetic analysis of BSND, CLCNKA, CLCNKB and GJB2 were performed by polymerase chain reaction and direct sequencing. Finally, double homozygous mutations c.22C > T (p.Arg8Trp) and c.127G > A (Val43Ile) were detected in exon 1 of BSND. Intriguingly, compound heterozygous mutations c.235delC (p.Leu79CysfsX3) and c.109G > A (p.Val37Ile) were also revealed in exon 2 of GJB2 in the same patient. No pathogenic mutations were found in CLCNKA and CLCNKB. Our results indicated that the homozygous mutation c.22C > T was the key genetic reason for the proband, and a digenic effect of BSND and GJB2 might contributed to sensorineural deafness. To our knowledge, it was the first report showing that the GJB2 gene mutations were detected in Bartter syndrome. PMID- 28012524 TI - A pearl in the ear: Intracranial complications of pediatric cholesteatomas. AB - A nine-year-old male had a cholesteatoma of the mastoid and middle ear found incidentally after myringotomy tube placement. Associated asymptomatic sigmoid plate dehiscence with sinus invasion or thrombosis and ossicular chain destruction complicated his case. He had canal wall down tympanomastoidectomy and was followed for 4.5 years. Disease recurrence necessitated revision. Our case highlights an unusual clinical presentation, possible complications, and the aggressive quality of a benign lesion common in the pediatric population. To our knowledge, this is the first report of an asymptomatic lateral sinus obstruction secondary to an invasive cholesteatoma in this population. PMID- 28012525 TI - Nasal septal perforation in children: Presentation, etiology, and management. AB - OBJECTIVE: The presentation, etiology, and treatment of nasal septal perforation have been described in the adult literature; however, reports in the pediatric population are limited. In this study, we review our experience with pediatric nasal septal perforations with a focus on presentation, pathogenesis, management, and outcomes of surgical repair. METHODS: A retrospective chart review was performed on pediatric patients diagnosed with nasal septal perforations from 1998 to 2015. Data regarding patient demographics, perforation characteristics, and treatment were extracted and analyzed. RESULTS: Twenty-seven patients met inclusion criteria. Mean age was 10.8 years (range 2 months-17 years). Nasal crusting (n = 19, 73%) and epistaxis (n = 15, 58%) were the most common complaints at presentation. The most common etiologies were trauma (n = 9, 33%), iatrogenic sources (n = 5, 19%), and neoplasm (n = 3, 11%). Septal perforations were primarily located in the anterior septum (n = 17, 81%) and the average size was 0.9 cm (+/-0.37) in diameter. Four patients were managed with a nasal septal button. Successful closure was achieved in four out of six patients (66.7%) who underwent surgical repair. CONCLUSIONS: In our series, septal perforations in children occurred most frequently due to digital nasal trauma, and crusting was the most common symptom. Factors to consider prior to repair include symptomatology, the etiology of the perforation, co-morbidities, ability to comply with post-operative care/restrictions, availability of adjacent tissue/grafts, and potential effects on nasal growth. Even with careful consideration of these factors, successful closure was limited to two-thirds of patients who were offered repair. PMID- 28012526 TI - Preferred parental method of post-operative tonsillectomy and adenoidectomy follow-up (phone call vs. clinic visit). AB - INTRODUCTION: Tonsillectomy is the second most common procedure performed in the United States. Over 530,000 tonsillectomies are performed on children under 15 years of age in the United States, accounting for 16% of surgeries in this age group, resulting in missed school for patients of school-age and also resulting in missed work for caregivers. This study compared parent preferences for in clinic follow-up (CFU) to telephone interview follow-up (TFU) after tonsillectomy. MATERIALS AND METHODS: One hundred twenty-one parents of children who underwent a tonsillectomy and/or adenoidectomy were recruited to complete a survey about their child's post-operative visit. RESULTS: Statistical analyses were performed using t-test, Wilcoxon rank-sum, and Fischer's exact tests where appropriate. 60.3% of the surveys were completed as a TFU and the remainder were completed as a CFU. There were no statistical differences in the children's age, the time to follow-up, satisfaction with their follow-up, or the frequency of unresolved symptoms. Of parents receiving TFU, 91.8% disagreed they would have preferred a CFU, with 86.3% strongly disagreeing, and only 5.5% expressing that they would have preferred a CFU. Of the parents with CFU, 47.9% expressed a preference for a TFU. For CFU, 43.9% of parents missed work and 58.1% of their school-age children missed school. CONCLUSION: Our study results indicate that parents receiving phone follow-up strongly preferred this method to an in-clinic follow-up, and that nearly half of all parents receiving in-clinic follow-up would have preferred a telephone follow-up. In select patients, telephone follow up after tonsillectomy may increase patient satisfaction and decrease days of missed work and school. PMID- 28012527 TI - Improving access to school based education for South African children in rural areas who have a tracheostomy: A case series and recommendations. AB - OBJECTIVES: Currently few children with tracheostomies attend rural mainstreams schools in South Africa limiting their ability to gain an education. We sought to document the current school experience for the few children attending school who have tracheostomies and devise educational tools for teachers and administrators that will facilitate greater acceptance and safety in classrooms for this population. METHODS: The four patients that are currently attending school with a tracheostomy were identified from the patient records of a tertiary hospital with a pediatric tracheostomy home based care service. With the aid of a Zulu language translator, the mothers and classroom teachers completed a semi structured interview and closed item questionnaire in their home and school, respectively. Schools were visited to understand and describe the settings in which the children and their teachers were being asked to function. Tools for education were developed in conjunction with key stakeholders at schools already hosting such children. RESULTS: The key teacher-identified barriers to enrollment were: teacher unfamiliarity with tracheostomies, uncertainty about the school's liability, and concerns about the response of other children. The safety barriers identified were: greater than 60 children per classroom - limiting teacher's ability to attend to the child with a tracheostomy, lack of running water, pit latrines separate from school threatening hygiene and isolating the child when they leave to use the latrines & sandy classrooms which can result in sand entering the airway. Identified needs for successful school placement include providing tracheostomy supplies and suctioning equipment, hand hygiene materials and training teachers in: identification of respiratory distress, performance of emergency tracheostomy changes, CPR. CONCLUSIONS: Children with tracheostomies could likely successfully attend South African rural mainstream public schools with a training program for teachers. As a first step, an introductory booklet for teachers that explains tracheostomies and provides educational and safety suggestions was created. A list of recommendations for successful inclusion of students in the school system was developed together with and delivered to key stakeholders. PMID- 28012529 TI - Cone-beam computed tomography in children with cochlear implants: The effect of electrode array position on ECAP. AB - OBJECTIVES: To assess the feasibility of using cone-beam computed tomography (CBCT) in young children with cochlear implants (CIs) and study the effect of intracochlear position on electrophysiological and behavioral measurements. METHODS: A total of 40 children with either unilateral or bilateral cochlear implants were prospectively included in the study. Electrode placement and insertion angles were studied in 55 Cochlear(r) implants (16 straight arrays and 39 perimodiolar arrays), using either CBCT or X-ray imaging. CBCT or X-ray imaging were scheduled when the children were leaving the recovery room. We recorded intraoperative and postoperative neural response telemetry threshold (T NRT) values, intraoperative and postoperative electrode impedance values, as well as behavioral T (threshold) and C (comfort) levels on electrodes 1, 5, 10, 15 and 20. RESULTS: CBCT imaging was feasible without any sedation in 24 children (60%). Accidental scala vestibuli insertion was observed in 3 out of 24 implants as assessed by CBCT. The mean insertion angle was 339.7 degrees +/-35.8 degrees . The use of a perimodiolar array led to higher angles of insertion, lower postoperative T-NRT, as well as decreased behavioral T and C levels. We found no significant effect of either electrode array position or angle of insertion on electrophysiological data. CONCLUSION: CBCT appears to be a reliable tool for anatomical assessment of young children with CIs. Intracochlear position had no significant effect on the electrically evoked compound action potential (ECAP) threshold. Our CBCT protocol must be improved to increase the rate of successful investigations. PMID- 28012528 TI - The effect of IV dexamethasone versus local anesthetic infiltration technique in postoperative nausea and vomiting after tonsillectomy in children: A randomized double-blind clinical trial. AB - BACKGROUND: Local anesthetic infiltration and corticosteroids had shown effectiveness in reducing post tonsillectomy nausea, vomiting and pain. OBJECTIVES: To compare the effect of intravenous dexamethasone versus pre incision infiltration of local anesthesia in pediatric tonsillectomy on postoperative nausea and vomiting (PONV). The secondary objective was postoperative pain. METHODS: A randomized double-blind clinical trial was conducted at a tertiary care teaching hospital. Children admitted to undergo tonsillectomy aged between 4 and 13 years from January 2015 to August 2015 were enrolled and divided into two groups. Both groups had general anesthesia. Group I received intravenous dexamethasone 0.5 mg/kg (maximum dose 16 mg) with placebo pre-incision infiltration. Group II received pre-incision infiltration a total of 2-4 ml local anesthesia mixture with saline and an equivalent volume of intravenous saline. RESULTS: Group I consisted of 64 patients while group II had 65 patients. In the PACU, 15.6% of patients in group I experienced vomiting compared to 3.1% in group II (p-value = 0.032). After 24 h, the incidence of PONV was significantly higher in group I compared to group II (26.6% vs. 9.2% respectively, p-value = 0.019). At 48 h postoperatively, PONV was significantly higher in group I (p-value = 0.013). The incidence was similar in both groups after three, four and five postoperative days. Baseline pain and pain during swallowing were significantly different at 6, 12 and 24 h as well as days 1 through 5. Pain upon jaw opening was significantly different at 6, 12 and 24 h between the two groups. Pain while eating soft food was significantly different at 24 h and days 2 through 5. In the PACU, 20.3% of patients in group I received diclofenac compared to 3.1% in group II (p-value = 0.005). From day 1 till day 5, analgesic consumption was significantly higher in group I. CONCLUSION: Local anesthetic infiltration in addition to NSAIDS and paracetamol could serve as a multimodal analgesia and decrease PONV. TRIAL REGISTRATION: NCT02355678. PMID- 28012530 TI - Acute mastoiditis in children: Middle ear cultures may help in reducing use of broad spectrum antibiotics. AB - BACKGROUND: Acute mastoiditis (AM) is a suppurative infection of the mastoid air cells, representing the most frequent complication of acute otitis media. AM remains an important entity in children due to its potential complications and sequelae. We aim to describe the cases of AM admitted at our department, identify risk factors potentially associated with complications and analyse the changes in clinical approach of AM over time. METHODS: Case review of clinical files of children admitted with acute mastoiditis from June 1996 to May 2013 at a Lisbon metropolitan area hospital. Data was divided into two groups (prior and after May 2005) in order to evaluate changes in AM approach over the years. RESULTS: 135 AM episodes were included. The median age was 3.8 years and 42% children were less than 24 months of age. Symptoms at presentation included fever (69%), ear pain (56%) and otorrhea (40%). Complications occurred in 22% patients and were more common in children under 24 months (33% vs 15%, p <= 0.01). Leukocyte count was significantly higher in children with complications (16.7 vs 14.5 * 109/MUL, p <= 0.05) as was C-Reactive Protein value (13 vs 6.3 mg/dL, p <= 0.001). There was a significant association between the development of complications and C-Reactive Protein value at admission (OR 1.892; IC95%: 1.018-2.493, p <= 0.01). The optimal cut-off value was 7.21 mg/dL. Over time there was a significant increase in middle ear cultures obtained by tympanocentesis during surgery (2% vs 16%, p <= 0,01) and also a decrease in the use of broad spectrum antibiotherapy as initial treatment (52% vs 25%,p <= 0,001). CONCLUSIONS: Children under 24 months, with high leukocyte count or with high C-Reactive Protein value should be monitored closely since complications tend to be more frequent. A CRP value of 7.21 mg/dL at admission seems to be a good cut-off to monitor children for potential complications. Throughout the period analysed more cultures were performed allowing identification of the pathogens and implementation of appropriate antibiotic therapy. PMID- 28012531 TI - Improvement of psychiatric symptoms in youth following resolution of sinusitis. AB - INTRODUCTION: Accumulating evidence supports a role for inflammation in psychiatric illness, and the onset or exacerbation of psychiatric symptoms may follow non-CNS infections. Here, we provide the first detailed description of obsessive-compulsive and related psychiatric symptoms arising concurrently with sinusitis. METHODS: We reviewed the charts of 150 consecutive patients evaluated in our Pediatric Acute-onset Neuropsychiatric Syndromes clinic for documented sinusitis as defined by the American Academy of Pediatrics guidelines. Sinusitis treatments, sinonasal imaging, and neuropsychiatric symptoms before, during, and after sinusitis onset were noted. Patients were included in the final review if they had a clear diagnosis of isolated sinusitis (without concurrent illness and/or immunodeficiency), and were evaluated during an episode of sinusitis. RESULTS: 10/150 (6.6%) patients had isolated sinusitis at the time of their neuropsychiatric deterioration. Eight patients received antibiotics to treat sinusitis, three of whom also received sinus surgery. Neuropsychiatric symptoms improved in all eight patients concurrent with resolution of sinusitis per parent report and clinician assessment. One patient did not follow through with recommended sinus surgery or antibiotics and her psychiatric symptoms persisted. One patient was lost to follow-up. CONCLUSIONS: Improvement of psychiatric symptoms correlated with resolution of sinus disease in this retrospective study. Identification, treatment, and resolution of underlying infections, including sinusitis, may have the potential to change the trajectory of some neuropsychiatric illnesses. Randomized clinical trials are needed. PMID- 28012532 TI - Management of surgical difficulties during cochlear implant with inner ear anomalies. AB - OBJECTIVE: To review the difficulties that can occur during cochlear implant surgery in patients with inner ear abnormalities and the management thereof. METHODS: A retrospective chart review of 316 patients who received cochlear implants was conducted. The data collected included the types of inner ear anomalies, intraoperative findings, and the clinical management strategies. A review of the literature was also performed. RESULTS: A total of 24 patients with inner ear malformations who underwent 28 total cochlear implant procedures were identified. The anomalies included isolated large vestibular aqueducts in 8 (33.3%) patients, isolated semicircular canal dysplasia in 8 (33.3%) patients, classical Mondini malformation in 7 (29.1%) patients, and cochlear hypoplasia in 1 (4.1%) patient. Four (14.2%) patients exhibited intraoperative cerebrospinal fluid (CSF) gushers. One patient experienced delayed facial nerve paralysis, and an electrode was partially inserted into one patient. In 2 (7.14%) cases, the surgeries were aborted because of difficulties. CONCLUSION: Cochlear implantation for inner ear anomalies can be performed safely. Special attention should be given to preoperative imaging to anticipate the potential intraoperative risks that can occur in inner ear anomaly cases. Every surgery should be planned with a safe approach and specific requirements, e.g., regarding electrode type, and the surgeries must be performed by experienced surgeons who are capable of modifying their technique according to the surgical findings. PMID- 28012533 TI - A review of acute postoperative sialadenitis in children. AB - OBJECTIVE: Acute postoperative sialadenitis is a previously described rare entity that has occurred following general anesthesia and has also been associated with prolonged neurosurgical procedures. We aim to better characterize this entity while performing a literature review regarding potential etiologies, diagnosis, airway management and treatment options. METHODS: A retrospective chart review was performed at a pediatric tertiary care center from 2000 to 2014. Charts were selected for the study utilizing an ICD-9 diagnosis of sialadenitis occurring within two weeks of a surgical procedure. Data including age, gender, medical history, preoperative diagnosis, operation length, time to symptom onset, and subsequent management were collected. An additional literature review was performed focusing on reports of post-operative acute sialadenitis involving airway compromise. RESULT: 244 charts were reviewed and 4 patients met inclusion criteria. The average time to symptom onset was 4.3 days (range 1 h-12 days) following conclusion of the surgical procedure. Symptoms ranged from mild inflammation of the parotid gland to rapid swelling of the neck necessitating intubation. All patients were treated with standard sialadenitis treatment including hydration, antibiotics, and airway management as needed. CONCLUSION: To our knowledge this is the first case series reviewing this entity specifically within the pediatric population. There appears to be two distinct categories of postoperative sialadenitis; one of which presents very acutely and results in massive neck swelling and airway compromise. It is important for practicing Otolaryngologists to be aware of this potentially life-threatening complication in the immediate postoperative period. PMID- 28012534 TI - Laser CO2 tonsillotomy versus argon plasma coagulation (APC) tonsillotomy: A retrospective study with 10-year follow-up. AB - INTRODUCTION: Tonsillotomy is increasingly gaining acceptance as the treatment for tonsillar hyperplasia resulting in obstructive symptoms. The aim of this study was to compare the long-term results of CO2 laser tonsillotomy with those of argon plasma coagulation (APC) tonsillotomy. METHODS: The data of 64 children, aged 2-10 years (mean 4.7 years), treated in the Department of Otolaryngology, Head and Neck Surgery, in Homburg, Germany with APC (36 patients) or CO2 laser (28 patients) for tonsillar hyperplasia between June 2004 and December 2004 were available for analysis. RESULTS: Forty-five (APC: 26 patients, CO2: 19 patients) of the 64 patients (70.3%) could be contacted and were available for follow-up in a telephone survey conducted 10 years after surgery. The mean operation time was 17 min (range 10-25 min) in the APC group and 23 min (range 13-32 min) in the CO2 group (p = 0.0003). No case of intra- or postoperative bleeding was documented. One minor intraoperative complication in the form of a superficial lip burn was documented in the APC group. During the minimum 10 years of follow-up, 1 patient treated with APC underwent a surgical revision because of tonsillar regrowth, whereas in the group of patients treated with CO2, no surgical revision was needed. Regarding the parents' assessment of their children's symptoms, 89.4% of the parents of the CO2 laser group and 84.6% of the parents of the APC group reported that the overall long-term operation results of their children to be "very satisfying." Regarding complications, the need for secondary tonsillectomy, and parents' satisfaction, no statistically significant differences were found. CONCLUSIONS: Both CO2 laser tonsillotomy and APC tonsillotomy are safe procedures leading to very satisfying results with respect to intra- and postoperative complications. PMID- 28012535 TI - Peanut sprout extract attenuates cisplatin-induced ototoxicity by induction of the Akt/Nrf2-mediated redox pathway. AB - OBJECTIVE: Cisplatin is commonly used to treat solid tumors. However, permanent hearing loss is a major side effect of cisplatin chemotherapy and often results in dose reduction of the cisplatin chemotherapy. Peanut sprouts show cytoprotective properties owing to their antioxidant activities. This study was designed to investigate the effect of peanut sprout extract (PSE) on cisplatin induced ototoxicity in an auditory cell line, HEI-OC1 cells. METHODS: Cells were exposed to cisplatin for 24 h, with or without pre-treatment with PSE, cell viability was examined using the MTT assay. Apoptotic cells were identified by double staining with Hoechst 33258 and propidium iodide. Western blot analysis was performed to examine apoptotic proteins including C-PARP and C-caspase, anti apoptotic protein Bcl-2, and Nrf2 redox system activation. Mitochondrial reactive oxygen species (ROS) were investigated to examine whether PSE could scavenge cisplatin-induced ROS. Real-time PCR analyses were performed to investigate the mRNA levels of antioxidant enzymes including NQO1, HO-1, GPx2, Gclc, and catalase. RESULTS: The cisplatin-treated group showed reduced cell viability, increased apoptotic properties and markers, and increased ROS levels. PSE pre treatment before cisplatin exposure significantly increased cell viability and reduced apoptotic properties and ROS production. These effects resulted from the up-regulation of antioxidant genes, including NQO1, HO-1, GPx2, Gclc, and catalase through Akt phosphorylation and Nrf2 activation. CONCLUSION: Our results demonstrate that PSE protects from cisplatin-induced cytotoxicity by activating the antioxidant effects via the Akt/Nrf-2 pathway in this auditory cell line, and indicate that PSE may provide novel treatment to prevent cisplatin-induced ototoxicity. PMID- 28012536 TI - The impact of tobacco exposure on development of otorrhea after myringotomy tube placement. AB - INTRODUCTION: Otorrhea is a common sequela after myringotomy with tube placement (MTP). The purpose of this study was to identify any significant relationship between passive tobacco exposure and the development of post-tympanostomy tube otorrhea. METHODS: Retrospective chart review was performed on 774 cases of patients who underwent MTP by a single surgeon at a tertiary pediatric hospital from 2012 to 2014. Patients with multiple medical comorbidities, craniofacial anomalies, syndromes and those over 12 years of age were excluded. Multivariate logistic regression analysis was performed to determine if there was a relationship between risk factors (including tobacco exposure, age, pre-operative diagnosis, operative findings and duration of follow-up) and the development of post-tympanostomy tube otorrhea. RESULTS: One hundred and ninety-one patients (average age of 1.92 years) were included. Overall, 16.8% of patients (32/191) had exposure to tobacco smoke. Of patients with passive smoke exposure, 65.6% (21/32) developed otorrhea, as compared to 45.3% (72/159) of those without tobacco exposure. Passive exposure to tobacco smoke by (OR = 2.307; p = 0.009; 95% CI, 1.734-6.028) and younger age (p = 0.012; 95% CI, 0.602-0.938) were associated with increased risk for otorrhea. DISCUSSION: This study suggests that in a cohort of patients undergoing MTP, passive exposure to tobacco smoke significantly increases the risk of developing post-operative otorrhea. This information is valuable to include in parental preoperative counseling regarding tympanostomy tube placement. PMID- 28012537 TI - Risk of failure of adenotonsillectomy for obstructive sleep apnea in obese pediatric patients. AB - INTRODUCTION: Pediatric obesity is a leading risk factor for obstructive sleep apnea (OSA), a condition commonly treated with adenotonsillectomy (T&A). It has been hypothesized that obesity increases a child's risk of failing T&A for OSA, however this relationship has not yet been quantified. The primary objective of this study was to investigate the relationship between obesity as measured by perioperative Body Mass Index (BMI) and persistent OSA following T&A as measured by polysomnography (PSG). STUDY DESIGN: Retrospective chart review. METHODS: Pediatric patients who underwent T&A between Jan. 2004 and Jan. 2016 were included. We recruited both obese and non-obese patients to compare caregiver/self reported improvement. Obese patients were recruited from a weight management clinic and included if they had a BMI z-score >1.65 and had pre- and post-operative polysomnograms (PSGs). Control patients included those undergoing T&A for OSA at our institution with BMI <1.65. These patients were age matched to the obese patient population. Age, gender, perioperative BMI z-score, caregiver/self reported improvement, total Apnea-Hypopnea Index (AHI), and O2 saturation nadir were collected where available. Univariate linear regressions were calculated between perioperative BMI z-score and PSG data. RESULTS: 26 obese study and 47 control subjects were identified for analysis. T&A resulted in statistically significant improvements in total AHI (p = 0.030) and nadir O2 saturation (p = 0.013) in obese subjects. There was no significant difference between the rate of caregiver/self reported improvement in the two groups. There was a statistically significant correlation between perioperative BMI z-score and the change in total AHI (p = 0.049). Within our population, for every increase by 0.1 in perioperative BMI z-score, the improvement in total AHI post-operatively decreased by 1.63 events/hr. Further, patients with BMI more than 3 standard deviations away from the age-derived normative mean received essentially no benefit from T&A alone. CONCLUSIONS: Our study established an inverse linear relationship between perioperative BMI z-score and improvement in total AHI with essentially no improvement in patients with BMI z-scores >3. Further studies are required to further elucidate this relationship and investigate the role of additional procedures in the initial management of OSA in obese children. PMID- 28012538 TI - Assessment of complete unilateral cleft lip and palate patients: Determination of factors effecting dental arch relationships. AB - OBJECTIVES: The purpose of the current study was to assess the treatment outcome of non-syndromic patients having complete unilateral cleft lip and palate (CUCLP) by using GOSLON index and to determine any association of pre and/or postnatal factors with the treatment outcome. MATERIALS AND METHODS: One hundred and one sets of dental models of patients having CUCLP were assessed in this retrospective study. Five examiners that were blinded to case-specific information scored the dental models at two instances with an interval of two weeks to ensure memory bias elimination (5 * 101 * 2 = 1010 observations). Calibration courses were conducted prior to scoring and each examiner was provided with scoring sheets, pictures of GOSLON reference models and flowcharts explaining the scoring method. RESULTS: According to GOSLON index, a mean (SD) GOSLON score of 3.04 (1.25) was determined. Based on treatment outcome groups, 62 patients had favorable (grade 1, 2, and 3) and 39 cases had unfavorable (grade 4 and 5) treatment outcome. Chi-square tests revealed a significant association of gender (P = 0.002), cheiloplasty (P = 0.001) and palatoplasty (P < 0.001) with the treatment outcome. These associations were further explored by entering five independent variables in the logistic regression models. CONCLUSIONS: The current study found an intermediate treatment outcome of CUCLP cases using GOSLON index. Final logistic model showed that gender, cheiloplasty, and palatoplasty had significantly higher odds of influencing outcomes. Identification of these factors provides us an evidence of traditional and outdated surgical methods and encourages clinicians to adopt current techniques to improve treatment outcomes. This implementation will facilitate comparison between the traditional and current techniques of primary surgical repair. PMID- 28012539 TI - Systematic review and individual patient data analysis of pediatric head and neck squamous cell carcinoma: An analysis of 217 cases. AB - INTRODUCTION: Pediatric head and neck Squamous cell carcinoma (PHNSCC) is a rare disease. The optimum treatment and outcome remains poorly understood because of rarity. METHODS: We conducted an individual patient data analysis of PHNSCC. Two authors independently searched PubMed, google search, and Cochrane library for eligible studies using following search words: Pediatric Head and neck squamous cell carcinoma, Head and neck squamous cell carcinoma under age of 20, Head and neck squamous cell carcinoma in young, PHNSCC till June 1, 2016 published in English language. RESULTS: Total of 217 patients of PHNSCC were found in the literature. Median age among the cohort was 15 years (Range: 0-20 years) with a clear male preponderance. Oral cavity tumors were commonest 75 (70%) followed by laryngeal neoplasms 16(15%). Median disease free survival was 9 months (Range: 0 216 months). Median overall survival was 48 months (Range: 1-216 months). In univariate analysis treatment modality had significant impact on disease free survival (DFS). Whereas, patients treated with Surgery, Laryngeal primary had significantly better OS. Patients with associated fanconis anemia had significantly worse overall survival (OS). CONCLUSION: PHNSCC is a rare disease with poorer outcome. Associated DNA defects leads to poorer OS. Patients treated with surgery alone or surgery followed by adjuvant radiation had better DFS and OS. Molecular profiling and personalized therapy may improve survival with limited toxicity. PMID- 28012540 TI - First report of prevalence c.IVS1+1G>A and del (GJB6-13S1854) mutations in Syrian families with non-syndromic sensorineural hearing loss. AB - OBJECTIVE: Mutations in GJB2 and GJB6 genes are a frequent cause of congenital non-syndromic hearing loss (NSHL). Mutational screening has usually focused on coding region of GJB2 gene. A few studies have been conducted on the non-coding region and exon 1. c.IVS1+1G>A (a splice site mutation in GJB2 gene have been detected as disruptive mutation. Del (GJB6 D13S1830) is found in many populations, but del (GJB6 D13S1854) is reported from a few restricted countries. This study was carried out to investigate the prevalence of splice site mutation c.IVS1+1G>A and two common deletions in GJB6 gene as the genetic etiology of hearing impairment in 70 Syrian families. METHODS: The frequency of the c.IVS1+1G>A mutation and two deletions were determined by PCR-RFLP and A multiplex PCR assay. RESULT: Our results showed a high prevalence of IVS1+1G>A mutation (20%) and del(GJB6-D13S1854) (15.7%) in deaf families. The homozygous genotype (c.IVS1+1G>A/c.IVS1+1G>A) was observed in one family and the compound heterozygous genotypes (c.35delG/c.IVS1+1G>A) and (c.IVS1+1G>A/V153I) were observed in 7 families and one family respectively. Also, the heterozygous state (c.IVS1+1G>A/unknown) was detected in 5 families. The study of del((GJB6 D13S1854) was showed a compound heterozygous genotype del((GJB6 D13S1854)/c.IVS1+1G>A) in the same families (5 families) having heterozygous genotype of c.IVS1+1G>A mutation. Also, del(GJB6-D13S1854) is combined with c.35delG mutation in 2 families and it was observed in the heterozygous state del(GJB6-D13S1854)/unknown) in 4 families. In contrast, the del(GJB6-D13S1830) described in many population was absent in our patients. CONCLUSION: Our findings indicate to significant contribution of the splice site mutation and del(GJB6 D13S1854) in our deaf families and these mutations were important causes of hearing impairment. PMID- 28012541 TI - A novel TECTA mutation causes ARNSHL. AB - OBJECTIVE: Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous sensorineural disorder. Alpha-tectorin, which is encoded by the TECTA gene, is a non-collagenous component of the tectorial membrane in the inner ear defect of which leads to moderate to severe hearing loss (HL). METHODS: 25 unrelated Iranian multiplex ARNSHL families, negative for GJB2 mutations, were recruited in this study. Clinical inspections including audiometric and otologic examinations ruled out syndromic forms. Genetic linkage analysis was performed using six short tandem repeat markers closely linked to DFNB21. Haplotype and LOD score analysis were used to confirm possible linkage. All coding exons of TECTA were subject to DNA sequencing in the linked family. RESULTS: A novel homozygous variant (c.734G > A) was found in exon 5 of the TECTA gene in one family leading to a nonsense mutation (p.W245*). It co-segregated with HL in the family. This variant was not detected in 50 controls. All affected individuals in the family had moderate to severe HL. It full filled the criteria of a pathogenic variant. CONCLUSION: Our data confirms the phenotype-directed genotyping for DFNB21 deafness against the typical profound HL phenotype seen in the most families segregating ARNSHL. We recommend mutation screening of TECTA in ARNSHL families segregating moderate to severe HL phenotype. PMID- 28012542 TI - Audiological findings in children with ataxia-telangiectasia (A-T) syndrome. AB - AIM: To assess peripheral and central hearing in children with A-T. METHOD: 3 children diagnosed with A-T according to the diagnostic criteria for A-T of the European Society for Immunodeficiencies. Involuntary movements were seen in the form of chorea-athetosis together with tremors. They were examined to assess both peripheral and central hearing was assessed (hearing thresholds). Sound-field testing, tympanometry, acoustic reflexes, Otoacoustic Emissions (OAEs) and Auditory Brainstem Responses (ABR) were done for all of them. RESULTS: Basic Audiological evaluation is of a limited value as the children are not co operative. Sound field testing could not be done. Bilateral normal middle ear functions as reflected by Tympanometry and Acoustic Reflexes. Advanced Audiological evaluation including OAEs and ABR are more valuable in assessing hearing in children with A-T. Bilateral pass response at all test frequencies in DPOAEs. Abnormal ABR findings were obtained in the form of a delay in wave V latency more than 2 SD with subsequent increased in I-V interpeak latency with no significant interaural latency difference. CONCLUSION: Consistent with bilateral normal peripheral hearing sensitivity with central hearing affection. LIMITATIONS: The rarity of the disease, make it difficult to be applied on many cases. PMID- 28012543 TI - Paediatric haemoptysis and the otorhinolaryngologist: Systematic review. AB - OBJECTIVES: Childhood haemoptysis is an uncommon presentation to the otolaryngologist but has a varied aetiology and can be life-threatening. We performed a systematic review of the literature to assess paediatric otolaryngologists' experience with haemoptysis, the aetiology involved, investigations performed and management provided. Using this, we produce an evidence-based treatment algorithm to guide clinicians. METHODS: Systematic literature review of the PubMed, EMBASE and Cochrane Collaboration using the search terms 'paediatric', 'child', 'neonate', 'adolescent', 'haemoptysis', 'coughing blood', 'spitting blood' and 'otorhinolaryngology'. RESULTS: Five articles were retrieved meeting the search criteria including 106 patients (age range 3 weeks to 18 years). The 3 most common aetiologies were bronchitis (n = 9), idiopathic/ no cause found (n = 9) and pneumonia (n = 7). Flexible bronchoscopy was the commonest investigation performed in non-active cases whilst rigid bronchoscopy was performed for active haemoptysis to provide therapeutic interventions. Chest x-ray was performed as a screening investigation rather than CT scan, which was reserved to assess pathology further, in recurrent cases and when x-ray is inconclusive. Management depended on aetiology. There was no difference in aetiology between age ranges. CONCLUSIONS: Haemoptysis aetiology is varied and non-cancerous but is life-threatening in cases of pulmonary agenesis and vasculature abnormalities. No cause may be found. Clinicians' investigations and management plans should be based on the established care of haemoptysis. There is no difference between otolaryngologists and respiratory physicians' experience. PMID- 28012544 TI - Gynecologic Oncology 2017 Update: New Features and Expanded Scope. PMID- 28012545 TI - Sentinel Lymph Node Biopsy for Cervical Cancer Patients - What's It Gonna Take? PMID- 28012546 TI - Proximal Subungual Onychomycosis Due to Aspergillus niger: A Simulator of Subungual Malignant Melanoma. PMID- 28012547 TI - Exploratory laparoscopy in politrauma: Knife extraction. PMID- 28012549 TI - Confabulations and related disorders: We've come a long way, but there is still a lot to do! PMID- 28012548 TI - Facilitated Dissociation Kinetics of Dimeric Nucleoid-Associated Proteins Follow a Universal Curve. AB - Recent experimental work has demonstrated facilitated dissociation of certain nucleoid-associated proteins that exhibit an unbinding rate that depends on the concentration of freely diffusing proteins or DNA in solution. This concentration dependence arises due to binding competition with these other proteins or DNA. The identity of the binding competitor leads to different qualitative trends, motivating an investigation to understand observed differences in facilitated dissociation. We use a coarse-grained simulation that takes into account the dimeric nature of many nucleoid-associated proteins by allowing an intermediate binding state. The addition of this partially bound state allows the protein to be unbound, partially bound, or fully bound to a DNA strand, leaving opportunities for other molecules in solution to participate in the unbinding mechanism. Previous models postulated symmetric binding energies for each state of the coarse-grained protein corresponding to the symmetry of the dimeric protein; this model relaxes this assumption by assigning different energies for the different steps in the unbinding process. Allowing different unbinding energies not only has equilibrium effects on the system, but kinetic effects as well. We were able to reproduce the unbinding trends seen experimentally for both DNA and protein competitors. All trends collapse to a universal curve regardless of the unbinding energies used or the identity of the dissociation facilitator, suggesting that facilitated dissociation can be described with a single set of scaling parameters that are related to the energy landscape and geometric nature of the competitors. PMID- 28012550 TI - Relate it! Objective and subjective evaluation of mediator-based strategies for improving source memory in younger and older adults. AB - The present study examined younger and older adults' ability to improve their source memory for different types of sources through imaginal and verbal (sentence) mediators. Younger (18-29 years) and older (60-75 years) adults' strategy use and source memory for either text-type (bold vs italic) or person (woman vs man) sources was assessed; strategy use was either spontaneous or the generation of imaginal mediators was instructed before encoding. Younger and older adults did not differ in spontaneous use of mediator-based strategies; however, older adults generated more images but fewer verbal mediators than younger adults. Participants were able to increase mediator generation when instructed to, resulting in substantial increases in both item and source memory for the instructed conditions in both age groups. Use of verbal mediators was more likely for the more concrete person sources for which source memory was generally better. Importantly, these objective benefits of mediator-based strategies translated into subjective benefits for both younger and older adults: Increased use of either mediator type was correlated with lower experienced task difficulty; the instructions to use imaginal mediators resulted in a significant decrease in difficulty ratings on the group level. Participants were generally able to monitor mediator benefits to both item and source memory and accurately judged mediator strategies (especially imagery) as more effective than repetition; older adults, however, rated all strategies as less effective than younger adults. Implications of these findings, especially for neuropsychological studies on source monitoring, are discussed. PMID- 28012551 TI - Strain shielding in distal radius after wrist arthroplasty with a current generation implant: An in vitro analysis. AB - A systematic review of peer reviewed articles has shown that the main cause for wrist arthroplasty revision is carpal and radial prosthetic loosening and instability. To improve arthroplasty outcomes, successive generations of implants have been developed over time. The problem with the current generation of implants is the lack of long-term outcomes data. The aim of the present work was to test the hypothesis that the current generation Maestro WRS implant has a stress, strain and stability behaviour which may be associated with a reduced risk of long-term radial component loosening. This study was performed using synthetic radii to experimentally predict the cortex strain behaviour and implant stability considering different load conditions for both intact and implanted conditions. Finite element models were developed to assess the structural behaviour of cancellous-bone and bone-cement, these models were validated against experimentally measured cortex strains. Measured cortex strains showed a significant reduction between intact and implanted states. Cancellous bone adjacent to the radial body component suffers a two to threefold strain reduction, comparing with the intact condition, while along the radial stem, in the axial direction, a strain increase was observed. It is concluded that the use of contemporary Maestro WRS implant changes the biomechanical behaviour of the radius and is associated with a potential risk of bone resorption by stress shielding in the distal radius region for wrist loads in the range of daily activities. PMID- 28012552 TI - Smoking cessation advice in limb reconstruction: An opportunity not to be missed. AB - The adverse health effects of smoking are well known, including its effects on the musculoskeletal system. Limb reconstruction using external fixators is a high intensity process with high levels of patient contact time, complications and cost. The aim of this study was to examine smoking patterns in this group and in particular to assess trends in smoking cession. Data was collected from 41 patients all undergoing treatment using circular frame external fixation, for a variety of pathologies, most commonly acute tibial trauma. A patient reported questionnaire was used. Data was collected over a six-month period. In our population 56.1% of patients were smokers. During the study 47.8% patients stopped smoking and a further 39.1% decreased their smoking behaviour. 78.3% of patients could recall being given smoking cessation advice. In our group, 87% of patients were unaware of the effects of smoking on bone healing. Once made aware during discussion of proposed treatment, 73.9% stated that it was, in part, this knowledge that prompted them to positively change their smoking habits. The results of this study show that advice regarding smoking cessation during limb reconstruction treatment can potentially have a positive impact on patients smoking habits. The effect of smoking should be linked to the patient pathology and discussed during the consent process. Taking the time with the patient for this simple free intervention can have a positive impact on patient health, and potentially on the outcome of their current treatment, and is an opportunity not to be missed. PMID- 28012553 TI - Comparison of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Unprotected Left Main Coronary Artery Disease. AB - Coronary artery bypass grafting (CABG) decreases mortality in patients with significant left main (LM) coronary artery disease and for years remained the therapy of choice for patients with this ominous lesion. Advances in percutaneous coronary intervention (PCI) have enabled it to become an alternative to CABG. The results of observational registries and randomized comparisons have shown the safety and efficacy of PCI in appropriately selected patients with low or intermediate angiographic risk scores. Furthermore, the use of physiological measures of flow limitation and the use of intracoronary imaging techniques has added benefit and improved outcomes. The use of fractional flow reserve to more accurately evaluate the significance of intermediate lesions and guide the extent of revascularization has been an important refinement. Intravascular ultrasound and optical coherence tomography assessment of optimal stent deployment has led to reductions in restenosis. Newer generation stents, combined with improvements in specific techniques, especially at the LM bifurcation have extended PCI to more complex anatomic scenarios. The availability of left ventricular support devices in patients with complex coronary anatomy and severely depressed left ventricular function has added a margin of safety to LM and multivessel intervention. Randomized comparisons of CABG with PCI in carefully selected patients, using contemporaneous surgical and interventional techniques and optimal medical therapy, will further aid heart teams in the decision-making process. In conclusion, this review will give a concise overview of the management of unprotected LM disease. PMID- 28012554 TI - H2 consensus control of time-delayed multi-agent systems: A frequency-domain method. AB - An analytical H2 controller design approach of homogeneous multi-agent systems with time delays is presented to improve consensus performance. Firstly, a closed loop multi-input multi-output framework in frequency domain is introduced, and a consensus tracking condition is given. Secondly, the decomposition method is utilized to simplify the analysis of internal stability and H2 performance index of the whole system to a set of independent optimization problems. Finally, the H2 optimal controller can be computed from all the stabilizing controllers. The contributions of the new approach are that the design procedure is conducted analytically for arbitrary delayed multi-agent systems, and a simple quantitative tuning way is developed to trade off the nominal performance and robustness. The simulation examples show the effectiveness of the proposed control strategy. PMID- 28012555 TI - Corrigendum to "Surface water areas significantly impacted 2014 dengue outbreaks in Guangzhou, China" [Environ. Res. 150 (2016) 299-305]. PMID- 28012556 TI - [Crossed renal ectopia in a patient with a complicated sigma neoplasia]. AB - BACKGROUND: Crossed renal ectopia is a rare pathology that is often asymptomatic. Intraoperative detection with a sigma complicated neoplasia is more infrequent and requires correct management to avoid a renal ureteral injury. AIM: To present a case report of a patient with a sigma complicated neoplasia and a crossed renal ectopia detected incidentally. CASE REPORT: We present the case of a 62-year-old man that was submitted for emergency surgery for a sigma perforated neoplasm, and who presented with a previously undiagnosed left-side CRE. During surgery there was a need to insert 2-double-J stents as a guide to both ureters and to avoid any injury to them. DISCUSSION: Crossed renal ectopia is a rare, often asymptomatic entity, the diagnosis of which is usually incidental. In our case, the detection of a concomitant complicated neoplasm, required identification of both ureters due the anatomic doubt of its localization and to avoid them being injured. In conclusion, upon finding a casual crossed renal ectopia during an emergency surgery of sigma, we recommend the identification of the ureters to facilitate its location and to avoid any injury to the ureters. PMID- 28012557 TI - Exercise testing for long-term follow-up in arrhythmogenic right ventricular cardiomyopathy. AB - OBJECTIVES: We investigated arrhythmia, electrocardiography and physical work capacity (PWC) in the follow-up of ARVC. DESIGN: Twenty-three patients (13 men; age 41+/-12years) fulfilling diagnostic criteria were re-investigated after at least five years. RESULTS: Ventricular arrhythmia during exercise testing (ET) was present in 14 patients (61%) and showed variation between examinations. In eleven (48%), complex ventricular ectopic activity was observed at peak exercise or immediately thereafter. Mutations known to be pathogenic in ARVC were present in 13 patients (57%) of which 11 developed complex ventricular arrhythmia at ET. PWC at baseline was 190+/-66W (104+/-26%) decreasing to 151+/-61W (91+/-23%, p=0.008) after 10.7years. CONCLUSION: The appearance of ventricular arrhythmia during exercise testing showed temporal variation but was frequent in patients with relevant genetic mutation. Physical exercise capacity decreased over time in patients with ARVC in excess to the age-related deterioration and regardless of medication. PMID- 28012558 TI - Obstructive sleep apnea in a patient with orofacial pain secondary to cervical fixation. PMID- 28012559 TI - Authors' response to the letter to the editor pertaining to systematic review: Health care transition practice service models. PMID- 28012560 TI - Non-traditional roles of complement in type 2 diabetes: Metabolism, insulin secretion and homeostasis. AB - Type 2 Diabetes (T2D) is a disease of increasing importance and represents a growing burden on global healthcare and human health. In T2D, loss of effectiveness of insulin signaling in peripheral tissues cannot be compensated for by adequate insulin secretion, leading to hyperglycemia and resultant complications. In recent years, inflammation has been identified as a central component of T2D, both in inducing peripheral insulin resistance as well as in the pancreatic islet, where it contributes to loss of insulin secretion and death of insulin-secreting beta cells. In this review we will focus on non-traditional roles of complement proteins which have been identified in T2D-associated inflammation, beta cell secretory function, and in maintaining homeostasis of the pancreatic islet. Improved understanding of both traditional and novel roles of complement proteins in T2D may lead to new therapeutic approaches for this global disease. PMID- 28012561 TI - Peripheral apelin-13 administration inhibits gastrointestinal motor functions in rats: The role of cholecystokinin through CCK1 receptor-mediated pathway. AB - Apelin is the endogenous ligand of the G protein-coupled receptor APJ. The APJ receptor is widely expressed in gastrointestinal (GI) tissues including stomach and small intestine. Apelin administration was shown to induce the release of cholecystokinin (CCK) which is a well-known alimentary hormone with its inhibitory actions on GI motor functions through CCK1 receptors on vagal afferent fibers. We investigated whether; (i) peripherally injected apelin-13 alters GI motor functions, (ii) apelin-induced changes are mediated by APJ receptor or CCK1 receptor and (iii) vagal afferents are involved in inhibitory effects of apelin. Solid gastric emptying (GE) and colon transit (CT) were measured, whereas duodenal phase III-like contractions were recorded in rats administered with apelin-13 (300MUg/kg, ip). CCK1 receptor antagonist lorglumide (10mg/kg, ip) or APJ receptor antagonist F13A (300MUg/kg, ip) was administered 30min prior to the apelin-13 injections. Vagal afferent denervation was achieved by systemic administration of vanilloid receptor agonist capsaicin (125mg/kg, sc). Apelin-13 administration significantly (p<0.01) increased the CCK level in portal venous plasma samples. Compared with vehicle-treated rats, apelin-13 significantly delayed both GE (p<0.001) and CT (p<0.01). Pretreatment of lorglumide or F13A completely abolished the apelin-13-induced inhibitory effects on GE and CT, moreover, apelin-13 was found ineffective in rats underwent afferent denervation. F13A administration alone significantly accelerated the basal CT. Apelin-13 noticeably disturbed the duodenal fasting motor pattern by impairing phase III like contractions while increasing the amplitudes of phase II contractions which were prevented by pretreatment of lorglumide and capsaicin. Compared with vehicle treated rats, lorglumide and capsaicin significantly (p<0.05) reduced the apelin 13-induced increases in phase II motility index. Peripherally administered apelin 13 inhibits GI motor functions through CCK-dependent pathway which appears to be mediated by CCK1 receptors on vagal afferents. Peripheral apelin might contribute to the motility changes occurred in postprandial period. PMID- 28012562 TI - My dying student. PMID- 28012563 TI - Should methotrexate remain the first-line drug for psoriasis? PMID- 28012564 TI - An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: Methotrexate is one of the most commonly used systemic drugs for the treatment of moderate to severe psoriasis; however, high-quality evidence for its use is sparse and limited to use of oral dosing. We aimed to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis. METHODS: We did this prospective, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (METOP) at 16 sites in Germany, France, the Netherlands, and the UK. Eligible patients were aged 18 years or older, had a diagnosis of chronic plaque psoriasis for at least 6 months before baseline, had currently moderate to severe disease, and were methotrexate treatment-naive. Participants were randomly assigned (3:1), via a computer-generated random number sequence integrated into an electronic data capture system, to receive either methotrexate at a starting dose of 17.5 mg/week or placebo for the first 16 weeks, followed by methotrexate treatment of all patients up to 52 weeks (methotrexate-methotrexate vs placebo-methotrexate groups). Dose escalation to 22.5 mg/week was allowed after 8 weeks of methotrexate treatment if patients had not achieved at least a 50% reduction in baseline Psoriasis Area and Severity Index score (PASI), with corresponding volume increases in placebo injections. Treatment was combined with folic acid 5 mg/week. Group allocation was concealed from participants and investigators from the time of randomisation until an interim database lock at week 16, and was open label from week 16 onwards, with no masking of participants or investigators. The primary efficacy endpoint was a 75% reduction in PASI score (PASI 75) from baseline to week 16. We did analysis by modified intention to treat, with non responder imputation. This study is registered with EudraCT, number 2012-002716 10. FINDINGS: Between Feb 22, 2013, and May 13, 2015, we randomly assigned 120 patients to receive methotrexate (n=91) or placebo (n=29). At week 16, a PASI 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3.93, 95% CI 1.31 11.81; p=0.0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period. INTERPRETATION: Our findings show a favourable 52 week risk-benefit profile of subcutaneous methotrexate in patients with psoriasis. The route of administration and the intensified dosing schedule should be considered when methotrexate is used in this patient group. FUNDING: Medac. PMID- 28012565 TI - Healthcare utilization for arthritis by indigenous populations of Australia, Canada, New Zealand, and the United States: A systematic review?. AB - PURPOSE: Indigenous populations of Australia, Canada, New Zealand, and the United States of America (USA) experience a higher prevalence of arthritis conditions. Differences in clinical outcomes and mortality may reflect healthcare service use inequities. The objective of this study was to summarize healthcare service use patterns described in the existing literature in order to identify gaps and inform strategies to limit the pronounced negative impact of arthritis on Indigenous populations. METHODS: Medline, EMBASE, CINAHL, and Indigenous-specific electronic databases (to June 2015) were used to identify cohort, case-control and cross-sectional studies describing healthcare service use by Indigenous populations with specified inflammatory arthritis, osteoarthritis, or rheumatic disease conditions. We extracted information on the study setting and methodology, primary outcome and assessed study quality, and risk of bias. RESULTS: In total, 19 studies were identified describing three types of healthcare service use: physician visits, hospitalizations, and surgeries. In Canada and New Zealand, Indigenous populations had 36-51% fewer visits to specialists than the non-Indigenous population. Indigenous populations in Canada, New Zealand, and the USA had 37-300% more hospitalizations due to arthritis complications than the non-Indigenous population. Indigenous populations in Australia, Canada, and New Zealand had 27-85% fewer arthroplasties for osteoarthritis than the non-Indigenous population. CONCLUSIONS: Indigenous populations had higher hospitalization rates but lower use of specialized services for arthritis conditions. Strategies to improve access to specialized arthritis services might reduce health outcome inequities. PMID- 28012566 TI - New evidence on old drugs; warfarin versus aspirin after bioprosthetic aortic valve placement. PMID- 28012567 TI - beta-Amyrin synthase (EsBAS) and beta-amyrin 28-oxidase (CYP716A244) in oleanane type triterpene saponin biosynthesis in Eleutherococcus senticosus. AB - Siberian ginseng (Eleutherococcus senticosus) is a woody medical shrub belonging to the Araliaceae family. E. senticosus contains various types of saponins, including oleanane, noroleanane, lupane, and 3,4-secolupane types, depending on the aglycone structure. Oleanane-type triterpenes are the major saponin components in E. senticosus. Two enzymes (beta-amyrin synthase and beta-amyrin 28 oxidase) are essential for oleanane-type saponin biosynthesis from 2,3 oxidosqualene. In the present study, two full-length cDNAs encoding EsBAS and CYP716A244 were isolated based on transcriptomics analysis of plant leaves. Both beta-amyrin synthase (EsBAS) and beta-amyrin 28-oxidase (CYP716A244), isolated from E. senticosus, were functionally characterised. beta-amyrin production was confirmed by heterologous expression of the EsBAS gene in yeast and tobacco. Oleanolic acid production was confirmed by co-expression of both EsBAS and CYP716A244 in engineered yeast and transgenic tobacco. PMID- 28012568 TI - Improved survival after induction of sepsis by cecal slurry in PD-1 knockout murine neonates. AB - BACKGROUND: Sepsis and the ensuing immune dysfunction continue to be major contributors to neonatal morbidity and mortality. Neonatal sepsis also is associated with profound immune dysfunction. We have recently identified a role for a family of coinhibitory molecules that are altered in murine sepsis and in critically ill adult patients, which may be a target for development of novel therapies. There is, however, a paucity of data pertaining to the role of coinhibitory checkpoint proteins in the control and modulation of neonatal sepsis. METHODS: The cecal slurry model consists of harvesting the cecal content of an adult, wild-type, male mouse and combining it with 5% dextrose to create a cecal slurry with a concentration of 80 mg/mL (LD70 at 7 days). Neonatal mice (5 7 days of age) underwent intraperitoneal injection of the cecal slurry or 0.9% saline for the sham procedure. Wild-type (C57BL/6) or PD-1-/- mice were used; a 7 day survival study was undertaken. Cytometric bead array was used for cytokine expression. Blood and peritoneal fluid was cultured for bacterial burden. Flow cytometry was used to assess the peritoneal cavity cell populations. RESULTS: There was no mortality after the sham procedure in either wild-type or PD-1-/- pups. PD-1 markedly affected sepsis survival with significantly improved survival in the PD-1-/- pups (40% vs 80%; P < .01). This survival improvement was not associated with any difference in bacterial clearance. The bacterial burden was equivalent between wild-type and PD-1-/- pups at 24 hours after cecal slurry. However, PD-1-/- pups did display an increased circulating cytokine response to the cecal slurry compared with wild type, with increased expression of IL-6, IL 10, and TNF-alpha levels. Within the peritoneal cavity, sepsis induced an influx of neutrophils, a finding that was increased in PD-1-/- pups. Although the T-cell response was unaffected by PD-1, it was noted that cecal slurry induced a loss of peritoneal B cells in WT, while the peritoneal B-cell population was preserved in PD-1-/- pups. CONCLUSION: Our data suggest that the checkpoint protein, PD-1, plays an important role in controlling the immune response to sepsis in the neonate, ultimately affecting sepsis-related mortality in this neonatal murine model of sepsis. Akin to adult studies, these data further emphasize the potential therapeutic target for PD-1 across a spectrum of septic patients. PMID- 28012569 TI - Efficacy of Methylprednisolone Acetate Versus Triamcinolone Acetonide Intra articular Knee Injection in Patients With Chronic Inflammatory Arthritis: A 24 Week Randomized Controlled Trial. AB - PURPOSE: Triamcinolone hexacetonide (TH), triamcinolone acetonide (TA), and methylprednisolone acetate (MPA) are commonly used intra-articular steroid preparations. Studies suggest that intra-articular TH is more efficacious than MPA and TA in chronic inflammatory arthritis. However, it is unclear which of the latter two preparations has better efficacy. Thus, we compared intra-articular knee injections of MPA and TA in patients with chronic inflammatory arthritis. METHODS: This double-blind, randomized controlled trial included patients with rheumatoid arthritis or spondyloarthritis with an acutely swollen knee joint (>=1 week, <24 weeks). They were randomly assigned (1:1) to intra-articular knee injection with MPA or TA (80 mg, 2 mL of each). Evaluations were performed at 4, 12, and 24 weeks. Primary outcome was time to relapse (Kaplan-Meier) over 24 weeks, with relapse defined as return to baseline pain or swelling >=1 week. Secondary outcomes were change in pain and swelling (using a numerical rating scale), range of movement, and occurrence of adverse effects. Primary analysis was intention to treat, with last observation carried forward. FINDINGS: One hundred patients (89 with rheumatoid arthritis) were randomly assigned in equal numbers to the MPA and TA groups. Nine patients relapsed in each group over 24 weeks. The mean time to relapse was not significantly different between the MPA and TA groups (20.8 [95% CI, 18.8-22.7] weeks and 20.9 [95% CI, 19.0-22.8] weeks, respectively; P = 0.9; hazard ratio = 1.0 [95% CI, 0.4-2.5]). In both groups, there was a significant decline in pain and swelling scores at all visits (P < 0.001); however, there were no significant intergroup differences. At 24 weeks, mean change in pain in the MPA (-4.4 [3.1]) and TA groups (-3.9 [2.8]) was not significantly different (P = 0.46). No infection, hematoma or hypopigmentation occurred in any patient. In addition, no significant intergroup differences were found in joint swelling, range of movement, modified (28 joint) Disease Activity Score using 3 variables, or Health Assessment Questionnaire over 24 weeks. IMPLICATIONS: No significant differences were found in efficacy between intra articular knee injections with MPA and TA in these patients with chronic inflammatory arthritis. However, results need to be extrapolated cautiously because of the small sample size. Three-quarters of the patients remained relapse free at 24 weeks. Clinical Trials Registry of India (www.ctri.nic.in) identifier: CTRI/2015/09/006187. PMID- 28012570 TI - Ion-beam modification of 2-D materials - single implant atom analysis via annular dark-field electron microscopy. AB - Functionalisation of two-dimensional (2-D) materials via low energy ion implantation could open possibilities for fabrication of devices based on such materials. Nanoscale patterning and/or electronically doping can thus be achieved, compatible with large scale integrated semiconductor technologies. Using atomic resolution High Angle Annular Dark Field (HAADF) scanning transmission electron microscopy supported by image simulation, we show that sites and chemical nature of individual implants/ dopants in graphene, as well as impurities in hBN, can uniquely and directly be identified on grounds of their position and their image intensity in accordance with predictions from Z-contrast theories. Dopants in graphene (e.g., N) are predominantly substitutional. In other 2-Ds, e.g. dichalcogenides, the situation is more complicated since implants can be embedded in different layers and substitute for different elements. Possible configurations of Se-implants in MoS2 are discussed and image contrast calculations performed. Implants substituting for S in the top or bottom layer can undoubtedly be identified. We show, for the first time, using HAADF contrast measurement that successful Se-integration into MoS2 can be achieved via ion implantation, and we demonstrate the possibility of HAADF image contrast measurements for identifying impurities and dopants introduced into in 2-Ds. PMID- 28012571 TI - Perinatal nutrition interventions and post-partum depressive symptoms. AB - BACKGROUND: Postpartum depression (PPD) is the most prevalent mood disorder associated with childbirth. No single cause of PPD has been identified, however the increased risk of nutritional deficiencies incurred through the high nutritional requirements of pregnancy may play a role in the pathology of depressive symptoms. Three nutritional interventions have drawn particular interest as possible non-invasive and cost-effective prevention and/or treatment strategies for PPD; omega-3 (n-3) long chain polyunsaturated fatty acids (LCPUFA), vitamin D and overall diet. METHODS: We searched for meta-analyses of randomised controlled trials (RCT's) of nutritional interventions during the perinatal period with PPD as an outcome, and checked for any trials published subsequently to the meta-analyses. RESULTS: Fish oil: Eleven RCT's of prenatal fish oil supplementation RCT's show null and positive effects on PPD symptoms. Vitamin D: no relevant RCT's were identified, however seven observational studies of maternal vitamin D levels with PPD outcomes showed inconsistent associations. Diet: Two Australian RCT's with dietary advice interventions in pregnancy had a positive and null result on PPD. LIMITATIONS: With the exception of fish oil, few RCT's with nutritional interventions during pregnancy assess PPD. CONCLUSIONS: Further research is needed to determine whether nutritional intervention strategies during pregnancy can protect against symptoms of PPD. Given the prevalence of PPD and ease of administering PPD measures, we recommend future prenatal nutritional RCT's include PPD as an outcome. PMID- 28012572 TI - Mammalian Polycistronic mRNAs and Disease. AB - Our understanding of gene expression has come far since the 'one-gene one polypeptide' hypothesis proposed by Beadle and Tatum. In this review, we address the gradual recognition that a growing number of polycistronic genes, originally discovered in viruses, are being identified within the mammalian genome, and that these may provide new insights into disease mechanisms and treatment. We carried out a systematic literature review identifying 13 mammalian genes for which there is evidence for polycistronic expression via translation through an internal ribosome entry site (IRES). Although the canonical mechanism of translation initiation has been studied extensively, here we highlight a process of noncanonical translation, IRES-mediated translation, that is a growing source for understanding complex inheritance, the elucidation of disease mechanisms, and the discovery of novel therapeutic targets. Identification of additional polycistronic genes may provide new insights into disease therapy and allow for new discoveries of both translational and disease mechanisms. PMID- 28012573 TI - FGF2, FGF3 and FGF4 expression pattern during molars odontogenesis in Didelphis albiventris. AB - Odontogenesis is guided by a complex signaling cascade in which several molecules, including FGF2-4, ensure all dental groups development and specificity. Most of the data on odontogenesis derives from rodents, which does not have all dental groups. Didelphis albiventris is an opossum with the closest dentition to humans, and the main odontogenesis stages occur when the newborns are in the pouch. In this study, D. albiventris postnatals were used to characterize the main stages of their molars development; and also to establish FGF2, FGF3 and FGF4 expression pattern. D. albiventris postnatals were processed for histological and indirect immunoperoxidase analysis of the tooth germs. Our results revealed similar dental structures between D. albiventris and mice. However, FGF2, FGF3 and FGF4 expression patterns were observed in a larger number of dental structures, suggesting broader functions for these molecules in this opossum species. The knowledge of the signaling that determinates odontogenesis in an animal model with complete dentition may contribute to the development of therapies for the replacement of lost teeth in humans. This study may also contribute to the implementation of D. albiventris as model for Developmental Biology studies. PMID- 28012575 TI - Is a Respiratory Day Hospital Useful in Patients with Severe Disease? PMID- 28012576 TI - Use of Thoracic Ultrasound in the Detection of Pneumothorax Resolution after Drainage. PMID- 28012574 TI - Sezary syndrome without erythroderma: A review of 16 cases at Mayo Clinic. AB - BACKGROUND: Sezary syndrome (SS) is characterized by erythroderma with leukemic involvement. In atypical SS, leukemic involvement is present without erythroderma. Little is known about the presentation, prognosis, and outcome in these patients. OBJECTIVE: We sought to describe our experience with patients with SS without erythroderma. METHODS: We retrospectively identified patients with SS, but without erythroderma, at Mayo Clinic from 1976 to 2010. Patients all met criteria for high blood tumor burden. Their clinical characteristics, disease course, and prognosis were reviewed and compared with a previously described cohort of 176 patients with SS from this institution. RESULTS: Among 16 patients identified, all had cutaneous findings consistent with cutaneous T-cell lymphoma, most commonly erythematous patches (n = 6) and plaques (n = 12). All 16 patients were deceased at the time of the study. Median time from diagnosis of SS without erythroderma to the date of death was 3.6 years (range, 0.5-8.7 years). Survival was not different between patients with SS with and without erythroderma (hazard ratio 1.58; 95% confidence interval 0.94-2.66; P = .08). LIMITATIONS: This was a single-institution retrospective study. CONCLUSION: Leukemic involvement may confer shortened survival in patients with SS, because the presence of erythroderma did not affect survival. These atypical cases could potentially be more accurately described using the TNMB classification. PMID- 28012577 TI - Pulmonary disease caused by Mycobacterium szulgai. PMID- 28012579 TI - Long-acting octreotide is effective in the treatment of portal hypertensive colopathy. PMID- 28012578 TI - Percutaneous management of massive pulmonary thromboembolism. PMID- 28012580 TI - Colonic pseudopolyposis in inflammatory bowel disease. PMID- 28012581 TI - The Journal of Hospital Infection in 2017: looking back and looking forward. PMID- 28012582 TI - Manual resuscitators in successive use in the same patient: reservoir of multi- and extensively resistant bacteria. AB - To determine the bacterial load on manual resuscitators (MRs), swab samples of MR connectors from a Brazilian intensive care unit were collected at time zero, and after 24 and 48h use in the same patient. From 20 MRs, a total of 54 bacteria were isolated: six at t=0, 17 at t=24, and 31 at t=48. Staphylococcus aureus, Acinetobacter baumannii, Serratia marcescens, and Pseudomonas aeruginosa were the predominant isolates, and multidrug resistance was widespread in all species. Greater awareness of the need to ensure effective decontamination of MRs between patients, as well as more frequent replacement of MRs in individual patients, is recommended to minimize the risk of (re)colonization/infection of the respiratory tract. PMID- 28012583 TI - NKT cells in leishmaniasis. AB - The role of NKT cells in the resistance or susceptibility towards Leishmania infections remains to be defined, since controversial data persist. The response of these cells seems to depend on many variables such as the infection site, the number of infecting parasites, the virulence of the strain and the Leishmania species. We here revise the activation pathways leading to NKT cell activation. NKT cells can be activated by the direct pathway, in which Leishmania glycolipids are presented by CD1d molecules on antigen presenting cells, such as dendritic cells (DC), leading to the secretion of diverse cytokines by NKT. NKT cells can also be activated by the indirect pathway, in which Leishmania glycolipids, such as LPG, stimulate TLR2 in DC, inducing their IL-12 production, which in turn activates NKT cells. The review further analyzes the role of NKT cells in disease development, both in humans as in mouse models. Finally we propose the activation of NKT cells for controlling Leishmania infections. PMID- 28012584 TI - Severe disease in Cystic Fibrosis and fecal calprotectin levels. AB - Fecal calprotectin (FC) is used to asses the presence of intestinal inflammation also in patients with Cystic Fibrosis (CF) and recent studies showed a correlation between bowel and lung disease in these patients. The aim of this study was to analyze the levels of FC in CF and correlate them with different phenotypes of disease. We enrolled a cohort of 54 CF patients and 50 healthy controls. In these patients, calprotectin has been assayed on a stools sample using an ELISA kit. In all patients we analyzed, FC levels were elevated above the cut-off value and significantly higher than in healthy controls. Among CF patients, FC was significantly higher in patients older than 18 years, with pancreatic insufficiency, underweight status, Pseudomonas Aeruginosa airways colonization, CF-related diabetes mellitus, reduced lung function, or high number of pulmonary exacerbations. These results suggest that in patients with CF, FC levels are not only influenced by the CF enteropathy but also by the severity of the genetic disease. Since we found higher FC levels in patients with a severe phenotype (P. Aeruginosa airways colonization, FEV1<50% of predicted, pancreatic insufficiency, underweight status,) we suggest that this marker could be useful to monitor longitudinally a clinical worsening. PMID- 28012585 TI - Giant inguinoscrotal hernia. PMID- 28012586 TI - Isotopic separation of acetaldehyde and methanol from their deuterated isotopologues on a porous layer open tubular column allows quantification by stable isotope dilution without mass spectrometric detection. AB - An isotopic separation of acetaldehyde and acetaldehyde-2,2,2-d3 was achieved in a temperature programmed run on a porous layer open tubular (PLOT) capillary column coated with particles of divinylbenzene ethylene glycol/dimethylacrylate (Rt(r)-U-BOND). This is the prerequisite for the development of quantitative analytical methods based on a stable isotope dilution assay (SIDA) without a mass spectrometric detection (non-MS SIDA). For routine analysis a flame ionization detector (FID) can thus be applied as a robust and low-cost alternative. In a preliminary study, static headspace extraction and gas chromatographic separation (HS-GC-FID) of acetaldehyde in aqueous solutions was shown as an application. Good linearity was obtained in a calibration range from 0.4 to 40mgL-1, with peak integration benefitting from the inverse isotope effect encountered on the specific porous polymer. Furthermore, separation of methanol and deuterated methanol (d3) could also be achieved under the same chromatographic conditions. The achieved isotopic separation of these important volatile compounds now allows non-MS SIDA-based methods that are still to be developed. PMID- 28012587 TI - Hollow fiber liquid-phase microextraction-gas chromatography-mass spectrometry method to analyze bisphenol A and other plasticizer metabolites. AB - Phthalates and bisphenol A are important environmental pollutants due to their toxicity for humans and animals, including actions in the endocrine system. Their metabolites in urine can be used as biomarkers to assess human exposure. This paper describes the development of a new method to determine bisphenol A and eight phthalate metabolites in urine samples using hollow fiber liquid phase microextraction (HF-LPME) and gas chromatography-mass spectrometry (GC-MS). This method showed linearity, precision, limits of detection, and quantification suitable to analyze these compounds at low concentration levels in urine. Limits of detection ranged from 0.777 to 23.3MUgL-1, showing sensitivity for evaluating environmental exposure. Relative standard deviation (RSD) ranged from 11.7 to 19.7%. The developed method presented a good biomarker alternative for evaluating environmental exposure to bisphenol A and phthalates. PMID- 28012588 TI - Determination of biogenic amines in canned fish samples using head-space solid phase microextraction based on nanostructured polypyrrole fiber coupled to modified ionization region ion mobility spectrometry. AB - The head-space solid phase microextraction (HS-SPME) was applied to extraction and determination of histamine (HIS), putrescine (PUT), cadaverine (CAD), tyramine (TYR) in canned fish samples by ion mobility spectrometry (IMS) without any derivatization process. HIS and CAD have the same mobilities in nitrogen as buffer gas and their corresponding peaks are severely overlapped in ion mobility spectrum. Peak separation was acquired in the presence of 18-crown-6 vapor as complexation reagent into carrier gas and modified ionization region of IMS (MIR IMS) at optimum flow rate. The interaction between 18-crown-6 and the mentioned amines forms nanocluster product ions with different cross section areas and ion mobilities. The effects of main extraction parameters on the efficiency of HS SPME-MIR-IMS were investigated and optimized. Relative standard deviations (RSD%) of the biogenic amines determination at 50MUgL-1 concentration level were obtained in range 5.7%-6.3%. Limits of detection for analytes were in the range of 0.6-1ngg-1. HS-SPME-MIR-IMS results indicate that the proposed method can be successfully used in biogenic amines analysis in water and food samples. Method validation was conducted by comparing our results with those obtained through GC MS method. PMID- 28012589 TI - Cocaine abuse determination by ion mobility spectrometry using molecular imprinting. AB - A cocaine-based molecular imprinted polymer (MIP) has been produced by bulk polymerization and employed as selective solid-phase extraction support for the determination of cocaine in saliva samples by ion mobility spectrometry (IMS). The most appropriate conditions for washing and elution of cocaine from MIPs were studied and MIPs were characterized in terms of analyte binding capacity, reusability in water and saliva analysis, imprinting factor and selectivity were established and compared with non-imprinted polymers. The proposed MIP-IMS method provided a LOD of 18MUgL-1 and quantitative recoveries for blank saliva samples spiked from 75 to 500MUgL-1 cocaine. Oral fluid samples were collected from cocaine consumers and analysed by the proposed MIP-IMS methodology. Results, ranging from below the LOD to 51+/-2mgL-1, were statistically comparable to those obtained by a confirmatory gas chromatography-mass spectrometry method. Moreover, results were compared to a qualitative lateral flow immunoassay procedure providing similar classification of the samples. Thus, MIP-IMS can be considered an useful alternative that provided fast, selective and sensitive results with a cost affordable instrumentation that does not require skilled operators. PMID- 28012590 TI - Assay to measure sphingomyelinase and ceramidase activities efficiently and safely. AB - As part of the sphingomyelin pathway, sphingomyelinases and ceramidases have attracted much attention in basic as well as clinical research. However, current assays still often rely on a radioactive substrate, extensive manual purification steps, and hazardous solvents for chromatographic analysis. We here show the equivalence of a fluorescent sphingomyelin substrate and present a new versatile solvent replacing the chloroform/methanol mixture. By further modifications including the omission of the manual extraction steps, chloroform and methanol are eliminated from the entire procedure and render the assay flexible to repeated analyses at multiple time intervals. These improvements allow for the rapid detection of both enzymes in a high throughput microtiter format. Moreover, we demonstrate the relevance of the plastic assay material and the interchangeability between serum and different plasma sources. PMID- 28012591 TI - Facile preparation of polysaccharide functionalized macroporous adsorption resin for highly selective enrichment of glycopeptides. AB - A facile approach for preparation of hydrophilic polysaccharide-functionalized macroporous adsorption resin (MAR) was presented. Polydisperse MAR with approximately 250MUm in diameter was synthesized via suspension polymerization and then modified with polysaccharides, sodium hyaluronate (HA) and chitosan (CS), through layer-by-layer (LbL) self-assembly process. The preparation method was facile, low cost and easy to expand production from tens of grams to one kilogram. The resulting MAR@(HA/CS)20 possesses highly hydrophilic property and rapid adsorption behavior. The specificity and efficiency of MAR@(HA/CS)20 to glycopeptide was demonstrated by trapping N-linked glycopeptide from tryptic digests of human immunoglobulin G (IgG) and horseradish peroxidase (HRP) with a homemade solid-phase extraction (SPE) column. The detection sensitivity for glycopeptide determined by MALDI-TOF MS was as low as 5 fmol for standard tryptic digest of human IgG. The enrichment recoveries were higher than 73%. Furthermore, in the analysis of real biological sample, 745 unique N-glycosylation sites in 1353 unique glycopeptides mapped to 379 N-glycosylated proteins were identified in three replicate analyses of protein sample extracted from mouse liver, showing the great potential of MAR@(HA/CS)20 in the enrichment and identification of low abundance N-linked glycopeptides in complicated biological samples. PMID- 28012592 TI - Metabolomics study of Populus type propolis. AB - Herein, we propose rapid and simple spectroscopic methods to determine the chemical composition of propolis derived from various Populus species using a metabolomics approach. In order to correlate variability in Populus type propolis composition with the altitude of its collection, NMR, IR, and UV spectroscopy followed by OPLS was conducted. The botanical origin of propolis was established by comparing propolis spectral data to those of buds of various Populus species. An O2PLS method was utilized to integrate two blocks of data. According to OPLS and O2PLS, the major compounds in propolis samples, collected from temperate continental climate above 500m, were phenolic glycerides originating from P. tremula buds. Flavonoids were predominant in propolis samples collected below 400m, originating from P. nigra and P. x euramericana buds. Samples collected at 400-500m were of mixed origin, with variable amounts of all detected metabolites. PMID- 28012593 TI - Amber lenses for virtual darkness: Confirmed as a mood stabilizer. PMID- 28012594 TI - Senses make sense: An individualized multisensory stimulation for dementia. AB - Nonpharmacologic interventions have been recommended as first-line treatments for dementia, and multisensory stimulation environment has been used as a non pharmacological treatment to dementia patients in the last decade. However, the clinical effect of multisensory stimulation environment remains temporary and uncertain. Individualized medicine has been suggested to hold great promise in medicine, and it should be equally important for dementia. Reminiscence integrating individual experiences into therapeutic schemes has shown potential in the field of improving cognitive functions and depressive symptoms for dementia patients, and interactive music also demonstrated a positive outcome by using individualized music for the hearing aspect. We therefore hypothesize that an individualized multisensory stimulation in a natural and realistic environment integrating personal experience may be an effective intervention for patients suffering from dementia. PMID- 28012595 TI - Orbital autoimmune inflammatory disorders - Protein regional variability might explain specific lesion location. AB - In ophthalmology, inflammatory diseases target different highly specific regions within the small confine of the orbit. Some entities even prefer a particular location or depth within the same tissue (ex. anterior, intermediate or posterior uveitides, chorioretinitides with unique topographic presentations). Though the location of a lesion strongly influences and helps us in our differential diagnosis, we still don't understand why specific anatomic sites are susceptible to a disease while other areas are spared. We postulate that regional variability in tissue protein expression can sway the immune system's capacity to trigger an autoimmune response. In addition to this site-specific quantitative and qualitative variability in potential antigen expression, we believe that other proteins implicated in the immune cascade, as well as geographic areas of relative resistance, tolerance and susceptibility, may be unequally distributed within the orbit. To illustrate our hypotheses, we review three major types of ocular myositis and describe how the extraocular muscles different embryologic origins and protein disparities might explain the fundamental clinical differences between these orbital inflammatory diseases. We hope that future differential genomics, proteinomics, epigenomics and analysis of RNA species of affected tissues, compared to their non-affected, yet microscopically similar, counterparts, will help us understand why diseases occur where they do. Hopefully, understanding these immune triggers will pave the way to new treatment options for ocular inflammatory diseases and for other auto-inflammatory conditions with a marked predilection for any given site. PMID- 28012596 TI - Breath Alkane as an index of severity for oral submucous fibrosis: A new perspective? AB - Oral submucous fibrosis (OSMF) is a devastating disease commonly seen in the Asian subcontinent that results in significant functional morbidity for patients and has a high potential for malignant transformation. Over the last three decades, different diagnostic methods have been described to quantify and grade OSMF severity. Some methods have been used with perceived favorable outcomes although recurrence and malignant transformation remains a problem in many cases, and OSMF presents a major therapeutic challenge. We present a simple, noninvasive and less time-consuming diagnostic method which measures the severity of OSMF, helping to predict its malignant transformation and monitoring the effect of medical therapy on this disease. PMID- 28012597 TI - Cervical spine disorders and its association with tinnitus: The "triple" hypothesis. AB - Subjective tinnitus and cervical spine disorders (CSD) are among the most common complaints encountered by physicians. Although the relationship between tinnitus and CSD has attracted great interest during the past several years, the pathogenesis of tinnitus induced by CSD remains unclear. Conceivably, CSD could trigger a somatosensory pathway-induced disinhibition of dorsal cochlear nucleus (DCN) activity in the auditory pathway; furthermore, CSD can cause inner ear blood impairment induced by vertebral arteries hemodynamic alterations and trigeminal irritation. In genetically -predisposed CSD patients with reduced serotoninergic tone, signals from chronically stimulated DCNs could activate specific cortical neuronal networks and plastic neural changes resulting in tinnitus. Therefore, an early specific tailored CSD treatments and/or boosting serotoninergic activity may be required to prevent the creation of 'tinnitus memory circuits' in CSD patients. PMID- 28012598 TI - Mechanisms underpinning protection against eccentric exercise-induced muscle damage by ischemic preconditioning. AB - Eccentric exercise training is effective for increasing muscle mass and strength, and improving insulin sensitivity and blood lipid profiles. However, potential muscle damage symptoms such as prolonged loss of muscle function and delayed onset of muscle soreness may restrict the use of eccentric exercise, especially in clinical populations. Therefore, strategies to reduce eccentric exercise induced muscle damage (EIMD) are necessary, and an extensive number of scientific studies have tried to identify potential intervention modalities to perform eccentric exercises without adverse effects. The present paper is based on a narrative review of current literature, and provides a novel hypothesis by which an ischemic preconditioning (IPC) of the extremities may reduce EIMD. IPC consists of an intermittent application of short-time non-lethal ischemia to an extremity (e.g. using a tourniquet) followed by reperfusion and was discovered in clinical settings in an attempt to minimize inflammatory responses induced by ischemia and ischemia-reperfusion-injury (I/R-Injury) during surgery. The present hypothesis is based on morphological and biochemical similarities in the pathophysiology of skeletal muscle damage during clinical surgery and EIMD. Even though the primary origin of stress differs between I/R-Injury and EIMD, subsequent cellular alterations characterized by an intracellular accumulation of Ca2+, an increased production of reactive oxygen species or increased apoptotic signaling are essential elements for both. Moreover, the incipient immune response appears to be similar in I/R-Injury and EIMD, which is indicated by an infiltration of leukocytes into the damaged soft-tissue. Thus far, IPC is considered as a potential intervention strategy in the area of cardiovascular or orthopedic surgery and provides significant impact on soft-tissue protection and downregulation of undesired excessive inflammation induced by I/R-Injury. Based on the known major impact of IPC on skeletal muscle physiology and immunology, the present paper aims to illustrate the potential protective effects of IPC on EIMD by discussing possible underlying mechanisms. PMID- 28012599 TI - Blood oxidative stress (BLOS) is a secondary host defense system responding normally to anaerobic wound infection and inadvertently to dietary ultra exogenous sulfide formation (USF). AB - Blood oxidative stress (BLOS) is the presence of white blood cells and platelets that are generating high levels of reactive oxygen species (ROS). A mathematical model links the level of BLOS or BLOS# and plasma sulfide concentration. An increase in the BLOS# reduces the plasma sulfide concentration. The reported maximum plasma sulfide concentration for defined health conditions were used to calculate the minimum BLOS#. Elevated BLOS generates high plasma concentration of ROS, which triggers multiple responses in the body that protect the host. First, insulin production by the pancreas is inhibited, which results in elevated blood glucose levels. This results in advanced glycation end products (AGE), which thicken the blood vessel wall. Elevated blood glucose levels also increases urination, which reduces the availability of substrates for infectious bacteria. Second, one or more signaling molecules are stimulated to produce vascular hypertrophy resulting in hypertension. Third, the initial stage of atherosclerosis thickens the blood vessel wall while also protecting the inner surface of the blood vessels from localized infection. The first three mechanisms provide added protection against pathogen migration through the blood vessel wall and reduce the cross-sectional area of blood vessels, which increases the retention time (RT) for improved ROS inactivation of pathogens. Fourth, genes expressed in the liver, which are associated with drug oxidation and uptake transport, are inhibited. This inhibition protects the host from any toxins produced by an anaerobic infection. Elevated BLOS also reduces plasma sulfide concentration, which inhibits wound healing and extends aerobic conditions of the wound. The normal induction of BLOS offers a short-term, cascade of several primary mechanisms for secondary defense against anaerobic infection of a wound. Normal induction of BLOS is due to ultra-exogenous sulfide formation (USF) generated by a local anaerobic infection of a wound in the natural environment. The presence of BLOS without infection is indicative of inadvertent dietary induction. Long-term dietary BLOS results in many severe inflammatory diseases and cancers that are common in an ageing population. Glands were identified as more susceptible to cancers caused by long-term dietary BLOS. Variable BLOS levels in patients of clinical trials may also be reducing effectiveness of experimental drugs and causing drug toxicity. If BLOS is confirmed as a secondary defense against infection that is inadvertently triggered by diet, then a large number of common health problems may be treated and managed by apheresis and dietary changes. PMID- 28012600 TI - The gut-blood barrier permeability - A new marker in cardiovascular and metabolic diseases? AB - Recent studies suggest that blood-borne metabolites of gut microbiota, such as trimethylamine N-oxide (TMAO) are involved in the aetiology of cardiovascular diseases and may serve as markers of cardiovascular risk. To enter the bloodstream the microbiota-derived molecules need to pass the gut-blood barrier (GBB). The GBB plays an important role in maintaining organism homeostasis. It is a complex multi-layer system which determines the absorption of nutrients, water and many other substances. The integrity and permeability of the GBB may be impaired in numerous diseases including gastrointestinal, metabolic and cardiovascular diseases. Here, we propose that the evaluation of the GBB permeability may have a significant diagnostic potential in cardiovascular and metabolic diseases. Second, we suggest that the GBB permeability is a variable that confounds diagnostic value of new gut microbiota-derived biomarkers such as TMAO. Therefore, cardiovascular risk assessment requires the evaluation of both TMAO and the GBB permeability. PMID- 28012601 TI - Relative imbalance as etiology of laryngomalacia - A new theory. AB - Laryngomalacia literally means weak larynx. It is the most common cause of noisy breathing in infants and children constituting around 70% of cases. Its aetiology is not clear and various theories are proposed. Treatment remains following the child with regular weight monitoring in view of expected spontaneous resolution. However we cannot predict which child will resolve spontaneously and which child may need surgical intervention. We propose a new theory based on relative imbalance of demand supply of air, suggesting the increase in demand causing turbulent airflow, increasing suction pressure and causing collapse of laryngeal structures. This theory also helps us in predicting early, which child will resolve spontaneously and which child will need surgery. The methodology to evaluate hypothesis along with techniques and tools are also suggested. PMID- 28012602 TI - Hydrogen donors and acceptors and basic amino acids jointly contribute to carcinogenesis. AB - A hypothesis is postulated that high content of hydrogen donors and acceptors, and basic amino acids cause the intracellular trapping of the H+ and Cl- ions, which increases cancer risks as local formation of HCl is mutagenic to DNA. Other cations such as Ca2+, and weak acids such as short-chain organic acids may attenuate the intracellular gathering of the H+ and Cl-, two of the most abundant ions in the cells. Current data on increased cancer risks in diabetic and obese patients are consistent with the assumption that hydrogen bonding propensity on glucose, triglycerides and other molecules is among the causative factors. PMID- 28012603 TI - Overexpressed PLTP in macrophage may promote cholesterol accumulation by prolonged endoplasmic reticulum stress. AB - It is well known that phospholipid transfer protein (PLTP) is involved in the lipid metabolism and development of atherosclerosis (AS). Abundant PLTP is considered to be expressed on the foam cells derived from monocyte/macrophages in atherosclerotic plaques, suggesting that high level of active PLTP may promote the formation of foam cells. However, the exact role of PLTP on the process of macrophage derived foam cell formation remains unclear. The accumulation of free cholesterol (FC) in the cytoplasm may lead to the prolonged endoplasmic reticulum stress (ERs) and the imbalance of intracellular cholesterol homeostasis. Different PLTP level definitely alternates the phospholipids (PL) and cholesterol level in plasma, strongly suggesting that active PLTP may change the level of FC and PL intracellularly, which subsequently induced the ERs in macrophage. Thus, we hypothesize that high level of PLTP may promote the accumulation of cholesterol in macrophage via the alteration ratio of FC to PL. Therefore, validating this hypothesis may clarify the role of PLTP in macrophage ERs in AS and also raise a novel strategy in the regression of AS plaques via restoring intracellular membrane lipid homeostasis and attenuating ERs. PMID- 28012604 TI - Cognitive eloquence in neurosurgery: Insight from graph theoretical analysis of complex brain networks. AB - The structure and function of the brain can be described by complex network models, and the topological properties of these models can be quantified by graph theoretical analysis. This has given insight into brain regions, known as hubs, which are critical for integrative functioning and information transfer, both fundamental aspects of cognition. In this manuscript a hypothesis is put forward for the concept of cognitive eloquence in neurosurgery; that is regions (cortical, subcortical and white matter) of the brain which may not necessarily have readily identifiable neurological function, but if injured may result in disproportionate cognitive morbidity. To this end, the effects of neurosurgical resection on cognition is reviewed and an overview of the role of complex network analysis in the understanding of brain structure and function is provided. The literature describing network, behavioral, and cognitive effects resulting from lesions to, and disconnections of, centralized hub regions will be emphasized as evidence for the espousal of the concept of cognitive eloquence. PMID- 28012605 TI - Corrigendum to "Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define proteomic events of the novel paradigm for Alzheimer's with metals as primary disease cause" [Med. Hypotheses 85 (2015) 779-790]. PMID- 28012606 TI - Could ethanol-induced alterations in the expression of glutamate transporters in testes contribute to the effect of paternal drinking on the risk of abnormalities in the offspring? AB - It has been known that a preconception paternal alcoholism impacts adversely on the offspring but the mechanism of the effect is uncertain. Several findings suggest that there are signalling systems in testis that are analogous to those known to be altered by alcoholism in brain. We propose that chronic alcohol affects these systems in a manner similar to that in brain. Specifically, we hypothesise that excessive alcohol may disturb glutamatergic-like signalling in testis by increasing expression of the glutamate transporter GLAST (EAAT1). We discuss ways how to test the hypothesis as well as potential significance of some of the tests as tools in the diagnostics of chronic alcoholism. PMID- 28012607 TI - Do Demodex mites play a role in pterygium development? AB - Numerous reports point to Demodex mites as the aetiology of certain eye and skin conditions, hence it is highly probable that infestation with these mites may also play a role in the aetiology and pathogenesis of pterygium. Therefore here we present a hypothesis: whether the presence of Demodex mites in eyelash hair follicles significantly correlates with the presence of pterygia, which could point to a potential role of these mites in the development of such lesions. We present preliminary data for supporting this hypothesis. These results were collected from a group of 69 subjects, including 39 with pterygium. Subjects were studied for the presence of Demodex folliculorum and/or D. brevis within eyelash follicles. The sample was defined as positive if at least one parasite, larva or egg were present. Preliminary statistical analyses were performed, and indicated a significant relationship between Demodex mite infestation and the presence of pterygium (p<0.05). This suggests that demodicosis could be one of the factors causing pterygium and significantly contribute to its development. Subjects who had both pterygium and Demodex infestation formed a dominant group. The proportion of subjects with both pterygia and Demodex presence is high at 93.33%, while the proportion of subjects without pterygia who have mites is low at 20.51%. Aforementioned results support our working hypothesis that infestation with Demodex mites may result in pterygium development and therefore patients diagnosed with pterygium should be assessed for the presence of Demodex to verify our preliminary results. In the present paper, we discuss potential influence of Demodex on conjunctiva and propose a hypothetical pathological mechanism linking the development of pterygia with demodicosis. PMID- 28012608 TI - Internal limiting membrane: The innermost retinal barrier. AB - Recently, peeling of internal limiting membrane (ILM) has become one of the most common and effective surgical procedures for macular disorders. The authors discuss the adverse effects of such procedures and explore the possible functions of the membrane. We also suggest a barrier function of this membrane in addition to its possible other physiological roles. Thus, apart from the well-known inner and outer retinal barriers, ILM might be the third and innermost retinal barrier. The possible evidences supporting this hypothesis are presented. PMID- 28012609 TI - Lutein and atherosclerosis: Belfast versus Toulouse revisited. AB - In 1995 we reported that mean plasma lutein concentrations in salaried men and women from Toulouse in Southern France were double those in subjects recruited from general practitioner lists in Belfast, Northern Ireland. At the time incidence of coronary heart disease (CHD) in Southern France was among the lowest in Europe and was much higher in Northern Ireland. Plasma lutein is a biomarker of vegetable and fruit intake and evidence suggests that high concentrations are generally associated with better cardiometabolic health. At the time we speculated like others that role of the carotenoids may well have been to prevent oxidation of lipid in the lipoproteins and so reduce the uptake of oxidised lipid by macrophages and its deposition within the intimal layers of the major arteries as plaque. It is now widely accepted that CHD is an inflammatory disease and that macrophages within plaque together with tissue damage contribute to this inflammation. Stimulated macrophages release cytokines to activate the immune system both locally and systemically. Precursor complement proteins in the blood are activated to assist immune cells in phagocytosis and cell repair. Individuals with a history of arteriosclerosis display significantly higher concentrations of complement factors C3 and C3a than subjects without such a history. Metabolism of C3 via the alternate complement pathway can give rise to the membrane attack complex (MAC) which creates a hole or pore in pathogens or host cells, killing the cell. Recent studies in patients with early age related macular disease (AMD) who also exhibit similar elevated concentrations of complement proteins in their blood, showed supplementation with lutein progressively decreased the amount of the MAC and other complement factors in the blood. Lutein was used in the supplementation experiments because it is an important constituent of macular pigment. Thus the healthier cardiometabolic features displayed by the people in Toulouse may have been due to the effects of concurrent high concentrations of plasma lutein on the immune system and complement in particular. Other carotenoids may exert similar antioxidant effects but we and others found no differences in antioxidant nutrients between subjects in Toulouse and Belfast or between subjects with asymptomatic markers of atherosclerosis and controls. PMID- 28012610 TI - Secondary to excessive melatonin synthesis, the consumption of tryptophan from outside the blood-brain barrier and melatonin over-signaling in the pars tuberalis may be central to the pathophysiology of winter depression. AB - Seasonal affective disorder is defined as recurrent episodes of major depression, mania, or hypomania with seasonal onset and remission. In this class of mood disturbances, a unipolar major depressive disorder known as winter depression is common in populations living in northern latitudes far from the equator. Winter depression repeatedly occurs in the autumn or winter and remits in the spring or summer, and its etiopathogenesis is currently unknown. However, one can surmise that excessive melatonin production during the reduced duration of daily sunlight in the autumn and winter plays a role in its pathophysiology. Melatonin is synthesized from tryptophan within the pineal gland, which is located outside the blood-brain barrier, and overproduction of melatonin may lead to augmented consumption of tryptophan, from which serotonin is synthesized. As tryptophan is captured from the blood and excessively utilized by the pineal gland, tryptophan blood levels may decline; as such, it is more difficult for tryptophan to pass through the blood-brain barrier and reach the serotonergic neurons as the ratio of tryptophan to the other amino acids that compete for the same transporter to enter the brain is diminished. As such, less tryptophan is available for serotonin synthesis. Moreover, melatonin is known to modulate thyrotropin expression in the thyrotrophic cells of the pars tuberalis of the pituitary gland, and overproduction of melatonin in the autumn or winter months may cause excessive signaling in the pars tuberalis, diminishing its release of thyrotropin and resulting in central hypothyroidism. Both conditions reduced serotonin production and central hypothyroidism may cause depression. Furthermore, the excessive synthesis of melatonin during the autumn and winter may negatively affect the expression of neuromedin U in the pars tuberalis, causing an increased appetite, which is common in winter depression patients. The hypersomnia common in winter depressive patients can be ascribed to excessive circulating melatonin, a hormone that increases the propensity for sleep. Furthermore, central hypothyroidism may also increase sleepiness, as it is known that hypothyroid patients usually experience excessive somnolence. In this theoretical article, we also propose studies to evaluate winter depression patients with regard to the necessity, or not, of offering them an increased amount of tryptophan in their diets during the autumn and winter. We also suggest that the administration of triiodothyronine to winter depressive patients may mitigate their central hypothyroidism. PMID- 28012611 TI - Does complement Factor H-Related protein 5 Nephropathy (Troodos Nephropathy) protect from rickettsial infections? AB - Complement Factor H-Related protein 5 Nephropathy (CFHR5N) is an endemic hereditary renal disease in the island of Cyprus. Although only very recently recognized, it has provided insight into previously unknown genetic aspects of complement-mediated renal diseases and in fact it has contributed to the introduction of the new disease classification, 'C3 Glomerulopathy'. Herein, based on evidence from epidemiological, genetic, clinical and basic research studies, the hypothesis that CFHR5N could be protective from rickettsial infections is proposed. Confirming this hypothesis, could have significant implications for the study of Complement Factor- H Related Proteins (CFHRs) in renal diseases and rickettsial molecular microbiology. PMID- 28012613 TI - Towards improvement of facilitating the contralateral limb cannulation of currently available endografts for the treatment of Abdominal Aortic Aneurysms: First innovate then intervene! PMID- 28012612 TI - Paying the price for body evolution: The role of evolution in disorders of body representation. AB - Since its beginning, research about cognitive representation of our bodies has debated over multiple representations models. Furthermore, recent years have seen a rise in the study of body representation disorders and related impairments. However, why human beings manifest so many deficits is still a mystery. Considering human evolution, frontal brain regions are well known for their changes in dimensions and connections. Less known is that parietal and temporal lobes encountered similar changes. These areas, especially in the right hemisphere, are crucial for body representation. Our hypothesis is that evolution of these areas determined a more varied and widespread cross wiring between the temporal and parietal lobes, increasing their communication pathways and their reciprocal influence. As such, these connections could lead to an increased probability of interconnected body and emotional disorders in humans. The prediction of this hypothesis is that all body representation disorders have an associated emotional component and vice versa. Evidence supporting the interconnection between emotional and body representation disorders derives from psychiatric diseases such as eating disorders. This hypothesis opens up new directions to understand body representation and points towards innovative solutions for the clinical treatments of body representation/emotional impairments. PMID- 28012614 TI - Changes in the Professional Lives of Cardiologists Over 2 Decades. AB - The American College of Cardiology third decennial Professional Life Survey was completed by 2,313 cardiologists: 964 women (42%) and 1,349 men (58%). Compared with 10 and 20 years ago, current results reflect a substantially lower response rate (21% vs. 31% and 49%, respectively) and an aging workforce that is less likely to be in private practice. Women continue to be more likely to practice in academic centers, be pediatric cardiologists, and have a noninvasive subspecialty. Men were more likely to indicate that family responsibilities negatively influenced their careers than previously, whereas women remained less likely to marry or have children. Men and women reported similar, high levels of career satisfaction, with women reporting higher satisfaction currently. However, two-thirds of women continue to experience discrimination, nearly 3 times the rate in men. Personal life choices continue to differ substantially for men and women in cardiology, although differences have diminished. PMID- 28012615 TI - ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2016 Appropriate Use Criteria for Coronary Revascularization in Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society of Thoracic Surgeons. PMID- 28012616 TI - [Sensitivity and specificity of abdominal adiposity with metabolic syndrome in the elderly]. AB - OBJECTIVES: It is recognised that abdominal adiposity is associated with cardiovascular risk factors, such as intolerance to glucose, hypertension and dyslipidaemia. The objective of the present study was to assess the relationship of trunk fat and visceral fat index, obtained by anthropometric and bioelectrical impedance, with metabolic syndrome (SM) in an elderly population. METHODS: The study included 208 subjects (78 men and 130 women) with a mean age of 82.5 years. Abdominal obesity was assessed by anthropometry and bioelectrical impedance. ROC curves were calculated in order to assess the ability of these variables to diagnose metabolic syndrome. RESULTS: There are differences between men and women in body mass index, waist to height ratio, waist circumference, and bioelectrical impedance measurements as trunk fat and visceral fat (p<.05). Also, found differences in anthropometric indices and variables and abdominal bioelectrical impedance between subjects with and without SM (p<.05) and only exist differences in blood glucose, triglycerides and HDL cholesterol (p<.05). There are significant correlations between anthropometric variables and abdominal bioelectrical impedance (p<.05). Areas under the curve (AUC) of waist to height index, waist circumference, sagittal abdominal diameter, and trunk fat were greater than 0.8 (all p<.01), and in women did not exceed values of 0.65. The cut off points obtained for BMI were 26.81 and 23.53kg/m2, 102 and 91cm for waist circumference, 22.1 and 20.7cm for sagittal abdominal diameter, 34% and 43.7% for trunk fat, and 17 and 11.5 for visceral fat ratio in men and women, respectively. CONCLUSIONS: There are different levels of predictive ability for metabolic syndrome according to gender. Trunk fat and visceral fat index and anthropometric measures have higher predictive ability for metabolic syndrome in men than in women. PMID- 28012617 TI - Growth performance, feeding behavior, and selected blood metabolites of Holstein dairy calves fed restricted amounts of milk: No interactions between sources of finely ground grain and forage provision. AB - The objective of this study was to investigate the effects of grain sources and forage provision on growth performance, blood metabolites, and feeding behaviors of dairy calves. Sixty 3-d-old Holstein dairy calves (42.2 +/- 2.5 kg of body weight) were used in a 2 * 3 factorial arrangement with the factors being grain sources (barley and corn) and forage provision (no forage, alfalfa hay, and corn silage). Individually housed calves were randomly assigned (n = 10 calves per treatment: 5 males and 5 females) to 6 treatments: (1) barley grain (BG) without forage supplement, (2) BG with alfalfa hay (AH) supplementation, (3) BG with corn silage (CS) supplementation, (4) corn grain (CG) without forage supplement, (5) CG with AH supplementation, and (6) CG with CS supplementation. All calves had ad libitum access to water and starter feed throughout the experiment. All calves were weaned on d 49 and remained in the study until d 63. Starter feed intake and average daily gain (ADG) was greater for calves fed barley than those fed corn during the preweaning and overall periods. Calves supplemented with CS had greater final body weight and postweaning as well as overall starter feed intake than AH and non-forage-supplemented calves. During the preweaning and overall periods, feeding of CS was found to increase ADG compared with feeding AH and nonforage diets. However, feed efficiency was not affected by dietary treatments. Calves supplemented with CS spent more time ruminating compared with AH and control groups; nonnutritive oral behaviors were the greatest in non-forage supplemented calves. Regardless of the grain sources, the rumen pH value was greater for AH calves compared with CS and non-forage-supplemented calves. Blood concentration of BHB was greater for CS-supplemented calves compared with AH and non-forage-supplemented calves. Furthermore, body length and heart girth were greater for calves fed barley compared with those fed corn, and also in forage supplemented calves compared with non-forage-supplemented calves. These results showed no interactions between grain sources and forage provision on calf performance; however, the inclusion of CS and barley in starter diets could enhance the growth performance of Holstein calves during the transition from liquid to solid feed. PMID- 28012618 TI - Short communication: Influence of pulsed light treatment on the quality and sensory characteristics of Cheddar cheese. AB - The objective of this study was to examine the effect of pulsed light (PL) treatment on the color, oxidative stability, and onset of molding of Cheddar cheese. Slices of sharp white Cheddar cheese of 2.5 * 5 cm were treated on one side with PL doses from 1.02 to 12.29 J/cm2, sealed in polyethylene bags, and stored at 6 degrees C for up to 1 mo. Peroxide value, color parameters, and the onset of molding were evaluated. No significant changes in color or peroxide value were observed for PL-treated samples compared with the untreated controls. Pulsed light was able to significantly delay surface molding during refrigerated storage, with a PL dose of 9.22 J/cm2 delaying the onset of molding by 7 d. The effect of PL on the taste, appearance, and acceptability of Cheddar cheese slices treated with a PL dose of 9.22 J/cm2 on each side was assessed. In triangle tests, 60 untrained panelists were unable to detect significant differences between the control and PL-treated samples, although PL had a significant effect on overall liking, flavor, and appearance. These findings suggest that although PL can be effective for surface decontamination of cheese, it may have some detrimental effects on sensory properties. PMID- 28012619 TI - Relationship of mammary gland health status and other noninfectious factors with electrical conductivity of milk in Manchega ewes. AB - Measuring the electrical conductivity (EC) of milk during milking has been extensively studied in cattle as a low-cost mastitis detection method that can be easily automated. The aim of this work was to study the effect of the health status of the glands and several noninfectious factors (lactation stage, milking session, and lactation number) that affect the use of EC measurement of milk to detect mastitis in dairy sheep livestock. Likewise, we studied the relation between EC and milk composition (macrocomposition and mineral content) and between EC and somatic cell count (SCC). Finally, we evaluated the use of EC thresholds as a mastitis detection method. To this end, we monitored the glandular milk EC throughout 2 consecutive lactations, during which 42 and 40 ewes were controlled, respectively. We carried out 7 biweekly checks, analyzing the EC, SCC, composition, and mineral content of glandular milk at morning and evening milkings. Before the morning milking, samples were aseptically collected for bacteriological analysis, and the results along with the SCC were used to classify the glands according to their sanitary status (healthy, latently infected, or infected). Lactation stage, parity, milking (morning or evening), health status, and the interactions of parity with health status, lactation stage with health status, and parity with lactation stage all had a significant effect on SCC and EC of the milk. The correlation between EC and SCC was only significant when all the data were analyzed jointly (r = 0.33) and for SCC >= 600.000 cells/mL (r = 0.25). The changes in milk composition, mainly in fat content, largely explained the variation in EC (R2 = 0.69). For the same EC threshold, the specificity and sensitivity varied depending on the parity or the milking, with the negative predictive value obtained being higher than the positive predictive value at all times. We concluded that developing methods of detecting mastitis in sheep by milk EC readings would require consideration of noninfectious factors that also affect the gauging of EC. One option to consider would be individualized daily monitoring of the glands, as demonstrated in other species such as cattle and goat. PMID- 28012620 TI - Short communication: Improving the activity of bile salt hydrolases in Lactobacillus casei based on in silico molecular docking and heterologous expression. AB - Bile salt hydrolase (BSH) plays an essential role in the cholesterol-removing effect of lactic acid bacteria, which hydrolyze conjugated bile salts to amino acid and deconjugated bile salts. However, Lactobacillus casei lacks the bsh gene, which may make it highly sensitive to bile salt stress. We wanted to improve the BSH activity of L. casei for various food-industry applications (e.g., milk fermentation). Plate assay testing indicated that Lactobacillus plantarum AR113 has the highest BSH activity. We cloned and sequenced 4 bsh genes from the genome of L. plantarum AR113. Structure modeling and molecular docking of BSH indicated that BSH1 and BSH3 could react efficiently with bile salts, so we selected BSH1 and BSH3 for heterologous expression in L. casei. Compared with single expression of BSH1 or BSH3, co-expression of both protein sequences showed the highest hydrolysis activity by HPLC analysis. Our results suggested that heterologous expression of BSH in L. casei can significantly improve host activity against bile salts, and in silico molecular docking could be an efficient method of rapid screening for BSH with high activity. PMID- 28012621 TI - Development and application of a sensitive, rapid, and reliable immunomagnetic separation-PCR detection method for Cronobacter spp. AB - Cronobacter spp. have been linked to clinical cases of infection in both adults and infants. Enrichment of Cronobacter spp. before detection has been necessary but is quite time consuming. Hence, we sought to develop an immunomagnetic separation (IMS) PCR method that could shorten the time of enrichment before the detection of Cronobacter spp. The polyclonal antibody used in this immunomagnetic separation was prepared based on the outer membrane protein A of Cronobacter sakazakii China Center of Industrial Culture Collection 21560 and had high specificity to the target. The primers used in the IMS-PCR method also showed high specificity. The detection limit of IMS-PCR for pure C. sakazakii culture was 5.2 * 102 cfu/mL. Cronobacter sakazakii in artificially contaminated powdered infant formula (PIF) was also detected at a detection limit of 5.2 * 102 cfu/mL. After 8 h of enrichment, the detection limit in PIF was lower than 5.2 * 101 cfu/mL. An interference test using Escherichia coli in artificially contaminated PIF showed that the IMS-PCR method developed in this study had a good ability to resist interference. Finally, the IMS-PCR method was applied to the detection of Cronobacter in food samples and was shown to be reliable. Thus, this newly developed IMS-PCR detection method was quite sensitive, rapid, and reliable and could be applied to the detection of Cronobacter in foods. PMID- 28012622 TI - Variable liver fat concentration as a proxy for body fat mobilization postpartum has minor effects on insulin-induced changes in hepatic gene expression related to energy metabolism in dairy cows. AB - The liver plays a central role in adaptation for energy requirements around calving, and changes in the effects of insulin on hepatic energy metabolism contribute to metabolic adaptation in dairy cows. Hepatic insulin effects may depend on body fat mobilization. The objective of this study was to investigate the effects of insulin on the hepatic gene expression of enzymes involved in energy metabolism and factors related to nutrition partitioning in cows with high and low total liver fat concentration (LFC) after calving. Holstein cows were retrospectively grouped according to their LFC after calving as a proxy for body fat mobilization. Cows were classified as low (LLFC; LFC <24% fat/dry matter; n = 9) and high (HLFC; LFC >24.4% fat/dry matter; n = 10) fat-mobilizing after calving. Euglycemic-hyperinsulinemic clamps [6 mU/(kg * min) of insulin for 6 h] were performed in wk 5 antepartum (ap) and wk 3 postpartum (pp). Before and at the end of the euglycemic-hyperinsulinemic clamps, liver biopsies were taken to measure the mRNA abundance of enzymes involved in carbohydrate and lipid metabolism, expression related to the somatotropic axis, and adrenergic and glucocorticoid receptors. The mRNA abundance of pyruvate carboxylase, cytosolic phosphoenolpyruvate carboxykinase (PEPCK; PCK1), acyl-CoA-dehydrogenase very long chain (ACADVL), and hydroxyl-methyl-glutaryl-CoA-synthase 1 increased, but the mRNA abundance of solute carrier family 2 (SLC2A2 and SLC2A4), growth hormone receptor 1A (GHR1A), insulin-like growth factor 1 (IGF1), sterol regulatory element binding factor 1, adrenoceptor alpha 1A, and glucocorticoid receptor decreased from ap to pp. Insulin treatment was associated with decreased PCK1, mitochondrial PEPCK, glucose-6-phosphatase, propionyl-CoA-carboxylase alpha, carnitine-palmitoyl-transferase 1A, ACADVL, and insulin receptor mRNA, but increased IGF1 and SLC2A4 mRNA ap and pp and GHR1A mRNA pp. The mRNA abundance of SLC2A4 was greater, and the mRNA abundance of GHR1A and IGF1 tended to be lower in LLFC than in HLFC. Administration of insulin, albeit at a supraphysiological dose, was associated with inhibition of gene expression related to glucose production and beta-oxidation, but we observed variable effects in the degree of insulin depression of individual genes. Insulin status is important for regulation of nutrient partitioning, but different LFC pp had very little influence on changes in hepatic gene expression following administration of insulin. PMID- 28012623 TI - Investigating the within-herd prevalence and risk factors for ketosis in dairy cattle in Ontario as diagnosed by the test-day concentration of beta hydroxybutyrate in milk. AB - An observational study of 790 to over 3,000 herds was conducted to estimate the within-herd prevalence and cow-level risk factors for ketosis in dairy cattle in herds that participate in a Dairy Herd Improvement Association (DHIA) program. Ketosis or hyperketolactia (KET) was diagnosed as milk beta-hydroxybutyrate >=0.15 mmol/L at first DHIA test when tested within the first 30 d in milk. Seven hundred ninety-five herds providing at least 61 first milk tests from June 2014 to December 2015 were used to estimate the provincial within-herd prevalence of KET. All herds on DHIA in Ontario (n = 3,042) were used to construct cow-level multilevel logistic regression models to investigate the association of DHIA collected variables with the odds of KET at first DHIA milk test. Primiparous and multiparous animals were modeled independently. The cow-level KET prevalence in Ontario was 21%, with an average within-herd prevalence of 21% (standard deviation = 10.6) for dairy herds enrolled in a DHIA program. The prevalence of KET had a distinct seasonality with the lowest prevalence occurring from July to November. Automatic milking systems (AMS) were associated with increased within herd prevalence, as well as increased odds of KET in multiparous animals at first test (odds ratio: 1.45; 95% confidence interval: 1.30 to 1.63). Jersey cattle had over 1.46 times higher odds of KET than Holstein cattle. Milk fat yield >=1.12 kg/d at the last test of the previous lactation was associated with decreased odds of KET in the current lactation (odds ratio: 0.56; 95% confidence interval: 0.53 to 0.59). Increased days dry and longer calving intervals, for multiparous animals, and older age at first calving for primiparous animals increased the odds of KET at first test. This study confirms previous findings that increased days dry, longer calving intervals, and increased age at first calving are associated with increased odds of KET and is the first report of increased KET in herds with AMS and in relation to milk fat yield at the final test of the previous lactation. Feeding management on AMS herds likely contributes to the increased prevalence of KET and further work is required to investigate modifications to current management to minimize risk. Milk fat yield during the previous lactation may be representative of energy partitioning. PMID- 28012624 TI - Effects of Saccharomyces cerevisiae fermentation products on dairy calves: Performance and health. AB - The aim of the study was to evaluate the effects of Saccharomyces cerevisiae fermentation products (SCFP) on performance and health of calves during the first 63 d of age. Sixty Holstein calves (30 males and 30 females) at 2 d of age were blocked by sex and date of birth then randomly assigned within blocks to 1 of 3 treatments. A texturized calf starter was fed ad libitum containing 0 (control), 0.5, or 1% SCFP (Original XPC, Diamond V, Cedar Rapids, IA) of DM. In addition, the supplemented calves were fed 1 g/d SCFP (SmartCare, Diamond V) in milk until d 30. All calves were fed 4 L of colostrum within 1 h of birth and were subsequently fed milk twice daily until weaned at 56 d of age. Male calves were harvested on d 56. Performance and health of weaned female calves were monitored until 63 d of age to determine the effect of preweaning treatment of SCFP on weaning stress. Starter intake, fecal scores, and medical treatments were recorded daily. Body weight measures and blood samples were collected on d 2, 28, 56, and 63. Serum was analyzed for blood urea nitrogen, fatty acids, insulin-like growth factor-1, glucose, and total protein. Oxidative biomarkers and total antioxidant capacity were also evaluated in the serum. Body weight, DMI, blood parameters, and oxidative biomarkers did not differ among treatments. Supplementation of SCFP lowered fecal scores in the pre- and postweaning periods. Saccharomyces cerevisiae fermentation products can be used to reduce the diarrhea in calves grown under normal commercial conditions. PMID- 28012625 TI - Short communication: Interaction of the isomers carvacrol and thymol with the antibiotics doxycycline and tilmicosin: In vitro effects against pathogenic bacteria commonly found in the respiratory tract of calves. AB - Bovine respiratory disease is the major problem faced by cattle, specially calves, leading to reduced animal performance and increased mortality, consequently causing important economic losses. Hence, calves must be submitted to antibiotic therapy to counteract this infection usually initiated by the combination of environmental stress factors and viral infection, altering the animal's defense mechanism, and thus allowing lung colonization by the opportunistic bacteria Mannheimia haemolytica and Pasteurella multocida. Essential oils appear to be candidates to replace antibiotics or to act as antibiotic adjuvants due to their antimicrobial properties. In the present study, we aimed to evaluate the 4 essential oil components carvacrol, thymol, trans anethole, and 1,8 cineole as antibacterial agents or as adjuvants for the antibiotics doxycycline and tilmicosin against M. haemolytica and P. multocida. Bacteria were cultured according to standard protocols, followed by the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration. A checkerboard assay was applied to detect possible interactions between components, between antibiotics, and between components and antibiotics. Doxycycline at 0.25 and 0.125 MUg/mL inhibited the growth of P. multocida and M. haemolytica, respectively, whereas tilmicosin MIC values were 1.0 and 4.0 MUg/mL for P. multocida and M. haemolytica, respectively. Carvacrol MIC values were 2.5 and 1.25 mM for P. multocida and M. haemolytica, respectively, whereas thymol MIC values were 1.25 and 0.625 mM for P. multocida and M. haemolytica, respectively. Trans-anethole and 1,8 cineole did not present any antibacterial effect even at 40 mM against the investigated pathogens. All minimum bactericidal concentration values were the same as MIC, except when thymol was tested against M. haemolytica, being twice the MIC data (i.e., 1.25 mM thymol). Based on fractional inhibitory concentration checkerboard assay, no interaction was observed between doxycycline and tilmicosin. Carvacrol and thymol presented an additive effect when one of them was combined with tilmicosin. Additive effect was also observed when doxycycline was combined with thymol. Synergism was observed when carvacrol was combined with doxycycline or with thymol. Although the antibacterial effects of the tested essential oil components were observed at high concentrations for in vitro conditions, the additive and synergic effects of carvacrol and thymol with antibiotics suggest the option to apply them as antibiotic adjuvants. PMID- 28012626 TI - Early lactation production, health, and welfare characteristics of cows selected for extended lactation. AB - Some cows are able to achieve relatively high milk yields during extended lactations beyond 305 d in milk, and farmers may be able to use this potential by selecting the most suitable cows for an extended lactation. However, the decision to postpone insemination has to rely on information available in early lactation. The main objectives of this study were, therefore, to assess the association between the information available in early lactation and the relative milk production of cows on extended lactation, and to investigate if this information can be used to differentiate time of first insemination between cows. Data came from 4 Danish private herds practicing extended lactation in which some cows are selected to have a delayed time of planned first insemination. Average herd size varied from 93 to 157 cows, and milk yield varied from 7,842 to 12,315 kg of energy-corrected milk (ECM) per cow per year across herds. The analysis was based on 422 completed extended lactations (427 +/- 87 d), and each lactation was assigned to 1 of 3 (low, medium, and high) milk performance groups (MPG) within parity group within herd based on a standardized lactation yield. For cows in the high MPG, peak ECM yield, and ECM yield at dry off were significantly greater, the relative reduction in milk yield between 60 and 305 d in milk was significantly smaller, and a smaller proportion had a body condition score (scale: 1-5) at dry off of 3.5 or greater compared with cows in low MPG. Previous lactation days in milk at peak ECM yield and ECM yield at dry off were higher, the relative reduction in milk yield between 60 and 305 d in milk was smaller, and the number of inseminations per conception was higher for multiparous cows in high MPG compared with low. Current lactation ECM yield at second and third milk recording were greater for cows in high MPG compared with low. A principal component analysis indicated that variables related to fertility, diseases, and milk yield explained most of the total variation between primiparous cows, whereas variables related to milk yield, fertility, and days in milk at peak yield were the most dominating for multiparous cows. Our study indicated that milk yields in previous lactation and at second and third milk recording correlate well with milk production potential, and therefore, may be promising indicators when selecting the most suitable cows for extended lactation. PMID- 28012627 TI - Short communication: Identification of variation in the ovine prolactin gene of Chios sheep with a cost-effective sequence-based typing assay. AB - The present study identified single nucleotide polymorphisms (SNP) in the coding and untranslated regions of the ovine prolactin gene of Chios sheep. By developing a cost-effective direct sequence-based typing assay, around 600 bp of reliable sequencing data and clear identification of heterozygous positions was achieved. Five SNP were found, located in exons 2 (KC764410:g.567G>A, g.625C>T, g.683C>A) and 3 (KC764410:g.2015C>A, g.2101G>A), whereas the remaining exons were monomorphic. The identified SNP were synonymous, with the exception of the g.567G>A SNP, which results in an Arg to His amino acid change. As the sequencing cost of the sequence-based typing assay was 20 orders of magnitude lower compared with a standard Sanger method, the assay was also used as a genotyping tool. The identified polymorphism was genotyped for 247 ewes and was subsequently used in mixed model association analyses of milk yield, milk fat content, and litter size at birth. The association analysis revealed a significant dominance effect of 0.17 +/- 0.07 of the g.2015C>A SNP on milk fat percentage, whereas a dominance effect of -21.33 +/- 10.51 of the same SNP on total lactation milk yield was also estimated. The g.2015C>A SNP explained 2.47 and 3.68% of the total phenotypic variance of milk yield and milk fat percentage, respectively, whereas the corresponding values for the animal variance were 7.14 and 11.75%. A suggestive association of the nonsynonymous g.567G>A SNP with litter size at birth was also detected. PMID- 28012628 TI - Syneresis and rheological behaviors of set yogurt containing green tea and green coffee powders. AB - This study aimed to investigate the effect of added green coffee powder (GCP) and green tea powder (GTP) on syneresis behavior and consistency of set yogurts. Adding GCP (1 or 2%) decreased syneresis rate. The effect of GTP on the syneresis rate was concentration dependent. In comparison to the control, GTP decreased syneresis rate when it was added at 0.02%, but it caused an increase when added at 2%. No significant difference was observed in the syneresis rates when GTP was added at 1 and 0.01%, until 14 and 7 d of storage, respectively. The Herschel Bulkley model parameters indicated that the consistency of control was considerably lower than that of GCP yogurts during 14 d, whereas it was higher at the end of storage. The GTP yogurt results showed that the consistency coefficients of GTP yogurts were different from those of control samples until 14 d of storage. In conclusion, GTP and GCP behaved differently in acidified gel networks of set yogurt, modifying its rheological behavior, as they have different profiles and concentrations of polyphenols. PMID- 28012629 TI - Relationship between glucocorticoids and prolactin during mammary gland stimulation in dairy cows. AB - The objectives of this study were to determine the role of glucocorticoids in the regulation of prolactin (PRL) release induced by mammary gland stimulation and to investigate whether the milk depression induced by glucocorticoids in dairy cows is due to a decrease in PRL release. In experiment 1, 8 dairy cows were used in a 4 * 4 Latin square design. Four hours after the morning milking, the cows received 1 of the following treatments: (1) a 5-min manual stimulation of the mammary gland; (2) an i.v. injection of 1 mg of dexamethasone; (3) 2 infusions of 2.5 g of metyrapone (an inhibitor of cortisol biosynthesis) in the omasum 4 and 2 h before a 5-min stimulation of the mammary gland; or (4) no treatment. Sixty minutes later, the mammary gland of each cow was stimulated for 5 min. Blood samples were collected from 20 min before to 120 min after the start of the treatment. When the mammary gland was stimulated twice in 60 min, less PRL and cortisol were released during the second stimulation. Metyrapone did not affect PRL or cortisol release. Dexamethasone decreased serum cortisol concentration but did not affect PRL concentration. In experiment 2, 16 cows were used in a crossover experimental design consisting of 2 experimental weeks separated by 1 resting week. During the first week, cows were treated as follows: (1) 4 cows were injected with 0.5 g of domperidone (a PRL secretagogue) in canola oil on d 1 and 2 and 20 mg of dexamethasone on d 1; (2) 4 cows were injected with 0.5 g of domperidone on d 1 and 2; (3) 4 cows were injected with canola oil on d 1 and 2 and with 20 mg of dexamethasone on d 1; and (4) 4 cows were injected with canola oil on d 1 and 2. During the second experimental week, the same 4 treatments were repeated, except the cows that did not receive dexamethasone in the first week received it on d 1 of the second week, and cows that did receive it in the first week did not receive it in the second week. On d 1 and 2 of each week, blood samples were collected during morning milking for PRL determination. Dexamethasone reduced milk production and decreased both basal and milking induced PRL release. It also increased milk fat and protein percentages and decreased milk lactose content. Domperidone increased basal PRL levels in serum and milk but did not affect milk yield. Although we cannot rule out the possibility that inhibition of PRL secretion or reduction of mammary gland PRL responsiveness play a role in the inhibition of milk production by glucocorticoids, the fact that enhancement of PRL secretion by domperidone could not prevent the depression of milk yield suggests that other mechanisms are involved. PMID- 28012630 TI - Antimicrobial resistance patterns of bovine Salmonella enterica isolates submitted to the Wisconsin Veterinary Diagnostic Laboratory: 2006-2015. AB - Salmonellosis on the dairy continues to have a significant effect on animal health and productivity and in the United States. Additionally, Salmonella enterica ssp. enterica causes an estimated 1.2 million cases of human illness annually. Contributing to the morbidity and mortality in both human and domestic animal species is emergence of antimicrobial resistance by Salmonella species and increased incidence of multidrug-resistant isolates. This study describes serotype distribution and the antimicrobial resistance patterns for various Salmonella serotypes isolated from bovine samples submitted to the Wisconsin Veterinary Diagnostic Laboratory (WVDL) over the past 10 yr. Salmonella serotyping and antimicrobial susceptibility testing data were obtained from the laboratory information management system at WVDL. Data from accessions were limited to bovine samples submitted to the WVDL between January 2006 and June 2015 and those that had both a definitive serotype and complete results for antimicrobial susceptibility testing. A total of 4,976 isolates were identified. Salmonella enterica ser. Dublin was the most prevalent serotype identified among bovine samples submitted to the WVDL, accounting for a total of 1,153 isolates (23% of total isolates) over the study period. Along with Dublin, Salmonella enterica ser. Cerro (795, 16%), Newport (720, 14%), Montevideo (421, 8%), Kentucky (419, 8%), and Typhimurium (202, 4%) comprised the top 6 most commonly isolated serotypes during that time. Overall, resistance of bovine Salmonella isolates in the study population remained stable, although decreases in resistance were noted for gentamicin, neomycin, and trimethoprim sulfamethoxazole during the study period. All isolates remained susceptible to enrofloxacin. These data show that antimicrobial susceptibility for bovine Salmonella has changed in the population served by WVDL in the past 10 yr. This information is important for understanding Salmonella disease ecology in Wisconsin. Our findings are also relevant for animal and public health by improving informed antimicrobial use, new drug development, and regulation of their use in food animals. PMID- 28012631 TI - Estimating US dairy clinical disease costs with a stochastic simulation model. AB - A farm-level stochastic model was used to estimate costs of 7 common clinical diseases in the United States: mastitis, lameness, metritis, retained placenta, left-displaced abomasum, ketosis, and hypocalcemia. The total disease costs were divided into 7 categories: veterinary and treatment, producer labor, milk loss, discarded milk, culling cost, extended days open, and on-farm death. A Monte Carlo simulation with 5,000 iterations was applied to the model to account for inherent system variation. Four types of market prices (milk, feed, slaughter, and replacement cow) and 3 herd-performance factors (rolling herd average, product of heat detection rate and conception rate, and age at first calving) were modeled stochastically. Sensitivity analyses were conducted to study the relationship between total disease costs and selected stochastic factors. In general, the disease costs in multiparous cows were greater than in primiparous cows. Left-displaced abomasum had the greatest estimated total costs in all parities ($432.48 in primiparous cows and $639.51 in multiparous cows). Cost category contributions varied for different diseases and parities. Milk production loss and treatment cost were the 2 greatest cost categories. The effect of market prices were consistent in all diseases and parities; higher milk and replacement prices increased total costs, whereas greater feed and slaughter prices decreased disease costs. PMID- 28012632 TI - Hepatic expression of aminoadipate semialdehyde synthase is unchanged by postruminal lysine supply in lactating dairy cows. AB - Lysine supply is potentially limiting for milk production in dairy cows. The availability of Lys to the mammary gland and other tissues is a function of the quantity of metabolizable Lys supplied and Lys catabolism by the liver. Likewise, Lys catabolism may be influenced by Lys supply. This study evaluated the effect of increased postruminal Lys supply on the expression of aminoadipate semialdehyde synthase (AASS, a committing step in Lys catabolism in the liver) and ornithine transcarbamoylase and argininosuccinate synthase (key urea cycle enzymes that are responsive to protein supply). Eight multiparous peak Holstein cows were used in a replicated 4 * 4 Latin square. Cows were fed a Lys-limiting ration and infused postruminally with 0, 9, 27, or 63 g/d of Lys. The study consisted of 10 d of pretreatment followed by 10 d of Lys infusion. On the last day of each period, liver and milk samples were collected for mRNA analysis, and blood samples were collected for analysis of amino acids and Lys metabolites. Milk protein percent increased by 5.9%, plasma Lys increased by 74%, and alpha aminoadipic acid increased by 51% with postruminal infusion of 63 g/d Lys compared with 0 g/d. Expression of AASS, ornithine transcarbamoylase, and argininosuccinate synthase mRNA in liver did not differ with postruminal infusion of Lys. Milk fat globule mRNA for major milk proteins and AASS were not affected by Lys infusion. Postruminal infusion of Lys resulted in an 86% greater increase in AASS mRNA in the liver compared with mammary mRNA. These changes suggest that hepatic Lys metabolism is not responsive to Lys supply at the transcription level, and that the availability of Lys to extrahepatic tissue may be determined by hepatic Lys metabolism. PMID- 28012633 TI - Effect of submucosal dexamethasone injection on postoperative pain, oedema, and trismus following mandibular third molar surgery: a prospective, randomized, double-blind clinical trial. AB - The aim of this study was to investigate the effect of the submucosal injection of 1ml dexamethasone (4mg/ml) on pain, swelling, and trismus following the extraction of retained lower third molars. Ninety patients (mean age 23.5 years) were split randomly into three equal study groups (30 patients in each): the 'before' group received dexamethasone 15min before surgery and placebo 15min after surgery; the 'after' group received placebo 15min before surgery and dexamethasone 15min after surgery; the 'placebo' group received placebo 15min before surgery and placebo 15min after surgery. Postoperative pain was recorded by the patients using a visual analogue scale, numerical rating scale, and the McGill Pain Questionnaire at 1, 2, 4, 6, 8, 12, and 24h after surgery. The patients also recorded the total number of analgesic doses consumed during the 24h after the procedure. Swelling (determined using linear measurements of the face) and trismus (determined through measurement of maximum mouth opening) were assessed at 48h, 72h, and 7 days following surgery. Better control of pain, swelling, and trismus was demonstrated for dexamethasone in comparison to placebo. Postoperative dexamethasone provided better pain control than preoperative dexamethasone. There was no difference in total rescue analgesic intake between the preoperative and postoperative dexamethasone groups. PMID- 28012634 TI - Why We Need More and Better Cardiovascular Disease Quality Indicators. PMID- 28012635 TI - The Effect of Capsulotomy and Capsular Repair on Hip Distraction: A Cadaveric Investigation. AB - PURPOSE: To quantify how increasing interportal capsulotomy size affects the force required to distract the hip and to biomechanically compare simple side-to side suture repair to acetabular-based suture anchors as capsular repair techniques. METHODS: Twelve fresh-frozen cadaveric hip specimens were dissected to the capsuloligamentous complex of the hip joint and fixed in a material testing system, such that a pure axial distraction of the iliofemoral ligament could be achieved. After each hip in was tested an intact state, sequential distraction was tested with 2, 4, 6, and 8 cm capsulotomies. Specimens were assigned randomly to be repaired with either 4 side-to-side suture repair (n = 6) or 2 double-loaded all-suture anchors (n = 6). The distraction force as well as the relative distraction force percentage normalized to the intact capsule were compared between suture repair and suture anchor repair groups. RESULTS: Increasing the size of the capsulotomy resulted in less force required to distract the hip to 6 mm. The force decreased as the capsulotomy was extended with statistical significance in distraction force seen between the intact state and the 4 cm (P = .003), 6 cm (P < .001), and 8 cm (P <= .001) capsulotomy but not for the intact state compared to the 2 cm capsulotomy (P = .28). Statistical significance in relative distraction force was seen for each of the capsulotomy conditions (P < .001 for all conditions compared with the intact state). The side to-side suture repair construct (104.3% of intact force) required greater force to distraction to 6 mm compared with the suture anchor repair (87.1% of intact force) (P = .008). CONCLUSIONS: An interportal capsulotomy significantly affected the force required to distract the hip in a cadaveric model, with the larger the size of capsulotomy resulting in less force required to distract the hip. When we performed an interportal capsulotomy, the iliofemoral ligament strength was altered significantly but capsular repair with either side-to-side sutures or suture anchor-based repair was able to restore the capsular strength to a native intact hip. We found, however, that the side-to-side suture repair was better able to restore the distraction force compared with suture anchor repair. CLINICAL RELEVANCE: Capsular management during hip arthroscopy remains a debated topic, with multiple techniques involving both capsulotomy and capsular closure published in the literature. This study provides insight into capsular stability against axial stress under capsulotomy and capsular repair conditions. PMID- 28012636 TI - Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Meta analysis of Randomized Controlled Trials. AB - PURPOSE: To use meta-analysis techniques to evaluate the efficacy and safety of platelet-rich plasma (PRP) injections for the treatment knee of osteoarthritis (OA). METHODS: We performed a systematic literature search in PubMed, Embase, Scopus, and the Cochrane database through April 2016 to identify Level I randomized controlled trials that evaluated the clinical efficacy of PRP versus control treatments for knee OA. The primary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores. The primary outcomes were compared with their minimum clinically important differences (MCID)-defined as the smallest difference perceived as important by the average patient. RESULTS: We included 10 randomized controlled trials with a total of 1069 patients. Our analysis showed that at 6 months postinjection, PRP and hyaluronic acid (HA) had similar effects with respect to pain relief (WOMAC pain score) and functional improvement (WOMAC function score, WOMAC total score, International Knee Documentation Committee score, Lequesne score). At 12 months postinjection, however, PRP was associated with significantly better pain relief (WOMAC pain score, mean difference -2.83, 95% confidence interval [CI] -4.26 to 1.39, P = .0001) and functional improvement (WOMAC function score, mean difference -12.53, 95% CI -14.58 to -10.47, P < .00001; WOMAC total score, International Knee Documentation Committee score, Lequesne score, standardized mean difference 1.05, 95% CI 0.21-1.89, P = .01) than HA, and the effect sizes of WOMAC pain and function scores at 12 months exceeded the MCID (-0.79 for WOMAC pain and -2.85 for WOMAC function score). Compared with saline, PRP was more effective for pain relief (WOMAC pain score) and functional improvement (WOMAC function score) at 6 months and 12 months postinjection, and the effect sizes of WOMAC pain and function scores at 6 months and 12 months exceeded the MCID. We also found that PRP did not increase the risk of adverse events compared with HA and saline. CONCLUSIONS: Current evidence indicates that, compared with HA and saline, intra-articular PRP injection may have more benefit in pain relief and functional improvement in patients with symptomatic knee OA at 1 year postinjection. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I studies. PMID- 28012637 TI - Determination of clinical significance of coagulase-negative staphylococci in blood cultures. AB - The aim of this study was to investigate the criteria used to distinguish coagulase-negative staphylococci (CoNS) bacteremia from contamination. We evaluated 162 adult patients with CoNS-positive blood cultures (BCs). Of the 162 patients, 35 (21.6%) had at least 2 positive BCs and 127 (78.4%) had a single positive BC. According to the Laboratory-Confirmed Bloodstream Infection (LCBI) criteria, 24 (14.8%) patients with the same species of CoNS had true bacteremia, and 138 (85.2%) patients had contaminants. Despite the detection of the same CoNS species, 9 of the 24 patients had different CoNS genotypes. Using clinical assessments, only 20 patients were diagnosed with true bacteremia, 8 of them had a single positive BC. We concluded that only using the LCBI criteria or clinical evaluations of a patient were not sufficient to distinguish CoNS bacteremia from contamination. Molecular identification should also be performed as a diagnostic laboratory parameter for CoNS bacteremia. PMID- 28012638 TI - Analytical and clinical comparison of Elecsys syphilis (Roche(r)) - Architect syphilis TP and reformulated Architect syphilis TP (Abbott(r)) assay. AB - The performance of Elecsys Syphilis was compared to Architect Syphilis TP and Reformulated Architect Syphilis TP. The overall sensitivity and specificity were 98.4% and 99.5%, 97.7% and 97.1%, and 99.2% and 99.7% respectively. The assays are comparable and considered adequate for syphilis screening. PMID- 28012639 TI - [Guidelines for multivitamin administration in fortified human milk prepared for preterm infants]. AB - BACKGROUND: To reach nutritional standards, human milk has to have 2g/dL of protein. In 2013, Lafeber stated that when human milk is fortified up to 2g/dL, it may increase its osmolality up to 500 mOsm/kg. He also warned that care must be taken when adding a drug or vitamins to human milk. AIM: We studied, for the first time, the impact of adding multivitamins (ADEC) on human fortified milk osmolality. METHOD: The osmolality of 36 pasteurized, fortified human milk samples was measured. The amount of milk required as a solvent to maintain osmolality below 500 mOsm/kg was then determined. RESULTS: The osmolality of 2mL of fortified human milk reached up to 750 mOsm/kg when the multivitamins ADEC was added. The osmolality decreased proportionately as the solution was diluted and if vitamins are added in two half-doses each time. It is only with 20mL of milk that the osmolality lowers to its initial rate of 430 mOsm/kg. The stronger the milk's fortification is, the greater impact it has on the milk's osmolality. CONCLUSION: New nutritional recommendations for premature infants are needed. In the meantime, when the fortified milk intake is under 20mL, it is preferable to extend parenteral intakes with fat-soluble vitamins or reduce doses of vitamins in milk. Also, we should use enriched human milk as a fortifier and be cautious with indiscriminate fortification or when adding drugs and electrolyte solutions. PMID- 28012640 TI - White matter integrity and symptom dimensions of schizophrenia: A diffusion tensor imaging study. AB - Impaired fiber bundle connectivity between brain regions is a key neuropathological finding in schizophrenia. Symptom dimensions in schizophrenia can be clustered into factor models. Single syndromes have been related to grey and white matter brain structure alterations. We associated all core syndromes of schizophrenia in a single patient group with changes in white matter integrity. Diffusion weighted images (3T MRI) and SAPS/SANS scores were measured in 26 male patients and 26 healthy controls. First, group differences in fractional anisotropy (FA) were calculated with TBSS. Second, core symptom dimensions of schizophrenia were correlated with FA within these altered tracts. We found differences between groups in nine white matter tracts. Hallucinations were positively correlated with FA in the left uncinate fasciculus and left corticospinal tract. Ego-disturbances (passivity phenomena) showed a positive correlation with FA in the right anterior thalamic radiation. Positive formal thought disorders (FTD) corresponded negatively with FA in the right cingulum bundle. Negative symptoms were positively associated with the right anterior thalamic radiation and negatively with the right ventral cingulum bundle. For the first time, we analyzed the whole range of psychopathological factors in one schizophrenia patient group. We could validate our novel results for positive FTD and passivity phenomena by replicating findings for hallucinations and negative symptoms. Only those brain circuits which are most vulnerable at a given time during neurodevelopment are affected by a particular pathological impact (genetic, environmental). This scenario could explain the predominance of particular psychopathological syndromes related to specific white matter anomalies. PMID- 28012641 TI - The Unintended Consequences of Over-Reducing Cardiopulmonary Bypass Circuit Prime Volume. AB - BACKGROUND: The Society of Thoracic Surgeon blood conservation guidelines recommend minimizing cardiopulmonary bypass circuit prime volume (PV) as an integral, evidence-based (Class I, Level A) blood conservation strategy. We used a large, multiinstitutional registry to evaluate the effectiveness of restricting cardiopulmonary bypass PV on intraoperative red blood cell (RBC) transfusion. METHODS: We reviewed 47,273 isolated coronary artery bypass graft procedures performed among 189 institutions between April 2012 and May 2015. The primary outcome was intraoperative transfusion of at least 1 unit RBC; the secondary outcome was intraoperative transfusion of 4 or more units RBC. We estimated the adjusted odds of each transfusion type using separate multivariable logistic regression models that controlled for 13 confounding factors. The effect of PV on odds of transfusion was modeled using restricted cubic splines to assess possible nonlinearity. RESULTS: We found a statistically significant nonlinear pattern in the relation between PV and odds of transfusion of both 1 or more units RBC (chi2 = 116.3, df = 4, p < 0.001) and 4 or more units RBC (chi2 = 25.9, df = 4, p < 0.001). The lowest probability of transfusion of 1 or more units RBC was estimated at a ratio of PV to estimated blood volume of 0.152 (p < 0.001). CONCLUSIONS: Efforts to minimize PV below 15% of a patient's estimated blood volume do not protect patients from intraoperative RBC transfusion, and may increase exposure. Prime volume can affect both patient morbidity and the economic impact associated with blood utilization. Further studies on the effect of PV on blood transfusion are warranted. PMID- 28012642 TI - Postoperative Cerebral and Somatic Near-Infrared Spectroscopy Saturations and Outcome in Hypoplastic Left Heart Syndrome. AB - BACKGROUND: Circulatory vulnerability reflected by low systemic venous oxygen saturation after surgical palliation of hypoplastic left heart syndrome predicts adverse neurologic outcome and reduced survival, and targeting venous saturation may improve outcome. We herein test the hypothesis that near-infrared spectroscopy (NIRS)-derived cerebral and somatic/renal regional saturations can predict survival. METHODS: Patient data, from a prospective Institutional Review Board-approved registry of hemodynamic measures after initial palliation of hypoplastic left heart syndrome, were analyzed with logistic and multivariable mixed regression methods to determine relationships between standard hemodynamic measures, direct and NIRS measures of saturation, and outcome. The primary outcome measure was survival through hospital discharge and 30 days. RESULTS: From the entire cohort of 329 patients, complete data for comparative analysis of physiologic predictors were available from 194 patients. The early survival rate was 92.1%; extracorporeal membrane oxygenation was used in 8.8% of patients. The mean arterial pressure, arterial cerebral, and somatic cerebral NIRS saturation differences were significantly higher for survivors versus nonsurvivors. Multivariable analysis found cerebral and somatic NIRS saturations, heart rate, and arterial pressure as predictors of outcome. Bivariate analysis of mean arterial pressure and somatic saturation allowed early identification of low cardiac output and high mortality risk. CONCLUSIONS: Continuous noninvasive measurement of regional cerebral and somatic NIRS saturations in the early postoperative period can predict outcomes of early mortality and extracorporeal membrane oxygenation use in hypoplastic left heart syndrome. Because outcomes were strongly determined by NIRS measures at 6 hours, early postoperative NIRS measures may be rational targets for goal-directed interventions. PMID- 28012643 TI - Reoperation for Coronary Artery Bypass Grafting Surgery: Outcomes and Considerations for Expanding Interventional Procedures. AB - BACKGROUND: Owing to an inevitable degeneration of grafts over time, patients may require consideration for repeat coronary artery bypass graft (CABG) surgery. As our understanding of preoperative risks associated with redo CABG surgery is limited and availability of data is limited to historical cohorts, we sought to evaluate our contemporary 20-year experience with this challenging patient population. METHODS: Between January 1993 and June 2014, 748 patients underwent redo CABG surgery at our institution. Median age at reoperation was 69 years (range, 36 to 88), and 644 (86%) were male. Median follow-up was 15.1 years and was 100% complete. Preoperatively, 191 patients (26%) had diabetes mellitus, 562 (75%) had hypertension, 206 (28%) had peripheral vascular disease with 121 (16%) having a history of cerebrovascular disease, and 459 (61%) had prior myocardial infarction. Number of prior CABG operations was 1 in 682 patients (91%), 2 in 62 patients (8%), and 3 in 4 patients (1%). RESULTS: All patients underwent isolated redo CABG surgery; all 748 (100%) procedures were performed using cardiopulmonary bypass, with median time on pump of 95 minutes (maximum, 378) and cross-clamp time of 48 minutes (maximum, 176). There were 47 early deaths (6%); early nonfatal morbidity included renal failure in 51 patients (7%), stroke in 15 (2%), and pneumonia in 22 (3%). Overall 1-, 5-, and 10-year survival was 89%, 77%, and 51%, respectively. Age (hazard ratio [HR] 1.74, p < 0.001), diabetes (HR 1.51, p < 0.001), peripheral vascular disease (HR 1.51, p < 0.001), and end-stage renal disease with dialysis (HR 11.85, p < 0.001) were associated with increased long term mortality, whereas higher left ventricular ejection fraction (per 10% increase) was protective (HR 0.78, p < 0.001). CONCLUSIONS: Redo CABG can be performed safely with low early and late morbidity and mortality. Important predictors of long-term mortality such as age, diabetes, renal disease, and peripheral vascular disease were identified and should guide the treatment strategy chosen for this challenging group of patients. PMID- 28012645 TI - The role of fibroblast growth factor 21 in atherosclerosis. AB - The metabolic properties of the endocrine fibroblast growth factor 21 (FGF21) have been extensively studied in the past decade. Previous studies have demonstrated the lipid-lowering, anti-inflammatory and anti-oxidant properties of FGF21. FGF21 is mainly secreted in the liver and adipose tissue in response to a range of physiological and pathological stimuli. In animal and in vitro studies, FGF21 has been shown to improve lipid profiles and inhibit key processes in the pathogenesis of atherosclerosis. It exerts its effects on the cardiovascular system via adiponectin dependent and independent mechanisms. However, the signalling pathways by which FGF21 exerts its effects on endothelial cells remains unknown and needs to be further investigated. The elevation of circulating FGF21 levels in cardiovascular disease has also raised questions as to whether FGF21 can be used as a biomarker to predict subclinical atherosclerosis and cardiovascular events. Recent findings from population studies must be validated in independent cohorts before FGF21 can be used as a biomarker in the clinical setting. The anti-atherosclerotic effects of FGF21 have been investigated in two recent clinical trials, where treatment with an FGF21 analog significantly improved the cardiometabolic profile in obese patients with type 2 diabetes. This review will evaluate recent advances that suggest there may be a role for FGF21 in atherosclerosis. PMID- 28012644 TI - Ankle-brachial index and physical function in older individuals: The Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND AND AIMS: Most prior studies investigating the association of lower extremity peripheral artery disease (PAD) with physical function were small or analyzed selected populations (e.g., patients at vascular clinics or persons with reduced function), leaving particular uncertainty regarding the association in the general community. METHODS: Among 5262 ARIC participants (age 71-90 years during 2011-2013), we assessed the cross-sectional association of ankle-brachial index (ABI) with the Short Physical Performance Battery (SPPB) score (0-12), its individual components (chair stands, standing balance, and gait speed) (0-4 points each), and grip strength after accounting for potential confounders, including a history of coronary disease, stroke, or heart failure. RESULTS: There were 411 participants (7.8%) with low ABI <=0.90 and 469 (8.9%) participants with borderline low ABI 0.91-1.00. Both ABI <=0.90 and 0.91-1.00 were independently associated with poor physical function (SPPB score <=6) compared to ABI 1.11-1.20 (adjusted odds ratio 2.10 [95% CI 1.55-2.84] and 1.86 [1.38-2.51], respectively). The patterns were largely consistent across subgroups by clinical conditions (e.g., leg pain or other cardiovascular diseases), in every SPPB component, and for grip strength. ABI >1.3 (472 participants [9.0%]), indicative of non compressible pedal arteries, was related to lower physical function as well but did not necessarily reach significance. CONCLUSIONS: In community-dwelling older adults, low and borderline low ABI suggestive of PAD were independently associated with poorer systemic physical function compared to those with normal ABI. Clinical attention to PAD as a potential contributor to poor physical function is warranted in community-dwelling older adults. PMID- 28012646 TI - Myocardin: A novel player in atherosclerosis. AB - Myocardin (MYOCD) the most important coactivator of serum response factor (SRF), plays a critical role specifically in the development of cardiac myocytes and vascular smooth muscle cells (VSMCs). Binding of Myocardin to the SRF on the CArG box-containing target genes can transcriptionally activate a variety of downstream muscle-specific genes, such as Sm22alpha, Acta2, Myh11, and several other signaling pathways. Myocardin expression represents a contractile and differentiated SMC phenotype. Loss of Myocardin, however, represents a synthetic and dedifferentiated phenotype, a hallmark in atherosclerosis. Growing evidence shows that Myocardin is involved in lipid metabolism and vascular inflammation, the primary pathogenesis of atherosclerosis. Moreover, Myocardin expression level is altered in atherosclerotic patients and animal models, suggesting more extensive and important roles for Myocardin in atherosclerosis. In the current review, we summarized recent progress on the regulation and signaling of Myocardin, and highlighted its impacts on atherosclerotic disease. PMID- 28012647 TI - CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. AB - BACKGROUND AND AIMS: Vascular smooth muscle cells (VSMC) migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. CD98 is a transmembrane protein made of two subunits, CD98 heavy chain (CD98hc) and one of six light chains, and is known to be involved in cell proliferation and survival. Because the influence of CD98hc on atherosclerosis development is unknown, our aim was to determine if CD98hc expressed on VSMC plays a role in shaping the morphology of atherosclerotic plaques by regulating VSMC function. METHODS: In addition to determining the role of CD98hc in VSMC proliferation and apoptosis, we utilized mice with SMC-specific deletion of CD98hc (CD98hcfl/flSM22alphaCre+) to determine the effects of CD98hc deficiency on VSMC function in atherosclerotic plaque. RESULTS: After culturing for 5 days in vitro, CD98hc-/- VSMC displayed dramatically reduced cell counts, reduced proliferation, as well as reduced migration compared to control VSMC. Analysis of aortic VSCM after 8 weeks of HFD showed a reduction in CD98hc-/- VSMC proliferation as well as increased apoptosis compared to controls. A long-term atherosclerosis study using SMC-CD98hc-/-/ldlr-/- mice was performed. Although total plaque area was unchanged, CD98hc-/- mice showed reduced presence of VSMC within the plaque (2.1 +/- 0.4% vs. 4.3 +/- 0.4% SM22alpha-positive area per plaque area, p < 0.05), decreased collagen content, as well as increased necrotic core area (25.8 +/- 1.9% vs. 10.9 +/- 1.6%, p < 0.05) compared to control ldlr-/- mice. CONCLUSIONS: We conclude that CD98hc is required for VSMC proliferation, and that its deficiency leads to significantly reduced presence of VSMC in the neointima. Thus, CD98hc expression in VSMC contributes to the formation of plaques that are morphologically more stable, and thereby protects against atherothrombosis. PMID- 28012649 TI - Reservoirs as hotspots of fluvial carbon cycling in peatland catchments. AB - Inland water bodies are recognised as dynamic sites of carbon processing, and lakes and reservoirs draining peatland soils are particularly important, due to the potential for high carbon inputs combined with long water residence times. A carbon budget is presented here for a water supply reservoir (catchment area~9km2) draining an area of heavily eroded upland peat in the South Pennines, UK. It encompasses a two year dataset and quantifies reservoir dissolved organic carbon (DOC), particulate organic carbon (POC) and aqueous carbon dioxide (CO2(aq)) inputs and outputs. The budget shows the reservoir to be a hotspot of fluvial carbon cycling, as with high levels of POC influx it acts as a net sink of fluvial carbon and has the potential for significant gaseous carbon export. The reservoir alternates between acting as a producer and consumer of DOC (a pattern linked to rainfall and temperature) which provides evidence for transformations between different carbon species. In particular, the budget data accompanied by 14C (radiocarbon) analyses provide evidence that POC-DOC transformations are a key process, occurring at rates which could represent at least ~10% of the fluvial carbon sink. To enable informed catchment management further research is needed to produce carbon cycle models more applicable to these environments, and on the implications of high POC levels for DOC composition. PMID- 28012648 TI - Impact of vasomotion type on prognosis of coronary artery spasm induced by acetylcholine provocation test of left coronary artery. AB - BACKGROUND AND AIMS: The impact of vasomotion types on long-term clinical outcomes in patients with coronary artery spasm (CAS) induced by the acetylcholine provocation test (ACH-test) remains unclear. METHODS: We evaluated 4644 consecutive patients with typical resting chest pain (CP), but no angiographically significant coronary artery lesion (<50% stenosis), who underwent an ACH-test. According to their vasomotor response, patients were categorized into four types: normal vasomotion (no CP, no ischemic electrocardiographic changes, and no vasoconstriction), microvascular spasm (CP with <75% vasoconstriction but with CP relief after nitroglycerin infusion), epicardial spasm (CP with >=75% vasoconstriction), and ACH-test inconclusive (vasoconstriction and/or electrocardiographic changes, but no CP). We investigated CP recurrence requiring follow-up angiography and major adverse cardiovascular events (MACEs) during 5 years. RESULTS: CP recurred in 7.9% of patients and was more frequent in abnormal vasomotion types (normal vasomotion, microvascular spasm, epicardial spasm, and inconclusive type: 5.4%, 9.8%, 10.9%, and 8.2%, respectively, log-rank p = 0.009). In multivariate analysis adjusted for medication use after the ACH-test, vasomotion subtype was not an independent predictor, whereas male sex, fixed lesion on baseline angiography, and medications including calcium channel blockers (CCBs), nitrates, and statins were independent positive predictors for recurrent CP. Alcohol consumption at the initial interview was a negative predictor. MACEs were observed in 1.6%, and the incidence was similar among subtypes (p = 0.421). CONCLUSIONS: Recurrent CP and long-term outcomes are independent of vasomotion subtypes, but long-term use of CCBs, nitrates, and statins is a significant predictor for recurrent CP. PMID- 28012650 TI - Occurrence, spatial distribution, historical trend and ecological risk of phthalate esters in the Jiulong River, Southeast China. AB - The occurrence and spatial distribution of phthalate esters (PAEs) in the Jiulong River of southeast China were investigated in water and sediment samples collected from 35 stations along the river in Mar. 2014. The historical trend of the past 26years was reconstructed with a sediment core collected in Dec. 2012 via a 210Pb dating technique. The potential ecological risk of PAEs was assessed using the risk quotient (RQ) method. Of the 16 PAE congeners analyzed, only 6 PAEs, including dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DIBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DINP), were identified and quantified; the remaining 10 PAEs were below their respective limits of quantification (LOQs) for the analytical methods used here. The cumulative concentration of 6 PAEs (?6PAEs) found in the samples spanned a range of 3.48-17.7MUg/L in water and 0.046 1.65mg/kg in sediment. The most abundant PAEs in the water-phase were DEHP and DIBP, together accounting for 84.9% of ?6PAEs in the North River, 82.8% of ?6PAEs in the West River and 91.6% of ?6PAEs in the estuary. DEHP and DINP were the richest congeners in the sediment-phase, with proportions of 84.9% in the North River, 81.0% in the West River and 65.4% in the estuary. The spatial distribution of ?6PAEs in water and sediment phases showed that the riverside environment had influence on the distribution pattern. The reconstruction profile of the PAE congeners and the ?6PAEs vs the depth of the sediment core indicated that PAEs became increasingly present pollutants around 2006 in the Jiulong River. The results of the potential ecological risk assessment of the RQ method revealed that DIBP and DEHP posed a high risk because of their relatively higher concentrations, while DBP and DINP posed a medium risk to the aquatic system. The baseline data of PAEs in this river will be benefits to the regulatory attention and future strategies of the pollutants control along the river network. PMID- 28012651 TI - Cool barnacles: Do common biogenic structures enhance or retard rates of deterioration of intertidal rocks and concrete? AB - Sedentary and mobile organisms grow profusely on hard substrates within the coastal zone and contribute to the deterioration of coastal engineering structures and the geomorphic evolution of rocky shores by both enhancing and retarding weathering and erosion. There is a lack of quantitative evidence for the direction and magnitude of these effects. This study assesses the influence of globally-abundant intertidal organisms, barnacles, by measuring the response of limestone, granite and marine-grade concrete colonised with varying percentage covers of Chthamalus spp. under simulated, temperate intertidal conditions. Temperature regimes at 5 and 10mm below the surface of each material demonstrated a consistent and statistically significant negative relationship between barnacle abundance and indicators of thermal breakdown. With a 95% cover of barnacles, subsurface peak temperatures were reduced by 1.59 degrees C for limestone, 5.54 degrees C for concrete and 5.97 degrees C for granite in comparison to no barnacle cover. The amplitudes of short-term (15-30min) thermal fluctuations conducive to breakdown via 'fatigue' effects were also buffered by 0.70 degrees C in limestone, 1.50 degrees C in concrete and 1.63 degrees C in granite. Furthermore, concentrations of potentially damaging salt ions were consistently lower under barnacles in limestone and concrete. These results indicate that barnacles do not enhance, but likely reduce rates of mechanical breakdown on rock and concrete by buffering near-surface thermal cycling and reducing salt ion ingress. In these ways, we highlight the potential role of barnacles as agents of bioprotection. These findings support growing international efforts to enhance the ecological value of hard coastal structures by facilitating their colonisation (where appropriate) through design interventions. PMID- 28012652 TI - Assessing correlations between monomethylmercury accumulation in fish and trophic states of artificial temperate reservoirs. AB - We investigated monomethylmercury (MMHg) concentrations in 448 samples of four common fish species (barbel steed, largemouth bass, leopard mandarin, and bluegill) and the trophic states of 14 artificial reservoirs in South Korea in order to understand how trophic states of reserviors affect MMHg concentrations in fish. The trophic state index (TSI) of each reservoir was determined using empirical equations based on the monthly chlorophyll-a, total phosphorus, and Secchi depth, collected over a three-year period. The length-normalized MMHg concentrations in fish showed a negative correlation with the TSI based on chlorophyll-a (r2=0.90) and total phosphorus (r2=0.75) that may be a result of particle dilution of MMHg in surface waters. This study revealed that MMHg accumulation in fish was better correlated with TSI than MMHg in water, therefore, we suggest that the measurement of TSI based on chlorophyll-a and total phosphorus is an effective way to predict MMHg bioaccumulation across diverse reservoirs. PMID- 28012653 TI - Reconstructing the historical water regime of the contributing basins to the Hawizeh marsh: Implications of water control structures. AB - The Hawizeh marsh, a unique wetland which is part of the Mesopotamian marshes, is recognized as a wetland of international importance. The marsh has been shrinking and there has been little research into its degradation. This study aims to reconstruct historical water regimes in the contributing basins (Tigris and Karkheh river Basins, TKRB) to investigate factors that have affected the wellbeing of the marsh. The Soil and Water Assessment Tool (SWAT) was used for this study. The model was calibrated and validated using nine river gauging stations. Results indicated that inflows to the marsh decreased by 65% and 80% in the '90s and 2000s, respectively, compared to the '80s. The reductions in streamflow were caused by decrease in precipitation and water abstraction. The annual precipitation decreased by 14% and 38% in the '90s and 2000s, respectively, compared to the '80s. Highest water abstraction was seen in Karkheh dam which caused a reduction of 45% in the annual streamflows. Average annual evaporative losses from Tharthar lake (2700km2) were very high (2260hm3 [cubic hectometer]). Although the Hawizeh marsh has been shrinking for the last three decades, recent satellite images (2013) have shown that the marsh has been reviving, mainly due to increased precipitation from 2011 to 2013. The revival of the marsh is promising; however, if the planned dams on TKRB are implemented, the future of the marsh remains uncertain. The sustainability of the Hawizeh marsh will require integrated water resources management among the riparian countries to rehabilitate and maintain this unique wetland. PMID- 28012654 TI - The role of calcium concentration in the invasive capacity of Corbicula fluminea in crystalline basins. AB - The natural variation of environmental factors in freshwater basins determines their biodiversity. Among them, calcium is a key physiological compound for freshwater invertebrates. It is required for shell formation, muscle contraction, it mediates gene expression and allows counteracting acidosis during stress periods, among other functions. Although the distribution of different freshwater species has been suggested to be linked with the environmental calcium concentration, as yet, no research studies have confirmed this. Identifying whether environmental calcium concentrations might determine the invasion success of alien species would be critical in developing and implementing effective management strategies to control them. Here, a multidisciplinary approach integrating field surveys, analytical chemistry techniques, molecular biology analyses and a lab-scale experiment was taken to decipher whether the environmental calcium concentration might hamper the establishment of Corbicula fluminea in northwestern Iberian rivers. A Principal Component Analysis on water chemistry variables from 13 water bodies identified environmental calcium concentration, among others, as one key factor that best characterized the distribution area of C. fluminea. The calcium content in animals' bodies from two representative rivers was dependent on the environmental calcium concentration of freshwater basins; the lower the concentration, the lower the body's content. The expression of stress- and calcium homeostasis-related genes was higher in C. fluminea from low calcium concentration environments than in those from calcium rich freshwater basins. Finally, under experimental conditions, lower water calcium concentrations decreased C. fluminea growth rates. The present data suggest, for the first time, that environmental calcium concentration may act as a determinant factor on the invasion success of C. fluminea in freshwater environments. Our results provide new clues for the identification of basins with increased risk of potential invasion by C. fluminea based on environmental calcium levels. PMID- 28012655 TI - Using residents' worries about technology as a way of resolving environmental remediation dilemmas. AB - The choice of technologies used to remediate contaminated environments are increasingly made via engagement with affected local residents. Despite this, little is known about how residents perceive remediation technology applications. Building on the findings of broader technology worry research, and drawing on data from a telephone survey of 2009 residents living near thirteen contaminated sites in Australia, regression analysis of closed-ended survey questions and coding analysis of open-ended survey questions are combined to identify the main predictors of worries concerning particular remediation technologies, and how worry affects them. This suggests respondents are more worried about the application of chemical remediation technologies than the application of physical and thermal technologies, which in turn caused more worry than the application of biotechnology. The paper suggests that these worries can be reduced via direct engagement with residents about remediation technologies, suggesting that such engagement can provide knowledge that improves remediation technology decisions. PMID- 28012657 TI - Effect of surface application of ammonium thiosulfate on field-scale emissions of 1,3-dichloropropene. AB - Soil fumigation is important for food production but has the potential to discharge toxic chemicals into the environment, which may adversely affect human and ecosystem health. A field experiment was conducted to evaluate the effect of applying ammonium thiosulfate fertilizer to the soil surface prior to fumigating with 1,3-dichloropropene (1,3-D). The ammonium thiosulfate solution was applied as a spray with minimal water to minimize the effect on emissions from saturating (e.g. sealing) the soil pores with water. Two independent data sets were collected for determining the emission rate. One data set was used with three micrometeorological approaches: aerodynamic, integrated horizontal flux and theoretical profile shape; the other dataset with two indirect, back calculation methods that used the CALPUFF and ISCST3 dispersion models. Using the five methodologies, the 1,3-D emission rate was obtained for 16days. The maximum emission rates ranged from 7 to 20MUgm-2s-1, the maximum 24-hour averaged emission rates ranged from 5 to 13MUgm-2s-1, and the total 1,3-D emissions ranged from 12 to 26%. Comparing to fumigation without ammonium thiosulfate spray revealed that emissions were reduced from 3% (CALPUFF) to 29% (ADM). Using a simulation model, ammonium thiosulfate spray would be expected to reduce emissions by almost 21%. These data provide evidence that emissions of 1,3-D can be reduced by spraying ammonium thiosulfate fertilizer on the soil surface prior to soil fumigation, and provides another emission-reduction strategy to those recently reported (e.g., deep injection, water seals and organic amendments). PMID- 28012656 TI - Combined ecotoxicological risk assessment in the frame of European authorization of pesticides. AB - Organisms are frequently exposed to mixtures of chemical contaminants in the environment, causing a potential "cocktail effect", or combined effect. The joint action of different molecules with similar or different modes of action could result in a potentially unlimited number of additives, synergistic or antagonistic combinations. Since the large number of contaminants makes it impossible to perform ecotoxicity tests for each potential mixture, a robust approach for prospective environmental risk assessment of chemical mixtures is needed. A number of recent publications by the European Commission and the authorities in charge prove the increasing interest that is spreading in the European community towards the topic of the assessment of chemical mixtures. The current EU regulation for Plant Protection Products authorization (Reg. 1107/2009 EC) explicitly requires the evaluation of the potential combined effects of active substances. We reviewed current methods and limitations of mixture assessment of pesticides (7 fungicides and 4 herbicides) through the analysis of the approaches adopted to investigate possible risks for different non-target organisms. The Concentration Addition (CA) approach was the most used approach to predict multiple toxicity to non-target organisms. The guidance for birds and mammals first introduced standard procedures to assess the multiple toxicity based on on CA concept. The recent aquatic EFSA guidance introduced some requirements to evaluate potential mixture toxicity, while the current guidance requirements for terrestrial organisms still lack clear indications on how to conduct the assessment. Moreover, new indications come from the draft guidance for the assessment of terrestrial plants and in-soil organisms. However, the approval and implementation of these new guidelines are still at a developmental stage. Some final considerations are drawn on the future possibilities to improve risk assessment procedures so as to identify harmful effects of pesticides mixtures on non-target organisms. PMID- 28012658 TI - Sorption of triclosan to carbon nanotubes: The combined effects of sonication, functionalization and solution chemistry. AB - The sonication effect on the sorption behavior of carbon nanotubes (CNTs) with different functional groups has been poorly understood in previous studies, especially when combined with solution chemistry that may affect both the sorption and dispersion of CNTs. Our results show that sonication accelerated sorption of triclosan and increased the sorption capacities of CNTs with and without functionalizations at a neutral pH. Regardless of how sonication on CNTs was applied, the sorption decreased in the following order: pristine CNTs>CNTs OH>CNTs-COOH. Sorption decreased with the increase of pH for all types of CNTs due to the electrostatic repulsion between triclosan and CNTs. The pH effect is greater for pristine CNTs than functionalized CNTs, while the sonication effect is greater for functionalized CNTs than pristine CNTs. Sonication increased sorption at a low pH (i.e., <9.5) but decreased sorption at a high pH (i.e., >9.5) for all types of CNTs, which may be due to the difference in the structure of CNTs at different pHs. Within 0.001-0.1M NaCl, sorption increased and then decreased for all types of CNTs with and without sonication, which can be explained by the balance between the salting-out effect and electrostatic screening effect. PMID- 28012659 TI - Heavy rainfall and risk of infectious intestinal diseases in the most populous city in Vietnam. AB - The association between heavy rainfall and infectious intestinal diseases (IID) has not been well described and little research has been conducted in developing countries. This study examines the association between heavy rainfall and hospital admissions for IID in Ho Chi Minh City, the most populous city in Vietnam. An interrupted time-series method was used to examine the effect of each individual heavy rainfall event (HRE) on IID. The percentage changes in post-HRE level and trends of IID were estimated for 30days following each HRE. Then a random-effect meta-analysis was used to quantify the pooled estimate of effect sizes of all HREs on IID. The pooled estimates were calculated over a 21day lag period. The effects of a HRE on IID varied across individual HREs. The pooled estimates indicate that the levels of IID following a HRE increased from 7.3% to 13.5% for lags from 0 to 21days, however statistically significant increases were only observed for lags from 4 to 6days (13.5%, 95%CI: 1.4-25.4; 13.3%, 95%CI: 1.5 25.0; and 12.9%, 95%CI: 1.6-24.1 respectively). An average decrease of 0.11% (95%CI: -0.55-0.33) per day was observed for the post-HRE trend. This finding has important implications for the projected impacts on residents living in this city which is highly vulnerable to increased heavy rainfall associated with climate change. Adaptation and intervention programs should be developed to prevent this additional burden of disease and to protect residents from the adverse impacts of extreme weather events. PMID- 28012660 TI - Including hydrological self-regulating processes in peatland models: Effects on peatmoss drought projections. AB - The water content of the topsoil is one of the key factors controlling biogeochemical processes, greenhouse gas emissions and biosphere - atmosphere interactions in many ecosystems, particularly in northern peatlands. In these wetland ecosystems, the water content of the photosynthetic active peatmoss layer is crucial for ecosystem functioning and carbon sequestration, and is sensitive to future shifts in rainfall and drought characteristics. Current peatland models differ in the degree in which hydrological feedbacks are included, but how this affects peatmoss drought projections is unknown. The aim of this paper was to systematically test whether the level of hydrological detail in models could bias projections of water content and drought stress for peatmoss in northern peatlands using downscaled projections for rainfall and potential evapotranspiration in the current (1991-2020) and future climate (2061-2090). We considered four model variants that either include or exclude moss (rain)water storage and peat volume change, as these are two central processes in the hydrological self-regulation of peatmoss carpets. Model performance was validated using field data of a peatland in northern Sweden. Including moss water storage as well as peat volume change resulted in a significant improvement of model performance, despite the extra parameters added. The best performance was achieved if both processes were included. Including moss water storage and peat volume change consistently reduced projected peatmoss drought frequency with >50%, relative to the model excluding both processes. Projected peatmoss drought frequency in the growing season was 17% smaller under future climate than current climate, but was unaffected by including the hydrological self-regulating processes. Our results suggest that ignoring these two fine-scale processes important in hydrological self-regulation of northern peatlands will have large consequences for projected climate change impact on ecosystem processes related to topsoil water content, such as greenhouse gas emissions. PMID- 28012661 TI - Off-site transport of nitrogen fertilizer with runoff from golf course fairway turf: A comparison of creeping bentgrass with a fine fescue mixture. AB - Maintaining quality golf course turf often requires irrigation and application of fertilizer. The transport of excess nutrients with runoff water from highly managed and fertilized biological systems to surrounding surface waters has been shown to result in enhanced algal blooms and promotion of eutrophication. Environmental stewardship includes looking for new approaches to reduce adverse environmental impacts of current practices. One strategy is to replace traditional turfgrass with low-maintenance turfgrass species. Fescue grasses have been shown to provide characteristics desirable for golf course fairways. Thus side-by-side studies comparing runoff from plots planted in creeping bentgrass (CGB) or fine fescue mixture (FFM), similarly managed as a golf course fairway, were conducted to measure runoff volumes and the amount of ammonium nitrogen (NH4 N) and nitrate nitrogen (NO3-N) transported off-site with runoff. Greater runoff volumes and mass of applied nutrients were measured in the runoff from the FFM, representing a 38% and 56% median increase in the off-site mass transport of NH4 N and NO3-N with surface flow. Shoot density, thatch depth and soil moisture were the most important factors related to runoff volume. Results of this research will be useful to grounds superintendents and researchers for selecting and developing management strategies to improve environmental stewardship of managed turf while providing desired turf quality. PMID- 28012662 TI - Editorial Comment. PMID- 28012664 TI - Multifractal behavior of an air pollutant time series and the relevance to the predictability. AB - Compared with the traditional method of detrended fluctuation analysis, which is used to characterize fractal scaling properties and long-range correlations, this research provides new insight into the multifractality and predictability of a nonstationary air pollutant time series using the methods of spectral analysis and multifractal detrended fluctuation analysis. First, the existence of a significant power-law behavior and long-range correlations for such series are verified. Then, by employing shuffling and surrogating procedures and estimating the scaling exponents, the major source of multifractality in these pollutant series is found to be the fat-tailed probability density function. Long-range correlations also partly contribute to the multifractal features. The relationship between the predictability of the pollutant time series and their multifractal nature is then investigated with extended analyses from the quantitative perspective, and it is found that the contribution of the multifractal strength of long-range correlations to the overall multifractal strength can affect the predictability of a pollutant series in a specific region to some extent. The findings of this comprehensive study can help to better understand the mechanisms governing the dynamics of air pollutant series and aid in performing better meteorological assessment and management. PMID- 28012663 TI - Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion. AB - BACKGROUND: Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative. OBJECTIVE: The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method. METHODS: The study evaluated 60 children with mild asthma aged 5 to 12 years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity. RESULTS: The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18 mm/wk (SD, 0.55 mm/wk) versus 0.45 mm/wk (SD, 0.39 mm/wk), with a mean difference of 0.27 mm/wk (95% CI, 0.05-0.48 mm/wk; P = .02). In contrast, there was no difference in 24-hour UFC excretion: 6.91 nmol/mmol (SD, 4.67 nmol/mmol) versus 7.58 nmol/mmol (SD, 6.17 nmol/mmol), with a mean difference of 0.67 nmol/mmol (95% CI, -1.13 to 2.48 nmol/mmol; P = .46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR. CONCLUSION: These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future. PMID- 28012665 TI - Development of an on-line source-tagged model for sulfate, nitrate and ammonium: A modeling study for highly polluted periods in Shanghai, China. AB - An on-line source-tagged model coupled with an air quality model (Nested Air Quality Prediction Model System, NAQPMS) was applied to estimate source contributions of primary and secondary sulfate, nitrate and ammonium (SNA) during a representative winter period in Shanghai. This source-tagged model system could simultaneously track spatial and temporal sources of SNA, which were apportioned to their respective primary precursors in a simulation run. The results indicate that in the study period, local emissions in Shanghai accounted for over 20% of SNA contributions and that Jiangsu and Shandong were the two major non-local sources. In particular, non-local emissions had higher contributions during recorded pollution periods. This suggests that the transportation of pollutants plays a key role in air pollution in Shanghai. The temporal contributions show that the emissions from the "current day" (emission contribution from the current day during which the model was simulating) contributed 60%-70% of the sulfate and ammonium concentrations but only 10%-20% of the nitrate concentration, while the previous days' contributions increased during the recorded pollution periods. Emissions that were released within three days contributed over 85% averagely for SNA in January 2013. To evaluate the source-tagged model system, the results were compared by sensitivity analysis (emission perturbation of -30%) and backward trajectory analysis. The consistency of the comparison results indicated that the source-tagged model system can track sources of SNA with reasonable accuracy. PMID- 28012666 TI - Ambient and laboratory evaluation of a low-cost particulate matter sensor. AB - Low-cost, light-scattering-based particulate matter (PM) sensors are becoming more widely available and are being increasingly deployed in ambient and indoor environments because of their low cost and ability to provide high spatial and temporal resolution PM information. Researchers have begun to evaluate some of these sensors under laboratory and environmental conditions. In this study, a low cost, particulate matter sensor (Plantower PMS 1003/3003) used by a community air quality network is evaluated in a controlled wind-tunnel environment and in the ambient environment during several winter-time, cold-pool events that are associated with high ambient levels of PM. In the wind-tunnel, the PMS sensor performance is compared to two research-grade, light-scattering instruments, and in the ambient tests, the sensor performance is compared to two federal equivalent (one tapered element oscillating microbalance and one beta attenuation monitor) and gravimetric federal reference methods (FEMs/FRMs) as well as one research-grade instrument (GRIMM). The PMS sensor response correlates well with research-grade instruments in the wind-tunnel tests, and its response is linear over the concentration range tested (200-850 MUg/m3). In the ambient tests, this PM sensor correlates better with gravimetric methods than previous studies with correlation coefficients of 0.88. However additional measurements under a variety of ambient conditions are needed. Although the PMS sensor correlated as well as the research-grade instrument to the FRM/FEMs in ambient conditions, its response varies with particle properties to a much greater degree than the research-grade instrument. In addition, the PMS sensors overestimate ambient PM concentrations and begin to exhibit a non-linear response when PM2.5 concentrations exceed 40 MUg/m3. These results have important implications for communicating results from low-cost sensor networks, and they highlight the importance of using an appropriate correction factor for the target environmental conditions if the user wants to compare the results to FEM/FRMs. PMID- 28012667 TI - Does long-term fungicide exposure affect the reproductive performance of leaf shredders? A partial life-cycle study using Hyalella azteca. AB - Leaf-shredding amphipods play a critical role in the ecosystem function of leaf litter breakdown, a key process in many low order streams. Fungicides, however, may adversely influence shredders' behavior and the functions they provide, while there is only limited knowledge concerning effects on their reproductive performance. To assess the latter, a semi-static 56-day partial life-cycle bioassay using the model shredder Hyalella azteca (n = 30) was performed applying two environmentally relevant concentrations of a model fungicide mixture (i.e., 5 and 25 MUg/L) composed of five fungicides with different modes of toxic action. Variables related to the food processing (leaf consumption and feces production), growth (body length and dry weight), energy reserves (lipid content), and reproduction (amplexus pairs, number and length of offspring) were determined to understand potential implications in the organisms' energy budget. While the fungicides did not affect leaf consumption, both fungicide treatments significantly reduced amphipods' feces production (~20%) compared to the control. This observation suggests an increased food utilization to counteract the elevated and stress-related energy demand: although growth as well as energy reserves were unaffected, amplexus pairs were less frequently observed in both fungicide treatments (~50-100%) suggesting a tradeoff regarding energy allocation favoring the maintenance of fundamental functions at the organism level over reproduction. As a result, the time to release of first offspring was delayed in both fungicide treatments (7 and 14 days) and the median number of offspring was significantly lower in the 25-MUg/L treatment (100%), whereas offspring length remained unaffected. The results of this study thus indicate that chronic fungicide exposures can negatively impact shredders' reproductive performance. This may translate into lower abundances and thus a reduced contribution to leaf litter breakdown in fungicide-impacted streams with potentially far-reaching consequences for detritus-based food webs. PMID- 28012668 TI - Diclofenac in Arabidopsis cells: Rapid formation of conjugates. AB - Pharmaceutical and personal care products (PPCPs) are continuously introduced into the soil-plant system, through practices such as agronomic use of reclaimed water and biosolids containing these trace contaminants. Plants may accumulate PPCPs from soil, serving as a conduit for human exposure. Metabolism likely controls the final accumulation of PPCPs in plants, but is in general poorly understood for emerging contaminants. In this study, we used diclofenac as a model compound, and employed 14C tracing, and time-of-flight (TOF) and triple quadruple (QqQ) mass spectrometers to unravel its metabolism pathways in Arabidopsis thaliana cells. We further validated the primary metabolites in Arabidopsis seedlings. Diclofenac was quickly taken up into A. thaliana cells. Phase I metabolism involved hydroxylation and successive oxidation and cyclization reactions. However, Phase I metabolites did not accumulate appreciably; they were instead rapidly conjugated with sulfate, glucose, and glutamic acid through Phase II metabolism. In particular, diclofenac parent was directly conjugated with glutamic acid, with acyl-glutamatyl-diclofenac accounting for >70% of the extractable metabolites after 120-h incubation. In addition, at the end of incubation, >40% of the spiked diclofenac was in the non extractable form, suggesting extensive sequestration into cell matter. The rapid formation of non-extractable residue and dominance of diclofenac-glutamate conjugate uncover previously unknown metabolism pathways for diclofenac. In particular, the rapid conjugation of parent highlights the need to consider conjugates of emerging contaminants in higher plants, and their biological activity and human health implications. PMID- 28012669 TI - Co-transport of chlordecone and sulfadiazine in the presence of functionalized multi-walled carbon nanotubes in soils. AB - Batch and saturated soil column experiments were conducted to investigate sorption and mobility of two 14C-labeled contaminants, the hydrophobic chlordecone (CLD) and the sulfadiazine (SDZ), in the absence or presence of functionalized multi-walled carbon nanotubes (MWCNTs). The transport behaviors of CLD, SDZ, and MWCNTs were studied at environmentally relevant concentrations (0.1 10 mg L-1) and they were applied in the column studies at different times. The breakthrough curves and retention profiles were simulated using a numerical model that accounted for the advective-dispersive transport of all compounds, attachment/detachment of MWCNTs, equilibrium and kinetic sorption of contaminants, and co-transport of contaminants with MWCNTs. The experimental results indicated that the presence of mobile MWCNTs facilitated remobilization of previously deposited CLD and its co-transport into deeper soil layers, while retained MWCNTs enhanced SDZ deposition in the topsoil layers due to the increased adsorption capacity of the soil. The modeling results then demonstrated that the mobility of engineered nanoparticles (ENPs) in the environment and the high affinity and entrapment of contaminants to ENPs were the main reasons for ENP-facilitated contaminant transport. On the other hand, immobile MWCNTs had a less significant impact on the contaminant transport, even though they were still able to enhance the adsorption capacity of the soil. PMID- 28012670 TI - Perfluoroalkyl acids and their precursors in indoor air sampled in children's bedrooms. AB - The contamination levels and patterns of perfluoroalkyl acids (PFAAs) and their precursors in indoor air of children's bedrooms in Finland, Northern Europe, were investigated. Our study is among the most comprehensive indoor air monitoring studies (n = 57) and to our knowledge the first one to analyse air in children's bedrooms for PFASs (17 PFAAs and 9 precursors, including two acrylates, 6:2 FTAC and 6:2 FTMAC). The most frequently detected compound was 8:2 fluorotelomer alcohol (8:2 FTOH) with the highest median concentration (3570 pg/m3). FTOH concentrations were generally similar to previous studies, indicating that in 2014/2015 the impact of the industrial transition had been minor on FTOH levels in indoor air. However, in contrast to earlier studies (with one exception), median concentrations of 6:2 FTOH were higher than 10:2 FTOH. The C8 PFAAs are still the most abundant acids, even though they have now been phased out by major manufacturers. The mean concentrations of FOSE/As, especially MeFOSE (89.9 pg/m3), were at least an order of magnitude lower compared to previous studies. Collectively the comparison of FTOHs, PFAAs and FOSE/FOSAs with previous studies indicates that indoor air levels of PFASs display a time lag to changes in production of several years. This is the first indoor air study investigating 6:2 FTMAC, which was frequently detected (58%) and displayed some of the highest maximum concentrations (13 000 pg/m3). There were several statistically significant correlations between particular house and room characteristics and PFAS concentrations, most interestingly higher EtFOSE air concentrations in rooms with plastic floors compared to wood or laminate. PMID- 28012671 TI - Occurrence and inputs of perfluoroalkyl substances (PFASs) from rivers and drain outlets to the Bohai Sea, China. AB - Concentrations of 19 PFASs in riverwater, coastal wastewater and effluents from WWTPs which were directly discharged into the Bohai Sea of China were measured and their inputs to this sea area were calculated accordingly. For riverwater samples, the total PFAS concentrations ranged from 13.1 to 69 238 ng/L. PFAS levels in riverwater collected from Liaoning Province were comparable to those from Shandong Province, while they were two orders of magnitude greater than those from Hebei Province and the city of Tianjin. The dominant PFAS patterns were spatially different. PFBS and PFOA were the predominant PFASs in riverwater samples at sites where fluorochemical industry parks are located in Liaoning Province and Shandong Province, respectively. For other sites, PFOA and PFOS were the most abundant PFASs. In contrast, the total PFAS concentrations in coastal wastewater and effluent samples ranged from 16.7 to 7 522 ng/L and from 13.1 to 319 ng/L, respectively. PFOA was dominant in these samples. Inputs of PFASs to the Bohai Sea via riverine flow, discharge of coastal wastewater and effluents were estimated to be 87.3 tons per year. As compared with coastal wastewater and effluent discharge, riverine input was a major source for the PFAS pollution in the Bohai Sea except for PFBS. PMID- 28012672 TI - Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity. AB - Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-GloTM CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC50 ranging from 9.34 MUM to 79.85 MUM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC50 of 0.81 MUM, 0.93 MUM, 1.27 MUM, 2.22 MUM, and 2.74 MUM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated (R2 between 0.83 and 0.97, p < 0.001). Our results indicated that the risk assessment of triazole pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s. PMID- 28012673 TI - Characteristics of cadmium uptake and membrane transport in roots of intact wheat (Triticum aestivum L.) seedlings. AB - Wheat is one of several cereals that is capable of accumulating higher amounts of Cd in plant tissues. It is important to understand the Cd2+ transport processes in roots that result in excess Cd accumulation. Traditional destructive technologies have limited capabilities in analyzing root samples due to methodological limitations, and sometimes may result in false conclusions. The mechanisms of Cd2+ uptake into the roots of wheat seedlings (Triticum aestivum L.) were investigated by assessing the impact of various inhibitors and channel blockers on Cd accumulation as well as the real-time net Cd2+ flux at roots with the non-destructive scanning ion-selective electrode technique. The P-type ATPase inhibitor Na3VO4 (500 MUM) had little effect on Cd uptake (p < 0.05) and the kinetics of transport in the root of wheat, suggesting that Cd2+ uptake into wheat root cells is not directly dependent on H+ gradients. While, the uncoupler 2,4-dinitrophenol significantly limited Cd2+ uptake (p < 0.05) and transport kinetics in the root of wheat, suggesting the existence of metabolic mediation in the Cd2+ uptake process by wheat. The Cd content at the whole-plant level in wheat was significantly (p < 0.05) decreased upon pretreatment with the Ca2+ channel blockers La3+ or Gd3+ and Verapamil, but not in case of pretreatment with the K+ channel blocker tetraethylammonium (TEA). In addition, the inhibitors of the Ca2+ channel, as well as high concentrations of Ca2+, reduced the real-time net Cd2+ fluxes at the root surface in SIET experiments. These results indicate that Cd2+ moves across the plasma lemma of the wheat root via Ca2+ channels. In addition, our results suggested a role for protein synthesis in mediating Cd2+ uptake and transport by wheat. PMID- 28012674 TI - Impact of occult hepatitis B on the clinical outcomes of patients with chronic hepatitis C virus infection: A 10-year follow-up. AB - BACKGROUND/PURPOSE: Occult hepatitis B infection (OHB) is not rare in countries that are endemic for hepatitis B virus (HBV) and in patients with chronic hepatitis C virus (HCV) infection. Notably, OHB has been shown to play a role in the progression of liver diseases, including the development of hepatocellular carcinoma (HCC); however, the data is inconsistent. We aim to clarify the contribution of concurrent OHB to the progression of liver diseases in a long term cohort of patients with HCV infection and to investigate the value of total anti-hepatitis B core (anti-HBc) antibody as a surrogate OHB biomarker. METHODS: We included 250 chronic anti-HCV-positive patients who had resolved HBV infection (anti-HBc positive and hepatitis B surface antigen negative). OHB was then detected using a sensitive commercial assay for serum HBV DNA with a low limit of detection of 6 IU/mL. Clinical outcomes, including the development of liver cirrhosis, HCC, and all-cause deaths, were compared between OHB-positive and OHB negative patients. RESULTS: At baseline, only 183 (73.20%) patients had positive HCV ribonucleic acid, and 56 (30.60%) of these 183 patients with active HCV infection had OHB. The presence of OHB did not correlate with any adverse clinical outcome in multivariate analyses. In addition, chronic hepatitis C patients with OHB did not have a higher level of serum total anti-HBc. CONCLUSION: OHB infection may not contribute to the development of adverse liver outcomes in patients with chronic HCV. PMID- 28012675 TI - Saccadic entropy of head impulses in acute unilateral vestibular loss. AB - BACKGROUND/PURPOSE: To evaluate the complexity of vestibular-ocular reflex (VOR) in patients with acute unilateral vestibular loss (AUVL) via entropy analysis of head impulses. METHODS: Horizontal head impulse test (HIT) with high-velocity alternating directions was used to evaluate 12 participants with AUVL and 16 healthy volunteers. Wireless electro-oculography and electronic gyrometry were used to acquire eye positional signals and head velocity signals. The eye velocity signals were then obtained through differentiation, band-pass filtering. The approximate entropy of eye velocity to head velocity (RApEn) was used to evaluate chaos property. VOR gain, gain asymmetry ratio, and RApEn asymmetry ratio were also used to compare the groups. RESULTS: For the lesion-side HIT of the patient group, the mean VOR gain was significantly lower and the mean RApEn was significantly greater compared with both nonlesion-side HIT and healthy controls (p < 0.01, one-way analysis of variance). Both the RApEn asymmetry ratio and gain asymmetry ratio of the AUVL group were significantly greater compared with those of the control group (p < 0.05, independent sample t test). CONCLUSION: Entropy and gain analysis of HIT using wireless electro-oculography system could be used to detect the VOR dysfunctions of AUVL and may become effective methods for evaluating vestibular disorders. PMID- 28012676 TI - Residents' perception of duty hour limits through teaching hospital accreditation status-experience in Taiwan. AB - Residents' work overload is a rising issue in Taiwan. Duty hours of the residents in the United States have been limited by the Accreditation Council for Graduate Medical Education Common Program Requirements since 2003; similar standards were not implemented in Taiwan until 2013. Taiwanese duty hour standards are the work hour limits adopted as part of the required teaching hospital accreditation status. In January 2015, the Ministry of Health and Welfare conducted a national survey for all house officers in Taiwan. We collected data including those on demographics and perceptions of residents regarding duty hour limits. Most respondents reported positive perceptions of the duty hour standards. They felt that these limits will improve resident education, quality of life, and patient safety. The strong incentive to follow the regulations (through teaching hospital accreditation) could help protect residents (and patients) from unsafe working conditions. However, further studies on the influence of shortened duty hour on professional development are necessary for future improvement. PMID- 28012677 TI - A noninterventional observational registry of patients with multiple myeloma treated with lenalidomide in Taiwan. AB - BACKGROUND/PURPOSE: The incidence of multiple myeloma in Asia has risen in the past 30 years. Lenalidomide, an IMiD immunomodulatory agent, has improved the overall survival in patients with relapsed/refractory multiple myeloma (RRMM) when used with dexamethasone versus dexamethasone alone. This observational registry (T-CC-MM-009; NCT01752075) assessed the safety and efficacy of lenalidomide plus dexamethasone in a large Chinese population of patients with RRMM. METHODS: This registry followed the first 100 patients treated with lenalidomide plus dexamethasone in Taiwan. Patients were >=18 years old and had >=1 prior treatment. The recommended starting dose for the first four 28-day cycles was 25 mg lenalidomide on days 1-21 and 40 mg dexamethasone on days 1-4, 9 12, and 17-20. Thereafter, dexamethasone was given on days 1-4 only. The primary objective was safety; secondary objectives were efficacy, lenalidomide dosage, and reasons for discontinuation. RESULTS: The median duration of treatment was 34.6 weeks, and 75.5% completed >=3 cycles. Most patients (82.7%) experienced >=1 treatment-related adverse event; the most commonly reported were neutropenia (23.5%), thrombocytopenia (19.4%), anemia (16.3%), fatigue (16.3%), and hypoesthesia (15.3%). Bleeding events (25.5% of patients) were mostly grade 1/2 (80%). Three patients (3%) had venous thromboembolic events. Two invasive second primary malignancies were reported; however, time to onset was <1 year, suggesting they may not be related to lenalidomide. The overall response rate was 34.7%; median time to disease progression was 20.5 months. CONCLUSION: These data confirm the safety and efficacy of lenalidomide plus dexamethasone for patients with RRMM in Taiwan. PMID- 28012678 TI - End-of-life parental communication priorities among bereaved fathers due to cancer. AB - OBJECTIVES: To elicit widowed fathers' perspectives on which domains of parenting related communication they consider most important for dying parents to discuss at the end of life (EOL). METHODS: Two hundred seventy nine fathers widowed by cancer completed a survey about their own depression and bereavement symptoms, their wife's illness, and EOL parental communication priorities. Chi square and Fisher's exact tests and logistic regression were used to evaluate relationships between maternal EOL characteristics and fathers' responses to parenting-related EOL communication priorities. RESULTS: Fathers identified raising children in a manner that reflected maternal wishes, whether/how to talk with children about their mother's death, and how the mother wanted to be remembered as the most important EOL communication domains. Fathers who reported that their dying wives were worried about the children were more likely to prioritize raising children in ways that reflect her wishes (p=0.01). Other EOL characteristics were not associated with communication domains. CONCLUSIONS: Communicating with children and maintaining emotional connection with the deceased parent are important priorities for bereaved fathers who lost a spouse to cancer. PRACTICE IMPLICATIONS: Health care providers working with seriously ill parents may improve family outcomes by supporting communication at the EOL between co parents. PMID- 28012679 TI - How does decision complexity affect shared decision making? An analysis of patient-provider antiretroviral initiation dialogue. AB - OBJECTIVES: This study analyzed patient-provider dialogue regarding anti retroviral therapy (ART) initiation, assessing the degree to which shared decision making (SDM) occurred. METHODS: We analyzed 24 audio-recorded dialogues between 14 HIV providers and their patients regarding ART initiation. We coded transcribed dialogues for seven SDM elements. We stratified dialogues into three levels of decision complexity (basic, intermediate, complex) based on patient CD4 counts and evaluated SDM criteria fulfillment at each level of decision complexity. RESULTS: There were five basic, twelve intermediate, and seven complex decisions in our sample. While only two met the defined criteria for SDM, the mean number of SDM elements present increased with each level of decision complexity. Discussion of the clinical issue requiring the decision occurred most frequently (88%), while discussion of pros/cons (13%), patient's understanding (21%), and decision alternatives (29%) occurred least frequently. CONCLUSION/PRACTICE IMPLICATIONS: While few dialogues met the defined SDM criteria, providers are having conversations that respond to decision complexity. Clinicians should be aware that discussion of pros/cons, alternatives, and uncertainties are frequently skipped, even when these elements are clearly relevant, as in complex decisions. In addition, rhetorical questions to assess patient preferences and understanding are insufficient to fully engage patients in SDM. PMID- 28012681 TI - Navigating the Journey from Medical School Classroom to Third Year Clerkship. PMID- 28012680 TI - Knowledge, attitudes, and beliefs related to hypertension and hyperlipidemia self management among African-American men living in the southeastern United States. AB - OBJECTIVE: Perceptions of illness affect cardiovascular disease (CVD) self management. This study explores knowledge, attitudes, and beliefs regarding hypertension and hyperlipidemia management among 34 African-American men with hypertension and/or hyperlipidemia, age 40-65, living in the Southeastern United States. METHODS: In-person focus groups were conducted using semi-structured interview questions informed by the Health Belief Model (HBM). RESULTS: Participants had a high level of knowledge about hypertension self-management, but less about cholesterol self-management. Perceived severity of both conditions was acknowledged, though participants perceived hypertension as more severe. Barriers to self-management included medication side effects and unhealthy dietary patterns. Facilitators included social support, positive healthcare experiences, and the value placed on family. Cultural implications highlighted the importance of food in daily life and social settings. Participants expressed how notions of masculinity affected self-management-noting the impact of feelings of vulnerability and perceived lack of control stemming from diagnosis and treatment expectations. CONCLUSIONS: The findings highlight gaps in knowledge of hyperlipidemia versus hypertension, and the impact of cultural context and perceptions on engagement in self-management behaviors. PRACTICE IMPLICATIONS: Public health practitioners and healthcare providers serving African-American men should address cultural factors and notions of masculinity which can hinder effective disease management among this population. PMID- 28012682 TI - Disclosing genetic risk of Alzheimer's disease to cognitively impaired patients and visit companions: Findings from the REVEAL Study. AB - OBJECTIVE: To describe the impact of genetic information on Alzheimer's disease (AD) risk communication to patients with mild cognitive impairment (MCI) and their visit companions. METHODS: Participants of the fourth REVEAL Study trial were randomized to receive AD risk assessments with or without genotype results. We coded 79 audio recorded risk disclosure sessions with the Roter Interaction Analysis System. Multilevel analyses explored differences in communication when disclosed risks were based on age and MCI diagnosis alone or in addition to APOE genotype status. RESULTS: The addition of genotype results diminished the patient centered nature of the sessions (p<0.001). When epsilon4 positive relative to epsilon4 negative results were disclosed, visit companions were more verbally active (p<0.05), disclosed more medical information (p<0.05), were more positive verbally and non-verbally (p<0.05) and were more proactive in setting the visit agenda (p<0.05). CONCLUSIONS: Delivery of complex genetic risk information reduces the patient-centeredness of disclosure sessions. Visit companions are more actively engaged in session communication when patients are at increased genetic risk for AD. PRACTICE IMPLICATIONS: AD risk discussions can be improved by supporting the positive role of visit companions and addressing the challenges inherent in the delivery of complex genetic information in a patient-centered manner. PMID- 28012683 TI - Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC producing Klebsiella pneumoniae? AB - The effect of real-time pharmacokinetic/pharmacodynamic (PK/PD) optimisation of high-dose continuous-infusion meropenem on the clinical outcome of patients receiving combination antimicrobial therapy for treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections was retrospectively assessed. Data for all patients with KPC-Kp-related infections who received antimicrobial combination therapy containing high-dose continuous-infusion meropenem optimised by means of therapeutic drug monitoring (TDM) were retrieved. Optimal PK/PD exposure was considered a steady-state concentration to minimum inhibitory concentration ratio (Css/MIC) of 1-4. Univariate binary logistic regression analysis was performed to identify independent predictors of clinical outcome. Among the 30 eligible patients, 53.3% had infections caused by meropenem resistant KPC-Kp (MIC >= 16 mg/L). Tigecycline and colistin were the two antimicrobials most frequently combined with meropenem. Mean doses of continuous infusion meropenem ranged from 1.7 to 13.2 g/daily. The Css/MIC ratio was >=1 in 73.3% of cases and >=4 in 50.0%. Clinical outcome was successful in 73.3% of cases after a median treatment length of 14.0 days. In univariate analysis, a significant correlation with successful clinical outcome was found for a Css/MIC ratio >=1 (OR = 10.556, 95% CI 1.612-69.122; P = 0.014), a Css/MIC ratio >=4 (OR = 12.250, 95% CI 1.268-118.361; P = 0.030) and a Charlson co-morbidity index of >=4 (OR = 0.158, 95% CI 0.025-0.999; P = 0.05). High-dose continuous-infusion meropenem optimised by means of real-time TDM may represent a valuable tool in improving clinical outcome when dealing with the treatment of infections caused by KPC-Kp with a meropenem MIC <= 64 mg/L. PMID- 28012684 TI - Bioavailability of voriconazole in hospitalised patients. AB - An important element in antimicrobial stewardship programmes is early switch from intravenous (i.v.) to oral antimicrobial treatment, especially for highly bioavailable drugs. The antifungal agent voriconazole is available both in i.v. and oral formulations and bioavailability is estimated to be >90% in healthy volunteers, making this drug a suitable candidate for such a transition. Recently, two studies have shown that the bioavailability of voriconazole is substantially lower in patients. However, for both studies various factors that could influence the voriconazole serum concentration, such as inflammation, concomitant intake of food with oral voriconazole, and gastrointestinal complications, were not included in the evaluation. Therefore, in this study a retrospective chart review was performed in adult patients treated with both oral and i.v. voriconazole at the same dose and within a limited (<=5 days) time interval in order to evaluate the effect of switching the route of administration on voriconazole serum concentrations. A total of 13 patients were included. The mean voriconazole trough concentration was 2.28 mg/L [95% confidence interval (CI) 1.29-3.26 mg/L] for i.v. voriconazole administration and 2.04 mg/L (95% CI 0.78-3.30 mg/L) for oral administration. No significant difference was found in the mean oral and i.v. trough concentrations of voriconazole (P = 0.390). The mean bioavailability was 83.0% (95% CI 59.0-107.0%). These findings suggest that factors other than bioavailability may cause the observed difference in voriconazole trough concentrations between oral and i.v. administration in the earlier studies and stress the need for an antimicrobial stewardship team to guide voriconazole dosing. PMID- 28012685 TI - pncA mutations are associated with slower sputum conversion during standard treatment of multidrug-resistant tuberculosis. AB - Despite the strong association between drug resistance and genetic mutations, the value of molecular diagnosis of drug resistance to guide the treatment of multidrug-resistant tuberculosis (MDR-TB) remains unclear. This is particularly relevant in resource-limited areas where it is difficult to perform drug susceptibility testing (DST). Here we investigated the association between drug susceptibility phenotypes and genotypes and treatment outcomes in patients with MDR-TB. This study enrolled 74 consecutive patients with confirmed MDR-TB between 2010 and 2011, and outcomes were followed-up over the 24-month treatment course. All of the isolates were tested for phenotypic susceptibility to second-line drugs using the Mycobacteria Growth Indicator Tube (MGIT)-based system, and genotypic mutations were assessed by DNA sequencing. Among the 74 MDR-TB isolates, 29 (39.2%) were resistant to fluoroquinolones and/or second-line injectable drugs, of which 21 (72.4%) harboured a mutation in drug resistance related genes (gyrA, rrs or eis). In addition, 32 individuals (43.2%) also had pyrazinamide (PZA)-resistant isolates, with 28 (87.5%) containing the pncA mutation. By backward selection in the multivariate logistic regression and Cox proportional hazard models, PZA resistance and its related pncA gene mutation demonstrated a correlation with a lower likelihood of culture conversion at 8 weeks and treatment success. Meanwhile, the fluoroquinolone resistance-related gyrA gene mutation was negatively correlated with treatment success. DST for PZA and fluoroquinolones together with genetic information appears to provide a clinically useful indicator of the treatment outcome of MDR-TB in China. PMID- 28012686 TI - Practical synthesis of capromorelin, a growth hormone secretagogue, via a crystallization-induced dynamic resolution. AB - A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (+/-)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3 c]pyridin-3(3aH)-one [(+/-)-2] by L-tartaric acid salt formation, yielding (R) 2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of ~98%. Treatment of (R)-2.L-tartaric acid with ammonium hydroxide provided (R)-2 without loss of chiral purity. In situ generated (R)-2 was coupled with (R) 3-(benzyloxy)-2-(2-(tert-butoxycarbonyl)-2-methylpropanamido)propanoic acid [(R) 3] to give predominantly a single diastereomer of N-Boc-protected capromorelin [(1R,3aR)-4]. This process was used to prepare bulk quantities of capromorelin from (+/-)-2 to support preclinical toxicology studies. PMID- 28012687 TI - Assessing the Risk of Antibiotic Resistance Transmission from the Environment to Humans: Non-Direct Proportionality between Abundance and Risk. AB - The past decade has witnessed a burst of study regarding antibiotic resistance in the environment, mainly in areas under anthropogenic influence. Therefore, impacts of the contaminant resistome, that is, those related to human activities, are now recognized. However, a key issue refers to the risk of transmission of resistance to humans, for which a quantitative model is urgently needed. This opinion paper makes an overview of some risk-determinant variables and raises questions regarding research needs. A major conclusion is that the risks of transmission of antibiotic resistance from the environment to humans must be managed under the precautionary principle, because it may be too late to act if we wait until we have concrete risk values. PMID- 28012688 TI - Darwin's Body-Snatchers? AB - For decades creationists have claimed that Charles Darwin sought the skulls of full-blooded Aboriginal Tasmanian people when only four were left alive. It is said that Darwin letters survive which reveal this startling and distasteful truth. Tracing these claims back to their origins, however, reveals a different, if not unfamiliar story. PMID- 28012689 TI - Oncofertility for women with gynecologic malignancies. AB - The emerging field of oncofertility addresses fertility and the reproductive health needs for cancer patients, a key topic in cancer survivorship. Given that the standard treatment for gynecologic malignancies involves removal of reproductive organs, pelvic radiation, or chemotherapy, the effect of such treatment on fertility and options for fertility preservation are even more relevant than for other malignancies. In young women with new diagnoses of cervical, endometrial, or ovarian cancers, viable strategies for fertility preservation without compromising oncological outcome exist and should be considered. We present here a comprehensive review of the literature as it pertains to gynecologic malignancies on 1) the effects of radiation and chemotherapy on fertility, 2) fertility-sparing surgeries and the role of assisted reproductive technology, and 3) fertility preservation in adolescent girls and women with BRCA germline mutations. PMID- 28012690 TI - Embolization for Bleeding after Hepatic Radiofrequency Ablation. AB - PURPOSE: To evaluate safety and clinical efficacy of embolization for management of bleeding after hepatic radiofrequency (RF) ablation. MATERIALS AND METHODS: From January 2000 to December 2014, 5,196 patients with 9,743 tumors underwent 8,303 RF ablation sessions. Of these patients, 62 experienced bleeding after hepatic RF ablation; 15 patients (12 men and 3 women; mean age 62 y; range, 49-76 y) underwent embolization and composed the final study cohort. Tumors were hepatocellular carcinomas in 13 (87%) patients and metastatic adenocarcinomas from colorectal cancer in 2 (13%) patients. Mean number of tumors was 1.5 (22 nodules; range, 1-3). Tumor locations were segment I (n = 1), segment II (n = 2), segment III (n = 1), segment IV (n = 1), segment V (n = 3), segment VI (n = 5), segment VII (n = 1), and segment VIII (n = 9). Mean tumor size was 2.3 cm (range, 0.9-5 cm). RESULTS: Median time interval between presentation and angiography was 22 hours (mean 38.4 h; range, 3-168 h). On angiography, contrast extravasation with or without pseudoaneurysm was seen in all 15 patients; 14 patients underwent transarterial embolization, and 1 patient underwent percutaneous transhepatic portal vein embolization. Successful hemostasis was achieved in all patients. There was no rebleeding within 30 days after embolization. No embolization related major complications were observed. CONCLUSIONS: Embolization is safe and effective for controlling bleeding related to hepatic RF ablation without the need for surgery. PMID- 28012691 TI - Multicentre survey on the current surgical management of oesophageal atresia in Belgium and Luxembourg. AB - INTRODUCTION: The surgical management of oesophageal atresia (OA) differs between pediatric surgical teams without consensus. We aimed to describe the current practice of OA treatment in Belgium and Luxembourg and compare this to the literature. MATERIALS AND METHODS: A questionnaire was created and sent to all 18 hospitals (14 pediatric surgical units) performing OA surgery in Belgium and Luxembourg. The results were compared to the literature. RESULTS: Most units treat an average of 2-5 OA+TOF (71%) and <=1 pure OA (pOA) per year (86%). The preferred surgical approach for OA+TOF is thoracotomy (86%), mostly extra-pleural (75%). Thoracoscopic OA repair is performed in 21%. All centers perform an end-to end anastomosis (interrupted sutures), and all leave a transanastomotic tube. A chest drain is routinely used in 8units (57%). In pOA the preferred surgical approach is gastrostomy formation with delayed primary anastomosis (77%). The timing for delayed anastomosis is 2 to 24months. Intra-operative lengthening is mostly attempted with Foker technique (46%). If oesophageal replacement is needed, gastric interposition is mostly used (75%). A postoperative contrast study is routinely performed in 86% for OA+TOF and in 100% for pOA. Anti-reflux medication is routinely prescribed by all units but one. CONCLUSION: There are still many differences and controversies in the perioperative management of OA. Part of this is based on habits and is difficult to change without scientific evidence. There is a need for prospective (inter)national registries to further identify the existing differences, leading to a more widely accepted consensus. LEVEL OF EVIDENCE: Level III. PMID- 28012692 TI - Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: Two randomized, controlled, crossover intervention trials. AB - BACKGROUND & AIMS: Polyphenol intake has been linked to improvements in human vascular function, although data on hydroxycinnamates, such as chlorogenic acid (CGA) have not yet been studied. We aimed to investigate the impact of coffee intake rich in chlorogenic acid on human vascular function and whether CGAs are involved in potential effects. METHODS: Two acute randomized, controlled, cross over human intervention trials were conducted. The impact of coffee intake, matched for caffeine but differing in CGA content (89, and 310 mg) on flow mediated dilatation (FMD) was assessed in 15 healthy male subjects. In a second intervention trial conducted with 24 healthy male subjects, the impact of pure 5 caffeoylquinic acid (5-CQA), the main CGA in coffee (5-CQA; 450 mg and 900 mg) on FMD was also investigated. RESULTS: We observed a bi-phasic FMD response after low and high polyphenol, (89 mg and 310 mg CGA) intake, with increases at 1 (1.10 +/- 0.43% and 1.34 +/- 0.62%, respectively) and 5 (0.79% +/- 0.32 and 1.52% +/- 0.40, respectively) hours post coffee consumption. FMD responses to coffee intake was closely paralleled by the appearance of CGA metabolites in plasma, notably 3 , 4- and 5-feruloylquinic acid and ferulic-4'-O-sulfate at 1 h and isoferulic-3' O-glucuronide and ferulic-4'-O-sulfate at 5 h. Intervention with purified 5-CQA (450 mg) also led to an improvement in FMD response relative to control (0.75 +/- 1.31% at 1 h post intervention, p = 0.06) and concomitant appearance of plasma metabolites. CONCLUSIONS: Coffee intake acutely improves human vascular function, an effect, in part, mediated by 5-CQA and its physiological metabolites. STUDY REGISTRATION: The National Institutes of Health (NIH) on ClinicalTrials.govNCT01813981 and NCT01772784. PMID- 28012693 TI - Tumoral calcinosis of the cervical spine in a dialysis patient. Case report and review of the literature. AB - The authors present a case of tumoral calcinosis (TC) in a patient with chronic renal insufficiency. The clinical course, imaging features and microscopic findings are detailed. A 60-year-old woman with a 4-year history of hemodialysis presented with a painful mass in the right posterior cervical triangle. The neuroimaging revealed polycystic mass bulging from the C3-C5 facet joints and lamina on the right. The majority of cystic mass was excised and microscopic features of the specimen were consistent with TC. Tumoral calcinosis is a rare disease characterized by calcium salt deposits in periarticular soft tissue, which enlarge to form tumor-like cystic masses containing chalky calcareous material. TC is typically seen around large joints but rarely in the spine. Review of past publications provided six cases of TC involving the spine in dialyzed patients. PMID- 28012695 TI - Birth Weight for Gestational Age, Anthropometric Measures, and Cardiovascular Disease Markers in Children. AB - OBJECTIVE: To examine the association of birth weight for gestational age with anthropometric measures and cardiometabolic markers in a population-based sample of Canadian children. STUDY DESIGN: The study used data from 2016 children aged 6 12 years from the first 2 cycles of the Canadian Health Measures Survey, a population-based survey of Canadian residents. The main exposure was birth weight for gestational age (small [SGA], large [LGA], and appropriate for gestational age [AGA]). The outcomes were anthropometric measures, blood pressure, and laboratory cardiovascular disease markers. The association between the exposure and the outcomes was examined using multiple regression. Analyses were weighted to account for the complex sampling design and for nonresponse. RESULTS: SGA infants had lower and LGA infants had higher z scores for anthropometric measures compared with the AGA group but most differences were not statistically significant. There were no differences between the SGA or LGA infants and the AGA group in blood pressure or individual cardiometabolic markers but SGA infants were significantly less likely to have elevated levels of 3 or more components of the metabolic syndrome compared with their AGA peers. CONCLUSIONS: Former SGA and LGA infants have lower (SGA) and higher (LGA) body mass index and waist circumference, respectively, than their AGA peers. The known long-term increased cardiovascular disease risk among SGA or LGA infants was not reflected in the blood pressure and laboratory measurements at age 6-12 years. PMID- 28012694 TI - Antibiotic Use in Children - A Cross-National Analysis of 6 Countries. AB - OBJECTIVES: To describe the rates of pediatric antibiotic use across 6 countries on 3 continents. STUDY DESIGN: Cross-national analysis of 7 pediatric cohorts in 6 countries (Germany, Italy, South Korea, Norway, Spain, and the US) was performed for 2008-2012. Antibiotic dispensings were identified and grouped into subclasses. We calculated the rates of antimicrobial prescriptions per person year specific to each age group, comparing the rates across different countries. RESULTS: A total of 74 744 302 person-years from all participating centers were included in this analysis. Infants in South Korea had the highest rate of antimicrobial consumption, with 3.41 prescribed courses per child-year during the first 2 years of life. This compares with 1.6 in Lazio, Italy; 1.4 in Pedianet, Italy; 1.5 in Spain; 1.1 in the US; 1.0 in Germany; and 0.5 courses per child year in Norway. Of antimicrobial prescriptions written in Norway, 64.8% were for first-line penicillins, compared with 38.2% in Germany, 31.8% in the US, 27.7% in Spain, 25.1% in the Italian Pedianet population, 9.8% in South Korea, and 8% in the Italian Lazio population. CONCLUSIONS: We found substantial differences of up to 7.5-fold in pediatric antimicrobial use across several industrialized countries from Europe, Asia, and North America. These data reinforce the need to develop strategies to decrease the unnecessary use of antimicrobial agents. PMID- 28012696 TI - Postoperative myocardial infarction after acute type A dissection: Another day, another database? PMID- 28012698 TI - Deep brain stimulation for cerebral palsy and the international classification of function. PMID- 28012697 TI - The host defense peptide LL-37 a possible inducer of the type I interferon system in patients with polymyositis and dermatomyositis. AB - The type I interferon (IFN) system has recently been suggested to play important and essential roles in the pathogenesis of myositis. However, a clarification of how type I IFNs could function as triggering factor(s) in the pathogenesis of myositis has yet failed. Through activation of the type I IFN system, the host defense peptide LL-37 carries numerous immunomodulatory properties and is implicated in the pathogenesis of several other autoimmune diseases, including systemic lupus erythematosus (SLE). The expression of LL-37 can be regulated by various endogenous factors including the active form of vitamin D (25(OH)D3). The aim of this study was to explore a potential role of LL-37 in relation to the type I IFN system in patients with polymyositis (PM) and dermatomyositis (DM) and to compare these with SLE patients and healthy controls. We investigated muscle (3 PM, 5 DM) and symptomatic (5 DM) and non-symptomatic (3 PM, 3 DM) skin biopsies from patients with short disease duration and muscle biopsies (3 PM, 1 DM) from patients with long disease duration. Six SLE patients with symptomatic and non-symptomatic skin and five muscle and six skin biopsies from healthy individuals served as controls. Tissue specimens were immunohistochemically stained for LL-37, neutrophils (CD66b), plasmacytoid dendritic cells (BDCA-2), myxovirus resistance protein A (MxA), and macrophages (CD68, CD163). In addition, LL-37 and CD66b double staining was also performed. Serum levels of 25(OH)D3 were investigated in PM and DM patients with short disease duration (3 PM, 5 DM) and in 40 healthy controls. We found that the expression of LL-37, BDCA-2 (the major producer of type I IFNs), MxA (an interferon-inducible protein), and macrophages were higher in muscle tissue of PM and DM patients compared to healthy controls. The LL-37 expression was mainly derived from neutrophils. Neutrophils were increased in both symptomatic and non-symptomatic skin of myositis and SLE patients and BDCA-2 was increased in symptomatic DM skin when compared to healthy controls. Moreover, the expression of MxA in symptomatic and non-symptomatic skin of SLE patients was higher when compared to both myositis patients and healthy controls. There was no difference in the expression of LL-37 in skin of myositis and SLE patients compared to healthy controls. All PM and DM patients with a short disease duration had low 25(OH)D3 levels compared to healthy controls. In conclusion, the present study supports our hypothesis that LL-37 may activate type I IFNs, which could initiate and perpetuate an inflammatory process. The prolonged exposure of the immune system to type I IFNs may eventually break tolerance and lead to autoimmune myositis. PMID- 28012699 TI - Fear of fear, severe tics and deep brain stimulation in childhood Tourette Syndrome: The long and winding road. PMID- 28012700 TI - Heat Shock Proteins and Cancer. AB - Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significant role in cellular proliferation, differentiation, and carcinogenesis. In this article we comprehensively review the roles of major HSPs in cancer biology and pharmacology. HSPs are thought to play significant roles in the molecular mechanisms leading to cancer development and metastasis. HSPs may also have potential clinical uses as biomarkers for cancer diagnosis, for assessing disease progression, or as therapeutic targets for cancer therapy. PMID- 28012701 TI - Assessment of the liver and spleen in children with Gaucher disease type I with diffusion-weighted MR imaging. AB - PURPOSE: To assess hepatic and splenic apparent diffusion coefficient (ADC) in children with Gaucher disease type I with diffusion-weighted MR imaging and to correlate hepatic and splenic ADC with parameters of disease severity. SUBJECTS AND METHODS: Prospective study was conducted upon 25 children (11 treated and 14 untreated) with Gaucher disease and 12 age and sex matched control children. They underwent diffusion-weighted MR imaging of abdomen. Hepatic and splenic ADC and volume were calculated. RESULTS: There was statistically difference in hepatic and splenic apparent diffusion coefficient (P=0.001) between patients and controls. The cutoff ADC of liver and spleen used to differentiate patients from controls were 0.47 and 0.39*10-3mm2 with area and curve of 0.947 and 0.886 respectively. There was significant difference in hepatic and splenic ADC between untreated and treated patients (P=0.003 and 0.001). Hepatic ADC correlated with splenic volume (r=-0.721), hepatic volume (r=-0.555) and chitotriosidase (r= 0.413). Splenic ADC correlated with splenic volume (r=-0.652), hepatic volume (r= 0.544) and chitotriosidase (r=-0.355). CONCLUSION: Hepatic and splenic ADC can detect hepatic and splenic infiltration in Gaucher disease and correlated with some parameters of disease severity. PMID- 28012702 TI - Author's response Re: Bringing women into the spotlight: The impact of preoperative anemia in gynecological surgery. PMID- 28012703 TI - Physicochemical characterization and immunological properties of Pichia pastoris based HPV16L1 and 18L1 virus like particles. AB - There continues to be an urgent need for cost-effective prophylaxis for HPV associated cancers in socio-economically underdeveloped nations. Presently HPV vaccines, which are commercially available, are adjuvanted virus-like particles (VLPs) expressed from various recombinant expression systems. They have been characterized by different methods as safe, pure, and potent HPV vaccine antigens. We cloned and expressed L1 proteins of HPV16 & 18 in Pichia pastoris and tested their immunogenicity. We observed that HPVL1 proteins (16L1 and 18L1) are expressed in Pichia pastoris at high levels. Critical physicochemical parameters of these HPV recombinant L1 proteins were characterized by SDS PAGE, western blotting, peptide mapping, glycosylation pattern, mass spectrometry, host cell DNA and protein analysis, electron microscopy, and immunogenicity analysis. These data establish a blueprint of HPV recombinant protein antigens for standardizing & developing an alternative high-quality, cost-effective vaccine for HPV as well as similar recombinant protein-based vaccines. PMID- 28012704 TI - Tomosynthesis: A new radiologic technique for rapid diagnosis of scaphoid fractures. AB - Scaphoid fractures constitute 71% of all carpal bone fractures.1 Early diagnosis and treatment has significant bearing on fracture union rates and better clinical outcomes. While displaced fractures can be readily seen on plain radiograph, undisplaced fractures can require advanced imaging modalities to confirm that diagnosis. Advanced imaging such as Magnetic Resonance Imaging (MRI), Computerised tomography (CT) and bone scintigraphy are routinely used for the diagnosis of scaphoid fractures but require significant radiation exposure, increased cost and can be difficult to access.2 Tomosynthesis is an emerging imaging modality which uses conventional x-ray systems to produce cross-sectional images. There has yet to be extensive research carried out investigating the diagnostic value of tomosynthesis in scaphoid fractures. The aim of this study is to optimise patient positioning for the diagnosis of scaphoid fractures in a cadaveric model and compare the diagnostic yield of tomography to conventional CT. Using four cadaveric specimens, three limb positions were examined in unfractured and fractured scaphoids to determine the optimal limb positions required for visualisation of the scaphoid. As a result of this study, the optimal position for visualisation of the scaphoid and diagnosis of scaphoid fractures has been determined. The results demonstrate that tomosynthesis is as effective as CT scanning in identifying scaphoid fractures in both sensitivity and specificity. By comparison to CT, tomosynthesis is cheaper, has lower radiation exposure, requires fewer hospital resources and can be performed quickly. Tomosynthesis is a valid diagnostic tool for the diagnosis of scaphoid fractures. PMID- 28012705 TI - Methodology for analyzing environmental quality indicators in a dynamic operating room environment. AB - BACKGROUND: Sufficient quantities of quality air and controlled, unidirectional flow are important elements in providing a safe building environment for operating rooms. METHODS: To make dynamic assessments of an operating room environment, a validated method of testing the multiple factors influencing the air quality in health care settings needed to be constructed. These include the following: temperature, humidity, particle load, number of microbial contaminants, pressurization, air velocity, and air distribution. The team developed the name environmental quality indicators (EQIs) to describe the overall air quality based on the actual measurements of these properties taken during the mock surgical procedures. These indicators were measured at 3 different hospitals during mock surgical procedures to simulate actual operating room conditions. EQIs included microbial assessments at the operating table and the back instrument table and real-time analysis of particle counts at 9 different defined locations in the operating suites. Air velocities were measured at the face of the supply diffusers, at the sterile field, at the back table, and at a return grille. RESULTS: The testing protocol provided consistent and comparable measurements of air quality indicators between institutions. At 20 air changes per hour (ACH), and an average temperature of 66.3 degrees F, the median of the microbial contaminants for the 3 operating room sites ranged from 3-22 colony forming units (CFU)/m3 at the sterile field and 5-27 CFU/m3 at the back table. At 20 ACH, the median levels of the 0.5-um particles at the 3 sites were 85,079, 85,325, and 912,232 in particles per cubic meter, with a predictable increase in particle load in the non-high-efficiency particulate air-filtered operating room site. Using a comparison with cleanroom standards, the microbial and particle counts in all 3 operating rooms were equivalent to International Organization for Standardization classifications 7 and 8 during the mock surgical procedures. CONCLUSIONS: The EQI protocol was measurable and repeatable and therefore can be safely used to evaluate air quality within the health care environment to provide guidance for operational practices and regulatory requirements. PMID- 28012706 TI - Anything goes? Regulation of the neural processes underlying response inhibition in TBI patients. AB - Despite evidence for beneficial use of methylphenidate in response inhibition, no studies so far have investigated the effects of this drug in the neurobiology of inhibitory control in traumatic brain injury (TBI), even though impulsive behaviours are frequently reported in this patient group. We investigated the neural basis of response inhibition in a group of TBI patients using functional magnetic resonance imaging and a stop-signal paradigm. In a randomised double blinded crossover study, the patients received either a single 30mg dose of methylphenidate or placebo and performed the stop-signal task. Activation in the right inferior frontal gyrus (RIFG), an area associated with response inhibition, was significantly lower in patients compared to healthy controls. Poor response inhibition in this group was associated with greater connectivity between the RIFG and a set of regions considered to be part of the default mode network (DMN), a finding that suggests the interplay between DMN and frontal executive networks maybe compromised. A single dose of methylphenidate rendered activity and connectivity profiles of the patients RIFG near normal. The results of this study indicate that the neural circuitry involved in response inhibition in TBI patients may be partially restored with methylphenidate. Given the known mechanisms of action of methylphenidate, the effect we observed may be due to increased dopamine and noradrenaline levels. PMID- 28012707 TI - Effectiveness of ureteroscopy among the youngest patients: One centre's experience in an endemic region in Turkey. AB - BACKGROUND: In recent years, the incidence of urinary stone disease reportedly has been increasing. The use of shockwave lithotripsy has seen low success rates, the inefficacy of a single session, and the need for general anaesthesia in children; additionally, children are exposed to radiation. These suboptimal treatment conditions have all led to ureteroscopy (URS) becoming the treatment method of choice for paediatric ureter stones. The aim of this study is to examine the effectiveness of 4.5-Fr URS when used on children younger than 1 year of age. PATIENTS AND METHODS: The operation results of 34 patients (12 girls and 22 boys) who had undergone intervention for ureter stones at our clinic were retrospectively evaluated. For URS, a 4.5-Fr semi-rigid ureteroscope was used; a Holmium:YAG laser machine was used as a lithotripter. RESULT: The mean patient age was 9.6 months (range 4-12 months) (Table). The mean stone surface area was 25.39 mm2 (range 11.84-84.78 mm2). In six cases, a ureteral catheter was inserted, because of minimal oedema in the ureters; in nine cases, a Double J (DJ) stent was inserted. The mean operation time was 45.3 min (range 22-87 min). In the first week of control with urinary ultrasonography and kidney-ureter and bladder radiograph, a stone-free condition was determined in 28 (82.3%) patients. In two cases-in which sufficient fragmentation could not be achieved, because of minimal bleeding during operation-during the exertion of a DJ stent, another URS was performed. In the first postoperative month, a stone-free condition was established in 32 (94.1%) patients. The mean hospital stay period was 28.6 h (range 12-72 h). There were seven cases (20.5%) with Clavien II-III complications. CONCLUSION: Use of a ureteroscope is safe and effective with paediatric patients: we found that a 4.5-Fr ureteroscope can be safely used on children under 1 year of age. We therefore consider a 4.5-Fr ureteroscopic instrument to be an appropriate tool for treating URS in children within this age range. PMID- 28012709 TI - The History and Challenges of Blood Donor Screening in China. AB - Since the establishment of People's Republic of China in 1949, the Chinese government has encountered several catastrophes related to transfusion transmitted diseases. The government's increasing attention to blood safety has prompted the initiation of a series of policies and measures that have enhanced the level of safety for the blood supply and met the basic clinical demands of blood for 1.3 billion people in the country. Blood donation screening strategies in China predominantly comprise donor screening and donor testing. Donor screening includes selection of low-risk blood donors by the use of a donor history questionnaire, predonation physical examination, and initial rapid donor testing. Donor testing includes direct pathogen detection and serology tests. The year 1998 marked the most transformative change in blood donor selection and screening policies in China. Before 1998, paid donation was the predominant mode of blood donation. Donor screening and donor testing were conducted before donation, and only those who were eligible were allowed to donate. To ensure the safety of blood, donor testing was performed again after donation. After the implementation of the Blood Donation Law in 1998, to promote voluntary and unpaid donation, predonation donor testing was eliminated to reduce the amount of waiting time and to provide a more convenient donation experience for blood donors. However, it is the national requirement that donated blood should undergo 2 rounds of testing using different equipment or reagents, conducted by different personnel. Donor selection has transitioned from paid donation and obligatory donation to voluntary donation with fixed volunteer groups, as the latter mode of donation provides the lowest risks. Donations are currently screened for syphilis, hepatitis C virus, HIV, and hepatitis B virus (HBV). Units, previously typed only for ABO, are now routinely tested for both ABO and Rh(D). Innovations in testing technologies and methods have also brought changes to screening parameters. For instance, screening for HBV pathogens evolved from the early use of hemagglutination method to the later use of radioimmunoassay, independent enzyme-linked immunosorbent assay, and now the widespread application of nucleic acid test (NAT). Since 2010, the Chinese government has established NAT capacity in several blood centers; and in 2015, the government invested 900 million RMB on the nationwide expansion of NAT. Although the Chinese government has worked to enhance blood safety, many challenges remain. Concern exists for rising rates of HIV infection. The existence of occult HBV infection and the transmission of emerging blood-borne diseases continue to challenge the safety of the blood supply. PMID- 28012708 TI - Secondary Motor Cortex: Where 'Sensory' Meets 'Motor' in the Rodent Frontal Cortex. AB - In rodents, the medial aspect of the secondary motor cortex (M2) is known by other names, including medial agranular cortex (AGm), medial precentral cortex (PrCm), and frontal orienting field (FOF). As a subdivision of the medial prefrontal cortex (mPFC), M2 can be defined by a distinct set of afferent and efferent connections, microstimulation responses, and lesion outcomes. However, the behavioral role of M2 remains mysterious. Here, we focus on evidence from rodent studies, highlighting recent findings of early and context-dependent choice-related activity in M2 during voluntary behavior. Based on the current understanding, we suggest that a major function for M2 is to flexibly map antecedent signals such as sensory cues to motor actions, thereby enabling adaptive choice behavior. PMID- 28012710 TI - Potential anticancer activity of lichen secondary metabolite physodic acid. AB - Secondary metabolites present in lichens, which comprise aliphatic, cycloaliphatic, aromatic and terpenic compounds, are unique with respect to those of higher plants and show interesting biological and pharmacological activities. However, only a few of these compounds, have been assessed for their effectiveness against various in vitro cancer models. In the present study, we investigated the cytotoxicity of three lichen secondary metabolites (atranorin, gyrophoric acid and physodic acid) on A375 melanoma cancer cell line. The tested compounds arise from different lichen species collected in different areas of Continental and Antarctic Chile. The obtained results confirm the major efficiency of depsidones. In fact, depsides atranorin and gyrophoric acid, showed a lower activity inhibiting the melanoma cancer cells only at more high concentrations. Whereas the depsidone physodic acid, showed a dose-response relationship in the range of 6.25-50 MUM concentrations in A375 cells, activating an apoptotic process, that probably involves the reduction of Hsp70 expression. Although the molecular mechanism, by which apoptosis is induced by physodic acid remains unclear, and of course further studies are needed, the results here reported confirm the promising biological properties of depsidone compounds, and may offer a further impulse to the development of analogues with more powerful efficiency against melanoma cells. PMID- 28012711 TI - HIV Prevention Advice for People With Serious Mental Illness: Cochrane Nursing Care Field - Cochrane Review Summary. PMID- 28012712 TI - Unintended Consequences of Adjusting Citalopram Prescriptions Following the 2011 FDA Warning. AB - OBJECTIVES: In 2011, the U.S. Food and Drug Administration (FDA) issued a safety announcement cautioning providers against prescribing citalopram above 40 mg per day given concerns for QT prolongation. We assessed the impact of a health system quality improvement initiative to identify patients taking higher than the recommended dose of citalopram. DESIGN: Retrospective cohort study. SETTING: Nine primary care clinics within the University of Michigan from March 2012 to February 2013. PARTICIPANTS: Adult patients taking a higher-than-recommended dose of citalopram following the FDA warning in 2011 (N = 199). MEASUREMENTS: Frequency of EKG monitoring, clinical factors associated with patients whose citalopram dose or use was adjusted, and potential impact of these changes on overall health care utilization was assessed. RESULTS: In patients prescribed higher-than-recommended doses of citalopram and who received a note from a pharmacist regarding the FDA warnings, only 8.5% received electrocardiogram (EKG) monitoring. Patients who were converted to an alternative antidepressant from citalopram were more likely to receive subsequent new prescriptions for benzodiazepines and sedative hypnotics (chi2 = 7.9, p = 0.048). Patients who had any adjustments to their antidepressant medication had greater overall health care utilization (OR: 25.0; 95% CI: 5.7-109.6; p < 0.001) than patients remaining on the same dose of citalopram. CONCLUSIONS: Despite a targeted quality intervention to address the FDA warning regarding citalopram, the warning was associated with low levels of EKG monitoring, increased anxiolytic and sedative medication use, and higher healthcare utilization. This finding may represent destabilization of patients on previously therapeutic doses of their antidepressant and an unintended consequence of the FDA warning. PMID- 28012713 TI - Accurate Quantification of T Cells by Measuring Loss of Germline T-Cell Receptor Loci with Generic Single Duplex Droplet Digital PCR Assays. AB - Quantifying T cells accurately in a variety of tissues of benign, inflammatory, or malignant origin can be of great importance in a variety of clinical applications. Flow cytometry and immunohistochemistry are considered to be gold standard methods for T-cell quantification. However, these methods require fresh, frozen, or fixated cells and tissue of a certain quality. In addition, conventional and droplet digital PCR (ddPCR), whether followed by deep sequencing techniques, have been used to elucidate T-cell content by focusing on rearranged T-cell receptor (TCR) genes. These approaches typically target the whole TCR repertoire, thereby supplying additional information about TCR use. We alternatively developed and validated two novel generic single duplex ddPCR assays to quantify T cells accurately by measuring loss of specific germline TCR loci and compared them with flow cytometry-based quantification. These assays target sequences between the Ddelta2 and Ddelta3 genes (TRD locus) and Dbeta1 and Jbeta1.1 genes (TRB locus) that become deleted systematically early during lymphoid differentiation. Because these ddPCR assays require small amounts of DNA instead of freshly isolated, frozen, or fixated material, initially unanalyzable (scarce) specimens can be assayed from now on, supplying valuable information about T-cell content. Our ddPCR method provides a novel and sensitive way for quantifying T cells relatively fast, accurate, and independent of the cellular context. PMID- 28012714 TI - Erratum to "Prevalence of driving under the influence of psychoactive substances and road traffic crashes among Brazilian crack-using drivers" [Drug Alcohol Depend. 168 (2016) 255-262]. PMID- 28012715 TI - Hospital costs of complications after esophagectomy for cancer. AB - OBJECTIVE: The purpose of this study was to estimate the economic burden of postoperative complications after esophagectomy for cancer, in order to optimally allocate resources for quality improvement initiatives in the future. METHODS: A retrospective analysis of prospectively collected clinical and financial outcomes after esophageal cancer surgery in a tertiary referral center in the Netherlands was performed. Data was extracted from consecutive patients registered in the Dutch Upper GI Cancer Audit between 2011 and 2014 (n = 201). Costs were measured up to 90-days after hospital discharge and based on Time-Driven Activity-Based Costing. The additional costs were estimated using multiple linear regression models. RESULTS: The average total cost for one patient after esophagectomy was ?37,581 (+/-31,372). The estimated costs of an esophagectomy without complications were ?23,476 (+/-6496). Mean costs after minor (47%) and severe complications (29%) were ?31,529 (+/-23,359) and ?59,167 (+/-42,615) (p < 0.001), respectively. The 5% most expensive patients were responsible for 20.3% of the total hospital costs assessed in this study. Patient characteristics associated with additional costs in multivariable analysis included, age >70 (+?2,922, p = 0.036), female gender (+?4,357, p = 0.005), COPD (+?5,415, p = 0.002), and a history of thromboembolic events (+?6,213, p = 0.028). Complications associated with a significant increase in costs in multivariable analysis included anastomotic leakage (+?4,123, p = 0.008), cardiac complications (+?5,711, p = 0.003), chyle leakage (+?6,188, p < 0.001) and postoperative bleeding (+?31,567, p < 0.001). CONCLUSIONS: Complications and severity of complications after esophageal surgery are associated with a substantial increase in costs. Although not all postoperative complications can be prevented, implementation of preventive measures to reduce complications could result in a considerable cost reduction and quality improvement. PMID- 28012716 TI - Jennifer Keiser - Tackling Drug Resistance before It Arises. PMID- 28012717 TI - Schistosoma hemozoin and its possible roles. AB - More than 95years ago Schistosoma pigment had been deemed as a degradation product of haemoglobin. Until the 1950s, scientists initiated to pay attention to understand the hematophagous habit of schistosomes, and to study the degradation of haemoglobin as well as the formation of hemozoin inside the gut of the worms. For a long time, the formation of hemozoin in both Plasmodium and in Schistosoma was considered to be the major route of heme detoxification, and hemozoin served a role in waste disposal. At the beginning of this century, the chemical structure of Schistosoma pigment was confirmed to be identical to that of malarial pigment (hemozoin) and its synthetic analogue, beta-hematin. Since then, studies on Schistosoma hemozoin have been investigated by some workers and the results showed that Schistosoma hemozoin may play important roles in pathogenicity, immune modulation, iron supply for egg formation, and interaction with some anti-schistosomal drugs. In this review, we briefly review and discuss the hematophagous habit of schistosomes, degradation of haemoglobin, formation of hemozoin in the worm gut, and possible roles of hemozoin. PMID- 28012718 TI - Skin-Resident Effector Memory CD8+CD28- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis. AB - Loss of CD28 expression by CD8+ T cells occurs with age and during chronic inflammatory conditions. CD8+CD28- T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8+CD28- T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8+CD28 T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8+CD28- T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8+CD28- T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8+CD28- T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease. PMID- 28012719 TI - Cysteamine supplementation revealed detrimental effect on cryosurvival of buffalo sperm based on computer-assisted semen analysis and oxidative parameters. AB - The aim of this study was to investigate the effect of addition of cysteamine to the semen extender on post-thaw semen quality. A total of 30 ejaculates were collected from six bulls. Each ejaculate was divided into five equal parts and diluted to final concentration of 80 million sperms/mL using Optixcell(r)(IMV, France) semen extender supplemented with different concentrations of cysteamine (0, 0.75, 1.25, 2.5 and 5mM) and cryopreserved. In the frozen-thawed samples, the VAP, VSL, VCL ALH and sperm motility of control samples was greater (P<0.05) than cysteamine treated samples. The sperm abnormality and malondialdehyde (MDA) concentration were found highest in 5mM cysteamine treated samples. The cysteamine treated samples travelled significantly less distance in cervical mucus as compared to control. Further, cysteamine decreased acrosomal integrity of sperm. In incubation test, control samples showed better sperm motility as compared to treatment groups. Further, cysteamine supplementation decreased the total antioxidants and increased the MDA concentration of sperm. From the study, we hypothesized that cysteamine cannot stimulate synthesis of glutathione (GSH) intracellularly in sperm to combat free radicals because during the maturation, sperm lost its cytoplasm which is necessary for biochemical reaction in which cysteamine reacts with cystine to form a mixed disulfide which taken up by cells and split into cysteine in the cytoplasm. Synthesis of GSH depends on the availability of cysteine. In conclusion, the results of our study strongly emphasize that cysteamine would not be a suitable additive in extender for freezing buffalo bull semen. PMID- 28012720 TI - Pelvic Tilt Evaluation From Frontal Radiographs: The Validity, Interobserver Reliability and Intraobserver Reproducibility of the Sacro-Femoral-Pubic Parameter. AB - BACKGROUND: The sacro-femoral-pubic (SFP) parameter, calculated using the SFP angle measured on a frontal pelvis radiograph, has previously been shown to have a strong correlation with sagittal pelvic tilt (PT) measured on a lateral x-ray. The purpose of this study is to assess the validity, interobserver reliability and intraobserver reproducibility of the SFP parameter in predicting the sagittal PT. METHODS: This is a retrospective study of 100 patients with frontal and lateral radiographs of the pelvis. Two observers independently measured the SFP angle on frontal x-ray (midpoint of S1 end plate to centroid of acetabula to upper midpoint of the pubic symphysis) and PT on lateral x-ray (midpoint of sacral plate to the centroid of acetabula to vertical plane). The SFP parameter was defined using the equation: SFP parameter = 75 - SFP angle. The interobserver reliability and intraobserver reproducibility were calculated using interclass correlation coefficient (ICC). Validity of the SFP parameter was calculated using Pearson correlation coefficient. RESULTS: The intraobserver reproducibility of the SFP parameter was excellent (ICC >0.90) for both observers. The interobserver reliability of all measurements was substantial for the SFP parameter (ICC >0.80) and PT (ICC >0.70). The concurrent validity of the SFP parameter was substantial (r = 0.70). CONCLUSION: Calculating PT from a frontal radiograph using the equation for the SFP parameter is a valid, reliable, and reproducible formula that may be used to predict sagittal PT. PMID- 28012721 TI - The Clinical Severity of Patients Diagnosed With an In-Hospital Pulmonary Embolism Following Modern, Elective Joint Arthroplasty Is Unrelated to the Location of Emboli in the Pulmonary Vasculature. AB - BACKGROUND: In the event of a postoperative pulmonary embolism (PE), it is generally believed that patients with centrally located emboli will have worse clinical symptoms than those with segmental or subsegmental ones. We studied if a relationship exists between the clinical severity at the time of PE diagnosis and the location of the emboli within the pulmonary vasculature. METHODS: All 269 patients who developed an in-hospital, computed tomography pulmonary angiography proved, PE following elective total hip arthroplasty or total knee arthroplasty in our institution were studied. The clinical severity of the PE was calculated using the Pulmonary Embolism Severity Index (PESI) that classifies patients in 5 classes (class 5: most severe). All computed tomography pulmonary angiographies were re-reviewed to determine the location of the emboli within the pulmonary vasculature (central, segmental, or subsegmental-unilateral or bilateral). The association between PESI and the PE location was examined. RESULTS: The most proximal location of the emboli was central in 62, segmental in 139, and subsegmental in 68. There were 180 unilateral and 89 bilateral PE patients. There was no association between the PESI and the location of the emboli within the pulmonary vasculature (P = .32). Patients with bilateral or unilateral lung involvement had similar PESI (P = .78). CONCLUSION: The PESI, a recognized, validated predictor of mortality after PE was similar in patients with central, segmental, or subsegmental PE; and in patients with unilateral or bilateral lung involvement. The present study may aid clinicians while assessing and discussing the severity of PE symptoms with patients at the time of diagnosis. PMID- 28012722 TI - Femoral Implant Design Modification Decreases the Incidence of Patellar Crepitus in Total Knee Arthroplasty. AB - BACKGROUND: Patellar crepitus is a complication most commonly seen in patients implanted with a posterior-stabilized total knee arthroplasty (TKA). Recently, design changes in the patellofemoral geometry and the intercondylar box ratio have been optimized in newer TKA designs. A comparative study was performed to analyze the incidence of patellar crepitus between a historical vs modern TKA design. METHODS: A retrospective review of all patients at our institution that underwent a primary TKA with either a PFC Sigma or Attune posterior-stabilized TKA (DePuy, Inc, Warsaw, IN), with a minimum of 1-year follow-up duration was performed. A total of 1165 participants implanted with the PFC Sigma and 728 with the Attune design were analyzed. Patellar crepitus incidence, functional scores, and range of motion were recorded at each follow-up appointment. Statistical analyses were performed between the 2 groups to determine if there were differences in clinical outcomes. RESULTS: The incidence of crepitus in participants implanted with the Attune was 0.55% vs 6.26% in the PFC Sigma cohort (P < .001) at 1 year vs. 0.83% vs 9.4%, respectively at 2 years post operatively (P < .001). There were small differences in extension, flexion, and Knee Society Scores between the 2 groups that were not clinically meaningful. CONCLUSION: The Attune posterior-stabilized TKA demonstrated substantially less patellofemoral crepitus incidence than the historical control. We hypothesize that these findings are related to femoral component changes including a thinner and narrower anterior flange and a reduced femoral intercondylar box ratio. PMID- 28012723 TI - Incidence of Ceramic Liner Malseating After Ceramic-on-Ceramic Total Hip Arthroplasty Associated With Osteolysis: A 5- to 15-Year Follow-Up Study. AB - BACKGROUND: The aim of our study was to evaluate the clinical and radiographic outcomes of malseating of the acetabular liner in ceramic-on-ceramic total hip arthroplasty (THA). METHODS: Outcomes for 160 ceramic-on-ceramic THAs, contributed by 116 women and 39 men, were evaluated. Clinical and radiographic measurements were obtained over a 5- to 15-year follow-up for analysis. RESULTS: Liner malseating was identified in 20% of cases. Outcomes for 32 cases with liner malseating (group A) were compared to outcomes for 128 joints with correct liner seating (group B). The Harris hip score at the last follow-up was 90.1 for group A and 89.6 for group B. Osteolysis was identified in 5 cases in group A (15.6%), compared to 3 cases in group B (P < .001). No significant between-group differences were identified with regard to ceramic fracture, audible squeaking, loosening of components, and revision THA. The mean annual liner wear rate was comparable between groups, 0.0045 mm/y for group A and 0.0039 mm/y for group B. The 10-year Kaplan-Meier survivorship, based on an end point of revision THA, was 100% for group A and 99.0% for group B. CONCLUSION: Over a moderate-length follow up of 5-15 years, malseating of the acetabular liner was not associated with negative clinical outcomes or THA survivorship. Malseating did increase the incidence of osteolysis, a risk factor for adverse effects. Long-term follow-up studies are needed to fully quantify the effects of malseating of the acetabular liner. PMID- 28012724 TI - The Evaluation of Comorbidities Relative to Length of Stay for Total Joint Arthroplasty Patients. AB - BACKGROUND: The ability to identify those at risk for longer inpatient stay helps providers with postoperative planning and patient expectations. Decreasing length of stay (LOS) in the future will be determined by appropriate patient selection, risk stratification, and preoperative patient optimization. The purpose of this study was to identify factors that place patients at risk for extended postoperative LOSs. METHODS: The study cohort included 2009 primary total knee arthroplasty (TKA) patients and 905 total hip arthroplasty (THA) patients. Patient comorbidities were prospectively identified and the LOS for each patient was tracked after a primary arthroplasty. Statistical analysis was performed to correlate which comorbidities were associated with longer inpatient stays. RESULTS: In the TKA population, gender, smoking status, venous thromboembolism history, body mass index, and diabetes status were not found to be a significant predictor for the LOS. Age was found to be a factor in univariate regression testing (P < .001). In the THA population, univariate testing showed female gender (P < .001), smoking status (P = .002), and age (P < .001) to be factors, but like the TKA population, venous thromboembolism history or diabetes status was not significant. In THA multivariate analysis, age (P < .001) and female gender (P = .018) continued to be factors, but smoking was determined to be a confounding variable. CONCLUSION: Age and gender were associated with a longer LOS after THA, whereas only age was a significant factor after TKA. Development of age-adjusted LOS models may help aid patient expectations and risk management. PMID- 28012725 TI - The Pressure Recording Analytical Method (PRAM): Technical Concepts and Literature Review. PMID- 28012726 TI - Treatment of Vasoplegic Syndrome With Intravenous Hydroxocobalamin During Liver Transplantation. PMID- 28012727 TI - Diagnosis of gynecological pseudoaneurysms and embolization with cyanoacrylate. AB - Pseudoaneurysms of the uterine artery are an uncommon cause of severe gynecological bleeding secondary to surgical manipulation of the pelvis or to instrumental delivery. The different imaging techniques are of vital importance in the diagnosis. Angiography is the technique used for confirmation and also for treatment in many cases. Endovascular treatment by embolizing the pseudoaneurysm has become established as the treatment of choice, making it possible to avoid hysterectomy in women of childbearing age. This article presents two cases of gynecological bleeding due to pseudoaneurysms (one secondary to surgery and one secondary to childbirth) that were embolized in a novel way using cyanoacrylate. PMID- 28012728 TI - Magnetic resonance imaging in the new paradigm for the diagnosis of prostate cancer. AB - For various reasons, prostate cancer is a major public health problem. It is a very common cancer, but has a very low mortality rate because it comprises two types of disease: one insignificant, indolent, and much more common, and the other aggressive, significant, and much less common. The routine diagnostic approach to prostate cancer has been systematic blind biopsies, which has low detection rates and might detect low risk, insignificant prostate cancer, leading to overdiagnosis and overtreatment of indolent cancers. The possibility of including multiparametric magnetic resonance imaging in the diagnostic management to improve the detection of aggressive cancer while reducing the overdiagnosis of indolent cancer represents a change in the diagnostic management. This article updates knowledge about the diagnostic management of prostate cancer including multiparametric magnetic resonance imaging. PMID- 28012729 TI - Neurologic emergencies in HIV-negative immunosuppressed patients. AB - HIV-negative immunosuppressed patients comprise a heterogeneous group including transplant patients, patients undergoing treatment with immunosuppressors, uremic patients, alcoholics, undernourished patients, diabetics, patients on dialysis, elderly patients, and those diagnosed with severe or neoplastic processes. Epileptic seizures, focal neurologic signs, and meningoencephalitis are neurologic syndromes that require urgent action. In most of these situations, neuroimaging tests are necessary, but the findings can be different from those observed in immunocompetent patients in function of the inflammatory response. Infectious disease is the first diagnostic suspicion, and the identification of an opportunistic pathogen should be oriented in function of the type and degree of immunosuppression. Other neurologic emergencies include ischemic stroke, cerebral hemorrhage, neoplastic processes, and pharmacological neurotoxicity. This article reviews the role of neuroimaging in HIV-negative immunodepressed patients with a neurologic complication that requires urgent management. PMID- 28012730 TI - Magnetic resonance imaging of the prostate: interpretation using the PI-RADS V2. AB - OBJECTIVE: Version 2 of the Prostate Imaging and Reporting and Data System (PI RADS) was developed to help in the detection, location, and characterization of prostate cancer with magnetic resonance imaging (MRI). Its recommendations for standardizing image acquisition parameters aims to reduce variability in the interpretation of MRI studies of the prostate; this approach, together with structured reporting, has the added value of improving communication among radiologists and between radiologists and urologists. This article aims to explain the PI-RADS v2 classification in a simple way, using illustrative images for each of the categories, as well as to recommend the use of a standard technique that helps ensure the reproducibility of multiparametric MRI. CONCLUSION: The PI-RADS v2 is simple to appy when reading multiparametric MRI studies of the prostate. It is important for radiologists doing prostate imaging to use the PI-RADS v2 in daily practice to write clear and concise reports that improve communication between radiologists and urologists. PMID- 28012731 TI - Another stage of development: Biological degeneracy and the study of bodily ageing. AB - Ageing is a poorly understood process of human development mired by a scientific approach that struggles to piece together distributed variable factors involved in ongoing transformations of living systems. Reconfiguring existing research paradigms, we review the concept of 'degeneracy', which has divergent popular and technical definitions. The technical meaning of degeneracy refers to the structural diversity underlying functional plasticity. Degeneracy is a distributed system property that can be observed within individual brains or across different brains. For example, dementias with similar behavioural anomalies can result from a diverse range of cellular "faults", which is an example of degeneracy because the symptoms are similar in spite of different underlying mechanisms. Degeneracy is a valuable epistemological tool that can transformatively enhance scientific models of bodily ageing. We propose that movement science is one of the first areas that can productively integrate degeneracy into models of bodily ageing. We also propose model organisms such as eusocial honey bees in which degeneracy can be studied at the molecular and cellular level. Developing a vocabulary for thinking about how distributed variable factors are interlinked is important if we are to understand bodily ageing not as a single entity, but as the heterogeneous construction of changing biological, social, and environmental processes. PMID- 28012732 TI - GABAergic control of neostriatal dopamine D2 receptor binding and behaviors in the rat. AB - PURPOSE: The present study assessed the influence of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline on neostriatal dopamine D2 receptor binding in relation to motor and exploratory behaviors in the rat. METHODS: D2 receptor binding was measured in baseline and after challenge with either 1mg/kg muscimol or 1mg/kg bicuculline. In additional rats, D2 receptor binding was measured after injection of saline. After treatment with muscimol, bicuculline and saline, motor and exploratory behaviors were assessed for 30min in an open field prior to administration of [123I]S-3-iodo-N-(1-ethyl-2 pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([123I]IBZM). For baseline and challenges, striatal equilibrium ratios (V3") were computed as estimation of the binding potential. RESULTS: Muscimol but not bicuculline reduced D2 receptor binding relative to baseline and to saline. Travelled distance, duration of rearing and frequency of rearing and of head-shoulder motility were lower after muscimol compared to saline. In contrast, duration of rearing and grooming and frequency of rearing, head-shoulder motility and grooming were elevated after bicuculline relative to saline. Moreover, bicuculline decreased duration of sitting and head-shoulder motility. CONCLUSIONS: The muscimol-induced decrease of motor/exploratory behaviors can be related to an elevation of striatal dopamine levels. In contrast, bicuculline is likely to elicit a decline of synaptic dopamine, which, however, is compensated by the time of D2 receptor imaging studies. The results indicate direct GABAergic control over D2 receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies. PMID- 28012733 TI - Feeding behaviour of a serpulid polychaete: Turning a nuisance species into a natural resource to counter algal blooms? AB - Occurrence of algal blooms in coastal waters is predicted to be more prevalent in future. To minimize their occurrence, manipulating the grazing pressure by suspension feeders is a potential management strategy, but its effectiveness may depend on their feeding preference. Therefore, we assessed the clearance rate of a widespread serpulid polychaete Hydroides elegans in larval and adult stages on various coastal phytoplankton. Additionally, the growth and development of H. elegans after consuming these phytoplankton were determined to reflect its sustainability to counter algal blooms. Results showed that H. elegans can consume and utilize different phytoplankton, except diatom Thalassiosira pseudonana, for growth and development in both life stages. Given the fast colonizing ability which allows easy manipulation of abundance, H. elegans is considered practically and biologically ideal for tackling algal blooms. Other suspension feeders with different feeding niches could be used in combination to maximize the versatility of the top-down control. PMID- 28012734 TI - Baseline aquatic contamination and endocrine status in a resident fish of Biscayne National Park. AB - Surface water, sediment, and fish from Biscayne Bay, coastal wetlands adjacent to the Bay, and canals discharging into the Bay were sampled for determination of baseline contamination in Biscayne National Park. While the number of contaminants detected in canal waters was greater during the wet season than the dry season, no seasonal difference was evident for Biscayne Bay or coastal wetland waters. Estrogen equivalency (as 17beta-estradiol equivalents), as predicted by the Yeast Estrogen Screen, for extracts of passive water samplers deployed in canals and wetlands was elevated during the wet relative to the dry season. Generally, contamination in water, sediments, and fish was greater in the canals than in Biscayne Bay and the wetlands. Guideline levels for sediment contaminant were exceeded most frequently in canals relative to the coastal wetlands and the Bay. Further investigation is necessary to better understand the impact of contaminants in Biscayne National Park. PMID- 28012735 TI - Cross-reactivities of mammalian MAPKs antibodies in rotifer and copepod: Application in mechanistic studies in aquatic ecotoxicology. AB - The mitogen-activated protein kinases (MAPKs) family is known to mediate various biological processes in response to diverse environmental pollutants. Although MAPKs are well characterized and studied in vertebrates, in invertebrates the cross-reactivities of MAPKs antibodies were not clearly known in response to environmental pollutants due to limited information of antibody epitopes with material resources for invertebrates. In this paper, we performed phylogenetic analysis of MAPKs genes in the marine rotifer Brachionus koreanus and the copepods Paracyclopina nana and Tigriopus japonicus. Also in rotifer and copepods, several studies of Western blot of MAPK signaling pathways were shown in response to environmental pollutants, including multi-walled carbon nanotubes (MWCNTs), water-accommodated fractions (WAFs) of crude oil, and microplastics. This paper will provide a better understanding of the underlying mechanistic scenario in terms of cross-reactivities of mammalian antibodies in rotifer and copepod. PMID- 28012736 TI - Spatial distribution and biological effects of trace metals (Cu, Zn, Pb, Cd) and organic micropollutants (PCBs, PAHs) in mussels Mytilus galloprovincialis along the Algerian west coast. AB - Native mussels Mytilus galloprovincialis are used as bioindicator organisms to assess the concentration levels and toxic effects of persistent chemicals, polychlorobiphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and heavy metals using biomarker responses, such as catalase (CAT), glutathione s transferase (GST), and condition indices, for the Algerian coast. The results show that mussels of Oran Harbour are extremely polluted by PCBs and PAHs, i.e., 97.6 and 2892.1MUg/kg d.w., respectively. Other sites present low levels of pollution. Furthermore, high concentrations of zinc, lead and cadmium are found in mussels from fishing, agricultural and estuarine sites, respectively, while low concentrations of copper are found in all of the sites studied. CAT activity is negatively correlated with Cd and Cu, and Zn is positively correlated with GST and CAT. Site classification tools reveal the potential toxicity of coastal areas exposed to anthropogenic pressure and a gradient of toxicity along the Algerian west coast. PMID- 28012737 TI - Rebuttal to published article "A review of ghost gear entanglement amongst marine mammals, reptiles and elasmobranchs" by M. Stelfox, J. Hudgins, and M. Sweet. PMID- 28012738 TI - Radionuclide (226Ra, 232Th, 40K) accumulation among plant species in mangrove ecosystems of Pattani Bay, Thailand. AB - Little is known regarding phytoremediation of radionuclides from soil; even less is known about radionuclide contamination and removal in tropical ecosystems such as mangrove forests. In mangrove forests in Pattani Bay, Thailand, 18 plant species from 17 genera were evaluated for radionuclide concentrations within selected plant parts. Two shrub species, Avicennia marina and Pluchea indica, accumulated the highest 232Th (24.6Bqkg-1) and 40K (220.7Bqkg-1) activity concentrations in roots, respectively. Furthermore, the aquatic species Typha angustifolia accumulated highest 232Th, 40K and 226Ra activity concentrations (85.2, 363.5, 16.6Bqkg-1, respectively) with the highest transfer factors (TFs) (3.0, 2.0, 5.9, respectively) in leaves. Leaves of T. angustifolia had an absorbed dose rate in air (D) over the recommended value (74.8nGyh-1) that was considered sufficiently high to be of concern for human consumption. PMID- 28012739 TI - Managing the risk of non-indigenous marine species transfer in Singapore using a study of vessel movement. AB - Shipping is recognized as a major vector for the global transfer of non indigenous marine species (NIMS). As a major transshipment port, Singapore can minimize the risk of NIMS transfer by implementing pragmatic management strategies, such as using vessel movement information to assess the risk of NIMS transfer. Findings from vessel movement information in a major port terminal in Singapore showed that vessel residence time is short, with >92% of vessels spending seven days or less. There was little variation in vessel residence time to vessel arrival numbers, while the top three last ports of call were found to be from regional ports. Using two key features obtained from vessel movement records, 1) vessel residence time and 2) biogeographic origin of the vessels' last port of call, a simple risk assessment matrix was constructed and applied to assess the level of risk of NIMS transfer by transiting vessels. PMID- 28012740 TI - Ignitability of crude oil and its oil-in-water products at arctic temperature. AB - A novel platform and procedure were developed to characterize the ignitability of Alaska North Slope (ANS) crude oil and its water-in-oil products with water content up to 60% at low temperatures (-20-0 degrees C). Time to ignition, critical heat flux, in-depth temperature profiles were investigated. It was observed that a cold boundary and consequent low oil temperature increased the thermal inertia of the oil/mixture and consequently the time to sustained ignition also increased. As the water content in the ANS water-in-oil mixture increased, the critical heat flux for ignition was found to increase. This is mainly because of an increase in the thermal conductivity of the mixture with the addition of saltwater. The results of the study can be used towards design of ignition strategies and technologies for in situ burning of oil spills in cold climates such as the Arctic. PMID- 28012741 TI - Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis. AB - Myasthenia Gravis is an autoantibody-mediated, neuromuscular junction disease, and is usually associated with thymic abnormalities presented as thymic tumors (~10%) or hyperplastic thymus (~65%). The exact role of thymus in Myasthenia Gravis development is not clear, yet many patients benefit from thymectomy. The apoptotic ligand TNF-Related Apoptosis-Inducing Ligand is thought to be involved in the regulation of thymocyte counts, although conflicting results are reported. We investigated differential expression profiles of TNF-Related Apoptosis Inducing Ligand and its transmembrane receptors, Nuclear Factor-kB activation status, and apoptotic cell counts in healthy thymic tissue and pathological thymus from Myasthenia Gravis patients. All tissues expressed TNF-Related Apoptosis-Inducing Ligand and its receptors, with hyperplastic tissue having the highest expression levels of death receptors DR4 and DR5. No detectable Nuclear Factor-kB activation, at least via the canonical Protein Kinase A-mediated p65 Ser276 phosphorylation, was evident in any of the tissues studied. Apoptotic cell counts were higher in MG-associated tissue compared to the normal thymus. Possible use of the TNF-Related Apoptosis-Inducing Ligand within the concept of an apoptotic ligand-mediated medical thymectomy in thymoma- or thymic hyperplasia associated Myasthenia Gravis is also discussed. PMID- 28012742 TI - Minor snake venom proteins: Structure, function and potential applications. AB - Snake venoms present a great diversity of pharmacologically active compounds that may be applied as research and biotechnological tools, as well as in drug development and diagnostic tests for certain diseases. The most abundant toxins have been extensively studied in the last decades and some of them have already been used for different purposes. Nevertheless, most of the minor snake venom protein classes remain poorly explored, even presenting potential application in diverse areas. The main difficulty in studying these proteins lies on the impossibility of obtaining sufficient amounts of them for a comprehensive investigation. The advent of more sensitive techniques in the last few years allowed the discovery of new venom components and the in-depth study of some already known minor proteins. This review summarizes information regarding some structural and functional aspects of low abundant snake venom proteins classes, such as growth factors, hyaluronidases, cysteine-rich secretory proteins, nucleases and nucleotidases, cobra venom factors, vespryns, protease inhibitors, antimicrobial peptides, among others. Some potential applications of these molecules are discussed herein in order to encourage researchers to explore the full venom repertoire and to discover new molecules or applications for the already known venom components. PMID- 28012744 TI - Augmentation index is increased in patients with inflammatory bowel disease, a meta-analysis. PMID- 28012743 TI - Structural and functional diversity of transient heme binding to bacterial proteins. AB - BACKGROUND: Heme is an important nutritional iron source for almost all bacteria. Elevated heme concentrations, in contrast, are toxic e.g. due to the generation of reactive oxygen species. The cellular heme concentration thus requires tight regulation. The observation of heme acting as an effector molecule in heme-uptake and -utilization processes is rather new and many of these processes are unknown or rarely understood on the molecular level. SCOPE OF REVIEW: We describe processes involving transient heme-protein interaction in bacteria and highlight the regulatory function of heme at key steps during heme uptake and utilization. We furthermore focus on essential structural aspects of heme binding to respective proteins. MAJOR CONCLUSIONS: The structural and functional basis for heme-regulated processes in bacteria is diverse and ranges from increased degradation to extended half-life and from inhibition to activation of the respective heme-regulated protein. The large variety of effects is attributed to the versatile ability of heme to interact with proteins in different ways. GENERAL SIGNIFICANCE: Knowledge of the molecular mechanism of transient heme protein interaction is central to understand the heme-regulated processes in bacteria. The heme-binding proteins involved in these processes represent potential targets for the development of novel antibacterial drugs. New antibacterial strategies are urgently needed to combat antibiotic resistance. PMID- 28012745 TI - Corrigendum to "Cadmium, iron and zinc interaction and hematological parameters in rat dams and their offspring" [J. Trace Elem. Med. Biol. 38 (2016) 108-116]. PMID- 28012746 TI - Differentiation of Renal Masses Using A-Mode Ultrasound. PMID- 28012748 TI - Editorial Comment. PMID- 28012747 TI - The American Urological Association Symptom Index for Benign Prostatic Hyperplasia. AB - A symptom index for benign prostatic hyperplasia (BPH) was developed and validated by a multidisciplinary measurement committee of the American Urological Association (AUA). Validation studies were conducted involving a total of 210 BPH patients and 108 control subjects. The final AUA symptom index includes 7 questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On revalidation, the index was internally consistent (Cronbach's alpha = 0.86) and the score generated had excellent test-retest reliability (r = 0.92). Scores were highly correlated with subjects' global ratings of the magnitude of their urinary problem (r = 0.65 to 0.72) and powerfully discriminated between BPH and control subjects (receiver operating characteristic area 0.85). Finally, the index was sensitive to change, with preoperative scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (p <0.001). The AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols. PMID- 28012749 TI - Editorial Comment. PMID- 28012750 TI - Purification of a Human Prostate Specific Antigen. AB - Rabbit antiserum raised against the crude extract of normal human prostatic tissue contained antibodies to a prostatic tissue-specific antigen as shown by immunoprecipitation techniques. Using this antiserum a prostate antigen was detected in normal, benign hypertrophic, and malignant prostatic tissues, but not in other human tissues. The prostate antigen was purified to homogeneity from prostatic tissues and showed a single protein band on analytical polyacrylamide gel electrophoresis and isoelectric focusing. This report thus presents the first demonstration of the purification of a prostate-specific antigen that does not represent prostatic acid phosphatase. PMID- 28012751 TI - A New Plastic Operation for Stricture at the Uretero-Pelvic Junction: Report of 20 Operations. PMID- 28012753 TI - A One Stage Hypospadias Repair. PMID- 28012752 TI - Percutaneous Stone Manipulation. AB - Percutaneous stone manipulation by direct ultrasound disintegration, extraction or chemolysis was done on 34 patients. A total of 15 patients presented with an operatively established nephrostomy, while percutaneous nephrostomy and subsequent dilation of the nephrostomy channel were done in 19. The rate of complete stone clearance was 19 of 20 stones after percutaneous nephrostomy and 8 of 16 stones in the group with an operatively established nephrostomy. The primary goal, to remove obstructing pelvic stones, was achieved in all cases. There were no untoward side effects, such as back pressure damage owing to flushing of the collecting system during ultrasound disintegration, or persistent infection. Complications in 3 patients were managed conservatively. PMID- 28012754 TI - First Clinical Experience with Extracorporeally Induced Destruction of Kidney Stones by Shock Waves. AB - We performed extracorporeally induced destruction of kidney stones on 72 patients. No complications have resulted from the tissue exposure to high energy shock waves. Clearance studies before and after the shock wave treatment indicate no changes in renal function. The method was used successfully in all patients with stones in the renal pelvis. In none of these patients was an open operation required. Two patients with ureteral stones also were treated with shock waves but had to be operated upon because of insufficient destruction of the stone. PMID- 28012756 TI - Vesical and Ureteral Damage from Voiding Dysfunction in Boys Without Neurologic or Obstructive Disease. PMID- 28012755 TI - Comparison of Digital Rectal Examination and Serum Prostate Specific Antigen in the Early Detection of Prostate Cancer: Results of a Multicenter Clinical Trial of 6,630 Men. AB - To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandom-E or Tandem R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 MUg./l. or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 MUg./l., 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 MUg./l. or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings. PMID- 28012758 TI - Clean, Intermittent Self-Catheterization in the Treatment of Urinary Tract Disease. PMID- 28012757 TI - Laparoscopic Nephrectomy: Initial Case Report. AB - A tumor-bearing right kidney was completely excised from an 85-year-old woman using a laparoscopic approach. A newly devised method for intra-abdominal organ entrapment and a recently developed laparoscopic tissue morcellator made it possible to deliver the 190 gm. kidney through an 11 mm. incision. PMID- 28012759 TI - The Male Factor in Fertility and Infertility. II. Spermatozoon Counts in 1000 Men of Known Fertility and in 1000 Cases of Infertile Marriage. PMID- 28012760 TI - Prediction of Prognosis for Prostatic Adenocarcinoma by Combined Histological Grading and Clinical Staging. PMID- 28012761 TI - 25-Year Experience with Replacement of the Human Bladder (Camey Procedure). AB - The Carney enterocystoplasty is a technique for constructing a functional, continent bladder in male patients following cystoprostatectomy for carcinoma. The technique is described and 84 patients treated during a 25-year interval are reviewed. PMID- 28012762 TI - The Effect of Castration on Benign Hypertrophy of the Prostate in Man. PMID- 28012763 TI - Studies on the Growth of Cells: The Cultivation of Bladder and Prostatic Tumors Outside the Body. PMID- 28012764 TI - The Ultimate Results in the Treatment of Carcinoma of the Prostate by the Radical Removal of the Prostate, Vesical Neck and Seminal Vesicles. PMID- 28012765 TI - Impotence Following Radical Prostatectomy: Insight into Etiology and Prevention. AB - This study was undertaken to identify the cause of impotence in men undergoing radical prostatectomy, with the hope that this information may provide insight into the possible prevention of this complication. The autonomic innervation of the corpora cavernosa in the male fetus and newborn was traced to determine the topographical relationship between the pelvic nerve plexus, and the prostate, urethra and urogenital diaphragm. We have demonstrated that the branches of the pelvic plexus that innervate the corpora cavernosa are situated between the rectum and urethra, and penetrate the urogenital diaphragm near or in the muscular wall of the urethra. Injuries to the pelvic plexus can occur in 2 ways: 1) during division of the lateral pedicle and 2) at the time of apical dissection with transection of the urethra. Thirty-one men who underwent radical retropubic prostatectomy were evaluated to determine risk factors that correlated with postoperative impotence: 5 (16 per cent) were fully potent, 7 (23 per cent) had partial erections that were inadequate for sexual intercourse and 19 (61 per cent) had total erectile impotence. The 2 factors that had a favorable influence on postoperative potency were age and pathologic stage of the lesion: 31 per cent of the patients less than 60 years old were potent versus only 6 per cent of the patients more than 60 years, while 33 per cent of the patients with tumor microscopically confined to the prostatic capsule were potent versus only 5 per cent of those with capsular penetration. When the factors of age and capsular penetration were combined 60 per cent of the men less than 60 years old who had an intact prostatic capsule were potent. Arterial insufficiency and psychogenic factors were excluded as major contributing factors by the finding of normal penile blood flow and absence of nocturnal penile tumescence in the impotent patients. We conclude that impotence after radical prostatectomy results from injury to the pelvic nerve plexus that provides autonomic innervation to the corpora cavernosa. Further studies will be necessary to determine whether refinements in surgical technique, especially during ligation of the lateral pedicle and apical dissection, can prevent this complication. PMID- 28012766 TI - The Results of Radical Nephrectomy for Renal Cell Carcinoma. PMID- 28012767 TI - Physiological and Pharmacological Studies of the Prostate Gland: IV. Response of Prostatic Muscle to Drugs. PMID- 28012768 TI - Laparoscopic Radical Prostatectomy with a Remote Controlled Robot. AB - PURPOSE: Robotics in surgery is a recent innovation. This technology offers a number of attractive features in laparoscopy. It overcomes the difficulties with fixed port sites by restoring all 6 degrees of freedom at the instrument tips, provides new possibilities for miniaturization of surgical tasks and allows remote controlled surgery. We investigated the applicability of remote controlled robotic surgery to laparoscopic radical prostatectomy. MATERIALS AND METHODS: Our previous experience with laparoscopic prostatectomy served as a basis for adapting robotic surgery to this procedure. A surgeon at a different location who activated the tele-manipulators of the da Vinci* robotic system performed all steps of the intervention. A scrub nurse and second surgeon who stood at patient side had limited roles to port and instrument placement, exposure of the operative field, assistance in hemostasis and removal of the operative specimen. Our patient was a 63-year-old man presenting with a T1c tumor discovered on 1 positive sextant biopsy with a 3+3 Gleason score and 7 ng./ml. preoperative serum prostate specific antigen. RESULTS: The robot provided an ergonomic surgical environment and remarkable dexterity enhancement. Operating time was 420 minutes, and the hospital stay lasted 4 days. The bladder catheter was removed 3 days postoperatively, and 1 week later the patient was fully continent. Pathological examination showed a pT3a tumor with negative margins. CONCLUSIONS: Robotically assisted laparoscopic radical prostatectomy is feasible. This new technology enhances surgical dexterity. Further developments in this field may have new applications in laparoscopic tele-surgery. PMID- 28012769 TI - Comment. PMID- 28012770 TI - Intracavitary Bacillus Calmette-Guerin in the Treatment of Superficial Bladder Tumors. AB - Patients with recurrent superficial bladder tumors have been treated by vesical and intradermal administration of Bacillus Calmette-Guerin. The pattern of recurrence in 9 patients has been altered favorably. Although the findings are still preliminary they appear to hold promise of a new therapeutic approach to the treatment of a group of neoplasms for which effective therapy is still lacking. PMID- 28012772 TI - Reply by Authors. PMID- 28012771 TI - An Operative Technique for the Correction of Vesicoureteral Reflux. PMID- 28012774 TI - [Intermittent left bundle branch block - reversal to normal conduction during general anesthesia]. AB - BACKGROUND AND OBJECTIVES: Transient changes in intraoperative cardiac conduction are uncommon. Rare cases of the development or remission of complete left bundle branch block under general and locoregional anesthesia associated with myocardial ischemia, hypertension, tachycardia, and drugs have been reported. Complete left bundle branch block is an important clinical manifestation in some chronic hypertensive patients, which may also be a sign of coronary artery disease, aortic valve disease, or underlying cardiomyopathy. Although usually permanent, it can occur intermittently depending on heart rate (when heart rate exceeds a certain critical value). CASE REPORT: This is a case of complete left bundle branch block recorded in the preoperative period of urgent surgery that reverted to normal intraoperative conduction under general anesthesia after a decrease in heart rate. It resurfaced, intermittently and in a heart-rate-dependent manner, in the early postoperative period, eventually reverting to normal conduction in a sustained manner during semi-intensive unit monitoring. The test to identify markers of cardiac muscle necrosis was negative. Pain due to the emergency surgical condition and in the early postoperative period may have been the cause of the increase in heart rate up to the critical value, causing blockage. CONCLUSIONS: Although the development or remission of this blockade under anesthesia is uncommon, the anesthesiologist should be alert to the possibility of its occurrence. It may be benign; however, the correct diagnosis is very important. The electrocardiographic manifestations may mask or be confused with myocardial ischemia, factors that are especially important in a patient under general anesthesia unable to report the characteristic symptoms of ischemia. PMID- 28012773 TI - OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3, Randomized, Placebo Controlled Trial. AB - PURPOSE: Overactive bladder affects 12% to 17% of the general population and almost a third experience urinary incontinence, which may severely impact health related quality of life. Oral anticholinergics are the mainstay of pharmacological treatment but they are limited by inadequate efficacy or side effects, leading to a high discontinuation rate. We report the results of the first large (557 patients), phase 3, placebo controlled trial of onabotulinumtoxinA in patients with overactive bladder and urinary incontinence inadequately managed with anticholinergics. MATERIALS AND METHODS: Eligible patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days and 8 or more micturitions per day were randomized 1:1 to receive intradetrusor injection of onabotulinumtoxinA 100 U or placebo. Co-primary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life. Adverse events were assessed. RESULTS: OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (-2.65 vs -0.87, p <0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p <0.001). All other overactive bladder symptoms improved vs placebo (p <=0.05). OnabotulinumtoxinA improved patient health related quality of life across multiple measures (p <0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of urinary retention was observed. CONCLUSIONS: OnabotulinumtoxinA 100 U showed significant, clinically relevant improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with anticholinergics and was well tolerated. PMID- 28012775 TI - Comparison of functional assays used in the clinical development of a placental malaria vaccine. AB - BACKGROUND: Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria are in clinical development. The purpose of this study was to evaluate the robustness and comparability of binding inhibition assays used in the clinical development of placental malaria vaccines. METHODS: The ability of sera from animals immunised with different VAR2CSA constructs to inhibit IE binding to CSA was investigated in three in vitro assays using 96-well plates, petri dishes, capillary flow and an ex vivo placental perfusion assay. RESULTS: The inter-assay variation was not uniform between assays and ranged from above ten-fold in the flow assay to two fold in the perfusion assay. The intra-assay variation was highest in the petri dish assay. A positive correlation between IE binding avidity and the level of binding after antibody inhibition in the petri dish assay indicate that high avidity IE binding is more difficult to inhibit. The highest binding inhibition sensitivity was found in the 96-well and petri dish assays compared to the flow and perfusion assays where binding inhibition required higher antibody titers. CONCLUSIONS: The inhibitory capacity of antibodies is not easily translated between assays and the high sensitivity of the 96-well and petri dish assays stresses the need for comparing serial dilutions of serum. Furthermore, IE binding avidity must be in the same range when comparing data from different days. There was an overall concordance in the capacity of antibody-mediated inhibition, when comparing the in vitro assays with the perfusion assay, which more closely represents in vivo conditions. Importantly the ID1-ID2a protein in a liposomal formulation, currently in a phase I trial, effectively induced antibodies that inhibited IE adhesion in placental tissue. PMID- 28012776 TI - A novel "in-feed" delivery platform applied for oral DNA vaccination against IPNV enables high protection in Atlantic salmon (Salmon salar). AB - BACKGROUND: DNA vaccination has emerged as a promising tool against infectious diseases of farmed fish. Oral delivery allows stress-free administration that is ideal for mass immunization and of paramount importance for infectious pancreatic necrosis (IPN) and other viral disease that affect young salmonids and cause economic losses in aquaculture worldwide. METHODS: We describe the development and in vivo assessment of an "in-feed" formulation strategy for oral immunization with liposomal DNA vaccines, by delivering a vaccine construct coding for an immunogenic region of the VP2 capsid protein. A challenge against IPNV was carried out to determine the vaccine efficacy, by comparing the mortality of pre smolt Atlantic salmons immunized and non-immunized with the oral vaccine. The antibody response (ELISA) and hematological parameters after immunization were examined, as well as the vaccine effect on the growth and internal structures of fry salmons (histological analysis). The vaccine distribution in the experimental tank after oral administration was investigated by HPLC and PCR amplification. RESULTS: The oral vaccine induced detectable levels of VP2-specific antibodies and conferred significant protection following IPNV challenge, with relative percent survivals (RPS) of 58.2%, for single dose (1mgpDNA/kgfish?d), and 66% for double dose (2mgpDNA/kgfish?d). We further provide evidence in favour of the vaccine safety to fish and demonstrated absence of pDNA in the tank water, but presence of vaccine residues in faeces and unconsumed feed sediments (solid wastes). CONCLUSION: The delivery platform for liposomal DNA vaccination via feed was successfully proved against IPNV in Atlantic salmon, showing the oral vaccine to be immunogenic and safe for fish, and providing significant protection after oral administration. The "in-feed" technology for oral DNA vaccination holds potential to be applied against IPNV and other pathogens that currently threaten the aquaculture worldwide. PMID- 28012777 TI - Sequential administration of a MVA-based MUC1 cancer vaccine and the TLR9 ligand Litenimod (Li28) improves local immune defense against tumors. AB - TG4010 is an immunotherapeutic vaccine based on Modified Vaccinia virus Ankara (MVA) encoding the human tumor-associated antigen MUC1 and human IL-2. In combination with first-line standard of care chemotherapy in advanced metastatic non-small-cell lung cancer (NSCLC), repeated subcutaneous injection of TG4010 improved progression-free survival in phase 2b clinical trials. In preclinical tumor models, MVATG9931, the research version of TG4010, conferred antigen specific responses against the weak antigen human MUC1. The combination of a suboptimal dose of MVATG9931 and the type B TLR9 ligand Litenimod (Li28) markedly increased survival in a subcutaneous RMA-MUC1 tumor model compared to the treatment with MVATG9931 or Li28 alone. The requirements for this protection were (i) de novo synthesis of MUC1, (ii) Li28 delivered several hours after MVATG9931 at the same site, (iii) at least two vaccination cycles, and (iv) implantation of MUC1-positive tumor cells in the vicinity to the vaccination site. Subcutaneously injected MVATG9931 allowed transient local gene expression and induced the local accumulation of MCP-1, RANTES, M-CSF, IL-15/IL-15R and IP-10. After repeated injection, CD4+ and CD8+ T lymphocytes, B lymphocytes, NK cells, pDCs, neutrophils, and macrophages accumulated around the injection site, local RANTES levels remained high. Delayed injection of Li28 into this environment, led to further accumulation of macrophages, the secretion of IL-18 and IL-1 beta, and an increase of the percentage of activated CD69+ NK cell. Combination treatment augmented the number of activated CD86+ DCs in the draining lymph nodes and increased the percentage of KLRG1+ CD127-CD8+ T cells at the injection site. In vivo depletion of macrophages around the injection site by Clodronate liposomes reduced local IL-18 levels and diminished survival rates significantly. Thus, sequential administration of MVATG9931 and Li28 improves local innate and adaptive immune defense against tumors, arguing for intratumoral delivery of this peculiar sequential combination therapy. PMID- 28012778 TI - B cell and antibody responses in mice induced by a putative cell surface peptidase of Pneumocystis murina protect against experimental infection. AB - RATIONALE: Pneumocystis pneumonia is a major cause of morbidity and mortality in HIV-infected subjects, cancer patients undergoing chemotherapy and solid organ transplant recipients. No vaccine is currently available. By chemical labeling coupled with proteomic approach, we have identified a putative surface protein (SPD1, Broad Institute gene accession number PNEG_01848) derived from single suspended P. murina cysts. SPD1 was expressed in an insect cell line and tested for vaccine development. METHODS: Mice were immunized with SPD1 plus adjuvant MF 59 by subcutaneous injection. Three weeks after the last immunization, CD4+ cells were depleted with anti-CD4 antibody GK1.5. The mice were then challenged with 2*105Pneumocystis organisms. Mice were sacrificed at 4 and 6weeks after PC challenge. Spleen/lung cells and serum were harvested. B cells and memory B cells were assessed via flow cytometry. Specific Pneumocystis IgG antibody was measured by ELISA before and after challenge. Infection burden was measured as real-time PCR for P. murina rRNA. RESULTS: Normal mice infected with Pneumocystis mounted a serum IgG antibody response to SPD1. Serum from rhesus macaques exposed to Pneumocystis showed a similar serum IgG response to purified SPD1. SPD1 immunization increased B cell and memory B cell absolute cell counts in CD4 depleted Balb/c mice post Pneumocystis challenge in spleen and lung. Immunization with SPD1 significantly increased specific Pneumocystis IgG antibody production before and after challenge. Mice immunized with SPD1 showed significantly decreased P. murina copy number compared with mice that did not receive SPD1 at 6weeks after challenge. CONCLUSION: Immunization with SPD1 provides protective efficacy against P. murina infection. SPD1 protection against Pneumocystis challenge is associated with enhanced memory B cell production and higher anti Pneumocystis IgG antibody production. SPD1 is a potential vaccine candidate to prevent or treat pulmonary infection with Pneumocystis. PMID- 28012779 TI - Vaccination of alpacas against Rift Valley fever virus: Safety, immunogenicity and pathogenicity of MP-12 vaccine. AB - Rift Valley fever (RVF) is an emerging zoonosis of major public health concern in Africa and Arabia. Previous outbreaks attributed camelids a significant role in the epidemiology of Rift Valley fever virus (RVFV), making them an important target species for vaccination. Using three alpacas as model-organisms for dromedary camels, the safety, immunogenicity and pathogenicity of the MP-12 vaccine were evaluated in this study. To compare both acute and subacute effects, animals were euthanized at 3 and 31days post infection (dpi). Clinical monitoring, analysis of liver enzymes and hematological parameters demonstrated the tolerability of the vaccine, as no significant adverse effects were observed. Comprehensive analysis of serological parameters illustrated the immunogenicity of the vaccine, eliciting high neutralizing antibody titers and antibodies targeting different viral antigens. RVFV was detected in serum and liver of the alpaca euthanized 3dpi, whereas no virus was detectable at 31dpi. Viral replication was confirmed by detection of various RVFV-antigens in hepatocytes by immunohistochemistry and the presence of mild multifocal necrotizing hepatitis. In conclusion, results indicate that MP-12 is a promising vaccine candidate but still has a residual pathogenicity, which requires further investigation. PMID- 28012780 TI - Achieving a "Grand Convergence" in global health by 2035. AB - Historical evidence demonstrates the validity of the concept "Grand Convergence". The Lancet commission identified the major challenges facing low and lower middle income countries including the unfinished agenda, non-communicable diseases and injuries and an approach to funding and achieving these objectives along with progress towards universal health care. The role of vaccines is summarized as a major approach to accomplish a Grand Convergence in a generation. PMID- 28012781 TI - The molecular and cellular mechanisms of itch and the involvement of TRP channels in the peripheral sensory nervous system and skin. AB - Itch is an unpleasant cutaneous sensation that can arise following insect bites, exposure to plant ingredients, and some diseases. Itch can also have idiopathic causes. Itch sensations are thought to protect against external insults and toxic substances. Although itch is not directly lethal, chronic and long lasting itch in certain diseases can worsen quality of life. Therefore, the mechanisms responsible for chronic itch require careful investigation. There is a significant amount of basic research concerning itch, and the effect of various itch mediators on primary sensory neurons have been studied. Interestingly, many mediators of itch involve signaling related to transient receptor potential (TRP) channels. TRP channels, especially thermosensitive TRP channels, are expressed by primary sensory neurons and skin keratinocytes, which receive multimodal stimuli, including those that cause itch sensations. Here we review the molecular and cellular mechanisms of itch and the involvement of TRP channels in mediating itch sensations. PMID- 28012782 TI - Epithelioid Hemangioendothelioma Presenting as Inferior Vena Cava Obstruction Diagnosed Using an Endovascular Thrombectomy Device. AB - Epithelioid hemangioendothelioma is a rare vascular sarcoma that arises from the lining (intima) of blood vessels. We report a case of a 43-year-old male patient, who presented with inferior vena cava (IVC) obstruction and acute bilateral lower extremity deep vein thrombosis. Mechanical thrombectomy was performed with an endovascular thrombectomy device, followed by stent placement in the IVC. The initial pathology on the retrieved specimen obtained from the thrombectomy device revealed an undifferentiated neoplasm, and definitive surgical resection of the retroperitoneal soft-tissue tumor of the IVC documented a rare case of epithelioid hemangioendothelioma. PMID- 28012784 TI - Positional modification techniques for supine obstructive sleep apnea: A systematic review and meta-analysis. AB - This review aimed to determine the effectiveness of positional modification techniques in preventing supine sleep, sleep-disordered breathing and other clinically important outcomes in patients with supine obstructive sleep apnea (OSA). Randomized controlled trials comparing positional modification techniques with any other therapy or placebo were included. Electronic searches of databases including CENTRAL, MEDLINE, CINAHL, Embase, and Web of Science up to April 2016 were performed. Meta-analysis was undertaken where possible. This comprehensive meta-analysis found benefit for positional modification techniques in those with supine OSA in terms of reduction in apnea-hypopnea index (AHI) and time spent supine. Whilst positional modification techniques were effective in terms of a reduction in AHI, continuous positive airway pressure (CPAP) was more effective than these techniques. A reliable diagnosis of supine OSA should be considered, and further research is required on patient-centred outcomes including comfort, barriers to adherence, cost-analysis, and long term outcomes including the effect on cardiovascular disease, the metabolic syndrome, and insulin resistance. PMID- 28012785 TI - Compensation for Acid-Base Disorders. AB - Hydrogen concentration is a critical determinant of many physiologic functions and is tightly regulated. Any alteration in acid-base equilibrium sets into motion a compensatory response by either the lungs or the kidneys. The compensatory response attempts to return the ratio between Pco2 and [HCO3-] to normal and thereby minimize the pH change. A primary increase or decrease in one component is associated with a predictable compensatory change in the same direction in the other component, and the expected compensation can be estimated clinically in dogs and cats. PMID- 28012783 TI - Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2. AB - Diabetic retinopathy is a major vision threatening disease among working age adults, and increased oxidative stress is one of the prime causative factors in its pathogenesis. Increased reactive oxygen species (ROS) in the cytosol damage mitochondria, and due to compromised antioxidant signaling system and dysfunctional mitochondria with damaged mitochondrial DNA, ROS continue to pile up, accelerating capillary cell loss. In addition to other cellular and enzymatic defense systems, the retina is also equipped with the nuclear erythroid-2-p45 related factor-2 (Nrf2) antioxidant response element signaling pathway, which controls the expression of genes important in detoxification and elimination of ROS. However, in diabetes, its transcriptional activity is impaired, further exacerbating and exposing the retina to elevated stress. Diabetic milieu also alters epigenetic factors responsible for chromatin modifications and gene regulation, and kelch-like ECH-associated protein 1 (Keap1), important in regulating Nrf2-antioxidant signaling axis, is epigenetically modified, impeding nuclear translocation of Nrf2, and this inhibits the transcription of genes with Antioxidant Response Element. This review discusses antioxidant signaling, especially the role of Nrf2, in diabetic retinopathy, and possible involvement of epigenetic modifications in antioxidant signaling and Nrf2 transcriptional activity. Therapies targeting Nrf2 activation, including epigenetic modifications, have potentional to prevent mitochondrial damage and inhibit the development, and progression of this sight-threatening disease which most of the patients get after 20-25 years of diabetes. PMID- 28012786 TI - A Quick Reference on Hypocalcemia. AB - Primary hypoparathyroidism should be considered in dogs with vague signs, including tremors, facial rubbing, and seizures. Ionized hypocalcemia should be considered in dogs with protein-losing enteropathy, especially lymphangiectasia caused by hypovitaminosis D. Ionized hypocalcemia typically occurs only in advanced chronic kidney disease. PMID- 28012787 TI - A Quick Reference on Hypercalcemia. AB - In dogs, neoplasia is the most common cause of hypercalcemia, followed by primary hyperparathyroidism, chronic kidney disease, and hypoadrenocorticism. In cats, idiopathic hypercalcemia is the most common cause, followed by chronic kidney disease and then neoplasia. Prognosis and treatment ultimately depend on the cause of the hypercalcemia. PMID- 28012788 TI - Lipid Therapy for Intoxications. AB - This review discusses the use of intravenous lipid emulsion (ILE) in the treatment of intoxications with lipophilic agents in veterinary medicine. Despite growing scientific evidence that ILE has merit in the treatment of certain poisonings, there is still uncertainty on the optimal composition of the lipid emulsion, the dosing, the mechanism of action, and the efficacy. Therefore, a critical view of the clinician on the applicability of this modality in intoxications is still warranted. The use of ILE therapy is advocated as an antidote in cases of intoxications with some lipophilic substances. PMID- 28012789 TI - Reliability and validity of the Finnish version of the motor observation questionnaire for teachers. AB - OBJECTIVES: Observational screening instruments are often used as an effective, economical first step in the identification of children with Developmental Coordination Disorder (DCD). The aim was to investigate the psychometric properties of the Finnish version of the Motor Observation Questionnaire for Teachers (MOQ-T-FI). METHODS: The psychometric properties were tested using two separate samples (S1: age range 6-12, M 9y 5mo, females 101, males 92; S2: age range 6-9, M 7y 7mo, females 404, males 446). Teachers completed the MOQ-T-FI in both samples, and in sample 2 teachers' ratings were compared to student's performance on the Movement Assessment Battery for Children-Second Edition (MABC 2). Internal consistency was investigated by using Cronbach's alpha, predictive validity by receiver operating characteristic (ROC) analysis, concurrent validity by correlation analysis, and construct validity by factor analysis. RESULTS: The MOQ-T-FI behaves consistently with its original Dutch version. The internal consistency was excellent (alpha=0.97). The bifactor model, with one general factor and two specific factors, fit the data significantly better than the first order model. The concurrent validity with the MABC-2 was moderate (r=0.37 p<0.001). Sensitivity was 82.5% and specificity 44.5%, respectively. CONCLUSION: Notwithstanding the low specificity the MOQ-T-FI can be considered as a promising screening tool in the school environment for Finnish children at risk of motor learning problems. PMID- 28012790 TI - The role of parental microRNA alleles in recurrent pregnancy loss: an association study. AB - The medical evaluation of recurrent pregnancy loss (RPL), the occurrence of two or more consecutive pregnancy losses prior to 20th week of gestation, is mainly focused on maternal factors. However, paternally expressed genes may also play a role in implantation and placenta quality. This study aimed to investigate the possible association between parental miR-196a2C>T and miR-499aT>C polymorphisms and RPL in a case-control study including 200 RPL couples and 400 healthy men and women. Genotyping was performed using Tetra-ARMS-PCR and PCR-RFLP for miR 196a2C>T and miR-499aT>C polymorphisms, respectively. In men, the association was observed between miR-499a and RPL under dominant (P = 0.006; odds ratio [OR] = 2.36; 95% confidence interval [CI], 1.28-4.37), recessive (P < 0.0001; OR = 2.89; 95% CI, 1.92-4.36) and additive (P < 0.001; OR = 2.77; 95% CI, 1.52-5.10) models. In women, the association was found between miR-196a2 and RPL under recessive (P = 0.02; OR = 2.19; 95% CI, 1.16-4.14) and additive (P = 0.03; OR = 1.53; 95% CI, 1.04-2.27) models. Hence, evidence was provided for association of genetic variation in parental microRNA polymorphisms with RPL. Further studies are required to validate the significance of the studied genetic variations in diverse ethnic populations. PMID- 28012791 TI - Aromatic profile and sensory characterisation of ultrasound treated cranberry juice and nectar. AB - Ultrasonication is a nonthermal food processing technology that is used in several applications (extraction, pretreatment before drying, freezing, inactivation of microorganisms etc.). The objective of this study was to investigate the effect of high power ultrasound and pasteurisation on the aroma profile and sensory properties of cranberry juice and nectar. Samples were treated according to the experimental design, with high power sonicator at ultrasound frequency of 20kHz under various conditions (treatment time 3, 6 and 9min, sample temperature: 20, 40 and 60 degrees C and amplitude 60, 90 and 120MUm). The aromatic profiles of juices showed that, compared to the untreated samples of juices and nectars, the ultrasonic treatment led to the formation of new compounds or to the disappearance of compounds that were found in the untreated samples. Samples treated at the highest amplitude (120MUm) were used for evaluation and comparison with untreated and pasteurised samples using electronic tongue study. Principle component analysis (PCA) confirmed the results of electronic tongue study, which showed that the ultrasound-treated and pasteurised juices had different scores compared to the untreated samples. Sensory evaluation showed that ultrasonically treated and pasteurised juices received lower scores in comparison with the untreated samples. PMID- 28012792 TI - Reply to Alongi et al. PMID- 28012793 TI - PET imaging of zirconium-89 labelled cetuximab: A phase I trial in patients with head and neck and lung cancer. AB - BACKGROUND AND PURPOSE: PET imaging of cetuximab uptake may help selecting cancer patients with the highest chance of benefit. The aim of this phase I trial was to determine the safety of the tracer 89Zr-cetuximab and to assess tumour uptake. METHODS: Two dose schedules were used; two consecutive doses of 60MBq 89Zr cetuximab or a single dose of 120MBq, both preceded by 400mg/m2 of unlabelled cetuximab. Toxicity (CTCAE 3.0) was scored twice weekly. PET-CT scans were acquired on days 4, 5 and 6 (step 1) or 5, 6, 7 (step 2). Because tumour uptake could not be assessed satisfactorily, a third step was added including EGFR overexpressing tumours. RESULTS: Nine patients were included (6 NSCLC; 3 HNC). No additional toxicity was associated with administration of 89Zr-cetuximab compared to standard cetuximab. A tumour to blood ratio (TBR)>1 was observed in all but one patient, with a maximum of 4.56. TBR was not different between dose schedules. There was a trend for higher TBR at intervals>5days after injection. CONCLUSIONS: Both presented 89Zr-cetuximab administration schedules are safe. The recommended dose for future trials is 60MBq, with a minimum time interval for scanning of 6days. PMID- 28012794 TI - Improved overall survival with adjuvant radiotherapy for high-intermediate and high risk Stage I endometrial cancer. AB - BACKGROUND/PURPOSE: To perform a large analysis of Stage I endometrioid-type endometrial cancer patients to determine the impact of adjuvant radiotherapy (ART) on survival. MATERIAL/METHODS: 132,976 FIGO Stage I endometrioid-type endometrial cancer patients treated surgically were identified within the National Cancer Database (NCDB) comprising Commission on Cancer facilities in the United States. Patients were categorized as observation (OBS) or ART (vaginal brachytherapy, external beam radiotherapy, or both). Univariable generalized linear mixed effects models were used to estimate the odds of receiving ART, and a multivariable frailty survival model was used to estimate the instantaneous hazard of death for those receiving OBS versus ART. Due to the presence of a significant interaction, these estimates were stratified by PORTEC-based low, low intermediate, high-intermediate, and high risk groups. RESULTS: 104,645 (79%) underwent OBS while 28,331 (21%) received ART. Of those receiving ART, 12,913 (46%) received VBT alone, 12,857 (45%) received EBRT alone, and 2561 (9%) received EBRT+VBT. On univariable analysis, increasing stage/myometrial invasion, higher grade, older age, presence of lymphovascular space invasion, and larger tumor size predicted poorer survival (all p<0.01). On multivariable analysis, patients at high-intermediate risk and high risk experienced improved survival with ART with a hazard ratio of 0.796 (95% CI: 0.731-0.867; p<0.001) and 0.783 (95% CI: 0.693-0.885; p<0.001), respectively. There was no survival benefit for ART among patients at low or low-intermediate risk. CONCLUSIONS: In Stage I high intermediate and high risk endometrioid-type endometrial cancer patients, ART significantly improves overall survival. PMID- 28012795 TI - Determining the need and utilization of radiotherapy in cancers of the breast, cervix, lung, prostate and rectum: A population level study. AB - PURPOSE: Determining the appropriate rate of radiotherapy (RT) utilization is important for health care planning and resource allocation. The difference between the observed and the appropriate RT rate is influenced by the choice of a criterion based benchmarking (CBB) or evidence-based estimates (EBEST) measure. Our primary objective was to determine the utilization of radiotherapy for cancers of the breast (B), cervix (C), lung (L), prostate (P) and rectum (R) in Alberta (AB) Canada and to compare the observed RT rates to estimates of need derived from the criterion based benchmarking (CBB) and evidence-based estimates (EBEST). MATERIALS AND METHODS: All incident cases of B,C,L,P and R cancers diagnosed in AB during 2004-8 (prior to the decentralization of provincial RT capacity) were identified from the Alberta Cancer Registry. Patients receiving RT within one year (RT-1y) of diagnosis were identified and the proportion receiving RT-1y was then calculated. Factors associated with RT utilization were analysed by region. Estimates of the need for RT were derived from CBB and EBEST methods in the literature. RESULTS: A total of n=68,164 cancer cases were identified from the ACR. RT-1y rates (95% C.I.) were B: 51.5% (50.1-52.9), C: 48.9% (43.8-54.0), L: 37.1% (35.4-38.8), P: 26.9% (25.1-28.7) and R: 39.3% (36.5-42.1). Observed rates of RT in AB were lower than estimates derived using the CBB and EBEST estimates. Shortfalls varied across cancer sites according to whether a CBB or EBEST estimate was used ranging from a low of -0.3% in cancer of the cervix to a high of 30.3% in rectal cancer. CONCLUSIONS: RT shortfalls exist in the utilization of RT in AB, Canada despite centralized cancer care and a publically funded health care system. Decisions to address shortfalls need to be mindful of how model selection can impact on findings. PMID- 28012796 TI - Antigenic fractions from Taenia crassiceps metacestodes obtained by hydrophobicity for the immunodiagnosis of active and inactive forms of neurocysticercosis in human cerebrospinal fluid samples. AB - This study aimed to evaluate the total extract of Taenia crassiceps metacestodes (TC) and its antigenic fractions obtained by Triton X-114 fractionation techniques, such as detergent (DC) and aqueous (AC), in the immunodiagnosis of human neurocysticercosis (NCC). Cerebrospinal fluid samples were divided into two groups: Group 1 (n=40), which was further divided into active (n=20) and inactive (n=20) NCC, and Group 2 (control group), which comprised 39 CSF samples from patients who had another neurological disorder, were suffering from other infectious diseases of the brain or had other parasitic infections. The total extracts and antigenic fractions were tested by enzyme-linked immunosorbent assay (ELISA) to detect human IgG anti-Taenia solium. T. crassiceps fractions (DC and AC) showed the same value of sensitivity (Se), 100%, for active and inactive NCC and a specificity (Sp) of 97.4%. The DS fraction obtained from T. solium showed 100% Se for active NCC, 95% Se for inactive NCC and a 92.3% Sp. The AS fraction obtained from T. solium showed 100% Se for both active and inactive NCC and a 94.9% Sp. There was a positive correlation between the total saline extract of T. crassiceps (TC) and T. solium (TS) and their fractions (DC, AC, DS and AS). Positive predictive value, negative predictive value, diagnostic efficiency and Youden index were calculated. In conclusion, these results demonstrated that detergent and aqueous fractions obtained from T. crassiceps metacestodes are important sources of specific antigens and are efficient for immunodiagnosis of active and inactive NCC. PMID- 28012797 TI - Ataxia-telangiectasia mutated interactor regulates head and neck cancer metastasis via KRas expression. AB - OBJECTIVES: Relapse is the most serious problem affecting the morbidity and mortality rates of patients with head and neck squamous cell carcinoma (HNSCC). Although HNSCC has been studied for several decades, the exact mechanism of cancer recurrence remains unclear. MATERIALS AND METHODS: ataxia-telangiectasia mutated interactor (ATMIN) messenger RNA(mRNA) expression was detected in HNSCC samples by quantitative RT-PCR, and was analyzed with patients' clinical outcomes by Kaplan-Meier analyses. The ectopic ATMIN expression or ATMIN silencing on invasion ability was evaluated in HNSCC cell lines. Lymph node metastasis ability was investigated by buccal orthotopic implantation in vivo. All statistical tests were two-sided. RESULTS: ATMIN mRNA expression was positively correlated with patients' clinical outcomes. ATMIN blockage reduced invasion, migration, and metastasis abilities both in vitro and in vivo. Evidence from a buccal orthotopic implantation mice model showed that silenced ATMIN expression prolongs mice survival and reduced lymph node metastasis. In high-throughput microarray and bioinformative analyses, KRas was identified as a crucial downstream effector in ATMIN-mediated HNSCC metastasis and was positively associated with patients' clinical stages and ATMIN mRNA expression. CONCLUSIONS: The role of ATMIN and its regulatory mechanisms in HNSCC progression are reported for the first time. The study results improve our understanding of the ATMIN-KRas axis leading to HNSCC migration or invasion and metastasis and facilitates the identification of possible therapy targets of downstream genes for designing effective therapeutic strategies in personalized medicine. PMID- 28012798 TI - Generation of human pluripotent stem cell-derived hepatocyte-like cells for drug toxicity screening. AB - Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes are limited, making it difficult to supply the abundant quantities required for large-scale drug toxicity screening. Therefore, there is an urgent need for a novel unlimited, efficient, inexpensive, and predictive model which can be applied for large-scale drug toxicity screening. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are able to replicate indefinitely and differentiate into most of the body's cell types, including hepatocytes. It is expected that hepatocyte-like cells generated from human ES/iPS cells (human ES/iPS-HLCs) will be a useful tool for drug toxicity screening. To apply human ES/iPS-HLCs to various applications including drug toxicity screening, homogenous and functional HLCs must be differentiated from human ES/iPS cells. In this review, we will introduce the current status of hepatocyte differentiation technology from human ES/iPS cells and a novel method to predict drug-induced liver injury using human ES/iPS-HLCs. PMID- 28012799 TI - Clinic Personnel, Facilitator, and Parent Perspectives of eHealth Familias Unidas in Primary Care. AB - INTRODUCTION: The purpose of this qualitative study was to understand the feasibility and acceptability of implementing eHealth Familias Unidas, an Internet-based, family-based, preventive intervention for Hispanic adolescents, in primary care. METHODS: Semistructured individual interviews with clinic personnel and facilitators (i.e., physicians, nurse practitioners, administrators, and mental health workers; n = 9) and one focus group with parents (n = 6) were audiorecorded, transcribed verbatim, and analyzed using a general inductive approach. RESULTS: Nine major themes emerged, including recommendations to minimize disruption to clinic flow, improve collaboration and training of clinic personnel and the research team, promote the clinic as a trusted setting for improving children's behavioral health, and highlight the flexibility and convenience of the eHealth format. DISCUSSION: This study provides feasibility and acceptability findings, along with important considerations for researchers and primary care personnel interested in collaborating to implement an eHealth preventive intervention in pediatric primary care. PMID- 28012800 TI - Separation Anxiety Disorder in School-Age Children: What Health Care Providers Should Know. AB - Separation anxiety disorder (SAD) is the most common childhood anxiety disorder, and it has many consequences, particularly for school-age children. These consequences include excessive worry, sleep problems, distress in social and academic settings, and a variety of physical symptoms that, left untreated, can cause social and academic decline. Pediatric providers routinely see children in the primary care office and have the unique opportunity to diagnose, treat, and manage children with SAD. Despite this, SAD continues to be underdiagnosed and undertreated because of a gap in the literature regarding evidence-based practice guidelines for pediatric providers. The purpose of this article is to discuss the diagnosis and management of SAD in school-age children and highlight the role of pediatric providers in managing separation anxiety. PMID- 28012801 TI - Occurrence and variation of lipophilic shellfish toxins in phytoplankton, shellfish and seawater samples from the aquaculture zone in the Yellow Sea, China. AB - Lipophilic shellfish toxins (LSTs) produced by diverse microalgae have become a potential threat to the marine aquaculture industry in coastal regions throughout the world. In this study, phytoplankton, scallop, and seawater samples were collected and monitored in the aquaculture zone of Liuqing Bay located in the coast of Qingdao, Yellow Sea, in 2014 and 2015. Dissolved LSTs in seawater were adsorbed by solid phase adsorption toxin tracking (SPATT) bags and solid phase extraction (SPE) cartridges, respectively. PTX2 was found to be the predominant LSTs, while OA and DTX1 were detected at trace levels in the three species of Dinophysis and Phalacroma genera picked from the investigation zone. The highest quota of PTX2 occurred in D. fortii (0.28 pg cell-1), followed by D. acuminata complex (0.08 pg cell-1) and P. rotundatum (=D. rotundata) (0.02 pg cell-1). PTX2 (nd~5.7 MUg kg-1), OA (nd~2.8 MUg kg-1) and DTX1 (nd~1.6 MUg kg-1) were also observed in cultivated scallops, but in addition to the former, PTX2sa, 7-epi PTX2sa and an isobaric form of DTX1 suspected as DTX1b were also found in the SPATT bags. The isobaric compound of DTX1 only appeared in the SPATT bags deployed in field samples of seawater. A significant higher quantity of OA was adsorbed by SPATT bags compared to DTX1, although similar concentrations of both toxins were adsorbed by SPE cartridges from the aquaculture zone. AZA2 was also found in the concentrated phytoplankton cells, which demonstrated that AZA producing microalgae were present in this investigated area. The variation in concentrations of PTX2 adsorbed by SPATT bags could reflect the change of Dinophysis density in seawater, but there was a time lag behind the peaks of Dinophysis density. Comparative results did not support the SPATT technology as a useful warning tool for toxic algal blooms and toxin accumulation in bivalves. The data suggest that the contamination of LSTs was prevalent in the coast of Qingdao and the environmental behavior of LSTs should be explored further. PMID- 28012802 TI - Some pharmacological effects of Tityus obscurus venom in rats and mice. AB - There are a great number of studies about Brazilian scorpions. However, little is known about the venom of scorpions of northern Brazil, mainly about Tityus obscurus, which is responsible for the most number of accidents in the Amazon. Thus, this study aimed to evaluate some pharmacological effects of T. obscurus venom in rats and mice. In rats, the venom (10 mg/kg i.p.) caused hemorrhagic patches in the lung parenchyma but did not lead to pulmonary edema. There was a decrease in general activity, observed in the activity box after venom injection. The venom did not induce changes in the occurrence and intensity of experimentally induced convulsions, nor did it cause hippocampal neuronal loss. In mice, the LD50 obtained was 3.13 mg/kg (i.p.). Different doses of the venom (0.2; 1; 5; 10; 15 MUg/30 MUL per hind paw) induced edematogenic and moderate nociceptive activity in mice. The Tiyus serrulatus venom used as comparison caused more intense symptomatology in mice. Comparing to the venom of other Tityus scorpions of medical importance, that have convulsant and intense nociceptive effects and cause lung edema, as described in the literature, we can conclude that the venom of T. obscurus probably has different characteristics. PMID- 28012803 TI - Airway and Pulmonary beta2-Adrenergic Vasodilatory Function in Current Smokers and Never Smokers. AB - BACKGROUND: Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of beta2-adrenoceptor-mediated vasodilation in smokers and never smokers. METHODS: In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 MUg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived. RESULTS: Albuterol induced a substantial drop in mean (+/- SE) PVR (-67.2% +/- 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% +/- 3% vs -3.1% +/- 6%; P < .02). CONCLUSIONS: These results are consistent with a dysfunction in a beta2-adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium. PMID- 28012804 TI - Improved Cough and Cough-Specific Quality of Life in Patients Treated for Scleroderma-Related Interstitial Lung Disease: Results of Scleroderma Lung Study II. AB - BACKGROUND: Cough is a common symptom of scleroderma-related interstitial lung disease (SSc-ILD), but its relationship to other characteristics of SSc-ILD, impact on cough-specific quality of life (QoL), and response to therapy for SSc ILD have not been well studied. METHODS: We investigated frequent cough (FC) in patients with SSc-ILD (N = 142) enrolled in the Scleroderma Lung Study II, a randomized controlled trial comparing mycophenolate mofetil (MMF) and oral cyclophosphamide (CYC) as treatments for interstitial lung disease (ILD). We determined the impact of FC on QoL (Leicester Cough Questionnaire [LCQ]), evaluated the change in FC in response to treatment for SSc-ILD, and examined the relationship between gastroesophageal reflux disease (GERD) and cough during the trial. RESULTS: Study participants who reported FC at baseline (61.3%) reported significantly more dyspnea, exhibited more extensive ILD on high-resolution CT, had a lower diffusing capacity for carbon monoxide, and reported more GERD symptoms than did those without FC. Cough-specific QoL was modestly impaired in patients with FC (total LCQ score, 15.4 +/- 3.7; normal range, 3-21 [higher scores indicate worse QoL]). The proportion of patients with FC at baseline declined by 44% and 41% over 2 years in the CYC and MMF treatment arms, respectively, and this decline was significantly related to changes in GERD and ILD severity. CONCLUSIONS: FC occurs commonly in SSc-ILD, correlates with both the presence and severity of GERD and ILD at baseline, and declines in parallel with improvements in both ILD and GERD over a 2-year course of therapy. Frequent cough might serve as a useful surrogate marker of treatment response in SSc-ILD trials. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00883129; URL: www.clinicaltrials.gov. PMID- 28012805 TI - Clinical Implications of Sarcopenia on Decreased Bone Density in Men With COPD. AB - BACKGROUND: Sarcopenia and osteoporosis are systemic features of COPD. The present study investigated the association between sarcopenia and osteopenia/osteoporosis and the factors associated with low bone mineral density (BMD) in men with COPD. METHODS: Data from 777 men with COPD who underwent both pulmonary function test and dual-energy x-ray absorptiometry were extracted from the Korean National Health and Nutritional Examination Survey database between 2008 and 2011. Sarcopenia was assessed with the appendicular skeletal mass index (ASMI) and osteopenia/osteoporosis with the T-score. RESULTS: As the severity of airflow limitation increased, the prevalence of sarcopenia increased (Ptrend < .001). Additionally, as the degree of sarcopenia became severe, the prevalence of osteopenia/osteoporosis increased (Ptrend < .001), and a significant positive correlation was noted between appendicular skeletal muscle mass and BMD (ASMI/T score: r = 0.408; P < .001). Sarcopenia was independently associated with an increased risk of low BMD in men with COPD (OR, 2.31; 95% CI, 1.53-3.46; P < .001). Old age and low fat mass were significantly associated with low BMD in both sarcopenic and non-sarcopenic participants. High serum hemoglobin and insulin levels were associated with a reduced risk of low BMD only in the sarcopenic participants, whereas exercise and dietary intake were associated with a reduced risk only in the non-sarcopenic participants. CONCLUSIONS: Sarcopenia is closely correlated with osteopenia/osteoporosis in men with COPD. Moreover, different factors are associated with low BMD according to the presence/absence of sarcopenia in that population. PMID- 28012806 TI - Shift Work and Shift Work Sleep Disorder: Clinical and Organizational Perspectives. AB - Throughout the industrialized world, nearly one in five employees works some form of nontraditional shift. Such shift work is associated with numerous negative health consequences, ranging from cognitive complaints to cancer, as well as diminished quality of life. Furthermore, a substantial percentage of shift workers develop shift work disorder, a circadian rhythm sleep disorder characterized by excessive sleepiness, insomnia, or both as a result of shift work. In addition to adverse health consequences and diminished quality of life at the individual level, shift work disorder incurs significant costs to employers through diminished workplace performance and increased accidents and errors. Nonetheless, shift work will remain a vital component of the modern economy. This article reviews seminal and recent literature regarding shift work, with an eye toward real-world application in clinical and organizational settings. PMID- 28012807 TI - Photodynamic inactivation of oral paracoccidioidomycosis affecting woman with systemic lupus erythematosus: An unusual case report. AB - Paracoccidioidomycosis (PCM) is a systemic disease caused by the dimorphic fungus Paracocdioides brasiliensis. The infection primarily reaches the lungs by the inhalation of fungi spores and later can disseminate to other organs causing secondary oral lesions. Systemic lupus erythematosus (SLE), on the other hand, is an autoimmune chronic inflammatory disease that affects various organ systems, including skin and oral cavity. Here we report a 39-year-old female patient bearing SLE and presenting an ulcerated lesion on the hard palate extending to the superior alveolar ridge, diagnosed as PCM. Itraconazole 200mg was prescribed and photodynamic therapy (PDT) was also instituted in a way to help dealing with the PCM infection while assisting such an immunocompromised patient to heal. PDT consisted of topically placing toluidine blue dye at 37.5mg/L for 5min, followed by low-level laser irradiation (660nm; 100J/cm2; 40mW of power; 100s per point). Forty days after beginning the treatment, the patient showed total regression of the oral lesion and absence of painful symptoms. The serologic test was performed again after six months of therapy and was negative; the patient continues to be followed periodically. PMID- 28012809 TI - Prevalence of co-infection between respiratory syncytial virus and influenza in children. AB - BACKGROUND: Respiratory syncytial virus (RSV) and influenza have varying degree of seasonal overlap. OBJECTIVE: To determine the prevalence of co-infection of RSV and influenza compared to the prevalence of those infections independently when both are in season. METHODS: This was a retrospective cross-sectional study of children evaluated between July 2010 and June 2013 for viral respiratory infection using multiplex PCR. Seasonality was defined retrospectively as weeks when >2% of the total annual positive tests were obtained and was calculated for influenza A, influenza B, and RSV independently. Periods of overlapping seasonality of RSV and influenza A and RSV and influenza B were identified. The expected incidences of co-infection were modeled as the product of the incidences of the individual viruses. RESULTS: 13,664 specimens were sent for PCR during the study period. Over all 3 seasons, RSV overlapped with influenza A and B for 22 and 18weeks, respectively; in 2011-12, RSV overlapped with neither influenza A nor B. Based on modeling, there were 6-7 fold fewer cases of RSV/influenza co infection observed than expected: RSV/influenza A 77 vs. 12, (p<=0.001; RSV/influenza B 76 vs. 11 (p<=0.001). CONCLUSIONS: The observed incidence of co infectivity of RSV and influenza was significantly less than the expected incidence even when both were co-circulating. In light of these data, it may be reasonable to forgo rapid influenza testing or empiric antiviral treatment for children whom rapid RSV testing is positive and who are at low risk of influenza related complications, especially in times of antiviral therapy shortages. PMID- 28012808 TI - Post-partum hemorrhage complicated by reverse-Takotsubo cardiogenic shock; a novel therapeutic approach. AB - Takotsubo Cardiomyopathy (TTC) is a type of transient, yet severe left ventricular systolic dysfunction, rarely complicating extreme emotional stress ("primary" TTC) or critical medical/surgical illness ("secondary" TTC forms). Although usually reversible, TTC may result in cardiogenic shock with dismal prognosis. "Secondary" TTC forms are particularly in danger for this complication, bearing significantly worse short and long-term prognosis. Herein, we report a rare case of a life-threatening "secondary" TTC in a patient with post-cesarean section severe hemorrhage, and we point out that early co administration of esmolol and levosimendan might be an effective and safe therapeutic approach in "reversing" TTC-induced cardiogenic shock, especially when invasive therapeutic strategies are practically unfeasible. PMID- 28012810 TI - The Role of Gender and Physical Performance on Injuries: An Army Study. AB - INTRODUCTION: In basic combat training, women experience twice as many injuries as men; however, evidence at the operational Army level is limited. This study aims to investigate the association between gender and injury likelihood while controlling for certain confounding factors in the operational Army. METHODS: Data were analyzed in 2015 from a cross-sectional study utilizing data from a 2010-2011 survey of light infantry Army Soldiers. Gender, age, body fat, tobacco use, Army Physical Fitness Test (2-mile run, push-ups, and sit-ups), occupational physical demand, and injury data were obtained via paper survey. ORs and 95% CIs from a multivariable analysis were calculated. RESULTS: Surveys were completed by 4,384 male and 363 female Soldiers. Injury incidence was 42% for men and 53% for women. After adjusting for the aforementioned variables, injury likelihood was higher in Soldiers aged >=27 years (OR [age 27-29/22-26 years]=1.26, 95% CI=1.07, 1.48; OR [age >=30/22-26 years]=1.28, 95% CI=1.08, 1.51), Soldiers with body fat >=23.38% (OR [body fat >=23.38%/<=19.28%]=1.30, 95% CI=1.08, 1.57), and Soldiers with the slowest 2-mile run times (OR [>=15.68/<=14.13 minutes]=1.53, 95% CI=1.26, 1.85). Women were no more likely than men to sustain an injury. CONCLUSIONS: When accounting for age, body fat, physical performance, and occupational physical demand, there was no gender difference in the likelihood of injury among Soldiers. Although women, on average, have lower aerobic and muscular performance than men, results suggest men and women of similar physical performance experience similar injury likelihood. PMID- 28012811 TI - Denominator Issues for Personally Generated Data in Population Health Monitoring. PMID- 28012812 TI - Disparities in Tuberculosis Treatment Completion by Incarceration Status, U.S., 1999-2011. AB - INTRODUCTION: Treatment completion is the cornerstone of tuberculosis (TB) control strategy globally. Although the majority of reported TB cases in the U.S. have documented treatment completion, individuals diagnosed while incarcerated are less likely to have documentation of whether or not they completed treatment. This study assessed trends and correlates of no documented treatment completion among individuals incarcerated at diagnosis. METHODS: U.S. National TB Surveillance System (1999-2011) data on cases eligible for treatment completion were analyzed during 2014-2015. Treatment outcomes and trends in no documented completion were assessed by incarceration status. Multivariable logistic regression identified correlates of no documented completion among people incarcerated at diagnosis. RESULTS: A lower proportion of individuals incarcerated at diagnosis had documented TB treatment completion than non incarcerated individuals (75.6% vs 93.7%), and a higher proportion were lost to follow-up (10.7% vs 2.2%) or moved (9.4% vs 2.3%) during treatment (p<0.001). The 1999-2011 trend in no documented completion significantly increased among those incarcerated at diagnosis and declined among non-incarcerated individuals. Being foreign born was the strongest correlate of no documented completion among people incarcerated at diagnosis (AOR=2.86, 95% CI= 2.35, 3.49). Social risk factors for TB (e.g., homelessness, substance abuse), although common among incarcerated individuals, did not emerge as correlates of no documented completion. CONCLUSIONS: People diagnosed with TB disease at U.S. correctional facilities, especially the foreign born, require enhanced strategies for documenting TB treatment completion. Strengthened collaboration between correctional and public health agencies could improve continuity of care among released inmates. PMID- 28012813 TI - Preventive Medicine's Identity Crisis. PMID- 28012814 TI - Parental-Reported Full Influenza Vaccination Coverage of Children in the U.S. AB - INTRODUCTION: Depending upon influenza vaccination history, children aged 6 months-8 years need one or two doses of influenza vaccine to be considered fully vaccinated. The objectives of this study were to quantify the percentage of children aged 6 months-8 years who were fully vaccinated against influenza based on parental report, overall, by state, and by sociodemographic characteristics, and to examine sociodemographic characteristics associated with being fully vaccinated. METHODS: Data from the National Immunization Survey-Flu for the 2012 2013 and 2013-2014 influenza seasons were analyzed in 2015 using the Kaplan-Meier method to produce vaccination coverage estimates. Wald chi-square tests were used to test for bivariate associations, and Cox proportional hazards models were used to test for demographic characteristics independently associated with the child being fully vaccinated. RESULTS: The percentages of children aged 6 months-8 years who were fully vaccinated during the 2012-2013 and 2013-2014 influenza seasons were 41.0% and 45.2%, respectively. Full vaccination varied widely by state and was more likely for children requiring only one dose. Based on the statistical models, children likely to be fully vaccinated were older, non-black, had a mother with an education >12 years, or lived in a high-income household. CONCLUSIONS: Most children in the U.S. are not fully vaccinated against influenza. Reminder systems and interventions that reduce or remove barriers to children receiving their second doses of influenza vaccine may improve full influenza vaccination coverage among all children. PMID- 28012815 TI - An uncommon manifestation of acute leukemia. PMID- 28012816 TI - "Small white sign" in Barrett's esophageal cancer under the squamous epithelium. PMID- 28012817 TI - How robust is our peer-review system? A review of emerging models. PMID- 28012818 TI - Tissue specific regulation of the chick Sox10E1 enhancer by different Sox family members. AB - The transcription factor Sox10 is a key regulator of vertebrate neural crest development and serves crucial functions in the differentiation of multiple neural crest lineages. In the chick neural crest, two cis-regulatory elements have been identified that mediate Sox10 expression: Sox10E2, which initiates expression in cranial neural crest; Sox10E1 driving expression in vagal and trunk neural crest. Both also mediate Sox10 expression in the otic placode. Here, we have dissected and analyzed the Sox10E1 enhancer element to identify upstream regulatory inputs. Via mutational analysis, we found two critical Sox sites with differential impact on trunk versus otic Sox10E1 mediated reporter expression. Mutation of a combined SoxD/E motif was sufficient to completely abolish neural crest but not ear enhancer activity. However, mutation of both the SoxD/E and another SoxE site eliminated otic Sox10E1 expression. Loss-of-function experiments reveal Sox5 and Sox8 as critical inputs for trunk neural crest enhancer activity, but only Sox8 for its activity in the ear. Finally, we show by ChIP and co-immunoprecipitation that Sox5 directly binds to the SoxD/E site, and that it can interact with Sox8, further supporting their combinatorial role in activation of Sox10E1 in the trunk neural crest. The results reveal important tissue-specific inputs into Sox10 expression in the developing embryo. PMID- 28012819 TI - Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial. AB - PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). DESIGN: Phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. METHODS: At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 MUg, 10 MUg, 15 MUg, or 20 MUg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. RESULTS: Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP reduction from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-MUg, 10-MUg, 15-MUg, and 20-MUg dose strengths of implant, respectively, vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, respectively. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes). CONCLUSIONS: Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months. PMID- 28012820 TI - Oral supplementation with bovine whey-derived Ig-rich fraction and lactoferrin improves SCORAD and DLQI in atopic dermatitis. PMID- 28012821 TI - Validation of chemiluminescent enzyme immunoassay in detection of autoantibodies in pemphigus and pemphigoid. AB - BACKGROUND: A novel chemiluminescent enzyme immunoassay (CLEIA) was recently developed to quantify autoantibodies specific for desmogleins (Dsgs) and BP180, the target antigens of pemphigus and pemphigoid. This assay is automated and highly accurate and efficient. OBJECTIVE: To validate the use of the CLEIA for detection of autoantibodies during the clinical courses of patients with pemphigus and pemphigoid. METHODS: To define cut-off values for Dsg1, Dsg3, and BP180, we evaluated 47 serum samples from patients with pemphigus foliaceus (PF), 59 from those with pemphigus vulgaris (PV), 52 from those with bullous pemphigoid (BP), and 995 from healthy individuals. We also evaluated any fluctuations in CLEIA titers according to disease activity during the clinical course of 10 cases each of PF, PV, and BP. We used clinical symptom scores, the pemphigus disease area index (PDAI) and the bullous pemphigoid disease area index (BPDAI), to evaluate disease activity. RESULTS: The cut-off values for the CLEIA titers determined by the Youden index were 15.4U/mL for Dsg1, 14.9U/mL for Dsg3, and 16.8U/mL for BP180. CLEIA titers fluctuated in parallel with the PDAI/BPDAI scores in 28 of the 30 cases with PF, PV, or BP. Although the CLEIA and enzyme linked immunosorbent assay (ELISA) values in the same samples differed substantially in some cases, the concordance rates of positive/negative results between the CLEIA and ELISA were 96% for Dsg1, 97% for Dsg3, and 96% for BP180. CONCLUSION: The CLEIA, a newly developed, highly effective autoantibody detection system, is as reliable as ELISA for evaluation of the clinical courses of pemphigus and pemphigoid. PMID- 28012822 TI - HMGB1/RAGE axis promotes autophagy and protects keratinocytes from ultraviolet radiation-induced cell death. AB - BACKGROUND: The primary cause of skin cancer is ultraviolet (UV) light from the sun. Keratinocytes are the predominant cell type in the epidermis and form a barrier against environmental damage, especially from UV light irradiation. Autophagy is a self-digestion mechanism for energy homeostasis at critical times during development and as a response to stress. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein that is associated with cell autophagy. OBJECTIVE: We investigated the role of HMGB1 in keratinocytes exposed to UV irradiation and its regulation of keratinocyte autophagy. METHODS: Specimens of UV-exposed human skin were assayed immunohistochemically for HMGB1. HaCaT immortalized human keratinocytes were used to investigate the mechanism of HMGB1 translocation induced by UV irradiation. Levels of cytosolic reactive oxygen species (ROS) were determined by H2DCF assay, apoptosis was assayed by flow cytometry and western-blot after lentivirus-mediated shRNA targeting of HMGB1 in keratinocytes by UV irradiation. Phosphorylated-Erk1/2 expression was assayed by western blotting. RESULTS: HMGB1 and its receptor (receptor for advanced glycation end products, RAGE) were both expressed by HaCaT cells, and HMGB1 was transferred from the nucleus to the cytoplasm after UV irradiation in both HaCaT and human skin keratinocytes. Knockdown of HMGB1 expression by lentivirus-mediated shRNA limited UV-induced autophagy and led to increased apoptosis of HaCaT cells. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. UV irradiation led to phosphorylation of Erk1/2 in HaCaT cells. Inhibition of RAGE and Erk1/2 limited HaCaT cell autophagy. CONCLUSION: Autocrine HMGB1 modulated HaCaT autophagy via a RAGE/HMGB1/extracellular signal-regulated Erk1/2-dependent pathway to protect keratinocytes from apoptosis during UV irradiation. PMID- 28012823 TI - Primary Care Management of Skin Abscesses Guided by Ultrasound. AB - BACKGROUND: Primary care providers often manage skin abscesses in the outpatient setting. Estimating the size and depth of an abscess, and distinguishing abscess from cellulitis by clinical examination can be challenging due to surrounding firm tissue induration. Definitive treatment of abscess requires incision and drainage, and the approach chosen may be altered by abscess size, depth, and surrounding neurovascular structures. METHODS: For 31 consecutive patients seen in the primary care outpatient clinic, we prospectively compared the estimated size of skin abscesses by clinical examination with that determined by ultrasound. Prior to incision and drainage, a limited point-of-care ultrasound examination was performed and the abscess dimensions were measured, the depth was determined, and adjacent vascular structures were noted. Based on ultrasound findings, physicians reported whether the decision to perform the procedure or the techniques used to perform the procedure were altered by the scan. RESULTS: The clinical examination was inaccurate for size estimation by >0.5 cm in 16 of 31 patients (52%). Ultrasound examination changed the physician decision of whether or not incision and drainage should be performed in 7 patients (23%) and altered the technique/approach in an additional 10 patients (32%); thus, management was changed in 55% of cases. Physician confidence in performing the procedure was improved in 16 cases (52%). CONCLUSION: Outpatient procedural management of skin abscesses by primary care physicians was altered in more than half the cases by performing point-of-care ultrasound prior to incision and drainage. PMID- 28012824 TI - Free-Floating Right Heart Thrombi. PMID- 28012825 TI - Detection of the antipsychotic drug quetiapine in the blood, urine and hair samples of the victim of a drug-facilitated sexual assault. AB - A drug rape facilitated with the sedative antipsychotic drug quetiapine is presented here. A teenage girl and her girlfriend went to the home of an adult couple they had met at a bar. Here, the teenage girl (victim) felt tired after consuming some alcoholic drinks and fell asleep. While she was asleep, the others left her at the house alone and returned to the bar. Later, the girl woke up to witness the adult male having intercourse with her, but she was not able to resist the attack. She fell asleep again and slept through the next day and a half, after which she left the house. Forty-three hours after the suspected drug facilitated sexual assault (DFSA), blood and urine samples were collected and the initial toxicological screening detected quetiapine. Confirmation and quantification by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) revealed a concentration of 0.007mg/kg quetiapine in blood and 0.19mg/l in urine. Six months after the DFSA, a hair sample was collected and segmental hair analysis was performed on four washed segments (0 3cm, 3-5cm, 5-7cm, and 7-9cm). The last segment contained 0.011ng/mg of quetiapine, whereas the other segments were negative. The low level of quetiapine in the hair segment and its absence in the other segments indicate that the victim had only consumed one or a few doses of quetiapine within that period and was not a regular user. This study describes the first drug-facilitated assault involving a single dose of quetiapine that was detected by hair, blood and urine analysis. This case illustrates the importance of having very sensitive analytical methods for measurement of a single dose in blood and urine and how the extended detection window for hair analysis can reveal more information in such cases. PMID- 28012826 TI - Increase of posterior connectivity in aging within the Ventral Attention Network: A functional connectivity analysis using independent component analysis. AB - Multiple studies have found neurofunctional changes in normal aging in a context of selective attention. Furthermore, many articles report intrahemispheric alteration in functional networks. However, little is known about age-related changes within the Ventral Attention Network (VAN), which underlies selective attention. The aim of this study is to examine age-related changes within the VAN, focusing on connectivity between its regions. Here we report our findings on the analysis of 27 participants' (13 younger and 14 older healthy adults) BOLD signals as well as their performance on a letter-matching task. We identified the VAN independently for both groups using spatial independent component analysis. Three main findings emerged: First, younger adults were faster and more accurate on the task. Second, older adults had greater connectivity among posterior regions (right temporoparietal junction, right superior parietal lobule, right middle temporal gyrus and left cerebellum crus I) than younger adults but lower connectivity among anterior regions (right anterior insula, right medial superior frontal gyrus and right middle frontal gyrus). Older adults also had more connectivity between anterior and posterior regions than younger adults. Finally, correlations between connectivity and response time on the task showed a trend toward connectivity in posterior regions for the older group and in anterior regions for the younger group. Thus, this study shows that intrahemispheric neurofunctional changes in aging also affect the VAN. The results suggest that, in contexts of selective attention, posterior regions increased in importance for older adults, while anterior regions had reduced centrality. PMID- 28012827 TI - Comparison of level and degree of upper airway obstruction by Muller's maneuver and drug-induced sleep endoscopy in obstructive sleep apnea patients. AB - OBJECTIVE: This study aimed to compare and analyze the level and degree of observed upper airway obstruction in patients with obstructive sleep apnea (OSA) using Muller's maneuver (MM) and drug-induced sleep endoscopy (DISE). We sought to find a method for evaluating the upper airway that could be used to determine surgical sites. METHODS: This study included 80 OSA patients who visited Kyung Hee Medical Center and underwent polysomnography (PSG) from March 2013 to March 2014. Obstructive levels observed by MM were classified into retropalatal level, or the lateral wall and retroglossal level. These levels were compared with those determined by DISE through the VOTE classification. RESULTS: Based on the results of MM and DISE, lateral wall and retropalatal level obstructions showed relatively high conformity, while retroglossal level obstruction exhibited considerable differences. When evaluated at each level, patients with obstruction on MM also showed partial or complete obstruction on DISE at same level, and patients with no obstruction on DISE also showed no obstruction on MM at same level. CONCLUSION: Both examination methods revealed the same obstruction levels in all cases except epiglottic level, but there were some differences in obstructive degree. MM is capable of detecting obstruction levels in the upper airway and can be used to determine surgical sites in cases when DISE cannot be used due to a patient's condition or a clinic's circumstances. PMID- 28012828 TI - Can Patient Variables Measured on Arrival to the Emergency Department Predict Disposition in Medium-acuity Patients? AB - BACKGROUND: Emergency department crowding has led to innovative "front end" care models to safely and efficiently care for medium and lower acuity patients. In the United States, most treatment algorithms rely on the emergency severity index (ESI) triage tool to sort patients. However, there are no objective criteria used to differentiate ESI 3 patients. OBJECTIVE: We seek to derive and validate a model capable of predicting patient discharge disposition (DD) using variables present on arrival to the emergency department for ESI 3 patients. METHODS: Our retrospective cohort study included adult patients with an ESI triage designation 3 treated in an academic emergency department over the course of 2 successive years (2013-2015). The main outcome was DD. Two datasets were used in the modeling process. One dataset, the derivation dataset (n = 25,119), was used to develop the statistical model, while the second dataset, the validation dataset (n = 24,639), was used to evaluate the statistical model's prediction performance. RESULTS: All variables included in the derivation model were uniquely associated with DD status (p < 0.001). We assessed multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for age (2.50 [95% CI 2.35 2.65]), arrival mode (1.85 [95% CI 1.74-1.96]), heart rate (1.31 [95% CI 1.26 1.37]), sex (1.35 [95% CI 1.28-1.43]), oxygen saturation (1.06 [95% CI 1.01 1.10]), temperature (1.10 [95% CI 1.06-1.15]), systolic blood pressure (1.18 [95% CI 1.12-1.25]), diastolic blood pressure (1.16 [95% CI 1.09-1.22]), respiratory rate (1.05 [95% CI 1.01-1.10]), and pain score (1.13 [95% CI 1.06-1.21]). The validation C-statistic was 0.73. CONCLUSION: We derived and validated a model and created a nomogram with acceptable discrimination of ESI 3 patients on arrival for purposes of predicting DD. Incorporating these variables into the care of these patients could improve patient flow by identifying patients who are likely to be discharged. PMID- 28012829 TI - L1 retrotransposition alters the hippocampal genomic landscape enabling memory formation. AB - Somatic LINE-1 (L1) retrotransposition is a source of genomic mosaicism and potential phenotypic diversity among neurons during brain development. In the adult brain, L1 expression can be triggered by different environmental alterations, but its functional role in this context remains unknown. Here we demonstrate a neural activation-dependent increase in the number of L1 retrotransposon insertions in the hippocampus. Using both pharmacologic and genetic approaches in mice, we demonstrate that L1 expression in the adult hippocampus enables long-term memory formation. These results provide experimental evidence that L1 retrotransposition-induced genomic mosaicism is involved in cognitive processes such as memory formation. PMID- 28012830 TI - Individual differences in stress vulnerability: The role of gut pathobionts in stress-induced colitis. AB - Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius-free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories. PMID- 28012831 TI - Selective inhibition of MAO-A activity results in an antidepressant-like action of 2-benzoyl 4-iodoselenophene in mice. AB - Depression is a leading cause of disability worldwide. For this reason, the aim of this study was to investigate the possible antidepressant-like activity of 2 benzoyl-4-iodoselenophene (C17H11IOSe), a selenophene compound, in two well consolidated behavioral assays for screening antidepressant activity (forced swimming test and tail suspension test) in mice. In order to investigate the mechanism of action of C17H11IOSe, it was investigated the activities of cerebral enzymes: monoamine oxidase MAO A and B and Na+, K+ ATPase, and if an inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA) (100mg/kg) blocks the antidepressant-like effect of C17H11IOSe. Swiss mice received (C17H11IOSe) (5 50mg/kg) or canola oil by the intragastric (i.g.) route before behavioral tests. The results showed that C17H11IOSe at dose range of 5-50mg/kg decreased immobility time in the tail suspension test. In the forced swimming test, C17H11IOSe reduced the immobility time at the doses of 10 and 50mg/kg. C17H11IOSe differently affected the cerebral cortical Na+, K+ ATPase; the effects on this enzyme were dependent of the dose tested. At a dose of 10mg/kg, the compound increased Na+, K+ ATPase activity, while the activity was inhibited at a dose of 50mg/kg. pCPA blocked the antidepressant-like action of C17H11IOSe in mice. Therefore, C17H11IOSe (5-50mg/kg) selectively inhibited MAO-A activity in cerebral cortices of mice. The modulation of serotonergic system contributed to the antidepressant-like action of C17H11IOSe in mice. PMID- 28012832 TI - Randall Sakai, a friend and colleague. PMID- 28012833 TI - Randall Sakai. PMID- 28012834 TI - The Associations Between E-Cigarettes and Binge Drinking, Marijuana Use, and Energy Drinks Mixed With Alcohol. AB - PURPOSE: Use of e-cigarettes by youth is proliferating worldwide, but little is known about the behavioral profile of youth e-cigarette users and the association of e-cigarette use with other health-risky behaviors. This study examines the associations between e-cigarette use and tobacco, marijuana, and alcohol use among a large sample of Canadian youth. METHODS: Using Canadian data from 39,837 grade 9 to 12 students who participated in year 3 (2014-2015) of the COMPASS study, logistic regression models were used to examine how current use of e cigarettes were associated with tobacco, marijuana, binge drinking, and energy drinks mixed with alcohol. Pearson's chi-square tests were used to examine subgroup differences by sex. RESULTS: Overall, 9.75% of respondents were current e-cigarette users. Current cigarette smokers (odds ratio [OR] = 3.009), current marijuana users (OR = 5.549), and noncurrent marijuana users (OR = 3.653) were more likely to report using e-cigarettes than noncigarette smokers and nonmarijuana users. Gender differences among males and females showed higher risk of e-cigarette use among female current marijuana users (OR = 7.029) relative to males (OR = 4.931) and female current smokers (OR = 3.284) compared to males (OR = 2.862). Compared to nonbinge drinkers, weekly (OR = 3.253), monthly (OR = 3.113), and occasional (OR = 2.333) binge drinkers were more likely to use e cigarettes. Similarly, students who consume energy drinks mixed with alcohol (OR = 1.650) were more likely to use e-cigarettes compared to students who do not consume them. CONCLUSIONS: We identify that youth who binge drink or use marijuana have a greater increased risk for using e-cigarettes compared to cigarette smokers. These data suggest that efforts to prevent e-cigarette use should not only be discussed in the domain of tobacco control. PMID- 28012835 TI - Impaired endothelial function and arterial stiffness in patients with type 2 diabetes - The effect of a very low-dose combination of fluvastatin and valsartan. AB - AIM: Patients with type 2 diabetes are at increased cardiovascular risk. The aim was to explore whether the impaired arterial wall characteristics typical of these patients could be improved by the unique beneficial effects of a very low dose combination of fluvastatin and valsartan (low-flu/val). METHODS: Forty middle-aged males (50.4+/-6.1years) with type 2 diabetes were recruited to a double-blind, randomized study. Patients (N=20) received low-flu/val (10/20mg) or placebo (N=20) over 30days in addition to their regular therapy. Brachial artery flow mediated dilation (FMD), common carotid artery pulse wave velocity (PWV) and beta-stiffness were assessed before and after treatment, and 3 and 6months after treatment discontinuation. The treatment was then repeated. RESULTS: Arterial wall characteristics significantly improved. After 30days of intervention, FMD increased from 2.4+/-0.3 to 4.2+/-0.3 (p<0.001), PWV decreased from 6.4+/-0.1 to 5.8+/-0.2 (p<0.001) and beta stiffness decreased from 7.8+/-0.4 to 6.7+/-0.4 (p<0.001). Lipids and arterial pressure did not change. After treatment discontinuation, the beneficial effects decreased over the following months. The repetition of treatment completely regained the initial benefits. No changes were observed in the placebo group. CONCLUSIONS: Low-flu/val added on-top of optimal therapy substantially improves arterial wall characteristics in patients with type 2 diabetes. PMID- 28012836 TI - Validation of maternal recall of early pregnancy medication exposure using prospective diary data. AB - PURPOSE: Data about maternal recall accuracy for classifying early pregnancy medication exposure are meager. Nonetheless, studies often rely on recall to evaluate potential impact of pharmaceuticals on the developing fetus. METHODS: Right from the Start is a community-based pregnancy cohort that enrolled women from North Carolina, Tennessee, and Texas. A subset of 318 women participated in daily medication diaries initiated before conception (2006-2012). We examined nonsteroidal anti-inflammatory drugs (NSAIDs) as an example of a drug type that is difficult to study due to its intermittent and primarily over-the-counter use as well as its incomplete documentation in medical and pharmaceutical records. Selective serotonin reuptake inhibitors (SSRI) were assessed as a prescription medication comparator. Maternal recall of NSAID and SSRI use in early pregnancy was examined by comparing diary data (gold standard) to first-trimester interview. RESULTS: Sensitivity and specificity for recall of NSAID exposure were 78.6% and 62.3%, respectively (kappa statistic: 0.41), with 72.3% agreement for exposure classification. Sensitivity and specificity for recall of SSRI exposure were 77.8% and 99.0%, respectively (kappa statistic: 0.79), with 97.8% agreement. CONCLUSIONS: Our findings suggest the validity of maternal recall varies with medication type and prospective data collection should be prioritized when studying early pregnancy drug exposures. PMID- 28012837 TI - Feasibility and Efficacy of Nurse-Driven Acute Stroke Care. AB - BACKGROUND: Acute stroke care requires rapid assessment and intervention. Replacing traditional sequential algorithms in stroke care with parallel processing using telestroke consultation could be useful in the management of acute stroke patients. The purpose of this study was to assess the feasibility of a nurse-driven acute stroke protocol using a parallel processing model. METHODS: This is a prospective, nonrandomized, feasibility study of a quality improvement initiative. Stroke team members had a 1-month training phase, and then the protocol was implemented for 6 months and data were collected on a "run-sheet." The primary outcome of this study was to determine if a nurse-driven acute stroke protocol is feasible and assists in decreasing door to needle (intravenous tissue plasminogen activator [IV-tPA]) times. RESULTS: Of the 153 stroke patients seen during the protocol implementation phase, 57 were designated as "level 1" (symptom onset <4.5 hours) strokes requiring acute stroke management. Among these strokes, 78% were nurse-driven, and 75% of the telestroke encounters were also nurse-driven. The average door to computerized tomography time was significantly reduced in nurse-driven codes (38.9 minutes versus 24.4 minutes; P < .04). CONCLUSIONS: The use of a nurse-driven protocol is feasible and effective. When used in conjunction with a telestroke specialist, it may be of value in improving patient outcomes by decreasing the time for door to decision for IV-tPA. PMID- 28012838 TI - Clinical Outcome of Mechanical Thrombectomy for Stroke in the Elderly. AB - BACKGROUND: Endovascular revascularization with mechanical devices has proven an effective treatment for proximal occlusions of the major intracranial arteries in stroke patients, but there is only limited information as to whether there should be an age limit for its use. We aimed to evaluate the safety and effectiveness of endovascular revascularization in stroke patients aged 80 years and older, and compare the results with younger patients. METHODS: We prospectively collected 81 consecutive patients subjected to mechanical thrombectomy for proximal occlusion of the anterior circulation during a period of 27 months. According to age, patients were divided into those aged less than 80 years (younger group) and those aged 80 years and older (elderly group). We analyzed favorable outcome, successful and futile recanalization, neurological improvement, in-hospital complications, and mortality in both groups. RESULTS: A favorable outcome (modified Rankin Scale score <=2 at 3 months) was reached by 51.6% in the elderly group and 64% of younger patients, and neurological improvement (improvement of >=4 points on National Institutes of Health Stroke Scale) was present in 77.4% of the elderly group. Overall, successful recanalization rates were 95.1% and futile recanalization reached 39% without statistically significant differences between both groups. Elderly patients presented more in-hospital complications (61.3% versus 38%) and higher mortality rates (16.1% versus 8%). CONCLUSIONS: Clinical independence was reached in over half of elderly stroke patients treated with mechanical thrombectomy, supporting the use of this treatment without age restriction. PMID- 28012839 TI - Prevalence and Risk Factors for Delirium in Acute Stroke Patients. A Retrospective 5-Years Clinical Series. AB - BACKGROUND: Delirium is characterized by disturbances of attention and cognition that cause functional decline and complications. The predisposing factors of delirium are age, male gender, systemic or metabolic disorders, dementia, and stroke. This study aims to evaluate the prevalence of delirium and to identify risk factors. METHODS: This is a retrospective study that includes patients admitted over 5 years with acute stroke. Patients with transient ischemic attack or venous thrombosis were excluded. Delirium was defined according the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Demographical characteristics, clinical-radiological profile, dependence on discharge (modified Rankin Scale score of >=3 and Barthel Index < 65%), and mortality during hospitalization were compared between patients with and without delirium. RESULTS: A total of 1161 patients were admitted (910 ischemic and 162 hemorrhagic). During hospitalization, 118 patients presented with delirium (10.2%) and 93 died (8%). On discharge, 517 patients were dependent (44.5%). Delirium was significantly associated with age, male gender, cortical infarcts in anterior circulation, higher leukocyte count, cholesterol and fibrinogen levels, lower albumin, atrial fibrillation, previous diagnosis of Alzheimer's disease, and hemorrhagic stroke. Logistic regression results showed that only previous Alzheimer's disease was related to delirium (odds ratio 21.68 [95% confidence interval 1.190-395.026, P = .038]). Dependence on discharge was associated with delirium. CONCLUSIONS: Ten percent of the patients presented with delirium associated with older age, Alzheimer's disease, and cortical anterior stroke. Patients with delirium had a higher risk of functional dependence on discharge. PMID- 28012840 TI - Synthesis and biological characterisation of ester and amide derivatives of fusidic acid as antiplasmodial agents. AB - A series of novel fusidic acid (FA) derivatives was synthesized by replacing the carboxylic acid group with various ester and amide groups and evaluated in vitro for their antiplasmodial activity against the chloroquine-sensitive NF54 and multidrug-resistant K1 strains of the malarial parasite Plasmodium falciparum. Most of these derivatives showed a 4-49 and 5-17-fold increase in activity against NF54 and KI strains, respectively, as compared to FA and had a good selectivity index. These derivatives are stable over the incubation period and do not appear to be prodrugs of fusidic acid. PMID- 28012841 TI - Endocrine disruptors and the tumor microenvironment: A new paradigm in breast cancer biology. AB - Breast cancer is one of the most frequently diagnosed malignancies in women and is characterized by predominantly estrogen dependent growth. Endocrine disruptors (EDCs) have estrogenic properties which have been shown to increase breast cancer risk. While the direct effects of EDCs on breast cancer cell biology and tumor progression have been well studied, the roles for EDCs on tumor microenvironment composition, signaling and structure are incompletely defined. Estrogen targeting of tumor stromal cells can drive paracrine signaling to breast cancer cells regulating tumorigenesis and progression. Additionally, estrogen and estrogen receptor signaling has been shown to alter breast architecture and extracellular matrix component synthesis. Unsurprisingly, EDCs have been shown to induce structural changes in the mammary gland as well as increased collagen fibers in the tissue stroma. Previous work demonstrates that human mesenchymal stem cells (hMSC) are essential components of the tumor microenvironment and are direct targets of both estrogens and EDCs. Furthermore, estrogen-stem cell cross talk has been implicated in breast cancer progression and results in increased tumor cell proliferation, angiogenesis and invasion. This review aims to dissect the possible relationship and mechanisms between EDCs, the tumor microenvironment, and breast cancer progression. PMID- 28012842 TI - Reconstruction of the Isolated Columellar Defect: A Novel 2-Stage Technique and Review of the Literature. AB - The importance of the nasal complex cannot be overstated from a functional, social, and psychological perspective. The goal of reconstruction is to restore the trilaminar composition of the nose. This is accomplished by recreating the nasal lining and providing a cartilaginous framework to simultaneously support a patent airway and project the defining features to the overlying soft tissue. The columella is one of the smallest subunits of the nose, but the loss of this structure has important esthetic and structural implications. The ideal operation for an isolated defect of the columella remains elusive. The ideal reconstruction would match the pigmentation and texture of the surrounding nasal skin and provide a convex contour with underlying structural support. In addition, the donor site would not create a secondary deformity by disrupting normal anatomy. This report describes a novel 2-stage technique for reconstruction of the columella and reviews the current literature. PMID- 28012843 TI - Validation of a Novel Cognitive Simulator for Orbital Floor Reconstruction. AB - PURPOSE: The increasing focus on patient safety in current medical practice has promoted the development of surgical simulation technology in the form of virtual reality (VR) training designed largely to improve technical skills and less so for nontechnical aspects of surgery such as decision making and material knowledge. The present study investigated the validity of a novel cognitive VR simulator called Touch Surgery for a core maxillofacial surgical procedure: orbital floor reconstruction (OFR). MATERIALS AND METHODS: A cross-sectional study was carried out on 2 groups of participants with different experience levels. Novice graduate dental students and expert surgeons were recruited from a local dental school and academic residency programs, respectively. All participants completed the OFR module on Touch Surgery. The primary outcome variable was simulator performance score. Post-module questionnaires rating specific aspects of the simulation experience were completed by the 2 groups and served as the secondary outcome variables. The age and gender of participants were considered additional predictor variables. From these data, conclusions were made regarding 3 types of validity (face, content, and construct) for the Touch Surgery simulator. Dependent-samples t tests were used to explore the consistency in simulation performance scores across phases 1 and 2 by experience level. Two multivariate ordinary least-squares regression models were fit to estimate the relation between experience and phase 1 and 2 scores. RESULTS: Thirty-nine novices and 10 experts who were naive to Touch Surgery were recruited for the study. Experts outperformed novices on phases 1 and 2 of the OFR module (P < .001), which provided the measurement of construct validation. Responses to the questionnaire items used to assess face validity were favorable from the 2 groups. Positive questionnaire responses also were recorded from experts alone on items assessing the content validity for the module. Participant age and gender were not relevant predictors of performance scores. CONCLUSION: Construct, content, and face validities were observed for the OFR module on a novel cognitive simulator, Touch Surgery. Therefore, OFR simulation on the smart device platform could serve as a useful cognitive training and assessment tool in maxillofacial surgery residency programs. PMID- 28012844 TI - Maxillofacial Features Related to Mandibular Asymmetries in Skeletal Class III Patients. AB - PURPOSE: To analyze components related to different degrees of mandibular asymmetry in adults with skeletal Class III using cone-beam computed tomographic (CBCT) images. MATERIALS AND METHODS: CBCT images from 138 patients were analyzed. Asymmetry was determined by the deviation of the gnathion point in relation to the midsagittal plane and classified as relative symmetry, moderate mandibular asymmetry, or severe mandibular asymmetry. Several maxillary and mandibular measurements were used to compare different degrees of mandibular asymmetry and the difference between measurements of the contralateral and deviated sides. RESULTS: For patients with moderate and severe mandibular asymmetry, there were statistically relevant differences between bilateral measurements of the sagittal position of the condylar heads, the transverse and sagittal positioning of the gonion, ramus height, and mandibular body length, the transverse and vertical positioning of the jugale point, including a vertical positioning of the gonion only for severe asymmetry. In patients with severe mandibular asymmetry, there was a highly relevant correlation of gnathion lateral displacement with lower dental midline displacement and with the difference in height of the mandibular rami between the deviated and contralateral sides. CONCLUSION: In patients with skeletal Class III, not only lateral displacement of the menton but also a series of morphologic changes differed markedly for each degree of mandibular asymmetry. PMID- 28012845 TI - Role of melatonin in mitigating nonylphenol-induced toxicity in frontal cortex and hippocampus of rat brain. AB - Nonylphenol (NP), an environmental endocrine disruptor mimics estrogen and is a potential toxicant both under in vitro and in vivo conditions. In this study, the effect of melatonin on NP- induced neurotoxicity and cognitive alteration was investigated in adult male Wistar rats. Melatonin supplementation has been known to protect cells from neurotoxic injury. The animals were divided into three groups namely, control (vehicle) which received olive oil orally and treated rats received NP (25 mg/kg, per os) thrice a week for 45 days while the third group i.e., NP + melatonin, animals were co-administered melatonin (10 mg/kg, i.p.) along with NP. On the 46th day, rats were assessed for anxiety, motor co ordination, grip strength and cognitive performance using Morris water maze test and then sacrificed for biochemical and histopathological assays in brain tissues. Melatonin improved the behavioral performance in NP exposed group. The results showed that NP significantly decreased the activity of acetylcholine esterase (AchE), monoamine oxidase (MAO) and Na+/K+-ATPase, in rat brain tissue along with other enzymes of antioxidant milieu. The outcome of the study shows that NP, like other persistent endocrine disrupting pollutants, creates a potential risk of cognitive, neurochemical and histopathological perturbations as a result of environmental exposure. Taken together, our study demonstrates that melatonin is protective against NP-induced neurotoxicity. PMID- 28012846 TI - Neuroprotection of agomelatine against cerebral ischemia/reperfusion injury through an antiapoptotic pathway in rat. AB - Agomelatine is an agonist of the melatonergic MT1/MT2 receptors and an antagonist of the serotonergic 5-HT receptors. Its actions mimic melatonin in antioxidative and anti-inflammation. However, the protective mechanism of agomelatine in ischemic/reperfusion (I/R) injury has not been investigated. In this study, cerebral I/R injury rats were induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The rats were randomly divided into 6 groups (12 rats per group): sham-operated; vehicle-treated I/R; 20 mg/kg, 40 mg/kg, and 80 mg/kg agomelatine-treated I/R; and 10 mg/kg melatonin-treated I/R. Agomelatine and melatonin were intraperitoneally administrated to the rats 1 h before MCAO induction. After reperfusion for 24 h, the brain samples were harvested for evaluating the infarct volume, histological changes, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining as well as cleaved caspase-3, Bax, Bcl-XL, nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase (HO-1) levels. Agomelatine treatment significantly decreased apoptosis, with decreases in Bax and cleaved caspase-3, and increased Bcl-XL, along with a decrease in apoptotic neuronal cells. Moreover, agomelatine was also found to markedly increase the expression of HO-1, the antioxidative enzymes, and the activity of superoxide dismutase (SOD) mediated by Nrf2 pathway. Agomelatine treatment protects the brain from cerebral I/R injury by suppressing apoptosis and agomelatine has antioxidant properties. Hence, there exists the possibility of developing agomelatine as a potential candidate for treating ischemic stroke. PMID- 28012847 TI - Echinococcus granulosus: Evidence of a heterodimeric glutathione transferase built up by phylogenetically distant subunits. AB - In the cestode parasite Echinococcus granulosus, three phylogenetically distant cytosolic glutathione transferases (GSTs) (EgGST1, 2 and 3) were identified. Interestingly, the C-terminal domains of EgGST3 and EgGST2 but not EgGST1, exhibit all amino acids involved in Sigma-class GST dimerization. Here, we provide evidence indicating that EgGST2 and EgGST3 naturally form a heterodimeric structure (EgGST2-3), and also we report the enzymatic activity of the recombinant heterodimer. EgGST2-3 might display novel properties able to influence the infection establishment. This is the first report of a stable heterodimeric GST built up by phylogenetically distant subunits. PMID- 28012849 TI - Patients With Barrett's Esophagus and Confirmed Persistent Low-Grade Dysplasia Are at Increased Risk for Progression to Neoplasia. AB - BACKGROUND & AIMS: For patients with Barrett's esophagus, the diagnosis of low grade dysplasia (LGD) is subjective, and reported outcomes vary. We analyzed data from a multicenter study of endoscopic therapy to identify factors associated with progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with LGD of the esophagus. METHODS: We performed a retrospective analysis of data from 255 patients with a primary diagnosis of LGD (78% men; mean age, 63 years) who participated in a randomized controlled trial of surveillance vs radiofrequency ablation in Europe. Three expert pathologists independently reviewed baseline and subsequent LGD specimens. The presence and degree of dysplasia was separately recorded for each biopsy and classified according to the Vienna Classification system. The primary end point was development of HGD or EAC. We performed univariate logistic regression analyses to assess the association between outcomes and factors such as number of pathologists confirming LGD, multifocality of LGD, and persistence of LGD over time. RESULTS: Of the 255 patients, 45 (18%) developed HGD or EAC during a median 42-month follow-up period (interquartile range, 25-61 months); patients were examined by a median 4 endoscopies (interquartile range, 3-6 endoscopies). The number of pathologists confirming LGD was strongly associated with progression to neoplasia; risk for progression increased greatly when all 3 pathologists agreed on LGD (odds ratio, 47.14; 95% confidence interval, 13.10-169.70). When LGD was detected at baseline and confirmed by a subsequent endoscopy, the odds for progression to neoplasia also increased greatly (odds ratio, 9.28; 95% confidence interval, 4.39-19.64). Multifocal LGD was not significantly associated with progression to neoplasia. CONCLUSIONS: The number of pathologists confirming LGD and persistence of LGD over time increase risk for development of HGD or EAC in patients with Barrett's esophagus and LGD. These simple, readily available variables can help stratify risk and select patients for prophylactic ablation therapy. PMID- 28012848 TI - Detection of Sessile Serrated Adenomas in the Proximal Colon Using Wide-Field Fluorescence Endoscopy. AB - BACKGROUND & AIMS: Many cancers in the proximal colon develop via from sessile serrated adenomas (SSAs), which have flat, subtle features that are difficult to detect with conventional white-light colonoscopy. Many SSA cells have the V600E mutation in BRAF. We investigated whether this feature could be used with imaging methods to detect SSAs in patients. METHODS: We used phage display to identify a peptide that binds specifically to SSAs, using subtractive hybridization with HT29 colorectal cancer cells containing the V600E mutation in BRAF and Hs738.St/Int cells as a control. Binding of fluorescently labeled peptide to colorectal cancer cells was evaluated with confocal fluorescence microscopy. Rats received intra-colonic 0.0086 mg/kg, 0.026 mg/kg, or 0.86 mg/kg peptide or vehicle and morbidity, mortality, and injury were monitored twice daily to assess toxicity. In the clinical safety study, fluorescently labeled peptide was topically administered, using a spray catheter, to the proximal colon of 25 subjects undergoing routine outpatient colonoscopies (3 subjects were given 2.25 MUmol/L and 22 patients were given 76.4 MUmol/L). We performed blood cell count, chemistry, liver function, and urine analyses approximately 24 hours after peptide administration. In the clinical imaging study, 38 subjects undergoing routine outpatient colonoscopies, at high risk for colorectal cancer, or with a suspected unresected proximal colonic polyp, were first evaluated by white-light endoscopy to identify suspicious regions. The fluorescently labeled peptide (76.4 MUmol/L) was administered topically to proximal colon, unbound peptide was washed away, and white-light, reflectance, and fluorescence videos were recorded digitally. Fluorescence intensities of SSAs were compared with those of normal colonic mucosa. Endoscopists resected identified lesions, which were analyzed histologically by gastrointestinal pathologists (reference standard). We also analyzed the ability of the peptide to identify SSAs vs adenomas, hyperplastic polyps, and normal colonic mucosa in specimens obtained from the tissue bank at the University of Michigan. RESULTS: We identified the peptide sequence KCCFPAQ and measured an apparent dissociation constant of Kd = 72 nM and an apparent association time constant of K = 0.174 min-1 (5.76 minutes). During fluorescence imaging of patients during endoscopy, regions of SSA had 2.43-fold higher mean fluorescence intensity than that for normal colonic mucosa. Fluorescence labeling distinguished SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. The peptide had no observed toxic effects in animals or patients. In the analysis of ex vivo specimens, peptide bound to SSAs had significantly higher mean fluorescence intensity than to hyperplastic polyps. CONCLUSIONS: We have identified a fluorescently labeled peptide that has no observed toxic effects in animals or humans and can be used for wide-field imaging of lesions in the proximal colon. It distinguishes SSAs from normal colonic mucosa with 89% sensitivity and 92% specificity. This targeted imaging method might be used in early detection of premalignant serrated lesions during routine colonoscopies. ClinicalTrials.gov ID: NCT02156557. PMID- 28012850 TI - Behavioral characterization of female zinc transporter 3 (ZnT3) knockout mice. AB - Zinc is an important element in all cells of the body, having structural, enzymatic, and regulatory functions. In some neurons, zinc is loaded into synaptic vesicles by zinc transporter 3 (ZnT3) and released into the synaptic cleft, where it can modulate neuronal function. ZnT3 knockout (KO) mice lack ZnT3 and thus lack synaptic zinc. Previous studies have examined the behavioral phenotype of ZnT3 KO mice, mostly using mixed-sex or male-only groups. In the present study we focused specifically on the behavior of female ZnT3 KO mice (2-3 months old). An extensive battery of tests was administered to assess sensorimotor and cognitive behaviours, as well as to examine for a possible schizophrenia-like phenotype. ZnT3 KO mice performed similarly to wild type controls in the majority of tests. However, they were less accurate in the skilled reach task, suggesting impaired skilled motor learning, and faster to descend a vertical pole. ZnT3 KO mice were also slower in the open field and made fewer chamber entries in the social preference test, suggesting decreased exploratory locomotion. No differences were observed in the Morris water task or fear conditioning test. This is the first study to show a behavioural phenotype specifically for female ZnT3 KO mice. Comparing our results to previous studies, it appears that there may be sex-specific effects of eliminating ZnT3. Female ZnT3 KO mice exhibit abnormalities in locomotion and at skilled motor learning, but we were unable to detect spatial or fear learning deficits previously described in male ZnT3 KO mice. PMID- 28012851 TI - Dynamic MR Spectroscopy of brain metabolism using a non-conventional spectral averaging scheme. AB - PURPOSE: MRS acquisition based on the blood oxygenation level dependent (BOLD) contrast mechanism was implemented at 3T to investigate the impact of a non conventional spectral averaging scheme (determined by the number of RF excitations, NEX) on the dynamics of cerebral metabolism during neuroactivation. Using NEX=2, water and metabolite BOLD responses were compared to previous results from standard experiments. METHODS: Spectra were recorded from the visual cortex of five healthy volunteers during single and block visual stimulations. The height, width and area of the spectral peaks were calculated (using SAGE v7) in order to estimate their percentage changes from baseline (representing the BOLD change) following visual stimulation. BOLD changes were statistically significant at a significance level of p<0.05 by paired t-test. RESULTS: Significantly greater BOLD changes in all spectra were observed in the single than block stimulation (p<0.05). The water resonance showed significant (p<0.01) BOLD changes in all peak parameters in both paradigms. All metabolites showed significant increase in spectral height (p<0.01) in the single paradigm, but none of them (except the height of Cho) showed significant BOLD response in the block paradigm. BOLD changes observed in the block paradigm were generally lower than reported changes. CONCLUSIONS: The time interval of 6s offered by NEX=2 during which each line of spectral data is recorded by the scanner is rather long, leading to some BOLD data loss particularly in a block experimental design. PMID- 28012852 TI - Mapping effective connectivity in the human brain with concurrent intracranial electrical stimulation and BOLD-fMRI. AB - BACKGROUND: Understanding brain function requires knowledge of how one brain region causally influences another. This information is difficult to obtain directly in the human brain, and is instead typically inferred from resting-state fMRI. NEW METHOD: Here, we demonstrate the safety and scientific promise of a novel and complementary approach: concurrent electrical stimulation and fMRI (es fMRI) at 3T in awake neurosurgical patients with implanted depth electrodes. RESULTS: We document the results of safety testing, actual experimental setup, and stimulation parameters, that safely and reliably evoke activation in distal structures through stimulation of amygdala, cingulate, or prefrontal cortex. We compare connectivity inferred from the evoked patterns of activation with that estimated from standard resting-state fMRI in the same patients: while connectivity patterns obtained with each approach are correlated, each method produces unique results. Response patterns were stable over the course of 11min of es-fMRI runs. COMPARISON WITH EXISTING METHOD: es-fMRI in awake humans yields unique information about effective connectivity, complementing resting-state fMRI. Although our stimulations were below the level of inducing any apparent behavioral or perceptual effects, a next step would be to use es-fMRI to modulate task performances. This would reveal the acute network-level changes induced by the stimulation that mediate the behavioral and cognitive effects seen with brain stimulation. CONCLUSIONS: es-fMRI provides a novel and safe approach for mapping effective connectivity in the human brain in a clinical setting, and will inform treatments for psychiatric and neurodegenerative disorders that use deep brain stimulation. PMID- 28012853 TI - Rat brain sagittal organotypic slice cultures as an ex vivo dopamine cell loss system. AB - BACKGROUND: Organotypic brain slice cultures are a useful tool to study neurological function as they provide a more complex, 3-dimensional system than standard 2-dimensional in vitro cell cultures. NEW METHOD: Building on a previously developed mouse brain slice culture protocol, we have developed a rat sagittal brain slice culture system as an ex vivo model of dopamine cell loss. RESULTS: We show that rat brain organotypic slice cultures remain viable for up to 6 weeks in culture. Using Fluoro-Gold axonal tracing, we demonstrate that the slice 3-dimensional cytoarchitecture is maintained over a 4 week culturing period, with particular focus on the nigrostriatal pathway. Treatment of the cultures with 6-hydroxydopamine and desipramine induces a progressive loss of Fluoro-Gold-positive nigral cells with a sustained loss of tyrosine hydroxylase positive nigral cells. This recapitulates the pattern of dopaminergic degeneration observed in the rat partial 6-hydroxydopamine lesion model and, most importantly, the progressive pathology of Parkinson's disease. COMPARISON WITH EXISTING METHODS: Our slice culture platform provides an advance over other systems, as we demonstrate for the first time 3-dimensional cytoarchitecture maintenance of rat nigrostriatal sagittal slices for up to 6 weeks. CONCLUSION: Our ex vivo organotypic slice culture system provides a long term cellular platform to model Parkinson's disease, allowing for the elucidation of mechanisms involved in dopaminergic neuron degeneration and the capability to study cellular integration and plasticity ex vivo. PMID- 28012854 TI - Discriminative spatial-frequency-temporal feature extraction and classification of motor imagery EEG: An sparse regression and Weighted Naive Bayesian Classifier based approach. AB - BACKGROUND: Common spatial pattern (CSP) is most widely used in motor imagery based brain-computer interface (BCI) systems. In conventional CSP algorithm, pairs of the eigenvectors corresponding to both extreme eigenvalues are selected to construct the optimal spatial filter. In addition, an appropriate selection of subject-specific time segments and frequency bands plays an important role in its successful application. NEW METHOD: This study proposes to optimize spatial frequency-temporal patterns for discriminative feature extraction. Spatial optimization is implemented by channel selection and finding discriminative spatial filters adaptively on each time-frequency segment. A novel Discernibility of Feature Sets (DFS) criteria is designed for spatial filter optimization. Besides, discriminative features located in multiple time-frequency segments are selected automatically by the proposed sparse time-frequency segment common spatial pattern (STFSCSP) method which exploits sparse regression for significant features selection. Finally, a weight determined by the sparse coefficient is assigned for each selected CSP feature and we propose a Weighted Naive Bayesian Classifier (WNBC) for classification. RESULTS: Experimental results on two public EEG datasets demonstrate that optimizing spatial-frequency-temporal patterns in a data-driven manner for discriminative feature extraction greatly improves the classification performance. COMPARISON WITH EXISTING METHODS: The proposed method gives significantly better classification accuracies in comparison with several competing methods in the literature. CONCLUSIONS: The proposed approach is a promising candidate for future BCI systems. PMID- 28012855 TI - Prostanoids counterbalance the synergism between endothelin-1 and angiotensin II in mesenteric veins of trained rats. AB - Exercise-induced adaptations of the modulating mechanisms that influence the angiotensin (Ang II) responses assume different features depending on the venous bed. In femoral veins, exercise mobilizes vasodilator prostanoids to cooperate with NO in order to maintain reduced Ang II responses. On the other hand, exercise's influence on the Ang II responses in veins that drain blood from the mesenteric region has been poorly described. Therefore, the present study aimed to identify the effects of a single bout of exercise, as well as exercise training, on the Ang II responses in mesenteric veins. The present study also aimed to investigate the involvement of prostanoids, NO and ET-1 in eventual exercise-induced modifications in these veins. To this end, mesenteric veins taken from resting-sedentary, exercised-sedentary, resting-trained and exercised trained animals were studied in organ baths. In addition, the mRNA expression of prepro-endothelin-1 (ppET-1), as well as that of the ETA and ETB receptors, were quantified by real-time PCR in these veins. The results show that, either in absence or in presence of L-NAME, the Ang II responses were not different between groups. In the presence of indomethacin, higher Ang II responses were observed in the resting-trained animals than in the resting-sedentary animals. This difference, however, disappeared when L-NAME, BQ-123 or BQ-788 were added during incubation. In addition, no differences in ppET-1, ETA or ETB mRNA expression were observed between groups. Furthermore, in the presence of PD123,319, the Ang II responses in the exercised-sedentary animals were higher than those in the resting-sedentary animals. In conclusion, exercise training mobilizes endothelin 1 (ET-1) to reinforce the Ang II-induced responses mainly through ETA activation. On the other hand, vasodilator prostanoids are mobilized to act in parallel with NO in order to counterbalance the Ang II responses that have been potentiated by ET-1 in these trained animals. PMID- 28012856 TI - Increased FNDC5/Irisin expression in human hepatocellular carcinoma. AB - The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy regulating hormone, is associated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, the hepatic expression of FNDC5/Irisin is still unknown. The gene expression of FNDC5/Irisin, associated to key regulators of DNL, inflammation and cancer progression was evaluated in liver tissue of 18 patients with HCC undergoing liver transplantation and of 18 deceased donors. Hepatic mRNA expression of FNDC5/Irisin and stearoyl-CoA desaturase (SCD-1), main enzymatic regulator of DNL, were significantly higher in HCC patients than in donors (p<0.0001 and p=0.015, respectively). The hepatic mRNA expression of the neurogenic locus notch homolog protein 1 (NOTCH1) tended to be higher in HCC patients than in donors (p=0.06). Only in HCC patients, hepatic FNDC5/Irisin strongly correlated with the transcription factor sterol regulatory element-binding factor 1, SCD-1, NOTCH1, tumor necrosis factor-alpha and Interleukin-6 mRNA expression. Further, in HCC patients, FNDC5/Irisin mRNA tended to correlate to plasma lipid profile namely triglycerides, palmitic/linoleic acid and polyunsaturated fatty acid/saturated fatty acid ratios. In conclusion, HCC-liver tissue over-expressed FNDC5/Irisin in association with gene expression of mediators involved in lipogenesis, inflammation and cancer, suggesting a possible protective role of the hormone from the liver damage. PMID- 28012857 TI - An enzymatic assay based on luciferase Ebola virus-like particles for evaluation of virolytic activity of antimicrobial peptides. AB - Antimicrobial peptides are currently considered as promising antiviral compounds. Current assays to evaluate the effectivity of peptides against enveloped viruses based on liposomes or hemolysis are encumbered by the artificial nature of liposomes or distinctive membrane composition of used erythrocytes. We propose a novel assay system based on enzymatic Ebola virus-like particles containing sensitive luciferase reporter. The assay was validated with several cationic and anionic peptides and compared with lentivirus inactivation and hemolytic assays. The assay is sensitive and easy to perform in standard biosafety level laboratory with potential for high-throughput screens. The use of virus-like particles in the assay provides a system as closely related to the native viruses as possible eliminating some issues associated with other more artificial set ups. We have identified CAM-W (KWKLWKKIEKWGQGIGAVLKWLTTWL) as a peptide with the greatest antiviral activity against infectious lentiviral vectors and filoviral virus-like particles. PMID- 28012858 TI - Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice. AB - Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35g/kg i.v.) and following glucose plus glucagon (10MUg/kg i.v.) using deconvolution of plasma C peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20min post). Using the previously determined insulin secretion profiles and the insulin concentration time measurements, a population modeling analysis was applied to estimate the one compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC0 20) compared to that with glucose alone (p<0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4+/ 0.34mL/min for glucose alone and 5.8+/-1.5mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion. PMID- 28012859 TI - Endogenous Opiates and Behavior: 2015. AB - This paper is the thirty-eighth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2015 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia, stress and social status, tolerance and dependence, learning and memory, eating and drinking, drug abuse and alcohol, sexual activity and hormones, pregnancy, development and endocrinology, mental illness and mood, seizures and neurologic disorders, electrical-related activity and neurophysiology, general activity and locomotion, gastrointestinal, renal and hepatic functions, cardiovascular responses, respiration and thermoregulation, and immunological responses. PMID- 28012860 TI - Role of transcranial Doppler measurements in postpartum patients with post-dural puncture headache: a pilot study. PMID- 28012861 TI - IJOA: a global vehicle to bolster the objectives of obstetric anaesthesiology. PMID- 28012862 TI - Impact of obesity on post-dural puncture headache. AB - INTRODUCTION: Previous studies have suggested an inverse relationship between obesity and development of post-dural puncture headache following spinal anesthesia. However, few have investigated the relationship between obesity and headaches after accidental dural puncture with an epidural needle. This study explored whether obesity has any association with headaches following an accidental dural puncture. METHODS: Records of patients who received epidural analgesia for labor and vaginal delivery between January 2011 and June 2015 were reviewed. Body mass index, American Society of Anesthesiologists Physical Status and age were analyzed. Chi-squared analysis was performed to determine the relationship between the incidence and severity of post-dural puncture headaches and body mass index. RESULTS: A total of 17497 epidurals were placed for vaginal deliveries. Of these, 164 patients met our criteria for accidental dural puncture, of whom 51.2% developed post-dural puncture headaches. Of patients who developed a post-dural puncture headache 35.7% required an epidural blood patch. Data analysis showed no significant relationship between body mass index and incidence of post-dural puncture headaches regardless of body mass index classification (P>0.05). There was no association between body mass index and the intensity of post-dural puncture headache (P=0.29). CONCLUSION: Patients with a high body mass index do not appear to be protected from experiencing a post-dural puncture headache after an accidental dural puncture during placement of labor epidural analgesia. Additionally, the intensity of post-dural puncture headache does not vary with body mass index. PMID- 28012863 TI - Hepatitis C virus eradication in the elderly: The challenge worth a long-life elixir? PMID- 28012865 TI - Simultaneous nitrification/denitrification and stable sludge/water separation achieved in a conventional activated sludge process with severe filamentous bulking. AB - This study investigated the long-term treatment performance of a conventional activated sludge (AS) process operating at a microaerobic DO level (0.5-1.0mg.L 1) in the aeration tank and a long settling time of >10h in the clarification tank for sewage treatment. The microaerobic DO conditions led to severe sludge bulking. However, good sludge/water separation and excellent pollutant removal performance (COD, 95+/-2%; NH4+-N, 99+/-1%; and TN, 69+/-6%) were stably achieved in the microaerobic AS system during its 150days of continuous operation. This is the first report to demonstrate that a long settling time effectively overcame the effect of severe filamentous bulking in conventional AS process, and that microaerobic DO conditions achieved excellent simultaneous nitrification and denitrification reactions in the aeration tank. The process characteristics of the microaerobic AS system differed substantially from those existing biological denitrification processes, including A/O, CANON, and OLAND processes. PMID- 28012864 TI - Germline and somatic DICER1 mutations in familial and sporadic liver tumors. AB - BACKGROUND & AIMS: Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence. METHODS: We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs). RESULTS: A pathological study identified hepatocellular adenomas and well differentiated carcinomas in both patients. Tumors exhibited Wnt/beta-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations (p=0.03). miRNA profiling identified a specific expression profile in DICER1-mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations. CONCLUSIONS: Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with beta-catenin activation. LAY SUMMARY: DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs. PMID- 28012866 TI - Epidemiological updates of venous thromboembolism in a Chinese population. AB - BACKGROUND/OBJECTIVE: Deep vein thrombosis (DVT) was thought to be uncommon in Asians and routine thromboprophylaxis in the form of anticoagulation for surgical patients was considered to be unnecessary. The current study aims to provide a contemporary epidemiology of venous thromboembolism in a population-based scale. METHODS: Information from January 1, 2010 to December 31, 2011 was retrieved from a centralized computer public healthcare database serving mainly an ethnic Han Chinese population of 7.1 million. The incidence, demographics, and hospital mortality rates of DVT and pulmonary embolism (PE) were obtained, and analyzed for different surgical categories. RESULTS: The overall annual incidences of DVT, PE alone, and PE with DVT were 30.0 per 100,000 population, 8.7 per 100,000 population, and 3.0 per 100,000 population, respectively. Overall male to female ratio was 1:1.24. Venous thromboembolic disease was more common with increasing age in both sexes. Thirty days' mortality rates associated with DVT, PE alone, and PE with DVT were 9.0%, 17.4%, and 13.3% respectively. Among the patients who received 103,023 major and intermediate surgical procedures in the study period, the mean incidence of postoperative DVT, PE alone, and PE with DVT were only 0.20% (203.5 patients), 0.08% (85.5 patients), and 0.04% (40.5 patients) respectively. CONCLUSION: Compared with a similar study 10 years ago, there seemed to be a general increase in incidence of DVT and PE. This study showed that postoperative thromboembolic events were not uncommon, with DVT occurring in up to 0.2% of patients and PE in 0.12% of patients in this longitudinal survey. PMID- 28012867 TI - Chronic oral administration of MPEP, an antagonist of mGlu5 receptor, during gestation and lactation alters mGlu5 and A2A receptors in maternal and neonatal brain. AB - Antidepressant and anxiolytic drugs are widely consumed even by pregnant and lactating women. The metabotropic glutamate receptor 5 (mGlu5) antagonist 2 methyl-6-(phenylethynyl)-pyridine (MPEP) exerts antidepressant- and anxiolytic like actions. Given that treatment for anxiety and depression use to be prolonged in time, it is conceivable a possible modulation of metabotropic glutamate receptors (mGlu receptors) after prolonged MPEP exposure, which could also modify adenosine A2A receptors (A2AR) since functional cross-talk between them has been reported. Here we report that MPEP crosses placental barrier and reaches neonatal brain through maternal milk using LC-MS/MS methods. Therefore, we analyzed mGlu receptors, mainly mGlu5, and A2AR in both maternal and fetal brain after chronic maternal consumption of MPEP during gestation and/or lactation using radioligand binding, Western-blotting, real-time PCR and phospholipase C (PLC) activity assays. In maternal brain, chronic MPEP consumption caused a significant loss of mGlu, including mGlu5, and A2AR receptors level in plasma membrane. PLC activity assays showed that mGlu5 signaling pathway was desensitized. No variations on mRNA level coding A2AR, A1R and mGlu5 were found after MPEP treatments. In female neonatal brain, maternal consumption of MPEP caused a significant increase in mGlu, including mGlu5, and A2AR receptors level. Neither mGlu receptors nor A2AR were modified in male neonatal brain after maternal MPEP intake. Finally, neither molecular nor behavioral changes (anxiety- and depression-like behavior) were observed in 3-month-old female offspring. In summary, mGlu5 and A2AR are altered in both maternal and female neonatal brain after chronic maternal consumption of MPEP during gestation and/or lactation. PMID- 28012868 TI - Assessing human brain impedance using simultaneous surface and intracerebral recordings. AB - Most of the literature on the brain impedance proposes a frequency-independent resistive model. Recently, this conclusion was tackled by a series of papers (Bedard et al., 2006; Bedard and Destexhe, 2009; Gomes et al., 2016), based on microscopic sale modeling and measurements. Our paper aims to investigate the impedance issue using simultaneous in vivo depth and surface signals recorded during intracerebral electrical stimulation of epileptic patients, involving a priori different tissues with different impedances. Our results confirm the conclusions from Logothethis et al. (2007): there is no evidence of frequency dependence of the brain tissue impedance (more precisely, there is no difference, in terms of frequency filtering, between the brain and the skull bone), at least at a macroscopic scale. In order to conciliate findings from both microscopic and macroscopic scales, we recall different neural/synaptic current generators' models from the literature and we propose an original computational model, based on fractional dynamics. PMID- 28012869 TI - New developments in Neuroscience for 2017. PMID- 28012871 TI - Quantification of low molecular weight compounds by MALDI imaging mass spectrometry - A tutorial review. AB - Matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) permits label-free in situ analysis of chemical compounds directly from the surface of two-dimensional biological tissue slices. It links qualitative molecular information of compounds to their spatial coordinates and distribution within the investigated tissue. MALDI-MSI can also provide the quantitative amounts of target compounds in the tissue, if proper calibration techniques are performed. Obviously, as the target molecules are embedded within the biological tissue environment and analysis must be performed at their precise locations, there is no possibility for extensive sample clean-up routines or chromatographic separations as usually performed with homogenized biological materials; ion suppression phenomena therefore become a critical side effect of MALDI-MSI. Absolute quantification by MALDI-MSI should provide an accurate value of the concentration/amount of the compound of interest in relatively small, well defined region of interest of the examined tissue, ideally in a single pixel. This goal is extremely challenging and will not only depend on the technical possibilities and limitations of the MSI instrument hardware, but equally on the chosen calibration/standardization strategy. These strategies are the main focus of this article and are discussed and contrasted in detail in this tutorial review. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 28012870 TI - Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression. AB - Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness. PMID- 28012872 TI - Mapping the naloxone binding sites on the mu-opioid receptor using cell-based photocrosslinkers. AB - Naloxone is an alkaloid antagonist that acts as an antidote to opioids through the mu-opioid receptor (MOR), a G protein-coupled receptor. However, its binding site on the MOR remains unknown. To investigate the binding interfaces necessary for naloxone and MOR, available structural information was combined with a cell based photocrosslinking approach. Computer prediction revealed that four binding sites on MOR were required for naloxone binding. In addition, in the photocrosslinking approach, an amber stop codon was used to replace the sense codon of the MOR at 266 selected individual positions, in order to introduce the photoreactive amino acid p-benzoyl-l-phenylalanine (BzF) into MOR to evaluate the results of the computer analysis. The BzF-incorporated MOR mutant genes were expressed in CHO cells, in which MOR retained the ability to interact with its ligands, such as morphine, and exhibited MOR-dependent activation of ERK signaling following morphine stimulation. Notably, after treatment with tritium labeled naloxone and exposure to UV light, we observed naloxone crosslinking with BzF replacement at hydrophobic residues and some polar/uncharged residues in the computer-predicted sites 1 and 3, indicating that these two sites in the MOR interact with naloxone. In conclusion, these results indicate that MOR has two naloxone binding sites and that the hydrophobic and polar/uncharged residues within these sites are important for naloxone binding. PMID- 28012873 TI - Posner-Schlossman syndrome. AB - Posner-Schlossman syndrome, or glaucomatocyclitic crisis, is a unilateral ocular condition characterized by recurrent attacks of nongranulomatous anterior uveitis and raised intraocular pressure that can result in chronic secondary glaucoma. This relatively rare disease is most likely the result of recurrent cytomegalovirus infection and affects predominantly middle-aged males. Diagnosis is largely clinical, with aqueous and blood sampling aiding the identification of any underlying infectious cause. Successful disease management is often achieved by topical treatment, although systemic therapy and even surgical intervention may be required. We discuss our current understanding of Posner-Schlossman syndrome, from its pathophysiology through to recommended treatment options. PMID- 28012876 TI - In search of a disease. AB - A 10-year-old child presented with right eyelid swelling and a palpable orbital mass. Diagnostic evaluation with the aid of excisional biopsy revealed a pseudoencapsulated mass associated with high levels of serum perinuclear antineutrophil cytoplasmic antibodies. Family history of rheumatic diseases, response to treatment with corticosteroids and immunosuppressant drugs, and clinical and histopathologic features suggested an orbital autoimmune response in which perinuclear antineutrophil cytoplasmic antibodies were detected, and a diagnosis of probable IgG4-related disease was made. PMID- 28012874 TI - Management of high-risk corneal transplantation. AB - The cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal grafting has high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates because of a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered; however, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been used for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use, as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments, as well as tolerance inducing methods, show promising horizons in the management of high-risk corneal transplantation in near future. PMID- 28012875 TI - Advances in understanding and management of retinopathy of prematurity. AB - The understanding, diagnosis, and treatment of retinopathy of prematurity have changed in the 70 years since the original description of retrolental fibroplasia associated with high oxygenation. It is now recognized that retinopathy of prematurity differs in appearance worldwide and as ever smaller and younger premature infants survive. New methods are being evaluated to image the retina, diagnose severe retinopathy of prematurity, and determine windows of time for treatment to save eyes and improve visual and neural outcomes. New treatments to promote physiologic retinal vascular development, vascular repair, and inhibit vasoproliferation by regulating proteins involved in vascular endothelial growth factor, insulin-like growth factor, or erythropoietin signaling. Reducing excessive oxidative/nitrosative stress and understanding progenitor cells and neurovascular and glial vascular interactions are being studied. PMID- 28012877 TI - Optimizing cataract surgery in patients with age-related macular degeneration. AB - Age-related macular degeneration (AMD) is one of the leading causes of visual impairment. The development of cataract in AMD patients poses challenges in assessing timing of surgery, predicting potential benefit to the patient of surgery, and predicting short- and long-term effects of surgery on progression of their AMD. Although traditional cataract surgery remains the mainstay of treatment, recently several devices have been developed to address the specific needs of AMD patients with cataract. We look at the associations between cataract and AMD and outline the treatment approaches to cataract surgery in AMD, looking at the potential benefits and risks of both traditional approaches and newer devices. We provide clinicians treating patients with AMD and cataract with a framework for choosing the appropriate management. PMID- 28012879 TI - Dermatofibroma of the eyelid with monster cells. AB - Dermatofibromas are most frequently encountered in women on the lower extremities, often after minor trauma. A recurrent lesion of the right lower eyelid developed in a 64-year-old woman. It harbored "monster cells" that were large, with either multiple nuclei or a single, large, convoluted, and hyperchromatic nucleus. The presence of these cells does not signify a malignant transformation. The background cells were either histiocytoid (many were adipophilin positive), spindled cells, or dendritiform cells without mitoses. Factor XIIIa, CD68, and CD163 immunostaining was positive, and a subpopulation of CD1a+ Langerhans cells was intermixed. Facial and eyelid dermatofibromas are more likely to recur and deserve wider, tumor-free surgical margins. Their microscopic differential diagnosis includes a cellular scar, peripheral nerve tumor, atypical fibrous xanthoma, and dermatofibrosarcoma protuberans. PMID- 28012880 TI - KIAA1199/CEMIP/HYBID overexpression predicts poor prognosis in pancreatic ductal adenocarcinoma. AB - BACKGROUND: KIAA1199 (also known as CEMIP or HYBID), a newly identified protein involved in hyaluronan degradation, has been suggested to play a critical role in cancer progression. The aim of this study was to investigate the expression and functional significance of KIAA1199 in pancreatic ductal adenocarcinoma (PDAC). METHODS: Using quantitative real-time RT-PCR, we analyzed KIAA1199 mRNA expression in 6 PDAC cell lines and frozen tissues from 14 patients with PDAC. We also used immunohistochemistry to analyze KIAA1199 protein expression in formalin fixed, paraffin-embedded tissues from 98 patients with PDAC. The KIAA1199 expression pattern was then correlated with clinicopathological variables and patient outcome. The effect of KIAA1199 on migratory ability of PDAC cells was determined by KIAA1199 knockdown with small-interfering RNA (siRNA). RESULTS: The KIAA1199 mRNA expression was significantly higher in PDAC tissues than in the corresponding non-tumor tissues (P < 0.0001). Immunohistochemical analysis revealed high expression of KIAA1199 in 26 (26.5%) of 98 PDAC tissues. The overall survival was significantly shorter in patients with high KIAA1199 expression than in patients with low KIAA1199 expression (P = 0.0001). In multivariate analysis, high KIAA1199 expression (P = 0.003) and UICC stage (P = 0.003) were independent factors predicting poor prognosis. Furthermore, the KIAA1199 mRNA expression was higher in most PDAC cell lines and siRNA knockdown of KIAA1199 resulted in decreased migration. CONCLUSION: These findings suggest that overexpression of KIAA1199 may contribute to increased migration of PDAC cells and predict shorter survival after surgical resection. PMID- 28012881 TI - Improving our understanding, and detection, of glaucomatous damage: An approach based upon optical coherence tomography (OCT). AB - Although ophthalmologists are becoming increasingly reliant upon optical coherence tomography (OCT), clinicians who care for glaucoma patients are not taking full advantage of the potential of this powerful technology. First, we ask, how would one describe the nature of glaucomatous damage if only OCT scans were available? In particular, a schematic model of glaucomatous damage is developed in section 2, and the nature of glaucomatous damage seen on OCT scans described in the context of this model in section 3. In particular, we illustrate that local thinning of the circumpapillary retinal nerve fiber layer (cpRNFL) around the optic disc can vary in location, depth, and/or width, as well as homogeneity of damage. Second, we seek to better understand the relationship between the thinning of the cpRNFL and the various patterns of sensitivity loss seen on visual fields obtained with standard automated perimetry. In sections 4 and 5, we illustrate why one should expect a wide range of visual field patterns, and iilustrate why they should not be placed into discrete categories. Finally, section 6 describes how the clinician can take better advantage of the information in OCT scans. The approach is summarized in a single-page report, which can be generated from a single wide-field scan. The superiority of this approach, as opposed to the typical reliance on summary metrics, is described. PMID- 28012878 TI - Viral posterior uveitis. AB - The causes of posterior uveitis can be divided into infectious, autoimmune, or masquerade syndromes. Viral infections, a significant cause of sight-threatening ocular diseases in the posterior segment, include human herpesviruses, measles, rubella, and arboviruses such as dengue, West Nile, and chikungunya virus. Viral posterior uveitis may occur as an isolated ocular disease in congenital or acquired infections or as part of a systemic viral illness. Many viruses remain latent in the infected host with a risk of reactivation that depends on various factors, including virulence and host immunity, age, and comorbidities. Although some viral illnesses are self-limiting and have a good visual prognosis, others, such as cytomegalovirus retinitis or acute retinal necrosis, may result in serious complications and profound vision loss. Since some of these infections may respond well to antiviral therapy, it is important to work up all cases of posterior uveitis to rule out an infectious etiology. We review the clinical features, diagnostic tools, treatment regimens, and long-term outcomes for each of these viral posterior uveitides. PMID- 28012882 TI - Out-of-hospital cardiac arrest without return of spontaneous circulation in the field: Who are the survivors? AB - BACKGROUND: Return of spontaneous circulation (ROSC) in the field is a vital determinant contributing to survival from out-of-hospital cardiac arrest (OHCA). However, nearly one third of survivors at the Dallas-Fort Worth (DFW) Resuscitation Outcomes Consortium (ROC) site did not obtain ROSC in the field. METHODS: A retrospective, observational analysis was performed on all adult patients with non-traumatic OHCA treated on scene and transported to hospital, who did not gain ROSC in the field at DFW ROC site between 2006 through 2011.We described the demographics, pre-hospital characteristics and outcomes of all enrolled cases. Those patients without ROSC in the field, who did and did not meet Termination of Resuscitation (TOR) criteria in the field, were also compared. RESULTS: Among a total of 5099 treated and transported non-traumatic OHCA cases, 83.2% (4243) were included in this study as patients without ROSC gained in the field, of which 66.6% (2827) met TOR criteria but still were treated and transported; 1.9% (79) survived to hospital discharge. Further analysis showed that 39.2% (31) of survivors met TOR rule, accounting for 1.1% of those patients who should have been declared dead in the field. Shockable initial rhythms, EMS-witnessed arrest, bystander CPR and age were factors significant to predict survival from OHCA without ROSC in the field. Of concern, 1.7% (47) of patients who met TOR presented initially shockable rhythms but no shocks were delivered in the field. CONCLUSIONS: We suggest that all treated non-traumatic OHCA patients should be transported to hospital. PMID- 28012883 TI - Patient Perspectives on Communication of Individualized Survival Estimates in Heart Failure. AB - BACKGROUND: Despite the availability of validated risk scores for survival in heart failure (HF), individualized estimates are not typically provided directly to patients. METHODS AND RESULTS: We explored patient perspectives regarding conveyance of individualized Seattle Heart Failure Model (SHFM) survival estimates. In 2014 and 2015, 24 HF patients completed a semistructured interview at the initial offering of SHFM survival estimates (baseline) and a follow-up interview. Themes emerging from questions of interest were identified: 1) preferences for receiving estimates: patients generally wished to see their SHFM estimates (acceptors; n = 17, and ideally would have received such information early after HF "diagnosis"; 2) reactions: viewing their personalized estimates restored some control and hope for most patients and rarely increased anxiety; 3) application: some acceptors found the information to be helpful in considering future plans, but its usefulness in specific decisions was restricted owing to perceived model limitations; 4) understanding uncertainty: participants contextualized estimates through observations that uncertainty is pervasive in life; acceptors qualitatively understood the population-based nature of the estimates. CONCLUSIONS: The majority of patients valued receiving individualized prognostic survival estimates. Acceptors generally understood the nature of the information and found it to provide clarity, control, and hope rather than invoking confusion or anxiety. PMID- 28012884 TI - Erythrocytes properties in varicose veins patients. AB - Varicose veins (VV) are enlarged veins of the subcutaneous tissue, usually caused by faulty or damaged venous valves leading to impaired blood flow. Blood stasis, excessive clotting disorder and alterations in the vein walls are symptoms of Virchow's triad which may affect the morphotic elements of blood, including erythrocytes. The aim of this study was to investigate alterations in the properties of the erythrocytes taken from varicose veins in comparison to those from antecubital vein of patients with chronic venous disease. The investigation was conducted on whole erythrocytes using spin labeling method in EPR spectroscopy and flow cytometry. The internal viscosity of cells was determined by Tempamine. The conformation state of internal proteins, mainly hemoglobin and membrane proteins was determined by maleimide spin label (MSL, 4-maleimido 2,2,6,6-tetramethylpiperidine-1-oxyl). The plasma membrane fluidity was measured using two spin labeled fatty acids (5- and 16-doxylstearic acid), while conformational state of membrane protein was measured using two covalently bound spin labels MSL and ISL [4-(2-iodoacetamido)-2,2,6,6-tetramethylpiperidine-1 oxyl]. The osmotic fragility and the shape and size of the erythrocytes were also determined. A decrease in internal viscosity of the erythrocytes from varicose vein was observed. A significant decrease in lipid membrane fluidity indicated by 5-DS, which is located at the polar region of lipid layer was found in the erythrocytes from varicose vein in comparison to normal vein. A significant decrease in the motion of MSL and ISL attached to erythrocyte membrane proteins from varicose vein was found. Changes in the plasma membrane of the erythrocytes from varicose vein were also confirmed by measuring osmotic fragility. These cells were more sensitive to hemolysis than red blood cells from the peripheral blood vein. Meanwhile, no significant differences in size and shape were observed between the erythrocytes taken from varicose veins and those from peripheral veins. In conclusion, the erythrocytes from varicose veins exhibited decreased intracellular viscosity and decreased plasma membrane fluidity. At the same time, conformational changes of membrane proteins and higher osmotic fragility of these cells were found in comparison to the erythrocytes obtained from peripheral veins in the same patients with chronic venous disease. Our findings strongly suggest that presented abnormalities in the erythrocyte plasma membrane may have significant pathophysiological implications, including shortened cell survival and alterations in the hemorheology of the varicose vein blood. PMID- 28012885 TI - Vagus Nerve Stimulation Removal or Replacement Involving the Lead and the Electrode: Surgical Technique, Institutional Experience and Outcome. AB - OBJECTIVE: To analyze the outcome of epileptic patients who had redo surgery involving the vagus nerve stimulation's lead. METHODS: We reviewed the clinical and surgical records of all patients who had a complete vagus nerve stimulation (VNS) removal or replacement or any redo surgical procedure involving the system lead at Sainte-Anne Hospital in Paris, France. RESULTS: Between the years 1999 and 2016, 41 redo surgical procedures involving the lead or electrode were achieved, of which 23 were complete VNS explantations, 12 were complete system replacements, 5 were lead changes only, and 1 was isolated lead removal. 41% of the surgical procedures were achieved in female patients. This population has a median age at VNS implantation of 33.6 years (interquartile range [IQR], [21.4 38.6]. Median time between the VNS implantation and the redo surgery involving the lead was 4.9 years (IQR, 2.9-8). The reason for VNS removal was mainly a lack of clinical effectiveness. No preoperative or postoperative complications occurred after complete VNS system removal or lead replacement. The effectiveness of the VNS therapy remained unchanged after lead replacement. No vagus nerve injury was reported, nor did symptoms suggest that it was disabled. CONCLUSIONS: Complete removal or replacement of the VNS system including the lead and the electrode is feasible and safe. These procedures should be offered to patients who would no longer benefit from the VNS or when only a lead change is needed. PMID- 28012886 TI - Biomechanical and Endplate Effects on Nutrient Transport in the Intervertebral Disc. AB - BACKGROUND: Physical data are lacking on nutrient transport in human intervertebral discs (IVDs), which support regeneration. Our objective was to study nutrient transport in porcine IVDs to determine the effects of biomechanical and physiological factors. METHODS: In vitro testing of whole porcine IVDs was performed under different loading conditions. Fifty cervical, thoracic, and lumbar discs with attached end plates were removed from 4 Yorkshire pigs (90-150 lbs). Discs were placed in Safranin O or Fast Green FCF histological stains in diffusion or diurnal compression-tested groups. The end plate was studied by the use of polyurethane to block it. Traction was studied with a mechanical testing frame. Discs were cut transversely and photographed. Images were analyzed for depth of annulus fibrosus (AF) stained. The nucleus pulposus (NP) was assigned a staining score. RESULTS: Results showed no difference in AF staining between the 2 stains (P = 0.60). The depth of AF staining did not increase (P = 0.60) due to convection or disc height change via diurnal loading. The NP in all open end plate samples was stained completely by day 3. NP staining was decreased in blocked end plate samples (P = 0.07) and AF staining was significantly less in traction samples than in diffusion-only samples (P = 0.04). CONCLUSIONS: This method showed that most small molecule nutrient transport occurs via the end plate. Compressive load was a negligible benefit or hindrance to transport. Traction hindered transport in the short term. This method can be used to study strategies for increasing nutrient transport in IVDs. PMID- 28012887 TI - "The Actualized Neurosurgeon": A Proposed Model of Surgical Resident Development. AB - BACKGROUND: Modern neurosurgical training is both physically and emotionally demanding, posing significant challenges, new and old, to residents as well as programs attempting to train safe, competent surgeons. Models to describe resident development, such as the Accreditation Council for Graduate Medical Education competencies and milestones, address the acquisition of specific skills but largely ignore the stresses and pressures unique to each stage of resident training. METHODS: We propose an alternative model of resident development adapted from the developmental psychology literature. RESULTS: Our model identifies the challenges that must be met at each stage of junior, intermediate, and senior and chief residency, leading ultimately to an "actualized" neurosurgeon (i.e., one who has maximized his or her potential). Failure to overcome any 1 of these challenges can lead to specific long-lasting consequences, including regret, identity crisis, incompetence, and bitterness. In contrast, the actualized surgeon is one who has successfully acquired the virtues of hope, will, purpose, fidelity, productivity, leadership, competence, and wisdom. The actualized surgeon not only functions safely, confidently, and professionally, but also successfully navigates the challenges of residency and emerges from them having fulfilled his or her maximal potential. CONCLUSIONS: This developmental perspective provides an individualized description of healthy surgical development. Our model allows programs to identify the basis for residents who fail to progress, counsel residents during their training, and perhaps help identify resident candidates who are better prepared to meet the developmental challenges of residency training. PMID- 28012888 TI - Magnetic Resonance-Guided Laser Ablation: A Viable Treatment Alternative for Recurrent Meningioma? PMID- 28012889 TI - Analysis of Risk Factors for Secondary New Vertebral Compression Fracture Following Percutaneous Vertebroplasty in Patients with Osteoporosis. AB - OBJECTIVE: The aim of this article was to analyze risk factors for secondary new vertebral compression fractures (SNVCFs) after percutaneous vertebroplasty in patients with osteoporosis. METHODS: We investigated medical records and radiologic images of patients undergoing percutaneous vertebroplasty for osteoporotic vertebral compression fracture between October 2009 and September 2014. We assessed patients' age, past medical history, and bone mineral content using computed tomography. Procedure-specific outcomes were assessed, including ratio of injected bone cement to vertebral body volume, bone cement distribution in the vertebral body (to identify degree of consistency in bone cement injection), presence of bone cement leakage into adjacent disc space, segmental kyphosis, and time interval between first and second fracture events. RESULTS: Percutaneous vertebroplasty was performed in 293 patients (60 men and 233 women) with 336 affected levels. Of this cohort, 34 (14.6%) patients sustained SNVCFs. We compared patients in 2 groups: patients who experienced SNVCFs, and patients who did not experience fractures. Significant differences were identified in bone mineral content (P = 0.000) and bone cement distribution (P = 0.000). Patients exhibiting bone cement leakage into disc space revealed a higher incidence of SNVCF than patients without leakage (P = 0.039). CONCLUSIONS: Poor bone mineral content can be a predictive factor of SNVCFs. To prevent SNVCFs, bone cement should be injected as evenly as possible into the vertebral body. Bone cement leakage into the disc space should be avoided. PMID- 28012890 TI - A Simple Infection Control Protocol Durably Reduces External Ventricular Drain Infections to Near-Zero Levels. AB - OBJECTIVE: External ventricular drains (EVDs) historically have a high rate of infection, and EVD infections are a cause of significant morbidity and mortality. We have shown previously that a simple infection control protocol reduced the rate of EVD infections during a 3-year period, and the present study examines whether infection rates were durably reduced over an additional 4 years. METHODS: Retrospective analysis of EVDs placed in the intensive care unit of a tertiary neurosurgical center over an additional 4 year follow-up period. RESULTS: In the 4-year follow-up period, 189 EVDs were placed in 173 patients. The previously observed decrease in cerebrospinal fluid culture positivity from 9.8% in the baseline period to 0.8% in the first 3 years of the protocol period continued in the 4-year follow-up period (0%, 0 of 189 EVD placements, 0 per 1000 catheter days; P < 0.001 compared with baseline). The previously observed decrease in the rate of ventriculitis from 6.3% to 0.8% also continued in the follow-up period (0%, 0 of 189 EVD placements, 0 per 1000 catheter-days; P < 0.001 compared with baseline). Over the total 7 years of protocol use, the rate of culture positivity was 0.3% (1 of 308 EVD placements, 0.29 per 1000 catheter-days) and the rate of ventriculitis was 0.3% (1 of 308 EVD placements, 0.29 per 1000 catheter-days). The only observed infection over 7 years occurred in a patient who removed their own EVD. CONCLUSIONS: A straightforward EVD infection control protocol substantially and durably reduces EVD infections to a near-zero rate. PMID- 28012892 TI - Head anatomy of adult Coniopteryx pygmaea: Effects of miniaturization and the systematic position of Coniopterygidae (Insecta: Neuroptera). AB - External and internal head structures of adult Coniopteryx pygmaea Enderlein, 1906, one of the smallest known lacewings, are described in detail for the first time. Possible effects of miniaturization and two hypotheses on the phylogenetic position of Coniopterygidae are evaluated and compared with data from literature. Several convergent modifications in C. pygmaea and other miniaturized insect species are outlined, e.g., a relative increase in the size of the brain, simplification of the tracheal system with respect to the number of tracheae, and reduction of the number of ommatidia and diameter of the facets. Further, the ocular ridge is bell-shaped and countersunk into the head capsule. The cuticle is weakly sclerotized and equipped with wax glands which are unique in Neuroptera. The total number of muscles is not affected by miniaturization. The phylogenetic analysis yields Coniopterygidae as sistergroup to the dilarid clade based on one larval character, the shape of the stylets. The enforced basal position of Coniopterygidae is supported by one disputable synapomorphy of the remaining Neuroptera, the presence of paraglossae in adults. PMID- 28012893 TI - Matrix gla protein: An extracellular matrix protein regulates myostatin expression in the muscle developmental program. AB - AIM: Skeletal muscle development involves interactions between intracellular and extracellular factors that act in concert to regulate the myogenic process. Matrix gla protein (MGP), a well-known inhibitor of calcification in soft tissues, has been reported to be highly up-regulated during myogenesis. Our interest in the regulation of muscle satellite cells (MSCs) by extracellular matrix (ECM) led us to investigate the effects of MGP during the progression of myogenesis. METHODOLOGY: Participation of MGP in the myogenic process was investigated in vitro using C2C12 cells, and knockdown of its gene was performed to determine its effects on the expression of myogenic regulatory factors (MRFs) and other ECM genes. In addition, interactions between MGP, Fibromodulin (FMOD), and Myostatin (MSTN) were investigated by conducting co-immunoprecipitation and in silico studies. KEY FINDINGS: Matrix gla protein knockdown (MGPkd) shows pronounced effects during myogenesis as evidenced by the down regulation of myogenic marker (MYOG and MYOD), and ECM (COL1alpha1 and FMOD) genes. Down regulation of MSTN expression in MGPkd cells suggests its role in coordinating the regulation of MSTN expression. Having strong affinity for ACVRIIB receptor, in silico data confirms MGP interference in the interaction of MSTN with ACVRIIB. These findings show MGP inhibits MSTN functionally by disrupting its binding to receptor. SIGNIFICANCE: The present study provides insights of an ECM protein that participates in the regulation of the myogenic program by inhibiting the activity of the myogenic negative regulator MSTN, which suggests that MGP might be used for designing novel inhibitors that can promote muscle regeneration or treat muscle atrophy. PMID- 28012891 TI - Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs. AB - Many neurodegenerative diseases are characterized by deficiencies in neuronal axonal transport, a process in which cellular cargo is shuttled with the aid of molecular motors from the cell body to axonal termini and back along microtubules (MTs). Proper axonal transport is critical to the normal functioning of neurons, and impairments in this process could contribute to the neuronal damage and death that is characteristic of neurodegenerative disease. Although the causes of axonal transport abnormalities may vary among the various neurodegenerative conditions, in many cases it appears that the transport deficiencies result from a diminution of axonal MT stability. Here we review the evidence of MT abnormalities in a number of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury, and highlight the potential benefit of MT-stabilizing agents in improving axonal transport and nerve function in these diseases. Moreover, we discuss the challenges associated with the utilization of MT-stabilizing drugs as therapeutic candidates for neurodegenerative conditions. PMID- 28012894 TI - The genotoxic potency of glycidol established from micronucleus frequency and hemoglobin adduct levels in mice. AB - Glycidol is a genotoxic animal carcinogen that has raised concern due to its presence in food, as glycidyl fatty acid esters. Here we investigated the genotoxicity of glycidol in BalbC mice (0-120 mg/kg) by monitoring the induction of micronuclei in peripheral blood as a marker of chromosomal damage. The scoring of the micronuclei was assessed by flow cytometry. In the treated mice, the internal dose of glycidol, expressed as area under the concentration-time curve, AUC (mol * L-1 * h; Mh), was measured by dihydroxypropyl adducts to hemoglobin (Hb). The study showed that glycidol induced linear dose-dependent increases of Hb adducts (20 pmol/g Hb per mg/kg) and of micronuclei frequencies (120/00 per mMh). Compared to calculations based on administered dose, an improved dose response relationship was observed when considering internal dose, achieved through the applied combination of sensitive techniques used for the scoring of micronuclei and AUC estimation of glycidol in the same mice. By comparing with earlier studies on micronuclei induction in mice exposed to ionizing radiation we estimated the radiation dose equivalent (rad-eq.) of glycidol to be ca 15 rad eq./mMh. PMID- 28012895 TI - Protocatechuic acid methyl ester ameliorates fluoride toxicity in A549 cells. AB - The present study is aimed to determine the potential benefits of protocatechuic acid methyl ester (PCAME) against fluoride (F-) induced lung toxicity using A549 cells. The cells were treated with sodium fluoride (NaF) alone and in combination with PCAME for different time points (0-24 h) and evaluated for intracellular reactive oxygen species (ROS) production, F- content, oxidative stress markers, apoptosis and mRNA expression of redox signaling and inflammatory genes. The results shown that PCAME alleviates the toxic effects of F-via modulating its bioavailability, intracellular calcium level, mitochondrial membrane integrity and redox signaling in A549 cells. F- induced changes in ROS generation, oxidative stress markers, TUNEL positive cells and mRNA levels of inflammatory genes were further normalized by PCAME. Taken together, these findings revealed that PCAME effectively attenuated the F- induced changes in oxidative stress, inflammation and apoptosis markers by reducing its cellular content, ROS generation and biochemical and molecular changes. Thus PCAME can be used as a nutraceutical agent for F- toxicity. PMID- 28012896 TI - Dietary determinants of cadmium exposure in the Strong Heart Family Study. AB - Urinary cadmium (Cd) concentrations in the Strong Heart Family Study (SHFS) participants are higher than in the general US population. This difference is unlikely to be related to tobacco smoking. We evaluated the association of consumption of processed meats and other dietary products with urinary Cd concentrations in the SHFS, a family-based study conducted in American Indian communities. We included 1725 participants with urine Cd concentrations (standardized to urine creatinine) and food frequency questionnaire data grouped in 24 categories, including processed meat. Median (IQR) urinary Cd concentrations were 0.42 (0.20-0.85) MUg/g creatinine. The age, sex, smoking, education, center, body mass index, and total kcal adjusted geometric mean ratio (GMR) (95%CI) of urinary cadmium concentrations per IQR increase in each dietary category was 1.16 (1.04-1.29) for processed meat, 1.10 (1.00-1.21) for fries and chips, 0.87 (0.80-0.95) for dairy products, and 0.89 (0.82-0.97) for fruit juices. The results remained similar after further adjustment for the dietary categories associated with urinary Cd in the previous model except for fries and chips, which was no longer statistically significant. These findings revealed the potential importance of processed meat products as a dietary source of cadmium. PMID- 28012897 TI - Visualization of herpes simplex virus type 1 virions using fluorescent colors. AB - Our laboratory was one of the first to engineer a live fluorescent tag, enhanced green fluorescent protein (eGFP), that marked the capsid of herpes simplex virus type 1 (HSV-1) and subsequently maturing virus as the particle made its way to the cell surface. In the present study we sought to increase the repertoire of colors available as fusion to the small capsid protein, VP26, so that they can be used alone or in conjunction with other fluorescent tags (fused to other HSV proteins) to follow the virus as it enters and replicates within the cell. We have now generated viruses expressing VP26 fusions with Cerulean, Venus, mOrange, tdTomato, mCherry, and Dronpa3 fluorescent proteins. These fusions were made in a repaired UL35 gene (VP26) background. These fusions do not affect the replication properties of the virus expressing the fusion polypeptide and the fusion tag was stably associated with intranuclear capsids and mature virions. Of note we could not isolate viruses expressing fusions with fluorescent proteins that have a tendency to dimerize. PMID- 28012898 TI - Development of a high-throughput multiplexed real time RT-PCR assay for detection of human pegivirus 1 and 2. AB - Human Pegivirus 2 (HPgV-2) was recently identified in the bloodstream of HCV infected and multiply transfused individuals. Initial reports show HPgV-2 circulates at a low prevalence in HCV co-infected individuals, necessitating testing of large cohorts of samples to identify infected persons. The identification of additional HPgV-2 cases was facilitated by the development of a high throughput and reliable molecular reverse transcription polymerase chain reaction (RT-PCR) assay intended for use on the automated Abbott m2000 system with a capability of extracting and testing 96 samples at once. A dual target approach was taken to reduce the risk of a false-negative result, amplifying sequences within the 5' UTR and NS2/3 coding regions of HPgV-2. The assay was expanded to multiplex detection of the other human Pegivirus, HPgV-1 (formerly GBV-C), to allow simultaneous prevalence comparison. The limit of detection (LOD; 95% detection) for HPgV-2 was experimentally determined to be 126 copies/mL. Through use of the newly developed multiplex assay, 21 strains of HPgV-2 circulating in HCV past or present infections were identified, with all strains confirmed by next generation sequencing. The multiplexed assay has high specificity and showed no cross-reactivity of HPgV-2 with HPgV-1 or other Flaviviruses. This automated assay will be instrumental in future studies addressing HPgV-2 pathogenicity, prevalence, and sequence diversity. PMID- 28012899 TI - Corning HYPERFlask(r) for viral amplification and production of diagnostic reagents. AB - Viral preparations are essential components in diagnostic research and development. The production of large quantities of virus traditionally is done by infecting numerous tissue culture flasks or roller bottles, which require large incubators and/or roller bottle racks. The Corning HYPERFlask(r) is a multilayer flask that uses a gas permeable film to provide gas exchange between the cells and culture medium and the atmospheric environment. This study evaluated the suitability of the HYPERFlask for production of Lassa, Ebola, Bundibugyo, Reston, and Marburg viruses and compared it to more traditional methods using tissue culture flasks and roller bottles. The HYPERFlask produced cultures were equivalent in virus titer and indistinguishable in immunodiagnostic assays. The use of the Corning HYPERFlask for viral production is a viable alternative to traditional tissue culture flasks and roller bottles. HYPERFlasks allow for large volumes of virus to be produced in a small space without specialized equipment. PMID- 28012900 TI - Pathogenic conversion of coagulase-negative staphylococci. AB - Humans and animals are colonized by members of the genus Staphylococcus, however only some of these species evolved to cause invasive disease. The genetic basis for conversion of commensal staphylococci into pathogens is not known. We hypothesized that Staphylococcus aureus genes for coagulation and agglutination in vertebrate blood (coa, vwb and clfA) may support pathogenic conversion. Expression of coa and vwb in Staphylococcus epidermidis or Staphylococcus simulans supported a coagulase-positive phenotype but not the ability to cause disease in a mouse model of bloodstream infection. However, the simultaneous expression of coa, vwb and clfA in coagulase-negative staphylococci enabled bacterial agglutination in plasma and enhanced survival of S. simulans in human whole blood. Agglutination of S. simulans in the bloodstream of infected mice upon expression of coa, vwb and clfA provided also a mean for dissemination and replication in distal organs. Thus, the acquisition of genes for bacterial agglutination with fibrin appear sufficient for the conversion of commensal staphylococci into invasive pathogens. PMID- 28012901 TI - Pravastatin and simvastatin inhibit the adhesion, replication and proliferation of Toxoplasma gondii (RH strain) in HeLa cells. AB - The conventional treatment for toxoplasmosis with pyrimethamine and sulfadiazine shows toxic effects to the host, and it is therefore necessary to search for new drugs. Some studies suggest the use of statins, which inhibit cholesterol synthesis in humans and also the initial processes of isoprenoid biosynthesis in the parasite. Thus, the objective of this study was to evaluate the activity of the statins pravastatin and simvastatin in HeLa cells infected in vitro with the RH strain of T. gondii. HeLa cells (1*105) were infected with T. gondii tachyzoites (5*105) following two different treatment protocols. In the first protocol, T. gondii tachyzoites were pretreated with pravastatin (50 and 100MUg/mL) and simvastatin (1.56 and 3.125MUg/mL) for 30min prior to infection. In the second, HeLa cells were first infected (5*105) with tachyzoites and subsequently treated with pravastatin and simvastatin for 24h at the concentrations noted above. Initially, we evaluated the cytotoxicity of drugs by the MTT assay, number of tachyzoites adhered to cells, number of infected cells, and viability of tachyzoites by trypan blue exclusion. The supernatant of the cell cultures was collected post-treatment for determination of the pattern of Th1/Th2/Th17 cytokines by cytometric bead array. There was no cytotoxicity to HeLa cells with 50 and 100MUg/mL pravastatin and 1.56 and 3.125MUg/mL simvastatin. There was no change in the viability of tachyzoites that received pretreatment. Regarding the pre- and post-treatment of the cells with pravastatin and simvastatin alone, there was a reduction in adhesion, invasion and proliferation of cells to T. gondii. As for the production of cytokines, we found that IL-6 and IL-17 were significantly reduced in cells infected with T. gondii and treated with pravastatin and simvastatin, when compared to control. Based on these results, we can infer that pravastatin and simvastatin alone possess antiproliferative effects on tachyzoites forms of T. gondii, giving these drugs new therapeutic uses. PMID- 28012902 TI - First characterization of viruses from freshwater snails of the genus Biomphalaria, the intermediate host of the parasite Schistosoma mansoni. AB - We report the genome sequence and organization of five viruses infecting snails of both Biomphalaria glabrata and Biomphalaria pfeifferi, which are vectors of the intestinal schistosomiasis. Four viruses presented a polyadenylated positive single strand RNA genome encoding one or two large open reading frames (ORFs) flanked by untranslated region. Conserved protein motifs typical of the picorna like virus superfamily were identified in these viruses but they all presented different genome organization. Phylogenetic analysis confirmed their assignment to this superfamily. The partially characterized fifth virus presented sequence similarity for Totiviridae, a family of non-polyadenylated double-strand RNA viruses. Virus distribution and relative abundance between the five strains of Biomphalaria originating from different geographical areas was determined. Our results provide valuable information of new viruses from Biomphalaria and pave the way for future studies dedicated to their impact on snail fitness and Biomphalaria/Schistosoma interactions. PMID- 28012903 TI - Multiple-host pathogens in domestic hunting dogs in Nicaragua's Bosawas Biosphere Reserve. AB - Nicaragua's Bosawas Biosphere Reserve is a vast forested area inhabited largely by indigenous Mayangna and Miskitu people. Most Bosawas residents rely on subsistence hunting and swidden agriculture, and hunting dogs are important for finding and securing wild game. We investigated the health of hunting dogs in three communities differing in location, size, and economy. Dogs in all communities were nutritionally compromised and experienced a heavy burden of disease. Seroprevalence of canine distemper, canine parvovirus, Rickettsia rickettsii, and Leptospira spp. exceeded 50% of dogs. At least one dog was actively shedding leptospires in urine, and many dogs were anemic and/or dehydrated. These dogs interact with wildlife in the forest and humans and domestic livestock in the communities, and may therefore serve as sources of zoonotic and wildlife diseases. Bosawas represents one of the largest intact tracts of habitat for jaguars (Panthera onca) in Central America, and given that these communities are located within the forest, jaguars may be at risk from disease spillover from hunting dogs. Dog owners reported that four of 49 dogs had been attacked and killed by jaguars in the past year, and that retaliatory killing of jaguars was sometimes practiced. Disease spillover from dogs to wildlife could occur both in the course of dogs' hunting activities as well as during jaguar attacks. A better understanding of dog depredation by jaguars, pathogen exposure in jaguars, and a management strategy for the hunting dog population, are urgently needed to mitigate these dual threats to jaguars, improve the lives of hunting dogs, and safeguard the health of their owners. PMID- 28012904 TI - Riggia puyensis n. sp. (Isopoda: Cymothoidae) parasitizing Chaetostoma breve and Chaetostoma microps (Siluriformes: Loricariidae) from Ecuador. AB - A new isopod was found parasitizing Chaetostoma breve and Chaetostoma microps from the Puyo and Bobonaza rivers. The parasite found belongs to the Cymothoidae family and could be located within the genus Riggia instead of Artystone by the presence of abdominal plates fused with the telson. The specimens found represent a new species, Riggia puyensis n. sp., and could be distinguished from Riggia cryptocularis by the presence of developed eyes. The main difference of the new specie from Riggia nana and Riggia brasiliensis is the size, bigger compared with the first and smaller compared with the last species. Riggia acuticaudata have the maxilliped with simple setae, the palp without spination, and maxillule with five spines (two terminal and three subterminal) instead in R. puyensis n. sp. the maxilliped have plumose setae, the palp have spination (with one apical spine, two setae on middle article and one in the basal article) and the maxillule have five spines: two terminal, two subterminal and other spine lower to the others. Riggia paranaensis have similar size, same number of segments in the antena, and similar maxilla to R. puyensis n. sp., but the antennule in the new specie have seven segments instead 6 in R. paranaensis, the antennule and antenna present spines not mentioned in R. paranaensis. Besides, the relative position of the mandible in R. puyensis n. sp. is different compared with R. paranaensis, the maxillule have the same number of spines but with different disposition, and the maxilliped have simple setae in R. paranaensis but those are plumose in the new specie. PMID- 28012905 TI - A cysteine protease from Spirometra erinaceieuropaei plerocercoid is a critical factor for host tissue invasion and migration. AB - Sparganosis in humans caused by the plerocercoid larvae of Spirometra erinaceieuropaei is found worldwide, especially in Eastern Asia and the Far East. Previous studies have suggested that dissolution of plerocercoid body, plerocercoid invasion of host tissue, and migration are important processes for sparganosis progression. However, the mechanisms underlying these processes have yet to be determined. Here, we demonstrated the enzymatic property and involvement of a native 23kDa cysteine protease (Se23kCP), purified from plerocercoids, in sparganosis pathogenesis. Se23kCP is mature protease consisting of 216 amino acids and has a high sequence similarity with cathepsin L in various organisms. Se23kCP conjugated with N-glycans, which have a core fucose residue. Both cysteine and serine protease-specific activities were determined in Se23kCP and their optimal pHs were found to be different, indicating that Se23kCP has a wide range of substrate specificity. Se23kCP was secreted from tegumental vacuoles of the plerocercoid to host subcutaneous tissues and degraded human structural proteins, such as collagen and fibronectin. In addition, the plerocercoid body was lysed by Se23kCP, which facilitated larval invasion of host tissue. Our findings suggest that Se23kCP induces host tissue invasion and migration, and might be an essential molecule for sparganosis onset and progression. PMID- 28012906 TI - Infestation of cockroaches (Insecta: Blattaria) in the human dwelling environments: A systematic review and meta-analysis. AB - Periplaneta americana, Blatta orientalis, Blattella germanica and Supella longipalpa are the most common worldwide cockroaches that mentioned in the "22 common pest" or "22 dirty" species named as "group I". They are able to infest any type of buildings. A meta-analysis review was conducted between January 2015 and July 2016 on any literature published about infestation of cockroaches. Scientific reports and papers about infestation of cockroaches and relevant topics were collected from various specific scientific websites such as PubMed, Web of Science, ScienceDirect, Springer, Elsevier, Scopus, and Google Scholar. About 271 scientific reports and papers were collected and after a preliminary review, 63 were selected to become part of the detailed synthesis review and meta analysis. Results showed that the global world mean infestation trend of cockroaches, and B. germanica and P. americana cockroach species ranged 49.0 55.0, 40.0-70.0 and 60.0-70.0%, respectively suggests that their infestation trend are increasing. The global world mean infestation of cockroaches, and B. germanica and P. americana cockroach species were 52.3, 55.2 and 65.4, respectively. There was a significant difference between the global world mean infestation of cockroaches and P. americana cockroach species (P=0.019). The global mean infestation trend of cockroaches in the human dwelling environments and world ranged 55.0-65.0 and 50.0-70.0%, respectively suggests that their infestation trend are increasing. The global world mean infestation of cockroaches in the human dwelling environments and world were 60.4 and 57.7%, respectively. Although some factors affect the infestation of cockroaches and the sanitation and quality structure of the buildings are also being improved. While as present study reveal that the globally the world infestation trend of cockroaches are being increased and recent studies also indicate that the prevalence of asthma has increased dramatically over the decades suggest that infestation of cockroaches can directly affect the development of asthma. PMID- 28012907 TI - Culex (Melanoconion) panocossa from peninsular Florida, USA. AB - Culex (Melanoconion) panocossa is a suspected vector of Venezuelan equine encephalitis virus in Central America. Prior to this report, Cx. panocossa was known from Central America (Belize, Costa Rica, El Salvador, Guatemala, southern Mexico, Panama), northern South America (Colombia, Venezuela) and the Greater Antilles (Cuba and Jamaica). Larvae (n=5) and adults (n=4286) of Cx. panocossa were collected at two locations near Homestead, FL, which indicates substantial established populations of this probable vector species in the continental US. Since larvae of Cx. panocossa are associated with Pistia spp. (water lettuce), the distribution of this mosquito is likely to expand in Florida, where water lettuce is a major invasive plant in freshwater ecosystems. The putative establishment of Cx. panocossa in Florida is of significant concern from a public health perspective, as its proliferation in developed areas could link historically sylvatic transmission foci of Everglades virus with populated centers such as the greater Miami Metropolitan area. PMID- 28012908 TI - Flux balance analysis of photoautotrophic metabolism: Uncovering new biological details of subsystems involved in cyanobacterial photosynthesis. AB - We have constructed and experimentally tested a comprehensive genome-scale model of photoautotrophic growth, denoted iSyp821, for the cyanobacterium Synechococcus sp. PCC 7002. iSyp821 incorporates a variable biomass objective function (vBOF), in which stoichiometries of the major biomass components vary according to light intensity. The vBOF was constrained to fit the measured cellular carbohydrate/protein content under different light intensities. iSyp821 provides rigorous agreement with experimentally measured cell growth rates and inorganic carbon uptake rates as a function of light intensity. iSyp821 predicts two observed metabolic transitions that occur as light intensity increases: 1) from PSI-cyclic to linear electron flow (greater redox energy), and 2) from carbon allocation as proteins (growth) to carbohydrates (energy storage) mode. iSyp821 predicts photoautotrophic carbon flux into 1) a hybrid gluconeogenesis-pentose phosphate (PP) pathway that produces glycogen by an alternative pathway than conventional gluconeogenesis, and 2) the photorespiration pathway to synthesize the essential amino acid, glycine. Quantitative fluxes through both pathways were verified experimentally by following the kinetics of formation of 13C metabolites from 13CO2 fixation. iSyp821 was modified to include changes in gene products (enzymes) from experimentally measured transcriptomic data and applied to estimate changes in concentrations of metabolites arising from nutrient stress. Using this strategy, we found that iSyp821 correctly predicts the observed redistribution pattern of carbon products under nitrogen depletion, including decreased rates of CO2 uptake, amino acid synthesis, and increased rates of glycogen and lipid synthesis. PMID- 28012909 TI - Outcomes and Radiographic Findings of Isolated Spontaneous Superior Mesenteric Artery Dissection. AB - OBJECTIVES: This study aimed to investigate the features, treatments, and prognosis of patients with symptomatic and asymptomatic isolated SMA dissection. METHODS: Data from 35 consecutive patients in whom isolated SMA dissection was diagnosed on computed tomography angiography (CTA) between 2004 and 2015 at two general hospitals in Japan, were collected retrospectively. Nineteen symptomatic patients were compared, and 16 asymptomatic patients with incidentally revealed SMA dissection were also compared. In addition, the vascular remodelling and outcomes during follow-up were evaluated. RESULTS: The patient characteristics in the symptomatic and incidental groups were comparable except for age; mean ages were 55.9 +/- 13.9 and 65.3 +/- 10.9 years, respectively. Most of the symptomatic patients were managed conservatively (including antiplatelet therapy, anticoagulants, blood pressure control, or bowel rest). In addition, one patient was initially treated by endovascular intervention because of intestinal ischaemia, and another was switched from conservative to surgical treatment. The in-hospital outcome was good with no mortality. In the incidental group, all 16 patients were observed as outpatients without additional treatment. Complete remodelling of the false lumen was observed in 31% of patients with follow-up CTA, and was associated with the presence of symptoms and the absence of false lumen with blood flow at diagnosis. Neither recurrent or new onset abdominal pain, intervention for SMA dissection, nor SMA related death was observed in either group during the follow-up period (750 +/- 779 and 1200 +/- 951 days). CONCLUSIONS: The characteristics of asymptomatic patients with incidentally revealed SMA dissection were comparable with those of symptomatic patients, except for age. During follow-up, factors favouring complete remodelling of false lumens were the presence of symptoms, and the absence of false lumen blood flow at diagnosis. PMID- 28012910 TI - A Single Bout of Arm-crank Exercise Promotes Positive Emotions and Post-Exercise Hypotension in Patients with Symptomatic Peripheral Artery Disease. AB - OBJECTIVE/BACKGROUND: The objective was to analyze the acute effects of a single bout of arm cranking exercise on affective and cardiovascular parameters in patients with symptomatic peripheral artery disease (PAD). METHODS: This was a prospective, controlled, crossover study. Eleven men with symptomatic PAD underwent two experimental sessions in a random order: control or arm crank exercise (15 * 2 minutes bouts of arm crank exercise interrupted by 2 minutes rest intervals). During exercise, ratings of perceived exertion (Borg scale) and affective responses (pleasure/displeasure) were obtained at the first, fifth, tenth, and fifteenth bouts. Before and after the experimental sessions, cardiovascular parameters (blood pressure and heart rate) were obtained. Data were analysed by a two-way repeated measure analysis of variance with significance achieved at p < .05. RESULTS: During the arm crank exercise, patients reported positive feelings of pleasure. During exercise, heart rate (HR) remained within 80-90% of peak HR. Additionally, patients performed arm crank exercise with moderate levels of perceived exertion (Borg rating of 11-13) and with pleasant affective scores (Feeling Scale of +1 to +5). Blood pressure (systolic, diastolic, and mean) increase was lower after arm crank exercise than for control (greatest net effect: -15 +/- 11 mmHg [p < .001]; -9 +/- 5 mmHg [p < .001]; -9 +/- 6 mmHg [p < .001], respectively), while HR increased (greatest net effect: +9 +/- 6 beats per minute; p < .001). CONCLUSION: A single bout of arm crank exercise promotes pleasurable feelings while reducing blood pressure in patients with symptomatic PAD. PMID- 28012911 TI - Influence of 300 degrees C thermal conversion of Fe-Ce hydrous oxides prepared by hydrothermal precipitation on the adsorptive performance of five anions: Insights from EXAFS/XANES, XRD and FTIR (companion paper). AB - In this work, we report atomic-scale reconstruction processes in Fe-Ce oxide based composites (hydrothermally precipitated at Fe-to-Ce dosage ratios of 1:0, 2:1, 1:1, 1:2, and 0:1), upon treatment at 300 degrees C. The structural changes are correlated with the adsorptive removal of arsenate, phosphate, fluoride, bromide, and bromate. The presence of the carbonate-based Ce-component and surface sulfate in precursor samples creates favorable conditions for phase transformation, resulting in the formation of novel (unknown) layered compounds of Fe and Ce. These compounds are of the layered double hydroxide type, with sulfate in the interlayer space. In spite of general awareness of the importance of surface area in adsorptive removal, the increase in surface area upon thermal treatment did not increase adsorption of the studied anions. However, EXAFS simulations and the adsorption tests provided evidence of regularities between local structures of Fe in composites obtained at 80 and 300 degrees C and adsorption performance of most studied anions. The best adsorption of tetrahedral anions was demonstrated by samples whose simulated outer Fe shells resulted from oscillations from both O and Fe atoms. In contrast, the loss of extended x-ray absorption fine structure was correlated with the decrease of adsorptive removal. Both Fe K-edge and Ce L3 -edge EXAFS suggested the formation of solid solutions. For the first time, the utilization of extended x-ray absorption fine structure is suggested as a methodological approach (first expressed in the companion paper) to estimate the surface reactivity of inorganic materials intended for use as anion exchange adsorbents. PMID- 28012912 TI - Bone tissue response induced by bioactive polymer functionalized Ti6Al4V surfaces: In vitro and in vivo study. AB - Ti6Al4V is commonly used for orthopedic applications. This study was designed to test the potentially added benefit of Ti6Al4V functionalized with a bioactive polymer poly(sodium styrene sulfonate) both in vitro and in vivo. Cell-based assays with MC3T3-E1 osteoblast-like cells were used to measure the cell adhesion strength, cell spreading, focal contact formation, cell differentiation and the mineralization of extracellular matrix on grafted and ungrafted Ti6Al4V discs in combination with FBS and collagen type I. Bone morphogenetic protein-2 (BMP-2) was also included in the cell differentiation assay. Results showed that the grafted surface combined with collagen I gave superior levels in every parameter tested with cell-based assays and was almost equivalent to BMP-2 for cell differentiation. In vivo testing was conducted in rabbits (n=42) with cylinders of grafted and ungrafted Ti6Al4V implanted in defects made to the femoral and lateral condyles and animals that were maintained to 1, 3 and 12months. Hydroxyapatite coated Ti6Al4V cylinders were included as a clinical reference control. Osseointegration was assessed post-mortem using histomorphometric analysis conducted on resin sections of explanted undecalcified bone. Two histomorphometric parameters, that of bone-to-implant contact and the bone area, were analyzed by a trained observer blinded to sample identity. Results showed osseointegration on grafted Ti6Al4V was marginally better than both ungrafted and hydroxyapatite coated Ti6Al4V. Overall, the study found that the grafted Ti6Al4V significantly promoted all aspects of osteogenesis tested in vitro and, although in vivo outcomes were less compelling, histomorphometry showed osseointegration of grafted Ti6Al4V implants was equivalent or better than controls. PMID- 28012913 TI - Facile route for synthesis of mesoporous graphite encapsulated iron carbide/iron nanosheet composites and their electrocatalytic activity. AB - Mesoporous graphite encapsulated Fe3C/Fe nanosheet composites have been synthesized by a facile template free method using ferric nitrate, glycine and glucose as raw materials. X-ray diffraction, transmission electron microscopy, high-resolution transmission electron microscopy and Raman spectrometer have been used to characterize the composites. The formation process and morphology of the products have been discussed in detail. Interestingly, this facile route can synthesize graphite encapsulated Fe3C, Fe3C/Fe and Fe composites with two dimensional nanosheet structure by tuning the reaction temperature and the Fe3C and Fe nanoparticles with size less than 30nm are well dispersed on the carbon sheet. The mesoporous graphite encapsulated Fe3C/Fe nanosheet composites with a high specific surface area have application in non-noble metal electrocatalysis for hydrogen evolution reaction. PMID- 28012914 TI - Ionogels of pseudogemini supra-amphiphiles in ethylammonium nitrate: Structures and properties. AB - Thermoreversible ionogels formed by pseudogemini surfactants were prepared in protic ionic liquid, ethylammonium nitrate (EAN). Gemini-type supra-amphiphiles were formed by single-chain surfactants and bola-type molecules in a 2:1M ratio. The structures of aggregates including polymorphous lamellar structures and fibrous networks constituted by multilayer lamellae were determined by optical microscopy observations, transmission electron microscopy (TEM) observations, small-angle X-ray scattering (SAXS) and X-ray diffraction (XRD) measurements. The mechanism of molecular arrangement in aggregates was proposed. Transformation temperatures of samples which are closely related to the stability of well ordered molecules in aggregates, as well as the rheological properties of ionogels were investigated systematically. The work affords a new way to construct ionogel by using the supramolecular self-assembly of pseudogemini-type molecules, and brings new ideas for the future construction of ionogels. PMID- 28012915 TI - One-step preparation of magnetic recyclable quinary graphene hydrogels with high catalytic activity. AB - Metal nanoparticles (NPs) displayed overwhelming superiority in catalysis towards the corresponding bulk-phase materials; nevertheless, how to further improve catalytic activity was still an ongoing subject. Herein, we have combined one step redox reaction and following freeze-dried technology to construct the quinary reduced graphene oxide nanosheets (rGS)/Fe2O3-PdPt/polypyrrole (PPy) hydrogels. Compared with traditional catalysts, their catalytic property was improved via two ways: construction of three-dimensional (3D) rGS hydrogels instead of two-dimensional rGS and synthesis of bimetallic alloys instead of monometallic NPs. The highly dispersed PdPt with diameter as small as 3.2nm uniformly loaded on hydrogel surface. Due to special interconnected and porous structure, the reactants were easily adsorbed in hydrogels and contacted with PdPt alloys. To explain the contributions of bimetallic alloys and 3D rGS structure on enhanced catalytic activity, the catalytic property of quinary hydrogels was compared with reference samples. Besides superior activity, they also displayed good reusability, since hydrogels could be magnetically recycled owing to the existence of Fe2O3 NPs. PMID- 28012916 TI - High efficient and selective removal of Pb2+ through formation of lead molybdate on alpha-MoO3 porous nanosheets array. AB - 2D hand-like structured alpha-MoO3 porous nanosheets were grown in-situ onto a capillary by a simple hydrothermal route, on which titanium dioxide seed layer was sol-dip-coated in advance. The alpha-MoO3 porous nanosheets array exhibits an exceptional lead ion uptake capacity up to 1450.0mg.g-1, and can effectively reduce Pb2+ concentration from 20mg.L-1 to a low level of smaller than 3MUg.L-1, well below the acceptable limits in drinking water standards (10MUg.L-1) and can efficiently remove 99.9% lead ion within a few minutes at room temperature. Furthermore, alpha-MoO3 porous nanosheets array also has high selectivity toward Pb2+ better than Cu2+, Zn2+, Cr3+ and Cd2+. The mechanism for adsorption was discussed according to the results of Zeta potential, IR, XPS and XRD analyses. The excellent removal performance of the array to Pb2+ is resulted from the electrostatic adsorption interaction and the formation of new species lead molybdate. PMID- 28012917 TI - Synthesis and properties of ZnO-HMD@ZnO-Fe/Cu core-shell as advanced material for hydrogen storage. AB - In this paper, a new synthetic strategy towards functionalized ZnO-HMD@ZnO-Fe/Cu core-shell using sol-gel process modified by chemical grafting of hexamethylenediamine (HMD) on the core and in-situ dispersion of Cu0/Fe0 as metallic nanoparticles (M-NPs) on the shell. The as-prepared core-shell materials were fully characterized by transmission electron microscopy, X-ray powder diffractometry, diffuse reflectance and FT-IR spectrophotometery, photoluminescence, and complexes impedance spectroscopy measurements. The XRD patterns agreed with that of the ZnO typical wurtzite structure, indicating good crystallinity of ZnO-HMD@ZnO-Fe/Cu, with the presence of Fe0 and Cu0 phases. Hexamethylenediamine grafting and M-NPs insertion were highly activated and enhanced the core and shell interface by the physiochemical interaction. After functionalization, luminescence intensities and electrical properties of both core and core-shell nanoparticles are improved, indicating the effects of the surface groups on the charge transfer of ZnO-HMD@ZnO-Fe/Cu. The hydrogen capacity retention was depended strongly on the composition and structure of the obtained core-shell. Iron/Copper-loaded ZnO-HMD@ZnO materials exhibited the highest capacity for hydrogen storage. The excellent stability and performance of the ZnO HMD@ZnO-Fe/Cu core-shell make it an efficient candidate for hydrogen storage. PMID- 28012918 TI - Enhanced chemotherapeutic efficacy of apigenin liposomes in colorectal cancer based on flavone-membrane interactions. AB - Recent endeavors in exploiting vast array of natural phytochemicals to ameliorate colorectal cancer led us to investigate apigenin, a naturally occurring dietary flavone as a potential chemo-therapeutic agent. The present study focuses on establishing apigenin as a potential chemotherapeutic agent for alleviating colorectal cancer and reports the development of a stable liposomal nanocarrier with high encapsulation of the hydrophobic flavone apigenin for enhanced chemotherapeutic effects. The enhanced pharmacological activity of apigenin has been assigned to its ability to interact and subsequently influence membrane properties which also resulted in optimal yield of a stable, rigidified, non leaky nano-carrier with ideal release kinetics. Extensive testing of drug and its liposomal counterpart for potential clinical chemotherapeutic applications yielded hemocompatibility and cytocompatibility with normal fibroblast cells while enhanced antineoplastic activity was observed in tumor xenograft model. The increased chemotherapeutic potential of liposomal apigenin highlights the clinical potential of apigenin-based vesicles. PMID- 28012919 TI - Ilex paraguariensis and its main component chlorogenic acid inhibit fructose formation of advanced glycation endproducts with amino acids at conditions compatible with those in the digestive system. AB - We have previously shown that Ilex paraguariensis extracts have potent antiglycation actions. Associations of excess free fructose consumption with inflammatory diseases have been proposed to be mediated through in situ enteral formation of fructose AGEs, which, after being absorbed may contribute to inflammatory diseases via engagement of RAGE. In this proof of principle investigation we show fluorescent AGE formation between amino acids (Arg, Lys, Gly at 10-50mM) and fructose (10-50mM) under time, temperature, pH and concentrations compatible with the digestive system lumen and its inhibition by Ilex paraguariensis extracts. Incubation of amino acids with fructose (but not glucose) leads to a time dependent formation of AGE fluorescence, already apparent after just 1h incubation, a time frame well compatible with the digestive process. Ilex paraguariensis (mate tea) inhibited AGE formation by 83% at 50MUl/ml (p<0.001). Its main phenolics, caffeic acid and cholorogenic acid were as potent as aminoguanidine-a specific antiglycation agent: IC50 of 0.9mM (p<0.001). Our results suggest that AGE adducts form between fructose and amino acids at times and concentrations plausibly found in the intestines. The reaction is inhibited by mate tea and its individual phenolics (caffeic acid and chlorogenic acids). The study provides the first evidence for the proposed mechanism to explain epidemiological correlations between excess fructose consumption and inflammatory diseases. Enteral fructose-AGE formation would be inhibited by co-intake of Ilex paraguariensis, and potentially other beverages, fruits and vegetables that contain comparable concentrations of phenolics as in IP (mate tea). PMID- 28012920 TI - Naphthofuranone derivatives and other constituents from Pachira aquatica with inhibitory activity on superoxide anion generation by neutrophils. AB - Two new naphthofuranone derivatives, 11-hydroxy-2-O-methylhibiscolactone A (1) and O-methylhibiscone D (2), have been isolated from the stems of Pachira aquatica, together with 18 known compounds (3-20). The structures of two new compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, 11-hydroxy-2-O-methylhibiscolactone A (1), isohemigossylic acid lactone-7-methyl ether (4), gmelofuran (6), and 5-hydroxyauranetin (8) exhibited inhibition (IC50<=28.84MUM) of superoxide anion generation by human neutrophils in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). PMID- 28012921 TI - Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation. AB - High morbidity and mortality associated with human cases of highly pathogenic avian influenza (HPAI) viruses, including H5N1 influenza virus, have been reported. The purpose of the present study was to evaluate the antiviral effects of peramivir against HPAI viruses. In neuraminidase (NA) inhibition and virus replication inhibition assays, peramivir showed strong inhibitory activity against H5N1, H7N1 and H7N7 HPAI viruses with sub-nanomolar activity in enzyme assays. In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation. PMID- 28012922 TI - Identification of heat resistant Escherichia coli by qPCR for the locus of heat resistance. AB - Three qPCR assays targeting the locus of heat resistance to identify heat resistant clinical Escherichia coli isolates are described. Of 613 isolates, 3 (0.5%) possessed the locus. The assays are a rapid, highly sensitive and specific alternative to screening by heat shock and can be used in food safety surveillance. PMID- 28012923 TI - Anti-inflammatory effects of ethanolic extract of Rosmarinus officinalis L. and rosmarinic acid in a rat model of neuropathic pain. AB - BACKGROUND: Rosemary, Rosmarinus (R.) officinalis L. is a well-known plant with several useful properties such as analgesic, anti-inflammatory and anti neurodegenerative. It has been used in folk medicine to alleviate rheumatic pain, stomachache and dysmenorrhea. Rosemary has several constituents such as rosmarinic acid which can be responsible for therapeutic properties been noted with rosemary. The aim of this study was to investigate the potential anti inflammatory effects of R. officinalis and rosmarinic acid in a rat model of sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain to verify usage of rosemary in folk medicine. METHODS: Rats underwent CCI, were treated with either normal saline, ethanolic extract of aerial parts of R. officinalis (400mg/kg, i.p.) or rosmarinic acid (40mg/kg, i.p.) from the day of surgery (day 0) for 14days. The anti-inflammatory effects of R. officinalis extract and rosmarinic acid were evaluated by assessing the levels of some spinal inflammatory markers including cyclooxygenase-2 (COX2), prostaglandin E2 (PGE-2), interleukin 1 beta (IL-1beta), matrix metallopeptidase 2 (MMP2) through western blotting and nitric oxide (NO) production via Griess reaction on days 7 and 14 post-surgery. RESULTS: CCI rats exhibited a marked expression in the levels of inflammatory markers (COX2, PGE-2, IL-1beta, MMP2 and NO) on both days 7 (p<0.001) and 14 (p<0.001). Rosmarinic acid and ethanolic extract of R. officinalis were able to decrease amounts of mentioned inflammatory markers on both days 7 (p<0.001) and 14 (p<0.001). CONCLUSION: Our data support the traditional use of R. officinalis as an effective remedy for pain relief and inflammatory disorders. It also suggests that the ethanolic extract of R. officinalis and rosmarinic acid through modulating neuro-inflammation might be potential candidates in treating neuropathic pain and different neurological disorders associated with inflammation. PMID- 28012924 TI - MiR-129 regulates cisplatin-resistance in human gastric cancer cells by targeting P-gp. AB - Development of multiple drug resistance (MDR) to chemotherapy is the major reason for the failure of gastric cancer (GC) treatment. P-glycoprotein (P-gp), which is encoded by MDR gene 1, as one of the mechanisms responsible for MDR. Mounting evidence has demonstrated that the drug-induced dysregulation of microRNAs (miRNAs) function may mediate MDR in cancer cells. However, the underling mechanisms of miRNA-mediated MDR in GC remain unclear. Here, we found that miR 129 was downregulated in cisplatin-resistant GC tissues/cells. Our results also showed that overexpression of miR-129 decreased cisplatin-resistance in cisplatin resistant GC cells, and miR-129 knockdown reduced chemosensitivity to cisplatin in cisplatin-sensitive GC cells. Furthermore, miR-129 activated the intrinsic apoptotic pathway via upregulating caspase-9 and caspase-3. Most importantly, we further confirmed that P-gp is the functional target of miR-129 by regulating cisplatin-resistance in GC cells. These results suggested that miR-129 reversed cisplatin-resistance through inhibiting the P-gp expression in GC cells. PMID- 28012926 TI - miR-590 accelerates lung adenocarcinoma migration and invasion through directly suppressing functional target OLFM4. AB - MicroRNA-590 (miR-590) shows oncogenic functions in various tumor types, but little is known about biological functions of miR-590 in lung adenocarcinoma. In this study, we observe that miR-590 is not only overexpressed in lung adenocarcinoma tissues and metastatic lymph nodes, but also significantly increased in lung adenocarcinoma cell lines. Moreover, gain-of-function and loss of-function studies show miR-590 serve as a tumor suppressor regulating lung adenocarcinoma cells migration and invasion. Furthermore, OLFM4 is proved to as a functional target for miR-590 to regulate lung adenocarcinoma cells migration and invasion. In conclusion, miR-590 regulates lung adenocarcinoma metastasis through directly modulating functional target OLFM4. PMID- 28012925 TI - Cigarette smoke extract induces epithelial-mesenchymal transition of human bladder cancer T24 cells through activation of ERK1/2 pathway. AB - Bladder cancer is a common genitourinary malignant disease worldwide. Abundant evidence has shown that cigarette smoke (CS) is a crucial risk factor for bladder cancer. Nevertheless, the mechanism underlying the relationship between cigarette smoking and bladder cancer remains unclear. In the present study, we investigated the effects of cigarette smoke extract (CSE) on mitogen-activated protein kinase (MAPK) pathway activation and EMT alterations in human bladder cancer T24 cells, and the preventive effect of extracellular regulated protein kinases 1 and 2 (ERK1/2) inhibitor U0126 was further examined. Our results illustrated that CSE exposure induced morphological change of human bladder cancer T24 cells, enhanced migratory and invasive capacities, reduced epithelial marker expression and elevated mesenchymal marker expression. Meanwhile, exposure of T24 cells to CSE resulted in activation of ERK1/2 pathway as well as activator protein 1 (AP-1) proteins. Interestingly, treatment with ERK1/2 inhibitor U0126 effectively abrogated CSE-triggered EMT and ERK1/2/AP-1 activation. These findings provide novel insight into the molecular mechanisms of CS-associated bladder cancer and may open up new avenues in the search for potential target of bladder cancer intervention. PMID- 28012927 TI - Role of Scoparia dulcis linn on noise-induced nitric oxide synthase (NOS) expression and neurotransmitter assessment on motor function in Wistar albino rats. AB - Noise pollution is one of the most widespread and fast growing environmental and occupational menaces in the modern era. Exposure to noise above 100dB is not adaptable through the brain homeostatic mechanism. Yet, the detrimental effects of noise have often been ignored. Developing reliable animal models to understand the neurobiology of noise stress and advance our research in the field of medicine to impede this growing stressor is needed. In this study experimental animals were divided into four groups, (i) Control and (ii) S. dulcis extract (200mg/kgbw) treated control group. (iii) To mimic the influence of noise, animals in this group were exposed to noise stress (100dB/4h/day) for 15days and finally, (iv) Noise exposed treated with S. dulcis extract (200mg/kgbw) group. Rota-rod and narrow beam performance results showed impaired motor co-ordination in noise exposed group on both 1st and 15th day when compared to controls. This impaired motor function on exposure to noise could be attributed to the altered norepinephrine, dopamine and serotonin levels in both the striatum and cerebellum. Moreover, the motor impaired associated changes could also be attributed to upregulated nNOS and iNOS protein expression in the cerebellum resulting in increased nitric oxide radical production. This increased reactive free radicals species can initiate lipid peroxidation mediated changes in the cerebellar Purkinje cells, which is responsible for initiating inhibitory motor response and ultimately leading to impaired motor co-ordination. Treatment with S. dulcis extract (200mg/kgbw) could control motor impairment and regulate neurotransmitter level as that of control groups when compared to noise exposed group. One key aspect of therapeutic efficacy of the plant could have resulted due to attenuated lipid peroxidation mediated damages on the cerebellar Purkinje cells thereby regulating motor impairment. Thus, targeting the antioxidant and free radicals scavenging properties of the plant could serve as a potential therapeutic to combat this environmental stressor. PMID- 28012928 TI - Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity: A biochemical, histopathological, and immunohistochemical study. AB - Cisplatin (cis-diamminedichloroplatinum, CDDP) is an effective DNA alkylating agent used in the treatment of different types of tumors; however, its clinical use is associated with hepato-cardiotoxicity. The current study was designed to assess the potential protective effect of parsley oil (PO) against CDDP-induced hepato-cardiotoxicity. For this purpose, 25 adult male rats were assigned into five groups, each containing five animals. Group I (control) was administered saline solution. Group II was administered PO at a dosage of 0.42ml/kg BW. Group III were administered CDDP at a dosage of 5mg/kg BW. Group IV was administered PO in addition to CDDP. Group V was administered saline solution in addition to CDDP, after which they were administered PO for five days. Oral administration of either saline solution or PO was performed each day for 10days, while administration of CDDP was via a single intraperitoneal injection five days following the commencement of the experiment. The recorded results revealed that CDDP induced obvious hepatic and cardiac injuries that were indicated by biochemical, histopathological, and immunohistochemical alterations, including elevation of serum hepatic and cardiac injury markers as well as proinflammatory cytokines. Moreover, CDDP induced an increase in the level of hepatic and cardiac injury biomarkers, decreases in the activities of antioxidant enzymes, a decrease in GSH concentration, and an increase in MDA concentration. CDDP also induced histopathological hepatocellular and myocardial changes, and overexpression of p53 and COX-2 in hepatic and cardiac tissues. Administration of PO either as a preventative medicine or as treatment significantly improved all the observed deleterious effects induced by CDDP in rat liver and heart. Thus, it may be concluded that PO, with its antioxidant, anti-inflammatory, and antiapoptotic activities, can potentially be used in the treatment of CDDP-induced hepatic and cardiac injuries. PMID- 28012929 TI - Schiff base-Poloxamer P85 combination demonstrates chemotherapeutic effect on prostate cancer cells in vitro. AB - Prostate cancer is a multistep and complicated cancer type that is regulated by androgens at the cellular level and remains the second commonest cause of death among men. Discovery and development of novel chemotherapeutic agents enabling rapid tumor cell death with minimal toxic effects to healthy tissues might greatly improve the safety of chemotherapy. The present study evaluates the anti cancer activity of a novel heterodinuclear copper(II)Mn(II) complex (Schiff base) in combination with poly(ethylene oxide) and poly(propylene oxide) block copolymer (Pluronic) P85. We used assays for cell proliferation, apoptosis, cell migration and invasion, DNA binding and cleavage to elucidate the molecular mechanisms of action, in addition to the anti-inflammatory potency of the new combination. The combined treatment of Schiff base and P85 lead to a remarkable anti-cancer effect on prostate cancer cell lines. Cell proliferation was inhibited in Schiff base-P85 treatment. The activity of this formulation is on DNA binding and cleavage and prevents inflammation in in vitro conditions. This is the first study presenting the anti-cancer activity of the present Schiff base derivative and its combination with P85 to treat prostate cancer in vitro. PMID- 28012930 TI - Ascorbic acid, but not dehydroascorbic acid increases intracellular vitamin C content to decrease Hypoxia Inducible Factor -1 alpha activity and reduce malignant potential in human melanoma. AB - INTRODUCTION: Accumulation of hypoxia inducible factor-1 alpha (HIF-1alpha) in malignant tissue is known to contribute to oncogenic progression and is inversely associated with patient survival. Ascorbic acid (AA) depletion in malignant tissue may contribute to aberrant normoxic activity of HIF-1alpha. While AA supplementation has been shown to attenuate HIF-1alpha function in malignant melanoma, the use of dehydroascorbic acid (DHA) as a therapeutic means to increase intracellular AA and modulate HIF-1alpha function is yet to be evaluated. Here we compared the ability of AA and DHA to increase intracellular vitamin C content and decrease the malignant potential of human melanoma by reducing the activity of HIF-1alpha. METHODS: HIF-1alpha protein accumulation was evaluated by western blot and transcriptional activity was evaluated by reporter gene assay using a HIF-1 HRE-luciferase plasmid. Protein expressions and subcellular localizations of vitamin C transporters were evaluated by western blot and confocal imaging. Intracellular vitamin C content following AA, ascorbate 2-phosphate (A2P), or DHA supplementation was determined using a vitamin C assay. Malignant potential was accessed using a 3D spheroid Matrigel invasion assay. Data was analyzed by One or Two-way ANOVA with Tukey's multiple comparisons test as appropriate with p<0.05 considered significant. RESULTS: Melanoma cells expressed both sodium dependent vitamin C (SVCT) and glucose (GLUT) transporters for AA and DHA transport respectively, however advanced melanomas responded favorably to AA, but not DHA. Physiological glucose conditions significantly impaired intracellular vitamin C accumulation following DHA treatment. Consequently, A2P and AA, but not DHA treated cells demonstrated lower HIF-1alpha protein expression and activity, and reduced malignant potential. The ability of AA to regulate HIF-1alpha was dependent on SVCT2 function and SVCT2 was not significantly inhibited at pH representative of the tumor microenvironment. CONCLUSIONS: The use of ascorbic acid as an adjuvant cancer therapy remains under investigated. While AA and A2P were capable of modulating HIF-1alpha protein accumulation/activity, DHA supplementation resulted in minimal intracellular vitamin C activity with decreased ability to inhibit HIF 1alpha activity and malignant potential in advanced melanoma. Restoring AA dependent regulation of HIF-1alpha in malignant cells may prove beneficial in reducing chemotherapy resistance and improving treatment outcomes. PMID- 28012931 TI - Disseminated cutaneous leishmaniasis: ulcerovegetative and ulcero-crusted lesions. PMID- 28012932 TI - How to detect new viral outbreaks or epidemics? We need to survey the circulation of viruses in humans and other animals using fast, sensible, cheap, and broad spectrum methodologies. PMID- 28012933 TI - Newborn with rash due to Klebsiella infection. PMID- 28012934 TI - Costs associated with treatment of severe combined immunodeficiency-rationale for newborn screening in Sweden. PMID- 28012936 TI - Results of daily oral dosing with up to 60,000 international units (iu) of vitamin D3 for 2 to 6 years in 3 adult males. AB - In the 1930's and 1940's, vitamin D was reported to be an effective treatment for a number of diseases, including asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. High doses were used, 60,000 to 300,000 IU a day for asthma, and 200,000 to 600,000 IU a day for rheumatoid arthritis. Toxicity from hypercalcemia occurred after prolonged oral dosing with these supraphysiologic doses. Assays for measuring vitamin D in the blood were not available, and blood levels of vitamin D associated with hypercalcemia were unknown. A 2011 report on vitamin D toxicity showed that hypercalcemia resolved when 25-hydroxyvitamin D (25OHD) blood levels dropped below 400ng/ml in 2 patients with blood levels ranging from 645ng/ml to 1220ng/ml after accidental ingestion of massive doses of vitamin D. We now know that vitamin D is made in the skin in amounts ranging up to 25,000 IU a day with exposure to UVB radiation. There is little data on the safety and blood levels of 25OHD and calcium after prolonged daily intake of amounts of vitamin D in this range. In this report, one subject took increasing daily doses of vitamin D3 for 6 years starting in April 2009: 6500 IU for 6 months; increasing to 10,000 IU for 13 months; 20,000 IU for 24 months; 40,000 IU for 12 months; 50,000 IU for 10 months, and 60,000 IU since October 2014. 25OHD blood levels were 28, 81, 204, 216, 225, 166, and 218ng/ml. Subject 2 began 10,000 IU in Nov 2011, increased to 20,000 IU in Feb 2014, 25,000 IU in June 2014, and 30,000 IU in Oct 2014, and then decreased to 20,000 IU in June 2015. 25OHD blood levels were 96.6, 161.1 and 106.9ng/ml. He reported marked clinical improvement in his asthma. Subject 3 started on daily 10,000 IU in Sept 2013, increasing to 20,000 IU on Nov 2013. 25OHD blood levels were 31.4, 102, 164, 148, and 143ng/ml. No one developed hypercalcemia or any adverse events. The major finding of this case series is prolonged daily dosing of vitamin D3 with doses of 10,000 to 60,000 IU was safely tolerated. PMID- 28012937 TI - Affinity chromatography: A versatile technique for antibody purification. AB - Antibodies continue to be extremely utilized entities in myriad applications including basic research, imaging, targeted delivery, chromatography, diagnostics, and therapeutics. At production stage, antibodies are generally present in complex matrices and most of their intended applications necessitate purification. Antibody purification has always been a major bottleneck in downstream processing of antibodies, due to the need of high quality products and associated high costs. Over the years, extensive research has focused on finding better purification methodologies to overcome this holdup. Among a plethora of different techniques, affinity chromatography is one of the most selective, rapid and easy method for antibody purification. This review aims to provide a detailed overview on affinity chromatography and the components involved in purification. An array of support matrices along with various classes of affinity ligands detailing their underlying working principles, together with the advantages and limitations of each system in purifying different types of antibodies, accompanying recent developments and important practical methodological considerations to optimize purification procedure are discussed. PMID- 28012938 TI - Editorial Comment. PMID- 28012935 TI - Idiopathic systemic capillary leak syndrome (Clarkson disease). AB - In 1960, Dr Bayard Clarkson described a woman experiencing sporadic recurrent episodes of shock and anasarca. Plasma from an acute attack induced a shock-like syndrome when injected into rats. The enigmatic systemic capillary leak syndrome (SCLS) named for Dr Clarkson is characterized by transient and severe but reversible hemoconcentration and hypoalbuminemia caused by leakage of fluids and macromolecules into tissues. Although less than 500 cases of SCLS have been reported in the literature since 1960, the condition is probably underdiagnosed because of a lack of awareness and a high mortality without treatment. Allergists should be vigilant of this diagnosis because its presentation can resemble more common plasma leakage syndromes, including angioedema or systemic anaphylaxis. Although the precise molecular cause of SCLS remains unknown, substantial advances over the last 5 years have increased our understanding of SCLS pathogenesis. PMID- 28012939 TI - Surface modified zeolite-based granulates for the sustained release of diclofenac sodium. AB - In this study, a granulate for the oral controlled delivery of diclofenac sodium (DS), an anionic sparingly soluble nonsteroidal anti-inflammatory drug, has been realized by wet granulation, using a surface modified natural zeolite (SMNZ) as an excipient. The surface modification of the zeolite has been achieved by means of a cationic surfactant, so as to allow the loading of DS through ionic interaction and bestow a control over the drug release mechanism. The granules possessed a satisfactory dosage uniformity, a flowability suitable for an oral dosage form manufacturing, along with a sustained drug release up to 9h, driven by both ion exchange and transport kinetics. Furthermore, the obtained granulate did not elicit a significant cytotoxicity and could also induce a prolonged anti inflammatory effect on RAW264.7 cells. Taking also into account that natural zeolites are generally abundant and economic, SMNZ can be considered as an attracting alternative excipient for the production of granules with sustained release features. PMID- 28012940 TI - Development of nanostructured lipid carriers containing salicyclic acid for dermal use based on the Quality by Design method. AB - The aim of our present work was to evaluate the applicability of the Quality by Design (QbD) methodology in the development and optimalization of nanostructured lipid carriers containing salicyclic acid (NLC SA). Within the Quality by Design methology, special emphasis is layed on the adaptation of the initial risk assessment step in order to properly identify the critical material attributes and critical process parameters in formulation development. NLC SA products were formulated by the ultrasonication method using Compritol 888 ATO as solid lipid, Miglyol 812 as liquid lipid and Cremophor RH 60(r) as surfactant. LeanQbD Software and StatSoft. Inc. Statistica for Windows 11 were employed to indentify the risks. Three highly critical quality attributes (CQAs) for NLC SA were identified, namely particle size, particle size distribution and aggregation. Five attributes of medium influence were identified, including dissolution rate, dissolution efficiency, pH, lipid solubility of the active pharmaceutical ingredient (API) and entrapment efficiency. Three critical material attributes (CMA) and critical process parameters (CPP) were identified: surfactant concentration, solid lipid/liquid lipid ratio and ultrasonication time. The CMAs and CPPs are considered as independent variables and the CQAs are defined as dependent variables. The 23 factorial design was used to evaluate the role of the independent and dependent variables. Based on our experiments, an optimal formulation can be obtained when the surfactant concentration is set to 5%, the solid lipid/liquid lipid ratio is 7:3 and ultrasonication time is 20min. The optimal NLC SA showed narrow size distribution (0.857+/-0.014) with a mean particle size of 114+/-2.64nm. The NLC SA product showed a significantly higher in vitro drug release compared to the micro-particle reference preparation containing salicylic acid (MP SA). PMID- 28012941 TI - Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise. AB - Age-related arterial inflammation is associated with dysfunction of the arteries and increased risk for cardiovascular disease. To determine if aging increases arterial immune cell infiltration as well as the populations of immune cells principally involved, we tested the hypothesis that large elastic and resistance arteries in old mice would exhibit increased immune cell infiltration compared to young controls. Additionally, we hypothesized that vasoprotective lifestyle interventions such as lifelong caloric restriction or 8weeks of voluntary wheel running would attenuate age-related arterial immune cell infiltration. The aorta and mesenteric vasculature with surrounding perivascular adipose was excised from young normal chow (YNC, 4-6months, n=10), old normal chow (ONC, 28-29months, n=11), old caloric restricted (OCR, 28-29months, n=9), and old voluntary running (OVR, 28-29months, n=5) mice and digested to a single cell suspension. The cells were then labeled with antibodies against CD45 (total leukocytes), CD3 (pan T cells), CD4 (T helper cells), CD8 (cytotoxic T cells), CD19 (B cells), CD11b, and F4/80 (macrophages) and analyzed by flow cytometry. Total leukocytes, T cells (both CD4+ and CD8+ subsets), B cells, and macrophages in both aorta and mesentery were all 5- to 6-fold greater in ONC compared to YNC. Age-related increases in T cell (both CD4+ and CD8+), B cell, and macrophage infiltration in aorta were abolished in OCR mice. OVR mice exhibited 50% lower aortic T cell and normalized macrophage infiltration. B cell infiltration was not affected by VR. Age-related mesenteric CD8+ T cell and macrophage infiltration was normalized in OCR and OVR mice compared to young mice, whereas B cell infiltration was normalized by CR but not VR. Splenic CD4+ T cells from ONC mice exhibited a 3 fold increase in gene expression for the T helper (Th) 1 transcription factor, Tbet, and a 4-fold increase in FoxP3, a T regulatory cell transcription factor, compared to YNC. Splenic B cells and mesenteric macrophages from old mice exhibited decreased proinflammatory cytokine gene expression regardless of treatment group. These results demonstrate that aging is associated with infiltration of immune cells around both the large-elastic and resistance arteries and that the vasoprotective lifestyle interventions, CR and VR, can ameliorate age-related arterial immune cell infiltration. PMID- 28012942 TI - A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study. AB - BACKGROUND: A physician is frequently unable to distinguish bacterial from viral infections. ImmunoXpert is a novel assay combining three proteins: tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP). We aimed to externally validate the diagnostic accuracy of this assay in differentiating between bacterial and viral infections and to compare this test with commonly used biomarkers. METHODS: In this prospective, double-blind, international, multicentre study, we recruited children aged 2-60 months with lower respiratory tract infection or clinical presentation of fever without source at four hospitals in the Netherlands and two hospitals in Israel. A panel of three experienced paediatricians adjudicated a reference standard diagnosis for all patients (ie, bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. The panel was masked to the assay results. We identified majority diagnosis when two of three panel members agreed on a diagnosis and unanimous diagnosis when all three panel members agreed on the diagnosis. We calculated the diagnostic performance (ie, sensitivity, specificity, positive predictive value, and negative predictive value) of the index test in differentiating between bacterial (index test positive) and viral (index test negative) infection by comparing the test classification with the reference standard outcome. FINDINGS: Between Oct 16, 2013 and March 1, 2015, we recruited 777 children, of whom 577 (mean age 21 months, 56% male) were assessed. The majority of the panel diagnosed 71 cases as bacterial infections and 435 as viral infections. In another 71 patients there was an inconclusive panel diagnosis. The assay distinguished bacterial from viral infections with a sensitivity of 86.7% (95% CI 75.8-93.1), a specificity of 91.1% (87.9-93.6), a positive predictive value of 60.5% (49.9-70.1), and a negative predictive value of 97.8% (95.6-98.9). In the more clear cases with unanimous panel diagnosis (n=354), sensitivity was 87.8% (74.5-94.7), specificity 93.0% (89.6-95.3), positive predictive value 62.1% (49.2-73.4), and negative predictive value 98.3% (96.1-99.3). INTERPRETATION: This external validation study shows the diagnostic value of a three-host protein-based assay to differentiate between bacterial and viral infections in children with lower respiratory tract infection or fever without source. This diagnostic based on CRP, TRAIL, and IP-10 has the potential to reduce antibiotic misuse in young children. FUNDING: MeMed Diagnostics. PMID- 28012943 TI - Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study. AB - BACKGROUND: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. METHODS: We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. FINDINGS: In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non adherence to mass drug administration was low. INTERPRETATION: Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme. FUNDING: Bill & Melinda Gates Foundation. PMID- 28012944 TI - Global elimination of lymphatic filariasis. PMID- 28012945 TI - Effect of a host-protein based assay on the differentiation of bacterial and viral infections in pre-school children. PMID- 28012946 TI - Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice. AB - Many clinical and molecular features of the fragile X syndrome, a common form of intellectual disability and autism, can be modeled by deletion of the Fmr1 protein (Fmrp) in mice. Previous studies showed a decreased expression of several components of the GABAergic system in Fmr1 knockout mice. Here, we used this mouse model to investigate the functional consequences of Fmrp deletion on hippocampal GABAergic inhibition in the CA1-region of the hippocampus. Whole-cell patch-clamp recordings demonstrated a significantly reduced amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and a decrease in the amplitude and frequency of spontaneous IPSCs. In addition, miniature IPSCs were reduced in amplitude and frequency and decayed significantly slower than mIPSCs in controls. Quantitative real-time PCR revealed a significantly lower expression of alpha2, beta1 and delta GABAA receptor subunits in the hippocampus of the juvenile mice (P22) compared to wild-type littermates. Correspondingly, we found also at the protein level reduced amounts of alpha2, beta1 and delta subunits in Fmr1 knockout mice. Overall, these results demonstrate that the reduction in several components of the GABAergic system is already present at young age and that this reduction results in measurable abnormalities on GABAA receptor-mediated phasic inhibition. These abnormalities might contribute to the behavioral and cognitive deficits of this fragile X mouse model. PMID- 28012947 TI - The GSK-3-inhibitor VP2.51 produces antidepressant effects associated with adult hippocampal neurogenesis. AB - Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that has been implicated in the mechanism of action of mood stabilizers. According to the neurogenic hypothesis of depression, newborn neurons in the adult dentate gyrus are required for the antidepressant effects of certain agents. We demonstrate that administration of the GSK-3 inhibitor VP2.51 (2.5 mg/kg ip, for 3.5 weeks) increases cell proliferation (pH3+ cells), as well as the short- and long-term survival of newborn neurons (assessed by the 24 h survival of BrdU+ and DCX+ neurons), while significantly increasing the commitment of cells to the granule neuron lineage (Prox1 immunoreactivity). In parallel, VP2.51 induces a net antidepressant effect, as judged by the decrease in the immobility time in the forced swim test of naive mice (non-stressed mice), as well as a therapeutic effect on previously stressed mice (Porsolt-induced stress). Interestingly, the morphological changes were found prominently in the ventral region of the hippocampus. We found that these effects are neurogenesis dependent by combining the antimitotic temozolomide (50 mg/kg ip) with the drug. Importantly VP2.51 did not provoke changes in weight or in a battery of behavioral tests (learning/memory and activity tests). As the effects of VP2.51 were concomitant with the increase in beta-catenin expression and a shift towards the inactive form of GSK-3, we suggest that VP2.51 has therapeutic benefits following stress, and it may be a preventive treatment in situations where a potential depressive state and/or loss of memory is associated with diminished neurogenesis, through selective GSK3-beta inhibition. PMID- 28012949 TI - Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke. AB - BACKGROUND: and purpose: Currently there is no effective treatment for neonatal arterial ischemic stroke (AIS). Cannabidiol (CBD) is neuroprotective in models of newborn hypoxic-ischemic brain damage and adult stroke. The purpose of this work was to study the protective effect of CBD in a neonatal rat model of AIS. METHODS: Middle Cerebral Artery Occlusion (MCAO) was achieved in neonatal Wistar rats by introducing a nylon filament to the left MCA for 3 h; 15 min after removing the occluder vehicle (MCAO-V) or CBD single dose 5 mg/kg (MCAO-C) were administered i. p. Similarly manipulated but non-occluded rats served as controls (SHM). A set of behavioral tests was then conducted one week (P15) or one month (P38) after MCAO. Brain damage was then assessed by magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (H+-MRS) and histologic (TUNEL for cell death, immunohistochemistry for neuron, astrocyte and microglia identification) studies. RESULTS: CBD administration improved neurobehavioral function regarding strength, hemiparesis, coordination and sensorimotor performance as assessed at P15 and P38. MRI indicated that CBD did not reduce the volume of infarct but reduced the volume of perilesional gliosis. H+-MRS indicated that CBD reduced metabolic derangement and excitotoxicty, and protected astrocyte function. Histologic studies indicated that CBD reduced neuronal loss and apoptosis, and modulated astrogliosis and microglial proliferation and activation. CONCLUSIONS: CBD administration after MCAO led to long-term functional recovery, reducing neuronal loss and astrogliosis, and modulating apoptosis, metabolic derangement, excitotoxicity and neuro-inflammation. PMID- 28012948 TI - Orbitofrontal participation in sign- and goal-tracking conditioned responses: Effects of nicotine. AB - Pavlovian conditioned stimuli can acquire incentive motivational properties, and this phenomenon can be measured in animals using Pavlovian conditioned approach behavior. Drugs of abuse can influence the expression of this behavior, and nicotine in particular exhibits incentive amplifying effects. Both conditioned approach behavior and drug abuse rely on overlapping corticolimbic circuitry. We hypothesize that the orbitofrontal cortex (OFC) regulates conditioned approach, and that one site of nicotine action is in the OFC where it reduces cortical output. To test this, we repeatedly exposed rats to 0.4 mg/kg nicotine (s.c.) during training and then pharmacologically inactivated the lateral OFC or performed in vivo electrophysiological recordings of lateral OFC neurons in the presence or absence of nicotine. In Experiment 1, animals were trained in a Pavlovian conditioning paradigm and behavior was evaluated after inactivation of the OFC by microinfusion of the GABA agonists baclofen and muscimol. In Experiment 2, we monitored phasic firing of OFC neurons during Pavlovian conditioning sessions. Nicotine reliably enhanced conditioned responding to the conditioned cue, and inactivation of the OFC reduced conditioned responding, especially the sign-tracking response. OFC neurons exhibited phasic excitations to cue presentation and during goal tracking, and nicotine acutely blunted this phasic neuronal firing. When nicotine was withheld, both conditioned responding and phasic firing in the OFC returned to the level of controls. These results suggest that the OFC is recruited for the expression of conditioned responses, and that nicotine acutely influences this behavior by reducing phasic firing in the OFC. PMID- 28012950 TI - A "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype. AB - OBJECTIVE: Mutations in the GBA gene are associated with Parkinson's disease (PD). A definite description of the clinical characteristics of PD patients who are compound heterozygotes or homozygotes for mutations in the GBA gene (GD-PD) requires further elucidation. METHODS: We assessed motor, cognitive, olfactory and autonomic functions as well as demographic data and medical history in a cohort of Ashkenazi Jewish PD patients who were screened for seven common mutations in the GBA gene. We then compared three groups of patients (matched for age and disease duration) who were distinguished by their GBA mutation status, idiopathic PD (iPD), GBA heterozygote PD (GBA-PD) and GD-PD. RESULTS: Out of a total of 1050 AJ PD patients screened, 12 were found to be either homozygotes or compound heterozygotes for mutations in the GBA gene. These patients had an earlier age of onset, more severe motor impairment, poorer cognition and lower olfactory scores. They also had a higher prevalence of REM sleep behavior disorder and higher frequencies of hallucinations compared to both GBA-PD and iPD. CONCLUSIONS: The severity of PD phenotype is related to the burden of GBA mutations with GD-PD patients manifesting a more severe phenotype. PMID- 28012951 TI - Apomorphine and levodopa in Parkinson's disease: Two revolutionary drugs from the 1950's. AB - This article reviews the history of apomorphine and levodopa, which were both discovered in the 1950's and have revolutionized treatment paradigms of Parkinson's disease. Although the discovery of levodopa is a prime example of successful translation of basic neuroscience into clinical routine, the history of apomorphine was based on less solid evidence. Despite this, both drugs are, more than 6 decades after the first clinical experiments, still the two most efficacious medications to treat patients with Parkinson's disease. New and promising delivery strategies for both levodopa and apomorphine are currently under investigation to further improve clinical responses. PMID- 28012952 TI - Frontotemporal dementia as the presenting phenotype of p.A53T mutation carriers in the alpha-synuclein gene. AB - INTRODUCTION: The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinson's disease (PD). METHODS: Here, we describe two apparently unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Abeta42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia. RESULTS: Both patients exhibited an early onset frontal-dysexecutive dysfunction with apathy and emotional blunting resembling frontotemporal dementia (FTD). Motor symptoms typical of Parkinson's disease appeared only later in the disease course and were less prominent than cognitive ones, which included language impairment. Autonomic dysfunction and myoclonus also emerged in a more advanced disease stage. In both patients, Brain Magnetic Resonance Imaging showed fronto-temporo-parietal atrophy, and CSF analysis showed elevated tau protein levels. In contrast, tau protein levels were normal in a cohort of 7 other p.A53T mutation carriers (5 symptomatic/2 asymptomatic). A screen of Greek patients presenting with frontotemporal dementia failed to identify any additional subjects with the p.A53T SNCA mutation. CONCLUSION: Although cognitive decline has been recognized as a feature of the full-blown clinical picture of p.A53T related parkinsonism, a predominant frontotemporal dementia-like phenotype at presentation has not been previously described. This may represent a subtype of this disorder, with distinctive clinical, imaging and CSF biochemical characteristics, in which additional genetic or epigenetic factors may play a role. PMID- 28012953 TI - New insights in the neurological phenotype of aceruloplasminemia in Caucasian patients. AB - INTRODUCTION: The diagnosis aceruloplasminemia is usually made in patients with advanced neurological manifestations of the disease. In these patients prognosis is poor, disabilities are severe and patients often die young. The aim of our study was to facilitate recognition of aceruloplasminemia at a disease stage at which treatment can positively influence outcome. Currently, the neurological phenotype of aceruloplasminemia has been mainly described in Japanese patients. This 'classical' phenotype consists of cerebellar ataxia, hyperkinetic movement disorders and cognitive decline. In this study we describe the spectrum of neurological disease in Caucasian patients. METHODS: Data on neurological presentation and follow-up were gathered from both our patients, homozygous for the G631R mutation in the CP gene, and other published Caucasian cases. Neurological features of aceruloplasminemia in Caucasian patients were compared to those summarized in Japanese patients. RESULTS: 21 Caucasian patients, both ours and the described cases, displayed a wide range of movement disorders with predominant chorea, parkinsonism and ataxia, and also tremor and dystonia. In addition to cognitive decline, nearly half of the Caucasian patients presented with psychiatric changes, including depression, anxiety and behavioral changes. In one-third of the neurologically symptomatic Caucasian patients, cognitive- or psychiatric changes were the first neurological manifestations of aceruloplasminemia. CONCLUSIONS: Aceruloplasminemia in Caucasian patients can present with a wider range and a different order of neurological symptoms than previously described in Japanese patients. Psychiatric changes and parkinsonism can be added to the spectrum of neurological disease. Cognitive- or psychiatric changes may be the first neurological manifestations of aceruloplasminemia. PMID- 28012954 TI - A novel Haemosporida clade at the rank of genus in North American cranes (Aves: Gruiformes). AB - The unicellular blood parasites in the order Haemosporida are highly diverse, infect many vertebrates, are responsible for a large disease burden among humans and animals, and have reemerged as an important model system to understand the evolutionary and ecological dynamics of host-parasite interactions. The phylogenetics and systematics of Haemosporida are limited by poor sampling of different vertebrate host taxa. We surveyed the Haemosporida of wild whooping cranes (Grus americana) and sandhill cranes (Grus canadensis) (Aves: Gruiformes) using a combination of morphological and molecular approaches. We identified Haemoproteus antigonis in blood smears based on published morphological descriptions. Phylogenetic analysis based on partial cytochrome b (cytb) and cytochrome oxidase (coI) sequences placed H. antigonis parasites in a novel clade, distinct from all avian Haemosporida genera for which cytb and/or coI sequences are available. Molecular clock and divergence estimates suggest this crane clade may represent a new genus. This is the first molecular description of H. antigonis and the first report of H. antigonis in wild whooping cranes, an endangered bird in North America. Further sampling of Haemosporida, especially from hosts of the Gruiformes and other poorly sampled orders, will help to resolve the relationship of the H. antigonis clade to other avian Haemosporida genera. Our study highlights the potential of sampling neglected host species to discover novel lineages of diverse parasite groups. PMID- 28012955 TI - Exploring the shell-based taxonomy of the Sri Lankan land snail Corilla H. and A. Adams, 1855 (Pulmonata: Corillidae) using mitochondrial DNA. AB - The land-snail genus Corilla is endemic to Sri Lanka and India's Western Ghats. The ten extant Sri Lankan species belong to two distinct shell forms that are associated respectively with lowland and montane rainforest. We here present the first molecular phylogenetic analysis for Corilla. Our dataset includes nine nominal Sri Lankan species and is based on three mitochondrial genes (CO1, ND1 and 16S). Although the deeper nodes in the trees are not fully resolved, the results do suggest speciation in Corilla has involved repeated, ecologically driven convergence in shell form. The mtDNA data agree with the current shell based taxonomy for C. adamsi, C. beddomeae, C. carabinata, C. humberti and C. colletti, consistently supporting the first four as monophyletic, and supporting the last also as monophyletic in nearly all analyses. Corilla adamsi, C. beddomeae and C. colletti may each contain at least one additional, previously undescribed species. The relationship between northern and eastern C. odontophora couldn't be reliably resolved, but our results suggest that they are distinct species and that there is further species-level or intraspecific (geographical) differentiation within eastern C. odontophora. The current, morphologically defined species limits of the three remaining nominal species, C. gudei, C. erronea and C. fryae, are inconsistent with the mtDNA sequence data. Northern and southern C. gudei appear to be distinct species: the sister taxon of southern C. gudei is C. humberti, and most analyses showed that the sister taxon of northern C. gudei is the lowland C. carabinata. Corilla erronea and C. fryae constitute a well supported clade in which both nominal species are paraphyletic. While most intra-clade CO1 p-distances are moderate to relatively large, the phylogenetic structuring within the clade does not seem to correspond to any obvious morphological, elevational or geographical patterns. These results are difficult to interpret, and further detailed study is needed before the taxonomic status of C. erronea and C. fryae can be resolved. PMID- 28012956 TI - Systematics and biogeography of the Automolus infuscatus complex (Aves; Furnariidae): Cryptic diversity reveals western Amazonia as the origin of a transcontinental radiation. AB - A revision of the avian Neotropical genus Automolus and the Furnariidae family points to the paraphyly of A. infuscatus and reveals a species complex comprising A. infuscatus, A. ochrolaemus, A. paraensis, A. leucophthalmus, A. lammi and A. subulatus, the latter historically classified in the genus Hyloctistes. Detailed knowledge of the taxonomy, geographic distribution, phylogenetic relationship and divergence times of a taxon allows exploration of its evolutionary history and the testing of different scenarios of diversification. In this context, we studied the A. infuscatus complex using molecular data in order to unveil its cryptic diversity and reveal its evolutionary history. For that we sequenced two mitochondrial (ND2 and cytb) and three nuclear markers (G3PDH, ACO, Fib7) for 302 individuals belonging to all species in the complex and most described subspecies. Our analysis supports the paraphyly of A. infuscatus, indicating the existence of at least two distinct clades not closely related. The remaining species were all recovered as monophyletic. Notwithstanding, a well-structured intraspecific diversity was found with 19 lineages suggesting substantial cryptic diversity within the described species. A. subulatus was recovered within the complex, corroborating its position inside the genus. In spite of the high congruence between distributions of different lineages, with several sister lineages currently separated by the same barriers, the temporal incongruence between divergences over the same barriers reveals a complex evolutionary history. While older events might be related to the emergence of barriers such as the Andes and major Amazonian rivers, younger events suggest dispersal after the consolidation of those barriers. Our analysis suggests that the complex had its origin around 6million years (Ma) and inhabited Western Amazonia in Late Miocene Early Pliocene. Considering the riparian habit of species in its sister clade, the rise and early diversifications of the complex may be related to the establishment of terra firme forests as it changed from a floodplain to a fluvial system. The late Amazonian colonization by A. subulatus and A. ochrolaemus lineages may have been hampered by the previous existence of well established A. infuscatus lineages in the region. PMID- 28012957 TI - Phylogenetic relationships of weaverbirds (Aves: Ploceidae): A first robust phylogeny based on mitochondrial and nuclear markers. AB - Weaverbirds are a diverse passerine group with species diversity concentrated in sub-Saharan Africa. No comprehensive phylogenetic hypothesis regarding relationships of weaverbirds has been produced, however, so we developed a first extensive phylogeny for the family Ploceidae, based on a multilocus dataset of three mitochondrial loci and four nuclear markers. Analysis of these data offered strong support for monophyly of the family and revealed seven distinct clades within Ploceidae. A major feature of our results is broad polyphyly of Ploceus: Asian Ploceus species should retain the generic name, whereas African Ploceus, together with Anaplectes, should be placed in Malimbus. In light of deep divergence, we assign the Malagasy Ploceus species to their own genus, Nelicurvius. Divergence time analysis based on DNA substitution rates suggests a mid-Miocene origin of the family. This study lays a foundation for an array of future studies of character evolution, biogeography, and evolutionary history of the family. PMID- 28012958 TI - Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepatocellular carcinoma cells. AB - The aim of the study is to demonstrate the effect of Romidepsin in hepatocellular carcinoma (HCC) by inducing G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis through JNK/c-Jun/caspase3 pathway in vitro and in vivo. Human HCC cell lines were cultured with Romidepsin and DMSO (negative control) and 5 fluorouracil (positive control). Then the cells' viability and apoptosis were determined by cell proliferation assay and flow cytometry. Protein concentrations and expression changes were measured by Western blot. Subsequently, Huh7 cells were subcutaneously inoculated into the nude mice, which were employed to further probe the tumor-suppressive effect of Romidepsin in vivo. Romidepsin treatment led to a time- and dose-dependent induction of cell cycle arrest in the G2/M phase and apoptosis. G2/M phase arrest inhibited the proliferation of HCC cells by alterations in p21/cdc25C/cdc2/cyclinB proteins. Increased concentrations of Erk and JNK phosphorylations were observed in a dose-dependent manner in the Romidepsin group, but p38 phosphorylation was not affected. G2/M phase arrest and the apoptosis of HCC cells induced by Romidepsin were mediated by the activation of Erk/MAPK pathways and JNK/MAPK pathways. The tumor size was significantly larger in the negative control group compared to Romidepsin group and no significant loss in body weight was observed in the Romidepsin group. Our findings offer proof-of-concept for use of Romidepsin as a novel class of chemotherapy in the treatment of HCC. PMID- 28012959 TI - Non-coding RNAs as antibiotic targets. AB - Antibiotics inhibit a wide range of essential processes in the bacterial cell, including replication, transcription, translation and cell wall synthesis. In many instances, these antibiotics exert their effects through association with non-coding RNAs. This review highlights many classical antibiotic targets (e.g. rRNAs and the ribosome), explores a number of emerging targets (e.g. tRNAs, RNase P, riboswitches and small RNAs), and discusses the future directions and challenges associated with non-coding RNAs as antibiotic targets. PMID- 28012960 TI - Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity. AB - Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes. Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Human Umbilical Vein Endothelial Cells (HUVECs) were grown in either physiological or intermittent high concentrations of glucose for 5days in the presence or absence of Cobalt (III) Protoporphyrin IX chloride (CoPP, HO-1 inducer) or 4-Phenyl Butyric Acid (PBA, ER stress inhibitor). Using an integrated cellular and molecular approach, we then assessed ER stress and inflammatory responses, in addition to apoptosis and angiogenic capacity in these cells. Our results show that HO-1 induction prevented high glucose-mediated increase of mRNA and protein expression of key ER stress markers. Cells incubated with high glucose exhibited high levels of oxidative stress, activation of major inflammatory and apoptotic responses [nuclear factor (NF)-kappaB and c-Jun N-terminal kinase (JNK)] and increased rate of apoptosis; however, cells pre-treated with CoPP or PBA were fully protected. In addition, high glucose enhanced caspases 3 and 7 cleavage and activity and augmented cleaved poly ADP ribose polymerase (PARP) expression whereas HO-1 induction prevented these effects. Finally, HO-1 induction and ER stress inhibition prevented high glucose-induced reduction in NO release and impaired the angiogenic capacity of HUVECs, and enhanced vascular endothelial growth factor (VEGF)-A expression. Altogether, we show here the critical role of ER stress-mediated cell death in diabetes-induced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress. PMID- 28012961 TI - High affinity binding of the peptide agonist TIP-39 to the parathyroid hormone 2 (PTH2) receptor requires the hydroxyl group of Tyr-318 on transmembrane helix 5. AB - TIP39 ("tuberoinfundibular peptide of 39 residues") acts via the parathyroid hormone 2 receptor, PTH2, a Family B G protein-coupled receptor (GPCR). Despite the importance of GPCRs in human physiology and pharmacotherapy, little is known about the molecular details of the TIP39-PTH2 interaction. To address this, we utilised the different pharmacological profiles of TIP39 and PTH(1-34) at PTH2 and its related receptor PTH1: TIP39 being an agonist at the former but an antagonist at the latter, while PTH(1-34) activates both. A total of 23 site directed mutations of PTH2, in which residues were substituted to the equivalent in PTH1, were made and pharmacologically screened for agonist activity. Follow-up mutations were analysed by radioligand binding and cAMP assays. A model of the TIP39-PTH2 complex was built and analysed using molecular dynamics. Only Tyr318 Ile displayed reduced TIP39 potency, despite having increased PTH(1-34) potency, and further mutagenesis and analysis at this site demonstrated that this was due to reduced TIP39 affinity at Tyr318-Ile (pIC50=6.01+/-0.03) compared with wild type (pIC50=7.81+/-0.03). The hydroxyl group of the Tyr-318's side chain was shown to be important for TIP39 binding, with the Tyr318-Phe mutant displaying 13 fold lower affinity and 35-fold lower potency compared with wild type. TIP39 truncated by up to 5 residues at the N-terminus was still sensitive to the mutations at Tyr-318, suggesting that it interacts with a region within TIP39(6 39). Molecular modelling and molecular dynamics simulations suggest that the selectivity is based on an interaction between the Tyr-318 hydroxyl group with the carboxylate side chain of Asp-7 of the peptide. PMID- 28012962 TI - Prolonged infusion of sedatives and analgesics in adult intensive care patients: A systematic review of pharmacokinetic data reporting and quality of evidence. AB - Although pharmacokinetic (PK) data for prolonged sedative and analgesic agents in intensive care unit (ICU) has been described, the number of publications in this important area appear relatively few, and PK data presented is not comprehensive. Known pathophysiological changes in critically ill patients result in altered drug PK when compared with non-critically ill patients. ClinPK Statement was recently developed to promote consistent reporting in PK studies, however, its applicability to ICU specific PK studies is unclear. In this systematic review, we assessed the overall ClinPK Statement compliance rate, determined the factors affecting compliance rate, graded the level of PK evidence and assessed the applicability of the ClinPK Statement to future ICU PK studies. Of the 33 included studies (n=2016), 22 (67%) were low evidence quality descriptive studies (Level 4). Included studies had a median compliance rate of 80% (IQR 66% to 86%) against the ClinPK Statement. Overall pooled compliance rate (78%, 95% CI 73% to 83%) was stable across time (P=0.38), with higher compliance rates found in studies fitting three compartments models (88%, P<0.01), two compartments models (83%, P<0.01) and one compartment models (77%, P=0.17) than studies fitting noncompartmental or unspecified models (69%) (P<0.01). Data unique to the interpretation of PK data in critically ill patients, such as illness severity (48%), organ dysfunction (36%) and renal replacement therapy use (32%), were infrequently reported. Discrepancy between the general compliance rate with ClinPK Statement and the under-reporting of ICU specific parameters suggests that the applicability of the ClinPK Statement to ICU PK studies may be limited in its current form. PMID- 28012963 TI - Gender related differences in treatment and response to statins in primary and secondary cardiovascular prevention: The never-ending debate. AB - Statins are a main curbstone in the prevention of cardiovascular disease (CVD), pandemic in 21st century. CVD displays evident sex and gender differences, not only in clinical manifestation and outcomes but also in pharmacological treatment. Whether statin therapy should be differentially prescribed according to sex is a matter of debate. Aside a different pharmacological action, statins are not proven to be less effective in one gender comparing to the other, nor to be less safe. Nevertheless, up to date evidence shows that statins have not been adequately tested in women, especially in primary prevention trials. Since data lacking, making a treatment decision on women is potentially harmful, although female individuals represent the majority of the population and they have a greater lifetime CVD risk. Therefore, adequately powered randomized control trials with longer follow-up are warranted to establish if a benefit on CV events and mortality prevention exists in both sexes. The aim of the present review is to summarize the sex and gender differences in statin use: it raises concerns and updates perspectives towards an evidence-based and sex-tailored prevention of CVD management. PMID- 28012964 TI - Resveratrol regulates gene transcription via activation of stimulus-responsive transcription factors. AB - Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin of grapes and other fruits and plants, is a common constituent of our diet and of dietary supplements. Many health-promoting benefits have been connected with resveratrol in the treatment of cardiovascular diseases, cancer, diabetes, inflammation, neurodegeneration, and diseases connected with aging. To explain the pleiotropic effects of resveratrol, the molecular targets of this compound have to be identified on the cellular level. Resveratrol induces intracellular signal transduction pathways which ultimately lead to changes in the gene expression pattern of the cells. Here, we review the effect of resveratrol on the activation of the stimulus-responsive transcription factors CREB, AP-1, Egr-1, Elk-1, and Nrf2. Following activation, these transcription factors induce transcription of delayed response genes. The gene products of these delayed response genes are ultimately responsible for the changes in the biochemistry and physiology of resveratrol-treated cells. The activation of stimulus-responsive transcription factors may explain many of the intracellular activities of resveratrol. However, results obtained in vitro may not easily be transferred to in vivo systems. PMID- 28012966 TI - Effectiveness of a smoking restriction policy on smoking behaviour in the military. PMID- 28012965 TI - Smoking environment cues reduce ability to resist smoking as measured by a delay to smoking task. AB - INTRODUCTION: Environments associated with smoking may promote lapse and relapse in smokers attempting to quit. Here we examined the effects of exposure to visual smoking environment cues on smoking urge and the ability to resist smoking, as measured with a delay-to-smoking task in which monetary contingencies are provided for resisting smoking. METHODS: Adult daily smokers (n=22) completed two experimental sessions, each following 6h smoking abstinence. Sessions differed only in the type of cue participants were exposed to (smoking environments vs. nonsmoking environments). Participants completed subjective ratings of smoking urge, withdrawal and other reactions (i.e. craving, affect). Behavioral outcomes on the delay-to-smoking task included latency to first cigarette, number of cigarettes smoked and average number of puffs per cigarette. RESULTS: Across cue exposure sessions, 64% of participants initiated smoking (no effect of condition was observed). However, exposure to smoking environments as compared to the nonsmoking environments resulted in greater craving, faster initiation of smoking, and more smoked cigarettes. Greater craving was associated with a shorter time to initiate smoking, but this effect did not differ across sessions. In contrast, withdrawal was more strongly associated with number of cigarettes smoked during smoking environment sessions. CONCLUSION: Together, these results suggest smoking environments increase smoking urge and promote smoking behavior. Further research is necessary to examine the specific and interactive effects of smoking-related environments on real-world smoking lapse and relapse. PMID- 28012967 TI - Line scanning fMRI reveals earlier onset of optogenetically evoked BOLD response in rat somatosensory cortex as compared to sensory stimulation. AB - The combination of optogenetic control and fMRI readout in the brain is increasingly used to assess neuronal networks and underlying signal processing. However, how exactly optogenetic activation or inhibition reproduces normal physiological input has not been fully unraveled. To assess details of temporal dynamics of the hemodynamic response, temporal resolution in rodent fMRI is often not sufficient. Recent advances in human fMRI using faster acquisition schemes cannot be easily translated to small animals due to smaller dimensions, fast physiological motion, and higher sensitivity to artefacts. Here, we applied a one dimensional line scanning acquisition with 50ms temporal resolution in rat somatosensory cortex. We observed that optogenetic activation reproduces the hemodynamic response upon sensory stimulation, but shows a 160 to 340ms earlier onset of the response. This difference is explained by direct activation of all opsin-expressing and illuminated cortical layers, while hemodynamic response to sensory stimulation is delayed during intracortical transmission between cortical layers. Our results confirm that optogenetic activation is a valid model for physiological neuronal input, and that differences in temporal behavior of only a few hundred milliseconds can be resolved in rodent fMRI. PMID- 28012968 TI - Beta-band activity represents the recent past during episodic encoding. AB - While much research has focused on understanding how individual stimuli are encoded in episodic memory, less is known about how a series of events is bound into a coherent episode. Cognitive models of episodic memory propose that information about presented stimuli is integrated into a composite representation reflecting one's past experience, allowing events separated in time to become associated. Recent evidence suggests that neural oscillatory activity may be critically involved in this process. To examine how oscillatory activity contributes to binding of information across events, we measured scalp EEG as participants studied categorized lists of people, places, and objects. We assessed their memory for the lists using free recall, allowing us to characterize the temporal and semantic organization of the studied items in memory. Using pattern classification, we identified EEG activity during encoding at a range of frequencies and scalp locations that was sensitive to the category of presented stimuli. In the beta band (16-25Hz) at right posterior electrodes, we observed activity that was also sensitive to the category of recently presented stimuli. This neural activity showed two characteristics consistent with a representation of the recent past: It became stronger when multiple items from the same category were presented in succession, and it contained a fading trace of the previous category after a category shift. When items were separated by an inter-item distraction task, this integrative beta-band activity was disrupted. Distraction also led to decreased semantic organization of the studied materials without affecting their temporal organization; this suggests that distraction disrupts the integration of semantic information over time, preventing encoding of items in terms of the semantic context of earlier items. Our results provide evidence that beta-band activity is involved in maintaining information about recent events, allowing construction of a coherent representation of a temporally extended episode in memory. PMID- 28012969 TI - Integrated transcriptomic and metabolomic analysis shows that disturbances in metabolism of tumor cells contribute to poor survival of RCC patients. AB - PURPOSE: Cellular metabolism of renal cell carcinoma (RCC) tumors is disturbed. The clinical significance of these alterations is weakly understood. We aimed to find if changes in metabolic pathways contribute to survival of RCC patients. MATERIAL AND METHODS: 35 RCC tumors and matched controls were used for metabolite profiling using gas chromatography-mass spectrometry and transcriptomic analysis with qPCR-arrays targeting the expression of 93 metabolic genes. The clinical significance of obtained data was validated on independent cohort of 468 RCC patients with median follow-up of 43.22months. RESULTS: The levels of 31 metabolites were statistically significantly changed in RCC tumors compared with controls. The top altered metabolites included beta-alanine (+4.2-fold), glucose (+3.4-fold), succinate (-11.0-fold), myo-inositol (-4.6-fold), adenine (-4.2 fold), uracil (-3.7-fold), and hypoxanthine (-3.0-fold). These disturbances were associated with altered expression of 53 metabolic genes. ROC curve analysis revealed that the top metabolites discriminating between tumor and control samples included succinate (AUC=0.91), adenine (AUC=0.89), myo-inositol (AUC=0.87), hypoxanthine (AUC=0.85), urea (AUC=0.85), and beta-alanine (AUC=0.85). Poor survival of RCC patients correlated (p<0.0001) with altered expression of genes involved in metabolism of succinate (HR=2.7), purines (HR=2.4), glucose (HR=2.4), beta-alanine (HR=2.5), and myo-inositol (HR=1.9). CONCLUSIONS: We found that changes in metabolism of succinate, beta-alanine, purines, glucose and myo-inositol correlate with poor survival of RCC patients. PMID- 28012970 TI - Isoliquiritigenin inhibits TNF-alpha-induced release of high-mobility group box 1 through activation of HDAC in human intestinal epithelial HT-29 cells. AB - The suppression of pro-inflammatory cytokine-induced inflammation responses is an attractive pharmacological target for the development of therapeutic strategies for inflammatory bowel disease (IBD). In the present study, we evaluated the anti inflammatory properties of flavonoid isoliquiritigenin (ISL) in intestinal epithelial cells and determined its mechanism of action. ISL suppressed the expression of inflammatory molecules, including IL-8, IL-1beta and COX-2, in TNF alpha-stimulated HT-29 cells. Moreover, ISL induced activation of Nrf2 and expression of its target genes, such as HO-1 and NQO1. ISL also inhibited the TNF alpha-induced NF-kappaB activation in HT-29 cells. High-mobility group box 1 (HMGB1), which is one of the critical mediators of inflammation, is actively secreted from inflammatory cytokine-stimulated immune or non-immune cells. ISL inhibited HMGB1 secretion by preventing TNF-alpha-stimulated HMGB1 relocation, whereas the RNA and protein expression levels of cellular HMGB1 did not change in response to TNF-alpha or ISL. Moreover, we found that HMGB1 acetylation was associated with HMGB1 translocation to the cytoplasm and the extracellular release in TNF-alpha-stimulated HT-29 cells; however, ISL significantly decreased the amount of acetylated HMGB1 in both the cytoplasm and extracellular space of HT-29 cells. Histone deacetylase (HDAC) inhibition by Scriptaid abrogated ISL induced HDAC activity and reversed the ISL-mediated decrease in acetylated HMGB1 release in TNF-alpha-stimulated HT-29 cells, suggesting that, at least in TNF alpha-stimulated HT-29 cells, ISL suppresses acetylated HMGB1 release via the induction of HDAC activity. Together, the current results suggest that inhibition of HMGB1 release via the induction of HDAC activity using ISL may be a promising therapeutic intervention for IBD. PMID- 28012971 TI - Effects of a human recombinant alkaline phosphatase during impaired mitochondrial function in human renal proximal tubule epithelial cells. AB - Sepsis-associated acute kidney injury is a multifactorial syndrome in which inflammation and renal microcirculatory dysfunction play a profound role. Subsequently, renal tubule mitochondria reprioritize cellular functions to prevent further damage. Here, we investigated the putative protective effects of human recombinant alkaline phosphatase (recAP) during inhibition of mitochondrial respiration in conditionally immortalized human proximal tubule epithelial cells (ciPTEC). Full inhibition of mitochondrial oxygen consumption was obtained after 24h antimycin A treatment, which did not affect cell viability. While recAP did not affect the antimycin A-induced decreased oxygen consumption and increased hypoxia-inducible factor-1alpha or adrenomedullin gene expression levels, the antimycin A-induced increase of pro-inflammatory cytokines IL-6 and IL-8 was attenuated. Antimycin A tended to induce the release of detrimental purines ATP and ADP, which reached statistical significance when antimycin A was co-incubated with lipopolysaccharide, and were completely converted into cytoprotective adenosine by recAP. As the adenosine A2A receptor was up-regulated after antimycin A exposure, an adenosine A2A receptor knockout ciPTEC cell line was generated in which recAP still provided protection. Together, recAP did not affect oxygen consumption but attenuated the inflammatory response during impaired mitochondrial function, an effect suggested to be mediated by dephosphorylating ATP and ADP into adenosine. PMID- 28012972 TI - A novel peptide, 9R-P201, strongly inhibits the viability, proliferation and migration of liver cancer HepG2 cells and induces apoptosis by down-regulation of FoxM1 expression. AB - Overexpression of FoxM1 was closely related to the proliferation, metastasis, chemo-resistance and poor prognosis of various cancers. FoxM1 was regarded as the Achilles' heel of cancer and a potential target for anti-cancer drug discovery. We previously obtained several high affinity peptides from the phage random library against the DNA binding domain of FoxM1c (FoxM1c-DBD) protein. Here in this paper, we found that 9R-P201, one of the novel peptides, showed stronger inhibition to HepG2 cancer cells than those of DU145, HUVEC and L-02 cells with an IC50 of 43.6ug/ml (13.1uM). The peptide was highly effective to liver cancer cells with an IC50 for L-02 cells of 2855.9ug/ml. We confirmed that 9R-P201 aggregated in the cell nucleus and the expression of FoxM1 was significantly down regulated at both transcriptional and translational levels in HepG2 cells, leading to the suppression of cell proliferation, migration, angiogenesis, and induction of apoptosis. Whole genomic RNA sequencing analysis revealed that 357 genes were significantly and differentially expressed, most of them were enriched in cancer-associated biological processes. Finally, treatment of HepG2 xenografts with 9R-P201 resulted in growth inhibition and down-regulation of foxM1 expression in tumors. Collectively, our findings suggested that 9R-P201 could strongly inhibit the viability, proliferation and migration of liver cancer HepG2 cells and induce apoptosis by down-regulation of FoxM1 and regulation of related gene expression in signal transduction passways. Thus, 9R-P201 holds great potential as a lead anti-cancer drug targeting FoxM1. PMID- 28012973 TI - Methotrexate prevents epidural fibrosis through endoplasmic reticulum stress signalling pathway. AB - Lumbar laminectomy is one of the most common treatments for lumbar disc herniation and other lumbar disorders with serious complications, such as failed back surgery syndrome, mainly caused by epidural fibrosis (EF). The developing fibrosis causes radicular pain after the laminectomy or discectomy. Methotrexate (MTX) is a folic acid antagonist that has shown anti-proliferative effects in previous studies. The aim of our experiment is to study whether MTX has positive effects on the outcome of the laminectomy in rats. Our finding first demonstrated the beneficial effect of topical application of MTX in laminectomy models. As the results of a macroscopic scoring system, hydroxyproline content analysis, histological evaluation, the number of fibroblasts and immunohistochemistry showed that MTX suppressed the EF compared with the control group, and the inhibiting effect was in a dose-dependent manner. Furthermore, we hypothesized that the endoplasmic reticulum (ER) stress mediated the suppression effect of the EF. To verify this point of view, fibroblast cells cultured from epidural scar tissues of rats were used. CCK-8 assay, Western blot (for apoptotic genes, such as cleaved PARP) and annexin V-FITC/PI double-labelling showed that MTX could induce cell apoptosis. The expression of CHOP and GRP78 and the activation of ER stress-associated genes strongly suggested that ER stress mediated the apoptotic signalling pathway; immunohistochemistry of GRP78 and CHOP further verified this. Our findings indicate that topical application of MTX could indeed reduce EF, and the application of MTX could induce apoptosis through ER stress in rats. PMID- 28012974 TI - The surge of flavonoids as novel, fine regulators of cardiovascular Cav channels. AB - Ion channels underlie a wide variety of physiological processes that involve rapid changes in cell dynamics, such as cardiac and vascular smooth muscle contraction. Overexpression or dysfunction of these membrane proteins are the basis of many cardiovascular diseases that represent the leading cause of morbidity and mortality for human beings. In the last few years, flavonoids, widely distributed in the plant kingdom, have attracted the interest of many laboratories as an emerging class of fine ion, in particular Cav, channels modulators. Pieces of in vitro evidence for direct as well as indirect effects exerted by various flavonoids on ion channel currents are now accumulating in the scientific literature. This activity may be responsible, at least in part, for the beneficial and protective effects of dietary flavonoids toward cardiovascular diseases highlighted in several epidemiological studies. Here we examine numerous studies aimed at analysing this feature of flavonoids, focusing on the mechanisms that promote their sometimes controversial activities at cardiovascular Cav channels. New methodological approaches, such as molecular modelling and docking to Cav1.2 channel alpha1c subunit, used to elucidate flavonoids intrinsic mechanism of action, are introduced. Moreover, flavonoid-membrane interaction, bioavailability, and antioxidant activity are taken into account and discussed. PMID- 28012975 TI - Prey dynamics under generalist predator culling in stage structured models. AB - In this paper, by means of mathematical dynamical models we investigate the impacts of predator culling on a prey population structured in two stage classes, juveniles and adults, assuming stage specific predation by two generalist predators with functional responses types 2 and 3 in all possible combinations. According to the chosen set of parameter values, these impacts can manifest through possible demographic Allee effects, sustained population oscillations, alternative stable states (e.g., predator-pit-like behavior) and Hydra effect, which are all discussed, in turn, in terms of species conservation, harvest yield and pest biological control. PMID- 28012976 TI - One-stage versus two-stage breast reconstruction: prudence in surgical decision making. PMID- 28012978 TI - Correction to Lancet Oncol 2017; 18: 205, 206, 208, 210. PMID- 28012977 TI - Two-stage implant-based breast reconstruction compared with immediate one-stage implant-based breast reconstruction augmented with an acellular dermal matrix: an open-label, phase 4, multicentre, randomised, controlled trial. AB - BACKGROUND: The evidence justifying the use of acellular dermal matrices (ADMs) in implant-based breast reconstruction (IBBR) is limited. We did a prospective randomised trial to compare the safety of IBBR with an ADM immediately after mastectomy with that of two-stage IBBR. METHODS: We did an open-label, randomised, controlled trial in eight hospitals in the Netherlands. Eligible women were older than 18 years with breast carcinoma or a gene mutation linked with breast cancer who intended to undergo skin-sparing mastectomy and immediate IBBR. Randomisation was done electronically, stratified per centre and in blocks of ten to achieve roughly balanced groups. Women were assigned to undergo one stage IBBR with ADM (Strattice, LifeCell, Branchburg, NJ, USA) or two-stage IBBR. The primary endpoint was quality of life and safety was assessed by the occurrence of adverse outcomes. Analyses were done per protocol with logistic regression and generalised estimating equations. This study is registered at Nederlands Trial Register, number NTR5446. FINDINGS: 142 women were enrolled between April 14, 2013, and May 29, 2015, of whom 59 (91 breasts) in the one stage IBBR with ADM group and 62 (92 breasts) in the two-stage IBBR group were included in analyses. One-stage IBBR with ADM was associated with significantly higher risk per breast of surgical complications (crude odds ratio 3.81, 95% CI 2.67-5.43, p<0.001), reoperation (3.38, 2.10-5.45, p<0.001), and removal of implant, ADM, or both (8.80, 8.24-9.40, p<0.001) than two-stage IBBR. Severe (grade 3) adverse events occurred in 26 (29%) of 91 breasts in the one-stage IBBR with ADM group and in five (5%) of 92 in the two-stage IBBR group. The frequency of mild to moderate adverse events was similar in the two groups. INTERPRETATION: Immediate one-stage IBBR with ADM was associated with adverse events and should be considered very carefully. Understanding of selection of patients, risk factors, and surgical and postsurgical procedures needs to be improved. FUNDING: Pink Ribbon, Nuts-Ohra, and LifeCell. PMID- 28012979 TI - Contribution of a reflective debriefing to nursing students' clinical judgment in patient deterioration simulations: A mixed-methods study. AB - BACKGROUND: While reflection is a hallmark of debriefing, there is little understanding of how it contributes to nursing students' clinical judgment. OBJECTIVES: The aim of this study was to describe how nursing students perceived that the Reflective dEbriefing after a PatieNt Deterioration simulation (REsPoND) fostered learning and how it contributed to their clinical judgment in patient deterioration simulations. DESIGN: A sequential explanatory mixed-methods study. PARTICIPANTS: Nineteen students who showed the greatest clinical judgment score variation in a randomized controlled trial of the effectiveness of REsPoND. METHODS: Students participated in interviews on their learning experience in REsPoND. Data were subjected to thematic analysis and themes were contrasted according to students' score variations. RESULTS: Through guided exchanges with their peers, students configured a causes-observations-interventions framework that embodied their understanding of the patient's situation. They evaluated their own simulation performance based on that framework. The contribution of REsPoND to students' clinical judgment differed depending on (1) the value placed on the review of the simulation through a systematic assessment approach; (2) their focus on anticipating the situation or on performing in the simulation; and (3) their preference for who participated more in debriefing. CONCLUSION: Clinical judgment might be improved when a systematic assessment approach is used to structure debriefing. The relationship between reflection and self-assessment during debriefing remains to be disentangled. PMID- 28012980 TI - Academic dishonesty among Italian nursing students: A longitudinal study. AB - Considering the ethical issues related to nursing and that Ethics is an integral part of the nursing education in the degree course, one would suppose that academic dishonesty might be less frequent in nursing students than in students of other disciplines. However, several studies show that this trend of deceitful behaviour seems to be similar among the university nursing students and those of other disciplines. The aim of this study is to investigate the phenomenon of academic dishonesty in the classroom from a longitudinal perspective within a cohort of Italian nursing students. A non-experimental longitudinal design was used. All nursing students were recruited from the Nursing Science Bachelor Degree Program of a big Italian university in the centre of Italy and participants were part of an ongoing longitudinal research project which started in 2011 on nursing students' wellbeing. The results show that students get accustomed to taking academically deceitful actions. They come to consider their behaviours acceptable and normal, thereby stabilizing them, which increases the probability of stabilizing subsequent deceitful behaviours. The stability through time of academic cheating behaviours committed during higher education, within the study's timeframe, provides important perspectives into the establishment of rigorous standards of ethical and moral behaviours by the students. PMID- 28012981 TI - The impact of instituting Process-Oriented Guided-Inquiry Learning (POGIL) in a fundamental nursing course. AB - BACKGROUND: POGIL, using small groups of students, who assume the roles of leader, manager, recorder, and reflector to complete problem based activities in science courses, has demonstrated significant improvement in students' grades and course satisfaction in science courses and a nursing Fundamentals course. Using POGIL with nursing students in fundamentals nursing courses could help to improve final grades and course satisfaction while promoting active learning, critical thinking, and teamwork. OBJECTIVES: To examine differences in final course grades, Assessment Technologies Institute, LLC (ATi) scores and course satisfaction in 2 groups of fundamentals nursing students where one group experienced Process Oriented Guided Inquiry Learning (POGIL) as a teaching strategy and one group did not. Satisfaction with performing in the varied roles used during POGIL was also examined. DESIGN/METHODS: This quantitative descriptive study used a comparative design, with one group of students who experienced POGIL while analyzing case scenarios in class and a control group who did not experience POGIL. A t-test was used to compare final grades, ATi scores, and satisfaction survey results. SETTING: A mid-size, private university in the northeastern United States was the setting. PARTICIPANTS: A convenience sample of pre-licensure baccalaureate nursing students taking Fundamental in Nursing Courses during the junior semester. RESULTS: The experimental group (N=63) had higher final course grades (p=0.046), better understanding of the course material (p=0.005), and greater satisfaction with grades (p=0.008) than the control group (N=75). CONCLUSION: The results of this study revealed that Fundamental nursing students who experienced POGIL had significantly higher final grades and course satisfaction compared with students who did not experience POGIL. The active learning and teamwork experienced during POGIL, may be beneficial to students as they transition to practicing nurses. Additional research using POGIL with a variety of nursing courses could be beneficial in educating undergraduate nursing students. PMID- 28012982 TI - Clostridium difficile infection: Evolution, phylogeny and molecular epidemiology. AB - Over the recent decades, Clostridium difficile infection (CDI) has emerged as a global public health threat. Despite growing attention, C. difficile remains a poorly understood pathogen, however, the exquisite sensitivity offered by next generation sequencing (NGS) technology has enabled analysis of the genome of C. difficile, giving us access to massive genomic data on factors such as virulence, evolution, and genetic relatedness within C. difficile groups. NGS has also demonstrated excellence in investigations of outbreaks and disease transmission, in both small and large-scale applications. This review summarizes the molecular epidemiology, evolution, and phylogeny of C. difficile, one of the most important pathogens worldwide in the current antibiotic resistance era. PMID- 28012983 TI - Antibacterial activity of 14, 15-dihydroajugapitin and 8-o-acetylharpagide isolated from Ajuga bracteosa Wall ex. Benth against human pathogenic bacteria. AB - Ajuga bracteosa Wall ex. Benth. (Lamiaceae) commonly known as Bungle Weed has been in use since ancient times and is mentioned Ayurvedic literature. The upper ground parts of the plant are used for treatment of various diseases. The weed is credited with astringent, febrifugal, stimulant, aperient, tonic, diuretic and depurative properties and is used for the treatment of gout and rheumatism, palsy and amenorrhoea. Two compounds 1) 14, 15-dihydroajugapitin and 2) 8-o acetylharpagide were isolated from the aerial parts of the plant and tested for antibacterial activity against various pathogenic bacteria by agar well diffusion method. Compound 1 and 2 showed maximum antibacterial activity against Escherichia coli with zone of inhibitions of 25. 0 +/- 1.4 mm and 22.6 +/- 0.9 mm respectively. The MIC value of compound 1 and 2 ranged between 500 and 1000 MUg/ml. It could be concluded that both compounds isolated from the aerial parts of Ajuga bracteosa possess antibacterial activity against pathogens. PMID- 28012984 TI - Virulence factors and antimicrobial susceptibility profile of extraintestinal Escherichia coli isolated from an avian colisepticemia outbreak. AB - In this study an avian colisepticemia outbreak was investigated. Two isolates from a chicken with colisepticemia were characterized for antimicrobial susceptibility and virulence factors profile. For this purpose 7 antimicrobial and 29 genes (fimH, hrlA/hek, iha, papC, sfa/focCD, tsh, mat, tia, gimB, ibeA, chuA, fyuA, ireA, iroN, irp2, iucD, sitD. chr., sitD. ep., iss, neuC, ompA, traT, astA, hlyA, sat, vat, pic, malX, cvi/cva) were tested. The outbreak happened in a hick chicken breeding located in the northwestern region of Rio Grande do Sul state in South of Brazil and caused 28.3% (102 deads of a total of 360 chickens) of mortality rate. Escherichia coli isolates obtained from the avian spleen and liver belong to the same phylogenetic group A and present resistance to all antimicrobials tested (ampicillin, tetracycline, gentamicin, neomycin, sulfa + trimethoprim, enrofloxacin, and norfloxacin). Both isolates harbor virulence factors related to adhesion (fimH, papC, mat), invasion (tia), iron acquisition system (iroN) and serum resistance (iss, ompA, traT), showing that these groups are important for Avian Pathogenic E. coli (APEC). However, they present different virulence profiles for some genes, whereas liver-isolate carries more hrlA/hek (adhesin), gimB (invasin), sitD ep. (iron acquisition system), sat (toxin) and hylA (toxin) genes, the spleen-isolate harbors fyuA (iron acquisition system) gene. Here, we highlight a coinfection by different strains of APEC in the same animal with colisepticemia, the great antimicrobial resistance of these bacterial isolates and the genetic traits that modulate the virulence for high mortality rate of chickens for human consumption. PMID- 28012985 TI - Effect of polymyxin resistance (pmr) on biofilm formation of Cronobacter sakazakii. AB - Cronobacter sakazakii (C.sakazakii) has been identified as a wide-spread conditioned pathogen associated with series of serious illnesses, such as neonatal meningitis, enterocolitis, bacteremia or sepsis. As food safety is concerned, microbial biofilm has been considered to be a potential source of food contamination. The current study aims to investigate the ability of biofilm formation of two C. sakazakii strains (wild type BAA 894 and pmrA mutant). Crystal violet (CV), XTT (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino carbonyl)-2H-(tetrazolium hydroxide)] assays, and scanning electron microscopy (SEM) are performed on different time points during biofilm formation of C. sakazakii strains. Furthermore, RNA-seq strategy is utilized and the transcriptome data is analyzed to study the expression of genes related to biofilm formation along with whole genome sequencing. For biomass, in the first 24 h, pmrA mutant produced approximately 5 times than wildtype. However, the wild type exhibited more biomass than pmrA mutant during the post maturation stage (7 14 d). In addition, the wildtype showed higher viability than pmrA mutant during the whole biofilm formation. This study represents the first evidence on the biofilm formation of C. sakazakii pmrA mutant, which may further aid in the prevention and control for the food contamination caused by C. sakazakii. PMID- 28012986 TI - Increased secretion of exopolysaccharide and virulence potential of a mucoid variant of Salmonella enterica serovar Montevideo under environmental stress. AB - During an investigation to increase the recovery of Salmonella enterica from Oregano, an increased expression of exopolysaccharide was induced in Salmonella serovar Montevideo. The atypical mucoid (SAL242S) and the non-mucoid (SAL242) strains of Montevideo were compared and characterized using various methods. Serotyping analysis demonstrated that both strains are the same serovar Montevideo. Electron microscopy (EM) of cultured SAL242S cells revealed the production of a prominent EPS-like structure enveloping aggregates of cells that are composed of cellulose. Mucoid cells possessed a higher binding affinity for Calcofluor than that of the non-mucoid strain. Genotypic analysis revealed no major genomic differences between these morphotypes, while expression analyses using a DNA microarray shows that the mucoid variant exhibited heightened expression of genes encoding proteins produced by the SPI-1 type III secretion system. This increased expression of SPI1 genes may play a role in protecting Salmonella from environmental stressors. Based on these observations, Salmonella serovar Montevideo mucoid variant under stressful or low-nutrient environments presented atypical growth patterns and phenotypic changes, as well as an upregulated expression of virulence factors. These findings are significant in the understanding of survival abilities of Salmonella in a various food matrices. PMID- 28012987 TI - Characterization of non-lethal West Nile Virus (WNV) infection in horses: Subclinical pathology and innate immune response. AB - Most natural West Nile virus (WNV) infections in humans and horses are subclinical or sub-lethal and non-encephalitic. Yet, the main focus of WNV research remains on the pathogenesis of encephalitic disease, mainly conducted in mouse models. We characterized host responses during subclinical WNV infection in horses and compared outcomes with those obtained in a novel rabbit model of subclinical WNV infection (Suen et al. 2015. Pathogens, 4: 529). Experimental infection of 10 horses with the newly emerging WNV-strain, WNVNSW2011, did not result in neurological disease in any animal but transcriptional upregulation of both type I and II interferon (IFN) was seen in peripheral blood leukocytes prior to or at the time of viremia. Likewise, transcript upregulation for IFNs, TNFalpha, IL1beta, CXCL10, TLRs, and MyD88 was detected in lymphoid tissues, while IFNalpha, CXCL10, TLR3, ISG15 and IRF7 mRNA was upregulated in brains with histopathological evidence of mild encephalitis, but absence of detectable viral RNA or antigen. These responses were reproduced in the New Zealand White rabbits (Oryctolagus cuniculus) experimentally infected with WNVNSW2011, by intradermal footpad inoculation. Kinetics of the anti-WNV antibody response was similar in horses and rabbits, which for both species may be explained by the early IFN and cytokine responses evident in circulating leukocytes and lymphoid organs. Given the similarities to the majority of equine infection outcomes, immunocompetent rabbits appear to represent a valuable small-animal model for investigating aspects of non-lethal WNV infections, notably mechanisms involved in abrogating morbidity. PMID- 28012988 TI - The host immune enhancing agent Korean red ginseng oil successfully attenuates Brucella abortus infection in a murine model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng Meyer (Araliaceae), is one of the most valuable traditional Chinese medicines and is used for the treatment of various human diseases. In this study, we elucidated the protective mechanism of the essential oil from Korean red ginseng (RGO) against Brucella infection. MATERIALS AND METHODS: The effects of RGO on Brucella abortus viability, NO production, uptake and intracellular growth in macrophages were investigated. Mice were intraperitoneally infected with B. abortus and orally treated with RGO for 14 days. The weights and bacterial numbers from each spleen were monitored, and the sera were evaluated for cytokine production. RESULTS: B. abortus viability was not affected, whereas NO production, internalization and intracellular replication were inhibited in RGO-treated macrophages. Bacterial adherence, F-actin polymerization and MAPK signaling protein phosphorylation (ERK1/2, JNK and p38alpha) were reduced and the co-localization of B. abortus containing phagosomes with LAMP-1 was augmented in RGO-treated cells compared to untreated cells. RGO displayed protective effects against cell damage by inhibiting nitrite production during B. abortus infection in macrophages. Moreover, the spleen weight and bacterial burden were lower in the RGO-treated group than in the control group. The uninfected RGO-treated mice displayed increased TNF-alpha and IFN-gamma production, whereas the B. abortus-infected RGO treated mice showed reduced IL-10 production compared to the control. CONCLUSION: RGO exhibits protective effects against B. abortus infection in vitro and in vivo, which emphasize the beneficial effects of RGO in the prevention and treatment of brucellosis. PMID- 28012989 TI - Rhamnolipids form drug-loaded nanoparticles for dermal drug delivery. AB - Bacterial biosurfactants are nature's strategy to solubilize and ingest hydrophobic molecules and nutrients using a fully biodegradable transport system. Eight structurally defined rhamnolipids were selected and investigated as potential drug carrier systems. Depending on the molecular structures defining their packing parameters, the rhamnolipids were found to form spherical nanoparticles with precisely defined average sizes between 5 and 100nm, low polydispersity, and stability over a broad concentration range as revealed from dynamic light scattering and electron microscopy. As rhamnolipids were tolerated well by the human skin, rhamnolipid nanoparticles were considered for dermal drug delivery and thus loaded with hydrophobic drug molecules. Using the drug model, Nile red, dexamethasone, and tacrolimus nanoparticles charged with up to 30% drug loading (w/w) were obtained. Nanoparticles loaded with Nile red were investigated for dermal drug delivery in a Franz cell using human skin. Fluoresence microscopy of skin slices indicated the efficient penetration of the model drug into human skin, both into the stratum corneum and although to a lesser extent into the lower epidermis. Rhamnolipid nanocarriers were found to be non-toxic to primary human fibroblasts in a proliferation assay and thus are considered candidates for the dermal delivery of drugs. PMID- 28012990 TI - Assessment of skin barrier function and biochemical changes of ex vivo human skin in response to physical and chemical barrier disruption. AB - Topical dermatotherapy is intended to be used on diseased skin. Novel drug delivery systems even address differences between intact and diseased skin underlining the need for pre-clinical assessment of different states of barrier disruption. Herein, we studied how short-term incubation in culture media compared to incubation in humidified chambers affects human skin barrier function and viability. On both models we assessed different types and intensities of physical and chemical barrier disruption methods with regard to structural integrity, biophysical parameters and cytokine levels. Tissue degeneration and proliferative activity limited the use of tissue cultures to 48h. Viability is better preserved in cultured tissue. Tape-stripping (50*TS) and 4h sodium lauryl sulfate (SLS) pre-treatment were identified as highly reproducible and effective procedures for barrier disruption. Transepidermal water loss (TEWL) values reproducibly increased with the intensity of disruption while sebum content and skin surface pH were of limited value. Interleukin (IL)-6/8 and various chemokines and proteases were increased in tape-stripped skin which was more pronounced in SLS-treated skin tissue extracts. Thus, albeit limited to 48h, cultured full-thickness skin maintained several barrier characteristics and responded to different intensities of barrier disruption. Potentially, these models can be used to assess pre-clinically the efficacy and penetration of anti inflammatory compounds. PMID- 28012991 TI - In vitro and in vivo evaluation of anti-nucleolin-targeted magnetic PLGA nanoparticles loaded with doxorubicin as a theranostic agent for enhanced targeted cancer imaging and therapy. AB - A superparamagnetic iron oxide nanoparticles (SPIONs)/doxorubicin (Dox) co-loaded poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles targeted with AS1411 aptamer (Apt) against murine C26 colon carcinoma cells is successfully developed via a modified multiple emulsion solvent evaporation method for theranostic purposes. The mean size of SPIO/Dox-NPs (NPs) was 130nm with a narrow particle size distribution and Dox loading of 3.0%. The SPIO loading of 16.0% and acceptable magnetic properties are obtained and analyzed using thermogravimetric and vibration simple magnetometer analysis, respectively. The best release profile from NPs was observed in PBS at pH 7.4, in which very low burst release was observed. Nucleolin is a targeting ligand to facilitate anti-tumor delivery of AS1411-targeted NPs. The Apt conjugation to NPs (Apt-NPs) enhanced cellular uptake of Dox in C26 cancer cells. Apt-NPs enhance the cytotoxicity effect of Dox followed by a significantly higher tumor inhibition and prolonged animal survival in mice bearing C26 colon carcinoma xenografts. Furthermore, Apt-NPs enhance the contrast of magnetic resonance images in tumor site. Altogether, these Apt-NPs could be considered as a powerful tumor-targeted delivery system for their potential as dual therapeutic and diagnostic applications in cancers. PMID- 28012992 TI - Fifty shades of inhibition. AB - Inhibitory circuits are essential for brain function. Our understanding of their synaptic organization has advanced extensively with the identification and classification of an impressive variety of neuron groups, receptor types, and patterns of connectivity. However, the conceptual discussion regarding the role of in neural circuits still revolves around the idea that its primary role is to regulate circuit excitability. Here, I will focus on recent findings from cortical circuits and argue that inhibitory circuits are central to the integration of incoming inputs and can promote sophisticated fine-scale control of local circuits. I propose that inhibitory circuits should not be viewed so much as brakes on principal neurons activity, but as primary contributors to a variety of neural network functions. PMID- 28012993 TI - Optimization and evaluation of Oridonin-loaded Soluplus(r)-Pluronic P105 mixed micelles for oral administration. AB - In this study, a new type of mixed micelles was developed using Soluplus(r) (SOL) and Pluronic(r) P105 (P105) for the encapsulation of Oridonin (ORN). Oridonin loaded micelles (ORN-M) were simply prepared using solvent evaporation and characterized for particle size, particle morphology, encapsulation efficiency, and drug loading. In addition, the in vitro drug release behavior of ORN-M was assessed using the widely applied dialysis bag technique. The pharmacokinetic property of ORN was explored in rats after oral administration of ORN-M. Optimized ORN-M were of a small size (137.2+/-1.65nm) and spherical shape when the ratio of SOL:P105 was 3:1, with entrapment efficiency 90.48+/-1.85% and drug loading 15.08+/-0.38%. Oral absorption capacity of ORN was greatly enhanced with a relative bioavailability of 210.55% in comparison to that of in-house suspensions, which suggests that ORN-M shows significantly improved bioavailability and drug absorption characteristics. Overall, the optimized SOL P105 dual mixed micelles show great potential for use as oral drug carriers for cancer treatment. PMID- 28012994 TI - Nanocrystal formulations of a poorly soluble drug. 1. In vitro characterization of stability, stabilizer adsorption and uptake in liver cells. AB - In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v. injection of the particles. Two polyethylene oxide containing stabilizers; (distearoyl phosphatidylethanol amine (DSPE)) -PEG2000 and the triblock copolymer Pluronic F127, were investigated, with and without polyvinylpyrrolidone K30/Aerosol OT (PVP/AOT) present. The solubility in water was around 10nM for the compound, measured from nanocrystals, but 1000 times higher in 4% human serum albumin. The particles were physically stable during the time investigated. The zeta potential was around -30 and -10mV for DSPE-PEG2000 and Pluronic F127 stabilized particles, respectively, at the conditions selected. The dissolution rate was similar for all four formulations and similar to the theoretically predicted rate. Critical micelle concentrations were determined as 56nM and 1.4MUM for DSPE-PEG2000 and Pluronic F127, respectively. The adsorption isotherms for the PEG lipid showed a maximum adsorbed amount of about 1.3mg/m2, with and without PVP/AOT. Pluronic F127 showed a higher maximum amount adsorbed, at around 3.1mg/m2, and marginally lower with PVP/AOT present. Calculated data showed that the layer of Pluronic F127 was thicker than the corresponding DSPE-PEG2000 layer. The total amount of particles distributed mainly to the liver, and the hepatocellular distribution in vitro (Liver sinusoidal endothelial cells and Kupffer cells), differed depending on the stabilizing mixture on the particles. Overall, DSPE-PEG2000 stabilized nanocrystals (with PVP/AOT) accumulated to a larger degree in the liver compared to particles with Pluronic F127 on the surface. A theoretical model was developed to interpret in vivo pharmacokinetic profiles, explaining the balance between dissolution and liver uptake. With the present, fundamental data of the nanocrystal formulations, the platform for forthcoming in vivo studies was settled. PMID- 28012995 TI - Silk fibroin nanoparticles: Efficient vehicles for the natural antioxidant quercetin. AB - This article describes how silk fibroin nanoparticles (SFNs) are capable of adsorbing and releasing quercetin (Q) and how its integrity is highly preserved, as confirmed by antioxidant activity assays. Q loading onto SFNs was optimized in terms of the Q/SFN ratio (w/w), time of adsorption and solvent mixture. Quercetin loaded silk fibroin nanoparticles (QSFNs) were characterized using the dynamic light scattering technique to measure the diameter (Z-Average) and Z-potential (zeta). Loaded particles were slightly bigger than the SFNs, while their zeta was less negative. The antioxidant activity against DPPH showed that the Q loaded in QSFNs not only retains the antioxidant activity but also has a synergistic scavenging activity due the intrinsic antioxidant activity of the SF. The drug loading content (DLC) and the encapsulation efficiency (EE) varied with the relation between Q and SFN in the loading solution. The sustained release of Q occurred throughout the experiment both in phosphate buffer saline (pH 7.4) and simulated intestinal fluid (pH 6.8). The results point to SFNs as promising candidates for Q loading, transport and gastrointestinal delivery with potential applications in nanomedicine, while retaining their nano-size and their antioxidant properties. PMID- 28012996 TI - Life events, salivary cortisol, and cognitive performance in nondemented subjects: a population-based study. AB - Older people are particularly exposed to stressful events, known to activate the hypothalamus-pituitary-adrenal axis resulting in increased cortisol levels. High cortisol has been associated with deleterious effects on cognition. We hypothesized that stressful life events could increase cortisol secretion leading to cognitive impairment. A cross-sectional analysis was conducted using data from Colaus/PsyColaus, a longitudinal population-based study among Lausanne residents. Salivary cortisol samples were obtained from 796 nondemented subjects aged at least 65. A neuropsychological battery was used to assess cognitive performance and determine the Clinical Dementia Rating Sum of Boxes (CDRSOB). Lifetime life events and their subjective impact were assessed using a validated questionnaire. The total impact of life events was associated neither with cortisol area under the curve (AUC) nor with CDRSOB nor with any cognitive domain performance. The CDRSOB was associated with the cortisol AUC, controlling for age, sex, body mass index, education and depressive symptoms (p = 0.003; B = 0.686 [0.240; 1.333]; r = 0.114). This association between CDRSOB and the cortisol AUC remained significant after controlling for life events total impact (p = 0.040; B = 0.591 [0.027; 1.155]; r = 0.106). These findings do not support the hypothesis that stressful life events increase cortisol secretion leading to cognitive impairment. The association of higher cortisol levels with poorer cognition might be not a mere reflection of stressful events but rather explained by other factors, yet to be elucidated. PMID- 28012997 TI - Infectious hematopoietic necrosis virus (IHNV) outbreak in farmed rainbow trout in Iran: Viral isolation, pathological findings, molecular confirmation, and genetic analysis. AB - Infectious hematopoietic necrosis virus (IHNV) is the etiological agent of a contagious disease (IHN) mainly in salmonid fish. In the present study, we isolated and identified IHNV in trout fry from Iranian trout farms with unexplained high mortality in 2016. The affected fry showed cumulative mortality of 90% with the gross pathological signs including exophthalmia and hemorrhage of the eye, skin darkening, abdominal distension, ulceration of the snout, and the visceral pallor and yellowish fluid in the intestine. Histopathological examination revealed marked necrosis in the anterior kidney, liver and spleen with the intracytoplasmic inclusion bodies in the liver sections. Also, intranuclear inclusion body and marginated chromatin were observable in the hematopoietic cells of the kidney. The homogenates tissues of infected fry induced IHNV-positive cytopathic effects (CPE) in EPC cells and confirmed by RT PCR reactions and sequencing. Phylogenetic analysis revealed the Iranian IHNV isolates belonged to the European (E) genogroup with 100% identity to some Italian isolates. This is the first report of IHNV infection in farmed trout fry in Iran describing the viral isolation, clinical symptoms, histopathological findings, molecular confirmation, and genetic analysis suggestion of the specific country of origin. PMID- 28012998 TI - Viral small RNAs reveal the genomic variations of three grapevine vein clearing virus quasispecies populations. AB - Viral small RNAs (vsRNAs) include viral small interfering RNAs (vsiRNAs) that are initiators and products of RNA silencing, and small RNAs that are derived from viral RNAs with function still unknown. Sequencing of vsRNAs allows assembling of viral genomes and revelation of viral population variations at genomic levels. Grapevine vein clearing virus (GVCV) is a new member of the family Caulimoviridae whose DNA genome is replicated by reverse transcription of pre-genomic RNA molecules. In this short report, three genomic sequences of GVCV were assembled from vsRNAs that were isolated and sequenced from three individual grapevines in commercial vineyards and compared to the GVCV-CHA reference genome. Profiles of single nucleotide polymorphism among three viral populations indicated a closer relatedness between two populations in different grape cultivars at the same location than those in the same grape cultivar at different locations, suggesting the spread of GVCV populations among vineyards of close proximity. Classic types of vsiRNAs (21-nt, 22-nt, and 24-nt) were found in the three GVCV vsiRNA populations, but these did not produce alignment hotspots on the GVCV-CHA reference genome. The number of 36-nt reads is the highest among vsRNAs, the role of these vsRNAs remains unclear. The analysis of vsRNAs provides a first holistic picture of genomic variations among GVCV viral quasispecies populations that help monitor epidemics and evolution of GVCV populations, an emerging virus that is becoming a threat to grape production in the Midwest region of the USA. PMID- 28012999 TI - Epidural anaesthesia for caesarean section in pituitary dwarfism. AB - We describe the anaesthetic management for caesarean section in a 32-year-old patient with pituitary dwarfism. In addition to supportive treatment, we offered a postoperative epidural analgesia pump. The patient recovered well without any complications. PMID- 28013001 TI - Mitochondrial functions of THP-1 monocytes following the exposure to selected natural compounds. AB - The immune system is an important target of various xenobiotics, which may lead to severe adverse effects including immunosuppression or inappropriate immunostimulation. Mitochondrial toxicity is one possibility by which xenobiotics exert their toxic effects in cells or organs. In this study, we investigated the impact of three natural compounds, cyclosporine A (CsA), deoxynivalenol (DON) and cannabidiol (CBD) on mitochondrial functions in the THP-1 monocytic cell line. The cells were exposed for 24h to two different concentrations (IC10 and IC50 determined by MTT) of each compound. The cells showed concentration-dependent elevated intracellular reactive oxygen species (iROS) and induction of apoptosis (except DON) in response to the three test compounds. Mitochondrial functions were characterized by using bioenergetics profiling experiments. In THP-1 monocytes, the IC50 of CsA decreased basal and maximal respiration as well as ATP production with an impact on spare capacity indicating a mitochondrial dysfunction. Similar reaction patterns were observed following CBD exposure. The basal respiration level and ATP-production decreased in the THP-1 cells exposed to the IC50 of DON with no major impact on mitochondrial function. In conclusion, impaired mitochondrial function was accompanied by elevated iROS and apoptosis level in a monocytic cell line exposed to CsA and CBD. Mitochondrial dysfunction may be one explanation for the cytotoxicity of CBD and CsA also in other in immune cells. PMID- 28013000 TI - Galanin contributes to monoaminergic dysfunction and to dependent neurobehavioral comorbidities of epilepsy. AB - Status epilepticus (SE) in rats, along with chronic epilepsy, leads to the development of behavioral impairments resembling depressive disorder and/or attention deficit/hyperactivity disorder (ADHD), thus reflecting respective comorbidities in epilepsy patients. Suppressed neurotransmitter tone in the raphe nucleus (RN)-prefrontal cortex (PFC) serotonergic pathway and in the locus coeruleus (LC)-PFC noradrenergic pathway underlies depressive- and impulsive-like behavioral deficits respectively. We examined possible mechanisms leading to the monoamine dysfunction in brainstem efferents, namely modulatory effects of the neuropeptide galanin on serotonin (5-HT) and norepinephrine (NE) signaling. SE was induced in young adult male Wistar rats by LiCl and pilocarpine. Epileptic rats were categorized vis-a-vis behavioral deficits as not impaired, "depressed" and "impulsive". Depressive- and impulsive-like behaviors were examined in the forced swimming test (FST). The strength of serotonergic transmission in RN-PFC and of noradrenergic transmission in LC-PFC was analyzed using in vivo fast scan cyclic voltammetry. Galanin receptor type 1 (GalR1)/type 2 (GalR2) antagonist M40, and a preferential GalR2 antagonist M871 were administered over 3days locally into either RN or LC by means of ALZET osmotic minipumps connected to locally implanted infusion cannulas. Intra-RN injection of M40 improved serotonergic tone and depressive-like behavior in epileptic "depressed" rats. Intra-LC injection of M40 improved noradrenergic tone and impulsive-like behavior in epileptic "impulsive" rats. The effects of M40 were only observed in impaired subjects. The treatment did not modify neurotransmission and behavior in naive and epileptic not impaired rats; in "depressed" rats the effects were limited to serotonergic transmission and immobility, while in "impulsive" rats - to noradrenergic transmission and struggling behavior. Intra-RN administration of M871 exacerbated depressive-like behavior, but had no effects on any other of the examined parameters in any category of animals. These findings suggest that endogenous galanin, acting through GalR1 may be involved in the pathophysiology of epilepsy-associated depression and ADHD via inhibiting RN-PFC serotonergic and LC-PFC noradrenergic transmissions respectively. PMID- 28013002 TI - Enhanced Endometriosis Archiving Software (ENEAS): An Application for Storing, Retrieving, Comparing, and Sharing Data of Patients Affected by Endometriosis Integrated in the Daily Practice. AB - Endometriosis is a chronic benign disease affecting women of fertile age, associated with pelvic pain and subfertility, often with negative impacts on quality of life. Meetings involving 5 gynecologists skilled in endometriosis management and 2 informatics technology consultants competent in data management and website administration were enlisted to create an endometriosis databank known as ENEAS (Enhanced Endometriosis Archiving Software). This processing system allows users to store, retrieve, compare, and correlate all data collected in conjunction with different Italian endometriosis centers, with the collective objective of obtaining homogeneous data for a large population sample. ENEAS is a web-oriented application that can be based on any open-source database that can be installed locally on a server, allowing collection of data on approximately 700 items, providing standardized and homogeneous data for comparison and analysis. ENEAS is capable of generating a sheet incorporating all data on the management of endometriosis that is both accurate and suitable for each individual patient. ENEAS is an effective and universal web application that encourages providers in the field of endometriosis to use a common language and share data to standardize medical and surgical treatment, with the main benefits being improved patient satisfaction and quality of life. PMID- 28013003 TI - Arrhythmogenic substrates in the left atrium in patients with prior mitral valve surgery. PMID- 28013005 TI - Effects of beta-sheet crystals and a glycine-rich matrix on the thermal conductivity of spider dragline silk. AB - We measured the thermal conductivity of Araneus ventricosus' spider dragline silk using a suspended microdevice. The thermal conductivity of the silk fiber was approximately 0.4Wm-1K-1 at room temperature and gradually increased with an increasing temperature in a manner similar to that of other disordered crystals or proteins. In order to elucidate the effect of beta-sheet crystals in the silk, thermal denaturation was used to reduce the quantity of the beta-sheet crystals. A calculation with an effective medium approximation supported this measurement result showing that the thermal conductivity of beta-sheet crystals had an insignificant effect on the thermal conductivity of SDS. Additionally, the enhancement of bonding strength in a glycine-rich matrix by atomic layer deposition did not increase the thermal conductivity. Thus, this study suggests that the disordered part of the glycine-rich matrix prevented the peptide chains from being coaxially extended via the cross-linking covalent bonds. PMID- 28013004 TI - Synthesis of amine-functionalized Fe3O4@C nanoparticles for laccase immobilization. AB - Amine-functionalized Fe3O4@C nanoparticles with an average diameter of 266nm have been successfully synthesized by a solvothermal reduction method. The structure, morphology and properties of the Fe3O4@C nanoparticles were investigated through different analytical tools. Due to the magnetic nature and the presence of amine functionalized groups, the as-prepared Fe3O4@C nanoparticles were employed as magnetic carriers for laccase immobilization. The results indicated that the loading of laccase onto the amine-functionalized Fe3O4@C nanoparticles was approximately 195mg/g. In comparison with free laccase, the pH, operational and storage stabilities of the immobilized laccase were significantly improved. After 10 consecutive operations, the immobilized laccase retained above 60% residual activity. The removal rates of o-phenylenediamine (OPD) by immobilized laccase were 88%, which were much higher than that of free laccase (50%). It hoped that the amine-functionalized Fe3O4@C nanoparticles may find an application in biotechnology and catalysis. PMID- 28013006 TI - Glycation of human gammaB-crystallin: A biophysical investigation. AB - Glycation of ocular lens proteins plays a vital role in the development of diabetic cataract. In order to investigate the role of glycation in cataractogenesis, the extent of glycation of human gammaB-crystallin was determined by an in vitro glycation study in a solution of high glucose content for upto 28days. The glycated protein has been purified and the formation of advanced glycation end products (AGEs) has been monitored spectroscopically. Size exclusion chromatographic studies showed that the covalent intermolecular crosslinking in the dimer formed was not due to disulfide bond formation. MALDI TOF spectroscopy was employed to determine the number of glucose moieties attached to the protein due to glycation. PMID- 28013007 TI - Effect of chromium(III) gallate complex on stabilization of collagen. AB - To improve the stability of the collagen, here we studied the interaction of chromium(III) polyphenolic complex, [Cr(GA)2] (GA: Gallic acid) with collagen using various spectroscopic techniques. Circular dichroism studies show that the [Cr(GA)2] and gallic acid did not induce any structural perturbations on the triple helix of the collagen. Both differential scanning calorimetric(DSC) data and micro-shrinkage temperature studies showed that [Cr(GA)2] stabilized the collagen by 6+/-1 degrees C compared to gallic acid. Hydrodynamic studies revealed that the viscosity of collagen drastically reduced in the presence of [Cr(GA)2] while gallic acid did not. Fibrillation assay displayed a significant delay in fibril formation with Cr(III) complex compared to gallic acid treated collagen. The inhibition of fibril formation was further confirmed by microscopic data in which collagen fibres are seen with GA while [Cr(GA)2] treated collagen exhibit a thin microfibrils. From AFM studies, the d-periodicity of collagen was found to be decreased with [Cr(GA)2] while increased with gallic acid. The present study deliberate the advantage of metal complex containing polyphenolic ligand as crosslinking agent due to its synergistic effect of both metal center as well as polyphenolic groups in the stabilization of collagen structure. PMID- 28013008 TI - Independent metal-thiolate cluster formation in C-terminal Cys-rich region of a rice type 1 metallothionein isoform. AB - In this study we examined the independent self assembly of metal-binding in C terminal Cys- rich region of a type 1 metallothionein (MT) isoform from rice (OsMTI-1b). To this end the N-terminal of OsMTI-1b (C-OsMTI-1b) was heterologously expressed in Escherichia coli as fusion protein with glutathione-S transferase (GST). As compared with control (The E. coli cells containing pET41a without gene), transgenic E. coli cells expressing GST-C-OsMTI-1b accumulated more Ni2+, Cd2+, and Zn2+ from culture medium and showed increased tolerance against these metals. The recombinant GST-C-OsMTI-1b was purified using affinity chromatography. According to in vitro assays the protein GST-C-OsMTI-1b was able to form complexes with Ni2+, Cd2+ and Zn2+. These results demonstrate the formation of independent metal-thiolate cluster at C-terminal Cys-rich region of OsMTI-1b without participation of N-terminal Cys-rich region. PMID- 28013009 TI - Differential modulation of the chaperone-like activity of HSP-1/2, a major protein of horse seminal plasma by anionic and cationic surfactants. AB - The major protein of equine seminal plasma, HSP-1/2 exhibits chaperone-like activity (CLA) by protecting various target proteins against thermal, chemical and oxidative stress. Polydispersity and surface hydrophobicity of HSP-1/2 were found to be important for its CLA. Surfactants are known to alter certain properties of proteins, e.g. hydrophobicity, charge and conformation either by altering properties of the medium or by direct binding. In the current study, thermal aggregation of alcohol dehydrogenase (ADH) and enolase has been studied in the presence of HSP-1/2, different surfactants and their combinations. The results obtained show that anionic surfactants (SDS, sodium dodecyl benzene sulfate) and neutral surfactants (tween-20, triton X-100) increase the CLA of HSP 1/2 and also inhibit aggregation of the target proteins independently. On the other hand, cationic surfactants (CTAB, alanine palmityl ester) increased the thermal aggregation of ADH and enolase and also decreased the CLA of HSP-1/2. These results are of significant interest as they show that surfactants such as SDS and tween-20 can potentially be used as anti-aggregation agents to prevent thermal aggregation of target proteins. PMID- 28013010 TI - Improving special hydrolysis characterization into Talaromyces thermophilus F1208 xylanase by engineering of N-terminal extension and site-directed mutagenesis in C-terminal. AB - The purpose of this study was to gain insights into the hydrolysis characteristics of xylanase in producing xylo-oligosaccharides and to improve these by protein engineering. In this study, a hybrid enzyme (T-XynFM) was created from Talaromyces thermophilus F1208 xylanase (T-Xyn) by replacement of the N-terminal extension Phe1-Pro16 with Ala1-Gln8 and substitution of amino acid Phe193 (185) with Ser in the C-terminal. The enzyme showed optimum activity at 55 degrees C and pH 6.5. Its residual activity was more than 55% after treatment at 50 degrees C, pH 6.5 for 12h Km values of T-XynFM for beechwood xylan, birchwood xylan, and oat-spelt xylan were 10.31, 10.03, and 8.90mgmL-1, respectively. The enzyme displayed special hydrolysis characteristics: almost no xylose was produced on using xylotriose (X3), xylotetraose (X4), and xylopentaose as substrates. Moreover, over 60% X4 existed in hydrolyzed products of X3, indicating that T-XynFM possesses formidable transglycosylation properties. PMID- 28013011 TI - An efficient removal of RB5 from aqueous solution by adsorption onto nano ZnO/Chitosan composite beads. AB - In this study, the removal of Reactive Black 5 (RB-5) by nano-ZnO/Chitosan composite beads (nano-ZnO/CT-CB) from aqueous solution was investigated. ZnO nanoparticles were prepared by the via the microwave-assisted combustion technique. And then nano-ZnO/Chitosan composite beads were prepared by polymerization in the presence of nano-ZnO and chitosan. Characterization of composite beads were conducted using SEM, TEM, FTIR, TGA and XRD. Several important parameters influencing the removal of RB 5 such as contact time, pH and temperature were investigated systematically by batch experiments. At optimum conditions of pH 4 and adsorbent concentration of 0.2g, dye removal efficiency was found 76%. Langmuir, Freundlich and Temkin adsorption models were used to describe adsorption isotherms and constants. The maximum adsorption capacity (qm) by Langmuir isotherm has been found to be 189.44mg/g. Isotherms have also been used to obtain the thermodynamic parameters such as free energy, enthalpy and entropy of adsorption. The positive value of the enthalpy change (32.7kJ/mol) indicated that the adsorption is an endothermic process. The obtained results showed that the tested adsorbents are efficient and alternate low-cost adsorbent for removal of dyes from aqueous media. PMID- 28013012 TI - In silico-in vitro-in vivo studies of experimentally designed carvedilol loaded silk fibroin-casein nanoparticles using physiological based pharmacokinetic model. AB - The study aimed to design and develop carvedilol loaded silk fibroin-casein nanoparticles using 32 full factorial design. Silk fibroin and casein concentration were selected as the independent variables and their effect were observed on dependent variables: particle size, polydispersity index, encapsulation efficiency, drug release, and dissolution efficiency. The developed optimized formulation was characterized using fourier transform infrared spectroscopy, differential scanning calorimetry, and Powder X-ray diffraction. Surface morphology of optimized formulation using scanning electron microscopy, transmission electron microscopy, and atomic force microscopy revealed spherical nature of particles without any evidence of aggregation. The optimized formulation showed a 2.04-fold increase in Cmax, and 6.87-fold increase in bioavailability as compared to aqueous suspension. The formulation showed sustained release as confirmed by increases in mean residence time. The in vivo in silico simulation using physiologically based pharmacokinetics (PBPK) model and population simulation (100 subjects) revealed a reasonable degree of superimposition of simulated and observed pharmacokinetic parameters based on overall fold error (<=2.0). The enhanced bioavailability with sustained effect demonstrates potential of silk fibroin as an alternative carrier for drug delivery and presents GastoplusTM as efficient tool for in vivo in silico simulations. PMID- 28013013 TI - A Canine Model of Chronic Graft-versus-Host Disease. AB - In long-term survivors of allogeneic hematopoietic cell transplantation (HCT), chronic graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and a major determinant of quality of life. Chronic GVHD responds poorly to current immunosuppressive drugs, and while T cell depletion may be preventive, this gain is offset by increased relapse rates. A significant impediment to progress in treating chronic GVHD has been the limitations of existing animal models. The goal of this study was to develop a reproducible comprehensive model of chronic GVHD in the dog. Ten recipient dogs received 920 cGy total body irradiation, infusion of marrow, and an infusion of buffy coat cells from a dog leukocyte antigen (DLA)-mismatched unrelated donor. Postgrafting immunosuppression consisted of methotrexate (days 1, 3, 6, 11) and cyclosporine. The duration of cyclosporine administration was limited to 80 days instead of the clinically used 180 days. This was done to contain costs, as chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure and 9 dogs showed stable engraftment. Eight of the 9 developed de novo chronic GVHD. Dogs progressed with clinical signs of chronic GVHD over a period of 43 to 164 (median, 88) days after discontinuation of cyclosporine. Target organs showed the spectrum of chronic GVHD manifestations that are typically seen clinically. These included lichenoid changes of the skin, fasciitis, ocular involvement (xerophthalmia), conjunctivitis, bronchiolitis obliterans, salivary gland involvement, gingivitis, esophageal involvement, and hepatic involvement. Peripheral blood lymphocyte surface antigen expression of CD28 and inducible costimulator was elevated in dogs with GHVD compared with those in normal dogs, but not significantly so. Serum levels of IL-8 and monocyte chemotactic protein-1 in GVHD-affected dogs at time of euthanasia were elevated, whereas levels of IL-15 were depressed compared with those in normal dogs. Results indicate that the canine model is well suited for future studies aimed at preventing or treating chronic GVHD. PMID- 28013014 TI - Metabolic Complications Precede Alloreactivity and Are Characterized by Changes in Suppression of Tumorigenicity 2 Signaling. AB - New-onset post-transplantation diabetes mellitus (PTDM) occurs commonly after allogeneic hematopoietic cell transplantation (HCT) and is associated with inferior survival. We hypothesize that PTDM and nonrelapse mortality (NRM) are related to IL-33/suppression of tumorigenicity 2 (ST2) signaling and that soluble ST2 (sST2) levels will predict PTDM diagnosis. sST2 was measured at engraftment and day +30 in 36 euglycemic HCT recipients followed prospectively for PTDM (cohort 1). Results were confirmed in a validation cohort of 26 patients without pre-existing diabetes analyzed retrospectively for PTDM (cohort 2). Twelve patients with established diabetes before HCT were analyzed in cohort 3. When compared with recipients without PTDM, patients developing PTDM (n = 24) from cohort 1 had elevated sST2 levels at engraftment (P = .02) and at day +30 (P < .01). Cohort 2 confirmed this finding at engraftment (P = .01). Cohort 3 patients with pretransplantation diabetes had higher sST2 at engraftment than patients maintaining euglycemia after HCT from cohort 2 (P = .03). Multivariate analysis of cohorts 1 and 2 showed high engraftment sST2 predicted increased PTDM and NRM risk, independent of conditioning and grades 3 to 4 acute graft-versus-host disease. sST2 was elevated in PTDM, indicating a relationship between glucose homeostasis and the IL-33/ST2 axis after transplantation. Correction of metabolic complications may decrease sST2 and improve NRM. PMID- 28013015 TI - Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia. AB - Severe aplastic anemia (SAA) is a life-threatening hematopoietic stem cell disorder that is treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IST). The management of patients with refractory SAA after IST is a major challenge. Alternative donor BMT is the best chance for cure in refractory SAA, but morbidity and mortality from graft failure and complications of graft-versus-host disease (GVHD) have limited enthusiasm for this approach. Here, we employed post-transplantation high-dose cyclophosphamide in an effort to safely expand the donor pool in 16 consecutive patients with refractory SAA who did not have a matched sibling donor. Between July 2011 and August 2016, 16 patients underwent allogeneic (allo) BMT for refractory SAA from 13 haploidentical donors and 3 unrelated donors. The nonmyeloablative conditioning regimen consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation. Post-transplantation cyclophosphamide 50 mg/kg/day i.v. on days +3 and +4 was administered for GVHD prophylaxis. Additionally, patients received mycophenolate mofetil on days +5 through 35 and tacrolimus from day +5 through 1 year. The median age of the patients at the time of transplantation was 30 (range, 11 to 69) years. The median time to neutrophil recovery over 1000 * 103/mm3 for 3 consecutive days was 19 (range, 16 to 27) days, to red cell engraftment was 25 (range, 2 to 58) days, and to last platelet transfusion to keep platelets counts over 50 * 103/mm3 was 27.5 (range, 22 to 108) days. Graft failure, primary or secondary, was not seen in any of the patients. All 16 patients are alive, transfusion independent, and without evidence of clonality. The median follow-up is 21 (range, 3 to 64) months. Two patients had grade 1 or 2 skin-only acute GVHD. These same 2 also had mild chronic GVHD of the skin/mouth requiring systemic steroids. One of these GVHD patients was able to come off all IST by 15 months and the other by 17 months. All other patients stopped IST at 1 year. Nonmyeloablative alloBMT using post-transplantation cyclophosphamide allowed for safe expansion of the donor pool to include HLA-haploidentical donors. This approach appears promising in refractory SAA patients. Importantly, engraftment was 100%, pre-existing clonal disease was eradicated, and the risk of GVHD was low. PMID- 28013016 TI - Storage Duration of Autologous Stem Cell Preparations Has No Impact on Hematopoietic Recovery after Transplantation. AB - Peripheral blood stem cells (PBSCs) are widely used for autologous blood stem cell transplantation (ABSCT). These cells must be stored for months or even years, usually at temperatures <=-140 degrees C, until their use. Although several in vitro studies on CD34+ viability and clonogenic assays of PBSCs after long-term storage have been reported, only a few publications have investigated the influence of long-term storage on in vivo hematopoietic reconstitution. In this study, we retrospectively analyzed hematopoietic recovery after storage of PBSCs via controlled-rate freezing (CRF) and cryostorage in 10% DMSO at <=-140 degrees C in 105 patients with multiple myeloma who received high-dose melphalan before ABSCT. Three groups of PBSC transplantation (n = 247) were delineated based on the storage period: short-term (<=12 months, n = 143), medium-term (>12 and <=60 months, n = 75), and long-term storage (>60 months, n = 29). A neutrophil increase of >=.5 * 109/L in medium-term or long-term PBSC cryopreservation groups was observed at day 14 after ABSCT; this increase was comparable to patients who received briefly stored PBSCs (day 15). No negative effect of PBSC storage duration was observed on leucocyte or neutrophil reconstitution. Platelet reconstitutions of >=20 * 109/L and 50 * 109/L were observed after median times of 10 to 11 and 13 to 14 days after ABSCT, respectively. No influence of PBSC storage duration on platelet recovery of >=20 * 109/L and >=50 * 109/L was observed in the 3 storage groups (P = .07, P = .32). The number of previous ABSCTs also had no significant impact upon hematopoietic reconstitution. In conclusion, these results indicate that long-term cryopreservation of PBSC products at vapor nitrogen temperature after CRF does not have a negative effect on hematopoietic recovery even after prolonged storage. PMID- 28013017 TI - Direct detection of cysteine using functionalized BaTiO3 nanoparticles film based self-powered biosensor. AB - Simple, novel, and direct detection of clinically important biomolecules have continuous demand among scientific community as well as in market. Here, we report the first direct detection and facile fabrication of a cysteine responsive, film-based, self-powered device. NH2 functionalized BaTiO3 nanoparticles (BT-NH2 NPs) suspended in a three-dimensional matrix of an agarose (Ag) film, were used for cysteine detection. BaTiO3 nanoparticles (BT NPs) semiconducting as well as piezoelectric properties were harnessed in this study. The changes in surface charge properties of the film with respect to cysteine concentrations were determined using a current-voltage (I-V) technique. The current response increased with cysteine concentration (linear concentration range=10uM-1mM). Based on the properties of the composite (BT/Ag), we created a self-powered cysteine sensor in which the output voltage from a piezoelectric nanogenerator was used to drive the sensor. The potential drop across the sensor was measured as a function of cysteine concentrations. Real-time analysis of sensor performance was carried out on urine samples by non-invasive method. This novel sensor demonstrated good selectivity, linear concentration range and detection limit of 10uM; acceptable for routine analysis. PMID- 28013018 TI - Sensitive detection of Listeria monocytogenes based on highly efficient enrichment with vancomycin-conjugated brush-like magnetic nano-platforms. AB - Pathogens pose a significant threat to public health worldwide. Despite many technological advances in the rapid diagnosis of pathogens, sensitive pathogen detection remains challenging because target pathogenic bacteria usually exist in complex samples at very low concentrations. Here, the construction of multivalent brush-like magnetic nanoprobes and their application for the efficient enriching of pathogens are demonstrated. Brush-like magnetic nanoprobes were constructed by modification with poly-L-lysine (PLL) onto amino-modified magnetic beads, followed by coupling of PEG (amine-PEG5000-COOH) to the amine sites of PLL. Subsequently, vancomycin (Van), a small-molecule antibiotic with affinity to the terminal peptide (D-alanyl-D-alanine) on the cell wall of Gram-positive bacteria, was conjugated to the carboxyl of the PEG. The use of multivalent brush-like magnetic nanoprobes (Van-PEG-PLL-MNPs) results in a high enrichment efficiency (>94%) and satisfactory purity for Listeria monocytogenes (employed as a model) within 20min, even at bacterial concentrations of only 102cfumL-1. Integrated with the enrichment of the Van-PEG-PLL-MNP nano-platform and electrochemiluminescence (ECL) detection, Listeria monocytogenes can be rapidly and accurately detected at levels as low as 10cfumL-1. The approach described herein holds great potential for realizing rapid and sensitive pathogen detection in clinical samples. PMID- 28013019 TI - A novel immunosensing platform for highly sensitive prostate specific antigen detection based on dual-quenching of photocurrent from CdSe sensitized TiO2 electrode by gold nanoparticles decorated polydopamine nanospheres. AB - Herein, a novel photoelectrochemical (PEC) immunosensing platform for highly sensitive detection of prostate specific antigen (PSA) was constructed based on dual-quenching of photocurrent from CdSe sensitized TiO2 electrode by gold nanoparticles decorated dopamine-melanin nanospheres (AuNPs-Dpa-melanin CNSs). In this proposal, CdSe sensitized TiO2 was used as photoelectrochemical matrix and the functional AuNPs-Dpa-melanin CNSs were used as signal quenching element. The dual quenching of the gold nanoparticles decorated Dpa-melanin CNSs to the CdSe sensitized TiO2 was achieved as follows: (i) the strong energy transfer between the CdSe quantum dots (QDs) and Au NPs diminishes the photocurrent signal of CdSe QDs; (ii) the steric hindrance of AuNPs-Dpa-melanin CNSs partly obstructs the diffusion of the electron donor, i.e. ascorbic acid, to the surface of photoelectrode, which make the depleting efficiency of the photogenerated holes decrease, leading to a declined photocurrent intensity. On the basis of the dual quenching effect of AuNPs-Dpa-melanin CNSs, a competitive immunosensing platform for PSA was designed upon the specific binding of anti-PSA to PSA and PSA functionalized AuNPs-Dpa-melanin CNSs conjugates. This proposed immunosensor possesses wide linear range from 1.0*10-11gmL-1 to 1.0*10-7gmL-1 with the detection limit of 2.7pgmL-1. Moreover, the applicability of the present method was demonstrated in the determination of PSA in human serum. The strategy creates new paradigms for PSA and other tumor markers detection and demonstrates high sensitivity, good specificity, and satisfied applicability in complex biological samples. PMID- 28013020 TI - Nitrogen-doped graphene quantum dots-labeled epitope imprinted polymer with double templates via the metal chelation for specific recognition of cytochrome c. AB - A novel fluorescent sensor nitrogen-doped graphene quantum dots (N GQDs)/SiO2/molecular imprinting polymer(N-GQDs/SiO2/MIP)was fabricated by surface imprinting and epitope imprinting to recognize and detect the target protein cytochrome c (Cyt C) with fluorescence quenching. In the polymerization process, the C- and N-terminal nonapeptides of Cyt C were selected as the double templates which were fixed by functional monomer (zinc acrylate) through metal chelation and steady six-membered ring. The linear range of fluorescence quenching for this receptor towards Cyt C was 0.20-60MUM, and the detection limit was 0.11MUM. The precision for six times replicate determination of Cyt C at 30MUM was 1.20%, and the imprinting factor (IF) was 3.06. The recoveries of the material to Cyt C in urine were 99.3-114.0%. In brief, this work proposed a strategy to prepare a new type fluorescent imprinting polymer based on N-GQDs and provided an attractive perspective for the detection of protein by using the combination of N-GQDs and molecular imprinting technique. PMID- 28013021 TI - Kanamycin detection based on the catalytic ability enhancement of gold nanoparticles. AB - In this paper, we demonstrated that kanamycin could enhance the peroxidase-like activity of citrate-capped gold nanoparticles (AuNPs) through two steps: the attachment of kanamycin onto AuNPs through -NH2 (on kanamycin) and -COOH (on AuNPs) interactions; and the specifically interaction between glucoside on kanamycin and AuNPs which changes the surface property of AuNPs, and produced *OH radicals and Au3+ in the solution, and catalyzed the chromogenic reactions between 3, 3', 5, 5'-tetramethylbenzidine (TMB) and H2O2. Based on this principle, a novel method for kanamycin detection has been developed. This method exhibited high sensitivity and selectivity, as low as 0.1nM kanamycin could be detected with a linear range from 0.1nM to 20nM and 20nM to 300nM, respectively. This method was also successfully applied for the detection of kanamycin content in milk and meat samples. PMID- 28013022 TI - Nano-scale actin-network characterization of fibroblast cells lacking functional Arp2/3 complex. AB - Arp2/3 complex is thought to be the primary protrusive force generator in cell migration by controlling the assembly and turnover of the branched filament network that pushes the leading edge of moving cells forward. However, mouse fibroblasts without functional Arp2/3 complex migrate at rates similar to wild type cells, contradicting this paradigm. We show by correlative fluorescence and large-scale cryo-tomography studies combined with automated actin-network analysis that the absence of functional Arp2/3 complex has profound effects on the nano-scale architecture of actin networks. Our quantitative analysis at the single-filament level revealed that cells lacking functional Arp2/3 complex fail to regulate location-dependent fine-tuning of actin filament growth and organization that is distinct from its role in the formation and regulation of dendritic actin networks. PMID- 28013023 TI - Metabolic roles of poly(ADP-ribose) polymerases. AB - Poly(ADP-ribosyl)ation (PARylation) is an evolutionarily conserved reaction that had been associated with numerous cellular processes such as DNA repair, protein turnover, inflammatory regulation, aging or metabolic regulation. The metabolic regulatory tasks of poly(ADP-ribose) polymerases (PARPs) are complex, it is based on the regulation of metabolic transcription factors (e.g. SIRT1, nuclear receptors, SREBPs) and certain cellular energy sensors. PARP over-activation can cause damage to mitochondrial terminal oxidation, while the inhibition of PARP-1 or PARP-2 can induce mitochondrial oxidation by enhancing the mitotropic tone of gene transcription and signal transduction. These PARP-mediated processes impact on higher order metabolic regulation that modulates lipid metabolism, circadian oscillations and insulin secretion and signaling. PARP-1, PARP-2 and PARP-7 are related to metabolic diseases such as diabetes, alcoholic and non-alcoholic fatty liver disease (AFLD, NAFLD), or on a broader perspective to Warburg metabolism in cancer or the metabolic diseases accompanying aging. PMID- 28013024 TI - Sex differences in total frontal plane knee movement and velocity during a functional single-leg landing. AB - OBJECTIVES: Females land with more knee valgus than males. While most studies have evaluated lower extremity mechanics during double leg landing, most sports require single-leg landing from a double or single leg takeoff. Further, knee movement occurs toward both varus and valgus during functional landing. The purpose of this study was to determine if differences exist between females and males in total frontal plane movement and velocity of the knee during single-leg landing. DESIGN: Experimental cohort. SETTING: Motion analysis laboratory. PARTICIPANTS: Forty healthy, physically-active females (n = 20) and males (n = 20). MAIN OUTCOME MEASURES: Three-dimensional motion analysis was completed on the lower extremities during double-leg jumping followed by a single-leg landing. Student's t-tests (p <= 0.05) were used to determine if differences exist in frontal plane knee angles (valgus and varus excursion) and angular velocities between females and males. RESULTS: Females demonstrated greater knee valgus and varus excursion, and valgus and varus velocities compared to males (p < 0.05). CONCLUSIONS: These findings suggest that total movement in the frontal plane at the knee may be an important factor in injury mechanics in females. Further, single-leg landing from a functional jump should be considered when comparing landing biomechanics between females and males. PMID- 28013025 TI - An automated assay for the assessment of cardiac arrest in fish embryo. AB - Studies on fish embryo models are widely developed in research. They are used in several research fields including drug discovery or environmental toxicology. In this article, we propose an entirely automated assay to detect cardiac arrest in Medaka (Oryzias latipes) based on image analysis. We propose a multi-scale pipeline based on mathematical morphology. Starting from video sequences of entire wells in 24-well plates, we focus on the embryo, detect its heart, and ascertain whether or not the heart is beating based on intensity variation analysis. Our image analysis pipeline only uses commonly available operators. It has a low computational cost, allowing analysis at the same rate as acquisition. From an initial dataset of 3192 videos, 660 were discarded as unusable (20.7%), 655 of them correctly so (99.25%) and only 5 incorrectly so (0.75%). The 2532 remaining videos were used for our test. On these, 45 errors were made, leading to a success rate of 98.23%. PMID- 28013026 TI - Nonsubsampled rotated complex wavelet transform (NSRCxWT) for medical image fusion related to clinical aspects in neurocysticercosis. AB - Neurocysticercosis (NCC) is a parasite infection caused by the tapeworm Taenia solium in its larvae stage which affects the central nervous system of the human body (a definite host). It results in the formation of multiple lesions in the brain at different locations during its various stages. During diagnosis of such symptomatic patients, these lesions can be better visualized using a feature based fusion of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). This paper presents a novel approach to Multimodality Medical Image Fusion (MMIF) used for the analysis of the lesions for the diagnostic purpose and post treatment review of NCC. The MMIF presented here is a technique of combining CT and MRI data of the same patient into a new slice using a Nonsubsampled Rotated Complex Wavelet Transform (NSRCxWT). The forward NSRCxWT is applied on both the source modalities separately to extract the complementary and the edge related features. These features are then combined to form a composite spectral plane using average and maximum value selection fusion rules. The inverse transformation on this composite plane results into a new, visually better, and enriched fused image. The proposed technique is tested on the pilot study data sets of patients infected with NCC. The quality of these fused images is measured using objective and subjective evaluation metrics. Objective evaluation is performed by estimating the fusion parameters like entropy, fusion factor, image quality index, edge quality measure, mean structural similarity index measure, etc. The fused images are also evaluated for their visual quality using subjective analysis with the help of three expert radiologists. The experimental results on 43 image data sets of 17 patients are promising and superior when compared with the state of the art wavelet based fusion algorithms. The proposed algorithm can be a part of computer-aided detection and diagnosis (CADD) system which assists the radiologists in clinical practices. PMID- 28013027 TI - Forces directing germ-band extension in Drosophila embryos. AB - Body axis elongation by convergent extension is a conserved developmental process found in all metazoans. Drosophila embryonic germ-band extension is an important morphogenetic process during embryogenesis, by which the length of the germ-band is more than doubled along the anterior-posterior axis. This lengthening is achieved by typical convergent extension, i.e. narrowing the lateral epidermis along the dorsal-ventral axis and simultaneous extension along the anterior posterior axis. Germ-band extension is largely driven by cell intercalation, whose directionality is determined by the planar polarity of the tissue and ultimately by the anterior-posterior patterning system. In addition, extrinsic tensile forces originating from the invaginating endoderm induce cell shape changes, which transiently contribute to germ-band extension. Here, we review recent progress in understanding of the role of mechanical forces in germ-band extension. PMID- 28013028 TI - H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability. AB - Transcriptional enhancers play a key role in cell type-specific gene expression and cell fate transition. Enhancers are marked by histone H3K4 mono- and di methylation (H3K4me1/2). The tumor suppressor MLL4 (KMT2D) is a major enhancer H3K4 mono- and di-methyltransferase with a partial functional redundancy with MLL3 (KMT2C). However, the functional role of MLL4 enzymatic activity remains elusive. To address this issue, we have generated MLL4 enzyme-dead knock-in (KI) embryonic stem (ES) cells and mice, which carry Y5477A/Y5523A/Y5563A mutations in the enzymatic SET domain of the MLL4 protein. Homozygous MLL4 enzyme-dead KI (Mll4KI/KI) mice are embryonic lethal and die around E10.5, which phenocopies Mll4 knockout mice. Interestingly, enzyme-dead MLL4 protein in ES cells is highly unstable. Like Mll4 knockout ES cells, Mll4KI/KI ES cells show reduced levels of H3K4me1/2. Furthermore, we show that ectopic expression of histone H3.3 lysine 4 to-methionine (K4M) mutant, which reduces endogenous H3K4 methylation levels in ES cells, decreases the protein stability of MLL3 and MLL4 but not that of H3K4 methyltransferases SET1A (KMT2F) and SET1B (KMT2G). Taken together, our findings indicate that MLL4 protein stability is tightly regulated by its H3K4 methyltransferase activity. PMID- 28013029 TI - Charting Developmental Dissolution of Pluripotency. AB - The formation of tissues and organs during metazoan development begs fundamental questions of cellular plasticity: How can the very same genome program have diverse cell types? How do cell identity programs unfold during development in space and time? How can defects in these mechanisms cause disease and also provide opportunities for therapeutic intervention? And ultimately, can developmental programs be exploited for bioengineering tissues and organs? Understanding principle designs of cellular identity and developmental progression is crucial for providing answers. Here, I will discuss how the capture of embryonic pluripotency in murine embryonic stem cells (ESCs) in vitro has allowed fundamental insights into the molecular underpinnings of a developmental cell state and how its ordered disassembly during differentiation prepares for lineage specification. PMID- 28013030 TI - Interaction of E. coli Hsp90 with DnaK Involves the DnaJ Binding Region of DnaK. AB - The 90-kDa heat shock protein (Hsp90) is a widely conserved and ubiquitous molecular chaperone that participates in ATP-dependent protein remodeling in both eukaryotes and prokaryotes. It functions in conjunction with Hsp70 and the Hsp70 cochaperones, an Hsp40 (J-protein) and a nucleotide exchange factor. In Escherichia coli, the functional collaboration between Hsp90Ec and Hsp70, DnaK, requires that the two chaperones directly interact. We used molecular docking to model the interaction of Hsp90Ec and DnaK. The top-ranked docked model predicted that a region in the nucleotide-binding domain (NBD) of DnaK interacted with a region in the middle domain of Hsp90Ec. We then made substitution mutants in DnaK residues suggested by the model to interact with Hsp90Ec. Of the 12 mutants tested, 11 were defective or partially defective in their ability to interact with Hsp90Ecin vivo in a bacterial two-hybrid assay and in vitro in a bio-layer interferometry assay. These DnaK mutants were also defective in their ability to function collaboratively in protein remodeling with Hsp90Ec but retained the ability to act with DnaK cochaperones. Taken together, these results suggest that a specific region in the NBD of DnaK is involved in the interaction with Hsp90Ec, and this interaction is functionally important. Moreover, the region of DnaK that we found to be necessary for Hsp90Ec binding includes residues that are also involved in J-protein binding, suggesting a functional interplay among DnaK, DnaK cochaperones, and Hsp90Ec. PMID- 28013032 TI - Radiation therapy for malignant phyllodes tumor of the breast: An analysis of SEER data. AB - PURPOSE: Malignant phyllodes tumor of the breast (MPTB) accounts for less than 1% of whole breast neoplasm. Surgery is regarded as the primary treatment of choice in patients with MPTB, but the necessity of postoperative radiation therapy (RT) has been a subject of debate. Our aim was to evaluate effects of postoperative RT for MPTB using a large population database. METHODS: Using the Surveillance, Epidemiology, and End Results Program (SEER) database (1983-2013), clinico pathologic prognostic factors were evaluated. Postoperative RT, tumor extent, grade, and lymph node (LN) metastasis were included in the analysis. Univariate and multivariate Cox proportional hazards regressions were performed to evaluate prognostic power of variables on cancer specific survival (CSS). RESULTS: A total of 1974 patients with MPTB were reviewed. Of these, 825 (42%) and 1149 (58%) patients underwent mastectomy and breast conserving surgery (BCS), respectively. In each group, 130 (16%) and 122 (11%) patients received postoperative RT. For patients with adverse risk factors including high grade and large tumor size, postoperative RT was more likely to be performed. In multivariate analysis, age, ethnicity, tumor size, tumor extension and LN status were correlated with prognosis in mastectomy group, while postoperative RT did not affect CSS. In BCS group, age and grade were significant prognostic factors on CSS, meanwhile postoperative RT did not impact CSS in multivariate analysis. CONCLUSION: Although patients with more adverse prognostic factors underwent postoperative RT, RT groups were not inferior to non-RT group on CSS regardless of surgery (mastectomy or BCS). PMID- 28013033 TI - Differential sensitivity to estrogen-induced opsin expression in two poeciliid freshwater fish species. AB - The sensory system shapes an individual's perception of the world, including social interactions with conspecifics, habitat selection, predator detection, and foraging behavior. Sensory signaling can be modulated by steroid hormones, making these processes particularly vulnerable to environmental perturbations. Here we examine the influence of exogenous estrogen manipulation on the visual physiology of female western mosquitofish (Gambusia affinis) and sailfin mollies (Poecilia latipinna), two poeciliid species that inhabit freshwater environments across the southern United States. We conducted two experiments to address this aim. First, we exposed females from both species to a one-week dose response experiment with three treatments of waterborne beta-estradiol. Next, we conducted a one-week estrogen manipulation experiment with a waterborne estrogen (beta-Estradiol), a selective estrogen receptor modulator (tamoxifen), or combination estrogen and tamoxifen treatment. We used quantitative PCR (qPCR) to examine the expression of cone opsins (SWS1, SWS2b, SWS2a, Rh2, LWS), rhodopsin (Rh1), and steroid receptor genes (ARalpha, ARbeta, ERalpha, ERbeta2, GPER) in the eyes of individual females from each species. Results from the dose response experiment revealed estradiol sensitivity in opsin (SWS2a, Rh2, Rh1) and androgen receptor (ARalpha, ARbeta) gene expression in mosquitofish females, but not sailfins. Meanwhile, our estrogen receptor modulation experiments revealed estrogen sensitivity in LWS opsin expression in both species, along with sensitivity in SWS1, SWS2b, and Rh2 opsins in mosquitofish. Comparisons of control females across experiments reveal species-level differences in opsin expression, with mosquitofish retinas dominated by short-wavelength sensitive opsins (SWS2b) and sailfins retinas dominated by medium- and long-wavelength sensitive opsins (Rh2 and LWS). Our research suggests that variation in exogenous levels of sex hormones within freshwater environments can modify the visual physiology of fishes in a species specific manner. PMID- 28013034 TI - Spatiotemporal expression analysis of nuclear estrogen receptors in the zebrafish ovary and their regulation in vitro by endocrine hormones and paracrine factors. AB - Estradiol (E2) stimulates luteinizing hormone receptor (lhcgr) expression via nuclear estrogen receptors (nERs) in the zebrafish ovary. We have demonstrated that endocrine hormones such as gonadotropin (hCG) and paracrine factors such as epidermal growth factor (EGF) and pituitary adenylate cyclase-activating peptide (PACAP) can modulate E2-induced lhcgr expression in vitro. These observations raised a question on whether these hormones and factors exert their effects via regulating the expression of nERs. In this study, we first characterized the spatiotemporal expression profiles of three nER subtypes in the zebrafish ovary, including esr1 (ERalpha), esr2a (ERbeta2) and esr2b (ERbeta1). All three nERs increased their expression at the pre-vitellogenic stage and peaked at mid- (esr1 and esr2a) or late vitellogenic (esr2b) stage, followed by a significant decline at the full-grown stage. RT-PCR analysis showed that esr1 and esr2b were exclusively expressed in the follicle layer while esr2a was expressed in both compartments. We then examined how E2, hCG, PACAP and EGF regulated the expression of nERs in cultured zebrafish follicle cells. E2 quickly increased esr1 but reduced esr2a and esr2b expression from 1.5 to 12h of treatment. Similarly, EGF down-regulated esr2a significantly at 1.5h and this effect was further intensified at 24h. hCG decreased the expression of all three nER subtypes with similar potency throughout the 24-h time-course. Interestingly, PACAP exerted a biphasic regulation on esr2a. Our present study suggests that nERs, especially esr2a, provide potential target points for other hormones and factors to modulate E2 activity during folliculogenesis in the zebrafish. PMID- 28013031 TI - Functional and Molecular Insights of Hydrogen Sulfide Signaling and Protein Sulfhydration. AB - Hydrogen sulfide (H2S), a novel gasotransmitter, is endogenously synthesized by multiple enzymes that are differentially expressed in the peripheral tissues and central nervous systems. H2S regulates a wide range of physiological processes, namely cardiovascular, neuronal, immune, respiratory, gastrointestinal, liver, and endocrine systems, by influencing cellular signaling pathways and sulfhydration of target proteins. This review focuses on the recent progress made in H2S signaling that affects mechanistic and functional aspects of several biological processes such as autophagy, inflammation, proliferation and differentiation of stem cell, cell survival/death, and cellular metabolism under both physiological and pathological conditions. Moreover, we highlighted the cross-talk between nitric oxide and H2S in several bilogical contexts. PMID- 28013035 TI - Reoperation for Urinary Incontinence: A Nationwide Cohort Study, 1998-2007: Commentary on: Reoperation for Urinary Incontinence. PMID- 28013036 TI - The Involvement of Hepatocyte Growth Factor-MET-Matrix Metalloproteinase 1 Signaling in Bladder Cancer Invasiveness and Proliferation. Effect of the MET Inhibitor, Cabozantinib (XL184), on Bladder Cancer Cells. AB - OBJECTIVE: To clarify the invasive mechanisms of muscle-invasive bladder cancer (BCa) would be useful for the determination of appropriate treatment strategies. We previously showed that hepatocyte growth factor (HGF)-MET signaling is correlated with invasiveness of BCa cells. Here, we investigated the effects of the MET inhibitor, cabozantinib (XL184), on BCa cells. METHODS: We first conducted Western blot analysis to investigate MET expression in BCa cell lines. Next, we examined the effect of cabozantinib on their proliferation and invasive abilities using MTT and Matrigel invasion assays, respectively. Invasion assays were performed using the xCELLigence system. Additionally, to investigate the biological function of HGF-MET signaling, we analyzed gene expression profiles and performed real-time polymerase chain reaction analyses of 5637 cells that were cultivated with or without HGF stimulation, with or without cabozantinib. RESULTS: MET was highly expressed in 4 of 5 BCa cell lines, and 5637 and T24 cells showed especially high protein expression of MET. Cabozantinib suppressed cell proliferation and invasion (cell index; mock, 1.49 vs HGF, 2.26 vs HGF + XL184, 1.47, P < .05). Gene expression profile analysis indicated that matrix metalloproteinase 1 (MMP1) was significantly elevated at the mRNA level with addition of HGF. Moreover, cabozantinib suppressed HGF-induced MMP1 expression in 5637 T24 cells. CONCLUSIONS: These data indicate that cabozantinib suppressed MMP1 expression by blocking HGF-MET signaling and that HGF-MET-MMP1 signaling is involved in the invasiveness and proliferation of BCa cells. These results suggest that cabozantinib might prove useful for future treatment of muscle invasive BCa. PMID- 28013037 TI - Reply by the Authors. PMID- 28013038 TI - Potential Implications of Shortening Length of Stay Following Radical Cystectomy in a Pre-ERAS Population. AB - OBJECTIVE: To investigate whether shortened inpatient length of stay (LOS) after radical cystectomy (RC) is associated with increased complication rates after hospital discharge. MATERIALS AND METHODS: The analytic cohort comprised 484 consecutive patients with 90-day follow-up who underwent RC at our institution from 2005 to 2012 and with LOS <=9 days. Patients were categorized according to LOS as short (s-LOS; <=5 days) or routine (r-LOS; 6-9 days). The primary outcome was major complications (Clavien-Dindo grades 3-5) occurring within 90 days after discharge. A Cox proportional hazards model was used to determine the association between LOS and post-discharge major complications. Hospital readmission was a secondary outcome. RESULTS: Patients in the s-LOS cohort had fewer comorbidities (P < .01), less frequently received neoadjuvant chemotherapy (P = .02), and more often underwent robotic RC (P < .01). Major outpatient complications occurred in 18.1% of s-LOS patients vs 11.2% of r-LOS patients, and s-LOS was associated with a significant independent increase in the risk of major outpatient complications (hazard ratio 1.91, 95% confidence interval 1.03-3.56, P = .04). There was also a statistically significant association between s-LOS and readmission (hazard ratio 1.60, 95% confidence interval 1.01-2.44, P = .048). CONCLUSION: Early discharge post RC appears to be associated with an increased risk of major outpatient complications, suggesting that attempts to reduce LOS may need to be supplemented by additional outpatient services to diminish this effect. Further attention should be given to understanding how to better support patients discharged after a short LOS. PMID- 28013039 TI - Gaze leading is associated with liking. AB - Gaze plays a pivotal role in human communication, especially for coordinating attention. The ability to guide the gaze orientation of others forms the backbone of joint attention. Recent research has raised the possibility that gaze following behaviors could induce liking. The present study seeks to investigate this hypothesis. We designed two physically different human avatars that could follow the gaze of users via eye-tracking technology. In a preliminary experiment, 20 participants assessed the baseline appeal of the two avatars and confirmed that the avatars differed in this respect. In the main experiment, we compared how 19 participants rated the two avatars in terms of pleasantness, trustworthiness and closeness when the avatars were following their gaze versus when the avatar generated gaze movements autonomously. Although the same avatar as in the preliminary experiment was rated more favorably, the pleasantness attributed to the two avatars increased when they followed the gaze of the participants. This outcome provides evidence that gaze following fosters liking independently of the baseline appeal of the individual. PMID- 28013040 TI - Affective speech prosody perception and production in stroke patients with left hemispheric damage and healthy controls. AB - PURPOSE: 'Affective prosody' defines the supra-segmental features of speech that, when manipulated, can change the type and intensity of emotion conveyed by the speaker. Although the right hemisphere is predominantly linked to the processing of affective prosodic cues, existing literature also suggests that damage to the left hemisphere can result in similar deficits. This study aims to demonstrate, and add to the evidence, that patients with left-hemisphere injury experience difficulties with affective prosodic perception and production, measured via a new combination of assessments and analyses. It is also hypothesised that aphasia severity will be correlated with impaired processing of affective prosody. RESULTS: Stroke and control participants differed significantly on prosody perception tests of matching auditory affective cues to visual images. Prosodic production was measured by participants vocalising different affective expressions of words and monosyllables - from which significant differences were found in perceptual judgements of emotion accuracy and intensity, and acoustic analyses of pitch range and variance. There were significant correlations between participants' Western Aphasia Battery (WAB) scores, quality of life, and prosody production. CONCLUSION: Individuals with left-hemisphere damage after stroke have impaired affective prosodic perception and production that may be associated with reduced quality of life. PMID- 28013041 TI - CA3 hippocampal field: Cellular changes and its relation with blood nitro oxidative stress reveal a balancing function of CA3 area in rats exposed to repetead restraint stress. AB - Rats exposed to repeated restraint stress exhibit structural and functional deficits in hippocampus that are similar to those observed in patients with depressive illnesses. Blood corticosterone concentrations are proportionally increased with catalase and glutathione-peroxidase activity and are inversely proportional with 3-nitrotyrosine concentrations.Cytochrome c oxidase, adenosin tryphosphatase and monoamine oxidase activities of CA3 hippocampal field mark a stress-time dependent decrease. Acridine-orange labeling of the CA3 field reveals an enhancing green fluorescence of glyocites in stress conditions. After three days of restraint stress, the secretory activity of CA3 neurons did not show significant decrease, and neurons appeared with normal shapes and distribution. CA3 neurons after seven days of restraint stress have marked a slight decrease of secretory activity. In contrast to a well-preserved histological appearance of the CA3 neurons, local and blood stress-related reactions are observed. CA3-glial activation and disturbance of blood oxidative homeostasis are tandem processes during three and seven days of RS. This study depicts the balancing role of CA3 area in time-varying stress conditions. PMID- 28013042 TI - Production of stable GFP-expressing neural cells from P19 embryonal carcinoma stem cells. AB - Murine P19 embryonal carcinoma (EC) cells are convenient to differentiate into all germ layer derivatives. One of the advantages of P19 cells is that the exogenous DNA can be easily inserted into them. Here, at the first part of this study, we generated stable GFP-expressing P19 cells (P19-GFP+). FACS and western blot analysis confirmed stable expression of GFP in the cells. We previously demonstrated the efficient induction of neuronal differentiation from mouse ES and EC cells by application of a neuroprotective drug, selegiline In the second part of this study selegiline was used to induce differentiation of P19-GFP+ into stable GFP-expressing neuron-like cells. Cresyl violet staining confirmed neuronal morphology of the differentiated cells. Furthermore, real-time PCR and immunoflourescence approved the expression of neuron specific markers. P19-GFP+ cells were able to survive, migrate and integrated into host tissues when transplanted to developing chick embryo CNS. The obtained live GFP-expressing cells can be used as an abundant source of developmentally pluripotent material for transplantation studies, investigating the cellular and molecular aspects of early differentiation. PMID- 28013043 TI - A field evaluation of an isothermal DNA amplification assay for the detection of Theileria annulata infection in cattle. AB - A loop-mediated isothermal amplification (LAMP) assay was evaluated for the detection of Theileria annulata infection in cattle. The results were compared with a real-time PCR used for the quantification of T. annulata parasitaemia. One hundred bovine blood samples from 16 cattle farms were tested with LAMP and real time PCR, with T. annulata DNA being detected in 66% and 67% of the samples, respectively. The results showed that the LAMP assay detects a parasitaemia as low as 0.00025%, indicating a high analytical sensitivity of LAMP for clinical diagnosis of bovine theileriosis. PMID- 28013044 TI - Involvement of salsolinol in the suckling-induced oxytocin surge in sheep. AB - During lactation, the main surge of oxytocin is induced by a suckling stimulus. Previous studies have shown that salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4 tetrahydroisoquinoline), a dopamine-derived compound, stimulates both the synthesis and the release of oxytocin in lactating sheep. The objective of the present study was to verify the hypothesis that salsolinol is involved in the mechanism that generates the oxytocin surge that occurs during suckling. Thus, a structural analogue of salsolinol, 1-methyl-3,4-dihydroisoquinoline (1MeDIQ), known to antagonize some of its actions, was infused into the third ventricle of the brain of lactating sheep nursing their offspring. Serial 30-min infusion of 1MeDIQ (4 * 60 MUg/60 MUL) or vehicle were administered at 30-min interval from 10 AM to 2 PM. The experimental period in every ewe consisted of a nonsuckling period (10 AM-12 PM) and a suckling period (12 PM-2 PM). Blood samples were collected every 10 min, to measure plasma oxytocin concentration by RIA. In control sheep, oxytocin surges of high amplitude were observed during the suckling period. The oxytocin surges induced by suckling were significantly (P < 0.01) diminished in sheep receiving 1MeDIQ infusions as compared to those that received control infusions. However, no significant effect of 1MeDIQ was observed on basal oxytocin release, before suckling. Furthermore, oxytocin release, as measured by the area under the hormone response curve (AUC), was significantly decreased by the administration of 1MeDIQ during the suckling period. This study shows that elimination of the effect of salsolinol within the central nervous system of lactating sheep attenuates the oxytocin surge induced by suckling. Therefore, salsolinol may be an important factor in the oxytocin-stimulating pathway in lactating mammals. PMID- 28013045 TI - The mechanism underlying Ler-mediated alleviation of gene repression by H-NS. AB - Secretion of effector proteins in Enteropathogeneic Escherichia coli (EPEC) and Enterohemorrhagic Escherichia coli (EHEC) is mediated by a specialized type III secretion system, components of which are encoded in the LEE operons 1 to 5. H NS, a global repressor in E. coli, silences the expression of LEE operons. Ler, a master regulator in LEE operons, shares 24% amnio acid identity and 44% amino acid similarity to H-NS. Interestingly, rather than a gene silencer, its main role has been characterized as an antagonizing protein that relieves H-NS mediated transcriptional silencing. In the previous study we reported molecular mechanism for the repression of LEE5 promoter in EPEC and EHEC by H-NS as a protein interaction between upstream DNA-bound H-NS and the alphaCTD of promoter bound RNA polymerase. The mechanism underlying Ler-mediated alleviation of the genes repression by H-NS is largely unknown. We examined regulatory effect of these proteins on LEE5p activity using various in vitro tools. Our results revealed that binding affinity of Ler to the LEE5p DNA is about 40 folds greater than that of H-NS as determined by surface plasmon resonance. We verified that Ler binding removed H-NS bound to the same stretch of DNA on LEE5 promoter resulting in a derepression. PMID- 28013046 TI - Loss of TRADD attenuates pressure overload-induced cardiac hypertrophy through regulating TAK1/P38 MAPK signalling in mice. AB - We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR. Phosphorylated and total TAK1, Akt, and p38 MAPK levels were examined by Western blotting. The ratios of lung or heart/body weight, wall thickness/chamber diameter of left ventricular and cross area of cardiomyocyte were significantly reduced in TRADD knockout (KO) mice than those of wild-type mice after TAC. Moreover, cardiac hypertrophic and fibrotic markers were downregulated in TRADD knockout mice than those of wild-type mice following TAC. Protein expression analysis showed phosphorylated TAK1, p38 MAPK and AKT were upregulated after TAC in both wild-type and TRADD KO mice, phosphorylation of TAK1 and p38 MAPK was reduced more remarkably after TRADD deficiency, while phosphorylated AKT expression was similar between TRADD KO and wild-type mice following TAC. Our data suggest that TRADD KO blunts pressure overload-induced cardiac hypertrophy through mediating TAK1/p38 MAPK but not AKT phosphorylation in mice. PMID- 28013047 TI - Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through regulating hepatic glucose metabolism in type 2 diabetic rats. AB - Infusion of mesenchymal stem cells (MSCs) has been identified in the rapid alleviation in hyperglycemia of diabetic individuals, but the mechanism involved has not been adequately explained by these cells' potential role in modulating system insulin sensitivity and islet regeneration. In this study, we demonstrated adipose-derived mesenchymal stem cells (ASCs) produced significantly lower blood glucose via promoting hepatic glycogen synthesis and inhibiting hepatic glucose production within 24 h after infusion in T2DM rats. In vitro, HepG2 cells treated with palmitate (PA) were used as a model of hepatic glucose metabolism disorder to confirm that ASCs stimulates the phosphorylation of hepatic AMP-activated protein kinase (AMPK) to restores hepatic glucose metabolism in type 2 diabetes. In summary, this study indicated that ASCs improve hyperglycemia via regulating hepatic glucose metabolism. Additionally, the effect of ASCs on hepatic glucose metabolism depended on the AMPK signaling pathway. Thus, this is the new research of the molecular mechanisms of MSCs administration to improve glucose metabolism, and it may indicate a new treatment target of MSCs in T2DM. PMID- 28013048 TI - Pou1f1, the key transcription factor related to somatic growth in tilapia (Orechromis niloticus), is regulated by two independent post-transcriptional regulation mechanisms. AB - This study aims to determine the post-transcriptional regulation mechanism of the transcription factor pou1f1 (pou class 1 homeobox 1), which is the key gene for pituitary development, somatic growth in vertebrates, and transcription of several hormone genes in teleost fish. MicroRNA miR-223-3p was identified as a bona fide target of pou1f; overexpression of miR-223-3p in primary pituitary cells led to the down-regulation of pou1f1 and downstream genes, and inhibition of miR-223-3p led to the up-regulation of pou1f1 in Nile tilapia dispersed primary pituitary cells. An adenylate-uridylate-rich element (AU-Rich element) was found in the 3'UTR of pou1f1 mRNA, and deletion of the AU-Rich element led to slower mRNA decay and therefore more protein output. A potential mutual relationship between miR-223-3p and the AU-rich element was also investigated, and the results demonstrated that with or without the AU-Rich element, miR-223-3p induced the up-regulation of a reporter system under serum starvation conditions, indicating that miR-223-3p and the AU-Rich element function independent of each other. This study is the first to investigate the post-transcriptional mechanism of pou1f1, which revealed that miR-223-3p down-regulated pou1f1 and downstream gene expressions, and the AU-Rich element led to rapid decay of pou1f1 mRNA. MicroRNA miR-223-3p and the AU-Rich element co-regulated the post-transcriptional expression of pou1f1 independently in Nile tilapia, demonstrating that pou1f1 is under the control of a dual post-transcription regulation mechanism. PMID- 28013049 TI - Induction of autophagy by phosphate starvation in an Atg11-dependent manner in Saccharomyces cerevisiae. AB - Upon nutrient starvation, eukaryotic cells exploit autophagy to reconstruct cellular components. Although autophagy is induced by depletion of various nutrients such as nitrogen, carbon, amino acids, and sulfur in yeast, it was previously ambiguous whether phosphate depletion could trigger the induction of autophagy. Here, we showed that phosphate depletion induced autophagy in Saccharomyces cerevisiae, albeit to a lesser extent than nitrogen starvation. It is known that rapid inactivation of the target of rapamycin complex 1 (TORC1) signaling pathway contributes to Atg13 dephosphorylation, which is one of the cues for autophagy induction. We found that phosphate starvation caused Atg13 dephosphorylation with slower kinetics than nitrogen starvation, suggesting that poor autophagic activity during phosphate starvation was associated with slower inactivation of the TORC1 pathway. Phosphate starvation-induced autophagy requires Atg11, an adaptor protein for selective autophagy, but not its cargo recognition domain. These results suggested that Atg11 plays important roles in low-level nonselective autophagy. PMID- 28013050 TI - Parkinsonism-associated protein DJ-1 is a bona fide deglycase. AB - We discovered recently that Parkinsonism-associated DJ-1 and its bacterial homologs function as protein deglycases that repair glyoxal- and methylglyoxal glycated proteins. Protein glycation levels are 2- to 10-fold increased in deglycase-depleted cells, and deglycase mutants display up to 500-fold loss of viability in methylglyoxal or glucose-containing media, suggesting that these deglycases play important roles in protecting cells against electrophile and carbonyl stress. Although the deglycase activity of DJ-1 is well supported by extensive biochemical work, Pfaff et al. (J. Biol. Chem. in presshttp://dx.doi.org/10.1074/jbc.M116.743823) claimed in a recent study that deglycation of the hemithioacetal formed upon cysteine glycation by methylglyoxal results from a Tris buffer artefact. Here, we show that this is not the case, and that DJ-1 and its homologs are the bona fide deglycases awaited since the Maillard discovery. PMID- 28013051 TI - Diurnal variations in polyunsaturated fatty acid contents and expression of genes involved in their de novo synthesis in pigs. AB - The daily variations in circulating fatty acid (FA) contents and lipid metabolism have been well documented. However, whether long chain polyunsaturated FA (PUFA) contents and expression of genes involved in their de novo synthesis exhibit daily rhythms are yet unknown. We conducted the present study to investigate the daily variations in PUFA contents in plasma and liver of pigs. Moreover, diurnal expression of genes encode fatty acid desaturases and elongases, which are key enzymes catalyzed de novo synthesis of long chain PUFA, were also explored. The results showed that long chain PUFA contents in plasma and liver both exhibited diurnal rhythms. Diurnal variations were also observed in mRNA expression of FASD1 (Delta 5-desaturase), FASD2 (Delta 6-desaturase), ELOVL5 (fatty acid elongase 5) and ELOVL2 in liver, with an unexpectedly high level at night. Moreover, our results showed a similarity between the diurnal patterns of FASD1, FASD2, ELOVL2, ELOVL5 and Period 2. These results indicated a high activity of the desaturase-elongase pathway at night in pigs. These findings have important physiological and pathophysiological implications, since long chain PUFA are essential for cell function and closely involved in the development of metabolic syndrome. PMID- 28013052 TI - Yellow fever vaccination - Once in a lifetime? PMID- 28013053 TI - Surviving Naegleria fowleri infections: A successful case report and novel therapeutic approach. AB - Naegleria fowleri is a deadly human pathogen recognized as the causative agent of Primary Amoebic Meningitis (PAM). N. fowleri is commonly found in warm freshwater environments such as natural or man-made lakes, hot springs, and resort spas frequented by tourists. PAM infections have a mortality rate between 95 and 99% with minimal progress being made toward a successful treatment therapy. We report the case of a 12-year old American female who survived a PAM infection and propose a new drug therapy which includes the antimicrobial drug Miltefosine. PMID- 28013054 TI - The role of day-to-day emotions, sleep, and social interactions in pediatric anxiety treatment. AB - Do day-to-day emotions, social interactions, and sleep play a role in determining which anxious youth respond to supportive child-centered therapy (CCT) versus cognitive behavioral therapy (CBT)? We explored whether measures of day-to-day functioning (captured through ecological momentary assessment, sleep diary, and actigraphy), along with clinical and demographic measures, were predictors or moderators of treatment outcome in 114 anxious youth randomized to CCT or CBT. We statistically combined individual moderators into a single, optimal composite moderator to characterize subgroups for which CCT or CBT may be preferable. The strongest predictors of better outcome included: (a) experiencing higher positive affect when with one's mother and (b) fewer self-reported problems with sleep duration. The composite moderator indicated that youth for whom CBT was indicated had: (a) more day-to-day sleep problems related to sleep quality, efficiency, and waking, (b) day-to-day negative events related to interpersonal concerns, (c) more DSM-IV anxiety diagnoses, and (d) college-educated parents. These findings illustrate the value of both day-to-day functioning characteristics and more traditional sociodemographic and clinical characteristics in identifying optimal anxiety treatment assignment. Future studies will need to enhance the practicality of real-time measures for use in clinical decision making and evaluate additional anxiety treatments. PMID- 28013056 TI - Matrix Metalloproteinase 14 promotes lung cancer by cleavage of Heparin-Binding EGF-like Growth Factor. AB - Molecularly targeted therapies benefit approximately 15-20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC. Overexpression of a soluble dominant negative MMP14 (DN-MMP14) or pharmacological inhibition of MMP14 blocked invasion of lung cancer cells through a collagen I matrix in vitro and reduced tumor incidence in an orthotopic K-RasG12D/+p53-/- mouse model of lung cancer. Additionally, MMP14 activity mediated proteolytic processing and activation of Heparin-Binding EGF like Growth Factor (HB-EGF), stimulating the EGFR signaling pathway to increase proliferation and tumor growth. This study highlights the potential for development of therapeutic strategies that target MMP14 in NSCLC with particular focus on MMP14-HB-EGF axis. PMID- 28013055 TI - Attention bias towards negative emotional information and its relationship with daily worry in the context of acute stress: An eye-tracking study. AB - Cognitive theories of anxiety psychopathology cite biased attention towards threat as a central vulnerability and maintaining factor. However, many studies have found threat bias indices to have poor reliability and have failed to observe the theorized relationship between threat bias and anxiety symptoms; this may be due to the non-unitary nature of threat bias and the influence of state level variables on its expression. Accumulating data suggests that state anxious mood is important for the robust expression of threat bias and for relations to emerge between threat bias and symptoms, though this possibility has not been experimentally tested. Eye-tracking was used to assess multiple forms of threat bias (i.e., early vigilance, sustained attention, facilitated engagement, delayed disengagement) thought to be related to anxiety. A non-clinical sample (N = 165) was recruited to test the hypothesis that biased attention towards threat, but not dysphoric or positive emotional stimuli, during an anxious mood induction, but not at a pre-stress baseline, would prospectively predict greater worry symptoms on days in which more naturalistic stressors occurred. Results revealed the hypothesized moderation effect for sustained attention towards threat after the mood induction but not at baseline, though sustained attention towards dysphoric stimuli also moderated the effect of stressors on worry. Worry-relevant sustained attention towards negative emotional stimuli may be a partially mood context dependent phenomenon. PMID- 28013057 TI - Neural control of ventilation prevents both over-distension and de-recruitment of experimentally injured lungs. AB - BACKGROUND: Endogenous pulmonary reflexes may protect the lungs during mechanical ventilation. We aimed to assess integration of continuous neurally adjusted ventilatory assist (cNAVA), delivering assist in proportion to diaphragm's electrical activity during inspiration and expiration, and Hering-Breuer inflation and deflation reflexes on lung recruitment, distension, and aeration before and after acute lung injury (ALI). METHODS: In 7 anesthetised rabbits with bilateral pneumothoraces, we identified adequate cNAVA level (cNAVAAL) at the plateau in peak ventilator pressure during titration procedures before (healthy lungs with endotracheal tube, [HLETT]) and after ALI (endotracheal tube [ALIETT] and during non-invasive ventilation [ALINIV]). Following titration, cNAVAAL was maintained for 5min. In 2 rabbits, procedures were repeated after vagotomy (ALIETT+VAG). In 3 rabbits delivery of assist was temporarily modulated to provide assist on inspiration only. Computed tomography was performed before intubation, before ALI, during cNAVA titration, and after maintenance at cNAVAAL. RESULTS: During ALIETT and ALINIV, normally aerated lung-regions doubled and poorly aerated lung-regions decreased to less than a third (p<0.05) compared to HLETT; no over-distension was observed. Tidal volumes were<5ml/kg throughout. Removing assist during expiration resulted in lung de-recruitment during ALIETT, but not during ALINIV. During ALIETT+VAG the expiratory portion of EAdi disappeared, resulting in cyclic lung collapse and recruitment. CONCLUSIONS: When using cNAVA in ALI, vagally mediated reflexes regulated lung recruitment preventing both lung over-distension and atelectasis. During non-invasive cNAVA the upper airway muscles play a role in preventing atelectasis. Future studies should be performed to compare these findings with conventional lung-protective approaches. PMID- 28013058 TI - Leg compressions improve ventilatory efficiency while reducing peak and post exercise blood lactate, but does not improve perceived exertion, exercise economy or aerobic exercise capacity in endurance-trained runners. AB - PURPOSE: The objective of this study was to determine if leg compressions would alter cardiorespiratory and perceived exertion measures during rest, submaximal and maximal exercise in endurance-trained runners. METHOD: Thirteen young, endurance trained runners (10 males, 20.9+/-3y, 58.9+/-5.7mlkgmin-1) completed a randomized design, leg compressions and non-compression control condition. The incremental graded exercise test consisted of baseline rest and submaximal intensities at 23%, 70%, 75%, 85% and then a progressive increase to 100% VO2max. Running economy (RE), rating of perceived exertion (RPE), breathing rate (BR), heart rate (HR), ventilation (VE), blood lactate, VO2max and ventilatory efficiency (VE/VO2) were the primary outcome variables. RESULTS: Relative to the control condition, VO2 at rest, during submaximal and at max were not different. Additionally, RE, RPE, BR, and HR were similar under both conditions. Leg compressions reduced lactate at VO2max by 11% (P<0.05) and at 10min post-exercise recovery by 18% (P<0.01). Additionally, peak VE was significantly reduced in the compression condition by 8% (P<0.0001) relative to the control condition. Ventilatory efficiency was improved in compressions compared to control condition at 85 and 100% VO2max (condition*time interaction, P<0.0001). CONCLUSION: These data suggest that leg compressions do not alter RE, RPE, BR, HR, or VO2, during exercise. However, compressions may be beneficial for submaximal and maximal ventilatory efficiency while improving lactate clearance at VO2max and during recovery in trained runners. PMID- 28013059 TI - Role of gender in basic cough research. AB - Cough hypersensitivity affects mainly postmenopausal women. Pathogenesis remains unknown in their case; therefore, an optimal treatment is unavailable. Only male guinea pigs are used in basic cough research and exclusion of females leads to gender bias. Nowadays, the efforts of grant agencies aim to support projects which take gender into account and involve both sexes to reduce gender bias. The aim of our pilot study is to assess the suitability of female guinea pig model in cough research. Cough response to citric acid (0.4M) was obtained in female and male guinea pigs (n=12 each). Reproducibility of cough response was tested four times a week apart. The cough was detected from the airflow traces and cough sound analysis. Our initial results show that cough response of female guinea pigs is higher than in males. Variability of females is also higher than in males. Further investigations are necessary to validate this model in different conditions to achieve gender equality in cough studies. PMID- 28013060 TI - The blood transfer conductance for nitric oxide: Infinite vs. finite thetaNO. AB - Whether the specific blood transfer conductance for nitric oxide (NO) with hemoglobin (thetaNO) is finite or infinite is controversial but important in the calculation of alveolar capillary membrane conductance (DmCO) and pulmonary capillary blood volume (VC) from values of lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO). In this review, we discuss the background associated with thetaNO, explore the resulting values of DmCO and VC when applying either assumption, and investigate the mathematical underpinnings of DmCO and VC calculations. In general, both assumptions yield reasonable rest and exercise DmCO and VC values. However, the finite thetaNO assumption demonstrates increasing VC, but not DmCO, with submaximal exercise. At relatively high, but physiologic, DLNO/DLCO ratios both assumptions can result in asymptotic behavior for VC values, and under the finite thetaNO assumption, DmCO values. In conclusion, we feel that the assumptions associated with a finite thetaNO require further in vivo validation against an established method before widespread research and clinical use. PMID- 28013061 TI - Voltage- and receptor-mediated activation of a non-selective cation channel in rat carotid body glomus cells. AB - A recent study showed that hypoxia activates a Ca2+-sensitive, Na+-permeable non selective cation channel (NSC) in carotid body glomus cells. We studied the effects of mitochondrial inhibitors that increase Ca2+ influx via Ca2+ channel (Cav), and receptor agonists that release Ca2+ from endoplasmic reticulum (ER) on NSC. Mitochondrial inhibitors (NaCN, FCCP, H2S, NO) elevated [Ca2+]i and activated NSC. Angiotensin II and acetylcholine that elevate [Ca2+]i via the Gq IP3 pathway activated NSC. However, endothelin-1 (Gq) and 5-HT (Gq) showed little or no effect on [Ca2+]i and did not activate NSC. Adenosine (Gs) caused a weak rise in [Ca2+]i but did not activate NSC. Dopamine (Gs) and gamma-aminobytyric acid (Gi) were ineffective in raising [Ca2+]i and failed to activate NSC. Store operated Ca2+ entry (SOCE) produced by depletion of Ca2+ stores with cyclopiazonic acid activated NSC. Our results show that Ca2+ entry via Cav, ER Ca2+ release and SOCE can activate NSC. Thus, NSC contributes to both voltage- and receptor-mediated excitation of glomus cells. PMID- 28013062 TI - Sex and pairing status impact how zebra finches use social information in foraging. AB - Many factors, including the demonstrator's sex, status, and familiarity, shape the nature and magnitude of social learning. Given the important role of pair bonds in socially-monogamous animals, we predicted that these intimate relationships would promote the use of social information, and tested this hypothesis in zebra finches (Taeniopygia guttata). Observer birds witnessed either their mate or another familiar, opposite-sex bird eat from one, but not a second novel food source, before being allowed to feed from both food sources themselves. Birds used social information to make foraging decisions, but not all individuals used this information in the same way. While most individuals copied the foraging choice of the demonstrator as predicted, paired males did not, instead avoiding the feeder demonstrated by their mate. Our findings reveal that sex and pairing status interact to influence the use of social information and suggest that paired males might use social information to avoid competing with their mate. PMID- 28013063 TI - Emotional attachment of pre-weaning pups to mothers and fathers in mandarin voles. AB - Studies into the effects of maternal and paternal deprivation on the brain and behavior are traditionally done on animals from postnatal day 0 to 14 when parents display high levels of licking and grooming. Deprivation experiments that reveal attachment conducted during this period are confounded because physiological and emotional deprivation occur simultaneously. Whether rodent pups of greater physiological independence from postnatal 14 to 21days show emotional attachment towards mothers and fathers remains unclear. Here we establish a new animal model for attachment experiments in animals 14-21days old using monogamous mandarin voles (Microtus mandarinus). Levels of emotional attachment of pups from postnatal 14 to 21days were measured using preference tests. Pups spent more time in contact with their mothers, more time approaching, sniffing, climbing and walking near their mothers, and emitted more calls on their mother's side compared to an unknown female. They also showed a preference for their fathers over an unknown male. While pups displayed attachment to both their mothers and fathers, levels directed towards mothers were higher in tests when mothers and fathers were presented simultaneously. These results indicate that mandarin voles can be used as an animal model to investigate the effects of early emotional attachment disruption on the adult brain and behavior. PMID- 28013064 TI - Nest-site selection, nesting behaviour and spatial ecology of female Nile crocodiles (Crocodylus niloticus) in South Africa. AB - Nesting biology and ecology have been investigated for Nile crocodiles (Crocodylus niloticus), but information on behaviour and movement patterns of nesting females during nest guarding is scant. Consequently, we investigated the home ranges, nest-site selection strategies, movement patterns, activity levels and nest fidelity of four nesting females using telemetry. Gravid females selected winter basking/breeding areas close (351+/-2m) to nest-sites. Mean home range and core-use areas of nesting females were 8539+/-4752m2, and 4949+/-3302m2 respectively. Mean home range (0.85ha) was significantly smaller than those of non-nesting females (108.4ha) during nesting season. Activity levels and mean daily movements while nesting were 8.1+/-2.5% and 213+/-64m, respectively, and increased to 47.9+/-11.7% and 2176+/-708m post-nesting. Overall levels of nest fidelity were 82.8+/-11.7%, (day 78.1+/-15.9%; night 87.3+/-7.8%). Highest nest fidelity recorded during incubation was 99.7% over 96days. Telemetry data from nesting females were helpful for elucidating spatial and behavioural patterns during the nest guarding period, and provided novel insights into this biologically important event. PMID- 28013065 TI - An unlikely DNA cleaving agent: A photo-active trinuclear Cu(II) complex based on hexaazatriphenylene. AB - This paper describes the synthesis of a trinuclear Cu(II) complex (4) containing a central 1,4,5,8,9,12-hexaazatriphenylene-hexacarboxylate (hat) core (3). Low, micromolar concentrations of the negatively charged parent ligand 3 and the neutral trinuclear complex 4 were found to photocleave negatively charged pUC19 plasmid DNA with high efficiency at neutral pH (350nm, 50min, 22 degrees C). The interactions of complex 4 with double-helical DNA were studied in detail. Scavenger and colorimetric assays pointed to the formation of Cu(I), superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals during photocleavage reactions. UV-visible absorption, circular dichroism, DNA thermal denaturation, and fluorescence data suggested that the Cu(II) complex contacts double-stranded DNA in an external fashion. The persistent association of ligand 3 and complex 4 with Na(I) and/or other cations in aqueous solution might facilitate electrostatic DNA interactions. PMID- 28013066 TI - Antileukemic activity of an arsenomolybdate in the human HL-60 and U937 leukemia cells. AB - The antileukemic activity, mechanisms and serum albumin interactions of an arsenomolybdate, K2Na[AsMo6O21(O2CCH2NH3)3].6H2O (1), was evaluated in the human leukemia HL-60 and U937 cells. The results indicated that 1 could inhibit the proliferation of both leukemia cell lines in a dose-dependent manner with the 50% lethal concentration (IC50) value of 8.61MUM for HL-60 and 14.50MUM for U937 at 24h, compare to the positive controls, all-trans retinoic acid (ATRA) with IC50 value of 20.76MUM and 14.85MUM,and As2O3 with IC50 value of 6.40MUM and 8.75MUM at 24h, respectively (P<0.05). Furthermore, the anti-leukemia activity of compound 1 might be medicated by arresting the leukemic cells in the G1 phase and inducing apoptosis via caspase-3 and bcl-2 regulatory proteins. Spectroscopic techniques results showed that the fluorescence of human serum albumin was quenched by compound 1, and the quenching mechanism was mainly static quenching. Compound 1 might be a potential medicinal candidate against acute promyelocytic leukemia. PMID- 28013067 TI - Lost emotion: Disrupted brain-based tracking of dynamic affective episodes in anxiety and depression. AB - In our day-to-day lives we are confronted with dynamic sensory inputs that elicit a continuously evolving emotional response. Insight into the brain basis of the dynamic nature of emotional reactivity may be critical for understanding chronic symptoms of anxiety and depression. Here, individuals with generalized anxiety disorder, major depressive disorder, and healthy controls watched a video with dynamic affective content while fMRI activity was recorded. Across all participants there was a large-scale tracking of affective content in emotion processing regions and the default mode network. Anxious and depressed individuals displayed less brain-based coupling within these regions and the extent of this uncoupling correlated with variability in emotional numbing. Thus, abnormal neural tracking of affective information during dynamic emotional episodes appears to represent a disconnection between affective cues in the environment and an individual's response to these cues-providing a putative neural basis for context insensitive affective reactivity and emotional numbing. PMID- 28013068 TI - Evidence for the changes of pituitary volumes in patients with post-traumatic stress disorder. AB - In pubertal and postpubertal patients with post-traumatic stress disorder (PTSD), significantly greater pituitary gland volumes have been reported. Moving from this point, in the present study, we aimed to investigate pituitary gland volumes in patients with PTSD and hypothesized that volumes of the gland would be structurally changed. Volumetric magnetic resonance imaging of the pituitary gland was performed among sixteen patients with PTSD and fifteen healthy control subjects. We found that the mean volume of the pituitary gland was statistically significant and smaller than that of healthy subjects (0.69+/-0.08cm3 for patient group and 0.83+/-0.21 for control subjects). Consequently, in the present study, we found that patients with PTSD had smaller pituitary gland volumes than those of healthy controls like other anxiety disorders. It is important to provide support for this finding in future longitudinal investigations. PMID- 28013070 TI - Corrigendum to "Evaluation of chitosan quaternary ammonium salt-modified resin denture base material" [Int. J. Biol. Macromol. 85 (2016) 102-110]. PMID- 28013069 TI - Cognitive bias modification and CBT as early interventions for adolescent social and test anxiety: Two-year follow-up of a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: This two-year follow-up study evaluated the long-term outcomes of two early interventions that aimed at reducing social and test anxiety in young adolescents at risk for developing social anxiety disorder. METHODS: In this RCT, moderately socially anxious adolescents (N=240, mean age 13.6 years) were randomly assigned to a 10-week internet-based multifaceted cognitive bias modification training (CBM), a 10-week school-based cognitive behavioral group training (CBT), or a no-intervention control condition. Using multiple imputation, this study examined the changes in primary and secondary outcome measures from pretest to follow-up in a repeated measures design. RESULTS: Primary outcome: Self-reported social and test anxiety generally decreased from pre-test to two-year follow-up, regardless of treatment condition. The percentage of adolescents who developed a social anxiety disorder was very low (6%) and similar across conditions. Secondary outcome: There were beneficial changes in self-esteem, self-reported prosocial behaviors, and fear of negative evaluation, but none of these were related to treatment condition. Automatic social-threat associations did not significantly change. The CBM intervention was effective in changing interpretative bias as indexed by the Recognition Task but this long-term effect did not transfer to the Adolescent Interpretation and Belief Questionnaire. LIMITATIONS: There was a substantial (50%) though seemingly non-selective attrition at follow-up. CONCLUSIONS: This RCT does not support the longer-term efficacy of school-based CBT or CBM as an early intervention for social and test anxiety. Rather, it emphasizes the positive 'natural' course of highly socially anxious adolescents over two years. PMID- 28013071 TI - From fat to FAT (CD36/SR-B2): Understanding the regulation of cellular fatty acid uptake. AB - The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been elucidated in appreciable detail in the last decades. Two main players in this field, each discovered in the early 1990s, are (i) a membrane-associated protein first identified in adipose ('fat') tissue and referred to as putative fatty acid translocase (FAT)/CD36 (now officially designated as SR-B2) which facilitates the transport of fatty acids across the plasma membrane, and (ii) the family of transcription factors designated peroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARbeta/delta) for which fatty acids and fatty acid metabolites are the preferred ligand. CD36/SR-B2 is the predominant membrane protein involved in fatty acid uptake into intestinal enterocytes, adipocytes and cardiac and skeletal myocytes. The rate of cellular fatty acid uptake is regulated by the subcellular vesicular recycling of CD36/SR-B2 from endosomes to the plasma membrane. Fatty acid-induced activation of PPARs results in the upregulation of the expression of genes encoding various proteins and enzymes involved in cellular fatty acid utilization. Both CD36/SR-B2 and the PPARs have been implicated in the derangements in fatty acid and lipid metabolism occurring with the development of pathophysiological conditions, such as high fat diet-induced insulin resistance and diabetic cardiomyopathy, and have been suggested as targets for metabolic intervention. In this brief review we discuss the discovery and current understanding of both CD36/SR-B2 and the PPARs in metabolic homeostasis. PMID- 28013072 TI - Expression of alpha-1,6-fucosyltransferase (FUT8) in rice grain and immunogenicity evaluation of plant-specific glycans. AB - Rice seed is a cost-effective bioreactor for the large-scale production of pharmaceuticals. However, convincing evidence of the immunogenicity of plant specific glycans is still limited although plant-specific glycans are considered potential allergic antigens. In the present study, we found that the alpha-1,3 fucose content of the glycoprotein produced from rice seed was much lower than that in leaf, and conversely, a higher beta-1,2-xylose content was detected in seed than that in leaf. We detected the alpha-1,6-fucose content in the glutelin and recombinant human alpha1-antitrypsin (OsrAAT). The further results in a line containing AAT and FUT8 genes indicated that the alpha-1,6-fucose content of modified glycosylated recombinant alpha1-antitrypsin (mgOsrAAT) was 38.4%, while glutelin was only 6.8%. Interestingly, the alpha-1,3-fucose content of mgOsrAAT was significantly reduced by 59.8% compared with that of OsrAAT. Furthermore, we assessed the immunogenicity of OsrAAT, mgOsrAAT and human alpha1-antitrypsin (hAAT) using an animal system. The PCA results indicated no significant differences in the IgG, IgM and IgE titers among OsrAAT, mgOsrAAT and hAAT. Further studies revealed that those antibodies were mainly from alpha-1,3-fucose, but not from beta-1,2-xylose, indicating that alpha-1,3-fucose was the major immunogenic resource. Our results demonstrated that alpha-1,3-fucose contents in seed proteins was much less than that of leaf, and could not be a plant-specific glycan because it also exists in human proteins. PMID- 28013073 TI - Assessment risk of phosphorus leaching from calcareous soils using soil test phosphorus. AB - Accurate estimation of phosphorus (P) leaching is important because excess P may reduce surface and ground water quality. Little attention has been paid to estimate P leaching from soil tests in calcareous soils. The relation between different soil tests P (STP), P sorption index (PSI) and degree of P saturation (DPS) and leaching of P were examined for assessing the risk of P loss from calcareous soils. Columns leaching repacked with native soils were leached with either distilled water or 10 mM CaCl2 solutions, separately. Four leaching events were performed at four days, and 28.7 mm of distilled water or 10 mM CaCl2 solutions was applied at each leaching events. Compared with distilled water, CaCl2 had a small ability to solubilize P from soils. Concentration of P in leachate in both leaching solutions was exceeding 0.1 mg l-1 associated with eutrophication. Cumulative P leached P was ranged from 0.17 to 18.59 mg P kg-1 and 0.21-8.16 mg P kg-1, when distilled water and 10 mM CaCl2 solutions were applied, respectively and it was higher in sandy clay loam soils compared with clay soils. Among evaluated environmental soil P tests, PCaCl2-3h (P extracted by 10 mM CaCl2 for 3 h), PCaCl2-1h (P extracted by 10 mM CaCl2 for 1 h) were more accurate than other soil P tests for predicting P concentration in the leachates in both leaching solutions and accounting for 83% and 72% of variation of P concentration, respectively. The water extractable P (WEP) (r = 0.771) and Olsen P (POls)(r = 0.739) were significantly related to the leached P concentration using distilled water solution in a split line model, with a change point of 27.4 mg P kg-1 and 61.5 mg P kg-1, respectively. Various DPS were calculated and related to the leached P concentration. Based on P extracted by Mehlich-3 (PM3) and HCl (PHCl) and PSI, the change point of the relationship between leached P concentration and DPSM3-3 (PM3(PM3+PSI)*100) and DPSHCl-2 (PHCl(PHCl+PSI)*100) for both leaching solutions was approximately the same, thus a mean value of 49% for DPSM3-3 and 73% for DPSHCl-2 was obtained. Soils were grouped into four categories of increasing P leaching potential based on WEP, POls, and DPSM3-3. The results indicated that 8.00%-25.50% of the soil grouped in no risk category whereas 8.00%-13.70% of the soils fell into the high risk category. PMID- 28013074 TI - Efficient removal of oil from oil contaminated water by superhydrophilic and underwater superoleophobic nano/micro structured TiO2 nanofibers coated mesh. AB - In this report, we investigated the TiO2 nanofibers coated stainless steel mesh as a novel underwater superoleophobic membrane for the effective separation of contaminated oil-water mixtures. The membrane was fabricated by spray deposition of hydrothermally synthesized TiO2 nanofibers on stainless steel mesh. The fabricated membrane exhibits superhydrophilicity and supereleophobicity properties in air and underwater respectively allowing the separation of oil water efficiently. Randomly deposited TiO2 nanofibers on mesh exhibit rough surface property and hence superhydrophilic nature. Water oil separation efficiencies of ~90 and ~99% were achieved with this filter for less viscous and highly viscous oil respectively. Additionally, the TiO2 nanofibers coated mesh can degrade immiscible organic molecules due to photocatalytic activity of TiO2 nanofibers under UV light. As a result of self-cleaning property of TiO2 nanofibers coated mesh, the durability of the filter membrane is enhanced. PMID- 28013075 TI - Derivation of freshwater water quality criteria for dibutyltin dilaurate from measured data and data predicted using interspecies correlation estimate models. AB - Dibutyltin dilaurate (DBTL) is an organotin compound that has been widely detected in aquatic environments. However, the ecological risk assessment for DBTL is hard to perform due to the absence of water quality criteria (WQC) and lack of toxicity data. In this study, toxicity data were obtained from acute and chronic toxicity tests using aquatic species resident in China. Based on the species sensitivity distributions (SSDs) constructed from these test data, the acute water quality criterion (AWQC) and chronic water quality criterion (CWQC) were then derived to be 132 MUg/L and 31.9 MUg/L for DBTL. In order to valid the predicted data in the application to the protective criteria development and hazard assessment, the web-based interspecies correlation estimation (Web-ICE) system was used to estimate acute toxicities. Here two acute toxicity data groups for surrogate species were chosen from experimental data and QSAR Toolbox predicted data separately, giving estimated data for prediction species using Web ICE software. According to Kolmogorov-Smirnov test results, Web-ICE-based SSDs and measurement-based SSD were not significantly different. The results showed that the differences between measurement-based (132 MUg/L) and Web-ICE-based AWQCs (39.7 MUg/L and 58.5 MUg/L) were statistically acceptable. Under certain conditions, it is therefore worth considering using the QSAR Toolbox plus Web-ICE method here to provide a beneficial supplement for developing preliminarily screen level toxicities in WQC when little or no relevant information are available. Besides, the geographic distribution of species was demonstrated not to be a significant factor in SSD establishment and WQC derivation. PMID- 28013076 TI - Sorption and degradation of phthalate esters by a novel functional hyper-cross linked polymer. AB - A novel functional hyper-cross-linked polymer (NFHP) modified with trimethylamine was prepared. NFHP was characterized by FTIR, XPS, XRD, SEM and Micromeritics ASAP-2010 automatic surface area analysis instrument. Adsorption and hydrolysis degradation of phthalate acid esters (PAEs) by NFHP were also investigated as a function of temperature, equilibrium concentration and PAEs types. Results indicated that NFHP could adsorb and catalyze hydrolysis of PAEs simultaneously. There was a positive relationship between the removal capacity and temperature, equilibrium concentration, and PAEs hydrophobicity. However, the increase of PAEs equilibrium concentration and hydrophobicity resulted in the decreased level of their hydrolysis, while high temperature promoted the hydrolysis of PAEs. Film diffusion was the rate controlling step of the removal process. The apparent removal rate of PAEs increased as temperature increased due to the higher diffusion coefficient at higher temperature. The results of continuous fixed-bed runs demonstrated that NFHP was capable of synchronously removing PAEs and their hydrolysis products from tap water. In the effluent solution, the PAEs concentration was below the detection limit (0.01 mg/L) of HPLC within 1400 BVs. Moreover, the exhausted NFHP beads can be completely regenerated for repeated use. Physical adsorption, hydrolysis degradation and ion-exchange played significant roles in removing of PAEs and their hydrolysis products. The analysis of hydrolysis products, FTIR and XPS spectra proved that physical adsorption, hydrolysis and ion-exchange were the main removal mechanism. The results reported herein suggested that this novel material has a great potential in efficient removal of PAEs from wastewater. PMID- 28013077 TI - Single-stage versus two-stage anaerobic fluidized bed bioreactors in treating municipal wastewater: Performance, foulant characteristics, and microbial community. AB - This study examined the receptive performance, membrane foulant characteristics, and microbial community in the single-stage and two-stage anaerobic fluidized membrane bioreactor (AFMBR) treating settled raw municipal wastewater with the aims to explore fouling mechanisms and microbial community structure in both systems. Both AFMBRs exhibited comparable organic removal efficiency and membrane performances. In the single-stage AFMBR, less soluble organic substances were removed through biosorption by GAC and biodegradation than those in the two-stage AFMBR. Compared to the two-stage AFMBR, the formation of cake layer was the main cause of the observed membrane fouling in the single-stage AFMBR at the same employed flux. The accumulation rate of the biopolymers was linearly correlated with the membrane fouling rate. In the chemical-cleaned foulants, humic acid-like substances and silicon were identified as the predominant organic and inorganic fouants respectively. As such, the fluidized GAC particles might not be effective in removing these substances from the membrane surfaces. High-throughout pyrosequencing analysis further revealed that beta-Proteobacteria were predominant members in both AFMBRs, which contributed to the development of biofilms on the fluidized GAC and membrane surfaces. However, it was also noted that the abundance of the identified dominant in the membrane surface-associated biofilm seemed to be related to the permeate flux and reactor configuration. PMID- 28013078 TI - Toxicity of oil sands acid-extractable organic fractions to freshwater fish: Pimephales promelas (fathead minnow) and Oryzias latipes (Japanese medaka). AB - The Alberta oil sands are one of the largest global petroleum deposits and, due to non-release practices for oil sands process-affected waters, produced tailings are stored in large ponds. The acid extractable organic (AEO) compounds in oil sands process-affected water are of greatest concern due to their persistence and toxicity to a variety of aquatic biota. The present study evaluated the toxicity of the five AEO fractions to two fish species: Oryzias latipes (Japanese medaka) and Pimephales promelas (fathead minnow). The fractions (F1-F5) were comprised of AEO with increasing mean molecular weight and subsequent increases in cyclicity, aromaticity, degree of oxygenation, and heteroatom content. The lowest molecular weight fraction, F1, displayed the lowest acute toxicity to both fish species. For fathead minnow, F5 displayed the greatest toxic potency, while F2 to F4 displayed intermediate toxicities. For Japanese medaka, F2 and F3 displayed the greatest acute toxicities and F1, F4 and F5 were significantly less potent. Overall, fathead minnow were more acutely sensitive to AEO than Japanese medaka. The present study indicates that AEO toxicity may not be solely driven by a narcotic mode of action, but chemical composition such as aromaticity and heteroatom content and their relation to toxicity suggest other drivers indicative of additional modes of toxic action. PMID- 28013079 TI - Development of dual-fluorescence cell-based biosensors for detecting the influence of environmental factors on nanoparticle toxicity. AB - With the expanding use of engineered nanoparticles (NPs), development of a high throughput, sensitive method for evaluating NP safety is important. In this study, we developed cell-based biosensors to efficiently and conveniently monitor NP toxicity. The biosensor cells were obtained by transiently transfecting human cells with biosensor plasmids containing a mCherry gene regulated by an inducible promoter [an activator protein 1 (AP-1) promoter, an interleukin 8 (IL8) promoter, or a B cell translocation gene 2 (BTG2) promoter], with an enhanced green-fluorescent protein gene driven by the cytomegalovirus promoter as the internal control. After optimizing flow cytometric analysis, these dual fluorescence cell-based biosensors were capable of accurately and rapidly detecting NP toxicity. We found that the responses of AP-1, BTG2, and IL8 biosensors in assessing the toxicity of silver nanoparticles (Ag NPs) showed good dose-related increases after exposure to Ag NPs and were consistent with data acquired by conventional assays, such as western blot, real-time polymerase chain reaction, and immunofluorescence. Further investigation of the effects of environmental factors on Ag NP toxicity revealed that aging in water, co-exposure with fulvic acid, and irradiation with ultraviolet A light could affect Ag NP induced biosensor responses. These results indicated that these novel dual fluorescence biosensors can be applied to accurately and sensitively monitor NP toxicity. PMID- 28013080 TI - Bioavailability assessment of thiacloprid in soil as affected by biochar. AB - Biochars can significantly sorb pesticides, and reduce their bioavailability in agricultural soils. In this study, the effects of a type of biochar (BC500) on the sorption, degradation, bioaccumulation and bioavailability of thiacloprid, which is a commonly used insecticide, were investigated. The thiacloprid sorption constant (Kf values) increased by 14 times after 2% BC500 application, and the degradation of the insecticide decreased with increasing amounts of the biochars in the soil. Coupled with the exhaustive extraction and single-point Tenax method, the bioavailability of thiacloprid was predicted in the presence of the biochar. In soils amended with BC500, the thiacloprid concentrations accumulated in Tenax correlated well with those observed in earthworms (R2 = 0.887), whereas the concentrations extracted by exhaustive method followed a less significant relationship with those in earthworms (R2 = 0.624). The results of Tenax extractions and earthworm bioassays indicate that biochar reduces the bioavailability of thiacloprid in soil, but the delayed degradation and increased earthworm accumulation in aged biochar-amended soil imply that the environmental risks of biochar application to earthworms remain. PMID- 28013081 TI - Perceived barriers and facilitators of mental health service utilization in adult trauma survivors: A systematic review. AB - Many trauma survivors seem to be reluctant to seek professional help. The aim of the current review was to synthesize relevant literature, and to systematically classify trauma survivors' perceived barriers and facilitators regarding mental health service utilization. The systematic search identified 19 studies addressing military personnel and 17 studies with trauma survivors of the general population. The data analysis revealed that the most prominent barriers included concerns related to stigma, shame and rejection, low mental health literacy, lack of knowledge and treatment-related doubts, fear of negative social consequences, limited resources, time, and expenses. Perceived facilitators lack attention in research, but can be influential in understanding mental health service use. Another prominent finding was that trauma survivors face specific trauma-related barriers to mental health service use, especially concerns about re-experiencing the traumatic events. Many trauma survivors avoid traumatic reminders and are therefore concerned about dealing with certain memories in treatment. These perceived barriers and facilitators were discussed regarding future research and practical implications in order to facilitate mental health service use among trauma survivors. PMID- 28013082 TI - The need for a behavioural analysis of behavioural addictions. AB - This review discusses research on behavioural addictions (i.e. associative learning, conditioning), with reference to contemporary models of substance addiction and ongoing controversies in the behavioural addictions literature. The role of behaviour has been well explored in substance addictions and gambling but this focus is often absent in other candidate behavioural addictions. In contrast, the standard approach to behavioural addictions has been to look at individual differences, psychopathologies and biases, often translating from pathological gambling indicators. An associative model presently captures the core elements of behavioural addiction included in the DSM (gambling) and identified for further consideration (internet gaming). Importantly, gambling has a schedule of reinforcement that shows similarities and differences from other addictions. While this is more likely than not applicable to internet gaming, it is less clear whether it is so for a number of candidate behavioural addictions. Adopting an associative perspective, this paper translates from gambling to video gaming, in light of the existing debates on this matter and the nature of the distinction between these behaviours. Finally, a framework for applying an associative model to behavioural addictions is outlined, and it's application toward treatment. PMID- 28013083 TI - Secondary development in the stem: when Arabidopsis and trees are closer than it seems. AB - Secondary growth, the increase in girth of plant organs, is primarily driven by the vascular and cork cambium. In perennial dicotyledons and gymnosperms, it represents a major source of biomass accumulation in the form of wood. However, the molecular framework underlying secondary growth is largely based on studies in the annual herbaceous plant Arabidopsis thaliana. In this review, we will focus on a selection of major regulators of stem secondary growth, which have recently been shown to play a role in woody species. In particular, we will focus on thermospermine and its bivalent role in controlling xylem differentiation and cell proliferation and we will highlight the contributions of the different LRR Receptor-Like Kinase signaling hubs. PMID- 28013084 TI - Expression, purification and characterization of the authentic form of human growth hormone receptor antagonist G120R-hGH obtained in Escherichia coli periplasmic space. AB - The human growth hormone receptor antagonist G120R-hGH precludes dimerization of GH and prolactin receptors and consequently JAK/STAT signaling. Some modifications in this antagonist resulted in a drug specific for the GH receptor, called Pegvisomant (Somavert(r)). However, the original G120R-hGH is usually synthesized in bacterial cytoplasm as inclusion bodies, not being a commercial product. The present work describes the synthesis and characterization of G120R hGH secreted into bacterial periplasm and obtained with a vector based on a constitutive lambda-PL promoter. This antagonist can be useful for studies aiming at investigating the effects of a simultaneous inhibition of GH and prolactin signaling, as a potential anti-tumoral or anti-diabetic compound. G120R-hGH, synthesized using the W3110 E. coli strain, showed a yield of 1.34 +/- 0.24 MUg/ml/A600 (~0.79 mg G120R-hGH/g of wet weight cells) after cultivation at 30 degrees C up to 3 A600 units and induction at 37 degrees C, for 6 h, with final 4.3 +/- 0.3 A600. A laboratory scale purification was carried out using three chromatographic steps with a total yield of 32%, reaching 98% purity. The obtained protein was characterized by SDS-PAGE, Western Blotting, Mass spectrometry, RP-HPLC, HPSEC and in vitro proliferation bioassay. The proliferation assay, based on Ba/F3-LLP cells, shows that G120R-hGH (100 ng/ml) significantly inhibited (64%) the proliferative action of hGH (1 ng/ml). This is the first time that G120R-hGH is synthesized in bacterial periplasmic space and therefore correctly folded, without the initial methionine. The reasons for a divergent efficacy for antagonizing hGH versus hPRL is currently unknown and deserves further investigation. PMID- 28013085 TI - Efficient expression of recombinant human heavy chain ferritin (FTH1) with modified peptides. AB - Human heavy chain ferritin (FTH1) can self-assemble into a diameter of 12-nm spherical cage with an interior cavity of 8 nm in diameter. FTH1 has great potential as a nanocage in molecular imaging and drug delivery. Different peptides have been fused with FTH1 for targeting delivery; however, the expression of FTH1 modified with peptides in soluble form is not equivalent to natural FTH1. As shown in recent study, a novel scaffold protein --thioredoxin from the archaebacterium Pyrococcus furiosus (PfTrx)--exhibits a superior solubilization capacity and thermal stability [19]. Here we report a new construct (FTH1-PfTrx-His) that can be easily expressed and purified in Escherichia coli. Of note, different peptides inserted into FTH1-PfTrx-His did not influence the expression of proteins. Finally, the doxorubicin packaging ability of FTH1-PfTrx-His is comparable to natural FTH1. Our results showed that FTH1-PfTrx-His had a potential role as a novel peptide-modified ferritin carrier for drugs or imaging probes. PMID- 28013086 TI - Rational synthetic pathway refactoring of natural products biosynthesis in actinobacteria. AB - Natural products (NPs) and their derivatives are widely used as frontline treatments for many diseases. Actinobacteria spp. are used to produce most of NP antibiotics and have also been intensively investigated for NP production, derivatization, and discovery. However, due to the complicated transcriptional and metabolic regulation of NP biosynthesis in Actinobacteria, especially in the cases of genome mining and heterologous expression, it is often difficult to rationally and systematically engineer synthetic pathways to maximize biosynthetic efficiency. With the emergence of new tools and methods in metabolic engineering, the synthetic pathways of many chemicals, such as fatty acids and biofuels, in model organisms (e.g. Escherichia coli ), have been refactored to realize precise and flexible control of production. These studies also offer a promising approach for synthetic pathway refactoring in Actinobacteria. In this review, the great potential of Actinobacteria as a microbial cell factory for biosynthesis of NPs is discussed. To this end, recent progress in metabolic engineering of NP synthetic pathways in Actinobacteria are summarized and strategies and perspectives to rationally and systematically refactor synthetic pathways in Actinobacteria are highlighted. PMID- 28013087 TI - Psychometric properties of the written version of the autobiographical memory test in a japanese community sample. AB - The autobiographical memory test (AMT) is a widely used measure to assess the specificity of autobiographical memories. Reduced Autobiographical Memory Specificity (AMS) or increased overgeneralization of memories is considered as a cognitive hallmark of depression. Therefore, reduced AMS is the subject of much psychopathological research, and is a promising target for psychological interventions. Although considerable evidence has been gathered on the clinical relevance of reduced AMS over the past decades, studies on AMS have been mainly conducted in Western populations, and few have been conducted in Asian populations. This could be because of the unknown psychometric properties of the AMT given cultural and language differences. Therefore, the present study examined the psychometric properties of the AMT in a Japanese community sample (N=1240). Our data replicated that (a) the AMT has a uni-factorial structure; (b) AMS has a small but statistically significant negative correlation with depressive symptoms; (c) AMS shows a significant declining trend as a function of age, which influences the magnitude of the association between AMS and depressive symptoms in older adults. These findings suggest that the AMT has robust psychometric properties across different languages and cultural backgrounds. PMID- 28013089 TI - A GIS policy approach for assessing the effect of fertilizers on the quality of drinking and irrigation water and wellhead protection zones (Crete, Greece). AB - Fertilizers have undoubtedly contributed to the significant increase in yields worldwide and therefore to the considerable improvement of quality of life of man and animals. Today, attention is focussed on the risks imposed by agricultural fertilizers. These effects include the dissolution and transport of excess quantities of fertilizer major- and trace-elements to the groundwater that deteriorate the quality of drinking and irrigation water. In this study, a map for the Fertilizer Water Pollution Index (FWPI) was generated for assessing the impact of agricultural fertilizers on drinking and irrigation water quality. The proposed methodology was applied to one of the most intensively cultivated with tree crops area in Crete (Greece) where potential pollutant loads are derived exclusively from agricultural activities and groundwater is the main water source. In this region of 215 km2, groundwater sampling data from 235 wells were collected over a 15-year time period and analyzed for the presence of anionic (NuOmicron-3, PO-34) and cationic (K+1, Fe+2, Mn+2, Zn+2, Cu+2, B+3) fertilizer trace elements. These chemicals are the components of the primary fertilizers used in local tree crop production. Eight factors/maps were considered in order to estimate the spatial distribution of groundwater contamination for each fertilizer element. The eight factors combined were used to generate the Fertilizer Water Pollution Index (FWPI) map indicating the areas with drinking/irrigation water pollution due to the high groundwater contamination caused by excessive fertilizer use. Moreover, by taking into consideration the groundwater flow direction and seepage velocity, the pathway through which groundwater supply become polluted can be predicted. The groundwater quality results show that a small part of the study area, about 8 km2 (3.72%), is polluted or moderately polluted by the excessive use of fertilizers. Considering that in this area drinking water sources (wells) are located, this study highlights an analytic method for delineation wellhead protection zones. All these approaches were incorporated in a useful GIS decision support system that aids decision makers in the difficult task of protection groundwater resources. PMID- 28013088 TI - Risk of malignant childhood germ cell tumors in relation to demographic, gestational, and perinatal characteristics. AB - BACKGROUND: Childhood germ cell tumors (GCTs) are a rare assortment of neoplasms, with mostly unknown etiology, that are believed to originate very early in life. Few studies have examined risk factors by histologic subtype, despite evidence of different risk profiles. MATERIALS AND METHODS: In this population-based case control study, 451 childhood malignant GCT cases ages 0-5 years were identified from the California Cancer Registry. Differentiating between common histologic subtypes, we identified 181 yolk sac tumors, 216 teratomas, and 54 rarer subtypes. Cases were linked to their birth certificates and 271,381 controls, frequency matched by birth year, were randomly selected from California birthrolls to investigate the contributions of demographic, gestational, and pregnancy factors using unconditional logistic regression analysis. RESULTS: Compared to non-Hispanic whites, Asian/Pacific Islander children were at an increased risk for developing GCTs (odds ratio [OR]=1.94; 95% confidence interval [CI]=1.47, 2.56). Among pregnancy complications and procedures, yolk sac tumors were positively associated with the presence of fetopelvic disproportion (OR=2.97; 95% CI=1.55, 5.68), while teratomas were strongly associated with polyhydramnios or oligohydramnios (OR=14.76; 95% CI=7.21, 30.19) and the presence of an ear, face, or neck anomaly at birth (OR=93.70; 95% CI=42.14, 208.82). CONCLUSIONS: Malignant yolk sac tumors and malignant teratomas exhibited distinct demographic and gestational characteristics; additionally, complications in pregnancy and labor may be brought on by specific histologic subtypes. PMID- 28013090 TI - Walking duration and slope steepness determine the effect of downslope walking on the soleus H-reflex pathway. AB - The purpose of this study was to determine if the effect of downslope walking (DSW) on spinal excitability depends on walking duration and slope steepness, and if findings from the soleus (Sol) generalize to the tibialis anterior (TA). Sol and TA Hmax and Mmax were measured before and after four DSW doses (time/slope, min/%) on separate days (10/-15, 20/-15, 10/-25, 20/-25, n=14), and one 20-min bout of level walking (LW, n=12), always at 2.5 mph. Heart rate (HR) and ratings of perceived exertion (RPE) were measured during walking. DSW for all doses except 10/-15 caused greater Sol Hmax/Mmax depression than LW (p<=0.02), and 20/ 25 caused greater Hmax/Mmax depression than 10/-15 (p<=0.01). TA H-reflex curves were substantially smaller than Sol H-reflex curves, and this study was unable to detect an effect of LW or DSW on TA Hmax/Mmax. Although HR and RPE were significantly higher during DSW at -25% than at -15% slope, group HR and RPE nevertheless peaked at relatively low values of 101.4+/-14.2 bpm and 12.6+/-2.3, respectively. In conclusion, DSW duration and slope steepness interact to determine the magnitude of Sol H-reflex depression, but these effects do not generalize to the TA. PMID- 28013091 TI - Effects of LY466195, a selective kainate receptor antagonist, on ethanol preference and drinking in rats. AB - There is evidence that variation in the gene encoding a kainate receptor subunit contributes to alcohol dependence risk. Further, there is suggestive evidence that alcohol consumption is mediated, in part, by kainate receptors. In this study, we used a novel kainate receptor antagonist, LY466195, to examine the potential role of kainate receptors in alcohol drinking behavior using a rodent model of voluntary ethanol consumption. Male Sprague Dawley and Long Evans rats were given access to 20% ethanol using the intermittent two-bottle choice paradigm. Following 6 weeks of ethanol consumption, rats were pretreated with an acute dose of LY466195 (0, 4.0 and 10.0mg/kg, i.p.) prior to a two-bottle choice test session. Acute administration of LY466195 did not significantly affect ethanol-drinking behavior in Sprague Dawley rats. In contrast, Long Evans rats pretreated with 10.0mg/kg LY466195 showed a significant reduction in alcohol preference compared to vehicle-treated controls. Decreased alcohol preference in the Long Evans rats was associated with increased water intake and no change in the amount of ethanol consumed. Taken together, these results suggest that systemic administration of a selective kainate receptor antagonist reduces ethanol preference in rats, an effect that could be due to non-specific effects on overall drinking behavior. PMID- 28013092 TI - Overexpression of Mitofusin2 decreased the reactive astrocytes proliferation in vitro induced by oxygen-glucose deprivation/reoxygenation. AB - Glia scar is a hallmark in late-stage of brain stroke disease, which hinder axonal regeneration and neuronal repair. Mitofusin2 (Mfn2) is a newly found cellular proliferation inhibitor. This study is to elucidate the role of Mfn2 in reactive astrocytes induced by oxygen-glucose deprivation/reoxygenation(OGD/R) model in vitro. Up-expression in EdU staining and protein level of GFAP, PCNA and CyclinD1, demonstrates the distinct activation and proliferation of astrocytes after the stimulation of OGD/R. Meanwhile, Mfn2 was proved to be down-regulated both in gene and protein levels. Pretreatment of cells with adenoviral vector encoding Mfn2 gene increased Mfn2 expression and subsequently attenuated OGD induced astrocyte proliferation. Down-regulation of Ras-p-Raf1-p-ERK1/2 pathway and cell cycle arrest were found to be relevant. Together, these results suggested that overexpression of Mfn2 can effectively inhibit the proliferation of reactive astrogliosis, which might contribute to a promising therapeutic intervention in cerebral ischemic injury. PMID- 28013093 TI - Effects of preweaning environmental enrichment on hippocampus-dependent learning and memory in developing rats. AB - Previous studies have shown that environmental enrichment (EE) improves learning and memory in adult animals. However, the effects of preweaning EE (preEE) on hippocampus-dependent learning and memory as well as its possible mechanisms are poorly understood. Here we report that preEE enhanced the exploratory activity in rats immediately after weaning, and the EE group showed greater performance in a passive avoidance task than the control group (p<0.05), but not in the locomotion activity. Electrophysiology analysis showed that rats exposed to preEE exhibited larger field excitatory postsynaptic potentials after long-term potentiation induction than those in the control group (p<0.05). The protein levels of phosphorylated extracellular signal-regulated kinases as well as activity regulated cytoskeleton-associated protein were significantly upregulated in the preEE group compared to the control group (p<0.05). Our results indicate that preEE can enhance hippocampus-dependent learning and memory function as postweaning EE does, and the upregulated activation of the ERK signal transduction pathway may be the underlying molecular mechanism. PMID- 28013094 TI - Reasons for death in patients with sepsis and septic shock. AB - PURPOSE: Understanding the underlying cause of mortality in sepsis has broad implications for both clinical care and interventional trial design. However, reasons for death in sepsis remain poorly understood. We sought to characterize reasons for in-hospital mortality in a population of patients with sepsis or septic shock. MATERIALS AND METHODS: We performed a retrospective review of patients admitted to the intensive care unit with sepsis or septic shock who died during their index admission. Reasons for death were classified into 6 categories determined a priori by group consensus. Interrater reliability was calculated and Fleiss kappa reported. The associations between selected patient characteristics (eg, serum lactate) and reason for death were also assessed. RESULTS: One hundred fifteen patients were included. Refractory shock (40%) and comorbid withdrawal of care (44%) were the most common reasons for death. Overall interrater agreement was substantial (kappa = 0.61, P<.01). Lactate was higher in patients who died because of refractory shock as compared with those who died for other reasons (4.7 vs 2.8 mmol/L, P<.01). CONCLUSION: In this retrospective cohort, refractory shock and comorbid withdrawal of care were the most common reasons for death. Following prospective validation, the classification methodology presented here may be useful in the design/interpretation of trials in sepsis. PMID- 28013095 TI - Decreased high-density lipoprotein cholesterol level is an early prognostic marker for organ dysfunction and death in patients with suspected sepsis. AB - PURPOSE: We sought to determine whether an early high-density lipoprotein cholesterol (HDL-C) measurement at emergency department (ED) admission is prognostic of multiorgan dysfunction syndrome (MODS) and death in a suspected sepsis cohort. MATERIALS AND METHODS: Two hundred patients with clinically suspected sepsis were recruited at admission to our tertiary care hospital's ED. Lipids were measured at the time of first ED blood draw. Clinical data were collected via chart review. Primary outcomes of interest were development of MODS and 28-day mortality. Secondary outcomes included need for critical care, single organ failures, days alive and free of vasopressor and ventilator support, and 90 day mortality. RESULTS: High-density lipoprotein cholesterol was greatly decreased in patients who developed MODS and/or died and remained stable over the first week of admission. Receiver operator characteristic analysis demonstrated that HDL-C had superior predictive ability compared with all routine clinical markers for both development of MODS and 28-day mortality, and identified an HDL C cutoff of 25.1 mg/dL below which patients were at significantly greater risk for development of all adverse outcomes. CONCLUSIONS: Plasma HDL-C level was characterized by early decrease and high stability, and was the best prognostic marker for adverse outcomes in a suspected sepsis cohort. PMID- 28013096 TI - A systematic review of injecting-related injury and disease among people who inject drugs. AB - BACKGROUND: Non-viral injecting-related injuries and diseases (IRID), such as abscesses and vascular damage, can result in significant morbidity and mortality if untreated. There has been no systematic assessment of the prevalence of non viral IRID among people who inject drugs; this review aimed to address this gap, as well as identify risk factors for experience of specific IRID. METHODS: We searched MEDLINE, Embase and CINAHL databases to identify studies on the prevalence of, or risk factors for, IRID directly linked to injecting in samples of people who inject illicit drugs. RESULTS: We included 33 studies: 29 reported IRID prevalence in people who inject drugs, and 17 provided data on IRID risk factors. Skin and soft tissue infections at injecting sites were the most commonly reported IRID, with wide variation in lifetime prevalence (6-69%). Female sex, more frequent injecting, and intramuscular and subcutaneous injecting appear to be associated with skin and soft tissue infections at injecting sites. Cleaning injecting sites was protective against skin infections. Other IRID included infective endocarditis (lifetime prevalence ranging from 0.5-12%); sepsis (2-10%); bone and joint infections (0.5-2%); and thrombosis and emboli (3 27%). CONCLUSIONS: There were significant gaps in the data, including a dearth of research on prevalence of IRID in low- and middle-income countries, and potential risk and protective factors for IRID. A consistent approach to measurement, including standardised definitions of IRID, is required for future research. PMID- 28013097 TI - Toward precision smoking cessation treatment II: Proximal effects of smoking cessation intervention components on putative mechanisms of action. AB - BACKGROUND: Understanding how smoking cessation treatments exert their effects can inform treatment development and use. Factorial designs allow researchers to examine whether multiple intervention components affect hypothesized change mechanisms, and whether the affected mechanisms are related to cessation. METHODS: This is a secondary data analysis of smokers recruited during primary care visits (N=637, 55% women, 87% white) who were motivated to quit. Participants in this fractional factorial experiment were randomized to one level of each of six intervention factors: Prequit Nicotine Patch vs None, Prequit Nicotine Gum vs None, Preparation Counseling vs None, Intensive In-Person Counseling vs Minimal, Intensive Phone Counseling vs Minimal, and 16 vs 8 Weeks of Combination Nicotine Replacement (nicotine patch+nicotine gum). Data on putative mechanisms (e.g., medication use, withdrawal, self-efficacy) and smoking status were gathered using daily assessments and during follow-up assessment calls. RESULTS: Some intervention components influenced hypothesized mechanisms. Prequit Gum and Patch each reduced prequit smoking and enhanced prequit coping and self-efficacy. In-Person Counseling increased prequit motivation to quit, postquit self-efficacy, and postquit perceived intratreatment support. Withdrawal reduction and reduced prequit smoking produced the strongest effects on cessation. The significant effect of combining Prequit Gum and In-Person Counseling on 26-week abstinence was mediated by increased prequit self-efficacy. CONCLUSIONS: This factorial experiment identified which putative treatment mechanisms were influenced by discrete intervention components and which mechanisms influenced cessation. Such information supports the combined use of prequit nicotine gum and intensive in-person counseling as cessation interventions that operate via increased prequit self-efficacy. PMID- 28013098 TI - Toward precision smoking cessation treatment I: Moderator results from a factorial experiment. AB - BACKGROUND: The development of tobacco use treatments that are effective for all smokers is critical to improving clinical and public health. The Multiphase Optimization Strategy (MOST) uses highly efficient factorial experiments to evaluate multiple intervention components for possible inclusion in an optimized tobacco use treatment. Factorial experiments permit analyses of the influence of patient characteristics on main and interaction effects of multiple, relatively discrete, intervention components. This study examined whether person-factor and smoking characteristics moderated the main or interactive effects of intervention components on 26-week self-reported abstinence rates. METHODS: This fractional factorial experiment evaluated six smoking cessation intervention components among primary care patients (N=637): Prequit Nicotine Patch vs. None, Prequit Nicotine Gum vs. None, Preparation Counseling vs. None, Intensive Cessation In Person Counseling vs. Minimal, Intensive Cessation Telephone Counseling vs. Minimal, and 16 vs. 8 Weeks of Combination Nicotine Replacement Therapy (NRT; nicotine patch+nicotine gum). RESULTS: Both psychiatric history and smoking heaviness moderated intervention component effects. In comparison with participants with no self-reported history of a psychiatric disorder, those with a positive history showed better response to 16- vs. 8-weeks of combination NRT, but a poorer response to counseling interventions. Also, in contrast to light smokers, heavier smokers showed a poorer response to counseling interventions. CONCLUSIONS: Heavy smokers and those with psychiatric histories demonstrated a differential response to intervention components. This research illustrates the use of factorial designs to examine the interactions between person characteristics and relatively discrete intervention components. Future research is needed to replicate these findings. PMID- 28013099 TI - Gender differences in substance abuse, PTSD and intentional self-harm among veterans health administration patients. AB - BACKGROUND: Epidemiologic studies have reported substance abuse and posttraumatic stress disorder (PTSD) diagnoses as risk factors for suicide among Veterans Health Administration (VHA) patients. Research on risk factors for suicide may not generalize to our understanding of non-fatal intentional self-harm (ISH), given the evidence that these outcomes have unique risk factors. The aims of this study were to examine (1) gender-stratified rates of non-fatal ISH in VHA patients with alcohol abuse/dependence, drug abuse/dependence, and PTSD and (2) gender-stratified interaction between alcohol abuse and dependence and drug abuse and dependence and PTSD in predicting non-fatal ISH. METHODS: Participants include all VHA care users who received a PTSD diagnosis in Massachusetts from 2000 to 2008 (n=16,004) and an age- and gender-matched comparison group (n=52,502). Data were obtained from the VHA administrative registries. RESULTS: We found evidence of stronger interactions between substance abuse diagnoses and PTSD in predicting non-fatal ISH for females than for males. The interaction contrast (IC) for alcohol abuse and dependence and PTSD in predicting non-fatal ISH among female VHA patients was 62.35/100,000 person-years; for male VHA patients the comparable IC was 21.49/100,000 person-years. For female VHA patients the IC for drug abuse and dependence and PTSD predicting ISH was 256.33/100,000 person-years; no interaction was observed for male VHA patients. CONCLUSIONS: This study contributes to the scant literature on gender differences in substance abuse and PTSD among VHA patients. The findings highlight comorbid diagnoses as particularly important risk factors for non-fatal ISH among female VHA patients. PMID- 28013100 TI - The impact of highly active antiretroviral therapy on obstetric conditions: A review. AB - HIV is the leading cause of maternal and neonatal morbidity and mortality in resource constrained countries. Highly active antiretroviral treatment (HAART) initiated in pregnancy has now almost eliminated mother to child transmission of the virus, and is beginning to show the desired effect of reducing HIV related maternal mortality. By modulating host immunological responses HAART has the potential to alter infections during pregnancy, in addition to modifying clinical conditions such as preeclampsia. There is increasing evidence of the benefits of HAART given to pregnant women, however there is paucity of data that distinguishes HIV or HAART as the cause or exacerbation of pre-existing medical conditions or conditions specific to pregnancy. Anaemia is the commonest haematological disorder seen in HIV infected women and is more pronounced during pregnancy. The use of HAART has the potential to reduce the incidence and severity of the disease. Tuberculosis (TB) is the commonest chest infection amongst HIV infected people, being more common amongst pregnant than non-pregnant women. It is the leading cause of death from infectious diseases amongst women of reproductive age, and accounts for at least a quarter of all cases of maternal deaths associated with non-pregnancy related infections (NPRI). TB can manifest at any stage of the HIV infection, including during treatment with HAART. The latter (ie TB manifestation during HAART treatment) is thought to be the commonest manifestation of what is now known as immune reconstitution inflammatory syndrome (IRIS). In a South African report on maternal deaths, 55% of women who died of TB were on HAART, and a further 35% of women in the NPRI category died from other pneumoniae, notably pneumocystis jorevicci, which is also related to HIV infection. With regards to puerperal sepsis, studies are yet to show the impact of HAART independent of antibiotics in reducing infectious morbidity in HIV infected women. Preeclampsia has been associated with HIV infection, where most studies point towards a reduced risk in HIV infected women. There is increasing evidence that this reduced risk is reversed in the presence of HAART, with women accessing HAART having almost the same risk as HIV uninfected women. HIV or its treatment may be associated with increased risk of obstetric haemorrhage, and an increasing trend of obstetric haemorrhage as a cause of maternal deaths has been recently reported, proportionally in line with the introduction and increasing availability of HAART for pregnant women The mechanism by which this may occur remains elusive since pregnancy is a pro thrombotic state, however, HIV-related thrombocytopenia or vasculitis could account for the association, if found. HAART would then be expected to reverse this. HAART especially protease inhibitor containing combinations, have been associated with preterm deliveries and low birth weight, particularly when initiated prior to the index pregnancy. With these overall findings of the effect of HAART on obstetric conditions, this review is intended to encourage heightened surveillance of adverse events associated with HAART use in pregnant women. PMID- 28013101 TI - Ex vivo blood vessel bioreactor for analysis of the biodegradation of magnesium stent models with and without vessel wall integration. AB - : Current in vitro models fail in predicting the degradation rate and mode of magnesium (Mg) stents in vivo. To overcome this, the microenvironment of the stent is simulated here in an ex vivo bioreactor with porcine aorta and circulating medium, and compared with standard static in vitro immersion and with in vivo rat aorta models. In ex vivo and in vivo conditions, pure Mg wires were exposed to the aortic lumen and inserted into the aortic wall to mimic early- and long-term implantation, respectively. Results showed that: 1) Degradation rates of Mg were similar for all the fluid diffusion conditions (in vitro static, aortic wall ex vivo and in vivo); however, Mg degradation under flow condition (i.e. in the lumen) in vivo was slower than ex vivo; 2) The corrosion mode in the samples can be mainly described as localized (in vitro), mixed localized and uniform (ex vivo), and uniform (in vivo); 3) Abundant degradation products (MgO/Mg(OH)2 and Ca/P) with gas bubbles accumulated around the localized degradation regions ex vivo, but a uniform and thin degradation product layer was found in vivo. It is concluded that the ex vivo vascular bioreactor provides an improved test setting for magnesium degradation between static immersion and animal experiments and highlights its promising role in bridging degradation behavior and biological response for vascular stent research. STATEMENT OF SIGNIFICANCE: Magnesium and its alloys are candidates for a new generation of biodegradable stent materials. However, the in vitro degradation of magnesium stents does not match the clinical degradation rates, corrupting the validity of conventional degradation tests. Here we report an ex vivo vascular bioreactor, which allows simulation of the microenvironment with and without blood vessel integration to study the biodegradation of magnesium implants in comparison with standard in vitro test conditions and with in vivo implantations. The bioreactor did simulate the corrosion of an intramural implant very well, but showed too high degradation for non-covered implants. It is concluded that this system is in between static incubation and animal experiments concerning the predictivity of the degradation. PMID- 28013102 TI - Core-shell microparticles for protein sequestration and controlled release of a protein-laden core. AB - : Development of multifunctional biomaterials that sequester, isolate, and redeliver cell-secreted proteins at a specific timepoint may be required to achieve the level of temporal control needed to more fully regulate tissue regeneration and repair. In response, we fabricated core-shell heparin poly(ethylene-glycol) (PEG) microparticles (MPs) with a degradable PEG-based shell that can temporally control delivery of protein-laden heparin MPs. Core shell MPs were fabricated via a re-emulsification technique and the number of heparin MPs per PEG-based shell could be tuned by varying the mass of heparin MPs in the precursor PEG phase. When heparin MPs were loaded with bone morphogenetic protein-2 (BMP-2) and then encapsulated into core-shell MPs, degradable core shell MPs initiated similar C2C12 cell alkaline phosphatase (ALP) activity as the soluble control, while non-degradable core-shell MPs initiated a significantly lower response (85+19% vs. 9.0+4.8% of the soluble control, respectively). Similarly, when degradable core-shell MPs were formed and then loaded with BMP-2, they induced a ~7-fold higher C2C12 ALP activity than the soluble control. As C2C12 ALP activity was enhanced by BMP-2, these studies indicated that degradable core-shell MPs were able to deliver a bioactive, BMP-2-laden heparin MP core. Overall, these dynamic core-shell MPs have the potential to sequester, isolate, and then redeliver proteins attached to a heparin core to initiate a cell response, which could be of great benefit to tissue regeneration applications requiring tight temporal control over protein presentation. STATEMENT OF SIGNIFICANCE: Tissue repair requires temporally controlled presentation of potent proteins. Recently, biomaterial-mediated binding (sequestration) of cell-secreted proteins has emerged as a strategy to harness the regenerative potential of naturally produced proteins, but this strategy currently only allows immediate amplification and re-delivery of these signals. The multifunctional, dynamic core shell heparin-PEG microparticles presented here overcome this limitation by sequestering proteins through a PEG-based shell onto a protein-protective heparin core, temporarily isolating bound proteins from the cellular microenvironment, and re-delivering proteins only after degradation of the PEG-based shell. Thus, these core-shell microparticles have potential to be a novel tool to harness and isolate proteins produced in the cellular environment and then control when proteins are re-introduced for the most effective tissue regeneration and repair. PMID- 28013103 TI - Ebola virus VP35 blocks stress granule assembly. AB - Stress granules (SGs) are dynamic cytoplasmic aggregates of translationally silenced mRNAs that assemble in response to environmental stress. SGs appear to play an important role in antiviral innate immunity and many viruses have evolved to block or subvert SGs components for their own benefit. Here, we demonstrate that intracellular Ebola virus (EBOV) replication and transcription-competent virus like particles (trVLP) infection does not lead to SG assembly but leads to a blockade to Arsenite-induced SG assembly. Moreover we show that EBOV VP35 represses the assembly of canonical and non-canonical SGs induced by a variety of pharmacological stresses. This SG blockade requires, at least in part, the C terminal domain of VP35. Furthermore, results from our co-immunoprecipitation studies indicate that VP35 interacts with multiple SG components, including G3BP1, eIF3 and eEF2 through a stress- and RNA-independent mechanism. These data suggest a novel function for EBOV VP35 in the repression of SG assembly. PMID- 28013104 TI - The impact of nUrsiNg DEliRium Preventive INnterventions in the Intensive Care Unit (UNDERPIN-ICU): A study protocol for a multi-centre, stepped wedge randomized controlled trial. AB - BACKGROUND: Delirium is a common disorder in Intensive Care Unit (ICU) patients and is associated with serious short- and long-term consequences, including re intubations, ICU readmissions, prolonged ICU and hospital stay, persistent cognitive problems, and higher mortality rates. Considering the high incidence of delirium and its consequences, prevention of delirium is imperative. This study focuses on a program of standardized nursing and physical therapy interventions to prevent delirium in the ICU, called UNDERPIN-ICU (nUrsiNg DEliRium Preventive INterventions in the ICU). OBJECTIVE: To determine the effect of the UNDERPIN-ICU program on the number of delirium-coma-free days in 28days and several secondary outcomes, such as delirium incidence, the number of days of survival in 28 and 90days and delirium-related outcomes. DESIGN AND SETTING: A multicenter stepped wedge cluster randomized controlled trial. METHODS: Eight to ten Dutch ICUs will implement the UNDERPIN-ICU program in a randomized order. Every two months the UNDERPIN-ICU program will be implemented in an additional ICU following a two months period of staff training. UNDERPIN-ICU consists of standardized protocols focusing on several modifiable risk factors for delirium, including cognitive impairment, sleep deprivation, immobility and visual and hearing impairment. PARTICIPANTS: ICU patients aged >=18years (surgical, medical, or trauma) and at high risk for delirium, E-PRE-DELIRIC >=35%, will be included, unless delirium was detected prior ICU admission, expected length of ICU stay is less then one day or when delirium assessment is not possible. DISCUSSION: For every intervention the balance between putative benefit and potential unwanted side effects needs to be considered. In non-ICU patients, it has been shown that a similar program resulted in a significant reduction of delirium incidence and duration. Recent small studies using multi component interventions to prevent delirium in ICU patients have also shown beneficial effect, without unwanted side effects. We therefore feel that the proportionality of potential positive effects of the UNDERPIN-ICU program, weighed against potential unwanted side effects is favourable. Since this has not been rigorously proven in ICU patients, we will study the effects of this program in ICU patients using a stepped wedge design. TRIAL REGISTRATION: The study is registered in the clinical trials registry: https://clinicaltrials.gov/. REPORTING METHOD: Standard Protocol Items: Recommendations for Interventional Trails (SPIRIT). PMID- 28013105 TI - The effects of azacitidine on the response and prognosis of myelodysplastic syndrome and acute myeloid leukemia involving a bone marrow erythroblast frequency of >50. AB - We reviewed the cases of 68 consecutive patients who were diagnosed with myelodysplastic syndrome (MDS, n=61) or acute erythroleukemia (AEL, n=7) according to the World Health Organization (WHO) 2008 criteria and had previously been treated with azacitidine, a hypomethylating agent. Fifteen MDS patients had bone marrow erythroblast frequencies of >=50%, and 6 out of the 7 AEL patients were reclassified as MDS (refractory anemia with excess blasts [RAEB]-1: 1, RAEB 2: 5) according to the revised WHO 2016 criteria. There was no difference between the overall response ratio (41%), as determined by a hematological improvement in at least one of 3 lineages, of these erythroid rich patients and that of the control group, which comprised 46 MDS patients with bone marrow erythroblast frequencies of <50%. Three MDS patients that exhibited erythroid predominance achieved complete remission. The overall survival period (median: 15 months) of the erythroblast-predominant group was not inferior to that of the control group (median: 16 months). These results indicate that azacitidine is a promising treatment option for MDS/AEL irrespective of the numbers of erythroid cells in the patient's bone marrow. PMID- 28013106 TI - CPX-351 exhibits potent and direct ex vivo cytotoxicity against AML blasts with enhanced efficacy for cells harboring the FLT3-ITD mutation. AB - PURPOSE: Identify AML patients most likely to respond to CPX-351, a nano-scale liposome formulation containing cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio. METHODS: We examined the ex vivo cytotoxic activity of CPX-351 against leukemic cells isolated from 53 AML patients and an additional 127 samples including acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative neoplasms, or chronic lymphocytic leukemia/lymphoma. We assessed activity with respect to common molecular lesions and used flow cytometry to assess CPX-351 cellular uptake. RESULTS: AML specimen sensitivity to CPX-351 was similar across conventional risk groups. FLT3-ITD cases were five fold more sensitive to CPX-351. CPX-351 was active across other indications with nearly all cases exhibiting IC50 values markedly lower than reported 72-h plasma drug concentration in patients receiving CPX-351. The range and distribution of CPX-351 IC50 values were comparable for AML, CLL, and ALL, whereas MDS/MPN cases were less sensitive. CPX-351 uptake analysis revealed a correlation between uptake of CPX-351 and cytotoxic potency. CONCLUSIONS: Our findings are consistent with clinical data, in which CPX-351 activity is retained in high-risk AML patients. Ex vivo analysis of cytotoxic potency may provide a means to identify specific AML subsets, such as FLT3-ITD, that benefit most from CPX-351 and warrant additional clinical evaluation. PMID- 28013107 TI - The making of a population: Challenges, implications, and consequences of the quantification of social difference. AB - How do we make a difference? This paper traces the connections made between quantified knowledge, population health, and social justice by examining the efforts of population scientists to assess sexuality as a point of difference within population-based data systems, including on national health and social surveys, electronic medical records, and the Census. Population scientists emphasize the importance of measuring social difference in order to identify and remedy structural disadvantage. This evaluation requires the assessment of difference and the comparison of distinct groups across standardized outcome measures. In quantifying social difference, however, population scientists obscure or minimize several difficulties in creating comparable populations. I explore some of these challenges by highlighting three central tensions: the separation of difference from other aspects and categories of social experience, the reduction of difference through the use of one over several possible measures, and the enactment of difference as quantified knowledge loops back into society. As a theoretical inquiry into the form of social difference as it is conceptualized, operationalized, and materialized across the science-society nexus, this paper identifies the various commitments made during processes of scientific evaluation. By attending to the values and priorities that exist within and through practices of quantification, I aim to address the problem of measuring social difference as it pertains to the issues of social justice and health equity. PMID- 28013108 TI - Commentary to: Fergie, Hunt and Hilton "Social media as a space for support: Young adults' perspectives on user-generated content about diabetes and mental health." PMID- 28013109 TI - The impact of HTA and procurement practices on the selection and prices of medical devices. AB - Technological innovation in healthcare yields better health outcomes but also drives healthcare expenditure, and governments are struggling to maintain an appropriate balance between patient access to modern care and the economic sustainability of healthcare systems. Health Technology Assessment (HTA) and centralized procurement are increasingly used to govern the introduction and diffusion of new technologies in an effort to make access to innovation financially sustainable. However, little empirical evidence is available to determine how they affect the selection of new technologies and unit prices. This paper focuses on medical devices (MDs) and investigates the combined effect of various HTA governance models and procurement practices on the two steps of the MD purchasing process (i.e., selecting the product and setting the unit price). Our analyses are based on primary data collected through a national survey of Italian public hospitals. The Italian National Health Service is an ideal case study because it is highly decentralized and because regions have adopted different HTA governance models (i.e., regional, hospital-based, double-level or no HTA), often in combination with centralized regional procurement programs. Hence, the Italian case allows us to test the impact of different combinations of HTA models and procurement programs in the various regions. The results show that regional HTA increases the probability of purchasing the costliest devices, whereas hospital-based HTA functions more like a cost-containment unit. Centralized regional procurement does not significantly affect MD selection and is associated with a reduction in the MD unit price: on average, hospitals located in regions with centralized procurement pay 10.1% less for the same product. Hospitals located in regions with active regional HTA programs pay higher prices for the same device (+23.2% for inexpensive products), whereas hospitals that have developed internal HTA programs pay 8.3% on average more for the same product. PMID- 28013110 TI - Does the relationship between health-related quality of life and subjective well being change over time? An exploratory study among breast cancer patients. AB - It has been suggested recently that measures of Subjective Well-Being (SWB) instead of preferences could be employed to determine relative weights for the dimensions of health-related quality of life (HRQol) with the aim of developing health utility indexes for economic evaluation purposes. In this context, this paper addresses the possibility of reprioritization response shift in SWB. It examines whether the association between dimensions of HRQol and SWB changes over time in chronically ill patients. 215 women newly diagnosed for breast cancer in a French hospital between 2010 and 2012 completed the Satisfaction with Life Scale (SWLS) and the EORTC QLQ-C30 HRQol questionnaires over a two-year period. We estimated hierarchical random coefficients models for the repeated SWLS measures while allowing for time-varying parameters for the scales of the QLQ-C30 to test for reprioritization. Our findings suggest that women adapt to breast cancer by giving greater weight over time to the social dimension of HRQol. This possibility of reprioritization response shift should be considered in researches trying to develop SWB-based health utility values to inform the allocation of resources in health care. PMID- 28013111 TI - Risk of Rectal Cancer After Colectomy for Patients With Ulcerative Colitis: A National Cohort Study. AB - BACKGROUND & AIMS: Patients with ulcerative colitis (UC) have an increased risk of rectal cancer, therefore reconstruction with an ileal pouch-anal anastomosis (IPAA) generally is preferred to an ileorectal anastomosis (IRA) after subtotal colectomy. Similarly, completion proctectomy is recommended for patients with ileostomy and a diverted rectum, although this approach has been questioned because anti-inflammatory agents might reduce cancer risk. We performed a national cohort study in Sweden to assess the risk of rectal cancer in patients with UC who have an IRA, IPAA, or diverted rectum after subtotal colectomy. METHODS: We collected data from the Swedish National Patient Register for a cohort of 5886 patients with UC who underwent subtotal colectomy with an IRA, IPAA, or diverted rectum from 1964 through 2010. Patients who developed rectal cancer were identified from the Swedish National Cancer Register. The risk of rectal cancer was compared between this cohort and the general population by standardized incidence ratio analysis. RESULTS: Rectal cancer occurred in 20 of 1112 patients (1.8%) who received IRA, 1 of 1796 patients (0.06%) who received an IPAA, and 25 of 4358 patients (0.6%) with a diverted rectum. Standardized incidence ratios for rectal cancer were 8.7 in patients with an IRA, 0.4 in patients with an IPAA, and 3.8 in patients with a diverted rectum. Risk factors for rectal cancer were primary sclerosing cholangitis in patients with an IRA (hazard ratio, 6.12), and colonic severe dysplasia or cancer before subtotal colectomy in patients with a diverted rectum (hazard ratio, 3.67). CONCLUSIONS: In an analysis of the Swedish National Patient Register, we found that the risk for rectal cancer after colectomy in patients with UC is low, in relative and absolute terms, after reconstruction with an IPAA. An IRA and diverted rectum are associated with an increased risk of rectal cancer, compared with the general population, but the absolute risk is low. Patients and their health care providers should consider these findings in making decisions to leave the rectum intact, perform completion proctectomy, or reconstruct the colon with an IRA or IPAA. PMID- 28013113 TI - Direct-Acting Antiviral-Induced Hepatitis C Virus Clearance and Herpesvirus Reactivation: A Double Face of Janus? PMID- 28013112 TI - Urine Interleukin 18 and Lipocalin 2 Are Biomarkers of Acute Tubular Necrosis in Patients With Cirrhosis: A Systematic Review and Meta-analysis. AB - BACKGROUND & AIMS: Acute kidney injury (AKI) is a common complication in patients with cirrhosis that increases mortality. The most common causes of AKI in these patients are prerenal azotemia, acute tubular necrosis (ATN), and hepatorenal syndrome; it is important to determine the etiology of AKI to select the proper treatment and predict patient outcome. Urine biomarkers could be used to differentiate between patients with ATN and functional causes of AKI. We performed a systematic review and meta-analysis of published studies to determine whether urine levels of interleukin (IL)18 and lipocalin 2 or neutrophil gelatinase-associated lipocalin (NGAL) are associated with the development of ATN in patients with cirrhosis. METHODS: We searched MEDLINE, Scopus, ISI Web of Knowledge, and conference abstracts through December 31, 2015, for studies that assessed urine biomarkers for detection of acute kidney injury in patients with cirrhosis or reported an association between urine biomarkers and all-cause mortality in these patients. We included only biomarkers assessed in 3 or more independent studies, searching for terms that included urine biomarkers, cirrhosis, NGAL, and IL18. We calculated the pooled sensitivities and specificities for detection and calculated the area under the receiver operating characteristic curve (AUC) values using a bivariate logistic mixed-effects model. We used the chi2 test to assess heterogeneity among studies. RESULTS: We analyzed data from 8 prospective studies, comprising 1129 patients with cirrhosis. We found urine levels of the markers discriminated between patients with ATN and other types of kidney impairments, with AUC values of 0.88 for IL18 (95% confidence interval [CI], 0.79-0.97) and 0.89 for NGAL (95% CI, 0.84-0.94). Urine levels of IL18 identified patients who would die in the hospital or within 90 days (short-term mortality) with an AUC value of 0.76 (95% CI, 0.68-0.85); NGAL identified these patients with the same AUC (0.76; 95% CI, 0.71-0.82). CONCLUSIONS: In a systematic review and meta-analysis, we found that urine levels of IL18 and NGAL from patients with cirrhosis discriminate between those with ATN and other types of kidney impairments, with AUC values of 0.88 and 0.89, respectively. Urine levels of IL18 and NGAL identified patients with short-term mortality with an AUC value of 0.76. These biomarkers might be used to determine prognosis and select treatments for patients with cirrhosis. PMID- 28013114 TI - Diffuse Esophageal Glycogenic Acanthosis and Colon Polyposis in a Patient With Cowden Syndrome. PMID- 28013115 TI - Use of Proton Pump Inhibitors and Risks of Fundic Gland Polyps and Gastric Cancer: Systematic Review and Meta-analysis. PMID- 28013116 TI - Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression. AB - BACKGROUND & AIMS: Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics. METHODS: We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 427) or ulcerative colitis (n = 510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP associated with the use of corticosteroids, immune-suppressive medications, and biologics by patients with IBD. RESULTS: Our analysis included 937 patients and 6066 patient-years of follow-up evaluation (median, 14.8 y per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 patient-years of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 patient-years of exposure), and biologics (193 patients; 20.5%; 670 patient-years of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 patient-years of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 patient-years of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01-1.0) to corticosteroids, 0.1 (95% CI, 0.02-0.5) cases per 100 patient-years of exposure to immunosuppressants, 0.3 (95% CI, 0.04-1.1) cases per 100 patient years of exposure to biologics, 0.6 (95% CI, 0.01-3.2) cases per 100 patient years of exposure to double therapy, and 0 (95% CI, 0.0-19.5) cases per 100 patient-years of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 patient-years of exposure. CONCLUSIONS: In a population-based cohort of patients with IBD treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such as patients receiving triple therapy. PMID- 28013117 TI - Hepatocellular Carcinoma Is the Most Common Indication for Liver Transplantation and Placement on the Waitlist in the United States. AB - BACKGROUND & AIMS: Management strategies for patients with hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) have changed, along with liver allocation policies based on model for end-stage liver disease score. We investigated etiologic-specific trends in liver transplantation in the United States during different time periods. METHODS: We performed a retrospective study, using the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data, to identify all adult patients registered for liver transplantation in the United States from January 1, 2004, through December 31, 2015. For subjects listed with multiple diagnoses, HCC was considered the primary listing diagnosis. To determine whether availability of direct-acting antiviral agents, which began in 2011, affected pretransplant (death or drop-out) and post-transplant outcomes for patients with HCV infection, we compared data from the time periods of 2004 to 2010 and 2011 to 2014. We used competing-risk analysis to compare differences in end points between these periods. Differences between periods in pretransplantation and post transplantation outcomes were estimated using Kaplan-Maier analysis and compared using the log-rank test. Associations between year of listing and pre-liver transplant outcome, and year of liver transplant and survival after transplant, were examined using the log-rank test. Proportional hazard regression was used to evaluate the reliability of the time period effect with potential confounders. RESULTS: Among 109,018 registrants, 18.5% were registered for liver transplantation because of HCC. In 2015, HCC was the leading diagnosis among registrants (23.9% of registrations) and recipients (27.2% of recipients). Between 2004 and 2015, the ratio of registrants with vs without HCC increased 5.6 fold for patients with HCV infection, 1.9-fold for patients with hepatitis B virus (HBV) infection, 2.7-fold for patients with alcohol abuse, and 10.2-fold for patients with nonalcoholic steatohepatitis. After adjusting for covariates, we associated the period of 2011 to 2014 with a decreased probability that HCC registrants would undergo liver transplantation (hazard ratio [HR], 0.62; P < .0001). The period of 2011 to 2014 also was associated with a decreased probability of drop-out owing to deterioration or death from HCV-induced (HR, 0.90; P = .0003), HBV-induced (HR, 0.71; P = .002), or alcohol-induced (HR, 0.90; P = .01) liver disease, and an increased probability of delisting as a result of clinical improvement in patients with HCV infection (HR, 3.4; P < .0001), HBV infection (HR, 2.3; P = .004), or alcohol abuse (HR, 2.2; P < .0001). The period of 2011 to 2014 was associated with a decreased risk of graft loss or death, with the largest effect seen in HCV-infected recipients (HR, 0.76; P < .0001). CONCLUSIONS: HCC was the leading indication for liver transplantation in the United States in 2015. Despite this, the probability of liver transplantation decreased the most in registrants with HCC. Pretransplantation and post transplantation outcomes have improved, particularly in patients with HCV infection. PMID- 28013118 TI - Real World Data of Daclatasvir and Asunaprevir Combination Therapy for HCV Genotype 1b Infection in Patients With Renal Dysfunction. PMID- 28013119 TI - Giant Esophageal Fibrovascular Polyp: A Rare Cause of Dysphagia. PMID- 28013120 TI - Intraarticular and intravenous administration of 99MTc-HMPAO-labeled human mesenchymal stem cells (99MTC-AH-MSCS): In vivo imaging and biodistribution. AB - INTRODUCTION: Therapeutic application of intravenous administered (IV) human bone marrow-derived mesenchymal stem cells (ahMSCs) appears to have as main drawback the massive retention of cells in the lung parenchyma, questioning the suitability of this via of administration. Intraarticular administration (IAR) could be considered as an alternative route for therapy in degenerative and traumatic joint lesions. Our work is outlined as a comparative study of biodistribution of 99mTc-ahMSCs after IV and IAR administration, via scintigraphic study in an animal model. METHODS: Isolated primary culture of adult human mesenchymal stem cells was labeled with 99mTc-HMPAO for scintigraphic study of in vivo distribution after intravenous and intra-articular (knee) administration in rabbits. RESULTS: IV administration of radiolabeled ahMSCs showed the bulk of radioactivity in the lung parenchyma while IAR images showed activity mainly in the injected cavity and complete absence of uptake in pulmonary bed. CONCLUSIONS: Our study shows that IAR administration overcomes the limitations of IV injection, in particular, those related to cells destruction in the lung parenchyma. After IAR administration, cells remain within the joint cavity, as expected given its size and adhesion properties. ADVANCES IN KNOWLEDGE: Intra-articular administration of adult human mesenchymal stem cells could be a suitable route for therapeutic effect in joint lesions. IMPLICATIONS FOR PATIENT CARE: Local administration of adult human mesenchymal stem cells could improve their therapeutic effects, minimizing side effects in patients. PMID- 28013121 TI - Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for 211At labeling at high activities and radiation doses of 211At alpha particles. AB - INTRODUCTION: Alpha particles are radiation of high energy and short range, properties that can lead to radiolysis-mediated complications in labeling chemistry at the high radioactivity levels required for clinical application. In previous papers in this series, we have shown that radiation dose has a profound effect on the astatine species that are present in the labeling reaction and their suitability for the synthesis of N-succinimidyl 3-[211At]astatobenzoate. The purpose of this study was to evaluate the effects of adding N chlorosuccinimide (NCS) to the methanol solution used for initial isolation of 211At after distillation, a process referred to as 211At stabilization, on 211At chemistry after exposure to high radiation doses. METHODS: High performance liquid chromatography was used to evaluate the distribution of 211At species present in methanol in the 500-65,000Gy radiation dose range and the synthesis of SAB from N-succinimidyl 3-(tri-n-butylstannyl)benzoate in the 500-120,000Gy radiation dose range using different 211At timeactivity combinations under conditions with/without 211At stabilization. RESULTS: In the absence of NCS stabilization, a reduced form of astatine, At(2), increased with increasing radiation dose, accounting for about half the total activity by about 15,000Gy, while with stabilization, At(2) accounted for <10% of 211At activity even at doses >60,000Gy. SAB yields without stabilization rapidly declined with increasing dose, falling to ~20% at about 5000Gy while with stabilization, yields >80% were obtained with 211At solutions stored for more than 23h and receiving radiation doses >100,000Gy. CONCLUSIONS: Adding NCS to the methanol solution used for initial isolation of 211At is a promising strategy for countering the deleterious effects of radiolysis on 211At chemistry. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This strategy could facilitate the ability to perform 211At labeling at sites remote from its production and at the high activity levels required for clinical applications. PMID- 28013122 TI - Development of [11C]/[3H]THK-5351 - A potential novel carbon-11 tau imaging PET radioligand. AB - INTRODUCTION: Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of Abeta aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [18F]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [11C]THK-5351. In parallel, THK-5351 was also labeled with tritium ([3H]THK-5351) for use in in vitro autoradiography (ARG). METHODS: The carbon-11 labeling was performed starting with di-protected enantiomeric pure precursor - tert-butyl 5-(6-((2S)-3-fluoro-2-(tetrahydro-2H-pyran-2 yloxy)propoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [11C]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand, [11C]THK-5351 - (S)-1-fluoro-3-(2-(6-([11C]methylamino)pyridin-3 yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [3H]THK 5351 were undertaken using similar approach, resulting in [3H]THK-5351 with RCP >99.8% and specific radioactivity of 1.3GBq/MUmol. RESULTS: [11C]THK-5351 was produced in good yield (1900+/-355MBq), specific radioactivity (SRA) (361+/ 119GBq/MUmol at EOS+20min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [3H]THK-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [3H]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [3H]THK-5351 binding. PMID- 28013123 TI - A randomized, double-blind, placebo-controlled, crossover trial evaluating the effect of intranasal insulin on cognition and mood in individuals with treatment resistant major depressive disorder. AB - BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) is identified as a primary therapeutic target; no current treatment is approved for the treatment of cognitive dysfunction in MDD. We examined whether intranasal insulin offered a beneficial effect across measures of cognitive function in adults with MDD. METHODS: Thirty-five adults (18-65 years of age: 47.09+/-9.89) meeting criteria for a major depressive episode as per the Diagnostic and Statistical Manual (DSM)-IV-Treatment Revised were included in this randomized, double blind, placebo-controlled, crossover design study. Subjects were not stratified based on baseline cognitive deficit. Subjects were randomized to 4 weeks of either intranasal insulin 40 International Units (IU) taken four times a day (i.e., morning, afternoon, evening, and before bed) (QID) (n=19) or placebo (n=16). RESULTS: No between group differences were observed in change from baseline on total Montgomery Asberg Depression Rating Scale (MADRS) score (25.98+/-2.81), in either of the Positive or Negative subscales of the Positive and Negative Affect Schedule (PANAS), or on a global index of neurocognition. The possibility of practice and/or carry over effect could not be excluded. Methodological refinement (e.g., stratification of subjects based on baseline cognitive deficit) may have augmented assay sensitivity. CONCLUSION: Intranasal insulin did not demonstrate statistically significant improvements on overall mood, aspects of emotional processing, neurocognitive function, or self-reported quality of life patient reported outcomes. PMID- 28013124 TI - The role of affect in predicting depressive symptomatology in remitted recurrently depressed patients. AB - BACKGROUND: Major depressive disorder is an emotional disorder. It is important to improve our understanding of the role of affect in relapse/recurrence of depression. Therefore, this study examines whether affect plays a role in prospectively predicting depressive symptomatology and if there are indications for emotional scarring as a consequence of undergoing depressive episodes. METHODS: In 107 patients remitted from recurrent depression affect was examined in predicting depressive symptomatology as measured with the Inventory of Depressive Symptomatology - Self Report. Affect was measured with the Positive and Negative Affect Schedule and with a one item Visual Analogue Mood Scale. Indication of emotional scarring was examined by comparing number of previous depressive episodes to levels of affect. RESULTS: Less positive affect as assessed after remission predicted increased depressive symptomatology six months later, even after we controlled for baseline symptomatology. Negative affect also predicted depressive symptomatology six months later, but not after controlling for baseline depressive symptomatology. No relationship was found between affect and number of previous episodes. LIMITATIONS: All participants in this study had two or more previous depressive episodes and received CBT during the acute phase of their depression. The instruments that measured mood and affect were administered within 4 weeks of each other. CONCLUSIONS: Positive affect and negative affect as assessed after remission in recurrent depression can predict depressive symptomatology. Especially positive affect seems to play an independent role in predicting depressive symptomatology. Directly targeting positive affect in relapse prevention during remission might be a way to enhance treatment effects. PMID- 28013125 TI - The effect of treatment as usual on major depressive disorder: A meta-analysis. AB - BACKGROUND: Health-economic models are used to evaluate the long-term cost effectiveness of an intervention and typically include treatment as usual (TAU) as comparator. Part of the data used for these models are acquired from the literature and thus valid information is needed on the effects of TAU on depression. The aim of the current meta-analysis was to examine positive and negative outcomes of major depression for patients receiving TAU. METHODS: We conducted a systematic literature search in PubMed, EMBASE, PsycInfo, and the Cochrane Central Register of Controlled Trials. Eligible studies were randomized controlled trials including a TAU group for depression. The quality of the included studies was assessed using the criteria described in the "Risk of bias assessment tool". Four separate meta-analyses were performed to estimate remission, response, reliable change and deterioration rates at short-term (<=6 months from baseline). RESULTS: Thirty-eight studies including 2099 patients in the TAU were identified. Nine studies (24%) met five or six quality criteria, 17 studies (44%) met three or four quality criteria and 12 studies (32%) met one or two quality criteria. After adjusting for publication bias, the first meta analysis (n=33) showed that 33% of the patients remitted from depression. The second meta-analysis (n=13) demonstrated that 27% of the patients responded to treatment, meaning that their depressive symptom decreased at least 50% from baseline to follow-up measurement. The third meta-analysis (n=7) indicated that 31% of the patients showed a reliable change, meaning that their depressive symptoms improved more than expected by random variation alone. Finally, 12% of the patients deteriorated, meaning that their depressive symptoms became more severe. LIMITATIONS: Statistical heterogeneity was substantial in most analyses and was not fully explained by subgroup analyses. The quality of the included studies was moderate. This may result in overestimation of the true effects. CONCLUSIONS: The treatments labelled as TAU for depression were clinically and statistically heterogeneous. We demonstrated that a few patients benefited from TAU and a small number of patients suffered from worsened depressive symptoms at the short term. The results can be included in health-economic models that compare depression treatments to TAU. PMID- 28013126 TI - Optimization of MBR hydrodynamics for cake layer fouling control through CFD simulation and RSM design. AB - Membrane fouling is an important issue for membrane bioreactor (MBR) operation. This paper aims at the investigation and the controlling of reversible membrane fouling due to cake layer formation and foulants deposition by optimizing MBR hydrodynamics through the combination of computational fluid dynamics (CFD) and design of experiment (DOE). The model was validated by comparing simulations with measurements of liquid velocity and dissolved oxygen (DO) concentration in a lab scale submerged MBR. The results demonstrated that the sludge concentration is the most influencing for responses including shear stress, particle deposition propensity (PDP), sludge viscosity and strain rate. A medium sludge concentration of 8820mgL-1 is optimal for the reduction of reversible fouling in this submerged MBR. The bubble diameter is more decisive than air flowrate for membrane shear stress due to its role in sludge viscosity. The optimal bubble diameter was at around 4.8mm for both of shear stress and PDP. PMID- 28013127 TI - A discretized model for enzymatic hydrolysis of cellulose in a fed-batch process. AB - In the enzymatic hydrolysis of cellulose, several phenomena have been proposed to cause a decrease in the reaction rate with increasing conversion. The importance of each phenomenon is difficult to distinguish from batch hydrolysis data. Thus, kinetic models for the enzymatic hydrolysis of cellulose often suffer from poor parameter identifiability. This work presents a model that is applicable to fed batch hydrolysis by discretizing the substrate based on the feeding time. Different scenarios are tested to explain the observed decrease in reaction rate with increasing conversion, and comprehensive assessment of the parameter sensitivities is carried out. The proposed model performed well in the broad range of experimental conditions used in this study and when compared to literature data. Furthermore, the use of data from fed-batch experiments and discretization of the model substrate to populations was found to be very informative when assessing the importance of the rate-decreasing phenomena in the model. PMID- 28013128 TI - Acidogenic fermentation characteristics of different types of protein-rich substrates in food waste to produce volatile fatty acids. AB - In this study, tofu and egg white, representing typical protein-rich substrates in food waste based on vegetable and animal protein, respectively, were investigated for producing volatile fatty acids (VFAs) by acidogenic fermentation. VFA production, composition, conversion pathways and microbial communities in acidogenesis from tofu and egg white with and without hydrothermal (HT) pretreatment were compared. The results showed HT pretreatment could improve the VFA production of tofu but not for egg white. The optimum VFA yields were 0.46g/gVS (tofu with HT) and 0.26g/gVS (egg white without HT), respectively. Tofu could directly produce VFAs through the Stickland reaction, while egg white was converted to lactate and VFAs simultaneously. About 30-40% of total protein remained in all groups after fermentation. Up to 50% of the unconverted soluble protein in the HT groups was protease. More lactate-producing bacteria, mainly Leuconostoc and Lactobacillus, were present during egg white fermentation. PMID- 28013129 TI - Microbial community analysis of bulk sludge/cake layers and biofouling-causing microbial consortia in a full-scale aerobic membrane bioreactor. AB - Pyrosequencing was used to investigate biofouling-causing microbial consortia at the community level in bulk sludge and cake layers within a full-scale membrane bioreactor (MBR). The analysis revealed Chao's estimates of total operational taxonomic units (OTUs) of 1726, 1806, and 1362 for bulk sludge, cake outer layer, and cake inner layer, respectively. The bulk sludge and cake outer layer OTUs clustered together, whereas the cake inner layer OTUs formed a separate group, indicating that environmental conditions affected the microbial community composition within the MBR. Bacteroidetes, Proteobacteria, and Chloroflexi were the dominant phyla in both the bulk sludge and the cake layers. Comparison at the genus level showed twelve distinct genera in the cake layers that were absent in bulk sludge. Twenty distinct genera were recorded in the inner cake layer. Those genera are likely the microbial colonization pioneers in full-scale membrane bioreactors. PMID- 28013130 TI - Biosynthesis of uniformly labeled 13C- and 14C-arachidonic acid in Mortierella alpina. AB - Arachidonic acid (ARA) is one of the most abundant polyunsaturated fatty acids (PUFAs) in the mammalian brain. Many enzymatically- and nonenzymatically-produced metabolic products have important and potent pharmacological properties. However, uniformly isotope labeled forms of ARA are not commercially available for studying the metabolic fates of ARA. This study describes a simple and efficient protocol for the biosynthesis of U-13C-ARA from U-13C-glucose, and U-14C-ARA from U-14C-glucose by Mortierella alpina. The protocols yield approximately 100nmol quantities of U-13C-ARA with an isotopic purity of 95% from a 500MUl batch volume, and approximately 2MUCi quantities of U-14C-ARA with an apparent specific activity in excess of 1200Ci/mol from a 250MUl batch volume. PMID- 28013131 TI - Effect of various types of thermal pretreatment techniques on the hydrolysis, compositional analysis and characterization of water hyacinth. AB - The aim of this work was to study the effect of four different types of thermal pretreatment techniques i.e., hot air oven, microwave, autoclave and hot water bath on the hydrolysis, compositional analysis and characterization of water hyacinth. To determine the most efficient thermal pretreatment technique exhibiting enhanced solubilisation. Highest solubilisation was achieved by hot air oven (55.5%), followed by microwave, hot water bath and autoclave. Bio chemical methane potential (BMP) test of hot air oven pretreated and untreated water hyacinth was conducted. Cumulative methane production of 3039+/-32mLCH4/gVS was achieved by hot air oven pretreated water hyacinth at 90 degrees C for 1h which was way higher than the cumulative methane production of untreated water hyacinth 2396+/-19mLCH4/gVS on the 35th day. Compositional analysis and characterization of water hyacinth were also investigated to study the changes in the pretreated samples. PMID- 28013132 TI - Improving cellulase productivity of Penicillium oxalicum RE-10 by repeated fed batch fermentation strategy. AB - Medium optimization and repeated fed-batch fermentation were performed to improve the cellulase productivity by P. oxalicum RE-10 in submerged fermentation. First, Plackett-Burman design (PBD) and central composite design (CCD) were used to optimize the medium for cellulase production. PBD demonstrated wheat bran and NaNO3 had significant influences on cellulase production. The CCD results showed the maximum filter paper activity (FPA) production of 8.61U/mL could be achieved in Erlenmeyer flasks. The maximal FPA reached 12.69U/mL by submerged batch fermentation in a 7.5-L stirred tank, 1.76-fold higher than that on the original medium. Then, the repeated fed-batch fermentation strategy was performed successfully for increasing the cellulase productivity from 105.75U/L/h in batch fermentation to 158.38U/L/h. The cellulase activity and the glucan conversion of delignined corn cob residue hydrolysis had no significant difference between the enzymes sampled from different cycles of the repeated fed-batch fermentation and that from batch culture. PMID- 28013133 TI - Integrated approach for selecting efficient Saccharomyces cerevisiae for industrial lignocellulosic fermentations: Importance of yeast chassis linked to process conditions. AB - In this work, four robust yeast chassis isolated from industrial environments were engineered with the same xylose metabolic pathway. The recombinant strains were physiologically characterized in synthetic xylose and xylose-glucose medium, on non-detoxified hemicellulosic hydrolysates of fast-growing hardwoods (Eucalyptus and Paulownia) and agricultural residues (corn cob and wheat straw) and on Eucalyptus hydrolysate at different temperatures. Results show that the co consumption of xylose-glucose was dependent on the yeast background. Moreover, heterogeneous results were obtained among different hydrolysates and temperatures for each individual strain pointing to the importance of designing from the very beginning a tailor-made yeast considering the specific raw material and process. PMID- 28013134 TI - Production of a generic microbial feedstock for lignocellulose biorefineries through sequential bioprocessing. AB - Lignocellulosic materials, mostly from agricultural and forestry residues, provide a potential renewable resource for sustainable biorefineries. Reducing sugars can be produced only after a pre-treatment stage, which normally involves chemicals but can be biological. In this case, two steps are usually necessary: solid-state cultivation of fungi for deconstruction, followed by enzymatic hydrolysis using cellulolytic enzymes. In this research, the utilisation of solid state bioprocessing using the fungus Trichoderma longibrachiatum was implemented as a simultaneous microbial pretreatment and in-situ enzyme production method for fungal autolysis and further enzyme hydrolysis of fermented solids. Suspending the fermented solids in water at 50 degrees C led to the highest hydrolysis yields of 226mg/g reducing sugar and 7.7mg/g free amino nitrogen (FAN). The resultant feedstock was shown to be suitable for the production of various products including ethanol. PMID- 28013135 TI - Effects of magnetic nanoparticles on aerobic granulation process. AB - A novel granulation strategy by introducing magnetic nanoparticles (MNPs) into activated sludge system was investigated in this study. The study of the physicochemical characteristics (appearances, sizes, sludge volume index, and chemical oxygen demand) demonstrated that MNPs could decrease the granulation time and improve the retention of biomass, meanwhile enhanced the compact structure of the granules. The secretion and functional groups especially OH and CO of extracellular polymeric substances (EPS) also had significant changes under the long-term influence of MNPs. The contents of proteins (PN) and polysaccharides (PS) in R2 (with MNPs) were 95.7523mg/gVSS and 43.7129mg/gVSS, while in R1 (without MNPs) they were 85.7523mg/gVSS and 32.8632mg/gVSS, respectively. The contact angles of sludge against water dramatically increased with the increase of MNPs concentration, which means that the addition of MNPs could improve the sludge surface hydrophobicity, playing a positive role in the aggregation process. PMID- 28013136 TI - Enhanced hydrogen production of Enterobacter aerogenes mutated by nuclear irradiation. AB - Nuclear irradiation was used for the first time to generate efficient mutants of hydrogen-producing bacteria Enterobacter aerogenes, which were screened with larger colour circles of more fermentative acid by-products. E. aerogenes cells were mutated by nuclear irradiation of 60Co gamma-rays. The screened E. aerogenes ZJU1 mutant with larger colour circles enhanced the hydrogenase activity from 89.8 of the wild strain to 157.4mLH2/(gDWh). The hereditary stability of the E. aerogenes ZJU1 mutant was certified after over ten generations of cultivation. The hydrogen yield of 301mLH2/gglucose with the mutant was higher by 81.8% than that of 166mL/gglucose with the wild strain. The peak hydrogen production rate of 27.2mL/(L.h) with the mutant was higher by 40.9% compared with that of 19.3mL/(L.h) with the wild strain. The mutant produced more acetate and butyrate but less ethanol compared with the wild strain during hydrogen fermentation. PMID- 28013137 TI - Performance evaluation of Malathion biodegradation in batch and continuous packed bed bioreactor (PBBR). AB - The aim of this work was to study the biodegradation of Malathion in batch and continuous packed bed (Polyurethane foam; PUF) bioreactor (PBBR). After 10days, 89% Malathion removal was observed in batch PBBR. Continuous PBBR was operated at various flow rates (5-30mL/h) under optimum condition over a period of 75days. Inlet loading rates and elimination capacities were observed in the range of 36 216 and 7.20-145.4mg/L/day with an average removal efficiency of more than 90% under steady state conditions. GC/MS analysis confirms phosphorodithionicacid,O,O,S-trimethylester and diethylmercaptosuccinate as metabolites. Biodegradation of Malathion under inhibitory and non-inhibitory conditions was studied using Monod and Andrew-Haldane models and the kinetic constants were calculated and found to be MUmax: 0.271 per day; Ks: 126.3mg/L using Monod and MUmax: 0.315 per day; Ks: 151.32mg/L; Ki: 594.75mg/L using Andrew Haldane models. PMID- 28013138 TI - Production of FucoPol by Enterobacter A47 using waste tomato paste by-product as sole carbon source. AB - Out-of-specification tomato paste, a by-product from the tomato processing industry, was used as the sole substrate for cultivation of the bacterium Enterobacter A47 and production of FucoPol, a value-added fucose-rich extracellular polysaccharide. Among the different tested fed-batch strategies, pH stat, DO-stat and continuous substrate feeding, the highest production (8.77gL-1) and overall volumetric productivity (2.92gL-1d-1) were obtained with continuous substrate feeding at a constant flow rate of 11gh-1. The polymer produced had the typical FucoPol composition (37mol% fucose, 27mol% galactose, 23mol% glucose and 12mol% glucuronic acid, with an acyl groups content of 13wt%). The average molecular weight was 4.4*106Da and the polydispersity index was 1.2. This study demonstrated that out-of-specification tomato paste is a suitable low-cost substrate for the production of FucoPol, thus providing a route for the valorization of this by-product into a high-value microbial product. PMID- 28013139 TI - Using polyvinylpyrrolidone to enhance the enzymatic hydrolysis of lignocelluloses by reducing the cellulase non-productive adsorption on lignin. AB - Polyvinylpyrrolidone (PVP) is an antifouling polymer to resist the adsorption of protein on solid surface. Effects of PVP on the enzymatic hydrolysis of pretreated lignocelluloses and its mechanism were studied. Adding 1g/L of PVP8000, the enzymatic digestibility of eucalyptus pretreated by dilute acid (Eu DA) was increased from 28.9% to 73.4%, which is stronger than the classic additives, such as PEG, Tween and bovine serum albumin. Compared with PEG4600, the adsorption of PVP8000 on lignin was larger, and the adsorption layer was more stable and hydrophilic. Therefore, PVP8000 reduced 73.1% of the cellulase non productive adsorption on lignin and enhanced the enzymatic hydrolysis of lignocelluloses greatly. PMID- 28013140 TI - Assessment of municipal wastewaters at various stages of treatment process as potential growth media for Chlorella sorokiniana under different modes of cultivation. AB - Wastewater utilization for microalgal biomass production is potentially the most economical route for its fuel and feed applications. In this study, suitability of various wastewater streams within a domestic wastewater treatment plant was evaluated for microalgal cultivation. Pre-treatment methods were evaluated to minimize bacterial load. Biomass, cell physiology, nutrient removal efficiencies and biochemical constituents of Chlorella sorokiniana were investigated in influent (INF) and anaerobic tank centrate (AC) under mixotrophic (Mixo) and heterotrophic (Hetero) cultivation. Promising biomass (77.14mgL-1d-1), lipid (24.91mgL-1d-1), protein (22.36mgL-1d-1) and carbohydrate (20.10mgL-1d-1) productivities were observed in Mixo AC with efficient ammonium (94.29%) and phosphate (83.30%) removal. Supplementation of urea at a concentration of 1500mgL 1 further enhanced biomass (162.50mgL-1d-1), lipid (24.91mgL-1d-1), protein (22.36mgL-1d-1) and carbohydrate (20.10mgL-1d-1) productivities in Mixo AC. Urea supplemented mixotrophic cultivation of microalgae in AC is developed as a biomass production strategy. PMID- 28013141 TI - Closed nutrient recycling via microbial catabolism in an eco-engineered self regenerating mixed anaerobic microbiome for hydrogenotrophic methanogenesis. AB - A novel eco-engineered mixed anaerobic culture was successfully demonstrated for the first time to be capable of continuous regeneration in nutrient limiting conditions. Microbial catabolism has been found to support a closed system of nutrients able to enrich a culture of lithotrophic methanogens and provide microbial cell recycling. After enrichment, the hydrogenotrophic species was the dominating methanogens while a bacterial substratum was responsible for the redistribution of nutrients. q-PCR results indicated that 7% of the total population was responsible for the direct conversion of the gases. The efficiency of H2/CO2 conversion to CH4 reached 100% at a gassing rate of above 60v/v/d. The pH of the culture media was effectively sustained at optimal levels (pH 7-8) through a buffering system created by the dissolved CO2. The novel approach can reduce the process nutrient/metal requirement and enhance the environmental and financial performance of hydrogenotrophic methanogenesis for renewable energy storage. PMID- 28013142 TI - Preventing distracted driving among college students: Addressing smartphone use. AB - Based on the National Highway Traffic Safety Association's (NHTSA) Report, fatalities due to distracted driving are on the rise and the highest proportion of fatalities by age group is the 20-29 year old category. To date little has been done to educate college students about the dangers of distracted driving and engage these students in promoting a safe driving culture. Intervening among college students has the potential for making real-time behavior change, can foster a lifetime of safe driving habits among these students, and can help contribute to a culture of safe driving that can be created and sustained through positive messages from peers. The goals of this study were to develop, implement and evaluate a distracted driving presentation for college students to change knowledge, attitude and behavior on distracted driving. A 30-min, multi-media presentation on distracted driving was presented to 19 colleges and universities, totaling 444 college students (mean age 23.7+/-7.0 years of age, 61% females, 39% males). Students completed three surveys: prior to the workshop (interview 1), immediately after the workshop (interview 2), and 3 months following the workshop (interview 3). We assessed changes between interview 1 and interview 2 and found 15 of the 15 attitude-knowledge based questions significantly improved after the course. In addition, we assessed changes from interviews 1 and 3, and found 11 of the 15 attitude-knowledge based questions maintained their significance. Responses to behavior related questions at three months were also compared to baseline, and significant improvements were found for 12 of the 14 questions. While this study was successful in improving the short-term attitude-knowledge and behaviors on distracted driving, work is needed to sustain (and evaluate) long-term effects. PMID- 28013143 TI - Bendiocarb induced histopathological and biochemical alterations in rat liver and preventive role of vitamins C and E. AB - In this study, biochemical changes and histological structure of rat liver after bendiocarb administration and possible preventive effects of vitamins C and E were studied. The animals were given with bendiocarb, vitamin C and vitamin E, daily 0,8mg/kg of body weight (bw), 100mg/kg-bw and 100mg/kg-bw for 28days, respectively. Lipid peroxidation, antioxidant enzyme activities, histological alterations and antioxidant capacity assays of liver and also liver function tests and lipid profile were measured. Bendiocarb treatment decreased the antioxidant enzyme activities, FRAP and TEAC values and increased malondialdehyde levels compared to control. Also, there were statistically significant alterations in liver function tests, lipid profile parameters and histopathological changes in bendiocarb treated groups. Vitamins C and E showed protective effects against examining parameters. According to results we can say that co-treatment of vitamin C and vitamin E may be more effective than use of them alone. PMID- 28013144 TI - Effect of temperature on beam damage of asbestos fibers in the transmission electron microscope (TEM) at 100kV. AB - Damage to asbestos fibers by the transmission electron microscope (TEM) electron beam is a known limitation of this powerful method of analysis. Although it is often considered only in terms of loss of crystallinity, recent studies have shown that the damage may also change the elemental composition of fibers, thus causing significant identification errors. In this study, the main objective was to assess whether temperature is a factor influencing damage to asbestos fibers and, if so, how it can be used to minimize damage. It was found that lowering the temperature to 123K can inhibit, for a given time, the manifestation of the damage. The significant decrease of atom diffusion at low temperature momentarily prevents mass loss, greatly reducing the possibility of misidentification of anthophyllite asbestos fibers. The results obtained in this study strongly suggest that the predominant mechanism damage is probably related to the induced electric-field model relegating radiolysis to the status of a subsidiary damage mechanism. PMID- 28013145 TI - ISO-MANM: An imitation based optimization tool for multilayer microwave absorbers. AB - We investigate the performance of 109 types of composition with complex permittivity and permeability properties in the frequency range of 1-12GHz. The components of these compositions are based on conductive and nonconductive polymer composites, ferrites, hexaferrites, and carbon materials. A new swarm based algorithm has been introduced to solve microwave absorbing nanomaterials (MANM) problem, called Imitation Based Optimization (ISO). The individuals in the ISO imitate each other and move to better locations. ISO has high ability to trade-off between the exploration and exploitation with setting the input parameters. Also, it can simultaneously deal with contentious and discrete spaces. The results show that our proposed method has high quality outcomes and can be used in various applications. Various outputs will be achieved by the presented tool for the aforementioned compositions as a general reference. Considering the ability of the presented tool for selecting layer priority, layer arrangement, layer thickness, frequency range, and incidence angles, a variety of analyses can be carried out. Another ability of the presented tool is analysis of the reflection loss at different incident angles in the microwave frequency range. Using the introduced tool, the reflection loss with TM and TE polarization analysis also can be calculated. PMID- 28013146 TI - Rational design of cyclic peptides to disrupt TGF-Beta/SMAD7 signaling in heterotopic ossification. AB - The human TGF-beta/SMAD7 signaling has been recognized as an attractive target of heterotopic ossification (HO). Here, we report a successful rational design of cyclic peptides to disrupt the signaling pathway by targeting TGF-beta-receptor complex. The intermolecular interaction between TGF-beta and its cognate receptor is characterized in detail using molecular dynamics simulation, binding energetic analysis, and alanine scanning. With the computational analysis a binding loop of receptor protein is identified that plays an essential role in the peptide mediated TGF-beta-receptor interaction. Subsequently, the loop is stripped from the protein context to generate a linear peptide segment, which possesses considerable flexibility and intrinsic disorder, and thus would incur a large entropy penalty upon binding to TGF-beta. In order to minimize the unfavorable entropic effect, the linear peptide is cyclized by adding a disulfide bond between the N- and C-terminal cysteine residues of the peptide, resulting in a cyclic peptide. In vitro fluorescence anisotropy assays substantiate that the cyclic peptide can bind tightly to TGF-beta with determined Kd value of 54MUM. We also demonstrated that structural optimization can further improve the peptide affinity by site-directed mutagenesis of selected residues based on the computationally modeled complex structure of TGF-beta with the cyclic peptide. PMID- 28013147 TI - Hexim1 heterozygosity stabilizes atherosclerotic plaque and decreased steatosis in ApoE null mice fed atherogenic diet. AB - Hexim-1 is an inhibitor of RNA polymerase II transcription elongation. Decreased Hexim-1 expression in animal models of chronic diseases such as left ventricular hypertrophy, obesity and cancer triggered significant changes in adaptation and remodeling. The main aim of this study was to evaluate the role of Hexim1 in lipid metabolism focused in the progression of atherosclerosis and steatosis. We used the C57BL6 apolipoprotein E (ApoE null) crossed bred to C57BL6Hexim1 heterozygous mice to obtain ApoE null - Hexim1 heterozygous mice (ApoE-HT). Both ApoE null backgrounds were fed high fat diet for twelve weeks. Then, we evaluated lipid metabolism, atherosclerotic plaque formation and liver steatosis. In order to understand changes in the transcriptome of both backgrounds during the progression of steatosis, we performed Affymetrix mouse 430 2.0 microarray. After 12 weeks of HFD, ApoE null and ApoE-HT showed similar increase of cholesterol and triglycerides in plasma. Plaque composition was altered in ApoE-HT. Additionally, liver triglycerides and steatosis were decreased in ApoE-HT mice. Affymetrix analysis revealed that decreased steatosis might be due to impaired inducible SOCS3 expression in ApoE-HT mice. In conclusion, decreased Hexim-1 expression does not alter cholesterol metabolism in ApoE null background after HFD. However, it promotes stable atherosclerotic plaque and decreased steatosis by promoting the anti-inflammatory TGFbeta pathway and blocking the expression of the inducible and pro-inflammatory expression of SOCS3 respectively. PMID- 28013148 TI - Imaging In focus: Reflected light imaging: Techniques and applications. AB - Reflectance imaging is a broad term that describes the formation of images by the detection of illumination light that is back-scattered from reflective features within a sample. Reflectance imaging can be performed in a variety of different configurations, such as confocal, oblique angle illumination, structured illumination, interferometry and total internal reflectance, permitting a plethora of biomedical applications. Reflectance imaging has proven indispensable for critical investigations into the safety and understanding of biomedically and environmentally relevant nano-materials, an area of high priority and investment. The non-destructive in vivo imaging ability of reflectance techniques permits alternative diagnostic strategies that may eventually facilitate the eradication of some invasive biopsy procedures. Reflectance can also provide additional structural information and clarity necessary in fluorescent based in vivo studies. Near-coverslip interrogation techniques, such as reflectance interferometry and total internal reflection, have provided a label free means to investigate cell-surface contacts, cell motility and vesicle trafficking in vivo and in vitro. Other key advances include the ability to acquire superresolution reflectance images providing increased spatial resolution. PMID- 28013149 TI - How charge distribution influences the function of membrane-active peptides: Lytic or cell-penetrating? AB - Lytic and cell-penetrating peptides (CPPs) are both membrane-active peptides sharing similar physicochemical properties. Although their respective functions have been intensively investigated, the difference of intrinsic properties between these two types of peptides is rarely discussed. In this study, we designed a series of analogs of a recently discovered CPP ZXR-1 (FKIGGFIKKLWRSKLA) by varying the charge distributions both on the helical wheel projection and along the sequence. These peptides showed different functions on cell membranes, including membrane lytic (peptide Z1), cell-penetrating (peptide ZXR-1, Z2 and Z3), and inactive (peptide Z4) peptides. The three groups of peptides displayed different interactions with model lipid monolayer, and found that peptide insertion might be an important dynamic step to distinguish lytic and cell penetrating functions. Based on the analysis of charge distribution patterns, it was proposed that the charge distributions on the helical wheel and along the sequence are both able to influence the functions of the membrane active peptides. This finding provides a further understanding about the effect of charge distribution on the functions of membrane-active peptides, and will be helpful for the design of functional peptides. PMID- 28013150 TI - Old adult fallers display reduced flexibility of arm and trunk movements when challenged with different walking speeds. AB - Specific patterns of pelvic and thorax motions are required to maintain stability during walking. This cross-sectional study explored older-adults' gait kinematics and their kinematic adaptations to different walking speeds, with the purpose of identifying mechanisms that might be related to increased risk for falls. Fifty eight older adults from self-care residential facilities walked on a treadmill, whose velocity was systematically increased with increments of 0.1meters/second (m/s) from 0.5 to 0.9m/s, and then similarly decreased. Thorax, pelvis, trunk, arms, and legs angular total range of motion (tROM), stride time, stride length, and step width were measured. Twenty-one of the subjects reported falling, and 37 didn't fall. No significant effect of a fall history was found for any of the dependent variables. A marginally significant interaction effect of fall history and walking speed was found for arms' tROM (p=0.098). Speed had an effect on many of the measures for both groups. As the treadmill's velocity increased, the non fallers increased their arm (15.9+/-8.6 degrees to 26.6+/-12.7 degrees ) and trunk rotations (4.7+/-1.9 degrees to 7.2+/-2.8 degrees ) tROM, whereas for the fallers the change of arm (14.7+/-14.8 degrees to 20.8+/-13 degrees ) and trunk (5.5+/-2.9 degrees to 7.3+/-2.3 degrees ) rotations tROM were moderate between the different walking speeds. We conclude that walking speed manipulation exposed different flexibility trends. Only non-fallers demonstrated the ability to adapt trunk and arm ROM to treadmill speed i.e., had a more flexible pattern of behavior for arm and trunk motions, supporting the upper-body's importance for stability while walking. PMID- 28013151 TI - Indoor 222Rn concentration in the exhibition and storage rooms of Polish geological museums. AB - The radon exhaled from radioactive mineral collections exhibited in five Polish geological museums may influence its total indoor concentration. Radon concentrations measured in the exhibition halls do not pose a risk for visitors or museum staff. However, air exceeding the ICRP (2007) action limit for workers (equal to 300Bq/m3) was noted in the storage rooms of two museums. Significant222Rn activity concentrations equal to more than ~300kBq/m3were measured inside lead containers where radioactive minerals were stored. PMID- 28013152 TI - Incorporation of no-carrier added 200,203Pb and 200,201,202Tl in calcium alginate and hesperidin incorporated calcium alginate beads. AB - When radioisotopes are injected to human body, instantly free radicals are generated due to the interaction of ionizing radiation with water and fluids present in the body. The vehicle carrying radionuclides into human body should therefore be designed in a way which could also eliminate or reduce such possibilities. For the first time we have used free radical scavenger hesperidin, a polyphenolic compound having a benzo-gamma-pyrone with a benzene ring moiety for extraction of no-carrier added (NCA) 200,203Pb and 200,201,202Tl. We have modified CA beads by incorporation of a polyphenol (hesperidin) (CA-Hes). This tailor made beads were characterized and tested for their efficacy towards extraction of no-carrier-added lead and thallium radioisotopes from 40MeV alpha particle irradiated Hg2Cl2 target. PMID- 28013153 TI - A novel Tc-99m and fluorescence labeled peptide as a multimodal imaging agent for targeting angiogenesis in a murine hindlimb ischemia model. AB - The serine-aspartic acid-valine (SDV) peptide binds specifically to integrin alphavbeta3. We developed a Tc-99m and TAMRA labeled peptide, Tc-99m SDV-ECG-K TAMRA for multimodal imaging of angiogenesis. Tc-99m SDV-ECG-K-TAMRA was prepared in high yield (>96%) and showed low cytotoxicity. Tc-99m tetrofosmin images 1 week after operation, revealed significantly decreased perfusion of the ischemic hindlimb, and the perfusion recovered gradually for 4 weeks. In contrast, Tc-99m SDV-ECG-K-TAMRA uptake was maximal 1 week after the operation (ischemic-to-non ischemic uptake ratio =5.03+/-1.01) and decreased gradually. The ischemic-to-non ischemic ratio of Tc-99m SDV-ECG-K-TAMRA and Tc-99m tetrofosmin was strongly negatively correlated (r =-0.94). A postmortem analysis revealed increased angiogenesis markers and uptake of Tc-99m SDV-ECG-K-TAMRA by ischemic tissue. Our in vivo and in vitro studies revealed substantial uptake of Tc-99m SDV-ECG-K TAMRA by ischemic tissue. Tc-99m SDV-ECG-K-TAMRA could be a good candidate dual modality imaging agent to assess angiogenesis. PMID- 28013154 TI - Neutron capture cross sections of 70Zn and the decay of 71mZn. AB - Radiative neutron capture was studied in the 70Zn(n,gamma)71m,gZn reaction in order to determine the thermal neutron capture cross sections for the reactions. The resonance integrals were also measured to facilitate corrections for the epithermal neutron component. In addition, cross sections for the 64Zn(n,gamma)65Zn and 68Zn(n,gamma)69mZn reactions were determined. Through high resolution gamma-ray spectrometry in the 71mZn decay, a new set of gamma-ray energies and intensities was obtained of roughly an order of magnitude greater precision than the previous set, and several transitions new to the decay scheme are proposed. The implications for the properties of the levels of 71Ga are discussed. More precise values of the decay half-lives for 69mZn, 71gZn, and 71mZn have been determined. PMID- 28013155 TI - Development of a nickel plated aluminum krypton-81m target system. AB - A fully automated system was developed to produce rubidium-81 (81Rb), based on the natKr (p, n) 81Rb reaction. The energy incident on the target was 26MeV. Only 6MeV was stopped inside the gas and the remainder was stopped by a specially designed flange. The target body was characterized by its conical shape and its inner walls were chemically plated with 100+/-10um of nickel (Ni). Ni is advantageous as a fairly good conductor of heat whose surface can resist solutions. Additionally, the Ni plated target allowed potassium chloride to dissolve 81Rb, with no further effect on the target body. The system produced 81Rb with a production yield of approximately 4.5mCi/uAh, which is close to the calculated expected yield of 5.3mCi/uAh. The system is able to deliver reliable and reproducible radioactivity for patients and can be operated up to 1500uAh before preventive maintenance is due. Key steps in designing the 81Rb target for selected energy ranges are reported here. PMID- 28013156 TI - Colorimetric sensor arrays based on pattern recognition for the detection of nitroaromatic molecules. AB - This research demonstrated that, in a colorimetric sensor array, 2,4,6 trinitrotoluene (TNT), 2,6-dinitrotoluene (2,6-DNT), 2,4-dinitrotoluene (2,4-DNT) and 4-nitrotoluene (4-MNT) were identifiable through a unique pattern in a qualitative and semi-quantitative manner. The adsorption capacity of the molecularly imprinted colloidal particles (MICs) for their corresponding templates was 0.27mmol TNT/g, 0.22mmol 2,6-DNT/g, 0.31mmol 2,4-DNT/g and 0.16mmol 4-MNT/g, respectively. Every optical sensor utilized in the arrays contained three-dimensional molecularly imprinted photonic crystal (MIPC) sensor with different imprinted templates. The intelligent materials can display different colors from green to red to 20mM corresponding nitroaromatics with varying diffraction red shifts of 84nm (TNT), 46nm (2,6-DNT), 54nm (2,4-DNT) and 35nm (4 MNT), respectively. With the assistance of principal component analysis (PCA) and rational design, the sensor array can illustrate the influence of the nitryl quantity and generate a separate response region of nitroaromatics for pattern recognition with 95.25% of variance explained in the measurements by the first three principal components (PCs). The statistical analysis endowed the cross reactive array with better classification and identification ability and this novel detection platform provided a wider applied range among other harmful chemicals in a simple sensor array with customized functionality. PMID- 28013157 TI - Phototransformation of iodate by UV irradiation: Kinetics and iodinated trihalomethane formation during subsequent chlor(am)ination. AB - The photodegradation of IO3- at 254nm and the formation of iodinated trihalomethanes (I-THMs) during subsequent chlorination or chloramination in the presence of natural organic matter (NOM) were investigated in this study. The thermodynamically stable IO3- can be degraded by UV irradiation with pseudo-first order kinetics and the quantum yield was calculated as 0.0591moleinstein-1. Solution pH posed no remarkable influence on the photolysis rate of IO3-. The UV phototransformation of IO3- was evidenced by the determination of iodide (I-) and hypoiodous acid (HOI) in solution. NOM sources not only enhanced the photodegradation rate of IO3- by photoejecting solvated electrons, but also greatly influenced the production I-THMs in subsequent chlor(am)ination processes. In UV irradiation and sequential oxidation processes by chlorine or chloramine, the I-THMs formation was susceptible to NOM sources, especially the two major fractions of aqueous humic substances (humic acid and fulvic acid). The toxicity of disinfected waters greatly increased in chloramination over chlorination of the UV photodecomposed IO3-, as far more I-THMs especially CHI3, were formed. As "the fourth iodine source" of iodinated disinfection by-products, the occurrence, transportation and fate of IO3- in aquatic environment should be of concern instead of being considered a desired iodine sink. PMID- 28013158 TI - Preparation and characterization of porous reduced graphene oxide based inverse spinel nickel ferrite nanocomposite for adsorption removal of radionuclides. AB - For the removal of uranium(VI) (U(VI)) and thorium(IV) (Th(IV)), graphene oxide based inverse spinel nickel ferrite (GONF) nanocomposite and reduced graphene oxide based inverse spinel nickel ferrite (rGONF) nanocomposite were prepared by co-precipitation of GO with nickel and iron salts in one pot. The spectral characterization analyses revealed that GONF and rGONF have a porous surface morphology with an average particle size of 41.41nm and 32.16nm, respectively. The magnetic property measurement system (MPMS) studies confirmed the formation of ferromagnetic GONF and superparamagnetic rGONF. The adsorption kinetics studies found that the pseudo-second-order kinetics was well tune to the U(VI) and Th(IV) adsorption. The results of adsorption isotherms showed that the adsorption of U(VI) and Th(IV) were due to the monolayer on homogeneous surface of the GONF and rGONF. The adsorptions of both U(VI) and Th(IV) were increased with increasing system temperature from 293 to 333+/-2K. The thermodynamic studies reveal that the U(VI) and Th(IV) adsorption onto GONF and rGONF was endothermic. GONF and rGONF, which could be separated by external magnetic field, were recycled and re-used for up to five cycles without any significant loss of adsorption capacity. PMID- 28013159 TI - Effective removal of hydrogen sulfide using 4A molecular sieve zeolite synthesized from attapulgite. AB - In this work, 4A molecular sieve zeolite was synthesized from attapulgite (ATP) in different conditions and was applied initially for H2S removal. The sorbent was characterized by scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectra and N2 adsorption/desorption. The effects of the synthesis condition and adsorption temperature were studied by dynamic adsorption experiment. The optimal adsorption temperature is 50 degrees C. The H2S adsorption results have showed that the optimal synthesis conditions are as follows: the ratio of silicon to aluminum and ratio of sodium to silicon are both 1.5, the ratio of water to sodium is 30, crystallization temperature and crystallization time is 90 degrees C, 4h, respectively. The breakthrough and saturation sulfur sorption capacities of zeolite synthesized under optimum conditions are up to nearly 10 and 15mg/g-sorbent, respectively, and the H2S removal rate is nearly 100%. The adsorption kinetics nonlinear fitting results show that the adsorption system follows Bingham model. These results indicate that 4A molecular sieve zeolite synthesized from attapulgite can be used for H2S removal promisingly. PMID- 28013160 TI - Effects of untreated and treated wastewater at the morphological, physiological and biochemical levels on seed germination and development of sorghum (Sorghum bicolor (L.) Moench), alfalfa (Medicago sativa L.) and fescue (Festuca arundinacea Schreb.). AB - Wastewater reuse in agriculture may help mitigate water scarcity. This may be reached if high quality treatments removing harmful pollutants are applied. The aim of the present study was to compare the effect of untreated (UTW) and treated wastewater (TW) on germination and seedlings development of alfalfa (Medicago sativa L.), fescue (Festuca arundinacea Schreb.) and sorghum (Sorghum bicolor (L.) Moench). UTW presented high turbidity (130 NTU), chemical and biological oxygen demand (COD, 719mgL-1, BOD5, 291mgL-1) and metal concentrations. These levels caused mortality (18% for fescue), decreased germination speed in seeds (37.5% for alfalfa) and reductions of root and stem length in seedlings (80% and 22% respectively for alfalfa). Adverse effects on seeds germination were reflected at the biochemical level by increased H2O2 levels (6 times for sorghum after 5days) and by increased Malondialdehyde (MDA) levels (more than 600 times for sorghum roots) during seedlings development. When TW was used, these parameters were close to control seeds ones. They were also dependent on plant species and developmental stage. Therefore, for efficient reclaimed wastewater reuse in irrigation, suitable crops, displaying wide tolerance to toxic contents during germination and later seedling development stages have to be selected. PMID- 28013161 TI - Development and evaluation of predictive model for bovine serum albumin-water partition coefficients of neutral organic chemicals. AB - The binding of organic chemicals to serum albumin can significantly reduce their unbound concentration in blood and affect their biological reactions. In this study, we developed a new QSAR model for bovine serum albumin (BSA) - water partition coefficients (KBSA/W) of neutral organic chemicals with large structural variance, logKBSA/W values covering 3.5 orders of magnitude (1.19 4.76). All chemical geometries were optimized by semi-empirical PM6 algorithm. Several quantum chemical parameters that reflect various intermolecular interactions as well as hydrophobicity were selected to develop QSAR model. The result indicates the regression model derived from logKow, the most positive net atomic charges on an atom, Connolly solvent excluded volume, polarizability, and Abraham acidity could explain the partitioning mechanism of organic chemicals between BSA and water. The simulated external validation and cross validation verifies the developed model has good statistical robustness and predictive ability, thus can be used to estimate the logKBSA/W values for chemicals in application domain, accordingly to provide basic data for the toxicity assessment of the chemicals. PMID- 28013162 TI - Bacteria and endothelial cells: a toxic relationship. AB - Pathogenic bacteria use the bloodstream as a highway for getting around the body, and thus have to find ways to enter and exit through the endothelium. Many bacteria approach this problem by producing toxins that can breach the endothelial barrier through diverse creative mechanisms, including directly killing endothelial cells (ECs), weakening the cytoskeleton within ECs, and breaking the junctions between ECs. Toxins can also modulate the immune response by influencing endothelial biology, and can modulate endothelial function by influencing the response of leukocytes. Understanding these interactions, in both the in vitro and in vivo contexts, is of critical importance for designing new therapies for sepsis and other severe bacterial diseases. PMID- 28013163 TI - Photocrosslinked poly(amidoamine) nanoparticles for central nervous system targeting. AB - This study presents an innovative method for the synthesis of polymeric nanoparticles (NPs) for central nervous system (CNS) targeting. The method is based on Ultraviolet light (UV)-induced crosslinking of diacrylamide-terminated oligomers of poly(amidoamine)s (PAAs), a widely used class of synthetic polymers in biomedical field research, especially in drug delivery thanks to their excellent biocompatibility and controlled biodegradability. Previous attempts aiming at preparing PAA-based NPs by self-assembly were challenged by lack of structural stability and consequently their early degradation and premature drug release. Here, the UV-induced crosslinked PAA NPs demonstrated to overcome main disadvantages of the self-assembled ones, as they showed improved stability and controlled release properties. Besides the remarkable efficiency to produce monodisperse and stable PAA NPs, the UV-induced crosslinking method is featured by great versatility and low environmental impact, since it does not require use of organic solvents and multiple purification steps. The capability of PAA NPs to encapsulate a fluorescently labelled model protein was experimentally demonstrated in this study. Cell culture experiments showed that PAA NPs were biocompatible and highly permeable across an in vitro blood-brain barrier model, thus highlighting their great potential as drug delivery vectors for CNS delivery. PMID- 28013164 TI - Polymeric drug delivery micelle-like nanocarriers for pulmonary administration of beclomethasone dipropionate. AB - In this paper, the potential of novel polymeric micelles as drug delivery systems for Beclomethasone Dipropionate (BDP) administration into the lung is investigated. These nanostructures are obtained starting from alpha,beta-poly(N-2 hydroxyethyl)-d,l-aspartamide (PHEA), which was subsequently functionalized with O-(2-aminoethyl)-O'-methylpolyethylenglycole (PEG2000), ethylenediamine (EDA) and lipoic acid (LA), obtaining PHEA-PEG2000-EDA-LA graft copolymer. Empty and drug loaded micelles possess adequate chemical-physical characteristics for pulmonary administration such as spherical shape, slightly positive surface charge and mean size of about 200nm. Besides, BDP-loaded micelles, obtained with a Drug Loading equal to 5wt%, result to be stable in physiological-mimicking media, protecting the drug from hydrolysis and giving a sustained drug release profile. Moreover, the micelle-like structure and surface characteristics seems to improve drug permeation through the mucus layer. Finally, it is also demonstrated that BDP loaded PHEA-PEG2000-EDA-LA micelles are able to increase cell uptake of BDP of about 44wt% compared to Clenil(r) on 16-HBE cells and possess an higher biocompatibility in comparison with the same commercial formulation. PMID- 28013165 TI - In vitro cytotoxicity evaluation of graphene oxide from the peroxidase-like activity perspective. AB - In this study, PEGylated graphene oxide (PEG-GO)-hemin composite structure was constructed. Hemin in the form of nanoscaled aggregates were immobilized on PEG GO sheets by the pi-pi stacking super-molecular interaction. Via catalyzing the oxidation of chromogenic substrates, we elicited the obtained PEG-GO-Hemin composite sheets have much higher peroxidase-like activity compared to hemin or PEG-GO alone, which is due to the introduction of enzyme active center of hemin with high dispersity, the excellent affinity to organic substrate through pi-pi stacking and/or electrostatic adsorption and the rapid electron transfer capability of PEG-GO. Similarly, PEG-GO-Hemin was found to be able to catalyze the oxidation of low density lipoprotein (LDL) by H2O2, resulting in toxicity to porcine iliac endothelial cells (PIECs) in vitro. Furthermore, we also demonstrated that PEG-GO sheets showed enhanced peroxidase activity when met hemin containing proteins including hemoglobin and cytochrome c. High glucose level (HG) in human umbilical vein endothelial cells (HUVECs) can induce cytochrome c to release from the respiratory chain, thus applying PEG-GO under HG condition could cause a much higher peroxidase-like activity, resulting in the production of hydroxyl radical (OH) and cytochrome c radical (cytochrome c), which eventually enhance the apoptosis. These results suggest GO has potential hazard for biomedical applications in some pathophysiological conditions. PMID- 28013166 TI - Bacterial adhesion to polyvinylamine-modified nanocellulose films. AB - Cellulose nanofibril (CNF) materials have been widely studied in recent years and are suggested for a wide range of applications, e.g., medical and hygiene products. One property not very well studied is the interaction between bacteria and these materials and how this can be controlled. The current work studies how bacteria adhere to different CNF materials modified with polyelectrolyte multilayers. The tested materials were TEMPO-oxidized to have different surface charges, periodate-oxidized to vary the water interaction and hot-pressed to alter the surface structure. Then, multilayers were constructed using polyvinylamine (PVAm) and polyacrylic acid. Both the material surface charge and water interaction affect the amount of polymer adsorbed to the surfaces. Increasing the surface charge decreases the adsorption after the first PVAm layer, possibly due to conformational changes. Periodate-oxidized and crosslinked films have low initial polymer adsorptions; the decreased swelling prevents polymer diffusion into the CNF micropore structure. Microscopic analysis after incubating the samples with bacterial suspensions show that only the materials with the lowest surface charge enable bacteria to adhere to the surface because, when adsorbing up to 5 layers PVAm/PAA, the increased anionic surface charge appears to decrease the net surface charge. Both the amounts of PVAm and PAA influence the net surface charge and thus the bacterial adhesion. The structure generated by the hot-pressing of the films also strongly increases the number of bacteria adhering to the surfaces. These results indicate that the bacterial adhesion to CNF materials can be tailored using polyelectrolyte multilayers on different CNF substrates. PMID- 28013167 TI - Influence of surfactin on physical and oxidative stability of microemulsions with docosahexaenoic acid. AB - Docosahexaenoic acid (DHA), one of the most important omega-3 polyunsaturated fatty acids (PUFAs), shows significant health benefits for human beings. In order to stabilize nutrients like DHA, microemulsion is normally used through the addition of surfactant, and surfactin as a natural peptide biosurfactant shows strong surface activity. In this study, we investigated the effects of surfactin on the stability of docosahexaenoic acid single cell oil (DHASCO) microemulsions. The microemusion region was significantly increased with elevated surfactin concentration from 0 to 0.2mmol/L, and reached a maximum. The o/w region of DHASCO microemulsion could significantly increase and the diameters of microemulsion particles were reduced from 140 to 15nm after addition of 0.2mmol/L surfactin into emulsion system. Generally, the physical and anti-oxidation stability of the o/w DHASCO microemulsion with surfactin was highly enhanced. DHA oxidation in microemulsion with surfaction was significantly reduced even stored at 37 degrees C for 60days as compared to non-surfactin. The excellent properties of microemulsion with surfactin could be useful in functional food and medicine. PMID- 28013168 TI - Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes. AB - BACKGROUND: Gastric cancer (GC) is the fifth leading cause of cancer-related deaths worldwide. As an effective and easily performed method, microscopy-based Lauren classification has been widely accepted by gastrointestinal surgeons and pathologists for GC subtyping, but molecular characteristics of different Lauren subtypes were poorly revealed. METHODS: GSE62254 was used as a derivation cohort, and GSE15459 was used as a validation cohort. The difference between diffuse and intestinal GC on the gene expression level was measured. Gene ontology (GO) enrichment analysis was performed for both subgroups. Hierarchical clustering and heatmap exhibition were also performed. Kaplan-Meier plot and Cox proportional hazards model were used to evaluate survival grouped by the given genes or hierarchical clusters. RESULTS: A total of 4598 genes were found differentially expressed between diffuse and intestinal GC. Immunity- and cell adhesion-related GOs were enriched for diffuse GC, whereas DNA repair- and cell cycle-related GOs were enriched for intestinal GC. We proposed a 40-gene signature (chi2=30.71, P<.001) that exhibits better discrimination for prognosis than Lauren classification (chi2=12.11, P=.002). FRZB [RR (95% CI)=1.824 (1.115-2.986), P=.017] and EFEMP1 [RR (95% CI)=1.537 (0.969-2.437), P=.067] were identified as independent prognostic factors only in diffuse GC but not in intestinal GC patients. KRT23 [RR (95% CI)=1.616 (0.938-2.785), P=.083] was identified as an independent prognostic factor only in intestinal GC patients but not in diffuse GC patients. Similar results were achieved in the validation cohort. CONCLUSION: We found that GCs with different Lauren classifications had different molecular characteristics and identified FRZB, EFEMP1, and KRT23 as subtype-specific prognostic factors for GC patients. PMID- 28013169 TI - Clinical presentation and outcome of avoidant/restrictive food intake disorder in a Japanese sample. AB - We conducted a study of the clinical presentation and outcome in patients with avoidant/restrictive food intake disorder (ARFID), aged 15-40years, and compared this group to an anorexia nervosa (AN) group in a Japanese sample. A retrospective chart review was completed on 245 patients with feeding and eating disorders (FEDs), analyzing prevalence, clinical presentation, psychopathological properties, and outcomes. Using the DSM-5 criteria, 27 (11.0%) out of the 245 patients with a FED met the criteria for ARFID at entry. All patients with ARFID were women. In terms of eating disorder symptoms, all patients with ARFID had restrictive eating related to emotional problems and/or gastrointestinal symptoms. However, none of the ARFID patients reported food avoidance related to sensory characteristics or functional dysphagia. Additionally, none of them exhibited binge eating or purging behaviors, and none of them reported excessive exercise. The ARFID group had a significantly shorter duration of illness, lower rates of admission history, and less severe psychopathology than the AN group. The ARFID group reported significantly better outcome results than the AN group. These results suggest that patients with ARFID in this study were clinically distinct from those with AN and somewhat different from pediatric patients with ARFID in previous studies. PMID- 28013170 TI - Proteomic analysis of common bean stem under drought stress using in-gel stable isotope labeling. AB - Drought is an abiotic stress that strongly influences plant growth, development and productivity. Proteome changes in the stem of the drought-tolerant common bean (Phaseolus vulgaris L.) cultivar Tiber have were when the plants were exposed to drought. Five-week-old plants were subjected to water deficit by withholding irrigation for 7, 12 and 17days, whereas control plants were regularly irrigated. Relative water content (RWC) of leaves, as an indicator of the degree of cell and tissue hydration, showed the highest statistically significant differences between control and drought-stressed plants after 17days of treatment, where RWC remained at 90% for control and declined to 45% for stressed plants. Plants exposed to drought for 17days and control plants at the same developmental stage were included in quantitative proteomic analysis using in-gel stable isotope labeling of proteins in combination with mass spectrometry. The quantified proteins were grouped into several functional groups, mainly into energy metabolism, photosynthesis, proteolysis, protein synthesis and proteins related to defense and stress. 70kDa heat shock protein showed the greatest increase in abundance under drought of all the proteins, suggesting its role in protecting plants against stress by re-establishing normal protein conformations and thus cellular homeostasis. The abundance of proteins involved in protein synthesis also increased under drought stress, important for recovery of damaged proteins involved in the plant cell's metabolic activities. Other important proteins in this study were related to proteolysis and folding, which are necessary for maintaining proper cellular protein homeostasis. Taken together, these results reveal the complexity of pathways involved in the drought stress response in common bean stems and enable comparison with the results of proteomic analysis of leaves, thus providing important information to further understand the biochemical and molecular mechanisms of drought response in this important legume. PMID- 28013171 TI - Asparagine slows down the breakdown of storage lipid and degradation of autophagic bodies in sugar-starved embryo axes of germinating lupin seeds. AB - The research was conducted on embryo axes of yellow lupin (Lupinus luteus L.), white lupin (Lupinus albus L.) and Andean lupin (Lupinus mutabilis Sweet), which were isolated from imbibed seeds and cultured for 96h in vitro under different conditions of carbon and nitrogen nutrition. Isolated embryo axes were fed with 60mM sucrose or were sugar-starved. The effect of 35mM asparagine (a central amino acid in the metabolism of germinating lupin seeds) and 35mM nitrate (used as an inorganic kind of nitrogen) on growth, storage lipid breakdown and autophagy was investigated. The sugar-starved isolated embryo axes contained more total lipid than axes fed with sucrose, and the content of this storage compound was even higher in sugar-starved isolated embryo axes fed with asparagine. Ultrastructural observations showed that asparagine significantly slowed down decomposition of autophagic bodies, and this allowed detailed analysis of their content. We found peroxisomes inside autophagic bodies in cells of sugar-starved Andean lupin embryo axes fed with asparagine, which led us to conclude that peroxisomes may be degraded during autophagy in sugar-starved isolated lupin embryo axes. One reason for the slower degradation of autophagic bodies was the markedly lower lipolytic activity in axes fed with asparagine. PMID- 28013172 TI - Mitochondrial complex II-derived superoxide is the primary source of mercury toxicity in barley root tip. AB - Enhanced superoxide generation and significant inhibition of succinate dehydrogenase (SDH) activity followed by a strong reduction of root growth were detected in barley seedlings exposed to a 5MUM Hg concentration for 30min, which increased further in an Hg dose-dependent manner. While at a 25MUM Hg concentration no cell death was detectable, a 50MUM Hg treatment triggered cell death in the root meristematic zone, which was markedly intensified after the treatment of roots with 100MUM Hg and was detectable in the whole root tips. Generation of superoxide and H2O2 was a very rapid response of root tips occurring even after 5min of exposure to Hg. Application of an NADPH oxidase inhibitor or the inhibition of electron flow in mitochondria by the inhibition of complex I did not influence the Hg-induced H2O2 production. Treatment of roots with thenoyltrifluoroacetone, a non-competitive inhibitor of SDH, markedly reduced root growth and induced both superoxide and H2O2 production in a dose dependent manner. Similar to results obtained in intact roots, Hg strongly inhibited SDH activity in the crude mitochondrial fraction and caused a considerable increase of superoxide production, which was markedly reduced by the competitive inhibitors of SDH. These results indicate that the mitochondrial complex II-derived superoxide is the primary source of Hg toxicity in the barley root tip. PMID- 28013173 TI - Specific roles of cyclic electron flow around photosystem I in photosynthetic regulation in immature and mature leaves. AB - Cyclic electron flow (CEF) around photosystem I (PSI) is essential for photosynthesis in mature leaves. However, the physiological roles of CEF in immature leaves are little known. Here, we measured the PSI and PSII activities, light response changes in PSI and PSII energy quenching for immature and mature leaves of Erythrophleum guineense grown under full sunlight. Comparing with the maximum quantum yield of PSII (Fv/Fm), the immature leaves had much lower values of the maximum photo-oxidizable P700 (Pm) than the mature leaves, suggesting the unsynchronized development of PSI and PSII activities. Furthermore, the immature leaves displayed significantly lower capacities for the photosynthetic electron flow through PSII (ETRII) and CEF. However, when exposed to high light, the immature leaves displayed higher levels of non-photochemical quenching (NPQ) and P700 oxidation ration [Y(ND)] than mature leaves. Under high light, the similar NPQ values were accompanied with much lower CEF activity in the immature leaves. These results suggest that, in immature leaves, CEF primarily contributes to photoprotection for PSI and PSII via acidification of thylakoid lumen. By comparison, in mature leaves, a large fraction of CEF-dependent generation of DeltapH contributes to ATP synthesis and a relative small proportion favors photoprotection via lumen acidification. These findings highlight the specific roles of CEF in photosynthetic regulation in immature and mature leaves. PMID- 28013174 TI - Dwarf and short grain 1, encoding a putative U-box protein regulates cell division and elongation in rice. AB - Plant hormones coordinate a plant's responses to environmental stimuli and the endogenous developmental programs for cell division and elongation. Brassinosteroids are among the most important of these hormones in plant development. Recently, the ubiquitin-26S-proteasome system was identified to play a key role in hormone biology. In this study, we analyzed the function of a rice (Oryza sativa) gene, DSG1, which encodes a U-box E3 ubiquitin ligase. In the dsg1 mutant (an allelic mutant of tud1), the lengths of the roots, internodes, panicles, and seeds were shorter than that in the wild-type, which was due to defects in cell division and elongation. In addition, the leaves of the dsg1 mutant were wider and curled. The DSG1 protein is nuclear- and cytoplasm localized and does not show tissue specificity in terms of its expression, which occurs in roots, culms, leaves, sheaths, and spikelets. The dsg1 mutant is less sensitive to brassinosteroid treatment than the wild-type, and DSG1 expression is negatively regulated by brassinosteroids, ethylene, auxin, and salicylic acid. These results demonstrate that DSG1 positively regulates cell division and elongation and may be involved in multiple hormone pathways. PMID- 28013175 TI - Isolation and expression features of hexose kinase genes under various abiotic stresses in the tea plant (Camellia sinensis). AB - Hexokinases (HXKs, EC 2.7.1.1) and fructokinases (FRKs, EC 2.7.1.4) play important roles in carbohydrate metabolism and sugar signaling during the growth and development of plants. However, the HXKs and FRKs in the tea plant (Camellia sinensis) remain largely unknown. In this manuscript, we present the molecular characterization, phylogenetic relationships, conserved domains and expression profiles of four HXK and seven FRK genes of the tea plant. The 11 deduced CsHXK and CsFRK proteins were grouped into six main classes. All of the deduced proteins, except for CsFKR7, possessed putative ATP-binding motifs and a sugar recognition region. These genes exhibited tissue-specific expression patterns, which suggests that they play different roles in the metabolism and development of source and sink tissues in the tea plant. There were variations in CsHXKs and CsFRKs transcript abundance in response to four abiotic stresses: cold, salt, drought and exogenous abscisic acid (ABA). Remarkably, CsHXK3 and CsHXK4 were significantly induced in the leaves and roots under cold conditions, CsHXK1 was apparently up-regulated in the leaves and roots under salt and drought stresses, and CsHXK3 was obviously stimulated in the leaves and roots under short-term treatment with exogenous ABA. These findings demonstrate that CsHXKs play critical roles in response to abiotic stresses in the tea plant. Our research provides a fundamental understanding of the CsHXK and CsFRK genes of the tea plant and important information for the breeding of stress-tolerant tea cultivars. PMID- 28013176 TI - The prevalence of synaesthesia depends on early language learning. AB - According to one theory, synaesthesia develops, or is preserved, because it helps children learn. If so, it should be more common among adults who faced greater childhood learning challenges. In the largest survey of synaesthesia to date, the incidence of synaesthesia was compared among native speakers of languages with transparent (easier) and opaque (more difficult) orthographies. Contrary to our prediction, native speakers of Czech (transparent) were more likely to be synaesthetes than native speakers of English (opaque). However, exploratory analyses suggested that this was because more Czechs learned non-native second languages, which was strongly associated with synaesthesia, consistent with the learning hypothesis. Furthermore, the incidence of synaesthesia among speakers of opaque languages was double that among speakers of transparent languages other than Czech, also consistent with the learning hypothesis. These findings contribute to an emerging understanding of synaesthetic development as a complex and lengthy process with multiple causal influences. PMID- 28013177 TI - Probing folk-psychology: Do Libet-style experiments reflect folk intuitions about free action? AB - There is an ongoing debate in philosophy and psychology about when one should consider an action to be free. Several aspects are frequently suggested as relevant: (a) a prior intention, (b) a conscious action-related thought, (c) prior deliberation, (d) a meaningful choice, (e) different consequences of the action, and (f) the duration between intention and action. Here we investigated which criteria laypeople adopt and thus probed their intuitions about free actions in three surveys based on daily life scenarios. First, our results indicate that laypeople consider a conscious intention important for an action to be free. Second, laypeople consider spontaneous actions without consequences to be freer than actions with prior deliberation. Third, laypeople consider proximal rather than distal intentions relevant when it comes to judging actions as free. Taken together, these results suggest that simple laboratory experiments on action choices reflect laypeople's intuitions of free actions to a considerable degree. PMID- 28013178 TI - Morphology and ontogenesis of Stylonychia (Metastylonychia) nodulinucleata nov. subgen. (Ciliophora, Hypotricha) from Australia. AB - Using standard methods, we describe the morphology and ontogenesis of a possibly very rare ciliate, Stylonychia (Metastylonychia) nodulinucleata nov. subgen (basionym: Stylonychia nodulinucleataShi and Li, 1993), isolated from soil of the Murray River floodplain in Australia. Further, we provide an English translation of the Chinese original description. Whether the Australian population is conspecific with the Chinese Stylonychia nodulinucleata requires a careful redescription of the latter. The new subgenus is characterized by a moniliform macronuclear strand and an ontogenetic feature, viz., that all cirri remain intact during anlagen formation. The moniliform macronuclear strand and the curved dorsal kineties resemble the stylonychid genus Coniculostomum. The species is easily recognized by the large size of the body and oral apparatus, the moniliform macronucleus, and the enormous caudal cirri reaching half of body length. Very likely, Stylonychia (Metastylonychia) nodulinucleata has a restricted distribution. PMID- 28013179 TI - Simultaneous quantification and semi-quantification of ginkgolic acids and their metabolites in rat plasma by UHPLC-LTQ-Orbitrap-MS and its application to pharmacokinetics study. AB - A highly sensitive method using ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) has been developed and validated for the simultaneous identification and quantification of ginkgolic acids and semi-quantification of their metabolites in rat plasma. For the five selected ginkgolic acids, the method was found to be with good linearities (r>0.9991), good intra- and inter-day precisions (RSD<15%), and good accuracies (RE, from -10.33% to 4.92%) as well. Extraction recoveries, matrix effects and stabilities for rat plasm samples were within the required limits. The validated method was successfully applied to investigate the pharmacokinetics of the five ginkgolic acids in rat plasma after oral administration of 3 dosage groups (900mg/kg, 300mg/kg and 100mg/kg). Meanwhile, six metabolites of GA (15:1) and GA (17:1) were identified by comparison of MS data with reported values. The results of validation in terms of linear ranges, precisions and stabilities were established for semi-quantification of metabolites. The curves of relative changes of these metabolites during the metabolic process were constructed by plotting the peak area ratios of metabolites to salicylic acid (internal standard, IS), respectively. Double peaks were observed in all 3 dose groups. Different type of metabolites and different dosage of each metabolite both resulted in different Tmax. PMID- 28013180 TI - Determination of glycerol in oils and fats using liquid chromatography chloride attachment electrospray ionization mass spectrometry. AB - Existing liquid chromatography - mass spectrometry method for the analysis of short chain carboxylic acids was expanded and validated to cover also the measurement of glycerol from oils and fats. The method employs chloride anion attachment and two ions, [glycerol+35Cl]- and [glycerol+37Cl]-, as alternative quantifiers for improved selectivity of glycerol measurement. The averaged within run precision, between run precision and accuracy ranged between 0.3-7%, 0.4-6% and 94-99%, respectively, depending on the analyte ion and sample matrix. Selected renewable diesel feedstocks were analyzed with the method. PMID- 28013181 TI - Platelets modulate endothelial cell response to dynamic shear stress through PECAM-1. AB - INTRODUCTION: Both vascular endothelial cells and platelets are sensitive to blood flow induced shear stress. We have recently reported that platelet endothelial cell interaction could greatly affect platelet activation under flow. In the present study, we aimed to investigate how platelet-endothelial cell interaction affected endothelial cell inflammatory responses under flow. MATERIALS AND METHODS: Human coronary artery endothelial cells were exposed to normal or low pulsatile shear stress with or without the presence of platelets. Following shear exposure, endothelial cell ICAM-1 expression was measured using ELISA, Western blot and PCR; cell surface PECAM-1 expression/phosphorylation was measured using ELISA. Platelet adhesion to endothelial cells was quantified using immunofluorescence microscopy. To determine the role of PECAM-1 in platelet endothelial cell interaction, endothelial cell PECAM-1 expression was suppressed using siRNA. RESULTS: Pathological low shear stress induced a significant increase in endothelial cell ICAM-1 expression, at both protein and mRNA levels. Platelet adhesion to endothelial cells increased significantly under low shear stress, co-localizing with PECAM-1 at endothelial cell junctions. The presence of platelets inhibited low shear stress-induced ICAM-1 upregulation. When endothelial cell PECAM-1 expression was suppressed, platelet adhesion to endothelial cells under low shear stress decreased significantly; endothelial cell ICAM-1 expression was not affected by shear stress, with or without platelets. CONCLUSIONS: These results suggested that PECAM-1 could mediate platelet adhesion to endothelial cells under shear stress. Platelets binding to endothelial cells interfered with endothelial cell mechanotransduction through PECAM-1, affecting endothelial cell inflammatory responses towards pathological shear flow. PMID- 28013182 TI - A review on biogenic synthesis of ZnO nanoparticles using plant extracts and microbes: A prospect towards green chemistry. AB - Nanotechnology is emerging as an important area of research with its tremendous applications in all fields of science, engineering, medicine, pharmacy, etc. It involves the materials and their applications having one dimension in the range of 1-100nm. Generally, various techniques are used for syntheses of nanoparticles (NPs) viz. laser ablation, chemical reduction, milling, sputtering, etc. These conventional techniques e.g. chemical reduction method, in which various hazardous chemicals are used for the synthesis of NPs later become liable for innumerable health risks due to their toxicity and endangering serious concerns for environment, while other approaches are expensive, need high energy for the synthesis of NPs. However, biogenic synthesis method to produce NPs is eco friendly and free of chemical contaminants for biological applications where purity is of concerns. In biological method, different biological entities such as extract, enzymes or proteins of a natural product are used to reduce and stabilised formation of NPs. The nature of these biological entities also influence the structure, shape, size and morphology of synthesized NPs. In this review, biogenic synthesis of zinc oxide (ZnO) NPs, procedures of syntheses, mechanism of formation and their various applications have been discussed. Various entities such as proteins, enzymes, phytochemicals, etc. available in the natural reductants are responsible for synthesis of ZnO NPs. PMID- 28013183 TI - Anti-inflammatory, analgesic and COX-2 inhibitory activity of novel thiadiazoles in irradiated rats. AB - In this work, novel series of pyran, thiophene and thienopyrimidine derivatives based on 2-acetamide-thiadiazole scaffold were designed and synthesized for evaluation as selective COX-2 inhibitors in-vitro and investigated in-vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats, since its well-known that ionizing radiation plays an important role in exaggerating the inflammatory responses and in enhancing the release of inflammatory mediators in experimental animals. Toxicological studies were carried out to evaluate the ulcerogenic activity, acute toxicity and kidney and liver functions for the most potent compounds. In order to understand the binding mode of the synthesized compounds into the active site of COX-2, docking study was performed. Most of the tested compounds showed high inhibitory ability to COX-2. Among them, thiadiazole derivatives bearing thiophene and thienopyrimidine moieties were the most active derivatives, compound 26 showed extremely high selectivity index (SI) of >555.5MUM which is nearly two folds better than celecoxib (>277.7MUM), in addition to compounds 3, 16, 17, 21 and 26 with SI in the range of >308.6- >384.6MUM. The 4-chlorothieno[2.3-d]pyrimidine derivative of thiadiazole 21 showed the highest anti-inflammatory activity in this study having 24.49% of oedema compared to celecoxib (18.61%) in addition to compounds 17 and 26 with 24.70 and 25.40% of oedema, respectively, while the thiadiazol-2-acetamide derivative 2 was the most potent analgesic compound with the highest nociceptive threshold (85.72g) very close to that of celecoxib (90.23g). These compounds showed high safety margin on gastric mucosa with no ulceration effect. Also the most active in-vivo anti-inflammatory compounds 17, 21 and 26 were found to be non-toxic in experimental rats with normal kidney and liver functions. Docking study of the synthesized compounds showed similar orientation as celecoxib within the active site of COX-2 enzyme and similar ability to emerge deeply in the additional pocket and binding with Arg513 and His90 the key amino acids responsible for selectivity. PMID- 28013184 TI - Variables determining mortality in patients with Acinetobacter baumannii meningitis/ventriculitis treated with intrathecal colistin. AB - AIM: To examine the variables associated with mortality in patients with Acinetobacter baumannii-related central nervous system infections treated with intrathecal colistin. MATERIALS AND METHODS: This multi-centre retrospective case control study included patients from 11 centres in Turkey, as well as cases found during a literature review. Only patients with CNS infections caused by multidrug resistant or extensively drug-resistant Acinetobacter baumannii treated with intrathecal colistin were included in this study. The variables associated with mortality were determined by dividing the patients into groups who died or survived during hospitalisation, and who died or survived from Acinetobacter meningitis. RESULTS: Among the 77 cases enrolled in the study, 35 were found through a literature review and 42 were cases from our centres. Forty-four cases (57.1%) were male and the median age was 48 years (range: 20-78 years). Thirty seven patients (48%) died during hospitalisation. The variables associated with increased all-cause mortality during hospitalisation included old age (odds ratio, 1.035; 95% confidence interval (CI), 1.004-1.067; p=0.026) and failure to provide cerebrospinal fluid sterilisation (odds ratio, 0.264; 95% confidence interval, 0.097-0.724; p=0.01). There is a trend (P=0.062) towards higher mortality with using of meropenem during meningitis treatment. Fifteen cases (19%) died from meningitis. There were no significant predictors of meningitis related mortality. CONCLUSIONS: The mortality rate for central nervous system infections caused by multidrug-resistant or extensively drug-resistant Acinetobacter baumannii is high. Old age and failure to provide CSF sterilisation are associated with increased mortality during hospitalisation. PMID- 28013185 TI - Wild small mammals as sentinels for the environmental transmission of antimicrobial resistance. AB - Antimicrobial resistance (AMR) represents a serious threat to human health worldwide. We have tested the use of free-living small mammals (mice, voles and shrews) as sentinels of variation in the distribution of AMR in the environment and the potential for transmission from the natural environment to animal hosts. Escherichia coli isolated from the faeces of small mammals trapped at paired coastal and inland sites were tested for resistance to four antibiotics: trimethoprim, ampicillin, ciprofloxacin and cefotaxime. Coastal individuals were over twice as likely to carry AMR E. coli than inland individuals (79% and 35% respectively), and both between-site and between-species variation was observed. Animals from coastal populations also excreted increased numbers of AMR E. coli and a greater diversity of E. coli phylotypes, including human-associated pathogenic strains. Small mammals appear to be useful bioindicators of fine-scale spatial variation in the distribution of AMR and, potentially, of the risks of AMR transmission to mammalian hosts, including humans. PMID- 28013186 TI - Ponciretin attenuates ethanol-induced gastric damage in mice by inhibiting inflammatory responses. AB - BACKGROUND: Poncirin (PO) and isosakuranetin (or ponciretin [PT]) are compounds found in fruits of the genus Citrus. They are frequently used in traditional Chinese medicine for the treatment of inflammation and asthma. Therefore, we examined their anti-gastritis effects in vitro and in vivo. METHODS: The anti inflammatory effects of PO and PT were examined using ethanol- or LPS-stimulated KATO III cells. Gastritis was induced in ICR mice via intragastric injection of absolute ethanol. Levels of inflammatory markers were measured by enzyme-linked immunosorbent assay, immunoblotting, and quantitative polymerase chain reaction. RESULTS: Treatment with PT or PO inhibited the secretion of interleukin (IL)-8 and tumor necrosis factor (TNF) in ethanol- or LPS-stimulated KATO III cells. They also reduced the activation of nuclear factor kappa B (NF-kappaB). Pre treatment with PT or PO significantly protected against ethanol-induced hemorrhagic gastritis, characterized by edema, tissue erosions, and mucosal friability in mice. Treatment with PT or PO suppressed ethanol-induced NF-kappaB activation and the release of TNF, IL-8, and IFN-gamma. The protective effect of PT was greater than that of PO and comparable to ranitidine, a positive control. CONCLUSION: PT may attenuate ethanol-induced gastritis by inhibiting the infiltration of immune cells, including neutrophils, via the regulation of CXCL4 (or IL-8) secretion and the activation NF-kappaB. PMID- 28013187 TI - Halofuginone inhibits TNF-alpha-induced the migration and proliferation of fibroblast-like synoviocytes from rheumatoid arthritis patients. AB - Fibroblast-like synoviocytes (FLSs) display an aggressive phenotype that is a critical factor in cartilage destruction in rheumatoid arthritis (RA). Increased FLS migration and proliferation are essential to the pathology of RA. Halofuginone has been found to inhibit cell migration and proliferation in cancer cells. However, whether halofuginone has a role in the treatment of RA FLSs is unclear. In this study, we found that halofuginone reduced migration, invasion, cell proliferation and MMPs expression in RA FLSs. In addition, we demonstrated that halofuginone inhibited reorganization of the actin cytoskeleton during cell migration. To gain insight into the molecular mechanisms, we evaluated the effect of halofuginone on the MAPK and AKT pathways. Our results indicated that halofuginone inhibited the activity of MAPK and AKT. Taken together, these results suggest that halofuginone may protect against joint destruction in RA by regulating synoviocyte migration, invasion and cell proliferation by inhibiting MAPK and AKT activation. PMID- 28013189 TI - EVALUATION OF THYROID RADIATION DOSE USING CONE BEAM COMPUTED TOMOGRAPHY. AB - Cone beam computed tomography (CBCT) became common in various dental specialties over the past decade. This technology is used by dental professionals regarding the investigation of maxillofacial structures. Due to the diagnostic quality and possibility of 3D view, this method has become an additional method of human exposure to ionizing radiation. This study aims to evaluate the amount of ionizing radiation absorbed by thyroid gland using CBCT. Measurements were performed by LiF dosimeters (TLD-100), positioned on a phantom for head and neck, which was irradiated by Newtom 3G-CBCT. The average of phantom surface radiation dose at the thyroid gland was 0.48 mGy. The data obtained during this study are suitable to reference values; therefore, it is important to recall that the as low as reasonably achievable principle must be applied in all procedures, thereby safeguarding the patient and also the professional. PMID- 28013188 TI - A capture method based on the VC1 domain reveals new binding properties of the human receptor for advanced glycation end products (RAGE). AB - The Advanced Glycation and Lipoxidation End products (AGEs and ALEs) are a heterogeneous class of compounds derived from the non-enzymatic glycation or protein adduction by lipoxidation break-down products. The receptor for AGEs (RAGE) is involved in the progression of chronic diseases based on persistent inflammatory state and oxidative stress. RAGE is a pattern recognition receptor (PRR) and the inhibition of the interaction with its ligands or of the ligand accumulation have a potential therapeutic effect. The N-terminal domain of RAGE, the V domain, is the major site of AGEs binding and is stabilized by the adjacent C1 domain. In this study, we set up an affinity assay relying on the extremely specific biological interaction AGEs ligands have for the VC1 domain. A glycosylated form of VC1, produced in the yeast Pichia pastoris, was attached to magnetic beads and used as insoluble affinity matrix (VC1-resin). The VC1 interaction assay was employed to isolate specific VC1 binding partners from in vitro generated AGE-albumins and modifications were identified/localized by mass spectrometry analysis. Interestingly, this method also led to the isolation of ALEs produced by malondialdehyde treatment of albumins. Computational studies provided a rational-based interpretation of the contacts established by specific modified residues and amino acids of the V domain. The validation of VC1-resin in capturing AGE-albumins from complex biological mixtures such as plasma and milk, may lead to the identification of new RAGE ligands potentially involved in pro inflammatory and pro-fibrotic responses, independently of their structures or physical properties, and without the use of any covalent derivatization process. In addition, the method can be applied to the identification of antagonists of RAGE-ligand interaction. PMID- 28013190 TI - Mycobacterium indicus pranii (Mw)-mediated protection against visceral leishmaniasis by reciprocal regulation of host dual-specificity phosphatases. AB - Leishmania donovani resides within the host macrophages by dampening host defence mechanisms and thereby it modulates the host cell functions for its survival. Multiple host cell factors compete during the interplay between the host and the parasite. Roles for dual-specificity phosphatases (DUSPs) are implicated in various pathological conditions. However, the reciprocity of these DUSPs was unknown in L. donovani infection in a susceptible model. Here, we show that Mycobacterium indicus pranii (Mw), an immunomodulator, reciprocally regulates DUSP1 and DUSP6 through the TLR4 pathway. Association of PKC-beta with DUSP6 increases after Mw treatment resulting in decreased IL-10, phosphorylation of ERK1/2 and Arginase-1, whereas Mw treatment decreases the association between PKC epsilon and DUSP1 resulting in increased IL-12, phosphorylation of p38 and inducible nitric oxide synthase expression. Silencing of DUSP1 or over-expression of DUSP6 in L. donovani-infected BALB/c mice decreases the parasite burden by inducing IL-12 and reducing IL-10 production. Therefore, we identify DUSP1 and DUSP6 as therapeutic targets, functions of which could be favourably modulated by Mw during L. donovani infection. PMID- 28013191 TI - PartitionFinder 2: New Methods for Selecting Partitioned Models of Evolution for Molecular and Morphological Phylogenetic Analyses. AB - PartitionFinder 2 is a program for automatically selecting best-fit partitioning schemes and models of evolution for phylogenetic analyses. PartitionFinder 2 is substantially faster and more efficient than version 1, and incorporates many new methods and features. These include the ability to analyze morphological datasets, new methods to analyze genome-scale datasets, new output formats to facilitate interoperability with downstream software, and many new models of molecular evolution. PartitionFinder 2 is freely available under an open source license and works on Windows, OSX, and Linux operating systems. It can be downloaded from www.robertlanfear.com/partitionfinder. The source code is available at https://github.com/brettc/partitionfinder. PMID- 28013192 TI - Progressive multifocal leucoencephalopathy with Behcet's disease: an insight into pathophysiology. PMID- 28013193 TI - Medication use among pregnant women with systemic lupus erythematosus and general population comparators. AB - Objective: The aim was to characterize SLE medication trends before, during and after pregnancy and to compare other commonly used medications during SLE pregnancies with non-SLE pregnancies. Methods: Women with pregnancies ending in live birth or stillbirth were identified from the Swedish Medical Birth Register (2006-12). National registers were used to identify women with prevalent SLE during pregnancy and a sample without SLE and to identify prescription medications dispensed from 3 months pre-pregnancy until 6 months postpartum. We reported the prevalence of DMARDs, systemic CSs and NSAIDs (aspirin reported separately) in SLE pregnancies. We calculated prevalence estimates of other medications that were dispensed during pregnancy to ? 5% of SLE pregnancies and for the same medications among non-SLE pregnancies. Results: There were 483 pregnancies among women with SLE and 5723 pregnancies among women without SLE. In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy; the prevalence was 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs and varied by pregnancy period. The prevalence of common medications among SLE pregnancies was 1.2- to 20-fold higher than among non-SLE pregnancies; for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%) and levothyroxine (15.9 vs 4.9%). Conclusion: In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Commonly used medications in SLE pregnancies had far higher prevalence estimates compared with non-SLE pregnancies. Research regarding benefits and risks of commonly used medications on SLE pregnancies, breast milk and long-term outcomes for offspring is needed. PMID- 28013194 TI - Is diffuse idiopathic skeletal hyperostosis a disease or a syndrome? PMID- 28013195 TI - Nicotine drives neutrophil extracellular traps formation and accelerates collagen induced arthritis. AB - Objectives: The aim was to investigate the effects of nicotine on neutrophil extracellular traps (NETs) formation in current and non-smokers and on a murine model of RA. Methods: We compared spontaneous and phorbol 12-myristate 13-acetate induced NETosis between current and non-smokers by DNA release binding. Nicotine induced NETosis from non-smokers was assessed by DNA release binding, NET specific (myeloperoxidase (MPO)-DNA complex) ELISA and real-time fluorescence microscopy. We also used immunofluorescent staining to detect nicotinic acetylcholine receptors (nAChRs) on neutrophils and performed a functional analysis to assess the role of nAChRs in nicotine-induced NETosis. Finally, we investigated the effects of systemic nicotine exposure on arthritis severity and NETosis in the CIA mouse model. Results: Neutrophils derived from current smokers displayed elevated levels of spontaneous and phorbol 12-myristate 13-acetate induced NETosis. Nicotine induced dose-dependent NETosis in ex vivo neutrophils from healthy non-smokers, and co-incubation with ACPA-immune complexes or TNF alpha facilitated a synergistic effect on NETosis. Real-time fluorescence microscopy revealed robust formation of NET-like structures in nicotine-exposed neutrophils. Immunofluorescent staining demonstrated the presence of the alpha7 subunit of the nAChR on neutrophils. Stimulation of neutrophils with an alpha7 specific nAChR agonist induced NETosis, whereas pretreatment with an nAChR antagonist attenuated nicotine-induced NETosis. Nicotine administration to mice with CIA exacerbated inflammatory arthritis, with higher plasma levels of NET associated MPO-DNA complex. Conclusion: We demonstrate that nicotine is a potent inducer of NETosis, which may play an important role in accelerating arthritis in the CIA model. This study generates awareness of and the mechanisms by which nicotine-containing products, including e-cigarettes, may have deleterious effects on patients with RA. PMID- 28013197 TI - Achieving consensus on minimum data items (including core outcome domains) for a longitudinal observational cohort study in rheumatoid arthritis. AB - Objectives: To obtain consensus on the minimum data items for an observational cohort study in RA in the UK and to make available the process for similar studies and other rheumatic conditions. Methods: Individuals with a diverse range of expertise and backgrounds were invited to participate in a process of proposing a minimum core dataset (MCD) for research studies, commissioned by Arthritis Research UK as part of the larger INBANK project. The group included patients and representatives from clinical and academic rheumatology, outcomes science, stratified medicine, health economics, and national professional and academic bodies/committees. A process was devised based on OMERACT principles for reviewing aims/objectives, defining the scope, identifying the important research questions and selecting key domains. Results: Following the initial multistakeholder meeting, subsequent teleconferences and email communications: consensus was obtained on the most important and relevant research questions; agreement on how the OMERACT Core Areas (life impact, pathophysiological manifestations, resource use and death) could form the basis of a MCD; and consensus on 22 items for inclusion into a MCD. Workshops were undertaken for two essential items that required further exploration: work/social participation and co-morbidity. Conclusion: Reaching a consensus for the proposed minimal data items for long-term observational cohort studies of RA in the UK posed novel challenges and opportunities, and was largely successful. Further work is needed for selecting instruments for two important items and for achieving compatibility with other UK national initiatives, and more widely across Europe. PMID- 28013196 TI - Assessment and management of musculoskeletal disorders among patients living with HIV. AB - HIV is a global pandemic. However, anti-retroviral therapy has transformed the prognosis and, providing compliance is good, a normal life expectancy can be anticipated. This has led to increasing numbers of people with chronic prevalent, treated infection living to older ages. Musculoskeletal pain is commonly reported by HIV patients and, with resumption of near-normal immune function, HIV-infected patients develop inflammatory rheumatic diseases that require assessment and management in rheumatology clinics. Moreover, it is becoming apparent that avascular necrosis and osteoporosis are common comorbidities of HIV. This review will contextualize the prevalence of musculoskeletal symptoms in HIV, informed by data from a UK-based clinic, and will discuss the management of active inflammatory rheumatic diseases among HIV-infected patients taking anti retroviral therapy, highlighting known drug interactions. PMID- 28013198 TI - Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. AB - Objectives: To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-alpha inhibitor tocilizumab (TCZ). Methods: Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg +/- DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure. Results: In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean ( s . d .) change, -2.17 (2.16) * 10 9 /l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 * 10 9 /l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose. Conclusion: Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines. PMID- 28013199 TI - Na+ deposition in the fibrotic skin of systemic sclerosis patients detected by 23Na-magnetic resonance imaging. AB - Objective: Skin fibrosis is the predominant feature of SSc and arises from excessive extracellular matrix deposition. Glycosaminoglycans are macromolecules of the extracellular matrix, which facilitate Na + accumulation in the skin. We used 23 Na-MRI to quantify Na + in skin. We hypothesized that skin Na + might accumulate in SSc and might be a biomarker for skin fibrosis. Methods: In this observational case-control study, skin Na + was determined by 23 Na-MRI using a Na + volume coil in 12 patients with diffuse cutaneous SSc and in 21 control subjects. We assessed skin fibrosis by the modified Rodnan skin score prior to 23 Na-MRI and on follow-up 12 months later. Results: 23 Na-MRI demonstrated increased Na + in the fibrotic skin of SSc patients compared with skin from controls [mean ( s . d .): 27.2 (5.6) vs 21.4 (5.3) mmol/l, P < 0.01]. Na + content was higher in fibrotic than in non-fibrotic SSc skin [26.2 (4.8) vs 19.2 (3.4) mmol/l, P < 0.01]. Furthermore, skin Na + amount was correlated with changes in follow-up modified Rodnan skin score (R 2 = 0.68). Conclusions: 23 Na MRI detected increased Na + in the fibrotic SSc skin; high Na + content was associated with progressive skin disease. Our findings provide the first evidence that 23 Na-MRI might be a promising tool to assess skin Na + and thereby predict progression of skin fibrosis in SSc. PMID- 28013200 TI - Quality and acceptability of measures of exercise adherence in musculoskeletal settings: a systematic review. AB - Objective: To recommend robust and relevant measures of exercise adherence for application in the musculoskeletal field. Method: A systematic review of measures was conducted in two phases. Phase 1 sought to identify all reproducible measures used to assess exercise adherence in a musculoskeletal setting. Phase 2 identified published evidence of measurement and practical properties of identified measures. Eight databases were searched (from inception to February 2016). Study quality was assessed against the Consensus-based Standards for the Selection of Health Measurement Instruments guidelines. Measurement quality was assessed against accepted standards. Results: Phase 1: from 8511 records, 326 full-text articles were reviewed; 45 reproducible measures were identified. Phase 2: from 2977 records, 110 full-text articles were assessed for eligibility; 10 articles provided evidence of measurement/practical properties for just seven measures. Six were exercise adherence-specific measures; one was specific to physical activity but applied as a measure of exercise adherence. Evidence of essential measurement and practical properties was mostly limited or not available. Assessment of relevance and comprehensiveness was largely absent and there was no evidence of patient involvement during the development or evaluation of any measure. Conclusion: The significant methodological and quality issues encountered prevent the clear recommendation of any measure; future applications should be undertaken cautiously until greater clarity of the conceptual underpinning of each measure is provided and acceptable evidence of essential measurement properties is established. Future research should seek to engage collaboratively with relevant stakeholders to ensure that exercise adherence assessment is high quality, relevant and acceptable. PMID- 28013201 TI - Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis. AB - Objectives: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA. Methods: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). Results: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates. Conclusion: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. Systematic review registration number: PROSPERO CRD42014014842. PMID- 28013202 TI - Performance of screening tools for psoriatic arthritis: a cross-sectional study in primary care. AB - Objective: . To compare the screening performance of the Psoriasis Epidemiology Screening Tool (PEST), Psoriatic Arthritis Screening and Evaluation (PASE) and Early Arthritis for Psoriatic Patients (EARP) questionnaires for detecting PsA among psoriasis patients in a primary care setting. Methods: In a cross-sectional study, 473 primary care psoriasis patients at risk for PsA completed the PEST, PASE and EARP questionnaires and were clinically evaluated by a trained research nurse. A PsA case was defined by a rheumatologist according to the CASPAR criteria. Sensitivity and specificity were determined for the PEST and EARP cut offs (?3) and the PASE cut-offs (?44 and ?47). Results: PsA was diagnosed in 53 patients. The PEST had a sensitivity of 0.68 and a specificity of 0.71. The PASE was validated for two different cut-offs. The cut-off of 47 led to a sensitivity of 0.59 and a specificity of 0.66, whereas the lower cut-off of 44 led to a sensitivity of 0.66 and a specificity of 0.57. For the EARP we found a sensitivity of 0.87 with a specificity of 0.34. Conclusion: The PEST questionnaire has the most favourable trade-off between sensitivity and specificity to screen for PsA. However, as the prevalence of psoriasis and PsA is fairly low in primary care, screening only psoriasis patients with musculoskeletal complaints may be a better allocation of resources. PMID- 28013206 TI - Systemic lupus erythematosus diagnosis and management. AB - SLE presents many challenges for clinicians. The onset of disease may be insidious, with many different symptoms and signs, making early and accurate diagnosis challenging. Tests for SLE in the early stages lack specificity; those that are useful later often appear only after organ damage is manifest. Disease patterns are highly variable; flares are not predictable and not always associated with biomarkers. Children with SLE may have severe disease and present special management issues. Older SLE patients have complicating co-morbid conditions. Therapeutic interventions have improved over recent decades, but available drugs do not adequately control disease in many patients, and successful outcomes are limited by off-target effects; some of these become manifest with longer duration of treatment, now in part revealed by improved rates of survival. Despite all of these challenges, advances in understanding the biological basis of SLE have translated into more effective approaches to patient care. This review considers the current state of SLE diagnosis and management, with a focus on new approaches and anticipated advances. PMID- 28013204 TI - Modelling clinical systemic lupus erythematosus: similarities, differences and success stories. AB - Mouse models of SLE have been indispensable tools to study disease pathogenesis, to identify genetic susceptibility loci and targets for drug development, and for preclinical testing of novel therapeutics. Recent insights into immunological mechanisms of disease progression have boosted a revival in SLE drug development. Despite promising results in mouse studies, many novel drugs have failed to meet clinical end points. This is probably because of the complexity of the disease, which is driven by polygenic predisposition and diverse environmental factors, resulting in a heterogeneous clinical presentation. Each mouse model recapitulates limited aspects of lupus, especially in terms of the mechanism underlying disease progression. The main mouse models have been fairly successful for the evaluation of broad-acting immunosuppressants. However, the advent of targeted therapeutics calls for a selection of the most appropriate model(s) for testing and, ultimately, identification of patients who will be most likely to respond. PMID- 28013205 TI - Clinical correlates of faecal incontinence in systemic sclerosis: identifying therapeutic avenues. AB - Objectives: The aim was to establish the prevalence and severity of faecal incontinence (FI) in SSc, its association with other intestinal manifestations and potential predictors of FI, and its impact on quality of life. Methods: A multicentre, cross-sectional study of 298 SSc subjects followed in the Canadian Scleroderma Research Group cohort was performed using validated questionnaires: Jorge-Wexner score (an FI severity scale), Bristol stool scale (a visual scale of stool consistency) and FI Quality-of-Life scale. Constipation was defined by the Rome III criteria. Associations between the Jorge-Wexner score and other clinical variables were determined using multivariate regression analyses. Results: Eighty one (27.2%) subjects had FI, which was mild in 37 (12.4%) and moderate to severe in 44 (14.8%). Most patients had well-formed stools, 111 (38.8%) reported constipation and 38 (13.4%) had been previously treated for small intestinal bacterial overgrowth (SIBO). Variables independently associated with FI were: loose vs well-formed stools [odds ratio (OR) = 7.01, 95% CI: 2.09, 23.51)], constipation (OR = 3.64, 95% CI: 1.61, 8.27, P = 0.002), history of SIBO (OR = 2.97, 95% CI: 1.06, 8.27) and urinary incontinence (OR = 2.45, 95% CI: 1.14, 5.27). Quality of life measured with the FI Quality-of-Life scale was inversely correlated with FI severity (correlation coefficients between -0.602 and -0.702, P < 0.001). Conclusion: FI was common and often severe in SSc. Loose stools, SIBO, constipation and urinary incontinence were strongly associated with FI. Other than targeting anorectal dysfunction, concomitant treatment of clinical correlates could lead to improvement in FI and quality of life in SSc. PMID- 28013203 TI - Systemic lupus erythematosus biomarkers: the challenging quest. AB - SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune system. Decades of investigation of blood biomarkers has resulted in incremental improvements in the understanding of SLE. Owing to the heterogeneity of immune dysregulation, no single biomarker has emerged as a surrogate for disease activity or prediction of disease. Beyond identification of surrogate biomarkers, a multitude of clinical trials have sought to inhibit elevated SLE biomarkers for therapeutic benefit. Armed with new -omics technologies, the necessary yet daunting quest to identify better surrogate biomarkers and successful therapeutics for SLE continues with tenacity. PMID- 28013208 TI - It hasn't gone away: the problem of glucocorticoid use in lupus remains. AB - The treatment of SLE remains complex, and management is constrained by a lack of safe, effective, targeted therapies. Physicians, also, are constrained by a lack of evidence-based approaches with existing agents, including glucocorticoids, utilized in the majority of patients. While Cushingoid side effects of glucocorticoids are widely recognized, emerging literature now suggests that glucocorticoid use actually contributes to harmful outcomes in SLE, over and above these effects. These studies provide a compelling case for a re-evaluation of the long-term use of glucocorticoids in SLE, focusing on minimizing glucocorticoid exposure as part of the strategy to improve long-term outcomes. In this article, we review the evidence for the harmful effects of glucocorticoids in SLE, and propose therapeutic options that reduce reliance on glucocorticoids. We propose that it is time for the lupus community to have a louder conversation about glucocorticoid use, and for any residual complacency about their risk benefit ratio to be banished. PMID- 28013207 TI - An investigation into the prevalence of sleep disturbances in primary Sjogren's syndrome: a systematic review of the literature. AB - Objectives: To identify whether sleep disturbances are more prevalent in primary SS (pSS) patients compared with the general population and to recognize which specific sleep symptoms are particularly problematic in this population. Methods: Electronic searches of the literature were conducted in PubMed, Medline (Ovid), Embase (Ovid), PsychINFO (Ovid) and Web of Science and the search strategy registered a priori . Titles and abstracts were reviewed by two authors independently against a set of prespecified inclusion/exclusion criteria, reference lists were examined and a narrative synthesis of the included articles was conducted. Results: Eight whole-text papers containing nine separate studies met the inclusion criteria and were included in the narrative analysis. Few of these studies met all of the quality assessment criteria. The studies used a range of self-reported measures and objective measures, including polysomnography. Mixed evidence was obtained for some of the individual sleep outcomes, but overall compared with controls, pSS patients reported greater subjective sleep disturbances and daytime somnolence and demonstrated more night awakenings and pre-existing obstructive sleep apnoea. Conclusions: A range of sleep disturbances are commonly reported in pSS patients. Further polysomnography studies are recommended to confirm the increased prevalence of night awakenings and obstructive sleep apnoea in this patient group. pSS patients with excessive daytime somnolence should be screened for co-morbid sleep disorders and treated appropriately. Interventions targeted at sleep difficulties in pSS, such as cognitive behavioural therapy for insomnia and nocturnal humidification devices, have the potential to improve quality of life in this patient group and warrant further investigation. PMID- 28013209 TI - The incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK Clinical Practice Research Datalink. AB - Objective: To estimate the incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink and Hospital Episode Statistics (HES). We calculated incidence rate ratios, adjusted for age, gender and ethnicity, using Poisson regression. Results: We identified 462 cases diagnosed between 1997 and 2013. Our overall estimate of incidence was 11.8 (95% CI: 10.7, 12.9)/million person-years. The incidence was 0.88 (95% CI: 0.40, 1.96) in children (aged <16 years) and 14.0 (95% CI: 12.8, 15.4) in adults. The incidence was lower in females (adjusted incidence rate ratio = 0.68; 95% CI: 0.56, 0.81) and highest in the 55-69 year age group (adjusted incidence rate ratio = 6.8, 95% CI: 4.9, 9.6; reference group 16-39 years). The incidence was not significantly different in the Black/Minority Ethnic population from that in the White population (adjusted odds ratio = 0.78, 95% CI: 0.53, 1.13, P = 0.13). The prevalence in 2013 was 134.9 (95% CI: 121.3, 149.6)/million. Mortality was 13.6% at 1-year, and higher in the HES- than in the Clinical Practice Research Datalink-identified cases (hazard ratio = 3.16, 95% CI: 2.19, 4.56, P < 0.001). Conclusion: By combining primary and secondary care datasets, we have found the incidence and mortality of granulomatosis with polyangiitis to be higher than previously reported. We predict that at present each year in the UK there will be ~700 new cases, of whom 95 will die within 12 months. PMID- 28013210 TI - Castleman disease and lymphocytic interstitial pneumonia: a complex diagnostic and management challenge. PMID- 28013211 TI - Effect of anti-TNF and conventional synthetic disease-modifying anti-rheumatic drug treatment on work disability and clinical outcome in a multicentre observational cohort study of psoriatic arthritis. AB - Objectives: To determine the effect of medical treatment on work disability in patients with active PsA in a real-world setting. Methods: Four hundred patients with active PsA commencing or switching to anti-TNF or conventional synthetic DMARD (csDMARD) were recruited to a multicentre UK prospective observational cohort study. Work disability was measured using the work productivity and activity-specific health problem instrument and peripheral joint activity was measured with the disease activity in PsA composite measure. Results: Four hundred patients were recruited, of whom 229 (57.25%) were working (of any age). Sixty-two patients of working age (24%) were unemployed. At 6 months there was a 10% improvement in presenteeism ( P = 0.007) and a 15% improvement in work productivity ( P = 0.001) among working patients commenced on csDMARDs ( n = 164) vs a larger and more rapid 30% improvement in presenteeism ( P < 0.001) and 40% improvement in work productivity ( P < 0.001) among those commenced on anti-TNF therapy ( n = 65). Clinical response was poor among patients commenced on a csDMARD ( n = 272), with an 8.4 point improvement in disease activity in PsA ( P < 0.001) vs those commenced on anti-TNF therapy ( n = 121), who had a 36.8 point improvement ( P < 0.001). Conclusion: We report significant and clinically meaningful improvements in both work disability and clinical outcomes after commencement of anti-TNF therapy in a real-world setting. Improvements in all outcomes among those commencing csDMARDs were slower and of a smaller magnitude. PMID- 28013212 TI - Editor's Highlight: Organ-Specific Epigenetic Changes Induced by the Nongenotoxic Liver Carcinogen Methapyrilene in Fischer 344 Rats. AB - Continuous lifetime exposure to certain natural and man-made chemicals is a major cause of cancers in humans; therefore, evaluating the carcinogenic risks of chemicals remains important. Currently, substantial progress has been made in identification of genotoxic carcinogens; in contrast, predicting the carcinogenic potential of nongenotoxic compounds is a challenge due to many different modes of action that may lead to tumorigenesis. In the present study, we investigated the effects of the nongenotoxic liver carcinogen methapyrilene and the nongenotoxic noncarcinogen usnic acid, at doses that do not exhibit organ cytotoxicity, on epigenomic alterations in the livers and kidneys of Fischer 344 (F344) rats. We demonstrate that a repeat-dose oral treatment of male F344 rats with methapyrilene for 6 weeks caused target organ-specific epigenetic alterations in the livers. In contrast, only very slight epigenetic changes were found in the livers of F344 rats treated with hepatotoxicant, but noncarcinogen, usnic acid. The methapyrilene-induced epigenetic changes consisted of changes in histone lysine acetylation and methylation, with the greatest increase occurring in global and gene-specific histone H3 lysine 9 (H3K9) deacetylation. Importantly, the results of the present study show an association between gene-specific histone H3K9 deacetylation and a reduced expression of critical cancer-related genes, including prospero homeobox 1 (Prox1), HNF1 homebox A (Hnf1a), and peroxisome proliferator activated receptor alpha (Ppara), which provides a mechanistic link between methapyrilene-induced epigenetic aberrations and liver carcinogenesis. PMID- 28013213 TI - Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes. AB - High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)-which is characterized by hepatic ductular inflammation-is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesized that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays. Extracts from several sample sites around a landfill site contained a chemical(s) which activated the human ERalpha in a dose-dependent manner. Extracts from 3 separate control sampling sites were absent of any detectable activity. The mouse ERalpha and 2 variant mouse ERbeta cDNAs were cloned and extracts from sample sites around a landfill site also activated these receptors. One variant murine ERbeta was constitutively active when expressed in cholangiocytes, was readily inactivated by ICI182780 and activated in a dose responsive, ICI182780-inhibitable manner by oestrogen. However, when this receptor was activated by extracts from landfill site soils, ICI182780 failed to antagonize activation. ERbeta was readily detectable in murine cholangiocytes and exposing mice acutely to a pooled ER activating soil extracts also gave rise to a mild cholestatic injury. These data indicate that the environment around landfill sites may contain higher levels of xenoestrogens; that these chemicals have "super-activating" characteristics with a variant ERbeta and therefore these chemicals could be a component of a xenobiotic insult that triggers PBC. PMID- 28013214 TI - Effects of an Environmentally Relevant Phthalate Mixture on Cultured Mouse Antral Follicles. AB - Phthalates are used in building materials, medical devices, and personal care products. Most studies on phthalates have focused on single phthalates, but it is important to study mixtures of phthalates because humans are exposed to such mixtures daily. We tested the hypothesis that phthalate mixture exposure decreases antral follicle growth, compromises steroidogenic capacity, and induces atresia. Antral follicles from adult CD-1 mice were cultured with vehicle control or phthalate mixture (1-500 ug/ml) for 96 h. The mixture was made of 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. During culture, antral follicle diameters were measured every 24 h to monitor growth. After culture, media were subjected to measurements of sex steroid hormones and follicles were subjected to evaluation of gene expression and atresia. The phthalate mixture (100 and 500 ug/ml) decreased antral follicle growth starting at 24 h compared to controls. The mixture at 10, 100, and 500 ug/ml also decreased androstenedione, testosterone, estrone, and estradiol levels compared to control. The mixture (10, 100, and 500 ug/ml) reduced atresia rating, but it induced more oocyte fragmentation compared to control. The phthalate mixture at different doses adversely affected cell cycle regulators, antioxidant enzymes, apoptotic factors, steroidogenic enzymes, and receptors. Collectively, these data indicate that exposure to an environmentally relevant phthalate mixture reduces antral follicle growth, induces oocyte fragmentation, and decreases hormone production by adversely affecting the expression of cell cycle regulators, apoptotic factors, steroidogenic enzymes, and receptors. PMID- 28013215 TI - Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats. AB - Perfluoroalkyl sulfonates (PFSAs) such as perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) have very long serum elimination half-lives in humans, and preferentially distribute to serum and liver. The enterohepatic circulation of PFHxS and PFOS likely contributes to their extended elimination half-lives. We previously demonstrated that perfluorobutane sulfonate (PFBS), PFHxS, and PFOS are transported into hepatocytes both in a sodium-dependent and a sodium-independent manner. We identified Na+/taurocholate cotransporting polypeptide (NTCP) as the responsible sodium-dependent transporter. Furthermore, we demonstrated that the human apical sodium-dependent bile salt transporter (ASBT) contributes to the intestinal reabsorption of PFOS. However, so far no sodium-independent uptake transporters for PFSAs have been identified in human hepatocytes or enterocytes. In addition, perfluoroalkyl carboxylates (PFCAs) with 8 and 9 carbons were shown to preferentially distribute to the liver of rodents; however, no rat or human liver uptake transporters are known to transport these PFCAs. Therefore, we tested whether PFBS, PFHxS, PFOS, and PFCAs with 7-10 carbons are substrates of organic anion transporting polypeptides (OATPs). We used CHO and HEK293 cells to demonstrate that human OATP1B1, OATP1B3, and OATP2B1 can transport PFBS, PFHxS, PFOS, and the 2 PFCAs (C8 and C9). In addition, we show that rat OATP1A1, OATP1A5, OATP1B2, and OATP2B1 transport all 3 PFSAs. In conclusion, our results suggest that besides NTCP and ASBT, OATPs also are capable of contributing to the enterohepatic circulation and extended human serum elimination half-lives of the tested perfluoroalkyl acids. PMID- 28013216 TI - Diesel Exhaust Particles Contribute to Endothelia Apoptosis via Autophagy Pathway. AB - Epidemiological studies suggest that an increase of PM2.5 diesel exhaust particles (DEP) in ambient air corresponds to increased myocardial infarctions and atherosclerosis. When exposed to DEP, endothelial cells exhibit increases in oxidative stress and apoptosis, but the role of autophagy in this DEP-induced cell death remains unclear. Here, we suggest that acute DEP exposure produces intracellular reactive oxygen species (ROS) leading to induction of DEP internalization, endothelial dysfunction, and pro-inflammation in an in vitro human umbilical vein endothelial cells (HUVEC) model. This study found that increases in intracellular oxidative stress and cellular internalization of DEP occurred within 2 h of exposure to DEP. After 2 h of DEP exposure, Mdm2 expression was increased, which triggered cellular autophagy after 4 h of DEP exposure and suppressed cellular senescence. Unfortunately, phagocytized DEP could not be eliminated by cellular autophagy, which led to a continuous buildup of ROS, an increased release of cytokines, and an increased expression of anchoring molecules. After 12 h of DEP exposure, HUVEC reduced Mdm2 expression leading to increased p53 expression, which triggered apoptosis and ultimately resulted in endothelial dysfunction. On the other hand, when cells lacked the ability to induce autophagy, DEP was unable to induce cell senescence and most of the cells survived with only a small percentage of the cells undergoing necrosis. The results presented in this study clearly demonstrate the role cellular autophagy plays in DEP-induced atherosclerosis. PMID- 28013217 TI - Strain and Sex Differences in the Vestibular and Systemic Toxicity of 3,3' Iminodipropionitrile in Mice. AB - The nitrile 3,3'-iminodipropionitrile (IDPN) causes a loss of hair cells in the vestibular epithelium of the inner ear in several species of both mammals and nonmammals. It is of interest as a model compound in ototoxicity and vestibular regeneration research, but its effects on the mouse, including the potential relevance of strain and sex differences for susceptibility, have not yet been thoroughly characterized. In this study, we compared the vestibular toxicity of IDPN in dose-response studies (0, 8, 12, 16, and 24 mmol/kg IDPN p.o.) in males and females of 2 different mouse strains (RjOrl:Swiss/CD-1 and 129S1/SvImJ). 3,3' Iminodipropionitrile caused a dose-dependent loss of vestibular function in all sex and strain groups, as assessed by a specific battery of behavioral tests. However, large differences in systemic toxicity were recorded, with high systemic toxicity in 129S1 mice of both sexes compared to limited effects on the Swiss mice. Both male and female Swiss mice showed a marked increase of hindlimb stride width after exposure. The Swiss, but not the 129S1, mice treated with IDPN showed hyperactivity in the open field. The dose-response relationships in the behavioral effects were matched by the extent of hair cell loss assessed by scanning electron microscopy. Altogether, the data demonstrated prominent strain dependent differences in the systemic toxicity of IDPN between 129S1 and Swiss mice, in contrast to no differences between the strains and small differences between the sexes in its vestibular toxicity. These results support the use of Swiss mice exposed to IDPN as a mouse lesion model for research in vestibular therapy and regeneration. PMID- 28013218 TI - Editor's Highlight: Genetic Targets of Acute Toluene Inhalation in Drosophila melanogaster. AB - Interpretation and use of data from high-throughput assays for chemical toxicity require links between effects at molecular targets and adverse outcomes in whole animals. The well-characterized genome of Drosophila melanogaster provides a potential model system by which phenotypic responses to chemicals can be mapped to genes associated with those responses, which may in turn suggest adverse outcome pathways associated with those genes. To determine the utility of this approach, we used the Drosophila Genetics Reference Panel (DGRP), a collection of ~200 homozygous lines of fruit flies whose genomes have been sequenced. We quantified toluene-induced suppression of motor activity in 123 lines of these flies during exposure to toluene, a volatile organic compound known to induce narcosis in mammals via its effects on neuronal ion channels. We then applied genome-wide association analyses on this effect of toluene using the DGRP web portal (http://dgrp2.gnets.ncsu.edu), which identified polymorphisms in candidate genes associated with the variation in response to toluene exposure. We tested ~2 million variants and found 82 polymorphisms located in or near 66 candidate genes that were associated with phenotypic variation for sensitivity to toluene at P < 5 * 10-5, and human orthologs for 52 of these candidate Drosophila genes. None of these orthologs are known to be involved in canonical pathways for mammalian neuronal ion channels, including GABA, glutamate, dopamine, glycine, serotonin, and voltage sensitive calcium channels. Thus this analysis did not reveal a genetic signature consistent with processes previously shown to be involved in toluene-induced narcosis in mammals. The list of the human orthologs included Gene Ontology terms associated with signaling, nervous system development and embryonic morphogenesis; these orthologs may provide insight into potential new pathways that could mediate the narcotic effects of toluene. PMID- 28013219 TI - The Role of miR-182-5p in Hepatocarcinogenesis of Trichloroethylene in Mice. AB - Trichloroethylene (TCE), commonly used as an industrial solvent, is ubiquitous in our living environment. TCE exposure can induce hepatocellular carcinoma (HCC) in mice, but the underlying mechanisms remain elusive. To understand the role of miRNA in the hepatocarcinogenesis of TCE, we examined the miRNA expression profiles by microarray in the liver of B6C3F1 male mice exposed to TCE at 0 or 1000 mg/kg b.w. Nine differentially expressed miRNAs were identified, out of which miR-182-5p exhibited the highest increase in expression. Moreover, the TCE induced upregulation of miR182-5p in mouse liver was dose dependent and correlated with promoter DNA hypomethylation. Treatment of mouse liver cell lines (BNL CL.2 and Hepa1-6) with TCE at non-toxic doses (0.1 and/or 0.3 mM) significantly increased the expression level of miR-182-5p accompanied with elevated cell proliferation. The TCE-induced cell proliferation was further found to be mediated by miR-182-5p overexpression. Additionally, tumor suppressor gene Cited2, which was downregulated in TCE exposed mouse liver cells, was proved to be a direct target of miR-182-5p. In conclusion, TCE might up-regulate miR-182-5p expression by DNA hypomethylation, which could suppress Cited2 and improve cell proliferation rate, resulting in liver tumor. PMID- 28013220 TI - From the Cover: Potentiation of Drug-Induced Phospholipidosis In Vitro through PEGlyated Graphene Oxide as the Nanocarrier. AB - Cationic amphiphilic drugs (CADs) are small molecules that can induce phospholipidosis (PLD), causing the intracellular accumulation of phospholipid in the lamellar bodies. Nanotechnology based drug delivery systems have been used widely, while it is unknown if drug-induced PLD (DIP) can be potentiated through drug retention by indigestible nanocarriers. Due to the high drug loading capacity of graphene, we investigated if PEGylated graphene oxide (PEG-GO) loaded with CAD could potentiate DIP. Tamoxifen induced the accumulation of NBD-PE, a fluorescence labeled phospholipid in human hepatoma HepG2 cells, while PEG-GO loaded with tamoxifen (PEG-GO/tamoxifen) further potentiated PLD. PEG GO/tamoxifen induced more gene expression of PLD marker than tamoxifen alone. PEG GO enhanced DIP was also observed for other CAD, indicating that nanocarrier potentiated DIP could be universal. More lamellar bodies were observed in PEG GO/tamoxifen treated cells than tamoxifen alone by transmission electron microscopy. When compared with tamoxifen alone, PEG-GO/tamoxifen showed a delayed but potent PLD. In addition, the retarded PLD recovery by PEG-GO/tamoxifen indicated that the reversibility of DIP was interfered. Confocal microscopy revealed the increased number of lysosomes, greater expression of lysosomal associated membrane protein 2 (LAMP2) (a PLD marker), and an increase in the co localization between lysosome/LAMP2 and NBD-PE by PEG-GO/tamoxifen rather than tamoxifen alone. Finally, we found that PEG-GO or/and tamoxifen-induced PLD seemed to have no correlation with autophagy. This research suggests pharmaceutical companies and regulatory agencies that if nanoparticles are used as the vectors for drug delivery, the adverse drug effects may be further potentiated probably through the long-term accumulation of nanocarriers. PMID- 28013221 TI - Biochemical characterization of the flagellar stator-associated inner membrane protein FliL from Vibrio alginolyticus. AB - The flagellar motor is embedded in the cell envelope and rotates upon interaction between the stator and the rotor. The rotation is powered by ion flow through the stator. A single transmembrane protein named FliL is associated with torque generation in the flagellar motor. We established an Escherichia coli over expression system for FliL of Vibrio alginolyticus, a marine bacterium that has a sodium-driven polar flagellum. We successfully expressed, purified, and crystallized the ca. 17 kDa full-length FliL protein and generated a construct that expresses only the ca. 14 kDa periplasmic region of FliL (DeltaTM FliL). Biochemical characterization and NMR analysis revealed that DeltaTM FliL weakly interacted with itself to form an oligomer. We speculate that the observed dynamic interaction may be involved in the role of FliL in flagellar motor function. PMID- 28013222 TI - Generation and characterization of monoclonal antibodies against human LGR6. AB - Leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) is a seven pass transmembrane protein known to be a marker of stem cells in several organs. To deepen our understanding of the cell biology of LGR6-positive cells, including stem cells, we generated monoclonal antibodies (mAbs) against human LGR6. DNA immunization followed by whole-cell immunization with LGR6-expressing transfectants was performed to obtain mAbs that recognized the native form of LGR6. Hybridomas were screened by flow cytometry using LGR6-transfected cells. Because the molecules of LGR4, LGR5, and LGR6 are 50% homologous at the amino acid level, specificity of the mAbs was confirmed by transfectants expressing LGR4, LGR5, or LGR6. Three LGR6-specific mAbs were generated. Two of the three mAbs (designated 43A6 and 43D10) recognized the large N-terminal extracellular domain of LGR6, and competitively blocked the binding of R-spondin 1, which is known to be the ligand for LGR6. The other mAb, 43A25, recognized the seven-pass transmembrane domain of LGR6, and was able to be used for immunoblot analysis. In addition, mAbs 43A6 and 43D10 detected endogenous expression of LGR6 in cancer cell lines. We expect that our mAbs will contribute to widening our understanding of LGR6-positive cells in humans. PMID- 28013223 TI - Site-1 protease is required for the generation of soluble (pro)renin receptor. AB - The extracellular domain of the (pro)renin receptor [(P)RR] is cleaved to generate the soluble form of (P)RR [s(P)RR]. Multiple clinical studies have revealed the association between serum/plasma s(P)RR levels and certain diseases, thereby suggesting a potential role for s(P)RR as a disease biomarker. Here, we investigated whether site-1 protease (S1P) is responsible for cleaving (P)RR to generate s(P)RR. Reduction of endogenous S1P with siRNA attenuated s(P)RR generation in Chinese hamster ovary (CHO) cells exogenously expressing human (P)RR with a C-terminal decahistidine tag [CHO/h(P)RR-10His cells]; conversely, overexpression of S1P by transient transfection increased s(P)RR generation. The S1P inhibitor PF429242 suppressed s(P)RR generation in CHO/h(P)RR-10His and human cervical carcinoma HeLa cells; however, the ADAM inhibitor GM6001 had no effect. The furin inhibitor Dec-RVKR-CMK had no effect on the amount of s(P)RR, but caused a slight increase in the size of the s(P)RR. Moreover, the reversible vesicle-trafficking inhibitor brefeldin A (BFA) enhanced the generation of large sized s(P)RR; PF429242, but not Dec-RVKR-CMK, suppressed this BFA-induced s(P)RR formation. The size of s(P)RR generated during BFA treatment was reduced after removal of BFA; Dec-RVKR-CMK, but not PF429242, suppressed this conversion. Together, these results suggest that s(P)RR is generated by sequential processing by S1P and furin. PMID- 28013224 TI - Context-dependent regulation of the beta-catenin transcriptional complex supports diverse functions of Wnt/beta-catenin signaling. AB - Wnt/beta-catenin signaling is activated repeatedly during an animal's lifespan, and it controls gene expression through its essential nuclear effector, beta catenin, to regulate embryogenesis, organogenesis, and adult homeostasis. Although the beta-catenin transcriptional complex has the ability to induce the expression of many genes to exert its diverse roles, it chooses and transactivates a specific gene set from among its numerous target genes depending on the context. For example, the beta-catenin transcriptional complex stimulates the expression of cell cycle-related genes and consequent cell proliferation in neural progenitor cells, while it promotes the expression of neural differentiation-related genes in differentiating neurons. Recent studies using animal and cell culture models have gradually improved our understanding of the molecular basis underlying such context-dependent actions of the beta-catenin transcriptional complex. Here, we describe eight mechanisms that support beta catenin-mediated context-dependent gene regulation, and their spatio-temporal regulation during vertebrate development. In addition, we discuss their contribution to the diverse functions of Wnt/beta-catenin signaling. PMID- 28013225 TI - Wnt-expressing cells in the intestines: guides for tissue remodeling. AB - The crypt is a minimal functional unit in the intestinal epithelium. This unique structure is maintained by surrounding mesenchymal cells that focally interact with associated epithelial cells. Canonical and non-canonical Wnt ligands enable specific microenvironments localized to each end of the crypt major axis. While canonical Wnt-expressing cells are localized near the crypt bottom where intestinal stem cells reside, non-canonical Wnt-expressing cells are positioned beneath the luminal surface of epithelial cells. During wound healing, propagation and appropriate relocation of each cell population are thought to ensure subsequent crypt regeneration. In this review, I integrate information from recent studies on Wnt-expressing cells and intestinal fibroblast lineages and discuss their roles in homeostasis and wound healing. More information on the lineages of Wnt-expressing cells will help clarify the mechanisms of epithelial tissue formation. PMID- 28013226 TI - Disseminated Intravascular Coagulation. AB - OBJECTIVES: To provide a review of the definition, pathophysiology, differential diagnosis, and treatment of disseminated intravascular coagulation (DIC). METHODS: A case scenario and a review of the literature related to the pertinent facts concerning DIC are provided. RESULTS: DIC is a systemic pathophysiologic process and not a single disease entity, resulting from an overwhelming activation of coagulation that consumes platelets and coagulation factors and causes microvascular fibrin thrombi, which can result in multiorgan dysfunction syndrome from tissue ischemia. Some conditions associated with acute DIC include septic shock, exsanguinating trauma, burns, or acute promyelocytic leukemia. CONCLUSIONS: The massive tissue factor stimulus results in excess intravascular thrombin, which overcomes the anticoagulant systems and leads to thrombosis. Because of consumption of coagulation factors and platelets, DIC also has a hemorrhagic phase. Treatment of the bleeding patient with DIC is supportive with the use of blood components. PMID- 28013227 TI - A prospective study of the association between orthostatic hypotension and falls: definition matters. AB - Background: falls are a common cause of morbidity and mortality in older people. Orthostatic hypotension (OH) is considered an important risk factor for falls, but longitudinal studies have failed to show a clear association. This disparity may be because conventional methods of measuring blood pressure (BP) changes are too imprecise and/or the diagnostic criteria for OH are inappropriate. Over recent years, beat-to-beat BP monitoring techniques, which enabled accurate measurement of vasodepression, have become widely used and in 2011 the American Academy of Neurology produced revised diagnostic criteria for OH. Objective: to use beat-to-beat monitoring to compare the prevalence of OH using the standard and revised diagnostic criteria and to establish which criteria are most valuable in predicting future falls. Design: two hundred and ninety-seven community dwelling older people aged >=65 years underwent assessment. Active stand using digital photoplethysmography was used to record postural change in BP. One hundred participants were asked to complete prospective weekly falls diaries for 12 months. Results: OH, defined according to the revised American Academy of Neurology diagnostic criteria, affected 25% of participants and was an independent predictor of falls (odds ratio 10.299, 95% confidence interval [95% CI]: 1.703-61.43, P = 0.011) and time to first fall (hazard ratio 3.017, 95% CI: 1.291-7.050, P = 0.011). OH, defined according to standard criteria, affected 80% of the population and was not associated with falls. Conclusion: OH, defined according to 2011 criteria, is associated with falls and time to first fall. These findings indicate that beat-to-beat monitoring and the 2011 criteria for OH are valuable in the clinical assessment of older fallers. PMID- 28013228 TI - Comparative effectiveness of radical prostatectomy and curative radiotherapy in localized prostate cancer: long-term follow-up. AB - We sought to investigate the long-term outcomes after radical prostatectomy (RP) and external-beam radiation therapy (EBRT) for the treatment of localized prostate cancer in Japanese patients. RP and radiation therapy are curative treatments for localized prostate cancer. However, there is controversy around which treatment is superior in Japanese patients. The aim of our retrospective study was to compare the long-term clinical outcomes of each treatment. We retrospectively evaluated the overall survival (OS), cancer-specific survival (CSS) and biochemical failure-free survival (BFS) for patients who had been diagnosed with localized prostate cancer and treated with RP (n = 248) or conventional 2D or 3D-CRT EBRT (n = 182) between 1995 and 2009. The median OS was superior in the RP group compared with that in EBRT group (P < 0.001), although CSS was comparable for both treatment groups; BFS was superior for the EBRT group compared with that for the RP group (P = 0.04). Univariate analysis identified a prostate-specific antigen count (PSA)of >=20 vs <20 mg/ml, clinical T-stage of the tumor and Gleason score as predictors for CSS. However, multivariate analysis did not identify a factor for CSS. Subgroup analysis was also performed based on clinical T stage, PSA and Gleason score, but there was no difference in each subgroup between RP and EBRT. Both treatments provided satisfactory clinical outcomes in terms of disease control in localized prostate cancer. PMID- 28013229 TI - Realizing pipe dreams - a detailed picture of vascular development. PMID- 28013230 TI - Evolution of plant conducting cells: perspectives from key regulators of vascular cell differentiation. AB - One crucial problem that plants faced during their evolution, particularly during the transition to growth on land, was how to transport water, nutrients, metabolites, and small signaling molecules within a large, multicellular body. As a solution to this problem, land plants developed specific tissues for conducting molecules, called water-conducting cells (WCCs) and food-conducting cells (FCCs). The well-developed WCCs and FCCs in extant plants are the tracheary elements and sieve elements, respectively, which are found in vascular plants. Recent molecular genetic studies revealed that transcriptional networks regulate the differentiation of tracheary and sieve elements, and that the networks governing WCC differentiation are largely conserved among land plant species. In this review, we discuss the molecular evolution of plant conducting cells. By focusing on the evolution of the key transcription factors that regulate vascular cell differentiation, the NAC transcription factor VASCULAR-RELATED NAC-DOMAIN for WCCs and the MYB-coiled-coil (CC)-type transcription factor ALTERED PHLOEM DEVELOPMENT for sieve elements, we describe how land plants evolved molecular systems to produce the specialized cells that function as WCCs and FCCs. PMID- 28013232 TI - Memory-Guided Stumbling Correction in the Hindlimb of Quadrupeds Relies on Parietal Area 5. AB - In complex environments, tripping over an unexpected obstacle evokes the stumbling corrective reaction, eliciting rapid limb hyperflexion to lift the leg over the obstruction. While stumbling correction has been characterized within a single limb in the cat, this response must extend to both forelegs and hindlegs for successful avoidance in naturalistic settings. Furthermore, the ability to remember an obstacle over which the forelegs have tripped is necessary for hindleg clearance if locomotion is delayed. Therefore, memory-guided stumbling correction was studied in walking cats after the forelegs tripped over an unexpected obstacle. Tactile input to only one foreleg was often sufficient in modulating stepping of all four legs when locomotion was continuous, or when hindleg clearance was delayed. When obstacle height was varied, animals appropriately scaled step height to obstacle height. As tactile input without foreleg clearance was insufficient in reliably modulating stepping, efference, or proprioceptive information about modulated foreleg stepping may be important for producing a robust, long-lasting memory. Finally, cooling-induced deactivation of parietal area 5 altered hindleg stepping in a manner indicating that animals no longer recalled the obstacle over which they had tripped. Altogether, these results demonstrate the integral role area 5 plays in memory-guided stumbling correction. PMID- 28013231 TI - Neurexins 1-3 Each Have a Distinct Pattern of Expression in the Early Developing Human Cerebral Cortex. AB - Neurexins (NRXNs) are presynaptic terminal proteins and candidate neurodevelopmental disorder susceptibility genes; mutations presumably upset synaptic stabilization and function. However, analysis of human cortical tissue samples by RNAseq and quantitative real-time PCR at 8-12 postconceptional weeks, prior to extensive synapse formation, showed expression of all three NRXNs as well as several potential binding partners. However, the levels of expression were not identical; NRXN1 increased with age and NRXN2 levels were consistently higher than for NRXN3. Immunohistochemistry for each NRXN also revealed different expression patterns at this stage of development. NRXN1 and NRXN3 immunoreactivity was generally strongest in the cortical plate and increased in the ventricular zone with age, but was weak in the synaptogenic presubplate (pSP) and marginal zone. On the other hand, NRXN2 colocalized with synaptophysin in neurites of the pSP, but especially with GAP43 and CASK in growing axons of the intermediate zone. Alternative splicing modifies the role of NRXNs and we found evidence by RNAseq for exon skipping at splice site 4 and concomitant expression of KHDBRS proteins which control this splicing. NRXN2 may play a part in early cortical synaptogenesis, but NRXNs could have diverse roles in development including axon guidance, and intercellular communication between proliferating cells and/or migrating neurons. PMID- 28013233 TI - The Influence of Alertness on the Spatial Deployment of Visual Attention is Mediated by the Excitability of the Posterior Parietal Cortices. AB - With a reduced level of alertness, healthy individuals typically show a rightward shift when deploying visual attention in space. The impact of alertness on the neural networks governing visuospatial attention is, however, poorly understood. By using a transcranial magnetic stimulation twin-coil approach, the present study aimed at investigating the effects of an alertness manipulation on the excitability of the left and the right posterior parietal cortices (PPCs), crucial nodes of the visuospatial attentional network. Participants' visuospatial attentional deployment was assessed with a free visual exploration task and concurrent eye tracking. Their alertness level was manipulated through the time of the day, that is, by testing chronotypically defined evening types both during their circadian on- and off-peak times. The results revealed an increased excitability of the left compared with the right PPC during low alertness. On the horizontal dimension, these results were accompanied by a significant rightward shift in the center and a bilateral narrowing in the periphery of the visual exploration field, as well as a central upward shift on the vertical dimension. The findings show that the manipulation of non-spatial attentional aspects (i.e., alertness) can affect visuospatial attentional deployment and modulate the excitability of areas subtending spatial attentional control. PMID- 28013234 TI - Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex. AB - Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident-intruder stress produced age- and sex specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence. PMID- 28013235 TI - Kinase impact assessment in the landscape of fusion genes that retain kinase domains: a pan-cancer study. AB - Assessing the impact of kinase in gene fusion is essential for both identifying driver fusion genes (FGs) and developing molecular targeted therapies. Kinase domain retention is a crucial factor in kinase fusion genes (KFGs), but such a systematic investigation has not been done yet. To this end, we analyzed kinase domain retention (KDR) status in chimeric protein sequences of 914 KFGs covering 312 kinases across 13 major cancer types. Based on 171 kinase domain-retained KFGs including 101 kinases, we studied their recurrence, kinase groups, fusion partners, exon-based expression depth, short DNA motifs around the break points and networks. Our results, such as more KDR than 5'-kinase fusion genes, combinatorial effects between 3'-KDR kinases and their 5'-partners and a signal transduction-specific DNA sequence motif in the break point intronic sequences, supported positive selection on 3'-kinase fusion genes in cancer. We introduced a degree-of-frequency (DoF) score to measure the possible number of KFGs of a kinase. Interestingly, kinases with high DoF scores tended to undergo strong gene expression alteration at the break points. Furthermore, our KDR gene fusion network analysis revealed six of the seven kinases with the highest DoF scores (ALK, BRAF, MET, NTRK1, NTRK3 and RET) were all observed in thyroid carcinoma. Finally, we summarized common features of 'effective' (highly recurrent) kinases in gene fusions such as expression alteration at break point, redundant usage in multiple cancer types and 3'-location tendency. Collectively, our findings are useful for prioritizing driver kinases and FGs and provided insights into KFGs' clinical implications. PMID- 28013236 TI - Comparing genome versus proteome-based identification of clinical bacterial isolates. AB - Whole-genome sequencing (WGS) is gaining importance in the analysis of bacterial cultures derived from patients with infectious diseases. Existing computational tools for WGS-based identification have, however, been evaluated on previously defined data relying thereby unwarily on the available taxonomic information.Here, we newly sequenced 846 clinical gram-negative bacterial isolates representing multiple distinct genera and compared the performance of five tools (CLARK, Kaiju, Kraken, DIAMOND/MEGAN and TUIT). To establish a faithful 'gold standard', the expert-driven taxonomy was compared with identifications based on matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectrometry (MS) analysis. Additionally, the tools were also evaluated using a data set of 200 Staphylococcus aureus isolates.CLARK and Kraken (with k =31) performed best with 626 (100%) and 193 (99.5%) correct species classifications for the gram-negative and S. aureus isolates, respectively. Moreover, CLARK and Kraken demonstrated highest mean F-measure values (85.5/87.9% and 94.4/94.7% for the two data sets, respectively) in comparison with DIAMOND/MEGAN (71 and 85.3%), Kaiju (41.8 and 18.9%) and TUIT (34.5 and 86.5%). Finally, CLARK, Kaiju and Kraken outperformed the other tools by a factor of 30 to 170 fold in terms of runtime.We conclude that the application of nucleotide-based tools using k-mers-e.g. CLARK or Kraken-allows for accurate and fast taxonomic characterization of bacterial isolates from WGS data. Hence, our results suggest WGS-based genotyping to be a promising alternative to the MS-based biotyping in clinical settings. Moreover, we suggest that complementary information should be used for the evaluation of taxonomic classification tools, as public databases may suffer from suboptimal annotations. PMID- 28013237 TI - Optimization of cell lines as tumour models by integrating multi-omics data. PMID- 28013238 TI - Genetic characterization of plasmid-mediated quinolone resistance gene qnrS2 in Pseudoalteromonas and Shewanella isolates from seawater. AB - Three qnrS2-containing isolates of Pseudoalteromonas and Shewanella were collected from the seawater samples of Qingdao in China during 2014. They displayed resistance to ampicillin, ciprofloxacin, kanamycin, nalidixic acid and sulfamethoxazole. The qnrS2 genes were identified in the chromosomes of Pseudoalteromonas strains E8 and S16, and in a 140-kb plasmid in Shewanella strain S14, respectively. In addition, two copies of qnrS2 were identified in the strain E8. Sequence analyses revealed that there was an identical DNA segment located in the downstream of qnrS2 in strain S14 and E8, coding for a TetR transcriptional regulator, two putative integrases and a hypothetical protein. However, different genetic structures were identified in the upstream sequences: the terB gene associated with tellurite resistance in the strain S14, and a putative integron with dfrA6 and aadA13 gene cassettes or the Tn7-related gene complex tnsABC in the strain E8. In Pseudoalteromonas strain S16, qnrS2 was bracketed by the endonuclease I and III genes, and the electron transport complex rsxCDGE was located in the upstream sequences. This is the first report of two copies of the qnrS2 gene existing in one bacterial chromosome, and also the first identification of qnrS2 in Shewanella. PMID- 28013239 TI - Insights into the function of FhaA, a cell division-associated protein in mycobacteria. AB - FhaA is a forkhead-associated domain-containing protein, the depletion of which leads to accumulation of peptidoglycan (PG) precursors at the septum and poles in Mycobacterium smegmatis (M. smegmatis), by a mechanism undefined thus far. To elucidate its function, we constructed an fhaA (MSMEG_0035) knockout (DeltafhaA) strain in M. smegmatis and demonstrated that this gene is dispensable for in vitro growth. The mutant showed a short cell length phenotype due to a probable defect in cell elongation/cell wall synthesis, which was reversed by complementation with both M. smegmatis and Mycobacterium tuberculosis (M. tb) fhaA (Rv0020c), confirming their association with the observed phenotype. The identification of penicillin binding protein A (PbpA), a PG biosynthesis enzyme as an interacting partner for mycobacterial FhaA, provided a hint into the functioning of FhaA. A drastic reduction in the levels of ectopically expressed PbpA in the DeltafhaA mutant vs wild-type M. smegmatis suggested that FhaA interacts with and stabilises PbpA. In addition, the fhaA deletion mutant was sensitive to multiple classes of antibiotics pointing to a general permeability defect. Our findings uncover a role for FhaA in PG biosynthesis and suggest its involvement in the maintenance of mycobacterial cell envelope integrity. PMID- 28013240 TI - A class II hydrophobin gene, Trhfb3, participates in fungal asexual development of Trichoderma reesei. AB - Hydrophobin proteins originate from filamentous fungi, which are able to self assemble at water-air interfaces. Hydrophobins have multiple functions in fungal growth and development. In this study, the function of the Trhfb3 gene encoding a class II hydrophobin was characterized in Trichoderma reesei. The null mutant of Trhfb3 presented a wettable phenotype and a significantly reduced conidial production compared with the parent strain. The DeltaTrhfb3 mutant also exhibited less biomass formation than the parent strain. In addition, Trhfb3 was expressed on carbon sources that induce lignocellulytic enzymes, with the highest expression level detected on cellobiose. The results show that Trhfb3 has a role in vegetative growth and asexual development in T. reesei. PMID- 28013241 TI - Lethal gene drive selects inbreeding. AB - The use of 'selfish' gene drive systems to suppress or even extinguish populations has been proposed on theoretical grounds for almost half a century. Creating these genes has recently become possible with CRISPR technology. One seemingly feasible approach, originally proposed by Burt, is to create a homing endonuclease gene (HEG) that inserts into an essential gene, enabling heterozygote viability but causing homozygote lethality. With 100% segregation distortion in gametes, such genes can cause profound population suppression if resistance does not evolve. Here, population genetic models are used to consider the evolution of inbreeding (specifically selfing) as a possible response to a recessively lethal HEG with complete segregation distortion. Numerical analyses indicate a rich set of outcomes, but selfing often evolves in response to the HEG, with a corresponding partial restoration of mean fitness. Whether selfing does indeed evolve and its effect in restoring fitness depends heavily on the magnitude of inbreeding depression. Overall, these results point toward an underappreciated evolutionary response to block the harmful effects of a selfish gene. They raise the possibility that extreme population suppression may be resisted by mechanisms that are independent of the molecular basis of gene drive. At the same time, the evolution of inbreeding is not assured even if the genetic basis for inbreeding is present. As the models here strictly apply to hermaphrodites (plants), an important next step is to consider inbreeding in populations with separate sexes. PMID- 28013242 TI - Development and Validation of a Gas Chromatography Method for Quality Control of Residual Solvents in Azilsartan Bulk Drugs. AB - A new gas chromatographic method for the simultaneous determination of six organic residual solvents (acetonitrile, tetrahydrofuran, ethanol, acetone, 2 propanol and ethyl acetate) in azilsartan bulk drug is described. The chromatographic determination was achieved on an OV-624 capillary column employing programmed temperature within 21 min. The validation was carried out according to International Conference on Harmonization validation guidelines. The method was shown to be specific (no interference in the blank solution), sensitive (Limit of detection can achieve 1.5 MUg/mL), precise (relative standard deviation of repeatability and intermediate precision <=5.0%), linear (r>= 0.999), accurate (recoveries range from 98.8% to 107.8%) and robust (carrier gas flow from 2.7 to 3.3 mL/min, initial oven temperature from 35 degrees C to 45 degrees C, temperature ramping rate from 19 degrees C/min to 21 degrees C/min, final oven temperature from 145 degrees C to 155 degrees C, injector temperature from 190 degrees C to 210 degrees C and detector temperature from 240 degrees C to 260 degrees C did not significantly affect the system suitability, test parameters and peak areas). This extensively validated method has been applied to the determination of residual solvents in real azilsartan bulk samples. PMID- 28013243 TI - Predicting risk of substantial weight gain in German adults-a multi-center cohort approach. AB - Background: A risk-targeted prevention strategy may efficiently utilize limited resources available for prevention of overweight and obesity. Likewise, more efficient intervention trials could be designed if selection of subjects was based on risk. The aim of the study was to develop a risk score predicting substantial weight gain among German adults. Methods: We developed the risk score using information on 15 socio-demographic, dietary and lifestyle factors from 32 204 participants of five population-based German cohort studies. Substantial weight gain was defined as gaining >=10% of weight between baseline and follow-up (>6 years apart). The cases were censored according to the theoretical point in time when the threshold of 10% baseline-based weight gain was crossed assuming linearity of weight gain. Beta coefficients derived from proportional hazards regression were used as weights to compute the risk score as a linear combination of the predictors. Cross-validation was used to evaluate the score's discriminatory accuracy. Results: The cross-validated c index (95% CI) was 0.71 (0.67-0.75). A cutoff value of >=475 score points yielded a sensitivity of 71% and a specificity of 63%. The corresponding positive and negative predictive values were 10.4% and 97.6%, respectively. Conclusions: The proposed risk score may support healthcare providers in decision making and referral and facilitate an efficient selection of subjects into intervention trials. PMID- 28013244 TI - A European perspective on GIS-based walkability and active modes of transport. AB - Background: The association between GIS-based walkability and walking for transport is considered to be well established in USA and in Australia. Research on the association between walkability and cycling for transport in European cities is lacking. The aim of this study was to test the predictive validity of established walkability measures and to explore alternative walkability measures associated with walking and cycling for transport in a European context. Methods: Outcome data were derived from the representative cross-sectional survey ( n  = 843) ‘Radfreundliche Stadt’ of adults in the city of Graz (Austria). GIS-based walkability was measured using both established measures (e.g. gross population density, household unit density, entropy index, three-way intersection density, IPEN walkability index) and alternative measures (e.g. proportion of mixed land use, four-way intersection density, Graz walkability index). ANCOVAs were conducted to examine the adjusted association between walkability measures and outcomes. Results: Household unit density, proportion of mixed land use, three-way intersection density and IPEN walkability index were positively associated with walking for transport, but the other measures were not. All walkability measures were positively associated with cycling for transport. Conclusion: The established walkability measures were applicable to a European city such as Graz. The alternative walkability measures performed well in a European context. Due to measurement issues the association between these walkability measures and walking for transport needs to be investigated further. PMID- 28013245 TI - European studies on prevalence and risk of autism spectrum disorders according to immigrant status-a review. AB - Background: Autism spectrum disorders (ASDs), once considered to be rare, are now reaching prevalence estimates of 1% and higher. Studies conducted in North America indicate large racial/ethnic disparities in the diagnosis of ASDs. Others show, that immigrant children have similar prevalence rates of ASDs as native children, although they are diagnosed later compared with native children. In relation to a EU funded network action, Enhancing the Scientific Study of Early Autism, it was considered important to review the literature on this subject. Method: A comprehensive literature search was undertaken for original articles reporting on prevalence and risk for ASD in Europe among immigrants and ethnic minorities and data across studies were compared. Results: Seventeen studies conducted in Europe concerning immigrants and ethnic minorities were found. Fifteen studies suggest a higher prevalence rate of ASDs among children of immigrants in comparison to native children (RR = 1.02-1.74; OR = 0.6-10.5). One study revealed higher prevalence of autism (OR = 2.2; 95% CI 1.6-3.1) and lower prevalence of Asperger syndrome in immigrants (OR = 0.6; 95% CI 0.3-0.97). One study showed a lower prevalence of Asperger syndrome in immigrants (aOR = 0.1, 95% CI 0.01-0.5). The majority of those analyses involved immigrants from outside Europe, e.g. from Africa and South America. Conclusion: After analysing the results of studies conducted in Europe, it is unclear if higher prevalence estimates of ASDs among immigrants in this region reflect true differences, especially considering many potential confounding factors, e.g. genetic, biological, environmental and cultural. Considering the number of people migrating within Europe there is a substantial need to study further the prevalence of ASDs in immigrant groups. PMID- 28013246 TI - Adherence to cancer treatment guidelines: influence of general and cancer specific guideline characteristics. AB - Background: Guideline adherence remains a challenge in clinical practice, despite guidelines' ascribed potential to improve patient outcomes. We studied the level of adherence to recommendations from Dutch national cancer treatment guidelines, and the influence of general and cancer-specific guideline characteristics on adherence. Methods: Based on data from a national cancer registry, adherence was evaluated for 15 treatment recommendations for breast, colorectal, prostate and lung cancer, and melanoma. Recommendations were selected by representatives of the medical specialist associations responsible for developing and implementing the guidelines. We used multivariable multilevel analysis to calculate mean adherence and variation between individual hospitals. Results: Mean adherence to the different treatment recommendations ranged from 40 to 99%. Adherence differed only slightly between older and newer guidelines and between recommendations with low, moderate or high levels of evidence (range 79-84% and 77-91%, respectively), while adherence differed more between recommendations for different cancer types (range 54-99%), different treatment modalities (adherence ranged from 40 to 92%) or recommendations that advised against or recommended in favour of particular treatment (adherence ranged from 75 to 98%). Conclusion: We found significant variation in adherence between different cancer treatment guidelines. While some guideline characteristics that seem to explain this variation may be considered difficult to modify, the potential for variance across cancer types and treatment modalities suggests that adherence could be further improved. At the same time, these results warrant tailored strategies for the improvement of adherence to clinical practice guidelines. PMID- 28013247 TI - Evidence for Hepatitis A virus endemic circulation in Israel despite universal toddlers' vaccination since 1999 and low clinical incidence in all age groups. AB - Background: Universal toddlers vaccination (UTV) introduced in 1999, reduced hepatitis A incidence in Israel from 50.4 to <1.0/100,000. The current Hepatitis A virus (HAV) molecular epidemiology in Israel was studied 13-14y post UTV introduction.. Methods: An outbreak in Tel-Aviv with 75 cases in 2012-2013 was investigated. Real-time RT-PCR and sequencing of the VP1-2A region (1100bp) was done on: a. serum samples from patients with acute Hepatitis A (12/ 75 in Tel Aviv and 31 patients hospitalized in 3 other major cities in 2011-2013); b. in sewage samples (27 from metropolitan Tel-Aviv, 14 from the other 3 cities and 6 from Gaza). Results: The outbreak began among intravenous drug users then spread to the general population. Patients' mean age was 33.2y, 4/75(5.3%) had been vaccinated and 58/75(77.3%) were hospitalized. No common environmental source was found. HAV was detected in sewage samples: 16/27(59.2%) from Tel-Aviv; 4/14(28.6%) collected throughout Israel and 6/6 (100%) from Gaza. Genotype IB predominated (52/53 sequenced samples) and identical strains were demonstrated in the Israeli and Palestinian populations by phylogenetic analysis. Conclusions: Despite the UTV success, HAV circulation in the Israeli population continues, apparently due to its close contacts with the endemic Palestinian population. Reassessment of vaccination policy is recommended. PMID- 28013248 TI - Kynurenine Pathway Activation in Human African Trypanosomiasis. AB - Background: The kynurenine pathway of tryptophan oxidation is associated with central nervous system (CNS) inflammatory pathways. Inhibition of this pathway ameliorates CNS inflammation in rodent models of the late (meningoencephalitic) stage of human African trypanosomiasis (HAT). In this study, we evaluate whether the kynurenine pathway is activated in clinical HAT and associated with CNS inflammatory responses. Methods: We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in patients infected with Trypanosoma brucei rhodesiense, using liquid chromatography-mass spectrometry. Results: Kynurenine concentration in CSF was increased in both the early and late stages of disease, with a progressive increase in tryptophan oxidation associated with stage progression. Kynurenine pathway activation was associated with increases in neuroinflammatory markers, but there was no clear relationship to neurological symptoms. Conclusions: CNS kynurenine pathway activation occurs during HAT, including cases prior to the current diagnostic cutoff for late-stage infection, providing evidence for early CNS involvement in HAT. Metabolite data demonstrate that the kynurenine-3-monooxygenase and kynurenine aminotransferase branches of the kynurenine pathway are active. The association between tryptophan oxidation and CNS inflammatory responses as measured by CSF interleukin 6 (IL-6) concentration supports a role of kynurenine metabolites in the inflammatory pathogenesis of late-stage HAT. PMID- 28013249 TI - The global distribution of bamboos: assessing correlates of introduction and invasion. AB - There is a long history of species being moved around the world by humans. These introduced species can provide substantial benefits, but they can also have undesirable consequences. We explore the importance of human activities on the processes of species dissemination and potential invasions using the grass subfamily Bambusoideae ("bamboos"), a group that contains taxa that are widely utilised and that are often perceived as weedy. We (1) compiled an inventory of bamboo species and their current distributions; (2) determined which species have been introduced and become invasive outside their native ranges; and (3) explored correlates of introduction and invasion. Distribution data were collated from Kew's GrassBase, the Global Biodiversity Information Facility and other online herbarium information sources. Our list comprised 1662 species in 121 genera, of which 232 (14%) have been introduced beyond their native ranges. Twelve species were found to be invasive. A non-random selection of bamboos have been introduced and become invasive. Asiatic species in particular have been widely introduced. There was a clear over-representation of introduced species in the genera Bambusa and Phyllostachys which also contain most of the listed invasive species. The introduction of species also correlated with certain traits: taxa with larger culm dimensions were significantly more likely to have been moved to new areas; and those with many cultivars had a higher rate of dissemination and invasion. It is difficult to determine whether the patterns of introduction and invasion are due simply to differences in propagule pressure, or whether humans have deliberately selected inherently invasive taxa. In general, we suggest that human usage is a stronger driver of introductions and invasions in bamboos than in other taxa that have been well studied. It is likely that as bamboos are used more widely, the number and impact of invasions will increase unless environmental risks are carefully managed. PMID- 28013250 TI - Ecological disequilibrium drives insect pest and pathogen accumulation in non native trees. AB - Non-native trees have become dominant components of many landscapes, including urban ecosystems, commercial forestry plantations, fruit orchards, and as invasives in natural ecosystems. Often, these trees have been separated from their natural enemies (i.e. insects and pathogens) leading to ecological disequilibrium, that is, the immediate breakdown of historically co-evolved interactions once introduced into novel environments. Long-established, non native tree plantations provide useful experiments to explore the dimensions of such ecological disequilibria. We quantify the status quo of non-native insect pests and pathogens catching up with their tree hosts (planted Acacia, Eucalyptus and Pinus species) in South Africa, and examine which native South African enemy species utilise these trees as hosts. Interestingly, pines, with no confamilial relatives in South Africa and the longest residence time (almost two centuries), have acquired only one highly polyphagous native pathogen. This is in contrast to acacias and eucalypts, both with many native and confamilial relatives in South Africa that have acquired more native pathogens. These patterns support the known role of phylogenetic relatedness of non-native and native floras in influencing the likelihood of pathogen shifts between them. This relationship, however, does not seem to hold for native insects. Native insects appear far more likely to expand their feeding habits onto non-native tree hosts than are native pathogens, although they are generally less damaging. The ecological disequilibrium conditions of non-native trees are deeply rooted in the eco-evolutionary experience of the host plant, co-evolved natural enemies, and native organisms from the introduced range. We should expect considerable spatial and temporal variation in ecological disequilibrium conditions among non-native taxa, which can be significantly influenced by biosecurity and management practices. PMID- 28013251 TI - Contrasting effects of ploidy level on seed production in a diploid tetraploid system. AB - Previous studies demonstrated the effects of polyploidy on various aspects of plant life. It is, however, difficult to determine which plant characteristics are responsible for fitness differences between cytotypes. We assessed the relationship between polyploidy and seed production. To separate the effects of flowering phenology, flower head size and herbivores from other possible causes, we collected data on these characteristics in single flower heads of diploid and tetraploid Centaurea phrygia in an experimental garden. We used structural equation modelling to identify the main pathways determining seed production. The results showed that the relationship between polyploidy and seed production is mediated by most of the studied factors. The different factors acted in opposing directions. Wider flower heads displayed higher above the ground suggested higher seed production in diploids. In contrast, earlier flowering and a lower abundance of herbivores suggested higher seed production in tetraploids. However, because phenology was the strongest driver of seed production in this system, the sum of all the pathways suggested greater seed production in tetraploids than in diploids. The pathway linking ploidy level directly to seed production, representing unstudied factors, was not significant. This suggests that the factors studied likely are drivers of the between-cytotype differences. Overall, this study demonstrated that tetraploids possess overall higher fitness estimated as seed production. Regardless of the patterns observed here, strong between year fluctuations in the composition and diversity of insect communities have been observed. The direction of the selection may thus vary between years. Consequently, understanding the structure of the interactions is more important for understanding the system than the overall effects of cytotype on a fitness trait in a specific year. Such knowledge can be used to model the evolution of species traits and plant-herbivore and plant-pollinator interactions in diploid polyploid systems. PMID- 28013252 TI - An examination of nucleotypic effects in diploid and polyploid cotton. AB - Nucleotypic effects are phenotypic changes related to the total nuclear DNA amount per cell. These effects are commonly observed among and within genera for certain cell types, and the generality of the positive correlation between genome size and cell size has been well established. However, there are few studies of nucleotypic effects which incorporate into the analysis both ploidy level and genome size (given as Mbp determined by 2C values). To test the hypothesis that cell size scales with genome size and ploidy, we measured the guard cell length, epidermal pavement cell surface area, and pollen grain diameter using individuals of multiple species and accessions of the cotton genus (Gossypium), in which different species exhibit three-fold variation in genome size. We measured cell sizes using calibrated microscopic image analysis. Significant relationships were found between genome size and cell size, with stronger correlations between guard cell length and genome size than with epidermal pavement cell surface area. We also found a relationship between pollen grain diameter and genome size. These results indicate that nucleotypic effects occur within Gossypium, scale with ploidy level, and are stronger in less variable cell types. PMID- 28013253 TI - Factors Affecting the Target Oxygen Saturation in the First Minutes of Life in Preterm Infants. AB - Background: The aim of this study was to describe the effect of factors on time to reach a pulse oxygen saturation (SpO2) level of 90% in preterm infants in the delivery room. Methods: Preterm (<35 gestational age) infants who did not require supplemental oxygen were included in the study. Continuous recordings were taken by pulse oximetry during the first 15 min of life. Results: Of 151 preterm infants, 79 (52.3%) were female and 126 (83.5%) were delivered by cesarean section. Target saturation level (>=90%) was achieved faster in preductal measurements. Mean times taken to have a preductal and postductal SpO2 level of 90% were significantly lower in preterm babies born by vaginal delivery, with umbilical arterial pH >= 7.20 and whose mothers were non-smokers during pregnancy. Conclusions: Differences in achievement of target saturation level were influenced by multiple factors (birth way, probe location, maternal smoking and umbilical blood gas pH) in the delivery room during resuscitation of preterm babies. PMID- 28013254 TI - Stroke in Pediatric Diabetic Ketoacidosis: Case Series. AB - Diabetic ketoacidosis (DKA) can present with various neurological complications, but stroke is rare. Here, we present three children with recent-onset diabetes with DKA, two of them had deep coma not responding to standard DKA regimen and the third one had seventh nerve palsy noted after recovering from coma. Computed tomography scan of head showed hemorrhage in the area of midbrain in one patient and infarcts in two patients. In any child of DKA with severe neurological impairment, possibility of stroke should be entertained. PMID- 28013255 TI - Preventing Neural Tube Defects. PMID- 28013256 TI - From training to practice: the impact of ENGAGE, Ireland's national men's health training programme. AB - Ireland's National Men's Health Policy recommended developing training programmes tailored to the needs of those working in health and allied health professionals and ENGAGE was developed to meet that recommendation. This study evaluated the impact of ENGAGE on frontline service providers' self-reported knowledge, skills, capacity and practice up to 5-months post training. Between 2012 and 2015, ENGAGE Trainers (n = 57) delivered 62 1-day training programmes to 810 participants. This study was conducted on a subset of those training days (n = 26) and participants. Quantitative methodologies were used to collect pre (n = 295), post (n = 295) and 5-month post (n = 128) training questionnaire data. Overall, participants were highly satisfied with the training immediately post training (8.60 +/- 1.60 out of 10) and at 5-month follow up (8.06 +/- 1.43 out of 10). Participants' self-reported level of knowledge, skill and capacity in identifying priorities, engaging men and influencing practice beyond their own organisation increased immediately following training (P < 0.001) and, with the exception of improving capacity to engage men and influencing practice beyond their organisation, these improvements were sustained at 5-month post training (P < 0.001). The vast majority of service providers (93.4%) reported that ENGAGE had impacted their work practice up to 5-month post training. The findings suggest that ENGAGE has succeeded in improving service providers' capacity to engage and work with men; improving gender competency in the delivery of health and health related services may increase the utilisation of such services by men and thereby improve health outcomes for men. PMID- 28013257 TI - Use of Proton Pump Inhibitors and the Risk of Listeriosis: A Nationwide Registry based Case-Control Study. AB - Background: Recent studies suggest that proton pump inhibitors (PPIs) may increase the risk for listeriosis. We investigated a potential association in cases of nonpregnancy-associated listeriosis using registry data. Methods: We conducted a population-based, case-control study using Danish health registries. Cases (n = 721) were defined as patients aged >=45 years notified with listeriosis from July 1994 to December 2012. We selected 34800 controls using risk-set sampling. Controls were individually matched for age, sex, and municipality. Data on use of PPIs and other drugs and hospitalization diagnoses over a 5-year period were extracted from nationwide health registries. A comorbidity index (CMI) was constructed. We calculated the association between use of PPIs and related drugs within 30 days (current use) and other time windows before the index date. Using conditional logistic regression, matched odds ratios (ORs) adjusted for CMI and confounders were estimated. Results: The adjusted OR for current use of PPIs and development of listeriosis was 2.81 (95% confidence interval [CI], 2.14-3.69). PPI usage up to 90 days before the index date remained statistically significant. Subgroup analyses revealed increasing ORs with decreasing age and level of comorbidity and an increased OR for concurrent glucocorticoid treatment (OR, 4.61; 95% CI, 3.01-7.06). No significant association was found for current use of histamine-2-receptor antagonists (adjusted OR, 1.82; 95% CI, 0.89-3.71). Conclusions: Prescribed PPIs were associated with increased risk of listeriosis. The risk waned with time since last prescription redemption. PPIs may have unwanted side effects in vulnerable populations. PMID- 28013259 TI - Use of Neuraminidase Inhibitors for Treatment of Severe Influenza: Times Are Changing. PMID- 28013258 TI - Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae in a Network of Long Term Acute Care Hospitals. AB - Background: The rapid emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a major public health threat, including in the long-term acute care hospital (LTACH) setting. Our objective in this study was to describe the epidemiologic characteristics of CRKP in a network of US LTACHs. Methods: An observational study was performed among 64 LTACHs from January 2014 to March 2015. Clinical cultures were included, with the first CRKP isolate recovered from each patient per study quarter evaluated. LTACH and geographic area-based CRKP prevalence and clinical and microbiologic characteristics were described. Results: A total of 3846 K. pneumoniae cultures were identified, with an overall carbapenem resistance rate of 24.6%. There were significant differences in CRKP rates across geographic regions, with the highest in the West (42.2%). Of 946 CRKP isolates, 507 (53.6%) were from a respiratory source, 350 (37.0%) from a urinary source, and 9 (9.4%) from blood. Among 821 unique patients with CRKP colonization or infection, the median age was 73 years. There was a high prevalence of respiratory failure (39.8%) and the presence of a central venous catheter (50.9%) or tracheostomy (64.8%). Resistance rates of CRKP isolates were high for amikacin (59.2%) and fluoroquinolones (>97%). The resistance rate to colistin/polymyxin B was 16.1%. Conclusions: Nearly 25% of K. pneumoniae clinical isolates in a US network of LTACHs were CRKP. Expansion of national surveillance efforts and improved communication among LTACHs and acute care hospitals will be critical for reducing the continued emergence of CRKP across the healthcare continuum. PMID- 28013260 TI - Cancer Incidence in Persons Living With HIV. PMID- 28013262 TI - Reply to Meijide et al. PMID- 28013261 TI - Increased Antiviral Treatment Among Hospitalized Children and Adults With Laboratory-Confirmed Influenza, 2010-2015. AB - (See the Editorial Commentary by Martin on pages 368-9.)Using population-based surveillance data, we analyzed antiviral treatment among hospitalized patients with laboratory-confirmed influenza. Treatment increased after the influenza A(H1N1) 2009 pandemic from 72% in 2010-2011 to 89% in 2014-2015 (P < .001). Overall, treatment was higher in adults (86%) than in children (72%); only 56% of cases received antivirals on the day of admission. PMID- 28013263 TI - Invasive Systemic Infection After Hospital Treatment for Diabetic Foot Ulcer: Risk of Occurrence and Effect on Survival. AB - BACKGROUND: Diabetic foot ulcers (DFUs) threaten limbs and prompt hospitalization. After hospitalization, remote-site invasive systemic infection related to DFU (DFU-ISI) may occur. The characteristics of DFU-ISIs and their effect on mortality risk have not been defined. METHODS: We conducted a retrospective cohort study of 819 diabetic patients hospitalized for treatment of 1212 unique DFUs during a 9-year period. We defined the index ulcer as that present at the first (index) DFU admission to our hospital. We defined DFU-ISI as a nonfoot infection that occurred after the index hospitalization and was caused by a microorganism concomitantly or previously cultured from the index ulcer. We determined the frequency, risk factors, and mortality risk associated with DFU ISIs. RESULTS: After 1212 index DFU hospitalizations, 141 patients had 172 DFU ISIs. Of the initial 141 DFU-ISIs, 64% were bacteremia, 13% deep abscesses, 10% pneumonia, 7% endocarditis, and 6% skeletal infections. Methicillin-resistant Staphylococcus aureus (MRSA) caused 57% of the ISIs. Patients with initial DFU cultures yielding MRSA and protracted open ulcers had a high 24-month cumulative probability of DFU-ISI (31%) and all-cause mortality rate (13%). Analysis with Cox regression modeling showed that complicated ulcer healing (hazard ratio, 3.812; 95% confidence interval, 2.434-5.971) and initial DFU culture yielding MRSA (2.030; 1.452-2.838) predicted DFU-ISIs and that DFU-ISIs were associated with increased mortality risk (1.987; 1.106-3.568). CONCLUSIONS: DFU-ISIs are important late complications of DFUs. Prevention of DFU-ISIs should be studied prospectively. Meanwhile, clinicians should aggressively incorporate treatment to accelerate ulcer healing and address MRSA into the care of diabetic patients with foot ulcers. PMID- 28013264 TI - Comparing the Outcomes of Patients With Carbapenemase-Producing and Non Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Bacteremia. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are associated with considerable mortality. As mechanisms of carbapenem resistance are heterogeneous, it is unclear if mortality differs based on resistance mechanisms. We sought to determine whether CRE resistance mechanism determination is prognostically informative. METHODS: We conducted an observational study comparing 14-day mortality between patients with carbapenemase-producing (CP)-CRE compared with non-CP-CRE bacteremia. Clinical data were collected on all patients. A comprehensive DNA microarray-based assay was performed on all isolates to identify beta-lactamase-encoding genes. RESULTS: There were 83 unique episodes of monomicrobial CRE bacteremia during the study period: 37 (45%) CP-CRE and 46 (55%) non-CP-CRE. The majority of CP-CRE isolates were bla KPC (92%), followed by bla NDM (5%) and bla OXA-48-type (3%). CP-CRE isolates were more likely to have meropenem minimum inhibitory concentrations (MICs) >=16 ug/mL, while non-CP-CRE isolates were more likely to have meropenem MICs <=1 ug/mL (P value < .001). A total of 18 (22%) patients died within 14 days, including 12 (32%) in the CP-CRE group and 6 (13%) in the non-CP-CRE group. Adjusting for severity of illness on day 1 of bacteremia, underlying medical conditions, and differences in antibiotic treatment administered, the odds of dying within 14 days were more than 4 times greater for CP-CRE compared with non-CP-CRE bacteremic patients (adjusted odds ratio, 4.92; 95% confidence interval, 1.01-24.81). CONCLUSION: Our findings suggest that CP-CRE may be more virulent than non-CP-CRE and are associated with poorer outcomes. This underscores the added importance of delineating underlying resistance mechanisms of CRE to direct antibiotic treatment decisions. PMID- 28013265 TI - Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis. AB - BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469. PMID- 28013266 TI - Natural History of Cryptosporidiosis in a Birth Cohort in Southern India. AB - BACKGROUND: Cryptosporidium is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention. METHODS: Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for Cryptosporidium species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against Cryptosporidium gp15 and/or Cp23 antigens between consecutive sera. RESULTS: Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4-17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), Cryptosporidium was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (P < .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. Cryptosporidium hominis (73.3%) was the predominant Cryptosporidium species, and there was no species-specific protection. CONCLUSIONS: There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection. PMID- 28013267 TI - Shedding of Hepatitis C Virus Into the Rectum of HIV-infected Men Who Have Sex With Men. AB - BACKGROUND: For over a decade we have known of an epidemic of sexually transmitted hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM), but there still remains significant controversy over which bodily fluid(s) are responsible for HCV transmission in these men. METHODS: We enrolled HIV-infected MSM with recent and chronic HCV infection and quantified HCV from rectal fluid obtained by blind swab. We compared the rectal HCV viral load (VL) with paired blood HCV VL. RESULTS: We found rectal HCV shedding in 20 (47%) of 43 men, only one (2%) of whom had visible bleeding. Detection of rectal HCV shedding was associated with blood VL > 5 log10 IU/mL (p = .01), and 85% with blood VL > 5 log10 IU/mL had rectal shedding. The HCV VL of the rectal fluid ranged from 2.6 to 5.5 log10 IU/mL. Based on the median rectal fluid VL, the surface of an average human penis would be exposed to at least 2,300 IU of HCV for the duration of anal intercourse. CONCLUSION: This study provides the first direct evidence to our knowledge that a sufficient quantity of HCV is shed into the rectum in HIV infected men with HCV infection to directly infect an inserted penis or be passed indirectly through fomite-like transmission to the rectum of sex partner. We must develop an appropriate public health campaign to educate MSM about these routes of HCV infection to reverse the HCV epidemic among HIV-infected MSM. PMID- 28013269 TI - Modelling the Population Health Effects of E-Cigarettes Use: Current Data Can Help Guide Future Policy Decisions. PMID- 28013268 TI - RNA G-quadruplexes: emerging mechanisms in disease. AB - RNA G-quadruplexes (G4s) are formed by G-rich RNA sequences in protein-coding (mRNA) and non-coding (ncRNA) transcripts that fold into a four-stranded conformation. Experimental studies and bioinformatic predictions support the view that these structures are involved in different cellular functions associated to both DNA processes (telomere elongation, recombination and transcription) and RNA post-transcriptional mechanisms (including pre-mRNA processing, mRNA turnover, targeting and translation). An increasing number of different diseases have been associated with the inappropriate regulation of RNA G4s exemplifying the potential importance of these structures on human health. Here, we review the different molecular mechanisms underlying the link between RNA G4s and human diseases by proposing several overlapping models of deregulation emerging from recent research, including (i) sequestration of RNA-binding proteins, (ii) aberrant expression or localization of RNA G4-binding proteins, (iii) repeat associated non-AUG (RAN) translation, (iv) mRNA translational blockade and (v) disabling of protein-RNA G4 complexes. This review also provides a comprehensive survey of the functional RNA G4 and their mechanisms of action. Finally, we highlight future directions for research aimed at improving our understanding on RNA G4-mediated regulatory mechanisms linked to diseases. PMID- 28013270 TI - Impact of the 2015 CMS Inpatient Psychiatric Facility Quality Reporting Rule on Tobacco Treatment. AB - Introduction: In its fiscal year 2015 final rule, the Centers for Medicare & Medicaid Services (CMS) required reporting of tobacco treatment quality measures as part of the Inpatient Psychiatric Facilities Prospective Payment System (IPF PPS). This pre-intervention, post-intervention policy analysis evaluates the impact of that policy at a large academic medical center that opted to improve performance as it implemented reporting measures. Methods: Electronic medical record data were collected retrospectively for all adult (>=18 years) inpatient psychiatric admissions from January 1, 2014 to December 31, 2015. Data from admissions were analyzed to determine changes in the provision of tobacco treatment including the proportions of patients screened for tobacco use, receiving tobacco cessation counseling, and receiving tobacco cessation medication(s) using a chi-square test. Covariate analysis of treatment differences based on psychiatric diagnosis was analyzed using Cochran-Mantel Haenszel and Breslow-Day test. Results: Post-policy screening for admissions increased significantly (85% vs. 97%; p < .001). Referral to cessation counseling increased 18-fold (4% vs. 74%; p < .001). Receipt of Counselling (8% vs. 67%; p < .001) and referral for cessation medication (32% vs. 68%; p < .001) also increased dramatically. Though statistically non-significant, the number of tobacco users who actually received medications increased markedly between 2014 and 2015, 24% versus 35%. Gains in screening, referral, and treatment did not differ by psychiatric diagnosis. Conclusions: The Inpatient Psychiatric Facilities Quality Reporting (IPFQR) Program resulted in a 10-fold increase in the number of smokers who received inpatient tobacco treatment. Should CMS link prospective payment to performance, it could have a major impact on quality of care for tobacco dependence. Implications: This is the first study to examine the implementation and impact of new 2015 IPFQR program tobacco measures. This study may illustrate the potential effect that performance based penalties can have should facilities be required to do more than simply report on these tobacco measures. This study exemplifies the impact these new reporting measures can have when psychiatric facilities move beyond letter of the policy, to continually assess organizational performance and implement changes to improve treatment delivery. PMID- 28013271 TI - Frequency of Youth E-Cigarette and Tobacco Use Patterns in the United States: Measurement Precision Is Critical to Inform Public Health. AB - Introduction: E-cigarette use occurs with tobacco product use in youth. Methods: Using the 2014 National Youth Tobacco Survey (NYTS), we examined past 30-day frequency of cigarette, cigar, smokeless, and e-cigarette use in the context of past 30-day and ever tobacco product use in US middle and high school students (N = 22 007). Frequency of product-specific use was examined by exclusive versus concurrent use with another product in the past 30 days (poly-use). Results: In 2014, the majority (83%) of US middle and high school students had not used tobacco or e-cigarettes in the past 30 days. In the 9.3% of youth reporting any past 30-day e-cigarette use, 63% also reported using a tobacco product; among the 3.3% past 30-day exclusive e-cigarette users, about two-thirds (2.1%) had ever used combustible or non-combustible tobacco products and one-third (1.2%) had not. Few never tobacco users had used e-cigarettes on 10 or more days in the past month (absolute percent < 0.1%). Among past 30-day cigarette and smokeless users, the two highest frequency categories were 1-2 days and daily use; among past 30 day e-cigarette and cigar users, prevalence decreased with increasing frequency of use. The majority of past 30-day cigarette, cigar, smokeless, and e-cigarette users reported poly-use. Conclusions: Prevalence estimates for a single product mask the complex patterns of frequency, temporality, and poly-use in youth. Two thirds of past 30-day exclusive e-cigarette users have ever used tobacco. Poly use is the dominant pattern of tobacco and e-cigarette use among US middle and high school students. Implications: Our study highlights the complexity of tobacco use patterns in US middle and high school students. Future studies addressing the full public health impact of movement into or out of combustible tobacco use will require longitudinal data with appropriate measures of tobacco and e-cigarette product-specific use (eg, frequency and intensity), as well as adequate sample size and a sufficient number of waves to determine how use of individual products, like e-cigarettes, impact progression into or out of more stable patterns of tobacco and e-cigarette use. PMID- 28013272 TI - Trauma-Focused Smoking Cessation for Smokers Exposed to the World Trade Center Disaster: A Randomized Clinical Trial. AB - Introduction: The main objective was to evaluate the efficacy of an 8-session, group-based comprehensive smoking cessation and trauma management (CSC-T) treatment among daily smokers (>=5 cigarettes/day) exposed to the World Trade Center (WTC) disaster with elevated WTC-related post-traumatic stress disorder (PTSD) symptoms. Methods: Participants (N = 90) were randomly assigned to CSC-T (N = 44; 63.6% white; 27.3% female; mean age = 51.32 +/- 7.87) or comprehensive smoking cessation (CSC) alone (N = 46; 71.7% white; 28.3% female; mean age = 48.74 +/- 10.66), which was comparable in length and time. Assessments included a diagnostic clinical interview and self-report measures of PTSD and respiratory symptoms, and smoking behavior, and biologically confirmed smoking abstinence. Evaluations occurred at a baseline visit, each treatment session, and at 1-, 2-, 4-, 12-, and 26-weeks post-treatment. Results: The two treatments did not differ in regard to PTSD symptom improvement. After quit day (week 6), the two groups had similar 7-day (~15%) and 6-month (~20%) abstinence rates as well as average number of cigarettes smoked, and PTSD and respiratory symptoms. Conclusions: It is possible that the Cognitive Behavioral Therapy skills specific to quitting smoking, group-based support, and degree of therapist contact, that were available in both treatments may have played a role in equalizing the abstinence rates between the two conditions. Although the current study found no evidence that the CSC-T was superior to the CSC alone treatment, the abstinence rates observed were high relative to previous trials of smokers with diagnosed PTSD. Further development of smoking cessation programs tailored to the needs of smokers with PTSD symptoms continues to be needed. Implications: This study suggests that a CSC program aids in smoking abstinence for smokers with PTSD symptoms and that incorporating trauma management skills, may not add additional benefits for abstinence and PTSD and respiratory symptom relief. Further work is needed to improve smoking cessation efforts for smokers with PTSD symptoms. PMID- 28013273 TI - CATchUP: A Web Database for Spatiotemporally Regulated Genes. AB - For proper control of biological activity, some key genes are highly expressed in a particular spatiotemporal domain. Mining of such spatiotemporally expressed genes using large-scale gene expression data derived from a broad range of experimental sources facilitates our understanding of genome-scale functional gene networks. However, comprehensive information on spatiotemporally expressed genes is lacking in plants. To collect such information, we devised a new index, Deltadmax, which is the maximum difference in relative gene expression levels between sample runs which are neighboring when sorted by the levels. Employing this index, we comprehensively evaluated transcripts using large-scale RNA sequencing (RNA-Seq) data stored in the Sequence Read Archive for eight plant species: Arabidopsis thaliana (Arabidopsis), Solanum lycopersicum (tomato), Solanum tuberosum (potato), Oryza sativa (rice), Sorghum bicolor (sorghum), Vitis vinifera (grape), Medicago truncatula (Medicago), and Glycine max (soybean). Based on the frequency distribution of the Deltadmax values, approximately 70,000 transcripts showing 0.3 or larger Deltadmax values were extracted for the eight species. Information on these genes including the Deltadmax values, functional annotations, conservation among species, and experimental conditions where the genes show high expression levels is provided in a new database, CATchUP (http://plantomics.mind.meiji.ac.jp/CATchUP). The CATchUP database assists in identifying genes specifically expressed under particular conditions with powerful search functions and an intuitive graphical user interface. PMID- 28013274 TI - Duplication and Whorl-Specific Down-Regulation of the Obligate AP3-PI Heterodimer Genes Explain the Origin of Paeonia lactiflora Plants with Spontaneous Corolla Mutation. AB - Herbaceous peony (Paeonia lactiflora) is a globally important ornamental plant. Spontaneous floral mutations occur frequently during cultivation, and are selected as a way to release new cultivars, but the underlying evolutionary developmental genetics remain largely elusive. Here, we investigated a collection of spontaneous corolla mutational plants (SCMPs) whose other floral organs were virtually unaffected. Unlike the corolla in normal plants (NPs) that withered soon after fertilization, the transformed corolla (petals) in SCMPs was greenish and persistent similar to the calyx (sepals). Epidermal cellular morphology of the SCMP corolla was also similar to that of calyx cells, further suggesting a sepaloid corolla in SCMPs. Ten floral MADS-box genes from these Paeonia plants were comparatively characterized with respect to sequence and expression. Codogenic sequence variation of these MADS-box genes was not linked to corolla changes in SCMPs. However, we found that both APETALA3 (AP3) and PISTILLATA (PI) lineages of B-class MADS-box genes were duplicated, and subsequent selective expression alterations of these genes were closely associated with the origin of SCMPs. AP3-PI obligate heterodimerization, essential for organ identity of corolla and stamens, was robustly detected. However, selective down-regulation of these duplicated genes might result in a reduction of this obligate heterodimer concentration in a corolla-specific manner, leading to the sepaloid corolla in SCMPs, thus representing a new sepaloid corolla model taking advantage of gene duplication. Our work suggests that modifying floral MADS-box genes could facilitate the breeding of novel cultivars with distinct floral morphology in ornamental plants, and also provides new insights into the functional evolution of the MADS-box genes in plants. PMID- 28013275 TI - Structures of Bordered Pits Potentially Contributing to Isolation of a Refilled Vessel from Negative Xylem Pressure in Stems of Morus australis Poir.: Testing of the Pit Membrane Osmosis and Pit Valve Hypotheses. AB - Two hypotheses have been proposed to explain the mechanism preventing the refilling vessel water from being drained to the neighboring functional vessels under negative pressure. The pit membrane osmosis hypothesis proposes that the xylem parenchyma cells release polysaccharides that are impermeable to the intervessel pit membranes into the refilling vessel; this osmotically counteracts the negative pressure, thereby allowing the vessel to refill. The pit valve hypothesis proposes that gas trapped within intervessel bordered pits isolates the refilling vessel water from the surrounding functional vessels. Here, using the single-vessel method, we assessed these hypotheses in shoots of mulberry (Morus australis Poir.). First, we confirmed the occurrence of xylem refilling under negative pressure in the potted mulberry saplings. To examine the pit membrane osmosis hypothesis, we estimated the semi-permeability of pit membranes for molecules of various sizes and found that the pit membranes were not semi permeable to polyethylene glycol of molecular mass <20,000. For the pit valve hypothesis, we formed pit valves in the intervessel pits in the short stem segments and measured the maximum liquid pressure up to which gases in bordered pits were retained. The threshold pressure ranged from 0.025 to 0.10 MPa. These values matched the theoretical value calculated from the geometry of the pit chamber (0.0692-0.101 MPa). Our results suggest that gas in the pits is retained by surface tension, even under substantial positive pressure to resolve gases in the refilling vessel, whereas the molecule size required for the pit membrane osmosis mechanism in mulberry would be unrealistically large. PMID- 28013276 TI - Changes in Cell Wall Polymers and Degradability in Maize Mutants Lacking 3'- and 5'-O-Methyltransferases Involved in Lignin Biosynthesis. AB - Caffeoyl coenzyme A 3-O-methyltransferase (CCoAOMT) and caffeic acid-O methyltransferase (COMT) are key enzymes in the biosynthesis of coniferyl and sinapyl alcohols, the precursors of guaiacyl (G) and syringyl (S) lignin subunits. The function of these enzymes was characterized in single and double mutant maize plants. In this work, we determined that the comt (brown-midrib 3) mutant plants display a reduction of the flavonolignin unit derived from tricin (a dimethylated flavone), demonstrating that COMT is a key enzyme involved in the synthesis of this compound. In contrast, the ccoaomt1 mutants display a wild-type amount of tricin, suggesting that CCoAOMT1 is not essential for the synthesis of this compound. Based on our data, we suggest that CCoAOMT1 is involved in lignin biosynthesis at least in midribs. The phenotype of ccoaomt1 mutant plants displays no alterations, and their lignin content and composition remain unchanged. On the other hand, the ccoaomt1 comt mutant displays phenotypic and lignin alterations similar to those already described for the comt mutant. Although stems from the three mutants display a similar increase of hemicelluloses, the effect on cell wall degradability varies, the cell walls of ccoaomt1 being the most degradable. This suggests that the positive effect of lignin reduction on cell wall degradability of comt and ccoaomt1 comt mutants is counteracted by changes occurring in lignin composition, such as the decreased S/G ratio. In addition, the role of the flavonolignin unit derived from tricin in cell wall degradability is also discussed. PMID- 28013277 TI - Enhancing the GABI-Kat Arabidopsis thaliana T-DNA Insertion Mutant Database by Incorporating Araport11 Annotation. AB - SimpleSearch provides access to a database containing information about T-DNA insertion lines of the GABI-Kat collection of Arabidopsis thaliana mutants. These mutants are an important tool for reverse genetics, and GABI-Kat is the second largest collection of such T-DNA insertion mutants. Insertion sites were deduced from flanking sequence tags (FSTs), and the database contains information about mutant plant lines as well as insertion alleles. Here, we describe improvements within the interface (available at http://www.gabi-kat.de/db/genehits.php) and with regard to the database content that have been realized in the last five years. These improvements include the integration of the Araport11 genome sequence annotation data containing the recently updated A. thaliana structural gene descriptions, an updated visualization component that displays groups of insertions with very similar insertion positions, mapped confirmation sequences, and primers. The visualization component provides a quick way to identify insertions of interest, and access to improved data about the exact structure of confirmed insertion alleles. In addition, the database content has been extended by incorporating additional insertion alleles that were detected during the confirmation process, as well as by adding new FSTs that have been produced during continued efforts to complement gaps in FST availability. Finally, the current database content regarding predicted and confirmed insertion alleles as well as primer sequences has been made available as downloadable flat files. PMID- 28013278 TI - ThaleMine: A Warehouse for Arabidopsis Data Integration and Discovery. AB - ThaleMine (https://apps.araport.org/thalemine/) is a comprehensive data warehouse that integrates a wide array of genomic information of the model plant Arabidopsis thaliana. The data collection currently includes the latest structural and functional annotation from the Araport11 update, the Col-0 genome sequence, RNA-seq and array expression, co-expression, protein interactions, homologs, pathways, publications, alleles, germplasm and phenotypes. The data are collected from a wide variety of public resources. Users can browse gene-specific data through Gene Report pages, identify and create gene lists based on experiments or indexed keywords, and run GO enrichment analysis to investigate the biological significance of selected gene sets. Developed by the Arabidopsis Information Portal project (Araport, https://www.araport.org/), ThaleMine uses the InterMine software framework, which builds well-structured data, and provides powerful data query and analysis functionality. The warehoused data can be accessed by users via graphical interfaces, as well as programmatically via web services. Here we describe recent developments in ThaleMine including new features and extensions, and discuss future improvements. InterMine has been broadly adopted by the model organism research community including nematode, rat, mouse, zebrafish, budding yeast, the modENCODE project, as well as being used for human data. ThaleMine is the first InterMine developed for a plant model. As additional new plant InterMines are developed by the legume and other plant research communities, the potential of cross-organism integrative data analysis will be further enabled. PMID- 28013279 TI - Inducible Transposition of a Heat-Activated Retrotransposon in Tissue Culture. AB - A transposition of a heat-activated retrotransposon named ONSEN required compromise of a small RNA-mediated epigenetic regulation that includes RNA directed DNA methylation (RdDM) machinery after heat treatment. In the current study, we analyzed the transcriptional and transpositional activation of ONSEN to better understand the underlying molecular mechanism involved in the maintenance and/or induction of transposon activation in plant tissue culture. We found the transposition of heat-primed ONSEN during tissue culture independently of RdDM mutation. The heat activation of ONSEN transcripts was not significantly up regulated in tissue culture compared with that in heat-stressed seedlings, indicating that the transposition of ONSEN was regulated independently of the transcript level. RdDM-related genes were up-regulated by heat stress in both tissue culture and seedlings. The level of DNA methylation of ONSEN did not show any change in tissue culture, and the amount of ONSEN-derived small RNAs was not affected by heat stress. The results indicated that the transposition of ONSEN was regulated by an alternative mechanism in addition to the RdDM-mediated epigenetic regulation in tissue culture. We applied the tissue culture-induced transposition of ONSEN to Japanese radish, an important breeding species of the family Brassicaceae. Several new insertions were detected in a regenerated plant derived from heat-stressed tissues and its self-fertilized progeny, revealing the possibility of molecular breeding without genetic modification. PMID- 28013280 TI - Intrinsic Emotional Fluctuation in Daily Negative Affect across Adulthood. AB - Objectives: The study explored daily negative affect (NA) fluctuation, its associations with age, and its developmental characteristics. Method: The sample (n = 790) was drawn from the Midlife Development in the United States; participants completed two 8-day daily diaries 10 years apart. Multilevel models were estimated within each diary component, where two single daily NA (depression and nervousness) and daily NA diversity were predicted separately by daily stressor exposures, physical health symptoms, age, gender, education, and neuroticism. The variances of within-person residual were output for single NA and NA diversity as intrinsic emotion fluctuation (IEF) within each diary component (i.e., controlled for within- and between-person contextual factors). Then multilevel growth models were fit to explore the developmental characteristics of day-to-day IEF across 10 years. Results: At the daily level, older age was associated with less IEF in depression and nervousness. Over time, IEF in depression decreased. Additionally, IEF in NA diversity increased for older participants longitudinally. Discussion: IEF represents a new conceptualization of midlife individuals' daily emotional ups and downs, specifically, the intrinsic within-person volatility of emotions. The magnitude of IEF and its longitudinal dynamics may have implications for health and well being of middle-aged adults. PMID- 28013281 TI - Prognostic usefulness of contemporary stress echocardiography in patients with left bundle branch block and impact of contrast use in improving prediction of outcome. AB - Aims: Patients with symptomatic left bundle branch block (LBBB) may have myocardial ischaemia due to both coronary artery disease and/or cardiomyopathy (microcirculatory abnormalities) and may have concomitant left ventricular (LV) dysfunction. We aimed to assess the feasibility and prognostic value of contemporary stress echocardiography (SE), which can uncover both pathophysiologies in LBBB patients in routine clinical practice, and also aimed to assess the additive value of contrast SE. Methods and results: Accordingly, 190 consecutive patients (age 70.5 +/- 11.3 years, LV ejection fraction = 50.1 +/ 10%) with symptomatic LBBB who underwent SE over 6 years were assessed, of which 142 (75%) underwent contrast SE and 176 (92.6%) had diagnostic SE. Inducible ischaemia was present in 25 (14.2%) patients. During follow-up (35.4 +/- 20.2 months) there were 32 deaths (18%) and 18 (10.2%) first cardiovascular (CV) events (acute myocardial infarction/mortality) in the 176 patients with diagnostic studies. Wall thickening score index at peak stress (WTSIpeak), which measures combined LV function and inducible ischaemia, was an independent predictor of mortality (HR = 3.78, 95% CI = 1.39-10.31, P = 0.01) and CV events (HR = 3.96, 95% CI = 1.1-14.3, P = 0.036). An abnormal SE (myocardial ischaemia and/or abnormal LV function) predicted an almost three-fold increase in all-cause mortality and CV events compared with normal SE. Amongst the confounders affecting assessment of wall thickening in LBBB and conventional prognostic variables, use of contrast was an independent predictor (P = 0.034) of WTSI1.16 (optimal predictor of mortality/CV outcome). Conclusion: SE in patients with LBBB demonstrated high feasibility and the combination of LV systolic function and myocardial ischaemia provided important prognostic information. Contrast-enhanced SE improved the prediction of outcome. PMID- 28013282 TI - Fractional flow reserve derived from coronary computed tomography angiography: diagnostic performance in hypertensive and diabetic patients. AB - Aims: Fractional flow reserve (FFR) derived from coronary computed tomography (FFRCT) has high diagnostic performance in stable coronary artery disease (CAD). The diagnostic performance of FFRCT in patients with hypertension (HTN) and diabetes (DM), who are at risk of microvascular impairment, is not known. Methods and results: We analysed the diagnostic performance of FFRCT, in patients (vessels) with DM (n = 16), HTN (n = 186), DM + HTN (n = 58) vs. controls (n = 107) with or with suspected CAD. Patients (vessels) were further divided according to left ventricular mass index (LVMI) tertiles. Reference standard was invasively measured FFR <=0.80. Per-patient diagnostic accuracy (95% CI) in control patients was 71.7% (61.6-81.8) vs. 79.3 (74.0-85.0) (P = 0.12), 75.0% (47.6-92.7) (P = 0.52), and 75.9% (62.8-86.1) (P = 0.39) in patients with HTN, DM, and HTM + DM, respectively. There was no difference in discrimination of ischaemia by FFRCT between groups. On a per-vessel level, there was no significant difference in diagnostic performance or discrimination of ischaemia by FFRCT between groups. There was a decline in both per-patient and -vessel diagnostic specificity of FFRCT in the upper LVMI tertile when compared with lower tertiles; however, discrimination of ischaemia by FFRCT was unaltered across LVMI tertiles. Conclusion: The diagnostic performance of FFRCT is independent of the presence of HTN and DM. FFRCT is a robust method in a broad stable CAD population, including patients at high risk for microvascular disease. PMID- 28013283 TI - Delayed and decreased LV untwist and unstrain rate in mutation carriers for hypertrophic cardiomyopathy. AB - Background: The echocardiographic focus to detect abnormalities in genetically hypertrophic cardiomyopathy (HCM) affected subjects without left ventricular (LV) hypertrophy (G+/LVH-) has been on diastolic abnormalities in transmitral flow and longitudinal myocardial function with tissue Doppler imaging. The aim of this study was to assess diastolic LV unstrain and untwist. Methods and results: Forty one consecutive genotyped family members of HCM patients (mean age 37 +/- 11 years, 16 men) and 41 age- and gender-matched healthy volunteers underwent speckle-tracking echocardiography to measure untwist and unstrain. No significant differences between G+/LVH- and control subjects were seen in maximal systolic twist and global longitudinal strain. In diastole, the early peak untwist rate was significantly lower in G+/LVH- subjects compared with control subjects (62 +/ 19 degrees s - 1 vs. 76 +/- 30 degrees s - 1, P <0.05), whereas the late peak untwist rate tended to be higher. Untwist from maximal twist until the first 20% of diastole was delayed in G+/LVH- subjects (39.3 +/- 12.9% vs. 51.3 +/- 15.6%, P <0.005). Late diastolic unstrain rate was significantly higher in G+/LVH- subjects in the inferoseptal wall (111 +/- 33 s - 1 vs. 94 +/- 32 s - 1, P = 0.024), the inferolateral wall (105 +/- 42 vs. 75 +/- 35 s - 1, P = 0.007) and the anteroseptal wall (97 +/- 26 vs. 80 +/- 23 s - 1, P = 0.010). Unstrain from maximal twist until the first 20% of diastole was delayed in G+/LVH- subjects in the inferoseptal (18.9 +/- 14.0% vs. 30.1 +/- 17.7%, P = 0.005), inferolateral (27.1 +/- 16.3% vs. 39.2 +/- 18.0%, P = 0.015) and anteroseptal (19.1 +/- 14.7% vs. 35.8 +/- 18.5%, P = 0.0003) segments. Conclusions: In mutation carriers, for HCM LV, untwist and unstrain are delayed and untwist rate and unstrain rate are decreased. PMID- 28013284 TI - CT sizing for left atrial appendage closure is associated with favourable outcomes for procedural safety. AB - Aims: We evaluated the utility of computerized tomography (CT) with respect to sizing work-up for percutaneous left atrial appendage (LAA) closure, and implications for procedural safety and outcomes. Methods and results: Contrast enhanced multi-detector CT was routinely conducted to guide sizing for LAA closure in addition to transoesophageal echocardiography (TOE). Procedural safety and efficacy were prospectively assessed. Across 73 consecutive cases there were no device-related procedural complications, and no severe leaks. Systematic bias in orifice sizing by TOE vs. CT was significant on retrospective analysis (bias 3.0 mm vs. maximum diameter on CT; bias -1.1 mm vs. mean diameter on CT). Importantly, this translated to an altered device size selection in more than half of all cases, and median size predicted by CT was one interval greater than that predicted by TOE (27 mm vs. 24 mm). Of particular note, gross sizing error by TOE vs. CT was observed in at least 3.4% of cases. Degree of discrepancy between TOE and CT was correlated with LAA orifice eccentricity, orifice size, and left atrial volume. Mean orifice size by CT had the greatest utility for final Watchman device-size selection. Conclusions: In this single-centre registry of LAA closure, routine incorporation of CT was associated with excellent outcomes for procedural safety and absence of major residual leak. Mean orifice size may be preferable to maximum orifice size. A particular value of CT may be the detection and subsequent avoidance of gross sizing error by 2D TOE that occurs in a small but important proportion of cases. PMID- 28013285 TI - Not all plaque ruptures are born equal: an optical coherence tomography study. AB - Aims: Plaque rupture (PR) represents the most common substrate of coronary thrombosis, in at least 50% of cases. Chronic low grade inflammation is a common background for atherosclerosis development; however, increased plaque inflammation may predispose by itself to PR. In the last decade, studies performed by optical coherence tomography (OCT) have allowed to establish the severity of plaque inflammation by assessing macrophage infiltration (MOI). Our retrospective study aimed at assessing the role of plaque inflammation in PR among patients with acute coronary syndrome (ACS) using OCT. Methods and results: We enrolled 56 patients with ACS exhibiting PR at the site of the culprit stenosis identified by OCT. Patients were divided into two cohorts according to the presence of MOI at OCT analysis, defined as signal-rich, distinct, or confluent punctate regions that exceed the intensity of background speckle noise. Serum high-sensitivity C-reactive protein (CRP) was measured on admission by latex-enhanced immunophelometric assay. Thirty-seven (66%) patients had MOI at the site of PR, whereas 19 (34%) patients had no evidence of MOI. Patients with MOI showed a higher rate of CRP values >3 mg/dL as compared with those without MOI (92% vs. 47%, P = 0.004). In contrast, patients without MOI had a higher prevalence of hypertension compared with those with MOI (89% vs. 59%, P = 0.021). Furthermore, the group with MOI exhibited a significantly higher rate of lipid rich plaques (86% vs. 50%, P = 0.008), a higher rate of multifocal disease (59% vs. 10%, P < 0.001), and an MOI in both culprit and remote lesions (97% vs. 0%, P < 0.001) compared with those without MOI. At multivariate analysis, CRP value >3 mg/dL was the only independent predictor of MOI in the culprit plaque (OR 8.72, 95% CI 1.78-41.67, P= 0.007). Conclusions: In conclusion, PR can be caused by predominant inflammatory or non-inflammatory mechanisms, over a common low-grade chronic inflammatory background well known from pathology observations. PMID- 28013286 TI - Positive Predictive Value of PCP Immunoassay at UC San Diego Health. PMID- 28013287 TI - ELBERTE v LATVIA: The To be or not to be question of Consent. AB - 'Informed consent' is essentially an ethical and legal practice and has long been the central theme in the discussions over tissue research. This commentary discusses the case of Elberte v Latvia (Application no 61243/08, January 2015) which is a new direction in consent for use of tissues in health research. However it has offered lesser clarity in different ways. The case considers the importance of consent and also requires that the close relatives be given a right to consent under certain circumstances. This poses two important questions which will be dealt with under this commentary, one the factual right of the relatives to offer consent for another and secondly the impact such consent may have on tissue research. PMID- 28013288 TI - Structural cerebral abnormalities and neurodevelopmental status in single ventricle congenital heart disease before Fontan procedure. AB - Objectives: Neonates with single ventricle congenital heart disease are at risk for structural cerebral abnormalities. Little is known about the further evolution of cerebral abnormalities until Fontan procedure. Methods: Between August 2012 and July 2015, we conducted a prospective cross-sectional two centre study using cerebral magnetic resonance imaging (MRI) and neuro-developmental outcome assessed by the Bayley-III. Forty-seven children (31 male) were evaluated at a mean age of 25.9 +/- 3.4 months with hypoplastic left heart syndrome (25) or other single ventricle (22). Results: Cerebral MRI was abnormal in 17 patients (36.2%) including liquor space enlargements (10), small grey (9) and minimal white (5) matter injuries. Eight of 17 individuals had combined lesions. Median (range) cognitive composite score (CCS) (100, 65-120) and motor composite score (MCS) (97, 55-124) were comparable to the reference data, while language composite score (LCS) (97, 68-124) was significantly lower ( P = 0.040). Liquor space enlargement was associated with poorer performance on all Bayley-III subscores (CCS: P = 0.02; LCS: P = 0.002; MCS: P = 0.013). The number of re operations [odds ratio (OR) 2.2, 95% confidence interval (CI) 1.1-4.3] ( P = 0.03) and re-interventions (OR 2.1, 95% CI 1.1-3.8) ( P = 0.03) was associated with a higher rate of overall MRI abnormalities. Conclusions: Cerebral MRI abnormalities occur in more than one third of children with single ventricle, while the neuro-developmental status is less severely affected before Fontan procedure. Liquor space enlargement is the predominant MRI finding associated with poorer neuro-developmental status, warranting further studies to determine aetiology and further evolution until school-age. PMID- 28013289 TI - Impact of synthetic elements on aortic root haemodynamics: computed fluid dynamics of aortic root reconstruction and valve reimplantation. AB - Objectives: The aim was to evaluate the impact of the aortic valve reimplantation (David) and of the aortic root (AoR) remodelling (Yacoub) on the AoR haemodynamics. Methods: In an experimental setup where the clinical scenario of Yacoub, ( n = 5, domestic pig) and of David ( n = 5, domestic pig) procedure was performed in each AoR, six high-fidelity (200 Hz) sonomicrometric crystals were implanted. Crystals were positioned at three commissures with their projection at the root base. In post-measurement processing 3D deformation of both AoR was determined and used for computed fluid dynamic modelling in order to evaluate pressure, velocity and shear stress profiles. Results: In David AoR: high pressure (> 150 mmHg) and low to moderate shear stress (0-30 Pa) were found from the period of isovolemic contraction to the closure of the aortic valve. At mid diastole pressure augmentation (> 120 mmHg) a low shear stress (0-10 Pa) was registered at the leaflets, three commissures, and intervalvular triangles. In Yacoub AoR: high pressure (110-130 mmHg) with moderate low shear stress (0-30 Pa) was only registered at isovolemic contraction. Conclusions: The results show that haemodynamic conditions following a David procedure have a less favourable pattern as compared to a Yacoub AoR. In David AoR, high pressure and low shear stress are present during 2/3 of the cardiac cycle, whereas in Yacoub root, these conditions are present only for a short period of isovolemic contraction. PMID- 28013291 TI - SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. AB - Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss. Whole-exome sequencing revealed SLC44A4, which encodes the choline transport protein, as the pathogenic gene in this family. In the zebrafish model, downregulation of slc44a4 using morpholinos led to significant abnormalities in the zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. SH-SY5Y cells transfected with SLC44A4 showed higher choline uptake and acetylcholine release than that of cells transfected with mutant SLC44A4. We concluded that mutation of SLC44A4 may cause defects in the Choline- acetylcholine system, which is crucial to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury, leading to hearing loss. PMID- 28013290 TI - Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability. AB - The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the alpha/beta-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of beta-tubulin to fold or become assembled into the alpha/beta-heterodimer, nor did it influence the incorporation of mutant containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects. PMID- 28013292 TI - MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Menetrier-like gastropathy. AB - We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Menetrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Menetrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non compaction (LVNC), we investigated members of our family with Menetrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Menetrier disease. PMID- 28013293 TI - Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples. TSC1/TSC2 complex upregulation of OPN expression is mediated by transcription factor SOX9 in an mTOR-independent manner. Moreover, ablation of OPN by deficient TSC1/TSC2 complex contributed to inactivation of AKT in TSC cells. Lastly, the abundance of OPN dictated the potency of cell proliferation and tumour development. Therefore, loss of TSC1/TSC2 complex led to mTOR independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade. We suggest that the decreased SOX9-OPN-AKT signalling pathway safeguard against the development of malignant tumours in TSC patients. PMID- 28013294 TI - Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms. AB - Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C > T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency. PMID- 28013295 TI - Emerging Roles of the Endolumenal Functional Lumen Imaging Probe in Gastrointestinal Motility Disorders. AB - Gastrointestinal sphincters play a vital role in gut function and motility by separating the gut into functional segments. Traditionally, function of sphincters including the esophagogastric junction is studied using endoscopy and manometry. However, due to its dynamic biomechanical properties, data on distensibility and compliance may provide a more accurate representation of the sphincter function. The endolumenal functional lumen imaging probe (EndoFLIP) system uses a multi-detector impedance planimetry system to provide data on tissue distensibility and geometric changes in the sphincter as measured through resistance to volumetric distention with real-time images. With the advent of EndoFLIP studies, esophagogastric junction dysfunction and other disorders of the stomach and bowels may be better evaluated. It may be utilized as a tool in predicting effectiveness of endoscopic and surgical treatments as well as patient outcomes. PMID- 28013296 TI - Thoracoabdominal Asynchrony Is Not Associated with Oxyhemoglobin Saturation in Recovering Premature Infants. AB - BACKGROUND: Recovering premature infants are at risk for hypoxemia and lack of synchrony between their rib cage and abdomen due to airflow obstruction and poor respiratory compliance. Thoracoabdominal asynchrony (TAA) is a useful marker of resistive and elastic lung properties. Whether TAA predicts oxygenation is unknown. OBJECTIVES: We investigated oxyhemoglobin saturation (SpO2%) and TAA (phase angle, phi) in preterm infants with/without high-humidity nasal cannula (HHNC). METHODS: A cross-sectional observational study was conducted in 92 infants at 32 weeks' postmenstrual age. We measured SpO2% with pulse oximetry and TAA with phi via respiratory inductance plethysmography in infants (mean gestational age: 26.4 + 1.3 weeks) who required room air (n = 18) or HHNC with/without supplemental oxygen (1-5 liters per minute, FiO2 0.21-0.33, n = 74). We calculated median SpO2% from 24.7 + 10.0 min of quiet sleep and median phi from up to 60 breaths. RESULTS: Infants breathing room air alone had marked TAA (phi = 83.6 + 32.9 degrees , range: 10.9-148.5) as did those receiving varying degrees of ventilatory and oxygen support via HHNC (range of group means, phi = 47.0-90.0 degrees ). Infants breathing room air had statically greater median SpO2% than those receiving support (96.3 + 0.6% vs. 91.3 + 0.6%; ANOVA p = 0.001). SpO2% was not associated with TAA in either group (r2 = 0.09). CONCLUSION: Recovering premature infants exhibited TAA regardless of need for ventilatory support and supplemental oxygen. TAA was not associated with SpO2% in either group. Maintenance of SpO2% does not require correction of TAA. PMID- 28013297 TI - Weight Status Is Associated with Blood Pressure, Vital Capacity, Dental Decay, and Visual Acuity among School-Age Children in Chengdu, China. AB - AIMS: To examine the association of weight status with the prevalence of blood pressure (BP), vital capacity, dental decay, and visual acuity among school-age children in Chengdu, China and to find the potential role of weight status to predict the common and frequently occurring diseases among school-age children. METHODS: A cross-sectional study was conducted among 12,297 children aged 6-18 years from 10 schools in the Jinniu District of Chengdu, China. Body height, weight, waist circumference (WC), and BP were measured. Vital capacity, dental decay, and visual acuity were detected. RESULTS: The overall prevalence of underweight, overweight, obesity, abdominal obesity, high BP, bad vital capacity weight index, dental decay, and low vision were 7.18, 13.47, 7.57, 18.90, 2.78, 21.93, 38.81, and 45.79%, respectively. After controlling for age, gender, and WC, it was found that overweight and obese children had a higher risk of developing high BP than normal weight children ([OR 4.20, p < 0.001] and [OR 8.76, p < 0.001], respectively), And adjusting for age, gender, and chest circumference, the risk of having bad vital capacity weight index among children with overweight and obesity was higher ([OR 2.15, p < 0.001] and [OR 5.40, p < 0.001], respectively), and the risk with underweight was lower (OR 0.35, p < 0.001). After eliminating the influential factors of gender and age, children who were underweight were 1.16 times (OR 1.16, p = 0.048) more likely to have caries than children with normal weight, but obese children were found to have a lower prevalence for dental cavities than children with normal weight (OR 0.79, p = 0.002). Underweight and obese children had a higher prevalence of low vision; the OR of the appearance of low vision was 1.21 (p = 0.016) for underweight children and 1.23 (p = 0.009) for obese children after adjusting the age and gender. CONCLUSIONS: Abnormal weight status among Chengdu urban school-age children was found to be a severe health problem, and it was strongly associated with BP, vital capacity, dental decay, and visual acuity. PMID- 28013299 TI - Autoimmunity in Primary Antibody Deficiencies. AB - Primary antibody deficiencies (PADs) are the most common inherited primary immunodeficiencies in humans, characterized by hypogammaglobulinemia, an inability to produce specific antibodies, and recurrent infections mainly caused by encapsulated bacteria. However, it has been shown that inflammatory disorders, granulomatous lesions, lymphoproliferative diseases, cancer, and autoimmunity are associated with the various types of PAD. Both systemic and organ-specific autoimmune diseases could be attributed to B-cell defects in PAD patients. Immune thrombocytopenic purpura and autoimmune hemolytic anemia are the most common autoimmune disorders in this group of patients. The aim of this review is to describe the proposed mechanisms for autoimmunity and to review the literature with respect to the reported autoimmune disorders in each type of PAD. PMID- 28013298 TI - Body Dissatisfaction in Individuals with Obesity Compared to Normal-Weight Individuals: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Body dissatisfaction has been identified as a psychological correlate of obesity that is related to disordered eating, poor self-esteem, and depression. However, not all individuals with obesity are equally vulnerable to these correlates, and 'normative discontent' is present in individuals with normal weight, too. In this light, the complex relationship of body image and individual weight status seems like a worthwhile direction of research inquiry. As such, this review aims to systematically explore the degree of body dissatisfaction in individuals with obesity compared to normal-weight individuals. METHODS: A systematic literature search was conducted. All quantitative studies of adult samples reporting results regarding differences in body dissatisfaction between individuals with normal weight and obesity were included. RESULTS: 17 articles were found. Across studies, individuals with obesity reported higher body dissatisfaction than normal-weight individuals (questionnaires: d = 0.89, 95% CI = 0.63-1.16, p < 0.001; silhouette scales: d = 1.41, 95% CI = 0.57-2.25, p < 0.001). Meta-regression revealed a significant association of female gender and higher body dissatisfaction (b = 0.60, p = 0.007). CONCLUSION: The findings underline the severity of body dissatisfaction among individuals with obesity and especially among women. Future research recommendations are discussed. PMID- 28013300 TI - Notch4 Signaling Pathway of Endothelial Progenitor Cells in a Kawasaki Disease Model Induced by Lactobacillus casei Cell Wall Extract. AB - The Notch4 signaling pathway of endothelial progenitor cells (EPCs) may play a crucial role in Kawasaki disease (KD). We investigated the proliferation, adhesion, migration, angiogenesis, and expression levels of Notch4, recombination signal-binding protein-Jkappa (RBP-Jkappa), P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) of bone marrow (BM) EPCs in a KD model induced by Lactobacillus casei cell wall extract. The numbers of BM EPCs decreased significantly in the KD models. The Notch4 expression level on the EPC surface was higher in the KD models than in the controls. The proliferative, adhesive, migratory, and angiogenic properties, and double immunofluorescence-binding rate of BM EPCs were significantly impaired in the KD models. The levels of Notch4 and P-selectin mRNA were lower in the KD models than in the controls on day 3. The RBP-Jkappa mRNA levels were lower in the KD models than in the controls on days 3 and 7. The levels of RBP-Jkappa and vascular endothelial growth factor receptor-2 proteins decreased in the early stage. In conclusion, the BM EPC functions and bioactivities in the KD models were impaired, and the Notch4 signaling pathway is associated with KD. PMID- 28013301 TI - Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375. AB - Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient tasisulam clearance leading to toxic side effects. To reduce the negative effects of tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375. The results revealed that the analog had inhibitory effects on the proliferation comparable to tasisulam in both investigated cell lines. These results could contribute to a reduced toxicity of tasisulam and lead to further clinical trials in metastatic melanoma. PMID- 28013302 TI - TREX1 Mutation in Leukodystrophy with Calcifications and Persistent Gadolinium Enhancement. PMID- 28013303 TI - The Impact of Peroxisome Proliferator-Activated Receptor Gamma and Its Interaction with Abdominal Obesity on Diabetic Nephropathy in Chinese Han. AB - BACKGROUND: Several studies have focused on the association between peroxisome proliferators-activated receptor gamma (PPARG) polymorphism and diabetic nephropathy (DN); however, the results of these studies were inconsistent, and until now, no population-based study has focused on the impact of PPARG gene abdominal obesity interaction on DN risk. The aim of this study was to investigate the impact of PPARG polymorphisms and its interaction with abdominal obesity on DN risk in the Chinese Han population. METHODS: A total of 848 patients with type 2 diabetes mellitus, including 420 DN patients and 428 controls were recruited. Generalized multifactor dimensionality reduction (GMDR) and logistic regression model were used to examine the association and interaction between single nucleotide polymorphism and abdominal obesity on DN; OR and 95% CI were calculated. RESULTS: We found a significant association between CG or GG in rs1805192 and increased DN risk. DN risk was higher in the carriers of CG or GG genotype of rs1805192 than those with CC genotype; OR (95% CI) was 1.31 (1.11-1.58). GMDR analysis suggested a significant 2-locus model (p = 0.0107) involving rs1805192 and abdominal obesity, indicating a potential gene environment interaction between rs1805192 and abdominal obesity. Overall, the 2 locus models had a cross-validation consistency of 10 of 10, and the testing accuracy of 62.17%. CONCLUSIONS: Our results support an important association between rs1805192 minor allele (G allele) of PPARG and increased DN risk; the interaction analysis showed a combined effect of interaction between rs1805192 and abdominal obesity on DN risk. The results obtained from this study are meaningful for studies on individualized PPARG agonist in treating DN for different persons, such as abdominal obese or non-abdominal obese subject. PMID- 28013304 TI - Benzodiazepine Use and Risk of Dementia in the Elderly Population: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Benzodiazepines are a widely used medication in developed countries, particularly among elderly patients. However, benzodiazepines are known to affect memory and cognition and might thus enhance the risk of dementia. The objective of this review is to synthesize evidence from observational studies that evaluated the association between benzodiazepines use and dementia risk. SUMMARY: We performed a systematic review and meta-analysis of controlled observational studies to evaluate the risk of benzodiazepines use on dementia outcome. All control observational studies that compared dementia outcome in patients with benzodiazepine use with a control group were included. We calculated pooled ORs using a random-effects model. Ten studies (of 3,696 studies identified) were included in the systematic review, of which 8 studies were included in random effects meta-analysis and sensitivity analyses. Odds of dementia were 78% higher in those who used benzodiazepines compared with those who did not use benzodiazepines (OR 1.78; 95% CI 1.33-2.38). In subgroup analysis, the higher association was still found in the studies from Asia (OR 2.40; 95% CI 1.66-3.47) whereas a moderate association was observed in the studies from North America and Europe (OR 1.49; 95% CI 1.34-1.65 and OR 1.43; 95% CI 1.16-1.75). Also, diabetics, hypertension, cardiac disease, and statin drugs were associated with increased risk of dementia but negative association was observed in the case of body mass index. There was significant statistical and clinical heterogeneity among studies for the main analysis and most of the sensitivity analyses. There was significant statistical and clinical heterogeneity among the studies for the main analysis and most of the sensitivity analyses. Key Messages: Our results suggest that benzodiazepine use is significantly associated with dementia risk. However, observational studies cannot clarify whether the observed epidemiologic association is a causal effect or the result of some unmeasured confounding variable. Therefore, more research is needed. PMID- 28013305 TI - Development of the Corpus Callosum: An MRI Study. AB - The size and shape of the corpus callosum and its major components (genu, body, and splenium) were measured by magnetic resonance imaging (MRI) in 118 normocephalic individuals aged from 1 postnatal week to 18.7 years. Genu, body, splenial, and total corpus callosal areas increased by 40-100% during the first year of life (p < 0.05). The genu expanded to a greater extent than the splenium during the first 6 years, while the splenium expanded to a greater extent between 7 and 18 years. The age-related difference in the maximal expansion of these structures indicated an anterior to posterior wave of corpus callosal enlargement during maturation, probably the consequence of differential axonal myelination. No sex differences existed during these two developmental phases for the genu, splenial, or total corpus callosal areas with or without scaling to the cerebral hemispheric volume. During infancy (0-24 months), however, the mean female splenial ratio (length/height) of 0.79 was greater than the male ratio of 0.65 (p = 0.024). The cerebral hemispheric length/height ratio was also greater in females, indicating that during infancy the female brain (and its component the corpus callosal splenium) is relatively longer than the male brain. This sex difference was confined to the splenium and disappeared with increasing age. PMID- 28013307 TI - Why Almost Always Animals? Ranking Fluency Tasks for the Detection of Dementia Based on Receiver Operating Characteristic (ROC) and Quality ROC Analyses. AB - BACKGROUND/AIMS: Category fluency tasks have been widely used to assess cognitive functioning in both clinical and experimental environments as an index of cognitive and psycholinguistic dysfunctions in dementia. Typically, a reduced group of semantic categories has been selected for neuropsychological assessment (e.g., animals, fruits or vegetables), although empirical support for the prevalence of one category among others is absent in the literature. METHODS: We provide an empirical evaluation of the ability of 14 category fluency tasks to discriminate between subjects with dementia of the Alzheimer type and healthy elderly participants. As a novelty, we used both receiver operating characteristic (ROC) curves and quality ROC calibrated analyses to characterize the interplay of sensitivity and specificity of every category fluency task performance as a screening tool. The use of calibrated measures provided us with a useful tool for comparing the diagnostic ability of the different categories, as well as making rankings of categories based on the quality indices of efficiency, sensitivity, and specificity. RESULTS: The habitually used category of animals is far from being the most efficient one in terms of its diagnostic power to evaluate dementia. CONCLUSION: Our study might guide the selection of suitable category fluency tasks according to the diagnostic purposes in dementia. PMID- 28013306 TI - Inhibition of Rac1 Signaling Downregulates Inflammasome Activation and Attenuates Lung Injury in Neonatal Rats Exposed to Hyperoxia. AB - BACKGROUND: Inflammatory injury, particularly the production of active interleukin (IL)-1beta plays a major role in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. The release of active IL-1beta is controlled by posttranscriptional modifications of its proform (pro-IL-1beta) through the inflammasome. Rac1 is a member of the Rho family of GTPases that regulate the inflammatory process. OBJECTIVE: This study tested the hypothesis that Rac1 signaling increases inflammasome activation that results in damaging inflammation, and that the inhibition of Rac1 signaling prevents lung injury, by inhibiting inflammasome activation in a newborn rat model of BPD induced by hyperoxia. METHODS: Newborn rat pups were exposed to room air or hyperoxia (85% O2) and received daily intraperitoneal injections of placebo (normal saline) or NSC23766, a specific Rac1 inhibitor, for 10 days. The effects on lung inflammation, alveolarization, vascular development, vascular remodeling, right ventricular systolic pressure, and right ventricular hypertrophy (RVH) were then assessed. RESULTS: Hyperoxia exposure upregulated Rac1 and increased the production of active IL-1beta, which was accompanied by increasing expression of the inflammasome. In addition, hyperoxia induced the pathological hallmarks of BPD. However, treatment with NSC23766 significantly decreased inflammasome activation and macrophage infiltration, improved alveolar and vascular development, and reduced pulmonary vascular remodeling and RVH. CONCLUSION: These results indicate that Rac1 signaling regulates the expression of the inflammasome and plays a pivotal role in the pathogenesis of hyperoxia-induced neonatal lung injury. Therefore, targeting Rac1 signaling may provide a novel strategy to prevent and treat BPD in preterm infants. PMID- 28013308 TI - Neonatal Pneumothorax: A Descriptive Regional Danish Study. AB - BACKGROUND: Neonatal pneumothorax (PTX) can occur due to underlying pulmonary disease and/or ventilatory support. PTX can also develop at the onset of respiration. PTX can be life-threatening, and prompt diagnosis is essential to reduce mortality. OBJECTIVE: To analyse aetiology, demographic aspects, age at diagnosis, required treatment (specifically drainage), and prognosis of all cases of neonatal PTX observed in the North Jutland Region of Denmark from 1 January 2006 to 31 December 2014. METHOD: Retrospective, descriptive, population-based cohort study. RESULTS: During the study period there were 48,968 live births and 71 cases of PTX, giving an incidence of PTX of 0.14% (95% Cl: 0.11-0.18). Of these, 21% were bilateral and 59% tension PTX. Fifty-two percent of neonates affected were born at term. Almost all neonates had underlying lung disease, most commonly transient tachypnea of the newborn (TTN) in 39% and respiratory distress syndrome (RDS) in 42%. Only 3% were considered to have developed PTX at the onset of respiration. In preterm neonates, the median age at diagnosis was 28.5 h (IQR: 18.3-48.6), whereas in infants born at term the median age was 6.1 h (IQR: 1.1 17.2) (p < 0.001). Thirteen percent of PTX infants died. Fifty-nine percent of the infants required drainage of the PTX, more frequently those with RDS than TTN. CONCLUSION: Almost all infants with PTX had underlying lung disease, divided equally between RDS and TTN. The diagnosis of PTX was made earlier in infants with TTN than RDS. Neonates with RDS required drainage more often than those with TTN. PMID- 28013309 TI - Clinical and Genetic Characterization of Tunisian Children with Hereditary 1,25 Dihydroxyvitamin D-Resistant Rickets. AB - BACKGROUND: Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by the early onset of rickets and is caused by mutations in the vitamin D receptor (VDR) gene. Some HVDRR patients also have alopecia. PATIENTS AND METHODS: We retrospectively studied the clinical features, laboratory findings, genetic defects, as well as responses to treatment in a series of children with HVDRR. RESULTS: Eight patients from 7 families met the inclusion criteria. Alopecia was noted in 7 patients. Two different homozygous mutations in the VDR gene were identified in 6 patients: the p.K45E mutation located in the DNA-binding domain (5 patients with alopecia) and a novel p.T415R mutation located in the ligand-binding domain. A p.E143del CYP24A1 mutation, in the gene encoding the 25-hydroxyvitamin D3-24-hydroxylase, was identified in 2 brothers carrying the VDR gene mutation p.K45E. Six patients were treated with intermittent intravenous calcium treatment via the peripheral route with a clear improvement in 5 cases. CONCLUSION: To the best of our knowledge, this is the first major series reporting on HVDRR in Tunisia. The same mutation (p.K45E) was found in 5 apparently unrelated affected individuals. We have also extended the mutation spectrum by studying 1 novel VDR mutation. PMID- 28013310 TI - Innate Obesity, Revealed by Selection Markers, Confers Significant Imprint of Hypothalamic Genes Controlling Energy Expenditure. AB - The incidence of obesity is rapidly escalating and has reached epidemic proportions. In all species, including rodents, humans, and sheep, there is large variation in the degree of weight gain across individuals in response to an obesogenic environment. This individual variation is, at least in part, determined by innate differences in energy expenditure, of which adaptive thermogenesis is a key component. The hypothalamus is essential to the control of body weight and adiposity. Appetite-regulating peptides within the hypothalamus exert reciprocal effects on food intake and energy expenditure, such that neuropeptides that stimulate food intake inhibit thermogenesis and vice versa. This review discusses the role of the hypothalamic neuropeptides in determining innate predisposition to obesity in 3 animal models being obesity-prone and obesity-resistant rodents, genetically lean and obese sheep, and animals selected for high/low cortisol responsiveness. In rodents, leptin resistance is a primary feature of the propensity to become obese. This contrasts that of larger mammals, such as sheep, where altered susceptibility to obesity manifests within the melanocortin and/or orexin pathways. This review highlights fundamental species differences within the hypothalamus that lead to altered susceptibility to weight gain and increased propensity to become obese. PMID- 28013311 TI - A New Horizon in Liver Disease. PMID- 28013313 TI - Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis. AB - BACKGROUND: The risk factors for necrotizing enterocolitis (NEC) are well known, but the factors involved in the different NEC presentations remain unclear. OBJECTIVES: We hypothesized that digestive dysfunction and intestinal inflammation are mainly affected by severe NEC lesions. METHODS: In 48 preterm pigs, the association between the macroscopic NEC score (range 1-6) and the expression of 48 genes related to inflammation, morphological, and digestive parameters in the distal small intestine was investigated. RESULTS: Only severe NEC cases (score of 5-6) were associated with the upregulation of genes involved in inflammation (CCL2, CCL3, CD14, CD163, CXCL8, HP, IL1B, IL1RN, IL6,IL10, NFKBIA, PTGS2 and TNFAIP3) compared to pigs that appeared healthy (score of 1-2) or showed mild NEC (score of 3-4). Pigs with a score of 5-6 had higher intestinal tissue IL-1beta levels and a lower mucosal mass, villus height, and aminopeptidase N activity compared to pigs with a score of 1-4, and lower crypts and activities of lactase, dipeptidylpeptidase IV, and aminopeptidase A than pigs with a score of 1-2. CONCLUSIONS: The expression of a range of inflammation related genes was increased only in pigs with severe NEC, concomitant with morphological changes and decreased hydrolase activity. A severe inflammatory response and digestive dysfunction are associated mainly with severe NEC. Still, it remains difficult to separate the initial causes of NEC and the later intestinal consequences of NEC in both infants and experimental models. PMID- 28013312 TI - Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs. AB - Mycobacterium bovis bacille Calmette-Guerin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs. PMID- 28013314 TI - Nursing students' perceptions of their educational environment in the bachelor's programs of the Shifa College of Nursing, Pakistan. AB - PURPOSE: The objective of this study was to evaluate nursing students' perceptions of their educational environment in a private college. Perceptions were compared between genders and 2 bachelor's programs. METHODS: A total of 219 students participated in this study, drawn from the Generic Bachelor of Science in Nursing (GBSN) and the Post-Registered Nurse Bachelor of Science in Nursing (PRBSN) programs of the Shifa College of Nursing, Islamabad, Pakistan. The Dundee Ready Education Environment Measure was utilized for data collection. Descriptive statistics were used to calculate total scores, as well as means and standard deviations, and the t-test was applied for comparisons according to program and gender. RESULTS: The overall total mean score (119 of 200) is suggestive of more positive than negative perceptions of the educational environment. The mean score of 13 of 28 on the social self-perception subscale suggests that the social environment was felt to be 'not a nice place.' The t-test revealed more positive perceptions among students enrolled in the PRBSN program (P<0.0001) than among those enrolled in the GBSN program and more positive perceptions among female students than among male students (P<0.0001). CONCLUSION: Commonalities and differences were found in the perceptions of the nursing students. Both positive and negative perceptions were reported; the overall sense of a positive environment was present, but the social component requires immediate attention, along with other unsatisfactory components. Establishing a supportive environment conducive to competence-based learning would play an important role in bringing desirable changes to the educational environment. PMID- 28013315 TI - Baicalin Inhibits Renal Cell Apoptosis and Protects Against Acute Kidney Injury in Pediatric Sepsis. AB - BACKGROUND Pediatric sepsis has high morbidity in children, may lead to acute kidney injury (AKI), and further aggravate the disease. Baicalin is a kind of flavonoid in Scutellaria baicalensis Georgi and has been reported to protect against several diseases, but its roles in septic AKI remain unclear. This study aimed to uncover the effects of baicalin in AKI during pediatric sepsis. MATERIAL AND METHODS Blood urea nitrogen (BUN) and serum creatinine (Cr) levels were detected in 50 pediatric patients, who underwent basic therapy with or without baicalin adjunctive therapy. Mouse sepsis models were constructed by cecal ligation and puncture (CLP) and treated with baicalin intragastrically, after which BUN and Cr examination, TUNEL apoptosis assay, and expression analyses of BAX and BCL2 were performed. RESULTS Baicalin adjunctive therapy significantly decreased BUN and Cr levels in pediatric sepsis patients (P<0.05). CLP led to elevated BUN and Cr levels in the mouse model (P<0.01), indicating kidney injury accompanied by sepsis. Baicalin decreased BUN and Cr levels (P<0.05), and reduced the apoptotic cell percent in the renal tissue (P<0.05) of the CLP model. It inhibited BAX and promoted BCL2 in the renal tissue, which was consistent with cell apoptosis changes. CONCLUSIONS Baicalin is capable of suppressing renal cell apoptosis and protecting against AKI in pediatric sepsis. This study provides a potential adjunctive therapy for treating AKI in pediatric sepsis, and further research is necessary to reveal its deeper mechanisms. PMID- 28013316 TI - Inhibition of MicroRNA-149-5p Induces Apoptosis of Acute Myeloid Leukemia Cell Line THP-1 by Targeting Fas Ligand (FASLG). AB - BACKGROUND This study was aimed to reveal the role of miR-149-5p in acute myeloid leukemia (AML) cells apoptosis and the possible mechanism involved. MATERIAL AND METHODS The expression of miR-149-5p in leukemia cell lines, as well as the blood and bone marrow (BM) samples from leukemia patients, were monitored by reverse transcription polymerase chain reaction (RT-PCR). AML cell line THP-1 was transfected with miR-149-5p mimic or inhibitor, and then cell apoptosis was determined using the APO Percentage assay kit. The target of miR-149-5p was predicted by using the microRNA.org database, and verified by RT-PCR, Western blot, and Dual-Luciferase reporter assays. Further, small interfering RNA (siRNA) against the target gene was co-transfected with miR-149-5p inhibitor, and then the cell apoptosis and the expression of apoptosis-related proteins were assessed. RESULTS MiR-149-5p was significantly up-regulated in leukemia cell lines and samples from leukemia patients (P<0.01 or P<0.001), especially in THP-1 cells and samples from AML patients. Cell apoptosis was significantly decreased by miR-149-5p overexpression (P<0.01) and increased by miR-149-5p suppression (P<0.05). Fas Ligand (FASLG) was a direct target of miR-149-5p, and was negatively regulated by miR-149-5p. More importantly, the inductive effects of miR-149-5p suppression on cell apoptosis were abrogated by si-FASLG (P<0.01). Furthermore, the up-regulative effects of miR-149-5p suppression on the phosphorylated form of Fas-associated via death domain (p-FADD), caspase-8, caspase-2, caspase-3, and the cleaved forms of these caspases were abrogated by si-FASLG. CONCLUSIONS Inhibition of miR-149-5p can induce apoptosis in THP-1 cells. These inductive effects might be via targeting FASLG and activating FADD and caspases. PMID- 28013317 TI - Determination of serum neutrophil gelatinase-associated lipocalin at the early stage of acute pancreatitis. AB - AIM: e aim of the study was to assess the diagnostic value of serum concentrations of neutrophil gelatinase-associated lipocalin (sNGAL) for the determination of the severity of acute pancreatitis (AP) at the early stage of the disease. MATERIALS AND METHOD: The study group consisted of 65 patients(34 men and 31 women),aged 62.2 +/- 16.0, admitted to the Surgery Department of the District Hospital in Sucha Beskidzka, Poland, with the diagnosis of AP according to the revised Atlanta classification (2012). sNGAL was measured with ELISA at 24, 48 and 72 hours following the onset of AP symptoms. The correlations were analyzed between sNGAL and clinical, as well as laboratory parameters, used for the assessment of AP severity. RESULTS: Severe AP was associated with higher sNGAL at 24, 48 and 72 hours, while moderately severe AP was associated with higher sNGAL at 48 and 72 hours as compared to mild disease. The BISAP score >=3 during the first 24 hours of hospital stay, and the duration of hospital stay were significantly correlated with sNGAL. Also, sNGAL positively correlated with white blood cells, C-reactive protein and fibrinogen and negatively with albumin throughout the study. The diagnostic accuracy of sNGAL for the differentiation between mild AP and more severe disease was 75%, 77% and 85% at 24, 48 and 72 hours, respectively. CONCLUSIONS: Serum NGAL concentrations are associated with inflammatory markers, BISAP score and the severity of AP. sNGAL may serve as an additional prognostic biomarker in the early assessment of AP severity. PMID- 28013318 TI - Tubal telocytes: factor infertility reason? AB - Infertility is actually widespread pathological condition, which affected one in every four couples in developing countries. Approximately one third of all cases are connected with tubal factor infertility, o en accompanies by endometriosis, acute salpingitis, urogenital infections etc. The newly identified telocytes (TCs) have multiple potential bio-functions and might participate in the fertility problems. They influence on structural and functional integrity of oviduct tissue. Despite recent discovery, TCs involvement in the majority of physiological and pathological processes is still unclear and require significant increasing of deep observations and data analysis. Focusing on female reproductive system help better understands the main reasons of infertility, while evaluation of TCs impact on Fallopian tube and uterus contractility might be a key point of its correction. The article summarizes the main features of telocytes in Fallopian tubes, emphasizing their involvement in pathophysiological processes and tubal factor infertility. PMID- 28013319 TI - Determinants of BMI category changes during middle childhood and adolescence in girls. AB - The aim of the study was to analyse the changes in BMI category between 7 and 16 18 years of age on the basis of continuous studies and evaluate which factors are related to the increase and decrease in BMI category. Data were collected from 1008 secondary school students aged 16-18 y. Body height and weight were measured and BMI was calculated. Information on height and body mass in earlier periods of life was retrieved from medical records. Age at menarche and socio-economic status was established on the basis of a questionnaire. Most girls who were underweight at 7 y. as well as those who were overweight or obese at 7 y. at the age of 16-18 y. reach correct body weight. The probability of the BMI category changing to higher one at 16-18 y. was related to short stature at 7, 9 and 14 y., low socio-economic status, living in the village and primary level of mother education. A drop in the BMI category was linked to the incidence of overweight and obesity at the age of 9 and 14 y. and tall stature at the age of 7 and 9 years. High socio-economic status was connected with a change in the category from "correct weight" at the age of 7 y. to "underweight" at 16-18 y., whereas the socio-economic status did not have a significant effect on the change of the category "overweight & obesity" at 7 y. to "correct weight" at 16-18 y. PMID- 28013320 TI - Angiogenesis and pro-angiogenic factors in uterine fibroids - facts and myths. AB - Uterine leiomyomata present major problem for females. Although they are benign tumors their frequency is associated with many symptoms like infertility, abdominal pain, menorrhagia. Authors based on their own morphological studies and review of the literature try to indicate main factors causing angiogenesis within leiomyomata and its influence on tumor growth. The strongest proangiogenic factor seems to be hypoxia, which stimulates up- and down-regulation of numerous genetically determined substances. Also mechanical pressure acting upon newly growing vessels is one of the factors which may determine formation of so called "vascular pseudocapsule" around the lesion. PMID- 28013321 TI - Three-dimensional model of the skull and the cranial bones reconstructed from CT scans designed for rapid prototyping process. AB - This paper presents the effects of building mesh models of the human skull and the cranial bones from a series of CT-scans. With the aid of computer so ware, 3D reconstructions of the whole skull and segmented cranial bones were performed and visualized by surface rendering techniques. The article briefly discusses clinical and educational applications of 3D cranial models created using stereolitographic reproduction. PMID- 28013322 TI - A giant pancreatic pseudocyst treated by open cystogastrostomy. AB - We report a case of a giant pancreatic pseudocyst in a 33-year-old woman presenting with abdominal pain, loss of appetite and abdominal distension. CT scans revealed a giant pancreatic pseudocyst measuring 10.3 cm * 9.6 cm * 9.3 cm anteroposteriorly, with significant compression of the stomach. An open retrogastric cystogastrostomy was performed through a midline incision, and 3 L of fluid was drained from the pseudocyst. Recovery has been uneventful. PMID- 28013323 TI - Ghrelin, pancreatic polypeptide plasma concentrations and gastric myoelectric activity in celiac disease. AB - BACKGROUND/AIMS: The aim of the study was to analyze the effect of celiac disease(CED) on the upper-gut motility and release of enteral hormones (ghrelin and pancreatic peptide (PP)). MATERIALS AND METHODS: the study included 25 patients diagnosed with CED and 30 healthy controls. Gastric myoelectric activities (EGG) in a fasted and fed state were recorded. The plasma concentrations of ghrelin and PP were determined. R e s u l t s: CED patients presented in a fasted state a decreased percentage of normogastria 54.8 +/- 24.5 vs. 86 +/- 12.3%, p = 0.02 and slow wave coupling (SWC) 52.7 +/- 13.4 vs. 77.4 +/ 11.9%; p = 0.00001 with increased dominant power (DP) 11.6 +/- 1.5 vs. 11.1 +/- 1.1. Contrary to the controls, they did not show an improvement in the percentage of normogastria, DP and SWC when examined in a fed state (p <0.05). Furthermore, CED patients presented with significantly lower fasting plasma concentrations of ghrelin 156.8 +/- 86.7 vs. 260.2 +/- 87.6 pg/ml, p = 0.0002 and significantly higher fasting PP levels than did the controls 265.2 +/- 306.3 vs. 54.1 +/- 54.6 pg/ml, p = 0.0005. C o n c l u s i o n: CED affects gastric myoelectric activity (decreasing normogastria and coupling) and causes changes in fasting concentrations of enteral hormones (decrease in ghrelin and an increase in PP). Gastric myoelectric response to food is abolished in CED patients, probably due to the neurohormonal changes induced by primary inflammation associated with this disease. PMID- 28013324 TI - Legislation regulating availability of breast cancer treatment with particular focus on prophylactic mastectomy. AB - Breast cancer is one of the most common diseases in the Polish society. In 2015, around 17,000 Polish women were diagnosed with this type of cancer. A comparison of relative survival rates for different European countries shows that the Polish oncological care system is inefficient in terms of breast cancer treatment. Women in Poland have substantially lower chances of surviving the first five years a er being diagnosed than women in most other European countries. An inspiration, and at the same time the main theme of the paper is assessing the availability of a controversial treatment, i.e. risk-reducing mastectomy, to patients at high risk of breast cancer. The primary goal connected with this issue is an analysis of breast cancer prevention in Poland in light of applicable provisions of law and, in a broader context, availability of oncological services in the scope of breast cancer prevention and treatment in Poland. The following research methods were adopted in the implementation of the above mentioned objectives: non-systematic review of the PubMed medical database, review of literature and other available sources of information, including press releases, conference materials and online sources. Furthermore, relevant acts of law have been selected and analysed, with the use of a pre-specified glossary of key terms. Cancers are becoming an increasingly big issue. Every year the incidence rates are higher, and in consequence the number of patients receiving cancer-related benefits grows. The current legal regulations governing the availability of cancer-related benefits seem to be insuficient. PMID- 28013325 TI - Intra-articular pathologies associated with chronic ankle instability. AB - Chronic ankle instability causes intra-articular lesions, which may lead to secondary degenerative changes. The aim of this study was to evaluate the usefulness of the ankle arthroscopy for the evaluation and treatment of intra articular pathologies associated with chronic ankle instability. Between January 2013 and March 2016, 25 anterior ankle arthroscopies with modi ed anatomic Brostrom-Duquennoy-Tourne lateral ankle ligaments reconstructions were performed. In arthroscopy all patients (100%) had some intra-articular pathologies: 75% synovitis or so tissue scarring, 19% - deep chondral defect, 56% - superficial chondral lesion, 52% - osteophytes, 24% - bony or avulsion fragments, 20% - loose bodies. All intra-articular pathologies were treated during procedure. In conclusion, it is recommended to perform anterior ankle arthroscopy in addition to lateral ankle ligament reconstruction to diagnose and treat intra-articular lesions. PMID- 28013326 TI - Chronic rhinosinusitis: New understanding of specific and general Quality of life scores. AB - Our goal in treating chronic rhinosinusitis (CRS) is to reduce sinonasal symptoms and improve quality of life (QoL). In patients with CRS, sinonasal symptoms have a significant impact on QoL. Various validated measures exist to quantify QoL such as the 22-item Sinonasal Outcomes Test (SNOT- 22) and MSNOT-20 Young Persons Questionnaire (MSYPQ) specific to CRS, while others measure general QoL, such as the EuroQol 5-Dimensional general health-related QoL survey (EQ5D). PMID- 28013327 TI - Television coverage of mental illness in Canada: 2013-2015. AB - The aim of this study is to assess television news coverage of mental illness in Canadian media, including change over time. Data consist of news clips mentioning terms including 'mental illness' (N = 579). These were systematically collected and coded over 3 years (2013-2015) using a media retrieval software. Trend analysis indicated a significant linear increase for positively oriented coverage. In 2013, less than 10% of clips had a positive overall tone, whereas in 2015, this figure reached over 40%. Articles linking mental illness to violence significantly decreased, though these remain over 50%. Improvement may be due to educational initiatives targeted at journalists. PMID- 28013328 TI - Network approach to the symptom-level association between alcohol use disorder and posttraumatic stress disorder. AB - PURPOSE: The high prevalence of alcohol use disorder among individuals with a history of trauma and posttraumatic stress disorder is well documented. The current study applied network analysis to map the structure of symptom associations between these disorders. METHODS: Data come from a community sample of 449 Australian adults with a history of trauma and alcohol consumption during the last 12 months. Data analysis consisted of the construction of the comorbidity network of PTSD/AUD symptoms, identification of the bridging symptoms, computation of the centrality measures, and evaluation of the robustness of the results. RESULTS: Results highlighted two main symptom clusters, corresponding to two disorders, and that only nine edges connected the two clusters. Bridging symptoms connecting the two clusters were: alcohol use in dangerous situations, physical or mental health problems as a result of alcohol use, loss of interest or reduced social activities, and reckless/self-destructive behaviour. CONCLUSIONS: Identification of both central symptoms, because of their key role in the constellation and strong associations with majority of symptoms, and bridge symptoms, because of their mediating role between two disorders, has some implications in terms of self-medication and risk-taking/self-regulation theories of comorbidity and provides a number of clinical implications, which warrants further exploration within clinical samples. PMID- 28013330 TI - A "UFO" in the right pulmonary artery after cardiac surgery. PMID- 28013329 TI - Effects of neuromuscular blockers on transpulmonary pressures in moderate to severe acute respiratory distress syndrome. AB - PURPOSE: To investigate whether neuromuscular blocking agents (NMBA) exert beneficial effects in acute respiratory distress syndrome (ARDS) by reason of their action on respiratory mechanics, particularly transpulmonary pressures (P L). METHODS: A prospective randomised controlled study in patients with moderate to severe ARDS within 48 h of the onset of ARDS. All patients were monitored by means of an oesophageal catheter and followed up for 48 h. Moderate ARDS patients were randomised into two groups according to whether they were given a 48-h continuous infusion of cisatracurium besylate or not (control group). Severe ARDS patients did not undergo randomisation and all received cisatracurium besylate per protocol. The changes during the 48-h study period in oxygenation and in respiratory mechanics, including inspiratory and expiratory P L and driving pressure, were assessed and compared. Delta P L (?P L) was defined as inspiratory P L minus expiratory P L. RESULTS: Thirty patients were included, 24 with moderate ARDS and 6 with severe ARDS. NMBA infusion was associated with an improvement in oxygenation in both moderate and severe ARDS, accompanied by a decrease in both plateau pressure and total positive end-expiratory pressure. The mean inspiratory and expiratory P L were higher in the moderate ARDS group receiving NMBA than in the control group. In contrast, there was no change in either driving pressure or ?P L related to NMBA administration. CONCLUSIONS: NMBA could exert beneficial effects in patients with moderate ARDS, at least in part, by limiting expiratory efforts. PMID- 28013331 TI - Correlations between serum adipocytokine concentrations, disease stage, radiological status and total body fat content in the patients with primary knee osteoarthritis. AB - PURPOSE: The study was designed to investigate whether serum concentrations of leptin, resistin and adiponectin in obese and normal-weight patients with primary knee osteoarthritis (OA) correlate with clinical and radiological stages of the disease and percentage of total body fat. METHODS: Seventy-three patients with knee OA, divided into obese and normal-weight groups, were clinically evaluated according to the Knee Society Score (KSS), and radiologically assessed using Kellgren and Lawrence scale. The percentage of total body fat and some anthropometric data were also given. Serum leptin, resistin and adiponectin concentrations were measured by Elisa and were correlated with the clinical, radiological and anthropometric parameters. RESULTS: Leptin concentrations were significantly higher (p = 0.001) in the obese patients and positively correlated (R = 0.63) with radiologically assessed OA grade, but only in the normal-weight group. Resistin and adiponectin concentrations were identical in obese and normal weight patients and negatively correlated (R = -0.41) with the clinical status of obese patients. In both groups, percentage of total body fat positively correlated (R = 0.29 and R = 0.53 for obese and normal-weight respectively) with radiologically assessed OA grade. However, no correlations were found with clinical status of the patients. CONCLUSIONS: It was found that in the obese patients with knee OA, increased percentage of total body fat and elevated serum leptin concentration might favour the advancement of clinical but not radiologically assessed changes in the joint structures, while in normal-weight patients it correlates only with radiologically assessed changes but does not affect to an appreciable extent the clinical status of the patients. PMID- 28013332 TI - Early experience with dual mobility acetabular systems featuring highly cross linked polyethylene liners for primary hip arthroplasty in patients under fifty five years of age: an international multi-centre preliminary study. AB - PURPOSE: To evaluate early performance of contemporary dual mobility acetabular systems with second generation annealed highly cross-linked polyethylene for primary hip arthroplasty of patients under 55 years of age. METHODS: A prospective observational five years study across five centers in Europe and the USA of 321 patients with a mean age of 48.1 years was performed. Patients were assessed for causes of revision, hip instability, intra-prosthetic dissociation, Harris hip score and radiological signs of osteolysis. RESULTS: There were no dislocations and no intra-prosthetic dissociations. Kaplan Meier analysis demonstrated 97.51% survivorship for all cause revision and 99.68% survivorship for acetabular component revision at five years. Mean Harris hip score was 93.6. Two acetabular shells were revised for neck-rim implant impingement without dislocation and ten femoral stems were revised for causes unrelated to dual mobility implants. CONCLUSION: Contemporary highly cross-linked polyethylene dual mobility systems demonstrate excellent early clinical, radiological, and survivorship results in a cohort of patients that demand high performance from their implants. It is envisaged that DM and second generation annealed HXLPE may reduce THA instability and wear, the two most common causes of THA revision in hip arthroplasty. PMID- 28013333 TI - Semaphorin 3A expression following intestinal ischemia/reperfusion injury in Sox10-Venus mice. AB - PURPOSE: Semaphorin 3A (Sema3A) is a protein secreted during development of the nervous system that plays an important role in neuronal pathophysiology. However, there is no known correlation between Sema3A and intestinal ischemia/reperfusion (I/R) injury. We assessed Sema3A expression and distribution in relation to enteric nervous system (ENS) damage seen after intestinal I/R injury in Sox10 Venus mice. METHODS: Intestinal I/R injury was induced by vascular occlusion for 3 h. Ileal specimens were harvested 0, 3, 12, 24, 48, and 96 h after reperfusion. Stereoscopic microscopy and fluorescence microscopy were used to assess sox10 Venus+ cells and PGP9.5+ cells. RESULTS: By 3 h after reperfusion, Sema3A expression had increased to a maximum and Sox10-Venus+ cells had faded to a minimum in harvested ileal segments. Both differences were statistically significant. By 96 h after reperfusion, both Sema3A and Sox10-Venus+ cell fluorescence had reverted to original levels. Hematoxylin and eosin staining identified histologic damage mimicking Sema3A expression, while PGP9.5+ cell response was minimal. CONCLUSION: We are the first to demonstrate a correlation between Sema3A expression and ENS damage following intestinal I/R in Sox10-Venus mice. PMID- 28013334 TI - Cerebellopontine angle medulloblastoma with extensive nodularity in a child: case report and review of the literature. AB - BACKGROUND: Cerebellar medulloblastomas (MBs) are one of the most common posterior fossa tumors in children but rarely occur in the cerebellopontine angle (CPA). Only 39 cases of CPA MBs were reported in the literature, and most of them were classic and desmoplastic MBs. CASE PRESENTATION: A 22-month-old girl presented with progressive cerebellar ataxia. Magnetic resonance imaging showed a large tumor in the right CPA and obstructive hydrocephalus. Surgical resection was performed and achieved total tumor removal. Microscopic examination and immunohistochemical staining revealed the diagnosis of MB with extensive nodularity. The patient recovered from her symptoms during follow-up and was transferred for adjuvant chemotherapy. CONCLUSION: MB should be considered as a differential diagnosis of a lesion in the CPA. The treatment and outcome of CPA MBs are similar to cerebellar MBs. PMID- 28013335 TI - Hydroxyapatite ceramic implants for cranioplasty in children: a single-center experience. AB - PURPOSE: The use of hydroxyapatite ceramic (HAC) implants for the treatment of skull defects in pediatric patients started 2010 at our institution. Ceramic implants facilitate osteoblast migration and therefore optimize osteointegration with the host bone. The purpose of this study is to report a single-center experience with this treatment modality. METHODS: A retrospective review of all patients from July 2010 through June 2014 undergoing a cranioplasty using hydroxyapatite ceramic implant and managed at a single institution was performed. Indication for cranioplasty, the hospital course, and follow-up were reviewed. Bone density was measured in Hounsfield Units (HU) and osteointegration was calculated using Mimics Software(r) (Mimics Innovation Suite v17.0 Medical, Materialize, Leuven, Belgium). RESULTS: Over the 4-year period, six patients met criteria for the study. Five patients had an osteointegration of nearly 100%. One patient had an incomplete osteointegration with a total bone-implant contact area of 69%. The mean bone density was 2800 HU (2300-3000 HU). Bone density alone is estimated to have a Hounsfield value between 400 and 2000 HU depending on the body region and bone quality. There were no major complications, and the patients were highly satisfied with the esthetical result. CONCLUSION: Hydroxyapatite ceramic implants for cranioplasty in pediatric patients are a good choice for different indications. The implants show excellent osteointegration and esthetical results. PMID- 28013336 TI - Hybrid Markov chain models of S-I-R disease dynamics. AB - Deterministic epidemic models are attractive due to their compact nature, allowing substantial complexity with computational efficiency. This partly explains their dominance in epidemic modelling. However, the small numbers of infectious individuals at early and late stages of an epidemic, in combination with the stochastic nature of transmission and recovery events, are critically important to understanding disease dynamics. This motivates the use of a stochastic model, with continuous-time Markov chains being a popular choice. Unfortunately, even the simplest Markovian S-I-R model-the so-called general stochastic epidemic-has a state space of order [Formula: see text], where N is the number of individuals in the population, and hence computational limits are quickly reached. Here we introduce a hybrid Markov chain epidemic model, which maintains the stochastic and discrete dynamics of the Markov chain in regions of the state space where they are of most importance, and uses an approximate model namely a deterministic or a diffusion model-in the remainder of the state space. We discuss the evaluation, efficiency and accuracy of this hybrid model when approximating the distribution of the duration of the epidemic and the distribution of the final size of the epidemic. We demonstrate that the computational complexity is [Formula: see text] and that under suitable conditions our approximations are highly accurate. PMID- 28013337 TI - Sarcopenia is associated with an increased risk of advanced colorectal neoplasia. AB - BACKGROUND/AIMS: Although sarcopenia is associated with an increased risk for mortality after the curative resection of colorectal cancer, its influence on the development of advanced colonic neoplasia remains unclear. METHODS: This study included 1270 subjects aged 40 years or older evaluated with first-time screening colonoscopy at Seoul National University Boramae Health Care Center from January 2010 to February 2015. Skeletal muscle mass was measured with a body composition analyzer (direct segmental multifrequency bioelectrical impedance analysis method). Multiple logistic regression analysis was performed to determine whether sarcopenia is associated with advanced colorectal neoplasia. RESULTS: Of 1270 subjects, 139 (10.9%) were categorized into the sarcopenia group and 1131 (89.1%) into the non-sarcopenia group. In the non-sarcopenia group, 55 subjects (4.9%) had advanced colorectal neoplasia. However, in the sarcopenia group, 19 subjects (13.7%) had advanced colorectal neoplasia, including 1 subject with invasive colorectal cancer (0.7%). In addition, subjects with sarcopenia had a higher prevalence of advanced adenoma (P < 0.001) than those without sarcopenia. According to the multiple logistic regression analysis adjusted for variable confounders, age (odds ratio 1.062, 95% confidence interval 1.032-1.093; P < 0.001), male sex (odds ratio 1.749, 95% confidence interval 1.008-3.036; P = 0.047), and sarcopenia (odds ratio 2.347, 95% confidence interval 1.311-4.202; P = 0.004) were associated with an advanced colorectal neoplasia. CONCLUSION: Sarcopenia is associated with an increased risk of advanced colorectal neoplasia. PMID- 28013339 TI - Genetics of obesity: can an old dog teach us new tricks? AB - At one level, obesity is clearly a problem of simple physics, a result of eating too much and not expending enough energy. The more complex question, however, is why do some people eat more than others? Studies of human and mouse genetics over the past two decades have uncovered a number of pathways within the brain that play a key role in the control of food intake. A prime example is the leptin melanocortin pathway, which we now know greatly contributes to mammalian appetitive behaviour. However, genetic disruption of this pathway remains rare and does not represent the major burden of the disease that is carried by those of us with 'common obesity'. In recent years, genome-wide association studies have revealed more than 100 different candidate genes linked to BMI, with most (including many components of the melanocortin pathway) acting in the central nervous system and influencing food intake. So while severe disruption of the melanocortin pathway results in severe obesity, subtle variations in these genes influence where you might sit in the normal distribution of BMI. As we now enter this 'post-genomics' world, can this new information influence our treatment and management of obese patients? PMID- 28013340 TI - Frequent and intensive physical activity reduces risk of cardiovascular events in type 1 diabetes. AB - AIMS/HYPOTHESIS: Cardiovascular disease (CVD) is the most common cause of premature death and disability among patients with type 1 diabetes. Diabetic nephropathy accounts for the increased cardiovascular morbidity and mortality of these patients. We recently showed that the intensity of exercise predicts the incidence and progression of diabetic nephropathy in patients with type 1 diabetes. Little is known about the relationship between physical activity and CVD. Therefore, we studied how physical activity affects the risk of CVD events in patients with type 1 diabetes. METHODS: A 10 year follow-up study including 2180 type 1 diabetes patients from the nationwide multicentre Finnish Diabetic Nephropathy Study (FinnDiane). Leisure time physical activity (LTPA) was assessed by a previously validated self-report questionnaire. A CVD event was defined as a verified myocardial infarction, coronary procedure or stroke. Patients were analysed separately for the risk of developing a first ever CVD event and for the risk of a recurrent CVD event following a baseline event. RESULTS: A total of 206 patients had an incident CVD event during follow-up. A higher total LTPA and higher intensity, frequency and duration of activity were associated with a lower risk of incident CVD events. The observed association between exercise frequency and incident CVD remained significant when adjusted for classic risk factors. Exercise intensity also had a borderline effect on the recurrence-free time in patients with a major CVD event at baseline. CONCLUSIONS/INTERPRETATION: This study suggests that exercise, particularly high frequency and high intensity exercise, may reduce the risk of CVD events in patients with type 1 diabetes. PMID- 28013338 TI - Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling. AB - Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro invasive contributions of stromal cells in physiologically relevant three dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological- or siRNA based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca2+-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction. PMID- 28013341 TI - Emerging role of intestinal microbiota and microbial metabolites in metabolic control. AB - The role of the intestinal microbiota and microbial metabolites in the maintenance of host health and development of metabolic disease has gained significant attention over the past decade. Mechanistic insight revealing causality, however, is scarce. Work by Ussar and co-workers demonstrates that a complex interaction between microbiota, host genetics and environmental factors is involved in metabolic disease development in mice. In addition, Perry and co workers show that the microbial metabolite acetate augments insulin resistance in rats. These studies underscore an important role of the microbiota in the development of obesity and symptoms of type 2 diabetes in rodents. If causality can be demonstrated in humans, development of novel diagnostic and therapeutic tools that target the gut microbiota will have high potential. PMID- 28013343 TI - Warthin tumor within the superficial lobe of the parotid gland: a suggested criterion for diagnosis. AB - The location of Warthin tumor (WT) in the parotid gland impacts the surgical approach and may be indicative of the elusive origin of this intriguing entity. Location in the deep versus superficial lobe of the gland is not directly addressed when defining WT characteristics. Our observation, of rare occurrence of deep lobe WT, if at all, led to the current investigation. The study design is cohort study. This is a retrospective chart review of all patients undergoing parotidectomy for WT in two tertiary academic referral centers: the Sheba Medical Center (SMC), Israel, and the Christiana Care (CC), Newark, Delaware, USA. 122 consecutive adult patients underwent parotidectomy for WT (72 from SMC and 50 from CC). Seventy percent were males, with a mean age of 60.6 years. Bilateral WT or multi-centric WT were found in 9.8 and 17.2% of the cases, respectively. In one case, the tumor was described as originating in the deep lobe. In all other cases, the tumor originated and was limited to the superficial lobe. 99.2% of WT originated in the superficial lobe, corresponding with the few reports directly addressing its location in the gland. The reason for the tumor to be limited almost uniformly to the superficial lobe is unknown, and could be related to the etiopathogenesis of this elusive entity. We suggest adding tumor location within the superficial lobe to the common characteristics of WT (male, smoking, and lower pole) that serve as "common criterion" while evaluating a parotid lesion. PMID- 28013342 TI - The TLR4-NOS1-AP1 signaling axis regulates macrophage polarization. AB - OBJECTIVE: Macrophages polarize to proinflammatory M1 or anti-inflammatory M2 states with distinct physiological functions. This transition within the M1-M2 phenotypes decides the nature, duration and severity of an inflammatory response. Although there is a substantial understanding of the fate of these phenotypes, the underlying molecular mechanism of transition within the M1-M2 phenotypes is not well understood. We have investigated the role of neuronal nitric oxide synthase (NOS1)-mediated regulation of activator protein 1 (AP-1) transcription factor in macrophages as a critical effector of macrophage phenotypic change. MATERIALS AND METHODS: Raw 264.7 and THP1 macrophages were stimulated with LPS (250 ng/ml) to activate the inflammatory signaling pathway. We analyzed the effect of pharmacological NOS1 inhibitor: TRIM (1-(2- Trifluoromethylphenyl) imidazole) on LPS-induced inflammatory response in macrophages. RESULTS: We determined that NOS1-derived nitric oxide (NO) facilitate Fos and Jun interaction which induces IL-12 & IL-23 expression. Pharmacological inhibition of NOS1 inhibits ATF2 and Jun dimer. Switching of Fos and Jun dimer to ATF2 and Jun dimerization controls phenotype transition from IL-12high IL-23high IL-10low to IL-12low IL-23lowIL-10high phenotype, respectively. CONCLUSION: These findings highlight a key role of the TLR4-NOS1-AP1 signaling axis in regulating macrophage polarization. PMID- 28013344 TI - Residual stones after percutaneous nephrolithotomy: comparison of intraoperative assessment and postoperative non-contrast computerized tomography. AB - OBJECTIVES: To compare the intraoperative surgeon perspective for detection of residual fragments (RFs) after percutaneous nephrolithotomy (PNL) with postoperative NCCT. METHODS: A prospective study of adult patients who underwent PNL between March and September 2014 was conducted. Stone complexity was evaluated using the Guy's stone score (GSS). All patients were evaluated by pre- and postoperative NCCT. After the procedure, the surgeon had been asked whether there were residual stones or not. The sensitivity, specificity and predictive values were tested against postoperative NCCT. Predictors of accurate intraoperative assessment were determined using univariate and multivariate statistical analyses. RESULTS: The study included 306 consecutive patients. The surgeons reported no residual stones in 236 procedures; of whom 170 (72%) were reported stone-free by NCCT. On the other hand, 65 out of 70 procedures (93%) reported with residual stones by the surgeons were true by NCCT. The sensitivity was 50% and the NPV was 72%, while the specificity was 97% and the PPV was 93%. On multivariate analysis, only lower GSS (p < 0.001) was independently associated with true negative surgeon opinion. CONCLUSIONS: Although there was a high surgeon ability to detect post-PNL residual stones, postoperative imaging is mandatory because of the high false negative rates and low NPV. The surgeon opinions can be judged only in stones with lower GSS. The NPV could be enhanced if a consistent definition of clinically significant RFs is introduced. PMID- 28013345 TI - Simulated physiological stretch increases expression of extracellular matrix proteins in human bladder smooth muscle cells via integrin alpha4/alphav-FAK ERK1/2 signaling pathway. AB - OBJECTIVES: To investigate the effect of simulated physiological stretch on the expression of extracellular matrix (ECM) proteins and the role of integrin alpha4/alphav, focal adhesion kinase (FAK), extracellular regulated protein kinases 1/2 (ERK1/2) in the stretch-induced ECM protein expression of human bladder smooth muscle cells (HBSMCs). METHODS: HBSMCs were seeded onto silicone membrane and subjected to simulated physiological stretch at the range of 5, 10, and 15% elongation. Expression of primary ECM proteins in HBSMCs was analyzed by real-time polymerase chain reaction and Western blot. Specificity of the FAK and ERK1/2 was determined by Western blot with FAK inhibitor and ERK1/2 inhibitor (PD98059). Specificity of integrin alpha4 and integrin alphav was determined with small interfering ribonucleic acid (siRNA) transfection. RESULTS: The expression of collagen I (Col1), collagen III (Col3), and fibronectin (Fn) was increased significantly under the simulated physiological stretch of 10 and 15%. Integrin alpha4 and alphav, FAK, ERK1/2 were activated by 10% simulated physiological stretch compared with the static condition. Pretreatment of ERK1/2 inhibitor, FAK inhibitor, integrin alpha4 siRNA, or integrin alphav siRNA reduced the stretch induced expression of ECM proteins. And FAK inhibitor decreased the stretch induced ERK1/2 activity and ECM protein expression. Integrin alpha4 siRNA or integrin alphav siRNA inhibited the stretch-induced activity of FAK. CONCLUSION: Simulated physiological stretch increases the expression of ECM proteins in HBSMCs, and integrin alpha4/alphav-FAK-ERK1/2 signaling pathway partly modulates the mechano-transducing process. PMID- 28013346 TI - The expression of Foxp3 and TLR4 in cervical cancer: association with immune escape and clinical pathology. AB - PURPOSE: To explore the expression of forkhead/winged helix transcription factor p3(Foxp3) and toll-like receptor 4(TLR4) in cervical cancer and evaluate their clinical significance. METHODS: Foxp3 and TLR4 protein expression was detected in 105 cervical tissue specimens including cervical cancer, cervical intraepithelial neoplasia (CIN), and healthy control samples using immunohistochemistry. Their relationship with clinicopathologic parameters was also determined. RESULTS: Foxp3 and TLR4 had high levels of expression in cervical cancer cells (91.43 and 82.86%, respectively). Foxp3 levels were significantly associated with FIGO stage (P < 0.001) and tumor size (P = 0.034), while TLR4 levels were associated with clinical FIGO stage (P = 0.033) and lymph node metastasis (P = 0.031). Their expression levels were not correlated with age, histologic type, or differentiation (all P > 0.05). These findings suggest that Foxp3 and TLR4 may be useful prognostic indicators of cervical carcinoma. In addition, there were significant positive relationships between Foxp3 and TLR4 expression (r = 0.703, P < 0.001), which shows a possible link and synergistic role of Foxp3 and TLR4 in promoting the immune escape of cervical cancer. CONCLUSIONS: Foxp3 and TLR4 may be useful biomarkers for patient prognosis and cervical cancer prediction and treatment. PMID- 28013347 TI - MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-kappaB signaling pathway. AB - Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and pro-fibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subcutaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the AT1 receptor. Finally, we demonstrated the direct interaction between Ang II and MD2 protein via hydrogen bonds on Arg-90, Glu-92, and Asp-100. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling. PMID- 28013348 TI - Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice. AB - Diabetes is associated with a number of co-morbidities including an increased risk of developing cardiovascular diseases. The activation of Ca2+-activated proteases of the calpain family has been implicated in platelet activation associated with diabetes and this study aimed to determine the role of calpain activation in the development of endothelial dysfunction. Diabetes induction in mice attenuated acetylcholine-induced relaxation of mesenteric artery rings, an effect prevented in mice receiving a calpain inhibitor. A nitric oxide independent but diclofenac-sensitive component of the relaxation-response was altered and correlated with a loss of prostacyclin (PGI2) generation and reduced vascular levels of PGI2 synthase. Calpain inhibition was also able to restore PGI2 synthase levels and PGI2 generation in arteries from diabetic animals. The effects of diabetes were reproduced in vitro by a combination of high glucose and palmitate, which elicited calpain activation, PGI2 synthase cleavage and inactivation as well as endothelial dysfunction in mesenteric arteries from wild type mice. PGI2 cleavage was not observed in arteries from calpain 1-/- mice or mice overexpressing the endogenous calpain inhibitor calpastatin. Finally, proteomic analyses revealed that calpain 1 cleaved the C-terminal domain of PGI2 synthase close to the catalytic site of the enzyme. These data demonstrate that diabetes leads to the activation of calpain 1 in mesenteric arteries and can initiate endothelial dysfunction by cleaving and inactivating the PGI2 synthase. Given that calpain inhibition prevented diabetes-induced endothelial dysfunction in mesenteric arteries, calpains represent an interesting therapeutic target for the prevention of cardiovascular complication of diabetes. PMID- 28013349 TI - Pharmacology and toxicology of the novel investigational agent Cantrixil (TRX-E 002-1). AB - PURPOSE: Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development. METHODS: A GLP dog CV study using a 4 * 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities. Mutagenic potential was assessed using the bacterial reverse mutation assay. Clastogenicity was assessed by determining micronuclei formation in the bone marrow of SPF Arc(S) Swiss mice dosed at clinical concentrations. TRX-E-002-1 toxicology was evaluated in GLP-compliant MTD and 28-day repeat-dose studies in rats and dogs. RESULTS: In vitro TRX-E-002-1 has potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. TRX E-002-1 increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis. In vivo, Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with Cisplatin. Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer. CONCLUSIONS: In animals, this clinical formulation and route of administration of Cantrixil demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile and constituted a successful Investigational New Drug application to the US Food and Drug Administration. PMID- 28013350 TI - Textural features of 18F-fluorodeoxyglucose positron emission tomography scanning in diagnosing aortic prosthetic graft infection. AB - BACKGROUND: The clinical problem in suspected aortoiliac graft infection (AGI) is to obtain proof of infection. Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography scanning (PET) has been suggested to play a pivotal role, an evidence-based interpretation is lacking. The objective of this retrospective study was to examine the feasibility and utility of 18F-FDG uptake heterogeneity characterized by textural features to diagnose AGI. METHODS: Thirty patients with a history of aortic graft reconstruction who underwent 18F-FDG PET/CT scanning were included. Sixteen patients were suspected to have an AGI (group I). AGI was considered proven only in the case of a positive bacterial culture. Positive cultures were found in 10 of the 16 patients (group Ia), and in the other six patients, cultures remained negative (group Ib). A control group was formed of 14 patients undergoing 18F-FDG PET for other reasons (group II). PET images were assessed using conventional maximal standardized uptake value (SUVmax), tissue-to background ratio (TBR), and visual grading scale (VGS). Additionally, 64 different 18F-FDG PET based textural features were applied to characterize 18F FDG uptake heterogeneity. To select candidate predictors, univariable logistic regression analysis was performed (alpha = 0.16). The accuracy was satisfactory in case of an AUC > 0.8. RESULTS: The feature selection process yielded the textural features named variance (AUC = 0.88), high grey level zone emphasis (AUC = 0.87), small zone low grey level emphasis (AUC = 0.80), and small zone high grey level emphasis (AUC = 0.81) most optimal for distinguishing between groups I and II. SUVmax, TBR, and VGS were also able to distinguish between these groups with AUCs of 0.87, 0.78, and 0.90, respectively. The textural feature named short run high grey level emphasis was able to distinguish group Ia from Ib (AUC = 0.83), while for the same task the TBR and VGS were not found to be predictive. SUVmax was found predictive in distinguishing these groups, but showed an unsatisfactory accuracy (AUC = 0.75). CONCLUSION: Textural analysis to characterize 18F-FDG uptake heterogeneity is feasible and shows promising results in diagnosing AGI, but requires additional external validation and refinement before it can be implemented in the clinical decision-making process. PMID- 28013351 TI - Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward. AB - RATIONALE: Neurokinin-1 receptor (NK1R) signaling modulates behaviors associated with psychostimulants and opioids. Psychostimulants, such as amphetamine (AMPH) and cocaine, bind to monoamine transporters and alter their functions. Both dopamine and norepinephrine transporters are regulated by NK1R activation suggesting a role for NK1R mediated catecholamine transporter regulation in psychostimulant-mediated behaviors. OBJECTIVES: The effect of in vivo administration of aprepitant (10 mg/kg) on the expression of AMPH (0.5 and 2 mg/kg) and cocaine (5 and 20 mg/kg)-induced conditioned place preference (CPP) as well as locomotor activation was examined in C57BL/6J mice. The effect of aprepitant on morphine (1 and 5 mg/kg)-induced CPP was also examined to identify the specific actions of aprepitant on psychostimulant versus opioid-induced behaviors. RESULTS: Aprepitant administration significantly attenuated the CPP expression and locomotor activation produced by AMPH and cocaine. In contrast, aprepitant significantly enhanced the expression of CPP produced by morphine while significantly suppressing the locomotor activity of the mice conditioned with morphine. Aprepitant by itself did not induce significant CPP or conditioned place aversion or locomotor activation or suppression. CONCLUSIONS: Attenuation of AMPH or cocaine-induced CPP and locomotor activation by aprepitant suggests a role for NK1R signaling in psychostimulant-mediated behaviors. Stimulation of morphine-induced CPP expression and suppression of locomotor activity of morphine conditioned mice suggest differential effects of NK1R antagonism on conditioned psychostimulant versus opioid reward. Collectively, these findings indicate that clinically used NK1R antagonist, aprepitant may serve as a potential therapeutic agent in the treatment of psychostimulant abuse. PMID- 28013352 TI - Methylphenidate during early consolidation affects long-term associative memory retrieval depending on baseline catecholamines. AB - RATIONALE: Synaptic memory consolidation is thought to rely on catecholaminergic signaling. Eventually, it is followed by systems consolidation, which embeds memories in a neocortical network. Although this sequence was demonstrated in rodents, it is unclear how catecholamines affect memory consolidation in humans. OBJECTIVES: Here, we tested the effects of catecholaminergic modulation on synaptic and subsequent systems consolidation. We expected enhanced memory performance and increased neocortical engagement during delayed retrieval. Additionally, we tested if this effect was modulated by individual differences in a cognitive proxy measure of baseline catecholamine synthesis capacity. METHODS: Fifty-three healthy males underwent a between-subjects, double-blind, placebo controlled procedure across 2 days. On day 1, subjects studied and retrieved object-location associations and received 20 mg of methylphenidate or placebo. Drug intake was timed so that methylphenidate was expected to affect early consolidation but not encoding or retrieval. Memory was tested again while subjects were scanned three days later. RESULTS: Methylphenidate did not facilitate memory performance, and there was no significant group difference in activation during delayed retrieval. However, memory representations differed between groups depending on baseline catecholamines. The placebo group showed increased activation in occipito-temporal regions but decreased connectivity with the hippocampus, associated with lower baseline catecholamine synthesis capacity. The methylphenidate group showed stronger activation in the postcentral gyrus, associated with higher baseline catecholamine synthesis capacity. CONCLUSIONS: Altogether, methylphenidate during early consolidation did not foster long-term memory performance, but it affected retrieval-related neural processes depending on individual levels of baseline catecholamines. PMID- 28013353 TI - Changes in stress-stimulated allopregnanolone levels induced by neonatal estradiol treatment are associated with enhanced dopamine release in adult female rats: reversal by progesterone administration. AB - BACKGROUND: Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. OBJECTIVE: We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood. METHODS: Female rats were treated with 10 MUg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC). RESULTS: Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors. CONCLUSIONS: The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders. PMID- 28013354 TI - GABAA receptor occupancy by subtype selective GABAAalpha2,3 modulators: PET studies in humans. AB - RATIONALE: Sedation, dependence, and abuse liability limit the use of non selective gamma-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAalpha2,3 receptor positive modulators with limited sedative effects. OBJECTIVES: The current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability. METHOD: Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA receptor occupancy was described by hyperbolic function, and K i,plasma (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests. RESULTS: The [11C]flumazenil binding was reduced in a dose dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K i,plasma estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively. CONCLUSION: High GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects. PMID- 28013355 TI - Effect of sildenafil on the activity of some antidepressant drugs and electroconvulsive shock treatment in the forced swim test in mice. AB - Sildenafil, a potent and selective inhibitor of phosphodiesterase type 5, is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. It is often taken by patients suffering from depression and receiving antidepressant drug treatment. However, its influence on the efficacy of antidepressant treatment was not sufficiently studied. Therefore, the aim of the present study was to investigate the influence of sildenafil on the anti-immobility action of several antidepressant drugs (i.e., sertraline, fluvoxamine, citalopram, maprotiline, trazodone, and agomelatine) as well as on antidepressant-like effect of electroconvulsive stimulations in the forced swim test in mice. The obtained results showed that acute sildenafil treatment enhanced the antidepressant-like activity of all of the studied drugs. The observed effects were not due to the increase in locomotor activity. The interactions between sildenafil and sertraline, maprotiline, and trazodone were pharmacodynamic in nature, as sildenafil did not affect concentrations of these drugs neither in serum nor in brain tissue. Increased concentrations of fluvoxamine, citalopram, and agomelatine in brain tissue evoked by sildenafil co-administration suggest that pharmacokinetic interactions between sildenafil and these drugs are very likely. Sildenafil injected acutely did not alter the antidepressant-like efficacy of electroconvulsive stimulations in mice, as assessed in the forced swim test. Interestingly, repeated (14 days) administration of sildenafil decreased the anti immobility action of the electroconvulsive stimulations. In conclusion, the present study shows that sildenafil may alter the effectiveness of antidepressant treatment. Further studies are warranted to better characterize the influence of sildenafil on the activity of antidepressant drugs and electroconvulsive therapy. PMID- 28013356 TI - Diuretic effect of extracts, fractions and two compounds 2alpha,3beta,19alpha trihydroxy-urs-12-en-28-oic acid and 5-hydroxy-3,6,7,8,4'-pentamethoxyflavone from Rubus rosaefolius Sm. (Rosaceae) leaves in rats. AB - Although diuretics have been widely used to treat hypertension along with others cardiovascular and renal disorders, no scientific data have been recorded to support the diuretic properties of Rubus rosaefolius Sm. (Rosaceae), a plant popularly used in Brazil to treat hypertension. Male Wistar rats were orally treated with: vehicle; hydrochlorothiazide; aqueous (AERR) and methanolic (MERR) extracts; dichloromethane (DCM), hexane (HEX) and ethyl acetate (EA) fractions; and the isolated compounds 2alpha,3beta,19alpha-trihydroxy-urs-12-en-28-oic acid (TUA) and 5-hydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF). At the end of the experiment (after 8 or 24 h), urine volume and other urine or plasma parameters were measured. AERR and MERR, at 100 and 30 mg/kg, respectively, induced diuretic, natriuretic and kaliuretic effect. Additionally, the DCM and HEX, but not EA, at 10 mg/kg, also increased urine volume and Na+ and K+ excretion. Both active constituents, TUA and PMF, at doses of 1 and 3 mg/kg, showed an augmented diuretic and natriuretic index. While TUA revealed a kaliuretic action, PMF did not interfere with potassium excretion. The compounds increased urinary creatinine, but not urea, levels. TUA was able to decrease calcium excretion, as well as HCTZ, while PMF effect was associated with increased urinary prostaglandin E2 levels. The non-selective muscarinic receptor antagonist (atropine) prevented TUA-induced diuresis. In addition, indomethacin (a cyclooxygenase inhibitor) and atropine, exhibited the ability to block the diuretic effects prompted by PMF. Our study demonstrates the diuretic effect of extracts, fractions and two natural compounds obtained from R. rosaefolius leaves in rats. PMID- 28013358 TI - Prevalence and associations of neuropathic pain in a cohort of multi-ethnic Asian low back pain patients. AB - The prevalence of neuropathic low back pain differs in different ethnic populations. The aims of the study are to determine its frequency and associations in a multi-ethnic cohort of Asian low back pain patients. This was a cross-sectional study of low back patients seen at the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. Neuropathic low back pain patients were identified using the painDETECT questionnaire and compared with non-neuropathic (unclear or nociceptive) low back pain patients, in terms of socio-demographic and clinical factors, pain severity (numerical pain rating scale, NPRS), disability (Roland Morris Disability Questionnaire, RMDQ), as well as anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Of 210 patients, 26 (12.4%) have neuropathic low back pain. Neuropathic pain is associated with non Chinese ethnicity, higher body mass index and pain radiation below the knee. Patients with neuropathic pain have significantly higher NPRS and RMDQ scores, and there are more subjects with anxiety on HADS. However, there are no differences between the groups in age, gender, pain duration or underlying diagnosis of low back pain. The prevalence of neuropathic low back pain in a multi-ethnic Malaysian cohort is lower than previously reported in other populations with possible differences between ethnic groups. It is associated with greater pain severity, disability and anxiety. PMID- 28013359 TI - Comparison of engraftment following different stem cell mobilization modalities in patients with multiple myeloma treated with a uniform induction regimen containing bortezomib, cyclophosphamide and dexamethasone. AB - Bortezomib-based induction followed by autologous stem cell transplantation is a common treatment for multiple myeloma (MM). Stem cell (SC) mobilization with granulocyte-colony stimulating factor (G-CSF) alone has become an alternative to G-CSF combined with chemotherapeutic agents. This study aimed to compare the efficacy of the two mobilization modalities following induction with a uniform regimen containing bortezomib, cyclophosphamide and dexamethasone (VCD). We retrospectively evaluated results of SC mobilization using either G-CSF alone or combined with high-dose cyclophosphamide (HD-CY) in MM patients after VCD induction. The primary endpoints of the study were engraftment and mobilization associated toxicity. Parameters of stem cell collection, transplantation and engraftment were assessed. Data of 92 patients were analyzed [56 (61%) mobilized with HD-CY + G-CSF and 36 (39%) with G-CSF only]. HD-CY + G-CSF provided a higher number of CD34 + cells (15.9 vs 8.1 * 106/kg, p = 0.001) with fewer apheresis sessions. However, while no adverse events were observed in patients receiving G CSF alone, nine patients (16%) receiving HD-CY + G-CSF developed neutropenic fever requiring hospitalization. Although a greater number of cells was transplanted following mobilization with HD-CY + G-CSF, neutrophil and platelet engraftment and duration of transplant-related hospitalization were similar in both cohorts. G-CSF alone provided a sufficient SC amount, without exposing patients to additional toxicity. While HD-CY + G-CSF resulted in a superior SC yield in MM patients induced with VCD, this advantage should be balanced against adverse effects of this mobilization regimen. PMID- 28013360 TI - Blastic plasmacytoid dendritic cell neoplasm with transient response to pralatrexate. PMID- 28013357 TI - Physical activity but not sedentary activity is reduced in primary Sjogren's syndrome. AB - The aim of the study was to evaluate the levels of physical activity in individuals with primary Sjogren's syndrome (PSS) and its relationship to the clinical features of PSS. To this cross-sectional study, self-reported levels of physical activity from 273 PSS patients were measured using the International Physical Activity Questionnaire-short form (IPAQ-SF) and were compared with healthy controls matched for age, sex and body mass index. Fatigue and other clinical aspects of PSS including disease status, dryness, daytime sleepiness, dysautonomia, anxiety and depression were assessed using validated tools. Individuals with PSS had significantly reduced levels of physical activity [median (interquartile range, IQR) 1572 (594-3158) versus 3708 (1732-8255) metabolic equivalent of task (MET) * min/week, p < 0.001], but similar levels of sedentary activity [median (IQR) min 300 (135-375) versus 343 (223-433) (MET) * min/week, p = 0.532] compared to healthy individuals. Differences in physical activity between PSS and controls increased at moderate [median (IQR) 0 (0-480) versus 1560 (570-3900) MET * min/week, p < 0.001] and vigorous intensities [median (IQR) 0 (0-480) versus 480 (0-1920) MET * min/week, p < 0.001]. Correlation analysis revealed a significant association between physical activity and fatigue, orthostatic intolerance, depressive symptoms and quality of life. Sedentary activity did not correlate with fatigue. Stepwise linear regression analysis identified symptoms of depression and daytime sleepiness as independent predictors of levels of physical activity. Physical activity is reduced in people with PSS and is associated with symptoms of depression and daytime sleepiness. Sedentary activity is not increased in PSS. Clinical care teams should explore the clinical utility of targeting low levels of physical activity in PSS. PMID- 28013361 TI - Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes. AB - Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1 hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions. PMID- 28013363 TI - Bone Structure and Turnover Status in Postmenopausal Women with Atypical Femur Fracture After Prolonged Bisphosphonate Therapy. AB - Atypical femur fracture (AFF), a serious complication of long-term bisphosphonate therapy, is usually preceded by an incomplete fracture appearing on the lateral femur. AFF is most likely the result of severely suppressed bone turnover (SSBT). However, the differences in bone structure and turnover between patients with incomplete and complete AFF remain unknown. We examined trans-iliac bone biopsies from 12 white postmenopausal women with AFF (incomplete = 5; complete = 7) on BP therapy of >5 years and 43 healthy white premenopausal women. Histomorphometric measurements were performed separately in cancellous, intracortical and endosteal envelopes. Of the 43 histomorphometric measurements on 3 difference bone surfaces (cancellous, intracortical and endosteal), only 2 bone resorption variables (Oc.S/BS and Oc.S/NOS) on the endosteal surface were significantly lower in patients with complete AFF than those with incomplete AFF. Compared to healthy premenopausal women, the trabecular bone volume, thickness and number were all significantly lower in patients with AFF. The dynamic bone formation variables in patients with AFF were significantly reduced on all bone surfaces. The likelihood of a biopsy with no tetracycline labeling was significantly higher in AFF patients than in healthy premenopausal women. Based on these results, we conclude that there are no significant differences in bone turnover between patients with incomplete and complete AFF, suggesting that the suppression of bone turnover had already existed in the femur with incomplete AFF. Compared to healthy premenopausal women, bone turnover is similarly suppressed in patients with either type of AFF. PMID- 28013362 TI - The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children. AB - A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood. PMID- 28013364 TI - Rest-activity patterns and falls and fractures in older men. AB - : Dysregulated rest-activity rhythm (RAR) patterns have been associated with several health conditions in older adults. This study showed that later acrophase was associated with a modestly greater risk of falls but not fractures in elderly men. Associations between dysregulated RAR patterns and osteoporosis risk warrant further investigation. PURPOSE: The purpose of this study was to investigate the relationship between rest-activity rhythm (RAR) patterns and risk of falls/fractures in older men. We hypothesized that dysregulated RAR would be associated with incident falls/fractures. METHODS: We used wrist-worn actigraphy to measure RAR over 4.8 +/- 0.8 24-h periods in men (>=67 years) enrolled in the multicenter Outcomes of Sleep Disorders in Men (MrOS Sleep) Study (n = 3001). Men were contacted every 4 months to report occurrence of falls/fractures. RAR parameters included amplitude (difference between peak and nadir activity in counts/minute), mesor (activity counts/minute), acrophase (time of day of peak activity), and pseudo-F statistic (rhythm robustness) and were evaluated as continuous variables with associations reported per SD increase/decrease in models adjusted for confounders. Logistic regression was used to estimate the likelihood (odds ratio, OR) of recurrent falls in the year after the visit. Proportional hazards models were used to estimate the risk (hazard ratio, HR) of fractures. RESULTS: One year after the visit, 417 men (14%) had recurrent (>=2) falls. Later acrophase (OR 1.18, 95% CI 1.06-1.32) was associated with a modestly greater likelihood of falls. In 8.6 years (SD 2.6 years) of >97% complete follow up, 256 men (8.53%) had a major osteoporotic fracture, 85 (2.8%) had a clinical spine fracture, and 110 (3.7%) had a hip fracture. No consistent, significant associations were observed between RAR patterns and fractures. CONCLUSIONS: Later acrophase was associated with a modestly greater risk of falls; this association did not translate into a higher fracture risk in this cohort of elderly men. PMID- 28013365 TI - How can we define and analyse drug exposure more precisely to improve the prediction of hospitalizations in longitudinal (claims) data? AB - BACKGROUND: Risk prediction models can be powerful tools to support clinical decision-making, to help targeting interventions, and, thus, to improve clinical and economic outcomes, provided that model performance is good and sensitivity and specificity are well balanced. Drug utilization as a potential risk factor for unplanned hospitalizations has recently emerged as a meaningful predictor variable in such models. Drug treatment is a rather unstable (i.e. time dependent) phenomenon and most drug-induced events are concentration-dependent and therefore individual drug exposure will likely modulate the risk. This especially applies to longitudinal monitoring of appropriate drug treatment within claims data as another promising application for prediction models. METHODS AND RESULTS: To guide future research towards this direction, we firstly reviewed current risk prediction models for unplanned hospitalizations that explicitly included information on drug utilization and were surprised to find that these models rarely attempted to consider dose and frequent modulators of drug clearance such as interactions with co-medication or co-morbidities. As another example, they often presumed class effects where in fact, differences between active moieties were well established. In addition, the study designs and statistical risk analysis disregarded the fact that medication and risk modulators and, thus, adverse events can vary over time. In a simulation study, we therefore evaluated the potential benefit of time-dependent Cox models over standard binary regression approaches with a fixed follow-up period. CONCLUSIONS: Longitudinal drug information could be utilized much more efficiently both by precisely estimating individual drug exposure and by applying more refined statistical methodology to account for time-dependent drug utilization patterns. PMID- 28013366 TI - Teaming up synthetic chemistry and histochemistry for activity screening in galectin-directed inhibitor design. AB - A hallmark of endogenous lectins is their ability to select a few distinct glycoconjugates as counterreceptors for functional pairing from the natural abundance of cellular glycoproteins and glycolipids. As a consequence, assays to assess inhibition of lectin binding should necessarily come as close as possible to the physiological situation, to characterize an impact of a synthetic compound on biorelevant binding with pharmaceutical perspective. We here introduce in a proof-of-principle manner work with sections of paraffin-embedded tissue (jejunum, epididymis) and labeled adhesion/growth-regulatory galectins, harboring one (galectin-1 and galectin-3) or two (galectin-8) types of lectin domain. Six pairs of synthetic lactosides from tailoring of the headgroup (3'-O-sulfation) and the aglycone (beta-methyl to aromatic S- and O-linked extensions) as well as three bi- to tetravalent glycoclusters were used as test compounds. Varying extents of reduction in staining intensity by synthetic compounds relative to unsubstituted/free lactose proved the applicability and sensitivity of the method. Flanking cytofluorimetric assays on lectin binding to native cells gave similar grading, excluding a major impact of tissue fixation. The experiments revealed cell/tissue binding of galectin-8 preferentially via one domain, depending on the cell type so that the effect of an inhibitor in a certain context cannot be extrapolated to other cells/tissues. Moreover, the work with the other galectins attests that this assay enables comprehensive analysis of the galectin network in serial tissue sections to determine overlaps and regional differences in inhibitory profiles. PMID- 28013367 TI - Actin polymerization plays a significant role in asbestos-induced inflammasome activation in mesothelial cells in vitro. AB - Asbestos exposure leads to malignant mesothelioma (MM), a deadly neoplasm of mesothelial cells of various locations. Although there is no doubt about the role of asbestos in MM tumorigenesis, mechanisms are still not well explored. Recently, our group demonstrated that asbestos causes inflammasome priming and activation in mesothelial cells, which in part is dependent on oxidative stress. Our current study sheds light on yet another mechanism of inflammasome activation by asbestos. Here we show the role of actin polymerization in asbestos-induced activation of the nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. Using human mesothelial cells, we first demonstrate that asbestos and carbon nanotubes induced caspase-1 activation and high-mobility group box 1, interleukin 1 beta and interleukin 18 secretion was blocked by Cytochalasin D (Cyto D) an actin polymerization inhibitor. Next, to understand the mechanism, we assessed whether phagocytosis of fibers by mesothelial cells is affected by actin polymerization inhibition. Transmission electron microscopy showed the inhibition of fiber uptake by mesothelial cells in the presence of Cyto D. Furthermore, localization of components of the inflammasome, apoptotic speck-like protein containing a CARD domain (ASC) and NLRP3, to the perinuclear space in mitochondria or endoplasmic reticulum in response to fiber exposure was also interrupted in the presence of Cyto D. Taken together, our studies suggest that actin polymerization plays important roles in inflammasome activation by fibers via regulation of phagocytosis and/or spatial localization of inflammasome components. PMID- 28013368 TI - Lectins: a primer for histochemists and cell biologists. AB - An experimental observation on selecting binding partners underlies the introduction of the term 'lectin'. Agglutination of erythrocytes depending on their blood-group status revealed the presence of activities in plant extracts that act in an epitope-specific manner like antibodies. As it turned out, their binding partners on the cell surface are carbohydrates of glycoconjugates. By definition, lectins are glycan-specific (mono- or oligosaccharides presented by glycoconjugates or polysaccharides) receptors, distinguished from antibodies, from enzymes using carbohydrates as substrates and from transporters of free saccharides. They are ubiquitous in Nature and structurally widely diversified. More than a dozen types of folding pattern have evolved for proteins that bind glycans. Used as tool, this capacity facilitates versatile mapping of glycan presence so that plant/fungal and also animal/human lectins have found a broad spectrum of biomedical applications. The functional pairing with physiological counterreceptors is involved in a wide range of cellular activities from cell adhesion, glycoconjugate trafficking to growth regulation and lets lectins act as sensors/effectors in host defense. PMID- 28013369 TI - Peroxisomal abnormalities in the immortalized human hepatocyte (IHH) cell line. AB - The immortalized human hepatocyte (IHH) cell line is increasingly used for studies related to liver metabolism, including hepatic glucose, lipid, lipoprotein and triglyceride metabolism, and the effect of therapeutic interventions. To determine whether the IHH cell line is a good model to investigate hepatic peroxisomal metabolism, we measured several peroxisomal parameters in IHH cells and, for comparison, HepG2 cells and primary skin fibroblasts. This revealed a marked plasmalogen deficiency and a deficient fatty acid alpha-oxidation in the IHH cells, due to a defect of PEX7, a cytosolic receptor protein required for peroxisomal import of a subset of peroxisomal proteins. These abnormalities have consequences for the lipid homeostasis of these cells and thus should be taken into account for the interpretation of data previously generated by using this cell line and when considering using this cell line for future research. PMID- 28013370 TI - Giant crystals inside mitochondria of equine chondrocytes. AB - The present study reports for the first time the presence of giant crystals in mitochondria of equine chondrocytes. These structures show dark contrast in TEM images as well as a granular substructure of regularly aligned 1-2 nm small units. Different zone axes of the crystalline structure were analysed by means of Fourier transformation of lattice-resolution TEM images proving the crystalline nature of the structure. Elemental analysis reveals a high content of nitrogen referring to protein. The outer shape of the crystals is geometrical with an up to hexagonal profile in cross sections. It is elongated, spanning a length of several micrometres through the whole cell. In some chondrocytes, several crystals were found, sometimes combined in a single mitochondrion. Crystals were preferentially aligned along the long axis of the cells, thus appearing in the same orientation as the chondrocytes in the tissue. Although no similar structures have been found in the cartilage of any other species investigated, they have been found in cartilage repair tissue formed within a mechanically stimulated equine chondrocyte construct. Crystals were mainly located in superficial regions of cartilage, especially in joint regions of well-developed superficial layers, more often in yearlings than in adult horses. These results indicate that intramitochondrial crystals are related to the high mechanical stress in the horse joint and potentially also to the increased metabolic activity of immature individuals. PMID- 28013371 TI - The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts. AB - Independently of the lipid-lowering effects, statin has been reported to attenuate the development of diabetic cardiomyopathy. However, the effect of statin in glucose-controlled diabetic condition has not been demonstrated. We evaluated the effect of fluvastatin on cardiac function, fibrosis, and angiotensin-converting enzyme-2 (ACE2) expression in glucose-controlled diabetic rats. Male Wistar rats were randomly divided into four groups: control (Group C), diabetes (Group D), diabetes with insulin (Group I), and diabetes with insulin and fluvastatin (Group I+F). Diabetes was induced by a single injection of streptozotocin (65 mg/kg). After 8 weeks, the hearts were extracted following echocardiographic evaluation. Cardiac fibrosis was analyzed using Masson's trichrome stain. Collagens I and III and ACE2 expressions were evaluated by immunohistochemistry and western blot. Group D showed reduced cardiac systolic function compared to the other groups (all P < 0.05). However, diastolic function estimated by E/A ratio was significantly decreased in groups D and I (median: 0.88 and 1.45, respectively) compared to groups C and I+F (2.97 and 2.15) (all P < 0.05). Cardiac fibrosis was more severe in groups D and I than in groups C and I+F (all P < 0.05) on Masson's trichrome stain. On immunohistochemistry, ACE2 expression was significantly decreased only in group D (all P < 0.05). However, collagen I and III showed higher expressions in group D compared to groups C and I+F while no significant difference was observed compared with group I (all P < 0.05). On western blot, collagen I and ACE2 expressions in group D (median: 1.78 and 0.35, respectively) were significantly different from groups C (references: 1) and I+F (0.76 and 1.21) (all P < 0.05), but not from group I (1.19 and 0.92). Our study suggested a combination of fluvastatin and insulin would be more effective than insulin alone in diabetic hearts. However, the exact mechanism remains to be elucidated. PMID- 28013373 TI - An update on idiopathic intracranial hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is still a grey area in the knowledge of the aetiology, diagnosis and management of neurosurgical diseases. The definition of IIH has been reviewed over time and many hypotheses have been expressed as cause of the disease. The literature supplies very little evidence-based information to guide our decision-making process when it comes to treat the disease. In this review we sum up the latest information regarding the aetiology and therapy of IIH. Additionally, we make an attempt to unify the diagnostic criteria of Dandy, Friedman and Wall established from 1937 to date. METHOD: In this narrative review, we attempt to update the current standpoint to IIH, evaluate the input until now and consider future directions for research. The vast majority of the literature consisted of cohort studies, case control studies, systematic reviews and other narrative reviews. RESULTS: Pathophysiology: The incidence of IIH is steadily increasing. Several pathophysiological theories have been proposed in the literature based on the flow of cerebrospinal fluid. DIAGNOSIS: We attempt to fuse all the three diagnostic approaches published in the literature that detect IIH, while preserving the individual characteristics of each approach. TREATMENT: Based on evidence-based trials, the current use of acetazolamide in comparison with placebo or with topiramate has been evaluated. In the interventions' field, there seems to be a consonance about the alarming symptoms and what the most suitable operation is in each case. There is some disagreement about the indications for venous sinus transversus stenting and its risk/benefit ratio. CONCLUSIONS: Until now there is no class I guideline to which our decision-making can be based on for the management of IIH. A lack of systematic reviews and randomised control trials has been noted. If we focused our research on that, we could develop a standardised treatment protocol. PMID- 28013372 TI - MiR-21 and miR-205 are induced in invasive cutaneous squamous cell carcinomas. AB - Cutaneous squamous cell carcinoma (cSCC) is a malignant proliferation of keratinocytes with an uncertain molecular basis causing significant morbidity. MicroRNAs (miRs) are small RNA molecules that regulate gene expression on post- transcriptional level. MiRs are critical to various biological processes. To determine if miRs play a role in pathogenesis of invasive cSCC, we collected patients' specimens from in situ and invasive cSCC (n = 19) and examined miRs expression levels using qPCR. Specifically, we evaluated miR-21, miR-103a, miR 186, miR-200b, miR-203, and miR-205 expression levels due to their role in skin biology and epithelial to mesenchymal transition. MiR levels were compared between in situ and invasive cSCCs. We found statistically significant (p <= 0.05) upregulation of miR-21 and miR-205 in invasive cSCC compared to cSCC in situ. We concluded that miR-21 and miR-205 may have diagnostic value in determining the invasive properties of cSCCs and that each cSCC displays unique miR profile, underscoring the possibility of personalized medicine approach in developing potential novel, less invasive treatments. PMID- 28013374 TI - Mosquito repellent activity of volatile oils from selected aromatic plants. AB - Essential oils from fresh leaves of four aromatic plants viz., Ocimum sanctum, Mentha piperita, Eucalyptus globulus and Plectranthus amboinicus were extracted by hydrodistillation. The test solutions were prepared as 20% essential oil in ethanol and positive control as 20% DEET in ethanol. Essential oil blend was prepared as 5% concentration. Nulliparous, 3-5-day-old female adult Aedes aegypti mosquitoes were used for repellency screening as per ICMR protocol. The study showed that the repellency of 20% essential oil of O. sanctum, M. piperita and P. amboinicus were comparable with that of the standard DEET (20%) as no mosquito landing on the test was observed up to 6 h. The E. globulus oil exhibited mosquito repellency only upto 11/2 h. Considerable mosquito landing and feeding was displayed in negative control. In the case of the oil blend, no landing of mosquitoes was seen up to 6 h as that of positive control. The results showed that the essential oil blend from O. sanctum, M. piperita, E. globulus and P. amboinicus could repel Ae. aegypti mosquitoes or prevent from feeding as in the case of DEET even at a lower concentration of 5%. This study demonstrates the potential of essential oils from O. sanctum, M. piperita, E. globulus and P. amboinicus and their blend as mosquito repellents against Ae. aegypti, the vector of dengue, chikungunya and yellow fever. PMID- 28013376 TI - A high-vacuum wound drainage system reduces pain and length of treatment for pediatric soft tissue abscesses. AB - : Open incision and drainage (I&D) and wound packing is accepted as the standard treatment for soft tissue abscesses. However, conventional I&D has a number of problems in practice which prompt us to improve the I&D methods that would minimize the pain associated with packing during dressing changes. In order to compare the pain associated with dressing changes in the conventional I&D group to the vacuum system group and the treatment time of both groups, we performed a randomized trial in pediatric patients between 0 and 18 years of age who are undergoing abscess drainage in the operating room from April 2011 to April 2015. Patients treated with open I&D (n = 648) were compared to those treated with placement of high-vacuum wound drainage system (n = 776) through the abscess cavities. Both groups received equivalent antibiotic treatment, and all patients were followed up in the outpatient clinics until the infection has been resolved. The mean FACES scale pain scores were significantly higher in the open I&D group than in the vacuum system group. The vacuum system group had a shorter length of stay and less need for community doctor or outpatient dressing changes than the open I&D group (p < 0.001). No recurrent abscesses were observed in the vacuum system group, and 10 patients in the open I&D group required another drainage at the exact same location. CONCLUSION: High-vacuum wound drainage system was an efficient and safe alternative to the traditional I&D for community-acquired soft tissue abscesses with few complications in short term. What is Known: * Open incision and drainage (I&D) followed by irrigation and wound packing is the standard treatment for soft tissue abscesses. * The painful daily packing may cause emotional trauma to the child and lead to an unwelcoming challenge to the caretakers and health care providers. What is New: * We modified the method of I&D by adding primary suturing of the wound and placement of a high-vacuum wound drainage system. * This technique was proved to be an efficient and safe alternative to the traditional I&D method for soft tissue abscesses with small complications in short term. PMID- 28013375 TI - Alterations in pancreatic beta cell function and Trypanosoma cruzi infection: evidence from human and animal studies. AB - The parasite Trypanosoma cruzi causes a persistent infection, Chagas disease, affecting millions of persons in endemic areas of Latin America. As a result of immigration, this disease has now been diagnosed in non-endemic areas worldwide. Although, the heart and gastrointestinal tract are the most studied, the insulin secreting beta cell of the endocrine pancreas is also a target of infection. In this review, we summarize available clinical and laboratory evidence to determine whether T. cruzi-infection-mediated changes of beta cell function is likely to contribute to the development of hyperglycemia and diabetes. Our literature survey indicates that T. cruzi infection of humans and of experimental animals relates to altered secretory behavior of beta cells. The mechanistic basis of these observations appears to be a change in stimulus-secretion pathway function rather than the loss of insulin-producing beta cells. Whether this attenuated insulin release ultimately contributes to the pathogenesis of diabetes in human Chagas disease, however, remains to be determined. Since the etiologies of diabetes are multifactorial including genetic and lifestyle factors, the use of cell- and animal-based investigations, allowing direct manipulation of these factors, are important tools in testing if reduced insulin secretion has a causal influence on diabetes in the setting of Chagas disease. Long-term clinical investigations will be required to investigate this link in humans. PMID- 28013377 TI - Hospital clowning: a paediatrician's view. AB - : This study investigates the current position of hospital clowns from the perspective of paediatricians and paediatric residents. A total of 14 attending paediatricians and paediatric residents participated in two focus group sessions. Data were analysed using Atlas.ti 5.0. In general, physicians reported positive experiences regarding the interaction between hospital clowns and paediatric patients on the ward. Physicians were more interested in research on children's perception of hospital clowns than in research on the clinical efficacy of hospital clowning. No direct collaboration between physicians and hospital clowns was reported. However, physicians proposed conditions which may streamline their encounters with hospital clowns such as clear communication prior to hospital clown visits, and the condition that visits do not impede medical interventions. CONCLUSION: Overall, paediatricians and paediatric residents view the positive impact on paediatric patients as the most important aspect of hospital clown visits, rather than the clinical efficacy of hospital clowning. In light of the growing number of hospital clowns worldwide, this article provides recommendations for arranging their encounters with paediatricians and paediatric residents to maintain optimal health care. What is known: * Previous studies show a clinically significant pain- and anxiety-reducing effect of hospital clowning in paediatric patients admitted to hospitals or undergoing (invasive) medical procedures. * In general, paediatricians have positive ideas about hospital clowns, aside from personal prejudices. What is new: * This novel study gives deeper insight into day-to-day interaction between paediatricians and hospital clowns on the ward. * This study provides recommendations for clinical practice to arrange encounters between physicians and hospital clowns during hospital clown visits. PMID- 28013378 TI - The tandem repeated organization of NB-LRR genes in the clubroot-resistant CRb locus in Brassica rapa L. AB - To facilitate prevention of clubroot disease, a major threat to the successful cultivation of Chinese cabbage (Brassica rapa L.), we bred clubroot-resistant (CR) cultivars by introducing resistance genes from CR turnips via conventional breeding. Among 11 CR loci found in B. rapa, we identified CRb in Chinese cabbage cultivar 'CR Shinki' as a single dominant gene for resistance against Plasmodiophora brassicae pathotype group 3, against which the stacking of Crr1 and Crr2 loci was not effective. However, the precise location and pathotype specificity of CRb have been controversial, because CRa and Rcr1 also map near this locus. Previously, our fine-mapping study revealed that CRb is located in a 140-kb genomic region on chromosome A03. Here, we determined the nucleotide sequence of an approximately 64-kb candidate region in the resistant line; this region contains six open reading frames (ORFs) similar to NB-LRR encoding genes that are predicted to occur in tandem with the same orientation. Among the six ORFs present, only four on the genome of the resistant line showed a strong DNA sequence identity with each other, and only one of those four could confer resistance to P. brassicae isolate No. 14 of the pathotype group 3. These results suggest that these genes evolved through recent gene duplication and uneven crossover events that could lead to the acquisition of clubroot resistance. The DNA sequence of the functional ORF was identical to that of the previously cloned CRa gene; thus, we showed that the independently identified CRb and CRa are one and the same clubroot-resistance gene. PMID- 28013379 TI - Dynamic modelling of solids in a full-scale activated sludge plant preceded by CEPT as a preliminary step for micropollutant removal modelling. AB - The presence of micropollutants in the environment has triggered research on quantifying and predicting their fate in wastewater treatment plants (WWTPs). Since the removal of micropollutants is highly related to conventional pollutant removal and affected by hydraulics, aeration, biomass composition and solids concentration, the fate of these conventional pollutants and characteristics must be well predicted before tackling models to predict the fate of micropollutants. In light of this, the current paper presents the dynamic modelling of conventional pollutants undergoing activated sludge treatment using a limited set of additional daily composite data besides the routine data collected at a WWTP over one year. Results showed that as a basis for modelling, the removal of micropollutants, the Burger-Diehl settler model was found to capture the actual effluent total suspended solids (TSS) concentrations more efficiently than the Takacs model by explicitly modelling the overflow boundary. Results also demonstrated that particular attention must be given to characterizing incoming TSS to obtain a representative solids balance in the presence of a chemically enhanced primary treatment, which is key to predict the fate of micropollutants. PMID- 28013380 TI - The impact of age on the postoperative response of the diastolic function and left ventricular mass regression after surgical or transcatheter aortic valve replacement for severe aortic stenosis. AB - PURPOSE: We examined the impact of advanced age on left ventricular mass regression and the change in the diastolic function after aortic valve replacement in patients with aortic stenosis. METHODS: The present study included 129 patients who underwent either surgical or transcatheter aortic valve replacement and 1-year postoperative echocardiography. The patient characteristics and echocardiographic findings were compared between patients who were <80 years of age (group Y: n = 69) and those who were >=80 years of age (group O: n = 60). RESULTS: Preoperative echocardiography revealed that although the left ventricular mass was similar between the groups, the patients in group O had more severe diastolic dysfunction in comparison to those in group Y. Postoperatively, left ventricular mass regression was significantly greater (p = 0.02) and diastolic dysfunction was less prevalent in group Y (p = 0.02) in comparison to group O. The change in E/e' was significantly correlated with the left ventricular mass regression in group Y (p = 0.02), but not in Group O (p = 0.21). CONCLUSIONS: The patients in group O were less susceptible to improvements in myocardial remodeling and the diastolic function in comparison to those in group Y. The altered physiological response to aortic valve replacement might help to determine the appropriate timing of surgery in elderly patients. PMID- 28013381 TI - Pilot study of the effect of cholecalciferol supplementation on hepcidin in children with chronic kidney disease: Results of the D-fense Trial. AB - BACKGROUND: Hepcidin is a key mediator of the anemia of chronic kidney disease (CKD). There is emerging evidence that 25-hydroxyvitamin D (25D) regulates hepcidin production. METHODS: A randomized controlled trial of daily vitamin D supplementation for 12 weeks was performed with the aim to test the effects of 4000 versus 400 IU of cholecalciferol on serum hepcidin levels in children with non-dialysis CKD recruited at a tertiary care children's hospital. Hepcidin was quantified using a validated competitive enzyme-linked immunosorbent assay. 25D levels were measured using the chemiluminescence Liaison 25(OH)D assay system. Co variables included hemoglobin, C-reactive protein, ferritin, and serum calcium and phosphorus for safety monitoring. RESULTS: A total of 34 subjects were randomized to either the intervention or control group, of whom 26.5% were female and 23.5% were African American. The mean age of the study cohort was 10.9 [standard deviation (SD) 5.8] years, the mean baseline glomerular filtration rate was 60 (SD 17.6) ml/min/1.73 m2, and mean baseline 25D level was 29.7 (SD 11.5) ng/ml. At baseline, 50% of subjects were 25D deficient. There were no significant differences in baseline characteristics between the intervention and control groups. Treatment with 4000 IU cholecalciferol was not associated with significant change in hepcidin level at 4 or 12 weeks, and multivariable generalized estimating equation regression demonstrated no significant difference in change in hepcidin over the treatment period in either arm. The median C reactive protein level decreased significantly at 12 weeks in the intervention group. CONCLUSIONS: These results do not suggest that daily nutritional vitamin D supplementation modifies serum hepcidin levels in children with CKD. Further study will be required to determine whether supplementation may be effective in children with more advanced CKD or those on dialysis. PMID- 28013383 TI - Long-term effect of temperature on honey yield and honeybee phenology. AB - There is growing concern about declines in pollinator species, and more recently reservations have been expressed about mismatch in plant-pollinator synchrony as a consequence of phenological change caused by rising temperatures. Long-term changes in honeybee Apis mellifera phenology may have major consequences for agriculture, especially the pollinator market, as well as for honey production. To date, these aspects have received only modest attention. In the current study, we examine honeybee and beekeeping activity in southern Poland for the period 1965-2010, supplemented by hive yields from a beekeeper in southern UK in the same period. We show that despite negative reports on honeybee condition, and documented climate change, the studied apiary managed to show a marked increase in honey production over the 46 year study period, as did that from the UK. The proportion of the annual yield originating from the first harvest decreased during the study period and was associated with rising temperatures in summer. Honeybee spring phenology showed strong negative relationships with temperature but no overall change through time because temperatures of key early spring months had not increased significantly. In contrast, increasing yields and an increased number of harvests (and hence a later final harvest and longer season) were detected and were related to rising temperatures in late spring and in summer. PMID- 28013382 TI - Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome. AB - BACKGROUND: Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis. METHODS: Targeted next-generation sequencing results of an individual with Alport syndrome were analyzed and the results confirmed by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant's effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy. RESULTS: A novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen alpha5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen alpha5(IV) protein in the basement membranes of plucked hair follicles. Using this approach we demonstrated reduced collagen alpha5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing. CONCLUSIONS: Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance. PMID- 28013384 TI - International Conference on Extremophiles 2016. PMID- 28013385 TI - A double-stranded probe coupled with isothermal amplification for qualitative and quantitative detection of avian reovirus. AB - We applied a probe-based real-time loop-mediated isothermal amplification (Cy5 RTqLAMP) technique targeting the avian reovirus (ARV) S3 gene to develop a rapid, sensitive, and specific method for virus detection and quantification. This test specifically detected the presence of ARV, but not other viruses or bacteria present in clinical or artificially spiked samples, including Newcastle disease virus, infectious bursal disease virus, fowl adenovirus, Marek's disease virus, Escherichia coli, and Salmonella spp. This test can detect ARV in less than one hour with an analytical sensitivity of 10 viral gene copies and 1 fg of total cDNA. The Cy5-RTqLAMP does not yield false positive results and is 100 times more sensitive than conventional PCR. This test was shown to be able to detect the presence of ARV in clinical samples. A similar strategy may be used for detection of other important human and animal viral pathogens. PMID- 28013386 TI - Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans. AB - PURPOSE: Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA). METHODS: FBF (Doppler ultrasound) was assessed at rest and during 5 min of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: (1) oral SDF (n = 10), (2) intra arterial L-NMMA (n = 20), (3) SDF and L-NMMA (n = 10). FBF responses to intra arterial sodium nitroprusside (NTP, NO donor) were also assessed. RESULTS: FBF increased with exercise (p < 0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17 +/- 1 to 15 +/- 1 mL/dL/min, p < 0.01). Although the hyperemic response to NTP was augmented by SDF (area under the curve: 41 +/- 7 vs 61 +/- 11 AU, p < 0.01), there was no effect of SDF on exercise hyperemia (p = 0.33). CONCLUSIONS: Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans. PMID- 28013387 TI - Cardiovascular function during supine rest in endurance-trained males with New Zealand blackcurrant: a dose-response study. AB - PURPOSE: Blackcurrant contains anthocyanins that could alter cardiovascular function and reduce cardiovascular disease risk. We examined dose responses of New Zealand blackcurrant (NZBC) extract on cardiovascular function during supine rest. METHODS: Fifteen endurance-trained male cyclists (age: 38 +/- 12 years, height: 178 +/- 5 cm, body mass: 76 +/- 10 kg, [Formula: see text]: 56 +/- 8 mL kg-1 min-1, mean +/- SD) were randomly assigned using a counterbalanced Latin square design to complete four conditions, a control of no NZBC, or one of three doses (300, 600 or 900 mg day-1) of NZBC extract (CurraNZTM) for 7-days with a 14 day washout. Cardiovascular function (i.e., blood pressure, heart rate, ejection time, cardiac output, stroke volume, and total peripheral resistance) during supine rest was examined (Portapres(r) Model 2). RESULTS: Systolic and diastolic blood pressure, heart rate and ejection time were unchanged by NZBC. A dose effect (P < 0.05) was observed for cardiac output, stroke volume, and total peripheral resistance. A trend for a dose effect was observed for mean arterial blood pressure. Cardiac output increased by 0.6 +/- 0.6 L min-1 (15%) and 1.0 +/- 1.0 L min-1 (28%) and stroke volume by 5 +/- 8 mL (7%) and 6 +/- 17 mL (18%) between control and 600, and 900 mg day-1, respectively. Total peripheral resistance decreased by 4 +/- 3 mmHg L-1 min-1 (20%) and 5 +/- 9 mmHg L-1 min-1 (20%) for 600, and 900 mg day-1. CONCLUSION: Seven-days intake of New Zealand blackcurrant extract demonstrated dose-dependent changes on some cardiovascular parameters during supine rest in endurance-trained male cyclists. PMID- 28013388 TI - Swallowing Function and Kinematics in Stroke Patients with Tracheostomies. AB - The purpose of this study was to compare the swallowing function and kinematics in stroke patients with and without tracheostomies. In this retrospective matched case-control study, we compared stroke patients with (TRACH group, n = 24) and without (NO-TRACH group, n = 24) tracheostomies. Patients were matched for age, sex, and stroke-type. Swallowing function was evaluated using the videofluoroscopic dysphagia scale (VDS) and functional oral intake scale (FOIS) obtained from videofluoroscopic swallow study (VFSS) images. Swallowing kinematics were evaluated using a two-dimensional kinematic analysis of the VFSS images. Mean duration of tracheostomy was 132.38 +/- 150.46 days in the TRACH group. There was no significant difference in the total VDS score between the TRACH (35.17 +/- 15.30) and NO-TRACH groups (29.25 +/- 16.66, p = 0.247). FOIS was significantly lower in the TRACH group (2.33 +/- 1.40) than in the NO-TRACH group (4.33 +/- 1.79, p = 0.001). The TRACH group had a significantly lower maximum vertical displacement (15.23 +/- 7.39 mm, p = 0.011) and velocity (54.99 +/- 29.59 mm/s, p = 0.011), and two-dimensional velocity (61.07 +/- 24.89 mm/s, p = 0.013) of the larynx than the NO-TRACH group (20.18 +/- 5.70 mm, 82.23 +/- 37.30 mm/s, and 84.40 +/- 36.05 mm/s, respectively). Maximum horizontal velocity of the hyoid bone in the TRACH group (36.77 +/- 16.97 mm/s) was also significantly lower than that in the NO-TRACH group (47.49 +/- 15.73 mm/s, p = 0.032). This study demonstrated that stroke patients with tracheostomies had inferior swallowing function and kinematics than those without tracheostomies. A prospective longitudinal study is needed to elucidate the effect of a tracheostomy on swallowing recovery in stroke patients. PMID- 28013390 TI - Antagonistic effects of biological invasion and environmental warming on detritus processing in freshwater ecosystems. AB - Global biodiversity is threatened by multiple anthropogenic stressors but little is known about the combined effects of environmental warming and invasive species on ecosystem functioning. We quantified thermal preferences and then compared leaf-litter processing rates at eight different temperatures (5.0-22.5 degrees C) by the invasive freshwater crustacean Dikerogammarus villosus and the Great Britain native Gammarus pulex at a range of body sizes. D. villosus preferred warmer temperatures but there was considerable overlap in the range of temperatures that the two species occupied during preference trials. When matched for size, G. pulex had a greater leaf shredding efficiency than D. villosus, suggesting that invasion and subsequent displacement of the native amphipod will result in reduced ecosystem functioning. However, D. villosus is an inherently larger species and interspecific variation in shredding was reduced when animals of a representative size range were compared. D. villosus shredding rates increased at a faster rate than G. pulex with increasing temperature suggesting that climate change may offset some of the reduction in function. D. villosus, but not G. pulex, showed evidence of an ability to select those temperatures at which its shredding rate was maximised, and the activation energy for shredding in D. villosus was more similar to predictions from metabolic theory. While per capita and mass-corrected shredding rates were lower in the invasive D. villosus than the native G. pulex, our study provides novel insights in to how the interactive effects of metabolic function, body size, behavioural thermoregulation, and density produce antagonistic effects between anthropogenic stressors. PMID- 28013389 TI - Epithelial-mesenchymal plasticity in circulating tumor cells. AB - Epithelial-to-Mesenchymal Transition (EMT) is a complex process that supports the migratory capacity of epithelial tumor cells and is thought to play a crucial role in promoting cancer metastasis. Despite the wealth of experimental data, the exact role of EMT in cancer patients remains more controversial. Over the past 10 years, sensitive technologies that allow the detection and molecular characterization of circulating tumor cells (CTCs) in the peripheral blood of tumor patients have been developed. These analyses help to shed new light into the importance of EMT for human tumor cell dissemination. CTCs with mesenchymal features can be attributed in some clinical studies (in particularly on breast cancer) to higher disease stages, presence of metastases, and even to therapy response and worse outcome. However, the published studies addressing the impact of mesenchymal-like CTCs show heterogeneity with regard to assay specificity, size of cancer and control groups, and endpoint parameters. In the present review, we present the key features of the biology of CTCs in relation to epithelial-to-mesenchy-mal plasticity, describe the current technologies for enrichment and detection of CTCs with high epithelial-mesenchymal plasticity, and discuss the clinical studies that have assessed the relevance of mesenchymal CTCs in carcinoma patients. PMID- 28013391 TI - Laser pointers: how much does the general medical community know? PMID- 28013392 TI - The clinical depth of field achievable with trifocal and monofocal intraocular lenses: theoretical considerations and proof of concept clinical results. AB - BACKGROUND: To estimate the depth of field (DOF) achievable with multi-and monofocal intraocular lenses (IOLs) and compare with actual measurements of DOF in cases implanted with a trifocal IOL and biconvex monofocal IOL METHODS: I) Computer simulations were produced to describe the relationship between DOF, pupil size, preoperative ametropia, and retinal blur tolerance limit for a model eye implanted with either multi- or monofocal IOLs. II) Monocular DOF and pupil size were measured under distance viewing conditions between 3 and 6 months postoperative following uneventful cataract surgery. Cases were implanted with either i) trifocal aspheric IOL (n = 36), or ii) biconvex aspheric monofocal IOL (n = 26). DOF was also measured at 0.33 m in cases implanted with i). RESULTS: Simulations revealed significant associations between DOF, pupil size, and retinal blur tolerance limit. The mean (+/-SD) DOF & pupil sizes were at distance for i) above 2.59D (0.68) & 3.54 mm (0.377), and for ii) above 1.67D (0.51) & 2.90 mm (0.351), and for i) above 3.16D (0.46) at near. The difference between groups were significant for DOF and pupil size at distance (p < 0.001). DOF was significantly greater at near compared with distance in i) above (p < 0.001). For a pupil size of 3 mm, the simulations produce similar DOF values when the tolerance limit of retinal blur is 10 MU. CONCLUSIONS: The DOF was significantly better after implanting the trifocal IOL compared with the monofocal IOL, and DOF is increased under near viewing conditions. The clinical results are similar to calculated DOF values when the tolerance limit of retinal blur is 10 MU. PMID- 28013393 TI - NGF/anti-VEGF combined exposure protects RCS retinal cells and photoreceptors that underwent a local worsening of inflammation. AB - PURPOSE: Our previous study highlighted the potential nerve growth factor (NGF) effect on damaged photoreceptors from a rat model of spontaneous Retinitis Pigmentosa (RP). Herein, we tested the combined NGF/anti-vascular endothelial growth factor (alphaVEGF) effect on cultured retinal cells isolated from Royal College of Surgeons (RCS) rats receiving an intravitreal VEGF injection (iv-VEGF) to exacerbate retinal inflammation/neovascularization. METHODS: RCS (n = 75) rats were equally grouped as untreated (n = 25), iv-saline (single saline intravitreal injection; n = 25) and iv-VEGF (single VEGF intravitreal injection; n = 25). Morphological and biochemical analysis or in vitro stimulations with the biomolecular investigation were carried out on explanted retinas. Isolated retinal cells were treated with NGF and alphaVEGF, either alone or in combination, for 6 days and cells were harvested for morphological and biomolecular analyses. RESULTS: Infiltrating inflammatory cells were detected in iv-VEGF exposed RCS retinas, indicative of exacerbated inflammation and neovascularization. In cell cultures, NGF/alphaVEGF significantly increased retinal cell survival as well as rhodopsin expression and neurite outgrowth in photoreceptors. Particularly, NGF/alphaVEGF upregulated Bcl-2 mRNA, downregulated Bax mRNA, upregulated trkANGFR mRNA and finally upregulated both NGF mRNA and protein. CONCLUSIONS: These data confirm and extend our previous findings on NGF photoreceptor crosstalk, highlighting that the NGF/alphaVEGF combination might be an interesting approach for improving neuroprotection of RCS retinal cells and likewise photoreceptors in the presence of neovascularization. Further studies are required to translate this in vitro approach into clinical practice. PMID- 28013394 TI - Purification, characterization, and application of a thermostable dextranase from Talaromyces pinophilus. AB - Dextranase can hydrolyze dextran to low-molecular-weight polysaccharides, which have important medical applications. In the study, dextranase-producing strains were screened from various soil sources. The strain H6 was identified as Talaromyces pinophilus by a standard ITS rDNA analysis. Crude dextranase was purified by ammonium sulfate fractionation and Sepharose 6B chromatography, which resulted in a 6.69-fold increase in the specific activity and an 11.27% recovery. The enzyme was 58 kDa, lower than most dextranase, with an optimum temperature of 45 degrees C and an optimum pH of 6.0, and identified as an endodextranase. It was steady over a pH range from 3.0 to 10.0 and had reasonable thermal stability. The dextranase activity was increased by urea, which enhanced its activity to 115.35% and was conducive to clinical dextran production. Therefore, T. pinophilus H6 dextranase could show its superiority in practical applications. PMID- 28013395 TI - Molecular methods resolve the bacterial composition of natural marine biofilms on galvanically coupled stainless steel cathodes. AB - Navy vessels consist of various metal alloys and biofilm accumulation at the metal surface is thought to play a role in influencing metal deterioration. To develop better strategies to monitor and control metallic biofilms, it is necessary to resolve the bacterial composition within the biofilm. This study aimed to determine if differences in electrochemical current could influence the composition of dominant bacteria in a metallic biofilm, and if so, determine the level of resolution using metagenomic amplicon sequencing. Current was generated by creating galvanic couples between cathodes made from stainless steel and anodes made from carbon steel, aluminum, or copper nickel and exposing them in the Delaware Bay. Stainless steel cathodes (SSCs) coupled to aluminum or carbon steel generated a higher mean current (0.39 mA) than that coupled to copper nickel (0.17 mA). Following 3 months of exposure, the bacterial composition of biofilms collected from the SSCs was determined and compared. Dominant bacterial taxa from the two higher current SSCs were different from that of the low-current SSC as determined by DGGE and verified by Illumina DNA-seq analysis. These results demonstrate that electrochemical current could influence the composition of dominant bacteria in metallic biofilms and that amplicon sequencing is sufficient to complement current methods used to study metallic biofilms in marine environments. PMID- 28013397 TI - Cortico-subthalamic inputs from the motor, limbic, and associative areas in normal and dopamine-depleted rats are not fully segregated. AB - The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the "hyperdirect" pathway. The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented. Using extracellular electrophysiological approaches, we investigated to what degree the motor and non-motor regions in the STN are segregated in control and dopamine (DA) depleted rats. We performed electrical stimulation of different cortical areas and recorded STN neuronal responses. We showed that motor and non-motor cortico-subthalamic pathways are not fully segregated, but partially integrated in the rat. This integration was mostly present through the indirect pathway. The spatial distribution and response latencies were the same in sham and 6 hydroxydopamine lesioned animals. The inhibitory phase was, however, less apparent in the lesioned animals. In conclusion, this study provides the first evidence that motor and non-motor cortico-subthalamic pathways in the rat are not fully segregated, but partially integrated. This integration was mostly present through the indirect pathway. We also show that the inhibitory phase induced by GABAergic inputs from the external segment of the globus pallidus is reduced in the DA-depleted animals. PMID- 28013396 TI - Transcriptomic analysis displays the effect of (-)-roemerine on the motility and nutrient uptake in Escherichia coli. AB - Among the different families of plant alkaloids, (-)-roemerine, an aporphine type, was recently shown to possess significant antibacterial activity in Escherichia coli. Based on the increasing demand for antibacterials with novel mechanisms of action, the present work investigates the potential of the plant derived alkaloid (-)-roemerine as an antibacterial in E. coli cells using microarray technology. Analysis of the genome-wide transcriptional reprogramming in cells after 60 min treatment with 100 MUg/mL (-)-roemerine showed significant changes in the expression of 241 genes (p value <0.05 and fold change >2). Expression of selected genes was confirmed by qPCR. Differentially expressed genes were classified into functional categories to map biological processes and molecular pathways involved. Cellular activities with roles in carbohydrate transport and metabolism, energy production and conversion, lipid transport and metabolism, amino acid transport and metabolism, two-component signaling systems, and cell motility (in particular, the flagellar organization and motility) were among metabolic processes altered in the presence of (-)-roemerine. The down regulation of the outer membrane proteins probably led to a decrease in carbohydrate uptake rate, which in turn results in nutrient limitation. Consequently, energy metabolism is slowed down. Interestingly, the majority of the expressional alterations were found in the flagellar system. This suggested reduction in motility and loss in the ability to form biofilms, thus affecting protection of E. coli against host cell defense mechanisms. In summary, our findings suggest that the antimicrobial action of (-)-roemerine in E. coli is linked to disturbances in motility and nutrient uptake. PMID- 28013398 TI - Means-tested public support and the interaction between long-term care insurance and informal care. AB - This paper investigates theoretically how the structure of means-tested public long-term care (LTC) support influences the relationship between LTC insurance and informal care. Three types of public support encountered in various means tested LTC schemes are examined. First, the level to be considered for means testing only takes into account the level of wealth of the recipient without considering the cost of LTC or the possible insurance benefits. Second, the public support also considers the LTC needs of the recipient. Third, the means test structure takes into consideration insurance benefits as well. Our results show that the optimal levels of insurance and informal care as well as their relationship are strongly influenced by the ways means-tested public support for LTC is structured, which have important implications in terms of public policy for the financing of LTC needs. PMID- 28013399 TI - Keeping up with the Red Queen: the pace of aging as an adaptation. AB - For decades, a vast majority of biogerontologists assumed that aging is not and cannot be an adaptation. In recent years, however, several authors opposed this predominant view and repeatedly suggested that not only is aging an adaptation but that it is the result of a specific aging program. This issue almost instantaneously became somewhat controversial and many important authors produced substantial works refuting the notion of the aging program. In this article we review the current state of the debate and list the most important arguments proposed by both sides. Furthermore, although classical interpretations of the evolution of aging are in sharp contrast with the idea of programmed aging, we suggest that the truth might in fact very well lie somewhere in between. We also propose our own interpretation which states that although aging is in essence inevitable and results from damage accumulation rather than from a specific program, the actual rate of aging in nature may still be adaptive to some extent. PMID- 28013400 TI - The Health and Sociocultural Correlates of AIDS Genocidal Beliefs and Medical Mistrust Among African American MSM. AB - This study examined social and health-related correlates of AIDS conspiracy theories among 464 African American men who have sex with men (MSM). Exploratory factor analysis revealed two subscales within the AIDS conspiracy beliefs scale: medical mistrust and AIDS genocidal beliefs. Multiple regression analyses revealed medical mistrust and AIDS genocidal beliefs were both associated negative condom use attitudes and higher levels of internalized homonegativity. Medical mistrust was also associated with lower knowledge of HIV risk reduction strategies. Finally, we conducted bivariate regressions to examine the subsample of participants who reported being HIV-positive and currently taking HIV antiretroviral therapy (ART) to test associations between sexual behavior and HIV treatment and AIDS conspiracy theories. Among this subsample, medical mistrust was associated with having a detectable viral load and not disclosing HIV-status to all partners in the previous 3 months. Collectively, these findings have implications for HIV prevention and treatment for African American MSM. PMID- 28013401 TI - Prolonged Production and Aggregation Complexity of Cold-Active Lipase from Pseudomonas proteolytica (GBPI_Hb61) Isolated from Cold Desert Himalaya. AB - Pseudomonas, being the common inhabitant of colder environments, are suitable for the production of cold-active enzymes. In the present study, a newly isolated strain of Pseudomonas from cold desert site in Indian Himalayan Region, was investigated for the production of cold-active lipase. The bacteria were identified as Pseudomonas proteolytica by 16S rDNA sequencing. Lipase production by bacteria was confirmed by qualitative assay using tributyrin and rhodamine-B agar plate method. The bacterium produced maximum lipase at 25 degrees C followed by production at 15 degrees C while utilizing olive, corn, as well as soybean oil as substrate in lipase production broth. Enzyme produced by bacteria was partially purified using ammonium sulphate fractionation. GBPI_Hb61 showed aggregation behaviour which was confirmed using several techniques including gel filtration chromatography, dynamic light scattering, and native PAGE. Molecular weight determined by SDS-PAGE followed by in-gel activity suggested two lipases of nearly similar molecular weight of ~50 kDa. The enzyme showed stability in wide range of pH from 5 to 11 and temperature up to 50 degrees C. The enzyme from GBPI_Hb61 exhibited maximum activity toward p-nitrophenyldecanoate (C10). The stability of enzyme was not affected with methanol while it retained more than 75% activity when incubated with ethanol, acetone, and hexane. The bacterium is likely to be a potential source for production of cold-active lipase with efficient applicability under multiple conditions. PMID- 28013402 TI - Psychometric properties of the Japanese version of the Weiss Functional Impairment Rating Scale: Self-Report. AB - The Weiss Functional Impairment Rating Scale Self-Report has been translated into nine languages and has been widely used in assessing functional impairment of adults with ADHD. This study is a psychometric validation of the WFIRS-S in Japanese. The WFIRS-S-J and other questionnaires were administered to 46 adults with attention-deficit-hyperactivity disorder (ADHD), 104 control adults, and 889 university students. ADHD diagnoses were made using the Japanese semi-structured diagnostic interview for adult ADHD, which is compatible with the DSM-5. All subscales of the WFIRS-S-J had Cronbach's alpha values of around 0.80. Total scores on the WFIRS-S-J had high test-retest reliability after a 2-week interval. The total score, subscale scores, and 59 of the individual item scores of the 70 items in the WFIRS-S-J were significantly higher in the ADHD group than in the other two groups, although more than half of the items in subdomain G (risk) showed floor effects and did not reach significance. Generally WFIRS-S-J subdomain scores were moderately correlated with scores on the Japanese version of Conners' Adult ADHD Rating Scales Self-Report subscales. WFIRS-S-J scores were also correlated (albeit more weakly; 0.31 <= r <= 0.55) with Beck Depression Inventory II total scores. The WFIRS-S-J showed acceptable psychometric properties, although further study is necessary. PMID- 28013403 TI - Xyloglucan breakdown by endo-xyloglucanase family 74 from Aspergillus fumigatus. AB - Xyloglucan is the most abundant hemicellulose in primary walls of spermatophytes except for grasses. Xyloglucan-degrading enzymes are important in lignocellulosic biomass hydrolysis because they remove xyloglucan, which is abundant in monocot derived biomass. Fungal genomes encode numerous xyloglucanase genes, belonging to at least six glycoside hydrolase (GH) families. GH74 endo-xyloglucanases cleave xyloglucan backbones with unsubstituted glucose at the -1 subsite or prefer xylosyl-substituted residues in the -1 subsite. In this work, 137 GH74-related genes were detected by examining 293 Eurotiomycete genomes and Ascomycete fungi contained one or no GH74 xyloglucanase gene per genome. Another interesting feature is that the triad of tryptophan residues along the catalytic cleft was found to be widely conserved among Ascomycetes. The GH74 from Aspergillus fumigatus (AfXEG74) was chosen as an example to conduct comprehensive biochemical studies to determine the catalytic mechanism. AfXEG74 has no CBM and cleaves the xyloglucan backbone between the unsubstituted glucose and xylose-substituted glucose at specific positions, along the XX motif when linked to regions deprived of galactosyl branches. It resembles an endo-processive activity, which after initial random hydrolysis releases xyloglucan-oligosaccharides as major reaction products. This work provides insights on phylogenetic diversity and catalytic mechanism of GH74 xyloglucanases from Ascomycete fungi. PMID- 28013404 TI - Degrons of yeast and mammalian ornithine decarboxylase enzymes make potent combination for regulated targeted protein degradation. AB - Elevation of polyamine levels in eukaryotes leads to rapid degradation of ornithine decarboxylase (ODC), the first enzyme of polyamine biosynthesis pathway. ODC in yeast (yODC) has two domains, the Nalpha/beta domain consisting of alpha/beta barrel domain (alpha/beta) preceded by an overhang of 50 residues at its N-terminus (N50) and beta sheet domain at its C-terminus. Two degradation determinant signals or degrons in yODC sequence, namely the N50 and the antizyme binding element (AzBE) housed in the alpha/beta domain, are responsible for its degradation by proteasomes. Antizyme (Az) induced under polyamine excess binds to AzBE and delivers ODC to proteasome, while the N50 threads the protein into proteasome. It was previously reported by us that the peptide Nalpha/beta of yODC acts as an independent transplantable degron, whose action can be modulated with the help of antizyme by varying polyamine levels. Mammalian ODC (mODC), in spite of its 40% sequence homology with yODC, is devoid of N50 of yODC and instead sports a C-terminal tail of 37 residues (CmODC). CmODC acts as an independent transplantable degron with no equivalent in yODC. The present study investigates the merits of employing the two degrons Nalpha/beta and CmODC together for targeted protein degradation by expressing them in a chimeric fusion with green fluorescent protein (GFP). Our results establish that under the regulation of antizyme, the signals Nalpha/beta and CmODC acting together enhance degradation better than either degron in isolation. The combination of Nalpha/beta and CmODC can be employed to study the function of novel proteins through their rapid removal. PMID- 28013405 TI - Production and quality control assessment of a GLP-grade immunotoxin, D2C7 (scdsFv)-PE38KDEL, for a phase I/II clinical trial. AB - D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel recombinant Pseudomonas exotoxin A based immunotoxin (IT), targeting both wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins overexpressed in glioblastomas. Initial pre-clinical testing demonstrated the anti-tumor efficacy of D2C7-IT against orthotopic glioblastoma xenograft models expressing EGFRwt, EGFRvIII, or both EGFRwt and EGFRvIII. A good laboratory practice (GLP) manufacturing process was developed to produce sufficient material for a phase I/II clinical trial. D2C7-IT was expressed under the control of the T7 promoter in Escherichia coli BLR (lambda DE3). D2C7-IT was produced by a 10-L batch fermentation process and was then purified from inclusion bodies using anion exchange, size exclusion, and an endotoxin removal process that achieved a yield of over 300 mg of purified protein. The final vialed batch of D2C7-IT for clinical testing was at a concentration of 0.12 +/- 0.1 mg/mL, the pH was at 7.4 +/- 0.4, and endotoxin levels were below the detection limit of 10 EU/mL (1.26 EU/mL). The stability of the vialed D2C7-IT has been monitored over a period of 42 months through protein concentration, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing, size exclusion chromatography, cytotoxicity, sterility, and pH measurements. The vialed D2C7-IT is currently being tested in a phase I/II clinical trial by intratumoral convection-enhanced delivery for 72 h in patients with recurrent glioblastoma (NCT02303678, D2C7 for Adult Patients with Recurrent Malignant Glioma; clinicaltrials.gov ). PMID- 28013406 TI - Simulated microgravity affects some biological characteristics of Lactobacillus acidophilus. AB - The effects of weightlessness on enteric microorganisms have been extensively studied, but have mainly been focused on pathogens. As a major component of the microbiome of the human intestinal tract, probiotics are important to keep the host healthy. Accordingly, understanding their changes under weightlessness conditions has substantial value. This study was carried out to investigate the characteristics of Lactobacillus acidophilus, a typical probiotic for humans, under simulated microgravity (SMG) conditions. The results revealed that SMG had no significant impact on the morphology of L. acidophilus, but markedly shortened its lag phase, enhanced its growth rate, acid tolerance ability up to pH < 2.5, and the bile resistance at the bile concentration of <0.05%. SMG also decreased the sensitivity of L. acidophilus to cefalexin, sulfur gentamicin, and sodium penicillin. No obvious effect of SMG was observed on the adhesion ability of L. acidophilus to Caco-2 cells. Moreover, after SMG treatment, both the culture of L. acidophilus and its liquid phase exhibited higher antibacterial activity against S. typhimurium and S. aureus in a time-dependent manner. The SMG treatment also increased the in vitro cholesterol-lowering ability of L. acidophilus by regulating the expression of the key cholesterol metabolism genes CYP7A1, ABCB11, LDLR, and HMGCR in the HepG2 cell line. Thus, the SMG treatment did have considerable influence on some biological activities and characteristics of L. acidophilus related to human health. These findings provided valuable information for understanding the influence of probiotics on human health under simulated microgravity conditions, at least. PMID- 28013407 TI - Proteomic-based biomarker discovery for development of next generation diagnostics. AB - In the post-genome age, proteomics is receiving significant attention because they provide an invaluable source of biological structures and functions at the protein level. The search for disease-specific biomarkers for diagnostic and/or therapeutic applications is one of the areas that proteomics is having a significant impact. Thus, the identification of a "good" biomarker enables a more accurate early diagnosis and prognosis of disease. Rapid advancements in mass spectrometry (MS) instrumentation, liquid chromatography MS (LCMS), protein microarray technology, and other protein profiling methodologies have a substantial expansion of our toolbox to identify disease-specific protein and peptide biomarkers. This review covers a selection of widely used proteomic technologies for biomarker discovery. In addition, we describe the most commonly used approaches for diagnosis based on proteomic biomarkers and further discuss trends and critical challenges during development of cost-effective rapid diagnostic tests and microfluidic diagnostic systems based on proteomic biomarkers. PMID- 28013408 TI - The worldwide incidence of neonaticide: a systematic review. AB - Neonaticide is the killing of a neonate on the day of its birth by his/her own mother. Neonaticidal women were reported to be predominantly young, unmarried, and primiparous. The motive for murdering the newborn relates to the shame, the fear of rejection, and abandonment by significant others, and the social stigmas associated with an illegitimate birth. The goal of the present study was to conduct a systematic review of the scientific literature and identify population based studies reporting the incidence of neonaticide in different countries. A total of 485 abstracts were screened. After applying the inclusion/exclusion criteria, 10 studies were selected. Additional searches identified two more articles. Most of these studies were from Europe, where incidence varied from 0.07 (Finland, 1980-2000 period) to 8.5 neonaticides per 100000 births (Austria, 1975-2001 period). More recent studies have indicated that a growing proportion of neonaticidal women are married, multiparous, and suffers from mental disorders. Preventive measures, such as anonymous free delivery, were shown to reduce the incidence of neonaticide, although this effect may be short-lived. Despite social and institutional changes, neonaticide persists even in the most socially advanced, liberal, and prosperous societies in the world. PMID- 28013409 TI - Symptoms of anxiety and depression during pregnancy and their association with low birth weight in Chinese women: a nested case control study. AB - This study is a nested case control study from a population-based cohort study conducted in Wuhan, China. The aim is to estimate the association between symptoms of depression during pregnancy (DDP), anxiety during pregnancy(ADP), and depression with anxiety during pregnancy (DADP) and low birth weight (LBW) and to examine the extent to which preterm birth (PTB) moderates these associations. Logistic regression analyses were used to model associations between DDP, ADP, and DADP and LBW. Models were stratified by the presence or absence of PTB to examine moderating effects. From the cohort study, 2853 had a LBW baby (cases); 5457 pregnant women served as controls. Women with DDP or ADP only were not at higher risk of having a LBW baby, but DADP was associated with increased risk of LBW (crude OR 1.41, 95% CI 1.17-1.70; adjusted OR 1.29, 95% CI 1.07-1.57), and the significant association was particularly evident between DADP and LBW in PTB, but not in full-term births. Our data suggests that DADP is related to an increased risk of LBW and that this association is most present in PTBs. PMID- 28013410 TI - The durum wheat plasma membrane Na+/H+ antiporter SOS1 is involved in oxidative stress response. AB - We have shown previously that the durum wheat TdSOS1 excludes Na+ and Li+ ions outside cells. Moreover, this protein is activated by Arabidopsis kinase SOS2 through phosphorylation. The elimination of both SOS2 phosphorylation sites and the auto-inhibitory domain produces a hyperactive TdSOS1?972 form, which have a maximal activity independent from the regulatory SOS2/SOS3 complex. We demonstrated that the expression of TdSOS1 enhances salt tolerance of the transgenic Arabidopsis plants. In this study, we analyzed the response to H2O2 induced oxidative stress of the transgenic Arabidopsis expressing one of the two TdSOS1 forms. Firstly, we showed that the exogenous H2O2 treatment leads to an accumulation of SOS1 transcripts in leaves and roots of the durum wheat and also in the transgenic plants. These transgenic plants showed significant oxidative stress tolerance compared to control plants, especially the plants expressing the hyperactive form. This tolerance was manifested by high proline accumulation and low malonyldialdehyde (MDA), O2- and H2O2 contents. Furthermore, the activities of three essential ROS scavenging enzymes (SOD, CAT, and POD) were higher in the transgenic plants under oxidative stress, as compared to control plants. Taken together, these data suggested that TdSOS1 plays a crucial role in response to oxidative stress. PMID- 28013411 TI - Genomic effects of glucocorticoids. AB - Glucocorticoids and their receptor (GR) have been an important area of research because of their pleiotropic physiological functions and extensive use in the clinic. In addition, the association between GR and glucocorticoids, which is highly specific, leads to rapid nuclear translocation where GR associates with chromatin to regulate gene transcription. This simplified model system has been instrumental for studying the complexity of transcription regulation processes occurring at chromatin. In this review we discuss our current understanding of GR action that has been enhanced by recent developments in genome wide measurements of chromatin accessibility, histone marks, chromatin remodeling and 3D chromatin structure in various cell types responding to glucocorticoids. PMID- 28013412 TI - The inhibition of voltage-gated H+ channel (HVCN1) induces acidification of leukemic Jurkat T cells promoting cell death by apoptosis. AB - Cellular energetic deregulation is widely known to produce an overproduction of acidic species in cancer cells. This acid overload must be counterbalanced with a high rate of H+ extrusion to maintain cell viability. In this sense, many H+ transporters have been reported to be crucial for cell survival and proposed as antineoplastic target. By the way, voltage-gated proton channels (Hv1) mediate highly selective H+ outward currents, capable to compensate acid burden in brief periods of time. This structure is canonically described acting as NADPH oxidase counterbalance in reactive oxygen species production. In this work, we show, for the first time in a oncohematologic cell line, that inhibition of Hv1 channels by Zn2+ and the more selective blocker 2-(6-chloro-1H-benzimidazol-2-yl)guanidine (ClGBI) progressively decreases intracellular pH in resting conditions. This acidification is evident minutes after blockade and progresses under prolonged exposure (2, 17, and 48 h), and we firstly demonstrate that this is followed by cell death through apoptosis (annexin V binding). Altogether, these results contribute strong evidence that this channel might be a new therapeutic target in cancer. PMID- 28013413 TI - Selective persistence of Propionibacterium species FMA5 following sealing of infected dentinal matrix. AB - The objective of the present study was to test the hypothesis that nutrient deprivation by effective isolation should inactivate causative saccharolytic bacteria occupying carious lesions. Vital maxillary third molar teeth were prepared by removing only the superficial necrotic material, leaving behind infected dentinal matrix, before the cavity was sealed with glass ionomer cement (GIC). Before sealing, lesions were biopsied to provide reference bacterial DNA for microbial analysis. After an interval of 10-12 months, the teeth were extracted and, after careful removal of GIC restoration, the underlying dentine was biopsied again for post-treatment microbial analysis. Microbial diversity for nine taxa in 45 carious lesions, before and after minimal intervention therapy, was quantified by real-time polymerase chain reaction (PCR). Except for Propionibacterium sp. FMA5, Fusobacterium nucleatum and Pseudoramibacter alactolyticus, representation of all other taxa showed reduction in the post restoration biopsy samples. However, Propionibacterium sp. FMA5 was the only species predominantly detected in 80% of the pre-intervention, 82% of the post restoration and 73% of the paired pre- and post-restoration biopsy samples. The median bacterial load for Propionibacterium sp. FMA5, lactobacilli and bacteria from the family Coriobacteriaceae was higher than the median bacterial load for the remaining six taxa. Significant reduction in the median bacterial load for lactobacilli was evident in post-restoration biopsy samples, implying effective control by GIC after minimal intervention. However, the median bacterial load for Propionibacterium sp. FMA5 increased in post-restoration biopsy samples. Incorporation of antimicrobial agents effective against Propionibacterium species FMA5 could add to more effective conservative management of advanced carious lesions. PMID- 28013414 TI - Gonorrhea infection increases the risk of prostate cancer in Asian population: a nationwide population-based cohort study. AB - This nationwide population-based retrospective cohort study evaluated the risk of developing prostate cancer among patients with gonorrhea. We identified cases of newly diagnosed gonorrhea in men between 2000 and 2010 from the Taiwan National Health Insurance Research Database. Each patient with gonorrhea was matched to four controls, based on age and index year. All subjects were followed up from the index date to December 31, 2010. The Cox proportional hazards regression model was used to assess the risk of prostate cancer. A total of 355 men were included in the study group, and 1,420 age-matched subjects without gonorrhea were included in the control group. After adjusting for age, comorbidities, urbanization level, hospital level, and monthly income, gonorrhea was significantly associated with an increased risk of prostate cancer (adjusted hazard ratio = 5.66, 95% confidence interval = 1.36-23.52). Men aged 45-70 years and those with lower monthly income were more strongly associated with prostate cancer in the study group than the control group. The higher risk for developing prostate cancer were also found in those without syphilis, without genital warts, without diabetes mellitus, without chronic obstructive pulmonary disease, without benign prostatic hypertrophy, without chronic prostatitis, and without alcoholism. The Kaplan-Meier analysis showed the risk of prostate cancer was significantly higher in the study group than in the control group. Gonorrhea may be involved in the development of prostate cancer. More intensive screening and prevention interventions for prostate cancer should be recommended in men with gonorrhea. PMID- 28013415 TI - Prognostic impact of preoperative anemia on non-muscle-invasive bladder carcinoma treated with GreenLight laser vaporization. AB - In this study, we aimed to evaluate the impact of preoperative anemia (PA) on oncological outcomes among patients with non-muscle-invasive bladder cancer (NMIBC) treated with GreenLight laser vaporization of bladder tumor (PV-BT). Between January 2010 and December 2015, 407 patients with NMIBC who underwent PV BT surgery were stratified into normal and anemia groups based on the World Health Organization classification (anemia cutoff value: hemoglobin level, <13.0 m g/dL in men and <12.0 mg/dL in women). The Student's t test and chi-square test were performed to assess the effects of PA on clinical and pathological characteristics of patients with NMIBC. The Kaplan-Meier method was used to investigate the influence of PA on oncological survival outcomes. Before PV-BT, 139 patients (34.2%) were anemic. No significant differences in age, sex, smoking habit, tumor size, focality, grade, and stage were found between the anemia and normal groups. At a median follow-up period of 32.5 months (range, 8-60 months), 74 patients (18.2%) had urothelial recurrence, 30 (7.4%) died from any cause, and 21 (5.2%) died from bladder cancer. In the Kaplan-Meier analysis, preoperative anemia was significantly associated with decreased cancer-specific survival (CSS) and overall survival (OS) of the patients with NMIBC. However, recurrence-free survival (RFS) showed no statistically significant difference between the PA and normal groups. The preoperative anemic patients with NMIBC who underwent PV-BT surgery had worse CSS and OS. PA can be a useful and cost-effective prognostic marker in the clinical practice for NMIBC treatment. PMID- 28013416 TI - Posttraumatic growth and cancer: a study 5 years after treatment end. AB - PURPOSE: Cancer survivors often report posttraumatic growth (PTG). The aims of this study were to assess the presence of PTG in Italian long-term disease-free cancer survivors (LCS) and to explore the association between the dimensions of PTG and clinical, demographic variables, various agents of perceived social support and psychological distress. METHODS: Five hundred forty LCS were assessed with Posttraumatic Growth Inventory (PTGI), Multidimensional Scale of Perceived Social Support (MSPSS), Zung Self-Rating Depression Scale, and State-Trait Anxiety Inventory-Y (STAI-Y). RESULTS: Mean age was 57.08 years, mean survival was 11.04 years (range 5-32), and the most common cancer diagnosis was breast cancer (56.9%). The PTGI average total score was higher in more educated LCS, in those employed, in LCS with longer time from diagnosis, and in those with no comorbidities. In this study, PTG was not found correlated with distress, but it correlated with perceived social support, age, education, and employment. CONCLUSIONS: The absence of a correlation between PTG and psychological distress and the low levels of PTG found let us question the importance of talking about PTG when working as psychotherapists with LCS. It may be suggested that the need of finding benefit and PTG in LCS has been overcome by other experiences or worries happened after the cancer, and LCS may not focus anymore on positive changes occurred. The relevance of work and of perceived social support as linked to PTG stresses the need to protect the LCS's relationship with work and to promote and sustain their social network, and this can help them to experience sharing and closeness to others. PMID- 28013417 TI - Left atrial mechanics strongly predict functional capacity assessed by cardiopulmonary exercise testing in subjects without structural heart disease. AB - Left atrium function is essential for cardiovascular performance and is evaluable by two-dimensional speckle-tracking echocardiography (2D-STE). Our aim was to determine how echocardiographic parameters interrelate with exercise capacity and ventilatory efficiency in subjects with no structural heart disease. Asymptomatic volunteers, in sinus rhythm and with normal biventricular size and function, were recruited from a community-based population. Individuals with moderate-to-severe valvular disease, pulmonary hypertension, and history of cardiac disease were excluded. We performed a transthoracic echocardiogram and assessed left atrial (LA) and left ventricular (LV) mechanics via 2D-STE. Cardiopulmonary exercise testing by treadmill took place immediately thereafter. Peak oxygen uptake (VO2) served as measure of functional capacity and ventilation/carbon dioxide output (VE/VCO2) slope as surrogate of ventilation/perfusion mismatch. 20 subjects were included (age 51 +/- 14 years, male gender 65%). Peak VO2 strongly correlated with age (r = -0.83; P < 0.01), with E/e' ratio (r = -0.72; P < 0.01), and with LA reservoir- and conduit-phase mechanics, particularly with LA conduit strain rate (SR) (r = -0.82; P < 0.01), but showed no correlation with LA volume index or LV mechanics. A similar pattern of associations was identified for VE/VCO2 slope. In multivariate analysis, LA conduit SR (beta = -0.69; P = 0.02) emerged as sole independent correlate of peak VO2, adjusted for age and for E/e' ratio (adjusted r 2 = 0.76; P < 0.01). Conduit and reservoir components of LA mechanics displayed strong associations with peak VO2 and VE/VCO2 slope. LA conduit-phase SR seems best suited as echocardiographic marker of functional capacity in subjects with no structural heart disease. PMID- 28013418 TI - Left ventricular reverse remodeling in dilated cardiomyopathy- maintained subclinical myocardial systolic and diastolic dysfunction. AB - In idiopathic dilated cardiomyopathy (DCM), myocardial deformational parameters and their relationships remain incompletely characterized. We measured those parameters in patients with DCM, during left ventricular reverse remodeling (LVRR). Prospective study of 50 DCM patients (in sinus rhythm), with left ventricular ejection fraction (EF) <40%. LVRR was defined as an increase of ten units of EF and decrease of diastolic left ventricular diameter (LVDD) in the absence of resynchronization therapy. Performed morphological analysis, myocardial performance quantification (LV and RV Tei indexes) and LV averaged peak systolic longitudinal strain (SSR long) and circumferential strain (SSR circ). At baseline, mean EF was 25.4 +/- 9.8%, LVDD was 62.4 +/- 7.4 mm, LVDD/BSA of 34.2 +/- 4.5 mm/m2 and 34% had MR grade >II/IV. LVRR occurred in 34% of patients within 17.6 +/- 15.6 months and was associated with a reduced rate of death or heart failure hospitalization (5.9% vs. 33.3; p = 0.03). Patients with LVRR had a final EF of 48.9 +/- 7.9% (Delta LV EF of 22.4%) and there was a significant decrease (p < 0.05) in: LVDD/BSA, LV systolic diameter/BSA, LV diastolic volume, LV systolic volume, LV mass; an increase (p < 0.05) in sphericity index. However, measures of diastolic function (LA volume/BSA, e'velocity and' E/e'ratio), final LV and RV Tei indexes were not significantly different from baseline. Additionally, final SSR circ and SSR long values were not different from basal. Patients who recovered EF >50% (n = 10), SSR circ and SSR long were inferior to normal. Improvement in EF occurred in one-third of DCM pts and was associated with a decrease of major cardiac events. There was an improvement of diastolic and systolic volumes and in sphericity index, confirming truly LV reverse reshaping. However, myocardial performance indexes, SSR long and SSR circ in reverse-remodeled DCM were still abnormal, suggesting a maintained myocardial systolic and diastolic dysfunction. PMID- 28013419 TI - Clinical outcomes after minimally invasive transforaminal lumbar interbody fusion and lateral lumbar interbody fusion for treatment of degenerative lumbar disease: a systematic review and meta-analysis. AB - The surgical procedures used for arthrodesis in the lumbar spine for degenerative lumbar diseases remain controversial. This systematic review aims to assess and compare clinical outcomes along with the complications and fusion of each technique (minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) or minimally invasive lateral lumbar interbody fusion (MIS LLIF)) for treatment of degenerative lumbar diseases. Relevant studies were identified from Medline and Scopus from inception to July 19, 2016 that reported Oswestry Disability Index (ODI), back and leg pain visual analog score (VAS), postoperative complications, and fusion of either technique. Fifty-eight studies were included for the analysis of MIS-TLIF; 40 studies were included for analysis of LLIF, and 1 randomized controlled trial (RCT) study was included for comparison of MIS-TLIF to LLIF. Overall, there were 9506 patients (5728 in the MIS-TLIF group and 3778 in the LLIF group). Indirect meta-analysis, MIS-TLIF provided better postoperative back and leg pain (VAS), disabilities (ODI), and risk of having complications when compared to LLIF technique, but the fusion rate was not significantly different between the two techniques. However, direct meta-analysis between RCT study and pooled indirect meta-analysis of MIS-TLIF have better pain, disabilities, and complication but no statistically significant difference when compared to LLIF. In LLIF, the pooled mean ODI and VAS back pain were 2.91 (95% CI 2.49, 3.33) and 23.24 (95% CI 18.96, 27.51) in MIS approach whereas 3.14 (95% CI 2.29, 4.04) and 28.29 (95% CI 21.92, 34.67) in traditional approach. In terms of complications and fusion rate, there was no difference in both groups. In lumbar interbody fusion, MIS-TLIF had better ODI, VAS pain, and complication rate when compared to LLIF with direct and indirect meta-analysis methods. However, in terms of fusion rates, there were no differences between the two techniques. PMID- 28013420 TI - Two-Year Impact of Prevention Programs on Adolescent Depression: an Integrative Data Analysis Approach. AB - This paper presents the first findings of an integrative data analysis of individual-level data from 19 adolescent depression prevention trials (n = 5210) involving nine distinct interventions across 2 years post-randomization. In separate papers, several interventions have been found to decrease the risk of depressive disorders or elevated depressive/internalizing symptoms among youth. One type of intervention specifically targets youth without a depressive disorder who are at risk due to elevated depressive symptoms and/or having a parent with a depressive disorder. A second type of intervention targets two broad domains: prevention of problem behaviors, which we define as drug use/abuse, sexual risk behaviors, conduct disorder, or other externalizing problems, and general mental health. Most of these latter interventions improve parenting or family factors. We examined the shared and unique effects of these interventions by level of baseline youth depressive symptoms, sociodemographic characteristics of the youth (age, sex, parent education, and family income), type of intervention, and mode of intervention delivery to the youth, parent(s), or both. We harmonized eight different measures of depression utilized across these trials and used growth models to evaluate intervention impact over 2 years. We found a significant overall effect of these interventions on reducing depressive symptoms over 2 years and a stronger impact among those interventions that targeted depression specifically rather than problem behaviors or general mental health, especially when baseline symptoms were high. Implications for improving population-level impact are discussed. PMID- 28013421 TI - Measuring core temperature using the proprietary application and thermo smartphone adapter. AB - Fast and accurate measurement of core body temperature is crucial for accidental hypothermia treatment. We have developed a novel light and small adapter to the headset jack of a mobile phone based on Android. It has been applied to measure temperature and set up automatic notifications (e.g. Global Positioning System coordinates to emergency services dispatcher, ECMO coordinator). Its validity was confirmed in comparison with Vital Signs Monitor Spacelabs Healthcare Elance 93300 as a reference method, in a series of 260 measurements in the temperature range of 10-42 degrees C. Measurement repeatability was verified in a battery of 600 measurements (i.e. 100 readings at three points of 10, 25, 42 degrees C for both esophageal and tympanic catheters). Inter-method difference of <=0.5 degrees C was found for 98.5% for esophageal catheter and 100% for tympanic catheter measurements, with concordance correlation coefficient of 0.99 for both. The readings were almost completely repeatable with water bath measurements (difference of <=0.5 degrees C in 10 degrees C: 100% for both catheters; in 25 degrees C: 99% for esophageal catheter and 100% tympanic catheter; in 42 degrees C: 100% for both catheters). This lightweight adapter attached to smartphone and standard disposable probes is a promising tool to be applied on-site for temperature measurement in patients at risk of hypothermia. PMID- 28013422 TI - Acute fluoxetine treatment increases aggressiveness in juvenile matrinxa (Brycon amazonicus). AB - Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor known for its effects modifying aggressiveness, personality traits, and anxiety-like behaviors. The aim of the present study was to evaluate the influence of the acute treatment, by immersion, with FLX on aggressive behavior of resident Brycon amazonicus fish. Fish pretreated with FLX presented an increase in aggressiveness, evidenced by the increase on the number of bites and chases against the intruder and a decrease in latency for the first attack, when compared to control fish. Together with previous studies, these results show the complexity of the neural modulation of the aggressive behavior in fish by 5 HTergic system. PMID- 28013423 TI - Cloning, expression profiling and promoter functional analysis of Bone morphogenetic protein 6 and 7 in tongue sole (Cynoglossus semilaevis). AB - Bone morphogenetic proteins (BMPs) play crucial roles in vertebrate developmental process and are associated with the mechanisms which drive early skeletal development. As a first approach to elucidating the role of BMPs in regulating fish bone formation and growth, we describe the cloning, expression profiling and promoter functional analysis of bmp6 and bmp7 in tongue sole (Cynoglossus semilaevis). The full length of bmp6 and bmp7 cDNA sequences is 1939 and 1836 bp, which encodes a protein of 428 and 427 amino acids, respectively. Tissue expression distribution of bmp6 and bmp7 was examined in 14 tissues of mature individuals by quantitative real-time PCR (qRT-PCR). The results revealed that bmp6 was predominantly expressed in the gonad, and bmp7 exhibited the highest expression level in the dorsal fin. Further comparison of bmp6 expression levels between female and male gonads showed that the expression in the ovary was significantly higher than in the testis. Moreover, bmp6 and bmp7 expression levels were detected at 15 sampling time points of early developmental stages (egg, larva, juvenile and fingerling stages). The highest expression level of bmp6 was observed in the egg stage (multi-cell and gastrula stage); while bmp7 exhibited the highest expression in the larva stage (1-4 days old). The high expression levels of BMP6 in the ovary as well as at early embryonic stages indicated that the maternally stored transcripts of bmp6 might play a role in early embryonic development. Whole-mount in situ hybridization showed that bmp6 and bmp7 exhibited similar spatial expression patterns. Both bmp6 and bmp7 signals were first detected in the head and anterior regions in newly hatched larvae, and then, the mRNAs appeared in the crown-like larval fin, jaw, operculum and fins (pectoral, dorsal, pelvic and anal) along with early development. Subsequently, we characterized the 5'-flanking regions of bmp6 and bmp7 by testing the promoter activity by luciferase reporter assays. Positive regulatory regions were, respectively, detected at the location of -272 to +28 and -740 to 396 in bmp6 and bmp7 gene. The predicted transcription factor binding sites (CREB, AP1 and methyl-CpG-binding protein) in the regions might participate in the transcriptional regulation of these two genes. PMID- 28013424 TI - Effects of different salinities on growth performance, survival, digestive enzyme activity, immune response, and muscle fatty acid composition in juvenile American shad (Alosa sapidissima). AB - The effects of salinity on survival, growth, special activity of digestive enzymes, nonspecific immune response, and muscle fatty acid composition were evaluated in the American shad (Alosa sapidissima). Juveniles of 35 days after hatching were reared at 0 (control), 7, 14, 21, and 28 ppt for 60 days. At the end of the experiment, juvenile American shad presented higher survival and specific growth rate (SGR) in salinity group (7, 14, and 21 ppt) than control group (P < 0.05). The special activity of trypsin and chymotrypsin was highest in fish reared at 21 ppt, while the highest lipase special activity was obtained in control group (P < 0.05). The special activity of alkaline phosphatase (ALP), lysozyme (LZM), superoxide dismutase (SOD), and catalase (CAT) showed significant increases in salinity group (14 and 21 ppt) compared to control group (P < 0.05). Lower muscle ash contents were detected in salinity group (14, 21, and 28 ppt) than control group (P < 0.05), while the contents of crude lipid and crude protein were significantly higher than control group (P < 0.05). The level of monounsaturated fatty acids (MUFA) exhibited a decreasing trend, while an increased level of polyunsaturated fatty acids (PUFA) was detected with the increase of salinity. Among the PUFA, the content of n-3 fatty acids in muscle tissue was found to be increasing with the increasing salinity, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Results indicate that appropriate increase in salinity was reasonable and beneficial for juvenile American shad culture after a comprehensive consideration, especially salinity range from 14 to 21 ppt. PMID- 28013425 TI - The Impact of Cuban Economic Reform on Older Persons. AB - This paper discusses the economic reforms initiated by Cuban President Raul Castro in 2008 and its effect on the country's fast-growing, vulnerable population of older persons 60+ years of age. Cubans are living longer and the country has a very low birthrate. These two factors combined have reduced the proportion of the population in the work force. This adversely affects the economy. Population aging is a major reason why the government has introduced structural reforms and reduced social spending, which have weakened the welfare state on which older persons depend. Many older persons have become critical of the reforms over time. Policy makers need to address the impact the reforms are having on older Cubans and consider them as active participants in economic reform. Data for this paper come from qualitative, case study research carried out in Havana between the years 2008-15 and from a review of the literature on aging and economic reforms in Cuba. Two case studies illustrate the impact of the economic reforms on older persons. PMID- 28013426 TI - Examining the effect of self-explanation on cognitive integration of basic and clinical sciences in novices. AB - Several studies have shown that cognitive integration of basic and clinical sciences supports diagnostic reasoning in novices; however, there has been limited exploration of the ways in which educators can translate this model of mental activity into sound instructional strategies. The use of self-explanation during learning has the potential to promote and support the development of integrated knowledge by encouraging novices to elaborate on the causal relationship between clinical features and basic science mechanisms. To explore the effect of this strategy, we compared diagnostic efficacy of teaching students (n = 71) the clinical features of four musculoskeletal pathologies using either (1) integrated causal basic science descriptions (BaSci group); (2) integrated causal basic science descriptions combined with self-explanation prompts (SE group); (3) basic science mechanisms segregated from the clinical features (SG group). All participants completed a diagnostic accuracy test immediately after learning and 1-week later. The results showed that the BaSci group performed significantly better compared to the SE (p = 0.019) and SG groups (p = 0.004); however, no difference was observed between the SE and SG groups (p = 0.91). We hypothesize that the structure of the self-explanation task may not have supported the development of a holistic conceptual understanding of each disease. These findings suggest that integration strategies need to be carefully structured and applied in ways that support the holistic story created by integrated basic science instruction in order to foster conceptual coherence and to capitalize on the benefits of cognition integration. PMID- 28013427 TI - Collaborating to improve the use of free-energy and other quantitative methods in drug discovery. AB - In May and August, 2016, several pharmaceutical companies convened to discuss and compare experiences with Free Energy Perturbation (FEP). This unusual synchronization of interest was prompted by Schrodinger's FEP+ implementation and offered the opportunity to share fresh studies with FEP and enable broader discussions on the topic. This article summarizes key conclusions of the meetings, including a path forward of actions for this group to aid the accelerated evaluation, application and development of free energy and related quantitative, structure-based design methods. PMID- 28013428 TI - Purification and Characterization of Xylanases from the Fungus Chrysoporthe cubensis for Production of Xylooligosaccharides and Fermentable Sugars. AB - Xylanases from the pathogen fungus Chrysoporthe cubensis were produced under solid state fermentation (SSF) using wheat bran as carbon source. The enzymatic extracts were submitted to ion exchange (Q Sepharose) and gel filtration chromatography methods (Sephadex S-200) for purification. The xylanases were divided into three groups: P1 showed better performance at 60 degrees C and pH 4.0, P2 at 55 degrees C and pH 3.0, and P3 at 80 degrees C and pH 3.0. Oat spelt xylan was the best substrate hydrolyzed by P1 and P3, while beechwood xylan was better degraded by P2. Carboxymethyl cellulose (CMC) and p-nitrophenyl-beta-D xylopyranoside (p-NPbetaXyl) were not hydrolyzed by any of the xylanases. The K M' or K M values, using oat spelt xylan as substrate, were 2.65 mg/mL for P1, 1.81 mg/mL for P2, and 1.18 mg/mL for P3. Xylobiose and xylotriose were the main xylooligosaccharides of oat spelt xylan degradation, indicating that the xylanases act as endo-beta-1,4-xylanases. Xylanases also proved to be efficient for hydrolysis of sugarcane bagasse when used as supplement of a commercial cocktail due to the increase of the reducing sugar release. PMID- 28013429 TI - Enhanced Production of Poly-gamma-glutamic Acid by Bacillus licheniformis TISTR 1010 with Environmental Controls. AB - Bacillus licheniformis TISTR 1010 was used for glutamic acid-independent production of poly-gamma-glutamic acid (gamma-PGA). A fed-batch production strategy was developed involving feedings of glucose, citric acid, and ammonium chloride at specified stages of the fermentation. With the dissolved oxygen concentration controlled at >=50% of air saturation and the pH controlled at ~7.4, the fed-batch operation at 37 degrees C afforded a peak gamma-PGA concentration of 39.9 +/- 0.3 g L-1 with a productivity of 0.926 +/- 0.006 g L-1 h-1. The observed productivity was nearly threefold greater than previously reported for glutamic acid-independent production using the strain TISTR 1010. The molecular weight of gamma-PGA was in the approximate range of 60 to 135 kDa. PMID- 28013430 TI - Activation and Stabilization of Olive Recombinant 13-Hydroperoxide Lyase Using Selected Additives. AB - The stabilization of olive recombinant hydroperoxide lyases (rHPLs) was investigated using selected chemical additives. Two rHPLs were studied: HPL full length and HPL with its chloroplast transit peptide deleted (matured HPL). Both olive rHPLs are relatively stable at 4 degrees C, and enzyme activity can be preserved (about 100% of the rHPL activities are maintained) during 5 weeks of storage at -20 or at -80 degrees C in the presence of glycerol (10%, v/v). Among the additives used in this study, glycine (2.5% w/v), NaCl (0.5 M), and Na2SO4 (0.25 M) provided the highest activation of HPL full-length activity, while the best matured HPL activity was obtained with Na2SO4 (0.25 M) and NaCl (1 M). Although the inactivation rate constants (k) showed that these additives inactivate both rHPLs, their use is still relevant as they strongly increase HPL activity. Results of C6-aldehyde production assays also showed that glycine, NaCl, and Na2SO4 are appropriate additives and that NaCl appears to be the best additive, at least for hexanal production. PMID- 28013431 TI - Effects of A.marina-Derived Isoquercitrin on TNF-Related Apoptosis-Inducing Ligand Receptor (TRAIL-R) Expression and Apoptosis Induction in Cervical Cancer Cells. AB - TNF-related apoptosis-inducing ligand (TRAIL) is an anticancer agent, which has greater apoptosis inducing capacity, but most of the cancer cells become resistant to TRAIL-induced apoptosis. The combined treatment of TRAIL with natural products could restore the cancer cell sensitivity to recombinant human TRAIL (rhTRAIL) protein and might enhance the TNF-related apoptosis-inducing ligand receptor (TRAIL-R) expression. This investigation was aimed to isolate flavonoids from leaves of Avicennia marina and evaluate their potential for sensitization of rhTRAIL in human cervical cancer cells (SiHa). The methanolic extract of A.marina leaves were purified and structure was elucidated as isoquercitrin by NMR and LC-MS analysis. Isolated isoquercitrin showed cytotoxicity against SiHa cell line at IC50 of 980 MUM. Messenger RNA (mRNA) expression of TRAIL-Rs was quantified by qRT-PCR, combination of isoquercitrin, and/or rhTRAIL increased TRAIL-R1 and TRAIL-R2 gene expression by 7 folds and 4 folds, respectively. Also, FACS assay revealed that combined treatment has increased the early apoptosis up to 7.24%. In the present study, we found that isoquercitrin enhances the mRNA expression of TRAIL-Rs, but the percentage of apoptosis was meager, possibly due to the influence of other anti-apoptotic proteins. PMID- 28013432 TI - Association of human leukocyte A, B, and DR antigens in Colombian patients with diagnosis of spondyloarthritis. AB - There is substantial evidence that non-B27 major histocompatibility complex (MHC) genes are associated with spondyloarthritis (SpA). Studies in Mexican and Tunisian populations demonstrated the association of SpA and human leukocyte antigen (HLA) B15. The purpose of this study was to evaluate the association of HLA-A, B, and DR antigens in a group of Colombian patients with a diagnosis of SpA. A total of 189 patients and 100 healthy subjects were included in the present study. All subjects underwent a complete characterization of HLA alleles A, B, and DR. Of the 189 studied patients, 35 were reactive arthritis (ReA), 87 were ankylosing spondylitis (AS), and 67 undifferentiated SpA (uSpA). According to the Assessment of Spondyloarthritis International Society (ASAS) criteria, 167 were axial SpA (axSpA) and 171 were peripheral SpA (pSpA). 63.8% were men, with a mean age of 35.9 +/- 12.7 years. 40.7% (77/189) of patients were HLA-B27 positive of which 52.9% had AS and 42.5% axSpA. 23.2% (44/189) of patients were HLA-B15 positive: 23.8% were uSpA, 12.57% were axSpA, and 11.7% were pSpA. In addition, HLA-DRB1*01 was associated with AS (58.6%) and axSpA (42.5%). Also, HLA-DRB1*04 was present in 62 patients with AS (71.2%) and in 26 with axSpA (15.5%). In this population, we found a strong association between the presence of HLA-B27 and the diagnosis of axSpA and AS, but the HLA-B15 is also significantly associated with all subtypes of the disease, predominantly with pSpA. Additionally, HLA-DR1 and DR4 were associated in a cohort of patients with SpA from Colombia. PMID- 28013433 TI - Correlation between rapid-3, DAS28, CDAI and SDAI as a measure of disease activity in a cohort of Colombian patients with rheumatoid arthritis. AB - The objective of this study is to correlate the patient-driven tool Routine Assessment of Patient Index Data 3 (RAPID-3) with other common tools used in daily practice to measure disease activity in rheumatoid arthritis (RA).One hundred nineteen RA patients according to 1987 American College of Rheumatology criteria who consecutively attended a RA outpatient clinic between August and December 2015 were evaluated. Data was stored in an electronic form that included demographic information, comorbidities, concomitant medication, and laboratory results. The disease activity was determined by tender and swollen joint count, pain and disease activity visual analog scales (VAS), disease activity score 28 (DAS28), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and multidimensional health assessment questionnaire (MDHAQ). Correlations between RAPID-3 and other disease activity tools were assessed. Mean age was 61 +/- 13.8 years with a median disease duration of 14 years (IQR 5-21), 77% were females. Median scores were MDHAQ 0.5 (IQR 0.1-1.2), DAS 28 3.8 (IQR 2.7 5.1), and RAPID-3 12.3 (IQR 6-19). A strong correlation was obtained between RAPID-3 and DAS 28 (r 0.719, p < 0.001), CDAI (r 0.752, p < 0.001), and SDAI (r 0.758, p < 0.001). RAPID-3 had a high correlation with tools regularly used for disease activity assessment of RA patients in daily practice. The ease of its application favors routine use as it does not require laboratory results and joint counts. PMID- 28013434 TI - The effect of local injection of methylprednisolone acetate on the hypothalamic pituitary-adrenal axis among patients with greater trochanteric pain syndrome. AB - Greater trochanteric pain syndrome (GTPS) is a common clinical entity for which the most effective treatment is local corticosteroid injection (LCI). There are no studies on the effect of LCI among patients with GTPS on the hypothalamic pituitary-adrenal axis. The present study recruited nonselected patients diagnosed with GTPS. After consenting, participants received low dose (1 MUg) of adrenocorticotropin hormone (ACTH) stimulation test at 09:00. Immediately following the test, participants received a LCI of 80 mg of methylprednisolone acetate at the greater trochanteric region. The ACTH stimulation test was repeated 1, 2, 4, and 6 weeks following the LCI. Cortisol samples were obtained at just prior to (basal) and 30 min (post-stimulation) following every ACTH stimulation test. Serum cortisol levels of <500 MUmol/l obtained 30 min following the ACTH stimulation test were considered evidence of secondary adrenal insufficiency. The study enrolled 22 patients, 21 of whom completed participation. There were 19 female participants (~90%), and mean age of all the participants was 55.2 +/- 8.6 years. Four participants showed evidence of secondary adrenal insufficiency, which was observed only at weeks 1 and 2 following the LCI. Mean serum cortisol level among these four participants 30 min following the ACTH stimulation test was 354 MUmol/l, with a range of 268-430 MUmol/l. LCI of 80 mg of methylprednisolone acetate in the greater trochanteric area among patients with GTPS was associated with transient secondary adrenal insufficiency in ~20% of the patients, mainly 1 week following the injection. PMID- 28013435 TI - Evaluation of quality indicators and disease damage in childhood-onset systemic lupus erythematosus patients. AB - The aim of this study was to describe compliance with select quality indicators and assess organ-specific dysfunction in a childhood-onset systemic lupus erythematosus population by using a validated damage index and to evaluate associations between compliance with quality indicators and disease damage. A retrospective chart review was performed on patients diagnosed with systemic lupus erythematosus prior to age 18 followed at a single center in the USA from 1999 to 2012 (n = 75). Data regarding quality indicators and outcome variables, including the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were collected. The median disease duration was 3.8 years. The proportion of patients or patient-years in which care complied with the proposed quality measures was 94.4% for hydroxychloroquine use, 84.3% for vitamin D recommendation,75.8% for influenza vaccination (patient-years), 67.2% for meningococcal vaccination, 49.0% for ophthalmologic examination (patient years), 31.7% for pneumococcal vaccination, and 28.6% for bone mineral density evaluation. Disease damage was present in 41.3% of patients at last follow-up, with an average damage index score of 0.81. Disease damage at last follow-up was associated with minority race/ethnicity (p = 0.008), bone mineral density evaluation (p = 0.035), and vitamin D recommendation (p = 0.018). Adherence to quality indicators in a childhood-onset systemic lupus erythematosus population is varied, and disease damage is prevalent. This study highlights the importance of quality improvement initiatives aimed at optimizing care delivery to reduce disease damage in pediatric lupus patients. PMID- 28013436 TI - Opiorphin in burning mouth syndrome patients: a case-control study. AB - OBJECTIVES: Opiorphin is a pentapeptide isolated from human saliva that suppresses pain from chemically induced inflammation and acute physical pain. Burning mouth syndrome (BMS) is a chronic condition of a burning sensation in the mouth, where no underlying dental or medical cause can be identified. We aimed to measure the level of opiorphin in whole unstimulated (UWS) and stimulated (SWS) saliva of patients with BMS. MATERIALS AND METHODS: Originally developed and validated LC-MS/MS method was used for opiorphin quantification. Samples were obtained from 29 BMS patients and 29 age- and sex-matched controls. RESULTS: The average concentration of opiorphin in UWS and SWS in the BMS group was 8.13 +/- 6.45 and 5.82 +/- 3.59 ng/ml, respectively. Opiorphin in BMS patients' UWS was significantly higher, compared to the control group (t = 2.5898; p = 0.0122). SWS opiorphin levels were higher, but not significantly, in BMS patients than in controls. CONCLUSIONS: Our results indicate that higher quantities of salivary opiorphin in BMS may be a consequence of chronic pain, but we cannot exclude that they occur as a result of emotional and behavioral imbalances possibly associated with BMS. To our knowledge, this is the first original article measuring opiorphin in a pain disorder. CLINICAL RELEVANCE: Opiorphin may be a measurable biomarker for chronic pain, which could help in objectifying otherwise exclusively a subjective experience. Increased opiorphin could serve as a universal objective indicator of painful conditions. Since opiorphin may also reflect emotional and socio-relational imbalances occurring with BMS, it could as well represent a biomarker for BMS. Knowledge on opiorphin's involvement in pain pathways could contribute to developing new clinical diagnostic methods for BMS. PMID- 28013437 TI - Exploration of bacterial species associated with the salivary microbiome of individuals with a low susceptibility to dental caries. AB - OBJECTIVE: Dental caries is caused by acidogenic plaque microbiota formed on saliva-bathed tooth surfaces, in which multiple organisms act collectively to initiate and expand a cavity. We explored bacterial species associated with the salivary microbiome of individuals with low susceptibility to dental caries. MATERIALS AND METHODS: The bacterial composition of saliva from 19 young adults was analyzed using barcoded pyrosequencing of the 16S rRNA gene; we compared 10 caries-experienced (CE) and nine caries-free (CF) individuals. A quantitative PCR assay of saliva from 139 orally healthy adults aged 40-59 years was carried out to confirm the result obtained by pyrosequencing analysis. RESULTS: The microbiomes of CF individuals showed more diverse communities with a significantly greater proportion of the genus Porphyromonas. Among operational taxonomic units (OTUs) corresponding to the genus Porphyromonas, the OTU corresponding to P. pasteri was the most predominant and its relative abundance in CF individuals was significantly greater than in CE individuals (P < 0.001, Wilcoxon rank sum test). A quantitative PCR assay of saliva confirmed that the amounts of P. pasteri were significantly higher in individuals with lower caries experience (filled teeth <15, n = 67) than in those with higher caries experience (filled teeth >=15, n = 72) (P < 0.001, Student's t test). CONCLUSION: These results revealed an association between a greater abundance of P. pasteri and lower susceptibility to dental caries. CLINICAL RELEVANCE: P. pasteri may be a bacterial species that could potentially be used as a marker for maintaining a healthy oral microbiome against dental caries. PMID- 28013438 TI - Outcomes of implant therapy in patients with a history of aggressive periodontitis. A systematic review and meta-analysis. AB - OBJECTIVE: To investigate the outcomes of implant therapy in partially dentate patients treated for aggressive periodontitis (GAgP) in comparison to periodontally healthy (HP) and patients treated for chronic periodontitis (CP) utilizing radiographic and clinical parameters. MATERIAL AND METHODS: An electronic search of databases, supplemented by hand searching, was conducted to identify relevant clinical studies. Sequential screenings at the title, abstract and full-text levels were performed independently and in duplicate. A random effects meta-analysis was conducted and bias corrected bootstrap 95 % confidence intervals were estimated for group comparisons. RESULTS: The search strategy revealed a total of 899 results. After title screening, abstract scanning, and full-text reading, seven articles fulfilled the inclusion criteria. The 3-year survival rate for CP and HP patients was 100 % while in GAgP subjects, the respective value was 97.98 %; this difference being statistically significant. The 3-year mean marginal bone loss (MBL) was 1.07 mm for the GAgP group, 0.47 mm for the CP group, and 0.69 mm for the HP group. A significant difference between the GAgP and CP groups was identified (p < 0.05). The weighted mean differences of MBL concerning the above groups were also calculated and examined for statistical significance in both 1 and 3 years. CONCLUSIONS: The 3-year survival rate and peri-implant marginal bone loss was found statistically significantly lower in GAgP subjects (SR 97.98 % vs 100 %) in comparison to HP and CP individuals. CLINICAL RELEVANCE: The outcome of implant therapy in terms of survival rate and marginal bone loss is considered very important for the clinician in decision making when placing implants in patients with a history of aggressive periodontitis. PMID- 28013439 TI - Reply: "Patients treated with neoadjuvant chemotherapy + radical surgery + adjuvant chemotherapy in locally advanced cervical cancer: long-term outcomes, survival and prognostic factors in a single-center 10-years follow-up". PMID- 28013440 TI - Equine salmonellosis in southern Brazil. AB - The Salmonella sp. genus is identified in several species, and the zoonosis it causes is one of the most important types worldwide. The specifics of salmonellosis vary according to the function of the serovar involved, the species affected, age and predisposing factors. However, few cases of equine salmonellosis have been reported. This study presents ten confirmed salmonellosis cases in equines in southern Brazil. Six were adult animals with stress factors preceding the disease, while four were foals, three of which presented with hyperacute manifestations. The main clinical signs were diarrhea, anorexia, and hyperthermia. Lesions varied in distribution and severity, although fibrinonecrotic or necrohemorrhagic enteritis was observed in all animals, mainly in the large intestine (large colon and cecum-8/10) and small intestine (3/10). Substantial liquid content, mainly hemorrhagic, was observed in all animals. The most characteristic microscopic lesion was mucosa necrosis, which is often accompanied by fibrin deposition, followed by necrosis of follicular centers and vascular changes. Bacterial isolation revealed seven isolates. Five were serotyped, and the serovars Typhimurium and Anatum were associated with two cases each, while Muenster was associated with a case whose lesion pattern varied. Immunohistochemical staining was positive in all cases. All diagnoses were based on the clinical history, macroscopic and histological lesions, and the bacterial isolation and/or immunostaining associated with histological lesions. PMID- 28013441 TI - Pragmatic Competency and Obsessive-Compulsive Disorder: A Comparative Assessment with Normal Controls. AB - Unlike such cognitive impairments as autism and schizophrenia, the speech pattern in obsessive-compulsive disorder (OCD) has largely remained underrepresented. We examined the pragmatic competence of OCD-affected individuals under two variant modes: pragmatic recognition and pragmatic production. In the recognition phase, the informants completed a discourse completion test around two speech acts of request and apology (20 high power distance situations). The production phase was carried out through an interview during which the informants' communication behaviors were rated on the basis of the Orion's pragmatic language skills checklist (OPLS) subscales. No significant difference was observed between the normal and OCD groups in terms of pragmatic recognition. Moreover, considering the OPLS subscales, although the normal controls significantly outperformed in non-verbal communication and expressive skills, the overall pragmatic production ability of the two groups was statistically alike. The results are discussed in relation to the two competing disorders of autism and social anxiety. PMID- 28013442 TI - DMSO-free cryopreservation of adipose-derived mesenchymal stromal cells: expansion medium affects post-thaw survival. AB - Off-the-shelf availability of human adipose-derived mesenchymal stromal cells (ASCs) for regenerative medicine application requires the development of nontoxic, safe, and efficient protocols for cryopreservation. Favorably, such cell processing protocols should not contain xenogeneic or toxic components, such as fetal bovine serum (FS) and dimethyl sulfoxide (DMSO). The objective of the study was to assess the sensitivity of ASCs to DMSO-free cryopreservation protocol depending on their expansion conditions: conventional, based on the application of FS or xeno-free, using PL as a medium supplement. ASCs expansion was carried out in alpha-MEM supplemented either with FS or PL. For DMSO- and xeno-free cryopreservation ASCs were pretreated with different concentrations of sucrose during 24 h of culture. Pretreated ASCs were cryopreserved in alpha-MEM containing 100-300 mM of sucrose with the cooling rate of 1 degree/min. ASCs were tested for survival (Trypan Blue test), viability (MTT test), recovery (Alamar Blue test), proliferation and ability to multilineage differentiation. The optimal concentrations of sucrose for ASCs pretreatment and as an additive in cryoprotective solution, which provided highest cell survival, comprised 100 and 200 mM, correspondingly. Survival and recovery rates of platelet lysate (PL) expanded ASCs after DMSO-free cryopreservation comprised 59 and 51%, and were higher than in FS-cultured cells. After DMSO-free cryopreservation PL-processed ASCs had a shorter population doubling time and higher capacity for osteogenic differentiation than FS-processed cultures. The described DMSO- and xeno-free processing may form the basis for the development of safe and efficient protocols for manufacturing and banking of ASCs, providing their off-the-shelf availability for regenerative medicine applications. PMID- 28013444 TI - Current state of knowledge of hepatic encephalopathy (part IV): Management of Hepatic Encephalopathy by liver support systems. AB - Hepatic Encephalopathy is a devastating complication of End-Stage Liver Disease. In its severe grades it requires extra intervention beyond the standard medical approaches. In this article were view the role of liver support systems in managing hepatic encephalopthy. PMID- 28013443 TI - Periostin is required for matricellular localization of CCN3 in periodontal ligament of mice. AB - CCN3 is a matricellular protein that belongs to the CCN family. CCN3 consists of 4 domains: insulin-like growth factor-binding protein-like domain (IGFBP), von Willebrand type C-like domain (VWC), thrombospondin type 1-like domain (TSP1), and the C-terminal domain (CT) having a cysteine knot motif. Periostin is a secretory protein that binds to extracellular matrix proteins such as fibronectin and collagen. In this study, we found that CCN3 interacted with periostin. Immunoprecipitation analysis revealed that the TSP1-CT interacted with the 4 repeats of the Fas 1 domain of periostin. Immunofluorescence analysis showed co localization of CCN3 and periostin in the periodontal ligament of mice. In addition, targeted disruption of the periostin gene in mice decreased the matricellular localization of CCN3 in the periodontal ligament. Thus, these results indicate that periostin was required for the matricellular localization of CCN3 in the periodontal ligament, suggesting that periostin mediated an interaction between CCN3 and the extracellular matrix. PMID- 28013445 TI - A vascular cause of neck pain. PMID- 28013446 TI - Evaluation of the validity of osteoporosis and fracture risk assessment tools (IOF One Minute Test, SCORE, and FRAX) in postmenopausal Palestinian women. AB - : The need for simple self-assessment tools is necessary to predict women at high risk for developing osteoporosis. In this study, tools like the IOF One Minute Test, Fracture Risk Assessment Tool (FRAX), and Simple Calculated Osteoporosis Risk Estimation (SCORE) were found to be valid for Palestinian women. The threshold for predicting women at risk for each tool was estimated. PURPOSE: The purpose of this study is to evaluate the validity of the updated IOF (International Osteoporosis Foundation) One Minute Osteoporosis Risk Assessment Test, FRAX, SCORE as well as age alone to detect the risk of developing osteoporosis in postmenopausal Palestinian women. METHODS: Three hundred eighty two women 45 years and older were recruited including 131 women with osteoporosis and 251 controls following bone mineral density (BMD) measurement, 287 completed questionnaires of the different risk assessment tools. Receiver operating characteristic (ROC) curves were evaluated for each tool using bone BMD as the gold standard for osteoporosis. RESULTS: The area under the ROC curve (AUC) was the highest for FRAX calculated with BMD for predicting hip fractures (0.897) followed by FRAX for major fractures (0.826) with cut-off values ?1.5 and ?7.8%, respectively. The IOF One Minute Test AUC (0.629) was the lowest compared to other tested tools but with sufficient accuracy for predicting the risk of developing osteoporosis with a cut-off value ?4 total yes questions out of 18. SCORE test and age alone were also as good predictors of risk for developing osteoporosis. According to the ROC curve for age, women >=64 years had a higher risk of developing osteoporosis. Higher percentage of women with low BMD (T-score <=-1.5) or osteoporosis (T-score <=-2.5) was found among women who were not exposed to the sun, who had menopause before the age of 45 years, or had lower body mass index (BMI) compared to controls. Women who often fall had lower BMI and approximately 27% of the recruited postmenopausal Palestinian women had accidents that caused fractures. CONCLUSIONS: Simple self-assessment tools like FRAX without BMD, SCORE, and the IOF One Minute Tests were valid for predicting Palestinian postmenopausal women at high risk of developing osteoporosis. PMID- 28013447 TI - Impact of structural and economic factors on hospitalization costs, inpatient mortality, and treatment type of traumatic hip fractures in Switzerland. AB - : The assessment of structural and potentially economic factors determining cost, treatment type, and inpatient mortality of traumatic hip fractures are important health policy issues. We showed that insurance status and treatment in university hospitals were significantly associated with treatment type (i.e., primary hip replacement), cost, and lower inpatient mortality respectively. INTRODUCTION: The purpose of this study was to determine the influence of the structural level of hospital care and patient insurance type on treatment, hospitalization cost, and inpatient mortality in cases with traumatic hip fractures in Switzerland. METHODS: The Swiss national medical statistic 2011-2012 was screened for adults with hip fracture as primary diagnosis. Gender, age, insurance type, year of discharge, hospital infrastructure level, length-of-stay, case weight, reason for discharge, and all coded diagnoses and procedures were extracted. Descriptive statistics and multivariate logistic regression with treatment by primary hip replacement as well as inpatient mortality as dependent variables were performed. RESULTS: We obtained 24,678 inpatient case records from the medical statistic. Hospitalization costs were calculated from a second dataset, the Swiss national cost statistic (7528 cases with hip fractures, discharged in 2012). Average inpatient costs per case were the highest for discharges from university hospitals (US$21,471, SD US$17,015) and the lowest in basic coverage hospitals (US$18,291, SD US$12,635). Controlling for other variables, higher costs for hip fracture treatment at university hospitals were significant in multivariate regression (p < 0.001). University hospitals had a lower inpatient mortality rate than full and basic care providers (2.8% vs. both 4.0%); results confirmed in our multivariate logistic regression analysis (odds ratio (OR) 1.434, 95% CI 1.127 1.824 and OR 1.459, 95% confidence interval (CI) 1.139-1.870 for full and basic coverage hospitals vs. university hospitals respectively). The proportion of privately insured varied between 16.0% in university hospitals and 38.9% in specialized hospitals. Private insurance had an OR of 1.419 (95% CI 1.306-1.542) in predicting treatment of a hip fracture with primary hip replacement. CONCLUSION: The seeming importance of insurance type on hip fracture treatment and the large inequity in the distribution of privately insured between provider types would be worth a closer look by the regulatory authorities. Better outcomes, i.e., lower mortality rates for hip fracture treatment in hospitals with a higher structural care level advocate centralization of care. PMID- 28013448 TI - Change in Glutenin Macropolymer Secondary Structure in Wheat Sourdough Fermentation by FTIR. AB - Wheat sourdough was prepared by fermentation with Lactobacillus plantarum M616 and yeast in the present study. The change in secondary structure of glutenin macropolymer (GMP) in wheat sourdough fermentation for 4 and 12 h was determined using Fourier transform infrared spectroscopy, and then the resultant spectra were Fourier self-deconvoluted of the amide I band in the region from 1600 to 1700 cm-1. Significant different spectra especially in the amide I band for GMP from sourdough fermented with L. plantarum M616 (SL) and with L. plantarum M616 and yeast (SLY) were found in respect of control dough (CK), dough with acids (SA), and sourdough fermented with yeast (SY) at 4 and 12 h of fermentation. The loss of alpha-helix structure in SL, SLY, and SA samples was noticed during fermentation. Compared with CK and SY, SL, SLY, and SA samples showed significant decrease (p < 0.05) in the relative areas of alpha-helix at the same stage of fermentation. In addition, beta-turns in SL sourdough decrease, and the relative areas of random coil increase significantly (p < 0.05). These changes in the secondary structure mean that the flexibility of glutenin macropolymer in sourdough increases and it makes GMP degradation easier during fermentation. The modified secondary structure of GMP makes more sensitive to proteolysis by means of cereal enzymes. PMID- 28013449 TI - Follicular lymphoma-related colitis resembling ulcerative colitis. AB - Among the various manifestations of colonic involvement in malignant lymphomas, an ulcerative colitis-like appearance is rare. Herein, we describe a case in which extranodal colonic involvement resembled ulcerative colitis in a patient with advanced follicular lymphoma. A 59-year-old Japanese man with diarrhea and body weight loss was referred to our hospital. Computed tomography (CT) revealed systemic lymphadenopathy, splenomegaly, and thickening of the sigmoid colon and rectum walls. 18F-fluorodeoxy-glucose positron emission tomography (18F-FDG PET/CT) revealed intense tubular 18F-FDG accumulation extending from the rectum to the colon at the hepatic flexure and much weaker accumulation in the systemic lymph nodes, bone marrow, and spleen. The isotope-enriched areas had an ulcerative colitis-like appearance as shown via colonoscopy. The patient was ultimately diagnosed with follicular lymphoma (stage IV A, grade 1) based on a pathological examination of the neck lymph nodes, iliac bone marrow, and colon. After six courses of chemotherapy (R-CHOP), 18F-FDG-PET/CT confirmed complete remission of the lymphoma including the colonic lesion. This is presumably the first case of ulcerative-like colitis caused by a follicular lymphoma. As a novel approach, the lymphoma-related colitis was detected by comparing the pathology results and the 18F-FDG-PET/CT results. PMID- 28013450 TI - Post-implant Analysis of Epidemiologic and Eating Behavior Data Related to Weight Loss Effectiveness in Obese Patients Treated with Gastric Electrical Stimulation. AB - OBJECTIVE: To determine possible preoperative predictors for obtaining clinically meaningful weight loss with gastric electrical stimulation (GES) using the "Three Factor Eating Questionnaire" (TFEQ) as well as epidemiological data. METHODS: Ninety-seven obese participants in a prospective multicenter randomized study conducted in nine European centers were implanted laparoscopically with the abiliti(r) closed-loop GES system (CLGES). Five clinical variables and three preoperative TFEQ factor scores (F1-cognitive-restraint, F2-disinhibition, and F3 hunger) were analyzed in order to determine predictors of weight loss success defined as excess weight loss (EWL) > 30% and failure defined as EWL < 20% at 12 months post-surgery. RESULTS: The mean 12-month %EWL with CLGES was 35.1 +/- 19.7%, with a success rate of 52% and a failure rate of 19%. Significant predictors of success were body mass index (BMI) < 40 kg/m2 and age >= 50 years, increasing probability of success by 22 and 29%, respectively. A low F1-cognitive restraint score was a significant predictor of failure (p = 0.004). The best predictive model for success included F1-cognitive-restraint, F2-disinhibition, BMI < 40, and age >= 50 (p = 0.002). CONCLUSION: This retrospective analysis has shown that age, preoperative BMI, and F1-cognitive-restraint and F2-disinhibition scores from a preoperatively administered TFEQ are predictive of weight loss outcomes with CLGES and may be used for patient selection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01448785. PMID- 28013451 TI - A New Algorithm to Reduce the Incidence of Gastroesophageal Reflux Symptoms after Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is one of the most prefered treatment option for morbid obesity. However, the effects of LSG on gastroesophageal reflux disease (GERD) are controversial. Asymptomatic GERD and hiatal hernia (HH) is common in obese patients. Therefore, it is important to identify the high risk patients prior to surgery. This study aims to evaluate efficacy of cruroplasty for HH during LSG in morbidly obese patients using ambulatory pH monitoring (APM) results, and to investigate the patients' selection criteria for this procedure. METHODS: This retrospective study includes outcomes of 59 patients who underwent LSG and HH repair according to our patient selection algorithm. Outcomes included preoperative GERD Health-Related Quality of Life (GERD-HRQL) questionnaire, APM results, percentage of postoperative excess weight loss, and total weight loss. RESULTS: For a total of 402 patients, APM was applied in 70 patients who had a positive score of GERD-HRQL, and 59 patients underwent LSG and concomitant HH repair who had a DeMeester score of 14.7% or above. There was no statistically significant difference in weight loss at 6 and 12-month follow-up. Two patients (3.3%) had symptoms of GERD at 12 months postoperatively, and only one (1.6%) patient required treatment of proton pump inhibitor for reflux. In the total cohort, 11 (2.7%) patients also evolved de novo GERD symptoms. CONCLUSIONS: This study confirm that careful attention to patient selection and surgical technique can reduce the symptoms of GERD at short term. Routine bilateral crus exploration could be a major risk factor of postoperative GERD. PMID- 28013452 TI - Plasma Apelin and Asymmetric Dimethylarginine (ADMA) Levels Shortly After Laparoscopic Greater Curvature Plication. AB - OBJECTIVES: We sought to investigate the short-term effect of weight loss following restrictive bariatric surgery on plasma concentrations of apelin and asymmetric dimethylarginine (ADMA) in individuals with morbid obesity. SUBJECTS/METHODS: Thirty-seven morbidly obese individuals underwent laparoscopic greater curvature plication (LGCP). Anthropometric indices and plasma concentrations high-sensitivity C-reactive protein (hsCRP), apelin, and ADMA were measured before and 6 weeks after LGCP. RESULTS: The percentage of total weight loss was 12.9 +/- 4.4% 6 weeks after the operation. ADMA and apelin levels decreased significantly (p < 0.001 and 0.032, respectively) following LGCP. Significant decrements occurred in weight, body mass index, waist and hip circumference (p < 0.001), and waist-to-hip ratio (p = 0.013). The levels of triglycerides (p = 0.017), low-density lipoprotein cholesterol (p = 0.020), fasting plasma glucose (p = 0.033), fasting plasma insulin (p = 0.042), and the homeostasis model assessment index of insulin resistance (p = 0.034) also significantly decreased compared to the baseline measures. No significant change was observed in hsCRP levels and systolic and diastolic blood pressures. There was no significant correlation between changes in levels of apelin or ADMA and changes in anthropometric indices and other laboratory parameters. CONCLUSIONS: Surgically induced weight loss rapidly decreases plasma levels of ADMA and apelin in morbidly obese patients. These changes do not seem correlated with changes in anthropometric and laboratory parameters associated with obesity. PMID- 28013453 TI - PK/PD Target Attainment With Ceftolozane/Tazobactam Using Monte Carlo Simulation in Patients With Various Degrees of Renal Function, Including Augmented Renal Clearance and End-Stage Renal Disease. AB - INTRODUCTION: Ceftolozane/tazobactam is an antibacterial agent with potent in vitro activity against Gram-negative pathogens, including many extended-spectrum beta-lactamase-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa. Because ceftolozane/tazobactam is primarily excreted renally, appropriate dose adjustments are needed for patients with renal impairment. Monte Carlo simulations were used to determine the probability of pharmacokinetic/pharmacodynamic target attainment for patients with varying degrees of renal function, including augmented renal clearance (ARC) and end stage renal disease (ESRD) with hemodialysis. METHODS: Monte Carlo simulations were conducted for 1000 patients with ARC and normal renal function, mild renal impairment, moderate renal impairment, or severe renal impairment, and for 5000 patients with ESRD. Simulated dosing regimens were based on approved doses for each renal function category. Attainment targets for ceftolozane were 24.8% (bacteriostasis), 32.2% (1-log kill; bactericidal), and 40% (2-log kill) fT > minimum inhibitory concentration (MIC). The target for tazobactam was to achieve a 20% fT > minimum effective concentration (MEC) at an MEC of 1 mg/L, which was derived from a neutropenic mouse thigh infection model and was confirmed by efficacy data from clinical studies for complicated intraabdominal infections and complicated urinary tract infections. RESULTS: In patients with ARC or normal renal function, >=91% achieved bactericidal activity (32.2% fT > MIC) up to an MIC of 4 mg/L with a 1000-mg ceftolozane dose. In patients with renal impairment (mild, moderate, severe, ESRD), >=93% achieved bactericidal activity up to an MIC of 8 mg/L. In patients of all renal function categories, the approved dosing regimens of tazobactam achieved >=91% target attainment against a target of 20% fT > MEC. CONCLUSIONS: At the approved dosing regimens for ceftolozane/tazobactam, >=91% of patients in all renal function categories, including ARC (up to 200 mL/min) and ESRD, reached target attainment for bactericidal activity at MICs that correspond to susceptibility breakpoints for Enterobacteriaceae and P. aeruginosa. PMID- 28013454 TI - Comparative genomic analysis of three white spot syndrome virus isolates of different virulence. AB - Three white spot syndrome virus (WSSV) isolates of different virulence were identified in our previous study, the high-virulent strain WSSV-CN01, the moderate-virulent strain WSSV-CN02 and the low-virulent strain WSSV-CN03. In this study, the genomes of these three WSSV isolates were sequenced, annotated and compared. The genome sizes for WSSV-CN01, WSSV-CN02, and WSSV-CN03 are 309,286, 294,261, and 284,148 bp, bearing 177, 164, and 154 putative protein-coding genes, respectively. The genomic variations including insertions, deletions, and substitutions were investigated. Thirty four genes show >20% variation in their sequences in WSSV-CN02 or WSSV-CN03, in comparison with WSSV-CN01, including six envelope protein genes (wsv237/vp41A, wsv238/vp52A, wsv338/vp62, wsv339/vp39, wsv077/vp36A, and wsv242/vp41B), and two immediate-early genes (wsv108 and wsv178). The genomic variations among WSSV isolates of different virulence, especially those in the coding regions, certainly provide new insight into the understanding of the molecular basis of WSSV pathogenesis. PMID- 28013455 TI - Laparoscopic appendectomy: Hem-o-lok versus Endoloop in stump closure. AB - There are several techniques described to close the appendicular stump during laparoscopic appendectomy. The aim of this study was to investigate the safety and usefulness of the Hem-o-lok clip for the closure of appendicular stump, comparing these data with those concerning the endo-loop. We conducted a retrospective study that compared two groups of patients who underwent laparoscopic appendectomy from 2010 to 2015 at our institution. We used the Endoloop to close the stump in the first group (group I) and the Hem-o-lok in the second group (group II). We reviewed patient's data including: complications, operative time, length of stay, costs. There were 121 patients in group I and 138 patients in group II. The mean operative times were 40.5 min in group I and 36.4 min in the group II. No intraoperative complications and no mortality were observed in either group. The mean postoperative length of hospital stay was similar for both groups. There was no rehospitalization after discharge. The complication rate did not reach statistical significance between the groups. The cost of the procedure using the Hem-o-lok has been lower than using the Endoloop. Both the Endoloop and Hem-o-lok are safe for the closure of the appendicular stump. Hem-o-lok appears to be superior than Endoloop in terms of easeness of use and cheapness, maintaining the same safety. PMID- 28013456 TI - Selenium Administration Alleviates Toxicity of Chromium(VI) in the Chicken Brain. AB - Selenium (Se) can play a protective role against heavy metal toxicity. This experiment aims to evaluate the effect of Se supplementation at different doses on the chicken brains. Oxidative stress was induced in the chicken brains by chromium(VI). A total of 105 Hyland brown male chickens were randomly divided into seven groups, including the control group, poisoned group [6%LD50 K2Cr2O7 body weight (B.W.)], and detoxification groups K2Cr2O7 (6%LD50) + Se (0.31, 0.63, 1.25, 2.50, and 5.00 Na2SeO3 mg/kg B.W.) orally in water for 42 days. The chickens were detected by the activities of mitochondrial membrane potential, 2' benzoyloxycinnamaldehyde, superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and Ca2+-ATPase. Cr(VI) administration caused histopathological damage. In addition, changes in oxidative stress indicators were observed in the chicken's brains. Se supplement increased the levels of GSH, mitochondrial membrane potential (MMP), and Ca2+-ATPase and reduced MDA activity in the detoxification groups. However, the high-dose Se supplementation groups of 2.50 and 5.00 mg/kg reduced the activities of GSH, MMP, and Ca2+-ATPase; increased the brain-body ratio; and increased SOD activity. In conclusion, Cr(VI) exposure caused oxidative stress. Se exerted a remission effect on toxic responses in the chicken brains. However, a high Se concentration was synergistic to the toxic effect of Cr(VI). PMID- 28013457 TI - Selective evolution of Toll-like receptors 3, 7, 8, and 9 in bats. AB - Previous studies have shown that bats are reservoirs of a large number of viruses, many of which cause illness and mortality in humans and other animals. However, these bat-associated pathogens cause little, if any, clinicopathology in bats. This long-term adaptation should be reflected somewhat in the immune system. Toll-like receptors (TLRs) are the first line of immune defense against pathogens in vertebrates. Therefore, this study focuses on the selection of TLRs involved in virus recognition. The coding sequences of TLR3, TLR7, TLR8, and TLR9 were sequenced in ten bats. The selection pressure acting on each gene was also detected using branch- and site-specific methods. The results showed that the ancestor of bats and certain other bat sublineages evolved under positive selection for TLR7, TLR8, and TLR9. The highest proportion of positive selection occurred in TLR9, followed by TLR8 and TLR7. All of the positively selected sites were located in the leucine-rich repeat (LRR) domain, which implied their important roles in pathogen recognition. However, TLR3 evolved under negative selection. Our results are not in line with previous studies which identified more positively selected sites in TLR8 in mammalian species. In this study, the most positively selected sites were found in TLR9. This study encompassed more species that were considered natural reservoirs of viruses. The positive selection for TLR7, TLR8, and TLR9 might contribute to the adaptation of pathogen host interaction in bats, especially in bat TLR9. PMID- 28013458 TI - Inverted left appendage: an unexpected echocardiographic image finding after left ventricular assist device implantation. PMID- 28013459 TI - Molecular and structural changes induced by essential oil treatments in Vicia faba roots detected by FTIR and FTNIR spectroscopy. AB - Essential oils have recognized antimicrobial and antifungal properties which allow their utilization in agriculture like an alternative to pesticides, but their utilization requires the knowledge of all the potential structural changes and damages produced by the interaction with the vegetal organisms. In this paper, we investigated the effects of two essential oils, the tea tree oil (TTO) and the mixture of clove and rosemary oils (C + R), on the molecular structure of Vicia faba roots by Fourier transform infrared (FTIR) and Fourier near infrared transform (FTNIR) spectroscopy. FTIR spectroscopy showed structural modifications of the absorption bands related to DNA (1100 and 1050 cm-1, carbohydrate backbones, and nucleotide bands within 900 and 850 cm-1), proteins (1700 and 1600 cm-1 amide I band, 1580 and 1520 cm-1 amide II band), and lipids (methylene group of aliphatic chains between 2950 and 2800 cm-1). The changes in the secondary structures of proteins consisted of a denaturation depending on increased presence of random coil structures. In addition, in the samples treated with TTO oils, we observed the presence of protein oxidation, an effect negligible instead for the C + R-treated samples. The modified shapes of the infrared methyl bands of aliphatic chains suggested an increased lipid disorder which could also determine lipid peroxidation. The changes observed for the DNA structures at the highest concentration of the above essential oils can be related to the genotoxic effect of eugenol, an important constituent of both TTO and C + R mixture oils. FTNIR spectroscopy showed the modified shape of the second overtone bands belonging to methyl and methylene groups, between 8500 and 8000 cm-1. This confirmed the increased lipid disorders already observed by FTIR spectroscopy. The results obtained on the probe organism V. faba show that FTIR and FTNIR spectroscopy can become a useful support to the conventional cytogenetic tests used in the evaluation of the allelopathic uses of essential oils in agriculture. PMID- 28013460 TI - Arsenic trioxide induces ROS activity and DNA damage, leading to G0/G1 extension in skin fibroblasts through the ATM-ATR-associated Chk pathway. AB - Arsenic (As) toxicity is a global health problem, affecting millions of people. Exposure to arsenic, mostly via drinking water, has been associated with cancer of skin, lungs, and blood, in addition to several kinds of skin lesions. The present study focused on the effect of arsenic trioxide (As2O3) on normal skin fibroblast cells. Specifically, the effect of As2O3 on ROS generation and oxidative stress was investigated. Proteins involved in the DNA damage signaling pathway and cell cycle were also studied. As2O3 induced the generation of intracellular ROS. Immunohistochemistry analysis revealed a dose-dependent increase in the number of 8-OHdG-positive cells, an indication of oxidative stress. Cell cycle analysis by flow cytometry demonstrated that As2O3 caused a significant percentage of cells to accumulate in the G0/G1 phase with a concomitant reduction in the S phase. Increases in the activated forms of DNA damage signaling proteins, ATM and ATR, and their effector molecules, Chk2 and p53, were also observed. In addition, expression of oncogene p21 was also increased. The study shows that exposure of normal skin fibroblast cells to As2O3 could lead to cell cycle arrest through ATM/ATR and DNA damage signaling pathways. In conclusion, we report here that arsenic trioxide increases cellular oxidative stress leading to shift in cell cycle and leads to DNA damage through ATM/ATR and the CHK-dependent signaling pathway. PMID- 28013461 TI - Simultaneous sulfide removal, nitrification, and electricity generation in a microbial fuel cell equipped with an oxic cathode. AB - With sulfide as an anodic electron donor and ammonium as a cathodic substrate, the feasibility of simultaneous sulfide removal, nitrification, and electricity generation was investigated in a microbial fuel cell (MFC) equipped with an oxic cathode. Successful simultaneous sulfide removal, nitrification, and electricity generation in this MFC were achieved in 35 days, with the sulfide and ammonium removal percent of 92.7 +/- 1.4 and 96.4 +/- 0.3%, respectively. The maximum power density increased, but the internal resistance decreased with the increase of feeding sulfide concentration from 62.9 +/- 0.3 to 238.5 +/- 0.2 mg S/L. Stable ammonium removal with complete nitrification, preparing for future denitrification, was obtained throughout the current study. Sulfide removal loading significantly increased with the increase of feeding sulfide concentration at each external resistance, but no significant correlation between sulfide removal loading and external resistance was found at each feeding sulfide concentration. The charge recovery and anodic coulombic efficiency (CE) significantly decreased with the increase of external resistance. High feeding sulfide concentration led to low anodic CE. Granular sulfur deposition was found on the anode graphite fiber. The appropriate feeding sulfide concentration for sulfide removal and sulfur deposition was deemed to be 178.0 +/- 1.7 mg S/L, achieving a sulfur deposition percent of 69.7 +/- 0.6%. PMID- 28013462 TI - Dynamic monitoring and prediction of Dianchi Lake cyanobacteria outbreaks in the context of rapid urbanization. AB - Water crises have been among the most serious environmental problems worldwide since the twenty-first century. A water crisis is marked by a severe shortage of water resources and deteriorating water quality. As an important component of water resources, lake water quality has deteriorated rapidly in the context of fast urbanization and climate change. This deterioration has altered the water ecosystem structure and influenced lake functionality. To curb these trends, various strategies and procedures have been used in many urban lakes. Among these procedures, accurate and responsive water environment monitoring is the basis of the forecasting and prevention of large-scale cyanobacteria outbreaks and improvement of water quality. To dynamically monitor and predict the outbreak of cyanobacteria in Dianchi Lake, in this study, wireless sensors networks (WSNs) and the geographic information system (GIS) are used to monitor water quality at the macro-scale and meso-scale. Historical, real-time water quality and weather condition data were collected, and a combination prediction model (adaptive grey model (AGM) and back propagation artificial neural network (BPANN)) was proposed. The correlation coefficient (R) of the simulation experiment reached 0.995. Moreover, we conducted an empirical experiment in Dianchi Lake, Yunnan, China using the proposed method. R was 0.93, and the predicting error was 4.77. The results of the experiment suggest that our model has good performance for water quality prediction and can forecast cyanobacteria outbreaks. This system provides responsive forewarning and data support for lake protection and pollution control. PMID- 28013463 TI - Evaluation of combined noxious effects of siduron and cadmium on the earthworm Eisenia fetida. AB - Environmental contaminants do not often occur as individual chemicals but rather in complex mixtures whose joint effects can create a strong toxicity to surrounding organisms. To determine the combined harmful effects of siduron (herbicide) and cadmium (heavy metal) toward Eisenia fetida earthworms, samples of worm's coelomocytes were subjected to siduron and cadmium (Cd) at sublethal concentrations (lower than LC50)-siduron 0, 0.8, 2.4, and 7.2 MUg cm-2 Cd 0, 0.4, 0.8, and 1.6 MUg cm-2 in filter paper contact assay, both as individual compounds and combinations. The CI-isobologram model was utilized to reveal the types of toxicological interactions between siduron and cadmium in inducing DNA damage toward earthworms. The results indicated that tail DNA percentage (TDNA %) at individual siduron and cadmium concentrations (with the exception of the lowest concentration of Cd 0.04 MUgcm -2) were highly significant compared to those of the control (p < 0.01). Tail moments (TM) at individual Cd concentrations (0.8 and 1.6 MUg cm -2) were highly significant compared to those of the control (p < 0.05), while the increase of TM for individual siduron was only significant (p < 0.05) at 7.2 MUg cm -2 which is the highest dose/concentration of siduron used in this study. The combinations of siduron and Cd indicated a significant synergism (CI < 1) at the lower effect levels and a significant antagonism (CI > 1) at the higher effect levels. The synergistic effect for a particular combination of chemicals suggests that there might be a possible risk connected to the coincidence of these chemicals. PMID- 28013464 TI - In situ remediation of contaminated marinesediment: an overview. AB - Sediment tends to accumulate inorganic and persistent hydrophobic organic contaminants representing one of the main sinks and sources of pollution. Generally, contaminated sediment poses medium- and long-term risks to humans and ecosystem health; dredging activities or natural resuspension phenomena (i.e., strongly adverse weather conditions) can remobilize pollution releasing it into the water column. Thus, ex situ traditional remediation activities (i.e., dredging) can be hazardous compared to in situ techniques that try to keep to a minimum sediment mobilization, unless dredging is compulsory to reach a desired bathymetric level. We reviewed in situ physico-chemical (i.e., active mixing and thin capping, solidification/stabilization, chemical oxidation, dechlorination, electrokinetic separation, and sediment flushing) and bio-assisted treatments, including hybrid solutions (i.e., nanocomposite reactive capping, bioreactive capping, microbial electrochemical technologies). We found that significant gaps still remain into the knowledge about the application of in situ contaminated sediment remediation techniques from the technical and the practical viewpoint. Only activated carbon-based technologies are well developed and currently applied with several available case studies. The environmental implication of in situ remediation technologies was only shortly investigated on a long-term basis after its application, so it is not clear how they can really perform. PMID- 28013465 TI - Decomposition of 3,5-dinitrobenzamide in aqueous solution during UV/H2O2 and UV/TiO2 oxidation processes. AB - 3,5-Dinitrobenzamide has been widely used as a feed additive to control coccidiosis in poultry, and part of the added 3,5-dinitrobenzamide is excreted into wastewater and surface water. The removal of 3,5-dinitrobenzamide from wastewater and surface water has not been reported in previous studies. Highly reactive hydroxyl radicals from UV/hydrogen peroxide (H2O2) and UV/titanium dioxide (TiO2) advanced oxidation processes (AOPs) can decompose organic contaminants efficiently. In this study, the decomposition of 3,5 dinitrobenzamide in aqueous solution during UV/H2O2 and UV/TiO2 oxidation processes was investigated. The decomposition of 3,5-dinitrobenzamide fits well with a fluence-based pseudo-first-order kinetics model. The decomposition in both two oxidation processes was affected by solution pH, and was inhibited under alkaline conditions. Inorganic anions such as NO3-, Cl-, SO42-, HCO3-, and CO32- inhibited the degradation of 3,5-dinitrobenzamide during the UV/H2O2 and UV/TiO2 oxidation processes. After complete decomposition in both oxidation processes, approximately 50% of 3,5-dinitrobenzamide was decomposed into organic intermediates, and the rest was mineralized to CO2, H2O, and other inorganic anions. Ions such as NH4+, NO3-, and NO2- were released into aqueous solution during the degradation. The primary decomposition products of 3,5 dinitrobenzamide were identified using time-of-flight mass spectrometry (LCMS-IT TOF). Based on these products and ions release, a possible decomposition pathway of 3,5-dinitrobenzamide in both UV/H2O2 and UV/TiO2 processes was proposed. PMID- 28013466 TI - Determination of optimum polymeric coagulant in palm oil mill effluent coagulation using multiple-objective optimisation on the basis of ratio analysis (MOORA). AB - The main limitation of a conventional palm oil mill effluent (POME) ponding system lies in its inability to completely decolourise effluent. Decolourisation of effluent is aesthetically and environmentally crucial. However, determination of the optimum process parameters is becoming more complex with the increase of the number of coagulants and responses. The primary objective of this study is to determine the optimum polymeric coagulant in the coagulation-flocculation process of palm oil mill effluent by considering all output responses, namely lignin tannin, low molecular mass coloured compounds (LMMCC), chemical oxygen demand (COD), ammonia nitrogen (NH3-N), pH and conductivity. Here, multiple-objective optimisation on the basis of ratio analysis (MOORA) is employed to discretely measure multiple response characteristics of five different types of coagulants as a function of assessment value. The optimum coagulant is determined based on the highest assessment value and was identified as QF25610 (cationic polyacrylamide). On the other hand, the lowest assessment value was represented by AN1800 (anionic polyacrylamide). This study highlights the simplicity of MOORA approach in handling various input and output parameters, and it may be useful in other wastewater treatment processes as well. PMID- 28013467 TI - Molecular-based detection of potentially pathogenic bacteria in membrane bioreactor (MBR) systems treating municipal wastewater: a case study. AB - Although membrane bioreactor (MBR) systems provide better removal of pathogens compared to conventional activated sludge processes, they do not achieve total log removal. The present study examines two MBR systems treating municipal wastewater, one a full-scale MBR plant and the other a lab-scale anaerobic MBR. Both of these systems were operated using microfiltration (MF) polymeric membranes. High-throughput sequencing and digital PCR quantification were utilized to monitor the log removal values (LRVs) of associated pathogenic species and their abundance in the MBR effluents. Results showed that specific removal rates vary widely regardless of the system employed. Each of the two MBR effluents' microbial communities contained genera associated with opportunistic pathogens (e.g., Pseudomonas, Acinetobacter) with a wide range of log reduction values (< 2 to >5.5). Digital PCR further confirmed that these bacterial groups included pathogenic species, in several instances at LRVs different than those for their respective genera. These results were used to evaluate the potential risks associated both with the reuse of the MBR effluents for irrigation purposes and with land application of the activated sludge from the full-scale MBR system. PMID- 28013468 TI - Performance and emission analysis on blends of diesel, restaurant yellow grease and n-pentanol in direct-injection diesel engine. AB - Yellow grease from restaurants is typically waste cooking oil (WCO) free from suspended food particles with free fatty acid (FFA) content less than 15%. This study proposes an approach to formulate a renewable, eco-friendly fuel by recycling WCO with diesel (D) and n-pentanol (P) to improve fuel-spray characteristics. Three ternary blends (D50-WCO45-P5, D50-WCO40-P10 and D50-WCO30 P20) were selected based on the stability tests and prepared with an objective to substitute diesel by 50% with up to 45% recycled component (WCO) and up to 20% bio-component (n-pentanol) by volume. The fuel properties of these ternary blends were measured and compared. The emission impacts of these blends on a diesel engine were analysed in comparison with diesel and D50-WCO50 (50% of diesel + 50% of WCO) under naturally articulated and EGR (exhaust gas recirculation) approaches. Doping of n-pentanol showed improved fuel properties when compared to D50-WCO50. Viscosity is reduced up to 45%. Cetane number and density were comparable to that of diesel. Addition of n-pentanol to D50-WCO50 presented improved brake specific fuel consumption (BSFC) for all ternary blends. Brake thermal efficiency (BTE) of D50-WCO30-P20 blend is comparable to diesel due to improved atomization. Smoke opacity reduced, HC emissions increased and CO emissions remained unchanged with doping n-pentanol in the WCO. NOx emission increases with increase in n-pentanol and remained lower than diesel and all load conditions. However, NOx can be decreased by up to threefold using EGR. By adopting this approach, WCO can be effectively reused as a clean energy source by negating environmental hazards before and after its use in diesel engines, instead of being dumped into sewers and landfills. PMID- 28013469 TI - Bacterial communities associated with anaerobic debromination of decabromodiphenyl ether from mangrove sediment. AB - This study evaluated decabromodiphenyl ether (BDE-209) anaerobic debromination and bacterial community changes in mangrove sediment. BDE-209 debromination rates were enhanced with zerovalent iron compared to without zerovalent iron in the sediment. BDE-209 debromination rates in microcosms constructed with sediments collected in autumn were higher than in microcosms constructed with sediments collected in spring and were higher at the Bali sampling site than the Guandu sampling site. The intermediate products resulting from the reductive debromination of BDE-209 in sediment were nona-BDE (BDE-206, BDE-207), octa-BDEs (BDE-196, BDE-197), hepta-BDEs (BDE-183, BDE-184, BDE-191), hexa-BDEs (BDE-137, BDE-138, BDE-154, BDE-157), penta-BDEs (BDE-85, BDE-99, BDE-100, BDE-126), tetra BDEs (BDE-47, BDE-49, BDE-66, BDE-77), tri-BDEs (BDE-17, BDE-28), and di-BDEs (BDE-15). Fifty bacterial genera associated with BDE-209 debromination were identified. Overall, 12 of the 50 bacterial genera were reported to be involved in dehalogenation of aromatic compounds. These bacteria have high potential to be BDE-209 debromination bacteria. Different combinations of bacterial community composition exhibit different abilities for BDE-209 anaerobic debromination. PMID- 28013470 TI - A socio-scientific analysis of the environmental and health benefits as well as potential risks of cassava production and consumption. AB - Due to its high adaptability, cassava (Manihot esculenta Crantz) is one of the world's most cultivated and consumed plants after maize and rice. However, there are relatively few scientific studies on this important crop. The objective of this review was therefore to summarize and discuss the available information on cassava cropping in order to promote sustainable practices in terms of production and consumption. Cassava cultivation has been expanding recently at the global scale and is widely consumed in most regions of South America, Africa, and Asia. However, it is also characterized by the presence in its roots of potentially toxic hydrocyanic acid. Furthermore, cassava can also absorb pollutants as it is currently cultivated near roads or factories and generally without consideration for potential sources of soil, water, or atmospheric pollution. Careful washing, peeling, and adequate preparation before eating are therefore crucial steps for reducing human exposure to both environmental pollutants and natural hydrocyanic acid. At present, there is not enough precise data available on this staple food crop. To improve our knowledge on the nutritive benefits versus health risks associated with cassava consumption, further research is necessary to compare cassava cultivars and precisely study the influence of preparation methods. PMID- 28013471 TI - Inflammation and oxidation: do they improve after kidney transplantation? Relationship with mortality after transplantation. AB - : Patients with chronic kidney disease (CKD) are characterized by a state of inflammation and oxidative stress that seems to improve after kidney transplantation (KT). Nevertheless, there is controversy regarding what is the best marker that better define inflammation and specially oxidative stress. OBJECTIVE: To evaluate the biomarkers which are associated with improvements in inflammation and lipid peroxidation in patients who have undergone KT. To evaluate the relationship between inflammation, lipid peroxidation and mortality in KT. PATIENTS: 196 KT (between 2003 and 2008). 67.9% men; median age: 51.9 years. Inflammation markers analyzed previous KT and 3 months after KT: c reactive protein(CRP), interleukin 6(IL-6), tumor necrosis factor alpha(TNFalpha), soluble tumor necrosis factor receptor alpha(sTNFRalpha), soluble interleukin-2 receptor (sIL-2R). Lipid peroxidation markers analyzed: oxidized low-density lipoprotein (oxLDL) and anti-oxLDL antibodies. Calculation of glomerular filtration rate after KT: MDRD equation. RESULTS: Following KT, there is a significant decrease in CRP (p = 0.006), IL-6 (p = 0.0037), TNFalpha (p < 0.0001), sTNFRalpha (p < 0.0001) and sIL-2R (p < 0.0001), while levels of oxLDL increase after KT (p < 0.0001) and there is not a significantly difference in anti-oxLDL. 12.8% of the patients had died in 2012. These patients had higher levels of IL-6 (p = 0.011) and sTNFRalpha (p < 0.006) after KT and a lower MDRD (p < 0.0001), hemoglobin (p = 0.012) and albumin (p = 0.007). We observed no statistically differences in the levels of markers previous KT. Of the patients who died, the 43.5% of them had anti-oxLDL antibody levels greater than 75th percentile (P75: 3781 UI/ml, p = 0.028). In the multivariate analysis, age (OR:1.12; p = 0.0129), MDRD (OR:0.92; p = 0.013) and P75 of anti-oxLDL(OR: 5.19; p = 0.026) were independent risk factors for mortality. Independent risk factors for survival were: P75 of IL-6 (HR: 2.45; p = 0.027), oxLDL (HR:19.85; p = 0.002) and anti-oxLDL (HR: 9.55; p = 0.003). CONCLUSIONS: KT improved inflammation but not lipid oxidative state. KT patients who died had a higher inflammatory state (with higher levels of IL-6 and sTNFRalpha), a worse lipid oxidative state and a worse renal function 3 months after KT. Age, anti-oxLDL and renal function at 3 months after KT were independent risk factors for mortality. PMID- 28013472 TI - Development and evaluation of wheel-controlled pitch-adjustable electrolarynx. AB - Tone is important in tonal languages, especially in Mandarin. However, there is presently no commercially available electrolarynx (EL) for laryngectomized Mandarin speakers. Moreover, few studies have focused on this area. Our purpose is to design an EL that produces the four Mandarin tones and to evaluate its performance. We designed a wheel-controlled pitch-adjustable EL and manufactured a prototype (Wheel-EL). Using monosyllables, disyllabic segments, and frequently used phrases, we evaluated speech produced by Wheel-EL and by monotone (M TruTone) and variable-frequency modes (V-TruTone) of the commercially available TruTone EL. The pitch contours of the high-level (HL), middle-rising (MR), and falling-rising (FR) tones produced by Wheel-EL most closely matched the natural speech characteristics of a native speaker. However, redundant sounds were generated in the high-falling (HF) tone. The statistical accuracy of Wheel-EL's tone and word perception was significantly higher than that of other EL types. However, no significant differences existed in acceptability among the three EL speech types. Wheel-EL produces better HL, MR, and FR tones in Mandarin than either M-TruTone or V-TruTone. Nevertheless, redundant sounds affect HF phonation. Accurate tone judgment can improve the intelligibility of EL speech in Mandarin but has no obvious effect on acceptability. PMID- 28013473 TI - Pollution in the urban soils of Lianyungang, China, evaluated using a pollution index, mobility of heavy metals, and enzymatic activities. AB - Soil samples from 16 urban sites in Lianyungang, China were collected and analyzed. A pollution index was used to assess the potential ecological risk of heavy metals and a sequential extraction procedure was used to evaluate the relative distribution of Cu, Zn, Pb, Cd, Cr, and As in exchangeable, carbonate, Fe/Mn oxide, organic/sulfide, and residual fractions. The mobility of heavy metals and urease (URE) activity, alkaline phosphatase (ALP) activity, and invertase (INV) activity of soils was determined. The results showed that the average concentrations of Cu, Zn, Pb, Cd, Cr, and As in Lianyungang soils were much higher than those in the coastal city soil background values of Jiangsu and China. Among the five studied regions (utilities, commercial, industrial, tourism, and roadside), the industrial region had the highest metal concentrations demonstrating that land use had a significant impact on the accumulation of heavy metals in Lianyungang soils. Compared to the other metals, Cd showed the highest ecological risk. According to chemical partitioning, Cu was associated with the organic/sulfides and Pb and Zn were mainly in the carbonate and the Fe/Mn oxide phase. The greatest amounts of Cd were found in exchangeable and carbonate fractions, while Cr and As were mainly in the residual fraction. Cd had the highest mobility of all metals, and the order of mobility (highest to lowest) of heavy metals in Lianyungang soils was Cd > Zn > Pb > Cu > As > Cr. Soil urease activity, alkaline phosphatase activity, and invertase activity varied considerably in different pollution degree sites. Soil enzyme activities had the lowest levels in roadside and industrial regions. Across all the soil data in the five regions, the total Cu, Zn, Pb, Cd, Cr, and As level was negatively correlated with urease activity, alkaline phosphatase activity, and invertase activity, but the relationship was not significant. In the industrial region, alkaline phosphatase activity had significant negative correlations with total Cu, Pb, Cr, Zn, Cd, and heavy metal fractions. This showed that alkaline phosphatase activity was sensitive to heavy metals in heavily contaminated regions, whereas urease and invertase were less affected. The combination of the various methods may offer a powerful analytical technique in the study of heavy metal pollution in street soil. PMID- 28013474 TI - Use of continuous monitoring to assess stream nitrate flux and transformation patterns. AB - Delivery of nitrogen from farmed fields to the stream network is an ongoing water quality issue in central North America and other parts of the world. Although fertilization and other farming practices have been refined to produce environmental improvements, stemming loss of nitrogen, especially in the soluble nitrate form, is a problem that has seemingly defied solution. The Iowa Nutrient Reduction Strategy is a policy initiative designed to implement conservation and other farm management practices to produce reductions in nitrate loading. The strategy does not focus on how the streams themselves may or may not be processing nitrogen and reducing downstream loading. We used continuous high frequency nitrate and discharge monitoring over 3 years at two sites separated by 18 km in a low-order, agricultural stream in eastern Iowa to estimate how nitrogen is processed, and whether or not these processes are reducing downstream loading. We conclude that the upstream to downstream nitrate concentration decline between the two sites was not driven by denitrification. These data also show that nitrate concentrations are closely coupled to discharge during periods of adequate moisture, but decoupling of concentration from discharge occurs during dry periods. This decoupling is a possible indicator of in-stream nitrate processing. Finally, nitrate concentrations are likely diluted by water sourced from non-row crop land covers in the lower reaches of the watershed. PMID- 28013475 TI - Enrichment of 15N/14N in wastewater-derived effluent varies with operational performance of treatment systems: implications for isotope monitoring in receiving environments. AB - Stable nitrogen isotope ratios are routinely used to trace the dispersion and assimilation of wastewater-derived N in receiving environments, but few isotope studies have investigated wastewater treatment plants and ponds themselves. An improved understanding of N isotope compositions in effluent will help assess treatment plant processes and performance and will help trace sources of excess nutrients in receiving environments. Here, we assess N budgets and treatment processes in seven wastewater treatment plants and wastewater stabilisation ponds in northern Australia based on concentrations and isotope ratios of N in effluent. We show that delta15N values in effluent are linked to treatment type, effectiveness of conversion of ammonia and levels of gaseous N emissions. These relationships suggest that N isotope monitoring of wastewater treatment plants and ponds can provide an integrated assessment of treatment performance and gaseous N emissions on a pond- or plant-wide scale that is not readily available through other methods. Our findings further imply that monitoring N isotope ratios in receiving environments cannot be assumed to be universally effective as their sensitivity to uptake of wastewater-derived N will vary with the characteristics of individual treatment systems. Paradoxically, N isotope monitoring is less effective where treatment systems are functioning poorly and where monitoring needs are the greatest. PMID- 28013476 TI - Live diatoms as indicators of urban stormwater runoff. AB - Diatom bioassessment of streams/rivers does not distinguish between live (cells with intact chloroplasts) and dead (empty cells) individuals, even though most diatom samples collected from the field will be composed of a mixture of both. This study aimed to evaluate whether percentage of live diatoms (PLD), live diatom density and chlorophyll a, and diatom species compositions can be used as indicators of hydrologic disturbance in an urban stream. We deployed artificial substrates on a monthly basis and collected periphyton samples weekly over the course of one calendar year (n = 182) in three tributaries of urbanized Ruddiman Creek (Michigan, USA). We also collected samples before and after six major storm events (>0.5 cm rain). We found no temporal patterns in PLD (Mann-Kendall test p > 0.05) or species composition (non-metric multidimensional scaling (NMDS) ordination), which may be explained by a diatom composition already tolerant to frequent disturbance. There was no difference in PLD before and after storm events, which might partially be explained by their disturbance resistance due to different assemblage ages (1, 2, and 4 weeks old) before the storms. High flow had differential effects on diatom species; loosely attached Navicula and Nitzschia species were more easily removed compared to stalk-forming Gomphonema parvulum. The most important environmental variable that was found to affect live diatom density and chlorophyll was stream width, which has an indirect effect (as a measure of discharge) on periphyton assemblages. In conclusion, PLD was found to be unsuitable metric for assessing stormwater runoff in urban streams where periphyton may not have enough time to form mature communities. PMID- 28013477 TI - Inhibition of pro-/active MMP-2 by green tea catechins and prediction of their interaction by molecular docking studies. AB - Matrix metalloproteinases (MMPs) play a crucial role in developing different types of lung diseases, e.g., pulmonary arterial hypertension (PAH). Green tea polyphenolic catechins such as EGCG and ECG have been shown to ameliorate various types of diseases including PAH. Our present study revealed that among the four green tea catechins (EGCG, ECG, EC, and EGC), EGCG and ECG inhibit pro-/active MMP-2 activities in pulmonary artery smooth muscle cell (PASMC) culture supernatant. Based on the above, we investigated the interactions of pro-/active MMP-2 with the green tea catechins by computational methods. In silico analysis revealed a strong interaction of pro-/active MMP-2 with EGCG/ECG, and galloyl group has been observed to be responsible for this interaction. The in silico analysis corroborated our experimental observation that EGCG and ECG are active in preventing both the proMMP-2 and MMP-2 activities. Importantly, these two catechins appeared to be better inhibitors for proMMP-2 in comparison to MMP-2 as revealed by gelatin zymogram and also by molecular docking studies. In many type of cells, activation of proMMP-2 occurs via an increase in the level of MT1-MMP (MMP-14). We, therefore, determined the interactions of MT1-MMP with the green tea catechins by molecular docking analysis. The study revealed a strong interaction of MT1-MMP with EGCG/ECG, and galloyl group has been observed to be responsible for the interaction. PMID- 28013478 TI - Increased Urge to Gamble Following Near-Miss Outcomes May Drive Purchasing Behaviour in Scratch Card Gambling. AB - Previous research into scratch card gambling has highlighted the effects of these games on players' arousal and affective states. Specifically, near-miss outcomes in scratch cards (uncovering 2 of 3 needed jackpot symbols) have been associated with high levels of physiological and subjective arousal and negative emotional evaluations, including increased frustration. We sought to extend this research by examining whether near-misses prompted increases in gambling urge, and the subsequent purchasing of additional scratch cards. Participants played two scratch cards with varying outcomes with half of the sample experiencing a near miss for the jackpot prize, and the other half experiencing a regular loss. Players rated their urge to continue gambling after each game outcome, and following the initial playing phase, were then able to use their winnings to purchase additional cards. Our results indicated that near-misses increased the urge to gamble significantly more than regular losses, and urge to gamble in the near-miss group was significantly correlated with purchasing at least one additional card. Although some players in the loss group purchased another card, there was no correlation between urge to gamble and purchasing in this group. Additionally, participants in the near-miss group who purchased additional cards reported higher levels of urge than those who did not purchase more cards. This was not true for the loss group: participants who experienced solely losing outcomes reported similar levels of urge regardless of whether or not they purchased more scratch cards. Despite near-misses' objective status as monetary losses, the increased urge that follows near-miss outcomes may translate into further scratch card gambling for a subset of individuals . PMID- 28013479 TI - Idling in Mao's Shadow: Heroin Addiction and the Contested Therapeutic Value of Socialist Traditions of Laboring. AB - The Chinese government has come under attack by international critics for forcing drug users to labor in the name of treatment. While joining these activists in criticizing conditions in compulsory labor centers, former detainees who congregated at a drop-in center in southern Yunnan also defended the therapeutic potential of socialist legacies of laboring. Shuttling between laboring in state compulsory centers and idling in a market economy, long-term heroin users saw their difficulties in recovering from addiction as inextricably linked to their inability to find suitable work opportunities. Certain drop-in center attendees maintained that earlier Communist laboring projects had helped wayward citizens, including drug addicts, "merge into" society as productive workers. This group evoked the stable long-term jobs and benefits once provided by local state-owned enterprises and the radical revolutionary power of "remolding through labor" they imagined to have existed in the first years of the People's Republic as powerful alternatives to their recent crisis of idling. The nuanced ways that drop-in center regulars revisited the potential healing power of earlier traditions of socialist laboring as remedies to their contemporary struggles complicates long standing debates about coercion in treatment and the responsibility of the postsocialist state towards marginalized workers. PMID- 28013480 TI - Disseminated Cryptococcosis Due to Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Absence of Pulmonary Alveolar Proteinosis. AB - INTRODUCTION: Autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can cause acquired pulmonary alveolar proteinosis (PAP). Cases of acquired PAP susceptible to typical respiratory pathogens and opportunistic infections have been reported. Anti-GM-CSF autoantibodies have been reported in a few patients with cryptococcal meningitis. This study evaluated the presence of neutralizing anti-GM-CSF autoantibodies in patients without known congenital or acquired immunodeficiency with severe pulmonary or extrapulmonary cryptococcal infection but without PAP. METHODS: We took a clinical history and performed an immunologic evaluation and screening of anti-cytokine autoantibodies in patients with cryptococcal meningitis. The impact of autoantibodies to GM-CSF on immune function was assessed by intracellular staining of GM-CSF-induced STAT5 phosphorylation and MIP-1alpha production in normal peripheral blood mononuclear cells incubated with plasma from patients or normal control subjects. RESULTS: Neutralizing anti-GM-CSF autoantibodies were identified in four patients with disseminated cryptococcosis, none of whom exhibited PAP. Plasma from patients blocked GM-CSF signaling and inhibited STAT5 phosphorylation and production of MIP-1alpha. One patient died of disseminated cryptococcosis involving the central nervous system, which was associated with defective GM-CSF activity. CONCLUSIONS: Anti-GM-CSF autoantibodies increase susceptibility to cryptococcal infection in adults without PAP. Cryptococcal central nervous system infection associated with anti-GM-CSF autoantibodies could result in neurological sequelae or be life threatening. Therefore, timely detection of neutralizing anti-GM-CSF autoantibodies and development of an effective therapy are necessary to prevent deterioration of cryptococcal infection in these patients. PMID- 28013481 TI - The Confluence of Psychiatric Symptoms and Neurodegenerative Disease: Impact on Genetic Counseling. AB - Hereditary neurodegenerative diseases can present with a psychiatric prodrome that overlaps with psychiatric symptoms that are not primary to these diseases. When individuals present for predictive testing while experiencing such symptoms, clinicians including genetic counselors, must proceed with caution and evaluate each situation on a case-by-case basis. Legitimate reasons may exist for moving forward with testing. Additionally predicting the consequences of testing is unrealistic so that the clinicians must do their best to prepare patients for both positive and negative results. A multidisciplinary team following the Huntington disease protocol remains the gold standard care for predictive testing for such patients. We discuss 3 case histories that demonstrate the complex nature of genetic counseling and testing in the presence of psychiatric symptoms, whether emanating from the disease itself or the results of living in an affected family. PMID- 28013482 TI - Factors that influence a mobilized HSC product. PMID- 28013483 TI - Spousal hematopoietic stem cell transplantation. AB - We report a pilot series of five patients who received stem cell transplantation (SCT) from a spouse for post-transplant relapse or rejection. The inclusion criterion regarding HLA disparities was three or fewer antigen mismatches in the graft-versus-host direction at the HLA-A, B, and DR loci. Four patients received spousal SCT as a third transplant attempt after post-transplant relapse and one as rescue for graft rejection. The reduced intensity conditioning (RIC) regimen consisted of fludarabine, melphalan, and anti-thymocyte globulin (ATG) with 3 Gy of total body irradiation (TBI) for relapse cases and ATG plus 4 Gy of TBI for the rejection case. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. Peripheral blood stem cells were transplanted. Granulocyte engraftment was achieved in all cases between days 9 and 11 (median, 10) with complete spousal chimerism. In three of the five patients, no acute GVHD was observed, while one case developed grade III GVHD and one case grade IV. All four patients evaluable for the anti-leukemic effect achieved complete remission; however, all relapsed between 106 and 334 day post-transplant, and died between days 152 and 548. We suggest that spousal SCT can be performed as a repetitive SCT using a RIC regimen with low-dose ATG and steroid-containing GVHD prophylaxis. PMID- 28013484 TI - Antidepressant-like effects of ginsenoside Rg3 in mice via activation of the hippocampal BDNF signaling cascade. AB - Current antidepressants are clinically effective only after several weeks of administration. Ginsenoside Rg3 is one component of ginsenosides, with a similar chemical structure to ginsenoside Rg1. Here, we investigated the antidepressant effects of Rg3 in mouse models of depression. The antidepressant actions of Rg3 were first examined in the forced swim test (FST) and tail suspension test (TST), and then assessed in the chronic social defeat stress (CSDS) model of depression. The changes in the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway after CSDS and Rg3 treatment were investigated. A tryptophan hydroxylase inhibitor and a BDNF signaling inhibitor were also used to determine the pharmacological mechanisms of Rg3. It was found that Rg3 produced antidepressant effects in the FST and TST without affecting locomotor activity. Rg3 also prevented the CSDS-induced depressive-like symptoms. Moreover, Rg3 fully restored the CSDS-induced decrease in the hippocampal BDNF signaling pathway, and use of the BDNF signaling inhibitor blocked the antidepressant effects of Rg3. In conclusion, ginsenoside Rg3 has antidepressant effects via promotion of the hippocampal BDNF signaling pathway. PMID- 28013485 TI - Influence of saline-based hydroxyethyl starch on umbilical cord blood electrolytes. AB - Hydroxyethyl starch (HES) is widely used to prevent and treat spinal anesthesia induced hypotension during cesarean section. However, the use of saline-based HES may lead to hyperchloremia. This study aimed to clarify the effects of saline based HES on umbilical cord chloride level at delivery. We retrospectively analyzed 93 consecutive single-pregnancy patients who underwent cesarean section with combined spinal-epidural anesthesia. The patients were divided into two groups, depending on the use of 6% HES 130/0.4: group A (461 +/- 167 ml of saline based HES was administered; 43 patients) and group B (HES not administered; 50 patients). The major outcome was umbilical cord chloride level at delivery. The volume infused from operating room admission until delivery was not significantly different between groups. The umbilical cord chloride level at delivery was statistically significantly higher in group A than in group B, but clinically similar (108 +/- 2 vs. 107 +/- 2 mmol/l, P = 0.02). No differences were observed in the Apgar score or other umbilical cord laboratory data at delivery (Na+, K+, pH, base excess). In conclusion, we suggest that although the use of up to 500 ml of saline-based HES during cesarean section influences umbilical cord blood electrolytes, the effect is not of a clinically significant magnitude. PMID- 28013486 TI - Syndrome of the trephined revealed by vertical diplopia. PMID- 28013487 TI - Surgical treatment of migraine headaches. AB - The senior author (BG) introduced the modern concept of migraine surgery in 2000. Since then, over 40 articles have been published by eight centers across the US, Europe, and Asia, describing positive outcomes after surgery in 68-95% of cases. Surgeons, neurologists, and patients are increasingly interested in this new treatment method. However, the majority of publications on this topic are found in surgical literature, with few articles presented in neurology journals. This review is an introduction to migraine surgery for neurologists from a surgeons view. It discusses the surgical treatment of migraine headaches based on the discoveries made and articles published by the senior author. It outlines the current history of migraine surgery, presents evidence supporting its effectiveness, and tries to dispel claims that what we are seeing is a placebo effect. It further describes detection of trigger sites and outlines surgical techniques of peripheral nerve decompression. We hope that this review will generate a positive discussion between surgeons and neurologists and lead to more interdisciplinary collaboration for the benefit of the patients in the future. PMID- 28013488 TI - Caution! Self-supplementation may be injurious to your health. PMID- 28013489 TI - RSK2 and its binding partners in cell proliferation, transformation and cancer development. AB - RSK2 is a serine/threonine kinase and a member of the p90 ribosomal S6 kinase (p90RSK; RSKs) family, which regulates cell proliferation and transformation induced by tumor promoters such as epithelial growth factor (EGF), 12-O tetradecanoylphorbol-13-acetate (TPA), and ultraviolet (UV) radiation. RSKs respond to many growth factors, hormones, neurotransmitters and environmental stresses. In signaling cascades, RSK2 is regulated under the control of extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2) activities and is positioned upstream of transcription and epigenetic factors involved in cell proliferation, cell transformation and cancer development, as well as some kinases that modulate cell cycle progression. Over the last decade, our research group has studied the etiological roles of RSK2 in human cancer development, discovering that RSK2 plays a key role in cell proliferation, transformation and cancer development in humans. Based on our research, we concluded that RSK2 plays a key role as an onco-kinase by combinational protein-protein interaction with different binding partners depending on the cellular context. In this review, we discuss the function of the RSK2 signaling axis by interactions with binding partners in cancer development. PMID- 28013490 TI - Is there a link between urinary microbiota and bladder cancer? PMID- 28013491 TI - LncRNA NEAT1 Impacts Cell Proliferation and Apoptosis of Colorectal Cancer via Regulation of Akt Signaling. AB - Long noncoding RNA (lncRNA) have been reported to modulate oncogenesis and be used to be target for tumor. The role of lncRNA NEAT1 (nuclear paraspeckle assembly transcript 1, Gene ID: 283131) in colorectal cancer (CRC) keeps unknown. This work was to investigate the pattern of lncRNA NEAT1 (NEAT1) expression in CRC and its functional value and biological significance. NEAT1 expression was analyzed in 56 cancer tissues and cell lines in CRC cases. Results showed that NEAT1 was significantly overexpressed in CRC cells and tissues. Clinicpathologic detection verified that high NEAT1 expression associated with bulk in CRC. The serum contents of NEAT1 were observably elevated comparing with healthy cases (P < 0.05). The levels of NEAT1 were elevated in distinguishing CRC from normal (ROCAUC = 0.9471; P < 0.01). Moreover, Kaplan-Meier analysis found that NEAT1 elevation led to adverse survival (P < 0.05). Further experiments illustrated that of NEAT1 knockdown signally inhibited growth and facilitated apoptosis. Importantly, we confirmed that Akt signaling pathway was inactivated after loss of NEAT1 in CRC. Taken together, this work support the first evidence that NEAT1 can be used to be a promising biomarker and target for novel treatment for human CRC. PMID- 28013492 TI - Meta-Analysis for the Therapeutic Effect of Neoadjuvant Therapy in Resectable Esophageal Cancer. AB - We aimed to review the therapeutic effects of neoadjuvant chemoradiotherapy (NCRT), chemotherapy (NCT), and radiotherapy (NRT) on patients with resectable Esophageal cancer (EsC) by comparison with surgery alone (SA). PubMed, EMBASE and Cochrane were searched for eligible studies published up to March 2015. Cochrane reviews were used for quality assessment. Eight primary outcomes were analyzed. Risk ratios (RRs)/ hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were calculated using the random- or fixed- effects model. Heterogeneity was assessed using the Chi-square-based Q statistic and the I 2 test. Publication bias was examined by the Begg's funnel plot. Totally 24 articles including 4718 EsC cases were eligible for this meta-analysis. The quality of the literatures was relatively high. Significant difference was found in five-year survival rate (RR = 1.45, 95% CI: 1.17-1.79, P < 0.01) between patients treated with NCT and SA, while the eight enrolled primary outcomes were all statistically different between NCRT and SA, and significant difference was identified in three-year survival between NCRT and NCT (RR = 1.35, 95% CI: 1.14 1.60, P < 0.01). No obvious publication bias was observed. NCRT and NCT provide an obvious benefit for EsC treatment over SA, and NCRT possesses a clear advantage compared with NCT. PMID- 28013493 TI - Antimicrobial Peptides: An Introduction. AB - The "golden era" of antibiotic discovery has long passed, but the need for new antibiotics has never been greater due to the emerging threat of antibiotic resistance. This urgency to develop new antibiotics has motivated researchers to find new methods to combat pathogenic microorganisms resulting in a surge of research focused around antimicrobial peptides (AMPs; also termed host defense peptides) and their potential as therapeutics. During the past few decades, more than 2000 AMPs have been identified from a diverse range of organisms (animals, fungi, plants, and bacteria). While these AMPs share a number of common features and a limited number of structural motifs; their sequences, activities, and targets differ considerably. In addition to their antimicrobial effects, AMPs can also exhibit immunomodulatory, anti-biofilm, and anticancer activities. These diverse functions have spurred tremendous interest in research aimed at understanding the activity of AMPs, and various protocols have been described to assess different aspects of AMP function including screening and evaluating the activities of natural and synthetic AMPs, measuring interactions with membranes, optimizing peptide function, and scaling up peptide production. Here, we provide a general overview of AMPs and introduce some of the methodologies that have been used to advance AMP research. PMID- 28013494 TI - Tools for Designing Amphipathic Helical Antimicrobial Peptides. AB - Methods are described for the design of amphipathic helical AMPs, to improve potency and/or increase selectivity with respect to host cells. One method is based on the statistical analysis of known helical AMPs to derive a sequence template and ranges of charge, hydrophobicity, and amphipathicity (hydrophobic moment) values that lead to broad-spectrum activity, but leaves optimization for selectivity to subsequent rounds of SAR determinations. A second method uses a small database of anuran AMPs with known potency (MIC values vs. E. coli) and selectivity (HC50 values vs. human erythrocytes), as well as the concept of longitudinal moment, to suggest sequences or sequence variations that can improve selectivity. These methods can assist in the initial design of novel AMPs with useful properties in vitro, but further development requires knowledge-based decisions and a sound prior understanding of how structural and physical attributes of this class of peptides affect their mechanism of action against bacteria and host cells. PMID- 28013495 TI - Chemical Synthesis of Antimicrobial Peptides. AB - Solid-phase peptide synthesis (SPPS) is the method of choice for chemical synthesis of peptides. In this nonspecialist review, we describe commonly used resins, linkers, protecting groups, and coupling reagents in 9 fluorenylmethyloxycarbonyl (Fmoc) SPPS. Finally, a detailed protocol for manual Fmoc SPPS is presented. PMID- 28013496 TI - Microwave-Assisted Synthesis of Antimicrobial Peptides. AB - Antimicrobial peptides (AMPs) are emerging as one of the unsurpassed therapeutic tools to treat various devastating diseases that are affecting millions of lives. Conventional synthesis of peptides requires longer times, and hence automated microwave technology could be regarded as an alternative implement which offers advantages like less reaction times and higher yields. In this sense, we herein describe a methodology to prepare AMPs through solid-phase peptide synthesis under microwave conditions. We have used LL37 as an example to discuss the synthetic protocol including the difficulties involved in the preparation of so called long and difficult peptides and also remedial procedures to overcome these obstacles. PMID- 28013497 TI - High-Performance Liquid Chromatography and Mass Spectrometry-Based Design of Proteolytically Stable Antimicrobial Peptides. AB - The emergence of multiresistant bacteria worldwide together with the shortage of effective antibiotics in the market emphasizes the need for the design and development of the promising agents for the treatment of superbug-associated infections. Antimicrobial peptides (AMPs) have been considered as excellent candidates to tackle this issue, and thousands of peptides of different lengths, amino acid compositions, and mode of action have been discovered and prepared to date. Nevertheless, it is of great importance to develop innovative formulation strategies for delivering these AMPs and to improve their low bioavailability and metabolic stability, particularly against proteases, if these peptides are to find applications in the clinic and administered orally or parenterally or used as dietary supplements. The purpose of this chapter is to describe basic experimental principles, based on analytical reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry (MS), for the prospective design of orally bioavailable AMPs considering the structural characteristics of the peptides and the substrate specificity of proteases that abound in the body especially at sites of infection. PMID- 28013498 TI - Determination of Structure and Micellar Interactions of Small Antimicrobial Peptides by Solution-State NMR. AB - NMR spectroscopy is a well-established technique to determine the structure of peptides and small proteins in solution, also when bound to detergent micelles or phospholipid bicelles. The structure of the peptide alone is, however, not conveying the full picture, if the peptide is bound to a micelle, since it does not tell anything about the orientation of the peptide in the micelle. This article describes how to obtain that information together with information on peptide structure. PMID- 28013499 TI - Mass Spectrometry Approaches for Determining the Structure of Antimicrobial Peptides. AB - In the past decades, a great amount of antimicrobial peptides (AMPs) has been discovered, the structure identification of which relies heavily on de novo sequencing by Edman degradation or mass spectrometry. Here we outline the basic procedures for the exact mass measurement approaches that use off-line low-energy CID ESI Qq-TOF MS/MS in positive-ion mode, which is typically applied to de novo sequencing of peptides, to elucidate the structure of AMPs. Ambiguity I/L and partial sequence order were elucidated by Edman degradation or/and structural similarity analysis to known sequence. The approaches can determine the structure of peptides composed of as much as 38 amino acids in our practice. PMID- 28013500 TI - Molecular Dynamics Simulation and Analysis of the Antimicrobial Peptide-Lipid Bilayer Interactions. AB - A great deal of research has been undertaken in order to discover antimicrobial peptides (AMPs) with unexploited mechanisms of action to counteract the health threatening issues associated with bacterial resistance. The intrinsic effectiveness of AMPs is strongly influenced by their initial interactions with the bacterial cell membrane. Understanding these interactions in the atomistic details is important for the design of the less prone bacteria-resistant peptides. However, these studies always require labor-intensive and difficult steps. With this regard, modeling studies of the AMPs binding to simple lipid membrane systems, e.g., lipid bilayers, is of great advantage. In this chapter, we present an applicable step-by-step protocol to run the molecular dynamics (MD) simulation of the interaction between cyclo-RRWFWR (c-WFW) (a small cyclic AMP) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer using the Groningen machine for chemical simulations (GROMACS) package. The protocol as described here may simply be optimized for other peptide-lipid systems of interest. PMID- 28013501 TI - Calorimetry Methods to Study Membrane Interactions and Perturbations Induced by Antimicrobial Host Defense Peptides. AB - Biological membranes play an important role in determining the activity and selectivity of antimicrobial host defense peptides (AMPs). Several biophysical methods have been developed to study the interactions of AMPs with biological membranes. Isothermal titration calorimetry and differential scanning calorimetry (ITC and DSC, respectively) are powerful techniques as they provide a unique label-free approach. ITC allows for a complete thermodynamic characterization of the interactions between AMPs and membranes. DSC allows one to study the effects of peptide binding on the packing of the phospholipids in the membrane. Used in combination with mimetic models of biological membranes, such as phospholipid vesicles, the role of different phospholipid headgroups and distinct acyl chains can be characterized. In these protocols the use of ITC and DSC methods for the study of peptide-membrane interactions will be presented, highlighting the importance of membrane model systems selected to represent bacterial and mammalian cells. These studies provide valuable insights into the mechanisms involved in the membrane binding and perturbation properties of AMPs. PMID- 28013502 TI - Fluorescence and Absorbance Spectroscopy Methods to Study Membrane Perturbations by Antimicrobial Host Defense Peptides. AB - Antimicrobial peptides (AMPs) are currently intensely studied because of their potential as new bactericidal and bacteriostatic agents. The mechanism of action of numerous AMPs involves the permeabilization of bacterial membranes. Several methods have been developed to study peptide-membrane interactions; in particular optical spectroscopy methods are widely used. The intrinsic fluorescence properties of the Trp indole ring in Trp-containing AMPs can be exploited by measuring the fluorescence blue shift and acrylamide-induced fluorescence quenching. One important aspect of such studies is the use of distinct models of the bacterial membrane, in most cases large unilamellar vesicles (LUVs) with different, yet well-defined, phospholipid compositions. Deploying LUVs that are preloaded with fluorescent dyes, such as calcein, also allows for the study of vesicle permeabilization by AMPs. In addition, experiments using genetically engineered live Escherichia coli cells can be used to distinguish between the effects of AMPs on the outer and inner membranes of gram-negative bacteria. In combination, these methods can provide a detailed insight into the mode of action of AMPs. PMID- 28013503 TI - Applying Fluorescence Correlation Spectroscopy to Investigate Peptide-Induced Membrane Disruption. AB - There is considerable interest in understanding the interactions of antimicrobial peptides with phospholipid membranes. Fluorescence correlation spectroscopy (FCS) is a powerful experimental technique that can be used to gain insight into these interactions. Specifically, FCS can be used to quantify leakage of fluorescent molecules of different sizes from large unilamellar lipid vesicles, thereby providing a tool for estimating the size of peptide-induced membrane disruptions. If fluorescently labeled lipids are incorporated into the membranes of the vesicles, FCS can also be used to obtain information about whether leakage occurs due to localized membrane perturbations or global membrane destabilization. Here, we outline a detailed step-by-step protocol on how to optimally implement an FCS based leakage assay. To make the protocol easily accessible to other researchers, it has been supplemented with a number of practical tips and tricks. PMID- 28013504 TI - Macromolecule Biosynthesis Assay and Fluorescence Spectroscopy Methods to Explore Antimicrobial Peptide Mode(s) of Action. AB - Antimicrobial peptides (AMPs) are viable alternatives to the currently available antimicrobials, and numerous studies have investigated their possible use as therapeutic agents for specific clinical applications. AMPs are a diverse class of antimicrobials that often act upon the bacterial cell membrane but may exhibit additional modes of action. Identification of the multiple modes of action requires a comprehensive study at subinhibitory concentrations and careful data analysis since additional modes of action can be eclipsed by AMP action on the cell membrane.Techniques that measure the biosynthesis rate of macromolecules (e.g., DNA, RNA, protein, and cell wall) and the cytoplasmic membrane proton motive force (PMF) energy can help to unravel the diverse modes of action of AMPs. Here, we present an overview of macromolecule biosynthesis rate measurement and fluorescence spectroscopy methods to identify AMP mode(s) of action. Detailed protocols designed to measure inhibition of DNA, RNA, protein, and cell wall synthesis or membrane de-energization are presented and discussed for optimal application of these two techniques as well as to enable accurate interpretation of the experimental findings. PMID- 28013505 TI - Using Confocal Microscopy and Computational Modeling to Investigate the Cell Penetrating Properties of Antimicrobial Peptides. AB - Antimicrobial peptides (AMPs) may display the ability to penetrate cells, which may be relevant for their antibiotic activity. To investigate the relevance of the penetrating activity for the antibiotic activity of AMPs, here we describe a method based on the combined use of confocal microscopy and computational modeling coupled with cell death kinetics. PMID- 28013506 TI - Atomic Force Microscopy Study of the Interactions of Indolicidin with Model Membranes and DNA. AB - The cell membrane is the first barrier and quite often the primary target that antimicrobial peptides (AMPs) have to destroy or penetrate to fulfill their mission. Upon penetrating through the membrane, the peptides can further attack intracellular targets, in particular DNA. Studying the interaction of an antimicrobial peptide with a cell membrane and DNA holds keys to understanding its killing mechanisms. Commonly, these interactions are studied by using optical or scanning electron microscopy and appropriately labeled peptides. However, labeling can significantly affect the hydrophobicity, conformation, and size of the peptide, hence altering the interaction significantly. Here, we describe the use of atomic force microscopy (AFM) for a label-free study of the interactions of peptides with model membranes under physiological conditions and DNA as a possible intracellular target. PMID- 28013507 TI - Protocols for Studying the Interaction of MSI-78 with the Membranes of Whole Gram Positive and Gram-Negative Bacteria by NMR. AB - Antimicrobial peptides (AMPs) may interact with a variety of target cell components, including the lipid bilayer, non-lipidic cell envelope components, and/or intracellular targets. However, most biophysical experiments aimed at elucidating the detailed mechanism of AMPs are limited to simple model membrane systems and neglect potentially functional interactions between AMPs and non lipidic cell components. One of the biophysical techniques commonly used to study how AMPs interact with lipid bilayers is solid-state deuterium NMR. In this chapter we provide protocols to prepare deuterium-labeled intact Gram-negative and Gram-positive bacteria and to observe these samples using solid-state deuterium NMR. Such experiments have the potential to provide important information about how non-lipidic cell envelope components modulate AMP interactions with the cytoplasmic membrane of bacteria. PMID- 28013508 TI - Preparation of Membrane Models of Gram-Negative Bacteria and Their Interaction with Antimicrobial Peptides Studied by CD and NMR. AB - The antibiotic activity of antimicrobial peptides is generally derived via some type of disruption of the cell membrane(s). The most common models used to mimic the properties of bacterial membranes consist of mixtures of various zwitterionic and anionic phospholipids. This approach works reasonably well for Gram-positive bacteria. However, since the membranes of Gram-negative bacteria contain lipopolysaccharides, as well as zwitterionic and anionic phospholipids, a more complex model is required to simulate the outer membrane of Gram-negative bacteria. Herein we present a protocol for the preparation of models of the outer membranes of the Gram-negative bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa. This protocol can be used to prepare models of other Gram-negative bacteria provided the strain-specific lipopolysaccharides are available. PMID- 28013509 TI - Studying the Interaction of Magainin 2 and Cecropin A with E. coli Bacterial Cells Using Circular Dichroism. AB - The potential of antimicrobial peptides (AMPs) as an effective therapeutic alternative to classic and current antibiotics has encouraged studies to understand how they interact with the bacterial membrane. Here we describe how to detect, by circular dichroism (CD), the secondary structures of two antimicrobial peptides, magainin 2 and cecropin A, in the presence of E. coli bacterial cells. PMID- 28013510 TI - Studying the Mechanism of Membrane Permeabilization Induced by Antimicrobial Peptides Using Patch-Clamp Techniques. AB - Many short peptides selectively permeabilize the bacteria plasma membrane, leading to their lyses and death: they are therefore a source of antibacterial molecules and inspiration for novel and more selective drugs, which may have wider application in many other fields, as selective anticancer drugs. In this chapter, it is presented a new method to investigate the permeabilization properties of antimicrobial peptides under strict physiological conditions, employing the patch-clamp technique coupled to a fast perfusion system. PMID- 28013511 TI - Assays for Identifying Inducers of the Antimicrobial Peptide LL-37. AB - One promising approach to meet the growing problem of antibiotic resistance is to modulate host defense mechanisms, i.e., host-directed therapy (HDT), in the fight against infections. Induction of endogenous antimicrobial peptides (AMPs) via small molecular compounds, such as 1,25-dihydroxyvitamin D3 or phenylbutyrate, could provide one such HDT-based approach.We have developed a cell-based screening assay for the identification of novel compounds with the capacity to induce AMP expression and here follows the detailed protocol. PMID- 28013512 TI - Methods for Elucidating the Mechanism of Action of Proline-Rich and Other Non lytic Antimicrobial Peptides. AB - A distinct group of antimicrobial peptides kills bacteria by interfering with internal cellular functions and without concurrent lytic effects on cell membranes. Here we describe some methods to investigate the mechanisms of action of these antimicrobial peptides. They include assays to detect the possible temporal separation between membrane permeabilization and bacterial killing events, to assess the capacity of antimicrobial peptides to cross the bacterial membranes and reside in the cytoplasm, and later to inhibit vital cell functions such as DNA transcription and protein translation. PMID- 28013513 TI - The Interaction of Antimicrobial Peptides with the Membrane and Intracellular Targets of Staphylococcus aureus Investigated by ATP Leakage, DNA-Binding Analysis, and the Expression of a LexA-Controlled Gene, recA. AB - The analysis of how antimicrobial peptides (AMPs) interact with bacterial membranes and intracellular targets is important for our understanding of how these molecules affect bacteria. Increased knowledge may aid the design of AMPs that work on their target bacterium without inducing bacterial resistance. Here, we describe different methods to investigate the mode of action of peptides against the Gram-positive bacterium Staphylococcus aureus. ATP leakage analysis can be used to evaluate the ability of AMPs to perturb bacteria. DNA-binding and SOS response induction can be analyzed to investigate intracellular targets. PMID- 28013514 TI - Methods for Investigating Biofilm Inhibition and Degradation by Antimicrobial Peptides. AB - Multidrug-resistant bacteria are a growing problem worldwide. One extensively studied resistance mechanism is biofilm colonization-microbial colonies formed by many Gram-positive and Gram-negative bacteria species. Cationic antimicrobial peptides (AMPs) are innate immune system molecules serving as a first line of defense in fighting invading pathogens. The AMPs' underlying mechanism and biophysical properties required for anti-biofilm activity are not fully known. Here we present protocols for investigating AMPs' biological activity against major stages of biofilm life cycle, namely, planktonic stage (MIC assay), initial adhesion to surfaces (bacterial attachment assay), and formation or degradation of sessile microcolonies (biofilm formation and degradation assays). Furthermore, we demonstrate experiments that allow determination and comparison between peptide biophysical properties (secondary structure, hydrophobicity, and oligomerization) and how they affect their mechanism (peptide-binding assays) of anti-biofilm activity. PMID- 28013515 TI - Protocols for Studying Inhibition and Eradication of Bacterial Biofilms by Antimicrobial Peptides. AB - Many pathogenic microorganisms have the ability to form biofilms that are impervious to conventional antibiotics making these pathogens resistant to multiple antibiotics. This necessitates the development of novel antimicrobial compounds with less chance of resistance development and the ability to penetrate the extracellular polymer matrix of bacterial biofilms. In this report, simple assays to test the antibiofilm potential of antimicrobial peptides are described. PMID- 28013516 TI - Protocols for Studying Antimicrobial Peptides (AMPs) as Anticancer Agents. AB - Antimicrobial peptides (AMPs) are a class of small cationic peptides that are important for host defense. In a manner that is similar to AMP-mediated destruction of microbial pathogens, certain AMPs can physically associate with the anionic lipid membrane components of cancer cells, resulting in destabilization of the lipid membrane and subsequent peptide binding to intracellular targets, which ultimately leads to the death of the cancer cell. In comparison, normal healthy cells possess a neutral membrane charge and are therefore less affected by AMPs. Based on the selective cytotoxicity of certain AMPs for cancer cells, these peptides represent a potential reservoir of novel anticancer therapeutic agents. The development and improvement of AMPs as anticancer agents requires appropriate methods for determining the effects of these peptides on the viability and function of cancer cells. In this chapter, we describe methods to assess the ability of AMPs to cause cell membrane damage (measured by propidium iodide uptake), apoptosis and/or necrosis (measured by annexin V-FLUOS/propidium iodide staining), and mitochondrial membrane destabilization (measured by 3,3'-dihexyloxacarbocyanine iodide staining), as well as reduced motility (measured by a migration and invasion assay) of cancer cells growing in suspension or as monolayers. We also describe a tubule-forming assay that can be used to assess the effect of AMPs on angiogenesis. PMID- 28013517 TI - Using Oral and Colon Cancer Cells for Studying the Anticancer Properties of Antimicrobial Peptides. AB - Antimicrobial peptides (AMPs) are of importance in defense mechanism of many organisms and are potential candidate for treatment of infections in animals and humans. AMPs exhibit a wide range of immunomodulatory activities related to innate immunity, wound healing, and inflammation. AMPs also serve as drug delivery vectors, antitumor agents, and mitogenic agents. Here, we describe the investigation of anticancer and cytotoxic activities of antimicrobial peptides by colorimetric MTT assay using smooth muscle, dental pulp stem cell, human colon cancer cell line (SW620), and human oral squamous carcinoma cell line (HSC4). PMID- 28013518 TI - Using Disease-Associated Enzymes to Activate Antimicrobial Peptide Prodrugs. AB - Prodrugs of antimicrobial peptides can be generated by modifying their sequences at their N-termini with a linker and a negatively charged promoiety. These modifications can be selectively reversed by a disease-associated enzyme, thereby confining the activity of the peptide to pathologically affected body parts. A general method for the generation of prodrug candidates, based on a linker constituting the substrate of a disease-associated protease and an oligo-glutamic acid promoiety, as well as a protocol to validate the activation of the prodrug, are described herein. PMID- 28013519 TI - Anti-inflammatory Properties of Antimicrobial Peptides and Peptidomimetics: LPS and LTA Neutralization. AB - Lipopolysaccharide (LPS) and lipoteichoic acid (LTA) neutralization constitute potential non-antibiotic treatment strategies for sepsis - a systemic infection induced inflammatory response. Studies on LPS- and LTA-neutralizing compounds are abundant in literature, and a number of peptides and peptidomimetics appear to display promising activity. However, in this ongoing search for potential antisepsis drug leads, it will be preferable that the assays used by different research groups lead to readily comparable data for the most efficient compounds. Here, we propose and describe standardized methods to be used for testing of novel compounds for their LPS- and LTA-neutralizing capacity with a focus on functional suppression of pro-inflammatory responses in cell-based systems. To best mimic the human in vivo conditions, we suggest the use of freshly isolated human leukocytes combined with an appropriate method for the chosen cytokine (e.g., IL-6 or TNF-alpha). The described protocols comprise isolation, stimulation, and viability test of the human leukocytes. PMID- 28013520 TI - Protocols for Screening Antimicrobial Peptides That Influence Virulence Gene Expression in Staphylococcus aureus. AB - Compounds that inhibit virulence gene expression in bacterial pathogens have received increasing interest as possible alternatives to the traditional antibiotic treatment of infections. For the human pathogen Staphylococcus aureus, we have developed two simple assays based on reporter gene fusions to central virulence genes that are easily applicable for screening various sources of natural and synthetic peptides for anti-virulence effects. The plate assay is qualitative but simultaneously assesses the effect of gradient concentrations of the investigated compound, whereas the liquid assay is quantitative and can be employed to address whether a compound is acting on the central quorum sensing regulatory system, agr, that controls a large number of virulence genes in S. aureus. PMID- 28013521 TI - Methods for In Vitro Analysis of Antimicrobial Activity and Toxicity of Anti keratitis Peptides: Bacterial Viability in Tears, MTT, and TNF-alpha Release Assays. AB - Ease of access to the cornea makes antimicrobial peptides (AMPs) ideal candidates for topical drug application. However, before bringing them to the clinic, it is fundamental to evaluate in vitro: (1) the ability of AMPs to kill bacteria in the presence of human tears, by counting the number of surviving bacteria on agar plates; (2) the potential cytotoxicity of AMPs to mammalian cells by a colorimetric method based on the production of a colored formazan crystals by metabolically active cells; and (3) the ability of AMPs to neutralize the toxic effect of the bacterial cell wall component, lipopolysaccharide (LPS), by measuring the level of the pro-inflammatory cytokine, TNF-alpha, released from LPS-activated macrophages, using a sandwich enzyme-linked immunosorbent assay. PMID- 28013522 TI - Methods for In Vivo/Ex Vivo Analysis of Antimicrobial Peptides in Bacterial Keratitis: siRNA Knockdown, Colony Counts, Myeloperoxidase, Immunostaining, and RT-PCR Assays. AB - Antimicrobial peptides (AMPs) are essential components of the innate immune response. They have direct killing ability as well as immunomodulatory functions. Here, we describe techniques to identify specific AMPs involved in the protection against microbial keratitis, a vision threatening infection of the cornea of the eye which is the most serious complication of contact lens wear. Specifically we detail the use of siRNA technology to temporarily knockdown AMP expression at the murine ocular surface in vivo and then describe ex vivo assays to determine the level of bacteria, relative number of neutrophils, and levels of cytokines, chemokines, and AMPs in infected corneas. PMID- 28013523 TI - Hemolytic Activity of Antimicrobial Peptides. AB - For antimicrobial peptides to be interesting for systemic applications, they must show low toxicity against erythrocytes. In this chapter, we describe a protocol for measuring the ability of AMPs to lyse human red blood cells, using melittin as positive control. PMID- 28013524 TI - Evaluation of the InteRRliner automated erythrocyte sedimentation rate analyzer for a large academic laboratory. PMID- 28013525 TI - Interaction of primary human trabecular meshwork cells with metal alloy candidates for microinvasive glaucoma surgery. AB - BACKGROUND: Microinvasive glaucoma surgery (MIGS) is a relatively new addition to the glaucoma treatment paradigm. Small metallic stents are inserted into the trabecular meshwork in order to increase aqueous humour drainage. MIGS procedures are rapidly being adopted owing to a more favourable side effect profile when compared with traditional surgery. Remarkably, this rapid rate of utilization has occurred without any published studies on the effect of metal alloys used in these stents on human trabecular meshwork cells (HTMCs). Therefore, this study aimed to determine the effect of candidate metal alloys for MIGS on HTMC morphology, viability and function. METHODS: Human trabecular meshwork cells were cultured on the surfaces of titanium (polished and sandblasted), a titanium nickel (nitinol) alloy and glass (as control substratum). Fluorescence imaging was used to assess cell morphology and spreading. A lactate dehydrogenase cytotoxicity assay, cell death detection ELISA, MTT cell viability assay, BrdU cell proliferation assay and fibronectin ELISA were also conducted. RESULTS: Cells cultured on sandblasted titanium exhibited significantly greater spreading than cells cultured on other substrata. In comparison, HTMCs cultured on nitinol displayed poor spreading. Significantly more cell death, by both necrosis and apoptosis, occurred on nitinol than on titanium and glass. Also, cell viability and proliferation were suppressed on nitinol compared with titanium or glass. Finally, HTMCs on both titanium and nitinol produced greater amounts of fibronectin than cells grown on glass. CONCLUSIONS: Substratum topography and metal alloy composition were found to impact morphology, viability and function of primary HTMC cultures. PMID- 28013526 TI - Myeloperoxidase in blood neutrophils during normal and abnormal menstrual cycles in women of reproductive age. AB - INTRODUCTION: We previously reported that granulocyte colony-stimulating factor (G-CSF) plays a critical role in ovulation, suggesting that neutrophils may maintain ovulation. We assessed myeloperoxidase (MPO), a major and specific enzyme of neutrophils, in women with abnormal and normal menstrual cycles to clarify the relationship between MPO and ovulation. METHODS: We analyzed MPO activity in blood neutrophils of women with abnormal menstrual cycles (indicative of anovulation, n = 12) and age- and body mass index-matched normal menstrual cycles (indicative of ovulation, n = 24) using two parameters as a marker of MPO, Neut X and mean peroxidase index (MPXI). RESULTS: MPO of women with abnormal menstrual cycles was significantly lower than that of women with normal menstrual cycles [Neut X: 62.6 +/- 1.1 (mean +/- standard error of the mean) vs. 66.2 +/- 0.3, P = 0.009; MPXI: -0.54 +/- 1.66 vs. 4.91 +/- 0.53, P = 0.008]. Among women with normal menstrual cycles, MPO was highest in the follicular phase (Neut X: 67.0 +/- 0.3; P = 0.033). CONCLUSION: The difference in MPO between women with abnormal and normal menstrual cycles and the upregulation of MPO before ovulation suggest that neutrophils and MPO are closely related to ovulation. PMID- 28013527 TI - Japanese Society for Laboratory Hematology flow cytometric reference method of determining the differential leukocyte count: external quality assurance using fresh blood samples. AB - INTRODUCTION: To provide target values for the manufacturers' survey of the Japanese Society for Laboratory Hematology (JSLH), accurate standard data from healthy volunteers were needed for the five-part differential leukocyte count. To obtain such data, JSLH required an antibody panel that achieved high specificity (particularly for mononuclear cells) using simple gating procedures. We developed a flow cytometric method for determining the differential leukocyte count (JSLH Diff) and validated it by comparison with the flow cytometric differential leukocyte count of the International Council for Standardization in Haematology (ICSH-Diff) and the manual differential count obtained by microscopy (Manual Diff). METHODS: First, the reference laboratory performed an imprecision study of JSLH-Diff and ICSH-Diff, as well as performing comparison among JSLH-Diff, Manual Diff, and ICSH-Diff. Then two reference laboratories and seven participating laboratories performed imprecision and accuracy studies of JSLH-Diff, Manual Diff, and ICSH-Diff. Simultaneously, six manufacturers' laboratories provided their own representative values by using automated hematology analyzers. RESULTS: The precision of both JSLH-Diff and ICSH-Diff methods was adequate. Comparison by the reference laboratory showed that all correlation coefficients, slopes and intercepts obtained by the JSLH-Diff, ICSH-Diff, and Manual-Diff methods conformed to the criteria. When the imprecision and accuracy of JSLH-Diff were assessed at seven laboratories, the CV% for lymphocytes, neutrophils, monocytes, eosinophils, and basophils was 0.5~0.9%, 0.3~0.7%, 1.7~2.6%, 3.0~7.9%, and 3.8~10.4%, respectively. More than 99% of CD45 positive leukocytes were identified as normal leukocytes by JSLH-Diff. CONCLUSIONS: When JSLH-Diff method were validated by comparison with Manual-Diff and ICSH-Diff, JSLH-Diff showed good performance as a reference method. PMID- 28013529 TI - Synchronous T lymphoblastic lymphoma and myeloid neoplasm with PDGFRA rearrangement. PMID- 28013528 TI - Pathogens and antibiotic sensitivities in endophthalmitis. AB - BACKGROUND: Antibiotic prophylaxis in cataract surgery is intended to minimize endophthalmitis. We describe pathogenic organisms, antibiotic sensitivities and antibiotic prophylaxis in culture-proven endophthalmitis cases. DESIGN: Retrospective consecutive case series and community-based setting were used. PARTICIPANTS: Two hundred fifteen cases of endophthalmitis after cataract surgery performed during 2007-2012 in Kaiser Permanente, California. METHODS AND MAIN OUTCOME MEASURES: Descriptive analysis of isolated organisms and antibiotic sensitivities in relation to antibiotic prophylaxis in culture-proven endophthalmitis cases. RESULTS: The majority of culture-confirmed organisms (n = 83) were Gram positive (96%), most notably coagulase-negative Staphylococci (n = 34, 52%), of which all that underwent testing were sensitive to vancomycin (n = 32). Among 19 cases that had received only topical antibiotic prophylaxis, seven (37%) were resistant to the antibiotic given: 50% of cases (5 of 10 isolates) that had received ofloxacin were resistant to this antibiotic, 40% (2 of 5 isolates) that had received gatifloxacin were resistant. In contrast, 100% of cases (n = 4) that had received aminoglycosides were susceptible. Few culture confirmed cases occurred in patients who received intracameral antibiotic (n = 4). CONCLUSIONS: In cases where fluoroquinolones were administered as antibiotic prophylaxis, isolates demonstrated a degree of bacterial resistance. The majority of endophthalmitis cases isolated occured following topical antibiotic prophylaxis only and were attributed to Gram-positive organisms, while few occurred in association with intracameral antibiotic. PMID- 28013530 TI - Molecular genetic analysis of ten unrelated Iranian patients with congenital factor XIII deficiency. PMID- 28013531 TI - Prognosis of Hepatocellular Carcinoma after Liver Transplantation: Comparative Analysis with Partial Hepatectomy. AB - BACKGROUND: Liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). The aim of this study was to investigate the recurrence rate of HCC after LT and prognostic factors for recurrence by comparing LT with non-transplanted resection. METHODS: The participants were 338 patients who underwent LT between 1996 and 2012 at Seoul National University Hospital (LT group) and 520 HCC patients who underwent partial hepatectomy between 1995 and 2006 (control group, non-LT group). RESULTS: In the LT group, 68 of 338 patients (19.8%) showed relapse, and the recurrence rate was lower than that in the non-LT group (64.9%, 357/520, p < .001). Stratification analysis by American Joint Committee on Cancer (AJCC) stage showed that the stage I-II LT group had a lower recurrence rate than the non-LT group. Univariate comparative analysis demonstrated that multiplicity of tumor, tumor size, gross type, Edmondson- Steiner (ES) nuclear grade, extent of tumor, angioinvasion, AJCC stage, Milan criteria, University of California at San Francisco criteria on explant pathology (all p < .001), positive expression of cytokeratin 19 (p = .002), and preoperative alpha-fetoprotein (AFP) (p < .001) were predictors of tumor recurrence. In multivariate analysis, LT, preoperative AFP, multiplicity of tumor, extent of tumor, size of tumor, and ES nuclear grade were independent prognostic factors. CONCLUSIONS: LT might have a protective effect against the late recurrence of stage I-II HCC compared to non-LT, and the prognostic factors for recurrence were similar to previously well-known prognostic factors for HCC. PMID- 28013532 TI - Aurora Kinase A Is a Prognostic Marker in Colorectal Adenocarcinoma. AB - BACKGROUND: Aurora kinase A (AURKA), or STK15/BTAK, is a member of the serine/threonine kinase family and plays important roles in mitosis and chromosome stability. This study investigated the clinical significance of AURKA expression in colorectal cancer patients in Korea. METHODS: AURKA protein expression was evaluated by immunohistochemistry in 151 patients with colorectal adenocarcinoma using tissue microarray blocks. We analyzed the relationship between clinicopathological characteristics and AURKA expression. In addition, the prognostic significance of various clinicopathological data for progression free survival (PFS) was assessed. Also we evaluated copy number variations by array comparative genomic hybridization and AURKA gene amplification using fluorescence in situ hybridization in colorectal carcinoma tissues. RESULTS: AURKA gene amplification was found more frequently in the 20q13.2-13.33 gain positive group than the group with no significant gain on the AURKA-containing locus. AURKA protein expression was detected in 45% of the cases (68/151). Positive staining for AURKA was observed more often in male patients (p = .035) and distally located tumors (p = .021). PFS was shorter in patients with AURKA expression compared to those with low-level AURKA expression (p < .001). Univariate analysis revealed that AURKA expression (p = .001), age (p = .034), lymphatic invasion (p = .001), perineural invasion (p = .002), and TNM stage (p = .013) significantly affected PFS. In a multivariate analysis of PFS, a Cox proportional hazard model confirmed that AURKA expression was an independent and significant prognostic factor in colorectal adenocarcinoma (hazard ratio, 3.944; p < .001). CONCLUSIONS: AURKA could serve as an independent factor to predict a poor prognosis in Korean colorectal adenocarcinoma patients. PMID- 28013533 TI - Evaluation of Pathologic Complete Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: Experience in a Single Institution over a 10-Year Period. AB - BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) has been associated with favorable clinical outcome in breast cancer patients. However, the possibility that the prognostic significance of pCR differs among various definitions has not been established. METHODS: We retrospectively evaluated the pathologic response after NAC in 353 breast cancer patients and compared the prognoses after applying the following different definitions of pCR: ypT0/is, ypT0, ypT0/is ypN0, and ypT0 ypN0. RESULTS: pCR was significantly associated with improved distant disease-free survival (DDFS) regardless of the definition (ypT0/is, p = .002; ypT0, p = .008; ypT0/is ypN0, p < .001; ypT0 ypN0, p = .003). Presence of tumor deposits of any size in the lymph nodes (LNs; ypN >= 0(i+)) was associated with worse DDFS (ypT0 ypN0 vs ypT0 ypN >= 0(i+), p = .036 and ypT0/is ypN0 vs ypT0/is ypN >= 0(i+), p = .015), and presence of isolated tumor cells was associated with decreased overall survival (OS; ypT0/is ypN0 vs ypT0/is ypN0(i+), p = .013). Residual ductal carcinoma in situ regardless of LN status showed no significant difference in DDFS or OS (DDFS: ypT0 vs ypTis, p = .373 and ypT0 ypN0 vs ypTis ypN0, p = .462; OS: ypT0 vs ypTis, p = .441 and ypT0 ypN0 vs ypTis ypN0, p = .758). In subsequent analysis using ypT0/is ypN0, pCR was associated with improved DDFS and OS in triple negative tumors (p < .001 and p = .003, respectively). CONCLUSIONS: Based on our study results, the prognosis and rate of pCR differ according to the definition of pCR and ypT0/is ypN0 might be considered a more preferable definition of pCR. PMID- 28013534 TI - KRAS Mutation Test in Korean Patients with Colorectal Carcinomas: A Methodological Comparison between Sanger Sequencing and a Real-Time PCR-Based Assay. AB - BACKGROUND: Mutations in the KRAS gene have been identified in approximately 50% of colorectal cancers (CRCs). KRAS mutations are well established biomarkers in anti-epidermal growth factor receptor therapy. Therefore, assessment of KRAS mutations is needed in CRC patients to ensure appropriate treatment. METHODS: We compared the analytical performance of the cobas test to Sanger sequencing in 264 CRC cases. In addition, discordant specimens were evaluated by 454 pyrosequencing. RESULTS: KRAS mutations for codons 12/13 were detected in 43.2% of cases (114/264) by Sanger sequencing. Of 257 evaluable specimens for comparison, KRAS mutations were detected in 112 cases (43.6%) by Sanger sequencing and 118 cases (45.9%) by the cobas test. Concordance between the cobas test and Sanger sequencing for each lot was 93.8% positive percent agreement (PPA) and 91.0% negative percent agreement (NPA) for codons 12/13. Results from the cobas test and Sanger sequencing were discordant for 20 cases (7.8%). Twenty discrepant cases were subsequently subjected to 454 pyrosequencing. After comprehensive analysis of the results from combined Sanger sequencing-454 pyrosequencing and the cobas test, PPA was 97.5% and NPA was 100%. CONCLUSIONS: The cobas test is an accurate and sensitive test for detecting KRAS-activating mutations and has analytical power equivalent to Sanger sequencing. Prescreening using the cobas test with subsequent application of Sanger sequencing is the best strategy for routine detection of KRAS mutations in CRC. PMID- 28013535 TI - Human Herpes Virus 8/Epstein-Barr Virus-Copositive, Plasmablastic Microlymphoma Arising in Multicentric Castleman's Disease of an Immunocompetent Patient. PMID- 28013536 TI - Clinical, Histopathological and Molecular Characteristics of Metastatic Breast Cancer in North-Eastern Kazakhstan: a 10 Year Retrospective Study AB - Background: Breast cancer (BC) is the top cancer among women worldwide and has been the most frequentmalignancy among Kazakhstan women over the past few decades. Information on clinical and histopathologicalfeatures of metastatic breast cancer (MBC), as well as the distribution of molecular subtypes is limited for Kazakhpeople. Materials and Methods: The present observational retrospective study was carried out at Regional OncologicDispensaries in the North-East Region of Kazakhstan (in Semey and Pavlodar cities). Slinical and histopathologicaldata were obtained for a total of 570 MBC patients in the 10 year period from 2004 2013, for whom data on molecularsubtype were available for 253. Data from hospital charts were entered into SPSS 20 for analysis by one-way ANOVAanalysis of associations of different variables with 1-5 year survival. Pearson correlation and linear regression modelswere used to examine the relation between parameters with a p-value < 0.05 considered statistically significant. Results:No significant relationships were evident between molecular subtype and survival, site of metastases, stage or ethnicity.Young females below the age of 44 were slightly more likely to have triple negative lesions. While the ductal typegreatly predomonated, luminal A and B cases had a higher percentage with lobular morphology. Conclusions: In thisselect group of metastatice brease cancer, no links were noted for survival with molecular subtype, in contrast to muchof the literature. PMID- 28013537 TI - Methylmercury Mass Budgets and Distribution Characteristics in the Western Pacific Ocean. AB - Methylmercury (MeHg) accumulation in marine organisms poses serious ecosystem and human health risk, yet the sources of MeHg in the surface and subsurface ocean remain uncertain. Here, we report the first MeHg mass budgets for the Western Pacific Ocean estimated based on cruise observations. We found the major net source of MeHg in surface water to be vertical diffusion from the subsurface layer (1.8-12 nmol m-2 yr-1). A higher upward diffusion in the North Pacific (12 nmol m-2 yr-1) than in the Equatorial Pacific (1.8-5.7 nmol m-2 yr-1) caused elevated surface MeHg concentrations observed in the North Pacific. We furthermore found that the slope of the linear regression line for MeHg versus apparent oxygen utilization in the Equatorial Pacific was about 2-fold higher than that in the North Pacific. We suggest this could be explained by redistribution of surface water in the tropical convergence-divergence zone, supporting active organic carbon decomposition in the Equatorial Pacific Ocean. On the basis of this study, we predict oceanic regions with high organic carbon remineralization to have enhanced MeHg concentrations in both surface and subsurface waters. PMID- 28013538 TI - Sb@Ni12@Sb20-/+ and Sb@Pd12@Sb20n Cluster Anions, Where n = +1, -1, -3, -4: Multi Oxidation-State Clusters of Interpenetrating Platonic Solids. AB - K5Sb4 and K3Sb7 Zintl ion precursors react with Pd(PPh3)4 in ethylenediamine/toluene/PBu4+ solutions to give crystals of Sb@Pd12@Sb20n-/PBu4+ salts, where n = 3, 4. The clusters are structurally identical in the two charge states, with nearly perfect Ih point symmetry, and can be viewed as an Sb@Pd12 icosahedron centered inside of an Sb20 dodecahedron. The metric parameters suggest very weak Sb-Sb and Pd-Pd interactions with strong radial Sb-Pd bonds between the Sb20 and Pd12 shells. All-electron DFT analysis shows the 3- ion to be diamagnetic with Ih symmetry and a 1.33 eV HOMO-LUMO gap, whereas the 4- ion undergoes a Jahn-Teller distortion to an S = 1/2 D3d structure with a small 0.1 eV gap. The distortion is predicted to be small and is not discernible by crystallography. Laser desorption-ionization time-of-flight mass spectrometry (LDI-TOF MS) studies of the crystalline samples show intense parent Sb@Pd12@Sb20- ions (negative ion mode) and Sb@Pd12@Sb20+ (positive ion mode) along with series of Sb@Pd12-y@Sb20-x-/+ ions. Ni(cyclooctadiene)2 reacts with K3Sb7 in en/tol/Bu4PBr solvent mixtures to give black precipitates of Sb@Ni12@Sb20n- salts that give similar Sb@Ni12@Sb20-/+ parent ions and Sb@Ni12-y@Sb20-x-/+ degradation series in the respective LDI-TOF MS studies. The solid-state and gas-phase studies of the icosahedral Sb@M12@Sb20n-/n+ ions show that the clusters can exist in the -4, -3, -1, +1 (M = Pd) and +1, -1 (M = Ni) oxidation states. These multiple-charge-state clusters are reminiscent of redox-active fullerenes (e.g., C60n, where n = +1, 0, -1, -2, -3, -4, -5, -6). PMID- 28013539 TI - Time-Resolved IR Spectroscopy Reveals a Mechanism with TiO2 as a Reversible Electron Acceptor in a TiO2-Re Catalyst System for CO2 Photoreduction. AB - Attaching the phosphonated molecular catalyst [ReIBr(bpy)(CO)3]0 to the wide bandgap semiconductor TiO2 strongly enhances the rate of visible-light-driven reduction of CO2 to CO in dimethylformamide with triethanolamine (TEOA) as sacrificial electron donor. Herein, we show by transient mid-IR spectroscopy that the mechanism of catalyst photoreduction is initiated by ultrafast electron injection into TiO2, followed by rapid (ps-ns) and sequential two-electron oxidation of TEOA that is coordinated to the Re center. The injected electrons can be stored in the conduction band of TiO2 on an ms-s time scale, and we propose that they lead to further reduction of the Re catalyst and completion of the catalytic cycle. Thus, the excited Re catalyst gives away one electron and would eventually get three electrons back. The function of an electron reservoir would represent a role for TiO2 in photocatalytic CO2 reduction that has previously not been considered. We propose that the increase in photocatalytic activity upon heterogenization of the catalyst to TiO2 is due to the slow charge recombination and the high oxidative power of the ReII species after electron injection as compared to the excited MLCT state of the unbound Re catalyst or when immobilized on ZrO2, which results in a more efficient reaction with TEOA. PMID- 28013541 TI - Electron-Transfer Rates in Host-Guest Assemblies at beta-Cyclodextrin Monolayers. AB - The effect of the distance between a beta-cyclodextrin (betaCD) host core and a conductive substrate on the electron-transfer rate of complexed guests as well as of free-diffusing electrochemically active probes has been studied. First we have evaluated a set of short-tethered betaCD adsorbates bearing different anchoring groups in order to get a reliable platform for the study of short-distance electron transfer. An electrochemically active trivalent guest was immobilized on these host monolayers in a selective and reversible manner, providing information about the packing density. Iodine- and nitrile-functionalized betaCD monolayers gave coverages close to maximum packing. Electron transfer in the presence of Fe(CN)63-/4- studied by impedance spectroscopy revealed that the electron transfer of the diffusing probe was 3 orders of magnitude faster than when the betaCD cores were separated from the surface by undecyl chains. When an electrochemically active guest was immobilized on the surface, electron-transfer rate measurements by cyclic voltammetry and capacitance spectroscopy showed differences of up to a factor of 8 for different betaCD monolayers. These results suggest that increasing the distance between the betaCD core and the underlying conductive substrate leads to a diminishing of the electron-transfer rate. PMID- 28013540 TI - Interactions of Cationic/Anionic Mixed Surfactant Aggregates with Phospholipid Vesicles and Their Skin Penetration Ability. AB - This work studied the interactions of an oppositely charged surfactant mixture of oleyl bis(2-hydroxyethyl)methyl ammonium bromide (OHAB) and sodium dodecyl sulfate (SDS) with 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine (DOPC) vesicles as well as the penetration of the OHAB/SDS mixture through model skin, aimed at understanding the relationship between the ability of different surfactant aggregates in solubilizing phospholipid vesicles and their potential in irritating skin. By changing the molar fraction of OHAB (XOHAB), five kinds of aggregates are constructed: OHAB and SDS separately form cationic and anionic small micelles, whereas the OHAB/SDS mixtures form cationic and anionic vesicles at XOHAB = 0.30 and 0.70, respectively, and weakly charged vesicles at XOHAB = 0.50. The mixtures have much lower critical micellar concentrations (CMCs) and much larger aggregates than either OHAB or SDS alone, and the CMC and the size of the OHAB/SDS vesicles decrease with the increase in XOHAB. The phase diagrams indicate that the OHAB/SDS mixtures show much stronger ability in solubilizing the DOPC vesicles than individual OHAB and SDS and decrease in the order of XOHAB = 0.30 > 0.50 > 0.70 ? 1.00 > 0. However, the ability of the surfactants in penetrating the model skin decreases reversely, and the penetration of the surfactants are significantly reduced by mixing. These results indicate that the surfactant mixture with a larger aggregate size and a smaller CMC value displays much stronger ability in solubilizing the DOPC vesicles but much weaker ability in penetrating the skin. PMID- 28013542 TI - Vertebrate Bitter Taste Receptors: Keys for Survival in Changing Environments. AB - Research on bitter taste receptors has made enormous progress during recent years. Although in the early period after the discovery of this highly interesting receptor family special emphasis was placed on the deorphanization of mainly human bitter taste receptors, the research focus has shifted to sophisticated structure-function analyses, the discovery of small-molecule interactors, and the pharmacological profiling of nonhuman bitter taste receptors. These findings allowed novel perspectives on, for example, evolutionary and ecological questions that have arisen and that are discussed. PMID- 28013543 TI - Metal-free Cross-Dehydrogenative Coupling of HN-azoles with alpha-C(sp3)-H Amides via C-H Activation and Its Mechanistic and Application Studies. AB - A metal-free one step coupling reaction between various N-azole rings and diverse alpha-C(sp3)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1H benzotriazoles, 1H-1,2,3-triazoles, 1H-1,2,4-triazoles, 1H-tetrazoles, 1H pyrazoles, and 1H-benzimidazoles, and alpha-C(sp3)-H containing amides, such as N,N-dimethylacetamide, N,N-dimethylbenzamide, N-methylacetamide, N,N diethylacetamide, N-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized N-azoles via direct covalent N-H bond transformations onto N-C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of alpha-C(sp3)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives. PMID- 28013544 TI - Sensitive Flow-through Immunoassay for Rapid Multiplex Determination of Cereal borne Mycotoxins in Feed and Feed Ingredients. AB - An easy-to-operate membrane-based flow-through test for multiplex screening of four mycotoxins (zearalenone, deoxynivalenol, aflatoxin B1, and ochratoxin A) in a variety of cereal-based feed ingredients and compound feeds, such as wheat, barley, soybean, wheat bran, rice, rice bran, maize, rapeseed meal, and sunflower meal, and various types of complete feed (duckling feed, swine feed, broiler feed, piglet feed) was developed and validated. First, the antibodies were evaluated by enzyme-linked immunosorbent assay and then employed in the membrane rapid test. The cutoff levels for zearalenone, deoxynivalenol, aflatoxin B1, and ochratoxin A were 50, 200, 1, and 10 MUg/kg, respectively, based on European regulations and consumers' requirements. As sample pretreatment, consecutive steps of extraction, dilution, solid-phase extraction by addition of C18 sorbent, and final filtration of supernatant were followed. Both the sample preparation and the analysis procedure were simple, cost-effective, and easy to perform on site in a nonlaboratory environment. The impact of sample processing on the result of the experiment was investigated supported by experimental design. The validation procedure was performed on the basis of Commission Regulation 2006/401/EC. The numbers of false-positive and false-negative outcomes were <5%, going along with the Commission Decision 2002/657/EC. Liquid chromatography tandem mass spectrometry was performed as a confirmatory technique. PMID- 28013545 TI - Room Temperature Magnetically Ordered Polar Corundum GaFeO3 Displaying Magnetoelectric Coupling. AB - The polar corundum structure type offers a route to new room temperature multiferroic materials, as the partial LiNbO3-type cation ordering that breaks inversion symmetry may be combined with long-range magnetic ordering of high spin d5 cations above room temperature in the AFeO3 system. We report the synthesis of a polar corundum GaFeO3 by a high-pressure, high-temperature route and demonstrate that its polarity arises from partial LiNbO3-type cation ordering by complementary use of neutron, X-ray, and electron diffraction methods. In situ neutron diffraction shows that the polar corundum forms directly from AlFeO3-type GaFeO3 under the synthesis conditions. The A3+/Fe3+ cations are shown to be more ordered in polar corundum GaFeO3 than in isostructural ScFeO3. This is explained by DFT calculations which indicate that the extent of ordering is dependent on the configurational entropy available to each system at the very different synthesis temperatures required to form their corundum structures. Polar corundum GaFeO3 exhibits weak ferromagnetism at room temperature that arises from its Fe2O3-like magnetic ordering, which persists to a temperature of 408 K. We demonstrate that the polarity and magnetization are coupled in this system with a measured linear magnetoelectric coupling coefficient of 0.057 ps/m. Such coupling is a prerequisite for potential applications of polar corundum materials in multiferroic/magnetoelectric devices. PMID- 28013546 TI - Mixed-Metal Carbonate Fluorides as Deep-Ultraviolet Nonlinear Optical Materials. AB - Noncentrosymmetric mixed-metal carbonate fluorides are promising materials for deep-ultraviolet (DUV) nonlinear optical (NLO) applications. We report on the synthesis, characterization, structure-property relationships, and electronic structure calculations on two new DUV NLO materials: KMgCO3F and Cs9Mg6(CO3)8F5. Both materials are noncentrosymmetric (NCS). KMgCO3F crystallizes in the achiral and nonpolar NCS space group P62m, whereas Cs9Mg6(CO3)8F5 is found in the polar space group Pmn21. The compounds have three-dimensional structures built up from corner-shared magnesium oxyfluoride and magnesium oxide octahedra. KMgCO3F (Cs9Mg6(CO3)8F5) exhibits second-order harmonic generation (SHG) at both 1064 and 532 nm incident radiation with efficiencies of 120 (20) * alpha-SiO2 and 0.33 (0.10) * beta-BaB2O4, respectively. In addition, short absorption edges of <200 and 208 nm for KMgCO3F and Cs9Mg6(CO3)8F5, respectively, are observed. We compute the electron localization function and density of states of these two compounds using first-principles density functional theory, and show that the different NLO responses arise from differences in the denticity and alignment of the anionic carbonate units. Finally, an examination of the known SHG active AMCO3F (A = alkali metal, M = alkaline earth metal, Zn, Cd, or Pb) materials indicates that, on average, smaller A cations and larger M cations result in increased SHG efficiencies. PMID- 28013547 TI - New Insight into the Role of Sucrose in the Generation of alpha-Diketones upon Coffee Roasting. AB - The origin and formation pathways of the buttery-smelling alpha-diketones 2,3 butanedione and 2,3-pentanedione upon coffee roasting were studied by means of biomimetic in-bean experiments combined with labeling experiments. For this purpose natural sucrose in the coffee bean was replaced by fully or partially 13C labeled sucrose or by a mixture of unlabeled and fully 13C-labeled sucrose (CAMOLA approach). The obtained data point out that sucrose contributes to both alpha-diketones; however, its importance and reaction pathways clearly differ. Whereas the major part of 2,3-pentanedione originates from sucrose (about 76%), its contribution to 2,3-butanedione is much lower (about 35%). Formation from intact sugar skeleton is the major pathway generating 2,3-pentanedione from sucrose, whereas 2,3-butanedione is mainly generated by recombination of sucrose fragments. The contribution of glucose and fructose moieties of sucrose to both alpha-diketones is comparable. Finally, kinetic experiments with fully labeled sucrose showed that the contribution of sucrose changes during roasting. PMID- 28013548 TI - The relationship between attitudes toward suicide and willingness to pay for suicide prevention: a cross-sectional study in Japan. AB - There are gaps in our knowledge of the role attitudes toward suicide play in determining people's willingness to participate (WTP) for suicide prevention. We conducted a large nationwide cross-sectional study with the aim of clarifying the relationship between WTP for reducing suicide risk and attitudes toward suicide. Ordinal logistic regression analyses (n = 1771) showed that there were significant associations of WTP for suicide prevention with 'Suicide as a right' (beta = -.15, 95% CI: -.25 to -.04, p = .006), 'Preventability/readiness to help' (beta = .81, 95% CI: .69-.94, p < .001) and 'Common occurrence' (beta = .32, 95% CI: .19-.46, p < .001). 'Incomprehensibility/unpredictability' did not show an association with WTP. Taxpayer acceptance for suicide prevention is more likely to be achieved through provision of information that increases endorsement of 'preventability/readiness to help' and 'common occurrence' factors, and decreases 'suicide as a right' scores. PMID- 28013550 TI - C-Reactive Protein Is the Origin for Novel Biomarkers. PMID- 28013551 TI - Choice of Arterial Access for Coronary Angiography. PMID- 28013552 TI - Depression and sleep quality in older adults: a meta-analysis. AB - The literature emphasizes depression and poor sleep quality as problems that affect many elderly individuals. However, these problems have been related in few studies and there is no meta-analysis performed so far on this relationship. The present research reviewed the studies performed on the subjective sleep quality in order to understand how it relates to depression in older adults. The review was conducted in January 2016 and comprised publications between 2005 and 2015. Based on the electronic databases Web of Science and EBSCO, we used the keywords 'sleep quality', 'depression', and 'older' to identify the empirical studies performed. After assessing the collected studies, we selected those that presented the elderly as participants, resulting in nine papers (N = 3069). A random-effects method was used to evaluate the relationship between depression and sleep. We found that an older person's lack of good sleep quality is significantly related with depression. The main limitation of this study was the difficulty in collecting a greater number of studies. Future research should consider the importance of additional variables (e.g. moderators) in order to understand and investigate viable interventions for prevention and health promotion in the elderly. PMID- 28013553 TI - In vitro anti-MRSA activity of Couroupita guianensis extract and its component Tryptanthrin. AB - Couroupita guianensis is known in Brazil as 'Abrico-de-Macaco' and it has some attributes such as: antihypertensive, analgesic and anti-inflammatory activities. This study evaluated the antimicrobial activity of ethanolic extract and fractions of C. guianensis flowers and isolation of bioactive component. These extracts and fractions were subjected to agar diffusion, MIC, TLC and bioautography to bacteria, filamentous fungi and yeasts. Among the fractions of EtOH extract, the DCM fraction was the most active, particularly against Methicillin-resistant Staphylococcus aureus (MRSA) with MIC of 156 MUg/mL. The active compound in this fraction was identified as Tryptanthrin, which showed promising antibacterial activity for MRSA showing MIC of 62.5 MUg/mL. Ultrastructural analysis of MRSA incubated in the presence of Tryptanthrin by transmission electron microscope showed significant alterations in the cellular structure. Cytotoxicity tests demonstrated that DCM fraction and Tryptanthrin showed low toxicity, which makes it a promising candidate for alternative therapies to control and combat diseases. PMID- 28013554 TI - The emerging roles of B cells as partners and targets in periodontitis. AB - Initial studies of periodontal disease suggested that T cell-mediated immunity against oral Gram-negative microorganisms is a key player in the pathogenesis of this inflammatory disease. Recent investigations, however, revealed that B cells are also engaged. Given their chief role in innate-like and adaptive immune responses, B cells could exert protective functions in periodontitis. However, the periodontal bacteria-specific antibody response is generally unable to halt disease progression in affected subjects, suggesting that the antibodies produced could exhibit low anti-bacterial blocking functions or opsonophagocytic potential, and/or unfavorable effects. Moreover, although microbial antigens are involved in the induction of the inflammatory responses in human adult periodontitis, endogenous antigens also may contribute to the chronicity of this common disease. Not only antibodies to self-antigens, such as collagen, are locally produced, but the autoreactivities observed in aggressive periodontitis are more severe and diverse than those observed in chronic periodontitis, suggesting that autoimmune reactivity could play a role in the tissue destruction of periodontal disease. Further support for a pathological role of B cells in periodontitis comes from the finding that B cell-deficient mice are protected from bacterial infection-induced alveolar bone loss. Studies in patients indicate that B cells and plasma cells, together with osteoclastogenic factors (RANKL and osteoprotegerin) and specific cytokines involved in their growth and differentiation (BAFF and APRIL) participate in the induction of the pathological bone loss in periodontitis. This novel insight suggests that selective targeting of B cells could represent a future therapeutic avenue for severe periodontal disease. PMID- 28013555 TI - Primary and secondary metabolites of an European edible mushroom and its nutraceutical value: Suillus bellinii (Inzenga) Kuntze. AB - In this work, we report the study on the composition in primary and secondary metabolites of the polar and less-polar fractions obtained from the fruiting bodies of Suillus bellinii (Inzenga) Kuntze collected from Central Italy. Thirteen compounds were identified through a series of classical chromatographic methods and through spectroscopic techniques (nuclear magnetic resonance (NMR) and mass spectrometry (MS)), namely suillin (1), ergosterol (2), glutamic acid (3), isoleucine (4), leucine (5), threonine (6), tyrosine (7), valine (8), D mannitol (9), sucrose (10), D-sorbitol (11), fumaric acid (12) and alanine (13). These results allowed us to make specific considerations about the possible applications of this mushroom, which vary from medicine, due to the high cytotoxic and antitumor properties of suillin (1), to nutritional values, due to the presence of essential nutrients as amino acids and pre-vitamin D2 (ergosterol), together with low-calories sweeteners, confirming the close association between the identified components and the health-promoting properties of this species. PMID- 28013556 TI - alpha-Glucosidase inhibitors and phytotoxins from Streptomyces xanthophaeus. AB - Twenty-four metabolites 1-24 were isolated from the fermentation broth of Streptomyces xanthophaeus. Their structures were elucidated on the basis of spectroscopic analysis and by comparison of their NMR data with literature data reported. Daidzein (1), genistein (2) and gliricidin (3) inhibited alpha glucosidase in vitro with IC50 values of 174.2, 36.1 and 47.4 MUM, respectively, more potent than the positive control, acarbose. Docking study revealed that the amino acid residue Thr 215 is the essential binding site for active ligands 2. In addition, the phytotoxic effects of all compounds were assayed on radish seedlings, five of which, 3, 8, 13, 15 and 18, inhibited the growth of radish (Raphanus sativus) seedlings with inhibitory rates of >60% at a concentration of 100 ppm, which was comparable or superior to the positive control glyphosate. This is the first report of the phytotoxicity of the compounds. PMID- 28013557 TI - Awareness, Comprehension, and Use of Newly-Mandated Nutrition Labels Among Mestiza and Indigenous Ecuadorian Women in the Central Andes Region of Ecuador. AB - BACKGROUND: In 2014, Ecuador became the first country in Latin America to adopt the nutritional traffic light labeling system as a public policy aimed at guiding informed food choices. OBJECTIVE: To describe the differences in comprehension and use of the new nutrition label in 2 different ethnic populations residing in a limited resource area of central Ecuador. METHODS: A total of 394 women (18-75 years, 54.8% indigenous and 45.2% mixed-race mestizas) were randomly selected in the Chimborazo Province and were requested by a questionnaire to provide information regarding their awareness and comprehension of the traffic light nutritional labeling system and personal use of the food label in food selection. RESULTS: Indigenous women had a high percentage who lacked any formal education (43.5%) and a greater proportion were not aware of the labeling system when compared with the mestizas (84.3% vs 46%; P = .001). In both groups, the main reason for not reading labels was lack of understanding of its meaning (50% indigenous vs 32.7% mestiza; P < .05). The reported use of the labeling system for food choices was low-on average, 32% of the mestizas and 5% of the indigenous women reported using nutrition label information to guide their purchase and consumption of packaged food items. CONCLUSION: The use of nutritional labeling is low in both mestiza and indigenous Ecuadorians, although higher among the mestizas. Among the indigenous women, mostly likely owing to less education, limited nutrition-related health knowledge, and higher risk for food insecurity, the utility of the new traffic light food label is limited. PMID- 28013558 TI - Reconciling technology and humanistic care: Lessons from the next generation of physicians. AB - PURPOSE: There is concern among physicians that the rising use of technology in medicine may have a negative impact on compassionate patient-centered care. This study explores medical student attitudes and ideas about technology in medicine in order to consider ways to achieve symbiosis between technology use and the delivery of humanistic, patient-centered care. METHODS: This qualitative study uses data from 138 essays written by medical students in the United States and Canada responding to the prompt "Using a real life experience, describe how technology played a role, either negatively or positively, in the delivery of humanistic patient care." Data were analyzed for themes about technology and the impact on humanistic patient care. RESULTS: Seven themes emerged from the medical students' essays: Patient Perspective; Life-Giving versus Life-Prolonging; Boundaries between Human and Technology; Distancing versus Presence; Adapting to Change; Tools to Enhance Care; and Definitions of Technology. CONCLUSION: Listening to medical students lends insight into ways to integrate technology into the healthcare environment, to ensure that physicians' ability to deliver compassionate care is enhanced, not hindered. Utilizing perceptions of the next generation of physicians, educational and developmental strategies are proposed to ensure the successful integration of technology with humanistic patient centered care. PMID- 28013559 TI - Key factors influencing the incidence of hemolysis: A critical appraisal of current evidence. AB - Hemolysis is a leading cause of pre-analytical laboratory errors. The identification of contributing factors is an important step towards the development of effective practices to reduce and prevent hemolysis. We performed a review of PUBMED, Embase, Medline and CINAHL to identify articles published between January 2000 and August 2016 that identified factors influencing in vitro hemolysis rates. The 40 studies included in this review provide excellent evidence that hemolysis rates are higher in Emergency Departments (EDs), for non antecubital draws, for specimens drawn using an intravenous catheter compared to venipuncture and for samples transported by pneumatic tube compared to by hand. There is also good evidence that hemolysis rates are higher when specimens are not collected by professional phlebotomists, larger volume specimen tubes are used, specimen tubes are filled less than halfway and tourniquet time is greater than one minute. The results of this review suggest that hospitals and clinical laboratories should consider deploying phlebotomists in EDs, drawing all blood through a venipuncture, using the antecubital region as the optimum blood collection site and transporting specimens by laboratory assistant/other personnel, or if this in not practical, ensuring that pneumatic transport systems are validated, maintained and monitored. Studies also recommend making hemolysis a hospital-wide issue and ensuring high-quality staff training and adherence to standard operating procedures to reduce hemolysis rates. Awareness of the factors that influence hemolysis rates, and adoption of strategies to mitigate these risk factors, is an important step towards creating quality practices to reduce hemolysis rates and improve the quality of patient care. PMID- 28013560 TI - Biomarkers for monitoring chemotherapy-induced cardiotoxicity. AB - Cardiotoxicity, including acute and late-onset cardiotoxicity, is a well-known adverse effect of many types of antitumor agents. Early identification of patients with cardiotoxicity is important to ensure prompt treatment and minimize toxic effects. The etiology of chemotherapy-induced cardiotoxicity is multifactorial. Traditional methods for assessment of chemotherapy-induced cardiotoxicity typically involve serial measurements of cardiac function via multi-modality imaging techniques. Typically, however, significant left ventricular dysfunction has already occurred when cardiotoxicity is detected by imaging techniques. Biomarkers, most importantly cardiac natriuretic peptides and troponins, are promising markers for identifying patients potentially at risk for clinical heart failure symptoms. This review summarizes the recent progress in clinical utilization of biomarkers for early diagnosis of acute cardiotoxicity and for prediction of late-onset cardiotoxicity. We also discuss the conflicting results of different studies and the association of results with study design. PMID- 28013561 TI - The effect of smoking on placental pendrin expression. AB - Pendrin is important for transport of iodine across the placenta. Thiocyanate coming from cigarette is a competitive inhibitor of iodine transport. We aimed to evaluate the pendrin immunostaining intensity in placentas of smoker and non smoker women. Placental tissues from 61 women, of which 28 were in smoking, and 33 were in non-smoking group were evaluated by immunohistochemical staining. Positive immunostaining was evaluated using a semiquantitative score: 0, negative; +, mild; ++, moderate; and +++, intense. Birth weight was significantly lower in the smoker group (p = 0.024). There was a negative correlation between birth weight and intensity of placental pendrin immunostaining in the smoker group (r = -0.44, p = 0.02). Placentas of the smoking women showed significantly higher immunostaining with pendrin than the control group (p = 0.006). Thiocyonate coming from cigarettes may competitively inhibit pendrin mediated iodine transport in the placenta and adversely affect foetal development by this mechanism. PMID- 28013562 TI - Deciphering acute coronary syndrome biomarkers: High-resolution proteomics in platelets, thrombi and microparticles. AB - Acute coronary syndromes (ACS) encompass unstable angina, non-ST segment elevation myocardial infarction, ST-segment elevation myocardial infarction and sudden cardiac death. They are commonly associated with the presence of vulnerable plaques in the coronary arteries and occur when a thrombus formed from a ruptured atheromatous plaque causes a prolonged occlusion of a coronary artery. The erosion of the vulnerable plaques results in the formation of luminal thrombi secondary to platelet activation and the release of thrombogenic elements within the atherosclerotic lesions. Proteomic approaches offer an unbiased platform for the comprehensive analysis of the whole proteome in a certain physiological time. Although mRNA expression is widely considered to be indicative of protein expression, protein levels are the result of protein synthesis and degradation, and RNA levels are not informative of protein degradation. In contrast, the proteomic technology investigates protein expression directly. This is particularly important in the context of atherosclerosis in which protein degradation is as decisive as protein synthesis. Moreover, proteomics reveals post-translational modifications known to be determinant for many human diseases. Clinically, there is increasing evidence for the role of proteomic technology in biomarker discovery that will provide novel information on the molecular events associated with ACS, and potentially lead to the identification of novel drug targets. In this review, we describe in detail the importance of proteomic approaches to identify new biomarkers associated with ACS from three perspectives: biomarkers associated with platelet metabolism; the study of proteomics of intravascular thrombi; and proteome analysis of membrane microparticles released from activated cells, mostly by platelets. PMID- 28013563 TI - PAX-5 Positivity in Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma: A Case Report and Review of Literature. AB - Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a subtype of T-cell lymphomas that may mimic several other malignancies morphologically. With the help of immunohistochemistry, most cases of ALCL can be diagnosed on the basis of expression of T-cell lineage associated antigens. However, aberrations in the expression of immunohistochemical markers pose diagnostic challenges. The morphological and immunophenotypic features of ALCL show considerable overlap with classical Hodgkin lymphoma (CHL), which is a B cell lymphoma. The 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues suggests that staining for the B-cell transcription factor, paired box 5 (PAX-5), is helpful in differentiating between them, as it is weakly positive in most CHL and should be negative in ALCL. We report a rare case of ALK-negative ALCL, which was positive for PAX-5 and CD15, mimicking CHL by immunohistochemistry, resulting in a diagnostic dilemma. PMID- 28013564 TI - Cathecol-O-methyltransferase inhibitors: another possibly useful pharmacological tool for treating Parkinson's disease in pregnancy? PMID- 28013565 TI - The current state of adverse event reporting in hemophilia. AB - INTRODUCTION: Replacement of the missing clotting factor is the mainstay of hemophilia treatment. Whilst historically many hemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor is the main adverse event of treatment. Areas covered: This paper provides an overview of the current national and international adverse event reporting systems, what these surveillance schemes taught us about side effects of the products presently in use, and elaborates on how to adapt these systems to the challenges we face with the changing treatment landscape. Expert commentary: Treatment of inherited bleeding disorders was accompanied by severe complications in the past, resulting in major morbidity and mortality. Current products are much safer, but still require monitoring via efficient safety surveillance systems. Adverse events are reported in national and international systems. With many new products entering the market, as well as non-factor replacement therapies, new safety issues may arise. It is important to identify potential adverse events early by making surveillance systems suitable to pick up unknown or unexpected effects, and to recognize and communicate patterns of adverse events rapidly. PMID- 28013566 TI - Two new coumarins from the bark of Streblus indicus (Bur.) Corner. AB - Two new coumarins 7-O-(6-O-(5-O-3,4,5-tri-methoxycinnamate-beta-d-apiofuranosyl beta-d-glucopyranosyl)-6-methoxy coumarin (1) and 7-O-(6-O-(4-(2-hydroxy-1 hydroxymethyl-ethoxy)-3-methoxy-cinnamyl)-beta-d-glucopyranosyl)-6-methoxy coumarin (2), along with 10 known metabolites, were isolated from the bark of Streblus indicus, their structures were identified by comparison of experimental and published spectroscopic data. (S)-marmesinin (6) and scoparone (7) exhibited moderate antimicrobial activity in vitro against Staphylococcus aureus strain with the MIC values of 62.5 and 125.0 MUg/mL, respectively. Betulinic acid showed inhibitory activity in vitro against MCF-7 cell with IC50 value of 9.5 +/- 0.1 MUM. PMID- 28013567 TI - Multinucleate giant cell angiohistiocytoma of the vaginal wall. PMID- 28013569 TI - Emergency Surgery. PMID- 28013568 TI - Evaluation of the sedative and hypnotic effects of astragalin isolated from Eucommia ulmoides leaves in mice. AB - The purpose of this study was to evaluate the effects of astragalin on the central nervous system. Astragalin is a monomeric compound found in the leaves of Eucommia ulmoides using a system solvent method. In the experiments, astragalin showed significant effects on mice, including reduced spontaneous activity, increased sleep ratio, shortened sleep latency and lengthened sleep time with a subthreshold or superthreshold dose of pentobarbital sodium. In addition, astragalin effectively reduced the convulsion rate and prolonged convulsion latency. These findings confirmed that astragalin had excellent sedative and hypnotic effects and has potential to be commercialised as a novel nutraceutical agent to promote calming and improve central nervous system-associated pathologies. PMID- 28013570 TI - Polymorphisms and expression of toll-like receptors in autoimmune thyroid diseases. AB - Graves' disease (GD) and Hashimoto's disease (HD) are autoimmune thyroid diseases (AITDs). Prognosis of AITDs varies in each patient. Toll-like receptors (TLRs) are pattern-recognition receptors that activate signaling pathways involved in the production of proinflammatory cytokines. UNC93B1 is a transcription factor of TLR7 and TLR9. In this study, we examined the association of TLR expression and TLR and UNC93B1 polymorphisms with the development and prognosis of AITDs. The ratio of intracellular TLR7 (iTLR7) and iTLR9 intensities in B cells was lower in patients with GD in remission than in patients with intractable GD (p = 0.0007). The frequency of G allele of TLR7 rs3853839 G/C polymorphism was significantly higher in male patients with GD and intractable GD than in control subjects (p = 0.0062 and 0.0173, respectively). The frequencies of T allele of TLR9 rs187084 C/T polymorphism and C allele of TLR9 rs352140 C/T polymorphism were significantly higher in patients with intractable GD who had GG genotype of TLR7 rs3853839 polymorphism, which is associated with higher TLR7 expression, than in patients with GD in remission (p = 0.0334 and 0.0023, respectively). The frequencies of AA genotype and A allele of UNC93B1 rs308328 polymorphism were significantly higher in patients with GD than in patients with HD (p = 0.0406 and 0.0316, respectively). These results suggested that the ratio of iTLR7 and iTLR9 intensities was associated with the development and intractability of GD and that TLR7 and UNC93B1 polymorphisms were associated with the development of GD. PMID- 28013571 TI - Short Montreal Cognitive Assessment. AB - The diagnostic accuracy of the short Montreal Cognitive Assessment (s-MoCA), a cognitive screening instrument recently derived by item response theory and computerized adaptive testing from the original MoCA, for the diagnosis of dementia and mild cognitive impairment (MCI) was assessed in 2 patient cohorts referred to a dedicated memory clinic in order to examine the validity and reproducibility of s-MoCA. Diagnosis used standard clinical diagnostic criteria for dementia and MCI as reference standard (prevalence of cognitive impairment = 0.43 and 0.46 in each cohort, respectively). There were significant differences in s-MoCA test scores for dementia, MCI, and subjective memory impairment ( P <= .01), and s-MoCA effect sizes (Cohen d) were medium to large (range: 0.65-1.42) for the diagnosis of dementia and MCI. Using the cut-off for s-MoCA specified in the index study, it proved highly sensitive (>0.9) for diagnosis of dementia but with poor specificity (<=0.25), with moderate sensitivity (>=0.75) and specificity (>=0.60) for diagnosis of MCI. In conclusion, in these pragmatic diagnostic test accuracy studies, s-MoCA proved acceptable and sensitive for the diagnosis of cognitive impairment in a memory clinic setting, with a performance similar to that of the original MoCA. PMID- 28013572 TI - Prescription Stimulant Misuse and ADHD Symptomatology Among College Students in Iceland. AB - OBJECTIVE: Misuse of prescription stimulant medication is a prevalent problem on American college campuses; however, few studies have been conducted beyond the United States. Although Iceland has the highest methylphenidate prescription rates in the world, prevalence of stimulant misuse within the Icelandic college student population remains to be investigated. METHOD: We examined the prevalence of prescription stimulant misuse among N = 521 college students in Iceland, using an online survey. RESULTS: Overall prevalence of lifetime stimulant misuse was approximately 13%; 11% among participants without a prescription for stimulant medication, and 42% among participants holding a prescription. The primary reported reason for misuse was academic enhancement; risk factors included male sex, anxiety symptoms, and ADHD symptomatology. CONCLUSION: The present findings have implications for public health policy in Iceland, particularly as it relates to the college population. Prevention and intervention programs that provide college students with safer strategies to manage academic demands are warranted. PMID- 28013573 TI - Evaluation of miR-216a and miR-217 as Potential Biomarkers of Acute Exocrine Pancreatic Toxicity in Rats. AB - Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers. PMID- 28013574 TI - Predictive Value of Serum Albumin Level for the Prognosis of Severe Sepsis Without Exogenous Human Albumin Administration: A Prospective Cohort Study. AB - BACKGROUND:: The prognostic significance of serum albumin levels in patients with sepsis has previously been reported; however, these studies have not excluded the potential confounding effect of exogenous albumin administration. In this study, we investigate the predictive value of serum albumin for the prognosis of severe sepsis without the interference of exogenous albumin administration. METHODS:: A prospective cohort study was conducted from April to November 2014 in the internal and surgical intensive care units of a tertiary care hospital. During the study period, due to a supply shortage, patients were not treated with human albumin. Serum albumin levels were measured, and laboratory and clinical data were collected at the onset of severe sepsis. Prognostic factors were analyzed using receiver operating characteristic curve and multivariate Cox proportional hazard regression analysis. Survival was assessed by Kaplan-Meier method. RESULTS:: One hundred sixteen patients were included in the study. The overall 28 day mortality was 26.7%. The most common infection sources were lower respiratory tract, abdomen/pelvis, and bloodstream. Compared to patients who survived, those who died had lower serum albumin levels and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Receiver operating characteristic curves demonstrate that albumin level is a strong predictor of 28-day mortality, and the optimal cutoff value maximizing sensitivity and specificity is 29.2 g/L. Through multivariate Cox regression analysis, low serum albumin levels (<29.2 g/L) and APACHE II scores are identified as independent risk factors for mortality. Patients with lower serum albumin levels more often had abdominal/pelvic sources of infection, acute kidney or liver injury, septic shock, and higher APACHE II and SOFA scores. The 28-day survival rate was lower for patients with serum albumin below 29.2 g/L than for patients with serum albumin at or above this level. CONCLUSION:: Having excluded potential confounding effect of exogenous albumin administration, low serum albumin levels are associated with an increased risk of death in patients with severe sepsis. PMID- 28013575 TI - Appendiceal Endometriosis. PMID- 28013576 TI - Trade, Labour Markets and Health. AB - Previous analyses indicate that there are a number of potentially serious health risks associated with the Trans-Pacific Partnership (TPP). The objective of this work is to provide further insight into the potential health impacts of the TPP by investigating labour market pathways. The impact of the TPP on employment and working conditions is a major point of contention in broader public debates. In public health literature, these factors are considered fundamental determinants of health, yet they are rarely addressed in analyses of trade and investment agreements. We therefore undertake a prospective policy analysis of the TPP through a content analysis of the agreement's Labour Chapter. Provisions of the Chapter are analyzed with reference to the health policy triangle and four main areas through which labour markets influence health: power relations, social policies, employment conditions and working conditions. Findings indicate that implementation of the TPP can have important impacts on health through labour market pathways. While the Labour Chapter is being presented by proponents of the agreement as a vehicle for improvement in labour standards, we find little evidence to support this view. Instead, we find several ways the TPP may weaken employment relations to the detriment of health. PMID- 28013577 TI - Plate fixation of periprosthetic femur fractures: What happens to the cement mantle? AB - Osteosynthesis of periprosthetic femur fractures by screw fixation around the implanted prosthetic stem is currently regarded as the biomechanically superior option compared with cerclage. The aim of this biomechanical study was damage analysis of the cement mantle after revision screw insertion. A prosthetic stem (Bicontact) was implanted in 20 cadaveric femora in cemented technique. A locking compression plate (Synthes) was then applied to the lateral femur at the level of the prosthetic stem. The method of plate fixation to the femur was assigned randomly to three groups: bicortical non-locking screws, monocortical locking screws, and bicortical locking screws. This was followed by applying a fluctuating axial load (2100 N, 0.5 Hz) for 20,000 cycles. After testing, macroscopic and microscopic evaluations of the cement mantle were conducted. Cracks formed in the cement mantle in 14% of the 80 screw holes. The type of screw (bicortical or monocortical; locking or non-locking) had no significant effect on the number of cracks (p = 0.52). The relationship between manifestation of crack damage and cement mantle thickness was not significant (p = 0.36), whereas the relationship between crack formation and screw position was significant (p = 0.019). Those screws whose circumference was only partially within the cement mantle yielded a significantly lower number of cracks compared with screws positioned completely within the cement mantle or even touching the prosthetic stem. In order to reduce the incidence of crack formation in the cement mantle during plate osteosynthesis of periprosthetic femur fractures, the screws should not be either placed within the cement mantle or make direct contact with the stem. PMID- 28013578 TI - Molecular docking, synthesis, and biological evaluation of naphthoquinone as potential novel scaffold for H5N1 neuraminidase inhibition. AB - A series of dimeric naphthoquinones containing natural 2-hydroxy-1-4 naphthoquinone moiety was designed, synthesized, and evaluated against neuraminidase of H5N1 virus. p-hydroxy derivatives showed higher inhibition when compared to p-halogenated compounds. Molecular docking studies conducted with H5N1 neuraminidase clearly demonstrated different binding modes of the most active compound onto the open and closed conformations of loop 150. The results thus provide not only evidences of a novel scaffold evaluated as inhibitor, but also a rational explanation involving molecular modeling and the role of loop 150 in the binding. PMID- 28013579 TI - A Rodent Model of Night-Shift Work Induces Short-Term and Enduring Sleep and Electroencephalographic Disturbances. AB - Millions of people worldwide are working at times that overlap with the normal time for sleep. Sleep problems related to the work schedule may mediate the well established relationship between shift work and increased risk for disease, occupational errors and accidents. Yet, our understanding of causality and the underlying mechanisms that explain this relationship is limited. We aimed to assess the consequences of night-shift work for sleep and to examine whether night-shift work-induced sleep disturbances may yield electrophysiological markers of impaired maintenance of the waking brain state. An experimental model developed in rats simulated a 4-day protocol of night-work in humans. Two groups of rats underwent 8-h sessions of enforced ambulation, either at the circadian time when the animal was physiologically primed for wakefulness (active-workers, mimicking day-shift) or for sleep (rest-workers, mimicking night-shift). The 4 day rest-work schedule induced a pronounced redistribution of sleep to the endogenous active phase. Rest-work also led to higher electroencephalogram (EEG) slow-wave (1-4 Hz) energy in quiet wakefulness during work-sessions, suggesting a degraded waking state. After the daily work-sessions, being in their endogenous active phase, rest-workers slept less and had higher gamma (80-90 Hz) activity during wake than active-workers. Finally, rest-work induced an enduring shift in the main sleep period and attenuated the accumulation of slow-wave energy during NREM sleep. A comparison of recovery data from 12:12 LD and constant dark conditions suggests that reduced time in NREM sleep throughout the recorded 7-day recovery phase induced by rest-work may be modulated by circadian factors. Our data in rats show that enforced night-work-like activity during the normal resting phase has pronounced acute and persistent effects on sleep and waking behavior. The study also underscores the potential importance of animal models for future studies on the health consequences of night-shift work and the mechanisms underlying increased risk for diseases. PMID- 28017124 TI - Measurement of Scientific Productivity in R&D Sector: Changing paradigm. AB - Scientific Productivity is a demand of policy makers for a judicious utilization of massive R&D budget allocated and utilized. A huge mass of intellectual assets is employed, which after investing manpower, infrastructure and lab consumables demand for a major outcome which contributes towards building nation's economy. Scientific productivity was only measured through publications or patents. Patents, earmarked as a strong parameter for innovation generation, where, Word Intellectual Property Organisation generated a data on applications for the top 20 offices for patents, where Australia, Brazil and Canada occupied top 3 positions. India ranked 9th with the total patent applications rising from 39762 (2010) to 42854 (2014) i.e. 15%, whereas, it contributes around 2% Patents (innovative productivity) on global scale. Many studies have come forward interestingly within scientific and academic domains in the form of measurement of scientific performance, however, development of productivity indicators and calculation of Scientific Productivity (SP) as a holistic evaluation system is a significant demand. SP, a herculean task is envisaged for productivity analysis and would submit significant factors towards fabricating an effective measurement engine in a holistic manner viable for an individual and organization, being supplementary to each other. This review projects the significance of performance measurement system in R&D through identification and standardization of key parameters. It also includes emphasis on inclusion of standardized parameters, effective for performance measurement which is applicable for scientists, technical staff as well as lab as a facility. This review aims at providing an insight to the evaluators, policy makers, and high level scientific panels to stimulate the scientific intellects on identified indicators so that their work proceeds to generate productive outcome contributing to the economic growth. PMID- 28017123 TI - Current State of Bioabsorbable Polymer-Coated Drug-Eluting Stents. AB - Drug-eluting stents (DES) have been shown to significantly reduce clinical and angiographic restenosis compared to bare metal stents (BMS). The polymer coatings on DES elute antiproliferative drugs to inhibit intimal proliferation and prevent restenosis after stent implantation. Permanent polymers which do not degrade in vivo may increase the likelihood of stent-related delayed arterial healing or polymer hypersensitivity. In turn, these limitations may contribute to an increased risk of late clinical events. Intuitively, a polymer which degrades after completion of drug release, leaving an inert metal scaffold in place, may improve arterial healing by removing a chronic source of inflammation, neoatherosclerosis, and/or late thrombosis. In this way, a biodegradable polymer may reduce late ischemic events. Additionally, improved healing after stent implantation could reduce the requirement for long-term dual antiplatelet therapy and the associated risk of bleeding and cost. This review will focus on bioabsorbable polymer-coated DES currently being evaluated in clinical trials. PMID- 28017125 TI - Review of Theoretical Models to Study Natural Products with Antiprotozoal Activity. AB - In nature, pathogenic parasite species with different susceptibility patterns of antiparasitic drugs abound. In this sense, natural products derived from plants are a potency for drugs with potential antiparasitic activity. Unfortunately, there are many metabolites and studying all of them would be costly in terms of money and resources. To this end, theoretical studies such as QSAR models could be useful. These, for the most part, predict the biological activity of the drugs against a single species of parasite. Consequently, foretell the probability with which a drug is active against many different species with a single QSAR model is an important achievement. This review consists of three parts: the first part is a review of metabolites found in nature that have antiparasitic activity, in particular the antiprotozoal (Leishmania and Trypanosoma); the second part includes a review of theoretical studies looking for a model that predicts the antiprotozoal activity of natural products; the third and final part concerns the study of theoretical models focused on the interaction between drug and receptor, analyzing new metabolites with antiprotozoal activity. PMID- 28017126 TI - Recent Advances in Transcranial Focused Ultrasound (FUS) Triggered Brain Delivery. AB - BACKGROUND: Successful delivery of therapeutic agents in the brain is very challenging, which makes treatment of various brain disorders very difficult. One of the major causes of this difficulty is the presence of physiological barriers in the brain like blood brain barrier (BBB) and blood cerebrospinal fluid (CSF) barrier. These barriers are very specific and restrict the entry of water soluble agents and ionized molecule. OBJECTIVE: The current article focuses on the transcranial route, transcranial focused ultrasound (FUS), and the techniques involved in transcranial focused ultrasound (FUS) delivery and recent updates of this system. RESULTS: The study describes that the FUS in conjunction with various other techniques opens the BBB very effectively. CONCLUSION: The administration of therapeutic agent using various FUS techniques opens a new perspective in treating CNS diseases. PMID- 28017128 TI - Role of Azoles in Cancer Prevention and Treatment: Present and Future Perspectives. AB - BACKGROUND: Cancer has gradually become one of the leading causes of death worldwide. The incidence of cancer among the population has increased alarmingly over the last two decades, primarily due to an increasing population of immune compromised patients and the continuing rise in anti-cancer drug resistance. Azole found privileged structure in medicinal chemistry and pharmaceutical industry and also found to be showing antioxidant; antimicrobial, anthelmintic, anticancer, antiviral, anti-parasitic, anti-inflammatory, anti-HIV, and antihypertensive activities. OBJECTIVE: In this review, we highlight some areas of current interest in context to azoles and their derivatives as potential chemotherapeutic agents and inhibitors. METHOD: A comprehensive literature search was performed for writing this review. An updated view on different derivatives of azoles and use in cancer management has been discussed. RESULTS: Here we have discussed the present scenario of azoles and their derivatives as potential chemotherapeutic agents and inhibitors. Along with, the future perspectives of azoles in cancer prevention and treatment are also discussed. CONCLUSION: The information provided in this review might be useful to researchers in designing of novel and potent multifunctional azole analogues for the treatment of cancer and other multifactorial diseases. PMID- 28017127 TI - Marginal Vitamin A Deficiency Exacerbates Memory Deficits Following Abeta1-42 Injection in Rats. AB - BACKGROUND: Although clinical vitamin A deficiency (VAD), which is a public health problem developing throughout the world, has been well controlled, marginal vitamin A deficiency (MVAD) is far more prevalent, especially among pregnant women and preschool children in China. Increasing evidence suggests that VAD is involved in the pathogenesis of Alzheimer's disease (AD). However, whether MVAD, beginning early in life, increases the risk of developing AD has yet to be determined. OBJECTIVE: The goal of this study was to investigate the long-term effects of MVAD on the pathogenesis of AD in rats. METHOD: An MVAD model was generated from maternal MVAD rats and maintained with an MVAD diet after weaning. The males were bilaterally injected with aggregated amyloid beta (Abeta)1-42 into the CA3 area of the hippocampus, and the AD-associated cognitive and neuropathological phenotypes were examined. RESULTS: We found that MVAD feeding significantly aggravated Abeta1-42-induced learning and memory deficits in the Morris water maze test. MVAD did not induce the mRNA expression of retinoic acid receptors (RARs), a disintegrin and metalloprotease 10 (ADAM10) or insulin degrading enzyme (IDE) in Abeta1-42-injected rats. Moreover, RARalpha and RARgamma mRNA were positively correlated with ADAM10 mRNA, whereas RARbeta mRNA was positively correlated with IDE mRNA. CONCLUSION: Our study suggests that MVAD beginning from the embryonic period perturbs the ADassociated genes, resulting in an enhanced risk of developing AD. PMID- 28017129 TI - Kynurenine System and Multiple Sclerosis, Pathomechanism and Drug Targets with An Emphasis on Laquinimod. AB - Multiple sclerosis is a common chronic, disabling autoimmune neurological disease affecting mainly young adults. In its pathomechanism, neurodegenerative and acute inflammatory characteristics are both involved. Disease-modifying therapies aim to reduce relapse-rate and slow down the deterioration in neurological functions. The currently available therapies fail to exert neuroprotective effects and most of them are associated with potentially toxic side-effects, therefore, ongoing research aims to develop novel drug candidates to cover these therapeutic gaps. The kynurenine pathway has been implicated in both the physiological processes of the central nervous system and in the pathomechanism of several neurological disorders as well. Alterations of the kynurenine pathway metabolites have been detected in multiple sclerosis and a number of potential therapeutic targets related to this metabolic route have been already identified. Laquinimod is a quinoline carboxamide showing structural similarities with kynurenic acid, which proved to have beneficial effects on reduction of brain atrophy and disability progression. The kynurenine pathway is therefore a promising target for the development of future drugs for the treatment of autoimmune diseases such as multiple sclerosis. PMID- 28017130 TI - Exercise Induced Neuroplasticity to Enhance Therapeutic Outcomes of Cognitive Remediation in Schizophrenia: Analyzing the Role of Brai nderived Neurotrophic Factor. AB - BACKGROUND: Cognitive impairment is a major manifestation of schizophrenia and a crucial treatment target as these deficits are closely related to patients' functional outcomes. Cognitive remediation is the gold-standard practice to address cognitive deficits in schizophrenia. There is clear evidence stating that cognitive remediation improves cognitive function and promotes structural neuroplastic changes in patients with schizophrenia, with brain-derived neurotrophic factor (BDNF) expression emerging as a potential biomarker for its efficacy. This is particularly important as there is clear evidence relating atypical BDNF expression to cognitive impairment in patients with schizophrenia. Despite the valuable role of cognitive remediation in the management of schizophrenia, there is still a need to develop methods that allow maximizing its efficacy. METHOD AND RESULTS: In this review, we present a hypothesis arguing that cognitive remediation efficacy for patients with schizophrenia can be enhanced by aerobic exercise-induced BDNF upregulation. There have been a few trials reporting that combining aerobic exercise with cognitive training was superior to cognitive training alone to improve cognitive functioning in patients with schizophrenia. Furthermore, there is preliminary evidence suggesting that combined aerobic and cognitive training can increase peripheral BDNF levels. CONCLUSION: Thereby, engaging in aerobic exercise in close temporal proximity to cognitive remediation may allow achieving a state of neuroplastic readiness in the brain, facilitating cognitive functioning enhancement. Although this hypothesis still lacks evidence, future clinical trials using cognitive remediation for schizophrenia should explore strategies to maximize neuroplasticity and achieve optimal cognitive improvements. PMID- 28017131 TI - Axotomy Leads to Reduced Calcium Increase and Earlier Termination of CCL2 Release in Spinal Motoneurons with Upregulated Parvalbumin Followed by Decreased Neighboring Microglial Activation. AB - BACKGROUND: Motoneurons with naturally elevated calcium binding protein content, such as parvalbumin, are more resistant against injury. Furthermore, increase of intracellular calcium, which plays a pivotal role in injury of neurons, could be moderated by elevating their calcium binding proteins. OBJECTIVE: To test whether by elevating parvalbumin content of motoneurons, activation of neighboring microglial cells, a robust component of the inflammatory reaction after injury, could be influenced. METHODS: Mice overexpressing neuronal parvalbumin were derived and the spinal motoneurons were challenged by cutting the sciatic nerve. At postoperative days 1, 4, 7, 14 and 21 the change of the chemokine ligand 2 immunostaining in the motoneurons and the activation of microglial cells, measured as alterations in CD11b immunostaining were determined. Calcium level of motoneurons was tested electron microscopically at postoperative day 7. RESULTS: After axotomy, increased level of chemokine ligand 2 was detected in the lumbar motoneurons. The staining intensity reached its maximum at day 7 and decayed faster in transgenic mice compared to controls. Microglial activation around motoneurons attenuated faster in parvalbumin overexpressing mice, too, but the decrease of microglial activation was delayed compared to the decline of the chemokine ligand 2 signal. At the time when the microglial reaction peaked, no intracellular calcium increase was detected in the motoneurons of transgenic mice, in contrast to the twofold increase in wild type animals. CONCLUSION: Increased calcium buffering capacity, which augments resistance of motoneurons against calcium-mediated injury, leads to earlier termination of motoneuronal emission of CCL2 followed by a reduction of neighboring microglial activation after axotomy. PMID- 28017132 TI - Magnetite Nanoparticles-Supported APTES as a Powerful and Recoverable Nanocatalyst for the Preparation of 2-Amino-5,10-dihydro- 5,10-dioxo-4H benzo[g]chromenes and Tetrahydrobenzo[g]quinoline-5,10- diones. AB - AIM AND OBJECTIVE: This study introduces a green and effective approach for the preparation of biologically-active heterocyclic compounds including 2-amino-5,10 dihydro-5,10-dioxo-4Hbenzo[ g]chromenes and tetrahydrobenzo[g]quinoline-5,10 diones using one-pot multi-component reactions in the presence of Fe3O4@SiO2-NH2 nanocomposite. The preparation and use of aminofunctionalized Fe3O4@SiO2 as a powerful and reusable nanocatalyst is described. The catalyst was characterized by spectral techniques including FT-IR, SEM, XRD, EDX and VSM analysis. This method offers the advantages of high yields, short reaction times, comfortable work-up and reusability of the catalyst. MATERIAL AND METHOD: The amino functionalization silica-coated magnetite nanocomposite was prepared by three step method and the structure elucidation of the nanocatalyst has been done using various spectroscopic analyses. Then, the Fe3O4@SiO2-NH2 nanocomposite was used in the multicomponent synthesis of 2-amino-5,10-dihydro-5,10-dioxo-4H benzo[g]chromenes and tetrahydrobenzo[g]quinoline-5,10-diones under reflux conditions. All of the products were analyzed with m.p., 1H NMR, 13C NMR and FT IR spectroscopy techniques. The study on the recoverability of the nanocatalyst showed the recovered Fe3O4@SiO2-NH2 nanocomposite could be reused sixth consecutive times with a little-decreased activity. RESULTS: Amino-functionalized SiO2 coated Fe3O4 nanocomposite exhibited superparamagnetic behavior and strong magnetization at room temperature. The average crystallite sizes of the catalyst was about 50-60 nm. The obtained magnetic nanocomposite showed excellent catalytic activity as a new heterogeneous magnetic catalyst for the synthesis of some benzo[g]chromenes and tetrahydrobenzo[g]quinoline-5,10-diones. We propose that NH2 groups on the surfaces of nanocomposite act as the Bronsted base and cause to dehydrogenation of substrates to promote the reactions. CONCLUSION: It was found that Fe3O4@SiO2-NH2 nanocomposite act as an eco-friendly and efficient catalyst for one-pot synthesis of three/four component condensation reactions. In this research, aminofunctionalized Fe3O4@SiO2 was used as recoverable catalyst for the synthesis of 2-amino-5,10- dihydro-5,10-dioxo-4H-benzo[g]chromenes and tetrahydrobenzo[g]quinoline-5,10-diones under reflux conditions. The significant advantages of this method are the reasonably simple work-up, little catalyst loading, short reaction times, excellent yields, non-hygroscopic quality and reusability of the nanocatalyst which is in good agreement with green chemistry disciplines. PMID- 28017133 TI - Editorial: Frontier View on Drug Discoveries for Different Diseases - Part I. PMID- 28017134 TI - Contrast Functions of alphaA- and alphaB-Crystallins in Cancer Development. AB - alpha-Crystallins, initially identified as the structural proteins of the ocular lens, belong to the small heat shock protein family. They play significant roles in maintaining the lens transparency and preventing protein aggregation. alpha Crystallins exist in two isoforms: alphaA and alphaB, and they display differential tissue distribution. Their mutations are implicated in several human diseases including cardiac myopathies, neurodegenerative diseases, cataracts and various types of cancers. Increased alphaB expression was detected in retinoblastoma, breast cancer, glioblastoma, prostate and renal cell carcinomas, indicating its role in promoting tumor growth. A complex picture emerges for alphaA. Although earlier studies suggest that alphaA may promote cancer development, recent studies from our laboratory demonstrate that alphaA can act as a tumor suppressor inhibiting cell transformation and retarding cell migration through modulating MAP kinase activity. In this review, we summarize the recent progress about the functions of alphaA and alphaB in cancer development. PMID- 28017135 TI - Roles of SUMOylation in Heart Development and Cardiovascular Diseases. AB - Heart is an extremely important organ, and cardiovascular disorders emerge as primary life-threatening disease in human life. Aberrant post-translational modifications (PTMs) on cardiac proteins are closely correlated with pathological abnormalities in heart. SUMOylation, one of the most prevalent PTMs with thousands of substrates throughout the cell including critical subcellular organelles, has been shown to precisely finetune the cell survival and proliferation during heart development, and delicately control the function of mitochondrion and sarcoplasmic reticulum in physiological heart functioning. The silver lining is pathologically cardiacspecific SUMOylation being considered as target for cardiovascular disease intervention and treatment. Here, we summarize the recent progress in heart-specific functions of the SUMOylation pathway. In particular, we discuss the biological significance of SUMO conjugation/deconjugation during heart development, and in physiological cardiovascular health involving cardiac mitochondrial function, cardiac contractility, stress adaption and protein homeostasis. We also discuss the crosstalks between sumoylation and other post-translational modifications such as acetylation and ubiquitination. These crosstalks not only shed light to our understanding of the regulatory mechanisms on cardiovascular disorders but also contributes to their future therapy. PMID- 28017136 TI - Regulation of CREB Functions by Phosphorylation and Sumoylation in Nervous and Visual Systems. AB - CREB is an ubiquitous transcription factor regulating diverse cellular responses. Its phosphorylation at S133 is an essential event for its activation in both nervous and visual systems. The activated CREB is implicated in the regulation of development, protection, learning, memory and plasticity in the nerve system. Moreover, sumoylation, an important post-translational modification of protein, plays a key role in sustaining CREB activation in the rat hippocampus in order to enhance the long-term memory and other aspects. In the visual system, although the CREB activation by phosphorylation at S133 is similar to that as observed in the nervous system, the role of CREB sumoylation remains to be explored. This review will discuss the aspects of CREB functions and their regulation by phosphorylation and sumoylation in both systems. PMID- 28017137 TI - Effects of Crosstalks Between Sumoylation and Phosphorylation in Normal Cellular Physiology and Human Diseases. AB - Post-translational modifications (PTMs) such as phosphorylation, acetylation, methylation, ubiquitylation, sumoylation are important mechanisms to regulate functions of different proteins. Among various PTMs, phosphorylation, discovered about 60 years ago, is probably the most common modification. In contrast, sumoylation, identified about two decades ago is emerging as a key regulatory mechanism modulating protein functions. Although studies on protein phosphorylation and sumoylation have been extensively reviewed, much less attention has been paid to their cross-talk and their co-regulation of the same protein target. Here we summarize various examples of the cross-talks between protein phosphorylation and sumoylation, and discuss their functions in regulating normal physiology and pathogenesis. PMID- 28017138 TI - Sumoylation Pathway as Potential Therapeutic Targets in Cancer. AB - Sumoylation is a covalent protein posttranslational modification that conjugates the small ubiquitin-like peptide SUMO to substrate. Sumoylation is critically implicated in multiple biological processes, including cell proliferation, differentiation, senescence and apoptosis, etc. Therefore, it is not surprising that dysregulation of sumoylation has been implicated in tumorigenesis and different types of cancer were found to be addicted to functional sumoylation pathway. The potential role for sumoylation as a therapeutic target in caner is emerging. In this review, we summarize current knowledge regarding the involvement of sumoylation in genome stability and DNA damage response. We will further discuss the therapeutic potential of sumoylation as synthetic lethal partner and as a key signaling pathway in cancer stem cells. PMID- 28017139 TI - Sumoylation in Cellular Senescence and Aging. AB - Sumoylation is a reversible post-translational modification that conjugates small peptide SUMO (small ubiquitin-like modifier) to a target protein. Global protein sumoylation and expression of components in sumoylation pathway were recently found to be altered in the process of organismal aging. In addition, key factors controlling cellular senescence are known to be sumoylated. This review will summarize current information on the function of sumoylation in cellular senescence and aging. PMID- 28017140 TI - Molecular, Cellular and Pharmaceutical Aspects of Filling Biomaterials During the Management of Extraction Sockets. AB - After a tooth extraction both hard and soft tissues undergo dimensional changes. The use of a ridge preservation technique at the moment of the tooth extraction could help could help to prevent the volume loss, thus simplifying the subsequent prosthetic and/or implant therapy. Some studies were conducted in order to examine the biomaterials and the surgical technique used for ridge preservation procedures. Clinical, histological, volumetric and molecular outcomes were registered and analyzed in different studies, in order to comprehend the biological events and the consequences of a socket preservation procedure and to allow the clinician to make the correct choice. PMID- 28017141 TI - Rhinocerebral Mucormycosis with Orosinusal Involvement: Diagnostic and Surgical Treatment Guidelines. AB - BACKGROUND: Rhinocerebral mucormycosis is a rare, rapidly progressive and potentially lethal disease almost exclusively affecting immunocompromised hosts or patients with metabolic disorders, such as poorly controlled diabetes mellitus. METHODS: This work is aimed to describe five cases of rhinocerebral mucormycosis to review and possibly define diagnostic and surgical treatment guidelines. In all the patients, surgical debridement, systemic and local antifungal therapy, and oral rehabilitation using filling prostheses were performed. RESULTS: None of the patients revealed recurrence of the infection, as confirmed by radiological and clinical long term follow up. CONCLUSION: Given the lethal nature of the disease, the authors underline the importance of early diagnosis and of a multidisciplinary approach in order to undertake correct surgical and medical treatments, while keeping the underlying disease under control. PMID- 28017142 TI - Gliclazide-Induced Insulin Autoimmune Syndrome: A Rare Case Report and Review on Literature. AB - BACKGROUND: Insulin Autoimmune Syndrome (IAS) is a rare condition characterized by the combination of recurrent severely spontaneous hypoglycemia without evidence of exogenous insulin administration, high concentration of total serum insulin, and the presence of a high titer of insulin autoantibody (IAA). But now we describe a case with IAS caused by gliclazide and hardly occuring hypoglycemia. CASE REPORT: A 70-year-old man with type 2 diabetes presented to our department with poor glycemic control without evidence of hypoglycemia, but the levels of serum insulin and IAA were very high. He had no exogenous insulin administration history. Switching antidiabetic therapy from gliclazide to acarbose and metformin, the patient's serum insulin level and IAA decreased gradually. Accordingly, the glycemic control improved and there was no episode of hypoglycemia. CONCLUSION: Hence, clinicians should pay more attention to type 2 diabetic patients treated with gliclazide and detect their serum insulin concentration and IAA to exclude or diagnose IAS and perform the best therapeutic regimen to these patients. PMID- 28017143 TI - A HR-MS Based Method for the Determination of Chorismate Synthase Activity. AB - Chorismate synthase (Cs) catalyzes the last step of Shikimate pathway involving a unique biochemical reaction of anti-1,4 elimination of 3-phosphate group and the C-(6proR) hydrogen from 5-enolpyruvylshikimate-3-phosphate (EPSP) leading to the formation of chorismate, which is the common precursor for aromatic amino acid, ubiquinone, and folate biosynthesis in plants and several bacterial, fungal, and parasitic pathogens. Absence of Shikimate pathway in the vertebrate host, make Cs an appealing target for drug discovery against these pathogens. Here, we report a new method for detection of chorismate through a specific liquid chromatography, coupled with negative electrospray ionization high-resolution tandem mass spectrometry (ESI-HRMS) for determination of Cs enzyme activity. For this, we used a coupled enzyme reaction consisting of purified recombinant MtbEPSPs (EPSP synthase from Mycobacterium tuberculosis) for biosynthesis of EPSP, which is the substrate for Chorismate synthase along with MtbCs (Chorismate synthase both from Mycobacterium tuberculosis) for the formation of chorismate, followed by its detection through LC/HRMS. Since, the reaction components of Cs enzyme activity assay which otherwise may interfere with the other known spectrophotometric methods of checking Cs enzyme activity have no effect on this LC/HRMS based method, this method offer advantages over other existing methods for detection of Cs activity. Further, this LC/HRMS based method could be applicable for detection of enzyme activity of both monofunctional and bifunctional Cs from different species irrespective of their specific requirements of anaerobic or aerobic reaction conditions. PMID- 28017144 TI - Potential Use of Food Protein-Derived Peptides in the Treatment of Inflammatory Diseases. AB - In recent years, major developments in the field of inflammatory pathophysiology have clearly shown that arthritis, diabetes, intestinal bowel diseases, and obesity, which affect many people around the world, are essentially inflammatory in nature. Different anti-inflammatory drugs have been used to treat these conditions. Some people are able to take these drugs without difficulty, yet others experience negative side effects. Hence, the search for new, natural anti inflammatory alternatives has rapidly increased in recent years. Evidence has shown that food protein-derived peptides may be one alternative for treating inflammatory diseases. Peptides are encrypted in food proteins, can be released under hydrolysis conditions, and do not cause adverse effects. Despite limited information on the mechanism of action of peptides, in vitro and animal model studies have demonstrated their potential anti-inflammatory activity. Several in vitro studies have demonstrated that peptides can inhibit different pathways of inflammation processes such as that of the nuclear factor kappalight- chain of activated B cells (NF-kappaB). They can also induce the production of nitric oxide synthase (iNOs) and c-Jun N-terminal kinases (JNK) as well as influence PepT1 and CaRS, the transporters of peptides to the gastrointestinal tract that are responsible for the absorption of dietary peptides in the intestine. However, contradictory evidence has been reported in clinical assays. Hence, in this review, we present the latest research on the anti-inflammatory activity of food protein-derived peptides and provide future perspectives on the use of peptides as potential natural sources of therapeutic treatments. PMID- 28017145 TI - Protein and Peptide Biopharmaceuticals: An Overview. AB - Bioactive proteins and peptides are recognised as novel therapeutic molecules with varying biological properties for potential medical applications. Development of protein and peptidebased therapeutic products for human use is growing steadily as they continue to receive an increasing rate of approval by the United States Food and Drugs Administration (US FDA). In this short review, we describe the current status and methodologies involved in the synthesis of protein and peptide biopharmaceuticals with an emphasis on the drivers and restrains to their exploitation in the therapeutic products sector. PMID- 28017146 TI - Current HPLC Methods for Assay of Nano Drug Delivery Systems. AB - In nano drug formulations the mechanism of release is a critical process to recognize controlled and targeted drug delivery systems. In order to gain high bioavailability and specificity from the drug to reach its therapeutic goal, the active substance must be loaded into the nanoparticles efficiently. Therefore, the amount in biological fluids or tissues and the remaining amount in nano carriers are very important parameters to understand the potential of the nano drug delivery systems. For this aim, suitable and validated quantitation methods are required to determine released drug concentrations from nano pharmaceutical formulations. HPLC (High Performance Liquid Chromatography) is one of the most common techniques used for determination of released drug content out of nano drug formulations, in different physical conditions, over different periods of time. Since there are many types of HPLC methods depending on detector and column types, it is a challenge for the researchers to choose a suitable method that is simple, fast and validated HPLC techniques for their nano drug delivery systems. This review's goal is to compare HPLC methods that are currently used in different nano drug delivery systems in order to provide detailed and useful information for researchers. PMID- 28017147 TI - Synergistic Interplay of Medicinal Chemistry and Formulation Strategies in Nanotechnology - From Drug Discovery to Nanocarrier Design and Development. AB - Over the last few decades, nanotechnology has given rise to promising new therapies and diagnostic tools for a wide range of diseases, especially cancer. The unique properties of nanocarriers such as liposomes, polymeric nanoparticles, micelles, and bioconjugates have mainly been exploited to enhance drug solubility, dissolution, and bioavailability. The most important advantage offered by nanotechnology is the ability to specifically target organs, tissues, and individual cells, which ultimately reduces the systemic side effects and improves the therapeutic index of drug molecules. The contribution of medicinal chemistry to nanotechnology is evident in the abundance of new active molecules that are being discovered but are faced with tremendous delivery challenges by conventional formulation strategies. Additionally, medicinal chemistry plays a crucial role in all the steps involved in the preparation of nanocarriers, where structure-activity relationships of the drug molecule as well as the nanocarrier are harnessed to enhance the design, efficacy, and safety of nanoformulations. The aim of this review is to provide an overview of the contributions of medicinal chemistry to nanotechnology, from supplying drug candidates and inspiring high-throughput nanocarrier design strategies, to structure-activity relationship elucidation and construction of computational models for better understanding of nanocarrier physicochemical properties and biological behavior. These two fields are undoubtedly interconnected and we will continue to see the fruits of that communion for years to come. PMID- 28017148 TI - Chemical Structure and Surface Modification of Dendritic Nanomaterials Tailored for Therapeutic and Diagnostic Applications. AB - Dendritic nanomaterials have attracted a great deal of scientific interest due to their high capacity for multifunctionalization and potential in various biomedical applications, such as drug/gene delivery and diagnostic systems. Depending on the molecular structure and starting monomers, several different types of dendrimers have been developed, including poly(amidoamine) (PAMAM), poly(propylenimine) (PPI), and poly(L-lysine) (PLL) dendrimers, in addition to modified dendritic nanomaterials, such as Janus dendrimers and dendritic block copolymers. The chemical structure and surface modification of dendritic nanomaterials have been found to play a critical role in governing their biological behaviors. In this review, we present a comprehensive overview focusing on the synthesis and chemical structures of dendrimers and modified dendritic nanomaterials that are currently being investigated for drug delivery, gene delivery, and diagnostic applications. In addition, the impact of chemical surface modification and functionalization to the dendritic nanomaterials on their therapeutic and diagnostic applications are highlighted. PMID- 28017149 TI - HTLV-1 Associated Neurological Disorders. AB - Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which is endemic to certain regions of the world and infects around 10-20 million people. HTLV-1 is the etiologic agent of Adult T cell leukemia/lymphoma and HTLV-1 associated neurological disorders including mainly HTLV-1 associated myelopathy/Tropical spastic paraparesis. The involvement of the central nervous diseases occurs among: HTLV-1 infected patients from endemic areas, HIV positive individuals and drug users. The ability of HTLV-1 to cause associated neuropathies starts with the virus crossing the blood brain barrier (BBB), then entering and infecting the cells of the central nervous system. As a consequence, to the viral attack, HTLV 1 infected lymphocytes produce pro-inflammatory cytokines like tumor necrosis factor alpha, Interleukin 1 beta and interleukin 6 which further disrupts the BBB. Different serological tests have been used in the diagnosis of HTLV-1. These include: ELISA, Western Blotting (WB), Immunofluorescence, Particle Agglutination and Polymerase Chain Reaction which is used as a confirmatory test. Danazol, pentoxifylline, azathioprine and vitamin C have been used in the treatment of the HTLV-1 associated neurological disorders. Other antiviral drugs (lamivudine, zidovudine), monoclonal antibodies (Daclizumab) and therapeutic agents (valporic acid, interferons) have also been evaluated. No known drug, so far, has been shown to be efficacious. The aim of this review is to present the complexities of HTLV-1 associated neurological disorders and their current ongoing treatment. In addition to discussing future possible therapeutic strategies, by targeting HTVL 1 viral components and gene/s products, for the treatment of those neurological conditions. PMID- 28017150 TI - Nanotechnology in Neuroscience and its Perspective as Gene Carrier. AB - Gene therapy has a strong potential in neuroscience by suppressing or replacing abnormalities in genetic materials. The employment of nano-gene carrier for neurological disorders is comparatively young and restricted since the aim to effectively deliver therapeutic agents into the central nervous system (CNS) commonly has confronted difficulties of several natural occurring barriers in the body and unfavorable characteristics of pharmaceutical agents. Two major anatomical and biochemical barriers are blood-brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB), which significantly prevent permeation of most drugs and genes to brain parenchyma. In this concern, nanotechnology emerges as an innovative method for transporting therapeutics to the CNS. Diverse nano systems have been closely investigated, some of which have demonstrated initial success for in vivo studies. The perspectives of nanotechnology for gene therapy would be a promising field to be further explored in the near future. PMID- 28017151 TI - Synopsis on Managment Strategies for Neurodegenerative Disorders: Challenges from Bench to Bedside in Successful Drug Discovery and Development. AB - The maintenance of health requires successful cell functioning, which in turn depends upon the proper and active conformation of proteins besides other biomolecules. However, occasionally these proteins may misfold and lead to the appearance and progression of protein conformational diseases. These diseases apart from others include several neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other lesser known diseases. Although much knowledge has been gained, these NDDs still warrant advance research in the elucidation of their mechanisms as well as effective therapeutic interventions and proper management. There is an ever-growing and urgent need to improve the diagnosis and management of NDDs due to their devastating nature, serious social impact and neuropsychiatric symptoms. It is also envisioned that we may be able to encourage, develop, and strengthen the cell defenses against amyloid toxicity and prevent neuronal destruction and consequently neurodegeneration. In this review, the implications of protein misfolding and aggregation in NDDs are discussed along with some of the most recent findings on the curative and beneficial effects of natural molecules such as polyphenols. This paper also reviews the anti-aggregation and protective effects of some organic and peptidic compounds duly supported experimentally, as prospective future therapeutics for NDDs. The synopses presented in this review shall prove helpful in further understanding of the causes, cures and management of lethal NDDs. PMID- 28017152 TI - rDNA Mediated Bioconjugates: Fusion Proteins and their Intended Use in Medicine. AB - Protein bioconjugates can be synthesized by using chemical reactions, enzymatic reactions or genetic engineering technologies. Naturally occurred protein fusion event is used on purpose in the development of better biopharmaceuticals by applying genetic engineering methodologies. This review will mainly focus on the types of fusion proteins produced with the use of recombinant DNA technology, by combining genes or parts of genes from the same or different organisms, in order to be used in pharmaceutical applications for several purposes. Main concerns for the development of better biopharmaceuticals include quality, efficacy, safety, immunogenicity and toxicity issues. Extending half-life of the drug to increase patient compliance, targeting the drugs to reduce toxicity, improving the manufacturing environment to reduce the costs and revealing protein interaction technologies to find novel and superior drugs are the main aims of fusion protein production. Here, related tags and examples of fusion methods for different purposes will be explained precisely. PMID- 28017153 TI - Template Synthesis of Tubular Nanostructures for Loading Biologically Active Molecules. AB - The template synthesis is a low cost, simple and versatile nanofabrication method to produce cylindrical/tubular nanostructures with controllable dimensions such as length, diameter and aspect ratio. This method utilizes nanoporous membranes such as anodized aluminum oxide (AAO) or polycarbonate (PC) as templates which have nanosized specific, cylindrical and uniform inner pores to be coated with the desired material. Template synthesized nanotubular structures have been produced from variety of materials including ceramics, polymers and proteins for loading biologically active molecules. Available procedures of material deposition into the template nanopores consist of several techniques like wetting (melt or solution wetting), layer-by-layer (LbL) assembly and sol-gel chemistry. Template synthesis enables not only control of the geometry of the resulting nanostructures but also provides nanovehicles having separated inner and outer surfaces which can be variously functionalized. Tubular nanostructures fabricated by this method have numerous potential applications including delivery of biologically active molecules such as drugs, gene, enzymes and proteins. In this review we aimed to present up-to-date works on the template based synthesis which has greatly facilitated the fabrication of polymer and protein tubular nanostructures, principally. The strategies regarding the synthesis and designing of these promising tubular nanostructures together with recent approaches relevant of drug delivery was also presented. PMID- 28017154 TI - Advances in Micelle-based Drug Delivery: Cross-linked Systems. AB - There are several barriers that drug molecules encounter in body beginning from kidney filtration and reticulo-endothelial system (RES) clearance to cellular trafficking. Multifunctional nanocarriers have a great potential for the delivery of drugs by enhancing therapeutic activity of existing methodologies. A variety of nanocarriers are constructed by different material types, which have unique physicochemical properties for drug delivery applications. Micelles formed by amphiphilic polymers are one of the most important drug/nanocarrier formulation products, in which the core part is suitable for encapsulation of hydrophobic agent whereas the outer shell can be utilized for targeting the drug to the disease area. Micelles as self-assembled nanostructures may encounter difficulties in biodistribution of encapsulated drugs because they have a tendency to be dissociated in dilution or high ionic strength. Therefore, therapeutic efficiency is decreased and it requires high amount of drug to be administered to achieve more efficient result. To overcome this problem, covalently stabilized structures produced by cross-linking in core or shell part, which can prevent the micelle dissociation and regulate drug release, have been proposed. These systems can be designed as responsive systems in which cross links are degradable or hydrolysable under specific conditions such as low pH or reductive environment. These are enhancing characteristics in drug delivery because their cleavage allows the release of bioactive agent encapsulated in the carrier at a certain site or time. This review describes the chemical methodologies for the preparation of cross-linked micelles, and reports an update of latest studies in literature. PMID- 28017155 TI - Nanofibers: New Insights for Drug Delivery and Tissue Engineering. AB - Nanofibers became one of the major research areas for drug delivery and tissue engineering applications in the last decade. Depending on the simplicity of the preparation method and high drug loading capacity, nanofibers provide many advantages for therapeutic perspectives. In addition, combined systems such as embedding nanoparticles into the nanofiber structures provide a second option for delivery of dual active ingredients in the same formulation. The release rate of the active ingredients can also be modified easily by the formulation parameters depending on the desired release time for treatment. Nanofibers systems are used for the delivery of antibiotics, anticancer drugs, analgesics, hemostatic agents and various proteins for tissue engineering purposes. In addition, various applications such as medical device coating also provide new insights for the clinical use of nanofibers. The most commonly used technique for preparation of nanofibers is the electrospinning, which provides feasibility background for scale up process from laboratory to the industrial applications. The main boundary for nanofibers is the limitations for systemic route. Nanofibers are mainly designed for the delivery of active ingredients for local purposes. Regardless of the therapeutic aim, nanofibers are also perfect 3 dimensional structures that are suitable for tissue regeneration. They provide matrix structure for cell regeneration especially in applications for wound healing. This review is mainly focused on the recent advances on the preparation of nanofibers, applications for drug delivery, tissue engineering and wound healing purposes. PMID- 28017156 TI - Sugar Based Biopolymers in Nanomedicine; New Emerging Era for Cancer Imaging and Therapy. AB - Since last decade, sugar based biopolymers are recognized in nanomedicine as promising materials for cancer imaging and therapy. Their durable, biocompatible and adhesive properties enable the fine tuning of their molecular weights (MW) and their miscellaneous nature makes the molecules acquire various conformations. These in turn provide effective endocytosis by cancer cell membranes that have already been programmed for internalization of different kinds of sugars. Therefore, biocompatible sugar based nanoparticles (SBNPs) are suitable for both cell-selective delivery of drugs and imaging through the human body. Recently, well known sugar-based markers have displayed superior performance to overcome tumor metastasis. Thereby, targeting strategies for cancer cells have been broadened to sugar-based markers as noticed in various clinic phases. In these studies, biopolymers such as chitosan, hyaluronic acid, mannan, dextran, levan, pectin, cyclodextrin, chondroitin sulphate, alginates, amylose and heparin are chemically functionalized and structurally designed as new biocompatible nanoparticles (NPs). The future cancer treatment strategies will mainly comprise of these multifunctional sugar based nanoparticles which combine the therapeutic agents with imaging technologies with the aim of rapid monitoring response to therapies. While each individual imaging and treatment step requires a long time period in effective treatment of diseases, these multifunctional sugar based nanoparticles will have the advantage of rapid detection, right drug efficiency evaluation and immediate interfere opportunity to some important diseases, especially rapidly progressing cancers. In this article, we evaluated synthesis, characterization and applications of main sugar based biopolymers and discussed their great promise in nano-formulations for cancer imaging and therapy. However much should be done and optimized prior to clinical applications of these nano formulations for an efficient drug treatment without overall toxicity for getting most effective clinical results. PMID- 28017157 TI - Nanocarriers for Effective Brain Drug Delivery. AB - Drug delivery to the brain is an engaged research topic in the field of nanomedicine. The passage of therapeutics into the brain parenchyma is more complicated than other body tissues due to it is limited by restrict barrier structure called blood-brain barrier (BBB). Nanotechnology holds great promise to overcome the BBB and thereby enable treatment of neurodegenerative diseases. Nanocarriers have been investigated several times as effective brain drug delivery systems in the past few decades. Physicochemical properties and surface modifications of these carriers play a significant role in terms of brain up taking of nanocarriers. Chemical structures of possible nano sized drug delivery systems have an importance in terms of interactions between cell membranes of brain endothelial cell lines and these interactions can be modified with surface coating strategies using suitable agents. Particle size, surface charge and total molecular mass are also crucial issues which require special attention in order to better understand appropriate properties of nanocarriers to overcome the BBB structure. Different strategies have been demonstrated to facilitate the passage of nanoparticles into the brain parenchyma including attachment of targeting ligands on the nanoparticles' surfaces; this attempt provides site specific action in the brain tissues. This study aims to provide a review of nanocarriers for effective brain drug delivery, in the light of current literature. PMID- 28017158 TI - Amphiphilic Cyclodextrin Derivatives for Targeted Drug Delivery to Tumors. AB - Villiers has extensively studied cyclodextrins, a family of macrocyclic oligosaccharides linked by alpha-1,4 glycosidic bonds, in different fields since their discovery in 1891. The unique structure enabling inclusion complexation for natural cyclodextrins and cyclodextrin derivatives make them attractive for novel drug delivery systems. Cyclodextrins can be modified with long aliphatic chains to render an amphiphilic property and these different amphiphilic cyclodextrins are able to form nanoparticles without surfactants. In the literature, several different amphiphilic cyclodextrins are reported and applied to drug delivery and targeting especially to tumors. Specificly, folateconjugated amphiphilic cyclodextrin derivatives are used for active tumor targeting of poorly water soluble drugs and improve the efficacy and safety of therapeutic agents. On the other hand, effect of positive surface charge has also been under research in the recent years. Polycationic amphiphilic cyclodextrins have shown promise towards forming small complexes with negatively charged molecules such as drugs or plasmid DNA. Polycationic amphiphilic cyclodextrins enhance interaction with cell membrane due to their net positive surface charge. The scope of this review is to describe potential uses and pharmaceutical applications of tumor-targeted amphiphilic cyclodextrins, with focus on folate-conjugated cyclodextrin derivatives and polycationic cyclodextrin derivatives both studied by our group at Hacettepe University. PMID- 28017159 TI - Target Recognition Molecules and Molecular Modeling Studies. AB - Targeted delivery systems aim to deliver drugs to their intended site of action and as such they are expected to show more desired effects and less unwanted effects. The system itself is composed of a vesicle-encapsulated drug with "target recognition molecules" on the envelop. Ideally, these target recognition molecules, being either small non-peptidic molecules or peptides, are basically high-affinity ligands for a receptor or other protein that is expressed specifically and at high concentrations on the target cells. This review will focus on several widely used examples of target recognition molecules and on how molecular modelling studies have been used in the development of nano drug carrier systems in general. PMID- 28017160 TI - The effects of intra-cerebroventricular administered rocuronium on the central nervous system of rats and determination of its epileptic seizure-inducing dose. AB - BACKGROUND: The aim of this study was to investigate the effects of intracerebroventricularly administered rocuronium bromide on the central nervous system, determine the seizure threshold dose of rocuronium bromide in rats, and investigate the effects of rocuronium on the central nervous system at 1/5, 1/10, and 1/100 dilutions of the determined seizure threshold dose. METHODS: A permanent cannula was placed in the lateral cerebral ventricle of the animals. The study was designed in two phases. In the first phase, the seizure threshold dose of rocuronium bromide was determined. In the second phase, Group R 1/5 (n=6), Group 1/10 (n=6), and Group 1/100 (n=6) were formed using doses of 1/5, 1/10, and 1/100, respectively, of the obtained rocuronium bromide seizure threshold dose. RESULTS: The rocuronium bromide seizure threshold value was found to be 0.056+/-0.009MUmoL. The seizure threshold, as a function of the body weight of rats, was calculated as 0.286MUmoL/kg-1. A dose of 1/5 of the seizure threshold dose primarily caused splayed limbs, posturing, and tremors of the entire body, whereas the dose of 1/10 of the seizure threshold dose caused agitation and shivering. A dose of 1/100 of the seizure threshold dose was associated with decreased locomotor activity. CONCLUSIONS: This study showed that rocuronium bromide has dose-related deleterious effects on the central nervous system and can produce dose-dependent excitatory effects and seizures. PMID- 28017161 TI - Ultrasound-guided peripheral nerve blocks in anticoagulated patients - case series. AB - BACKGROUND AND OBJECTIVES: The advent of ultrasound has brought many benefits to peripheral nerve blocks. It includes both safety and effectiveness, given the possibility of visualizing the neurovascular structures and the needle during the procedure. Despite these benefits, there is no consensus in the literature on the use of this technique in anticoagulated patients or with other coagulation disorders. Moreover, peripheral blocks vary in depth, spreadability, and possibility of local compression. However, few societies take it into account when drawing up its recommendations, establishing a single recommendation for performing peripheral blocks, regardless of the route used. The objective of this series is to expand the discussion on peripheral nerve block in anticoagulated patients. CASE REPORTS: This series reports 9 cases of superficial peripheral nerve blocks guided by ultrasound in patients with primary or secondary dyscrasias. All blocks were performed by experienced anesthesiologists in the management of ultrasound, and there was no bruising or neurological injuries in the cases. CONCLUSIONS: This case series support the discussion on conducting surface peripheral nerve blocks and easy local knowledge as the axillary, interscalene, femoral, saphenous or popliteal in anticoagulated patients, on dual antiaggregation therapy and/or with other coagulation disorders, provided that guided by ultrasound and performed by an anesthesiologist with extensive experience in guided nerve blocks. However, larger series should be performed to prove the safety of the technique for these patients. PMID- 28017162 TI - Quadratus lumborum block in chronic pain after abdominal hernia repair: case report. AB - BACKGROUND AND OBJECTIVES: The quadratus lumborum blockade was described by R. Blanco in its two approaches (I and II). The local anesthetic deposition in this location can provide blockade to T6-L1 dermatomes. We performed this fascia blockade guided by ultrasound for treating a chronic neuropathic pain in the abdominal wall. CASE REPORT: Male patient, 61 years old, 83kg, with a history of thrombocytopenia due to alcoholic cirrhosis, among others; had chronic pain in the abdominal wall after multiple abdominal hernia repairs in the last year and a half, with poor response to treatment with neuromodulators and opioids. On clinical examination, he revealed a neuropathic pain, with prevalence of allodynia to touch, covering the entire anterior abdominal wall, from T7 to T12 dermatomes. We opted for a quadratus lumborum block type II, guided by ultrasound, with administration of 0.2% ropivacaine (25mL) and depot (vial) methylprednisolone (20mg) on each side. The procedure gave immediate relief of symptoms and, after six months, the patient still had a significant reduction in allodynia without compromising the quality of life. CONCLUSIONS: We consider that performing the quadratus lumborum block type II was an important analgesic option in the treatment of a patient with chronic pain after abdominal hernia repair, emphasizing the effects of local anesthetic spread to the thoracic paravertebral space. The technique has proven to be safe and well tolerated. The publication of more clinical cases reporting the effectiveness of this blockade for chronic pain is desirable. PMID- 28017163 TI - Post-spinal hyperacute subdural hematoma. PMID- 28017164 TI - Preventing atelectasia at robotic surgery. PMID- 28017165 TI - Simple method for determining the size of the ProSeal laryngeal mask airway in children: a prospective observational study. AB - BACKGROUND AND OBJECTIVES: The size of the ProSeal laryngeal mask airway in children is determined by the patient's weight. However, in some instances, an alternative method may be required. This study aimed to compare sizing by the auricle with conventional ProSeal laryngeal mask airway sizing by weight in children. METHODS: After approval by the institutional ethics board and written informed consent from parents, 197 children with American Society of Anesthesiologists physical status I-II who were scheduled for a routine genitourinary operation were included in the study. The correct ProSeal laryngeal mask airway size was determined according to the size of the auricle in children. The results were compared with the standard weight-based method recommended by the manufacturer's guidelines. The patients were classified into different groups depending on the ProSeal laryngeal mask airway sizes as determined by both methods. Agreement between both techniques was evaluated with kappa coefficient statistics. RESULTS: Insertion and adequate ventilation were achieved in 185 patients at the first attempt, and 12 patients required a second attempt. Three patients had to be intubated. Agreement between the two methods of size selection of the ProSeal laryngeal mask airway was moderate using kappa statistics. CONCLUSIONS: Choosing the size of the ProSeal laryngeal mask airway in children according to the auricle of the child is valid and practical. In particular, this is an alternative method in situations where the patient's weight is unknown, such as in emergency situations. PMID- 28017166 TI - Comparison of transforaminal and interlaminar epidural steroid injections for the treatment of chronic lumbar pain. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: We compared the 12 month outcomes of fluoroscopically guided transforaminal epidural steroid injections with interlaminar epidural steroid injections for the treatment of chronic lumbar spinal pain. Chronic lower back pain is a multifactorial disorder with many possible etiologies. The lifetime prevalence of spinal pain is reportedly 65-80% in the neck and lower back. Epidural injection of corticosteroids is a commonly used intervention for managing chronic spinal pain. METHODS: Patients who did not benefit from previous treatments were included in this study. Injections were performed according to magnetic resonance imaging findings at the nearest level of lumbar pathology; 173 patients received interlaminar epidural steroid injections and 126 patients received transforaminal epidural steroid injections. All of the patients were regularly followed up for 12 months using a verbal numeric rating scale. Magnetic resonance imaging findings, complications, verbal numeric rating scale, and satisfaction scores were recorded. RESULTS: Lumbar disk pathology was the most frequently encountered problem. The interlaminar epidural steroid injections were preferred at the L4-L5 intervertebral level. Verbal numeric rating scale scores significantly decreased during the 12-month period compared to basal scores (p<0.001). Significant differences between the two groups according to verbal numeric rating scale and satisfaction scores were not observed (p>0.05). There were no major complications; however, the interlaminar epidural steroid injections group had 22 (12.7%) minor complications, and the transforaminal epidural steroid injections group had 12 (9.5%) minor complications. CONCLUSIONS: This study showed that interlaminar epidural steroid injections can be as effective as transforaminal epidural steroid injections when performed at the nearest level of lumbar pathology using fluoroscopy in 12-month intervals. PMID- 28017167 TI - Effects of different levels of end-expiratory pressure on hemodynamic, respiratory mechanics and systemic stress response during laparoscopic cholecystectomy. AB - OBJECTIVE: General anesthesia causes reduction of functional residual capacity. And this decrease can lead to atelectasis and intrapulmonary shunting in the lung. In this study we want to evaluate the effects of 5 and 10cmH2O PEEP levels on gas exchange, hemodynamic, respiratory mechanics and systemic stress response in laparoscopic cholecystectomy. METHODS: American Society of Anesthesiologist I II physical status 43 patients scheduled for laparoscopic cholecystectomy were randomly selected to receive external PEEP of 5cmH2O (PEEP 5 group) or 10cmH2O PEEP (PEEP 10 group) during pneumoperitoneum. Basal hemodynamic parameters were recorded, and arterial blood gases (ABG) and blood sampling were done for cortisol, insulin and glucose level estimations to assess the systemic stress response before induction of anesthesia. Thirty minutes after the pneumoperitoneum, the respiratory and hemodynamic parameters were recorded again and ABG and sampling for cortisol, insulin, and glucose levels were repeated. Lastly hemodynamic parameters were recorded; ABG analysis and sampling for stress response levels were taken after 60minutes from extubation. RESULTS: There were no statistical differences between the two groups about hemodynamic and respiratory parameters except mean airway pressure (Pmean). Pmean, compliance and PaO2; pH values were higher in 'PEEP 10 group'. Also, PaCO2 values were lower in 'PEEP 10 group'. No differences were observed between insulin and lactic acid levels in the two groups. But postoperative cortisol level was significantly lower in 'PEEP 10 group'. CONCLUSION: Ventilation with 10cmH2O PEEP increases compliance and oxygenation, does not cause hemodynamic and respiratory complications and reduces the postoperative stress response. PMID- 28017168 TI - Comparisons of the effects of the sevoflurane and propofol on acute ischemia reperfusion and DNA damages in rabbits. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to compare the effects of sevoflurane and propofol anesthesia on oxidative DNA damage that occurs in low extremity ischemia and is caused by tourniquet application. METHODS: Fourteen New Zealand rabbits were randomly allocated into two equal groups. Group S (n=7) received sevoflurane (2.5-4 percent) inhalation and Group P (n=7) received a propofol infusion (1-2mg.kg-1.min-1), after which a pneumatic tourniquet was placed on the right lower extremity. Blood samples were collected prior to tourniquet placement (baseline), 120min after ischemia, 15min after ischemia and 120minutes (min) after ischemia. Malondialdehyde (MDA) levels were analyzed to determine lipid peroxidation, and single cell gel electrophoresis (SCGE) was used to determine DNA damage. RESULTS: At 15min after ischemia, the MDA levels in Group P (8.15+/-2.61MUM) were higher than baseline (6.26+/-3.19MUM, p=0.026) and Group S (4.98+/-0.77MUM, p=0.01). DNA damage was similar in both groups, although DNA damage was higher than baseline (tail moment 0.63+/-0.27, tail intensity 3.76+/-1.26) in Group P at the 15th minute of reperfusion (tail moment 1.05+/ 0.45, p=0.06; tail intensity 5.33+/-1.56, p=0.01). The increase in tail moment and tail intensity returned to normal levels in both groups 2hours after the termination of ischemia. CONCLUSION: Given that oxidative stress and genotoxic effect disappear in the late stages of reperfusion, we conclude that neither sevoflurane nor propofol can be considered superior to the other in anesthesia practices for extremity surgeries involving the use of a tourniquet. PMID- 28017169 TI - The effect of intra-articular levobupivacaine on shoulder cartilage at different doses-experimental study. AB - BACKGROUND AND OBJECTIVES: In this study it was aimed to examine the histological and morphometric effects on cartilage structure of intra-articular application of levobupivacaine to the shoulder joint. METHODS: In twenty New Zealand adult male rabbits, 35 shoulders were used for the study and prepared in 5 groups of 7. These groups were defined as Groups L1, L2, L3 and L4 which were right shoulders administered with 0.25% and 0.5% levobupivacaine, Group C which were left shoulders as the control group and Groups S1 and S2 which were left shoulders administered with 0.9% saline. On the 2nd and 15th days the animals were killed, the glenohumeral joints were evaluated macroscopically then cartilage samples were taken. These samples were evaluated with Mankin score, and histomorphometrically by measuring the thickness of the cartilage between the superficial cartilage layer and the tidemark and the thickness of calcified cartilage between the tidemark and the subchondral bone. RESULTS: Macroscopically, on the 15th day the joint fluid was seen to have reduced in all the groups. After microscopic evaluation, the highest Mankin score (mean: 3.14+/ 2.1/14) was in the L4 group (15th day 0.5% levobupivacaine) and was found to be statistically significant (p<0.05). No statistically significant difference was determined between the other groups. CONCLUSIONS: Histologically, as the highest Mankin score was in the L4 group, this indicates that in a single intra-articular injection of levobupivacaine a low concentration should be selected. LEVEL OF EVIDENCE: Level 5, animal study. PMID- 28017170 TI - Effects of lidocaine and magnesium sulfate in attenuating hemodynamic response to tracheal intubation: single-center, prospective, double-blind, randomized study. AB - BACKGROUND AND OBJECTIVES: Hemodynamic response to airway stimuli is a common phenomenon and its management is important to reduce the systemic repercussions. The objective of this study is to compare the efficacy of intravenous magnesium sulfate versus lidocaine on this reflex hemodynamics after laryngoscopy and tracheal intubation. METHODS: This single-center, prospective, double-blind, randomized study evaluated 56 patients ASA 1 or 2, aged 18-65 years, scheduled for elective surgeries under general anesthesia with intubation. The patients were allocated into two groups: Group F received 30mg.kg-1 of magnesium sulphate and Group L, 2mg.kg-1 of lidocaine, continuous infusion, immediately before the anesthetic induction. Blood pressure (BP), heart rate (HR), and bispectral index (BIS) were measured in both groups at six different times related to administration of the study drugs. RESULTS: In both groups there was an increase in HR and BP after laryngoscopy and intubation, compared to baseline. Group M showed statistically significant increase in the values of systolic and diastolic blood pressure after intubation, which was clinically unimportant. There was no difference in the BIS values between groups. Among patients receiving magnesium sulfate, three (12%) had high blood pressure versus only one among those receiving lidocaine (4%), with no statistical difference. CONCLUSION: Magnesium sulfate and lidocaine have good efficacy and safety for hemodynamic management in laryngoscopy and intubation. PMID- 28017171 TI - Perineural dexmedetomidine effects on sciatic nerve in rat. AB - The present study was designed to test the hypothesis that high dose dexmedetomidine would increase the duration of antinociception to a thermal stimulus in a rat model of sciatic nerve blockade without causing nerve damage. The rats were anesthetized with isoflurane. After electromyography (EMG) recordings, right sciatic nerves were explored and perineural injections were delivered: Group D (n=7), 40MUgMUgkg-1 dexmedetomidine administration, Group II (n=6), (0.2mL) saline administration, Group III (n=2), only surgically exploration of the right sciatic nevre. Time to paw withdrawal latency (PAW) to a thermal stimulus for both paws and an assessment of motor function were measured every 30min after the nerve block until a return to baseline. The compound muscle action potential (CMAP) of right and left sciatic nerves were recorded 10 times per each nerve once more after perineural injections at 14 day. After EMG recordings, right and the part of left sciatic nerve were excised at a length of at minimum 15mm for histopathological examination. Comparison of right/left CMAP amplitude ratios before and 14 days after the procedure showed a statistically significant difference (p=0.000). There were no differences in perineural inflammation between the Group D, Group S, and Group E at 14 days. PMID- 28017173 TI - Femoral nerve block versus intravenous fentanyl in adult patients with hip fractures - a systematic review. AB - BACKGROUND: Hip fractures configure an important public health issue and are associated with high mortality taxes and lose of functionality. Hip fractures refer to a fracture occurring between the edge of the femoral head and 5cm below the lesser trochanter. They are common in orthopedic emergencies. The number of proximal femoral fractures is likely to increase as the population ages. The average cost of care during the initial hospitalization for hip fracture can be estimated about US$ 7,000 per patient. Femoral fractures are painful and need immediate adequate analgesia. Treating pain femoral fractures is difficult because there are limited numbers of analgesics available, many of which have side effects that can limit their use. Opiates are the most used drugs, but they can bring some complications. In this context, femoral nerve blocks can be a safe alternative. It is a specific regional anesthetic technique used by doctors in emergency medicine to provide anesthesia and analgesia of the affected leg. OBJECTIVE: To compare the analgesic efficacy of intravenous fentanyl versus femoral nerve block before positioning to perform spinal anesthesia in patients with femoral fractures assessed by Pain Scales. METHODS: A systematic review of scientific literature was conducted. Studies described as randomized controlled trials comparing femoral nerve block and traditional fentanyl are included. Two reviewers (MR and FH) independently assessed potentially eligible trials for inclusion. The methodology assessment was based on the tool developed by the Cochrane Collaboration for assessment of bias for randomized controlled trials. The Cochrane Library, Pubmed, Medline and Lilacs were searched for all articles published, without restriction of language or time. RESULTS: Two studies were included in this review. Nerve blockade seemed to be more effective than intravenous fentanyl for preventing pain in patients suffering from a femoral fracture. It also reduced the use of additional analgesia and made lower the risk for systemic complications. Femoral nerve block reduced the time to perform spinal anesthesia to the patient who will be subjected to surgery and facilitate the sitting position for this. CONCLUSION: The use of femoral nerve block can reduce the level of pain and the need for additional analgesia. There are less adverse systemic events associated with this and the procedure itself does not offer greater risks. More studies are required for further conclusions. PMID- 28017172 TI - Design and validation of an oral health questionnaire for preoperative anaesthetic evaluation. AB - BACKGROUND AND OBJECTIVES: Dental injuries incurred during endotracheal intubation are more frequent in patients with previous oral pathology. The study objectives were to develop an oral health questionnaire for preanaesthesia evaluation, easy to apply for personnel without special dental training; and establish a cut-off value for detecting persons with poor oral health. METHODS: Validation study of a self-administered questionnaire, designed according to a literature review and an expert group's recommendations. The questionnaire was applied to a sample of patients evaluated in a preanaesthesia consultation. Rasch analysis of the questionnaire psychometric properties included viability, acceptability, content validity and reliability of the scale. RESULTS: The sample included 115 individuals, 50.4% of men, with a median age of 58 years (range: 38 71). The final analysis of 11 items presented a Person Separation Index of 0.861 and good adjustment of data to the Rasch model. The scale was unidimensional and its items were not biased by sex, age or nationality. The oral health linear measure presented good construct validity. The cut-off value was set at 52 points. CONCLUSIONS: The questionnaire showed sufficient psychometric properties to be considered a reliable tool, valid for measuring the state of oral health in preoperative anaesthetic evaluations. PMID- 28017174 TI - Benefit of general anesthesia monitored by bispectral index compared with monitoring guided only by clinical parameters. Systematic review and meta analysis. AB - BACKGROUND: The bispectral index parameter is used to guide the titration of general anesthesia; however, many studies have shown conflicting results regarding the benefits of bispectral index monitoring. The objective of this systematic review with meta-analysis is to evaluate the clinical impact of monitoring with the bispectral index parameter. METHODS: The search for evidence in scientific information sources was conducted during December 2013 to January 2015, the following primary databases: Medline/PubMed, LILACS, Cochrane, CINAHL, Ovid, SCOPUS and TESES. The criteria for inclusion in the study were randomized controlled trials, comparing general anesthesia monitored, with bispectral index parameter with anesthesia guided solely by clinical parameters, and patients aged over 18 years. The criteria for exclusion were studies involving anesthesia or sedation for diagnostic procedures, and intraoperative wake-up test for surgery of the spine. RESULTS: The use of monitoring with the bispectral index has shown benefits reducing time to extubation, orientation in time and place, and discharge from both the operating room and post anesthetic care unit. The risk of nausea and vomiting after surgery was reduced by 12% in patients monitored with bispectral index. Occurred a reduction of 3% in the risk of cognitive impairment postoperatively at 3 months postoperatively and 6% reduction in the risk of postoperative delirium in patients monitored with bispectral index. Furthermore, the risk of intraoperative memory has been reduced by 1%. CONCLUSION: Clinically, anesthesia monitoring with the BIS can be justified because it allows advantages from reducing the recovery time after waking, mainly by reducing the administration of general anesthetics as well as the risk of adverse events. PMID- 28017175 TI - Anesthesia for cesarean section in a patient with isolated unilateral absence of a pulmonary artery. AB - BACKGROUND AND OBJECTIVES: Congenital unilateral absence of a pulmonary artery (UAPA) is a rare anomaly. Although there are several reports regarding pregnancy in patients with unilateral absence of a pulmonary artery, there are no case reports describing anesthesia for Cesarean section in a patient with unilateral absence of a pulmonary artery. CASE REPORT: We present a patient with unilateral absence of a pulmonary artery who underwent Cesarean sections twice at the ages of 24 and 26 years under spinal anesthesia for surgery and epidural analgesia for postoperative pain relief. Both times, spinal anesthesia and epidural analgesia enabled successful anesthesia management without the development of either pulmonary hypertension or right heart failure. CONCLUSION: Spinal anesthesia combined with epidural analgesia is a useful anesthetic method for a Cesarean section in patients with unilateral absence of a pulmonary artery. PMID- 28017176 TI - Levosimendan as a treatment for acute renal failure associated with cardiogenic shock after hip fracture. AB - Inotropic drugs are part of the treatment of heart failure; however, inotropic treatment has been largely debated due to the increased incidence of adverse effects and increased mortality. Recently levosimendan, an inotropic positive agent, has been proved to be effective in acute heart failure, reducing the mortality and improving cardiac and renal performance. We report the case of a 75 year-old woman with history of heart and renal failure and hip fracture. Levosimendan was used in preoperative preparation as an adjuvant therapy, to improve cardiac and renal function and to allow surgery. PMID- 28017177 TI - Maintenance of balance between airway pressure and intracranial pressure in a patient with tracheal stenosis undergoing craniotomy: a case report. AB - BACKGROUND AND OBJECTIVES: Tracheal stenosis is a rare but a life-threatening condition and anesthesia of a patient with tracheal stenosis is challenging for anesthesiologists. Maintaining stable hemodynamics and ventilation parameters are important issues in neuroanesthesia. Any increase in airway peak pressure and ETCO2 will result in increase in intracranial pressure which must be avoided during craniotomies. Tracheal stenosis could be a reason for increased airway pressure. CASE REPORT: We described a patient undergoing craniotomy with tracheal stenosis. CONCLUSION: Detailed preparation for intubation, to stabilize airway dynamics and to make the right decision for the surgery were important points. To maintain of a good balance between cerebral dynamics and airway dynamics were the pearls of this case. PMID- 28017178 TI - Anesthesia for pulmonary trunk aneurysmorrhaphy. AB - BACKGROUND AND OBJECTIVES: The aneurysm in the pulmonary trunk is a rare disease. Because of its location, a rupture can lead to right ventricular failure and sudden death. Aneurysmorraphy is the most widely used surgical treatment in these cases. The aim of this study is to report a successful balanced general anesthesia for aneurysmorraphy of pulmonary trunk. CASE REPORT: Male patient, 28 years, asymptomatic, diagnosed with an aneurysm in the pulmonary trunk. According to the location of the aneurysm and the consequent failure of the pulmonary valve, an aneurysmorraphy was indicated, with implantation of vascular-valvular prosthesis (valved tube). We opted for a balanced general anesthesia, seeking to prevent an increase in systemic and pulmonary vascular resistances, thus avoiding to cause stress on the wall of the aneurysmal vessel. CONCLUSIONS: A balanced general anesthesia, in combination with adequate ventilation to prevent elevation in pulmonary vascular pressure, was appropriate for surgical repair of an aneurysm in the pulmonary trunk. PMID- 28017179 TI - Does mental status impact therapist and patient communication in emergency department brief interventions addressing alcohol use? AB - Motivational interviewing (MI) is often incorporated into screening, brief intervention, and referral to treatment (SBIRT) interventions in critical care settings to address alcohol and other drug use. However, cognitive status has been linked to differential response to MI sessions in emergency department (ED) settings. The current study examined one possible explanation for this differential response: whether higher versus lower mental status impacts patient response to clinician statements during MI sessions conducted in an ED. Participants were 126 patients receiving an MI-based single-session alcohol brief intervention, and 13 therapists who provided treatment. Participants completed a mental status exam (MSE) as part of the screening process. Intervention sessions were audio-taped, and transcribed and coded using the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003). The MISC 2.0 coded therapist behaviors that are related to the use of motivational interviewing, and patient language reflecting movement toward (change talk) or away from (sustain talk) changing personal alcohol use. Overall, patients responded in a similar manner to therapist MI behaviors regardless of high versus low level of mental functioning at the time of the intervention. Group differences emerged on patient response to only three specific therapist skills: giving information, open questions, and complex reflection. Thus, the differential effects of SBIRT in critical care settings do not appear to be a result of differences in the therapist and patient communication process. PMID- 28017180 TI - Comparison of 12-step groups to mutual help alternatives for AUD in a large, national study: Differences in membership characteristics and group participation, cohesion, and satisfaction. AB - BACKGROUND: Many studies suggest that participation in 12-step groups contributes to better recovery outcomes, but people often object to such groups and most do not sustain regular involvement. Yet, research on alternatives to 12-step groups is very sparse. The present study aimed to extend the knowledge base on mutual help group alternatives for those with an alcohol use disorder (AUD), sampling from large, active, abstinence-focused groups including Women for Sobriety (WFS), LifeRing, and SMART Recovery (SMART). This paper presents a cross-sectional analysis of this longitudinal study, using baseline data to describe the profile and participation characteristics of attendees of these groups in comparison to 12-step members. METHODS: Data from participants 18 and over with a lifetime AUD (N=651) were collected using Web-based surveys. Members of alternative 12-step groups were recruited in collaboration with group directors, who helped publicize the study by emailing meeting conveners and attendees and posting announcements on social media. A comparison group of current (past-30-day) 12-step attendees was recruited from an online meeting hub for recovering persons. Interested parties were directed to a Webpage where they were screened, and eligible participants completed an online survey assessing demographic and clinical variables; in-person and online mutual help involvement; and group satisfaction and cohesion. Analyses involved comparing those identifying WFS, SMART, and LifeRing as their primary group to 12-step members on the above characteristics. RESULTS: Compared to 12-step members, members of the mutual help alternatives were less religious and generally higher on education and income. WFS and LifeRing members were also older, more likely to be married, and lower on lifetime drug and psychiatric severity; meanwhile, LifeRing and SMART members were less likely to endorse the most stringent abstinence goal. Finally, despite lower levels of in-person meeting attendance, members of all the 12-step alternatives showed equivalent activity involvement and higher levels of satisfaction and cohesion, compared to 12-step members. CONCLUSIONS: Results suggest differences across 12-step groups and their alternatives that may be relevant when advising clients on a choice of mutual help group. Meanwhile, findings for high levels of participation, satisfaction, and cohesion among members of the mutual help alternatives suggest promise for these groups in addressing addiction problems. PMID- 28017181 TI - Racial/ethnic differences in initiation of and engagement with addictions treatment among patients with alcohol use disorders in the veterans health administration. AB - OBJECTIVE: Specialty addictions treatment can improve outcomes for patients with alcohol use disorders (AUD). Thus, initiation of and engagement with specialty addictions treatment are considered quality care for patients with AUD. Previous studies have demonstrated racial/ethnic differences in alcohol-related care but whether differences exist in initiation of and engagement with specialty addictions treatment among patients with clinically recognized alcohol use disorders is unknown. We investigated racial/ethnic variation in initiation of and engagement with specialty addictions treatment in a national sample of Black, Hispanic, and White patients with clinically recognized alcohol use disorders (AUD) from the US Veterans Health Administration (VA). METHODS: National VA data were extracted for all Black, Hispanic, and White patients with a diagnosed AUD during fiscal year 2012. Mixed effects regression models estimated the odds of two measures of initiation (an initial visit within 180days of diagnosis; and initiation defined consistent with Healthcare Effectiveness Data and Information Set (HEDIS) as a documented visit <=14days after index visit or inpatient admission), and three established measures of treatment engagement (>=3 visits within first month after initiation; >=2 visits in each of the first 3months after initiation; and >=2 visits within 30days of HEDIS initiation) for Black and Hispanic relative to White patients after adjustment for facility- and patient level characteristics. RESULTS: Among 302,406 patients with AUD, 30% (90,879) initiated treatment within 180days of diagnosis (38% Black, 32% Hispanic, and 27% White). Black patients were more likely to initiate treatment than Whites for both measures of initiation [odds ratio (OR) for initiation: 1.4, 95% confidence interval (CI) 1.4-1.4; OR for HEDIS initiation: 1.1, 95% CI: 1.1-1.1]. Hispanic patients were more likely than White patients to initiate treatment within 180days (OR: 1.2, 95% CI 1.2-1.3) but HEDIS initiation did not differ between Hispanic and White patients. Engagement results varied depending on the measure but was more likely for Black patients relative to White for all measures (OR for engagement in first month: 1.1, 95% CI: 1.0-1.1; OR for engagement in first three months: 1.2, 95% CI: 1.1-1.2; OR for HEDIS measure: 1.1, 95% CI: 1.0-1.1), and did not differ between Hispanic and White patients. CONCLUSIONS: After accounting for facility- and patient-level characteristics, Black and Hispanic patients with AUD were more likely than Whites to initiate specialty addictions treatment, and Black patients were more likely than Whites to engage. Research is needed to understand underlying mechanisms and whether differences in initiation of and engagement with care influence health outcomes. PMID- 28017182 TI - Prevalence of restless legs syndrome during detoxification from alcohol and opioids. AB - BACKGROUND AND AIMS: Restless legs syndrome (RLS) is a movement disorder associated with adverse health outcomes and decreased quality of life. Small case series suggest that symptoms of RLS occur during opioid withdrawal. However, the prevalence is unknown. METHODS: We conducted an observational study to determine the prevalence of RLS among inpatients patients receiving buprenorphine detoxification from opioids. To assess the specificity of RLS to opioid detoxification, we also evaluated patients receiving detoxification from alcohol as a comparison group. The diagnosis of RLS was established using a validated questionnaire. RESULTS: The sample consisted of 124 adults with primary opioid use disorder and 180 with primary alcohol use disorder. In the total sample, 33.6% met a likely RLS diagnosis: 50.8% of those with opioid use disorder and 21.7% of those with alcohol use disorder (chi2 = 27.96[1,304] p < .001). In the logistic regression analysis controlling for socio-demographic and clinical variables, diagnosis of opioid use disorder was associated with more than twice the likelihood of RLS diagnosis (OR=2.05, 95% CI 1.09-3.88) relative to diagnosis of alcohol use disorder. CONCLUSIONS: Approximately half of patients undergoing inpatient opioid detoxification exhibited the symptoms characteristic of RLS. We believe that these data support the existence of a secondary form of RLS associated with opioid withdrawal. PMID- 28017183 TI - Quitting smoking during substance use disorders treatment: Patient and treatment related variables. AB - Although individuals in substance use disorders (SUD) treatment continue to smoke at high rates, regulatory, policy and programming changes promoting tobacco cessation are being implemented and some patients quit successfully. We examined associations of smoking patterns, tobacco advertising receptivity, anti-tobacco message awareness, health risk perception, attitudes towards addressing smoking and availability of smoking cessation services with quitting smoking during SUD treatment. Surveys were completed by 1127 patients in 24 programs chosen randomly, stratified by program type (residential, methadone maintenance, outpatient), from among publicly funded, adult treatment programs within the National Drug Abuse Treatment Clinical Trials Network. Among respondents who had been in SUD treatment for at least one month, there were 631 current smokers and 52 former smokers who reported quitting smoking during treatment for at least one month prior to survey completion; these respondents comprised our sample (N=683). Results showed that participants who reported health concerns as a reason for quitting were 1.27 times more likely to have quit during treatment (p=0.015) than those reporting health concerns affected quitting a little or not at all. Additionally, participants who reported that smoking cessation was part of their personal treatment plan during SUD treatment were 1.08 times more likely to have quit during treatment (p<0.001). Participants in methadone treatment were 49% less likely to report successfully quitting during treatment than those in outpatient treatment (95%CI: 0. 35-0.75, p<0.001). Leveraging health concerns about smoking and including smoking cessation in an individualized treatment plan may help increase smoking cessation during SUD treatment. PMID- 28017184 TI - Patient-reported pathways to opioid use disorders and pain-related barriers to treatment engagement. AB - BACKGROUND: Risk factors associated with developing opioid use disorders (OUD) are documented, but less is known about different pathways to initiation of opioids or opioid dependence, or how such pathways affect treatment engagement. METHODS: We recruited 283 adults with electronic medical record (EMR) evidence of opioid dependence diagnoses. Open-ended and structured interview items focused on prior opioid treatment experiences, barriers to and knowledge of treatment options. Interviews were audio-recorded, transcribed, and coded. In exploratory analyses, we used a modified grounded theory approach to organize emergent, patient-reported themes describing participants' perceived pathways to opioid dependence. RESULTS: 121 participants described one or more pathways to OUD. Qualitative analyses revealed five pathway themes. Three pathways were related to pain control: inadequately controlled chronic pain, exposure to opioids during acute pain episodes, and chronic pain among individuals with prior substance use disorders. A fourth pathway included individuals for whom opioids provided relief from emotional distress; the fifth related to recreational or non-medically supervised opioid use. We identified pain-related barriers to reducing/stopping opioids and treatment engagement barriers among individuals who perceived themselves solely as pain patients. CONCLUSION: Patients' perceptions of inadequately controlled pain, patients' previous substance use disorders, and the relief from emotional distress that some patients feel while using opioids are relevant when making clinical decisions about whether to initiate or sustain opioid therapy, and for how to monitor certain individuals. Among individuals with pain and OUD, treatment barriers include fear of uncontrolled pain, and stigmatization of being treated alongside people with non-medical opioid use. PMID- 28017185 TI - Failure to get into substance abuse treatment. AB - Among substance abusers in the US, the discrepancy in the number who access substance abuse treatment and the number who need treatment is sizable. This results in a major public health problem of access to treatment. The purpose of this study was to examine characteristics of Persons Who Use Drugs (PWUDs) that either hinder or facilitate access to treatment. 2646 participants were administered the Risk Behavior Assessment (RBA) and the Barratt Impulsiveness Scale. The RBA included the dependent variable which was responses to the question "During the last year, have you ever tried, but been unable, to get into a drug treatment or detox program?" In multivariate analysis, factors associated with being unable to access treatment included: Previously been in drug treatment (OR=4.51), number of days taken amphetamines in the last 30days (OR=1.18), traded sex for drugs (OR=1.53), homeless (OR=1.73), Nonplanning subscale of the Barratt Impulsiveness Scale (OR=1.19), age at interview (OR=0.91), and sexual orientation, with bisexual men and women significantly more likely than heterosexuals to have tried but been unable to get into treatment. The answers to the question on "why were you unable to get into treatment" included: No room, waiting list; not enough money, did not qualify, got appointment but no follow through, still using drugs, and went to jail before program start. As expected, findings suggest that limiting organizational and financial obstacles to treatment may go a long way in increasing drug abuse treatment accessibility to individuals in need. Additionally, our study points to the importance of developing approaches for increasing personal planning skills/reducing Nonplanning impulsivity among PWUDs when they are in treatment as a key strategy to ensure access to additional substance abuse treatment in the future. PMID- 28017186 TI - Carvedilol does not reduce cocaine use in methadone-maintained cocaine users. AB - INTRODUCTION: The goal of this study was too test the efficacy of carvedilol (CAR), an adrenergic blocker, for reducing cocaine use in individuals with cocaine use disorder (CUD). We conducted a 17-week, double-blind, randomized controlled trial with 3 treatment arms: 25mg CAR, 50mg CAR, and placebo. METHODS: One hundred and six treatment-seeking opioid and cocaine-dependent participants, who were also maintained on methadone during study participation, were randomized to placebo (n=34), 25mg/day CAR (n=37) or 50mg/day CAR (n=35). The main outcome measures were cocaine and opioid use as assessed by urine drug screening and self reported drug use. RESULTS: No significant group differences were found for treatment retention with 56% of the placebo, 76% of the 25mg and 66% of the 50mg CAR groups (p>0.05) completing treatment. The percentage (SD) of cocaine positive urines during the trial showed an overall treatment effect: 59.2 (38.9) for the placebo, 50.8 (33.8) for the 25mg and 75.1 (33.2) for the 50mg CAR group. In post hoc comparisons, neither the 25 nor 50mg CAR condition differed significantly from the placebo; however, the 25mg CAR group had a significantly lower proportion of cocaine-positive urines than the 50mg group. No significant group differences were found for the percentage of self-reported days of cocaine abstinence during the trial: 72.9 (25.3) for placebo, 72.9 (29) for CAR 25mg, and 59.3 (31.7) for CAR 50mg. Significant groups differences in the proportion of opioid positive urines submitted were not observed (p>0.05). Baseline cocaine withdrawal severity did not predict treatment response (p>0.05). CONCLUSIONS: These findings did not support the efficacy of CAR for the treatment of cocaine use in cocaine and opioid dependent participants maintained on methadone. Further, CAR doses >25mg should not be used to avoid possible increases in cocaine and opioid use. PMID- 28017187 TI - AiRCare: A naturalistic evaluation of the effectiveness of a protracted telephone based recovery assistance program on continuing care outcomes. AB - BACKGROUND & OBJECTIVE: Substance use disorder treatments are increasingly being contextualized within a disease management framework. Within this context, there is an identified need to maintain patients in treatment for longer periods of time in order to help them learn how to manage their disease. One way to meet this need is through telephone-based interventions that engage patients, and include more active outreach attempts and involvement of the patient's family. This study sought to evaluate the effectiveness of three formats of an intensive 12-month post-discharge telephone-based case management approach (AiRCare) on adherence to continuing care plans and substance use outcomes. METHODS: Data were abstracted from electronic medical records for 379 patients (59.9% male) discharged from a residential treatment program located in the southwestern U.S. from 2013 to 2015. Patients were categorized into one of three groups and received telephone contacts based on their self-selection upon admission to residential treatment (i.e., patient only, family only, and both patient and family). Outcome variables included re-engagement and re-admission rates, quality of life, abstinence rates at 6 and 12 months, and compliance with continuing care plans. RESULTS & CONCLUSIONS: Favorable short- and long-term outcomes were found for the majority of patients, irrespective of case management group. There appeared to be some value in the addition of family contacts to patient contacts with respect to reducing risk for 12-month re-admission to residential care. These positive but preliminary indications of the effectiveness of AiRCare require replication in a well-powered, randomized controlled trial. PMID- 28017188 TI - Comparing Trigger Point Dry Needling and Manual Pressure Technique for the Management of Myofascial Neck/Shoulder Pain: A Randomized Clinical Trial. AB - OBJECTIVE: The aim of this study was to investigate short-term and long-term treatment effects of dry needling (DN) and manual pressure (MP) technique with the primary goal of determining if DN has better effects on disability, pain, and muscle characteristics in treating myofascial neck/shoulder pain in women. METHODS: In this randomized clinical trial, 42 female office workers with myofascial neck/shoulder pain were randomly allocated to either a DN or MP group and received 4 treatments. They were evaluated with the Neck Disability Index, general numeric rating scale, pressure pain threshold, and muscle characteristics before and after treatment. For each outcome parameter, a linear mixed-model analysis was applied to reveal group-by-time interaction effects or main effects for the factor "time." RESULTS: No significant differences were found between DN and MP. In both groups, significant improvement in the Neck Disability Index was observed after 4 treatments and 3 months (P < .001); the general numerical rating scale also significantly decreased after 3 months. After the 4-week treatment program, there was a significant improvement in pain pressure threshold, muscle elasticity, and stiffness. CONCLUSION: Both treatment techniques lead to short term and long-term treatment effects. Dry needling was found to be no more effective than MP in the treatment of myofascial neck/shoulder pain. PMID- 28017189 TI - [Anesthesia for pulmonary trunk aneurysmorrhaphy]. AB - BACKGROUND AND OBJECTIVES: The aneurysm in the pulmonary trunk is a rare disease. Because of its location, a rupture can lead to right ventricular failure and sudden death. Aneurysmorraphy is the most widely used surgical treatment in these cases. The aim of this study is to report a successful balanced general anesthesia for aneurysmorraphy of pulmonary trunk. CASE REPORT: Male patient, 28 years, asymptomatic, diagnosed with an aneurysm in the pulmonary trunk. According to the location of the aneurysm and the consequent failure of the pulmonary valve, an aneurysmorraphy was indicated, with implantation of vascular-valvular prosthesis (valved tube). We opted for a balanced general anesthesia, seeking to prevent an increase in systemic and pulmonary vascular resistances, thus avoiding to cause stress on the wall of the aneurysmal vessel. CONCLUSIONS: A balanced general anesthesia, in combination with adequate ventilation to prevent elevation in pulmonary vascular pressure, was appropriate for surgical repair of an aneurysm in the pulmonary trunk. PMID- 28017190 TI - Pearls and pitfalls of open access: The immortal life of Henrietta Lacks. PMID- 28017191 TI - The role of very high high-sensitivity C-reactive protein levels on mortality after stroke. AB - : High-sensitivity C-reaction protein (hsCRP) levels are correlated with risk of vascular disease. The clinical implications of markedly elevated hsCRP levels in the setting of acute stroke are less understood. OBJECTIVE: To determine the association of very high admission hsCRP levels (>=10mg/L) on all-cause mortality in patients with acute stroke. METHODS: A retrospective cohort study of 1176 patients hospitalized with acute stroke between 2005 and 2012 who had a hsCRP assay drawn within seven days of admission. Mortality data was obtained using Ohio Death Index. Cox proportional analysis was used to determine hazard ratios of death among patients with hsCRP values >10mg/L after adjusting for age, sex, race and relevant co-morbid conditions. NIHSS was also adjusted in a subset of patients in whom it was available (n=378). RESULTS: Patients with hsCRP >10mg/L had 2.65 (95% CI: 1.99, 3.53) increased hazard of all-cause mortality compared to stroke patients with hsCRP <=10mg/L. Association of hsCRP with mortality was greater for patients with low NIHSS and declined in patients with increasing NIHSS scores. A higher proportion of patients with hsCRP >10 died from nonvascular causes than patients with hsCRP <=10mg/L. CONCLUSION: Very high levels of hsCRP may be a useful marker to identify stroke patients at increased risk for death, especially those with stroke of mild severity. More research is needed to determine how this information can be used to improve patient care, especially in patients with mild stroke. PMID- 28017192 TI - Successful antibacterial therapy of a spinal epidural abscess in pregnancy: A case report and review of the literature. PMID- 28017194 TI - Pure word deafness due to herpes simplex encephalitis. PMID- 28017193 TI - Does stroke etiology play a role in predicting outcome of acute stroke patients who underwent endovascular treatment with stent retrievers? AB - AIMS: The goal of the study was to identify whether the stroke etiology play a role in the recanalization and outcome of patients who underwent mechanical thrombectomy with stent retrievers. METHODS AND RESULTS: A retrospective analysis of a prospectively collected database included consecutive patients treated with stent retrievers. We included patients with cardioembolic stroke and large vessel atherosclerotic disease and compared risk factors for stroke, baseline NIHSS and Alberta Stroke Program Early CT scores (ASPECTS), stroke outcome, recanalization rate, onset-to-recanalization, onset-to-groin puncture time and the procedural time between two groups. Male sex was statistically more common in patients with large vessel atherosclerotic disease. Mean time from symptom onset- to the achievement of recanalization in patients with LVAD was 242+/-72.4 compared with cardioembolic stroke patients (301+/-70.7; p=0.014). Time for groin puncture to recanalization was longer in patients with cardioembolic stroke compared to LVAD group (97.5+/-44.3 vs 58.2+/-21.8; p=0.002). Time for microcatheter to successful recanalization or procedural termination was longer in patients with cardioembolic stroke compared to LVAD group (63.6+/-30.2 vs 34.2+/-19.4; p<0.001) with cardioembolic stroke had significantly worse long-term outcome (mRS 3-6) compared to those with LVAD (60.6% vs 26.3%; p=0.036). CONCLUSION: Stroke etiology may play a role in the outcome of acute stroke patients who underwent endovascular stroke therapy. Cardioembolic strokes may be more resistant to endovascular acute stroke treatment. PMID- 28017195 TI - Safety and efficacy of fractionated stereotactic radiotherapy and stereotactic radiosurgery for treatment of pituitary adenomas: A systematic review and meta analysis. AB - Accumulated studies have not provided conclusive evidence in regards to the comparative efficacy and safety of fractionated stereotactic radiotherapy and stereotactic radiosurgery for treatment of pituitary adenomas. To address this issue, we performed a meta-analysis with eight studies identified from Medline, PubMed, Cochrane, Google Scholar, and published up to September 17, 2015. Eligible studies reported the disease control rate, endocrine cure rate (for functional adenomas), the rate of occurrence of new-onset hypopituitarism, and visual disturbance rate in patients treated with either stereotactic radiosurgery or fractionated stereotactic radiotherapy. Eight studies enrolled a total of 634 patients with pituitary adenoma, 273 patients underwent a stereotactic radiosurgery and 361 patients underwent fractionated stereotactic radiotherapy. No significant differences were found in efficacy measures, such as disease control rate and endocrine cure rate, between stereotactic radiosurgery and fractionated stereotactic radiotherapy (OR=1.156, p=0.666; OR=0.659, p=0.153, respectively). Additionally, meta-analysis of safety measures, such as the rate of new-onset hypopituitarism and visual disturbance rate, did not show significant differences between different treatments (OR=1.365, p=0.469; OR=0.872, p=0.845 respectively). In conclusion, both stereotactic radiosurgery and fractionated stereotactic radiotherapy have comparable efficacy and safety in the management of pituitary adenoma patients. PMID- 28017196 TI - Relationship between resting state functional magnetic resonance imaging and memory function in mesial temporal lobe epilepsy. AB - OBJECT: To study memory impairment mechanisms of the medial temporal lobe epilepsy (MTLE) by analyzing the functional connectivity (FC) through resting state functional magnetic resonance imaging (rs-fMRI). METHODS: Rs-fMRI data were acquired from 13 patients with left MTLE and 11 patients with right MTLE. Another 13 healthy volunteers were selected as controls. The altered FC pattern between the unilateral hippocampus and other regions of the brain in MTLE patients was compared to that of the normal control group. Then the correlation between the strength of FC and the clinical memory scale scores in patients with MTLE was determined. RESULTS: The scores of the following check points of MTLE patients including point to memory, recognition of nonsense figure, associative learning, the image free recall, portrait characteristic recall and memory quotient were significantly lower than those in the normal group (all P<0.05). The scores of point to memory and recognition of nonsense figure were different between R-MTLE and L-MTLE patients. Different correlations between the strength of FC and the clinical memory scale scores were detected between R-MTLE and L-MTLE patients. CONCLUSIONS: The memory function of patients with MTLE was impaired. Patients with L-MTLE showed lower score on pure verbal memory test and those with R-MTLE showed weaker performance on pure visual memory test. Patients with MTLE showed extensive abnormal FC between hippocampus and particular encephalic regions. PMID- 28017197 TI - Conceptualizing cognitive health to optimize dementia prevention and care. PMID- 28017198 TI - Co-existence of spastic paraplegia-30 with novel KIF1A mutation and spinocerebellar ataxia 31 with intronic expansion of BEAN and TK2 in a family. PMID- 28017199 TI - Effects of left DLPFC versus right PPC tDCS on multiple sclerosis fatigue. AB - BACKGROUND AND OBJECTIVE: Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Its classical treatments are still faced with limited benefits and numerous side effects. Hence, we aimed to evaluate the effects of transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, on such a challenging symptom. Our secondary outcomes included the assessment of tDCS impact on mood and attentional performance. METHODS: Ten fatigued MS patients were enrolled in a double-blind, sham controlled, and cross-over study. Each patient randomly received three anodal tDCS blocks: active stimulation over the left dorsolateral prefrontal cortex (DLPFC), active stimulation over the right posterior parietal cortex (PPC), and sham stimulation over either cortical site. Both cortical targets are key components in the MS fatigue networks. The blocks consisted of five consecutive daily sessions and were held apart by a washout interval of three weeks. RESULTS: Only active left DLPFC stimulation significantly ameliorated fatigue. Mood improvement was exclusively obtained following active right PPC stimulation. Neither intervention had effects on attention. CONCLUSION: Our study supports the role of anodal tDCS over the left prefrontal in treating MS fatigue. The lack of tDCS effects on attention might be related to the heterogeneity of the studied cohort, the relatively small sample size, the protocol design and duration. Modifying these variables and coupling tDCS with neuroimaging might improve the clinical outcomes and enhance our understanding of the tDCS mechanism of actions. PMID- 28017200 TI - The characteristics of spinal imaging in different types of demyelinating diseases. AB - BACKGROUND: Transverse myelitis is the common presentation in demyelinating conditions. OBJECTIVE: To determine the characteristics of spinal lesions among each type of demyelinating diseases. METHODS: Medical records and spinal imaging of patients who were [1] older than 18years, [2] had at least one attack of TM, [3] had available spinal MRI data and [4] were tested for aquaporin-4 antibody were included. RESULTS: One hundred and fifty-eight patients were eligible (27 clinically isolated syndrome [CIS], 38 MS, 55 seropositive neuromyelitis optica spectrum disorders [NMOSD], 9 seronegative NMOSD, and 29 idiopathic transverse myelitis [IDD-TM]). All groups showed female preponderance and no difference of age at onset. In each patient group, no significant difference in the mean number of spinal lesions was found. The most common levels of involvement were thoracic in IDD-TM, cervical in CIS and MS, as well as cervico-thoracic in both NMOSD groups. Long extensive TM was the most common finding in both the seropositive and seronegative NMOSD groups compared to the other groups. Peripheral location and <30% of spinal cord area involvement were the characteristic findings in CIS and MS. Central location and intermediately involved of the cross-sectional cord area were the determinants for the seropositive and seronegative NMOSD groups, respectively. CONCLUSION: Spinal MRI findings can help to differentiate among demyelinating diseases in who presented with TM. PMID- 28017201 TI - Lower body mass index is associated with orthostatic hypotension in Parkinson's disease. AB - INTRODUCTION: Lower body mass index (BMI) is associated with orthostatic hypotension (OH) in the general population, especially in the elderly; however, no studies have addressed this issue in Parkinson's disease (PD). METHODS: We investigated the results of the head-up tilt test and BMI of patients with PD, and evaluated whether BMI is related to orthostatic systolic blood pressure (SBP) change during the head-up tilt test. PD patients were divided into male and female groups, and further divided into middle-aged (age<65years) and elderly (age>=65years) subgroups in each sex. RESULTS: OH was observed in 13 of 64 male and 12 of 75 female patients with PD. BMI was lower in patients with OH than in those without, in both men and women. In the elderly group, a significant correlation between BMI and orthostatic SBP change was found (men, r=0.47, p=0.006; women, r=0.43, p=0.005), and a BMI below mean-0.5 standard deviation increased OH odds (men: BMI<20.5; odds ratio, 6.79; 95% CI, 1.06-43.36; women: BMI<18.5; odds ratio, 5.11; 95% CI, 1.05-24.96). CONCLUSION: Lower BMI is a predisposing factor of OH in elderly patients with PD. PMID- 28017202 TI - Family carers' experiences of receiving the news of a diagnosis of Motor Neurone Disease: A national survey. AB - Family carers have a central role in the care and support of people with MND and face the challenges of the disease from diagnosis to progression and the multiple losses of MND, but their support needs are often neglected. This study aimed to investigate the experiences of family carers at the time of diagnosis and their satisfaction with receiving the news. An anonymous postal survey was facilitated by all MND Associations in Australia (2014) and 190 family carers completed the questionnaire. The questions centred on the SPIKES protocol for communicating bad news. Two-thirds of family carers rated the skills of their neurologists as above average and were satisfied with the delivery of the diagnosis, in terms of having a significantly longer consultation time, the neurologist being warm and caring, satisfaction with the amount and content of information they received and relevant supports, and a plan for following up support. Conversely those who rated the neurologist's skills as below average commented on the difficulties they encountered and the long term emotional stress engendered by poor communication. The study emphasises previous research that suggested that neurologists may require education and training in communicating the diagnosis and this should include family carers as a vital member in MND care. PMID- 28017203 TI - Pregnancy in neuromyelitis optica spectrum disorder: A multicenter study from South China. AB - OBJECTIVE: This study aimed to assess the effect of pregnancy on the course of neuromyelitis optica spectrum disorder (NMOSD), and the effect of this disease on pregnancy outcomes. METHODS: Consecutive patients with NMOSD were recruited between September 2015 and April 2016 at an outpatient clinic from four referral institutes in South China. Demographic, clinical, and pregnancy data were retrieved by questionnaires to analyze the association between NMOSD and pregnancy, as well as the potential risk factors for relapse. RESULTS: Among 249 patients with NMOSD, 55 had pregnancy-related attacks. The annual relapse rate in the first (3.20+/-6.82) and second (3.25+/-3.32) 3-month postpartum periods was marginally higher than that before pregnancy (1.44+/-0.92, p=0.682) and during pregnancy (1.23+/-1.32, p=0.758). The Kurtzke Expanded Disability Status Scale score increased from 1.55+/-0.38 before pregnancy to 2.88+/-2.14 at postpartum (p<0.001). NMOSD significantly increased the premature birth rate in patients after disease onset (8.33%) compared with before disease onset (1.95%, p=0.025). Multivariate analysis showed that negative anti-aquaporin-4 IgG, concomitance with autoimmune diseases/antibodies, and no treatment in remission were risk factors of recurrence. CONCLUSION: Our study shows a significant association between pregnancy and NMOSD in the Chinese population. Larger scale prospective studies are warranted in the future. PMID- 28017204 TI - Monocyte to HDL cholesterol ratio is associated with discharge and 3-month outcome in patients with acute intracerebral hemorrhage. AB - BACKGROUND: Monocyte and monocyte to high-density lipoprotein ratio (MHR) recently emerged as markers of inflammation and have been reported to be novel prognostic indicators of cardiovascular diseases. We investigated the association of monocyte and MHR with hospital discharge and 3-month outcome after acute intracerebral hemorrhage (ICH). METHODS: A total of 316 patients with acute ICH were enrolled from November 2011 to March 2014. Demographic characteristics, lifestyle risk factors, medical history, admission laboratory parameters, and monocyte level were recorded. Clinical outcome was disability or death (defined as having a modified Rankin Scale score>=2) upon discharge or at 3months. RESULTS: 202 patients (63.9%) experienced disability or death at hospital discharge, and 176 patients (55.7%) at 3months post-ICH. Admission monocyte level was associated with clinical outcome at 3months (adjusted OR, 4.17; 95% CI, 1.45 12.00; P-trend=0.028) when highest and lowest quartiles were compared. However, no significant association was found between monocyte and discharge outcome (P trend=0.102). Compared to the lowest category of MHR, the highest category was associated with a 3.87-fold increase in the odds of disability or death at discharge (95% CI, 1.17-12.76; P-trend=0.045) and 3.08-fold increased odds of disability or death at 3-month (95% CI, 1.05-9.08; P-trend=0.024). CONCLUSIONS: In patients with acute ICH, higher MHR was associated with increased risk of disability or death at discharge and at 3months post-ICH, however higher monocyte was only associated with increased risk of 3-month disability or death. PMID- 28017205 TI - Meige's syndrome: History, epidemiology, clinical features, pathogenesis and treatment. AB - 'Meige's syndrome' is a type of cranial dystonia characterized by blepharospasm and oromandibular dystonia and can be associated with complex movement of lower facial muscles, mouth, jaw, tongue, pharyngeal and cervical muscles. Frequently, blepharospasm is the earliest clinical manifestation, which spreads over a period of time to involve other cranial and extra-cranial muscles. Common characteristics of this syndrome are well known, but their variety is wide. Different eponyms such as "Breughel syndrome", "Wood syndrome", "Blepharospasm plus", "Segmental cranial dystonia" and "Segmental cranio-cervical dystonia" have been used to describe this entity with numerous anatomical variations. In the majority of the patients Meige's syndrome is primary or idiopathic, where the cause of spasm is not known, however secondary cases can occur following prolonged use of neuroleptics or secondary to underlying brain disorders. This syndrome has also been described in patients with essential tremor, Parkinson's disease and atypical Parkinsonism. Neurophysiological features are similar to other focal dystonia characterized by abnormal plasticity and impaired inhibition. Most of the patients are successfully treated with injection of botulinum toxin, however deep brain stimulation has emerged as a good therapeutic option in intractable patients. The objective of this review is to understand whether patients who develop Meige's syndrome are different from patients who manifest blepharospasm or oromandibular dystonia alone. PMID- 28017206 TI - Sevoflurane pre-conditioning increases phosphorylation of Erk1/2 and HO-1 expression via inhibition of mPTP in primary rat cortical neurons exposed to OGD/R. AB - BACKGROUND: As an indispensable clinical inhalation anesthetic, sevoflurane is widely used for peri-operative sedation. The neuroprotective effect of sevoflurane pre-conditioning against cerebral ischemia/reperfusion has been gradually realized, but the underlying mechanism during the early reperfusion period has not been established. METHOD: Primary cultured cortical neurons were treated with 2% sevoflurane pre-conditioning for 30min, exposed to oxygen-glucose deprivation for 90min, and followed by 60min of reperfusion (OGD/R). Additionally, neuronal cells were treated with an inhibitor of extracellular signal-related kinases 1 and 2 (Erk1/2) phosphorylation (PD98059), a mPTP opener (atractyloside), or a mPTP opening inhibitor (cyclosporine A) before sevoflurane pre-conditioning. RESULT: Sevoflurane pre-conditioning decreased neuronal apoptosis (assessed by TUNEL), oxidative stress (assessed by malondialdehyde [MDA], superoxide dismutase [SOD], and heme oxygenase [HO]-1), and opening of mitochondrial permeability transition pores [mPTPs] (assessed by calcein-cobalt), but increased neuronal viability (assessed by MTT) and mitochondrial membrane potential (assessed by JC-1) after OGD/R exposure compared with OGD/R treatment alone. Pre-treatment with the mPTP opener and inhibitor of Erk1/2 phosphorylation abolished the protective effect induced by sevoflurane pre-conditioning. Pre treatment with the mPTP opener attenuated the phosphorylation of Erk1/2 in mitochondria of neuronal cultures exposed to OGD/R induced by sevoflurane pre conditioning. The mPTP opening inhibitor, like sevoflurane pre-conditioning, increased phosphorylation of Erk1/2 after OGD/R exposure, while PD98059 failed to reverse inhibition of mPTP opening in cultures exposed to OGD/R induced by sevoflurane pre-conditioning. CONCLUSION: The neuroprotective mechanism of sevoflurane pre-conditioning might be associated with increased Erk1/2 phosphorylation in mitochondria via inhibition of mPTP opening in the early reperfusion period. PMID- 28017207 TI - The Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS): Development and assessment of reliability. AB - PURPOSE: The causes, risk factors and prognosis of spontaneous intracerebral haemorrhage (ICH) are partly determined by anatomical location (specifically, lobar vs. non-lobar (deep and infratentorial) regions). We systematically developed a rating instrument to reliably classify ICH location. METHODS: We used a two-stage iterative Delphi-style method for instrument development. The resultant Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS) was validated on CT and MRI scans from a cohort of consecutive patients with acute spontaneous symptomatic ICH by three independent raters. We tested interrater and intrarater reliability using kappa statistics. RESULTS: Our validation cohort included 227 patients (58% male; median age: 72.4 (IQR: 67.1-74.6)). The interrater reliability for the main analyses (i.e. including any lobar ICH; all deep and infratentorial anatomical categories (lentiform, caudate thalamus; brainstem; cerebellum); and uncertain location) was excellent (all kappa values>0.80) both in pair-wise between-rater comparisons and across all raters. The intrarater reliability was substantial to almost perfect (k=0.83; 95%CI: 0.77 0.88 and k=0.95; 95%CI: 0.92-0.96 respectively). All kappa statistics remained consistent for individual cerebral lobar regions. CONCLUSIONS: The CHARTS instrument can be used to reliably and comprehensively map the anatomical location of spontaneous ICH, and may be helpful for studying important questions regarding causes, risk factors, prognosis, and for stratification in clinical trials. PMID- 28017208 TI - Subjective hearing impairment after subarachnoid haemorrhage: Prevalence and risk factors. AB - BACKGROUND: Sensorineural hearing impairment is a key symptom in patients with superficial siderosis of the central nervous system, a disease caused by chronic or intermittent haemorrhage into the subarachnoid space. We investigated the prevalence and risk factors of subjective hearing impairment after SAH. METHODS: We systematically interviewed all SAH patients admitted between June 2011 and December 2014, who were able to visit the SAH outpatient clinic six to eight weeks after hospital discharge. We calculated the proportion of patients with subjective hearing impairment noticed after SAH onset, and adjusted risk ratios (aRR) with 95% confidence intervals (CI) for potential risk factors with Poisson regression. RESULTS: We included 277 patients. Subjective hearing impairment was reported by 54/277 (19%) patients (aneurysmal SAH: 42/212 [20%;95%CI:15-26%]; perimesencephalic haemorrhage 8/36 [22%;95%CI:12-38%], non-aneurysmal non perimesencephalic SAH: 4/29 [14%;95%CI:6-31%]). Hearing impairment was associated with a poor clinical condition on admission (defined as PAASH score 4-5) (aRR3.00;95%CI:1.43-6.28), aneurysm rupture at the middle cerebral artery (aRR2.72;95%CI:1.38-5.39), and moderate/severe disability 3months after ictus (aRR2.25;95%CI:1.28-3.97), but not with large amounts of extravasated blood (highest vs. lowest tertile of Hijdra score) (aRR0.77;95%CI:0.33-1.81) or endovascular treatment (aRR1.19;95%CI:0.61-2.33). CONCLUSION: Subjective hearing impairment occurs in 1 of every 5 SAH patients. It is related to the clinical condition on admission, aneurysm rupture at the middle cerebral artery, and functional outcome, but not to the amount of subarachnoid blood or the method of aneurysm occlusion. Audiometric tests, auditory cognitive assessments, and follow up studies are needed to determine the cause and prognosis of hearing impairment after SAH. PMID- 28017209 TI - High-dose methotrexate with leucovorin rescue: For monumentally severe CNS inflammatory syndromes. AB - BACKGROUND: At sufficiently high doses, methotrexate (HDMTX) achieves substantial CNS penetration, whereas other tissues can be rescued from the effects of HDMTX by leucovorin rescue (LR), which does not penetrate the blood-brain barrier. OBJECTIVES: To report on the efficacy and safety of HDMTX with LR (HDMTX-LR), in the treatment of acute demyelinating inflammatory CNS syndromes refractory to conventional immunotherapy. METHODS: We performed a retrospective chart review of 12 patients treated (6 multiple sclerosis [MS], 4 neuromyelitis optica [NMO], and 2 Sjogren's syndrome myelopathy [SSM]) with HDMTX-LR after failing to improve, or exhibiting worsening following conventional immunotherapy. 11 patients were followed for a total of 6months following HDMTX-LR (one was lost to follow up after 1month); and clinical findings were documented at 1month, 3months, and 6months following HDMTX-LR therapy. RESULTS: Ten patients demonstrated both clinical and radiologic evidence of near, if not complete, abolishment of disease activity, in conjunction with impressive reconstitution of neurologic function in the 6-month period following HDMTX-LR. Mean Kurtzke Expanded Disability Status Scale (EDSS) prior to HDMTX-LR was 8.1 (+/-1.4). Following HDMTX-LR, mean EDSS was 6.6 (+/-2.4) at 1month, 5.8 (+/-2.3) at 3months, and 5.7 (+/-2.3) at 6months. CONCLUSIONS: In this retrospective assessment of treatment-recalcitrant fulminant inflammatory CNS syndromes, HDMTX-LR was observed to be a safe and highly effective treatment, producing the rapid and near complete cessation of disease activity, in conjunction with an important corresponding and 'durable remission' in the majority of our small treatment cohort. PMID- 28017210 TI - Opsoclonus-myoclonus ataxia syndrome secondary to venlafaxine intoxication. PMID- 28017211 TI - How to assess tendon reflexes of the lower limb in the elderly. AB - BACKGROUND: Clinicians frequently experience difficulty in eliciting the reflexes of elderly patients using standard methods due to paratonia/frontal rigidity. If reflexes are incorrectly thought to be absent, important diagnostic errors may be made. Neurologists use alternative methods when technical difficulties require them, but these are not widely used by non-neurologists. METHODS: A neurologist and a medical student both used standard and non-standard techniques to assess reflexes of the lower limb in geriatric inpatients, aged over 65, to determine which method permitted the most confident assessment of the presence of knee and ankle reflexes. RESULTS: 45 patients were assessed. The consultant found that in 20 patients (44%) all three knee reflex methods examined produced similar results. When the methods produced different results, the "superior patellar supine" method was the best single method overall (best or equal best in 19 patients (42%)). For the ankle reflex all four reflex methods examined produced similar results in only 7 patients (16%). When the methods produced different results the "Achilles strike elevated" method was best or equal best in 32 patients (71%) and the "plantar strike" method in 29 patients (64%). If the student had relied on standard methods alone, reflexes would have been incorrectly called absent in 28 limbs (37%) for knee jerks and 52 limbs (84%) for ankle jerks. Supplementing standard methods with alternative methods reduced these error rates to 19% and 21% respectively. CONCLUSIONS: Our findings indicate that a reasonable practical approach is to assess the knee reflex with the standard method and then, if a definite reflex has not been recorded, move on to use the "superior patellar supine" method; and for the ankle reflex begin with the "plantar strike method" and then, if necessary, move on to use the "Achilles strike elevated" method. PMID- 28017212 TI - Corrigendum to "Sexual dysfunction in multiple sclerosis: A 6-year follow-up study" [J. Neurol. Sci. 358 (2015) 317-323]. PMID- 28017214 TI - Stroke severity may predict causes of readmission within one year in patients with first ischemic stroke event. AB - INTRODUCTION: Readmissions after stroke are costly. Risk assessment using information available upon admission could identify high-risk patients for potential interventions to reduce readmissions. Baseline stroke severity has been suspected to be a factor in readmission; however, the exact nature of the impact has not been adequately understood. METHODS: Hospitalized adult patients with first-ever ischemic stroke were identified from a nationwide administrative database. Stroke severity was assessed using a validated claims-based stroke severity index. Cox proportional hazards models were used to investigate the relationship between stroke severity and first readmission within one year. RESULTS: Of the 10,877 patients, 4295 (39.5%) were readmitted in one year. The cumulative risk of readmission was 34.1%, 44.7%, and 62.9% in patients with mild, moderate, and severe stroke, respectively. Patients with greater stroke severity had a significantly higher adjusted risk of first readmission for infection, metabolic disorders, neurological sequelae, and pulmonary diseases, whereas those with lesser stroke severity were prone to first readmission due to accidents. Stroke severity did not affect the risk of first readmission for recurrent stroke/transient ischemic attack, other cardiovascular events, malignancy, ulcers/upper gastrointestinal bleeding, kidney diseases, and others. CONCLUSIONS: Stroke severity in patients with first-ever ischemic stroke not only predicts readmission but also relates to the cause of readmission. Our results might provide important information for tailoring discharge planning to prevent readmissions. PMID- 28017213 TI - Revised diagnostic criteria for neurocysticercosis. AB - BACKGROUND: A unified set of criteria for neurocysticercosis (NCC) has helped to standardize its diagnosis in different settings. METHODS: Cysticercosis experts were convened to update current diagnostic criteria for NCC according to two principles: neuroimaging studies are essential for diagnosis, and all other information provides indirect evidence favoring the diagnosis. Recent diagnostic advances were incorporated to this revised set. RESULTS: This revised set is structured in absolute, neuroimaging and clinical/exposure criteria. Absolute criteria include: histological confirmation of parasites, evidence of subretinal cysts, and demonstration of the scolex within a cyst. Neuroimaging criteria are categorized as major (cystic lesions without scolex, enhancing lesions, multilobulated cysts, and calcifications), confirmative (resolution of cysts after cysticidal drug therapy, spontaneous resolution of single enhancing lesions, and migrating ventricular cysts on sequential neuroimaging studies) and minor (hydrocephalus and leptomeningeal enhancement). Clinical/exposure criteria include: detection of anticysticercal antibodies or cysticercal antigens by well standardized tests, systemic cysticercosis, evidence of a household Taenia carrier, suggestive clinical manifestations, and residency in endemic areas. Besides patients having absolute criteria, definitive diagnosis can be made in those having two major neuroimaging criteria (or one major plus one confirmative criteria) plus exposure. For patients presenting with one major and one minor neuroimaging criteria plus exposure, definitive diagnosis of NCC requires the exclusion of confounding pathologies. Probable diagnosis is reserved for individuals presenting with one neuroimaging criteria plus strong evidence of exposure. CONCLUSIONS: This revised set of diagnostic criteria provides simpler definitions and may facilitate its more uniform and widespread applicability in different scenarios. PMID- 28017215 TI - Transcriptional and epigenetic phenomena in peripheral blood cells of monozygotic twins discordant for alzheimer's disease, a case report. AB - Target genes in Alzheimer's disease (AD) have been identified. In monozygotic twins discordant for AD we analysed the expression of selected genes, and their possible regulation by epigenetic mechanisms in peripheral blood mononuclear cells, possibly useful to discover biomarkers. Amyloid precursor protein, sirtuin 1 and peptidyl prolyl isomerase 1 gene expressions were highly up-regulated in the AD twin versus the healthy one. Consistently with sirtuin 1 role in controlling acetylation status, we observed a substantial reduction of the acetylation on histone 3 lysine 9, associated with gene transcription in the AD twin. Noteworthy in the AD twin we also observed an increased gene expression in two histone deacetylases (HDACs) isoforms: HDAC2 and HDAC9. A general DNA hypomethylation of all gene promoters studied was also observed in both twins. Our results unravel transcriptional and epigenetic differences potentially helpful to better understand environmental factors and phenotypic differences in monozygotic twins. PMID- 28017216 TI - Olfactory ability in normal pressure hydrocephalus as compared to Alzheimer's disease and healthy controls. AB - OBJECTIVES: Normal pressure hydrocephalus (NPH) is a treatable neurological disorder that appears in older adults, lacks specific diagnostic criteria, and resembles symptoms seen in Alzheimer's disease (AD). Presently, differentiating NPH from AD in the early stages of symptom presentation remains difficult. This study established whether olfactory testing may be useful in this regard. In addition, we determined whether olfactory function of NPH patients differed before and after extended lumbar drainage (ELD), as well as six months after surgical implantation of a ventriculoperitoneal (VP) shunt. PATIENTS AND METHODS: Twenty-two NPH patients (mean age=77.6yrs), 14 age- and gender-matched healthy controls (mean age=79.9yrs), and 7 AD patients (mean age=75.5yrs) were administered the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Eighteen of the 22 NPH patients were also tested following ELD and 8 patients were tested six months following implantation of VP shunt. RESULTS: Prior to ELD, patients with NPH scored significantly higher on the UPSIT than those with AD [respective means (SDs)=26.9 (7.1) & 14.1 (4.7)]. While the mean NPH score was significantly below that of the matched controls [control mean (SD)=32.7 (6.7)], their test scores were nonetheless within the general normal range, as determined from published normative data (48th percentile). The UPSIT scores did not differ significantly among the three longitudinal time points in the NPH patients. CONCLUSION: Olfactory testing may be useful in differentiating between patients with NPH and patients with AD. Odor identification test scores of NPH patients are not influenced by the release of intracranial pressure via ELD or six months following implantation of a VP shunt. PMID- 28017217 TI - Lack of decussation of pyramids in Kallmann syndrome presenting with mirror movements. PMID- 28017218 TI - Clinical characteristics, and impairment and disability scale scores for different CIDP Disease Activity Status classes. AB - INTRODUCTION: Selecting proper outcome measures is important for clinical practice and clinical studies assessing treatable neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP). OBJECTIVES: To explore clinical characteristics and impairment and disability scores in CIDP patients, and assess their relationship to different CIDP Disease Activity Status (CDAS) classes. METHODS: We performed a retrospective chart review of CIDP patients attending the neuromuscular clinic between January 2014 and December 2015, and explored clinical characteristics, and various impairment and disability scores for different CDAS classes. RESULTS: The total cohort included 69 CIDP patients. A higher CDAS class was correlated with more frequent motor and sensory deficits, worse sensory sum score, worse scores on the disability scales, including the Rasch-built overall disability scale (RODS) and Overall Neuropathy Limitation Scale (ONLS), and lower treatment responsiveness. ONLS and RODS scales were significantly correlated (r=-0.86, p<0.0001). A change of one point or more in the ONLS score, was associated with a corresponding change of 4.1-4.5 points in the RODS score. DISCUSSION: The study results show that a higher CDAS class is correlated with a more severe neuropathy. This was reflected by the sensory sum score, RODS and ONLS. These results might help profile CIDP patients at different CDAS classes for clinical practice and future clinical studies. PMID- 28017219 TI - Predictors of health-related quality of life in people with amyotrophic lateral sclerosis: Methodological issues. PMID- 28017220 TI - Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel DARS2 mutation and isolated progressive spastic paraparesis. PMID- 28017221 TI - Decision-making performance in Parkinson's disease correlates with lateral orbitofrontal volume. AB - BACKGROUND: Patients with Parkinson's disease (PD) exhibit poor decision-making, and the underlying neural correlates are unclear. We used voxel-based morphometry with Diffeomorphic Anatomical Registration through Exponentiated Lie algebra to examine this issue. METHODS: The decision-making abilities of 20 patients with PD and 37 healthy controls (HCs) were measured with a computerized Iowa Gambling Task (IGT). We assessed the local gray matter volumes of the patients and HCs and their correlations with decision-making performance, disease duration, disease severity, and anti-Parkinsonism medication dose. RESULTS: Compared with the HCs, the patients with PD exhibited poor IGT performances. The gray matter volumes in the medial orbitofrontal cortex, left inferior temporal cortex, and right middle frontal gyrus were decreased in the patients. Results in the regression analysis showed that lateral orbitofrontal volume correlated with performance in the IGT in PD. Regions that correlated with disease duration, severity, and medication dose did not overlap with orbitofrontal regions. CONCLUSION: Our results indicate that the lateral and medial orbitofrontal cortex are related to decision-making in PD patients. Since the medial orbitofrontal cortex is shown to be involved in monitoring reward, reward monitoring seems to be impaired as a whole in PD patients. Meanwhile, the lateral region is related to evaluation of punishment, which is considered to have an influence on individual differences in decision making performance in PD patients. PMID- 28017222 TI - Association between human herpesvirus & human endogenous retrovirus and MS onset & progression. AB - This review discusses the role of Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6) and human endogenous retroviruses (HERVs) in the onset and progression of multiple sclerosis (MS). Although EBV has been established as one of the causal factors in MS onset, its role in MS progression is still uncertain. Moreover, interactions between EBV and other risk factor on MS development still need more investment. With less consistent evidence than EBV, HHV6 has also been implicated in the pathogenesis of MS; moreover, it showed a closer connection with the disease activity. Recent studies found that HERVs were associated with the development and progression of MS. Some antiviral treatments have shown promise for clinical interventions in the future. Future studies are yet needed to fully clarify the role of these agents in MS onset and disease course and the modes by which they realise these effects. PMID- 28017223 TI - Parent vessel occlusion for treatment of cerebral aneurysms: Is there still an indication? A series of 17 patients. AB - INTRODUCTION/PURPOSE: Flow diversion has allowed cerebrovascular neurosurgeons and neurointerventionalists to treat complex, large aneurysms, previously treated with trapping, bypass, and/or parent vessel sacrifice. However, a minority of aneurysms remain that cannot be treated endovascularly, and microsurgical treatment is too dangerous. However, balloon test occlusion (macro and micro), micro WADA testing, ICG, intra-angiography and intra-operative monitoring are all available to clinically test the hypothesis that vessel sacrifice is safe. We describe a dual-institution series of aneurysms successfully treated with parent vessel occlusion (PVO). MATERIALS/METHODS: Prospectively collected databases of all endovascular and open cerebrovascular cases performed at Maine Medical Center and Vanderbilt University Medical Center from 2011 to 2013 were screened for patients treated with primary vessel sacrifice. A total of 817 patients were screened and 17 patients were identified who underwent parent vessel sacrifice as primary treatment. RESULTS: All 17 patients primarily treated with PVO are described below. Nine patients presented with SAH, and 3/17 involved anterior circulation. Complete occlusion was achieved in 15/17 patients. In the remaining 2 patients, significant reduction in the aneurysm occurred. Modified Rankin Score (mRS) of 0, signifying complete independence, was achieved for 16/17 patients. One patient died due to an extracranial process. CONCLUSIONS: Parent vessel sacrifice remains a viable and durable solution in select ruptured and unruptured intracranial aneurysms. Many adjuncts are available to aid in the decision making. In this small series, patients naturally divided into vertebral dissecting aneurysms, giant aneurysms and small distal aneurysms. Outcomes were favorable in this highly selected group. PMID- 28017224 TI - Hemorrhagic transformation and cerebral edema in acute ischemic stroke: Link to cerebral autoregulation. AB - BACKGROUND: Hemorrhagic transformation and cerebral edema are feared complications of acute ischemic stroke but mechanisms are poorly understood and reliable early markers are lacking. Early assessment of cerebrovascular hemodynamics may advance our knowledge in both areas. We examined the relationship between dynamic cerebral autoregulation (CA) in the early hours post ischemia, and the risk of developing hemorrhagic transformation and cerebral edema at 24h post stroke METHODS: We prospectively enrolled 46 patients from our center with acute ischemic stroke in the middle cerebral artery territory. Cerebrovascular resistance index was calculated. Dynamic CA was assessed by transfer function analysis (coherence, phase and gain) of the spontaneous blood flow velocity and blood pressure oscillations. Infarct volume, hemorrhagic transformation, cerebral edema, and white matter changes were collected from computed tomography performed at presentation and 24h. RESULTS: At admission, phase was lower (worse CA) in patients with hemorrhagic transformation [6.6+/-30 versus 45+/-38 degrees ; adjusted odds ratio 0.95 (95% confidence internal 0.94 0.98), p=0.023] and with cerebral edema [6.6+/-30 versus 45+/-38 degrees , adjusted odds ratio 0.96 (0.92-0.999), p=0.044]. Progression to edema was associated with lower cerebrovascular resistance (1.4+/-0.2 versus 2.3+/ 1.5mmHg/cm/s, p=0.033) and increased cerebral blood flow velocity (51+/-25 versus 42+/-17cm/s, p=0.033) at presentation. All hemodynamic differences resolved at 3months CONCLUSIONS: Less effective CA in the early hour post ischemic stroke is associated with increased risk of hemorrhagic transformation and cerebral edema, possibly reflecting breakthrough hyperperfusion and microvascular injury. Early assessment of dynamic CA could be useful in identifying individuals at risk for these complications. PMID- 28017225 TI - Stroke survivors in Nigeria: A door-to-door prevalence survey from the Niger Delta region. AB - The burden of stroke has been projected to increase in low-and middle-income countries due to the ongoing epidemiological transition. However, community-based stroke prevalence studies are sparse in sub-Saharan Africa particularly in Nigeria. This study aimed to provide a comparative estimate of the prevalence of stroke survivors in the rural Niger Delta region. A three-phased door-to-door survey was conducted using WHO modified instruments. In the first-phase, 2028 adults (>=18years) participants randomly selected from two rural communities were screened by trained health research assistants for probable stroke. In the second phase, suspected cases were screened with stroke-specific tool. Positive cases were made to undergo complete neurological evaluation by two study neurologist in phase-three. Stroke diagnosis was based on clinical evaluation using WHO criteria. Overall, 27 (8 first-ever and 19 recurrent cases) stroke survivors with crude prevalence of 13.31/1000 (95% CI, 8.32-18.31) and a non-significant difference in prevalence between the two study communities were found, (P=0.393I). In addition, age-adjusted prevalence of stroke survivors was 14.6/1000 person, about 7-folds higher than previous estimates outside the Niger Delta region. The prevalence increases significantly with advancing in age, P<0.001. Among others, hypertension (92.59%) was the commonest risk factor and comorbidity found. Improved stroke surveillance and care, as well as better management of the underlying risk factors, primarily undetected or uncontrolled high blood pressure, remains a public health priority. PMID- 28017226 TI - Severe subthalamic stimulation-induced dysarthria alleviated by a novel paradigm: A case report. PMID- 28017227 TI - Comparison of stent versus medical therapy for symptomatic patients with intracranial atherosclerotic stenosis: A meta-analysis. AB - PURPOSE: To compare the outcomes of intracranial stent implantation and medical therapy for treatment of severe intracranial stenosis. METHODS: Articles were identified from Medline, Cochrane, EMBASE, and Google Scholar published up to August 25, 2016. Eligible studies reported stroke occurrence, transient ischemic attack (TIA), and event-free survival rates in patients who suffered recent TIA or stroke caused by stenosis of a major intracranial artery and treated with either medical therapy or stenting. 4 studies enrolled a total 739 patients. RESULTS: While no association between intracranial endovascular therapy and short term stroke risk was found (pooled OR=1.349, 95% CI=0.541 to 3.367, P=0.521), significantly higher rate of stroke occurrence was observed in patients treated with stent therapy within 30days of treatment (pooled OR=3.143, 95% CI=1.755 to 5.628, P<0.001). No association was found between the type of treatment and TIA occurrence (pooled OR=0.702, 95% CI=0.277 to 1.781, P=0.457) and event-free survival rate (pooled HR=1.170, 95% CI=0.947 to 1.447, P=0.145). CONCLUSION: Patients with symptomatic intracranial atherosclerotic stenosis undergoing stent therapy may have higher risk of short-term stroke. PMID- 28017228 TI - Apomorphine pump in advanced Parkinson's disease: Effects on motor and nonmotor symptoms with brain metabolism correlations. AB - INTRODUCTION: Patients with advanced Parkinson's disease (PD) and contraindications for subthalamic nucleus deep brain stimulation (DBS) could particularly benefit from subcutaneous infusion therapy with apomorphine. This original study was designed to evaluate the general efficacy of add-on apomorphine in motor and nonmotor symptoms in advanced PD, while characterizing the changes induced in brain glucose metabolism. The aim was to look at the underlying anatomical-functional pathways. METHODS: 12 patients with advanced PD were assessed before and after 6months of add-on apomorphine, using resting-state 18F-fluorodeoxyglucose positron emission tomography and exhaustive clinical assessments. RESULTS: After 6months of therapy, oral treatment was significantly reduced. Both motor and nonmotor scores improved, with a beneficial effect on executive functions, quality of life and apathy. Significant metabolic changes were observed, with overall increases in the right fusiform gyrus and hippocampus, alongside a decrease in the left middle frontal gyrus. Consistent correlations between significant changes in clinical scores and metabolism were established. CONCLUSION: Well tolerated, add-on apomorphine appears to be an interesting option for patients with fluctuations and contra-indications for DBS. Changes in brain metabolism, with beneficial effects on motor and nonmotor symptoms were observed after 6months. These preliminary results have to be confirmed by further studies. PMID- 28017229 TI - Vestibular evoked myogenic potentials and MRI in early multiple sclerosis: Validation of the VEMP score. AB - BACKGROUND: To validate the VEMP score as a measure of brainstem dysfunction in patients with the first symptom of multiple sclerosis (MS) (clinically isolated syndrome (CIS)) and to investigate the correlation between VEMP and brainstem MRI results. METHODS: 121 consecutive CIS patients were enrolled and brainstem functional system score (BSFS) was determined. Ocular VEMP (oVEMP) and cervical VEMP (cVEMP) were analyzed for latencies, conduction block and amplitude asymmetry ratio and the VEMP score was calculated. MRI was analyzed for the presence of brainstem lesions as a whole and separately for the presence of pontine, midbrain and medulla oblongata lesions. RESULTS: Patients with signs of brainstem involvement during the neurological examination (with BSFS >=1) had a higher oVEMP score compared to patients with no signs of brainstem involvement. A binary logistic regression model showed that patients with brainstem lesion on the MRI are 6.780 times more likely to have BSFS >=1 (p=0.001); and also, a higher VEMP score is associated with BSFS >=1 (p=0.042). Furthermore, significant correlations were found between clinical brainstem involvement and brainstem and pontine MRI lesions, and prolonged latencies and/or absent VEMP responses. CONCLUSIONS: The VEMP score is a valuable tool in evaluation of brainstem involvement in patients with early MS. PMID- 28017230 TI - Longitudinal study of cognitive and cerebral metabolic changes in Parkinson's disease. AB - OBJECTIVE: To investigate the cortical metabolic alterations that precedes longitudinal cognitive decline in Parkinson's disease (PD). METHODS: We analyzed the data of 46 PD patients who did not have dementia at baseline and completed 3 year follow-up. Based on the results of general cognitive, memory and visuospatial tests, patients were classified into cognitively normal PD (PD CogNL), PD with mild cognitive impairment (PD-MCI), and PD dementia (PDD). The regional cerebral glucose metabolism at rest was measured using 18F fluorodeoxyglucose positron emission tomography. Voxel-wise effect size analyses were performed to delineate abnormal metabolic patterns associated with changes in cognitive status in PD. RESULTS: At baseline, 29 patients had PD-CogNL, and 17 patients had PD-MCI. At follow-up, 28 patients had PD-CogNL, 12 patients had PD MCI, and 6 patients developed PDD. Seventeen of 29 PD-CogNL patients remained to be PD-CogNL, and 9 PD-CogNL patients converted to PD-MCI. Eleven PD-MCI patients reverted to normal cognition during follow-up. 3 PD-CogNL and 3 PD-MCI patients developed PDD. Cognitively stable PD-CogNL group had frontal predominant hypometabolism. PDD converters showed parieto-occipital hypometabolism at baseline regardless of whether a patient's initial cognitive status is PD-CogNL or PD-MCI. CONCLUSIONS: Parieto-occipital hypometabolism is a good predictor of early dementia conversion in PD. PMID- 28017231 TI - An AOA2 patient with a novel compound heterozygous SETX frame shift mutations. PMID- 28017232 TI - Stiff person syndrome masquerading as multiple sclerosis. AB - BACKGROUND: Stiff person syndrome (SPS) is a rare neuroimmunological disorder presenting with a wide variety of signs and symptoms that mimic neuro inflammatory diseases, such as multiple sclerosis (MS), thus delaying diagnosis. METHODS: We performed a retrospective chart review of over 100 patients with SPS who were treated at Johns Hopkins Hospital and identified five patients previously diagnosed with MS. RESULTS: Patients were female with a mean age of 53years old (range 43-64). Mean time to SPS diagnosis was 5.5years. They presented with typical SPS features (axial/leg spasms, torso rigidity, hyperlordosis, and gait instability) as well as atypical features (hemiparesis, hemisensory dysfunction, fine motor impairment) and were all initially given a diagnosis of MS. In all patients, brain MRI demonstrated non-specific white matter lesions and CSF was negative for intrathecal antibodies in the 4 out of 5 patients who underwent lumbar puncture. SPS diagnosis was supported by elevated anti-glutamic acid decarboxylase (GAD65) antibodies in each patient. Two patients were treated with disease-modifying therapies for MS before being diagnosed with SPS. Following diagnosis with SPS, the patients were treated with varying combinations of immunosuppressants and symptomatic therapies resulting in stabilization or improvement in four of the patients. CONCLUSION: We present five patients with SPS, who were initially thought to have MS, including one patient treated with three different MS therapies due to "disease progression". These cases demonstrate the need to consider less common neuroimmunological disorders, such as SPS, especially in patients with atypical features for MS. PMID- 28017233 TI - Bridging-therapy with intravenous recombinant tissue plasminogen activator improves functional outcome in patients with endovascular treatment in acute stroke. AB - BACKGROUND: Although endovascular treatment for proximal cerebral vessel occlusion is very effective, it remains controversial if intravenous thrombolysis (IVT) prior to endovascular treatment is superior compared to endovascular treatment alone. In this study we compared functional outcomes and recanalization rates of endovascularly treated stroke patients with and without bridging IVT. METHODS: Patients with acute large artery occlusion within the anterior and posterior cerebral circulation eligible for intraarterial revascularization with and without prior IVT were included in this monocentric, prospective observational study. Modified Rankin Scale (mRS) and National Institute of Health Stroke Scale (NIHSS) were determined at baseline, discharge and 90-days follow up after stroke. Successful reperfusion was defined as a Thrombolysis in Cerebral Infarction (TICI) scale 2b-3. RESULTS: Of the 109 patients included, 81 (74%) received bridging therapy with i.v.-rtPA prior to endovascular treatment, 28 (26%) received endovascular treatment alone. There was no difference in groin-to reperfusion time between the groups (54 vs 50min; p=0.657), but a trend towards a higher reperfusion rate in patients with bridging therapy (69 vs 15 patients, p=0.099). Mean improvement of the NIHSS during hospitalization was 8 points (SD; +/-8) in the bridging-group and 2 points (SD, +/-7) in the non-bridging-group (p=0.001). Number of patients with discharge mRS 0-2 (34 vs 5; p=0.024) and 90 days mRS 0-2 (35 vs 6; p=0.061) was higher in the bridging-group compared to the non-bridging-group. CONCLUSIONS: This study provides evidence that bridging therapy with i.v.-rtPA improves functional outcome in patients eligible for endovascular treatment. Further studies are needed to confirm our findings and to identify patients most likely benefitting from bridging therapy. PMID- 28017234 TI - Characteristics of isolated spinal cord involvement in neurobrucellosis with no corresponding MRI activity: A case report and review of the literature. PMID- 28017235 TI - Migraine affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-analysis of community-based studies involving 6 million participants. AB - OBJECTIVE: To study the weighted average global prevalence of migraine at the community level. STUDY DESIGN AND SETTING: A systematic review using advanced search strategies employing PubMed/MEDLINE, Scopus, and Web of Science was conducted for community-based and non-clinical studies by combining the terms "migraine", "community-based", and names of every country worldwide spanning all previous years from January 1, 1920 until August 31, 2015. Methods were in accordance with PRISMA and MOOSE guidelines. A meta-analysis with subgroup analysis was performed to identify pooled migraine prevalence and examine cohort heterogeneity. RESULTS: A total of 302 community-based studies involving 6,216,995 participants (median age 35years, male-to-female ratio of 0.91) were included. Global migraine prevalence was 11.6% (95% CI 10.7-12.6%; random effects); 10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in North America, 16.4% in Central and South America. When the pooled cohort was stratified, the prevalence was 13.8% among females, 6.9% among males, 11.2% among urban residents, 8.4% among rural residents, and 12.4% among school/college students. Our result showed a pattern of rising global migraine prevalence. CONCLUSION: Migraine affects one in ten people worldwide featuring recent rise. Higher prevalence was found among females, students, and urban residents. PMID- 28017236 TI - Historical evidence supports El Greco's depiction of a neurological condition in his attributed self-portrait. AB - Icono-diagnosis, the retrospective image-based diagnosis of pathologies, was applied to the canvas "Portrait of an Old Man" (1595-1600), an attributed self portrait painted by El Greco. The presence of congenital enophthalmos, strabismus, probable amblyopia and signs of left neglect were found. We assume these sign may be consistent an ischemic event affecting the right middle cerebral artery supply territory. Historically, motor activity was not compromised and the painter was able to return to portraiture. Documental evidence indicates, that a few years later (1608), El Greco suffered another cerebrovascular event resulting in agraphia. The pictorial and historical evidence is consistent with multiple ischemic events resulting in progressive disabilities with fluctuating course characterized by temporary improvements and worsening before his death in 1614. PMID- 28017237 TI - Serum antibodies targeting neurons of the monoaminergic systems in Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an autoimmune disease with progressive flaccid paralysis of the extremities. Several auto-antibodies have been identified, binding to myelin, gangliosides, astrocytes or proteins at the nodes of Ranvier. Some epitopes are not confined to the peripheral nerve, suggesting that auto antibodies may also contribute to symptoms of the central nervous system, which are common in GBS and include anxiety, depression, hallucinations, oneiroid psychosis or fatigue. This notion is supported by treating patients with plasma exchange, resulting in improvement of both central and peripheral symptoms. We analyzed binding of GBS sera to neurons of cholinergic, serotonergic, dopaminergic, nor-adrenergic or histaminergic nuclei using immunohistochemistry of the rat brain. We hypothesized that GBS sera harbor antibodies against monoaminergic structures in the brain, as these circuits influence larger neuronal networks with relevance for multiple neuropsychiatric symptoms. Indeed, several GBS sera strongly and specifically reacted with monoaminergic neurons, in particular cholinergic nuclei of the diagonal band, neurons of the basal nucleus of Meynert, nor-adrenergic neurons of the nucleus coeruleus, neurons in the raphe or the ambiguous nucleus. The frequency significantly exceeded those of sera from patients with multiple sclerosis, non-autoimmune neurological disorders and healthy controls. The binding to neuronal surfaces makes it conceivable that the auto-antibodies can interfere with ion channels and receptors and thus contribute to the variable clinical spectrum of neuropsychiatric and autonomic abnormalities in GBS. Future research should include the target identification of promising GBS sera and aim to determine the functional effects of these antibodies. PMID- 28017238 TI - Association of glutathione S-transferase omega polymorphism and spinocerebellar ataxia type 2. AB - BACKGROUND: Spinocerebellar ataxia type 2 is a neurodegenerative disorder caused by a CAG repeat expansion in ATXN2 gene. There is high clinical variability among affected patients suggesting the occurring of modifier genes influencing the clinical phenotype. OBJECTIVE: The objective is to assess the association of GSTO1 rs4925 and GSTO2 rs2297235 SNPs on the clinical phenotype in SCA2 patients. METHODS: A case-control study was performed in a sample of 120 SCA2 Cuban patients and 100 healthy subjects. Age at onset, 60 degrees Maximal Saccade Velocity and SARA score were used as clinical markers. GSTO1 rs4925 and GSTO2 rs2297235 SNPs were determined by PCR/RFLP. RESULTS: Distribution of the GSTO1 alleles and genotypes was nearly equal between the control group and SCA2 patients. GSTO1 genotypes were not associated to clinical markers in SCA2 patients. Distribution of the GSTO2 "G" allele and "AG" genotype differed significantly between SCA2 patients and controls. Symptomatic SCA2 individuals had a 2.29-fold higher chance of carrying at least one "G" allele at GSTO2 rs2297235 than controls (OR=2.29, 95% CI: 1.29-4.04). GSTO2 genotypes were significantly associated to age at onset (p=0.037) but not to 60 degrees Maximal Saccade Velocity or SARA score in SCA2 patients. CONCLUSION: The GSTO1 rs4925 polymorphism is not associated to SCA2. Meanwhile, the GSTO2 rs2297235 "AG" genotype is associated to SCA2 but failed to show any association with clinical markers, with the exception of a potential association with the age at disease onset. PMID- 28017239 TI - The resurgence of meningeal tuberculosis in Mexico: A social phenomenon. PMID- 28017240 TI - Focal muscle vibration, an effective rehabilitative approach in severe gait impairment due to multiple sclerosis. AB - Gait impairment is one of the most frequent and life-altering consequences of Multiple sclerosis (MS), frequently associated with lower limb spasticity. Focal muscle vibration (fMV) is a technique that applies a vibratory stimulus to a specific muscle or its tendon, reducing spasticity. The aim of our study is to evaluate the efficacy of fMV in ameliorating gait impairment in MS patients with severe lower limb spasticity, measured by Gait Analysis (GA) and objective and patient-oriented scales scores. Fourteen patients affected by Secondary Progressive MS (SPMS) with a lower limb spasticity with a low or no response to antispastic drugs, received repetitive fMV (r-fMV) over the quadriceps and the lumbar paraspinal muscles. The effect of r-fMV on gait was measured by a GA evaluation and objective and patient-oriented scales scores, performed before r fMV (T0), and 1week (T1) and 1month (T2) after the last session of r-fMV. After the r-fMV the most of spatio-temporal parameters calculated by GA were improved. Moreover, clinical evaluation related results showed an improvement of SM patients' quality of life. In conclusion, r-fMV improves gait function in MS patients affected by severe spasticity of lower limb, non-responsive to common oral antispastic drugs. PMID- 28017241 TI - Prevalence of depression and anxiety in Multiple Sclerosis: A systematic review and meta-analysis. AB - OBJECTIVE: Prevalence rates of depression and anxiety in patients with Multiple Sclerosis (MS) vary widely across studies. Aim of this systematic review and meta analysis was to a) estimate the prevalence of depression and anxiety in MS, and specifically b) explore sources of heterogeneity (assessment method, prevalence period, study quality, recruitment resource, region) by extensive analyses. METHODS: A computerized search in PubMed, EMBASE, and PsycINFO for studies on depression and anxiety in MS was performed up to December 2014. RESULTS: Fifty eight articles with a total sample size of 87,756 MS patients were selected. Pooled mean prevalence was 30.5% (95% CI=26.3%-35.1%) for depression, and 22.1% (95% CI=15.2%-31.0%) for anxiety. Prevalence of clinically significant depressive or anxiety symptoms was higher (35% and 34%) compared with disorders (21%; p=0.001 and 10%; p<0.001). Prevalence of a depressive disorder was relatively lower in studies from Europe. Anxiety disorder was more prevalent in community based samples. Sources of high heterogeneity were not revealed. CONCLUSIONS: Data of a large number of patients indicate increased prevalence of depression and anxiety in MS. Further research is needed to identify sources of heterogeneity. Issues to consider are the definition of depression and anxiety, patient recruitment, and patient characteristics. PMID- 28017242 TI - Physical activity, sedentary behavior, and aerobic capacity in persons with multiple sclerosis. AB - BACKGROUND: There is substantial evidence that exercise training improves aerobic capacity among people with multiple sclerosis (MS), but less is known about the associations between physical activity and sedentary behaviors with aerobic capacity. OBJECTIVE: This study examined if objectively-measured moderate-to vigorous (MVPA) and light (LPA) physical activity and sedentary behavior were associated with peak aerobic capacity (VO2peak) measured using an established protocol for conducting a maximal, incremental exercise test in persons with MS. METHODS: The study involved a cross-sectional, observational study design and included 49 persons with MS. Participants wore an accelerometer around the waist during the waking hours for a 7-day period as a measure of physical activity and sedentary behaviors, and completed a maximal, incremental exercise test on an electronically-braked, computer-controlled cycle ergometer with open-circuit spirometry for measuring VO2peak. RESULTS: VO2peak was significantly correlated with MVPA (r=0.53, p<0.001) and LPA (r=0.39, p<0.01), but not sedentary behavior (r=-0.12, p=0.44). Linear regression analysis indicated that MVPA (B=0.19, SE B=0.04, beta=0.51, p<0.001) and LPA (B=0.02, SE B=0.01, beta=0.30, p<0.05), but not sedentary behavior (B=-0.01, SE B=0.01, beta=-0.14, p=0.26), explained significant variance in VO2peak (R2=0.40). CONCLUSION: We provide the first evidence that MVPA and LPA represent concurrent correlates of VO2peak and both could be targeted for improving aerobic capacity in persons with MS. PMID- 28017243 TI - Exome sequencing reveals two FA2H mutations in a family with a complicated form of Hereditary Spastic Paraplegia and psychiatric impairments. PMID- 28017244 TI - Toll like receptor 3 and viral infections of nervous system. AB - Members of the toll-like receptor (TLR) family are pathogen recognition receptors that recognize pathogen-associated molecular patterns. TLRs mediate the modulation of innate immune responses and influence the development of adaptive immunity. TLR3 is the first identified antiviral TLR that recognizes dsRNA. TLR3 plays a central role in the activation of host immune responses to viral infections and shows detrimental or protective effects against various viral infections. Several viruses are neurotropic and can infect the central nervous system, leading to neuropathologies such as encephalitis, encephalopathy, meningitis, and neuritis. Single nucleotide polymorphism (SNP) in the TLR3 gene is associated with the susceptibility to a spectrum of nervous system viral infections. In this review, we discussed the existing knowledge of TLR3 immune responses on the basis of the experimental evidence and coherent picture of the SNP in TLR3 that is associated with various neurotropic virus infections. PMID- 28017245 TI - Corrigendum to 'Role of neurodevelopment involved genes in psychiatric comorbidities and modulation of inflammatory processes in Alzheimer's disease' [J. Neurol. Sci. 370 (November 2016) 162-166]. PMID- 28017246 TI - In response to letter to Editor by Nosaka et al. on our paper: Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy. J Neurol Sci 2015;349:190-195. PMID- 28017247 TI - Clinical characteristics of parkinsonism in frontotemporal dementia according to subtypes. AB - BACKGROUND: We investigated the prevalence of parkinsonism in frontotemporal dementia (FTD) subtypes and the cognitive and behavioral differences between FTD with and without parkinsonism in a well-structured, prospective cohort. METHODS: One hundred and ninety-one FTD patients were enrolled and all patients underwent comprehensive neurological evaluations, neuropsychological tests, and the Unified Parkinson's Disease Rating Scale. RESULTS: The prevalence of parkinsonism was 38.7% (74 patients), and included 33 (46.5%) behavioral variant FTD (bvFTD), 16 (24.2%) semantic dementia (SD), 19 (45.2%) progressive nonfluent aphasia (PNFA), and 6 (50%) FTD associated with motor neuron disease (FTD-MND). SD patients with parkinsonism had higher CDR sum of boxes scores (9.7+/-4.5 vs 6.2+/-4.5, p=0.024), frontal behavioral inventory total score (33.7+/-20.5 vs 24.3+/-14.5, p=0.045), and executive function score of frontal executive dysfunction, disinhibition, and apathy (28.9+/-13.7 vs 19.2+/-12.9, p=0.021) than those without parkinsonism. Seoul Instrumental Activities of Daily Living score (bvFTD: 23.5+/-11.7 vs 17.3+/-11.3, p=0.031, SD: 23.1+/-11.1 vs 11.3+/-9.3, p=0.005) was higher for bvFTD and SD with parkinsonism than for those without parkinsonism. CONCLUSIONS: Parkinsonism is found to be more common in patients with bvFTD, PNFA, and FTD-MND patients than those with SD. Behavioral disturbances were more prominent in SD with parkinsonism than without. Additional studies are needed to determine the pathomechanism and optimal treatment of parkinsonism in different FTD subtypes. PMID- 28017248 TI - Treatment of blepharospasm with apraclonidine. AB - OBJECTIVE: To describe improvement in blepharospasm with apraclonidine. BACKGROUND: Blepharospasm is a focal dystonia involving chiefly the orbicularis oculi and periocular muscles resulting in involuntary sustained eyelid closure. Botulinum toxin injection is the mainstay of treatment with meaningful improvement in over 85% of patients, but the effects often wear off within 3 4months. Apraclonidine is an alpha-2 adrenergic receptor agonist, which causes contraction of superior tarsal (Muller) muscle which may improve blepharospasm related eyelid closure. We propose that apraclonidine may be a useful short-term treatment in patients with blepharospasm, particularly during wearing off from botulinum toxin injection. METHODS: Patients who had pre-mature wearing off of botulinum injection effect were evaluated before and after the administration of 2 drops of apraclonidine 0.5%-1% solution to each eye. Subjective patient impressions and examiner's impression of symptoms pre and post-apraclonidine administration were recorded. A blinded rater evaluated the videos and provided an independent assessment of the severity of symptoms pre- and post administration, using a 0-4 scale. RESULTS: Our study included 7 patients (4 male) with a mean age of 61years and mean duration of blepharospasm of 3.6years. There was a subjective, albeit transient (about 2-4h) improvement in blepharospasm reported by all patients and by the examiner. The mean severity scores, based on blinded video ratings, showed a reduction from of 3.4 pre administration to 2.3 post-administration of apraclonidine (p<0.025). No adverse effects were noted. CONCLUSIONS: Apraclonidine is a potentially useful medication for short term management of blepharospasm symptoms while awaiting botulinum toxin injection. PMID- 28017249 TI - Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing. AB - d-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood. PMID- 28017250 TI - Evaluation parameters between intra-voxel incoherent motion and diffusion weighted imaging in grading and differentiating histological subtypes of meningioma: A prospective pilot study. AB - PURPOSE: To prospectively evaluate the usage of intra-voxel incoherent motion (IVIM) magnetic resonance imaging (MRI) parameters in grading and differentiating histological subtypes of meningiomas and in comparing their ability with the traditional diffusion-weighted imaging (DWI) parameter (apparent diffusion coefficient, ADC). METHODS: In this prospective study, 102 participants underwent IVIM MRI and DWI. Traditional DWI and IVIM MRI were performed by using 2 b values (0, 1000s/mm2) and 12 b values (0-3500s/mm2), respectively. Finally, the values of ADC and IVIM parameters were collected from 72 Grade I and 11 Grade II meningiomas. RESULTS: The mean ADC values of Grade II and Grade I meningiomas were 0.909+/-0.268*10-3mm2/s and 0.905+/-0.194*10-3mm2/s, respectively, p=0.967. The D values were lower in Grade II meningiomas than in Grade I meningiomas (0.459+/-0.072*10-3mm2/s vs. 0.524+/-0.030*10-3mm2/s, respectively, p=0.005). In ROC curves, the cut-off D value that separated Grade II meningiomas from Grade I meningiomas was 0.479*10-3mm2/s with a sensitivity of 90.9% and a specificity of 76.7%. The secretory and angiomatous meningiomas had higher IVIM parameters than the other subtypes (all p<0.05). D* was significantly lower in fibrous meningiomas than in other meningiomas (2.783+/-1.179*10-3mm2/s vs. 5.125+/ 1.918*10-3mm2/s, p<0.001). D, rD and rf values correlated negatively with Ki-67 index while D* and rD* value had positive relation with Ki-67 values. CONCLUSION: IVIM MRI is a promising technique for distinguishing different grades of meningiomas. Different subtypes of meningiomas have different IVIM features, which may help to treatment decision and prognosis evaluation. PMID- 28017251 TI - A SLC20A2 mutation identified in an asymptomatic patient with brain calcification. PMID- 28017252 TI - Microcephaly and arthrogryposis multiplex congenita: The full-blown CNS spectrum in newborns with ZIKV infection. AB - The recent alarming statements concerning the newborn ZIKV-induced microcephaly epidemics in the Northeast of Brazil, released by the Brazilian Ministry of Health, as well as important international health agencies, such as the World Health Organization and the Pan American Health Organization, raised many "why and how" questions so far, that will hopefully be scientifically answered, as more researches in that regard come up in the long term. In this paper, we describe another potentially ZIKV-induced central nervous system and musculoskeletal disorder that has accompanied microcephaly in these children: atrhogryposis multiplex congenita. The goal is to bring up some hypotheses for possible underlying molecular mechanisms based on published data taken from animal models, such as ovine and cattle, which once infected by other types of arboviroses and viruses that also belong to the Flaviviridae family, presented, too, with the full-blown CNS spectrum of malformations at birth. PMID- 28017253 TI - Therapeutic route of patients at the acute phase of their stroke in Burkina Faso. AB - INTRODUCTION: The advent of the neurovascular units and thrombolysis has improved support for stroke in developed countries. Our objective was to study the therapeutic route of stroke patients in Burkina Faso, a country with limited resources. METHODS: It was a prospective cohort study over a period of 4months, from February 02, 2014 to June 05, 2014, in medical emergencies and Neurology department of the teaching hospital Yalgado Ouedraogo. The study focused on patients diagnosed with stroke through brain imaging when they first entered hospital or during hospitalization. Variables of the study included socio demographic data of the patients, route of the patients, nature of the stroke, treatment and clinical course. RESULTS: The time between the onset of clinical signs and the first contact with a peripheral public health unit extended from 30min to 24h with an average of 6h and 56min. The minimum time between the first contact with a peripheral public health unit and medical emergencies of the Teaching Hospital Yalgado Ouedraogo was 15min, and the maximum, two weeks. After their arrival in medical emergencies, patients spent on average 21h and 18min to achieve the cerebral CT scan. Concerning the treatment, the thrombolysis, which was not available yet, had never been prescribed, while 19% of patients were eligible according to the 4h30mn period criteria. CONCLUSION: Our study shows that the long delay in the access of neurological expertise is, in most cases, related to the therapeutic route of patients. Thus, the setting-up of a stroke sector would improve the management and the prognosis of cases in Burkina Faso. PMID- 28017254 TI - Role of vitamin A metabolism in IIH: Results from the idiopathic intracranial hypertension treatment trial. AB - INTRODUCTION: Vitamin A and its metabolites (called retinoids) have been thought to play a role in the development of idiopathic intracranial hypertension (IIH). The IIH Treatment Trial (IIHTT) showed the efficacy of acetazolamide (ACZ) in improving visual field function, papilledema grade, quality of life and cerebrospinal fluid (CSF) pressure. We postulated that IIH patients would demonstrate elevated measures of vitamin A metabolites in the serum and CSF. METHODS: Comprehensive measures of serum vitamin A and its metabolites were obtained from 96 IIHTT subjects, randomly assigned to treatment with ACZ or placebo, and 25 controls with similar gender, age and body mass index (BMI). These included retinol, retinol binding protein, all-trans retinoic acid (ATRA), alpha- and beta-carotenes, and beta-cryptoxanthin. The IIHTT subjects also had CSF and serum vitamin A and metabolite measurements obtained at study entry and at six months. RESULTS: At study entry, of the vitamin A metabolites only serum ATRA was significantly different in IIHTT subjects (median 4.33nM) and controls (median 5.04nM, p=0.02). The BMI of IIHTT subjects showed mild significant negative correlations with serum ATRA, alpha- and beta-carotene, and beta cryptoxanthin. In contrast, the control subject BMI correlated only with serum ATRA. At six months, the serum retinol, alpha-carotene, beta-carotene, and CSF retinol were increased from baseline in the ACZ treated group, but only increases in alpha-carotene (p=0.02) and CSF ATRA (p=0.04) were significantly greater in the ACZ group compared with the placebo group. No other vitamin A measures were significantly altered over the six months in either treatment group. Weight loss correlated with only with the change in serum beta-carotene (r=-0.44, p=0.006) and the change in CSF retinol (r=-0.61, p=0.02). CONCLUSION: Vitamin A toxicity is unlikely a contributory factor in the causation of IIH. Our findings differ from those of prior reports in part because of our use of more accurate quantitative methods and measuring vitamin A metabolites in both serum and CSF. ACZ may alter retinoid metabolism in IIH patients. PMID- 28017256 TI - Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up. AB - Neuromyelitis optinca (NMO) represents a serious demyelinating disease of the central nervous system selectively attacking the spinal cord and optic nerve. Early differential diagnosis from multiple sclerosis is of vital importance, as NMO mandates immunosuppressive and not immunomodulatory treatment. Rituximab has been recently introduced as a treatment option for NMO. However, optimal surrogate measures and treatment intervals are still unclear. Five patients (females, mean age 54+/-10.21years) with NMO and NMO spectrum disorders (NMOSD) were evaluated with respect to disability and relapse rate. All patients were found positive for NMO IgG. All patients (three with NMO and two with NMOSD, 1 patient with recurrent optic neuritis and 1 patient with recurrent myelitis) had received rituximab treatment for six years. One patient with NMOSD received cyclophosphamide prior to rituximab while two were misdiagnosed as multiple sclerosis and had received interferon treatment. All received rituximab infusion of 375mg/m2 once per week for 4weeks and then every two months for the first two years and then every six months. B-cell counts were measured every two months and were kept in almost undetectable levels. No relapse was noted during the treatment period while EDSS score was improved in all patients. No severe adverse effects occurred during RTX treatment. Rituximab treatment on NMO and NMOSD patients showed significant improvement in disability and relapse-rate without any significant adverse effects. PMID- 28017255 TI - Cognitive deficits in non-demented diabetic elderly appear independent of brain amyloidosis. AB - BACKGROUND: To determine the effects of Type 2 diabetes (DM2) on levels of brain amyloidosis and cognition in a community-dwelling cohort of nondemented elderly individuals. METHODS: 33 subjects (16 DM2, 17 nondiabetic) were prospectively recruited. Subjects underwent a PET scan using the amyloid tracer, Pittsburgh Compound B, and a neuropsychological evaluation. Associations between DM2, brain amyloidosis, and cognition were assessed using multivariate regressions, adjusting for age and APOE4 status. RESULTS: DM2 subjects had lower global cognitive function (p=0.018), as measured by the Repeatable Battery for the Assessment of Neuropsychological Status. There was no difference in brain amyloidosis between groups (p=0.25). CONCLUSIONS: Community-dwelling, nondemented individuals with DM2 had greater cognitive deficits, which do not appear to be mediated by brain amyloidosis. Further studies exploring potential mediators of these cognitive deficits should be performed. PMID- 28017257 TI - Autosomal Recessive Cerebellar Ataxia type 1 mimicking multiple sclerosis: A report of two siblings with a novel mutation in SYNE1 gene in a Saudi family. AB - Autosomal Recessive Cerebellar Ataxia type 1 (ARCA1), also known as recessive ataxia of Beauce, is an adult onset pure cerebellar ataxia that typically presents with cerebellar ataxia and/or dysarthria. A mutation in the synaptic nuclear envelope protein 1 (SYNE1) gene that is located on chromosome 6p25 results in premature termination of the protein. It was first reported in 2007 as the first identified gene responsible for a recessively inherited pure cerebellar ataxia. In this article, we are presenting two brothers with ARCA1 who were misdiagnosed and treated as multiple sclerosis for more than a decade. We are not only presenting a rare mutation in a Saudi family, but we are also expanding on the heterogeneity of the clinical presentation of this disorder and elaborating on the pathophysiology of neurological involvement. These cases illustrate that white matter abnormalities on MRI may occur in ARCA1. The clinical and radiological spectrum of ARCA1 indicate that this disease is more than a pure cerebellar degeneration. ARCA1 should be considered in the differential diagnosis of patients diagnosed with MS especially in the presence of strong family history. The disease is gradually progressive, and clinical features are atypical for MS. Applying diagnostic criteria for MS is extremely important for confirming or excluding the diagnosis. Detailed history and physical examination are of paramount importance to score the final diagnosis. Another less likely possibility is a chance association, which may question the biological relevance of our data. To confirm or exclude this possibility, further studies reporting different cohorts need to be conducted. PMID- 28017258 TI - Long-term follow-up after near-infrared spectroscopy coronary imaging: Insights from the lipid cORe plaque association with CLinical events (ORACLE-NIRS) registry. AB - BACKGROUND: Coronary lipid core plaque may be associated with the incidence of subsequent cardiovascular events. METHODS: We analyzed outcomes of 239 patients who underwent near-infrared spectroscopy (NIRS) coronary imaging between 2009 2011. Multivariable Cox regression was used to identify variables independently associated with the incidence of major adverse cardiovascular events (MACE; cardiac mortality, acute coronary syndromes (ACS), stroke, and unplanned revascularization) during follow-up. RESULTS: Mean patient age was 64+/-9years, 99% were men, and 50% were diabetic, presenting with stable coronary artery disease (61%) or an acute coronary syndrome (ACS, 39%). Target vessel pre stenting median lipid core burden index (LCBI) was 88 [interquartile range, IQR 50-130]. Median LCBI in non-target vessels was 57 [IQR 26-94]. Median follow-up was 5.3years. The 5-year MACE rate was 37.5% (cardiac mortality was 15.0%). On multivariable analysis the following variables were associated with MACE: diabetes mellitus, prior percutaneous coronary intervention performed at index angiography, and non-target vessel LCBI. Non-target vessel LCBI of 77 was determined using receiver-operating characteristic curve analysis to be a threshold for prediction of MACE in our cohort. The adjusted hazard ratio (HR) for non-target vessel LCBI >=77 was 14.05 (95% confidence interval (CI) 2.47 133.51, p=0.002). The 5-year cumulative incidence of events in the above threshold group was 58.0% vs. 13.1% in the below-threshold group. CONCLUSION: During long-term follow-up of patients who underwent NIRS imaging, high LCBI in a non-PCI target vessel was associated with increased incidence of MACE. PMID- 28017260 TI - Comparison of dissection with harmonic scalpel and conventional bipolar electrocautery in deep inferior epigastric perforator flap surgery: A consecutive cohort study. AB - Reduced tissue damage is a theoretical advantage of using an ultrasonic harmonic scalpel. We hypothesized that the harmonic scalpel would outperform electrocautery in deep inferior epigastric perforator flap surgery, possibly resulting in a shorter operative time and reduced postoperative drainage and pain. Between January and August 2015, 24 consecutive patients were assigned to immediate deep inferior epigastric perforator flap elevation (12 for bipolar electrocautery and 12 for harmonic scalpel). The main outcome variables were total operative time, flap elevation time (starting from the fascia incision), and drainage volume. We compared the number of perforators isolated and the Moon and Taylor classification of the pedicle. Data were tested for normality using the Kolmogorov-Smirnov test before analysis. Continuous variables were compared by Wilcoxon rank-sum test. Data were analyzed using the statistical software SAS, version 9.3 (SAS Institute, Cary, NC, USA). Both groups were comparable with respect to clinical characteristics (mean age, body mass index, and flap weights). There was a statistically significant difference in the operative time between dissection with the harmonic scalpel and electrocautery (305.2 vs. 380.3 min, respectively, p = 0.002). The flap elevation time was reduced, particularly when using the harmonic scalpel where its usage seems crucial for dissecting deep inferior epigastric perforators (59.8 vs. 145.9 min, respectively, p < 0.0001). No statistical difference was observed in the drainage volume and length of hospital stay between the groups. We conclude that the harmonic scalpel may be more reliable and efficient as an alternative to electrocautery. PMID- 28017259 TI - Zotarolimus-eluting Resolute Integrity versus everolimus-eluting Xience Xpedition stents in the management of very long (>30mm) de novo coronary artery stenosis. AB - BACKGROUND: Procedural and clinical outcomes in patients with very long (>30mm) coronary lesions who underwent stent-based percutaneous coronary interventions are still unfavorable. Therefore, we compared the relative efficacy and safety of resolute zotarolimus-eluting stents (R-ZES) and Xpedition everolimus-eluting stents (X-EES) for patients with de novo very long coronary lesions. METHODS: This comparative single-centre, retrospective study compared long R-ZES and X-EES in consecutive patients admitted with very long (>=30mm) native ACC/AHA type C coronary lesions in 2014. All patients were followed up clinically at 1, 3, 6 and 12months. In this study, only symptom-driven angiogram was advised. The study end point was to evaluate immediate procedural success and one-year rate of target lesion failure (TLF), which is a composite of cardiac death, target lesion myocardial infarction, or target lesion revascularization (TLR). RESULTS: Total number of patients enrolled in this study was 185 (R-ZES=107; X-EES=78). The baseline characteristics and post procedural success rate were similar between R ZES and X-EES groups, including the post stenting lesion lengths (36.6+/-1.92mm vs 40.71+/-6.175mm, P=0.09). At 12-month follow-up, there were no significant between-group differences in the rate of adverse clinical events (death, myocardial infarction, stent thrombosis, target lesion revascularization, and composite outcomes). Procedural success was achieved in 94% in R-ZES group and 93% in X-EES group (P=0.24). The incidence of TLF was 5% in R-ZES and 4% in X-EES groups (HR-1.25; 95% CI-0.86-5.6; P=0.19). CONCLUSION: Patients with de novo long coronary artery disease, R-ZES implantation showed similar clinical outcome as compared with X-EES implantation. PMID- 28017261 TI - Is sentinel lymph node biopsy warranted for desmoplastic melanoma? A systematic review. AB - BACKGROUND: Desmoplastic melanoma (DM) is an uncommon malignancy associated with a high local recurrence rate. The aim of this systematic review was to determine the positivity rate of sentinel lymph node biopsy (SLNB) in patients with DM. The secondary outcome was to establish if SLNB is warranted for both pure DM (PDM) and mixed DM (MDM). METHODS: A full systematic literature review of SLNB in DM was performed by two authors in January 2016. Ovid MEDLINE, Ovid EMBASE and the Cochrane Central Register of Controlled Trials were searched. RESULTS: Sixteen studies involving 1519 patients having SLNB in DM were included, of which 99 patients had positive SLNB (6.5%). Two articles reported a significantly reduced disease-free survival (DFS) with positive SLNB and three published a reduced melanoma-specific survival (MSS). Six studies compared SLNB in MDM and PDM. Of the 275 patients, 38 (13.8%) had a positive SLNB in MDM compared to 17 of 313 patients (5.4%) with positive SLNB in PDM. CONCLUSIONS: Rates of positive SLNB in DM are reduced compared to other variants of melanoma; however, nodal status may still predict DFS and MSS. MDM is associated with a higher rate of micro metastases to regional lymph nodes than PDM, and DFS and MSS may be lesser in MDM than in PDM. We would recommend the consideration of SLNB in MDM. However, with such low rates of positive SLNB in PDM, and in the absence of high-risk features to stratify patients, we would not recommend SLNB in PDM. PMID- 28017262 TI - Correlation between acoustic rhinometry, computed rhinomanometry and cone-beam computed tomography in mouth breathers with transverse maxillary deficiency. AB - INTRODUCTION: To provide clinical information and diagnosis in mouth breathers with transverse maxillary deficiency with posterior crossbite, numerous exams can be performed; however, the correlation among these exams remains unclear. OBJECTIVE: To evaluate the correlation between acoustic rhinometry, computed rhinomanometry, and cone-beam computed tomography in mouth breathers with transverse maxillary deficiency. METHODS: A cross-sectional study was conducted in 30 mouth breathers with transverse maxillary deficiency (7-13 y.o.) patients with posterior crossbite. The examinations assessed: (i) acoustic rhinometry: nasal volumes (0-5cm and 2-5cm) and minimum cross-sectional areas 1 and 2 of nasal cavity; (ii) computed rhinomanometry: flow and average inspiratory and expiratory resistance; (iii) cone-beam computed tomography: coronal section on the head of inferior turbinate (Widths 1 and 2), middle turbinate (Widths 3 and 4) and maxilla levels (Width 5). Acoustic rhinometry and computed rhinomanometry were evaluated before and after administration of vasoconstrictor. Results were compared by Spearman's correlation and Mann-Whitney tests (alpha=0.05). RESULTS: Positive correlations were observed between: (i) flow evaluated before administration of vasoconstrictor and Width 4 (Rho=0.380) and Width 5 (Rho=0.371); (ii) Width 2 and minimum cross-sectional areas 1 evaluated before administration of vasoconstrictor (Rho=0.380); (iii) flow evaluated before administration of vasoconstrictor and nasal volumes of 0-5cm (Rho=0.421), nasal volumes of 2-5cm (Rho=0.393) and minimum cross-sectional areas 1 (Rho=0.375); (iv) Width 4 and nasal volumes of 0-5cm evaluated before administration of vasoconstrictor (Rho=0.376), nasal volumes of 2-5cm evaluated before administration of vasoconstrictor (Rho=0.376), minimum cross-sectional areas 1 evaluated before administration of vasoconstrictor (Rho=0.410) and minimum cross sectional areas 1 after administration of vasoconstrictor (Rho=0.426); (v) Width 5 and Width 1 (Rho=0.542), Width 2 (Rho=0.411), and Width 4 (Rho=0.429). Negative correlations were observed between: (i) Width 4 and average inspiratory resistance (Rho=-0.385); (ii) average inspiratory resistance evaluated before administration of vasoconstrictor and nasal volumes of 0-5cm (Rho=-0.382), and average expiratory resistance evaluated before administration of vasoconstrictor and minimum cross-sectional areas 1 (Rho=-0.362). CONCLUSION: There were correlations between acoustic rhinometry, computed rhinomanometry, and cone-beam computed tomography in mouth breathers with transverse maxillary deficiency. PMID- 28017263 TI - Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects. AB - The vagus nerve is strategically located in the body, and has multiple homeostatic and health-promoting effects. Low vagal activity predicts onset and progression of diseases. These are the reasons to activate this nerve. This study examined the effects of transcutaneous vagus nerve stimulation (t-VNS) on a main index of vagal activity, namely heart rate variability (HRV). In Study 1, we compared short (10min) left versus right ear t-VNS versus sham (no stimulation) in a within-subjects experimental design. Results revealed significant increases in only one HRV parameter (standard deviation of the RR intervals (SDNN)) following right-ear t-VNS. Study 2 examined the prolonged effects of t-VNS (1h) in the right ear. Compared to baseline, right-t-VNS significantly increased the LF and LF/HF components of HRV, and SDNN in women, but not in men. These results show limited effects of t-VNS on HRV, and are discussed in light of neuroanatomical and statistical considerations and future directions are proposed. PMID- 28017264 TI - Severe acute peripheral edema induced by noninvasive blood pressure cuff in an elderly patient with hypoalbuminemia under general anesthesia. PMID- 28017266 TI - Correction. PMID- 28017265 TI - Cortical specialisation to social stimuli from the first days to the second year of life: A rural Gambian cohort. AB - Brain and nervous system development in human infants during the first 1000days (conception to two years of age) is critical, and compromised development during this time (such as from under nutrition or poverty) can have life-long effects on physical growth and cognitive function. Cortical mapping of cognitive function during infancy is poorly understood in resource-poor settings due to the lack of transportable and low-cost neuroimaging methods. Having established a signature cortical response to social versus non-social visual and auditory stimuli in infants from 4 to 6 months of age in the UK, here we apply this functional Near Infrared Spectroscopy (fNIRS) paradigm to investigate social responses in infants from the first postnatal days to the second year of life in two contrasting environments: rural Gambian and urban UK. Results reveal robust, localized, socially selective brain responses from 9 to 24 months of life to both the visual and auditory stimuli. In contrast at 0-2 months of age infants exhibit non-social auditory selectivity, an effect that persists until 4-8 months when we observe a transition to greater social stimulus selectivity. These findings reveal a robust developmental curve of cortical specialisation over the first two years of life. PMID- 28017267 TI - The role of surgeon in the perioperative management of neurological diseases. PMID- 28017268 TI - Developing and Implementing a Web-Based Departmental Faculty Scholarly and Service Activity Database. PMID- 28017269 TI - What You Need to Know-A Primer for Radiologists Entering Breast Imaging. PMID- 28017270 TI - Effect of Fixed-Volume and Weight-Based Dosing Regimens on the Cost and Volume of Administered Iodinated Contrast Material at Abdominal CT. AB - PURPOSE: To determine the magnitude of subject-level and population-level cost savings that could be realized by moving from fixed-volume low-osmolality iodinated contrast material administration to an effective weight-based dosing regimen for contrast-enhanced abdominopelvic CT. METHODS: HIPAA-compliant, institutional review board-exempt retrospective cohort study of 6,737 subjects undergoing contrast-enhanced abdominopelvic CT from 2014 to 2015. Subject height, weight, lean body weight (LBW), and body surface area (BSA) were determined. Twenty-six volume- and weight-based dosing strategies with literature support were compared with a fixed-volume strategy used at the study institution: 125 mL 300 mgI/mL for routine CT, 125 mL 370 mgI/mL for multiphasic CT (single-energy, 120 kVp). The predicted population- and subject-level effects on cost and contrast material utilization were calculated for each strategy and sensitivity analyses were performed. RESULTS: Most subjects underwent routine CT (91% [6,127/6,737]). Converting to lesser-volume higher-concentration contrast material had the greatest effect on cost; a fixed-volume 100 mL 370 mgI/mL strategy resulted in $132,577 in population-level savings with preserved iodine dose at routine CT (37,500 versus 37,000 mgI). All weight-based iodine-content dosing strategies (mgI/kg) with the same maximum contrast material volume (125 mL) were predicted to contribute mean savings compared with the existing fixed volume algorithm ($4,053-$116,076/strategy in the overall study population, $1 $17/strategy per patient). Similar trends were observed in all sensitivity analyses. CONCLUSIONS: Large cost and material savings can be realized at abdominopelvic CT by adopting a weight-based dosing strategy and lowering the maximum volume of administered contrast material. PMID- 28017271 TI - Impact of an Incentive Compensation Plan on Academic Productivity. PMID- 28017272 TI - R-SCAN: Imaging for Pediatric Minor Head Trauma. PMID- 28017273 TI - Social Media in Radiology: A Primer. PMID- 28017274 TI - MACRA, MIPS, and the New Medicare Quality Payment Program: An Update for Radiologists. AB - The Medicare Access and CHIP Reauthorization Act (MACRA) of 2015 advances the goal of tying Medicare payments to quality and value. In April 2016, CMS published an initial proposed rule for MACRA, renaming it the Quality Payment Program (QPP). Under QPP, clinicians receive payments through either advanced alternative payment models or the Merit-Based Incentive Payment System (MIPS), a consolidation of existing federal performance programs that applies positive or negative adjustments to fee-for-service payments. Most physicians will participate in MIPS. This review highlights implications of the QPP and MIPS for radiologists. Although MIPS incorporates radiology-specific quality measures, radiologists will also be required to participate in other practice improvement activities, including patient engagement. Recognizing physicians' unique practice patterns, MIPS will provide special considerations in performance evaluation for physicians with limited face-to-face patient interaction. Although such considerations will affect radiologists' likelihood of success under QPP, many practitioners will be ineligible for the considerations under currently proposed criteria. Reporting using qualified clinical data registries will benefit radiologists' performance by allowing expanded arrays of MIPS and non-MIPS specialty-specific measures. A group practice reporting option will substantially reduce administrative burden but introduce new challenges by requiring uniform determination of patient-facing status and performance measurement for all of the group's physicians (diagnostic radiologists, interventional radiologists, and nonradiologists) under the same taxpayer identification number. Given that the initial MIPS performance period begins in 2017, radiologists must begin preparing for QPP and taking actions to ensure their future success under this new quality based payment system. PMID- 28017275 TI - Trends in Publications in Radiology Journals Designated as Relating to Patient Centered Care. AB - PURPOSE: To assess trends in publications in radiology journals designated as dealing with patient-centered care. METHODS: PubMed was searched for articles in radiology journals for which the article's record referenced patient centered/patient-centric care. Among these, original research articles were identified and assigned major themes. Trends were assessed descriptively. RESULTS: A total of 115 articles in radiology journals designated as dealing with patient-centered care were identified, including 40 original research articles. The number of articles annually ranged from 0 to 4 in 2000-2008, 5 to 9 in 2010 2012, 14 to 15 in 2013-2014, and 25 in 2015. Only four radiology journals had published more than one of the original research articles. Original research articles' most common themes were: optimization of patients' access to reports and images (n=7); patients' examination experience (5); image evaluation (n=4); radiologists meeting with patients (n=4); improving patients' knowledge of imaging (n=3); examination wait times/efficiency (n=3); examination utilization/appropriateness (n=3); and IT enhancements (n=3). A total of 13 of 40 original research articles solicited opinions from patients. One study involved patients in educating trainees regarding patient-centered care. No study involved patients in system-level decisions regarding health care design and delivery. CONCLUSION: Articles dealing with patient-centered care in radiology are increasing, though they remain concentrated in a limited number of journals. Though major themes included image/report access, patient experiences, and radiologists meeting with patients, many studies dealt with less clearly patient centric topics such as examination interpretation, while inclusion of patients in systems design was lacking. Further research in radiology is encouraged to target a broader range of ideals of patient-centered care, such as diversity, autonomy, and compassion, and to incorporate greater patient engagement. PMID- 28017276 TI - Patient journey in decompensated heart failure: An analysis in departments of cardiology and geriatrics in the Greater Paris University Hospitals. AB - BACKGROUND: Hospitalization for worsening/acute heart failure is increasing in France, and limited data are available on referral/discharge modalities. AIM: To evaluate patients' journeys before and after hospitalization for this condition. METHODS: On 1 day per week, between October 2014 and February 2015, this observational study enrolled 260 consecutive patients with acute/worsening heart failure in all 10 departments of cardiology and four of the departments of geriatrics in the Greater Paris University Hospitals. RESULTS: First medical contact was an emergency unit in 45% of cases, a general practitioner in 16% of cases, an emergency medical ambulance in 13% of cases and a cardiologist in 13% of cases; 78% of patients were admitted directly after first medical contact. In hospital stay was 13.2+/-11.3 days; intensive care unit stay (38% of the population) was 6.4+/-5 days. In-hospital mortality was 2.7%. Overall, 63% of patients were discharged home, whereas 21% were transferred to rehabilitation units. A post-discharge outpatient visit was made by only 72% of patients within 3 months (after a mean of 45+/-28 days). Only 53% of outpatient appointments were with a cardiologist. CONCLUSION: Emergency departments, ambulances and general practitioners are the main points of entry before hospitalization for acute/worsening heart failure. Home discharge occurs in two of three cases. Time to first patient post-discharge visit is delayed. Therefore, actions to improve the patient journey should target primary care physicians and emergency structures, and efforts should be made to reduce the time to the first visit after discharge. PMID- 28017277 TI - Outcomes after surgery for acute type A aortic dissection in "non-Marfan syndrome" patients with long life expectancy: A 24-year follow-up. AB - BACKGROUND: Long-term survival and risk of reoperation in "non-Marfan syndrome" patients with a long life expectancy who undergo emergency surgery for acute type A aortic dissection (aTAAD) are not well known. AIM: To analyse survival, risk of reoperation and quality of life in this population. METHODS: From 1990 to 2010, all patients aged<=50 years and not affected by Marfan syndrome, who underwent emergency surgery for aTAAD at two institutions, were included in this analysis. Patients were categorized into four groups according to the extension of the aortic replacement: SUPRACORONARY, ROOT, ARCH and EXTENSIVE. RESULTS: Sixty-six patients (mean age 45+/-4 years; range 34-50 years) were considered eligible for this analysis. Overall in-hospital mortality was 24% (16/66 patients); and 25%, 23%, 20.5% and 43% in the SUPRACORONARY, ROOT, ARCH and EXTENSIVE groups, respectively. Mean follow-up among survivors was 10.5+/-7.2 years (range: 0.1 24.7 years). Overall 10-year survival was 55+/-6%; and 75+/-12%, 69+/-13%, 47+/ 8% and 28+/-17% in the SUPRACORONARY, ROOT, ARCH and EXTENSIVE groups, respectively. Overall freedom from reoperation on the aorta was 73+/-7.5%; and 40+/-20%, 75+/-21%, 78+/-8% and 100% in the SUPRACORONARY, ROOT, ARCH and EXTENSIVE groups, respectively. CONCLUSIONS: In our experience, patients who underwent isolated supracoronary ascending aorta or root replacement showed the most satisfactory late survival. However, because the risk of reoperation is low when the replacement is extended to the root, our data suggest that root replacement could represent a good compromise between operative mortality and long-term survival. PMID- 28017278 TI - Three-dimensional transoesophageal echocardiography for cardiac output in critically ill patients: A pilot study of ultrasound versus the thermodilution method. AB - BACKGROUND: Three-dimensional transoesophageal echocardiography (3D-TOE) is a new noninvasive tool for quantitative assessment of left ventricular (LV) volumes and ejection fraction. AIM: The objective of this pilot study was to evaluate the feasibility and accuracy of 3D-TOE for the estimation of cardiac output (CO), using transpulmonary thermodilution with the Pulse index Contour Continuous Cardiac Output (PiCCO) system as the reference method, in intensive care unit (ICU) patients. METHODS: Fifteen ICU patients on mechanical ventilation prospectively underwent PiCCO catheter implantation and 3D-TOE. 3D-TOE LV end diastolic and end-systolic volumes were determined using semi-automated software. CO was calculated as the product of LV stroke volume (end-diastolic volume-end systolic volume) multiplied by heart rate. CO was also determined invasively by transpulmonary thermodilution as the reference method. RESULTS: Among 30 haemodynamic evaluations, 29 (97%) LV 3D-TOE datasets were suitable for CO calculation. The mean 3D-TOE image acquisition and post-processing times were 46 and 155seconds, respectively. There was a correlation (r=0.78; P<0.0001) between PiCCO and 3D-TOE CO. Compared with PiCCO, the 3D-TOE CO mean bias was 0.38L/min, with limits of agreement of -1.97 to 2.74L/min. CONCLUSIONS: Noninvasive estimation of CO by 3D-TOE is feasible in ICU patients. This new semi-automated modality is an additional promising tool for noninvasive haemodynamic assessment of ICU patients. However, the wide limits of agreement with thermodilution observed in this pilot study require further investigation in larger cohorts of patients. PMID- 28017279 TI - Cardiovascular remodeling and the peripheral serotonergic system. AB - Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3, 5-HT1B/1D, 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5 HT2A/2B) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system. PMID- 28017280 TI - Nutritional beliefs and practices among diabetic pregnant mothers in a tertiary care hospital in Bangladesh. AB - BACKGROUND & AIM: Pregnant mothers with diabetes, especially in developing countries, are particularly prone to suffer from dietary imbalances due to superstitions and irrational beliefs and practices. The study aimed to explore the existing beliefs and practices related to food intake among Bangladeshi diabetic pregnant mothers. MATERIAL & METHODS: A cross-sectional study was conducted among 200 diabetic pregnant mothers (age in yrs, M+/-SD, 30+/-4), selected purposively from outpatient department of Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine & Metabolic Disorders. An interviewer-administered questionnaire was used to collect data. SPSS 16.0 were used for data analysis. RESULTS: About 40% mothers had uncontrolled glycaemic status. 43% mothers believed that food should not be taken during the 'call for prayer' and 91% of them practiced it. For 'eclipse' the percentage of such kind of belief was much higher (80%) and 90% of them practiced it. With varying proportion for particular fishes 44-58% respondents believed that some fishes should be avoided due to the increased movement of child, fetal malformation and disease. 93% actually practiced it. 28% had adverse beliefs about duck meat, 78% pineapple and 8% had about coconut. The corresponding percentages for practice were 82%, 99% and 50% respectively. Mentally and physically abnormal child, different kinds of child illness and threat of abortion were among the reasons for misbeliefs about those foods. CONCLUSION: There are a number of nonscientific beliefs and prejudices among this pregnant mother regarding the intake of food. PMID- 28017281 TI - Neutrophil-Lymphocyte ratio and Platelet-Lymphocyte ratio as useful predictive markers of prediabetes and diabetes mellitus. AB - AIMS: Chronic inflammation plays a central role in the development and progression of diabetes, and in the pathogenesis of its complications. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are indicators of subclinical inflammation. Mean platelet volume (MPV) is one of the platelet function indices. We investigated the association of NLR, PLR and MPV with prediabetes and type 2 diabetes mellitus and determine whether or not these are reliable markers for diagnosis. MATERIALS AND METHODS: Participants were divided into four groups; 1: normal glucose tolerance, 2: impaired glucose tolerance (prediabetic), 3: newly diagnosed diabetic by OGTT. 4: group is previously diagnosed diabetic without complication. Outcomes were compared between groups. RESULTS: There are significant differences between all groups in NLR (p=0.004) and PLR (p=0.021) values. NLR values are significantly higher in prediabetic (1.60+/-0.85), firstly diagnosed diabetic (1.58+/-0.78) and clear diabetic (2.07+/-0.95) groups compared to normal group (1.37+/-0.69) (mean, SD). PLR values are significantly lower in prediabetic (90.35+/-44.34) and firstly diagnosed diabetic (86.38+/-45.24) groups compared to normal group (100.55+/ 48.14) but significantly higher in clear diabetic group (122.45+/-37.43). There are no significant differences between all groups in MPV values. CONCLUSION: Inflammation marker NLR significantly increases in prediabetic and diabetic patients. PLR significantly decreases in prediabetes and early stages of diabetes but increases in later stages. NLR and PLR values may be reliable predictive markers in prediabetes and diabetes mellitus. PMID- 28017282 TI - Metabolic syndrome in vitiligo patients among a semi-urban Maharashtrian population: A case control study. AB - AIM: To assess the prevalence of metabolic syndrome and its correlation with the severity and duration of vitiligo. METHODS: One hundred vitiligo patients and 100 age-and-sex matched controls were included, whose waist circumference and blood pressure were measured; fasting serum cholesterol, triglycerides and glucose levels quantified; disease severity assessed and metabolic syndrome defined by National Cholesterol Education Program (NCEP) criteria. RESULTS: Metabolic syndrome (24%:12%), hypertriglyceridemia (41%:24%), impaired glucose tolerance (25%:16%) [P<0.05] and low HDL (P=0.044) were significantly more prevalent in cases as compared to controls as were the mean values of triglycerides and fasting blood sugar. Increased mean age of vitiligo patients correlated with the presence of metabolic syndrome. CONCLUSION: Metabolic syndrome had significant presence in but remained unaffected by the severity of vitiligo in our study patients. PMID- 28017283 TI - The association of food insecurity with health outcomes for adults with disabilities. AB - BACKGROUND: Adults with disabilities are more likely to live in households that are food insecure and are more likely to experience health disparities than adults without disabilities. Research examining the intersection of food insecurity and health outcomes for adults with disabilities has so far been lacking, however. OBJECTIVE/HYPOTHESIS: The research presented here tests whether living in a food insecure household is associated with poorer self-reported health and mental health and different health care utilization, controlling for disability status and other sociodemographic characteristics. METHODS: Multivariate regression analyses are conducted using linked data from the 2011 National Health Interview Survey and the 2012 Medical Expenditures Panel Survey. RESULTS: Adults with and without disabilities who live in food insecure households have higher odds of reporting fair or poor health or mental health in either the current year or the subsequent year. Health care utilization patterns differ for adults who are food insecure as well, both within and across years. CONCLUSIONS: Efforts to address health disparities among adults with disabilities should consider the possible additional impact of food insecurity on health outcomes. PMID- 28017285 TI - Infectious corneal ulcers. PMID- 28017286 TI - Diagnosis and management of herpes zoster ophthalmicus. PMID- 28017284 TI - Tumor cell dormancy. AB - Metastasis is the primary cause of death in cancer patients and current treatments fail to provide durable responses. Efforts to treat metastatic disease are hindered by the fact that metastatic cells often remain dormant for prolonged intervals of years, or even decades. Tumor dormancy reflects the capability of disseminated tumor cells (DTCs), or micrometastases, to evade treatment and remain at low numbers after primary tumor resection. Unfortunately, dormant cells will eventually produce overt metastasis. Innovations are needed to understand metastatic dormancy and improve cancer detection and treatment. Currently, few models exist that faithfully recapitulate metastatic dormancy and metastasis to clinically relevant tissues, such as the bone. Herein, we discuss recent advances describing genetic cell-autonomous and systemic or local changes in the microenvironment that have been shown to endow DTCs with properties to survive and eventually colonize distant organs. PMID- 28017287 TI - [Retrospective study of the assessment and management of benzodiazepine withdrawal syndrome in hospital between 2000 and 2015]. AB - INTRODUCTION: Benzodiazepines are prescribed in many indications and are provider of adverse effects in case of abrupt withdrawal or poorly framed. Withdrawal rules are established by the High Authority for Health. METHODS: To evaluate the diagnostic and therapeutic modalities of the benzodiazepine withdrawal syndrome, we performed a retrospective single-center study at the University Hospital of Reims, between January 2000 and May 2015, in patients with a withdrawal syndrome following hospital coding. A collection of clinical and laboratory data was performed for each patient, as well as how to obtain the diagnosis, their care and their future. RESULTS: Sixty-eight cases were initially collected, but 16 cases were included. In benzodiazepine withdrawal took place outside the hospital in 68% of cases. The causes were varied: lack of renewal, not issued by the pharmacist, pill errors. Disorders found during the withdrawal symptoms were variable, there were particular digestive, neurological and psychiatric disorders. The use of biological assessments did not provide diagnostic support, however, in 68% of cases a toxicological assay has helped to support. The management of the withdrawal syndrome has been done primarily by reintroducing the same treatment (60%), while in 27% of alprazolam is introduced relay benzodiazepines. It is noted one death possibly linked to the withdrawal syndrome. CONCLUSION: Despite recommendations and information about the terms of stops, some clinical situations result in withdrawal symptoms, a patient died in our study, death appears in connection with the withdrawal situation. Note that the human factor is the main factor related to the circumstances of occurrence of withdrawal. PMID- 28017288 TI - Using Objective Structured Clinical Examinations to Assess Intern Orthopaedic Physical Examination Skills: A Multimodal Didactic Comparison. AB - : Patient care is 1 of the 6 core competencies defined by the Accreditation Council for Graduate Medical Education (ACGME). The physical examination (PE) is a fundamental skill to evaluate patients and make an accurate diagnosis. The purpose of this study was to investigate 3 different methods to teach PE skills and to assess the ability to do a complete PE in a simulated patient encounter. DESIGN: Prospective, uncontrolled, observational. SETTING: Northeastern academic medical center. PARTICIPANTS: A total of 32 orthopedic surgery residents participated and were divided into 3 didactic groups: Group 1 (n = 12) live interactive lectures, demonstration on standardized patients, and textbook reading; Group 2 (n = 11) video recordings of the lectures given to Group 1 and textbook reading alone; Group 3 (n = 9): 90-minute modules taught by residents to interns in near-peer format and textbook reading. RESULTS: The overall score for objective structured clinical examinations from the combined groups was 66%. There was a trend toward more complete PEs in Group 1 taught via live lectures and demonstrations compared to Group 2 that relied on video recording. Near-peer taught residents from Group 3 significantly outperformed Group 2 residents overall (p = 0.02), and trended toward significantly outperforming Group 1 residents as well, with significantly higher scores in the ankle (p = 0.02) and shoulder (p = 0.02) PE cases. CONCLUSIONS: This study found that orthopedic interns taught musculoskeletal PE skills by near-peers outperformed other groups overall. An overall score of 66% for the combined didactic groups suggests a baseline deficit in first-year resident musculoskeletal PE skills. The PE should continue to be taught and objectively assessed throughout residency to confirm that budding surgeons have mastered these fundamental skills before going into practice. PMID- 28017289 TI - Draft genome of Nocardia farcinica TRH1, a linear and polycyclic aromatic hydrocarbon-degrading bacterium isolated from the coast of Trindade Island, Brazil. AB - Here, we report the draft genome sequence and annotation of Nocardia farcinica TRH1, a petroleum hydrocarbons degrading Actinobacteria isolated from the coastal water of Trindade Island, Brazil. PMID- 28017290 TI - Late Xanthomatous Pseudotumor Following Treatment for Breast Cancer. PMID- 28017291 TI - Rationale, design and goals of the HeartFlow assessing diagnostic value of non invasive FFRCT in Coronary Care (ADVANCE) registry. AB - BACKGROUND: Coronary CT angiography (CTA) is a reliable tool for the detection of coronary artery disease (CAD) that conveys significant prognostic information. It does not provide data on the hemodynamic significance of a given lesion, particularly in intermediate-grade stenosis. Fractional flow reserve by CT (FFRCT) can accurately predict the hemodynamic significance of coronary lesions. The primary objective of this registry is to determine whether the integration of FFRCT as an adjunct to coronary CTA will lead to a significant change in the management of CAD in patients with stable angina. METHODS: The ADVANCE Registry is a multi-center, prospective registry designed to evaluate utility, clinical outcomes and resource utilization following FFRCT-guided treatment in clinically stable, symptomatic patients diagnosed with CAD by coronary CTA. Approximately 5000 patients will be enrolled from up to 50 sites in Europe, USA, Canada and Asia. Requirement for enrollment is the presence of atherosclerosis on coronary CTA. For each enrolled patient, a clinical management review committee will use data from coronary CTA and FFRCT to determine the management plan using the following criteria: (a) optimal medical therapy, (b) percutaneous coronary intervention, (c) coronary artery bypass graft surgery, or (d) more information required. The primary endpoint of the registry is the reclassification rate between the management plan based on coronary CTA alone versus CTA plus FFRCT. The secondary endpoints of the registry include the evaluation of the rate of invasive coronary angiography (ICA), revascularization, major adverse coronary events, resource utilization, cumulative radiation dose exposure and the rate of ICA without obstructive CAD at 3-year follow-up. CONCLUSIONS: The ADVANCE registry is designed to assess the real-world impact of FFRCT on the clinical management of stable CAD when used along with coronary CTA. PMID- 28017292 TI - Bullosis Diabeticorum in a Young Child: Case Report of a Very Rare Entity and a Literature Review. AB - Bullosis diabeticorum (BD), or diabetic bulla, is 1 of the cutaneous manifestations of diabetes mellitus, reported in 0.5% of people with diabeties in the United States, mostly in adult men who have had long-lasting and uncontrolled diabetes associated with diabetic peripheral neuropathy. However, BD in young children is a mostly unrecognized entity. We present a case of BD in a 3-year-old girl with type 1 diabetes mellitus who had been treated with insulin for 7 months prior to hospitalization. Dermatologic examination revealed a large, tense bulla filled with clear fluid and not associated with pain or pruritus, localized on the lateral margin of the right hand. A 4 mm punch biopsy was taken from the peripheral edge of the bulla under local anesthesia, and histology showed subepidermal bulla and sparse nonspecific infiltrate in the dermis; direct immunofluorescence was negative to complements C3, IgM, IgG and IgA. The particularities of the present case include the bulla in the absence of local trauma or any other complications of diabetes and associated with well-controlled type 1 diabetes. The diagnosis was certified by histology, direct immunofluorescence and clinical outcome. To the best of our knowledge, BD in young children has been previously reported in only 2 other publications. PMID- 28017293 TI - Decline in acute urinary toxicities with increased institutional experience: 15 year experience of permanent seed prostate brachytherapy in a single Australasian institution. AB - PURPOSE: To evaluate the incidence of acute urinary toxicity after permanent seed prostate brachytherapy (BT) over a 15-year period. METHODS AND MATERIALS: The study consisted of 782 prostate cancer patients treated with BT. All patients completed self-administered International Prostate Symptoms Score (IPSS) at baseline and during regular follow-up. We evaluated the risk of acute urinary retention (AUR) up to 3 months post-BT and lower urinary tract symptom (LUTS) resolution (defined as return to within two points of baseline IPSS score) at regular intervals, up to 24 months post-BT. Univariate and multivariate logistic regressions were used to evaluate the effect of various patient, tumor, and treatment factors on the risk of AUR and the likelihood of LUTS resolution. RESULTS: Ninety-six patients (12%) developed AUR at a median of 1 day post-BT. Increased peak urinary flow is independently associated with lower risk of AUR (odds ratio [OR] = 0.94; 95% confidence interval [CI] = 0.91-0.97). Decline in incidence of AUR was observed over time with increased institutional experience (p = 0.03). Of the 646 patients with a minimum of 24-month follow-up, 29%, 49%, and 72% had LUTS resolution at 6, 12, and 24 months, respectively. Patients who had pre-BT transurethral resection of prostate (OR = 2.4; 95% CI = 1.5-4.0), cytoreductive neo-adjuvant androgen deprivation (OR = 2.0; 95% CI = 1.0-4.0), and higher baseline IPSS (OR = 1.1; 95% CI = 1.07-1.19) are more likely to report LUTS resolution at 24 months. CONCLUSIONS: We reported decline in AUR over time with increased institutional experience in one of the largest Australasian BT series. Approximately three-quarters of patients achieved LUTS resolution at 24 month follow-up. PMID- 28017294 TI - Variation of facial features among three African populations: Body height match analyses. AB - Body height is one of the variables that show a correlation with facial craniometry. Here we seek to discriminate the three populations (Nigerians, Ugandans and Kenyans) using facial craniometry based on different categories of body height of adult males. A total of 513 individuals comprising 234 Nigerians, 169 Ugandans and 110 Kenyans with mean age of 25.27, s=5.13 (18-40 years) participated. Paired and unpaired facial features were measured using direct craniometry. Multivariate and stepwise discriminate function analyses were used for differentiation of the three populations. The result showed significant overall facial differences among the three populations in all the body height categories. Skull height, total facial height, outer canthal distance, exophthalmometry, right ear width and nasal length were significantly different among the three different populations irrespective of body height categories. Other variables were sensitive to body height. Stepwise discriminant function analyses included maximum of six variables for better discrimination between the three populations. The single best discriminator of the groups was total facial height, however, for body height >1.70m the single best discriminator was nasal length. Most of the variables were better used with function 1, hence, better discrimination than function 2. In conclusion, adult body height in addition to other factors such as age, sex, and ethnicity should be considered in making decision on facial craniometry. However, not all the facial linear dimensions were sensitive to body height. PMID- 28017296 TI - Long-term Clinical Outcome After Descemet Membrane Endothelial Keratoplasty. PMID- 28017295 TI - Older adults show higher increases in lower-limb muscle activity during whole body vibration exercise. AB - The purpose of this study was to compare lower limb muscle activity during whole body vibration (WBV) exercise between a young and an older study population. Thirty young (25.9+/-4.3yrs) and thirty older (64.2+/-5.3yrs) individuals stood on a side-alternating WBV platform while surface electromyography (sEMG) was measured for the tibialis anterior (TA), gastrocnemius medialis (GM), soleus (SOL), vastus lateralis (VL), vastus medialis (VM), and biceps femoris (BF). The WBV protocol included nine vibration settings consisting of three frequencies (6, 11, 16Hz) x three amplitudes (0.9, 2.5, 4.0mm), and three control trials without vibration (narrow, medium, wide stance). The vertical platform acceleration (peak values of maximal displacement from equilibrium) was quantified during each vibration exercise using an accelerometer. The outcomes of this study showed that WBV significantly increased muscle activity in both groups for most vibration conditions in the TA (averaged absolute increase: young: +3.9%, older: +18.4%), GM (young: +4.1%, older: +9.5%), VL (young: +6.3%, older: +12.6%) and VM (young: +5.4%, older: +8.0%), and for the high frequency-amplitude combinations in the SOL (young: +7.5%, older: +12.6%) and BF (young: +1.9%, older: +7.5%). The increases in sEMG activity were significantly higher in the older than the young adults for all muscles, i.e., TA (absolute difference: 13.8%, P<0.001), GM (4.6%, P=0.034), VL (7.6%, P=0.001), VM (6.7%, P=0.042), BF (6.4%, P<0.001), except for the SOL (0.3%, P=0.248). Finally, the vertical platform acceleration was a significant predictor of the averaged lower limb muscle activity in the young (r=0.917, P<0.001) and older adults (r=0.931, P<0.001). In conclusion, the older population showed greater increases in lower limb muscle activity during WBV exercise than their young counterparts, meaning that they might benefit more from WBV exercises. Additionally, training intensity can be increased by increasing the vertical acceleration load. PMID- 28017297 TI - Prevalence and predictors of depression among general surgery residents. AB - BACKGROUND: Recent resident suicides have highlighted the need to address depression among medical trainees. This study sought to identify the prevalence and predictors of depression among surgical residents. METHODS: Surgical residents at a single institution were surveyed. Depression and personal traits were assessed using validated measures; participant demographics were also obtained. RESULTS: 73 residents completed the survey (response rate 63%). 36% met criteria for at least mild depression, of which 20% met criteria for moderate to severe depression. In multivariate linear regression analyses controlling for demographic factors, trait emotional intelligence alone was a significant inverse predictor of depression (beta = -0.60, p < 0.001). CONCLUSIONS: Depression is prevalent among general surgery residents. Identifying protective factors and at risk populations may allow for effective initiatives to be developed to address depression, and optimize the mental health of trainees. PMID- 28017298 TI - A pilot program to improve nursing and surgical intern collaboration: Lessons learned from a mixed-methods study. AB - BACKGROUND: Inter-professional collaboration is an integral component of a successful healthcare team. We sought to evaluate the impact of nursing student participation in a one-day intensive inter-professional education (IPE) training session with surgical interns on participant attitudes toward inter-professional collaboration. METHODS: Following IRB approval, pre and post IPE session survey responses were compared to determine the impact on participant attitudes toward inter-professional collaboration. Pre and post session semi-structured interviews were transcribed and analyzed to identify relevant themes. RESULTS: Surgical interns (n = 38) more than nursing students (n = 11), demonstrated a measurable improvement in attitude towards 'collaboration and shared education' (interns: median score pre = 26, post = 28, p = 0.0004; nursing student: median score pre = 27, post = 28, p = 0.02). Qualitative analysis of interviews identified major themes that supplemented this finding. CONCLUSION: An eight hour, one day IPE session has a positive impact on collaborative attitudes and supports the case for increased inter-professional education amongst interns and nursing students. PMID- 28017299 TI - Is intraoperative parathyroid hormone monitoring necessary for primary hyperparathyroidism with concordant preoperative imaging? AB - BACKGROUND: The purpose of this study was to determine if intraoperative parathyroid hormone (PTH) monitoring is necessary in patients with concordant ultrasound and sestamibi imaging. METHODS: Clinical factors, intraoperative findings and outcome were correlated with imaging results in patients with primary hyperparathyroidism who underwent parathyroidectomy with concordant ultrasound and sestamibi imaging. RESULTS: There were 127 patients with primary hyperparathyroidism and concordant imaging who underwent parathyroidectomy. Seven patients (5.5%) had intraoperative findings that were discordant with imaging: 2 (1.6%) had an adenoma at a different location, 2 (1.6%) had double adenomas and 3 (2.4%) had asymmetric hyperplasia. Gland weight and preoperative PTH levels were greater for patients with concordant operative and imaging findings (p < 0.05). CONCLUSION: Six percent of patients with concordant ultrasound and sestamibi imaging had unexpected intraoperative findings. Intraoperative PTH monitoring remains a necessary adjunct even with concordant imaging to ensure identification of abnormal parathyroid glands and cure of hyperparathyroidism. PMID- 28017300 TI - Acute Frequency-Dependent Hypomania Induced by Ventral Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Case Report. PMID- 28017301 TI - Prognostic Value of Hypoalbuminemia After Transcatheter Aortic Valve Implantation (from the Japanese Multicenter OCEAN-TAVI Registry). AB - Hypoalbuminemia, a frailty criterion, belongs to a group of co-morbidities not captured as a traditional risk factor. We assessed its prognostic value in patients who underwent transcatheter aortic valve implantation (TAVI). The study included 1,215 consecutive patients from the Optimized Catheter Valvular Intervention -TAVI Japanese multicenter registry. Hypoalbuminemia was defined as serum albumin level <3.5 g/dl. Baseline characteristics, procedural outcomes, and all-cause, cardiovascular and noncardiovascular mortality rates after TAVI were compared between patients with albumin level <3.5 g/dl (hypo[h]-ALB group, n = 284) and those with albumin level >3.5 g/dl (nonhypo[nh]-ALB group, n = 931). Several baseline characteristics differed significantly between both groups, including age (85.1 +/- 5.1 vs 84.2 +/- 4.9 years, p = 0.012), ejection fraction (58.5 +/- 14.3% vs 62.9 +/- 12.4%, p <0.001), baseline kidney function, or liver disease. The 30-day mortality rate in all patients showed significant differences between the 2 groups (3.9% vs 1.3%, p = 0.005). During a mean follow-up of 330 days, cumulative all-cause, cardiovascular, and noncardiovascular mortality rates were significantly higher in the hALB group than in the nhALB group (log-rank test, p <0.001, p = 0.0021, and p <0.001, respectively). The groups were also analyzed using a propensity matching model for adjusting the baseline differences. The analysis revealed that the poorer prognosis of the hALB group in terms of cumulative all-cause and noncardiovascular mortality was retained (p = 0.038, and p = 0.0068, respectively); however, differences in cardiovascular mortality rates in the 2 groups were attenuated (p = 0.93). In conclusion, hypoalbuminemia was associated with poor prognosis, highlighted by the increase in noncardiovascular mortality. Baseline albumin level could be a useful marker for risk stratification before TAVI. PMID- 28017302 TI - Cardiodynamicsgram as a New Diagnostic Tool in Coronary Artery Disease Patients With Nondiagnostic Electrocardiograms. AB - Cardiodynamicsgram (CDG) has emerged recently as a noninvasive spatiotemporal electrocardiographic method for subtle cardiac dynamics information analysis within electrocardiogram (ECG). This study sought to evaluate the clinical utility of CDG for early coronary artery disease (CAD) detection in suspected patients with CAD presenting with nondiagnostic ECGs. A total of 421 suspected patients with CAD presenting with nondiagnostic ECG were enrolled. Standard 12 lead ECG and CDG were performed simultaneously, 1 day before invasive coronary angiography. Diagnostic accuracy of CDG for early CAD detection was assessed with reference to coronary angiography as the gold standard. Coronary angiography showed >=1 coronary arteries stenosis of >50% in 347 patients. Of these 347 patients with CAD, 294 patients were positive in CDG. Of 74 non-CAD controls, 63 patients were negative in CDG. Diagnostic accuracy of CDG at presentation for CAD was 84.6%, sensitivity 84.7%, and specificity 83.7%. In patients presenting with nondiagnostic ECGs, an abnormal status can be detected early through noninvasive CDG. CDG is highly sensitive for the early diagnosis of CAD. Underlying causes of false-negative CDG findings included number of diseased coronary arteries and collateral circulation. Subtle myocardial damage that was not detectable on coronary angiography might be the major cause of false-positive findings. PMID- 28017304 TI - E-Cigarettes-What a Practicing Cardiologist Needs to Know. AB - Cardiologists and other physicians caring for patients who either smoke tobacco or are potential or active users of E-cigarettes have many questions about this increasingly popular method for delivering nicotine to the brain: (1) What are E cigarettes? (2) What harm do E-cigarettes pose to users and bystanders? (3) Can E cigarettes help tobacco smokers quit? (4) Are E-cigarettes a gateway to tobacco smoking, addicting new users, particularly the young, to nicotine? and (5) Should E-cigarettes be tolerated, or even favored over tobacco, as a less harmful substitute for those unable to stop smoking tobacco? This editorial summarizes evidence and expert opinion, preparing the physician for informed discussion of this controversial subject with their patients and colleagues. Although E cigarettes may be less harmful than tobacco cigarettes, they are definitely not harmless. Particularly concerning are the well-financed commercial interests marketing E-cigarettes to our youth. As new regulatory policies are developed, we must not allow E-cigarettes to reverse our progress in reducing tobacco smoking, the leading cause of preventable death in the United States. PMID- 28017303 TI - Usefulness of Serum Triiodothyronine (T3) to Predict Outcomes in Patients Hospitalized With Acute Heart Failure. AB - Thyroid hormone plays an important role in cardiac function. Low levels of serum triiodothyronine (T3) due to nonthyroidal illness syndrome may have adverse effects in heart failure (HF). This study was designed to assess the ability of T3 to predict in-hospital outcomes in patients with acute HF. In total, 137 patients without thyroid disease or treatment with drugs which affect TH levels, who were hospitalized with acute HF were prospectively enrolled and studied. TH levels were tested upon hospital admission, and outcomes were compared between patients with low (<2.3 pg/ml) and normal (>=2.3 pg/ml) free T3 levels as well as between those with low (<0.6 ng/ml) and normal (>=0.6 ng/ml) total T3 levels. Low free T3 correlated with an increased length of stay in the hospital (median 11 vs 7 days, p <0.001) and higher rates of intensive care unit admission (31.8% vs 16.9%, p = 0.047), with a trend toward increased need for invasive mechanical ventilation (9.0% vs 1.4%, p = 0.056). Low total T3 correlated with an increased length of stay in the hospital (median 11 vs 7 days, p <0.001) and increased need for invasive mechanical ventilation (9.8% vs 1.3%, p = 0.045). In conclusion, low T3 predicts worse hospital outcomes in patients with acute HF and can be useful in the risk stratification of these patients. PMID- 28017305 TI - Predicting Unsuccessful Electrical Cardioversion for Acute Atrial Fibrillation (from the AF-CVS Score). AB - Electrical cardioversion (ECV) is the standard treatment for acute atrial fibrillation (AF), but identification of patients with increased risk of ECV failure or early AF recurrence is of importance for rational clinical decision making. The objective of this study was to derive and validate a clinical risk stratification tool for identifying patients at high risk for unsuccessful outcome after ECV for acute AF. Data on 2,868 patients undergoing 5,713 ECVs of acute AF in 3 Finnish hospitals from 2003 through 2010 (the FinCV study data) were included in the analysis. Patients from western (n = 3,716 cardioversions) and eastern (n = 1,997 cardioversions) hospital regions were used as derivation and validation datasets. The composite of cardioversion failure and recurrence of AF within 30 days after ECV was recorded. A clinical scoring system was created using logistic regression analyses with a repeated-measures model in the derivation data set. A multivariate analysis for prediction of the composite end point resulted in identification of 5 clinical variables for increased risk: Age (odds ratio [OR] 1.31, confidence interval [CI] 1.13 to 1.52), not the First AF (OR 1.55, CI 1.19 to 2.02), Cardiac failure (OR 1.52, CI 1.08 to 2.13), Vascular disease (OR 1.38, CI 1.11 to 1.71), and Short interval from previous AF episode (within 1 month before ECV, OR 2.31, CI 1.83 to 2.91) [hence, the acronym, AF CVS]. The c-index for the AF-CVS score was 0.67 (95% CI 0.65 to 0.69) with Hosmer Lemeshow p value 0.84. With high (>5) scores (i.e., 12% to 16% of the patients), the rate of composite end point was ~40% in both cohorts, and among low-risk patients (score <3), the composite end point rate was ~10%. In conclusion, the risk of ECV failure and early recurrence of AF can be predicted with simple patient and disease characteristics. PMID- 28017307 TI - Neoadjuvant chemotherapy for advanced-stage ovarian cancer: Are the ASCO and SGO recommendations warranted? PMID- 28017306 TI - Extent of pelvic lymphadenectomy and use of adjuvant vaginal brachytherapy for early-stage endometrial cancer. AB - OBJECTIVE: To examine trends of adjuvant radiotherapy choice and to examine associations between pelvic lymphadenectomy and radiotherapy choice for women with early-stage endometrial cancer. METHODS: The Surveillance, Epidemiology, and End Results Program was used to identify surgically treated stage I-II endometrial cancer between 1983 and 2012 (type 1 n=79,474, and type 2 n=25,020). Piecewise linear regression models were used to examine temporal trends of intracavitary brachytherapy (ICBT) and whole pelvic radiotherapy (WPRT) use, pelvic lymphadenectomy rate, and sampled node counts. Multivariable binary logistic regression models were used to identify independent predictors for ICBT use. RESULTS: There was a significant increase in ICBT use and decrease in WPRT use during the study period. ICBT use exceeded WPRT use in 2003 for type 1 stage IA, and in 2007 for type 1 stage IB and type 2 stage IA diseases. In addition, number of sampled pelvic nodes significantly increased over time in type 1-2 stage I-II diseases (mean, 7.0-12.7 in 1988 to 15.2-17.6 in 2012, all P<0.001). On multivariable analysis, extent of sampled pelvic nodes was significantly associated with ICBT use for type 1 cancer: adjusted-odds ratios for 1-10 and >10 nodes versus no lymphadenectomy in stage IA (1.38/2.40), IB (2.75/6.32), and II (1.36/2.91) diseases. Similar trends were observed for type 2 cancer: adjusted odds ratios for stage IA (1.69/3.73), IB (2.25/5.65), and II (1.36/2.19) diseases. CONCLUSION: Our results suggest that surgeons and radiation oncologists are evaluating the extent of pelvic lymphadenectomy when counseling women with early-stage endometrial cancer for adjuvant radiotherapy. PMID- 28017308 TI - Respiratory Distress in a 3-Month-Old Infant with a Mass Obstructing the Right Main-Stem Bronchus: An Unusual Localization of Infantile Hemangioma. PMID- 28017309 TI - An accurate account of crib bumper cases. PMID- 28017310 TI - Conceptual Design of Future Children's Hospitals in Europe. The Role of Public and Private Stakeholders as Transferors of New Concepts from Theory into Practice. PMID- 28017312 TI - Labeling Stents/Scaffolds for Diabetes: Real Science or Marketing Stunt? PMID- 28017311 TI - Efficacy and Safety of the Absorb Everolimus-Eluting Bioresorbable Scaffold for Treatment of Patients With Diabetes Mellitus: Results of the Absorb Diabetic Substudy. AB - OBJECTIVES: The study sought to evaluate the efficacy and safety of the Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) (Abbott Vascular, Abbott Park, Illinois) in patients with diabetes mellitus. BACKGROUND: Randomized, controlled trials have demonstrated comparable clinical outcomes following percutaneous coronary intervention with either Absorb BVS or metallic Xience everolimus-eluting stent. However, these trials lack power required to provide reliable treatment effect estimates in this high-risk population. METHODS: In a pre-specified, powered analysis, patients with diabetes who received >=1 Absorb were pooled from the ABSORB II, III, and JAPAN randomized trials and from the single arm ABSORB EXTEND registry. The study composite primary endpoint was target lesion failure (TLF) at 1 year following Absorb BVS compared with a performance goal of 12.7%. RESULTS: Among 754 diabetic patients included in analysis (27.3% insulin treated), the 1-year TLF rate was 8.3% (upper 1-sided 95% confidence limit: 10.1%; p = 0.0001 vs. performance goal). Scaffold thrombosis (definite or probable) was observed in 2.3% of patients. Multivariable regression identified older age, insulin treatment, and smaller pre-procedure reference vessel diameter as significant independent predictors of 1-year TLF. CONCLUSIONS: The Absorb diabetic substudy suggests efficacy and safety of the Absorb BVS for treatment of patients with diabetes mellitus. PMID- 28017313 TI - Percutaneous Pulmonary Embolus Mechanical Thrombectomy. PMID- 28017314 TI - Coronary Artery Aneurysm After Bioresorbable Vascular Scaffold Implantation With Post-Dilation: Is Less More? PMID- 28017315 TI - Vertebral Artery Rupture Treated by Transcatheter Arterial Embolization. PMID- 28017316 TI - Guidewire Self-Extrusion After Entrapment of Distal Protection Device During Saphenous Vein Graft Angioplasty. PMID- 28017317 TI - A Validation Study of the Automated Self-Administered 24-Hour Dietary Recall for Children, 2014 Version, at School Lunch. AB - BACKGROUND: Obtaining valid and reliable estimates of usual dietary intake at a reasonable cost is a challenge in school-based nutrition research. The Automated Self-Administered 24-Hour Dietary Recall for Children, 2014 version (ASA24 Kids 2014), a self-administered, computerized 24-hour dietary recall, offers improved feasibility over traditional interviewer-administered 24-hour recalls. OBJECTIVE: This mixed-methods study examined ASA24 Kids-2014's validity for measuring dietary intake from National School Lunch Program lunches. PARTICIPANTS/SETTING: After 24% attrition, 96 middle-school students from three urban schools in eastern Pennsylvania participated in the study. A subsample of 27 participants completed qualitative interviews. Data were collected in the spring of 2014. MAIN OUTCOME MEASURES: Self-reported ASA24 Kids-2014 data were compared to direct observations of school lunch, which served as the criterion measure. Dependent variables included eight meal components selected from the National School Lunch Program guidelines (fruit, vegetables, grains, protein-rich foods, dairy, oils, solid fats, and added sugars). A supplemental interview collected qualitative data regarding students' perceptions of content and substantive validity. STATISTICAL ANALYSES: The Wilcoxon signed rank test and Spearman's rho examined criterion-related validity; qualitative content analysis examined content and substantive validity. RESULTS: Participants inaccurately recalled food items eaten at lunch, as 58% of foods were reported in error. However, among foods recalled correctly, no statistically significant differences emerged for estimates of portions consumed for six meal components (fruit, vegetables, grains, protein-rich foods, oils, and added sugars). In addition, statistically significant positive correlations emerged between ASA24 Kids-2014 and direct observation for all estimates. Qualitative data identified students' interest and motivation, comprehension, memory, and English-language fluency as relevant sources of error. CONCLUSIONS: Middle school students have difficulty recalling food items eaten at school lunch; however, they are somewhat successful at estimating intake of accurately recalled foods using ASA24 Kids-2014. Like many self-administered computerized recalls, it remains limited by substantial error. Findings have implications for the development of ASA24 Kids-2014 among diverse youth in urban school settings. PMID- 28017318 TI - Defective interhemispheric inhibition in drug-treated focal epilepsies. AB - BACKGROUND: Focal epilepsies (FEs) arise from a lateralized network, while in generalized epilepsies (GEs) there is a bilateral involvement from the outset. Intuitively, the corpus callosum is the anatomical substrate for interhemispheric spread. OBJECTIVE: We used transcranial magnetic stimulation (TMS) to explore whether there are any physiological differences in the corpus callosum of drug treated patients with FE and those with genetic GE (GGE), compared to healthy subjects (HS). METHODS: TMS was used to measure the interhemispheric inhibition (IHI) from right-to-left primary motor cortex (M1) and viceversa in 16 patients with FE, 17 patients with GGE and 17 HS. A conditioning stimulus (CS) was given to one M1 10 and 50 ms before a test stimulus delivered to the contralateral M1. Motor evoked potentials (MEPs) were analysed both as a function of the side of stimulation and of the epileptic focus (left-right). RESULTS: In HS, IHI was reproducible with suppression of MEPs at ISIs of 10 and 50 ms. Similar effects occurred in GGE patients. FE patients behaved differently, since IHI was significantly reduced bilaterally. When FE patients were stratified according to the side of their epileptic focus, the long-ISI IHI (=50 ms) appeared to be defective only when the CS was applied over the "focal" hemisphere. CONCLUSIONS: FE patients had a defective inhibitory response of contralateral M1 to inputs travelling from the "focal" hemisphere that was residual to the drug action. Whilst IHI changes would not be crucial for the GGE pathophysiology, they may represent one key factor for the contralateral spread of focal discharges, and seizure generalization. PMID- 28017319 TI - Fatal Status Dystonicus in Tardive Dystonia Due to Depletion of Deep Brain Stimulation's Pulse Generator. PMID- 28017320 TI - Cathodal transcranial direct current stimulation reduces seizure frequency in adults with drug-resistant temporal lobe epilepsy: A sham controlled study. PMID- 28017321 TI - Neural correlates of successful orbitofrontal 1 Hz rTMS following unsuccessful dorsolateral and dorsomedial prefrontal rTMS in major depression: A case report. PMID- 28017322 TI - Transcutaneous auricular vagus nerve stimulation in disorders of consciousness monitored by fMRI: The first case report. PMID- 28017323 TI - Multiple myeloma: Presenting as intracranial plasmacytoma. PMID- 28017324 TI - The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation. AB - Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68+iNOS+ cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68+ cells following Mincle induction. Adaptive transfer of Mincle+ M1 macrophages largely promoted cisplatin-induced renal inflammation, which was prevented by the knockdown of Mincle in the transferred cells. Mincle was tightly regulated by TLR4/NF-kappaB signaling as evidenced by the binding of NF kappaB/p65 to the promoter region of Mincle in LPS-primed macrophages. Blocking TLR4 or NF-kappaB suppressed LPS-induced Mincle expression on macrophages. Importantly, Mincle was found to be essential for maintaining the inflammatory phenotypes of M1 macrophages through the Syk signaling pathway since knockdown of Mincle or inhibition of Syk suppressed LPS-induced IL-1beta, MCP-1, and iNOS expression. Thus, Mincle is induced specifically on M1 macrophages, where Mincle Syk signaling promotes and maintains inflammatory phenotypes of M1 macrophages in acute renal inflammation. Hence, targeting Mincle may be a novel therapy for acute kidney injury associated with M1 macrophages. PMID- 28017327 TI - [Lost guide wire - lessons learned]. AB - Central venous catheter placement is a relatively common procedure in current practice, but it is not devoid of risks. Utmost care must be taken to follow a correct technique, and only appropriately trained and/or supervised medical professionals should perform this invasive act. One of the possible complications, completely avoidable by appropriate care, is the intravascular loss of the guide wire during insertion, which is a potentially serious complication. We describe one such case. PMID- 28017326 TI - The association of anticoagulation, ischemic stroke, and hemorrhage in elderly adults with chronic kidney disease and atrial fibrillation. AB - The utility of anticoagulants for ischemic stroke prophylaxis in elderly patients with chronic kidney disease (CKD) and atrial fibrillation remains uncertain. In this population-based retrospective cohort study, we determined the association of anticoagulant use with ischemic stroke or hemorrhage in elderly patients (66 years and older) with advanced chronic kidney disease (eGFR under 45 ml/min/1.73m2) and atrial fibrillation. We followed 6,544 patients with CKD and new onset atrial fibrillation, of whom 1,475 filled a prescription for an anticoagulant. We used propensity-score matched Cox proportional hazards and competing risk models to determine the time to first event of ischemic stroke, hemorrhage or mortality. After matching to examine exposure to anticoagulants, 1,417 matched pairs were identified. The crude rate of ischemic stroke and hemorrhage were 41.3 and 61.3 with anticoagulants and 34.4 and 34.3 without anticoagulants per 100 person-years, respectively. The hazard ratios of ischemic stroke, hemorrhage, and mortality for receipt of an anticoagulation prescription were 1.10 (95% confidence interval, 0.78-1.56), 1.42 (1.04-1.93), and 0.74 (0.62 0.88) as compared to non-receipt of anticoagulation. After accounting for the competing risk of death, the hazard ratios for ischemic stroke and hemorrhage were 1.12 (0.90-1.39) and 1.60 (1.31-1.97), respectively. The findings were consistent in a sensitivity analysis accounting for time varying anticoagulant exposure. Thus, in older patients with CKD and atrial fibrillation, receipt of an anticoagulant was not associated with a lower risk of ischemic stroke, but a higher risk of hemorrhage and a lower risk of mortality. PMID- 28017325 TI - Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. AB - Inflammation is a consequence of chronic kidney disease (CKD) and is associated with adverse outcomes in many clinical settings. Inflammation stimulates production of fibroblast growth factor 23 (FGF23), high levels of which are independently associated with mortality in CKD. Few large-scale prospective studies have examined inflammation and mortality in patients with CKD, and none tested the interrelationships among inflammation, FGF23, and risk of death. Therefore, we conducted a prospective investigation of 3875 participants in the Chronic Renal Insufficiency Cohort (CRIC) study with CKD stages 2 to 4 to test the associations of baseline plasma interleukin-6, high-sensitivity C-reactive protein, and FGF23 levels with all-cause mortality, censoring at the onset of end stage renal disease. During a median follow-up of 6.9 years, 550 participants died (20.5/1000 person-years) prior to end-stage renal disease. In separate multivariable-adjusted analyses, higher levels of interleukin-6 (hazard ratio per one standard deviation increase of natural log-transformed levels) 1.35 (95% confidence interval, 1.25-1.46), C-reactive protein 1.28 (1.16-1.40), and FGF23 1.45 (1.32-1.60) were each independently associated with increased risk of death. With further adjustment for FGF23, the risks of death associated with interleukin 6 and C-reactive protein were minimally attenuated. Compared to participants in the lowest quartiles of inflammation and FGF23, the multivariable-adjusted hazard ratio of death among those in the highest quartiles of both biomarkers was 4.38 (2.65-7.23) for interleukin-6 and FGF23, and 5.54 (3.04-10.09) for C-reactive protein and FGF23. Thus, elevated levels of interleukin-6, C-reactive protein, and FGF23 are independent risk factors for mortality in CKD. PMID- 28017328 TI - An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling. AB - Signaling receptors dynamically exit cilia upon activation of signaling pathways such as Hedgehog. Here, we find that when activated G protein-coupled receptors (GPCRs) fail to undergo BBSome-mediated retrieval from cilia back into the cell, these GPCRs concentrate into membranous buds at the tips of cilia before release into extracellular vesicles named ectosomes. Unexpectedly, actin and the actin regulators drebrin and myosin 6 mediate ectosome release from the tip of cilia. Mirroring signal-dependent retrieval, signal-dependent ectocytosis is a selective and effective process that removes activated signaling molecules from cilia. Congruently, ectocytosis compensates for BBSome defects as ectocytic removal of GPR161, a negative regulator of Hedgehog signaling, permits the appropriate transduction of Hedgehog signals in Bbs mutants. Finally, ciliary receptors that lack retrieval determinants such as the anorexigenic GPCR NPY2R undergo signal dependent ectocytosis in wild-type cells. Our data show that signal-dependent ectocytosis regulates ciliary signaling in physiological and pathological contexts. PMID- 28017329 TI - Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor. AB - The removal of unwanted or damaged mitochondria by autophagy, a process called mitophagy, is essential for key events in development, cellular homeostasis, tumor suppression, and prevention of neurodegeneration and aging. However, the precise mechanisms of mitophagy remain uncertain. Here, we identify the inner mitochondrial membrane protein, prohibitin 2 (PHB2), as a crucial mitophagy receptor involved in targeting mitochondria for autophagic degradation. PHB2 binds the autophagosomal membrane-associated protein LC3 through an LC3 interaction region (LIR) domain upon mitochondrial depolarization and proteasome dependent outer membrane rupture. PHB2 is required for Parkin-induced mitophagy in mammalian cells and for the clearance of paternal mitochondria after embryonic fertilization in C. elegans. Our findings pinpoint a conserved mechanism of eukaryotic mitophagy and demonstrate a function of prohibitin 2 that may underlie its roles in physiology, aging, and disease. PMID- 28017330 TI - Mortality following helicopter versus ground transport of injured children. AB - INTRODUCTION: Injured children may be transported to trauma centers by helicopter air ambulance (HAA); however, a benefit in outcomes to this expensive resource has not been consistently shown in the literature and there is concern that HAA is over-utilized. A study that adequately controls for selection biases in transport mode is needed to determine which injured children benefit from HAA. The purpose of this study was to determine if HAA impacts mortality differently in minimally and severely injured children and if there are predictors of over triage of HAA in children that can be identified. METHODS: Children <=18 years of age transported by HAA or ground ambulance (GA) from scene to a trauma center were identified from the 2010-2011 National Trauma Data Bank. Analysis was stratified by Injury Severity Score (ISS) into low ISS (<=15) and high ISS (>15) groups. Following propensity score matching of HAA to GA patients, conditional multivariable logistic regression was performed to determine if transport mode independently impacted mortality in each stratum. Rates and predictors of over triage of HAA were also determined. RESULTS: Transport by HAA occurred in 8218 children (5574 low ISS, 2644 high ISS) and by GA in 35305 (30506 low ISS, 4799 high ISS). Overall mortality was greater in HAA patients (4.0 vs 1.4%, p<0.001). After propensity score matching, mortality was equivalent between HAA and GA for low ISS patients (0.2 vs 0.2%, p=0.82) but, for high ISS patients, mortality was lower in HAA (9.0 vs 11.1% p=0.014). On multivariable analysis, HAA was associated with decreased mortality in high ISS patients (OR=0.66, p=0.017) but not in low ISS patients (OR=1.13, p=0.73). Discharge within 24h of HAA transport occurred in 36.5% of low ISS patients versus 7.4% high ISS patients (p<0.001). CONCLUSIONS: Based on a national cohort adjusted for nonrandom assignment of transport mode, a survival benefit to HAA transport exists only for severely injured children with ISS >15. Many children with minor injuries are transported by helicopter despite frequent dismissal within 24h and no mortality benefit. PMID- 28017331 TI - Editorial Comment. PMID- 28017332 TI - Author Reply. PMID- 28017333 TI - Editorial Comment. PMID- 28017334 TI - Editorial Comment. PMID- 28017335 TI - Two Decades of Lung Retransplantation: A Single-Center Experience. AB - BACKGROUND: Lung retransplantation (ReTx) comprises an increasing share of lung transplants and recently has shown improved outcomes. The aim of this study was to identify risk factors affecting overall survival after pulmonary ReTx. METHODS: The United Network for Organ Sharing database was used to identify patients undergoing lung transplantation at our institution from 1995 to 2014. Of the total 542 lung transplants performed, 87 (16.1%) were ReTxs. The primary outcome was overall survival. Multivariate Cox regression models were used to assess the effect of recipient and donor characteristics on survival. RESULTS: Of the patients who underwent ReTx, median survival was 2 years. Predictors of worse survival include recipient age between 50 and 60 years (relative risk, 4.3; p = 0.02) or older than 60 years (relative risk, 10.2; p < 0.001), and time to ReTx of less than 2 years (relative risk, 3.8; p = 0.01). ReTx for bronchiolitis obliterans syndrome had longer median survival than for restrictive chronic lung allograft dysfunction (2.7 years vs 0.9 years; p = 0.055). Overall survival of ReTx patients after initiation of the lung allocation score was not significantly different (p = 0.21). CONCLUSIONS: Lung ReTx outcomes are significantly worse than for primary transplantation but may be appropriate in well-selected patients with certain diagnoses. Lung ReTx in patients older than 50 years or within 2 years of primary lung transplantation was associated with decreased survival. Further work is warranted to identify patients who benefit most from ReTx. PMID- 28017336 TI - Spasm and Reopening of the Right Gastroepiploic Artery Conduit After Coronary Artery Bypass Grafting. AB - BACKGROUND: The right gastroepiploic artery (RGEA) has advantages for use as an arterial conduit in coronary artery bypass graft surgery but perioperative spasm often develops. This study assessed the spasm and occlusion rates of RGEA conduits and elucidated the mechanism of reopening of occluded RGEA conduits. METHODS: Patients who received an RGEA conduit in coronary artery bypass graft surgery were studied (n = 976; 700 composite, 276 in situ, 16 free grafts; 16 received both in situ and composite grafts). Early, 1-year, and 5-year angiographies were performed in 961 patients (98.5%), 815 patients (83.5%), and 618 patients (63.3%), respectively. RESULTS: Graft spasm was demonstrated in early angiograms in 72 proximal graft trunks of 1,608 distal anastomoses (4.5%) constructed using an RGEA conduit. Early occlusion rates of composite, in situ, and free RGEA conduits were 1.1%, 2.5%, and 0%, respectively; 8.5%, 7.5%, and 21.4%, respectively, at 1 year; and 10.5%, 14.1%, and 37.5%, respectively, at 5 years. Nineteen of 23 patients who had RGEA conduit occlusions at early angiography (1 occluded anastomosis per patient) were reevaluated at 1 year, and 9 of them (47.4%) had become patent. Of 83 patients with occluded RGEA composite grafts (90 occluded RGEA conduit anastomoses) at 1-year angiography, 8 were reopened at 5 years (8.9%). Progression of native target coronary artery disease was observed in all 8 patients with reopened occluded RGEA conduits at 5 years but not in 9 patients with reopened RGEA conduits at 1 year. CONCLUSIONS: Reopening of occluded RGEA conduits occurred early and midterm postoperatively. Reopening appeared related to recovery from graft spasm, and could occur as late as midterm if associated with progression of native coronary artery disease. PMID- 28017337 TI - Biatrial or Left Atrial Lesion Set for Ablation During Mitral Surgery: Risks and Benefits. AB - BACKGROUND: Controversy exists when performing surgical atrial fibrillation ablation whether there is an increase in postoperative complications using biatrial (BA) lesions compared with only left atrial (LA) lesions, and some studies indicate similar efficacy. This study compares the clinical outcomes of BA and LA ablation lesions in mitral valve surgery patients. METHODS: From 2004 through 2014, 2,137 patients had mitral valve surgery with or without other surgeries in a single center. Of those, 836 (39%) had preoperative atrial fibrillation, and of those, 724 (86%) underwent atrial fibrillation ablation surgery; 257 patients had BA lesion sets and 359 had LA lesion sets. Propensity score matching of BA and LA patients was performed. RESULTS: Baseline differences included more postoperative complications in the BA group, specifically, permanent pacemaker placement (13% versus 7%; p = 0.006). Freedom from atrial fibrillation off antiarrhythmic drugs (72% BA versus 75% LA; p = 0.50), postoperative ablation (7% BA versus 5% LA; p = 0.20), stroke (0.11 versus 0.11 per 10 person-years; p = 0.91), and survival were similar between the groups. After matching, patients in the LA group had a higher freedom from postoperative ablation (p = 0.015), but no difference in freedom from atrial fibrillation off antiarrhythmic drugs (79% BA versus 69% LA; p = 0.09), and no difference in permanent pacemaker placement (10% versus 12%; p = 0.57). CONCLUSIONS: Patients undergoing mitral surgery with LA or BA ablation had similar outcomes, survival, and complications. Limiting lesions to the LA is an effective alternative to BA ablation for patients undergoing ablation with concomitant mitral valve surgery. PMID- 28017338 TI - Complications Associated With Femoral Cannulation During Minimally Invasive Cardiac Surgery. AB - BACKGROUND: Different types of cannulation techniques are available for minimally invasive cardiac surgery. At our institution, we favor a femoral platform for most minimally invasive cardiac procedures. Here, we review our results utilizing this cannulation approach. METHODS: We retrospectively reviewed all minimally invasive valve surgeries that were performed at our institution between January 2009 and January 2015. Operative times, lengths of stay, postoperative complications, and mortality were analyzed. RESULTS: We identified 2,645 consecutive patients. The mean age was 69.7 +/- 12.77 years, and 1,412 patients (53.4%) were male. Three hundred fifty-eight patients (13.5%) had a history of cerebrovascular accident, 422 (16%) had previous heart surgery, and 276 (10.4%) had a history of peripheral vascular disease. The procedures performed were isolated aortic valve replacements (42.1%), isolated mitral valve operations (40.6%), tricuspid valve repairs (0.57%), double valve surgery (15%), triple valve surgery (0.3%), and ascending aortic aneurysm resection with and without circulatory arrest (5%). Femoral cannulation and central cannulation were utilized in 2,400 patients (90.7%) and 244 patients (9.3%), respectively. The median aortic cross-clamp time and cardiopulmonary bypass time were 81 minutes (interquartile range, 65 to 105) and 113 minutes (interquartile range, 92 to 142), respectively. The median postoperative hospital length of stay was 6 days (interquartile range, 5 to 9). There were 31 cerebrovascular accidents (1.17%), no aortic dissections, two compartment syndromes, two femoral arterial pseudoaneurysms, and 174 (6.65%) groin wound seromas. The overall 30-day mortality was 57 patients (2.15%). CONCLUSIONS: Minimally invasive cardiac surgical procedures utilizing femoral cannulation techniques have a low risk of complications. PMID- 28017339 TI - Malignant Oestrogen-producing Teratoma in a Cat. AB - A 5-year-old female domestic shorthair cat was presented with abdominal distension and serum biochemical evaluation indicated a high concentration of oestradiol (32.81 pg/ml). Exploratory laparotomy revealed a large cystic mass in the right ovary with cystic fluid containing a high level of oestradiol (18.80 pg/ml). The tumour was composed of immature neuroectodermal tissue, mature cartilage, smooth muscle, adipose tissue and aggregated, poorly differentiated mesenchymal cells. It contained cysts of various sizes that were lined by epithelium of different types. The basal layer of the lining epithelium was shown to express aromatase by immunohistochemistry. The findings suggest that this was a novel, malignant, oestrogen-secreting teratoma and that the aromatase-positive, neoplastic cells may have been the source of elevated levels of serum oestrogen. PMID- 28017340 TI - Feline Respiratory Extramedullary Plasmacytoma with Lymph Node Metastasis and Intrahistiocytic Amyloid. AB - A 14-year-old domestic longhaired cat presented with a 2-year history of nasal discharge and a recent onset of inappetence and submandibular lymphadenopathy. The cat was humanely destroyed after developing severe respiratory distress. Necropsy examination revealed thickened nasal turbinates and soft palate, and friable red-tan material within the frontal sinus, nasal cavity and nasopharynx. The lungs contained multifocal irregular friable tan nodules. Multiple lymph nodes were enlarged, friable and red-tan in colour. Histopathology revealed a mature type extramedullary plasmacytoma (EMP) within the frontal sinus, nasal cavity, soft palate, larynx, trachea, lungs and multiple lymph nodes. The lymph nodes and larynx also contained marked granulomatous inflammation with extensive intrahistiocytic (and lesser amounts of extracellular) lambda light chain amyloid, confirmed by electron microscopy and immunohistochemistry. Neoplastic cells expressed CD79a and MUM1. This is the first report of an infiltrative EMP of the feline respiratory tract with lymph node metastasis and predominantly intrahistiocytic amyloid. PMID- 28017341 TI - From latent to patent: rethinking prediction of tuberculosis. PMID- 28017342 TI - Will ex-vivo lung perfusion allow a move towards daytime lung transplantation surgery? PMID- 28017343 TI - Knowledge of cancer symptoms and anxiety affect patient delay in seeking diagnosis in patients with heterogeneous cancer locations. AB - PURPOSE: This research was aimed at identifying factors that predict patient delay in treatment initiation in patients with suspected cancer disease. We sought to determine the differences between delaying and nondelaying patients with reference to their knowledge of cancer symptoms, sociodemographic variables, and the levels of state anxiety and trait anxiety. METHODS: The study involved 301 randomly selected patients with suspected cancer disease before their first oncology appointment at a regional oncology center in Poland. Data were collected by means of a semistructured interview conducted by a trained psychologist. To evaluate the knowledge of cancer symptoms, the symptoms mentioned by subjects were compared to the list of symptoms from cancer awareness measure. Anxiety levels were assessed using the State-Trait Anxiety Inventory. RESULTS: In the course of logistic regression analysis a model was developed, in which knowledge of cancer symptoms and state anxiety allowed to predict patient delay. Knowledge of every additional cancer symptom decreased the chance of patient delay by 16.4% point [95% CI: 1.4-29.2]. An increase in state anxiety for every point of the scale decreased the chance of delay by 2.5% points [95% CI: 0.2-4.6]. Trait anxiety and the studied sociodemographic variables proved to be nonsignificant predictors of patient delay. CONCLUSIONS: Knowledge of cancer symptoms and the level of state anxiety allowed to predict patient delay in the initiation of treatment. Owing to the heterogeneity of the tumor locations within the sample, the obtained model can be used in large scale prevention programs designed for the whole population. PMID- 28017344 TI - Extended non-vitamin K antagonist oral anticoagulation therapy for prevention of recurrent venous thromboembolism. AB - Evidence from the use of traditional therapy (low-molecular-weight heparin/vitamin K antagonists) for venous thromboembolism (VTE) treatment and prevention suggests that extending treatment beyond the acute phase reduces recurrence. More recently, several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved in the acute setting; accumulating evidence suggests continuing treatment with these agents beyond 12months offers additional benefits to patients with VTE. This review examines the evidence for NOAC use in longer duration anticoagulation treatment, and discusses guidelines from major societies. Clinical data from the phase III extension studies for apixaban, dabigatran and rivaroxaban are presented, and the clinical and economic costs and benefits are examined. Evidence from other therapy areas utilising extended treatment regimens highlights the possible impact of factors relevant to extended anticoagulation therapy. Phase IV studies of NOACs are presented. US and European guidelines advise long-term therapy in certain instances, taking into account evidence on NOAC use in VTE accumulated recently. They support NOAC use where they have been selected as the initial therapy choice and therapy needs to be extended beyond 3months. The phase III extension studies demonstrate the benefits of extended NOAC use versus treatment cessation, with reduced recurrence rates versus placebo, although associated with a potential moderate increase in bleeding risk. Phase IV data are also emerging, with the recent XALIA study showing that a broad range of patients with VTE can benefit from continued rivaroxaban treatment; ongoing research will yield data on long-term use of the other NOACs in routine clinical practice. PMID- 28017345 TI - Axillary brachial plexus block duration with mepivacaine in patients with chronic renal failure. Case-control study. AB - INTRODUCTION: Regional anaesthesia is commonly preferred for arteriovenous fistula (AVF) creation. Previous studies suggest a shorter block duration in patients with chronic renal failure, maybe because of the changes in regional blood flow. The aim of our study was to evaluate the duration of the axillary block with 1.5% mepivacaine in patients with chronic renal failure scheduled for AVF compared with healthy controls. METHODS: Patients scheduled for AVF creation for the first time (GIRC) were included. They were compared with patients without renal failure (GC), with similar anthropometric characteristics. Ultrasound guided axillary blocks with 20mL of 1.5% mepivacaine were performed on all patients. We evaluated onset time, humeral artery diameter and blood flow before and after the block, as well as the block duration. RESULTS: Twenty-three patients (GIRC: 12 and GC: 11) were included. No differences between groups were observed in block duration (GIRC: 227+/-43min vs GC: 229+/-27min; P=.781), or in onset time (GIRC: 13+/-5min vs GC: 12.2+/-3min; P=.477). The humeral blood flow before and after block was significantly lower in the GIRC (pre-block: GIRC: 52+/ 21ml/min GC: 100+/-62ml/min; P=.034 and p ost block: GIRC: 130+/-57ml/min and GC: 274+/-182ml/min; P=.010). There was no significant correlation between the duration of the block and the preblock humeral blood flow (Spearman Rho: 0.106; P=.657) or the postblock humeral blood flow (Spearman Rho: 0.267; P=.254). CONCLUSION: The duration of the axillary block with 1.5% mepivacaine in patients with chronic renal failure was similar to that of the control patients. The duration of axillary brachial plexus block seems not to be related to changes in regional blood flow. PMID- 28017348 TI - Late Gadolinium Enhancement and the Risk for Ventricular Arrhythmias or Sudden Death in Dilated Cardiomyopathy: Systematic Review and Meta-Analysis. AB - OBJECTIVES: The aim of this study was to evaluate the association between late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging and ventricular arrhythmias or sudden cardiac death (SCD) in patients with dilated cardiomyopathy (DCM). BACKGROUND: Risk stratification for SCD in DCM needs to be improved. METHODS: A systematic review and meta-analysis were conducted. A systematic search of PubMed and Ovid was performed, and observational studies that analyzed the arrhythmic endpoint (sustained ventricular arrhythmia, appropriate implantable cardioverter-defibrillator [ICD] therapy, or SCD) in patients with DCM, stratified by the presence or absence of LGE, were included. RESULTS: Twenty-nine studies were included, accounting for 2,948 patients. The studies covered a wide spectrum of DCM, with a mean left ventricular ejection fraction between 20% and 43%. LGE was significantly associated with the arrhythmic endpoint both in the overall population (odds ratio: 4.3; p < 0.001) and when including only those studies that performed multivariate analysis (hazard ratio: 6.7; p < 0.001). The association between LGE and the arrhythmic endpoint remained significant among studies with mean left ventricular ejection fractions >35% (odds ratio: 5.2; p < 0.001) and was maximal in studies that included only patients with primary prevention ICDs (odds ratio: 7.8; p = 0.008). CONCLUSIONS: Across a wide spectrum of patients with DCM, LGE is strongly and independently associated with ventricular arrhythmia or SCD. LGE could be a powerful tool to improve risk stratification for SCD in patients with DCM. These results raise 2 major questions to be addressed in future studies: whether patients with LGE could benefit from primary prevention ICDs irrespective of their left ventricular ejection fractions, while patients without LGE might not need preventive ICDs despite having severe left ventricular dysfunction. PMID- 28017350 TI - Myocardial Injury, Obesity, and the Obesity Paradox: The ARIC Study. AB - OBJECTIVES: This study sought to determine whether pre-heart failure (HF) myocardial injury explains the differential mortality after HF across weight categories. BACKGROUND: Obesity is a risk factor for HF, but pre-HF obesity is associated with lower mortality after incident HF. High-sensitivity cardiac troponin T (hs-cTnT) is a sensitive marker of myocardial injury, and predicts incident HF and mortality. METHODS: Stratifying 1,279 individuals with incident HF hospitalizations by their pre-HF hs-cTnT levels (< and >= 14 ng/l), we examined the association of pre-HF body mass index (BMI) with mortality after incident HF hospitalization in the ARIC (Atherosclerosis Risk In Communities) study. RESULTS: Mean age at HF was 74 years (53% women, 27% black). Individuals with pre-HF hs-cTnT >=14 ng/l had higher mortality after incident HF (hazard ratio [HR]: 1.46; 95% confidence interval [CI]: 1.18 to 1.80) compared to individuals with hs-cTnT <14 ng/l in an adjusted model including BMI. Compared with normal weight subjects, the mortality was lower in overweight (HR: 0.69, 95% CI 0.48-0.98) and obese individuals (HR: 0.50; 95% CI: 0.35 to 0.72) with hs-cTnT <14 ng/l; and in those with hs-cTnT >=14 ng/l (overweight HR: 0.50; 95% CI: 0.30 to 0.83; obese HR: 0.56; 95% CI: 0.34 to 0.91; interaction: p = 0.154 between BMI and hs-cTnT). The lower mortality risk in obese and overweight subjects remained similar when log hs-cTnT was added as a continuous variable to a multivariable model, and in sensitivity analyses after further adjusting for left ventricular hypertrophy or high-sensitivity C-reactive protein. CONCLUSION: Although greater pre-existing subclinical myocardial injury was associated with higher mortality after incident HF hospitalization, it did not explain the obesity paradox in HF, which was observed irrespective of subclinical myocardial injury. (Atherosclerosis Risk In Communities [ARIC]; NCT00005131). PMID- 28017351 TI - Cost-Effectiveness of Left Ventricular Assist Devices in Ambulatory Patients With Advanced Heart Failure. AB - OBJECTIVES: This study assessed the cost-effectiveness of left ventricular assist devices (LVADs) as destination therapy in ambulatory patients with advanced heart failure. BACKGROUND: LVADs improve survival and quality of life in inotrope dependent heart failure, but data are limited as to their value in less severely ill patients. METHODS: We determined costs of care among Medicare beneficiaries before and after LVAD implantation from 2009 to 2010. We used these costs and efficacy data from published studies in a Markov model to project the incremental cost-effectiveness ratio (ICER) of destination LVAD therapy compared with that of medical management. We discounted costs and benefits at 3% annually and report costs as 2016 U.S. dollars. RESULTS: The mean cost of LVAD implantation was $175,420. The mean cost of readmission was lower before LVAD than after ($12,377 vs. $19,465, respectively; p < 0.001), while monthly outpatient costs were similar ($3,364 vs. $2,974, respectively; p = 0.54). In the lifetime simulation model, LVAD increased quality-adjusted life-years (QALYs) (4.41 vs. 2.67, respectively), readmissions (13.03 vs. 6.35, respectively), and costs ($726,200 vs. $361,800, respectively) compared with medical management, yielding an ICER of $209,400 per QALY gained and $597,400 per life-year gained. These results were sensitive to LVAD readmission rates and outpatient care costs; the ICER would be $86,900 if these parameters were 50% lower. CONCLUSIONS: LVADs in non-inotrope dependent heart failure patients improved quality of life but substantially increased lifetime costs because of frequent readmissions and costly follow-up care. LVADs may provide good value if outpatient costs and adverse events can be reduced. PMID- 28017352 TI - The Influence of Age on Hemodynamic Parameters During Rest and Exercise in Healthy Individuals. AB - OBJECTIVES: In this study, the authors sought to obtain hemodynamic estimates across a wide age span and in both sexes for future reference and compare these estimates with current guideline diagnostic hemodynamic thresholds for abnormal filling pressure and pulmonary hypertension. BACKGROUND: At present, the influence of age on hemodynamic function is largely unknown. Because many diseases with proposed cardiac impact are more prevalent in the older population, it is pivotal to know how hemodynamic parameters are affected by age itself to discern the influence of disease from that of physiological aging. METHODS: Sixty two healthy participants, evenly distributed with respect to age (20 to 80 years) and sex (32 women/30 men), were prospectively enrolled in the study. Participants were all deemed healthy by medical history, echocardiography, exercise test, spirometry, blood tests, and electrocardiogram. Participants had hemodynamic parameters measured using right heart catheterization during rest, passive leg raise, and incremental exercise. RESULTS: During rest, all hemodynamic parameters were similar between age groups, apart from blood pressure. During leg raise and incremental exercise, there was augmented filling pressure (p < 0.0001) and diminished cardiac output (p = 0.001) and hence a higher pressure:flow ratio (pulmonary artery pressure/capillary wedge pressure to cardiac output) with progressive age, evident from the earliest ages. All indexed hemodynamic measures were similar between sexes. The diagnostic threshold (pulmonary capillary wedge pressure >=25 mm Hg) currently used during exercise testing to diagnose abnormal left ventricular filling pressure was measured in 30% of our healthy elderly participants. CONCLUSIONS: Cardiac aging was progressive without sex differences in healthy participants. The hemodynamic reference values obtained suggest that the diagnostic threshold for abnormal filling pressure should be individually determined according to age of the patient. PMID- 28017353 TI - Significance of Residual Mitral Regurgitation After Continuous Flow Left Ventricular Assist Device Implantation. AB - OBJECTIVES: This study hypothesized that the presence of residual mitral regurgitation (MR) post-continuous flow (CF) left ventricular assist device (LVAD) implantation based on quantitative assessment would be negatively associated with right ventricular (RV) size and function and clinical outcomes. BACKGROUND: MR is associated with elevated left atrial pressure, secondary pulmonary hypertension and RV dysfunction. Implantation of a LVAD leads to mechanical unloading of the left ventricle and generally improves MR. The clinical significance of residual MR in patients supported with CF LVADs is uncertain. Most studies evaluating the presence of MR in LVAD patients have utilized predominantly qualitative assessments of MR. METHODS: We retrospectively identified patients implanted with CF LVADs at our institution from 2007 to 2013 who had a pre-operative transthoracic echocardiogram (TTE) within 3 months of LVAD implant and who had a post-operative TTE at least 1 month post-LVAD. MR was assessed quantitatively using the ratio of MR color jet area (CJA)/left atrial area (LAA) in apical views. We also compared quantitative RV metrics, hospitalizations, and mortality in patients with and without significant residual MR (defined as MR CJA/LAA >0.2) on post-implantation TTE. RESULTS: Sixty-nine patients were included in this study. Post-LVAD implantation, 55 patients (80%) had mild or less MR (mean MR CJA/LAA 0.08) but 14 (20%) had significant residual MR (mean MR CJA/LAA 0.34). Patients with residual MR had significantly larger RV size (right ventricular end diastolic dimension 49 mm vs. 45 mm; p = 0.04) and worse RV function (tricuspid annular plane systolic excursion 10 mm vs. 12 mm; p = 0.02; and right ventricular fractional area change 29% vs. 34%; p = 0.02). Post implantation pulmonary artery pressures were higher in patients with residual MR (pulmonary artery systolic 43 mm Hg vs. 35 mm Hg; p = 0.05). In patients with residual MR there was slightly greater posterior displacement of the mitral coaptation point on pre-operative TTE (28 mm vs. 26 mm; p = 0.16) but this difference was not significant. Time from LVAD implantation to first hospitalization was shorter in patients with residual MR (62 days vs. 103 days; p = 0.05) as was time from LVAD implantation to death (80 days vs. 421 days; p = 0.03). CONCLUSIONS: Significant residual MR post-LVAD implantation assessed by a quantitative measure is associated with persistent pulmonary hypertension, worse RV function, and significantly shorter time to hospitalization and death. MR post LVAD implantation may serve as a surrogate for adverse outcomes post-LVAD implantation. PMID- 28017354 TI - Does Size Matter With Continuous Left Ventricular Assist Devices? PMID- 28017355 TI - Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: Association With Exercise Capacity, Left Ventricular Filling Pressures, Natriuretic Peptides, and Left Atrial Volume. AB - OBJECTIVES: This study sought to study the association of atrial fibrillation (AF) with exercise capacity, left ventricular filling pressure, natriuretic peptides, and left atrial size in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: The diagnosis of HFpEF in patients with AF remains a challenge because both contribute to impaired exercise capacity, and increased natriuretic peptides and left atrial volume. METHODS: We studied 94 patients with symptomatic heart failure and left ventricular ejection fractions >=45% using treadmill cardiopulmonary exercise testing and right- and/or left-sided cardiac catheterization with simultaneous echocardiography. RESULTS: During catheterization, 62 patients were in sinus rhythm, and 32 patients had AF. There were no significant differences in age, sex, body size, comorbidities, or medications between groups; however, patients with AF had lower peak oxygen consumption (VO2) compared with those with sinus rhythm (10.8 +/- 3.1 ml/min/kg vs. 13.5 +/- 3.8 ml/min/kg; p = 0.002). Median (25th to 75th percentile) N terminal pro-B-type natriuretic peptide (NT-proBNP) was higher in AF versus sinus rhythm (1,689; 851 to 2,637 pg/ml vs. 490; 272 to 1,019 pg/ml; p < 0.0001). Left atrial volume index (LAVI) was higher in AF than sinus rhythm (57.8 +/- 17.0 ml/m2 vs. 42.5 +/- 15.1 ml/m2; p = 0.001). Invasive hemodynamics showed higher mean pulmonary capillary wedge pressure (PCWP) (19.9 +/- 3.7 vs. 15.2 +/- 6.8) in AF versus sinus rhythm (all p < 0.001), with a trend toward higher left ventricular end-diastolic pressure (17.7 +/- 3.0 mm Hg vs. 15.7 +/- 6.9 mm Hg; p = 0.06). After adjusting for clinical covariates and mean PCWP, AF remained associated with reduced peak VO2 increased log NT-proBNP, and enlarged LAVI (all p <=0.005). CONCLUSIONS: AF is independently associated with greater exertional intolerance, natriuretic peptide elevation, and left atrial remodeling in HFpEF. These data support the application of different thresholds of NT-proBNP and LAVI for the diagnosis of HFpEF in the presence of AF versus the absence of AF. PMID- 28017356 TI - Race-Related Differences in Left Ventricular Structural and Functional Remodeling in Response to Increased Afterload: The ARIC Study. AB - OBJECTIVES: The aim of this study was to evaluate racial differences in arterial elastance (Ea), which reflects the arterial afterload faced by the left ventricle, and its associations with cardiac structure and function. The hypothesis under study was that the left ventricle in blacks displays heightened afterload sensitivity compared with whites. BACKGROUND: Chronic increasing in arterial afterload may be an important trigger for left ventricular (LV) remodeling and dysfunction that lead to heart failure. Racial differences in the predisposition to heart failure are well described, but the underlying mechanisms remain unclear. METHODS: In total, 5,727 community-based, older ARIC (Atherosclerosis Risk In Community) study participants (22% black) who underwent echocardiography between 2011 and 2013 were studied. RESULTS: Blacks were younger (mean age 75 +/- 5 years vs. 76 +/- 5 years), were more frequently female (66% vs. 57%), and had higher prevalence rates of obesity (46% vs. 31%), hypertension (94% vs. 80%), and diabetes mellitus (47% vs. 34%) than whites. Adjusting for these baseline differences, Ea was higher among blacks (1.96 +/- 0.01 mm Hg/ml vs. 1.80 +/- 0.01 mm Hg/ml). In blacks, Ea was associated with greater LV remodeling (LV mass index, beta = 3.21 +/- 0.55 g/m2, p < 0.001) and higher LV filling pressures (E/e' ratio, beta = 0.42 +/- 0.11, p < 0.001). These relationships were not observed in whites (LV mass, beta = 0.16 +/- 0.32 g/m2, p = 0.61, p for interaction <0.001; E/e' ratio, beta = -0.32 +/- 0.06, p < 0.001, p for interaction <0.001). CONCLUSIONS: These community-based data suggest that black Americans display heightened afterload sensitivity as a stimulus for LV structural and functional remodeling, which may contribute to their greater risk for heart failure compared with white Americans. PMID- 28017357 TI - Review: The role of multiple placental glucocorticoid receptor isoforms in adapting to the maternal environment and regulating fetal growth. AB - The physiological mechanisms that confer different outcomes in morbidity and mortality of the fetus exposed to stressful environments may be driven by significant differences in the expression and function of the placental glucocorticoid receptor (GR). The recent discovery that the placenta contains at least 8 different isoforms of the GR raises questions about the regulation and physiological relevance of the many GR variants expressed in the placenta. The current data also highlights that individual differences in glucocorticoid sensitivity, variations in the effect of different complications of pregnancy on birth outcomes and sex differences in the response to stress, may all be dependent on a specific GR isoform expression profile. This review will investigate the current state of knowledge of GR isoforms in the placenta and discuss the potential role of these multiple isoforms in regulating glucocorticoid sensitivity. PMID- 28017358 TI - Differentiation of mesenchymal stem cells from human amniotic fluid to vascular endothelial cells. AB - Endothelial dysfunction is a principle feature of vascular-related disease. Endothelial cells have been acquired for the purposes of the restoration of damaged tissue in therapeutic angiogenesis. However, their use is limited by expansion capacity and the small amount of cells that are obtained. Human amniotic fluid mesenchymal stem cells (hAF-MSCs) are considered an important source for vascular tissue engineering. In this study, hAF-MSCs were characterized and then induced in order to differentiate into the endothelial like cells. Human amniotic fluid cells (hAFCs) were obtained from amniocentesis at the second trimester of gestation. The cells were characterized as mesenchymal stem cells by flow cytometry. The results showed that the cells were positive for mesenchymal stem cell markers CD44, CD73, CD90 and HLA-ABC, and negative for CD31, Amniotic fluid stem cells marker: CD117, anti-human fibroblasts, HLA-DR and hematopoietic differentiation markers CD34 and CD45. The hAF-MSCs were differentiated into endothelial cells under the induction of vascular endothelial growth factor (VEGF) and analyzed for the expression of the endothelial-specific markers and function. The expression of the endothelial-specific markers was determined by reverse transcriptase-quantitative PCR (RT-qPCR), while immunofluorescent analysis demonstrated that the induced hAF-MSCs expressed von Willebrand factor (vWF), vascular endothelial growth factor receptor 2 (VEGFR2), CD31 and endothelial nitric oxide synthase (eNOS). The network formation assay showed that the induced hAF-MSCs formed partial networks. All results indicated that hAF-MSCs have the potential to be differentiated into endothelial-like cells, while human amniotic fluid might be a suitable source of MSCs for vascularized tissue engineering. PMID- 28017359 TI - Mucin secreting cells in the stomach and colon are altered by combination antiretroviral treatment in an obese rat model. AB - Mucins, secreted by intestinal goblet cells, form an integral part of the intestinal biofilm, which is important for the functioning of a healthy gastrointestinal tract (GIT). This mucous layer is sensitive to factors such as diet, drugs and inflammation. Histochemically, mucins can be classified as neutral or acidic, where acidic mucins can contain sulphate groups (sulphomucins) or sialic acid (sialomucins). The aim of the present study was to determine the composition of various mucin secreting cells using histochemical stains in rats fed on a high calorie diet (HCD) treated with antiretroviral therapy (ART). Wistar rats (N=24) were divided into a lean control group (C/ART-), high calorie diet group (C/HCD+), ART group (C/ART+) and HCD and ART group (HCD+/ART+). The body of the stomach as well as the colon were stained with Alcian Blue Periodic Schiff (ABPAS) to distinguish between neutral and acidic mucins and Alcian Blue Aldehyde Fuschin (ABAF) to distinguish between sialo-and sulphomucins. An increase of the total gastric mucous cells was observed in the HCD+/ART+ group compared to the C/ART- group using both ABPAS and ABAF. A decrease of neutral cells in the distal part of the colonic crypts in the C/HCD+ and C/ART+ groups compared to the C/ART- group were observed. Mixed goblet cells in the colonic crypts of the C/ART- and HCD+/ART+ groups were decreased in comparison to the C/ART+ group. The study showed that the total mean percentage of mucous cells in the stomach as well as the total amount of neutral goblet cells in the colon were most affected by ART and a HCD. These changes in a rat model suggest that the quality of the biofilm may be altered and should be considered when ART is prescribed to obese patients. PMID- 28017360 TI - Estimation of daily PM10 concentrations in Italy (2006-2012) using finely resolved satellite data, land use variables and meteorology. AB - Health effects of air pollution, especially particulate matter (PM), have been widely investigated. However, most of the studies rely on few monitors located in urban areas for short-term assessments, or land use/dispersion modelling for long term evaluations, again mostly in cities. Recently, the availability of finely resolved satellite data provides an opportunity to estimate daily concentrations of air pollutants over wide spatio-temporal domains. Italy lacks a robust and validated high resolution spatio-temporally resolved model of particulate matter. The complex topography and the air mixture from both natural and anthropogenic sources are great challenges difficult to be addressed. We combined finely resolved data on Aerosol Optical Depth (AOD) from the Multi-Angle Implementation of Atmospheric Correction (MAIAC) algorithm, ground-level PM10 measurements, land use variables and meteorological parameters into a four-stage mixed model framework to derive estimates of daily PM10 concentrations at 1-km2 grid over Italy, for the years 2006-2012. We checked performance of our models by applying 10-fold cross-validation (CV) for each year. Our models displayed good fitting, with mean CV-R2=0.65 and little bias (average slope of predicted VS observed PM10=0.99). Out-of-sample predictions were more accurate in Northern Italy (Po valley) and large conurbations (e.g. Rome), for background monitoring stations, and in the winter season. Resulting concentration maps showed highest average PM10 levels in specific areas (Po river valley, main industrial and metropolitan areas) with decreasing trends over time. Our daily predictions of PM10 concentrations across the whole Italy will allow, for the first time, estimation of long-term and short-term effects of air pollution nationwide, even in areas lacking monitoring data. PMID- 28017361 TI - Analysis of the sensitivity of in vitro bioassays for androgenic, progestagenic, glucocorticoid, thyroid and estrogenic activity: Suitability for drinking and environmental waters. AB - The presence of endocrine disrupting chemicals in the aquatic environment poses a risk for ecosystem health. Consequently there is a need for sensitive tools, such as in vitro bioassays, to monitor endocrine activity in environmental waters. The aim of the current study was to assess whether current in vitro bioassays are suitable to detect endocrine activity in a range of water types. The reviewed assays included androgenic (n=11), progestagenic (n=6), glucocorticoid (n=5), thyroid (n=5) and estrogenic (n=8) activity in both agonist and antagonist mode. Existing in vitro bioassay data were re-evaluated to determine assay sensitivity, with the calculated method detection limit compared with measured hormonal activity in treated wastewater, surface water and drinking water to quantify whether the studied assays were sufficiently sensitive for environmental samples. With typical sample enrichment, current in vitro bioassays are sufficiently sensitive to detect androgenic activity in treated wastewater and surface water, with anti-androgenic activity able to be detected in most environmental waters. Similarly, with sufficient enrichment, the studied mammalian assays are able to detect estrogenic activity even in drinking water samples. Fewer studies have focused on progestagenic and glucocorticoid activity, but some of the reviewed bioassays are suitable for detecting activity in treated wastewater and surface water. Even less is known about (anti)thyroid activity, but the available data suggests that the more sensitive reviewed bioassays are still unlikely to detect this type of activity in environmental waters. The findings of this review can help provide guidance on in vitro bioassay selection and required sample enrichment for optimised detection of endocrine activity in environmental waters. PMID- 28017362 TI - Brain Pericytes As Mediators of Neuroinflammation. AB - Brain pericytes are perivascular cells that regulate capillary function, and this localization puts them in a pivotal position for the regulation of central nervous system (CNS) inflammatory responses at the neurovascular unit. Neuroinflammation, driven by microglia and astrocytes or resulting from peripheral leukocyte infiltration, has both homeostatic and detrimental consequences for brain function and is present in nearly every neurological disorder. More recently, brain pericytes have been shown to have many properties of immune regulating cells, including responding to and expressing a plethora of inflammatory molecules, presenting antigen, and displaying phagocytic ability. In this review we highlight the emerging role of pericytes in neuroinflammation and discuss pericyte-mediated neuroinflammation as a potential therapeutic target for the treatment of a range of devastating brain disorders. PMID- 28017363 TI - Statins for Primary Prevention of Cardiovascular Disease. AB - The US Preventive Services Task Force has recently recommended the use of statins in primary prevention of cardiovascular disease in adults. Doubts remain as to whether this approach is really cost-effective, and additional drawbacks include the increasing burden of potential side effects and incremental costs due to laboratory monitoring. PMID- 28017364 TI - Contrasting effects of hypoxia on copper toxicity during development in the three spined stickleback (Gasterosteus aculeatus). AB - Hypoxia is a global problem in aquatic systems and often co-occurs with pollutants. Despite this, little is known about the combined effects of these stressors on aquatic organisms. The objective of this study was to investigate the combined effects of hypoxia and copper, a toxic metal widespread in the aquatic environment. We used the three-spined stickleback (Gasterosteus aculeatus) as a model because of its environmental relevance and amenability for environmental toxicology studies. We focused on embryonic development as this is considered to be a sensitive life stage to environmental pollution. We first investigated the effects of hypoxia alone on stickleback development to generate the information required to design subsequent studies. Our data showed that exposure to low oxygen concentrations (24.7 +/- 0.9% air saturation; AS) resulted in strong developmental delays and increased mortalities, whereas a small decrease in oxygen (75.0 +/- 0.5%AS) resulted in premature hatching. Stickleback embryos were then exposed to a range of copper concentrations under hypoxia (56.1 +/- 0.2%AS) or normoxia (97.6 +/- 0.1%AS), continuously, from fertilisation to free swimming larvae. Hypoxia caused significant changes in copper toxicity throughout embryonic development. Prior to hatching, hypoxia suppressed the occurrence of mortalities, but after hatching hypoxia significantly increased copper toxicity. Interestingly, when exposures were conducted only after hatching, the onset of copper-induced mortalities was delayed under hypoxia compared to normoxia, but after 48 h, copper was more toxic to hatched embryos under hypoxia. This is the second species for which the protective effect of hypoxia on copper toxicity prior to hatching, followed by its exacerbating effect after hatching is demonstrated, suggesting the hypothesis that this pattern may be common for teleost species. Our research highlights the importance of considering the interactions between multiple stressors, as understanding these interactions is essential to facilitate the accurate prediction of the consequences of exposure to complex stressors in a rapidly changing environment. PMID- 28017365 TI - Acclimation to salt modifies the activation of several osmotic stress-activated lipid signalling pathways in Chlamydomonas. AB - Osmotic stress rapidly activates several phospholipid signalling pathways in the unicellular alga Chlamydomonas. In this report, we have studied the effects of salt-acclimation on growth and phospholipid signalling. Growing cells on media containing 100 mM NaCl increased their salt-tolerance but did not affect the overall phospholipid content, except that levels of phosphatidylinositol phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] were reduced by one-third. When these NaCl-acclimated cells were treated with increasing concentrations of salt, the same lipid signalling pathways as in non acclimated cells were activated. This was witnessed as increases in phosphatidic acid (PA), lyso-phosphatidic acid (L-PA), diacylglycerol pyrophosphate (DGPP), PI(4,5)P2 and its isomer PI(3,5)P2. However, all dose-dependent responses were shifted to higher osmotic-stress levels, and the responses were lower than in non acclimated cells. When NaCl-acclimated cells were treated with other osmotica, such as KCl and sucrose, the same effects were found, illustrating that they were due to hyperosmotic rather than hyperionic acclimation. The results indicate that acclimation to moderate salt stress modifies stress perception and the activation of several downstream pathways. PMID- 28017366 TI - Differences in the structure of copepod assemblages in four tropical estuaries: Importance of pollution and the estuary hydrodynamics. AB - We examined the relationship between pollution and structure of copepod assemblages in estuaries, using sampling standardization of salinity range to reduce the effects of "Estuarine Quality Paradox". Copepod assemblages were analyzed in four Southeast Brazilian estuaries with different water quality levels and different hydrodynamic characteristics. The pollution negatively impacted the descriptors of the assemblage structure. The distribution of structure of copepod assemblages also showed a main separation trend between the most polluted estuaries and those less polluted. Temperature was the main factor affecting the assemblage structuring in the four estuaries. This factor acted in synergism with the effects of pollution impact and physical characteristics of the estuaries on the structure of copepod assemblages, supporting the potential vulnerability of coastal environments due to nutrient enrichment associated with climate change. Our study demonstrated the importance of sampling standardization of the salinity range in estuaries for reliable analysis of pollution effects on biota. PMID- 28017367 TI - Preliminary assessment of metal distribution in the surface sediments along the coastline of the southern Caspian Sea. AB - In the present study, the concentrations of metals in sediments along the coastline of the southern Caspian Sea were investigated. For this purpose, sediments were collected from 13 sampling sites in the southern Caspian Sea. The samples were then analyzed by inductively coupled plasma-optical emission spectrometry. Results showed that compound oxides may be responsible for the distribution of metals in the sediments of the southern Caspian Sea. According to mean effects range-median quotient, 61.5% of the studied sites from the southern Caspian Sea had a 21% probability of metal toxicity. On the basis of the enrichment factor, all metals were in the category of deficiency to minimal enrichment. Pollution load index showed that the other sampling sites had no pollution. PMID- 28017368 TI - Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation. PMID- 28017369 TI - A systematic review and meta-analysis of in situ versus composite bilateral internal thoracic artery grafting. AB - OBJECTIVES: This meta-analysis examines whether there is any advantage of coronary artery bypass graft with bilateral internal thoracic artery (BITA) as an in situ versus composite graft. METHODS: We searched MEDLINE and EMBASE Databases from 1996 to 2016 for studies that compared coronary artery bypass graft with BITA as in situ versus composite graft. Data were extracted by 2 independent investigators and meta-analyzed with the use of random effects. RESULTS: Two randomized controlled trials (RCTs; n = 705), 2 matched (n = 1688), and 4 unadjusted observational studies (n = 3517) met inclusion criteria. Composite grafting trended towards greater distal anastomoses (+0.22, 95% confidence interval, -0.01 to +0.45 anastomoses/patient; P = .06 [4 unadjusted observational studies]) and greater distal anastomoses using an internal thoracic artery (+0.80, 95% confidence interval, 0.41-1.18 anastomoses/patient; P < .001 [1 RCT]). There were no differences in perioperative or longer-term composite cardiovascular outcomes comparing in situ versus composite BITA or individual outcomes of mortality, repeat revascularization, myocardial infarction, and cardiovascular mortality. Pooled results differed by study type with pooled results from lower-risk-of-bias RCTs typically showing increases in events rates, and pooled results from higher-risk-of-bias unadjusted observational studies typically showing decreases in event rates of in situ versus composite BITA. Post hoc subgroup analysis suggested possible improvements in all-cause mortality and revascularization for in situ BITA in studies with short-term (<5 years) versus longer-term follow-up, regardless of study type. CONCLUSIONS: Our meta-analysis found that use of BITA as a composite graft configuration facilitated greater internal thoracic artery revascularization but both grafting strategies offer similar clinical outcomes. Our study supports the use of in situ and composite BITA for select patients but high-quality, long-term prospective trials are needed. PMID- 28017370 TI - De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome. AB - Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation. PMID- 28017371 TI - Mixed Model Association with Family-Biased Case-Control Ascertainment. AB - Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold-based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where case and control subjects are ascertained non-randomly with respect to family relatedness. Previous work has shown that this type of ascertainment can severely bias heritability estimates; we show here that it also impacts mixed model association statistics. We introduce a family-based association statistic (LT-Fam) that is robust to this problem. Similar to LTMLM, LT-Fam is computed from posterior mean liabilities (PML) under a liability threshold model; however, LT-Fam uses published narrow sense heritability estimates to avoid the problem of biased heritability estimation, enabling correct calibration. In simulations with family-biased case control ascertainment, LT-Fam was correctly calibrated (average chi2 = 1.00-1.02 for null SNPs), whereas the Armitage trend test (ATT), standard mixed model association (MLM), and case-control retrospective association test (CARAT) were mis-calibrated (e.g., average chi2 = 0.50-1.22 for MLM, 0.89-2.65 for CARAT). LT Fam also attained higher power than other methods in some settings. In 1,259 type 2 diabetes-affected case subjects and 5,765 control subjects from the CARe cohort, downsampled to induce family-biased ascertainment, LT-Fam was correctly calibrated whereas ATT, MLM, and CARAT were again mis-calibrated. Our results highlight the importance of modeling family sampling bias in case-control datasets with related samples. PMID- 28017373 TI - Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. AB - From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders. PMID- 28017374 TI - Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood Onset, Slowly Progressive Nemaline Myopathy. AB - Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present. PMID- 28017372 TI - A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. AB - Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations. PMID- 28017377 TI - Letter to the Editor for "Evaluating the effectiveness of ultraviolet-C lamps for reducing keyboard contamination in the intensive care unit: A longitudinal analysis". PMID- 28017376 TI - Myogenic potential of mouse embryonic stem cells lacking functional Pax7 tested in vitro by 5-azacitidine treatment and in vivo in regenerating skeletal muscle. AB - Regeneration of skeletal muscle relies on the presence of satellite cells. Satellite cells deficiency accompanying some degenerative diseases is the reason for the search for the "replacement cells" that can be used in the muscle therapies. Due to their unique properties embryonic stem cells (ESCs), as well as myogenic cells derived from them, are considered as a promising source of therapeutic cells. Among the factors crucial for the specification of myogenic precursor cells is Pax7 that sustains proper function of satellite cells. In our previous studies we showed that ESCs lacking functional Pax7 are able to form myoblasts in vitro when differentiated within embryoid bodies and their outgrowths. In the current study we showed that ESCs lacking functional Pax7, cultured in vitro in monolayer in the medium supplemented with horse serum and 5azaC, expressed higher levels of factors associated with myogenesis, such as Pdgfra, Pax3, Myf5, and MyoD. Importantly, skeletal myosin immunolocalization confirmed that myogenic differentiation of ESCs was more effective in case of cells lacking Pax7. Our in vivo studies showed that ESCs transplanted into regenerating skeletal muscles were detectable at day 7 of regeneration and the number of Pax7-/- ESCs detected was significantly higher than of control cells. Our results support the concept that lack of functional Pax7 promotes proliferation of differentiating ESCs and for this reason more of them can turn into myogenic lineage. PMID- 28017378 TI - Cast-cap splint in the management of medication-related osteonecrosis of the jaw. AB - We describe the management of a pathological fracture in a patient with medication-related osteonecrosis using a cast-cap splint. In selected cases this is a simple solution to what can be a difficult condition to treat. PMID- 28017379 TI - Patient and Provider Attitudes on Appropriate Use Criteria for Myocardial Perfusion Imaging. PMID- 28017375 TI - Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. AB - Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits. PMID- 28017380 TI - Understanding the Role of the LA in Functional Responses to Heart Failure. PMID- 28017381 TI - Employment Status After Training in Advanced CV Imaging. PMID- 28017382 TI - LA Strain When Ejection Fraction Is Preserved: A New Measure of Diastolic Function? PMID- 28017383 TI - Routine Clinical Quantitative Rest Stress Myocardial Perfusion for Managing Coronary Artery Disease: Clinical Relevance of Test-Retest Variability. AB - OBJECTIVES: Positron emission tomography (PET) quantifies stress myocardial perfusion (in cc/min/g) and coronary flow reserve to guide noninvasively the management of coronary artery disease. This study determined their test-retest precision within minutes and daily biological variability essential for bounding clinical decision-making or risk stratification based on low flow ischemic thresholds or follow-up changes. BACKGROUND: Randomized trials of fractional flow reserve-guided percutaneous coronary interventions established an objective, quantitative, outcomes-driven standard of physiological stenosis severity. However, pressure-derived fractional flow reserve requires invasive coronary angiogram and was originally validated by comparison to noninvasive PET. METHODS: The time course and test-retest precision of serial quantitative rest-rest and stress-stress global myocardial perfusion by PET within minutes and days apart in the same patient were compared in 120 volunteers undergoing serial 708 quantitative PET perfusion scans using rubidium 82 (Rb-82) and dipyridamole stress with a 2-dimensional PET-computed tomography scanner (GE DST 16) and University of Texas HeartSee software with our validated perfusion model. RESULTS: Test-retest methodological precision (coefficient of variance) for serial quantitative global myocardial perfusion minutes apart is +/-10% (mean DeltaSD at rest +/-0.09, at stress +/-0.23 cc/min/g) and for days apart is +/-21% (mean DeltaSD at rest +/-0.2, at stress +/-0.46 cc/min/g) reflecting added biological variability. Global myocardial perfusion at 8 min after 4-min dipyridamole infusion is 10% higher than at standard 4 min after dipyridamole. CONCLUSIONS: Test-retest methodological precision of global PET myocardial perfusion by serial rest or stress PET minutes apart is +/-10%. Day-to-different day biological plus methodological variability is +/-21%, thereby establishing boundaries of variability on physiological severity to guide or follow coronary artery disease management. Maximum stress increases perfusion and coronary flow reserve, thereby reducing potentially falsely low values mimicking ischemia. PMID- 28017385 TI - Usefulness of Late Iodine Enhancement on Spectral CT in Acute Myocarditis. PMID- 28017384 TI - Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis. AB - OBJECTIVES: Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. BACKGROUND: Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. METHODS: In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 +/- 0.8 years of follow up. RESULTS: iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 +/- 7.2 ml/m2 vs. 16.1 +/- 3.2 ml/m2 in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m2; 51% of patients), extracellular expansion (iECV >=22.5 ml/m2; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009). CONCLUSIONS: CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936). PMID- 28017386 TI - Association of Patient Beliefs and Preferences With Subsequent Testing After Initial Evaluation for Ischemic Heart Disease. PMID- 28017388 TI - A New Dimension in Prediction of Cardiovascular Outcomes. PMID- 28017387 TI - LA Phasic Volumes and Reservoir Function in the Elderly by Real-Time 3D Echocardiography: Normal Values, Prognostic Significance, and Clinical Correlates. AB - OBJECTIVES: This study sought to assess the prevalence and prognostic value of abnormalities in left atrial (LA) phasic volumes and reservoir function in a community cohort. BACKGROUND: LA enlargement is associated with adverse cardiovascular outcomes. Real-time 3-dimensional (RT3D) echocardiography allows assessment of LA phasic volumes and reservoir function. However, there is a paucity of data regarding normal values, clinical correlates, and prognostic value of RT3D echocardiography-derived LA phasic volumes and reservoir function, especially in the elderly, a subgroup at high risk for cardiovascular events. METHODS: Left atrial maximum volume (LAVimax), minimum volume (LAVimin), and reservoir function assessed as emptying volume (LAEV), emptying fraction (LAEF), and expansion index (LAEI), were measured by RT3D echocardiography in participants from a community-based cohort study. Cut-off values for LA phasic volumes were derived from a healthy subgroup of participants free of cardiovascular disease and risk factors (n = 142; 66 +/- 9 years of age; 55% women). Annual follow-up examinations were performed for cardiovascular outcomes (myocardial infarction, ischemic stroke, and vascular death). RESULTS: The cohort included 706 participants (71 +/- 9 years of age; 59% women). LAVimax and LAVimin were not associated with age in the healthy subgroup but progressively increased with age in the entire cohort (p < 0.001). During a median follow-up of 7 years (minimum 0.06, maximum 9.5 years), 78 cardiovascular events occurred. In univariate analysis, LAVimax, LAVimin, and reservoir function parameters were significantly associated with outcome. In multivariate analysis, LAVimin >=20.5 ml/m2 (adjusted hazard ratio [aHR]: 1.79; 95% confidence interval [CI]:1.02 to 3.16) and LAEV <=5.7 ml/m2 (aHR: 1.98; 95% CI: 1.02 to 3.85) remained significantly associated with events. LAVimin and LA reservoir function showed incremental prognostic value over that of LAVimax. CONCLUSIONS: LA phasic volumes and reservoir functions assessed by RT3D echocardiography were strong independent predictors of cardiovascular events in a community-based elderly cohort. LAVimin and reservoir function assessment may improve cardiovascular outcome prediction over LAVimax. PMID- 28017390 TI - Rocking and Flashing With RV Pacing: Implications for Resynchronization Therapy. PMID- 28017389 TI - LA Strain for Categorization of LV Diastolic Dysfunction. AB - OBJECTIVES: This study sought to observe the relationship between left atrial (LA) strain and left ventricular diastolic function and determine whether LA strain could be used to detect diastolic dysfunction (DD) and classify its degree when present. BACKGROUND: The assessment of diastolic function is complex and multiparametric because most conventional parameters do not follow the progression of DD. Strain imaging is an emerging index of LA function, with recent data demonstrating that LA strain is diminished in diastolic heart failure. However, LA strain is not part of the standard assessment of diastolic function. We hypothesized that LA strain decreases with worsening DD in a stepwise fashion and could thus be useful in evaluating DD. METHODS: We performed a retrospective derivation and validation cohort study to derive and test LA strain thresholds for DD grades (0 to 3) in patients with preserved left ventricular ejection fraction (N = 229). Two-dimensional speckle tracking was used to measure peak LA strain, which was applied as a single parameter to classify DD. American Society of Echocardiography guidelines were used as the reference standard. RESULTS: In the derivation cohort (n = 90), peak LA strain was significantly different between DD groups, with gradual decreases seen with worsening DD. Receiver-operating characteristic analysis resulted in 3 distinct LA strain thresholds for categorization of DD grades, with good to excellent diagnostic utility (area under the curve: 0.86 to 0.91). In an independent validation group (n = 139) with a spectrum of diastolic function, 11 patients (8%) had indeterminate DD grades using standard criteria, whereas LA strain was measured in all patients and its cutoffs resulted in diagnostic accuracy up to 95%. CONCLUSIONS: LA strain measurements are feasible and allow accurate categorization of DD, because unlike the traditional parameters, it changes progressively with severity of DD. LA strain may become a useful tool for diastolic assessment in future clinical practice. PMID- 28017391 TI - Clinical PET Flow Reserve Imaging: Is There Precision to Treat Patients or Populations? PMID- 28017392 TI - Myocardial Fibrosis in Aortic Stenosis. PMID- 28017393 TI - Long-Term Outcome After CRT in the Presence of Mechanical Dyssynchrony Seen With Chronic RV Pacing or Intrinsic LBBB. AB - OBJECTIVES: The aim of this study was to compare the volumetric response and the long-term survival after cardiac resynchronization therapy (CRT) in patients with intrinsic left bundle branch block (LBBB) versus chronic right ventricular pacing (RVP) with respect to the presence of mechanical dyssynchrony (MD). BACKGROUND: Chronic RVP induces an iatrogenic LBBB and asynchronous left ventricular contraction that is potentially reversible by upgrading to CRT. METHODS: A total of 914 patients eligible for CRT (117 with conventional pacemakers and 797 with intrinsic LBBB) were included in the study. MD was visually assessed before CRT and was defined as the presence of either apical rocking and/or septal flash on baseline echocardiograms. Patients with a left ventricular end-systolic volume decrease of >=15% during the follow-up were considered responders. Patients were followed for all-cause mortality during the median follow-up of 48 months (interquartile range: 29 to 66 months). RESULTS: MD was observed in 51% of patients with RVP versus 77% in patients with intrinsic LBBB (p < 0.001). Patients with RVP and MD had a similar likelihood of volumetric response as did patients with intrinsic LBBB and MD (adjusted odds ratio: 0.71; 95% confidence interval: 0.33 to 1.53; p = 0.385). There was no significant difference in long term survival between patients with RVP and intrinsic LBBB (adjusted hazard ratio: 1.101; 95% confidence interval: 0.658 to 1.842; p = 0.714). Patients with visual MD and either intrinsic LBBB or RVP had a more favorable survival than those without MD (p < 0.001). CONCLUSIONS: The likelihood of volumetric response and a favorable long-term survival of patients with RVP was similar to those of patients with intrinsic LBBB and were mainly determined by the presence of MD and not by the nature of LBBB. PMID- 28017394 TI - Fate of Nonculprit Plaques in Patients With STEMI Undergoing Primary PCI Followed by Statin Therapy: A Serial Optical Coherence Tomography Analysis From the OCTAVIA Study. PMID- 28017395 TI - Left Atrial Function Dynamics During Exercise in Heart Failure: Pathophysiological Implications on the Right Heart and Exercise Ventilation Inefficiency. AB - OBJECTIVES: The hypothesis of this study was that left atrial (LA) dynamic impairment during exercise may trigger right ventricular (RV)-to-pulmonary circulation (PC) uncoupling and ventilation inefficiency. BACKGROUND: LA function plays a key role in the hemodynamics of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Extensive investigation of LA dynamics, however, has been performed exclusively at rest. METHODS: A total of 49 patients with HFrEF, 20 patients with HFpEF, and 32 healthy subjects with normal LA size and reservoir function (LA volume index <34 ml/m2 and peak left atrial strain [LA-strain] during LA relaxation >23%) were prospectively enrolled. They underwent cardiopulmonary exercise testing and contemporary echo-Doppler assessment of LA-strain and LA-strain rate and of RV-to PC coupling (pulmonary arterial systolic pressure/tricuspid annular peak systolic excursion ratio), measured at rest, at 40% of predicted peak oxygen consumption, and during recovery. RESULTS: In control subjects, LA-strain increased during exercise and recovery. Patients with HFpEF exhibited some LA-strain increase during exercise and recovery, whereas no changes occurred in those with HFrEF. The baseline LA-strain rate was greater in control subjects; a significant enhancement during recovery was observed only in this group. In both the HFpEF and HFrEF cohorts, RV-to-PC uncoupling and LA-strain at rest, exercise, and recovery significantly correlated with pulmonary arterial systolic pressure/tricuspid annular peak systolic excursion, as well as ventilation versus carbon dioxide slope, in a continuous fashion across groups (r = -0.63 and r = 0.59, r = -0.65 and r = -0.50, and r = -0.70 and r = -0.53 for control subjects, HFpEF, and HFrEF, respectively; p < 0.05). CONCLUSIONS: In heart failure, an impaired LA-strain response is a key hemodynamic trigger for RV-to-PC uncoupling and exercise ventilation inefficiency with some overlap between HFpEF and HFrEF phenotypes. Reversibility of LA dynamics seems to be an unmet target of specific therapeutic interventions. PMID- 28017396 TI - The Pickelhaube Sign: Novel Echocardiographic Risk Marker for Malignant Mitral Valve Prolapse Syndrome. PMID- 28017397 TI - Corrigendum to "Does the distance between tumor and margin in radical prostatectomy specimens correlate with prognosis: relation to tumor location" (Hum Pathol 2016;56:11-15). PMID- 28017398 TI - Moral Duties of Genomics Researchers: Why Personalized Medicine Requires a Collective Approach. AB - Advances in genome sequencing together with the introduction of personalized medicine offer promising new avenues for research and precision treatment, particularly in the field of oncology. At the same time, the convergence of genomics, bioinformatics, and the collection of human tissues and patient data creates novel moral duties for researchers. After all, unprecedented amounts of potentially sensitive information are being generated. Over time, traditional research ethics principles aimed at protecting individual participants have become supplemented with social obligations related to the interests of society and the research enterprise at large, illustrating that genomic medicine is also a social endeavor. In this review we provide a comprehensive assembly of moral duties that have been attributed to genomics researchers and offer suggestions for responsible advancement of personalized genomic cancer care. PMID- 28017400 TI - The Lancet Planetary Health: a new journal for a new discipline-a call for papers. PMID- 28017399 TI - Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double blind, placebo-controlled, phase 2 trial. AB - BACKGROUND: A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone-China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18-50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1.6 * 1011 viral particles), low-dose vaccine (8.0 * 1010 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. FINDINGS: During Oct 10-28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0.0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251.0 [95% CI 976.6-1602.5] in low-dose group and 1728.4 [1459.4-2047.0] in high-dose group) and peaked at day 28 (1471.8 [1151.0-1881.8] and 2043.1 [1762.4-2368.4]), but declined quickly in the following months (223.3 [148.2-336.4] and 254.2 [185.0 349.5] at day 168). Geometric mean titres in the placebo group remained around 6.0-6.8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. INTERPRETATION: The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8.0 * 1010 viral particles was the optimal dose. FUNDING: Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. PMID- 28017401 TI - Non-healing ulcerative paronychia. PMID- 28017402 TI - First Ebola virus vaccine to protect human beings? PMID- 28017404 TI - Multiple myeloma: new treatments gain momentum. PMID- 28017403 TI - Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster randomised trial (Ebola Ca Suffit!). AB - BACKGROUND: rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa. METHODS: We did an open-label, cluster-randomised ring vaccination trial (Ebola ca Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinee region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2*107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged >=18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (<=20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6-17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. FINDINGS: In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68.9-100.0, p=0.0045), and the calculated intraclass correlation coefficient was 0.035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79.3 100.0, p=0.0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53.9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87.5% of all 7211 adverse events). Headache (1832 [25.4%]), fatigue (1361 [18.9%]), and muscle pain (942 [13.1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza like illness); all three recovered without sequelae. INTERPRETATION: The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. FUNDING: WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Medecins Sans Frontieres, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway's GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development). PMID- 28017405 TI - Safety and immunogenicity of a recombinant adenovirus vector-based Ebola vaccine. PMID- 28017407 TI - Fluid and Electrolyte Therapy in Diabetic Ketoacidosis. AB - Diabetic ketoacidosis is a dynamic disease that requires regular reassessment of an affected patient. Typical treatment regimens include crystalloid fluid therapy, insulin, and supplementation of dextrose, phosphorus, and potassium. This article presents an approach to and considerations for treatment of a diabetic ketoacidotic dog or cat. PMID- 28017406 TI - Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. AB - BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for patients with newly diagnosed myeloma. The combination of the proteasome inhibitor bortezomib with lenalidomide and dexamethasone has shown significant efficacy in the setting of newly diagnosed myeloma. We aimed to study whether the addition of bortezomib to lenalidomide and dexamethasone would improve progression-free survival and provide better response rates in patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant. METHODS: In this randomised, open-label, phase 3 trial, we recruited patients with newly diagnosed multiple myeloma aged 18 years and older from participating Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutions (both inpatient and outpatient settings). Key inclusion criteria were presence of CRAB (C=calcium elevation; R=renal impairment; A=anaemia; B=bone involvement) criteria with measurable disease (measured by assessment of free light chains), Eastern Cooperative Oncology Group (ECOG) performance status of 0-3, haemoglobin concentration 9 g/dL or higher, absolute neutrophil count 1 * 103 cells per mm3 or higher, and a platelet count of 80 000/mm3 or higher. We randomly assigned (1:1) patients to receive either an initial treatment of bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group). Randomisation was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes vs no). The VRd regimen was given as eight 21-day cycles. Bortezomib was given at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1-14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28 day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1-21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22. The primary endpoint was progression-free survival using a prespecified one sided stratified log rank test at a significance level of 0.02. Analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00644228. FINDINGS: Between April, 2008, and February, 2012, we randomly assigned 525 patients at 139 participating institutions (264 to VRd and 261 to Rd). In the randomly assigned patients, 21 patients in the VRd group and 31 in the Rd group were deemed ineligible based mainly on missing, insufficient, or early or late baseline laboratory data. Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0.712, 96% CI 0.56-0.906; one-sided p value 0.0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0.709, 95% CI 0.524-0.959; two-sided p value 0.025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment related deaths in the Rd group, and two in the VRd group. INTERPRETATION: In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile. FUNDING: NIH, NCI, NCTN, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation. PMID- 28017408 TI - A Quick Reference on High Anion Gap Metabolic Acidosis. AB - High anion gap (AG) metabolic acidoses can be identified by a decrease in pH, decrease in HCO3- or base excess, and an increased AG. The AG represents the difference between unmeasured cations and unmeasured anions; it increases secondary to the accumulation of anions other than bicarbonate and chloride. The most common causes of high AG acidosis are renal failure, diabetic ketoacidosis, and lactic acidosis. Severe increases in concentration of phosphorus can cause hyperphosphatemic acidosis. PMID- 28017409 TI - A Quick Reference on Hyperchloremic Metabolic Acidosis. AB - Metabolic acidosis results from an increase in the concentration of a strong anion. Metabolic acidosis is divided into hyperchloremic metabolic acidosis and high anion gap acidosis based on the changes in the anion gap. Hyperchloremic metabolic acidosis is the result of chloride retention, excessive loss of sodium relative to chloride, or excessive gain of chloride relative to sodium. Clinical signs are related to the underlying disease that accompanies the metabolic acidosis. Treatment of hyperchloremic acidosis is based on addressing the underlying disease process. PMID- 28017410 TI - Disorders of Sodium and Water Homeostasis. AB - This review article discusses normal and abnormal sodium balance in small animals. The terms and concepts central to understanding normal sodium and water balance are presented as well as of the physiology of body fluid compartments and the movement of fluid between those compartments. As dysnatremia is a very common disorder across the spectrum of critically ill patients, the main focus of the article is to present several clinical examples of both acute and chronic hypernatremia and hyponatremia and their practical, clinical management. PMID- 28017411 TI - Less Hidden Celiac Disease But Increased Gluten Avoidance Without a Diagnosis in the United States: Findings From the National Health and Nutrition Examination Surveys From 2009 to 2014. AB - OBJECTIVE: To investigate the trends in the prevalence of diagnosed celiac disease (CD), undiagnosed CD, and people without celiac disease avoiding gluten (PWAG) in the civilian noninstitutionalized US population from 2009 to 2014. PATIENTS AND METHODS: We studied the occurrence of CD and PWAG in the 2009 to 2014 National Health and Nutrition Examination Surveys. The serum of all participants aged 6 years or older from the National Health and Nutrition Examination Surveys from 2009 to 2014 was tested for CD serology at Mayo Clinic. Participants were interviewed for a diagnosis of CD and the use of a gluten-free diet (GFD). The design effects of the survey and sample weights were incorporated in all statistical analyses. RESULTS: In the US general population, the prevalence of CD did not change significantly from 0.7% (95% CI, 0.6%-0.8%) in 2009 to 2010 to 0.8% (95% CI, 0.4%-1.2%) in 2011 to 2012 to 0.7% (95% CI, 0.3% 1.0%) in 2013 to 2014. However, the prevalence of undiagnosed CD decreased from 0.6% in 2009 to 2010 to 0.3% in 2013 to 2014. In contrast, the prevalence of PWAG increased significantly from 0.5% (95% CI, 0.2%-0.9%) in 2009 to 2010 to 1.0% (95% CI, 0.6%-1.4%) in 2011 to 2012 to 1.7% (95% CI, 1.1%-2.4%) in 2013 to 2014 (P=.005 for trend). CONCLUSION: Although the overall prevalence of CD remained stable from 2009 to 2014, the proportion of individuals with CD that is hidden considerably decreased. Moreover, the proportion of individuals without CD but following a GFD increased markedly from 2009 to 2014. Long-term health consequences of a GFD warrant further investigation. PMID- 28017412 TI - Intracorporal knot tying techniques - which is the right one? AB - INTRODUCTION: Intracorporal knot tying (ICKT) and suturing in minimal invasive surgery (MIS) represent a key skill for advanced procedures such as Nissen fundoplication. Suture placement under tension is particularly challenging during MIS. The aim of this study was to compare ICKT of the common surgical square knot and the slipping knot on a simulated suture placement under tension. Furthermore, we objectively assessed the surgical skill of ICKT following 3hours of hands-on training. METHODS: A box trainer was used for laparoscopic knot tying with predefined openings. A 12cm suture was placed in central view. We used a standardized silicon suture pad with a defined wound dehiscence of 0.5cm and marked needle entrance and exit targets next to the incision. Twenty participants were divided among three groups in this study. The first group (n=5) consisted of senior physicians. The second group (n=5) was made up of surgical residents in the first to fourth year of residency training. The third group (n=10) contained medical students between their third and sixth year of study without any prior experience in laparoscopic surgery. Residents and students received a 3-hour hands-on training in surgical square and slipping knot tying. Each participant tied two of each knot types before and after the hands-on training. Knot quality, performance, total time and suture placement accuracy were the parameters for assessment in this study. RESULTS: The knot quality was greater for the slipping knot compared with the square knot in all groups. There were no significant intragroup differences in knot tying performance, task time and accuracy of both suture methods. Students and residents improved in all categories for both ICKT techniques after training. DISCUSSION: We compared ICKT of the surgical square knot with the slipping knot on a simulated suture placement under tension during a standardized training program for medical students and surgical residents. In our study, the average quality of the slipping knot was significantly superior to the square knot in all participants. The knot tying performance, task time, and accuracy of students and residents after hands-on training were not significantly different between both suture methods. This suggests that the two ICKT techniques have similar properties except the quality advantages of the slipping knot. Although students and residents improved in all categories for both ICKT techniques after training, they did not achieve expert level for task times and accuracy. CONCLUSIONS: In this pilot trail, the quality of the slipping knot was superior to the surgical square knot during intracorporal suturing under tension. Our 3-hour sequential training program improved laparoscopic suturing and knot tying skills in all participants. Our findings suggest that training centers for MIS using validated training programs should be a continuous and integral part of surgical education. LEVEL OF EVIDENCE: USPSTF Level III: monocentric, prospective, pilot Trial. PMID- 28017413 TI - Endangered academia: preserving the pediatric surgeon scientist. AB - BACKGROUND: Pediatric surgery is one of the most difficult surgical fellowships to obtain. It requires stellar academic credentials and, often, dedicated time pursuing research. It is unknown, however, if pediatric surgeons maintain high academic output as faculty members. We hypothesized that the majority of pediatric surgeons do not pursue robust research activities as faculty, and therefore, over time, their academic productivity decreases. METHODS: Numbers of publications, citations, H-index, and NIH funding rates were determined for 4354 surgical faculty at the top-55 NIH based departments of surgery using websites, Scopus, NIH RePORTER, and Grantome. Continuous variables were compared with ANOVA and post-hoc Bonferroni; categorical variables by chi2 test. p<0.05 was significant. RESULTS: In this dataset, 321 pediatric surgery (PS) faculty represented 7.4% of the cohort. Among PS faculty, 31% were assistant professors, 24% associate professors, 31% full professors and 13% had no academic rank. PS faculty had significantly more publications, a higher H index, and more high level NIH funding early in their careers at the assistant professor level compared to general surgeons. PS faculty at the associate professor level had equivalent high level NIH funding, but lower recentness and academic power compared to general surgeons. Professors of PS rebounded slightly, with only observed deficiencies in number of citations compared to general surgeons. CONCLUSIONS: PS faculty in assistant professor ranks has higher scholarly productivity compared to equivalently ranked general surgeons. Despite some mild academic setbacks in midcareer, pediatric surgeons are able to maintain similar academic productivity to their general surgery colleagues by the time they are full professors. LEVEL OF EVIDENCE: 2. PMID- 28017414 TI - Improved outcomes for inborn babies with uncomplicated gastroschisis. AB - INTRODUCTION: Gastroschisis (GS) is a common abdominal wall defect necessitating neonatal surgery and intensive care. We hypothesized that inborn patients had improved outcomes compared to patients born at an outside hospital (outborn) and transferred for definitive treatment. METHODS: A single center, retrospective chart review at a pediatric tertiary care center was performed from 2010 to 2015. All patients whose primary surgical treatment of GS was performed at this center were included. We compared patients delivered within our center (inborn) to patients delivered outside of our center and transferred for surgical care (outborn). Babies with complicated gastroschisis were excluded. RESULTS: During the study period 79 patients with GS were identified. Of these, 53 were inborn and 26 were outborn. Sixteen patients were excluded for complicated GS. The rate of complicated GS was higher in the outborn group (32%) compared to the inborn population (11%) (p=0.03). Duration of stay, readmission rate and time on TPN were all significantly decreased for inborn patients, while time to definitive closure was similar. Mortality was 0% for both inborn and outborn patients. CONCLUSION: Patients with uncomplicated GS seem to benefit from delivery with immediate pediatric surgical care available eliminating the need for transfer. LEVEL OF EVIDENCE: III. PMID- 28017415 TI - Comparison of industrial emissions and carpet dust concentrations of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in a multi center U.S. study. AB - Proximity to facilities emitting polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) has been associated with increased risk of non-Hodgkin lymphoma (NHL). There is limited information about whether proximity to industrial sources leads to indoor PCDD/F contamination of homes. We measured carpet dust concentrations (pg/g) of 17 toxic PCDD/F congeners and calculated their toxic equivalence (TEQ) in 100 homes in a population-based case-control study of NHL in Detroit, Los Angeles, Seattle, and Iowa (1998-2000). We took global positioning system readings at residences and obtained coordinates and PCDD/F emissions (ng TEQ/yr) from an Environmental Protection Agency database for 6 facility types: coal-fired electricity generating plants, cement kilns burning non-hazardous waste, hazardous waste incinerators, medical waste incinerators, municipal solid waste incinerators, and sewage sludge incinerators. For each residence, we computed an inverse distance-squared weighted average emission index (AEI [pg TEQ/km2/yr]) for all facilities within 5km from 1983 to 2000. We also computed AEIs for each of the 6 facility types. We evaluated relationships between PCDD/F dust concentrations and the all-facility AEI or categories of facility-type AEIs using multivariable linear regression, adjusting for study center, demographics, and home characteristics. A doubling of the all-facility AEI was associated with a 4-8% increase in PCDD/F dust concentrations of 7 of 17 PCDD/F congeners and the TEQ (p-value<0.1). We also observed positive associations between PCDD/F dust concentrations and facility-type AEIs (highest vs. lowest exposure category) for municipal solid waste incinerators (9 PCDD/F, TEQ), and medical waste incinerators (7 PCDD/F, TEQ) (p<0.1). Our results from diverse geographical areas suggest that industrial PCDD/F emission sources contribute to residential PCDD/F dust concentrations. Our emissions index could be improved by incorporating local meteorological data and terrain characteristics. Future research is needed to better understand the links between nearby emission sources, human exposure pathways, and health risks. PMID- 28017416 TI - Municipal wastewater effluent licensing: A global perspective and recommendations for best practice. AB - Advances in wastewater treatment have greatly improved the quality of municipal wastewater effluents in many parts of the world, but despite this, treated wastewaters can still pose a risk to the environment. Licensing plays a crucial role in the regulation of municipal wastewater effluents by setting standards or limits designed to protect the economic, environmental and societal values of waterbodies. Traditionally these standards have focused on physical and chemical water quality parameters within the discharge itself, however these approaches do not adequately account for emerging contaminants, potential effects of chemical mixtures, or variations in the sensitivity and resilience of receiving environments. In this review we focus on a number of industrialised countries and their approach to licensing. We consider how we can ensure licensing is effective, particularly when considering the rapid changes in our understanding of the impacts of discharges, the technical advances in our ability to detect chemicals at low concentrations and the progress in wastewater treatment technology. In order to meet the challenges required to protect the values of our waterways, licensing of effluents will need to ensure that there is no disconnect between the core values to be protected and the monitoring system designed to scrutinise performance of the WWTP. In many cases this may mean an expansion in the monitoring approaches used for both the effluent itself and the receiving waterbody. PMID- 28017417 TI - An enhanced export coefficient based optimization model for supporting agricultural nonpoint source pollution mitigation under uncertainty. AB - In this research, an export coefficient based dual inexact two-stage stochastic credibility constrained programming (ECDITSCCP) model was developed through integrating an improved export coefficient model (ECM), interval linear programming (ILP), fuzzy credibility constrained programming (FCCP) and a fuzzy expected value equation within a general two stage programming (TSP) framework. The proposed ECDITSCCP model can effectively address multiple uncertainties expressed as random variables, fuzzy numbers, pure and dual intervals. Also, the model can provide a direct linkage between pre-regulated management policies and the associated economic implications. Moreover, the solutions under multiple credibility levels can be obtained for providing potential decision alternatives for decision makers. The proposed model was then applied to identify optimal land use structures for agricultural NPS pollution mitigation in a representative upstream subcatchment of the Miyun Reservoir watershed in north China. Optimal solutions of the model were successfully obtained, indicating desired land use patterns and nutrient discharge schemes to get a maximum agricultural system benefits under a limited discharge permit. Also, numerous results under multiple credibility levels could provide policy makers with several options, which could help get an appropriate balance between system benefits and pollution mitigation. The developed ECDITSCCP model can be effectively applied to addressing the uncertain information in agricultural systems and shows great applicability to the land use adjustment for agricultural NPS pollution mitigation. PMID- 28017418 TI - Bacterial characterization in ambient submicron particles during severe haze episodes at Ji'nan, China. AB - In January 2014, severe haze episodes which sweep across Chinese cities have attracted public concern and interest at home and abroad. In addition to the physicochemical properties of air pollutants, bacteria are thought to be responsible for the spread of respiratory diseases and various allergies. We attempted the bacterial characterization of submicron particles (PM0.18-0.32, PM0.32-0.56, and PM0.56-1) under severe haze episodes using high-throughput sequencing and real-time quantitative PCR detecting system based on 21 samples collected from January to March 2014 at Ji'nan, China. The high bacterial concentration in PM0.32-0.56 (7314cells m-3), PM0.18-0.32 (7212cells m-3), and PM0.56-1 (6982cells m-3) showed significant negative correlations with SO2, NO2, and O3. Under sufficient sequencing depth, 37 phyla, 71 classes, 137 orders, 236 families, and 378 genera were classified, and the bacterial community structure varied significantly in different size fractions. For example, Holophagaceae (Acidobacteria) in PM0.32-0.56 showed 6-fold higher abundance than that in PM0.18 0.32. Moreover, functional categories and bacterial species (Lactococcus piscium, Pseudomonas fragi, Streptococcus agalactiae, and Pseudomonas cichorii) that may potentially be responsible for infections and allergies were also discovered. Source track analysis showed that the ambient bacteria mainly originated from soils, leaf surfaces, and feces. Our results highlighted the importance of airborne microbial communities by understanding the concentration, structure, ecological and health effects, especially those in submicron particles during haze episodes. PMID- 28017419 TI - Integrating remote sensing with nutrient management plans to calculate nitrogen parameters for swine CAFOs at the sprayfield and sub-watershed scales. AB - North Carolina (NC) regulates swine concentrated animal feeding operations (CAFOs) using five-year nutrient management plans (NMPs) requiring the plant available nitrogen sprayed (PANspray) to be less than that utilized by crops (PANcrops), i.e. the PAN balance (defined as PANbal=PANspray-PANcrops) remains negative, which avoids over-spraying liquid effluent onto crops. Objectives of this research are first to characterize Duplin County sprayfields and PANbal by creating the first, open-source sprayfield spatial database created for swine CAFOs in NC (for Duplin County). Second, this paper finds that for two sub watershed scales 199 additional catchments and 1 additional HUC12 were identified as having permitted lagoon effluent applied compared to using CAFO point locations for a total of 510 catchments and 34 HUC12s with swine CAFO sprayfields. Third, a new method disaggregates annual PANbal from NMPs using remote sensing crop data. And finally, probability that sprayfields have excess PANbal is estimated due to k, a PAN availability coefficient. The remote sensing approach finds that 9-14% of catchments in a given year and 24% of catchments over a five year period have a positive PANbal. An additional 3-4% of catchments have probability of a positive PANbal due to variability in k. This work quantifies the impact of crop rotations on of sprayfields at the catchment spatial scale with respect to PANbal and highlights some of the limitations of NMPs have for estimation of PANbal. We recommend that NMPs be permitted based on the crop rotation scenario utilizing the least PAN and that swine producer compliance to manure management practice be encouraged. PMID- 28017420 TI - Comparison of Visual Outcomes of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients with and without Diabetes Mellitus. AB - PURPOSE: Diabetic patients have a greater risk of nonarteritic anterior ischemic optic neuropathy (NAION) than nondiabetic patients. We compare visual outcomes, prevalence of bilateral/sequential ION, and predictors of visual outcomes in NAION between diabetic and nondiabetic patients. DESIGN: Case-control study. PARTICIPANTS: All 231 patients with NAION seen by the Neuro-Ophthalmology Service, Wilmer Eye Institute, between 2002 and 2011 were screened for study inclusion. METHODS: Patients presenting within 4 weeks of symptom onset (30 with diabetes mellitus, 62 control patients) were included in baseline demographic assessments of vascular risk factors. Interval and final visual outcomes (logarithm of the minimum angle of resolution [logMAR] visual acuity [VA]) were evaluated in the 81 patients in this group with clinical follow-up for >=3 months, and population average logistic regression models were used to determine risk factors for worse visual outcomes. MAIN OUTCOME MEASURES: Visual acuity at last follow-up. RESULTS: The median follow-up duration was 38.7 weeks in diabetic patients and 52.9 weeks in nondiabetic patients. The majority (92.5%) of patients presented within 2 weeks of symptom onset. In nondiabetic patients, the most prevalent risk factor for NAION was hyperlipidemia (62.9%); for diabetic patients, NAION risk factors included hypertension (83.3%), hyperlipidemia (83.3%), and small cup-to-disc ratio (63.3%). Sequential NAION occurred in 36.8% of diabetic patients and 20.9% of nondiabetic patients. At last follow-up, 48% of diabetic and 62% of nondiabetic patients had VA better than 20/40. Similar proportions of diabetic and nondiabetic patients (8 [27%] diabetic and 14 [22.5%] nondiabetic patients) recorded a final follow-up vision of 1.0 logMAR or worse at a minimum of 3 months. Ischemic heart disease (odds ratio [OR], 7.21; P < 0.001) and greater age (OR, 1.05; P = 0.045) were associated with increased risk for final VA <20/200 in the multiple regression model (OR, 4.35; P = 0.011). CONCLUSIONS: The VA at presentation and at final follow-up in diabetic patients with NAION were not significantly different from nondiabetic controls, although diabetic patients had a higher prevalence of cardiovascular risk factors. Ischemic heart disease and greater age, but not diabetes, independently correlated with worse VA outcome. PMID- 28017421 TI - Steroid-Sparing Effect of 0.1% Tacrolimus Eye Drop for Treatment of Shield Ulcer and Corneal Epitheliopathy in Refractory Allergic Ocular Diseases. AB - PURPOSE: To evaluate the effects of 0.1% topical tacrolimus alone or in combination with steroids for the treatment of shield ulcers and corneal epitheliopathy in patients with refractory allergic ocular diseases. DESIGN: Open cohort study. PARTICIPANTS: Patients with refractory allergic conjunctivitis epitheliopathy, shield ulcers, or corneal plaques (N = 791). METHODS: The 791 patients were treated with topical tacrolimus alone or in combination with topical or oral steroids. The effectiveness of the treatments was determined by a corneal epitheliopathy score during the 3-month follow-up period. The clinical signs were rated on a 4-grade scale. Corneal epitheliopathy with no corneal staining was graded as 0, and shield ulcers or plaques were graded as 3, the highest grade. The effects of tacrolimus with and without topical steroids on the epitheliopathy scores were assessed after adjustments for the severity of the clinical signs and characteristics. MAIN OUTCOME MEASURES: Changes in the corneal epitheliopathy score. RESULTS: Adjusted mean epitheliopathy score at the baseline was 1.73 (95% confidence interval [CI], 1.65-1.81) for patients treated with tacrolimus alone, and this was significantly reduced by -0.93 at 1 month. The reduction of the score by topical and oral steroids was -0.02 for fluorometholone, 0.02 for betamethasone, and -0.02 for oral steroids, and these reductions were not significant compared with the reduction effect of topical tacrolimus alone at -0.93. The 238 patients with shield ulcer (score 3) were analyzed with adjustments, and the mean epitheliopathy score at 1 month was reduced to 1.38 with tacrolimus alone (95% CI, 1.24-1.51), 1.41 (95% CI, 1.26 1.56) with adjuvant fluorometholone, and 1.46 (95% CI, 1.32-1.61) with adjuvant betamethasone. No significant difference was observed in the adjunctive topical steroids. The presence of severe palpebral conjunctival symptoms, including giant papillae, was a significant resisting factor for topical tacrolimus. CONCLUSIONS: The significant effects of topical tacrolimus alone on shield ulcers and corneal epitheliopathy suggest that it may be used without the need for steroids. PMID- 28017422 TI - Quantifying Fall-Related Hazards in the Homes of Persons with Glaucoma. AB - OBJECTIVE: To characterize fall-related hazards in the homes of persons with suspected or diagnosed glaucoma, and to determine whether those with worse visual field (VF) damage have fewer home hazards. DESIGN: Cross-sectional study using baseline (2013-2015) data from the ongoing Falls in Glaucoma Study (FIGS). PARTICIPANTS: One-hundred seventy-four of 245 (71.0%) FIGS participants agreeing to the home assessment. METHODS: Participants' homes were assessed using the Home Environment Assessment for the Visually Impaired (HEAVI). A single evaluator assessed up to 127 potential hazards in 8 home regions. In the clinic, binocular contrast sensitivity (CS) and better-eye visual acuity (VA) were evaluated, and 24-2 VFs were obtained to calculate average integrated VF (IVF) sensitivity. MAIN OUTCOME MEASURES: Total number of home hazards. RESULTS: No significant visual or demographic differences were noted between participants who did and did not complete the home assessment (P > 0.09 for all measures). Mean age among those completing the home assessment (n = 174) was 71.1 years, and IVF sensitivity ranged from 5.6 to 33.4 dB (mean = 27.2 dB, standard deviation [SD] = 4.0 dB). The mean number of items graded per home was 85.2 (SD = 13.2), and an average of 32.7 (38.3%) were identified as hazards. IVF sensitivity, CS, and VA were not associated with total home hazards or the number of hazards in any given room (P > 0.06 for all visual measures and rooms). The bathroom contained the greatest number of hazards (mean = 7.9; 54.2% of graded items classified as hazardous), and the most common hazards identified in at least 1 room were ambient lighting <300 lux and exposed light bulbs. Only 27.9% of graded rooms had adequate lighting. IVF sensitivity, CS, and VA were not associated with home lighting levels (P > 0.18 for all), but brighter room lighting was noted in the homes of participants with higher median income (P < 0.001). CONCLUSIONS: Multiple home fall hazards were identified in the study population, and hazard numbers were not lower for persons with worse VF damage, suggesting that individuals with more advanced glaucoma do not adapt their homes for safety. Further work should investigate whether addressing home hazards is an effective intervention for preventing falls in this high-risk group. PMID- 28017423 TI - Operating Room Performance Improves after Proficiency-Based Virtual Reality Cataract Surgery Training. AB - PURPOSE: To investigate the effect of virtual reality proficiency-based training on actual cataract surgery performance. The secondary purpose of the study was to define which surgeons benefit from virtual reality training. DESIGN: Multicenter masked clinical trial. PARTICIPANTS: Eighteen cataract surgeons with different levels of experience. METHODS: Cataract surgical training on a virtual reality simulator (EyeSi) until a proficiency-based test was passed. MAIN OUTCOME MEASURES: Technical performance in the operating room (OR) assessed by 3 independent, masked raters using a previously validated task-specific assessment tool for cataract surgery (Objective Structured Assessment of Cataract Surgical Skill). Three surgeries before and 3 surgeries after the virtual reality training were video-recorded, anonymized, and presented to the raters in random order. RESULTS: Novices (non-independently operating surgeons) and surgeons having performed fewer than 75 independent cataract surgeries showed significant improvements in the OR-32% and 38%, respectively-after virtual reality training (P = 0.008 and P = 0.018). More experienced cataract surgeons did not benefit from simulator training. The reliability of the assessments was high with a generalizability coefficient of 0.92 and 0.86 before and after the virtual reality training, respectively. CONCLUSIONS: Clinically relevant cataract surgical skills can be improved by proficiency-based training on a virtual reality simulator. Novices as well as surgeons with an intermediate level of experience showed improvement in OR performance score. PMID- 28017424 TI - Predictors of Long-Term Visual Outcome in Intermediate Uveitis. AB - PURPOSE: To describe factors that predict visual loss and complications in intermediate uveitis. DESIGN: Cross-sectional study. PARTICIPANTS: Subjects with intermediate uveitis were identified from a database of 1254 uveitis patients seen in the clinic of a single consultant (S.L.L.) between 2011 and 2013. METHODS: Information was gathered from the clinical notes of all subjects examined in clinic. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), moderate visual loss (MVL; <=20/50), severe visual loss (SVL; <=20/200). RESULTS: Three hundred and five subjects (550 eyes) were included in the study, comprising 24.3% of subjects seen in clinic. Mean (+/- standard deviation) age at diagnosis was 40.9+/-16.9 years, and 64.6% of subjects were female. Median follow-up was 8.2 years (mean, 9.7 years, 5452 eye-years). Systemic diagnosis was made in 36.1% of patients, with sarcoidosis (22.6%) and multiple sclerosis (4.6%) the most frequent systemic associations. Median BCVA was 20/30 (mean logarithm of the minimum angle of resolution [logMAR] 0.26+/-0.38, n = 550 eyes) at presentation, 20/30 (mean logMAR 0.22+/-0.42, n = 430) at 5 years, and 20/30 (mean logMAR 0.23+/-0.46, n = 260) at 10 years. Macular edema was observed in 224 eyes (40.7%) and was associated with idiopathic disease (P = 0.001) and diabetes (P = 0.001). Topical therapy was used in 82.7%, and 34.2% received local injections of corticosteroids. A total of 50.5% required oral steroids and 13.8% required second-line immunosuppression. Subjects with a diagnosis of sarcoidosis were less likely to require a second-line agent (4.3% vs. 16.2%, P = 0.011). On multivariate analysis, visual acuity at referral, retinal pigment epithelial atrophy, and macular scarring were associated with increased risk of MVL; and visual acuity at referral, local therapy, macular scarring, retinal detachment, and hypotony and phthisis were associated with increased risk of SVL. CONCLUSIONS: Intermediate uveitis has a long disease course with frequent complications and often requires systemic treatment. Despite this, most subjects are still able to achieve good long-term visual outcomes. PMID- 28017425 TI - Vaccination of rhesus macaques with the live-attenuated HSV-1 vaccine VC2 stimulates the proliferation of mucosal T cells and germinal center responses resulting in sustained production of highly neutralizing antibodies. AB - We have shown that the live-attenuated HSV-1 VC2 vaccine strain with mutations in glycoprotein K (gK) and the membrane protein UL20 is unable to establish latency in vaccinated animals and produces a robust immune response capable of completely protecting mice against lethal vaginal HSV-1 or HSV-2 infections. To better understand the immune response generated by vaccination with VC2, we tested its ability to elicit immune responses in rhesus macaques. Vaccinated animals showed no signs of disease and developed increasing HSV-1 and HSV-2 reactive IgG1 after two booster vaccinations, while IgG subtypes IgG2 and IgG3 remained at low to undetectable levels. All vaccinated animals produced high levels of cross protective neutralizing antibodies. Flow cytometry analysis of cells isolated from draining lymph nodes showed that VC2 vaccination stimulated significant increases in plasmablast (CD27highCD38high) and mature memory (CD21-IgM-) B cells. T cell analysis on cells isolated from draining lymph node biopsies demonstrated a statistically significant increase in proliferating (Ki67+) follicular T helper cells and regulatory CXCR5+ CD8+ cytotoxic T cells. Analysis of plasma isolated two weeks post vaccination showed significant increases in circulating CXCL13 indicating increased germinal center activity. Cells isolated from vaginal biopsy samples collected over the course of the study exhibited vaccination-dependent increases in proliferating (Ki67+) CD4+ and CD8+ T cell populations. These results suggest that intramuscular vaccination with the live attenuated HSV-1 VC2 vaccine strain can stimulate robust IgG1 antibody responses that persist for >250days post vaccination. In addition, vaccination lead to the maturation of B cells into plasmablast and mature memory B cells, the expansion of follicular T helper cells, and affects in the mucosal immune responses. These data suggest that the HSV VC2 vaccine induces potent immune responses that could help define correlates of protection towards developing an efficacious HSV-1/HSV 2 vaccine in humans. PMID- 28017426 TI - Viral vector vaccines protect cockatiels from inflammatory lesions after heterologous parrot bornavirus 2 challenge infection. AB - Avian bornaviruses are causative agents of proventricular dilatation disease (PDD), a chronic neurologic and often fatal disorder of psittacines including endangered species. To date no causative therapy or immunoprophylaxis is available. Our previous work has shown that viral vector vaccines can delay the course of homologous bornavirus challenge infections but failed to protect against PDD when persistent infection was not prevented. The goal of this study was to refine our avian bornavirus vaccination and infection model to better represent natural bornavirus infections in order to achieve full protection against a heterologous challenge infection. We observed that parrot bornavirus 2 (PaBV-2) readily infected cockatiels (Nymphicus hollandicus) by combined intramuscular and subcutaneous injection with as little as 102.7foci-forming units (ffu) per bird, whereas a 500-fold higher dose of the same virus administered via peroral and oculonasal route did not result in persistent infection. These results indicated that experimental bornavirus challenge infections with this virus should be performed via the parenteral route. Prime boost vaccination of cockatiels with Newcastle disease virus (NDV) and modified vaccinia virus Ankara (MVA) vectors expressing the nucleoprotein and phosphoprotein genes of PaBV-4 substantially blocked bornavirus replication following parenteral challenge infection with 103.5ffu of heterologous PaBV-2. Only two out of six vaccinated birds had very low viral levels detectable in a few organs. As a consequence, only one vaccinated bird developed mild PDD associated microscopic lesions, while mock-vaccinated controls were not protected against PaBV-2 infection and inflammation. Our results demonstrate that NDV and MVA vector vaccines can protect against invasive heterologous bornavirus challenge infections and subsequent PDD. These vector vaccines represent a promising tool to combat avian bornaviruses in psittacine populations. PMID- 28017427 TI - The economic impact of prenatal varicella immunity among pregnant women in Alberta. AB - In light of the changing epidemiology of varicella, we sought to examine varicella antibody levels in the prenatal population in the Canadian province of Alberta. All prenatal varicella screening tests performed between August 1, 2002 and February 2, 2014 (454,592) were included in this study. Test results, demographics and vaccination status were examined to identify varicella seroprevalence and correlates for being seronegative. An overall seroprevalence for varicella of 95.8% was found across all pregnancy screenings. Significant independent correlates of seronegativity included younger age (AOR: 4.72 (95% CI: 3.87-5.77) for <20years of age vs. >40years of age) and having immigrated to Alberta from Africa or Asia (AOR: 4.55 (95% CI: 4.10-5.05) and AOR: 5.83 (95%CI; 5.48-6.19), respectively). Women who were initially seronegative for varicella antibodies and who received both postnatal vaccination and post-vaccination prenatal screening (2566) were examined to assess seroconversion. 66.3% of women who were tested up to six months post-vaccination were seropositive, however only 36.9% of women tested after 36months were seropositive. Finally, 40.9% of all prenatal varicella specimens tested were deemed redundant, i.e. women had either a history of (1) ?2 doses of varicella vaccine, (2) varicella infection, or (3) a previous positive varicella serology. Eliminating this redundant screening could provide an estimated $96,000 in savings annually in laboratory and Public Health follow-up costs alone. As the number of women with vaccine-derived immunity through universal childhood vaccination increase in the prenatal population, screening methods may need to adapt to ensure varicella immunity is accurately conducted and assessed. PMID- 28017428 TI - The induction of CD80 and apoptosis on B cells and CD40L in CD4+ T cells in response to seasonal influenza vaccination distinguishes responders versus non responders in healthy controls and aviremic ART-treated HIV-infected individuals. AB - BACKGROUND: Studies have shown that HIV infection is associated with an impaired influenza vaccine response. We examined the role of cellular phenotypes and function in influenza vaccine responsiveness in healthy controls and aviremic HIV infected subjects on antiretroviral treatment (ART). METHODS: 16 healthy controls and 26 ART+ aviremic HIV+ subjects were enrolled in the current study. Blood was collected at pre-vaccination (D0), and on days 7-10 (D7) and 14-21 (D14) following the 2013-2014 seasonal influenza vaccine administrations. Subjects were classified as responders if neutralizing titers against H1N1 virus increased ?4 fold at D14 compared to D0. A serial analysis of B and CD4+ T cell frequencies and activation was performed on D0 and D7 by flow cytometry. RESULTS: 9 of 26 (34.6%) HIV-infected individuals and 7 of 16 (43.8%) healthy controls were classified as responders to influenza vaccines. Total B cell apoptosis (annexin V) was increased on D7 post-vaccination in non-responders but not in responders among both controls and HIV+ subjects. Surface CD80 expression on memory B cells and intracellular CD40L expression on memory CD4+ T cells were induced on D7 in responders of controls but not in non-responders. The CD80 and CD40L induction was not demonstrable in HIV-infected subjects regardless of responders and non responders. Memory CD4+ T cell cycling tended to increase on D7 in the four study groups but did not achieve significance. All the other parameters were indistinguishable between responders and non-responders, regardless of HIV infection status. CONCLUSION: The perturbation of activation and apoptotic induction on B cells or CD4+ T cells after seasonal influenza vaccination in non responders and HIV-infected subjects may help understand the mechanism of impaired vaccine responsiveness. PMID- 28017429 TI - Risk factors related to the failure of prevention of hepatitis B virus Mother-to Child transmission in Yunnan, China. AB - OBJECTIVE: To investigate the relationship between the failure of prevention of hepatitis B virus Mother-to-Child transmission and HBV serological pattern, viral load as well as HBV genotypes. METHODS: 2765 pairs of mother-infant matched samples were collected. These pregnant women were HBsAg positive and delivered at hospital from January 1st, 2011 to June 30th, 2011. Of these samples, 26 pairs of sera samples were randomly selected from 114 pairs of samples which failed in the prevention of hepatitis B virus Mother-to-Child transmission. Serological tests, viral load and genotype detection were performed for further analysis. Additionally, the selected subjects were followed and tested again in 2014. RESULTS: HBeAg positive rates were 76.92% and 69.23% in mother group and infant group respectively, showed no statistical difference. The average HBV DNA levels were >2*105IU/ml in both mother group and infant group. Genotype analysis revealed that 11 pairs of mother-infant matched samples belonged to C gene type and another 11 pairs were B gene type. Different genotypes were observed in 4 pairs of mother-infant matched samples. CONCLUSION: HbeAg positive and high HBV DNA level were two major risk factors of HBV mother to child transmission. Additionally, nosocomial infection was another potential way of HBV vertical transmission, especially in remote area of Yunnan province. PMID- 28017431 TI - WHO consultation on group B Streptococcus vaccine development: Report from a meeting held on 27-28 April 2016. AB - Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality assured standardized antibody assays to identify correlates of protection. PMID- 28017430 TI - A systems approach to vaccine decision making. AB - Vaccines reside in a complex multiscale system that includes biological, clinical, behavioral, social, operational, environmental, and economical relationships. Not accounting for these systems when making decisions about vaccines can result in changes that have little effect rather than solutions, lead to unsustainable solutions, miss indirect (e.g., secondary, tertiary, and beyond) effects, cause unintended consequences, and lead to wasted time, effort, and resources. Mathematical and computational modeling can help better understand and address complex systems by representing all or most of the components, relationships, and processes. Such models can serve as "virtual laboratories" to examine how a system operates and test the effects of different changes within the system. Here are ten lessons learned from using computational models to bring more of a systems approach to vaccine decision making: (i) traditional single measure approaches may overlook opportunities; (ii) there is complex interplay among many vaccine, population, and disease characteristics; (iii) accounting for perspective can identify synergies; (iv) the distribution system should not be overlooked; (v) target population choice can have secondary and tertiary effects; (vi) potentially overlooked characteristics can be important; (vii) characteristics of one vaccine can affect other vaccines; (viii) the broader impact of vaccines is complex; (ix) vaccine administration extends beyond the provider level; and (x) the value of vaccines is dynamic. PMID- 28017432 TI - Beyond cost-effectiveness: Using systems analysis for infectious disease preparedness. AB - Until the recent outbreaks, Ebola vaccines ranked low in decision makers' priority lists based on cost-effectiveness analysis and (or) corporate profitability. Despite a relatively small number of Ebola-related cases and deaths (compared to other causes), Ebola vaccines suddenly leapt to highest priority among international health agencies and vaccine developers. Clearly, earlier cost-effectiveness analyses badly missed some factors affecting real world decisions. Multi-criteria systems analysis can improve evaluation and prioritization of vaccine development and also of many other health policy and investment decisions. Neither cost-effectiveness nor cost-benefit analysis can capture important aspects of problems such as Ebola or the emerging threat of Zika, especially issues of inequality and disparity-issues that dominate the planning of many global health and economic organizations. Cost-benefit analysis requires assumptions about the specific value of life-an idea objectionable to many analysts and policy makers. Additionally, standard cost-effectiveness calculations cannot generally capture effects on people uninfected with Ebola for example, but nevertheless affected through such factors as contagion, herd immunity, and fear of dread disease, reduction of travel and commerce, and even the hope of disease eradication. Using SMART Vaccines, we demonstrate how systems analysis can visibly include important "other factors" and more usefully guide decision making and beneficially alter priority setting processes. PMID- 28017433 TI - Passive antibodies derived from intramuscularly immunized toxoid fusion 3xSTaN12S dmLT protect against STa+ enterotoxigenic Escherichia coli (ETEC) diarrhea in a pig model. AB - Enterotoxigenic Escherichia coli (ETEC) strains are among the most common causes of children's diarrhea and travelers' diarrhea. Developing effective vaccines against ETEC associated diarrhea becomes a top priority. ETEC heat-labile toxin (LT) and heat-stable toxin (STa) toxoid fusion 3xSTaN12S-dmLT was demonstrated recently to induce neutralizing antitoxin antibodies in intraperitoneally or subcutaneously immunized mice. However, whether antibodies derived from this toxoid fusion are protective against ETEC diarrhea has not been examined. In this study, we intramuscularly immunized pregnant gilts with toxoid fusion 3xSTaN12S dmLT, challenged suckling piglets with a STa-positive ETEC strain, and assessed protective efficacy of passive acquire antitoxin antibodies against ETEC diarrhea. Data showed all three immunized gilts developed anti-STa IgG and IgA antibodies, and piglets born to the immunized dams acquired anti-STa and anti-LT antibodies. When challenged with a STa+ ETEC strain, none of the piglets born to the immunized dams developed watery diarrhea, with 20 piglets remained normal and the other 8 piglets developed mild diarrhea indicated with stained butt. In contrast, the control dams and born piglets had no anti-STa or anti-LT antibodies detected, and 26 out 32 piglets developed watery diarrhea after challenge of the STa+ ETEC strain. These results indicated that passive acquired anti-STa antibodies are protective against ETEC diarrhea, and suggested potential application of toxoid fusion 3xSTaN12S-dmLT in ETEC vaccine development. PMID- 28017434 TI - Cost-effectiveness of increasing cervical cancer screening coverage in the Middle East: An example from Lebanon. AB - BACKGROUND: Most cervical cancer (CC) cases in Lebanon are detected at later stages and associated with high mortality. There is no national organized CC screening program so screening is opportunistic and limited to women who can pay out-of-pocket. Therefore, a small percentage of women receive repeated screenings while most are under-or never screened. We evaluated the cost-effectiveness of increasing screening coverage and extending intervals. METHODS: We used an individual-based Monte Carlo model simulating HPV and CC natural history and screening. We calibrated the model to epidemiological data from Lebanon, including CC incidence and HPV type distribution. We evaluated cytology and HPV DNA screening for women aged 25-65years, varying coverage from 20 to 70% and frequency from 1 to 5years. RESULTS: At 20% coverage, annual cytologic screening reduced lifetime CC risk by 14% and had an incremental cost-effectiveness ratio of I$80,670/year of life saved (YLS), far exceeding Lebanon's gross domestic product (GDP) per capita (I$17,460), a commonly cited cost-effectiveness threshold. By comparison, increasing cytologic screening coverage to 50% and extending screening intervals to 3 and 5years provided greater CC reduction (26.1% and 21.4, respectively) at lower costs compared to 20% coverage with annual screening. Screening every 5years with HPV DNA testing at 50% coverage provided greater CC reductions than cytology at the same frequency (23.4%) and was cost-effective assuming a cost of I$18 per HPV test administered (I$12,210/YLS); HPV DNA testing every 4years at 50% coverage was also cost effective at the same cost per test (I$16,340). Increasing coverage of annual cytology was not found to be cost-effective. CONCLUSION: Current practice of repeated cytology in a small percentage of women is inefficient. Increasing coverage to 50% with extended screening intervals provides greater health benefits at a reasonable cost and can more equitably distribute health gains. Novel HPV DNA strategies offer greater CC reductions and may be more cost effective than cytology. PMID- 28017435 TI - Informing vaccine decision-making: A strategic multi-attribute ranking tool for vaccines-SMART Vaccines 2.0. AB - SMART Vaccines 2.0 software is being developed to support decision-making among multiple stakeholders in the process of prioritizing investments to optimize the outcomes of vaccine development and deployment. Vaccines and associated vaccination programs are one of the most successful and effective public health interventions to prevent communicable diseases and vaccine researchers are continually working towards expanding targets for communicable and non communicable diseases through preventive and therapeutic modes. A growing body of evidence on emerging vaccine technologies, trends in disease burden, costs associated with vaccine development and deployment, and benefits derived from disease prevention through vaccination and a range of other factors can inform decision-making and investment in new and improved vaccines and targeted utilization of already existing vaccines. Recognizing that an array of inputs influences these decisions, the strategic multi-attribute ranking method for vaccines (SMART Vaccines 2.0) is in development as a web-based tool-modified from a U.S. Institute of Medicine Committee effort (IOM, 2015)-to highlight data needs and create transparency to facilitate dialogue and information-sharing among decision-makers and to optimize the investment of resources leading to improved health outcomes. Current development efforts of the SMART Vaccines 2.0 framework seek to generate a weighted recommendation on vaccine development or vaccination priorities based on population, disease, economic, and vaccine-specific data in combination with individual preference and weights of user-selected attributes incorporating valuations of health, economics, demographics, public concern, scientific and business, programmatic, and political considerations. Further development of the design and utility of the tool is being carried out by the National Vaccine Program Office of the Department of Health and Human Services and the Fogarty International Center of the National Institutes of Health. We aim to demonstrate the utility of SMART Vaccines 2.0 through the engagement of a community of relevant stakeholders and to identify a limited number of pilot projects to determine explicitly defined attribute preferences and the related data and model requirements that are responsive to user needs and able to improve the use of evidence for vaccine-related decision-making and consequential priorities of vaccination options. PMID- 28017437 TI - Introduction to the vaccine supplement. PMID- 28017436 TI - Moving beyond traditional valuation of vaccination: Needs and opportunities. AB - Economic evaluations of vaccination traditionally focus on a relatively narrow set of vaccine benefits, such as averted medical care costs among those who are immunized. In recent years, researchers have identified additional vaccination benefits that should be incorporated into economic evaluations in order to reflect vaccination's full value. Early efforts to estimate the magnitude of these broader benefits suggest that vaccination has been substantially undervalued, which has important implications for public and private vaccine policy and human health and welfare. More and better data will be required to advance this emerging line of research on the value of vaccination. The article discusses promising data sources and methods and research questions needing to be addressed. PMID- 28017438 TI - The role of vaccines and vaccine decision-making to achieve the goals of the Grand Convergence in public health. AB - On 17 and 18 July 2015, a meeting in Siena jointly sponsored by ADITEC and GlaxoSmithKline (GSK) was held to review the goals of the Global Health 2035 Grand Convergence, to discuss current vaccine evaluation methods, and to determine the feasibility of reaching consensus on an assessment framework for comprehensively and accurately capturing the full benefits of vaccines. Through lectures and workshops, participants reached a consensus that Multi-Criteria Decision-Analysis is a method suited to systematically account for the many variables needed to evaluate the broad benefits of vaccination, which include not only health system savings, but also societal benefits, including benefits to the family and increased productivity. Participants also agreed on a set of "core values" to be used in future assessments of vaccines for development and introduction. These values include measures of vaccine efficacy and safety, incident cases prevented per year, the results of cost-benefit analyses, preventable mortality, and the severity of the target disease. Agreement on this set of core assessment parameters has the potential to increase alignment between manufacturers, public health agencies, non-governmental organizations (NGOs), and policy makers (see Global Health 2035 Mission Grand Convergence [1]). The following sections capture the deliberations of a workshop (Working Group 4) chartered to: (1) review the list of 24 parameters selected from SMART vaccines (see the companion papers by Timmis et al. and Madhavan et al., respectively) to determine which represent factors (see Table 1) that should be taken into account when evaluating the role of vaccines in maximizing the success of the Global Health 2035 Grand Convergence; (2) develop 3-5 "core values" that should be taken into account when evaluating vaccines at various stages of development; and (3) determine how vaccines can best contribute to the Global Health 2035 Grand Convergence effort. PMID- 28017439 TI - What drivers will influence global immunizations in the era of grand convergence in global health? AB - Recent projections suggest that by 2035 global health will look dramatically different than it does today. In what's called a 'grand convergence' the world is likely to be characterized by far more similarities than differences in the prevailing health and medical problems across populations. This manuscript considers how key drivers for vaccine use and uptake might change as a result of the grand convergence and how decisions taken now might anticipate those changes in ways that position immunizations to continue playing an important role in the future. PMID- 28017440 TI - The role of the vaccines industry in Mission Grand Convergence. AB - The vast majority of vaccines used throughout the world are supplied by the private sector. It is essential therefore that the industry is closely engaged in future policy developments at a national and international level and is able to respond to the changing needs and priorities that may be required to ensure the success of Mission Grand Convergence. Uniquely, the major vaccine companies have the expertise and technical capacity to develop, produce and supply vaccines on a global scale. Through partnering with Governments, charities and NGOs, they must play a pivotal role in the Mission and, at the same time as agreeing on objectives that may not be entirely market driven, must be able to sustain their commercial obligations to shareholders. Similarly, small and medium sized companies, with the global investor market and government incentives that underpin and support them, also have a very important role to play; for example in innovation around a given disease and on technology, process and platform development across the whole value chain. The industry at large is therefore an essential player. Indeed Mission Grand Convergence can only succeed with the full and willing participation of the vaccines industry. PMID- 28017442 TI - Prioritizing vaccines for developing world diseases. AB - A major disparity in the burden of health will need to be addressed to achieve the "Grand Convergence" by 2035. In particular people living in low and middle income countries have a much higher burden of infectious diseases. Although vaccines have been very effective in reducing the global burden of infectious disease, there are no registered vaccines to address 60% of the current burden of infectious disease, especially in developing countries. Thus there is a pressing need for new vaccines and for prioritizing vaccine development given that resources for developing new vaccines are strictly limited. As part of the GLOBAL HEALTH 2035: Mission Grand Convergence meeting one working group assessed the SMART vaccine algorithm as a mechanism for prioritizing vaccine development for diseases of priority in the developing world. In particular, the working group considered which criteria in the standard SMART set were considered "key" criteria and whether other criteria should be considered, when prioritizing vaccines for this important set of countries. PMID- 28017441 TI - Extensive swelling of the limb and systemic symptoms after a fourth dose of acellular pertussis containing vaccines in England in children aged 3-6years. AB - Extensive limb swelling (ESL) after a booster dose of acellular pertussis (aP) containing vaccine can cause concern and has the potential to be confused with cellulitis. In the United Kingdom aP-containing vaccine was introduced for primary immunisation at 2, 3 and 4months of age in 2004, with the first cohorts eligible to receive a fourth dose in 2007 at school entry. We assessed the frequency of ESL (here defined as swelling >100mms diameter) in 973 children receiving a fourth dose of one of four aP vaccines given combined with inactivated polio, tetanus and either low dose diphtheria (TdaP/IPV) or high dose diphtheria (DTaP/IPV) vaccine; 2 of the 3 DTaP/IPV vaccines also contained Haemophilus influenza b conjugate vaccine (Hib). Post-vaccination symptoms and local reactions were recorded in 7-day diaries or by a telephone follow up if no diary was returned. Local swellings >50mm diameter were reported by 2.2% TdaP/IPV recipients compared with 6.6-11.1% of DTaP/IPV recipients; the corresponding proportions for redness >50mms was 7.0% for TdaP/IPV and 13.3-17.7% for DTaP/IPV recipients. Among the latter, the addition of Hib did not affect the frequency or size of local reactions. Pain at the injection site and systemic symptoms did not differ between the four vaccine groups. A history of atopy was not associated with development of local swelling or redness. A total of 13 children (1.3%) experienced an ESL, three after TdaP/IPV. ESLs resolved without systemic upset within a few days and were usually painless; medical advice was only sought for two children. Parents should be informed about the possible occurrence of an ESL with the pre-school aP-containing booster vaccine but can be reassured that it is a benign and transient condition. PMID- 28017443 TI - European strategy for vaccine development against infectious diseases. AB - Immunisation efforts save millions of lives every year, but vaccines hold the potential to deliver even greater health benefits for mankind. Vaccine research and development is highly complex, and it requires concerted public funding efforts to support. In this paper we discuss EU funding priorities and the resulting recent advancements in European vaccine research, and we lay out the EU strategy for aiding promising vaccine candidates to successfully reach the market. PMID- 28017444 TI - Planning and priority setting for vaccine development and immunization. AB - We review a sequence of strategic planning efforts over time in the United States, all involving processes to prioritize new vaccine candidates. The Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine has been involved in three priority setting processes, each using different metrics and methodologies: infant mortality equivalents (1985-1986), cost-effectiveness (2000), and more recently, the implementation of a software system based on a broader multi-criteria systems approach that can include either of the earlier metrics among other various considerations (2015). The systems approach offers users the flexibility to select, combine, rank, weigh and evaluate different attributes representing their perspectives, assumptions, and particular needs. This approach also overcomes concerns relating to the previous single-metric ranking approaches that yielded lists that, once published, were static, and could not readily accommodate new information about emerging pathogens, new scientific advances, or changes in the costs and performance features of interventions. We discuss the rationale and reasoning behind the design of this multi-criteria decision support approach, stakeholder feedback about the tool, and highlight the potential advantages from using this expanded approach to better inform and support vaccine policies. PMID- 28017445 TI - Core values for vaccine evaluation. AB - Currently, most health economic modelling approaches tend to inadequately incorporate crucial disease-specific criteria and other attributes of benefit resulting from vaccination, which limits their utility for evaluating vaccines and, in consequence, for optimally guiding vaccine decision-making. Additionally, vaccine evaluation methods are frequently poorly standardised and non transparent, leading to a potentially low level of accountability that can hinder acceptance of resulting decisions. To address these issues, we have considered whether it is possible to identify a set of universal vaccine-disease considerations, which we have called Core Values. To begin to identify such a set of criteria, and to establish whether strong agreement around such core values exists, we conducted two studies based on the Delphi technique. Both studies surveyed a cohort consisting of expert members of the global vaccine community with diverse professional backgrounds. Formal statistical analysis of both studies identified four attributes with strong agreement: 1. Incidence disease cases prevented per year, 2. Cost-effectiveness (including cost-benefit and cost utility analysis), 3. High mortality disease (case-fatality-rate), and 4. Severity of target disease (risk of morbidity and mortality). These results suggest the feasibility of identifying a clear consensus on a specific set of Core Values for Vaccine Evaluation. PMID- 28017446 TI - Corrigendum to "Direct and indirect photodegradation pathways of cytostatic drugs under UV germicidal irradiation: Process kinetics and influences of water matrix species and oxidant dosing" [J. Hazard. Mater. (2016) http://dx.doi.org/10.1016/j.jhazmat.2016.11.016]. PMID- 28017447 TI - Association between cachexia, chemotherapy and outcomes in older cancer patients: A systematic review. AB - BACKGROUND & AIMS: The aims of this systematic review were (i) to determine the prevalence of malnutrition and cachexia in older cancer patients in a chemotherapy setting, and (ii) to report the chemotherapy-related causes of malnutrition and (iii) the consequences of malnutrition on the outcomes of these patients. METHODS: We searched MEDLINE for articles published in English or French between 2005 and 2016 and which reported retrospective or prospective, observational or interventional studies of the prevalence of malnutrition and its consequences in patients 65 years or older with solid tumors and chemotherapy related causes of malnutrition. RESULTS AND CONCLUSION: Malnutrition is prevalent up to 83% in older patients with cancer scheduled to receive chemotherapy. One third or more of patients were malnourished before receiving chemotherapy. A weight loss of 10% or more during the past three or six months was reported in 8% 40% of cancer patients, while a body mass index <21 kg/m2 was found in 10.7%-23%. Malnutrition was more prevalent in digestive (28%-75%) than in non-digestive cancers (8%-46.9%), and also in metastatic cancers (64%-76.5%). During the course of chemotherapy, weight loss was observed in 40%-91.6% of patients, depending on cancer location. The most frequently reported chemotherapy-related digestive symptoms likely to impair nutritional status were dry mouth, nausea, stomach pain, diarrhea and constipation. Low Mini-Nutritional-Assessment score was an independent predictor of early discontinuation of chemotherapy and increased the risk of mortality. PMID- 28017448 TI - 25-Hydroxyvitamin D concentrations, asthma and eczema in childhood: The generation R study. AB - BACKGROUND & AIMS: A role of vitamin D in the development of respiratory and allergic disease in children remains unclear. It may be likely that vitamin D has an effect on airway inflammation, but only few studies examined the effect in children. We aimed to examine whether serum 25-hydroxyvitamin D (25(OH) vitamin D) concentrations are associated with the fraction of exhaled nitric oxide (FeNO), airway interrupter resistance (Rint), physician diagnosed asthma ever, wheezing and eczema in a population-based cohort study in 6 year old children. METHODS: Serum 25(OH) vitamin D concentration was assessed in 3815 children. 25(OH) vitamin D concentrations >=75 nmol/L were considered as sufficient, between 50 and 75 nmol/L as insufficient, and <50 nmol/L as deficient. FeNO and Rint were measured at the research center. Data on physician diagnosed asthma, wheezing, and eczema were obtained by parent-reported questionnaires. RESULTS: In comparison with sufficient 25(OH) vitamin D concentration, deficient concentrations were associated with elevated FeNO of >=25 ppb (OR: 2.54; 95% CI: 1.34-4.80). In addition, deficient and insufficient 25(OH) vitamin D concentrations were associated with a lower Rint (Z-score: -1.26; 95% CI: -1.66 to -0.85) (beta: -0.75; 95% CI: -1.08 to -0.42), and increased risks of eczema (OR: 1.65; 95% CI: 1.13-2.41) (OR: 1.44; 95% CI: 1.06-1.95). Insufficient 25(OH) vitamin D concentration were associated with a decreased risk of physician diagnosed asthma ever (OR: 0.59; 95% CI: 0.38-0.94). CONCLUSIONS: Our results indicate that lower 25(OH) vitamin D levels are associated with elevated FeNO levels, but lower Rint values. Lower 25(OH) vitamin D levels are also associated with a decreased risk for asthma diagnoses but an increased risk for eczema. PMID- 28017449 TI - Anabolic resistance does not explain sarcopenia in patients with type 2 diabetes mellitus, compared with healthy controls, despite reduced mTOR pathway activity. AB - BACKGROUND: Ageing and type 2 diabetes mellitus (T2DM) are risk factors for skeletal muscle loss. We investigated whether anabolic resistance to feeding might underlie accelerated muscle loss in older people with T2DM and whether dysregulated mTOR signalling was implicated. SUBJECTS: 8 obese men with T2DM, and 12 age-matched controls were studied (age 68 +/- 3 vs. 68+/-6 y; BMI: 30 +/- 2 vs. 27 +/- 5 kg m-2). METHODS: Body composition was measured by dual-X-ray absorptiometry. Insulin and glucose were clamped at post-absorptive concentrations (13 +/- 2 vs. 9 +/- 3 mU l-1; 7.4 +/- 1.9 vs. 4.6 +/- 0.4 mmol l 1; T2DM vs. controls). Fractional synthetic rates (FSR) of myofibrillar and sarcoplasmic proteins were measured as the rate of incorporation of [13C] leucine during a primed, constant infusion of [1-13C] alpha-ketoisocaproic acid, 3 h after 10 or 20 g of essential amino acids (EAA) were orally administered. Protein expression of total and phosphorylated mTOR signalling proteins was determined by Western blot analysis. RESULTS: Despite a significantly lower appendicular lean mass index and a greater fat mass index in T2DM vs. controls, basal myofibrillar and sarcoplasmic and post-prandial myofibrillar FSR were similar. After 20 g EAA, stimulation of sarcoplasmic FSR was slightly blunted in T2DM patients. Furthermore, feeding 20 g EAA increased phosphorylation of mTOR, p70S6k and 4E BP1 by 60-100% in controls with no response observed in T2DM. CONCLUSIONS: There was clear dissociation between changes in mTOR signalling versus changes in protein synthesis rates. However, the intact anabolic response of myofibrillar FSR to feeding in both groups suggests anabolic resistance may not explain accelerated muscle loss in T2DM. PMID- 28017450 TI - Prevalence of stroke-related sarcopenia and its association with poor oral status in post-acute stroke patients: Implications for oral sarcopenia. AB - BACKGROUND & AIMS: The aim of the study was to investigate the prevalence of stroke-related sarcopenia and its association with poor oral status in post-acute stroke patients. METHODS: This cross-sectional study included 202 consecutive stroke patients who were admitted to convalescent rehabilitation wards in Japan. The Revised Oral Assessment Guide (ROAG) was used to assess oral status. Sarcopenia was defined as a loss of skeletal muscle mass index (SMI) with bioelectrical impedance and decreased muscle strength as measured by handgrip strength; cut-off values were adopted from the Asian Working Group for Sarcopenia. Univariate and multivariate analyses were applied to examine the associations between oral status, SMI, and HG. RESULTS: Study participants included 107 males and 95 females with a mean age of 72 +/- 12 years. According to the ROAG, 82.2% of participants had slight to severe oral problems (median score: 11 [9-14]). The prevalence of stroke-related sarcopenia was 53.5%. Both SMI (mean: 6.1 +/- 1.3) and handgrip strength (median: 15 [7-25]) were significantly lower in the group with oral problems (SMI = 5.8 +/- 1.2, handgrip strength = 12 [6-20]) compared to individuals without oral problems (SMI = 7.4 +/ .8, handgrip strength = 27 [23-34]) (p < .001). The ROAG score was independently associated with SMI and handgrip strength, after adjusting for sex, age, stroke severity, activities of daily living, cognitive level, nutritional status, comorbidities, and time from stroke onset. CONCLUSIONS: Poor oral status was associated with sarcopenia, reduced muscle mass and strength in post-acute stroke patients. Poor oral status and stroke-related sarcopenia were very common among the patients in this study, suggesting that healthcare providers should monitor for oral sarcopenia in post-acute stroke patients. PMID- 28017451 TI - Cholesterol-loaded cyclodextrin improves ram sperm cryoresistance in skim milk extender. AB - Cholesterol-loaded cyclodextrin (CLC) is known to improve ram sperm cryosurvival. This study expands on previous research to: (1) determine the mechanism by which CLC improves ram sperm cryosurvival and (2) compare the efficiency of a novel, skim milk-based extender containing CLC to a traditional egg yolk-based extender. Hypothesis #1 was that CLC enhances membrane cholesterol content to increase the resistance of ram sperm to cold and osmotic stress, thereby improving cryosurvival. We first assessed the ability of fresh sperm treated with CLC to withstand cold shock. Second, fresh sperm were treated with CLC to evaluate their tolerance to osmotic stress. Third, to confirm that cholesterol is incorporated into the sperm using CLC, we quantified sperm cholesterol. To test Hypothesis #2 that CLC is most effective in a medium without competing cholesterol, we compared sperm cryosurvival and fertility in skim milk-based extender containing CLC versus in a traditional egg yolk-based freezing extender without CLC. Our data confirmed that CLC treatment improves ram sperm cold shock and osmotic stress resistance, and augments sperm cholesterol content. Semen in skim milk-based extender containing CLC prior to freezing, had more motile sperm with intact acrosomes after thawing compared to semen in egg yolk-based extender. In contrast, sperm plasma membrane integrity and in vivo fertility of the semen cryopreserved in the skim milk-based extender with CLC did not differ from semen that was cryopreserved in egg yolk-based extender. Further research is warranted to combine CLC with other cryoprotection strategies or to modify the insemination protocol. PMID- 28017452 TI - The Ecology and Evolution of Stoichiometric Phenotypes. AB - Ecological stoichiometry has generated new insights into how the balance of elements affects ecological interactions and ecosystem processes, but little is known about the ecological and evolutionary dynamics of stoichiometric traits. Understanding the origins and drivers of stoichiometric trait variation between and within species will improve our understanding about the ecological responses of communities to environmental change and the ecosystem effects of organisms. In addition, studying the plasticity, heritability, and genetic basis of stoichiometric traits might improve predictions about how organisms adapt to changing environmental conditions, and help to identify interactions and feedbacks between phenotypic evolution and ecosystem processes. PMID- 28017453 TI - Risk factors for equine fractures in Thoroughbred flat racing in North America. AB - The aim of this paper is to identify risk factors associated with equine fractures in flat horse racing of Thoroughbreds in North America. Equine fractures were defined as any fracture sustained by a horse during a race. This was a cohort study that made use of all starts from the racecourses reporting injuries. The analysis was based on 2,201,152 racing starts that represent 91% of all official racing starts in the USA and Canada from 1st January 2009-31st December 2014. Approximately 3,990,000 workout starts made by the 171,523 Thoroughbreds that raced during that period were also included in the analysis. During this period the incidence of equine fractures was 2 per 1000 starts. The final multivariable logistic regression models identified risk factors significantly associated (p<0.05) with equine fracture. For example, horses were found to have a 32% higher chance of sustaining a fracture when racing on a dirt surface compared to a synthetic surface; a 35% higher chance if they had sustained a previous injury during racing and a 47% higher chance was also found for stallions compared to mares and geldings. Furthermore, logistic regression models based on data available only from the period 2009-2013 were used to predict the probability of a Thoroughbred sustaining a fracture for 2014. The 5% of starts that had the highest score in our predictive models for 2014 were found to have 2.4 times (95% CI: 1.9-2.9) higher fracture prevalence than the mean fracture prevalence of 2014. The results of this study can be used to identify horses at higher risk on entering a race and could help inform the design and implementation of preventive measures aimed at minimising the number of Thoroughbreds sustaining fractures during racing in North America. PMID- 28017454 TI - Assessment of factors influencing the within-batch seroprevalence of human enteropathogenic Yersinia spp. of pigs at slaughter age and the analogy with microbiology. AB - The microbiologically and serologically-based prevalence of human enteropathogenic Yersinia spp. at moment of slaughter varies between pig farms due to different herd-level factors. A face-to-face questionnaire concerning a broad range of farm aspects (e.g., management and housing system, biosecurity, and hygiene measurements) was performed on one hundred farms. Factors influencing the seropositivity of 7047 pigs against human pathogenic Yersinia spp. were determined and compared to the microbiology. At the slaughterhouse, pieces of diafragm of on average 70 slaughter pigs per batch were sampled to determine the level of antibodies against enteropathogenic Yersinia spp. After univariable mixed-effect logistic regressions, variables that were related to the seropositivity (p<0.05) were included in a multivariable model (p<0.1). The factors remaining significantly associated in the latter model were an increasing number of piglet suppliers (zero up to eleven suppliers) (Odds Ratio=1.4), a high density of pig farms in the area (high versus low density) (Odds Ratio=2.3), the use of semislatted floors in the fattening pig unit (semi slatted floor versus fully slatted floor) (Odds Ratio=3.8) and the possibility of snout contact in the fattening pig unit (snout contact or not) (Odds Ratio=0.1). Decreasing the risk of infection with human enteropathogenic Yersinia spp. at moment of slaughter or during rearing is possible by changing farm management factors. PMID- 28017455 TI - Guidelines for the Treatment of Smoking in Hospitalized Patients. AB - Between 15 and 27% of patients admitted to Spanish hospitals are smokers. Hospitalization is an ideal time for a smoker to decide to quit. We performed a MEDLINE search of controlled, randomized or observational studies associated with helping hospitalized patients quit smoking, published between January 1, 2002 and September 30, 2015. On the basis of the results of those studies, we have issued some recommendations for the treatment of smoking in hospitalized patients. The recommendations were drawn up according to the GRADE system. Offering the smoker psychological counselling and prolonging follow-up for at least 4 weeks after discharge is the most effective recommendation for helping hospitalized patients to quit. PMID- 28017456 TI - Diagnosis of endolymphatic hydrops by means of 3T magnetic resonance imaging after intratympanic administration of gadolinium. AB - OBJECTIVE: To detect and graduate endolymphatic hydrops or endolymphatic space dilations in patients with suspected Meniere's disease or immune-mediated inner ear disease by magnetic resonance imaging. MATERIAL AND METHODS: A prospective study was performed including all the patients with clinical suspicion of Meniere's disease or immune-mediated inner ear disease treated at the Otolaryngology department during a one year period. In all cases, magnetic resonance imaging (MRI) was performed in a 3T scanner. IR sequence was performed after 24 to 28h prior intratimpanic injection of gadolinium on both ears. Two neurorradiologist graduated endolymphatic space volume as agreed on normal, moderate and significant in the obtained images. RESULTS: The presence of hydrops was documented by MRI in six patients with definite or probable Meniere's disease. In two of the four cases without vertigo hydrops was not demonstrated. In the other two cases with a high clinical suspicion of immune-mediated disease but with negative autoimmune tests hydrops was proved. There was only disagreement on cochlear hydrops presence on two patients. CONCLUSION: The detection of endolymphatic hydrops in patients with definite or probable Meniere's disease served to confirm the final diagnosis. Moreover, hydrops was detected in patients with suspected immune-mediated inner ear disease, which could have an impact on the diagnosis and treatment of these patients. Therefore, we suggest that this test could be included for the diagnosis of these inner ear diseases. PMID- 28017457 TI - ALPPS: The argument for. PMID- 28017458 TI - Specific adverse events are associated with response to exemestane therapy in postmenopausal breast cancer patients: Results from the TEAMIIA study (BOOG2006 04). AB - PURPOSE: In the adjuvant setting, specific adverse events (AEs) such as vasomotor symptoms (VMS) and musculoskeletal AEs are associated with relapse-free survival in aromatase inhibitor (AI)-treated patients. In the neoadjuvant setting, specific AEs may be associated with tumor response to AIs as well. METHODS: Between 2007 and 2012, 107 patients participated in the prospective TEAMIIA trial, a prospective, phase II trial investigating 6 months of neoadjuvant exemestane in patients with strongly ER-positive breast cancer. Radiological response (>=30% decrease in tumor size) was studied in relation to VMSs and MSAEs. Pearson's Chi-Square tests and multivariate logistic regression analyses were used to evaluate of statistical significance (p < 0.05). RESULTS: Out of 102 patients 26 patients (25.4%) experienced at least one episode of VMS and 27 patients (26.4%) experienced MSAE. Out of 240 reported adverse events, 71 were specific AEs (40 MSAEs, 31 VMSs). Radiological response was greater in patients who reported VMSs compared to patients who did not (70.8% vs. 49.3%, multivariate OR 2.91, 95% C.I. 1.03-8.26, P = 0.045). No significant advantage towards better response was observed in patients who experienced MSAEs (60.0% vs. 53.3%, univariate OR 1.33, 95% C.I. 0.53-3.38, P = 0.545). CONCLUSION: VMSs are associated with tumor response to neoadjuvant exemestane and may be useful for predicting treatment outcomes of AI treatment at an early stage in patients treated with neoadjuvant AIs. PMID- 28017459 TI - Translational Research - The Panoramic Scope of Pediatric Nursing and New Horizons for Improving the Health of Children, Adolescents, and Their Families. PMID- 28017460 TI - Vocal Tract Adjustments of Dysphonic and Non-Dysphonic Women Pre- and Post Flexible Resonance Tube in Water Exercise: A Quantitative MRI Study. AB - OBJECTIVE: To compare vocal tract (VT) adjustments of dysphonic and non-dysphonic women before and after flexible resonance tube in water exercise (FRTWE) at rest and during phonation using magnetic resonance imaging. STUDY DESIGN: Prospective study. METHODS: Twenty women, aged 20-40 years, 10 dysphonic with vocal nodules (VNG) and 10 controls (CG), underwent four sets of sagittal VT MRI: two pre FRTWE, at rest and during phonation, and two post-FRTWE, during phonation and at rest. The subjects performed 3 minutes of exercise. Nine parameters at rest and 21 during phonation were performed. RESULTS: Pre-FRTWE, eight significant differences were found, three at rest and five during phonation: at rest - laryngeal vestibule area, distance from epiglottis to pharyngeal posterior wall (PPW) and interarytenoid complex length were smaller in the VNG; during phonation - laryngeal vestibule area, angle between PPW and vocal fold (VF), epiglottis to PPW, and anterior commissure of the larynx to laryngeal posterior wall were smaller in the VNG; tongue area was larger in the VNG. Post-FRTWE, only three significant differences were found, two during phonation and one at rest: during phonation - angle between PPW and VF and the membranous portion of the VF length were smaller in the VNG; at rest - distance from epiglottis to PPW was smaller in the VNG. CONCLUSIONS: Results suggest that the habitual VT adjustments of dysphonic and non-dysphonic women are different at rest and during phonation. The FRTWE promoted positive VT changes in the VNG, reducing the intergroup differences. PMID- 28017461 TI - Comparing Chalk With Cheese-The EGG Contact Quotient Is Only a Limited Surrogate of the Closed Quotient. AB - The electroglottographic (EGG) contact quotient (CQegg), an estimate of the relative duration of vocal fold contact per vibratory cycle, is the most commonly used quantitative analysis parameter in EGG. The purpose of this study is to quantify the CQegg's relation to the closed quotient, a measure more directly related to glottal width changes during vocal fold vibration and the respective sound generation events. Thirteen singers (six females) phonated in four extreme phonation types while independently varying the degree of breathiness and vocal register. EGG recordings were complemented by simultaneous videokymographic (VKG) endoscopy, which allows for calculation of the VKG closed quotient (CQvkg). The CQegg was computed with five different algorithms, all used in previous research. All CQegg algorithms produced CQegg values that clearly differed from the respective CQvkg, with standard deviations around 20% of cycle duration. The difference between CQvkg and CQegg was generally greater for phonations with lower CQvkg. The largest differences were found for low-quality EGG signals with a signal-to-noise ratio below 10 dB, typically stemming from phonations with incomplete glottal closure. Disregarding those low-quality signals, we found the best match between CQegg and CQvkg for a CQegg algorithm operating on the first derivative of the EGG signal. These results show that the terms "closed quotient" and "contact quotient" should not be used interchangeably. They relate to different physiological phenomena. Phonations with incomplete glottal closure having an EGG signal-to-noise ratio below 10 dB are not suited for CQegg analysis. PMID- 28017462 TI - Strain-Initialized Robust Bone Surface Detection in 3-D Ultrasound. AB - Three-dimensional ultrasound has been increasingly considered as a safe radiation free alternative to radiation-based fluoroscopic imaging for surgical guidance during computer-assisted orthopedic interventions, but because ultrasound images contain significant artifacts, it is challenging to automatically extract bone surfaces from these images. We propose an effective way to extract 3-D bone surfaces using a surface growing approach that is seeded from 2-D bone contours. The initial 2-D bone contours are estimated from a combination of ultrasound strain images and envelope power images. Novel features of the proposed method include: (i) improvement of a previously reported 2-D strain imaging-based bone segmentation method by incorporation of a depth-dependent cumulative power of the envelope into the elastographic data; (ii) incorporation of an echo decorrelation measure-based weight to fuse the strain and envelope maps; (iii) use of local statistics of the bone surface candidate points to detect the presence of any bone discontinuity; and (iv) an extension of our 2-D bone contour into a 3-D bone surface by use of an effective surface growing approach. Our new method produced average improvements in the mean absolute error of 18% and 23%, respectively, on 2-D and 3-D experimental phantom data, compared with those of two state-of-the art bone segmentation methods. Validation on 2-D and 3-D clinical in vivo data also reveals, respectively, an average improvement in the mean absolute fitting error of 55% and an 18-fold improvement in the computation time. PMID- 28017463 TI - Monitoring of anti-Xa activity and factors related to bleeding events: A study in Japanese patients with nonvalvular atrial fibrillation receiving rivaroxaban. AB - BACKGROUND: Anti-Xa activity (AXA) in patients with nonvalvular atrial fibrillation (NVAF) and relationship to bleeding events remains unclear. METHODS: We evaluated AXA in 94 patients at both trough and peak rivaroxaban concentrations. Rivaroxaban dosage was determined according to creatinine clearance (CrCl): 10 and 15mg once daily for patients with CrCl 15-49 and CrCl >=50mL/min, respectively. AXA value distribution and its association with bleeding events were examined in enrolled subjects. RESULTS: The mean peak AXA level was significantly higher than the mean trough level (1.98+/-0.81 vs. 0.16+/ 0.15IU/mL; p<0.001). The peak AXA level significantly differed among patients with CrCl 15-29, 30-49, 50-79, and >=80mL/min (2.51+/-0.83, 1.72+/-0.76, 2.05+/ 0.82, and 1.66+/-0.51IU/mL, respectively; p=0.004). Major and non-major clinically relevant bleeding events occurred in 22 patients (23.4% and 14.6% per year, respectively). The mean peak AXA level was significantly higher in patients who experienced bleeding events than in those who did not (2.40+/-0.70 vs. 1.84+/ 0.80IU/mL; p=0.001). A Cox multivariate analysis showed that the peak AXA level was independently related to the incidence of major and non-major clinically relevant bleeding events (p=0.012). Cumulative bleeding rates were significantly higher in patients with high peak AXA levels (p<0.001). CONCLUSION: Peak AXA level was an independent predictor for bleeding events in Japanese NVAF patients receiving rivaroxaban. PMID- 28017464 TI - A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules. AB - Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological, and mathematical) methods for material (e.g., materials, intermediates, products) and process (e.g., temperature, pressure, throughput, etc.) analysis. This supports rational process modeling and enhanced control strategies for improved product quality and process efficiency. Therefore, it is often difficult to orient and find the relevant, integrated aspects of the current state-of-the-art. Especially, the link between fundamental research, in terms of sensor and control system development, to the application both in laboratory and manufacturing scale, is difficult to comprehend. This review compiles a nonexhaustive overview on current approaches from the recognized academia and industrial practices of PAT, including screening, selection, and final implementations in solid oral dosage manufacturing, through a wide diversity of use cases. Finally, the authors attempt to extract a common consensus toward developing PAT application guidance for different unit operations of drug product manufacturing. PMID- 28017465 TI - Refractory hypoxemic respiratory failure from metal fume inhalation: Emergency department procedures. PMID- 28017466 TI - Trazodone utilization among the elderly in Spain. A population based study. AB - INTRODUCTION: Trazodone was authorized for the treatment of depression in the 1970s. Several additional therapeutic uses have been proposed due to its heterogeneous mechanism. This study aims to determine the use of trazodone in the elderly in Spain. METHODS: A nationwide, longitudinal and descriptive analysis was conducted using data from patients aged >65 years with a first prescription of trazodone during the period 2002-2011. Information on dose, comorbidities and relevant co-medication was gathered from the Spanish Primary Care database BIFAP. Incidence rates of trazodone use per 10,000 person-years were calculated by sex and age. RESULTS: A total of 11,766 patients receiving a first prescription of trazodone were included. The incidence rate of trazodone use was 47.2 (95% CI: 46.33-48.04) per 10,000 person-years. An increasing trend in the use of trazodone was observed (5-fold increase in 2011 as compared to 2002). The most common therapeutic indications were: depression (21.41%), Alzheimer/dementia (20.36%), sleep disorders (16.22%), and anxiety disorder (8.91%). The median dose was 100mg/day. The use of trazodone concomitantly with interacting medicines was frequent: anti-hypertensives (53.60%), and CNS depressors (59.32%). CONCLUSIONS: Trazodone use is increasing in elderly patients, and a high proportion of use in non-approved indications was observed. Trazodone is not being used at high doses, but interacting medicines were frequent, and it may pose additional risks for elderly patients. PMID- 28017467 TI - Translation and validation of the Spanish version of the Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD). AB - INTRODUCTION: The Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD) is a brief instrument that assesses functioning in people with intellectual development disorder and mental health problems/behaviour disorders. The aim of the present study was to examine the evidence on the validity of the scores based on the Spanish version of the HoNOS-LD. MATERIAL AND METHODS: The study included 111 participants that were assessed by the Spanish version of the HoNOS-LD and other questionnaires that measured different variables related to the scale. Thirty-three participants were assessed by 2 examiners, and retested 7 days later, in order to study inter-examiner reliability and test-retest reliabilities. RESULTS: Based on clinical and conceptual criteria, and on the results of the parallel analysis, a factorial solution with one factor was selected. Internal consistency was good (Omega coefficient of 0.87). Inter-examiner and test-retest reliabilities were excellent (intraclass correlation coefficients of 0.95 and 0.98, respectively). Correlations between sections of the HoNOS-LD and the related instruments showed the expected direction, and were highly significant (P<.001), and the HoNOS-LD score increased with the intensity of the support required by the participants. These results showed evidence of the validity of association with other external variables. CONCLUSIONS: The Spanish version of the HoNOS-LD is a brief, valid and reliable instrument, which will enable a routine assessment of functioning for different uses, including diagnosis and intervention. PMID- 28017468 TI - All-Suture Anchors: Biomechanical Analysis of Pullout Strength, Displacement, and Failure Mode. AB - PURPOSE: To evaluate the biomechanical and design characteristics of all-suture anchors. METHODS: All-suture anchors were tested in fresh porcine cortical bone and biphasic polyurethane foam blocks by cyclic loading (10-100 N for 200 cycles), followed by destructive testing parallel to the insertion axis at 12.5 mm/s. Endpoints included ultimate failure load, displacement at 100 and 200 cycles, stiffness, and failure mode. Anchors tested included JuggerKnot (1.4, 1.5, and 2.8), Iconix (1, 2, and 3), Y-knot (1.3, 1.8, and 2.8), Q-Fix (1.8 and 2.8), and Draw Tight (1.8 and 3.2). RESULTS: The mean ultimate failure strength of the triple-loaded anchors (564 +/- 42 N) was significantly greater than the mean ultimate failure strength of the double-loaded anchors (465 +/- 33 N) (P = .017), and the double-loaded anchors were stronger than the single-loaded anchors (256 +/- 35 N) (P < .0001). No difference was found between the results in porcine bone and biphasic polyurethane foam. None of these anchors demonstrated 5 mm or 10 mm of displacement during cyclic loading. The Y-Knot demonstrated greater displacement than the JuggerKnot and Q-Fix (P = .025) but not the Iconix and Draw Tight (P > .05). The most common failure mode varied and was suture breaking for the Q-Fix (97%), JuggerKnot (81%), and Iconix anchors (58%), anchor pullout with the Draw Tight (76%), whereas the Y-Knot was 50% suture breaking and 50% anchor pullout. CONCLUSIONS: The ultimate failure load of an all-suture anchor is correlated directly with its number of sutures. With cyclic loading, the Y-Knot demonstrated greater displacement than the JuggerKnot and Q-Fix but not the Iconix and Draw Tight. JuggerKnot (81%) and Q-Fix (97%) anchors failed by suture breaking, whereas the Draw Tight anchor failed by anchor pullout (76%). CLINICAL RELEVANCE: All-suture anchors vary in strength and performance, and these factors may influence clinical success. Biphasic polyurethane foam is a validated model for suture anchor testing. PMID- 28017469 TI - Distal Tibia Allograft Glenoid Reconstruction in Recurrent Anterior Shoulder Instability: Clinical and Radiographic Outcomes. AB - PURPOSE: To assess the clinical and radiographic outcomes of patients with recurrent anterior shoulder instability treated with fresh distal tibia allograft (DTA) glenoid reconstruction. METHODS: Consecutive patients with a minimum 15% anterior glenoid bone loss associated with recurrent anterior instability who underwent stabilization with DTA glenoid reconstruction were retrospectively reviewed. Patients were evaluated with the American Shoulder and Elbow Society score, Western Ontario shoulder instability index, and single numerical assessment evaluation score at a minimum 2 years after surgery. All patients also underwent postoperative imaging evaluation with computed tomography where graft incorporation and allograft angle were measured. Statistical analysis was performed with paired t-tests, with P < .05 considered significant. RESULTS: A total of 27 patients (100% male) with an average age of 31 +/- 5 years and an average follow-up of 45 months (range, 30-66) were included. There were significant improvements in preoperative to postoperative American Shoulder and Elbow Society score (63-91, P < .01), Western Ontario shoulder instability index (46% to 11% of normal, P < .01), and single numerical assessment evaluation score (50-90.5, P < .01) outcomes. Analysis of computed tomography data at an average 1.4 years postoperatively (available for 25 patients) showed an allograft healing rate of 89% (range, 80% to 100%), average allograft angle of 14.9 degrees (range, 6.6 degrees to 29.3 degrees ), and average allograft lysis of 3% (range, 0% to 25%). Grafts with lesser allograft angles (<15 degrees ) were better opposed to the anterior glenoid, showing superior healing and graft incorporation. There were no cases of recurrent instability. CONCLUSIONS: At an average follow-up of 45 months, fresh DTA reconstruction for recurrent anterior shoulder instability results in a clinically stable joint with excellent clinical outcomes and minimal graft resorption. Optimal allograft placement resulted in superior bony incorporation with the native glenoid. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28017470 TI - A Central Amygdala CRF Circuit Facilitates Learning about Weak Threats. AB - Fear is a graded central motive state ranging from mild to intense. As threat intensity increases, fear transitions from discriminative to generalized. The circuit mechanisms that process threats of different intensity are not well resolved. Here, we isolate a unique population of locally projecting neurons in the central nucleus of the amygdala (CeA) that produce the neuropeptide corticotropin-releasing factor (CRF). CRF-producing neurons and CRF in the CeA are required for discriminative fear, but both are dispensable for generalized fear at high US intensities. Consistent with a role in discriminative fear, CRF neurons undergo plasticity following threat conditioning and selectively respond to threat-predictive cues. We further show that excitability of genetically isolated CRF-receptive (CRFR1) neurons in the CeA is potently enhanced by CRF and that CRFR1 signaling in the CeA is critical for discriminative fear. These findings demonstrate a novel CRF gain-control circuit and show separable pathways for graded fear processing. PMID- 28017471 TI - The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy. AB - The neuromuscular disorder spinal muscular atrophy (SMA), the most common inherited killer of infants, is caused by insufficient expression of survival motor neuron (SMN) protein. SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression. We identified a long non coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2. Targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice. This study is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 can be combined with SMN2 splicing modification to ameliorate SMA and demonstrates the promise of combinatorial ASOs for the treatment of neurogenetic disorders. PMID- 28017473 TI - Huntingtin-Mediated Multipolar-Bipolar Transition of Newborn Cortical Neurons Is Critical for Their Postnatal Neuronal Morphology. AB - In the developing cortex, projection neurons undergo multipolar-bipolar transition, radial-directed migration, and maturation. The contribution of these developmental steps to the structure of the adult cortex is not completely understood. Here, we report that huntingtin (HTT), the protein mutated in Huntington's disease, is enriched in polarizing projection neurons. The depletion of HTT in postmitotic projection neurons leads to the mislocalization of layer specific neuronal populations in the mouse neocortex. HTT is required for the multipolar-bipolar transition of projection neurons and for the maintenance of their bipolar shape during their radial migration. HTT mediates these effects in vivo through the regulation of RAB11-dependent N-Cadherin trafficking. Importantly, HD pathological HTT alters RAB11-dependent neuronal migration. Finally, we show that the cortical defects resulting from the postmitotic loss of HTT specifically during embryonic development affect neuronal morphology at adulthood. Our data reveal a new HTT-RAB11-N-Cadherin pathway regulating multipolar-bipolar transition with direct implications for mature brain. VIDEO ABSTRACT. PMID- 28017472 TI - Loss of Nardilysin, a Mitochondrial Co-chaperone for alpha-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration. AB - We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of alpha-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in alpha ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration. PMID- 28017474 TI - Optic neuritis associated to treatment with infliximab. PMID- 28017475 TI - [Spontaneous bacterial peritonitis with listeria monocytogenes leading to a cirrhosis discovery]. PMID- 28017476 TI - Double strand break induction and kinetics indicate preserved hypersensitivity in keratinocytes to subtherapeutic doses for 7weeks of radiotherapy. AB - BACKGROUND AND PURPOSE: Previously we reported that hyper-radiosensitivity (HRS) was evidenced by quantifying DNA double strand break (DSB) foci in epidermis biopsies collected after delivering radiotherapeutic one and five dose fractions. The aim of this study was to determine whether HRS was preserved throughout a 7 week radiotherapy treatment, and also to examine the rate of foci decline and foci persistence between dose fractions. MATERIALS AND METHODS: 42 patients with prostate cancer received 7-week fractionated radiotherapy treatment (RT) with daily dose fractions of 0.05-1.10Gy to the skin. Before RT, and at several times throughout treatment, skin biopsies (n=452) were collected at 30min, and 2, 3, 24, and 72h after dose fractions. DSB-foci markers, gammaH2AX and 53BP1, were labelled in epidermal keratinocytes with immunofluorescence and immunohistochemical staining. Foci were counted both with digital image analysis and manually. RESULTS: HRS in keratinocytes was evidenced by the dose-response relationships of DSB foci, observed throughout the treatment course, independent of sampling time and quantification method. Foci observed at 24h after dose fractions indicated considerable DSB persistence. Accordingly, foci significantly accumulated after 5 consecutive dose fractions. For doses below 0.3Gy, persistent foci could be observed even at 72h after damage induction. A comparison of gammaH2AX and 53BP1 quantifications in double-stained biopsies showed similar HRS dose-response relationships. CONCLUSIONS: These results represented the first evidence of preserved HRS, assessed by gammaH2AX- and 53BP1-labelled DSB foci, throughout a 7-week treatment course with daily repeated subtherapeutic dose fractions. PMID- 28017477 TI - Executive summary of the diagnosis and treatment of urinary tract infection: Guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). AB - Most urinary tract infections (UTI) are uncomplicated infections occurring in young women. An extensive evaluation is not required in the majority of cases, and they can be safely managed as outpatients with oral antibiotics. Escherichia coli is by far the most common uropathogen, accounting for >80% of all cases. Other major clinical problems associated with UTI include asymptomatic bacteriuria, and patients with complicated UTI. Complicated UTIs are a heterogeneous group associated with conditions that increase the risk of acquiring infection or treatment failure. Distinguishing between complicated and uncomplicated UTI is important, as it influences the initial evaluation, choice, and duration of antimicrobial therapy. Diagnosis is especially challenging in the elderly and in patients with in-dwelling catheters. The increasing prevalence of resistant uropathogens, including extended-spectrum beta-lactamases and carbapenemase-producing Enterobacteriaceae, and other multidrug-resistant Gram negative organisms further compromises treatment of both complicated and uncomplicated UTIs. The aim of these Clinical Guidelines is to provide a set of recommendations for improving the diagnosis and treatment of UTI. PMID- 28017478 TI - Authors' reply to Ruan et al.: No pain, no bias? PMID- 28017479 TI - Diffusion characteristics of the fornix in patients with Alzheimer's disease. AB - White matter degradation is a major part of the pathogenesis of Alzheimer's disease (AD). The fornix is the predominant outflow tract from the hippocampus, and alterations to its microstructure in patients with AD are still being explored. Diffusion tensor imaging (DTI) is an in vivo neuroimaging technique that can provide unique information about alterations in tissue microstructure, which can indicate underlying neurobiological process at the microstructural level. In this prospective study, DTI was used to assess and analyze the microstructural features of the fornix in subjects with AD (n = 17), mild cognitive impairment (MCI; n = 12) and healthy controls (n = 17). DTI was performed using Explore DTI software and the FSL package. Within the fornix, patients with AD showed decreased fractional anisotropy values and length of fiber tracts of the fornix relative to healthy controls, but higher mean diffusivity values. MCI subjects showed a trend towards elevated mean diffusivity values in the fornix. The data suggest that DTI provides supporting information on the microstructural alteration of the fornix in patients with AD, and that these diffusion characteristics of the fornix may be helpful for the clinical diagnosis of AD. PMID- 28017480 TI - Cognitive reserve moderates the association between functional network anti correlations and memory in MCI. AB - Cognitive reserve (CR) shows protective effects on cognitive function in older adults. Here, we focused on the effects of CR at the functional network level. We assessed in patients with amnestic mild cognitive impairment (aMCI) whether higher CR moderates the association between low internetwork cross-talk on memory performance. In 2 independent aMCI samples (n = 76 and 93) and healthy controls (HC, n = 36), CR was assessed via years of education and intelligence (IQ). We focused on the anti-correlation between the dorsal attention network (DAN) and an anterior and posterior default mode network (DMN), assessed via sliding time window analysis of resting-state functional magnetic resonance imaging (fMRI). The DMN-DAN anti-correlation was numerically but not significantly lower in aMCI compared to HC. However, in aMCI, lower anterior DMN-DAN anti-correlation was associated with lower memory performance. This association was moderated by CR proxies, where the association between the internetwork anti-correlation and memory performance was alleviated at higher levels of education or IQ. In conclusion, lower DAN-DMN cross-talk is associated with lower memory in aMCI, where such effects are buffered by higher CR. PMID- 28017482 TI - Presence of environmental coagulase-positive staphylococci, their clonal relationship, resistance factors and ability to form biofilm. AB - Coagulase-positive staphylococci (CoPS) are opportunistic pathogens carrying various mechanisms of resistance that have a large number of virulence factors, and whose ability to induce illness is associated with the host. This study aimed to investigate the presence of environmental coagulase-positive staphylococci, their susceptibility profile, clonal relationship and ability to form biofilm. The 16S rRNA genes from CoPS isolates were analyzed, and their antibiotic susceptibility was evaluated using the agar dilution method in accordance with Clinical and Laboratory Standards Institute guidelines. The clonal profile was obtained by pulsed-field gel electrophoresis (PFGE) and biofilm formation was measured by a crystal violet retention assay. A total of 72 Staphylococcus spp. strains were isolated from air, metal surfaces, and nostrils from humans, dogs, cats, and birds. Three species were identified: Staphylococcus aureus (17%), Staphylococcus intermedius (63%), and Staphylococcus pseudintermedius (21%). Ninety three percent (93%) of the strains were resistant to at least one of 13 tested antibiotics. S. pseudintermedius strains were the only resistant ones to methicillin while most of these isolates were multidrug-resistant, had significantly higher ability to form biofilm and PFGE grouped into seven different patterns, without showing clonal dispersion among animals and environmental isolates. This study suggests that dogs, cat, and air are environmental sources potentially carrying multidrug-resistant S. pseudintermedius, which survives in different environments through biofilm formation and multidrug resistance, characteristics that can be transmitted horizontally to other bacteria and exacerbate the problem of antibiotic resistance in humans. PMID- 28017481 TI - ATXN2 trinucleotide repeat length correlates with risk of ALS. AB - We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 * 10-18), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R2 = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk. PMID- 28017483 TI - Granulomatosis with polyangiitis confined to lacrimal gland, a case report. AB - CLINICAL CASE: A 43 year-old woman consulted due to 2 months of swelling on the superolateral side of the left orbit, with pain and erythema. An excisional biopsy was performed that revealed vasculitis with polyangiitis of the lacrimal gland. A systemic study showed that no other system was compromised. DISCUSSION: Orbital involvement occurs in up to 60% of patients with granulomatosis with polyangiitis. The involvement of the lacrimal gland is rare and often unilateral. Serological tests are generally negative, both in initial stages, as in localized forms of the disease. PMID- 28017484 TI - Choroidal haemangioma and photodynamic therapy. Anatomical and functional response of patients with choroidal hemangioma treated with photodynamic therapy. AB - OBJECTIVE: To study the effectiveness and limitations of photodynamic therapy (PDT) as treatment of choice in patients with symptomatic circumscribed choroidal haemangioma. METHODS: A retrospective study was conducted on 16 patients (13 men and 3 women, with mean age of 54.88 years) with circumscribed choroidal haemangioma, who attended our centre and were treated with PDT in the last 7 years. RESULTS: All patients had circumscribed choroidal haemangioma, which caused a decrease in visual acuity (VA) secondary to the presence of intraretinal microcystic oedema or neurosensory detachment. The mean initial VA was 0.23, and the final mean VA after performing PDT was 0.38 (all the VA were measured in decimal scale). It should be noted that patients needed a mean of 1.69 PDT sessions. Three of the patients needed rescue treatment with trans-pupillary thermotherapy, intravitreal injection of anti-vascular endothelial growth factor (ranibizumab, aflibercept) or a dexamethasone intravitreal implant (Ozurdex(r)). The indication for a change of treatment was the persistence of intraretinal microcystic oedema and/or neurosensory detachment (or incomplete resolution) after 3 PDT sessions. As overall results, 62.5% of patients evolved into anatomical and functional (increase in AV or stability) resolution. CONCLUSIONS: PDT is a straight forward and fast procedure, with a good anatomical and functional response, causing minimal damage to adjacent vessels. PMID- 28017485 TI - Clinical history in ophthalmological patients treated with multivitamin complexes. PMID- 28017486 TI - Outcomes and complications after phacoemulsification in retinoblastoma patients with cataract after radiation treatment. AB - PURPOSE: To describe the visual outcome and complications associated with phacoemulsification in patients with bilateral retinoblastoma (Rb), with lens opacification secondary to external beam radiotherapy. METHODS: A descriptive study was performed on patients with Rb, treated in Federico Gomez Children's Hospital, Mexico, from January 1997 to August 2015, with external beam radiotherapy eye salvaging. Statistical analysis was performed using Stata 10. RESULTS: A total of 15 patients were included. The mean age at phacoemulsification was 7.5 years. Mean preoperative visual acuity was 1.0LogMAR (range 0.4-1.6), and the mean postoperative visual acuity was 0.7LogMAR (range 0.1-1.6). Twelve patients had visual improvement (P<.05). The visual acuity decreased in one patient with vitreous haemorrhage and secondary glaucoma, and 2 patients with exudative maculopathy secondary to radiation. Mean follow up was 46 months and not a single patient showed tumour re-activation. CONCLUSIONS: Cataract surgery produces a statistically significant improvement in visual acuity. These patients have increased risk for eye complications in the mid- and long-term. It is important to conduct a close follow up due to reactivation of tumour. PMID- 28017487 TI - Dandy-Walker Malformation: A Case Study of an Infant With an Increasing Head Circumference and Delayed Developmental Milestones. PMID- 28017488 TI - Complementary and Alternative Medicine in the School-Age Child With Autism. AB - This case study examines some common complementary and alternative treatments used in the management of behavioral and gastrointestinal symptoms associated with autism including food selectivity, abdominal pain, nausea, gastroesophageal reflux, constipation, and diarrhea. The current literature on the safety and efficacy of these treatments for pediatric patients is reviewed. This study examines therapies including gluten-free and casein-free diet, probiotics, vitamin B12, omega-3 fatty acid supplementation, chelation therapy, acupuncture, and chiropractic manipulations used in treating these core symptoms of autism. PMID- 28017490 TI - Association between preoperative serum vitamin D and high-density lipoprotein cholesterol levels and effects on breast cancer prognosis. PMID- 28017489 TI - The Impact of Telehealth and Care Coordination on the Number and Type of Clinical Visits for Children With Medical Complexity. AB - INTRODUCTION: The purpose of this analysis was to evaluate the effects of an advanced practice nurse-delivered telehealth intervention on health care use by children with medical complexity (CMC). Because CMC account for a large share of health care use costs, finding effective ways to care for them is an important challenge requiring exploration. METHOD: This was a secondary analysis of data from a randomized clinical trial with a control group and two intervention groups. The focus of the analysis was planned and unplanned clinical and therapy visits by CMC over a 30-month data collection period. Nonparametric tests were used to compare visit counts among and within the three groups. RESULTS: The number of unplanned visits decreased over time across all groups, with the greatest decrease in the video telehealth intervention group. Planned visits were higher in the video telehealth group across all time periods. DISCUSSION: Advanced practice registered nurse-delivered telehealth care coordination may support a shift from unplanned to planned health care service use among CMC. PMID- 28017491 TI - Internal mammary sentinel lymph node biopsy: An effective way to search benefit patients and guide internal mammary chain irradiation. PMID- 28017492 TI - Superior canal dehiscence with tegmen defect revealed by otoscopy: Video clip demonstration of pulsatile tympanic membrane. AB - Superior canal dehiscence is a pathologic condition of the otic capsule acting as aberrant window of the inner ear. It results in reduction of inner ear impedance and in abnormal exposure of the labyrinthine neuroepithelium to the action of the surrounding structures. The sum of these phenomena leads to the onset of typical cochleo-vestibular symptoms and signs. Among them, pulsatile tinnitus has been attributed to a direct transmission of intracranial vascular activities to labyrinthine fluids. We present the first video-otoscopic documentation of spontaneous pulse-synchronous movements of the tympanic membrane in two patients with superior canal dehiscence. Pulsating eardrum may represent an additional sign of third-mobile window lesion. PMID- 28017493 TI - Music-evoked emotions in schizophrenia. AB - BACKGROUND/OBJECTIVES: Previous studies have reported that people with schizophrenia have impaired musical abilities. Here we developed a simple music based assay to assess patient's ability to associate a minor chord with sadness. We further characterize correlations between impaired musical responses and psychiatric symptoms. METHOD: We exposed participants sequentially to two sets of sound stimuli, first a C-major progression and chord, and second a C-minor progression and chord. Participants were asked which stimulus they associated with sadness, the first set, the second set, or neither. The severity of psychiatric symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Study participants were 29 patients diagnosed with schizophrenia and 29 healthy volunteers matched in age, gender and musical background. RESULT: 37.9% (95% confidence interval [CI]:19.1-56.7) of patients with schizophrenia associated the minor chord set as sad, compared with 97.9% (95%CI: 89.5-103.6) of controls. Four patients were diagnosed with treatment-resistant schizophrenia, and all four failed to associate the minor chord with sadness. Patients who did not recognize minor chords as sad had significantly higher scores on all PANSS subscales. CONCLUSIONS: A simple test allows music-evoked emotions to be assessed in schizophrenia patient, and may show potential relationships between music evoked emotions and psychiatric symptoms. PMID- 28017494 TI - Formal thought disorder in schizophrenia and bipolar disorder: A systematic review and meta-analysis. AB - Historically, formal thought disorder has been considered as one of the distinctive symptoms of schizophrenia. However, research in last few decades suggested that there is a considerable clinical and neurobiological overlap between schizophrenia and bipolar disorder (BP). We conducted a meta-analysis of studies comparing positive (PTD) and negative formal thought disorder (NTD) in schizophrenia and BP. We included 19 studies comparing 715 schizophrenia and 474 BP patients. In the acute inpatient samples, there was no significant difference in the severity of PTD (d=-0.07, CI=-0.22-0.09) between schizophrenia and BP. In stable patients, schizophrenia was associated with increased PTD compared to BP (d=1.02, CI=0.35-1.70). NTD was significantly more severe (d=0.80, CI=0.52 0.1.08) in schizophrenia compared to BP. Our findings suggest that PTD is a shared feature of both schizophrenia and BP but persistent PTD or NTD can distinguish subgroups of schizophrenia from BP and schizophrenia patients with better clinical outcomes. PMID- 28017495 TI - Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages. AB - Oral squamous cell carcinoma (OSCC) is the most common solid tumor in the oral cavity. Development and progression of OSCC is associated with the elevated presence of inhibitory M2 type tumor-associated macrophages (TAMs). However, the underlying mechanism leading to the enrichment of M2 TAMs and the pathway through which TAMs foster tumor progression are still unclear. In this study, we harvested TAMs and tumor cells from primary OSCC resections of stage II and stage III patients. We showed that compared to peritumoral macrophages, TAMs presented upregulated expression of PD-L1 and elevated capacity in inducing T cell apoptosis. The level of PD-L1 expression directly correlated with the level of T cell apoptosis. Interestingly, peripheral blood monocytes with low initial PD-L1 level had upregulated PD-L1 expression and acquired the ability to induce T cell apoptosis, after incubation with primary tumor cells from OSCC patients. The PD L1 expression by monocytes depended on interleukin 10 (IL-10), since blockade of IL-10 in the tumor-monocyte coculture abrogated PD-L1 upregulation. IL-10 mRNA expression in tumor cells and monocytes also preceded PD-L1 mRNA expression in monocytes. Furthermore, the IL-10 concentration in the tumor microenvironment directly correlated with the PD-L1 level on TAMs. Together, these results suggest that OSCC could directly suppress antitumor T cell immunity through conditioning TAMs. PMID- 28017496 TI - Toll-Like Receptor 3 and Interferon beta mRNA Expressions Were Increased in Peripheral Blood of Ischemic Stroke Patients with Good Outcome. AB - BACKGROUND: Innate immunity plays an important role in brain ischemic injury, but there are only few studies on the effects of toll-like receptors (TLRs) on cerebral infarction patients up to now. We aimed to evaluate the TLR mRNA expression of patients with different outcomes. METHODS: Eighty-six cases suffering from cerebral infarction within 14 days were assigned into the good outcome group (n = 47) and the bad outcome group (n = 39) depending on the modified Rankin Scale scores (mRS <=2 at 90 days following stroke onset was good outcome). We measured the mRNA expression of TLRs in peripheral blood mononuclear cells of patients at 24 hours, 3 days, 4 days, 7 days, and 14 days from onset. The National Institutes of Health Stroke Scale score and infarction volume were assessed on admission and at 7-14 days, respectively. RESULTS: Only TLR3 mRNA expression of the good outcome group was higher than that of the bad outcome group at acute and subacute phases. TLR7 expressions of the good outcome group increased within 3 days following stroke onset. Moreover, the two groups had no significant differences in terms of mRNA expressions of TLR2, TLR4, TLR8, and TLR9. The expression of interferon beta of the good outcome group was higher than that of the bad outcome group, and it had a positive correlation with the expressions of TLR3 and interferon regulatory factor 3. CONCLUSIONS: TLR3 and interferon beta mRNA expressions were increased in the peripheral blood of ischemic stroke patients with good outcome, which may imply their neuroprotection. PMID- 28017497 TI - Developmental hemostasis: A lifespan from neonates and pregnancy to the young and elderly adult in a European white population. AB - Absolute values of reference ranges for coagulation assays in humans vary within the entire lifespan and confirm the concept of developmental hemostasis. It is known that physiologic concentrations of coagulation factors (F) gradually increase over age: they are lower in premature infants as compared to full-term babies, healthy children or adults. Here we demonstrate in a cohort of 1011 blood donors and in a group of 193 healthy pregnant women, that the process of developmental hemostasis proceeds in adults. During the course of pregnancy F and activation markers steadily increase until delivery with a parallel decrease noticed for protein S. From adolescents, young adults to the elderly there is a further increase of F, reaching significance starting between 35 and 50years of age compared to younger subjects. Covering the entire lifespan FVIII and von Willebrand-factor showed the lowest values in carriers of blood group "O". Apart from pregnancy differences related to gender, pill users, smoking habits or the presence of thrombophilic variants were reported. Laboratory test results should be compared to age-related reference intervals when hemostatic defects are suspected to avoid misclassifications as being "healthy", prone to "bleeding" or vice versa to "thrombosis". PMID- 28017498 TI - Red Cell Immunohematology Research Conducted in China. AB - ABO subtypes and RhD variants are the most studied blood groups in China. Some of the polymorphisms in these two blood groups have direct clinical relevance. Molecular diagnosis of blood group polymorphisms is underway in China. In addition, research groups have developed methods such as screening for blood group mimetic peptides using phage display technology. New reagents, akin to antibodies directed against RhD and ABO, are being investigated using aptamer based techniques. Progress is also being made in the development of synthetic exoglycosidases for conversion of group A and/or B antigens to group O. Development of methoxy-polyethylene-glycol modified red cells has been successful in vitro but has not reached clinical application. In this paper, we summarize red cell immunohematology research that has been conducted in China. PMID- 28017499 TI - Neuronal Adaptation: Tired Neurons or Wired Networks? AB - Neuronal adaptation - time-dependent modulation of sensory responses following sequential stimuli - is thought to be a consequence of synaptic plasticity. But recent, empirically-grounded, modeling by Quiroga and colleagues demonstrates that the adaptation of visual cortical responses can be described by recurrent network connections with fixed synaptic weights. PMID- 28017500 TI - Methods for using argon-39 to age-date groundwater using ultra-low-background proportional counting. AB - Argon-39 can be used as a tracer for age-dating glaciers, oceans, and more recently, groundwater. With a half-life of 269 years, 39Ar fills an intermediate age range gap (50-1,000 years) not currently covered by other common groundwater tracers. Therefore, adding this tracer to the data suite for groundwater studies provides an important tool for improving our understanding of groundwater systems. We present the methods employed for arriving at an age-date for a given sample of argon degassed from groundwater. PMID- 28017501 TI - Recirculation of FNPP1-derived radiocaesium observed in winter 2015/2016 in coastal regions of Japan. AB - We conducted enhanced surface water sampling at more than 80 stations in coastal regions on both the Japan Sea and Pacific Ocean sides of Japan in winter 2015/2016 to examine the recirculation behaviour of FNPP1-derived radiocaesium in the surface layer 5 years after the 2011 FNPP1 accident. We found that a small part of the FNPP1-derived radiocaesium had already recirculated in the surface layer and reached the Japanese coast. PMID- 28017502 TI - Simultaneous measurement of tritium and radiocarbon by ultra-low-background proportional counting. AB - Use of ultra-low-background capabilities at Pacific Northwest National Laboratory provide enhanced sensitivity for measurement of low-activity sources of tritium and radiocarbon using proportional counters. Tritium levels are nearly back to pre-nuclear test backgrounds (~2-8 TU in rainwater), which can complicate their dual measurement with radiocarbon due to overlap in the beta decay spectra. We present results of single-isotope proportional counter measurements used to analyze a dual-isotope methane sample synthesized from ~120mg of H2O and present sensitivity results. PMID- 28017503 TI - Response to "Radiotelemetric EEG recordings in mice - Critical role of transmitter bandwidth and nominal sampling rate in frequency analysis". PMID- 28017504 TI - Erratum to "Safety, efficacy and outcome-related factors of perampanel over 12months in a real-world setting: The FYDATA study" [Epilepsy Res. 126 (2016) 201 210]. PMID- 28017505 TI - Endurance training-induced changes in the GH-IGF-I axis influence maximal muscle strength in previously untrained men. AB - OBJECTIVE: In this study we have determined the effects of 20weeks of endurance running training on the GH-IGF-I axis changes in the context of the skeletal muscle performance and physical capacity level. DESIGN: Before and after the endurance training program a maximal incremental exercise tests, a 1500m race and a muscle strength measurements were performed and the blood samples were taken to determine both resting as well as end-exercise serum growth hormone (GH), insulin like growth hormone-I (IGF-I), insulin-like growth hormone binding protein-3 (IGFBP-3) and plasma interleukin-6 (IL-6) concentrations. RESULTS: 20weeks of endurance running training improved power output generated at the end of the maximal incremental test by 24% (P<0.012), 1500m running time by 13% (P<0.012) and maximal muscle strength by 9% (P<0.02). End-exercise IGF-I/IGFBP-3 ratio was decreased by 22% after the training (P<0.04) and the magnitude of IGF-I/IGFBP-3 ratio decrease (DeltaIGF-I/IGFBP-3ex) was 2.3 times higher after the training (P<0.04). The magnitude of the exercise-induced changes in IGFBP-3 concentration was also significantly higher (P<0.04) and there was a trend toward lower end exercise IGF-I concentration (P=0.08) after the training. These changes were accompanied by a significantly higher (30%) end-exercise IL-6 concentration (P<0.01) as well as by a 3.4 times higher magnitude of IL-6 increase (P<0.02) after the training. Moreover, there were strong positive correlations between changes in resting serum IGF-I concentration (DeltaIGF-Ires) and IGF-I/IGFBP-3 ratio (DeltaIGF-I/IGFBP-3res) and changes in muscle strength (DeltaMVC) (r=0.95, P=0.0003 and r=0.90, P=0.002, respectively). CONCLUSIONS: The training-induced changes in the components of the GH-IGF-I axis may have additive effects on skeletal muscle performance and physical capacity improvement. PMID- 28017506 TI - Insulin producing cells generation by overexpression of miR-375 in adipose derived mesenchymal stem cells from diabetic patients. AB - Diabetes Mellitus (DM) is a systematic disease, which happens because of destruction of islets of Langerhans in the pancreas and systematic resistance to insulin. The lack of donor for pancreas transplantation and risk of transplant rejection is the main challenge in the treatment of this disease. Stem cells are proper and sufficient source for creating insulin-producing cells (IPC). In this study adipose tissue was provided from diabetic patients operated for liposuction and then adipose derived stem cells (ADSCs) were isolated, characterized and then treated by lentiviruses containing miR-375, after 7, 14 and 21 days of induction, islet-like clusters (ILC) specific genes including insulin and PDX1 were evaluated by Real Time RT-PCR. Finally, immunocytochemistry was also used for evaluation of these markers in the protein level. The results were shown that insulin and PDX1 genes and proteins expression significantly increased in transduced stem cells compared to the control group. According to the results it can be concluded that islet-like clusters can be achieved from ADSCs by overexpression of miR-375. PMID- 28017507 TI - Salmon roe (ikura)-induced anaphylaxis in a child. PMID- 28017509 TI - Male Osteoporosis Awareness in the Elderly: an Analysis of Dual-Energy X-Ray Absorptiometry Use in Australia Between 1995 and 2015. AB - Osteoporosis is commonly perceived to be a disease confined to aging females, despite ongoing educational interventions. There are few data on the temporal change of dual-energy X-ray absorptiometry (DXA) use in aging males compared to females. Australian Medicare DXA claims between 1995 and 2015 were analyzed to investigate gender differences and temporal change of DXA use in males and females aged 45-85 yr. In females aged 45-54 and 55-64 yr, there was a progressive increase in DXA claims per capita between 1995 until 2002, with little subsequent change from 2002 to 2015 in the younger group, but a slow subsequent increase in females aged 55-64 yr. In males aged 45-54 and 55-64 yr, there was a progressive increase in DXA claims per capita between 1995 and 2002 with an ongoing slow increase from 2002 to 2015. In older females and males aged 65-74, 75-84, or >=85 yr, there was a progressive increase in DXA claims per capita between 1995 and 2002, with a slow increase thereafter until 2007. After 2007, following the introduction of Medicare eligibility for age over 70, claims per capita increased sharply in all 3 age groups, with a subsequent ongoing increase. The male : female claim ratio in all groups demonstrates low relative male DXA use, with the ratio consistently below 1.0. Following the 2007 Medicare change, the male : female ratio improved in the 65-74, 75-84, and >=85 age groups. The rate of increase in the male : female ratio in subjects >=85 yr was significantly greater than that in the 65-74 (p < 0.001) and 75-84 (p < 0.001) age groups. DXA use in males is consistently lower than that in females. Government funding intervention appears to have been most effective in relation to very elderly males over 85 yr but less so in relation to the age group 65-84. There is a need for improved education of health professionals about the risk of osteoporosis in males aged 65-84 yr. PMID- 28017508 TI - Sex differences in activation of lung-related type 2 innate lymphoid cells in experimental asthma. PMID- 28017511 TI - Out-of-hospital cardiac arrest in pregnancy with good neurological outcome for mother and infant. AB - Cardiac arrest in pregnancy is rare (about 1:30000 pregnancies) and out-of hospital cardiac arrests are even less frequent. Resuscitation of the pregnant mother is challenging and requires attention to the altered physiology, specific pathologies and the presence and well-being of the fetus. Once circulation has been restored, the lack of high-grade evidence regarding delivery of the baby and post-resuscitation care makes decision making complex. We present a case of out of-hospital maternal cardiac arrest with successful resuscitation and good neurological outcome for mother and infant. The principal emphases are on decision making, resuscitation and education. PMID- 28017510 TI - Characterization of the Physiological Displacement of the Aortic Arch Using Non Rigid Registration and MR Imaging. AB - OBJECTIVES: The aim of this work was to study physiological aortic arch three dimensional displacement using non-rigid registration methods and magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ten healthy volunteers underwent thoracic MRI. Prospective cardiac gating was performed with a 3D turbo field echo sequence to obtain end-systolic and end-diastolic MR images. The rigid and elastic behavior between these two cardiac phases was detected and compared using either an affine or an elastic registration method. To assess reproducibility, a second MRI acquisition was performed 14 days later. RESULTS: Affine registration between the end-systolic and end-diastolic MR images showed significant global translations of the aortic arch and the supra-aortic vessels in the x, y, and z directions (2.02 +/- 1.6, -0.71 +/- 1.1, and -1.21 +/- 1.4 mm, respectively). Corresponding elastic registration indicated significant local displacement with a vector magnitude of 5.1 +/- 0.89 mm for the brachiocephalic artery (BCA), of 4.26 +/- 0.83 mm for the left common carotid artery (LCCA), and of 4.8 +/- 0.86 mm for the left subclavian artery (LSCA). There was a difference in displacement between the supra-aortic trunks of the order of 2 mm. Vector displacement was not statistically different between the repeated acquisitions. CONCLUSIONS: The present results showed important deformations in the ostia of supra-aortic vessels during the cardiac cycle. It seems that aortic arch motions should be taken into account when designing and manufacturing fenestrated endografts. The elastic registration method provides more precise results, but is more complex and time-consuming than other methods. PMID- 28017512 TI - Apnoeic oxygenation during maternal cardiac arrest in a parturient with extreme obesity. PMID- 28017514 TI - Acro-osteolysis and calcinosis in patient with scleroderma: A case report. AB - Acro-osteolysis is a rare disease characterized by bone resorption involving the distal phalanges of the hand. We present a unique case of progressive acro osteolysis of the distal phalanges and articular calcifications in a patient with scleroderma. The calcified deposit in a proximal interphalangeal joint was excised under local anesthesia. The medical treatment was arranged under the supervision of a rheumatologist. PMID- 28017513 TI - From Catheter to Kidney Stone: The Uropathogenic Lifestyle of Proteus mirabilis. AB - Proteus mirabilis is a model organism for urease-producing uropathogens. These diverse bacteria cause infection stones in the urinary tract and form crystalline biofilms on indwelling urinary catheters, frequently leading to polymicrobial infection. Recent work has elucidated how P. mirabilis causes all of these disease states. Particularly exciting is the discovery that this bacterium forms large clusters in the bladder lumen that are sites for stone formation. These clusters, and other steps of infection, require two virulence factors in particular: urease and MR/P fimbriae. Highlighting the importance of MR/P fimbriae is the cotranscribed regulator, MrpJ, which globally controls virulence. Overall, P. mirabilis exhibits an extraordinary lifestyle, and further probing will answer exciting basic microbiological and clinically relevant questions. PMID- 28017515 TI - Extreme proximal migration of dislocated lunate over carpal ligament - A case report. AB - Dislocation of the lunate and proximal pole of the scaphoid with displacement of the fragments proximal to the radiocarpal joint, characterized as a total dislocation, is very rare, with only six cases reported. Dislocated lunate are generally located around the radiocarpal joint or within carpal ligament. However, there have been no reports of dislocated lunate over the carpal ligament. We present a patient with volar dislocation of the lunate that featured extreme migration to approximately 6 cm proximal to flexor digitorum superficialis through the transcarpal ligament. PMID- 28017516 TI - Inappropriate Sexual Behaviors Among Community-Dwelling Patients with Dementia. AB - OBJECTIVE: Inappropriate sexual behaviors (ISBs) represent challenging and stressful manifestations of dementia and are highly burdening for patients, families, and healthcare providers. Nevertheless, ISBs have so far attracted limited clinical and scientific interest compared with other neuropsychiatric symptoms occurring in dementing illnesses. The authors aimed to systematically investigate the prevalence and characteristics of ISBs in a population of patients with dementia attending a memory clinic. METHODS: In this cross sectional study, individuals with dementia attending our memory clinic were consecutively enrolled between January 2015 and February 2016. Participating subjects underwent a detailed medical history collection and a comprehensive cognitive, functional, and neuropsychiatric assessment. The presence of ISBs (in the previous 30 days) was investigated by the adoption of an ad hoc questionnaire, administered to informants. A logistic regression model was carried out to identify sociodemographic and clinical variables associated with ISBs. RESULTS: In the 195 patients (48.7% women) with dementia recruited for the study, ISBs were detected in 35 patients (17.9% of the total sample). The logistic regression model showed that male sex (OR: 5.14; 95% CI: 1.44-18.41) and anxiety (OR: 4.92; 95% CI: 1.44-16.84) were statistically significantly associated with the presence of ISBs. CONCLUSION: ISBs represent common manifestations of dementing illnesses. Given the significant burden of ISBs on patients and families and the impact on care management, their occurrence should always be investigated in the clinical care of individuals with dementia. For this purpose, specific screening/assessment tools should be properly designed and validated. PMID- 28017517 TI - Childhood Adversity's Enduring Impact on Homeless Older Adults. PMID- 28017518 TI - Effectiveness of a stress management pilot program aimed at reducing the incidence of sports injuries in young football (soccer) players. AB - OBJECTIVES: Several attempts to reduce the incidence of sport injuries using psychosocial interventions produced fruitful, although inconclusive results. This paper presents the effectiveness and implementation issues of a pilot 3-month stress-management and muscle relaxation program aimed at reducing sport injury incidence. DESIGN: Pre-post treatment-non treatment group comparison. PROGRAM ADMINISTRATION: The program was administered by a trained psychologist on a once a-week, 1-h session basis. PARTICIPANTS: Seventy-four male soccer players from four National Youth league teams voluntarily participated. Teams were randomly assigned to either treatment/non-treatment group. MEASURES: Injury protocol, Self monitoring cards, Athletes' satisfaction and commitment survey, Coaches' interview. RESULTS: Group main effect and Time-Group interaction effect were both statistically significant, F(1,60) = 8.30, p = 0.005, eta2p = 0.121, with the average number of injuries larger in the post-treatment phase of non-treatment group (p = 0.005, eta2p = 0.077). There was a significant decrease in the average number of injuries for the intervention group before and after implementing the program (p < 0.001, eta2p = 0.309). CONCLUSIONS: A controlled implementation of a psychosocial program was effective in reducing youth soccer sport injuries, with a high level of satisfaction and commitment from the athletes, as well as high acceptance from the coaches. PMID- 28017519 TI - Direct variable cost of the topical treatment of stages III and IV pressure injuries incurred in a public university hospital. AB - AIM: to estimate the direct variable costs of the topical treatment of stages III and IV pressure injuries of hospitalized patients in a public university hospital, and assess the correlation between these costs and hospitalization time. MATERIALS AND METHODS: Forty patients of both sexes who had been admitted to the Sao Paulo Hospital, Sao Paulo, SP, Brazil, from 2011 to 2012, with pressure injuries in the sacral, ischial or trochanteric region were included. The patients had a total of 57 pressure injuries in the selected regions, and the lesions were monitored daily until patient release, transfer or death. The quantities and types of materials, as well as the amount of professional labor time spent on each procedure and each patient were recorded. The unit costs of the materials and the hourly costs of the professional labor were obtained from the hospital's purchasing and human resources departments, respectively. Spearman's correlation coefficient and the Mann-Whitney and Kruskal-Wallis tests were used for the statistical analyses. RESULTS: The mean topical treatment costs for stages III and IV PIs were significantly different (US$ 854.82 versus US$ 1785.35; p = 0.004). The mean topical treatment cost of stages III and IV pressure injuries per patient was US$ 1426.37. The mean daily topical treatment cost per patient was US$ 40.83. There was a significant correlation between hospitalization time and the total costs of labor and materials (p < 0.05). There was no significant difference between hospitalization time periods for stages III and IV pressure injuries (40.80 days and 45.01 days, respectively; p = 0.834). CONCLUSION: The mean direct variable cost of the topical treatment for stages III and IV pressure injuries per patient in this public university hospital was US$ 1426.37. PMID- 28017520 TI - Microbial Dysbiosis in Common Variable Immune Deficiencies: Evidence, Causes, and Consequences. AB - Common variable immunodeficiency (CVID) is an immune disorder that not only causes increased susceptibility to infection, but also to inflammatory complications such as autoimmunity, lymphoid proliferation, malignancy, and granulomatous disease. Recent findings implicate the microbiome as a driver of this systemic immune dysregulation. Here, we critically review the current evidence for a role of the microbiome in the pathogenesis of CVID immune dysregulation, and describe the possible immunologic mechanisms behind causes and consequences of microbial dysbiosis in CVID. We integrate this evidence into a model describing a role for the gut microbiota in the maintenance of inflammation and immune dysregulation in CVID, and suggest research strategies to contribute to the development of new diagnostic tools and therapeutic targets. PMID- 28017521 TI - The Ciliopathy-Associated Cep104 Protein Interacts with Tubulin and Nek1 Kinase. AB - Cilia are thin cell projections with essential roles in cell motility, fluid movement, sensing, and signaling. They are templated from centrioles that dock against the plasma membrane and subsequently extend their peripheral microtubule array. The molecular mechanisms underpinning cilia assembly are incompletely understood. Cep104 is a key factor involved in cilia formation and length regulation that rides on the ends of elongating and shrinking cilia. It is mutated in Joubert syndrome, a genetically heterogeneous ciliopathy. Here we provide structural and biochemical data that Cep104 contains a tubulin-binding TOG (tumor overexpressed gene) domain and a novel C2HC zinc finger array. Furthermore, we identify the kinase Nek1, another ciliopathy-associated protein, as a potential binding partner of this array. Finally, we show that Nek1 competes for binding to Cep104 with the distal centriole-capping protein CP110. Our data suggest a model for Cep104 activity during ciliogenesis and provide a novel link between Cep104 and Nek1. PMID- 28017522 TI - Structural Basis for Ligand Binding to the Guanidine-I Riboswitch. AB - The guanidine-I riboswitch is a conserved RNA element with approximately 2,000 known examples across four phyla of bacteria. It exists upstream of nitrogen metabolism and multidrug resistance transporter genes and alters expression through the specific recognition of a free guanidinium cation. Here we report the structure of a guanidine riboswitch aptamer from Sulfobacillus acidophilus at 2.7 A resolution. Helices P1, P1a, P1b, and P2 form a coaxial stack that acts as a scaffold for ligand binding. A previously unidentified P3 helix docks into P1a to form the guanidinium binding pocket, which is completely enclosed. Every functional group of the ligand is recognized through hydrogen bonding to guanine bases and phosphate oxygens. Guanidinium binding is further stabilized through cation-pi interactions with guanine bases. This allows the riboswitch to recognize guanidinium while excluding other bacterial metabolites with a guanidino group, including the amino acid arginine. PMID- 28017524 TI - Active vitamin D treatment in CKD patients raises serum sclerostin and this effect is modified by circulating pentosidine levels. AB - BACKGROUND AND AIMS: 1,25(OH)2Vitamin D increases the expression of the sclerostin gene. Whether vitamin D receptor activation (VDRA) influences serum sclerostin in CKD and whether compounds interfering with VDRA like Advanced Glycosylation End Products (AGEs) may alter the sclerostin response to VDRA is unknown. METHODS AND RESULTS: Eighty-eight stage G3-4 CKD patients randomly received 2 MUg paricalcitol (PCT)/day (n = 44) or placebo (n = 44) for 12 weeks. Sclerostin, a major AGE compound like pentosidine, and bone mineral disorder biomarkers were measured at baseline, at 12 weeks and 2 weeks after stopping the treatments. At baseline, in the whole study population sclerostin correlated with male gender (P = 0.002), BMI (P < 0.001), waist circumference (P < 0.001), serum pentosidine (P = 0.002) and to a weaker extent, with diabetes (P = 0.04), 1,25(OH)2Vitamin D (r = 0.22, P = 0.04) and serum phosphate (r = -0.26, P = 0.01). Sclerostin increased during PCT treatment (average + 15.7 pg/ml, 95% CI: 3.0 to +34.3) but not during placebo (P = 0.03) and the PCT effect was abolished 2 weeks after stopping this drug. The increase in sclerostin levels induced by PCT was modified by prevailing pentosidine levels (P = 0.01) and was abolished by statistical adjustment for simultaneous changes in PTH but not by FGF23 changes. CONCLUSIONS: VDRA by paricalcitol causes a moderate increase in serum sclerostin in CKD patients. Such an effect is abolished by adjustment for PTH, suggesting that it may serve to counter PTH suppression. The sclerostin rise by PCT is attenuated by pentosidine, an observation in keeping with in vitro studies showing that AGEs alter the functioning of the VDRA. PMID- 28017525 TI - Waist circumference and waist:height ratio percentiles using LMS method in Chilean population. AB - BACKGROUND AND AIMS: The concern over the weight gain problem continues to grow among both the international scientific community and public health authorities, since overweight and obesity prevalence rates continue to increase worldwide. In Chile, two out of three people are overweight, whereas 25% of the adult population is obese. Abdominal fat, has been linked to the development of a number of metabolic disorders. Waist circumference (WC) and the waist:height ratio (WHtR) have recently been evidenced as good predictors of metabolic risk for both adults and children. Thus, the present work aims at establishing smoothed centile charts and LMS tables for WC and WHtR for Chilean adults based on data from the National Health Survey-ENS, in order to have reliable information for identifying groups at risk. METHODS AND RESULTS: A sample of 4788 subjects aged 15-75 years old (mean age 46 +/- 18 years old) was considered. Body weight, height, and WC were measured and Body Mass Index (BMI) and WHtR were also determined. Percentiles were calculated using the L (curve Box-Cox), M (curve median), S (curve coefficient of variation) method. In the obese group the WC cutoff values were 99.75 cm and 92.35 cm for men and women, respectively. The cutoff point for WHtR was 0.59 for both obese men and women. CONCLUSION: The study shows, for the first time, reference values for WC and WHtR for Chilean adults. PMID- 28017526 TI - Contribution of fibroblast growth factor 23 to Framingham risk score for identifying subclinical atherosclerosis in Chinese men. AB - BACKGROUND AND AIMS: Fibroblast growth factor 23 (FGF23) was demonstrated to be involved in the occurrence and development of cardiovascular disease (CVD). The goal of the present study was to investigate the relationship between serum FGF23 levels and carotid intima-media thickness (C-IMT) in men with a low-to-moderate CVD risk. METHODS AND RESULTS: Subjects with normal kidney function were selected from the Shanghai Obesity Study. Serum FGF23 levels were determined by sandwich enzyme-linked immunosorbent assay. C-IMT was measured by ultrasonography. The Framingham risk score (FRS) was used to assess CVD risk. A total of 392 men with low CVD risk and 372 men with moderate CVD risk were enrolled. The recognition rate of an elevated C-IMT was 85.66% with the combination of a moderate CVD risk and high serum FGF23 levels, which was greater than that with either parameter alone (65.44% and 61.03%, respectively). Subjects with high serum FGF23 levels, and either low or moderate CVD risk, were more likely to have elevated C-IMT than those with low serum FGF23 levels and low CVD risk (P = 0.014 and 0.001, respectively). The serum FGF23 levels were independently and positively associated with C-IMT in subjects with low or moderate CVD risk (both P = 0.007). CONCLUSION: In men with low-to-moderate CVD risk, serum FGF23 levels were associated independently and positively with C-IMT. As a complementary index, serum FGF23 levels strengthen the capacity of the FRS to identify subclinical atherosclerosis. PMID- 28017523 TI - Healthcare resource use, direct and indirect costs of hypoglycemia in type 1 and type 2 diabetes, and nationwide projections. Results of the HYPOS-1 study. AB - BACKGROUND AND AIMS: To obtain an accurate picture of the total costs of hypoglycemia, including the indirect costs and comparing the differences between type 1 (T1DM) and type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: HYPOS-1 was a multicenter, retrospective cohort study which analyzed the data of 2229 consecutive patients seen at 18 diabetes clinics. Data on healthcare resource use and indirect costs by diabetes type were collected via a questionnaire. The domains of inpatient admission and hospital stay, work days lost, and third-party assistance were also explored. Resource utilization was reported as estimated incidence rates (IRs) of hypoglycemic episodes per 100 person-years and estimated costs as IRs per person-years. For every 100 patients with T1DM, 9 emergency room (ER) visits and 6 emergency medical service calls for hypoglycemia were required per year; for every 100 patients with T2DM, 3 ER visits and 1 inpatient admission were required, with over 3 nights spent in hospital. Hypoglycemia led to 58 work days per 100 person-years lost by the patient or a family member in T1DM versus 19 in T2DM. The costs in T1DM totaled ?90.99 per person-year and ?62.04 in T2DM. Direct and indirect costs making up the total differed by type of diabetes (60% indirect costs in T1DM versus 43% in T2DM). The total cost associated with hypoglycemia in Italy is estimated to be ?107 million per year. CONCLUSIONS: Indirect costs meaningfully contribute to the total costs associated with hypoglycemia. As compared with T1DM, T2DM requires fewer ER visits and incurs lower indirect costs but more frequent hospital use. PMID- 28017527 TI - DNA damage, repair monitoring and epigenetic DNA methylation changes in seedlings of Chernobyl soybeans. AB - This pilot study was carried out to assess the effect of radio-contaminated Chernobyl environment on plant genome integrity 27 years after the accident. For this purpose, nuclei were isolated from root tips of the soybean seedlings harvested from plants grown in the Chernobyl area for seven generations. Neutral, neutral-alkaline, and methylation-sensitive comet assays were performed to evaluate the induction and repair of primary DNA damage and the epigenetic contribution to stress adaptation mechanisms. An increased level of single and double strand breaks in the radio-contaminated Chernobyl seedlings at the stage of primary root development was detected in comparison to the controls. However, the kinetics of the recovery of DNA breaks of radio-contaminated Chernobyl samples revealed that lesions were efficiently repaired at the stage of cotyledon. Methylation-sensitive comet assay revealed comparable levels in the CCGG methylation pattern between control and radio-contaminated samples with a slight increase of approximately 10% in the latter ones. The obtained preliminary data allow us to speculate about the onset of mechanisms providing an adaptation potential to the accumulated internal irradiation after the Chernobyl accident. Despite the limitations of this study, we showed that comet assay is a sensitive and flexible technique which can be efficiently used for genotoxic screening of plant specimens in natural and human-made radio-contaminated areas, as well as for safety monitoring of agricultural products. PMID- 28017528 TI - The Proposed MACRA/MIPS Threshold for Patient-Facing Encounters: What It Means for Radiologists. AB - PURPOSE: In implementing the Merit-Based Incentive Payment System (MIPS), CMS will provide special considerations to physicians with infrequent face-to-face patient encounters by reweighting MIPS performance categories to account for the unique circumstances facing these providers. The aim of this study was to determine the impact of varying criteria on the fraction of radiologists who are likely to receive special considerations for performance assessment under MIPS. METHODS: Data from the 2014 Medicare Physician and Other Supplier file for 28,710 diagnostic radiologists were used to determine the fraction of radiologists meeting various proposed criteria for receiving special considerations. For each definition, the fraction of patient-facing encounters among all billed codes was determined for those radiologists not receiving special considerations. RESULTS: When using the criterion proposed by CMS that physicians will receive special considerations if billing <=25 evaluation and management services or surgical codes, 72.0% of diagnostic radiologists would receive special considerations, though such encounters would represent only 2.1% of billed codes among remaining diagnostic radiologists without special considerations. If CMS were to apply an alternative criterion of billing <=100 evaluation and management codes exclusively, 98.8% of diagnostic radiologists would receive special considerations. At this threshold, patient-facing encounters would represent approximately 10% of billed codes among remaining radiologists without special considerations. CONCLUSIONS: The current CMS proposed criterion for special considerations would result in a considerable fraction of radiologists being evaluated on the basis of measures that are not reflective of their practice and beyond their direct control. Alternative criteria could help ensure that radiologists are provided a fair opportunity for success in performance review under the MIPS. PMID- 28017529 TI - What Patients Think About Their Interventional Radiologists: Assessment Using a Leading Physician Ratings Website. AB - PURPOSE: The aim of this study was to evaluate patient satisfaction scores for interventional radiologists (IRs) across the United States using a leading physician ratings website. METHODS: The physician ratings website Healthgrades was manually queried for all 2,774 Medicare-participating self-designated IRs. All patient-reviewed IRs for whom the primary "likelihood of recommending to family and friends" field was scored were included, resulting in 781 included IRs. Physician characteristics were extracted from Medicare data sets. All available patient satisfaction scores (1 [poor] to 5 [excellent]: likelihood to recommend, ease of scheduling, office environment, staff friendliness, trust in physician's decisions, how well physician explains condition, how well physician listens and answers questions, whether physician spends appropriate time with patients) and wait times were extracted from Healthgrades. Associations among measures were explored. RESULTS: IRs' mean likelihood-to-recommend score was 4.3 +/- 1.2 (median, 5.0; 64.5% received a score of 5; 10.5% received scores < 3). Mean scores ranged from 4.4 to 4.5 for office-related factors and from 4.3 to 4.5 for physician-related factors. Likelihood-to-recommend scores showed substantial correlations with office-related factors (r = 0.738 to 0.780) and physician related factors (r = 0.918 to 0.946). Likelihood to recommend was significantly higher for IRs with shorter wait times (P < .001) but was not associated with physician gender or geographic region (P = 0.370-0.791), nor was there any correlation with physician age, years since graduation, or group practice size (r = -0.089 to 0.096). CONCLUSIONS: Satisfaction scores on a leading physician ratings website generally range from very good to excellent for US IRs. Most patients leaving reviews are likely to recommend their own IRs to friends or family members. The likelihood to recommend is strongly associated with differences in wait times. PMID- 28017530 TI - Faith H. Osier - The Changing Landscape of Malaria in Africa. PMID- 28017531 TI - Recent advancements in the development of anti-tuberculosis drugs. AB - Modern chemotherapy has significantly improved patient outcomes against drug sensitive tuberculosis. However, the rapid emergence of drug-resistant tuberculosis, together with the bacterium's ability to persist and remain latent present a major public health challenge. To overcome this problem, research into novel anti-tuberculosis targets and drug candidates is thus of paramount importance. This review article provides an overview of tuberculosis highlighting the recent advances and tools that are employed in the field of anti-tuberculosis drug discovery. The predominant focus is on anti-tuberculosis agents that are currently in the pipeline, i.e. clinical trials. PMID- 28017533 TI - Re-emergent tremor in Parkinson's disease: Clinical and accelerometric properties. AB - Re-emergent tremor (RET) and the classical parkinsonian rest tremor were considered as two different phenomena of the same central tremor circuit. However, clinical and accelerometric characteristics of these tremors were not previously compared in a single study. We evaluated disease characteristics and accelerometric measurements of two tremor types in 42 patients with Parkinson's disease. Disease specific features and accelerometric measurements of peak frequency, amplitude at peak frequency and the root mean square (RMS) amplitude of two tremor types were compared. Eighteen patients had RET and the mean latency of the RET was 9.48 (+/-9.2)s. Groups of only rest tremor and RET did not differ significantly in age of disease onset, disease duration and severity and mean levodopa equivalent dose. Comparison of peak frequency and amplitude at peak frequency were not different between the groups, but RMS amplitude was significantly higher in the RET group (p=0.03). RMS amplitude of RET was also correlated with disease severity (r=.48, p=0.04). These results support the previous notion that rest tremor and RET are analogue, both are triggered by the same central ossilator with RET being only the suppression of the rest tremor due to arm repositioning. PMID- 28017534 TI - Direct motor evoked potentials and cortical mapping using the NIM(r) nerve monitoring system: A technical note. AB - Motor evoked potentials (MEPs) are commonly used to prevent neurological injury when operating in close proximity to the motor cortex or corticospinal pathway. We report a novel application of the NIM(r) nerve monitoring system (Medtronic@ NIM response 3.0) for intraoperative direct cortical (dc)-MEPs monitoring. A 69 year-old female patient presented with a 4month history of progressive left hemiparesis resulting from a large right sided posterior frontal meningioma that abutted and compressed the motor cortex. Motor cortical mapping and MEPs were indicated. The patient was anesthetized and maintained on total intravenous anesthetics. Compound muscle action potentials (CMAP) of the right upper limb were monitored using the NIM system. After a craniotomy was performed, we first used the Ojemann stimulator (monopolar) for dc-stimulation and then switched to use the monopolar nerve stimulator probe of the NIM system. The CMAP response was successfully elicited using the NIM stimulating probe (pulse width=250s, train frequency=7pulses/s, current=20mA). A gross total resection of the tumor was achieved with intermittent cortical mapping of MEPs. There were no intraoperative complications and the patient's motor function was preserved after the surgery. In this case, we reported the successful use of the NIM nerve monitoring system to elicit dc-MEPs under general anesthesia. The advantages of using this system include a simple set up and application, neurosurgeon familiarity, wide availability and lower cost. dc-MEPs can be achieved using the NIM system. We conclude that the NIM nerve monitoring system is a feasible alternative to standard neurophysiological monitoring systems. PMID- 28017532 TI - Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kdelta inhibitors. AB - A novel class of potent PI3Kdelta inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kalpha program, turned moderately selective PI3Kdelta compounds into highly potent and selective PI3Kdelta inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kdelta IC50?1nM in the enzyme assay, some of the most selective PI3Kdelta inhibitors published to date, with a cell potency in a JeKo-cell assay of 20 120nM. PMID- 28017536 TI - Toxicological potential of acyl glucuronides and its assessment. AB - Idiosyncratic drug toxicity (IDT) is a serious problem in drug development. Reactive metabolites are postulated to be one of the causes for IDT. Conjugated metabolites are generally non-reactive except for acyl glucuronides (AGs), which are sufficiently reactive to covalently bind to endogenous proteins. Thus, it has been suggested that AGs would contribute to IDT caused by carboxylic acid containing drugs. Glucuronidation of a carboxylate residue is catalyzed by UDP glucuronosyltransferase 1A and 2B isoforms. Unstable AGs undergo intramolecular rearrangements as well as non-enzymatic and enzymatic hydrolysis. The instability and reactivity toward proteins have been well studied for a large number of AGs. Moreover, the half-life of AGs in neutral buffer is becoming a common marker for the prediction of toxicity caused by carboxylic acid-containing drugs in the screening of new chemical entities; however, the underlying mechanisms of the toxicity are not elucidated. Recently, an immunostimulation assay has been proposed for the assessment of the toxicological potential of AGs, which may have a better predictability compared with half-life and peptide adduct assays. In addition to in vitro studies, studies in model animals indicate the in vivo toxicological potential of AGs and help understand the mechanisms of the AG toxicity. PMID- 28017535 TI - Bilateral Testicular Metastases and Filariasis in Prostatic Adenocarcinoma. PMID- 28017537 TI - Human leukocyte antigen and idiosyncratic adverse drug reactions. AB - A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose response is restricted by specific HLA risk alleles have been detected from IADR patients, also suggesting an adaptive immune pathogenesis. T-cells from carbamazepine SJS/TEN patients are activated by direct pharmacological interaction between carbamazepine and HLA-B*15:02 expressed on antigen presenting cells (APCs). Abacavir-specific, HLA-B*57:01 restricted T-cells are activated by APCs presenting peptides which are only displayed by the HLA molecule when abacavir is bound during peptide loading. Finally, HLA-B*57:01-restricted activation of T-cells from patients with flucloxacillin-induced liver injury is dependent on processing of drug protein adducts. Based on these observations, it is now possible to utilize blood from healthy drug-naive volunteers to study the priming of naive T-cells to drugs. Future development of these methodologies may lead to the development of assays that predict intrinsic immunogenicity of drugs and chemicals at the preclinical stage of drug development. PMID- 28017538 TI - Sedimentation properties in density gradients correspond with levels of sperm DNA fragmentation, chromatin compaction and binding affinity to hyaluronic acid. AB - Mature spermatozoa bind hyaluronic acid in the extracellular matrix via hyaladherins. Immature spermatozoa may be unable to interact because they do not express the appropriate hyaladherins on their surface. Fresh human semen samples were fractionated using differential density gradient centrifugation (DDGC) and the ability of these fractions to bind hyaluronic acid was evaluated. The presence of sperm hyaladherins was also assessed. CD44 was located mainly on the acrosome and equatorial segment and became more restricted to the equatorial segment in capacitated spermatozoa. Hyaluronic acid-TRITC (hyaluronic acid conjugated with tetramethylrhodamine isothiocyanante), a generic hyaluronic-acid binding reagent, labelled the membrane and the neck region, particularly after capacitation. Sperm populations obtained after DDGC or after interaction with hyaluronic acid were assessed for DNA fragmentation and chromatin maturity. Strong relationships between both measures and sperm sedimentation and hyaluronic acid-binding profiles were revealed. Capacitation enhanced hyaluronic acid binding of both DDGC-pelleted sperm and sperm washed free of seminal fluid. In conclusion, hyaladherins were detected on human sperm and a higher capacity for sperm hyaluronic-acid-binding was shown to correspond with their DDGC sedimentation profiles and with lower levels of DNA fragmentation and better chromatin maturity. Capacitation induced changes in the distribution and presence of hyaladherins may enhance hyaluronic-acid-binding. PMID- 28017539 TI - Staphylococcus aureus from the German general population is highly diverse. AB - OBJECTIVES: This prospective cohort study evaluates colonization dynamics and molecular characteristics of methicillin-susceptible and - resistant Staphylococcus aureus (MSSA/MRSA) in a German general population. METHODS: Nasal swabs of 1878 non-hospitalized adults were screened for S. aureus. Participants were screened thrice in intervals of 6-8 months. Isolates were characterized by spa and agr typing, mecA and mecC possession, respectively, and PCRs targeting virulence factors. RESULTS: 40.9% of all participants carried S. aureus at least once while 0.7% of the participants carried MRSA (mainly spa t011). MSSA isolates (n=1359) were associated with 331 different spa types; t084 (7.7%), t091 (6.1%) and t012 (71, 5.2%) were predominant. Of 206 participants carrying S. aureus at all three sampling time points, 14.1% carried the same spa type continuously; 5.3% carried different spa types with similar repeat patterns, but 80.6% carried S. aureus with unrelated spa types. MSSA isolates frequently harboured genes encoding enterotoxins (sec: 16.6%, seg: 63.1%, sei: 64.5%) and toxic shock syndrome toxin (tst: 17.5%), but rarely Panton-Valentine leukocidin (lukS-PV/lukF PV: 0.2%). CONCLUSIONS: MSSA colonizing human nares in the community are clonally highly diverse. Among those constantly carrying S. aureus, clonal lineages changed over time. The proportion of persistent S. aureus carriers was lower than reported elsewhere. PMID- 28017540 TI - Transcription Factor EB Expression in Early Breast Cancer Relates to Lysosomal/Autophagosomal Markers and Prognosis. AB - BACKGROUND: Disrupting the autophagic balance to trigger autophagic death may open new strategies for cancer therapy. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and may play a role in cancer biology and clinical behavior. METHODS: The expression of TFEB and the lysosomal cancer cell content (expression of lysosomal associated membrane protein 2a [LAMP2a] and cathepsin D) was studied in a series of 100 T1-stage breast carcinomas. Expression patterns were correlated with autophagy/hypoxia-related proteins, angiogenesis, and clinical outcome. The effect of hypoxic/acidic conditions on TFEB kinetics was studied in the MCF-7 cancer cell line. RESULTS: Overexpression of TFEB in cancer cell cytoplasm and the perinuclear/nuclear area was noted in 23 (23%) of 100 cases. High LAMP2a and cathepsin D expression was noted in 30 (30%) of 100 and 28 (28%) of 100 cases, respectively. TFEB expression was directly linked with LAMP2a (P < .0001, r = 0.53), cathepsin D (P = .0002, r = 0.36), light chain 3A (LC3A) (P = .02, r = 0.22), and hypoxia-inducible factor 2-alpha (HIF-2alpha) (P = .01, r = 0.25) expression and inversely with progesterone receptor (P = .01, r = 0.22). High vascular density was directly linked with LAMP2a (P = .05, r = 0.18) and cathepsin D (P = .005, r = 0.28). In Kaplan-Meier survival analysis, TFEB and cathepsin D expression were related to an ominous prognosis (P = .001 and P = .03, respectively). In multivariate analysis, TFEB expression sustained its independent prognostic significance (P = .05, hazard ratio 2.1). In in vitro experiments, acidity triggered overexpression of TFEB and nuclear translocation. CONCLUSION: Intense TFEB expression and lysosomal biogenesis, evident in one fourth of early breast carcinomas, define poor prognosis. Tumor acidity is among the microenvironmental conditions that trigger TFEB overactivity. TFEB is a sound target for the development of lysosomal targeting therapies. PMID- 28017541 TI - Production of flavor compounds from olive mill waste by Rhizopus oryzae and Candida tropicalis. AB - The purpose of this study was to investigate the production of flavor compounds from olive mill waste by microbial fermentation of Rhizopus oryzae and Candida tropicalis. Olive mill waste fermentations were performed in shake and bioreactor cultures. Production of flavor compounds from olive mill waste was followed by Gas Chromatography-Mass spectrometry, Gas chromatography- olfactometry and Spectrum Sensory Analysis(r). As a result, 1.73-log and 3.23-log cfu/mL increases were observed in the microbial populations of R. oryzae and C. tropicalis during shake cultures, respectively. C. tropicalis can produce a higher concentration of d-limonene from olive mill waste than R. oryzae in shake cultures. The concentration of d-limonene was determined as 185.56 and 249.54MUg/kg in the fermented olive mill waste by R. oryzae and C. tropicalis in shake cultures respectively. In contrast, R. oryzae can produce a higher concentration of d limonene (87.73MUg/kg) d-limonene than C. tropicalis (11.95MUg/kg) in bioreactor cultures. Based on sensory analysis, unripe olive, wet towel, sweet aromatic, fermented aromas were determined at high intensity in olive mill waste fermented with R. oryzae meanwhile olive mill waste fermented with C. tropicalis had only a high intensity of unripe olive and oily aroma. PMID- 28017542 TI - Basi cervical inflammatory mass. PMID- 28017543 TI - Cost-effectiveness analysis of the orbital atherectomy system: Two-year follow up. AB - BACKGROUND: The presence of coronary artery calcification is associated with a significant burden of coronary artery disease along with being a predictor of increased adverse ischemic events. The Diamondback 360(r) Coronary Orbital Atherectomy System (OAS) is a novel device designed to facilitate treatment of calcified lesions. This study aimed to evaluate the cost-effectiveness of OAS compared to standard treatment. METHODS: A decision tree model utilizing ORBIT II clinical trial and Medicare data from the health system perspective was constructed. Target population was U.S. patients age>=65 with coronary atherosclerosis due to a calcified coronary lesion, both inpatients and outpatients, and combined over a time horizon of two years for costs and lifetime for mortality. OAS was compared to standard treatment (use of balloon angioplasty to prepare stent-placement site). Outcomes were costs of index event and target vessel revascularization in two years, life-years gained, and incremental cost effectiveness ratios (ICERs). RESULTS: On average, OAS was projected to cost $1702 less than standard treatment for inpatients, $2360 more than standard treatment for outpatients, and $959 more than standard treatment overall; the projected mortality reduction implies 0.41 life-years gained. Compared to standard treatment, OAS was dominant in an inpatient setting, had an ICER of $5759 per QALY in the outpatient setting, and had an ICER of $2340 per QALY overall. These ICERs are below the accepted threshold for highly cost-effective interventions of $50,000 per QALY. CONCLUSIONS: Compared to standard treatment, OAS is likely to be cost-effective and was projected to be cost-saving in an inpatient setting. SUMMARY: A decision tree from the health system perspective was used to evaluate the cost-effectiveness of Diamondback 360(r) Coronary Orbital Atherectomy System (OAS), a novel device designed to facilitate treatment of calcified lesions. OAS was projected to cost $1702 less than standard treatment for inpatients, $2360 more than standard treatment for outpatients, and $959 more than standard treatment overall; the projected mortality reduction implies 0.41 life-years gained. Compared to standard treatment, OAS was dominant in an inpatient setting, had an ICER of $5759 per QALY in the outpatient setting, and overall had an ICER of $2340 per QALY. PMID- 28017544 TI - Context Specificity in Causal Signaling Networks Revealed by Phosphoprotein Profiling. AB - Signaling networks downstream of receptor tyrosine kinases are among the most extensively studied biological networks, but new approaches are needed to elucidate causal relationships between network components and understand how such relationships are influenced by biological context and disease. Here, we investigate the context specificity of signaling networks within a causal conceptual framework using reverse-phase protein array time-course assays and network analysis approaches. We focus on a well-defined set of signaling proteins profiled under inhibition with five kinase inhibitors in 32 contexts: four breast cancer cell lines (MCF7, UACC812, BT20, and BT549) under eight stimulus conditions. The data, spanning multiple pathways and comprising ~70,000 phosphoprotein and ~260,000 protein measurements, provide a wealth of testable, context-specific hypotheses, several of which we experimentally validate. Furthermore, the data provide a unique resource for computational methods development, permitting empirical assessment of causal network learning in a complex, mammalian setting. PMID- 28017545 TI - High-sensitivity Troponin T Assay in Asymptomatic High Cardiovascular Risk Patients. The TUSARC Registry. AB - INTRODUCTION AND OBJECTIVES: High-sensitivity troponin T assays (Hs-TnT) have been carried out in selected populations in clinical trials and in registries of the general population with low cardiovascular risk (CVR). The aim of this study was to determine the proportion of individuals with detectable Hs-TnT and the proportion of individuals with elevated Hs-TnT in a Spanish population of asymptomatic individuals with very high CVR, as well as the parameters associated with Hs-TnT elevation. METHODS: The study included 690 patients. Hs-TnT detection and Hs-TnT elevation (>=99th percentile value), as well the association of elevated Hs-TnT and clinical, analytical, and treatment data were analyzed. RESULTS: Hs-TnT was analyzed in 646 patients and was detected in 645. Elevated TnT was detected in 212 patients (32.9%). On multivariate analysis, elevated TnT was independently associated with male sex (OR, 2.81; 95%CI, 1.67-4.73; P < .001), older age (OR, 1.06; 95%CI, 1.04-1.09; P < .001), a higher body mass index (OR, 1.07; 95%CI, 1.02-1.12; P < .002), insulin therapy (OR, 1.99; 95%CI, 1.15 3.46; P = .01), history of heart failure (OR, 3.92; 95%CI, 1.24-12.39; P = .02), and estimated glomerular filtration rate calculated by CKD-EPI (OR, 0.96; 95%CI, 0.95-0.97; P < .001). CONCLUSIONS: In a Spanish population of asymptomatic individuals at very high CVR, Hs-TnT was associated with older age, male sex, higher body mass index, insulin therapy, history of heart failure, and lower glomerular filtration rate. PMID- 28017546 TI - A double-blind randomized prospective study comparing prilocaine versus ropivacaine in upper blepharoplasty. AB - BACKGROUND: Upper blepharoplasties are a common procedure in plastic surgery. This procedure can be performed effectively under local anesthesia with or without sedation. The ideal local anesthetic should cause less intraoperative bleeding and less postoperative edema. Our study aimed to show the difference between the two local anesthetics 1% prilocaine (Xylonaest) in combination with epinephrine 1:100,000 and ropivacaine (Naropin) in combination with epinephrine 1:100,000 including sodium chloride, particularly in regard to swelling and bleeding in patients undergoing upper blepharoplasties. MATERIAL AND METHODS: In this double-blind, prospective, randomized study, 31 patients between March 2014 and September 2014 were included. The anesthetic agents used in all cases were 1% prilocaine (Xylonaest) in combination with epinephrine 1:100,000 for one side and ropivacaine consisting of 10-mg Naropin, 5-ml sodium chloride, and 1-ml epinephrine for the other side. The data presented in this study were collected by one of the surgeons performing the surgery. Intraoperative bleeding and postoperative edema were both calculated using a score of five points for each. RESULTS: The average bleeding tendency was 3.39 for prilocaine and 1.71 for local ropivacaine, showing a significant difference (p < 0.0001) between both local anesthetics in bleeding tendency. There was also a significant minor swelling at all times on the side on which ropivacaine was used. DISCUSSION: In our study, we demonstrated that ropivacaine (Naropin) has less intra- and postoperative side effects including swelling and bleeding compared with prilocaine (Xylonaest). PMID- 28017547 TI - A systematic review of waterborne infections from nontuberculous mycobacteria in health care facility water systems. AB - Healthcare-acquired infections are an increasing problem for health care providers and policy makers. Water is an overlooked source of infectious microorganisms in health care facilities. Waterborne nontuberculous mycobacteria (NTM) are ubiquitous, and particularly problematic in health care facility water systems, and cause a variety of diseases. The purpose of this review is to assess health care associated NTM infections from health care facility water systems. We documented susceptible populations, modes of transmission, and the median attack rate (e.g. patients infected per patients exposed). We aimed to identify transmission risk factors and inform evidence-based policies for infection control and prevention. We searched Embase, PubMed, Web of Science and clinicaltrials.gov without date restrictions. English language articles with original data on NTM waterborne infections in health care settings were included. Randomized controlled trials, descriptive studies (case reports, case series), case-control studies, cohort studies, cross-sectional surveys, and quasi experimental studies on nosocomial waterborne infections were included. Three investigators independently screened titles and abstracts for relevant articles, and one screened full-text articles. Data were extracted by one investigator, and a second confirmed accuracy for 10% of results. We included 22 observational studies. Immunocompromised, post-surgical, and hemodialysis patients were commonly affected populations. A range of exposure routes such as uncovered central venous catheters (CVCs), wound exposure, and contamination during surgical procedures was reported. The median attack rate was 12.1% (interquartile range, 11-27.2). Waterborne NTM infection affects susceptible patients through common, preventable exposure routes. Effective prevention strategies will require both medical and environmental health expertise, and inter-professional cooperation will optimize these efforts. PMID- 28017548 TI - Evaluating the role of TMEM230 variants in Parkinson's disease. PMID- 28017549 TI - Gender effect on non-motor symptoms in Parkinson's disease: are men more at risk? AB - INTRODUCTION: Several gender differences have been reported in Parkinson's Disease (PD). We evaluated the burden of non-motor symptoms (NMS) in PD and the possible gender differences in their occurrence. METHODS: The FRAGAMP study is a large multicenter case-control study. PD patients and controls underwent a face to-face interview and a neurological examination performed by trained neurologists. Presence of NMS was investigated using a standardized questionnaire; cognitive impairment and depression were assessed using the Mini Mental State Examination and the Hamilton Depression Rating Scale respectively. RESULTS: 585 PD patients (59.5% men) and 481 controls (34.9% men) were enrolled in the study. All NMS were significantly more frequent among PD patients than controls. PD women showed a significantly higher frequency of depression and urinary disturbances than parkinsonian men; a close frequency among PD women and men was recorded for hallucination, cognitive impairment and sleep disorders. Nonetheless, with respect to the control population, according to logistic regression stratified by sex and adjusted by age, PD men showed a stronger positive significant association with almost all NMS compared to women, excepting for urinary disturbances. The strongest association among PD men was recorded for cognitive impairment (adjusted OR 5.44 for men and 2.82 for women) and depression (adjusted OR 30.88 for men and 12.72 for women). CONCLUSIONS: With respect to the general population, presence of NMS was stronger associated with male gender. Our data suggest that the presence of NMS among PD men is more strictly due to the neurodegenerative processes related to PD. PMID- 28017550 TI - A novel bioconversion for value-added products from food waste using Musca domestica. AB - Food waste, as a major part of the municipal solid waste has been generated increasingly worldwide. Efficient and feasible utilization of this waste material for productivity process is significant for both economical and environmental reasons. In the present study, Musca domestica larva was used as the carrier to conduct a bioconversion with food waste to get the value-added maggot protein, oil and organic fertilizers. Methods of adult flies rearing, culture medium adjuvant selection, maggot culture conditions, stocking density and the valorization of the waste have been explored. From the experimental results, every 1000g culture mediums (700g food waste and 300g adjuvant) could be disposed by 1.5g M. domestica eggs under proper culture conditions after emergence in just 4days, 42.95+/-0.25% of which had been consumed and the culture medium residues could be used as good organic fertilizers, accompanying with the food waste consumption, ~53.08g dried maggots that contained 57.06+/-2.19% protein and 15.07+/-2.03% oil had been produced. The maggot protein for its outstanding pharmacological activities is regarded as a good raw material in the field of medicine and animal feeding. Meanwhile, the maggot oil represents a potential alternative feedstock for biodiesel production. In our study, the maggot biodiesel was obtained after the procedure of transesterification reaction with methanol and the productivity was 87.71%. PMID- 28017551 TI - Effect of volumetric organic loading rate (OLR) on H2 and CH4 production by two stage anaerobic co-digestion of food waste and brown water. AB - Two-stage anaerobic digestion system consisting of two continuously stirred tank reactors (CSTRs) operating at mesophillic conditions (37 degrees C) were studied. The aim of this study is to determine optimum Hydraulic Retention Time (HRT) of the two-stage anaerobic digester system for hydrogen and methane production. This paper also discusses the effect of OLR with change in HRT on the system. Four different HRTs of 48, 24, 12, 8h were monitored for acidogenic reactor, which provided OLR of 17.7, 34.8, 70.8, 106gVS/L.d respectively. Two HRTs of 15days and 20days were studied with OLR of 1.24 and 1.76gVS/L.d respectively in methanogenic reactor. Hydrogen production at higher OLR and shorter HRT seemed favorable 106gVS/L.d (8h) in acidogenic reactor system. In methanogenic reactor system HRT of 20day with OLR of 1.24gVS/L.d was found optimum in terms of methane production and organic removal. The result of this study illustrated the optimum HRT of 8h and 20days in acidogenic stage and methanogenic stage for maximum hydrogen and methane production. PMID- 28017552 TI - [Spanish adaptation of the 2016 European Guidelines on cardiovascular disease prevention in clinical practice]. AB - The VI European Guidelines for Cardiovascular Prevention recommend combining population and high-risk strategies with lifestyle changes as a cornerstone of prevention, and propose the SCORE function to quantify cardiovascular risk. The guidelines highlight disease specific interventions, and conditions as women, young people and ethnic minorities. Screening for subclinical atherosclerosis with noninvasive imaging techniques is not recommended. The guidelines distinguish four risk levels (very high, high, moderate and low) with therapeutic objectives for lipid control according to risk. Diabetes mellitus confers a high risk, except for subjects with type 2 diabetes with less than <10 years of evolution, without other risk factors or complications, or type 1 diabetes of short evolution without complications. The decision to start pharmacological treatment of arterial hypertension will depend on the blood pressure level and the cardiovascular risk, taking into account the lesion of target organs. The guidelines don't recommend antiplatelet drugs in primary prevention because of the increased bleeding risk. The low adherence to the medication requires simplified therapeutic regimes and to identify and combat its causes. The guidelines highlight the responsibility of health professionals to take an active role in advocating evidence-based interventions at the population level, and propose effective interventions, at individual and population level, to promote a healthy diet, the practice of physical activity, the cessation of smoking and the protection against alcohol abuse. PMID- 28017553 TI - Coronary Computed Tomographic Angiography - The evidence dominates! PMID- 28017554 TI - Trends and predictors of HIV-1 acquired drug resistance in Minas Gerais, Brazil: 2002-2012. AB - Several studies show that the prevalence of multidrug-resistant HIV-1 virus is declining over time. A retrospective cohort study was carried out to evaluate the trends of drug resistance in antiretroviral treatment-exposed individuals in a state of a middle-income country, Minas Gerais, southeast region of Brazil. We analyzed 2115 HIV-1 sequences from 2002 up to 2012, from 52 cities of Minas Gerais. The groups were analyzed according to the definitions: "IAS - 3 class mutations", if >=1 drug resistance mutation from IAS 2015 list (DRM) was present in each class; "No fully susceptible drugs" as the absence of any fully susceptible drug in Stanford algorithm; and "GSS>=2", when a maximum calculated GSS (genotypic susceptibility score) was >=2 or >=3, counting only drugs available in Brazil and USA at given calendar years. Time trends of resistance were analyzed by Cochran-Armitage test. We observed a decrease in the rate resistance mutations for PI, NRTI, "IAS - 3 class mutations", and "No fully susceptible drugs" over these 11 years, from 69.2% to 20.7%, 92.3% to 90.2%, 46.2% to 22.5%, and 12.8% to 5.7%, respectively (p<0.05). Resistance to NNRTI increased from 74.4% to 81.6%, mainly because of K103N mutation. The GSS score >=2 increased during the years from 35.9% to 87.3% (p<0.001). We demonstrate that resistance to PI and to the three main classes simultaneously are declining, although the number of patients on of antiretroviral therapy has doubled in the last ten years in Brazil (125,000 in 2002 to 400,000 in 2014). Broader resistance testing and the availability of more therapeutic options might have influenced this decline. The increase in NNRTI resistance can limit this class as first line treatment in Brazil in the future. PMID- 28017555 TI - A preliminary examination of self-concept in older adolescents and young adults with Gilles de la Tourette syndrome. AB - INTRODUCTION: Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterised by multiple tics and often associated with behavioural problems. Although there is evidence of significantly reduced self-esteem in children and adolescents with GTS, little is known about perceived self-concept and its clinical determinants at the transition age between adolescence and adulthood. We therefore set out to investigate self-concept in a clinical sample of young patients with GTS at this crucial age for personal development. METHODS: In addition to standard demographic and clinical data, we collected self-ratings using a standardised battery of psychometric instruments, as well as the Multidimensional Self Concept Scale, a comprehensive questionnaire developed to assess self-concept in subjects aged 9- to 19 years, tapping into the social, competence, affect, academic, family, and physical domains. RESULTS: We found that patients diagnosed with at least one co-morbid psychiatric disorder ("GTS-plus" phenotype) reported significantly lower self-concept than patients with "pure GTS", whereas tic-related variables had no impact on self-concept. Anxiety symptoms were the main determinants of self-concept, especially trait anxiety with regard to social and affective domains. Affective symptoms could also have a negative impact on the physical, affective, competence, and social domains of self-concept. CONCLUSION: Routine screening for anxiety and affective symptoms should be recommended in all patients with GTS seen at transition clinics from paediatric to adult care, in order to implement effective treatment interventions whenever possible. PMID- 28017556 TI - Bilateral globus pallidus internus deep brain stimulation for dyskinetic cerebral palsy supports success of cochlear implantation in a 5-year old ex-24 week preterm twin with absent cerebellar hemispheres. AB - BACKGROUND: Early onset dystonia (dyskinesia) and deafness in childhood pose significant challenges for children and carers and are the cause of multiple disability. It is particularly tragic when the child cannot make use of early cochlear implantation (CI) technology to relieve deafness and improve language and communication, because severe cervical and truncal dystonia brushes off the magnetic amplifier behind the ears. Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) neuromodulation can reduce dyskinesia, thus supporting CI neuromodulation success. METHODS: We describe the importance of the order of dual neuromodulation surgery for dystonia and deafness. First with bilateral GPi DBS using a rechargeable ACTIVA-RC neurostimulator followed 5 months later by unilateral CI with a Harmony (BTE) Advanced Bionics Hi Res 90 K cochlear device. This double neuromodulation was performed in series in a 12.5 kg 5 year-old ex-24 week gestation-born twin without a cerebellum. RESULTS: Relief of dyskinesia enabled continuous use of the CI amplifier. Language understanding and communication improved. Dystonic storms abated. Tolerance of sitting increased with emergence of manual function. Status dystonicus ensued 10 days after ACTIVA RC removal for infection-erosion at 3 years and 10 months. He required intensive care and DBS re-implantation 3 weeks later together with 8 months of hospital care. Today he is virtually back to the level of functioning before the DBS removal in 2012 and background medication continues to be slowly weaned. CONCLUSION: This case illustrates that early neuromodulation with DBS for dystonic cerebral palsy followed by CI for deafness is beneficial. Both should be considered early i.e. under the age of five years. The DBS should precede the CI to maximise dystonia reduction and thus benefits from CI. This requires close working between the paediatric DBS and CI services. PMID- 28017557 TI - Epileptic phenotypes, electroclinical features and clinical characteristics in 17 children with anti-NMDAR encephalitis. AB - BACKGROUND: Anti-N-methyl d-aspartate receptor (NMDAR) encephalitis is a rare disorder characterized by seizures, neuropsychiatric symptoms, dyskinesia and autonomic instability. OBJECTIVE: Aim of the present study was to evaluate the seizure phenotypes and electroencephalogram (EEG) features in children with anti NMDAR encephalitis. METHODS: Seizure types, electroclinical features and clinical characteristics of 17 children with anti-NMDAR encephalitis were analysed in a retrospective case series from nine centres in Europe. RESULTS: Nearly half (8/17) of the children presented with psychiatric symptoms, whereas in 4/17 patients seizures were the first symptom and in 5/17 both symptoms occurred at the same time. During the following course seizures were reported in 16/17 children. The first EEG detected generalized slowing in 11/17 patients, focal slowing in 3/17 and normal background activity in only 3/17 children. The extreme delta brush (EDB) pattern was detected in 9/17 (53%) patients. CONCLUSION: In addition to psychiatric symptoms, children with anti-NMDAR encephalitis often show generalized slowing in EEG with or without seizures at initial presentation. EDB is present in half of all children and is potentially a helpful tool for early detection of this immune-mediated disease. PMID- 28017558 TI - Challenges to eliminate rabies virus infection in China by 2020. PMID- 28017560 TI - Responding to the threat of urban yellow fever outbreaks. PMID- 28017559 TI - Spread of yellow fever virus outbreak in Angola and the Democratic Republic of the Congo 2015-16: a modelling study. AB - BACKGROUND: Since late 2015, an epidemic of yellow fever has caused more than 7334 suspected cases in Angola and the Democratic Republic of the Congo, including 393 deaths. We sought to understand the spatial spread of this outbreak to optimise the use of the limited available vaccine stock. METHODS: We jointly analysed datasets describing the epidemic of yellow fever, vector suitability, human demography, and mobility in central Africa to understand and predict the spread of yellow fever virus. We used a standard logistic model to infer the district-specific yellow fever virus infection risk during the course of the epidemic in the region. FINDINGS: The early spread of yellow fever virus was characterised by fast exponential growth (doubling time of 5-7 days) and fast spatial expansion (49 districts reported cases after only 3 months) from Luanda, the capital of Angola. Early invasion was positively correlated with high population density (Pearson's r 0.52, 95% CI 0.34-0.66). The further away locations were from Luanda, the later the date of invasion (Pearson's r 0.60, 95% CI 0.52-0.66). In a Cox model, we noted that districts with higher population densities also had higher risks of sustained transmission (the hazard ratio for cases ceasing was 0.74, 95% CI 0.13-0.92 per log-unit increase in the population size of a district). A model that captured human mobility and vector suitability successfully discriminated districts with high risk of invasion from others with a lower risk (area under the curve 0.94, 95% CI 0.92-0.97). If at the start of the epidemic, sufficient vaccines had been available to target 50 out of 313 districts in the area, our model would have correctly identified 27 (84%) of the 32 districts that were eventually affected. INTERPRETATION: Our findings show the contributions of ecological and demographic factors to the ongoing spread of the yellow fever outbreak and provide estimates of the areas that could be prioritised for vaccination, although other constraints such as vaccine supply and delivery need to be accounted for before such insights can be translated into policy. FUNDING: Wellcome Trust. PMID- 28017561 TI - Discretized multi-level elution trajectory: A proof-of-concept demonstration. AB - Biomolecular and pharmaceutical downstream processing is dominated by chromatographic separation, which is associated with high product quality, low capacity and high costs. The separation can be optimized to minimize the costs while achieving a high purity. This paper presents an experimental validation of a discretized multi-level elution (DiME) trajectory, implemented on commercially available chromatography equipment. The tertiary protein separation of ribonuclease A, cytochrome C and lysozyme was used as a case study. A mechanistic model was calibrated using step and linear gradient experiments. The model was simulated together with the state sensitivities with respect to model parameters, which was used in the Levenberg-Marquardt algorithm to fit the model response to the experimental data. The model was used to solve the dynamic optimization problem of maximizing the yield of cytochrome C given a 95% purity requirement, 1000s processing time and 50 salt concentration levels in the elution trajectory. The model was spatially discretized using finite volumes and temporally discretized using direct collocation. The corresponding non-linear programming problem was solved with IPOPT. Once the optimal salt trajectory was found it was experimentally implemented on an AKTA Pure using an OPC interface. The optimal trajectory was analyzed in-line by UV absorbance measurements and off-line by analysis of collected fractions. The results presented in this study show the successful experimental realization of DiME trajectories and how to use model calibration, optimization and control to realize DiME trajectories for any chromatography separation problem. PMID- 28017562 TI - Optimization of non-linear gradient in hydrophobic interaction chromatography for the analytical characterization of antibody-drug conjugates. AB - The goal of this work was to evaluate the potential of non-linear gradients in hydrophobic interaction chromatography (HIC), to improve the separation between the different homologous species (drug-to-antibody, DAR) of commercial antibody drug conjugates (ADC). The selectivities between Brentuximab Vedotin species were measured using three different gradient profiles, namely linear, power function based and logarithmic ones. The logarithmic gradient provides the most equidistant retention distribution for the DAR species and offers the best overall separation of cysteine linked ADC in HIC. Another important advantage of the logarithmic gradient, is its peak focusing effect for the DAR0 species, which is particularly useful to improve the quantitation limit of DAR0. Finally, the logarithmic behavior of DAR species of ADC in HIC was modelled using two different approaches, based on i) the linear solvent strength theory (LSS) and two scouting linear gradients and ii) a new derived equation and two logarithmic scouting gradients. In both cases, the retention predictions were excellent and systematically below 3% compared to the experimental values. PMID- 28017563 TI - Carbohydrate analysis on hybrid poly(dimethylsiloxane)/glass chips dynamically coated with ionic complementary peptide. AB - A facile and efficient dynamic coating method using an ionic complementary peptide was established for high-performance separation of 8-aminopyrene-1,3,6 trisulfonic acid (APTS)-labeled carbohydrates in a hybrid poly(dimethylsiloxane) (PDMS)/glass microfluidic channel. EAK16-II with a sequence of [(Ala-Glu-Ala-Glu Ala-Lys-Ala-Lys)2] can readily self-organize into a complete coating layer tightly adsorbed on both hydrophobic PDMS and hydrophilic glass surfaces, which efficiently suppressed nonspecific analyte adsorption and minimized electroosmotic flow (EOF). Separation conditions were systematically investigated with respect to EAK16-II concentration, running buffer, buffer pH, and field strength (Esep). Under the optimal conditions, rapid and reproducible separations of maltodextrin ladder, glycans from glucosamine capsules, tablets, and pomegranate peel extracts were achieved with over 450000 theoretical plates per meter in the hybrid PDMS/glass microchannels dynamically coated with 1.0mg/mL EAK16-II-0.05% n-dodecyl beta-d-maltoside (DDM), and the relative standard deviation (RSD) values were less than 3.2% (n=4) for the migration times. The present work provides a facile and efficient means to minimize EOF and nonspecific analyte adsorption in microfluidic chips fabricated in various substrates, thereby broadening the applications of microfluidic chips in complicated biological assays. PMID- 28017564 TI - Rapid and sensitive analysis of polychlorinated biphenyls and acrylamide in food samples using ionic liquid-based in situ dispersive liquid-liquid microextraction coupled to headspace gas chromatography. AB - A simple and rapid ionic liquid (IL)-based in situ dispersive liquid-liquid microextraction (DLLME) method was developed and coupled to headspace gas chromatography (HS-GC) employing electron capture (ECD) and mass spectrometry (MS) detection for the analysis of polychlorinated biphenyls (PCBs) and acrylamide at trace levels from milk and coffee samples. The chemical structures of the halide-based ILs were tailored by introducing various functional groups to the cations to evaluate the effect of different structural features on the extraction efficiency of the target analytes. Extraction parameters including the molar ratio of IL to metathesis reagent and IL mass were optimized. The effects of HS oven temperature and the HS sample vial volume on the analyte response were also evaluated. The optimized in situ DLLME method exhibited good analytical precision, good linearity, and provided detection limits down to the low ppt level for PCBs and the low ppb level for acrylamide in aqueous samples. The matrix-compatibility of the developed method was also established by quantifying acrylamide in brewed coffee samples. This method is much simpler and faster compared to previously reported GC-MS methods using solid-phase microextraction (SPME) for the extraction/preconcentration of PCBs and acrylamide from complex food samples. PMID- 28017565 TI - Iron (II, III) oxide/multi-walled carbon nanotube composite as solid-phase extraction sorbent followed by ultra-high performance liquid chromatography tandem mass spectrometry for simultaneous determination of zearalenone and type A trichothecenes in Salviae miltiorrhizae Radix et Rhizoma (Danshen). AB - For the first time, a reliable solid-phase extraction (SPE) procedure using iron (II, III) oxide (Fe3O4)/multi-walled carbon nanotube (MWCNT) composite as sorbents was proposed for purification and enrichment of zearalenone (ZEA) and four type A trichothecenes (T-2 toxin (T-2), HT-2 toxin (HT-2), neosolaniol (NEO) and diacetoxyscirpenol (DAS)) in Salviae miltiorrhiza Radix et Rhizoma (Danshen). The Fe3O4/MWCNT composite was synthesized by assembling Fe3O4 with MWCNT by sonication through an "aggregation wrap" mechanism and several key parameters affecting the performance of SPE procedure such as the composition of sample loading solutions, washing and elution solvents were thoroughly investigated. After optimization, 2% acetonitrile aqueous solution as the loading solution, 5% methanol aqueous solution as the washing solution and acetone containing 0.5% formic acid as the elution solvent presented an excellent purification efficiency for the five targets in Danshen. Under the optimal sample pretreatment conditions followed by analysis with ultra-high performance liquid chromatography-tandem mass spectrometry, satisfactory linearity (R2>=0.991), high sensitivity (limit of quantification in the range of 1.20-4.80MUgkg-1), good recovery (73.7-91.9%) and acceptable precision (RSD, 2.1-13.3%) were obtained. The applicability of the validated method was further verified in real Salviae miltiorrhiza Radix et Rhizoma samples. PMID- 28017566 TI - Magnetic ionic liquid aqueous two-phase system coupled with high performance liquid chromatography: A rapid approach for determination of chloramphenicol in water environment. AB - A novel organic magnetic ionic liquid based on guanidinium cation was synthesized and characterized. A new method of magnetic ionic liquid aqueous two-phase system (MILATPs) coupled with high-performance liquid chromatography (HPLC) was established to preconcentrate and determine trace amount of chloramphenicol (CAP) in water environment for the first time. In the absence of volatile organic solvents, MILATPs not only has the excellent properties of rapid extraction, but also exhibits a response to an external magnetic field which can be applied to assist phase separation. The phase behavior of MILATPs was investigated and phase equilibrium data were correlated by Merchuk equation. Various influencing factors on CAP recovery were systematically investigated and optimized. Under the optimal conditions, the preconcentration factor was 147.2 with the precision values (RSD%) of 2.42% and 4.45% for intra-day (n=6) and inter-day (n=6), respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.14ngmL-1 and 0.42ngmL-1, respectively. Fine linear range of 12.25ngmL-1-2200ngmL-1 was obtained. Finally, the validated method was successfully applied for the analysis of CAP in some environmental waters with the recoveries for the spiked samples in the acceptable range of 94.6%-99.72%. Hopefully, MILATPs is showing great potential to promote new development in the field of extraction, separation and pretreatment of various biochemical samples. PMID- 28017567 TI - Drug-to-antibody determination for an antibody-drug-conjugate utilizing cathepsin B digestion coupled with reversed-phase high-pressure liquid chromatography analysis. AB - Antibody drug conjugates or ADCs are currently being evaluated for their effectiveness as targeted chemotherapeutic agents across the pharmaceutical industry. Due to the complexity arising from the choice of antibody, drug and linker; analytical methods for release and stability testing are required to provide a detailed understanding of both the antibody and the drug during manufacturing and storage. The ADC analyzed in this work consists of a tubulysin drug analogue that is randomly conjugated to lysine residues in a human IgG1 antibody. The drug is attached to the lysine residue through a peptidic, hydrolytically stable, cathepsin B cleavable linker. The random lysine conjugation produces a heterogeneous mixture of conjugated species with a variable drug-to-antibody ratio (DAR), therefore, the average amount of drug attached to the antibody is a critical parameter that needs to be monitored. In this work we have developed a universal method for determining DAR in ADCs that employ a cathepsin B cleavable linker. The ADC is first cleaved at the hinge region and then mildly reduced prior to treatment with the cathepsin B enzyme to release the drug from the antibody fragments. This pre-treatment allows the cathepsin B enzyme unrestricted access to the cleavage sites and ensures optimal conditions for the cathepsin B to cleave all the drug from the ADC molecule. The cleaved drug is then separated from the protein components by reversed phase high performance liquid chromatography (RP-HPLC) and quantitated using UV absorbance. This method affords superior cleavage efficiency to other methods that only employ a cathepsin digestion step as confirmed by mass spectrometry analysis. This method was shown to be accurate and precise for the quantitation of the DAR for two different random lysine conjugated ADC molecules. PMID- 28017568 TI - Integration of the free liquid membrane into electrokinetic supercharging - capillary electrophoresis for the determination of cationic herbicides in environmental water samples. AB - A new approach based on the integration of the free liquid membrane (FLM) into electrokinetic supercharging (EKS) was demonstrated to be a new powerful tool used in order to enhance online preconcentration efficiency in capillary electrophoresis (CE). A small plug of water immiscible organic solvent was used as a membrane interface during the electrokinetic sample injection step in EKS in order to significantly enhance the analyte stacking efficiency. The new online preconcentration strategy was evaluated for the determination of paraquat and diquat present in the environmental water samples. The optimised FLM-EKS conditions employed were as follows: hydrodynamic injection (HI) of 20mM potassium chloride as leading electrolyte at 50mbar for 75s (3% of the total capillary volume) followed by the HI of tris(2-ethylhexyl) phosphate (TEHP) as FLM at a 1mm length (0.1% of the capillary volume). The sample was injected at 10kV for 360s, followed by the HI of 20mM cetyl trimethylammonium bromide (CTAB) as terminating electrolyte at 50mbar for 50s (2% of the total capillary volume). The separation was performed in 12mM ammonium acetate and 30mM NaCl containing 20% MeOH at +25kV with UV detection at 205nm. Under optimised conditions, the sensitivity was enhanced between 1500- and 1866-fold when compared with the typical HI at 50mbar for 50s. The detection limit of the method for paraquat and diquat was 0.15-0.20ng/mL, with RSDs below 5.5%. Relative recoveries in spiked river water were in the range of 95.4-97.5%. A comparison was also made between the proposed approach with sole preconcentration of the field-enhanced sample injection (FASI) and EKS in the absence of the FLM. PMID- 28017569 TI - A Targeted High-Throughput Next-Generation Sequencing Panel for Clinical Screening of Mutations, Gene Amplifications, and Fusions in Solid Tumors. AB - Clinical next-generation sequencing (NGS) assay choice requires careful consideration of panel size, inclusion of appropriate markers, ability to detect multiple genomic aberration types, compatibility with low quality and quantity of nucleic acids, and work flow feasibility. Herein, in a high-volume clinical molecular diagnostic laboratory, we have validated a targeted high-multiplex PCR based NGS panel (OncoMine Comprehensive Assay) coupled with high-throughput sequencing using Ion Proton sequencer for routine screening of solid tumors. The panel screens 143 genes using low amounts of formalin-fixed, paraffin-embedded DNA (20 ng) and RNA (10 ng). A large cohort of 121 tumor samples representing 13 tumor types and 6 cancer cell lines was used to assess the capability of the panel to detect 148 single-nucleotide variants, 49 insertions or deletions, 40 copy number aberrations, and a subset of gene fusions. High levels of analytic sensitivity and reproducibility and robust detection sensitivity were observed. Furthermore, we demonstrated the critical utility of sequencing paired normal tissues to improve the accuracy of detecting somatic mutations in a background of germline variants. We also validated use of the Ion Chef automated bead templating and chip loading system, which represents a major work flow improvement. In summary, we present data establishing the OncoMine Comprehensive Assay-Ion Proton platform to be well suited for implementation as a routine clinical NGS test for solid tumors. PMID- 28017570 TI - The clinical relevance of imatinib plasma trough concentrations in chronic myeloid leukemia. A Belgian study. AB - : This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02, R2=0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822ng/mL vs 1099ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p=0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. IN CONCLUSION: in patients treated with imatinib at a fixed daily dose of 400mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients. PMID- 28017571 TI - Response to Letter to the Editor on "The Impact of Imaging Modality on the Measurement of Coronal Plane Alignment After Total Knee Arthroplasty". PMID- 28017572 TI - Data Sharing Between Providers and Quality Initiatives Eliminate Unnecessary Nursing Home Admissions. AB - BACKGROUND: The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) has monitored discharge disposition, after total hip and knee arthroplasties, since inception in 2012 and found the standardized risk of extended care facility (ECF) placement to be highly variable between hospitals. METHODS: The variation in standardized risks of ECF placement among MARCQI member sites was reported to the collaborative. At the May 2, 2014 quarterly meeting, a quality initiative was started, emphasizing the wide variability between hospitals, the contribution of hospital and surgeon to that variability using median odds ratios, and the need for outlier hospitals to initiate quality improvement (QI) processes. Patients from 29 hospitals that were members of MARCQI before the intervention were included in this analysis. We compared standardized risks before and after the intervention in the entire cohort, and for 3 hospitals that implemented institution-specific QI projects. We report changes in ECF placement, length of stay, emergency room visits, and readmissions over time. RESULTS: This study includes 31,347 patients before and 20,879 patients after the implementation of the quality initiative. The range in standardized risk dropped from 9.4%-46.1% to 9.4%-32.4% and the average dropped from 23.0% to 19.6%. Three outlier hospitals decreased their absolute risk of ECF placement by 12.2%, 8.9%, and 12.4% after QI, without increases in adverse outcomes. CONCLUSION: Discharge to ECF after primary hip and knee arthroplasties is highly variable and influenced by hospital and surgeon practices. Hospital level QI measures can decrease ECF admissions. PMID- 28017573 TI - Corrigendum to 'Minimum 10-Year Follow-Up of Cementless Total Hip Arthroplasty Using a Contemporary Triple-Tapered Titanium Stem' [Journal of Arthroplasty 31 (2016) 2231-2236]. PMID- 28017574 TI - Correcting Severe Varus Deformity Using Trial Components During Total Knee Arthroplasty. AB - BACKGROUND: Extensive medial soft tissue release may be necessary to correct severe varus deformity during total knee arthroplasty (TKA). However, this procedure may result in instability. Here, we describe a novel soft tissue balancing technique, which can minimize medial release in severe varus deformity during TKA. METHODS: Fifty knees (40 patients) with hip-knee-ankle angle of more than 20 degrees of varus were corrected using this technique (group 1). After achieving flexion gap balancing by needle puncturing and spreading of the superficial medial collateral ligament, extension gap balancing was obtained by gradual extension with the trial components in place. After group 1 was set, a one-to-one patient-matched control group who had mild varus deformity was selected by propensity score matching (50 knees, 48 patients, group 2). At postoperative 1 year, mediolateral laxity was compared between the 2 groups using the stress radiographs. Clinical outcomes were also compared using the Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: There were no differences in mean medial and lateral laxities between groups 1 and 2 at 1 year after the operation (medial laxity: 2.3 degrees +/- 1.4 degrees and 2.7 degrees +/- 1.3 degrees , respectively, P = .310) (lateral laxity: 3.6 degrees +/- 1.7 degrees and 3.2 degrees +/- 2.0 degrees , respectively, P = .459). There were no significant differences in postoperative clinical scores and knee alignment. CONCLUSION: Our technique of obtaining extension gap balancing using trial components led to safe and effective balancing by avoiding unnecessary extensive release in severe varus deformity during TKA. PMID- 28017575 TI - The correlation between serum total bilirubin and outcomes in patients with different subtypes of coronary artery disease. AB - BACKGROUNDS: The relation between serum total bilirubin (TBi) and mortality in patients with established coronary artery disease (CAD) remains undefined. We try to investigate the role of the subtypes of CAD in the association. METHODS: A total of 3013 patients with angiographically obstructive CAD were enrolled. A retrospective analysis was conducted. Patients were divided into 3 groups as follows: stable CAD (SCAD), unstable angina pectoris (UAP) and acute myocardial infarction (AMI). The predictive values of TBi for 30-day and long-term mortality were assessed using logistic and Cox regression, respectively. RESULTS: Higher initial serum TBi levels were significantly associated with increased risk of short-term mortality (OR 2.35, 95% CI 1.15-4.77) in AMI group. However, the association was absent among patients with SCAD and UAP. Serum TBi was able to independently predict the long-term mortality in SCAD (HR 0.34, 95% CI 0.16-0.70) and UAP (HR 0.49, 95% CI 0.31-0.78) groups. However, there was no significant relation between TBi and long-term mortality in AMI groups. CONCLUSION: The different subtypes of CAD affected the relation between serum TBi and clinical prognosis. Initial serum TBi was positively correlated with short-term mortality of AMI patients, and negatively correlated with long-term mortality in SCAD or UAP patients. PMID- 28017576 TI - Clinical correlates of persistently elevated liver enzymes in type 2 diabetic outpatients. AB - AIMS: To evaluate the prevalence and the clinical implication of persistently elevated liver enzymes in diabetic subjects, with no evidence of viral hepatitis infection or alcohol abuse. METHODS: Clinical, lifestyle, anthropometric data and laboratory test values were collected in 916 type 2 diabetic subjects, examined for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltranspeptidase (gamma-GT) levels at two different time points. RESULTS: Five hundred forty four patients (59.4%) showed normal (NLT group) and 182 (19.9%) persistently elevated (ELT group) liver tests in both determinations. ELT patients were prevalently men (P=0.016), younger (P<0.0001) and with a lower duration of diabetes (P=0.008). Adjusting for age and sex, ELT subjects had significantly higher BMI (P<0.001), waist circumference (P=0.010), systolic (P=0.017) and diastolic blood pressure (P<0.001), and higher levels of fasting blood glucose (P=0.023), and triglycerides (P<0.0001). Current hypoglycemic and/or hypolipidemic drugs were comparable between the two groups. At multivariate analysis, male gender (OR=3.017, P=0.012), worse metabolic control (HbA1c, OR=1.408, P=0.017), and a younger age (OR=1.054, P=0.007) predicted the presence of persistently elevated liver enzymes. CONCLUSIONS: Persistently elevated liver enzymes are a common finding in outpatient type 2 diabetic subjects, particularly in young men with suboptimal metabolic control and with the features of metabolic syndrome. The persistence of abnormal liver tests may be of potential utilization in clinical practice for the screening of patients at high risk of NAFLD. PMID- 28017577 TI - Ebstein's Anomaly: Genetics, Clinical Manifestations, and Management. AB - Ebstein's anomaly is uncommon. Genetic bases of this congenital heart defect may be related to the mutations in myosin heavy chain 7 and NKX2.5, among others. Asymptomatic patients with Ebstein's anomaly can be conservatively treated and kept under close follow-up, whereas surgical operation is indicated for those patients with evidence of right heart dilation and progressively impaired ventricular systolic function. A biventricular repair consisting of the reconstruction of a competent monocuspid tricuspid valve, right ventriculorrhaphy, subtotal atrial septal defect closure, and aggressive reduction atrioplasty is suitable for most patients, and 1.5-ventricular repair (bidirectional Glenn shunt) is indicated for patients with poor right ventricular function; by contrast, heart transplantation is used in patients with severe left ventricular dysfunction. PMID- 28017578 TI - Drug development for refractory epilepsy: The past 25 years and beyond. AB - Despite the exponential growth of approved antiepileptic drugs (AEDs) over the past 25 years, epilepsy remains uncontrolled in approximately a third of patients. This article summarises the clinical trials and properties of the AEDs developed over this period, and reviews the pre-clinical and clinical development paradigms of modern AEDs. We discuss possible reasons for the apparent failure to develop more efficacious compounds. We also review the current regulatory frameworks for drug approval in the United States and Europe, and the changes on the horizon. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning pharmacoresistance and the epilepsies by recent research has enabled a revised approach to the development of more promising therapies. A new era of pharmacological treatment for epilepsy appears imminent. Future research in pharmacotherapy for drug-resistant epilepsy will be advanced through concerted effort between scientists, clinicians, and the industry. PMID- 28017579 TI - Seizures caused by brain tumors in children. AB - PURPOSE: To review the epidemiology, clinical features, and treatment of seizures secondary to pediatric brain tumors. METHOD: Literature review. RESULTS: Pediatric brain tumors are the most common solid pediatric tumor and the most common cause of death in pediatric cancer. Seizures are one of the most common symptoms of pediatric brain tumors. Factors associated with increased risk of seizures include supratentorial location, gray matter involvement, low-grade, and certain histological features-especially dysembryoplastic neuroepithelial tumor, ganglioglioma, and oligodendroglioma. Leukemic infiltration of the brain, brain metastases of solid tumors, and brain injury secondary to chemotherapy or radiotherapy can also cause seizures. Mechanisms by which brain tumors cause seizures include metabolic, and neurotransmitter changes in peritumoral brain, morphologic changes - including malformation of cortical development - in peritumoral brain, and presence of peritumoral blood products, gliosis, and necrosis. As there is a high degree of uncertainty on how effective different antiepileptic drugs are for seizures caused by brain tumors, choices are often driven by the interaction and side effect profile. Classic antiepileptic drugs - phenobarbital, phenytoin, or carbamazepine - should be avoided as they may alter the metabolism of chemotherapeutic agents. Newer drugs - valproate, lamotrigine, topiramate, zonisamide, and levetiracetam - may be the preferred option in patients with tumors because of their very limited interaction with chemotherapy. CONCLUSION: Seizures are a common presentation of pediatric brain tumors, especially in supratentorial tumors with gray matter involvement. Antiepileptic drug therapy is usually driven by the interaction and side effect profile and newer drugs with few interactions are generally preferred. PMID- 28017580 TI - Functional MRI-based connectivity analysis: A promising tool for the investigation of the pathophysiology and comorbidity of epilepsy. AB - Epilepsy has been recognized as a brain network disorder. Therefore, functional MRI (fMRI)-based connectivity is an ideal technique for exploring the complex effects of epilepsy on the brain. Functional connectivity studies have provided insights into the physiopathogenesis of the epileptic network underlying focal epilepsies, genetic generalized epilepsy, and specific epileptic syndromes. An increasing number of studies have focused on the deleterious effects of epilepsy on other brain networks to help to explain cognitive deficits and psychiatric symptoms. Anti-epileptic treatment studies have yielded information about the side effects and the restoration of functional abnormalities after using the drug. Researchers who have examined predictors of surgical outcomes have suggested that there might be identifiable pre-surgical patterns of functional connectivity that are associated with a greater likelihood of positive cognitive or seizure outcomes. However, knowledge regarding the role of fMRI connectivity remains limited in clinical settings. Further validation through invasive investigations and follow-up studies is required for its reliable application in the clinical management of individual patients. PMID- 28017581 TI - The misdiagnosis of epilepsy: Appraising risks and managing uncertainty. AB - PURPOSE: To present evidence from the literature on the rates, underlying causes and consequences of the misdiagnosis of epilepsy and place these meaningfully within a practical framework of risk appraisal and managed diagnostic uncertainty towards informing a clinical practice that might make misdiagnosis less likely. METHOD: Narrative review. RESULTS: Misdiagnosis of epilepsy remains common and the consequences for the individual significant. Evidence and critical appraisal are presented as regards the absolute level of risk associated with the false positive diagnosis epilepsy, and reasons as to why those risks need to be appraised against the risks associated to false negative diagnosis. CONCLUSIONS: Diagnostic error is not entirely avoidable and a degree of uncertainty, and perforce risk, is intrinsic to the diagnostic process of epilepsy. The risks of a false negative diagnosis of epilepsy must be appraised against the also significant risks of a false positive diagnosis. PMID- 28017582 TI - Outcomes of conservative management of spontaneous celiac artery dissection. AB - OBJECTIVE: Spontaneous celiac artery (CA) dissection without associated aortic dissection is a rare condition. Although this condition has been diagnosed more frequently with the advent of improved diagnostic imaging modalities, its pathogenesis and treatment strategy remain to be established. The present study examined the clinical features and outcomes of conservative management of this disease. METHODS: The study included 12 patients (10 men and two women) in whom spontaneous CA dissection was diagnosed between 2007 and 2015. The medical records of each patient were retrospectively reviewed. RESULTS: The mean age at diagnosis was 56.4 years (range, 42-77 years). Eight patients presented with abdominal or back pain, and the remaining four patients were asymptomatic and diagnosed incidentally. Four patients had a history of hypertension, and six had a history of smoking. Celiac trunk compression by the median arcuate ligament was found in two patients. The dissection extended into the common hepatic artery in five patients and into the splenic artery in four patients. Retroperitoneal hemorrhage was found in 2 patients, splenic infarction in 3, and transient mild liver dysfunction in 2. All patients were treated conservatively: two patients received short-term anticoagulation and antiplatelet therapy, and antihypertensive treatment was initiated in three patients. The mean follow-up period was 35.5 months (range, 5-101 months). Distal extension of the dissection occurred in one patient within a week of the initial symptom, which was also managed conservatively. Late aneurysmal degeneration was not observed in any of the patients, and none required endovascular or surgical treatment. CONCLUSIONS: If the general condition of the patient is stable, then CA dissection can be managed with careful conservative treatment, even in patients with associated retroperitoneal hemorrhage. Long-term anticoagulation or antiplatelet medication may not be necessary in most patients with this condition. PMID- 28017583 TI - Three-dimensional contrast-enhanced ultrasound improves endoleak detection and classification after endovascular aneurysm repair. AB - BACKGROUND: Three-dimensional contrast-enhanced ultrasound (3D-CEUS) is a novel technology allowing surgeons to view duplex ultrasound images in three dimensions with ultrasound contrast highlighting blood flow in endoleaks after endovascular aneurysm repair (EVAR). It potentially reduces the need for computed tomography angiography (CTA) and catheter angiography. This study compares 3D-CEUS with both CTA and the final vascular multidisciplinary team (MDT) diagnosis using all available imaging. Interoperator variability for detection of endoleak and the influence of 3D-CEUS on patient management were studied. METHODS: A consecutive 100 patients undergoing CTA for EVAR surveillance were invited to undergo standard CEUS and 3D-CEUS on the same day, with 3D-CEUS reported independently by two blinded vascular scientists. Presence and type of endoleak were compared between CTA, standard CEUS, 3D-CEUS, and the final diagnostic decision made in the vascular MDT meeting. Interoperator reliability of 3D-CEUS was analyzed using the kappa statistic. RESULTS: The 100 paired CTA, CEUS, and 3D-CEUS studies were analyzed. Compared with CTA, the sensitivity, specificity, positive predictive value, and negative predictive value of 3D-CEUS to endoleak were 96%, 91%, 90%, and 96%, respectively. Compared with the MDT decision with access to all imaging modalities, the sensitivity, specificity, positive predictive value, and negative predictive value of 3D-CEUS were 96%, 100%, 100%, and 96%. The kappa statistic for interoperator agreement was 0.89. CONCLUSIONS: 3D-CEUS was more sensitive and accurate than CTA for endoleak detection and classification after EVAR. 3D-CEUS is now our initial investigation of choice in cases of sac expansion during duplex ultrasound follow-up or if there is diagnostic uncertainty on standard duplex ultrasound or CTA. PMID- 28017584 TI - Feasibility of three-dimensional magnetic resonance angiography-fluoroscopy image fusion technique in guiding complex endovascular aortic procedures in patients with renal insufficiency. AB - OBJECTIVE: Three-dimensional image fusion of preoperative computed tomography (CT) angiography with fluoroscopy using intraoperative noncontrast cone-beam CT (CBCT) has been shown to improve endovascular procedures by reducing procedure length, radiation dose, and contrast media volume. However, patients with a contraindication to CT angiography (renal insufficiency, iodinated contrast allergy) may not benefit from this image fusion technique. The primary objective of this study was to evaluate the feasibility of magnetic resonance angiography (MRA) and fluoroscopy image fusion using noncontrast CBCT as a guidance tool during complex endovascular aortic procedures, especially in patients with renal insufficiency. METHODS: All endovascular aortic procedures done under MRA image fusion guidance at a single-center were retrospectively reviewed. The patients had moderate to severe renal insufficiency and underwent diagnostic contrast enhanced magnetic resonance imaging after gadolinium or ferumoxytol injection. Relevant vascular landmarks electronically marked in MRA images were overlaid on real-time two-dimensional fluoroscopy for image guidance, after image fusion with noncontrast intraoperative CBCT. Technical success, time for image registration, procedure time, fluoroscopy time, number of digital subtraction angiography (DSA) acquisitions before stent deployment or vessel catheterization, and renal function before and after the procedure were recorded. The image fusion accuracy was qualitatively evaluated on a binary scale by three physicians after review of image data showing virtual landmarks from MRA on fluoroscopy. RESULTS: Between November 2012 and March 2016, 10 patients underwent endovascular procedures for aortoiliac aneurysmal disease or aortic dissection using MRA image fusion guidance. All procedures were technically successful. A paired t-test analysis showed no difference between preimaging and postoperative renal function (P = .6). The mean time required for MRA-CBCT image fusion was 4:09 +/- 01:31 min:sec. Total fluoroscopy time was 20.1 +/- 6.9 minutes. Five of 10 patients (50%) underwent stent graft deployment without any predeployment DSA acquisition. Three of six vessels (50%) were cannulated under image fusion guidance without any precannulation DSA runs, and the remaining vessels were cannulated after one planning DSA acquisition. Qualitative evaluation showed 14 of 22 virtual landmarks (63.6%) from MRA overlaid on fluoroscopy were completely accurate, without the need for adjustment. Five of eight incorrect virtual landmarks (iliac and visceral arteries) resulted from vessel deformation caused by endovascular devices. CONCLUSIONS: Ferumoxytol or gadolinium-enhanced MRA imaging and image fusion with fluoroscopy using noncontrast CBCT is feasible and allows patients with renal insufficiency to benefit from optimal guidance during complex endovascular aortic procedures, while preserving their residual renal function. PMID- 28017585 TI - Evaluation of the stromal vascular fraction of adipose tissue as the basis for a stem cell-based tissue-engineered vascular graft. AB - OBJECTIVE: One of the rate-limiting barriers within the field of vascular tissue engineering is the lengthy fabrication time associated with expanding appropriate cell types in culture. One particularly attractive cell type for this purpose is the adipose-derived mesenchymal stem cell (AD-MSC), which is abundant and easily harvested from liposuction procedures. Even this cell type has its drawbacks, however, including the required culture period for expansion, which could pose risks of cellular transformation or contamination. Eliminating culture entirely would be ideal to avoid these concerns. In this study, we used the raw population of cells obtained after digestion of human liposuction aspirates, known as the stromal vascular fraction (SVF), as an abundant, culture-free cell source for tissue-engineered vascular grafts (TEVGs). METHODS: SVF cells and donor-paired cultured AD-MSCs were first assessed for their abilities to differentiate into vascular smooth muscle cells (SMCs) after angiotensin II stimulation and to secrete factors (eg, conditioned media) that promote SMC migration. Next, both cell types were incorporated into TEVG scaffolds, implanted as an aortic graft in a Lewis rat model, and assessed for their patency and composition. RESULTS: In general, the human SVF cells were able to perform the same functions as AD-MSCs isolated from the same donor by culture expansion. Specifically, cells within the SVF performed two important functions; namely, they were able to differentiate into SMCs (SVF calponin expression: 16.4% +/- 7.7% vs AD-MSC: 19.9%% +/- 1.7%) and could secrete promigratory factors (SVF migration rate relative to control: 3.1 +/- 0.3 vs AD-MSC: 2.5 +/- 0.5). The SVF cells were also capable of being seeded within biodegradable, elastomeric, porous scaffolds that, when implanted in vivo for 8 weeks, generated patent TEVGs (SVF: 83% patency vs AD-MSC: 100% patency) populated with primary vascular components (eg, SMCs, endothelial cells, collagen, and elastin). CONCLUSIONS: Human adipose tissue can be used as a culture-free cell source to create TEVGs, laying the groundwork for the rapid production of cell-seeded grafts. PMID- 28017586 TI - Operative variables are better predictors of postdischarge infections and unplanned readmissions in vascular surgery patients than patient characteristics. AB - OBJECTIVE: Although postoperative readmissions are frequent in vascular surgery patients, the reasons for these readmissions are not well characterized, and effective approaches to their reduction are unknown. Our aim was to analyze the reasons for vascular surgery readmissions and to report potential areas for focused efforts aimed at readmission reduction. METHODS: The 2012 to 2013 American College of Surgeons National Quality Improvement Program (ACS NSQIP) data set was queried for vascular surgery patients. Multivariable models were developed to analyze risk factors for postdischarge infections, the major drivers of unplanned 30-day readmissions. RESULTS: We identified 86,403 vascular surgery patients for analysis. Thirty-day readmission occurred in 8827 (10%), of which 8054 (91%) were unplanned. Of the unplanned readmissions, 61% (n = 4951) were related to the index vascular surgery procedure. Infectious complications were the most common reason for a surgery-related readmission (1940 [39%]), with surgical site infection being the most common type of infection related to unplanned readmission. Multivariable analysis showed the top five preoperative risk factors for postdischarge infections were the presence of a preoperative open wound, inpatient operation, obesity, work relative value unit, and insulin dependent diabetes (but not diabetes managed with oral medications). Cigarette smoking was a weak predictor and came in tenth in the mode (overall C index, 0.657). When operative and postoperative factors were included in the model, total operative time was the strongest predictor of postdischarge infectious complications (odds ratio [OR] 1.2 for each 1-hour increase in operative time), followed by presence of a preoperative open wound (OR, 1.5), inpatient operation (OR, 2), obesity (OR, 1.8), and discharge to rehabilitation facility (OR, 1.7; P < .001 for all). Insulin-dependent diabetes, cigarette smoking, dialysis dependence, and female gender were also predictive, albeit with smaller effects (OR, 1.1-1.3 for all; P < .001). The overall fit of the multivariable model was fair (C statistic, 0.686). CONCLUSIONS: Infectious complications dominate the reasons for unplanned 30-day readmissions in vascular surgery patients. We have identified preoperative, operative, and postoperative risk factors for these infections with the goal of reducing these complications and thus readmissions. Expected patient risk factors, such as diabetes, obesity, renal insufficiency, and cigarette smoking, were less important in predicting infectious complications compared with operative time, presence of a preoperative open wound, and inpatient operation. Our findings suggest that careful operative planning and expeditious operations may be the most effective approaches to reducing infections and thus readmissions in vascular surgery patients. PMID- 28017587 TI - Knockout-Rescue Embryonic Stem Cell-Derived Mouse Reveals Circadian-Period Control by Quality and Quantity of CRY1. AB - To conduct comprehensive characterization of molecular properties in organisms, we established an efficient method to produce knockout (KO)-rescue mice within a single generation. We applied this method to produce 20 strains of almost completely embryonic stem cell (ESC)-derived mice ("ES mice") rescued with wild type and mutant Cry1 gene under a Cry1-/-:Cry2-/- background. A series of both phosphorylation-mimetic and non-phosphorylation-mimetic CRY1 mutants revealed that multisite phosphorylation of CRY1 can serve as a cumulative timer in the mammalian circadian clock. KO-rescue ES mice also revealed that CRY1-PER2 interaction confers a robust circadian rhythmicity in mice. Surprisingly, in contrast to theoretical predictions from canonical transcription/translation feedback loops, the residues surrounding the flexible P loop and C-lid domains of CRY1 determine circadian period without changing the degradation rate of CRY1. These results suggest that CRY1 determines circadian period through both its degradation-dependent and -independent pathways. PMID- 28017588 TI - Mutations in Cas9 Enhance the Rate of Acquisition of Viral Spacer Sequences during the CRISPR-Cas Immune Response. AB - CRISPR loci and their associated (Cas) proteins encode a prokaryotic immune system that protects against viruses and plasmids. Upon infection, a low fraction of cells acquire short DNA sequences from the invader. These sequences (spacers) are integrated in between the repeats of the CRISPR locus and immunize the host against the matching invader. Spacers specify the targets of the CRISPR immune response through transcription into short RNA guides that direct Cas nucleases to the invading DNA molecules. Here we performed random mutagenesis of the RNA guided Cas9 nuclease to look for variants that provide enhanced immunity against viral infection. We identified a mutation, I473F, that increases the rate of spacer acquisition by more than two orders of magnitude. Our results highlight the role of Cas9 during CRISPR immunization and provide a useful tool to study this rare process and develop it as a biotechnological application. PMID- 28017589 TI - Distinctive Patterns of Transcription and RNA Processing for Human lincRNAs. AB - Numerous long intervening noncoding RNAs (lincRNAs) are generated from the mammalian genome by RNA polymerase II (Pol II) transcription. Although multiple functions have been ascribed to lincRNAs, their synthesis and turnover remain poorly characterized. Here, we define systematic differences in transcription and RNA processing between protein-coding and lincRNA genes in human HeLa cells. This is based on a range of nascent transcriptomic approaches applied to different nuclear fractions, including mammalian native elongating transcript sequencing (mNET-seq). Notably, mNET-seq patterns specific for different Pol II CTD phosphorylation states reveal weak co-transcriptional splicing and poly(A) signal independent Pol II termination of lincRNAs as compared to pre-mRNAs. In addition, lincRNAs are mostly restricted to chromatin, since they are rapidly degraded by the RNA exosome. We also show that a lincRNA-specific co-transcriptional RNA cleavage mechanism acts to induce premature termination. In effect, functional lincRNAs must escape from this targeted nuclear surveillance process. PMID- 28017590 TI - Fluorescence Amplification Method for Forward Genetic Discovery of Factors in Human mRNA Degradation. AB - Nonsense-mediated decay (NMD) degrades mRNAs containing a premature termination codon (PTC). PTCs are a frequent cause of human genetic diseases, and the NMD pathway is known to modulate disease severity. Since partial NMD attenuation can potentially enhance nonsense suppression therapies, better definition of human specific NMD is required. However, the majority of NMD factors were first discovered in model organisms and then subsequently identified by homology in human. Sensitivity and throughput limitations of existing approaches have hindered systematic forward genetic screening for NMD factors in human cells. We developed a method of in vivo amplification of NMD reporter fluorescence (Fireworks) that enables CRISPR-based forward genetic screening for NMD pathway defects in human cells. The Fireworks genetic screen identifies multiple known NMD factors and numerous human candidate genes, providing a platform for discovery of additional key factors in human mRNA degradation. PMID- 28017592 TI - A Histologic Basis for the Efficacy of SBRT to the lung. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) is the standard of care for medically inoperable patients with early-stage NSCLC. However, NSCLC is composed of several histological subtypes and the impact of this heterogeneity on SBRT treatments has yet to be established. METHODS: We analyzed 740 patients with early-stage NSCLC treated definitively with SBRT from 2003 through 2015. We calculated cumulative incidence curves using the competing risk method and identified predictors of local failure using Fine and Gray regression. RESULTS: Overall, 72 patients had a local failure, with a cumulative incidence of local failure at 3 years of 11.8%. On univariate analysis, squamous histological subtype, younger age, fewer medical comorbidities, higher body mass index, higher positron emission tomography standardized uptake value, central tumors, and lower radiation dose were associated with an increased risk for local failure. On multivariable analysis, squamous histological subtype (hazard ratio = 2.4 p = 0.008) was the strongest predictor of local failure. Patients with squamous cancers fail SBRT at a significantly higher rate than do those with adenocarcinomas or NSCLC not otherwise specified, with 3-year cumulative rates of local failure of 18.9% (95% confidence interval [CI]: 12.7-25.1), 8.7% (95% CI: 4.6-12.8), and 4.1% (95% CI: 0-9.6), respectively. CONCLUSION: Our results demonstrate an increased rate of local failure in patients with squamous cell carcinoma. Standard approaches for radiotherapy that demonstrate efficacy for a population may not achieve optimal results for individual patients. Establishing the differential dose effect of SBRT across histological groups is likely to improve efficacy and inform ongoing and future studies that aim to expand indications for SBRT. PMID- 28017591 TI - A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly. AB - Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A. PMID- 28017593 TI - Use of Different Vegetable Products to Increase Preschool-Aged Children's Preference for and Intake of a Target Vegetable: A Randomized Controlled Trial. AB - BACKGROUND: Children's low vegetable consumption requires effective strategies to enhance preference for and intake of vegetables. OBJECTIVE: The study compared three preparation practices for a target vegetable (spinach) on their effectiveness in increasing preschool-aged children's preference for and intake of the target vegetable in comparison to a control vegetable (green beans). DESIGN: We conducted a randomized controlled trial with four parallel groups: plain spinach, creamed spinach, spinach ravioli, and green beans. During the intervention, children were served the vegetable at their main meal six times over 6 weeks at home. PARTICIPANTS/SETTING: Children aged 2 to 4 years were recruited from six child-care centers located in Wageningen, the Netherlands, and randomly assigned to one of the four groups, with vegetable products provided by the researchers. The study was performed between September 2014 and January 2015. In total, 103 children participated, with 26, 25, 26, and 26 in the plain spinach, creamed spinach, spinach ravioli, and green beans groups, respectively. MAIN OUTCOME MEASURES: Preference for and ad libitum intake of cooked spinach were assessed during a test meal at the day-care center pre- and postintervention. Food neophobia was assessed via the Child Food Neophobia Scale. STATISTICAL ANALYSES PERFORMED: General linear model repeated measures analysis, including food neophobia, spinach liking, exposure, and consumption scores as covariates, was performed to test for effects of group on intake. Logistic regression was used to assess changes in preference between pre- and postintervention. RESULTS: All four groups significantly increased their spinach intake from pre- (53 g) to postintervention (91 g) by an average of 70%. For preference, no significant shift toward the target vegetable was found from pre- to postintervention. The effect on intake depended on the child's neophobia status and preintervention spinach consumption, with children with neophobia being less responsive to the intervention and with children who ate more spinach before the intervention being more responsive to the intervention. CONCLUSIONS: These findings suggest that repeated exposure to differently prepared spinach products, or even another green vegetable, improved children's spinach intake. However, children with neophobia may need a different approach. PMID- 28017594 TI - Delivering Summer Electronic Benefit Transfers for Children through the Supplemental Nutrition Assistance Program or the Special Supplemental Nutrition Program for Women, Infants, and Children: Benefit Use and Impacts on Food Security and Foods Consumed. AB - BACKGROUND: The Summer Electronic Benefit Transfers for Children (SEBTC) demonstration piloted summer food assistance through electronic benefit transfers (EBTs), providing benefits either through the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) or the Supplemental Nutrition Assistance Program (SNAP) EBT. OBJECTIVE: To inform food assistance policy and describe how demonstrations using WIC and SNAP models differed in benefit take-up and impacts on food security and children's food consumption. DESIGN: Sites chose to deliver SEBTC using the SNAP or WIC EBT system. Within each site, in 2012, households were randomly assigned to a benefit group or a no-benefit control group. PARTICIPANTS: Grantees (eight states and two Indian Tribal Organizations) selected school districts serving many low-income children. Schoolchildren were eligible in cases where they had been certified for free or reduced-price meals during the school year. Before the demonstration, households in the demonstration sample had lower incomes and lower food security, on average, than households with eligible children nationally. INTERVENTION: Grantees provided selected households with benefits worth $60 per child per summer month using SNAP or WIC EBT systems. SNAP-model benefits covered most foods. WIC-model benefits could only be used for a specific package of foods. OUTCOME MEASURES: Key outcomes were children's food security (assessed using the US Department of Agriculture food security scale) and food consumption (assessed using food frequency questions). STATISTICAL ANALYSES: Differences in mean outcomes between the benefit and control groups measured impact, after adjusting for household characteristics. RESULTS: In WIC sites, benefit-group households redeemed a lower percentage of SEBTC benefits than in SNAP sites. Nonetheless, the benefit groups in both sets of sites had similar large reductions in very low food security among children, relative to no-benefit controls. Children receiving benefits consumed more healthful foods, and these impacts were larger in WIC sites. CONCLUSIONS: Results suggest the WIC SEBTC model deserves strong consideration. PMID- 28017595 TI - Brain prolactin is involved in stress-induced REM sleep rebound. AB - REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound. PMID- 28017596 TI - The role of the kisspeptin system in regulation of the reproductive endocrine axis and territorial behavior in male side-blotched lizards (Uta stansburiana). AB - The neuropeptide kisspeptin and its receptor are essential for activation of the hypothalamic-pituitary-gonadal (HPG) axis and regulating reproduction. While the role of kisspeptin in regulating the HPG axis in mammals has been well established, little is known about the functional ability of kisspeptins to activate the HPG axis and associated behavior in non-mammalian species. Here we experimentally examined the effects of kisspeptin on downstream release of testosterone and associated aggression and display behaviors in the side-blotched lizard (Uta stansburiana). We found that exogenous treatment with kisspeptin resulted in an increase in circulating testosterone levels, castration blocked the kisspeptin-induced increase in testosterone, and testosterone levels in kisspeptin-treated animals were positively related to frequency of aggressive behaviors. This evidence provides a clear link between kisspeptin, testosterone, and aggressive behavior in lizards. Thus, it is likely that kisspeptin plays an important role more broadly in non-mammalian systems in the regulation of reproductive physiology and related behaviors. PMID- 28017597 TI - Repeated restraint stress lowers the threshold for response to third ventricle CRF administration. AB - Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague-Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0-3.0MUg). The lowest dose of CRF (0.25MUg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper responsiveness to CRF and mild stress in RRS rats during the post-restraint period. PMID- 28017598 TI - Biodegradable poly-epsilon-caprolactone microcarriers for efficient production of human mesenchymal stromal cells and secreted cytokines in batch and fed-batch bioreactors. AB - Large numbers of human mesenchymal stromal cells (MSCs) used for a variety of applications in tissue engineering and cell therapy can be generated by scalable expansion in a bioreactor using microcarriers (MCs) systems. However, the enzymatic digestion process needed to detach cells from the growth surface can affect cell viability and potentially the potency and differentiation efficiency. Thus, the main aim of our study was to develop biocompatible and biodegradable MCs that can support high MSC yields while maintaining their differentiation capability and potency. After cell expansion, the cells that covered MCs can be directly implanted in vivo without the need for cell harvesting or use of scaffold. Poly-epsilon-caprolactone (PCL) is known as a biocompatible and biodegradable material. However, it cannot be used for generation of MCs because its high density (1.14 g/cm3) would exclude its applicability for suspension MCs in stirred reactors. In this article, we describe expansion and potency of MSCs propagated on low-density (1.06 g/cm3) porous PCL MCs coated with extracellular matrices (LPCLs) in suspended stirred reactors. Using these LPCLs, cell yields of about 4 * 104 cells/cm2 and 7- to 10-fold increases were obtained using four different MSC lines (bone marrow, cord blood, fetal and Wharton's jelly). These yields were comparable with those obtained using non-degradable MCs (Cytodex 3) and higher than two-dimensional monolayer (MNL) cultures. A fed-batch process, which demonstrated faster cell expansion (4.5 * 104 cells/cm2 in 5 days as compared with 7 days in batch culture) and about 70% reduction in growth media usage, was developed and scaled up from 100-mL spinner flask to 1-L controlled bioreactor. Surface marker expression, trilineage differentiation and clonogenic potential of the MSCs expanded on LPCL were not affected. Cytokine secretion kinetics, which occurred mostly during late logarithmic phase, was usually comparable with that obtained in Cytodex 3 cultures and higher than MNL cultures. In conclusion, biodegradable LPCL can be used to efficiently expand a variety of MSC lines in stirred scalable reactors in a cost-effective manner while maintaining surface markers expression, differentiation capability and high levels of cytokine secretion. This study is the first step in testing these cell biodegradable porous MC aggregates for tissue engineering and cell therapy, such as bone and cartilage regeneration, or wound healing. PMID- 28017599 TI - A consensus introduction to serum replacements and serum-free media for cellular therapies. AB - The cell therapy industry is a fast-growing industry targeted toward a myriad of clinical indications. As the cell therapy industry matures and clinical trials hit their pivotal Phase 3 studies, there will be a significant need for scale-up, process validation, and critical raw material quality assurance. Part of the well discussed challenges of upscaling manufacturing processes there is a less discussed issue relating to the availability of raw materials in the needed quality and quantities. The FDA recently noted that over 80% of the 66 investigational new drug (IND) applications for mesenchymal stem cell (MSC) products analyzed described the use of FBS during manufacturing. Accumulated data from the past years show an acceleration in serum consumption by at least 10%-15% annually, which suggests that the global demand for serum may soon exceed the supply. Ongoing concerns of safety issues due to risks of various pathogen contaminations, as well as issues related to the aforementioned serum variability that can affect final product reproducibility, are strong motivators to search for serum substitutes or serum-free media. it is important to note that there are no accepted definitions for most of these terms which leads to misleading's and misunderstandings, where the same term might be defined differently by different vendors, manufacturer, and users. It is the drug developer's responsibility to clarify what the supplied labels mean and to identify the correct questions and audits to ensure quality. The paper reviews the available serum replacements, main components, basic strategies for replacement of serum and suggests definitions. PMID- 28017600 TI - Ulk1 protects against ethanol-induced neuronal stress and cognition-related behavioral deficits. AB - Alcoholism is a psychiatric condition that develops through neuroadaptations in response to neuronal stresses caused by chronic ethanol intake. Neurons can adapt to ethanol-induced metabolic changes by activating cellular protective mechanisms, including autophagy. Here we show that expression of Ulk1, a gene critical to the regulation of autophagy, was affected in the prefrontal cortex (PFC) of mice following chronic intermittent ethanol (CIE) exposure. Consequently, overall levels of Ulk1 activity in the PFC were downregulated, leading to accumulation of p62, a protein that serves as a target for autophagic degradation. In addition, Ulk1-null mice demonstrated decline in the exploratory activity, deficits in the ability to recognize novel objects following CIE exposure, and reduced rate of voluntary ethanol drinking. The data suggest the neuroprotective role for Ulk1-mediated autophagy in the suppression of neuropsychiatric manifestation during ethanol exposure. PMID- 28017601 TI - Identification and Characterization of the Sulfazecin Monobactam Biosynthetic Gene Cluster. AB - The monobactams, exemplified by the natural product sulfazecin, are the only class of beta-lactam antibiotics not inactivated by metallo-beta-lactamases, which confer bacteria with extended-spectrum beta-lactam resistance. We screened a transposon mutagenesis library from Pseudomonas acidophila ATCC 31363 and isolated a sulfazecin-deficient mutant that revealed a gene cluster encoding two non-ribosomal peptide synthetases (NRPSs), a methyltransferase, a sulfotransferase, and a dioxygenase. Three modules and an aberrant C-terminal thioesterase (TE) domain are distributed across the two NRPSs. Biochemical examination of the adenylation (A) domains provided evidence that L-2,3 diaminopropionate, not L-serine as previously thought, is the direct source of the beta-lactam ring of sulfazecin. ATP/PPi exchange assay also revealed an unusual substrate selectivity shift of one A domain when expressed with or without the immediately upstream condensation domain. Gene inactivation analysis defined a cluster of 13 open reading frames sufficient for sulfazecin production, precursor synthesis, self-resistance, and regulation. The identification of a key intermediate supported a proposed NRPS-mediated mechanism of sulfazecin biosynthesis and beta-lactam ring formation distinct from the nocardicins, another NRPS-derived subclass of monocyclic beta-lactam. These findings will serve as the basis for further biosynthetic research and potential engineering of these important antibiotics. PMID- 28017602 TI - A Common Platform for Antibiotic Dereplication and Adjuvant Discovery. AB - Solving the antibiotic resistance crisis requires the discovery of new antimicrobial drugs and the preservation of existing ones. The discovery of inhibitors of antibiotic resistance, antibiotic adjuvants, is a proven example of the latter. A major difficulty in identifying new antibiotics is the frequent rediscovery of known compounds, necessitating laborious "dereplication" to identify novel chemical entities. We have developed an antibiotic resistance platform (ARP) that can be used for both the identification of antibiotic adjuvants and for antibiotic dereplication. The ARP is a cell-based array of mechanistically distinct individual resistance elements in an identical genetic background. In dereplication mode, we demonstrate the rapid identification, and thus discrimination, of common antibiotics. In adjuvant discovery mode, we show that the ARP can be harnessed in screens to identify inhibitors of resistance. The ARP is therefore a powerful tool that has broad application in confronting the resistance crisis. PMID- 28017603 TI - Guideline for Reporting Interventions on Spinal Manipulative Therapy: Consensus on Interventions Reporting Criteria List for Spinal Manipulative Therapy (CIRCLe SMT). AB - OBJECTIVE: The aim of the Consensus on Interventions Reporting Criteria List for Spinal Manipulative Therapy (CIRCLe SMT) study was to develop a criteria list for reporting spinal manipulative therapy (SMT). METHODS: A Delphi procedure was conducted from September 2011 to April 2013 and consisted of international experts in the field of SMT. The authors formed a steering committee and invited participants, selected initial items, structured the comments of the participants after each Delphi round, and formulated the feedback. To ensure content validity, a large number of international experts from different SMT-related disciplines were invited to participate. A workshop was organized following the consensus phase, and it was used to discuss and refine the wording of the items. RESULTS: In total, 123 experts from 18 countries participated. These experts included clinicians (70%), researchers (93%), and academics working in the area of SMT (27%), as well as journal editors (14%). (Note: The total is more than 100% because most participants reported 2 jobs.) Three Delphi rounds were necessary to reach a consensus. The criteria list comprised 24 items under 5 domains, including (1) rationale of the therapy, (2) description of the intervention, (3) SMT techniques, (4) additional intervention/techniques, and (5) quantitative data. CONCLUSIONS: A valid criteria list was constructed with the aim of promoting consistency in reporting SMT intervention in scientific publications. PMID- 28017604 TI - Effect of the Abdominal Hollowing and Bracing Maneuvers on Activity Pattern of the Lumbopelvic Muscles During Prone Hip Extension in Subjects With or Without Chronic Low Back Pain: A Preliminary Study. AB - OBJECTIVE: The purpose of this study was to compare the effect of abdominal hollowing (AH) and abdominal bracing (AB) maneuvers on the activity pattern of lumbopelvic muscles during prone hip extension (PHE) in participants with or without nonspecific chronic low back pain (CLBP). METHODS: Twenty women with or without CLBP participated in this cross-sectional observational study. The electromyographic activity (amplitude and onset time) of the contralateral erector spinae (CES), ipsilateral erector spinae (IES), gluteus maximus, and biceps femoris muscles was measured during PHE with and without abdominal maneuvers. A 3-way mixed model analysis of variance and post hoc tests were used for statistical analysis. RESULTS: Between-group comparisons showed that the CES onset delay during PHE alone was greater (P = .03) and the activity level of IES, CES, and biceps femoris in all maneuvers (P < .05) was higher in patients with CLBP than in asymptomatic participants. In asymptomatic participants, PHE + AH significantly decreased the signal amplitude (AMP) of IES (P = .01) and CES (P = .02) muscles. In participants with CLBP, IES muscle AMP was lower during PHE + AH compared with PHE + AB and PHE alone. With regard to onset delay, the results also showed no significant difference between maneuvers within either of the 2 groups (P > .05). CONCLUSIONS: Performance of the AH maneuver decreased the erector spinae muscle AMP in both groups, and neither maneuver altered the onset delay of any of the muscles in either group. The low back pain group showed higher levels of activity in all muscles (not statistically significant in gluteus maximus during all maneuvers). The groups were similar according to the onset delay of any of the muscles during either maneuver. PMID- 28017605 TI - An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks. AB - The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light but resistant to temperature shifts that entrain peripheral clocks [1-5]. The SCN expresses many functionally important neuropeptides, including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks and organizes circadian behavior [5-16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17, 18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip-/- mice under light-dark cycles and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1- and Vip-deficient mice and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1 and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions. PMID- 28017606 TI - Generation of a Spindle Checkpoint Arrest from Synthetic Signaling Assemblies. AB - The spindle checkpoint acts as a mitotic surveillance system, monitoring interactions between kinetochores and spindle microtubules and ensuring high fidelity chromosome segregation [1-3]. The checkpoint is activated by unattached kinetochores, and Mps1 kinase phosphorylates KNL1 on conserved MELT motifs to generate a binding site for the Bub3-Bub1 complex [4-7]. This leads to dynamic kinetochore recruitment of Mad proteins [8, 9], a conformational change in Mad2 [10-12], and formation of the mitotic checkpoint complex (MCC: Cdc20-Mad3-Mad2 [13-15]). MCC formation inhibits the anaphase-promoting complex/cyclosome (Cdc20 APC/C), thereby preventing the proteolytic destruction of securin and cyclin and delaying anaphase onset. What happens at kinetochores after Mps1-dependent Bub3 Bub1 recruitment remains mechanistically unclear, and it is not known whether kinetochore proteins other than KNL1 have significant roles to play in checkpoint signaling and MCC generation. Here, we take a reductionist approach, avoiding the complexities of kinetochores, and demonstrate that co-recruitment of KNL1Spc7 and Mps1Mph1 is sufficient to generate a robust checkpoint signal and prolonged mitotic arrest. We demonstrate that a Mad1-Bub1 complex is formed during synthetic checkpoint signaling. Analysis of bub3Delta mutants demonstrates that Bub3 acts to suppress premature checkpoint signaling. This synthetic system will enable detailed, mechanistic dissection of MCC generation and checkpoint silencing. After analyzing several mutants that affect localization of checkpoint complexes, we conclude that spindle checkpoint arrest can be independent of their kinetochore, spindle pole, and nuclear envelope localization. PMID- 28017607 TI - A Simple Computational Model of the Bee Mushroom Body Can Explain Seemingly Complex Forms of Olfactory Learning and Memory. AB - Honeybees are models for studying how animals with relatively small brains accomplish complex cognition, displaying seemingly advanced (or "non-elemental") learning phenomena involving multiple conditioned stimuli. These include "peak shift" [1-4]-where animals not only respond to entrained stimuli, but respond even more strongly to similar ones that are farther away from non-rewarding stimuli. Bees also display negative and positive patterning discrimination [5], responding in opposite ways to mixtures of two odors than to individual odors. Since Pavlov, it has often been assumed that such phenomena are more complex than simple associate learning. We present a model of connections between olfactory sensory input and bees' mushroom bodies [6], incorporating empirically determined properties of mushroom body circuitry (random connectivity [7], sparse coding [8], and synaptic plasticity [9, 10]). We chose not to optimize the model's parameters to replicate specific behavioral phenomena, because we were interested in the emergent cognitive capacities that would pop out of a network constructed solely based on empirical neuroscientific information and plausible assumptions for unknown parameters. We demonstrate that the circuitry mediating "simple" associative learning can also replicate the various non-elemental forms of learning mentioned above and can effectively multi-task by replicating a range of different learning feats. We found that PN-KC synaptic plasticity is crucial in controlling the generalization-discrimination trade-off-it facilitates peak shift and hinders patterning discrimination-and that PN-to-KC connection number can affect this trade-off. These findings question the notion that forms of learning that have been regarded as "higher order" are computationally more complex than "simple" associative learning. PMID- 28017608 TI - Biogeography of the Global Ocean's Mesopelagic Zone. AB - The global ocean's near surface can be partitioned into distinct provinces on the basis of regional primary productivity and oceanography [1]. This ecological geography provides a valuable framework for understanding spatial variability in ecosystem function but has relevance only partway into the epipelagic zone (the top 200 m). The mesopelagic (200-1,000 m) makes up approximately 20% of the global ocean volume, plays important roles in biogeochemical cycling [2], and holds potentially huge fish resources [3-5]. It is, however, hidden from satellite observation, and a lack of globally consistent data has prevented development of a global-scale understanding. Acoustic deep scattering layers (DSLs) are prominent features of the mesopelagic. These vertically narrow (tens to hundreds of m) but horizontally extensive (continuous for tens to thousands of km) layers comprise fish and zooplankton and are readily detectable using echosounders. We have compiled a database of DSL characteristics globally. We show that DSL depth and acoustic backscattering intensity (a measure of biomass) can be modeled accurately using just surface primary productivity, temperature, and wind stress. Spatial variability in these environmental factors leads to a natural partition of the mesopelagic into ten distinct classes. These classes demark a more complex biogeography than the latitudinally banded schemes proposed before [6, 7]. Knowledge of how environmental factors influence the mesopelagic enables future change to be explored: we predict that by 2100 there will be widespread homogenization of mesopelagic communities and that mesopelagic biomass could increase by approximately 17%. The biomass increase requires increased trophic efficiency, which could arise because of ocean warming and DSL shallowing. PMID- 28017609 TI - Extreme Ontogenetic Changes in a Ceratosaurian Theropod. AB - Ontogenetic variation is documented within many dinosaur species, but extreme ontogenetic changes are rare among dinosaurs, particularly among theropods. Here, we analyze 19 specimens of the Jurassic ceratosaurian theropod Limusaurus inextricabilis, representing six ontogenetic stages based on body size and histological data. Among 78 ontogenetic changes we identify in these specimens, the most unexpected one is the change from fully toothed jaws in the hatchling and juvenile individuals to a completely toothless beaked jaw in the more mature individuals, representing the first fossil record of ontogenetic edentulism among the jawed vertebrates. Jaw morphological data, including those derived from Mi-CT and SR-MUCT scanning of Limusaurus specimens, reveal dental alveolar vestiges and indicate that ontogenetic tooth loss in Limusaurus is a gradual, complex process. Our discovery has significant implications for understanding the evolution of the beak, an important feeding structure present in several tetrapod clades, including modern birds. This radical morphological change suggests a dietary shift, probably from omnivory for juvenile Limusaurus to herbivory for adult Limusaurus, which is also supported by additional evidence from gastroliths and stable isotopes. Incorporating new ontogenetic information from Limusaurus into phylogenetic analyses demonstrates surprisingly little effect on its placement when data from different stages are used exclusively, in contrast to previous analyses of tyrannosaurids, but produces subtle differences extending beyond the placement of Limusaurus. PMID- 28017610 TI - Bone Microvasculature Tracks Red Blood Cell Size Diminution in Triassic Mammal and Dinosaur Forerunners. AB - Vertebrate red blood cells (RBCs) display a range of sizes, spanning orders of magnitude in volume in different clades [1]. The importance of this size variation to diffusion during exercise is reinforced by functional links between RBC and capillary diameters [2, 3]. Small RBCs, such as those of mammals (which lack nuclei) and birds, contribute to shorter diffusion distances and permit relatively fast O2 uptake kinetics [4]. Although constraints on RBC size have been tied to the cell's need to attend capillary sizes for effective gas diffusion [3], as well as to genome size evolution [5, 6], major questions persist concerning patterns of RBC size evolution and its paleobiological significance. Here, we evaluate the relationship between RBC sizes and bone histometry and use microstructural evidence to trace their evolution in a phylogeny of extinct tetrapods. We find that several fossilizable aspects of bone microstructure, including the sizes of vascular and lacunar (cellular) spaces, provide useful indicators of RBC size in tetrapods. We also show that Triassic non-mammalian cynodonts had reduced and densely packed vascular canals identical to those of some mammals and likely accommodated smaller, more mammal-like RBCs. Reduced channel diameters accommodating smaller RBCs predated the origin of crown mammals by as much as 70 million years. This discovery offers a new proxy for the physiologic status of the mammal and avian stem groups and contextualizes the independent origins of their increased activity metabolism. PMID- 28017611 TI - Regulation of Differentiation of Nitrogen-Fixing Bacteria by Microsymbiont Targeting of Plant Thioredoxin s1. AB - Legumes associate with rhizobia to form nitrogen (N2)-fixing nodules, which is important for plant fitness [1, 2]. Medicago truncatula controls the terminal differentiation of Sinorhizobium meliloti into N2-fixing bacteroids by producing defensin-like nodule-specific cysteine-rich peptides (NCRs) [3, 4]. The redox state of NCRs influences some biological activities in free-living bacteria, but the relevance of redox regulation of NCRs in planta is unknown [5, 6], although redox regulation plays a crucial role in symbiotic nitrogen fixation [7, 8]. Two thioredoxins (Trx), Trx s1 and s2, define a new type of Trx and are expressed principally in nodules [9]. Here, we show that there are four Trx s genes, two of which, Trx s1 and s3, are induced in the nodule infection zone where bacterial differentiation occurs. Trx s1 is targeted to the symbiosomes, the N2-fixing organelles. Trx s1 interacted with NCR247 and NCR335 and increased the cytotoxic effect of NCR335 in S. meliloti. We show that Trx s silencing impairs bacteroid growth and endoreduplication, two features of terminal bacteroid differentiation, and that the ectopic expression of Trx s1 in S. meliloti partially complements the silencing phenotype. Thus, our findings show that Trx s1 is targeted to the bacterial endosymbiont, where it controls NCR activity and bacteroid terminal differentiation. Similarly, Trxs are critical for the activation of defensins produced against infectious microbes in mammalian hosts. Therefore, our results suggest the Trx-mediated regulation of host peptides as a conserved mechanism among symbiotic and pathogenic interactions. PMID- 28017612 TI - RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer. AB - Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor kappaB (NF-kappaB) activation. Loss of Ripk1 induced the TNF dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-kappaB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis. PMID- 28017613 TI - Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. AB - It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities. PMID- 28017614 TI - FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. AB - N6-Methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response. PMID- 28017615 TI - Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect. AB - Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress. PMID- 28017616 TI - GAS2L1 Is a Centriole-Associated Protein Required for Centrosome Dynamics and Disjunction. AB - Mitotic spindle formation and chromosome segregation require timely separation of the two duplicated centrosomes, and this process is initiated in late G2 by centrosome disjunction. Here we report that GAS2L1, a microtubule- and actin binding protein, associates with the proximal end of mature centrioles and participates in centriole dynamics and centrosome disjunction. GAS2L1 attaches microtubules and actin to centrosomes, and the loss of GAS2L1 inhibits centrosome disjunction in G2 and centrosome splitting induced by depletion of the centrosome linker rootletin. Conversely, GAS2L1 overexpression induces premature centrosome separation, and this activity requires GAS2L1 association with actin, microtubules, and the microtubule end-binding proteins. The centrosome-splitting effect of GAS2L1 is counterbalanced by rootletin, reflecting the opposing actions of GAS2L1 and the centrosome linker. Our work reveals a GAS2L1-mediated centriole tethering mechanism of microtubules and actin, which provide the forces required for centrosome dynamics and separation. PMID- 28017618 TI - Selective Lysosomal Transporter Degradation by Organelle Membrane Fusion. AB - Lysosomes rely on their resident transporter proteins to return products of catabolism to the cell for reuse and for cellular signaling, metal storage, and maintaining the lumenal environment. Despite their importance, little is known about the lifetime of these transporters or how they are regulated. Using Saccharomyces cerevisiae as a model, we discovered a new pathway intrinsic to homotypic lysosome membrane fusion that is responsible for their degradation. Transporter proteins are selectively sorted by the docking machinery into an area between apposing lysosome membranes, which is internalized and degraded by lumenal hydrolases upon organelle fusion. These proteins have diverse lifetimes that are regulated in response to protein misfolding, changing substrate levels, or TOR activation. Analogous to endocytosis for controlling surface protein levels, the "intralumenal fragment pathway" is critical for lysosome membrane remodeling required for organelle function in the context of cellular protein quality control, ion homeostasis, and metabolism. PMID- 28017617 TI - miR-263a Regulates ENaC to Maintain Osmotic and Intestinal Stem Cell Homeostasis in Drosophila. AB - Proper regulation of osmotic balance and response to tissue damage is crucial in maintaining intestinal stem cell (ISC) homeostasis. We found that Drosophila miR 263a downregulates the expression of epithelial sodium channel (ENaC) subunits in enterocytes (ECs) to maintain osmotic and ISC homeostasis. In the absence of miR 263a, the intraluminal surface of the intestine displays dehydration-like phenotypes, Na+ levels are increased in ECs, stress pathways are activated in ECs, and ISCs overproliferate. Furthermore, miR-263a mutants have increased bacterial load and expression of antimicrobial peptides. Strikingly, these phenotypes are reminiscent of the pathophysiology of cystic fibrosis (CF) in which loss-of-function mutations in the chloride channel CF transmembrane conductance regulator can elevate the activity of ENaC, suggesting that Drosophila could be used as a model for CF. Finally, we provide evidence that overexpression of miR-183, the human ortholog of miR-263a, can also directly target the expressions of all three subunits of human ENaC. PMID- 28017619 TI - Casein Kinase 1 Coordinates Cohesin Cleavage, Gametogenesis, and Exit from M Phase in Meiosis II. AB - Meiosis consists of DNA replication followed by two consecutive nuclear divisions and gametogenesis or spore formation. While meiosis I has been studied extensively, less is known about the regulation of meiosis II. Here we show that Hrr25, the conserved casein kinase 1delta of budding yeast, links three mutually independent key processes of meiosis II. First, Hrr25 induces nuclear division by priming centromeric cohesin for cleavage by separase. Hrr25 simultaneously phosphorylates Rec8, the cleavable subunit of cohesin, and removes from centromeres the cohesin protector composed of shugoshin and the phosphatase PP2A. Second, Hrr25 initiates the sporulation program by inducing the synthesis of membranes that engulf the emerging nuclei at anaphase II. Third, Hrr25 mediates exit from meiosis II by activating pathways that trigger the destruction of M phase-promoting kinases. Thus, Hrr25 synchronizes formation of the single-copy genome with gamete differentiation and termination of meiosis. PMID- 28017620 TI - Biological variability of the sweat chloride in diagnostic sweat tests: A retrospective analysis. AB - BACKGROUND: The sweat test is the current gold standard for the diagnosis of cystic fibrosis (CF). CF is unlikely when sweat chloride (Clsw) is lower than 30mmol/L, Clsw>60 is suggestive of CF, with intermediate values between 30 and 60mmol/L. To correctly interpret a sweat chloride value, the biological variability of the sweat chloride has to be known. METHODS: Sweat tests performed in two centers using the classic Gibson and Cooke method were retrospectively reviewed (n=5904). Within test variability of Clsw was measured by comparing results from right and left arm collected on the same day. Between test variability was calculated from subjects with sweat tests performed on more than one occasion. RESULTS: Within test variability of Clsw calculated in 1022 subjects was low with differences between -3.2 (p5) and +3.6mmol/L (p95). Results from left and right arm were classified differently in only 3 subjects. Between test variability of Clsw in 197 subjects was larger, with differences between 18.2mmol/L (p5) and +14.1mmol/L (p95) between repeat tests. Changes in diagnostic conclusion were seen in 55/197 subjects, the most frequent being changing from indeterminate to 'CF unlikely' range (48/102). CONCLUSION: Variability of sweat chloride is substantial, with frequent changes in diagnostic conclusion, especially in the intermediate range. PMID- 28017621 TI - Occurrence of ticks in the subcutaneous tissue of red foxes, Vulpes vulpes in Czech Republic and Romania. AB - An extensive survey of parasites in red foxes (Vulpes vulpes) was independently conducted in Romania and the Czech Republic. Carcasses were examined by necropsy, and small, dark nodules apparently containing ticks were noticed in the subcutaneous tissue of several foxes. Histopathological examination was performed using hematoxylin and eosin (HE) staining. Of the 91 foxes examined from the Czech Republic, 14 (15.4%) were harboring ticks in the subcutaneous tissue. In the majority of these cases, 1-3 nodules/fox were found, with a maximum of 31 nodules/fox. In Romania a single examined fox had subcutaneous ticks. All ticks collected from subcutaneous tissue were partially engorged adults. Based on morphological features, Ixodes ricinus, I. hexagonus, I. crenulatus and Dermacentor reticulatus were identified. The histopathological examination revealed chronic granulomatous panniculitis with peripheral fibrosis and intralesional presence of the ticks. Only few data are available regarding ticks localized in the subcutaneous tissue of any host. All the ticks were dead or already decomposed and it is evident that subcutaneous location does not represent an evolutionary advantage, as the detachment and finishing the life cycle is impossible. PMID- 28017622 TI - First report of exotic ticks (Amblyomma rotundatum) parasitizing invasive cane toads (Rhinella marina) on the Island of Hawai'i. AB - Our surveys of 1401 invasive cane toads (Rhinella marina) from the Hawaiian islands of Hawai'i, O'ahu, and Maui revealed the presence of an exotic tick, Amblyomma rotundatum. Immature and adult female ticks infested three wild adult toads at a single site in the vicinity of a zoo south of Hilo, Island of Hawai'i, Hawai'i, USA. We found no tick-infested toads on O'ahu or Maui. This tick infests cane toads in their native Neotropical range, but it was excluded from Hawai'i when the original founder toads were introduced over 80 years ago. The circumstances of our discovery suggest that A. rotundatum was independently and belatedly introduced to Hawai'i with imported zoo animals, and Hawai'i now joins Florida as the second U.S. state where this tick is established. PMID- 28017623 TI - Pathogenetic implications of the age at time of diagnosis and skin location for acrodermatitis chronica atrophicans. AB - BACKGROUND: The pathogenesis of acrodermatitis chronica atrophicans (ACA) is not well understood. OBJECTIVE: The purpose of this study was to gain a better understanding of ACA by utilizing a large data set of adult Slovenian patients with Lyme borreliosis. METHODS: The age of 590 ACA patients was compared with that of patients with other manifestations of Lyme borreliosis. The location of the ACA lesion on the body was compared with that of erythema migrans (EM). RESULTS: Patients diagnosed with ACA were on average 14.3 years older than patients with EM (p<0.001). ACA patients were also significantly older than patients with Lyme neuroborreliosis or Lyme arthritis (p<0.001). The average delay in diagnosis of ACA was 1.6 years (range 0.1-20 years). For 572 (96.9%) of the ACA patients, the site of the skin lesion(s) was confined to an extremity vs. 79.6% for patients with EM, p<0.001. For the 20 ACA patients who reported a preceding untreated EM lesion at the same body site, the mean time between the development of the EM and the onset of ACA was 3.0+/-4.4 (median 1.3, range 0.1 15.0) years. CONCLUSIONS: ACA is more likely to be diagnosed in older individuals than any other manifestation of Lyme borreliosis. ACA is more likely than EM to be localized anatomically to the extremities. Available data favor the hypothesis that ACA occurs most often on the extremities of older individuals because of predisposing age-related anatomic or physiologic changes, but more data are needed to define the latency period and other aspects of the pathogenesis of this skin condition. PMID- 28017624 TI - Physical activity in Indian country. AB - This is an invited commentary article, and so no abstract is required. By way of a brief description, this article shares promising efforts, strategies and approaches in effectively and culturally supporting Native communities in promoting the health of their children through movement, the connection to their land, language, culture and traditional knowledge. PMID- 28017625 TI - First case of DRESS syndrome attributed to a spider bite. PMID- 28017627 TI - Fungal Sensitization Is Associated with Increased Risk of Life-Threatening Asthma. AB - BACKGROUND: Fungal sensitization in patients with asthma has been associated with severe asthma and worse asthma outcomes. OBJECTIVE: The purpose of this study was to determine the relationship between fungal and nonfungal sensitization, asthma severity, and clinical outcomes. METHODS: A retrospective review of patients with asthma evaluated in an urban pulmonary subspecialty clinic in the United States was performed. Patients with fungal and nonfungal allergen sensitization were identified based on serum-specific immunoglobulin E (sIgE) testing. Demographic, clinical, laboratory, and spirometric data were obtained. The relationship between fungal sensitization and asthma outcomes was examined. RESULTS: Of 390 patients with asthma identified, 307 had sIgE testing, of whom 53 (17.3%) had fungal sensitization, 117 (38.1%) had nonfungal sensitization, and 137 (44.6%) had no sensitization. Patients with fungal sensitization were more likely to be sensitized to >=5 allergens than patients with nonfungal sensitization (66% for fungal vs 29% for nonfungal, P < .001). Serum IgE concentrations were highest in patients with fungal sensitization compared with patients with no sensitization or nonfungal sensitization (median, 825, 42, and 203 IU/mL, respectively, P < .001). Fungal sensitized patients were more likely to require intensive care unit (ICU) admission and mechanical ventilation than those with no sensitization or nonfungal sensitization (13.2%, 3.7%, and 3.4%, respectively, for ICU admission, P = .02; 11.3%, 1.5%, and 0.9%, respectively, for ventilation, P < .001). CONCLUSIONS: Fungal sensitization is common in patients with asthma in an urban setting and is associated with greater sensitization to nonfungal allergens and increased risk of life-threatening asthma. PMID- 28017626 TI - An Examination of the Food Allergy Quality of Life Questionnaire Performance in a Countrywide American Sample of Children: Cross-Cultural Differences in Age and Impact in the United States and Europe. AB - BACKGROUND: It is important to ensure that tools are valid and reliable in the context in which they are used. The development of age and country norms is part of this process. OBJECTIVES: The primary aim of the present study was to examine the performance of the Food Allergy Quality of Life Questionnaire - Parent Form (FAQLQ-PF) in a countrywide American sample of children with food allergy. The secondary aim was to compare age differences in impact across 9 European countries. METHODS: In a cross-sectional quantitative design, questionnaires were completed by the parents of 1029 food-allergic children (0-12 years). Participants were recruited via support groups and allergists. Data were analyzed by using multivariate analysis of variance and tests for internal consistency and validity. The average score was calculated for each age group in 15 studies in Ireland, Switzerland, the Netherlands, Spain, Portugal, Germany, Italy, Denmark, Israel, and the United Kingdom. RESULTS: The FAQLQ-PF has high convergent validity (child: r = 0.49, n = 695, P = .01; parent: r = 0.36, n = 696, P = .01) and discriminant validity, parent: t (719) = 4.67, P = .001 (anaphylaxis yes vs no); t (513), P = .009 (single vs multiple allergens). Internal consistency was excellent (r = 0.96). US health-related quality of life was worse than European health-related quality of life, as indicated by higher FAQLQ-PF scores in US samples. Burden increased with age in all populations. CONCLUSIONS: The FAQLQ-PF is appropriate for use in an American population. Findings will form the basis for further work in the development of an online manual with food allergy-normed age scores to allow for precise measurement, interpretation of scores, and comparison across countries and cultures, in clinical and research settings. PMID- 28017628 TI - Eosinophilic esophagitis during peanut oral immunotherapy with omalizumab. PMID- 28017630 TI - Malar Rash in a Child with Chronic Granulomatous Disease. PMID- 28017629 TI - Identifying Risk of Future Asthma Attacks Using UK Medical Record Data: A Respiratory Effectiveness Group Initiative. AB - BACKGROUND: Asthma attacks are common, serious, and costly. Individual factors associated with attacks, such as poor symptom control, are not robust predictors. OBJECTIVE: We investigated whether the rich data available in UK electronic medical records could identify patients at risk of recurrent attacks. METHODS: We analyzed anonymized, longitudinal medical records of 118,981 patients with actively treated asthma (ages 12-80 years) and 3 or more years of data. Potential risk factors during 1 baseline year were evaluated using univariable (simple) logistic regression for outcomes of 2 or more and 4 or more attacks during the following 2-year period. Predictors with significant univariable association (P < .05) were entered into multiple logistic regression analysis with backward stepwise selection of the model including all significant independent predictors. The predictive accuracy of the multivariable models was assessed. RESULTS: Independent predictors associated with future attacks included baseline-year markers of attacks (acute oral corticosteroid courses, emergency visits), more frequent reliever use and health care utilization, worse lung function, current smoking, blood eosinophilia, rhinitis, nasal polyps, eczema, gastroesophageal reflux disease, obesity, older age, and being female. The number of oral corticosteroid courses had the strongest association. The final cross-validated models incorporated 19 and 16 risk factors for 2 or more and 4 or more attacks over 2 years, respectively, with areas under the curve of 0.785 (95% CI, 0.780 0.789) and 0.867 (95% CI, 0.860-0.873), respectively. CONCLUSIONS: Routinely collected data could be used proactively via automated searches to identify individuals at risk of recurrent asthma attacks. Further research is needed to assess the impact of such knowledge on clinical prognosis. PMID- 28017631 TI - Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: A systematic review and meta-analysis. AB - OBJECTIVE: Numerous studies have assessed the association between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). However, results have been conflicting due to variability in definitions of NAFLD and ascertainment of CVD, often combining clinical and surrogate endpoints. We therefore systematically reviewed published literature to assess the association between NAFLD and clinical cardiovascular events (CVE) and performed a meta analysis. METHODS: We searched PubMed, Medline, Cochrane, CINAHL, and Web of Science databases using terms "nonalcoholic fatty liver disease", "nonalcoholic steatohepatitis", "cardiovascular disease", and their combinations to identify prospective studies published from inception through March 2016. Data from selected studies was extracted and meta-analysis was then performed using random effects model. RESULTS: A total of six studies with 25,837 patients (NAFLD: 5953; controls: 19,884) were included in the final analysis. Patients with NAFLD had a significantly higher risk of clinical CVE compared to controls (RR: 1.77; 95% CI: 1.26-2.48, p<0.001). Exclusion sensitivity analysis did not alter the above results. The association remained consistent for subgroups with clinical coronary artery disease (RR: 2.26; 95% CI: 1.04-4.92, p<0.001) and ischemic stroke (RR: 2.09; 95% CI: 1.46-2.98, p<0.001). The risk of cardiovascular mortality was also increased in the NAFLD group (RR 1.46, 95% CI 1.31-1.64, p<0.001). CONCLUSION: NAFLD patients have a significantly higher risk for clinical CVE compared to those without. These results need to be confirmed in large prospective studies. PMID- 28017632 TI - Relationship between plasma osteocalcin, glycaemic control and components of metabolic syndrome in adult Nigerians with type 2 diabetes mellitus. AB - AIMS: To determine the levels of plasma osteocalcin (OC) in Nigerians with type 2 diabetes mellitus (DM) and compare these to levels in non-diabetic controls (NDM). To assess the relationship of OC to glycaemic control and parameters of metabolic syndrome (MetS) and compare its levels in Nigerians with and without MetS. METHODS: The waist circumference (WC), body mass index (BMI) and blood pressure of 200 study participants were taken. Plasma osteocalcin, fasting glucose (FPG), glycated haemoglobin (HbA1c), high density lipoprotein cholesterol (HDL-c) and triglyceride (TG) levels were determined. Metabolic syndrome was defined by the International Diabetes Federation criteria. Statistical significance was set at 0.05. RESULTS: Osteocalcin levels were lower in the DM group (p=0.002) and inversely related to FPG (r=-0.198, p=0.003), HbA1c (r= 0.313, p<0.001), BMI (r=-0.331, p<0.001), WC (r=-0.339, p<0.001) and TG (r= 0.145, p=0.040), but directly related to HDL-c levels (r=0.166, p=0.019). Osteocalcin was higher in participants without MetS (Median 8.75ng/mL IQR[5.48 12.68]ng/mL) than in those with MetS (Median 4.74ng/Ml, IQR[2.80-9.12]ng/mL), p<0.001. CONCLUSIONS: Plasma osteocalcin levels are inversely associated with good glycaemic control and components of MetS and are lower in individuals with DM and in those with MetS. These findings support a vital role of the bone, in the regulation of glucose and energy metabolism, in Nigerians. Further extensive studies are required to explore the potentials of OC in the management of DM and MetS. PMID- 28017633 TI - Complement 3 serum levels as a pro-inflammatory biomarker for insulin resistance in obesity. AB - INTRODUCTION: Obesity is frequently characterized by chronic inflammation and insulin resistance (IR). Obesity-associated inflammation is responsible for the complement system activation of which the third component (C3) plays the central role. OBJECTIVE: to discuss several aspects of the central component of the complement system in relation to obesity and obesity-associated IR. METHODS: A critical review of the relevant published English articles from 2003- 2014 was carried out using several search engines including PubMed, Google Scholar, and ScienceDirect. Keywords were used, including complement system, C3, obesity induced inflammation, IR, ASP, and adipose tissue. CONCLUSION: The defect in the adipose tissue secretory function during obesity may result in different metabolic disorders including IR. The C3 role during obesity-associated inflammation in IR is emerging. More longitudinal studies are warranted to evaluate the role of C3 among other pro-inflammatory biomarkers for IR. PMID- 28017634 TI - Family history of diabetes and the risk of gestational diabetes mellitus in Iran: A systematic review and meta-analysis. AB - OBJECTIVE: Gestational diabetes is the most prevalent metabolic disorder being firstly diagnosed during pregnancy. The relationship between the family history of diabetes and the gestational diabetes mellitus (GDM) has been investigated in several primary studies with a number of contradictions in the results. Hence, the purpose of the present study is to determine the relationship between the GDM and the family history of diabetes using the meta-analysis method. METHOD: All published papers in main national and international databases were systematically searched with some specific keywords to find the related studies between 2000 and 2016. We calculated the odds ratio (OR) with 95% confidence interval (CI) in analysis for each study using a random-effect and Mantel-Haenzel method. We also determined heterogeneity among these 33 articles and their publication bias. RESULTS: We entered 33 relevant studies of 2516 articles into the meta-analysis process including 2697 women with family history of diabetes mellitus as well as 29134 women without. Of them, 954 and 4372 subjects developed GDM respectively. Combining the results of the primary studies using the meta-analysis method, the overall odds ratio of family history for developing GDM was estimated as of 3.46 (95% CI: 2.80-4.27). CONCLUSION: This meta-analysis study revealed that the family history of diabetes is an important risk factor for the gestational diabetes mellitus. PMID- 28017636 TI - Identification and first characterization of SmEps8, a potential interaction partner of SmTK3 and SER transcribed in the gonads of Schistosoma mansoni. AB - In eukaryotes the roles of protein kinases (PKs) regulating important biological processes such as growth and differentiation are well known. Molecular, biochemical, and physiological analyses trying to unravel principles of schistosome development have substantiated the importance for PKs also in this parasite. Amongst others the role of SmTK3 was studied, one of the first cellular PKs characterized from Schistosoma mansoni. Its function was demonstrated in mitogenic and differentiation processes in the gonads. Furthermore, first insights were obtained for the downstream part of a signal transduction cascade SmTK3 is involved in, which includes the diaphanous homolog SmDia. Here we attempted to further unravel the SmTK3 signaling cascade by searching for upstream interaction partners. Using yeast three-hybrid (Y3H) analyses we detected the epidermal growth factor receptor (EGFR) pathway substrate 8 of S. mansoni (SmEps8) as the most interesting candidate. By detailed interaction analyses we showed a contribution of the Src homology (SH) domains SH2 and SH3 of SmTK3 to binding, with a clear bias towards SH2. Compared to full-length SmEps8, binding was enhanced when only its 5' part including the phosphotyrosine binding domain (PTB) was used for interaction analyses including the SH2 domain of SmTK3, although phosphorylation seemed not to play a decisive role for binding. RT-PCR analyses and in situ hybridization experiments demonstrated similar transcription patterns of SmTK3 and SmEPS8, which co-localize in the reproductive organs. Furthermore, first evidence was obtained for SmEps8 interaction and colocalization with SER, one of the epidermal growth factor receptor (EGFR) homologs detected in S. mansoni. The results of this study provide first evidence for a SER-SmEps8-SmTK3-SmDia signal transduction pathway controlling differentiation processes in the gonads of S. mansoni. PMID- 28017635 TI - Use of FTA(r) card methodology for sampling and molecular characterization of Echinococcus granulosus sensu lato in Africa. AB - Cystic Echinococcosis is a parasitic disease caused by the cestode Echinococcus granulosus widely distributed in Africa. Monitoring of this parasite requires access to cyst samples on intermediate hosts observed at the slaughterhouse. In order to facilitate sampling in the field and analysis, the French National Reference Laboratory for Echinococcus spp. has developed a tissue derived from DNA sampling with FTA(r) card technology. The DNA samples were taken by applying the FTA(r) paper on the germinal layer after opening the cysts. The sampling technique was validated using frozen cysts (n = 76) stored in the laboratory and from field samples (n = 134) taken at the slaughterhouse by veterinarian technicians during meat inspection in Morocco, Mali and Mauritania. DNA was extracted after several weeks of storage at room temperature. PCR assays were performed using primers for generic cestode (cox1) and amplified fragments were sequenced. All samples taken in the lab and 80% of field samples were capable of molecular characterization. Cyst-derived DNA from FTA(r) samples can be useful for easy sampling, storage and rapid, safe and cheap shipment. The use of the FTA methodology will facilitate studies in the field to investigate the presence and genetic characterization of E. granulosus sensu lato in African countries. PMID- 28017637 TI - Psychological and neural mechanisms associated with effort-related cardiovascular reactivity and cognitive control: An integrative approach. AB - Numerous studies have assessed cardiovascular (CV) reactivity as a measure of effort mobilization during cognitive tasks. However, psychological and neural processes underlying effort-related CV reactivity are still relatively unclear. Previous research reliably found that CV reactivity during cognitive tasks is mainly determined by one region of the brain, the dorsal anterior cingulate cortex (dACC), and that this region is systematically engaged during cognitively demanding tasks. The present integrative approach builds on the research on cognitive control and its brain correlates that shows that dACC function can be related to conflict monitoring and integration of information related to task difficulty and success importance-two key variables in determining effort mobilization. In contrast, evidence also indicates that executive cognitive functioning is processed in more lateral regions of the prefrontal cortex. The resulting model suggests that, when automatic cognitive processes are insufficient to sustain behavior, the dACC determines the amount of required and justified effort according to task difficulty and success importance, which leads to proportional adjustments in CV reactivity and executive cognitive functioning. These propositions are discussed in relation to previous findings on effort related CV reactivity and cognitive performance, new predictions for future studies, and relevance for other self-regulatory processes. PMID- 28017638 TI - The influence of self-construal type on outcome evaluation: Evidence from event related potentials. AB - Recent studies have revealed a close relationship between the self and reward networks. One of our previous studies has found that outcome evaluation (including the processing of reward and punishment) is modulated by self reflection. A question remaining unclear is how different types of self-construal influence outcome evaluation. Self-construal refers to the way in which people perceive themselves to be linked (or not) with other people. Two subtypes of self construal have been identified: independent self and interdependent self. In the present study, 27 normal adults read essays that contained independent or interdependent pronouns (i.e., I or we) and then performed a gambling task while brain event-related potentials (ERPs) were recorded. The ERP analysis focused on the feedback-related negativity (FRN) and the P3 component. Outcome feedback evoked a larger FRN in the independent self-priming condition than in the interdependent self-priming condition. In contrast, the P3 amplitude was insensitive to self-construal manipulation. The present findings suggest that different types of transient self-construal manifest differently in outcome evaluation processes, supporting the existence of a close link between the self and reward networks. PMID- 28017640 TI - Cystic fibrosis: a call for papers for the ECFS meeting. PMID- 28017639 TI - Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection. AB - Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Galpha13 but not Galpha12, Galphaq, or Galphai. Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P3 KO mouse heart. CYM-51736, an S1P3 specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P3 receptor- and Galpha13-mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P3 receptors could provide therapeutic benefits in ischemic heart disease. PMID- 28017641 TI - WY-14643, a selective agonist of peroxisome proliferator-activated receptor alpha, ameliorates lipopolysaccharide-induced depressive-like behaviors by preventing neuroinflammation and oxido-nitrosative stress in mice. AB - Depression is a common disease that afflicts one in six people at some points in life. Numerous hypotheses have been raised in past years, but the exact mechanism that can be used to explain the development of depression remains obscure. Recently, more and more attentions are being focused on neuroinflammation and oxidative stress in depression. WY-14643, an agonist of peroxisome proliferator activated receptor-alpha (PPAR-alpha), has been reported to inhibit neuroinflammation and oxidative stress, and one of our previous studies have showed that WY-14643 possesses antidepressive activities. On that account, we investigated the effect of WY-14643 pretreatment on lipopolysaccharide (LPS) induced depressive-like behaviors, neuroinflammation and oxido-nitrosative stress in mice. Results showed that WY-14643 pretreatment at the doses of 5 and 10mg/kg significantly ameliorated LPS (0.83mg/kg)-induced depressive-like behaviors in the tail suspension test (TST), forced swimming test (FST) and sucrose preference experiment. Further analysis showed that WY-14643 pretreatment not only inhibited the production of pro-inflammatory cytokines induced by LPS, such as interleukin 6 (IL-6), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha), but also prevented the LPS-induced enhancement of oxidative and nitrosative stress in the hippocampus and prefrontal cortex. In addition, the LPS induced decreases in hippocampal and prefrontal cortical brain-derived neurotrophic factor (BDNF) levels were reversed by WY-14643 pretreatment. Taken together, our data provide further evidence to show that WY-14643 could be an agent that can be used to treat depression, and inhibition of neuroinflammation and oxido-nitrosative stress may be the potential mechanism for the antidepressive effect of WY-14643. PMID- 28017642 TI - Immunity duration of a recombinant adenovirus type-5 vector-based Ebola vaccine and a homologous prime-boost immunisation in healthy adults in China: final report of a randomised, double-blind, placebo-controlled, phase 1 trial. AB - BACKGROUND: The 2013-15 Ebola virus disease epidemic in west Africa greatly accelerated the development of Ebola vaccine. We aimed to analyse the immune persistence induced by one shot of an adenovirus type-5 vector-based Ebola virus vaccine up to 6 months and the effect of boosting with a homologous vector in healthy adults in China. METHODS: In a randomised, double-blind, placebo controlled, phase 1 clinical trial in one site in Jiangsu Province, China, 120 healthy adults aged 18-60 years received an initial dose of intramuscular adenovirus type-5 Ebola virus vaccine of 4.0 * 1010 viral particles, 1.6 * 1011 viral particles, or placebo, and were followed up to day 168. Participants were subsequently re-recruited to receive a booster dose of the same vaccine or placebo, in the same dose, at month 6. Women who were pregnant, breastfeeding, or planned to become pregnant during the next month were excluded. Randomisation was conducted by computer-generated block randomisation. Randomisation data were unmasked for interim analysis of the data obtained between days 0-28 but not disclosed to participants or site staff. Safety and immunogenicity analysis were done on the intention-to-treat population. We aimed to assess the safety profile of the experimental vaccine and the immunity responses to a single-dose immunisation or a homologous prime-boost regimen. Primary outcomes were Ebola glycoprotein-specific ELISA antibody responses 28 days post-boost and the occurrences of adverse reactions post-boost. The original trial and the extended booster study were registered with ClinicalTrials.gov, numbers NCT02326194 and NCT02533791, respectively. FINDINGS: Between Dec 28, 2014, and Jan 9, 2015, we enrolled 210 volunteers. 90 participants were not randomised due to not meeting inclusion criteria (61), meeting exclusion criteria (4), or withdrawal of consent (25). 120 people were randomly assigned to receive intramuscular Ebola vaccine at 4.0 * 1010 viral particles (low dose, n=40), Ebola vaccine at 1.6 * 1011 viral particles (high dose, n=40), or placebo (n=40, in two groups of 20). After prime vaccination, the geometric mean titer (GMT) of ELISA EC90 peaked at 682.7 (95% CI 424.3-1098.5) in the low-dose vaccine group and 1305.7 (970.1-1757.2) in the high dose vaccine group at day 28, and then fell gradually through the next a few months to 575.5 (394.8-838.8) in the high-dose vaccine group and 197.9 (107.9 362.7) in the low-dose vaccine group at day 168. No specific response was recorded in the placebo group with a GMT of 5.0. Of the 120 participants involved in the initial trial, ten participants declined to participate, and 110 were included in the boost immunisation: 38 received the low dose, 35 received the high dose, and 37 received the placebo. At day 28 after boost vaccination, the ELISA EC90 titres rapidly rose to 6110 (95% CI 4705-7935) in the low-dose group and to 11825 (8904-15705) in the high dose group. 78 of 110 participants reported at least one solicited adverse reaction within the first 7 days after booster administration. Both of the groups who received vaccine showed significantly higher incidence of mild or moderate solicited adverse reactions than did the placebo group. INTERPRETATION: The adenovirus 5-vectored Ebola vaccine of 1.6 * 1011 viral particles was highly immunogenic and safe. The lower dose of 4.0 * 1010 viral particles was also safe, but immunogenicity seemed to be more vulnerable to the pre-existing immunity of adenovirus 5. A homologous priming boosting regimen with adenovirus type-5 Ebola vaccine at 6 months interval was able to elicit greater antibody responses with longer duration. These results support an immunisation strategy to implement a booster injection for a more durable protection against Ebola virus disease. FUNDING: Chinese Ministry of Science and Technology and The National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. PMID- 28017644 TI - Piercing the "armor" of lung cancer with genome medicine. PMID- 28017643 TI - The posterior neural plate in axolotl gives rise to neural tube or turns anteriorly to form somites of the tail and posterior trunk. AB - Classical grafting experiments in the Mexican axolotl had shown that the posterior neural plate of the neurula is no specified neuroectoderm but gives rise to somites of the tail and posterior trunk. The bipotentiality of this region with neuromesodermal progenitor cell populations was revealed more recently also in zebrafish, chick, and mouse. We reinvestigated the potency of the posterior plate in axolotl using grafts from transgenic embryos, immunohistochemistry, and in situ hybridization. The posterior plate is brachyury positive except for its more anterior parts which express sox2. Between anterior and posterior regions of the posterior plate a small domain with sox2+ and bra+ cells exists. Lineage analysis of grafted GFP-labeled posterior plate tissue revealed that posterior GFP+ cells move from dorsal to ventral, form the posterior wall, turn anterior bilaterally, and join the gastrulated paraxial presomitic mesoderm. More anterior sox2+/GFP+ cells, however, are integrated into the developing spinal cord. Tail notochord is formed from axial mesoderm involuted already during gastrulation. Thus the posterior neural plate is a postgastrula source of paraxial mesoderm, which performs an anterior turn, a novel morphogenetic movement. More anterior plate cells, in contrast, do not turn anteriorly but become specified to form tail spinal cord. PMID- 28017645 TI - Focal seizure induced by preoperative navigated transcranial magnetic stimulation in a patient with anaplastic oligoastrocytoma. PMID- 28017646 TI - Targeting the transcription factor Myb by small-molecule inhibitors. AB - The transcription factor Myb is a key regulator of hematopoietic cell proliferation, differentiation, and survival and has been implicated in the development of leukemia and several other human cancers. Pharmacological inhibition of Myb is therefore emerging as a potential therapeutic strategy. Recently, the first low-molecular-weight compounds that show Myb inhibitory activity have been identified. Characterization of these compounds suggests disruption of the protein-protein-interaction of Myb and the coactivator p300 as a suitable strategy to inhibit Myb. PMID- 28017648 TI - Non-invasive PET imaging of brain inflammation at disease onset predicts spontaneous recurrent seizures and reflects comorbidities. AB - Brain inflammation is an important factor in the conversion of a healthy brain into an epileptic one, a phenomenon known as epileptogenesis, offering a new entry point for prognostic tools. The development of anti-epileptogenic therapies to treat before or at disease onset is hampered by our inability to predict the severity of the disease outcome. In a rat model of temporal lobe epilepsy we aimed to assess whether in vivo non-invasive imaging of brain inflammation at disease onset was predictive of spontaneous recurrent seizures (SRS) frequency and severity of depression-like and sensorimotor-related comorbidities. To this end, translocator protein, a biomarker of inflammation, was imaged by means of positron emission tomography (PET) 2 and 4weeks post-status epilepticus using [18F]-PBR111. Translocator protein was highly upregulated 2weeks post-status epilepticus in limbic structures (up to 2.1-fold increase compared to controls in temporal lobe, P<0.001), whereas 4weeks post-status epilepticus, upregulation decreased (up to 1.6-fold increase compared to controls in temporal lobe, P<0.01) and was only apparent in a subset of these regions. Animals were monitored with video-electroencephalography during all stages of disease (acute, latent - first seizures appearing around 2weeks post-status epilepticus - and chronic phases), for a total of 12weeks, in order to determine SRS frequency for each subject (range 0.00-0.83SRS/day). We found that regional PET uptake at 2 and 4weeks post status epilepticus correlated with the severity of depression-like and sensorimotor-related comorbidities during chronic epilepsy (P<0.05 for each test). Regional PET imaging did not correlate with SRS frequency, however, by applying a multivariate data-driven modeling approach based on translocator protein PET imaging at 2weeks post-status epilepticus, we accurately predicted the frequency of SRS (R=0.92; R2=0.86; P<0.0001) at the onset of epilepsy. This study not only demonstrates non-invasive imaging of translocator protein as a prognostic biomarker to ascertain SRS frequency, but also shows its capability to reflect the severity of depression-like and sensorimotor-related comorbidities. Our results are an encouraging step towards the development of anti-epileptogenic treatments by providing early quantitative assessment of SRS frequency and severity of comorbidities with high clinical relevance. PMID- 28017649 TI - Corrigendum to A gene trap dissociation insertion line, associated with a RING-H2 finger gene, shows tissue specific and developmental regulated expression of the gene in Arabidopsis [Gene 290 (2002): 63-71]. PMID- 28017647 TI - Preclinical approaches in chronic myeloid leukemia: from cells to systems. AB - Advances in the design of targeted therapies for the treatment of chronic myeloid leukemia (CML) have transformed the prognosis for patients diagnosed with this disease. However, leukemic stem cell persistence, drug intolerance, drug resistance, and advanced-phase disease represent unmet clinical needs demanding the attention of CML investigators worldwide. The availability of appropriate preclinical models is essential to efficiently translate findings from the bench to the clinic. Here we review the current approaches taken to preclinical work in the CML field, including examples of commonly used in vivo models and recent successes from systems biology-based methodologies. PMID- 28017650 TI - Dysregulation of mitophagy in carcinogenesis and tumor progression. AB - The mitochondrial role in carcinogenesis and cancer progression is an area of active research, with many unresolved questions. Various aspects of altered mitochondrial function have been implicated in tumorigenesis and tumor progression, including mitochondrial dysfunction, a metabolic switch to aerobic glycolysis, and dysregulation of mitophagy. Mitophagy is a highly specific quality control process which eliminates dysfunctional mitochondria and promotes mitochondrial turnover, and is involved in the adaptation to nutrient stress by controlling mitochondrial mass. The dysregulation of mitochondrial turnover has both a positive and negative role in cancer. This review will begin with a basic overview of the molecular mechanisms of mitophagy, and highlight recent trends in mitophagy from cancer studies. We will conclude this review by discussing areas of research in normal mitophagy that have yet to be explored in the context of cancer such as mitochondrial proteases, the mitochondrial unfolded protein response, and mitokine action. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 28017651 TI - Surgical treatment of salivary malignant tumors. AB - Salivary gland malignant tumors (SGMT) are of key interest for head and neck surgeons since surgery with adjuvant radiotherapy is considered the treatment of choice in most of the cases. Some factors, namely rarity, high histologic heterogeneity, and possible occurrence in all the head and neck subsites, contribute to make this topic very controversial; some unclear aspects pertain surgical treatment. When dealing with major salivary gland malignant tumors (MaSGMT), the most debated issues remain the extent of surgery and management of facial nerve. In minor salivary gland malignant tumors (MiSGMT), conversely, surgical planning is influenced by the specific pattern of growth of the different neoplasms as well as the site of origin of the lesion. Finally, two additional issues, the treatment of the neck (therapeutic or elective) and reconstructive strategy after ablative surgery, are of pivotal importance in management of both MaSGMT and MiSGMT. In this review, we discuss the most relevant and controversial issues concerning surgery of SGMT. PMID- 28017652 TI - ATR gene mutations in HPV negative oropharyngeal cancer. PMID- 28017653 TI - Measurement of the Intertablet Coating Uniformity of a Pharmaceutical Pan Coating Process With Combined Terahertz and Optical Coherence Tomography In-Line Sensing. AB - We present in-line coating thickness measurements acquired simultaneously using 2 independent sensing modalities: terahertz pulsed imaging (TPI) and optical coherence tomography (OCT). Both techniques are sufficiently fast to resolve the coating thickness of individual pharmaceutical tablets in situ during the film coating operation, and both techniques are direct structural imaging techniques that do not require multivariate calibration. The TPI sensor is suitable to measure coatings greater than 50 MUm and can penetrate through thick coatings even in the presence of pigments over a wide range of excipients. Due to the long wavelength, terahertz radiation is not affected by scattering from dust within the coater. In contrast, OCT can resolve coating layers as thin as 20 MUm and is capable of measuring the intratablet coating uniformity and the intertablet coating thickness distribution within the coating pan. However, the OCT technique is less robust when it comes to the compatibility with excipients, dust, and potentially the maximum coating thickness that can be resolved. Using a custom built laboratory scale coating unit, the coating thickness measurements were acquired independently by the TPI and OCT sensors throughout a film coating operation. Results of the in-line TPI and OCT measurements were compared against one another and validated with off-line TPI and weight gain measurements. Compared with other process analytical technology sensors, such as near-infrared and Raman spectroscopy, the TPI and OCT sensors can resolve the intertablet thickness distribution based on sampling a significant fraction of the tablet populations in the process. By combining 2 complementary sensing modalities, it was possible to seamlessly monitor the coating process over the range of film thickness from 20 MUm to greater than 250 MUm. PMID- 28017654 TI - Hippocalcin Promotes Neuronal Differentiation and Inhibits Astrocytic Differentiation in Neural Stem Cells. AB - Hippocalcin (HPCA) is a calcium-binding protein that is restricted to nervous tissue and contributes to neuronal activity. Here we report that, in addition to inducing neurogenesis, HPCA inhibits astrocytic differentiation of neural stem cells. It promotes neurogenesis by regulating protein kinase Calpha (PKCalpha) activation by translocating to the membrane and binding to phosphoinositide dependent protein kinase 1 (PDK1), which induces PKCalpha phosphorylation. We also found that phospholipase D1 (PLD1) is implicated in the HPCA-mediated neurogenesis pathway; this enzyme promotes dephosphorylation of signal transducer and activator of transcription 3 (STAT3[Y705]), which is necessary for astrocytic differentiation. Moreover, we found that the SH2-domain-containing tyrosine phosphatase 1 (SHP-1) acts upstream of STAT3. Importantly, this SHP-1-dependent STAT3-inhibitory mechanism is closely involved in neurogenesis and suppression of gliogenesis by HPCA. Taken together, these observations suggest that HPCA promotes neuronal differentiation through activation of the PKCalpha/PLD1 cascade followed by activation of SHP-1, which dephosphorylates STAT3(Y705), leading to inhibition of astrocytic differentiation. PMID- 28017655 TI - CD59 Regulation by SOX2 Is Required for Epithelial Cancer Stem Cells to Evade Complement Surveillance. AB - Cancer stem cells (CSCs) are highly associated with therapy resistance and metastasis. Interplay between CSCs and various immune components is required for tumor survival. However, the response of CSCs to complement surveillance remains unknown. Herein, using stem-like sphere-forming cells prepared from a mammary tumor and a lung adenocarcinoma cell line, we found that CD59 was upregulated to protect CSCs from complement-dependent cytotoxicity. CD59 silencing significantly enhanced complement destruction and completely suppressed tumorigenesis in CSC xenografted nude mice. Furthermore, we identified that SOX2 upregulates CD59 in epithelial CSCs. In addition, we revealed that SOX2 regulates the transcription of mCd59b, leading to selective mCD59b abundance in murine testis spermatogonial stem cells. Therefore, we demonstrated that CD59 regulation by SOX2 is required for stem cell evasion of complement surveillance. This finding highlights the importance of complement surveillance in eliminating CSCs and may suggest CD59 as a potential target for cancer therapy. PMID- 28017656 TI - Primary Human Testicular Cells Self-Organize into Organoids with Testicular Properties. AB - So far, successful de novo formation of testicular tissue followed by complete spermatogenesis in vitro has been achieved only in rodents. Our findings reveal that primary human testicular cells are able to self-organize into human testicular organoids (TOs), i.e., multi-cellular tissue surrogates, either with or without support of a biological scaffold. Despite lacking testis-specific topography, these mini-tissues harbored spermatogonia and their important niche cells, which retained specific functionalities during long-term culture. These observations indicate the posibility of in vitro re-engineering of a human testicular microenvironment from primary cells. Human TOs might help in the development of a biomimetic testicular model that would exert a tremendous impact on research and development, clinical treatment of infertility, and screening in connection with drug discovery and toxicology. PMID- 28017657 TI - Direct Reprogramming of Mouse Fibroblasts toward Leydig-like Cells by Defined Factors. AB - Leydig cells (LCs) play crucial roles in producing testosterone, and their dysfunction leads to male hypogonadism. LC transplantation is a promising alternative therapy for male hypogonadism. However, the source of LCs limits this strategy for clinical applications. Here, we report our success in reprogramming mice fibroblasts into LCs by expressing three transcriptional factors, Dmrt1, Gata4, and Nr5a1. The induced Leydig-like cells (iLCs) expressed steroidogenic genes, had a global gene expression profile similar to that of adult LCs, and acquired androgen synthesis capabilities. When iLCs were transplanted into rats or mice testes that were selectively depleted of endogenous LCs, the transplanted cells could survive and function in the interstitium of testis, resulting in the restoration of normal levels of serum testosterone. These findings demonstrate that the fibroblasts were able to be directly converted into iLCs by few defined factors, which may facilitate future applications in regenerative medicine. PMID- 28017658 TI - Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum. AB - Metabolites and cofactors are emerging as key regulators of cell plasticity and reprogramming, and their role in the control of pluripotency is just being discovered. Here we provide unprecedented evidence that embryonic stem cell (ESC) pluripotency relies on the relative levels of two physiological metabolites, namely ascorbic acid (vitamin C, VitC) and l-proline (l-Pro), which affect global DNA methylation, transcriptional profile, and energy metabolism. Specifically, while a high VitC/l-Pro ratio drives ESCs toward a naive state, the opposite condition (l-Pro excess) captures a fully reversible early primed pluripotent state, which depends on autocrine fibroblast growth factor and transforming growth factor beta signaling pathways. Our findings highlight the pivotal role of metabolites availability in controlling the pluripotency continuum from naive to primed states. PMID- 28017660 TI - Prevotella as a Hub for Vaginal Microbiota under the Influence of Host Genetics and Their Association with Obesity. AB - While the vaginal ecosystem is maintained through mutualistic relationships between the host and the vaginal bacteria, the effect of host genetics on the vaginal microbiota has not been well characterized. We examined the heritability of vaginal microbiota and its association with obesity in 542 Korean females, including 222 monozygotic and 56 dizygotic twins. The vaginal microbiota significantly varied depending on host menopausal status and bacterial vaginosis. Lactobacillus and Prevotella, whose relative abundances are strongly associated with bacterial vaginosis, were the most heritable bacteria among the beneficial and potentially pathogenic vaginal microbiota, respectively. Candidate gene analysis revealed an association between genetic variants of interleukin-5 and the abundance of Prevotella sp. Furthermore, host obesity significantly increased the diversity of the vaginal microbiota in association with Prevotella. Our results provide insight into the effect of host genetics on the vaginal microbiota and their association with both vaginal and non-vaginal health. PMID- 28017659 TI - The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. AB - During antibacterial autophagy, ubiquitination of intracellular bacteria recruits proteins that mediate bacterial delivery to the lysosome for degradation. Smurf1 is an E3 ubiquitin ligase whose role in selective bacterial autophagy is unknown. We show that Smurf1 facilitates selective autophagy of the human pathogen Mycobacterium tuberculosis (Mtb). Smurf1-/- macrophages are defective in recruiting polyubiquitin, the proteasome, the ubiquitin-binding autophagy adaptor NBR1, the autophagy protein LC3, and the lysosomal marker LAMP1 to Mtb-associated structures and are more permissive for Mtb growth. This function of Smurf1 requires both its ubiquitin-ligase and C2 phospholipid-binding domains, and involves K48- rather than K63-linked ubiquitination. Chronically infected Smurf1 /- mice have increased bacterial load, increased lung inflammation, and accelerated mortality. SMURF1 controls Mtb replication in human macrophages and associates with bacteria in lungs of patients with pulmonary tuberculosis. Thus, Smurf1 is required for selective autophagy of Mtb and host defense against tuberculosis infection. PMID- 28017662 TI - Mechanism of inhibition by chlorpromazine of the human pain threshold sodium channel, Nav1.7. AB - Chlorpromazine is a phenothiazine derivative which is primarily used for schizophrenia and occasionally for migraine. Because Nav1.7 plays an important role in pain sensation, we investigated whether chlorpromazine blocks the human Nav1.7 (hNav1.7) sodium current in HEK293 cells stably expressing hNav1.7 using the whole-cell patch-clamp technique. The peak current of hNav1.7 was reduced by chlorpromazine in a concentration-dependent manner with a half-maximal inhibitory concentration of 25.9+/-0.6MUM and a Hill coefficient of 2.3+/-0.1. The calmodulin inhibitory peptide did not abolish the blockade of hNav1.7 currents by chlorpromazine. The blockade of hNav1.7 currents by chlorpromazine was completely and repeatedly reversible after washout. The half-maximal voltage of activation of hNav1.7 was not changed by chlorpromazine. However, chlorpromazine caused hyperpolarized the steady-state inactivation of hNav1.7. The recovery from inactivation in the presence of chlorpromazine was slower than in the absence of chlorpromazine. Chlorpromazine also showed strong use-dependent inhibition of the hNav1.7 current. Our results demonstrate that chlorpromazine blocks the hNav1.7 current in concentration-, state- and use-dependent manners and suggest that it merits further study for potential use in pain management. PMID- 28017663 TI - Onartuzumab ineffective in non-small-cell lung cancer. PMID- 28017661 TI - Recent H3N2 Viruses Have Evolved Specificity for Extended, Branched Human-type Receptors, Conferring Potential for Increased Avidity. AB - Human and avian influenza viruses recognize different sialic acid-containing receptors, referred to as human-type (NeuAcalpha2-6Gal) and avian-type (NeuAcalpha2-3Gal), respectively. This presents a species barrier for aerosol droplet transmission of avian viruses in humans and ferrets. Recent reports have suggested that current human H3N2 viruses no longer have strict specificity toward human-type receptors. Using an influenza receptor glycan microarray with extended airway glycans, we find that H3N2 viruses have in fact maintained human type specificity, but they have evolved preference for a subset of receptors comprising branched glycans with extended poly-N-acetyl-lactosamine (poly-LacNAc) chains, a specificity shared with the 2009 pandemic H1N1 (Cal/04) hemagglutinin. Lipid-linked versions of extended sialoside receptors can restore susceptibility of sialidase-treated MDCK cells to infection by both recent (A/Victoria/361/11) and historical (A/Hong Kong/8/1968) H3N2 viruses. Remarkably, these human-type receptors with elongated branches have the potential to increase avidity by simultaneously binding to two subunits of a single hemagglutinin trimer. PMID- 28017664 TI - Cetuximab chemoradiotherapy in HIV-associated anal cancer. PMID- 28017665 TI - Advanced atherosclerosis is associated with inflammation, vascular dysfunction and oxidative stress, but not hypertension. AB - Although hypertension may involve underlying inflammation, it is unknown whether advanced atherosclerosis - a chronic inflammatory condition - can by itself promote hypertension. We thus tested if advanced atherosclerosis in chronically hypercholesterolemic mice is associated with systemic and end-organ inflammation, vascular dysfunction and oxidative stress, and whether blood pressure is higher than in control mice. Male ApoE-/- and wild-type (C57Bl6J) mice were placed on a high fat or chow diet, respectively, from 5 to 61 weeks of age. Expression of several cytokines (including IL-6, TNF-alpha, IFN-gamma and/or IL-1beta) was elevated in plasma, brain, and aorta of ApoE-/- mice. Aortic superoxide production was ~3.5-fold greater, and endothelium-dependent relaxation was markedly reduced in aorta and mesenteric artery of ApoE-/- versus wild-type mice. There was no difference in blood pressure of aged ApoE-/- (104+/-3mmHg, n=13) and wild-type mice (113+/-1mmHg, n=18). To clarify any effects of aging alone, findings from 61 week-old wild-type mice were compared with those from young (8 12 weeks old) chow-fed wild-type mice. The data indicate that aging alone increased renal and aortic expression of numerous cytokines (including CCL2, CCL7 and IL-1beta). Aging had no effect on blood pressure, systemic inflammation, oxidative stress or endothelial function. Despite systemic and end-organ inflammation, oxidative stress and endothelial dysfunction, advanced atherosclerosis does not necessarily result in elevated blood pressure. PMID- 28017666 TI - GABA Australis, some reflections on the history of GABA receptor research in Australia. AB - Research on GABA receptors has a long history in Australia dating from 1958 with David Curtis and his colleagues in Canberra. This review traces many of the advances made in Australia guided by highly cited publications and some obscure ones. It covers the discovery of key chemicals with which to investigate GABA receptor function including bicuculline, muscimol, phaclofen, THIP and (+)-CAMP. Also described are findings relevant to the involvement of mutant GABA receptors in inherited epilepsy. The modulation of GABA receptors by a bewildering range of chemicals, especially by flavonoids and terpenoids, is discussed. PMID- 28017667 TI - Assessment of optimal initial dosing regimen with vancomycin pharmacokinetics model in very low birth weight neonates. AB - INTRODUCTION: Pharmacokinetic of vancomycin in very low birth weight neonates showed big variety, and limited data were available due to very minor population. These facts make it difficult to adjust its optimal initial dosage. Therefore, this study was to develop optimal dosing regimen of vancomycin in very low birth weight neonates. METHODS: Between 2010 and 2015, low birth weight neonates (<=1500 g) were included in a population pharmacokinetics analysis. Based on the pharmacokinetic parameters we estimated, we simulated individual blood concentrations of vancomycin and evaluated the probability of its pharmacokinetics/pharmacodynamics (PK/PD) target attainment, such as 24-h area under the concentration-time curve (AUC24)/MIC (>=400) and blood trough concentration (10-20 MUg/mL), as primary measure for several dosing regimens by Monte Carlo simulation method. RESULTS: Ten patients were prescribed vancomycin and detected its blood concentrations as routine pharmacy practice to adjust the dosage. A one-compartment model was used and clearance significantly correlated with serum creatinine and the volume of infusion. In this model, vancomycin dose at 10 mg/kg three times a day (TID) was predicted to result 86.7% of neonates for an MIC of 1 MUg/mL achieving AUC/MIC of >=400 and 30.6% of the neonates for an MIC of 2 MUg/mL. Moreover, the probability of reaching the target trough concentration was 70.5% for patients treated with vancomycin 10 mg/kg TID. DISCUSSION: We recommended vancomycin 10 mg/kg TID as initial dosage regimens for low birth weight neonates infected with the pathogens showed MIC of <=1 MUg/mL. PMID- 28017668 TI - Exposure to a maternal cafeteria diet changes open-field behaviour in the developing offspring. AB - The early postnatal period is a sensitive period in rodents as behavioural systems are developing and maturing during this time. However, little is currently known about the behavioural effects of feeding a hyper-energetic cafeteria diet (CD) during the lactational period when offspring behaviour is tested during early adolescence. To this end, 23days old offspring from dams (Wistar) fed on CD during lactation were tested in either the open-field or the elevated plus-maze for exploration and anxiety-related behaviour. On postnatal day 9, maternal behaviour and non-maternal behaviour of the dam was assessed. It was hypothesized that lactational CD feeding would reduce anxiety in the offspring. CD-fed dams had a higher energy intake, due to an overconsumption of sugars and fats. When offspring from these dams were exposed to the open field after weaning, their locomotor activity was increased. They entered the more aversive inner zone of the open-field after a shorter latency, made more entries into and spent more time in the inner zone. Anxiety-related behaviour was not affected upon exposure to the elevated plus maze, suggesting anxiolysis in the open-field only. Increased maternal licking/grooming behaviour could possibly contribute to the anxiolytic phenotype as observed in the offspring from the CD group. In conclusion, we demonstrate that lactational overfeeding impacts on the development of behaviour in the early adolescent rat. PMID- 28017669 TI - Depression can be prevented by astaxanthin through inhibition of hippocampal inflammation in diabetic mice. AB - The critical factor considered in a depression induced by diabetes is the inflammation eliciting hippocampal, amygdala and thalamic neuronal injury. Therefore, inhibiting inflammatory reactions in the brain and reducing neuronal injury can alleviate depression in rodents suffering from diabetes mellitus. The oral administration of astaxanthin has been employed in emotional disorders and diabetic complications due to its anti-depressant, anti-inflammatory and anti apoptotic functions. However, it has not been reported whether astaxanthin can improve diabetes-related depression-like behavior, and its potential mechanisms have not been elucidated. The objective of the present study is to elucidate the effect of astaxanthin on depression in diabetic mice and to understand the underlying molecular mechanisms. In this study, experimental diabetic mice were given a single intraperitoneal injection of streptozotocin (STZ, 150mg/kg, dissolved in citrate buffer) after fasting for 12h. The diabetic model was assessed 72h after STZ injection, and mice with a fasting blood glucose level more than or equal to 16.7mmol/L were used in this study, and oral astaxanthin (25mg/kg) was provided uninterrupted for ten weeks. Depression-like behavior was evaluated by the tail suspension test (TST) and forced swimming test (FST). The glial fibrillary acidic protein (GFAP) and cleaved caspase-3-positive cells were measured by immunohistochemistry, and the western blotting was used to test the protein levels of interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and cyclooxygenase (COX-2). The results showed that astaxanthin had an anti depressant effect on diabetic mice. Furthermore, we observed that astaxanthin significantly reduced the number of GFAP-positive cells in the hippocampus and hypothalamus, and also the expression of cleaved caspase-3 in the hippocampus, amygdala and hypothalamus was decreased as well. Moreover, astaxanthin could down regulate the expression of IL-6, IL-1beta and COX-2 in the hippocampus. These findings suggest that the mechanism of astaxanthin in preventing depression in diabetic mice involves the inhibition of inflammation/inflammation inhibition, thereby protecting neurons in hippocampus, amygdala and hypothalamus against hyperglycemic damage. PMID- 28017670 TI - Presynaptic facilitation by tetracaine of glutamatergic spontaneous excitatory transmission in the rat spinal substantia gelatinosa - Involvement of TRPA1 channels. AB - The amide-type local anesthetic (LA) lidocaine activates transient receptor potential (TRP) ankyrin-1 (TRPA1) channels to facilitate spontaneous l-glutamate release onto spinal substantia gelatinosa (SG) neurons, which play a crucial role in regulating nociceptive transmission. In contrast, the ester-type LA procaine reduces the spontaneous release of l-glutamate in SG neurons. In order to determine whether TRPA1 activation by LAs is specific to amide-types, we examined the actions of tetracaine, another ester-type LA, and other amide-type LAs on glutamatergic spontaneous excitatory transmission in SG neurons by focusing on TRP activation. Whole-cell patch-clamp recordings were performed on SG neurons of adult rat spinal cord slices at a holding potential of -70mV. Bath-applied tetracaine increased spontaneous excitatory postsynaptic current (sEPSC) frequency in a concentration-dependent manner. Tetracaine activity was resistant to the voltage-gated Na+-channel blocker tetrodotoxin, the TRP vanilloid-1 antagonist capsazepine, and the TRP melastatin-8 antagonist BCTC, but was inhibited by the non-selective TRP antagonist ruthenium red and the TRPA1 antagonist HC-030031. With respect to amide-type LAs, prilocaine had a tendency to increase sEPSC frequency, while ropivacaine and levobupivacaine reduced the frequency. In conclusion, tetracaine facilitated spontaneous l-glutamate release from nerve terminals by activating TRPA1 channels in the SG, resulting in an increase in the excitability of SG neurons. TRPA1 activation was not specific to amide-type or ester-type LAs. The facilitatory action of LAs may be involved in pain occurring after recovery from spinal anesthesia. PMID- 28017671 TI - Analysis of the prevalence of drug-resistant hepatitis B virus in patients with antiviral therapy failure in a Chinese tertiary referral liver centre (2010 2014). AB - OBJECTIVES: To study the prevalence of drug-resistant HBV in patients with therapy failure in a Chinese tertiary referral liver centre. METHODS: 1223 HBV infected patients who underwent genotypic resistance testing between 2010-2014 were studied. RESULTS: 3TC genotypic resistance was the most common (46.5%), followed by LdT resistant (46.2%), ETV intermediate (37.9%), ADV resistant (11.4%), TDF intermediate (11.4%) and ETV resistant (1.7%). The 3TC resistance rate increased from 39.8% in 2010 to 56.6% in 2013, before decreasing to 49.5% in 2014, evidence of a lagging effect of l-nucleoside consumption. M204I, N236T and L180M+M204V+V173L/S202G were the most common substitutions for l-nucleoside (3TC and LdT), ADV and ETV genotypic resistant phenotypes, respectively. 3TC-exposed patients showed a high multiple genetic resistance rate (3TC-resistant+LdT resistant+ETV intermediate; 58.8%). Resistance rates to 3TC, LdT and ETV in HCC patients were significantly higher than in cirrhosis and CHB patients. Resistance rates to different drugs showed no statistical difference between genotype B and C patients, whilst some amino acid substitution showed genotype bias, e.g. N236T incidence in genotype B was significantly higher than in genotype C (43.2% vs. 5.9%; P<0.0001), and genotype C isolates had a significantly higher A181V/T incidence than genotype B (54.9% vs. 19.3%; P<0.0001). CONCLUSIONS: 3TC genotypic resistance was most common in this centre, whilst ETV had the lowest resistance rate. HBV genotypes had no impact on antiviral drug resistance, except for some drug resistance substitutions bias. Optional initial therapy and subsequent rescue treatment should be based on knowledge of nucleos(t)ide analogue resistance. PMID- 28017672 TI - Draft genome sequence of a multidrug-resistant CMY-2-producing Salmonella enterica subsp. enterica serovar Minnesota ST3088 isolated from chicken meat. PMID- 28017673 TI - Outcome After Surgery for Acute Aortic Dissection: Influence of Preoperative Antiplatelet Therapy on Prognosis. AB - OBJECTIVES: Outcome in patients with acute coronary syndrome (ACS) is improved with dual antiplatelet therapy (DAPT). Patients with acute aortic dissection type A (AAD) often present with similar symptoms and may therefore be prescribed DAPT before diagnosis. The aim of this study was to evaluate the use of antiplatelet therapy (APT) prior to AAD surgery and patient outcome, including indications according to the European Society of Cardiology's (ESC) recent guidelines. DESIGN: A retrospective, observational study. SETTING: A tertiary University Hospital, Rigshospitalet, Heart Centre, Copenhagen, Denmark. PARTICIPANTS: The study included 171 patients operated for AAD during 2010 to 2014. INTERVENTIONS: The independent relationship of preoperative APT was explored on 30-day mortality, intraoperative bleeding and perioperative transfusion requirements. Furthermore, the indications for APT were obtained. MEASUREMENTS AND MAIN RESULTS: Patients receiving APT (n = 73) did not have an increased 30-day mortality (29% v 20%, p = 0.18). However, APT increased intraoperative bleeding by 45% (p<0.001) and increased perioperative transfusion of red blood cells by 71%, fresh frozen plasma by 52%, and platelets by 56% (p = 0.002). Among patients receiving APT preoperatively, 26 patients received acetylsalicylic acid (ASA) alone and 46 patients received DAPT. Bleeding was significantly more pronounced in patients receiving DAPT (5.6+/-4.1 L), compared to ASA alone (3.6+/-3.1 L) and no APT (3.3+/-4.8 L) (p<0.001). However, there was no significant difference in mortality between groups. DAPT, including ticagrelor, increased intraoperative bleeding by 62% compared to DAPT with clopidogrel (p = 0.004). Among patients receiving DAPT, only 30% of the patients fulfilled ESC criteria for ACS treatment. CONCLUSIONS: The use of APT was associated with increased intraoperative bleeding and transfusion requirement; however, it was not associated with a statistically significant increased mortality. Only a minority of patients fulfilled ESC criteria for ACS treatment with DAPT. PMID- 28017674 TI - Near-Death Episode in a Young Adult. PMID- 28017675 TI - Retained Metallic Foreign Body After Heart Transplantation or Another Explanation? PMID- 28017676 TI - Complex Considerations and Anesthetic Management in Patient With Multiple Intracardiac Myxomas. PMID- 28017677 TI - Preoperative Renal Resistive Index Predicts Risk of Acute Kidney Injury in Patients Undergoing Cardiac Surgery. AB - OBJECTIVE: To investigate whether an elevated preoperative renal resistive index (RRI) predicts acute kidney injury (AKI) in patients undergoing cardiac surgery. DESIGN: Prospective cohort study. SETTING: University hospital. PARTICIPANTS: Cohort of 96 adult cardiac surgical patients. INTERVENTIONS: Resistive index was measurement the day before surgery. MEASUREMENTS AND MAIN RESULTS: Renal Doppler was used to measure the resistive index in renal cortical or arcuate arteries the day before surgery. An elevated RRI was defined as>=0.7. AKI was defined as an absolute increase in postoperative compared with preoperative serum creatinine levels by>=26 umol/L or a relative increase by>=50% or a postoperative urine output<0.5 mL/kg for 6 hours or longer. The relative risk of AKI in patients with an elevated RRI compared with those without an elevated RRI was analyzed using logistic regression. Among patients with an RRI<0.7, 6 (16%) developed AKI compared with 21 (36%) with an RRI>=0.7. The mean increases in postoperative serum creatinine levels were 12 MUmol/L in those with an RRI<0.7 and 30 MUmol/L in those with an RRI>=0.7. The crude odds ratio for AKI in patients with an RRI>=0.7 was 3.03 (1.09-8.42) compared with those with an RRI<0.7. After multivariable adjustment, the odds ratio was 2.95 (0.97-9.00). CONCLUSIONS: Patients with an elevated preoperative RRI have an increased risk of developing AKI after cardiac surgery. In combination with other markers, the RRI might be a tool for identifying patients with an increased risk of developing AKI. PMID- 28017678 TI - Deep Anterior Lamellar Keratoplasty After Descemet Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: To report the indications and long-term outcomes of deep anterior lamellar keratoplasty (DALK) performed after Descemet stripping automated endothelial keratoplasty (DSAEK) in cases of visually significant stromal opacities. DESIGN: Retrospective, interventional, consecutive case series. METHODS: Setting: Private hospital. STUDY POPULATION: Thirteen eyes that underwent DALK after DSAEK at our institution. Indications for DALK after DSAEK included both stromal opacities persisting after DSAEK and stromal opacities occurring secondarily in post-DSAEK corneas. DALK was always performed in a standardized fashion including exchange of a disc of full-thickness recipient cornea (up to the DSAEK stromal surface),7.0 mm in diameter, with a donor lamella obtained by microkeratome-assisted dissection, punched to 7.0 mm and sutured into place with a double running 10-0 nylon suture. MAIN OUTCOME MEASURES: Best spectacle-corrected visual acuity (BSCVA), manifest refraction, and endothelial cell density (ECD). RESULTS: Mean follow-up was 26 +/- 18 months (range = 6-60 months). Indications for DSAEK were full-thickness graft failure (n = 8), DSAEK graft failure (n = 3), and pseudophakic bullous keratopathy (n = 2). Indications for subsequent DALK were persisting stromal opacity (n = 9) and stromal opacities newly occurred after DSAEK as a result of HSV keratitis (n = 2) or interface infection (n = 2). After complete suture removal, mean BSCVA was 20/28 (0.14 +/- 0.8 logMAR) in eyes without ocular comorbidities affecting visual acuity (n = 7), while refractive astigmatism was within 4 diopter (D) in all but 1 eye (average = 3.2 +/- 1.4 D). No intraoperative complications were recorded. CONCLUSIONS: Performing DALK on DSAEK eliminates the need for open-sky surgery, achieving visual results comparable to those of penetrating keratoplasty, while sparing a healthy endothelial graft. PMID- 28017679 TI - Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats. AB - Although Metformin, a first-line antidiabetic drug, can ameliorate ischemia/reperfusion (I/R) induced brain damage, but how metformin benefits injured hippocampus and the mechanisms are still largely unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of metformin against ischemic brain damage induced by cerebral I/R and to explore whether the Akt-mediated down-regulation of the phosphorylation of JNK3 signaling pathway contributed to the protection provided by metformin. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The open field tasks and Morris water maze were used to assess the effect of metformin on anxiety-like behavioral and cognitive impairment after I/R. Cresyl Violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of Akt1, JNK3, c-Jun and the expression of cleaved caspase-3. Through ischemia/reperfusion (I/R) rat model, we found that metformin could attenuate the deficits of hippocampal related behaviors and inhibit cell apoptosis. The western blot data showed that metformin could promote the activation of Akt1 and reduce the phosphorylation of JNK3 and c-Jun as well as elevation of cleaved caspase-3 in I/R brains. PI3K inhibitor reversed all the protective effects, further indicating that metformin protect hippocampus from ischemic damage through PI3K/Akt1/JNK3/c-Jun signaling pathway. PMID- 28017680 TI - Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. AB - The endocannabinoid system serves many physiological roles, including in the regulation of energy balance, food reward, and voluntary locomotion. Signaling at the cannabinoid type 1 receptor has been specifically implicated in motivation for rodent voluntary exercise on wheels. We studied four replicate lines of high runner (HR) mice that have been selectively bred for 81 generations based on average number of wheel revolutions on days five and six of a six-day period of wheel access. Four additional replicate lines are bred without regard to wheel running, and serve as controls (C) for random genetic effects that may cause divergence among lines. On average, mice from HR lines voluntarily run on wheels three times more than C mice on a daily basis. We tested the general hypothesis that circulating levels of endocannabinoids (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA]) differ between HR and C mice in a sex-specific manner. Fifty male and 50 female mice were allowed access to wheels for six days, while another 50 males and 50 females were kept without access to wheels (half HR, half C for all groups). Blood was collected by cardiac puncture during the time of peak running on the sixth night of wheel access or no wheel access, and later analyzed for 2-AG and AEA content by ultra-performance liquid chromatography coupled to tandem mass spectrometry. We observed a significant three-way interaction among sex, linetype, and wheel access for 2-AG concentrations, with females generally having lower levels than males and wheel access lowering 2-AG levels in some but not all subgroups. The number of wheel revolutions in the minutes or hours immediately prior to sampling did not quantitatively predict plasma 2-AG levels within groups. We also observed a trend for a linetype-by wheel access interaction for AEA levels, with wheel access lowering plasma concentrations of AEA in HR mice, while raising them in C mice. In addition, females tended to have higher AEA concentrations than males. For mice housed with wheels, the amount of running during the 30min before sampling was a significant positive predictor of plasma AEA within groups, and HR mice had significantly lower levels of AEA than C mice. Our results suggest that voluntary exercise alters circulating levels of endocannabinoids, and further demonstrate that selective breeding for voluntary exercise is associated with evolutionary changes in the endocannabinoid system. PMID- 28017681 TI - Exposure to short photoperiod regime reduces ventral subicular lesion-induced anxiety-like behavior in Wistar rats. AB - Neurodegeneration of hippocampal structures is implicated in Alzheimer's disease (AD). Patients with AD exhibit 'sundown syndrome' featuring mood swings and anxiety. Although there are studies demonstrating circadian rhythm disruption associated with sundown phenomenon, the mechanisms underlying the emotional disturbances remain elusive. In the present study, we examined the relationship between subiculum (a key hippocampal output structure) and anxiety. Our study demonstrates that bilateral ventral subicular lesion (VSL) leads to anxiogenic behavior. In the elevated plus maze test, VSL rats made less number of entries into the open arms and spent significantly more time in the closed arms. Similarly, in the light-dark exploration test, VSL rats spent significantly more time in the dark chamber and made fewer entries into the light chamber. VSL also produced significant neurodegeneration in the paraventricular, suprachiasmatic and dorsomedial nuclei of the hypothalamus. Exposing VSL rats to a short photoperiod regime (SPR; 06/18h light-dark cycle) for 21days ameliorated the anxiety-like behavior. VSL rats on SPR also exhibited increased food consumption and higher core body temperature. Our study supports the hypothesis that the ventral subiculum regulates anxiety-like behavior and that SPR helps in the alleviation of such behavior. Even though the mechanisms underlying anxiolytic effects of light-dark cycle manipulation are yet to be elucidated, such non pharmacological strategies can help to mitigate anxiety-like behavior. A proper understanding of the effectiveness of photoperiod manipulation will help in developing strategies in the management of emotional disturbances associated with affective and neurodegenerative disorders including AD. PMID- 28017682 TI - Cross-talking between lymphocytes and platelets and its regulation by nitric oxide and peroxynitrite in physiological condition and endotoxemia. AB - AIMS: Cross-talk between platelets and lymphocytes may play a role in different pathological conditions like sepsis. This study aimed to investigate the effect of lymphocytes on platelet aggregation in lipopolysaccharide (LPS)-stimulated and non-stimulated cells. MAIN METHODS: Lymphocytes and platelet-rich plasma (PRP) were obtained from rat arterial blood. Platelets (1.2*108platelets/ml) were incubated with lymphocytes (0.8*106cells/ml) in the presence or not of LPS (100MUg/ml), after which ADP (5MUM)-induced platelet aggregation was carried out. KEY FINDINGS: Lymphocytes inhibited by 51% the platelet aggregation, which was significantly prevented by the non-selective NO inhibitor l-NAME (300MUM) or the selective iNOS inhibitor 1400W (100MUM), as well as by the soluble guanylyl cyclase (sGC) inhibitor ODQ (10MUM). The platelet inhibition by lymphocytes was accompanied by 2-fold increase of intraplatelet cGMP levels. Next, lymphocytes and platelets were co-incubated with LPS for 6h. In LPS-treated cells, lymphocytes produced a larger inhibition of platelet aggregation (62%), despite the same elevation of cGMP levels (2.2-fold increase). This inhibitory effect was prevented by l-NAME and 1400W, but rather unaffected by ODQ. The peroxynitrite (ONOO-) scavenger -(-)epigallocatechin gallate (ECG, 100MUM) abolished the inhibition by lymphocytes on platelet aggregation in LPS-treated cells, but not in non-treated cells. SIGNIFICANCE: Our results show that lymphocytes act to inhibit platelet aggregation via iNOS-derived NO release and cGMP generation. In presence of LPS, ONOO- production accounts for the platelet inhibition. PMID- 28017683 TI - Iron oxide nanoparticle surface decorated with cRGD peptides for magnetic resonance imaging of brain tumors. AB - In this article, a specific targeting Magnetic Resonance Imaging (MRI) nanoplatform, composed by iron oxide nanoparticle (NP) with cRGD peptides as targeting agent onto NP surface, is explored for the diagnosis of brain tumors by MRI using intracranial U87MG mice xenograft tumor. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editor: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader. PMID- 28017684 TI - Increased levels of cell-free mitochondrial DNA in the cerebrospinal fluid of patients with multiple sclerosis. AB - Mitochondrial DNA (mtDNA) can act as damage-associated molecular pattern molecule (DAMP) and initiate an inflammatory response. We hypothesized that the concentration of mtDNA might reflect inflammatory activity in multiple sclerosis and investigated therefore levels of cell-free mitochondrial DNA in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. Significantly higher levels of mtDNA were found in patients compared to controls and there was an inverse correlation between disease duration and mtDNA concentration. Our study suggests that mitochondria can be involved early in multiple sclerosis, but whether this is as an initiator of the inflammatory response or part of its maintenance is unclear. Further, our study suggests that changes in mtDNA may provide a novel marker for early disease activity. PMID- 28017685 TI - Physical exercise before pregnancy helps the development of mouse embryos produced in vitro. AB - Effects of pre-gestational physical activity on the later development of embryos generated in vitro were evaluated. Kunming mice were divided into two groups, namely exercised and unexercised, with the former undergoing physical training on a motor-driven leveled treadmill over a period of 4weeks (5days/week and 60min/day). After that, following superovulation, collection of oocytes from both groups was performed for in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). Notably and specifically, natural mating between the unexercised mice was also done for in vivo fertilization (IVIF). Observation on the preimplantation embryo development showed that SCNT embryos from exercised group (NEM) had significant higher rates of cleavage and formation of blastocyst containing more blastomeres compared to SCNT embryos from unexercised group (NCM); while IVF embryos in exercised group (FEM) showed a significant higher rate of cleavage and blastocyst formation. Further analysis of embryos from the trained group on the molecular level demonstrated a prominent increase in terms of ATP levels, mitochondria membrane potential (Deltapsim) and mtDNA copy number and an obvious decrease in H2O2 concentration than those from the respective control group. Meanwhile, epigenetically, methylation levels of CpG sites on imprinting control regions of imprinted genes (Igf2, Igf2r, Meg 3 and H19) in the NEM embryos were normalized in exercise groups compared to the NCM embryos, which were comparable to the in vivo-derived embryos. Moreover, global DNA and histone methylation (H3K4m2, H3K9m3 and H3K36m) further confirmed that NEM-derived embryos and in vivo-derived ones stay in the same cluster, indicating that physical activity in pre-pregnancy facilitates the maintenance of epigenetic modifications. Generally, these results strongly suggest that physical exercise before pregnancy is in favor of the later embryo development. PMID- 28017686 TI - Enrollment of older adults on oncology trials: An FDA perspective. PMID- 28017687 TI - Further psychometric validation of the GAH scale: Responsiveness and effect size. AB - OBJECTIVES: The purpose of this study was to assess the responsiveness of the newly developed Geriatric Assessment in Hematology (GAH) scale to clinical change in older patients diagnosed with hematologic malignancies. METHODS: A prospective observational study conducted in 164 patients aged >=65years and diagnosed with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphocytic leukemia (CLL). Responsiveness of the GAH scales was studied by means of the Eastern Cooperative Oncology Group (ECOG) score, the Karnofsky performance status (KPS) score, the visual analog scale (VAS), and the physician's subjective assessment, used as clinical anchors to identify whether patients had changed clinically (either improved or worsened) or not since the baseline visit. Responsiveness was evaluated on the basis of effect size (ES). RESULTS: 164 patients (men, 63.7%; median age, 77.0 (72.8-81.4) participated. Statistically significant correlations were obtained between the investigator's qualitative assessment and changes in ECOG, KPS, and VAS scores. Likewise, a statistically significant correlation was obtained between the investigator's qualitative assessment and changes in the GAH scale score. Responsiveness of the GAH scale to detect clinical change was satisfactory (ES 0.34). CONCLUSION: Findings confirm that the GAH scale is responsive to clinical changes in patients' health status. Additionally, the GAH scale is a promising tool to improve clinical decision-making in older patients with hematological malignancies. PMID- 28017688 TI - Effect of position on the residual heart rate variability in patients after orthotopic heart transplantation. AB - BACKGROUND: This study investigated the effects of position on heart rate variability (HRV) in patients some years after orthotopic heart transplantation (OHT) surgery. METHODS: Spectral HRV analysis was performed on 15 patients after OHT and 16 patients with coronary artery disease (CAD). HRV measures were compared between OHT and CAD patients in four randomly ordered positions [supine, right lateral decubitus (RLD), left lateral decubitus (LLD), and upright]. Multivariable linear regression analysis was used to identify the factors associated with cardiac function and HRV of OHT patients in supine position, and the factors associated with the outcome (OHT or CAD) of the patients. RESULTS: The powers in all frequency ranges were significantly decreased in all four positions in OHT patients about 9 years after OHT surgery, as compared with those of CAD patients. Both RLD and LLD positions can lead to a significantly higher normalized high-frequency power in OHT patients than the supine position, as compared with the CAD patients. The LLD position seemed to be better than the other recumbent positions in terms of vagal enhancement in the OHT patients. Multivariable linear regression analysis showed that the left ventricular ejection fraction of OHT patients can be predicted from a linear combination of the OHT to HRV interval, and normalized very low-frequency power in the supine position. Furthermore, better cardiac function and the presence of cardiomyopathy would increase the necessity of OHT surgery, while the use of nitrates would decrease the necessity of OHT surgery. CONCLUSION: Both the RLD and LLD positions, especially the LLD position, can lead to a higher vagal modulation in OHT patients about 9 years after OHT surgery, provided that the HRV measures can still be regarded as indicators of autonomic nervous modulation in such patients. Moreover, left ventricular ejection fraction, cardiomyopathy, and the use of nitrates were all associated with the necessity of OHT surgery. PMID- 28017689 TI - Is hysterosalpingography a good tool to confirm the patency of tubes? PMID- 28017690 TI - Deciphering flux adjustments of engineered E. coli cells during fermentation with changing growth conditions. AB - Microbial fermentation conditions are dynamic, due to transcriptional induction, nutrient consumption, or changes to incubation conditions. In this study, 13C metabolic flux analysis was used to characterize two violacein-producing E. coli strains with vastly different productivities, and to profile their metabolic adjustments resulting from external perturbations during fermentation. The two strains were first grown at 37 degrees C in stage 1, and then the temperature was transitioned to 20 degrees C in stage 2 for the optimal expression of the violacein synthesis pathway. After induction, violacein production was minimal in stage 3, but accelerated in stage 4 (early production phase) and 5 (late production phase) in the high producing strain, reaching a final concentration of 1.5mmol/L. On the contrary, ~0.02mmol/L of violacein was obtained from the low producing strain. To have a snapshot of the temporal metabolic changes in each stage, we performed 13C-MFA via isotopomer analysis of fast-turnover free metabolites. The results indicate strikingly stable flux ratios in the central metabolism throughout the early growth stages. In the late stages, however, the high producer rewired its flux distribution significantly, which featured an upregulated pentose phosphate pathway and TCA cycle, reflux from acetate utilization, negligible anabolic fluxes, and elevated maintenance loss, to compensate for nutrient depletion and drainage of some building blocks due to violacein overproduction. The low producer with stronger promoters shifted its relative fluxes in stage 5 by enhancing the flux through the TCA cycle and acetate overflow, while exhibiting a reduced biomass growth and a minimal flux towards violacein synthesis. Interestingly, the addition of the violacein precursor (tryptophan) in the medium inhibited high producer but enhanced low producer's productivity, leading to hypotheses of unknown pathway regulations (such as metabolite channeling). PMID- 28017691 TI - Cultural background, non-therapeutic circumcision and the risk of meatal stenosis and other urethral stricture disease: Two nationwide register-based cohort studies in Denmark 1977-2013. AB - BACKGROUND: Meatal stenosis is markedly more common in circumcised than genitally intact males, affecting 5-20 per cent of circumcised boys. However, no population based study has estimated the relative risk of meatal stenosis and other urethral stricture diseases (USDs) or the population attributable fraction (AFp) associated with non-therapeutic circumcision. METHODS: In two nationwide cohort studies (comprising 4.0 million males of all ages and 810 719 non-Muslim males aged 0-36 years, respectively), we compared hospital contact rates for USD during 1977-2013 between circumcised and intact Danish males. Hazard ratios (HRs) were obtained using Cox proportional hazards regression, and the AFp estimated the proportion of USD cases in <10 year-old boys that is due to non-therapeutic circumcision. RESULTS: Muslim males had higher rates of meatal stenosis than ethnic Danish males, particularly in <10 year-old boys (HR 3.44, 95 per cent confidence interval 2.42-4.88). HRs linking circumcision to meatal stenosis (10.3, 4.53-23.4) or other USDs (5.14, 3.48-7.60) were high, and attempts to reduce potential misclassification and confounding further strengthened the association, particularly in <10 year-old boys (meatal stenosis: 26.3, 9.37-73.9; other USDs: 14.0, 6.86-28.6). Conservative calculations revealed that at least 18, 41, 78, and 81 per cent of USD cases in <10 year-old boys from countries with circumcision prevalences as in Denmark, the United Kingdom, the United States and Israel, respectively, may be attributable to non-therapeutic circumcision. CONCLUSION: Our study provides population-based epidemiological evidence that circumcision removes the natural protection against meatal stenosis and, possibly, other USDs as well. PMID- 28017692 TI - Efficient targeted mutagenesis in Epichloe festucae using a split marker system. AB - A split-marker system for targeted gene deletion was developed for the model grass endophytic fungus Epichloe festucae. Compared to the conventional system that yields up to 25% homologous recombinants, the method resulted in 33-74% targeted deletions in E. festucae using as little as 1.5kb of targeting sequence. PMID- 28017693 TI - Microcystins activate nuclear factor erythroid 2-related factor 2 (Nrf2) in human liver cells in vitro - Implications for an oxidative stress induction by microcystins. AB - Microcystins, a potential threat to drinking water quality, are hepatotoxic but it has remained unclear if microcystins induce oxidative stress. We investigated if four microcystins could activate the Nrf2 pathway, a regulator of oxidative stress response. Nrf2 activity was significantly increased by microcystin-LR and RR at 10 MUM, by microcystin-LY at 3 MUM, by [D-Asp3]-LR and by microcystin-LR at 1 MUM. Our results lend support to the suggestion that microcystins may induce oxidative stress response. PMID- 28017694 TI - Pitfalls to avoid when using phage display for snake toxins. AB - Antivenoms against bites and stings from snakes, spiders, and scorpions are associated with immunological side effects and high cost of production, since these therapies are still derived from the serum of hyper-immunized production animals. Biotechnological innovations within envenoming therapies are thus warranted, and phage display technology may be a promising avenue for bringing antivenoms into the modern era of biologics. Although phage display technology represents a robust and high-throughput approach for the discovery of antibody based antitoxins, several pitfalls may present themselves when animal toxins are used as targets for phage display selection. Here, we report selected critical challenges from our own phage display experiments associated with biotinylation of antigens, clone picking, and the presence of amber codons within antibody fragment structures in some phage display libraries. These challenges may be detrimental to the outcome of phage display experiments, and we aim to help other researchers avoiding these pitfalls by presenting their solutions. PMID- 28017695 TI - miR-29c is implicated in the cardioprotective activity of Panax notoginseng saponins against isoproterenol-induced myocardial fibrogenesis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burkill) F.H. Chen (Araliaceae) has a long history of clinical application in China for the treatment of cardiovascular diseases. Panax notoginseng saponins (PNS) have been proven to be the major cardioprotective substances of Panax notoginseng (Burkill) F.H. Chen (Araliaceae). AIM OF THE STUDY: The current study further investigated the molecular mechanisms associated with the cardioprotective effect of PNS. MATERIALS AND METHODS: C57BL/6J mice were subject to isoproterenol (ISO)-induced myocardial injury in the absence or presence of PNS treatment. Histological, immunohistochemical and molecular biological approaches were taken to assess the effects of PNS treatment on ISO-induced myocardial injury and ensuing fibrogenesis. RESULTS: PNS treatment significantly attenuated ISO-induced myocardial injury and fibrosis. The expression of an anti-fibrotic microRNA, miR 29c, was significantly decreased in ISO-challenged mouse hearts. In contrast, PNS treatment resulted in increased cardiac expression of miR-29c. The expression of miR-29c target genes including Collagen (Col) 1a1, Col1a2, Col3a1 and Col5a1, fibrillin 1 (Fbn1) as well as TGFbeta1 was significantly increased by ISO, which exhibited decreased expression by PNS intervention. CONCLUSIONS: Our results demonstrate for the first time that the cardioprotective effects of PNS could in part implicate increased expression of miR-29c in the heart, which may help increase the understanding of the pharmacological activities of PNS in treating cardiovascular disorders. PMID- 28017696 TI - Ethnobiological treatments of neurological conditions in the Chota Nagpur Plateau, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: World Health Organization (WHO) has recognized the contribution of traditional medicine in the primary health care system. WHO also considers neurological disorders as one of the prime concern to the public health. Inadequate and inaccessible health facilities in the rural and underprivileged areas have forced the various tribal and non-tribal communities to use ethno-phyto and ethno-zoo therapeutics against different ailments. Chota Nagpur Plateau, India is one of the richest in India in terms of plant and animal diversity, and houses a number of indigenous communities often practising their own ethnobiological medicines. These undocumented indigenous treasure must be preserved and could be utilized in discovering lead compounds against human ailments including neuroprotective and psychoactive disorders. MATERIALS AND METHODS: A number of ethnobiological surveys were carried out during 2012-2015 in the three districts of the Bengal part of Manbhum region, Chota Nagpur Plateau via conducting open and semi-structured interviews among the traditional medicine men (65:59 males and 6 females aged between 22 and 85 years). This dataset was statistically analysed by calculating seven quantitative indexes such as use value (UV), informants' consensus factor (ICF), fidelity level (FL), relative importance (RI), cultural importance index (CII), index of agreement on remedies (IAR) and cultural agreement index (CAI). RESULTS: Sixty five traditional medicine men (TMM) reported 47 traditional formulations involving 58 plant species and 17 animal species used against 13 neurological and psychological disorders and as pro-cognitives. Fabaceae was represented by the highest number of medicinal plant species (9 species) whereas herbs (48%) and roots (28%) represented the most common plant habit and plant part, respectively. Quantitative ethnobiology revealed the frequency and coherence of ethnomedicinal reports. The plant Piper nigrum (1.35) and the animal, Spilostethus hospes (0.50) showed the highest UV. Among the ethnobotanicals, maximum RI value was noted for Hemidesmus indicus (0.91) and IAR was found to be maximum (1.00) for 8 plant species. Among the ethnozoologicals, Spilostethus hospes (0.67) displayed maximum RI value whereas Axis axis (2.32) displayed maximum CAI value. CONCLUSION: TMM possessed knowledge on preparations, dose dependence, administration, safety, possible toxicity and side effects of using traditional formulations. TMM practising age old traditional therapeutics serve as alternative medical option for the underprivileged rural ethnic people in these remote areas of the country. PMID- 28017697 TI - Anti-inflammatory and antioxidant effect of modified Bazhengsan in a rat model of chronic bacterial prostatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bazhengsan is a commonly used traditional Chinese prescription for the treatment of the urogenital system diseases for thousands of years, which decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in Song Dynasty. AIM OF THE STUDY: In this study, the potential of modified Bazhengsan (mBazhengsan) as a chronic bacterial prostate inflammation inhibitor was investigated in a rat model. MATERIALS AND METHODS: Rat prostates were injected with Escherichia coli to induce inflammation by the sterile operation. The decoction of mBazhengsan was administered intragastrically once every day from the seventh day of modeling. After 8 weeks, prostates were lavaged with phosphate buffer saline (PBS) and lavages were collected to use for leukocyte and lecithin body count, and then prostate tissues were removed to detect prostate weight, prostate index and microbiological analyses. Prostate histopathological changes were detected by hematoxylin-eosin (HE) staining and masson staining. Bacterial growth in prostate was evaluated by the numbers of tissue culture colonies. The levels of interleukin (IL)-8, IL 1beta and tumor necrosis factor (TNF)-a in serums and secretory immunoglobulin (SIg)-A in prostate fluids as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in prostate tissues were detected by analysis kits. RESULTS: Compared with model group, treatment with mBazhengsan could significantly inhibit the recruitment of leukocyte to prostate tissues and the deposition of collagen fibers in stromas, suppressed bacterial growth in prostate tissues, decreased the numbers of leukocyte and lecithin body in prostate fluids, lowered prostate index, down-regulated the levels of inflammatory mediators (IL-1beta, IL-8 and TNF-a) in serums and up-regulated the levels of SIgA in prostate fluids, and reduced the production of free radical in prostate tissues. CONCLUSION: mBazhengsan can significantly suppress rat prostate inflammation and oxidative stress reaction, showing great therapeutic potential to the chronic bacterial prostatitis. PMID- 28017698 TI - Metabonomics of ageing - Towards understanding metabolism of a long and healthy life. AB - Systems biology approaches have been increasingly employed in clinical studies to enhance our understanding of the role of genetics, environmental factors and their interactions on nutritional, health and disease status. Amongst the new omics technologies, metabonomics has emerged as a robust platform to capture metabolic and nutritional requirements by enabling, in a minimally invasive fashion, the monitoring of a wide range of biochemical compounds. Their variations reflect comprehensively the various molecular regulatory processes, which are tightly controlled and under the influence of genetics, diet, gut microbiota and other environmental factors. They are providing key insights into complex metabolic phenomena as well as into differences and specificities at individual and population level. The aim of this review is to evaluate promising metabolic insights towards understanding metabolism of a long and healthy life from pre-clinical and clinical metabonomics studies. We will also discuss analytical approaches to enable data integration, with an emphasis on the longitudinal component. Herein, we will illustrate current examples, challenges and perspectives in the applications of metabonomics monitoring and modelling approaches in the context of healthy ageing research. PMID- 28017699 TI - Aging rather than stress strongly influences amino acid metabolisms in the brain and genital organs of female mice. AB - Aging and stress affect quality of life, and proper nourishment is one of means of preventing this effect. Today, there is a focus on the amount of protein consumed by elderly people; however, changes in the amino acid metabolism of individuals have not been fully considered. In addition, the difference between average life span and healthy life years is larger in females than it is in males. To prolong the healthy life years of females, in the present study we evaluated the influence of stress and aging on metabolism and emotional behavior by comparing young and middle-aged female mice. After 28 consecutive days of immobilization stress, behavioral tests were conducted and tissue sampling was performed. The results showed that the body weight of middle-aged mice was severely lowered by stress, but emotional behaviors were hardly influenced by either aging or stress. Aging influenced changes in amino acid metabolism in the brain and increased various amino acid levels in the uterus and ovary. In conclusion, we found that aged mice were more susceptible to stress in terms of body-weight reduction, and that amino acid metabolisms in the brain and genital organs were largely influenced by aging rather than by stress. PMID- 28017700 TI - 'Corrigenda to "Suppression of brain cholesterol synthesis in male Mecp2 deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis" [Brain Res. 1654 (2017) 77-84]'. PMID- 28017701 TI - UPEI-400, a conjugate of lipoic acid and scopoletin, mediates neuroprotection in a rat model of ischemia/reperfusion. AB - Previously, our laboratory provided evidence that lipoic acid (LA) covalently bonded to various antioxidants, resulted in enhanced neuroprotection compared to LA on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. The present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of LA and scopoletin covalently bonded together, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Using a rat stroke model, male rats were anesthetized (Inactin(r); 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 h (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 h of reperfusion (ischemia/reperfusion; I/R). Pre administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p < 0.05), but not in the pMCAO model of stroke. UPEI 400 was ~1000 times more potent compared to scopoletin alone. Since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death. PMID- 28017702 TI - Arsenite in drinking water produces glucose intolerance in pregnant rats and their female offspring. AB - Drinking water is the main source of arsenic exposure. Chronic exposure has been associated with metabolic disorders. Here we studied the effects of arsenic on glucose metabolism, in pregnant and post-partum of dams and their offspring. We administered 5 (A5) or 50 (A50) mg/L of sodium arsenite in drinking water to rats from gestational day 1 (GD1) until two months postpartum (2MPP), and to their offspring from weaning until 8 weeks old. Liver arsenic dose-dependently increased in arsenite-treated rats to levels similar to exposed population. Pregnant A50 rats gained less weight than controls and recovered normal weight at 2MPP. Arsenite-treated pregnant animals showed glucose intolerance on GD16-17, with impaired insulin secretion but normal insulin sensitivity; they showed dose dependent increased pancreas insulin on GD18. All alterations reverted at 2MPP. Offspring from A50-treated mothers showed lower body weight at birth, 4 and 8 weeks of age, and glucose intolerance in adult females, probably due to insulin secretion and sensitivity alterations. Arsenic alters glucose homeostasis during pregnancy by altering beta-cell function, increasing risk of developing gestational diabetes. In pups, it induces low body weight from birth to 8 weeks of age, and glucose intolerance in females, demonstrating a sex specific response. PMID- 28017703 TI - Prepubertal subchronic exposure to soy milk and glyphosate leads to endocrine disruption. AB - Lactose intolerance is characterized by low or inexistent levels of lactase, and the main treatment consists of dietary changes, especially replacing dairy milk by soy milk. Soy contains phytoestrogens, substances with known estrogenic activity, besides, glyphosate-based herbicides are extensively used in soy crops, being frequently a residue in soy beans, bringing to a concern regarding the consumption of soy-based products, especially for children in breastfeeding period with lactose intolerance. This study evaluated the pubertal toxicity of a soy milk rich feeding (supplemented or not with glyphosate, doses of 50 and 100 mg/kg) during prepubertal period in male rats. Endocrine disruption was observed through decrease in testosterone levels, decrease in Sertoli cell number and increase in the percentage of degenerated Sertoli and Leydig cells in animals receiving soy milk supplemented with glyphosate (both doses) and in animals treated only with soy milk. Animals treated with soy milk with glyphosate (both doses) showed decrease spermatids number and increase of epididymal tail mass compared to control, and decrease in the diameter of seminiferous tubules compared to soy milk control group. Animals receiving soy milk supplemented with 100 mg/kg glyphosate showed decrease in round spermatids and increase in abnormal sperm morphology, compared to control. PMID- 28017704 TI - New Media for Educating Urology Residents: An Interview Study in Canada and Germany. AB - OBJECTIVE: To investigate the usage and perceived usefulness of new media for educating urology residents in Canada and Germany. DESIGN: We designed an 11-item online survey to assess the use and perceived usefulness of new media for education. We performed a comparative analysis. SETTING: The survey was distributed via e-mail to 143 Canadian and 721 German urology residents. PARTICIPANTS: The survey included 58 urology residents from Canada and 170 from Germany. RESULTS: A total of 58 residents from Canada (41% response rate) and 170 from Germany (24% response rate) responded to this survey. Residents spent 45% of their education time on new media. The Internet was used by 91% (n = 208) of the residents for professional education purposes, with a median time of 270 minutes (interquartile range [IQR]: 114-540) per month. Apps were used by 54% (n = 118) of the residents, with a median time of 101 minutes (IQR: 45-293) per month. A total of 23% (n = 47) of the residents used social media (SoMe) for education, with a median time of 90 minutes (IQR: 53-80) per month. In all, 100% (n = 228) rated the Internet, 76% (n = 173) apps, and 43% (n = 97) SoMe as being useful for professional education purposes. A total of 90% (n = 205) watched medical videos for education, and 89% (n = 203) of these videos were on surgical procedures. Canadian urology residents used more new media sources for professional education than did the Germans (58% vs. 41%, p < 0.001). The time spent for education on new media was higher among Canadian residents for the Internet (p < 0.001), apps (p < 0.001), and SoMe (p = 0.033). Canadian residents reported more privacy concerns (p < 0.001). CONCLUSIONS: New media play a dominant role in the education of urology residents. The primary source for personal education in urology is the Internet. Future studies and technological developments should investigate and improve new media tools to optimize education during residency. PMID- 28017705 TI - Provision of Rehabilitation Services in Residential Care Facilities: Evidence From a National Survey. AB - OBJECTIVE: To examine the association between organizational factors and provision of rehabilitation services that include physical therapy (PT) and occupational therapy (OT) in residential care facilities (RCFs) in the United States. DESIGN: A cross-sectional, observational study conducted using a national sample from the 2010 National Survey of Residential Care Facilities conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics. SETTINGS: U.S. RCFs. PARTICIPANTS: RCFs (N=2302; weighted sample, 31,134 RCFs). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The association between characteristics of the facilities, director and staff, and residents, and provision of PT and OT services was assessed using multivariate logistic regression analyses. RESULTS: Among all RCFs in the United States, 43.9% provided PT and 40.0% provided OT. Medicaid-certified RCFs, larger-sized RCFs, RCFs with a licensed director, RCFs that used volunteers, and RCFs with higher personal care aide hours per patient per day were more likely to provide both PT and OT, while private, for-profit RCFs were less likely to provide PT and OT. RCFs with a higher percentage of white residents were more likely to provide PT, while RCFs with chain affiliation were more likely to provide OT. CONCLUSIONS: Less than half of the RCFs in the United States provide PT and OT, and this provision of therapy services is associated with organizational characteristics of the facilities. Future research should explore the effectiveness of rehabilitation services in RCFs on residents' health outcomes. PMID- 28017706 TI - Effect of Unmodulated 5-kHz Alternating Currents Versus Transcutaneous Electrical Nerve Stimulation on Mechanical and Thermal Pain, Tactile Threshold, and Peripheral Nerve Conduction: A Double-Blind, Placebo-Controlled Crossover Trial. AB - OBJECTIVE: To investigate the effect of unmodulated 5-kHz alternating current on mechanical pain threshold (MPT), heat pain threshold (HPT), tactile threshold (TT), and peripheral nerve conduction (PNC) compared with transcutaneous electrical nerve stimulation (TENS) and sham stimulation. SETTING: National referral center. DESIGN: Randomized, double-blind, placebo-controlled crossover trial. PARTICIPANTS: Healthy volunteers (N=38). No dropouts or adverse events were reported. INTERVENTION: TENS, unmodulated 5-kHz currents, and sham stimulation were applied on the radial nerve for 20 minutes with a 24-hour washout period between them and concealed intervention allocation. MAIN OUTCOME MEASURES: Four measures were taken: before, during, and 2 after the interventions. Algometry was used to assess MPT, a Peltier thermode for HPT using the method of limits, Von Frey filaments for TT, and radial nerve compound action potential. RESULTS: No differences were observed on MPT, HPT, and PNC when 5-kHz current and TENS were compared. However, TT increased 56.2mN (95% confidence interval [CI], 28.8-83.6) in the TENS group compared with the 5-kHz current group during intervention. Compared with sham stimulation during intervention, MPT increased 4.7N (95% CI, 0.3-9.2) using 5-kHz current and 10.4N (95% CI, 3.5-17.3) with TENS. TT increased 17.2mN (95% CI, 4.7-29.7) with 5-kHz current and 73.4mN (95% CI, 47.5-99.2) with TENS. However, HPT increased 1.0 degrees C (95% CI, 0.2 2.0) only with TENS. For the PNC, no differences were found among the 3 groups. CONCLUSIONS: Unmodulated 5-kHz current produced an increase in somatosensory thresholds that was greater than placebo but not when compared with TENS; however, participants perceived 5-kHz currents to be more comfortable and showed more habituation to them. PMID- 28017707 TI - The rectangular flexion gap is associated with an increased knee flexion angle in a cruciate-sacrificing rotating platform mobile-bearing total knee arthroplasty. AB - BACKGROUND: The knee flexion angle after a total knee arthroplasty is an important indicator of clinical outcome. However, there is little appropriate information about the correlation between the ligament balancing and knee flexion angle after total knee arthroplasty. The purpose of this study was to investigate the effect of the ligamentous balance in extension and flexion on knee flexion angle one year after posterior cruciate ligament sacrificing rotating platform total knee arthroplasty. METHODS: Eighty-five total knee arthroplasties in 71 patients were investigated in this study. The postoperative knee flexion angle and the percentage of improvement in the balanced group in which the difference between varus and valgus was less than 2 degrees and the unbalanced group in extension and the rectangular group in which the asymmetry of the flexion gap was within 2 degrees and the trapezoidal group in flexion were compared. The factors affecting postoperative knee flexion angle were also investigated in a forced entry multiple regression analysis. RESULTS: The mean flexion angle improved significantly from 116.2 degrees to 122.5 degrees in the rectangular group. By contrast, in the trapezoidal group, no significant improvement was seen (from 115.5 degrees to 117.4 degrees ). The statistically significant difference was found between the rectangular and trapezoidal group in flexion in terms of the improvement of the knee flexion angle while there was no difference between the balanced and unbalanced group in extension. The multiple regression analysis showed that the asymmetry of the flexion gap was a predictor of the postoperative knee flexion angle. CONCLUSIONS: Asymmetric flexion gap affected negatively the postoperative knee flexion angle after posterior cruciate ligament sacrificing rotating platform total knee arthroplasty. A gap balancing technique is recommended for this type of implant. PMID- 28017708 TI - Comparison of morphology between patients with and without developmental spinal canal stenosis to inform the feasibility of C1 lateral mass screw insertion in the atlas. AB - BACKGROUND: C1 lateral mass screws are increasingly being used as an effective anchoring system. Insufficient posterior arch height increases difficulty of inserting the screws using the Tan method. The general aim of our retrospective cross-sectional study was to clarify the atlas morphology of patients with developmental spinal canal stenosis to evaluate the usefulness of the Tan method. METHODS: A computed tomography myelogram was performed in 85 Japanese patients presenting with spinal disorders. The following morphological measures at the level of the atlas were obtained: anterior-posterior length (APL), medial-lateral width (MLW), lateral mass transverse diameter (LMTD), dural sac area (DSA), spinal cord area (SCA), lateral mass height (LMH), lateral mass width (LMW), lateral mass length (LML), posterior arch length (PAL), posterior lamina height (PLH), and posterior vertebral groove height (PVGH). Patients were classified into two groups: patients with developmental spinal canal stenosis (DCS), identified by a longitudinal diameter of the spinal canal <12 mm and patients without developmental spinal canal stenosis (NDCS), identified by a longitudinal diameter of the spinal canal >=12 mm. Measures obtained on the computed tomography images were compared between the two groups. RESULTS: Among the 85 patients in our study group, developmental spinal stenosis was identified in 47 patients. The APL, DSA, PAL and PVGH measurements were significantly smaller among the 47 patients in the DCS group, compared to the 38 patients in the NDCS group (p < 0.01). The mean height of the PVGH was <4.0 mm in 63.5% of the total study group. CONCLUSIONS: The normally inserted C1 lateral mass screws have a diameter of 3.5-4.0 mm, and hence, the Tan method require a posterior arch height that exceeds this value. Our study provides evidence of a narrower posterior arch in Japanese individuals with developmental spinal canal stenosis. Therefore, the safe use of the Tan method to insert C1 lateral mass screws may be limited in Japanese individuals with developmental spinal canal stenosis. PMID- 28017709 TI - Anatomical analysis of the relation between human ligamentum flavum and posterior spinal bony prominence. AB - BACKGROUND: Posterior spinal bony prominences are commonly used as landmarks during posterior spinal surgery; however, the exact relationship of these structures with ligamentum flavum (LF) borders and attachments has not been clarified. MATERIALS AND METHODS: Whole spines were removed en bloc from 20 embalmed human cadavers. Plain radiographs and computed tomography (CT) scans of each whole spine were taken, and then the spine was divided in two parts along the pedicle bases. The LFs were painted with contrast dye, and second radiographs and CT scans were taken again. Radiographic data were analyzed using CT image analyzer. RESULTS: The craniolateral border of LF at four upper lumbar levels (from L1/2 to L4/5) located cranial to isthmus in both sides (3.5 mm), meanwhile, it located at or below isthmus in both sides at L5-S1 level (0.5 mm). In the midline, LF attached below the isthmus levels at four upper lumbar levels (4 mm), though it located in the same level of isthmus at L5-S1 (1 mm). The mean distance between medial border of pedicles and lateral border of LF increased from upper to the lower lumbar levels (6.5 mm at L1/2 - 11.4 mm at L5-S1). Distance between interlaminar space and cranial border of LF at the midline gradually increased from 8.2 mm at L1 toward 11.1 mm at L4, it was 9.3 mm in L5. CONCLUSIONS: From the data of new analytical method using contrasted LF and reconstructed CT, the detailed relations between bony prominence and the border of LF were uncovered. Based on these findings and reconstructed LF images superimposed on lamina, surgeons would design safe and adequate lumbar spinal decompression with imagination of overall pictures of the LF from the dorsal side. PMID- 28017710 TI - A vitamin D analogue, eldecalcitol, enhances expression of fast myosin heavy chain subtypes in differentiated C2C12 myoblasts. AB - BACKGROUND: Several lines of evidence indicate that the active form of vitamin D has an anabolic effect on skeletal muscle. Eldecalcitol, an analogue of the active form of vitamin D, has the potential to increase bone density and decrease fracture risk. The objective of this study was to investigate the effect of eldecalcitol in C2C12 myogenic cells. METHODS: C2C12 cells were grown to confluency and the culture medium was replaced with low-glucose DMEM containing 2% horse serum. Eldecalcitol was added at a concentration of 1, 10 or 100 nM. Gene expression profiles of vitamin D receptor (VDR), MyoD, IGF-1, neonatal myosin heavy chain (MHC), and the fast MHC subtypes Ia, IIa, IIb and IId/x were analyzed by quantitative RT-PCR. Protein expression of MHC subtypes was evaluated by western blotting and immunostaining. RESULTS: Eldecalcitol upregulated gene expression of VDR, MyoD and IGF-1. Incubation with eldecalcitol in the absence of serum followed by the addition of serum after 1 h was associated with greater increases in the expression of these genes compared with co-incubation with eldecalcitol and serum. Gene expression of MHC subtypes IIa, IIb and IId/x was significantly increased by eldecalcitol. Protein expression of fast MHC subtypes was significantly increased by eldecalcitol at 1 and 10 nM. CONCLUSION: Similar to the active form of vitamin D, eldecalcitol had an anabolic effect on fast MHC subtypes. Taking into account its pharmacokinetic profile, eldecalcitol is expected to be beneficial for the maintenance and improvement of muscle function in elderly individuals. PMID- 28017711 TI - Evaluation of the Hypothesis That Choking/ALTE May Mimic Abusive Head Trauma. AB - OBJECTIVE: Apparent life-threatening events (ALTEs), often accompanied by choking, have been hypothesized to cause subdural hemorrhages (SDH), retinal hemorrhages, and brain injury. If the choking/ALTE hypothesis were true, children who present with ALTE and SDH would have fewer extracranial injuries suspicious for abuse than those with SDH and no ALTE. We aimed to compare the prevalence of suspicious extracranial injuries in children who have ALTE-associated SDH to those with non-ALTE SDH. METHODS: We performed a 5-year retrospective case control study of children <2 years of age with SDH evaluated by the Child Abuse Pediatrics program at a children's hospital. Subjects were classified as ALTE associated SDH and non-ALTE SDH on the basis of ALTE definitions as proposed by the authors of the choking/ALTE hypothesis. The 2 groups were compared for the prevalence of suspicious extracranial injuries. RESULTS: Of 170 study subjects, 64 had an ALTE-associated SDH and 106 had non-ALTE SDH. ALTE-associated SDH subjects were nearly 5 times more likely to have at least one suspicious extracranial injury (odds ratio [OR] 4.8, 95% confidence interval [CI] 1.9-12.1) and were more likely to have individual types of suspicious extracranial injuries, including retinoschisis (OR 4.1, 95% CI 1.6-10.2), high-specificity bruising (OR 2.6, 95% CI 1.3-4.9), and internal abdominal injury (3.5, 95% CI 1.2 9.9). Subjects with ALTE-associated SDH were also significantly more likely to die or have persistent neurologic impairment. All 10 subjects with a dysphagic choking type ALTE had at least 1 suspicious extracranial injury. CONCLUSIONS: ALTEs are not supported as causative mechanisms for findings concerning abusive head trauma. PMID- 28017712 TI - Incidence, Predictors, and Mid-Term Outcomes of Possible Leaflet Thrombosis After TAVR. AB - OBJECTIVES: This study sought to clarify the incidence and predictors of hypoattenuated leaflet thickening (HALT) and mid-term outcomes after transcatheter aortic valve replacement. BACKGROUND: HALT detected on multidetector computed tomography (MDCT) scanning raised concerns about possible subclinical leaflet thrombosis. METHODS: We studied 70 of 100 consecutive patients from a single-center registry who underwent implantation with the Edwards SAPIEN-XT device. MDCT results, echocardiographic data, and laboratory findings obtained at the 6-month and 1-year follow-ups were analyzed. RESULTS: Of 70 patients, MDCT scans revealed HALT in 1 patient (1.4%) at discharge, 7 (10.0%) at 6 months, and 10 (14.3%) at 1 year post-transcatheter aortic valve replacement cumulatively. The degree of leaflet immobility correlated with the HALT area on 4 dimensional MDCT (r = 0.68) on the basis of data from 10 patients. HALT was associated with male sex (70% vs. 25%; p = 0.008) and larger sinus of Valsalva (31.0 +/- 2.0 mm vs. 28.6 +/- 2.6 mm; p = 0.005). HALT was found in 3 of 49 patients with a 23-mm bioprosthesis and in 7 of 21 patients with a 26-mm bioprosthesis (6.1% vs. 33.3%; p = 0.006). D-dimer levels were significantly increased in the HALT group at the 6-month (2.3 MUg/ml [interquartile range (IQR): 2.1 to 6.1 MUg/ml] vs. 1.1 MUg/ml [IQR: 0.8 to 2.2 MUg/ml]; p = 0.002) and 1-year (2.7 MUg/ml [IQR: 1.7 to 4.8 MUg/ml] vs. 1.2 MUg/ml [IQR: 0.9 to 2.1 MUg/ml]; p = 0.006) follow-ups, despite no differences at discharge. The pressure gradient was decreased in the HALT group at the 1-year follow-up (8.3 +/- 0.8 mm Hg vs. 11.1 +/- 4.9 mm Hg; p = 0.005). After detecting HALT, additional anticoagulation therapy was not administered. Clinical outcomes, including all cause mortality (0% vs. 1.7%; p = 1.00) and stroke (0% vs. 0%; p = 1.00), were similar between the groups. CONCLUSIONS: HALT with reduced leaflet motion was not rare but usually subclinical. Valve hemodynamics and mid-term outcomes were uneventful even without additional anticoagulant therapy in our limited number of cases. Male sex, larger sinus and bioprosthesis size, and elevated D-dimer levels during follow-up were associated with this phenomenon. PMID- 28017713 TI - When Should We Go With HALT? PMID- 28017714 TI - Long-Term Valve Performance of TAVR and SAVR: A Report From the PARTNER I Trial. AB - OBJECTIVES: The aim of this study was to evaluate the long-term performance of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) through longitudinal echocardiographic analysis. BACKGROUND: The long-term performance of the SAPIEN TAVR is not well-described. Therefore, we examined the hemodynamic and valvular profile of the SAPIEN TAVR over 5 years. METHODS: All patients receiving TAVR or SAVR with first post-implant (FPI) and 5 year echoes were analyzed for aortic valve (AV) peak velocity, AV mean gradient, AV area, peak left ventricular (LV) outflow tract and in-stent velocities, Doppler velocity index, aortic regurgitation (AR), LV mass index, stroke volume index, and cardiac index. The FPI and 5-year data were compared using a paired t test or McNemar's analyses. RESULTS: There were 86 TAVR and 48 SAVR patients with paired FPI and 5-year echocardiograms. Baseline characteristics were similar between groups. The AV area did not change significantly 5 years after TAVR (p = 0.35). The AV mean gradient also remained stable: 11.5 +/- 5.4 mm Hg at FPI to 11.0 +/- 6.3 mm Hg at 5 years (p = 0.41). In contrast, the peak AV and LV outflow tract velocities decreased (p = 0.03 and p = 0.008, respectively), as did in stent velocity (p = 0.015). Correspondingly, the TAVR Doppler velocity index was unchanged (p = 0.07). Among TAVR patients, there was no change in total AR (p = 0.40), transvalvular AR (p = 0.37), or paravalvular AR (p = 0.26). Stroke volume index and cardiac index remained stable (p = 0.16 and p = 0.25, respectively). However, there was a significant regression of LV mass index (p < 0.0001). The longitudinal evaluation among SAVR patients revealed similar trends. There was a low rate of adverse events among TAVR and SAVR patients alive at 5 years. CONCLUSIONS: Longitudinal assessment of the PARTNER I trial (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial) demonstrates that valve performance and cardiac hemodynamics are stable after implantation in both SAPIEN TAVR and SAVR in patients alive at 5 years. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). PMID- 28017715 TI - Midterm Sapien Transcatheter Valve Durability: Ready for Prime Time or Waiting to Fail? PMID- 28017716 TI - Effects of learning on mTOR pathway gene expression in the brain of zebrafish (Danio rerio) of different ages. AB - Target of rapamycin (TOR) is a protein kinase involved in the modulation of mRNA translation and, therefore, in the regulation of protein synthesis. In neurons, the role of TOR is particularly important in the consolidation of long-term memory (LTM). One of the modulators of TOR is brain-derived neurotrophic factor (BDNF), which activates the TOR signaling pathway to promote protein synthesis, synapse strengthening, and the creation of new neural networks. We investigated the gene expression pattern of this pathway during memory consolidation in zebrafish of different ages. Our findings demonstrate that TOR activation in old animals occurs in the early phase of consolidation, and follows a pattern identical to that of BDNF expression. In younger animals, this increase in activation did not occur, and changes in BDNF expression were also not so remarkable. Furthermore, the expression of the main proteins regulated by the synthesis of TOR (i.e., 4EBP and p70S6K) remained identical to that of TOR in all age groups. PMID- 28017717 TI - Preserving expression of Pdx1 improves beta-cell failure in diabetic mice. AB - Pdx1, a beta-cell-specific transcription factor, has been shown to play a crucial role in maintaining beta-cell function through transactivation of beta-cell related genes. In addition, it has been reported that the expression levels of Pdx1 are compromised under diabetic conditions in human and rodent models. We therefore aimed to clarify the possible beneficial role of Pdx1 against beta-cell failure and generated the transgenic mouse that expressed Pdx1 conditionally and specifically in beta cells (betaPdx1) and crossed these mice with Ins2Akita diabetic mice. Whereas Pdx1 mRNA levels were reduced in Ins2Akita mice compared with their non-diabetic littermates, the mRNA levels of Pdx1 were significantly recovered in the islets of betaPdx1; Ins2Akita mice. The betaPdx1; Ins2Akita mice exhibited significantly improved glucose tolerance, compared with control Ins2Akita littermates, accompanied by increased insulin secretion after glucose loading. Furthermore, histological examination demonstrated that betaPdx1; Ins2Akita mice had improved localization of SLC2A2 (GLUT2), and quantitative RT PCR showed the recovered expression of Mafa and Gck mRNAs in the islets of betaPdx1; Ins2Akita mice. These findings suggest that the sustained expression of Pdx1 improves beta-cell failure in Ins2Akita mice, at least partially through the preserving expression of beta-cell-specific genes as well as improved localization of GLUT2. PMID- 28017718 TI - Maturation and processing of the amyloid precursor protein is regulated by the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2). AB - The toxic amyloid beta-peptide (Abeta) is a key player in Alzheimer Disease (AD) pathogenesis and selective inhibition of the production of this peptide is sought for. Abeta is produced by the sequential cleavage of the Abeta precursor protein (APP) by beta-secretase (to yield APP-C-terminal fragment beta (APP-CTFbeta) and soluble APPbeta (sAPPbeta)) and gamma-secretase (to yield Abeta). We reasoned that proteins that associate with gamma-secretase are likely to regulate Abeta production and to be targets of pharmaceutical interventions and therefore performed a pull-down assay to screen for such proteins in rat brain. Interestingly, one of the purified proteins was potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2), which has been shown to be involved in epilepsy. We found that silencing of HCN2 resulted in decreased secreted Abeta levels. To further investigate the mechanism behind this reduction, we also determined the levels of full-length APP, sAPP and APP-CTF species after silencing of HCN2. A marked reduction in sAPP and APP-CTF, as well as glycosylated APP levels was detected. Decreased Abeta, sAPP and APP CTF levels were also detected after treatment with the HCN2 inhibitor ZD7288. These results indicate that the effect on Abeta levels after HCN2 silencing or inhibition is due to altered APP maturation or processing by beta-secretase rather than a direct effect on gamma-secretase. However, HCN2 and gamma-secretase were found to be in close proximity, as evident by proximity ligation assay and immunoprecipitation. In summary, our results indicate that silencing or inhibition of HCN2 affects APP processing and thereby could serve as a potential treatment strategy. PMID- 28017719 TI - Repression of miR-217 protects against high glucose-induced podocyte injury and insulin resistance by restoring PTEN-mediated autophagy pathway. AB - Podocyte damage is the initial hallmark of diabetic nephropathy (DN), leading to the increasing morbidity and mortality in diabetic patients. Recent researches have corroborated the critical roles of miRNAs in the pathological progression of DN. Here, elevation of miR-217 was verified in high glucose (HG)-stimulated podocytes. Moreover, blocking miR-217 expression antagonized HG-induced cell injury by attenuating the adverse role of HG on cell viability and inhibiting ROS levels and cell apoptosis. Simultaneously, miR-217 repression restored HG disrupted insulin resistance by elevating glucose uptake and nephrin expression, an essential component for insulin-induced glucose uptake. Mechanism assay substantiated the defective autophagy in HG-treated podocytes, which was resumed by miR-217 cessation. Importantly, suppressing autophagy pathway with 3-MA alleviated the protective roles of miR-217 down-regulation in podocyte injury and insulin resistance. Luciferase reporter analysis confirmed that PTEN was a target of miR-217 in podocytes. Additionally, blocking PTEN expression restrained autophagy restoration in miR-217-decreased cells. Furthermore, PTEN down regulation attenuated the beneficial role of miR-217 suppression in HG-induced injury and insulin resistance. Together, this study manifests that miR 217inhibition can protectively antagonize HG-induced podocyte damage and insulin resistance by restoring the defective autophagy pathway via targeting PTEN, representing a novel and promising therapeutic target against diabetic nephropathy. PMID- 28017720 TI - Retinal expression and localization of Mef2c support its important role in photoreceptor gene expression. AB - Photoreceptor-specific gene expression is controlled by a hierarchical network of transcription factors, including the master regulators cone-rod homeobox (Crx) and neural retina leucine zipper (Nrl). Myocyte-enhancer factor 2c (Mef2c) is an ubiquitously expressed transcription factor with important functions in the cardiovascular system. Here, we performed a detailed analysis of Mef2c expression, localization and function in the retina to further elucidate its potential role for photoreceptor gene regulation. We showed that murine retinal Mef2c mRNA expression was high at birth and peaked at late postnatal developmental stages. Using immunohistochemistry and Western blot, Mef2c protein was detected in the outer nuclear layer of adult mouse and human retinas and localized to the nucleus of 661W photoreceptor-like cells. Mef2c knock-down in 661W cells reduced the expression of arrestin 3 (Arr3) and medium-wave-sensitive cone opsin (Opn1mw) but increased transcript levels of mitogen-activated protein kinase 15 (Mapk15) and phosphodiesterase 6h (Pde6h). In conclusion, Mef2c is highly expressed in the retina where it modulates photoreceptor-specific gene expression. PMID- 28017721 TI - The role of the loop 1 region in MazFbs mRNA interferase from Bacillus subtilis in recognition of the 3' end of the RNA substrate. AB - MazFbs is an mRNA interferase from Bacillus subtilis specifically recognizing UACAU. The X-ray structure of its complex with an RNA substrate has been also solved. When its amino acid sequence is compared with that of MazFhw, an mRNA interferase from a highly halophilic archaeon, recognizing UUACUCA, the 9-residue loop-1 region is highly homologous except that the V16V17 sequence in MazFbs is replaced with TK in MazFhw. Thus, we examined the role of the VV sequence in RNA substrate recognition by replacing it with TK, GG, AA or LL. The substitution mutants thus constructed showed significant differences in cleavage specificity using MS2 phage RNA. The primer extension analysis of the cleavage sites revealed that the VV sequence plays an important role in the recognition of the 3'-end base of the RNA substrate. PMID- 28017722 TI - Biophysical characterization of Ca2+-binding of S100A5 and Ca2+-induced interaction with RAGE. AB - S100A5 is a calcium-binding protein of S100 family, which represents a major ligand to the receptor for advanced glycation end product (RAGE), a pattern recognition receptor engaged in diverse pathological processes. Here we have characterized calcium binding of S100A5 and the complex formation between S100A5 and RAGE using calorimetry and NMR spectroscopy. S100A5 binds to calcium ions in a sequential manner with the equilibrium dissociation constants (KD) of 1.3 MUM and 3.5 MUM, which corresponds to the calcium-binding at the C-terminal and N terminal EF-hands. Upon calcium binding, S100A5 interacts with the V domain of RAGE (RAGE-v) to form a heterotrimer (KD ~5.9 MUM) that is distinct among the S100 family proteins. Chemical shift perturbation data from NMR titration experiments indicates that S100A5 employs the periphery of the dimer interface to interact with RAGE-v. Distinct binding mode and stoichiometry of RAGE against different S100 family proteins could be important to modulate diverse RAGE signaling. PMID- 28017723 TI - Engineering thermostable (R)-selective amine transaminase from Aspergillus terreus through in silico design employing B-factor and folding free energy calculations. AB - Amine transaminases have recently gained a lot of attention for the synthesis of chiral amines. Using (R)-selective amine transaminase from Aspergillus terreus (AT-ATA) as a transaminase model, in silico design was applied employing B-factor and folding free energy (DeltaDeltaGfold) calculations. Mutation sites were selected by targeting flexible regions with the greatest B-factors, and were substituted with amino acids that were determined by folding free energy calculations (DeltaDeltaGfold < 0) to be more rigid than the original ones. By site-directed mutagenesis, we obtained four stabilized mutants (T130M, T130F, E133F and D134L) with improved stability from 19 candidates. Compared to the wild type, the best single mutant (T130M) showed an increase in thermal stability with a nearly 2.2-fold improvement of half-life (t1/2) at 40 degrees C and a 3.5 degrees C higher T1/210 min. The optimum catalytic temperature of T130F was increased by 10 degrees C. In addition, the T130M/E133F double mutant displayed the largest shift in thermostability with 3.3-fold improvement of t1/2 at 40 degrees C and a 5.0 degrees C higher T1/210 min. Modeling analysis showed that new hydrophobic interactions and hydrogen bonds might contribute to the observed thermostability improvement. PMID- 28017724 TI - Deficiency of succinyl-CoA synthetase alpha subunit delays development, impairs locomotor activity and reduces survival under starvation in Drosophila. AB - Succinyl-CoA synthetase/ligase (SCS) is a mitochondrial enzyme that catalyzes the reversible process from succinyl-CoA to succinate and free coenzyme A in TCA cycle. SCS deficiencies are implicated in mitochondrial hepatoencephalomyopathy in humans. To investigate the impact of SCS deficiencies in Drosophila, we generated a null mutation in Scs alpha subunit (Scsalpha) using the CRISPR/Cas9 system, and characterized their phenotype. We found that the Drosophila SCS deficiency, designated ScsalphaKO, contained a high level of succinyl-CoA, a substrate for the enzyme, and altered levels of various metabolites in TCA cycle and glycolysis, indicating that the energy metabolism was impaired. Unlike SCSalpha deficiencies in humans, there was no reduction in lifespan, indicating that Scsalpha is not critical for viability in Drosophila. However, they showed developmental delays, locomotor activity defects, and reduced survival under starvation. We also found that glycogen breakdown occurred during development, suggesting that the mutant flies were unable to produce sufficient energy to promote normal growth. These results suggested that SCSalpha is essential for proper energy metabolism in Drosophila. The ScsalphaKO flies should be useful as a model to understand the physiological role of SCSalpha as well as the pathophysiology of SCSalpha deficiency. PMID- 28017725 TI - Novel mechanism of aberrant ZIP4 expression with zinc supplementation in oral tumorigenesis. AB - Zrt-Irt-like protein 4 (ZIP4) is critical molecule for proper mammalian development and releasing zinc from vesicular compartments. Recent studies suggested that ZIP4 plays an important role of tumor progression in pancreatic, prostate, and hepatocellular cancers, however, little is known about the detail mechanism of ZIP4 in their cancers. In the present study, we examined the possibility of ZIP4 as a new molecular target for oral squamous cell carcinoma (OSCC). We evaluated ZIP4 expression in OSCC-derived cell lines and primary OSCC samples by quantitative RT-PCR, immunoblotting, and immunohistochemistry (IHC). We also analyzed the clinical correlation between ZIP4 status and clinical behaviors in patients with OSCC. In addition, ZIP4 knockdown cells (shZIP4 cells) and ZnCl2 treatment were used for functional experiments, including cellular proliferation assay, zinc uptake assay, and cell-cycle analysis. ZIP4 mRNA and protein were up-regulated significantly in OSCCs compared with normal counterparts in vitro and in vivo. IHC showed that ZIP4 expression in the primary OSCC was positively correlated with primary tumoral size. The shZIP4 cells showed decrease accumulation of intercellular zinc and decreased cellular growth by cell cycle arrest at the G1 phase, resulting from up-regulation of cyclin-dependent kinase inhibitors and down-regulation of cyclins and cyclin-dependent kinases. Since cellular growth of OSCC cells after treatment with zinc was significantly greater than control cells, we speculated that intercellular ZnCl2 accumulation is an important factor for cellular growth. Consistent with our hypothesis, not only decreased zinc uptake by ZIP4 knockdown but also chelating agent, N,N,N',N' tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), showed inhibitory effects of cellular proliferation. Therefore, our data provide evidence for an essential role of ZIP4 and intracellular zinc for tumoral growth in OSCC, suggesting that zinc uptake might be a potential therapeutic targeting event for OSCCs. PMID- 28017726 TI - The public health planners' perfect storm: Hurricane Matthew and Zika virus. AB - Hurricane Matthew threatened to be one of the most powerful Hurricanes to hit the United States in a century. Fortunately, it avoided making landfall on Florida, the eye of the Hurricane remaining centered 40 miles off the Florida coast. Even so it has resulted in over $7 Billion USD in damage according to initial estimates with much of the damage ongoing in severe flooding. Response to and recovery from Hurricane Matthew challenged Florida's public health services and resources just as emergency Zika-specific congressional funding to combat Zika outbreaks in Florida had become available. Hurricanes can disrupt the urban environment in a way that increases the likelihood of vector-borne illnesses and their aftermath can severely strain the very infectious disease and infection control academe needed to combat vector-borne outbreaks. This commentary attempts to examine the challenges posed by Hurricane Matthew in Florida's efforts to contain Zika. PMID- 28017727 TI - Silencing HS6ST3 inhibits growth and progression of breast cancer cells through suppressing IGF1R and inducing XAF1. AB - Heparan sulfate 6-O-sulfation is biologically edited by 6-O-sulfotransferases (HS6STs) within heparan sulfate chains. Three isoforms of HS6ST have been identified. These enzymes are found to be differentially expressed in a variety of tissues. Recently, several studies have shown that dysregulation of 6-O sulfotransferases could be involved in tumorigenesis of several cancers. This study aimed to analyze the expression and function of HS6ST3 in breast cancer. HS6ST3 was found up-regulated in T47D, MCF7 and MDA-MB231 breast cancer cell lines. HS6ST3 was then silenced in T47D and MCF7 using siRNA. Silencing HS6ST3 diminished tumor cell growth, migration and invasion, but enhanced cell adhesion and apoptosis in breast cancer. Gene microarray analysis revealed that silencing HS6ST3 significantly changed the expression of IGF1R and XAF1 in breast cancer cells. Further functional studies showed that the cellular processes were mediated by IGF1R and XAF1 after silencing HS6ST3 in breast cancer cells. Together these results indicate that HS6ST3 might be involved in the tumorigenesis of breast cancer and it could be a promising target in breast cancer therapy. PMID- 28017728 TI - The value of new genome references. AB - Genomic information has become a ubiquitous and almost essential aspect of biological research. Over the last 10-15 years, the cost of generating sequence data from DNA or RNA samples has dramatically declined and our ability to interpret those data increased just as remarkably. Although it is still possible for biologists to conduct interesting and valuable research on species for which genomic data are not available, the impact of having access to a high quality whole genome reference assembly for a given species is nothing short of transformational. Research on a species for which we have no DNA or RNA sequence data is restricted in fundamental ways. In contrast, even access to an initial draft quality genome (see below for definitions) opens a wide range of opportunities that are simply not available without that reference genome assembly. Although a complete discussion of the impact of genome sequencing and assembly is beyond the scope of this short paper, the goal of this review is to summarize the most common and highest impact contributions that whole genome sequencing and assembly has had on comparative and evolutionary biology. PMID- 28017729 TI - Honey and honey-based sugars partially affect reproductive trade-offs in parasitoids exhibiting different life-history and reproductive strategies. AB - Adult dietary regimes in insects may affect egg production, fecundity and ultimately fitness. This is especially relevant in parasitoid wasps where many species serve as important biological control agents of agricultural pests. Here, we tested the effect of honey and sugar diets on daily fecundity schedules, lifetime reproductive success and longevity in four species of parasitoid wasps when reared on their respective hosts. The parasitoid species were selected based on dichotomies in host usage strategies and reproductive traits. Gelis agilis and G. areator are idiobiont ecto-parasitoids that develop in non-growing hosts, feed on protein-rich host fluids to maximize reproduction as adults and produce small numbers of large eggs. Meteorus pulchricornis and Microplitis mediator are koinobiont endoparasitoids that develop inside the bodies of growing hosts, do not host-feed, and produce greater numbers of small eggs. Parasitoids were reared on diets of either pure honey (containing trace amounts of proteins), heated honey (with denatured proteins) and a honey-mimic containing sugars only. We hypothesized that the benefits of proteins in honey would enhance reproduction in the ectoparasitoids due to their high metabolic investment per egg, but not in the koinobionts. Pure honey diet resulted in higher lifetime fecundity in G. agilis compared with the honey-mimic, whereas in both koinobionts, reproductive success did not vary significantly with diet. Longevity was less affected by diet in all of the parasitoids, although there were variable trade-offs between host access and longevity in the four species. We argue that there are both trait based and association-specific effects of supplementary nutrients in honey on reproductive investment and success in parasitoid wasps. PMID- 28017730 TI - A simple analytic method for estimating T2 in the knee from DESS. AB - PURPOSE: To introduce a simple analytical formula for estimating T2 from a single Double-Echo in Steady-State (DESS) scan. METHODS: Extended Phase Graph (EPG) modeling was used to develop a straightforward linear approximation of the relationship between the two DESS signals, enabling accurate T2 estimation from one DESS scan. Simulations were performed to demonstrate cancellation of different echo pathways to validate this simple model. The resulting analytic formula was compared to previous methods for T2 estimation using DESS and fast spin-echo scans in agar phantoms and knee cartilage in three volunteers and three patients. The DESS approach allows 3D (256*256*44) T2-mapping with fat suppression in scan times of 3-4min. RESULTS: The simulations demonstrated that the model approximates the true signal very well. If the T1 is within 20% of the assumed T1, the T2 estimation error was shown to be less than 5% for typical scans. The inherent residual error in the model was demonstrated to be small both due to signal decay and opposing signal contributions. The estimated T2 from the linear relationship agrees well with reference scans, both for the phantoms and in vivo. The method resulted in less underestimation of T2 than previous single scan approaches, with processing times 60 times faster than using a numerical fit. CONCLUSION: A simplified relationship between the two DESS signals allows for rapid 3D T2 quantification with DESS that is accurate, yet also simple. The simplicity of the method allows for immediate T2 estimation in cartilage during the MRI examination. PMID- 28017731 TI - Consistent individual variation in day, night, and GnRH-induced testosterone concentrations in house sparrows (Passer domesticus). AB - The hypothalamic-pituitary-gonadal (HPG) axis, with gonadotropin-releasing hormone (GnRH) initiating the endocrine cascade, regulates testosterone secretion. Testosterone, through its pleiotropic effects, plays a crucial role in coordinating morphology, physiology and behavior in a reproductive context. The concentration of circulating testosterone, however, varies over the course of the day and in response to other internal or external stimuli, potentially making it difficult to relate testosterone sampled at one time point with traits of interest. Many researchers now utilize the administration of exogenous GnRH to elicit a standardized stimulation of testosterone secretion. However, it has remained unclear if and how this exogenously stimulated activation of the HPG axis is related with endogenously regulated testosterone that is capable of influencing testosterone related traits. Repeated measures of a hormone can uncover consistent individual variation in hormonal differences at the HPG axis level, variation that potentially stems from underlying genetic variation in a population experiencing identical environmental cues. Thus, we asked, using the house sparrow (Passer domesticus), how daily endogenous variation in testosterone profiles relates to GnRH-induced testosterone secretion. Further, we explore the relationship between endogenous daily testosterone peaks and GnRH-induced testosterone with badge size, a morphological trait related with status within a social group. We found that GnRH-induced testosterone levels reflect a highly repeatable hormonal phenotype that is strongly correlated with nighttime testosterone levels. The results demonstrate the usefulness of GnRH-induced testosterone in studies aimed at understanding individual variation and selection on endogenously regulated testosterone levels and the potential importance of nighttime testosterone levels to physiology and behavior. PMID- 28017732 TI - Photoperiodic and ovarian steroid regulation of histone deacetylase 1, 2, and 3 in Siberian hamster (Phodopus sungorus) reproductive tissues. AB - Epigenetic modifications in reproductive tissues have predominantly focused on pathological conditions, such as ovarian and uterine cancers. The contribution of DNA methylation and histone acetylation to the timing and control of fertility is not well described. Siberian hamsters provide an important model to investigate the relatively short-term regulation of fertility (e.g. estrous) as well as long term timing of breeding (e.g. seasonal). Recent work has shown that DNA methyltransferase 3a (dnmt3a) expression is associated with reproductive involution. Here, the objectives were to identify the impact of photoperiod on hdac1-3 expression in hamster testicular, ovarian and uterine tissue. Then, we assessed the effect of E2P4 and estrous cycling on hdac1-3 expression in uterine tissue. Testicular expression of hdac1 was significantly reduced, whereas hdac3 increased in reproductively photoregressed male hamsters; hdac2 expression did not significantly change across photoperiod conditions. There was no significant photoperiodic effect on ovarian expression of hdac1-3. Uterine expression of hdac3 expression was greater in long day hamsters; exposure to short days significantly reduced uterine hdac2 expression. Ovariectomized hamsters administered a single bolus injection of oil were found to have elevated uterine hdac2 compared to E2P4 treated females 12h and 24h post injection. Uterine hdac1 3 expression was relatively constant across the estrous cycle. Altogether these data indicate tissue-dependent photoperiodic regulation of hdac1-3 expression and that E2P4 may inhibit uterine hdac2 over long-term breeding cycles. PMID- 28017733 TI - Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease. AB - The occurrence of infections after allogeneic hematopoietic stem cell transplantation (HCT) is nearly universal. However, the relationship between infections and graft-versus-host disease (GVHD) is complex and attribution of infectious-related mortality is highly inconsistent, making comparison of infectious complication rates across allogeneic HCT clinical studies difficult. We categorized infectious complications from diagnosis or 1 year before HCT (whichever occurred later) through 2 years after HCT according to timing, frequency, causative organism, severity, and contribution to mortality for 431 consecutive patients who underwent allogeneic HCT from 2008 to 2011. We then assessed the contribution of risk factors, such as the frequency of pre-HCT infections and post-HCT GVHD, on post-HCT infection frequency and severity. We found that each pre-HCT bacterial infection/year leads to an additional 2.15 post HCT bacterial infection/year (P = .004). Pre-HCT viral and fungal infections were not predictors for post-HCT infections. Acute GVHD (aGVHD) significantly increased the risk of developing life-threatening (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.33 to 2.90) and fatal (HR, 2.8; 95% CI, 1.10 to 7.08) infections. Furthermore, patients who develop aGVHD experienced ~60% more infections than patients who never develop aGVHD. Quantification of infection frequency and severity for patients with and without GVHD may facilitate comparison of infectious outcomes across allogeneic HCT trials. PMID- 28017734 TI - Ex Vivo CD34+-Selected T Cell-Depleted Peripheral Blood Stem Cell Grafts for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia and Myelodysplastic Syndrome Is Associated with Low Incidence of Acute and Chronic Graft-versus-Host Disease and High Treatment Response. AB - Ex vivo CD34+-selected T cell depletion (TCD) has been developed as a strategy to reduce the incidence of graft-versus-host disease (GVHD) after allogeneic (allo) hematopoietic stem cell transplantation (HSCT). Clinical characteristics, treatment responses, and outcomes of patients developing acute (aGVHD) and chronic GVHD (cGVHD) after TCD allo-HSCT have not been well established. We evaluated 241 consecutive patients (median age, 57 years) with acute leukemia (n = 191, 79%) or myelodysplastic syndrome (MDS) (n = 50, 21%) undergoing CD34+ selected TCD allo-HSCT without post-HCST immunosuppression in a single institution. Cumulative incidences of grades II-IV and III-IV aGVHD at 180 days were 16% (95% confidence interval [CI], 12 to 21) and 5% (95% CI, 3 to 9), respectively. The skin was the most frequent organ involved, followed by the gastrointestinal tract. Patients were treated with topical corticosteroids, poorly absorbed corticosteroids (budesonide), and/or systemic corticosteroids. The overall day 28 treatment response was high at 82%. The cumulative incidence of any cGVHD at 3 years was 5% (95% CI, 3 to 9), with a median time of onset of 256 days (range, 95 to 1645). The 3-year transplant-related mortality, relapse, overall survival, and disease-free survival were 24% (95% CI, 18 to 30), 22% (95% CI, 17 to 27), 57% (95% CI, 50 to 64), and 54% (95% CI, 47 to 61), respectively. The 1-year and 3-year probabilities of cGVHD-free/relapse-free survival were 65% (95% CI, 59 to 71) and 52% (95% CI, 45 to 59), respectively. Our findings support the use of ex vivo CD34+-selected TCD allograft as a calcineurin inhibitor-free intervention for the prevention of GVHD in patients with acute leukemia and MDS. PMID- 28017735 TI - HMGCR inhibits the early stage of PCV2 infection, while PKC enhances the infection at the late stage. AB - Porcine circovirus type 2 (PCV2) is the smallest DNA virus, which causes porcine circovirus diseases and porcine circovirus-associated diseases (PCVD/PCVAD). Due the small size of viral genomic DNA, PCV2 replication predominantly relies on the host factors. In this study, effects of PKC and HMGCR on PCV2 infection were evaluated using real time PCR and western blot. We found that PKC and HMGCR participated in different stages of PCV2 infection. HMGCR works on the early stage of the infection to inhibit the virus infection, while PKC enhances the infection at the late stage. Furthermore, PKC enhances PCV2 replication by activating JNK1/2 and inactivating HMGCR via regulating phosphorylation of these two proteins, while HMGCR can suppress phosphorylation of JNK1/2. The results in the present study will provide new sights in the pathogenesis of PCV2 infection, as well as interactions between host factors during PCV2 infection. PMID- 28017736 TI - Comparative and temporal transcriptome analysis of peste des petits ruminants virus infected goat peripheral blood mononuclear cells. AB - Peste des petits ruminanats virus (PPRV), a morbillivirus causes an acute, highly contagious disease - peste des petits ruminants (PPR), affecting goats and sheep. Sungri/96 vaccine strain is widely used for mass vaccination programs in India against PPR and is considered the most potent vaccine providing long-term immunity. However, occurrence of outbreaks due to emerging PPR viruses may be a challenge. In this study, the temporal dynamics of immune response in goat peripheral blood mononuclear cells (PBMCs) infected with Sungri/96 vaccine virus was investigated by transcriptome analysis. Infected goat PBMCs at 48h and 120h post infection revealed 2540 and 2000 differentially expressed genes (DEGs), respectively, on comparison with respective controls. Comparison of the infected samples revealed 1416 DEGs to be altered across time points. Functional analysis of DEGs reflected enrichment of TLR signaling pathways, innate immune response, inflammatory response, positive regulation of signal transduction and cytokine production. The upregulation of innate immune genes during early phase (between 2 5 days) viz. interferon regulatory factors (IRFs), tripartite motifs (TRIM) and several interferon stimulated genes (ISGs) in infected PBMCs and interactome analysis indicated induction of broad-spectrum anti-viral state. Several Transcription factors - IRF3, FOXO3 and SP1 that govern immune regulatory pathways were identified to co-regulate the DEGs. The results from this study, highlighted the involvement of both innate and adaptive immune systems with the enrichment of complement cascade observed at 120h p.i., suggestive of a link between innate and adaptive immune response. Based on the transcriptome analysis and qRT-PCR validation, an in vitro mechanism for the induction of ISGs by IRFs in an interferon independent manner to trigger a robust immune response was predicted in PPRV infection. PMID- 28017737 TI - Application of polymer sensitive MRI sequence to localization of EEG electrodes. AB - BACKGROUND: The growing popularity of simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) opens up the possibility of imaging EEG electrodes while the subject is in the scanner. Such information could be useful for improving the fusion of EEG-fMRI datasets. NEW METHOD: Here, we report for the first time how an ultra-short echo time (UTE) MR sequence can image the materials of an MR-compatible EEG cap, finding that electrodes and some parts of the wiring are visible in a high resolution UTE. Using these images, we developed a segmentation procedure to obtain electrode coordinates based on voxel intensity from the raw UTE, using hand labeled coordinates as the starting point. RESULTS: We were able to visualize and segment 95% of EEG electrodes using a short (3.5min) UTE sequence. We provide scripts and template images so this approach can now be easily implemented to obtain precise, subject-specific EEG electrode positions while adding minimal acquisition time to the simultaneous EEG fMRI protocol. COMPARISON WITH EXISTING METHOD(S): T1 gel artifacts are not robust enough to localize all electrodes across subjects, the polymers composing Brainvision cap electrodes are not visible on a T1, and adding T1 visible materials to the EEG cap is not always possible. We therefore consider our method superior to existing methods for obtaining electrode positions in the scanner, as it is hardware free and should work on a wide range of materials (caps). CONCLUSIONS: EEG electrode positions are obtained with high precision and no additional hardware. PMID- 28017738 TI - Validation of the radiobiology toolkit TOPAS-nBio in simple DNA geometries. AB - Computational simulations offer a powerful tool for quantitatively investigating radiation interactions with biological tissue and can help bridge the gap between physics, chemistry and biology. The TOPAS collaboration is tackling this challenge by extending the current Monte Carlo tool to allow for sub-cellular in silico simulations in a new extension, TOPAS-nBio. TOPAS wraps and extends the Geant4 Monte Carlo simulation toolkit and the new extension allows the modeling of particles down to vibrational energies (~2eV) within realistic biological geometries. Here we present a validation of biological geometries available in TOPAS-nBio, by comparing our results to two previously published studies. We compare the prediction of strand breaks in a simple linear DNA strand from TOPAS nBio to a published Monte Carlo track structure simulation study. While TOPAS nBio confirms the trend in strand break generation, it predicts a higher frequency of events below an energy of 17.5eV compared to the alternative Monte Carlo track structure study. This is due to differences in the physics models used by each code. We also compare the experimental measurement of strand breaks from incident protons in DNA plasmids to TOPAS-nBio simulations. Our results show good agreement of single and double strand breaks predicting a similar increase in the strand break yield with increasing LET. PMID- 28017739 TI - MRS studies of neuroenergetics and glutamate/glutamine exchange in rats: Extensions to hyperammonemic models. AB - In vivo Magnetic Resonance Spectroscopy is a useful tool to characterize brain biochemistry as well as its alteration in a large number of major central nervous system diseases. The present review will focus on the study of the glutamate glutamine cycle, an important biochemical pathway in excitatory neurotransmission, analyzed using in vivo MRS of different accessible nuclei: 1H, 13C, 15N and 31P. The different methodological aspects of data acquisition, processing and absolute quantification of the MRS data for each nucleus will be presented, as well as the description of the mathematical modeling approach to interpret the MRS measurements in terms of biochemical kinetics. The unique advantages of MRS, especially its non-invasive nature enabling longitudinal monitoring of brain disease progression and/or effect of treatment is illustrated in the particular context of hyperammonemic disorders with a specific focus on animal models. We review the current possibilities given by in vivo MRS to investigate some of the molecular mechanisms involved in hyperammonemic disorders and to give a better understanding of the process of development of hepatic encephalopathy, a severe neuropsychiatric disorder that frequently accompanies liver disease. PMID- 28017740 TI - Determination of nucleoside triphosphatase activities from measurement of true inorganic phosphate in the presence of labile phosphate compounds. AB - One of the most common assays for nucleoside triphosphatase (NTPase) activity entails the quantification of inorganic phosphate (Pi) as a colored phosphomolybdate complex at low pH. While this assay is very sensitive, it is not selective for Pi in the presence of labile organic phosphate compounds (OPCs). Since NTPase activity assays typically require a large excess of OPCs, such as nucleotides, selectivity for Pi in the presence of OPCs is often critical in evaluating enzyme activity. Here we present an improved method for the measurement of enzymatic nucleotide hydrolysis as Pi released, which achieves selectivity for Pi in the presence of OPCs while also avoiding the costs and hazards inherent in other methods for measuring nucleotide hydrolysis. We apply this method to the measurement of ATP hydrolysis by nitrogenase and GTP hydrolysis by elongation factor G (EF-G) in order to demonstrate the broad applicability of our method for the determination of nucleotide hydrolysis in the presence of interfering OPCs. PMID- 28017741 TI - Morphology of Ruptured and Unruptured Intracranial Aneurysms. AB - BACKGROUND: In addition to size and location, the morphology of intracranial aneurysms has been proposed to predict rupture. This study was undertaken to compare morphologic features between ruptured and unruptured aneurysms and identify those associated with greater risk of rupture. METHODS: Between 2010 and 2014, 301 patients with subarachnoid hemorrhage and 204 with unruptured aneurysms were admitted to our hospital. Two investigators reviewed 3-dimensional angiograms of all aneurysms. Risk factors for rupture were identified. Morphology was classified into single-sac aneurysms with smooth margin, single-sac aneurysms with irregular margin, aneurysms with a daughter sac, and multilobulated aneurysms. The value of morphology in predicting rupture was tested with the use of logistic regression. RESULTS: A total of 420 aneurysms met the inclusion criteria. Multilobulated aneurysm was the most frequent finding among ruptured aneurysms, followed by single sac with irregular margin, aneurysm with daughter sac, and single sac with smooth margin (44.9%, 25.9%, 18%, and 11.2%, respectively). Among unruptured aneurysms, single sac with smooth margin was the most frequent finding, followed by single sac with irregular margin, multilobulated aneurysm, and aneurysm with daughter sac (38.1%, 29.8%, 20.9%, and 11.2%, respectively). Morphology was an independent predictor of rupture (receiver operating characteristic-area under the curve 0.693, P < 0.001). Risk of rupture increased by factor of 3 (5, 95% confidence interval [CI] 1.6-5.3) from single sac with regular margin to irregular margin, by factor of 5.5 (5, 95% CI 2.8-11.0) to daughter sac, and by factor of 7.3 (5, 95% CI 4.1-13.1) to multilobulated aneurysm. CONCLUSIONS: Morphology might have an independent predictive value of aneurysm rupture. Risk of rupture might increase according to extent of morphologic change. Prospective studies will be necessary to evaluate the influence of aneurysm morphology on natural history. PMID- 28017742 TI - Embolization Followed by Radiosurgery for the Treatment of Brain Arteriovenous Malformations (AVMs). AB - BACKGROUND: Embolization has been proposed to reduce the size of the arteriovenous malformation (AVM) nidus in advance of radiosurgical treatment. Embolization followed by radiosurgery for brain AVMs, however, is controversial. OBJECTIVE: We assessed the impact of embolization on nidal size before radiosurgical treatment and evaluated cure rates and complications by using embolization followed by radiosurgery. METHODS: A retrospective review of our institutional AVM database identified 91 patients treated from 1995 to 2009 with embolization followed by radiosurgery. Pre- and postembolization AVM volumes were measured with angiography, and the modified radiation-based AVM scores (RBAS) also were calculated pre- and postembolization. RBAS determined from pre embolization volumes were correlated with postradiosurgical obliteration. RESULTS: Median AVM volume declined from 18.8 mL (interquartile range, 10.2-32.2 mL) to 9.9 mL (3.1-19.2 mL) after embolization, P < 0.00003. Median RBAS scores decreased from 2.6 mL (1.8-3.9 mL) to 1.8 mL (1.0-2.8 mL), P < 0.00003. Two of 91 (2.2%) had new fixed deficits after embolization; however, no patient had new disabling deficits (modified Rankin Scale score >2). A total of 71 of 91 (79%) have had >3 years' follow-up, and 40 (56%) had complete obliteration, with 38 (53%) having excellent outcomes (complete obliteration without neurologic decline). Excellent outcome was seen in 90% of patients with modified RBAS score <1, 66% of patients with score 1-1.5, 50% patients with score 1.5-2, and 43% of patients with score >2. CONCLUSIONS: These data suggest that embolization of brain AVMs can safely and effectively reduce the treatment volume before radiosurgery. Combined therapy with embolization and radiosurgery does not appear to adversely affect rates of excellent outcome. PMID- 28017743 TI - Embolization of Dural Arteriovenous Fistula of the Cavernous Sinus Through Percutaneous Ultrasound-Guided Puncture of the Facial Vein. AB - BACKGROUND: The goal of dural arteriovenous fistula of the cavernous sinus treated with coils through ultrasound-guided access to the facial vein is to interrupt the fistulous communications and decrease the pressure in the cavernous sinus and consequently in the ophthalmic veins. The traditional approach in the treatment of these fistulae is transvenous endovascular occlusion of the cavernous sinus. Transvenous embolization has been proven to be safe and can provide complete and permanent occlusion of the fistula in a single session. The most commonly used venous pathway is the inferior petrosal sinus, but, if it is inaccessible, then, the superior ophthalmic vein is considered; nonetheless, it can require a surgical exposure. Other pathways include the transfemoral transfacial vein. An arterial approach is considered usually when venous approach pathways fail. Arterial occlusion of feeders supplying the fistula is associated with a greater risk of embolic complications. CASE DESCRIPTION: We report a case of dural arteriovenous fistula of the cavernous sinus treated with coils through ultrasound-guided access to the facial vein. CONCLUSIONS: We propose an alternative pathway when the conventional transvenous approach through the inferior petrosal sinus is excluded. An ultrasound-guided facial vein approach can be considered as a direct and safe alternative to reach the cavernous sinus and obtain exclusion of the fistula. PMID- 28017744 TI - First Case of Primary Sellar/Suprasellar-Intraventricular Ewing Sarcoma: Case Report and Review of the Literature. AB - BACKGROUND: Intracranial Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare and poorly differentiated neoplasms. Immunohistochemical and cytogenetic findings support the possibility of a unique nosologic entity. Primary intracranial localization of this tumor is extremely rare; a few cases are reported in the literature, with only some confirmed by genetic studies. CASE DESCRIPTION: We report a 12-year-old patient with a sellar/suprasellar mass with intraventricular extension that in all its features mimicked a transinfundibular craniopharyngioma. The patient underwent complete resection of the lesion via an endoscopic endonasal transtuberculum approach 6 days after ventriculoperitoneal shunt for acute obstructive hydrocephalus. Histopathologic and genetic examination demonstrated ES/pPNET. The diagnosis was confirmed by detection of a rearrangement of the EWSR1 gene by fluorescent in situ hybridization and identification of the diagnostic t(11;22) translocation by reverse transcriptase polymerase chain reaction. The patient remained in complete clinical remission 12 months after tumor resection followed by adjuvant chemotherapy with no radiologic evidence of tumor recurrence. CONCLUSIONS: To our knowledge, this is the first case of primary intrasellar/suprasellar-intraventricular ES/pPNET confirmed by molecular genetic analysis. Extensive investigations, including pathologic, immunohistochemical, and genetic studies, are needed for differentiation of these tumors from other, more common sellar/suprasellar tumors. Our case highlights that an interdisciplinary therapeutic approach is mandatory to guarantee a favorable outcome. PMID- 28017745 TI - Negative-Pressure Hydrocephalus: A Case Report on Successful Treatment Under Intracranial Pressure Monitoring with Bilateral Ventriculoperitoneal Shunts. AB - BACKGROUND: Negative-pressure hydrocephalus (NegPH), a very rare condition of unknown etiology and optimal treatment, usually presents postneurosurgery with clinical and imaging features of hydrocephalus, but with negative cerebrospinal fluid pressure. CASE DESCRIPTION: We describe a NegPH case of -3 mm Hg intracranial pressure that was successfully treated to achieve 5 mm Hg under continuous intracranial pressure monitoring with horizontal positioning, head down and legs elevated to 10 degrees -15 degrees , neck wrapping for controlled venous drainage, chest and abdomen bandages, infusion of 5% dextrose fluid to lower plasma osmolarity (Na+, 130-135 mmol/L), daily cerebrospinal fluid drainage >200 mL, and arterial blood gas partial pressure of carbon dioxide >40 mm Hg. PMID- 28017746 TI - Outcome Evaluation of Acute Ischemic Stroke Patients Treated with Endovascular Thrombectomy: A Single-Institution Experience in the Era of Randomized Controlled Trials. AB - BACKGROUND: Endovascular thrombectomy is an effective procedure to treat selected ischemic strokes, as shown in recent randomized controlled trials (RCTs). The generalizability of these trial data to real-world settings, however, is unknown. The aim of this study was to examine our single-center experience with endovascular thrombectomy for acute ischemic strokes and perform a comparative outcome analysis to the most recent RCTs. METHODS: We performed a 5-year retrospective analysis, from April 2011 to March 2016, on 66 consecutive patients with acute ischemic stroke who received endovascular thrombectomy at our institution. The Alberta Stroke Program Early CT Score (ASPECTS) and the National Institutes of Health Stroke Scale were used to assess preoperative status. Our primary outcomes were the modified Rankin Score (mRS) at 90 days and recanalization grade measured by the 6-point thrombolysis in cerebral infarction (TICI) grading system. RESULTS: Sixty-six patients received endovascular treatment during the study period. Among the patients examined, 35 (53%) had a favorable outcome (mRS 0-2 at 90 days), 23 (35%) a poor outcome (mRS 3-5), and 8 (12%) died. Successful recanalization (TICI score 3-5) was achieved in 68% of cases. In univariate analysis, patients with good outcome at 90 days had significantly greater ASPECTS, lower National Institutes of Health Stroke Scale, and higher TICI scores. In a multiple logistic regression model, higher ASPECTS and TICI scores were significantly and independently associated with favorable outcome. CONCLUSIONS: Excellent outcomes, as demonstrated by the recent RCTs, can be achieved in clinical practice and reproduced in dedicated tertiary centers. PMID- 28017747 TI - Complications and Management of Large Intracranial Vestibular Schwannomas Via the Retrosigmoid Approach. AB - OBJECTIVE: To investigate the common complications from the microsurgical treatment of large intracranial vestibular schwannoma (VS) via suboccipital retrosigmoid approach and to propose strategies for minimizing such complications. METHODS: We selected all patients with large unilateral VS from the collected database (1999-2013) who underwent microsurgical resection as their initial treatment for histopathologically confirmed VS. Tumors larger than 30 * 20 mm were defined as large. RESULTS: A total of 1167 patients with VS were included. Gross total tumor resection was achieved in 1006 patients (86.2%). The mortality rate is 0.77%. The facial nerve was preserved anatomically in 1083 cases (92.8%), and the functional valuation of the facial nerve according to postoperative House-Brackmann scale showed 423 patients (36.2%) in grades I-II, 534 cases (45.8%) in grade III, and 210 patients (18.0%) in grade IV-VI. The main short-term postoperative complication included new hearing loss (American Institute of Otolaryngology-Head and Neck Surgery grade D) in 634 cases (54.3%), disequilibrium in 250 cases (21.4%), labial herpes in 127 cases (10.9%), meningitis in 115 (9.85%) and lower cranial nerve deficit in 77 cases (6.59%). Follow-up data were available for 978 of the 1167 patients (83.8%). Long-term complications include hearing loss (American Institute of Otolaryngology-Head and Neck Surgery grade D) (75.8%), permanent facial paralysis (11.9%), facial numbness (10.9%), tinnitus (2.96%), chronic headache (2.25%), and taste disturbance (1.43%). CONCLUSIONS: The key factors for reducing surgical complications include careful assessment of the functions of acoustic and facial nerves as well as a thorough understanding of anatomy via the retrosigmoid approach before operation, skillful microsurgical technique, and monitoring of multiple cranial nerves during resection. PMID- 28017748 TI - Spheno-Orbital Meningiomas: A 16-Year Surgical Experience. AB - OBJECTIVE: To examine the efficacy of spheno-orbital meningioma (SOM) resection aimed at symptomatic improvement, rather than gross total resection, followed by radiation therapy for recurrence. METHODS: A retrospective review of all patients having undergone resection between 2000 and 2016 was performed. Demographics, operative details, postoperative outcomes, recurrence rates, and radiation treatment plans were analyzed. Statistical analysis was performed to assess for factors affecting recurrence (Fisher exact and Student t test), changes in exophthalmos index (EI) (Student t test), and progression-free survival (Kaplan Meier and log rank). RESULTS: Twenty-five patients were included; 92% of participants were women. Mean age was 51 years. World Health Organization grades were I (n = 21) and II (n = 4). Simpson grades were I (n = 14), II (n = 3), and IV (n = 8). Mean follow-up time was 44.8 months. Proptosis was significantly improved at the 3- to 6-month postoperative visit (mean DeltaEI, 0.15; P < 0.05) and at last follow-up (mean DeltaEI, 0.13; P < 0.05). Visual acuity was either improved or stable in 18 of 19 patients. There were 12 recurrences; mean time to recurrence was 21.8 months. Increased recurrence rate was significantly associated with younger age. Eight patients received fractionated radiation at time of recurrence. To date, all treated patients are progression free. CONCLUSIONS: Among this cohort, surgery provided a lasting improvement in proptosis and improved or stabilized visual deficits. Surgery followed by radiation at recurrence provided excellent tumor control and lends credence to the growing body of literature demonstrating effective control of subtotally resected skull base meningiomas. PMID- 28017749 TI - General Anesthesia During Endovascular Stroke Therapy Does Not Negatively Impact Outcome. AB - OBJECTIVE: Recent randomized trials have demonstrated that endovascular therapy improves outcomes in patients with an acute ischemic stroke from a large vessel occlusion. Subgroup analysis of the Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) study found that patients undergoing general anesthesia (GA) for the procedure did worse than those with nongeneral anesthesia (non-GA). Current guidelines now suggest that we consider non-GA over GA, without large, randomized trials specifically designed to address this issue. We sought to review our experience and outcomes in a program where we routinely use GA in patients undergoing mechanical thrombectomy with similar techniques. METHODS: Patients with anterior circulation strokes who received intravenous tissue plasminogen activator (IV tPA) and endovascular stroke therapy were included in the analysis. The National Institutes of Health Stroke Scale (NIHSS) on admission and discharge and modified Rankin scale scores at discharge were recorded and compared with the outcome measurements of MR CLEAN. RESULTS: Sixty patients were identified: 39 males and 21 females with a mean age of 62 (range of 29-88). Forty-seven patients were transferred from outside primary stroke centers, while 13 patients presented directly to our institution. Median NIHSS on admission was 15. The median time of symptom onset to endovascular therapy was 265 minutes, with an interquartile range of 81 minutes. Using the thrombolysis in cerebral infarction (TICI) scale, recanalization of TICI 2b-3 was achieved in 76.4% of recorded patients (42/55 recorded). At discharge, mortality was 16.7% (10/60), median NIHSS was 5, and 38.3% (23/60) of patients had a modified Rankin Scale score of 0-2. CONCLUSIONS: General anesthesia does not worsen outcome in patients undergoing mechanical thrombectomy when compared to historical subgroups. Despite a longer time from symptom onset to treatment, our outcomes for patients receiving GA compare favorably to the GA and non-GA groups in MR CLEAN. PMID- 28017750 TI - PulseRider for Treatment of Wide-Neck Bifurcation Intracranial Aneurysms: 6-Month Results. AB - BACKGROUND/OBJECTIVE: PulseRider is a new endovascular stent dedicated to treat bifurcation intracranial aneurysms with a wide neck. Our purpose was to evaluate 6-month clinical and anatomic results of the device when used to facilitate endovascular coiling of wide-neck bifurcation aneurysms. METHODS: Unruptured intracranial aneurysms coiled with PulseRider, in 6 European centers and 1 U.S. center, were retrospectively reviewed from June 2014 to October 2015. Immediate and 6-month results were evaluated independently by using the Raymond classification scale. Recanalization was defined as worsening, and progressive thrombosis was defined as improvement on the Raymond scale. RESULTS: Nineteen patients (10 women, 9 men; mean age, 63 years) harboring 19 bifurcation aneurysms (mean dome size, 8.8 mm; mean neck size, 5.8 mm) were included. Immediate angiographic outcome showed 11 complete aneurysm occlusions, 6 neck remnants, and 2 residual aneurysms. Follow-up at 6 months, obtained in all patients, included 12 complete aneurysm occlusions (63.1%), 6 neck remnants (31.6%), and 1 residual aneurysm (5.3%). Adequate occlusion (defined as complete occlusion and neck remnant combined) was observed in 94.7%. Progressive thrombosis was observed in 2 cases (10.6%) and recanalization in 1 case (5.3%). There was no in-stent stenosis or jailed branch occlusion. No bleeding was observed during the follow-up period. Permanent morbidity rate was 5.3% (1/19), and the mortality rate was 0% at 6 months. CONCLUSIONS: The PulseRider allows endovascular treatment of wide-neck bifurcation intracranial aneurysms. Larger series are needed to confirm our preliminary results. PMID- 28017751 TI - Solitary Fibrous Tumor of Central Nervous System: Clinical and Prognostic Study of 24 Cases. AB - BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors that occasionally occur in the central nervous system (CNS). It is difficult to fully understand their clinical characteristics, partly due to a limited number of reported cases. METHODS: We reviewed 24 patients admitted to our institution between 2009 and 2016 with CNS solitary fibrous tumors. We reviewed and analyzed patient profiles, such as demographics, presentations, imaging studies, extent of resection, and adjuvant treatment. Differences between malignant and benign SFTs were assessed using the chi2 test or Student's t-test. Kaplan-Meier analysis was used to estimate the disease-free survival (DFS) rate. The multivariate Cox regression analysis was performed to evaluate the possible predictive value of the DFS rate of the previously mentioned covariates. RESULTS: A total of 13 men and 11 women were enrolled in the study (the average age was 43). The median follow-up time was 58 months. Twenty-one patients underwent gross total resection (GTR), and 3 patients received a subtotal resection (STR). The tumors in 15 patients (62.5%) were atypical or malignant. One patient (4.2%) suffered SFT related death (multiple organ failure by tumor metastasis), and 3 patients (12.5%) experienced tumor recurrence. We found that a large tumor size (>=10 cm, P < 0.001) and STR (P < 0.001) were negatively associated with the DFS rate. CONCLUSION: CNS SFTs are rare, slow-growing, less aggressive, and recrudescent tumors. Complete resection is the most effective therapy. Large tumor size and STRs might shorten DFS time. PMID- 28017752 TI - A Strategy of Percutaneous Endoscopic Lumbar Discectomy for Migrated Disc Herniation. AB - OBJECTIVE: Percutaneous endoscopic lumbar discectomy (PELD) with remarkable advancements has led to successful results comparable with open discectomy; however, its application in herniated disc (HD) with migration is still challenging and technically demanding. The purpose of this study is to propose various strategies for PELD according to HD with migration. METHODS: A retrospective review was performed on 434 consecutive patients who had undergone PELD. HD with migration was classified into 4 zones: low-grade up/down and high grade up/down based on the extent and direction of migration. Clinical outcomes were assessed by visual analogue scale score for back and leg pain, Oswestry Disability Index, and modified Macnab criteria. Endoscopic approaches and techniques were analyzed depending on HD with migration. RESULTS: A total of 149 patients underwent PELD for HD with migration. There were 93 low-grade down HD patients, 13 high-grade down, 11 low-grade up, and 32 high-grade up. High-grade up HDs were removed with the outside or outside-in techniques from L1-2 to L4-5. High-grade down HDs were removed via the outside technique with additional foraminoplasty. Low-grade up/down HDs with disc space continuity were removed with the inside-out technique. Meanwhile, at the L5-S1 level, interlaminar PELD was used to treat high-grade up/down HD with migration. The mean visual analogue scale score for back pain, leg pain, and Oswestry Disability Index were significantly improved after PELD. Favorable outcome was achieved in 90.6% of cases. CONCLUSIONS: An appropriate strategy for PELD is important for successful removal of HD considering the extent of migration and direction. PMID- 28017754 TI - An Ethiopian Training Program in Neurosurgery with Norwegian Support. AB - After a 4-year planning period, a joint Ethiopian/Norwegian training program in neurosurgery was started in June 2006. The collaborating partners were Addis Ababa University; Department of Surgery, Tikur Anbessa Specialized Hospital; University of Bergen; Haukeland University Hospital; and Myungsung Christian Medical Center, a Korean missionary hospital in Addis Ababa, Ethiopia. A memorandum of understanding was signed at dean/chief executive officer levels. Although other initiatives have been involved in supporting neurosurgery in Addis Ababa during the same period, this institutionally founded program has been the main external contributor to neurosurgical capacity building through the education of 21 Ethiopian neurosurgeons, and in supporting a sustainable environment for neurosurgical training within a network of 5 centers in Addis Ababa. This article gives an account of the strategies underlying the program planning, the history of the program, and on the experience gained by it. Finally, ethical problems and challenges encountered in the program are discussed. PMID- 28017753 TI - Amplitude of Tissue Oxygenation Index Change Predicts Cerebral Hyperperfusion Syndrome During Carotid Artery Stenting. AB - OBJECTIVE: Hyperperfusion syndrome (HPS) after carotid artery stenting (CAS) is a rare but serious complication. HPS is associated with preoperative hemodynamic impairment as the result of poor collateral flow and intraoperative cerebral ischemia. Filter-type embolic protection devices maintain anterograde carotid flow during CAS and prevent HPS somewhat. The early treatment of patients undergoing CAS and at risk for HPS is essential. Near-infrared spectroscopy allows noninvasive, real-time measurement of frontal lobe regional cerebral O2 saturation (TOI; tissue oxygenation index). METHODS: The perioperative amplitude of TOI was monitored in 130 patients undergoing CAS while using a filter-type embolic protection device. Patients were divided retrospectively into good (n = 110) and poor/no crossflow groups (n = 20), and we compared the amplitude of the TOI change, correlation with ipsilateral regional cerebral blood flow, and clinical results. RESULTS: The incidence of HPS was significantly greater in the poor/no crossflow group (P = 0.019). In 2 patients with HPS, the amplitude of the TOI change was V-shaped, with a decrease after postdilatation and an increase above baseline 5 minutes after reperfusion. The TOI/baseline ratio was significantly decreased after internal carotid artery occlusion for postdilatation in the ipsilateral hemisphere in the poor/no crossflow group (P < 0.05). Significant linear correlations were observed between TOI/baseline ratio changes and preoperative cerebrovascular reactivity and the postoperative asymmetry index (r = -0.346, P = 0.002, r = 0.613, P < 0.001, respectively). CONCLUSIONS: The amplitude of the TOI change measured by near-infrared spectroscopy was an excellent predictor of cerebral HPS after CAS. PMID- 28017755 TI - Occipital Artery Pseudoaneurysm After Posterior Fossa Craniotomy. AB - BACKGROUND: Pseudoaneurysms of scalp arteries have been reported in rare cases after iatrogenic injury; however, they are far more commonly seen after traumatic injuries. They are usually associated with the superficial temporal artery; however, there have been a few reports of psuedoaneurysms of the occipital artery (OA). CASE DESCRIPTION: We present a unique case of an OA pseudoaneurysm presenting with delayed postoperative hemorrhage after a retrosigmoid craniotomy. The pseudoaneurysm was treated by coil embolization. CONCLUSIONS: The patient recovered fully after endovascular embolization. Other treatment options for pseudoaneurysms of facial, temporal, and scalp arteries include surgical clipping/trapping with excision, Hunterian ligation, or direct compression. Pseudoaneurysms of extracranial scalp arteries are rare and most often caused by traumatic compression of the artery against a bony ridge. Despite their rarity, pseudoaneurysms secondary to iatrogenic injury to extracranial arteries should be considered in the differential diagnosis in patients presenting with delayed incisional pain, redness, and swelling. PMID- 28017756 TI - A Clinical Comparison of Anterior Cervical Plates Versus Stand-Alone Intervertebral Fusion Devices for Single-Level Anterior Cervical Discectomy and Fusion Procedures. AB - OBJECTIVE: To compare radiologic and clinical outcomes, including rates of dysphagia and dysphonia, using a no-profile stand-alone intervertebral spacer with integrated screw fixation versus an anterior cervical plate and spacer construct for single-level anterior cervical discectomy and fusion (ACDF) procedures. METHODS: This multicenter, randomized, prospective study included 54 patients with degenerative disc disease requiring ACDF at a single level at C3 C7. Twenty-six patients underwent single-level ACDF with stand-alone spacers, and 28 with plate fixation and spacers. Analyses were based on comparison of perioperative outcomes, radiologic and clinical metrics, and incidence of dysphagia and/or dysphonia. RESULTS: Mean patient age was 48.8 +/- 10.1years (53.7% female). No significant differences were observed between groups in operative time (101.8 +/- 34.4 minutes, 114.4 +/- 31.5 minutes), estimated blood loss (44.8 +/- 76.5 mL, 82.5 +/- 195.1 mL), or length of hospital stay (1.2 +/- 0.6 days, 1.3 +/- 0.6 days). Mean visual analog scale pain scores and Neck Disability Index scores improved significantly from preoperative to last follow up (10.8 +/- 2.6 months) in both groups (P < 0.05). Mean Voice Handicap Index and Eating Assessment Tool scores improved significantly from discharge to last follow-up in both groups (P < 0.05). From discharge to 6 months, the stand-alone spacers group consistently demonstrated greater improvement in Voice Handicap Index. Preoperative intervertebral disc and neuroforaminal heights increased significantly across treatment groups (P < 0.01), and no cases required surgical revision at index or adjacent levels. CONCLUSIONS: Anterior cervical discectomy and fusion with stand-alone spacers resulted in similar clinical and radiologic outcomes as compared with plate and spacers and may help minimize postoperative dysphonia. PMID- 28017757 TI - Is Fractionated Gamma Knife Radiosurgery a Safe and Effective Treatment Approach for Large-Volume (>10 cm3) Intracranial Meningiomas? AB - BACKGROUND: Even with great advances in surgery and improved clinical outcome, morbidity and mortality are still high for large-volume intracranial meningiomas (MNGs). Recently, Gamma Knife radiosurgery (GKS) has proven to be a safe and effective treatment for many patients with intracranial MNGs. However, single session GKS may increase the risk of radiation-induced toxicity for large MNGs. Recently, fractionated GKS (FGKS) has been performed for an increasing number of patients with surgically high-risk and large intracranial tumors. In this study, we report our results on the efficacy and safety of FGKS for large MNGs. METHODS: The authors performed a retrospective review of 70 patients who underwent GKS for large-volume (>10 cm3) intracranial MNGs between 2004 and 2015, with a minimum follow-up of 12 months. The authors classified these patients into 2 groups of single-session GKS, FGKS. The patients were followed by clinical examination and serial imaging with magnetic resonance imaging. RESULTS: In the single-session GKS group (42 patients), the median tumor volume was 15.2 cm3 (range 10.3-48.3 cm3); the median prescription dose was 12 Gy (range 8-14 Gy), and the median follow-up duration was 57.8 months (range 14.5-128.4 months). In the FGKS group (28 patients), the median tumor volume was 21 cm3 (range 10.2-54.7 cm3), and the median prescription was 7.5 Gy in 2 fractions (range 5-8 Gy), 6 Gy in 3 fractions (range 5-6.5 Gy), and 4.5 Gy in 4 fractions. The median follow-up duration for the FGKS group was 50 months (range 12.5-90.6 months). The overall 5-year tumor control rate was 92.9% in the FGKS group and 88.1% in the single-session GKS group. Fourteen (33.3%) symptomatic complications after single-session GKS were noted, including 5 cases of hemiparesis, 4 of seizure, 3 of peritumoral edema, and 2 of hydrocephalus. Two (7.1%) symptomatic complications after FGKS were noted, including 2 cases of hemiparesis. The FGKS group had higher progression free survival (PFS) rate at 5 years (92.9% vs. 88.1%), but the differences did not reach statistical significance (P = 0.389). The patients in the FGKS group, however, experienced a lower complication rate compared with patients with a single-session GKS group (P = 0.017, hazard ratio, 5.7:1). CONCLUSION: When the large-volume (>10 cm3) intracranial MNGs are expected to have high morbidity after microsurgery and for patients that have a poor medical status for surgery, FGKS can be considered an alternative with good tumor control and lower complications rates compared with single-session GKS (P = 0.017). PMID- 28017758 TI - Hemodynamic Differences Between Ruptured and Unruptured Cerebral Aneurysms Simultaneously Existing in the Same Location: 2 Case Reports and Proposal of a Novel Parameter Oscillatory Velocity Index. AB - BACKGROUND: Studies have demonstrated certain hemodynamic characteristics featuring the rupture status of cerebral aneurysms using computational fluid dynamics. These studies were conducted based on the comparison of a large number of ruptured and unruptured aneurysms. However, not only aneurysm size and location but also perianeurysm environment, such as hemorrhage and intracranial pressure, affect hemodynamic changes. We hypothesized that a case in which ruptured and unruptured cerebral aneurysms simultaneously exist in the same location would be an ideal model to demonstrate hemodynamic characteristics of the rupture status. CASE DESCRIPTION: We report 2 rare cases with subarachnoid hemorrhage, each of which involved 2 aneurysms at the common parent artery. One patient had 2 anterior communicating artery aneurysms, and the other patient had 2 middle cerebral artery aneurysms. Preoperative morphologic and hemodynamic examinations were performed to diagnose the rupture status of the 2 aneurysms, and each ruptured aneurysm was then confirmed during surgical clipping. Morphologic evaluation revealed higher shape indexes in both ruptured aneurysms. Lower wall shear stress, wall shear stress gradient, and aneurysm formation indicator were observed in both ruptured aneurysms. In contrast, ruptured aneurysms had a higher oscillatory shear index and oscillatory velocity index, which was the novel hemodynamic parameter to quantify the fluctuation of flow velocity vector. CONCLUSIONS: Quantitative characterization of the hemodynamic environment can distinguish the rupture status by using appropriate models minimizing certain bias caused by subarachnoid hemorrhage and aneurysm location. PMID- 28017759 TI - The Monro-Kellie Doctrine in Action: Posterior Reversible Leukoencephalopathy Syndrome Caused by Intracranial Hypotension from Lumboperitoneal Shunt Placement. AB - BACKGROUND: Posterior reversible leukoencephalopathy syndrome (PRES) is linked to various etiologies, including most importantly systemic hypertension. Its association with intracranial hypotension (IH), a potential sequela of various neurosurgical procedures, is underrecognized. We report a case of lumboperitoneal shunt-induced IH resulting in PRES with the goal to increase awareness and elaborate on the potential biologic mechanism, based on the Monro-Kellie hypothesis. CASE DESCRIPTION: A 26-year-old woman with acquired immunodeficiency syndrome and epilepsy was admitted for recurrent cryptococcal meningitis and breakthrough seizures. There was radiologic evidence of ventricular enlargement, and opening pressure on serial lumbar punctures was constantly elevated. Owing to persistently elevated, symptomatic intracranial pressure and transient relief with serial lumbar punctures, a lumboperitoneal shunt was placed. The patient subsequently had a breakthrough seizure and became encephalopathic. Repeat head imaging showed reduced ventricular size, engorged venous sinuses, and tonsillar herniation in keeping with IH, coupled with extensive white matter abnormalities in bilateral parieto-occipital lobes indicative of PRES. The patient had an emergent programmable valve placed in the lumboperitoneal shunt to prevent excessive cerebrospinal fluid drainage, leading to clinical and radiologic improvement. Subsequent cerebrospinal fluid leak resulted in recurrent presentation. CONCLUSIONS: IH appears to be a distinct cause of PRES not previously reported in the neurosurgical literature. It occurs in susceptible patients, on average 1-5 days after the IH trigger, and seems clinically and radiologically similar to more common hypertensive cases in terms of initial presentation and prognosis. Increased vigilance is required for prompt recognition and management. PMID- 28017760 TI - Risk Factors for Chronic Subdural Hematoma Recurrence Identified Using Quantitative Computed Tomography Analysis of Hematoma Volume and Density. AB - OBJECTIVE: Chronic subdural hematoma (CSDH), a common condition in elderly patients, presents a therapeutic challenge with recurrence rates of 33%. We aimed to identify specific prognostic factors for recurrence using quantitative analysis of hematoma volume and density. METHODS: We retrospectively reviewed radiographic and clinical data of 227 CSDHs in 195 consecutive patients who underwent evacuation of the hematoma through a single burr hole, 2 burr holes, or a mini-craniotomy. To examine the relationship between hematoma recurrence and various clinical, radiologic, and surgical factors, we used quantitative image based analysis to measure the hematoma and trapped air volumes and the hematoma densities. RESULTS: Recurrence of CSDH occurred in 35 patients (17.9%). Multivariate logistic regression analysis revealed that the percentage of hematoma drained and postoperative CSDH density were independent risk factors for recurrence. All 3 evacuation methods were equally effective in draining the hematoma (71.7% vs. 73.7% vs. 71.9%) without observable differences in postoperative air volume captured in the subdural space. CONCLUSIONS: Quantitative image analysis provided evidence that percentage of hematoma drained and postoperative CSDH density are independent prognostic factors for subdural hematoma recurrence. PMID- 28017761 TI - Tenofovir alafenamide demonstrates broad cross-genotype activity against wild type HBV clinical isolates and maintains susceptibility to drug-resistant HBV isolates in vitro. AB - Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir (TFV). This study evaluated the antiviral activity of TAF against wild-type genotype A-H HBV clinical isolates as well as adefovir-resistant, lamivudine-resistant, and entecavir-resistant HBV isolates. Full length HBV genomes or the polymerase/reverse transcriptase (pol/RT) region from treatment-naive patients infected with HBV genotypes A-H were amplified and cloned into an expression vector under the control of a CMV promoter. In addition, 11 drug resistant HBV constructs were created by site-directed mutagenesis of a full length genotype D construct. Activity of TAF was measured by transfection of each construct into HepG2 cells and assessment of HBV DNA levels following treatment across a range of TAF concentrations. TAF activity in vitro was similar against wild-type genotype A-H HBV clinical isolates. All lamivudine- and entecavir-resistant isolates and 4/5 adefovir-resistant isolates were found to be sensitive to inhibition by TAF in vitro as compared to the wild-type isolate. The adefovir resistant isolate rtA181V + rtN236T exhibited low-level reduced susceptibility to TAF. TAF is similarly active in vitro against wild-type genotype A-H HBV clinical isolates. The TAF sensitivity results for all drug-resistant isolates are consistent with what has been observed with the parent drug TFV. The in vitro cell-based HBV phenotyping assay results support the use of TAF in treatment of HBV infected subjects with diverse HBV genotypes, in both treatment-naive and treatment-experienced HBV infected patients. PMID- 28017762 TI - Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid. AB - We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. PMID- 28017763 TI - Liquid-core alginate hydrogel beads loaded with functional compounds of radish by products by reverse spherification: Optimization by response surface methodology. AB - Liquid-core hydrogel beads (LHB) were formulated through reverse spherification, by sodium alginate and using calcium lactate (CL) to replace the common calcium source, calcium chloride. The effect of four independent variables: first gelation time (X1), CL concentration in first gelation (X2), secondary gelation time (X3), and CL concentration in secondary gelation (X4), on seven physical properties of LHB: diameter, hardness (Y1), loading efficiency (LE, Y2), release amount of total phenolic compounds (TP) in simulated gastric (Y3) and small intestinal (Y4) fluid, swelling capacity (Y5), and sphericity (Y6), were evaluated. Furthermore, a central composite design with response surface methodology was used for the optimization of LHB properties Y1-Y6, and the importance of the four independent variables to physical properties was analyzed. The diameter of LHB was in the range of 4.17-5.84mm. The optimal conditions of LHB formulation were first gelation time of 23.99min, 0.13M CL in the first gelation, secondary gelation time of 6.04min, and 0.058M CL in secondary gelation. The optimized formulation of LHB demonstrated 25.5N of hardness, 85.67% of LE and 27.38% of TP release in simulated gastric fluid with the small error values (-2.47 to 2.21%). PMID- 28017764 TI - Injectable photo crosslinked enhanced double-network hydrogels from modified sodium alginate and gelatin. AB - Recently, photocrosslinked hydrogels have attracted more and more attention in biomedical applications. In this study, a serials of injectable hydrogels were fabricated from aldehyde methacrylate sodium alginate and amino gelatin (AMSA/AG) using a two-step process. Here, sodium alginate, a kind of natural polysaccharide, was modified by oxidizer to form aldehyde sodium alginate (ASA), and methacrylate groups were further grafted on the main chain of ASA. Gelatin, the denatured form of collagen, was modified with ethylenediamine (ED) to graft more amino groups. When AMSA and AG aqueous solutions were mixed, the Schiff base reaction occurred quickly to form the primary network between aldehyde groups in AMSA and amino groups in AG, and then a 365nm ultraviolet (UV) light was used to initiate the radical reaction of methacrylate groups in AMSA to produce the secondary network. The structures and properties of AMSA/AG hydrogels were evaluated by Fourier Transforms Infrared spectroscopy (FTIR) and 1HNMR analysis. The swelling ratio confirmed the density of crosslinked networks, and the mechanical performance demonstrated that the UV initiated the double crosslinking network hydrogels have an improved mechanical properties compared to the single Schiff base networks hydrogels. The results showed that the photocrosslinked double network hydrogels have enhanced mechanical properties, good biocompatibility and controllable degradation rate. So, this hydrogels may have great potential utilized in regenerative medicine as therapeutic materials. PMID- 28017765 TI - Effects of tamoxifen-loaded solid lipid nanoparticles on the estrogen receptor alpha (ER-alpha) and vascular endothelial growth factor-A (VEGF-A) genes expression in the endometrial tissue of ovariectomized female Sprague-Dawley rats. AB - BACKGROUND: The effect of tamoxifen on endometrial carcinogenesis stems from its estrogen agonist effect. An in vivo study was carried out to compare the effect of tamoxifen-loaded solid lipid nanoparticles and free drug on the ER-alpha and VEGF-A genes expression. MATERIAL AND METHODS: Twenty-four female Sprague-Dawley rats divided into 4 groups of six rats were used for this study. The first and second groups were ovariectomized and given tamoxifen and tamoxifen-loaded SLN respectively for six days continuously. Group 3 served as the untreated ovariectomized control group and group 4 was made up of untreated normal healthy rats. At the end of the study, the rats were sacrificed and study of the genes expression and serum oxidative stress were carried out. RESULTS: The results of this study showed that treatment with tamoxifen-loaded SLN significantly reduced the mRNA levels of ERalpha and VEGF-A gene and the total oxidant status compared to the ovariectomized control group. CONCLUSIONS: The results of this study revealed that encapsulation of tamoxifen in solid lipid nanoparticles may have less adverse effects on the oxidative stress status and incidence of endometrial cancer. PMID- 28017766 TI - Folding and unfolding pathway of chaperonin GroEL monomer and elucidation of thermodynamic parameters. AB - The conformation and thermodynamic stability of monomeric GroEL were studied by CD and fluorescence spectroscopy. GroEL denaturation with urea and dilution in buffer leads to formation of a folded GroEL monomer. The monomeric nature of this protein was verified by size-exclusion chromatography and native PAGE. It has a well-defined secondary and tertiary structure, folding activity (prevention of aggregation) for substrate protein and is resistant to proteolysis. Being a properly folded and reversibly refoldable, monomeric GroEL is amenable for the study of thermodynamic stability by unfolding transition methods. We present the equilibrium unfolding of monomeric GroEL as studied by urea and heat mediated unfolding processes. The urea mediated unfolding shows two transitions and a single transition in the heat mediated unfolding process. In the case of thermal unfolding, some residual structure unfolds at a higher temperature (70-75 degrees C). The process of folding/unfolding is reversible in both cases. Analysis of folding/unfolding data provides a measure of DeltaGNUH2O, Tm, DeltaHvan and DeltaSvan of monomeric GroEL. The thermodynamic stability parameter DeltaGNUH2O is similar with both CD and intrinsic fluorescence i.e. 7.10+/-1.0kcal/mol. The calculated Tm, DeltaHvan and DeltaSvan from the thermal unfolding transition is 46+/-0.5 degrees C, 43.3+/-0.1kcal/mol and 143.9+/-0.1cal/mol/k respectively. PMID- 28017767 TI - Evaluation of in vitro assays for the assessment of the skin sensitization hazard of functional polysiloxanes and silanes. AB - The skin sensitization potential of chemicals has traditionally been evaluated in vivo according to OECD testing guidelines in guinea pigs or the mouse local lymph node assay. There has lately been a great emphasis on establishing in vitro test methods reflecting the key biological events in the adverse outcome pathway (AOP) for skin sensitization as published by the OECD. Against this background, a group of 8 polysiloxanes and silanes, seven of them aminofunctionalised, for which in vivo data were already available, has been tested in vitro in the direct peptide reactivity assay (DPRA), the KeratinoSensTM and the human cell line activation test (h-CLAT) and in the modified myeloid U937 skin sensitization test (mMUSST) as far as technically feasible. The main objective of the programme was to determine the utility of these systems for this heterogeneous group of silicone based substances, recognizing that some substances are outside the assays applicability domains. The presented data provided some interesting mechanistical insights into the performance of these assays for functionalised siloxanes and silanes. The data also allow for a preliminary evaluation of proposed integrated testing strategies (ITS) to determine the skin sensitization potential of chemicals which were not considered in the training sets of the respective ITS. PMID- 28017768 TI - Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. AB - The main objective of this work was to explore the potential of coupling fused deposition modeling in three-dimensional (3D) printing with hot-melt extrusion (HME) technology to facilitate additive manufacturing, in order to fabricate tablets with enhanced extended release properties. Acetaminophen was used as the model drug and different grades and ratios of polymers were used to formulate tablets. Three-point bending and hardness tests were performed to determine the mechanical properties of the filaments and tablets. 3D-printed tablets, directly compressed mill-extruded tablets, and tablets prepared from a physical mixture were evaluated for drug release rates using a USP-II dissolution apparatus. The surface and cross-sectional morphology of the 3D-printed tablets were assessed by scanning electron microscopy. Differential scanning calorimetry and thermogravimetric analysis were used to characterize the crystal states and thermal properties of materials, respectively. The 3D-printed tablets had smooth surfaces and tight structures; therefore, they showed better extended drug release rates than the directly compressed tablets did. Further, this study clearly demonstrated the feasibility of coupling HME with 3D printing technology, which allows for the formulation of drug delivery systems using different grades and ratios of pharmaceutical polymers. In addition, formulations can be made based on the personal needs of patients. PMID- 28017769 TI - Apoferritin nanocage as streptomycin drug reservoir: Technological optimization of a new drug delivery system. AB - The aim of this study is to formulate and characterize streptomycin-loaded apoferritin nanoparticles (ApoStrep NPs) for their potential therapeutic use in bacterial resistant infections (i.e. tuberculosis). ApoStrep NPs were prepared by disassembly/reassembly process via pH method and changing apoferritin/drug molar ratio, purified by dialyses process also associated with gel filtration chromatography and characterized in their chemico-physical and technological parameters as yield, size distribution, polidispersivity, morphology, internal structure, zeta potential and loading efficacy. The results showed that spherical reproducible NPs could be obtained by using apoferritin/drug molar ratio lower than 1:25 and purification based on the combination of dialysis and gel filtration chromatography. Photon correlation spectroscopy, Uv-visible detection and electron microscopy showed the maintenance of the native apoferritin chemico physical properties and structure. When formulated with apoferritin/drug 1:10 and 1:25 molar ratio, ApoStrep NPs showed remarkable encapsulation efficacy (35% and 28%, respectively) along with kinetic profile of drug delivery, approximately 15% at 37 degrees C in 72h, as evidenced by "in vitro" release experiments. PMID- 28017770 TI - Efficient gene delivery to primary human retinal pigment epithelial cells: The innate and acquired properties of vectors. AB - The purpose of this study is designing non-viral gene delivery vectors for transfection of the primary human retinal pigment epithelial cells (RPE). In the design process of gene delivery vectors, considering physicochemical properties of vectors alone does not seem to be enough since they interact with constituents of the surrounding environment and hence gain new characteristics. Moreover, due to these interactions, their cargo can be released untimely or undergo degradation before reaching to the target cells. Further, the characteristics of cells itself can also influence the transfection efficacy. For example, the non dividing property of RPE cells can impede the transfection efficiency which in most studies was ignored by using immortal cell lines. In this study, vectors with different characteristics differing in mixing orders of pDNA, PEI polymer, and PLGA/PEI or PLGA nanoparticles were prepared and characterized. Then, their characteristics and efficacy in gene delivery to RPE cells in the presence of vitreous or fetal bovine serum (FBS) were evaluated. All formulations showed no cytotoxicity and were able to protect pDNA from premature release and degradation in extracellular media. Also, the adsorption of vitreous or serum proteins onto the surface of vectors changed their properties and hence cellular uptake and transfection efficacy. PMID- 28017771 TI - Synthesis of asymmetric movement trajectories in timed rhythmic behaviour by means of frequency modulation. AB - Results from different empirical investigations on gestural aspects of timed rhythmic movements indicate that the production of asymmetric movement trajectories is a feature that seems to be a common characteristic of various performances of repetitive rhythmic patterns. The behavioural or neural origin of these asymmetrical trajectories is, however, not identified. In the present study we outline a theoretical model that is capable of producing syntheses of asymmetric movement trajectories documented in empirical investigations by Balasubramaniam et al. (2004). Characteristic qualities of the extension/flexion profiles in the observed asymmetric trajectories are reproduced, and we conduct an experiment similar to Balasubramaniam et al. (2004) to show that the empirically documented movement trajectories and our modelled approximations share the same spectral components. The model is based on an application of frequency modulated movements, and a theoretical interpretation offered by the model is to view paced rhythmic movements as a result of an unpaced movement being "stretched" and "compressed", caused by the presence of a metronome. We discuss our model construction within the framework of event-based and emergent timing, and argue that a change between these timing modes might be reflected by the strength of the modulation in our model. PMID- 28017772 TI - Novel beta-carboline-quinazolinone hybrids disrupt Leishmania donovani redox homeostasis and show promising antileishmanial activity. AB - Visceral Leishmaniasis is a deadly parasitic disease caused by Leishmania donovani. Paucity exists in the discovery of novel chemotherapeutics against Leishmaniasis. In this study, we synthesized a natural product inspired Diversity Oriented Synthesis library of L. donovani Trypanothione reductase (LdTR) inhibitor beta-carboline-quinazolinone hybrids, which are different in stereochemical architecture and diverse in the bioactive chemical space. It is noteworthy that chirality affects drug-to-protein binding affinity since proteins in any living system are present only in one of the chiral forms. Upon evaluation of the hybrids, one of the chiral forms i.e. Compound 1 showed profound cytotoxic effect in micromolar range as compared to its other chiral form i.e. Compound 2. In-silico docking studies confirmed high binding efficiency of Compound 1 with the catalytic pocket of LdTR. Treatment of L. donovani parasites with Compound 1 inhibits LdTR activity, induces imbalance in redox homeostasis by enhancing ROS, disrupts the mitochondrial membrane potential, modifies actin polymerization and alters the surface topology and architecture. All these cellular modifications eventually led to apoptosis-like death of promastigotes. Furthermore, we synthesized the analogues of Compound 1 and found that these compounds show profound antileishmanial activity in the nanomolar range both in promastigotes and intracellular amastigotes. The enhanced inhibitory potential of these compounds was further supported by in-silico analysis of protein-ligand interactions which revealed high binding efficiency towards the catalytic pocket of LdTR. Taken together, this study reports the serendipitous discovery of beta carboline-quinazolinone hybrids with enhanced antileishmanial activity along with the in-depth structure-activity relationships and mechanism of action of these analogues. PMID- 28017773 TI - Antileishmanial activity of verbascoside: Selective arginase inhibition of intracellular amastigotes of Leishmania (Leishmania) amazonensis with resistance induced by LPS plus IFN-gamma. AB - Verbascoside is the main component of the traditional medicinal plants that were used against protozoa parasites that cause malaria and leishmaniasis. Previously, we have described verbascoside inhibition of Leishmania amazonensis arginase as well as its antileishmanial action against extracellular promastigotes. In this study, we have assessed arginase parasite inhibition in intracellular amastigotes. In addition, we verified whether verbascoside can influence the host defense against the parasite by measuring gene expression of cytokines IL-1b, IL 10, IL-18, TNF-alpha and murine macrophage arginase as well as nitric oxide synthase enzymes. Our results show that verbascoside acts on intracellular amastigotes of L. amazonensis (EC50=32MUM) by selectively inhibiting the parasite arginase. Verbascoside did not affect the expression of cytokines or enzymes by murine macrophages. However, verbascoside was active against L. (L.) amazonensis amastigotes that were resistant to treatment with LPS and IFN-gamma. Verbascoside action on L. amazonensis can be associated with reduction of the protective oxidative mechanism of the parasite leading to impaired trypanothione synthesis that is induced by the parasite arginase inhibition. PMID- 28017774 TI - Identification of esterase involved in the metabolism of two corticosteroid soft drugs. AB - The soft drug approach is successful in obtaining high local therapeutic efficacy without systemic adverse effects, because soft drugs are designed to be bioconverted to inactive form by hydrolytic enzymes in systemic circulation. However, there is little information about the exact nature of these metabolic enzymes. In this study, the human enzymes for biotransformation of soft drugs were investigated. Loteprednol etabonate (LE) and etiprednol dicloacetate (ED) were designed from Delta1-cortienic acid (Delta1-CA), the inactive metabolite of prednisolone, by introducing two labile ester bonds to restore the corticosteroidal activity. We found that LE and ED were mainly deactivated in human plasma rather than the liver. Inactive monoesters were produced, but the second hydrolysis to Delta1-CA was much slower. ED was hydrolyzed 10 times faster than LE in plasma (t1/2=1.35+/-0.08, 12.07+/-0.52h respectively). Paraoxonase 1 that attached with high density lipoprotein (HDL) was found to be the major hydrolase for LE and ED in human plasma as demonstrated by enzyme inhibition and stimulation experiments and the hydrolysis in lipoproteins-rich plasma fractions. Human serum albumin (HSA) showed slight hydrolase activity against ED but not LE. LE was slowly hydrolyzed in liver (clearance: 0.21+/-0.04 and 2.41+/-0.13ml/h/kg in liver and plasma, respectively) but ED wasn't hydrolyzed at all, so LE has superior metabolism in two sites. The difficult diffusion of HDL into tissues from blood suggests the stable presence of LE at the administration site, while ED might be deactivated by its relatively rapid chemical hydrolysis and hydrolase activity of HSA, in the interstitial fluid of the administration tissue. Moreover, deactivation in plasma and strong protein binding (around 98%) minimize the adverse effects of LE and ED in the systemic circulation. PMID- 28017775 TI - The network of immunosuppressive pathways in glioblastoma. AB - Glioblastoma remains a fatal tumor despite increased knowledge regarding the complex signalling pathways that drive this devastating disease. Recently, immunotherapeutic approaches have shown remarkable and durable responses in various cancers including metastatic melanoma and advanced non-small cell lung cancer. So far, it remains unclear whether these immunotherapeutics may also work against glioblastoma and other tumors residing in the central nervous system. It is well known that patients with glioblastoma suffer from profound local immunosuppression that represents the major hurdle to overcome in the context of immunotherapy. Several studies have demonstrated that this immunosuppressive phenotype is orchestrated by glioma-derived membrane-bound and soluble factors as well as the particular microenvironment within the brain. Here, we discuss the molecular and cellular pathways involved in glioblastoma-mediated inhibition of the immune system and highlight possible treatment approaches aiming at reinvigorating anti-tumor immune responses. PMID- 28017776 TI - Nobiletin inhibits oxidized-LDL mediated expression of Tissue Factor in human endothelial cells through inhibition of NF-kappaB. AB - INTRODUCTION: Flavonoids are nutrients usually included in human diet with several significant biological activities. Nobiletin is a flavonoid that, besides having anti-inflammatory and anti-tumoral activity, seems to exert protective effects on cardiovascular system. Several studies investigated nobiletin as a natural drug to antagonize the atherosclerotic disease. On the contrary, literature about its potential role in modulating the main acute complication of atherosclerosis, thrombosis, is still scanty. Several studies have indicated that Tissue Factor (TF) plays a pivotal role in the pathophysiology of cardiovascular thrombotic events by triggering the formation of intracoronary thrombi. Oxidized LDL have an important role in promoting athero-thrombotic events. This study investigates whether nobiletin might exert protective cardiovascular effects by preventing the oxidized-LDL mediated expression of TF in human endothelial cells in vitro. Moreover, we have studied whether the nobiletin effects might be modulated by the inhibition of the NF-kappaB pathway. METHODS AND RESULTS: In HUVEC, ox-LDL induced TF-mRNA transcription as demonstrated by real time PCR and expression of functionally active TF as demonstrated by Western-blot, FACS analysis and pro-coagulant activity assay. Nobiletin prevented these ox-LDL mediated effects by exerting antioxidant effects, finally leading to inhibition of the transcription factor NF-kappaB. CONCLUSIONS: These data suggest that nobiletin might be a potential antithrombotic agent of dietary origin. This flavonoid, through its antioxidant proprieties, might potentially exert an antithrombotic activity by inhibiting TF expression/activity in a cell population never investigated before in this context and that is normally represented in vessel wall such as endothelial cells. PMID- 28017777 TI - The cardioprotective effect of sildenafil is mediated by the activation of malate dehydrogenase and an increase in the malate-aspartate shuttle in cardiomyocytes. AB - Recent evidence has shown the cardioprotective effect of PDE5 inhibition in myocardial ischemia/reperfusion injury, heart failure and cardiac hypertrophy. To investigate the biochemical changes that occur during PDE5 inhibition in cardiac cells, this study assessed the metabolic profile of the HL1 cell line, a murine atrial cell line with adult cardiomyocyte properties. After one hour of treatment with sildenafil, glycolysis was moderately but selectively stimulated, unlike the pentose phosphate pathway and the Krebs cycle. Moreover, malate and a Ketoglutarate accumulated, paralleled by a decrease in aspartate and glutamate. Interestingly, increased activity of malate dehydrogenase (MDH) was also detected in these cells after sildenafil treatment. Thus, we hypothesized that sildenafil stimulates the malate-aspartate shuttle (MAS) with the final effect of transferring electrons and protons from glycolysis-derived cytosolic NADH into the matrix for use by the electron transport chain, using malate as an electron carrier. Through this metabolic modification, sildenafil may counteract what is often observed in ischemia, i.e. reduced MAS flux as well as a dramatic acceleration of glycolysis, which switches to lactate production. Additionally, the results observed in HL1 cells were also found in isolated mouse hearts. The documented metabolic alteration in cardiomyocytes upon treatment with sildenafil occurred by stimulating cGMP production, which did not activate PKG (cGMP-PKG signaling), since the addition of DT-2, a PKG inhibitor, did not block malate accumulation and increased MDH activity. Conversely, the addition of chelerythrine, a PKC inhibitor, counteracted both malate accumulation and MAS activation, supporting previous evidence that, upon the addition of sildenafil, some PKC isoforms may be implicated in cardioprotection (cGMP-PKC signaling). Interestingly, an increase in cGMP, driven by sildenafil, another cGMP stimulator such as nitroprusside (SNP), or a C-type natriuretic peptide (CNP) which does not inhibit PDE5, led to MAS stimulation and increased MDH activity. PMID- 28017779 TI - Electroencephalographic frontal synchrony and caudal asynchrony during painful hand immersion in cold water. AB - Recent studies in our laboratory showed that cortical theta oscillations correlate with pain in rodent models. In this study, we sought to validate our pre-clinical data using EEG recordings in humans during immersion of the hand in ice cold water, a moderately noxious stimulus. Power spectral analysis shows that an increase in pain score is associated with an increase in power amplitude within a frequency range of 6-7Hz at the frontal (Fz) electrode. These results are consistent with our previous pre-clinical animal studies and the clinical literature. We also report a novel reduction in power at the caudal (O1) electrode within a broader 3-30Hz rand and decreased coherence between Fz and C3, C4 electrodes within the theta (4-8Hz) and low beta (13-21Hz) bands, while coherence (an indirect measure of functional connectivity) between Fz and O1 increased within the theta and alpha (8-12Hz) bands. We argue that pain is associated with EEG frontal synchrony and caudal asynchrony, leading to the disruption of cortico-cortical connectivity. PMID- 28017778 TI - RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G+-bacterial toxins. AB - Disruption of the endothelial barrier in response to Gram positive (G+) bacterial toxins is a major complication of acute lung injury (ALI) and can be further aggravated by antibiotics which stimulate toxin release. The integrity of the pulmonary endothelial barrier is mediated by the balance of disruptive forces such as the small GTPase RhoA, and protective forces including endothelium derived nitric oxide (NO). How NO protects against the barrier dysfunction is incompletely understood and our goal was to determine whether NO and S nitrosylation can modulate RhoA activity and whether this mechanism is important for G+ toxin-induced microvascular permeability. We found that the G+ toxin listeriolysin-O (LLO) increased RhoA activity and that NO and S-NO donors inhibit RhoA activity. RhoA was robustly S-nitrosylated as determined by biotin-switch and mercury column analysis. MS revealed that three primary cysteine residues are S-nitrosylated including cys16, cys20 and cys159. Mutation of these residues to serine diminished S-nitrosylation to endogenous NO and mutant RhoA was less sensitive to inhibition by S-NO. G+-toxins stimulated the denitrosylation of RhoA which was not mediated by S-nitrosoglutathione reductase (GSNOR), thioredoxin (TRX) or thiol-dependent enzyme activity but was instead stimulated directly by elevated calcium levels. Calcium-promoted the direct denitrosylation of WT but not mutant RhoA and mutant RhoA adenovirus was more effective than WT in disrupting the barrier integrity of human lung microvascular endothelial cells. In conclusion, we reveal a novel mechanism by which NO and S-nitrosylation reduces RhoA activity which may be of significance in the management of pulmonary endothelial permeability induced by G+-toxins. PMID- 28017780 TI - Acute effects of aceclofenac, COX-2 inhibitor, on penicillin-induced epileptiform activity. AB - PURPOSE: The effects of COX-2 inhibitors on seizure activity are controversial. The aim of the current study was to determine the post-treatment effect of aceclofenac on penicillin-induced experimental epilepsy. METHODS: Male Wistar rats were used in all experiments (n=18). The seizure activity was triggered by penicillin (i.c.). Aceclofenac was injected intraperitoneally at doses of 10mg/kg and 20mg/kg. RESULTS: Intraperitoneal administration of 10 and 20mg/kg aceclofenac doses, exhibited proconvulsant properties on seizure activity on rats. The mean spike frequency and amplitude of aceclofenac 10mg/kg were 41.89+/ 2.12 spike/min and 0.619+/-0.094mV, respectively. The mean spike frequency and amplitude of aceclofenac 20mg/kg were 35.26+/-2.72 spike/min and 0.843+/-0.089mV, respectively. CONCLUSION: The results indicated that not all of the COX-2 inhibitors may have anticonvulsant or proconvulsant features on patients with epilepsy susceptibility and must be used with great care. It was also suggested that not only cyclooxygenase metabolic pathway but also lipoxygenase pathway should be considered together in further detailed studies. PMID- 28017781 TI - Inotropic support against early brain injury improves cerebral hypoperfusion and outcomes in a murine model of subarachnoid hemorrhage. AB - Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2.5h after SAH induction or concomitant intravenous dobutamine infusion (15MUg/kg/min) with or without HIF inhibitor 2-methoxyestradiol (2ME2) (10mg/kg) administered intraperitoneally. Neurobehavioral function was assessed daily by neurological scores and open field testing. DCI was defined 3days later by detecting a new infarction on MRI. Global CBF depression was notable early after SAH, but dobutamine showed significant improvement in CBF, lower incidence of DCI, and better recovery of neuroscores and open field test variables compared with isoflurane postconditioning (P<0.05). CBF over the entire brain on day 1 predicted DCI with a cut-off of 36.5ml/100g/min (80% specificity and 67% sensitivity), with a better area under the curve (0.83 versus 0.75) than the hemispheric CBF measured on the perforated side. The dobutamine-mediated outcomes were attenuated (P<0.05) by 2ME2 pretreatment. The data suggest that cardiac support with dobutamine improves global CBF depression induced by early brain injury, leading to reduced prevalence of DCI and better functional outcomes after experimental SAH, in which HIF may be acting as a critical mediator. PMID- 28017783 TI - Anti-apoptotic and angiogenic effects of intelectin-1 in rat cerebral ischemia. AB - Ischemic stroke is an acute life-threatening disease, which causes neurological dysfunction. The formation of new blood vessels around the infarct is vital to the restoration of perfusion and healing of brain tissue. Studies have shown that intelectin-1 (omentin) promotes endothelial cell function and angiogenesis in response to ischemia and inhibits apoptosis in rats with unilateral hind limb surgery. In the present study, we investigated the neuroprotective role of intelectin-1 following focal cerebral ischemia. We specifically assessed the effect of increased expression of intelectin-1 in promoting angiogenesis and reducing apoptosis. The treatment was administered using a lentiviral vector, 7 days prior to surgery. The surgery was performed using the established middle cerebral artery occlusion (MCAO) model in rats, and the outcome was evaluated 7 days after injury. Our results demonstrated a significant reduction in brain infarction volume following LV-intelectin-1 treatment. Additionally, CD34 and capillary density were increased in the cerebral ischemic penumbra. Real-time PCR and Western blot revealed an increased expression of intelectin-1, and phosphorylation of eNOS and AKT with enhanced expression of bcl-2 in brain tissues. These data suggest that the successful delivery of LV-intelectin-1 ameliorated ischemic brain injury. It promoted endothelial cell function and revasc ularization, and inhibited apoptosis in response to ischemia by stimulating the Akt-eNOS signaling pathway. PMID- 28017784 TI - Ecophysiological perspectives on engineered nanomaterial toxicity in fish and crustaceans. AB - Engineered nanomaterials (ENMs) are incorporated into numerous industrial, clinical, food, and consumer products and a significant body of evidence is now available on their toxicity to aquatic organisms. Environmental ENM concentrations are difficult to quantify, but production and release estimates suggest wastewater treatment plant effluent levels ranging from 10-4 to >101MUgL 1 for the most common formulations by production volume. Bioavailability and ENM toxicity are heavily influenced by water quality parameters and the physicochemical properties and resulting colloidal behaviour of the particular ENM formulation. ENMs generally induce only mild acute toxicity to most adult fish and crustaceans under environmentally relevant exposure scenarios; however, sensitivity may be considerably higher for certain species and life stages. In adult animals, aquatic ENM exposure often irritates respiratory and digestive epithelia and causes oxidative stress, which can be associated with cardiovascular dysfunction and the activation of immune responses. Direct interactions between ENMs (or their dissolution products) and proteins can also lead to ionoregulatory stress and/or developmental toxicity. Chronic and developmental toxicity have been noted for several common ENMs (e.g. TiO2, Ag), however more data is necessary to accurately characterize long term ecological risks. The bioavailability of ENMs should be limited in saline waters but toxicity has been observed in marine animals, highlighting a need for more study on possible impacts in estuarine and coastal systems. Nano-enabled advancements in industrial processes like water treatment and remediation could provide significant net benefits to the environment and will likely temper the relatively modest impacts of incidental ENM release and exposure. PMID- 28017782 TI - Parkin and PINK1 functions in oxidative stress and neurodegeneration. AB - Loss-of-function mutations in the genes encoding Parkin and PINK1 are causally linked to autosomal recessive Parkinson's disease (PD). Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial-targeted kinase, function together in a common pathway to remove dysfunctional mitochondria by autophagy. Presumably, deficiency for Parkin or PINK1 impairs mitochondrial autophagy and thereby increases oxidative stress due to the accumulation of dysfunctional mitochondria that release reactive oxygen species. Parkin and PINK1 likely have additional functions that may be relevant to the mechanisms by which mutations in these genes cause neurodegeneration, such as regulating inflammation, apoptosis, or dendritic morphogenesis. Here we briefly review what is known about functions of Parkin and PINK1 related to oxidative stress and neurodegeneration. PMID- 28017785 TI - Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. AB - Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging. PMID- 28017786 TI - Overprotective social support leads to increased cardiovascular and subjective stress reactivity. AB - OBJECTIVE: Self-determination theory suggests that autonomy-enhancing social support helps individuals to perceive stressors as challenging rather than stressing. Overprotective support may reduce stress in the short-run but undermines autonomy, thus hampering stress-coping in the long run, particularly when social support is terminated. METHOD: Heartrate, blood-pressure and ratings were examined in N=44 undergraduate students receiving autonomy support (calculation steps) or overprotection (solutions) from a close friend or no support for solving arithmetic tasks as well as during a subsequent stress challenge (solving arithmetic tasks alone). RESULTS: Overprotection resulted in increased heartrate, diastolic blood-pressure, stress ratings, and decreased subjective control during stress-challenge. Autonomy support did not lead to unfavorable stress responding. CONCLUSION: The current findings are in line with assumptions derived from self-determination theory and indicate that autonomy support can help to prevent stress. Overprotection does not buffer stress and is associated with increased stress when discontinued. PMID- 28017787 TI - Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial. AB - INTRODUCTION: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial. METHODS: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC. RESULTS: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events. CONCLUSIONS: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study). PMID- 28017788 TI - Association of Serum Anti-GAD Antibody and HLA Haplotypes with Type 1 Diabetes Mellitus Triggered by Nivolumab in Patients with Non-Small Cell Lung Cancer. PMID- 28017789 TI - Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non Small Cell Lung Cancer. AB - EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design. PMID- 28017791 TI - Conditions to minimize soft single biomolecule deformation when imaging with atomic force microscopy. AB - A recurrent interrogation when imaging soft biomolecules using atomic force microscopy (AFM) is the putative deformation of molecules leading to a bias in recording true topographical surfaces. Deformation of biomolecules comes from three sources: sample instability, adsorption to the imaging substrate, and crushing under tip pressure. To disentangle these causes, we measured the maximum height of a well-known biomolecule, the tobacco mosaic virus (TMV), under eight different experimental conditions positing that the maximum height value is a specific indicator of sample deformations. Six basic AFM experimental factors were tested: imaging in air (AIR) versus in liquid (LIQ), imaging with flat minerals (MICA) versus flat organic surfaces (self-assembled monolayers, SAM), and imaging forces with oscillating tapping mode (TAP) versus PeakForce tapping (PFT). The results show that the most critical parameter in accurately measuring the height of TMV in air is the substrate. In a liquid environment, regardless of the substrate, the most critical parameter is the imaging mode. Most importantly, the expected TMV height values were obtained with both imaging with the PeakForce tapping mode either in liquid or in air at the condition of using self-assembled monolayers as substrate. This study unambiguously explains previous poor results of imaging biomolecules on mica in air and suggests alternative methodologies for depositing soft biomolecules on well organized self-assembled monolayers. PMID- 28017790 TI - The CB1 receptor is required for the establishment of the hyperlocomotor phenotype in developmentally-induced hypothyroidism in mice. AB - Alterations in motor functions are well-characterized features observed in humans and experimental animals with thyroid hormone dysfunctions during development. We have previously suggested the implication of the endocannabinoid system in the hyperlocomotor phenotype observed in developmentally induced hypothyroidism in rats. In this work we have further analyzed the implication of endocannabinoids in the effect of hypothyroidism on locomotor activity. To this end, we evaluated the locomotor activity in adult mice lacking the cannabinoid receptor type 1 (CB1R-/-) and in their wild type littermates (CB1R+/+), whose hypothyroidism was induced in day 12 of gestation and maintained during the experimental period. Our results show that hypothyroidism induced a hyperlocomotor phenotype only in CB1R+/+, but not in CB1R-/- mice. In contrast with our previous results in rats, the expression of CB1R in striatum and the motor response to the cannabinoid agonist HU210 was unaltered in hypothyroid CB1R+/+ mice suggesting that the cannabinoid system is not altered by hypothyroidism. Also, no effect of HU210 was observed in locomotion of CB1R-/- mice. Finally, since the dopaminergic system plays a major role in the control of locomotor activity we studied its function in hypothyroid wild type and knockout animals. Our results show no alteration in the behavioral response induced by the dopamine D1 receptor agonist SKF38393. However we observed a decreased response to the dopamine D2 receptor antagonist haloperidol only in hypothyroid CB1R+/+ mice, which might indicate potential alterations in D2R signaling in these animals. In conclusion, our data suggest that the cannabinoid system is necessary for the induction of hyperlocomotor phenotype in mice with developmentally induced hypothyroidism. PMID- 28017792 TI - VISLISI trial, a prospective clinical study allowing identification of a new metalloprotease and putative virulence factor from Staphylococcus lugdunensis. AB - OBJECTIVE: Staphylococcus lugdunensis is a coagulase-negative staphylococcus that displays an unusually high virulence rate close to that of Staphylococcus aureus. It also shares phenotypic properties with S. aureus and several studies found putative virulence factors. The objective of the study was to describe the clinical manifestations of S. lugdunensis infections and investigate putative virulence factors. METHOD: We conducted a prospective study from November 2013 to March 2016 at the University Hospital of Strasbourg. Putative virulence factors were investigated by clumping factor detection, screening for proteolytic activity, and sequence analysis using tandem nano-liquid chromatography-mass spectrometry. RESULTS: In total, 347 positive samples for S. lugdunensis were collected, of which 129 (37.2%) were from confirmed cases of S. lugdunensis infection. Eighty-one of these 129 patients were included in the study. Bone and prosthetic joints (PJI) were the most frequent sites of infection (n=28; 34.6%) followed by skin and soft tissues (n=23; 28.4%). We identified and purified a novel protease secreted by 50 samples (61.7%), most frequently associated with samples from deep infections and PJI (pr 0.97 and pr 0.91, respectively). Protease peptide sequencing by nano-liquid chromatography-mass spectrometry revealed a novel protease bearing 62.42% identity with ShpI, a metalloprotease secreted by Staphylococcus hyicus. CONCLUSION: This study confirms the pathogenicity of S. lugdunensis, particularly in bone and PJI. We also identified a novel metalloprotease called lugdulysin that may contribute to virulence. PMID- 28017793 TI - Narrow-spectrum beta-lactam monotherapy in hospital treatment of community acquired pneumonia: a register-based cohort study. AB - OBJECTIVES: To assess the clinical effect of empirical treatment with narrow spectrum beta-lactam monotherapy (NSBM) versus broad-spectrum beta-lactam monotherapy (BSBM) in non-severe community-acquired pneumonia (CAP). METHODS: Hospitalized patients >=18 years with CAP who received initial NSBM or BSBM, with a severity score according to CRB-65<=2 (C=confusion, R=respiratory rate >30/min, B=systolic blood pressure <90 mmHg or diastolic blood pressure <=60 mmHg, 65= >=65 years), in the Swedish Pneumonia Register from 2008 to 2011 were included. Primary outcome was 30-day mortality. Secondary outcomes were 90-day mortality, treatment at intensive care unit (ICU), and length of stay (LOS). Propensity score matching was performed to account for differences in baseline characteristics. RESULTS: There were 5961 patients with CRB-65<=1 and 1344 patients with CRB-65=2. In the propensity score matched cohorts the 30-day mortality was 40/1827 (2.2%) with NSBM and 56/1827 (3.1%) with BSBM in CRB-65<=1, and 57/524 (10.9%) and 51/524 (9.7%), respectively, in CRB-65=2. No significant differences in 30-day mortality were observed between NSBM and BSBM in patients with CRB-65<=1 or CRB-65=2, OR 1.41 (95% CI 0.94-2.14) and 0.88 (95% CI 0.59 1.32), respectively. There was no significant difference in 90-day mortality. Patients who received BSBM were more often treated at ICU and had longer LOS. CONCLUSIONS: Empirical NSBM appears to be effective in the majority of hospitalized immunocompetent adults with non-severe CAP and should be further evaluated in randomized trials. PMID- 28017795 TI - Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle. AB - In vivo reprogramming is a promising approach for tissue regeneration in response to injury. Several examples of in vivo reprogramming have been reported in a variety of lineages, but some including skeletal muscle have so far proven refractory. Here, we show that acute and chronic injury enables transcription factor-mediated reprogramming in skeletal muscle. Lineage tracing indicates that this response frequently originates from Pax7+ muscle stem cells. Injury is associated with accumulation of senescent cells, and advanced aging or local irradiation further enhanced in vivo reprogramming, while selective elimination of senescent cells reduced reprogramming efficiency. The effect of senescence appears to be, at least in part, due to the release of interleukin 6 (IL-6), suggesting a potential link with the senescence-associated secretory phenotype. Collectively, our findings highlight a beneficial paracrine effect of injury induced senescence on cellular plasticity, which will be important for devising strategies for reprogramming-based tissue repair. PMID- 28017794 TI - Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers. AB - In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration, and angiogenesis compared to UMC-iPSC-ECs and control cells. The "rescued" phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and was independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies. PMID- 28017797 TI - General method for the quantification of drug loading and release kinetics of nanocarriers. AB - Macromolecular nanostructures that are used as drug carriers are characterized by their loading and release kinetics. Release studies commonly employ the dialysis method, in which a cellulose membrane separates the solution of released drug from the nanocarrier solution. We demonstrate that it is necessary to take the effect of the dialysis membrane on the release kinetics into account. Using a two step approach, consisting of a calibration experiment of drug diffusion through the dialysis membrane in the absence of nanocarriers, and an experiment in the presence of nanocarriers, we are able to determine all kinetic rates and in particular to disentangle kinetic dialysis membrane properties from kinetic nanocarrier properties. We apply our general approach to experimental dexamethasone release data from core-multishell nanocarriers and demonstrate that our method yields a consistent description of the nanocarrier release kinetics. PMID- 28017796 TI - Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity. AB - Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ~50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications. PMID- 28017798 TI - N-glycosylation influences the catalytic activity of mosquito alpha-glucosidases associated with susceptibility or refractoriness to Lysinibacillus sphaericus. AB - Cqm1 and Aam1 are alpha-glucosidases (EC 3.2.1.20) expressed in Culex quinquefasciatus and Aedes aegypti larvae midgut, respectively. These orthologs share high sequence similarity but while Cqm1 acts as a receptor for the Binary (Bin) insecticidal toxin from Lysinibacillus sphaericus, Aam1 does not bind the toxin, rendering Ae. aegypti refractory to this bacterium. Aam1 is heavily glycosylated, contrasting to Cqm1, but little is known regarding how glycosylation impacts on its function. This study aimed to compare the N glycosylation patterns and the catalytic activities of Aam1 and Cqm1. Mutant proteins were generated where predicted Aam1 N-glycosylation sites (N-PGS) were either inserted into Cqm1 or abrogated in Aam1. The mutants validated four N-PGS which were found to localize externally on the Aam1 structure. These Aam1 and Cqm1 mutants maintained their Bin binding properties, confirming that glycosylation has no role in this interaction. The alpha-glucosidase activity of both proteins was next investigated, with Aam1 having a remarkably higher catalytic efficiency, influenced by changes in glycosylation. Molecular dynamics showed that glycosylated and nonglycosylated Aam1 models displayed distinct patterns that could influence their catalytic activity. Differential N glycosylation may then be associated with higher catalytic efficiency in Aam1, enhancing the functional diversity of related orthologs. PMID- 28017800 TI - Viral mouse models of multiple sclerosis and epilepsy: Marked differences in neuropathogenesis following infection with two naturally occurring variants of Theiler's virus BeAn strain. AB - Following intracerebral inoculation, the BeAn 8386 strain of Theiler's virus causes persistent infection and inflammatory demyelinating encephalomyelitis in the spinal cord of T-cell defective SJL/J mice, which is widely used as a model of multiple sclerosis. In contrast, C57BL/6 (B6) mice clear the virus and develop inflammation and lesions in the hippocampus, associated with acute and chronic seizures, representing a novel model of viral encephalitis-induced epilepsy. Here we characterize the geno- and phenotype of two naturally occurring variants of BeAn (BeAn-1 and BeAn-2) that can be used to further understand the viral and host factors involved in the neuropathogenesis in B6 and SJL/J mice. Next generation sequencing disclosed 15 single nucleotide differences between BeAn-1 and BeAn-2, of which 4 are coding changes and 3 are in the 5'-UTR (5' untranslated region). The relatively minor variations in the nucleotide sequence of the two BeAn substrains led to marked differences in neurovirulence. In SJL/J mice, inflammatory demyelination in the spinal cord and its clinical consequences were significantly more marked following infection with BeAn-1 than with BeAn-2. Both BeAn substrains caused lymphocyte infiltration and increase of MAC3-positive cells in the hippocampus, but hippocampal damage and seizures were only observed in B6 mice. Seizures occurred in one third of BeAn-2 infected B6 mice, but not in BeAn-1 infected B6 mice. By comparing individual mice by receiver operating characteristic (ROC) curve analysis, the severity of hippocampal neurodegeneration and amount of MAC3-positive microglia/macrophages discriminated seizing from non-seizing B6 mice, whereas T-lymphocyte brain infiltration was not found to be a crucial factor. These data add novel evidence to the view that differential outcome of infection may be not invariably linked to a distinct viral burden but to a finely tuned balance between antiviral immune responses that although essential for host resistance can also contribute to immunopathology. PMID- 28017801 TI - Spatial avascular growth of tumor in a homogeneous environment. AB - Describing tumor growth is a key issue in oncology for correctly understanding the underlying mechanisms leading to deleterious cancers. In order to take into account the micro-environment in tumor growth, we used a model describing - at the tissue level - the interactions between host (non malignant), effector immune and tumor cells to simulate the evolution of cancer. The spatial growth is described by a Laplacian operator for the diffusion of tumor cells. We investigated how the evolution of the tumor diameter is related to the dynamics (periodic or chaotic oscillations, stable singular points) underlying the interactions between the different populations of cells in proliferation sites. The sensitivity of this evolution to the key parameter responsible for the immuno evasion, namely the growth rate of effector immune cells and their inhibition rate by tumor cells, is also investigated. PMID- 28017802 TI - Signal transduction analysis of the NLRP3-inflammasome pathway after cellular damage and its paracrine regulation. AB - Activation of the NLRP3-inflammasome pathway and production of the inflammatory cytokine IL-1B after cellular damage caused by infarct or infection is a key process in several diseases such as acute myocardial infarction and inflammatory bowel disease. However, while the molecular triggers of the NLRP3-pathway after cellular damage are well known, the mechanisms that sustain or confine its activity are currently under investigation. We present here an Ordinary Differential Equation-based model that investigates the mechanisms of inflammasome activation and regulation in monocytes to predict IL-1beta activation kinetics upon a two-step activation by Damage-Associate-Molecular Particles (DAMP) and extracellular ATP. Assuming both activation signals to be concomitantly present or present with a delay of 12h, the model predicted a transient IL-1beta activation at different concentration levels dependent on signal synchronisation. Introducing a positive feedback loop mediated by active IL-1beta resulted in a sustained IL-1beta activation, hence arguing for a paracrine signalling between inflammatory cells to guarantee a temporally stable inflammatory response. We then investigate mechanisms that control termination of inflammation using two recently identified molecular intervention points in the inflammasome pathway. We found that a more upstream regulation, by attenuating production of the IL-1beta-proform, was more potent in attenuating active IL 1beta production than direct inhibition of the NLRP3-inflammasome. Interestingly, ablating this upstream negative feedback led to a high variability of IL-1beta production in monocytes from different subjects, consistent with a recent pre clinical study. We finally discuss the relevance and implications of our findings in disease models of acute myocardial infarction and spontaneous colitis. PMID- 28017799 TI - X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B. AB - X-linked Dystonia-Parkinsonism (XDP) is a progressive neurodegenerative disease involving the loss of medium spiny neurons within the striatum. An XDP-specific haplotype has been identified, consisting of seven sequence variants which cluster around the human TAF1 gene, but a direct relationship between any of these variants and disease pathogenesis has not yet been demonstrated. Because the pathogenic gene lesion remains unclear, it has been difficult to predict cellular pathways which are affected in XDP cells. To address that issue, we assayed expression of defined gene sets in XDP vs. control fibroblasts to identify networks of functionally-related transcripts which may be dysregulated in XDP patient cells. That analysis derived a 51-gene signature distinguishing XDP vs. control fibroblasts which mapped strongly to nuclear factor-kappa B (NFkappaB), a transcription factor pathway also implicated in the pathogenesis of other neurodegenerative diseases, including Parkinson's (PD) and Huntington's disease (HD). Constitutive and TNFalpha-evoked NFkappaB signaling was further evaluated in XDP vs. control fibroblasts based on luciferase reporter activity, DNA binding of NFkappaB subunits, and endogenous target gene transcription. Compared to control cells, XDP fibroblasts exhibited decreased basal NFkappaB activity and decreased levels of the active NFkappaB p50 subunit, but increased target gene expression in response to TNFalpha. NFkappaB signaling was further examined in neural stem cells differentiated from XDP and control induced pluripotent stem cell (iPSC) lines, revealing a similar pattern of increased TNFalpha responses in the patient lines compared to controls. These data indicate that an NFkappaB signaling phenotype is present in both patient fibroblasts and neural stem cells, suggesting this pathway as a site of dysfunction in XDP. PMID- 28017803 TI - Ca2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca2+ calmodulin kinases. AB - The antidepressant-sensitive norepinephrine (NE) transporter (NET) inactivates NE released during central and peripheral neuronal activity by transport into presynaptic cells. Altered NE clearance due to dysfunction of NET has been associated with the development of mental illness and cardiovascular diseases. NET activity in vivo is influenced by stress, neuronal activity, hormones and drugs. We investigated the mechanisms of Ca2+ regulation of NET and found that Ca2+ influenced both Vmax and Km for NE transport into cortical synaptosomes. Changes in extracellular Ca2+ triggered rapid and bidirectional surface trafficking of NET expressed in cultured cells. Deletion of residues 28-47 in the NET NH2-terminus abolished the Ca2+ effect on surface trafficking. Mutagenesis studies identified Thr30 in this region as the essential residue for both Ca2+- dependent phosphorylation and trafficking of NET. Depolarization of excitable cells increased surface NET in a Thr30 dependent manner. A proteomic analysis, RNA interference, and pharmacological inhibition supported roles of CaMKI and CaMKII in Ca2+-modulated NE transport and NET trafficking. Depolarization of primary noradrenergic neurons in culture with elevated K+ increased NET surface expression in a process that required external Ca2+ and depended on CaMK activity. Hippocampal NE clearance in vivo was also stimulated by depolarization, and inhibitors of CaMK signaling prevented this stimulation. In summary, Ca2+ signaling influenced surface trafficking of NET through a CaMK-dependent mechanism requiring Thr30. PMID- 28017804 TI - Persistent Fibrinolysis Shutdown Is Associated with Increased Mortality in Severely Injured Trauma Patients. AB - BACKGROUND: Acute fibrinolysis shutdown is associated with early mortality after trauma; however, no previous studies have investigated the incidence of persistent fibrinolysis or its association with mortality. We tested the hypothesis that persistent fibrinolysis shutdown is associated with mortality in critically ill trauma patients. STUDY DESIGN: Thromboelastography was performed on ICU admission in 181 adult trauma patients and at 1 week in a subset of 78 patients. Fibrinolysis shutdown was defined as LY30 <= 0.8% and was considered transient if resolved by 1 week postinjury or persistent if not. Logistic regression adjusted for age, sex, hemodynamics, and Injury Severity Score (ISS). RESULTS: Median age was 52 years, 88% were male, and median ISS was 27, with 56% transient fibrinolysis shutdown, 44% persistent fibrinolysis shutdown and 12% mortality. Median LY30 was 0.23% (interquartile range [IQR] 0% to 1.20%) at admission and 0.10% (IQR 0% to 2.05%) at 1 week. Transient shutdown more often occurred after head injury (p = 0.019); persistent shutdown was more often associated with penetrating injury (29% vs 9%; p = 0.020), lower LY30 at ICU admission (0.10% vs 1.15%; p < 0.0001) and at 1 week (0% vs 1.68%; p < 0.0001), and higher mortality (21% vs 5%; p = 0.036). Persistent fibrinolysis shutdown was associated with admission LY30 (odds ratio [OR] 0.05; 95% CI 0.01 to 0.34; p = 0.002) and transfusion of packed RBCs (OR 0.81; 95% CI 0.68 to 0.97; p = 0.021) and platelets (OR 2.81; 95% CI 1.16 to 6.84; p = 0.022); moreover, it was an independent predictor of mortality (OR 8.48; 95% CI 1.35 to 53.18; p = 0.022). CONCLUSIONS: Persistent fibrinolysis shutdown is associated with late mortality after trauma. A high index of suspicion should be maintained, especially in patients with penetrating injury, reduced LY30 on admission, and/or receiving blood product transfusion. Judicious use of tranexamic acid is advised in this cohort. PMID- 28017805 TI - Management of Immediate Post-Endovascular Aortic Aneurysm Repair Type Ia Endoleaks and Late Outcomes. AB - BACKGROUND: Post-endovascular aortic aneurysm repair (EVAR) endoleaks and the need for reintervention are challenging. Additional endovascular treatment is advised for type Ia endoleaks detected on post-EVAR completion angiogram. This study analyzed management and late outcomes of these endoleaks. STUDY DESIGN: This was a retrospective review of prospectively collected data from EVAR patients during a 10-year period. All post-EVAR type Ia endoleaks on completion angiogram were identified (group A) and their early (30-day) and late outcomes were compared with outcomes of patients without endoleaks (group B). Kaplan-Meier analysis was used for survival analysis, sac expansion, late type Ia endoleak, and reintervention. RESULTS: Seventy-one of 565 (12.6%) patients had immediate post-EVAR type Ia endoleak. Early intervention (proximal aortic cuffs and/or stenting) was used in 56 of 71 (79%) in group A vs 31 of 494 (6%) in group B (p < 0.0001). Late type Ia endoleak was noted in 9 patients (13%) in group A at a mean follow-up of 28 months vs 10 patients (2%) in group B at a mean follow-up of 32 months (p < 0.0001). Late sac expansion and reintervention rates were 9% and 10% for group A vs 5% and 3% for group B (p = 0.2698 and p = 0.0198), respectively. Freedom rates from late type Ia endoleaks at 1, 3, and 5 years for group A were 88%, 85%, and 80% vs 98%, 98%, and 96% for group B (p < 0.001); and for late intervention, were 94%, 92%, and 77% for group A, and 99%, 97%, and 95% for group B (p = 0.007), respectively. Survival rates were similar. CONCLUSIONS: Immediate post-EVAR type Ia endoleaks are associated with higher rates of early interventions, late endoleaks and reintervention, which will necessitate strict post-EVAR surveillance. PMID- 28017806 TI - Predicting In-Hospital and 1-Year Mortality in Geriatric Trauma Patients Using Geriatric Trauma Outcome Score. AB - BACKGROUND: The Geriatric Trauma Outcome Score (GTOS; [age] + [2.5 * Injury Severity Score] + 22 [if packed RBC transfused within <=24 hours of admission]), was developed and validated as a prognostic indicator for in-hospital mortality in elderly trauma patients. However, GTOS neither provides information about post discharge outcomes nor discriminates between patients dying with and without care restrictions. Isolating the latter, GTOS prediction performance was examined during admission and 1-year post discharge in a mature European trauma registry. STUDY DESIGN: All trauma admissions 65 years of age and older in a university hospital during 2007 to 2011 were considered. Data on age, Injury Severity Score, packed RBC transfusion within <=24 hours, therapy restrictions, discharge disposition, and mortality were collected. In-hospital deaths with therapy restrictions and patients discharged to hospice were excluded. The GTOS was the sole predictor in a logistic regression model estimating mortality probabilities. Performance of the model was assessed by misclassification rate, Brier score, Tjur R2, and area under the curve. RESULTS: The study population was 1,080 patients with a median age of 75 years, mean Injury Severity Score of 10, and packed RBCs transfused in 8.2%. In-hospital mortality was 14.9% and 7.7% after exclusions. Misclassification rate fell from 14% to 6.5% and Brier score from 0.09 to 0.05, and area under the curve increased from 0.87 to 0.88. Equivalent values for the original GTOS sample were 9.8%, 0.07, and 0.82, respectively. One year mortality follow-up showed a misclassification rate of 17.6% and Brier score of 0.13. CONCLUSIONS: Excluding patients with care restrictions and discharged to hospice improved GTOS performance for in-hospital mortality prediction. The GTOS is not adept at predicting 1-year mortality. PMID- 28017807 TI - Lymphadenectomy with Optimum of 29 Lymph Nodes Retrieved Associated with Improved Survival in Advanced Gastric Cancer: A 25,000-Patient International Database Study. AB - BACKGROUND: Gastric adenocarcinoma is an aggressive disease with frequent lymph node (LN) metastases for which lymphadenectomy results in a survival benefit. In the US, the National Comprehensive Cancer Network guidelines recommend D2 lymphadenectomy or a minimum of 15 LNs retrieved. However, retrieval of only 15 LNs is considered by most international guidelines as inadequate. We sought to evaluate the survival benefits associated with a more complete lymphadenectomy. STUDY DESIGN: An international database was constructed by combining gastric cancer cases from the Surveillance, Epidemiology, and End Results program database (n = 13,932) and the Yonsei University Gastric Cancer database (n = 11,358) (total n = 25,289). Kaplan-Meier survival analysis was performed along with Joinpoint analysis to obtain the optimal number of LNs to retrieve based on survival. Prognostic significance of number of nodes retrieved was then confirmed with univariate and multivariate analyses. RESULTS: Analysis for both mean and median survival yielded 29 LNs removed as the Joinpoint. This was confirmed with multivariate analysis, where 15 retrieved LNs cutoff fell out of the model and 29 retrieved LNs remained intact, with a hazard ratio of 0.799 (95% CI 0.759 to 0.842; p < 0.001). Stage-stratified Kaplan-Meier analysis for a cutoff point of 29 LNs also demonstrated a statistically significant improvement in survival. CONCLUSIONS: Joinpoint analysis has allowed for the creation of a model demonstrating the point at which additional dissection would not provide additional benefit. This large international dataset analysis demonstrates that the maximal survival advantage is seen by performing a lymphadenectomy with a minimum of 29 LNs retrieved. PMID- 28017808 TI - Preoperative Chlorhexidine Gluconate Use Can Increase Risk for Surgical Site Infections after Ventral Hernia Repair. AB - BACKGROUND: There is varying evidence about the use of preoperative chlorhexidine gluconate to decrease surgical site infection for elective surgery. This intervention has never been studied in ventral hernia repair, the most common general surgery procedure in the US. We aimed to determine whether preoperative chlorhexidine gluconate decreases the risk of 30-day wound morbidity in patients undergoing ventral hernia repair. STUDY DESIGN: All patients undergoing ventral hernia repair in the Americas Hernia Society Quality Collaborative were separated into 2 groups: 1 group received preoperative chlorhexidine scrub and the other did not. The 2 groups were evaluated for 30-day wound morbidity, including surgical site occurrence (SSO), surgical site infection (SSI), and SSO requiring procedural intervention. Statistical analysis was performed using multivariate regression analysis and propensity score modeling. Multiple factors were controlled for statistical analysis, including patient-related factors and operative factors. RESULTS: In total, 3,924 patients were included for comparison. After multivariate logistic regression modeling, the preoperative chlorhexidine scrub group had a higher incidence of SSOs (odds ratio [OR] = 1.34; 95% CI 1.11 to 1.61) and SSIs (OR = 1.46; 95% CI 1.03 to 2.07). After propensity score modeling, the increased risk of SSO and SSI persisted (SSO: OR = 1.39; 95% CI 1.15 to 1.70; SSI: OR = 1.45; 95% CI 1.011 to 2.072, respectively). CONCLUSIONS: Prehospital chlorhexidine gluconate scrub appears to increase the risk of 30-day wound morbidity in patients undergoing ventral hernia repair. These findings suggest that the generalized use of prehospital chlorhexidine might not be desirable for all surgical populations. PMID- 28017809 TI - Prevalence of Contralateral Tumors in Patients with Follicular Variant of Papillary Thyroid Cancer. AB - BACKGROUND: Thyroid lobectomy alone is being performed increasingly for patients with encapsulated follicular variant of papillary thyroid carcinoma (fvPTC). However, the prevalence of contralateral disease in these patients is unknown. We investigated the presence of synchronous disease in fvPTC to improve decision making about the extent of surgical resection and need for surveillance. STUDY DESIGN: We performed a retrospective review of patients who underwent thyroid surgery from October 2009 to February 2013 with a diagnosis of fvPTC as their primary lesion. We collected information on patient demographics, nodule size, multifocality, fine-needle aspiration results, lymphovascular invasion, extrathyroidal extension, and lymph node metastasis. Tumors were divided into noninvasive and invasive/infiltrative fvPTC categories. Characteristics of solitary and bilateral fvPTC were compared. RESULTS: We identified 124 patients with final pathology demonstrating fvPTC. The most common fine-needle aspiration diagnosis was "suspicious for malignancy" (n = 53). Sixty-five contralateral tumors were identified in 44 of 124 patients (35.5%) and included fvPTC (n = 40), classical PTC (n = 22), tall cell PTC (n = 2), and follicular carcinoma (n = 1). Fifty contralateral tumors were 1 to 5 mm, 10 measured 6 to 9 mm, and 5 were >=10 mm. Contralateral disease correlated significantly with lymphovascular invasion (p = 0.037) and larger primary lesions (p = 0.020). There was no significant difference noted in extrathyroidal extension or lymph node metastasis. Both noninvasive and invasive/infiltrative fvPTC demonstrated similar rates of contralateral disease. CONCLUSIONS: Bilateral disease is common in fvPTC, primarily in the form of papillary microcarcinomas. Future monitoring of the contralateral lobe should be discussed with fvPTC patients who do not undergo completion thyroidectomy. PMID- 28017810 TI - Access to Quaternary Care Surgery: Implications for Accountable Care Organizations. AB - BACKGROUND: Accountable care organizations (ACOs) attempt to provide the most efficient and effective care to patients within a region. We hypothesized that patients who undergo surgery closer to home have improved survival due to proximity of preoperative and post-discharge care. STUDY DESIGN: All (17,582) institutional American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) patients with a documented ZIP code and predicted risk, who underwent surgery at our institution (2005 to 2014), were evaluated. Google Maps calculated travel times, and patients were stratified by 1 hour of travel (local vs regional). Multivariable logistic regression and Cox proportional hazard models were used to evaluate the NSQIP risk-adjusted effects of travel time on operative morbidity, mortality, and long-term survival. RESULTS: Median travel time was 65 minutes, with regional patients demonstrating significantly higher rates of ascites, hypertension, diabetes, disseminated cancer, >10% weight loss, higher American Society of Anesthesiologists (ASA) score, higher predicted risk of morbidity and mortality, and lower functional status (all p < 0.01). After adjusting for ACS NSQIP-predicted risk, travel time was not significantly associated with 30-day mortality (odds ratio [OR] 1.06; p = 0.42) or any major morbidities (all p > 0.05). However, survival analysis demonstrated that travel time is an independent predictor of long-term mortality (OR 1.24; p < 0.001). CONCLUSIONS: Patients traveling farther for care at a quaternary center had higher rates of comorbidities and predicted risk of complications. Additionally, travel time predicts risk-adjusted long-term mortality, suggesting a major focus of ACOs will need to be integration of care at the periphery of their region. PMID- 28017811 TI - Use of Fluorescein Isothiocyanate-Inulin as a Marker for Intestinal Ischemic Injury. AB - BACKGROUND: Intestinal ischemia is observed in conditions such as mesenteric ischemia, or during traumatic events such as intestinal transplantation. Intestinal ischemia leads to pathophysiologic disruptions that present as increased fluid secretion into the intestinal lumen. We propose a novel method to detect real-time ischemic injury that is used in an in vitro model applicable to intestinal transplantation. STUDY DESIGN: Small intestine segments from rats were procured. The segments were attached to customized perfusion chambers. Both intestines were perfused on the vascular side with a Ringer buffer solution. The experimental buffer solution was bubbled with 100% nitrogen to mimic ischemia. Both lumens were perfused with 3 mL HEPES-Ringer solution containing 50 MUM fluorescein isothiocyanate (FITC)-inulin. Intraluminal samples were collected at 15-minute intervals to measure FITC-inulin concentration using a nanofluorospectrophotometer. Intestinal tissue samples were processed and evaluated by a blinded pathologist using the Park/Chiu scoring system for grading intestinal ischemia. RESULTS: Samples collected from the ischemic intestine showed a significant decrease in FITC-inulin fluorescence compared with the control intestine, indicating enhanced fluid secretion. Histopathologic samples from the experimental arm exhibited higher scores of ischemic injury in comparison with the control arm, confirming the FITC-inulin as a correlation to ischemia. CONCLUSIONS: Fluorescein isothiocyanate-inulin can be used as a real time volume marker to monitor the ischemic state of intestinal tissue. A positive correlation between the degree of fluid shift and presence of ischemic injury. The changes in fluorescence signal provide a potential selective method to measure real-time fluid changes inside an intestinal graft to evaluate viability. PMID- 28017812 TI - Distal Cholangiocarcinoma and Pancreas Adenocarcinoma: Are They Really the Same Disease? A 13-Institution Study from the US Extrahepatic Biliary Malignancy Consortium and the Central Pancreas Consortium. AB - BACKGROUND: Distal cholangiocarcinoma (DC) and pancreatic ductal adenocarcinoma (PDAC) are often managed as 1 entity, yet direct comparisons are lacking. Our aim was to use 2 large multi-institutional databases to assess treatment, pathologic, and survival differences between these diseases. STUDY DESIGN: This study included patients with DC and PDAC who underwent curative-intent pancreaticoduodenectomy from 2000 to 2015 at 13 institutions comprising the US Extrahepatic Biliary Malignancy and Central Pancreas Consortiums. Primary endpoint was disease-specific survival (DSS). RESULTS: Of 1,463 patients, 224 (15%) had DC and 1,239 (85%) had PDAC. Compared with PDAC, DC patients were less likely to be margin-positive (19% vs 25%; p = 0.005), lymph node (LN)-positive (55% vs 69%; p < 0.001), and receive adjuvant therapy (57% vs 71%; p < 0.001). Of DC patients treated with adjuvant therapy, 62% got gemcitabine alone and 16% got gemcitabine/cisplatin. Distal cholangiocarcinoma was associated with improved median DSS (40 months) compared with PDAC (22 months; p < 0.001), which persisted on multivariable analysis (hazard ratio 0.65; 95% CI 0.50 to 0.84; p = 0.001). Lymph node involvement was the only factor independently associated with decreased DSS for both DC and PDAC. The DC/LN-positive patients had similar DSS as PDAC/LN-negative patients (p = 0.74). Adjuvant therapy (chemotherapy +/- radiation) was associated with improved median DSS for PDAC/LN-positive patients (21 vs 13 months; p = 0.001), but not for DC patients (38 vs 40 months; p = 0.62), regardless of LN status. CONCLUSIONS: Distal cholangiocarcinoma and pancreatic ductal adenocarcinoma are distinct entities. Distal cholangiocarcinoma has a favorable prognosis compared with PDAC, yet current adjuvant therapy regimens are only associated with improved survival in PDAC, not DC. Therefore, treatment paradigms used for PDAC should not be extrapolated to DC, despite similar operative approaches, and novel therapies for DC should be explored. PMID- 28017813 TI - Association Between State Medical Malpractice Environment and Postoperative Outcomes in the United States. AB - BACKGROUND: The US medical malpractice system assumes that the threat of liability should deter negligence, but it is unclear whether malpractice environment affects health care quality. We sought to explore the association between state malpractice environment and postoperative complication rates. STUDY DESIGN: This observational study included Medicare fee-for-service beneficiaries undergoing one of the following operations in 2010: colorectal, lung, esophageal, or pancreatic resection, total knee arthroplasty, craniotomy, gastric bypass, abdominal aortic aneurysm repair, coronary artery bypass grafting, or cystectomy. The state-specific malpractice environment was measured by 2010 medical malpractice insurance premiums, state average award size, paid malpractice claims/100 physicians, and a composite malpractice measure. Outcomes of interest included 30-day readmission, mortality, and postoperative complications (eg sepsis, myocardial infarction [MI], pneumonia). Using Medicare administrative claims data, associations between malpractice environment and postoperative outcomes were estimated using hierarchical logistic regression models with hospital random-intercepts. RESULTS: Measures of malpractice environment did not have significant, consistent associations with postoperative outcomes. No individual tort reform law was consistently associated with improved postoperative outcomes. Higher-risk state malpractice environment, based on the composite measure, was associated with higher likelihood of sepsis (odds ratio [OR] 1.22; 95% CI 1.07 to 1.39), MI (OR 1.14; 95% CI 1.06 to 1.23), pneumonia (OR 1.09; 95% CI 1.03 to 1.16), acute renal failure (OR 1.15; 95% CI 1.08 to 1.22), deep vein thrombosis/pulmonary embolism (OR 1.22; 95% CI 1.13 to 1.32), and gastrointestinal bleed (OR 1.18; 95% CI 1.08 to 1.30). CONCLUSIONS: Higher risk malpractice environments were not consistently associated with a lower likelihood of surgical postoperative complications, bringing into question the ability of malpractice lawsuits to promote health care quality. PMID- 28017814 TI - New phenylpropanoid derivatives from the fruits of Xanthium sibiricum and their anti-inflammatory activity. AB - The fruits of Xanthium sibiricum Patr yielded five phenylpropanoid derivatives, named as xanthiumnolics A-E (1-5). Their structures were elucidated by spectroscopic analysis and comparison with literature data. The isolated ones were tested for their anti-inflammatory activities on lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW 264.7, and compound 5 showed strong inhibitory activities with IC50 value of 8.73MUM. PMID- 28017815 TI - Ultrastructure of chemoreceptive tarsal sensilla in an armored harvestman and evidence of olfaction across Laniatores (Arachnida, Opiliones). AB - Harvestmen (Arachnida, Opiliones) are especially dependent on chemical cues and are often regarded as animals that rely mainly on contact chemoreception. Information on harvestman sensilla is scarce when compared to other arachnid orders, especially concerning internal morphology. Using scanning (SEM) and transmission (TEM) electron microscopy, we investigated tarsal sensilla on the distal tarsomeres (DT) of all leg pairs in Heteromitobates discolor (Laniatores, Gonyleptidae). Furthermore, we explored the typological diversity of sensilla present on the DT I and II in members of the suborder Laniatores, which include two thirds of the formally described opilionid fauna, using species from 17 families representing all main laniatorian lineages. Our data revealed that DT I and II of H. discolor are equipped with wall-pored falciform hairs (two types), wall-pored sensilla chaetica (two types) and tip-pored sensilla chaetica, while DT III and IV are mainly covered with trichomes (non-sensory) and tip-pored sensilla chaetica. The ultrastructural characteristics support an olfactory function for all wall-pored sensilla and a dual gustatory/mechanoreceptive function for tip-pored sensilla chaetica. Based on our comparative SEM survey, we show that wall-pored sensilla occur in all investigated Laniatores, demonstrating their widespread occurrence in the suborder and highlighting the importance of both legs I and II as the sensory appendages of laniatorean harvestmen. Our results provide the first morphological evidence for olfactory receptors in Laniatores and suggest that olfaction is more important for harvestmen than previously thought. PMID- 28017816 TI - Letter to the Editor in response to Drs. Safiri and Ayubi. PMID- 28017817 TI - Toward a better understanding on the role of prediction error on memory processes: From bench to clinic. AB - Experimental psychology defines Prediction Error (PE) as a mismatch between expected and current events. It represents a unifier concept within the memory field, as it is the driving force of memory acquisition and updating. Prediction error induces updating of consolidated memories in strength or content by memory reconsolidation. This process has two different neurobiological phases, which involves the destabilization (labilization) of a consolidated memory followed by its restabilization. The aim of this work is to emphasize the functional role of PE on the neurobiology of learning and memory, integrating and discussing different research areas: behavioral, neurobiological, computational and clinical psychiatry. PMID- 28017819 TI - Action of tocilizumab on energy expenditure in rheumatoid arthritis: A prospective study using calorimetry and actimetry. PMID- 28017820 TI - The autoimmune tautology. A summary of evidence. PMID- 28017818 TI - Neural cascade of conflict processing: Not just time-on-task. AB - In visual conflict tasks (e.g., Stroop or flanker), response times (RTs) are generally longer on incongruent trials relative to congruent ones. Two event related-potential (ERP) components classically associated with the processing of stimulus conflict are the fronto-central, incongruency-related negativity (Ninc) and the posterior late-positive complex (LPC), which are derived from the ERP difference waves for incongruent minus congruent trials. It has been questioned, however, whether these effects, or other neural measures of incongruency (e.g., fMRI responses in the anterior cingulate), reflect true conflict processing, or whether such effects derive mainly from differential time-on-task. To address this question, we leveraged high-temporal-resolution ERP measures of brain activity during two behavioral tasks. The first task, a modified Erikson flanker paradigm (with congruent and incongruent trials), was used to evoke the classic RT and ERP effects associated with conflict. The second was a non-conflict control task in which, participants visually discriminated a single stimulus (with easy and hard discrimination conditions). Behaviorally, the parameters were titrated to yield similar RT effects of conflict and difficulty (27ms). Neurally, both within-task contrasts showed an initial fronto-central negative-polarity wave (N2-latency effect), but they then diverged. In the difficulty difference wave, the initial negativity led directly into the posterior LPC, whereas in the incongruency contrast the initial negativity was followed a by a second fronto central negative peak (Ninc), which was then followed by a considerably longer latency LPC. These results provide clear evidence that the longer processing for incongruent stimulus inputs do not just reflect time-on-task or difficulty, but include a true conflict-processing component. PMID- 28017822 TI - IL-17, now an important target for treatment in arthritis! PMID- 28017821 TI - Identification of a p.Arg708Gln variant in COL1A2 in atypical femoral fractures. AB - OBJECTIVES: Long-term bisphosphonates exposure is a proven risk factor for atypical femoral fractures (AFF) but several cases occur in untreated patients. The identification of other risk factors for AFF is critical for the management of osteoporosis. We here assessed the genetic factors associated with AFF regardless of the treatment. METHODS: Cases were identified through ICD-10 codes in 3 academic centers. Medical records were analyzed by 2 investigators that adjudicated X-rays for typical or atypical fractures. Genetic screening for ALPL, SOX9, COL1A1 and COL1A2 variants was performed after patient's information and consent. RESULTS: A total of 389 cases were identified and 268 were ruled out according to the ASBMR Task Force recommendations. On the remaining 121, 14 (11.6%) were AFF. Anti-osteoporotic drugs were more frequent in the AFF group compared to the typical fracture group (35% vs 5%, P<0.001) but only 4 (28.6%) patients with AFF had been exposed to bisphosphonates. Genetic analysis performed in 5 patients found one with a heterozygous mutation in COL1A2 (rs72658163, NM_000089.3:c.2123G>A, p.Arg708Gln). This rare variant (Minor Allele Frequency=0.0008) causes a missense mutation that alters collagen fibrillogenesis. Eight heterozygous polymorphisms for ALPL were also found in 3 patients. CONCLUSION: Genetic screening for variants in only 4 genes and 5 patients with AFF resulted in the identification of genetic variants in 3 patients including a rare variant in COL1A2, suggesting a possible genetic susceptibility to AFF. This finding should encourage clinician to further genotype patients with AFF in a collaborative multicentric project. PMID- 28017823 TI - Patient and physician agreement on reported Bath Ankylosing Spondylitis Disease Activity Index in patients with axial spondyloarthritis. PMID- 28017824 TI - Detection of Fusarium-specific T cells in hematologic patients with invasive fusariosis. PMID- 28017825 TI - Diagnosis of pulmonary tuberculosis and assessment of treatment response through analyses of volatile compound patterns in exhaled breath samples. AB - OBJECTIVES: We determined the performance of a sensor array (an electronic nose) made of 8 metalloporphyrins coated quartz microbalances sensors for the diagnosis and prognosis of pulmonary tuberculosis (TB) using exhaled breath samples. METHODS: TB cases and healthy controls were prospectively enrolled. Signals from volatile organic compounds (VOCs) in breath samples were measured at days 0, 2, 7, 14, and 30 of TB therapy and correlated with clinical and microbiological measurements. RESULTS: Fifty one pulmonary TB cases and 20 healthy HIV-uninfected controls were enrolled in the study. 31 (61%) of the 51 pulmonary TB cases were coinfected with HIV. At day 0 (before TB treatment initiation) the sensitivity of our device was estimated at 94.1% (95% confidence interval [CI], 83.8-98.8%) and specificity was 90.0% (95% CI, 68.3-98.8%) for distinguishing TB cases from controls. Time-dependent changes in the breath signals were identified as time on TB treatment progressed. Time-dependent signal changes were more pronounced among HIV-uninfected patients. CONCLUSION: The identification of VOCs' signals in breath samples using a sensor array achieved high sensitivity and specificity for the diagnosis of TB and allowed following signal changes during TB treatment. PMID- 28017826 TI - Determining vancomycin Etest MICs in patients with MRSA bloodstream infection does not support switching antimicrobials. AB - OBJECTIVES: Elevated vancomycin minimum inhibitory concentrations (MIC) have been reported to adversely affect clinical outcome in methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI). We therefore examined the association between vancomycin MIC and outcome considering various potential confounders. METHODS: Clinical data and bacterial isolates were prospectively collected from patients with MRSA BSI from 2006 to 2012 as part of the Invasive Staphylococcus aureus Infection Cohort (INSTINCT) study. Antimicrobial susceptibility was assessed by Etest, broth microdilution (BMD) and VITEK 2. Bacterial genotypes were determined by spa typing. Using univariate and Cox regression analyses, we investigated the impact of low (<=1.0 mg/L) and high (>=1.5 mg/L) vancomycin Etest MIC on clinical outcomes. RESULTS: Ninety-one MRSA BSI episodes were included, of which 79 (86.8%) were caused by spa types t003, t032 and t045. High vancomycin MICs were seen only if using Etest but not confirmed using standard reference BMD. When episodes were stratified into low and high vancomycin Etest MIC groups, 30-day overall mortality was 34.5% and 27.3%, respectively (P = 0.64, OR 0.71; 95% confidence interval [CI] 0.27-1.79). Variables significantly associated with all-cause mortality in the Cox model were age (P = 0.003), acute physiology score (P = 0.0006), and Charlson comorbidity index (P = 0.018). CONCLUSIONS: Vancomycin MICs may vary dependent on testing methodologies and local MRSA epidemiology. The patients' underlying disease and individual comorbidities rather than elevated vancomycin MICs determine adverse clinical outcomes in MRSA BSI. Routine Etest MIC testing of MRSA isolates is of limited value for treatment decisions. PMID- 28017828 TI - Effect of Dezocine on IL-12 and IL-10 secretion and lymphocyte activation by culturing dendritic cells from human umbilical cord blood. AB - Dezocine has been generally utilized for pain therapy and auxiliary anesthesia. Although it has some advantages on the prevention of some anesthesia related complications, its effect on immune responses remains unclear. Our study investigated the effects of Dezocine on IL-10 and IL-12 secretion and lymphocytes activation by culturing dendritic cells (DCs), and revealed the underlying mechanism. Mononuclear cells were divided into negative control group (GN), positive control group (GP), experimental group (GD; GD5, D7, D9). DCs morphological structure was performed by microscope and its phenotypes were evaluated by flow cytometry. IL-12 and IL-10 levels were determined by ELISA and lymphocyte proliferation capacity was performed by MTT assay. Results showed that typical morphological characters of DCs were observed in GP and GD. The positive cell percentages of CD83, HLA-DR, CD80, CD86 and CD40 in GD were lower than those in GP, but higher than the GN group (P<0.01). IL-12 level in GD was higher than in GP, however, IL-10 was opposite (P<0.01). The optical density in GD was lower than in GP (P<0.05). There were no dose-dependent relationships correlated with DCs phenotypes, IL-12 and IL-10 secretion and lymphocytes activation (P>0.05). Our conclusion was that Dezocine might play a role in immunity by regulating IL 12 and IL-10 secretion, and affecting lymphocyte activity in process of DCs maturation. Our findings reveal an unexpected immuno-regulatory function of Dezocine in DCs and provide an important insight for investigating the effect of opioid drugs in immunologic responses. PMID- 28017827 TI - Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease. AB - INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD). METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). RESULTS: The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. DISCUSSION: Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required. PMID- 28017829 TI - 12-Chloracetyl-PPD, a novel dammarane derivative, shows anti-cancer activity via delay the progression of cell cycle G2/M phase and reactive oxygen species mediate cell apoptosis. AB - (20R)-Dammarane-3beta, 12beta, 20, 25-tetrol (25-OH-PPD) is a ginsenoside isolated from Panax ginseng (C. A. Meyer). This compound exhibits anti-cancer activities on many human cancer cell lines. In this study, we investigated anti cancer mechanisms of 12beta-O-(L-Chloracetyl)-dammar-20(22)-ene-3beta,25-diol(12 Chloracetyl-PPD), a modified 25-OH-PPD. We found that compound 12-Chloracetyl-PPD resulted in a concentration-dependent inhibition of viability in prostate, breast, and gastric cancer cells, without affecting the viability of normal cell (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line HHDPC and rat myocardial cell line-H9C2). In MDA-MB-435 and C4-2B cancer cells, 12-Chloracetyl-PPD induced G2/M cell cycle arrest, down-regulated mouse double minute 2 (MDM2) expression, up-regulated p53 expression, triggered apoptosis, and stimulated reactive oxygen species production. Apoptosis can be attenuated by the reactive oxygen species scavenger N-acetylcysteine. Our results suggested that compound 12-Chloracetyl-PPD showed obvious anti-cancer activity based on delaying cell cycle arrest and inducing cell apoptosis by reactive oxygen species production, which supported development of 12-Chloracetyl-PPD as a potential agent for cancer chemotherapy. PMID- 28017830 TI - Dermal Fibroblasts Promote Alternative Macrophage Activation Improving Impaired Wound Healing. AB - Tight control of inflammation is required for tissue repair and wound healing and depends on alternative polarization of macrophages as checkpoint for inflammatory resolution. Its perturbations lead to impaired regeneration. Administration of cells/cell factors capable of reversing inflammation and rescuing alternative polarization could be promising for treating inflammatory diseases. We show that human dermal fibroblasts (dFb) are ideal candidates for such a task by demonstrating a new function of these cells, which is modulating macrophage polarization. Coculture of dFb with human monocytes in vitro or injection of dFb into mice with thioglycollate-induced peritonitis favors alternative macrophage activation and reduces inflammation by releasing tumor necrosis factor-inducible gene 6 protein and Cox-2 products. Silencing these factors in dFb abolishes the reported effects, demonstrating their importance for immunomodulation. Importantly, in a model of delayed wound healing due to prolonged inflammation (db/db mice), administration of dFb improves defective tissue repair with augmentation of alternative macrophage polarization and inflammation resolution. Human dFb are low immunogenic cells, easy to obtain, and can be expanded extensively in vitro conserving their immunomodulatory capacity; this, together with our findings, suggests that dFb might represent an alternative for cell based therapies of conditions characterized by excessive inflammation and delayed tissue repair. PMID- 28017831 TI - Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3beta/beta-catenin Pathway to Inhibit Wound Closure. AB - Glucocorticoids (GCs), key mediators of stress signals, are also potent wound healing inhibitors. To understand how stress signals inhibit wound healing, we investigated the role of membranous glucocorticoid receptor (mbGR) by using cell impermeable BSA-conjugated dexamethasone. We found that mbGR inhibits keratinocyte migration and wound closure by activating a Wnt-like phospholipase (PLC)/ protein kinase C (PKC) signaling cascade. Rapid activation of mbGR/PLC/PKC further leads to activation of known biomarkers of nonhealing found in patients, beta-catenin and c-myc. Conversely, a selective inhibitor of PKC, calphostin C, blocks mbGR/PKC pathway, and rescues GC-mediated inhibition of keratinocyte migration in vitro and accelerates wound epithelialization of human wounds ex vivo. This novel signaling mechanism may have a major impact on understanding how stress response via GC signaling regulates homeostasis and its role in development and treatments of skin diseases, including wound healing. To test tissue specificity of this nongenomic signaling mechanism, we tested retinal and bronchial human epithelial cells and fibroblasts. We found that mbGR/PLC/PKC signaling cascade exists in all cell types tested, suggesting a more general role. The discovery of this nongenomic signaling pathway, in which glucocorticoids activate Wnt pathway via mbGR, provides new insights into how stress-mediated signals may activate growth signals in various epithelial and mesenchymal tissues. PMID- 28017832 TI - Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification. AB - In this paper, we report three patients with severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Biallelic mutations were found in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein that interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen modifying enzyme LH3. Two patients were homozygous for the missense variant p.Gly131Glu, whereas one patient was compound heterozygous for p.Gly131Glu and the splice site mutation c.240-1G>C, previously reported in patients with arthrogryposis renal dysfunction and cholestasis syndrome. We demonstrated the pathogenicity of variant p.Gly131Glu by assessing the interactions of the mutant VPS33B construct and its ability to traffic LH3. Compared with wild-type VPS33B, the p.Gly131Glu mutant VPS33B had reduced coimmunoprecipitation and colocalization with Rab11a and Rab25 and did not rescue LH3 trafficking. Confirming the cell-based experiments, we found deficient LH3-specific collagen lysine modifications in patients' urine and skin fibroblasts. Additionally, the epidermal ultrastructure of the p.Gly131Glu patients mirrored defects in tamoxifen-inducible VPS33B-deficient Vps33bfl/fl-ERT2 mice. Both patients and murine models revealed an impaired epidermal structure, ascribed to aberrant secretion of lamellar bodies, which are essential for epidermal barrier formation. Our results demonstrate that p.Gly131Glu mutant VPS33B causes an autosomal recessive keratoderma-ichthyosis-deafness syndrome. PMID- 28017833 TI - Protein Palmitoylation by ZDHHC13 Protects Skin against Microbial-Driven Dermatitis. AB - Atopic dermatitis is a complex chronic inflammatory skin disorder that results from intimate interactions among genetic predisposition, host environment, skin barrier defects, and immunological factors. However, a clear genetic roadmap leading to atopic dermatitis remains to be fully explored. From a genome-wide mutagenesis screen, deficiency of ZDHHC13, a palmitoylacyl transferase, has previously been associated with skin and multitissue inflammatory phenotypes. Here, we report that ZDHHC13 is required for skin barrier integrity and that deficiency of ZDHHC13 renders mice susceptible to environmental bacteria, resulting in persistent skin inflammation and an atopic dermatitis-like disease. This phenotype is ameliorated in a germ-free environment and is also attenuated by antibiotic treatment, but not by deletion of the Rag1 gene, suggesting that a microbial factor triggers inflammation rather than intrinsic adaptive immunity. Furthermore, skin from ZDHHC13-deficient mice has both elevated levels of IL-33 and type 2 innate lymphoid cells, reinforcing the role of innate immunity in the development of atopic dermatitis. In summary, our study suggests that loss of ZDHHC13 in skin impairs the integrity of multiple barrier functions and leads to a dermatitis lesion in response to microbial encounters. PMID- 28017834 TI - Indocyanine green fluorescence imaging in hepatobiliary surgery. AB - Indocyanine green (ICG) is a fluorescent dye that has been widely used for fluorescence imaging during hepatobiliary surgery. ICG is injected intravenously, selectively taken up by the liver, and then secreted into the bile. The catabolism and fluorescence properties of ICG permit a wide range of visualization methods in hepatobiliary surgery. We have characterized the applications of ICG during hepatobiliary surgery into: 1) liver mapping, 2) cholangiography, 3) tumor visualization, and 4) partial liver graft evaluation. In this literature review, we summarize the current understanding of ICG use during hepatobiliary surgery. Intra-operative ICG fluorescence imaging is a safe, simple, and feasible method that improves the visualization of hepatobiliary anatomy and liver tumors. Intravenous administration of ICG is not toxic and avoids the drawbacks of conventional imaging. In addition, it reduces post operative complications without any known side effects. ICG fluorescence imaging provides a safe and reliable contrast for extra-hepatic cholangiography when detecting intra-hepatic bile leakage following liver resection. In addition, liver tumors can be visualized and well-differentiated hepatocellular carcinoma tumors can be accurately identified. Moreover, vascular reconstruction and outflow can be evaluated following partial liver transplantation. However, since tissue penetration is limited to 5-10mm, deeper tissue cannot be visualized using this method. Many instances of false positive or negative results have been reported, therefore further characterization is required. PMID- 28017835 TI - AAV-mediated transfer of RhoA shRNA and CNTF promotes retinal ganglion cell survival and axon regeneration. AB - The aim of the present study was to determine whether adeno-associated viral vector (AAV) mediated transfer of ciliary neurotrophic factor (CNTF) and RhoA shRNA has additive effects on promoting the survival and axon regeneration of retinal ganglion cells (RGCs) after optic nerve crush (ONC). Silencing effects of AAV-RhoA shRNA were confirmed by examining neurite outgrowth in PC12 cells, and by quantifying RhoA expression levels with western blotting. Young adult Fischer rats received an intravitreal injection of (i) saline, (ii) AAV green fluorescent protein (GFP), (iii) AAV-CNTF, (iv) AAV-RhoA shRNA, or (v) a combination of both AAV-CNTF and AAV-RhoA shRNA. Two weeks later, the ON was completely crushed. Three weeks after ONC, RGC survival was estimated by counting betaIII-tubulin positive neurons in retinal whole mounts. Axon regeneration was evaluated by counting GAP-43-positive axons in the crushed ON. It was found that AAV-RhoA shRNA decreased RhoA expression levels and promoted neurite outgrowth in vitro. In the ONC model, AAV-RhoA shRNA by itself had only weak beneficial effects on RGC axon regeneration. However, when combined with AAV-CNTF, AAV-RhoA shRNA significantly improved the therapeutic effect of AAV-CNTF on axon regeneration by nearly two fold, even though there was no significant change in RGC viability. In sum, this combination of vectors increases the regenerative response and can lead to more successful therapeutic outcomes following neurotrauma. PMID- 28017837 TI - In vitro and in vivo evaluation of in situ gelling systems for sustained topical ophthalmic delivery: state of the art and beyond. AB - In situ gelling delivery systems for the ocular administration of drugs has been a major focus of research over the past two decades, improving the treatment of diseases of the anterior segment of the eye by simple, safe, and reproducible drug administration. This drug delivery strategy results in high ocular bioavailability by avoiding rapid precorneal clearance resulting from nasolacrimal drainage and eye blinking. However, the development of such unconventional forms requires many parameters to be mastered, such as gelation time, viscoelastic behavior, mucoadhesion, and sustained release. In this review, we describe and assess the in vitro and in vivo methods available for in situ gelling ophthalmic delivery systems, highlighting the advantages of existing methods and, in some cases, the need for more relevant assays. PMID- 28017836 TI - Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy. AB - The cluster-determinant 44 (CD44) receptor has a high affinity for hyaluronic acid (HA) binding and is a desirable receptor for active targeting based on its overexpression in cancer cells compared with normal body cells. The nanocarrier affinity can be increased by conjugating drug-loaded carriers with HA, allowing enhanced cancer cell uptake via the HA-CD44 receptor-mediated endocytosis pathway. In this review, we discuss recent advances in HA-based nanocarriers and micelles for cancer therapy. In vitro and in vivo experiments have repeatedly indicated HA-based nanocarriers to be a target-specific drug and gene delivery platform with great promise for future applications in clinical cancer therapy. PMID- 28017838 TI - The embodied mind: A review on functional genomic and neurological correlates of mind-body therapies. AB - A broad range of mind-body therapies (MBTs) are used by the public today, and a growing body of clinical and basic sciences research has resulted in evidence based integration of many MBTs into clinical practice. Basic sciences research has identified some of the physiological correlates of MBT practices, leading to a better understanding of the processes by which emotional, cognitive and psychosocial factors can influence health outcomes and well-being. In particular, results from functional genomics and neuroimaging describe some of the processes involved in the mind-body connection and how these can influence health outcomes. Functional genomic and neurophysiological correlates of MBTs are reviewed, detailing studies showing changes in sympathetic nervous system activation of gene transcription factors involved in immune function and inflammation, electroencephalographic and neuroimaging studies on MBT practices, and persistent changes in neural function and morphology associated with these practices. While the broad diversity of study designs and MBTs studied presents a patchwork of results requiring further validation through replication and longitudinal studies, clear themes emerge for MBTs as immunomodulatory, with effects on leukocyte transcription and function related to inflammatory and innate immune responses, and neuromodulatory, with effects on brain function and morphology relevant for attention, learning, and emotion regulation. By detailing the potential mechanisms of action by which MBTs may influence health outcomes, the data generated by these studies have contributed significantly towards a better understanding of the biological mechanisms underlying MBTs. PMID- 28017839 TI - Association of trauma, Posttraumatic Stress Disorder and Conduct Disorder: A systematic review and meta-analysis. AB - OBJECTIVE: To summarize findings of previous studies on the prevalence of trauma and Posttraumatic Stress Disorder (PTSD) in Conduct Disorder (CD). METHOD: We conducted a systematic review and meta-analysis following the PRISMA guidelines. EBSCOhost, PubMed, CDSR and ARIF databases were searched in October 2016, employing relevant keywords. RESULTS: 19 studies met inclusion criteria. Meta analysis resulted in a lifetime PTSD prevalence of 11% (95% CI: 7-17%) in children and adolescents with CD, 14% (95% CI: 12-15%) in adults with pre existing CD and 32% (95% CI: 25-40%) in juvenile offenders with CD. Higher lifetime PTSD prevalence was observed in individuals with than without CD, and in females compared to males with CD. CONCLUSIONS: Studies focusing on the association of trauma, PTSD and CD are still relatively rare. Possible comorbidity models are discussed considering psychological and biological risk factors in a comprehensive model. The high rate of PTSD in CD may be due to shared risk factors; furthermore, CD might increase the risk for comorbid PTSD due to CD inherent risk taking behavior. To study pathways of risk, especially longitudinal studies are necessary. PMID- 28017840 TI - What do animals learn in artificial grammar studies? AB - Artificial grammar learning is a popular paradigm to study syntactic ability in nonhuman animals. Subjects are first trained to recognize strings of tokens that are sequenced according to grammatical rules. Next, to test if recognition depends on grammaticality, subjects are presented with grammar-consistent and grammar-violating test strings, which they should discriminate between. However, simpler cues may underlie discrimination if they are available. Here, we review stimulus design in a sample of studies that use particular sounds as tokens, and that claim or suggest their results demonstrate a form of sequence rule learning. To assess the extent of acoustic similarity between training and test strings, we use four simple measures corresponding to cues that are likely salient. All stimulus sets contain biases in similarity measures such that grammatical test stimuli resemble training stimuli acoustically more than do non-grammatical test stimuli. These biases may contribute to response behaviour, reducing the strength of grammatical explanations. We conclude that acoustic confounds are a blind spot in artificial grammar learning studies in nonhuman animals. PMID- 28017841 TI - The Headache of Acetaminophen Overdose: Getting the NAC. PMID- 28017842 TI - Measurement of Spleen Stiffness With Acoustic Radiation Force Impulse Imaging Predicts Mortality and Hepatic Decompensation in Patients With Liver Cirrhosis. AB - BACKGROUND & AIMS: Hepatic venous pressure gradient can predict mortality and hepatic decompensation in patients with cirrhosis. Measurement of hepatic venous pressure gradient requires an invasive procedure; therefore, prognostic markers are needed that do not require invasive procedures. We investigated whether measurements of spleen stiffness, made by acoustic radiation force impulse (ARFI) imaging, associated with mortality and decompensation in patients with cirrhosis, compared with liver stiffness and other markers. METHODS: We measured spleen stiffness in 393 patients diagnosed with cirrhosis (based on histologic or physical, laboratory, and radiologic findings) at a hospital in Japan from September 2010 through August 2013 (280 patients with compensated and 113 patients with decompensated cirrhosis). Patients underwent biochemical, ARFI, ultrasonography, and endoscopy evaluations every 3 or 6 months to screen for liver-related complications until their death, liver transplantation, or the end of the study period (October 2015). The primary outcome was the accuracy of spleen stiffness in predicting mortality and decompensation, measured by Cox proportional hazards model analysis. We compared spleen stiffness with other noninvasive parameters using the Harrell's C-index analysis. RESULTS: During a median follow-up period of 44.6 months, 67 patients died and 35 patients developed hepatic decompensation. In the multivariate analysis, spleen stiffness was an independent parameter associated with mortality, after adjustment for levels of alanine aminotransferase and serum sodium, and the model for end-stage liver disease score (P < .001). Spleen stiffness was associated independently with decompensation after adjustment for Child-Pugh score and model for end-stage liver disease score (P < .001). Spleen stiffness predicted mortality and decompensation with greater accuracy than other parameters (C-indexes for predicting mortality and decompensation were 0.824 and 0.843, respectively). A spleen stiffness cut-off value of 3.43 m/s identified the death of patients with a 95.3% negative predictive value and 75.8% accuracy. A spleen stiffness cut-off value of 3.25 m/s identified patients with decompensation with a 98.8% negative predictive value and 68.9% accuracy. CONCLUSIONS: Spleen stiffness, measured by ARFI imaging, can predict death of patients with cirrhosis with almost 76% accuracy and hepatic decompensation with almost 70% accuracy. It might be a useful noninvasive test to predict patient outcome. UMIN Clinical Trials Registry no. UMIN000004363. PMID- 28017843 TI - Mutation Profile and Fluorescence In Situ Hybridization Analyses Increase Detection of Malignancies in Biliary Strictures. AB - BACKGROUND & AIMS: It is a challenge to detect malignancies in biliary strictures. Various sampling methods are available to increase diagnostic yield, but these require additional procedure time and expertise. We evaluated the combined accuracy of fluorescence in situ hybridization (FISH) and polymerase chain reaction-based DNA mutation profiling (MP) of specimens collected using standard brush techniques. METHODS: We performed a prospective study of 107 consecutive patients treated for biliary strictures by endoscopic retrograde cholangiopancreatography from June 2012 through June 2014. We performed routine cytology and FISH analyses on cells collected by standard brush techniques, and analyzed supernatants for point mutations in KRAS and loss-of-heterozygosity mutations in tumor-suppressor genes at 10 loci (MP analysis was performed at Interpace Diagnostics). Strictures were determined to be nonmalignant based on repeat image analysis or laboratory test results 12 months after the procedure. Malignant strictures were identified based on subsequent biopsy or cytology analyses, pathology analyses of samples collected during surgery, or death from biliary malignancy. We determined the sensitivity and specificity with which FISH and MP analyses detected malignancies using the exact binomial test. RESULTS: Our final analysis included 100 patients; 41% had biliary malignancies. Cytology analysis identified patients with malignancies with 32% sensitivity and 100% specificity. Addition of FISH or MP results to cytology results increased the sensitivity of detection to 51% (P < .01) without reducing specificity. The combination of cytology, MP, and FISH analyses detected malignancies with 73% sensitivity (P < .001). FISH identified an additional 9 of the 28 malignancies not detected by cytology analysis, and MP identified an additional 8 malignancies. FISH and MP together identified 17 of the 28 malignancies not detected by cytology analysis. CONCLUSIONS: Addition of FISH and mutation analyses to cytology analysis significantly increased the level of sensitivity with which we detected malignancy in biliary strictures, with 100% specificity. These techniques can be performed using standard brush samples collected during endoscopic retrograde cholangiopancreatography, with mutations detected in free DNA in supernatant fluid of samples. The tests are complementary and therefore should be used sequentially in the diagnostic evaluation of biliary strictures. PMID- 28017844 TI - Is Autoimmunity Infectious? The Effect of Gastrointestinal Viral Infections and Vaccination on Risk of Celiac Disease Autoimmunity. PMID- 28017845 TI - Endoscopic Sleeve Gastroplasty Significantly Reduces Body Mass Index and Metabolic Complications in Obese Patients. AB - BACKGROUND & AIMS: Endoscopic sleeve gastroplasty (ESG) is an incisionless, minimally invasive bariatric procedure that reduces the length and width of the gastric cavity to facilitate weight loss. We performed a prospective study to evaluate the effects of ESG on total body weight loss and obesity-related comorbidities. METHODS: We collected data from 91 consecutive patients (mean age, 43.86 +/- 11.26 years; 68% female) undergoing ESG from August 2013 through March 2016. All patients had a body mass index (BMI) greater than 30 kg/m2 and had failed noninvasive weight-loss measures or had a BMI greater than 40 kg/m2 and were not considered as surgical candidates or refused surgery. All procedures were performed with a cap-based flexible endoscopic suturing system to facilitate a triangular pattern of sutures to imbricate the greater curvature of the stomach. Patients were evaluated after 6 months (n = 73), 12 months (n = 53), and 24 months (n = 12) for anthropometric features (BMI, weight, waist circumference, blood pressure) and underwent serologic (hemoglobin A1c), lipid panel, serum triglycerides, and liver function tests. The primary outcomes were total body weight loss at 6, 12, and 24 months. Secondary outcomes were the effects of ESG on metabolic factors (blood pressure, diabetes, hyperlipidemia, steatohepatitis) and safety. RESULTS: The patients' mean BMI before the procedure was 40.7 +/- 7.0 kg/m2. Patients had lost 14.4% of their total body weight at 6 months (80% follow up rate), 17.6% at 12 months (76% follow-up rate), and 20.9% at 24 months (66% follow-up rate) after ESG. At 12 months after ESG, patients had statistically significant reductions in levels of hemoglobin A1c (P = .01), systolic blood pressure (P = .02), waist circumference (P < .001), alanine aminotransferase (P < .001), and serum triglycerides (P = .02). However, there was no significant change in low-density lipoprotein after vs before ESG (P = .79). There was one serious adverse event (1.1%) (perigastric leak) that occurred that was managed non-operatively. CONCLUSIONS: ESG is a minimally invasive and effective endoscopic weight loss intervention. In addition to sustained total body weight loss up to 24 months, ESG reduced markers of hypertension, diabetes, and hypertriglyceridemia. PMID- 28017846 TI - Increased Post-procedural Non-gastrointestinal Adverse Events After Outpatient Colonoscopy in High-risk Patients. AB - BACKGROUND & AIMS: The incidence and predictors of non-gastrointestinal (GI) adverse events (AEs) after colonoscopy are not well-understood. We studied the effects of antithrombotic agents, cardiopulmonary comorbidities, and age on risk of non-GI AEs after colonoscopy. METHODS: We performed a retrospective longitudinal analysis to assess the diagnosis, procedure, and prescription drug codes in a United States commercial claims database (March 2010-March 2012). Data from patients at increased risk (n = 82,025; defined as patients with pulmonary comorbidities or cardiovascular disease requiring antithrombotic medications) were compared with data from 398,663 average-risk patients. In a 1:1 matched analysis, 51,932 patients at increased risk, examined by colonoscopy, were compared with 51,932 matched (on the basis of age, sex, and comorbidities) patients at increased risk who did not undergo colonoscopy. We tracked cardiac, pulmonary, and neurovascular events 1-30 days after colonoscopy. RESULTS: Thirty days after outpatient colonoscopy, non-GI AEs were significantly higher in patients taking antithrombotic medications (7.3%; odds ratio [OR], 10.75; 95% confidence interval, 10.13-11.42) or those with pulmonary comorbidities (1.8%; OR, 2.44; 95% confidence interval, 2.27-2.62) vs average-risk patients (0.7%) and in patients 60-69 years old (OR, 2.21; 95% confidence interval, 2.01-2.42) or 70 years or older (OR, 6.45; 95% confidence interval, 5.89-7.06), compared with patients younger than 50 years. The 30-day incidence of non-GI AEs in patients at increased risk who underwent colonoscopy was also significantly higher than in matched patients at increased risk who did not undergo colonoscopy in the anticoagulant group (OR, 2.31; 95% confidence interval, 2.01-2.65) and in the chronic obstructive pulmonary disease group (OR, 1.33; 95% confidence interval, 1.13-1.56). CONCLUSIONS: Increased number of comorbidities and older age (older than 60 years) are associated with increased risk of non-GI AEs after colonoscopy. These findings indicate the importance of determining comorbid risk and evaluating antithrombotic management before colonoscopy. PMID- 28017847 TI - Associations and the role of affiliative, agonistic, and socio-sexual behaviors among common bottlenose dolphins (Tursiops truncatus). AB - Little is known about the specific behavioral exchanges that occur on a day-to day basis between dyads of common bottlenose dolphins (Tursiops truncatus). This study assesses the proportion of time dyads spend in proximity (within ~2m) and the proportion of time spent in affiliative, agonistic, or socio-sexual contexts within and between age/sex dolphin pairings to better understand their social relationships. Observations of bottlenose dolphins housed at the Roatan Institute of Marine Sciences provided 10.5h of underwater footage from which to examine association coefficients and inter-individual interactions. These data suggest similar patterns to previous studies on bottlenose dolphins: mother-calf dyads shared the highest coefficients of association, followed by male-male, female female, and male-female dyads. Four classes of association coefficients were defined for the population including low, medium, medium-high and high. This study is the first to quantitatively assess association patterns concurrently with affiliative, agonistic, and socio-sexual behaviors for bottlenose dolphins. The predominant relationships were affiliative. PMID- 28017848 TI - Testing the predictions of coping styles theory in threespined sticklebacks. AB - Coping styles theory provides a framework for understanding individual variation in how animals respond to environmental change, and predicts how individual differences in stress responsiveness and behavior might relate to cognitive differences. According to coping styles theory, proactive individuals are bolder, less reactive to stressors, and more routinized than their reactive counterparts. A key tenet of coping styles theory is that variation in coping styles is maintained by tradeoffs with behavioral flexibility: proactive individuals excel in stable environments while more flexible, reactive individuals perform better in variable environments. Here, we assess evidence for coping styles within a natural population of threespined sticklebacks (Gasterosteus aculeatus). We developed a criterion-based learning paradigm to evaluate individual variation in initial and reversal learning. We observed strong individual differences in boldness, cortisol production, and learning performance. Consistent with coping styles, fish that released more cortisol were more timid in response to a predator attack and slower to learn a color discrimination task. However, there was no evidence that reactive individuals performed better when the environment changed (when the rewarded color was reversed). The failure to detect trade-offs between behavioral routinization and flexibility prompts other explanations for the maintenance of differing coping styles. PMID- 28017849 TI - Diffusion of Innovations model helps interpret the comparative uptake of two methodological innovations: co-authorship network analysis and recommendations for the integration of novel methods in practice. AB - OBJECTIVE: The objective of this study was to characterize the diffusion of methodological innovation. STUDY DESIGN AND SETTING: Comparative case study analysis of the diffusion of two methods that summarize confounder information into a single score: disease risk score (DRS) and high-dimensional propensity score (hdPS). We completed systematic searches to identify DRS and hdPS papers in the field of pharmacoepidemiology through to the end of 2013, plotted the number of papers and unique authors over time, and created sociograms and animations to visualize co-authorship networks. First and last author affiliations were used to ascribe institutional contributions to each paper and network. RESULTS: We identified 43 DRS papers by 153 authors since 1981, reflecting slow uptake during initial periods of uncertainty and broader diffusion since 2001 linked to early adopters from Vanderbilt. We identified 44 hdPS papers by 147 authors since 2009, reflecting rapid and integrated diffusion, likely facilitated by opinion leaders, early presentation at conferences, easily accessible statistical code, and improvement in funding. Most contributions (87% DRS, 96% hdPS) were from North America. CONCLUSION: When proposing new methods, authors are encouraged to consider innovation attributes and early evaluation to improve knowledge translation of their innovations for integration into practice, and we provide recommendations for consideration. PMID- 28017850 TI - Highway to cell. PMID- 28017851 TI - Immediate and delayed anxiety- and depression-like profiles in the adolescent Wistar-Kyoto rat model of endogenous depression following postweaning social isolation. AB - In order to understand links that exist between inherited risk or predisposition, brain and behavioural development, endocrine regulation and social/environmental stimuli, animal models are crucial. The Wistar-Kyoto (WKY) rat has been shown to have validity as a model of adult and adolescent depression. While sex- and age specific differences in some of the face, predictive and construct validities of the model such as depression-like behaviours have been established, anhedonia and anxiety using other induced anxiety paradigms such as elevated plus maze remain equivocal. First, post-weaning social isolation effects on inherent and induced anxiety behaviours were tested during two critical time periods, early- and mid adolescence. Isolation induced immediate effects on novel environment-induced hyperactivity and anxiety-related behaviours. Adolescent WKYs demonstrated reduced 50-kHz ultrasonic vocalizations suggesting agoraphobia-like behaviours. Second, isolated rats, despite being subsequently social-/group-housed demonstrated longer lasting effects on social interaction measures and anhedonia. This establishes that the depression-like profile observed during early- and mid adolescence persists into late adolescence and early adulthood in WKY. Further, that interventions at a later stage during adolescence may not be able to reverse early adolescent effects in the context of pre-disposition, thus highlighting the irreversibility of being double-hit during critical time periods of brain and behavioural development and maturation. PMID- 28017852 TI - Anxiety and risk assessment-related traits in a rat model of Spinocerebellar ataxia type 17. AB - Anxiety as a common feature of several neurodegenerative/polyglutamine diseases is an important aspect for the face validity of an animal model for Spinocerebellar Ataxia type 17 (SCA17). Risk assessment and anxiety-like traits were characterised in 3-6-9 months old rats of a transgenic model for SCA17 using the standard behavioural test elevated plus maze. In addition, c-Fos immunostainings in the basolateral amygdala evaluated neuronal activation in correlation to the behavioural responses. The most prominent behavioural effect was a higher level of risk assessment in the transgenic rats. In addition, an increase in anxiety-related behaviour in these rats was found. Although the EPM caused no overall effect on c-Fos expression, a negative correlation with the anxiety-like behavioural response was observed. Our results suggest that the SCA17 rat model displays an anxious phenotype already at 3 months of age resembling the generalized anxiety in early symptomatic SCA17 patients, thus confirming the validity of this rat model. PMID- 28017853 TI - Pre-treatment with nimodipine and 7.5% hypertonic saline protects aged rats against postoperative cognitive dysfunction via inhibiting hippocampal neuronal apoptosis. AB - OBJECTIVE: This study aimed to investigate the effects of pre-treatment with nimodipine and 7.5% hypertonic saline (HS) on postoperative cognitive dysfunction (POCD) in aged rats. METHODS: Healthy Sprague-Dawley aged rats were randomly assigned into 4 groups: POCD group, nimodipine group, HS group, and nimodipine+HS group. Rats in POCD group received normal saline injection and then splenectomy 30min later under 1.8% isoflurane inhalation for 2h. In remaining groups, rats received injection of 1mg/kg nimodipine (i.p) and/or 4ml/kg 7.5% HS (i.v) and then splenectomy. Morris water maze test was performed before and after surgery. The hippocampus was harvested for the detection of neuronal apoptosis rate (AR), cytoplasmic calcium ([Ca2+]i), Bcl-2 and Bax mRNA expression and hippocampal neuronal ultrastructure. RESULTS: When compared with POCD group, the latency to escape, neuronal AR, [Ca2+]i, Bax mRNA expression and Bax/Bcl-2 ratio reduced dramatically, but the times of crossing the platform and Bcl-2 mRNA expression increased significantly (P<0.05) in nimodipine group, NS group and nimodipine+HS group. In addition, the latency to escape, neuronal AR, [Ca2+]i, Bax mRNA expression and Bax/Bcl-2 ratio reduced markedly, but the times of crossing the platform and Bcl-2 mRNA expression increased significantly in nimodipine+HS group as compared to nimodipine group and NS group (P<0.05). Hippocampal neuronal ultrastructure damage was observed in all 4 groups, but it was the mildest in nimodipine+HS group. CONCLUSION: Pre-treatment with both nimodipine and 7.5% HS exerts better protective effects, which is related to the inhibition of hippocampal neuronal apoptosis. PMID- 28017854 TI - The effects of neonatal amygdala or hippocampus lesions on adult social behavior. AB - The present report details the final phase of a longitudinal evaluation of the social behavior in a cohort of adult rhesus monkeys that received bilateral neurotoxic lesions of the amygdala or hippocampus, or sham operations at 2 weeks of age. Results were compared to previous studies in which adult animals received amygdala lesions and were tested in a similar fashion. Social testing with four novel interaction partners occurred when the animals were between 7 and 8 years of age. Experimental animals interacted with two male and two female partners in two conditions - one in which physical access was restricted (the constrained social access condition) and a second in which physical access was unrestricted (the unconstrained social access condition). Across conditions and interaction partners, there were no significant effects of lesion condition on the frequency or duration of social interactions. As a group, the hippocampus-lesioned animals generated the greatest number of communicative signals during the constrained social access condition. Amygdala-lesioned animals generated more frequent stress related behaviors and were less exploratory. Amygdala and hippocampus-lesioned animals demonstrated greater numbers of stereotypies than control animals. Subtle, lesion-based differences in the sequencing of behaviors were observed. These findings suggest that alterations of adult social behavior are much less prominent when damage to the amygdala occurs early in life rather than in adulthood. PMID- 28017855 TI - Supermatrix phylogeny and biogeography of the Australasian Meliphagides radiation (Aves: Passeriformes). AB - With nearly 300 species, the infraorder Meliphagides represents one of the largest and most conspicuous Australasian bird radiations. Although the group has been the focus of a number of recent phylogenetic studies, a comprehensive species-level phylogenetic hypothesis is still lacking. This has impeded the assessment of broad-scale evolutionary, biogeographic and ecological hypotheses. In the present study, we use a supermatrix approach including five mitochondrial and four nuclear markers to infer a time-calibrated phylogeny of the Meliphagides. Our phylogeny, which includes 286 of the 289 (99%) currently recognized species, is largely congruent with previous estimates. However, the addition of 60 newly sequenced species reveals some novel relationships. Our biogeographic analyses suggest an Australian origin for the group in the early Oligocene (31.3Mya, 95% HPD 25.2-38.2Mya). In addition, we find that dispersal events out of Australia have been numerous and frequent, particularly to New Guinea, which has also been the source of multiple back-colonizations to the Australian mainland. The phylogeny provides an important framework for studying a wide variety of macroecological and macroevolutionary themes, including character evolution, origin and timing of diversification, biogeographic patterns and species responses to climate change. PMID- 28017856 TI - A morphological and phylogenetic investigation into divergence among sympatric Australian southern bull kelps (Durvillaea potatorum and D. amatheiae sp. nov.). AB - Genetic analyses can reveal a wealth of hitherto undiscovered cryptic biodiversity. For co-occurring and morphologically similar species, the combination of molecular, ecological and morphological analyses provides an excellent opportunity for understanding some of the processes that can lead to divergence and speciation. The Australian endemic brown macroalga Durvillaea potatorum (Phaeophyceae) was examined with a combination of genetic and morphological approaches to confirm the presence of two separate species and to infer the processes that led to their divergence. A total of 331 individuals from 11 sites around coastal Tasmania were collected and measured in situ for a range of morphological and ecological characteristics. Tissue samples were also collected for each individual to allow genetic analyses using mitochondrial (COI) and nuclear (28S) markers. Genetic analyses confirmed the presence of two deeply divergent clades. The significant morphological differentiation, despite high levels of intra-lineage variability, further supported their recognition as distinct species. We describe a new species, D. amatheiae sp. nov., which is characterised by a narrower and proportionately shorter stipe, shorter total length, and higher number of stipitate lateral blades and branches than D. potatorum (sensu stricto). The occurrence of both species in sympatry along Tasmania's eastern and western coasts, as well as their contrasting patterns of haplotype diversity, supports a hypothesis of geographical isolation, allopatric speciation and subsequent secondary contact in response to sea level and ocean current change throughout the Pleistocene glaciation cycles. This research contributes to resolving the phylogenetic relationships, taxonomy and evolution of the ecologically keystone kelp genus Durvillaea. PMID- 28017857 TI - Bioacoustic and multi-locus DNA data of Ninox owls support high incidence of extinction and recolonisation on small, low-lying islands across Wallacea. AB - Known for their rich biodiversity and high level of endemism, the islands of Wallacea serve as natural laboratories for the study of spatio-temporal evolution and patterns of species diversification. Our study focuses on the owl genus Ninox, particularly the Southern Boobook (N. novaeseelandiae) and Moluccan Boobook (N. squamipila) complexes, which are widely distributed across Australasia. We conducted bioacoustic and multi-locus DNA analyses of 24 Ninox owl taxa to evaluate relationships and levels of divergence within the two complexes and ultimately assess the relationship between patterns of taxonomic differentiation and bioclimatic factors. We found that taxa that are vocally and/or genetically distinct from populations on the Australian mainland are found on islands that are significantly larger and higher in altitude than taxa that are vocally and/or genetically indistinct from populations on the Australian mainland. This pattern suggests that taxa occurring on small, low-lying Wallacean islands are likely to be recent colonisers that have dispersed from Australia. Overall, our observations demonstrate that the genus Ninox is likely to have colonised the Wallacean region multiple times as small, low-lying islands undergo frequent extinction, whereas populations on large and high-altitude islands are more resilient. PMID- 28017858 TI - Revising the phylogenetic position of the extinct Mascarene Parrot Mascarinus mascarin (Linnaeus 1771) (Aves: Psittaciformes: Psittacidae). AB - The phylogenetic position of the extinct Mascarene Parrot Mascarinus mascarin from La Reunion has been unresolved for centuries. A recent molecular study unexpectedly placed M. mascarin within the clade of phenotypically very different Vasa parrots Coracopsis. Based on DNA extracted from the only other preserved Mascarinus specimen, we show that the previously obtained cytb sequence is probably an artificial composite of partial sequences from two other parrot species and that M. mascarin is indeed a part of the Psittacula diversification, placed close to P. eupatria and P. wardi. PMID- 28017859 TI - Antiparasitic activity of menadione (vitamin K3) against Schistosoma mansoni in BABL/c mice. AB - Schistosomiasis is one of the neglected tropical diseases affecting nearly quarter of a billion people in economically challenged tropical and subtropical countries of the world. Praziquantel (PZQ) is the only drug currently available to treat this parasitic disease in spite being ineffective against juvenile worms and concerns about developing resistance to treat reinfections. Our earlier in vitro viability studies demonstrated significant antiparasitic activity of menadione (MEN) (vitamin K3) against Schistosoma mansoni adult worms. To gain insight into plausible mechanism of antischistosomal activity of MEN, its effect on superoxide anion levels in adult worms were studied in vitro which showed significant increases in both female and male worms. Further confirmation of the deleterious morphological changes in their teguments and organelles were obtained by ultrastructural analysis. Genotoxic and cytotoxic studies in male Swiss mice indicated that MEN was well tolerated at the oral dose of 500mg/kg using the criteria of MNPCE frequency and PCE/RBC ratio in the bone marrow of infected animals. The in vivo antiparasitic activity of MEN was conducted in female BALB/c mice infected with S. mansoni and significant reductions (P<0.001) in total worm burden were observed at single oral doses of 40 and 400mg/kg (48.57 and 61.90%, respectively). Additionally, MEN significantly reduced (P<0.001) the number of eggs in the liver of infected mice by 53.57 and 58.76%, respectively. Similarly, histological analysis of the livers showed a significant reduction (P<0.001) in the diameter of the granulomas. Since MEN is already in use globally as an over the-counter drug for a variety of common ailments and a dietary supplement with a safety record in par with similar products when used in recommended doses, the above antiparasitic results which compare reasonably well with PZQ, make a compelling case for considering MEN to treat S. mansoni infection in humans. PMID- 28017860 TI - In vitro antileishmanial activity of novel azoles (3-imidazolylflavanones) against promastigote and amastigote stages of Leishmania major. AB - Leishmaniasis is a protozoan infectious disease widely distributed all around the world. First line drugs including antimoniales are insufficient due to resistance in endemic areas and high toxicity. Azole antifungals like ketoconazole (KCZ) are also used as antileishmanial agents for several decades. In the present study, we evaluated in vitro antileishmanial effects of new azole antifungals namely 3 imidazolylflavanones (IFs) and their oximes (IFOs) against Leishmania major (L. major) parasites. The obtained results showed remarkable effect of our compounds on promastigote and amastigote stages of L. major. In particular, the 4-chloro analog of flavanone (IF-2) and 3-chloro substituted flavanone oxime (IFO-3) with IC50 values <=8.9MUg/mL were 8-fold more potent than KCZ (IC50=72MUg/mL) against promastigote form of L. major. In amastigote stage, the compounds IF-2 and IFO-2 decreased the mean number of infected macrophages (MIR) more than KCZ (p<0.005). In addition, compounds IF-1, IF-2, IF-4, IFO-2, IFO-3 and IFO-5 decreased the mean number of amastigotes per macrophages (MNAPM) significantly more than KCZ (p<0.005). All compounds decreased both MIR and MNAPM significantly more than control (p<0.001). Compounds IF-2 and IFO-2 with parasite survival of 7.70% and 20% had the highest inhibition on intracellular amastigotes. Although most of compounds displayed acceptable selectivity index, compound IF-2 had the highest CC50 value (115.4MUg/mL) and SI (383.3). We concluded that our new synthetic azoles displaying potent activity against L. major could be considered as new hits for drug development in the field of antileishmanial therapy. PMID- 28017861 TI - Diagnosis of Mediterranean visceral leishmaniasis by detection of Leishmania related antigen in urine and oral fluid samples. AB - Implementation of simple diagnostic tests using non-invasive collection of biological specimens is of great importance in the diagnosis of pediatric visceral leishmaniasis caused by Leishmania infantum. Latex agglutination kit (KAtex(r)) is widely used in the diagnosis mainly in L. donovani endemic areas. However its utilization in L. infantum endemic regions remains limited and its use on noninvasive biological specimen apart urine was not reported. In this study, KAtex(r) kit was used to detect Leishmania-related antigen in urine and oral fluid of 35 L. infantum visceral leishmaniasis cases and 62 controls including non-infectious disease and infectious disease controls (34 and 28 respectively). Sensitivity and specificity of urine based KAtex(r) were 51.4% and 98.3% respectively, whereas, sensitivity and specificity of oral-fluid based KAtex(r) were 80% and 88.3% respectively. Although, sensitivity of oral-fluid KAtex(r) was high, its specificity varied significantly according to the presence or the absence of an infectious disease (71.4% versus 97%, p=0.01). PMID- 28017862 TI - Critical role of the peroxisomal protein PEX16 in white adipocyte development and lipid homeostasis. AB - The importance of peroxisomes for adipocyte function is poorly understood. Herein, we provide insights into the critical role of peroxin 16 (PEX16)-mediated peroxisome biogenesis in adipocyte development and lipid metabolism. Pex16 is highly expressed in adipose tissues and upregulated during adipogenesis of murine and human cells. We demonstrate that Pex16 is a target gene of the adipogenesis "master-regulator" PPARgamma. Stable silencing of Pex16 in 3T3-L1 cells strongly reduced the number of peroxisomes while mitochondrial number was unaffected. Concomitantly, peroxisomal fatty acid (FA) oxidation was reduced, thereby causing accumulation of long- and very long-chain (polyunsaturated) FAs and reduction of odd-chain FAs. Further, Pex16-silencing decreased cellular oxygen consumption and increased FA release. Additionally, silencing of Pex16 impaired adipocyte differentiation, lipogenic and adipogenic marker gene expression, and cellular triglyceride stores. Addition of PPARgamma agonist rosiglitazone and peroxisome related lipid species to Pex16-silenced 3T3-L1 cells rescued adipogenesis. These data provide evidence that PEX16 is required for peroxisome biogenesis and highlights the relevance of peroxisomes for adipogenesis and adipocyte lipid metabolism. PMID- 28017863 TI - Metabolomic profiling of prostate cancer by matrix assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry imaging using Matrix Coating Assisted by an Electric Field (MCAEF). AB - In this work, we combined the use of two MALDI matrices (quercetin and 9 aminoacridine), a recently developed new matrix coating technique - matrix coating assisted by an electric field (MCAEF), and matrix-assisted laser desorption/ionization - Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICRMS) to detect and image endogenous compounds in the cancerous and non-cancerous regions of three human prostate cancer (stage II) tissue specimens. After three rounds of imaging data acquisitions (i.e., quercetin for positive and negative ion detection and 9-aminoacridine for negative ion detection), and metabolite identification, a total of 1091 metabolites including 1032 lipids and 59 other metabolites were routinely detected and successfully localized. Of these compounds, 250 and 217 were only detected in either the cancerous or the non-cancerous regions respectively, although we cannot rule out the presence of these metabolites at concentrations below the detection limit. In addition, 152 of the other 624 metabolites showed differential distributions (p<0.05, t-test) between the two regions of the tissues. Further studies on a larger number of clinical specimens will need to be carried out to confirm this large number of apparently cancer-related metabolites. The successful determination of the spatial locations and abundances of these endogenous biomolecules indicated significant metabolism abnormalities - e.g., increased energy charge and under-expression of neutral acyl glycerides, in the prostate cancer samples. To our knowledge, this work has resulted in MALDI-MS imaging of the largest group of metabolites in prostate cancer thus far and demonstrated the importance of using complementary matrices for comprehensive metabolomic imaging by MALDI-MS. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 28017864 TI - Modifying effects of carboxyl group on the interaction of recombinant S100A8/A9 complex with tyrosinase. AB - Tyrosinase is a determinant enzyme for modulating melanin production as its abnormal activity can result in an increased amount of melanin. Reduction of tyrosinase activity has been targeted for preventing and healing hyperpigmentation of skin, such as melanoma and age related spots. The aim of this systematic study is to investigate whether recombinant S100A8/A9 and its modified form reduce the activity of mushroom tyrosinase (MT) through changing its structure. Recombinant His-Tagged S100A8 and S100A9 are expressed in Escherichia coli BL21 (DE3) and modified using Woodward's reagent K which is a carboxyl group modifier. The structures of S100A8/A9 and its modified form are studied using fluorescence and circular dichroism spectroscopy, and the activity of MT is measured using UV-visible spectrophotometry in the presence of its substrate, L-3,4-dihydroxyphenylalanine (L-DOPA). The results show a lower stability of the modified protein when compared with its unmodified form. The interaction of S100A8/A9 with MT changes the structure and successfully reduces the activity of mushroom tyrosinase. Recombinant S100A8/A9 complex decreases MT activity which can control malignant melanoma, the most dangerous type of skin cancer. PMID- 28017865 TI - A multi-scale method for modeling degradation of bioresorbable polyesters. AB - : A multi-scale model using the cellular automata (CA) and kinetic Monte Carlo (KMC) methods is presented to simulate the degradation process of bioresorbable polyesters such as polylactide (PLA), polyglycolide (PGA) and their copolymers. The model considers the underlying chemical and physical events such as polymer chain scission, oligomer production, crystallization induced by polymer chain scissions, oligomer diffusion and microstructure evolution due to erosion of the small chains. A macroscopic device is discretized into an array of mesoscopic cells. Each cellular lattice is assumed to be made of one polymer chain, which undergoes hydrolysis reaction. The polymer chain scission is modeled using a kinetic Monte Carlo method. Oligomer production, chain crystallization and formation of cavities due to polymer collapse are also modeled on the cellular lattice. Oligomer diffusion is modeled by using Fick's laws at the macroscopic scale. The diffusion coefficient is taken as dependent on the porosity caused by the formation of the cavities. The interactions among the microscopic hydrolysis reaction, mesoscopic formation of cavities and macroscopic diffusion are taken into account. The proposed method forms Multi Scale Cellular Monte Carlo Automata (MS-CMCA). The three-scale approach consists of continuous method and discrete method to deal with certainty problem with underlying stochastic phenomenon. Demonstration examples are provided which show that the model can fit with experimental data in the literature very well. STATEMENT OF SIGNIFICANCE: The original work in this paper is a multi-scale method (including micro scale, mesoscopic scale, macro scale and their coupling) for modeling degradation of bioresorbable polyesters and provides understanding to the process of degradation of biodegradable polymers. The result denotes the solution is reliable. As we know, there have no papers recently to implement three scales modeling and its coupling. There is a two-scale model of amorphous polyester degradation described by Han and Pan (Acta Biomaterialia 2011), our model accounts for effects of re crystallization to explain the degradation process from three scales and takes into account of copolymers. From our model, the molecular weight distribution with time, chain number with time, degree of crystallinity with time, the evolution of polymer inner shape, weight loss with time (which is found from calculation that both oligomer diffusion and small molecules solution work to the weight loss) can be obtained from the calculation of the three scale model. PMID- 28017866 TI - Collagen tethering of synthetic human antimicrobial peptides cathelicidin LL37 and its effects on antimicrobial activity and cytotoxicity. AB - : Wound infections, particularly of chronic wounds, pose a substantial challenge for designing antimicrobial dressings that are both effective against pathogens, and do not interfere with wound healing. Due to their broad-spectrum antimicrobial and immunomodulatory activities, naturally-occurring antimicrobial peptides (AMPs) are promising alternative treatments. However, their cytotoxicity at high concentrations and poor stability hinders their clinical use. To mitigate these undesirable properties, we investigated the effects of tethering human AMP cathelicidin LL37 to collagen, one of the main extracellular matrix proteins in wound sites, secreted by fibroblasts, and in commercially-available wound dressings. The active domain of human AMP cathelicidin, LL37, and two chimeric peptides containing LL37 fused to collagen binding domains (derived from collagenase - cCBD-LL37 or fibronectin - fCBD-LL37) were synthesized and adsorbed to PURACOL(r) type I collagen scaffolds. After 14days, 73%, 81% and 99% of LL37, cCBD-LL37 and fCBD-LL37, respectively, was retained on the scaffolds and demonstrated undiminished antimicrobial activity when challenged with both Gram positive and Gram-negative bacterial strains. Loaded scaffolds were not cytotoxic to fibroblasts despite retaining peptides at concentrations 24 times higher than the reported cytotoxic concentrations in solution. These findings indicate that biopolymer-tethered AMPs may represent a viable alternative for preventing and treating wound infection while also supporting tissue repair. STATEMENT OF SIGNIFICANCE: Over 6.5million people annually in the United States suffer chronic wounds; many will become infected with antibiotic-resistant bacteria. Treatments used to prevent and fight infection are toxic and may hinder wound healing. AMPs are broad-spectrum antimicrobials that also promote healing; however, their instability and toxicity are major challenges. To overcome treatment gaps, we functionalized collagen scaffolds with chimeric antimicrobial peptides (AMPs) with collagen binding domains to create antimicrobial and non-cytotoxic scaffolds that may promote healing. This is the first report of CBD-mediated delivery of AMPs onto collagen scaffolds that demonstrates no cytotoxicity toward fibroblasts. This study also suggests that retention of antimicrobial activity is CBD-dependent, which provides foundations for fundamental studies of CBD-AMP mechanisms and clinical explorations. PMID- 28017867 TI - Fabrication of macromolecular gradients in aligned fiber scaffolds using a combination of in-line blending and air-gap electrospinning. AB - : Although a variety of fabrication methods have been developed to generate electrospun meshes with gradient properties, no platform has yet to achieve fiber alignment in the direction of the gradient that mimics the native tendon-bone interface. In this study, we present a method combining in-line blending and air gap electrospinning to address this limitation in the field. A custom collector with synced rotation permitted fiber collection with uniform mesh thickness and periodic copper wires were used to induce fiber alignment. Two poly(ester urethane ureas) with different hard segment contents (BPUR 50, BPUR 10) were used to generate compositional gradient meshes with and without fiber alignment. The compositional gradient across the length of the mesh was characterized using a fluorescent dye and the results indicated a continuous transition from the BPUR 50 to the BPUR 10. As expected, the fiber alignment of the gradient meshes induced a corresponding alignment of adherent cells in static culture. Tensile testing of the sectioned meshes confirmed a graded transition in mechanical properties and an increase in anisotropy with fiber alignment. Finite element modeling was utilized to illustrate the gradient mechanical properties across the full length of the mesh and lay the foundation for future computational development work. Overall, these results indicate that this electrospinning method permits the fabrication of macromolecular gradients in the direction of fiber alignment and demonstrate its potential for use in interfacial tissue engineering. STATEMENT OF SIGNIFICANCE: The native tendon-bone interface contains a gradient of properties that ensures stability of the joint. Without this transition, failure can occur due to stress concentration at the bone insertion site. Electrospinning is a method commonly used to produce fibrous grafts with gradient properties; however, no current method allows for gradients in the direction of fiber alignment. This work details a novel electrospinning method to produce gradients in the direction of fiber alignment in order to better mimic transitional zones and improve regeneration of the tendon-bone interface. In addition to the biomechanical gradients demonstrated here, this method may also be used to generate gradients of macromolecular, biochemical, and cellular cues with broad potential utility in tissue engineering. PMID- 28017868 TI - Fabrication of amorphous strontium polyphosphate microparticles that induce mineralization of bone cells in vitro and in vivo. AB - : Here we describe the fabrication process of amorphous strontium-polyphosphate microparticles ("Sr-a-polyP-MP"). The effects of these particles on growth and gene expression were investigated with SaOS-2 cells as well as with human mesenchymal stem cells (MSC) and compared with those particles prepared of amorphous calcium-polyphosphate ("Ca-a-polyP-MP") and of strontium salt. The results revealed a markedly higher stimulation of growth of MSC by "Sr-a-polyP MP" compared to "Ca-a-polyP-MP" and a significant increase in mineralization of SaOS-2 cells, as well as an enhanced upregulation of the expression of the genes encoding for alkaline phosphatase and the bone morphogenetic protein 2 (BMP-2), likewise performed with SaOS-2 cells. On the other hand, "Sr-a-polyP-MP" only slightly changes the expression of the osteocyte-specific sclerostin, a negative regulator of the canonical Wnt signaling pathway and an inhibitor of bone cell differentiation as well as of mineralization in SaOS-2 cells. In contrast, "Ca-a polyP-MP" strongly increased the steady-state expression of the SOST (sclerostin) gene. In animal studies poly(d,l-lactide-co-glycolide (PLGA) microspheres, containing polyP particles, were implanted into critical-size calvarial defects in rats. The results show that the amorphous Sr-polyP-containing microspheres caused an increased healing/mineralization of the bone defect even after short implantation periods of 8-12weeks, if compared to the beta-tri-calcium phosphate control as well as to Ca-polyP. It is proposed that "Sr-a-polyP-MP" might elicit suitable properties to be applied as a regeneratively active implant material for bone repair. STATEMENT OF SIGNIFICANCE: In this manuscript, we fabricated amorphous strontium-polyphosphate microparticles ("Sr-a-polyP-MP") and studied their effects on bone mineral formation in vitro as well as in vivo. In vitro, those particles substantially increased the expression of the genes encoding for alkaline phosphatase, the bone morphogenetic protein 2 and the mineralization. In vivo, the "Sr-a-polyP-MP" packed into PLGA microspheres and implanted into critical-size calvarial defects in rats resulted in a speeded up of the healing/mineralization of the bone defect. Those properties qualify Sr-a-polyP as a suitable biomaterial for bone regenerative implants. PMID- 28017869 TI - Endosteal-like extracellular matrix expression on melt electrospun written scaffolds. AB - : Tissue engineering technology platforms constitute a unique opportunity to integrate cells and extracellular matrix (ECM) proteins into scaffolds and matrices that mimic the natural microenvironment in vitro. The development of tissue-engineered 3D models that mimic the endosteal microenvironment enables researchers to discover the causes and improve treatments for blood and immune related diseases. The aim of this study was to establish a physiologically relevant in vitro model using 3D printed scaffolds to assess the contribution of human cells to the formation of a construct that mimics human endosteum. Melt electrospun written scaffolds were used to compare the suitability of primary human osteoblasts (hOBs) and placenta-derived mesenchymal stem cells (plMSCs) in (non-)osteogenic conditions and with different surface treatments. Using osteogenic conditions, hOBs secreted a dense ECM with enhanced deposition of endosteal proteins, such as fibronectin and vitronectin, and osteogenic markers, such as osteopontin and alkaline phosphatase, compared to plMSCs. The expression patterns of these proteins were reproducibly identified in hOBs derived from three individual donors. Calcium phosphate-coated scaffolds induced the expression of osteocalcin by hOBs when maintained in osteogenic conditions. The tissue-engineered endosteal microenvironment supported the growth and migration of primary human haematopoietic stem cells (HSCs) when compared to HSCs maintained using tissue culture plastic. This 3D testing platform represents an endosteal bone-like tissue and warrants future investigation for the maintenance and expansion of human HSCs. STATEMENT OF SIGNIFICANCE: This work is motivated by the recent interest in melt electrospinning writing, a 3D printing technique used to produce porous scaffolds for biomedical applications in regenerative medicine. Our team has been among the pioneers in building a new class of melt electrospinning devices for scaffold-based tissue engineering. These scaffolds allow structural support for various cell types to invade and deposit their own ECM, mimicking a characteristic 3D microenvironment for experimental studies. We used melt electrospun written polycaprolactone scaffolds to develop an endosteal bone-like tissue that promotes the growth of HSCs. We combine tissue engineering concepts with cell biology and stem cell research to design a physiologically relevant niche that is of prime interest to the scientific community. PMID- 28017870 TI - Biocompatibility and bioactivity of porous polymer-derived Ca-Mg silicate ceramics. AB - : Magnesium is a trace element in the human body, known to have important effects on cell differentiation and the mineralisation of calcified tissues. This study aimed to synthesise highly porous Ca-Mg silicate foamed scaffolds from preceramic polymers, with analysis of their biological response. Akermanite (Ak) and wollastonite-diopside (WD) ceramic foams were obtained from the pyrolysis of a liquid silicone mixed with reactive fillers. The porous structure was obtained by controlled water release from selected fillers (magnesium hydroxide and borax) at 350 degrees C. The homogeneous distribution of open pores, with interconnects of modal diameters of 160-180MUm was obtained and maintained after firing at 1100 degrees C. Foams, with porosity exceeding 80%, exhibited compressive strength values of 1-2MPa. In vitro studies were conducted by immersion in SBF for 21days, showing suitable dissolution rates, pH and ionic concentrations. Cytotoxicity analysis performed in accordance with ISO10993-5 and ISO10993-12 standards confirmed excellent biocompatibility of both Ak and WD foams. In addition, MC3T3 E1 cells cultured on the Mg-containing scaffolds demonstrated enhanced osteogenic differentiation and the expression of osteogenic markers including Collagen Type I, Osteopontin and Osteocalcin, in comparison to Mg-free counterparts. The results suggest that the addition of magnesium can further enhance the bioactivity and the potential for bone regeneration applications of Ca-silicate materials. STATEMENTS OF SIGNIFICANCE: Here, we show that the incorporation of Mg in Ca-silicates plays a significant role in the enhancement of the osteogenic differentiation and matrix formation of MC3T3-E1 cells, cultured on polymer derived highly porous scaffolds. Reduced degradation rates and improved mechanical properties are also observed, compared to Mg-free counterparts, suggesting the great potential of Ca-Mg silicates as bone tissue engineering materials. Excellent biocompatibility of the new materials, in accordance to the ISO10993-5 and ISO10993-12 standard guidelines, confirms the preceramic polymer route as an efficient synthesis methodology for bone scaffolds. The use of hydrated fillers as porogens is an additional novelty feature presented in the manuscript. PMID- 28017871 TI - NO-mediated anticontractile effect of the endothelium is abolished in coronary arteries of adult rats with antenatal/early postnatal hypothyroidism. AB - INTRODUCTION: Thyroid hormones are essential for proper development of many systems and organs, including circulatory system. Thyroid deficiency during pregnancy may affect the cardiovascular function in children early on and later in adulthood. However, long-term effects of early thyroid deficiency are poorly understood. We hypothesized that antenatal/early postnatal hypothyroidism will influence anticontractile effect of NO in coronary arteries of adult rats. DESIGN AND METHODS: To model antenatal/early postnatal hypothyroidism dams were treated with 6-propyl-2-thiouracil (PTU) in drinking water (0.0007%, w/v) from the first day of pregnancy till 2 weeks after delivery. Control females were supplied with pure water. Their male offspring was grown up till the age of 10-12 weeks. Systolic blood pressure was measured using tail cuff method. Septal coronary arteries were isolated and studied in wire myograph. Blood serum thyroid hormones concentrations (ELISA) and NO metabolites level (Griess method) were evaluated. RESULTS: At the age of 10-12 weeks thyroid hormones, TSH concentrations, NO metabolites and systolic blood pressure level didn't differ between groups. Arterial responses to acetylcholine and exogenous NO-donor DEA/NO were similar in control and PTU groups. Along with that, in control rats endothelium denudation strongly potentiated basal tone of arteries and their contractile responses to thromboxane A2 receptor agonist U46619. The effects of endothelium denudation were absent in PTU rats indicating that anticontractile effect of endothelium is abolished in their arteries. Further, NO-synthase inhibitor L-NNA (100 MUM) caused significant elevation of basal tone and increased U46619-induced contraction of endothelium-intact arteries only in control rats, while had no effect in PTU group. CONCLUSIONS: Our data demonstrate that NO-mediated anticontractile effect of endothelium is eliminated in coronary arteries of adult rats, which suffered from antenatal/early postnatal hypothyroidism. Therefore, maternal thyroid hormones deficiency may have detrimental consequences in adult offspring including coronary circulation pathologies, despite normal blood levels of thyroid hormones. PMID- 28017872 TI - Nitrite-derived nitric oxide reduces hypoxia-inducible factor 1alpha-mediated extracellular vesicle production by endothelial cells. AB - INTRODUCTION: Extracellular vesicles (EVs) are small, spherical particles enclosed by a phospholipid bilayer (~30-1000 nm) released from multiple cell types, and have been shown to have pathophysiological roles in a plethora of disease states. The transcription factor hypoxia-inducible factor-1 (HIF-1) allows for adaptation of cellular physiology in hypoxia and may permit the enhanced release of EVs under such conditions. Nitric oxide (NO) plays a pivotal role in vascular homeostasis, and can modulate the cellular response to hypoxia by preventing HIF-1 accumulation. We aimed to selectively target HIF-1 via sodium nitrite (NaNO2) addition, and examine the effect on endothelial EV, size, concentration and function, and delineate the role of HIF-1 in EV biogenesis. METHODS: Endothelial (HECV) cells were exposed to hypoxic conditions (1% O2, 24 h) and compared to endothelial cells exposed to normoxia (21% O2) with and without the presence of sodium nitrite (NaNO2) (30 MUM). Allopurinol (100 MUM), an inhibitor of xanthine oxidoreductase, was added both alone and in combination with NaNO2 to cells exposed to hypoxia. EV and cell preparations were quantified by nanoparticle tracking analysis and confirmed by electron microscopy. Western blotting and siRNA were used to confirm the role of HIF-1alpha and HIF-2alpha in EV biogenesis. Flow cytometry and time-resolved fluorescence were used to assess the surface and intravesicular protein content. RESULTS: Endothelial (HECV) cells exposed to hypoxia (1% O2) produced higher levels of EVs compared to cells exposed to normoxia. This increase was confirmed using the hypoxia-mimetic agent desferrioxamine. Treatment of cells with sodium nitrite (NaNO2) reduced the hypoxic enhancement of EV production. Treatment of cells with the xanthine oxidoreductase inhibitor allopurinol, in addition to NaNO2 attenuated the NaNO2 attributed suppression of hypoxia-mediated EV release. Transfection of cells with HIF-1alpha siRNA, but not HIF-2alpha siRNA, prior to hypoxic exposure prevented the enhancement of EV release. CONCLUSION: These data provide evidence that hypoxia enhances the release of EVs in endothelial cells, and that this is mediated by HIF-1alpha, but not HIF-2alpha. Furthermore, the reduction of NO2- to NO via xanthine oxidoreductase during hypoxia appears to inhibit HIF-1alpha mediated EV production. PMID- 28017873 TI - Open reduction internal fixation versus percutaneous iliosacral screw fixation for unstable posterior pelvic ring disruptions. AB - BACKGROUND: Surgical stabilization of posterior pelvic ring fractures can be achieved by either open or closed methods. They all provide a comparable biomechanical stability. The aim of the present study is to compare the clinical results of both techniques for treating posterior pelvic ring injuries. MATERIAL AND METHODS: Seventy patients operated for unstable posterior pelvic ring disruptions were retrospectively reviewed. We compared 35 patients treated by open reduction internal fixation (ORIF group) versus 35 patients stabilized by using closed reduction and percutaneous iliosacral screw fixation (CRIF group) under fluoroscopic guidance. RESULTS: According to pelvic outcome scoring system of Pohlemann et al., 28 patients out of the ORIF group obtained good or excellent results (20 excellent and 8 good), five fair and two poor. In the CRIF group, 30 patients obtained good or excellent results (25 excellent and 5 good), four fair and one poor (P=0.64). The average intraoperative blood loss in the ORIF group was 500cc with average blood transfusion of 2units (1000cc) compared to blood loss 150cc in the CRIF group, with average blood transfusion of 1unit (500cc) (P=0.002). No intraoperative complications were reported in the ORIF group while operative guide wires were broken in two cases in the CRIF group (P=0.16). There were no neurological complications observed in the ORIF group, but one radiculopathy (L5 root palsy) occurred in the CRIF group (P=0.317). In the ORIF group, three patients had superficial wound infection and one patient had deep infection while in the CRIF group, we noted only one case of deep infection (P=0.083). CONCLUSION: No difference was noticed between ORIF and CRIF. The technical decision is variable according to time of surgery, fracture types, patient general condition, skin condition, presence of ipsilateral fractures of the acetabulum and feasibility of the closed reduction. More studies are needed to identify prognostic factors related to quality of the reduction. We need for creation of decisional algorithm for ORIF versus CRIF. LEVEL OF EVIDENCE: Level 4. PMID- 28017874 TI - Factors influencing progressive collapse of the transposed necrotic lesion after transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head. AB - BACKGROUND: Transtrochanteric anterior rotational osteotomy (ARO) for osteonecrosis of the femoral head (ONFH) can preserve for a long-time collapsed femoral head. Progressive collapse of anteriorly-transposed necrotic lesion leads to secondary arthritic changes and clinical failure. Critical factors influencing collapse of the transposed necrotic lesion after ARO remain largely unknown. Therefore, we performed a retrospective study of ARO to determine: (1) if preoperative collapse influences collapse of the transposed necrotic area, (2) if any other factor may influence collapse of the transposed necrotic area. HYPOTHESIS: We hypothesized the degree of preoperative femoral head collapse influences progressive collapse of the transposed necrotic lesion after ARO. MATERIALS AND METHODS: We reviewed 47 hips in 42 patients with ONFH treated with ARO between 2000 and 2005 with a mean follow-up of 11.4 years (10-14 years). The occurrence of progressive collapse of the transposed necrotic lesion after ARO was examined using lateral radiographs taken at least once every year after ARO. The following factors were statistically analyzed: age, sex, body mass index, Harris Hip Score (HHS), preoperative level of collapse, extent of the necrotic lesion and postoperative intact ratio (ratio of the transposed intact articular surface of the femoral head). RESULTS: Progressive collapse of the transposed necrotic lesion (progressive collapse group) was seen in 17 hips (36%) during a mean period of 1.8 years (0.5-3.7 years) after ARO, which has developed within 4 years in all cases. Preoperative level of collapse in the progressive collapse group (4.4+/-1.4mm) was significantly larger than that in the non-progressive collapse group (2.1+/-1.0mm), which was independently associated with progressive collapse of the transposed necrotic lesion in multivariate analysis (P<0.0001) with cut off point of 2.98mm. In univariate analysis, lower preoperative HHS, severe extent of the necrotic lesion and the lower postoperative intact ratio were also associated with progressive collapse of the transposed necrotic lesion, but were not associated as independent factors in multivariate analysis. DISCUSSION: The current study suggests that progressive collapse of the transposed necrotic lesion after ARO depends mainly on the preoperative level of collapse (cut-off point=2.98mm). LEVEL OF EVIDENCE: IV; retrospective case series. PMID- 28017875 TI - Correlation between radiographic parameters and functional scores in degenerative lumbar and thoracolumbar scoliosis. AB - INTRODUCTION: Adult scoliosis is a condition in which the spinal deformity occurs because of degeneration. Although various studies have agreed on the importance of restoring the sagittal balance, few have evaluated the relationship between functional scores and radiological parameters. The primary objective of this retrospective study was to demonstrate the correlation between radiographic parameters and functional outcomes in adult patients with lumbar or thoracolumbar degenerative scoliosis. The secondary objective was to assess the long-term effects of posterolateral fusion for treating this deformity. STUDY OUTLINE: This single-centre retrospective study included 47 patients over 50years of age who had degenerative lumbar scoliosis treated with an instrumented posterolateral fusion; the mean follow-up was 6.4years (range 2 to 20). METHODS: Radiographic analysis of A/P and lateral full spine standing radiographs was carried out with the KEOPS software. Three pelvic parameters (pelvic tilt, pelvic incidence, sacral slope), two spinal parameters (lumbar lordosis and thoracic kyphosis) and three sagittal balance parameters (C7 sagittal tilt, C7 Barrey's ratio and spinosacral angle) were calculated. The functional outcomes were evaluated through three self-assessment questionnaires: Oswestry Disability Index, SRS-30 and SF-36. The correlation between clinical and radiographic parameters was calculated with Spearman's correlation test. RESULTS: There was a significant correlation between the SF-36 (PCS) and the following three sagittal parameters: sacral slope (r=-0.31453; P=0.04), lumbar lordosis (r=-0.30198; P=0.0491) and spinosacral angle (r=-0.311967; P=0.0366). The mean ODI score was 33.61, which corresponds to minimal to moderate disability. The mean physical (PCS) and mental (MCS) component summary scores of the SF-36 were 37.70 and 38.40, respectively. The mean SRS-30 score was 3.07. CONCLUSION: It is essential that the sagittal balance be restored when treating degenerative lumbar scoliosis to generate better functional outcomes and better quality of life. To achieve this correction, instrumented posterolateral fusion appears to be a very reliable technique that leads to lasting improvement. LEVEL OF EVIDENCE: IV. PMID- 28017876 TI - Improved acetabular fracture diagnosis after training in a CT-based method. AB - BACKGROUND: Acetabular fractures remain challenging to diagnose, particularly when they are complex. An accurate diagnosis is nevertheless crucial to select the best surgical strategy. None of the training methods described to date relies on the Letournel classification with a detailed analysis of each abnormality seen by computed tomography (CT). We therefore prospectively assessed a CT-based diagnostic method by (1) determining the rate of correct diagnoses by orthopaedic surgeons before and after training in the method, (2) comparing the times needed to read the CT images before and after training, (3) and assessing the repeatability of the method. HYPOTHESIS: Training in the CT-based diagnostic method significantly increases the rate of correct diagnoses. METHOD: The CT based diagnostic method involves analysing eight anatomical landmarks in the anterior, posterior, and no man's land zones. From our institutional database (450 cases between 2007 and 2016), we selected 35 acetabular fractures that replicated the overall distribution of fracture types. The images were reviewed by 10 inexperienced and 3 experienced readers before and after they received training in the CT-based diagnostic method. The rates of correct diagnoses and times needed to read the images were compared. Finally, an additional reading was performed to allow an assessment of reproducibility. RESULTS: After training, the rate of correct diagnoses by the unexperienced readers improved by 16.64% for all fractures combined (from 212/350, 60.5% [37-83%] to 270/350, 77.14% [63-86%]; P=0.001) and by 25.9% for associated fractures (from 90/180, 50% [11-89%] to 114/140, 75.6% [61-90%]; P=0.003). Mean time required by the inexperienced readers to interpret the 35 sets of images decreased after training, from 66.1 to 47.6min (i.e., a 1.22-minute decrease per patient, P=0.001). None of the study variables changed significantly after training of the experienced readers (P>0.05). Reproducibility among the inexperienced readers was 0.78. CONCLUSION: Analysing the eight anatomical landmarks located in the anterior, posterior, and no man's land zones is a simple and reproducible method for diagnosing all fracture patterns defined by the Letournel classification. LEVEL OF EVIDENCE: Level III, non-randomised prospective case-control diagnostic study. PMID- 28017877 TI - Negative regulation of HLA-DR expression on endothelial cells by anti-blood group A/B antibody ligation and mTOR inhibition. AB - Donor-specific antibody (DSA), particularly against HLA class II, is a major cause of chronic antibody-mediated rejection (CAMR) after transplantation, although ABO-incompatible kidney transplantation has recently demonstrated favorable graft outcomes. The condition of no injury even in the presence of anti donor antibody has been referred to as "accommodation", which would be one of the key factors for successful long-term graft survival. The purpose of this study was to analyze the beneficial effect of anti-blood group A/B antibody ligation on endothelial cells against HLA-DR antibody-mediated, complement-dependent cytotoxicity (CDC). Blood group A/B-expressing endothelial cells EA.hy926 or Human Umbilical Vein Endothelia Cells (HUVEC) were incubated with IFNgamma in the presence or absence of anti-blood group A/B antibody or mTOR inhibitor (mTOR-i) for 48h. The effects on signaling pathway, HLA expression, complement regulatory factors, and CDC were investigated. Expression of HLA-DR on EA.hy926 or HUVEC were successfully elicited by IFNgamma treatment, although little or no expression was observed in quiescent cells. Pre-incubation with anti-blood group A/B antibody had resistance to HLA-DR antibody-mediated CDC against IFNgamma treated cells in a concentration-dependent manner. This finding was ascribed to decreased expression of HLA-DR by post-translational regulation and increased expression of CD55/59, which was related to ERK and mTOR pathway inhibition. mTOR i also inhibited HLA-DR expression by itself. Furthermore, the combination of mTOR-I and anti-blood group A/B ligation had an additive effect in preventing HLA DR antibody-mediated CDC. Anti-blood group A/B antibody might play a preventive role in CAMR. Inhibition of the ERK and mTOR pathways may contribute to the development of a novel treatment in the maintenance period after transplantation. PMID- 28017878 TI - Challenge of ex vivo-stimulated CD4+CD25+ regulatory T cell-mediated alloantigen specific immunosuppression by murine cardiac transplantation. PMID- 28017880 TI - Aberrant spontaneous low-frequency brain activity in amnestic mild cognitive impairment: A meta-analysis of resting-state fMRI studies. AB - Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have provided strong evidence of abnormal spontaneous brain activity in amnestic mild cognitive impairment (aMCI). However, the conclusions have been inconsistent. A meta-analysis of whole-brain rs-fMRI studies that measured differences in the amplitude of low-frequency fluctuations (ALFF) between aMCI patients and healthy controls was conducted using the Seed-based d Mapping software package. Twelve studies reporting 14 datasets were included in the meta-analysis. Compared to healthy controls, patients with aMCI showed decreased ALFFs in the bilateral precuneus/posterior cingulate cortices, bilateral frontoinsular cortices, left occipitotemporal cortex, and right supramarginal gyrus and increased ALFFs in the right lingual gyrus, left middle occipital gyrus, left hippocampus, and left inferior temporal gyrus. A meta-regression analysis demonstrated that the increased severity of cognitive impairment in aMCI patients was associated with greater decreases in ALFFs in the cuneus/precuneus cortices. Our comprehensive meta-analysis suggests that aMCI is associated with widespread aberrant regional spontaneous brain activity, predominantly involving the default mode, salience, and visual networks, which contributes to understanding its pathophysiology. PMID- 28017879 TI - Circadian rhythms, time-restricted feeding, and healthy aging. AB - Circadian rhythms optimize physiology and health by temporally coordinating cellular function, tissue function, and behavior. These endogenous rhythms dampen with age and thus compromise temporal coordination. Feeding-fasting patterns are an external cue that profoundly influence the robustness of daily biological rhythms. Erratic eating patterns can disrupt the temporal coordination of metabolism and physiology leading to chronic diseases that are also characteristic of aging. However, sustaining a robust feeding-fasting cycle, even without altering nutrition quality or quantity, can prevent or reverse these chronic diseases in experimental models. In humans, epidemiological studies have shown erratic eating patterns increase the risk of disease, whereas sustained feeding-fasting cycles, or prolonged overnight fasting, is correlated with protection from breast cancer. Therefore, optimizing the timing of external cues with defined eating patterns can sustain a robust circadian clock, which may prevent disease and improve prognosis. PMID- 28017882 TI - Prevalence of atopic dermatitis in infants by domestic water hardness and season of birth: Cohort study. AB - BACKGROUND: Atopic dermatitis (AD) appears to be more common in regions with hard domestic water and in children with a fall/winter birth. However, it is unknown whether a synergistic effect exists. OBJECTIVE: We sought to evaluate the association between domestic water hardness and season of birth, respectively, with onset of AD within the first 18 months of life in a large Danish birth cohort. METHODS: Of children from the Danish National Birth Cohort, 52,950 were included. History of physician-diagnosed AD and population characteristics were obtained from interviews. Birth data were obtained from the Civil Registration System, and domestic water hardness data were obtained from the Geological Survey of Denmark and Greenland. The relative prevalence (RP) of AD was calculated by using log-linear binomial regression. RESULTS: The prevalence of AD was 15.0% (7,942/52,950). The RP of AD was 5% (RPtrend, 1.05; 95% CI, 1.03-1.07) higher for each 5 degrees increase in domestic water hardness (range, 6.60-35.90 German degrees of hardness [118-641 mg/L]). Although the RP of AD was higher in children with a fall (RP, 1.24; 95% CI, 1.17-1.31) or winter (RP, 1.18; 95% CI, 1.11-1.25) birth, no significant interaction was observed with domestic water hardness. The population attributable risk of hard domestic water on AD was 2%. CONCLUSION: We observed that early exposure to hard domestic water and a fall/winter birth was associated with an increase in the relative prevalence of AD within the first 18 months of life. Although the 2 exposures did not interact synergistically, a dose response relationship was observed between domestic water hardness and AD. PMID- 28017881 TI - HIV-associated cellular senescence: A contributor to accelerated aging. AB - Due to the advent of antiretroviral therapy HIV is no longer a terminal disease and the HIV infected patients are becoming increasingly older. While this is a major success, with increasing age comes an increased risk for disease. The age related comorbidities that HIV infected patients experience suggest that they suffer from accelerated aging. One possible contributor to this accelerated aging is cellular senescence, an age-associated response that can occur prematurely in response to stress, and that is emerging as a contributor to disease and aging. HIV patients experience several stressors such as the virus itself, antiretroviral drugs and to a lesser extent, substance abuse that can induce cellular senescence. This review summarizes the current knowledge of senescence induction in response to these stressors and their relation to the comorbidities in HIV patients. Cellular senescence may be a possible therapeutic target for these comorbidities. PMID- 28017883 TI - Re: Chen H. et al: Efficacy of Daily Low-dose Tadalafil for Treating Overactive Bladder: Results of a Randomized, Double-blind, Placebo-controlled Trial (Urology 2016;100:59-64). PMID- 28017884 TI - A New Laser Platform for Holmium Laser Enucleation of the Prostate: Does the Lumenis Pulse 120H Laser Platform Improve Enucleation Efficiency? AB - OBJECTIVE: To determine whether the recently introduced Lumenis Pulse 120H laser platform, which offers a dual-pedal footswitch and preset energy modes to easily switch among laser settings, facilitates a more efficient process in holmium laser enucleation of the prostate (HoLEP) for surgical treatment of benign prostatic hyperplasia. PATIENTS AND METHODS: Patients at a single institution who underwent HoLEP with the new Lumenis Pulse 120H laser platform were matched 1:2 with patients who underwent the procedure with the previously used 100-watt VersaPulse single-pedal laser platform. Matching was performed by using propensity scores calculated by a logistic model that considered preoperative transrectal ultrasound prostate volume and patient age. The primary outcome was enucleation efficiency of each platform, determined by the weight of prostate tissue resected and enucleation time. The McNemar test and a conditional logistic model were used to associate predictors and cases. RESULTS: Twenty-nine patients who underwent HoLEP with the Lumenis Pulse 120H platform were matched with 58 patients who underwent the procedure with the 100-watt platform. We observed statistically significant differences in operating room total time, procedure time, and enucleation time. Other perioperative and postoperative outcomes were comparable between the 2 groups. Enucleation efficiency was similar between the 2 laser platforms (0.89 g per minute in the control group vs 0.84 g per minute in the Lumenis Pulse 120H group). CONCLUSION: The efficiency of the new Lumenis Pulse 120H laser platform is comparable to the 100-watt VersaPulse laser platform in HoLEP when comparing g of tissue enucleated per minute. PMID- 28017885 TI - The Role of the Urologist in the Era of In Vitro Fertilization-Intracytoplasmic Sperm Injection. AB - The use of in vitro fertilization and intracytoplasmic sperm injection has dramatically increased. In spite of this, the male partner in the couple is often not evaluated for fertility status or other general health conditions associated with male infertility. Such an approach goes against established guidelines recommending dual partner evaluations and does not address longer term male health risks. In this review, we discuss the urologist's role in the era of in vitro fertilization-intracytoplasmic sperm injection, which includes diagnosing serious conditions associated with infertility, treating reversible causes of infertility, defining untreatable causes of testis failure, and, when appropriate, facilitating sperm retrieval. PMID- 28017886 TI - A 72-Year-Old Man With Obstructive Voiding Symptoms, Elevated Prostate-specific Antigen Level, and Nodular Digital Rectal Examination. PMID- 28017887 TI - Controlled nanoparticle release from a hydrogel by DNA-mediated particle disaggregation. AB - For many pharmaceutical applications, it is important that different drugs are present in the human body at distinct time points. Typically, this is achieved by a sequential administration of different therapeutic agents. A much easier alternative would be to develop a drug delivery system containing a whole set of medically active compounds which are liberated in an orchestrated and controlled manner. Yet, such a controlled, sequential release of drugs from a carrier system that can be used in a physiological situation is difficult to achieve. Here, we combine two molecular mechanisms, i.e. a build-up of osmotic pressure by the depletion of a control molecule and triggered disaggregation of nanoparticle clusters by synthetic DNA sequences. With this approach, we gain spatio-temporal control over the release of molecules and nanoparticles from a gel environment. The strategy presented here has strong implications for developing complex drug delivery systems for wound healing applications or for the sustained release of pharmaceuticals from a drug-loaded gel and will lower the need for multiple drug administrations. PMID- 28017888 TI - Nanogels for intracellular delivery of biotherapeutics. AB - Many biomolecules, such as proteins and genes, are presently used as therapeutics. However, their delivery to target sites inside cells is challenging because of their large molecular size, difficulties to pass cellular membranes and their susceptibility for enzymatic and chemical degradation. Nanogels, three dimensional networks of hydrophilic polymers, are attractive carrier systems for these biotherapeutics because they protect the biologicals against degradation and, importantly, facilitate cell internalization. Furthermore, the development of responsive nanogel delivery systems has resulted in particles that release their payloads due to a certain physiological trigger inside cells, such as in the cytosol or endocytic compartments. This paper reviews and discusses the use of nanogels, with special emphasis on biologically responsive systems, for intracellular delivery of biotherapeutics. PMID- 28017889 TI - Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer. AB - Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5 fold and the AUC0-24h in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere(r). The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor-bearing mice by 94% compared to an equivalent dose of Taxotere(r), without inducing histological changes in the major organs. PMID- 28017890 TI - Rigidity of polymer micelles affects interactions with tumor cells. AB - Controlling the interaction of drug delivery systems (DDS) with tissues is critical for the success of therapies. Specifically in cancer, due to the high density of the tumors, tissue penetration of DDS is critical and may be challenging. In previous work we have shown that Solidified Polymer Micelles (SPMs) rapidly internalize into cells and tissues. Using AFM analysis, in the present work we measured differences in rigidity of SPM compared with Wet Polymer Micelles (WPM). We further examined whether the semi-solid form of hydrated SPMs has an effect on the interaction with tumor cells both in mono-layer systems and in multi-layer clusters of cells as spheroids. For that we have performed detailed characterization of SPM compared to WPM, including examinations of particle size, stability, drug release kinetics and cell transcytosis, in melanoma A-375 cells. Cell uptake measurements were done using fluorescent signal analysis, FACS and microscopy imaging, showing enhanced abilities of SPMs to penetrate cells and tissues. A simple physical model is presented that well agrees with the experiments and provides insight about the role of particle rigidity in the engulfment mechanism. We conclude that particle rigidity enhances cellular uptake and tissue penetration and that SPMs have a promising potential as an effective and highly permeable DDS. Our findings can be important in future rational design of DDS for particle adjustment to specific tissues and pathologies. PMID- 28017892 TI - Metronomic chemotherapy: A potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation. AB - Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor's neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule. PMID- 28017891 TI - Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy. AB - Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines. PMID- 28017893 TI - Circulating miRNA landscape identifies miR-1246 as promising diagnostic biomarker in high-grade serous ovarian carcinoma: A validation across two independent cohorts. AB - High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic neoplasm, with five-year survival rate below 30%. Early disease detection is of utmost importance to improve HGSOC cure rate. Sera from 168 HGSOC patients and 65 healthy controls were gathered together from two independent collections and stratified into a training set, for miRNA marker identification, and a validation set, for data validation. An innovative statistical approach for microarray data normalization was developed to identify differentially expressed miRNAs. Signature validation in both the training and validation sets was performed by quantitative Real Time PCR (RT-qPCR). In both the training and validation sets, miR-1246, miR-595 and miR-2278 emerged significantly over expressed in the sera of HGSOC patients compared to healthy controls. Receiver Operating Characteristic curve analysis revealed miR-1246 as the best diagnostic biomarker, with a sensitivity of 87%, a specificity of 77% and an accuracy of 84%. This study is the first step in the identification of circulating miRNAs with diagnostic relevance for HGSOC. According to its specificity and sensitivity, circulating miR-1246 levels are worthy to be further investigated as potential diagnostic biomarker for HGSOC. PMID- 28017894 TI - Metronomic chemotherapy for advanced breast cancer patients. AB - Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug free breaks that leads to antitumor activity. This schedule seems to have not only a direct cytotoxicity on cancer cells but also an effect on the tumor microenvironment by inhibiting tumor angiogenesis and modulating immune response. Metronomic chemotherapy was widely investigated in patients with breast cancer. The results of these studies showed that this strategy is not only effective but has a low toxicity profile too, proposing as a promising strategy for breast cancer patients. In this review we summarize the results of Phase II and III studies evaluating metronomic therapy in metastatic breast cancer. PMID- 28017895 TI - Mobbing among care workers in nursing homes: A cross-sectional secondary analysis of the Swiss Nursing Homes Human Resources Project. AB - BACKGROUND: As a category of bullying, mobbing is a form of violence in the workplace that damages the employing organization as well as the targeted employee. In Europe, the overall prevalence of mobbing in healthcare is estimated at 4%. However, few studies have explored mobbing among long-term care workers. OBJECTIVES: This study aims to examine the frequency of mobbing in Swiss nursing homes and its relationships with care workers' (i.e. registered nurse, licensed practical nurse, assistant nurse, nurse aide) health status, job satisfaction, and intention to leave, and to explore the work environment as a contributing factor to mobbing. DESIGN: A cross-sectional, multi-center sub-study of the Swiss Nursing Homes Human Resource Project (SHURP). SETTING: Nursing homes in Switzerland's three language regions. PARTICIPANTS: A total of 162 randomly selected nursing homes with 20 or more beds, including 5311 care workers with various educational levels. METHOD: Controlling for facility and care worker characteristics, generalized estimation equations were used to assess the relationships between mobbing and care workers' health status, job satisfaction, and intention to leave as well as the association of work environment factors with mobbing. RESULTS: In Swiss nursing homes, 4.6% of surveyed care workers (n=242) reported mobbing experiences in the last 6 months. Compared to untargeted persons, those directly affected by mobbing had higher odds of health complaints (Odds Ratios (OR): 7.81, 95% CI 5.56-10.96) and intention to leave (OR: 5.12, 95% CI 3.81-6.88), and lower odds of high job satisfaction (OR: 0.19, 95% CI 0.14 0.26). Odds of mobbing occurrences increased with declining teamwork and safety climate (OR: 0.41, 95% CI 0.30-0.58), less supportive leadership (OR: 0.42, 95% CI 0.30-0.58), and higher perceived inadequacy of staffing resources (OR: 0.66, 95% CI 0.48-0.92). CONCLUSIONS: Mobbing experiences in Swiss nursing homes are relatively rare. Alongside teamwork and safety climate, risk factors are strongly associated with superiors' leadership skills. Targeted training is necessary to sensitize managers to mobbing's indicators, effects and potential influencing factors. PMID- 28017897 TI - Assay of superoxide dismutase activity in a plate assay using WST-1. AB - One of the most convenient methods for measuring superoxide dismutase activity is a plate assay using xanthine oxidase and the water soluble tetrazolium WST-1. For reliable results with WST-1, certain aspects of the procedure need to be adhered to. This article describes an appropriate protocol that minimizes sources of variability. PMID- 28017896 TI - Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats. AB - Contrast-induced acute kidney injury (CI-AKI) is an iatrogenic renal injury and associated with substantial morbidity and mortality in susceptible individuals. Despite extensive study of a variety of agents for renal protection, limited strategies have been shown to be effective in the reduction of CI-AKI. O-linked beta-N-acetylglucosamine (O-GlcNAc) is a post-translational regulatory modification of intracellular proteins and governs the function of numerous proteins, both cytosolic and nuclear. Increasing evidence suggests that O-GlcNAc levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective. However, the underlying mechanisms by which augmented OGlcNAc signaling provides renoprotection against contrast media insults is still unknown. Here, we investigated the effect of augmented O-GlcNAc signaling via glucosamine on CI-AKI and explored the underlying molecular mechanisms, particularly its relationship with PI3-kinase (PI3K)/Akt signaling. We used a novel and reliable CI-AKI model consisting of 5/6 nephrectomized (NE) rats, and a low-osmolar contrast media (iohexol, 10mL/kg, 3.5gI) injected via the tail vein after dehydration for 48h. The results showed that augmented O-GlcNAc signaling by glucosamine prevented the kidneys against iohexol-induced injury characterized by the attenuation of renal dysfunction, tubular damage, apoptosis and oxidative stress. Furthermore, this renoprotection was blocked by treatment with alloxan, an O-GlcNAc transferase inhibitor. Augmented O-GlcNAc signaling also increased the protein expression levels of phospho-Akt (Ser473, but not Thr308 and Thr450), phospho-GSK-3beta, Nrf2, and Bcl-2, and decreased the levels of Bax and cleaved caspase-3. Both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway. We further identified O-GlcNAcylated Akt through immunoprecipitation and western blot. We confirmed that Akt was modified by O-GlcNAcylation, and glucosamine pretreatment increased the O-GlcNAcylation of Akt. Collectively, the results demonstrate that glucosamine induces renoprotection against CI-AKI through augmented O-GlcNAc and activation of PI3K/Akt signaling, making it a promising strategy for preventing CI-AKI. PMID- 28017898 TI - Oxidative stress induces mitotic arrest by inhibiting Aurora A-involved mitotic spindle formation. AB - Oxidative stress contributes to the oxidative modification of cellular components, including lipids, proteins and DNA, and results in DNA damage, cell cycle arrest, cellular dysfunction and apoptosis. However, the mechanism underlying oxidative stress-induced mitotic abnormalities is not fully understood. In this study, we demonstrated that exogenous and endogenous reactive oxygen species (ROS) promoted mitotic arrest. Delayed formation and abnormal function of the mitotic spindle, which directly impeded mitosis and promoted abnormal chromosome separation, was responsible for ROS-induced mitotic arrest. As a key regulator of mitotic spindle assembly, Aurora A kinase was hyperphosphorylated in early mitosis under oxidative stress, which may disturb the function of Aurora A in mitotic spindle formation. Our findings identified a mechanism by which ROS regulate mitotic progression and indicated a potential molecular target for the treatment of oxidative stress-related diseases. PMID- 28017899 TI - Nocodazole treatment interrupted Brucella abortus invasion in RAW 264.7 cells, and successfully attenuated splenic proliferation with enhanced inflammatory response in mice. AB - Brucellosis is one of the most important and widespread zoonosis worldwide responsible for serious economic losses and considerable public health burden. In this study, we investigated the modulatory effect of a microtubule-inhibitor, nocodazole, on B. abortus infection in murine macrophages and in a mouse model. Nocodazole activated macrophages and directly inhibited the growth of Brucella in a dose-dependent manner. Nocodazole increased adhesion but reduced invasion and intracellular growth of Brucella in macrophages although it did not affect co localization of Brucella with LAMP-1. In addition, nocodazole negatively affected actin polymerization, and weakly activated ERK and p38alpha but significantly activated JNK in non-infected cells. After subsequent infection, nocodazole weakly inhibited activation of ERK and p38alpha. For the in vivo tests, nocodazole -treated mice displayed elevated levels of IFN-gamma, MCP-1 and IL-10 while Brucella-infected nocodazole -treated mice showed high levels of TNF, IFN gamma, MCP-1, IL-10 and IL-6 as compared to controls. Furthermore, nocodazole treatment reduced inflammation and Brucella proliferation in the spleens of mice. These findings highlight the potential use of nocodazole for the control of brucellosis although further investigations are encouraged to validate its therapeutic use in animal hosts. PMID- 28017901 TI - Central serous chorioretinopathy following medial transposition of split lateral rectus muscle for complete oculomotor nerve palsy. AB - Central serous chorioretinopathy (CSCR) is an incompletely understood condition in which a primary dysfunction of the choriocapillaris, retinal pigment epithelium, or both causes a detachment of the neurosensory retina. We report the first case of CSCR as a complication of strabismus surgery and explore pathogenic mechanisms. PMID- 28017900 TI - The 95DeltaG mutation in the 5'untranslated region of the norA gene increases efflux activity in Staphylococcus epidermidis isolates. AB - In the Staphylococcus aureus ATCC25923 strain, the flqB mutation in the 5'untranslated region (5'UTR) of the norA gene causes increased norA mRNA expression and high efflux activity (HEA). The involvement of the norA gene 5'UTR in HEA has not been explored in S. epidermidis; therefore, we examined the function of this region in S. epidermidis clinical isolates. The selection of isolates with HEA was performed based on ethidium bromide (EtBr) MIC values and efflux efficiency (EF) using the semi-automated fluorometric method. The function of the 5'UTR was studied by quantifying the levels of norA expression (RT-qPCR) and by identifying 5'UTR mutations by sequence analysis. Only 10 isolates from a total of 165 (6.1%) had HEA (EtBr MIC = 300 MUg/ml and EF ranged from 48.4 to 97.2%). Eight of 10 isolates with HEA had the 5'UTR 95DeltaG mutation. Isolates carrying the 95DeltaG mutation had higher levels of norA expression compared with those that did not. To corroborate that the 95DeltaG mutation is involved in HEA, a strain adapted to EtBr was obtained in vitro. This strain also presented the 95DeltaG mutation and had a high level of norA expression and EF, indicating that the 95DeltaG mutation is important for the HEA phenotype. The 95DeltaG mutation produces a different structure in the Shine-Dalgarno region, which may promote better translation of norA mRNA. To our knowledge, this is the first report to demonstrate the participation of the 5'UTR 95DeltaG mutation of the norA gene in the HEA phenotype of S. epidermidis isolates. Here, we propose that the efflux of EtBr is caused by an increment in the transcription and/or translation of the norA gene. PMID- 28017902 TI - A severe pulmonary complication in a patient with COL4A1-related disorder: A case report. AB - Patients with COL4A1 mutation-related disorders demonstrate a variety of disease phenotypes, which caused by small-vessel dysfunction in the brain, eyes, kidney, muscle, or heart. The involvement of organs mainly depends on the expression of the COL4A1 gene. Complication or dysfunction of the alveolar tissue has not been reported in the literature on COL4A1 mutation-related disorders. We herein report the case of a boy with schizencephaly, renovascular hypertension, and retinal arteriosclerosis of unknown origin, who suffered from severe and repetitive alveolar hemorrhage at 9 years of age. A novel COL4A1 mutation was finally identified as the genetic cause. The pulmonary complication in the present case represents an important pathophysiological mechanism COL4A1 mutation-related disorders; lung tissue with COL4A1 gene mutations may be vulnerable and environmental substances and microorganisms in the air could accumulate to cause chronic damage in the alveolar tissues, especially in patients with tracheostoma and renovascular hypertension. PMID- 28017903 TI - Characterization and expression analysis of an intelectin gene from Megalobrama amblycephala with excellent bacterial binding and agglutination activity. AB - Intelectin is a recently discovered lectin that plays vital roles in the innate immune response, iron metabolism and early embryogenesis. The structure, expression pattern and function of intelectin in mammals and amphibians have been well studied, while not well known in fish. In this study, we cloned a intelectin (MamINTL) gene from blunt snout bream (Megalobrama amblycephala), examined its expression patterns and explored its roles in innate immune response. The MamINTL cDNA encoded 312 amino acids, with a pro-protein of 34 kDa. Sequence analysis revealed the presence of a fibrinogen-related domain and eight conserved cysteine residues in the MamINTL. The MamINTL mRNA was detectable at various developmental stages, while it increased significantly post hatching. In healthy adult M. amblycephala, MamINTL was detected in various tissues with the highest expression in the liver. Upon challenge with Aeromonas hydrophila, significantly up regulated expression of the MamINTL mRNA was observed in the liver, spleen, kidney, intestine and gill. In addition, increased level of MamINTL protein detected by Western Blotting was also observed in the liver, kidney and spleen, indicating the participation of MamINTL in the immune response. Immunohistochemistry analysis of the M. amblycephala liver sections showed significant changes in expression and location post infection. In addition, the recombinant MamINTL showed excellent binding and agglutination activity against GFP-expressed E. coli in a Ca2+-dependent manner. Generally, the present study provides clues for a better understanding of the characterization, expression patterns and functions of fish intelectins. PMID- 28017904 TI - Raman tags: Novel optical probes for intracellular sensing and imaging. AB - Optical labels are needed for probing specific target molecules in complex biological systems. As a newly emerging category of tags for molecular imaging in live cells, the Raman label attracts much attention because of the rich information obtained from targeted and untargeted molecules by detecting molecular vibrations. Here, we list three types of Raman probes based on different mechanisms: Surface Enhanced Raman Scattering (SERS) probes, bioorthogonal Raman probes, and Resonance Raman (RR) probes. We review how these Raman probes work for detecting and imaging proteins, nucleic acids, lipids, and other biomolecules in vitro, within cells, or in vivo. We also summarize recent noteworthy studies, expound on the construction of every type of Raman probe and operating principle, sum up in tables typically targeting molecules for specific binding, and provide merits, drawbacks, and future prospects for the three Raman probes. PMID- 28017905 TI - Stem cell-derived kidney cells and organoids: Recent breakthroughs and emerging applications. AB - The global rise in the numbers of kidney patients and the shortage in transplantable organs have led to an increasing interest in kidney-specific regenerative therapies, renal disease modelling and bioartificial kidneys. Sources for large quantities of high-quality renal cells and tissues would be required, also for applications in in vitro platforms for compound safety and efficacy screening. Stem cell-based approaches for the generation of renal-like cells and tissues would be most attractive, but such methods were not available until recently. This situation has drastically changed since 2013, and various protocols for the generation of renal-like cells and precursors from pluripotent stem cells (PSC) have been established. The most recent breakthroughs were related to the establishment of various protocols for the generation of PSC derived kidney organoids. In combination with recent advances in genome editing, bioprinting and the establishment of predictive renal screening platforms this results in exciting new possibilities. This review will give a comprehensive overview over current PSC-based protocols for the generation of renal-like cells, precursors and organoids, and their current and potential applications in regenerative medicine, compound screening, disease modelling and bioartificial organs. PMID- 28017906 TI - Distensibility index of the inferior vena cava in experimental acute respiratory distress syndrome. AB - We determined the accuracy of distensibility index of inferior vena cava (dIVC) for evaluation of fluid responsiveness in rats with acute respiratory distress syndrome (ARDS) and validated this index for use in rat models. In protocol 1, E. coli lipopolysaccharide was administered in Wistar rats (n=7). After 24h, animals were mechanically ventilated, and stroke volume (SV) and dIVC quantified after blood drainage and subsequent volume expansion (albumin 20%). A receiver operating characteristic (ROC) curve was plotted to determine the optimal dIVC cutoff. In protocol 2, rats (n=10) were divided into fluid-responders (SV increase >5%) and nonresponders (SV increase <5%). The dIVC cutoff obtained from protocol 1 was 25%. Fluid responders had a 2.5 relative risk of low dIVC (<25%). The sensitivity, specificity, positive predictive, and negative predictive values for dIVC were 74%, 62%, 59%, and 76%, respectively. In conclusion, a dIVC threshold <25% was associated with positive response after volume expansion and could be used to titrate fluids in endotoxin-induced ARDS. PMID- 28017908 TI - The child protection and juvenile justice nexus in Australia: A longitudinal examination of the relationship between maltreatment and offending. AB - There is convincing evidence that many young people who are in the justice system have had contact with child protection services and that victims of childhood maltreatment are at increased risk of subsequent youth justice involvement. In Australia, however, there have been few longitudinal studies that have examined these associations and relatively less is known in this area. This study examines the overlap between the child protection and youth justice involvement in South Australia, and determines how substantiated maltreatment and variations in these experiences (e.g., the type, timing and recurrence of maltreatment) relate to criminal convictions as a youth. The results show that although the majority of child-protection involved youth do not become convicted offenders, the odds of subsequent convictions are significantly greater both for those with notifications and substantiated maltreatment and for those who had been placed in out-of-home care. Multivariate analyses revealed that the strongest predictors for receiving a conviction among maltreated youth were: male gender, Aboriginal and Torres Strait Islander ethnicity, experiences of physical abuse and emotional abuse, a greater number of substantiations (recurrence), experiencing maltreatment that commenced in childhood and continued into adolescence, and placement in out-of-home care. The mechanisms through which maltreatment might be linked with behavior are then considered, along with directions for future research in this area. PMID- 28017907 TI - Phone-delivered mindfulness training to promote medication adherence and reduce sexual risk behavior among persons living with HIV: Design and methods. AB - INTRODUCTION: Two-thirds of people living with HIV (PLWH) show sub-optimal adherence to antiretroviral therapy (ART) and one-third engages in risky sex. Both non-adherence and risky sex have been associated with emotional distress and impulsivity. To allay distress and lessen impulsivity, mindfulness training (MT) can be helpful. In this trial, we will investigate the utility of phone-delivered MT for PWLH. The primary outcomes comprise feasibility and acceptability of phone delivery; secondary outcomes are estimates of efficacy of MT on adherence to ART and safer sexual practices as well as on their hypothesized antecedents. METHODS/DESIGN: Fifty participants will be enrolled in this parallel-group randomized clinical trial (RCT). Outpatients recruited from an HIV treatment clinic will be randomized (1:1 ratio) to either MT or to an attention-control intervention; both interventions will be administered during 8 weekly phone calls. ART adherence (self-reported measure and unannounced phone pill counts), sexual behavior (self-reports and biomarkers), mindfulness, depression, stress, and impulsivity will be measured at baseline, post-intervention, and 3months post intervention. CONCLUSIONS: MT has great potential to help PLWH to manage stress, depressive symptoms, and impulsivity. Positive changes in these antecedents are expected to improve safer sex practices and ART adherence. If results from this exploratory trial support our hypotheses, we will conduct a large RCT to test (a) the efficacy of MT on ART adherence and safer sex practices and (b) the hypothesis that improved ART adherence and safer sex will reduce viral load, and decrease the incidence of sexually transmitted infections, respectively. PMID- 28017909 TI - Validation of the Night Eating Diagnostic Questionnaire (NEDQ) and its relationship with depression, sleep quality, "food addiction", and body mass index. AB - Night eating syndrome (NES) is commonly assessed using the Night Eating Questionnaire (NEQ), a validated scale of symptom severity, which does not assess all diagnostic criteria. The Night Eating Diagnostic Questionnaire (NEDQ) assesses all diagnostic criteria, but has not been fully validated. The study purpose was to establish convergent validity for the NEDQ with the NEQ. It was also expected that higher NEDQ scores would be associated with elevated depression, poorer sleep quality, "food addiction," and BMI as in other studies of NES. Students (n = 254) and community members (n = 468) were administered the NEQ, NEDQ, Pittsburgh Sleep Quality Index, Zung Self-report Depression Scale (SDS), and the Yale Food Addiction Scale (YFAS). Convergent validity between the NEDQ and the NEQ was demonstrated; the scores were significantly positively correlated. There was good agreement between the NEDQ and the NEQ in diagnosis of NES; 56% of those diagnosed by the NEDQ met the threshold score on the NEQ, while the other 44% did not. Only 5 participants out of 33 who met the NEQ threshold score for NES did not meet the NEDQ diagnostic criteria. MANOVA revealed that higher NEDQ was associated with higher SDS and YFAS scores and poorer sleep quality. Full-syndrome NES by the NEDQ was associated with higher BMI in the community group unlike the student group. Scores on all the other questionnaires were higher in the community group. The discrepancies between NEDQ and NEQ diagnosis may be due to differences in construction of the questionnaires and specifically due to the NEDQ being designed for diagnosis. The NEQ provides a convenient global score for NES severity, whereas the NEDQ, which shows convergent validity with the NEQ, provides clinically useful diagnostic categories. PMID- 28017910 TI - Nutrition knowledge and Mediterranean diet adherence in the southeast United States: Validation of a field-based survey instrument. AB - The Mediterranean diet (MD) can reduce chronic disease risk and is a recommended diet for prevention and management of diabetes. Adherence to the MD in the southeast United States where obesity and diabetes are highly prevalent is unknown. The purpose of the present study was to: 1) construct a survey instrument relevant to the general population integrating both MD related nutrition knowledge and adherence questions from previously validated instruments, and 2) assess MD related nutrition knowledge and adherence in a sample population in the southest United States. Adherance was assessed using the validated short MD Adherence Screener (MEDAS). A MD nutrition knowledge (MDNK) questionnaire was developed from previously validated general nutrition knowledge questionnaires and was validated using 127 university students enrolled in three courses with varying levels of nutrition education. Cronbach's alpha for internal validity of MDNK was acceptable for a short questionnaire (0.653). Test-retest reliability was established (r = 0.853). Field validation of the three-part survey instrument (MEDAS, MDNK and demographic questions) was subsequently performed in 230 adults shopping at supermarkets and farmers markets in eastern Alabama. Total MDNK and MEDAS scores were significantly higher in students with formal nutrition education and in patrons of farmers markets. Greater MD adherence, assessed by dividing MEDAS scores into thirds, was found with increasing formal nutrition education in university students (p = 0.002) and in farmers market participants (p < 0.001). There was a weak but significant association between MDNK and MEDAS scores within university students and participants in the field. Together, the MDNK-MEDAS survey instrument is an effective tool for assessing baseline knowledge and adherence and can be used to target nutritional interventions to improve MD adherence for prevention and management of diabetes and other chronic disease. PMID- 28017911 TI - Apelin concentrations are associated with altered atherosclerotic plaque stability mediator levels and atherosclerosis in rheumatoid arthritis. AB - BACKGROUND AND AIMS: Apelin-APJ signaling reduces cardiovascular disease (CVD) risk. In rheumatoid arthritis (RA), the atherosclerosis burden and plaque vulnerability to rupture are increased. We explored relationships between apelin concentrations and subclinical CVD in RA. METHODS: Apelin levels were measured in 235 (114 black, 121 white) RA patients. Associations between apelin concentrations and ultrasound determined carotid artery intima-media thickness (cIMT) and plaque, and levels of matrix metalloproteinase (MMP)-2 and -9 that mediate plaque stability and vulnerability respectively, were identified in confounder adjusted multivariate regression analysis. RESULTS: In all patients, apelin concentrations were directly associated with those of MMP-2 (beta (SE) = 0.324 (0.112), p = 0.004) and inversely with those of MMP-9 (beta (SE) = -0.239 (0.060), p = 0.000). Apelin concentration-subclinical CVD relations were influenced by population origin, RA disease activity, erythrocyte sedimentation rate (ESR) and interleukin (IL)-6 concentrations (interaction p = 0.001 to 0.04). Accordingly, the apelin-MMP-2 concentration relationship was reproduced in white (beta (SE) = 0.367 (0.146), p = 0.01) but not black RA patients (beta (SE) = 0.197 (0.220), p = 0.4), and only in those without (but not with) large erythrocyte sedimentation rates (beta (SE) = 0.428 (0.143), p = 0.003) or interleukin-6 levels (beta (SE) = 0.485 (0.288), p = 0.04). By contrast, the apelin-MMP-9 concentration relation was reproduced more consistently. Apelin levels were inversely related to cIMT in patients with RA remission or mild (beta (SE) = -0.068 (0.033), p = 0.04) but not moderate or high disease activity (beta (SE) = 0.015 (0.112), p = 0.7). CONCLUSIONS: Apelin concentrations are associated with altered plaque stability mediator levels and atherosclerosis in patients with RA. These relations are partially dependent on population origin and systemic inflammatory status. PMID- 28017912 TI - Differences in the integrase and reverse transcriptase transmitted resistance patterns in Northern Poland. AB - INTRODUCTION: With the widespread introduction of the integrase (In) inhibitors into clinical practice, transmission of drug resistance to this class of antiretroviral medications may expand. The aim of this study was to analyze the recent patterns of In resistance in treatment naive individuals in Northern Poland and its association with transmitted protease (PR) and reverse transcriptase (RT) mutations. METHODS: Study included 172 PR, RT and InI sequences from antiretroviral treatment naive HIV-1 infected patients linked to care in Northern Poland from 2010 to 2015. Drug resistance was interpreted based on the WHO surveillance and IAS-USA mutation lists. For phylogeny maximum likelihood and Bayesian Monte Carlo Markov Chain analyses were used. RESULTS: Overall rate of transmitted drug resistance was 12.21%. Nucleoside reverse transcriptase inhibitor (NRTI) resistance associated substitutions were found in 11.05% of cases and non-nucleoside reverse transcriptase inhibitor resistance variants in 1.16%. In multivariate models transmitted resistance strongly associated with subtype D infections [66.67% compared to the 3.84% for subtype B (p=0.001)]. No transmission of major protease or integrase mutations were observed. Polymorphisms associated with resistance against integrase inhibitor, mostly E157Q, were found in 21.5% sequences and associated with female (31.91% vs. 15.2% for male, p=0.01), injection drug use (84.21% compared to 22.08% for heterosexual and 1.39% for men-who-have-sex-with-men transmissions, p<0.0001) as well as hepatitis C coinfection [63.64% for positive, versus 8.57% for HCV antibody negative, p<0.0001]. Clusters of nucleoside reverse transcriptase mutations in subtype D and integrase E157Q variants in subtype B were observed. CONCLUSIONS: Transmitted drug resistance frequency was high in subtype D but limited to clustered NRTI mutations, being infrequent among subtype B infected cases. Despite lack of major integrase resistance in treatment naive patients, variants potentially affecting susceptibility to this class were common, which indicates the potential need for extended surveillance in the near future. PMID- 28017914 TI - Widespread of NADC30-like PRRSV in China: Another Pandora's box for Chinese pig industry as the outbreak of highly pathogenic PRRSV in 2006? PMID- 28017913 TI - Usutu virus, Belgium, 2016. AB - During late summer 2016, in a northwest European region extending over Belgium, the Netherlands and the eastern border of the German state of North Rhine Westphalia, an outbreak of wild bird deaths occurred similar to those reported on the continent since 1996. Dead birds were necropsied and examined by complementary methods. Pathologic and immunohistological investigations strongly suggested an infection by Usutu virus. Subsequently, genomic segments of the said virus were detected, the virus was isolated and its complete genome was sequenced. The strain, designated Usutu-LIEGE, is a close phylogenetic relative of those isolated in Germany which form a distinct group within the USUV phylogeny, the so-called Europe_3 lineage. Should this outbreak recapitulate the characteristics of those in southwest Germany in 2011 and in/around Vienna (Austria) in 2001, it is expected that specific avian populations in the affected area will face a significant reduction in size for a few years. PMID- 28017915 TI - Natural recombination in alphaherpesviruses: Insights into viral evolution through full genome sequencing and sequence analysis. AB - Recombination in alphaherpesviruses was first described more than sixty years ago. Since then, different techniques have been used to detect recombination in natural (field) and experimental settings. Over the last ten years, next generation sequencing (NGS) technologies and bioinformatic analyses have greatly increased the accuracy of recombination detection, particularly in field settings, thus contributing greatly to the study of natural alphaherpesvirus recombination in both human and veterinary medicine. Such studies have highlighted the important role that natural recombination plays in the evolution of many alphaherpesviruses. These studies have also shown that recombination can be a safety concern for attenuated alphaherpesvirus vaccines, particularly in veterinary medicine where such vaccines are used extensively, but also potentially in human medicine where attenuated varicella zoster virus vaccines are in use. This review focuses on the contributions that NGS and sequence analysis have made over the last ten years to our understanding of recombination in mammalian and avian alphaherpesviruses, with particular focus on attenuated live vaccine use. PMID- 28017916 TI - Effects of smartphone use with and without blue light at night in healthy adults: A randomized, double-blind, cross-over, placebo-controlled comparison. AB - Smartphones deliver light to users through Light Emitting Diode (LED) displays. Blue light is the most potent wavelength for sleep and mood. This study investigated the immediate effects of smartphone blue light LED on humans at night. We investigated changes in serum melatonin levels, cortisol levels, body temperature, and psychiatric measures with a randomized, double-blind, cross over, placebo-controlled design of two 3-day admissions. Each subject played smartphone games with either conventional LED or suppressed blue light from 7:30 to 10:00PM (150 min). Then, they were readmitted and conducted the same procedure with the other type of smartphone. Serum melatonin levels were measured in 60-min intervals before, during and after use of the smartphones. Serum cortisol levels and body temperature were monitored every 120 min. The Profile of Mood States (POMS), Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), and auditory and visual Continuous Performance Tests (CPTs) were administered. Among the 22 participants who were each admitted twice, use of blue light smartphones was associated with significantly decreased sleepiness (Cohen's d = 0.49, Z = 43.50, p = 0.04) and confusion-bewilderment (Cohen's d = 0.53, Z = 39.00, p = 0.02), and increased commission error (Cohen's d = -0.59, t = -2.64, p = 0.02). Also, users of blue light smartphones experienced a longer time to reach dim light melatonin onset 50% (2.94 vs. 2.70 h) and had increases in body temperature, serum melatonin levels, and cortisol levels, although these changes were not statistically significant. Use of blue light LED smartphones at night may negatively influence sleep and commission errors, while it may not be enough to lead to significant changes in serum melatonin and cortisol levels. PMID- 28017917 TI - Intrinsic inter-network brain dysfunction correlates with symptom dimensions in late-life depression. AB - Prior studies have demonstrated dysfunctions within the core neurocognitive networks (the executive control [ECN], default mode [DMN] and salience [SN] networks) in late-life depression (LLD). Whether inter-network dysfunctional connectivity is present in LLD, and if such disruptions are associated with core symptom dimensions is unknown. A cross-sectional resting-state functional connectivity magnetic resonance imaging investigation was conducted of LLD (n = 39) and age- and gender-equated healthy comparison (HC) (n = 29) participants. Dual regression independent component analysis approach was used to identify components that represented the ECN, DMN and SN. The intrinsic inter-network connectivity was compared between LLD and HC participants and the relationship of inter-network connectivity abnormalities with dimensional measures was examined. Relative to HC participants, LLD subjects showed decreased inter-network connectivity between the bilateral ECN and default mode subcortical (thalamus, basal ganglia and ventral striatum) networks, and the left ECN and SN insula component; and increased inter-network connections between the left ECN and posterior DMN and salience (dorsal anterior cingulate) network components. Distinct inter-network connectivity abnormalities correlated with depression and anxiety severity, and executive dysfunction in LLD participants. LLD subjects also showed pronounced intra-network connectivity differences within the ECN, whereas fewer but significant DMN and SN disruptions were also detected. Investigating the intrinsic inter-network functional connectivity could provide a mechanistic framework to better understand the neural basis that underlies core symptom dimensions in LLD. Inter-network connectivity measures have the potential to be neuroimaging biomarkers of symptom dimensions comprising LLD, and may assist in developing symptom-specific treatment algorithms. PMID- 28017918 TI - Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex. AB - Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures. PMID- 28017920 TI - Common and distinct brain regions processing multisensory bodily signals for peripersonal space and body ownership. AB - We take the feeling that our body belongs to us for granted. However, recent research has shown that it is possible to alter the subjective sensation of body ownership (BO) by manipulating multisensory bodily inputs. Several frontal and parietal regions are known to specifically process multisensory cues presented close to the body, i.e., within the peripersonal space (PPS). It has been proposed that these PPS fronto-parietal regions also underlie BO. However, most previous studies investigated the brain mechanisms of either BO or of PPS processing separately and by using a variety of paradigms. Here, we conducted an extensive meta-analysis of functional neuroimaging studies to investigate PPS and BO processing in humans in order to: a) assess quantitatively where each one of these functions was individually processed in the brain; b) identify whether and where these processes shared common or engaged distinct brain mechanisms; c) characterize these areas in terms of whole-brain co-activation networks and functions, respectively. We identified (i) a bilateral PPS network including superior parietal, temporo-parietal and ventral premotor regions and (ii) a BO network including posterior parietal cortex (right intraparietal sulcus, IPS; and left IPS and superior parietal lobule, SPL), right ventral premotor cortex, and the left anterior insula. Co-activation maps related to both PPS and BO encompassed largely overlapping fronto-parietal networks, but whereas the PPS network was more frequently associated with sensorimotor tasks, the BO network was rather associated with attention and awareness tasks. Finally, the conjunction analysis showed that (iii) PPS and BO tasks anatomically overlapped only in two clusters located in the left parietal cortex (dorsally at the intersection between the SPL, the IPS and area 2 and ventrally between areas 2 and IPS). Distinct activations were located for PPS at the temporo-parietal junction and for BO in the anterior insula. These results in PPS and BO and provide evidence-based insight about the overlap of the two processes in the IPS region and the extensive connectivity between the two associated co-activation networks. They also show significant dissociations, with PPS fronto-parietal areas located more proximal to the central sulcus than BO areas. Such anatomical distinction may also reflect the different functions of the two processes, whereby PPS areas underlie a multisensory-motor interface for body-objects interaction and BO areas being involved in bodily awareness and self consciousness. PMID- 28017919 TI - Relationship of a common OXTR gene variant to brain structure and default mode network function in healthy humans. AB - A large body of research suggests that oxytocin receptor (OXTR) gene polymorphisms may influence both social behaviors and psychiatric conditions related to social deficits, such as autism spectrum disorders (ASDs), schizophrenia, and mood and anxiety disorders. However, the neural mechanism underlying these associations is still unclear. Relative to controls, patients with these psychiatric conditions show differences in brain structure, and in resting state fMRI (rs-fMRI) signal synchronicity among default mode network (DMN) regions (also known as functional connectivity). We used a stepwise imaging genetics approach in 328 healthy young adults to test the hypothesis that 10 SNPs in OXTR are associated with differences in DMN synchronicity and structure of some of the associated brain regions. As OXTR effects may be sex-dependent, we also tested whether our findings were modulated by sex. OXTR rs2254298 A allele carriers had significantly lower rsFC with PCC in a cluster extending from the right fronto-insular cortex to the putamen and globus pallidus, and in bilateral dorsal anterior cingulate cortex (dACC) compared to individuals with the GG genotype; all observed effects were found only in males. Moreover, compared to the male individuals with GG genotype ofrs2254298, the male A allele carriers demonstrated significantly thinner cortical gray matter in the bilateral dACC. Our findings suggest that there may be sexually dimorphic mechanisms by which a naturally occurring variation of the OXTR gene may influence brain structure and function in DMN-related regions implicated in neuropsychiatric disorders. PMID- 28017921 TI - Hemifield columns co-opt ocular dominance column structure in human achiasma. AB - In the absence of an optic chiasm, visual input to the right eye is represented in primary visual cortex (V1) in the right hemisphere, while visual input to the left eye activates V1 in the left hemisphere. Retinotopic mapping In V1 reveals that in each hemisphere left and right visual hemifield representations are overlaid (Hoffmann et al., 2012). To explain how overlapping hemifield representations in V1 do not impair vision, we tested the hypothesis that visual projections from nasal and temporal retina create interdigitated left and right visual hemifield representations in V1, similar to the ocular dominance columns observed in neurotypical subjects (Victor et al., 2000). We used high-resolution fMRI at 7T to measure the spatial distribution of responses to left- and right hemifield stimulation in one achiasmic subject. T2-weighted 2D Spin Echo images were acquired at 0.8mm isotropic resolution. The left eye was occluded. To the right eye, a presentation of flickering checkerboards alternated between the left and right visual fields in a blocked stimulus design. The participant performed a demanding orientation-discrimination task at fixation. A general linear model was used to estimate the preference of voxels in V1 to left- and right-hemifield stimulation. The spatial distribution of voxels with significant preference for each hemifield showed interdigitated clusters which densely packed V1 in the right hemisphere. The spatial distribution of hemifield-preference voxels in the achiasmic subject was stable between two days of testing and comparable in scale to that of human ocular dominance columns. These results are the first in vivo evidence showing that visual hemifield representations interdigitate in achiasmic V1 following a similar developmental course to that of ocular dominance columns in V1 with intact optic chiasm. PMID- 28017923 TI - Severe mitral regurgitation: do not clip the valve-clip the leaflet. PMID- 28017924 TI - Clinical detection of mutation carriers of hypertrophic cardiomyopathy in perspective: is cardiac imaging the crystal ball of the cardiologist? PMID- 28017925 TI - Intravascular ultrasound and near-infrared spectroscopic features of coronary lesions with intraplaque haemorrhage. AB - Aims: Intraplaque haemorrhage is considered a major contributor to lesion progression. We assessed coronary lesions with intraplaque haemorrhage using intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS). Methods and results: We evaluated coronary arteries from autopsy hearts using 40MHz IVUS and NIRS and compared the imaging findings to histopathology. A total of 2324 2 mm long histological segments from 101 coronary arteries from 56 autopsy hearts were included. Intraplaque haemorrhage was found pathologically in 0.8% (18/2324) of segments. Segments with intraplaque haemorrhage had more fibroatheromas (FAs) with a greater IVUS plaque burden, a greater prevalence of IVUS echolucent zones, and a higher NIRS-lipid core burden index (LCBI) compared to segments without intraplaque haemorrhage (FAs: 72.2% vs. 18.3%, P < 0.0001; plaque burden: 59.7% [95% confidence interval: 55.5, 64.0] vs. 48.6% [45.8, 51.3], P < 0.0001; echolucent zones: 88.9% vs. 2.8%, P < 0.0001; NIRS-LCBI: 176 [88, 264] vs. 72 [53, 91], P = 0.02). The 16 IVUS superficial echolucent zones with intraplaque haemorrhage had more late FAs but shorter echolucent zone lengths (0.9 mm [0.7, 1.1] vs. 1.7 mm [1.5, 1.9], P < 0.0001) compared to 65 IVUS superficial echolucent zones without intraplaque haemorrhage. Conclusions: Intracoronary imaging features consistent with intraplaque haemorrhage included a greater plaque burden, a higher NIRS-LCBI, and a greater prevalence of IVUS echolucent zones compared to lesions without intraplaque haemorrhage. PMID- 28017922 TI - Noise and non-neuronal contributions to the BOLD signal: applications to and insights from animal studies. AB - The BOLD signal reflects hemodynamic events within the brain, which in turn are driven by metabolic changes and neural activity. However, the link between BOLD changes and neural activity is indirect and can be influenced by a number of non neuronal processes. Motion and physiological cycles have long been known to affect the BOLD signal and are present in both humans and animal models. Differences in physiological baseline can also contribute to intra- and inter subject variability. The use of anesthesia, common in animal studies, alters neural activity, vascular tone, and neurovascular coupling. Most intriguing, perhaps, are the contributions from other processes that do not appear to be neural in origin but which may provide information about other aspects of neurophysiology. This review discusses different types of noise and non-neuronal contributors to the BOLD signal, sources of variability for animal studies, and insights to be gained from animal models. PMID- 28017926 TI - A rare cause of aortic regurgitation and complete atrioventricular block. PMID- 28017927 TI - Stress echocardiography: no more challenges! PMID- 28017928 TI - Evanescent atrial tumour after percutaneous coronary intervention. PMID- 28017929 TI - Increased Efficacy of Entomopathogenic Nematode-Insecticide Combinations Against Holotrichia oblita (Coleoptera: Scarabaeidae). AB - Combinations of entomopathogenic nematodes Steinernema longicaudum X-7 and Heterorhabditis bacteriophora H06 with chlorantraniliprole, diflubenzuron, and imidacloprid insecticides at different rates for the control of the white grub, Holotrichia oblita Faldermann (Coleoptera: Scarabaeidae), were evaluated both in the laboratory and in peanut fields. In the laboratory, the combinations had a synergistic or additive effect on the second-instar larvae of H. oblita and caused faster mortality than one nematode species or insecticide alone. Heterorhabditis bacteriophora-chlorantraniliprole and H. bacteriophora imidacloprid showed synergistic effects on the larvae. When higher concentrations of the insecticides were combined with nematodes, the stronger synergistic effects were found. In peanut fields, S. longicaudum-imidacloprid, H. bacteriophora-imidacloprid, or H. bacteriophora-chlorantraniliprole also showed synergistic effects against the larvae. The three nematode-insecticide combinations produced similar percentage reductions of the grub larvae and less percentages of injured legumes, compared with the chlorpyrifos treatment. Cost benefit analysis showed that H. bacteriophora 5.0 * 103 infective juveniles (IJs) per plant (equal to 7.5 * 108 IJ ha-1) combined with imidacloprid at the recommended concentration is a practical strategy for the practitioner to manage the white grubs in the peanut production. PMID- 28017930 TI - Commentary: Delay discounting and smoking: robust correlation, but uncertain causation. PMID- 28017931 TI - Commentary: Fundamental limitations of meta-analysis of cohort studies, epidemiological challenges and the stage of obesity epidemic. PMID- 28017932 TI - Caesarean section and risk of autism across gestational age: a multi-national cohort study of 5 million births. AB - Background: The positive association between caesarean section (CS) and autism spectrum disorder (ASD) may be attributed to preterm delivery. However, due to lack of statistical power, no previous study thoroughly examined this association across gestational age. Moreover, most studies did not differentiate between emergency and planned CS. Methods: Using population-based registries of four Nordic countries and Western Australia, our study population included 4 987 390 singletons surviving their first year of life, which included 671 646 CS deliveries and 31 073 ASD children. We used logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI) for CS, adjusted for gestational age, site, maternal age and birth year. Stratified analyses were conducted by both gestational age subgroups and by week of gestation. We compared emergency versus planned CS to investigate their potential difference in the risk of ASD. Results: Compared with vaginal delivery, the overall adjusted OR for ASD in CS delivery was 1.26 (95% CI 1.22-1.30). Stratified ORs were 1.25 (1.15-1.37), 1.16 (1.09-1.23), 1.34 (1.28-1.40) and 1.17 (1.04-1.30) for subgroups of gestational weeks 26-36, 37-38, 39-41 and 42-44, respectively. CS was significantly associated with risk of ASD for each week of gestation, from week 36 to 42, consistently across study sites (OR ranged 1.16-1.38). There was no statistically significant difference between emergency and planned CS in the risk of ASD. Conclusion: Across the five countries, emergency or planned CS is consistently associated with a modest increased risk of ASD from gestational weeks 36 to 42 when compared with vaginal delivery. PMID- 28017933 TI - 20 years experience with the Ross operation in middle-aged patients: the autologous principle is still alive. AB - Objectives: Review our long-term results with the Ross operation in middle-aged patients. Methods: Between 1995 and 2016, 129 consecutive patients (106 males); mean age (47.2 +/- 5.2 years) underwent a Ross operation. Right ventricular outflow tract (RVOT) reconstruction was performed with cryopreserved (n = 45) or decellularized allografts (n = 84). Mean follow-up was 8.4 +/- 5.3 years (0.1 20.5 years). We analyzed early and late mortality, as well as valve related events and the need for reoperations. Results: Early mortality was 1.6% and late survival was 87.6% at 16 years. There were 4 reoperations on the pulmonary autograft (96% freedom at 16 years) and 2 on the pulmonary allografts (99% freedom at 16 years). The 16-year freedom from more than mild aortic insufficiency (AI) and a late root diameter >45 mm was 64% and 71%, respectively. Patients with the preoperative diagnosis of AI are at greater risk for these complications. Among the allografts, decellularized allografts showed superior freedom from structural valve dysfunction. Conclusions: The Ross operation in this cohort was associated with long-term survival similar to the general population and low incidence of reoperations. Patients with the preoperative diagnosis of AI are at increased risk for late autograft insufficiency and root dilatation. Decellularized allografts presented the best results for reconstruction of the RVOT. These results support the conclusion that the Ross operation has an important role in the treatment of middle-aged patients with aortic valve disease, especially those with pure aortic stenosis. PMID- 28017934 TI - Association between sleep disordered breathing and electrocardiographic markers of atrial abnormalities: the MESA study. AB - Aims: Electrocardiographic (ECG) markers of left atrial (LA) abnormalities have been linked to increased risk of atrial fibrillation (AF). Sleep disordered breathing (SDB) has been associated with increased risk of AF. We aimed to examine the association of ECG markers of LA abnormalities with SDB. Methods and results: 1546 participants (mean age 67.2 years, 53.4% women, and 63.3% non whites) from the Multi-Ethnic Study of Atherosclerosis Exam 5 Sleep ancillary study were included in this analysis. ECG markers of LA abnormalities (P wave terminal force in V1 (PTFV1), maximum P wave duration, PR interval and heart rate corrected PR interval) were measured from resting standard digital ECG tracings using standardized processing. Linear and logistic regression analyses were utilized to examine the cross-sectional associations of measures of SDB (apnea hypopnea index [AHI] and % time spent with oxygen saturation <90% [%SpO290]) with each ECG marker. In a multivariable analysis adjusting for demographics, cardiovascular risk factors, and comorbidities, AHI was associated with greater PTFV1 but not with other ECG markers of LA abnormalities. A 1-SD increase of AHI (16.6/hr) was associated with higher levels of PTFV1 (175.1 uV.ms, 95% confidence interval [95%CI] 75.4, 274.7) and higher odds of abnormally elevated PTFV1 (>=4000 uV.ms) (Odds Ratio: 1.21 [95%CI 1.05, 1.39]). No association was found between %SpO290 and ECG markers of LA abnormalities. Conclusion: Severity of SDB, as measured by AHI, is associated with subclinical LA disease, as indicated by PTFV1. PTFV1 may be an important ECG marker linking SDB and AF. PMID- 28017935 TI - Neural networks as a tool to predict syncope risk in the Emergency Department. AB - Aims: There is no universally accepted tool for the risk stratification of syncope patients in the Emergency Department. The aim of this study was to investigate the short-term predictive accuracy of an artificial neural network (ANN) in stratifying the risk in this patient group. Methods and results: We analysed individual level data from three prospective studies, with a cumulative sample size of 1844 subjects. Each dataset was reanalysed to reduce the heterogeneity among studies defining abnormal electrocardiogram (ECG) and serious outcomes according to a previous consensus. Ten variables from patient history, ECG, and the circumstances of syncope were used to train and test the neural network. Given the exploratory nature of this work, we adopted two approaches to train and validate the tool. One approach used 4/5 of the data for the training set and 1/5 for the validation set, and the other approach used 9/10 for the training set and 1/10 for the validation set. The sensitivity, specificity, and area under the receiver operating characteristic curve of ANNs in identifying short-term adverse events after syncope were 95% [95% confidence interval (CI) 80 98%], 67% (95% CI 62-72%), 0.69 with the 1/5 approach and 100% (95% CI 84-100%), 79% (95% CI 72-85%), 0.78 with the 1/10 approach. Conclusion: The results of our study suggest that ANNs are effective in predicting the short-term risk of patients with syncope. Prospective studies are needed in order to compare ANNs' predictive capability with existing rules and clinical judgment. PMID- 28017936 TI - Catheter ablation reduces ventricular tachycardia burden in patients with arrhythmogenic right ventricular cardiomyopathy: insights from a north-western French multicentre registry. AB - Aims: Studies assessing radiofrequency ablation (RFA) of ventricular tachycardia (VT) in arrhythmogenic right ventricular cardiomyopathy (ARVC) report VT recurrences, but have not evaluated the impact of RFA on relevant clinical events during follow-up. We aimed to investigate relevant RFA outcomes in a multicentric registry. Methods and results: This study included 49 patients with ARVC (46 with definite diagnosis, 3 with borderline diagnosis according to revised Task Force Criteria) who underwent 92 RFA procedures (83 endocardial, 9 combined endo epicardial) between 1999-2015. Ventricular tachycardia recurrences and VT burden were assessed after each procedure or after the last RFA. Over a mean follow-up of 64 +/- 51 months, VT-free survival was 37% at 1 year, 19% at 5 years, and 14% at 10 years. Ventricular tachycardia burden was significantly reduced after one procedure (23 vs. 11 VT episodes/year, P < 0.01) and after the last RFA (14 vs. 2 VT episodes/year, P < 0.01). Over a mean follow-up of 49 +/- 52 months, clinical response after the last RFA (freedom from sudden cardiac death, VT requiring hospitalization, or heart transplantation) was 86% at 1 year, 69% at 5 years, and 60% at 10 years. Clinical response was associated with right ventricular dysfunction (RVD) and low numbers of mappable VT before the first RFA. Conclusion: RFA was predominantly targeted at the endocardial surface. Ventricular tachycardia recurrences were common, but few ARVC patients experienced major clinical events during follow-up. Further studies should investigate the benefit of extensive substrate ablation combined with endo epicardial strategies. PMID- 28017937 TI - Catheter ablation of atrial fibrillation in very young adults: a 5-year follow-up study. AB - Aims: Catheter ablation is an established therapy for symptomatic atrial fibrillation (AF). However, outcome data on catheter ablation for AF in young adults is scarce. Methods and results: From 2005-2014, 85 consecutive young adults (mean age 31 +/- 4 years; 69% men) with symptomatic paroxysmal AF (PAF, n = 52) and persistent (Pers) AF (n = 33) underwent pulmonary vein isolation (PVI) [+/-ablation of complex fractionated atrial electrograms/linear lesions in PVI non-responders] at our centre. Follow-up was based on outpatient visits including 24-h Holter-ECG at 3, 6 and, 12 months post ablation, and every 12 months thereafter. Recurrence was defined as any AF/atrial tachycardia episode >30s following a 3-month blanking period. Follow-up was available for 74/85 (87%) patients. After a median follow-up of 4.6 years (Q1: 2.6; Q3: 6.6) and a mean of 1.5 +/- 0.6 (median 1, range 1-3) ablation procedures 84% [including 13% on previously ineffective antiarrhythmic drugs (AAD)] of patients were in stable SR. Single-procedural 1-year/5-year arrhythmia-free survival was 66% [95% confidence interval (CI): 56-78%]/44% (95% CI: 33-59%), respectively. Structural heart disease [SHD; hazard ratio (HR) 2.79 (95% CI 1.52-5.12), P = 0.001] and obesity [HR 1.10 (95% CI 1.00-1.21) per unit increase in body mass index >27 kg/m2, P = 0.05] independently predicted AF recurrence. Major complications occurred in 6/122 (4.9%) procedures (PV stenosis in 3, cardiac tamponade in 1, stroke in 1, and arterial-venous fistula in 1). Conclusion: In the majority of very young adults catheter ablation for AF is effective, and associated with an acceptable complication rate. SHD and obesity are predictors for AF recurrence in this population. PMID- 28017938 TI - Elucidation of hidden slow conduction by double ventricular extrastimuli: a method for further arrhythmic substrate identification in ventricular tachycardia ablation procedures. AB - Aims: Identification of local abnormal electrograms (EGMs) during ventricular tachycardia substrate ablation (VTSA) is challenging when they are hidden within the far-field signal. This study analyses whether the response to a double ventricular extrastimulus during substrate mapping could identify slow conducting areas that are hidden during sinus rhythm. Methods and results: Consecutive patients (n = 37) undergoing VTSA were prospectively included. Bipolar EGMs with >3 deflections and duration <133 ms were considered as potential hidden slow conduction EGMs (HSC-EGM) if located within/surrounding the scar area. Whenever a potential HSC-EGM was identified, a double ventricular extrastimulus was delivered. If the local potential delayed, it was annotated as HSC-EGM. The incidence of HSC-EGM in core, border-zone, and normal-voltage regions was determined. Ablation was delivered at conducting channel entrances and HSC-EGMs. VT inducibility after VTSA obtained was compared with data from a historic control group. 2417 EGMs were analyzed. 575 (23.7%) qualified as potential HSC EGM, and 198 of them were tagged as HSC-EGMs. Scars in patients with HSC-EGMs (n = 21, 56.7%) were smaller (35.424.7 vs 67.639.1 cm2; P = 0.006) and more heterogeneous (core/scar area ratio 0.250.2 vs 0.450.19; P = 0.02). 28.8% of HSC EGMs were located in normal-voltage tissue; 81.3% were targeted for ablation. Patients undergoing VTSA incorporating HSC analysis needed less radiofrequency time (17.411 vs 2310.7 minutes; P = 0.016) and had a lower rate of VT inducibility after VTSA than the historic controls (24.3% vs 50%; P = 0.018). Conclusion: Ventricular tachycardia substrate ablation incorporating HSC analysis allowed further arrhythmic substrate identification (especially in normal-voltage areas) and reduced RF time and VT inducibility after VTSA. PMID- 28017939 TI - Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. AB - Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human huntingtin in live cells, we show that localization of huntingtin to DNA damage sites is dependent on the kinase activity of ataxia telangiectasia mutated (ATM) protein. Super-resolution microscopy and biochemical assays revealed that huntingtin co-localizes with and scaffolds proteins of the DNA damage response pathway in response to oxidative stress. In HD patient fibroblasts bearing typical clinical HD allele lengths, we demonstrate that there is deficient oxidative DNA damage repair. We propose that DNA damage in HD is caused by dysfunction of the mutant huntingtin protein in DNA repair, and accumulation of DNA oxidative lesions due to elevated reactive oxygen species may contribute to the onset of HD. PMID- 28017940 TI - [The significance of exercises and sports in the locomotive syndrome prevention.] AB - In Japan, the world's fastest aging country, the locomotive syndrome that shows a decrease in the mobility due to dysfunctions of the locomotor organs is a major risk factor of long-term care need in the old age. Exercises and sports habits are well reviewed to lead to the improvement and maintenance of motor function, and exercises are also useful in the prevention of a number of musculoskeletal diseases. In addition, several trials with the exercise intervention indicated improvement in motor function, suggesting exercises could prevent the locomotive syndrome. In future, prevalence of exercise habits may lead to decrease the prevalence of locomotive syndrome, resulting in elongation of the healthy life span. PMID- 28017941 TI - [A role of exercise and sports in the prevention of osteoporosis.] AB - Physical activity plays an important role in maintaining or enhancing bone health. Jumping exercise increases bone mineral content(BMC)in prepubescent children(premenarcheal girls). Bone mineral density(BMD)is higher in adolescent athletes who are engaged in weight-bearing activities. Jumping exercise, muscle strengthening exercise, and weight-bearing plus muscle strengthening exercises increase BMD in young adults and premenopausal women. Walking, aerobic weight bearing exercise, muscle strengthening exercise, and weight-bearing plus muscle strengthening exercises maintain or increase BMD in postmenopausal women. Proper exercise and sports activity at each life stage are important strategies for preventing osteoporosis. PMID- 28017942 TI - [Physical activity for knee osteoarthritis.] AB - Elder populations have been increasing in Japan and estimated 24 million people have knee osteoarthritis(OA). Recently, people have diverse sociological background and demand for participating sports has been growing. People may participate sports to prevent some diseases such as locomotive syndrome. According to the recent studies, excessive high impact sports increase the risk of OA, while daily life exercise decrease the risk. Epidemiological approach demonstrated that reduced knee extension muscle strength increases the risk of OA. We reviewed and discussed the recent topics including efficacy of physical therapy for knee OA and how much sports activities could be beneficial after knee surgery. PMID- 28017943 TI - [Pathophysiology of immobilization osteoporosis.] AB - Enhancement of bone resorption and suppression of bone formation in response to reduced mechanical stress cause rapid bone loss. pharmacotherapy for immobilization osteoporosis in motor paralysis and long-term bedrest is effective therapy. Early intervention for rapid bone loss is important for immobilization osteoporosis. PMID- 28017944 TI - [The effects of exercise and sports activities on bone and joint morbidities.] AB - Exercise and sports activities can afford mechanical stimuli to the bone and joint tissues which are required to maintain the tissue properties. Moreover, physical exercise is an important part of the management of bone and joint morbidities such as osteoporosis, osteoarthritis, and low back pain. On the other hand, excessive mechanical load involved in exercise and sports activities can be harmful potentially causing overuse injuries of the musculoskeletal tissues. Especially, safety margin for the amount of acceptable mechanical stress is narrow in the elderly due to preexisting musculoskeletal problems. Preparticipation medical checkup and construction of appropriate exercise program based on the physical assessment are mandatory to prevent overload applied to the bone and joint tissues. PMID- 28017945 TI - [Pathological state or cause of sarcopenia.] AB - Skeletal muscle atrophy by aging(Sarcopenia)is more likely to occur in lower limbs rather than upper ones, and in the thigh rather than in the lower leg, and in the anterior side of thigh rather than posterior, faster in men than in women. It differs from disuse muscle atrophy in that it occurs slowly and gradually, hard to be recovered, or fast twitch fibers are mainly involved. Many factors or phenomena are known to contribute to proceed sarcopenia. In the aged skeletal muscle tissue, the number of satellite cells or motor neurons decrease and the function of the neuro-muscular junction declines. Oxidative stress and chronic inflammation increase as aging which relate with sarcopenia. Inflammatory cytokines, such IL-6, TNF-alpha, IL-5 play the roles Muscle protein breakdown is up regulated through ubiquitin-dependent proteolysis. Oxidative stress influences mitochondrial dysfunction or induces apoptosis. Also as aging, anabolic factors which are preferable to protein synthesis, such as IGF-1, sex hormones, vitamin D, or branched chain amino acid. PMID- 28017946 TI - [The study for effect of running on bone.] AB - Running-exercise is a weight-bearing-exercise. Power of an effect for running exercise might be different by exercise intensity, running speed, and duration time. In general, running-exercise could be effective on bone. However, in case of Female Athlete Triad, under the condition of low energy availability running exercise should not be effective positively for bone. Influence of appropriate mechanical stress, stimulate calcium absorption, and so on through running exercise could be effective positively for bone. PMID- 28017947 TI - [The effects of jumping exercise on bones.] AB - Strain rate and strain magnitude are important factors when considering osteogenic response to the bone strain imposed by mechanical stress. Jumping is a high-impact exercise that includes these factors. Ten to twenty jumping repetitions per day can increase bone mass and strength. However, the returns diminish with more than ten jumping repetitions because mechanosensitivity declines. Jumping exercise increases bone strength and bone diameters in particular. Although jump training is not suitable for older people, jump training could be an effective tool to prevent osteopenia in younger age groups. PMID- 28017948 TI - [Influences of resistance training on bone.] AB - Resistance training has been known to be effective to maintain and improve bone mineral density(BMD)and bone strength. Resistance training in combination with other types of exercise might be effective for maintaining BMD in patients with osteoporosis. Resistance training improves a decrease in BMD through an enhancement of bone formation and a suppression of bone resorption. It is thought that resistance training might affect bone metabolism through direct biomechanical force on bone cells and endocrinological factors as well as the nervous system. PMID- 28017949 TI - [Impacts of physical exercise on remodeling and hypertrophy of skeletal muscle.] AB - The skeletal muscle has high sensitivity for the mechanical stress. Because it is enlarged by training, whereas it is easily withered by lack of exercise. When we exercise, skeletal muscle cells per se sense mechanical loading, and muscular remodeling and the muscular hypertrophy occur. It has been revealed that the intracellular signaling through PGC-1alpha participates in the remodeling of the skeletal muscle, while PGC-1alpha4, an isoform of PGC-1alpha, and the dystrophin glycoprotein complex play important roles in muscular hypertrophy. This review describes the impact of physical exercise gives on the remodeling and hypertrophy of muscle through the signaling. PMID- 28017950 TI - [Effects of exercise on joints.] AB - Joints are composed of several different tissues(cartilage, capsule, meniscus, and ligament), and articular cartilage plays an important role in maintaining mechanical competence during exercise. Weight-bearing exercise has several benefit, including improved blood and synovial fluid circulation in a given joint. Consistent moderate activities facilitate cycles of anabolism and catabolism. Mechanical stresses are crucial for the maintenance of the morphologic and functional integrity of articular cartilage. Healthy cartilage is exposed by hydrostatic pressure and tensile strain, when cartilage degeneration develops, abnormal cartilage is exposed by shear stress. Moderate(physiological)exercise is characterized by a range of equilibrium between matrix anabolic and catabolic processes, or anabolism beyond catabolism. Joints are susceptible to insufficient or excessive activities, leading to joint degeneration. Lack of exercise is known to induce joint contracture seen clinically as a consequence of disuse changes, and excess mechanical stresses induce joint destruction such as osteoarthritis. Joint diseases resulting from insufficient or excessive activities are new and major challenging issues with our aging population. Thus, it is highly desirable to have an effective and efficient treatment to improve and protect against these joint diseases, and thereby to solve these clearly unanswered issues. PMID- 28017951 TI - [The Effects of Exercising in Childhood on Bone Health.] AB - In contemporary Japan, there is a polarizing trend in children who exercise more than 1,800 minutes a week and those who exercise less than 60 minutes a week. Quite a lot of girls in particular hate exercise,and therefore they don't get enough of it. Osteoporosis is a preventable disease from childhood. It is crucial for girls to exercise and to provide appropriate stimulation to bones before menarche, which increases bone mineral content. Exercise and sports in childhood are characterized as the ways to the lifelong prevention strategies against osteoporosis and fractures. It is hoped that all children practice appropriate exercise program based on scientific evidence to promote bone health. In this review article, the effects of exercising in childhood on bone health, and the points to be noted regarding childhood sports are described. PMID- 28017952 TI - [Effect of exercise and sports activity on bone health during the period of adolescence to young adulthood.] AB - Physical activity may play an important role in maximizing bone mass during adolescence to young adulthood and may have long-lasting benefits on bone health. Because peak bone mass is thought to be attained by the end of the third decade, the early adult years may be the final opportunity for its augmentation. High impact weight-bearing exercise during youth may provide lifelong benefits in terms of bone mineral content, structure and strength, and consequently reduce fracture risk. Weight-bearing exercise in youth affects bone, and these effects may be preserved as BMC, geometric and structural advantages even after 40 years. In order to evaluate the bone strength enhanced by the exercise and sporting activity, not only measuring the BMD by DXA but also the cross sectional geometric bone analysis may clarify the further contributions. PMID- 28017953 TI - [Effects of exercise and sports on bone health in pre- and postmenopausal women.] AB - Exercise and sports are an important means of improving bone health in pre- and postmenopausal women. Generally accepted strategies to improve bone health in this population aim to minimize age-related bone loss. In terms of physical activity, those forms that feature high-impact or weight-bearing activity appear to exert positive influences on bone health. Results of recent meta-analyses have shown that high-impact exercise significantly improves bone mineral density(BMD)in pre- and postmenopausal women. Studies have also shown that walking as an exercise therapy for more than 6 months exerts significant and positive effects on femoral neck BMD in peri- and postmenopausal women. Exercise and sports can be strongly recommended as non-pharmacologic interventions for improving bone health in pre- and postmenopausal women. PMID- 28017954 TI - [The effect of exercise and sports on musculoskeletal health in the elderly.] AB - There is insufficient information on the effect of exercise and sports on musculoskeletal health in the elderly. Although the effects of sports are still unclear, the effects of exercise could be significant. For example, exercise improves osteoporosis by increasing bone mineral density and ameliorates sarcopenia by increasing muscle mass, muscular strength, and walking speed. As a result, fall risk is reduced and fracture risk is also likely to improve. Tai Chi is reportedly effective for joint pain and stiffness, and may improve symptoms of osteoarthritis. PMID- 28017955 TI - [Topics for basic research(osteoclast and bone resorption)in ASBMR 2016.] AB - This is a brief report summarizing topics in ASBMR 2016 held at Georgia World Congress Center in Atlanta on September 16-19th. In this paper, I report some topics from presentation of basic research(especially osteoclast and bone resorption)in ASBMR 2016. PMID- 28017956 TI - [Topics for clinical research.] AB - Results from phase 3 study of a new drug along with effects of longer duration of a currently used drug for osteoporosis were presented. While there were several papers concerning odanacatib, the clinical development of this drug was announced to be terminated just before the meeting. In addition, low treatment rate for patients with osteoporosis because of fear for rare adverse events was emphasized to be a crisis in the treatment of osteoporosis. Finally, a new treatment for hypophosphatemic diseases was introduced. There are many clinically important topics in this meeting. PMID- 28017957 TI - [Development of osteoporosis drugs -the past, the present and the future-.] AB - From 1990s to 2000s, new drugs for osteoporosis have been developed, and the bone metabolism researches have livened up. In those days, many a people gathered to the meeting from many countries, and the each booth of pharmaceutics was proud of its preeminence. The dedications by the society and its members have had osteoporosis diagnostics developed, the anchor drugs become prevalent, and the number of fractures reduced. Although the brilliant effects of Romosozumab and Abaloparatide were presented in the meeting held this year, the members had to accept the convergence state of new drug developments. But some problems have been still left unsolved, the development of more effective drugs to prevent fragile bone fractures without any adverse events, the safety of long term use of the osteoporosis drugs, and the effectiveness of drugs to prevent from fractures of the oldest old people. PMID- 28017958 TI - Theoretical Implications of Periacetabular Osteotomy in Various Dysplastic Acetabular Cartilage Defects as Determined by Finite Element Analysis. AB - BACKGROUND Different extents and locations of acetabular cartilage defect have been supposed to be a major cause of undesirable outcomes of periacetabular osteotomy (PAO) in patients with developmental dysplasia of the hip (DDH). This study aimed to verify whether different locations of cartilage deficiency affect the biomechanical environment in a three-dimensional model utilizing finite element analysis (FEA). MATERIAL AND METHODS We developed 3 DDH models - DDH-1 (normal shape), DDH-2 (superior defect), and DDH-3 (anterosuperior defect) - by deforming from a normal hip model. We also developed 3 PAO models - PAO-1, PAO-2, and PAO-3 - through rotating osteotomized fragments. RESULTS The maximum von Mises stress in the normal hip was 13.06 MPa. In the DDH-1 model, the maximum value on the load-bearing area decreased from 15.49 MPa pre-PAO to 14.28 MPa post PAO, while stresses in the DDH-2 and DDH-3 models were higher than in the DDH-1 model, both pre-PAO and post-PAO (30.46 MPa to 26.04 MPa for DDH-2; 33.89 MPa to 27.48 MPa for DDH-3). CONCLUSIONS This study shows that, both pre- and post-PAO, different types of cartilage deficiency affect the biomechanical environment. Furthermore, in dysplastic hips, obtaining accurate three-dimensional information about the acetabular cartilage can contribute substantially to PAO decision making. PMID- 28017959 TI - Interleukin-33 in the pathogenesis of liver fibrosis: alarming ILC2 and hepatic stellate cells. PMID- 28017960 TI - Concerning the KIR gene frequencies reported by Dr Araujo et al. PMID- 28017961 TI - Ginsenoside Rb2 enhances the anti-inflammatory effect of omega-3 fatty acid in LPS-stimulated RAW264.7 macrophages by upregulating GPR120 expression. AB - Recent studies confirm that chronic low-grade inflammation is closely associated with metabolic syndromes, and anti-inflammatory therapy is a potential approach for treating cardiovascular diseases and type 2 diabetes. Accumulating evidence suggests that GPR120 activation is a feasible solution to ameliorating chronic inflammation and improving glucose metabolism. In this study we investigated whether ginsenoside Rb2 (Rb2), which exhibited regulatory activities in glucose and lipid metabolism, affected GPR120 expression in lipopolysaccharide (LPS) activated mouse macrophage RAW264.7 cells, and examined the contribution of GPR120 activation to reducing the LPS-induced inflammatory response. LPS (100 ng/mL) activated the macrophages, resulting in dramatic increases in TNF-alpha, IL-6, IL-1beta and NO production. Treatment with a omega-3 fatty acid alpha linolenic acid (ALA, 50 MUmol/L) produced moderate reduction in LPS-stimulated inflammatory cytokines and NO production (TNF-alpha and IL-6 were decreased by 46% and 42%, respectively). Pre-incubation with Rb2 (1 or 10 MUmol/L) for 12 h before ALA treatment dramatically amplified the inhibitory effects of ALA (TNF alpha and IL-6 were decreased by 74% and 86%, respectively). Compared to the treatment with ALA alone, pre-incubation with Rb2 resulted in a more prominent reduction in LPS-stimulated expression of iNOS and COX-2 and LPS-stimulated IKK/NF-kappaB phosphorylation and MAPK pathway activation. Rb2 (0.1-100 MUmol/L) dose- and time-dependently increased both mRNA and protein expression of GPR120 in RAW264.7 cells, but treatment with Rb2 alone did not exert anti-inflammatory effect in LPS-activated RAW264.7 cells. In RAW264.7 cells transfected with GPR120 shRNA, the ameliorating effects of Rb2 on LPS-induced inflammation were abolished. In conclusion, Rb2 exerts anti-inflammatory effect in LPS-stimulated mouse macrophage RAW264.7 cells in vitro by increasing GPR120 expression and subsequently enhancing omega-3 fatty acid-induced GPR120 activation. PMID- 28017962 TI - SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway. AB - Traumatic brain injury (TBI) is a major cause of disability and death in patients who experience a traumatic injury. Mitochondrial dysfunction is one of the main factors contributing to secondary injury in TBI-associated brain damage. Evidence of compromised mitochondrial function after TBI has been, but the molecular mechanisms underlying the pathogenesis of TBI are not well understood. Silent information regulator family protein 1 (SIRT1), a member of the NAD+-dependent protein deacetylases, has been shown to exhibit neuroprotective activities in animal models of various pathologies, including ischemic brain injury, subarachnoid hemorrhage and several neurodegenerative diseases. In this study, we investigated whether SIRT1 also exert neuroprotective effect post-TBI, and further explored the possible regulatory mechanisms involved in TBI pathogenesis. A lateral fluid-percussion (LFP) brain injury model was established in rats to mimic the insults of TBI. The expression levels of SIRT1, p-p38, cleaved caspase 9 and cleaved caspase-3 were all markedly increased and reached a maximum at 12 h post-TBI. In addition, mitochondrial function was impaired, evidenced by the presence of swollen and irregularly shaped mitochondria with disrupted and poorly defined cristae, a relative increase of the percentage of neurons with low DeltaPsim, the opening of mPTP, and a decrease in neuronal ATP content, especially at 12 h post-TBI. Pretreatment with the SIRT1 inhibitor sirtinol (10 mg/kg, ip) induced p-p38 activation, exacerbated mitochondrial damage, and promoted the activation of the mitochondrial apoptosis pathway. In contrast, pretreatment with the p38 inhibitor SB203580 (200 MUg/kg, ip) significantly attenuated post-TBI-induced expression of both cleaved caspase-9 and cleaved caspase-3 and mitochondrial damage, whereas it had no effects on SIRT1 expression. Together, these results reveal that the 12 h after TBI may be a crucial time at which secondary damage occurs; the activation of SIRT1 expression and inhibition of the p38 MAPK pathway may play a neuroprotective role in preventing secondary damage post-TBI. For this reason, both SIRT1 and p38 are likely to be important targets to prevent secondary damage post-TBI. PMID- 28017963 TI - The impacts of the interaction of genetic variation, CYP11beta2 and NEDD4L, with sodium intake on pediatric obesity with gender difference: a 3-year panel study. AB - : Backgrounds/Objectives:This panel study was to predict the incidences of pediatric obesity by the interaction of sodium (Na) intake and nine single nucleotide polymorphisms (SNPs) of salt-sensitive genes (SSGs), ACE(angiotensin converting enzyme), ADD1 G460W,AGT M235T,CYP11beta2 (cytochrome P450 family 11 subfamily beta-2, -aldosterone synthase),GNB3 C285T,GRK4(A142V)(G-protein-coupled receptor kinases type 4),GRK4 (A486V),NEDD4L (neural precursor cell expressed developmentally downregulated 4 like; rs2288774) and SLC12A3 (solute carrier family 12 (Na/Cl transporters)-member 3), selected from genome-wide association study. SUBJECTS/METHODS: Non-obese (non-OB) Korean children of 9 years old were recruited from eight elementary schools in Seoul in 2007 and 2009, each. Follow up subjects (total=798) in 2010 and 2012 were final participants. Participants were classified as OB group for those whose body mass index were over the 85th percentile using the 'Korean National Growth Charts', and others were classified as non-OB. With nine SNPs typing, the genetic interaction with the variation of Na intake for 3 years was evaluated as an obesity risk. RESULTS: The obesity incidence rate for non-OB children at baseline after 3 years was 10.31%. Na intake in non-OB after 3 years was significantly decreased compared with the baseline, whereas Na intake reduction was undetectable in OB. We found gender differences on association between the changes of Na intake and the obesity incidence for 3 years by the SSG variation. Odds ratio for the obesity risk was 5.75 times higher in girls having hetero/mutant types of NEDD4L with higher Na intakes (Q2+Q3+Q4 in quartiles) compared with that in the wild type with the lowest Na intake (Q1). Girls with hetero/mutant of CYP11beta2 tended to increase the obesity incidence as Na intake increased (Q10.99 for calibration and validation sets using partial least square method at all the selected wavenumber range which indicate that the model was well developed. The study revealed that the spiked samples of goat body fat could be detected even at 1% level in ghee. PMID- 28017991 TI - Rheological properties and bread quality of frozen sweet dough with added xanthan and different freezing rate. AB - In this paper the effects of frozen storage time, xanthan gum and rate of freezing on frozen sweet dough properties and unfermented bread quality was investigated. Results revealed that the water holding capacity, WHC, K1 (stress decay rate) and K2 (residual stress at the end of the stress relaxation experiment) values of frozen dough decreased with increasing frozen storage time and decreasing freezing rate; while the lowest values for these parameters were obtained for samples without xanthan gum. The amount of unfreezable water increased and freezable water decreased with addition of xanthan gum. Glass transition temperature for fresh or frozen sweet were around -37 and -39 degrees C, respectively. Addition of xanthan gum increased the glass transition temperature of fresh and fozen sweet dough. Firmness and gumminess of sweet bread increased during frozen storage which led to lower specific volume of frozen sweet bread. Increasing freezing rate and addition of xanthan gum to dough formulation improved the texture and specific volume of the final bread. PMID- 28017992 TI - A comparative study of nutmeg (Myristica fragrans Houtt.) oleoresins obtained by conventional and green extraction techniques. AB - This study evaluated the effect of conventional maceration and ultrasound assisted extraction techniques on the extraction yield, chemical composition and sensory characteristics of nutmeg oleoresins. Extraction was performed using material: absolute ethanol ratio 1:4, at room temperature. The volatile components of the oleoresin were identified by gas chromatography-mass spectrometry. The results of the study showed that the yield ranged from 4.55 to 9.63 %. Fifty-three compounds in the nutmeg oleoresin have been identified to account for >90 % of the total oil content. Sabinene, myristicin, elemicin, alpha pinene, beta-pinene, limonene, terpinen-4-ol and myristic acid were found as major compounds of all the nutmeg oleoresins obtained by different techniques. The sensory characteristics of the oleoresin were strongly influenced by the ultrasonic intensity and duration of extraction. The experimental results showed that ultrasound assisted extraction technique at 40 % of the maximal output power and 10 min produced superior quality nutmeg oleoresin with a remarkable yield. PMID- 28017993 TI - Effect of carcass fat and conformation class on consumer perception of various grilled beef muscles. AB - The aim of the study was to analyse the attributes influencing consumer perception of grilled beef steaks. The objects were 30 carcasses out of which eight cuts were obtained (2100 single samples were prepared). A total of 350 consumers were asked to rate the meat samples (6 samples for each consumer) by assessing: tenderness, juiciness, flavour, overall acceptability and satisfaction. The MQ4, which is a combination of consumer rates for tenderness, juiciness, flavour and overall acceptability that is transformed into a single parameter with greater discriminatory ability, was calculated using linear discriminate analysis. The tenderloin was the cut that had the highest ratings for all attributes, however, tenderness, juiciness, MQ4 and consumer satisfaction evaluated for oyster blade were not significantly different from tenderloin. The results of this study indicated that consumer preferences regarding grilled steak were not influenced by fat class, conformation rib fat thickness and ossification score of the carcasses but only by the type of meat cuts. PMID- 28017994 TI - Stable nisin food-grade electrospun fibers. AB - Most of antimicrobial peptides interact with food components decreasing their activity, which limit their successful incorporation into packaging material, functional foods and edible films. The aim of this work was to develop a nisin carrier. Nanofibers of amaranth protein and pullulan (50:50) loaded with nisin were obtained by electrospinning. The nanofibers morphology was determined by scanning electron microscopy and fluorescent microscopy. The molecular interactions were characterized by infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. The nisin loading efficiency as well as the antimicrobial activity against Leuconostoc mesenteroides were evaluated. The micrographs of the obtained materials exhibited smooth and continuous fibers with no defects characterized by diameters between 124 and 173 nm. The FTIR analysis showed intermolecular interactions mainly by hydrogen bonding. The electrospinning process improved the thermal properties of the polymeric mixture displacing the Tm peak to higher temperatures and increasing crystallinity. The antimicrobial activity of nisin in broth and agar against L. mesenteroides was maintained after incorporation into fibers. The results presented an outlook for the potential use of protein amaranth nanofibers when incorporating antimicrobials as a food preservation strategy. PMID- 28017995 TI - Effect of partial substitution of NaCl by KCl on physicochemical properties, biogenic amines and N-nitrosamines during ripening and storage of dry-cured bacon. AB - Effects of three salting treatments (Formulation II: 80 % NaCl + 20 % KCl; Formulation III: 60 % NaCl + 40 % KCl and Formulation IV: 40 % NaCl + 60 % KCl) on physicochemical properties, residual nitrite, N-nitrosamines and biogenic amines were compared with those of control bacons (Formulation I: 100 % NaCl) during processing and storage. Results showed that there were no significant differences among treatments for moisture, pH, and total volatile basic nitrogen (TVBN) content in dry-cured bacons during processing. The replacement of 40 % or less NaCl by KCl had no negative effects on the sensory quality of bacons during processing. Formulation III significantly reduced putrescine, cadaverine and histamine contents and enhanced nitrite residues compared with the control. After 12-day ripening and during storage, the substitution of NaCl by 60 % KCl significantly increased the N-nitrosodimethylamine (NDMA) content than the control. Principal component analysis showed that there were positive correlations between TVBN, biogenic amines (putrescine, cadaverine, histamine and tyramine) and NDMA, and negative correlation between NDMA and nitrite. These findings suggested the partial substitution of NaCl by KCl could be utilized for producing reduced-sodium dry-cured bacons to improve safety of finished products. PMID- 28017996 TI - Extraction of anthocyanins from pericarp and lipids from seeds of mangosteen (Garcinia mangostana L.) by Ultrasound-assisted extraction (UAE) and evaluation of pericarp extract enriched functional ice-cream. AB - Ultrasound-assisted extraction (UAE) was used to extract the anthocyanins from pericarp and lipids from the seeds of mangosteen. The optimum time for extraction of anthocyanin by maceration method and shaking water bath was 6 and 4 h, respectively, whereas, it was 5 min only for ultrasonic assisted extraction method. The anthocyanin content, extracted by UAE, was 23.54 mg Cyn-3-Glu/100 g. The regression equation derived by response surface methodology (RSM), was used to predict the anthocyanin content extracted by using UAE. The gas chromatography flame ionized detector analysis showed that mangosteen seed contained both saturated (palmitic acid, 4.66 g/100 g; stearic acid, 47.64 g/100 g) and unsaturated fatty acids (oleic acid, 28.62 g/100 g; linoleic acid, 14.68 g/100 g). The mangosteen ice-cream exhibited up to 83.6 and 75.1 % DPPH inhibition, on addition of 2 and 1 % mangosteen pericarp extract respectively, where as control only 52.6 %. PMID- 28017997 TI - Nutraceutical properties of cumin residue generated from Ayurvedic industries using cell line models. AB - Spent cumin (SC), generated from Ayurvedic industry, was evaluated for its nutraceutical potential in terms of antioxidant, antidiabetic and anticancer properties, and compared with that of the raw cumin (RC). SC and RC seeds were extracted with ethyl acetate (E) and methanol (M). SCM (methanol extract) were rich in p-coumaric acid, ferulic acid, ellagic acid and cinnamic acid (6.4445, 5.8286, 2.1519, 4.3085 mg/g dry extract). SCM reduced Fe2+ ion (89.68 uM AA/g dry weight), scavenged DPPH radical (IC50-238.6 ug/mL), better alpha-amylase inhibition (IC50-337.22 ug/mL) and glucose uptake activity in 30.7% of L6 cells. SCM inhibited viability, retarded migration area up to 41.02%, arrested cell cycle at S phase and induced apoptosis in 2.45% of HT29 colon cancer cells. The results indicated that dietary interventions using nutraceutical food formulation made out of SC can play a significant role in the prevention and management of degenerative diseases. PMID- 28017998 TI - The chemical composition and sensory properties of raw, cooked and grilled thigh meat of broiler chickens fed with Fe-Gly chelate. AB - The study aimed to determine the effect of Fe-glycinate chelate (Fe-Gly) on the chemical composition and sensory value of thigh meat in Ross 308 broiler chickens. Two experimental factors were introduced: (1) organic or inorganic Fe, and (2) Fe level at 40, 20 or 10 mg/kg of feed. No negative effect of using 40, 20 or 10 mg Fe-glycine chelate was recorded on the chemical composition (crude protein, fat, ash, total cholesterol, Cu, Zn, Ca and total fatty acids: SFA, MUFA, PUFA and UFA, and the n-3 and n-6 fatty acid ratio) and on the sensory properties of raw, cooked and grilled thigh meat. However, an increase in Fe content in the meat of birds receiving 40 and 20 mg of Fe-Gly was found, which had no significant effect on the sensory attributes of meat. Based on the study results it can be concluded that Fe-Gly can be used in broiler feed instead of Fe sulphate. PMID- 28017999 TI - Encapsulation of antioxidant peptide enriched casein hydrolysate using maltodextrin-gum arabic blend. AB - Antioxidant peptide enriched casein hydrolysate (AO-CH) are receiving increasing attention due to their potential as functional ingredient. Encapsulation of AO-CH using maltodextrin-gum arabic (MD/GA) as wall material could represent an attractive approach to overcome the problems related to their direct application. Encapsulation parameter were optimized using different ratio of core to coat and proportion of coating material (10:0, 8:2, 6:4) under varying pH (2-8) for encapsulation efficiency (EE).The preparation P3 resulted in maximum EE (87%) using core to coat ratio 1:20, at pH 6.0 with 8:2 MD/GA ratio. The encapsulated preparation showed reduced bitterness (p < 0.05) compared to the casein hydrolysate together with maximum retention of antioxidant activity (93%). Further, the narrow range of particle size, indicates their better stability and represents a promising food additive for incorporation in food. PMID- 28018000 TI - Development of protein fortified mango based ready-to-serve beverage. AB - Fruit drinks contain negligible amount of protein as nutritional component. Fortification of fruit drinks with protein is a challenge due to protein stability in acidic and ionic environment. Mango ready-to-serve (RTS) beverage was fortified with modified whey protein and its rheological properties were studied. Whey protein was hydrolysed with papain to improve its stability in acidic medium. The water holding capacity of whey protein increased about two times after hydrolysis. Hydrolysed and native whey protein was used at 2, 3 and 4% levels for fortification of mango based RTS beverage. Addition of hydrolysed whey protein at all the three levels did not significantly change the flow behaviour of the beverage. Native whey protein fortification resulted in precipitation; however, addition of hydrolysed whey protein led to stable beverage formulation at all the three levels. Hydrolysed whey protein imparted slight bitter taste to the RTS beverage, which was masked by beta-cyclodextrin @ 0.15% of total protein. The mango RTS beverage with 3.0% hydrolysed whey protein was found acceptable with good sensory appeal and stability during thermal processing as well storage in glass bottles. PMID- 28018001 TI - Plasma membrane damage contributes to antifungal activity of citronellal against Penicillium digitatum. AB - The antifungal activity of citronellal, a typical terpenoid of plant essential oils, against Penicllium digitatum and the possible action mode involved were investigated. Results showed that the mycelial growth and spores' germination of P. digitatum were inhibited by citronellal in a dose-dependent manner. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were determined to be 1.60 uL/mL and 3.20 uL/mL, respectively. It was found that the plasma membrane of citronellal-treated P. digitatum spores was damaged, as confirmed by the propidium iodide stain results, as well as a higher extracellular conductivity and release of cell constituents in citronellal treated samples than those of control samples. Moreover, in vivo test results demonstrated that wax + citronellal (WC; 10 * MFC) treatment effectively reduced the incidence of green mold after 5 days of storage at 25 +/- 2 degrees C. These findings suggested that the plasma damage mechanism contributed to the antifungal activity of citronellal against P. digitatum. In addition, citronellal was suggested to be a potential alternative to fungicidal agents in controlling green mold of citrus fruit. PMID- 28018002 TI - Encapsulation of eugenyl acetate in PHBV using SEDS technique and in vitro release evaluation. AB - Eugenyl acetate obtained via enzymatic esterification using Lipozyme TL IM enzyme was encapsulated in biopolymer poly(3-hydroxybutyrate-co-hydroxyvalerate) (PHBV) through solution-enhanced dispersion by supercritical fluids (SEDS). Produced particles were characterized by SEM and confocal microscopy techniques and in addition in vitro release assays were performed in isopropanol and ethyl acetate. Experimental micronization conditions comprised 8 and 10 MPa, 308 and 313 K and eugenyl acetate concentration ranging from 5 to 20 mg mL-1, keeping PHBV concentration constant (20 mg mL-1 in dichloromethane). The maximum encapsulation efficiency was 58.0 % for 5 mg mL-1of eugenyl acetate at 8 MPa and 308 K. The morphology of the encapsulated particles for most of the trials was spherical, with particle size ranging from 0.061 to 0.276 MUm. Regarding the release in ethyl acetate and isopropanol solvents the higher the affinity of the encapsulated ester of these solvents, the faster the release was observed. These results demonstrate the importance of essential clove oil esterification reaction and encapsulation of the ester by SEDS method so that this encapsulated ester can be used in different industrial applications. PMID- 28018003 TI - Refuge alternatives relief valve testing and design. AB - The U.S. National Institute for Occupational Safety and Health (NIOSH) has been researching refuge alternatives (RAs) since 2007. RAs typically have built-in pressure relief valves (PRVs) to prevent the unit from reaching unsafe pressures. The U.S. Mine Safety and Health Administration requires that these valves vent the chamber at a maximum pressure of 1.25 kPa (0.18 psi, 5.0 in. H2O), or as specified by the manufacturer, above mine atmospheric pressure in the RA. To facilitate PRV testing, an instrumented benchtop test fixture was developed using an off-the-shelf centrifugal blower and ductwork. Relief pressures and flow characteristics were measured for three units: (1) a modified polyvinyl chloride check valve, (2) an off-the-shelf brass/cast-iron butterfly check valve and (3) a commercially available valve that was designed specifically for one manufacturer's steel prefabricated RAs and had been adapted for use in one mine operator's built-in-place RA. PRVs used in tent-style RAs were not investigated. The units were tested with different modifications and configurations in order to check compliance with Title 30 Code of Federal Regulations, or 30 CFR, regulations. The commercially available relief valve did not meet the 30 CFR relief pressure specification but may meet the manufacturer's specification. Alternative valve designs were modified to meet the 30 CFR relief pressure specification, but all valve designs will need further design research to examine survivability in the event of a 103 kPa (15.0 psi) impulse overpressure during a disaster. PMID- 28018004 TI - Reducing float coal dust: Field evaluation of an inline auxiliary fan scrubber. AB - Controlling float coal dust in underground coal mines before dispersal into the general airstream can reduce the risk of mine explosions while potentially achieving a more effective and efficient use of rock dust. A prototype flooded bed scrubber was evaluated for float coal dust control in the return of a continuous miner section. The scrubber was installed inline between the face ventilation tubing and an exhausting auxiliary fan. Airborne and deposited dust mass measurements were collected over three days at set distances from the fan exhaust to assess changes in float coal dust levels in the return due to operation of the scrubber. Mass-based measurements were collected on a per-cut basis and normalized on the basis of per ton mined by the continuous miner. The results show that average float coal dust levels measured under baseline conditions were reduced by more than 90 percent when operating the scrubber. PMID- 28018005 TI - Positioning Food Cultures: 'Alternative' Food as Distinctive Consumer Practice. AB - Many sociological studies to date have explored the role of food in marking distinctions between groups. Less well understood is how 'alternative' means of food consumption become figured in such relations. Drawing on accounts of food practice derived from 20 in-depth interviews and a two-year period of participant observation, this article considers the role of class culture in the practice of alternative food consumption. As participants speak their position, expressions of class arise through discussions of food practice. Having explored how food plays a part in marking boundaries of distinction between foods 'for us' and 'for them', we are reminded that in reproducing certain ideas about proper eating, we confine our imagining of alternative food futures to a limited politics of the possible. The article highlights implications for future development of equitable alternatives to conventional foodways. PMID- 28018006 TI - Embodying Deficiency Through 'Affective Practice': Shame, Relationality, and the Lived Experience of Social Class and Gender in Higher Education. AB - Based on empirical research with participants from working-class backgrounds studying and working in higher education in England, this article examines the lived experience of shame. Building on a feminist Bourdieusian approach to social class analysis, the article contends that 'struggles for value' within the field of higher education precipitate classed judgements, which have the potential to generate shame. Through an examination of the 'affective practice' of judgement, the article explores the contingencies that precipitate shame and the embodiment of deficiency. The article links the classed and gendered dimensions of shame with valuation, arguing that the fundamental relationality of social class and gender is not only generative of shame, but that shame helps in turn to structure both working-class experience and a view of the working classes as 'deficient'. PMID- 28018007 TI - Online Updating of Statistical Inference in the Big Data Setting. AB - We present statistical methods for big data arising from online analytical processing, where large amounts of data arrive in streams and require fast analysis without storage/access to the historical data. In particular, we develop iterative estimating algorithms and statistical inferences for linear models and estimating equations that update as new data arrive. These algorithms are computationally efficient, minimally storage-intensive, and allow for possible rank deficiencies in the subset design matrices due to rare-event covariates. Within the linear model setting, the proposed online-updating framework leads to predictive residual tests that can be used to assess the goodness-of-fit of the hypothesized model. We also propose a new online-updating estimator under the estimating equation setting. Theoretical properties of the goodness-of-fit tests and proposed estimators are examined in detail. In simulation studies and real data applications, our estimator compares favorably with competing approaches under the estimating equation setting. PMID- 28018008 TI - Van't Hoff global analyses of variable temperature isothermal titration calorimetry data. AB - Isothermal titration calorimetry (ITC) can provide detailed information on the thermodynamics of biomolecular interactions in the form of equilibrium constants, KA , and enthalpy changes, DeltaHA . A powerful application of this technique involves analyzing the temperature dependences of ITC-derived KA and DeltaHA values to gain insight into thermodynamic linkage between binding and additional equilibria, such as protein folding. We recently developed a general method for global analysis of variable temperature ITC data that significantly improves the accuracy of extracted thermodynamic parameters and requires no prior knowledge of the coupled equilibria. Here we report detailed validation of this method using Monte Carlo simulations and an application to study coupled folding and binding in an aminoglycoside acetyltransferase enzyme. PMID- 28018009 TI - Bioaugmentation of Soil Contaminated with Azoxystrobin. AB - The presence of fungicides in the natural environment, either resulting from deliberate actions or not, has become a serious threat to many ecosystems, including soil. This can be prevented by taking appropriate measures to clear the environment of organic contamination, including fungicides. Therefore, a study was conducted aimed at determining the effect of bioaugmentation of soil exposed to azoxystrobin on its degradation and activity of selected enzymes (dehydrogenases, catalase, urease, acidic phosphatase, alkaline phosphatase). A model experiment was conducted for 90 days on two types of soil: loamy sand (pHKCl-5.6) and sandy loam (pHKCl-7.0), which were contaminated by azoxystrobin at 22.50 mg kg-1 DM of soil and inoculated with a specific consortium of microorganisms. Four strains of bacteria were used in the experiment (Bacillus sp. LM655314.1, B. cereus KC848897.1, B. weihenstephanensis KF831381.1, B. megaterium KJ843149.1) and two strains of mould fungi (Aphanoascus terreus AB861677.1, A. fulvescens JN943451.1). Inoculation of soil with the consortium of microorganisms accelerated the degradation of azoxystrobin. The isolated microorganisms were more active in loamy sand because within 90 days azoxystrobin was degraded by 24% (Bacillus sp., B. cereus, B. weihenstephanensis, B. megaterium) to 78% (Aphanoascus terreus, A. fulvescens). In sandy loam, azoxystrobin was degraded by 9% (Aphanoascus terreus, A. fulvescens) to 29% (Bacillus sp., B. cereus, B. weihenstephanensis, B. megaterium and Aphanoascus terreus, A. fulvescens). The activity of soil enzymes was also changed as a result of inoculation of soil with microorganisms. The activity of all of the enzymes under study was found to have increased when soil augmentation was performed. PMID- 28018012 TI - Experimental identification of the behaviour of and lateral forces from freely walking pedestrians on laterally oscillating structures in a virtual reality environment. AB - Modelling pedestrian loading on lively structures such as bridges remains a challenge. This is because pedestrians have the capacity to interact with vibrating structures which can lead to amplification of the structural response. Current design guidelines are often inaccurate and limiting as they do not sufficiently acknowledge this effect. This originates in scarcity of data on pedestrian behaviour on vibrating ground and uncertainty as to the accuracy of results from previous experimental campaigns aiming to quantify pedestrian behaviour in this case. To this end, this paper presents a novel experimental setup developed to evaluate pedestrian actions on laterally oscillating ground in the laboratory environment while avoiding the implications of artificiality and allowing for unconstrained gait. A biologically-inspired approach was adopted in its development, relying on appreciation of operational complexities of biological systems, in particular their adaptability and control requirements. In determination of pedestrian forces to the structure consideration was given to signal processing issues which have been neglected in past studies. The results from tests conducted on the setup are related to results from previous experimental investigations and outputs of the inverted pendulum pedestrian model for walking on laterally oscillating ground, which is capable of generating self excited forces. PMID- 28018010 TI - Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis). AB - PURPOSE: To determine whether some of the most often used uveal melanoma cell lines resemble their original tumor. METHODS: Analysis of the literature, patient charts, histopathology, mutations, chromosome status, HLA type, and expression of melanocyte markers on cell lines and their primary tumors. We examined five cell lines and the primary tumors from which they were derived. RESULTS: Four of the five examined primary tumors were unusual: one occupied the orbit, two were recurrences after prior irradiation, and one developed in an eye with a nevus of Ota. One cell line did not contain the GNA11 mutation, but it was present in the primary tumor. Three of the primary tumors had monosomy 3 (two of these lacked BAP1 expression); however, all five cell lines showed disomy 3 and BAP1 expression. All of the cell lines had gain of 8q. Two cell lines lacked expression of melanocyte markers, although these were present in the corresponding primary tumor. CONCLUSIONS: All cell lines could be traced back to their original uveal melanoma. Four of the five primary tumors were unusual. Cell lines often differed from their primary tumor in chromosome status and melanocyte markers. However, their specific chromosome aberrations and capacity to continue proliferation characterize them as uveal melanoma cell lines. PMID- 28018011 TI - DESCARTES' RULE OF SIGNS AND THE IDENTIFIABILITY OF POPULATION DEMOGRAPHIC MODELS FROM GENOMIC VARIATION DATA. AB - The sample frequency spectrum (SFS) is a widely-used summary statistic of genomic variation in a sample of homologous DNA sequences. It provides a highly efficient dimensional reduction of large-scale population genomic data and its mathematical dependence on the underlying population demography is well understood, thus enabling the development of efficient inference algorithms. However, it has been recently shown that very different population demographies can actually generate the same SFS for arbitrarily large sample sizes. Although in principle this nonidentifiability issue poses a thorny challenge to statistical inference, the population size functions involved in the counterexamples are arguably not so biologically realistic. Here, we revisit this problem and examine the identifiability of demographic models under the restriction that the population sizes are piecewise-defined where each piece belongs to some family of biologically-motivated functions. Under this assumption, we prove that the expected SFS of a sample uniquely determines the underlying demographic model, provided that the sample is sufficiently large. We obtain a general bound on the sample size sufficient for identifiability; the bound depends on the number of pieces in the demographic model and also on the type of population size function in each piece. In the cases of piecewise-constant, piecewise-exponential and piecewise-generalized-exponential models, which are often assumed in population genomic inferences, we provide explicit formulas for the bounds as simple functions of the number of pieces. Lastly, we obtain analogous results for the "folded" SFS, which is often used when there is ambiguity as to which allelic type is ancestral. Our results are proved using a generalization of Descartes' rule of signs for polynomials to the Laplace transform of piecewise continuous functions. PMID- 28018013 TI - Functional CAR models for large spatially correlated functional datasets. AB - We develop a functional conditional autoregressive (CAR) model for spatially correlated data for which functions are collected on areal units of a lattice. Our model performs functional response regression while accounting for spatial correlations with potentially nonseparable and nonstationary covariance structure, in both the space and functional domains. We show theoretically that our construction leads to a CAR model at each functional location, with spatial covariance parameters varying and borrowing strength across the functional domain. Using basis transformation strategies, the nonseparable spatial functional model is computationally scalable to enormous functional datasets, generalizable to different basis functions, and can be used on functions defined on higher dimensional domains such as images. Through simulation studies, we demonstrate that accounting for the spatial correlation in our modeling leads to improved functional regression performance. Applied to a high-throughput spatially correlated copy number dataset, the model identifies genetic markers not identified by comparable methods that ignore spatial correlations. PMID- 28018014 TI - Active Clinical Trials for Personalized Medicine. AB - Individualized treatment rules (ITRs) tailor treatments according to individual patient characteristics. They can significantly improve patient care and are thus becoming increasingly popular. The data collected during randomized clinical trials are often used to estimate the optimal ITRs. However, these trials are generally expensive to run, and, moreover, they are not designed to efficiently estimate ITRs. In this article, we propose a cost-effective estimation method from an active learning perspective. In particular, our method recruits only the "most informative" patients (in terms of learning the optimal ITRs) from an ongoing clinical trial. Simulation studies and real-data examples show that our active clinical trial method significantly improves on competing methods. We derive risk bounds and show that they support these observed empirical advantages. Supplementary materials for this article are available online. PMID- 28018015 TI - Bayesian Nonparametric Estimation for Dynamic Treatment Regimes with Sequential Transition Times. AB - We analyze a dataset arising from a clinical trial involving multi-stage chemotherapy regimes for acute leukemia. The trial design was a 2 * 2 factorial for frontline therapies only. Motivated by the idea that subsequent salvage treatments affect survival time, we model therapy as a dynamic treatment regime (DTR), that is, an alternating sequence of adaptive treatments or other actions and transition times between disease states. These sequences may vary substantially between patients, depending on how the regime plays out. To evaluate the regimes, mean overall survival time is expressed as a weighted average of the means of all possible sums of successive transitions times. We assume a Bayesian nonparametric survival regression model for each transition time, with a dependent Dirichlet process prior and Gaussian process base measure (DDP-GP). Posterior simulation is implemented by Markov chain Monte Carlo (MCMC) sampling. We provide general guidelines for constructing a prior using empirical Bayes methods. The proposed approach is compared with inverse probability of treatment weighting, including a doubly robust augmented version of this approach, for both single-stage and multi-stage regimes with treatment assignment depending on baseline covariates. The simulations show that the proposed nonparametric Bayesian approach can substantially improve inference compared to existing methods. An R program for implementing the DDP-GP-based Bayesian nonparametric analysis is freely available at https://www.ma.utexas.edu/users/yxu/. PMID- 28018016 TI - An "Ethical Moment" in Data Sharing. AB - This study draws on interviews with forty-nine members of a biomedical research community in the UK that is involved in negotiating data sharing and access. During an interview, an interviewee used the words "ethical moment" to describe a confrontation between collaborators in relation to data sharing. In this article, I use this as a lens for thinking about relations between "the conceptual and the empirical" in a way that allows both analyst and actor to challenge the status quo and consider other ethical possibilities. Drawing on actor network theory (ANT), I approach "the empirical" using the concepts of controversy and ontological uncertainty as methodological tools to tackle the problem of ethics. I suggest that these concepts also provide a bridge for understanding the ontological structure of the virtual and the actual, as described in Deleuze's Difference and Repetition. While other science and technology studies scholars have sought to draw on Deleuze, this article addresses the integration of ethics and empirical research. It arises as a critical reaction to existing treatments of this problem as found in empirical ethics, especially in the sociology of bioethics, and indirectly in ANT texts. PMID- 28018017 TI - Cause-Specific Hazard Regression for Competing Risks Data Under Interval Censoring and Left Truncation. AB - Inference for cause-specific hazards from competing risks data under interval censoring and possible left truncation has been understudied. Aiming at this target, a penalized likelihood approach for a Cox-type proportional cause specific hazards model is developed, and the associated asymptotic theory is discussed. Monte Carlo simulations show that the approach performs very well for moderate sample sizes. An application to a longitudinal study of dementia illustrates the practical utility of the method. In the application, the age specific hazards of AD, other dementia and death without dementia are estimated, and risk factors of all competing risks are studied. PMID- 28018018 TI - Mutual Influences Between Parental Psychological Distress and Alcohol Use and Child Problem Behavior in a Cohort of Urban African Americans. AB - Parental psychological distress, parental alcohol involvement, and child/adolescent behavior problems frequently occur together with deleterious effects on individuals and families. Extant evidence suggests that parental and child problems are related; however, less is known about the patterns and directions of their relationships over time, particularly among African Americans. This study examined mutual influences between parental psychological distress and alcohol use, and child/adolescent problem behavior over a 10-year period (N = 459), using data from a prospective cohort study of urban African Americans. Using structural equation modeling, we found statistically significant effects between young adult parents' alcohol use and later adolescent problem behavior, as well as child problem behavior and parental alcohol use 10 years later, even after taking into account potential extraneous influences. Findings also demonstrated continuity in parental and child behaviors over time, and several contemporaneous associations. These findings have potential implications for intervention planning among African American families. PMID- 28018019 TI - The role of hypercorrection in the acquisition of L2 phonemic contrasts. PMID- 28018020 TI - Mental Illness in Assisted Living: Challenges for Quality of Life and Care. AB - An unknown number of mentally ill elders in the U.S. receive care in assisted living [AL], along with persons facing physical or cognitive challenges. While dementia is familiar in AL, our data indicate that neither staff nor residents are prepared to work or live with the mentally ill. Challenges are created for professionals, since these residents bring diverse needs. Daily inter-resident interactions are also disrupted or stressful. Qualitative data describe the impacts on quality of resident life as well as care and management dilemmas identified within five assisted living settings having varying presence of mental illness among residents. PMID- 28018021 TI - Exome Sequencing Identifies Compound Heterozygous Mutations in SCN5A Associated with Congenital Complete Heart Block in the Thai Population. AB - Background. Congenital heart block is characterized by blockage of electrical impulses from the atrioventricular node (AV node) to the ventricles. This blockage can be caused by ion channel impairment that is the result of genetic variation. This study aimed to investigate the possible causative variants in a Thai family with complete heart block by using whole exome sequencing. Methods. Genomic DNA was collected from a family consisting of five family members in three generations in which one of three children in generation III had complete heart block. Whole exome sequencing was performed on one complete heart block affected child and one unaffected sibling. Bioinformatics was used to identify annotated and filtered variants. Candidate variants were validated and the segregation analysis of other family members was performed. Results. This study identified compound heterozygous variants, c.101G>A and c.3832G>A, in the SCN5A gene and c.28730C>T in the TTN gene. Conclusions. Compound heterozygous variants in the SCN5A gene were found in the complete heart block affected child but these two variants were found only in the this affected sibling and were not found in other unaffected family members. Hence, these variants in the SCN5A gene were the most possible disease-causing variants in this family. PMID- 28018023 TI - Camels and Climate Resilience: Adaptation in Northern Kenya. AB - In the drylands of Africa, pastoralists have been facing new challenges, including those related to environmental shocks and stresses. In northern Kenya, under conditions of reduced rainfall and more frequent droughts, one response has been for pastoralists to focus increasingly on camel herding. Camels have started to be kept at higher altitudes and by people who rarely kept camels before. The development has been understood as a climate change adaptation strategy and as a means to improve climate resilience. Since 2003, development organizations have started to further the trend by distributing camels in the region. Up to now, little has been known about the nature of, reasons for, or ramifications of the increased reliance on camels. The paper addresses these questions and concludes that camels improve resilience in this dryland region, but only under certain climate change scenarios, and only for some groups. PMID- 28018022 TI - Human Ribosomal Proteins RPeL27, RPeL43, and RPeL41 Are Upregulated in Nasopharyngeal Carcinoma Cell Lines. AB - Apart from their canonical role in ribosome biogenesis, there is increasing evidence of ribosomal protein genes' involvement in various cancers. A previous study by us revealed significant differential expression of three ribosomal protein genes (RPeL27, RPeL41, and RPeL43) between cell lines derived from tumor and normal nasopharyngeal epithelium. However, the results therein were based on a semiquantitative assay, thus preliminary in nature. Herein, we provide findings of a deeper analysis of these three genes in the context to nasopharyngeal carcinoma (NPC) tumorigenesis. Their expression patterns were analyzed in a more quantitative manner at transcript level. Their protein expression levels were also investigated. We showed results that are contrary to previous report. Rather than downregulation, these genes were significantly overexpressed in NPC cell lines compared to normal control at both transcript and protein levels. Nevertheless, their association with NPC has been established. Immunoprecipitation pulldown assays indicate the plausible interaction of either RPeL27 or RPeL43 with POTEE/TUBA1A and ACTB/ACTBL2 complexes. In addition, RPeL43 is shown to bind with MRAS and EIF2S1 proteins in a NPC cell line (HK1). Our findings support RPeL27, RPeL41, and RPeL43 as potential markers of NPC and provide insights into the interaction targets of RPeL27 and RPeL43 proteins. PMID- 28018024 TI - Returns to food and agricultural R&D investments in Sub-Saharan Africa, 1975 2014. AB - Research-enabled growth in agricultural productivity is pivotal to sub-Saharan Africa's overall economic growth prospects. Yet, investments in research and development (R&D) targeted to many national food and agricultural economies throughout Africa are fragile and faltering. To gain insight into what could be driving this trend, this article updates, summarizes and reassesses the published evidence on the returns to African agricultural R&D. Based on a compilation of 113 studies published between 1975 and 2014 spanning 25 countries, the reported internal rates of return (IRRs) to food and agricultural research conducted in or of direct consequence for sub-Saharan Africa averaged 42.3%py. In addition to the 376 IRR estimates, the corresponding 129 benefit-cost ratios (BCRs) averaged 30.1. Most (96.5%) of the returns-to-research evaluations are of publicly performed R&D, and the majority (87.6%) of the studies were published in the period 1990-2009. The large dispersion in the reported IRRs and BCRs makes it difficult to discern meaningful patterns in the evidence. Moreover, the distribution of IRRs is heavily (positively) skewed, such that the median value (35.0%py) is well below the mean, like it is for research done elsewhere in the world (mean 62.4%py; median 38.0%py). Around 78.5% of the evaluations relate to the commodity-specific consequences of agricultural research, while 5.5% report on the returns to an "all agriculture" aggregate. The weight of commodity specific evaluation evidence is not especially congruent with the composition of agricultural production throughout Africa, nor, to the best that can be determined, the commodity orientation of public African agricultural R&D. PMID- 28018025 TI - Facing famine: Somali experiences in the famine of 2011. AB - In 2011-12, Somalia experienced the worst famine of the twenty- first century. Since then, research on the famine has focused almost exclusively on the external response, the reasons for the delay in the international response, and the implications for international humanitarian action in the context of the "global war on terror." This paper focuses on the internal, Somali response to the famine. Themes of diversification, mobility and flexibility are all important to understanding how people coped with the famine, but this paper focuses on the factor that seemed to determine whether and how well people survived the famine: social connectedness, the extent of the social networks of affected populations, and the ability of these networks to mobilize resources. These factors ultimately determined how well people coped with the famine. The nature of reciprocity, the resources available within people's networks, and the collective risks and hazards faced within networks, all determined people's individual and household outcomes in the famine and are related to the social structures and social hierarchies within Somali society. But these networks had a distinctly negative side as well-social identity and social networks were also exploited to trap humanitarian assistance, turn displaced people into "aid bait," and to a large degree, determined who benefited from aid once it started to flow. This paper addresses several questions: How did Somali communities and households cope with the famine of 2011 in the absence of any state-led response-and a significant delay in a major international response? What can be learned from these practices to improve our understanding of famine, and of mitigation, response and building resilience to future crises? PMID- 28018026 TI - Harnessing learning biases is essential for applying social learning in conservation. AB - Social learning can influence how animals respond to anthropogenic changes in the environment, determining whether animals survive novel threats and exploit novel resources or produce maladaptive behaviour and contribute to human-wildlife conflict. Predicting where social learning will occur and manipulating its use are, therefore, important in conservation, but doing so is not straightforward. Learning is an inherently biased process that has been shaped by natural selection to prioritize important information and facilitate its efficient uptake. In this regard, social learning is no different from other learning processes because it too is shaped by perceptual filters, attentional biases and learning constraints that can differ between habitats, species, individuals and contexts. The biases that constrain social learning are not understood well enough to accurately predict whether or not social learning will occur in many situations, which limits the effective use of social learning in conservation practice. Nevertheless, we argue that by tapping into the biases that guide the social transmission of information, the conservation applications of social learning could be improved. We explore the conservation areas where social learning is highly relevant and link them to biases in the cues and contexts that shape social information use. The resulting synthesis highlights many promising areas for collaboration between the fields and stresses the importance of systematic reviews of the evidence surrounding social learning practices. PMID- 28018028 TI - Qualitative and quantitative feedback following workshop training in evidence based practices: A dissemination study. PMID- 28018030 TI - Theory and Philosophy: Themes and Variations. PMID- 28018029 TI - The relationship between parental education and children's schooling in a time of economic turmoil: The case of East Zimbabwe, 2001 to 2011. AB - Using data collected from 1998 to 2011 in a general population cohort study in eastern Zimbabwe, we describe education trends and the relationship between parental education and children's schooling during the Zimbabwean economic collapse of the 2000s. During this period, the previously-rising trend in education stalled, with girls suffering disproportionately; however, female enrolment increased as the economy began to recover. Throughout the period, children with more educated parents continued to have better outcomes such that, at the population level, an underlying increase in the proportion of children with more educated parents may have helped to maintain the upwards education trend. PMID- 28018027 TI - Low incidence of inbreeding in a long-lived primate population isolated for 75 years. AB - ABSTRACT: When close relatives mate, offspring are expected to suffer fitness consequences due to inbreeding depression. Inbreeding has previously been quantified in two ways: using a sufficiently large panel of markers or deep and complete pedigrees over several generations. However, the application of both approaches is still limited by the challenge of compiling such data for species with long generation times, such as primates. Here, we assess inbreeding in rhesus macaques living on Cayo Santiago (Puerto Rico), a population genetically isolated since 1938, but descendant of a large set of presumably unrelated founders. Using comprehensive genetic data, we calculated inbreeding coefficients (F) for 2669 individuals with complete three generation pedigrees and 609 individuals with complete four generation pedigrees. We found that 0.79 and 7.39% of individuals had an F > 0 when using data from three and four generation pedigrees, respectively. No evidence of an increase in inbreeding over the study period (up to 23 years) was found. Furthermore, the observed mean relatedness of breeding pairs differed significantly from the distribution of parental relatedness expected as simulated based on previous reproductive data, suggesting that kin generally avoid breeding with each other. Finally, inbreeding was not a predictor of early mortality measured as survival until weaning and sexual maturation, respectively. Our results remain consistent with three estimators of inbreeding (standardized heterozygosity, internal relatedness, and homozygosity by loci) using up to 42 highly polymorphic microsatellites for the same set of individuals. Together, our results demonstrate that close inbreeding may not be prevalent even in populations isolated over long periods when mechanisms of inbreeding avoidance can operate. SIGNIFICANCE STATEMENT: When close relatives mate, offspring may suffer from such inbreeding, e.g., via lower survival and/or fertility. Using (i) a large panel of genetic markers and (ii) complete three or four generation pedigrees, respectively, we show that incidences of inbreeding in a long-lived primate population are rare, even after genetic isolation for 75 years. Moreover, our simulations suggest that kin in our population generally avoid breeding with each other. Finally, the few inbred individuals detected in our large sample did not suffer from lower survival. Given that many animal species face dramatic habitat loss combined with critical population declines, our study provides important implications for conservation biology in general and for population management in particular. PMID- 28018031 TI - Methodological Behaviorism from the Standpoint of a Radical Behaviorist. AB - Methodological behaviorism is the name for a prescriptive orientation to psychological science. Its first and original feature is that the terms and concepts deployed in psychological theories and explanations should be based on observable stimuli and behavior. I argue that the interpretation of the phrase "based on" has changed over the years because of the influence of operationism. Its second feature, which developed after the first and is prominent in contemporary psychology, is that research should emphasize formal testing of a theory that involves mediating theoretical entities from an nonbehavioral dimension according to the hypothetico-deductive method. I argue that for contemporary methodological behaviorism, explanations of the behavior of both participants and scientists appeal to the mediating entities as mental causes, if only indirectly. In contrast to methodological behaviorism is the radical behaviorism of B. F. Skinner. Unlike methodological behaviorism, radical behaviorism conceives of verbal behavior in terms of an operant process that involves antecedent circumstances and reinforcing consequences, rather than in terms of a nonbehavioral process that involves reference and symbolism. In addition, radical behaviorism recognizes private behavioral events and subscribes to research and explanatory practices that do not include testing hypotheses about supposed mediating entities from another dimension. I conclude that methodological behaviorism is actually closer to mentalism than to Skinner's radical behaviorism. PMID- 28018032 TI - About Teleological Behaviorism. AB - Misconceptions abound about teleological behaviorism (TB). Because very few people other than the author publicly call themselves teleological behaviorists, the fault must be mine. The present article is an attempt to clear up those misconceptions. First I will try to indicate what teleological behaviorism is not. Then, in the form of six fables (loosely connected stories, allegories, analogies, fairy tales, and arguments), I will try to give the reader an understanding of what teleological behaviorism actually is. PMID- 28018033 TI - Behaviorisms and Private Events. PMID- 28018034 TI - Faith, Fact, and Behaviorism. AB - David Hume argued that ought cannot be derived from is. That is, no set of facts, no amount of scientific knowledge, is by itself sufficient to urge us to action. Yet generations of well-meaning scientists (more and more as secular influences grow in the West) seem to have forgotten Hume's words of wisdom. All motivated action depends ultimately on beliefs that cannot be proved by the methods of science, that is, on faith. PMID- 28018035 TI - A Behavioral Analysis of Morality and Value. AB - Morality has long been conceived as divinely instituted, so otherworldly, rules meant not to describe or explain behavior but to guide it towards an absolute good. The philosophical formulation of this theory by Plato was later grafted onto Christian thought by Augustine and Aquinas. The equally ancient theory of the Greek sophist Protagoras (that the good is relative to personal preferences and morality to man-made social customs) was forgotten until revived in the 18th and 19th centuries by such empiricists as David Hume and J. S. Mill. Then it was dismissed again in the 20th century by G. E. Moore and W. D. Ross as naturalistic fallacy, that is, conflation of what is with what ought to be. However, those who took this dismissive attitude themselves made the reverse mistake of conflating what ideally ought to be with what actually is. In other words, they mistook ideals for actualities. As B. F. Skinner (1971) said in Beyond Freedom and Dignity, sorting things out requires behaviorist parsing of the good (the personally reinforcing) and duty (the socially reinforced). PMID- 28018036 TI - Values and Morality: Science, Faith, and Feminist Pragmatism. PMID- 28018037 TI - A Functional Analysis of Psychological Terms Redux. AB - In his seminal paper, "An Operational Analysis of Psychological Terms," Skinner (1945) offered the revolutionary suggestion that, rather than endlessly debating the meanings of psychological terms, psychologists should analyze the variables that control their occurrence as verbal behavior. Skinner's suggestion reflected the essence of his 1957 book, Verbal Behavior, wherein he argued that the behaviors of which language is composed (i.e., speaking and listening) are controlled by variables found in the social environment (which he called the verbal community), and that analyzing those variables would lead to an understanding of the behaviors. Although Skinner formally introduced his radical approach to language in 1945, it has yet to be fully realized. The result is that psychologists, including behavior analysts, still debate the definitions of terms. In the present paper, I review Skinner's functional approach to language and describe ways in which behavior analysts have already applied it to traditional psychological terms. I conclude by looking at other current terms in behavior analysis that engender some confusion and encourage behavior analysts to apply a functional analytic approach to their own verbal behavior. PMID- 28018038 TI - Some Implications of a Behavioral Analysis of Verbal Behavior for Logic and Mathematics. AB - The evident power and utility of the formal models of logic and mathematics pose a puzzle: Although such models are instances of verbal behavior, they are also essentialistic. But behavioral terms, and indeed all products of selection contingencies, are intrinsically variable and in this respect appear to be incommensurate with essentialism. A distinctive feature of verbal contingencies resolves this puzzle: The control of behavior by the nonverbal environment is often mediated by the verbal behavior of others, and behavior under control of verbal stimuli is blind to the intrinsic variability of the stimulating environment. Thus, words and sentences serve as filters of variability and thereby facilitate essentialistic model building and the formal structures of logic, mathematics, and science. Autoclitic frames, verbal chains interrupted by interchangeable variable terms, are ubiquitous in verbal behavior. Variable terms can be substituted in such frames almost without limit, a feature fundamental to formal models. Consequently, our fluency with autoclitic frames fosters generalization to formal models, which in turn permit deduction and other kinds of logical and mathematical inference. PMID- 28018039 TI - What Has Happened to Skinner's Empirical Epistemology? PMID- 28018040 TI - What Counts as Behavior? The Molar Multiscale View. AB - Because the definition of behavior changes as our understanding of behavior changes, giving a final definition is impossible. One can, however, rule out some possibilities and propose some others based on what we currently know. Behavior is not simply movement, but must be defined by its function. Also, our understanding of behavior must agree with evolutionary theory. I suggest 4 basic principles: (a) only whole organisms behave; (b) behavior is purposive; (c) behavior takes time; and (d) behavior is choice. Saying that parts of an organism behave is nonsense, and, moreover, evolutionary theory explains the existence of organisms mainly through their adaptive behavior. Behavior is purposive in that behavior is shaped by its consequences, through an organism's lifetime or through interactions with the environment across many generations of natural selection. Behavior takes time in that behavior is interaction with the environment that cannot take place at a moment. Moreover, at a moment in time, one cannot definitely identify the function of behavior. Identification of an activity requires a span of time. Behavior is choice in the sense that a suitable span of time always includes time spent in more than 1 activity. Activities include parts that are themselves activities on a smaller time scale and compete for time. Thus, behavior constitutes time allocation. An accounting problem arises whenever any behavior is attributed to multiple consequences. In the molar multiscale view, this raises the question of whether 2 activities can occur at the same time. The question remains open. PMID- 28018041 TI - Toward the Unification of Molecular and Molar Analyses. AB - Three categories of behavior analysis may be called molecular, molar, and unified. Molecular analyses focus on how manual shaping segments moment-to-moment behaving into new, unified, hierarchically organized patterns. Manual shaping is largely atheoretical, qualitative, and practical. Molar analyses aggregate behaviors and then compute a numerical average for the aggregate. Typical molar analyses involve average rate of, or average time allocated to, the aggregated behaviors. Some molar analyses have no known relation to any behavior stream. Molar analyses are usually quantitative and often theoretical. Unified analyses combine automated shaping of moment-to-moment behaving and molar aggregates of the shaped patterns. Unified controlling relations suggest that molar controlling relations like matching confound shaping and strengthening effects of reinforcement. If a molecular analysis is about how reinforcement organizes individual behavior moment by moment, and a molar analysis is about how reinforcement encourages more or less of an activity aggregated over time, then a unified analysis handles both kinds of analyses. Only theories engendered by computer simulation appear to be able to unify all three categories of behavior analysis. PMID- 28018042 TI - On Multiscaled and Unified. PMID- 28018043 TI - The Structure of Scientific Evolution. AB - Science is the construction and testing of systems that bind symbols to sensations according to rules. Material implication is the primary rule, providing the structure of definition, elaboration, delimitation, prediction, explanation, and control. The goal of science is not to secure truth, which is a binary function of accuracy, but rather to increase the information about data communicated by theory. This process is symmetric and thus entails an increase in the information about theory communicated by data. Important components in this communication are the elevation of data to the status of facts, the descent of models under the guidance of theory, and their close alignment through the evolving retroductive process. The information mutual to theory and data may be measured as the reduction in the entropy, or complexity, of the field of data given the model. It may also be measured as the reduction in the entropy of the field of models given the data. This symmetry explains the important status of parsimony (how thoroughly the data exploit what the model can say) alongside accuracy (how thoroughly the model represents what can be said about the data). Mutual information is increased by increasing model accuracy and parsimony, and by enlarging and refining the data field under purview. PMID- 28018044 TI - Representations of Complexity: How Nature Appears in Our Theories. AB - In science we study processes in the material world. The way these processes operate can be discovered by conducting experiments that activate them, and findings from such experiments can lead to functional complexity theories of how the material processes work. The results of a good functional theory will agree with experimental measurements, but the theory may not incorporate in its algorithmic workings a representation of the material processes themselves. Nevertheless, the algorithmic operation of a good functional theory may be said to make contact with material reality by incorporating the emergent computations the material processes carry out. These points are illustrated in the experimental analysis of behavior by considering an evolutionary theory of behavior dynamics, the algorithmic operation of which does not correspond to material features of the physical world, but the functional output of which agrees quantitatively and qualitatively with findings from a large body of research with live organisms. PMID- 28018046 TI - Theory and Philosophy: Future Directions. PMID- 28018045 TI - Theory and Behavior Analysis. PMID- 28018047 TI - Scalable Genomics with R and Bioconductor. AB - This paper reviews strategies for solving problems encountered when analyzing large genomic data sets and describes the implementation of those strategies in R by packages from the Bioconductor project. We treat the scalable processing, summarization and visualization of big genomic data. The general ideas are well established and include restrictive queries, compression, iteration and parallel computing. We demonstrate the strategies by applying Bioconductor packages to the detection and analysis of genetic variants from a whole genome sequencing experiment. PMID- 28018048 TI - Childhood Personality, Betrayal Trauma, and Leukocyte Telomere Length in Adulthood: A Lifespan Perspective on Conscientiousness and Betrayal Traumas as Predictors of a Biomarker of Cellular Aging. AB - Conscientiousness is associated with longevity. As such, identifying the biological pathways linking personality to mortality is important. This study employs longitudinal data spanning >40 years to test prospective associations with Leukocyte Telomere Length (LTL), a potential marker of cellular aging. Because telomeres shorten over time, and are sensitive to oxidative stress, shorter LTL may reflect cumulative damage associated with negative health behaviors and past stressful events. We investigated childhood conscientiousness as a protective factor, expecting an association with longer LTL in adulthood, possibly reflecting slower LTL shortening. Potential lifespan pathways involving childhood trauma, smoking behaviors, and Body Mass Index (BMI) were explored. Childhood conscientiousness showed a small raw association with LTL (r = .08, p = .04), although this effect did not persist when controlling for age and sex. Despite this lack of a direct effect on LTL, we detected an indirect effect operating jointly through BMI and smoking. Higher rates of childhood betrayal trauma were associated with shorter LTL. Contrary to our hypothesis that conscientiousness would buffer this effect, we found evidence for an interaction with childhood betrayal traumas where the association between childhood betrayal traumas and LTL was larger for those higher on conscientiousness in childhood. PMID- 28018049 TI - Lipid therapy and plasmapheresis in tricyclic poisoning. PMID- 28018050 TI - A 'snapshot' of physical activity and food habits among private school children in India. AB - Concerns about increasing obesity in poorer parts of the world, including India, have often been premised in terms of global shifts in activity levels and caloric consumption. Lifestyle changes have been documented in large cities, but we do not know whether these changes are reaching young people in less urban locations. This study used photo journals to explore children's perceptions of their food and activity habits in a remote Indian city. Children expressed interest in active pastimes, learning, and health, and indicated traditional, modern, local, and global influences in their lives. Findings offer context for research and interventions. PMID- 28018051 TI - Identification and characterization of phages parasitic on bradyrhizobia nodulating groundnut (Arachis hypogaea L.) in South Africa. AB - In this study, three lytic phages (namely, PRSA-1, PRSA-2 and PRSA-26) were isolated and characterized for their morphology, host range, profile and restriction endonuclease banding pattern of genome size. The susceptible rhizobial isolates were identified by nifH and glnII sequence analysis. The results showed that all phages had polyhedral head with non-contractile tail which confirmed their relationship with the Siphoviridae family. All the three phages produced highly distinct plaques on their host bradyrhizobial lawn, and were highly sensitive to chloroform. The phage genome sizes ranged from 34.7 to 53.1 kbp. The phages were tested against groundnut-nodulating bradyrhizobial strains TUTAHSA75, TUTAHSA155 and TUTAHSA126 isolated from South African soils. The results revealed different bacterial susceptibilities to phages. Bradyrhizobial isolate TUTAHSA126 was susceptible to all three phages (i.e. PRSA 1, PRSA-2 and PRSA-26), TUTAHSA155 to two phages (i.e. PRSA-1, PRSA-2), and TUTAHSA75 to only one phage (i.e. PRSA-1). Phylogenetic analysis of nifH and glnII gene sequences of the phage-susceptible bradyrhizobial isolates revealed their close relatedness to a diverse group of Bradyrhizobium species. Phage PRSA 1 could parasitize on all three bradyrhizobial strains, which indicates its potential role in horizontal gene transfer through lysogenic conversion, and/or genetic transduction in soil microbial environments. PMID- 28018052 TI - New avenues for matter-wave-enhanced spectroscopy. AB - We present matter-wave interferometry as a tool to advance spectroscopy for a wide class of nanoparticles, clusters and molecules. The high sensitivity of de Broglie interference fringes to external perturbations enables measurements in the limit of an individual particle absorbing only a single photon on average, or even no photon at all. The method allows one to extract structural and electronic information from the loss of the interference contrast. It is minimally invasive and works even for dilute ensembles. PMID- 28018053 TI - Executive Control of Actions Across Time and Space. AB - Many popular psychological accounts attribute adaptive human behavior to an "executive-control" system that regulates a lower-level "impulsive" or "associative" system. However, recent findings argue against this strictly hierarchical view. Instead, executive control of impulsive and inappropriate actions depends on an interplay between multiple basic cognitive processes. The outcome of these processes can be biased in advance. Executive-action control is also strongly influenced by personal experiences in the recent and distant past. Thus, executive control emerges from an interactive and competitive network. Main challenges for future research are to describe and understand these interactions and to put executive-action control in a wider sociocultural and evolutional context. PMID- 28018054 TI - The role of training in IBA implementation beyond primary health care settings in the UK. AB - There has been a considerable drive to encourage a wide range of professional groups to incorporate alcohol screening (or identification) and brief advice (IBA) into their everyday practice. This article aims to examine the role of training in promoting IBA delivery in contexts outside primary care and other health settings. The data are drawn mainly from a structured online survey supplemented by illustrative material from nine qualitative interviews and insights from an expert workshop. Findings support the results from other research that issues relating to role relevance and role security continue to act as barriers to professional change. Furthermore, issues of organisational commitment and organisational barriers are insufficiently addressed in strategy to promote wider use of IBA. The article concludes that development of appropriate training for alcohol IBA needs to take account of the role of IBA within a complex interactive system of related services and help seeking pathways and consider how training can contribute to changing both professional attitudes and behaviours and organisational approaches to implementing and sustaining IBA in everyday professional practice. PMID- 28018055 TI - Preserved hydride transfer mechanism in evolutionarily divergent thymidylate synthases. AB - Thymidylate synthase (TSase) catalyzes a hydride transfer in the last step of the de novo biosynthesis of the DNA nucleotide thymine. We compared two isozymes, namely, TSase from Escherichia coli (ecTSase) and TSase from Bacillus subtilis (bsTSase) that represent a case of divergent evolution. Interestingly, a highly conserved histidine (H147 of ecTSase) was proposed to serve a critical role in catalysis, but in bsTSase it is naturally substituted by valine (Val). Yet, bsTSase is more active than ecTSase, and the intrinsic kinetic isotope effects (KIEs) of both are temperature-independent, suggesting a similarly well-organized transition state (TS) for the catalyzed hydride transfer. To examine the role of that histidine (His) in TSase catalysis, we examined the kinetics of H147V ecTSase, which "bridges" between these two TSases. In contrast to both wild-type TSases, the single mutation results in deficient catalysis. The mutation leads to intrinsic KIEs that are temperature-dependent, indicating a substantial imperfection in its TS. The findings reveal two important features: a direct role of H147 in the hydride transfer step catalyzed by the ecTSase and the evolutionary compensation for its deficiency in bsTSase via extensive polymorphism across the protein. Very different active site residues are observed for these evolutionarily divergent isozymes, which result in a well-organized TS for both. It is suggested that evolutionary pressure compensated for the H to V substitution at the active site of bsTSase by polymorphism leading to a well organized TS in both enzymes. PMID- 28018057 TI - Treatment and Postsurgery Functional Outcome of Spaghetti Wrist. AB - Background The outcomes of treating severe wrist injuries are not well understood and despite their complexity and prevalence, particularly among young adults, spaghetti wrist is rarely investigated. The aim of this study is to evaluate the postsurgery, functional outcome of spaghetti wrist injuries. Material and Methods In this prospective cross-sectional study, 153 patients with spaghetti wrist injuries were followed up for approximately 20 months and were assessed regarding returning to work and postsurgical functional outcomes that included tendon functionality, opposition, intrinsic function, deformity, sensation, and grip strength. Results The mean age was 28.3 +/- 5 years. The most common cause of injury was glass window panes and bottles. Moreover, the most commonly involved structures were the tendons of flexor digitorum superficialis 3, 4, and 5. During the follow-up, the tendon functionality in 120 (78%), opposition in 115 (75.1%), and intrinsic function in 62 (40.5%) were "excellent." Hand sensation was "fair" in 75 patients (49.1%), "good" in 46 patients (30%), and "excellent" in 28 patients (18.3%). The average return time to activities of daily living was 10 months. Conclusion In this study, worse outcomes were seen in older patients and those with higher number of damaged structures (especially nerves). PMID- 28018056 TI - Onecut transcription factors in development and disease. AB - Developmental processes are remarkably well conserved among species, and among the most highly conserved developmental regulators are transcription factor families. The Onecut transcription factor family consists of three members known for their single "cut" DNA-binding domain and an aberrant homeodomain. The three members of the Onecut family are highly conserved from Drosophila to humans and have significant roles in regulating the development of diverse tissues derived from the ectoderm or endoderm, where they activate a number of gene families. Of note, the genetic interaction between Onecut family members and Neurogenin genes appears to be essential in multiple tissues for proper specification and development of unique cell types. This review highlights the importance of the Onecut factors in cell fate specification and organogenesis, highlighting their role in vertebrates, and discusses their role in the maintenance of cell fate and prevention of disease. We cover the essential spatial and temporal control of Onecut factor expression and how this tight regulation is required for proper specification and subsequent terminal differentiation of multiple tissue types including those within the retina, central nervous system, liver and pancreas. Beyond development, Onecut factors perform necessary functions in mature cell types; their misregulation can contribute to diseases such as pancreatic cancer. Given the importance of this family of transcription factors in development and disease, their consideration in essential transcription factor networks is underappreciated. PMID- 28018058 TI - Intramedullary Screw and Kirschner Wire Fixation for Unstable Scaphoid Nonunion. AB - Surgical treatment of scaphoid nonunion is not always successful, often requiring stabilization and bone grafting to achieve healing. Even after intramedullary screw fixation, residual instability may still hinder union. The purpose of this study was to describe the addition of Kirschner wires (KWs) through the capitate and the lunate to supplement an intramedullary screw for temporary enhanced stability, possibly improving healing of unstable fractures. A case-control study reviewing 25 cases with addition of KWs and 19 controls was performed. Demographic and fracture information, time to diagnosis, and healing time were documented. We found no differences in population characteristics, fracture characteristics, or outcome measures between patients treated with this method and those treated with a screw alone. We had no complications related to the addition of KWs. Preoperative lunate type and scapholunate gapping was suggestive but not significantly associated with KW insertion. Addition of KWs is safe and may be considered in scaphoid nonunion in the presence of intraoperative suboptimal stability. Intraoperative stability may possibly be inferred by reviewing preoperative radiographs for signs of instability. PMID- 28018059 TI - Art of reporting a case: Need to cultivate it! PMID- 28018060 TI - Isolated dorsal column dysfunction due to an intraspinal Osteolipoma - Case report and review of literature. AB - Osteolipoma is a rare variant of the ubiquitous lipoma. Published literature appears in the form of isolated case reports affecting soft tissue structures in the head, neck and rarely affecting the spine. We present a unique instance of an intraspinal osteolipoma in the cervical spine, without evidence of accompanying spinal dysraphism and an atypical clinical presentation of isolated dorsal column dysfunction. We describe the clinical presentation, operative procedure and post operative outcomes with histopathological findings of this rare entity. A 61-year old male presented with impaired dorsal column sensation due to an intraspinal extradural ossifying lesion in the cervical spinal canal. The patient underwent excision of the lesion with complete resolution of symptoms. Ossifying lesion in the spinal canal may be frequent finding on radiological imaging but presence of possible adipose tissue in the lesion should raise suspicion of rare clinical scenario of an osteolipoma. PMID- 28018061 TI - Bilateral sandwiched scapulae: A rare presentation of hereditary multiple exostoses. AB - Hereditary multiple exostoses, an autosomal dominant condition, is a common benign tumor which is characterized by the development of multiple osteochondromas. Bilateral dorsal and ventral involvement of scapulae is extremely rare without any reported case in the literature. An 18-year-old girl was referred because of bilateral prominent scapulae and left-sided pain on shoulder girdle motion especially at more than 90 degrees abduction and forward flexion. Radiograph evaluation showed multiple exostoses on ventral and dorsal surfaces of body of both scapulae; hence simple excision of the lesion was impossible. The patient was symptom-free about 18 months after partial scapulectomy of left side. Partial scapulectomy seems to be an effective treatment for the sandwiched scapula between dorsal and ventral benign tumors. PMID- 28018062 TI - Non-union fracture neck femur in a toddler: Reconstructed by valgus osteotomy - A minimally invasive approach. AB - BACKGROUND: Non-union is one of the devastating complications of fracture neck of femur. Though a very rarely encountered entity in a toddler (1-3 years paediatric age group), non-united femoral neck fractures are reported in developing countries because of mismanagement by quacks and delay in referrals. For operative treatment, many different procedures have been described, including close/open reduction and internal fixation using K-wires, cannulated screws, fibula or nails. There is no evidence in the literature that one or other implant influences the rate of postoperative complications, such as avascular femoral head necrosis or coxa vara. But, still the choice of fixation implant is debatable. CASE REPORT: We present a case of 3-year-old child of non-union femoral neck fracture treated with valgus osteotomy. Choice of implant was kept to bare minimum to reduce the cost of implant and magnitude of surgery, which made the surgery minimally invasive, which is not the case in other studies. Two solid cancellous screws and a Kirschner wire (K-wire) were used to acheive fixation. Implant was removed after one year. The patient was followed up for 2 years and was found to be asymptomatic clinically with restoration of neck shaft angle and no signs of AVN. CONCLUSION: Our method of intertrochanteric valgus osteotomy and internal fixation stabilized using K-wire and screws is a technically simple yet effective method of treating difficult fracture neck femur. Although a larger series and multicentric trails are needed, yet we would safely recommend extension of this technique to unstable fractures, to minimize the incidence of complications, cost and magnitude of surgery. PMID- 28018063 TI - Endoprosthetic reconstruction for metastatic phaeochromocytoma in the distal femur: A case report. AB - Metastatic spread of malignant phaeochromocytoma is known to involve multiple organs including the axial skeleton. Its presentation as a solitary lesion in the long bones of the extremities is extremely rare. We report a unique case of solitary metastatic phaeochromocytoma presenting in the distal femur, 16 years after excision of primary abdominal tumor. A 60 year old female, operated for adrenal phaeochromocytoma 16 years back was detected to have a bone tumor in her left distal femur. Chest and abdominal CT evaluation including bone scintigraphy confirmed the lesion to be solitary. Magnetic resonance imaging of the left femur revealed the tumor to be of aggressive nature. It involved whole of the distal femoral metaphysis with bone destruction, soft tissue extension and an impending pathological fracture. The tumor was histopathologically confirmed to be phaeochromocytoma. Patient underwent wide surgical resection of the tumor along with simultaneous endoprosthetic reconstruction. Following surgery, rehabilitation was rapid and effortless with patient ambulating independently. She had pain free full range of knee movements and resumed her daily activity uneventfully. On 18 months follow up the patient had no recurrence or complications. Late and solitary skeletal metastasis of malignant phaeochromocytoma although rare, can occur in the distal femur mimicking a primary bone tumor. Wide surgical excision and simultaneous endoprosthetic reconstruction should be considered as a treatment option. This not only permits limb salvage and early rehabilitation, but also restores form and function of the limb. PMID- 28018064 TI - Cortical blindness along with motor aphasia: An unusual presentation of fat embolism syndrome. AB - Fat embolism syndrome presented with the classical triad of respiratory manifestations (95%), cerebral effects (60%) and Petechial rash (33%). Focal neurological symptoms in the form of combined bilateral cortical blindness and motor aphasia even prior to respiratory symptoms have been never reported in previous literature. We describe a case of these rare focal neurological symptoms secondary to the fat embolism syndrome in a young adult male following closed femur fracture. PMID- 28018065 TI - Removal of the broken femoral nail with T-reamer technique: A three-case report. AB - Nonunion of femoral shaft fracture is an uncommon complication after closed intramedullary nailing which often leading to nail breakage. Removal of the broken femoral nail with closed manner is a challenging procedure for orthopedic surgeons. The removal technique with the T-reamer is a closed method, which does not require either a nonunion site opening or knee exposing. We reported 3 cases of nonunion femoral shaft with broken slotted and non-slotted hollow nail which were successfully removed without any complication. All fractures healed uneventfully without open the fracture site or bone grafting. PMID- 28018066 TI - Femoral fracture acting as an "ominous masquerade" in a 7-year-old child. AB - A pathological fracture is one which occurs in diseased bone with trivial trauma or even without it. However, fracture occurring as a result of significant injury can masquerade underlying ominous bone pathology, which is highly likely to be missed in the garb of overwhelming traumatic aetiology. Pathological fracture as the manifestation of tumour in children less than 10 years of age is rare.1, 2 Fracture following significant trauma masquerading as underlying malignancy is even rarer. We report a case of 7-year-old male child, he had history of significant trauma with fracture shaft of femur, pathology was "missed" initially in the outset of trauma and on subsequent follow up it was found to be osteosarcoma. PMID- 28018067 TI - A rare combination of sagittal plane fracture of talar body with medial malleolus fracture: Case report and review of literature. AB - Fractures of talus are relatively uncommon injuries with majority of them involving the neck region. Talar body fracture in sagittal plane in combination with medial malleolus fracture is very rare with few cases being reported in the literature earlier. We report such an unusual combination in an adolescent, which was treated with open reduction and internal fixation with screws for both talus and medial malleolus. This was followed by physiotherapy and non-weight bearing till the fracture united. PMID- 28018068 TI - Customized iliac prosthesis for reconstruction in giant cell tumour: A unique treatment approach. AB - Giant cell tumour (GCT) of flat bones of pelvis is extremely rare. GCT of the ilium and ischium represent less than 0.05% of all GCT. Iliac bone GCT has been treated traditionally by intra-lesion curettage with bone grafting, wide resection with or without reconstruction and hemi-pelvectomy in very aggressive tumours. None of the above treatments were without morbidities. Reconstruction using bone grafts and bone cement has also been inadequate. In GCT, where life expectancy is not decreased significantly, surgical treatment should be aimed at giving optimum functional outcome. We are reporting here a rare case of giant cell tumour of ilium bone in a 25-year-old female and its unique treatment approach. We designed a computed tomography (CT) based customized iliac prosthesis using Materialise Mimics and 3-Matic software. 3D model of pelvis was generated from the CT. After deciding the extent of resection on affected side, we virtually mirrored an identical portion of opposite ilium to the affected side. Connecting plates were made over the mirrored part and merged with it. Multiple relevant holes were made to attach various muscles to the prosthesis. Prosthesis was made in medical grade titanium by using Computerized Numerical Control (CNC) machine. The method is called as computer based subtractive manufacturing. Wide resection was done and the prosthesis was placed using multiple 3.5 millimetres screws through the connecting plates. Muscles were stitched to relevant holes using ethibond suture. Post-operative course was unremarkable. Patient was made to walk with full weight bearing after 5 weeks. Powers of abductors at 6 months is 4/5 and patient walks normally without a limp. PMID- 28018069 TI - Bilateral sequential knee dislocation in a patient with connective tissue disorder: Report of an unusual case and lessons learnt. AB - Tibiofemoral knee dislocation is a rare but serious limb-threatening injury. Without prompt recognition and management, amputation or long-term functional impairment may result. The authors present a case of bilateral sequential knee dislocation, secondary to low-energy trauma, in a patient with Systemic Lupus Erythematosus and antiphospholipid syndrome. Adequate stability was achieved on both occasions by reconstruction of the postero-lateral corner and MCL. During the first reconstruction, ipsi-lateral autograft, as well as hamstring tendons from the contra-lateral side, were used to strengthen the graft. For the second reconstruction, allografts were used. This case highlights that, a patient with soft-tissue disorder presenting with low-energy knee dislocation may be at risk of further dislocations. Treating surgeons should anticipate these issues and consider the role of allograft in ligamentous repair. PMID- 28018070 TI - Accordion Maneuver with Modified Ilizarov Frame for treatment of recalcitrant nonunion of shaft of femur in a patient with Pycnodysostosis. AB - Accordion Maneuver is a strong "Bloodless Tool" in the Ilizarov technology, that helps to bring about healing of nonunion of fractures of long bones. A 50 years old male, a rare case of Pycnodysostosis, presented to us with recalcitrant nonunion of the fracture shaft of the femur after two failed surgical attempts, with a broken plate in the last attempt. We treated this very difficult nonunion by Ilizarov monofocal osteosynthesis with Accordion Maneuver that finally yielded union. This appears to be the only case report of treating such a case with Accordion Maneuver. PMID- 28018071 TI - Reimplantation of contaminated extruded segment of lateral femoral condyle cleansed with 10% povidine-iodine in complex floating knee injury with excellent outcome: Case report with 2 year follow up. AB - Traumatic extrusion of bone is a rare complication of high energy open fractures, and there are only few studies published in literature on reimplantation of the extruded bone segment. Studies with clear guidelines regarding timing of reimplantation, stabilisation of extruded bone segments, bone disinfection and disinfection techniques are very few. Previous reports describe disinfection using thermal or chemical methods. We present a case scenario of successful reimplantation of an extruded metaphyseal segment of distal femoral condyle following cleaning with copious saline and soaked in 10% povidine-iodine for 20 min in a 21 year old male patient of a complex floating knee injury with excellent outcome based on Karlstrom and Olerud criteria. PMID- 28018072 TI - Distal radius fracture with associated ulnar head fracture. AB - Ulnar head and neck fractures are rare and the mechanism of injury is not always clear. We describe a case of a distal radioulnar joint (DRUJ) fracture dislocation. The fracture included a distal radius fracture with a vertical ulnar head fracture that was treated with open reduction and internal fixation with a headless screw. We describe the mechanism of injury and approach to the treatment of this injury. PMID- 28018073 TI - Isolated tubercular osteomyelitis of acromion: A case report and review of literature. AB - Tuberculosis is an infectious disease of public health interest, infecting one third of the world population. Up to 3% of all Tubercular cases have musculoskeletal involvement with less than 1% involving the scapular. To the best of our knowledge, we present the third case of acromion involvement in reported literature. An adolescent female with complains of shoulder pain with no restriction of movements, no local symptoms, no fever, no history of tuberculosis was being treated on analgesics for three months at a primary health centre. With a provisional diagnosis of Chondroblastoma, surgical exploration was done, but pus was drained. It was realized in retrospect that tuberculosis needs to be considered as a differential diagnosis for any undefined bony pain, however uncommon the site of involvement may be, especially in Indian subcontinent. PMID- 28018074 TI - Simultaneous posterior dislocation of primary total knee arthroplasty with ipsilateral tibial shaft fracture: A case report and review of literature. AB - Dislocation following total knee arthroplasty (TKA) is a rare but serious complication. Here, a 74-year-old woman with posterior dislocation of her right cruciate-retaining TKA and ipsilateral tibia diaphysis fracture was presented. She only slipped down on the ground with a quick twist of her right leg. She underwent revision semiconstrained TKA and osteosynthesis of tibial fracture with plate and screw. Her partially avulsed patellar tendon was repaired as well. She was ambulatory with a cane and satisfied with revision operation at last control. Extensor mechanism and functional posterior cruciate ligament is especially important in patients receiving cruciate-retaining TKA. As far as we know, simultaneous dislocation of TKA with fracture of tibia diaphysis has never been reported before. PMID- 28018075 TI - Intraosseous leiomyoma of the calcaneum: An unusual bone tumor of foot and review of literature. AB - Leiomyoma is a benign tumor of smooth muscle origin and commonly diagnosed in the uterus, gastrointestinal tract, skin, and mucous membranes. To the best of our knowledge, the only reported intraosseous leiomyomas in extremities occurred in the proximal aspect and distal aspect of the femur, in the tibia, and in the ulna. We are not aware of any previous reports of intraosseous leiomyomas in the foot. The radiograph of the intraosseous leiomyoma shows unilocular or multilocular lytic lesion with sclerotic rim. Due to lack of definitive radiological features on magnetic resonance imaging and computed tomography diagnosis of this rare tumor is established with histopathological study and immuno-histochemistry markers. Smooth muscle spindle cells and positive immunohistochemistry markers for muscle cells is hall mark for the diagnosis. The treatment of intraosseous leiomyoma is surgical intervention by excision with wide margin and curettage followed by filling the cavity. The diagnosis of this tumor is challenging due to its extraordinarily rare incidence. Intraosseous leiomyoma should be included in the differential diagnosis of intraosseous lesion with benign radiographic feature. We report of the first published case of primary intraosseous leiomyoma of calcaneum in a 22-year-old male patient. PMID- 28018076 TI - Myxoid liposarcoma of the hand - A rare entity. AB - Hand liposarcomas are not well recognized in common practice, which leads to erroneous diagnostics and delayed proper treatment. We reported a case of a myxoid liposarcoma classified as stage IIb, and developed in the palmar side of the left hand in a 38-year-old man. There was an initial tumor reduction by a sclerosing agent injection that proved to be a failure. An open excisional biopsy confirmed the diagnostic after pathology examination. Recurrence occurred after 2 years, followed by a second resection and an adjunctive radiotherapy. At 5 years follow-up, the patient was recurrence free. Although myxoid liposarcoma is rare in the hand, it should be considered in the differential diagnosis of a painless soft tissue mass in this region. PMID- 28018077 TI - Hip adductor pyomyositis from Streptococcus mitis in a four-year-old child. AB - : The unique aspect of this case study is the unusual history, presentation, ultrasonography, MRI and blood culture results, which lead to the diagnosis and treatment of adductor pyomyositis with a rare organism in a temperate country. The patient presented with a one-day history of malaise, fever, left groin pain and inability to weight bear on the left leg. There was no history of any trauma, predisposing infections or recent travel. Plain radiograph and ultrasound of the hip was normal with no effusion. Two consecutive blood cultures suggested Streptococcus mitis bacteraemia and MRI scan confirmed pyomyositis of the left hip adductors that was too small to drain. S. mitis is a normal commensal organism however it can lead to opportunistic infections particularly endocarditis. Echocardiogram revealed no cardiac complications, in particular no endocarditic vegetation. Patient was treated with intravenous benzylpenicillin for a week followed by oral phenoxymethylpenicillin for a week. Adductor pyomyositis must be considered as a differential diagnosis in a child with unusual presentation of hip pain. When an ultrasound is normal, MRI scan is warranted to confirm diagnosis. Septic screen should include blood cultures. The commonest causative organisms are the Staphylococcus family. However if S. mitis is isolated, cardiac sources of infection resulting in septic emboli must be investigated. Repeated MRI scans are required particularly if the patient does not respond to medical management. LEVEL OF EVIDENCE: IV. PMID- 28018078 TI - Subungual osteochondroma: Nail sparing excision. AB - Subungual osteochondroma is a relatively uncommon benign bone tumor affecting mostly children and young adults, and is a major source of pain and nail deformity. Treatment consists of marginal excision and meticulous wound closure. In this report, we present three cases of subungual osteochondroma arising from the dorsal aspect of distal phalanx of the great toe, which were managed by marginal excision with preservation of nail apparatus under digital block anesthesia with the use of a ring tourniquet. We emphasize on the use of ring tourniquet made by glove's finger and the technique of preserving the nail apparatus to prevent nail deformity. At final follow-up, there is no evidence of recurrence or nail deformity with good functional and cosmetic result. PMID- 28018079 TI - A case of bilateral aberrant pectoralis minor insertion with absent coracohumeral ligament: Clinical relevance and controversies. AB - Aberrant insertions of the pectoralis minor tendon are quite rare. Most cases are incidental findings during cadaver dissections, on an MRI or during surgical procedures of the shoulder joint. Rarely the aberrant insertion points can be a source of pain or restriction of the shoulder joint. From the literature review, we found that there has been no mention regarding the frequency of occurrence of this variation with respect to unilateral or bilateral occurence, and only three cases have been reported, in which aberrant bilateral insertions have been documented of which two were noted during cadaveric dissection and one radiologically. We report a rare case of aberrant bilateral insertions of the pectoralis minor, which was found during an arthroscopic procedure, and we discuss its clinical and surgical implications. PMID- 28018080 TI - Drill bit failure and retrieval during arthroscopic ACL reconstruction. AB - A case of broken drill bit during arthroscopic ACL reconstruction and the technique adopted to overcome this complication is presented. We also review the literature for intra-operative incidents and technical complications during arthroscopic ACL reconstruction and various precautions we should implement to prevent such technical pitfalls from coming into reality. PMID- 28018081 TI - Spontaneous osteonecrosis of navicular and talus (SONNT). AB - We describe a rare case of simultaneous and spontaneous osteonecrosis affecting bilateral navicular and talar bones in a young male. On both sides, there was associated symptomatic talonavicular and naviculocuneiform arthritis. The more symptomatic left foot was managed successfully by talonavicular-cuneiform (TNC) arthrodesis and core decompression of talar body. A probable cause of this rare disorder was most likely due to a developmental anomaly in the preaxial ray of the foot. As no literature is currently available for this rare condition, our case report is intended to provide a referral point for future studies in the early diagnosis and management of this condition. PMID- 28018082 TI - Ceramic trapezio-metacarpal arthroplasty: Probably half is better than full. AB - Trapezio-metacarpal arthroplasty is one of the several treatment options available for painful first carpo-metacarpal (CMC) osteoarthritis of hand. In India, we have only Moje ceramic implants available for CMC arthroplasty. Although the literature cites high frequency of loosening and failure with use of Moje ceramic prostheses, all these studies describe results with total carpometacarpal arthroplasty. We expected that hemi-arthroplasty alone, by virtue of trapezium preservation leading to optimal capsular and ligament tensioning will provide good outcome. We wish to present first case of long-term successful outcome of Moje hemi trapezio-metacarpal arthroplasty from India as well as internationally. PMID- 28018083 TI - Progression of bisphosphonate-associated impending atypical femoral fracture despite prophylactic cephalomedullary nailing: A case report and review of literature. AB - While bisphosphonates have been shown to be effective in reducing the incidence of typical osteoporotic fractures, long-term bisphosphonate may be associated with atypical femoral fractures. We report a case of a bisphosphonate-related impending atypical femoral fracture which progressed despite prophylactic cephalomedullary nailing. The fracture healed without further surgical intervention after correcting the patient's bone metabolic profile and stopping the possible offending factors. Although prophylactic fixation of these fractures is recommended, our case and relevant literature review demonstrate that a simple fixation without optimizing other possible predisposing factors may not prevent progression of these fractures. PMID- 28018084 TI - Recurrent anterior instability of the shoulder associated with coracoid fracture An unusual presentation. AB - Recurrent anterior shoulder instability following shoulder dislocation has an incidence as high as 68% among the younger population, however its association with coracoid fracture is extremely rare. Majority of coracoid fractures reported earlier have been shown to be associated with seizure disorder. We report a case of displaced coracoid fracture associated with recurrent anterior instability in a patient with no history of seizure disorder and its implications in causation as well as management are discussed. A 28 year old male, paramedic by profession, presented with complaints of multiple episodes of shoulder dislocation of right dominant extremity for last ten months. Pre-operative CT scan showed Hill-Sach's lesion associated with coracoid process fracture. In view of significant engaging Hill-Sach's lesion, bony reconstruction of glenoid to increase the articular arc was planned. However in view of the small coracoid fragment occurred due to fracture, Latarjet's procedure could not be planned and iliac crest bone graft (ICBG) was planned instead. Till date only 10 cases of coracoid fracture with anterior shoulder instability have been reported in English literature. Of the ten cases, six cases had history of seizure disorder while four cases had only traumatic association. In our case as coracoid fragment was small, it could not be used for Latarjet's procedure and instead was fixed to its proximal stump with suture anchors. This case highlight's rare injury pattern and emphasises on good clinico-radiological examination supplemented by high index of suspicion needed to diagnose this unusual presentation. PMID- 28018085 TI - Large Morel-Lavallee lesion presenting as fungating mass with skin ulceration. AB - A Morel-Lavallee lesion, a type of soft tissue degloving injury that has also been referred to as a chronic expanding hematoma, is a relatively rare condition that usually develops following traumatic injury. Here, we present a case of a 60 year-old male with a Morel-Lavallee lesion diagnosed over 5 years after a traumatic injury of the hip. He presented with a large fungating mass and overlying skin ulceration, which was highly suspicious for sarcoma. However, lack of other systemic findings and constitutional complaints, as well as negative imaging studies, did not support a diagnosis of malignancy. This information, combined with the history of remote trauma to the affected area, instead led us to suspect the alternative diagnosis of a Morel-Lavallee lesion. The diagnosis was later confirmed by pathology showing a chronic expanding hematoma. To our knowledge, a Morel-Lavallee lesion presenting as a fungating mass has not been previously described. PMID- 28018086 TI - Leukocyte-poor platelet-rich plasma to treat degenerative meniscal tear: A case report. AB - A traumatic and/or degenerative meniscus lesion is thought to be a clinical manifestation of early-onset osteoarthritis (OA), which is a chronic progressive condition that can cause substantial pain and disability. Platelet-rich plasma (PRP) is an emerging treatment option that has been reported to improve healing. Here, we present a case of a 29-year-old woman, with left anterior and medial knee pain, without history of trauma or injury. The patient was managed with leukocyte-poor PRP injections derived from her peripheral blood with high concentrations of platelets, platelet-derived growth factors, and bioactive proteins, with a total follow-up of 30 months. Post-treatment patient was evaluated at every follow-up for improvement using three independent measures, VAS, GROC, and KOOS. There was considerable improvement in the pain symptoms from baseline (VAS: 70 mm; GROC: n/a; and KOOS: 39) to 30 months (VAS: 40 mm; GROC: 5; and KOOS: 63.1) indicating that PRP injections can serve as therapeutic intervention for treatment of pain associated with early onset of OA. To further validate these results, more longitudinal and evidence-based studies are recommended, which may further guide the clinicians to manage early-onset OA with PRP. PMID- 28018087 TI - A unique case of bilateral trans-scaphoid perilunate dislocation with dislocation of lunate into the forearm. AB - INTRODUCTION: Perilunate dislocations are commonly seen after fall on an outstretched hand in extremes of dorsiflexion and ulnar deviation. A greater arc injury is one when there is an associated fracture of one or more bones around the lunate while a lesser arc injury is associated with pure ligamentous disruption around the lunate. CASE REPORT: We report a unique case of bilateral trans-scaphoid perilunate dislocation in a 35-year-old male labourer. This is the first reported case where the lunate dislocated into the forearm on the volar aspect. Urgent open reduction and stabilization of both wrists was done. Currently, the wrist is stable with functional range of motion with union of both scaphoid fractures at 1-year follow-up. DISCUSSION: A delay in management of perilunate dislocations is associated with unfavourable prognosis. Prompt reduction and fixation is of paramount importance. Radiocarpal arthritis is associated with delayed management. In our case, the patient has regained painless functional range of motion without any radiological evidence of arthritis. CONCLUSION: We thus conclude that all perilunate dislocations must undergo emergency reduction. Open reduction and ligamentous repair should be considered as the treatment of choice as it is associated with better functional outcomes in terms of pain and arthritis. PMID- 28018088 TI - Fracture of the scapholunate coalition. PMID- 28018089 TI - Intra-articular dislocation of patella reduced by closed method - A rare case report. AB - Intra-articular dislocation of the patella is a rare injury. Two types of intra articular dislocations have been described in literature. In horizontal type, the patella has rotated on its horizontal axis. In the second type, the patella rotates on its vertical axis. These dislocations frequently are difficult to reduce by closed methods, and open reduction generally is required. We describe here a case of horizontal intra-articular dislocation of patella in a young 25 year-old male managed successfully by closed reduction. PMID- 28018090 TI - Natural tibialization of fibula in non-union tibia: Two cases. AB - BACKGROUND: Non-union of tibia is known to be a common complication after fracture both bones of leg treated conservatively. During the course of natural healing, fibula usually unites early as it had more soft tissue attachment and vascular supply. Due to early union of fibula and absence of axial force across the tibia, it undergoes non-union. CASE CHARACTERISTICS: Two cases, a 32-year-old male and 65-year-old female treated conservatively for fracture both bones of leg long years back, presented to us with mild calf pain on and off. On radiological examination, there was non-union of tibia along with compensatory fibular hypertrophy to the extent that fibula became main weight bearing bone. OUTCOME: In both the cases, we observed gross fibular hypertrophy in presence of non-union of tibia. CONCLUSION: In conservatively treated cases of fracture, both bones of leg, non-union of tibia may coexist with compensatory hypertrophy of fibula to the extent that, it becomes main weight bearing bone of the leg. We are presenting here two cases of natural tibialization of fibula along with nonunion tibia. Our article supports the theory of Wolff's law. PMID- 28018091 TI - Primary leiomyosarcoma of femur. AB - Primary leiomyosarcoma of the bone is exceedingly rare. In this case, we describe a middle-aged female with a primary leiomyosarcoma of the distal femur. The patient was treated by hip disarticulation. The patient continues to be disease free at one-year follow-up. PMID- 28018093 TI - Clinico-radiological improvement in an immunocompetent patient presented with scedosporium apiospermum osteomyelitis. AB - Scedosporium apiospermum is frequently found as a saprophyte in soil, sewage and contaminated water. Its manifestations in immunocompetent patients are usually localised and in immunodeficient patients, it causes invasive systemic diseases. We are reporting the case of a 40-year-old male, who presented with pain, oedema and multiple discharging sinuses over the lateral aspect of the left foot with history of thorn prick. On examination, there were multiple active sinuses with tenderness and local rise in temperature. Calcaneum on palpation showed a thickened and irregular surface with limitation of ankle and subtalar movements. Blood investigations showed a moderate rise in ESR and CRP. X-rays showed typical features of chronic osteomyelitis with sclerosis, cavities and irregular bone contour. CT report showed features of osteomyelitis involving calcaneum, talus, cuneiforms and navicular bone with periarticular soft tissue involvement and mild focal collection in the calcaneum. On repeated culture, it was found to be scedosporium apiospermum fungus. We managed the case with voriconazole therapy and it responded with excellent clinical and radiological improvement by 9 months. PMID- 28018092 TI - Prosthetic hip infection with Edwardsiella tarda in sickle cell beta thalassemia disease: A case report. AB - Periprosthetic infection following total hip arthroplasty is a devastating complication that has been reported to occur in up to 1.6% of all primary total hip arthroplasties. We report a previously unrecognized gram-negative bacillus as the infecting agent in a patient with bilateral total hip arthroplasties for stage IV osteonecrosis. A 22-year-old male with combined sickle cell disease and beta thalassemia with a prior history of unknown hip surgeries and treatment for distal tibial osteomyelitis in Africa developed a periprosthetic joint infection; intra-operative cultures confirmed the infecting organism to be Edwardsiella tarda which was sensitive to late-generation cephalosporins and vancomycin. He was successfully treated with a staged revision total hip arthroplasty with an antibiotic spacer and has been infection-free since. E. tarda is a gram-negative bacillus which has not been previously associated with periprosthetic infection following TJA. This organism infects both humans and fish, and is particularly associated with commercial fishing and fish farming of freshwater and marine fish, potentially putting workers in these industries at risk. Little is known about antibacterial resistance in this organism. Infection by E. tarda presents a new organism which may affect individuals undergoing TJA, particularly if they have medical comorbidities that increase their risk for infection, or work in industries which put them at a higher risk of infection by this organism. Further study on the antimicrobial resistance patterns of this organism will be required to be able to treat potentially resistant organisms. PMID- 28018094 TI - A rare case of idiopathic thumb CMC joint neuropathic arthropathy complicated by blunt trauma. AB - Neuropathic arthropathy (Charcot joints), which most frequently affects the weight-bearing joints of the body, is commonly associated with a variety of medical and neurological conditions, and is notoriously difficult to treat due to the nature of the underlying pathology. We present a case of idiopathic neuropathic arthropathy of the thumb CMC joint of an elderly female complicated by blunt trauma to the thumb. To our knowledge, this is the first reported case in the literature of this rare association. PMID- 28018095 TI - Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota. AB - Over the last few years, the importance of the resident intestinal microbiota in the pathogenesis of several gastro-intestinal diseases has been largely investigated. Growing evidence suggest that microbiota can influence gastro intestinal motility. The current working hypothesis is that dysbiosis-driven mucosal alterations induce the production of several inflammatory/immune mediators which affect gut neuro-muscular functions. Besides these indirect mucosal-mediated effects, the present review highlights that recent evidence suggests that microbiota can directly affect enteric nerves and smooth muscle cells functions through its metabolic products or bacterial molecular components translocated from the intestinal lumen. Toll-like receptors, the bacterial recognition receptors, are expressed both on enteric nerves and smooth muscle and are emerging as potential mediators between microbiota and the enteric neuromuscular apparatus. Furthermore, the ongoing studies on probiotics support the hypothesis that the neuromuscular apparatus may represent a target of intervention, thus opening new physiopathological and therapeutic scenarios. PMID- 28018097 TI - Contraindications for video capsule endoscopy. AB - Video capsule endoscopy (VCE) has been applied in the last 15 years in an increasing field of applications. Although many contraindications have been put into perspective, some precautions still have to be considered. Known stenosis of the gastrointestinal tract is a clear contraindication for VCE unless surgery is already scheduled or at least has been considered as an optional treatment modality. In patients with a higher incidence of stenosis, as in an established diagnosis of Crohn's disease, clinical signs of obstruction, prior radiation or surgical small bowel resection, a preceding test with the self-dissolving patency capsule can override this contraindication. Endoscopic placement of the capsule should be considered in patients with swallowing disorders to avoid aspiration. Esophageal or gastric motility disorders may require endoscopic capsule transport or application of prokinetics if the real-time viewer proofs delayed transit. In pregnant women, VCE should be restricted to urgent cases where diagnosis cannot be postponed after delivery, as data on safety are missing. There is theoretical and clinical evidence that patients with implanted cardiac devices such as a pacemaker, cardioverters or left heart assist devices, can safely undergo VCE in spite of still existing contraindication by manufacturers. Children from the age of 2 years have safely undergone VCE. Although video capsules are not proven safe with magnetic resonance imaging (MRI), first single cases of patients incidentally undergoing MRI with an incorporated capsule have been reported, showing susceptibility artifacts but no signs of clinical harm. PMID- 28018096 TI - Hepatic steatosis and fibrosis: Non-invasive assessment. AB - Chronic liver disease is a major cause of morbidity and mortality worldwide and usually develops over many years, as a result of chronic inflammation and scarring, resulting in end-stage liver disease and its complications. The progression of disease is characterised by ongoing inflammation and consequent fibrosis, although hepatic steatosis is increasingly being recognised as an important pathological feature of disease, rather than being simply an innocent bystander. However, the current gold standard method of quantifying and staging liver disease, histological analysis by liver biopsy, has several limitations and can have associated morbidity and even mortality. Therefore, there is a clear need for safe and non-invasive assessment modalities to determine hepatic steatosis, inflammation and fibrosis. This review covers key mechanisms and the importance of fibrosis and steatosis in the progression of liver disease. We address non-invasive imaging and blood biomarker assessments that can be used as an alternative to information gained on liver biopsy. PMID- 28018098 TI - Therapeutic approaches for portal biliopathy: A systematic review. AB - Portal biliopathy (PB) is defined as the presence of biliary abnormalities in patients with non-cirrhotic/non-neoplastic extrahepatic portal vein obstruction (EHPVO) and portal cavernoma (PC). The pathogenesis of PB is due to ab extrinseco compression of bile ducts by PC and/or to ischemic damage secondary to an altered biliary vascularization in EHPVO and PC. Although asymptomatic biliary abnormalities can be frequently seen by magnetic resonance cholangiopancreatography in patients with PC (77%-100%), only a part of these (5% 38%) are symptomatic. Clinical presentation includes jaundice, cholangitis, cholecystitis, abdominal pain, and cholelithiasis. In this subset of patients is required a specific treatment. Different therapeutic approaches aimed to diminish portal hypertension and treat biliary strictures are available. In order to decompress PC, surgical porto-systemic shunt or transjugular intrahepatic porto systemic shunt can be performed, and treatment on the biliary stenosis includes endoscopic (Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy, balloon dilation, stone extraction, stent placement) and surgical (bilioenteric anastomosis, cholecystectomy) approaches. Definitive treatment of PB often requires multiple and combined interventions both on vascular and biliary system. Liver transplantation can be considered in patients with secondary biliary cirrhosis, recurrent cholangitis or unsuccessful control of portal hypertension. PMID- 28018099 TI - Understanding the role of PIN1 in hepatocellular carcinoma. AB - PIN1 is a peptidyl-prolyl cis/trans isomerase that binds and catalyses isomerization of the specific motif comprising a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) in proteins. PIN1 can therefore induce conformational and functional changes of its interacting proteins that are regulated by proline-directed serine/threonine phosphorylation. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of key phosphoproteins (e.g., cyclin D1, survivin, beta-catenin and x protein of hepatitis B virus) that are involved in the regulation of cell cycle progression, apoptosis, proliferation and oncogenic transformation. PIN1 has been found to be over-expressed in many cancers, including human hepatocellular carcinoma (HCC). It has been shown previously that overexpression of PIN1 contributes to the development of HCC in-vitro and in xenograft mouse model. In this review, we first discussed the aberrant transcription factor expression, miRNAs dysregulation, PIN1 gene promoter polymorphisms and phosphorylation of PIN1 as potential mechanisms underlying PIN1 overexpression in cancers. Furthermore, we also examined the role of PIN1 in HCC tumourigenesis by reviewing the interactions between PIN1 and various cellular and viral proteins that are involved in beta-catenin, NOTCH, and PI3K/Akt/mTOR pathways, apoptosis, angiogenesis and epithelial-mesenchymal transition. Finally, the potential of PIN1 inhibitors as an anti-cancer therapy was explored and discussed. PMID- 28018100 TI - Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects. AB - Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC. PMID- 28018101 TI - Management of neuroendocrine carcinomas of the pancreas (WHO G3): A tailored approach between proliferation and morphology. AB - Neuroendocrine carcinomas (NEC) of the pancreas are defined by a mitotic count > 20 mitoses/10 high power fields and/or Ki67 index > 20%, and included all the tumors previously classified as poorly differentiated endocrine carcinomas. These latter are aggressive malignancies with a high propensity for distant metastases and poor prognosis, and they can be further divided into small- and large-cell subtypes. However in the NEC category are included also neuroendocrine tumors with a well differentiated morphology but ki67 index > 20%. This category is associated with better prognosis and does not significantly respond to cisplatin based chemotherapy, which represents the gold standard therapeutic approach for poorly differentiated NEC. In this review, the differences between well differentiated and poorly differentiated NEC are discussed considering both pathology, imaging features, treatment and prognostic implications. Diagnostic and therapeutic flowcharts are proposed. The need for a revision of current classification system is stressed being well differentiated NEC a more indolent disease compared to poorly differentiated tumors. PMID- 28018102 TI - Apolipoprotein B100 is required for hepatitis C infectivity and Mipomersen inhibits hepatitis C. AB - AIM: To characterize the role of apolipoprotein B100 (apoB100) in hepatitis C viral (HCV) infection. METHODS: In this study, we utilize a gene editing tool, transcription activator-like effector nucleases (TALENs), to generate human hepatoma cells with a stable genetic deletion of APOB to assess of apoB in HCV. Using infectious cell culture-competent HCV, viral pseudoparticles, replicon models, and lipidomic analysis we determined the contribution of apoB to each step of the viral lifecycle. We further studied the effect of mipomersen, an FDA approved antisense inhibitor of apoB100, on HCV using in vitro cell-culture competent HCV and determined its impact on viral infectivity with the TCID50 method. RESULTS: We found that apoB100 is indispensable for HCV infection. Using the JFH-1 fully infectious cell-culture competent virus in Huh 7 hepatoma cells with TALEN-mediated gene deletion of apoB (APOB KO), we found a significant reduction in HCV RNA and protein levels following infection. Pseudoparticle and replicon models demonstrated that apoB did not play a role in HCV entry or replication. However, the virus produced by APOB KO cells had significantly diminished infectivity as measured by the TCID-50 method compared to wild-type virus. Lipidomic analysis demonstrated that these virions have a fundamentally altered lipidome, with complete depletion of cholesterol esters. We further demonstrate that inhibition of apoB using mipomersen, an FDA-approved anti-sense oligonucleotide, results in a potent anti-HCV effect and significantly reduces the infectivity of the virus. CONCLUSION: ApoB is required for the generation of fully infectious HCV virions, and inhibition of apoB with mipomersen blocks HCV. Targeting lipid metabolic pathways to impair viral infectivity represents a novel host targeted strategy to inhibit HCV. PMID- 28018103 TI - Portal hypertension in polycystic liver disease patients does not affect wait list or immediate post-liver transplantation outcomes. AB - AIM: To establish the impact of portal hypertension (PH) on wait-list/post transplant outcomes in patients with polycystic liver disease (PCLD) listed for liver transplantation. METHODS: A retrospective single-centre case controlled study of consecutive patients listed for liver transplantation over 12 years was performed from our centre. PH in the PCLD cohort was defined by the one or more of following parameters: (1) presence of radiological or endoscopic documented varices from our own centre or the referral centre; (2) splenomegaly (> 11 cm) on radiology in absence of splenic cysts accounting for increased imaging size; (3) thrombocytopenia (platelets < 150 * 109/L); or (4) ascites without radiological evidence of hepatic venous outflow obstruction from a single cyst. RESULTS: Forty seven PCLD patients (F: M = 42: 5) were listed for liver transplantation (LT) (single organ, n = 35; combined liver-kidney transplantation, n = 12) with 19 patients (40.4%) having PH. When comparing the PH group with non-PH group, the mean listing age (PH group, 50.6 (6.4); non-PH group, 47.1 (7.4) years; P = 0.101), median listing MELD (PH group, 12; non-PH group, 11; P = 0.422) median listing UKELD score (PH group, 48; non-PH group, 46; P = 0.344) and need for renal replacement therapy (P = 0.317) were similar. In the patients who underwent LT alone, there was no difference in the duration of ICU stay (PH, 3 d; non-PH, 2 d; P = 0.188), hospital stay length (PH, 9 d; non-PH, 10 d; P = 0.973), or frequency of renal replacement therapy (PH, 2/8; non-PH, 1/14; P = 0.121) in the immediate post-transplantation period. CONCLUSION: Clinically apparent portal hypertension in patients with PCLD listed for liver transplantation does not appear to have a major impact on wait-list or peri-transplant morbidity. PMID- 28018104 TI - CYP1A1, CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms. AB - AIM: To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer (SCRC) risk. METHODS: Six hundred forty one individuals (227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1*2A, CYP1A1*2C CYP2E1*5B and CYP2E1*6 polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The EPHX1 Tyr113His, EPHX1 His139Arg and CYP1A1*2C polymorphisms were detected by real-time PCR. Chi-squared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05. RESULTS: Age over 62 years was a risk factor for SCRC development (OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC (OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant (heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant (OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant (OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models (OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant (heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic: OR = 7.32, 95%CI: 1.85-28.96, P < 0.01), dominant (OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive (OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant (OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log additive models (OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B (C) and CYP2E1*6 (A) polymorphisms was associated with SCRC (P = 0.002). However, the CYP1A1*2A, CYP1A1*2C, EPHX1 Tyr113His and EPHX1 His139Arg polymorphisms were not associated with SCRC. CONCLUSION: In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC. PMID- 28018105 TI - Prognostic value of glycated hemoglobin in colorectal cancer. AB - AIM: To investigate the clinical significance of routinely used glycemic parameters in a cohort of colorectal cancer (CRC) patients. METHODS: Pre treatment fasting blood glucose, insulin, HbA1c and homeostasis model of risk assessment (HOMA-IR) were retrospectively evaluated in a case-control study of 224 CRC and 112 control subjects matched for sex, obesity and diabetes frequency and blood lipid profile. Furthermore, the prognostic value of routinely used glycemic parameters towards progression-free (PFS) and overall survival (OS) was prospectively evaluated. RESULTS: Fasting blood glucose, insulin, HOMA-IR and HbA1c (all P < 0.0001) levels were higher in non-diabetic CRC patients compared with obesity-matched controls. All parameters were associated with increased CRC risk at ROC analysis, but no relationship with clinical-pathological variables or survival outcomes was observed for glycemia, insulinemia or HOMA-IR. Conversely, advanced CRC stage (P = 0.018) was an independent predictor of increased HbA1c levels, which were also higher in patients who had disease progression compared with those who did not (P = 0.05). Elevated HbA1c levels showed a negative prognostic value both in terms of PFS (HR = 1.24) and OS (HR = 1.36) after adjustment for major confounders, which was further confirmed in a subgroup analysis performed after exclusion of diabetic patients. CONCLUSION: HbA1c might have a negative prognostic value in CRC, thus suggesting that glycemic metabolic markers should be carefully monitored in these patients, independently of overt diabetes. PMID- 28018106 TI - Elevated fibrinogen plasma level is not an independent predictor of poor prognosis in a large cohort of Western patients undergoing surgery for colorectal cancer. AB - AIM: To evaluate the clinical significance of the preoperative fibrinogen plasma level as a prognostic marker after surgery for colorectal cancer. METHODS: This retrospective study analysed 652 patients undergoing surgery for stage I-IV colorectal cancer between January 2005 and December 2012, at the Division of General Surgery A, University of Verona Hospital Trust, in whom preoperative fibrinogen plasma values were assessed at baseline. Fibrinogen is involved in tumourigenesis as well as tumour progression in several malignancies. Correlations between preoperative plasma fibrinogen values and clinicopathological characteristics were investigated. Univariate and multivariate survival analyses were performed to identify factors associated with overall and tumour-related survival. RESULTS: Among the 652 patients, the fibrinogen value was higher than the threshold of 400 mg/dL in 345 patients (53%). The preoperative mean +/- SD of fibrinogen was 426.2 +/- 23.2 mg/dL (median: 409 mg/dL; range: 143-1045 mg/dL). Preoperative fibrinogen values correlated with age (P = 0.003), completeness of tumour resection, potentially curative vs palliative (P < 0.001), presence of systemic metastasis (P < 0.001), depth of tumour invasion pT (P < 0.001), nodes involvement pN (P = 0.001) and CEA serum level (P < 0.001). The mean fibrinogen value (+/- SD) was 395.6 +/- 120.4 mg/dL in G1 tumours, 424.1 +/- 121.4 mg/dL in G2 tumours and 453.4 +/- 131.6 mg/dL in G3 tumours (P = 0.045). The overall survival and tumour-related survival were significantly higher in patients with fibrinogen values <= 400 mg/dL (P < 0.001). However, hyperfibrinogenemia did not retain statistical significance regarding either overall (P = 0.313) or tumour-related survival (P = 0.355) after controlling for other risk factors in a multivariate analysis. CONCLUSION: Preoperative fibrinogen levels correlate with cancer severity but do not help in predicting patient prognosis after colorectal cancer surgery. PMID- 28018107 TI - Inter- and intraobserver agreement in computed tomography enterography in inflammatory bowel disease. AB - AIM: To evaluate intra- and interobserver agreement in imaging features in inflammatory bowel disease and comparison with fecal calprotectin (FC) levels. METHODS: Our institutional computed tomography enterography (CTE) database was retrospectively queried to identify patients who underwent CTE from January 2014 to June 2015. Patient inclusion criteria were confirmed inflammatory bowel disease (IBD) and FC collected < 4 mo after CTE without any change in clinical treatment or surgical treatment during this interval. The exclusion criterion was poor image quality. Two blinded abdominal radiologists, with 12 and 3 years of experience analyzed the CTE regarding localization (small bowel, colonic, both, or no disease detected); type of IBD (inflammatory, stenosing, fistulizing, > 1 pattern, or normal); and signs of active disease (present or absent). In 42 of 44 patients evaluated, routine CTE reports were made by one of the readers who re evaluated the CTEs >= 6 mo later, to determine the intraobserver agreement. FC was considered a sign of disease activity when it was higher than 250 MUg/g. RESULTS: Forty-four patients with IBD (38 with Crohn's disease and 6 with ulcerative colitis) were included. There was a moderate interobserver agreement regarding localization of IBD (kappa = 0.540), type of disease (kappa = 0.410) and the presence of active signs in CTE (kappa = 0.419). There was almost perfect intraobserver agreement regarding localization, type and signs of active disease in IBD. The kappa values were 0.902, 0.937 and 0.830, respectively. After a consensus between both radiologists regarding inflammatory activity in CTE, we found that 24 (85.7%) of 28 patients who were classified with active disease had elevated FC, and six (37.5%) of 16 patients without inflammatory activity in CTE had elevated FC (P = 0.003). The correlation between elevated FC and the presence of active disease in CTE was significant (kappa = 0.495, P = 0.001). CONCLUSION: We found almost perfect intraobserver and moderate interobserver agreement in the signs of active disease in CTE with concurrence of high FC levels. PMID- 28018108 TI - Heparin bridge therapy and post-polypectomy bleeding. AB - AIM: To identify risk factors for post-polypectomy bleeding (PPB), focusing on antithrombotic agents. METHODS: This was a case-control study based on medical records at a single center. PPB was defined as bleeding that occurred 6 h to 10 d after colonoscopic polypectomy and required endoscopic hemostasis. As risk factors for PPB, patient-related factors including anticoagulants, antiplatelets and heparin bridge therapy as well as polyp- and procedure-related factors were evaluated. All colonoscopic hot polypectomies, endoscopic mucosal resections and endoscopic submucosal dissections performed between January 2011 and December 2014 were reviewed. RESULTS: PPB occurred in 29 (3.7%) of 788 polypectomies performed during the study period. Antiplatelet or anticoagulant agents were prescribed for 210 (26.6%) patients and were ceased before polypectomy except for aspirin and cilostazol in 19 cases. Bridging therapy using intravenous unfractionated heparin was adopted for 73 patients. The univariate analysis revealed that anticoagulants, heparin bridge, and anticoagulants plus heparin bridge were significantly associated with PPB (P < 0.0001) whereas antiplatelets and antiplatelets plus heparin were not. None of the other factors including age, gender, location, size, shape, number of resected polyps, prophylactic clipping and resection method were correlated with PPB. The multivariate analysis demonstrated that anticoagulants and anticoagulants plus heparin bridge therapy were significant risk factors for PPB (P < 0.0001). Of the 29 PPB cases, 4 required transfusions and none required surgery. A thromboembolic event occurred in a patient who took anticoagulant. CONCLUSION: Patients taking anticoagulants have an increased risk of PPB, even if the anticoagulants are interrupted before polypectomy. Heparin-bridge therapy might be responsible for the increased PPB in patients taking anticoagulants. PMID- 28018109 TI - Clinical implications of doubling time of gastrointestinal submucosal tumors. AB - AIM: To evaluate the efficacy of doubling time (DT) of gastrointestinal submucosal tumors (GIST). METHODS: From April 1987 through November 2012, a total of 323 patients were given a final histopathological diagnosis of GISTs on surgical resection or endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) in Kitasato University East Hospital or Kitasato University Hospital. We studied 53 of these patients (34 with resected tumors and 19 with unresected tumors) whose tumors could be measured on EUS on at least two successive occasions. The histopathological diagnosis was GIST in 34 patients, leiomyoma in 5, schwannoma in 3, ectopic pancreas in 1, hamartoma in 1, cyst in 1, Brunner's adenoma in 1, and spindle-cell tumor in 7. We retrospectively calculated the DT of GISTs on the basis of the time course of EUS findings to estimate the growth rate of such tumors. RESULTS: The DT was 17.2 mo for GIST, as compared with 231.2 mo for leiomyoma, 104.7 mo for schwannoma, 274.9 mo for ectopic pancreas, 61.2 mo for hamartoma, 49.0 mo for cyst, and 134.7 mo for Brunner's adenoma. The GISTs were divided into risk classes on the basis of tumor diameters and mitotic figures (Fletcher's classification). The classification was extremely low risk or low risk in 28 patients, intermediate risk in 3, and high risk in 3. DT of GIST according to risk was 24.0 mo for extremely low-risk plus low-risk GIST, 17.1 mo for intermediate-risk GIST, and 3.9 mo for high-risk GIST. DT of GIST was significantly shorter than that of leiomyoma plus schwannoma (P < 0.05), and DT of high-risk GIST was significantly shorter than that of extremely low-risk plus low-risk GIST (P < 0.05). CONCLUSION: For GIST, a higher risk grade was associated with a significantly shorter DT. Small SMTs should initially be followed up within 6 mo after detection. PMID- 28018110 TI - Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability. AB - AIM: To identify predictors for synchronous liver metastasis from resectable pancreatic ductal adenocarcinoma (PDAC) and assess unresectability of synchronous liver metastasis. METHODS: Retrospective records of PDAC patients with synchronous liver metastasis who underwent simultaneous resections of primary PDAC and synchronous liver metastasis, or palliative surgical bypass, were collected from 2007 to 2015. A series of pre-operative clinical parameters, including tumor markers and inflammation-based indices, were analyzed by logistic regression to figure out predictive factors and assess unresectability of synchronous liver metastasis. Cox regression was used to identify prognostic factors in liver-metastasized PDAC patients after surgery, with intention to validate their conformance to the indications of simultaneous resections and palliative surgical bypass. Survival of patients from different groups were analyzed by the Kaplan-Meier method. Intra- and post-operative courses were compared, including complications. PDAC patients with no distant metastases who underwent curative resection served as the control group. RESULTS: CA125 > 38 U/mL (OR = 12.397, 95%CI: 5.468-28.105, P < 0.001) and diabetes mellitus (OR = 3.343, 95%CI: 1.539-7.262, P = 0.002) independently predicted synchronous liver metastasis from resectable PDAC. CA125 > 62 U/mL (OR = 5.181, 95%CI: 1.612 16.665, P = 0.006) and age > 62 years (OR = 3.921, 95%CI: 1.217-12.632, P = 0.022) correlated with unresectability of synchronous liver metastasis, both of which also indicated a worse long-term outcome of liver-metastasized PDAC patients after surgery. After the simultaneous resections, patients with post operatively elevated serum CA125 levels had shorter survival than those with post operatively reduced serum CA125 levels (7.7 mo vs 16.3 mo, P = 0.013). The survival of liver-metastasized PDAC patients who underwent the simultaneous resections was similar to that of non-metastasized PDAC patients who underwent curative pancreatectomy alone (7.0 mo vs 16.9 mo, P < 0.001), with no higher rates of either pancreatic fistula (P = 0.072) or other complications (P = 0.230) and no greater impacts on length of hospital stay (P = 0.602) or post-operative diabetic control (P = 0.479). CONCLUSION: The criterion set up by CA125 levels could facilitate careful diagnosis of synchronous liver metastases from PDAC, and prudent selection of appropriate patients for the simultaneous resections. PMID- 28018111 TI - Clinical features of upper gastrointestinal serrated lesions: An endoscopy database analysis of 98746 patients. AB - AIM: To analyse the clinical features of patients with the serrated lesions in the upper gastrointestinal tract (UPGI) tract. METHODS: Patients who underwent routine esophagogastroduodenoscopy (EGD) at the Digestive Endoscopy Centre of General Hospital, Tianjin Medical University between January 2011 and December 2015 were consecutively recruited. Patients with UPGI serrated lesions were consecutively identified. The patients' demographics and histopathology were recorded. The colorectal findings for patients who underwent colonoscopy simultaneously or within six months were also extracted from the colonoscopy database. In addition, we analysed differences in colorectal neoplasia detection between the study patients and randomly selected patients matched for age and gender who did not exhibit serrated lesions and who also underwent colonoscopy in the same period. RESULTS: A total of 21 patients out of 98746 patients (0.02%) who underwent EGD were confirmed to have serrated lesions with predominantly crenated, sawtooth-like configurations. The mean age of the 21 patients was (55.3 +/- 17.2) years, and 11 patients were male (52.4%). In terms of the locations of the serrated lesions, 17 were found in the stomach (including 3 in the cardia, 9 in the corpus and 5 in the antrum), 3 were found in the duodenum, and 1 was found in the esophagus. Serrated lesions were found in different mucosal lesions, with 14 lesions were detected in polyps (8 hyperplastic polyps and 6 serrated adenomas with low grade dysplasia), 3 detected in Menetrier gastropathy, 3 detected in an area of inflammation or ulcer, and 1 detected in the intramucosal carcinoma of the duodenum. In addition, colonoscopy data were available for 18 patients, and a significantly higher colorectal adenoma detection rate was observed in the UPGI serrated lesions group than in the randomly selected age- and gender-matched group without serrated lesions who also underwent colonoscopy in the same period (38.9% vs 11.1%, OR = 5.091, 95%CI: 1.534-16.890, P = 0.010). The detection rate of advanced adenoma was also higher in the UPGI serrated lesions group (22.2% vs 4.2%, OR = 6.571, 95%CI: 1.322-32.660, P = 0.028). CONCLUSION: Serrated lesions in the UPGI were detected in various mucosal lesions with different pathological morphologies. Moreover colonoscopy is recommended for the detection of concurrent colorectal adenoma for these patients. PMID- 28018112 TI - Influence of capsaicin infusion on secondary peristalsis in patients with gastroesophageal reflux disease. AB - AIM: To determine whether capsaicin infusion could influence heartburn perception and secondary peristalsis in patients with gastroesophageal reflux disease (GERD). METHODS: Secondary peristalsis was performed with slow and rapid mid esophageal injections of air in 10 patients with GERD. In a first protocol, saline and capsaicin-containing red pepper sauce infusions were randomly performed, whereas 2 consecutive sessions of capsaicin-containing red pepper sauce infusions were performed in a second protocol. Tested solutions including 5 mL of red pepper sauce diluted with 15 mL of saline and 20 mL of 0.9% saline were infused into the mid-esophagus via the manometric catheter at a rate of 10 mL/min with a randomized and double-blind fashion. During each study protocol, perception of heartburn, threshold volumes and peristaltic parameters for secondary peristalsis were analyzed and compared between different stimuli. RESULTS: Infusion of capsaicin significantly increased heartburn perception in patients with GERD (P < 0.001), whereas repeated capsaicin infusion significantly reduced heartburn perception (P = 0.003). Acute capsaicin infusion decreased threshold volume of secondary peristalsis (P = 0.001) and increased its frequency (P = 0.01) during rapid air injection. The prevalence of GERD patients with successive secondary peristalsis during slow air injection significantly increased after capsaicin infusion (P = 0.001). Repeated capsaicin infusion increased threshold volume of secondary peristalsis (P = 0.002) and reduced the frequency of secondary peristalsis (P = 0.02) during rapid air injection. CONCLUSION: Acute esophageal exposure to capsaicin enhances heartburn sensation and promotes secondary peristalsis in gastroesophageal reflux disease, but repetitive capsaicin infusion reverses these effects. PMID- 28018113 TI - Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression. AB - AIM: To determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression. METHODS: We detected expression of Smoc2 in HCC tissues and corresponding non-tumor liver (CNL) tissues using PCR, western blot, and immunohistochemistry methods. Subsequently, we down-regulated and up-regulated Smoc2 expression using siRNA and lentivirus transfection assay, respectively. Then, we identified the effect of Smoc2 on cell proliferation and cell cycle using CCK-8 and flow cytometry, respectively. The common cell growth signaling influenced by Smoc2 was detected by western blot assay. RESULTS: The expression of Smoc2 was significantly higher in HCC tissues compared with CNL tissues. Overexpression of Smoc2 promoted HCC cell proliferation and cell cycle progression. Down-regulation of Smoc2 led to inhibition of cell proliferation and cell cycle progression. Smoc2 had positive effect on ERK and AKT signaling. CONCLUSION: Smoc2 promotes the proliferation of HCC cells through accelerating cell cycle progression and might act as an anti-cancer therapeutic target in the future. PMID- 28018114 TI - Low phase angle is associated with the development of hepatic encephalopathy in patients with cirrhosis. AB - AIM: Evaluate the association between phase angle and the development of hepatic encephalopathy in the long-term follow-up of cirrhotic patients. METHODS: This was a prospective cohort study. Clinical, nutritional and biochemical evaluations were performed. Mann-Whitney's U and chi2 tests were used as appropriate. Kaplan Meier curves and Cox proportional Hazards analysis were used to evaluate the prediction and incidence of hepatic encephalopathy. RESULTS: Two hundred and twenty were included; the most frequent etiology of cirrhosis was hepatitis C infection, 52% of the patients developed hepatic encephalopathy (18.6% covert and 33.3% overt); the main precipitating factors were infections and variceal bleeding. Kaplan-Meier curves showed a higher proportion of HE in the group with low phase angle (39%) compared to the normal phase angle group (13%) (P = 0.012). Furthermore, creatinine and phase angle remained independently associated to hepatic encephalopathy in the Cox regression multivariate analysis [hazard ratio = 1.80 (1.07-3.03)]. CONCLUSION: In our cohort of patients low phase angle was associated with an increased incidence of hepatic encephalopathy. Phase angle is a useful nutritional marker that evaluates cachexia and could be used as a part of the integral assessment in patients with cirrhosis. PMID- 28018116 TI - The Statistics and Mathematics of High Dimension Low Sample Size Asymptotics. AB - The aim of this paper is to establish several deep theoretical properties of principal component analysis for multiple-component spike covariance models. Our new results reveal an asymptotic conical structure in critical sample eigendirections under the spike models with distinguishable (or indistinguishable) eigenvalues, when the sample size and/or the number of variables (or dimension) tend to infinity. The consistency of the sample eigenvectors relative to their population counterparts is determined by the ratio between the dimension and the product of the sample size with the spike size. When this ratio converges to a nonzero constant, the sample eigenvector converges to a cone, with a certain angle to its corresponding population eigenvector. In the High Dimension, Low Sample Size case, the angle between the sample eigenvector and its population counterpart converges to a limiting distribution. Several generalizations of the multi-spike covariance models are also explored, and additional theoretical results are presented. PMID- 28018115 TI - Dangerous dietary supplements: Garcinia cambogia-associated hepatic failure requiring transplantation. AB - Commercial dietary supplements are marketed as a panacea for the morbidly obese seeking sustainable weight-loss. Unfortunately, many claims cited by supplements are unsupported and inadequately regulated. Most concerning, however, are the associated harmful side effects, often unrecognized by consumers. Garcinia cambogia extract and Garcinia cambogia containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we report the first known case of fulminant hepatic failure associated with this dietary supplement. One active ingredient in this supplement is hydroxycitric acid, an active ingredient also found in weight-loss supplements banned by the Food and Drug Administration in 2009 for hepatotoxicity. Heightened awareness of the dangers of dietary supplements such as Garcinia cambogia is imperative to prevent hepatoxicity and potential fulminant hepatic failure in additional patients. PMID- 28018117 TI - Single Drop Electroanalysis and Interfacial Interactions: Sensitivity versus Limit of Detection?. AB - We report single drop electroanalytical measurements of pharmaceutically and biologically relevant compounds using screen printed electrodes (SPEs) modified with carboxylated multiwalled carbon nanotubes (MWCNT-COOH) as the sensor surface. Acetaminophen, nicotine, ascorbic acid, and nicotinamide adenine dinucleotide reduced form (NADH) were detected in a single drop of solution. We show that combined polar and nonpolar interactions of analytes with -COOH functional groups and large surface area of MWCNT, respectively, allow highly sensitive analyte detection with wide dynamic range. Smaller analytes can bind to a significantly greater number of sensor sites than the bulkier analytes and offer better detection sensitivity. Results suggest that sensitivity is controlled by predominant nonpolar interactions that an analyte can undergo with the MWCNT-COOH SPE sensor surface, whereas limit of detection is controlled by the extent of polar interactions between an analyte and the sensor surface, facilitating interfacial charge transport and an electrochemical signal output. Furthermore, a combination of polar and nonpolar analyte interactions with the sensor surface shows a synergistic effect on sensitivity and detection limit. This could be a likely reason for why sensitivity does not need to always correlate with lower detection limits as variations in the interfacial interactions are critical. Application of the designed single drop method to real samples was validated by estimating the amounts of acetaminophen, nicotine, ascorbic acid, and NADH in commercially available pharmaceuticals with excellent recovery. PMID- 28018119 TI - Demystifying the "Victimized State": A Civil-Military Crisis in Waiting? AB - The purpose of this article is to illustrate prescient issues relating to current and ex-military communities in the United Kingdom who have featured heavily within the policy arena over the past decade in relation to several key areas of importance. It will be illustrated how this population becomes visible within the public imagination (via military losses), how discourses relating to the harms they experience are structured and articulated within political and policy domains (particularly in relation to mental health) via "state talk" (qua Sim), and what the potential social consequences are for politically rendering an unproblematized populist view of current and ex-military communities (i.e., pending crises). This argument is made with the express intention of reengaging critical recognition of the distancing of the military institution from the physical and psychological vulnerability of those who have participated in war and military environments. This is an argument returned to pertinence from the recent publication of the Chilcot Inquiry into British involvement in the Iraq war. PMID- 28018118 TI - A Longitudinal Investigation of Conflict and Delay Inhibitory Control in Toddlers and Preschoolers. AB - RESEARCH FINDINGS: Eighty-one children participated in a longitudinal investigation of inhibitory control (IC) from 2 to 4 years of age. Child IC was measured via maternal report and laboratory measures under conditions of conflict and delay. Performance on delay IC tasks at 3 years was related to performance on these same tasks at 2 and 4 years, but performance on conflict IC tasks was not related over time. Delay IC task performance was concurrently related to conflict IC task performance in 3- and 4-year-olds but not related in 2-year-olds. Measures of IC varied in their associations with measures of verbal ability and maternal report IC. Such findings highlight important similarities and distinctions between conflict and delay IC abilities in their relation to one another and to temperament and language over time. PRACTICE OR POLICY: Studies of IC and related concepts reveal that children who are regulated enjoy school more and have higher school competence, particularly in mathematics and reading achievement. Because conflict IC and delay IC show unique patterns of development over time, educators can expect classroom behaviors drawing upon the state-like conflict IC to show more fluctuation over time than those drawing on the trait like delay IC. PMID- 28018120 TI - Hedonic quality or reward? A study of basic pleasure in homeostasis and decision making of a motivated autonomous robot. AB - We present a robot architecture and experiments to investigate some of the roles that pleasure plays in the decision making (action selection) process of an autonomous robot that must survive in its environment. We have conducted three sets of experiments to assess the effect of different types of pleasure-related versus unrelated to the satisfaction of physiological needs-under different environmental circumstances. Our results indicate that pleasure, including pleasure unrelated to need satisfaction, has value for homeostatic management in terms of improved viability and increased flexibility in adaptive behavior. PMID- 28018121 TI - Adaptive behaviors in multi-agent source localization using passive sensing. AB - In this paper, the role of adaptive group cohesion in a cooperative multi-agent source localization problem is investigated. A distributed source localization algorithm is presented for a homogeneous team of simple agents. An agent uses a single sensor to sense the gradient and two sensors to sense its neighbors. The algorithm is a set of individualistic and social behaviors where the individualistic behavior is as simple as an agent keeping its previous heading and is not self-sufficient in localizing the source. Source localization is achieved as an emergent property through agent's adaptive interactions with the neighbors and the environment. Given a single agent is incapable of localizing the source, maintaining team connectivity at all times is crucial. Two simple temporal sampling behaviors, intensity-based-adaptation and connectivity-based adaptation, ensure an efficient localization strategy with minimal agent breakaways. The agent behaviors are simultaneously optimized using a two phase evolutionary optimization process. The optimized behaviors are estimated with analytical models and the resulting collective behavior is validated against the agent's sensor and actuator noise, strong multi-path interference due to environment variability, initialization distance sensitivity and loss of source signal. PMID- 28018122 TI - Conceptualizing and Measuring Safe, Stable, Nurturing Relationships and Environments in Educational Settings. AB - Most children and adolescents older than five years spend at least six hours of their day in school settings. Like parents, education professionals can promote health and protect youth from harm by providing safe, stable, nurturing relationships and environments. The Centers for Disease Control and Prevention (CDC) has developed a framework which posits that safe, stable, nurturing relationships and environments are Essentials for Childhood and are fundamental to promoting health and well-being; protecting youth from maltreatment and other violence and victimization; and ensuring optimal, healthy development. In this paper, the authors propose an approach to applying safe, stable, nurturing relationships and environments to the school ecology; review select survey measures to examine these constructs within educational settings; and suggest available indicators to measure safety, stability, and nurturance within the school context. PMID- 28018123 TI - Longitudinal Effects of a Second-Order Multi-Problem Factor of Sexual Risk, Marijuana Use, and Delinquency on Future Arrest Among Truant Youths. AB - Based on problem-behavior theory (Jessor & Jessor, 1977), a second-order problem behavior model of delinquency, marijuana use, and risky sexual behavior over five waves was estimated among truant adolescents. The study also investigated the influence of the problem factor on future arrest charges and the effect of socio demographics on problem behavior and future crime. Results confirm the existence of a second-order latent factor of problem behaviors. Problem behaviors predicted more future arrest charges. Age was related to problem behaviors and future arrest charges, and family income was related to problem behavior. Implications for future research and practice are discussed. PMID- 28018124 TI - Cross-Frequency rs-fMRI Network Connectivity Patterns Manifest Differently for Schizophrenia Patients and Healthy Controls. AB - Patterns of resting state fMRI functional network connectivity in schizophrenia patients have been shown to differ markedly from that of healthy controls. While some studies have explored connectivity within fixed frequency bands, the question of network phase synchrony across disparate frequency bands, or cross frequency connectivity, has remained surprisingly underexplored. Computational modeling at the neuronal scale however has long acknowledged the existence of coupled fast and slow subsystems. Here we present preliminary evidence that cross frequency coupling exists at the network level, that it patterns in meaningful ways over functional domains, and that this patterning differs between the healthy population and individuals with diagnosed schizophrenia. PMID- 28018125 TI - CFD analysis on gas distribution for different scrubber redirection configurations in sump cut. AB - The National Institute for Occupational Safety and Health's Office of Mine Safety and Health Research recently developed a series of models using computational fluid dynamics (CFD) to study the gas distribution around a continuous mining machine with various fan-powered flooded bed scrubber discharge configurations. CFD models using Species Transport Model without reactions in FLUENT were constructed to evaluate the redirection of scrubber discharge toward the mining face rather than behind the return curtain. The following scenarios are considered in this study: 100 percent of the discharge redirected back toward the face on the off-curtain side of the continuous miner; 100 percent of the discharge redirected back toward the face, but divided equally to both sides of the machine; and 15 percent of the discharge redirected toward the face on the off-curtain side of the machine, with 85 percent directed into the return. These models were compared against a model with a conventional scrubber discharge, where air is directed away from the face into the return. The CFD models were calibrated and validated based on experimental data and accurately predicted sulfur hexafluoride (SF6) gas levels at four gas monitoring locations. One additional prediction model was simulated to consider a different scrubber discharge angle for the 100 percent redirected, equally divided case. These models identified relatively high gassy areas around the continuous miner, which may not warrant their use in coal mines with medium to high methane liberation rates. This paper describes the methodology used to develop the CFD models, and the validation of the models based on experimental data. PMID- 28018126 TI - Sublimation-like Behavior of Cardiac Dynamics in Heart Failure: A Malignant Phase Transition? AB - An abrupt transition from sinus cardiac rhythm to atrial fibrillation (AF) is common in patients with chronic heart failure (CHF). We propose a conceptual framework for viewing this malignant transition in terms of a type of sublimation marked by the switch from highly periodic sinus interbeat interval dynamics characteristic of CHF to a state of random disorganization with AF. Sublimation of physical substances involves an increase in entropy via heat transfer. In contrast, the disease-related sublimation-like behavior involves a loss of information content, associated decreases in cardiac bioenergetic capacity and in multiscale entropy. PMID- 28018127 TI - Influence of "J"-Curve Spring Stiffness on Running Speeds of Segmented Legs during High-Speed Locomotion. AB - Both the linear leg spring model and the two-segment leg model with constant spring stiffness have been broadly used as template models to investigate bouncing gaits for legged robots with compliant legs. In addition to these two models, the other stiffness leg spring models developed using inspiration from biological characteristic have the potential to improve high-speed running capacity of spring-legged robots. In this paper, we investigate the effects of "J"-curve spring stiffness inspired by biological materials on running speeds of segmented legs during high-speed locomotion. Mathematical formulation of the relationship between the virtual leg force and the virtual leg compression is established. When the SLIP model and the two-segment leg model with constant spring stiffness and with "J"-curve spring stiffness have the same dimensionless reference stiffness, the two-segment leg model with "J"-curve spring stiffness reveals that (1) both the largest tolerated range of running speeds and the tolerated maximum running speed are found and (2) at fast running speed from 25 to 40/92 m s-1 both the tolerated range of landing angle and the stability region are the largest. It is suggested that the two-segment leg model with "J"-curve spring stiffness is more advantageous for high-speed running compared with the SLIP model and with constant spring stiffness. PMID- 28018128 TI - Lesser Toxicities of Belotecan in Patients with Small Cell Lung Cancer: A Retrospective Single-Center Study of Camptothecin Analogs. AB - Purpose. Topotecan and belotecan are camptothecin derivatives that are used to treat small cell lung cancer (SCLC). This study compared the toxicities and efficacies of belotecan and topotecan monotherapies in patients with SCLC. Methods. We retrospectively reviewed data from 94 patients with SCLC (with or without prior chemotherapy) who were treated using belotecan monotherapy (n = 59, 188 cycles) or topotecan monotherapy (n = 35, 65 cycles) between September 2003 and December 2011. Results. Thrombocytopenia occurred during 42% and 61.5% of the belotecan and topotecan cycles, respectively (p = 0.007). Significant differences between belotecan and topotecan were also observed for grade 4/5 lung infection (3.2% versus 10.8%, resp.; p = 0.003), all-grade headache (3.2% versus 10.8%, resp.; p = 0.017), and grade 4/5 increased liver enzymes (0.5% versus 4.6%, resp.; p = 0.023). The median TTPDs, CSSs, and OSs were 14 months and 11.6 months (p = 0.646), 10 months and 7 months (p = 0.179), and 34.5 months and 21.4 months (p = 0.914) after belotecan and topotecan monotherapy, respectively. Conclusions. Belotecan monotherapy may be safer than topotecan monotherapy in SCLC patients. And in terms of efficacy, belotecan could be comparable to topotecan monotherapy. PMID- 28018129 TI - Relationship between FEV1 and Cardiovascular Risk Factors in General Population without Airflow Limitation. AB - Purpose. We aimed to determine the value of lung function measurement for predicting cardiovascular (CV) disease by evaluating the association between FEV1 (%) and CV risk factors in general population. Materials and Methods. This was a cross-sectional, retrospective study of subjects above 18 years of age who underwent health examinations. The relationship between FEV1 (%) and presence of carotid plaque and thickened carotid IMT (>=0.8 mm) was analyzed by multiple logistic regression, and the relationship between FEV1 (%) and PWV (%), and serum uric acid was analyzed by multiple linear regression. Various factors were adjusted by using Model 1 and Model 2. Results. 1,003 subjects were enrolled in this study and 96.7% (n = 970) of the subjects were men. In both models, the odds ratio of the presence of carotid plaque and thickened carotid IMT had no consistent trend and statistical significance. In the analysis of the PWV (%) and uric acid, there was no significant relationship with FEV1 (%) in both models. Conclusion. FEV1 had no significant relationship with CV risk factors. The result suggests that FEV1 may have no association with CV risk factors or may be insensitive to detecting the association in general population without airflow limitation. PMID- 28018131 TI - The Politics of Global Value Chains: Import-dependent Firms and EU-Asia Trade Agreements. AB - In 2006, the European Commission released its Global Europe Communication, in which it announced a shift from a multilateral to a bilateral trade strategy. One of the key pillars of this new strategy was to strengthen the bilateral trade relations with key Asian countries. In contrast to existing analyses that focus on European Union (EU) decision makers' agency, we propose an explanation for this notable shift in the EU's trade policy that stresses the political role of import-dependent firms. In light of the increasing integration of such firms into global value chains, the article argues that a plausible case can be made, both theoretically and empirically, that import-dependent firms had a clear stake in the signing of preferential trade agreements between the EU and Asian countries and that their lobbying efforts significantly affected the EU's decision to start negotiations with South Korea, India and Vietnam. PMID- 28018130 TI - Postthoracotomy Ipsilateral Shoulder Pain: A Literature Review on Characteristics and Treatment. AB - Context. Postthoracotomy Ipsilateral Shoulder Pain (IPS) is a common and sometimes intractable pain syndrome. IPS is different from chest wall pain in type, origin, and treatments. Various treatments are suggested or applied for it but none of them is regarded as popular accepted effective one. Objectives. To review data and collect all present experiences about postthoracotomy IPS and its management and suggest future research directions. Methods. Search in PubMed database and additional search for specific topics and review them to retrieve relevant articles as data source in a narrative review article. Results. Even in the presence of effective epidural analgesia, ISP is a common cause of severe postthoracotomy pain. The phrenic nerve has an important role in the physiopathology of postthoracotomy ISP. Different treatments have been applied or suggested. Controlling the afferent nociceptive signals conveyed by the phrenic nerve at various levels-from peripheral branches on the diaphragm to its entrance in the cervical spine-could be of therapeutic value. Despite potential concerns about safety, intrapleural or phrenic nerve blocks are tolerated well, at least in a selected group of patient. Conclusion. Further researches could be directed on selective sensory block and motor function preservation of the phrenic nerve. However, the safety and efficacy of temporary loss of phrenic nerve function and intrapleural local anesthetics should be assessed. PMID- 28018132 TI - The gender congruency effect during bilingual spoken-word recognition. AB - We investigate the 'gender-congruency' effect during a spoken-word recognition task using the visual world paradigm. Eye movements of Italian-Spanish bilinguals and Spanish monolinguals were monitored while they viewed a pair of objects on a computer screen. Participants listened to instructions in Spanish (encuentra la bufanda / 'find the scarf') and clicked on the object named in the instruction. Grammatical gender of the objects' name was manipulated so that pairs of objects had the same (congruent) or different (incongruent) gender in Italian, but gender in Spanish was always congruent. Results showed that bilinguals, but not monolinguals, looked at target objects less when they were incongruent in gender, suggesting a between-language gender competition effect. In addition, bilinguals looked at target objects more when the definite article in the spoken instructions provided a valid cue to anticipate its selection (different-gender condition). The temporal dynamics of gender processing and cross-language activation in bilinguals are discussed. PMID- 28018133 TI - Multi-Objective Markov Decision Processes for Data-Driven Decision Support. AB - We present new methodology based on Multi-Objective Markov Decision Processes for developing sequential decision support systems from data. Our approach uses sequential decision-making data to provide support that is useful to many different decision-makers, each with different, potentially time-varying preference. To accomplish this, we develop an extension of fitted-Q iteration for multiple objectives that computes policies for all scalarization functions, i.e. preference functions, simultaneously from continuous-state, finite-horizon data. We identify and address several conceptual and computational challenges along the way, and we introduce a new solution concept that is appropriate when different actions have similar expected outcomes. Finally, we demonstrate an application of our method using data from the Clinical Antipsychotic Trials of Intervention Effectiveness and show that our approach offers decision-makers increased choice by a larger class of optimal policies. PMID- 28018134 TI - Prospective Childhood Risk Factors for Gang Involvement among North American Indigenous Adolescents. AB - The purpose of the study was to examine prospective childhood risk factors for gang involvement across the course of adolescence among a large eight-year longitudinal sample of 646 Indigenous (i.e., American Indian and Canadian First Nations) youth residing on reservation/reserve land in the Midwest of the United States and Canada. Risk factors at the first wave of the study (ages 10-12) were used to predict gang involvement (i.e., gang membership and initiation) in subsequent waves (ages 11-18). A total of 6.7% of the participants reported gang membership and 9.1% reported gang initiation during the study. Risk factors were distributed across developmental domains (e.g., family, school, peer, and individual) with those in the early delinquency domain having the strongest and most consistent effects. Moreover, the results indicate that the cumulative number of risk factors in childhood increases the probability of subsequent gang involvement. Culturally relevant implications and prevention/intervention strategies are discussed. PMID- 28018135 TI - Armed Kids, Armed Adults? Weapon Carrying From Adolescence to Adulthood. AB - While much existing research has examined either juvenile or adult weapon carrying, this study assesses whether carrying a weapon to school as a juvenile is predictive of bringing a handgun to school or work in adulthood. Data are drawn from the National Longitudinal Study of Adolescent Health. Results show a decline in weapon carrying behavior over time. However, youth who report school weapon carrying in adolescence are much more likely to report carrying a handgun to school or work in adulthood. Findings also demonstrate that victimization, rather than offending behavior, is predictive of adulthood handgun carrying at school and work. PMID- 28018136 TI - CBX Chromodomain Inhibition Enhances Chemotherapy Response in Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM) lacks effective therapeutic options leaving patients with a survival time of approximately one year. Recently, the alteration of chromatin modulators has been implicated in the pathogenesis and chemoresistance of numerous cancers; in particular, the Polycomb Group Proteins have been shown to play a role in glioblastoma progression and maintenance [1-5]. In this study, we aimed to identify drug combinations that decrease GBM cell viability by combining small molecule inhibitors against the Polycomb family with two standard chemotherapies. We identified dual inhibition of the CBX chromodomain with doxorubicin as a novel therapeutic strategy. While treatment with chromodomain inhibitor is non-toxic to cells alone, it dramatically increased the toxicity of standard chemotherapy drugs. We further validated an increase in DNA damage resulting in a G2/M block and subsequent apoptosis using the dual inhibitor treatment. PMID- 28018137 TI - DNA Hypomethylation in Intragenic and Intergenic Enhancer Chromatin of Muscle Specific Genes Usually Correlates with their Expression. AB - Tissue-specific enhancers are critical for gene regulation. In this study, we help elucidate the contribution of muscle-associated differential DNA methylation to the enhancer activity of highly muscle-specific genes. By bioinformatic analysis of 44 muscle-associated genes, we show that preferential gene expression in skeletal muscle (SkM) correlates with SkM-specific intragenic and intergenic enhancer chromatin and overlapping foci of DNA hypomethylation. Some genes, e.g., CASQ1 and FBXO32, displayed broad regions of both SkM- and heart-specific enhancer chromatin but exhibited focal SkM-specific DNA hypomethylation. Half of the genes had SkM-specific super-enhancers. In contrast to simple enhancer/gene expression correlations, a super-enhancer was associated with the myogenic MYOD1 gene in both SkM and myoblasts even though SkM has < 1 percent as much MYOD1 expression. Local chromatin differences in this super-enhancer probably contribute to the SkM/myoblast differential expression. Transfection assays confirmed the tissue-specificity of the 0.3-kb core enhancer within MYOD1's super enhancer and demonstrated its repression by methylation of its three CG dinucleotides. Our study suggests that DNA hypomethylation increases enhancer tissue-specificity and that SkM super-enhancers sometimes are poised for physiologically important, rapid up-regulation. PMID- 28018138 TI - Editing the Neuronal Genome: a CRISPR View of Chromatin Regulation in Neuronal Development, Function, and Plasticity. AB - The dynamic orchestration of gene expression is crucial for the proper differentiation, function, and adaptation of cells. In the brain, transcriptional regulation underlies the incredible diversity of neuronal cell types and contributes to the ability of neurons to adapt their function to the environment. Recently, novel methods for genome and epigenome editing have begun to revolutionize our understanding of gene regulatory mechanisms. In particular, the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has proven to be a particularly accessible and adaptable technique for genome engineering. Here, we review the use of CRISPR/Cas9 in neurobiology and discuss how these studies have advanced understanding of nervous system development and plasticity. We cover four especially salient applications of CRISPR/Cas9: testing the consequences of enhancer mutations, tagging genes and gene products for visualization in live cells, directly activating or repressing enhancers in vivo, and manipulating the epigenome. In each case, we summarize findings from recent studies and discuss evolving adaptations of the method. PMID- 28018139 TI - CRISPR-Mediated Epigenome Editing. AB - Mounting evidence has called into question our understanding of the role that the central dogma of molecular biology plays in human pathology. The conventional view that elucidating the mechanisms for translating genes into proteins can account for a panoply of diseases has proven incomplete. Landmark studies point to epigenetics as a missing piece of the puzzle. However, technological limitations have hindered the study of specific roles for histone post translational modifications, DNA modifications, and non-coding RNAs in regulation of the epigenome and chromatin structure. This feature highlights CRISPR systems, including CRISPR-Cas9, as novel tools for targeted epigenome editing. It summarizes recent developments in the field, including integration of optogenetic and functional genomic approaches to explore new therapeutic opportunities, and underscores the importance of mitigating current limitations in the field. This comprehensive, analytical assessment identifies current research gaps, forecasts future research opportunities, and argues that as epigenome editing technologies mature, overcoming critical challenges in delivery, specificity, and fidelity should clear the path to bring these technologies into the clinic. PMID- 28018140 TI - Friend or Foe: Epigenetic Regulation of Retrotransposons in Mammalian Oogenesis and Early Development. AB - Epigenetics is the study of phenotypic variation arising from developmental and environmental factors regulating gene transcription at molecular, cellular, and physiological levels. A naturally occurring biological process driven by epigenetics is the egg-to-embryo developmental transition when two fully differentiated adult cells - egg and sperm - revert to an early stem cell type with totipotency but subsequently differentiates into pluripotent embryonic stem cells that give rise to any cell type. Transposable elements (TEs) are active in mammalian oocytes and early embryos, and this activity, albeit counterintuitive because TEs can lead to genomic instability in somatic cells, correlates to successful development. TEs bridge genetic and epigenetic landscapes because TEs are genetic elements whose silencing and de-repression are regulated by epigenetic mechanisms that are sensitive to environmental factors. Ultimately, transposition events can change size, content, and function of mammalian genomes. Thus, TEs act beyond mutagenic agents reshuffling the genomes, and epigenetic regulation of TEs may act as a proximate mechanism by which evolutionary forces increase a species' hidden reserve of epigenetic and phenotypic variability facilitating the adaptation of genomes to their environment. PMID- 28018141 TI - What Drives Positive Selection in the Drosophila piRNA Machinery? The Genomic Autoimmunity Hypothesis. AB - In animals, PIWI-interacting RNAs (piRNAs) play a crucial role in genome defense. Moreover, because piRNAs can be maternally transmitted, they contribute to the epigenetic profile of inheritance. Multiple studies, especially in Drosophila, have demonstrated that the machinery of piRNA biogenesis is often the target of positive selection. Because transposable elements (TEs) are a form of genetic parasite, positive selection in the piRNA machinery is often explained by analogy to the signatures of positive selection commonly observed in genes that play a role in host-parasite dynamics. However, the precise mechanisms that drive positive selection in the piRNA machinery are not known. In this review, we outline several mechanistic models that might explain pervasive positive selection in the piRNA machinery of Drosophila species. We propose that recurrent positive selection in the piRNA machinery can be partly explained by an ongoing tension between selection for sensitivity required by genome defense and selection for specificity to avoid the off-target effects of maladaptive genic silencing by piRNA. PMID- 28018142 TI - The Role of the Ubiquitously Expressed Transcription Factor Sp1 in Tissue specific Transcriptional Regulation and in Disease. AB - Sp1 belongs to the 26 member strong Sp/KLF family of transcription factors. It is a paradigm for a ubiquitously expressed transcription factor and is involved in regulating the expression of genes associated with a wide range of cellular processes in mammalian cells. Sp1 can interact with a range of proteins, including other transcription factors, members of the transcription initiation complex and epigenetic regulators, enabling tight regulation of its target genes. In this review, we discuss the mechanisms involved in Sp1-mediated transcriptional regulation, as well as how a ubiquitous transcription factor can be involved in establishing a tissue-specific pattern of gene expression and mechanisms by which its activity may be regulated. We also consider the role of Sp1 in human diseases, such as cancer. PMID- 28018143 TI - Emerging Functions of Circular RNAs. AB - Many thousands of Circular RNAs (circRNAs) have recently been identified in metazoan genomes by transcriptome-wide sequencing. Most circRNAs are generated by back-splicing events from exons of protein-coding genes. A great deal of progress has recently been made in understanding the genome-wide expression patterns, biogenesis, and regulation of circRNAs. To date, however, few functions of circRNAs have been identified. CircRNAs are preferentially expressed in neural tissues and some are found at synapses, suggesting possible functions in the nervous system. Several circRNAs have been shown to function as microRNA "sponges" to counteract microRNA mediated repression of mRNA. New functions for circRNAs are arising, including protein sequestration, transcriptional regulation, and potential functions in cancer. Here, we highlight the recent progress made in understanding the biogenesis and regulation of circRNAs, discuss newly uncovered circRNA functions, and explain the methodological approaches that could reveal more exciting and unexpected roles for these RNAs. PMID- 28018145 TI - Epigenetics of Renal Development and Disease. AB - An understanding of epigenetics is indispensable to our understanding of gene regulation under normal and pathological states. This knowledge will help with designing better therapeutic approaches in regenerative tissue medicine. Epigenetics allows us to parse out the mechanisms by which transcriptional regulators gain access to specific gene loci thereby imprinting epigenetic information affecting chromatin function. This epigenetic memory forms the basis of cell lineage specification in multicellular organisms. Post-translational modifications to DNA and histones in the nucleosome core form characteristic epigenetic codes which are distinct for self-renewing and primed progenitor cell populations. Studies of chromatin modifiers and modifications in renal development and disease have been gaining momentum. Both congenital and adult renal diseases have a gene-environment component, which involves alterations to the epigenetic information imprinted during development. This epigenetic memory must be characterized to establish optimal treatment of both acute and chronic renal diseases. PMID- 28018147 TI - Receptor Signaling Directs Global Recruitment of Pre-existing Transcription Factors to Inducible Elements. AB - Gene expression programs are largely regulated by the tissue-specific expression of lineage-defining transcription factors or by the inducible expression of transcription factors in response to specific stimuli. Here I will review our own work over the last 20 years to show how specific activation signals also lead to the wide-spread re-distribution of pre-existing constitutive transcription factors to sites undergoing chromatin reorganization. I will summarize studies showing that activation of kinase signaling pathways creates open chromatin regions that recruit pre-existing factors which were previously unable to bind to closed chromatin. As models I will draw upon genes activated or primed by receptor signaling in memory T cells, and genes activated by cytokine receptor mutations in acute myeloid leukemia. I also summarize a hit-and-run model of stable epigenetic reprograming in memory T cells, mediated by transient Activator Protein 1 (AP-1) binding, which enables the accelerated activation of inducible enhancers. PMID- 28018144 TI - Deciphering the Epigenetic Code in Embryonic and Dental Pulp Stem Cells. AB - A close cooperation between chromatin states, transcriptional modulation, and epigenetic modifications is required for establishing appropriate regulatory circuits underlying self-renewal and differentiation of adult and embryonic stem cells. A growing body of research has established that the epigenome topology provides a structural framework for engaging genes in the non-random chromosomal interactions to orchestrate complex processes such as cell-matrix interactions, cell adhesion and cell migration during lineage commitment. Over the past few years, the functional dissection of the epigenetic landscape has become increasingly important for understanding gene expression dynamics in stem cells naturally found in most tissues. Adult stem cells of the human dental pulp hold great promise for tissue engineering, particularly in the skeletal and tooth regenerative medicine. It is therefore likely that progress towards pulp regeneration will have a substantial impact on the clinical research. This review summarizes the current state of knowledge regarding epigenetic cues that have evolved to regulate the pluripotent differentiation potential of embryonic stem cells and the lineage determination of developing dental pulp progenitors. PMID- 28018149 TI - Knowledge Gain of Pharmacy Students and Pharmacists Comparing Simulation Versus Traditional Learning Methodology. AB - OBJECTIVES: The purpose of this study was to evaluate the difference between education via written materials alone and written materials enhanced with hands on simulation. METHODS: A simulation case, educational module, and assessment regarding torsades de pointes (TdP) in an adolescent patient were designed. The written educational module was given to all study participants. A total of 92 third-year pharmacy students and 26 pharmacists participated in the study. RESULTS: When approximately half of the participants had been to simulation, an anonymous assessment was given. Responses from those who had been to simulation and those who had not, and whether they had read, skimmed or not read the educational material were compared. A non-paired Student t-test compared the percentage correct and responses of individual questions between groups. Mean participant scores of those who went to simulation (70% +/- 16%) were statistically significantly higher than mean scores of those who had not attended simulation (54% +/- 21%; p<0.0001). Furthermore, those who attended simulation and read the module (72% +/- 3%), skimmed (68% +/- 13%), or did not read the module (66% +/- 16%) had higher scores than those who did not attend simulation and read the module (62% +/- 26%), skimmed the module (54 +/- 17%) or did not read the module (51% +/- 20%). CONCLUSIONS: Hands-on simulation significantly improved assessment scores. Overall, reading the educational module and participating in simulation yielded the best scores. Participants who attended the simulation and did not read the module had higher average scores than participants who read the educational module and did not go to simulation. PMID- 28018150 TI - Frequency of and Risk Factors for Acute Kidney Injury Associated With Vancomycin Use in the Pediatric Intensive Care Unit. AB - BACKGROUND: Published information evaluating frequency of and risk factors for vancomycin-induced acute kidney injury (AKI) in the pediatric intensive care unit (PICU) population is conflicting. OBJECTIVES: The primary objective was to describe the proportion of our PICU patients who developed AKI with intravenous (IV) vancomycin. The secondary objective was to describe the associated potential risk factors. METHODS: Pediatric patients (0-18 years) who received their first IV vancomycin dose in the PICU were evaluated in this retrospective chart review. AKI was defined based on Pediatric-Modified RIFLE (pRIFLE) criteria. Patient demographics, vancomycin trough concentrations, concomitant nephrotoxins, and estimated creatinine clearance changes were analyzed. RESULTS: Of 265 patients included, the primary outcome of AKI (defined by meeting any pRIFLE criteria) occurred in 62 (23.4%) patients (48 category R, 11 category I, 3 category F). Patients who received vancomycin treatment for = 5 days were more likely to develop AKI (unadjusted odds ratio [uOR]: 2.52; 95% confidence interval [CI]: 1.11-5.73), as were patients with a maximum vancomycin trough level = 20 mg/L (OR: 2.99; 95% CI: 1.54-5.78) and patients on 1 (uOR: 2.29; 95% CI: 1.12-4.66) or more concurrent nephrotoxin (uOR: 3.11; 95% CI: 1.43-6.77). Among nephrotoxins, patients receiving furosemide concomitantly with vancomycin were more likely to develop AKI (uOR: 3.47; 95% CI: 1.92-6.27). After adjustment, only furosemide was a significant predictor of risk of AKI/AKI (adjusted OR: 3.52; 95% CI: 1.88 6.62). The study was limited by its retrospective and observational design, and confounding variables. CONCLUSIONS: Patients who were receiving vancomycin with concurrent furosemide were at highest risk of developing AKI. PMID- 28018148 TI - Epigenetics and Common Ophthalmic Diseases. AB - The study of ocular diseases and epigenetic dysregulation is an emerging area of research. The knowledge from the epigenetic mechanisms of DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs regarding the pathogenesis of ocular diseases will be helpful for improved treatment modalities for our patients. In particular, we focus upon the how epigenetic regulatory mechanisms impact five common ocular diseases: age related macular degeneration, age-related cataract, pterygium, retinoblastoma, and uveal melanoma. Hence, the foundation of this research paves the way for future specific therapeutic targets to treat and prevent vision loss. PMID- 28018146 TI - Pancreatic Cancer, A Mis-interpreter of the Epigenetic Language. AB - Pancreatic cancer is the third leading cause of cancer mortality in the U.S. with close to 40,000 deaths per year. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90 percent of all pancreatic cancer cases and is the most lethal form of the disease. Current therapies for PDAC are ineffective and most patients cannot be treated by surgical resection. Most research efforts have primarily focused on how genetic alterations cause, alter progression, contribute to diagnosis, and influence PDAC management. Over the past two decades, a model has been advanced of PDAC initiation and progression as a multi-step process driven by the acquisition of mutations leading to loss of tumor suppressors and activation of oncogenes. The recognition of the essential roles of these genetic alterations in the development of PDAC has revolutionized our knowledge of this disease. However, none of these findings have turned into effective treatment for this dismal malignancy. In recent years, studies in the areas of chromatin modifications, and non-coding RNAs have uncovered mechanisms for regulating gene expression which occur independently of genetic alterations. Chromatin-based mechanisms are interwoven with microRNA-driven regulation of protein translation to create an integrated epigenetic language, which is grossly dysregulated in PDAC. Thus in PDAC, key tumor suppressors that are well established to play a role in PDAC may be repressed, and oncogenes can be upregulated secondary to epigenetic alterations. Unlike mutations, epigenetic changes are potentially reversible. Given this feature of epigenetic mechanisms, it is conceivable that targeting epigenetic-based events promoting and maintaining PDAC could serve as foundation for the development of new therapeutic and diagnostic approaches for this disease. PMID- 28018151 TI - Survey Evaluating the Practice of Children's Hospitals Having Pharmacist Collaborative Drug Therapy Management Protocols. AB - OBJECTIVES: The purpose of this study is to determine how frequently children's hospitals in the United States are using pharmacist-physician collaborative drug therapy management (CDTM), and to characterize their use in this population. METHODS: A phone survey was created to collect data regarding the use of pharmacist-physician CDTM at children's hospitals. Children's hospitals were called between February 2014 and April 2014. Data were collected from either a clinical pharmacist or pharmacy director. Pharmacists were asked to answer questions regarding hospital demographics as well as to what extent and for which medications they use CDTM. Differences between types of hospitals were evaluated using Fisher exact test. RESULTS: A total of 171 children's hospitals were identified; 51.5% hospitals (n = 88) completed the survey. Of the 88 hospitals that completed the survey, 32 (31.7%) had some level of CDTM in place. Of the 28 children's hospitals with CDTM in place that completed the survey, all allowed pharmacists to modify doses and monitor therapy, and 75% provided pharmacists with the ability to initiate the first dose. The specific medications that were included in the CDTM protocols in children's hospitals included vancomycin (n = 23), aminoglycosides (n = 22), anticoagulation medications (n = 7), and total parenteral nutrition (n = 3). Training was required for pharmacists to participate in CDTM protocols at most hospitals (n = 26). Lack of support from medical staff was the most common perceived barrier. No differences were identified between types of children's hospitals. CONCLUSION: CDTM protocols are practiced in about one third of the children's hospitals. Pharmacists commonly initiate, monitor, and modify therapies as part of these protocols. The most frequently included medications were vancomycin and aminoglycosides. PMID- 28018152 TI - Evaluation of Medication-related Self-care Skills in Patients With Cystic Fibrosis. AB - BACKGROUND: As the life expectancy of patients with cystic fibrosis (CF) increases, the focus on ensuring success with medication therapies is increasingly important. The ability of patients to autonomously manage medications and related therapies is poorly described in the literature. OBJECTIVE: The goal of this project was to assess the level of medication-related knowledge and self-care skills in patients with CF. METHODS: This project took place in a Cystic Fibrosis Foundation accredited affiliate center. Eighty-nine patients between the ages of 6 and 60 were eligible to participate based on inclusion and exclusion criteria. Pharmacists administered a 16-item questionnaire and detailed medication history during clinic visits from January through May 2014. RESULTS: Forty-five patients 6 to 41 years old participated in the study. The skills most often performed independently were preparing nebulizer treatments (85%) and telling someone if they feel their medicines are causing a problem (89%). Skills least often performed were carrying a medication list (82%) and bringing a medication list to appointments (76%). In respondents 21 years of age and older, less than 75% of respondents were involved with obtaining financial resources, maintaining equipment, carrying a medication list, or rinsing their mouth after using inhaled medicines. Participants were able to provide drug name, dose, and frequency of use for pancreatic enzymes and azithromycin 37% and 24% of the time, respectively. CONCLUSIONS: In the population surveyed, many medication-related skills had not been acquired by early adulthood. Assessing and providing education for medication-related self care skills at all ages are needed. PMID- 28018153 TI - A Pediatric Diabetic Ketoacidosis Management Protocol Incorporating a Two-Bag Intravenous Fluid System Decreases Duration of Intravenous Insulin Therapy. AB - OBJECTIVES: Diabetic ketoacidosis (DKA) is a leading cause of morbidity and mortality in children with type 1 diabetes. We implemented a standardized DKA management protocol by using a 2-bag intravenous (IV) fluid system. The purpose of the study was to examine if the protocol improved clinical outcomes and process efficiency. METHODS: This was a retrospective study of patients who did and did not undergo the protocol. Patients were included if they were 18 years of age or younger, were diagnosed with DKA, admitted to an intensive care unit or stepdown unit, and received continuous IV insulin. RESULTS: Of 119 encounters evaluated, 46 (38.7%) received treatment with the protocol and 73 (61.3%) did not. The median time to normalization of ketoacidosis was 9 hours (IQR 5-12) and 9 hours (IQR 6.5-13) for protocol and non-protocol groups, respectively (p = 0.14). The median duration of IV insulin therapy was 16.9 hours (IQR 13.7-21.5) vs. 21 hours (IQR 15.3-26) for protocol and non-protocol groups (p = 0.03). The median number of adjustments to insulin drip rate was 0 (IQR 0-1) and 2 (IQR 0-3) for protocol and non-protocol groups (p = 0.0001). There was no difference in the incidence of hypokalemia, hypoglycemia, or cerebral edema. CONCLUSIONS: The protocol did not change time to normalization of ketoacidosis but did decrease the duration of insulin therapy, number of adjustments to insulin drip rate, and number of wasted IV fluid bags without increasing the incidence of adverse events. PMID- 28018154 TI - Antenatal Escitalopram Use and Necrotizing Enterocolitis in a Newborn: A Case Report. AB - The increased use of antidepressants during pregnancy has been associated with adverse effects in the newborn. We report a case of antenatal escitalopram use associated with necrotizing enterocolitis in a healthy term baby. We further discuss possible mechanisms that may explain this association. With increasing evidence of association of necrotizing enterocolitis with maternal exposure to antidepressants, more studies to find out causality and methods to predict babies at risk and their prudent management are needed. PMID- 28018155 TI - Neonatal Toxicity From Escitalopram Use In Utero: A Case Report. AB - Selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy can result in symptoms of serotonin syndrome or serotonin withdrawal. In contrast to other SSRIs, reports of serotonin behavioral syndrome following in utero exposure to escitalopram and citalopram are limited. We describe a case of suspected toxicity following in utero exposure to 20 mg escitalopram throughout pregnancy. The infant was transferred to our neonatal intensive unit at 9 hours of life for further evaluation of lethargy, weak cry, bradycardia, and non-reactive pupils. Hypoxic ischemic encephalopathy was suspected upon presentation, despite APGAR scores of 8 and 9. Upon admission, symptoms progressed to signs of hypertonia, irritability, high-pitched cry, and posturing. The patient was loaded with phenobarbital for empiric management of suspected seizures versus drug withdrawal. Both electroencephalogram and computed tomography scan results were normal; however, an electrocardiogram revealed a prolonged QTc interval of 531 milliseconds. Signs of irritability and QTc prolongation continued through day of life (DOL) 5. The infant was discharged on DOL 10 with no further symptoms. We hypothesize that this represented a case of serotonin toxicity due to in utero exposure to escitalopram and recommend close monitoring for neonatal behavioral syndrome symptoms and QTc prolongation in infants exposed to escitalopram during pregnancy. PMID- 28018156 TI - How a Drug Shortage Contributed to a Medication Error Leading to Baclofen Toxicity in an Infant. AB - We report the case of a 4-month-old girl who developed encephalopathy, seizures, and respiratory compromise as a result of baclofen toxicity. After some investigation, the accidental ingestion of baclofen was caused by an error in compounding the patient's prescribed omeprazole with baclofen rather than sodium bicarbonate at a retail pharmacy. This error occurred because these two drugs, which were available as powders, were located side by side on the pharmacy shelf. The pharmacist further reported that their normal practice was to use injectable sodium bicarbonate rather than powder to compound an omeprazole suspension; however, the injectable form was not available due to a national shortage. This report demonstrates how a drug shortage contributed to severe clinical consequences and intensive care hospitalization of a patient. It also highlights the need for system improvement to minimize drug shortages. PMID- 28018157 TI - Position Statement on Heparin Safety Concerns. PMID- 28018158 TI - Estrogen catechols detection as biomarkers in schistosomiasis induced cancer and infertility. AB - Urogenital schistosomiasis is a chronic infection caused by the human blood fluke Schistosoma haematobium. Schistosomiasis haematobium is a known risk factor for cancer leading to squamous cell carcinoma of the urinary bladder (SCC). This is a neglected tropical disease endemic in many countries of Africa and the Middle East. Schistosome eggs produce catechol-estrogens. These molecules are metabolized to active quinones that cause alterations in DNA (leading in other contexts to breast or thyroid cancer). Our group have shown that schistosome egg associated catechol estrogens induce tumor-like phenotypes in urothelial cells, originated from parasite estrogen-host cell chromosomal DNA adducts and mutations. Here we review recent findings on the role of estrogen-DNA adducts and how their shedding in urine may be prognostic of schistosome infection and/or represent potential biomarkers for urogenital schistosomiasis associated bladder cancer and infertility. PMID- 28018159 TI - Introducing the USA Plant, Algae and Microbial Metabolomics Research Coordination Network (PAMM-NET). PMID- 28018161 TI - Frequency-Amplitude Cross Interaction during Pulsatile Taste Delivery Using Gustometers. AB - In this article, we numerically resolve the flow profiles of tastant concentration in the pipe of a gustometer used to deliver alternative pulses in concentration, which is a typical case of Taylor dispersion. Using this model, we can define the cases where the experimenter will deliver to the assessors a concentration profile which is significantly different from that intended. This can be simply assessed a priori using a scaling argument which involves calculating a dimensionless frequency. This is a function of the pulses frequency, the dimensions of the pipe and the flow rate used. We show that unless this parameter is taken into account, modifying the pulse frequency will modify the pulse amplitude. This design criterion is absent from the literature but we suggest this is important for designing such experiments. PMID- 28018160 TI - A Sliced Inverse Regression (SIR) Decoding the Forelimb Movement from Neuronal Spikes in the Rat Motor Cortex. AB - Several neural decoding algorithms have successfully converted brain signals into commands to control a computer cursor and prosthetic devices. A majority of decoding methods, such as population vector algorithms (PVA), optimal linear estimators (OLE), and neural networks (NN), are effective in predicting movement kinematics, including movement direction, speed and trajectory but usually require a large number of neurons to achieve desirable performance. This study proposed a novel decoding algorithm even with signals obtained from a smaller numbers of neurons. We adopted sliced inverse regression (SIR) to predict forelimb movement from single-unit activities recorded in the rat primary motor (M1) cortex in a water-reward lever-pressing task. SIR performed weighted principal component analysis (PCA) to achieve effective dimension reduction for nonlinear regression. To demonstrate the decoding performance, SIR was compared to PVA, OLE, and NN. Furthermore, PCA and sequential feature selection (SFS) which are popular feature selection techniques were implemented for comparison of feature selection effectiveness. Among SIR, PVA, OLE, PCA, SFS, and NN decoding methods, the trajectories predicted by SIR (with a root mean square error, RMSE, of 8.47 +/- 1.32 mm) was closer to the actual trajectories compared with those predicted by PVA (30.41 +/- 11.73 mm), OLE (20.17 +/- 6.43 mm), PCA (19.13 +/- 0.75 mm), SFS (22.75 +/- 2.01 mm), and NN (16.75 +/- 2.02 mm). The superiority of SIR was most obvious when the sample size of neurons was small. We concluded that SIR sorted the input data to obtain the effective transform matrices for movement prediction, making it a robust decoding method for conditions with sparse neuronal information. PMID- 28018162 TI - A Bidirectional Brain-Machine Interface Featuring a Neuromorphic Hardware Decoder. AB - Bidirectional brain-machine interfaces (BMIs) establish a two-way direct communication link between the brain and the external world. A decoder translates recorded neural activity into motor commands and an encoder delivers sensory information collected from the environment directly to the brain creating a closed-loop system. These two modules are typically integrated in bulky external devices. However, the clinical support of patients with severe motor and sensory deficits requires compact, low-power, and fully implantable systems that can decode neural signals to control external devices. As a first step toward this goal, we developed a modular bidirectional BMI setup that uses a compact neuromorphic processor as a decoder. On this chip we implemented a network of spiking neurons built using its ultra-low-power mixed-signal analog/digital circuits. On-chip on-line spike-timing-dependent plasticity synapse circuits enabled the network to learn to decode neural signals recorded from the brain into motor outputs controlling the movements of an external device. The modularity of the BMI allowed us to tune the individual components of the setup without modifying the whole system. In this paper, we present the features of this modular BMI and describe how we configured the network of spiking neuron circuits to implement the decoder and to coordinate it with the encoder in an experimental BMI paradigm that connects bidirectionally the brain of an anesthetized rat with an external object. We show that the chip learned the decoding task correctly, allowing the interfaced brain to control the object's trajectories robustly. Based on our demonstration, we propose that neuromorphic technology is mature enough for the development of BMI modules that are sufficiently low-power and compact, while being highly computationally powerful and adaptive. PMID- 28018164 TI - An Insulin-Like Growth Factor in Rhodnius prolixus Is Involved in Post-feeding Nutrient Balance and Growth. AB - Growth of organisms is modulated by the availability of nutrients and energy, and is mostly regulated by insulin-like growth factors (IGFs) through the insulin signaling system. In insects, IGFs produced by the fat body induce cell division during the molt cycle, regulate adult body size, and have metabolic effects. Here, we describe an IGF from the hematophagous hemipteran Rhodnius prolixus and show its activity in regulating growth and metabolism in the post-feeding period during the fifth, and last, nymphal instar. Rhopr-IGF transcript is present in a variety of tissues, with greatest expression in the fat body, the dorsal vessel, and the CNS. We silenced the expression of the transcript using RNA interference, and at 2 weeks after feeding, insects with reduced Rhopr-IGF expression showed increased hemolymph lipid and carbohydrate levels when compared to controls, but no differences were observed in fat body lipid or carbohydrate content. In order to assess the role of Rhopr-IGF in post-feeding growth, double stranded IGF injected insects were followed through ecdysis, and this treatment resulted in shorter adults, with shorter and narrower wings, when compared to controls. The results suggest that Rhopr-IGF modulates growth in R. prolixus most likely through altering the usage of nutrients that are available in the hemolymph. PMID- 28018163 TI - Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis. AB - A physiological parallelism, or even a causal effect relationship, can be deducted from the analysis of the main characteristics of the "Alcohol Related Neurodevelopmental Disorders" (ARND), derived from prenatal alcohol exposure (PAE), and the behavioral performance in the Attention-deficit/hyperactivity disorder (ADHD). These two clinically distinct disease entities, exhibits many common features. They affect neurological shared pathways, and also related neurotransmitter systems. We briefly review here these parallelisms, with their common and uncommon characteristics, and with an emphasis in the subjacent molecular mechanisms of the behavioral manifestations, that lead us to propose that PAE in rats can be considered as a suitable model for the study of ADHD. PMID- 28018165 TI - Investigating the Group-Level Impact of Advanced Dual-Echo fMRI Combinations. AB - Multi-echo fMRI data acquisition has been widely investigated and suggested to optimize sensitivity for detecting the BOLD signal. Several methods have also been proposed for the combination of data with different echo times. The aim of the present study was to investigate whether these advanced echo combination methods provide advantages over the simple averaging of echoes when state-of-the art group-level random-effect analyses are performed. Both resting-state and task based dual-echo fMRI data were collected from 27 healthy adult individuals (14 male, mean age = 25.75 years) using standard echo-planar acquisition methods at 3T. Both resting-state and task-based data were subjected to a standard image pre processing pipeline. Subsequently the two echoes were combined as a weighted average, using four different strategies for calculating the weights: (1) simple arithmetic averaging, (2) BOLD sensitivity weighting, (3) temporal-signal-to noise ratio weighting and (4) temporal BOLD sensitivity weighting. Our results clearly show that the simple averaging of data with the different echoes is sufficient. Advanced echo combination methods may provide advantages on a single subject level but when considering random-effects group level statistics they provide no benefit regarding sensitivity (i.e., group-level t-values) compared to the simple echo-averaging approach. One possible reason for the lack of clear advantages may be that apart from increasing the average BOLD sensitivity at the single-subject level, the advanced weighted averaging methods also inflate the inter-subject variance. As the echo combination methods provide very similar results, the recommendation is to choose between them depending on the availability of time for collecting additional resting-state data or whether subject-level or group-level analyses are planned. PMID- 28018167 TI - Editorial: Non-invasive Brain Stimulation in Neurology and Psychiatry. PMID- 28018166 TI - Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review. AB - Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide. PMID- 28018168 TI - What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum? AB - Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease. PMID- 28018169 TI - High Transmembrane Voltage Raised by Close Contact Initiates Fusion Pore. AB - Membrane fusion lies at the heart of neuronal communication but the detailed mechanism of a critical step, fusion pore initiation, remains poorly understood. Here, through atomistic molecular dynamics simulations, a transient pore formation induced by a close contact of two apposed bilayers is firstly reported. Such a close contact gives rise to a high local transmembrane voltage that induces the transient pore formation. Through simulations on two apposed bilayers fixed at a series of given distances, the process in which two bilayers approaching to each other under the pulling force from fusion proteins for membrane fusion was mimicked. Of note, this close contact induced fusion pore formation is contrasted with previous reported electroporation under ad hoc applied external electric field or ionic charge in-balance. We show that the transmembrane voltage increases with the decrease of the distance between the bilayers. Below a critical distance, depending on the lipid composition, the local transmembrane voltage can be sufficiently high to induce the transient pores. The size of these pores is approximately 1~2 nm in diameter, which is large enough to allow passing of neurotransmitters. A resealing of the membrane pores resulting from the neutralization of the transmembrane voltage by ions through the pores was then observed. We also found that the membrane tension can either prolong the lifetime of transient pores or cause them to dilate for full collapse. This result provides a possible mechanism for fusion pore formation and regulation of pathway of fusion process. PMID- 28018170 TI - mRNA Transcriptomics of Galectins Unveils Heterogeneous Organization in Mouse and Human Brain. AB - Background: Galectins, a family of non-classically secreted, beta-galactoside binding proteins is involved in several brain disorders; however, no systematic knowledge on the normal neuroanatomical distribution and functions of galectins exits. Hence, the major purpose of this study was to understand spatial distribution and predict functions of galectins in brain and also compare the degree of conservation vs. divergence between mouse and human species. The latter objective was required to determine the relevance and appropriateness of studying galectins in mouse brain which may ultimately enable us to extrapolate the findings to human brain physiology and pathologies. Results: In order to fill this crucial gap in our understanding of brain galectins, we analyzed the in situ hybridization and microarray data of adult mouse and human brain respectively, from the Allen Brain Atlas, to resolve each galectin-subtype's spatial distribution across brain distinct cytoarchitecture. Next, transcription factors (TFs) that may regulate galectins were identified using TRANSFAC software and the list obtained was further curated to sort TFs on their confirmed transcript expression in the adult brain. Galectin-TF cluster analysis, gene-ontology annotations and co-expression networks were then extrapolated to predict distinct functional relevance of each galectin in the neuronal processes. Data shows that galectins have highly heterogeneous expression within and across brain sub structures and are predicted to be the crucial targets of brain enriched TFs. Lgals9 had maximal spatial distribution across mouse brain with inferred predominant roles in neurogenesis while LGALS1 was ubiquitously expressed in human. Limbic region associated with learning, memory and emotions and substantia nigra associated with motor movements showed strikingly high expression of LGALS1 and LGALS8 in human vs. mouse brain. The overall expression profile of galectin-8 was most preserved across both these species, however, galectin-9 showed maximal preservation only in the cerebral cortex. Conclusion: It is for the first time that a comprehensive description of galectins' mRNA expression profile in brain is presented. Results suggests that spatial transcriptome changes in galectins may contribute to differential brain functions and evolution across species that highlights galectins as novel signatures of brain heterogeneity and functions, which if disturbed, can promote several brain disorders. PMID- 28018171 TI - Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis. AB - In view of important neurobiological functions of the cell adhesion molecule contactin-6 (Cntn6) that have emerged from studies on null-mutant mice and autism spectrum disorders patients, we set out to examine pathways underlying functions of Cntn6 using a proteomics approach. We identified the cell adhesion GPCR latrophilin-1 (Lphn1, a.k.a. CIRL1/CL, ADGRL1) as a binding partner for Cntn6 forming together a heteromeric cis-complex. Lphn1 expression in cultured neurons caused reduction in neurite outgrowth and increase in apoptosis, which was rescued by coexpression of Cntn6. In cultured neurons derived from Cntn6-/- mice, Lphn1 knockdown reduced apoptosis, suggesting that the observed apoptosis was Lphn1-dependent. In line with these data, the number of apoptotic cells was increased in the cortex of Cntn6-/- mice compared to wild-type littermate controls. These results show that Cntn6 can modulate the activity of Lphn1 by direct binding and suggests that Cntn6 may prevent apoptosis thereby impinging on neurodevelopment. PMID- 28018172 TI - APP Causes Hyperexcitability in Fragile X Mice. AB - Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO /APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO /APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS. PMID- 28018173 TI - Positive Allosteric Modulation of Insect Olfactory Receptor Function by ORco Agonists. AB - Insect olfactory receptors (ORs) are heteromeric ligand-gated cation channels composed of a common olfactory receptor subunit (ORco) and a variable subunit (ORx) of as yet unknown structures and undetermined stoichiometries. In this study, we examined the allosteric modulation exerted on Anopheles gambiae heteromeric ORx/ORco olfactory receptors in vitro by a specific class of ORco agonists (OAs) comprising ORcoRAM2 and VUAA1. High OA concentrations produced stronger functional responses in cells expressing heteromeric receptor channels relative to cells expressing ORco alone. These OA-induced responses of ORx/ORco channels were also notably much stronger than those obtained upon administration of ORx-specific ligands to the same receptors. Most importantly, small concentrations of OAs were found to act as strong potentiators of ORx/ORco function, increasing dramatically both the efficacy and potency of ORx-specific odorants. These results suggest that insect heteromeric ORs are highly dynamic complexes adopting different conformations that change in a concerted fashion as a result of the interplay between the subunits of the oligomeric assemblies, and that allosteric modulation may constitute an important element in the modulation and fining tuning of olfactory reception function. PMID- 28018175 TI - Progressive Seizure Aggravation in the Repeated 6-Hz Corneal Stimulation Model Is Accompanied by Marked Increase in Hippocampal p-ERK1/2 Immunoreactivity in Neurons. AB - The 6-Hz corneal stimulation test is used to screen novel antiepileptic molecules to overcome the problem of drug refractoriness. Although recognized as a standard test, it has been evaluated only recently in the attempt to characterize the putative neuronal networks involved in seizures caused by corneal stimulation. In particular, by recording from the CA1 region we previously established that the hippocampus participates to propagation of seizure activity. However, these findings were not corroborated by using markers of neuronal activation such as FosB/DeltaFosB antigens. In view of this discrepancy, we performed new experiments to characterize the changes in levels of phosphorylated extracellular signal-regulated kinases1/2 (p-ERK1/2), which are also used as markers of neuronal activation. To this aim, mice underwent corneal stimulation up to three different times, in three sessions separated by an interval of 3 days. To characterize a group in which seizures could be prevented by pharmacological treatment, we also considered pretreatment with the ghrelin receptor antagonist EP-80317 (330 MUg/kg). Control mice were sham-treated. Video electrocorticographic (ECoG) recordings were obtained from mice belonging to each group of treatment. Animals were finally used to characterize the immunoreactivity for FosB/DeltaFosB and p-ERK1/2 in the hippocampus. As previously shown, FosB/DeltaFosB levels were highly increased throughout the hippocampus by the first induced seizure but, in spite of the progressively increased seizure severity, they were restored to control levels after the third stimulation. At variance, corneal stimulation caused a progressive increase in p ERK1/2 immunoreactivity all over the hippocampus, especially in CA1, peaking in the third session. Predictably, EP-80317 administration reduced both duration and severity of seizures, prevented the increase in FosB/DeltaFosB levels in the first session, and partially counteracted the increase in p-ERK1/2 levels in the third session. The vast majority of p-ERK1/2 immunopositive cells were co-labeled with FosB/DeltaFosB antibodies, suggesting the existence of a relationship between the investigated markers in a subpopulation of neurons activated by seizures. These findings suggest that p-ERK1/2 are useful markers to define the aggravation of seizures and the response to anticonvulsant treatments. In particular, p-ERK1/2 expression clearly identified the involvement of hippocampal regions during seizure aggravation in the 6-Hz model. PMID- 28018174 TI - Neurogenesis-Promoting Natural Product alpha-Asarone Modulates Morphological Dynamics of Activated Microglia. AB - alpha-Asarone is an active constituent of Acori Tatarinowii, one of the widely used traditional Chinese Medicine to treat cognitive defect, and recently is shown to promote neurogenesis. Here, we demonstrated that low level (3 MUM) of alpha-asarone attenuated LPS-induced BV2 cell bipolar elongated morphological change, with no significant effect on the LPS-induced pro-inflammatory cytokine expressions. In addition, time-lapse analysis also revealed that alpha-asarone modulated LPS-induced BV2 morphological dynamics. Consistently a significant reduction in the LPS-induced Monocyte Chemoattractant Protein (MCP-1) mRNA and protein levels was also detected along with the morphological change. Mechanistic study showed that the attenuation effect to the LPS-resulted morphological modulation was also detected in the presence of MCP-1 antibodies or a CCR2 antagonist. This result has also been confirmed in primary cultured microglia. The in vivo investigation provided further evidence that alpha-asarone reduced the proportion of activated microglia, and reduced microglial tip number and maintained the velocity. Our study thus reveals alpha-asarone effectively modulates microglial morphological dynamics, and implies this effect of alpha asarone may functionally relate to its influence on neurogenesis. PMID- 28018176 TI - Activated Microglia Induce Bone Marrow Mesenchymal Stem Cells to Produce Glial Cell-Derived Neurotrophic Factor and Protect Neurons Against Oxygen-Glucose Deprivation Injury. AB - In this study, we investigated interactions among microglia (MG), bone marrow mesenchymal stem cells (BMSCs) and neurons in cerebral ischemia and the potential mechanisms using an in vitro oxygen-glucose deprivation (OGD) model. Rat BMSCs were incubated with conditioned medium (CM) from in vitro cultures of OGD activated rat MG and murine BV2 MG cells. Effects of glial cell-derived neurotrophic factor (GDNF) on rat neuron viability, apoptosis, lactate dehydrogenase (LDH) leakage and mitochondrial membrane potential (MMP) were analyzed in this model. OGD-activated MG promoted GDNF production by BMSCs (P < 0.01). Tumor necrosis factor-alpha (TNFalpha), but not interleukin-6 (IL6) or interleukin 1beta (IL1beta), promoted GDNF production by BMSCs (P < 0.001). GDNF or CM pre-treated BMSCs elevated neuronal viability and suppressed apoptosis (P < 0.05 or P < 0.01); these effects were inhibited by the RET antibody. GDNF activated MEK/ERK and phosphoinositide-3-kinase (PI3K)/AKT signaling but not JNK/c-JUN. Furthermore, GDNF upregulated B cell lymphoma 2 (BCL2) and heat shock 60 kDa protein 1 (HSP60) levels, suppressed LDH leakage, and promoted MMP. Thus, activated MG produce TNFalpha to stimulate GDNF production by BMSCs, which prevents and repairs OGD-induced neuronal injury, possibly via regulating MEK/ERK and PI3K/AKT signaling. These findings will facilitate the prevention and treatment of neuronal injury by cerebral ischemia. PMID- 28018177 TI - Heterocellular Contacts with Mouse Brain Endothelial Cells Via Laminin and alpha6beta1 Integrin Sustain Subventricular Zone (SVZ) Stem/Progenitor Cells Properties. AB - Neurogenesis in the subventricular zone (SVZ) is regulated by diffusible factors and cell-cell contacts. In vivo, SVZ stem cells are associated with the abluminal surface of blood vessels and such interactions are thought to regulate their neurogenic capacity. SVZ neural stem cells (NSCs) have been described to contact endothelial-derived laminin via alpha6beta1 integrin. To elucidate whether heterocellular contacts with brain endothelial cells (BEC) regulate SVZ cells neurogenic capacities, cocultures of SVZ neurospheres and primary BEC, both obtained from C57BL/6 mice, were performed. The involvement of laminin-integrin interactions in SVZ homeostasis was tested in three ways. Firstly, SVZ cells were analyzed following incubation of BEC with the protein synthesis inhibitor cycloheximide (CHX) prior to coculture, a treatment expected to decrease membrane proteins. Secondly, SVZ cells were cocultured with BEC in the presence of an anti alpha6 integrin neutralizing antibody. Thirdly, BEC were cultured with beta1-/- SVZ cells. We showed that contact with BEC supports, at least in part, proliferation and stemness of SVZ cells, as evaluated by the number of BrdU positive (+) and Sox2+ cells in contact with BEC. These effects are dependent on BEC-derived laminin binding to alpha6beta1 integrin and are decreased in cocultures incubated with anti-alpha6 integrin neutralizing antibody and in cocultures with SVZ beta1-/- cells. Moreover, BEC-derived laminin sustains stemness in SVZ cell cultures via activation of the Notch and mTOR signaling pathways. Our results show that BEC/SVZ interactions involving alpha6beta1 integrin binding to laminin, contribute to SVZ cell proliferation and stemness. PMID- 28018178 TI - Associations of Unilateral Whisker and Olfactory Signals Induce Synapse Formation and Memory Cell Recruitment in Bilateral Barrel Cortices: Cellular Mechanism for Unilateral Training Toward Bilateral Memory. AB - Somatosensory signals and operative skills learned by unilateral limbs can be retrieved bilaterally. In terms of cellular mechanism underlying this unilateral learning toward bilateral memory, we hypothesized that associative memory cells in bilateral cortices and synapse innervations between them were produced. In the examination of this hypothesis, we have observed that paired unilateral whisker and odor stimulations led to odorant-induced whisker motions in bilateral sides, which were attenuated by inhibiting the activity of barrel cortices. In the mice that showed bilateral cross-modal responses, the neurons in both sides of barrel cortices became to encode this new odor signal alongside the innate whisker signal. Axon projections and synapse formations from the barrel cortex, which was co-activated with the piriform cortex, toward its contralateral barrel cortex (CBC) were upregulated. Glutamatergic synaptic transmission in bilateral barrel cortices was upregulated and GABAergic synaptic transmission was downregulated. The associative activations of the sensory cortices facilitate new axon projection, glutamatergic synapse formation and GABAergic synapse downregulation, which drive the neurons to be recruited as associative memory cells in the bilateral cortices. Our data reveal the productions of associative memory cells and synapse innervations in bilateral sensory cortices for unilateral training toward bilateral memory. PMID- 28018179 TI - Temporal Characterization of Microglia/Macrophage Phenotypes in a Mouse Model of Neonatal Hypoxic-Ischemic Brain Injury. AB - Immune cells display a high degree of phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with classical and alternative polarization phenotypes described for macrophages and to identify related cell populations in the brain following neonatal hypoxia-ischemia (HI). HI was induced in 9-day old mice and brain tissue was collected up to 7 days post-insult to investigate expression of genes associated with macrophage activation. Using cell-markers, CD86 (classic activation) and CD206 (alternative activation), we assessed temporal changes of CD11b+ cell populations in the brain and studied the protein expression of the immunomodulatory factor galectin-3 in these cells. HI induced a rapid regulation (6 h) of genes associated with both classical and alternative polarization phenotypes in the injured hemisphere. FACS analysis showed a marked increase in the number of CD11b+CD86+ cells at 24 h after HI (+3667%), which was coupled with a relative suppression of CD11b+CD206+ cells and cells that did not express neither CD86 nor CD206. The CD11b+CD206+ population was mixed with some cells also expressing CD86. Confocal microscopy confirmed that a subset of cells expressed both CD86 and CD206, particularly in injured gray and white matter. Protein concentration of galectin-3 was markedly increased mainly in the cell population lacking CD86 or CD206 in the injured hemisphere. These cells were predominantly resident microglia as very few galectin-3 positive cells co localized with infiltrating myeloid cells in Lys-EGFP-ki mice after HI. In summary, HI was characterized by an early mixed gene response, but with a large expansion of mainly the CD86 positive population during the first day. However, the injured hemisphere also contained a subset of cells expressing both CD86 and CD206 and a large population that expressed neither activation marker CD86 nor CD206. Interestingly, these cells expressed the highest levels of galectin-3 and were found to be predominantly resident microglia. Galectin-3 is a protein involved in chemotaxis and macrophage polarization suggesting a novel role in cell infiltration and immunomodulation for this cell population after neonatal injury. PMID- 28018180 TI - Local Field Potentials: Myths and Misunderstandings. AB - The intracerebral local field potential (LFP) is a measure of brain activity that reflects the highly dynamic flow of information across neural networks. This is a composite signal that receives contributions from multiple neural sources, yet interpreting its nature and significance may be hindered by several confounding factors and technical limitations. By and large, the main factor defining the amplitude of LFPs is the geometry of the current sources, over and above the degree of synchronization or the properties of the media. As such, similar levels of activity may result in potentials that differ in several orders of magnitude in different populations. The geometry of these sources has been experimentally inaccessible until intracerebral high density recordings enabled the co activating sources to be revealed. Without this information, it has proven difficult to interpret a century's worth of recordings that used temporal cues alone, such as event or spike related potentials and frequency bands. Meanwhile, a collection of biophysically ill-founded concepts have been considered legitimate, which can now be corrected in the light of recent advances. The relationship of LFPs to their sources is often counterintuitive. For instance, most LFP activity is not local but remote, it may be larger further from rather than close to the source, the polarity does not define its excitatory or inhibitory nature, and the amplitude may increase when source's activity is reduced. As technological developments foster the use of LFPs, the time is now ripe to raise awareness of the need to take into account spatial aspects of these signals and of the errors derived from neglecting to do so. PMID- 28018181 TI - Spatial Distribution of Attentional Modulation at Columnar Resolution in Macaque Area V4. AB - Attention to a location in a visual scene affects neuronal responses in visual cortical areas in a retinotopically specific manner. Optical imaging studies have revealed that cortical responses consist of two components of different sizes: the stimulus-nonspecific global signal and the stimulus-specific mapping signal (domain activity). It remains unclear whether either or both of these components are modulated by spatial attention. In this study, to determine the spatial distribution of attentional modulation at columnar resolution, we performed cerebral blood volume (CBV)-based optical imaging in area V4 of monkeys performing a color change detection task in which spatial attention was manipulated. We found that spatial attention enhanced global signals of the hemodynamic responses, but did not affect stimulus-selective domain activities. These results indicate the involvement of global signals in neural processing of spatial attention. We propose that global signals reflect the neural substrate of the normalization pool in normalization models of attention. PMID- 28018182 TI - Mapping Horizontal Spread of Activity in Monkey Motor Cortex Using Single Pulse Microstimulation. AB - Anatomical studies have demonstrated that distant cortical points are interconnected through long range axon collaterals of pyramidal cells. However, the functional properties of these intrinsic synaptic connections, especially their relationship with the cortical representations of body movements, have not been systematically investigated. To address this issue, we used multielectrode arrays chronically implanted in the motor cortex of two rhesus monkeys to analyze the effects of single-pulse intracortical microstimulation (sICMS) applied at one electrode on the neuronal activities recorded at all other electrodes. The temporal and spatial distribution of the evoked responses of single and multiunit activities was quantified to determine the properties of horizontal propagation. The typical responses were characterized by a brief excitatory peak followed by inhibition of longer duration. Significant excitatory responses to sICMS could be evoked up to 4 mm away from the stimulation site, but the strength of the response decreased exponentially and its latency increased linearly with the distance. We then quantified the direction and strength of the propagation in relation to the somatotopic organization of the motor cortex. We observed that following sICMS the propagation of neural activity is mainly directed rostro caudally near the central sulcus but follows medio-lateral direction at the most anterior electrodes. The fact that these interactions are not entirely symmetrical may characterize a critical functional property of the motor cortex for the control of upper limb movements. Overall, these results support the assumption that the motor cortex is not functionally homogeneous but forms a complex network of interacting subregions. PMID- 28018184 TI - Corrigendum: Distribution of 28 kDa Calbindin-Immunopositive Neurons in the Cat Spinal Cord. AB - [This corrects the article on p. 166 in vol. 9, PMID: 26858610.]. PMID- 28018183 TI - Changed Hub and Corresponding Functional Connectivity of Subgenual Anterior Cingulate Cortex in Major Depressive Disorder. AB - Major depressive disorder (MDD) is one of the most prevalent mental disorders. In the brain, the hubs of the brain network play a key role in integrating and transferring information between different functional modules. However, whether the changed pattern in functional network hubs contributes to the onset of MDD remains unclear. Using resting-state functional magnetic resonance imaging (rs fMRI) and graph theory methods, we investigated whether alterations of hubs can be detected in MDD. First, we constructed the whole-brain voxel-wise functional networks and calculated a functional connectivity strength (FCS) map in each subject in 34 MDD patients and 34 gender-, age- and education level-matched healthy controls (HCs). Next, the two-sample t-test was applied to compare the FCS maps between HC and MDD patients and identified significant decrease of FCS in subgenual anterior cingulate cortex (sgACC) in MDD patients. Subsequent functional connectivity analyses of sgACC showed disruptions in functional connectivity with posterior insula, middle and inferior temporal gyrus, lingual gyrus and cerebellum in MDD patients. Furthermore, the changed FCS of sgACC and functional connections to sgACC were significantly correlated with the Hamilton Depression Rating Scale (HDRS) scores in MDD patients. The results of the present study revealed the abnormal hub of sgACC and its corresponding disrupted frontal limbic-visual cognitive-cerebellum functional networks in MDD. These findings may provide a new insight for the diagnosis and treatment of MDD. PMID- 28018185 TI - Life and Understanding: The Origins of "Understanding" in Self-Organizing Nervous Systems. AB - This article is motivated by a formulation of biotic self-organization in Friston (2013), where the emergence of "life" in coupled material entities (e.g., macromolecules) was predicated on bounded subsets that maintain a degree of statistical independence from the rest of the network. Boundary elements in such systems constitute a Markov blanket; separating the internal states of a system from its surrounding states. In this article, we ask whether Markov blankets operate in the nervous system and underlie the development of intelligence, enabling a progression from the ability to sense the environment to the ability to understand it. Markov blankets have been previously hypothesized to form in neuronal networks as a result of phase transitions that cause network subsets to fold into bounded assemblies, or packets (Yufik and Sheridan, 1997; Yufik, 1998a). The ensuing neuronal packets hypothesis builds on the notion of neuronal assemblies (Hebb, 1949, 1980), treating such assemblies as flexible but stable biophysical structures capable of withstanding entropic erosion. In other words, structures that maintain their integrity under changing conditions. In this treatment, neuronal packets give rise to perception of "objects"; i.e., quasi stable (stimulus bound) feature groupings that are conserved over multiple presentations (e.g., the experience of perceiving "apple" can be interrupted and resumed many times). Monitoring the variations in such groups enables the apprehension of behavior; i.e., attributing to objects the ability to undergo changes without loss of self-identity. Ultimately, "understanding" involves self directed composition and manipulation of the ensuing "mental models" that are constituted by neuronal packets, whose dynamics capture relationships among objects: that is, dependencies in the behavior of objects under varying conditions. For example, movement is known to involve rotation of population vectors in the motor cortex (Georgopoulos et al., 1988, 1993). The neuronal packet hypothesis associates "understanding" with the ability to detect and generate coordinated rotation of population vectors-in neuronal packets-in associative cortex and other regions in the brain. The ability to coordinate vector representations in this way is assumed to have developed in conjunction with the ability to postpone overt motor expression of implicit movement, thus creating a mechanism for prediction and behavioral optimization via mental modeling that is unique to higher species. This article advances the notion that Markov blankets-necessary for the emergence of life-have been subsequently exploited by evolution and thus ground the ways that living organisms adapt to their environment, culminating in their ability to understand it. PMID- 28018187 TI - Editorial: Traumatic Brain Injury As a Systems Neuroscience Problem. PMID- 28018186 TI - Comparative Overview of Visuospatial Working Memory in Monkeys and Rats. AB - Neural mechanisms of working memory, particularly its visuospatial aspect, have long been studied in non-human primates. On the other hand, rodents are becoming more important in systems neuroscience, as many of the innovative research methods have become available for them. There has been a question on whether primates and rodents have similar neural backgrounds for working memory. In this article, we carried out a comparative overview of the neural mechanisms of visuospatial working memory in monkeys and rats. In monkeys, a number of lesion studies indicate that the brain region most responsible for visuospatial working memory is the ventral dorsolateral prefrontal cortex (vDLPFC), as the performance in the standard tests for visuospatial working memory, such as delayed response and delayed alternation tasks, are impaired by lesions in this region. Single unit studies revealed a characteristic firing pattern in neurons in this area, a sustained delay activity. Further studies indicated that the information maintained in the working memory, such as cue location and response direction in a delayed response, is coded in the sustained delay activity. In rats, an area comparable to the monkey vDLPFC was found to be the dorsal part of the medial prefrontal cortex (mPFC), as the delayed alternation in a T-maze is impaired by its lesion. Recently, the sustained delay activity similar to that found in monkeys has been found in the dorsal mPFC of rats performing the delayed response task. Furthermore, anatomical studies indicate that the vDLPFC in monkeys and the dorsal mPFC in rats have much in common, such as that they are both the major targets of parieto-frontal projections. Thus lines of evidence indicate that in both monkeys and rodents, the PFC plays a critical role in working memory. PMID- 28018188 TI - Cholinergic Interneurons Amplify Corticostriatal Synaptic Responses in the Q175 Model of Huntington's Disease. AB - Huntington's disease (HD) is a neurodegenerative disorder characterized by deficits in movement control that are widely viewed as stemming from pathophysiological changes in the striatum. Giant, aspiny cholinergic interneurons (ChIs) are key elements in the striatal circuitry controlling movement, but whether their physiological properties are intact in the HD brain is unclear. To address this issue, the synaptic properties of ChIs were examined using optogenetic approaches in the Q175 mouse model of HD. In ex vivo brain slices, synaptic facilitation at thalamostriatal synapses onto ChIs was reduced in Q175 mice. The alteration in thalamostriatal transmission was paralleled by an increased response to optogenetic stimulation of cortical axons, enabling these inputs to more readily induce burst-pause patterns of activity in ChIs. This adaptation was dependent upon amplification of cortically evoked responses by a post-synaptic upregulation of voltage-dependent Na+ channels. This upregulation also led to an increased ability of somatic spikes to invade ChI dendrites. However, there was not an alteration in the basal pacemaking rate of ChIs, possibly due to increased availability of Kv4 channels. Thus, there is a functional "re-wiring" of the striatal networks in Q175 mice, which results in greater cortical control of phasic ChI activity, which is widely thought to shape the impact of salient stimuli on striatal action selection. PMID- 28018189 TI - Auditory-Somatosensory Temporal Sensitivity Improves When the Somatosensory Event Is Caused by Voluntary Body Movement. AB - When we actively interact with the environment, it is crucial that we perceive a precise temporal relationship between our own actions and sensory effects to guide our body movements. Thus, we hypothesized that voluntary movements improve perceptual sensitivity to the temporal disparity between auditory and movement related somatosensory events compared to when they are delivered passively to sensory receptors. In the voluntary condition, participants voluntarily tapped a button, and a noise burst was presented at various onset asynchronies relative to the button press. The participants made either "sound-first" or "touch-first" responses. We found that the performance of temporal order judgment (TOJ) in the voluntary condition (as indexed by the just noticeable difference (JND)) was significantly better (M = 42.5 ms +/- 3.8 SEM) than that when their finger was passively stimulated (passive condition: M = 66.8 ms +/- 6.3 SEM). We further examined whether the performance improvement with voluntary action can be attributed to the prediction of the timing of the stimulation from sensory cues (sensory-based prediction), kinesthetic cues contained in voluntary action, and/or to the prediction of stimulation timing from the efference copy of the motor command (motor-based prediction). When three noise bursts were presented before the target burst with regular intervals (predictable condition) and when the participant's finger was moved passively to press the button (involuntary condition), the TOJ performance was not improved from that in the passive condition. These results suggest that the improvement in sensitivity to temporal disparity between somatosensory and auditory events caused by the voluntary action cannot be attributed to sensory-based prediction and kinesthetic cues. Rather, the prediction from the efference copy of the motor command would be crucial for improving the temporal sensitivity. PMID- 28018190 TI - Disruption of the Glutamate-Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females. AB - Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate-glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate-glutamine cycle involving astrocytes using an animal model of depression. Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 MUM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls. Conclusion: Twenty one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate-glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males. PMID- 28018191 TI - Hebb and Cattell: The Genesis of the Theory of Fluid and Crystallized Intelligence. AB - Raymond B. Cattell is credited with the development of the theory of fluid and crystallized intelligence. The genesis of this theory is, however, vague. Cattell, in different papers, stated that it was developed in 1940, 1941 or 1942. Carroll (1984, Multivariate Behavioral Research, 19, 300-306) noted the similarity of Cattell's theory to "Hebb's notion of two types of intelligence," which was presented at the 1941 APA meeting, but the matter has been left at that. Correspondence between Cattell, Donald Hebb and George Humphrey of Queen's University, Kingston, Ontario, however, indicates that Cattell adopted Hebb's ideas of intelligence A and B and renamed them. This paper describes Hebb's two types of intelligence, and shows how Cattell used them to develop his ideas of crystallized and fluid intelligence. Hebb and Cattell exchanged a number of letters before Cattell's paper was rewritten in such a way that everyone was satisfied. This paper examines the work of Hebb and Cattell on intelligence, their correspondence, the development of the ideas of fluid and crystallized intelligence, and why Cattell (1943, p. 179) wrote that "Hebb has independently stated very clearly what constitutes two thirds of the present theory." PMID- 28018193 TI - Are Modular Activations Altered in Lower Limb Muscles of Persons with Multiple Sclerosis during Walking? Evidence from Muscle Synergies and Biomechanical Analysis. AB - Background: Persons with Multiple Sclerosis frequently have gait deficits that lead to diminished activities of daily living. Identification of motoneuron activity patterns may elucidate new insight into impaired locomotor coordination and underlying neural systems. The aim of the present study was to investigate muscle synergies, identified by motor modules and their activation profiles, in persons with Multiple Sclerosis (PwMS) during walking compared to those of healthy subjects (HS), as well as, exploring relationship of muscle synergies with walking ability of PwMS. Methods: Seventeen PwMS walked at their natural speed while 12 HS walked at slower than their natural speeds in order to provide normative gait values at matched speeds (spatio-temporal, kinematic, and kinetic parameters and electromyography signals). Non-negative matrix factorization was used to identify muscle synergies from eight muscles. Pearson's correlation coefficient was used to evaluate the similarity of motor modules between PwMS and HS. To assess differences in module activations, each module's activation timing was integrated over 100% of gait cycle and the activation percentage was computed in six phases. Results: Fifty-nine% of PwMS and 58% of HS had 4 modules while the remaining of both populations had 3 modules. Module 2 (related to soleus, medial, and lateral gastrocnemius primarily involved in mid and terminal stance) and Module 3 (related to tibialis anterior and rectus femoris primarily involved in early stance, and early and late swing) were comparable across all subjects regardless of synergies number. PwMS had shorter stride length, longer double support phase and push off deficit with respect to HS (p < 0.05). The alterations of activation timing profiles of specific modules in PwMS were associated with their walking deficits (e.g., the reduction of Module 2 activation percentage index in terminal stance, PwMS 35.55 +/- 13.23 vs. HS 50.51 +/- 9.13% p < 0.05, and the push off deficit, PwMS 0.181 +/- 0.136 vs. HS 0.291 +/- 0.062 w/kg p < 0.05). Conclusion: During gait PwMS have synergies numbers similar to healthy persons. Their neurological deficit alters modular control through modifications of the timing activation profiles rather than module composition. These changes were associated with their main walking impairment, muscle weakness, and prolonged double support. PMID- 28018192 TI - Differences in Resting State Functional Connectivity between Young Adult Endurance Athletes and Healthy Controls. AB - Expertise and training in fine motor skills has been associated with changes in brain structure, function, and connectivity. Fewer studies have explored the neural effects of athletic activities that do not seem to rely on precise fine motor control (e.g., distance running). Here, we compared resting-state functional connectivity in a sample of adult male collegiate distance runners (n = 11; age = 21.3 +/- 2.5) and a group of healthy age-matched non-athlete male controls (n = 11; age = 20.6 +/- 1.1), to test the hypothesis that expertise in sustained aerobic motor behaviors affects resting state functional connectivity in young adults. Although generally considered an automated repetitive task, locomotion, especially at an elite level, likely engages multiple cognitive actions including planning, inhibition, monitoring, attentional switching and multi-tasking, and motor control. Here, we examined connectivity in three resting state networks that link such executive functions with motor control: the default mode network (DMN), the frontoparietal network (FPN), and the motor network (MN). We found two key patterns of significant between-group differences in connectivity that are consistent with the hypothesized cognitive demands of elite endurance running. First, enhanced connectivity between the FPN and brain regions often associated with aspects of working memory and other executive functions (frontal cortex), suggest endurance running may stress executive cognitive functions in ways that increase connectivity in associated networks. Second, we found significant anti-correlations between the DMN and regions associated with motor control (paracentral area), somatosensory functions (post-central region), and visual association abilities (occipital cortex). DMN deactivation with task positive regions has been shown to be generally beneficial for cognitive performance, suggesting anti-correlated regions observed here are engaged during running. For all between-group differences, there were significant associations between connectivity, self-reported physical activity, and estimates of maximum aerobic capacity, suggesting a dose-response relationship between engagement in endurance running and connectivity strength. Together these results suggest that differences in experience with endurance running are associated with differences in functional brain connectivity. High intensity aerobic activity that requires sustained, repetitive locomotor and navigational skills may stress cognitive domains in ways that lead to altered brain connectivity, which in turn has implications for understanding the beneficial role of exercise for brain and cognitive function over the lifespan. PMID- 28018194 TI - Cross-Sectional and Longitudinal Relationships between Depressive Symptoms and Brain Atrophy in MS Patients. AB - Introduction: Depressive symptoms are a frequent and distressing phenomenon in Multiple Sclerosis (MS) patients. Cross-sectional research links these symptoms to reduced brain gray matter volumes in parts of the prefrontal and temporal lobe as well as subcortical structures like the hippocampus, nucleus caudatus and globus pallidus. Nevertheless, prospective relationships between regional gray matter volume and the course of depressive symptoms are poorly understood. Methods: Forty-four patients with relapsing-remitting or secondary progressive MS participated in a prospective study with two assessments of depressive symptoms and high-resolution MRI with an inter-test-interval of 17 months. Relationships between baseline gray matter volume and baseline depressive symptoms, as well as prospective associations between the development of atrophy and depression were assessed using voxel-based morphometry (VBM). Results: Cross-sectional analyses revealed an association between depressive symptoms and gray matter loss in the left temporal lobe. Prospective analysis showed that gray matter losses in the right middle cingulate and middle frontal gyrus at baseline predicted increasing depressive symptoms during follow-up. Increase in depressive symptoms was related to a concomitant increase in atrophy in the left thalamus and right globus pallidus. Discussion: Our results fit well into the concept of a disturbed cortico-striatal-pallido-thalamic loop in depression. In this framework, progressive gray matter loss in limbic basal ganglia structures including globus pallidus and thalamus may lead to depression-typical deficits in hedonic motivation, whereas atrophy of the prefrontal cortex may contribute to maladaptive coping strategies, promoting an unfavorable development of depressive symptoms. PMID- 28018195 TI - Mediators of Physical Activity on Neurocognitive Function: A Review at Multiple Levels of Analysis. AB - Physical activity (PA) is known to maintain and improve neurocognitive health. However, there is still a poor understanding of the mechanisms by which PA exerts its effects on the brain and cognition in humans. Many of the most widely discussed mechanisms of PA are molecular and cellular and arise from animal models. While information about basic cellular and molecular mechanisms is an important foundation from which to build our understanding of how PA promotes cognitive health in humans, there are other pathways that could play a role in this relationship. For example, PA-induced changes to cellular and molecular pathways likely initiate changes to macroscopic properties of the brain and/or to behavior that in turn influence cognition. The present review uses a more macroscopic lens to identify potential brain and behavioral/socioemotional mediators of the association between PA and cognitive function. We first summarize what is known regarding cellular and molecular mechanisms, and then devote the remainder of the review to discussing evidence for brain systems and behavioral/socioemotional pathways by which PA influences cognition. It is our hope that discussing mechanisms at multiple levels of analysis will stimulate the field to examine both brain and behavioral mediators. Doing so is important, as it could lead to a more complete characterization of the processes by which PA influences neurocognitive function, as well as a greater variety of targets for modifying neurocognitive function in clinical contexts. PMID- 28018196 TI - Changes in Motor-Related Cortical Activity Following Deep Brain Stimulation for Parkinson's Disease Detected by Functional Near Infrared Spectroscopy: A Pilot Study. AB - It remains unclear how deep brain stimulation (DBS) modulates the global neuronal network involving cortical activity. We aimed to evaluate changes in cortical activity in six (two men; four women) patients with Parkinson's disease (PD) who underwent unilateral globus pallidus interna (GPI) DBS surgery using a multi channel near infrared spectroscopy (NIRS) system. As five of the patients were right-handed, DBS was performed on the left in these five cases. The mean age was 66.8 +/- 4.0 years. The unified Parkinson's disease rating scale (UPDRS) motor scores were evaluated at baseline and 1- and 6-month follow-up. Task-related NIRS experiments applying the block design were performed at baseline and 1-month follow-up. The mean of the total UPDRS motor score was 48.5 +/- 11.1 in the off medication state preoperatively. Postoperatively, total UPDRS motor scores improved to 26.8 +/- 16.6 (p < 0.05) and 22.2 +/- 8.6 (p < 0.05) at 1- and 6 month follow-up, respectively. A task-related NIRS experiment showed a postoperative increase in the cortical activity of the prefrontal cortex comparable to the preoperative state. To our knowledge, this is the first study to use a multi-channel NIRS system for PD patients treated with DBS. In this pilot study, we showed changes in motor-associated cortical activities following DBS surgery. Therapeutic DBS was concluded to have promoted the underlying neuronal network remodeling. PMID- 28018197 TI - Low-Level Contrast Statistics of Natural Images Can Modulate the Frequency of Event-Related Potentials (ERP) in Humans. AB - Humans are fast and accurate in categorizing complex natural images. It is, however, unclear what features of visual information are exploited by brain to perceive the images with such speed and accuracy. It has been shown that low level contrast statistics of natural scenes can explain the variance of amplitude of event-related potentials (ERP) in response to rapidly presented images. In this study, we investigated the effect of these statistics on frequency content of ERPs. We recorded ERPs from human subjects, while they viewed natural images each presented for 70 ms. Our results showed that Weibull contrast statistics, as a biologically plausible model, explained the variance of ERPs the best, compared to other image statistics that we assessed. Our time-frequency analysis revealed a significant correlation between these statistics and ERPs' power within theta frequency band (~3-7 Hz). This is interesting, as theta band is believed to be involved in context updating and semantic encoding. This correlation became significant at ~110 ms after stimulus onset, and peaked at 138 ms. Our results show that not only the amplitude but also the frequency of neural responses can be modulated with low-level contrast statistics of natural images and highlights their potential role in scene perception. PMID- 28018198 TI - Time Processing and Motor Control in Movement Disorders. AB - The subjective representation of "time" is critical for cognitive tasks but also for several motor activities. The neural network supporting motor timing comprises: lateral cerebellum, basal ganglia, sensorimotor and prefrontal cortical areas. Basal ganglia and associated cortical areas act as a hypothetical "internal clock" that beats the rhythm when the movement is internally generated. When timing information is processed to make predictions on the outcome of a subjective or externally perceived motor act, cerebellar processing and outflow pathways appear to be primarily involved. Clinical and experimental evidence on time processing and motor control points to a dysfunction of the neural networks involving basal ganglia and cerebellum in movement disorders. In some cases, temporal processing deficits could directly contribute to core motor features of the movement disorder, as in the case of bradykinesia in Parkinson's disease. For other movement disorders, the relationship between abnormal time processing and motor performance is less obvious and requires further investigation, as in the reduced accuracy in predicting the temporal outcome of a motor act in dystonia. We aim to review the literature on time processing and motor control in Parkinson's disease, dystonia, Huntington's disease, and Tourette syndrome, integrating the available findings with current pathophysiological models; we will highlight the areas in which future explorations are warranted, as well as the aspects of time processing in motor control that present translational aspects in future rehabilitation strategies. The subjective representation of "time" is critical for cognitive tasks but also for motor activities. Recently, greater attention has been devoted to improve our understanding of how temporal information becomes integrated within the mechanisms of motor control. Experimental evidence recognizes time processing in motor control as a complex neural function supported by diffuse cerebral networks including cortical areas, cerebellum, and other subcortical structures (Ivry and Spencer, 2004; Coull and Nobre, 2008). Timing is an essential component of motor control primarily within two types of motor tasks: (i) when producing sequential rhythmic movements or sustained movements of a definite duration (explicit timing); (ii) when the temporal information is used implicitly, such as when coordinating our movements to those of moving objects or individuals within the external environment (implicit timing). In this review, we will provide a brief description of the neural network supporting motor timing focusing only on instrumental information to explain the link between timing and motor control in movement disorders. Then we will review available data on motor timing in Parkinson's disease, dystonia, Huntington's disease, and Tourette syndrome, and discuss how this body of evidence integrates with the available information on the pathophysiology of these movement disorders. Finally, we will discuss the translational aspects of the explored neural mechanisms with respect to future rehabilitation strategies. PMID- 28018199 TI - Near-Infrared Spectroscopy based Neurofeedback of Prefrontal Cortex Activity: A Proof-of-Concept Study. AB - Neurofeedback is a promising tool for treatment and rehabilitation of several patient groups. In this proof of principle study, near-infrared spectroscopy (NIRS) based neurofeedback of frontal cortical areas was investigated in healthy adults. Main aims were the assessment of learning, the effects on performance in a working memory (n-back) task and the impact of applied strategies on regulation. 13 healthy participants underwent eight sessions of NIRS based neurofeedback within 2 weeks to learn to voluntarily up-regulate hemodynamic activity in prefrontal areas. An n-back task in pre-/post measurements was used to monitor neurocognitive changes. Mean oxygenated hemoglobin (O2Hb) amplitudes over the course of the sessions as well as during the n-back task were evaluated. 12 out of 13 participants were able to regulate their frontal hemodynamic response via NIRS neurofeedback. However, no systematic learning effects were observed in frontal O2Hb amplitudes over the training course in our healthy sample. We found an impact of applied strategies in only 5 out of 13 subjects. Regarding the n-back task, neurofeedback appeared to induce more focused and specific brain activation compared to pre-training measurement. NIRS based neurofeedback is a feasible and potentially effective method, with an impact on activation patterns in a working memory task. Ceiling effects might explain the lack of a systematic learning pattern in healthy subjects. Clinical studies are needed to show effects in patients exhibiting pathological deviations in prefrontal function. PMID- 28018200 TI - A Cultural Evolution Approach to Digital Media. AB - Digital media have today an enormous diffusion, and their influence on the behavior of a vast part of the human population can hardly be underestimated. In this review I propose that cultural evolution theory, including both a sophisticated view of human behavior and a methodological attitude to modeling and quantitative analysis, provides a useful framework to study the effects and the developments of media in the digital age. I will first give a general presentation of the cultural evolution framework, and I will then introduce this more specific research program with two illustrative topics. The first topic concerns how cultural transmission biases, that is, simple heuristics such as "copy prestigious individuals" or "copy the majority," operate in the novel context of digital media. The existence of transmission biases is generally justified with their adaptivity in small-scale societies. How do they operate in an environment where, for example, prestigious individuals possess not-relevant skills, or popularity is explicitly quantified and advertised? The second aspect relates to fidelity of cultural transmission. Digitally-mediated interactions support cheap and immediate high-fidelity transmission, in opposition, for example, to oral traditions. How does this change the content that is more likely to spread? Overall, I suggest the usefulness of a "long view" to our contemporary digital environment, contextualized in cognitive science and cultural evolution theory, and I discuss how this perspective could help us to understand what is genuinely new and what is not. PMID- 28018201 TI - Feature-Specific Event-Related Potential Effects to Action- and Sound-Related Verbs during Visual Word Recognition. AB - Grounded cognition theories suggest that conceptual representations essentially depend on modality-specific sensory and motor systems. Feature-specific brain activation across different feature types such as action or audition has been intensively investigated in nouns, while feature-specific conceptual category differences in verbs mainly focused on body part specific effects. The present work aimed at assessing whether feature-specific event-related potential (ERP) differences between action and sound concepts, as previously observed in nouns, can also be found within the word class of verbs. In Experiment 1, participants were visually presented with carefully matched sound and action verbs within a lexical decision task, which provides implicit access to word meaning and minimizes strategic access to semantic word features. Experiment 2 tested whether pre-activating the verb concept in a context phase, in which the verb is presented with a related context noun, modulates subsequent feature-specific action vs. sound verb processing within the lexical decision task. In Experiment 1, ERP analyses revealed a differential ERP polarity pattern for action and sound verbs at parietal and central electrodes similar to previous results in nouns. Pre-activation of the meaning of verbs in the preceding context phase in Experiment 2 resulted in a polarity-reversal of feature-specific ERP effects in the lexical decision task compared with Experiment 1. This parallels analogous earlier findings for primed action and sound related nouns. In line with grounded cognitions theories, our ERP study provides evidence for a differential processing of action and sound verbs similar to earlier observation for concrete nouns. Although the localizational value of ERPs must be viewed with caution, our results indicate that the meaning of verbs is linked to different neural circuits depending on conceptual feature relevance. PMID- 28018202 TI - Further Work on the Shaping of Cortical Development and Function by Synchrony and Metabolic Competition. AB - This paper furthers our attempts to resolve two major controversies-whether gamma synchrony plays a role in cognition, and whether cortical columns are functionally important. We have previously argued that the configuration of cortical cells that emerges in development is that which maximizes the magnitude of synchronous oscillation and minimizes metabolic cost. Here we analyze the separate effects in development of minimization of axonal lengths, and of early Hebbian learning and selective distribution of resources to growing synapses, by showing in simulations that these effects are partially antagonistic, but their interaction during development produces accurate anatomical and functional properties for both columnar and non-columnar cortex. The resulting embryonic anatomical order can provide a cortex-wide scaffold for postnatal learning that is dimensionally consistent with the representation of moving sensory objects, and, as learning progressively overwrites the embryonic order, further associations also occur in a dimensionally consistent framework. The role ascribed to cortical synchrony does not demand specific frequency, amplitude or phase variation of pulses to mediate "feature linking." Instead, the concerted interactions of pulse synchrony with short-term synaptic dynamics, and synaptic resource competition can further explain cortical information processing in analogy to Hopfield networks and quantum computation. PMID- 28018203 TI - Computational Properties of the Hippocampus Increase the Efficiency of Goal Directed Foraging through Hierarchical Reinforcement Learning. AB - The mammalian brain is thought to use a version of Model-based Reinforcement Learning (MBRL) to guide "goal-directed" behavior, wherein animals consider goals and make plans to acquire desired outcomes. However, conventional MBRL algorithms do not fully explain animals' ability to rapidly adapt to environmental changes, or learn multiple complex tasks. They also require extensive computation, suggesting that goal-directed behavior is cognitively expensive. We propose here that key features of processing in the hippocampus support a flexible MBRL mechanism for spatial navigation that is computationally efficient and can adapt quickly to change. We investigate this idea by implementing a computational MBRL framework that incorporates features inspired by computational properties of the hippocampus: a hierarchical representation of space, "forward sweeps" through future spatial trajectories, and context-driven remapping of place cells. We find that a hierarchical abstraction of space greatly reduces the computational load (mental effort) required for adaptation to changing environmental conditions, and allows efficient scaling to large problems. It also allows abstract knowledge gained at high levels to guide adaptation to new obstacles. Moreover, a context driven remapping mechanism allows learning and memory of multiple tasks. Simulating dorsal or ventral hippocampal lesions in our computational framework qualitatively reproduces behavioral deficits observed in rodents with analogous lesions. The framework may thus embody key features of how the brain organizes model-based RL to efficiently solve navigation and other difficult tasks. PMID- 28018204 TI - Bayesian Analysis of Perceived Eye Level. AB - To accurately perceive the world, people must efficiently combine internal beliefs and external sensory cues. We introduce a Bayesian framework that explains the role of internal balance cues and visual stimuli on perceived eye level (PEL)-a self-reported measure of elevation angle. This framework provides a single, coherent model explaining a set of experimentally observed PEL over a range of experimental conditions. Further, it provides a parsimonious explanation for the additive effect of low fidelity cues as well as the averaging effect of high fidelity cues, as also found in other Bayesian cue combination psychophysical studies. Our model accurately estimates the PEL and explains the form of previous equations used in describing PEL behavior. Most importantly, the proposed Bayesian framework for PEL is more powerful than previous behavioral modeling; it permits behavioral estimation in a wider range of cue combination and perceptual studies than models previously reported. PMID- 28018205 TI - Editorial: Imaging Synapse Structure and Function. PMID- 28018206 TI - The Role of Multiple Neuromodulators in Reinforcement Learning That Is Based on Competition between Eligibility Traces. AB - The ability to maximize reward and avoid punishment is essential for animal survival. Reinforcement learning (RL) refers to the algorithms used by biological or artificial systems to learn how to maximize reward or avoid negative outcomes based on past experiences. While RL is also important in machine learning, the types of mechanistic constraints encountered by biological machinery might be different than those for artificial systems. Two major problems encountered by RL are how to relate a stimulus with a reinforcing signal that is delayed in time (temporal credit assignment), and how to stop learning once the target behaviors are attained (stopping rule). To address the first problem synaptic eligibility traces were introduced, bridging the temporal gap between a stimulus and its reward. Although, these were mere theoretical constructs, recent experiments have provided evidence of their existence. These experiments also reveal that the presence of specific neuromodulators converts the traces into changes in synaptic efficacy. A mechanistic implementation of the stopping rule usually assumes the inhibition of the reward nucleus; however, recent experimental results have shown that learning terminates at the appropriate network state even in setups where the reward nucleus cannot be inhibited. In an effort to describe a learning rule that solves the temporal credit assignment problem and implements a biologically plausible stopping rule, we proposed a model based on two separate synaptic eligibility traces, one for long-term potentiation (LTP) and one for long-term depression (LTD), each obeying different dynamics and having different effective magnitudes. The model has been shown to successfully generate stable learning in recurrent networks. Although, the model assumes the presence of a single neuromodulator, evidence indicates that there are different neuromodulators for expressing the different traces. What could be the role of different neuromodulators for expressing the LTP and LTD traces? Here we expand on our previous model to include several neuromodulators, and illustrate through various examples how different these contribute to learning reward-timing within a wide set of training paradigms and propose further roles that multiple neuromodulators can play in encoding additional information of the rewarding signal. PMID- 28018208 TI - Global Efficiency of Structural Networks Mediates Cognitive Control in Mild Cognitive Impairment. AB - Background: Cognitive control has been linked to both the microstructure of individual tracts and the structure of whole-brain networks, but their relative contributions in health and disease remain unclear. Objective: To determine the contribution of both localized white matter tract damage and disruption of global network architecture to cognitive control, in older age and Mild Cognitive Impairment (MCI). Materials and Methods: Twenty-five patients with MCI and 20 age, sex, and intelligence-matched healthy volunteers were investigated with 3 Tesla structural magnetic resonance imaging (MRI). Cognitive control and episodic memory were evaluated with established tests. Structural network graphs were constructed from diffusion MRI-based whole-brain tractography. Their global measures were calculated using graph theory. Regression models utilized both global network metrics and microstructure of specific connections, known to be critical for each domain, to predict cognitive scores. Results: Global efficiency and the mean clustering coefficient of networks were reduced in MCI. Cognitive control was associated with global network topology. Episodic memory, in contrast, correlated with individual temporal tracts only. Relationships between cognitive control and network topology were attenuated by addition of single tract measures to regression models, consistent with a partial mediation effect. The mediation effect was stronger in MCI than healthy volunteers, explaining 23 36% of the effect of cingulum microstructure on cognitive control performance. Network clustering was a significant mediator in the relationship between tract microstructure and cognitive control in both groups. Conclusion: The status of critical connections and large-scale network topology are both important for maintenance of cognitive control in MCI. Mediation via large-scale networks is more important in patients with MCI than healthy volunteers. This effect is domain-specific, and true for cognitive control but not for episodic memory. Interventions to improve cognitive control will need to address both dysfunction of local circuitry and global network architecture to be maximally effective. PMID- 28018209 TI - Speech Comprehension Difficulties in Chronic Tinnitus and Its Relation to Hyperacusis. AB - Objective: Many tinnitus patients complain about difficulties regarding speech comprehension. In spite of the high clinical relevance little is known about underlying mechanisms and predisposing factors. Here, we performed an exploratory investigation in a large sample of tinnitus patients to (1) estimate the prevalence of speech comprehension difficulties among tinnitus patients, to (2) compare subjective reports of speech comprehension difficulties with behavioral measurements in a standardized speech comprehension test and to (3) explore underlying mechanisms by analyzing the relationship between speech comprehension difficulties and peripheral hearing function (pure tone audiogram), as well as with co-morbid hyperacusis as a central auditory processing disorder. Subjects and Methods: Speech comprehension was assessed in 361 tinnitus patients presenting between 07/2012 and 08/2014 at the Interdisciplinary Tinnitus Clinic at the University of Regensburg. The assessment included standard audiological assessments (pure tone audiometry, tinnitus pitch, and loudness matching), the Goettingen sentence test (in quiet) for speech audiometric evaluation, two questions about hyperacusis, and two questions about speech comprehension in quiet and noisy environments ("How would you rate your ability to understand speech?"; "How would you rate your ability to follow a conversation when multiple people are speaking simultaneously?"). Results: Subjectively-reported speech comprehension deficits are frequent among tinnitus patients, especially in noisy environments (cocktail party situation). 74.2% of all investigated patients showed disturbed speech comprehension (indicated by values above 21.5 dB SPL in the Goettingen sentence test). Subjective speech comprehension complaints (both for general and in noisy environment) were correlated with hearing level and with audiologically-assessed speech comprehension ability. In contrast, co-morbid hyperacusis was only correlated with speech comprehension difficulties in noisy environments, but not with speech comprehension difficulties in general. Conclusion: Speech comprehension deficits are frequent among tinnitus patients. Whereas speech comprehension deficits in quiet environments are primarily due to peripheral hearing loss, speech comprehension deficits in noisy environments are related to both peripheral hearing loss and dysfunctional central auditory processing. Disturbed speech comprehension in noisy environments might be modulated by a central inhibitory deficit. In addition, attentional and cognitive aspects may play a role. PMID- 28018207 TI - Neural Correlates for Apathy: Frontal-Prefrontal and Parietal Cortical- Subcortical Circuits. AB - Apathy is an uncertain nosographical entity, which includes reduced motivation, abulia, decreased empathy, and lack of emotional involvement; it is an important and heavy-burden clinical condition which strongly impacts in everyday life events, affects the common daily living abilities, reduced the inner goal directed behavior, and gives the heaviest burden on caregivers. Is a quite common comorbidity of many neurological disease, However, there is no definite consensus on the role of apathy in clinical practice, no definite data on anatomical circuits involved in its development, and no definite instrument to detect it at bedside. As a general observation, the occurrence of apathy is connected to damage of prefrontal cortex (PFC) and basal ganglia; "emotional affective" apathy may be related to the orbitomedial PFC and ventral striatum; "cognitive apathy" may be associated with dysfunction of lateral PFC and dorsal caudate nuclei; deficit of "autoactivation" may be due to bilateral lesions of the internal portion of globus pallidus, bilateral paramedian thalamic lesions, or the dorsomedial portion of PFC. On the other hand, apathy severity has been connected to neurofibrillary tangles density in the anterior cingulate gyrus and to gray matter atrophy in the anterior cingulate (ACC) and in the left medial frontal cortex, confirmed by functional imaging studies. These neural networks are linked to projects, judjing and planning, execution and selection common actions, and through the basolateral amygdala and nucleus accumbens projects to the frontostriatal and to the dorsolateral prefrontal cortex. Therefore, an alteration of these circuitry caused a lack of insight, a reduction of decision making strategies, and a reduced speedness in action decision, major responsible for apathy. Emergent role concerns also the parietal cortex, with its direct action motivation control. We will discuss the importance of these circuits in different pathologies, degenerative or vascular, acute or chronic. PMID- 28018210 TI - Measuring the Moment-to-Moment Variability of Tinnitus: The TrackYourTinnitus Smart Phone App. AB - Tinnitus, the phantom perception of sound without a corresponding external sound, is a frequent disorder which causes significant morbidity. So far there is no treatment available that reliably reduces the tinnitus perception. The research is hampered by the large heterogeneity of tinnitus and the fact that the tinnitus perception fluctuates over time. It is therefore necessary to develop tools for measuring fluctuations of tinnitus perception over time and for analyzing data on single subject basis. However, this type of longitudinal measurement is difficult to perform using the traditional research methods such as paper-and-pencil questionnaires or clinical interviews. Ecological momentary assessment (EMA) represents a research concept that allows the assessment of subjective measurements under real-life conditions using portable electronic devices and thereby enables the researcher to collect longitudinal data under real-life conditions and high cost efficiency. Here we present a new method for recording the longitudinal development of tinnitus perception using a modern smartphone application available for iOS and Android devices with no costs for the users. The TrackYourTinnitus (TYT) app is available and maintained since April 2014. A number of 857 volunteers with an average age of 44.1 years participated in the data collection between April 2014 and February 2016. The mean tinnitus distress at the initial measurement was rated on average 13.9 points on the Mini-Tinnitus Questionnaire (Mini-TQ; max. 24 points). Importantly, we could demonstrate that the regular use of the TYT app has no significant negative influence on the perception of the tinnitus loudness nor on the tinnitus distress. The TYT app can therefore be proposed as a safe instrument for the longitudinal assessment of tinnitus perception in the everyday life of the patient. PMID- 28018211 TI - Cistanche tubulosa Protects Dopaminergic Neurons through Regulation of Apoptosis and Glial Cell-Derived Neurotrophic Factor: in vivo and in vitro. AB - Parkinson's disease (PD) is a neurodegenerative disease with the pathological hallmark of reduced nigrostriatal dopamine. In traditional Chinese medicine (TCM) clinical practice, the nanopowder of Cistanche tubulosa has therapeutic effects on PD. To identify the therapeutic mechanism, this study tested the protective effect of different doses of MPP+-induced toxicity in MES23.5 cells using the MTT assay and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice (vehicles). Immunohistochemistry was used to assess cytomorphology and tyrosine hydroxylase (TH) expression. Behavioral tests in vehicles, high performance liquid chromatography (HPLC) tests in dopamine, immunohistochemistry and western blot analysis were used to detect the expression of TH, glial cell line-derived neurotrophic factor (GDNF) and its receptors. Our results demonstrated that the C. tubulosa nanopowder improved the viability of MPP+ treated cells, increased TH expression and reduced the number of apoptotic cells. It also increased Bcl2 protein expression and suppressed Bax protein expression in MPP+-treated cells in a dose-dependent manner. In addition, C. tubulosa nanopowder improved the behavioral deficits in vehicle mice, reduced the stationary duration of swimming, enhanced the ability for spontaneous activity and increased the expression of GDNF, the GDNF family receptor alpha (GFRalpha1) and Ret in cells of the substantia nigra (SN). Furthermore, the protein expression of GDNF, GFRalpha1 and Ret increased after treatment with different doses of C. tubulosa nanopowder, with a significant difference between the high dose and vehicle groups. The protein expression of Bcl2 and Bax were similar in the in vivo and in vitro, which suggested that C. tubulosa nanopowder has anti apoptotic effects in neurons. PMID- 28018212 TI - Mitochondrial Functional Changes Characterization in Young and Senescent Human Adipose Derived MSCs. AB - Mitochondria are highly dynamic organelles that in response to the cell's bio energetic state continuously undergo structural remodeling fission and fusion processes. This mitochondrial dynamic activity has been implicated in cell cycle, autophagy, and age-related diseases. Adult tissue-derived mesenchymal stromal/stem cells present a therapeutic potential. However, to obtain an adequate mesenchymal stromal/stem cell number for clinical use, extensive in vitro expansion is required. Unfortunately, these cells undergo replicative senescence rapidly by mechanisms that are not well understood. Senescence has been associated with metabolic changes in the oxidative state of the cell, a process that has been also linked to mitochondrial fission and fusion events, suggesting an association between mitochondrial dynamics and senescence. In the present work, we studied the mitochondrial structural remodeling process of mesenchymal stromal/stem cells isolated from adipose tissue in vitro to determine if mitochondrial phenotypic changes were associated with mesenchymal stromal/stem cell senescence. For this purpose, mitochondrial dynamics and oxidative state of stromal/stem cell were compared between young and old cells. With increased cell passage, we observed a significant change in cell morphology that was associated with an increase in beta-galactosidase activity. In addition, old cells (population doubling seven) also showed increased mitochondrial mass, augmented superoxide production, and decreased mitochondrial membrane potential. These changes in morphology were related to slightly levels increases in mitochondrial fusion proteins, Mitofusion 1 (MFN1), and Dynamin-related GTPase (OPA1). Collectively, our results showed that adipose tissue-derived MSCs at population doubling seven developed a senescent phenotype that was characterized by metabolic cell changes that can lead to mitochondrial fusion. PMID- 28018213 TI - Cognitive Change during the Life Course and Leukocyte Telomere Length in Late Middle-Aged Men. AB - Importance: Cognitive skills are known to decline through the lifespan with large individual differences. The molecular mechanisms for this decline are incompletely understood. Although leukocyte telomere length provides an index of cellular age that predicts the incidence of age-related diseases, it is unclear whether there is an association between cognitive decline and leukocyte telomere length. Objective: To examine the association between changes in cognitive function during adult life and leukocyte telomere length after adjusting for confounding factors such as education, mental health and life style. Design, Setting, and Participants: Two groups of men with negative (n = 97) and positive (n = 93) change in cognitive performance were selected from a birth cohort of 1985 Danish men born in 1953. Cognitive performance of each individual was assessed at age ~20 and 56 years. Leukocyte telomere length at age ~58 was measured using qPCR. Linear regression models were used to investigate the association between cognitive function and leukocyte telomere length. Results: Men with negative change in cognitive performance during adult life had significantly shorter mean leukocyte telomere length than men with positive change in cognitive performance (unadjusted difference beta = -0.09, 95% CI -0.16 to -0.02, p = 0.02). This association remained significant after adjusting for smoking, alcohol consumption, leisure time activity, body mass index (BMI) and cholesterol (adjusted difference beta = -0.09, 95% CI -0.17 to -0.01, p = 0.02) but was non-significant after adjusting for smoking, alcohol consumption, leisure time activity, BMI, cholesterol, current cognitive function, depression and education (adjusted difference beta = -0.07, 95% CI -0.16 to -0.01, p = 0.08). Conclusion and Relevance: Preclinical cognitive changes may be associated with leukocyte telomere length. PMID- 28018214 TI - Total Cerebral Small Vessel Disease MRI Score Is Associated with Cognitive Decline in Executive Function in Patients with Hypertension. AB - Objectives: Hypertension is a major risk factor for white matter hyperintensities (WMH), lacunes, cerebral microbleeds, and perivascular spaces, which are MRI markers of cerebral small vessel disease (SVD). Studies have shown associations between these individual MRI markers and cognitive functioning and decline. Recently, a "total SVD score" was proposed in which the different MRI markers were combined into one measure of SVD, to capture total SVD-related brain damage. We investigated if this SVD score was associated with cognitive decline over 4 years in patients with hypertension. Methods: In this longitudinal cohort study, 130 hypertensive patients (91 patients with uncomplicated hypertension and 39 hypertensive patients with a lacunar stroke) were included. They underwent a neuropsychological assessment at baseline and after 4 years. The presence of WMH, lacunes, cerebral microbleeds, and perivascular spaces were rated on baseline MRI. Presence of each individual marker was added to calculate the total SVD score (range 0-4) in each patient. Results: Uncorrected linear regression analyses showed associations between SVD score and decline in overall cognition (p = 0.017), executive functioning (p < 0.001) and information processing speed (p = 0.037), but not with memory (p = 0.911). The association between SVD score and decline in overall cognition and executive function remained significant after adjustment for age, sex, education, anxiety and depression score, potential vascular risk factors, patient group, and baseline cognitive performance. Conclusion: Our study shows that a total SVD score can predict cognitive decline, specifically in executive function, over 4 years in hypertensive patients. This emphasizes the importance of considering total brain damage due to SVD. PMID- 28018215 TI - Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases. AB - The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. PMID- 28018217 TI - Pharmacogenomic Study Reveals New Variants of Drug Metabolizing Enzyme and Transporter Genes Associated with Steady-State Plasma Concentrations of Risperidone and 9-Hydroxyrisperidone in Thai Autism Spectrum Disorder Patients. AB - The present study sought to investigate the genetic variants in drug metabolizing enzyme and transporter (DMET) genes associated with steady-state plasma concentrations of risperidone among Thai autism spectrum disorder (ASD) patients. ASD patients taking risperidone for at least 1 month were enrolled for this pharmacogenomic study. Genotyping profile was obtained using Affymetrix DMET Plus array interrogating 1931 variants in 231 genes. Steady-state plasma risperidone and 9-hydroxyrisperidone were measured using liquid chromatography/tandem mass spectrometry assay. The final analysis included 483 markers for 167 genes. Six variants, ABCB11 (c.3084A > G, c.*420A > G, c.*368G > A, and c.*236G > A) and ADH7 (c.690G > A and c.-5360G > A), were found to be associated with plasma concentrations of risperidone. 9-Hydroxyrisperidone and the total active-moiety levels were associated with six gene variants, SCLO1B1 (c.-11187G > A and c.521T > C), SLCO1B3 (c.334G > T, c.699A > G, and c.1557G > A), and SLC7A5 c.*438C > G. Polymorphisms in UGT2B4 c.*448A > G and CYP2D6 (c.1661G > C, c.4180G > C, and c. 2178G > A) showed considerable but not significant associations with metabolic ratio. This pharmacogenomic study identifies new genetic variants of DMET genes in monitoring risperidone therapy. PMID- 28018216 TI - Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging. AB - Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1) has been found to be consistently overexpressed by most tumor cells. Scavenger Receptor Class B Type I (SR-BI) is a high density lipoprotein (HDL) receptor that facilitates the uptake of cholesterol esters from circulating lipoproteins. Additional findings suggest a critical role for SR-BI in cholesterol metabolism, signaling, motility, and proliferation of cancer cells and thus a potential major impact in carcinogenesis and metastasis. Recent findings indicate that the level of SR-BI expression correlate with aggressiveness and poor survival in breast and prostate cancer. Moreover, genomic data show that depending on the type of cancer, high or low SR-BI expression may promote poor survival. This review discusses the importance of SR-BI as a diagnostic as well as prognostic indicator of cancer to help elucidate the contributions of this protein to cancer development, progression, and survival. In addition, the SR-B1 receptor has been shown to serve as a potential gateway for the delivery of therapeutic agents when reconstituted high density lipoprotein nanoparticles are used for their transport to cancer cells and tumors. Opportunities for the development of new technologies, particularly in the areas of cancer therapy and tumor imaging are discussed. PMID- 28018218 TI - Protective Effects of Pleurotus tuber-regium on Carbon- Tetrachloride Induced Testicular Injury in Sprague Dawley Rats. AB - The high rate of male infertility and the meager resources to manage same in sub Saharan Africa have necessitated the search for cost effective and available alternatives. Mushrooms have been used traditionally in folk medicine and as nutraceuticals. This study has investigated the effect of the wild mushroom Pleurotus tuber-regium on carbon tetrachloride (CCl4) deleterious effects on the reproductive system of male rats. Thirty six rats were divided into six groups of six animals each. Group I (negative control) received 10 ml/kg olive oil intraperitoneal weekly in addition to feed and water ad libitum. Group II (positive control) received CCl4 10 ml/kg (30% in Olive oil) weekly. Group III, IV, and V received 100 mg, 20 0mg, and 500 mg P. tuber-regium (33.3% in feed) daily in addition to 10 ml/kg CCl4 weekly. Group VI received 500 mg P. tuber regium (33.3% in feed) daily. After 4 weeks, sperm motility, epididymal count and vitality were determined. Serum malondialdehyde (MDA), testosterone, Luteinizing hormone (LH), Follicle stimulating hormone (FSH), prolactin and oestradiol were estimated using enzyme-linked immunosorbent assay (ELISA) kits. Histopathologic examinations of the testis were carried out. Carbon tetrachloride significantly reduced the sperm motility (54.33 +/- 3.79%), epididymal count (28.73 +/- 2.86 * 106/ml, vitality (4.96 +/- 0.62), LH (0.88 +/- 0.14), FSH (2.04 +/- 0.33), and Testosterone (2.02 +/- 0.24) when compared with control (89.33 +/- 9.01), 91.91 +/- 1.92 * 106/ml, 13.12 +/- 0.19, 2.74 +/- 0.32, 3.64 +/- 0.62, and 4.16 +/- 0.23, respectively, which were reversed by P. tuber-regium administration. Co administration of P. tuber-regium plus CCl4 significantly reduced MDA level. P. tuber-regium showed dose dependent ameliorative activity against CCl4 deleterious action on the testis and may be beneficial in the management of male infertility. PMID- 28018219 TI - Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway. AB - Silymarin (SMN) has been shown to possess a wide range of biological and pharmacological effects. Besides, SMN has antioxidant and free radical scavenging activities. Thioacetamide (TAA) is a well-documented liver toxin that requires oxidative bioactivation to elicit its hepatotoxic effect which ultimately modifies amine-lipids and proteins. Our study has been designed in a TAA exposed mouse model to investigate whether SMN could protect TAA-induced oxidative stress mediated hepatic and renal damage. Results suggest that TAA generated reactive oxygen species (ROS), caused oxidative stress and induced apoptosis in the liver and kidney cells via JNK as well as PKC and MAPKs signaling. All these detrimental effects of TAA could, however, be suppressed by SMN which not only scavenged ROS but also induced PI3K-Akt cell survival pathway in the liver and prevented apoptotic pathways in both the organs. Histological studies, collagen staining and DNA fragmentation analysis also supported our results. Combining, we say that SMN possess beneficial role against TAA mediated hepatic and renal pathophysiology. PMID- 28018220 TI - The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and Independent Pro-inflammatory Signaling in Human Vascular Smooth Muscle Cells. AB - Background and Aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7) is a member of the renin-angiotensin system (RAS) that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1 7) to counteract human aortic smooth muscle cell (HASMC) inflammation triggered by RAS-dependent and -independent stimuli, such as Ang II or interleukin (IL) 1beta. Methods and Results: In cultured HASMC, the expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide were stimulated by both Ang II and IL-1beta, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7) in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7), suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and nuclear factor (NF)-kappaB. Indeed, Ang-(1-7) markedly inhibited the activation of the NADPH oxidase and subsequently of NF-kappaB, as determined by lucigenin-derived chemiluminescence and electromobility shift assay, respectively. Conclusion: Ang-(1-7) can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7)/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases. PMID- 28018221 TI - Metabolomic Study on Idiosyncratic Liver Injury Induced by Different Extracts of Polygonum multiflorum in Rats Integrated with Pattern Recognition and Enriched Pathways Analysis. AB - Currently, numerous liver injury cases related to a famous Chinese herb- Polygonum Multiflorum (Heshouwu in Chinese) have attracted great attention in many countries. Our previous work showed that Heshouwu-induced hepatotoxicity belonged to idiosyncratic drug-induced liver injury (IDILI). Unfortunately, the components and mechanisms attributed to IDILI of Heshouwu are difficult to determine and thus remain unknown. Attempts to explore puzzles, we prepared the chloroform (CH)-, ethyl acetate (EA)-, and residue (RE) extracts of Heshouwu to investigate IDILI constituents and underlying mechanisms, using biochemistry, histopathology, and metabolomics examinations. The results showed that co treatment with non-toxic dose of lipopolysaccharide (LPS) and EA extract could result in evident liver injury, indicated by the significant elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, as well as obvious liver histologic damage; whereas other two separated fractions, CH and RE extracts, failed to induce observable liver injury. Furthermore, 21 potential metabolomic biomarkers that differentially expressed in LPS/EA group compared with other groups without liver injury were identified by untargeted metabolomics, mainly involved two pathways: tricarboxylic acid cycle and sphingolipid metabolism. This work illustrated EA extract had close association with the idiosyncratic hepatotoxicity of Heshouwu and provided a metabolomic insight into IDILI of different extracts from Heshouwu. PMID- 28018222 TI - Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3. AB - Medulloblastoma (MB), tumor of the cerebellum, remains a leading cause of cancer related mortality in childhood. We previously showed, in a mouse model of spontaneous MB (Ptch1+/-/Tis21-/-), that a defect of the migration of cerebellar granule neuron precursor cells (GCPs) correlates with an increased frequency of MB. This occurs because GCPs, rather than migrating internally and differentiating, remain longer in the proliferative area at the cerebellar surface, becoming targets of transforming insults. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. As it is known that preneoplastic GCPs (pGCPs) can still migrate and differentiate like normal GCPs, thus exiting the neoplastic program, in this study we tested the hypothesis that pGCPs within a MB lesion could be induced by Cxcl3 to migrate and differentiate. We observed that the administration of Cxcl3 for 28 days within the cerebellum of 1-month-old Ptch1+/-/Tis21-/- mice, i.e., when MB lesions are already formed, leads to complete disappearance of the lesions. However, a shorter treatment with Cxcl3 (2 weeks) was ineffective, suggesting that the suppression of MB lesions is dependent on the duration of Cxcl3 application. We verified that the treatment with Cxcl3 causes a massive migration of pGCPs from the lesion to the internal granular layer, where they differentiate. Thus, the induction of migration of pGCPs in MB lesions may open new ways to treat MB that exploit the plasticity of the pGCPs, forcing their differentiation. It remains to be tested whether this plasticity continues at advanced stages of MB. If so, these findings would set a potential use of the chemokine Cxcl3 as therapeutic agent against MB development in human preclinical studies. PMID- 28018223 TI - Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons from Embryonic Mouse Brain. AB - In the murine brain, the first post-mitotic cortical neurons formed during embryogenesis express store-operated channels (SOCs) sensitive to Pyr3, initially proposed as a blocker of the transient receptor potential channel of C type 3 (TRPC3 channel). However, Pyr3 does not discriminate between Orai and TRPC3 channels, questioning the contribution of TRPC3 in SOCs. This study was undertaken to clarify the molecular identity and the pharmacological profile of native SOCs from E13 cortical neurons. The mRNA expression of STIM1-2 and Orai1-3 was assessed by quantitative reverse transcription polymerase chain reaction. E13 cortical neurons expressed STIM1-2 mRNAs, with STIM2 being the predominant isoform. Only transcripts of Orai2 were found but no Orai1 and Orai3 mRNAs. Blockers of Orai and TRPC channels (Pyr6, Pyr10, EVP4593, SAR7334, and GSK-7975A) were used to further characterize the endogenous SOCs. Their activity was recorded using the fluorescent Ca2+ probe Fluo-4. Cortical SOCs were sensitive to the Orai blockers Pyr6 and GSK-7975A, as well as to EVP4593, zinc, copper, and gadolinium ions, the latter one being the most potent SOCs blocker tested (IC50 ~10 nM). SOCs were insensitive to the TRPC channel blockers Pyr10 and SAR7334. In addition, preventing mitochondrial Ca2+ uptake inhibited SOCs which were unaffected by inhibitors of the Ca2+-independent phospholipase A2. Altogether, Orai2 channels are present at the beginning of the embryonic murine cortico genesis and form the core component of native SOCs in the immature cortex. This Ca2+ route is likely to play a role in the formation of the brain cortex. PMID- 28018224 TI - Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human. AB - Deoxypodophyllotoxin (DPT) is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey, and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model. PMID- 28018225 TI - Role of Somatostatin in Preventing Post-endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis: An Update Meta-analysis. AB - Background: Acute pancreatitis is the most common serious complication of endoscopic retrograde cholangiopancreatography (ERCP). Although, somatostatin (SOM) has been used in the prevention of post-ERCP pancreatitis (PEP), the efficacy of SOM remains inconsistent. Methods: Electronic databases, including PubMed/MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), and the Science Citation Index were searched to retrieve relevant studies. Details of the study population, including patients' characteristics, sample size, regimen of drug administration and incidence of PEP, hyperamylasemia and abdominal pain were extracted by two investigators. Data were analyzed with Review Manager 5.3 software. Results: Eleven randomized controlled trials, enrolling a total of 4192 patients, were included in the meta analysis. After data were pooled, we observed decreased incidence of ERCP-induced outcomes, such as PEP (RR = 0.63, 95% CI: 0.40, 0.98; P = 0.04) and hyperamylasemia (RR = 0.75, 95% CI: 0.66, 0.84; P < 0.001) in patients treated with SOM than those with placebo. Subgroup analysis by ethnicity found decreased incidence of PEP and hyperamylasemia in Asia only. Subgroup analysis by treatment schedule and dosage revealed decreased incidence of PEP and hyperamylasemia when SOM were treated with a single bolus or long-term infusion, or at dose above 3000 MUg. We did not observed efficacy of SOM on abdominal pain in pooled or subgroup analysis. Conclusion: This meta-analysis of patients undergoing ERCP showed reduced incidence of PEP and hyperamylasemia when SOM was administrated with single bolus, long-term infusion, or high dosage. More data are needed to confirm our findings. PMID- 28018226 TI - P53-MDM2 Pathway: Evidences for A New Targeted Therapeutic Approach in B-Acute Lymphoblastic Leukemia. AB - The tumor suppressor p53 is a canonical regulator of different biological functions, like apoptosis, cell cycle arrest, DNA repair, and genomic stability. This gene is frequently altered in human tumors generally by point mutations or deletions. Conversely, in acute lymphoblastic leukemia (ALL) genomic alterations of TP53 are rather uncommon, and prevalently occur in patients at relapse or with poor prognosis. On the other hand, p53 pathway is often compromised by the inactivation of its regulatory proteins, as MDM2 and ARF. MDM2 inhibitor molecules are able to antagonize p53-MDM2 interaction allowing p53 to exert tumor suppressor transcriptional regulation and to induce apoptotic pathways. Recent preclinical and clinical studies propose that MDM2 targeted therapy represents a promising anticancer strategy restoring p53 dependent mechanisms in ALL disease. Here, we discussed the use of new small molecule targeting p53 pathways as a promising drug target therapy in ALL. PMID- 28018227 TI - Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction. AB - Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression. The long-lasting impact might be mediated by an enhancement of memory extinction or an impairment of memory reconsolidation. Here, we directly compared the effects of i.p. injections of cannabidiol (10 mg/kg) with those of the NMDA receptor antagonist MK-801 (0.1 mg/kg) and partial agonist D-cycloserine (DCS; 15 mg/kg) in order to determine the mnemonic basis of long-term fear reduction. We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test. The latter test reduction was replicated by DCS, but MK-801 instead elevated test freezing. In contrast, when initial conditioning was weaker, CBD and MK-801 had similar effects to increase freezing at the fear retention test relative to vehicle controls, whereas DCS had no observable impact. This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se. PMID- 28018228 TI - Myofilament Calcium Sensitivity: Role in Regulation of In vivo Cardiac Contraction and Relaxation. AB - Myofilament calcium sensitivity is an often-used indicator of cardiac muscle function, often assessed in disease states such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). While assessment of calcium sensitivity provides important insights into the mechanical force-generating capability of a muscle at steady-state, the dynamic behavior of the muscle cannot be sufficiently assessed with a force-pCa curve alone. The equilibrium dissociation constant (Kd) of the force-pCa curve depends on the ratio of the apparent calcium association rate constant (kon) and apparent calcium dissociation rate constant (koff) of calcium on TnC and as a stand-alone parameter cannot provide an accurate description of the dynamic contraction and relaxation behavior without the additional quantification of kon or koff, or actually measuring dynamic twitch kinetic parameters in an intact muscle. In this review, we examine the effect of length, frequency, and beta-adrenergic stimulation on myofilament calcium sensitivity and dynamic contraction in the myocardium, the effect of membrane permeabilization/mechanical- or chemical skinning on calcium sensitivity, and the dynamic consequences of various myofilament protein mutations with potential implications in contractile and relaxation behavior. PMID- 28018230 TI - Myofilament Calcium Sensitivity: Mechanistic Insight into TnI Ser-23/24 and Ser 150 Phosphorylation Integration. AB - Troponin I (TnI) is a major regulator of cardiac muscle contraction and relaxation. During physiological and pathological stress, TnI is differentially phosphorylated at multiple residues through different signaling pathways to match cardiac function to demand. The combination of these TnI phosphorylations can exhibit an expected or unexpected functional integration, whereby the function of two phosphorylations are different than that predicted from the combined function of each individual phosphorylation alone. We have shown that TnI Ser-23/24 and Ser-150 phosphorylation exhibit functional integration and are simultaneously increased in response to cardiac stress. In the current study, we investigated the functional integration of TnI Ser-23/24 and Ser-150 to alter cardiac contraction. We hypothesized that Ser-23/24 and Ser-150 phosphorylation each utilize distinct molecular mechanisms to alter the TnI binding affinity within the thin filament. Mathematical modeling predicts that Ser-23/24 and Ser-150 phosphorylation affect different TnI affinities within the thin filament to distinctly alter the Ca2+-binding properties of troponin. Protein binding experiments validate this assertion by demonstrating pseudo-phosphorylated Ser 150 decreases the affinity of isolated TnI for actin, whereas Ser-23/24 pseudo phosphorylation is not different from unphosphorylated. Thus, our data supports that TnI Ser-23/24 affects TnI-TnC binding, while Ser-150 phosphorylation alters TnI-actin binding. By measuring force development in troponin-exchanged skinned myocytes, we demonstrate that the Ca2+ sensitivity of force is directly related to the amount of phosphate present on TnI. Furthermore, we demonstrate that Ser 150 pseudo-phosphorylation blunts Ser-23/24-mediated decreased Ca2+-sensitive force development whether on the same or different TnI molecule. Therefore, TnI phosphorylations can integrate across troponins along the myofilament. These data demonstrate that TnI Ser-23/24 and Ser-150 phosphorylation regulates muscle contraction in part by modulating different TnI interactions in the thin filament and it is the combination of these differential mechanisms that provides understanding of their functional integration. PMID- 28018229 TI - The Calcium-Sensing Receptor and the Parathyroid: Past, Present, Future. AB - Parathyroid hormone (PTH) defends the extracellular fluid from hypocalcemia and has powerful and well-documented actions on the skeleton and renal tubular system. To achieve a satisfactory stable plasma calcium level, the secretion of PTH, and the resulting serum PTH level, is titrated carefully to the prevailing plasma ionized Ca2+ concentration via a Ca2+ sensing mechanism that mediates feedback inhibition of PTH secretion. Herein, I consider the properties of the parathyroid Ca2+ sensing mechanism, the identity of the Ca2+ sensor, the intracellular biochemical mechanisms that it controls, the manner of its integration with other components of the PTH secretion control mechanism, and its modulation by other nutrients. Together the well-established, recently elucidated, and yet-to-be discovered elements of the story constitute the past, present, and future of the parathyroid and its calcium-sensing receptor (CaSR). PMID- 28018231 TI - Slowly Adapting Sensory Units Have More Receptors in Large Airways than in Small Airways in Rabbits. AB - Sensory units of pulmonary slowly adapting receptors (SARs) are more active in large airways than in small airways. However, there is no explanation for this phenomenon. Although sensory structures in large airways resemble those in small airways, they are bigger and more complex. Possibly, a larger receptor provides greater surface area for depolarization, and thus has a lower activating threshold and/or a higher sensitivity to stretch, leading to more nerve electrical activities. Recently, a single sensory unit has been reported to contain multiple receptors. Therefore, sensory units in large airways may contain more SARs, which may contribute to high activities. To test this hypothesis, we used a double staining technique to identify sensory receptor sizes. We labeled the sensory structure with Na+/K+-ATPase antibodies and the myelin sheath with myelin basic protein (MBP) antibodies. A SAR can be defined as the end formation beyond MBP labeling. Thus, we are able to compare sizes of sensory structures and SARs in large (trachea and bronchi) vs. small (bronchioles <500 MUm in diameter) airways in the rabbit. We found that even though the sensory structure was bigger in large airways than in small airways (3340 +/- 223 vs. 1168 +/- 103 MUm2; P < 0.0001), there was no difference in receptor sizes (349 +/- 14 vs. 326 +/- 16 MUm2; > 0.05). However, the sensory structure contains more SARs in large airways than in small airways (9.6 +/- 0.6 vs. 3.6 +/- 0.3; P < 0.0001). Thus, our data support the hypothesis that greater numbers of SARs in sensory units of large airways may contribute to higher activities. PMID- 28018232 TI - Membrane Lipid Microenvironment Modulates Thermodynamic Properties of the Na+-K+ ATPase in Branchial and Intestinal Epithelia in Euryhaline Fish In vivo. AB - We have analyzed the effects of different native membrane lipid composition on the thermodynamic properties of the Na+-K+-ATPase in different epithelia from the gilthead seabream Sparus aurata. Thermodynamic parameters of activation for the Na+-K+-ATPase, as well as contents of lipid classes and fatty acids from polar lipids were determined for gill epithelia and enterocytes isolated from pyloric caeca, anterior intestine and posterior intestine. Arrhenius analyses of control animals revealed differences in thermal discontinuity values (Td) and activation energies determined at both sides of Td between intestinal and gill epithelia. Eyring plots disclosed important differences in enthalpy of activation (DeltaH?) and entropy of activation (DeltaS?) between enterocytes and branchial cells. Induction of n-3 LCPUFA deficiency dramatically altered membrane lipid composition in enterocytes, being the most dramatic changes the increase in 18:1n 9 (oleic acid) and the reduction of n-3 LCPUFA (mainly DHA, docosahexaenoic acid). Strikingly, branchial cells were much more resistant to diet-induced lipid alterations than enterocytes, indicating the existence of potent lipostatic mechanisms preserving membrane lipid matrix in gill epithelia. Paralleling lipid alterations, values of Ea1, DeltaH? and DeltaS? for the Na+-K+-ATPase were all increased, while Td values vanished, in LCPUFA deficient enterocytes. In turn, Differences in thermodynamic parameters were highly correlated with specific changes in fatty acids, but not with individual lipid classes including cholesterol in vivo. Thus, Td was positively related to 18:1n-9 and negatively to DHA. Td, Ea1 and DeltaH? were exponentially related to DHA/18:1n-9 ratio. The exponential nature of these relationships highlights the strong impact of subtle changes in the contents of oleic acid and DHA in setting the thermodynamic properties of epithelial Na+-K+-ATPase in vivo. The effects are consistent with physical effects on the lipid membrane surrounding the enzyme as well as with direct interactions with the Na+-K+-ATPase. PMID- 28018233 TI - Carbonic Anhydrase III Is Expressed in Mouse Skeletal Muscles Independent of Fiber Type-Specific Myofilament Protein Isoforms and Plays a Role in Fatigue Resistance. AB - Carbonic anhydrase III (CAIII) is a metabolic enzyme and a regulator for intracellular pH. CAIII has been reported with high level expression in slow twitch skeletal muscles. Here we demonstrate that CAIII is expressed in multiple slow and fast twitch muscles of adult mouse independent of the expression of myosin isoforms. Expressing similar fast type of myofilament proteins, CAIII positive tibial anterior (TA) muscle exhibits higher tolerance to fatigue than that of CAIII-negative fast twitch extensor digitorum longus (EDL) muscle in in situ contractility studies. We further studied the muscles of CAIII knockout (Car3-KO) mice. The loss of CAIII in soleus and TA muscles in Car3-KO mice did not change muscle mass, sarcomere protein isoform contents, and the baseline twitch and tetanic contractility as compared with age-matched wild type (WT) controls. On the other hand, Car3-KO TA muscle showed faster force reduction at the beginning but higher resistance at the end during a fatigue test, followed by slower post fatigue recovery than that of WT TA muscle. Superfused Car3-KO soleus muscle also had faster total force reduction during fatigue test than that of WT soleus. However, it showed a less elevation of resting tension followed by a better post fatigue recovery under acidotic stress. CAIII was detected in neonatal TA and EDL muscle, downregulated during development, and then re expressed in adult TA but not EDL muscles. The expression of CAIII in Tnnt1-KO myopathy mouse soleus muscle that has diminished slow fiber contents due to the loss of slow troponin T remained high. Car3-KO EDL, TA, and soleus muscles showed no change in the expression of mitochondria biomarker proteins. The data suggest a fiber type independent expression of CAIII with a role in the regulation of intracellular pH in skeletal muscle and may be explored as a target for improving fatigue resistance and for the treatment of TNNT1 myopathies. PMID- 28018234 TI - Deciphering the Function of Octopaminergic Signaling on Wing Polyphenism of the Pea Aphid Acyrthosiphon pisum. AB - Aphids exhibit wing polyphenism (winged or wingless) for adaption to predictable or temporally heterogeneous environmental changes; however, the underlying mechanism is still unclear. This morphological change could be stimulated by high aphid density, which in turn could affect octopaminergic signaling in aphids. Octopamine is a neurotransmitter synthesized in insects that can modify their physiological metabolism, locomotion, and other behaviors. We designed experiments to determine whether octopamine functions in wing formation of the pea aphid, Acyrthosiphon pisum (Harris). We determined gene expression of tyramine beta-hydroxylase (TbetaH), a key enzyme in octopamine synthesis at different developmental stages, in different body parts, and in different densities of aphids. We also used TbetaH RNAi, octopamine receptor agonists (octopamine and synephrine), and an antagonist (mianserin) to modify octopaminergic signaling. We found that transcription of TbetaH was related to aphid density, which affected the proportion of winged offspring. By manually modifying the mother's octopaminergic signaling, TbetaH expression was suppressed, and TbetaH (enzyme) activity decreased. The proportion of winged offspring was also affected. Our results showed that octopamine could be a link in the wing determination system, as well as environmental stimulation. The RNAi results showed that the decrease of TbetaH expression increased aphid's reproduction; however, the decrease of TbetaH expression declined the numbers of winged-offspring producers, but did not affect the proportion of winged nymphs produced by the winged-offspring producer. In conclusion, the decline in the proportion of winged daughters in the next generation was caused by the decline of winged nymph producers. PMID- 28018235 TI - Modulation of Muscle Fiber Compositions in Response to Hypoxia via Pyruvate Dehydrogenase Kinase-1. AB - Muscle fiber-type changes in hypoxic conditions in accordance with pyruvate dehydrogenase kinase (Pdk)-1 and hypoxia inducible factor (Hif)-1alpha were investigated in rats. Hif-1alpha and its down-stream molecule Pdk-1 are well known for readily response to hypoxia. We questioned their roles in relation to changes in myosin heavy chain (MyHC) composition in skeletal muscles. We hypothesize that the level of Pdk-1 with respect to the level of Hif-1alpha determines MyHC composition of the muscle in rats in hypoxia. Young male rats were housed in a chamber maintained at 11.5% (for sustained hypoxia) or fluctuating between 11.5 and 20.8% (for intermittent hypoxia or IH) oxygen levels. Then, muscle tissues from the geniohyoid (GH), soleus, and anterior tibialis (TA) were obtained at the end of hypoxic conditionings. After both hypoxic conditionings, protein levels of Pdk-1 and Hif-1 increased in GH muscles. GH muscles in acute sustained hypoxia favor an anaerobic glycolytic pathway, resulting in an increase in glycolytic MyHC IIb protein-rich fibers while maintain original fatigue-resistant MyHC IIa protein in the fibers; thus, the numbers of IIa- and IIb MyHC co-expressing fibers increased. Exogenous Pdk-1 over expression using plasmid vectors elevated not only the glycolytic MyHC IIb, but also IIx as well as IIa expressions in C2C12 myotubes in ambient air significantly. The increase of dual expression of IIa- and IIb MyHC proteins in fibers harvested from the geniohyoid muscle has a potential to improve endurance as shown in our fatigability tests. By increasing the Pdk-1/Hif-1 ratio, a mixed type muscle could alter endurance within the innate characteristics of the muscle toward more fatigue resistant. We conclude that an increased Pdk-1 level in skeletal muscle helps maintain MyHC compositions to be a fatigue resistant mixed type muscle. PMID- 28018237 TI - Multidimensional Liquid Chromatography Coupled with Tandem Mass Spectrometry for Identification of Bioactive Fatty Acyl Derivatives. AB - Recognition of the contributions of lipids to cellular physiology, both as structural components of the membrane and as modulatory ligands for membrane proteins, has increased in recent years with the development of the biophysical and biochemical tools to examine these effects. Their modulatory roles in ion channels and transporters function have been extensively characterized, with the molecular mechanisms of these activities being the subject of intense scrutiny. The physiological significance of lipids in biochemistry is expanding as numerous fatty acyls are discovered to possess signaling properties. These bioactive lipids are often found in quantities of pmol/g of tissue and are co-extracted with numerous lipophilic molecules, making their detection and identification challenging. Common analytical methodologies involve chromatographic separation and mass spectrometric techniques; however, a single chromatographic step is typically ineffective due to the complexity of the biological samples. It is, therefore, essential to develop approaches that incorporate multiple dimensions of separation. Described in this manuscript are normal phase and reversed phase separation strategies for lipids that include detection of the bioactive primary fatty acid amides and N-acyl glycines via tandem mass spectrometry. Concerted utilization of these approaches are then used to separate and sensitively identify primary fatty acid amides extracted from homogenized tissue, using mouse brains as a test case. PMID- 28018236 TI - Host-Microbiome Interaction and Cancer: Potential Application in Precision Medicine. AB - It has been experimentally shown that host-microbial interaction plays a major role in shaping the wellness or disease of the human body. Microorganisms coexisting in human tissues provide a variety of benefits that contribute to proper functional activity in the host through the modulation of fundamental processes such as signal transduction, immunity and metabolism. The unbalance of this microbial profile, or dysbiosis, has been correlated with the genesis and evolution of complex diseases such as cancer. Although this latter disease has been thoroughly studied using different high-throughput (HT) technologies, its heterogeneous nature makes its understanding and proper treatment in patients a remaining challenge in clinical settings. Notably, given the outstanding role of host-microbiome interactions, the ecological interactions with microorganisms have become a new significant aspect in the systems that can contribute to the diagnosis and potential treatment of solid cancers. As a part of expanding precision medicine in the area of cancer research, efforts aimed at effective treatments for various kinds of cancer based on the knowledge of genetics, biology of the disease and host-microbiome interactions might improve the prediction of disease risk and implement potential microbiota-directed therapeutics. In this review, we present the state of the art of sequencing and metabolome technologies, computational methods and schemes in systems biology that have addressed recent breakthroughs of uncovering relationships or associations between microorganisms and cancer. Together, microbiome studies extend the horizon of new personalized treatments against cancer from the perspective of precision medicine through a synergistic strategy integrating clinical knowledge, HT data, bioinformatics, and systems biology. PMID- 28018238 TI - Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants. AB - We mapped and characterized changes in the activity of brainstem cell groups under hypoxia in one-day-old newborn mice, an animal model in which the central nervous system at birth is particularly immature. The classical biphasic respiratory response characterized by transient hyperventilation, followed by severe ventilation decline, was associated with increased c-FOS immunoreactivity in brainstem cell groups: the nucleus of the solitary tract, ventral reticular nucleus of the medulla, retrotrapezoid/parafacial region, parapyramidal group, raphe magnus nucleus, lateral, and medial parabrachial nucleus, and dorsal subcoeruleus nucleus. In contrast, the hypoglossal nucleus displayed decreased c FOS immunoreactivity. There were fewer or no activated catecholaminergic cells activated in the medulla oblongata, whereas ~45% of the c-FOS-positive cells in the dorsal subcoeruleus were co-labeled. Approximately 30% of the c-FOS-positive cells in the parapyramidal group were serotoninergic, whereas only a small portion were labeled for serotonin in the raphe magnus nucleus. None of the c-FOS positive cells in the retrotrapezoid/parafacial region were co-labeled for PHOX2B. Thus, the hypoxia-activated brainstem neuronal network of one-day-old mice is characterized by (i) the activation of catecholaminergic cells of the dorsal subcoeruleus nucleus, a structure implicated in the strong depressive pontine influence previously reported in the fetus but not in newborns, (ii) the weak activation of catecholaminergic cells of the ventral reticular nucleus of the medulla, an area involved in hypoxic hyperventilation, and (iii) the absence of PHOX2B-positive cells activated in the retrotrapezoid/parafacial region. Based on these results, one-day-old mice could highlight characteristics for modeling the breathing network of premature infants. PMID- 28018239 TI - Crossing the Boundaries of Our Current Healthcare System by Integrating Ultra Weak Photon Emissions with Metabolomics. AB - The current healthcare system is hampered by a reductionist approach in which diagnostics and interventions focus on a specific target, resulting in medicines that center on generic, static phenomena while excluding inherent dynamic nature of biological processes, let alone psychosocial parameters. In this essay, we present some limitations of the current healthcare system and introduce the novel and potential approach of combining ultra-weak photon emission (UPE) with metabolomics technology in order to provide a dynamic readout of higher organizational systems. We argue that the combination of metabolomics and UPE can bring a new, broader, view of health state and can potentially help to shift healthcare toward more personalized approach that improves patient well-being. PMID- 28018240 TI - Distinctive Steady-State Heart Rate and Blood Pressure Responses to Passive Robotic Leg Exercise and Functional Electrical Stimulation during Head-Up Tilt. AB - Introduction: Tilt tables enable early mobilization of patients by providing verticalization. But there is a high risk of orthostatic hypotension provoked by verticalization, especially after neurological diseases such as spinal cord injury. Robot-assisted tilt tables might be an alternative as they add passive robotic leg exercise (PE) that can be enhanced with functional electrical stimulation (FES) to the verticalization, thus reducing the risk of orthostatic hypotension. We hypothesized that the influence of PE on the cardiovascular system during verticalization (i.e., head-up tilt) depends on the verticalization angle, and FES strengthens the PE influence. To test our hypotheses, we investigated the PE effects on the cardiovascular parameters heart rate (HR), and systolic and diastolic blood pressures (sBP, dBP) at different angles of verticalization in a healthy population. Methods: Ten healthy subjects on a robot assisted tilt table underwent four different study protocols while HR, sBP, and dBP were measured: (1) head-up tilt to 60 degrees and 71 degrees without PE; (2) PE at 20 degrees , 40 degrees , and 60 degrees of head-up tilt; (3) PE while constant FES intensity was applied to the leg muscles, at 20 degrees , 40 degrees , and 60 degrees of head-up tilt; (4) PE with variation of the applied FES intensity at 0 degrees , 20 degrees , 40 degrees , and 60 degrees of head-up tilt. Linear mixed models were used to model changes in HR, sBP, and dBP responses. Results: The models show that: (1) head-up tilt alone resulted in statistically significant increases in HR and dBP, but no change in sBP. (2) PE during head-up tilt resulted in statistically significant changes in HR, sBP, and dBP, but not at each angle and not always in the same direction (i.e., increase or decrease of cardiovascular parameters). Neither adding (3) FES at constant intensity to PE nor (4) variation of FES intensity during PE had any statistically significant effects on the cardiovascular parameters. Conclusion: The effect of PE on the cardiovascular system during head-up tilt is strongly dependent on the verticalization angle. Therefore, we conclude that orthostatic hypotension cannot be prevented by PE alone, but that the preventive effect depends on the verticalization angle of the robot-assisted tilt table. FES (independent of intensity) is not an important contributing factor to the PE effect. PMID- 28018241 TI - Master Athletes Are Extending the Limits of Human Endurance. AB - The increased participation of master athletes (i.e., >40 years old) in endurance and ultra-endurance events (>6 h duration) over the past few decades has been accompanied by an improvement in their performances at a much faster rate than their younger counterparts. Aging does however result in a decrease in overall endurance performance. Such age-related declines in performance depend upon the modes of locomotion, event duration, and gender of the participant. For example, smaller age-related declines in cycling performance than in running and swimming have been documented. The relative stability of gender differences observed across the ages suggests that the age-related declines in physiological function did not differ between males and females. Among the main physiological determinants of endurance performance, the maximal oxygen consumption (VO2max) appears to be the parameter that is most altered by age. Exercise economy and the exercise intensity at which a high fraction of VO2max can be sustained (i.e., lactate threshold), seem to decline to a lesser extent with advancing age. The ability to maintain a high exercise-training stimulus with advancing age is emerging as the single most important means of limiting the rate of decline in endurance performance. By constantly extending the limits of (ultra)-endurance, master athletes therefore represent an important insight into the ability of humans to maintain physical performance and physiological function with advancing age. PMID- 28018242 TI - Network Analysis-Based Approach for Exploring the Potential Diagnostic Biomarkers of Acute Myocardial Infarction. AB - Acute myocardial infarction (AMI) is a severe cardiovascular disease that is a serious threat to human life. However, the specific diagnostic biomarkers have not been fully clarified and candidate regulatory targets for AMI have not been identified. In order to explore the potential diagnostic biomarkers and possible regulatory targets of AMI, we used a network analysis-based approach to analyze microarray expression profiling of peripheral blood in patients with AMI. The significant differentially-expressed genes (DEGs) were screened by Limma and constructed a gene function regulatory network (GO-Tree) to obtain the inherent affiliation of significant function terms. The pathway action network was constructed, and the signal transfer relationship between pathway terms was mined in order to investigate the impact of core pathway terms in AMI. Subsequently, constructed the transcription regulatory network of DEGs. Weighted gene co expression network analysis (WGCNA) was employed to identify significantly altered gene modules and hub genes in two groups. Subsequently, the transcription regulation network of DEGs was constructed. We found that specific gene modules may provide a better insight into the potential diagnostic biomarkers of AMI. Our findings revealed and verified that NCF4, AQP9, NFIL3, DYSF, GZMA, TBX21, PRF1 and PTGDR genes by RT-qPCR. TBX21 and PRF1 may be potential candidates for diagnostic biomarker and possible regulatory targets in AMI. PMID- 28018243 TI - Effects of Multiple Sedentary Days on Metabolic Risk Factors in Free-Living Conditions: Lessons Learned and Future Recommendations. AB - Background: Recent experimental studies in adults have demonstrated that interruptions to prolonged sitting have beneficial effects on metabolic risk factors in adults, compared to prolonged sitting. We explored the hypothesis that multiple consecutive days of predominantly prolonged sedentary time may have an unfavorable effect on the postprandial response of C-peptide, glucose, and triglycerides in free-living healthy young men. Methods: In this explorative pilot study, healthy young men (n = 7; 18-23 years) consumed standardized mixed meals at 1 and 5 h during two experimental laboratory-sitting days, with 6 days of predominantly prolonged sedentary time in between. Serum and plasma samples were obtained hourly from 0 to 8 h for measurement of glucose, C-peptide, and triglycerides. Participant's sedentary time was monitored using an accelerometer during the prolonged sedentary days as well as during 6 normal days prior to the first laboratory day. Differences in postprandial levels were assessed using generalized estimating equations analysis. Due to the explorative nature of this study and the small sample size, p-value was set at <0.10. Results: Overall, when expressed as % of wear time, sedentary time was 5% higher during the 6 prolonged sedentary days, which was not significantly different compared to the 6 normal days (n = 4). Following 6 prolonged sedentary days, postprandial levels of C peptide were significantly higher than at baseline (B = 0.11; 90%CI = [0.002; 0.22]; n = 7). Postprandial levels of glucose and triglycerides were not significantly different between the 2 laboratory days. Conclusions: Due to the relatively high sedentary time at baseline, participants were unable to increase their sedentary time substantially. Nevertheless, postprandial C-peptide levels were slightly higher after 6 prolonged sedentary days than after 6 normal days. PMID- 28018244 TI - Differences in Muscle Oxygenation, Perceived Fatigue and Recovery between Long Track and Short-Track Speed Skating. AB - Due to the technical nature of speed skating, that is affecting physiological mechanisms such as oxygenation and blood flow, this sport provides a unique setting allowing us to uncover novel mechanistic insights of the physiological response to exercise in elite middle-distance and endurance sports. The present study aimed to examine the influence of skating mode (short-track vs. long-track) on muscle oxygenation, perceived fatigue, and recovery in elite speed skating. Muscle oxygenation of 12 talented short-track speed skaters was continuously monitored during a long-track (LT) and a short-track (ST) skating time-trial of maximal effort using near-infrared spectroscopy (NIRS) on the m. vastus lateralis for both legs. Video captures were made of each testing session for further interpretation of the muscle oxygenation. To determine recovery, perceived exertion was measured 2 and 4 h after each testing sessions. Repeated measures ANOVA's were used for statistical analysis (p < 0.05). After a rapid desaturation in both legs directly after the start, an asymmetry in muscle oxygenation between both legs was found during LT (tissue saturation-index (TSI%)-slope: left = 0.053 +/- 0.032; right = 0.023 +/- 0.020, p < 0.05) and ST speed skating (TSI%-slope: left = 0.050 +/- 0.052, right = 0.001 +/- 0.053, p < 0.05). Resaturation of the right leg was relatively lower in ST compared to LT. For the left leg, no difference was found between skating modes in muscle oxygenation. Respectively, two (ST = 5.8 +/- 2.0; LT = 4.2 +/- 1.5) and 4 h (ST = 4.6 +/- 1.9; LT = 3.1 +/- 1.6) after the time-trials, a higher rate of perceived exertion was found for ST. Based on our results, ST seems more physiologically demanding, and longer periods of recovery are needed after training compared to LT. Technical aspects unique to the exercise mode seem to impact on oxygenation, affecting processes related to the regulation of exercise intensity such as fatigue and recovery. PMID- 28018245 TI - Lateralization of Eye Use in Cuttlefish: Opposite Direction for Anti-Predatory and Predatory Behaviors. AB - Vertebrates with laterally placed eyes typically exhibit preferential eye use for ecological activities such as scanning for predators or prey. Processing visual information predominately through the left or right visual field has been associated with specialized function of the left and right brain. Lateralized vertebrates often share a general pattern of lateralized brain function at the population level, whereby the left hemisphere controls routine behaviors and the right hemisphere controls emergency responses. Recent studies have shown evidence of preferential eye use in some invertebrates, but whether the visual fields are predominately associated with specific ecological activities remains untested. We used the European common cuttlefish, Sepia officinalis, to investigate whether the visual field they use is the same, or different, during anti-predatory, and predatory behavior. To test for lateralization of anti-predatory behavior, individual cuttlefish were placed in a new environment with opaque walls, thereby obliging them to choose which eye to orient away from the opaque wall to scan for potential predators (i.e., vigilant scanning). To test for lateralization of predatory behavior, individual cuttlefish were placed in the apex of an isosceles triangular arena and presented with two shrimp in opposite vertexes, thus requiring the cuttlefish to choose between attacking a prey item to the left or to the right of them. Cuttlefish were significantly more likely to favor the left visual field to scan for potential predators and the right visual field for prey attack. Moreover, individual cuttlefish that were leftward directed for vigilant scanning were predominately rightward directed for prey attack. Lateralized individuals also showed faster decision-making when presented with prey simultaneously. Cuttlefish appear to have opposite directions of lateralization for anti-predatory and predatory behavior, suggesting that there is functional specialization of each optic lobe (i.e., brain structures implicated in visual processing). These results are discussed in relation to the role of lateralized brain function and the evolution of population level lateralization. PMID- 28018246 TI - Acetylcholine-Induced Inhibition of Presynaptic Calcium Signals and Transmitter Release in the Frog Neuromuscular Junction. AB - Acetylcholine (ACh), released from axonal terminals of motor neurons in neuromuscular junctions regulates the efficacy of neurotransmission through activation of presynaptic nicotinic and muscarinic autoreceptors. Receptor mediated presynaptic regulation could reflect either direct action on exocytotic machinery or modulation of Ca2+ entry and resulting intra-terminal Ca2+ dynamics. We have measured free intra-terminal cytosolic Ca2+ ([Ca2+]i) using Oregon-Green 488 microfluorimetry, in parallel with voltage-clamp recordings of spontaneous (mEPC) and evoked (EPC) postsynaptic currents in post-junctional skeletal muscle fiber. Activation of presynaptic muscarinic and nicotinic receptors with exogenous acetylcholine and its non-hydrolized analog carbachol reduced amplitude of the intra-terminal [Ca2+]i transients and decreased quantal content (calculated by dividing the area under EPC curve by the area under mEPC curve). Pharmacological analysis revealed the role of muscarinic receptors of M2 subtype as well as d-tubocurarine-sensitive nicotinic receptor in presynaptic modulation of [Ca2+]i transients. Modulation of synaptic transmission efficacy by ACh receptors was completely eliminated by pharmacological inhibition of N-type Ca2+ channels. We conclude that ACh receptor-mediated reduction of Ca2+ entry into the nerve terminal through N-type Ca2+ channels represents one of possible mechanism of presynaptic modulation in frog neuromuscular junction. PMID- 28018247 TI - Diaphragm Muscle Adaptation to Sustained Hypoxia: Lessons from Animal Models with Relevance to High Altitude and Chronic Respiratory Diseases. AB - The diaphragm is the primary inspiratory pump muscle of breathing. Notwithstanding its critical role in pulmonary ventilation, the diaphragm like other striated muscles is malleable in response to physiological and pathophysiological stressors, with potential implications for the maintenance of respiratory homeostasis. This review considers hypoxic adaptation of the diaphragm muscle, with a focus on functional, structural, and metabolic remodeling relevant to conditions such as high altitude and chronic respiratory disease. On the basis of emerging data in animal models, we posit that hypoxia is a significant driver of respiratory muscle plasticity, with evidence suggestive of both compensatory and deleterious adaptations in conditions of sustained exposure to low oxygen. Cellular strategies driving diaphragm remodeling during exposure to sustained hypoxia appear to confer hypoxic tolerance at the expense of peak force-generating capacity, a key functional parameter that correlates with patient morbidity and mortality. Changes include, but are not limited to: redox-dependent activation of hypoxia-inducible factor (HIF) and MAP kinases; time-dependent carbonylation of key metabolic and functional proteins; decreased mitochondrial respiration; activation of atrophic signaling and increased proteolysis; and altered functional performance. Diaphragm muscle weakness may be a signature effect of sustained hypoxic exposure. We discuss the putative role of reactive oxygen species as mediators of both advantageous and disadvantageous adaptations of diaphragm muscle to sustained hypoxia, and the role of antioxidants in mitigating adverse effects of chronic hypoxic stress on respiratory muscle function. PMID- 28018248 TI - Clinical Relevance of Informal Coercion in Psychiatric Treatment-A Systematic Review. AB - INTRODUCTION: Although informal coercion is frequently applied in psychiatry, its use is discussed controversially. This systematic review aimed to summarize literature on attitudes toward informal coercion, its prevalence, and clinical effects. METHODS: A systematic search of PubMed, Embase, PsycINF, and Google Scholar was conducted. Publications were included if they reported original data describing patients' and clinicians' attitudes toward and prevalence rates or clinical effects of informal coercion. RESULTS: Twenty-one publications out of a total of 162 articles met the inclusion criteria. Most publications focused on leverage and inducements rather than persuasion and threat. Prevalence rates of informal coercion were 29-59%, comparable on different study sites and in different settings. The majority of mental health professionals as well as one third to two-third of the psychiatric patients had positive attitudes, even if there was personal experience of informal coercion. We found no study evaluating the clinical effect of informal coercion in an experimental study design. DISCUSSION: Cultural and ethical aspects are associated with the attitudes and prevalence rates. The clinical effect of informal coercion remains unclear and further studies are needed to evaluate these interventions and the effect on therapeutic relationship and clinical outcome. It can be hypothesized that informal coercion may lead to better adherence and clinical outcome but also to strains in the therapeutic relationship. It is recommendable to establish structured education about informal coercion and sensitize mental health professionals for its potential for adverse effects in clinical routine practice. PMID- 28018249 TI - Interoceptive Processes in Anorexia Nervosa in the Time Course of Cognitive Behavioral Therapy: A Pilot Study. AB - OBJECTIVE: Previous studies report reduced interoceptive abilities in anorexia nervosa (AN) using various methods. Recent research suggests that different levels of interoceptive processes aiming at different subdomains of interoceptive abilities must be further distinguished as these levels can be differentially affected. Two important levels refer to interoceptive accuracy (IA) derived from objective performance tasks such as the heartbeat detection task and interoceptive sensibility (IS) as assessed by self-report. There is a lack of studies investigating both IA and IS in AN and examining them in the time course of therapy. The aim of this pilot study was to evaluate the different interoceptive processes - especially IA and IS - in the time course of therapy. METHODS: Fifteen patients with AN (restricting type) from the Psychosomatic Clinic in Windach were investigated three times (T1, T2, T3) during a standardized cognitive-behavioral therapy and compared with 15 matched healthy controls assessed at Ulm University in a comparable design. All participants performed the heartbeat detection task examining IA and completed standard psychological assessments including an assessment of IS. RESULTS: Patients with AN showed a significantly decreased weight, higher levels of depression, and both reduced IA and IS compared to healthy controls at T1. Following therapy, patients recovered in terms of weight and depression symptomatology. A descriptive trend for recovering from IA and IS was observed. DISCUSSION: Our findings suggest that interoceptive deficits are present in recovered patients. Therefore, further investigations are needed with more patients, differentiating between relapsed and recovered patients, and more specific training methods to improve interoceptive processes. PMID- 28018250 TI - Grit or Honesty-Humility? New Insights into the Moderating Role of Personality between the Health Impairment Process and Counterproductive Work Behavior. AB - It is acknowledged that chronic job demands may be depleting workers' stamina resulting in burnout conditions and ultimately causing further health problems. This relation, known as health impairment process, has recently been considered as a possible explanation for the emergence of counterproductive work behavior (CWB). The present work aims to examine the role of two personality traits (i.e., Grit and Honesty-Humility) in this process. The results, based on a sample of 208 private service sector employees, confirm the presence of a fully mediated process and show how Honesty-Humility positively moderates the relationship between job demands and exhaustion, whereas Grit has a negative effect on the relation between exhaustion and CWB. Implications for assessment procedure and hiring decisions are discussed. PMID- 28018251 TI - Effect of Growth Mindset on School Engagement and Psychological Well-Being of Chinese Primary and Middle School Students: The Mediating Role of Resilience. AB - The objective of positive education is not only to improve students' well-being but also their academic performance. As an important concept in positive education, growth mindset refers to core assumptions about the malleability of a person's intellectual abilities. The present study investigates the relation of growth mindsets to psychological well-being and school engagement. The study also explores the mediating function of resilience in this relation. We recruited a total of 1260 (658 males and 602 females) Chinese students from five diversified primary and middle schools. Results from the structural equation model show that the development of high levels of growth mindsets in students predicts higher psychological well-being and school engagement through the enhancement of resilience. The current study contributes to our understanding of the potential mechanisms by which positive education (e.g., altering the mindset of students) can impact psychological well-being and school engagement. PMID- 28018252 TI - Embodied Music Cognition: Trouble Ahead, Trouble Behind. PMID- 28018253 TI - Executive Function Mediates the Relations between Parental Behaviors and Children's Early Academic Ability. AB - The past decade has witnessed a growth of interest in parental influences on individual differences in children's executive function (EF) on the one hand and in the academic consequences of variation in children's EF on the other hand. The primary aim of this longitudinal study was to examine whether children's EF mediated the relation between three distinct aspects of parental behavior (i.e., parental scaffolding, negative parent-child interactions, and the provision of informal learning opportunities) and children's academic ability (as measured by standard tests of literacy and numeracy skills). Data were collected from 117 parent-child dyads (60 boys) at two time points ~1 year apart (M Age at Time 1 = 3.94 years, SD = 0.53; M Age at Time 2 = 5.11 years, SD = 0.54). At both time points children completed a battery of tasks designed to measure general cognitive ability (e.g., non-verbal reasoning) and EF (e.g., inhibition, cognitive flexibility, working memory). Our models revealed that children's EF (but not general cognitive ability) mediated the relations between parental scaffolding and negative parent-child interactions and children's early academic ability. In contrast, parental provision of opportunities for learning in the home environment was directly related to children's academic abilities. These results suggest that parental scaffolding and negative parent-child interactions influence children's academic ability by shaping children's emerging EF. PMID- 28018254 TI - Elaboration of the Environmental Stress Hypothesis-Results from a Population Based 6-Year Follow-Up. AB - The aim of this paper was to contribute to the elaboration of the Environmental Stress Hypothesis framework by testing eight hypotheses addressing the direct impact of gross motor coordination problems in elementary-school on selected physical, behavioral and psychosocial outcomes in adolescence. Results are based on a longitudinal sample of 940 participants who were (i) recruited as part of a population-based representative survey on health, physical fitness and physical activity in childhood and adolescence, (ii) assessed twice within 6 years, between the ages of 6 and 10 years old as well as between the ages of 12 and 16 years old (Response Rate: 55.9%) and (iii) classified as having gross motor coordination problems (N = 115) or having no gross motor coordination problems (N = 825) at baseline. Motor tests from the Korperkoordinationstest, measures of weight and height, a validated physical activity questionnaire as well as the Strength and Difficulties Questionnaire were conducted. Data were analyzed by use of binary logistic regressions. Results indicated that elementary-school children with gross motor coordination problems show a higher risk of persistent gross motor coordination problems (OR = 7.99, p < 0.001), avoiding organized physical activities (OR = 1.53, p < 0.05), an elevated body mass (OR = 1.78, p < 0.05), bonding with sedentary peers (OR = 1.84, p < 0.01) as well as emotional (OR = 1.73, p < 0.05) and conduct (OR = 1.79, p < 0.05) problems in adolescence in comparison to elementary-school children without gross motor coordination problems. However, elementary-school children with gross motor coordination problems did not show a significantly higher risk of peer problems (OR = 1.35, p = 0.164) or diminished prosocial behavior (OR = 1.90, p = 0.168) in adolescence, respectively in comparison to elementary-school children without gross motor coordination problems. This study is the first to provide population-based longitudinal data ranging from childhood to adolescence in the context of the Environmental Stress Hypothesis which can be considered a substantial methodological progress. In summary, gross motor coordination problems represent a serious issue for a healthy transition from childhood to adolescence which substantiates respective early movement interventions. PMID- 28018255 TI - An Affective Neuroscience Framework for the Molecular Study of Internet Addiction. AB - Internet addiction represents an emerging global health issue. Increasing efforts have been made to characterize risk factors for the development of Internet addiction and consequences of excessive Internet use. During the last years, classic research approaches from psychology considering personality variables as vulnerability factor, especially in conjunction with neuroscience approaches such as brain imaging, have led to coherent theoretical conceptualizations of Internet addiction. Although such conceptualizations can be valuable aid, the research field is currently lacking a comprehensive framework for determining brain-based and neurochemical markers of Internet addiction. The present work aims at providing a framework on the molecular level as a basis for future research on the neural and behavioral level, in order to facilitate a comprehensive neurobiological model of Internet addiction and its clinical symptomatology. To help establish such a molecular framework for the study of Internet addiction, we investigated in N = 680 participants associations between individual differences in tendencies toward Internet addiction measured by the Generalized Problematic Internet Use Scale-2 (GPIUS-2) and individual differences in primary emotional systems as assessed by the Affective Neuroscience Personality Scales (ANPS). Regression analysis revealed that the ANPS scales FEAR and SADNESS were the ANPS scales most robustly positively linked to several (sub)scales of the GPIUS-2. Also the scales SEEKING, CARE and PLAY explain variance in some of the GPIUS-2 subscales. As such, these scales are negatively linked to the GPIUS-2 subscales. As the ANPS has been constructed on substantial available brain data including an extensive molecular body with respect to evolutionary highly conserved emotional circuitry in the ancient mammalian brain, the present study gives first ideas on putative molecular mechanisms underlying different facets of Internet addiction as derived from associations between tendencies toward Internet addiction and individual differences in primary emotional systems. For example, as SADNESS is linked to the overall GPIUS-2 score, and the neuropeptide oxytocin is known to downregulate SADNESS, it is conceivable that the neuropeptide might play a role in Internet addition on the molecular level. Our findings provide a theoretical framework potentially illuminating the molecular underpinnings of Internet addiction. Finally, we also present data on the ANPS and smartphone addiction at the end of the paper. Similar to the reported associations between the ANPS and the GPIUS-2, these correlations might provide an initial outline for a framework guiding future studies that aim to address the molecular basis of smartphone addiction. PMID- 28018256 TI - Typing Style and the Use of Different Sources of Information during Typing: An Investigation Using Self-Reports. AB - We investigated to what extent different sources of information are used in typing on a computer keyboard. Using self-reports 10 finger typists and idiosyncratic typists estimated how much attention they pay to different sources of information during copy typing and free typing and how much they use them for error detection. 10 finger typists reported less attention to the keyboard and the fingers and more attention to the template and the screen than idiosyncratic typists. The groups did not differ in attention to touch/kinaesthesis in copy typing and free typing, but 10 finger typists reported more use of touch/kinaesthesis in error detection. This indicates that processing of tactile/kinaesthetic information may occur largely outside conscious control, as long as no errors occur. 10 finger typists reported more use of internal prediction of movement consequences for error detection than idiosyncratic typists, reflecting more precise internal models. Further in copy typing compared to free typing attention to the template is required, thus leaving less attentional capacity for other sources of information. Correlations showed that higher skilled typists, regardless of typing style, rely more on sources of information which are usually associated with 10 finger typing. One limitation of the study is that only self-reports were used. We conclude that typing task, typing proficiency, and typing style influence how attention is distributed during typing. PMID- 28018257 TI - Expectations and Decisions in the Volunteer's Dilemma: Effects of Social Distance and Social Projection. AB - In a Volunteer's Dilemma (VoD) one individual needs to bear a cost so that a public good can be provided. Expectations regarding what others will do play a critical role because they would ideally be negatively correlated with own decisions; yet, a social-projection heuristic generates positive correlations. In a series of 2-person-dilemma studies with over 1,000 participants, we find that expectations are indeed correlated with own choice, and that people tend to volunteer more than game-theoretic benchmarks and their own expectations would allow. We also find strong evidence for a social-distance heuristic, according to which a person's own probability to volunteer and the expectation that others will volunteer decrease as others become socially more remote. Experimentally induced expectations make opposite behavior more likely, but respondents underweight these expectations. As a result, there is a small but systematic effect of over-volunteering among psychologically close individuals. PMID- 28018258 TI - Through the Looking Glass: The Role of Ethnicity and Affiliation in Responses to Terrorism in the Media. AB - This study examined whether attitudinal and emotional responses to broadcasts of images of terrorist events differ according to ethnic group (Jewish and Arab Israelis) and outgroup affiliation during an intense wave of terrorism that occurred in Israel during 2015. Participants were 118 Jewish and 110 Arab Israelis adults randomly allocated to a terrorism or criminal violence television broadcast. State anxiety, state anger, stereotypes, and negative attitudes toward an adversary were examined prior and subsequent to the media exposure. Findings showed significant increases in anxiety, anger, stereotypes, and negative adversary perceptions in the terrorism exposure group compared to only anxiety increases in the criminal violence exposure. In the terrorism exposure group, Jewish participants showed greater increases in negative adversary perceptions of the Palestinians than Arab Israeli participants, but both groups showed similar significant increases in levels of anxiety and anger. Exposure to broadcasts of terrorism increased willingness to negotiate with the adversary among the Arab participants, but not among the Jewish participants. In the terrorism exposure group, both Jewish and Arab Israelis with high affiliation with the Palestinian cause showed less increases in stereotypes than those with low affiliation. Findings emphasize the role of ethnicity and outgroup affiliation in responses to media exposure to terrorism images. PMID- 28018259 TI - Coparenting Behaviors as Mediators between Postpartum Parental Depressive Symptoms and Toddler's Symptoms. AB - Postpartum parental depression, even of mild intensity and short duration, has negative consequences on child development, including increased externalizing and internalizing symptoms. Studies revealed that the links between parental depression and child development are mediated by parenting difficulties. On the other hand, the mediating role of problematic family-level relationships, such as low coparenting support and high conflict between the parents, has rarely been considered, although coparenting difficulties have been linked with both increased depressive symptoms in parents and increased symptoms in toddlers. In the present study, we proposed testing a comprehensive mediation model linking parental depression, coparenting, and child symptoms. At 3 months postpartum, a convenience sample of 69 parental couples completed the Edinburgh Postnatal Depression Scale. In addition, we assessed levels of coparenting support and conflict during a mother-father-infant play situation, the Lausanne Trilogue Play. At 18 months postpartum, both parents assessed child symptoms with the Symptom Checklist Questionnaire. The results showed that coparenting support mediated the links between parental depressive symptoms and child symptoms, but only for mothers: Maternal depressive symptoms were linked with lower coparenting support, which in turn predicted increased psychofunctional symptoms and behavior problems assessed by mothers. Although coparenting conflict behaviors were not predicted by parents' depressive symptoms, higher conflict was unexpectedly linked with fewer behavior problems assessed by both parents. The present study allowed us to unveil complex pathways between mild parental mood disturbances, family-level relationships, and child development in the first months of the child's life. PMID- 28018260 TI - Thrilling News Revisited: The Role of Suspense for the Enjoyment of News Stories. AB - Previous research on news perception has been dominated by a cognitively oriented perspective on reception processes, whereas emotions have been widely neglected. Consequently, it has remained open which features of a news story might elicit affective responses and hence modulate news perception, shifting the focus to the emotional potential of the narrative. According to the affective-disposition theory, the experience of suspense is the striving force of immersion in fictional dramas. Thereby, a positive affective disposition toward the protagonist of a story and a high likelihood of a bad ending should increase suspense that, in turn, should positively influence reading appreciation and lingering interest in the story. We investigated whether suspense and its determinants also play such a key role in the context of news stories. Study 1 (n = 263) successfully replicated results of an earlier study, whereas Studies 2 (n = 255) and 3 (n = 599) challenged the generalizability of some effects related to manipulated characteristics of a news story. In contrast, correlational relationships between perceived news characteristics and news evaluation were relatively stable. In particular, participants' liking of the protagonist and the perceived likelihood of a good ending were positively associated with suspense, reading appreciation, and lingering interest. This result indicates a preference for happy endings and contradicts the notion that likely negative outcomes are beneficial for suspense and the enjoyment of news stories, as postulated by the affective-disposition theory in the context of fictional dramas. Moreover, experienced suspense reliably mediated the correlations between, on the one hand, participants' liking of the protagonist and the perceived likelihood of a good ending and, on the other hand, reading appreciation and lingering interest. The news story's personal relevance was less influential than expected. Further, we observed a large absence of interaction effects, indicating that central characteristics of a news story can be independently varied to a large degree. In a nutshell, we may conclude that suspense significantly mediates the correlation between perceived news characteristics and the enjoyment of news stories, whereas manipulations of news characteristics do not necessarily influence the enjoyment of narratives as desired. PMID- 28018261 TI - How Many Is Enough?-Statistical Principles for Lexicostatistics. AB - Lexicostatistics has been applied in linguistics to inform phylogenetic relations among languages. There are two important yet not well-studied parameters in this approach: the conventional size of vocabulary list to collect potentially true cognates and the minimum matching instances required to confirm a recurrent sound correspondence. Here, we derive two statistical principles from stochastic theorems to quantify these parameters. These principles validate the practice of using the Swadesh 100- and 200-word lists to indicate degree of relatedness between languages, and enable a frequency-based, dynamic threshold to detect recurrent sound correspondences. Using statistical tests, we further evaluate the generality of the Swadesh 100-word list compared to the Swadesh 200-word list and other 100-word lists sampled randomly from the Swadesh 200-word list. All these provide mathematical support for applying lexicostatistics in historical and comparative linguistics. PMID- 28018262 TI - The Relationship between Emotion Comprehension and Internalizing and Externalizing Behavior in 7- to 10-Year-Old Children. AB - The influence of internalizing and externalizing problems on children's understanding of others' emotions has mainly been investigated on basic levels of emotion comprehension. So far, studies assessing more sophisticated levels of emotion comprehension reported deficits in the ability to understand others' emotions in children with severe internalizing or externalizing symptoms. The aim of this study was to investigate the relation between emotion comprehension and interindividual differences, with a focus on internalizing and externalizing behavior in children aged 7-10 years from the general population. A sample of 135 children was tested for emotion understanding using the Test of Emotion Comprehension. Information on internalizing and externalizing behavior was assessed with the Child Behavior Checklist 4/18. Age, bilingual upbringing, and amount of paternal working hours were significant control variables for emotion comprehension. In contrast to prior research, overall level of emotion understanding was not related to externalizing symptoms and correlated positively with elevated levels of somatic complaints and anxious/depressed symptoms. In addition, and in line with previous work, higher levels of social withdrawal were associated with worse performance in understanding emotions elicited by reminders. The present results implicate not only an altered understanding of emotions among more specific internalizing symptoms, but also that these alterations occur already on a low symptom level in a community based sample. PMID- 28018263 TI - Honor as Cultural Mindset: Activated Honor Mindset Affects Subsequent Judgment and Attention in Mindset-Congruent Ways. AB - Honor values articulate gender roles, the importance of reputation in maintaining one's place in society, and maintaining respect for the groups one belongs to. In that sense honor provides a template for organizing social interactions and hence may be functional even among people and societies that do not report valuing and endorsing honor. We test the prediction that honor influences judgment and attention when activated in two experiments (N = 538). Using a culture-as situated cognition perspective, we predicted that activating one aspect of honor would activate other aspects, even among individuals who do not much endorse honor values. We tested these predictions among European Americans, a group that is not typically associated with honor values. In each study, participants were randomly assigned to experimental or control groups, which differed in one way: the experimental group read statements about honor values as a first step and the control group did not. Participants then judged stick-figure pairs (judging which is male; Study 1, n = 130) or made lexical decisions (judging whether a letter string formed a correctly spelled word; Study 2, n = 408). In Study 1, experimental group participants were more likely to choose the visually agentic figure as male. In Study 2, experimental group participants were more accurate at noticing that the letter-string formed a word if the word was an honor-relevant word (e.g., noble), but they did not differ from the control group if the word was irrelevant to honor (e.g., happy). Participants in both studies were just above the neutral point in their endorsement of honor values. Individual differences in honor values endorsement did not moderate the effects of activating an honor mindset. Though honor is often described as if it is located in space, we did not find clear effects of where our letter strings were located on the computer screen. Our findings suggest a new way to consider how honor functions, even in societies in which honor is not a highly endorsed value. PMID- 28018264 TI - Implicit Prosody and Cue-based Retrieval: L1 and L2 Agreement and Comprehension during Reading. AB - This project focuses on structural and prosodic effects during reading, examining their influence on agreement processing and comprehension in native English (L1) and Spanish-English bilingual (L2) speakers. We consolidate research from several distinct areas of inquiry-cognitive processing, reading fluency, and L1/L2 processing-in order to support the integration of prosody with a cue-based retrieval mechanism for subject-verb agreement. To explore this proposal, the experimental design manipulated text presentation to influence implicit prosody, using sentences designed to induce subject-verb agreement attraction errors. Materials included simple and complex relative clauses with head nouns and verbs that were either matched or mismatched for number. Participants read items in one of three presentation formats (whole sentence, word-by-word, or phrase-by phrase), rated each item for grammaticality, and responded to a comprehension probe. Results indicated that while overall, message comprehension was prioritized over subject-verb agreement computation, presentation format differentially affected both measures in the L1 and L2 groups. For the L1 participants, facilitating the projection of phrasal prosody onto text (phrase-by phrase presentation) enhanced performance in agreement processing, while disrupting prosodic projection via word-by-word presentation decreased comprehension accuracy. For the L2 participants, however, phrase-by-phrase presentation was not significantly beneficial for agreement processing, and additionally resulted in lower comprehension accuracy. These differences point to a significant role of prosodic phrasing during agreement processing in both L1 and L2 speakers, additionally suggesting that it may contribute to a cue-based retrieval agreement model, either acting as a cue directly, or otherwise scaffolding the retrieval process. The discussion and results presented provide support both for a cue-based retrieval mechanism in agreement, and the function of prosody within such a mechanism, adding further insight into the interaction of retrieval processes, cognitive task load, and the role of implicit prosody. PMID- 28018265 TI - Problematic Social Situations for Peer-Rejected Students in the First Year of Elementary School. AB - This study examined the social situations that are problematic for peer-rejected students in the first year of elementary school. For this purpose, exploratory and confirmatory factor analyses were conducted on the Taxonomy of Problematic Social Situations for Children (TOPS, Dodge et al., 1985) in 169 rejected pupils, identified from a sample of 1457 first-grade students (ages 5-7) enrolled in 62 classrooms of elementary school. For each rejected student, another student of average sociometric status of the same gender was selected at random from the same classroom (naverage = 169). The model for the rejected students showed a good fit, and was also invariant in the group of average students. Four types of situations were identified in which rejected students have significantly more difficulties than average students. They are, in descending order: (a) respect for authority and rules, (b) being disadvantaged, (c) prosocial and empathic behavior, and (d) response to own success. Rejected boys have more problems in situations of prosociability and empathy than girls. The implications concerning the design of specific programs to prevent and reduce early childhood rejection in the classroom are discussed. PMID- 28018266 TI - Inhibitory Control Processes and the Strategies That Support Them during Hand and Eye Movements. AB - Background and Aims: Adaptive behavior depends on the ability to voluntarily suppress context-inappropriate behaviors, a process referred to as response inhibition. Stop Signal tests (SSTs) are the most frequently studied paradigm used to assess response inhibition. Previous studies of SSTs have indicated that inhibitory control behavior can be explained using a common model in which GO and STOP processes are initiated independent from one and another, and the process that is completed first determines whether the behavior is elicited (GO process) or terminated (STOP process). Consistent with this model, studies have indicated that individuals strategically delay their behaviors during SSTs in order to increase their stopping abilities. Despite being controlled by distinct neural systems, prior studies have largely documented similar inhibitory control performance across eye and hand movements. Though, no existing studies have compared the extent to which individuals strategically delay behavior across different effectors is not yet clear. Here, we compared the extent to which inhibitory control processes and the cognitive strategies that support them during oculomotor and manual motor behaviors. Methods: We examined 29 healthy individuals who performed parallel oculomotor and manual motor SSTs. Participants also completed a separate block of GO trials administered prior to the Stop Signal tests to assess baseline reaction times for each effector and reaction time increases during interleaved GO trials of the SST. Results: Our results showed that stopping errors increased for both effectors as the interval between GO and STOP cues was increased (i.e., stop signal delay), but performance deteriorated more rapidly for eye compared to hand movements with increases in stop signal delay. During GO trials, participants delayed the initiation of their responses for each effector, and greater slowing of reaction times on GO trials was associated with increased accuracy on STOP trials for both effectors. However, participants delayed their eye movements to a lesser degree than their hand movements, and strategic reaction time slowing was a stronger determinant of stopping accuracy for hand compared to eye movements. Overall, stopping accuracies for eye and hand movements were only modestly correlated, and the time it took individuals to cancel a response was not related for eye and hand movements. Discussion and Conclusion: Our findings that GO and STOP processes are independent and that individuals strategically delay their behavioral responses to increase stopping accuracy regardless of effector indicate that inhibitory control of oculomotor and manual motor behaviors both follow common guiding principles. Yet, our findings document that eye movements are more difficult to inhibit than hand movements, and the timing, magnitude, and impact of cognitive control strategies used to support voluntary response inhibition are less robust for eye compared to hand movements. This suggests that inhibitory control systems also show unique characteristics that are behavior-dependent. This conclusion is consistent with neurophysiological evidence showing important differences in the architecture and functional properties of the neural systems involved in inhibitory control of eye and hand movements. It also suggests that characterizing inhibitory control processes in health and disease requires effector-specific analysis. PMID- 28018267 TI - Preventing Internalizing Problems in 6-8 Year Old Children: A Universal School Based Program. AB - The Aussie Optimism Program: Feelings and Friends (AOP-FF) is a 10 week, universal mental health promotion program based on social/emotional and cognitive and behavioral strategies. The aim of the current study was to evaluate the efficacy of a universal Cognitive Behavioral Therapy based program in preventing and reducing internalizing problems in 6-8 year olds (Years 1-3 in Australia). Year 1-3 students from a low SES primary school (N = 206) were randomly assigned in classes to either an intervention or a control group and assessed at baseline and post-test. Results showed a significant (p = 0.009) and small to moderate (partial eta-squared = 0.034) pre-post decrease in parent-reported anxiety symptoms for the intervention group, in conjunction with a non-significant (p = 0.708) and negligible (partial eta-squared = 0.001) pre-post increase for the control group. A larger randomized controlled trial assessing longer term effects is needed. In addition the program needs to be simplified for year 1-2 students with a separate more developmentally appropriate program for year 3 students. PMID- 28018268 TI - Effects of Hand Proximity and Movement Direction in Spatial and Temporal Gap Discrimination. AB - Previous research on the interplay between static manual postures and visual attention revealed enhanced visual selection near the hands (near-hand effect). During active movements there is also superior visual performance when moving toward compared to away from the stimulus (direction effect). The "modulated visual pathways" hypothesis argues that differential involvement of magno- and parvocellular visual processing streams causes the near-hand effect. The key finding supporting this hypothesis is an increase in temporal and a reduction in spatial processing in near-hand space (Gozli et al., 2012). Since this hypothesis has, so far, only been tested with static hand postures, we provide a conceptual replication of Gozli et al.'s (2012) result with moving hands, thus also probing the generality of the direction effect. Participants performed temporal or spatial gap discriminations while their right hand was moving below the display. In contrast to Gozli et al. (2012), temporal gap discrimination was superior at intermediate and not near hand proximity. In spatial gap discrimination, a direction effect without hand proximity effect suggests that pragmatic attentional maps overshadowed temporal/spatial processing biases for far/near hand space. PMID- 28018269 TI - Theory of Mind and Its Neuropsychological and Quality of Life Correlates in the Early Stages of Amyotrophic Lateral Sclerosis. AB - This study aims to explore the potential impairment of Theory of Mind (ToM; i.e., the ability to represent cognitive and affective mental states to both self and others) and the clinical, neuropsychological and Quality of Life (QoL) correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration. Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioral, and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT), Advanced Test of ToM (ATT), and Eyes Task (ET). ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances, and "Mental Health" scores among QoL items. Our results suggest that not only "cognitive" but also "affective" subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients' "Mental Health." PMID- 28018270 TI - Psychological Effects of a 1-Month Meditation Retreat on Experienced Meditators: The Role of Non-attachment. AB - Background: There are few studies devoted to assessing the impact of meditation intensive retreats on the well-being, positive psychology, and personality of experienced meditators. We aimed to assess whether a 1-month Vipassana retreat: (a) would increase mindfulness and well-being; (b) would increase prosocial personality traits; and (c) whether psychological changes would be mediated and/or moderated by non-attachment. Method: A controlled, non-randomized, pre post-intervention trial was used. The intervention group was a convenience sample (n = 19) of experienced meditators who participated in a 1-month Vipassana meditation retreat. The control group (n = 19) comprised matched experienced meditators who did not take part in the retreat. During the retreat, the mean duration of daily practice was 8-9 h, the diet was vegetarian and silence was compulsory. The Experiences Questionnaire (EQ), Non-attachment Scale (NAS), Positive and Negative Affect Schedule (PANAS), Satisfaction With Life Scale (SWLS), Temperament Character Inventory Revised (TCI-R-67), Five Facets Mindfulness Questionnaire (FFMQ), Self-Other Four Immeasurables (SOFI) and the MINDSENS Composite Index were administered. ANCOVAs and linear regression models were used to assess pre-post changes and mediation/moderation effects. Results: Compared to controls, retreatants showed increases in non-attachment, observing, MINDSENS, positive-affect, balance-affect, and cooperativeness; and decreases in describing, negative-others, reward-dependence and self-directedness. Non attachment had a mediating role in decentring, acting aware, non-reactivity, negative-affect, balance-affect and self-directedness; and a moderating role in describing and positive others, with both mediating and moderating effects on satisfaction with life. Conclusions: A 1-month Vipassana meditation retreat seems to yield improvements in mindfulness, well-being, and personality, even in experienced meditators. Non-attachment might facilitate psychological improvements of meditation, making it possible to overcome possible ceiling effects ascribed to non-intensive practices. PMID- 28018271 TI - Comparing a Perceptual and an Automated Vision-Based Method for Lie Detection in Younger Children. AB - The present study investigates how easily it can be detected whether a child is being truthful or not in a game situation, and it explores the cue validity of bodily movements for such type of classification. To achieve this, we introduce an innovative methodology - the combination of perception studies (in which eye tracking technology is being used) and automated movement analysis. Film fragments from truthful and deceptive children were shown to human judges who were given the task to decide whether the recorded child was being truthful or not. Results reveal that judges are able to accurately distinguish truthful clips from lying clips in both perception studies. Even though the automated movement analysis for overall and specific body regions did not yield significant results between the experimental conditions, we did find a positive correlation between the amount of movement in a child and the perception of lies, i.e., the more movement the children exhibited during a clip, the higher the chance that the clip was perceived as a lie. The eye-tracking study revealed that, even when there is movement happening in different body regions, judges tend to focus their attention mainly on the face region. This is the first study that compares a perceptual and an automated method for the detection of deceptive behavior in children whose data have been elicited through an ecologically valid paradigm. PMID- 28018272 TI - A Special Chinese Reading Acceleration Training Paradigm: To Enhance the Reading Fluency and Comprehension of Chinese Children with Reading Disabilities. AB - According to a number of studies, use of a Reading Acceleration Program as reading intervention training has been demonstrated to improve reading speed and comprehension level effectively in most languages and countries. The objective of the current study was to provide further evidence of the effectiveness of a Reading Acceleration Program for Chinese children with reading disabilities using a distinctive Chinese reading acceleration training paradigm. The reading acceleration training paradigm is divided into a non-accelerated reading paradigm, a Character-accelerated reading paradigm and a Words-accelerated reading paradigm. The results of training Chinese children with reading disabilities indicate that the acceleration reading paradigm applies to children with Chinese-reading disabilities. In addition, compared with other reading acceleration paradigms, Words-accelerated reading training is more effective in helping children with reading disabilities read at a high speed while maintaining superior comprehension levels. PMID- 28018273 TI - Fast and Forceful: Modulation of Response Activation Induced by Shifts of Perceived Depth in Virtual 3D Space. AB - Reaction time (RT) can strongly be influenced by a number of stimulus properties. For instance, there was converging evidence that perceived size rather than physical (i.e., retinal) size constitutes a major determinant of RT. However, this view has recently been challenged since within a virtual three-dimensional (3D) environment retinal size modulation failed to influence RT. In order to further investigate this issue in the present experiments response force (RF) was recorded as a supplemental measure of response activation in simple reaction tasks. In two separate experiments participants' task was to react as fast as possible to the occurrence of a target located close to the observer or farther away while the offset between target locations was increased from Experiment 1 to Experiment 2. At the same time perceived target size (by varying the retinal size across depth planes) and target type (sphere vs. soccer ball) were modulated. Both experiments revealed faster and more forceful reactions when targets were presented closer to the observers. Perceived size and target type barely affected RT and RF in Experiment 1 but differentially affected both variables in Experiment 2. Thus, the present findings emphasize the usefulness of RF as a supplement to conventional RT measurement. On a behavioral level the results confirm that (at least) within virtual 3D space perceived object size neither strongly influences RT nor RF. Rather the relative position within egocentric (body-centered) space presumably indicates an object's behavioral relevance and consequently constitutes an important modulator of visual processing. PMID- 28018274 TI - Time-Series Analysis of Embodied Interaction: Movement Variability and Complexity Matching As Dyadic Properties. AB - There is a growing consensus that a fuller understanding of social cognition depends on more systematic studies of real-time social interaction. Such studies require methods that can deal with the complex dynamics taking place at multiple interdependent temporal and spatial scales, spanning sub-personal, personal, and dyadic levels of analysis. We demonstrate the value of adopting an extended multi scale approach by re-analyzing movement time-series generated in a study of embodied dyadic interaction in a minimal virtual reality environment (a perceptual crossing experiment). Reduced movement variability revealed an interdependence between social awareness and social coordination that cannot be accounted for by either subjective or objective factors alone: it picks out interactions in which subjective and objective conditions are convergent (i.e., elevated coordination is perceived as clearly social, and impaired coordination is perceived as socially ambiguous). This finding is consistent with the claim that interpersonal interaction can be partially constitutive of direct social perception. Clustering statistics (Allan Factor) of salient events revealed fractal scaling. Complexity matching defined as the similarity between these scaling laws was significantly more pronounced in pairs of participants as compared to surrogate dyads. This further highlights the multi-scale and distributed character of social interaction and extends previous complexity matching results from dyadic conversation to non-verbal social interaction dynamics. Trials with successful joint interaction were also associated with an increase in local coordination. Consequently, a local coordination pattern emerges on the background of complex dyadic interactions in the PCE task and makes joint successful performance possible. PMID- 28018275 TI - What Makes for the Most Intense Regrets? Comparing the Effects of Several Theoretical Predictors of Regret Intensity. AB - Several theories have been proposed to account for variation in the intensity of life regrets. Variables hypothesized to affect the intensity of regret include: whether the regretted decision was an action or an inaction, the degree to which the decision was justified, and the life domain of the regret. No previous study has compared the effects of these key predictors in a single model in order to identify which are most strongly associated with the intensity of life regret. In this study, respondents (N = 500) to a postal survey answered questions concerning the nature of their greatest life regret. A Bayesian regression analysis suggested that regret intensity was greater for-in order of importance decisions that breached participants' personal life rules, decisions in social life domains than non-social domains, and decisions that lacked an explicit justification. Although regrets of inaction were more frequent than regrets of action, regrets relating to actions were slightly more intense. PMID- 28018276 TI - Reading Disability and Quality of Life Based on Both Self- and Parent-Reports: Importance of Gender Differences. AB - Purpose: The aim of this study is to investigate self- and parent-rated quality of life (QoL) in children with a reading disability (RD) and the impact of comorbid psychopathology, with special focus on age and gender differences. Methods: Using the Dyslexia Differential Diagnosis Maastricht-Hungarian standard test, 127 children (aged < 18) were included in the RD group and 81 in the control group. To measure comorbid psychopathology, the Strengths and Difficulties Questionnaire (SDQ) was administered. To evaluate the children's QoL self- and parent-rated versions of the Measure of Quality of Life for Children and Adolescents (ILK) were used. Group differences in QoL and psychopathology were assessed using Mann-Whitney U-tests. Moderated mediational models were tested in which comorbid psychopathology mediated the relationship between group membership and self- and parent-rated QoL, which was dependent on gender. Child's age and parents' level of education were included as covariates. Results: The RD group showed lower QoL than the controls in several domains, according to the parent-report, while no differences between the two groups were found, according to self-report. In boys, results revealed conditional and indirect effects of group membership on self- and parent-rated QoL through comorbid psychopathology ( 0.046, BCa 95% CI: -0.135 to 0.043 and 0.064, BCa 95% CI: 0.024-0.111, respectively) as well as a conditional direct effect of group membership on parent-reported (-0.098, BCa 95% CI: 0.012-0.184), but not self-rated, QoL. No relationship was found for girls. Conclusions: This study highlights the importance of measuring QoL and comorbid psychopathology in children with RDs from more sources and accounting for gender and age differences. PMID- 28018277 TI - Dieting and Food Cue-Related Working Memory Performance. AB - Executive functioning (e.g., working memory) is tightly intertwined with self regulation. For example, food cue-elicited craving has been found to impair working memory performance. Furthermore, current dieters have been found to show lower working memory performance than non-dieters. Recent research, however, suggests that it is crucial to consider dieting success in addition to current dieting status or restrained eating in order to reveal cognitive mechanisms that are associated with successful eating-related self-regulation. The current study investigated food cue-related working memory performance as a function of dieting status and dieting success in female students. Participants performed an n-back task with pictures of food and neutral objects. Reaction time in response to food pictures was slower than in response to neutral pictures, whereas omission errors did not differ between picture types. Current food craving was increased after performing the food block, but not after the neutral block. There was an indirect effect of current dieting status on higher food craving after the food block, which was mediated by slower reaction time to food vs. neutral pictures. Furthermore, higher dieting success was associated with fewer omission errors in the food vs. neutral block in current dieters. There were no relationships of restrained eating with current food craving and task performance. Results further highlight the need to differentiate between successful and unsuccessful dieting in addition to current dieting status or restrained eating when examining possible mechanisms of overeating or successful restraint. Although palatable food cues induce food craving regardless of dieting success, they may boost executive functioning in successful dieters, which helps them to overcome these temptations. PMID- 28018278 TI - The Anatomy of Action Systems: Task Differentiation When Learning an EMG Controlled Game. AB - This study aims to determine to what extent the task for an action system in its initial development relies on functional and anatomical components. Fifty-two able-bodied participants were randomly assigned to one of three experimental groups or to a control group. As a pre- and post-test all groups performed a computer game with the same goal and using the same musculature. One experimental group also trained to perform this test, while the other two experimental groups learned to perform a game that differed either in its goal or in the musculature used. The observed change in accuracy indicated that retaining the goal of the task or the musculature used equally increased transfer performance relative to controls. Conversely, changing either the goal or the musculature equally decreased transfer relative to training the test. These results suggest that in the initial development of an action system, the task to which the system pertains is not specified solely by either the goal of the task or the anatomical structures involved. It is suggested that functional specificity and anatomical dependence might equally be outcomes of continuously differentiating activity. PMID- 28018279 TI - Commentary: Pride, Shame, and Group Identification. PMID- 28018280 TI - Capitalist Discourse, Subjectivity and Lacanian Psychoanalysis. AB - This paper studies how subjectivity in capitalist culture can be characterized. Building on Lacan's later seminars XVI, XVII, XVIII, and XIX, the author first outlines Lacan's general discourse theory, which includes four characteristic discourses: the discourse of the master, the discourse of the university, the discourse of the hysteric and the discourse of the analyst. Next, the author explores the subjectivity and the mode of dealing with jouissance and semblance, which is entailed in a fifth type of discourse, the capitalist discourse, discussed by Lacan (1972). Indeed, like the other discourses that Lacan discerns, the discourse of the capitalist can be thought of as a mode of dealing with the sexual non-rapport. It is argued that in the case of neurosis the discourse of the capitalist functions as an attempt to ignore the sexual non-rapport and the dimension of the unconscious. Psychosis, by contrast, is marked by an a priori exclusion from discourse. In that case, consumerist ways of relating to the other might offer a semblance, and thus the possibility of inventing a mode of relating to the other. Two clinical vignettes are presented to illustrate this perspective: one concerning the neurotic structure and one concerning the psychotic structure. PMID- 28018281 TI - Distraction by Novel and Pitch-Deviant Sounds in Children. AB - The control of attention is an important part of our executive functions and enables us to focus on relevant information and to ignore irrelevant information. The ability to shield against distraction by task-irrelevant sounds is suggested to mature during school age. The present study investigated the developmental time course of distraction in three groups of children aged 7-10 years. Two different types of distractor sounds that have been frequently used in auditory attention research-novel environmental and pitch-deviant sounds-were presented within an oddball paradigm while children performed a visual categorization task. Reaction time measurements revealed decreasing distractor-related impairment with age. Novel environmental sounds impaired performance in the categorization task more than pitch-deviant sounds. The youngest children showed a pronounced decline of novel-related distraction effects throughout the experimental session. Such a significant decline as a result of practice was not observed in the pitch-deviant condition and not in older children. We observed no correlation between cross modal distraction effects and performance in standardized tests of concentration and visual distraction. Results of the cross-modal distraction paradigm indicate that separate mechanisms underlying the processing of novel environmental and pitch-deviant sounds develop with different time courses and that these mechanisms develop considerably within a few years in middle childhood. PMID- 28018282 TI - Perceived Duration Increases with Contrast, but Only a Little. AB - Recent adaptation studies provide evidence for early visual areas playing a role in duration perception. One explanation for the pronounced duration compression commonly found with adaptation is that it reflects adaptation-driven stimulus specific reduction in neural activity in early visual areas. If this level of stimulus-associated neural activity does drive duration, then we would expect a strong effect of contrast on perceived duration as electrophysiological studies shows neural activity in early visual areas to be strongly related to contrast. We employed a spatially isotropic noise stimulus where the luminance of each noise element was independently sinusoidally modulated at 4 Hz. Participants matched the perceived duration of a high (0.9) or low (0.1) contrast stimulus to a previously presented standard stimulus (600 ms, contrast = 0.3). To achieve perceptually equivalent durations, the low contrast stimulus had to be presented for longer than the high contrast stimulus. This occurred when we controlled for stimulus size and when we adjusted for individual differences in perceived temporal frequency. Further, we show that the effect cannot be explained by shifts in perceived onset and offset and is not explained by a simple contrast driven response bias. The direction of our results is clearly consistent with the idea that level of neural activity drives duration. However, the magnitude of the effect (~10% duration difference over a 0.9-0.1 contrast reduction) is in marked contrast to the larger duration distortions that can be found with repetition suppression and the oddball effect; particularly when these may be associated with smaller differences in neural activity than that expected from our contrast difference. Taken together, these results indicate that level of stimulus-related neural activity in early visual areas is unlikely to provide a general mechanism for explaining differences in perceived duration. PMID- 28018283 TI - Curling Up With a Good E-Book: Mother-Child Shared Story Reading on Screen or Paper Affects Embodied Interaction and Warmth. AB - This study compared changes in cognitive, affective, and postural aspects of interaction during shared mother and child book reading on screen and on paper. Readers commonly express strong preferences for reading on paper, but several studies have shown marginal, if any, effects of text medium on cognitive outcomes such as recall. Shared reading with a parent is an engaging, affective and embodied experience across time, as well as a cognitive task, so it is important to understand how paper vs. screen affects broader aspects of these shared experiences. Mid-childhood sees a steep rise in screen use alongside a shift from shared to independent reading. We assessed how the medium of paper or screen might alter children's shared reading experiences at this transitional age. Twenty-four 7- to 9-year-old children and their mothers were videotaped sharing a story book for 8 min in each of four conditions: mother or child as reader, paper, or tablet screen as medium. We rated videotapes for interaction warmth and child engagement by minute and analyzed dyadic postural synchrony, mothers' commentaries and quality of children's recall, also interviewing participants about their experiences of reading and technology. We found no differences in recall quality but interaction warmth was lower for screen than for paper, and dropped over time, notably when children read on screen. Interactions also differed between mother-led and child-led reading. We propose that mother - child posture for paper reading supported more shared activity and argue that cultural affordances of screens, together with physical differences between devices, support different behaviors that affect shared engagement, with implications for the design and use of digital technology at home and at school. We advocate studying embodied and affective aspects of shared reading to understand the overall implications of screens in children's transition to independent reading. PMID- 28018284 TI - Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat. AB - Neuropathic pain is chronic pain that develops after nerve injury and is less frequent in infants and children than in adults. Likewise, in animal models of neuropathic pain, allodynia and hyperalgesia are non-existent or attenuated in the infant, with a "switch" during development by which acute nerve injury transitions to chronic pain. Concomitant with the delay in neuropathic pain, there is a parallel delay in the ability of nerve injury to activate the immune system. Models of neuropathic pain in the infant have used various ligation methods and find that neuropathic pain does not occur under after postnatal days 21-28 (PN21-PN28), linked to activation of immune processes and developmental regulation of anti-inflammatory cytokines. We applied a model of neuropathic pain in the adult using a transient compression of the cervical nerve or nerve root in infant rats (injured at 10, 14, 21, or 28 days of age) to define transition periods during which injury results in no change in thermal and mechanical pain sensitivity or in short-term changes in pain. There was little to no hyperalgesia when the injury was imposed at PN10, but significant thermal hyperalgesia and mechanical allodynia 1 day after compression injury when performed at PN14, 21, or 28. Thermal withdrawal latencies returned to near baseline by 7 days postsurgery when the injuries were at PN14, and lasted up to 14 days when the injury was imposed at PN28. There was mechanical allodynia following injury at 1 day postinjury and at 14 days after injury at PN14. Measurements of mRNA from spinal cord at 1, 7, and 14 days postinjury at PN14, 21, and 28 showed that both the magnitude and duration of elevated immune markers and chemokines/cytokines were greater in the older animals, corresponding to the development of hyperalgesia. Thus, we confirm the late onset of neuropathic pain but found no evidence of emergent hyperalgesia if the injury was before PN21. This may be due to the use of a transient, and not sustained, compression ligation model. PMID- 28018286 TI - Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Stem Cells in Subacute Ischemic Stroke Patients. AB - INTRODUCTION: Based on many preclinical and small clinical trials, stem cells can help stroke patient with the possibility of replacing the cells and supporting the remaining cells. The aim of this study was to evaluate the safety and feasibility of bone marrow mononuclear (BMMN) stem cell transplantation in subacute ischemic stroke patients. MATERIALS AND METHODS: Thirty-nine (n = 39) patients with subacute ischemic cerebral infarct due to large artery occlusion in the middle cerebral artery (MCA) territory were recruited. They were distributed into two groups: first group (n = 21) served as an experimental group, which received intra-arterial (IA) mononuclear stem cells (bone marrow-derived mononuclear cell), while the other group (n = 18) served as a control group. All the patients were evaluated clinically by National Institutes of Health Stroke Scale, modified Rankin Scale, Barthel Index, modified and standardized Arabic version of the Comprehensive Aphasia Test, and radiological for 12 months. RESULTS: The stem cell-treated group showed better improvement, but it was not significant when compared with the non-treated group. The volume of infarction changes at the end of the study was non-significant between both the groups. There was no, or minimal, adverse reactions in stem cell-treated group. CONCLUSION: The study results suggest that autologous BMMN stem cell IA transplantation in subacute MCA ischemic stroke patients is safe with very minimal hazards, but no significant improvement of motor, language disturbance, or infarction volume was detected in stem cell-treated group compared with the non-treated group. PMID- 28018285 TI - Neural Signature of DCD: A Critical Review of MRI Neuroimaging Studies. AB - The most common neurodevelopmental disorders (e.g., developmental dyslexia (DD), autism, attention-deficit hyperactivity disorder (ADHD)) have been the subject of numerous neuroimaging studies, leading to certain brain regions being identified as neural correlates of these conditions, referring to a neural signature of disorders. Developmental coordination disorder (DCD), however, remains one of the least understood and studied neurodevelopmental disorders. Given the acknowledged link between motor difficulties and brain features, it is surprising that so few research studies have systematically explored the brains of children with DCD. The aim of the present review was to ascertain whether it is currently possible to identify a neural signature for DCD, based on the 14 magnetic resonance imaging neuroimaging studies that have been conducted in DCD to date. Our results indicate that several brain areas are unquestionably linked to DCD: cerebellum, basal ganglia, parietal lobe, and parts of the frontal lobe (medial orbitofrontal cortex and dorsolateral prefrontal cortex). However, research has been too sparse and studies have suffered from several limitations that constitute a serious obstacle to address the question of a well-established neural signature for DCD. PMID- 28018287 TI - Altered Kinematics of Facial Emotion Expression and Emotion Recognition Deficits Are Unrelated in Parkinson's Disease. AB - BACKGROUND: Altered emotional processing, including reduced emotion facial expression and defective emotion recognition, has been reported in patients with Parkinson's disease (PD). However, few studies have objectively investigated facial expression abnormalities in PD using neurophysiological techniques. It is not known whether altered facial expression and recognition in PD are related. OBJECTIVE: To investigate possible deficits in facial emotion expression and emotion recognition and their relationship, if any, in patients with PD. METHODS: Eighteen patients with PD and 16 healthy controls were enrolled in this study. Facial expressions of emotion were recorded using a 3D optoelectronic system and analyzed using the facial action coding system. Possible deficits in emotion recognition were assessed using the Ekman test. Participants were assessed in one experimental session. Possible relationship between the kinematic variables of facial emotion expression, the Ekman test scores, and clinical and demographic data in patients were evaluated using the Spearman's test and multiple regression analysis. RESULTS: The facial expression of all six basic emotions had slower velocity and lower amplitude in patients in comparison to healthy controls (all Ps < 0.05). Patients also yielded worse Ekman global score and disgust, sadness, and fear sub-scores than healthy controls (all Ps < 0.001). Altered facial expression kinematics and emotion recognition deficits were unrelated in patients (all Ps > 0.05). Finally, no relationship emerged between kinematic variables of facial emotion expression, the Ekman test scores, and clinical and demographic data in patients (all Ps > 0.05). CONCLUSION: The results in this study provide further evidence of altered emotional processing in PD. The lack of any correlation between altered facial emotion expression kinematics and emotion recognition deficits in patients suggests that these abnormalities are mediated by separate pathophysiological mechanisms. PMID- 28018288 TI - Vitamin D on Early Stages of Diabetic Kidney Disease: A Cross-sectional Study in Patients with Type 1 Diabetes Mellitus. AB - CONTEXT: Genetic and environmental factors are involved in the pathogenesis of type 1 diabetes mellitus (T1DM), and vitamin D (VD) deficiency appears as a candidate to risk factor for developing diabetic kidney disease (DKD). OBJECTIVE: The purpose of study was to evaluate the existence of an association between low levels of VD and the presence and degree of DKD in T1DM. PATIENTS AND METHODS: We performed a cross-sectional study, between November 2014 and December 2015. Levels of 25(OH)D and albuminuria were analyzed in 37 patients with T1DM and normal glomerular filtration rate. Thirty-six subjects were evaluated as a control group. RESULTS: Patients with T1DM and hypovitaminosis D had higher levels of albuminuria compared to those with normal VD levels [albuminuria (log10) = 1.92 vs. 1.44; p < 0.05]. When we have separated the group of patients according to stage of DKD in patients with normo, micro, and macroalbuminuria, there are lower levels of 25(OH)D in the last when compared to the first two groups (26.7 +/- 6.2, 24.8 +/- 7.0, and 15.9 +/- 7.6 ng/ml; p < 0.05, respectively). In T1DM group, we have found correlations between VD levels and both albuminuria and DKD stages (r = -0.5; p < 0.01 and r = -0.4; p < 0.05, respectively). A simple linear regression model, with albuminuria as the dependent variable and VD as an independent variable, showed r2 = 0.2 and p < 0.01. CONCLUSION: Our data suggest an association between reduced levels of VD and the presence and severity of DKD. PMID- 28018289 TI - Choroidal and Retinal Abnormalities by Optical Coherence Tomography in Endogenous Cushing's Syndrome. AB - CONTEXT: Cortisol has been suggested as a risk factor for choroidal thickening, which may lead to retinal changes. OBJECTIVE: To compare choroidal thickness measurements using optical coherence tomography (OCT) in patients with endogenous active Cushing's syndrome (CS) and to evaluate the occurrence of retinal abnormalities in the same group of patients. DESIGN: Cross-sectional study. SETTING: Outpatient clinic. PATIENTS: Eleven female patients with CS in hypercortisolism state as determined by the presence of at least two abnormal measurements from urinary cortisol 24 h, no suppression of cortisol with low dose dexamethasone suppression test, and nocturnal salivary cortisol levels and 12 healthy controls. METHODS: Choroidal and retinal morphology was assessed using OCT. MAIN OUTCOME MEASURES: Choroidal thickness measurements and the presence of retinal changes. RESULTS: The mean subfoveal choroidal thickness was 372.96 +/- 73.14 um in the patients with CS and 255.63 +/- 50.70 um in the control group (p < 0.001). One patient (9.09%) presented with central serous chorioretinopathy and one patient (9.09%) with pachychoroid pigment epitheliopathy. CONCLUSION: Choroidal thickness is increased in the eyes of patients with active CS compared to healthy and matched control. Also, 18.18% of patients presented with macular changes, possibly secondary to choroidal thickening. While further studies are necessary to confirm our findings, excess corticosteroid levels seem to have a significant effect on the choroid and might be associated with secondary retinal diseases. PMID- 28018290 TI - Effects of Chronic Social Stress and Maternal Intranasal Oxytocin and Vasopressin on Offspring Interferon-gamma and Behavior. AB - Recent studies support the hypothesis that the adverse effects of early-life adversity and transgenerational stress on neural plasticity and behavior are mediated by inflammation. The objective of the present study was to investigate the immune and behavioral programing effects of intranasal (IN) vasopressin (AVP) and oxytocin (OXT) treatment of chronic social stress (CSS)-exposed F1 dams on F2 juvenile female offspring. It was hypothesized that maternal AVP and OXT treatment would have preventative effects on social stress-induced deficits in offspring anxiety and social behavior and that these effects would be associated with changes in interferon-gamma (IFNgamma). Control and CSS-exposed F1 dams were administered IN saline, AVP, or OXT during lactation and the F2 juvenile female offspring were assessed for basal plasma IFNgamma and perseverative, anxiety, and social behavior. CSS F2 female juvenile offspring had elevated IFNgamma levels and exhibited increased repetitive/perseverative and anxiety behaviors and deficits in social behavior. These effects were modulated by AVP and OXT in a context- and behavior-dependent manner, with OXT exhibiting preventative effects on repetitive and anxiety behaviors and AVP possessing preventative effects on social behavior deficits and anxiety. Basal IFNgamma levels were elevated in the F2 offspring of OXT-treated F1 dams, but IFNgamma was not correlated with the behavioral effects. These results support the hypothesis that maternal AVP and OXT treatment have context- and behavior-specific effects on peripheral IFNgamma levels and perseverative, anxiety, and social behaviors in the female offspring of early-life social stress-exposed dams. Both maternal AVP and OXT are effective at preventing social stress-induced increases in self-directed measures of anxiety, and AVP is particularly effective at preventing impairments in overall social contact. OXT is specifically effective at preventing repetitive/perseverative behaviors, yet is ineffective at preventing deficits in overall social behavior. PMID- 28018291 TI - Adrenal Gland Microenvironment and Its Involvement in the Regulation of Stress Induced Hormone Secretion during Sepsis. AB - Survival of all living organisms depends on maintenance of a steady state of homeostasis, which process relies on its ability to react and adapt to various physical and emotional threats. The defense against stress is executed by the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal medullary system. Adrenal gland is a major effector organ of stress system. During stress, adrenal gland rapidly responds with increased secretion of glucocorticoids (GCs) and catecholamines into circulation, which hormones, in turn, affect metabolism, to provide acutely energy, vasculature to increase blood pressure, and the immune system to prevent it from extensive activation. Sepsis resulting from microbial infections is a sustained and extreme example of stress situation. In many critical ill patients, levels of both corticotropin-releasing hormone and adrenocorticotropin, the two major regulators of adrenal hormone production, are suppressed. Levels of GCs, however, remain normal or are elevated in these patients, suggesting a shift from central to local intra-adrenal regulation of adrenal stress response. Among many mechanisms potentially involved in this process, reduced GC metabolism and activation of intra-adrenal cellular systems composed of adrenocortical and adrenomedullary cells, endothelial cells, and resident and recruited immune cells play a key role. Hence, dysregulated function of any of these cells and cellular compartments can ultimately affect adrenal stress response. The purpose of this mini review is to highlight recent insights into our understanding of the adrenal gland microenvironment and its role in coordination of stress-induced hormone secretion. PMID- 28018292 TI - Obesity: An Immunometabolic Perspective. AB - Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10. In contrast, obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-alpha), which recruit blood monocytes in adipose tissue, where they are converted to macrophages of the highly pro-inflammatory M1-type (ATM1). Activated ATM1 produce large amounts of pro-inflammatory mediators such as TNF alpha, interleukin-1beta, IL-6, leukotriene B4, nitric oxide (NO), and resistin that work in a paracrine fashion and cause IR in adipose tissue. In the liver, both pro-inflammatory Kupffer cells (M1-KCs) and recruited hepatic macrophages (Ly6Chigh) contribute to decreased hepatic insulin sensitivity. The present mini review will update the bidirectional interaction between the immune system and obesity-induced changes in metabolism in adipose tissue and liver and the metabolic consequences thereof. PMID- 28018293 TI - Dynamic Changes in DNA Methylation Occur during the First Year of Life in Preterm Infants. AB - BACKGROUND: Preterm birth associates with a substantially increased risk of later cardiovascular disease and neurodevelopmental disorders. Understanding underlying mechanisms will facilitate the development of screening and intervention strategies to reduce disease risk. Changes in DNA methylation have been proposed as one mechanism linking the early environment with later disease risk. We tested the hypothesis that preterm birth associates with altered DNA methylation in genes encoding insulin-like growth factor 2 (IGF2) and FK506-binding protein 5 (FKBP5), which appear particularly vulnerable to early life adversity. METHODS: Fifty preterm infants were seen and assessed at birth, term equivalent age, 3 months and 1-year corrected ages; 40 term infants were seen at birth, 3 months and 1 year. Saliva was collected for DNA extraction at birth, term, and 1 year. Pyrosequencing of bisulfite-converted DNA was performed to measure DNA methylation at specific CpG sites within the IGF2 and FKBP5 loci. RESULTS: Weight and head circumference was reduced in preterm infants at all time points. Preterm infants had a higher percentage body fat at term-corrected age, but this difference was not persistent. DNA methylation at the differentially methylated region (DMR) of IGF2 (IGF2DMR2) and FKBP5 was lower in preterm infants at birth- and term-corrected age compared to term infants at birth. IGF2DMR2 and FKBP5 methylation was related to birthweight SD score in preterm infants. Among preterm infants, social deprivation was an independent contributor toward reducing DNA methylation at IGF2DMR2 at birth- and term-corrected age and maternal smoking was associated with reduced DNA methylation at FKBP5 at birth. There were no persistent differences in DNA methylation at 1 year of age. CONCLUSION: Changes in DNA methylation were identified at key regions of IGF2/H19 and FKBP5 in preterm infants in early life. Potential contributing factors include maternal smoking and social deprivation. However, these changes did not persist at 1 year of age and further longitudinal studies are required to determine any associations between altered DNA methylation in the perinatal period of individuals born preterm and their long-term health. PMID- 28018294 TI - Zebrafish Models for Dyslipidemia and Atherosclerosis Research. AB - Atherosclerotic cardiovascular disease is the leading cause of death. Elevated circulating concentrations of lipids are a central pathogenetic driver of atherosclerosis. While numerous effective therapies for this condition have been developed, there is substantial unmet need for this pandemic illness. Here, I will review nutritional, physiological, genetic, and pathological discoveries in the emerging zebrafish model for studying dyslipidemia and atherosclerosis. The technical and physiological advantages and the pharmacological potential of this organism for discovery and validation of dyslipidemia and atherosclerosis targets are stressed through summary of recent findings. An emerging literature shows that zebrafish, through retention of a cetp ortholog gene and high sensitivity to ingestion of excess cholesterol, rapidly develops hypercholesterolemia, with a pattern of distribution of lipid species in lipoprotein particles similar to humans. Furthermore, recent studies leveraging the optical transparency of zebrafish larvae to monitor the fate of these ingested lipids have provided exciting insights to the development of dyslipidemia and atherosclerosis. Future directions for investigation are considered, with particular attention to the potential for in vivo cell biological study of atherosclerotic plaques. PMID- 28018295 TI - Combined Whole-Cell High-Throughput Functional Screening for Identification of New Nicotinamidases/Pyrazinamidases in Metagenomic/Polygenomic Libraries. AB - Nicotinamidases catalyze the hydrolysis of the amide bond in nicotinamide (NAM) to produce ammonia and nicotinic acid (NA). These enzymes are an essential component of the NAD+ salvage pathway and are implicated in the viability of several pathogenic organisms. Its absence in humans makes them a promising drug target. In addition, although they are key analytical biocatalysts for screening modulators in relevant biomedical enzymes, such as sirtuins and poly-ADP ribosyltransferases, no commercial sources are available. Surprisingly, the finding of an affordable source of nicotinamidase from metagenomic libraries is hindered by the absence of a suitable and fast screening method. In this manuscript, we describe the development of two new whole-cell methods using the chemical property of one of the products formed in the enzymatic reaction (pyrazinoic or NA) to form colored complexes with stable iron salts, such as ammonium ferrous sulfate or sodium nitroprusside (SNP). After optimization of the assay conditions, a fosmid polygenomic expression library obtained from deep-sea mesophilic bacteria was screened, discovering several positive clones with the ammonium ferrous sulfate method. Their quantitative rescreening with the SNP method allowed the finding of the first nicotinamidase with balanced catalytic efficiency toward NAM (nicotinamidase activity) and pyrazinamide (pyrazinamidase activity). Its biochemical characterization has also made possible the development of the first high-throughput whole-cell method for prescreening of new nicotinamidase inhibitors by the naked eye, saving time and costs in the design of future antimicrobial and antiparasitic agents. PMID- 28018296 TI - Serum Cytokine Signature That Discriminates Helicobacter pylori Positive and Negative Juvenile Gastroduodenitis. AB - Gastroduodenitis caused by H. pylori, often acquired in early childhood, is found in about 50% of the adult population. Although H. pylori infections can remain asymptomatic, its virulence factors usually trigger epithelial vacuolization and degeneration, loss of microvilli, disintegration of cytoplasm, and leukocyte accumulation. It is believed that leukocyte infiltration is driven by cytokines produced locally in infected tissue. However, so far little is known about changes in serum cytokines in juvenile patients infected with H. pylori. Serum cytokine profiles were analyzed in 62 juvenile patients diagnosed with gastroduodenitis using the Bio-Plex multiplex assay. H. pylori infection was confirmed in 32 patients, while 30 patients were H. pylori-free. Cytokines CXCL5 and CXCL6, potent neutrophil chemoattractants, were upregulated in all patients diagnosed with gastroduodenitis. Serum levels of IL8, a prototype neutrophil attractant, remained unchanged in subjects with gastroduodenitis relative to controls. Therefore, our data suggest that CXCL5 and CXCL6 play a role in directing neutrophil trafficking into inflamed gastroduodenal tissue. In addition, the CCL25/GM-CSF ratio differed significantly between H. pylori positive and -negative juveniles. Further, study is needed to evaluate the role of CCL25 and GM-CSF in the pathogenesis of the different etiologies of gastroduodenitis. PMID- 28018297 TI - Mechanisms of Antibacterial Action of Quinoxaline 1,4-di-N-oxides against Clostridium perfringens and Brachyspira hyodysenteriae. AB - Quinoxaline 1,4-di-N-oxides (QdNOs) are a class of bioreductive compounds, however, their antibacterial mechanisms are still unclarified. The aim of this study was to assess the ability of two representative QdNO drugs, cyadox (CYA) and olaquindox (OLA), to produce reactive oxide species (ROS) in Gram-positive anaerobe Clostridium perfringens CVCC1125 and Gram-negative anaerobe Brachyspira hyodysenteriae B204. In addition, the effects of QdNOs on the integrity of bacterial cell walls and membranes as well as the morphological alterations and DNA oxidative damage in C. perfringens and B. hyodysenteriae were analyzed. It was demonstrated that under anaerobic conditions, QdNOs were metabolized into the reduced products which did not show any antibacterial activity. A significant dose-related increase of intracellular ROS level and intracellular hydroxyl radicals were evident in bacteria exposed to QdNOs. The result of biochemical assay showed that the cell walls and membranes of the bacteria treated with QdNOs were damaged. After exposure to 1/2MIC to 4MIC of CYA and OLA, C. perfringens and B. hyodysenteriae became elongated and filamentous. Morphological observation with scanning and transmission electron microscopes revealed rupture, loss of cytoplasmic material and cell lysis in QdNO-treated bacteria, indicating serious damage of cells. There was an increase of 8-OHdG in the two strains treated by QdNOs, but it was lower in C. perfringens CVCC1125 than in B. hyodysenteriae B204. Agarose gel electrophoresis showed the degradation of chromosomal DNA in both of the two anaerobes treated by QdNOs. The results suggest that QdNOs may kill C. perfringens and B. hyodysenteriae via the generation of ROS and hydroxyl radicals from the bacterial metabolism of QdNOs, which cause oxidative damage in bacteria under anaerobic conditions. PMID- 28018298 TI - Do Bacterial "Virulence Factors" Always Increase Virulence? A Meta-Analysis of Pyoverdine Production in Pseudomonas aeruginosa As a Test Case. AB - Bacterial traits that contribute to disease are termed "virulence factors" and there is much interest in therapeutic approaches that disrupt such traits. What remains less clear is whether a virulence factor identified as such in a particular context is also important in infections involving different host and pathogen types. Here, we address this question using a meta-analytic approach. We statistically analyzed the infection outcomes of 81 experiments associated with one well-studied virulence factor-pyoverdine, an iron-scavenging compound secreted by the opportunistic pathogen Pseudomonas aeruginosa. We found that this factor is consistently involved with virulence across different infection contexts. However, the magnitude of the effect of pyoverdine on virulence varied considerably. Moreover, its effect on virulence was relatively minor in many cases, suggesting that pyoverdine is not indispensable in infections. Our works supports theoretical models from ecology predicting that disease severity is multifactorial and context dependent, a fact that might complicate our efforts to identify the most important virulence factors. More generally, our study highlights how comparative approaches can be used to quantify the magnitude and general importance of virulence factors, key knowledge informing future anti virulence treatment strategies. PMID- 28018300 TI - Viral Lysis of Photosynthesizing Microbes As a Mechanism for Calcium Carbonate Nucleation in Seawater. AB - Removal of carbon through the precipitation and burial of calcium carbonate in marine sediments constitutes over 70% of the total carbon on Earth and is partitioned between coastal and pelagic zones. The precipitation of authigenic calcium carbonate in seawater, however, has been hotly debated because despite being in a supersaturated state, there is an absence of persistent precipitation. One of the explanations for this paradox is the geochemical conditions in seawater cannot overcome the activation energy barrier for the first step in any precipitation reaction; nucleation. Here we show that virally induced rupturing of photosynthetic cyanobacterial cells releases cytoplasmic-associated bicarbonate at concentrations ~23-fold greater than in the surrounding seawater, thereby shifting the carbonate chemistry toward the homogenous nucleation of one or more of the calcium carbonate polymorphs. Using geochemical reaction energetics, we show the saturation states (Omega) in typical seawater for calcite (Omega = 4.3), aragonite (Omega = 3.1), and vaterite (Omega = 1.2) are significantly elevated following the release and diffusion of the cytoplasmic bicarbonate (Omegacalcite = 95.7; Omegaaragonite = 68.5; Omegavaterite = 25.9). These increases in Omega significantly reduce the activation energy for nuclei formation thresholds for all three polymorphs, but only vaterite nucleation is energetically favored. In the post-lysis seawater, vaterite's nuclei formation activation energy is significantly reduced from 1.85 * 10-17 J to 3.85 * 10-20 J, which increases the nuclei formation rate from highly improbable (<<1.0 nuclei cm 3 s-1) to instantaneous (8.60 * 1025 nuclei cm-3 s-1). The proposed model for homogenous nucleation of calcium carbonate in seawater describes a mechanism through which the initial step in the production of carbonate sediments may proceed. It also presents an additional role of photosynthesizing microbes and their viruses in marine carbon cycles and reveals these microorganisms are a collective repository for concentrated and reactive dissolved inorganic carbon (DIC) that is currently not accounted for in global carbon budgets and carbonate sediment diagenesis models. PMID- 28018299 TI - The Relationship between pH and Bacterial Communities in a Single Karst Ecosystem and Its Implication for Soil Acidification. AB - Enhanced monsoon duration and soil acidification from acid rain are expected to impact the distribution of microbial communities in surface and subsurface environments, although these impacts are poorly understood for most systems. In central China, soluble carbonate bedrock forms extensive karst landscapes. Current predictions are that the amount of monsoonal precipitation and acid rainfall in central China will increase, which is expected to lead to changes in the pH balance of karst ecosystems. To evaluate the role of pH, total organic carbon, and other geochemical parameters (e.g., Ca2+, Mg2+, NH4+, NOx, SO42-) in shaping bacterial communities within a single karst system in central China, samples were collected from the thin surface soils overlying Heshang Cave, cave sediments, and weathered cave passage rocks from the entrance, twilight, and dark zones, as well as from epikarstic drip waters inside the cave. Illumina sequencing of 16S rRNA genes and multivariate statistical analyses revealed that each tested community was distinct and the community variability was significantly correlated with pH, total organic carbon, and potassium concentrations. Specifically, surface soils were dominated by Acidobacteria, Verrucomicrobia and Planctomycetes, and diversity significantly decreased with acidic pH values. Nitrospirae, Gemmatimonadetes, Firmicutes, and Chloroflexi were unique to cave sediments, while Actinobacteria and Proteobacteria dominated weathered rocks and drip waters, respectively. The results reveal important implications regarding the effects of acidification on bacterial communities in karst areas, and on the control of pH in shaping bacterial communities throughout a karst system. Increased water flux into and through karst habitats due to monsoonal precipitation may result in deeper penetration of acidic solutions into karst and shift the bacterial communities inside the cave in the future. PMID- 28018301 TI - Screening and Identification of APOC1 as a Novel Potential Biomarker for Differentiate of Mycoplasma pneumoniae in Children. AB - Background: Although Mycoplasma pneumoniae (MP) is a common cause of community acquired pneumonia (CAP) in children, the currently used diagnostic methods are not optimal. Proteomics is increasingly being used to study the biomarkers of infectious diseases. Methods: Label-free quantitative proteomics and liquid chromatography-mass/mass spectrometry were used to analyze the fold change of protein expression in plasma of children with MP pneumonia (MPP), infectious disease control (IDC), and healthy control (HC) groups. Selected proteins that can distinguish MPP from HC and IDC were further validated by enzyme-linked immunosorbent assay (ELISA). Results: After multivariate analyses, 27 potential plasma biomarkers were identified to be expressed differently among child MPP, HC, and IDC groups. Among these proteins, SERPINA3, APOC1, ANXA6, KNTC1, and CFLAR were selected for ELISA verification. SERPINA3, APOC1, and CFLAR levels were significantly different among the three groups and the ratios were consistent with the trends of proteomics results. A comparison of MPP patients and HC showed APOC1 had the largest area under the curve (AUC) of 0.853, with 77.6% sensitivity and 81.1% specificity. When APOC1 levels were compared between MPP and IDC patients, it also showed a relatively high AUC of 0.882, with 77.6% sensitivity and 85.3% specificity. Conclusion: APOC1 is a potential biomarker for the rapid and noninvasive diagnosis of MPP in children. The present finding may offer new insights into the pathogenesis and biomarker selection of MPP in children. PMID- 28018302 TI - Proteomic Analysis of Differential Expression of Cellular Proteins in Response to Avian H9N2 Virus Infection of A549 Cells. AB - In this study, differentially expressed proteins in A549 cells (human lung adenocarcinoma epithelial cell line) infected with H9N2 avian influenza virus (AIV) were investigated by two-dimensional electrophoresis (2-DE). Sixteen different spots between the groups (ratio > 2, p < 0.05) were identified with mass spectrometry identification. Proteins located in the downstream of the NF kappaB and IFN transcription factor pathways were identified, e.g., ISG15. Actin and keratin were also identified, suggesting that the cytoskeleton may plays an important role in the AIV infection of mammalian cells. These findings could provide insights into the interaction between host and influenza viruses and might provide valuable information for clarifying the pathogenesis of viral infections as well. PMID- 28018304 TI - Identification of Electrode Respiring, Hydrocarbonoclastic Bacterial Strain Stenotrophomonas maltophilia MK2 Highlights the Untapped Potential for Environmental Bioremediation. AB - Electrode respiring bacteria (ERB) possess a great potential for many biotechnological applications such as microbial electrochemical remediation systems (MERS) because of their exoelectrogenic capabilities to degrade xenobiotic pollutants. Very few ERB have been isolated from MERS, those exhibited a bioremediation potential toward organic contaminants. Here we report once such bacterial strain, Stenotrophomonas maltophilia MK2, a facultative anaerobic bacterium isolated from a hydrocarbon fed MERS, showed a potent hydrocarbonoclastic behavior under aerobic and anaerobic environments. Distinct properties of the strain MK2 were anaerobic fermentation of the amino acids, electrode respiration, anaerobic nitrate reduction and the ability to metabolize n-alkane components (C8-C36) of petroleum hydrocarbons (PH) including the biomarkers, pristine and phytane. The characteristic of diazoic dye decolorization was used as a criterion for pre-screening the possible electrochemically active microbial candidates. Bioelectricity generation with concomitant dye decolorization in MERS showed that the strain is electrochemically active. In acetate fed microbial fuel cells (MFCs), maximum current density of 273 +/- 8 mA/m2 (1000 Omega) was produced (power density 113 +/- 7 mW/m2) by strain MK2 with a coulombic efficiency of 34.8%. Further, the presence of possible alkane hydroxylase genes (alkB and rubA) in the strain MK2 indicated that the genes involved in hydrocarbon degradation are of diverse origin. Such observations demonstrated the potential of facultative hydrocarbon degradation in contaminated environments. Identification of such a novel petrochemical hydrocarbon degrading ERB is likely to offer a new route to the sustainable bioremedial process of source zone contamination with simultaneous energy generation through MERS. PMID- 28018303 TI - Evolutionary Cell Biology of Division Mode in the Bacterial Planctomycetes Verrucomicrobia- Chlamydiae Superphylum. AB - Bacteria from the Planctomycetes, Verrucomicrobia, and Chlamydiae (PVC) superphylum are exceptions to the otherwise dominant mode of division by binary fission, which is based on the interaction between the FtsZ protein and the peptidoglycan (PG) biosynthesis machinery. Some PVC bacteria are deprived of the FtsZ protein and were also thought to lack PG. How these bacteria divide is still one of the major mysteries of microbiology. The presence of PG has recently been revealed in Planctomycetes and Chlamydiae, and proteins related to PG synthesis have been shown to be implicated in the division process in Chlamydiae, providing important insights into PVC mechanisms of division. Here, we review the historical lack of observation of PG in PVC bacteria, its recent detection in two phyla and its involvement in chlamydial cell division. Based on the detection of PG-related proteins in PVC proteomes, we consider the possible evolution of the diverse division mechanisms in these bacteria. We conclude by summarizing what is known and what remains to be understood about the evolutionary cell biology of PVC division modes. PMID- 28018305 TI - Inoculation of Soil with Plant Growth Promoting Bacteria Producing 1 Aminocyclopropane-1-Carboxylate Deaminase or Expression of the Corresponding acdS Gene in Transgenic Plants Increases Salinity Tolerance in Camelina sativa. AB - Camelina sativa (camelina) is an oilseed crop touted for use on marginal lands; however, it is no more tolerant of soil salinity than traditional crops, such as canola. Plant growth-promoting bacteria (PGPB) that produce 1-aminocyclopropane-1 carboxylate deaminase (ACC deaminase) facilitate plant growth in the presence of abiotic stresses by reducing stress ethylene. Rhizospheric and endophytic PGPB and the corresponding acdS- mutants of the latter were examined for their ability to enhance tolerance to salt in camelina. Stimulation of growth and tolerance to salt was correlated with ACC deaminase production. Inoculation of soil with wild type PGPB led to increased shoot length in the absence of salt, and increased seed production by approximately 30-50% under moderately saline conditions. The effect of ACC deaminase was further examined in transgenic camelina expressing a bacterial gene encoding ACC deaminase (acdS) under the regulation of the CaMV 35S promoter or the root-specific rolD promoter. Lines expressing acdS, in particular those using the rolD promoter, showed less decline in root length and weight, increased seed production, better seed quality and higher levels of seed oil production under salt stress. This study clearly demonstrates the potential benefit of using either PGPB that produce ACC deaminase or transgenic plants expressing the acdS gene under the control of a root-specific promoter to facilitate plant growth, seed production and seed quality on land that is not normally suitable for the majority of crops due to high salt content. PMID- 28018306 TI - The Plant as Metaorganism and Research on Next-Generation Systemic Pesticides - Prospects and Challenges. AB - Systemic pesticides (SPs) are usually recommended for soil treatments and as seed coating agents and are taken up from the soil by involving various plant-mediated processes, physiological, and morphological attributes of the root systems. Microscopic insights and next-generation sequencing combined with bioinformatics allow us now to identify new functions and interactions of plant-associated bacteria and perceive plants as meta-organisms. Host symbiotic, rhizo-epiphytic, endophytic microorganisms and their functions on plants have not been studied yet in accordance with uptake, tanslocation and action of pesticides. Root tips exudates mediated by rhizobacteria could modify the uptake of specific pesticides while bacterial ligands and enzymes can affect metabolism and fate of pesticide within plant. Over expression of specific proteins in cell membrane can also modify pesticide influx in roots. Moreover, proteins and other membrane compartments are usually involved in pesticide modes of action and resistance development. In this article it is discussed what is known of the physiological attributes including apoplastic, symplastic, and trans-membrane transport of SPs in accordance with the intercommunication dictated by plant-microbe, cell to cell and intracellular signaling. Prospects and challenges for uptake, translocation, storage, exudation, metabolism, and action of SPs are given through the prism of new insights of plant microbiome. Interactions of soil applied pesticides with physiological processes, plant root exudates and plant microbiome are summarized to scrutinize challenges for the next-generation pesticides. PMID- 28018307 TI - Variable Effects of Non-steroidal Anti-inflammatory Drugs (NSAIDs) on Selected Biochemical Processes Mediated by Soil Microorganisms. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used group of pharmaceuticals. The high consumption and the uncontrolled disposal of unused drugs into municipal waste or their deposit in landfills can result in an increased concentration of these compounds in soils. Moreover, these drugs can affect the microbial activity. However, there is a lack of knowledge about these effects or it is very limited. Therefore, the objective of this study was to compare the impact of selected commercially available NSAIDs, i.e., diclofenac (DCF), naproxen (NPX), ibuprofen (IBF) and ketoprofen (KTP), applied at concentrations of 1 and 10 mg/kg soil, on the activity of soil microorganisms during the 90-day experiment. To ascertain this impact, substrate-induced respiration (SIR), soil enzyme activities, i.e., dehydrogenase (DHA), acid and alkaline phosphatases (PHOS-H and PHOS-OH) and urease (URE) as well as changes in the rates of nitrification and ammonification processes were determined. In addition, the number of culturable bacteria and fungi were enumerated. In general, the obtained data showed a significant stimulatory effect of NSAIDs on the microbial activity. Higher concentrations of NSAIDs caused a greater effect, which was observed for SIR, PHOS-H, PHOS-OH, URE, N-NO3- and N-NH4+, even during the whole incubation period. Moreover, the number of heterotrophic bacteria and fungi increased significantly during the experiment, which was probably a consequence of the evolution of specific microorganisms that were capable of degrading NSAIDs and used them as an additional source of carbon and energy. However, an inhibitory effect of NPX, IBF or KTP for SIR, DHA, on both phosphatases and culturable bacteria and fungi was observed at the beginning of the experiment. At lower concentrations of NSAIDs, in turn, the effects were negligible or transient. In conclusion, the application of NSAIDs altered the biochemical and microbial activity of soil what may cause the disturbance in soil functioning. It is reasonable to assume that some components of the NSAID formulations could stimulate soil microorganisms, thus resulting in an increase in biochemical activities of the soil. PMID- 28018308 TI - Natural and Synthetic Variants of the Tricarboxylic Acid Cycle in Cyanobacteria: Introduction of the GABA Shunt into Synechococcus sp. PCC 7002. AB - For nearly half a century, it was believed that cyanobacteria had an incomplete tricarboxylic acid (TCA) cycle, because 2-oxoglutarate dehydrogenase (2-OGDH) was missing. Recently, a bypass route via succinic semialdehyde (SSA), which utilizes 2-oxoglutarate decarboxylase (OgdA) and succinic semialdehyde dehydrogenase (SsaD) to convert 2-oxoglutarate (2-OG) into succinate, was identified, thus completing the TCA cycle in most cyanobacteria. In addition to the recently characterized glyoxylate shunt that occurs in a few of cyanobacteria, the existence of a third variant of the TCA cycle connecting these metabolites, the gamma-aminobutyric acid (GABA) shunt, was considered to be ambiguous because the GABA aminotransferase is missing in many cyanobacteria. In this study we isolated and biochemically characterized the enzymes of the GABA shunt. We show that N acetylornithine aminotransferase (ArgD) can function as a GABA aminotransferase and that, together with glutamate decarboxylase (GadA), it can complete a functional GABA shunt. To prove the connectivity between the OgdA/SsaD bypass and the GABA shunt, the gadA gene from Synechocystis sp. PCC 6803 was heterologously expressed in Synechococcus sp. PCC 7002, which naturally lacks this enzyme. Metabolite profiling of seven Synechococcus sp. PCC 7002 mutant strains related to these two routes to succinate were investigated and proved the functional connectivity. Metabolite profiling also indicated that, compared to the OgdA/SsaD shunt, the GABA shunt was less efficient in converting 2-OG to SSA in Synechococcus sp. PCC 7002. The metabolic profiling study of these two TCA cycle variants provides new insights into carbon metabolism as well as evolution of the TCA cycle in cyanobacteria. PMID- 28018309 TI - Cyanobacteria in Sulfidic Spring Microbial Mats Can Perform Oxygenic and Anoxygenic Photosynthesis Simultaneously during an Entire Diurnal Period. AB - We used microsensors to study the regulation of anoxygenic and oxygenic photosynthesis (AP and OP, respectively) by light and sulfide in a cyanobacterium dominating microbial mats from cold sulfidic springs. Both photosynthetic modes were performed simultaneously over all H2S concentrations (1-2200 MUM) and irradiances (4-52 MUmol photons m-2 s-1) tested. AP increased with H2S concentration while the sum of oxygenic and anoxygenic photosynthetic rates was constant at each light intensity. Thus, the total photosynthetically driven electron transport rate was solely controlled by the irradiance level. The partitioning between the rates of these two photosynthetic modes was regulated by both light and H2S concentration. The plastoquinone pool (PQ) receives electrons from sulfide:quinone:reductase (SQR) in AP and from photosystem II (PSII) in OP. It is thus the link in the electron transport chain where both pathways intersect, and the compound that controls their partitioning. We fitted our data with a model of the photosynthetic electron transport that includes the kinetics of plastoquinone reduction and oxidation. The model results confirmed that the observed partitioning between photosynthetic modes can be explained by a simple kinetic control based on the affinity of SQR and PSII toward PQ. The SQR enzyme and PSII have similar affinities toward PQ, which explains the concurrent OP and AP over an astonishingly wide range of H2S concentrations and irradiances. The elegant kinetic control of activity makes the cyanobacterium successful in the fluctuating spring environment. We discuss how these specific regulation mechanisms may have played a role in ancient H2S-rich oceans. PMID- 28018310 TI - Response: Commentary: Morphologically Distinct Escherichia coli Bacteriophages Differ in Their Efficacy and Ability to Stimulate Cytokine Release In Vitro. PMID- 28018311 TI - Microbial Community Structure and Function of Soil Following Ecosystem Conversion from Native Forests to Teak Plantation Forests. AB - Soil microbial communities can form links between forest trees and functioning of forest soils, yet the impacts of converting diverse native forests to monoculture plantations on soil microbial communities are limited. This study tested the hypothesis that conversion from a diverse native to monoculture ecosystem would be paralleled by a reduction in the diversity of the soil microbial communities. Soils from Teak (Tectona grandis) plantations and adjacent native forest were examined at two locations in Trinidad. Microbial community structure was determined via Illumina sequencing of bacterial 16S rRNA genes and fungal internal transcribed spacer (ITS) regions, and by phospholipid fatty acid (PLFA) analysis. Functional characteristics of microbial communities were assessed by extracellular enzyme activity (EEA). Conversion to Teak plantation had no effect on species richness or evenness of bacterial or fungal communities, and no significant effect on EEA. However, multivariate analyses (nested and two-way crossed analysis of similarity) revealed significant effects (p < 0.05) of forest type (Teak vs. native) upon the composition of the microbial communities as reflected in all three assays of community structure. Univariate analysis of variance identified two bacterial phyla that were significantly more abundant in the native forest soils than in Teak soils (Cyanobacteria, p = 0.0180; Nitrospirae, p = 0.0100) and two more abundant in Teak soils than in native forest (candidate phyla TM7, p = 0.0004; WS6, p = 0.044). Abundance of an unidentified class of arbuscular mycorrhizal fungi (AMF) was significantly greater in Teak soils, notable because Teak is colonized by AMF rather than by ectomycorrihzal fungi that are symbionts of the native forest tree species. In conclusion, microbial diversity indices were not affected in the conversion of native forest to teak plantation, but examination of specific bacterial taxa showed that there were significant differences in community composition. PMID- 28018312 TI - Enzyme-Mediated Quenching of the Pseudomonas Quinolone Signal (PQS) Promotes Biofilm Formation of Pseudomonas aeruginosa by Increasing Iron Availability. AB - The 2-alkyl-3-hydroxy-4(1H)-quinolone 2,4-dioxygenase HodC was previously described to cleave the Pseudomonas quinolone signal, PQS, which is exclusively used in the complex quorum sensing (QS) system of Pseudomonas aeruginosa, an opportunistic pathogen employing QS to regulate virulence and biofilm development. Degradation of PQS by exogenous addition of HodC to planktonic cells of P. aeruginosa attenuated production of virulence factors, and reduced virulence in planta. However, proteolytic cleavage reduced the efficacy of HodC. Here, we identified the secreted protease LasB of P. aeruginosa to be responsible for HodC degradation. In static biofilms of the P. aeruginosa PA14 lasB::Tn mutant, the catalytic activity of HodC led to an increase in viable biomass in newly formed but also in established biofilms, and reduced the expression of genes involved in iron metabolism and siderophore production, such as pvdS, pvdL, pvdA, and pvdQ. This is likely due to an increase in the levels of bioavailable iron by degradation of PQS, which is able to sequester iron from the surrounding environment. Thus, HodC, despite its ability to quench the production of virulence factors, is contraindicated for combating P. aeruginosa biofilms. PMID- 28018313 TI - Outer Membrane Vesicles and Soluble Factors Released by Probiotic Escherichia coli Nissle 1917 and Commensal ECOR63 Enhance Barrier Function by Regulating Expression of Tight Junction Proteins in Intestinal Epithelial Cells. AB - The gastrointestinal epithelial layer forms a physical and biochemical barrier that maintains the segregation between host and intestinal microbiota. The integrity of this barrier is critical in maintaining homeostasis in the body and its dysfunction is linked to a variety of illnesses, especially inflammatory bowel disease. Gut microbes, and particularly probiotic bacteria, modulate the barrier integrity by reducing gut permeability and reinforcing tight junctions. Probiotic Escherichia coli Nissle 1917 (EcN) is a good colonizer of the human gut with proven therapeutic efficacy in the remission of ulcerative colitis in humans. EcN positively modulates the intestinal epithelial barrier through upregulation and redistribution of the tight junction proteins ZO-1, ZO-2 and claudin-14. Upregulation of claudin-14 has been attributed to the secreted protein TcpC. Whether regulation of ZO-1 and ZO-2 is mediated by EcN secreted factors remains unknown. The aim of this study was to explore whether outer membrane vesicles (OMVs) released by EcN strengthen the epithelial barrier. This study includes other E. coli strains of human intestinal origin that contain the tcpC gene, such as ECOR63. Cell-free supernatants collected from the wild-type strains and from the derived tcpC mutants were fractionated into isolated OMVs and soluble secreted factors. The impact of these extracellular fractions on the epithelial barrier was evaluated by measuring transepithelial resistance and expression of several tight junction proteins in T-84 and Caco-2 polarized monolayers. Our results show that the strengthening activity of EcN and ECOR63 does not exclusively depend on TcpC. Both OMVs and soluble factors secreted by these strains promote upregulation of ZO-1 and claudin-14, and down-regulation of claudin-2. The OMVs-mediated effects are TcpC-independent. Soluble secreted TcpC contributes to the upregulation of ZO-1 and claudin-14, but this protein has no effect on the transcriptional regulation of claudin-2. Thus, in addition to OMVs and TcpC, other active factors released by these microbiota strains contribute to the reinforcement of the epithelial barrier. PMID- 28018314 TI - Impact and Influence of the Natural Vibrio-Squid Symbiosis in Understanding Bacterial-Animal Interactions. AB - Animals are colonized by bacteria, and in many cases partners have co-evolved to perform mutually beneficial functions. An exciting and ongoing legacy of the past decade has been an expansion of technology to enable study of natural associations in situ/in vivo. As a result, more symbioses are being examined, and additional details are being revealed for well-studied systems with a focus on the interactions between partners in the native context. With this framing, we review recent literature from the Vibrio fischeri-Euprymna scolopes symbiosis and focus on key studies that have had an impact on understanding bacteria-animal interactions broadly. This is not intended to be a comprehensive review of the system, but rather to focus on particular studies that have excelled at moving from pattern to process in facilitating an understanding of the molecular basis to intriguing observations in the field of host-microbe interactions. In this review we discuss the following topics: processes regulating strain and species specificity; bacterial signaling to host morphogenesis; multiple roles for nitric oxide; flagellar motility and chemotaxis; and efforts to understand unannotated and poorly annotated genes. Overall these studies demonstrate how functional approaches in vivo in a tractable system have provided valuable insight into general principles of microbe-host interactions. PMID- 28018315 TI - Addressing the Antibiotic Resistance Problem with Probiotics: Reducing the Risk of Its Double-Edged Sword Effect. AB - Antibiotic resistance is a global public health problem that requires our attention. Indiscriminate antibiotic use is a major contributor in the introduction of selective pressures in our natural environments that have significantly contributed in the rapid emergence of antibiotic-resistant microbial strains. The use of probiotics in lieu of antibiotic therapy to address certain health conditions in both animals and humans may alleviate these antibiotic-mediated selective pressures. Probiotic use is defined as the actual application of live beneficial microbes to obtain a desired outcome by preventing diseased state or improving general health. Multiple studies have confirmed the beneficial effects of probiotic use in the health of both livestock and humans. As such, probiotics consumption is gaining popularity worldwide. However, concerns have been raised in the use of some probiotics strains that carry antibiotic resistance genes themselves, as they have the potential to pass the antibiotic resistance genes to pathogenic bacteria through horizontal gene transfer. Therefore, with the current public health concern on antibiotic resistance globally, in this review, we underscore the need to screen probiotic strains that are used in both livestock and human applications to assure their safety and mitigate their potential in significantly contributing to the spread of antibiotic resistance genes in our natural environments. PMID- 28018316 TI - Leveraging the Attributes of Mucor hiemalis-Derived Silver Nanoparticles for a Synergistic Broad-Spectrum Antimicrobial Platform. AB - Driven by the need to engineer robust surface coatings for medical devices to prevent infection and sepsis, incorporation of nanoparticles has surfaced as a promising avenue to enhance non-fouling efficacy. Microbial synthesis of such nanoscale metallic structures is of substantive interest as this can offer an eco friendly, cost-effective, and sustainable route for further development. Here we present a Mucor hiemalis-derived fungal route for synthesis of silver nanoparticles, which display significant antimicrobial properties when tested against six pathological bacterial strains (Klebsiella pneumoniae, Pseudomonas brassicacearum, Aeromonas hydrophila, Escherichia coli, Bacillus cereus, and Staphylococcus aureus) and three pathological fungal strains (Candida albicans, Fusarium oxysporum, and Aspergillus flavus). These antimicrobial attributes were comparable to those of established antibiotics (streptomycin, tetracycline, kanamycin, and rifampicin) and fungicides (amphotericin B, fluconazole, and ketoconazole), respectively. Importantly, these nanoparticles show significant synergistic characteristics when combined with the antibiotics and fungicides to offer substantially greater resistance to microbial growth. The blend of antibacterial and antifungal properties, coupled with their intrinsic "green" and facile synthesis, makes these biogenic nanoparticles particularly attractive for future applications in nanomedicine ranging from topical ointments and bandages for wound healing to coated stents. PMID- 28018317 TI - Environmental Viral Metagenomics Analyses in Aquaculture: Applications in Epidemiology and Disease Control. AB - Studies on the epidemiology of viral diseases in aquaculture have for a long time depended on isolation of viruses from infected aquatic organisms. The role of aquatic environments in the epidemiology of viral diseases in aquaculture has not been extensively expounded mainly because of the lack of appropriate tools for environmental studies on aquatic viruses. However, the upcoming of metagenomics analyses opens great avenues in which environmental samples can be used to study the epidemiology of viral diseases outside their host species. Hence, in this review I have shown that epidemiological factors that influence the composition of viruses in different aquatic environments include ecological factors, anthropogenic activities and stocking densities of cultured organisms based on environmental metagenomics studies carried out this far. Ballast water transportation and global trade of aquatic organisms are the most common virus dispersal process identified this far. In terms of disease control for outdoor aquaculture systems, baseline data on viruses found in different environments intended for aquaculture use can be obtained to enable the design of effective disease control strategies. And as such, high-risk areas having a high specter of pathogenic viruses can be identified as an early warning system. As for the control of viral diseases for indoor recirculation aquaculture systems (RAS), the most effective disinfection methods able to eliminate pathogenic viruses from water used in RAS can be identified. Overall, the synopsis I have put forth in this review shows that environmental samples can be used to study the epidemiology of viral diseases in aquaculture using viral metagenomics analysis as an overture for the design of rational disease control strategies. PMID- 28018319 TI - Effect of Endophyte Infection and Clipping Treatment on Resistance and Tolerance of Achnatherum sibiricum. AB - It is well-documented that endophytes can enhance the resistance of agronomical grasses, such as tall fescue and perennial ryegrass to herbivory. For native grasses, however, the related reports are limited, and the conclusions are variable. Achnatherum sibiricum is a grass native to the Inner Mongolian steppe. This grass is highly infected by endophytes but does not produce detectable endophyte-related alkaloids known under normal conditions. In this study, the contributions of endophytes to the resistance of A. sibiricum to Locusta migratoria were studied. We found that locusts preferred EF (endophyte-free) plants to EI (endophyte-infected) plants, and the weight of locusts fed on EI plants was significantly lower than those fed on EF plants. Hence, endophyte infection significantly enhanced the resistance of the host to L. migratoria. Endophyte infection significantly decreased the concentration of soluble sugar and amino acids while significantly increased the concentration of total phenolic content, and these metabolites may contribute to herbivore resistance of the host. The clipping treatment further strengthened the locust resistance advantage of EI over EF plants. After clipping, the weight of the locusts fed on EI plants significantly decreased compared with those fed on unclipped plants, whereas the weight of the locusts fed on EF plants increased significantly. The results suggested that endophyte infection could increase herbivore resistance while decreasing the tolerance of the host grass by mechanisms apart from endophyte conferred alkaloid defense. PMID- 28018318 TI - COX-2 Inhibition Reduces Brucella Bacterial Burden in Draining Lymph Nodes. AB - Brucella is a Gram-negative facultative intracellular bacterium responsible for a chronic disease known as brucellosis, the most widespread re-emerging zoonosis worldwide. Establishment of a Th1-mediated immune response characterized by the production of IL-12 and IFNgamma is essential to control the disease. Leukotrienes derived from arachidonic acid (AA) metabolism are known to negatively regulate a protective Th1 immune response against bacterial infections. Here, using genomics approaches we demonstrate that Brucella abortus strongly stimulates the prostaglandin (PG) pathway in dendritic cells (DC). We also show an induction of AA production by infected cells. This correlates with the expression of Ptgs2, a gene encoding the downstream cyclooxygenase-2 (COX-2) enzyme in infected DC. By comparing different infection routes (oral, intradermal, intranasal and conjunctival), we identified the intradermal inoculation route as the more potent in inducing Ptgs2 expression but also in inducing a local inflammatory response in the draining cervical lymph nodes (CLN). NS-398, a specific inhibitor of COX-2 enzymatic activity decreased B. melitensis burden in the CLN after intradermal infection. This effect was accompanied by a decrease of Il10 and a concomitant increase of Ifng expression. Altogether, these results suggest that Brucella has evolved to take advantage of the PG pathway in the harsh environment of the CLN in order to persist and subvert immune responses. This work also proposes that novel strategies to control brucellosis may include the use of COX-2 inhibitors. PMID- 28018320 TI - Single-Molecule Sequencing (PacBio) of the Staphylococcus capitis NRCS-A Clone Reveals the Basis of Multidrug Resistance and Adaptation to the Neonatal Intensive Care Unit Environment. AB - The multi-resistant Staphylococcus capitis clone NRCS-A has recently been described as a major pathogen causing nosocomial, late-onset sepsis (LOS) in preterm neonates worldwide. NRCS-A representatives exhibit an atypical antibiotic resistance profile. Here, the complete closed genome (chromosomal and plasmid sequences) of NRCS-A prototype strain CR01 and the draft genomes of three other clinical NRCS-A strains from Australia, Belgium and the United Kingdom are annotated and compared to available non-NRCS-A S. capitis genomes. Our goal was to delineate the uniqueness of the NRCS-A clone with respect to antibiotic resistance, virulence factors and mobile genetic elements. We identified 6 antimicrobial resistance genes, all carried by mobile genetic elements. Previously described virulence genes present in the NRCS-A genomes are shared with the six non-NRCS-A S. capitis genomes. Overall, 63 genes are specific to the NRCS-A lineage, including 28 genes located in the methicillin-resistance cassette SCCmec. Among the 35 remaining genes, 25 are of unknown function, and 9 correspond to an additional type I restriction modification system (n = 3), a cytosine methylation operon (n = 2), and a cluster of genes related to the biosynthesis of teichoic acids (n = 4). Interestingly, a tenth gene corresponds to a resistance determinant for nisin (nsr gene), a bacteriocin secreted by potential NRCS-A strain niche competitors in the gut microbiota. The genomic characteristics presented here emphasize the contribution of mobile genetic elements to the emergence of multidrug resistance in the S. capitis NRCS-A clone. No NRCS-A-specific known virulence determinant was detected, which does not support a role for virulence as a driving force of NRCS-A emergence in NICUs worldwide. However, the presence of a nisin resistance determinant on the NRCS-A chromosome, but not in other S. capitis strains and most coagulase-negative representatives, might confer a competitive advantage to NRCS-A strains during the early steps of gut colonization in neonates. This suggests that the striking adaptation of NRCS-A to the NICU environment might be related to its specific antimicrobial resistance and also to a possible enhanced ability to challenge competing bacteria in its ecological niche. PMID- 28018321 TI - CpG Oligodeoxynucleotides Induce Differential Cytokine and Chemokine Gene Expression Profiles in Dapulian and Landrace Pigs. AB - Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) mimic the immunostimulatory activity of microbial DNA by interacting with Toll-like receptor 9 (TLR9) to activate both the innate and adaptive immune responses in different species. However, few studies have been published to compare the effects of CpG ODN on different pig breeds. Therefore, in this study, whole blood gene expression profiles of DPL and Landrace pigs treated with CpG ODN were studied using RNA-seq technology. Five Hundred differentially expressed genes (DEGs) were identified between the two breeds. DPL pigs had significantly higher number of immune-relevant DEGs than the Landrace pigs after CpG ODN treatment. Pathway analysis showed that cytokine-cytokine receptor interaction and chemokine signaling pathway were the major enriched pathways of the immune-relevant DEGs. Further in vitro experiments showed that PBMCs of the DPL pigs had significantly higher levels of TLR9 mRNA than those of the Landrace pigs, both before and after CpG ODN stimulation. Cytokine and chemokine induction in the PBMCs of both breeds were also measured after CpG ODN stimulation. Our data showed that mRNA levels of cytokines (IFNalpha, IL8, IL12 p40) and chemokines (CXCL9, CXCL13) were significantly higher in the PBMCs of the DPL pigs than those of the Landrace pigs. Taken together, our data provide new information regarding the pig breed difference in response to CpG ODN stimulation and that higher levels of TLR9 mRNA in DPL pigs may be a major contributor for disease resistance. PMID- 28018322 TI - Potential for Nitrogen Fixation in the Fungus-Growing Termite Symbiosis. AB - Termites host a gut microbiota of diverse and essential symbionts that enable specialization on dead plant material; an abundant, but nutritionally imbalanced food source. To supplement the severe shortage of dietary nitrogen (N), some termite species make use of diazotrophic bacteria to fix atmospheric nitrogen (N2). Fungus-growing termites (subfamily Macrotermitinae) host a fungal exosymbiont (genus Termitomyces) that provides digestive services and the main food source for the termites. This has been thought to obviate the need for N2 fixation by bacterial symbionts. Here, we challenge this notion by performing acetylene reduction assays of live colony material to show that N2 fixation is present in two major genera (Macrotermes and Odontotermes) of fungus-growing termites. We compare and discuss fixation rates in relation to those obtained from other termites, and suggest avenues of research that may lead to a better understanding of N2 fixation in fungus-growing and other termites. PMID- 28018323 TI - Genetic Drivers of Multidrug Resistance in Candida glabrata. AB - Both the incidence of invasive fungal infections and rates of multidrug resistance associated with fungal pathogen Candida glabrata have increased in recent years. In this perspective, we will discuss the mechanisms underlying the capacity of C. glabrata to rapidly develop resistance to multiple drug classes, including triazoles and echinocandins. We will focus on the extensive genetic diversity among clinical isolates of C. glabrata, which likely enables this yeast to survive multiple stressors, such as immune pressure and antifungal exposure. In particular, over half of C. glabrata clinical strains collected from U.S. and non-U.S. sites have mutations in the DNA mismatch repair gene MSH2, leading to a mutator phenotype and increased frequencies of drug-resistant mutants in vitro. Furthermore, recent studies and data presented here document extensive chromosomal rearrangements among C. glabrata strains, resulting in a large number of distinct karyotypes within a single species. By analyzing clonal, serial isolates derived from individual patients treated with antifungal drugs, we were able to document chromosomal changes occurring in C. glabrata in vivo during the course of antifungal treatment. Interestingly, we also show that both MSH2 genotypes and chromosomal patterns cluster consistently into specific strain types, indicating that C. glabrata has a complex population structure where genomic variants arise, perhaps during the process of adaptation to environmental changes, and persist over time. PMID- 28018324 TI - Abundance of Common Aerobic Anoxygenic Phototrophic Bacteria in a Coastal Aquaculture Area. AB - Aerobic anoxygenic phototrophic bacteria (AAnPB) rely on not only heterotrophic but also phototrophic energy gain. AAnPB are known to have high abundance in oligotrophic waters and are the major portion of the bacterial carbon stock in the environment. In a yearlong study in an aquaculture area in the Uwa Sea, Japan, AAnPB, accounted for 4.7 to 24% of the total bacteria by count. Since the cell volume of AAnPB is 2.23 +/- 0.674 times larger than the mean for total bacteria, AAnPB biomass is estimated to account for 10-53% of the total bacterial assemblage. By examining pufM gene sequence, a common phylogenetic AAnPB species was found in all sampling sites through the year. The common species and other season-specific species were phylogenetically close to unculturable clones recorded in the Sargasso Sea and Pacific Ocean. The present study suggests that the common species may be a cosmopolitan species with worldwide distribution that is abundant not only in the oligotrophic open ocean but also in eutrophic aquaculture areas. PMID- 28018325 TI - Sensitive Quantitative Analysis of the Meconium Bacterial Microbiota in Healthy Term Infants Born Vaginally or by Cesarean Section. AB - For decades, babies were thought to be born germ-free, but recent evidences suggest that they are already exposed to various bacteria in utero. However, the data on population levels of such pioneer gut bacteria, particularly in context to birth mode, is sparse. We herein aimed to quantify such bacteria from the meconium of 151 healthy term Japanese infants born vaginally or by C-section. Neonatal first meconium was obtained within 24-48 h of delivery; RNA was extracted and subjected to reverse-transcription-quantitative PCR using specific primers for Clostridium coccoides group, C. leptum subgroup, Bacteroides fragilis group, Atopobium cluster, Prevotella, Bifidobacterium, Lactobacillus, Enterococcus, Enterobacteriaceae, Staphylococcus, Enterococcus, Streptococcus, C. perfringens, and C. difficile. We detected several bacterial groups in both vaginally- and cesarean-born infants. B. fragilis group, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were detected in more than 50% of infants, with counts ranging from 105 to 108 cells/g sample. About 30-35% samples harbored Bifidobacterium and Lactobacillus (104-105 cells/g); whereas C. coccoides group, C. leptum subgroup and C. perfringens were detected in 10-20% infants (103-105 cells/g). Compared to vaginally-born babies, cesarean-born babies were significantly less often colonized with Lactobacillus genus (6% vs. 37%; P = 0.01) and Lactobacillus gasseri subgroup (6% vs. 31%; P = 0.04). Overall, seven Lactobacillus subgroups/species, i.e., L. gasseri subgroup, L. ruminis subgroup, L. casei subgroup, L. reuteri subgroup, L. sakei subgroup, L. plantarum subgroup, and L. brevis were detected in the samples from vaginally born group, whereas only two members, i.e., L. gasseri subgroup and L. brevis were detected in the cesarean group. These data corroborate that several bacterial clades may already be present before birth in term infants' gut. Further, lower detection rate of lactobacilli in cesarean-born babies suggests that the primary source of lactobacilli in infant gut is mainly from maternal vaginal and-to a lesser extent-anal microbiota during vaginal delivery, and that the colonization by some important Lactobacillus species is delayed in babies delivered via cesarean-section. PMID- 28018326 TI - Pseudomonas aeruginosa Enolase Influences Bacterial Tolerance to Oxidative Stresses and Virulence. AB - Pseudomonas aeruginosa is a Gram negative opportunistic pathogenic bacterium, which causes acute and chronic infections. Upon entering the host, bacteria alter global gene expression to adapt to host environment and avoid clearance by the host. Enolase is a glycolytic enzyme involved in carbon metabolism. It is also a component of RNA degradosome, which is involved in RNA processing and gene regulation. Here, we report that enolase is required for the virulence of P. aeruginosa in a murine acute pneumonia model. Mutation of enolase coding gene (eno) increased bacterial susceptibility to neutrophil mediated killing, which is due to reduced tolerance to oxidative stress. Catalases and alkyl hydroperoxide reductases play a major role in protecting the cell from oxidative damages. In the eno mutant, the expression levels of catalases (KatA and KatB) were similar as those in the wild type strain in the presence of H2O2, however, the expression levels of alkyl hydroperoxide reductases (AhpB and AhpC) were significantly reduced. Overexpression of ahpB but not ahpC in the eno mutant fully restored the bacterial resistance to H2O2 as well as neutrophil mediated killing, and partially restored bacterial virulence in the murine acute pneumonia model. Therefore, we have identified a novel role of enolase in the virulence of P. aeruginosa. PMID- 28018327 TI - Correlation of Gut Microbiota Composition with Resistance to Experimental Autoimmune Encephalomyelitis in Rats. AB - Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS). It is widely accepted that autoimmune response against the antigens of the CNS is the essential pathogenic force in the disease. It has recently become increasingly appreciated that activated encephalitogenic cells tend to migrate toward gut associated lymphoid tissues (GALTs) and that interrupted balance between regulatory and inflammatory immunity within the GALT might have decisive role in the initiation and propagation of the CNS autoimmunity. Gut microbiota composition and function has the major impact on the balance in the GALT. Thus, our aim was to perform analyses of gut microbiota in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Albino Oxford (AO) rats that are highly resistant to EAE induction and Dark Agouti (DA) rats that develop EAE after mild immunization were compared for gut microbiota composition in different phases after EAE induction. Microbial analyses of the genus Lactobacillus and related lactic acid bacteria showed higher diversity of Lactobacillus spp. in EAE-resistant AO rats, while some members of Firmicutes and Proteobacteria (Undibacterium oligocarboniphilum) were detected only in feces of DA rats at the peak of the disease (between 13 and 16 days after induction). Interestingly, in contrast to our previous study where Turicibacter sp. was found exclusively in non-immunized AO, but not in DA rats, in this study it was detected in DA rats that remained healthy 16 days after induction, as well as in four of 12 DA rats at the peak of the disease. Similar observation was obtained for the members of Lachnospiraceae. Further, production of a typical regulatory cytokine interleukin-10 was compared in GALT cells of AO and DA rats, and higher production was observed in DA rats. Our data contribute to the idea that gut microbiota and GALT considerably influence multiple sclerosis pathogenesis. PMID- 28018328 TI - A Mechanism of Synergistic Effect of Streptomycin and Cefotaxime on CTX-M-15 Type beta-lactamase Producing Strain of E. cloacae: A First Report. AB - A blaCTX-M-15 gene is one of the most prevalent resistant marker found in member of enterobacteriaceae. It encodes cefotaxime hydrolysing beta-lactamase-15 (CTX-M 15) causing resistance against beta lactam antibiotics. Since single antibiotic therapy fails to control infection caused by multidrug resistance strain, therefore combination therapy was came into practice as an effective treatment. We have first time explained the mechanism where two antibiotics of different classes work against resistant strains. Binding parameters obtained by spectroscopic approach showed significant interaction and complex formation between drugs and CTX-M-15 enzyme with decreased ksv and kq values. CD analysis showed altered conformation and significant changes in alpha helical content of CTX-M-15 enzyme on interaction with streptomycin in combination with cephalosporin. Steady state kinetics revealed decrease in hydrolytic efficiency of enzyme to about 27% by cooperative binding behavior upon sequential treatment of enzyme with streptomycin and cefotaxime. Therefore, the study concludes that combination therapy against CTX-M-15 producing strain with Cefotaxime/Streptomycin in 1:10 molar ratio, decreases CTX-M-15 efficiency significantly because of the fact that streptomycin induced structural changes in CTX-M-15 hence cefotaxime was not properly bound on its active site for hydrolysis rather available for the target to inhibit bacterial cells. PMID- 28018329 TI - Propidium Monoazide Integrated with qPCR Enables the Detection and Enumeration of Infectious Enteric RNA and DNA Viruses in Clam and Fermented Sausages. AB - The increase of foodborne viral outbreaks highlights the need for a rapid and sensitive method for the prediction of viral infectivity in food samples. This study assesses the use of propidium monoazide (PMA) coupled with real-time PCR methods (RT-qPCR or qPCR for RNA or DNA viruses, respectively) in the determination of viral infectivity in complex animal-related food matrices. Clam and Spanish fermented sausage ("chorizo") samples were spiked with infectious and heat-inactivated human adenovirus-2 (HAdV-2) and mengovirus (vMC0). PMA-qPCR/RT qPCR discriminated infective virus particles, with significant reductions (>2.7 log10 or 99.7%). Additionally, infectious HAdV-2 and vMC0 were quantified by plaque assay (in plaque forming units, PFU), and compared with those in virus genomes copies (GCs) quantified by PMA-qPCR/RT-qPCR. A consistent correlation (R2 > 0.92) was showed between PFU and GCs along serial 10-fold dilutions in both DNA and RNA virus and in both food matrices. This study shows the use of PMA coupled to qPCR/RT-qPCR as a promising alternative for prediction of viral infectivity in food samples in comparison to more expensive and time-consuming methods and for those viruses that are not able to grow under available cell culture techniques. PMID- 28018330 TI - Porcine Epidemic Diarrhea Virus Shedding and Antibody Response in Swine Farms: A Longitudinal Study. AB - The porcine epidemic diarrhea virus (PEDV) causes an acute and highly contagious enteric disease characterized by severe enteritis, vomiting, watery diarrhea, and a high mortality rate in seronegative neonatal piglets. In the last few years, PED had a large economic impact on the swine industries in Asia and the US, and in 2014, the PEDV also re-emerged in Europe. Two main PEDV variants circulate worldwide but only the S INDEL variant, considered a mild strain, is spreading in Europe. To gain insights into the pathogenicity of this variant, its viral load and temporal shedding pattern were evaluated in piglets from infected farms. Quantitative real-time PCR (qPCR) targeting the spike gene, was validated according to the minimum information for quantitative real-time PCR experiments guidelines. The qPCR was applied to longitudinal studies conducted in four swine farms naturally infected with the PEDV S INDEL variant. Clinical data, fecal swabs, and blood samples were collected from 103 piglets at 15-30-day intervals for 2-5 months. On all four farms, diarrhea was observed in sows during gestation and in farrowing units, and the mortality rates of piglets were 18, 25, 30, and 35%. Different clinical pictures (0-50% of diarrhea positivity), viral titer levels (mean 5.3-7.2 log10 genome copies/mL), and antibody conditions (30-80% of positivity) were registered among sows on the four farms. The percentage of qPCR positive piglets varied greatly from the beginning (63-100%) to the end (0%) of the infection course. Clinical signs were present in 96% of the qPCR positive animals. Viral loads ranged from 8.5 log10 to 4 log10 genome copies/mL in suckling pigs at 3-6 days of age and were not statistically different among farms, despite the different patterns observed in sows. After 2-3 weeks, only a few piglets still showed detectable viral levels and clinical signs, and they developed antibody responses. Moreover, co-infections with other pathogens and biosecurity procedures limiting the circulation of the virus could have influenced the severity of PED infection. QPCR and clinical data were useful in understanding the dynamics of PEDV infections and, therefore, in implementing appropriate control measures. PMID- 28018331 TI - Construction of a Pan-Genome Allele Database of Salmonella enterica Serovar Enteritidis for Molecular Subtyping and Disease Cluster Identification. AB - We built a pan-genome allele database with 395 genomes of Salmonella enterica serovar Enteritidis and developed computer tools for analysis of whole genome sequencing (WGS) data of bacterial isolates for disease cluster identification. A web server (http://wgmlst.imst.nsysu.edu.tw) was set up with the database and the tools, allowing users to upload WGS data to generate whole genome multilocus sequence typing (wgMLST) profiles and to perform cluster analysis of wgMLST profiles. The usefulness of the database in disease cluster identification was demonstrated by analyzing a panel of genomes from 55 epidemiologically well defined S. Enteritidis isolates provided by the Minnesota Department of Health. The wgMLST-based cluster analysis revealed distinct clades that were concordant with the epidemiologically defined outbreaks. Thus, using a common pan-genome allele database, wgMLST can be a promising WGS-based subtyping approach for disease surveillance and outbreak investigation across laboratories. PMID- 28018332 TI - Commentary: SLAM- and Nectin-4-Independent Noncytolytic Spread of Canine Distemper Virus in Astrocytes. PMID- 28018333 TI - Phenylpyrroles: 30 Years, Two Molecules and (Nearly) No Resistance. AB - Phenylpyrroles are chemical analogs of the natural antifungal compound pyrrolnitrin. Fenpiclonil, but mainly fludioxonil are registered against multiple fungal crop diseases since over 25 years for seed or foliar treatment. They have severe physiological impacts on the pathogen, including membrane hyperpolarization, changes in carbon metabolism and the accumulation of metabolites leading to hyphal swelling and burst. The selection and characterization of mutants resistant to phenylpyrroles have revealed that these fungicides activate the fungal osmotic signal transduction pathway through their perception by a typical fungal hybrid histidine kinase (HHK). The HHK is prone to point mutations that confer fungicide resistance and affect its sensor domain, composed of tandem repeats of HAMP motifs. Fludioxonil resistant mutants have been selected in many fungal species under laboratory conditions. Generally they present severe impacts on fitness parameters. Since only few cases of field resistance specific to phenylpyrroles have been reported one may suspect that the fitness penalty of phenylpyrrole resistance is the reason for the lack of field resistance. PMID- 28018335 TI - Metabolic Conservation and Diversification of Metarhizium Species Correlate with Fungal Host-Specificity. AB - The ascomycete genus Metarhizium contains several species of insect pathogenic fungi ranging from specialists with narrow host ranges to generalists that can infect diverse invertebrates. Genetic and metabolic conservations and diversifications of Metarhizium species are not well understood. In this study, using the genome information of seven Metarhizium species, we performed a comparative analysis of gene clusters involved in secondary metabolisms (SMs) in these species. The results revealed that the generalist species contain more SM gene clusters than the specialists, and that both conserved and divergent evolutions may have occurred in SM genes during fungal speciation. In particular, the loss/gain events, as well as gene mutagenesis, are evident for the gene cluster responsible for the biosynthesis of non-ribosomal cyclopeptide destruxins. The presence of conserved SM gene clusters in Metarhizium and other divergently evolved insect pathogenic fungi implies their link to fungal entomopathogenicity. Mass spectrometry based metabolomic analyses were also conducted to investigate the chemical diversities of seven Metarhizium species. Consistent with the evolutionary relationships of SM genes among the seven species, significant differences are observed in fungal metabolic profiles, whether the same or different metabolites are produced in different species. Clustering analysis based on the metabolome data revealed that Metarhizium species could be grouped based on their association to fungal host specificity. Our metabolomics-based methods also facilitate the identification of bioactive metabolites that have not been reported previously in Metarhizium. The results of this study will benefit future investigations of the chemical biology of insect fungal interactions. PMID- 28018334 TI - Molecular and Proteomic Analysis of Levofloxacin and Metronidazole Resistant Helicobacter pylori. AB - Antibiotic resistance in bacteria incurs fitness cost, but compensatory mechanisms may ameliorate the cost and sustain the resistance even under antibiotics-free conditions. The aim of this study was to determine compensatory mechanisms of antibiotic resistance in H. pylori. Five strains of levofloxacin sensitive H. pylori were induced in vitro to develop resistance. In addition, four pairs of metronidazole-sensitive and -resistant H. pylori strains were isolated from patients carrying dual H. pylori populations that consist of both sensitive and resistant phenotypes. Growth rate, virulence and biofilm-forming ability of the sensitive and resistant strains were compared to determine effects of compensatory response. Proteome profiles of paired sensitive and resistant strains were analyzed by liquid chromatography/mass spectrophotometry (LC/MS). Although there were no significant differences in growth rate between sensitive and resistant pairs, bacterial virulence (in terms of abilities to induce apoptosis and form biofilm) differs from pair to pair. These findings demonstrate the complex and strain-specific phenotypic changes in compensation for antibiotics resistance. Compensation for in vitro induced levofloxacin resistance involving mutations of gyrA and gyrB was functionally random. Furthermore, higher protein translation and non-functional protein degradation capabilities in naturally-occuring dual population metronidazole sensitive-resistant strains may be a possible alternative mechanism underlying resistance to metronidazole without mutations in rdxA and frxA. This may explain the lack of mutations in target genes in ~10% of metronidazole resistant strains. PMID- 28018336 TI - Synergism of Cattle and Bison Inoculum on Ruminal Fermentation and Select Bacterial Communities in an Artificial Rumen (Rusitec) Fed a Barley Straw Based Diet. AB - This study evaluated the effect of increasing the proportion of bison relative to cattle inoculum on fermentation and microbial populations within an artificial rumen (Rusitec). The experiment was a completely randomized design with a factorial treatment structure (proportion cattle:bison inoculum; 0:100, 33:67, 67:33, and 100:0) replicated in two Rusitec apparatuses (n = 8 fermenters). The experiment was 15 d with 8 d of adaptation and 7 d of sampling. Fermenters were fed a diet of 70:30 barley straw:concentrate (DM basis). True digestibility of DM was determined after 48 h of incubation from d 13 to 15, and daily ammonia (NH3) and volatile fatty acid (VFA) production were measured on d 9-12. Protozoa counts were determined at d 9, 11, 13, and 15 and particle-associated bacteria (PAB) from d 13 to 15. Select bacterial populations in the PAB were measured using RT qPCR. Fermenter was considered the experimental unit and day of sampling as a repeated measure. Increasing the proportion of bison inoculum resulted in a quadratic effect (P < 0.05) on straw, concentrate and total true DM disappearance and on straw and total neutral detergent fiber (aNDF) disappearance, with greater disappearances observed with mixed inoculum. There were no effect of source or proportion of inoculum on ADF disappearance (P > 0.05). Increasing bison inoculum linearly increased (P < 0.05) concentrate aNDF disappearance, total and concentrate N disappearance as well as total daily VFA and acetate production. A positive quadratic response (P < 0.05) was observed for daily NH3-N, propionate, butyrate, valerate, isovalerate and isobutyrate production, as well as the acetate:propionate ratio. Increasing the proportion of bison inoculum linearly increased (P < 0.05) total protozoa numbers. No effects were observed on pH, total gas and methane production, microbial N synthesis, or copies of 16S rRNA associated with total bacteria, Selenomonas ruminantium or Prevotella bryantii. Increasing bison inoculum had a quadratic effect (P < 0.05) on Fibrobacter succinogenes, and tended to linearly (P < 0.10) increase Ruminococcus flavefaciens and decrease (P < 0.05) Ruminococcus albus copy numbers. In conclusion, bison inoculum increased the degradation of feed protein and fiber. A mixture of cattle and bison rumen inoculum acted synergistically, increasing the DM and aNDF disappearance of barley straw. PMID- 28018337 TI - Trace Elements Induce Predominance among Methanogenic Activity in Anaerobic Digestion. AB - Trace elements (TE) play an essential role in all organisms due to their functions in enzyme complexes. In anaerobic digesters, control, and supplementation of TEs lead to stable and more efficient methane production processes while TE deficits cause process imbalances. However, the underlying metabolic mechanisms and the adaptation of the affected microbial communities to such deficits are not yet fully understood. Here, we investigated the microbial community dynamics and resulting process changes induced by TE deprivation. Two identical lab-scale continuous stirred tank reactors fed with distiller's grains and supplemented with TEs (cobalt, molybdenum, nickel, tungsten) and a commercial iron additive were operated in parallel. After 72 weeks of identical operation, the feeding regime of one reactor was changed by omitting TE supplements and reducing the amount of iron additive. Both reactors were operated for further 21 weeks. Various process parameters (biogas production and composition, total solids and volatile solids, TE concentration, volatile fatty acids, total ammonium nitrogen, total organic acids/alkalinity ratio, and pH) and the composition and activity of the microbial communities were monitored over the total experimental time. While the methane yield remained stable, the concentrations of hydrogen sulfide, total ammonia nitrogen, and acetate increased in the TE-depleted reactor compared to the well-supplied control reactor. Methanosarcina and Methanoculleus dominated the methanogenic communities in both reactors. However, the activity ratio of these two genera was shown to depend on TE supplementation explainable by different TE requirements of their energy conservation systems. Methanosarcina dominated the well-supplied anaerobic digester, pointing to acetoclastic methanogenesis as the dominant methanogenic pathway. Under TE deprivation, Methanoculleus and thus hydrogenotrophic methanogenesis was favored although Methanosarcina was not overgrown by Methanoculleus. Multivariate statistics revealed that the decline of nickel, cobalt, molybdenum, tungsten, and manganese most strongly influenced the balance of mcrA transcripts from both genera. Hydrogenotrophic methanogens seem to be favored under nickel- and cobalt-deficient conditions as their metabolism requires less nickel-dependent enzymes and corrinoid cofactors than the acetoclastic and methylotrophic pathways. Thus, TE supply is critical to sustain the activity of the versatile high-performance methanogen Methanosarcina. PMID- 28018339 TI - Conceptual Spaces of the Immune System. AB - The immune system can be looked at as a cognitive system. This is often done in analogy to the neuro-psychological system. Here, it is demonstrated that the cognitive functions of the immune system can be properly described within a new theory of cognitive science. Gardenfors' geometrical framework of conceptual spaces is applied to immune cognition. Basic notions, like quality dimensions, natural properties and concepts, similarities, prototypes, saliences, etc., are related to cognitive phenomena of the immune system. Constraints derived from treating the immune system within a cognitive theory, like Gardenfors' conceptual spaces, might well prove to be instrumental for the design of vaccines, immunological diagnostic tests, and immunotherapy. PMID- 28018338 TI - The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. AB - The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD 1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells. PMID- 28018340 TI - Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR. AB - The heterotrimeric globular head (gC1q) domain of human C1q is made up of the C terminal ends of the three individual chains, ghA, ghB, and ghC. A candidate receptor for the gC1q domain is a multi-functional pattern recognition protein, gC1qR. Since understanding of gC1qR and gC1q interaction could provide an insight into the pleiotropic functions of gC1qR, this study was undertaken to identify the gC1qR-binding site on the gC1q domain, using the recombinant ghA, ghB, and ghC modules and their substitution mutants. Our results show that ghA, ghB, and ghC modules can interact with gC1qR independently, thus reinforcing the notion of modularity within the gC1q domain of human C1q. Mutational analysis revealed that while Arg162 in the ghA module is central to interaction between gC1qR and C1q, a single amino acid substitution (arginine to glutamate) in residue 114 of the ghB module resulted in enhanced binding. Expression of gC1qR and C1q in adherent monocytes with or without pro-inflammatory stimuli was also analyzed by qPCR; it showed an autocrine/paracrine basis of C1q and gC1qR interaction. Microscopic studies revealed that C1q and gC1qR are colocalized on PBMCs. Cell proliferation assays indicated that ghA, ghB, and ghC modules were able to attenuate phytohemagglutinin-stimulated proliferation of PBMCs. Addition of gC1qR had an additive effect on the anti-proliferative effect of globular head modules. In summary, our results identify residues involved in C1q-gC1qR interaction and explain, to a certain level, their involvement on the immune cell surface, which is relevant for C1q-induced functions including inflammation, infection, and immunity. PMID- 28018341 TI - Differential CCR7 Targeting in Dendritic Cells by Three Naturally Occurring CC Chemokines. AB - The CCR7 ligands CCL19 and CCL21 are increasingly recognized as functionally different (biased). Using mature human dendritic cells (DCs), we show that CCL19 is more potent than CCL21 in inducing 3D chemotaxis. Intriguingly, CCL21 induces prolonged and more efficient ERK1/2 activation compared with CCL19 and a C terminal truncated (tailless) CCL21 in DCs. In contrast, tailless-CCL21 displays increased potency in DC chemotaxis compared with native CCL21. Using a CCL21 specific antibody, we show that CCL21, but not tailless-CCL21, accumulates at the cell surface. In addition, removal of sialic acid from the cell surface by neuraminidase treatment impairs ERK1/2 activation by CCL21, but not by CCL19 or tailless-CCL21. Using standard laboratory cell lines, we observe low potency of both CCL21 and tailless-CCL21 in G protein activation and beta-arrestin recruitment compared with CCL19, indicating that the tail itself does not improve receptor interaction. Chemokines interact with their receptors in a stepwise manner with ultimate docking of their N-terminus into the main binding pocket. Employing site-directed mutagenesis we identify residues in this pocket of selective CCL21 importance. We also identify a molecular switch in the top of TM7 important for keeping CCR7 in an inactive conformation (Tyr312), as introduction of the chemokine receptor-conserved Glu (or Ala) induces high constitutive activity. Summarized, we show that the interaction of the tail of CCL21 with polysialic acid is needed for strong ERK signaling, whereas it impairs CCL21 mediated chemotaxis and has no impact on receptor docking consistent with the current model of chemokine:receptor interaction. This indicates that future selective pharmacological targeting of CCL19 versus CCL21 should focus on a differential targeting of the main receptor pocket, while selective targeting of tailless-CCL21 versus CCL21 and CCL19 requires targeting of the glycosaminoglycan (GAG) interaction. PMID- 28018342 TI - Detection of HLA Antibodies in Organ Transplant Recipients - Triumphs and Challenges of the Solid Phase Bead Assay. AB - This review outlines the development of human leukocyte antigen (HLA) antibody detection assays and their use in organ transplantation in both antibody screening and crossmatching. The development of sensitive solid phase assays such as the enzyme-linked immunosorbent assay technique, and in particular the bead based technology has revolutionized this field over the last 10-15 years. This revolution however has created a new paradigm in clinical decision making with respect to the detection of low level pretransplant HLA sensitization and its clinical relevance. The relative sensitivities of the assays used are discussed and the relevance of conflicting inter-assay results. Each assay has its advantages and disadvantages and these are discussed. Over the last decade, the bead-based assay utilizing the Luminex(r) fluorocytometer instrument has become established as the "gold standard" for HLA antibody testing. However, there are still unresolved issues surrounding this technique, such as the presence of denatured HLA molecules on the beads which reveal cryptic epitopes and the issue of appropriate fluorescence cut off values for positivity. The assay has been modified to detect complement binding (CB) in addition to non-complement binding (NCB) HLA antibodies although the clinical relevance of the CB and NCB IgG isotypes is not fully resolved. The increase sensitivity of the Luminex(r) bead assay over the complement-dependent cytotoxicity crossmatch has permitted the concept of the "virtual crossmatch" whereby the crossmatch is predicted to a high degree of accuracy based on the HLA antibody specificities detected by the solid phase assay. Dialog between clinicians and laboratory staff on an individual patient basis is essential for correct clinical decision making based on HLA antibody results obtained by the various techniques. PMID- 28018343 TI - Very Late Antigen-1 Marks Functional Tumor-Resident CD8 T Cells and Correlates with Survival of Melanoma Patients. AB - A major limiting factor in the success of immunotherapy is tumor infiltration by CD8+ T cells, a process that remains poorly understood. In the present study, we characterized homing receptors expressed by human melanoma-specific CD8+ T cells. Our data reveal that P-selectin binding and expression of the retention integrin, very late antigen (VLA)-1, by vaccine-induced T cells correlate with longer patient survival. Furthermore, we demonstrate that CD8+VLA-1+ tumor-infiltrating lymphocytes (TILs) are highly enriched in melanoma metastases in diverse tissues. VLA-1-expressing TIL frequently co-express CD69 and CD103, indicating tissue resident memory T cells (TRM) differentiation. We employed a mouse model of melanoma to further characterize VLA-1-expressing TIL. Our data show that VLA-1+ TRM develop in murine tumors within 2 weeks, where they exhibit increased activation status, as well as superior effector functions. In addition, in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors. Together, our data indicate that VLA-1+ TRM develop in tumors and play an important role in tumor immunity, presenting novel targets for the optimization of cancer immunotherapy. PMID- 28018345 TI - Increased Toll-Like Receptors Activity and TLR Ligands in Patients with Autoimmune Thyroid Diseases. AB - OBJECTIVE: Autoimmune thyroid disease (AITD) is an organ-specific disorder due to the interplay between environmental and genetic factors. Toll-like receptors (TLRs) are pattern recognition receptors expressed abundantly on monocytes. There is a paucity of data on TLR expression in AITD. The aim of this study was to examine TLR expression, activation, ligands, and downstream signaling adaptors in peripheral blood mononuclear cells (PBMCs) extracted from untreated AITD patients and healthy controls. METHOD: We isolated PBMC of 30 healthy controls, 36 patients with untreated Hashimoto's thyroiditis, and 30 patients with newly onset Graves' disease. TLR mRNA, protein expression, TLR ligands, and TLR adaptor molecules were measured using real-time PCR, Western blot, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). PBMC was simulated with TLR agonists. The effects of TLR agonists on the viability of human PBMC were evaluated using the MTT assay. The supernatants of cell cultures were measured for the pro inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor alpha (TNF alpha), and IL-10 by ELISA. RESULTS: TLR2, TLR3, TLR9, and TLR10 mRNA were significantly increased in AITD patients compared with controls. TLR2, TLR3, TLR9, high mobility group box 1 (HMGB1), and RAGE expression on monocytes was higher in patients than control at baseline and TLR agonists' stimulation. The release of TNF-alpha and IL-6 was significantly increased in PBMCs from AITD patients with TLR agonists, while IL-10 was significantly decreased. Downstream targets of TLR, myeloid differentiation factor 88 (MyD88), and myeloid toll/IL-1 receptor-domain containing adaptor-inducing interferon-beta were significantly elevated in AITD patients. Levels of TLR2 ligands, HMGB1, and heat shock protein 60 were significantly elevated in AITD patients compared with those in controls and positively correlated with TgAb and TPOAb, while sRAGE concentration was significantly decreased in AITD patients. CONCLUSION: This work is the first to show that TLR2, TLR3, and TLR9 expression and activation are elevated in the PBMCs of patients with AITD and TLRs may participate in the pathogenesis of AITD. PMID- 28018346 TI - Low Double-Negative CD3+CD4-CD8- T Cells Are Associated with Incomplete Restoration of CD4+ T Cells and Higher Immune Activation in HIV-1 Immunological Non-Responders. AB - Failure of immune reconstitution increases the risk of AIDS or non-AIDS related morbidity and mortality in HIV-1-infected patients. CD3+CD4-CD8- T cells, which are usually described as double-negative (DN) T cells, display CD4-like helper and immunoregulatory functions. Here, we have measured the percentage of DN T cells in the immune reconstituted vs. non-immune reconstituted HIV-1-infected individuals. We observed that immunological non-responders (INRs) had a low number of DN T cells after long-term antiretroviral therapy (ART), and the number of these cells positively correlated with the CD4+ T cell count. The ART did not result in complete suppression of immune activation recorded by the percentage of CD38+HLA-DR+CD8+ T cells in INRs, and a strong inverse correlation was observed between DN T cells and immune activation. A low proportion of TGF-beta1+DN T cells was found in INRs. Further mechanism study demonstrated that the level of TGF-beta1-producing DN T cells and immune activation had a negative correlation after ART. Taken together, our study suggests that DN T cells control the immunological response in HIV-1-infected patients. These findings expand our understanding of the mechanism of immune reconstitution and could develop specific treatments to return the immune system to homeostasis following initiation of HIV-1 therapy. PMID- 28018344 TI - Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination. AB - Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette-Guerin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell coreceptor checkpoints (e.g., programed death-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell coreceptors (e.g., OX40). Modification of the activity of key cell "immunometabolism" signaling pathway molecules, including mechanistic target of rapamycin, glycogen synthase kinase-3beta, wnt/beta catenin, adenosine monophosophate-activated protein kinase, and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., regulatory T cells, myeloid-derived suppressor cells) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient antitumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms, studies to improve TB vaccine responses using interventions based on "immuno-oncology" are needed to guide possible repurposing. Understanding the regulation of immune cell functions appropriated by Mtb to promote the imbalance between protective and pathogenic immune responses may guide the development of innovative drug-based adjunct approaches to substantially enhance the clinical efficacy of TB vaccines. PMID- 28018347 TI - Advances in Therapeutic Fc Engineering - Modulation of IgG-Associated Effector Functions and Serum Half-life. AB - Today, monoclonal immunoglobulin gamma (IgG) antibodies have become a major option in cancer therapy especially for the patients with advanced or metastatic cancers. Efficacy of monoclonal antibodies (mAbs) is achieved through both its antigen-binding fragment (Fab) and crystallizable fragment (Fc). Fab can specifically recognize tumor-associated antigen (TAA) and thus modulate TAA linked downstream signaling pathways that may lead to the inhibition of tumor growth, induction of tumor apoptosis, and differentiation. The Fc region can further improve mAbs' efficacy by mediating effector functions such as antibody dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody dependent cell-mediated phagocytosis. Moreover, Fc is the region interacting with the neonatal Fc receptor in a pH-dependent manner that can slow down IgG's degradation and extend its serum half-life. Loss of the antibody Fc region dramatically shortens its serum half-life and weakens its anticancer effects. Given the essential roles that the Fc region plays in the modulation of the efficacy of mAb in cancer treatment, Fc engineering has been extensively studied in the past years. This review focuses on the recent advances in therapeutic Fc engineering that modulates its related effector functions and serum half-life. We also discuss the progress made in aglycosylated mAb development that may substantially reduce the cost of manufacture but maintain similar efficacies as conventional glycosylated mAb. Finally, we highlight several Fc engineering-based mAbs under clinical trials. PMID- 28018348 TI - PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-gamma and Can Be Expressed in the Tumor Microenvironment. AB - The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The first transmissible tumor, now termed devil facial tumor 1 (DFT1), was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015, a second transmissible cancer [devil facial tumor 2 (DFT2)] was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promotes antitumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade antitumor immune responses. We developed recombinant proteins and monoclonal antibodies (mAbs) to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-gamma. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1+ non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, in vitro testing suggests that PD-1 binding to PD L1 and PD-L2 can be blocked by mAbs, which could be critical to understanding how the DFT allografts evade the immune system. PMID- 28018349 TI - Allorecognition by T Lymphocytes and Allograft Rejection. AB - Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. Allospecific T cells become activated through interaction of their T cell receptors with intact allogeneic major histocompatibility complex (MHC) molecules on donor cells (direct pathway) and/or donor peptides presented by self-MHC molecules on recipient antigen-presenting cells (APCs) (indirect pathway). In addition, recent studies show that alloreactive T cells can also be stimulated through recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-dressing) after their transfer via cell-cell contact or through extracellular vesicles (semi-direct pathway). The specific allorecognition pathway used by T cells is dictated by intrinsic and extrinsic factors to the allograft and can influence the nature and magnitude of the alloresponse and rejection process. Consequently, various organs and tissues such as skin, cornea, and solid organ transplants are recognized differently by pro-inflammatory T cells through these distinct pathways, which may explain why these grafts are rejected in a different fashion. On the other hand, the mechanisms by which anti inflammatory regulatory T cells (Tregs) recognize alloantigen and promote transplantation tolerance are still unclear. It is likely that thymic Tregs are activated through indirect allorecognition, while peripheral Tregs recognize alloantigens in a direct fashion. As we gain insights into the mechanisms underlying allorecognition by pro-inflammatory and Treg cells, novel strategies are being designed to prevent allograft rejection in the absence of ongoing immunosuppressive drug treatment in patients. PMID- 28018350 TI - Menage-a-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs. AB - In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2 and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing capacity of phorbol esters (phorbol-2-myristate-13-acetate), ionomycin, monosodium urate, and LPS. In contrast, an acidic environment impaired NET formation both spontaneous and induced. Our findings indicate that intracellular alkalinization of neutrophils in response to an alkaline environment leads to an increase of intracellular calcium and neutrophil activation. We further found that the anion channel blocker DIDS strongly reduced NET formation induced by bicarbonate. This finding suggests that the effects observed are due to a molecular program that renders neutrophils susceptible to NET formation. Inflammatory foci may be characterized by an acidic environment. Our data indicate that NET formation is favored by the higher pH at the border regions of inflamed areas. Moreover, our findings highlight the necessity for strict pH control during assays of NET formation. PMID- 28018351 TI - Allorecognition of HLA-C Mismatches by CD8+ T Cells in Hematopoietic Stem Cell Transplantation Is a Complex Interplay between Mismatched Peptide-Binding Region Residues, HLA-C Expression, and HLA-DPB1 Disparities. AB - HLA-C locus mismatches (MMs) are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C MMs, we have developed a one way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56-CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid (aa) MMs in the alpha1/alpha2 domains (peptide binding region). Because of the high rate of HLA-DPB1 incompatibilities in HLA-A , B-, C-, DRB1-, and DQB1-matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C-mismatched pairs with a positive assay in 52% of the combinations (2.3-18.6% activated CTLs), representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 MM did not induce any positive alloresponse in five MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic MM. A difference of at least 10 aa residues known to impact peptide/T cell receptor (TCR) binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p = 0.021). The same HLA-C MM, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by 10 or more aas in the peptide/TCR-binding region, when occurring together with HLA-DPB1 incompatibilities, should be considered as high-risk MMs in unrelated HSCT. PMID- 28018352 TI - The Capricious Nature of Bacterial Pathogens: Phasevarions and Vaccine Development. AB - Infectious diseases are a leading cause of morbidity and mortality worldwide, and vaccines are one of the most successful and cost-effective tools for disease prevention. One of the key considerations for rational vaccine development is the selection of appropriate antigens. Antigens must induce a protective immune response, and this response should be directed to stably expressed antigens so the target microbe can always be recognized by the immune system. Antigens with variable expression, due to environmental signals or phase variation (i.e., high frequency, random switching of expression), are not ideal vaccine candidates because variable expression could lead to immune evasion. Phase variation is often mediated by the presence of highly mutagenic simple tandem DNA repeats, and genes containing such sequences can be easily identified, and their use as vaccine antigens reconsidered. Recent research has identified phase variably expressed DNA methyltransferases that act as global epigenetic regulators. These phase-variable regulons, known as phasevarions, are associated with altered virulence phenotypes and/or expression of vaccine candidates. As such, genes encoding candidate vaccine antigens that have no obvious mechanism of phase variation may be subject to indirect, epigenetic control as part of a phasevarion. Bioinformatic and experimental studies are required to elucidate the distribution and mechanism of action of these DNA methyltransferases, and most importantly, whether they mediate epigenetic regulation of potential and current vaccine candidates. This process is essential to define the stably expressed antigen target profile of bacterial pathogens and thereby facilitate efficient, rational selection of vaccine antigens. PMID- 28018353 TI - Embracing Complexity beyond Systems Medicine: A New Approach to Chronic Immune Disorders. AB - In order to combat chronic immune disorders (CIDs), it is an absolute necessity to understand the bigger picture, one that goes beyond insights at a one-disease, molecular, cellular, and static level. To unravel this bigger picture we advocate an integral, cross-disciplinary approach capable of embracing the complexity of the field. This paper discusses the current knowledge on common pathways in CIDs including general psychosocial and lifestyle factors associated with immune functioning. We demonstrate the lack of more in-depth psychosocial and lifestyle factors in current research cohorts and most importantly the need for an all encompassing analysis of these factors. The second part of the paper discusses the challenges of understanding immune system dynamics and effectively integrating all key perspectives on immune functioning, including the patient's perspective itself. This paper suggests the use of techniques from complex systems science in describing and simulating healthy or deviating behavior of the immune system in its biopsychosocial surroundings. The patient's perspective data are suggested to be generated by using specific narrative techniques. We conclude that to gain more insight into the behavior of the whole system and to acquire new ways of combatting CIDs, we need to construct and apply new techniques in the field of computational and complexity science, to an even wider variety of dynamic data than used in today's systems medicine. PMID- 28018354 TI - Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks. AB - The major histocompatibility complex (MHC) class I chain-related A (MICA) is the most polymorphic non-classical MHC class I gene in humans. It encodes a ligand for NKG2D (NK group 2, member D), an activating natural killer (NK) receptor that is expressed mainly on NK cells and CD8+ T cells. The single-nucleotide polymorphism (SNP) rs1051792 causing a valine (Val) to methionine (Met) exchange at position 129 of the MICA protein is of specific interest. It separates MICA into isoforms that bind NKG2D with high (Met) and low affinities (Val). Therefore, this SNP has been investigated for associations with infections, autoimmune diseases, and cancer. Here, we systematically review these studies and analyze them in view of new data on the functional consequences of this polymorphism. It has been shown recently that the MICA-129Met variant elicits a stronger NKG2D signaling, resulting in more degranulation and IFN-gamma production in NK cells and in a faster costimulation of CD8+ T cells than the MICA-129Val variant. However, the MICA-129Met isoform also downregulates NKG2D more efficiently than the MICA-129Val isoform. This downregulation impairs NKG2D mediated functions at high expression intensities of the MICA-Met variant. These features of the MICA-129Met/Val dimorphism need to be considered when interpreting disease association studies. Particularly, in the field of hematopoietic stem cell transplantation, they help to explain the associations of the SNP with outcome including graft-versus-host disease and relapse of malignancy. Implications for future disease association studies of the MICA 129Met/Val dimorphism are discussed. PMID- 28018355 TI - Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses. AB - Antibodies raised in Indian rhesus macaques [Macaca mulatta (MM)] in many preclinical vaccine studies are often evaluated in vitro for titer, antigen recognition breadth, neutralization potency, and/or effector function, and in vivo for potential associations with protection. However, despite reliance on this key animal model in translation of promising candidate vaccines for evaluation in first in man studies, little is known about the properties of MM immunoglobulin G (IgG) subclasses and how they may compare to human IgG subclasses. Here, we evaluate the binding of MM IgG1, IgG2, IgG3, and IgG4 to human Fc gamma receptors (FcgammaR) and their ability to elicit the effector functions of human FcgammaR-bearing cells, and unlike in humans, find a notable absence of subclasses with dramatically silent Fc regions. Biophysical, in vitro, and in vivo characterization revealed MM IgG1 exhibited the greatest effector function activity followed by IgG2 and then IgG3/4. These findings in rhesus are in contrast with the canonical understanding that IgG1 and IgG3 dominate effector function in humans, indicating that subclass-switching profiles observed in rhesus studies may not strictly recapitulate those observed in human vaccine studies. PMID- 28018356 TI - Plasmacytoid Dendritic Cells Respond Directly to Apoptotic Cells by Secreting Immune Regulatory IL-10 or IFN-alpha. AB - Plasmacytoid dendritic cells (pDCs) play a pivotal role in driving the autoimmune disease systemic lupus erythematosus, via the secretion of IFN-alpha in response to nuclear self-antigens complexed with autoantibodies. Apoptotic cells, generated at sites of inflammation or secondary lymphoid organs, are exposed to activated pDCs and also express the same nuclear antigens on their cell surface. Here, we show that in the absence of autoantibodies, activated pDCs directly respond to apoptotic cell-expressed chromatin complexes by secreting IL-10 and IL 6, which also induces T cells to secrete IL-10. Conversely, when activated by the viral mimetic CpG-A, apoptotic cells enhance their secretion of IFN-alpha. This study demonstrates that activated pDCs respond directly to apoptotic cells and may maintain tolerance via IL-10, or promote inflammation through secretion of IFN-alpha, depending on the inflammatory context. PMID- 28018359 TI - Editorial: Bone Marrow T Cells at the Center Stage in Immunological Memory. PMID- 28018357 TI - The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung. AB - Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease. PMID- 28018360 TI - ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages. AB - Adenosine triphosphate (ATP) is released by bacteria and host cells during bacterial infection as well as sterile tissue injury, acting as an inducer of inflammasome activation. Previous studies have shown that ATP treatment leads to AMP-activated protein kinase (AMPK) activation. However, it is unclear whether AMPK signaling has been involved in the regulation of ATP-induced inflammasome activation and subsequent pyroptosis. In this study, we aimed to investigate this issue in lipopolysaccharide-activated murine macrophages. Our results showed that AMPK signaling was activated in murine macrophages upon ATP treatment, which was accompanied by inflammasome activation and pyroptosis as evidenced by rapid cell membrane rupture as well as mature interleukin (IL)-1beta and active caspase-1p10 release. The ATP-induced inflammasome activation and pyroptosis were markedly suppressed by an AMPK inhibitor compound C or small-interfering RNA-mediated knockdown of AMPKalpha, but could be greatly enhanced by metformin (a well-known AMPK agonist). Importantly, metformin administration increased the mortality of mice with bacterial sepsis, which was likely because metformin treatment enhanced the systemic inflammasome activation as indicated by elevated serum and hepatic IL-1beta levels. Collectively, these data indicated that the AMPK signaling positively regulated ATP-induced inflammasome activation and pyroptosis in macrophages, highlighting the possibility of AMPK-targeting therapies for inflammatory diseases involving inflammasome activation. PMID- 28018358 TI - Endothelial Response to Glucocorticoids in Inflammatory Diseases. AB - The endothelium plays a crucial role in inflammation. A balanced control of inflammation requires the action of glucocorticoids (GCs), steroidal hormones with potent cell-specific anti-inflammatory properties. Besides the classic anti inflammatory effects of GCs on leukocytes, recent studies confirm that endothelial cells also represent an important target for GCs. GCs regulate different aspects of endothelial physiology including expression of adhesion molecules, production of pro-inflammatory cytokines and chemokines, and maintenance of endothelial barrier integrity. However, the regulation of endothelial GC sensitivity remains incompletely understood. In this review, we specifically examine the endothelial response to GCs in various inflammatory diseases ranging from multiple sclerosis, stroke, sepsis, and vasculitis to atherosclerosis. Shedding more light on the cross talk between GCs and endothelium will help to improve existing therapeutic strategies and develop new therapies better tailored to the needs of patients. PMID- 28018361 TI - IFN-lambda: A New Inducer of Local Immunity against Cancer and Infections. AB - IFN-lambda is the newly established type III IFN with unique immunomodulatory functions. In contrast to the IFN-alpha/beta family and to some extent IFN-gamma, IFN-lambda is apparently acting in specific areas of the body to activate resident immune cells and induces a local immunity, instrumental in preventing particular infections and also keeping transformed cells under control. Mucosal areas of lung and gastrointestinal tracts are now under scrutiny to elucidate the immune mechanisms triggered by IFN-lambda and leading to viral protection. New evidence also indicates the crucial role of IFN-lambda in promoting innate immunity in solid cancer models. Based on its unique biological activities among the IFN system, new immunotherapeutic approaches are now emerging for the treatment of cancer, infection, and autoimmune diseases. In the present review, we highlight the recent advances of IFN-lambda immunomodulatory functions. We also discuss the perspectives of IFN-lambda as a therapeutic agent. PMID- 28018362 TI - Visualization of Probiotic-Mediated Ca2+ Signaling in Intestinal Epithelial Cells In Vivo. AB - Probiotics, such as lactic acid bacteria (LAB) and Bacillus subtilis var. natto, have been shown to modulate immune responses. It is important to understand how probiotic bacteria impact intestinal epithelial cells (IECs), because IECs are the first line of defense at the mucosal surface barrier and their activities substantially affect the gut microenvironment and immunity. However, to date, their precise mechanism remains unknown due to a lack of analytical systems available for live animal models. Recently, we generated a conditional Ca2+ biosensor Yellow Cameleon (YC3.60) transgenic mouse line and established 5D (x, y, z, time, and Ca2+) intravital imaging systems of lymphoid tissues including those in Peyer's patches and bone marrow. In the present study, we further advance our intravital imaging system for intestinal tracts to visualize IEC responses against orally administrated food compounds in real time. Using this system, heat-killed B. subtilis natto, a probiotic TTCC012 strain, is shown to directly induce Ca2+ signaling in IECs in mice housed under specific pathogen free conditions. In contrast, this activation is not observed in the Lactococcus lactis strain C60; however, when we generate germ-free YC3.60 mice and observe the LAB stimulation of IECs in the absence of gut microbiota, C60 is capable of inducing Ca2+ signaling. This is the first study to successfully visualize the direct effect of probiotics on IECs in live animals. These data strongly suggest that probiotic strains stimulate IECs under physiological conditions and that their activity is affected by the microenvironment of the small intestine, such as commensal bacteria. PMID- 28018363 TI - Plague Vaccine Development: Current Research and Future Trends. AB - Plague is one of the world's most lethal human diseases caused by Yersinia pestis, a Gram-negative bacterium. Despite overwhelming studies for many years worldwide, there is no safe and effective vaccine against this fatal disease. Inhalation of Y. pestis bacilli causes pneumonic plague, a fast growing and deadly dangerous disease. F1/LcrV-based vaccines failed to provide adequate protection in African green monkey model in spite of providing protection in mice and cynomolgus macaques. There is still no explanation for this inconsistent efficacy, and scientists leg behind to search reliable correlate assays for immune protection. These paucities are the main barriers to improve the effectiveness of plague vaccine. In the present scenario, one has to pay special attention to elicit strong cellular immune response in developing a next generation vaccine against plague. Here, we review the scientific contributions and existing progress in developing subunit vaccines, the role of molecular adjuvants; DNA vaccines; live delivery platforms; and attenuated vaccines developed to counteract virulent strains of Y. pestis. PMID- 28018364 TI - NKG2A-Expressing Natural Killer Cells Dominate the Response to Autologous Lymphoblastoid Cells Infected with Epstein-Barr Virus. AB - Epstein-Barr virus (EBV) is a human gamma-herpesvirus that establishes latency and lifelong infection in host B cells while achieving a balance with the host immune response. When the immune system is perturbed through immunosuppression or immunodeficiency, however, these latently infected B cells can give rise to aggressive B cell lymphomas. Natural killer (NK) cells are regarded as critical in the early immune response to viral infection, but their role in controlling expansion of infected B cells is not understood. Here, we report that NK cells from healthy human donors display increased killing of autologous B lymphoblastoid cell lines (LCLs) harboring latent EBV compared to primary B cells. Coculture of NK cells with autologous EBV+ LCL identifies an NK cell population that produces IFNgamma and mobilizes the cytotoxic granule protein CD107a. Multi-parameter flow cytometry and Boolean analysis reveal that these functional cells are enriched for expression of the NK cell receptor NKG2A. Further, NKG2A+ NK cells more efficiently lyse autologous LCL than do NKG2A- NK cells. More specifically, NKG2A+2B4+CD16-CD57-NKG2C-NKG2D+ cells constitute the predominant NK cell population that responds to latently infected autologous EBV+ B cells. Thus, a subset of NK cells is enhanced for the ability to recognize and eliminate autologous, EBV-infected transformed cells, laying the groundwork for harnessing this subset for therapeutic use in EBV+ malignancies. PMID- 28018365 TI - Cassava Breeding II: Phenotypic Correlations through the Different Stages of Selection. AB - Breeding cassava relies on a phenotypic recurrent selection that takes advantage of the vegetative propagation of this crop. Successive stages of selection (single row trial-SRT; preliminary yield trial-PYT; advanced yield trial-AYT; and uniform yield trials UYT), gradually reduce the number of genotypes as the plot size, number of replications and locations increase. An important feature of this scheme is that, because of the clonal, reproduction of cassava, the same identical genotypes are evaluated throughout these four successive stages of selection. For this study data, from 14 years (more than 30,000 data points) of evaluation in a sub-humid tropical environment was consolidated for a meta analysis. Correlation coefficients for fresh root yield (FRY), dry matter content (DMC), harvest index (HIN), and plant type score (PTS) along the different stages of selection were estimated. DMC and PTS measured in different trials showed the highest correlation coefficients, indicating a relatively good repeatability. HIN had an intermediate repeatability, whereas FRY had the lowest value. The association between HIN and FRY was lower than expected, suggesting that HIN in early stages was not reliable as indirect selection for FRY in later stages. There was a consistent decrease in the average performance of clones grown in PYTs compared with the earlier evaluation of the same genotypes at SRTs. A feasible explanation for this trend is the impact of the environment on the physiological and nutritional status of the planting material and/or epigenetic effects. The usefulness of HIN is questioned. Measuring this variable takes considerable efforts at harvest time. DMC and FRY showed a weak positive association in SRT (r = 0.21) but a clearly negative one at UYT (r = -0.42). The change in the relationship between these variables is the result of selection. In later stages of selection, the plant is forced to maximize productivity on a dry weight basis either by maximizing FRY or DMC, but not both. Alternatively, the plant may achieve high dry root yield by simultaneously attaining "acceptable" (but not maximum) levels of FRY and DMC. PMID- 28018366 TI - Identification of miRNAs Affecting the Establishment of Brassica Alboglabra Seedling. AB - MicroRNAs (miRNAs) are important for plant development including seed formation, dormancy, and germination, as well as seedling establishment. The Brassica vegetable seedling establishment stage influences the development of high quality seedlings, but also affects the nutrient content of sprouts. Chinese kale (Brassica alboglabra) seedlings at different growth stages were used to construct two small-RNA (sRNA) libraries. We comprehensively analyzed the miRNAs in 2- and 9-day-old seedlings. An average of 11,722,490 clean reads were generated after removing low-quality reads and adapter contaminants. The results revealed that 37.65 and 26.69% of the sRNAs in 2- and 9-day-old seedlings, respectively, were 24 nt long. In total, 254 known mature miRNA sequences from 228 miRNA families and 343 novel miRNAs were identified. Of these miRNAs, 224 were differentially expressed between the two analyzed libraries. The most abundant miRNAs identified by sequence homology were miR156, miR167, and miR157, each with more than 100,000 sequenced reads. Compared with the expression levels in 2-day-old seedlings, MiR8154 and miR390 were the most up- and down-regulated miRNAs respectively in 9 day-old seedlings. Gene ontology enrichment analysis of the differentially expressed-miRNA target genes affecting biological processes revealed that most genes were in the "regulation of transcription" category. Additionally, the expression patterns of some miRNAs and target genes were validated by quantitative real-time polymerase chain reaction. We determined that development associated miRNAs (e.g., bal-miR156/157/159/166/167/172/396), were highly expressed during seedling-establishment stage, as were stress-related (bal miR408) and metabolism-related (bal-miR826) miRNAs. Combined with the low level of targets SPL9 and AP2, it was concluded that miR156-SPL9 and miR172-AP modules play key roles during the B. alboglabra seedling establishment stage. PMID- 28018367 TI - EDTA Shuttle Effect vs. Lignosulfonate Direct Effect Providing Zn to Navy Bean Plants (Phaseolus vulgaris L 'Negro Polo') in a Calcareous Soil. AB - Zn-Lignosulfonates (LS) fertilizers are used as an eco-friendly alternative to chelate formulations. The mechanisms of Zn release in the rhizosphere by both types of products are compared. The ability to provide Zn to Phaseolus vulgaris L of non-modified and chemically modified ZnLS and ZnEDTA is compared in a hydroponic assay. Stable isotope 67Zn was used to study Zn source (fertilizer, ZnFer, or native, ZnNat) uptake and distribution in plants in two soil pot experiments. ZnEDTA was the best treatment to provide both ZnFer and ZnNat to navy bean plants. A shuttle effect mechanism and an isotopic exchange may occur. ZnLS from eucalyptus (ZnLSE) provides more Zn to the plant than LS from spruce. Chemical modifications of ZnLSE does not improve its efficiency. A double dose of ZnLSE provides similar ZnFer in leaves and similar soluble ZnFer content in soil than ZnEDTA. A model for the Zn fertilizers behavior in the soil and plant system is presented, showing the shuttle effect for the synthetic chelate and the direct delivery in the rhizosphere for the ZnLS complex. PMID- 28018368 TI - Microspore Induced Doubled Haploids Production from Ethyl Methanesulfonate (EMS) Soaked Flower Buds Is an Efficient Strategy for Mutagenesis in Chinese Cabbage. AB - Chinese cabbage buds were soaked with Ethyl methanesulfonate (EMS) to induce mutagenesis. The influence of different EMS concentrations and treatment durations on microspore development, embryo production rate and seedling rate were evaluated in five Chinese cabbage genotypes. Mutations in four color-related genes were identified using high resolution melting (HRM) curves of their PCR products. The greatest embryo production and seedling rates were observed when buds were treated with 0.03 to 0.1% EMS for 5 to 10 min, while EMS concentrations greater than 0.1% were lethal to the microspores. In total, 142 mutants with distinct variations in leaf shape, leaf color, corolla size, flower color, bolting time and downy mildew resistance were identified from 475 microspore culture derived Doubled Haploids. Our results demonstrate that microspore derived Doubled Haploids from EMS soaked buds represents an efficient approach to rapidly generate homozygous Chinese cabbage mutants. PMID- 28018369 TI - Insights into the Role of the Berry-Specific Ethylene Responsive Factor VviERF045. AB - During grape ripening, numerous transcriptional and metabolic changes are required in order to obtain colored, sweet, and flavored berries. There is evidence that ethylene, together with other signals, plays an important role in triggering the onset of ripening. Here, we report the functional characterization of a berry-specific Ethylene Responsive Factor (ERF), VviERF045, which is induced just before veraison and peaks at ripening. Phylogenetic analysis revealed it is close to the SHINE clade of ERFs, factors involved in the regulation of wax biosynthesis and cuticle morphology. Transgenic grapevines lines overexpressing VviERF045 were obtained, in vitro propagated, phenotypically characterized, and analyzed for the content of specific classes of metabolites. The effect of VviERF045 was correlated with the level of transgene expression, with high expressing lines showing stunted growth, discolored and smaller leaves, and a lower level of chlorophylls and carotenoids. One line with intermediate expression, L15, was characterized at the transcriptomic level and showed 573 differentially expressed genes compared to wild type plants. Microscopy and gene expression analyses point toward a major role of VviERF045 in epidermis patterning by acting on waxes and cuticle. They also indicate that VviERF045 affects phenolic secondary metabolism and induces a reaction resembling a plant immune response with modulation of receptor like-kinases and pathogen related genes. These results suggest also a possible role of this transcription factor in berry ripening, likely related to changes in epidermis and cuticle of the berry, cell expansion, a decrease in photosynthetic capacity, and the activation of several defense related genes as well as from the phenylpropanoid metabolism. All these processes occur in the berry during ripening. PMID- 28018371 TI - Thermal Time Model for Egyptian Broomrape (Phelipanche aegyptiaca) Parasitism Dynamics in Carrot (Daucus carota L.): Field Validation. AB - Carrot, a highly profitable crop in Israel, is severely damaged by Phelipanche aegyptiaca parasitism. Herbicides can effectively control the parasite and prevent damage, but for optimal results, knowledge about the soil-subsurface phenological stage of the parasite is essential. Parasitism dynamics models have been successfully developed for the parasites P. aegyptiaca, Orobanche cumana, and Orobanche minor in the summer crops, tomato, sunflower, and red clover, respectively. However, these models, which are based on a linear relationship between thermal time and the parasitism dynamics, may not necessarily be directly applicable to the P. aegyptiaca-carrot system. The objective of the current study was to develop a thermal time model to predict the effect of P. aegyptiaca parasitism dynamics on carrot growth. For development and validation of the models, data was collected from a temperature-controlled growth experiment and from 13 plots naturally infested with P. aegyptiaca in commercial carrot fields. Our results revealed that P. aegyptiaca development is related to soil temperature. Moreover, unlike P. aegyptiaca parasitism in sunflower and tomato, which could be predicted both a linear model, P. aegyptiaca parasitism dynamics on carrot roots required a nonlinear model, due to the wider range of growth temperatures of both the carrot and the parasite. Hence, two different nonlinear models were developed for optimizing the prediction of P. aegyptiaca parasitism dynamics. Both models, a beta function model and combined model composed of a beta function and a sigmoid curve, were able to predict first P. aegyptiaca attachment. However, overall P. aegyptiaca dynamics was described more accurately by the combined model (RMSE = 14.58 and 10.79, respectively). The results of this study will complement previous studies on P. aegyptiaca management by herbicides to facilitate optimal carrot growth and handling in fields infested with P. aegyptiaca. PMID- 28018370 TI - Whole-Genome Sequences of Xanthomonas euvesicatoria Strains Clarify Taxonomy and Reveal a Stepwise Erosion of Type 3 Effectors. AB - Multiple species of Xanthomonas cause bacterial spot of tomato (BST) and pepper. We sequenced five Xanthomonas euvesicatoria strains isolated from three continents (Africa, Asia, and South America) to provide a set of representative genomes with temporal and geographic diversity. LMG strains 667, 905, 909, and 933 were pathogenic on tomato and pepper, except LMG 918 elicited a hypersensitive reaction (HR) on tomato. Furthermore, LMG 667, 909, and 918 elicited a HR on Early Cal Wonder 30R containing Bs3. We examined pectolytic activity and starch hydrolysis, two tests which are useful in differentiating X. euvesicatoria from X. perforans, both causal agents of BST. LMG strains 905, 909, 918, and 933 were nonpectolytic while only LMG 918 was amylolytic. These results suggest that LMG 918 is atypical of X. euvesicatoria. Sequence analysis of all the publicly available X. euvesicatoria and X. perforans strains comparing seven housekeeping genes identified seven haplotypes with few polymorphisms. Whole genome comparison by average nucleotide identity (ANI) resulted in values of >99% among the LMG strains 667, 905, 909, 918, and 933 and X. euvesicatoria strains and >99.6% among the LMG strains and a subset of X. perforans strains. These results suggest that X. euvesicatoria and X. perforans should be considered a single species. ANI values between strains of X. euvesicatoria, X. perforans, X. allii, X. alfalfa subsp. citrumelonis, X. dieffenbachiae, and a recently described pathogen of rose were >97.8% suggesting these pathogens should be a single species and recognized as X. euvesicatoria. Analysis of the newly sequenced X. euvesicatoria strains revealed interesting findings among the type 3 (T3) effectors, relatively ancient stepwise erosion of some T3 effectors, additional X. euvesicatoria-specific T3 effectors among the causal agents of BST, orthologs of avrBs3 and avrBs4, and T3 effectors shared among xanthomonads pathogenic against various hosts. The results from this study supports the finding that T3 effector repertoire and host range are fundamental for the study of host-microbe interaction but of little relevance to bacterial speciation. PMID- 28018373 TI - Non-destructive Assessment of Plant Nitrogen Parameters Using Leaf Chlorophyll Measurements in Rice. AB - Non-destructive assessment of plant nitrogen (N) status is essential for efficient crop production and N management in intensive rice (Oryza sativa L.) cropping systems. Chlorophyll meter (SPAD-502) has been widely used as a rapid, non-destructive and cost-effective diagnostic tool for in-season assessment of crop N status. The present study was intended to establish the quantitative relationships between chlorophyll meters readings, plant N concentration (PNC), N nutrition index (NNI), accumulated N deficit (AND), and N requirement (NR), as well as to compare the stability of these relationships at different vegetative growth stages in Japonica and Indica rice cultivars. Seven multi-locational field experiments using varied N rates and seven rice cultivars were conducted in east China. The results showed that the PNC and chlorophyll meters readings increased with increasing N application rates across the cultivars, growing seasons, and sites. The PNC and chlorophyll meters readings under varied N rates ranged from 2.29 to 3.21, 1.06 to 1.82 and 37.10 to 45.4 and 37.30 to 46.6, respectively, at TL and HD stages for Japonica rice cultivars, while they ranged from 2.25 to 3.23, 1.34 to 1.91 and 35.6 to 43.3 and 37.3 to 45.5 for Indica rice cultivars, respectively. The quantitative relationships between chlorophyll meters readings, PNC, NNI, AND, and NR established at different crop growth stages in two rice ecotypes, were highly significant with R2 values ranging from 0.69 to 0.93 and 0.71 to 0.86 for Japonica and Indica rice, respectively. The strongest relationships were observed for AND and NR at panicle initiation and booting stages in both rice ecotypes. The validation of the relationships developed in the present study with an independent data exhibited a solid model performance and confirmed their robustness as a reliable and rapid diagnostic tool for in season estimation of plant N parameters for sustainable N management in rice. The results of this study will offer a suitable approach for managing N application precisely during the growth period of the rice crop in intensive rice cropping systems of east China. PMID- 28018372 TI - Roles of Aquaporins in Setaria viridis Stem Development and Sugar Storage. AB - Setaria viridis is a C4 grass used as a model for bioenergy feedstocks. The elongating internodes in developing S. viridis stems grow from an intercalary meristem at the base, and progress acropetally toward fully expanded cells that store sugar. During stem development and maturation, water flow is a driver of cell expansion and sugar delivery. As aquaporin proteins are implicated in regulating water flow, we analyzed elongating and mature internode transcriptomes to identify putative aquaporin encoding genes that had particularly high transcript levels during the distinct stages of internode cell expansion and maturation. We observed that SvPIP2;1 was highly expressed in internode regions undergoing cell expansion, and SvNIP2;2 was highly expressed in mature sugar accumulating regions. Gene co-expression analysis revealed SvNIP2;2 expression was highly correlated with the expression of five putative sugar transporters expressed in the S. viridis internode. To explore the function of the proteins encoded by SvPIP2;1 and SvNIP2;2, we expressed them in Xenopus laevis oocytes and tested their permeability to water. SvPIP2;1 and SvNIP2;2 functioned as water channels in X. laevis oocytes and their permeability was gated by pH. Our results indicate that SvPIP2;1 may function as a water channel in developing stems undergoing cell expansion and SvNIP2;2 is a candidate for retrieving water and possibly a yet to be determined solute from mature internodes. Future research will investigate whether changing the function of these proteins influences stem growth and sugar yield in S. viridis. PMID- 28018374 TI - Island Cotton Enhanced Disease Susceptibility 1 Gene Encoding a Lipase-Like Protein Plays a Crucial Role in Response to Verticillium dahliae by Regulating the SA Level and H2O2 Accumulation. AB - Cotton is one of the most economically important crops, but most cultivated varieties lack adequate innate immunity or resistance to Verticillium wilt. This results in serious losses to both yield and fiber quality. To identify the genetic resources for innate immunity and understand the pathways for pathogen defenses in this crop, here we focus on orthologs of the central Arabidopsis thaliana defense regulator Enhanced Disease Susceptibility 1 (EDS1). The full length cDNA of GbEDS1 was obtained by screening the full-length cDNA library of Gossypium barbadense combining with RACE strategy. Its open reading frame is 1848 bp long, encoding 615 amino acid residues. Sequence analysis showed that GbEDS1 contains a conserved N-terminal lipase domain and an EDS1-specific KNEDT motif. Expression profiling indicated that the gene is induced by Verticillium dahliae as well as salicylic acid (SA) treatment. Subcellular localization assays revealed that GbEDS1 is located in the cell cytoplasm and nucleus. Overexpression of GbEDS1 in Arabidopsis dramatically up-regulated SA and H2O2 production, resulting in enhanced disease resistance to V. dahliae. Silencing of GbEDS1 in G. barbadense significantly decreased SA and H2O2 accumulation, leading to the cotton more susceptibility. Moreover, combining the gene expression results from transgenic Arabidopsis and silenced-GbEDS1 cotton, it indicated that GbEDS1 could activate GbNDR1 and GbBAK1 expression. These findings not only broaden our knowledge about the biological role of GbEDS1, but also provide new insights into the defense mechanisms of GbEDS1 against V. dahliae in cotton. PMID- 28018375 TI - Genome-Wide Identification, Localization, and Expression Analysis of Proanthocyanidin-Associated Genes in Brassica. AB - Proanthocyanidins (PA) is a type of prominent flavonoid compound deposited in seed coats which controls the pigmentation in all Brassica species. Annotation of Brassica juncea genome survey sequences showed 72 PA genes; however, a functional description of these genes, especially how their interactions regulate seed pigmentation, remains elusive. In the present study, we designed 19 primer pairs to screen a bacterial artificial chromosome (BAC) library of B. juncea. A total of 284 BAC clones were identified and sequenced. Alignment of the sequences confirmed that 55 genes were cloned, with every Arabidopsis PA gene having 2-7 homologs in B. juncea. BLAST analysis using the recently released B. rapa or B. napus genome database identified 31 and 58 homologous genes, respectively. Mapping and phylogenetic analysis indicated that 30 B. juncea PA genes are located in the A-genome chromosomes except A04, whereas the remaining 25 genes are mapped to the B-genome chromosomes except B05 and B07. RNA-seq data and Fragments Per Kilobase of a transcript per Million mapped reads (FPKM) analysis showed that most of the PA genes were expressed in the seed coat of B. juncea and B. napus, and that BjuTT3, BjuTT18, BjuANR, BjuTT4-2, BjuTT4-3, BjuTT19-1, and BjuTT19-3 are transcriptionally regulated, and not expressed or downregulated in yellow-seeded testa. Importantly, our study facilitates in better understanding of the molecular mechanism underlying Brassica PA profiles and accumulation, as well as in further characterization of PA genes. PMID- 28018376 TI - Polychromatic Supplemental Lighting from underneath Canopy Is More Effective to Enhance Tomato Plant Development by Improving Leaf Photosynthesis and Stomatal Regulation. AB - Light insufficient stress caused by canopy interception and mutual shading is a major factor limiting plant growth and development in intensive crop cultivation. Supplemental lighting can be used to give light to the lower canopy leaves and is considered to be an effective method to cope with low irradiation stress. Leaf photosynthesis, stomatal regulation, and plant growth and development of young tomato plants were examined to estimate the effects of supplemental lighting with various composite spectra and different light orientations. Light-emitting diodes (LEDs) of polychromatic light quality, red + blue (R/B), white + red + blue (W/R/B), white + red + far-red (W/R/FR), and white + blue (W/B) were assembled from the underneath canopy or from the inner canopy as supplemental lighting resources. The results showed that the use of supplemental lighting significantly increased the photosynthetic efficiency, and reduced stomatal closure while promoting plant growth. Among all supplemental lighting treatments, the W/R/B and W/B from the underneath canopy had best performance. The different photosynthetic performances among the supplemental lighting treatments are resulted from variations in CO2 utilization. The enhanced blue light fraction in the W/R/B and W/B could better stimulate stomatal opening and promote photosynthetic electron transport activity, thus better improving photosynthetic rate. Compared with the inner canopy treatment, the supplemental lighting from the underneath canopy could better enhance the carbon dioxide assimilation efficiency and excessive energy dissipation, leading to an improved photosynthetic performance. Stomatal morphology was highly correlated to leaf photosynthesis and plant development, and should thus be an important determinant for the photosynthesis and the growth of greenhouse tomatoes. PMID- 28018378 TI - Molecular Identification of Broomrape Species from a Single Seed by High Resolution Melting Analysis. AB - Broomrapes are holoparasitic plants spreading through seeds. Each plant produces hundreds of thousands of seeds which remain viable in the soils for decades. To limit their spread, drastic measures are being taken and the contamination of a commercial seed lot by a single broomrape seed can lead to its rejection. Considering that broomrapes species identification from a single seed is extremely difficult even for trained botanists and that among all the described species, only a few are really noxious for the crops, numerous seed lots are rejected because of the contamination by seeds of non-noxious broomrape species. The aim of this study was to develop and evaluate a High Resolution Melting assay identifying the eight most noxious and common broomrape species (Phelipanche aegyptiaca, Orobanche cernua, O. crenata, O. cumana, O. foetida, O. hederae, O. minor, and P. ramosa) from a single seed. Based on trnL and rbcL plastidial genes amplification, the designed assay successfully identifies O. cumana, O. cernua, O. crenata, O. minor, O. hederae, and O. foetida; P. ramosa, and P. aegyptiaca can be differentiated from other species but not from each other. Tested on 50 seed lots, obtained results perfectly matched identifications performed by sequencing. Through the analysis of common seed lots by different analysts, the reproducibility of the assay was evaluated at 90%. Despite an original sample preparation process it was not possible to extract enough DNA from some seeds (10% of the samples). The described assay fulfills its objectives and allows an accurate identification of the targeted broomrape species. It can be used to identify contaminants in commercial seed lots or for any other purpose. The assay might be extended to vegetative material. PMID- 28018377 TI - An LRR/Malectin Receptor-Like Kinase Mediates Resistance to Non-adapted and Adapted Powdery Mildew Fungi in Barley and Wheat. AB - Pattern recognition receptors (PRRs) belonging to the multigene family of receptor-like kinases (RLKs) are the sensing devices of plants for microbe- or pathogen-associated molecular patterns released from microbial organisms. Here we describe Rnr8 (for Required for non-host resistance 8) encoding HvLEMK1, a LRR malectin domain-containing transmembrane RLK that mediates non-host resistance of barley to the non-adapted wheat powdery mildew fungus Blumeria graminis f.sp. tritici. Transgenic barley lines with silenced HvLEMK1 allow entry and colony growth of the non-adapted pathogen, although sporulation was reduced and final colony size did not reach that of the adapted barley powdery mildew fungus B. graminis f.sp. hordei. Transient expression of the barley or wheat LEMK1 genes enhanced resistance in wheat to the adapted wheat powdery mildew fungus while expression of the same genes did not protect barley from attack by the barley powdery mildew fungus. The results suggest that HvLEMK1 is a factor mediating non host resistance in barley and quantitative host resistance in wheat to the wheat powdery mildew fungus. PMID- 28018379 TI - Comparative Transcriptomics of Strawberries (Fragaria spp.) Provides Insights into Evolutionary Patterns. AB - Multiple closely related species with genomic sequences provide an ideal system for studies on comparative and evolutionary genomics, as well as the mechanism of speciation. The whole genome sequences of six strawberry species (Fragaria spp.) have been released, which provide one of the richest genomic resources of any plant genus. In this study, we first generated seven transcriptome sequences of Fragaria species de novo, with a total of 48,557-82,537 unigenes per species. Combined with 13 other species genomes in Rosales, we reconstructed a phylogenetic tree at the genomic level. The phylogenic tree shows that Fragaria closed grouped with Rubus and the Fragaria clade is divided into three subclades. East Asian species appeared in every subclade, suggesting that the genus originated in this area at ~7.99 Mya. Four species found in mountains of Southwest China originated at ~3.98 Mya, suggesting that rapid speciation occurred to adapt to changing environments following the uplift of the Qinghai Tibet Plateau. Moreover, we identified 510 very significantly positively selected genes in the cultivated species F. * ananassa genome. This set of genes was enriched in functions related to specific agronomic traits, such as carbon metabolism and plant hormone signal transduction processes, which are directly related to fruit quality and flavor. These findings illustrate comprehensive evolutionary patterns in Fragaria and the genetic basis of fruit domestication of cultivated strawberry at the genomic/transcriptomic level. PMID- 28018381 TI - Model-Assisted Estimation of the Genetic Variability in Physiological Parameters Related to Tomato Fruit Growth under Contrasted Water Conditions. AB - Drought stress is a major abiotic stress threatening plant and crop productivity. In case of fleshy fruits, understanding mechanisms governing water and carbon accumulations and identifying genes, QTLs and phenotypes, that will enable trade offs between fruit growth and quality under Water Deficit (WD) condition is a crucial challenge for breeders and growers. In the present work, 117 recombinant inbred lines of a population of Solanum lycopersicum were phenotyped under control and WD conditions. Plant water status, fruit growth and composition were measured and data were used to calibrate a process-based model describing water and carbon fluxes in a growing fruit as a function of plant and environment. Eight genotype-dependent model parameters were estimated using a multiobjective evolutionary algorithm in order to minimize the prediction errors of fruit dry and fresh mass throughout fruit development. WD increased the fruit dry matter content (up to 85%) and decreased its fresh weight (up to 60%), big fruit size genotypes being the most sensitive. The mean normalized root mean squared errors of the predictions ranged between 16-18% in the population. Variability in model genotypic parameters allowed us to explore diverse genetic strategies in response to WD. An interesting group of genotypes could be discriminated in which (i) the low loss of fresh mass under WD was associated with high active uptake of sugars and low value of the maximum cell wall extensibility, and (ii) the high dry matter content in control treatment (C) was associated with a slow decrease of mass flow. Using 501 SNP markers genotyped across the genome, a QTL analysis of model parameters allowed to detect three main QTLs related to xylem and phloem conductivities, on chromosomes 2, 4, and 8. The model was then applied to design ideotypes with high dry matter content in C condition and low fresh mass loss in WD condition. The ideotypes outperformed the RILs especially for large and medium fruit-size genotypes, by combining high pedicel conductance and high active uptake of sugars. Interestingly, five small fruit-size RILs were close to the selected ideotypes, and likely bear interesting traits and alleles for adaptation to WD. PMID- 28018380 TI - Functional Evaluation of Proteins in Watery and Gel Saliva of Aphids. AB - Gel and watery saliva are regarded as key players in aphid-pIant interactions. The salivary composition seems to be influenced by the variable environment encountered by the stylet tip. Milieu sensing has been postulated to provide information needed for proper stylet navigation and for the required switches between gel and watery saliva secretion during stylet progress. Both the chemical and physical factors involved in sensing of the stylet's environment are discussed. To investigate the salivary proteome, proteins were collected from dissected gland extracts or artificial diets in a range of studies. We discuss the advantages and disadvantages of either collection method. Several proteins were identified by functional assays or by use of proteomic tools, while most of their functions still remain unknown. These studies disclosed the presence of at least two proteins carrying numerous sulfhydryl groups that may act as the structural backbone of the salivary sheath. Furthermore, cell-wall degrading proteins such a pectinases, pectin methylesterases, polygalacturonases, and cellulases as well as diverse Ca2+-binding proteins (e.g., regucalcin, ARMET proteins) were detected. Suppression of the plant defense may be a common goal of salivary proteins. Salivary proteases are likely involved in the breakdown of sieve-element proteins to invalidate plant defense or to increase the availability of organic N compounds. Salivary polyphenoloxidases, peroxidases and oxidoreductases were suggested to detoxify, e.g., plant phenols. During the last years, an increasing number of salivary proteins have been categorized under the term 'effector'. Effectors may act in the suppression (C002 or MIF cytokine) or the induction (e.g., Mp10 or Mp 42) of plant defense, respectively. A remarkable component of watery saliva seems the protein GroEL that originates from Buchnera aphidicola, the obligate symbiont of aphids and probably reflects an excretory product that induces plant defense responses. Furthermore, chitin fragments in the saliva may trigger defense reactions (e.g., callose deposition). The functions of identified proteins and protein classes are discussed with regard to physical and chemical characteristics of apoplasmic and symplasmic plant compartments. PMID- 28018382 TI - Identification and Analysis of NaHCO3 Stress Responsive Genes in Wild Soybean (Glycine soja) Roots by RNA-seq. AB - Soil alkalinity is a major abiotic constraint to crop productivity and quality. Wild soybean (Glycine soja) is considered to be more stress-tolerant than cultivated soybean (G. max), and has considerable genetic variation for increasing alkalinity tolerance of soybean. In this study, we analyzed the transcriptome profile in the roots of an alkalinity tolerant wild soybean variety N24852 at 12 and 24 h after 90 mM NaHCO3 stress by RNA-sequencing. Compared with the controls, a total of 449 differentially expressed genes (DEGs) were identified, including 95 and 140 up-regulated genes, and 108 and 135 down regulated genes at 12 and 24 h after NaHCO3 treatment, respectively. Quantitative RT-PCR analysis of 14 DEGs showed a high consistency with their expression profiles by RNA-sequencing. Gene Ontology (GO) terms related to transcription factors and transporters were significantly enriched in the up-regulated genes at 12 and 24 h after NaHCO3 stress, respectively. Nuclear factor Y subunit A transcription factors were enriched at 12 h after NaHCO3 stress, and high percentages of basic helix-loop-helix, ethylene-responsive factor, Trihelix, and zinc finger (C2H2, C3H) transcription factors were found at both 12 and 24 h after NaHCO3 stress. Genes related to ion transporters such as ABC transporter, aluminum activated malate transporter, glutamate receptor, nitrate transporter/proton dependent oligopeptide family, and S-type anion channel were enriched in up-regulated DEGs at 24 h after NaHCO3 treatment, implying their roles in maintaining ion homeostasis in soybean roots under alkalinity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed "phenylpropanoid biosynthesis" and "phenylalanine metabolism" pathways might participate in soybean response to alkalinity. This study provides a foundation to further investigate the functions of NaHCO3 stress-responsive genes and the molecular basis of soybean tolerance to alkalinity. PMID- 28018383 TI - Identification of Flowering-Related Genes Responsible for Differences in Bolting Time between Two Radish Inbred Lines. AB - Late bolting after cold exposure is an economically important characteristic of radish (Raphanus sativus L.), an important Brassicaceae root vegetable crop. However, little information is available regarding the genes and pathways that govern flowering time in this species. We performed high-throughput RNA sequencing analysis to elucidate the molecular mechanisms that determine the differences in flowering times between two radish lines, NH-JS1 (late bolting) and NH-JS2 (early bolting). In total, 71,188 unigenes were identified by reference-guided assembly, of which 309, 788, and 980 genes were differentially expressed between the two inbred lines after 0, 15, and 35 days of vernalization, respectively. Among these genes, 218 homologs of Arabidopsis flowering-time (Ft) genes were identified in the radish, and 49 of these genes were differentially expressed between the two radish lines in the presence or absence of vernalization treatment. Most of the Ft genes up-regulated in NH-JS1 vs. NH-JS2 were repressors of flowering, such as RsFLC, consistent with the late-bolting phenotype of NH-JS1. Although, the functions of genes down-regulated in NH-JS1 were less consistent with late-bolting characteristics than the up-regulated Ft genes, several Ft enhancer genes, including RsSOC1, a key floral integrator, showed an appropriate expression to the late-bolting phenotype. In addition, the patterns of gene expression related to the vernalization pathway closely corresponded with the different bolting times of the two inbred lines. These results suggest that the vernalization pathway is conserved between radish and Arabidopsis. PMID- 28018384 TI - Allele Mining and Selective Patterns of Pi9 Gene in a Set of Rice Landraces from India. AB - Allelic variants of the broad-spectrum blast resistance gene, Pi9 (nucleotide binding site-leucine-rich repeat region) have been analyzed in Indian rice landraces. They were selected from the list of 338 rice landraces phenotyped in the rice blast nursery at central Rainfed Upland Rice Research Station, Hazaribag. Six of them were further selected on the basis of their resistance and susceptible pattern for virulence analysis and selective pattern study of Pi9 gene. The sequence analysis and phylogenetic study illustrated that such sequences are vastly homologous and clustered into two groups. All the blast resistance Pi9 alleles were grouped into one cluster, whereas Pi9 alleles of susceptible landraces formed another cluster even though these landraces have a low level of DNA polymorphisms. A total number of 136 polymorphic sites comprising of transitions, transversions, and insertion and deletions (InDels) were identified in the 2.9 kb sequence of Pi9 alleles. Lower variation in the form of mutations (77) (Transition + Transversion), and InDels (59) were observed in the Pi9 alleles isolated from rice landraces studied. The results showed that the Pi9 alleles of the selected rice landraces were less variable, suggesting that the rice landraces would have been exposed to less number of pathotypes across the country. The positive Tajima's D (0.33580), P > 0.10 (not significant) was observed among the seven rice landraces, which suggests the balancing selection of Pi9 alleles. The value of synonymous substitution (-0.43337) was less than the non-synonymous substitution (0.78808). The greater non-synonymous substitution than the synonymous means that the coding region, mainly the leucine rich repeat domain was under diversified selection. In this study, the Pi9 gene has been subjected to balancing selection with low nucleotide diversity which is different from the earlier reports, this may be because of the closeness of the rice landraces, cultivated in the same region, and under low pathotype pressure. PMID- 28018385 TI - Chloroplast Genome Sequence of Pigeonpea (Cajanus cajan (L.) Millspaugh) and Cajanus scarabaeoides (L.) Thouars: Genome Organization and Comparison with Other Legumes. AB - Pigeonpea (Cajanus cajan (L.) Millspaugh), a diploid (2n = 22) legume crop with a genome size of 852 Mbp, serves as an important source of human dietary protein especially in South East Asian and African regions. In this study, the draft chloroplast genomes of Cajanus cajan and Cajanus scarabaeoides (L.) Thouars were generated. Cajanus scarabaeoides is an important species of the Cajanus gene pool and has also been used for developing promising CMS system by different groups. A male sterile genotype harboring the C. scarabaeoides cytoplasm was used for sequencing the plastid genome. The cp genome of C. cajan is 152,242bp long, having a quadripartite structure with LSC of 83,455 bp and SSC of 17,871 bp separated by IRs of 25,398 bp. Similarly, the cp genome of C. scarabaeoides is 152,201bp long, having a quadripartite structure in which IRs of 25,402 bp length separates 83,423 bp of LSC and 17,854 bp of SSC. The pigeonpea cp genome contains 116 unique genes, including 30 tRNA, 4 rRNA, 78 predicted protein coding genes and 5 pseudogenes. A 50 kb inversion was observed in the LSC region of pigeonpea cp genome, consistent with other legumes. Comparison of cp genome with other legumes revealed the contraction of IR boundaries due to the absence of rps19 gene in the IR region. Chloroplast SSRs were mined and a total of 280 and 292 cpSSRs were identified in C. scarabaeoides and C. cajan respectively. RNA editing was observed at 37 sites in both C. scarabaeoides and C. cajan, with maximum occurrence in the ndh genes. The pigeonpea cp genome sequence would be beneficial in providing informative molecular markers which can be utilized for genetic diversity analysis and aid in understanding the plant systematics studies among major grain legumes. PMID- 28018386 TI - Editorial: Advances and Trends in Development of Plant Factories. PMID- 28018388 TI - Coronatine Inhibits Stomatal Closure through Guard Cell-Specific Inhibition of NADPH Oxidase-Dependent ROS Production. AB - Microbes trigger stomatal closure through microbe-associated molecular patterns (MAMPs). The bacterial pathogen Pseudomonas syringae pv. tomato (Pst) synthesizes the polyketide toxin coronatine, which inhibits stomatal closure by MAMPs and by the hormone abscisic acid (ABA). The mechanism by which coronatine, a jasmonic acid-isoleucine analog, achieves this effect is not completely clear. Reactive oxygen species (ROS) are essential second messengers in stomatal immunity, therefore we investigated the possible effect of coronatine on their production. We found that coronatine inhibits NADPH oxidase-dependent ROS production induced by ABA, and by the flagellin-derived peptide flg22. This toxin also inhibited NADPH oxidase-dependent stomatal closure induced by darkness, however, it failed to prevent stomatal closure by exogenously applied H2O2 or by salicylic acid, which induces ROS production through peroxidases. Contrary to what was observed on stomata, coronatine did not affect the oxidative burst induced by flg22 in leaf disks. Additionally, we observed that in NADPH oxidase mutants atrbohd and atrbohd/f, as well as in guard cell ABA responsive but flg22 insensitive mutants mpk3, mpk6, npr1-3, and lecrk-VI.2-1, the inhibition of ABA stomatal responses by both coronatine and the NADPH oxidase inhibitor diphenylene iodonium was markedly reduced. Interestingly, coronatine still impaired ABA-induced ROS synthesis in mpk3, mpk6, npr1-3, and lecrk-VI.2-1, suggesting a possible feedback regulation of ROS on other guard cell ABA signaling elements in these mutants. Altogether our results show that inhibition of NADPH oxidase-dependent ROS synthesis in guard cells plays an important role during endophytic colonization by Pst through stomata. PMID- 28018389 TI - Regulatory Role of OsMADS34 in the Determination of Glumes Fate, Grain Yield, and Quality in Rice. AB - Grasses produce seeds on spikelets, a unique type of inflorescence. Despite the importance of grass crops for food, the genetic mechanisms that control spikelet development remain poorly understood. In this study, we used m34-z, a new mutant allele of the rice (Oryza sativa) E-class gene OsMADS34, to examine OsMADS34 function in determining the identities of glumes (rudimentary glume and sterile lemma) and grain size. In the m34-z mutant, both the rudimentary glume and sterile lemma were homeotically converted to the lemma-like organ and acquired the lemma identity, suggesting that OsMADS34 plays important roles in the development of glumes. In the m34-z mutant, most of the grains from the secondary panicle branches (spb) were decreased in size, compared with grains from wild type, but no differences were observed in the grains from the primary panicle branches. The amylose content and gel consistency, and a seed-setting rate from the spb were reduced in the m34-z mutant. Interesting, transcriptional activity analysis revealed that OsMADS34 protein was a transcription repressor and it may influence grain yield by suppressing the expressions of BG1, GW8, GW2, and GL7 in the m34-z mutant. These findings revealed that OsMADS34 largely affects grain yield by affecting the size of grains from the secondary branches. PMID- 28018387 TI - Role of Ions in the Regulation of Light-Harvesting. AB - Regulation of photosynthetic light harvesting in the thylakoids is one of the major key factors affecting the efficiency of photosynthesis. Thylakoid membrane is negatively charged and influences both the structure and the function of the primarily photosynthetic reactions through its electrical double layer (EDL). Further, there is a heterogeneous organization of soluble ions (K+, Mg2+, Cl-) attached to the thylakoid membrane that, together with fixed charges (negatively charged amino acids, lipids), provides an electrical field. The EDL is affected by the valence of the ions and interferes with the regulation of "state transitions," protein interactions, and excitation energy "spillover" from Photosystem II to Photosystem I. These effects are reflected in changes in the intensity of chlorophyll a fluorescence, which is also a measure of photoprotective non-photochemical quenching (NPQ) of the excited state of chlorophyll a. A triggering of NPQ proceeds via lumen acidification that is coupled to the export of positive counter-ions (Mg2+, K+) to the stroma or/and negative ions (e.g., Cl-) into the lumen. The effect of protons and anions in the lumen and of the cations (Mg2+, K+) in the stroma are, thus, functionally tightly interconnected. In this review, we discuss the consequences of the model of EDL, proposed by Barber (1980b) Biochim Biophys Acta 594:253-308) in light of light harvesting regulation. Further, we explain differences between electrostatic screening and neutralization, and we emphasize the opposite effect of monovalent (K+) and divalent (Mg2+) ions on light-harvesting and on "screening" of the negative charges on the thylakoid membrane; this effect needs to be incorporated in all future models of photosynthetic regulation by ion channels and transporters. PMID- 28018390 TI - Emerging Technologies for the Production of Renewable Liquid Transport Fuels from Biomass Sources Enriched in Plant Cell Walls. AB - Plant cell walls are composed predominantly of cellulose, a range of non cellulosic polysaccharides and lignin. The walls account for a large proportion not only of crop residues such as wheat straw and sugarcane bagasse, but also of residues of the timber industry and specialist grasses and other plants being grown specifically for biofuel production. The polysaccharide components of plant cell walls have long been recognized as an extraordinarily large source of fermentable sugars that might be used for the production of bioethanol and other renewable liquid transport fuels. Estimates place annual plant cellulose production from captured light energy in the order of hundreds of billions of tons. Lignin is synthesized in the same order of magnitude and, as a very large polymer of phenylpropanoid residues, lignin is also an abundant, high energy macromolecule. However, one of the major functions of these cell wall constituents in plants is to provide the extreme tensile and compressive strengths that enable plants to resist the forces of gravity and a broad range of other mechanical forces. Over millions of years these wall constituents have evolved under natural selection to generate extremely tough and resilient biomaterials. The rapid degradation of these tough cell wall composites to fermentable sugars is therefore a difficult task and has significantly slowed the development of a viable lignocellulose-based biofuels industry. However, good progress has been made in overcoming this so-called recalcitrance of lignocellulosic feedstocks for the biofuels industry, through modifications to the lignocellulose itself, innovative pre-treatments of the biomass, improved enzymes and the development of superior yeasts and other microorganisms for the fermentation process. Nevertheless, it has been argued that bioethanol might not be the best or only biofuel that can be generated from lignocellulosic biomass sources and that hydrocarbons with intrinsically higher energy densities might be produced using emerging and continuous flow systems that are capable of converting a broad range of plant and other biomasses to bio-oils through so called 'agnostic' technologies such as hydrothermal liquefaction. Continued attention to regulatory frameworks and ongoing government support will be required for the next phase of development of internationally viable biofuels industries. PMID- 28018391 TI - Identification of Plastoglobules as a Site of Carotenoid Cleavage. AB - Carotenoids play an essential role in light harvesting and protection from excess light. During chloroplast senescence carotenoids are released from their binding proteins and are eventually metabolized. Carotenoid cleavage dioxygenase 4 (CCD4) is involved in carotenoid breakdown in senescing leaf and desiccating seed, and is part of the proteome of plastoglobules (PG), which are thylakoid-associated lipid droplets. Here, we demonstrate that CCD4 is functionally active in PG. Leaves of Arabidopsis thaliana ccd4 mutants constitutively expressing CCD4 fused to yellow fluorescent protein showed strong fluorescence in PG and reduced carotenoid levels upon dark-induced senescence. Lipidome-wide analysis indicated that beta-carotene, lutein, and violaxanthin were the principle substrates of CCD4 in vivo and were cleaved in senescing chloroplasts. Moreover, carotenoids were shown to accumulate in PG of ccd4 mutant plants during senescence, indicating translocation of carotenoids to PG prior to degradation. PMID- 28018392 TI - Narrow-Leafed Lupin (Lupinus angustifolius) beta1- and beta6-Conglutin Proteins Exhibit Antifungal Activity, Protecting Plants against Necrotrophic Pathogen Induced Damage from Sclerotinia sclerotiorum and Phytophthora nicotianae. AB - Vicilins (7S globulins) are seed storage proteins and constitute the main protein family in legume seeds, particularly in narrow-leafed lupin (Lupinus angustifolius L.; NLL), where seven vicilin genes, called beta1- to beta7 conglutin have been identified. Vicilins are involved in germination processes supplying amino acids for seedling growth and plant development, as well as in some cases roles in plant defense and protection against pathogens. The roles of NLL beta-conglutins in plant defense are unknown. Here the potential role of five NLL beta-conglutin family members in protection against necrotrophic fungal pathogens was investigated and it was demonstrated that recombinant purified 6xHis-tagged beta1- and beta6-conglutin proteins exhibited the strongest in vitro growth inhibitory activity against a range of necrotrophic fungal pathogens compared to beta2, beta3, and beta4 conglutins. To examine activity in vivo, two representative necrotrophic pathogens, the fungus Sclerotinia sclerotiorum and oomycete Phytophthora nicotianae were used. Transient expression of beta1- and beta6-conglutin proteins in Nicotiana benthamiana leaves demonstrated in vivo growth suppression of both of these pathogens, resulting in low percentages of hyphal growth and elongation in comparison to control treated leaves. Cellular studies using beta1- and beta6-GFP fusion proteins showed these conglutins localized to the cell surface including plasmodesmata. Analysis of cellular death following S. sclerotiorum or P. nicotianae revealed both beta1- and beta6 conglutins suppressed pathogen induced cell death in planta and prevented pathogen induced suppression of the plant oxidative burst as determined by protein oxidation in infected compared to mock-inoculated leaves. PMID- 28018393 TI - Identification and Network-Enabled Characterization of Auxin Response Factor Genes in Medicago truncatula. AB - The Auxin Response Factor (ARF) family of transcription factors is an important regulator of environmental response and symbiotic nodulation in the legume Medicago truncatula. While previous studies have identified members of this family, a recent spurt in gene expression data coupled with genome update and reannotation calls for a reassessment of the prevalence of ARF genes and their interaction networks in M. truncatula. We performed a comprehensive analysis of the M. truncatula genome and transcriptome that entailed search for novel ARF genes and the co-expression networks. Our investigation revealed 8 novel M. truncatula ARF (MtARF) genes, of the total 22 identified, and uncovered novel gene co-expression networks as well. Furthermore, the topological clustering and single enrichment analysis of several network models revealed the roles of individual members of the MtARF family in nitrogen regulation, nodule initiation, and post-embryonic development through a specialized protein packaging and secretory pathway. In summary, this study not just shines new light on an important gene family, but also provides a guideline for identification of new members of gene families and their functional characterization through network analyses. PMID- 28018394 TI - Global Transcriptional Analysis Reveals the Complex Relationship between Tea Quality, Leaf Senescence and the Responses to Cold-Drought Combined Stress in Camellia sinensis. AB - In field conditions, especially in arid and semi-arid areas, tea plants are often simultaneously exposed to various abiotic stresses such as cold and drought, which have profound effects on leaf senescence process and tea quality. However, most studies of gene expression in stress responses focus on a single inciting agent, and the confounding effect of multiple stresses on crop quality and leaf senescence remain unearthed. Here, global transcriptome profiles of tea leaves under separately cold and drought stress were compared with their combination using RNA-Seq technology. This revealed that tea plants shared a large overlap in unigenes displayed "similar" (26%) expression pattern and avoid antagonistic responses (lowest level of "prioritized" mode: 0%) to exhibit very congruent responses to co-occurring cold and drought stress; 31.5% differential expressed genes and 38% of the transcriptome changes in response to combined stresses were unpredictable from cold or drought single-case studies. We also identified 319 candidate genes for enhancing plant resistance to combined stress. We then investigated the combined effect of cold and drought on tea quality and leaf senescence. Our results showed that drought-induced leaf senescence were severely delayed by (i) modulation of a number of senescence-associated genes and cold responsive genes, (ii) enhancement of antioxidant capacity, (iii) attenuation of lipid degradation, (iv) maintenance of cell wall and photosynthetic system, (v) alteration of senescence-induced sugar effect/sensitivity, as well as (vi) regulation of secondary metabolism pathways that significantly influence the quality of tea during combined stress. Therefore, care should be taken when utilizing a set of stresses to try and maximize leaf longevity and tea quality. PMID- 28018395 TI - Proteomic Analysis Reveals the Positive Roles of the Plant-Growth-Promoting Rhizobacterium NSY50 in the Response of Cucumber Roots to Fusarium oxysporum f. sp. cucumerinum Inoculation. AB - Plant-growth-promoting rhizobacteria (PGPR) can both improve plant growth and enhance plant resistance against a variety of environmental stresses. To investigate the mechanisms that PGPR use to protect plants under pathogenic attack, transmission electron microscopy analysis and a proteomic approach were designed to test the effects of the new potential PGPR strain Paenibacillus polymyxa NSY50 on cucumber seedling roots after they were inoculated with the destructive phytopathogen Fusarium oxysporum f. sp. cucumerinum (FOC). NSY50 could apparently mitigate the injury caused by the FOC infection and maintain the stability of cell structures. The two-dimensional electrophoresis (2-DE) approach in conjunction with MALDI-TOF/TOF analysis revealed a total of 56 proteins that were differentially expressed in response to NSY50 and/or FOC. The application of NSY50 up-regulated most of the identified proteins that were involved in carbohydrate metabolism and amino acid metabolism under normal conditions, which implied that both energy generation and the production of amino acids were enhanced, thereby ensuring an adequate supply of amino acids for the synthesis of new proteins in cucumber seedlings to promote plant growth. Inoculation with FOC inhibited most of the proteins related to carbohydrate and energy metabolism and to protein metabolism. The combined inoculation treatment (NSY50+FOC) accumulated abundant proteins involved in defense mechanisms against oxidation and detoxification as well as carbohydrate metabolism, which might play important roles in preventing pathogens from attacking. Meanwhile, western blotting was used to analyze the accumulation of enolase (ENO) and S-adenosylmethionine synthase (SAMs). NSY50 further increased the expression of ENO and SAMs under FOC stress. In addition, NSY50 adjusted the transcription levels of genes related to those proteins. Taken together, these results suggest that P. polymyxa NSY50 may promote plant growth and alleviate FOC-induced damage by improving the metabolism and activation of defense-related proteins in cucumber roots. PMID- 28018396 TI - Transcriptome Analysis to Identify the Putative Biosynthesis and Transport Genes Associated with the Medicinal Components of Achyranthes bidentata Bl. AB - Achyranthes bidentata is a popular perennial medicine herb used for 1000s of years in China to treat various diseases. Although this herb has multiple pharmaceutical purposes in China, no transcriptomic information has been reported for this species. In addition, the understanding of several key pathways and enzymes involved in the biosynthesis of oleanolic acid and ecdysterone, two pharmacologically active classes of metabolites and major chemical constituents of A. bidentata root extracts, is limited. The aim of the present study was to characterize the transcriptome profile of the roots and leaves of A. bidentata to uncover the biosynthetic and transport mechanisms of the active components. In this study, we identified 100,987 transcripts, with an average length of 1146.8 base pairs. A total of 31,634 (31.33%) unigenes were annotated, and 12,762 unigenes were mapped to 303 pathways according to the Kyoto Encyclopedia of Genes and Genomes pathway database. Moreover, we identified a total of 260 oleanolic acid and ecdysterone genes encoding biosynthetic enzymes. Furthermore, the key enzymes involved in the oleanolic acid and ecdysterone synthesis pathways were analyzed using quantitative real-time polymerase chain reaction, revealing that the roots expressed these enzymes to a greater extent than the leaves. In addition, we identified 85 ATP-binding cassette transporters, some of which might be involved in the translocation of secondary metabolites. PMID- 28018397 TI - Function of AP2/ERF Transcription Factors Involved in the Regulation of Specialized Metabolism in Ophiorrhiza pumila Revealed by Transcriptomics and Metabolomics. AB - The hairy roots (HR) of Ophiorrhiza pumila produce camptothecin (CPT), a monoterpenoid indole alkaloid used as a precursor in the synthesis of chemotherapeutic drugs. O. pumila HR culture is considered as a promising alternative source of CPT, however, the knowledge about the biosynthetic pathway and regulatory mechanism is still limited. In this study, five genes that encode AP2/ERF transcription factors, namely OpERF1-OpERF5, were isolated from HR of O. pumila. Phylogenetic analysis of AP2/ERF protein sequences suggested the close evolutionary relationship of OpERF1 with stress-responsive ERF factors in Arabidopsis and of OpERF2 with ERF factors reported to regulate alkaloid production, such as ORCA3 in Catharanthus roseus, NIC2 locus ERF in tobacco, and JRE4 in tomato. We generated the transgenic HR lines of O. pumila, ERF1i and ERF2i, in which the expression of OpERF1 and OpERF2, respectively, was suppressed using RNA interference technique. The transcriptome and metabolome of these suppressed HR were analyzed for functional characterization of OpERF1 and OpERF2. Although significant changes were not observed in the metabolome, including CPT and related compounds, the suppression of OpERF2 resulted in reduced expression of genes in the 2-C-methyl-d-erythritol 4-phosphate and secologanin-strictosidine pathways, which supply a precursor, strictosidine, for CPT biosynthesis. Furthermore, while it was not conclusive for OpERF1, enrichment analysis of differentially expressed genes in the suppressed HR showed that the gene ontology terms for oxidation-reduction, presumably involved in secondary metabolite pathways, were enriched in the ERF2i downregulated gene set. These results suggest a positive role of OpERF2 in regulating specialized metabolism in O. pumila. PMID- 28018398 TI - Cadmium Accumulation Characteristics in Turnip Landraces from China and Assessment of Their Phytoremediation Potential for Contaminated Soils. AB - Heavy metal (HM) pollution is a global environmental problem that threatens ecosystem and human health. Cadmium (Cd) pollution is the most prominent HM pollution type because of its high toxicity, strong migration, and the large polluted area globally. Phytoremediation of contaminated soil is frequently practiced because of its cost-effectiveness and operability and because it has no associated secondary pollution. High-accumulation plants, including those identified as hyperaccumulators, play an important role in phytoremediation. Therefore, screening of plants to identify hyperaccumulators is important for continued phytoremediation. In the present study, we investigated the Cd tolerance and accumulation capabilities of 18 turnip landraces from China under a soil experiment with known Cd level. The results indicated that turnip has a high capacity for Cd accumulation. Furthermore, significant differences in Cd tolerance and accumulation characteristics were found among different landraces when they grew at 50 mg kg-1 (dry weight) Cd concentration. Among the studied landraces, five turnip landraces met the requirements of Cd hyperaccumulators and three landraces were identified as potential candidates. However, the total Cd content accumulated by individual plant of different turnip landraces was dependent on both the Cd accumulation capacity and plant biomass. Compared with some reported Cd hyperaccumulators, turnip not only shows a high Cd-accumulation capacity but also has rapid growth and a wide distribution area. These advantages indicate that turnip may have considerable potential for phytoremediation of Cd contaminated soil. Furthermore, the study also indicates that it is not advisable to consume turnip cultivated in an environment that exceeds safe Cd levels. PMID- 28018399 TI - The Onion (Allium cepa L.) R2R3-MYB Gene MYB1 Regulates Anthocyanin Biosynthesis. AB - Bulb color is an important consumer trait for onion (Allium cepa L., Allioideae, Asparagales). The bulbs accumulate a range of flavonoid compounds, including anthocyanins (red), flavonols (pale yellow), and chalcones (bright yellow). Flavonoid regulation is poorly characterized in onion and in other plants belonging to the Asparagales, despite being a major plant order containing many important crop and ornamental species. R2R3-MYB transcription factors associated with the regulation of distinct branches of the flavonoid pathway were isolated from onion. These belonged to sub-groups (SGs) that commonly activate anthocyanin (SG6, MYB1) or flavonol (SG7, MYB29) production, or repress phenylpropanoid/flavonoid synthesis (SG4, MYB4, MYB5). MYB1 was demonstrated to be a positive regulator of anthocyanin biosynthesis by the induction of anthocyanin production in onion tissue when transiently overexpressed and by reduction of pigmentation when transiently repressed via RNAi. Furthermore, ectopic red pigmentation was observed in garlic (Allium sativum L.) plants stably transformed with a construct for co-overexpression of MYB1 and a bHLH partner. MYB1 also was able to complement the acyanic petal phenotype of a defined R2R3 MYB anthocyanin mutant in Antirrhinum majus of the asterid clade of eudicots. The availability of sequence information for flavonoid-related MYBs from onion enabled phylogenetic groupings to be determined across monocotyledonous and dicotyledonous species, including the identification of characteristic amino acid motifs. This analysis suggests that divergent evolution of the R2R3-MYB family has occurred between Poaceae/Orchidaceae and Allioideae species. The DNA sequences identified will be valuable for future analysis of classical flavonoid genetic loci in Allium crops and will assist the breeding of these important crop species. PMID- 28018400 TI - Identification and Expression Analysis of Candidate Genes Involved in Carotenoid Biosynthesis in Chickpea Seeds. AB - Plant carotenoids have a key role in preventing various diseases in human because of their antioxidant and provitamin A properties. Chickpea is a good source of carotenoid among legumes and its diverse germplasm and genome accessibility makes it a good model for carotenogenesis studies. The structure, location, and copy numbers of genes involved in carotenoid biosynthesis were retrieved from the chickpea genome. The majority of the single nucleotide polymorphism (SNPs) within these genes across five diverse chickpea cultivars was synonymous mutation. We examined the expression of the carotenogenesis genes and their association with carotenoid concentration at different seed development stages of five chickpea cultivars. Total carotenoid concentration ranged from 22 MUg g-1 in yellow cotyledon kabuli to 44 MUg g-1 in green cotyledon desi at 32 days post anthesis (DPA). The majority of carotenoids in chickpea seeds consists of lutein and zeaxanthin. The expression of the selected 19 genes involved in carotenoid biosynthesis pathway showed common pattern across five cultivars with higher expression at 8 and/or 16 DPA then dropped considerably at 24 and 32 DPA. Almost all genes were up-regulated in CDC Jade cultivar. Correlation analysis between gene expression and carotenoid concentration showed that the genes involved in the primary step of carotenoid biosynthesis pathway including carotenoid desaturase and isomerase positively correlated with various carotenoid components in chickpea seeds. A negative correlation was found between hydroxylation activity and provitamin A concentration in the seeds. The highest provitamin A concentration including beta-carotene and beta-cryptoxanthin were found in green cotyledon chickpea cultivars. PMID- 28018402 TI - Biocontrol Potential of Streptomyces hydrogenans Strain DH16 toward Alternaria brassicicola to Control Damping Off and Black Leaf Spot of Raphanus sativus. AB - Biocontrol agents and their bioactive metabolites provide one of the best alternatives to decrease the use of chemical pesticides. In light of this, the present investigation reports the biocontrol potential of Streptomyces hydrogenans DH16 and its metabolites towards Alternaria brassicicola, causal agent of black leaf spot and damping off of seedlings of crucifers. In vitro antibiosis of strain against pathogen revealed complete suppression of mycelial growth of pathogen, grown in potato dextrose broth supplemented with culture supernatant (20% v/v) of S. hydrogenans DH16. Microscopic examination of the fungal growth showed severe morphological abnormalities in the mycelium caused by antifungal metabolites. In vivo studies showed the efficacy of streptomycete cells and culture supernatant as seed dressings to control damping off of Raphanus sativus seedlings. Treatment of pathogen infested seeds with culture supernatant (10%) and streptomycete cells significantly improved seed germination (75-80%) and vigor index (1167-1538). Furthermore, potential of cells and culture supernatant as foliar treatment to control black leaf spot was also evaluated. Clearly visible symptoms of disease were observed in the control plants with 66.81% disease incidence and retarded growth of root system. However, disease incidence reduced to 6.78 and 1.47% in plants treated with antagonist and its metabolites, respectively. Additionally, treatment of seeds and plants with streptomycete stimulated various growth traits of plants over uninoculated control plants in the absence of pathogen challenge. These results indicate that S. hydrogenans and its culture metabolites can be developed as biofungicides as seed dressings to control seed borne pathogens, and as sprays to control black leaf spot of crucifers. PMID- 28018401 TI - Systemic Responses of Barley to the 3-hydroxy-decanoyl-homoserine Lactone Producing Plant Beneficial Endophyte Acidovorax radicis N35. AB - Quorum sensing auto-inducers of the N-acyl homoserine lactone (AHL) type produced by Gram-negative bacteria have different effects on plants including stimulation on root growth and/or priming or acquirement of systemic resistance in plants. In this communication the influence of AHL production of the plant growth promoting endophytic rhizosphere bacterium Acidovorax radicis N35 on barley seedlings was investigated. A. radicis N35 produces 3-hydroxy-C10-homoserine lactone (3-OH-C10 HSL) as the major AHL compound. To study the influence of this QS autoinducer on the interaction with barley, the araI-biosynthesis gene was deleted. The comparison of inoculation effects of the A. radicis N35 wild type and the araI mutant resulted in remarkable differences. While the N35 wild type colonized plant roots effectively in microcolonies, the araI mutant occurred at the root surface as single cells. Furthermore, in a mixed inoculum the wild type was much more prevalent in colonization than the araI mutant documenting that the araI mutation affected root colonization. Nevertheless, a significant plant growth promoting effect could be shown after inoculation of barley with the wild type and the araI mutant in soil after 2 months cultivation. While A. radicis N35 wild type showed only a very weak induction of early defense responses in plant RNA expression analysis, the araI mutant caused increased expression of flavonoid biosynthesis genes. This was corroborated by the accumulation of several flavonoid compounds such as saponarin and lutonarin in leaves of root inoculated barley seedlings. Thus, although the exact role of the flavonoids in this plant response is not clear yet, it can be concluded, that the synthesis of AHLs by A. radicis has implications on the perception by the host plant barley and thereby contributes to the establishment and function of the bacteria-plant interaction. PMID- 28018403 TI - Comparative Analysis of Phenolic Compound Characterization and Their Biosynthesis Genes between Two Diverse Bread Wheat (Triticum aestivum) Varieties Differing for Chapatti (Unleavened Flat Bread) Quality. AB - Phenolic compounds (PCs) affect the bread quality and can also affect the other types of end-use food products such as chapatti (unleavened flat bread), now globally recognized wheat-based food product. The detailed analysis of PCs and their biosynthesis genes in diverse bread wheat (Triticum aestivum) varieties differing for chapatti quality have not been studied. In this study, the identification and quantification of PCs using UPLC-QTOF-MS and/or MS/MS and functional genomics techniques such as microarrays and qRT-PCR of their biosynthesis genes have been studied in a good chapatti variety, "C 306" and a poor chapatti variety, "Sonalika." About 80% (69/87) of plant phenolic compounds were tentatively identified in these varieties. Nine PCs (hinokinin, coutaric acid, fertaric acid, p-coumaroylqunic acid, kaempferide, isorhamnetin, epigallocatechin gallate, methyl isoorientin-2'-O-rhamnoside, and cyanidin-3 rutinoside) were identified only in the good chapatti variety and four PCs (tricin, apigenindin, quercetin-3-O-glucuronide, and myricetin-3-glucoside) in the poor chapatti variety. Therefore, about 20% of the identified PCs are unique to each other and may be "variety or genotype" specific PCs. Fourteen PCs used for quantification showed high variation between the varieties. The microarray data of 44 phenolic compound biosynthesis genes and 17 of them on qRT-PCR showed variation in expression level during seed development and majority of them showed low expression in the good chapatti variety. The expression pattern in the good chapatti variety was largely in agreement with that of phenolic compounds. The level of variation of 12 genes was high between the good and poor chapatti quality varieties and has potential in development of markers. The information generated in this study can be extended onto a larger germplasm set for development of molecular markers using QTL and/or association mapping approaches for their application in wheat breeding. PMID- 28018404 TI - Functional and Integrative Analysis of the Proteomic Profile of Radish Root under Pb Exposure. AB - Lead (Pb) is one of the most abundant heavy metal (HM) pollutants, which can penetrate the plant through the root and then enter the food chain causing potential health risks for human beings. Radish is an important root vegetable crop worldwide. To investigate the mechanism underlying plant response to Pb stress in radish, the protein profile changes of radish roots respectively upon Pb(NO3)2 at 500 mg L-1(Pb500) and 1000 mg L-1(Pb1000), were comprehensively analyzed using iTRAQ (Isobaric Tag for Relative and Absolute Quantification). A total of 3898 protein species were successfully detected and 2141 were quantified. Among them, a subset of 721 protein species were differentially accumulated upon at least one Pb treatment, and 135 ones showed significantly abundance changes under both two Pb-stressed conditions. Many critical protein species related to protein translation, processing, and degradation, reactive oxygen species (ROS) scavenging, photosynthesis, and respiration and carbon metabolism were successfully identified. Gene Ontology (GO) and pathway enrichment analysis of the 135 differential abundance protein species (DAPS) revealed that the overrepresented GO terms included "cell wall," "apoplast," "response to metal ion," "vacuole," and "peroxidase activity," and the critical enriched pathways were involved in "citric acid (TCA) cycle and respiratory electron transport," "pyruvate metabolism," "phenylalanine metabolism," "phenylpropanoid biosynthesis," and "carbon metabolism." Furthermore, the integrative analysis of transcriptomic, miRNA, degradome, metabolomics and proteomic data provided a strengthened understanding of radish response to Pb stress at multiple levels. Under Pb stress, many key enzymes (i.e., ATP citrate lyase, Isocitrate dehydrogenase, fumarate hydratase and malate dehydrogenase) involved in the glycolysis and TCA cycle were severely affected, which ultimately cause alteration of some metabolites including glucose, citrate and malate. Meanwhile, a series of other defense responses including ascorbate (ASA) glutathione (GSH) cycle for ROS scavenging and Pb-defense protein species (glutaredoxin, aldose 1-epimerase malate dehydrogenase and thioredoxin), were triggered to cope with Pb-induced injuries. These results would be helpful for further dissecting molecular mechanism underlying plant response to HM stresses, and facilitate effective management of HM contamination in vegetable crops by genetic manipulation. PMID- 28018405 TI - Modulation of Legume Defense Signaling Pathways by Native and Non-native Pea Aphid Clones. AB - The pea aphid (Acyrthosiphon pisum) is a complex of at least 15 genetically different host races that are native to specific legume plants, but can all develop on the universal host plant Vicia faba. Despite much research, it is still unclear why pea aphid host races (biotypes) are able to colonize their native hosts while other host races are not. All aphids penetrate the plant and salivate into plant cells when they test plant suitability. Thus plants might react differently to the various pea aphid host races. To find out whether legume species vary in their defense responses to different pea aphid host races, we measured the amounts of salicylic acid (SA), the jasmonic acid-isoleucine conjugate (JA-Ile), other jasmonate precursors and derivatives, and abscisic acid (ABA) in four different species (Medicago sativa, Trifolium pratense, Pisum sativum, V. faba) after infestation by native and non-native pea aphid clones of various host races. Additionally, we assessed the performance of the clones on the four plant species. On M. sativa and T. pratense, non-native clones that were barely able to survive or reproduce, triggered a strong SA and JA-Ile response, whereas infestation with native clones led to lower levels of both phytohormones. On P. sativum, non-native clones, which survived or reproduced to a certain extent, induced fluctuating SA and JA-Ile levels, whereas the native clone triggered only a weak SA and JA-Ile response. On the universal host V. faba all aphid clones triggered only low SA levels initially, but induced clone-specific patterns of SA and JA-Ile later on. The levels of the active JA-Ile conjugate and of the other JA-pathway metabolites measured showed in many cases similar patterns, suggesting that the reduction in JA signaling was due to an effect upstream of OPDA. ABA levels were downregulated in all aphid clone-plant combinations and were therefore probably not decisive factors for aphid-plant compatibility. Our results suggest that A. pisum clones manipulate plant-defense signaling to their own advantage, and perform better on their native hosts due to their ability to modulate the SA- and JA-defense signaling pathways. PMID- 28018407 TI - Indications of Selenium Protection against Cadmium and Lead Toxicity in Oilseed Rape (Brassica napus L.). AB - The present study investigated the beneficial role of selenium (Se) in protecting oilseed rape (Brassica napus L.) plants from cadmium (Cd+2) and lead (Pb+2) toxicity. Exogenous Se markedly reduced Cd and Pb concentration in both roots and shoots. Supplementation of the medium with Se (5, 10, and 15 mg kg-1) alleviated the negative effect of Cd and Pb on growth and led to a decrease in oxidative damages caused by Cd and Pb. Furthermore, Se-enhanced superoxide free radicals ([Formula: see text]), hydrogen peroxide (H2O2), and lipid peroxidation, as indicated by malondialdehyde accumulation, but decreased superoxide dismutase and glutathione peroxidase activities. Meanwhile, the presence of Cd and Pb in the medium affected Se speciation in shoots. The results suggest that Se could alleviate Cd and Pb toxicity by preventing oxidative stress in oilseed rape plant. PMID- 28018406 TI - Structural, Evolutionary, and Functional Analysis of the Class III Peroxidase Gene Family in Chinese Pear (Pyrus bretschneideri). AB - Peroxidases (PRXs) are widely existed in various organisms and could be divided into different types according to their structures and functions. Specifically, the Class III Peroxidase, a plant-specific multi-gene family, involves in many physiological processes, such as the metabolism of auxin, the extension and thickening of cell wall, as well as the formation of lignin. By searching the pear genome database, 94 non-redundant PRXs from Pyrus bretschneideri (PbPRXs) were identified. Subsequently, analysis of phylogenetic relationships, gene structures, conserved motifs, and microsynteny was performed. These PbPRXs were unevenly distributed among 17 chromosomes of pear. In addition, 26 segmental duplication events but only one tandem duplication were occurred in these PbPRXs, implying segmental duplication was the main contributor to the expansion of the PbPRX family. By the Ka/Ks analysis, 26 out of 27 duplicated PbPRXs has experienced purifying selection. Twenty motifs were identified in PbPRXs based on the MEME analysis, 11 of which were enriched in pear. A total of 41 expressed genes were identified from ESTs of pear fruit. According to qRT-PCR, the expression trends of five PbPRXs in subgroup C were consistent with the change of lignin content during pear fruit development. So we inferred that the five PbPRXs were candidate genes involved in the lignin synthesis pathway. These results provided useful information for further researches of PRX genes in pear. PMID- 28018408 TI - Integrating High Resolution Water Footprint and GIS for Promoting Water Efficiency in the Agricultural Sector: A Case Study of Plantation Crops in the Jordan Valley. AB - Addressing the global challenges to water security requires a better understanding of humanity's use of water, especially the agricultural sector that accounts for 70% of global withdrawals. This study combined high resolution-data with a GIS system to analyze the impact of agricultural practices, crop type, and spatial factors such as drainage basins, climate, and soil type on the Water Footprint (WF) of agricultural crops. The area of the study, the northern Lower Jordan Valley, covers 1121 ha in which three main plantation crops are grown: banana (cultivated in open-fields or net-houses), avocado and palm-dates. High resolution data sources included GIS layers of the cultivated crops and a drainage pipe-system installed in the study area; meteorological data (2000 2013); and crop parameters (yield and irrigation recommendations). First, the study compared the WF of the different crops on the basis of yield and energy produced as well as a comparison to global values and local irrigation recommendations. The results showed that net-house banana has the lowest WF based on all different criteria. However, while palm-dates showed the highest WF for the yield criteria, it had the second lowest WF for energy produced, emphasizing the importance of using multiple parameters for low and high yield crop comparisons. Next, the regional WF of each drainage basin in the study area was calculated, demonstrating the strong influence of the Gray WF, an indication of the amount of freshwater required for pollution assimilation. Finally, the benefits of integrating GIS and WF were demonstrated by computing the effect of adopting net-house cultivation throughout the area of study with a result a reduction of 1.3 MCM irrigation water per year. Integrating the WF methodology and local high-resolution data using GIS can therefore promote and help quantify the benefits of adopting site-appropriate crops and agricultural practices that lower the WF by increasing yield, reducing water consumption, and minimizing negative environmental impacts. PMID- 28018409 TI - Mechanical Behavior of Cells within a Cell-Based Model of Wheat Leaf Growth. AB - Understanding the principles and mechanisms of cell growth coordination in plant tissue remains an outstanding challenge for modern developmental biology. Cell based modeling is a widely used technique for studying the geometric and topological features of plant tissue morphology during growth. We developed a quasi-one-dimensional model of unidirectional growth of a tissue layer in a linear leaf blade that takes cell autonomous growth mode into account. The model allows for fitting of the visible cell length using the experimental cell length distribution along the longitudinal axis of a wheat leaf epidermis. Additionally, it describes changes in turgor and osmotic pressures for each cell in the growing tissue. Our numerical experiments show that the pressures in the cell change over the cell cycle, and in symplastically growing tissue, they vary from cell to cell and strongly depend on the leaf growing zone to which the cells belong. Therefore, we believe that the mechanical signals generated by pressures are important to consider in simulations of tissue growth as possible targets for molecular genetic regulators of individual cell growth. PMID- 28018410 TI - Molecular Evolution and Expression Divergence of the Aconitase (ACO) Gene Family in Land Plants. AB - Aconitase (ACO) is a key enzyme that catalyzes the isomerization of citrate to isocitrate in the tricarboxylic acid (TCA) and glyoxylate cycles. The function of ACOs has been well studied in model plants, such as Arabidopsis. In contrast, the evolutionary patterns of the ACO family in land plants are poorly understood. In this study, we systematically examined the molecular evolution and expression divergence of the ACO gene family in 12 land plant species. Thirty-six ACO genes were identified from the 12 land plant species representing the four major land plant lineages: Bryophytes, lycophytes, gymnosperms, and angiosperms. All of these ACOs belong to the cytosolic isoform. Three gene duplication events contributed to the expansion of the ACO family in angiosperms. The ancestor of angiosperms may have contained only one ACO gene. One gene duplication event split angiosperm ACOs into two distinct clades. Two clades showed a divergence in selective pressure and gene expression patterns. The cis-acting elements that function in light responsiveness were most abundant in the promoter region of the ACO genes, indicating that plant ACO genes might participate in light regulatory pathways. Our findings provide comprehensive insights into the ACO gene family in land plants. PMID- 28018411 TI - Melatonin Regulates Root Meristem by Repressing Auxin Synthesis and Polar Auxin Transport in Arabidopsis. AB - Melatonin (N-acetyl-5-methoxytryptamine) plays important roles in regulating both biotic and abiotic stress tolerance, biological rhythms, plant growth and development. Sharing the same substrate (tryptophan) for the biosynthesis, melatonin and auxin also have similar effects in plant development. However, the specific function of melatonin in modulating plant root growth and the relationship between melatonin and auxin as well as underlying mechanisms are still unclear. In this study, we found high concentration of melatonin remarkably inhibited root growth in Arabidopsis by reducing root meristem size. Further studies showed that melatonin negatively regulated auxin biosynthesis, the expression of PINFORMED (PIN) proteins as well as auxin response in Arabidopsis. Moreover, the root growth of the triple mutant pin1pin3pin7 was more tolerant than that of wild-type in response to melatonin treatment, suggesting the essential role of PIN1/3/7 in melatonin-mediated root growth. Combination treatment of melatonin and 5-Triiodobenzoic acid (TIBA) did not enhance melatonin mediated reduction of root meristem size, indicating that polar auxin transport (PAT) may be necessary for the regulation of root meristem size by melatonin treatment. Taken together, this study indicates that melatonin regulates root growth in Arabidopsis, through auxin synthesis and polar auxin transport, at least partially. PMID- 28018412 TI - The Role and Regulation of ABI5 (ABA-Insensitive 5) in Plant Development, Abiotic Stress Responses and Phytohormone Crosstalk. AB - ABA Insensitive 5 (ABI5) is a basic leucine zipper transcription factor that plays a key role in the regulation of seed germination and early seedling growth in the presence of ABA and abiotic stresses. ABI5 functions in the core ABA signaling, which is composed of PYR/PYL/RCAR receptors, PP2C phosphatases and SnRK2 kinases, through the regulation of the expression of genes that contain the ABSCISIC ACID RESPONSE ELEMENT (ABRE) motif within their promoter region. The regulated targets include stress adaptation genes, e.g., LEA proteins. However, the expression and activation of ABI5 is not only dependent on the core ABA signaling. Many transcription factors such as ABI3, ABI4, MYB7 and WRKYs play either a positive or a negative role in the regulation of ABI5 expression. Additionally, the stability and activity of ABI5 are also regulated by other proteins through post-translational modifications such as phosphorylation, ubiquitination, sumoylation and S-nitrosylation. Moreover, ABI5 also acts as an ABA and other phytohormone signaling integrator. Components of auxin, cytokinin, gibberellic acid, jasmonate and brassinosteroid signaling and metabolism pathways were shown to take part in ABI5 regulation and/or to be regulated by ABI5. Monocot orthologs of AtABI5 have been identified. Although their roles in the molecular and physiological adaptations during abiotic stress have been elucidated, knowledge about their detailed action still remains elusive. Here, we describe the recent advances in understanding the action of ABI5 in early developmental processes and the adaptation of plants to unfavorable environmental conditions. We also focus on ABI5 relation to other phytohormones in the abiotic stress response of plants. PMID- 28018413 TI - Setaria: A Food Crop and Translational Research Model for C4 Grasses. PMID- 28018414 TI - MADS-Box Genes and Gibberellins Regulate Bolting in Lettuce (Lactuca sativa L.). AB - Bolting in lettuce is promoted by high temperature and bolting resistance is of great economic importance for lettuce production. But how bolting is regulated at the molecular level remains elusive. Here, a bolting resistant line S24 and a bolting sensitive line S39 were selected for morphological, physiological, transcriptomic and proteomic comparisons. A total of 12204 genes were differentially expressed in S39 vs. S24. Line S39 was featured with larger leaves, higher levels of chlorophyll, soluble sugar, anthocyanin and auxin, consistent with its up-regulation of genes implicated in photosynthesis, oxidation-reduction and auxin actions. Proteomic analysis identified 30 differentially accumulated proteins in lines S39 and S24 upon heat treatment, and 19 out of the 30 genes showed differential expression in the RNA-Seq data. Exogenous gibberellins (GA) treatment promoted bolting in both S39 and S24, while 12 flowering promoting MADS-box genes were specifically induced in line S39, suggesting that although GA regulates bolting in lettuce, it may be the MADS-box genes, not GA, that plays a major role in differing the bolting resistance between these two lettuce lines. PMID- 28018415 TI - A Halotolerant Bacterium Bacillus licheniformis HSW-16 Augments Induced Systemic Tolerance to Salt Stress in Wheat Plant (Triticum aestivum). AB - Certain plant growth promoting bacteria can protect associated plants from harmful effects of salinity. We report the isolation and characterization of 1 aminocyclopropane-1-carboxylic acid (ACC) deaminase bacterium Bacillus licheniformis HSW-16 capable of ameliorating salt (NaCl) stress in wheat plants. The bacterium was isolated from the water of Sambhar salt lake, Rajasthan, India. The presence of ACC deaminase activity was confirmed by enzyme assay and analysis of AcdS gene, a structural gene for ACC deaminase. Inoculation of B. licheniformis HSW-16 protected wheat plants from growth inhibition caused by NaCl and increased plant growth (6-38%) in terms of root length, shoot length, fresh weight, and dry weight. Ionic analysis of plant samples showed that the bacterial inoculation decreased the accumulation of Na+ content (51%), and increased K+ (68%), and Ca2+ content (32%) in plants at different concentration of NaCl. It suggested that bacterial inoculation protected plants from the effect of NaCl by decreasing the level of Na+ in plants. Production of exopolysaccharide by the B. licheniformis HSW-16 can also protect from Na+ by binding this ion. Moreover, application of test isolate resulted in an increase in certain osmolytes such as total soluble sugar, total protein content, and a decrease in malondialdehyde content, illustrating their role in the protection of plants. The ability of B. licheniformis HSW-16 to colonize plant root surface was examined by staining the bacterium with acridine orange followed by fluorescence microscopy and polymerase chain reaction-based DNA finger printing analysis. These results suggested that B. licheniformis HSW-16 could be used as a bioinoculant to improve the productivity of plants growing under salt stress. PMID- 28018416 TI - Functional and RNA-Sequencing Analysis Revealed Expression of a Novel Stay-Green Gene from Zoysia japonica (ZjSGR) Caused Chlorophyll Degradation and Accelerated Senescence in Arabidopsis. AB - Senescence is not only an important developmental process, but also a responsive regulation to abiotic and biotic stress for plants. Stay-green protein plays crucial roles in plant senescence and chlorophyll degradation. However, the underlying mechanisms were not well-studied, particularly in non-model plants. In this study, a novel stay-green gene, ZjSGR, was isolated from Zoysia japonica. Subcellular localization result demonstrated that ZjSGR was localized in the chloroplasts. Quantitative real-time PCR results together with promoter activity determination using transgenic Arabidopsis confirmed that ZjSGR could be induced by darkness, ABA and MeJA. Its expression levels could also be up-regulated by natural senescence, but suppressed by SA treatments. Overexpression of ZjSGR in Arabidopsis resulted in a rapid yellowing phenotype; complementary experiments proved that ZjSGR was a functional homolog of AtNYE1 from Arabidopsis thaliana. Over expression of ZjSGR accelerated chlorophyll degradation and impaired photosynthesis in Arabidopsis. Transmission electron microscopy observation revealed that overexpression of ZjSGR decomposed the chloroplasts structure. RNA sequencing analysis showed that ZjSGR could play multiple roles in senescence and chlorophyll degradation by regulating hormone signal transduction and the expression of a large number of senescence and environmental stress related genes. Our study provides a better understanding of the roles of SGRs, and new insight into the senescence and chlorophyll degradation mechanisms in plants. PMID- 28018417 TI - Arabinogalactan Proteins as Interactors along the Crosstalk between the Pollen Tube and the Female Tissues. AB - Arabinogalactan proteins (AGPs) have long been considered to be implicated in several steps of the reproductive process of flowering plants. Pollen tube growth along the pistil tissues requires a multiplicity of signaling pathways to be activated and turned off precisely, at crucial timepoints, to guarantee successful fertilization and seed production. In the recent years, an outstanding effort has been made by the plant reproduction scientific community in order to better understand this process. This resulted in the discovery of a fairly substantial number of new players essential for reproduction, as well as their modes of action and interactions. Besides all the indications of AGPs involvement in reproduction, there were no convincing evidences about it. Recently, several studies came out to prove what had long been suggested about this complex family of glycoproteins. AGPs consist of a large family of hydroxyproline-rich proteins, predicted to be anchored to the plasma membrane and extremely rich in sugars. These two last characteristics always made them perfect candidates to be involved in signaling mechanisms, in several plant developmental processes. New findings finally relate AGPs to concrete functions in plant reproduction. In this review, it is intended not only to describe how different molecules and signaling pathways are functioning to achieve fertilization, but also to integrate the recent discoveries about AGPs along this process. PMID- 28018418 TI - Plastoquinone and Ubiquinone in Plants: Biosynthesis, Physiological Function and Metabolic Engineering. AB - Plastoquinone (PQ) and ubiquinone (UQ) are two important prenylquinones, functioning as electron transporters in the electron transport chain of oxygenic photosynthesis and the aerobic respiratory chain, respectively, and play indispensable roles in plant growth and development through participating in the biosynthesis and metabolism of important chemical compounds, acting as antioxidants, being involved in plant response to stress, and regulating gene expression and cell signal transduction. UQ, particularly UQ10, has also been widely used in people's life. It is effective in treating cardiovascular diseases, chronic gingivitis and periodontitis, and shows favorable impact on cancer treatment and human reproductive health. PQ and UQ are made up of an active benzoquinone ring attached to a polyisoprenoid side chain. Biosynthesis of PQ and UQ is very complicated with more than thirty five enzymes involved. Their synthetic pathways can be generally divided into two stages. The first stage leads to the biosynthesis of precursors of benzene quinone ring and prenyl side chain. The benzene quinone ring for UQ is synthesized from tyrosine or phenylalanine, whereas the ring for PQ is derived from tyrosine. The prenyl side chains of PQ and UQ are derived from glyceraldehyde 3-phosphate and pyruvate through the 2-C-methyl-D-erythritol 4-phosphate pathway and/or acetyl-CoA and acetoacetyl-CoA through the mevalonate pathway. The second stage includes the condensation of ring and side chain and subsequent modification. Homogentisate solanesyltransferase, 4-hydroxybenzoate polyprenyl diphosphate transferase and a series of benzene quinone ring modification enzymes are involved in this stage. PQ exists in plants, while UQ widely presents in plants, animals and microbes. Many enzymes and their encoding genes involved in PQ and UQ biosynthesis have been intensively studied recently. Metabolic engineering of UQ10 in plants, such as rice and tobacco, has also been tested. In this review, we summarize and discuss recent research progresses in the biosynthetic pathways of PQ and UQ and enzymes and their encoding genes involved in side chain elongation and in the second stage of PQ and UQ biosynthesis. Physiological functions of PQ and UQ played in plants as well as the practical application and metabolic engineering of PQ and UQ are also included. PMID- 28018419 TI - Bamboo Flowering from the Perspective of Comparative Genomics and Transcriptomics. AB - Bamboos are an important member of the subfamily Bambusoideae, family Poaceae. The plant group exhibits wide variation with respect to the timing (1-120 years) and nature (sporadic vs. gregarious) of flowering among species. Usually flowering in woody bamboos is synchronous across culms growing over a large area, known as gregarious flowering. In many monocarpic bamboos this is followed by mass death and seed setting. While in sporadic flowering an isolated wild clump may flower, set little or no seed and remain alive. Such wide variation in flowering time and extent means that the plant group serves as repositories for genes and expression patterns that are unique to bamboo. Due to the dearth of available genomic and transcriptomic resources, limited studies have been undertaken to identify the potential molecular players in bamboo flowering. The public release of the first bamboo genome sequence Phyllostachys heterocycla, availability of related genomes Brachypodium distachyon and Oryza sativa provide us the opportunity to study this long-standing biological problem in a comparative and functional genomics framework. We identified bamboo genes homologous to those of Oryza and Brachypodium that are involved in established pathways such as vernalization, photoperiod, autonomous, and hormonal regulation of flowering. Additionally, we investigated triggers like stress (drought), physiological maturity and micro RNAs that may play crucial roles in flowering. We also analyzed available transcriptome datasets of different bamboo species to identify genes and their involvement in bamboo flowering. Finally, we summarize potential research hurdles that need to be addressed in future research. PMID- 28018420 TI - Allocation of Nitrogen and Carbon Is Regulated by Nodulation and Mycorrhizal Networks in Soybean/Maize Intercropping System. AB - Soybean/maize intercropping has remarkable advantages in increasing crop yield and nitrogen (N) efficiency. However, little is known about the contributions of rhizobia or arbuscular mycorrhizal fungi (AMF) to yield increases and N acquisition in the intercropping system. Plus, the mechanisms controlling carbon (C) and N allocation in intercropping systems remain unsettled. In the present study, a greenhouse experiment combined with 15N and 13C labeling was conducted using various inoculation and nutrient treatments. The results showed that co inoculation with AMF and rhizobia dramatically increased biomass and N content of soybean and maize, and moderate application of N and phosphorus largely amplified the effect of co-inoculation. Maize had a competitive advantage over soybean only under co-inoculation and moderate nutrient availability conditions, indicating that the effects of AMF and rhizobia in intercropping systems are closely related to nutrient status. Results from 15N labeling showed that the amount of N transferred from soybean to maize in co-inoculations was 54% higher than that with AMF inoculation alone, with this increased N transfer partly resulting from symbiotic N fixation. The results from 13C labeling showed that 13C content increased in maize shoots and decreased in soybean roots with AMF inoculation compared to uninoculated controls. Yet, with co-inoculation, 13C content increased in soybean. These results indicate that photosynthate assimilation is stimulated by AM symbiosis in maize and rhizobial symbiosis in soybean, but AMF inoculation leads to soybean investing more carbon than maize into common mycorrhizal networks (CMNs). Overall, the results herein demonstrate that the growth advantage of maize when intercropped with soybean is due to acquisition of N by maize via CMNs while this crop contributes less C into CMNs than soybean under co-inoculation conditions. PMID- 28018421 TI - Differences in Crenate Broomrape Parasitism Dynamics on Three Legume Crops Using a Thermal Time Model. AB - Root parasitic weeds are a major limiting production factor in a number of crops, and control is difficult. Genetic resistance and chemical control lead the fight, but without unequivocal success. Models that help to describe and even predict the evolution of parasitism underground are a valuable tool for herbicide applications, and even could help in breeding programs. Legumes are heavily affected by Orobanche crenata (crenate broomrape) in the Mediterranean basin. This work presents a descriptive model based on thermal time and correlating growing degree days (GDD) with the different developmental stages of the parasite. The model was developed in three different legume crops (faba bean, grass pea and lentil) attacked by crenate broomrape. The developmental stages of the parasite strongly correlated with the GDD and differences were found depending on the host crop. PMID- 28018422 TI - Calcineurin B-like Protein CBL10 Directly Interacts with TOC34 (Translocon of the Outer Membrane of the Chloroplasts) and Decreases Its GTPase Activity in Arabidopsis. AB - As calcium sensor relays in plants, calcineurin B-like (CBL) proteins provide an important contribution to decoding Ca2+ signatures elicited by a variety of abiotic stresses. Currently, it is well known that CBLs perceive and transmit the Ca2+ signals mainly to a group of serine/threonine protein kinases called CBL interacting protein kinases (CIPKs). In this study, we report that the CBL10 member of this family has a novel interaction partner besides the CIPK proteins. Yeast two-hybrid screening with CBL10 as bait identified an Arabidopsis cDNA clone encoding a TOC34 protein, which is a member of the TOC (Translocon of the Outer membrane of the Chloroplasts) complex and possesses the GTPase activity. Further analyses showed that in addition to CBL10, CBL7 also interacts with TOC34 at much lower strength in the yeast two-hybrid system. However, the rest of the CBL family members failed to interact with TOC34. Bimolecular fluorescence complementation (BiFC) analysis verified that the CBL10-TOC34 interaction occurs at the outer membrane of chloroplasts in vivo. In addition, we also demonstrated that CBL10 physically associates with TOC34 in vitro, resulting in a significant decrease in the GTPase activity of the TOC34 protein. Taken together, our findings clearly indicate that a member of the CBL family, CBL10, can modulate not only the CIPK members but also TOC34, allowing the CBL family to relay the Ca2+ signals in more diverse ways than currently known. PMID- 28018423 TI - A Meta-Analysis Based Method for Prioritizing Candidate Genes Involved in a Pre specific Function. AB - The identification of genes associated with a given biological function in plants remains a challenge, although network-based gene prioritization algorithms have been developed for Arabidopsis thaliana and many non-model plant species. Nevertheless, these network-based gene prioritization algorithms have encountered several problems; one in particular is that of unsatisfactory prediction accuracy due to limited network coverage, varying link quality, and/or uncertain network connectivity. Thus, a model that integrates complementary biological data may be expected to increase the prediction accuracy of gene prioritization. Toward this goal, we developed a novel gene prioritization method named RafSee, to rank candidate genes using a random forest algorithm that integrates sequence, evolutionary, and epigenetic features of plants. Subsequently, we proposed an integrative approach named RAP (Rank Aggregation-based data fusion for gene Prioritization), in which an order statistics-based meta-analysis was used to aggregate the rank of the network-based gene prioritization method and RafSee, for accurately prioritizing candidate genes involved in a pre-specific biological function. Finally, we showcased the utility of RAP by prioritizing 380 flowering time genes in Arabidopsis. The "leave-one-out" cross-validation experiment showed that RafSee could work as a complement to a current state-of-art network-based gene prioritization system (AraNet v2). Moreover, RAP ranked 53.68% (204/380) flowering-time genes higher than AraNet v2, resulting in an 39.46% improvement in term of the first quartile rank. Further evaluations also showed that RAP was effective in prioritizing genes-related to different abiotic stresses. To enhance the usability of RAP for Arabidopsis and non-model plant species, an R package implementing the method is freely available at http://bioinfo.nwafu.edu.cn/software. PMID- 28018424 TI - Evaluation of Forensic DNA Traces When Propositions of Interest Relate to Activities: Analysis and Discussion of Recurrent Concerns. AB - When forensic scientists evaluate and report on the probative strength of single DNA traces, they commonly rely on only one number, expressing the rarity of the DNA profile in the population of interest. This is so because the focus is on propositions regarding the source of the recovered trace material, such as "the person of interest is the source of the crime stain." In particular, when the alternative proposition is "an unknown person is the source of the crime stain," one is directed to think about the rarity of the profile. However, in the era of DNA profiling technology capable of producing results from small quantities of trace material (i.e., non-visible staining) that is subject to easy and ubiquitous modes of transfer, the issue of source is becoming less central, to the point that it is often not contested. There is now a shift from the question "whose DNA is this?" to the question "how did it get there?" As a consequence, recipients of expert information are now very much in need of assistance with the evaluation of the meaning and probative strength of DNA profiling results when the competing propositions of interest refer to different activities. This need is widely demonstrated in day-to-day forensic practice and is also voiced in specialized literature. Yet many forensic scientists remain reluctant to assess their results given propositions that relate to different activities. Some scientists consider evaluations beyond the issue of source as being overly speculative, because of the lack of relevant data and knowledge regarding phenomena and mechanisms of transfer, persistence and background of DNA. Similarly, encouragements to deal with these activity issues, expressed in a recently released European guideline on evaluative reporting (Willis et al., 2015), which highlights the need for rethinking current practice, are sometimes viewed skeptically or are not considered feasible. In this discussion paper, we select and discuss recurrent skeptical views brought to our attention, as well as some of the alternative solutions that have been suggested. We will argue that the way forward is to address now, rather than later, the challenges associated with the evaluation of DNA results (from small quantities of trace material) in light of different activities to prevent them being misrepresented in court. PMID- 28018425 TI - The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem. AB - Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. Specifically, the ratio of Chi-square disease association statistics at a marker site and causal site is equivalent to the standard measure of pairwise linkage disequilibrium, r2. A complete derivation of this relationship from a general disease model is shown. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non interrogated causal site using data at closely linked markers. Lastly, we apply this way of examining association data from high-density genotyping in a large, publicly-available data set investigating extreme BMI. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods and provide new avenues for identifying causal sites/genes from fine-mapping studies. PMID- 28018426 TI - Combination of Five Body Positions Can Effectively Improve the Rate of Gastric Mucosa's Complete Visualization by Applying Magnetic-Guided Capsule Endoscopy. AB - Objectives. Achieving a comprehensive view of gastric mucosa has been a challenge for magnetic-guided capsule endoscopy (MGCE) for years. This study works on optimizing the performance of MGCE by changing the conventional positions to the five body positions. Methods. Sixty patients were enrolled in the study and underwent MGCE. All patients were asked to adopt five body positions (left lateral, supine, right lateral, knee-chest, and sitting). In each position, the ability to visualize the six gastric landmarks (cardia, fundus, body, angulus, antrum, and pylorus) was assessed. Rates of complete visualization were calculated for different position combinations. Results. Supine position was the best for cardia and body visualization (91.7% and 86.7%, resp., p < 0.001). Left lateral position was the best for fundus visualization (91.7%, p < 0.001). Knee chest position was the best for angulus observation (80.0%, p < 0.001). Right lateral and sitting positions were the best for antrum observation (88.3% and 90.0%, resp., p < 0.001). Right lateral position was the best for pylorus observation (81.7%, p < 0.001). The supine + right lateral + knee-chest combination achieved better angulus visualization than conventional 3-position combination (93.3% versus 63.3%, p < 0.001). Five-position combination significantly improved the comprehensive gastric landmark visualization (93.3%, p < 0.001). Conclusion. Compared with 3-position combination, 5-position combination should be adopted for gastric mucosal visualization by MGCE. PMID- 28018427 TI - Successful Nonoperative Management of High-Grade Blunt Renal Injuries. AB - Current management of high-grade blunt renal trauma favors a nonoperative approach when possible. We performed a retrospective study of high grade blunt renal injuries at our level I trauma center to determine the indications and success of nonoperative management (NOM). 47 patients with blunt grade IV or V injuries were identified between October 2004 and December 2013. Immediate operative patients (IO) were compared to nonoperatively managed (NOM). Of the 47 patients, 3 (6.4%) were IO and 44 (95.6%) NOM. IO patients had a higher heart rate on admission, 133 versus 100 in NOM (P = 0.01). IO patients had a higher rate of injury to the renal vein or artery (100%) compared to NOM group (18%) (P = 0.01). NOM failed in 3 of 44 patients (6.8%). Two required nonemergent nephrectomy and one required emergent exploration resulting in nephrectomy. Six NOM patients had kidney-related complications (13.6%). The renal salvage rate for the entire cohort was 87.2% and 93.2% for NOM. Nonoperative management for hemodynamically stable patients with high-grade blunt renal trauma is safe with a low risk of complications. Management decisions should consider hemodynamic status and visualization of active renal bleeding as well as injury grade in determining operative management. PMID- 28018428 TI - Pancreatic Surgery in the Older Population: A Single Institution's Experience over Two Decades. AB - Objectives. Surgery is the most effective treatment for pancreatic cancer. However, present literature varies on outcomes of curative pancreatic resection in the elderly. The objective of the study was to evaluate age as an independent risk factor for 90-day mortality and complications after pancreatic resection. Methods. Nine hundred twenty-nine consecutive patients underwent 934 pancreatic resections between March 1995 and July 2014 in a tertiary care center. Primary analyses focused on outcomes in terms of 90-day mortality and postoperative complications after pancreatic resection in these two age groups. Results. Even though patients aged 75 years or older had significantly more postoperative morbidities compared with the younger patient group, the age group was not associated with increased risk of 90-day mortality after pancreatic resection. Discussion. The study suggests that age alone should not preclude patients from undergoing curative pancreatic resection. PMID- 28018429 TI - 408 Cases of Genital Ambiguity Followed by Single Multidisciplinary Team during 23 Years: Etiologic Diagnosis and Sex of Rearing. AB - Objective. To evaluate diagnosis, age of referral, karyotype, and sex of rearing of cases with disorders of sex development (DSD) with ambiguous genitalia. Methods. Retrospective study during 23 years at outpatient clinic of a referral center. Results. There were 408 cases; 250 (61.3%) were 46,XY and 124 (30.4%) 46,XX and 34 (8.3%) had sex chromosomes abnormalities. 189 (46.3%) had 46,XY testicular DSD, 105 (25.7%) 46,XX ovarian DSD, 95 (23.3%) disorders of gonadal development (DGD), and 19 (4.7%) complex malformations. The main etiology of 46,XX ovarian DSD was salt-wasting 21-hydroxylase deficiency. In 46,XX and 46,XY groups, other malformations were observed. In the DGD group, 46,XY partial gonadal dysgenesis, mixed gonadal dysgenesis, and ovotesticular DSD were more frequent. Low birth weight was observed in 42 cases of idiopathic 46,XY testicular DSD. The average age at diagnosis was 31.7 months. The final sex of rearing was male in 238 cases and female in 170. Only 6.6% (27 cases) needed sex reassignment. Conclusions. In this large DSD sample with ambiguous genitalia, the 46,XY karyotype was the most frequent; in turn, congenital adrenal hyperplasia was the most frequent etiology. Malformations associated with DSD were common in all groups and low birth weight was associated with idiopathic 46,XY testicular DSD. PMID- 28018430 TI - GC Gene Polymorphisms and Vitamin D-Binding Protein Levels Are Related to the Risk of Generalized Aggressive Periodontitis. AB - Objective. To explore whether GC (group-specific component) rs17467825, rs4588, and rs7041 polymorphisms are associated with generalized aggressive periodontitis. Methods. This case-control study recruited 372 patients with generalized aggressive periodontitis (group AgP) and 133 periodontal healthy subjects (group HP). GC rs17467825, rs4588, and rs7041 genotypes and plasmatic vitamin D-binding protein (DBP) were measured. Analysis of single SNP and multiple SNPs was performed and relevance between plasmatic DBP and haplotypes was analyzed. Results. GC rs17467825 GG genotype was statistically associated with lower risk for generalized aggressive periodontitis under the recessive model (OR = 0.52, 95% CI: 0.30-0.92, p = 0.028). GC rs17467825 and rs4588 had strong linkage disequilibrium with r2 >= 0.8 and D' >= 0.8. Haplotype (GC rs17467825, rs4588) GC was associated with the less risk for generalized aggressive periodontitis (OR = 0.29, 95% CI: 0.09-0.96, p = 0.043). In group AgP, individuals with combined genotype (GC rs17467825, rs4588) AG+CA had significantly lower plasmatic DBP level than those with the other two combined genotypes (AG+CA versus AA+CC p = 0.007; AG+CA versus GG+AA p = 0.026). Conclusions. GC rs17467825 genotype GG and haplotype (GC rs17467825, rs4588) GC are associated with generalized aggressive periodontitis. The association may be acquired through regulating DBP levels. The functions of GC gene and DBP in inflammatory disease need to be further studied. PMID- 28018431 TI - Genetic and Clinical Features of Medullary Thyroid Carcinoma: The Experience of a Single Center in Costa Rica. AB - Background. Activating mutations in the RET gene leads to medullary thyroid carcinoma (MTC). Guidelines encourage performing RET analysis in subjects with hereditary and sporadic disease. Materials and Methods. Design. Observational, case series report study. Patients. Subjects diagnosed with MTC, with a thyroidectomy performed in a single center in Costa Rica between the years 2006 and 2015. Diagnosis and Follow-Up. Pre- and postoperative calcitonin, RET mutation, and neck ultrasound and tomography were obtained. Results. 21 subjects with histological diagnosis of MTC were followed up. The average age at diagnosis was 52.0 +/- 15.7 years. The preoperative mean value of calcitonin was 1340 +/- 665 pg/mL. Evidence of RET mutation was found in 26.3% of the patients, with only 2 of them grouped in the same kindred. We found statistically significant differences in mean ages between mutated (38.4 +/- 20.2 y) versus nonmutated RET gene (54.6 +/- 11.8 y, p = 0.04). There were no significant differences regarding tumor size, metastases, and surgical reintervention. Conclusions. We report the results of RET mutation analysis in subjects with MTC in a single center of Costa Rica. The availability of this tool increases the probability of identifying familial MTC, with the benefit of detecting affected subjects and their relatives at an earlier age. PMID- 28018432 TI - Adipose Derived-Mesenchymal Stem Cells Viability and Differentiating Features for Orthopaedic Reparative Applications: Banking of Adipose Tissue. AB - Osteoarthritis is characterized by loss of articular cartilage also due to reduced chondrogenic activity of mesenchymal stem cells (MSCs) from patients. Adipose tissue is an attractive source of MSCs (ATD-MSCs), representing an effective tool for reparative medicine, particularly for treatment of osteoarthritis, due to their chondrogenic and osteogenic differentiation capability. The treatment of symptomatic knee arthritis with ATD-MSCs proved effective with a single infusion, but multiple infusions could be also more efficacious. Here we studied some crucial aspects of adipose tissue banking procedures, evaluating ATD-MSCs viability, and differentiation capability after cryopreservation, to guarantee the quality of the tissue for multiple infusions. We reported that the presence of local anesthetic during lipoaspiration negatively affects cell viability of cryopreserved adipose tissue and cell growth of ATD-MSCs in culture. We observed that DMSO guarantees a faster growth of ATD MSCs in culture than trehalose. At last, ATD-MSCs derived from fresh and cryopreserved samples at -80 degrees C and -196 degrees C showed viability and differentiation ability comparable to fresh samples. These data indicate that cryopreservation of adipose tissue at -80 degrees C and -196 degrees C is equivalent and preserves the content of ATD-MSCs in Stromal Vascular Fraction (SVF), guaranteeing the differentiation ability of ATD-MSCs. PMID- 28018433 TI - Viral Agents Causing Acute Respiratory Infections in Children under Five: A Study from Eastern India. AB - Background. Acute respiratory infections (ARIs) are important cause of mortality and morbidity in children under five in developing country. Methods. This observational study was conducted over two-year period in a tertiary care teaching hospital of Eastern India. Nasal and throat swabs were collected, transported to the laboratory at 2-8 degrees C in viral transport media, and then processed for detection of viruses using mono/multiplex real-time polymerase chain reaction. Results. A total of 300 children aged 2-60 months with ARIs were included. The most common age group affected with LRI was 2-12 mo and with URI was >12-60 mo. Viruses were detected in 248 cases. In URI, 77 were positive for single virus and 19 were positive for more than one virus; in LRI, 113 were positive for single virus and 12 were positive for more than one virus. The most common viruses isolated from URI cases were rhinovirus and adenovirus. The most common viruses isolated from LRI cases were respiratory syncytial virus and influenza virus. Most cases occurred in the months of January, December, and August. Conclusion. Viruses constitute a significant cause of ARI in children under five. RSV, ADV, RV, and IFV were the most prevalent viruses isolated. PMID- 28018434 TI - A nonsense PAX6 mutation in a family with congenital aniridia. AB - Congenital aniridia is a rare ocular malformation that presents with severe hypoplasia of the iris and various ocular manifestations. Most cases of congenital aniridia are known to be related to mutations in the paired box gene-6 (PAX6), which is an essential gene in eye development. Herein, we report a familial case of autosomal dominant congenital aniridia with four affected members in 3 consecutive generations and describe the detailed ophthalmologic findings for one of these members. As expected, mutational analysis revealed a nonsense mutation (p.Ser122*) in the PAX6 gene. Thus, our findings reiterate the importance of PAX6 mutations in congenital aniridia. PMID- 28018435 TI - A familial case of Blau syndrome caused by a novel NOD2 genetic mutation. AB - Blau syndrome (BS) is a rare autosomal dominant, inflammatory syndrome that is characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are responsible for causing BS. To date, up to 30 Blau associated genetic mutations have been identified within this gene. We report a novel NOD2 genetic mutation that causes BS. A girl, aged 8 years, and her brother, aged 10 years, developed erythematous skin rashes and uveitis. The computed tomography angiogram of the younger sister showed features of midaortic dysplastic syndrome. The brother had more prominent joint involvement than the sister. Their father (38 years) was also affected by uveitis; however, only minimal skin involvement was observed in his case. The paternal aunt (39 years) and her daughter (13 years) were previously diagnosed with sarcoidosis. Mutational analysis revealed a novel c.1439 A>G mutation in the NOD2 gene in both siblings. The novel c.1439 A>G mutation in the NOD2 gene was found in a familial case of BS. Although BS is rare, it should always be considered in patients presenting with sarcoidosis-like features at a young age. Early diagnosis of BS and prompt multisystem workup including the eyes and joints can improve the patient's outcome. PMID- 28018436 TI - Chromosome 11q13 deletion syndrome. AB - Chromosome 11q13 deletion syndrome has been previously reported as either otodental syndrome or oculo-oto-dental syndrome. The otodental syndrome is characterized by dental abnormalities and high-frequency sensorineural hearing loss, and by ocular coloboma in some cases. The underlying genetic defect causing otodental syndrome is a hemizygous microdeletion involving the FGF3 gene on chromosome 11q13.3. Recently, a new form of severe deafness, microtia (small ear) and small teeth, without the appearance of eye abnormalities, was also reported. In this report, we describe a 1-year-old girl presenting with ptosis of the left upper eyelid, right auricular deformity, high-arched palate, delayed dentition, simian line on the right hand, microcephaly, and developmental delay. In this patient, we identified a deletion in the chromosome 11q13.2-q13.3 (2.75 Mb) region by using an array-comparative genomic hybridization analysis. The deletion in chromosome 11q13 results in a syndrome characterized by variable clinical manifestations. Some of these manifestations involve craniofacial dysmorphology and require a functional workup for hearing, ophthalmic examinations, and long term dental care. PMID- 28018437 TI - 1p36 deletion syndrome confirmed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. AB - Pediatric epilepsy can be caused by various conditions, including specific syndromes. 1p36 deletion syndrome is reported in 1 in 5,000-10,000 newborns, and its characteristic clinical features include developmental delay, mental retardation, hypotonia, congenital heart defects, seizure, and facial dysmorphism. However, detection of the terminal deletion in chromosome 1p by conventional G-banded karyotyping is difficult. Here we present a case of epilepsy with profound developmental delay and characteristic phenotypes. A 7 year- and 6-month-old boy experienced afebrile generalized seizure at the age of 5 years and 3 months. He had recurrent febrile seizures since 12 months of age and showed severe global developmental delay, remarkable hypotonia, short stature, and dysmorphic features such as microcephaly; small, low-set ears; dark, straight eyebrows; deep-set eyes; flat nasal bridge; midface hypoplasia; and a small, pointed chin. Previous diagnostic work-up, including conventional chromosomal analysis, revealed no definite causes. However, array-comparative genomic hybridization analysis revealed 1p36 deletion syndrome with a 9.15-Mb copy loss of the 1p36.33-1p36.22 region, and fluorescence in situ hybridization analysis (FISH) confirmed this diagnosis. This case highlights the need to consider detailed chromosomal study for patients with delayed development and epilepsy. Furthermore, 1p36 deletion syndrome should be considered for patients presenting seizure and moderate-to-severe developmental delay, particularly if the patient exhibits dysmorphic features, short stature, and hypotonia. PMID- 28018438 TI - Interstitial deletion of 5q33.3q35.1 in a boy with severe mental retardation. AB - Constitutional interstitial deletions of the long arm of chromosome 5 (5q) are quite rare, and the corresponding phenotype is not yet clearly delineated. Severe mental retardation has been described in most patients who present 5q deletions. Specifically, the interstitial deletion of chromosome 5q33.3q35.1, an extremely rare chromosomal aberration, is characterized by mental retardation, developmental delay, and facial dysmorphism. Although the severity of mental retardation varies across cases, it is the most common feature described in patients who present the 5q33.3q35.1 deletion. Here, we report a case of a de novo deletion of 5q33.3q35.1, 46,XY,del(5)(q33.3q35.1) in an 11-year-old boy with mental retardation; to the best of our knowledge this is the first case in Korea to be reported. He was diagnosed with severe mental retardation, developmental delay, facial dysmorphisms, dental anomalies, and epilepsy. Chromosomal microarray analysis using the comparative genomic hybridization array method revealed a 16-Mb-long deletion of 5q33. 3q35.1(156,409,412-172,584,708)x1. Understanding this deletion may help draw a rough phenotypic map of 5q and correlate the phenotypes with specific chromosomal regions. The 5q33.3q35.1 deletion is a rare condition; however, accurate diagnosis of the associated mental retardation is important to ensure proper genetic counseling and to guide patients as part of long-term management. PMID- 28018439 TI - Phelan-McDermid syndrome presenting with developmental delays and facial dysmorphisms. AB - Phelan-McDermid syndrome is a rare genetic disorder caused by the terminal or interstitial deletion of the chromosome 22q13.3. Patients with this syndrome usually have global developmental delay, hypotonia, and speech delays. Several putative genes such as the SHANK3, RAB, RABL2B, and IB2 are responsible for the neurological features. This study describes the clinical features and outcomes of Korean patients with Phelan-McDermid syndrome. Two patients showing global developmental delay, hypotonia, and speech delay were diagnosed with Phelan McDermid syndrome via chromosome analysis, fluorescent in situ hybridization, and multiplex ligation-dependent probe amplification analysis. Brain magnetic resonance imaging of Patients 1 and 2 showed delayed myelination and severe communicating hydrocephalus, respectively. Electroencephalography in patient 2 showed high amplitude spike discharges from the left frontotemporoparietal area, but neither patient developed seizures. Kidney ultrasonography of both the patients revealed multicystic kidney disease and pelviectasis, respectively. Patient 2 experienced recurrent respiratory infections, and chest computed tomography findings demonstrated laryngotracheomalacia and bronchial narrowing. He subsequently died because of heart failure after a ventriculoperitoneal shunt operation at 5 months of age. Patient 1, who is currently 20 months old, has been undergoing rehabilitation therapy. However, global developmental delay was noted, as determines using the Korean Infant and Child Development test, the Denver developmental test, and the Bayley developmental test. This report describes the clinical features, outcomes, and molecular genetic characteristics of two Korean patients with Phelan-McDermid syndrome. PMID- 28018440 TI - Glucose transport 1 deficiency presenting as infantile spasms with a mutation identified in exon 9 of SLC2A1. AB - Glucose transport 1 (GLUT-1) deficiency is a rare syndrome caused by mutations in the glucose transporter 1 gene (SLC2A1) and is characterized by early-onset intractable epilepsy, delayed development, and movement disorder. De novo mutations and several hot spots in N34, G91, R126, R153, and R333 of exons 2, 3, 4, and 8 of SLC2A1 are associated with this condition. Seizures, one of the main clinical features of GLUT-1 deficiency, usually develop during infancy. Most patients experience brief and subtle myoclonic jerk and focal seizures that evolve into a mixture of different types of seizures, such as generalized tonic clonic, absence, myoclonic, and complex partial seizures. Here, we describe the case of a patient with GLUT-1 deficiency who developed infantile spasms and showed delayed development at 6 months of age. She had intractable epilepsy despite receiving aggressive antiepileptic drug therapy, and underwent a metabolic workup. Cerebrospinal fluid (CSF) examination showed CSF-glucose-to blood-glucose ratio of 0.38, with a normal lactate level. Bidirectional sequencing of SLC2A1 identified a missense mutation (c.1198C>T) at codon 400 (p.Arg400Cys) of exon 9. PMID- 28018441 TI - A neonate with Joubert syndrome presenting with symptoms of Horner syndrome. AB - Joubert syndrome (JS) is characterized by the "molar tooth sign" (MTS) with cerebellar vermis agenesis, episodic hyperpnea, abnormal eye movements, and hypotonia. Ocular and oculomotor abnormalities have been observed; however, Horner syndrome (HS) has not been documented in children with JS. We present the case of a 2-month-old boy having ocular abnormalities with bilateral nystagmus, left-dominant bilateral ptosis, and unilateral miosis and enophthalmos of the left eye, which were compatible with HS. Brain magnetic resonance imaging (MRI) revealed the presence of the MTS. Neck MRI showed no definite lesion or mass around the cervical sympathetic chain. His global development was delayed. He underwent ophthalmologic surgery, and showed some improvement in his ptosis. To the best of our knowledge, the association of HS with JS has not yet been described. We suggest that early neuroimaging should be considered for neonates or young infants with diverse eye abnormalities to evaluate the underlying etiology. PMID- 28018442 TI - Long-term clinical course of a patient with mucopolysaccharidosis type IIIB. AB - Mucopolysaccharidosis type III (MPS III) is a rare genetic disorder caused by lysosomal storage of heparan sulfate. MPS IIIB results from a deficiency in the enzyme alpha-N-acetyl-D-glucosaminidase (NAGLU). Affected patients begin showing behavioral changes, progressive profound mental retardation, and severe disability from the age of 2 to 6 years. We report a patient with MPS IIIB with a long-term follow-up duration. He showed normal development until 3 years. Subsequently, he presented behavioral changes, sleep disturbance, and progressive motor dysfunction. He had been hospitalized owing to recurrent pneumonia and epilepsy with severe cognitive dysfunction. The patient had compound heterozygous c.1444C>T (p.R482W) and c.1675G>T (p.D559Y) variants of NAGLU. Considering that individuals with MPS IIIB have less prominent facial features and skeletal changes, evaluation of long-term clinical course is important for diagnosis. Although no effective therapies for MPS IIIB have been developed yet, early and accurate diagnosis can provide important information for family planning in families at risk of the disorder. PMID- 28018443 TI - Maternal 3-methylcrotonyl-coenzyme A carboxylase deficiency with elevated 3 hydroxyisovalerylcarnitine in breast milk. AB - : We report here a case of maternal 3-methylcrotonyl-coenzyme A carboxylase (3 MCC) deficiency in a Korean woman. Her 2 infants had elevated 3 hydroxyisovalerylcarnitine (C5-OH) on a neonatal screening test by liquid chromatography-tandem mass spectrometry (LC-MS/MS), but normal results were found on urine organic acid analysis. The patient was subjected to serial testing and we confirmed a maternal 3-MCC deficiency by blood spot and breast milk spot test by LC-MS/MS, serum amino acid analysis, urine organic acid and molecular genetic analysis that found c.838G>T (p.Asp280Tyr) homozygous mutation within exon 9 of the MCCB gene. Especially, we confirmed marked higher levels of C5-OH on breast milk spot by LC-MS/MS, in the case of maternal 3-MCC deficiency vs. CONTROLS: PMID- 28018444 TI - Compound heterozygous mutations of ACADS gene in newborn with short chain acyl CoA dehydrogenase deficiency: case report and literatures review. AB - Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive mitochondrial disorder of fatty acid beta-oxidation, and is associated with mutations in the acyl-CoA dehydrogenase (ACADS) gene. Recent advances in spectrometric screening for inborn errors of metabolism have helped detect several metabolic disorders, including SCADD, without symptoms in the neonate period. This allows immediate initiation of treatment and monitoring, so they remain largely symptomless metabolic disease. Here, we report a 15-month-old asymptomatic male, who was diagnosed with SCADD by newborn screening. Spectrometric screening for inborn errors of metabolism 72 hours after birth revealed an elevated butyrylcarnitine (C4) concentration of 2.25 umol/L (normal, <0.99 umol/L). Urinary excretion of ethylmalonic acid was also elevated, as detected by urine organic acid analysis. To confirm the diagnosis of SCADD, direct sequencing analysis of 10 coding exons and the exon-intron boundaries of the ACADS gene were performed. Subsequent sequence analysis revealed compound heterozygous missense mutations c.164C>T (p.Pro55Leu) and c.1031A>G (p.Glu344Gly) on exons 2 and 9, respectively. The patient is now growing up, unretarded by symptoms such as seizure and developmental delay. PMID- 28018445 TI - A novel BTK gene mutation, c.82delC (p.Arg28 Alafs*5), in a Korean family with X linked agammaglobulinemia. AB - X-linked agammaglobulinemia (XLA) is a hereditary humoral immunodeficiency that results from Bruton's tyrosine kinase (BTK) gene mutations. These mutations cause defects in B-cell development, resulting in the virtual absence of these lymphocytes from the peripheral circulation. Consequently, this absence leads to a profound deficiency of lg all isotypes, and an increased susceptibility to encapsulated bacterial infections. A 15-month-old Korean boy presented with recurrent sinusitis and otitis media after 6 months of age, and had a family history of 2 maternal uncles with XLA. Laboratory tests revealed a profound deficiency of Ig isotypes, and a decreased count of CD19+ B cells in the peripheral circulation. Based on his family history and our laboratory test results, he was diagnosed with XLA. We performed BTK gene analysis of peripheral blood samples obtained from family members to confirm the diagnosis. Mutational analysis revealed a novel hemizygous frameshift mutation (c.82delC, p.Arg28Alafs*5), in the BTK gene. His mother and maternal grandmother were heterozygous carriers of this mutation and his two maternal uncles were hemizygous at the same position. After XLA diagnosis, intravenous immunoglobulin (400 mg/kg, monthly) treatment was initiated; recurrent sinusitis and otitis media were subsequently brought under control. To our knowledge, this is the first reported case of a Korean pedigree with a novel mutation in the BTK gene. PMID- 28018446 TI - Familial Mediterranean fever presenting as fever of unknown origin in Korea. AB - Familial Mediterranean fever (FMF) is the most common Mendelian autoinflammatory disease, characterized by uncontrolled activation of the innate immune system that manifests as recurrent brief fever and polyserositis (e.g., peritonitis, pleuritic, and arthritis). FMF is caused by autosomal recessive mutations of the Mediterranean fever gene, MEFV which encodes the pyrin protein. Although FMF predominantly affects people from Mediterranean and Middle Eastern ethnic origins, 3 cases of FMF have been reported in Korea since 2012. We report another case of FMF in Korea in which the patient presented with a month-long fever without serositis. After treatment with colchicine was initiated, the patient's symptoms quickly subsided. The response to colchicine was helpful for diagnosis. We compare the FMF genotypes in Korea with in other countries. Studying FMF cases in Korea will help establish the best MEFV exons to use for screening and diagnosis of Korean FMF. PMID- 28018447 TI - Targeted busulfan and fludarabine-based conditioning for bone marrow transplantation in chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by impaired phagocytic function. Hematopoietic stem cell transplantation (HSCT) is a definitive cure for CGD; however, the use of HSCT is limited because of associated problems, including transplantation-related mortality and engraftment failure. We report a case of a patient with CGD who underwent successful HSCT following a targeted busulfan and fludarabine reduced-toxicity myeloablative conditioning. Intravenous busulfan was administered once daily for 4 consecutive days (days -8 to -5), and the target area under the curve was 75,000 ug.hr/L. Fludarabine (40 mg/m2) was administered once daily for 6 consecutive days from days -8 to -3. Antithymocyte globulin (2.5 mg/kg/day) was administered from days 4 to -2. The patient underwent successful engraftment and did not have any severe toxicity related to the transplantation. Conditioning with a targeted busulfan and fludarabine regimen could provide a better outcome for HSCT in CGD, with close regulation of the busulfan dose. PMID- 28018448 TI - A 2-month-old boy with hemolytic anemia and reticulocytopenia following intravenous immunoglobulin therapy for Kawasaki disease: a case report and literature review. AB - Herein, we report a rare case of hemolytic anemia with reticulocytopenia following intravenous immunoglobulin therapy in a young infant treated for Kawasaki disease. A 2-month-old boy presented with fever lasting 3 days, conjunctival injection, strawberry tongue, erythematous edema of the hands, and macular rash, symptoms and signs suggestive of incomplete Kawasaki disease. His fever resolved 8 days after treatment with aspirin and high dose infusion of intravenous immunoglobulin. The hemoglobin and hematocrit decreased from 9.7 g/dL and 27.1% to 7.4 g/dL and 21.3%, respectively. The patient had normocytic hypochromic anemia with anisocytosis, poikilocytosis, immature neutrophils, and nucleated red blood cells. The direct antiglobulin test result was positive, and the reticulocyte count was 1.39%. The patient had an uneventful recovery. However, reticulocytopenia persisted 1 month after discharge. PMID- 28018449 TI - Congenital miliary tuberculosis in an 18-day-old boy. AB - Congenital tuberculosis (TB) is a rare disease that is associated with high mortality. Mycobacterium tuberculosis, the causative agent, may be transmitted from the infected mother to the fetus by the transplacental route or by aspiration of infected amniotic fluid. Clinical symptoms and signs are not specific. Miliary patterns are the most common findings in the chest X-rays of many infants with congenital TB. In this case, an 18-day-old boy had jaundice on the fifth day of birth, and fever and respiratory distress appeared on the 18th day. Chest X-ray showed diffuse fine bilateral infiltration. Clinically, pneumonia or sepsis was suspected. Respiratory symptoms and chest X-ray findings worsened despite empirical antibiotic therapy. The lungs showed miliary infiltration suggestive of TB. Gastric aspirates were positive for M. tuberculosis. Respiratory distress and fever were gradually improved after anti TB medication. Congenital TB is difficult to detect because of minimal or no symptoms during pregnancy and nonspecific symptoms in neonates. Hence, clinicians should suspect the possibility of TB infection even if neonates have non-specific symptoms. Early diagnosis and meticulous treatment are required for the survival of neonates with TB. PMID- 28018450 TI - Acute gastritis associated with Epstein-Barr virus infection in a child. AB - Infectious mononucleosis is Epstein-Barr virus (EBV) inducing a self-limiting clinical syndrome characterized by fever, sore throat, hepatosplenomegaly, and generalized lymphadenopathy. Gastrointestinal symptoms of EBV infection are nonspecific and occur rarely. EBV inducing acute gastrointestinal pathology is poorly recognized without suspicion. Careful consideration is needed to diagnose gastric involvement of EBV infection including gastric lymphoma, gastric cancer, and gastritis. A few recent cases of gastritis associated with EBV infection have been reported in adolescents and adults. However, there is no report of EBV associated gastritis in early childhood. We experienced a rare case of 4-year-old girl with EBV gastritis confirmed by in situ hybridization. PMID- 28018451 TI - Eosinophilic gastroenteritis in an 18-year-old male with prolonged nephrotic syndrome. AB - Eosinophilic gastroenteritis is a rare disease characterized by prominent eosinophilic tissue infiltration of the gastrointestinal tract. Here, we report a case of eosinophilic gastroenteritis in an 18-year-old patient with prolonged nephrotic syndrome who presented with abdominal pain and peripheral hypereosinophilia. During the previous 2 years, he had visited local Emergency Department several times because of epigastric pain and nausea. He had been treated with steroid-dependent nephrotic syndrome since 3 years of age. Tests ruled out allergic and parasitic disease etiologies. Gastroduodenoscopy with biopsy revealed marked eosinophilic infiltration in the duodenum. Renal biopsy findings indicated minimal change disease spectrum without eosinophilic infiltration. The oral deflazacort dosage was increased, and the patient was discharged after abdominal pain resolved. To our knowledge, this is the first report of eosinophilic gastroenteritis in a patient with minimal change disease. PMID- 28018452 TI - Endovascular stenting of tracheoinnominate fistula after tracheostomy in a 14 year-old boy. AB - Tracheoinnominate artery fistula is a rare, fatal complication of tracheostomy, and prompt diagnosis and management are imperative. We report the case of tracheoinnominate artery fistula after tracheostomy in a 14-year-old boy with a history of severe periventricular leukomalacia, hydrocephalus, cerebral palsy, and epilepsy. The tracheoinnominate artery fistula was successfully treated with a stent graft insertion via the right common femoral artery. Endovascular repair of the tracheoinnominate artery fistula via stent grafting is a safe, effective, and minimally invasive treatment for patients in poor clinical conditions and is an alternative to traditional open surgical treatment. PMID- 28018453 TI - Anomalous right coronary artery from pulmonary artery discovered incidentally in an asymptomatic young infant. AB - Isolated anomalous right coronary artery originating from the pulmonary artery (ARCAPA) is a rare congenital coronary anomaly that is asymptomatic and discovered incidentally in most cases. ARCAPA is generally not considered a fatal defect in infancy or childhood, although cases of sudden death have been reported. Here, we report a 2-month-old female infant who presented with a prolonged fever that was determined to be caused by rhinovirus infection. Myocardial ischemia of the left ventricular posterior wall was already seen on echocardiography, and ARCAPA was discovered incidentally. The patient underwent successful surgical reimplantation of the right coronary artery to the aortic root to re-establish dual ostial circulation. PMID- 28018454 TI - Idiopathic midaortic syndrome with malignant hypertension in 3-year-old boy. AB - Midaortic syndrome (MAS) is a rare vascular disease that commonly causes renovascular hypertension. The lumen of the abdominal aorta narrows and the ostia of the branches show stenosis. MAS is associated with diminished pulses in the lower extremities compared with the upper extremities, severe hypertension with higher blood pressure in the upper rather than lower extremities, and an abdominal bruit. The clinical symptoms are variable, and recognition in children with hypertension can aid early diagnosis and optimal treatment. Hypertension with MAS is malignant and often refractory to several antihypertensive drugs. Recently, radiologic modalities have been developed and have led to numerous interventional procedures. We describe the case of a 3-year-old boy presenting with left ventricular hypertrophy whose severely elevated blood pressure led to the diagnosis of idiopathic MAS. This case highlights the importance of measuring blood pressure and conducting a detailed physical examination to diagnose MAS. This is the first reported case of idiopathic MAS diagnosed in childhood in Korea. PMID- 28018455 TI - Granular cell tumor of the esophagus in an adolescent. AB - Esophageal granular cell tumor (GCT) is a rare neoplasm originating from the Schwann cells of the submucosal neuronal plexus. Histology is the gold standard for its diagnosis. Endoscopic resection or surgical excision should be considered, depending on the potential for malignancy. Here, we report a case of an esophageal GCT in an adolescent. A 12-year-old boy presented with a 1-year history of dysphagia and vomiting. Upper gastrointestinal endoscopic examination and esophagography showed narrowing of the midesophagus, and computed tomography angiography of the thoracic aorta revealed an esophageal or periesophageal mass posterior to the paratracheal segment of the esophagus. The tumor was surgically excised, and based on the pathological findings, esophageal GCT was diagnosed. PMID- 28018456 TI - Esthesioneuroblastoma in a boy with 47, XYY karyotype. AB - Neuroblastomas are sometimes associated with abnormal constitutional karyotypes, but the XYY karyotype has been rarely described in neuroblastomas. Here, we report a case of an esthesioneuroblastoma in a boy with a 47, XYY karyotype. A 6 year-old boy was admitted to our hospital because of nasal obstruction and palpable cervical lymph node, which he first noticed several days previously. A polypoid mass in the right nasal cavity was detected through sinuscopy. Biopsy of the right nasal polyp was performed. Based on the result, the patient was diagnosed with a high-grade esthesioneuroblastoma. Nuclear imaging revealed increased uptake in both the right posterior nasal cavity and the right cervical IB-II space, suggesting metastatic lymph nodes. Cytogenetic analysis revealed a 47, XYY karyotype. Twelve courses of concurrent chemotherapy were administered. Three years after the completion of chemotherapy, the patient had had no disease recurrence. He manifested behavioral violence and temper tantrums, so we started methylphenidate for correction of the behavior. PMID- 28018457 TI - Relapsed Wilms' tumor with multiple brain metastasis. AB - Wilms' tumor is the most common malignant renal tumor in childhood. The brain metastasis of a Wilms' tumor with anaplastic histopathology is rare. We present the case of an 8-year-old girl with Wilms' tumor, who presented with multiple brain metastases 5 years after her primary diagnosis. The brain masses were diagnosed after a generalized tonic-clonic seizure attack. The big solid mass in the cerebellum was resected, and whole-brain radiotherapy was performed, after which, she succumbed to her disease. In the case of clinical suspicion, cranial surveillance should be included in the routine clinical work-up for Wilms' tumor. Combined aggressive therapy (surgery+radiotherapy+chemotherapy) should be applied whenever possible, for both better survival and palliative aspects. PMID- 28018458 TI - Successful treatment of tubulointerstitial nephritis and uveitis with steroid and azathioprine in a 12-year-old boy. AB - Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, often underdiagnosed or misdiagnosed in children. We describe the case of a 12-year-old boy who presented to Severance Hospital with a 1-month history of bilateral conjunctival injection. He was first evaluated by an Ophthalmologist in another hospital and diagnosed with panuveitis. Laboratory tests indicated renal failure, and a renal biopsy confirmed the diagnosis of acute tubulointerstitial nephritis. An extensive exclusion of all possible causes allowed a diagnosis of TINU syndrome. The patient was treated with a systemic corticosteroid (initially prednisolone, 2 mg/kg and later deflazacort 1 mg/kg) and topical steroid drops for 1 month. Azathioprine was later added to the treatment regimen and the systemic steroid was slowly tapered. The final outcome of renal-ocular disease was favorable in the patient. However, long-term follow-up is necessary to properly manage frequent relapses and incomplete renal recovery. TINU should be considered as a differential diagnosis in children with uveitis or acute renal failure. PMID- 28018459 TI - A novel mutation of CLCNKB in a Korean patient of mixed phenotype of Bartter Gitelman syndrome. AB - Bartter syndrome (BS) is an inherited renal tubular disorder characterized by low or normal blood pressure, hypokalemic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Type III BS is caused by loss-of-function mutations in CLCNKB encoding basolateral ClC-Kb. The clinical phenotype of patients with CLCNKB mutations has been known to be highly variable, and cases that are difficult to categorize as type III BS or other hereditary tubulopathies, such as Gitelman syndrome, have been rarely reported. We report a case of a 10-year-old Korean boy with atypical clinical findings caused by a novel CLCNKB mutation. The boy showed intermittent muscle cramps with laboratory findings of hypokalemia, severe hypomagnesemia, and nephrocalcinosis. These findings were not fully compatible with those observed in cases of BS or Gitelman syndrome. The CLCNKB mutation analysis revealed a heterozygous c.139G>A transition in exon 13 [p.Gly(GGG)465Glu(GAG)]. This change is not a known mutation; however, the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation. PMID- 28018460 TI - Unusual malignant neoplasms of ovary in children: two cases report. AB - Sex cord tumors with annular tubules are known to originate from the sex cord of embryonic gonads that synthesize Sertoli cells, Leydig cells, granulosa cells, and theca cells of the ovarian stroma, while ovarian small cell carcinoma of the hypercalcemic type is a type of neuroendocrine tumor. Both these tumors are uncommon, potentially malignant neoplasms in children. We report the case of a sex cord tumor with annular tubules in an 11-year-old girl and a case of small cell carcinoma of the hypercalcemic type in a 10-year-old girl. We also discuss the prognosis and management of these tumors. PMID- 28018461 TI - Hashimoto thyroiditis with an unusual presentation of cardiac tamponade in Noonan syndrome. AB - Noonan syndrome is an autosomal dominant, multisystem disorder. Autoimmune thyroiditis with hypothyroidism is an infrequent feature in patients with Noonan syndrome. A 16-year-old boy was admitted because of chest discomfort and dyspnea; an echocardiogram revealed pericardial effusion. Additional investigations led to a diagnosis of severe hypothyroidism due to Hashimoto thyroiditis. The patient was treated with L-thyroxine at 0.15 mg daily. However, during admission, he developed symptoms of cardiac tamponade. Closed pericardiostomy was performed, after which the patient's chest discomfort improved, and his vital signs stabilized. Herein, we report a case of an adolescent with Noonan syndrome, who was diagnosed with Hashimoto thyroiditis with an unusual presentation of cardiac tamponade. PMID- 28018462 TI - A novel mutation of ABCC8 gene in a patient with diazoxide-unresponsive congenital hyperinsulinism. AB - Congenital hyperinsulinism (CHI) is a rare condition that can cause irreversible brain damage during the neonatal period owing to the associated hypoglycemia. Hypoglycemia in CHI occurs secondary to the dysregulation of insulin secretion. CHI has been established as a genetic disorder of islet-cell hyperplasia, associated with a mutation of the ABCC8 or KCNJ11 genes, which encode the sulfonylurea receptor 1 and the inward rectifying potassium channel (Kir6.2) subunit of the ATP-sensitive potassium channel, respectively. We report the case of a female newborn infant who presented with repetitive seizures and episodes of apnea after birth, because of hypoglycemia. Investigations revealed hypoglycemia with hyperinsulinemia, but no ketone bodies, and a low level of free fatty acids. High dose glucose infusion, enteral feeding, and medications could not maintain the patient's serum glucose level. Genetic testing revealed a new variation of ABCC8 mutation. Therefore, we report this case of CHI caused by a novel mutation of ABCC8 in a half-Korean newborn infant with diazoxide-unresponsive hyperinsulinemic hypoglycemia. PMID- 28018463 TI - Concomitant occurrence of Turner syndrome and growth hormone deficiency. AB - Turner syndrome (TS) is a genetic disorder in phenotypic females that has characteristic physical features and presents as partial or complete absence of the second sex chromosome. Growth hormone deficiency (GHD) is a condition caused by insufficient release of growth hormone from the pituitary gland. The concomitant occurrence of TS and GHD is rare and has not yet been reported in Korea. Here we report 2 cases of TS and GHD. In case 1, GHD was initially diagnosed. Karyotyping was performed because of the presence of the typical phenotype and poor response to growth hormone therapy, which revealed 45,X/45,X+mar. The patient showed increased growth velocity after the growth hormone dose was increased. In case 2, a growth hormone provocation test and chromosomal analysis were performed simultaneously because of decreased growth velocity and the typical TS phenotype, which showed GHD and a mosaic karyotype of 45,X/46,XX. The patient showed spontaneous pubertal development. In female patients with short stature, it is important to perform a throughout physical examination and test for hormonal and chromosomal abnormalities because diagnostic accuracy is important for treatment and prognosis. PMID- 28018464 TI - A pediatric case of idiopathic Harlequin syndrome. AB - Harlequin syndrome, which is a rare disorder caused by dysfunction of the autonomic system, manifests as asymmetric facial flushing and sweating in response to heat, exercise, or emotional factors. The syndrome may be primary (idiopathic) with a benign course, or can occur secondary to structural abnormalities or iatrogenic factors. The precise mechanism underlying idiopathic harlequin syndrome remains unclear. Here, we describe a case of a 6-year-old boy who reported left hemifacial flushing and sweating after exercise. He had an unremarkable birth history and no significant medical history. Complete ophthalmological and neurological examinations were performed, and no other abnormalities were identified. Magnetic resonance imaging was performed to exclude lesions of the cerebrum and cervicothoracic spinal cord, and no abnormalities were noted. His final diagnosis was classic idiopathic harlequin syndrome. Herein, we report the first pediatric case of idiopathic harlequin syndrome in Korea. PMID- 28018465 TI - Ictal sinus pause and myoclonic seizure in a child. AB - Ictal tachycardia and bradycardia are common arrhythmias; however, ictal sinus pause and asystole are rare. Ictal arrhythmia is mostly reported in adults with temporal lobe epilepsy. Recently, ictal arrhythmia was recognized as a major warning sign of sudden unexpected death in epilepsy. We present an interesting case of a child with ictal sinus pause and asystole. A 27-month-old girl was hospitalized due to 5 episodes of convulsions during the past 2 days. Results of routine electroencephalography (EEG) were normal, but she experienced brief generalized tonic seizure for 3 days. During video-monitored EEG and echocardiography (ECG), she showed multiple myoclonic seizures simultaneously or independently, as well as frequent sinus pauses. After treatment with valproic acid, myoclonus and generalized tonic seizures were well controlled and only 2 sinus pauses were seen on 24-hour Holter ECG monitoring. Sinus dysfunction should be recognized on EEG, and it can sometimes be treated successfully with only antiepileptic medication. PMID- 28018466 TI - A young child of anti-NMDA receptor encephalitis presenting with epilepsia partialis continua: the first pediatric case in Korea. AB - Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis, recently recognized as a form of paraneoplastic encephalitis, is characterized by a prodromal phase of unspecific illness with fever that resembles a viral disease. The prodromal phase is followed by seizures, disturbed consciousness, psychiatric features, prominent abnormal movements, and autonomic imbalance. Here, we report a case of anti-NMDAR encephalitis with initial symptoms of epilepsia partialis continua in the absence of tumor. Briefly, a 3-year-old girl was admitted to the hospital due to right-sided, complex partial seizures without preceding febrile illness. The seizures evolved into epilepsia partialis continua and were accompanied by epileptiform discharges from the left frontal area. Three weeks after admission, the patient's seizures were reduced with antiepileptic drugs; however, she developed sleep disturbances, cognitive decline, noticeable oro-lingual-facial dyskinesia, and choreoathetoid movements. Anti-NMDAR encephalitis was confirmed by positive detection of NMDAR antibodies in the patient's serum and cerebrospinal fluid, and her condition slowly improved with immunoglobulin, methylprednisolone, and rituximab. At present, the patient is no longer taking multiple antiepileptic or antihypertensive drugs. Moreover, the patient showed gradual improvement of motor and cognitive function. This case serves as an example that a diagnosis of anti-NMDAR encephalitis should be considered when children with uncontrolled seizures develop dyskinesias without evidence of malignant tumor. In these cases, aggressive immunotherapies are needed to improve the outcome of anti-NMDAR encephalitis. PMID- 28018467 TI - A rare case of dysembryoplastic neuroepithelial tumor combined with encephalocraniocutaneous lipomatosis and intractable seizures. AB - Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome that affects ectomesodermal tissues (skin, eyes, adipose tissue, and brain). The neurologic manifestations associated with ECCL are various including seizures. However, ECCL patients very rarely develop brain tumors that originate from the neuroepithelium. This is the first described case of ECCL in combination with dysembryoplastic neuroepithelial tumor (DNET) that presented with intractable seizures. A 7-year-old girl was admitted to our center because of ECCL and associated uncontrolled seizures. She was born with right anophthalmia and lipomatosis in the right temporal area and endured right temporal lipoma excision at 3 years of age. Seizures began when she was 3 years old, but did not respond to multiple antiepileptic drugs. Brain magnetic resonance (MR) imaging performed at 8 and 10 years of age revealed an interval increase of multifocal hyperintense lesions in the basal ganglia, thalamus, cerebellum, periventricular white matter, and, especially, the right temporal area. A nodular mass near the right hippocampus demonstrated the absence of N-acetylaspartate decrease on brain MR spectroscopy and mildly increased methionine uptake on brain positron emission tomography, suggesting low-grade tumor. Twenty-four-hour video electroencephalographic monitoring also indicated seizures originating from the right temporal area. Right temporal lobectomy was performed without complications, and the nodular lesion was pathologically identified as DNET. The patient has been seizure-free for 14 months since surgery. Although ECCL associated brain tumors are very rare, careful follow-up imaging and surgical resection is recommended for patients with intractable seizures. PMID- 28018468 TI - Posterior reversible encephalopathy syndrome caused by presumed Takayasu arteritis. AB - Takayasu arteritis (TA) is a chronic inflammatory disease of unknown etiology that affects mainly the aorta, main aortic branches, and pulmonary arteries. Diverse neurological manifestations of TA have rarely been reported in children. Posterior reversible encephalopathy syndrome (PRES) is a neuroradiological condition that presents with headache, seizure, visual disturbances, and characteristic lesions on imaging. Inflammatory condition and severe hypertension in TA can cause PRES. We report of a 5-year-old girl with presumed TA who presented with PRES and chronic total occlusion in the renal artery. The findings on magnetic resonance imaging suggested PRES. Left nephrectomy was performed for total occlusion of the left renal artery, and the confirmatory diagnosis of TA was based on the pathologic findings of the renal artery. PMID- 28018469 TI - Type I Chiari malformation presenting orthostatic syncope who treated with decompressive surgery. AB - Chiari malformations are a congenital anomaly of the hindbrain. The most common, Chiari malformation type I (CM-I), is characterized by herniation of the cerebellar tonsils extending at least 3 mm below the plane of the foramen magnum. Consequently, CM-I is associated with hydrocephalus and symptoms involving compression of the cervicomedullary junction by ectopic tonsils. Several studies have reported the clinical symptoms associated with CM-I, including suboccipital headache, weakness in the upper extremities, facial numbness, loss of temperature sensation, ataxia, diplopia, dysarthria, dysphagia, vomiting, vertigo, nystagmus, and tinnitus. Syncope is one of the rarest presentations in patients with CM-I. There are many hypotheses regarding the causes of syncope in patients with CM-I; however, the mechanisms are not clearly understood. Although surgical decompression for CM-I in patients with syncope has yielded good clinical results in some studies, such cases are rarely reported. We report a case of orthostatic syncope in a patient with CM-I who was treated with surgical intervention. PMID- 28018470 TI - Megalencephaly-capillary malformation-polymicrogyria syndrome: the first case report in Korea. AB - Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP), previously known as macrocephaly-cutis marmorata telangiectatica congenita and macrocephaly capillary malformation syndrome, is a rare multiple-malformation syndrome that is characterized by progressive megalencephaly, capillary malformations of the midline face and body, or distal limb anomalies such as syndactyly. Herein, we report a female infant case that satisfies the recently proposed criteria of MCAP and describe the distinctive neuroradiological and morphological features. We have also reviewed recently published reports and the diagnostic criteria proposed by various authors in order to facilitate the clinical diagnosis of these children in pediatric neurology clinics. PMID- 28018471 TI - Paroxysmal kinesigenic dyskinesia in a patient with a PRRT2 mutation and centrotemporal spike discharges on electroencephalogram: case report of a 10-year old girl. AB - Coexistence of paroxysmal kinesigenic dyskinesia (PKD) with benign infantile convulsion (BIC) and centrotemporal spikes (CTS) is very rare. A 10-year-old girl presented with a 3-year history of frequent attacks of staggering while laughing and of suddenly collapsing while walking. Interictal electroencephalogram (EEG) revealed bilateral CTS, but no changes in EEG were observed during movement. The patient's medical history showed afebrile seizures 6 months after birth, while the family history showed that the patient's mother and relatives on the mother's side had similar dyskinesia. Genetic testing demonstrated that the patient had a heterozygous mutation, c.649_650insC, in the PRRT2 gene. To our knowledge, this constitutes only the second report of a patient with PKD, BIC, CTS, and a PRRT2 mutation. PMID- 28018472 TI - Concurrency of Guillain-Barre syndrome and acute transverse myelitis: a case report and review of literature. AB - Guillain-Barre syndrome and acute transverse myelitis manifest as demyelinating diseases of the peripheral and central nervous system. Concurrency of these two disorders is rarely documented in literature. A 4-year-old girl presenting with cough, fever, and an impaired walking ability was admitted to hospital. She had no previous complaints in her medical history. A physical examination revealed lack of muscle strength of the lower extremities and deep tendon reflexes. MRI could not be carried out due to technical problems; therefore, both Guillain Barre syndrome and acute transverse myelitis were considered for the diagnosis. Intravenous immunoglobulin treatment was started as first line therapy. Because this treatment did not relieve the patient's symptoms, spinal MRI was carried out on the fourth day of admission and demyelinating areas were identified. Based on the new findings, the patient was diagnosed with acute transverse myelitis, and high dose intravenous methylprednisolone therapy was started. Electromyography findings were consistent with acute polyneuropathy affecting both motor and sensory fibers. Therefore, the patient was diagnosed with concurrency of Guillain Barre syndrome and acute transverse myelitis. Interestingly, while concurrency of these 2 disorders is rare, this association has been demonstrated in various recent publications. Progress in diagnostic tests (magnetic resonance imaging and electrophysiological examination studies) has enabled clinicians to establish the right diagnosis. The possibility of concurrent Guillain-Barre syndrome and acute transverse myelitis should be considered if recovery takes longer than anticipated. PMID- 28018473 TI - Evaluation of the In Vivo Therapeutic Effects of Radix Paeoniae Rubra Ethanol Extract with the Hypoglycemic Activities Measured from Multiple Cell-Based Assays. AB - Background. Radix Paeoniae Rubra (Chi Shao) contains several phytochemicals with hypoglycemic actions. Current research aims to explore potential insulinotropic effects and long-term therapeutic efficacy of such herb against type 2 diabetes. Methods. Composition analysis for the ethanol extract (PRExt) was executed by high performance liquid chromatography. Polyphenol-enriched fraction was characterized by high pressure size exclusion chromatography. Multiple cell platforms were employed to evaluate hypoglycemic bioactivities. In animal experiments, blood glucose, the homeostasis model assessment (HOMA)-index assessment, glucose tolerance test, and in vivo glucose uptake were all measured. Additional effects of PRExt on obesity and hepatic steatosis were evaluated by serum and histological analysis. Results. PRExt provides multiple hypoglycemic effects including the enhancement of glucose-mediated insulin secretion. Pentagalloylglucose and polyphenol-enriched fraction are two insulinotropic constituents. Moreover, PRExt intraperitoneal injection causes acute hypoglycemic effects on fasted db/db mice. Oral administration of PRExt (200 mg/kg b.w.) gradually reduces blood glucose in db/db mice to the level similar to that in C57J/B6 mice after 30 days. The improvement of glucose intolerance, HOMA-index, and in vivo glucose uptake is evident in addition to the weight loss effect and attenuation of hepatic steatosis. Conclusion. PRExt is an effective antidiabetic herbal extract with multiple hypoglycemic bioactivities. PMID- 28018474 TI - Traditional Chinese Medicine Huannao Yicong Decoction Extract Decreases Tau Hyperphosphorylation in the Brain of Alzheimer's Disease Model Rats Induced by Abeta1-42. AB - Objective. Huannao Yicong Decoction (HYD, ) has been shown to improve the learning and memory capabilities of Alzheimer's disease (AD) subjects. However, the underlying mechanism remains to be determined. Methods. Sixty Sprague-Dawley rats were divided equally and randomly into five different groups including control, positive control, and HYD granules of low dose, medium dose, and high dose by daily gavage. The sham-treated rats were also given the same volume of sterile water by gavage. Twelve SD rats were treated with the same amount of physiological saline. Twelve weeks later, learning and memory capabilities, Abeta content of the right brain and the expression of glycogen synthase kinase-3beta (GSK-3beta), total tau protein kinase (TTBK1), and cyclin-dependent kinase-5 (CDK 5) were tested. Results. Our results showed that high dose HYD treatment significantly improved the learning and memory capability of the AD rats and decreased the expression of TTBK1, GSK-3beta, and CDK-5 in the hippocampal CA1 region. Conclusions. HYD treatment for 12 weeks significantly improved spatial learning and memory and effectively inhibited Abeta deposition, likely via reducing tau protein kinase expression and thus tau hyperphosphorylation and inflammatory injury. Taken together, these results suggest that HYD could be an effective treatment for AD. PMID- 28018475 TI - Concordant morphological and molecular clines in a contact zone of the Common and Spined toad (Bufo bufo and B. spinosus) in the northwest of France. AB - BACKGROUND: Hybrid zones are regions where individuals of two species meet and produce hybrid progeny, and are often regarded as natural laboratories to understand the process of species formation. Two microevolutionary processes can take place in hybrid zones, with opposing effects on population differentiation. Hybridization tends to produce genetic homogenization, reducing species differences, whereas the presence of mechanisms of reproductive isolation result in barriers to gene flow, maintaining or increasing differences between taxa. RESULTS: Here we study a contact zone between two hybridizing toad species, Bufo bufo and B. spinosus, through a combination of molecular (12 polymorphic microsatellites, four nuclear and two mitochondrial SNP markers) and morphological data in a transect in the northwest of France. The results show largely concordant clines across markers, defining a narrow hybrid zone of ca. 30 km wide. Most hybrids in the centre of the contact zone are classified as F2 or backcrossed individuals, with no individuals assigned to the F1 hybrid class. CONCLUSIONS: We discuss the implications of these results for our understanding of the evolutionary history of these species. We anticipate that the toad contact zone here described will become an important asset in the study of hybrid zone dynamics and evolutionary biology because of its easy access and the abundance of the species involved. PMID- 28018476 TI - The association between altered lipid profile and suicide attempt among Tunisian patients with schizophrenia. AB - BACKGROUND: There have been many studies on psychiatric disorders, but very little is known about the biology of suicide with schizophrenia. In the present study, we are looking for a possible connection between altered lipid profile and suicidal behavior in schizophrenic Tunisian patients. METHODS: Assay of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglycerides (TG) has been done for 126 schizophrenic patients with and without suicide attempts and 131 healthy controls recruited in the University Hospital of Monastir. RESULTS: TC and LDL-c levels were significantly higher in schizophrenic patients compared to controls. TC was significantly lower in schizophrenic patients with suicide attempt compared to those without suicide attempt. Depending to the sonority of suicide attempt, TC was significantly lower in patients with recent suicide attempt compared to those with lifetime suicide attempt and without suicide attempt (p < 0.001), and no significant differences between TG, LDL-c, and HDL-c were noted. CONCLUSIONS: Results of this study showed that TC levels in schizophrenic patients after a recent suicide attempt are significantly lower than in patients without suicide attempt and with lifetime suicide attempts. TC can be one of biological markers defined suicidal risk for schizophrenic patients. PMID- 28018477 TI - Differential activation of RAW 264.7 macrophages by size-segregated crystalline silica. AB - BACKGROUND: Occupational exposure to crystalline silica is a well-established occupational hazard. Once in the lung, crystalline silica particles can result in the activation of alveolar macrophages (AM), potentially leading to silicosis, a fibrotic lung disease. Because the activation of alveolar macrophages is the beginning step in a complicated inflammatory cascade, it is necessary to define the particle characteristics resulting in this activation. The aim of this research was to determine the effect of the size of crystalline silica particles on the activation of macrophages. METHODS: RAW 264.7 macrophages were exposed to four different sizes of crystalline silica and their activation was measured using electron microscopy, reactive oxygen species (ROS) generation by mitochondria, and cytokine expression. RESULTS: These data identified differences in particle uptake and formation of subcellular organelles based on particle size. In addition, these data show that the smallest particles, with a geometric mean of 0.3 MUm, significantly increase the generation of mitochondrial ROS and the expression of cytokines when compared to larger crystalline silica particles, with a geometric mean of 4.1 MUm. CONCLUSION: In summary, this study presents novel data showing that crystalline silica particles with a geometric mean of 0.3 MUm enhance the activation of AM when compared to larger silica particles usually represented in in vitro and in vivo research. PMID- 28018478 TI - Rapid differentiation of Xihuangcao from the three Isodon species by UPLC-ESI QTOF-MS/MS and chemometrics analysis. AB - BACKGROUND: Isodon lophanthoides, I. lophanthoides var. graciliflorus and I. serra are the three botanical sources of Xihuangcao, which are often used indiscriminately in herbal products. The aim of this study was to develop a rapid and accurate analytical method to identify the three different botanical sources of Xihuangcao by combining UPLC-ESI-QTOF-MS with chemometrics analysis. METHODS: Fifteen batches of plants were collected as reference materials and their chemical profiles were analyzed by UPLC-ESI-QTOF-MS. These data were subsequently processed by statistical methods, including principal component analysis (PCA), hierarchical cluster analysis (HCA) and orthogonal partial least squared discriminant analysis (OPLS-DA). An automated sample class prediction model was also built using Naive Bayes as a class prediction algorithm to rapidly determine the source species of twenty-seven batches of commercial Xihuangcao samples. RESULTS: The base peak chromatograms of the three authenticated species showed different patterns and twenty-seven peaks were chosen, including six diterpenoids, one phenolic acid and two glycosides to distinguish among these three species. The results showed good differentiation among the three species by PCA, HCA and OPLS-DA. Isodon lophanthoides var. graciliflorus was found to be the major botanical source of the commercial samples. CONCLUSION: UPLC-ESI-QTOF-MS and subsequent chemometrics analysis were demonstrated effective to differentiate among the three different species of plants used as Xihuangcao. PMID- 28018479 TI - Acupuncture as an intervention to reduce alcohol dependency: a systematic review and meta-analysis. AB - BACKGROUND: Acupuncture has been widely used as a treatment for alcohol dependence. An updated and rigorously conducted systematic review is needed to establish the extent and quality of the evidence on the effectiveness of acupuncture as an intervention for reducing alcohol dependence. This review aimed to ascertain the effectiveness of acupuncture for reducing alcohol dependence as assessed by changes in either craving or withdrawal symptoms. METHODS: In this systematic review, a search strategy was designed to identify randomised controlled trials (RCTs) published in either the English or Chinese literature, with a priori eligibility criteria. The following English language databases were searched from inception until June 2015: AMED, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and PubMed; and the following Chinese language databases were similarly searched: CNKI, Sino-med, VIP, and WanFang. Methodological quality of identified RCTs was assessed using the Jadad Scale and the Cochrane Risk of Bias tool. RESULTS: Fifteen RCTs were included in this review, comprising 1378 participants. The majority of the RCTs were rated as having poor methodological rigour. A statistically significant effect was found in the two primary analyses: acupuncture reduced alcohol craving compared with all controls (SMD = -1.24, 95% CI = -1.96 to -0.51); and acupuncture reduced alcohol withdrawal symptoms compared with all controls (SMD = -0.50, 95% CI = -0.83 to -0.17). In secondary analyses: acupuncture reduced craving compared with sham acupuncture (SMD = 1.00, 95% CI = -1.79 to -0.21); acupuncture reduced craving compared with controls in RCTs conducted in Western countries (SMD = -1.15, 95% CI = -2.12 to 0.18); and acupuncture reduced craving compared with controls in RCTs with only male participants (SMD = -1.68, 95% CI = -2.62 to -0.75). CONCLUSION: This study showed that acupuncture was potentially effective in reducing alcohol craving and withdrawal symptoms and could be considered as an additional treatment choice and/or referral option within national healthcare systems. PMID- 28018480 TI - Assessing the INDCs' land use, land use change, and forest emission projections. AB - BACKGROUND: In preparation for the 2015 international climate negotiations in Paris, Parties submitted Intended Nationally Determined Contributions (INDCs) to the United Nations Framework Convention on Climate Change (UNFCCC) expressing each countries' respective post-2020 climate actions. In this paper we assess individual Parties' expected reduction of emissions/removals from land use, land use change, and forest (LULUCF) sector for reaching their INDC target, and the aggregate global effect on the INDCs on the future development of emission and removals from the LULUCF sector. This has been done through analysis Parties' official information concerning the role of LULUCF mitigation efforts for reaching INDC targets as presented in National Communications, Biennial Update Reports, and Additional file 1. RESULTS: On the aggregate global level, the Parties themselves perceive that net LULUCF emissions will increase over time. Overall, the net LULUCF emissions are estimated to increase by 0.6 Gt CO2e year-1 (range: 0.1-1.1) in 2020 and 1.3 Gt CO2e year-1 (range: 0.7-2.1) in 2030, both compared to 2010 levels. On the other hand, the full implementation of the INDCs is estimated to lead to a reduction of net LULUCF emissions in 2030 compared to 2010 levels. It is estimated that if all conditional and unconditional INDCs are implemented, net LULUCF emissions would decrease by 0.5 Gt CO2e year-1 (range: 0.2-0.8) by 2020 and 0.9 Gt CO2e year-1 (range: 0.5-1.3) by 2030, both compared to 2010 levels. The largest absolute reductions of net LULUCF emissions (compared to 2010 levels) are expected from Indonesia and Brazil, followed by China and Ethiopia. CONCLUSIONS: The results highlights that countries are expecting a significant contribution from the LULUCF sector to meet their INDC mitigation targets. At the global level, the LULUCF sector is expected to contribute to as much as 20% of the full mitigation potential of all the conditional and unconditional INDC targets. However, large uncertainties still surround how Parties estimate, project and account for emissions and removals from the LULUCF sector. While INDCs represent a new source of land-use information, further information and updates of the INDCs will be required to reduce uncertainty of the LULUCF projections. PMID- 28018481 TI - Walking the tightrope-perspectives on local politicians' role in implementing a national social care policy on evidence-based practice. AB - BACKGROUND: Despite national policy recommending evidence-based practice (EBP), its application in social care has been limited. While local politicians can affect the process, little is known about their knowledge, attitudes and roles regarding EBP. The aim here is twofold: to explore the role of local politicians in the implementation of EBP in social care from both their own and a management perspective; and to examine factors politicians perceive as affecting their decisions and actions concerning the implementation of EBP policy. METHODS: Local politicians (N = 13) and managers (N = 22) in social care were interviewed. Qualitative thematic analysis with both inductive and deductive codes was used. RESULTS: Politicians were rather uninformed regarding EBP and national policy. The factors limiting their actions were, beside the lack of awareness, lack of ability to question existing working methods, and a need for support in the steering of EBP. Thus, personal interest played a significant part in what role the politicians assumed. This resulted in some politicians taking a more active role in steering EBP while others were not involved. From the managers' perspective, a more active steering by politicians was desired. Setting budget and objectives, as well as active follow-up of work processes and outcomes, were identified as means to affect the implementation of EBP. However, the politicians seemed unaware of the facilitating effects of these actions. CONCLUSIONS: Local politicians had a possibility to facilitate the implementation of EBP, but their role was unclear. Personal interest played a big part in determining what role was taken. The results imply that social care politicians might need support in the development of their steering of EBP. Moving the responsibility for EBP facilitation upwards in the political structure could be an important step in developing EBP in social care. PMID- 28018482 TI - Algae-based biofilm productivity utilizing dairy wastewater: effects of temperature and organic carbon concentration. AB - BACKGROUND: Biofilm-based microalgal growth was determined as functions of organic chemical loading and water temperature utilizing dairy wastewater from a full-scale dairy farm. The dairy industry is a significant source of wastewater worldwide that could provide an inexpensive and nutrient rich feedstock for the cultivation of algae biomass for use in downstream processing of animal feed and aquaculture applications. Algal biomass was cultivated using a Rotating Algal Biofilm Reactor (RABR) system. The RABR is a biofilm-based technology that has been designed and used to remediate municipal wastewater and was applied to treat dairy wastewater through nutrient uptake, and simultaneously provide biomass for the production of renewable bioproducts. RESULTS: Aerial algal biofilm growth rates in dairy wastewater at 7 and 27 degrees C temperatures were shown to be 4.55 +/- 0.17 g/m2-day and 7.57 +/- 1.12 g/m2-day ash free dry weight (AFDW), respectively. Analysis of Variance (ANOVA) calculations indicated that both an increase in temperature of the wastewater and an increase in the level of organic carbon, from 300 to 1200 mg L-1, contributed significantly to an increase in the rate of biomass growth in the system. However, ANOVA results indicated that the interaction of temperature and organic carbon content was not significantly related to the biofilm-based growth rate. CONCLUSION: A microalgae-based biofilm reactor was successfully used to treat turbid dairy wastewater. Temperature and organic carbon concentration had a statistically significant effect on algae based biofilm productivity and treatment of dairy wastewater. The relationships between temperature, TOC, and productivity developed in this study may be used in the design and assessment of wastewater remediation systems and biomass production systems utilizing algae-based biofilm reactors for treating dairy wastes. PMID- 28018483 TI - Can terminators be used as insulators into yeast synthetic gene circuits? AB - BACKGROUND: In bacteria, transcription units can be insulated by placing a terminator in front of a promoter. In this way promoter leakage due to the read through from an upstream gene or RNA polymerase unspecific binding to the DNA is, in principle, removed. Differently from bacterial terminators, yeast S. cerevisiae terminators contain a hexamer sequence, the efficiency element, that strongly resembles the eukaryotic TATA box i.e. the promoter sequence recognized and bound by RNA polymerase II. RESULTS: By placing different yeast terminators (natural and synthetic) in front of the CYC1 yeast constitutive promoter stripped of every upstream activating sequences and TATA boxes, we verified that the efficiency element is able to bind RNA polymerase II, hence working as a TATA box. Moreover, terminators put in front of strong and medium-strength constitutive yeast promoters cause a non-negligible decrease in the promoter transcriptional activity. CONCLUSIONS: Our data suggests that RNA polymerase II molecules upon binding the insulator efficiency element interfere with protein expression by competing either with activator proteins at the promoter enhancers or other RNA polymerase II molecules targeting the TATA box. Hence, it seems preferable to avoid the insulation of non-weak promoters when building synthetic gene circuit in yeast S. cerevisiae. PMID- 28018484 TI - Mechanistic insights into the effect of imidazolium ionic liquid on lipid production by Geotrichum fermentans. AB - BACKGROUND: Ionic liquid (IL) pretreatment has emerged as a promising technique that enables complete utilization of lignocellulosic biomass for biofuel production. However, imidazolium IL has recently been shown to exhibit inhibitory effect on cell growth and product formation of industrial microbes, such as oleaginous microorganisms. To date, the mechanism of this inhibition remains largely unknown. RESULTS: In this study, the feasibility of [Bmim][OAc] pretreated rice straw hydrolysate as a substrate for microbial lipid production by Geotrichum fermentans, also known as Trichosporon fermentans, was evaluated. The residual [Bmim][OAc] present in the hydrolysate caused a reduction in biomass and lipid content (43.6 and 28.1%, respectively) of G. fermentans, compared with those of the control (7.8 g/L and 52.6%, respectively). Seven imidazolium ILs, [Emim][DEP], [Emim]Cl, [Amim]Cl, [Bmim]Cl, [Bzmim]Cl, [Emim][OAc], and [Bmim][OAc], capable of efficient pretreatment of lignocellulosic biomass were tested for their effects on the cell growth and lipid accumulation of G. fermentans to better understand the impact of imidazolium IL on the lipid production. All the ILs tested inhibited the cell growth and lipid accumulation. In addition, both the cation and the anion of IL contributed to IL toxicity. The side chain of IL cations showed a clear impact on toxicity. On examining IL anions, [OAc]- was found to be more toxic than those of [DEP]- and Cl-. IL exhibited its toxicity by inhibiting sugar consumption and key enzyme (malic enzyme and ATP-citrate lyase) activities of G. fermentans. Cell membrane permeability was also altered to different extents in the presence of various ILs. Scanning electron microscopy revealed that IL induces fibrous structure on the surface of G. fermentans cell, which might represent an adaptive mechanism of the yeast to IL. CONCLUSIONS: This work gives some mechanistic insights into the impact of imidazolium IL on the cell growth and lipid accumulation of oleaginous yeast, which is important for IL integration in lignocellulosic biofuel production, especially for microbial lipid production. PMID- 28018485 TI - Hydrogen production by the hyperthermophilic bacterium Thermotoga maritima Part II: modeling and experimental approaches for hydrogen production. AB - BACKGROUND: Thermotoga maritima is a hyperthermophilic bacterium known to produce hydrogen from a large variety of substrates. The aim of the present study is to propose a mathematical model incorporating kinetics of growth, consumption of substrates, product formations, and inhibition by hydrogen in order to predict hydrogen production depending on defined culture conditions. RESULTS: Our mathematical model, incorporating data concerning growth, substrates, and products, was developed to predict hydrogen production from batch fermentations of the hyperthermophilic bacterium, T. maritima. It includes the inhibition by hydrogen and the liquid-to-gas mass transfer of H2, CO2, and H2S. Most kinetic parameters of the model were obtained from batch experiments without any fitting. The mathematical model is adequate for glucose, yeast extract, and thiosulfate concentrations ranging from 2.5 to 20 mmol/L, 0.2-0.5 g/L, or 0.01-0.06 mmol/L, respectively, corresponding to one of these compounds being the growth-limiting factor of T. maritima. When glucose, yeast extract, and thiosulfate concentrations are all higher than these ranges, the model overestimates all the variables. In the window of the model validity, predictions of the model show that the combination of both variables (increase in limiting factor concentration and in inlet gas stream) leads up to a twofold increase of the maximum H2 specific productivity with the lowest inhibition. CONCLUSIONS: A mathematical model predicting H2 production in T. maritima was successfully designed and confirmed in this study. However, it shows the limit of validity of such mathematical models. Their limit of applicability must take into account the range of validity in which the parameters were established. PMID- 28018486 TI - Hydrogen production by the hyperthermophilic bacterium Thermotoga maritima part I: effects of sulfured nutriments, with thiosulfate as model, on hydrogen production and growth. AB - BACKGROUND: Thermotoga maritima and T. neapolitana are hyperthermophile bacteria chosen by many research teams to produce bio-hydrogen because of their potential to ferment a wide variety of sugars with the highest theoretical H2/glucose yields. However, to develop economically sustainable bio-processes, the culture medium formulation remained to be optimized. The main aim of this study was to quantify accurately and specifically the effect of thiosulfate, used as sulfured nutriment model, on T. maritima growth, yields and productivities of hydrogen. The results were obtained from batch cultures, performed into a bioreactor, carefully controlled, and specifically designed to prevent the back-inhibition by hydrogen. RESULTS: Among sulfured nutriments tested, thiosulfate, cysteine, and sulfide were found to be the most efficient to stimulate T. maritima growth and hydrogen production. In particular, under our experimental conditions (glucose 60 mmol L-1 and yeast extract 1 g L-1), the cellular growth was limited by thiosulfate concentrations lower than 0.06 mmol L-1. Under these conditions, the cellular yield on thiosulfate (Y X/Thio) could be determined at 3617 mg mmol-1. In addition, it has been shown that the limitations of T. maritima growth by thiosulfate lead to metabolic stress marked by a significant metabolic shift of glucose towards the production of extracellular polysaccharides (EPS). Finally, it has been estimated that the presence of thiosulfate in the T. maritima culture medium significantly increased the cellular and hydrogen productivities by a factor 6 without detectable sulfide production. CONCLUSIONS: The stimulant effects of thiosulfate at very low concentrations on T. maritima growth have forced us to reconsider its role in this species and more probably also in all thiosulfato-reducer hyperthermophiles. Henceforth, thiosulfate should be considered in T. maritima as (1) an essential sulfur source for cellular materials when it is present at low concentrations (about 0.3 mmol g-1 of cells), and (2) as both sulfur source and detoxifying agent for H2 when thiosulfate is present at higher concentrations and, when, simultaneously, the pH2 is high. Finally, to improve the hydrogen production in bio-processes using Thermotoga species, it should be recommended to incorporate thiosulfate in the culture medium. PMID- 28018487 TI - Inherent variability of cancer-specific aneuploidy generates metastases. AB - BACKGROUND: The genetic basis of metastasis is still unclear because metastases carry individual karyotypes and phenotypes, rather than consistent mutations, and are rare compared to conventional mutation. There is however correlative evidence that metastasis depends on cancer-specific aneuploidy, and that metastases are karyotypically related to parental cancers. Accordingly we propose that metastasis is a speciation event. This theory holds that cancer-specific aneuploidy varies the clonal karyotypes of cancers automatically by unbalancing thousands of genes, and that rare variants form new autonomous subspecies with metastatic or other non-parental phenotypes like drug-resistance - similar to conventional subspeciation. RESULTS: To test this theory, we analyzed the karyotypic and morphological relationships between seven cancers and corresponding metastases. We found (1) that the cellular phenotypes of metastases were closely related to those of parental cancers, (2) that metastases shared 29 to 96% of their clonal karyotypic elements or aneusomies with the clonal karyotypes of parental cancers and (3) that, unexpectedly, the karyotypic complexity of metastases was very similar to that of the parental cancer. This suggests that metastases derive cancer-specific autonomy by conserving the overall complexity of the parental karyotype. We deduced from these results that cancers cause metastases by karyotypic variations and selection for rare metastatic subspecies. Further we asked whether metastases with multiple metastasis-specific aneusomies are assembled in one or multiple, sequential steps. Since (1) no stable karyotypic intermediates of metastases were observed in cancers here and previously by others, and (2) the karyotypic complexities of cancers are conserved in metastases, we concluded that metastases are generated from cancers in one step - like subspecies in conventional speciation. CONCLUSIONS: We conclude that the risk of cancers to metastasize is proportional to the degree of cancer-specific aneuploidy, because aneuploidy catalyzes the generation of subspecies, including metastases, at aneuploidy-dependent rates. Since speciation by random chromosomal rearrangements and selection is unpredictable, the theory that metastases are karyotypic subspecies of cancers also explains Foulds' rules, which hold that the origins of metastases are "abrupt" and that their phenotypes are "unpredictable." PMID- 28018489 TI - Barriers in the diagnosis and treatment of depression in women in the USA: where are we now? PMID- 28018488 TI - Relationship between patient-reported outcome measures (PROM) and three measures of foot-ankle alignment in patients with metatarsal head pain: a cross-sectional study. AB - BACKGROUND: The aim of the present study is to establish the relationship between foot-ankle patient-reported outcome measures (PROM) and three measures of foot ankle alignment (MoFAA) in patients with metatarsal head pain. METHODS: A cross sectional study where 206 patients completed three PROMs and a clinician recorded three MoFAA bilaterally (three times each). A reliability analysis of the MoFAA, a correlation analysis (between MoFAA and PROM) and regression analysis (dependent variable: PROM; independent variables: MoFAA) were performed. RESULTS: Pearson's coefficient changed in each PROM used, ranging from 0.243 (AAOS FAMShoeComfortScale-FVARight) to 0.807 (FFIIndex-first MTPJEright). Regression indices (R2-corrected) ranged between 0.117 (AAOS-FAMShoeComfortScale) and 0.701 (FFIIndex). CONCLUSIONS: The MoFAA correlated between moderately to strongly with the foot-ankle PROM selected. The level of correlation between MoFAA and PROM was higher when patients with metatarsal head pain were asked about foot health status, pain and function; however, the correlation was poor when the patient was asked about shoe aspects. In addition, the MoFAA variable that achieved the highest correlation value was the first metatarsophalangeal joint extension. The results obtained in this study could be used in future studies to develop tools for assessing and monitoring patients with metatarsal head pain. PMID- 28018490 TI - Detecting Levels of Polyquaternium-10 (PQ-10) via Potentiometric Titration with Dextran Sulphate and Monitoring the Equivalence Point with a Polymeric Membrane Based Polyion Sensor. AB - Polymeric quaternary ammonium salts (polyquaterniums) have found increasing use in industrial and cosmetic applications in recent years. More specifically, polyquaternium-10 (PQ-10) is routinely used in cosmetic applications as a conditioner in personal care product formulations. Herein, we demonstrate the use of potentiometric polyion-sensitive polymeric membrane-based electrodes to quantify PQ-10 levels. Mixtures containing both PQ-10 and sodium lauryl sulfate (SLS) are used as model samples to illustrate this new method. SLS is often present in cosmetic samples that contain PQ-10 (e.g., shampoos, etc.) and this surfactant species interferes with the polyion sensor detection chemistry. However, it is shown here that SLS can be readily separated from the PQ-10/SLS mixture by use of an anion-exchange resin and that the PQ-10 can then be titrated with dextran sulphate (DS). This titration is monitored by potentiometric polyanion sensors to provide equivalence points that are directly proportional to PQ-10 concentrations. PMID- 28018491 TI - Low-Intensity Amplitude Modulated Ultrasound Increases Osteoblastic Mineralization. AB - The purpose of this study was to assess the effect of pulsed amplitude modulated ultrasound (pAMUS) on the level of mineralization in osteoblast cell in comparison to cells stimulated with low-intensity pulsed ultrasound (LIPUS). To make the ultrasound effects more enhanced and targeted at region of interest, this study uses a novel approach of applying pulsed amplitude modulated ultrasound to osteoblast cells. The pAMUS signal was generated using two signal generators. Pulsed signal was amplified through a power amplifier and drove two identical focused ultrasound probes, focusing at the same point in the culture dish. The effects of pAMUS were evaluated using a pAMUS signal of 45 kHz and 100 kHz with 20% duty cycle. The hydrophone verified the formation of a focal point at equal distances (16 mm) from the surface of both transducers. Intensity profile using computer controlled 2D scanner showed circular focal point with a diameter of approximately 10 mm. The effect of the signal was studied using MC3T3 E1 cells cultured in osteogenic medium at time points Day 7, 12 and 18. The cells were analyzed for ALP activity and calcium mineralization. The pAMUS significantly increased the ALP activity and matrix calcification in comparison with LIPUS stimulated cultures. PMID- 28018492 TI - Locally Weighted Score Estimation for Quantile Classification in Binary Regression Models. AB - One common use of binary response regression methods is classification based on an arbitrary probability threshold dictated by the particular application. Since this is given to us a priori, it is sensible to incorporate the threshold into our estimation procedure. Specifically, for the linear logistic model, we solve a set of locally weighted score equations, using a kernel-like weight function centered at the threshold. The bandwidth for the weight function is selected by cross validation of a novel hybrid loss function that combines classification error and a continuous measure of divergence between observed and fitted values; other possible cross-validation functions based on more common binary classification metrics are also examined. This work has much in common with robust estimation, but diers from previous approaches in this area in its focus on prediction, specifically classification into high- and low-risk groups. Simulation results are given showing the reduction in error rates that can be obtained with this method when compared with maximum likelihood estimation, especially under certain forms of model misspecification. Analysis of a melanoma data set is presented to illustrate the use of the method in practice. PMID- 28018493 TI - Atrial Natriuretic Peptide and Acute Changes in Central Blood Volume by Hyperthermia in Healthy Humans. AB - BACKGROUND: Hyperthermia induces vasodilatation that reduces central blood volume (CBV), central venous pressure (CVP) and mean arterial pressure (MAP). Inhibition of atrial natriuretic peptide (ANP) could be a relevant homeostatic defense mechanism during hyperthermia with a decrease in CBV. The present study evaluated how changes in plasma ANP reflect the changes in CBV during hyperthermia. METHODS: Ten healthy subjects provided with a water perfused body suit increased body core temperature 1 degrees C. In situ labeled autologous red blood cells were used to measure the CBV with a gamma camera. Regions of interest were traced manually on the images of the whole body blood pool scans. Two measures of CBV were used: Heart/whole body ratio and thorax/whole body ratio. CVP and MAP were recorded. Arterial (ANPart) and venous plasma ANP were determined by radioimmunoassay. RESULTS: The ratio thorax/whole body and heart/whole body decreased 7 % and 11 %, respectively (p<0.001). MAP and CVP decreased during hyperthermia by 6.8 and 5.0 mmHg, respectively (p<0.05; p<0.001). Changes in both thorax/whole body (R=0.80; p<0.01) and heart/whole body ratios (R=0.78; p<0.01) were correlated with changes in ANPart. However, there was no correlation between venous ANP and changes in CBV, nor between ANPart and MAP or CVP. CONCLUSION: Arterial but not venous plasma concentration of ANP, is correlated to changes in CBV, but not to pressures. We suggest that plasma ANPart may be used as a surrogate marker of acute CBV changes. PMID- 28018494 TI - Research on Individual Differences in Executive Functions: Implications for the Bilingual Advantage Hypothesis. AB - Executive functions (EFs), such as response inhibition, interference control, and set shifting, are general-purpose control mechanisms that enable individuals to regulate their thoughts and behaviors. Because bilingual individuals use EF-like processes during language control, researchers have become interested in the hypothesis that this use might train EFs, resulting in better performance on non linguistic EF tasks. Although this bilingual advantage hypothesis seems straightforward to test, it involves a number of important decisions in terms of how to assess bilingualism and EFs. In this article, I focus on the complexity of measuring EFs, drawing on individual differences research (conducted with participants not selected for bilingualism). Specifically, I discuss issues related to (1) the measurement of EFs (particularly the effects of task impurity and unreliability) and (2) the multicomponent nature of EFs. Within each of these topics, I elaborate on consequences for research on bilingual advantages and provide some recommendations. PMID- 28018495 TI - Postoperative Venous Thromboembolism in Patients Undergoing Endovenous Laser and Radiofrequency Ablation of the Saphenous Vein. AB - Objective: Endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) are safe and effective treatments for varicose veins caused by saphenous reflux. Deep venous thrombosis (DVT) and endovenous heat-induced thrombosis (EHIT) are known complications of these procedures. The purpose of this article is to investigate the incidence of postoperative DVT and EHIT in patients undergoing EVLA and RFA. Methods: The patients were assessed by clinical examination and venous duplex ultrasonography before operation and at 24-72 hours, 1 month, and 1 year follow up after operation. Endovenous ablation (EVA) had been treated for 1026 limbs (835 patients) using an RFA; 1174 limbs (954 patients) using a 1470-nm wavelength diode laser with radial two-ring fiber (1470R); and 6118 limbs (5513 patients) using a 980-nm wavelength diode laser with bare-tip fiber (980B). Results: DVT was detected in 3 legs (0.3%) of RFA, 5 legs (0.4%) of 1470R, and 27 legs (0.4%) of 980B. One patient in three symptomatic DVT treated with 980B developed asymptomatic pulmonary embolus. In all, 31 of the 35 DVTs were confined to the calf veins. The incidence of EHIT classes 2 and 3 was 2.7% following RFA procedure, 6.7% after 1470R, and 7.5% after 980B. Conclusion: The incidence of EHIT following EVA was low, especially the RFA procedure. EHIT resolves within 2 4 weeks in most patients. DVT rates after EVA were compared with those published for saphenous vein stripping. (This is a translation of J Jpn Coll Angiol 2015; 55: 153-161.). PMID- 28018496 TI - An Experimental Model of Peripheral Vascular Disease Involving the Intravenous Injection of Oral Bacteria. AB - Objective: The purpose of this study was to observe the direct effects of oral bacteria, such as Porphyromonas gingivalis (Pg) and Treponema denticola (Td), on the peripheral vasculature. Materials and Methods: Beagles were directly injected (at various doses) with Pg or Td. Each leg vein was exposed, ligated at proximal and distal sites, and then injected with bacteria diluted with sterile saline. The collected vascular tissue was examined microscopically, and samples of the vascular tissue and blood were cultured and then subjected to the polymerase chain reaction (PCR) in order to detect the bacterial deoxyribonucleic acid (DNA). Results: No genes of the injected bacteria were detected in the Td inoculated blood or vascular tissue samples collected 2 weeks after the injection. The Pg gene was also not detected in the blood samples collected 4 weeks after the injection although it was detected in the vascular tissue using PCR. Microscopic examinations showed that the inflammatory reactions in the perivascular tissue increased in a bacterial dose-dependent manner, as expected. Conclusion: We observed the direct effects of oral bacteria on vascular tissue. Further studies are needed to investigate the correlations between oral bacteria and systemic diseases. (This article is a translation of Jpn J Phlebol 2015; 26: 41-6.). PMID- 28018497 TI - Morphological Comparison of Blood Vessels that were Heated with a Radiofrequency Device or a 1470-nm Laser and a Radial 2Ring Fiber. AB - Introduction: Radio waves and lasers can be used as heat sources during endovenous thermal ablation (EVTA) for saphenous vein insufficiency. A morphological comparison of veins that had been treated with EVTA was performed between those treated with an endovenous closure system (a radiofrequency [RF] system) and those treated with a Radial 2Ring fiber connected to a 1470-nm laser generator (2R). Methods: The experiment was conducted in a system that reproduces the physiological conditions found in the saphenous veins during EVTA. The 2R experiment was performed at two different power levels, 60 J/cm (2R-60) and 90 J/cm (2R-90). The heated vessels were morphologically examined in detail, and the detected morphological changes were classified into three groups: low-temperature changes (LTC), mid-temperature changes (MTC), and high-temperature changes (HTC). The thickness of the layers exhibiting each type of change was measured. Results: In the 2R groups, HTC, MTC, and LTC were observed from the superficial to deep layers. In the 2R-60 group, the layers exhibiting LTC, MTC, and HTC were 17 +/- 3.2, 42 +/- 10.5, and 190 +/- 14.6 um thick, respectively. In the 2R-90 group, these layers were 14 +/- 4.0, 105 +/- 64.2, and 363 +/- 71.3 um thick, respectively. In the RF group, only LTC were observed (thickness: 251 +/- 72.6 um). Conclusions: The RF device was able to heat the target vessels more efficiently than the laser device. (This article is a translation of Jpn J Phlebol 2015; 26: 23-8.). PMID- 28018498 TI - Insufficient Lymph Drainage Causes Abnormal Lipid Accumulation and Vein Wall Degeneration. AB - Objective: Previously, we analyzed human varicose veins (VV) using imaging mass spectrometry (IMS) and detected the abnormal accumulation of lipid molecules in the walls of VV, possibly due to insufficient lipid drainage by the lymphatic vessels. In this study, we created an animal model of lymphatic insufficiency to investigate the effects of insufficient lymph drainage on vein walls. Methods: In rats, the lymphatic collecting vessels surrounding the femoral vein were ligated on one side (the model tissue), which caused the local retention of lymphatic fluid in the perivascular tissue. The equivalent contralateral tissue was used as a control. A histological study of the femoral vein and the surrounding perivascular tissue was conducted. IMS was used to analyze the distribution of lipid molecules in the perivascular tissue. Results: Fourteen days after the procedure, the lymphatic vessels in the model tissue were significantly dilated. Furthermore, IMS revealed that the composition of the lipid molecules in the perivascular regions of the model tissue had altered. Compared with the control tissue, the model tissue exhibited marked perivascular accumulation of lysophosphatidylcholine (1-acyl 16:0), phosphatidylcholine (16:0/20:4), and triglycerides (52:2). Interestingly, the walls of the femoral veins running through the model tissue were 3.4-fold thicker than those of the femoral veins running through the control tissue. The number of tumor necrosis factor alpha positive adipocytes was increased in the perivascular regions of the model tissue. Conclusion: The findings of this study indicated that the accumulation of lymphatic fluid due to insufficient lymph drainage changes the structure of vein walls, and such changes might be associated with chronic venous insufficiency. (This is a translation of Jpn J Phlebol 2015; 26: 227-235.). PMID- 28018499 TI - Advantages of Selective Use of Intraluminal Shunt in Carotid Endarterectomy: A Study of 122 Cases. AB - Objectives: To assess the advantage of selective use of shunt in carotid endarterectomy (CEA) under local anesthesia. Materials and Methods: A total of 122 consecutive patients fulfilling international guidelines were included. Shunt was used selectively only in cases of bilateral severe carotid artery occlusive disease or in those patients who developed neurological symptoms on clamping of carotid artery. Follow up was done weekly for one month; then every month for 3 months; and then every 3 months for a year. Results: Shunt was used only in 5% (n = 6) patients. Of these, 2.5% (n = 3) patients were those who developed neurological symptoms on clamping the internal carotid and deployment of shunt resulted in complete resolution of symptoms. 2.5% (n = 3) had severe bilateral carotid stenosis and shunt was deployed. One of these patients developed stroke which was permanent. There was no mortality. The mean procedure time was 170 min in patients in whom shunt was used, when compared with 100 min in patients without shunt (P = 0.003). Conclusion: Use of shunt in carotid endarterectomy under local anesthesia as selective policy has an advantage in terms of cost effectiveness, operation time and prevention of potential complications. PMID- 28018500 TI - The Effect of Hachimi-Jio-Gan (Ba-Wei-Di-Huang-Wan) on the Quality of Life in Patients with Peripheral Arterial Disease - A Prospective Study Using Kampo Medicine. AB - Objective: To assess whether Hachimi-jio-gan (HJG), a preparation of Kampo medicine (traditional Japanese medicine), improves quality of life (QOL) in patients with peripheral arterial disease (PAD). Materials and Methods: Among the patients with PAD being followed in the Department of Cardiovascular Surgery at Tokyo Medical University Hachioji Medical Center, those with intermittent claudication (IC) and in stable condition regarding PAD severity were registered. We registered the patients from April 2014 to March 2015. We administered HJG extract for 6 months to the patients. The primary endpoint was Walking Impairment Questionnaire (WIQ) score, which was approved as an indicator of QOL of the patient with PAD. We assessed WIQ score both before and after administration of the HJG. Results: We analyzed 14 patients. WIQ items of pain, distance, and speed improved significantly. Furthermore, the median of the total score of WIQ improved significantly from 162.5 points to 308.0 points. All patients showed improvement in the total score and 7 patients out of 14 patients (50%) showed a remarkably effective improvement in score of more than 100 points. Conclusion: HJG might improve the QOL in patients with IC due to PAD. PMID- 28018501 TI - Regional Anesthesia with Dexmedetomidine Infusion: A Feasible Method for the Awake Test during Carotid Endarterectomy. AB - Background: Carotid endarterectomy (CEA) is the standard treatment modality for the prevention of stroke in patients with carotid stenosis. This study reports our experiences during CEA with routine awake tests under regional anesthesia (RA) combined with light sedation by dexmedetomidine infusion. Materials and Methods: We retrospectively reviewed 23 patients who had undergone CEA between April 2013 and June 2015. All patients underwent the awake test during CEA with cervical plexus block and light sedation by continuous dexmedetomidine infusion. Results: Mean operation and clamp times were 108.5 +/- 20.1 min and 30.1 +/- 6.9 min, respectively. Selective shunt placement was performed in three patients (13.0%). There were no cases of perioperative stroke, myocardial infarction, or death. There were no occurrences of residual stenosis, thrombosis, or dissection. One patient had a hypoglossal nerve injury but fully recovered before discharge. Mean (+/- standard deviation) hospital stay was 7.5 +/- 2.6 days. There were no incidences of death, stroke, or restenosis during a mean follow-up period of 9.2 +/- 8.8 months. Conclusions: RA with dexmedetomidine infusion appears to be a safe and feasible option. A lower shunt placement rate and favorable patient outcomes were observed following the awake test during CEA. PMID- 28018502 TI - Toe-Brachial Index in the Second Toe: Substitutability to Toe-Brachial Index in the Great Toe and Ankle-Brachial Index. AB - Objective: Toe-brachial index (TBI) is usually measured in the great toe (TBI-1). However, this is not always possible. To determine the usefulness of TBI measurement in the second toe (TBI-2), we examined the relation between systolic pressure in the second toe (toe pressure [TP-2]) and that in the great toe (TP-1) and evaluated the association between TBI and ankle-brachial index (ABI). Materials and Methods: We retrospectively analyzed patients who underwent a series of measurements of TBI-2, TBI-1, and ABI using an automatic oscillometric device at Kawasaki Medical School Hospital, Japan in 2012. Results: We evaluated 114 feet without severe ischemia symptoms in 57 patients (median age: 73 years). TP-2 was similar to TP-1 (correlation coefficient [r] = 0.769, 95% confidence interval [CI]: 0.681-0.836, p <0.001). ABI showed a mild correlation with TBI-2 (r = 0.463, 95% CI: 0.303-0.598, p <0.001) and a moderate correlation with TBI-1 (r = 0.586, 95% CI: 0.450-0.696, p <0.001). The TBIs of 0.65 and 0.5 corresponded to the ABIs of about 1.0 and 0.9, respectively, in both toes. Conclusion: TBI-2 measurement can be considered as an acceptable substitute to TBI-1 or ABI measurement to assess the patients in whom ABI and TBI-1 cannot be measured. PMID- 28018503 TI - Neurocognitive Improvement in Patients Undergoing Carotid Endarterectomy for Atherosclerotic Occlusive Carotid Artery Disease. AB - Objectives: To assess the improvement in neurocognitive functions after carotid endarterectomy (CEA) under local anesthesia (LA) in patients with carotid bifurcation occlusive disease. Place and duration of study: Department of Vascular Surgery, Combined Military Hospital Lahore from January 2013 to January 2015. Patients and Methods: A total of 79 patients with carotid artery occlusive disease, having no history of major stroke, depression, or dementia underwent CEA under LA. Cognitive functions were assessed 3 days before surgery and then 4 weeks and 12 weeks after the surgery using the Addenbrookes cognitive examination (ACE) score and General Practitioner Assessment of Cognition (GPCOG) Score. Results: In ACE score, Attention, Memory, Fluency, Language, and Visuospatial orientation improved by 33.3%, 30.7%, 21.4%, 38.4%, and 31.2%, respectively, by the end of 12 weeks. An overall improvement in neurocognition was 32% (P = 0.03). In GPCOG score, Orientation, Recall, and Memory improved by 33%, 20%, and 100%, respectively, with an overall improvement of 33.3% at the end of 12 weeks (P = 0.02). Conclusion: Both scoring systems show an overall improvement in neurocognition as well as improvements in all the subcategories in each system. Hence, we conclude statistically significant improvement in neurocognitive functions after CEA. PMID- 28018504 TI - Skin and Subcutaneous Tissue Ultrasonography Features in Breast Cancer-Related Lymphedema. AB - Objective: To investigate skin, subepidermal low echogenic band (SELEB), and subcutaneous tissue (SCT) thickness as well as the degree of increase in subcutaneous echogenicity (SEG) and subcutaneous echo-free space (SEFS) in arms with lymphedema (LE). Materials and Methods: The skin and SCT of both arms of 30 patients with unilateral stage II breast cancer-related LE were scanned at five points (medial/lateral upper arm/forearm and dorsum of the hand). SEG and SEFS grades were determined according to severity (range: 0-2). Results: All measured parameters, except the SEFS in the medial upper arm, were significantly higher on the LE side than on the normal (N) side. The parameters differed most remarkably in the medial forearm (MFA; skin: LE 1.7 +/- 0.8 mm vs. N 0.8 +/- 0.2 mm; SELEB: LE 1.0 +/- 0.6 mm vs. N 0.3 +/- 0.1 mm; SCT: LE 8.7 +/- 3.4 mm vs. N 3.8 +/- 2.0 mm; SEG: LE 0.9 +/- 0.5 vs. N 0.1 +/- 0.3; and SEFS: LE 0.5 +/- 0.7 vs. N 0). Conclusion: The differences in the thickness of the skin, SELEB, and SCT and the SEG and SEFS grades between the LE and N arms seemed most evident in the MFA. PMID- 28018505 TI - Comparison of Diagnostic Accuracy between Pulse Volume Recording Parameters and Exercise-Ankle-Brachial Pressure Index in Patients with Ankle-Brachial Pressure Index above 0.9. AB - Objective: The objective of this study was to clarify whether or not pulse volume recoding (PVR) parameters have screening capability equivalent to ankle-brachial pressure index after walking (Ex-ABI) for patients with 0.91 or higher ABI. Patients and Methods: The subjects were 87 patients (147 limbs) with symptoms of lower extremities with 0.91 or higher ABI. In all patients, upstroke time (UT), percentage of mean artery pressure (%MAP) of PVR and Ex-ABI were measured, and computed tomographic angiography (CTA) was concomitantly performed. Results: Area under the curve (AUC) of receiver operating characteristics (ROC) curves of Ex ABI, %MAP, and UT were 0.90, 0.70, and 0.81, respectively. A significant difference was noted in AUC between Ex-ABI and %MAP (p <0.001). When the cut-off values were set at %MAP >=45% and UT >=180 msec, the accuracies of %MAP and UT were markedly lower than that of Ex-ABI. When the cut-off values were corrected to the values determined from the ROC curves (%MAP >=41, UT >=164 msec), the diagnostic accuracy of UT increased markedly. Conclusion: In patients with 0.91 or higher ABI, screening capability of PVR parameters was markedly lower than that of Ex-ABI, but UT has screening capability close to that of Ex-ABI when the cut-off value is corrected downward. PMID- 28018506 TI - Recurrence of Aneurysm of the Ascending Aorta after Patch Repair: The Fate of an Aortic Patch. AB - Pseudoaneurysm of the ascending aorta is a rare but life- threatening complication after aortic cannulation and cardiovascular surgery, and it has the potential to rupture. We experienced a rare case of recurrence of aneurysm of the ascending aorta 7 years after patch repair of a small aneurysm at an aortic cannulation site. The repaired aorta had been wrapped with a Teflon felt strip during the previous surgery, and the wrapped aorta had become thin with deterioration of the normal structure of the aortic wall. PMID- 28018508 TI - Fatal Hemorrhage from Kidney after Endovascular Repair for Chronic Type B Dissection Complicated with Disseminated Intravascular Coagulation. AB - We report lethal hemorrhage from the kidney after thoracic endovascular repair for chronic type B dissection complicated by disseminated intravascular coagulation (DIC). A 70-year-old woman underwent thoracic endovascular repair to treat chronic DIC. Two weeks after surgery, refractory shock suddenly occurred and computed tomography showed a massive hematoma around the left kidney. Emergent renal artery angiography showed multiple bleeding points in the renal cortex. Immediate embolization of the renal artery was performed and her hemodynamic condition recovered. Physicians should be aware that massive hemorrhage from visceral organs is possible during the perioperative period of endovascular intervention for treatment of DIC. PMID- 28018507 TI - A Case of Patent Ductus Arteriosus in an Elderly Patient Treated by Thoracic Endovascular Aortic Repair. AB - The patient described herein was a 75-year-old female. Echocardiography showed patent ductus arteriosus (PDA). Heart failure symptoms gradually appeared, and she was referred to our department for treatment. Contrast-enhanced computed tomography (CT) revealed a tubular structure communicating between the aortic arch and pulmonary artery trunk, suggesting adult PDA. Thoracic endovascular aortic repair (TEVAR) was performed to close PDA. Completion angiography confirmed the disappearance of PDA. Post-TEVAR CT revealed no endoleak. The patient was discharged from the hospital on the 11th day after surgery. TEVAR is more useful and less invasive for adult PDA than conventional open surgery. PMID- 28018509 TI - Helicobacter pylori Eradication Therapy for Thrombocytopenia after Surgery for Abdominal Aortic Aneurysm with Disseminated Intravascular Coagulation. AB - Abdominal aortic aneurysm (AAA) is known to be rarely accompanied by disseminated intravascular coagulation (DIC). We report a case of AAA with DIC. An 81-year-old man with abdominal pain referred to our hospital. Computed tomography demonstrated an AAA (maximum diameter: 90 mm). The patient underwent a laparotomy, and an abdominal aorta replacement was performed. At the 3-month follow-up, the patient underwent Helicobacter pylori eradication treatment for 1 week. After treatment, the platelet count dramatically increased. The mechanism by which H. pylori eradication therapy improves hematological parameters has not been elucidated; however, this noninvasive treatment effectively resolved DIC associated with AAA. PMID- 28018510 TI - Spontaneous Evacuation of a Vascular Metallic Stent through a Graft-Duodenal Fistula with Concomitant Non-Surgical Fistula Closure. AB - We report a patient who developed ileus caused by vascular stent migration into the duodenum with periprosthetic retroperitoneal abscess. The patient previously underwent removal of an infected abdominal aortic aneurysm with concomitant axillobifemoral arterial reconstruction. An occlusion of the graft leg was treated by a unilateral aortoiliac bypass where endovascular surgery with a metallic stent was later needed. The abscess and ileus were vigorously drained. Following the spontaneous evacuation of the metallic stent via the digestive tract, the abscess was completely drained and fistula closure was achieved without surgical intervention. The patient has remained healthy 6 years thereafter. PMID- 28018511 TI - Open Surgery of a Descending Thoracic Aortic Aneurysm Impending Rupture with a Compression of Left Main Bronchus. AB - We describe the successful surgical treatment of an impending rupture of a saccular descending thoracic aortic aneurysm and accompanying compression of the left main bronchus. A 69-year-old man presented with a history of tingling chest pain lasting for a few hours. His left lung cannot be auscultated, and he was rapid progression of dyspnea. Computed tomography (CT) showed a saccular aneurysm compressing the left main bronchus. The patient was treated with conventional open surgery. The compression was immediately released. No additional surgical intervention was needed and his postoperative course was uneventful. After 6 months of surgery, he remains well. PMID- 28018512 TI - Prevention of Embolization in Concomitant Endovascular Therapy for Thoracic and Abdominal Aneurysms with Severely Atheromatous Aorta. AB - A 74-year-old man with multiple aortic aneurysms and shaggy aorta was simultaneously treated by conventional open repair for an abdominal aortic aneurysm and endoluminal stent grafting for a thoracic aortic aneurysm. We performed intermittent clamping of the visceral and carotid arteries under an extracorporeal circulation circuit without a blood flow pump, which lead to the avoidance of embolization in spite of the disadvantage of endoluminal stent grafting for atheromatous aorta. PMID- 28018513 TI - Aortic Pseudoaneurysm due to Simple Vertebral Compression Fracture Treated with Conservative Management. AB - Blunt aortic injures are rarely associated with minimal trauma. We present a 78 year-old man with an aortic pseudoaneurysm resulting from a simple vertebral compression fracture, which was conservatively managed. He was diagnosed with a compression fracture from a minor fall 10 days previously, and fortuitously he visited the hospital after which follow-up computed tomography (CT) for previous multiple aortic surgeries was performed. The enhanced CT revealed a pseudoaneurysm on the abdominal aorta, which was bleeding from a pinhole perforation. He was conservatively treated and follow-up CT 9 months later revealed that the pseudoaneurysm had disappeared. PMID- 28018514 TI - Radiopaque Ruler-Guided Frozen Elephant Trunk Technique. AB - Frozen elephant trunk (FET) technique combines open surgery and endovascular repair for extensive thoracic aortic aneurysms. When a FET is inserted into the descending thoracic aorta, it is difficult to confirm its proper positioning. Here we report a radiopaque ruler-guided FET technique. On the basis of preoperative computed tomography, we create a roadmap which shows the relationship between the descending thoracic aorta and vertebrae. During surgery, a radiopaque ruler placed beneath the patient's back provides the accurate target position under fluoroscopy. Our technique is effective to prevent spinal cord injury because it avoids an overly deep implantation of a FET. PMID- 28018515 TI - 2013 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report. AB - Since 2013, the Japanese Society for Vascular Surgery (JSVS) has started the project of nationwide registration and a tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), is created on the National Clinical Database (NCD) and collects data of patients' background, therapeutic measures, early results, and long term prognosis as long as five years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or EVT. In 2013, 1207 CLI limbs (male 874 limbs: 72%) were registered by 87 facilities. ASO has accounted for 98% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2016; 25: 215-232.). PMID- 28018516 TI - 2014 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report. AB - Since 2013, the Japanese Society for Vascular Surgery (JSVS) has started the project of nationwide registration and a tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), is created on the National Clinical Database (NCD) and collects data of patients' background, therapeutic measures, early results, and long-term prognosis as long as 5 years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or endovascular treatment (EVT). In 2014, 1347 CLI limbs (male 936 limbs: 69%) were registered by 95 facilities. Arteriosclerosis obliterans (ASO) has accounted for 97% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2016;25:293-310.). PMID- 28018517 TI - ? AB - [This corrects the article DOI: 10.3400/avd.cr.16-00052.]. PMID- 28018518 TI - Managing pain in frail elders. PMID- 28018519 TI - Extinction Coefficient of Gold Nanostars. AB - Gold nanostars (NStars) are highly attractive for biological applications due to their surface chemistry, facile synthesis and optical properties. Here, we synthesize NStars in HEPES buffer at different HEPES/Au ratios, producing NStars of different sizes and shapes, and therefore varying optical properties. We measure the extinction coefficient of the synthesized NStars at their maximum surface plasmon resonances (SPR), which range from 5.7 * 108 to 26.8 * 108 M-1cm 1. Measured values correlate with those obtained from theoretical models of the NStars using the discrete dipole approximation (DDA), which we use to simulate the extinction spectra of the nanostars. Finally, because NStars are typically used in biological applications, we conjugate DNA and antibodies to the NStars and calculate the footprint of the bound biomolecules. PMID- 28018520 TI - The Relationship between Social Support and Suicide Risk in a National Sample of Ethnically Diverse Sexual Minority Women. AB - This study examined the relationship between three types of social support and suicidal ideation and lifetime attempts among a national sample of ethnically diverse sexual minority women (SMW). Participants (N = 150) completed measures of social support and suicidal ideation/attempts. After controlling for socioeconomic status, social support explained 12.3% of the variance in past suicidal ideation and 10.7% in lifetime suicide attempts. Social support from family and significant other were both inversely associated with suicidal ideation, and social support from family inversely with lifetime attempts. Interventions that strengthen family relationships could be a buffer of suicidality in this population. PMID- 28018521 TI - The Effects of the Combination of a Refined Carbohydrate Diet and Exposure to Hyperoxia in Mice. AB - Obesity is a multifactorial disease with genetic, social, and environmental influences. This study aims at analyzing the effects of the combination of a refined carbohydrate diet and exposure to hyperoxia on the pulmonary oxidative and inflammatory response in mice. Twenty-four mice were divided into four groups: control group (CG), hyperoxia group (HG), refined carbohydrate diet group (RCDG), and refined carbohydrate diet + hyperoxia group (RCDHG). The experimental diet was composed of 10% sugar, 45% standard diet, and 45% sweet condensed milk. For 24 hours, the HG and RCDHG were exposed to hyperoxia and the CG and RCDG to ambient air. After the exposures were completed, the animals were euthanized, and blood, bronchoalveolar lavage fluid, and lungs were collected for analyses. The HG showed higher levels of interferon-gamma in adipose tissue as compared to other groups and higher levels of interleukin-10 and tumor necrosis factor-alpha compared to the CG and RCDHG. SOD and CAT activities in the pulmonary parenchyma decreased in the RCDHG as compared to the CG. There was an increase of lipid peroxidation in the HG, RCDG, and RCDHG as compared to the CG. A refined carbohydrate diet combined with hyperoxia promoted inflammation and redox imbalance in adult mice. PMID- 28018522 TI - Dysfunction of Autophagy: A Possible Mechanism Involved in the Pathogenesis of Vitiligo by Breaking the Redox Balance of Melanocytes. AB - Vitiligo is a common chronic acquired pigmentation disorder characterized by loss of functional melanocytes from the epidermis and follicular reservoir. Among multiple hypotheses which have been proposed in the pathogenesis of vitiligo, autoimmunity and oxidative stress-mediated toxicity in melanocytes remain most widely accepted. Macroautophagy is a lysosome-dependent degradation pathway which widely exists in eukaryotic cells. Autophagy participates in the oxidative stress response in many cells, which plays a protective role in preventing damage caused by oxidative stress. Recent studies have enrolled autophagy as an important regulator in limiting damage caused by UV light and lipid oxidation, keeping oxidative stress in a steady state in epidermal keratinocytes and maintaining normal proliferation and aging of melanocytes. Impairment of autophagy might disrupt the antioxidant defense system which renders melanocytes to oxidative insults. These findings provide supportive evidence to explore new ideas of the pathogenesis of vitiligo and other pigmentation disorders. PMID- 28018523 TI - Long-term outcomes of stereotactic body radiation therapy (SBRT) with fiducial tracking for inoperable stage I non-small cell lung cancer (NSCLC). AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) is considered standard of care in the medically inoperable patient population. Multiple methods of SBRT delivery exist including fiducial based tumor tracking, which allows for smaller treatment margins and avoidance of patient immobilization devices. We explore the long-term clinical outcomes of this novel fiducial-based SBRT method. METHODS: In this single institutional retrospective review, we detail the outcomes of medically inoperable pathologically confirmed stage I NSCLC. Patients were treated with the Cyberknife SBRT system using a planning target volume (PTV) defined as a 5-mm expansion from gross tumor volume (GTV) without creation of an internal target volume (ITV). Dose was delivered in three or five equal fractions of 10 to 20 Gy. Pretreatment and posttreatment pulmonary function test (PFT) changes and evidence of late radiological rib fractures were analyzed for the majority of patients. Actuarial local control, locoregional control, distant control, and overall survival were calculated using the Kaplan-Meier method. RESULTS: Sixty-one patients with a median age of 75 years were available for analysis. The majority (80 %) of patients were deemed to be medically inoperable due to underlying pulmonary dysfunction. Eleven patients (18 %) developed symptomatic pneumothoraces secondary to fiducial placement under CT guidance, which precipitously dropped to 0 % following transition to bronchoscopic fiducial placement. The 2-year rib fracture risk was 21.4 % with a median time to rib fracture of 2.9 years. PFTs averaged over all patients and parameters demonstrated small absolute declines, 5.7 % averaged PFT decline, at approximately 1 year of follow-up, but only the diffusing capacity of lung for carbon monoxide (DLCO) demonstrated a statistically significant decline (10.29 vs. 9.01 mL/min/mmHg, p = 0.01). Five year local control, locoregional control, and overall survival were 87.6, 71.8, and 39.3 %, respectively. CONCLUSIONS: Despite reduced treatment margins and lack of patient immobilization, SBRT with fiducial-based tumor tracking achieves clinically comparable long-term outcomes to other linac-based SBRT approaches. PMID- 28018524 TI - Retraction. AB - [This retracts the article on p. 173 in vol. 8, PMID: 27168883.]. PMID- 28018525 TI - Group Peer Review: The Breakfast of Champions. PMID- 28018526 TI - The Burnout Conundrum: Nature Versus Nurture? PMID- 28018527 TI - Establishing the First Residency Program in a New Sponsoring Institution: Addressing Regional Physician Workforce Needs. PMID- 28018528 TI - Spotting the Wolf in Sheep's Clothing: Predatory Open Access Publications. PMID- 28018529 TI - Lifestyle Medicine: A Primary Care Perspective. PMID- 28018530 TI - Education Scholarship Fellowships: An Emerging Model for Creating Educational Leaders. PMID- 28018531 TI - Well-Being in Residency: A Systematic Review. AB - BACKGROUND : Rates of physician burnout have increased in recent years, and high burnout levels are reported by physicians in training. OBJECTIVE : This review of the research on resident well-being seeks to identify factors associated with well-being, summarize well-being promotion interventions, and provide a framework for future research efforts. METHODS : Keywords were used to search PubMed, PsycINFO, and MEDLINE. Studies included were conducted between 1989 and 2014. The search yielded 82 articles, 26 which met inclusion criteria, and were assessed using the Medical Education Research Study Quality Instrument. RESULTS : Articles measured resident well-being and associated factors, predictors, effects, barriers, as well as interventions to improve well-being. Factors identified in psychological well-being research-autonomy, building of competence, and strong social relatedness-are associated with resident well-being. Sleep and time away from work are associated with greater resident well-being. Perseverance is predictive of well-being, and greater well-being is associated with increased empathy. Interventions focused on health and coping skills appear to improve well being, although the 3 studies that examined interventions were limited by small samples and single site administration. CONCLUSIONS : An important step in evolving research in this area entails the development of a clear definition of resident well-being and a scale for measuring the construct. The majority (n = 17, 65%) of existing studies are cross-sectional analyses of factors associated with well-being. The literature summarized in this review suggests future research should focus on factors identified in cross-sectional studies, including sleep, coping mechanisms, resident autonomy, building competence, and enhanced social relatedness. PMID- 28018532 TI - Global Health and Graduate Medical Education: A Systematic Review of the Literature. AB - BACKGROUND : Global health (GH) interest is increasing in graduate medical education (GME). The popularity of the GH topic has created growth in the GME literature. OBJECTIVE : The authors aim to provide a systematic review of published approaches to GH in GME. METHODS : We searched PubMed using variable keywords to identify articles with abstracts published between January 1975 and January 2015 focusing on GME approaches to GH. Articles meeting inclusion criteria were evaluated for content by authors to ensure relevance. Methodological quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI), which has demonstrated reliability and validity evidence. RESULTS : Overall, 69 articles met initial inclusion criteria. Articles represented research and curricula from a number of specialties and a range of institutions. Many studies reported data from a single institution, lacked randomization and/or evidence of clinical benefit, and had poor reliability and validity evidence. The mean MERSQI score among 42 quantitative articles was 8.87 (2.79). CONCLUSIONS : There is significant heterogeneity in GH curricula in GME, with no single strategy for teaching GH to graduate medical learners. The quality of literature is marginal, and the body of work overall does not facilitate assessment of educational or clinical benefit of GH experiences. Improved methods of curriculum evaluation and enhanced publication guidelines would have a positive impact on the quality of research in this area. PMID- 28018533 TI - Developing Emotional Intelligence in the Clinical Learning Environment: A Case Study in Cultural Transformation. AB - BACKGROUND : Burnout continues to erode the physician workforce, and there are few effective intervention studies to guide educators. OBJECTIVE : We explored residents' experience in a model environment emphasizing resident wellness, safety, and interpersonal skills. METHODS : As 1 of 14 participants in the national Preparing the Personal Physician for Practice (P4) project, the family medicine residency at Lehigh Valley Health Network implemented a series of curricular changes designed to transform the culture of education. This mixed methods case study utilizes the results from 3 quantitative self-report instruments for well-being, along with content analysis of transcripts from 20 focus groups and 33 resident advising sessions to describe experiences of the residents enrolled between July 2007 and June 2012. RESULTS : In the intervention, we found no statistically significant quantitative differences in the well-being of residents compared with the family medicine faculty and staff. Deductive (a priori and template) analysis and inductive thematic analysis of the residents' articulations of their experiences revealed 6 recurrent themes: naming/articulation of emotions, relationships, attitudes about self-care, self reflection, delivery of learning experiences, and availability of resources. CONCLUSIONS : Quantitative measures of well-being did not capture the experiential value of the curricular innovations implemented by the residency program, while qualitative analysis highlighted themes important to residents. While not all residents in the intervention expressed support for the changes, repeated references to the nurturing educational environment indicate recognition of, and favorable responses to, the creation of an emotionally intelligent learning community. PMID- 28018534 TI - Does Psychological Safety Impact the Clinical Learning Environment for Resident Physicians? Results From the VA's Learners' Perceptions Survey. AB - BACKGROUND : Psychological safety (PS) is the perception that it is safe to take interpersonal risks in the work environment. In teaching hospitals, PS may influence the clinical learning environment for trainees. OBJECTIVE : We assessed whether resident physicians believe they are psychologically safe, and if PS is associated with how they rate satisfaction with their clinical learning experience. METHODS : Data were extracted from the Learners' Perceptions Survey (LPS) of residents who rotated through a Department of Veterans Affairs health care facility for academic years 2011-2014. Predictors of PS and its association with resident satisfaction were adjusted to account for confounding and response rate biases using generalized linear models. RESULTS : The 13 044 respondents who completed the LPS (30% response rate) were comparable to nonpediatric, non obstetrics-gynecology residents enrolled in US residency programs. Among respondents, 11 599 (89%) agreed that ". . . members of the clinical team of which I was part are able to bring up problems and tough issues." Residents were more likely to report PS if they were male, were in a less complex clinical facility, in an other medicine or psychiatry specialty, or cared for patients who were aged, had multiple illnesses, or had social supports. Nonpsychiatric residents felt safer when treating patients with no concurrent mental health diagnoses. PS was strongly associated with how residents rated their satisfaction across 4 domains of their clinical learning experience (P < .001). CONCLUSIONS : PS appears to be an important factor in resident satisfaction across 4 domains that evaluators of graduate medical education programs should consider when assessing clinical learning experiences. PMID- 28018535 TI - Mind the Gap: The Prospects of Missing Data. AB - BACKGROUND : The increasing use of workplace-based assessments (WBAs) in competency-based medical education has led to large data sets that assess resident performance longitudinally. With large data sets, problems that arise from missing data are increasingly likely. OBJECTIVE : The purpose of this study is to examine (1) whether data are missing at random across various WBAs, and (2) the relationship between resident performance and the proportion of missing data. METHODS : During 2012-2013, a total of 844 WBAs of CanMEDs Roles were completed for 9 second-year emergency medicine residents. To identify whether missing data were randomly distributed across various WBAs, the total number of missing data points was calculated for each Role. To examine whether the amount of missing data was related to resident performance, 5 faculty members rank-ordered the residents based on performance. A median rank score was calculated for each resident and was correlated with the proportion of missing data. RESULTS : More data were missing for Health Advocate and Professional WBAs relative to other competencies (P < .001). Furthermore, resident rankings were not related to the proportion of missing data points (r = 0.29, P > .05). CONCLUSIONS : The results of the present study illustrate that some CanMEDS Roles are less likely to be assessed than others. At the same time, the amount of missing data did not correlate with resident performance, suggesting lower-performing residents are no more likely to have missing data than their higher-performing peers. This article discusses several approaches to dealing with missing data. PMID- 28018536 TI - Computer Modeling to Evaluate the Impact of Technology Changes on Resident Procedural Volume. AB - BACKGROUND : As resident "index" procedures change in volume due to advances in technology or reliance on simulation, it may be difficult to ensure trainees meet case requirements. Training programs are in need of metrics to determine how many residents their institutional volume can support. OBJECTIVE : As a case study of how such metrics can be applied, we evaluated a case distribution simulation model to examine program-level mediastinoscopy and endobronchial ultrasound (EBUS) volumes needed to train thoracic surgery residents. METHODS : A computer model was created to simulate case distribution based on annual case volume, number of trainees, and rotation length. Single institutional case volume data (2011-2013) were applied, and 10 000 simulation years were run to predict the likelihood (95% confidence interval) of all residents (4 trainees) achieving board requirements for operative volume during a 2-year program. RESULTS : The mean annual mediastinoscopy volume was 43. In a simulation of pre-2012 board requirements (thoracic pathway, 25; cardiac pathway, 10), there was a 6% probability of all 4 residents meeting requirements. Under post-2012 requirements (thoracic, 15; cardiac, 10), however, the likelihood increased to 88%. When EBUS volume (mean 19 cases per year) was concurrently evaluated in the post-2012 era (thoracic, 10; cardiac, 0), the likelihood of all 4 residents meeting case requirements was only 23%. CONCLUSIONS : This model provides a metric to predict the probability of residents meeting case requirements in an era of changing volume by accounting for unpredictable and inequitable case distribution. It could be applied across operations, procedures, or disease diagnoses and may be particularly useful in developing resident curricula and schedules. PMID- 28018537 TI - Contextualizing the Physician Charter on Professionalism in Qatar: From Patient Autonomy to Family Autonomy. AB - BACKGROUND : The Physician Charter on medical professionalism has been endorsed by professional organizations worldwide, yet it is unclear if this Western framework of professionalism is applicable in non-Western countries. OBJECTIVE : This study examines how physicians practicing in a Middle Eastern context perceive the terms, principles, and commitments outlined in the charter. METHODS : In May 2013, the authors conducted 6 focus groups with 43 clinician-educators practicing at Hamad Medical Corporation in Doha, Qatar, to discuss the applicability of the Physician Charter in a local context. The research team coded and analyzed transcripts to identify sociocultural influences on professionalism. RESULTS : Participants generally expressed agreement with the applicability of the charter's principles to physician professionalism in Qatar. However, 3 contextual factors (religious beliefs and practices, family-centered decision making, and multinationality) complicated the application of the core principles of patient autonomy and social justice. Islamic beliefs reinforced the importance of professional values such as altruism, but presented a barrier to the principle of self-determination for female patients. The family-centered culture in Qatar called for enlarging the scope of patient-centered decision making to include the patient's family. Qatar's multinational population prompted debate over equal treatment and how to conceptualize and implement the principle of social justice. CONCLUSIONS : Several sociocultural contexts influence the conceptualization of the principles of medical professionalism in Qatar. The findings suggest that contextual factors should be considered when developing or adopting a professionalism framework in an international setting and context. PMID- 28018538 TI - Taking Rater Exposure to Trainees Into Account When Explaining Rater Variability. AB - BACKGROUND : Rater-based judgments are widely used in graduate medical education to provide more meaningful assessments, despite concerns about rater reliability. OBJECTIVE : We introduced a statistical modeling technique that corresponds to the new rater reliability framework, and present a case example to provide an illustration of the utility of this new approach to assessing rater reliability. METHODS : We used mixed-effects models to simultaneously incorporate random effects for raters and systematic effects of rater role as fixed effects. Study data are clinical performance ratings collected from medical school graduates who were evaluated for their readiness for supervised clinical practice in authentic simulation settings at 2 medical schools in the Netherlands and Germany. RESULTS : The medical schools recruited a maximum of 30 graduates out of 60 (50%) and 180 (17%) eligible candidates, respectively. Clinician raters (n = 25) for the study were selected based on their level of expertise and experience. Graduates were assessed on 7 facets of competence (FOCs) that are considered important in supervisors' entrustment decisions across the 5 cases used. Rater role was significantly associated with 2 FOCs: (1) teamwork and collegiality, and (2) verbal communication with colleagues/supervisors. For another 2 FOCs, rater variability was only partially explained by the role of the rater (a proxy for the amount of direct interaction with the trainee). CONCLUSIONS : Consideration of raters as meaningfully idiosyncratic provides a new framework to explore their influence on assessment scores, which goes beyond considering them as random sources of variability. PMID- 28018539 TI - Promoting Resident Autonomy During Family-Centered Rounds: A Qualitative Study of Resident, Hospitalist, and Subspecialty Physicians. AB - BACKGROUND : Family-centered rounds (FCR) have become a leading model for pediatric inpatient rounding. Several studies have examined effective teaching strategies during FCR, but none have focused on promoting resident autonomy. OBJECTIVE : The aim of this study was to identify strategies used by attending physicians to promote resident autonomy during FCR. METHODS : We conducted a qualitative study of attending physicians and residents between December 2012 and February 2013 at an academic children's hospital, where FCR is the standard model for inpatient rounds. Attending physicians participated in individual interviews, and residents participated in 1 of 2 focus groups separated by level of training. Focus group and interview transcripts were coded and themed using qualitative content analysis. RESULTS : Ten attending physicians and 14 residents participated in interviews and focus groups. Attending physician behaviors that promoted resident autonomy included setting clear expectations, preforming a prerounds huddle, deliberate positioning, and delegating teaching responsibilities. These were further categorized as occurring during 1 of 4 distinct periods: (1) at the start of the rotation; (2) before daily FCR; (3) during daily FCR; and (4) after daily FCR. CONCLUSIONS : Residents and attending physicians identified similar strategies to promote resident autonomy during FCR. These strategies occurred during several distinct periods that were not limited to rounds. The results suggest strategies for attending physicians to help balance appropriate and safe patient care with developing resident autonomy in the clinical setting. PMID- 28018540 TI - Development of a Comprehensive Communication Skills Curriculum for Pediatrics Residents. AB - BACKGROUND : Effective communication is an essential element of medical care and a priority of medical education. Specific interventions to teach communication skills are at the discretion of individual residency programs. OBJECTIVE : We developed the Resident Communication Skills Curriculum (RCSC), a formal curriculum designed to teach trainees the communication skills essential for high quality practice. METHODS : A multidisciplinary working group contributed to the development of the RCSC, guided by an institutional needs assessment, literature review, and the Accreditation Council for Graduate Medical Education core competencies. The result was a cohesive curriculum that incorporates didactic, role play, and real-life experiences over the course of the entire training period. Methods to assess curricular outcomes included self-reporting, surveys, and periodic faculty evaluations of the residents. RESULTS : Curricular components have been highly rated by residents (3.95-3.97 based on a 4-point Likert scale), and residents' self-reported communication skills demonstrated an improvement over the course of residency in the domains of requesting a consultation, providing effective handoffs, handling conflict, and having difficult conversations (intern median 3.0, graduate median 4.0 based on a 5 point Likert scale, P <= .002). Faculty evaluations of residents have also demonstrated improvement over time (intern median 3.0, graduate median 4.5 based on a 5-point Likert scale, P < .001). CONCLUSIONS : A comprehensive, integrated communication skills curriculum for pediatrics residents was implemented, with a multistep evaluative process showing improvement in skills over the course of the residency program. Positive resident evaluations and informal comments from faculty support its general acceptance. The use of existing resources makes this curriculum feasible. PMID- 28018541 TI - Feasibility of a Comprehensive Wellness and Suicide Prevention Program: A Decade of Caring for Physicians in Training and Practice. AB - BACKGROUND : Comprehensive treatment models reduce distress and suicide risk in military, university, and community populations, but are not well studied with in medical trainees and physicians in practice. Physicians face unique internal and external barriers that limit access to psychological or psychiatric treatment, which may contribute to higher rates of burnout, depression, and suicide. OBJECTIVE : Our goal is to report on the feasibility and utilization of a wellness and suicide prevention program for residents, fellows, and faculty in an academic health center. METHODS : The program provides individual counseling, psychiatric evaluation, and wellness workshops for residents/fellows (N = 906) and faculty (N = 1400). Demand for services is demonstrated by the participation rate of eligible trainees. Acceptability within the target population is examined in a 2011 survey in which trainees (N = 116, 97% participation) and program directors (N = 23, 88% participation) rated their satisfaction. Start-up costs and funding sources to sustain a wellness program are outlined. RESULTS : Over 10 years, utilization of services grew from 5% in the program's first year (2004 2005) to a high of 25% of eligible trainees for 2013-2014, and faculty utilization grew to 6% to 8% for 2014-2015. Trainees and program directors reported a high level of satisfaction with this wellness program. Funding for clinic space and clinical staff is provided by the hospital via the graduate medical education budget. CONCLUSIONS : Increased utilization over 10 years, high satisfaction, and consistent institutional support suggest that this comprehensive model of care is feasible and valued. PMID- 28018542 TI - Perceptions on the Impact of a Just-in-Time Room on Trainees and Supervising Physicians in a Pediatric Emergency Department. AB - BACKGROUND : Just-in-time (JIT) training refers to education occurring immediately prior to clinical encounters. An in situ JIT room in a pediatric emergency department (ED) was created for procedural education. OBJECTIVE : We examined trainee self-reported JIT room use, its impact on trainee self perception of procedural competence/confidence, and the effect its usage has on the need for intervention by supervising physicians during procedures. METHODS : Cross-sectional survey study of a convenience sample of residents rotating through the ED and supervising pediatric emergency medicine physicians. Outcomes included JIT room use, trainee procedural confidence, and frequency of supervisor intervention during procedures. RESULTS : Thirty-one of 32 supervising physicians (97%) and 122 of 186 residents (66%) completed the survey, with 71% of trainees reporting improved confidence, and 68% reporting improved procedural skills (P < .05, +1.4-point average skills improvement on a 5-point Likert scale). Trainees perceived no difference among supervising physicians intervening in procedures with or without JIT room use (P = .30, paired difference -0.0 points). Nearly all supervisors reported improved trainee procedural confidence, and 77% reported improved trainee procedural skills after JIT room use (P < .05, paired difference +1.8 points); 58% of supervisors stated they intervene in procedures without trainee JIT room use, compared with 42% with JIT room use (P < .05, paired difference -0.4 points). CONCLUSIONS : Use of the JIT room led to improved trainee confidence and supervisor reports of less procedural intervention. Although it carries financial and time costs, an in situ JIT room may be important for convenient JIT training. PMID- 28018543 TI - Residency Applicant Preferences of Online Systems for Scheduling Interviews. AB - BACKGROUND : Residency applicants often have difficulty coordinating interviews with multiple programs. An online scheduling system might improve this process. OBJECTIVE : The authors sought to determine applicant mean time to schedule interviews and satisfaction using online scheduling compared with manual scheduling. METHODS : An electronic survey was sent to US graduates applying to any of 6 emergency medicine programs in the 2014-2015 application cycle. Of the participant programs, 3 used an online system and 3 did not. Applicants were asked to report estimated time to schedule with the online system compared to their average time using other methods, and to rate their satisfaction with the scheduling process. RESULTS : Of 1720 applicants to at least 1 of the 6 programs, 856 completed the survey (49.8%). Respondents reported spending less time scheduling interviews using the online system compared to other systems (median of 5 minutes [IQR 3-10] versus 60 minutes [IQR 15-240], respectively, P < .0001). In addition, applicants preferred using the online system (93.6% versus 1.4%, P < .0001.) Applicants were also more satisfied with the ease of scheduling their interviews using the online system (91.5% versus 11.0%, P < .0001) and felt that the online system aided them in coordinating travel arrangements (74.7% versus 41.5%, P < .01.). CONCLUSIONS : An online interview scheduling system is associated with time savings for applicants as well as higher satisfaction among applicants, both in ease of scheduling and in coordinating travel arrangements. The results likely are generalizable to other medical and surgical specialties. PMID- 28018544 TI - Impact of a Preinterview Dinner on Candidate Perception of a Fellowship Training Program. AB - BACKGROUND : The interview visit is an important component of residency and fellowship recruitment that requires a substantial expenditure of time and resources for both training programs and candidates. OBJECTIVE : Survey aimed to study the impact of a preinterview dinner on fellowship program candidates. METHODS : A single center preintervention and postintervention comparison study was conducted using an electronic survey distributed to all Pulmonary and Critical Care Fellowship candidates over 3 years (2013-2015). The interview visit in 2013 did not include a preinterview dinner (no-dinner group), while the candidates interviewing in 2014 and 2015 were invited to a preinterview dinner with current fellows on the evening before the interview day (dinner group). RESULTS : The survey was distributed to all candidates (N = 70) who interviewed between 2013 and 2015 with a 59% (n = 41) completion rate. Ninety percent of respondents (37 of 41) reported that a preinterview dinner is valuable, primarily to gain more information about the program and to meet current fellows. Among candidates who attended the dinner, 88% (23 of 26) reported the dinner improved their impression of the program. The dinner group was more likely to have a positive view of current fellows in the program as desirable peers compared to candidates in the no-dinner group. CONCLUSIONS : This pilot study suggests that a preinterview dinner may offer benefits for candidates and training programs and may enhance candidates' perceptions of the fellowship program relative to other programs they are considering. PMID- 28018545 TI - Unverifiable Academic Work by Applicants to Primary Care Sports Medicine Fellowship Programs in the United States. AB - BACKGROUND : In 2008, it was shown that 11% of applications to a primary care sports medicine program contained unverifiable citations for publications. In 2009, the American Medical Society for Sports Medicine changed the application requirements, requiring proof that all claimed citations (publications and presentations) be included with the fellowship application. OBJECTIVE : We determined the rate of unverifiable academic citations in applications to primary care sports medicine fellowship programs after proof of citations was required. METHODS : We retrospectively examined all applications submitted to 5 primary care sports medicine fellowship programs across the country for 3 academic years (2010-2013), out of 108 to 131 programs per year. For claimed citations that did not include proof of publication or presentation, we attempted to verify them using PubMed and Google Scholar searches, a medical librarian search, and finally directly contacting the publisher or sponsoring conference organization for verification. RESULTS : Fifteen of 311 applications contained at least 1 unverifiable citation. The total unverifiable rate was 4.8% (15 of 311) for publications and 11% (9 of 85) for presentations. These rates were lower than previously published within the same medical subspecialty. CONCLUSIONS : After requiring proof of publication and presentation citations within applications to primary care sports medicine fellowship programs, unverifiable citations persisted but were less than previously reported. PMID- 28018546 TI - The SQUIRE Guidelines: A Scholarly Approach to Quality Improvement. PMID- 28018547 TI - Using Data From Program Evaluations for Qualitative Research. PMID- 28018548 TI - Empowering Trainees to Aim For Physician Wellness. PMID- 28018549 TI - Wellness in Graduate Medical Education: Is It Time to Pull the Andon Cord? PMID- 28018550 TI - Risky Business: Psychological Safety and the Risks of Learning Medicine. PMID- 28018551 TI - Permission to Grieve? "What's Up With That?" PMID- 28018552 TI - Our Duty to the "VIP Patient". PMID- 28018553 TI - Reflective Writing to Teach Interdisciplinary Management of Delirium to Internal Medicine Residents. PMID- 28018554 TI - Sarah Palin Is My Muse-And Other Lessons Learned From a Sabbatical. PMID- 28018555 TI - Teaching the Boogie-Woogie Rather Than 99? A Reflection on How Words Travel in Medicine. PMID- 28018556 TI - What Is Known: Examining the Empirical Literature in Resident Work Hours Using 30 Influential Articles. AB - BACKGROUND : Examining influential, highly cited articles can show the advancement of knowledge about the effect of resident physicians' long work hours, as well as the benefits and drawbacks of work hour limits. OBJECTIVE : A narrative review of 30 articles, selected for their contribution to the literature, explored outcomes of interest in the research on work hours-including patient safety, learning, and resident well-being. METHODS : Articles were selected from a comprehensive review. Citation volume, quality, and contribution to the evolving thinking on work hours and to the Accreditation Council for Graduate Medical Education standards were assessed. RESULTS : Duty hour limits are supported by the scientific literature, particularly limits on weekly hours and reducing the frequency of overnight call. The literature shows declining hours and call frequency over 4 decades of study, although the impact on patient safety, learning, and resident well-being is not clear. The review highlighted limitations of the scientific literature on resident hours, including small samples and reduced generalizability for intervention studies, and the inability to rule out confounders in large studies using administrative data. Key areas remain underinvestigated, and accepted methodology is challenged when assessing the impact of interventions on the multiple outcomes of interest. CONCLUSIONS : The influential literature, while showing the beneficial effect of work hour limits, does not answer all questions of interest in determining optimal limits on resident hours. Future research should use methods that permit a broader, collective examination of the multiple, often competing attributes of the learning environment that collectively promote patient safety and resident learning and well-being. PMID- 28018557 TI - A Hybrid Computer-aided-diagnosis System for Prediction of Breast Cancer Recurrence (HPBCR) Using Optimized Ensemble Learning. AB - Cancer is a collection of diseases that involves growing abnormal cells with the potential to invade or spread to the body. Breast cancer is the second leading cause of cancer death among women. A method for 5-year breast cancer recurrence prediction is presented in this manuscript. Clinicopathologic characteristics of 579 breast cancer patients (recurrence prevalence of 19.3%) were analyzed and discriminative features were selected using statistical feature selection methods. They were further refined by Particle Swarm Optimization (PSO) as the inputs of the classification system with ensemble learning (Bagged Decision Tree: BDT). The proper combination of selected categorical features and also the weight (importance) of the selected interval-measurement-scale features were identified by the PSO algorithm. The performance of HPBCR (hybrid predictor of breast cancer recurrence) was assessed using the holdout and 4-fold cross-validation. Three other classifiers namely as supported vector machines, DT, and multilayer perceptron neural network were used for comparison. The selected features were diagnosis age, tumor size, lymph node involvement ratio, number of involved axillary lymph nodes, progesterone receptor expression, having hormone therapy and type of surgery. The minimum sensitivity, specificity, precision and accuracy of HPBCR were 77%, 93%, 95% and 85%, respectively in the entire cross-validation folds and the hold-out test fold. HPBCR outperformed the other tested classifiers. It showed excellent agreement with the gold standard (i.e. the oncologist opinion after blood tumor marker and imaging tests, and tissue biopsy). This algorithm is thus a promising online tool for the prediction of breast cancer recurrence. PMID- 28018558 TI - The effects of different polishing techniques on the staining resistance of CAD/CAM resin-ceramics. AB - PURPOSE: The purposes of this study were to evaluate the staining resistance of CAD/CAM resin-ceramics polished with different techniques and to determine the effectiveness of the polishing techniques on resin-ceramics, comparing it with that of a glazed glass-ceramic. MATERIALS AND METHODS: Four different CAD/CAM ceramics (feldspathic ceramic: C-CEREC Blocs, (SIRONA) and three resin-ceramics: L-Lava Ultimate, (3M ESPE), E-Enamic, (VITA) and CS-CeraSmart, (GC)) and one light cure composite resin: ME-Clearfil Majesty Esthetic (Kuraray) were used. Only C samples were glazed (gl). Other restorations were divided into four groups according to the polishing technique: nonpolished control group (c), a group polished with light cure liquid polish (Biscover LV BISCO) (bb), a group polished with ceramic polishing kit (Diapol, EVE) (cd), and a group polished with composite polishing kit (Clearfil Twist Dia, Kuraray) (kc). Glazed C samples and the polished samples were further divided into four subgroups and immersed into different solutions: distilled water, tea, coffee, and fermented black carrot juice. Eight samples (8 * 8 * 1 mm) were prepared for each subgroup. According to CIELab system, four color measurements were made: before immersion, immersion after 1 day, after 1 week, and after 1 month. Data were analyzed with repeated measures of ANOVA (alpha=.05). RESULTS: The highest staining resistance was found in gl samples. There was no difference among gl, kc and cd (P>.05). Staining resistance of gl was significantly higher than that of bb (P<.05). Staining resistances of E and CS were significantly higher than those of L and ME (P<.05). CONCLUSION: Ceramic and composite polishing kits can be used for resin ceramics as a counterpart of glazing procedure used for full ceramic materials. Liquid polish has limited indications for resin ceramics. PMID- 28018559 TI - Color variation induced by abutments in the superior anterior maxilla: an in vitro study in the pig gingiva. AB - PURPOSE: The aim of this work is to evaluate different types of materials used for making implant abutments, by means of an in vitro study and a review of the literature, in order to identify the indications for a better choice of an implant-supported restoration in the anterior section. MATERIALS AND METHODS: 5 implant abutments were tested in a random order in the superior anterior maxilla of pig gingiva (n = 8): titanium dioxide (Nobel Biocare); zirconium dioxide, Standard BO shade (Nobel Biocare, Kloten, Switzerland); zirconium dioxide, Light BI shade (Nobel Biocare); zirconium dioxide, Intense A 3.5 shade (Nobel Biocare); and aluminium oxide. Each abutment was tested for 2 mm and 3 mm thickness. To determine color variation, VITA Easyshade Advance spectrophotometer (Vita Zahnfabrik, Bad Sackingen, Germany) was used. RESULTS: Results showed that the color variation induced by the abutment would be affected by the abutment material and gingival thickness, when the gingival thickness is 2 mm. All materials except zirconium dioxide (Standard shade) caused a visible change of color. Then, as the thickness of the gingiva increased to 3 mm, the color variation was attenuated in a significant manner and became invisible for all types of abutments, except those made of aluminium oxide. CONCLUSION: Zirconium dioxide is the material causing the lowest color variation at 2 mm and at 3 mm, whereas aluminium oxide causes the highest color variation no matter the thickness. PMID- 28018560 TI - Mechanical properties related to the microstructure of seven different fiber reinforced composite posts. AB - PURPOSE: The aim of this in vitro study was to evaluate the mechanical properties (bending strength and hardness) of seven different fiber reinforced composite posts, in relation to their microstructural characteristics. MATERIALS AND METHODS: Two hundred eighty posts were divided into seven groups of 40, one group for each type of post analyzed. Within each group, 15 posts were subjected to three-point bending strength test, 15 to a microhardess meter for the Knoop hardness, and 10 to Scanning Electron Microscope in order to determine the diameter of the fibers and the percentage of fibers embedded in the matrix. To compare the flexural strength in relation to the type of fiber, matrix, and the hardness of the posts, a Kruskal-Wallis H test was used. The Jonckheere-Terpstra test was used to determine if the volume percent of fibers in the post influenced the bending strength. RESULTS: The flexural strength and the hardness depended on the type of fibers that formed the post. The lower flexural strength of a post could be due to deficient bonding between the fiber and the resin matrix. CONCLUSION: According to the results, other factors, besides the microstructural characteristics, may also influence the mechanical properties of the post. The feature that has more influence on the mechanical properties of the posts is the type of fiber. PMID- 28018561 TI - Comparison of the fit accuracy of zirconia-based prostheses generated by two CAD/CAM systems. AB - PURPOSE: The purposes of this study are to evaluate the internal and marginal adaptation of two widely used CAD/CAM systems and to study the effect of porcelain press veneering process on the prosthesis adaptation. MATERIALS AND METHODS: Molar of a lower jaw typodont resin model was prepared by adjusting a 1.0 mm circumferential chamfer, an occlusal reduction of 2.0 mm, and a 5 degrees convergence angle and was duplicated as an abrasion-resistant master die. The monolithic crowns and copings were fabricated with two different CAD/CAM system Ceramil and Zirkonzahn systems. Two kinds of non-destructive analysis methods are used in this study. First, weight technique was used to determine the overall fitting accuracy. And, to evaluate internal and marginal fit of specific part, replica technique procedures were performed. RESULTS: The silicone weight for the cement space of monolithic crowns and copings manufactured with Ceramil system was significantly higher than that from Zirkonzahn system. This gap might cause the differences in the silicone weight because the prostheses were manufactured according to the recommendation of each system. Marginal discrepancies of copings made with Ceramil system were between 106 and 117 um and those from Zirkonzahn system were between 111 and 115 um. Marginal discrepancies of copings made with Ceramil system were between 101 and 131 um and those from Zirkonzahn system were between 116 and 131 um. CONCLUSION: Marginal discrepancy was relatively lower in Ceramil system and internal gap was smaller in Zirkonzahn system. There were significant differences in the internal gap of monolithic crown and coping among the 2 CAD/CAM systems. Marginal discrepancy produced from the 2 CAD/CAM systems were within a reported clinically acceptable range of marginal discrepancy. PMID- 28018562 TI - Effect of cement type on the color attributes of a zirconia ceramic. AB - PURPOSE: This in vitro study evaluated the effects of four different cements on the color attributes of a zirconia ceramic. MATERIALS AND METHODS: 40 zirconia ceramic disk specimens (0.5 mm thickness, 10 mm diameter, 0.1 mm cement space) were fabricated by a computer-aided design and computer-aided manufacturing system. The specimens were divided into 4 groups of 10 specimens and cemented to composite substrates using four different cements including: Glass Ionomer, Panavia F2.0, Zinc Phosphate, and TempBond. The L*, a*, and b* color attributes of the specimens were measured before and after cementation by a spectrophotometer. Additionally, DeltaE values were measured to determine color changes for the groups and then compared with the perceptional threshold of DeltaE = 3.3. Repeated Measures ANOVA, Tukey Post Hoc, Bonferroni, One-way ANOVA, and One-sample t-test tests were used to analyze the data. All tests were carried out at the 0.05 level of significance. RESULTS: Statistically significant differences were detected in the DeltaE values for Zinc Phosphate (P<.0001) and TempBond (P<.0001) groups. However, there were no statistically significant differences in this respect for Glass Ionomer (P=.99) and Panavia F2.0 (P=1) groups. The means and standard deviations of the DeltaE values for Glass Ionomer, Panavia F2.0, Zinc Phosphate, and Tempbond groups were 2.11+/-0.66, 0.94+/-0.39, 5.77+/-0.83, and 7.50+/-1.16 Unit, respectively. CONCLUSION: Within the limitations of this study, it was concluded that Zinc Phosphate and Tempbond cements affected the color attributes of the tested zirconia ceramic beyond the perceptional threshold. However, Glass Ionomer and Panavia F2.0 cements created acceptable color changes. PMID- 28018563 TI - Comparing a tablet computer and paper forms for assessing patient-reported outcomes in edentulous patients. AB - PURPOSE: The aim of this study was to determine whether two methods of documentation, print and electronic forms, for the assessment of patient-reported outcomes (PRO) in complete denture wearers provide comparable results. The study also quantified the time needed for filling the forms by each method. MATERIALS AND METHODS: Thirty participants enrolled in a university clinic answered two forms (a questionnaire for denture satisfaction and OHIP-EDENT). They provided answers with two application methods in a random order, with a one-month interval between them: (1) electronic forms on a tablet computer; and (2) print forms. The methods were compared in terms of mean results, correlation/agreement, internal consistency, and spent time. RESULTS: Mean results for both methods were similar for each denture satisfaction item (100-mm VAS) and OHIP-EDENT summary score. Both questionnaires presented good internal consistency regardless of the application method (Cronbach's alpha=0.86 or higher). Correlation and agreement between the methods regarding specific items was at least moderate for the majority of cases. Mean time for the electronic and print forms were 9.2 and 8.5 minutes, respectively (paired t test, P=.06, non-significant). CONCLUSION: The electronic method is comparable to print forms for the assessment of important PRO of prosthetic treatment for edentulism, considering the results and time needed. Findings suggest the viability of replacing print forms with a tablet for applying the tested inventories in clinical trials. PMID- 28018564 TI - Evaluation of stability of interface between CCM (Co-Cr-Mo) UCLA abutment and external hex implant. AB - PURPOSE: The purpose of this study is to evaluate the stability of interface between Co-Cr-Mo (CCM) UCLA abutment and external hex implant. MATERIALS AND METHODS: Sixteen external hex implant fixtures were assigned to two groups (CCM and Gold group) and were embedded in molds using clear acrylic resin. Screw retained prostheses were constructed using CCM UCLA abutment and Gold UCLA abutment. The external implant fixture and screw-retained prostheses were connected using abutment screws. After the abutments were tightened to 30 Ncm torque, 5 kg thermocyclic functional loading was applied by chewing simulator. A target of 1.0 * 106 cycles was applied. After cyclic loading, removal torque values were recorded using a driving torque tester, and the interface between implant fixture and abutment was evaluated by scanning electronic microscope (SEM). The means and standard deviations (SD) between the CCM and Gold groups were analyzed with independent t-test at the significance level of 0.05. RESULTS: Fractures of crowns, abutments, abutment screws, and fixtures and loosening of abutment screws were not observed after thermocyclic loading. There were no statistically significant differences at the recorded removal torque values between CCM and Gold groups (P>.05). SEM analysis revealed that remarkable wear patterns were observed at the abutment interface only for Gold UCLA abutments. Those patterns were not observed for other specimens. CONCLUSION: Within the limit of this study, CCM UCLA abutment has no statistically significant difference in the stability of interface with external hex implant, compared with Gold UCLA abutment. PMID- 28018565 TI - Contour of lingual surface in lower complete denture formed by polished surface impression. AB - PURPOSE: The aim of this study was to analyze the shapes of lingual polished surfaces in lower complete dentures formed by polished surface impressions and to provide reference data for use when manufacturing edentulous trays and lower complete dentures. MATERIALS AND METHODS: Twenty-six patients with mandibular edentulism were studied. After lower wax dentures were fabricated, wax was removed from the lingual side of the wax denture and a lingual polished surface impression was obtained with tissue conditioner. The definitive denture was scanned with a three-dimensional scanner, and scanned images were obtained. At the cross-sections of the lingual frenum, lateral incisors, first premolars, first molars, and anterior border of the retromolar pads, three points were marked and eight measurements were taken. The Kruskal-Wallis test and a post hoc analysis with the Mann-Whitney test were performed. RESULTS: Each patient showed similar values for the same areas on the left and right sides without a statistically significant difference. The height of the contour of the lingual polished surface at the lingual frenum was halfway between the occlusal plane and lingual border, it moved gradually in a downward direction. The angle from the occlusal plane to the height of the contour of the lingual polished surface was increased as it progressed from the lingual frenum towards the retromolar pads. CONCLUSION: The shape of the mandibular lingual polished surface was convex at the lingual frenum, lateral incisors and gradually flattened towards the first molars and retromolar pads. PMID- 28018566 TI - Interfacial modulus mapping of layered dental ceramics using nanoindentation. AB - PURPOSE: The aim of this study was to test the modulus of elasticity (E) across the interfaces of yttria stabilized zirconia (YTZP) / veneer multilayers using nanoindentation. MATERIALS AND METHODS: YTZP core material (KaVo-Everest, Germany) specimens were either coated with a liner (IPS e.max ZirLiner, Ivoclar Vivadent) (Type-1) or left as-sintered (Type-2) and subsequently veneered with a pressable glass-ceramic (IPS e.max ZirPress, Ivoclar-Vivadent). A 5 um (nominal tip diameter) spherical indenter was used with a UMIS CSIRO 2000 (ASI, Canberra, Australia) nanoindenter system to test E across the exposed and polished interfaces of both specimen types. The multiple point load - partial unload method was used for E determination. All materials used were characterized using Scanning Electron Microscopy (SEM) and X - ray powder diffraction (XRD). E mappings of the areas tested were produced from the nanoindentation data. RESULTS: A significantly (P<.05) lower E value between Type-1 and Type-2 specimens at a distance of 40 um in the veneer material was associated with the liner. XRD and SEM characterization of the zirconia sample showed a fine grained bulk tetragonal phase. IPS e-max ZirPress and IPS e-max ZirLiner materials were characterized as amorphous. CONCLUSION: The liner between the YTZP core and the heat pressed veneer may act as a weak link in this dental multilayer due to its significantly (P<.05) lower E. The present study has shown nanoindentation using spherical indentation and the multiple point load - partial unload method to be reliable predictors of E and useful evaluation tools for layered dental ceramic interfaces. PMID- 28018567 TI - A comparison of the fracture resistances of endodontically treated mandibular premolars restored with endocrowns and glass fiber post-core retained conventional crowns. AB - PURPOSE: This in-vitro study aimed to evaluate the fracture resistances and failure modes of endodontically treated mandibular premolars restored with endocrowns and conventional post-core retained crowns. MATERIALS AND METHODS: Thirty mandibular premolars were assigned into three groups (n=10): GI, intact teeth; GE, teeth with endocrowns; GC, teeth with conventional post-core supported crowns. Except for the teeth in group GI, all specimens were cut to 1.5 mm above the cementoenamel junction and endodontically treated. Both endocrowns and conventional crowns were fabricated from lithium-disilicate blocks using a CEREC 3D CAD/CAM unit. All specimens were subjected to thermocycling and then to 45 degrees oblique compressive load until fracture occurred. The fracture resistance and failure mode of each specimen were recorded. Data were analyzed with one-way ANOVA and LSD Post Hoc Test (alpha=.05). RESULTS: The fracture resistances of GE and GC were significantly lower than that of GI (P<.01), while no significant difference was found between GE and GC (P=.702). As of the failure mode, most of the specimens in GE and GC were unfavorable while a higher occurrence of favorable failure mode was presented in GI. CONCLUSION: For the restoration of mandibular premolar, endocrown shows no advantage in fracture resistance when compared with the conventional method. Both of the two methods cannot rehabilitate endodontically treated teeth with the same fracture resistances that intact mandibular premolars have. PMID- 28018568 TI - The prognosis of splinted restoration of the most-distal implants in the posterior region. AB - PURPOSE: The aim of this study was to compare the efficacies of two-implant splinting (2-IS) and single-implant restoration (1-IR) in the first and second molar regions over a mean functional loading period (FLP) of 40 months, and to propose the appropriate clinical considerations for the splinting technique. MATERIALS AND METHODS: The following clinical factors were examined in the 1-IR and 2-IS groups based on the total hospital records of the patients: sex, mean age, implant location, FLP, bone grafting, clinical crown-implant ratio, crown height space, and horizontal distance. The mechanical complications [i.e., screw loosening (SL), screw fracture, crown fracture, and repeated SL] and biological complications [i.e., peri-implant mucositis (PM) and peri-implantitis (PI)] were also evaluated for each patient. In analysis of two groups, the chi-square test and Student's t-test were used to identify the relationship between clinical factors and complication rates. The optimal cutoff value for the FLP based on complications was evaluated using receiver operating characteristics analysis. RESULTS: In total, 234 patients with 408 implants that had been placed during 2005 - 2014 were investigated. The incident rates of SL (P<.001), PM (P=.002), and PI (P=.046) differed significantly between the 1-IR and 2-IS groups. The FLP was the only meaningful clinical factor for mechanical and biological complication rates in 2-IS. CONCLUSION: The mechanical complication rates were lower for 2-IS than for 1-IR, while the biological complication rates were higher for 2-IS. FLP of 39.80 and 46.57 months were the reference follow-up periods for preventing biological and mechanical complications, respectively. PMID- 28018569 TI - Effect of surface treatment methods on the shear bond strength of auto polymerized resin to thermoplastic denture base polymer. AB - PURPOSE: Polyamide polymers do not provide sufficient bond strength to auto polymerized resins for repairing fractured denture or replacing dislodged denture teeth. Limited treatment methods have been developed to improve the bond strength between auto-polymerized reline resins and polyamide denture base materials. The objective of the present study was to evaluate the effect of surface modification by acetic acid on surface characteristics and bond strength of reline resin to polyamide denture base. MATERIALS AND METHODS: 84 polyamide specimens were divided into three surface treatment groups (n=28): control (N), silica-coated (S), and acid-treated (A). Two different auto-polymerized reline resins GC and Triplex resins were bonded to the samples (subgroups T and G, respectively, n=14). The specimens were subjected to shear bond strength test after they were stored in distilled water for 1 week and thermo-cycled for 5000 cycles. Data were analyzed with independent t-test, two-way analysis of variance (ANOVA), and Tukey's post hoc multiple comparison test (alpha=.05). RESULTS: The bond strength values of A and S were significantly higher than those of N (P<.001 for both). However, statistically significant difference was not observed between group A and group S. According to the independent Student's t-test, the shear bond strength values of AT were significantly higher than those of AG (P<.001). CONCLUSION: The surface treatment of polyamide denture base materials with acetic acid may be an efficient and cost-effective method for increasing the shear bond strength to auto-polymerized reline resin. PMID- 28018570 TI - Immediate fixed partial denture after tooth extraction in patients with systemic diseases: A clinical report. AB - For patients with systemic diseases who face difficulties visiting dental clinics, wearing fixed partial denture in the anterior region on the same day of tooth extraction can reduce the total period of treatment and the number of visits, as well as post-treatment psychological effect on the patient. PMID- 28018571 TI - Short-term Mortality Prediction for Elderly Patients Using Medicare Claims Data. AB - Risk prediction is central to both clinical medicine and public health. While many machine learning models have been developed to predict mortality, they are rarely applied in the clinical literature, where classification tasks typically rely on logistic regression. One reason for this is that existing machine learning models often seek to optimize predictions by incorporating features that are not present in the databases readily available to providers and policy makers, limiting generalizability and implementation. Here we tested a number of machine learning classifiers for prediction of six-month mortality in a population of elderly Medicare beneficiaries, using an administrative claims database of the kind available to the majority of health care payers and providers. We show that machine learning classifiers substantially outperform current widely-used methods of risk prediction-but only when used with an improved feature set incorporating insights from clinical medicine, developed for this study. Our work has applications to supporting patient and provider decision making at the end of life, as well as population health-oriented efforts to identify patients at high risk of poor outcomes. PMID- 28018572 TI - Placental methylome analysis from a prospective autism study. AB - BACKGROUND: Autism spectrum disorders (ASD) are increasingly prevalent neurodevelopmental disorders that are behaviorally diagnosed in early childhood. Most ASD cases likely arise from a complex mixture of genetic and environmental factors, an interface where the epigenetic marks of DNA methylation may be useful as risk biomarkers. The placenta is a potentially useful surrogate tissue characterized by a methylation pattern of partially methylated domains (PMDs) and highly methylated domains (HMDs) reflective of methylation patterns observed in the early embryo. METHODS: In this study, we investigated human term placentas from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) prospective study by whole genome bisulfite sequencing. We also examined the utility of PMD/HMDs in detecting methylation differences consistent with ASD diagnosis at age three. RESULTS: We found that while human placental methylomes have highly reproducible PMD and HMD locations, there is a greater variation between individuals in methylation levels over PMDs than HMDs due to both sampling and individual variability. In a comparison of methylation differences in placental samples from 24 ASD and 23 typically developing (TD) children, a HMD containing a putative fetal brain enhancer near DLL1 was found to reach genome wide significance and was validated for significantly higher methylation in ASD by pyrosequencing. CONCLUSIONS: These results suggest that the placenta could be an informative surrogate tissue for predictive ASD biomarkers in high-risk families. PMID- 28018573 TI - Basic and complex emotion recognition in children with autism: cross-cultural findings. AB - BACKGROUND: Children with autism spectrum conditions (ASC) have emotion recognition deficits when tested in different expression modalities (face, voice, body). However, these findings usually focus on basic emotions, using one or two expression modalities. In addition, cultural similarities and differences in emotion recognition patterns in children with ASC have not been explored before. The current study examined the similarities and differences in the recognition of basic and complex emotions by children with ASC and typically developing (TD) controls across three cultures: Israel, Britain, and Sweden. METHODS: Fifty-five children with high-functioning ASC, aged 5-9, were compared to 58 TD children. On each site, groups were matched on age, sex, and IQ. Children were tested using four tasks, examining recognition of basic and complex emotions from voice recordings, videos of facial and bodily expressions, and emotional video scenarios including all modalities in context. RESULTS: Compared to their TD peers, children with ASC showed emotion recognition deficits in both basic and complex emotions on all three modalities and their integration in context. Complex emotions were harder to recognize, compared to basic emotions for the entire sample. Cross-cultural agreement was found for all major findings, with minor deviations on the face and body tasks. CONCLUSIONS: Our findings highlight the multimodal nature of ER deficits in ASC, which exist for basic as well as complex emotions and are relatively stable cross-culturally. Cross-cultural research has the potential to reveal both autism-specific universal deficits and the role that specific cultures play in the way empathy operates in different countries. PMID- 28018574 TI - Understanding and overcoming aminoglycoside resistance caused by N-6' acetyltransferase. AB - Aminoglycosides occupy a special niche amongst antibiotics in part because of their broad spectrum of action. Bacterial resistance is however menacing to render these drugs obsolete. A significant amount of work has been devoted to understand and overcome aminoglycoside resistance. This mini-review will discuss aminoglycoside-modifying enzymes (AMEs), with a special emphasis on the efforts to comprehend and block resistance caused by aminoglycoside 6'-N acetyltransferase (AAC(6')). PMID- 28018575 TI - How to improve influenza vaccine coverage of healthcare personnel. AB - Influenza causes substantial morbidity and mortality worldwide each year. Healthcare-associated influenza is a frequent event. Health care personnel (HCP) may be the source for infecting patients and may propagate nosocomial outbreaks. All HCP should receive a dose of influenza vaccine each year to protect themselves and others. This commentary will discuss the study recently published in the IJHPR by Nutman and Yoeli which assessed the beliefs and attitudes of HCP in an Israel hospital regarding influenza and the influenza vaccine. Unfortunately, as noted by Nutman and Yoeli in this issue many HCP in Israel choose not to receive influenza immunization and many harbor misconceptions regarding their risk for influenza as well as the benefits of influenza vaccine. We also discuss proven methods to increase acceptance by HCP for receiving an annual influenza vaccine. PMID- 28018576 TI - Israeli medical education: international perspectives, and reflections on challenges and changes. AB - Medical education is a dynamic and continually evolving process, some of which is style, and some of which is linked to changing perspectives in medical practice. A paper by Reis et al., taken in conjunction with the recent paper from an ad hoc International Review Committee (Schoenbaum et al.), provides a reflective view of where Israeli medical education stood in 2014 and places it in an international perspective. Reis at al also take this further, showing that in Israel change is occurring as a result of this review and comment on a number of important issues where further reflection, discussion, and work is required. PMID- 28018577 TI - The burden of disease from air pollution in Israel: How do we use burden estimates to advance public health? AB - In an article recently published in the IJHPR, Ginsberg and colleagues from Israel's Public Health Services estimate the disease burden from airborne particulate matter in Israel. Using national data on the concentration of PM2.5 (particulate matter less than 2.5 MUm in aerodynamic diameter) and risk estimates from meta-analyses, they calculate that about 2000 deaths (4.7% of total deaths) are attributable to air pollution. Although inherently subject to uncertainty, such estimates are useful for motivating public health protection and gauging the stringency of any needed regulations. However, Israel does not yet have an evidence-based process for air quality regulation comparable to that of the United States, which has evolved over the 45 years since passage of the Clean Air Act. In fact, Israel has only recently promulgated a national standard for airborne particulate matter and quantitative risk assessment has not been an element of regulatory decision-making. The report by Ginsberg and colleagues represents a useful beginning and should initiate discussion of the role of burden estimation and risk assessment more broadly in regulations intended to advance environmental health in Israel. PMID- 28018578 TI - Dystrophic mineralization of the arterial fibrovascular tissue associated with a vitamin D hypervitaminosis in an 8-year-old female Alpaca (Vicugna pacos). AB - BACKGROUND: Prophylactic Vitamin D supplementation is a common practice in Alpaca breeding in many regions around the world. An overdosage can lead to dystrophic mineralization of soft tissues. In this paper we illustrate a suspected case of hypervitaminosis D in an 8-year-old female Alpaca. CASE PRESENTATION: In June 2015, the carcass of an 8-year-old female Alpaca (Vicugna pacos) was submitted to the diagnostic laboratory of the Istituto Zooprofilattico Sperimentale delle Venezie (IZSVe) for necropsy. The animal had undergone a spontaneous abortion with uterine prolapse and delivery of the placenta, and had died shortly thereafter. Death occurred due to internal haemorrhage related to dystrophic mineralization of the left renal artery with subsequent rupture and damage of the renal hilum. During the necropsy, histopathological and serum biochemical analyses were performed. After laboratory analyses and the history of mineral and vitamin supplementation reported by the breeder, a hypervitaminosis D was suspected to be the most probable cause of the dystrophic mineralization observed in the left renal artery. CONCLUSIONS: Most of the information regarding Llamas and Alpacas comes from the South American and Australian regions. It is therefore important to provide scientific information about these animals in other regions of the world in order to have a better and wider understanding of the nutritional and environmental conditions necessary for optimal breeding. PMID- 28003875 TI - Optimal threshold estimation for binary classifiers using game theory. AB - Many bioinformatics algorithms can be understood as binary classifiers. They are usually trained by maximizing the area under the receiver operating characteristic ( ROC) curve. On the other hand, choosing the best threshold for practical use is a complex task, due to uncertain and context-dependent skews in the abundance of positives in nature and in the yields/costs for correct/incorrect classification. We argue that considering a classifier as a player in a zero-sum game allows us to use the minimax principle from game theory to determine the optimal operating point. The proposed classifier threshold corresponds to the intersection between the ROC curve and the descending diagonal in ROC space and yields a minimax accuracy of 1-FPR. Our proposal can be readily implemented in practice, and reveals that the empirical condition for threshold estimation of "specificity equals sensitivity" maximizes robustness against uncertainties in the abundance of positives in nature and classification costs. PMID- 28018580 TI - Engineering of Brome mosaic virus for biomedical applications. AB - Viral nanoparticles (VNPs) are becoming versatile tools in platform technology development. Their well-defined structures as well as their programmability through chemical and genetic modification allow VNPs to be engineered for potential imaging and therapeutic applications. In this article, we report the application of a variety of bioconjugation chemistries to the plant VNP Brome mosaic virus (BMV). Functional BMV nanoparticles displaying multiple copies of fluorescent dyes, PEG molecules, chemotherapeutic drug moieties, targeting proteins and cell penetrating peptides were formulated. This opens the door for the application of BMV in nanomedicine. PMID- 28018581 TI - Effect of the chemical composition of filter media on the microbial community in wastewater biofilms at different temperatures. AB - This study investigates the microbial community composition in the biofilms grown on two different support media in fixed biofilm reactors for aerobic wastewater treatment, using next generation sequencing (NGS) technology. The chemical composition of the new type of support medium (TDR) was found to be quite different from the conventionally used support medium (stone). The analysis of 16S rRNA gene fragments recovered from the laboratory scale biofilm system show that biofilm support media and temperature conditions influence bacterial community structure and composition. Greater bacterial diversity was observed under each condition, primarily due to the large number of sequences available and sustenance of rare species. There were 6 phyla found, with the highest relative abundance shown by the phylum Proteobacteria (52.71%) followed by Bacteroidetes (33.33%), Actinobacteria (4.65%), Firmicutes, Verrucomicrobia (3.1%) and Chloroflex (>1%). The dataset showed 17 genera of bacterial populations to be commonly shared under all conditions, suggesting the presence of a core microbial community in the biofilms for wastewater treatment. However, some genera in the biofilms on TDR were observed in high proportions, which may be attributed to its chemical composition, explaining the improved level of wastewater treatment. The findings show that the structure of microbial communities in biofilm systems for wastewater treatment is affected by the properties of support matrix. PMID- 28018582 TI - Carriage of ESBL/AmpC-producing or ciprofloxacin non-susceptible Escherichia coli and Klebsiella spp. in healthy people in Norway. AB - BACKGROUND: Asymptomatic carriage has been recognised as an important risk factor for infection caused by antibiotic resistant bacteria. A 14% global prevalence of Extended-Spectrum Beta-lactamase (ESBL) carriage was recently reported, but large intra-and interregional variations were observed. We investigated the faecal carriage rates of ESBL-, AmpC-producing and ciprofloxacin non-susceptible Escherichia coli and Klebsiella spp. in healthy Norwegians. METHODS: Rectal samples were obtained from 284 volunteers, together with demographic data and information on recent travel history. The rectal samples were screened by selective plating and E. coli and Klebsiella spp. identified using MALDI-TOF. Phenotypic and molecular characterization of resistant isolates was also performed. RESULTS: ESBL- or AmpC-producing E. coli and Klebsiella spp. were isolated from 4.9% and 3.2% of the study population, respectively. Carriage of ciprofloxacin non-susceptible isolates was detected in 9.9% of the volunteers. Molecular typing of ESBL/plasmid-mediated AmpC (pAmpC)-producing isolates suggested an allodemic situation rather than the dissemination of a specific clone in the Norwegian community. In concurrence with previous findings, travel to South-East Asia was associated with increased risk of carrying resistant E. coli or Klebsiella spp., highlighting the contribution of factors such as increased global mobility in erasing the boundaries between healthcare and community settings when it comes to spread of resistant bacteria. CONCLUSIONS: Overall, our study recognised Norway as a low-incidence country for faecal carriage of resistant bacteria among healthy individuals. Furthermore, our work denoted the importance of healthy humans as a reservoir for transmission of antibiotic resistant E. coli and Klebsiella spp. PMID- 28018583 TI - Ibandronate for the prevention of bone loss after allogeneic stem cell transplantation for hematologic malignancies: a randomized-controlled trial. AB - The purpose of this study was to evaluate the effects of ibandronate on bone loss following allogeneic stem cell transplantation (allo-SCT). A single-centered, open-label prospective randomized-controlled study following allo-SCT. The treatment group received 3 mg of intravenous ibandronate quarterly starting within 45 days of allo-SCT. All patients received daily calcium and vitamin D supplements. We compared the changes in bone mineral density (BMD) in the lumbar spine, femoral neck and total hip at 6 and 12 months following allo-SCT between the control and treatment groups. We also assessed relationships between bone loss and cumulative glucocorticoid dose, cumulative tacrolimus dose and acute and chronic graft-versus-host disease (GVHD) by linear regression. In all, 78 patients were enrolled. The treatment group had significantly less BMD loss in the lumbar spine at 6 months (mean percent change 0.06+/-4.03 (treatment group) versus -2.61+/-4.2 (control group)) and 12 months (mean percent change 1.27+/ 5.29 (treatment group) versus -1.81+/-4.49 (control group)) than the control group (P=0.03). Both groups lost more BMD in the femoral neck and total hip than in the lumbar spine at 6 and 12 months. The changes in BMD in the femoral neck and total hip did not differ significantly between groups. Both glucocorticoids and tacrolimus reduced BMD in the lumbar spine, but ibandronate prevented this loss. Ibandronate may reduce bone loss in the lumbar spine in patients who undergo allo-SCT, particularly those who have received high doses of glucocorticoids and/or tacrolimus. PMID- 28018584 TI - Confocal/two-photon microscopy in studying colonisation of cancer cells in bone using xenograft mouse models. AB - Confocal and two-photon microscopy has been widely used in bone research to not only produce high quality, three-dimensional images but also to provide valuable structural and quantitative information. In this article, we describe step-by step protocols for confocal and two-photon microscopy to investigate earlier cellular events during colonisation of cancer cells in bone using xenograft mouse models. This includes confocal/two-photon microscopy imaging of paraformaldehyde fixed thick bone sections and frozen bone samples. PMID- 28018585 TI - Parathyroid hormone reflects adiposity and cardiometabolic indices but not bone density in normal men. AB - Hyperparathyroidism may be associated with skeletal and cardiovascular abnormalities, but it is unclear whether these associations exist for high-normal levels of parathyroid hormone (PTH). We assessed relationships between PTH and anthropometric, skeletal and cardiometabolic indices in normal men. Body composition, blood pressure, biochemistry and bone mineral density (BMD) were evaluated in 151 healthy men. BMD was reassessed at 2 years, and coronary artery calcium (CAC) was measured at 3.5 years. Relationships between PTH and other baseline characteristics, CAC scores and change in BMD were evaluated. PTH correlated positively with baseline body mass index, fat mass, diastolic blood pressure, triglycerides, total and low-density lipoprotein (LDL) cholesterol, (r=0.19-0.25, P=0.02-0.002), and with category of CAC score. Relationships between PTH and cardiometabolic indices remained significant after adjustment for age, 25-hydroxyvitamin D and estimated glomerular filteration rate. Men in the top PTH tertile (?4.4 pmol l-1, n=51) were more likely to have LDL cholesterol ?3.5 mmol l-1, diastolic blood pressure ?85 mm Hg, and CAC score >0 than men in lower tertiles. PTH was not associated with history of fracture, baseline BMD, or change in BMD over 2 years. In summary, in this cohort of healthy men, PTH levels are linearly related to adiposity and to cardiometabolic indices, but not to BMD or bone loss. These findings suggest that adiposity should be considered as an independent cause of secondary hyperparathyroidism, and they may be relevant to patients with normocalcemic hyperparathyroidism, in whom high PTH levels may be a marker of adiposity and cardiometabolic risk rather than always indicating parathyroid autonomy. PMID- 28018586 TI - Prophylactic augmentation of the osteoporotic proximal femur-mission impossible? AB - The high incidence of secondary hip fractures and the associated markedly increased mortality call for preventive actions that could help to avoid these injuries. By providing immediate strengthening and not relying on patient compliance, internal prophylactic augmentation of the osteoporotic proximal femur may overcome the main limitations of systemic bone drugs and wearable protective pads. However, such a method would have to provide sufficient and reliable strengthening effect with minimal risks and side effects to justify the need of an invasive treatment. The requirements for an internal reinforcement approach are thus strict and include mechanical, biological, clinical, ethical and financial criteria. Here we first attempt to describe the properties of an ideal augmentation method. Previously published methodologies and techniques developed at our research institute, including approaches using cements, metals, other materials or combined approaches, are then reviewed and evaluated according to these aspects. We conclude that none of the discussed methodologies appears to be able to deliver a sufficiently high gain-versus-risk ratio that could justify the clinical application and thus augmentation of the osteoporotic proximal femur remains a challenge. Finally, we provide suggestions for the development and evaluation of future strategies. PMID- 28018587 TI - Case-controlled study on indirect hyperbilirubinemia in exclusively breast fed neonates and mutations of the bilirubin Uridine Diphosphate-Glucuronyl transferase gene 1A1. AB - OBJECTIVE: This study aims to investigate the association of neonatal indirect hyperbilirubinemia in exclusively breast-fed infants with UGT1A1 (Uridine Diphosphate-Glucuronyl transferase 1A1) polymorphism. METHODS: 50 neonates were classified into 2 groups: 1) 30 full term neonates with indirect hyperbilirubinemia (gestational age (GA) 39.5 +/- 1.2 weeks); 2) 20 apparently healthy full-term neonates. Group 1 was further subdivided based on percentage of body weight lost: (A) less than 10%; (B) 10% or more. RESULTS: There was a statistically significant decrease in weight at sample collection and significant increase in indirect bilirubin level in patients group compared to control group, there was statistically significant difference as regard to genotype frequency [G/G, G/A, A/A], and allele frequency (A,G) between patients and control group. There was statistically significant increase in indirect bilirubin level in G/A - A/A genotypes. By comparing subgroup (A) and subgroup (B), there was statistically significant increase in total bilirubin level in subgroup (B). There was statistically high significant difference regarding genotype frequency (G/G, G/A, A/A) and allele frequency (G, A) between subgroup A and B. Multiple stepwise regression analysis was done using hyperbilirubinemia as a dependent factor and body weight loss, genotype (G/A) and allele (A) as independent factors. Body weight loss, genotype (G/A) and allele (A) was found to be significant independent predictors for hyperbilirubinemia. CONCLUSION: The results of the present study revealed that UGT1A1 polymorphism can be used as a novel predictor for neonatal hyperbilirubinemia in breast fed full term neonates. PMID- 28018588 TI - Experimental use of a novel single-port gasless laparoendoscopic operative field formation device. AB - INTRODUCTION: Traditional laparaendoscopic surgery using CO2 pneumoperitoneum is associated with complications and the existing gasless laparaendoscopic surgery has shortcomings such as poor visibility in the operation field. To overcome the disadvantages of the current lifting gasless laparaendoscopic operation platforms, we developed an inflatable device for gasless laparoscopic operation field formation (LOFF) that can be internally installed and applied in practice. METHODS: We initially designed operation platforms for gasless laparaendoscopic single-port (GLESP) surgery. Subsequently, a triangular prismatic LOFF device was selected and applied successfully to GLESP cholecystectomy of five pigs. Ultimately, using pigs as a model, three surgical approaches (LOFF-assisted laparaendoscopic single-site (LOFF-LESS), LESS surgery, and traditional lifting (GLESP) were compared, and the advantages and drawbacks of inflatable devices for gasless laparoscopic operation field assessed. RESULTS: The use of the LOFF device in GLESP cholecystectomy was first evaluated. The time for surgical space formation (4.4 +/- 1.2 and 4.8 +/- 1.0), the operating time for gallbladder removal (25.2 +/- 4.8 and 25.4 +/- 2.7), and the loss of blood (9.4 +/- 3.1and 9.2 +/- 2.4) was similar between LESS and LOFF, respectively (Table 2). In contrast these parameters were higher in GLESP (6.6 +/- 1.0, 30.3 +/- 4.4 and 10.1 +/- 2.0, respectively. The LOFF-LESS surgery exhibited a clearer exposure of the surgical field and shorter operating time than the GLESP surgery. LESS technology showed less postoperation pain, fast recovery, and extremely high cosmetic satisfaction. CONCLUSION: The LOFF device provides a safe, effective, and feasible operation platform that can be internally installed and inflated for GLESP surgery during cholescytectomy in animal models. PMID- 28018589 TI - A case report of small bowel perforation secondary to cytomegalovirus related immune reconstitution inflammatory syndrome in an AIDS patient. AB - Non-traumatic small bowel perforation is rare in adults but carries a high morbidity and mortality. The diagnosis is made on clinical suspicion, and the most common causes in developing countries are infectious diseases, being cytomegalovirus infection in immunocompromised patients the main etiology. We describe a patient with a recently diagnosed advanced stage HIV infection and an intestinal perforation associated with cytomegalovirus immune reconstitution inflammatory syndrome after highly active antiretroviral therapy initiation. PMID- 28018590 TI - Use of Asian selected agricultural byproducts to modulate rumen microbes and fermentation. AB - In the last five decades, attempts have been made to improve rumen fermentation and host animal nutrition through modulation of rumen microbiota. The goals have been decreasing methane production, partially inhibiting protein degradation to avoid excess release of ammonia, and activation of fiber digestion. The main approach has been the use of dietary supplements. Since growth-promoting antibiotics were banned in European countries in 2006, safer alternatives including plant-derived materials have been explored. Plant oils, their component fatty acids, plant secondary metabolites and other compounds have been studied, and many originate or are abundantly available in Asia as agricultural byproducts. In this review, the potency of selected byproducts in inhibition of methane production and protein degradation, and in stimulation of fiber degradation was described in relation to their modes of action. In particular, cashew and ginkgo byproducts containing alkylphenols to mitigate methane emission and bean husks as a source of functional fiber to boost the number of fiber degrading bacteria were highlighted. Other byproducts influencing rumen microbiota and fermentation profile were also described. Future application of these feed and additive candidates is very dependent on a sufficient, cost effective supply and optimal usage in feeding practice. PMID- 28018591 TI - Characterization of heavy users of skin care products among Norwegian women from 2003 to 2011. AB - BACKGROUND: Several ingredients in personal care products (PCPs) have been classified as endocrine disruptors (EDs) and concern has been raised whether use of PCPs can affect human health. We aimed to characterize Norwegian female users of skin care products and compare life style characteristics between heavy users and non-users. METHODS: This cross-sectional study consisted of 114 202 women (age 41-76 years) participating in the Norwegian Women and Cancer study, a large population-based prospective cohort study. Based on self-reported questionnaire data, we classified the study subjects into five groups according to a calculated percentage of skin area creamed per day. Life-style characteristics were then compared between heavy users (using body lotion twice a day) and non-users. Change in use from 2003 to 2011 was assessed through repeated measurements (n = 8484). RESULTS: Heavy users of skin care products had a significantly lower BMI, higher level of physical activity, higher income, higher alcohol consumption, fewer children and a shorter total time of breastfeeding than non-users (p < 0.001). There were significantly fewer current smokers and more former smokers among heavy users than among non-users (p < 0.01). Current and earlier use of oral contraceptives, hormone replacement therapy or hormonal intra-uterine device were significantly more common among heavy users than among non-users (p < 0.01). The use of skin care products was, to a moderate extent (weighted kappa 0.52), consistent over time from 2003 to 2011, and as many as 91.5% of the women were classified into the same user group +/-1 category in 2003 and 2011. CONCLUSIONS: Heavy users of skin care products differ significantly from non-users on BMI, degree of daily physical activity, income, number of children, use of hormonal pharmaceuticals, smoking and alcohol consumption. Use of skin care products is common among women aged 41-76 years in Norway, and the use is consistent over time. PMID- 28018592 TI - DNA damage and repair capacity in lymphocyte of chronic obstructive pulmonary diseases patients during physical exercise with oxygen supplementation. AB - BACKGROUND: We hypothesized that the use of oxygen supplementation during aerobic exercise induces less DNA damage than exercise alone. The aim of this study is to assess the level of DNA damage induced by physical exercise with and without oxygen supplementation in chronic obstructive pulmonary diseases (COPD) patients. METHODS: Peripheral blood was collected before and after aerobic exercise in two conditions: (I) aerobic exercise without oxygen supplementation (AE group) and (II) with oxygen supplementation (AE-O2 group). Lymphocytes were collected to perform the alkaline version of the Comet Assay. To assess the susceptibility to exogenous DNA damage, the lymphocytes were treated with methyl methanesulphonate (MMS) for 1-h or 3-h. After 3-h treatment, the percentage of residual damage was calculated assuming the value of 1-h MMS treatment as 100%. RESULTS: AE group showed lower induced damage (1 h of MMS treatment) and consequently less DNA repair compared to AE-O2 group. AE-O2 group showed an increase in the induced DNA damage (1 h of MMS treatment) and an increased DNA repair capacity. Within the AE O2 group, in the post-exercise situation the induced DNA damage after 1 h of MMS treatment was higher (p = 0.01) than in the pre-exercise. CONCLUSION: COPD patients who performed physical exercise associated with oxygen supplementation had a better response to DNA damage induced by MMS and a better DNA repair when compared to the condition of physical exercise without oxygen supplementation. TRIAL REGISTRATION: UNISC N374.298. Registered 04 JUN 2013 (retrospectively registered). PMID- 28018593 TI - Cost of persistent asthma in Italy. AB - BACKGROUND: Asthma is a common disease of the airways with a significant burden for the society and for patients' quality of life. The Social Impact of Respiratory Integrated Outcomes (SIRIO) study estimated a mean cost of 1,177.40 ? per patient/year in Italy, in 2007. The aim of the present study was to update the cost of persistent asthma patients in Italy. METHODS: An observational, retrospective, bottom-up analysis was carried out starting from the data base operating in the Lung Unit of the Specialist Medical Centre (CEMS), Verona (Italy), over the period June 2013-December 2015. Patients' data were recorded over the 12 +/- 2 months before the enrollment and during 12 +/- 2 months of follow-up. The prospective was the Italian National Health Service and the broad Italian society. Clinical data were measured in terms of forced expiratory volume in 1 s (FEV1%) and number of relapses. Healthcare resources (namely; number of hospitalizations and/or ER admissions; number of visits; drug use and duration, and indirect costs) were recorded. RESULTS: The cohort consisted of 817 patients with persistent asthma of different severity. They had a 42.96% male prevalence; a mean (+/-SE) age of 49.06 (+/-0.64) years; a mean 87.47% (+/-0.81) FEV1% pred. in baseline, and 69.16% of subjects had comorbidities. The mean (+/-SE) number of relapses was 0.91 (+/-0.09) per patient/year before the enrolment. After 12 months, FEV1% significantly improved by +6.31% (+/-0.45) from the corresponding baseline value (p < 0.001). The number of relapses decreased of -0.46 (+/-0.09) (p < 0.001). The estimated total annual cost per asthmatic patient was 1,183.14 ? (+/-65.79 ?) during the 12 months before the enrolment, and 1,290.89 ? (+/ 68.74 ?) throughout the follow-up. The increase was mostly due to the significantly increased duration of therapeutic strategies. The costs of hospitalization, general practitioner and rescue medications were significantly decreased. CONCLUSIONS: The periodic update of cost analysis is a key to monitor the trend of main asthma outcomes and related expenditure over time. It allows to plan the most convenient actions in terms of prevention strategies and effective interventions, with the aim of optimizing the healthcare resources consumption and maximizing the impact on clinical outcomes and patients' quality of life. The role of an appropriate pharmacological strategy still proves crucial in minimizing asthma morbidity and the corresponding socio-economic impact. PMID- 28018594 TI - The Need for an Interdisciplinary Approach to Norm Diffusion: The Case of Fair and Equitable Benefit-sharing. AB - No systematic study discusses the evolution of fair and equitable benefit-sharing across various areas of international law (environment, human rights, oceans), as well as at different levels of regulation (regional and national laws and guidelines, private law contracts, transboundary codes of conduct, customary laws of indigenous peoples and local communities). This article explores the usefulness of an interdisciplinary approach to the study of norm diffusion for understanding how and why fair and equitable benefit-sharing is articulated in different sites. The article discusses mechanisms, actors and frames in norm diffusion, drawing on literature from sociology, international relations and law. The article uncovers underlying similarities in scholarship on norm diffusion across the disciplines considered. It also reflects on the value of an interdisciplinary approach that encourages legal scholars to consider the implications of power structures in the diffusion of law, while the nuances of legal knowledge may lead other social scientists to revisit accepted findings on norm diffusion. These findings appear particularly useful for informing an assessment of the potential of fair and equitable benefit-sharing to promote the conservation and sustainable use of natural resources in a fair and equitable manner in the face of power asymmetries. PMID- 28018595 TI - Outcomes of an inpatient refeeding protocol in youth with Anorexia Nervosa and atypical Anorexia Nervosa at Children's Hospitals and Clinics of Minnesota. AB - BACKGROUND: Historically, inpatient protocols have adopted relatively conservative approaches to refeeding in Anorexia Nervosa (AN) in order to reduce the risk of refeeding syndrome, a potentially fatal constellation of symptoms. However, increasing evidence suggests that patients with AN can tolerate higher caloric prescriptions during treatment, which may result in prevention of initial weight loss, shorter hospital stays, and less exposure to the effects of severe malnutrition. Therefore the present study sought to examine the effectiveness of a more accelerated refeeding protocol in an inpatient AN and atypical AN sample. METHODS: Participants were youth (ages 10-22) with AN (n = 113) and atypical AN (n = 16) who were hospitalized for medical stabilization. A retrospective chart review was conducted to assess changes in calories, weight status (percentage of median BMI, %mBMI), and indicators of refeeding syndrome, specifically hypophosphatemia, during hospitalization. Weight was assessed again approximately 4 weeks after discharge. RESULTS: No cases of refeeding syndrome were observed, though 47.3 % of participants evidenced hypophosphatemia during treatment. Phosphorous levels were monitored in all participants, and 77.5 % were prescribed supplemental phosphorous at the time of discharge. Higher rates of caloric changes were predictive of greater changes in %mBMI during hospitalization. Rates of caloric and weight change were not related to an increased likelihood of re admission. CONCLUSIONS: Results suggest that a more accelerated approach to inpatient refeeding in youth with AN and atypical AN can be safely implemented and is not associated with refeeding syndrome, provided there is close monitoring and correction of electrolytes. These findings suggest that this approach has the potential to decrease length of stay and burden associated with inpatient hospitalization, while supporting continued progress after hospitalization. PMID- 28018596 TI - Developing shared understandings of recovery and care: a qualitative study of women with eating disorders who resist therapeutic care. AB - BACKGROUND: This paper explores the differing perspectives of recovery and care of people with disordered eating. We consider the views of those who have not sought help for their disordered eating, or who have been given a diagnosis but have not engaged with health care services. Our aim is to demonstrate the importance of the cultural context of care and how this might shape people's perspectives of recovery and openness to receiving professional care. METHOD: This study utilised a mixed methods approach of ethnographic fieldwork and psychological evaluation with 28 women from Adelaide, South Australia. Semi structured interviews, observations, field notes and the Eating Disorder Examination were the primary forms of data collection. Data was analysed using thematic analysis. RESULTS & DISCUSSION: Participants in our study described how their disordered eating afforded them safety and were consistent with cultural values concerning healthy eating and gendered bodies. Disordered eating was viewed as a form of self-care, in which people protect and 'take care' of themselves. These subjectively experienced understandings of care underlie eating disorder behaviours and provide an obstacle in seeking any form of treatment that might lead to recovery. CONCLUSION: A shared understanding between patients and health professionals about the function of the eating disorder may avoid conflict and provide a pathway to treatment. These results suggest the construction of care by patients should not be taken for granted in therapeutic guidelines. A discussion considering how disordered eating practices are embedded in a matrix of care, health, eating and body practices may enhance the therapeutic relationship. PMID- 28018597 TI - Associations between unhealthy dieting behaviors and tobacco use among adolescents. AB - BACKGROUND: Cigarette smoking is an important risk factor for unhealthy dieting behaviors (UDBs) in youth. The role of alternative tobacco products and UDB engagement has yet to be examined empirically despite concerning trends in use. This study aimed to examine UDB prevalence in a U.S. geographic region-specific adolescent sample and associations with a variety of tobacco use behaviors and perceptions. METHODS: Weighted data from the 2013 Virginia Youth Survey were analyzed (n = 6903). UDBs assessed included past 30-day fasting, diet pill use, and vomiting/laxative use. Tobacco-related items were ever and past 30-day cigarette smoking, past 30-day smokeless tobacco and cigar use, and the perception that smokers have more friends. UDB prevalence was recoded by the number of behaviors endorsed (0, 1, and 2+). Bivariate and multinomial regression models were used to examine associations between covariates and number of UDBs endorsed by gender. RESULTS: Overall, nearly 16% engaged in at least one UDB. Fasting was most prevalent (14.2%) followed by vomiting/laxative (7.0%) and diet pill use (6.1%). Across gender, ever cigarette smoking, past 30-day cigar use, and the perception that smokers have more friends were positively associated with UDB engagement in relative isolation as well as in combination. CONCLUSIONS: Findings highlight the importance of tobacco-related factors for weight control behaviors and are the first to identify an association between UDB incidence and an alternative tobacco product, cigars. This work should inform prevention efforts for tobacco use and UDBs and underscores the need to address the use of any tobacco for weight control. PMID- 28018598 TI - CD34 and CD38 are prognostic biomarkers for acute B lymphoblastic leukemia. AB - CD34 and CD38 proteins are usually used as surface markers to identify HSCs and Leukemic stem cells. However, there have been cases that lacked CD34 or CD38 protein but still had leukemia initiating capacity in B-ALL suggesting the restrictive of these two markers. CD34 and CD38 expression were detected in most B-ALL and can serve as a specific biomarker for the prognosis of this subset of leukemia. Lack of CD34 or high CD38 expression is associated with favorable prognosis. PMID- 28018599 TI - Immune-related response assessment during PD-1 inhibitor therapy in advanced non small-cell lung cancer patients. AB - BACKGROUND: Tumor response characteristics using immune-related RECIST1.1 (irRECIST1.1) in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab monotherapy in the clinical setting have not been previously described with a direct comparison with the assessments according to the conventional RECIST1.1. METHODS: Fifty-six advanced NSCLC patients treated with nivolumab monotherapy after its Food and Drug Administration (FDA) approval were retrospectively studied. Tumor burden was quantified on serial CT scans during therapy using irRECIST1.1, which uses unidimensional measurements and includes new lesion measurements in total tumor burden. Response assessments by irRECIST1.1 were compared with assessments by RECIST1.1. Responses of individual lesions in different organs were also compared. RESULTS: Tumor burden change at best overall response ranged from -66.8 to +278.1% (median: +3.9%). Response rate was 14% (8/56; 8 partial responses, 0 complete responses) by irRECIST1.1 and by RECIST1.1. Time-to-progression (TTP) by irRECIST1.1 was longer than TTP by RECIST1.1 (median TTP: not reached vs. 1.9 months, respectively). No patients experienced pseudoprogression during the study. Among 128 target lesions, the lesion-based size change at best response differed significantly across different organs, with adrenal lesions and lymph nodes having greater size decrease, followed by lung, while liver and other miscellaneous lesions had lesser degree of size decrease (p = 0.002). CONCLUSIONS: Immune-related response evaluations using irRECIST1.1 in advanced NSCLC patients treated with nivolumab resulted in the identical response rate and longer TTP compared to RECIST1.1. No pseudoprogression cases were observed during the study. Adrenal lesions and lymph nodes were more responsive and liver lesions were less responsive to nivolumab. PMID- 28018600 TI - A quantum leap in cancer vaccines? PMID- 28018603 TI - Draft genome sequence of a human-associated isolate of Haloferax alexandrinus strain Arc-hr, an extremely halophilic archaea. AB - We report the draft genome sequence of Haloferax alexandrinus strain Arc-hr (CSUR P798), isolated from the human gut of a 10-year-old Amazonian individual. Its 3 893 626 bp genome exhibits a 66.00% GC content. The genome of the strain Arc-hr contains 37 genes identified as ORFans, seven genes associated to halocin and 11 genes associated with polyketide synthases or nonribosomal peptide synthetases. PMID- 28018602 TI - Fusion of the dendritic cell-targeting chemokine MIP3alpha to melanoma antigen Gp100 in a therapeutic DNA vaccine significantly enhances immunogenicity and survival in a mouse melanoma model. AB - BACKGROUND: Although therapeutic cancer vaccines have been mostly disappointing in the clinic, the advent of novel immunotherapies and the future promise of neoantigen-based therapies have created the need for new vaccine modalities that can easily adapt to current and future developments in cancer immunotherapy. One such novel platform is a DNA vaccine fusing the chemokine Macrophage Inflammatory Protein-3alpha (MIP-3alpha) to an antigen, here melanoma antigen gp100. Previous published work has indicated that MIP-3alpha targets nascent peptides to immature dendritic cells, leading to processing by class I and II MHC pathways. This platform has shown enhanced efficacy in prophylactic melanoma and therapeutic lymphoma model systems. METHODS: The B16F10 melanoma syngeneic mouse model system was utilized, with a standard therapeutic protocol: challenge with lethal dose of B16F10 cells (5 * 104) on day 0 and then vaccinate by intramuscular electroporation with 50 MUg plasmid on days three, 10, and 17. Efficacy was assessed by analysis of tumor burden, tumor growth, and mouse survival, using the statistical tests ANOVA, mixed effects regression, and log-rank, respectively. Immunogenicity was assessed by ELISA and flow cytometric methods, including intracellular cytokine staining to assess vaccine-specific T-cell responses, all tested by ANOVA. RESULTS: We demonstrate that the addition of MIP3alpha to gp100 significantly enhances systemic anti-gp100 immunological parameters. Further, chemokine-fusion vaccine therapy significantly reduces tumor burden, slows tumor growth, and enhances mouse overall survival compared to antigen-only, irrelevant antigen, and mock vaccines, with efficacy mediated by both CD4+ and CD8+ effector T cells. Antigen-only, irrelevant-antigen, and chemokine-fusion vaccines elicit significantly higher and similar CD4+ and CD8+ tumor-infiltrating lymphocyte (TIL) levels compared to mock vaccine. However, vaccine-specific CD8+ TILs are significantly higher in the chemokine-fusion vaccine group, indicating that the critical step induced by the fusion vaccine construct is the enhancement of vaccine-specific T-cell effectors. CONCLUSIONS: The current study shows that fusion of MIP3alpha to melanoma antigen gp100 enhances the immunogenicity and efficacy of a DNA vaccine in a therapeutic B16F10 mouse melanoma model. This study analyzes an adaptable and easily produced MIP3alpha-antigen modular vaccine platform that could lend itself to a variety of functionalities, including combination treatments and neoantigen vaccination in the pursuit of personalized cancer therapy. PMID- 28018604 TI - 'Acidaminococcus timonensis' sp. nov. and 'Acidaminococcus massiliensis' sp. nov. isolated from human gut. AB - We report here the main characteristics of 'Acidaminococcus timonensis' strain Marseille-P2764T, isolated from human right colon, and 'Acidaminococcus massiliensis' strain Marseille-P2828T, isolated from human duodenum. PMID- 28018605 TI - Identification and characterization of tomato gibberellin 2-oxidases (GA2oxs) and effects of fruit-specific SlGA2ox1 overexpression on fruit and seed growth and development. AB - Gibberellins (GAs) play a crucial role in growth and development of the tomato fruit. Previously published studies focusing on the effect of GAs on tomato fruits used chemical treatments, constitutive overexpression or silencing of GA biosynthetic and catabolic genes globally throughout the plant. Fruit-specific overexpression of GA catabolic enzyme genes GA2-oxidases (GA2oxs), however, may provide an alternative method to study the role of endogenous GAs on the fruit development. In this study, we have identified 11 SlGA2ox proteins in tomato that are classified into three subgroups. Motif analysis and multiple sequence alignments have demonstrated that all SlGA2oxs, except SlGA2ox10, have similar motif compositions and high-sequence conservation. Quantitative reverse transcription-PCR analysis has showed that SlGA2oxs exhibit differential expression patterns in tomato fruits at different developmental stages. When the fruit-specific promoter TFM7 was used to control the expression of SlGA2ox1, we observed no changes in growth and development of vegetative organs. However, fruit weight, seed number and germination rate were significantly affected. We also treated tomato fruits with GA biosynthesis inhibitor and observed phenotypes similar to those of the transgenic fruits. Furthermore, we have demonstrated that expression of cell expansion and GA responsive genes were downregulated in transgenic tomato fruits, supporting that overexpression of the SlGA2ox1 leads to reduction in endogenous GAs. This study provides additional evidence that endogenous GAs and the SlGA2ox1 gene play an important role in controlling on fruit weight, seed development and germination in tomato plant. PMID- 28018606 TI - Characterization of spermidine hydroxycinnamoyl transferases from eggplant (Solanum melongena L.) and its wild relative Solanum richardii Dunal. AB - Eggplant produces a variety of hydroxycinnamic acid amides (HCAAs) that have an important role in plant development and adaptation to environmental changes. In this study, we identified and characterized a spermidine hydroxycinnamoyl transferase (SHT) from eggplant (Solanum melongena) and its wild relative S. richardii, designated as SmSHT and SrSHT, respectively. SmSHT was abundant in flowers and fruits, whereas the level of SrSHT was remarkably low in all tissues. Heat-shock/drought treatment stimulated the expression of SmSHT in both leaves and fruits, indicating its involvement in plant stress response. Both SHT polypeptides had extremely high identity with just five amino-acid substitutions. Recombinant SmSHT catalyzed the synthesis of mono-, bi- and tri- acylated polyamines. Using caffeoyl-CoA as the acyl donor, SmSHT preferred spermidine as the acyl acceptor. When spermidine was the acyl acceptor, the donor preference order for SmSHT was caffeoyl-CoA>feruloyl-CoA>rho-coumaroyl-CoA. SrSHT exhibited the same substrate specificity as SmSHT, yet exhibited significantly higher catalytic activity than SmSHT. For example, under caffeoyl-CoA and spermidine, Kcat of SrSHT was 37.3% higher than SmSHT. Molecular modeling suggests that five amino-acid substitutions in SrSHT result in four alterations in their predicted 3D structures. In particular, the conserved Lys402 adjacent to the DFGWG motif, and Cys200 in the crossover loop in SmSHT were replaced by Glu and Ser in SrSHT. These substitutions may contribute to the enhanced activity in SrSHT. Our study provides a platform to generate HCAA rich fruits for eggplant and other solanaceous crops. PMID- 28018607 TI - Novel WISP3 mutations causing progressive pseudorheumatoid dysplasia in two Chinese families. AB - Progressive pseudorheumatoid dysplasia (PPD) is a rare disease caused by mutations in the gene for Wnt1-inducible signaling pathway protein 3 (WISP3). Here, we report the clinical and radiographic manifestations of two Chinese PPD patients. We performed whole-exome sequencing for one patient and sequenced the WISP3 for the other. Three WISP3 mutations (c.396T>G, c.721T>G and c.679dup) were identified; the two missense mutations were novel. Our study expanded the WISP3 mutation spectrum. PMID- 28018601 TI - The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia. AB - Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine's clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves. PMID- 28018608 TI - Digenic mutations of human OCRL paralogs in Dent's disease type 2 associated with Chiari I malformation. AB - OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, de novo DD2-causing 462 bp deletion disrupting exon 3 of OCRL1 and a maternally inherited, extremely rare (ExAC allele frequency 8.4*10-6) damaging missense mutation in INPP5B (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein's critical PH domain. In silico analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human OCRL paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3 metabolism in this mechanism. PMID- 28018609 TI - Depth and substratum differentiations among coexisting herbivorous cichlids in Lake Tanganyika. AB - Cichlid fish in Lake Tanganyika represent a system of adaptive radiation in which eight ancestral lineages have diversified into hundreds of species through adaptation to various niches. However, Tanganyikan cichlids have been thought to be oversaturated, that is, the species number exceeds the number of niches and ecologically equivalent and competitively even species coexist. However, recent studies have shed light on niche segregation on a finer scale among apparently equivalent species. We observed depth and substratum preferences of 15 herbivorous cichlids from four ecomorphs (i.e. grazer, browser, scraper and scooper) on a rocky littoral slope for 14 years. Depth differentiation was detected among grazers that defended feeding territories and among browsers with feeding territories. Cichlid species having no feeding territory also showed specificity on depth and substratum, resulting in habitat segregation among species that belong to the same ecomorph. Phylogenetically close species did not occupy adjacent depths, nor the opposite depth zones. Our findings suggest that apparently equivalent species of the same ecomorph coexist parapatrically along depth on a few-metre scale, or coexist with different substratum preferences on the rocky shore, and this niche segregation may have been acquired by competition between encountering equivalent species through repetitive lake-level fluctuations. PMID- 28018610 TI - Cycle and flow trusses in directed networks. AB - When we represent real-world systems as networks, the directions of links often convey valuable information. Finding module structures that respect link directions is one of the most important tasks for analysing directed networks. Although many notions of a directed module have been proposed, no consensus has been reached. This lack of consensus results partly because there might exist distinct types of modules in a single directed network, whereas most previous studies focused on an independent criterion for modules. To address this issue, we propose a generic notion of the so-called truss structures in directed networks. Our definition of truss is able to extract two distinct types of trusses, named the cycle truss and the flow truss, from a unified framework. By applying the method for finding trusses to empirical networks obtained from a wide range of research fields, we find that most real networks contain both cycle and flow trusses. In addition, the abundance of (and the overlap between) the two types of trusses may be useful to characterize module structures in a wide variety of empirical networks. Our findings shed light on the importance of simultaneously considering different types of modules in directed networks. PMID- 28018611 TI - Brief use of a specific gun in a violent game does not affect attitudes towards that gun. AB - Although much attention has been paid to the question of whether violent video games increase aggressive behaviour, little attention has been paid to how such games might encourage antecedents of gun violence. In this study, we examined how product placement, the attractive in-game presentation of certain real-world firearm brands, might encourage gun ownership, a necessary antecedent of gun violence. We sought to study how the virtual portrayal of a real-world firearm (the Bushmaster AR-15) could influence players' attitudes towards the AR-15 specifically and gun ownership in general. College undergraduates (N = 176) played one of four modified video games in a 2 (gun: AR-15 or science-fiction control) * 2 (gun power: strong or weak) between-subjects design. Despite collecting many outcomes and examining many potential covariates and moderators, experimental assignment did little to influence outcomes of product evaluations or purchasing intentions with regard to the AR-15. Attitudes towards public policy and estimation of gun safety were also not influenced by experimental condition, although these might have been better tested by comparison against a no-violence control condition. By contrast, gender and political party had dramatic associations with all outcomes. We conclude that, if product placement shapes attitudes towards firearms, such effects will need to be studied with stronger manipulations or more sensitive measures. PMID- 28018612 TI - Using sperm morphometry and multivariate analysis to differentiate species of gray Mazama. AB - There is genetic evidence that the two species of Brazilian gray Mazama, Mazama gouazoubira and Mazama nemorivaga, belong to different genera. This study identified significant differences that separated them into distinct groups, based on characteristics of the spermatozoa and ejaculate of both species. The characteristics that most clearly differentiated between the species were ejaculate colour, white for M. gouazoubira and reddish for M. nemorivaga, and sperm head dimensions. Multivariate analysis of sperm head dimension and format data accurately discriminated three groups for species with total percentage of misclassified of 0.71. The individual analysis, by animal, and the multivariate analysis have also discriminated correctly all five animals (total percentage of misclassified of 13.95%), and the canonical plot has shown three different clusters: Cluster 1, including individuals of M. nemorivaga; Cluster 2, including two individuals of M. gouazoubira; and Cluster 3, including a single individual of M. gouazoubira. The results obtained in this work corroborate the hypothesis of the formation of new genera and species for gray Mazama. Moreover, the easily applied method described herein can be used as an auxiliary tool to identify sibling species of other taxonomic groups. PMID- 28018613 TI - Synthesis and characterization of azo-guanidine based alcoholic media naked eye DNA sensor. AB - DNA sensing always has an open meadow of curiosity for biotechnologists and other researchers. Recently, in this field, we have introduced an emerging class of molecules containing azo and guanidine functionalities. In this study, we have synthesized three new compounds (UA1, UA6 and UA7) for potential application in DNA sensing in alcoholic medium. The synthesized materials were characterized by elemental analysis, FTIR, UV-visible, 1H NMR and 13C NMR spectroscopies. Their DNA sensing potential were investigated by UV-visible spectroscopy. The insight of interaction with DNA was further investigated by electrochemical (cyclic voltammetry) and hydrodynamic (viscosity) studies. The results showed that compounds have moderate DNA binding properties, with the binding constants range being 7.2 * 103, 2.4 * 103 and 0.2 * 103 M-1, for UA1, UA6 and UA7, respectively. Upon binding with DNA, there was a change in colour (a blue shift in the lambdamax value) which was observable with a naked eye. These results indicated the potential of synthesized compounds as DNA sensors with detection limit 1.8, 5.8 and 4.0 ng ul-1 for UA1, UA6 and UA7, respectively. PMID- 28018614 TI - Computer aided chemical design: using quantum chemical calculations to predict properties of a series of halochromic guaiazulene derivatives. AB - With the scientific community becoming increasingly aware of the need for greener products and methodologies, the optimization of synthetic design is of greater importance. Building on experimental data collected from a synthesized guaiazulene derivative, a series of analogous structures were investigated with time-dependent density functional theory (TD-DFT) methods in an effort to identify a compound with desirable photophysical properties. This in silico analysis may eliminate the need to synthesize numerous materials that, when investigated, do not possess viable characteristics. The synthesis of several computationally investigated structures revealed discrepancies in the calculation results. Further refined computational study of the molecules yielded results closer to those observed experimentally and helps set the stage for computationally guided design of organic photonic materials. Three novel derivatives were synthesized from guaiazulene, a naturally occurring chromophore, exhibiting distinct halochromic behaviour, which may have potential in a switchable optoelectronic system or combined with a photoacid generator for data storage. The protonated forms were readily excitable via two-photon absorption. PMID- 28018615 TI - DualPhos: a versatile, chemoselective reagent for two-carbon aldehyde to latent (E)-alkenal homologation and application in the total synthesis of phomolide G. AB - Advances on the use of the 2-pinacolacetal-tripropylphosphonium salt DualPhos as a general reagent for the two-carbon aldehyde to alkenal homologation and a chemoselective iron (III) chloride mediated deprotection are described. The strategy allows isolation of the latent alkenal intermediates or direct hydrolysis to (E)-alkenals. The robust chemical stability of the latent alkenals is demonstrated in a total synthesis of the macrolactone phomolide G. PMID- 28018616 TI - Collective behaviour in vertebrates: a sensory perspective. AB - Collective behaviour models can predict behaviours of schools, flocks, and herds. However, in many cases, these models make biologically unrealistic assumptions in terms of the sensory capabilities of the organism, which are applied across different species. We explored how sensitive collective behaviour models are to these sensory assumptions. Specifically, we used parameters reflecting the visual coverage and visual acuity that determine the spatial range over which an individual can detect and interact with conspecifics. Using metric and topological collective behaviour models, we compared the classic sensory parameters, typically used to model birds and fish, with a set of realistic sensory parameters obtained through physiological measurements. Compared with the classic sensory assumptions, the realistic assumptions increased perceptual ranges, which led to fewer groups and larger group sizes in all species, and higher polarity values and slightly shorter neighbour distances in the fish species. Overall, classic visual sensory assumptions are not representative of many species showing collective behaviour and constrain unrealistically their perceptual ranges. More importantly, caution must be exercised when empirically testing the predictions of these models in terms of choosing the model species, making realistic predictions, and interpreting the results. PMID- 28018617 TI - Cutting blade dentitions in squaliform sharks form by modification of inherited alternate tooth ordering patterns. AB - The squaliform sharks represent one of the most speciose shark clades. Many adult squaliforms have blade-like teeth, either on both jaws or restricted to the lower jaw, forming a continuous, serrated blade along the jaw margin. These teeth are replaced as a single unit and successor teeth lack the alternate arrangement present in other elasmobranchs. Micro-CT scans of embryos of squaliforms and a related outgroup (Pristiophoridae) revealed that the squaliform dentition pattern represents a highly modified version of tooth replacement seen in other clades. Teeth of Squalus embryos are arranged in an alternate pattern, with successive tooth rows containing additional teeth added proximally. Asynchronous timing of tooth production along the jaw and tooth loss prior to birth cause teeth to align in oblique sets containing teeth from subsequent rows; these become parallel to the jaw margin during ontogeny, so that adult Squalus has functional tooth rows comprising obliquely stacked teeth of consecutive developmental rows. In more strongly heterodont squaliforms, initial embryonic lower teeth develop into the oblique functional sets seen in adult Squalus, with no requirement to form, and subsequently lose, teeth arranged in an initial alternate pattern. PMID- 28018618 TI - Airplane tracking documents the fastest flight speeds recorded for bats. AB - The performance capabilities of flying animals reflect the interplay of biomechanical and physiological constraints and evolutionary innovation. Of the two extant groups of vertebrates that are capable of powered flight, birds are thought to fly more efficiently and faster than bats. However, fast-flying bat species that are adapted for flight in open airspace are similar in wing shape and appear to be similar in flight dynamics to fast-flying birds that exploit the same aerial niche. Here, we investigate flight behaviour in seven free-flying Brazilian free-tailed bats (Tadarida brasiliensis) and report that the maximum ground speeds achieved exceed speeds previously documented for any bat. Regional wind modelling indicates that bats adjusted flight speeds in response to winds by flying more slowly as wind support increased and flying faster when confronted with crosswinds, as demonstrated for insects, birds and other bats. Increased frequency of pauses in wing beats at faster speeds suggests that flap-gliding assists the bats' rapid flight. Our results suggest that flight performance in bats has been underappreciated and that functional differences in the flight abilities of birds and bats require re-evaluation. PMID- 28018619 TI - A computational method for sharp interface advection. AB - We devise a numerical method for passive advection of a surface, such as the interface between two incompressible fluids, across a computational mesh. The method is called isoAdvector, and is developed for general meshes consisting of arbitrary polyhedral cells. The algorithm is based on the volume of fluid (VOF) idea of calculating the volume of one of the fluids transported across the mesh faces during a time step. The novelty of the isoAdvector concept consists of two parts. First, we exploit an isosurface concept for modelling the interface inside cells in a geometric surface reconstruction step. Second, from the reconstructed surface, we model the motion of the face-interface intersection line for a general polygonal face to obtain the time evolution within a time step of the submerged face area. Integrating this submerged area over the time step leads to an accurate estimate for the total volume of fluid transported across the face. The method was tested on simple two-dimensional and three-dimensional interface advection problems on both structured and unstructured meshes. The results are very satisfactory in terms of volume conservation, boundedness, surface sharpness and efficiency. The isoAdvector method was implemented as an OpenFOAM(r) extension and is published as open source. PMID- 28018620 TI - Minerals in the gut: scoping a Cambrian digestive system. AB - The Sirius Passet Lagerstatte of North Greenland contains the first exceptionally preserved mat-ground community of the Cambrian, dominated, in terms of abundance, by trilobites but particularly characterized by iconic arthropods and lobopods, some also occurring in the Burgess shale. High-resolution photography, scanning electron imaging and elemental mapping have been carried out on a variety of specimens of the non-mineralized arthropod Campanamuta mantonae (Budd 2011 J. Syst. Palaeontol.9, 217-260 (doi:10.1080/14772019.2010.492644)) which has three dimensional gut and muscle preservation. Results show that the guts contain a high concentration of calcium phosphate (approximating to the mineral francolite), whereas the adjacent muscles are silicified. This indicates a unique, tissue-specific taphonomy for this Cambrian taxon. We hypothesize that the precipitation of calcium phosphate in the guts occurs rapidly after death by 'crystal seed' processes in suboxic, slightly acidic conditions; critically, the gut wall remained intact during precipitation. We postulate that the calcium phosphate was derived from ingested cellular material. Silicification of the muscles followed as the localized water chemistry became saturated in silica, high in Fe2+, and low in oxygen and sulfate. We document here the unique occurrence of two distinct but mechanistically similar taphonomic pathways within a diverse suite of possibilities in an Early Cambrian Lagerstatte. PMID- 28018621 TI - Phylogeny affects host's weight, immune response and parasitism in damselflies and dragonflies. AB - Host-parasite interactions are an intriguing part of ecology, and understanding how hosts are able to withstand parasitic attacks, e.g. by allocating resources to immune defence, is important. Damselflies and dragonflies show a variety of parasitism patterns, but large-scale comparative immune defence studies are rare, and it is difficult to say what the interplay is between their immune defence and parasitism. The aim of this study was to find whether there are differences in immune response between different damselfly and dragonfly species and whether these could explain their levels of gregarine and water mite parasitism. Using an artificial pathogen, a piece of nylon filament, we measured the encapsulation response of 22 different damselfly and dragonfly species and found that (i) there are significant encapsulation differences between species, (ii) body mass has a strong association with encapsulation and parasite prevalences, (iii) body mass shows a strong phylogenetic signal, whereas encapsulation response and gregarine and water mite prevalences show weak signals, and (iv) associations between the traits are affected by phylogeny. We do not know what the relationship is between these four traits, but it seems clear that phylogeny plays a role in determining parasitism levels of damselflies and dragonflies. PMID- 28018622 TI - The carbon and nitrogen ecophysiologies of two endemic tropical orchids mirrors those of their temperate relatives and the local environment. AB - Orchids are one of the most widely distributed plant families. However, current research on the ecophysiology of terrestrial orchids is biased towards temperate species. Thus, it is currently unknown whether tropical terrestrial orchids belong to similar trophic guilds as their temperate relatives. To examine the ecophysiologies of two tropical terrestrial orchids, I analysed the carbon and nitrogen stable isotope compositions and nitrogen concentrations of the Hawaiian endemics Anoectochilus sandvicensis and Liparis hawaiensis. I compared these values with those of surrounding vegetation and their temperate relatives. I found that A. sandvicensis was consistently enriched in the heavy isotope of nitrogen (15N) and had higher nitrogen (N) concentrations than surrounding vegetation, and these values were even higher than those of its temperate relatives. Carbon stable isotope composition among populations of A. sandvicensis varied by island. These results point to local environment and evolutionary history determining the ecophysiology of this species. Whereas L.hawaiensis was also enriched in 15N and had on average higher N concentrations than surrounding vegetation, these values were not significantly different from temperate relatives, indicating that evolutionary history may be a stronger predictor of this orchid species' ecophysiology than environment. I suggest that both Hawaiian species are potentially partially mycoheterotrophic. PMID- 28018623 TI - The effects of exposure to objective coherence on perceived meaning in life: a preregistered direct replication of Heintzelman, Trent & King (2013). AB - Having a sense of meaning in life (MIL) has been acknowledged as a catalyst to psychological flourishing. As such, understanding ways to promote MIL represents a worthy goal for those interested in bolstering positive outcomes. This study sought to replicate the findings of Heintzelman, Trent & King (2013 Psychol. Sci.24, 991-998 (doi:10.1177/0956797612465878)), who found that MIL could be influenced by external stimulation. Their findings suggest that exposure to coherent stimuli produces significantly higher MIL scores than exposure to incoherent stimuli. Using materials and methodology provided by the corresponding author of the original paper, this study attempted to directly test this manipulation under conditions with increased statistical power. All tests, however, failed to replicate. Possible explanations for these discrepant findings are discussed, and potential future directions for this area of the literature are proposed. PMID- 28018624 TI - DNA barcoding uncovers cryptic diversity in 50% of deep-sea Antarctic polychaetes. AB - The Antarctic marine environment is a diverse ecosystem currently experiencing some of the fastest rates of climatic change. The documentation and management of these changes requires accurate estimates of species diversity. Recently, there has been an increased recognition of the abundance and importance of cryptic species, i.e. those that are morphologically identical but genetically distinct. This article presents the largest genetic investigation into the prevalence of cryptic polychaete species within the deep Antarctic benthos to date. We uncover cryptic diversity in 50% of the 15 morphospecies targeted through the comparison of mitochondrial DNA sequences, as well as 10 previously overlooked morphospecies, increasing the total species richness in the sample by 233%. Our ability to describe universal rules for the detection of cryptic species within polychaetes, or normalization to expected number of species based on genetic data is prevented by taxon-specific differences in phylogenetic outputs and genetic variation between and within potential cryptic species. These data provide the foundation for biogeographic and functional analysis that will provide insight into the drivers of species diversity and its role in ecosystem function. PMID- 28018625 TI - Deciphering a survival strategy during the interspecific competition between Bacillus cereus MSM-S1 and Pseudomonas sp. MSM-M1. AB - Interspecific competition in bacteria governs colony growth dynamics and pattern formation. Here, we demonstrate an interesting phenomenon of interspecific competition between Bacillus cereus MSM-S1 and Pseudomonas sp. MSM-M1, where secretion of an inhibitor by Pseudomonas sp. is used as a strategy for survival. Although B. cereus grows faster than Pseudomonas sp., in the presence of Pseudomonas sp. the population of B. cereus reduces significantly, whereas Pseudomonas sp. do not show any marked alteration in their population growth. Appearance of a zone of inhibition between growing colonies of two species on nutrient agar prevents the expanding front of the MSM-S1 colony from accessing and depleting nutrients in the region occupied by MSM-M1, thereby aiding the survival of the slower growing MSM-M1 colonies. To support our experimental results, we present simulations, based on a chemotactic model of colony growth dynamics. We demonstrate that the chemical(s) secreted by Pseudomonas sp. is responsible for the observed inhibition of growth and spatial pattern of the B. cereus MSM-S1 colony. Our experimental results are in excellent agreement with the numerical results and confirm that secreted inhibitors enable Pseudomonas sp. to survive and coexist in the presence of faster growing B. cereus, in a common niche. PMID- 28018626 TI - Chimpanzee fathers bias their behaviour towards their offspring. AB - Promiscuous mating was traditionally thought to curtail paternal investment owing to the potential costs of providing care to unrelated infants. However, mounting evidence suggests that males in some promiscuous species can recognize offspring. In primates, evidence for paternal care exists in promiscuous Cercopithecines, but less is known about these patterns in other taxa. Here, we examine two hypotheses for paternal associations with lactating mothers in eastern chimpanzees (Pan troglodytes schweinfurthii): paternal effort, whereby males associate and interact more with their own infants, and mating effort, whereby males invest in mothers and offspring for mating privileges. We found that fathers associated more with their offspring than they did with non-kin infants, particularly early in life when infanticide risk is highest. Additionally, fathers and their infant offspring interacted more than expected. Notably, association between fathers and mother-infant pairs did not predict the probability of siring the mother's next offspring. Our results support the paternal effort, but not the mating effort hypothesis in this species. Chimpanzees are one of the most salient models for the last common ancestor between Pan and Homo, thus our results suggest that a capacity for paternal care, possibly independent of long-term mother-father bonds, existed early in hominin evolution. PMID- 28018627 TI - Age structure is critical to the population dynamics and survival of honeybee colonies. AB - Age structure is an important feature of the division of labour within honeybee colonies, but its effects on colony dynamics have rarely been explored. We present a model of a honeybee colony that incorporates this key feature, and use this model to explore the effects of both winter and disease on the fate of the colony. The model offers a novel explanation for the frequently observed phenomenon of 'spring dwindle', which emerges as a natural consequence of the age structured dynamics. Furthermore, the results indicate that a model taking age structure into account markedly affects the predicted timing and severity of disease within a bee colony. The timing of the onset of disease with respect to the changing seasons may also have a substantial impact on the fate of a honeybee colony. Finally, simulations predict that an infection may persist in a honeybee colony over several years, with effects that compound over time. Thus, the ultimate collapse of the colony may be the result of events several years past. PMID- 28018628 TI - Amy2B copy number variation reveals starch diet adaptations in ancient European dogs. AB - Extant dog and wolf DNA indicates that dog domestication was accompanied by the selection of a series of duplications on the Amy2B gene coding for pancreatic amylase. In this study, we used a palaeogenetic approach to investigate the timing and expansion of the Amy2B gene in the ancient dog populations of Western and Eastern Europe and Southwest Asia. Quantitative polymerase chain reaction was used to estimate the copy numbers of this gene for 13 ancient dog samples, dated to between 15 000 and 4000 years before present (cal. BP). This evidenced an increase of Amy2B copies in ancient dogs from as early as the 7th millennium cal. BP in Southeastern Europe. We found that the gene expansion was not fixed across all dogs within this early farming context, with ancient dogs bearing between 2 and 20 diploid copies of the gene. The results also suggested that selection for the increased Amy2B copy number started 7000 years cal. BP, at the latest. This expansion reflects a local adaptation that allowed dogs to thrive on a starch rich diet, especially within early farming societies, and suggests a biocultural coevolution of dog genes and human culture. PMID- 28018629 TI - The ecological connectivity of whale shark aggregations in the Indian Ocean: a photo-identification approach. AB - Genetic and modelling studies suggest that seasonal aggregations of whale sharks (Rhincodon typus) at coastal sites in the tropics may be linked by migration. Here, we used photo-identification (photo-ID) data collected by both citizen scientists and researchers to assess the connectedness of five whale shark aggregation sites across the entire Indian Ocean at timescales of up to a decade. We used the semi-automated program I3S (Individual Interactive Identification System) to compare photographs of the unique natural marking patterns of individual whale sharks collected from aggregations at Mozambique, the Seychelles, the Maldives, Christmas Island (Australia) and Ningaloo Reef (Australia). From a total of 6519 photos, we found no evidence of connectivity of whale shark aggregations at ocean-basin scales within the time frame of the study and evidence for only limited connectivity at regional (hundreds to thousands of kilometres) scales. A male whale shark photographed in January 2010 at Mozambique was resighted eight months later in the Seychelles and was the only one of 1724 individuals in the database to be photographed at more than one site. On average, 35% of individuals were resighted at the same site in more than one year. A Monte Carlo simulation study showed that the power of this photo-ID approach to document patterns of emigration and immigration was strongly dependent on both the number of individuals identified in aggregations and the size of resident populations. PMID- 28018630 TI - Detection and perception of generic host volatiles by mosquitoes modulate host preference: context dependence of (R)-1-octen-3-ol. AB - Natural selection favours a restricted host breadth in disease vector mosquitoes, indicating that there is an adaptive value associated with maintaining plasticity in host preference. One mechanism to maintain such plasticity is via the detection of generic cues by conserved peripheral olfactory pathways, which when perceived in different host odour contexts enable the identification of and discrimination among potential host species. Here, we show that the context of an odour cue shapes host perception in mosquitoes, by altering the release rate of the generic host-related volatile (R)-1-octen-3-ol, within its natural range, and in the background odour of known hosts and non-hosts. This result highlights that host recognition is contextual and dependent on quantitative and qualitative differences in odour blends and the olfactory codes evoked. From the perspective of vector management, understanding the perception of odour blends and their context is essential to the process of developing synthetic blends for the optimal attraction of mosquitoes in efforts to control and monitor populations. PMID- 28018631 TI - Life-history theory and climate change: resolving population and parental investment paradoxes. AB - Population growth in the next half-century is on pace to raise global carbon emissions by half. Carbon emissions are associated with fertility as a by-product of somatic and parental investment, which is predicted to involve time orientation/preference as a mediating psychological mechanism. Here, we draw upon life-history theory (LHT) to investigate associations between future orientation and fertility, and their impacts on carbon emissions. We argue 'K-strategy' life history (LH) in high-income countries has resulted in parental investment behaviours involving future orientation that, paradoxically, promote unsustainable carbon emissions, thereby lowering the Earth's K or carrying capacity. Increasing the rate of approach towards this capacity are 'r-strategy' LHs in low-income countries that promote population growth. We explore interactions between future orientation and development that might slow the rate of approach towards global K. Examination of 67 000 individuals across 75 countries suggests that future orientation interacts with the relationship between environmental risk and fertility and with development related parental investment, particularly investment in higher education, to slow population growth and mitigate per capita carbon emissions. Results emphasize that LHT will be an important tool in understanding the demographic and consumption patterns that drive anthropogenic climate change. PMID- 28018632 TI - The role of cell replacement in benthic-pelagic coupling by suspension feeders. AB - Benthic-pelagic coupling through suspension feeders and their detrital pathways is integral to carbon transport in oceans. In food-poor ecosystems however, a novel mechanism of carbon recycling has been proposed that involves direct uptake of dissolved carbon by suspension feeders followed by shedding of cells as particulate carbon. We studied cell replacement rates in a range of cold-water sponge species to determine how universal this mechanism might be. We show that cell replacement rates of feeding epithelia in explants vary from 30 hours up to 7 days, and change during different seasons and life-history stages. We also found that feeding epithelia are not replaced through direct replication but instead arise from a population of stem cells that differentiate and integrate into epithelial tissues. Our results reveal a surprising amount of complexity in the control of cell processes in sponges, with cell turnover depending on environmental conditions and using stem cells as rate-limiting mechanisms. Our results also suggest that for species in cold water with high particulate organic matter, cell turnover is not the mechanism delivering carbon flux to surrounding communities. PMID- 28018633 TI - Sensitivity of marine protected area network connectivity to atmospheric variability. AB - International efforts are underway to establish well-connected systems of marine protected areas (MPAs) covering at least 10% of the ocean by 2020. But the nature and dynamics of ocean ecosystem connectivity are poorly understood, with unresolved effects of climate variability. We used 40-year runs of a particle tracking model to examine the sensitivity of an MPA network for habitat-forming cold-water corals in the northeast Atlantic to changes in larval dispersal driven by atmospheric cycles and larval behaviour. Trajectories of Lophelia pertusa larvae were strongly correlated to the North Atlantic Oscillation (NAO), the dominant pattern of interannual atmospheric circulation variability over the northeast Atlantic. Variability in trajectories significantly altered network connectivity and source-sink dynamics, with positive phase NAO conditions producing a well-connected but asymmetrical network connected from west to east. Negative phase NAO produced reduced connectivity, but notably some larvae tracked westward-flowing currents towards coral populations on the mid-Atlantic ridge. Graph theoretical metrics demonstrate critical roles played by seamounts and offshore banks in larval supply and maintaining connectivity across the network. Larval longevity and behaviour mediated dispersal and connectivity, with shorter lived and passive larvae associated with reduced connectivity. We conclude that the existing MPA network is vulnerable to atmospheric-driven changes in ocean circulation. PMID- 28018634 TI - Characterization of stress coping style in Senegalese sole (Solea senegalensis) juveniles and breeders for aquaculture. AB - The aim of this work was to characterize stress coping styles of Senegalese sole (Solea senegalensis) juveniles and breeders and to select an operational behavioural screening test (OBST) that can be used by the aquaculture industry to classify and select between behavioural phenotypes in order to improve production indicators. A total of 61 juveniles and 59 breeders were subjected to five individual behavioural tests and two grouping tests. At the end of the individual tests, all animals were blood sampled in order to measure cortisol, glucose and lactate. Three tests (restraining, new environment and confinement) characterized the stress coping style behaviour of Senegalese sole juveniles and breeders and demonstrated inter-individual consistency. Further, the tests when incorporated into a principal components analysis (PCA) (i) identified two principal axes of personality traits: 'fearfulness-reactivity' and 'activity-exploration', (ii) were representative of the physiological axis of stress coping style, and (iii) were validated by established group tests. This study proposed for the first time three individual coping style tests that reliably represented proactive and reactive personalities of Senegalese sole juveniles and breeders. In addition, the three proposed tests met some basic operational criteria (rapid testing, no special equipment and easy to apply and interpret) that could prove attractive for fish farmers to identify fish with a specific behaviour that gives advantages in the culture system and that could be used to establish selection-based breeding programmes to improve domestication and production. PMID- 28018635 TI - Evolution in eggs and phases: experimental evolution of fecundity and reproductive timing in Caenorhabditis elegans. AB - To examine the role of natural selection in fecundity in a variety of Caenorhabditis elegans genetic backgrounds, we used an experimental evolution protocol to evolve 14 distinct genetic strains over 15-20 generations. We were able to generate 790 distinct genealogies, which provided information on both the effects of natural selection and the evolvability of each strain. Among these genotypes are a wild-type (N2) and a collection of mutants with targeted mutations in the daf-c, daf-d and AMPK pathways. Differences are observed in reproductive fitness along with related changes in reproductive timing. The majority of selective effects on fecundity occur during the first few generations of evolution, while the negative selection for reproductive timing occurs on longer time scales. In addition, positive selection on fecundity results in positive and negative strain-dependent selection on reproductive timing. A derivative of population size per generation called reproductive carry-over (RCO) may be informative in terms of developmental selection. While these findings transcend mutations in a specific gene, changes in the RCO measure may nevertheless be products of selection. In conclusion, the broader implications of these findings are discussed, particularly in the context of genotype-fitness maps and the role of uncharacterized mutations in individual variation and evolvability. PMID- 28018636 TI - Evolutionary implications of interspecific variation in a maternal effect: a meta analysis of yolk testosterone response to competition. AB - Competition between conspecifics during the breeding season can result in behavioural and physiological programming of offspring via maternal effects. For birds, in which maternal effects are best studied, it has been claimed that exposure to increased competition causes greater deposition of testosterone into egg yolks, which creates faster growing, more aggressive offspring; such traits are thought to be beneficial for high-competition environments. Nevertheless, not all species show a positive relationship between competitive interactions and yolk testosterone, and an explanation for this interspecific variation is lacking. We here test if the magnitude and direction of maternal testosterone allocated to eggs in response to competition can be explained by life-history traits while accounting for phylogenetic relationships. We performed a meta analysis relating effect size of yolk testosterone response to competition with species coloniality, nest type, parental effort and mating type. We found that effect size was moderated by coloniality and nest type; colonial species and those with open nests allocate less testosterone to eggs when in more competitive environments. Applying a life-history perspective helps contextualize studies showing little or negative responses of yolk testosterone to competition and improves our understanding of how variation in this maternal effect may have evolved. PMID- 28018637 TI - From resource to female defence: the impact of roosting ecology on a bat's mating strategy. AB - With their extraordinary species richness and diversity in ecological traits and social systems, bats are a promising taxon for testing socio-ecological hypotheses in order to get new insights into the evolution of animal social systems. Regarding its roosting habits, proboscis bats form an extreme by occupying sites which are usually completely exposed to daylight (e.g. tree trunks, vines or rocks). This is accompanied by morphological and behavioural adaptations to remain cryptic in exposed day roosts. With long-term behavioural observations and genetic parentage analyses of individually marked proboscis bats, we assessed its social dispersion and male mating strategy during day and night. Our results reveal nocturnal male territoriality-a strategy which most closely resembles a resource-defence polygyny that is frequent also in other tropical bats. Its contrasting clumped social dispersion during the day is likely to be the result of strong selection for crypsis in exposed roosts and is accompanied by direct female defence in addition to male territoriality. To the best of our knowledge, such contrasting male mating strategies within a single day-night cycle have not been described in a vertebrate species so far and illustrate a possible evolutionary trajectory from resource-defence to female defence strategy by small ecologically driven evolutionary steps. PMID- 28018638 TI - Exploring the trade-off between quality and fairness in human partner choice. AB - Partner choice is an important force underpinning cooperation in humans and other animals. Nevertheless, the mechanisms individuals use to evaluate and discriminate among partners who vary across different dimensions are poorly understood. Generally, individuals are expected to prefer partners who are both able and willing to invest in cooperation but how do individuals prioritize the ability over willingness to invest when these characteristics are opposed to one another? We used a modified Dictator Game to tackle this question. Choosers evaluated partners varying in quality (proxied by wealth) and fairness, in conditions when wealth was relatively stable or liable to change. When both partners were equally fair (or unfair), choosers typically preferred the richer partner. Nevertheless, when asked to choose between a rich-stingy and a poor-fair partner, choosers prioritized fairness over wealth-with this preference being particularly pronounced when wealth was unstable. The implications of these findings for real-world partner choice are discussed. PMID- 28018639 TI - A facile, versatile approach to hydroxyl-anchored metal oxides with high Cr(VI) adsorption performance in water treatment. AB - In this study, a facile and versatile urea-assisted approach was proposed to synthesize Chinese rose-like NiO, pinecone-like ZnO and sponge-like CoO adsorbents. The presence of urea during syntheses endowed these adsorbents with high concentration of surface hydroxyl groups, which was estimated as 1.83, 1.32 and 4.19 mmol [OH-] g-1 for NiO, ZnO and CoO adsorbents, respectively. These surface hydroxyl groups would facilitate the adsorption of Cr(vi) species (e.g. HCrO4-, Cr2O72- and CrO42-) from wastewater by exchanging with hydroxyl protons or hydroxide ions, and hence result in extremely high maximum adsorbed amounts of Cr(vi), being 2974, 14 256 and 408 mg g-1 for NiO, ZnO and CoO adsorbents in the pH range of 5.02-5.66 at 298 K, respectively. More strikingly, the maximum adsorbed amounts of Cr(vi) would be greatly enhanced as the adsorbing temperature is increased, and even amount to 23 411 mg g-1 for ZnO adsorbents at 323 K. Based on the kinetics and equilibrium studies of adsorptive removal of Cr(vi) from wastewater, our synthetic route will greatly improve the adsorptivity of the as synthesized metal-oxide adsorbents, and hence it will shed new light on the development of high-performance adsorbents. PMID- 28018640 TI - The potential of electricity transmission corridors in forested areas as bumblebee habitat. AB - Declines in pollinator abundance and diversity are not only a conservation issue, but also a threat to crop pollination. Maintained infrastructure corridors, such as those containing electricity transmission lines, are potentially important wild pollinator habitat. However, there is a lack of evidence comparing the abundance and diversity of wild pollinators in transmission corridors with other important pollinator habitats. We compared the diversity of a key pollinator group, bumblebees (Bombus spp.), between transmission corridors and the surrounding semi-natural and managed habitat types at 10 sites across Sweden's Uppland region. Our results show that transmission corridors have no impact on bumblebee diversity in the surrounding area. However, transmission corridors and other maintained habitats such as roadsides have a level of bumblebee abundance and diversity comparable to semi-natural grasslands and host species that are important for conservation and ecosystem service provision. Under the current management regime, transmission corridors already provide valuable bumblebee habitat, but given that host plant density is the main determinant of bumblebee abundance, these areas could potentially be enhanced by establishing and maintaining key host plants. We show that in northern temperate regions the maintenance of transmission corridors has the potential to contribute to bumblebee conservation and the ecosystem services they provide. PMID- 28018641 TI - Binocular combination of stimulus orientation. AB - When two sine waves that differ slightly in orientation are presented to the two eyes separately, a single cyclopean sine wave is perceived. However, it is unclear how the brain calculates its orientation. Here, we used a signal detection rating method to estimate the perceived orientation when the two eyes were presented with Gabor patches that differed in both orientation and contrast. We found a nearly linear combination of orientation when both targets had the same contrast. However, the binocular percept shifted away from the linear prediction towards the orientation with the higher contrast, depending on both the base contrast and the contrast ratio. We found that stimuli that differ slightly in orientation are combined into a single percept, similarly for monocular and binocular presentation, with a bias that depends on the interocular contrast ratio. Our results are well fitted by gain-control models, and are consistent with a previous study that favoured the DSKL model that successfully predicts binocular phase and contrast combination and binocular contrast discrimination. In this model, the departures from linearity may be explained on the basis of mutual suppression and mutual enhancement, both of which are stronger under dichoptic than monocular conditions. PMID- 28018642 TI - Competing metabolic strategies in a multilevel selection model. AB - The evolutionary mechanisms of energy efficiency have been addressed. One important question is to understand how the optimized usage of energy can be selected in an evolutionary process, especially when the immediate advantage of gathering efficient individuals in an energetic context is not clear. We propose a model of two competing metabolic strategies differing in their resource usage, an efficient strain which converts resource into energy at high efficiency but displays a low rate of resource consumption, and an inefficient strain which consumes resource at a high rate but at low yield. We explore the dynamics in both well-mixed and structured populations. The selection for optimized energy usage is measured by the likelihood that an efficient strain can invade a population of inefficient strains. It is found that the parameter space at which the efficient strain can thrive in structured populations is always broader than observed in well-mixed populations. PMID- 28018643 TI - A tilt after-effect for images of buildings: evidence of selectivity for the orientation of everyday scenes. AB - The tilt after-effect (TAE) is thought to be a manifestation of gain control in mechanisms selective for spatial orientation in visual stimuli. It has been demonstrated with luminance-defined stripes, contrast-defined stripes, orientation-defined stripes and even with natural images. Of course, all images can be decomposed into a sum of stripes, so it should not be surprising to find a TAE when adapting and test images contain stripes that differ by 15 degrees or so. We show this latter condition is not necessary for the TAE with natural images: adaptation to slightly tilted and vertically filtered houses produced a 'repulsive' bias in the perceived orientation of horizontally filtered houses. These results suggest gain control in mechanisms selective for spatial orientation in natural images. PMID- 28018644 TI - How self-organization can guide evolution. AB - Self-organization and natural selection are fundamental forces that shape the natural world. Substantial progress in understanding how these forces interact has been made through the study of abstract models. Further progress may be made by identifying a model system in which the interaction between self-organization and selection can be investigated empirically. To this end, we investigate how the self-organizing thermoregulatory huddling behaviours displayed by many species of mammals might influence natural selection of the genetic components of metabolism. By applying a simple evolutionary algorithm to a well-established model of the interactions between environmental, morphological, physiological and behavioural components of thermoregulation, we arrive at a clear, but counterintuitive, prediction: rodents that are able to huddle together in cold environments should evolve a lower thermal conductance at a faster rate than animals reared in isolation. The model therefore explains how evolution can be accelerated as a consequence of relaxed selection, and it predicts how the effect may be exaggerated by an increase in the litter size, i.e. by an increase in the capacity to use huddling behaviours for thermoregulation. Confirmation of these predictions in future experiments with rodents would constitute strong evidence of a mechanism by which self-organization can guide natural selection. PMID- 28018645 TI - A random walk description of individual animal movement accounting for periods of rest. AB - Animals do not move all the time but alternate the period of actual movement (foraging) with periods of rest (e.g. eating or sleeping). Although the existence of rest times is widely acknowledged in the literature and has even become a focus of increased attention recently, the theoretical approaches to describe animal movement by calculating the dispersal kernel and/or the mean squared displacement (MSD) rarely take rests into account. In this study, we aim to bridge this gap. We consider a composite stochastic process where the periods of active dispersal or 'bouts' (described by a certain baseline probability density function (pdf) of animal dispersal) alternate with periods of immobility. For this process, we derive a general equation that determines the pdf of this composite movement. The equation is analysed in detail in two special but important cases such as the standard Brownian motion described by a Gaussian kernel and the Levy flight described by a Cauchy distribution. For the Brownian motion, we show that in the large-time asymptotics the effect of rests results in a rescaling of the diffusion coefficient. The movement occurs as a subdiffusive transition between the two diffusive asymptotics. Interestingly, the Levy flight case shows similar properties, which indicates a certain universality of our findings. PMID- 28018646 TI - Scratch that itch: revisiting links between self-directed behaviour and parasitological, social and environmental factors in a free-ranging primate. AB - Different hypotheses explain variation in the occurrence of self-directed behaviour such as scratching and self-grooming: a parasite hypothesis linked with ectoparasite load, an environmental hypothesis linked with seasonal conditions and a social hypothesis linked with social factors. These hypotheses are not mutually exclusive but are often considered separately. Here, we revisited these hypotheses together in female Japanese macaques (Macaca fuscata fuscata) of Kojima islet, Japan. We input occurrences of scratching and self-grooming during focal observations in models combining parasitological (lice load), social (dominance rank, social grooming, aggression received and proximity), and environmental (rainfall, temperature and season) variables. Using an information theory approach, we simultaneously compared the explanatory value of models against each other using variation in Akaike's information criterion and Akaike's weights. We found that evidence for models with lice load, with or without environmental-social parameters, was stronger than that for other models. In these models, scratching was positively associated with lice load and social grooming whereas self-grooming was negatively associated with lice load and positively associated with social grooming, dominance rank and number of female neighbours. This study indicates that the study animals scratch primarily because of an immune/stimulus itch, possibly triggered by ectoparasite bites/movements. It also confirms that self-grooming could act as a displacement activity in the case of social uncertainty. We advocate that biological hypotheses be more broadly considered even when investigating social processes, as one does not exclude the other. PMID- 28018647 TI - Alloparenting is associated with reduced maternal lactation effort and faster weaning in wild chimpanzees. AB - Alloparenting, when individuals other than the mother assist with infant care, can vary between and within populations and has potential fitness costs and benefits for individuals involved. We investigated the effects of alloparenting on the speed with which infants were weaned, a potential component of maternal fitness because of how it can affect inter-birth intervals, in wild chimpanzees (Pan troglodytes schweinfurthii) at Ngogo, Uganda. We also provide, to our knowledge, the first description of alloparenting in this population and present a novel measure of the contribution of milk to infant diets through faecal stable nitrogen isotopes (delta15N). Using 42 mother-infant pairs, we tested associations of two alloparenting dimensions, natal attraction (interest in infants) and infant handling (holding, carrying), to the proportion of time mothers spent feeding and to maternal lactation effort (mean nursing rates and mother-infant delta15N differences). Neither natal attraction nor infant handling was significantly associated with feeding time. Infant handling was inversely associated with both measures of lactation effort, although natal attraction showed no association. Alloparenting may benefit mothers by enabling females to invest in their next offspring sooner through accelerated weaning. Our findings emphasize the significance of alloparenting as a flexible component of female reproductive strategies in some species. PMID- 28018648 TI - Carbon nitride supported copper nanoparticles: light-induced electronic effect of the support for triazole synthesis. AB - The composite framework of graphitic carbon nitride (gCN) supported copper nanoparticle can act as a high-performance photoreactor for the synthesis of 1,2,3-triazole derivatives under light irradiation in the absence of alkaline condition. The photoactivity of gCN originates from an electron transition from the valence band to the conduction band, in the presence of photon energy, and the hot electron acts as a scavenger of the terminal proton of the alkyne molecule to facilitate the formation of copper acetanilide complex. In this study, we have performed the experiment under a different photonic environment, including dark condition, and in the presence and absence of base. A comparative study was also executed using Cu-TiO2 system, as a reference material, in the support of our proposed mechanism. The recycling performance and the photocorrosion effect of the catalyst have also been reported in this study. PMID- 28018649 TI - Latitudinal diversity gradients in Mesozoic non-marine turtles. AB - The latitudinal biodiversity gradient (LBG)-the pattern of increasing taxonomic richness with decreasing latitude-is prevalent in the structure of the modern biota. However, some freshwater taxa show peak richness at mid-latitudes; for example, extant Testudines (turtles, terrapins and tortoises) exhibit their greatest diversity at 25 degrees N, a pattern sometimes attributed to recent bursts of climatically mediated species diversification. Here, we test whether this pattern also characterizes the Mesozoic distribution of turtles, to determine whether it was established during either their initial diversification or as a more modern phenomenon. Using global occurrence data for non-marine testudinate genera, we find that subsampled richness peaks at palaeolatitudes of 15-30 degrees N in the Jurassic, 30-45 degrees N through the Cretaceous to the Campanian, and from 30 degrees to 60 degrees N in the Maastrichtian. The absence of a significant diversity peak in southern latitudes is consistent with results from climatic models and turtle niche modelling that demonstrate a dearth of suitable turtle habitat in Gondwana during the Jurassic and Late Cretaceous. Our analyses confirm that the modern testudinate LBG has a deep-time origin and further demonstrate that LBGs are not always expressed as a smooth, equator-to pole distribution. PMID- 28018650 TI - Using Fisher information to track stability in multivariate systems. AB - With the current proliferation of data, the proficient use of statistical and mining techniques offer substantial benefits to capture useful information from any dataset. As numerous approaches make use of information theory concepts, here, we discuss how Fisher information (FI) can be applied to sustainability science problems and used in data mining applications by analysing patterns in data. FI was developed as a measure of information content in data, and it has been adapted to assess order in complex system behaviour. The main advantage of the approach is the ability to collapse multiple variables into an index that can be used to assess stability and track overall trends in a system, including its regimes and regime shifts. Here, we provide a brief overview of FI theory, followed by a simple step-by-step numerical example on how to compute FI. Furthermore, we introduce an open source Python library that can be freely downloaded from GitHub and we use it in a simple case study to evaluate the evolution of FI for the global-mean temperature from 1880 to 2015. Results indicate significant declines in FI starting in 1978, suggesting a possible regime shift. PMID- 28018651 TI - Stability in skipping gaits. AB - As an alternative to walking and running, humans are able to skip. However, adult humans avoid it. This fact seems to be related to the higher energetic costs associated with skipping. Still, children, some birds, lemurs and lizards use skipping gaits during daily locomotion. We combined experimental data on humans with numerical simulations to test whether stability and robustness motivate this choice. Parameters for modelling were obtained from 10 male subjects. They locomoted using unilateral skipping along a 12 m runway. We used a bipedal spring loaded inverted pendulum to model and to describe the dynamics of skipping. The subjects displayed higher peak ground reaction forces and leg stiffness in the first landing leg (trailing leg) compared to the second landing leg (leading leg). In numerical simulations, we found that skipping is stable across an amazing speed range from skipping on the spot to fast running speeds. Higher leg stiffness in the trailing leg permits longer strides at same system energy. However, this strategy is at the same time less robust to sudden drop perturbations than skipping with a stiffer leading leg. A slightly higher stiffness in the leading leg is most robust, but might be costlier. PMID- 28018652 TI - Postnatal ontogeny and the evolution of macrostomy in snakes. AB - Macrostomy is the anatomical feature present in macrostomatan snakes that permits the ingestion of entire prey with high cross-sectional area. It depends on several anatomical traits in the skeleton and soft tissues, of which the elongation of gnathic complex and backward rotation of the quadrate represent crucial skeletal requirements. Here, the relevance of postnatal development of these skull structures and their relationship with macrohabitat and diet are explored. Contrary to the condition present in lizards and basal snakes that occupy underground macrohabitats, elements of the gnathic complex of most macrostomatan snakes that exploit surface macrohabitats display conspicuous elongation during postnatal growth, relative to the rest of the skull, as well as further backward rotation of the quadrate bone. Remarkably, several clades of small cryptozoic macrostomatans reverse these postnatal transformations and return to a diet based on prey with low cross-sectional area such as annelids, insects or elongated vertebrates, thus resembling the condition present in underground basal snakes. Dietary ontogenetic shift observed in most macrostomatan snakes is directly linked with this ontogenetic trajectory, indicating that this shift is acquired progressively as the gnathic complex elongates and the quadrate rotates backward during postnatal ontogeny. The numerous independent events of reversion in the gnathic complex and prey type choice observed in underground macrostomatans and the presence of skeletal requirements for macrostomy in extinct non-macrostomatan species reinforce the possibility that basal snakes represent underground survivors of clades that had the skeletal requirements for macrostomy. Taken together, the data presented here suggest that macrostomy has been shaped during multiple episodes of occupation of underground and surface macrohabitats throughout the evolution of snakes. PMID- 28018653 TI - Next-generation freshwater bioassessment: eDNA metabarcoding with a conserved metazoan primer reveals species-rich and reservoir-specific communities. AB - Freshwater habitats are of high conservation value and provide a wide range of ecosystem services. Effective management requires regular monitoring. However, conventional methods based on direct observation or specimen collection are so invasive, expensive and labour-intensive that frequent monitoring is uncommon. Here, we test whether the evaluation of environmental DNA (eDNA) from water based on a simple protocol can be used for assessing biodiversity. We use universal metazoan primers for characterizing water eDNA across horizontal and vertical spatial dimensions in two reservoirs with known species diversity for two key taxa. eDNA obtained directly from 42 samples * 15 ml water (total = 630 ml) per reservoir yielded DNA signatures for more than 500 metazoan species, of which 105 could be identified to species/genus based on DNA barcodes. We show that eDNA can be used to assign each water sample to its reservoir of origin, and that eDNA outperforms conventional survey methods in single-sample richness comparisons, while revealing evidence for hundreds of unknown species that are undetected by conventional bioassessment methods. eDNA also confirms the presence of a recently discovered invasive snail species and provides evidence for the continued survival of a rare native species of goby not sighted in that habitat since 2007. eDNA thus promises to be a useful addition to the bioassessment toolbox for freshwater systems. PMID- 28018654 TI - Phenotypic variation and differentiated gene expression of Australian plants in response to declining rainfall. AB - Declining rainfall is projected to have negative impacts on the demographic performance of plant species. Little is known about the adaptive capacity of species to respond to drying climates, and whether adaptation can keep pace with climate change. In fire-prone ecosystems, episodic recruitment of perennial plant species in the first year post-fire imposes a specific selection environment, offering a unique opportunity to quantify the scope for adaptive response to climate change. We examined the growth of seedlings of four fire-killed species under control and drought conditions for seeds from populations established in years following fire receiving average-to-above-average winter rainfall, or well below-average winter rainfall. We show that offspring of plants that had established under drought had more efficient water uptake, and/or stored more water per unit biomass, or developed denser leaves, and all maintained higher survival in simulated drought than did offspring of plants established in average annual rainfall years. Adaptive phenotypic responses were not consistent across all traits and species, while plants that had established under severe drought or established in years with average-to-above-average rainfall had an overall different physiological response when growing either with or without water constraints. Seedlings descended from plants established under severe drought also had elevated gene expression in key pathways relating to stress response. Our results demonstrate the capacity for rapid adaptation to climate change through phenotypic variation and regulation of gene expression. However, effective and rapid adaptation to climate change may vary among species depending on their capacity to maintain robust populations under multiple stresses. PMID- 28018655 TI - Inferring phage-bacteria infection networks from time-series data. AB - In communities with bacterial viruses (phage) and bacteria, the phage-bacteria infection network establishes which virus types infect which host types. The structure of the infection network is a key element in understanding community dynamics. Yet, this infection network is often difficult to ascertain. Introduced over 60 years ago, the plaque assay remains the gold standard for establishing who infects whom in a community. This culture-based approach does not scale to environmental samples with increased levels of phage and bacterial diversity, much of which is currently unculturable. Here, we propose an alternative method of inferring phage-bacteria infection networks. This method uses time-series data of fluctuating population densities to estimate the complete interaction network without having to test each phage-bacteria pair individually. We use in silico experiments to analyse the factors affecting the quality of network reconstruction and find robust regimes where accurate reconstructions are possible. In addition, we present a multi-experiment approach where time series from different experiments are combined to improve estimates of the infection network. This approach also mitigates against the possibility of evolutionary changes to relevant phenotypes during the time course of measurement. PMID- 28018656 TI - European sea bass show behavioural resilience to near-future ocean acidification. AB - Ocean acidification (OA)-caused by rising concentrations of carbon dioxide (CO2) is thought to be a major threat to marine ecosystems and has been shown to induce behavioural alterations in fish. Here we show behavioural resilience to near future OA in a commercially important and migratory marine finfish, the Sea bass (Dicentrarchus labrax). Sea bass were raised from eggs at 19 degrees C in ambient or near-future OA (1000 uatm pCO2) conditions and n = 270 fish were observed 59 68 days post-hatch using automated tracking from video. Fish reared under ambient conditions, OA conditions, and fish reared in ambient conditions but tested in OA water showed statistically similar movement patterns, and reacted to their environment and interacted with each other in comparable ways. Thus our findings indicate behavioural resilience to near-future OA in juvenile sea bass. Moreover, simulated agent-based models indicate that our analysis methods are sensitive to subtle changes in fish behaviour. It is now important to determine whether the absences of any differences persist under more ecologically relevant circumstances and in contexts which have a more direct bearing on individual fitness. PMID- 28018657 TI - Chemical antipredator defence is linked to higher extinction risk. AB - Many attributes of species may be linked to contemporary extinction risk, though some such traits remain untested despite suggestions that they may be important. Here, I test whether a trait associated with higher background extinction rates, chemical antipredator defence, is also associated with current extinction risk, using amphibians as a model system-a group facing global population declines. I find that chemically defended species are approximately 60% more likely to be threatened than species without chemical defence, although the severity of the contemporary extinction risk may not relate to chemical defence. The results confirm that background and contemporary extinction rates can be predicted from the same traits, at least in certain cases. This suggests that associations between extinction risk and phenotypic traits can be temporally stable over long periods. The results also provide novel insights into the relevance of antipredator defences for species subject to conservation concerns. PMID- 28018658 TI - Lack of aggression and apparent altruism towards intruders in a primitive termite. AB - In eusocial insects, the ability to discriminate nest-mates from non-nest-mates is widespread and ensures that altruistic actions are directed towards kin and agonistic actions are directed towards non-relatives. Most tests of nest-mate recognition have focused on hymenopterans, and suggest that cooperation typically evolves in tandem with strong antagonism towards non-nest-mates. Here, we present evidence from a phylogenetically and behaviourally basal termite species that workers discriminate members of foreign colonies. However, contrary to our expectations, foreign intruders were the recipients of more rather than less cooperative behaviour and were not subjected to elevated aggression. We suggest that relationships between groups may be much more peaceable in basal termites compared with eusocial hymenoptera, owing to energetic and temporal constraints on colony growth, and the reduced incentive that totipotent workers (who may inherit breeding status) have to contribute to self-sacrificial intergroup conflict. PMID- 28018659 TI - Mutualists or parasites? Context-dependent influence of symbiotic fly larvae on carnivorous investment in the Albany pitcher plant. AB - Carnivorous plants allocate more resources to carnivorous structures under nutrient-limited conditions, and relative investment can also be influenced by animals (infauna) that live in association with these plants and feed on their prey. We investigated these effects within a population of the pitcher plant Cephalotus follicularis containing varying densities of larvae of the fly Badisis ambulans. For plants with a relatively high proportion of adult pitchers, increasing larval density was associated with lower relative leaf allocation to new pitcher buds. For plants with relatively few adult pitchers, however, there was greater relative leaf allocation to pitcher buds with increasing larval density. In a field experiment, there was no significant effect of experimental larval presence or absence on the change in carbon-to-nitrogen (C/N) ratio of plants. Although the direction of the correlation between B. ambulans larvae and relative investment in carnivorous and non-carnivorous structures depends on the relative number of mature structures, whether the larvae enhance or reduce nutrient stress under different conditions remains unclear. The change in C/N was, however, less variable for pitchers that contained larvae, suggesting a stabilizing effect. Eighteen of 52 experimental pitchers were damaged by an unknown species, causing the pitcher fluid to drain. These pitchers were significantly more likely to survive if they contained larvae. These results suggest that the relationship between infauna and host varies with the initial resource status and environmental context of the host plant. PMID- 28018660 TI - Manta birostris, predator of the deep? Insight into the diet of the giant manta ray through stable isotope analysis. AB - The characterization of diet for the giant manta ray Manta birostris has been problematic given their large-scale movement patterns and the difficulty in obtaining stomach contents from this species. The large majority of existing information is based on observational data limited to feeding events at the sea surface during daylight. Recently discovered aggregation sites for the giant manta ray off mainland Ecuador are some of the most accessible to date and provide a unique opportunity for researchers to gather much needed information on this elusive species. To assess how important surface zooplankton is to giant manta ray diet, we conducted stable isotope analysis (15N and 13C) on M. birostris muscle and surface zooplankton. Trophic position estimates placed M. birostris overall at a secondary consumer level of approximately 3.4 but there was large variation in delta15N and delta13C values among individuals. Manta birostris muscle tissue delta13C values were also not consistent with this species feeding predominantly on surface zooplankton and suggest that the majority of dietary intake is of mesopelagic origin. Given the conservative life history and fisheries pressure on large planktivores, knowledge of their trophic role and foraging strategies is essential to better understand their ecology and develop effective conservation measures. PMID- 28018661 TI - Shaping communicative colour signals over evolutionary time. AB - Many evolutionary forces can shape the evolution of communicative signals, and the long-term impact of each force may depend on relative timing and magnitude. We use a phylogenetic analysis to infer the history of blue belly patches of Sceloporus lizards, and a detailed spectrophotometric analysis of four species to explore the specific forces shaping evolutionary change. We find that the ancestor of Sceloporus had blue patches. We then focus on four species; the first evolutionary shift (captured by comparison of S. merriami and S. siniferus) represents an ancient loss of the belly patch by S. siniferus, and the second evolutionary shift, bounded by S. undulatus and S. virgatus, represents a more recent loss of blue belly patch by S. virgatus. Conspicuousness measurements suggest that the species with the recent loss (S. virgatus) is the least conspicuous. Results for two other species (S. siniferus and S. merriami) suggest that over longer periods of evolutionary time, new signal colours have arisen which minimize absolute contrast with the habitat while maximizing conspicuousness to a lizard receiver. Specifically, males of the species representing an ancient loss of blue patch (S. siniferus) are more conspicuous than are females in the UV, whereas S. merriami males have evolved a green element that makes their belly patches highly sexually dimorphic but no more conspicuous than the white bellies of S. merriami females. Thus, our results suggest that natural selection may act more immediately to reduce conspicuousness, whereas sexual selection may have a more complex impact on communicative signals through the introduction of new colours. PMID- 28018662 TI - The power of associative learning and the ontogeny of optimal behaviour. AB - Behaving efficiently (optimally or near-optimally) is central to animals' adaptation to their environment. Much evolutionary biology assumes, implicitly or explicitly, that optimal behavioural strategies are genetically inherited, yet the behaviour of many animals depends crucially on learning. The question of how learning contributes to optimal behaviour is largely open. Here we propose an associative learning model that can learn optimal behaviour in a wide variety of ecologically relevant circumstances. The model learns through chaining, a term introduced by Skinner to indicate learning of behaviour sequences by linking together shorter sequences or single behaviours. Our model formalizes the concept of conditioned reinforcement (the learning process that underlies chaining) and is closely related to optimization algorithms from machine learning. Our analysis dispels the common belief that associative learning is too limited to produce 'intelligent' behaviour such as tool use, social learning, self-control or expectations of the future. Furthermore, the model readily accounts for both instinctual and learned aspects of behaviour, clarifying how genetic evolution and individual learning complement each other, and bridging a long-standing divide between ethology and psychology. We conclude that associative learning, supported by genetic predispositions and including the oft-neglected phenomenon of conditioned reinforcement, may suffice to explain the ontogeny of optimal behaviour in most, if not all, non-human animals. Our results establish associative learning as a more powerful optimizing mechanism than acknowledged by current opinion. PMID- 28018663 TI - Geohistorical records indicate no impact of the Deepwater Horizon oil spill on oyster body size. AB - Documentation of the near- and long-term effects of the Deepwater Horizon (DWH) oil spill, one of the largest environmental disasters in US history, is still ongoing. We used a novel before-after-control-impact analysis to test the hypothesis that average body size of intertidal populations of the eastern oyster (Crassostrea virginica) inhabiting impacted areas in Louisiana decreased due to increased stress/mortality related to the oil spill. Time-averaged death assemblages of oysters were used to establish a pre-spill baseline of body-size structure for four impacted and four control locations along a 350 km stretch of Louisiana's coastline. Post-spill body sizes were then measured from live oysters at each site in order to evaluate the differences in body size between oiled (i.e. impact) and unoiled (i.e. control) locations before and after the spill. Our results indicate that average body size of oysters remained relatively unchanged after the oil spill. There were also no temporal patterns in temperature, salinity or disease prevalence that could have explained our results. Together, these findings suggest that oysters either recovered rapidly following the immediate impact of the DWH oil spill, or that its impact was not severe enough to influence short-term population dynamics of the oyster beds. PMID- 28018664 TI - Altered expression of pectoral myosin heavy chain isoforms corresponds to migration status in the white-crowned sparrow (Zonotrichia leucophrys gambelii). AB - Birds undergo numerous changes as they progress through life-history stages, yet relatively few studies have examined how birds adapt to both the dynamic energetic and mechanical demands associated with such transitions. Myosin heavy chain (MyHC) expression, often linked with muscle fibre type, is strongly correlated with a muscle's mechanical power-generating capability, thus we examined several morphological properties, including MyHC expression of the pectoralis, in a long-distance migrant, the white-crowned sparrow (Zonotrichia leucophrys gambelii) throughout the progression from winter, spring departure and arrival on breeding grounds. White-crowned sparrows demonstrated significant phenotypic flexibility throughout the seasonal transition, including changes in prealternate moult status, lipid fuelling, body condition and flight muscle morphology. Pectoral MyHC expression also varied significantly over the course of the study. Wintering birds expressed a single, newly classified adult fast 2 isoform. At spring departure, pectoral isoform expression included two MyHC isoforms: the adult fast 2 isoform along with a smaller proportion of a newly present adult fast 1 isoform. By spring arrival, both adult fast isoforms present at departure remained, yet expression had shifted to a greater relative proportion of the adult fast 1 isoform. Altering pectoral MyHC isoform expression in preparation for and during spring migration may represent an adaptation to modulate muscle mechanical output to support long-distance flight. PMID- 28018665 TI - Domain-specific functions of Stardust in Drosophila embryonic development. AB - In Drosophila, the adaptor protein Stardust is essential for the stabilization of the polarity determinant Crumbs in various epithelial tissues, including the embryonic epidermis, the follicular epithelium and photoreceptor cells of the compound eye. In turn, Stardust recruits another adaptor protein, PATJ, to the subapical region to support adherens junction formation and morphogenetic events. Moreover, Stardust binds to Lin-7, which is dispensable in epithelial cells but functions in postsynaptic vesicle fusion. Finally, Stardust has been reported to bind directly to PAR-6, thereby linking the Crumbs-Stardust-PATJ complex to the PAR-6/aPKC complex. PAR-6 and aPKC are also capable of directly binding Bazooka (the Drosophila homologue of PAR-3) to form the PAR/aPKC complex, which is essential for apical-basal polarity and cell-cell contact formation in most epithelia. However, little is known about the physiological relevance of these interactions in the embryonic epidermis of Drosophila in vivo. Thus, we performed a structure-function analysis of the annotated domains with GFP-tagged Stardust and evaluated the localization and function of the mutant proteins in epithelial cells of the embryonic epidermis. The data presented here confirm a crucial role of the PDZ domain in binding Crumbs and recruiting the protein to the subapical region. However, the isolated PDZ domain is not capable of being recruited to the cortex, and the SH3 domain is essential to support the binding to Crumbs. Notably, the conserved N-terminal regions (ECR1 and ECR2) are not crucial for epithelial polarity. Finally, the GUK domain plays an important role for the protein's function, which is not directly linked to Crumbs stabilization, and the L27N domain is essential for epithelial polarization independently of recruiting PATJ. PMID- 28018666 TI - Correction to 'Oldest fossil remains of the enigmatic pig-footed bandicoot show rapid herbivorous evolution'. AB - [This corrects the article DOI: 10.1098/rsos.160089.]. PMID- 28018667 TI - A continuous ideal free distribution approach to the dynamics of selfish, cooperative and kleptoparasitic populations. AB - Population distributions depend upon the aggregate behavioural responses of individuals to a range of environmental factors. We extend a model of ideally motivated populations to describe the local and regional consequences of interactions between three populations distinguished by their levels of cooperation and exploitation. Inspired by the classic prisoner's dilemma game, stereotypical fitness functions describe a baseline non-cooperative population whose per capita fitness decreases with density, obligate co-operators who initially benefit from the presence of conspecifics, and kleptoparasites who require heterospecifics to extract resources from the environment. We examine these populations in multiple combinations, determine where both local and regional coexistence is permitted, and investigate conditions under which one population will invade another. When they invade co-operators in resource-rich areas, kleptoparasites initiate a dynamic instability that leads to the loss of both populations; however, selfish hosts, who can persist at low densities, are immune to this risk. Furthermore, adaptive movement may delay the onset of instability as dispersal relieves dynamic stress. Selfish and cooperative populations default to mutual exclusion, but asymmetric variations in interference strength may relax this condition and permit limited sympatry within the environment. Distinct sub-communities characterize the overall spatial structure. PMID- 28018668 TI - Matrix basis for plane and modal waves in a Timoshenko beam. AB - Plane waves and modal waves of the Timoshenko beam model are characterized in closed form by introducing robust matrix basis that behave according to the nature of frequency and wave or modal numbers. These new characterizations are given in terms of a finite number of coupling matrices and closed form generating scalar functions. Through Liouville's technique, these latter are well behaved at critical or static situations. Eigenanalysis is formulated for exponential and modal waves. Modal waves are superposition of four plane waves, but there are plane waves that cannot be modal waves. Reflected and transmitted waves at an interface point are formulated in matrix terms, regardless of having a conservative or a dissipative situation. The matrix representation of modal waves is used in a crack problem for determining the reflected and transmitted matrices. Their euclidean norms are seen to be dominated by certain components at low and high frequencies. The matrix basis technique is also used with a non local Timoshenko model and with the wave interaction with a boundary. The matrix basis allows to characterize reflected and transmitted waves in spectral and non spectral form. PMID- 28018669 TI - Effects of omeprazole or pantoprazole on platelet function in non-ST-segment elevation acute coronary syndrome patients receiving clopidogrel. AB - BACKGROUND: This study evaluated the effect of omeprazole or pantoprazole on platelet reactivity in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients receiving clopidogrel. METHODS: Consecutive patients with NSTE-ACS (n = 620) from general hospital of Shenyang Military Command were randomized to the omeprazole or pantoprazole (20 mg/d) group (1:1), and received routine dual antiplatelet treatment. Patients' reversion rate of adenosine diphosphate-induced platelet aggregation (ADP-PA) was assessed at baseline, 12 to 24 h after administration of medication, and after 72 h of percutaneous coronary intervention (PCI). The primary endpoint of the study was platelet reactivity assessed with ADP-PA at 30 days after PCI. Adverse events (AEs) were recorded for 30-day and 180-day follow-up periods. RESULTS: There were no significant differences between both the groups in platelet response to clopidogrel at 12-24 h after drug administration (54.09% +/- 18.90% vs 51.62% +/- 19.85%, P = 0.12), 72 h after PCI (52.15% +/- 19.45% vs 49.66% +/- 20.05%, P = 0.18), and 30 days after PCI (50.44% +/- 14.54% vs 48.52% +/- 15.08%, P = 0.17). The rate of AEs did not differ significantly between groups during the 30-day (15.2% vs 14.8%, P = 0.91) and 180-day (16.5% vs 14.5%, P = 0.50) follow-up periods after PCI. CONCLUSIONS: The addition of omeprazole or pantoprazole to clopidogrel did not restrict the effect of platelet aggregation by reducing the conversion of clopidogrel. Compared with clopidogrel alone, pantoprazole-clopidogrel and omeprazole-clopidogrel combinations did not increase the incidence of adverse clinical events during 30-day and 180-day follow-up periods after PCI. TRIAL REGISTRATION: The study is registered in the National Institutes of Health website with identifier NCT01735227. Registered 14 November 2012. PMID- 28018670 TI - Inferior Oblique Weakening and Abnormal Head Position: Controlled Myotomy versus Recession. AB - Purpose. Randomized controlled trial aimed at comparing surgical outcomes in a group of patients suffering from hyperfunction of the inferior oblique (IO) muscle with abnormal head position (AHP). The surgical techniques being compared are Recession and (thread) Controlled Myotomy. Materials and Methods. The group of 20 patients suffering from medium-high hyperfunction of the IO was assessed through an ophthalmological and orthoptic examination. 10 patients underwent traditional Recession (Group A) and 10 were treated with Controlled Myotomy (Group B). Results. The average age was 19 years +/- 10.7 SD. After 1 year, 20% of Group A showed a small Vertical Deviation associated with a small AHP, while 80% had orthophoria and 40% of them had a small AHP. 80% of Group B showed a small Vertical Deviation associated with an equally small AHP, while 20% had orthophoria with a full resolution of AHP. Conclusion. Based on the results obtained and the fewer intrasurgical risks involved, thread Controlled Myotomy proved to be a valid alternative to Recession. Furthermore, in case of Recession, over the long period a small residual AHP remained in the patients who had orthophoria, unlike Myotomy which led to a total resolution. PMID- 28018671 TI - Accelerated Corneal Collagen Cross-Linking Using Topography-Guided UV-A Energy Emission: Preliminary Clinical and Morphological Outcomes. AB - Purpose. To assess the clinical and morphological outcomes of topography-guided accelerated corneal cross-linking. Design. Retrospective case series. Methods. 21 eyes of 20 patients with progressive keratoconus were enrolled. All patients underwent accelerated cross-linking using an ultraviolet-A (UVA) exposure with an energy release varying from 7.2 J/cm2 up to 15 J/cm2, according to the topographic corneal curvature. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity, topography, in vivo confocal microscopy (IVCM), and anterior segment optic coherence tomography (AS-OCT) were evaluated preoperatively and at the 1, 3, 6, and 12 months postoperatively. Results. 12 months after surgery UDVA and CDVA did not significantly vary from preoperative values. The average topographic astigmatism decreased from -4.61 +/- 0.74 diopters (D) to -3.20 +/- 0.81 D and coma aberration improved from 0.95 +/- 0.03 MUm to 0.88 +/- 0.04 MUm after surgery. AS-OCT and IVCM documented differential effects on the treated areas using different energies doses. The depths of demarcation line and keratocyte apoptosis were assessed. Conclusions. Preliminary results show correspondence between the energy dose applied and the microstructural stromal changes induced by the cross-linking at various depths in different areas of treated cornea. One year after surgery a significant reduction in the topographic astigmatism and comatic aberration was detected. None of the patients developed significant complications. PMID- 28018672 TI - Acute Acquired Comitant Esotropia in Adults: Is It Neurologic or Not? AB - Objectives. Acute acquired comitant esotropia (AACE) can be a diagnostic challenge for ophthalmologists and neurologists because of its association with neurological pathologies. Our study describes a series of adult patients with AACE of undetermined etiology. Methods. Data on the clinical findings of patients presented with AACE of undetermined etiology with a minimum follow-up of 1 year were retrieved from the medical records and the results analyzed. Results. A series of 9 esotropia cases (age range: 20-43 years) was reviewed. All patients had full duction and versions, without an A-pattern or V-pattern. All patients had esotropia for distance and near. Neurological evaluation in all cases was normal. Among patients, 3 were treated with prisms, 4 were treated with strabismus surgery, and 1 was treated with botulinum toxin injections; 1 patient declined treatment. In treated patients posttreatment sensory testing indicated restoration of binocularity that remained stable throughout follow-up of 1-9 years. The patient that declined treatment had binocular function with base-out prisms. Conclusion. Acute onset esotropia may be seen without a neurological pathology in adults. Good motor and sensory outcomes can be achieved in these patients with AACE of undetermined etiology via surgical and nonsurgical methods. PMID- 28018673 TI - Caregivers Lack of Disclosure Skills Delays Disclosure to Children with Perinatal HIV in Resource-Limited Communities: Multicenter Qualitative Data from South Africa and Botswana. AB - To promote the appropriate implementation of procedures for health disclosure to children, it is important to understand the reasons why caregivers delay the disclosure of healthcare information to children. This paper explored the views of caregivers on what makes disclosure to children with perinatal acquired HIV (PAH) difficult and what could make disclosure in these cases easier. Data were collected using focus group interviews with caregivers who were purposely selected from a multicenter study conducted in Botswana and South Africa. Forty seven nondisclosed caregivers of children between 5 and 18 years who were receiving ART were interviewed. Caregivers felt that children should be told of their HIV-positive status despite the fact that none had disclosed this information to the children. The caregivers reported lack of disclosure skills but believed they were primarily responsible for disclosure to children and required support from healthcare workers (HCWs) during the disclosure process. They believed that counseling on how to approach disclosure and training on when and how to disclose will make the disclosure process easier. HCWs have a crucial role to play in promoting disclosure to perinatally infected children. The development of appropriate disclosure guidelines and training for HCWs will facilitate disclosure to children. PMID- 28018674 TI - Early-Phase Recovery of Cardiorespiratory Measurements after Maximal Cardiopulmonary Exercise Testing in Patients with Chronic Obstructive Pulmonary Disease. AB - Background. This study investigated respiratory gas exchanges and heart rate (HR) kinetics during early-phase recovery after a maximal cardiopulmonary exercise test (CPET) in patients with chronic obstructive pulmonary disease (COPD) grouped according to airflow limitation. Methods. Thirty control individuals (control group: CG) and 81 COPD patients (45 with "mild" or "moderate" airflow limitation, COPDI-II, versus 36 with "severe" or "very severe" COPD, COPDIII-IV) performed a maximal CPET. The first 3 min of recovery kinetics was investigated for oxygen uptake ([Formula: see text]O2), minute ventilation ([Formula: see text]), respiratory equivalence, and HR. The time for [Formula: see text]O2 to reach 25% (T1/4[Formula: see text]O2) of peak value was also determined and compared. Results. The [Formula: see text]O2, [Formula: see text], and HR recovery kinetics were significantly slower in both COPD groups than CG (p < 0.05). Moreover, COPDIII-IV group had significantly higher [Formula: see text]O2 and [Formula: see text] during recovery than COPDI-II group (p < 0.05). T1/4[Formula: see text]O2 significantly differed between groups (p < 0.01; 58 +/- 18 s in CG, 79 +/- 26 s in COPDI-II group, and 121 +/- 34 s in COPDIII-IV) and was significantly correlated with forced expiratory volume in one second in COPD patients (p < 0.001, r = 0.53) and with peak power output (p < 0.001, r = 0.59). Conclusion. The COPD groups showed slower kinetics in the early recovery period than CG, and the kinetics varied with severity of airflow obstruction. PMID- 28018675 TI - Description of Ictal HFO Mapping in Patients with Both Temporal and Extratemporal Seizure Focus. AB - Objective. Review presurgical use of ictal HFO mapping to detect ictal activation areas with dual seizure focus in both the temporal and extratemporal cortex. Methods. Review of consecutive patients admitted to the University of South Alabama Epilepsy Monitoring Unit (SouthCEP) between January 2014 and October 2015, with suspected temporal lobe epilepsy and intracranial electrode recording. Ictal HFO localization was displayed in 3D reconstructed brain images using the patient's own coregistered magnetic resonance imaging (MRI) and computed tomography (CT) with the implanted electrodes. Results. Four of fifteen patients showed evidence of extratemporal involvement at the onset of the clinical seizures. Ictal HFO mapping involving both frontal and temporal lobe changed the surgical resection areas in three patients where the initial surgical plan included only the temporal lobe. Resection of the ictal HFO at the onset of the seizure and the initial propagation region was associated with seizure freedom in all patients; follow-up period ranged from 12 to 25 months. Significance. Extratemporal ictal involvement may not have clinical manifestations and may account for surgical failure in temporal lobe epilepsy. Ictal HFO mapping is useful to define the ictal cortical network and may help detect an extratemporal focus. PMID- 28018676 TI - Increased Serum Levels of Tumor Necrosis Factor-Alpha, Resistin, and Visfatin in the Children with Autism Spectrum Disorders: A Case-Control Study. AB - Background. Autism spectrum disorders (ASDs) are complex disorders where the pathogenesis is not fully understood. Several proinflammatory and immunoinflammatory disturbances have been observed in the etiology of ASD. There is, however, limited knowledge on variations of adipokines in ASD. The present study aimed to analyze the serum levels of resistin, visfatin, and tumor necrosis factor-alpha (TNF-alpha) in children with ASD in relation to body weight, gender, and ASD severity level. Method. In total, 30 children with ASD (mean age: 7.72 +/ 2.65 y; range; 4-12 y) and 30 healthy children (mean age: 8.4 +/- 2.66 y; range: 4-12 y), including males and females, were matched for age, gender, and body mass index (BMI). Serum samples were collected, and visfatin, resistin, and TNF-alpha serum levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Result. Serum visfatin, resistin, and TNF-alpha levels in children with ASD were significantly higher than that in the healthy patients (p < 0.05). Two significant correlations were found: a correlation between resistin and visfatin with TNF-alpha in children with ASD (R = 0.8 and R = 0.62, resp.) and a correlation between resistin and visfatin in children with ASD (R = 0.66). Conclusion. Higher TNF-alpha, resistin, and visfatin levels were found in children with ASD in comparison with controls, suggesting that elevated levels of serum proinflammatory agents may be implicated in the pathophysiology of ASD. PMID- 28018677 TI - Decreased Serum 25-hydroxyvitamin D Level Causes Interventricular Septal Hypertrophy in Patients on Peritoneal Dialysis: Cardiovascular Aspects of Endogenous Vitamin D Deficiency. AB - Introduction. In the present study, we aimed to analyze the relation of vitamin D with echocardiographic indexes in patients with end stage renal disease (ESRD) receiving renal replacement therapy (RRT). Methods. A total of 98 patients, 64 patients on hemodialysis (HD) (29F/35M, mean age 56.75 +/- 18.63 years) and 34 age matched patients on peritoneal dialysis (PD) (21F/13M, mean age 58.11 +/- 10.63 years), with similar duration of ESRD and RRT were enrolled into this cross sectional study. Echocardiographic examination was performed after dialysis session at normovolemic status. Fasting blood samples were obtained before dialysis session. Results. Patients on PD and female patients in both groups had significantly lower level of 25-OH-D3 level when compared to patients on HD or male patients (p: 0.0001 and p: 0.0001). When all participants were considered, there was no significant association between 25-OH-D3 and echocardiographic parameters; however, in patients on PD, a significant negative correlation was determined between 25-OH-D3 and diastolic blood pressure, interventricular septal hypertrophy (ISH), and left ventricular mass index (LVMI) (r: -0.424, p: 0.012; r: -0.508, p: 0.004; r: 0.489, p: 0.04, resp.). Conclusion. Low serum 25 hydroxyvitamin D levels is associated with ISH and LVMI in PD patients. PMID- 28018679 TI - Activation of Sphingosine 1-Phosphate Receptor 1 Enhances Hippocampus Neurogenesis in a Rat Model of Traumatic Brain Injury: An Involvement of MEK/Erk Signaling Pathway. AB - Among sphingosine 1-phosphate receptors (S1PRs) family, S1PR1 has been shown to be the most highly expressed subtype in neural stem cells (NSCs) and plays a crucial role in the migratory property of NSCs. Recent studies suggested that S1PR1 was expressed abundantly in the hippocampus, a specific neurogenic region in rodent brain for endogenous neurogenesis throughout life. However, the potential association between S1PR1 and neurogenesis in hippocampus following traumatic brain injury (TBI) remains unknown. In this study, the changes of hippocampal S1PR1 expression after TBI and their effects on neurogenesis and neurocognitive function were investigated, focusing on particularly the extracellular signal-regulated kinase (Erk) signaling pathway which had been found to regulate multiple properties of NSCs. The results showed that a marked upregulation of S1PR1 occurred with a peak at 7 days after trauma, revealing an enhancement of proliferation and neuronal differentiation of NSCs in hippocampus due to S1PR1 activation. More importantly, it was suggested that mitogen activated protein kinase-Erk kinase (MEK)/Erk cascade was required for S1PR1 meidated neurogenesis and neurocognitive recovery following TBI. This study lays a preliminary foundation for future research on promoting hippocampal neurogenesis and improving TBI outcome. PMID- 28018680 TI - Distinctive Structural and Effective Connectivity Changes of Semantic Cognition Network across Left and Right Mesial Temporal Lobe Epilepsy Patients. AB - Occurrence of language impairment in mesial temporal lobe epilepsy (mTLE) patients is common and left mTLE patients always exhibit a primary problem with access to names. To explore different neuropsychological profiles between left and right mTLE patients, the study investigated both structural and effective functional connectivity changes within the semantic cognition network between these two groups and those from normal controls. We found that gray matter atrophy of left mTLE patients was more severe than that of right mTLE patients in the whole brain and especially within the semantic cognition network in their contralateral hemisphere. It suggested that seizure attacks were rather targeted than random for patients with hippocampal sclerosis (HS) in the dominant hemisphere. Functional connectivity analysis during resting state fMRI revealed that subregions of the anterior temporal lobe (ATL) in the left HS patients were no longer effectively connected. Further, we found that, unlike in right HS patients, increased causal linking between ipsilateral regions in the left HS epilepsy patients cannot make up for their decreased contralateral interaction. It suggested that weakened contralateral connection and disrupted effective interaction between subregions of the unitary, transmodal hub of the ATL may be the primary cause of anomia in the left HS patients. PMID- 28018678 TI - Risk Factors for Postoperative Urinary Tract Infections in Patients Undergoing Total Joint Arthroplasty. AB - Background. Urinary tract infections (UTIs) are the most common minor complication following total joint arthroplasty (TJA) with incidence as high as 3.26%. Bladder catheterization is routinely used during TJA and the Centers for Medicare and Medicaid Services (CMS) has recently identified hospital-acquired catheter associated UTI as a target for quality improvement. This investigation seeks to identify specific risk factors for UTI in TJA patients. Methods. We retrospectively studied patients undergoing TJA for osteoarthritis between 2006 and 2013 in the American College of Surgeon's National Surgical Improvement Program Database (ACS-NSQIP). A univariate analysis screen followed by multivariate logistic regression identified specific patient demographics, comorbidities, preoperative laboratory values, and operative characteristics independently associated with postoperative UTI. Results. 1,239 (1.1%) of 115,630 TJA patients we identified experienced a postoperative UTI. The following characteristics are independently associated with postoperative UTI: female sex (OR 2.1, 95% CI 1.6-2.7), chronic steroid use (OR 2.0, 95% CI 1.2-3.2), ages 60 69 (OR 1.5, 95% CI 1.0-2.1), 70-79 (OR 2.0, 95% CI 1.4-2.9), and >=80 (OR 2.3, 95% CI 1.5-3.6), ASA Classes 3-5 (OR 1.5, 95% CI 1.2-1.9), preoperative creatinine >1.35 (OR 1.8, 95% CI 1.3-2.6), and operation time greater than 130 minutes (OR 1.8, 95% CI 1.3-2.4). Conclusions. In this large database query, postoperative UTI occurs in 1.1% of patients following TJA and several variables including female sex, age greater than 60, and chronic steroid use are independent risk factors for occurrence. Practitioners should be aware of populations at greater risk to support efforts to comply with CMS initiated quality improvement. PMID- 28018684 TI - A Large Isolated Hydatid Cyst of the Adrenal Gland: A Case Report and Review of the Literature. AB - A 44-year-old patient presented with two-year history of (R) lumbar pain. There was a strong history of childhood animals' contact, including dogs. A brother had multiple hydatid cysts requiring surgery. Initial ultrasound showed a large (R) adrenal mass measuring 10 * 9 * 8 cm. Subsequent CT scan confirmed a heavily calcified cyst in the (R) adrenal gland. Hormonal studies were normal. He had an uneventful course following a total adrenalectomy. Isolated adrenal hydatid is extremely rare with an incidence of less than 0.5%; however, the diagnosis should always be suspected in all patients from an endemic area presenting with an adrenal cystic mass. PMID- 28018685 TI - Coexistence of Factor VII Deficiency and Hereditary Spastic Paraplegia in Two Siblings. AB - We present the case of two patients aged 12 years and 7 years who were referred to our hospital for factor VII deficiency inherited in an autosomal recessive pattern, who had suffered from previous multiple joint haemarthroses. They presented with fine motor symptoms and difficulty in walking. During physical examination we observed neurological symptoms (general hypotonia, muscular hypotrophy, exaggerated tendon reflexes, pes cavus, and spastic gait). Given that the symptoms were not justified by the deficiency of coagulation factor VII and on suspicion of hereditary spastic paraplegia (HSP), tests were carried out. Findings from the tests confirmed the diagnosis of HSP (axonal degeneration of the central motor pathway and pyramidal tracts), further complicated by mixed neuropathy. This disease was also inherited in an autosomal recessive pattern with no direct genetic association with factor VII deficiency. Neurological symptoms had gone unnoticed due to a history of multiple joint haemarthrosis; musculoskeletal examination led to a satisfactory differential diagnosis. Haematological prophylaxis was commenced with rFVIIa at 30 mcg/kg, three days per week. A rehabilitation programme was prescribed so that the patient could remain independent for as long as possible, based on orthosis, physiotherapy, and occupational therapy. Response to treatment is currently satisfactory and no new bleeding has presented. As far as we are aware, the coexistence of these two diseases (factor VII deficiency and HSP) has not been previously reported in the literature. PMID- 28018681 TI - Unilateral Vocal Cord Paralysis following Insertion of a Supreme Laryngeal Mask in a Patient with Sjogren's Syndrome. AB - Since its introduction in 1988 by Dr. Archie Brain, the laryngeal mask airway (LMA) is being used with increasing frequency. Its ease of use has made it a very popular device in airway management and compared to endotracheal intubation it is less invasive. The use of LMA was on the rise, so has been the incidence of its related complications. We report severe unilateral vocal cord paralysis following the use of the supreme laryngeal mask (sLMA) in a patient with Sjogren's syndrome. In addition, we propose possible mechanisms of injury, review the existing case reports, and discuss our findings. PMID- 28018683 TI - Nodular Fasciitis Complicating a Staged Surgical Excision of Dermatofibrosarcoma Protuberans. AB - Dermatofibrosarcoma protuberans (DFSP) is an unusual spindle cell tumor with a high rate of local recurrence with traditional excision. Fortunately, Mohs micrographic surgery yields excellent cure rates for this neoplasm due to contiguous tumor spread and meticulous tumor mapping and margin analysis. We present the unique case of a patient treated with a modified Mohs technique with an analysis of the final margin with permanent sections, who developed a spindle cell neoplasm in the margins of her second stage excision consistent with nodular fasciitis. Distinguishing residual DFSP from a benign reactive process was an essential and challenging component of this patient's management. PMID- 28018682 TI - Bent Metal in a Bone: A Rare Complication of an Emergent Procedure or a Deficiency in Skill Set? AB - Intraosseous (IO) access is an important consideration in patients with difficult intravenous (IV) access in emergent situations. IO access in adults has become more popular due to the ease of placement and high success rates. The most common sites of access include the proximal tibia and the humeral head. The complications associated are rare but can be catastrophic: subsequent amputation of a limb has been described in the literature. We report a 25-year-old female presenting with diabetic ketoacidosis (DKA) in whom emergent IO access was complicated by needle bending inside the humerus. Conventional bedside removal was impossible and required surgical intervention in operating room. PMID- 28018687 TI - Fatal Dengue Myocarditis despite the Use of Extracorporeal Membrane Oxygenation. AB - Dengue is an important mosquitoes-borne viral disease which is endemic in tropics and subtropics region. Rapid spreading of disease to previously unaffected region was found in recent years. Atypical manifestations, such as myocarditis, were reported during large outbreak. There is a wide range of clinical manifestations of cardiac involvement in dengue, but rarely fatal. Here we reported a case of fulminant dengue myocarditis in fatal outcome despite cardiac mechanical support. PMID- 28018688 TI - Nigerian Female with Skin Lesions in the Leg and Face: Herpetic Sycosis Folliculitis. AB - Nongenital HSV 1 presents outside the mucus membrane. Our patient had unusual presentation that caused diagnostic dilemma. 30-year-old native Nigerian female coming with fiancee to the United States presented to our service one day after arrival through ER with a lesion on her right ankle. She was diagnosed with cellulitis, started on antibiotics, and admitted to hospital. She had fever of 39.1 degrees C. Head and neck exam showed multiple sized lesions over tongue and palate and inner aspect of lower lip. Abdomen and genital exam was normal. Skin exam showed lesions over the face and lesions over the lateral aspect of the right leg. There was ulcerated lesion over the right lateral malleolus with surrounding erythema and edema. Her tests showed elevated ESR of 98; HIV test was negative; CT scan of the ankle showed no abscess or osteomyelitis. TB quantiferon was indeterminate; AFB stain and culture were negative; HSV IgM was elevated at 1 : 16; RPR was negative; ANA was negative; malaria screen was negative, and blood cultures were negative for bacteria, fungus, and virus. Debrided wound had no growth of bacteria or fungus or virus. This case illustrates the unusual presentation of the HSV1 outside the mucus membrane and how it can be confused with other conditions that required extensive tests. Therapeutic trail with antiviral medications resolved lesions over the leg and face. PMID- 28018689 TI - Cryptococcus gattii in an Immunocompetent Patient in the Southeastern United States. AB - Cryptococcal infections are seen throughout the United States in both immunocompromised and immunocompetent patients. The most common form is C. neoformans. In the Northwestern United States, C. gattii has received considerable attention secondary to increased virulence resulting in significant morbidity and mortality. There are no cases in the extant literature describing a patient with C. gattii requiring neurosurgical intervention in Alabama. A middle aged immunocompetent male with no recent travel or identifiable exposure presented with meningitis secondary to C. gattii. The patient underwent 12 lumbar punctures and a ventriculoperitoneal shunt and required 83 days of inpatient therapy with 5-flucytosine and amphotericin B. The patient was found to have multiple intracranial lesions and a large intramedullary spinal cryptococcoma within his conus. Following an almost 3-month hospitalization the patient required treatment with oral voriconazole for one year. In the United States meningitis caused by C. gattii infection is not isolated to the Northwestern region. PMID- 28018686 TI - Minimally Invasive Diagnosis of Secondary Intracranial Lymphoma. AB - Diffuse large B cell lymphomas (DLBCL) are an aggressive group of non-Hodgkin lymphoid malignancies which have diverse presentation and can have high mortality. Central nervous system relapse is rare but has poor survival. We present the diagnosis of primary mandibular DLBCL and a unique minimally invasive diagnosis of secondary intracranial recurrence. This case highlights the manifold radiological contributions to the diagnosis and management of lymphoma. PMID- 28018690 TI - Multiple Renal Abscesses due to ESBL Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Causing Acute Pyelonephritis and Bacteremia: A Case Report with a Good Outcome (No Drainage Required). AB - Extended-spectrum beta-lactamase-producing Enterobacteriaceae urinary tract infections are challenging infections with increased mortality, morbidity, and failure of therapy. A 44-year-old Saudi male diabetic patient was seen at the ER of IMC Hospital with features of acute pyelonephritis: fever, burning urine, and left flank pain for three days. He was treated for cystitis at the Endocrine Clinic two weeks prior to his ER visit with nitrofurantoin and levofloxacin orally according to urine culture and sensitivity result. The patient was admitted, received IV meropenem, and continued to be febrile for three days. His urine and blood culture at ER grew the same ESBL-producing E. coli as in his urine culture from the Endocrine Clinic. His abdomen CT scan showed two left renal abscesses at the upper and middle poles. His temperature resolved on the fourth day of IV therapy. Intravenous meropenem was continued for 4 weeks after inserting PICC line and the patient was followed up by home healthcare. He was feeling better with occasional left flank pain and repeated abdomen CT scan showed complete resolution of both renal abscesses. PMID- 28018691 TI - Intra-Attack Vestibuloocular Reflex Changes in Meniere's Disease. AB - Meniere's attack has been shown to temporarily alter the vestibuloocular reflex (VOR). A patient with unilateral Meniere's disease was serially evaluated with the video Head Impulse Test during single, untreated episodes of acute vertigo. Spontaneous nystagmus activity was concurrently recorded in order to establish the three typical phases of Meniere's attack (irritative, paralytic, and recovery) and correlate them with VOR performance. The onset of attack was associated with a quick change in VOR gain on the side of the affected ear. While a rapidly progressive reduction of the VOR was evident at the paralytic nystagmus phase, in the recovery phase the VOR gain returned to normal and the direction of the previous nystagmus reversed. The membrane rupture potassium intoxication theory provides a good foundation with which to explain these dynamic VOR changes and the observed triphasic direction behavior of the spontaneous nystagmus. We additionally postulated that endolymphatic fluid displacement could have a synergic effect during the earliest phase of attack. PMID- 28018692 TI - Sudden Sensorineural Hearing Loss in the Only Hearing Ear: Large Vestibular Aqueduct Syndrome. AB - Sudden hearing loss in the only hearing ear cases are rarely published in the English literature; most of the cases are idiopathic. It is an otologic emergency needing urgent treatment. Delayed diagnosis can interfere with patient's social life with interrupting the verbal communication. In this case report we presented a 33-year-old female patient having sudden sensorineural hearing loss in the only hearing ear diagnosed as bilateral large vestibular aqueduct syndrome. PMID- 28018693 TI - Stickler Syndrome Type 1 with Short Stature and Atypical Ocular Manifestations. AB - Stickler syndrome or hereditary progressive arthroophthalmopathy is a heterogeneous group of collagen tissue disorders, characterized by orofacial features, ophthalmological features (high myopia, vitreoretinal degeneration, retinal detachment, and presenile cataracts), hearing impairment, mild spondyloepiphyseal dysplasia, and/or early onset arthritis. Stickler syndrome type I (ocular form) is caused by mutation in the COL2A1 gene. Ptosis and uveitis are relatively rare ophthalmological manifestations of this syndrome. We report an Indian boy having 2710C>T mutation in COL2A1 gene demonstrating short stature, ptosis, and uveitis with Stickler syndrome. PMID- 28018694 TI - Anterior Hypopituitarism and Treatment Response in Hunter Syndrome: A Comparison of Two Patients. AB - Hypopituitarism is a clinically important diagnosis and has not previously been reported in Hunter syndrome. We contrast two cases with anatomic pituitary anomalies: one with anterior panhypopituitarism and the other with intact pituitary function. Patient 1, a 10-year-old boy with Hunter syndrome, was evaluated for poor growth and an ectopic posterior pituitary gland. Endocrine testing revealed growth hormone (GH) deficiency, secondary adrenal insufficiency, and tertiary hypothyroidism. An improvement in growth velocity with hormone replacement (GH, thyroxine, and corticosteroid) was seen; however, final adult height remained compromised. Patient 2, a 13-year-old male with Hunter syndrome, was evaluated for growth failure. He had a large empty sella turcica with posteriorly displaced pituitary. Functional endocrine testing was normal and a trial of GH-treatment yielded no significant effect. Panhypopituitarism associated with pituitary anomalies has not been previously reported in Hunter syndrome and was an incidental finding of significant clinical importance. In the setting of documented anterior hypopituitarism, while hormone replacement improved growth velocity, final height remained impaired. In patient 2 with equivocal GH-testing results, treatment had no effect on linear growth. These cases highlight the importance of careful clinical assessment in Hunter syndrome and that judicious hormone replacement may be indicated in individual cases. PMID- 28018695 TI - From Benign to Malign in a Case of Cervical Adenopathy in a 17-Year-Old Adolescent: Diagnostic Traps. AB - Distinguishing between benign and malign adenopathies remains a challenge and could represent a source of error in a diagnosis. We report a case of right laterocervical adenopathy in a 17-year-old teenager admitted to hospital with an episode of fever associated with dysphagia, congested pharynx, and pultaceous deposits. Initially the adenopathy was considered to be secondary to a coinfection with Streptococcus B-hemolytic and Epstein-Barr virus, as suggested by the positive bacteriological and serological tests. The onset of the adenopathy before the episode and the ultrasound modifications raised the suspicion of a malignancy, later confirmed by the histopathologic examination of the lymph node excision. The final diagnosis was nodal metastasis of an undifferentiated lymphoepithelial carcinoma with an ENT starting point. Currently, the adolescent is hospitalised in the ENT ward, where the pharynx carcinoma with nodal metastasis was confirmed. Sometimes the infectious context can mask or unmask a malign chronic disease with insidious evolution. PMID- 28018697 TI - Self-Limited Kleptomania Symptoms as a Side Effect of Duloxetine. AB - Introduction. Impulse control disorders (ICDs) have been described as a side effect of dopamine agonists, frequently used in neurodegenerative conditions affecting the nigrostriatal pathway. Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine) have dose-dependent differential affinity for monoaminergic transporters, inhibiting the dopamine transporter at higher doses, thus increasing availability of synaptic dopamine, with the potential for similar impulse control side effects. Case Presentation. A 19-year-old Asian-American female with a history of depression developed new-onset stealing behaviors after an increase in her dose of duloxetine from 60 mg to 90 mg; she described these actions as "compulsive" and irresistible, later experiencing either relief or guilt, features compatible with an ICD. Her symptoms eventually subsided with continued use of 90 mg of duloxetine. Discussion. To the knowledge of the authors, this is the first report of a patient developing new-onset ICD behaviors after being placed on a higher dose of duloxetine, which can inhibit the dopamine transporter and cause difficulty with impulse control. The self-resolving nature of the symptoms may result from compensatory upregulation of dopamine transporters, increasing reuptake of dopamine. Asian populations may be at a higher risk due to the frequent occurrence of CYP2D6 polymorphisms, which decrease the conversion of duloxetine to its inactive metabolites. PMID- 28018698 TI - Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease. AB - Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases. PMID- 28018696 TI - Alagille Syndrome: A Case Report Highlighting Dysmorphic Facies, Chronic Illness, and Depression. AB - Alagille syndrome is a rare multisystem disorder affecting the liver, heart, vertebrae, eyes, and face. Alagille syndrome shares multiple phenotypic variants of other congenital or chronic childhood illnesses such as DiGeorge syndrome, Down syndrome, spina bifida, type 1 diabetes mellitus, and cystic fibrosis. All of these chronic illnesses have well-established links to psychiatric conditions. There are few community resources for Alagille patients, as it is an extremely rare condition. Despite the overlap with other chronic childhood illnesses, the psychiatric manifestations of Alagille syndrome have not been previously discussed in literature. The current study is a case report of a twelve-year-old female hospitalized in our pediatric psychiatric hospital for suicidal ideation with intent and plan. The patient had major depressive disorder, anxiety, other specified feeding and eating disorder, and attention-deficit/hyperactive disorder. PMID- 28018699 TI - Technical Considerations of Giant Right Coronary Artery Aneurysm Exclusion. AB - Giant coronary artery aneurysms are rare clinical entities. We report the case of a 49-year-old man who presented with dyspnoea and exertional chest pain. Investigations confirmed an aneurysmal right coronary artery measuring 4 cm with a fistulous communication to the right atrium. Following right atriotomy, the fistula was oversewn and the aneurysmal right coronary artery ligated at its origin and at several points along its course. A saphenous vein graft was anastomosed to the posterior descending artery. Persistent ventricular fibrillation occurred upon chest closure, attributed to ischaemia following ligation of the aneurysmal coronary artery. Emergent resternotomy and internal defibrillation were successfully performed. The sternum was stented open to reduce right ventricular strain and closed the following day. The patient made an unremarkable recovery. We here address the technical challenges associated with surgical repair of right coronary aneurysms and the physiology and management of potential complications. PMID- 28018700 TI - The Cause of Unexpected Acute Abdomen and Intra-Abdominal Hemorrhage in 24-Week Pregnant Woman: Bochdalek Hernia. AB - Bochdalek hernia (BH) is the most common type of congenital diaphragm hernia and is rarely seen in adults. In adult patients, BH often remains asymptomatic or presents with nondiagnostic symptoms and may lead to complications, though rarely. The necrosis and perforations occurring in the hernia may lead to mortality. In this report, we present a 34-year-old pregnant woman at 24 gestational weeks who presented with Bochdalek hernia causing gastric volvulus associated with perforation and intra-abdominal hemorrhage associated with splenic rupture. PMID- 28018701 TI - Metastatic Inflammatory Myofibroblastic Tumor of the Spleen: A Case Report and Review of the Literature. AB - Introduction. Inflammatory myofibroblastic tumors (IMT) of the spleen are rare neoplasms and only little is known about the origin and behavior of these tumors. Here we report the case of a 37-year-old woman with an atypical spindle cell neoplasm showing features strongly suggesting an IMT of the spleen with hepatic metastasis. Methods. A 37-year-old patient had been complaining about pain in the left upper abdomen for the last two months. A CT scan revealed a tumor mass in her spleen and liver. After complete staging, a splenectomy and atypical liver resection of segments VII and VIII were performed. Literature was screened for similar cases and existing further literature. Results. A R0 resection was achieved. Histological analysis showed a multinodular infiltration of the spleen by an atypical mesenchymal neoplasia. Immunohistochemically there was an expression of histiocytic markers (CD4, CD68) as well as smooth muscle cell markers (SMA, H-Caldesmon) in the tumor cells. A diagnosis of an atypical spindle cell neoplasm showing features most suggestive of an IMT was rendered. Conclusion. Synchronous hepatic metastasis of an IMT of the spleen is a rarity. Therefore no experience in the treatment of these tumors exists. Fibroblastic reticular cell tumor is a differential diagnosis, but differentiation of these two entities is difficult. PMID- 28018702 TI - Laparoscopic Fenestration of a Giant Pseudocyst after Totally Extra Peritoneal Inguinal Hernia Repair. AB - A giant pseudocyst is a rare complication after hernioplasty and is seldom seen. The pathophysiology is unclear; it characteristically does not contain epithelial lining and can be considered giant if the diameter exceeds 10 cm. Pseudocysts are mostly described after incisional hernia repairs and are usually treated with surgical resection. We report a case of a giant pseudocyst three years after totally extra peritoneal inguinal hernia repair. Laparoscopic fenestration without removing the pseudocyst with or without removal of the polypropylene mesh is a safe and effective minimal invasive approach to the treatment of a symptomatic pseudocyst and should also be considered in the approach of other large symptomatic cysts. PMID- 28018703 TI - Successful Stem Cell Transplantation in a Patient with Pretransplant Hepatic Inflammatory Pseudotumour. AB - Inflammatory pseudotumours (IPT) are rare benign neoplasms of unknown aetiology. We present a case of hepatic IPT which was incidentally discovered in a patient with relapsed B-acute lymphoblastic leukaemia (B-ALL) undergoing pretransplant workup. After investigation to exclude an infective cause she underwent a reduced intensity conditioning stem cell transplant (SCT) successfully and currently remains well and in remission. On repeat liver MRI after SCT, the IPT was seen to be resolving. To the best of our knowledge this is the first report of an adult patient with hepatic IPT successfully undergoing SCT. The reduction in size of the IPT after SCT also suggests an inflammatory rather than an infective aetiology for IPT. PMID- 28018704 TI - Synthesis and Characterization of Molecular Imprinting Polymer Microspheres of Piperine: Extraction of Piperine from Spiked Urine. AB - Molecularly imprinted polymer (MIP) microspheres for Piperine were synthesized by precipitation polymerization with a noncovalent approach. In this research Piperine was used as a template, acrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, and 2,2'-azobisisobutyronitrile (AIBN) as an initiator and acetonitrile as a solvent. The imprinted and nonimprinted polymer particles were characterized by using Fourier transform infrared spectroscopy (FT-IR) and Scanning Electron Microscopy (SEM). The synthesized polymer particles were further evaluated for their rebinding efficiency by batch binding assay. The highly selected imprinted polymer for Piperine was MIP 3 with a composition (molar ratio) of 0.5 : 3 : 8, template : monomer : cross-linker, respectively. The MIP 3 exhibits highest binding capacity (84.94%) as compared to other imprinted and nonimprinted polymers. The extraction efficiency of highly selected imprinted polymer of Piperine from spiked urine was above 80%. PMID- 28018705 TI - Antioxidant and Antibacterial Potential of Silver Nanoparticles: Biogenic Synthesis Utilizing Apple Extract. AB - The advancement of the biological production of nanoparticles using herbal extracts performs a significant role in nanotechnology discipline as it is green and does not engage harsh chemicals. The objective of the present investigation was to extract flavonoids in the mode of apple extract and synthesize its silver nanoparticles and ultimately nanoparticles loading into hydrogels. The presence of flavonoids in apple extract was characterized by preliminary testing like dil. ammonia test and confirmatory test by magnesium ribbon test. The synthesized silver nanoparticles were characterized using UV spectroscopy, particle size and surface morphology, and zeta potential. Silver nanoparticles loaded hydrogels were evaluated for physical appearance, pH, viscosity, spreadability, porosity, in vitro release, ex vivo permeation, and antibacterial (E. coli and S. aureus) and antioxidant studies (DPPH radical scavenging assay). Well dispersed silver nanoparticles below were observed in scanning electron microscope image. Hydrogels displayed in vitro release of 98.01% +/- 0.37% up to 24 h and ex vivo permeation of 98.81 +/- 0.24% up to 24 h. Hydrogel effectively inhibited the growth of both microorganism indicating good antibacterial properties. The value of percent radical inhibition was 75.16% +/- 0.04 revealing its high antioxidant properties. As an outcome, it can be concluded that antioxidant and antiageing traits of flavonoids in apple extract plus biocidal feature of silver nanoparticles can be synergistically and successfully utilized in the form of hydrogel. PMID- 28018708 TI - Clinical Outcomes of Descemet Membrane Endothelial Keratoplasty During the Surgeon Learning Curve Versus Descemet Stripping Endothelial Keratoplasty Performed at the Same Time. AB - PURPOSE: To compare outcomes after Descemet Membrane Endothelial Keratoplasty (DMEK) and traditional Descemet Stripping Endothelial Keratoplasty (DSEK) during the surgeon's DMEK learning curve in a prospective, non-randomized, consecutive, interventional case series. METHODS: Consecutive patients presenting to the university eye clinics and undergoing endothelial keratoplasty were included. Data including patient demographics, visual acuity, endothelial cell counts and complications were recorded at baseline, as well as 3 and 6 months post operatively. The primary outcome for this study was BSCVA at 6 months. Pre specified secondary outcomes included endothelial cell counts and complication rates. RESULTS: A total of 60 eyes of 42 consecutive patients met inclusion criteria, underwent endothelial keratoplasty, and were included in this analysis. Of these, 18 eyes of 14 patients had DSEK while 42 eyes of 28 patients had DMEK. After controlling for baseline visual acuity, study participants undergoing DMEK had a statistically significant approximately half-line improvement in visual acuity compared with DSEK at 3 months (P=0.05) but not at 6 months (P=0.22). DMEK patients experienced an average of 43% endothelial cell loss compared with 25% in DSEK. There were 5 primary graft failures after DMEK compared with 0 after DSEK and but this was not a statistically significant difference (P=0.09). CONCLUSION: During the surgeon's DMEK learning curve there was some evidence of improved visual acuity outcomes in DMEK. We observed worse 6-month endothelial cell loss among DMEK patients; however this may improve with surgeon experience. PMID- 28018709 TI - Segmentation guided registration of wide field-of-view retinal optical coherence tomography volumes. AB - Patient motion artifacts are often visible in densely sampled or large wide field of-view (FOV) retinal optical coherence tomography (OCT) volumes. A popular strategy for reducing motion artifacts is to capture two orthogonally oriented volumetric scans. However, due to larger volume sizes, longer acquisition times, and corresponding larger motion artifacts, the registration of wide FOV scans remains a challenging problem. In particular, gaps in data acquisition due to eye motion, such as saccades, can be significant and their modeling becomes critical for successful registration. In this article, we develop a complete computational pipeline for the automatic motion correction and accurate registration of wide FOV orthogonally scanned OCT images of the human retina. The proposed framework utilizes the retinal boundary segmentation as a guide for registration and requires only a minimal transformation of the acquired data to produce a successful registration. It includes saccade detection and correction, a custom version of the optical flow algorithm for dense lateral registration and a linear optimization approach for axial registration. Utilizing a wide FOV swept source OCT system, we acquired retinal volumes of 12 subjects and we provide qualitative and quantitative experimental results to validate the state-of-the-art effectiveness of the proposed technique. The source code corresponding to the proposed algorithm is available online. PMID- 28018711 TI - Cerebral capillary velocimetry based on temporal OCT speckle contrast. AB - We propose a new optical coherence tomography (OCT) based method to measure red blood cell (RBC) velocities of single capillaries in the cortex of rodent brain. This OCT capillary velocimetry exploits quantitative laser speckle contrast analysis to estimate speckle decorrelation rate from the measured temporal OCT speckle signals, which is related to microcirculatory flow velocity. We hypothesize that OCT signal due to sub-surface capillary flow can be treated as the speckle signal in the single scattering regime and thus its time scale of speckle fluctuations can be subjected to single scattering laser speckle contrast analysis to derive characteristic decorrelation time. To validate this hypothesis, OCT measurements are conducted on a single capillary flow phantom operating at preset velocities, in which M-mode B-frames are acquired using a high-speed OCT system. Analysis is then performed on the time-varying OCT signals extracted at the capillary flow, exhibiting a typical inverse relationship between the estimated decorrelation time and absolute RBC velocity, which is then used to deduce the capillary velocities. We apply the method to in vivo measurements of mouse brain, demonstrating that the proposed approach provides additional useful information in the quantitative assessment of capillary hemodynamics, complementary to that of OCT angiography. PMID- 28018707 TI - Recent advances in nano scaffolds for bone repair. AB - Biomedical applications of nanomaterials are exponentially increasing every year due to analogy to various cell receptors, ligands, structural proteins, and genetic materials (that is, DNA). In bone tissue, nanoscale materials can provide scaffold for excellent tissue repair via mechanical stimulation, releasing of various loaded drugs and mediators, 3D scaffold for cell growth and differentiation of bone marrow stem cells to osteocytes. This review will therefore highlight recent advancements on tissue and nanoscale materials interaction. PMID- 28018710 TI - Single cardiac cycle three-dimensional intracoronary optical coherence tomography. AB - While high-speed intracoronary optical coherence tomography (OCT) provides three dimensional (3D) visualization of coronary arteries in vivo, imaging speeds remain insufficient to avoid motion artifacts induced by heartbeat, limiting the clinical utility of OCT. In this paper, we demonstrate development of a high speed intracoronary OCT system (frame rate: 500 frames/s, pullback speed: 100 mm/s) along with prospective electrocardiogram (ECG) triggering technology, which enabled volumetric imaging of long coronary segments within a single cardiac cycle (70 mm pullback in 0.7 s) with minimal cardiac motion artifact. This technology permitted detailed visualization of 3D architecture of the coronary arterial wall of a swine in vivo and fine structure of the implanted stent. PMID- 28018712 TI - Spectral-spatial fusion model for robust blood pulse waveform extraction in photoplethysmographic imaging. AB - Photoplethysmographic imaging is an optical solution for non-contact cardiovascular monitoring from a distance. This camera-based technology enables physiological monitoring in situations where contact-based devices may be problematic or infeasible, such as ambulatory, sleep, and multi-individual monitoring. However, automatically extracting the blood pulse waveform signal is challenging due to the unknown mixture of relevant (pulsatile) and irrelevant pixels in the scene. Here, we propose a signal fusion framework, FusionPPG, for extracting a blood pulse waveform signal with strong temporal fidelity from a scene without requiring anatomical priors. The extraction problem is posed as a Bayesian least squares fusion problem, and solved using a novel probabilistic pulsatility model that incorporates both physiologically derived spectral and spatial waveform priors to identify pulsatility characteristics in the scene. Evaluation was performed on a 24-participant sample with various ages (9-60 years) and body compositions (fat% 30.0 +/- 7.9, muscle% 40.4 +/- 5.3, BMI 25.5 +/- 5.2 kg.m-2). Experimental results show stronger matching to the ground-truth blood pulse waveform signal compared to the FaceMeanPPG (p < 0.001) and DistancePPG (p < 0.001) methods. Heart rates predicted using FusionPPG correlated strongly with ground truth measurements (r2 = 0.9952). A cardiac arrhythmia was visually identified in FusionPPG's waveform via temporal analysis. PMID- 28018713 TI - In vivo label-free lymphangiography of cutaneous lymphatic vessels in human burn scars using optical coherence tomography. AB - We present an automated, label-free method for lymphangiography of cutaneous lymphatic vessels in humans in vivo using optical coherence tomography (OCT). This method corrects for the variation in OCT signal due to the confocal function and sensitivity fall-off of a spectral-domain OCT system and utilizes a single scattering model to compensate for A-scan signal attenuation to enable reliable thresholding of lymphatic vessels. A segment-joining algorithm is then incorporated into the method to mitigate partial-volume effects with small vessels. The lymphatic vessel images are augmented with images of the blood vessel network, acquired from the speckle decorrelation with additional weighting to differentiate blood vessels from the observed high decorrelation in lymphatic vessels. We demonstrate the method with longitudinal scans of human burn scar patients undergoing ablative fractional laser treatment, showing the visualization of the cutaneous lymphatic and blood vessel networks. PMID- 28018714 TI - Multi-modal automatic montaging of adaptive optics retinal images. AB - We present a fully automated adaptive optics (AO) retinal image montaging algorithm using classic scale invariant feature transform with random sample consensus for outlier removal. Our approach is capable of using information from multiple AO modalities (confocal, split detection, and dark field) and can accurately detect discontinuities in the montage. The algorithm output is compared to manual montaging by evaluating the similarity of the overlapping regions after montaging, and calculating the detection rate of discontinuities in the montage. Our results show that the proposed algorithm has high alignment accuracy and a discontinuity detection rate that is comparable (and often superior) to manual montaging. In addition, we analyze and show the benefits of using multiple modalities in the montaging process. We provide the algorithm presented in this paper as open-source and freely available to download. PMID- 28018717 TI - Robust respiration detection from remote photoplethysmography. AB - Continuous monitoring of respiration is essential for early detection of critical illness. Current methods require sensors attached to the body and/or are not robust to subject motion. Alternative camera-based solutions have been presented using motion vectors and remote photoplethysmography. In this work, we present a non-contact camera-based method to detect respiration, which can operate in both visible and dark lighting conditions by detecting the respiratory-induced colour differences of the skin. We make use of the close similarity between skin colour variations caused by the beating of the heart and those caused by respiration, leading to a much improved signal quality compared to single-channel approaches. Essentially, we propose to find the linear combination of colour channels which suppresses the distortions best in a frequency band including pulse rate, and subsequently we use this same linear combination to extract the respiratory signal in a lower frequency band. Evaluation results obtained from recordings on healthy subjects which perform challenging scenarios, including motion, show that respiration can be accurately detected over the entire range of respiratory frequencies, with a correlation coefficient of 0.96 in visible light and 0.98 in infrared, compared to 0.86 with the best-performing non-contact benchmark algorithm. Furthermore, evaluation on a set of videos recorded in a Neonatal Intensive Care Unit (NICU) shows that this technique looks promising as a future alternative to current contact-sensors showing a correlation coefficient of 0.87. PMID- 28018715 TI - Water-equivalent fiber radiation dosimeter with two scintillating materials. AB - An inorganic scintillating material plastic optical fiber (POF) dosimeter for measuring ionizing radiation during radiotherapy applications is reported. It is necessary that an ideal dosimeter exhibits many desirable qualities, including water equivalence, energy independence, reproducibility, dose linearity. There has been much recent research concerning inorganic dosimeters. However, little reference has been made to date of the depth-dose characteristics of dosimeter materials. In the case of inorganic scintillating materials, they are predominantly non water-equivalent, with their effective atomic weight (Zeff) being typically much greater than that of water. This has been a barrier in preventing inorganic scintillating material dosimeter from being used in actual clinical applications. In this paper, we propose a parallel-paired fiber light guide structure to solve this problem. Two different inorganic scintillating materials are embedded separately in the parallel-paired fiber. It is shown that the information of water depth and absorbed dose at the point of measurement can be extracted by utilizing their different depth-dose properties. PMID- 28018716 TI - Machine learning based detection of age-related macular degeneration (AMD) and diabetic macular edema (DME) from optical coherence tomography (OCT) images. AB - Non-lethal macular diseases greatly impact patients' life quality, and will cause vision loss at the late stages. Visual inspection of the optical coherence tomography (OCT) images by the experienced clinicians is the main diagnosis technique. We proposed a computer-aided diagnosis (CAD) model to discriminate age related macular degeneration (AMD), diabetic macular edema (DME) and healthy macula. The linear configuration pattern (LCP) based features of the OCT images were screened by the Correlation-based Feature Subset (CFS) selection algorithm. And the best model based on the sequential minimal optimization (SMO) algorithm achieved 99.3% in the overall accuracy for the three classes of samples. PMID- 28018718 TI - Fractional laser photothermolysis using Bessel beams. AB - Fractional photothermolysis uses lasers to generate a pattern of microscopic columnar thermal lesions within the skin stimulating collagen remodeling. In this paper we investigate the use of Bessel beams as an alternative to conventional Gaussian beams in creating laser photothermal lesions of different aspect ratios in skin. We show for the first time the improved photothermal lesion depth-to diameter aspect ratio using Bessel beams in ex vivo human skin as well as in numerical simulations using electric field Monte Carlo photon transport, finite difference methods and Arrhenius model. Bessel beams allow the creation of deep and narrow thermal lesions necessary for improved efficacy in fractional photothermolysis. PMID- 28018720 TI - Registration of free-hand OCT daughter endoscopy to 3D organ reconstruction. AB - Despite the trend to pair white light endoscopy with secondary image modalities for in vivo characterization of suspicious lesions, challenges remain to co register such data. We present an algorithm to co-register two different optical imaging modalities as a mother-daughter endoscopy pair. Using white light cystoscopy (mother) and optical coherence tomography (OCT) (daughter) as an example, we developed the first forward-viewing OCT endoscope that fits in the working channel of flexible cystoscopes and demonstrated our algorithm's performance with optical phantom and clinical imaging data. The ability to register multimodal data opens opportunities for advanced analysis in cancer imaging applications. PMID- 28018706 TI - Application of platelet-rich plasma with stem cells in bone and periodontal tissue engineering. AB - Presently, there is a high paucity of bone grafts in the United States and worldwide. Regenerating bone is of prime concern due to the current demand of bone grafts and the increasing number of diseases causing bone loss. Autogenous bone is the present gold standard of bone regeneration. However, disadvantages like donor site morbidity and its decreased availability limit its use. Even allografts and synthetic grafting materials have their own limitations. As certain specific stem cells can be directed to differentiate into an osteoblastic lineage in the presence of growth factors (GFs), it makes stem cells the ideal agents for bone regeneration. Furthermore, platelet-rich plasma (PRP), which can be easily isolated from whole blood, is often used for bone regeneration, wound healing and bone defect repair. When stem cells are combined with PRP in the presence of GFs, they are able to promote osteogenesis. This review provides in depth knowledge regarding the use of stem cells and PRP in vitro, in vivo and their application in clinical studies in the future. PMID- 28018719 TI - Supra-organization and optical anisotropies of the extracellular matrix in the amniotic membrane and limbal stroma before and after explant culture. AB - In this research we evaluated the supramolecular organizations and the optical anisotropical properties of the de-epithelialized human amniotic membrane and rabbit limbal stroma, before and after explant culture. Birefringence, monochromatic light spectral absorption and linear dichroism of the main extracellular matrix biopolymers, that is, the fibrillar collagens and proteoglycans, were investigated by polarized light microscopy combined with image analysis. Our results demonstrated that the culture procedure-induced stimuli altered the supra-organizational characteristics (in terms of collagens/proteoglycans spatial orientation and ordered-aggregational state) of the amniotic and limbal extracellular matrix, which led to changes in optical anisotropical properties. PMID- 28018721 TI - Human skull translucency: post mortem studies. AB - Measurements of optical translucency of human skulls were carried out. An incandescent light source and a CCD camera were used to measure the distribution of light transmitted through the skull in 10 subjects post-mortem. We noticed that intra-individual differences in optical translucency may be up to 100 times but inter-individual translucency differences across the skull reach 105 times. Based on the measurement results, a "theoretical" experiment was simulated. Monte Carlo calculations were used in order to evaluate the influence of the differences in optical translucency of the skull on results of NIRS measurements. In these calculations a functional stimulation was done, in which the oxyhemoglobin and deoxyhemoglobin concentrations in the brain cortex change by 5MUM and -5MUM respectively. The maximal discrepancies between assumed hemoglobin concentration changes and hemoglobin concentration changes estimated with Monte Carlo simulation may reach 50% depending of the translucency of the skull. PMID- 28018722 TI - Automatic selection of regularization parameters for dynamic fluorescence molecular tomography: a comparison of L-curve and U-curve methods. AB - Dynamic fluorescence molecular tomography (FMT) is a promising technique for the study of the metabolic process of fluorescent agents in the biological body in vivo, and the quality of the parametric images relies heavily on the accuracy of the reconstructed FMT images. In typical dynamic FMT implementations, the imaged object is continuously monitored for more than 50 minutes. During each minute, a set of the fluorescent measurements is acquired and the corresponding FMT image is reconstructed. It is difficult to manually set the regularization parameter in the reconstruction of each FMT image. In this paper, the parametric images obtained with the L-curve and U-curve methods are quantitatively evaluated through numerical simulations, phantom experiments and in vivo experiments. The results illustrate that the U-curve method obtains better accuracy, stronger robustness and higher noise-resistance in parametric imaging. Therefore, it is a promising approach to automatic selection of the regularization parameters for dynamic FMT. PMID- 28018723 TI - Spectrometer calibration for spectroscopic Fourier domain optical coherence tomography. AB - We propose a simple and robust procedure for Fourier domain optical coherence tomography (FdOCT) that allows to linearize the detected FdOCT spectra to wavenumber domain and, at the same time, to determine the wavelength of light for each point of detected spectrum. We show that in this approach it is possible to use any measurable physical quantity that has linear dependency on wavenumber and can be extracted from spectral fringes. The actual values of the measured quantity have no importance for the algorithm and do not need to be known at any stage of the procedure. As example we calibrate a spectral OCT spectrometer using Doppler frequency. The technique of spectral calibration can be in principle adapted to of all kind of Fourier domain OCT devices. PMID- 28018724 TI - GPU accelerated real-time confocal fluorescence lifetime imaging microscopy (FLIM) based on the analog mean-delay (AMD) method. AB - We demonstrated GPU accelerated real-time confocal fluorescence lifetime imaging microscopy (FLIM) based on the analog mean-delay (AMD) method. Our algorithm was verified for various fluorescence lifetimes and photon numbers. The GPU processing time was faster than the physical scanning time for images up to 800 * 800, and more than 149 times faster than a single core CPU. The frame rate of our system was demonstrated to be 13 fps for a 200 * 200 pixel image when observing maize vascular tissue. This system can be utilized for observing dynamic biological reactions, medical diagnosis, and real-time industrial inspection. PMID- 28018725 TI - Region-based diffuse optical tomography with registered atlas: in vivo acquisition of mouse optical properties. AB - The reconstruction quality in the model-based optical tomography modalities can greatly benefit from a priori information of accurate tissue optical properties, which are difficult to be obtained in vivo with a conventional diffuse optical tomography (DOT) system alone. One of the solutions is to apply a priori anatomical structures obtained with anatomical imaging systems such as X-ray computed tomography (XCT) to constrain the reconstruction process of DOT. However, since X-ray offers low soft-tissue contrast, segmentation of abdominal organs from sole XCT images can be problematic. In order to overcome the challenges, the current study proposes a novel method of recovering a priori organ-oriented tissue optical properties, where anatomical structures of an in vivo mouse are approximately obtained by registering a standard anatomical atlas, i.e., the Digimouse, to the target XCT volume with the non-rigid image registration, and, in turn, employed to guide DOT for extracting the optical properties of inner organs. Simulative investigations have validated the methodological availability of such atlas-registration-based DOT strategy in revealing both a priori anatomical structures and optical properties. Further experiments have demonstrated the feasibility of the proposed method for acquiring the organ-oriented tissue optical properties of in vivo mice, making it as an efficient way of the reconstruction enhancement. PMID- 28018728 TI - PHOEBE: a method for real time mapping of optodes-scalp coupling in functional near-infrared spectroscopy. AB - Recent functional near-infrared spectroscopy (fNIRS) instrumentation encompasses several dozen of optodes to enable reconstructing a hemodynamic image of the entire cerebral cortex. Despite its potential clinical applicability, widespread use of fNIRS with human subjects is currently limited by unresolved issues, namely the collection from the entirety of optical channels of signals with a signal-to-noise ratio (SNR) sufficient to carry out a reliable estimation of cortical hemodynamics, and the considerable amount of time that placing numerous optodes take with individuals for whom achieving good optical coupling to the scalp is difficult due to thick or dark hair. To address these issues, we developed a numerical method that: 1) at the channel level, computes an objective measure of the signal-to-noise ratio (SNR) related to its optical coupling to the scalp, akin to electrode conductivity used in electroencephalography (EEG), and 2) at the optode level, determines and displays the coupling status of all individual optodes in real time on a model of a human head. This approach aims to shorten the pre-acquisition preparation time by visually displaying which optodes require further adjustment for optimum scalp coupling, and to maximize the signal to-noise ratio (SNR) of all optical channels contributing to the functional hemodynamic mapping. The methodology described in this paper has been implemented in a software tool named PHOEBE (placing headgear optodes efficiently before experimentation) that is freely available for use by the fNIRS community. PMID- 28018726 TI - Preclinical detection of liver fibrosis using dual-modality photoacoustic/ultrasound system. AB - Liver fibrosis is a major cause for increasing mortality worldwide. Preclinical research using animal models is required for the discovery of new anti-fibrotic therapies, but currently relies on endpoint liver histology. In this study, we investigated a cost-effective and portable photoacoustic/ultrasound (PA/US) imaging system as a potential non-invasive alternative. Fibrosis was induced in mice using CCl4 followed by liver imaging and histological analysis. Imaging showed significantly increased PA features with higher frequency signals in fibrotic livers versus healthy livers. This corresponds to more heterogeneous liver structure resulting from collagen deposition and angiogenesis. Importantly, PA response and its frequency were highly correlated with histological parameters. These results demonstrate the preclinical feasibility of the PA imaging approach and applicability of dual PA/US system. PMID- 28018727 TI - Characterization of transfer function, resolution and depth of field of a soft X ray microscope applied to tomography enhancement by Wiener deconvolution. AB - Full field soft X-ray microscopy is becoming a powerful imaging technique to analyze whole cells preserved under cryo conditions. Images obtained in these X ray microscopes can be combined by tomographic reconstruction to quantitatively estimate the three-dimensional (3D) distribution of absorption coefficients inside the cell. The impulse response of an imaging system is one of the factors that limits the quality of the X-ray microscope reconstructions. The main goal of this work is to experimentally measure the 3D impulse response and to assess the optical resolution and depth of field of the Mistral microscope at ALBA synchrotron (Barcelona, Spain). To this end we measure the microscope apparent transfer function (ATF) and we use it to design a deblurring Wiener filter, obtaining an increase in the image quality when applied to experimental datasets collected at ALBA. PMID- 28018729 TI - Volumetric optical mapping in early embryonic hearts using light-sheet microscopy. AB - Optical mapping (OM) of electrical activity using voltage-sensitive fluorescent dyes is a powerful tool for the investigation of embryonic cardiac electrophysiology. However, because conventional OM integrates the signal in depth and projects it to a two-dimensional plane, information acquired is incomplete and dependent upon the orientation of the sample. This complicates interpretation of data, especially when comparing one heart to another. To overcome this limitation, we present volumetric OM using light-sheet microscopy, which enables high-speed capture of optically sectioned slices. Voltage-sensitive fluorescence images from multiple planes across entire early embryonic quail hearts were acquired, and complete, orientation-independent, four-dimensional maps of transmembrane potential are demonstrated. Volumetric OM data were collected while using optical pacing to control the heart rate, paving the way for physiological measurements and precise manipulation of the heartbeat in the future. PMID- 28018730 TI - Raman spectroscopy detects distant invasive brain cancer cells centimeters beyond MRI capability in humans. AB - Surgical treatment of brain cancer is limited by the inability of current imaging capabilities such as magnetic resonance imaging (MRI) to detect the entirety of this locally invasive cancer. This results in residual cancer cells remaining following surgery, leading to recurrence and death. We demonstrate that intraoperative Raman spectroscopy can detect invasive cancer cells centimeters beyond pathological T1-contrast-enhanced and T2-weighted MRI signals. This intraoperative optical guide can be used to detect invasive cancer cells and minimize post-surgical cancer burden. The detection of distant invasive cancer cells beyond MRI signal has the potential to increase the effectiveness of surgery and directly lengthen patient survival. PMID- 28018731 TI - Accurate measurement of the pulse wave delay with imaging photoplethysmography. AB - Assessment of the cardiovascular parameters using noncontact video-based or imaging photoplethysmography (IPPG) is usually considered as inaccurate because of strong influence of motion artefacts. To optimize this technique we performed a simultaneous recording of electrocardiogram and video frames of the face for 36 healthy volunteers. We found that signal disturbances originate mainly from the stochastically enhanced dichroic notch caused by endogenous cardiovascular mechanisms, with smaller contribution of the motion artefacts. Our properly designed algorithm allowed us to increase accuracy of the pulse-transit-time measurement and visualize propagation of the pulse wave in the facial region. Thus, the accurate measurement of the pulse wave parameters with this technique suggests a sensitive approach to assess local regulation of microcirculation in various physiological and pathological states. PMID- 28018733 TI - Light-sheet-based 2D light scattering cytometry for label-free characterization of senescent cells. AB - A light-sheet-based 2D light scattering cytometer is developed for label-free characterization of senescent cells. The light-sheet provides an illumination beam with controlled thickness for single cell excitation, and 2D light scattering patterns are obtained by using a defocused imaging method. The principle of this cytometer is validated by distinguishing microspheres with submicron resolution. Automatic classification of senescent and normal cells is achieved at single cell level by using the support vector machine (SVM) algorithm, where a sensitivity of 89.1% and a specificity of 96.4% are obtained. Our results suggest that the light-sheet-based 2D light scattering label-free cytometry has the capability to perform size differentiation of beads with submicron resolution and to classify different groups of cells without fluorescent labeling, showing the potential for clinical diagnosis of senescence related diseases. PMID- 28018732 TI - Safety assessment in macaques of light exposures for functional two-photon ophthalmoscopy in humans. AB - Two-photon ophthalmoscopy has potential for in vivo assessment of function of normal and diseased retina. However, light safety of the sub-100 fs laser typically used is a major concern and safety standards are not well established. To test the feasibility of safe in vivo two-photon excitation fluorescence (TPEF) imaging of photoreceptors in humans, we examined the effects of ultrashort pulsed light and the required light levels with a variety of clinical and high resolution imaging methods in macaques. The only measure that revealed a significant effect due to exposure to pulsed light within existing safety standards was infrared autofluorescence (IRAF) intensity. No other structural or functional alterations were detected by other imaging techniques for any of the exposures. Photoreceptors and retinal pigment epithelium appeared normal in adaptive optics images. No effect of repeated exposures on TPEF time course was detected, suggesting that visual cycle function was maintained. If IRAF reduction is hazardous, it is the only hurdle to applying two-photon retinal imaging in humans. To date, no harmful effects of IRAF reduction have been detected. PMID- 28018734 TI - Classification and analysis of human ovarian tissue using full field optical coherence tomography. AB - In this study, a full field optical coherence tomography (FFOCT) system was used to analyze and classify normal and malignant human ovarian tissue. 14 ovarian tissue samples (7 normal, 7 malignant) were imaged with the FFOCT system and five features were extracted by analyzing the normalized image histogram from 56 FFOCT images, based on the differences in the morphology of the normal and malignant tissue samples. A generalized linear model (GLM) classifier was trained using 36 images, and sensitivity of 95.3% and specificity of 91.1% was obtained. 20 images were used to test the model, and a sensitivity of 91.6% and specificity of 87.7% was obtained. PMID- 28018736 TI - Combined microfluidic-optical DNA analysis with single-base-pair sizing capability. AB - DNA sequencing by microchip capillary electrophoresis (CE) enables cheap, high speed analysis of low reagent volumes. One of its potential applications is the identification of genomic deletions or insertions associated with genetic illnesses. Detecting single base-pair insertions or deletions from DNA fragments in the diagnostically relevant size range of 150-1000 base-pairs requires a variance of sigma2 < 10-3. In a microfluidic chip post-processed by femtosecond laser writing of an optical waveguide we CE-separated 12 blue-labeled and 23 red labeled DNA fragments in size. Each set was excited by either of two lasers power modulated at different frequencies, their fluorescence detected by a photomultiplier, and blue and red signals distinguished by Fourier analysis. We tested different calibration strategies. Choice of the fluorescent label as well as the applied fit function strongly influence the obtained variance, whereas fluctuations between two consecutive experiments are less detrimental in a laboratory environment. We demonstrate a variance of sigma2 ~4 * 10-4, lower than required for the detection of single base-pair insertion or deletion in an optofluidic chip. PMID- 28018735 TI - Using DRS during breast conserving surgery: identifying robust optical parameters and influence of inter-patient variation. AB - Successful breast conserving surgery consists of complete removal of the tumor while sparing healthy surrounding tissue. Despite currently available imaging and margin assessment tools, recognizing tumor tissue at a resection margin during surgery is challenging. Diffuse reflectance spectroscopy (DRS), which uses light for tissue characterization, can potentially guide surgeons to prevent tumor positive margins. However, inter-patient variation and changes in tissue physiology occurring during the resection might hamper this light-based technology. Here we investigate how inter-patient variation and tissue status (in vivo vs ex vivo) affect the performance of the DRS optical parameters. In vivo and ex vivo measurements of 45 breast cancer patients were obtained and quantified with an analytical model to acquire the optical parameters. The optical parameter representing the ratio between fat and water provided the best discrimination between normal and tumor tissue, with an area under the receiver operating characteristic curve of 0.94. There was no substantial influence of other patient factors such as menopausal status on optical measurements. Contrary to expectations, normalization of the optical parameters did not improve the discriminative power. Furthermore, measurements taken in vivo were not significantly different from the measurements taken ex vivo. These findings indicate that DRS is a robust technology for the detection of tumor tissue during breast conserving surgery. PMID- 28018737 TI - Ultrafast time-stretch imaging at 932 nm through a new highly-dispersive fiber. AB - Optical glass fiber has played a key role in the development of modern optical communication and attracted the biotechnology researcher's great attention because of its properties, such as the wide bandwidth, low attenuation and superior flexibility. For ultrafast optical imaging, particularly, it has been utilized to perform MHz time-stretch imaging with diffraction-limited resolutions, which is also known as serial time-encoded amplified microscopy (STEAM). Unfortunately, time-stretch imaging with dispersive fibers has so far mostly been demonstrated at the optical communication window of 1.5 MUm due to lack of efficient dispersive optical fibers operating at the shorter wavelengths, particularly at the bio-favorable window, i.e., <1.0 MUm. Through fiber-optic engineering, here we demonstrate a 7.6-MHz dual-color time-stretch optical imaging at bio-favorable wavelengths of 932 nm and 466 nm. The sensitivity at such a high speed is experimentally identified in a slow data-streaming manner. To the best of our knowledge, this is the first time that all-optical time stretch imaging at ultrahigh speed, high sensitivity and high chirping rate (>1 ns/nm) has been demonstrated at a bio-favorable wavelength window through fiber optic engineering. PMID- 28018738 TI - Depth-resolved imaging of colon tumor using optical coherence tomography and fluorescence laminar optical tomography. AB - Early detection of neoplastic changes remains a critical challenge in clinical cancer diagnosis and treatment. Many cancers arise from epithelial layers such as those of the gastrointestinal (GI) tract. Current standard endoscopic technology is difficult to detect the subsurface lesions. In this research, we investigated the feasibility of a novel multi-modal optical imaging approach including high resolution optical coherence tomography (OCT) and high-sensitivity fluorescence laminar optical tomography (FLOT) for structural and molecular imaging. The C57BL/6J-ApcMin/J mice were imaged using OCT and FLOT, and the correlated histopathological diagnosis was obtained. Quantitative structural (scattering coefficient) and molecular (relative enzyme activity) parameters were obtained from OCT and FLOT images for multi-parametric analysis. This multi-modal imaging method has demonstrated the feasibility for more accurate diagnosis with 88.23% (82.35%) for sensitivity (specificity) compared to either modality alone. This study suggested that combining OCT and FLOT is promising for subsurface cancer detection, diagnosis, and characterization. PMID- 28018740 TI - Multimodal registration of SD-OCT volumes and fundus photographs using histograms of oriented gradients. AB - With availability of different retinal imaging modalities such as fundus photography and spectral domain optical coherence tomography (SD-OCT), having a robust and accurate registration scheme to enable utilization of this complementary information is beneficial. The few existing fundus-OCT registration approaches contain a vessel segmentation step, as the retinal blood vessels are the most dominant structures that are in common between the pair of images. However, errors in the vessel segmentation from either modality may cause corresponding errors in the registration. In this paper, we propose a feature based registration method for registering fundus photographs and SD-OCT projection images that benefits from vasculature structural information without requiring blood vessel segmentation. In particular, after a preprocessing step, a set of control points (CPs) are identified by looking for the corners in the images. Next, each CP is represented by a feature vector which encodes the local structural information via computing the histograms of oriented gradients (HOG) from the neighborhood of each CP. The best matching CPs are identified by calculating the distance of their corresponding feature vectors. After removing the incorrect matches the best affine transform that registers fundus photographs to SD-OCT projection images is computed using the random sample consensus (RANSAC) method. The proposed method was tested on 44 pairs of fundus and SD-OCT projection images of glaucoma patients and the result showed that the proposed method successfully registers the multimodal images and produced a registration error of 25.34 +/- 12.34 MUm (0.84 +/- 0.41 pixels). PMID- 28018739 TI - Active-passive path-length encoded (APPLE) Doppler OCT. AB - We present a novel active-passive path-length encoded (APPLE) swept source Doppler optical coherence tomography (DOCT) approach, enabling three-dimensional velocity vector reconstruction of moving particles without prior knowledge of the orientation of motion. The developed APPLE DOCT setup allows for non-invasive blood flow measurements in vivo and was primarily designed for quantitative human ocular blood flow investigations. The system's performance was demonstrated by in vitro flow phantom as well as in vivo retinal vessel bifurcation measurements. Furthermore, total retinal blood flow - a biomarker aiding in diagnosis and monitoring of major ocular diseases such as glaucoma, diabetic retinopathy or central/branch retinal vein occlusion - was determined in the eyes of healthy human volunteers. PMID- 28018742 TI - Multiplexed fluorescence readout using time responses of color coded signals for biomolecular detection. AB - Fluorescence readout is an important technique for detecting biomolecules. In this paper, we present a multiplexed fluorescence readout method using time varied fluorescence signals. To generate the fluorescence signals, coded strands and a set of universal molecular beacons are introduced. Each coded strand represents the existence of an assigned target molecule. The coded strands have coded sequences to generate temporary fluorescence signals through binding to the molecular beacons. The signal generating processes are modeled based on the reaction kinetics between the coded strands and molecular beacons. The model is used to decode the detected fluorescence signals using maximum likelihood estimation. Multiplexed fluorescence readout was experimentally demonstrated with three molecular beacons. Numerical analysis showed that the readout accuracy was enhanced by the use of time-varied fluorescence signals. PMID- 28018741 TI - Local motion-compensated method for high-quality 3D coronary artery reconstruction. AB - The 3D reconstruction of coronary artery from X-ray angiograms rotationally acquired on C-arm has great clinical value. While cardiac-gated reconstruction has shown promising results, it suffers from the problem of residual motion. This work proposed a new local motion-compensated reconstruction method to handle this issue. An initial image was firstly reconstructed using a regularized iterative reconstruction method. Then a 3D/2D registration method was proposed to estimate the residual vessel motion. Finally, the residual motion was compensated in the final reconstruction using the extended iterative reconstruction method. Through quantitative evaluation, it was found that high-quality 3D reconstruction could be obtained and the result was comparable to state-of-the-art method. PMID- 28018744 TI - Imaging behind opaque obstacle: a potential method for guided in vitro needle placement. AB - We report a simple real time optical imaging concept using an axicon lens to image the object kept behind opaque obstacles in free space. The proposed concept underlines the importance and advantages of using an axicon lens compared to a conventional lens to image behind the obstacle. The potential of this imaging concept is demonstrated by imaging the insertion of surgical needle in biological specimen in real time, without blocking the field of view. It is envisaged that this proposed concepts and methodology can make a telling impact in a wide variety of areas especially for diagnostics, therapeutics and microscopy applications. PMID- 28018745 TI - Efficient multi-site two-photon functional imaging of neuronal circuits. AB - Two-photon imaging using high-speed multi-channel detectors is a promising approach for optical recording of cellular membrane dynamics at multiple sites. A main bottleneck of this technique is the limited number of photons captured within a short exposure time (~1ms). Here, we implement temporal gating to improve the two-photon fluorescence yield from holographically projected multiple foci whilst maintaining a biologically safe incident average power. We observed up to 6x improvement in the signal-to-noise ratio (SNR) in Fluorescein and cultured hippocampal neurons showing evoked calcium transients. With improved SNR, we could pave the way to achieving multi-site optical recording of fluorogenic probes with response times in the order of ~1ms. PMID- 28018743 TI - Smartphone-based multispectral imaging: system development and potential for mobile skin diagnosis. AB - We investigate the potential of mobile smartphone-based multispectral imaging for the quantitative diagnosis and management of skin lesions. Recently, various mobile devices such as a smartphone have emerged as healthcare tools. They have been applied for the early diagnosis of nonmalignant and malignant skin diseases. Particularly, when they are combined with an advanced optical imaging technique such as multispectral imaging and analysis, it would be beneficial for the early diagnosis of such skin diseases and for further quantitative prognosis monitoring after treatment at home. Thus, we demonstrate here the development of a smartphone-based multispectral imaging system with high portability and its potential for mobile skin diagnosis. The results suggest that smartphone-based multispectral imaging and analysis has great potential as a healthcare tool for quantitative mobile skin diagnosis. PMID- 28018746 TI - Identifying Candidate Targets of Immune Responses in Zika Virus Based on Homology to Epitopes in Other Flavivirus Species. AB - INTRODUCTION: The current outbreak of Zika virus has resulted in a massive effort to accelerate the development of ZIKV-specific diagnostics and vaccines. These efforts would benefit greatly from the definition of the specific epitope targets of immune responses in ZIKV, but given the relatively recent emergence of ZIKV as a pandemic threat, few such data are available. METHODS: We used a large body of epitope data for other Flaviviruses that was available from the IEDB for a comparative analysis against the ZIKV proteome in order to project targets of immune responses in ZIKV. RESULTS: We found a significant level of overlap between known antigenic sites from other Flavivirus proteins with residues on the ZIKV polyprotein. The E and NS1 proteins shared functional antibody epitope sites, whereas regions of T cell reactivity were conserved within NS3 and NS5 for ZIKV. Discussion: Our epitope based analysis provides guidance for which regions of the ZIKV polyprotein are most likely unique targets of ZIKV-specific antibodies, and which targets in ZIKV are most likely to be cross-reactive with other Flavivirus species. These data may therefore provide insights for the development of antibody- and T cell-based ZIKV-specific diagnostics, therapeutics and prophylaxis. PMID- 28018747 TI - Exploring the Role of Ad Hoc Grassroots Organizations Providing Humanitarian Aid on Lesvos, Greece. AB - INTRODUCTION: Syrian refugees displaced into Turkey have attempted high-risk sea migrations to reach safer destinations in Europe, most often initially arriving on the Greek island of Lesvos. These refugees were often in need of basic humanitarian assistance that has been provided in part by a new category of ad hoc grassroots organizations (AHGOs). The aim of this study was to understand the internal and external operations of these AHGOs and their role on Lesvos. METHODS: The experiences of AHGOs were investigated through a qualitative research design utilizing semi-structured interviews with organization leaders and spokespersons. AHGOs identified through media and social media sources as new Lesvos-specific organizations were purposively invited to complete an interview over phone, Skype or email. Data analysis of the transcribed interviews was performed by Systematic Text Condensation. RESULTS: Forty-one organizations were contacted and 13 interviews were conducted. Most organizations were formed in autumn 2015 responding to the greater influx of refugees and migrants at that time and reported an absence of professional humanitarian agencies providing aid on Lesvos. Three categories emerged from the material. Features of organizations; Features of volunteers and; Evolution of AHGOs. The organizations perceived themselves capable of evaluating needs, mobilizing resources, funding and providing quick response. The volunteers came with limited humanitarian experience and from a wide variety of nationalities and professional backgrounds, and the organizations developed while on Lesvos. DISCUSSION: Knowledge from our findings of AHGOs response to this complex disaster on Lesvos could be utilized in future catastrophes. We conclude that AHGOs may prove effective at providing humanitarian aid in a surge response when international non-governmental organizations are unable to respond quickly. In future complex disasters AHGOs should be recognized as new humanitarian actors and conditions should be made favourable for their operations. PMID- 28018748 TI - Laboratory Investigation of Salmonella enterica serovar Poona Outbreak in California: Comparison of Pulsed-Field Gel Electrophoresis (PFGE) and Whole Genome Sequencing (WGS) Results. AB - INTRODUCTION: Recently, Salmonella enterica serovar Poona caused a multistate outbreak, with 245 out of 907 cases occurring in California. We report a comparison of pulsed-field gel electrophoresis (PFGE) results with whole genome sequencing (WGS) for genotyping of Salmonella Poona isolates. METHODS: CA Salmonella Poona isolates, collected from July to August 2015, were genotyped by PFGE using XbaI restriction enzyme. WGS was done using Nextera XT library kit with 2x300 bp or 2x250 bp sequencing chemistry on the Illumina MiSeq Sequencer. Reads were mapped to the de novo assembled serovar Poona draft genome (48 contigs, N50= 223,917) from the outbreak using CLCbio GW 8.0.2. The phylogenetic tree was generated based on hqSNPs calling. Genomes were annotated with CGE and PHAST online tools. In silico MLST was performed using the CGE online tool. RESULTS: Human (14) and cucumber (2) Salmonella Poona isolates exhibited 3 possibly related PFGE patterns (JL6X01.0018 [predominant], JL6X01.0375, JL6X01.0778). All isolates that were related by PFGE also clustered together according to the WGS. One isolate with a divergent PFGE pattern (JL6X01.0776) served as an outlier in the phylogenetic analysis and substantially differed from the outbreak clade by WGS. All outbreak isolates were assigned to MLST sequence type 447. The majority of the outbreak-related isolates possessed the same set of Salmonella Pathogenicity Islands with few variations. One outbreak isolate was sequenced and analyzed independently by CDC and CDPH laboratories; there was 0 SNP difference in results. Additional two isolates were sequenced by CDC and the raw data was processed through CDPH and CDC analysis pipelines. Both data analysis pipelines also generated concordant results. Discussion: PFGE and WGS results for the recent CA Salmonella enterica serovar Poona outbreak provided concordant assignment of the isolates to the outbreak cluster. WGS allowed more robust determination of genetic relatedness, provided information regarding MLST type, pathogenicity genes, and bacteriophage content. WGS data obtained independently at two laboratories showed complete agreement. PMID- 28018749 TI - Focused Training for Humanitarian Responders in Regional Anesthesia Techniques for a Planned Randomized Controlled Trial in a Disaster Setting. AB - BACKGROUND: Lower extremity trauma during earthquakes accounts for the largest burden of geophysical disaster-related injuries. Insufficient pain management is common in disaster settings, and regional anesthesia (RA) has the potential to reduce pain in injured patients beyond current standards. To date, no prospective research has evaluated the use of RA in a disaster setting. This cross-sectional study assesses knowledge translation and skill acquisition outcomes for lower extremity RA performed with and without ultrasound guidance among a cohort of Medecins Sans Frontieres (MSF) volunteers who will function as proceduralists in a planned randomized controlled trial evaluating the efficacy of RA for pain management in an earthquake setting. METHODS: Generalist humanitarian healthcare responders, including both physicians and nurses, were trained in ultrasound guided femoral nerve block (USGFNB) and landmark guided fascia iliaca compartment block (LGFICB) techniques using didactic sessions and interactive simulations during a one-day focused course. Outcome measures evaluated interval knowledge attainment and technical proficiency in performing the RA procedures. Knowledge attainment was assessed via pre- and post-test evaluations and procedural proficiency was evaluated through monitored simulations, with performance of critical actions graded by two independent observers. RESULTS: Twelve humanitarian response providers were enrolled and completed the trainings and assessments. Knowledge scores significantly increased from a mean pre-test score of 79% to post-test score of 88% (p<0.001). In practical evaluation of the LGFICB, participants correctly performed a median of 15.0 (Interquartile Range (IQR) 14.0-16.0) out of 16 critical actions. For the USGFNB, the median score was also 15.0 (IQR 14.0-16.0) out of 16 critical actions. Inter-rater reliability for completion of critical actions was excellent, with inter-rater agreement of 83.3% and 91.7% for the LGFICB and USGFNB evaluations, respectively. DISCUSSION: Prior to conducting a trial of RA in a disaster setting, providers need to gain understanding and skills necessary to perform the interventions. This evaluation demonstrated attainment of high knowledge and technical skill scores in both physicians and nurses after a brief training in regional anesthesia techniques. This study demonstrates the feasibility of rapidly training generalist humanitarian responders to provide both LGFICB and USGFNB during humanitarian emergencies. PMID- 28018750 TI - Red Algal Phylogenomics Provides a Robust Framework for Inferring Evolution of Key Metabolic Pathways. AB - Red algae comprise an anciently diverged, species-rich phylum with morphologies that span unicells to large seaweeds. Here, leveraging a rich red algal genome and transcriptome dataset, we used 298 single-copy orthologous nuclear genes from 15 red algal species to erect a robust multi-gene phylogeny of Rhodophyta. This tree places red seaweeds (Bangiophyceae and Florideophyceae) at the base of the mesophilic red algae with the remaining non-seaweed mesophilic lineages forming a well-supported sister group. The early divergence of seaweeds contrasts with the evolution of multicellular land plants and brown algae that are nested among multiple, unicellular or filamentous sister lineages. Using this novel perspective on red algal evolution, we studied the evolution of the pathways for isoprenoid biosynthesis. This analysis revealed losses of the mevalonate pathway on at least three separate occasions in lineages that contain Cyanidioschyzon, Porphyridium, and Chondrus. Our results establish a framework for in-depth studies of the origin and evolution of genes and metabolic pathways in Rhodophyta. PMID- 28018751 TI - Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle. AB - There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. In-vivo fluorescence images, as well as ex-vivo fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs. PMID- 28018752 TI - Visible-Light-Initiated Thiol-Michael Addition Polymerizations with Coumarin Based Photobase Generators: Another Photoclick Reaction Strategy. AB - An efficient visible-light-sensitive photobase generator for thiol-Michael addition reactions was synthesized and evaluated. This highly reactive catalyst was designed by protecting a strong base (tetramethyl guanidine, TMG) with a visible-light-responsive group which was a coumarin derivative. The coumarin coupled TMG was shown to exhibit extraordinary catalytic activity toward initiation of the thiol-Michael reaction, including thiol-Michael addition-based polymerization, upon visible-light irradiation, leading to a stoichiometric reaction of both thiol and vinyl functional groups. Owing to its features, this visible-light photobase generator enables homogeneous network formation in thiol Michael polymerizations and also has the potential to be exploited in other visible-light-induced, base-catalyzed thiol-click processes such as thiol isocynate and thiol-epoxy network-forming reactions. PMID- 28018753 TI - Genetic determinants of swallowing impairment, recovery and responsiveness to treatment. AB - PURPOSE OF REVIEW: Here we review the latest literature and evidence in the field of genetics and determinants of swallowing and its treatments-specifically, this is a very recent concept in the field of oropharyngeal dysphagia, with only now an emerging research interest in the relationship between our genetic makeup and the effect this has on swallowing function and dysfunction. As such our review will look at preclinical, clinical and hypothesis generating research covering all aspects of the genetics of swallowing, giving new importance to the genotype phenotype influences pertaining to dysphagia and its recovery. RECENT FINDINGS: There appear to be a number of candidate gene systems that interact with swallowing or its neurophysiology, which include brain-derived neurotrophic factor, apolipoprotein E and catechol-O-methyltransferase, that have been shown to impact on either swallowing function or the brain's ability to respond to neurostimulation and induce plasticity. In addition, a number of genetic disorders, where dysphagia is a clinical phenomenon, have given us clues as to how multiple genes or the polygenetics of dysphagia might interact with our swallowing phenotype. SUMMARY: There is currently limited research in the field of genetic factors that influence (human) swallowing and oropharyngeal dysphagia, but this is an emerging science and one which, in the future, may herald a new era in precision medicine and better targeting of therapies for dysphagia based on an individual's genetic makeup. PMID- 28018755 TI - The Associations of Biculturalism to Prosocial Tendencies and Positive Self Evaluations. AB - Although some research exists on biculturalism and negative adjustment, few studies have examined the mechanisms that account for the positive correlates of biculturalism in U.S. Latino youth. Two competing reverse causal models were tested. Specifically, we examined how biculturalism among 574 U.S. Mexican adolescents (n =296 girls; M = 17.84 years, SD = .46 years) was related to prosocial tendencies and positive self evaluation (i.e., self-esteem and general self-efficacy). The findings yielded supportive evidence for both reverse causal models suggesting that prosocial tendencies may mediate the relations between biculturalism and positive self evaluations, and that positive self evaluations may mediate the relations between biculturalism and prosocial tendencies. The implications of the role of biculturalism for understanding prosocial development and positive self evaluations in U.S. Mexican youth are discussed. PMID- 28018754 TI - Dysphagia Management and Stroke Units. AB - Dysphagia is one of the many complications of stroke. It is common and is an independent marker of outcome. Dysphagia management is important. Although the speech and language pathologist is the key worker in dysphagia management, they are supported by all members of the multi-disciplinary team. Stroke patients should be screened on admission for the presence of dysphagia and assessed by the speech and language therapist (or appropriate professional), where indicated investigation should be undertaken to understand the swallowing physiology and to guide treatment. Management, at present, is based around texture modification of food/liquids and swallowing manoeuvres. Rehabilitation of swallowing remains in its infancy, but there is a lot of promising research with neurostimulation, medication and devices to strengthen muscles involved in swallowing. PMID- 28018756 TI - Incidence of Potential Drug-Drug Interactions in a Limited and Stereotyped Prescription Setting - Comparison of Two Free Online Pharmacopoeias. AB - BACKGROUND: Drug-drug interactions (DDIs) are very common adverse events in health care delivery settings. The use of electronic pharmacopeias can potentially reduce the incidence of DDIs, but they are often thought to be cumbersome to use. This study is aimed at studying the incidence of potential DDIs in a surgical department, where a limited number of drugs are used in stereotyped combinations. We also compared two popular drug compendia in detecting potential DDIs. METHODS: The prescriptions of selected patients were entered into Epocrates(r) and Medscape(r) for Android smartphones. Potential DDIs were generated and their categories were noted. The warnings generated by Epocrates(r) were compared with those generated by Medscape(r) and an agreement index was calculated. RESULTS: Three hundred and thirty-one patients were included for analysis who had received a total of 2,878 drug orders. The incidence of potential DDIs was very high - 89% of all prescriptions. Phenytoin was the drug most commonly implicated, followed by furosemide. Of the DDIs detected, 0.14% were potentially serious and the drug combinations were contraindicated. There was a significant discrepancy between the categories of potential DDIs detected by Epocrates(r) and Medscape(r). No clinically significant DDI was detected in any patient in this cohort. CONCLUSIONS: Despite routinely using only a limited number of drugs in stereotyped combinations, prescriptions in surgical departments may not be immune from a significant incidence of DDIs. The use of free apps could reduce the incidence of DDIs, enhance patient safety, and also aid in educating trainees. PMID- 28018757 TI - Trends in Usage and Outcomes for Expanded Criteria Donor Kidney Transplantation in the United States Characterized by Kidney Donor Profile Index. AB - There has been increasing concern in the kidney transplant community about the declining use of expanded criteria donors (ECD) despite improvement in survival and quality of life. The recent introduction of the Kidney Donor Profile Index (KDPI), which provides a more granular characterization of donor quality, was expected to increase utilization of marginal kidneys and decrease the discard rates. However, trends and practice patterns of ECD kidney utilization on a national level based on donor organ quality as per KDPI are not well known. We, therefore, performed a trend analysis of all ECD recipients in the United Network for Organ Sharing (UNOS) registry between 2002 and 2012, after calculating the corresponding KDPI, to enable understanding the trends of usage and outcomes based on the KDPI characterization. High-risk recipient characteristics (diabetes, body mass index >=30 kg/m2, hypertension, and age >=60 years) increased over the period of the study (trend test p<0.001 for all). The proportion of ECD transplants increased from 18% in 2003 to a peak of 20.4% in 2008 and then declined thereafter to 17.3% in 2012. Using the KDPI >85% definition, the proportion increased from 9.4% in 2003 to a peak of 12.1% in 2008 and declined to 9.7% in 2012. Overall, although this represents a significant utilization of kidneys with KDPI >85% over time (p<0.001), recent years have seen a decline in usage, probably related to regulations imposed by Centers for Medicare & Medicaid Services (CMS). When comparing the hazards of graft failure by KDPI, ECD kidneys with KDPI >85% have a slightly lower risk of graft failure compared to standard criteria donor (SCD) kidneys with KDPI >85%, with a hazard ratio (HR) of 0.95, a confidence interval (CI) of 0.94-0.96, and statistical significance of p<0.001. This indicates that some SCD kidneys may actually have a lower estimated quality, with a higher Kidney Donor Risk Index (KDRI), than some ECDs. The incidence of delayed graft function (DGF) in ECD recipients has significantly decreased over time from 35.2% in 2003 to 29.6% in 2011 (p=0.007), probably related to better understanding of the donor risk profile along with increased use of hypothermic machine perfusion and pretransplant biopsy to aid in optimal allograft selection. The recent decline in transplantation of KDPI >85% kidneys probably reflects risk-averse transplant center behavior. Whether discard of discordant SCD kidneys with KDPI >85% has contributed to this decline remains to be studied. PMID- 28018758 TI - Cervical Fracture/Subluxation in a Patient with a Prior C2-Sacrum Fusion: Case Report and Review of Literature. AB - Traumatic injury to an adjacent segment of a previously fused spine is a rare complication of scoliosis surgery. The adjacent spinal segments may be more vulnerable to traumatic fracture or dislocation due to increased strain. We present a patient with prior C2 to sacrum fusion who suffered a C2 fracture/dislocation after falling. A 52-year-old female with a previous C2 to the sacrum fusion for idiopathic scoliosis presented with severe and progressively worsening neck pain after multiple falls. Imaging showed anterior displacement of the C2 vertebral body, fracture of C2, and anterior subluxation of the C1-2 complex on C3. The patient underwent posterior occiput to cervical fusion and reduction of the C1-C2 complex. Our case describes a potential complication of long-segment fusion. Adjacent segments may be more prone to fracture-dislocation because of increased intradiscal pressure and strain. Clinicians should have a high suspicion of fractures in patients with prior spinal fusions in the setting of trauma. PMID- 28018759 TI - Could the Use of an Enhanced Recovery Protocol in Laparoscopic Donor Nephrectomy be an Incentive for Live Kidney Donation? AB - INTRODUCTION AND BACKGROUND: Gastrointestinal (GI) recovery after major abdominal surgery can be delayed from an ongoing need for narcotic analgesia thereby prolonging hospitalization. Enhanced recovery after surgery (ERAS) is a multimodal perioperative care pathway designed to facilitate early recovery after major surgery by maintaining preoperative body composition and physiological organ function and modifying the stress response induced by surgical exposure. Enhanced recovery programs (ERPs) in colorectal surgery have decreased the duration of postoperative ileus and the hospital stay while showing equivalent morbidity, mortality, and readmission rates in comparison to the traditional standard of care. This study is a pilot trial to evaluate the benefits of ERAS protocols in living kidney donors undergoing laparoscopic nephrectomy. METHODS: This is a single-center, non-randomized, retrospective analysis comparing the outcomes of the first 40 live kidney donors subjected to laparoscopic nephrectomy under the ERAS protocol to 40 donors operated prior to ERAS with traditional standard of care. Our ERAS protocol includes reduced duration of fasting with preoperative carbohydrate loading, intraoperative fluid restriction to 3 ml/kg/hr, target urine output of 0.5 ml/kg/hr, use of subfascial Exparel injection (bupivacaine liposome suspension), and postoperative narcotic-free pain regimen with acetaminophen, ketorolac, or tramadol. Short-term patient outcomes were compared using Pearsons's Chi-Squared test for categorical variables and the Kruskal-Wallis test for continuous variables. Additionally, a multivariate analysis was conducted to evaluate factors influencing patient length of stay and likelihood of readmission. RESULTS: ERAS protocol reduced the postoperative median length of stay decreased from 2.0 to 1.0 days (p=0.001). Overall pain scores were significantly lower in the ERAS group (peak pain score 6.0 vs. 8.00, p< 0.001; morning after surgery pain score 3.0 vs. 7.0, p=0.001; lowest pain score 0.0 vs. 2.0, p=0.016) despite the absence of postoperative narcotics. The average duration of surgery was shorter in the ERAS group (248 vs. 304 minutes, p<0.001). The average amount of intraoperative fluid used was significantly lower in the ERAS group (2500 ml vs. 3525 ml, p<0.001) without affecting the donor renal function. The incidence of delayed graft function was similar in the two groups (p=0.541). A trend toward lower readmission was noted with the ERAS protocol (12.8% vs. 27.5%, p=0.105). GI dysfunction was the most common reason for readmission. CONCLUSION: Application of an ERAS protocol in a laparoscopic living donor nephrectomy was associated with reduced length of hospitalization and improved pain scores related likely to intraoperative use of subfascial Exparel and a shorter duration of ileus. Restricted use of intraoperative fluids prevents excessive third spacing and bowel edema, enhancing gut recovery without adversely impacting recipient graft function. This study suggests that ERAS has the potential to enhance the advantages of laparoscopic surgery for live kidney donation through optimizing donor outcomes and perioperative patient satisfaction. PMID- 28018760 TI - Early Results of Pilot Study Using Hepatitis C Virus (HCV) Positive Kidneys to Transplant HCV Infected Patients with End-Stage Renal Disease Allowing for Successful Interferon-Free Direct Acting Antiviral Therapy after Transplantation. AB - INTRODUCTION: Hepatitis C virus (HCV) infection in kidney transplant (KTX) patients reduces long-term patient and graft survival. Direct-acting antivirals (DAA) are > 90% effective in achieving sustained viral response (SVR); however, DAAs are not routinely available to patients with end-stage renal disease (ESRD). The University of Utah Transplant Program developed a protocol to allow HCV positive potential KTX recipients to accept HCV-positive donors' kidneys. Three months after successful KTX, they were eligible for DAA therapy. METHODS: HCV positive patients approved for KTX by the University of Utah Transplant Selection Committee were eligible to be enrolled in this study. Patients consented for the use of HCV-positive donor organs. Three to six months after successful KTX, these patients were treated for HCV with interferon-free direct-acting antiviral regimens according to viral genotype and prior treatment experience. RESULTS: Between 2014-2015, 12 HCV-positive patients were listed for KTX. Eight patients were kidney only eligible, seven patients received HCV-positive deceased donor kidneys, and one received an HCV-negative organ. Currently, six patients have completed treatment, all have achieved sustained viral response (SVR), and one patient is currently awaiting treatment. All seven patients have functioning kidney grafts. Wait time for KTX was reduced amongst all blood groups from an average of 1,350 days to only 65 days. CONCLUSIONS: HCV-positive patients with ESRD can successfully receive an HCV-positive donor's kidney. Once transplanted, these patients can receive DAA therapy and achieve SVR. Use of HCV-positive organs reduced time on the waitlist by greater than three years and expanded the donor organ pool. PMID- 28018761 TI - Improving Donor Conversion Rates at a Level One Trauma Center: Impact of Best Practice Guidelines. AB - BACKGROUND: Organ availability is a consistently limiting factor in transplant surgery. A primary driver of this limitation is donor conversion rate, which is defined as the percentage of eligible donors for whom procurement is actually performed. An alternative way to increase organ availability is through improved utilization of organs from donors after cardiac death (DCD). Recently, a concerted, multidisciplinary effort has been made within our system to improve conversion rates and DCD utilization, thus increasing organ availability. STUDY DESIGN: Retrospective analysis of a prospectively collected database from TransLife, our local organ procurement organization (OPO), as well as the Orlando Regional Medical Center (ORMC) trauma registry, from 2009-2012 (up to 2013 for DCD). During which time, this organization implemented best practice guidelines to improve conversions and DCD utilization. We analyzed yearly conversion rates, DCD donations and population demographics before and after implementation of these policies. RESULTS: During the study period, donor conversion rates significantly improved from 58% in 2009 to 82% percent in 2012 hospital-wide (P<0.05); and from 50% in 2009 to 81% in 2012 among trauma patients alone (P<0.05). In addition, total organs transplanted increased from 13 to 31 organs (P<0.05) after implementation of best practice guidelines. No significant differences in trauma population demographics were noted during the study period. CONCLUSIONS: Based on our experience, the establishment of best practice policies for referral of potential donors, coupled with programs to educate hospital staff on the existence and importance of these policies, leads to significant improvement in donor conversion rates and increased utilization of DCD donors. PMID- 28018762 TI - Biological Treatment Approaches for Degenerative Disc Disease: A Review of Clinical Trials and Future Directions. AB - Biologic-based treatment strategies for musculoskeletal diseases have gained traction over the past 20 years as alternatives to invasive, costly, and complicated surgical interventions. Spinal degenerative disc disease (DDD) is among the anatomic areas being investigated among this group, notably due to its high incidence and functional debilitation. In this review, we report the literature encompassing the use of biologic-based therapies for DDD. Articles published between January 1995 and November 2015 were reviewed, with a subset meeting the primary and secondary inclusion criteria of clinical trial results that could be sub-classified into bimolecular, cell-based, or gene therapies, as well as studies investigating the utility of allogeneic and tissue-engineered intervertebral discs. Ongoing clinical trials that have not yet published results are also mentioned to present the current state of the field. This exciting area has demonstrated positive and encouraging results across multiple strategies; thus, future bimolecular and regenerative techniques and understanding will likely lead to an increase in the number of human clinical trials assessing these therapies. PMID- 28018763 TI - Predicting Central Venous Pressure by Measuring Femoral Venous Diameter Using Ultrasonography. AB - OBJECTIVES: The objective of this exploratory study was to find out the correlation of femoral vein diameter (FVD) to central venous pressure (CVP) measurements and to derive a prediction equation to help ascertain the fluid volume status in a critical patient. PATIENTS AND METHODS: This was a single centered prospective cohort study designed and conducted by the critical care department of Shifa International hospital in Islamabad, Pakistan. Patients were enrolled from the medical and surgical intensive care units. The inclusion criteria consisted of patients > 18 years of age, and an intrathoracic central venous catheterization (CVC) in place for producing CVP waveform through the transducer. Patients having contraindications to CVP placement and those unable to lie supine were excluded from the study. Critical Care fellows with sufficient training in performing venous ultrasonography measured the FVD. They were blinded to the CVP values of the same patients. RESULTS: The study included 108 patients. Among these 70/108 (64.8%) were males. Mean age was 53.85 (SD=16.74). The CVP and femoral vein diameter were measured in all patients. Mean CVP was 9.89 cmH2O (SD=3.46) and mean femoral vein diameter was 0.92 cm (SD=0.27). Multiple regression was used to generate a prediction model. FVD, age and sex of the patient were used as predictor variables to predict CVP diameter. The model was statistically significant with a p-value of < 0.000 and an F-value of 104.806. R squared value for this model came out to be 0.744, thus the model was able to explain about 74.4% of the variance in the values observed for CVP. When controlled for age and sex, FVD was found highly correlated with CVP diameter with a p-value of < 0.000. A regression equation was derived that can be used to generate predicted values of CVP in millimeters of mercury with an R-square of 0.745 if FVD in centimeters is provided; CVP (cmH2O) = -0.039 + 10.718* FVD. CONCLUSIONS: FVD was found highly correlated to CVP measurements and it suggests an alternate non-invasive method of ascertaining the volume status in the critically ill. PMID- 28018764 TI - Specialty Preferences and the Factors Influencing Them Among Pre-Clerkship Medical Students: The First Study from Alfaisal University-College of Medicine, Saudi Arabia. AB - AIM: To explore the specialty preferences and the factors influencing them among pre-clerkship (second-year and third-year) medical students at Alfaisal University-College of Medicine, Riyadh, Saudi Arabia. METHODS: An online, anonymous, cross-sectional, self-rating survey was administered. The survey explored socio-demographical data, specialty preferences and the factors influencing such preferences. A gender-wise statistical analysis was performed. RESULTS: Two hundred fifty-two students participated in the survey (n=252/308; response rate: 81.8%). The three main specialties chosen by males were general surgery (33.1%), pediatrics (7.9%), and neurology-ophthalmology (5.5%). Females also opted for general surgery (20.8%) followed by dermatology (11.2%) and pediatrics (8.8%). Gender-wise specialty preferences were noted: general surgery (p<0.028) and anesthesiology (p<0.045) by males, whereas obstetrics & gynecology (p<0.017) and dermatology (p<0.005) by females. Overall, the three major influences in choosing a specialty were "specialty interest" (86.5%), "specialty flexibility" (64.3%), and "anticipated income" (61.9%). Statistically significant differences were noticed between genders regarding the following factors: "specialty prestige" (p<0.005) by males and "culture-no opposite gender patients" by females (p<0.009). CONCLUSION: The overall two preferred specialties were general surgery (27%) and pediatrics (8.3%). Career counseling should be offered to students about each specialty's challenges/opportunities with an ultimate goal to match the country-specific demand and supply of physicians. PMID- 28018765 TI - Effect of Multidisciplinary Case Conferences on Physician Decision Making: Breast Diagnostic Rounds. AB - PURPOSE: To evaluate the utility of multidisciplinary case conferences (MCCs) on physician decision making in benign and malignant breast disease management. METHODS: Patients with interesting or challenging diagnostic or management issues were discussed at biweekly diagnostic breast MCCs. Prior to discussion, a clinical summary and intended management plan prior to the MCC was presented. For each case, diagnostic images/histopathology were centrally reviewed after which group discussion achieved a management consensus which was documented prospectively. Initial management plans were compared to the post-MCC consensus. A change in a management plan was defined as a consensus plan different from the pre-MCC plan or no definite plan prior to the MCC. RESULTS: From November 2014 to December 2015, 76 patients (43 malignant and 33 benign diagnoses) were discussed in 19 MCCs. All cases presented resulted in a consensus management recommendation. Thirty-one case discussions (41%) resulted in a changed management plan (20 malignant and 11 benign diagnoses). Management changes included avoidance of immediate surgery (9% of cases), change in the type of surgery (5%), non-invasive investigation to invasive/surgical intervention (7%), and detection of a new suspicious lesion (1%). CONCLUSION: MCCs had a substantial impact on physician decision making. Management plans changed in 41% of cases presented, the majority due to new/clarified diagnostic information. Presentation of cases at MCCs should be encouraged, especially for challenging diagnostic or management issues regarding malignant or benign breast diagnoses. PMID- 28018766 TI - Differentiation of Lung Cancer, Empyema, and Abscess Through the Investigation of a Dry Cough. AB - An acute dry cough results commonly from bronchitis or pneumonia. When a patient presents with signs of infection, respiratory crackles, and a positive chest radiograph, the diagnosis of pneumonia is more common. Antibiotic failure in a patient being treated for community-acquired pneumonia requires further investigation through chest computed tomography. If a lung mass is found on chest computed tomography, lung empyema, abscess, and cancer need to be included on the differential and managed aggressively. This report describes a 55-year-old Caucasian male, with a history of obesity, recovered alcoholism, hypercholesterolemia, and hypertension, presenting with an acute dry cough in the primary care setting. The patient developed signs of infection and was found to have a lung mass on chest computed tomography. Treatment with piperacillin tazobactam and chest tube placement did not resolve the mass, so treatment with thoracotomy and lobectomy was required. It was determined through surgical investigation that the patient, despite having no risk factors, developed a lung abscess. Lung abscesses rarely form in healthy middle-aged individuals making it an unlikely cause of the patient's presenting symptom, dry cough. The patient cleared his infection with proper management and only suffered minor complications of mild pneumoperitoneum and pneumothorax during his hospitalization. PMID- 28018767 TI - A Rare Case of Hemophagocytic Lymphohistiocytosis Associated with Parvovirus B19 Infection. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening syndrome resulting from excessive immune activation. Secondarily, HLH is often associated with autoimmune disease, infection, and malignancy. The most common infectious trigger is Epstein-Barr virus (EBV) infection. HLH is rarely triggered by parvovirus B19. We discuss a case of a 62-year-old male who presented with multi organ failure with presumed septic shock who eventually was diagnosed with HLH, with positive parvovirus B19 deoxyribonucleic acid (DNA) polymerase chain reaction (PCR). Prompt treatment with dexamethasone resulted in significant clinical resolution. PMID- 28018768 TI - Rare Intradural Cervical Nerve Root Metastasis of Follicular Thyroid Carcinoma. AB - Intradural extramedullary nerve root metastasis is extremely unusual with only a handful of cases reported, and it presents most commonly in the thoracic and lumbosacral regions. We report the first case of metastasis to a ventral cervical nerve root in a patient with low-grade follicular thyroid carcinoma thought to be in remission for several years. Histopathology demonstrated malignant transformation and invasion of the nerve root. This case underscores that any history of malignancy regardless of staging, grading, or remission status should raise the suspicion of metastasis as it can mimic other spine and nerve sheath tumors and represent malignant transformation. Gross total resection can be safely achieved with intraoperative neuromonitoring and result in improved function; however, treatment is likely palliative. PMID- 28018769 TI - Significance of Interviral Recombination as Novel Mechanism for Extending Viral Disease Repertoire. AB - The recent observation of interviral recombination between members of two distinct classes of DNA viruses has opened the gates to a new field of human disease development. In all cases studied thus far interviral recombination is a rare event that requires special circumstances for intracellular interaction of participating viral genomes. The rarity and special requirements do not detract from the potential clinical significance of resulting recombinants, as exemplified by recombination between JC viral and Epstein-Barr viral genomes. This significance depends largely upon the mechanisms of recombination that would generate specific forms of recombinant viral genomes. At this time little is known regarding mechanisms of interviral recombination. DNA break-induced replication seems presently to be a highly plausible means of initiating formation of different, potentially active recombination products. Generalizing interviral recombination to a variety of viruses will open a fertile field for discovery as multiple diseases of mysterious etiology are investigated. PMID- 28018770 TI - Role of Physical Exercise, Education and Work Related Measures with the Longevity of Work in Older Population in United States. AB - Growth of older population in United States (US) raises concerns for evaluation of health indices that could sustain their workability. This study aimed to characterize the association of health practices used by older working population and measures of quality and duration of their work. Forty (40) non-treatment seeking healthy working individuals residing within United States within 22 - 75 years of age were included in this study. Data were collected from the Customized Employee Biographical Questionnaire (EBQ) and Occupational Health Surveillance Questionnaire (OHRQ) by age groups as 22 - 31, 32 - 41, 42 - 51, 52 - 61 and 62+ and statistically analyzed. Length of working (LOW) showed close association with the duration of physical exercise (DPE) at adjusted R2 = 0.295 and type of work (TOW) at adjusted R2 = 0.598; and Education in the 62+ (oldest) age group. However such relationship was not observed in the 52 - 61 years age group even when DPE and Education were not significantly different from the 62+ group. In the 42 - 51 age group, significant correlation of LOW with DPE and TOW was found. Duration of physical activity could be an important factor associated with the duration of work in the oldest group. Type of work could be significant modifier in determining the length of working in older age-groups. Predecessor elderly groups might need to incorporate some of the measures that were significant in the oldest group, to improve their expectations to work longer. Larger studies could identify and capture various other measures that could be important both for the regional and national US perspective. PMID- 28018771 TI - Skincare Bootcamp: The Evolving Role of Skincare. AB - BACKGROUND: Although cosmetic procedures have a significant impact on certain aspects of aging, such as deep, wrinkling, sagging, and volume loss, they fail to address the overall quality of the skin. METHODS: Daily skincare routines potentially can have a significant long-term impact on the overall quality of a person's complexion. RESULTS: By expanding our product knowledge, we can help our patients individualize their at-home skincare routine using effective products and ingredients designed to address their specific skin concern and support the professional care we deliver. CONCLUSIONS: Here, we discuss the types of products and ingredients suitable for the most common dermatologic concerns, from wrinkling to skin sensitivity, acne to sun damage. PMID- 28018772 TI - Understanding How to Prevent and Treat Adverse Events of Fillers and Neuromodulators. AB - Experience teaches cosmetic surgeons to become good, but avoiding and treating adverse events make them great. In no area is this more true than in cosmetic procedures involving fillers and neuromodulators. By utilizing knowledge of materials and anatomy involved, specialists seek to avoid complications. A well trained physician is able to reduce the sequelae from an adverse event by acting promptly using algorithms and a methodical approach to treatments. In this article I discuss the difference between perceived and true complications from fillers and neuromodulators, how to avoid, what to look for and how to treat to provide patients with the best possible outcomes, and make the physicians life less stressful. PMID- 28018773 TI - Noninvasive Submental Fat Compartment Treatment. AB - BACKGROUND: KYBELLA, ATX-101, is an injectable form of sodium deoxycholic acid. It is currently the only Food and Drug Administration-approved injectable drug for the reduction of submental fat. OBJECTIVES: A literature review and discussion of the treatment of submental fat. RESULTS: KYBELLA is a well tolerated alternative for the treatment of submental fat. CONCLUSIONS: KYBELLA is a safe and efficacious, first in class, injectable drug for the reduction of submental fat. PMID- 28018774 TI - The Unique Value of Core-only Continuing Medical Education. AB - The importance of training in minimally invasive cosmetic procedures is essential to insure safe outcomes for patients. Board certification in the appropriate specialty is one way to improve aesthetic outcomes. Meetings that consider appropriate residency training for admission can help achieve this goal. PMID- 28018775 TI - Review of 3-dimensional Facial Anatomy: Injecting Fillers and Neuromodulators. AB - To achieve consistent results utilizing facial injectables, practitioners must understand the pertinent anatomy of the forehead, temple, cheek, nose, and perioral areas. A detailed understanding of facial blood vessels, nerves, and musculature is essential for safe and effective placement of fillers and neuromodulators. PMID- 28018776 TI - Three-dimensional Facial Anatomy: Structure and Function as It Relates to Injectable Neuromodulators and Soft Tissue Fillers. AB - BACKGROUND: The advent of new neuromodulators and soft-tissue fillers continues to expand the nonsurgical repertoire of the core cosmetic physician. METHODS: The authors review relevant facial anatomy as it relates to facial aging and the resultant structural changes that occur. These changes are important for the cosmetic physician to identify and understand in order to perform both safe and effective placement of neuromodulators and soft-tissue fillers. In this anatomic review, the authors review key structures that serve as landmarks for successful treatment using both neuromodulators and fillers. CONCLUSIONS: Knowledge of key facial anatomical structures allows the cosmetic physician to perform injection of neuromodulators and soft-tissue fillers in a reproducible manner to optimizing patient safety and results. PMID- 28018777 TI - Global Updates on the Future Directions of Neurotoxins and Fillers. AB - Neurotoxins and fillers continue to remain in high demand, comprising a large part of the growing business of cosmetic minimally invasive procedures. Multiple Food and Drug Administration-approved safe yet different products exist within each category, and the role of each product continues to expand. The authors review the literature to provide an overview of the use of neurotoxins and fillers and their future directions. PMID- 28018779 TI - Exponential operations and aggregation operators of interval neutrosophic sets and their decision making methods. AB - An interval neutrosophic set (INS) is a subclass of a neutrosophic set and a generalization of an interval-valued intuitionistic fuzzy set, and then the characteristics of INS are independently described by the interval numbers of its truth-membership, indeterminacy-membership, and falsity-membership degrees. However, the exponential parameters (weights) of all the existing exponential operational laws of INSs and the corresponding exponential aggregation operators are crisp values in interval neutrosophic decision making problems. As a supplement, this paper firstly introduces new exponential operational laws of INSs, where the bases are crisp values or interval numbers and the exponents are interval neutrosophic numbers (INNs), which are basic elements in INSs. Then, we propose an interval neutrosophic weighted exponential aggregation (INWEA) operator and a dual interval neutrosophic weighted exponential aggregation (DINWEA) operator based on these exponential operational laws and introduce comparative methods based on cosine measure functions for INNs and dual INNs. Further, we develop decision-making methods based on the INWEA and DINWEA operators. Finally, a practical example on the selecting problem of global suppliers is provided to illustrate the applicability and rationality of the proposed methods. PMID- 28018778 TI - Technical Considerations for Filler and Neuromodulator Refinements. AB - Background: The toolbox for cosmetic practitioners is growing at an unprecedented rate. There are novel products every year and expanding off-label indications for neurotoxin and soft-tissue filler applications. Consequently, aesthetic physicians are increasingly challenged by the task of selecting the most appropriate products and techniques to achieve optimal patient outcomes. Methods: We employed a PubMed literature search of facial injectables from the past 10 years (2005-2015), with emphasis on those articles embracing evidence-based medicine. We evaluated the scientific background of every product and the physicochemical properties that make each one ideal for specific indications. The 2 senior authors provide commentary regarding their clinical experience with specific technical refinements of neuromodulators and soft-tissue fillers. Results: Neurotoxins and fillers are characterized by unique physical characteristics that distinguish each product. This results in subtle but important differences in their clinical applications. Specific indications and recommendations for the use of the various neurotoxins and soft-tissue fillers are reviewed. The discussion highlights refinements in combination treatments and product physical modifications, according to specific treatment zones. Conclusions: The field of facial aesthetics has evolved dramatically, mostly secondary to our increased understanding of 3-dimensional structural volume restoration. Our work reviews Food and Drug Administration-approved injectables. In addition, we describe how to modify products to fulfill specific indications such as treatment of the mid face, decolletage, hands, and periorbital regions. Although we cannot directly evaluate the duration or exact physical properties of blended products, we argue that "product customization" is safe and provides natural results with excellent patient outcomes. PMID- 28018780 TI - 1,3-Dipolar [3 + 2] cycloaddition reactions of N,C,C-trisubstituted nitrones with ring-acceptor methylenecyclopropanes: a computational study. AB - BACKGROUND: 1,3-Dipolar [3 + 2]-cycloaddition of nitrones to the carbon-carbon double bonds of methylenecyclopropanes yields a mixture of regioisomeric 4- and 5 isoxazolidines. The mechanisms of the reactions of N,C,C-trisubstituted nitrones with ring acceptor substituted dimethyl methylenecyclopropanes-1,2-dicarboxylate and aryl methylidene cyclopropanes-1,1-dicarboxylate have been investigated with the Becke 3-Parameter Lee-Yang-Par exchange-correlation functional, a Hartree Fock DFT hybrid functional, to delineate the factors responsible for the regioselectivity of these class of reactions. FINDINGS: The energetics of the reaction of the phenyl-substituted nitrone with unsubstituted methylenecyclopropane indicate that the formation of the 5-spirocyclopropane is favored over the 4-spirocyclopropane kinetically and thermodynamically. However, the energetics of the reaction of the same phenyl nitrone with vicinal ester ( CO2CH3)-substituted methylenecyclopropane show an inversion in the regioselectivity favoring the formation of the 4-regioisomer over the 5 regioisomer. For the reactions of N,C,C-trisubstituted nitrone with vicinal ester (-CO2CH3)-substituted methylenecyclopropane (-R1=H, -R2=Ph and -R1=CH3 and R2=CO2CH3) and geminal ester (-CO2CH3)-substituted methylenecyclopropane (R3=H, R4=H; R3=OCH3, R4=CH3; and R3=H, R4=Cl), the energetics indicate that the 5 spirocyclopropane is favored over the 4-spirocyclopropane. The calculations also indicate that electron-donating groups increase regioselectivity of the 5 regioisomers over the 4-regioisomers. CONCLUSION: The regioselectivity of these reactions is determined by both electronic and steric factors. The pathways with the lower activation barrier leads to the more stable regioisomer in all cases, implying that the pathways that are kinetically favored are also thermodynamically favored. However, it is also clear from the energetics that these reactions are not reversible and are therefore under kinetic control. Therefore the selectivity of the reactions is governed solely by the difference in activation barriers leading to the two isomers and not in any way by the thermodynamic stability of the isomers formed. PMID- 28018781 TI - Complementary feeding practices among mothers and nutritional status of infants in Akpabuyo Area, Cross River State Nigeria. AB - BACKGROUND: Malnutrition in infants during weaning has been attributed to inappropriate complementary feeding practices and it underlies more than one third of child mortality in Nigeria. Thus, addressing the influence of complementary feeding practice on nutritional status may be an important approach to reducing the burden of child malnutrition. This cross-sectional study investigated the association between complementary feeding practices among mothers and nutritional status of their infants in Akpabuyo Local Government Area, Nigeria. The study enrolled 330 mother-child pairs from 10 randomly selected out of 32 Health Facilities in Akpabuyo. Socio-demographic information, child and maternal characteristics were obtained using an interviewer administered questionnaire. Complementary feeding practices were assessed with World Health Organization infant and young child feeding indicators. Nutritional indicators wasting, underweight and stunting were determined. RESULTS: Prevalence of timely introduction of complementary feeding among infants aged 6-8 months was 85.4%, minimum dietary diversity rate was 31.5%, and minimum meal frequency 36.7%, the rate of minimum acceptable diet was 7.3%. One-third (33.3%) of the infants were underweight, 26.4%, wasted and 24.6%, stunted. Children who did not receive timely complementary foods had higher odds for wasting (OR 5.15; 95% CI 1.50-17.73). Children who did not receive the minimum dietary diversity had higher odds for underweight than children who received the minimum dietary diversity (OR 2.07; 95% CI 1.17-3.70). Children who did not receive the minimum feeding frequency were more likely to be stunted than their peers who received the minimum feeding frequency (OR 1.57; 95% CI 1.53-4.03). CONCLUSION: Sub optimal complementary feeding predisposed to infant's malnutrition. PMID- 28018782 TI - Training and business performance: the mediating role of absorptive capacities. AB - BACKGROUND: Training has been the focus of considerable conceptual and empirical attention but is considered a relevant factor for competitive edge in companies because it has a positive impact on business performance. This study is justified by the need for deeper analysis of the process involving the transfer of training into performance. This paper's originality lies in the implementation of the absorptive capacities approach as an appropriate conceptual framework for designing a model that reflects the connection between training and business performance through absorptive capacities. RESULTS: Based on the above conceptual framework and using the dual methodological implementation, a new method of analyzing the relationship between training and performance was obtained: efforts in training will not lead to performance without the mediation of absorptive. CONCLUSIONS: Training turns into performance if absorptive capacities are involved in this process. The suggested model becomes an appropriate framework for explaining the process of transformation of training into organizational performance, in which absorptive capacities play a key role. The findings obtained can go further owing to fs/QCA: of the different absorptive capacities, that of exploitation is a necessary condition to achieve better organizational performance. Therefore, training based on absorptive capacity will guide and facilitate the design of appropriate human resource strategies so that training results in improved performance. This conclusion is relevant for the development of a new facet of absorptive capacities by relating it to training and resulting in first-level implications for human resource management. PMID- 28018783 TI - Strategies to reconstruct 3D Coffea arabica L. plant structure. AB - Accurate model of structural elements is necessary to model the foliage and fruit distributions in cultivated plants, both of them being key parameters for yield prediction. However, the level of details in architectural data collection could vary, simplifying the data collection when plants get older and because of the high time cost required. In the present study, we aimed at reconstructing and analyzing plant structure, berry distributions and yield in Coffea arabica (Arabica coffee), by using both detailed or partial morphological information and probabilistic functions. Different datasets of coffee plant architectures were available with different levels of detail depending on the tree age. Three scales of decomposition-plant, axes and metamers were used reconstruct the plant architectures. CoffePlant3D, a software which integrates a series of mathematical, computational and statistical methods organized in three newly developed modules, AmostraCafe3D, VirtualCafe3D and Cafe3D, was developed to accurately reconstruct coffee plants in 3D, whatever the level of details available. The number of metamers of the 2nd order axes was shown to be linearly proportional to that of the orthotropic trunk, and the number of berries per metamer was modeled as a Gaussian function within a specific zone along the plagiotropic axes. This ratio of metamer emission rhythm between the orthotropic trunk and plagiotropic axes represents the pillar of botanical events in the C. arabica development and was central in our modeling approach, especially to reconstruct missing data. The methodology proposed for reconstructing coffee plants under the CoffePlant3D was satisfactorily validated across dataset available and could be performed for any other Arabica coffee variety. PMID- 28018784 TI - Efficient method for transfer of microinjected eggs to mouse ampulla for generating transgenic mice. AB - BACKGROUND: The new method described here is highly efficient in transferring microinjected mouse eggs (MEs) through the bursa membrane of a surrogate mother mouse to the ampulla of the oviduct without damaging the blood vessels on the bursa membrane. RESULTS: This method causes no loss of blood, and it produces newborn pups/founders from approximately 70% of the transferred MEs, because only a small hole is made on the blood vessel-free area of the bursa membrane and ampulla of the surrogate mother mouse. The infundibulum remains intact. The small hole on the bursa membrane/ampulla may already heal up before the delivery of the new pups. The method described here consists of a simple operation with a home assembled drill head holding a self-closing fine forceps on one end, while the drill head assembly body is hooked up with the light housing clamp of a dissecting light microscope. The drill head assembly body can be alternatively hooked/tied up to an appropriate size of clamp (purchased from Home Depot) screwed to any light stand with folding segments. CONCLUSION: This system is able to steadily hold the self-closing fine forceps without shaking and to let the operator use their two hands to steadily hold and quickly insert the pipet carrying the MEs into the ampulla without any delay. Generally MEs stay alive for approximately 15 min at room temperature. The shorter the insertion time is, the more MEs that will survive. Thus, this method may produces more pups/founders. PMID- 28018785 TI - Pressure drop of two-phase helium along long cryogenic flexible transfer lines to support a superconducting RF operation at its cryogenic test stand. AB - BACKGROUND: Establishing a stand-alone cryogenic test stand is of vital importance to ensure the highly reliable and available operation of superconducting radio-frequency module in a synchrotron light source. Operating a cryogenic test stand relies strongly on a capability to deliver two-phase helium along long cryogenic transfer lines. A newly constructed cryogenic test stand with flexible cryogenic transfer lines of length 220 m at National Synchrotron Radiation Research Center is required to support a superconducting radio frequency module operated at 126.0 kPa with a 40-W dynamic load for a long-term reliability test over weeks. It is designed based on a simple analytical approach with the introduction of a so-called tolerance factor that serves to estimate the pressure drops in transferring a two-phase helium flow with a substantial transfer cryogenic heat load. Tolerance factor 1.5 is adopted based on safety factor 1.5 commonly applied in cryogenic designs to estimate the total mass flow rate of liquid helium demanded. A maximum 60-W dynamic load is verified with experiment measured with heater power 60 W instead after the cryogenic test stand has been installed. RESULTS: Aligning the modeled cryogenic accumulated static heat load with the results measured in situ, actual tolerance factor 1.287 is obtained. The feasibility and validity of our simple analytical approach with actual tolerance factor 1.287 have been scrutinized by using five test cases with varied operating conditions. Calculated results show the discrepancies of the pressure drops between the estimated and measured values for both liquid helium and cold gaseous helium transfer lines have an underestimate 0.11 kPa and an overestimate 0.09 kPa, respectively. A discrepancy is foreseen, but remains acceptable for engineering applications from a practical point of view. CONCLUSIONS: The simple analytical approach with the introduction of a tolerance factor can provide not only insight into optimizing the choice of each lossy cryogenic piping element of the transfer lines in the design phase but also firm guidance for upgrading the present cryogenic transfer lines for its subsequent application. PMID- 28018786 TI - Chinese insurance agents in "bad barrels": a multilevel analysis of the relationship between ethical leadership, ethical climate and business ethical sensitivity. AB - BACKGROUND: The moral hazards and poor public image of the insurance industry, arising from insurance agents' unethical behavior, affect both the normal operation of an insurance company and decrease applicants' confidence in the company. Contrarily, these scandals may demonstrate that the organizations were "bad barrels" in which insurance agents' unethical decisions were supported or encouraged by the organization's leadership or climate. OBJECTIVE: The present study brings two organization-level factors (ethical leadership and ethical climate) together and explores the role of ethical climate on the relationship between the ethical leadership and business ethical sensitivity of Chinese insurance agents. RESULTS: Through the multilevel analysis of 502 insurance agents from 56 organizations, it is found that organizational ethical leadership is positively related to the organizational ethical climate; organizational ethical climate is positively related to business ethical sensitivity, and organizational ethical climate fully mediates the relationship between organizational ethical leadership and business ethical sensitivity. CONCLUSIONS: Organizational ethical climate plays a completely mediating role in the relationship between organizational ethical leadership and business ethical sensitivity. The integrated model of ethical leadership, ethical climate and business ethical sensitivity makes several contributions to ethics theory, research and management. PMID- 28018787 TI - Heavy metal accumulation during the last 30 years in the Karnaphuli River estuary, Chittagong, Bangladesh. AB - Heavy metal contamination of aquatic environment has attracted global attention owing to its abundance, persistence, and environmental toxicity, especially in developing countries like Bangladesh. Five heavy metals, namely chromium (Cr), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) were investigated in surface and core sediments of the Karnaphuli River (KR) estuary in Chittagong, Bangladesh, in order to reveal the heavy metal contamination history in estuarine sediments and its response to catastrophic events and human activities. The surface sediment was predominantly composed of silt and sand, and the surface sediment was contaminated with Cr and Pb. Based on the 210Pb chronology, the sedimentation rate in the inter-tidal zone of KR estuary was 1.02 cm/a before 2007, and 1.14 cm/a after 2008. The core sediment collected from 8 to 20 cm below the surface mainly originated from terrestrial materials induced by catastrophic events such as cyclone, heavy rainfall and landslides in 2007 and 2008. The values of contamination factor (CF) showed that the sediment became moderately contaminated with Cr and Pb in the last 30 years. The variation and accumulation of heavy metals in core sediment before 2000 was mainly related to natural variations in sediment sources; however, in subsequent years, the anthropogenic inputs of heavy metals have increased due to rapid physical growth of urban and industrial areas in the Chittagong city. In general, the accumulation pattern of heavy metals after normalization to Aluminum in sediments of KR estuary indicated an accelerated rate of urbanization and industrialization in the last 30 years, and also suggested the influence of natural catastrophic event on estuarine environment. PMID- 28018788 TI - Efficacy of triple antiemetic therapy (palonosetron, dexamethasone, aprepitant) for chemotherapy-induced nausea and vomiting in patients receiving carboplatin based, moderately emetogenic chemotherapy. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a major adverse toxicity of cancer chemotherapy. Recommended treatments for prevention of CINV vary among published guidelines, and optimal care for CINV caused by moderately emetogenic chemotherapy has not been established. This study assessed the efficacy and safety of triple antiemetic therapy comprising palonosetron, dexamethasone and aprepitant for carboplatin-based chemotherapy. Chemotherapy naive patients with lung cancer scheduled for a first course of a carboplatin containing regimen formed the study cohort. Patients were pretreated with antiemetic therapy comprising palonosetron (0.75 mg, i.v.) and dexamethasone (9.9 mg, i.v.) on day 1, and aprepitant (125 mg, p.o.) on day 1 followed by 80 mg on days 2 and 3. Primary endpoint was the proportion of patients who did not experience vomiting and did not require rescue medication [complete response (CR)] in the acute phase (0-24 h), late phase (24-168 h) and overall. Secondary endpoint was the proportion of patients who experienced no vomiting episodes and no more than mild nausea without the need for rescue medication [complete control (CC)]. RESULTS: Prevalence of a CR during the acute phase, delayed phase, and overall was 100, 91.9 and 91.9%, whereas that of CC was 100, 84.4 and 84.4%, respectively. The most common adverse event was mild constipation; severe adverse events related to antiemetic treatment were not observed. CONCLUSION: Triple antiemetic therapy comprising palonosetron, dexamethasone and aprepitant shows excellent effects in the prevention of CINV in patients receiving a carboplatin containing regimen. PMID- 28018789 TI - Evaluation of spatial analysis application for urban emergency management. AB - BACKGROUND: This paper provides multidisciplinary scope to the utilization of geospatial data frameworks for urban disaster management with accentuation on particular events. The emergency management events presented in this review are universally known and represent high risk for different parts of the world. RESULTS: The discussion starts with addressing the application issues related to how spatial analysis can be used intending to disaster management operations by characterizing its ease of use and impediments in managing the inquiries of vulnerability and hazard assessment. It also highlights best practices for the approaches to integrating spatial data for hazard mapping and risk perception. CONCLUSIONS: The goal of this study is to give conceptual coverage to appropriate solutions for emergency preparedness and response, using spatial analysis and GIS. The paper emphasized that among different issues that may confront the use of spatial analysis, is the accuracy of data and time of processing, in addition to collective coordination of stakeholders working in the field. The findings of this research conclude that a challenge to possible risk reduction is furnishing disaster managers with access to information and methodologies that may help them in analyzing, evaluating and mapping hazard models. PMID- 28018790 TI - Reliability of the Aboriginal Children's Health and Well-Being Measure (ACHWM). AB - PURPOSE: The aim of this research was to evaluate the reliability of the Aboriginal Children's Health and Well-Being Measure(c) (ACHWM). METHODS: Two cohorts of children from Wiikwemkoong Unceded Territory were recruited for this study. Each child completed the ACHWM independently on a computer tablet running a customized survey app. The data from the first and second cohorts were used to estimate the internal consistencies using Cronbach's alpha. A subgroup of the second cohort completed the survey twice, within the same day. The data from this subgroup was used to evaluate the test-retest reliability using a random effects Intra-class Correlation Coefficient (ICC). RESULTS: There were 124 participants in the first cohort and 132 participants in the second cohort. The repeated measures subgroup was comprised of 29 participants from the second cohort. The internal consistency statistic (Cronbach's alpha) was 0.93 for the first and second cohorts. The test-retest reliability ICC was 0.94 (95% CI 0.86-0.97) for the ACHWM summary scores based on the repeated measures subgroup. CONCLUSIONS: These results establish the internal consistency and the test-retest validity of the ACHWM. This important finding will enable Aboriginal communities to use this measure with confidence and promote the voices of their children in reporting their health. The ACHWM is an essential data gathering tool that enables evidence based health care for Aboriginal communities. PMID- 28018791 TI - Successful ceritinib treatment in a man with MPE and an ALK fusion gene mutation after multiple treatments. AB - INTRODUCTION: Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor. It inhibits two of the most common ALK-mutants that confer resistance to crizotinib. Ceritinib was approved by Food and Drug Administration in April 2014. However, the efficacy of ceritinib in Asian patients have not been widely studied. Decrease of malignant pleural effusion (MPE) has been rarely reported after treatment with ceritinib. CASE DESCRIPTION: A 50-year old man diagnosed with stage IV lung adenocarcinoma presented with MPE and an ALK fusion gene mutation. The patient showed partial response to ceritinib after 2-month treatment. Ultrasound showed MPE significantly decreased. DISCUSSION AND EVALUATION: Ceritinib is a good choice, as a targeted therapy, which is more prospect in the advanced cancer patients than the traditional therapy. CONCLUSION: Ceritinib seems to have a good efficacy in reducing MPE in advanced Asian lung adenocarcinoma patients, when other chemotherapy failed. PMID- 28018792 TI - Erratum to: Identification of mutations, gene expression changes and fusion transcripts by whole transcriptome RNAseq in docetaxel resistant prostate cancer cells. AB - [This corrects the article DOI: 10.1186/s40064-016-3543-0.]. PMID- 28018793 TI - Erratum to: On the average temperature of airless spherical bodies and the magnitude of Earth's atmospheric thermal effect. AB - [This corrects the article DOI: 10.1186/2193-1801-3-723.]. PMID- 28018794 TI - Rice grain nutritional traits and their enhancement using relevant genes and QTLs through advanced approaches. AB - BACKGROUND: Rice breeding program needs to focus on development of nutrient dense rice for value addition and helping in reducing malnutrition. Mineral and vitamin deficiency related problems are common in the majority of the population and more specific to developing countries as their staple food is rice. RESULTS: Genes and QTLs are recently known for the nutritional quality of rice. By comprehensive literature survey and public domain database, we provided a critical review on nutritional aspects like grain protein and amino acid content, vitamins and minerals, glycemic index value, phenolic and flavonoid compounds, phytic acid, zinc and iron content along with QTLs linked to these traits. In addition, achievements through transgenic and advanced genomic approaches have been discussed. The information available on genes and/or QTLs involved in enhancement of micronutrient element and amino acids are summarized with graphical representation. CONCLUSION: Compatible QTLs/genes may be combined together to design a desirable genotype with superior in multiple grain quality traits. The comprehensive review will be helpful to develop nutrient dense rice cultivars by integrating molecular markers and transgenic assisted breeding approaches with classical breeding. PMID- 28018796 TI - An empirical research on evaluating banks' credit assessment of corporate customers. AB - BACKGROUND: Under the rapid change of the global financial environment, the risk control of the credit granting is viewed as the foremost task to each bank. With the impact one by one from financial crisis and European debt crisis, the steady bank business is also facing the severe challenge. Banks approve the credits for their customers and then make money from the interest. CASE PRESENTATION: Credit granting is not only the primary job but also the main source of income. The quality of credit granting concerns not just the reclaims of creditor's rights; it also affects the successful running of banks. DISCUSSION AND EVALUATION: To enhance the reliability and usefulness of bank credit risk assessment, we first will delve in the facets and indexes in the bank credit risk assessment. Then, we will examine the different dimensions of cause-effect relationships and correlations in the assessment process. Finally, the study focuses on how to raise the functions and benefits of the bank credit risk assessment. CONCLUSIONS: In those five credit risk evaluation dimensions, A "optional capability" and D "competitiveness" are of high relation and high prominence among those dimensions, influencing other items obviously. By actively focusing on these two dimensions and improving their credit risk assessment ability will solve the foremost problems and also solve other facets of credit risk assessment problems at the same time. PMID- 28018795 TI - Nephrotoxicity of methadone: a systematic review. AB - BACKGROUND: Methadone is commonly administered for chronic pain relief and treatment of opioid dependence. Concurrent with its increased consumption, toxicities and fatalities have increased. One of the adverse effects of opioid analgesics, including methadone, is that of nephrotoxicity. Opioids can have an effect on renal function through several different mechanisms. METHODS: We searched common bibliographical databases for the terms methadone, toxicity, poisoning, kidney, renal, and nephrotoxicity and summarize our findings in this review. RESULTS: Methadone can have both direct and indirect effects on the kidney. These effects include rhabdomyolysis (leading to acute kidney injury), volumetric changes, renal lipidosis and amyloidosis, kidney growth during pregnancy, and kidney transplant rejection. CONCLUSION: Improved understanding of the effects of methadone on kidney function can promote safer and more confident use of the drug. PMID- 28018797 TI - Long memory mean and volatility models of platinum and palladium price return series under heavy tailed distributions. AB - South Africa is a cornucopia of the platinum group metals particularly platinum and palladium. These metals have many unique physical and chemical characteristics which render them indispensable to technology and industry, the markets and the medical field. In this paper we carry out a holistic investigation on long memory (LM), structural breaks and stylized facts in platinum and palladium return and volatility series. To investigate LM we employed a wide range of methods based on time domain, Fourier and wavelet based techniques while we attend to the dual LM phenomenon using ARFIMA-FIGARCH type models, namely FIGARCH, ARFIMA-FIEGARCH, ARFIMA-FIAPARCH and ARFIMA-HYGARCH models. Our results suggests that platinum and palladium returns are mean reverting while volatility exhibited strong LM. Using the Akaike information criterion (AIC) the ARFIMA-FIAPARCH model under the Student distribution was adjudged to be the best model in the case of platinum returns although the ARCH effect was slightly significant while using the Schwarz information criterion (SIC) the ARFIMA-FIAPARCH under the Normal Distribution outperforms all the other models. Further, the ARFIMA-FIEGARCH under the Skewed Student distribution model and ARFIMA-HYGARCH under the Normal distribution models were able to capture the ARCH-effect. In the case of palladium based on both the AIC and SIC, the ARFIMA FIAPARCH under the GED distribution model is selected although the ARCH-effect was slightly significant. Also, ARFIMA-FIEGARCH under the GED and ARFIMA-HYGARCH under the normal distribution models were able to capture the ARCH-effect. The best models with respect to prediction excluded the ARFIMA-FIGARCH model and were dominated by the ARFIMA-FIAPARCH model under Non-normal error distributions indicating the importance of asymmetry and heavy tailed error distributions. PMID- 28018798 TI - Exact solutions for unsteady free convection flow over an oscillating plate due to non-coaxial rotation. AB - BACKGROUND: Non-coaxial rotation has wide applications in engineering devices, e.g. in food processing such as mixer machines and stirrers with a two-axis kneader, in cooling turbine blades, jet engines, pumps and vacuum cleaners, in designing thermal syphon tubes, and in geophysical flows. Therefore, this study aims to investigate unsteady free convection flow of viscous fluid due to non coaxial rotation and fluid at infinity over an oscillating vertical plate with constant wall temperature. METHODS: The governing equations are modelled by a sudden coincidence of the axes of a disk and the fluid at infinity rotating with uniform angular velocity, together with initial and boundary conditions. Some suitable non-dimensional variables are introduced. The Laplace transform method is used to obtain the exact solutions of the corresponding non-dimensional momentum and energy equations with conditions. Solutions of the velocity for cosine and sine oscillations as well as for temperature fields are obtained and displayed graphically for different values of time (t ), the Grashof number (Gr), the Prandtl number ([Formula: see text]), and the phase angle ([Formula: see text]). Skin friction and the Nusselt number are also evaluated. RESULTS: The exact solutions are obtained and in limiting cases, the present solutions are found to be identical to the published results. Further, the obtained exact solutions also validated by comparing with results obtained by using Gaver Stehfest algorithm. CONCLUSION: The interested physical property such as velocity, temperature, skin friction and Nusselt number are affected by the embedded parameters time (t), the Grashof number (Gr), the Prandtl number ([Formula: see text]), and the phase angle ([Formula: see text]). PMID- 28018799 TI - Caudal Duplication Syndrome: the Vital Role of a Multidisciplinary Approach and Staged Correction. AB - Caudal duplication syndrome is a rare entity that describes the association between congenital anomalies involving caudal structures and may have a wide spectrum of clinical manifestations. A full-term male presented with combination of anomalies including anorectal malformation, duplication of the colon and lower urinary tract, split of the lower spine, and lipomyelomeningocele with tethering of the cord. We report this exceptional case of caudal duplication syndrome with special emphasis on surgical strategy and approach combining all disciplines involved. The purpose of this report is to present the pathology, assessment, and management strategy of this complex case. PMID- 28018800 TI - Total Esophageal Gastric Dissociation for the Failed Antireflux Procedure in a Child with Microgastria. AB - Microgastria is a very rare anomaly characterized by a very small tubular stomach that presents with severe gastroesophageal reflux disease due to the small reservoir capacity of the stomach. We present a patient with microgastria-related reflux and a failed fundoplication who was treated with total esophageal gastric dissociation (TEGD) resulting in an excellent outcome. In our experience with this good long-term result, we would suggest that TEGD be added to the armamentarium of procedures that can be used in the treatment of microgastria. PMID- 28018801 TI - Thoracoscopic Approach for Congenital Diaphragmatic Hernia: A Useful Tool in Diagnosis and Treatment of Unexpected Associated Lung Lesion. AB - We report the case of a neonate affected by prenatally diagnosed congenital diaphragmatic hernia (CDH), treated by thoracoscopy. During the procedure, we detected an associated extralobar pulmonary sequestration (EPS), which was preoperatively undiagnosed, and we removed it. EPS has been shown to be associated with CDH in up to 15 to 40% of cases. A possible explanation hypothesized is that pulmonary sequestration, which develops at 4 to 5 weeks of gestation, can disturb the fusion of the diaphragm and closure of the pleuroperitoneal canal. The thoracoscopic approach permitted us to identify the thoracic EPS that probably would have been otherwise missed. PMID- 28018802 TI - Anterior Sagittal Approach and Total Urogenital Mobilization for the Treatment of Persistent Urogenital Sinus in a 2-Year-Old Girl. AB - Persistent urogenital sinus (UGS) is a developmental anomaly. It represents one of the most complex problems that a pediatric surgeon may deal with. We report the case of a patient with UGS treated at 3 years of age by anterior sagittal transrectal approach and en bloc sinus mobilization. The procedure was performed with the patient prone with the initial idea of performing an anterior sagittal transrectal approach. The described approach allows an excellent anatomical view with a midline muscle sparing incision, along with an easy identification of the vaginal confluence with the benefit of avoiding dissection between the urethra and vagina. PMID- 28018803 TI - Neonatal Gardner Fibroma Leads to Detection of Familial Adenomatous Polyposis: Two Case Reports. AB - Gardner fibromas (GFs) have only recently been described as poorly circumscribed tumor-like lesions, which are exceedingly rare in children. GFs are associated with APC gene mutations and therefore with familial adenomatous polyposis (FAP). So far there is only very limited literature on GF in the neonatal period. We present two children with GF diagnosed at birth and subsequent FAP with very different clinical courses. In one case, the disease led to extensive surgery of the thoracic wall and detection of FAP in the father with the need of immediate proctocolectomy. In the other patient (with a positive family history for FAP) the disease remained stable. Our cases indicate that the diagnosis of GF in the neonatal period requires the exclusion of FAP both in the child as well as the parents. Since the clinical behavior of GF cannot be predicted, continuous monitoring is mandatory. Depending on tumor site and growth, individual therapeutic options must be thoroughly considered. Surgical resection, if necessary, has to be inevitably total to prevent recurrence. PMID- 28018804 TI - Extracalvarial Composite Infantile Myofibromatosis: Case Report and Literature Review. AB - Infantile soft tissue tumors of the head are very rare and the majority of them are myofibromas. The authors present the case of a 1-day-old boy with a scalp tumor with several distinct histopathological features including myofibroma, hemangiopericytoma, and fibrosarcoma consistent with the diagnosis of composite infantile myofibromatosis. Genetic testing was negative for trisomy 17, translocation (12; 15), FUS, and ETV6 translocations. Despite the ominous histopathological features, the clinical course was benign. The authors review here available literature concerning current concepts of making the diagnosis of composite infantile myofibromatosis and discuss treatment options. PMID- 28018805 TI - Three-Dimensional Custom-Made Titanium Ribs for Reconstruction of a Large Chest Wall Defect. AB - Reconstruction of large chest wall defects always demand surgeons of having lots of means available (both materials and resourceful) to apply a cover to chest wall defects which can range from a few centimeters to the lack of a few entire ribs. In this study, we present the case of a teenager who suffered from a complete resection of three ribs because of Ewing sarcoma dependent on the sixth rib. Given the size of the defect, a multidisciplinary approach was chosen to provide rigid and soft tissue coverage and minimal functional and aesthetic impact. Custom-made titanium implants were designed based on three-dimensional computed tomography scan reconstruction. The surgical specimen via a left lateral thoracotomy (fifth, sixth, and seventh entire ribs) was resected, leaving a defect of 35 * 12 * 6 cm. A Gore-Tex patch (W. L. Gore & Associates, Arizona, United States) was placed and, after that, the implants were anchored to the posterior fragment of the healthy ribs and to the costal cartilage anteriorly. Finally, the surgical site was covered with a latissimus dorsi flap. The postoperative course was uneventful. After 9 months of follow-up, the patient has full mobility. This case shows that the implant of custom-made ribs, combined with other techniques, is a good surgical choice for reconstruction of large chest wall defects. The implant of custom-made ribs, combined with other techniques, is a good surgical choice for reconstruction of large chest wall defects. PMID- 28018806 TI - Management of Familial Ovarian Teratoma: The Need for Guidance. AB - Ovarian teratomas in prepubertal females are uncommon, but familial ones are exceedingly rare. We report an ovarian teratoma in an 8-year-old girl, her mother, and her maternal grandmother. The risk of a metachronous tumor and subsequent complications (such as torsion) in the contralateral ovary remain unclear. There is no clear guidance on follow-up management of patient and family members in the literature. We have reviewed the literature and discuss the challenges for the pediatric surgeon arising from such cases. PMID- 28018807 TI - Urethral Duplication with Two Hypospadic Meati-An Unusual Variant. AB - Duplication of the urethra is a rare congenital anomaly, with approximately 300 cases reported in the literature. We report a unique case of this condition in a male infant. This case differs from the classical Effman type II-A2 duplication because of the presence of two hypospadic urethral meati, as opposed to a ventral or dorsal accessory meatus with a normally positioned distal urethra. The patient underwent a single-stage repair consisting of a proximal urethra-urethral anastomosis and distal urethral tubularization at 21 months of age with excellent results in terms of both function and cosmesis. PMID- 28018808 TI - The 17th Annual Congress of the European Pediatric Surgeons' Association. PMID- 28018809 TI - Airway Management via Laryngeal Mask in Laryngotracheal Resection. AB - We present a case of impassable subglottic stenosis scheduled for tracheal resection and reconstruction managed by establishing a supraglottic airway. Despite careful preoperative evaluation, the stenosis was localized higher than anticipated, rendering conventional intubation impossible. Laryngeal mask bridging to cross-field ventilation was feasible and jet ventilation and cardiopulmonary bypass were available as emergency strategies. Surgery and emergence went uneventful. Perioperative considerations are discussed in this report. PMID- 28018810 TI - Transmediastinal Trachea Closure after Dilational Tracheotomy Positioned Too Low Down. AB - Dilational tracheotomy is a minimally invasive method that can be performed at the bedside on patients requiring long-term mechanical ventilation. In our 70 year-old male patient, percutaneous dilational tracheotomy (Ciaglia Blue Rhino, Cook Medical Inc., Bloomington, Indiana, United States) was performed because of bilateral pneumonia with sepsis. There were no initial problems. Nine days later, while the patient was being repositioned, the tracheal cannula became dislocated. Despite extending the cervical incision it was not possible to recannulate. The tracheal hole could not be felt with certainty by palpating through the incision. After several unsuccessful attempts, the patient was intubated orally. The only way to achieve sufficient ventilation was to hold the tracheostoma closed. Bronchoscopy showed that the entry point of the tracheal cannula was ventral and ~1.5 cm above the main carina. The tube was then advanced into the right main bronchus and the patient was thus ventilated unilaterally. On exposure of the trachea, a grade 3 goiter was revealed. Total neck length was short. Only after the video mediastinoscope had been inserted was it possible to show the tracheal defect below the brachiocephalic trunk. After blunt mobilization of both main bronchi, it was possible to close the tracheal defect with simple interrupted sutures. Conventional tracheotomy was then performed at the level of the second tracheal ring. As a result, mechanical ventilation was once again possible without difficulty and thoracotomy was not necessary. PMID- 28018811 TI - Management of Postintubational Tracheal Injury by Endoscopic Stent Placement: Case Report and Review of the Literature. AB - Endobronchial stent placement is a novel therapy for treatment of iatrogenic tracheal tears. A review of the available literature shows surgery and long-term intubation being the established treatment strategy. We describe the case of a 64 year-old woman with a tracheal rupture following endotracheal intubation for routine surgery. Pneumo-mediastinum and chest pain were the predominant symptoms. She was treated with a covered self-expandable metal stent that closed the tear and led to immediate symptom relief. After six weeks and complete healing of the trachea, the stent could be explanted. No stent complications occurred. A new algorithm for the treatment of these ruptures has been proposed. PMID- 28018812 TI - Pneumopericardium Leading to Cardiac Tamponade in a Patient with Lung Cancer. AB - Pneumopericardium resulting in cardiac tamponade in patients with lung cancer is not documented. We report a case of squamous cell carcinoma of the lung complicated by pneumopericardium and subsequent cardiac tamponade. The patient underwent an urgent pericardial window with rapid improvement in symptoms. We discuss the possible pathogenesis and treatment options for this rare condition. PMID- 28018813 TI - Lung Transplantation in a Multidrug-Resistant Gram-Negative Acinetobacter Baumannii-Colonized Patient: A Case Report. AB - Colonization or infection with various pathogens is frequently found in patients listed for lung transplantation. We describe a case of a 50-year-old woman with alpha-1-antitrypsin deficiency, which was listed for double-lung transplantation, with multidrug-resistant gram-negative Acinetobacter baumannii (MRGN4-Ab) skin colonization. Transplantation was successfully performed. Colistin (Polymyxine E) was administered intravenously and through inhalation in the first month. MRGN4 Ab was still detectable in skin swabs without evidence of infection. After good recovery and clinical inapparence, the patient was discharged 2 months after transplantation. PMID- 28018815 TI - Sutureless Aortic Valve Replacement in a Patient with Transfemoral Aortic Valve Replacement and Left Ventricular Hypertrophy. AB - Background Transarterial valve intervention (TAVI) is valuable in high-risk patients, however, in case of left ventricular outflow tract (LVOT) obstruction, conventional surgery, including partial myectomy, is indicated. Case Description An 84-year-old female patient presented with increasing fatigue after TAVI in 2012, demonstrated a narrowed LVOT. Conventional surgery was performed, including removal of the transcathether valve, partial septal myectomy, and implantation of a sutureless valve. The postoperative course was uncomplicated. Conclusion Aortic valve stenosis combined with severe left-ventricular hypertrophy is not ideal for TAVI. Conventional surgery, performing partial septal myectomy and implantation of sutureless aortic prosthesis, seems more appropriate. PMID- 28018814 TI - Spontaneous Rupture of a Mediastinal Bronchial Artery Aneurysm Induced by Anticoagulant Agent. AB - Nontraumatic spontaneous rupture of a bronchial artery aneurysm is rarely seen. In this report, we described such a phenomenon in a patient induced by usage of anticoagulant agent. The patient had no antecedent history of trauma, hypertension, or apparent aortic pathology. The patient who had been taking low molecular-weight heparin and warfarin to treat deep vein thrombosis complained of a sudden upper abdomen pain with shortness of breath and hypoxemia. The patient was diagnosed and treated for an acute hemomediastinum caused by a ruptured bronchial artery aneurysm. If the patient had continued to take the anticoagulant antithrombotic drugs, it may cause a more virulent bleeding. Taken together, CT angiography is a useful diagnosis tool for patients with sudden chest pain and abdominal pain, and rare cause should be considered. PMID- 28018816 TI - Rapid-Deployment Aortic Valve Replacement after Previous Mechanical Valve Implantation. AB - Recent studies report a reproducible reduction of myocardial ischemic and cardiopulmonary bypass times along with excellent hemodynamics and low rates of paravalvular leakage for rapid-deployment valves. A 68-year-old female patient with aortic stenosis and a mechanical mitral valve which was implanted in 2006 received rapid-deployment aortic valve replacement. The procedure could be performed with a cross-clamp time of 45 minutes and a cardiopulmonary bypass time of 60 minutes. Postoperative course was uncomplicated and the patient was discharged to the referring hospital on postoperative day 8. PMID- 28018817 TI - Transcatheter Valve Unable to Cure Patient-Prosthesis Mismatch of Mosaic Bioprosthesis. AB - Transcatheter aortic valve implantation (TAVI) has been recently established as a less invasive alternative to conventional aortic valve replacement (CAVR) in patients presenting with expected high procedural risk. The rapid technologic advances and the recent improvement of clinical outcomes with TAVI have made it possible to treat degenerated bioprosthesis using the valve-in-valve implantation concept (Walther T, Simon P, Dewey T, et al. Transapical minimally invasive aortic valve implantation: multicenter experience. Circulation 2007;116(11, Suppl):I240-I245; Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve replacement in selected high-risk patients with aortic stenosis. Circulation 2007;116(7):755-763). Recently, concerns were raised regarding the appropriate sizing of transcatheter valve prosthesis and its effect on residual stenosis (Klaaborg KE, Egeblad H, Jakobsen CJ, et al. Transapical transcatheter treatment of a stenosed aortic valve bioprosthesis using the Edwards SAPIEN Transcatheter Heart Valve. Ann Thorac Surg 2009;87(6):1943-1946; Zedig R, Achouh P, Berrebi A, et al. Valve- in- a- valve implantation: a word of caution. Ann Thorac Surg 2009;87:1943-1946), eventually resulting in a patient prosthesis mismatch (PPM). We report a case with severe PPM after inserting a 23 mm Sapien (Edwards Lifesciences, Irvine, United States) valve into degenerated 23 mm Medtronic Mosaic prosthesis (Medtronic, Minneapolis, Minnesota, United States). PMID- 28018818 TI - Surgical Myectomy after Failed Ablation for Hypertrophic Obstructive Cardiomyopathy. AB - Background Hypertrophic cardiomyopathy is a genetic disease of the myocardial sarcolemma characterized by left ventricular hypertrophy. When obstruction to the left ventricular outflow tract is present and symptoms are refractory to medication, surgical myectomy or alcohol septal ablation is indicated. Case Description We report a case of a patient presented for myectomy due to recurrence only 1 year after alcohol ablation. Interesting findings were a firm subaortic membrane and a direct insertion of the papillary muscle into the mitral valve. Conclusion After myectomy and extensive papillary muscle mobilization, a significant relief of obstruction was achieved. PMID- 28018819 TI - A Technical Modification for Establishing Selective Antegrade Cerebral Perfusion during Pulmonary Endarterectomy. AB - Pulmonary endarterectomy (PEA) due to chronic thromboembolic pulmonary hypertension (CTEPH) is mainly performed in deep hypothermic circulatory arrest without additional cerebroprotective means. A 49-year-old man was treated by PEA for CTEPH by using selective antegrade cerebral perfusion by advancing the tip of the systemic perfusion cannula into the brachiocephalic trunk. The postoperative course was uneventful. PMID- 28018820 TI - Acute Pulmonary Artery Obstruction as the Primary Manifestation of a Rapidly Growing Intimal Sarcoma in a 54-Year-Old Patient. AB - Pulmonary artery sarcoma is a rare malignant neoplasm that is often misdiagnosed and most often only recognized postmortem during the autopsy. We present the case of a male patient with a rapidly progressive pulmonary tumor who underwent urgent pneumonectomy for increasing symptoms of chest pain and septic clinical picture. Histological analysis revealed the diagnosis of a pulmonary artery sarcoma. Despite an R1-resection and adjuvant chemotherapy, the patient is in good clinical health and free of tumor relapse 1 year after the surgery. PMID- 28018821 TI - Pimobendan in Chronic Right Heart Failure in a Left Ventricular Assist Device Patient. AB - We report the case of a 76-year-old patient who developed chronic right heart failure 1 year after left ventricular assist device implantation due to ischemic cardiomyopathy. Initial recompensation was achieved through dobutamin, sildenafil, and levosimendan treatment. Yet, discharge was successful only after the off-label use of the oral calcium sensitizer pimobendan. Ten months after discharge, the patient presents with no clinical signs of right heart failure and significantly improved right heart function without any impairment in quality of life. PMID- 28018822 TI - Catheter Insertion via Extracorporeal Membrane Oxygenation Cannula during Transcatheter Aortic Valve Implantation. AB - Background Patients referred to transcatheter aortic valve implantation (TAVI) present with multiple risk factors for intraprocedural complications. Case Description We describe a TAVI procedure with sudden hemodynamic collapse and cardiopulmonary resuscitation. Therefore, extracorporeal membrane oxygenation cannulas were immediately implanted via vessels of the groin. A Y-connector was inserted into the arterial line of the extracorporeal membrane oxygenator using an additional sheath facilitating to insert a pigtail catheter to guide the further valve implantation. Conclusion This case report provides an option to insert a pigtail catheter after implantation of extracorporeal membrane oxygenator cannulas without need for additional vascular access. PMID- 28018823 TI - 3D Heart Model and 4D Flow MRI 20 Years after Spiral Arterial Switch Operation. AB - Case of a patient is presented here 20 years after spiral direct anastomosis of the great arteries in an arterial switch operation. Three-dimensional model of the heart combined with four-dimensional flow magnetic resonance imaging presents a novel comprehensive way to assess surgical results. PMID- 28018824 TI - Pericarditis in a Child with an Intrapericardial Bronchogenic Cyst. AB - Background An intrapericardial bronchogenic cyst (IBC) is a rare congenital malformation seemingly asymptomatic in most subjects. Case Description A 9-year old boy presented with persistent chest pain and fever. Imaging revealed a large pericardial effusion with a tumor located at the left atrial appendage extending behind the great vessels. Mass rupture with scattered mucoid debris was found intra-operatively. The tumor was excised and the IBC was confirmed by immunohistochemistry. A postcardiotomy syndrome occurred four weeks post operative. It was treated conservatively. Since then, follow-up visits have remained uneventful. Conclusion IBCs are a scarce, but serious cause of persistent inflammation in children. PMID- 28018825 TI - Late Clinical Presentation of Inferior Vena Cava Deviation into the Left Atrium Following Atrial Septal Defect Repair in the Childhood. AB - A 19-year-old woman underwent ASD closure with patch in the childhood. Fifteen years later, she presented with severe cyanosis and dyspnea on exertion. Clinical diagnostics revealed a dislocation of the patch resulting in a right-to-left shunt (RLS) that was compensated in the past years by a recurrent ASD allowing a left-to-right shunt (LRS). The existing balance between interatrial shunts vanished by the growth of the patient leading to the clinical deterioration. After successful redo surgery, the patient was discharged home 8 days postoperatively. PMID- 28018826 TI - Hemopericardium Due to Idiopathic Coronary Artery Rupture Treated with Saphenous Vein Patch Plasty. AB - We report a case of an idiopathic coronary artery rupture in a 41-year-old male patient who was admitted to the hospital with cardiac tamponade. On opening the chest via a median sternotomy and establishing cardiopulmonary bypass the hemopericardium's cause could be identified as a perforation of the right posterior descending coronary artery which was treated with a saphenous vein patch plasty. With idiopathic coronary artery rupture being a rare diagnosis, one should always consider it in a young patient presenting with cardiac tamponade. PMID- 28018827 TI - Redo Operation of Recurrent Giant Coronary Artery Aneurysm: Optimizing Surgical Strategy. AB - Background Giant coronary artery aneurysms (GCAA) are extremely rare, but they can cause life-threatening complications. Indications for surgical intervention are the occurrence of complications such as fistulas, compression, embolization, or rapid enlargement. The optimal therapeutic approach is still under debate. Until now, there are no publications dealing with the follow-up after surgical treatment. Moreover, the surgical strategy in redo operations has not been described yet. Case Description We report on surgery in a 50-year-old man with a recurrent GCAA after previous dissection and reduction. Conclusion Our recommendation is complete resection and bypassing instead of a mere diameter reduction to avoid further progression of the disease. PMID- 28018828 TI - Paradoxical Embolus Stuck in a Patent Foramen Ovale. AB - In-hospital mortality rate of an embolus in transit is as high as 44.7%. In some cases, a paradoxical embolus can get stuck in a patent foramen ovale. Because of the high mortality rate, this condition should be considered as an emergency case. Echocardiography has been established as the gold standard method for the diagnosis. A negative echocardiography, however, does not rule out an embolus in transit. To rule out pulmonary embolisms, a computed tomography scan of the chest should also be performed. A cardiothoracic surgeon should be consulted immediately upon diagnosis of an embolus in transit. There is no medical consensus for the treatment of the above mentioned condition, however, surgical treatment appears to be the best approach in patients who are surgical candidates. PMID- 28018829 TI - Long-Range Real Migration of Implantable Cardioverter Defibrillator Lead. AB - The need for pacemaker and implantable cardioverter defibrillator (ICD) lead revisions and extractions is steadily increasing. Despite the lack of representative studies, the risk of lead extraction is frequently considered to be lower than leaving nonfunctional leads in situ. We report the case of a patient who was referred to our institution for exchange of a malfunctioning ICD lead. The diagnostic work-up revealed a long-segment transmural migration of the ICD lead at the site of the subclavian and innominate vein. Due to the unpredictable risk of vein perforation, we abandoned the extraction procedure. PMID- 28018830 TI - Chronic Perforation of the Aortic Arch by Kirschner Wires. AB - Perforation of the heart or great vessels by orthopedic wires is a rare complication that mostly results in severe or even lethal organ injury. Therefore, such conditions mostly require immediate surgical removal of the wires. However, in some individual cases, a conservative approach may be preferable. We describe a case of a 70-year-old woman whose aortic arch has been penetrated by two Kirschner wires used for fixation of a right clavicle fracture 13 years ago. Notably, the complication was an incidental finding during computed tomography angiography for clarification of transient nonspecific neurological symptoms. PMID- 28018831 TI - Endovascular and Operative Treatment of the Aortic Arch in a High-Risk Marfan Patient. AB - In this case, we describe a combined endovascular and operative management for aortic arch repair in a 57-year-old Marfan patient with complex aortic arch geometry previously treated with several open surgeries for acute type A dissection. The patient, who was presented to our department with dorsal pain, deemed to be at high operative risk for another open aortic surgery due to massive aortic calcification. It is an unusual method of placing a custom-made stent-graft system in the false aortic lumen with operative and endovascular treatment of the supra-aortic vessels. PMID- 28018832 TI - Limited Distal Arch Open Stenting for Type B Aortic Dissection with an Enlarged Ulcer-Like Projection, Complicated by Abdominal Aortic Occlusion. AB - A 79-year-old man underwent bifurcated graft replacement for abdominal aortic aneurysm, but the graft was totally occluded owing to an acute type B aortic dissection. We could not have access to the root for performing endovascular stenting for dissecting aneurysm. Furthermore, it was difficult to remove the aneurysm via a left thoracotomy because it was impossible to perfuse the lower body with blood from the femoral artery and also a left axillary arterial cannulation was unusable. Herein, we report a patient who was successfully treated with open surgical aortic stenting for an enlarged ulcer-like projection complicated by a type B aortic dissection. PMID- 28018833 TI - Aneurysmal Bone Cyst Arising from the First Rib: A Rare Cause of Thoracic Outlet Syndrome. AB - Aneurysmal bone cyst is a rare benign cystic bone lesion with an incidence of only 0.14 per 100,000 individuals and most commonly affects the metaphyses of long bones, spine, and pelvis. We present a very rare case of a 17-year-old boy with a rapidly expanding aneurysmal bone cyst arising from the first rib, resulting in neurogenic thoracic outlet syndrome secondary to its compression of the brachial plexus. The patient's symptoms resolved after en bloc resection. To our knowledge there have been no other reports in the literature of thoracic outlet syndrome due to aneurysmal bone cyst arising from the first rib. PMID- 28018834 TI - Detailed Measurement of Wall Strain with 3D Speckle Tracking in the Aortic Root: A Case of Bionic Support for Clinical Decision Making. AB - Three-dimensional (3D) wall motion tracking (WMT) based on ultrasound imaging enables estimation of aortic wall motion and deformation. It provides insights into changes in vascular compliance and vessel wall properties essential for understanding the pathogenesis and progression of aortic diseases. In this report, we employed the novel 3D WMT analysis on the ascending aorta aneurysm (AA) to estimate local aortic wall motion and strain in case of a patient scheduled for replacement of the aortic root. Although progression of the diameter indicates surgical therapy, at present we addressed the question for optimal surgical time point. According to the data, AA in our case has enlarged diameter and subsequent reduced circumferential wall strain, but area tracking data reveals almost normal elastic properties. Virtual remodeling of the aortic root opens a play list for different loading conditions to determine optimal surgical intervention in time. PMID- 28018835 TI - Open Access Publishing: A Remark on Quality Control. PMID- 28018836 TI - Novel Therapeutics for Addiction: Behavioral and Neuroeconomic Approaches. AB - The maturing fields of behavioral- and neuro-economics provides conceptual understanding of the Competing Neurobehavioral Decision Systems theory (CNDS) and reinforcer pathology (i.e. high valuation of and excessive preference for drug reinforcers) allowing us to coherently categorize treatments into a theoretically comprehensive framework of addiction. In this chapter, we identify and clarify how existing and novel interventions can ameliorate reinforcer pathology in light of the CNDS and be leveraged to treat addiction. PMID- 28018837 TI - Recent Advances in Mercury Research. AB - Mercury (Hg) is a highly toxic, non-essential, naturally occurring metal with a variety of uses. Mercury is not required for any known biological process and its presence in the human body may be detrimental, especially to the nervous system. Both genetic and behavioral studies suggest that mercury levels, age (both of exposure and at testing), and genetic background determine disease processes and outcome. The metal receptors and genes responsible for mercury metabolism also appear to play a pivotal role in the etiology of mercury-induced pathology. This review presents information about the latest advances in mercury research, with particular focus on low-level exposures and the contribution of genetics to toxic outcome. Future studies should address the contribution of genetics and low-level mercury exposure to disease, namely gene x environment interactions, taking into consideration age of exposure as developing animals are exquisitely more sensitive to this metal. In addition to recent advances in understanding the pathology associated with mercury exposure, the review highlights transport mechanisms, cellular distribution and detoxification of mercury species in the body. PMID- 28018838 TI - A motion sensing-based framework for robotic manipulation. AB - To data, outside of the controlled environments, robots normally perform manipulation tasks operating with human. This pattern requires the robot operators with high technical skills training for varied teach-pendant operating system. Motion sensing technology, which enables human-machine interaction in a novel and natural interface using gestures, has crucially inspired us to adopt this user-friendly and straightforward operation mode on robotic manipulation. Thus, in this paper, we presented a motion sensing-based framework for robotic manipulation, which recognizes gesture commands captured from motion sensing input device and drives the action of robots. For compatibility, a general hardware interface layer was also developed in the framework. Simulation and physical experiments have been conducted for preliminary validation. The results have shown that the proposed framework is an effective approach for general robotic manipulation with motion sensing control. PMID- 28018839 TI - A distributed ASTRA toolbox. AB - While iterative reconstruction algorithms for tomography have several advantages compared to standard backprojection methods, the adoption of such algorithms in large-scale imaging facilities is still limited, one of the key obstacles being their high computational load. Although GPU-enabled computing clusters are, in principle, powerful enough to carry out iterative reconstructions on large datasets in reasonable time, creating efficient distributed algorithms has so far remained a complex task, requiring low-level programming to deal with memory management and network communication. The ASTRA toolbox is a software toolbox that enables rapid development of GPU accelerated tomography algorithms. It contains GPU implementations of forward and backprojection operations for many scanning geometries, as well as a set of algorithms for iterative reconstruction. These algorithms are currently limited to using GPUs in a single workstation. In this paper, we present an extension of the ASTRA toolbox and its Python interface with implementations of forward projection, backprojection and the SIRT algorithm that can be distributed over multiple GPUs and multiple workstations, as well as the tools to write distributed versions of custom reconstruction algorithms, to make processing larger datasets with ASTRA feasible. As a result, algorithms that are implemented in a high-level conceptual script can run seamlessly on GPU enabled computing clusters, up to 32 GPUs or more. Our approach is not limited to slice-based reconstruction, facilitating a direct portability of algorithms coded for parallel-beam synchrotron tomography to cone-beam laboratory tomography setups without making changes to the reconstruction algorithm. PMID- 28018841 TI - 1% low-fat milk has perks!: An evaluation of a social marketing intervention. AB - This study evaluated the effect of a 12-week social marketing intervention conducted in 2012 promoting 1% milk use relying on paid advertising. Weekly milk sales data by type of milk (whole, 2%, 1%, and nonfat milk) were collected from 80 supermarkets in the Oklahoma City media market, the intervention market, and 66 supermarkets in the Tulsa media market (TMM), the comparison market. The effect was measured with a paired t-test. A mixed segmented regression model, controlling for the contextual difference between supermarkets and data correlation, identified trends before, during, and after the intervention. Results show the monthly market share of 1% milk sales changed from 10.0% to 11.5%, a 15% increase. Evaluating the volume sold, the monthly mean number of gallons of 1% milk sold increased from 890.5 gal (SD = 769.8) per supermarket from before the intervention to 1070.7 gal (SD = 922.5) following the intervention (t(79) = 9.4, p = 0.000). Moreover, average weekly sales of 1% milk were stable prior to the intervention (b = - 0.2 gal/week, 95% CI [- 0.6 gal/week, 0.3 gal/week]). During each additional week of the intervention, 1% milk sales increased by an average of 4.1 gal in all supermarkets (95% CI [3.5 gal/week, 4.6 gal/week]). Three months later, albeit attenuated, a significant increase in 1% milk sales remained. In the comparison market, no change in the market share of 1% milk occurred. Paid advertising, using the principles of social marketing, can be effective in changing an entrenched and habitual nutrition habit. PMID- 28018840 TI - Hand Impairment in Systemic Sclerosis: Various Manifestations and Currently Available Treatment. AB - Systemic sclerosis (SSc) is an autoimmune disease initially recognized by hand involvement due to characteristic Raynaud's phenomenon (RP), puffy hands, skin thickening, and contractures resembling claw deformities. SSc contributes to hand impairment through inflammatory arthritis, joint contractures, tendon friction rubs (TFRs), RP, digital ulcers (DU), puffy hands, skin sclerosis, acro osteolysis, and calcinosis. These manifestations, which often co-exist, can contribute to difficulty with occupational activities and activities of daily living (ADL), which can result in impaired quality of life. However, despite this knowledge, most diagnostic and treatment principles in SSc are focused on visceral manifestations due to known associations with morbidity and mortality. Treatment of inflammatory arthritis is symptom based and involves corticosteroids <=10mg daily, methotrexate, tumor necrosis factor inhibitors, tocilizumab, and abatacept. Small joint contractures are managed by principles of occupational hand therapy and rarely surgical procedures. TFRs may be treated similar to inflammatory arthritis with corticosteroids. All patients with RP and DU should keep digits covered and warm and avoid vasoconstrictive agents. Pharmacologic management of RP begins with use of calcium channel blockers, but additional agents that may be considered are fluoxetine and phosphodiesterase 5 (PDE5) inhibitors. DU management also involves vasodilators including calcium channel blockers and PDE5 inhibitors; bosentan has also been shown to prevent DU. In patients with severe RP and active DU, intravenous epoprostenol or iloprost can be used and surgical procedures, such as botulinum injections and digital sympathectomies, may be considered. For those with early diffuse cutaneous SSc needing immunosuppression for skin sclerosis, methotrexate or mycophenolate mofetil can be used, but the agent of choice depends on co-existing manifestations, such as inflammatory arthritis and/or lung involvement. Various pharmacologic agents for calcinosis have been considered but are generally ineffective; however, surgical options, including excision of areas of calcinosis, can be considered. Overall management of hand impairment for all patients with SSc should include occupational hand therapy techniques such as range of motion exercises, paraffin wax, and devices to assist in ADL. Thus, treatment options for the various manifestations contributing to hand impairment in SSc are limited and often modestly efficacious at best. Robust studies are needed to address the manifestations of SSc that contribute to hand impairment. PMID- 28018842 TI - C. dubliniensis in an immunocompetent patient with metal lingual frenulum piercing. AB - Candida spp. are opportunistic unicellular fungi, known to cause oral, vaginal, lung and occasionally systemic infections. Characteristically, they colonize the oral cavity, the mucosal surfaces of the cheek, palate, and tongue. Usually harmless, oral Candidas may become pathogenic under immunosuppressive conditions, dentures presence, or salivary flow impairment. Accurate species identification is important because C. dubliniensis can rapidly develop fluconazole resistance. We report C. dubliniensis in an immunocompetent patient with a metal lingual frenulum piercing. PMID- 28018843 TI - Genomic advancement: Aiming to affirm and improve human life. PMID- 28018844 TI - Wheat quality improvement at CIMMYT and the use of genomic selection on it. AB - The International Center for Maize and Wheat Improvement (CIMMYT) leads the Global Wheat Program, whose main objective is to increase the productivity of wheat cropping systems to reduce poverty in developing countries. The priorities of the program are high grain yield, disease resistance, tolerance to abiotic stresses (drought and heat), and desirable quality. The Wheat Chemistry and Quality Laboratory has been continuously evolving to be able to analyze the largest number of samples possible, in the shortest time, at lowest cost, in order to deliver data on diverse quality traits on time to the breeders for making selections for advancement in the breeding pipeline. The participation of wheat quality analysis/selection is carried out in two stages of the breeding process: evaluation of the parental lines for new crosses and advanced lines in preliminary and elite yield trials. Thousands of lines are analyzed which requires a big investment in resources. Genomic selection has been proposed to assist in selecting for quality and other traits in breeding programs. Genomic selection can predict quantitative traits and is applicable to multiple quantitative traits in a breeding pipeline by attaining historical phenotypes and adding high-density genotypic information. Due to advances in sequencing technology, genome-wide single nucleotide polymorphism markers are available through genotyping-by-sequencing at a cost conducive to application for genomic selection. At CIMMYT, genomic selection has been applied to predict all of the processing and end-use quality traits regularly tested in the spring wheat breeding program. These traits have variable levels of prediction accuracy, however, they demonstrated that most expensive traits, dough rheology and baking final product, can be predicted with a high degree of confidence. Currently it is being explored how to combine both phenotypic and genomic selection to make more efficient the genetic improvement for quality traits at CIMMYT spring wheat breeding program. PMID- 28018845 TI - Maximizing the potential of multi-parental crop populations. AB - Most agriculturally significant crop traits are quantitatively inherited which limits the ease and efficiency of trait dissection. Multi-parent populations overcome the limitations of traditional trait mapping and offer new potential to accurately define the genetic basis of complex crop traits. The increasing popularity and use of nested association mapping (NAM) and multi-parent advanced generation intercross (MAGIC) populations raises questions about the optimal design and allocation of resources in their creation. In this paper we review strategies for the creation of multi-parent populations and describe two complementary in silico studies addressing the design and construction of NAM and MAGIC populations. The first simulates the selection of diverse founder parents and the second the influence of multi-parent crossing schemes (and number of founders) on haplotype creation and diversity. We present and apply two open software resources to simulate alternate strategies for the development of multi parent populations. PMID- 28018846 TI - Developing integrated crop knowledge networks to advance candidate gene discovery. AB - The chances of raising crop productivity to enhance global food security would be greatly improved if we had a complete understanding of all the biological mechanisms that underpinned traits such as crop yield, disease resistance or nutrient and water use efficiency. With more crop genomes emerging all the time, we are nearer having the basic information, at the gene-level, to begin assembling crop gene catalogues and using data from other plant species to understand how the genes function and how their interactions govern crop development and physiology. Unfortunately, the task of creating such a complete knowledge base of gene functions, interaction networks and trait biology is technically challenging because the relevant data are dispersed in myriad databases in a variety of data formats with variable quality and coverage. In this paper we present a general approach for building genome-scale knowledge networks that provide a unified representation of heterogeneous but interconnected datasets to enable effective knowledge mining and gene discovery. We describe the datasets and outline the methods, workflows and tools that we have developed for creating and visualising these networks for the major crop species, wheat and barley. We present the global characteristics of such knowledge networks and with an example linking a seed size phenotype to a barley WRKY transcription factor orthologous to TTG2 from Arabidopsis, we illustrate the value of integrated data in biological knowledge discovery. The software we have developed (www.ondex.org) and the knowledge resources (http://knetminer.rothamsted.ac.uk) we have created are all open-source and provide a first step towards systematic and evidence-based gene discovery in order to facilitate crop improvement. PMID- 28018847 TI - Uncertainty and innovation: Understanding the role of cell-based manufacturing facilities in shaping regulatory and commercialization environments. AB - The purpose of this qualitative study is to elucidate stakeholder perceptions of, and institutional practices related to cell-based therapies and products (CTP) regulation and commercialization in Canada. The development of reproducible, safe and effective CTPs is predicated on regulatory and commercialization environments that enable innovation. Manufacturing processes constitute a critical step for CTP development in this regard. The road from CTP manufacturing to translation in the clinic, however, has yet to be paved. This study aims to fill an empirical gap in the literature by exploring how CTP manufacturing facilities navigate Canadian regulatory and commercialization environments, which together drive the translation of novel CTPs from bench to bedside. Using the multi-level model of practice-driven institutional change proposed by Smets et al., we demonstrate how CTP manufacturing practices are governed by established standards, yet meaningfully shape higher-order regulatory and commercial norms in CTP research and development. We identify four key themes that undergird such processes of innovation: 1) managing regulatory uncertainty, which stems from an inability to classify CTPs within existing regulatory categories for approval and commercialization purposes; 2) building a 'business case' whereby a CTP's market potential is determined in large part by proving its safety and effectiveness; 3) standardizing manufacturing procedures that mobilize CTPs from a research and development phase to a commercialization one; and 4) networking between researchers and regulators to develop responsible commercialization processes that reflect the uniqueness of CTPs as distinct from other biologics and medical devices. PMID- 28018848 TI - Mitochondrial transfer: Implications for assisted reproductive technologies. AB - The use of mitochondrial transfer as a clinic procedure is drawing closer to reality. Here we provide a detailed overview of mitochondrial transfer techniques - both established and recent - including pronuclear, spindle, ooplasmic and blastomere transfer. Reasons as to why some techniques are more suitable for the prevention of mitochondrial DNA disease than others, as well as the advantages and disadvantages of each methodology, are discussed. The possible clinical introduction of these techniques has raised concerns about the adverse effects they may have on resultant embryos and offspring. Success rates of each technique, embryo viability and developmental consequences post mitochondrial transfer are addressed through analysis of evidence obtained from both animal and human studies. Counterarguments against potential mitochondrial-nuclear genome incompatibility are also provided. Additional clinical applications of mitochondrial transfer techniques are discussed. These include the rescue or enhancement of fertility in women of advanced maternal age or those suffering from diabetes. An alternative to using mitochondrial DNA transfer for germ line therapies is the therapeutic use of somatic cell nuclear transfer for the generation of personalised stem cells. Although ethically challenging, this method could offer patients already suffering from mitochondrial DNA diseases a novel treatment option. PMID- 28018849 TI - Translating genetics beyond bench and bedside: A comparative perspective on health care infrastructures for 'familial' breast cancer. AB - Developments in genomics research are considered to have great potential for improving health care - making genomics an urgent site for translational efforts. Yet while much emphasis is put on the technical challenges of translation, there is less scholarly attention for the social infrastructures through which novel medical interventions may be delivered to patient populations. Reflecting the idea that cancer is at the frontier of genomic applications in health care, this paper explores how the assessment of familial breast cancer risks was 'translated' into routine health care in Germany, the Netherlands and the United Kingdom. The paper identifies regulation, institutionalization and standardization as key mechanisms of translation that find distinct expression in particular sociocultural contexts and shape both the social and technical making of genomics into routine clinical practice. Translation is therefore an area of social as well as technical concern, and therefore requires collective decision making. PMID- 28018850 TI - Right ventricular reverse remodelling in Idiopathic Pulmonary Arterial Hypertension diagnosed during pregnancy: Is it possible? AB - We present a case of a 36-year-old woman who developed a severe form of Idiopathic Pulmonary Arterial Hypertension (IPAH) during pregnancy and after emergency delivery. The management of IPAH during or after pregnancy is complex. Due to the severity of her IPAH, an upfront triple combination therapy, including i.v. epoprostenol, was started. The rapid institution of this treatment regimen allowed a complete right ventricular reverse remodelling after 1 year of therapy, leading to a down-titration until complete suspension of epoprostenol from the treatment regimen. PMID- 28018851 TI - Functional and structural connectivity of the amygdala in obsessive-compulsive disorder. AB - BACKGROUND: The amygdala is known to be involved in anxiety processing, but its role in the psychopathology of obsessive-compulsive disorder (OCD) is still unclear. AIMS: In this MRI study we investigated potential alterations in structural and functional connectivity of the amygdala in 42 adult patients with OCD and 37 healthy subjects. METHOD: Psychophysiological interaction analysis was used to explore amygdala functional connectivity during a negative affective task. Probabilistic tractography was then employed to study structural connectivity and integrity of underlying white matter fiber tracts. RESULTS: Compared to controls, OCD patients showed a significantly increased functional connectivity of the left amygdala with mostly parieto-occipital regions during task. No structural connectivity differences could be found between the groups. In addition, only patients showed a significant association between functional and structural connectivity of these regions. Moreover, symptom severity was negatively associated with structural integrity of the underlying white matter tracts. CONCLUSIONS: Present results emphasize the relevance of the amygdala for OCD and may reflect that neuronal alterations in structural connectivity could be associated with functional connectivity alterations in broader networks. PMID- 28018852 TI - The delta between postoperative seizure freedom and persistence: Automatically detected focal slow waves after epilepsy surgery. AB - OBJECTIVE: In this study, we use a novel automated method for localization and quantitative comparison of magnetoencephalographic (MEG) delta activity in patients with and without recurrent seizures after epilepsy surgery as well as healthy controls. METHODS: We identified the generators of delta activity by source location in frequency domain between 1 and 4 Hz in spontaneous MEG data. Comparison with healthy control subjects by z-transform emphasized relative changes of activation in patients. The individual results were compared to spike localizations and statistical group analysis was performed. Additionally, MEG results were compared to 1-4 Hz activity in invasive EEG (iEEG) in two patients, in whom this data was available. RESULTS: Patients with recurrent seizures exhibited significantly increased focal MEG delta activity both in comparison to healthy controls and seizure free patients. This slow activity showed a correlation to interictal epileptic activity and was not explained by consequences of the resection alone. In two patients with iEEG, iEEG analysis was concordant with the MEG findings. SIGNIFICANCE: The quantity of delta activity could be used as a diagnostic marker for recurrent seizures. The close relation to epileptic spike localizations and the resection volume of patients with successful second surgery imply involvement in seizure recurrence. This initial evidence suggests a potential application in the planning of second epilepsy surgery. PMID- 28018853 TI - MRI FLAIR lesion segmentation in multiple sclerosis: Does automated segmentation hold up with manual annotation? AB - INTRODUCTION: Magnetic resonance imaging (MRI) has become key in the diagnosis and disease monitoring of patients with multiple sclerosis (MS). Both, T2 lesion load and Gadolinium (Gd) enhancing T1 lesions represent important endpoints in MS clinical trials by serving as a surrogate of clinical disease activity. T2- and fluid-attenuated inversion recovery (FLAIR) lesion quantification - largely due to methodological constraints - is still being performed manually or in a semi automated fashion, although strong efforts have been made to allow automated quantitative lesion segmentation. In 2012, Schmidt and co-workers published an algorithm to be applied on FLAIR sequences. The aim of this study was to apply the Schmidt algorithm on an independent data set and compare automated segmentation to inter-rater variability of three independent, experienced raters. METHODS: MRI data of 50 patients with RRMS were randomly selected from a larger pool of MS patients attending the MS Clinic at the Brain and Mind Centre, University of Sydney, Australia. MRIs were acquired on a 3.0T GE scanner (Discovery MR750, GE Medical Systems, Milwaukee, WI) using an 8 channel head coil. We determined T2-lesion load (total lesion volume and total lesion number) using three versions of an automated segmentation algorithm (Lesion growth algorithm (LGA) based on SPM8 or SPM12 and lesion prediction algorithm (LPA) based on SPM12) as first described by Schmidt et al. (2012). Additionally, manual segmentation was performed by three independent raters. We calculated inter-rater correlation coefficients (ICC) and dice coefficients (DC) for all possible pairwise comparisons. RESULTS: We found a strong correlation between manual and automated lesion segmentation based on LGA SPM8, regarding lesion volume (ICC = 0.958 and DC = 0.60) that was not statistically different from the inter-rater correlation (ICC = 0.97 and DC = 0.66). Correlation between the two other algorithms (LGA SPM12 and LPA SPM12) and manual raters was weaker but still adequate (ICC = 0.927 and DC = 0.53 for LGA SPM12 and ICC = 0.949 and DC = 0.57 for LPA SPM12). Variability of both manual and automated segmentation was significantly higher regarding lesion numbers. CONCLUSION: Automated lesion volume quantification can be applied reliably on FLAIR data sets using the SPM based algorithm of Schmidt et al. and shows good agreement with manual segmentation. PMID- 28018854 TI - Cholinergic depletion and basal forebrain volume in primary progressive aphasia. AB - Primary progressive aphasia (PPA) is a heterogeneous syndrome with various neuropathological causes for which no medical treatment with proven efficacy exists. Basal forebrain (BF) volume loss has been reported in PPA but its relation to cholinergic depletion is still unclear. The primary objective of this study was to investigate whether cholinergic alterations occur in PPA variants and how this relates to BF volume loss. An academic memory clinic based consecutive series of 11 PPA patients (five with the semantic variant (SV), four with the logopenic variant (LV) and two with the nonfluent variant (NFV)) participated in this cross-sectional in vivo PET imaging study together with 10 healthy control subjects. Acetylcholinesterase (AChE) activity was quantitatively measured in the neo- and allocortex using N-[11C]-Methylpiperidin-4-yl propionate (PMP)-PET with arterial sampling and metabolite correction. Whole brain and BF volumes were quantified using voxel-based morphometry on high-resolution magnetic resonance imaging (MRI) scans. In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. BF volume did not correlate with AChE activity levels in PPA. To conclude, in our sample of PPA patients, LV but not SV was associated with cholinergic depletion. BF atrophy in PPA does not imply cholinergic depletion. PMID- 28018855 TI - Genome sequencing of three bacteria associated to black band disease from a Colombian reef-building coral. AB - We announce the draft genome sequence of three Gram-negative bacteria isolated from coral tissues affected with the black band disease (BBD), identified with the NCBI's Assembly Database accession numbers: MBQF, MAYB and MBQE. These genome drafts constitute an useful tool for the characterisation of these bacteria and for the understanding of the relationship between the microbial consortia associated with the disease and the onset and progression of the pathology. PMID- 28018856 TI - Time and Circumstances: Cancer Cell Metabolism at Various Stages of Disease Progression. AB - Over the past decade, research into the unique ways, in which cancer cells skew their metabolism, has had a renaissance-for the repeated time over more than 80 years since the discovery of an inherent preference for glycolysis. Importantly, the Warburg effect that arises in primary neoplasms is not the sole prominent metabolic phenomenon. Once the transformed cells are shed from their initial growth and begin the process of metastasis, their energy requirements change and they adapt to the increased demand for adenosine triphosphate, which if not satisfied would lead to anoikis. At that stage, oxidoreductases and the respiratory chain are activated. Furthermore, the intrinsic metabolic characteristics of tumor cells may be influenced by extrinsic factors, comprising metabolite secretions from stromal cells or acidification and nutrient deprivation in the late-stage hypoxic environment. While there is metabolic adjustment in cancer cells throughout the disease history, its phenotypic manifestation changes at various times. This stage selectivity has implications for pharmacotherapy ambitions. PMID- 28018857 TI - Murine Models of Splenic Marginal Zone Lymphoma: A Role for Cav1? AB - Dozens of murine models of indolent and aggressive B-cell lymphomas have been generated to date. These include those manifesting chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), as well as xenografts of mantle cell lymphoma (MCL). These models have led to an improved understanding of disease etiology, B-cell biology, immunomodulation, and the importance of the tumor microenvironment. Despite these efforts in CLL, DLBCL, and MCL, considerably little progress toward a model of splenic marginal zone lymphoma (SMZL) has been accomplished. Herein, we describe the similarities and differences between CLL, MCL, and SMZL and highlight effective murine models that mimic disease in the two former, in hopes of informing a potential model of the latter. At the time of writing this review, the precise molecular events of SMZL remain to be determined and a treatment regimen remains to be identified. Therefore, based on the efforts put forth in the B-cell lymphoma field throughout the past three decades, the established role of caveolin-1 in B- and T-cell biology as an oncogene or tumor suppressor, and the recurrent deletion or loss of heterozygosity (LOH) of 7q in many cancers, we make recommendations for a murine model of SMZL. PMID- 28018858 TI - Coxsackievirus B3 Directly Induced Th17 Cell Differentiation by Inhibiting Nup98 Expression in Patients with Acute Viral Myocarditis. AB - Th17 cells play a key role in the progression of coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). However, the direct effect of virus on Th17 cell differentiation is still unknown. Recently, nucleoporin (Nup) 98 has been proved to be associated with lymphocyte differentiation. Therefore, we investigated whether Nup98 mediated Th17 cell differentiation in AVMC. In our study, patients with AVMC and healthy controls were recruited. The results showed that CVB3 could enter into the CD4+ T cells in AVMC patients and healthy controls. After transfecting purified CD4+ T cells with CVB3 in vitro, the Th17 cell frequency, IL-17 secretion, and RORgammaT synthesis were increased while the Nup98 levels were decreased. Furthermore, down-regulating Nup98 expression by siRNA-Nup98 in CD4+ T cells resulted in the elevated Th17 cell frequency and IL-17 secretion, along with enhanced levels of RORgammaT, dissociative p300/CBP, and acetylated Stat3. Up-regulation of Nup98 expression by pcDNA3.1-Nup98 showed the opposite effects. Our results suggested that CVB3 directly induced CD4+ T cell differentiation into Th17 cells by inhibiting Nup98 expression, representing a therapeutic target in AVMC. PMID- 28018859 TI - Autophagy, TGF-beta, and SMAD-2/3 Signaling Regulates Interferon-beta Response in Respiratory Syncytial Virus Infected Macrophages. AB - Human respiratory syncytial virus (RSV) is a lung tropic virus causing severe airway diseases including bronchiolitis and pneumonia among infants, children, and immuno-compromised individuals. RSV triggers transforming growth factor-beta (TGF-beta) production from lung epithelial cells and TGF-beta facilitates RSV infection of these cells. However, it is still unknown whether RSV infected myeloid cells like macrophages produce TGF-beta and the role of TGF-beta if any during RSV infection of these cells. Our study revealed that RSV infected macrophages produce TGF-beta and as a consequence these cells activate TGF-beta dependent SMAD-2/3 signaling pathway. Further mechanistic studies illustrated a role of autophagy in triggering TGF-beta production from RSV infected macrophages. In an effort to elucidate the role of TGF-beta and SMAD-2/3 signaling during RSV infection, we surprisingly unfolded the requirement of TGF beta-SMAD2/3 signaling in conferring optimal innate immune antiviral response during RSV infection of macrophages. Type-I interferon (e.g., interferon-beta or IFN-beta) is a critical host factor regulating innate immune antiviral response during RSV infection. Our study revealed that loss of TGF-beta-SMAD2/3 signaling pathway in RSV infected macrophages led to diminished expression and production of IFN-beta. Inhibiting autophagy in RSV infected macrophages also resulted in reduced production of IFN-beta. Thus, our studies have unfolded the requirement of autophagy-TGF-beta-SMAD2/3 signaling network for optimal innate immune antiviral response during RSV infection of macrophages. PMID- 28018860 TI - Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia. AB - In the last decade it has become clear that, similarly to nucleated cells, enucleated red blood cells (RBCs) are susceptible to programmed apoptotic cell death. Erythrocytic apoptosis seems to play a role in physiological clearance of aged RBCs, but it may also be implicated in anemia of different etiological sources including drug therapy and infectious diseases. In malaria, severe anemia is a common complication leading to death of children and pregnant women living in malaria-endemic regions of Africa. The pathogenesis of malarial anemia is multifactorial and involves both ineffective production of RBCs by the bone marrow and premature elimination of non-parasitized RBCs, phenomena potentially associated with apoptosis. In the present overview, we discuss evidences associating erythrocytic apoptosis with the pathogenesis of severe malarial anemia, as well as with regulation of parasite clearance in malaria. Efforts to understand the role of erythrocytic apoptosis in malarial anemia can help to identify potential targets for therapeutic intervention based on apoptotic pathways and consequently, mitigate the harmful impact of malaria in global public health. PMID- 28018861 TI - Tissue-Associated Bacterial Alterations in Rectal Carcinoma Patients Revealed by 16S rRNA Community Profiling. AB - Sporadic and inflammatory forms of colorectal cancer (CRC) account for more than 80% of cases. Recent publications have shown mechanistic evidence for the involvement of gut bacteria in the development of both CRC-forms. Whereas, colon and rectal cancer have been routinely studied together as CRC, increasing evidence show these to be distinct diseases. Also, the common use of fecal samples to study microbial communities may reflect disease state but possibly not the tumor microenvironment. We performed this study to evaluate differences in bacterial communities found in tissue samples of 18 rectal-cancer subjects when compared to 18 non-cancer controls. Samples were collected during exploratory colonoscopy (non-cancer group) or during surgery for tumor excision (rectal cancer group). High throughput 16S rRNA amplicon sequencing of the V4-V5 region was conducted on the Ion PGM platform, reads were filtered using Qiime and clustered using UPARSE. We observed significant increases in species richness and diversity in rectal cancer samples, evidenced by the total number of OTUs and the Shannon and Simpson indexes. Enterotyping analysis divided our cohort into two groups, with the majority of rectal cancer samples clustering into one enterotype, characterized by a greater abundance of Bacteroides and Dorea. At the phylum level, rectal-cancer samples had increased abundance of candidate phylum OD1 (also known as Parcubacteria) whilst non-cancer samples had increased abundance of Planctomycetes. At the genera level, rectal-cancer samples had higher abundances of Bacteroides, Phascolarctobacterium, Parabacteroides, Desulfovibrio, and Odoribacter whereas non-cancer samples had higher abundances of Pseudomonas, Escherichia, Acinetobacter, Lactobacillus, and Bacillus. Two Bacteroides fragilis OTUs were more abundant among rectal-cancer patients seen through 16S rRNA amplicon sequencing, whose presence was confirmed by immunohistochemistry and enrichment verified by digital droplet PCR. Our findings point to increased bacterial richness and diversity in rectal cancer, along with several differences in microbial community composition. Our work is the first to present evidence for a possible role of bacteria such as B. fragilis and the phylum Parcubacteria in rectal cancer, emphasizing the need to study tissue associated bacteria and specific regions of the gastrointestinal tract in order to better understand the possible links between the microbiota and rectal cancer. PMID- 28018862 TI - Delta Hemolysin and Phenol-Soluble Modulins, but Not Alpha Hemolysin or Panton Valentine Leukocidin, Induce Mast Cell Activation. AB - Mast cells are located at host interfaces, such as the skin, and contribute to the first-line defense against pathogens by releasing soluble mediators, including those that induce itching and scratching behavior. Here, we show that delta-hemolysin (Hld) and phenol soluble modulins (PSMs) PSMalpha1 and PSMalpha3, but not alpha-hemolysin (Hla) or Panton-Valentine leukocidin (PVL), induce dose dependent tryptase, and lactate dehydrogenase (LDH) release by the HMC-1 human mast cell line. Using supernatants from isogenic strains, we verified that tryptase and LDH release was Hld- and PSMalpha-dependent. PSMalpha1 and Hld production was detected in 65 and 17% of human Staphylococcus aureus-infected skin abscess specimens, respectively, but they were produced in vitro by all clinical isolates. The results suggest that Hld and PSM-alpha1 produced in vivo during S. aureus skin infections induce the release of mast cell mediators responsible for itching and scratching behavior, which may enhance skin to skin transmission of S. aureus via the hands. As Hld and PSMs are upregulated by accessory gene regulator (agr), their association may contribute to the elective transmission of S. aureus strains with a functional agr system. PMID- 28018863 TI - Immunization with the MipA, Skp, or ETEC_2479 Antigens Confers Protection against Enterotoxigenic E. coli Strains Expressing Different Colonization Factors in a Mouse Pulmonary Challenge Model. AB - Achieving cross-protective efficacy against multiple bacterial strains or serotypes is an important goal of vaccine design. Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrheal disease in underdeveloped nations. We have been interested in identifying and characterizing ETEC antigens that generate protective immune responses independent of ETEC colonization factor (CF) expression. Our previous studies used proteomics to identify the ETEC MipA, Skp, and ETEC_2479 proteins as effective in protecting mice from homologous challenge with ETEC H10407 using a pulmonary inoculation model. This model permits analysis of mouse survival, bacterial clearance, and the production of secretory IgA (sIgA) and has been employed previously for studies of enteric pathogens for which robust oral challenge models do not exist. MipA belongs to a family of proteins involved in remodeling peptidoglycan. Skp rescues misdirected outer membrane proteins. ETEC_2479 is predicted to function as an outer membrane porin. These proteins are conserved in pathogenic ETEC strains as well as in commensal Proteobacteria. Antibodies produced against the ETEC MipA, Skp, and ETEC_2479 proteins also reduced the adherence of multiple ETEC strains differing in CF type to intestinal epithelial cells. Here we characterized the ability of 10 heterologous ETEC strains that differ in CF type to cause clinical signs of illness in mice after pulmonary challenge. ETEC strains C350C1A, E24377A, E7476A, WS2173A, and PE360 caused variable degrees of lethality in this mouse model, while ETEC strains B7A, WS6866B, 2230, ARG-2, and 8786 did not. Subsequent challenge experiments in which mice were first vaccinated intranasally with MipA, Skp, or ETEC_2479, when combined with cholera toxin, showed both that each antigen was protective and that protection was strongly correlated with fecal IgA concentrations. We conclude that the MipA, Skp, or ETEC_2479 antigens generate protection in the mouse pulmonary challenge model against ETEC strains that express different CFs. PMID- 28018864 TI - Mycobacterium bovis Induces Endoplasmic Reticulum Stress Mediated-Apoptosis by Activating IRF3 in a Murine Macrophage Cell Line. AB - Mycobacterium bovis (M. bovis) is highly adapted to macrophages and has developed multiple mechanisms to resist intracellular assaults. However, the host cells in turn deploy a multipronged defense mechanism to control bacterial infection. Endoplasmic reticulum (ER) stress-mediated apoptosis is one such primary defense mechanism. However, the role of interferon regulatory factor 3 (IRF3) between ER stress and apoptosis during M. bovis infection is unknown. Here, we demonstrate that M. bovis effectively induced apoptosis in murine macrophages. Caspase-12, caspase-9, and caspase-3 were activated over a 48 h infection period. The splicing of XBP-1 mRNA and the level of phosphorylation of eIF2alpha, indicators of ER stress, significantly increased at early time points after M. bovis infection. The expansion of the ER compartment, a morphological hallmark of ER stress, was observed at 6 h. Pre-treatment of Raw 264.7 cells with 4-PBA (an ER stress-inhibitor) reduced the activation of the ER stress indicators, caspase activation and its downstream poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylation of TBK1 and IRF3 and cytoplasmic co-localization of STING and TBK1. M. bovis infection led to the interaction of activated IRF3 and cytoplasmic Bax leading to mitochondrial damage. Role of IRF3 in apoptosis was further confirmed by blocking this molecule with BX-795 that showed significant reduction expression of caspase-8 and caspase-3. Intracellular survival of M. bovis increased in response to 4-PBA and BX-795. These findings indicate that STING TBK1-IRF3 pathway mediates a crosstalk between ER stress and apoptosis during M. bovis infection, which can effectively control intracellular bacteria. PMID- 28018866 TI - Bacillus sp. QSI-1 Modulate Quorum Sensing Signals Reduce Aeromonas hydrophila Level and Alter Gut Microbial Community Structure in Fish. AB - Quorum sensing (QS) is a cell density dependent process that enables bacteria to communicate with each other based on the production, secretion and sensing of the auto-inducer molecules and then subsequently regulate virulence associated gene expression. Interrupting quorum sensing may represent a novel alternative approach to combat bacterial pathogen. Several bacteria can produce quorum quenching (QQ) enzymes. However, the role of QQ bacteria in shaping the microbiota and the level of N-acyl-homoserine lactones (AHLs, a prevalent type of QS molecules) producing bacteria remains largely unknown. The objective of this study was to examine the presence of AHLs in the fish intestine and investigate the modulation of gut microbiota and its effect on Aeromonas hydrophila level by a QQ enzyme producing probiotic Bacillus sp. QSI-1. AHLs were found in fish gut content and were confirmed in Aeromonas species using Chromobacterium violaceum CV026 and Agrobacterium tumefaciens AT 136 (pZLR4) as reporter strains. We demonstrated that the composition of fish gut microbiota was affected by quenching bacteria QSI-1, and the percentage of A. hydrophila was decreased significantly. Taken together, these results provide valuable insights into QQ enzyme producing probiotics can modulate the microbiota structure and decrease the percentage of AHL-producing pathogenic bacteria in the gut. These data strongly suggest that QQ probiotics may serve as non-antibiotic feed additive in aquaculture to control bacterial diseases. PMID- 28018867 TI - Iran Diabetes Research Roadmap (IDRR): the study protocol. AB - BACKGROUND: Diabetes mellitus is a common metabolic disorder which is increasing worldwide. This study aimed to undertake a survey of the diabetes research in Iran to identify gaps and highlight strengths in order to develop a roadmap for diabetes research in Iran for the next years. METHODS: To develop a roadmap and to identify major areas of diabetes research, we carried out a systematic assessment of Iranian diabetes research publications. All obtained studies were categorized to 11 groups and each group was classified according to the "study design", "subject area", "World Health Organization (WHO) classification", and "Australian Standard Research Classifications". The number of publications per each year was calculated. Research trends in publications in each area were assessed and compared. CONCLUSION: By this study, we will provide the highlighted priorities, the gaps of research and strategic mapping of each area of diabetes research that could serve as a precious guideline for national research initiatives in the field of diabetes. By a strategic map, we can achieve many advances in the all aspects of diabetes research that finally impact on the health, quality of life and well-being of diabetic patients. PMID- 28018865 TI - Catecholamine-Stimulated Growth of Aeromonas hydrophila Requires the TonB2 Energy Transduction System but Is Independent of the Amonabactin Siderophore. AB - The growth-stimulating effects of catecholamine stress hormones have been demonstrated in many pathogens. However, catecholamine-induced growth and its underlying mechanisms remain poorly understood in Aeromonas hydrophila. The present study sought to demonstrate that norepinephrine (NE), epinephrine (Epi), dopamine (Dopa), and L-dopa stimulate the growth of A. hydrophila in iron restricted media containing serum. NE exhibited the strongest growth stimulation, which could be blocked by adrenergic antagonists. Furthermore, it was demonstrated that NE could sequester iron from transferrin, thereby providing a more accessible iron source for utilization by A. hydrophila. The deletion of the amoA gene associated with amonabactin synthesis revealed that the amonabactin siderophore is not required for NE-stimulated growth. However, the deletion of the TonB2 energy transduction system resulted in the loss of growth promotion by NE, indicating that a specific TonB-dependent outer membrane receptor might be involved in the transport of iron from transferrin. Collectively, our data show that catecholamine sensing promotes the growth of A. hydrophila in a manner that is dependent on the TonB2 energy transduction system. PMID- 28018868 TI - Pediatric palliative care in Canada in 2012: a cross-sectional descriptive study. AB - BACKGROUND: Pediatric palliative care focuses on comprehensive symptom management and enhancing quality of life for children with life-threatening conditions and their families. Our aim was to describe Canadian programs that provided specialized pediatric palliative care in 2012 and the children who received it and to estimate the proportion of children who might benefit that received specialized care. METHODS: A cross-sectional descriptive design was used. Specialized pediatric palliative care programs were included in the study if they offered multidisciplinary consulting pediatric palliative care services to a wide range of children and served all populations of children with life-threatening illness regardless of diagnosis. Investigators in programs that had taken part in a prior study were invited to participate. New programs that met the inclusion criteria were identified through snowball sampling within pediatric palliative care networks. Program data were obtained via surveys with coinvestigators, and health record reviews were used to obtain information about the children who received care through the programs. RESULTS: All 13 programs identified, including 3 with a free-standing hospice, agreed to take part in the study. Of the 1401 children who received care, 508 (36.2%) were under 1 year of age, and 504 (36.0%) had a congenital illness or condition originating in the perinatal period. Of the 431 children who died in 2012, 105 (24.4%) died in a critical care setting. Programs with a hospice provided care to 517 children (36.9%). Children in this group tended to be older, more often had a neurologic illness and received care for a longer time than those who received care from programs without a hospice. Overall, 18.6% (95% confidence interval 17.1%-20.3%) of deceased children who might have benefitted from specialized pediatric palliative care based on diagnosis received such care, with 110 (25.2%) receiving care for less than 8 days. INTERPRETATION: Program growth and changes in patients' demographic and clinical characteristics indicate improved reach of programs. However, barriers remain that prevent most children with life-threatening conditions from receiving specialized pediatric palliative care services. PMID- 28018869 TI - Pathogens and antimicrobial susceptibility profiles in critically ill patients with bloodstream infections: a descriptive study. AB - BACKGROUND: Surveillance of antimicrobial resistance is vital to guiding empirical treatment of infections. Collating and reporting routine data on clinical isolate testing may offer more timely information about resistance patterns than traditional surveillance network methods. METHODS: Using routine microbiology testing data collected from the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness retrospective cohort study, we conducted a descriptive secondary analysis among critically ill patients in whom bloodstream infections had been diagnosed in 14 intensive care units (ICUs) in Canada. The participating sites were located within tertiary care teaching hospitals and represented 6 provinces and 10 cities. More than 80% of the study population was accrued from 2011-2013. We assessed the epidemiologic features of the infections and corresponding antimicrobial susceptibility profiles. Susceptibility testing was done according to Clinical Laboratory Standards Institute guidelines at accredited laboratories. RESULTS: A total of 1416 pathogens were isolated from 1202 patients. The most common organisms were Escherichia coli (217 isolates [15.3%]), Staphylococcus aureus (175 [12.4%]), coagulase-negative staphylococci (117 [8.3%]), Klebsiella pneumoniae (86 [6.1%]) and Streptococcus pneumoniae (85 [6.0%]). The contribution of individual pathogens varied by site. For 13 ICUs, gram-negative susceptibility rates were high for carbapenems (95.4%), tobramycin (91.2%) and piperacillin-tazobactam (90.0%); however, the proportion of specimens susceptible to these agents ranged from 75.0%-100%, 66.7%-100% and 75.0%-100%, respectively, across sites. Fewer gram-negative bacteria were susceptible to fluoroquinolones (84.5% [range 64.1% 97.2%]). A total of 145 patients (12.1%) had infections caused by highly resistant microorganisms, with significant intersite variation (range 2.6%-24.0%, chi2 = 57.50, p < 0.001). INTERPRETATION: We assessed the epidemiologic features of bloodstream infections in a geographically diverse cohort of critically ill Canadian patients using routine pathogen and susceptibility data extracted from readily available microbiology testing databases. Expanding data sharing across more ICUs, with serial measurement and prompt reporting, could provide much needed guidance for empiric treatment for patients as well as system-wide prevention methods to limit antimicrobial resistance. PMID- 28018870 TI - Cancer incidence attributable to tobacco in Alberta, Canada, in 2012. AB - BACKGROUND: Strong and consistent epidemiologic evidence shows that tobacco smoking causes cancers at various sites. The purpose of this study was to quantify the proportion and total number of site-specific cancers in Alberta attributable to tobacco exposure. METHODS: The proportion of incident cancer cases attributable to active and passive tobacco exposure in Alberta was estimated with population attributable risks. Data from the Canadian Community Health Survey (CCHS) for 2000-2007 were used to estimate prevalence of active (current or former smoker) and passive (second-hand smoke) tobacco exposure in Alberta. RESULTS: According to the 2000/01 CCHS, 29.1% and 38.6% of Albertans were estimated to be current and former smokers, respectively. According to the 2003 CCHS, 23.7% of Albertans who had never smoked reported regular second-hand exposure to tobacco. Population attributable risk estimates for tobacco-related cancer sites ranged from about 4% for ovarian cancer to 74% for laryngeal cancer. About 5% of incident lung cancers in men and women who never smoked could be attributed to passive tobacco exposure. Overall, 37.0% of tobacco-related cancers in Alberta (or 15.7% of all cancers) were estimated to be attributable to active tobacco smoking in 2012. INTERPRETATION: A notable proportion of cancers associated with tobacco use were estimated to be attributable to active smoking in Alberta. Strategies to reduce the prevalence of active tobacco smoking in Alberta could have a considerable impact on future cancer incidence. PMID- 28018872 TI - Trends in binge drinking in Canada from 1996 to 2013: a repeated cross-sectional analysis. AB - BACKGROUND: Heavy drinking is a major factor in morbidity and mortality worldwide. Little information is available on trends in Canada regarding alcohol abuse. We sought to estimate abstinence, binge drinking and alcohol intake exceeding low-risk drinking guidelines in the Canadian population from 1996 to 2013. METHODS: The data sources for this analysis were a series of cross sectional national health surveys of the Canadian population carried out by Statistics Canada between 1996 and 2013. These were cross-sectional files from the National Population Health Surveys of 1996 and 1998, plus the Canadian Community Health Surveys from 2000 to 2013. Respondents were aged 18 years and older. RESULTS: The proportion of binge drinkers increased steadily from 13.7% (95% confidence interval [CI] 13.2%-14.2%) in 1996 to 19.7% (95% CI 19.1%-20.3%) in 2013. The corresponding proportions for men were 20.8% (95% CI 19.9%-21.7%) in 1996, and 25.7% (95% CI 24.7%-26.6%) in 2013; for women, these proportions were 6.9% (95% CI 6.4%-7.5%) in 1996, and 13.8% (95% CI 13.1%-14.5%) in 2013. No significant increases were seen in the proportion of people who exceeded low-risk drinking guidelines or of abstainers during the same period. INTERPRETATION: The rate of self-reported binge drinking in Canada has increased from 1996 to 2013, relatively more so among women than among men. No evidence of an increase in the proportion of people exceeding low-risk drinking guidelines or of abstainers was seen during the same period. These results suggest that binge drinking is of particular concern regarding intervention strategies aimed at improvement of public health. PMID- 28018871 TI - Integration of chronic disease prevention and management services into primary care: a pragmatic randomized controlled trial (PR1MaC). AB - BACKGROUND: Chronic disease prevention and management programs are usually single disease oriented. Our objective was to evaluate an intervention that targeted multiple chronic conditions and risk factors. METHODS: We conducted a pragmatic randomized controlled trial involving patients aged 18-75 years with at least 1 of the targeted chronic conditions or risk factors from 8 primary care practices in the Saguenay region of Quebec, Canada, to evaluate an intervention that included self-management support and patient-centred motivational approaches. Self-management (primary outcome) was evaluated using the Health Education Impact Questionnaire (heiQ). Secondary outcomes included self-efficacy, health-related quality of life, psychological distress and health behaviours. RESULTS: Three hundred thirty-two patients were recruited and randomly assigned (n = 166 for both intervention and control groups) and evaluated after 3 months. The intervention group showed improvement in 6 of the 8 heiQ domains: health-directed behaviour (relative risk [RR] 1.71, 95% confidence interval [CI] 1.13 to 2.59), emotional well-being (RR 1.73, 95% CI 1.07 to 2.79), self-monitoring and insight (RR 2.40, 95% CI 1.19 to 4.86), constructive attitudes and approaches (RR 2.40, 95% CI 1.37 to 4.21), skill and technique acquisition (RR 1.70, 95% CI 1.14 to 2.53), and health service navigation (RR 1.93, 95% CI 1.08 to 3.47). Improvement was also observed in the Physical Component Summary (p = 0.017) and the Single Index (p = 0.041) of the 12-Item Short Form Health Survey (version 2). The intervention group improved in fruit and vegetable consumption (odds ratio [OR] 2.36, 95% CI 1.41 to 3.95) and physical activity (OR 3.81, 95% CI 1.65 to 8.76). One-year improvement was maintained in the intervention group for several outcomes. INTERPRETATION: It is possible to implement an intervention integrating chronic disease prevention and management services into primary care settings. We obtained positive and promising results using this intervention. Trial registration: ClinicalTrials.gov, no.: NCT01319656. PMID- 28018873 TI - Restrictions for reimbursement of direct-acting antiviral treatment for hepatitis C virus infection in Canada: a descriptive study. AB - BACKGROUND: In Canada, interferon-free, direct-acting antiviral hepatitis C virus (HCV) regimens are costly. This presents challenges for universal drug coverage of the estimated 220 000 people with chronic HCV infection nationwide. The study objective was to appraise criteria for reimbursement of 4 HCV direct-acting antivirals in Canada. METHODS: We reviewed the reimbursement criteria for simeprevir, sofosbuvir, ledipasvir-sofosbuvir and paritaprevir-ritonavir ombitasvir plus dasabuvir in the 10 provinces and 3 territories. Data were extracted from April 2015 to June 2016. The primary outcomes extracted from health ministerial websites were: 1) minimum fibrosis stage required, 2) drug and alcohol use restrictions, 3) HIV coinfection restrictions and 4) prescriber type restrictions. RESULTS: Overall, 85%-92% of provinces/territories limited access to patients with moderate fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis stage F2 or greater, or equivalent). There were no drug and alcohol use restrictions; however, several criteria (e.g., active injection drug use) were left to the discretion of the physician. Quebec did not reimburse simeprevir and sofosbuvir for people coinfected with HIV; no restrictions were found in the remaining jurisdictions. Prescriber type was restricted to specialists in up to 42% of provinces/territories. INTERPRETATION: This review of criteria of reimbursement of HCV direct-acting antivirals in Canada showed substantial interjurisdictional heterogeneity. The findings could inform health policy and support the development and adoption of a national HCV strategy. PMID- 28018875 TI - Diagnostic accuracy of developmental screening in primary care at the 18-month health supervision visit: a cross-sectional study. AB - BACKGROUND: Communication delays are often the first presenting problem in infants with a range of developmental disabilities. Our objective was to assess the validity of the 18-month Nipissing District Developmental Screen compared with the Infant Toddler Checklist, a validated tool for detecting expressive language and other communication delays. METHODS: A cross-sectional design was used. Children aged 18-20 months were recruited during scheduled health supervision visits. Parents completed both the 18-month Nipissing District Developmental Screen and the Infant Toddler Checklist. We assessed criterion validity (diagnostic test properties, overall agreement) for 1 or more "no" responses (1+NDDS flag) and 2 or more "no" responses (2+NDDS flag) using the Infant Toddler Checklist as a criterion measure. RESULTS: The study included 348 children (mean age 18.6 +/- 0.7 mo). The 1+NDDS flag had good sensitivity (94%, 95% confidence interval [CI] 70%-100%, and 86%, 95% CI 64%-96%), poor specificity (63%, 95% CI 58%-68%, and 63%, 95% CI 58%-69%), and fair agreement (0.26) to identify expressive speech and other communication delays, respectively. The 2+NDDS flag had low to fair sensitivity (50%, 95% CI 26%-74%, and 73%, 95% CI 50% 88%), good specificity (86%, 95% CI 82%-90%, and 88%, 95% CI 84%-92%) and moderate agreement (0.45) to identify expressive speech and other communication delays, respectively. INTERPRETATION: The low specificity of the 1+NDDS flag may lead to overdiagnosis, and the low sensitivity of the 2+NDDS flag may lead to underdiagnosis, suggesting that infants who could benefit from early intervention may not be identified. The Nipissing District Developmental Screen does not have adequate characteristics to accurately identify children with a range of communication delays. PMID- 28018874 TI - Hospital admissions for lower respiratory tract infections among infants in the Canadian Arctic: a cohort study. AB - BACKGROUND: It is unknown whether this burden of disease of lower respiratory tract infections is comparable across the Canadian Arctic. The objectives of this surveillance study were to compare the rates of hospital admission for lower respiratory tract infection and the severity of infection across Arctic Canada, and to describe the responsible viruses. METHODS: We performed a prospective multicentre surveillance study of infants less than 1 year of age admitted in 2009 with lower respiratory tract infection to all hospitals (5 regional, 4 tertiary) in the Northwest Territories, Nunavut and Nunavik to assess for regional differences. Nasopharyngeal aspirates were processed by means of a polymerase chain reaction respiratory viral panel, testing for 20 respiratory viruses and influenza A (H1N1). The role of coinfection was assessed by means of regression analysis for length of stay (short: < 7 d; long: > 14 d). Outcomes compared included rates of lower respiratory tract infection, respiratory syncytial virus infection, transfer to tertiary hospital and severe lower respiratory tract infection (respiratory failure, intubation and mechanical ventilation, and/or cardiopulmonary resuscitation). RESULTS: There were 348 admissions for lower respiratory tract infection in the population of interest in 2009. Rates of admission per 1000 live births varied significantly, from 39 in the Northwest Territories to 456 in Nunavik (p < 0.001). The rates of tertiary admissions and severe lower respiratory tract infection per 1000 live births in the Northwest Territories were 5.6 and 1.4, respectively, compared to 55.9 and 17.1, respectively, in Nunavut and 52.0 and 20.0, respectively, in Nunavik (p <= 0.001). Respiratory syncytial virus was the most common virus identified (124 cases [41.6% of those tested]), and coinfection was detected in 51 cases (41.1%) of infection with this virus. Longer length of stay was associated with coinfection (odds ratio [OR] 2.64) and underlying risk factors (OR 4.39). Length of stay decreased by 32.2% for every 30-day increase in age (OR 0.68). INTERPRETATION: Nunavut and Nunavik have very elevated rates of lower respiratory tract infection, with severe outcomes. Respiratory syncytial virus was the most common virus identified, and coinfection was associated with longer length of stay. Targeted public health interventions are required to reduce the burden of disease for infants residing in these Arctic regions. PMID- 28018876 TI - Frequency of MCR-1-mediated colistin resistance among Escherichia coli clinical isolates obtained from patients in Canadian hospitals (CANWARD 2008-2015). AB - BACKGROUND: Colistin is often used as an antimicrobial of last resort for the treatment of infections caused by multidrug-resistant gram-negative bacilli. In 2015, plasmid-mediated colistin resistance in Escherichia coli due to MCR-1 was described. The purpose of this study was to evaluate the frequency of colistin resistance among E. coli clinical isolates obtained from patients in Canadian hospitals as part of the Canadian Ward Surveillance Study (CANWARD) and to determine how often the mcr-1 gene is detected among the colistin-resistant subset. METHODS: From January 2008 to December 2015 (excluding 2011), 10 to 15 sentinel hospitals submitted consecutive clinical isolates (1 per patient per infection site) from blood (100-240), respiratory (100-150), urine (25-100) and wound (25-100) infections. We performed susceptibility testing using Clinical and Laboratory Standards Institute broth microdilution methods. Isolates that showed resistance to colistin as defined by European Committee on Antimicrobial Susceptibility Testing breakpoints (minimum inhibitory concentration >= 4 ug/mL) were evaluated for the mcr-1 gene by polymerase chain reaction. RESULTS: In total, 5571 E. coli clinical isolates were obtained over the study years. Twelve isolates (0.2%) were resistant to colistin. The proportion of colistin-resistant isolates varied from 0.0% to 0.5% depending on the study year, and there was no clear trend toward increasing resistance over time. Typically the colistin resistant isolates remained susceptible to antimicrobials from several other classes. Two colistin-resistant isolates (0.04%) were found to harbour the mcr-1 gene. INTERPRETATION: The results suggest that colistin resistance among E. coli human clinical isolates, including resistance mediated by the mcr-1 gene, remains rare in Canada. PMID- 28018877 TI - Validity of Canadian discharge abstract data for hypertension and diabetes from 2002 to 2013. AB - BACKGROUND: Surveillance using coded administrative health data has shown that the prevalence of hypertension and diabetes in Canada increased substantially between 1998 to 2008. These findings require an assumption that the validity of hypertension and diabetes coding is stable over time. We tested this assumption by examining temporal trends in the validity of coding for hypertension and diabetes in the Canadian hospital Discharge Abstract Database. METHODS: We used the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database, a clinical registry, as the reference standard to evaluate the validity of the Discharge Abstract Database in recording hypertension and diabetes in Alberta. The APPROACH database contains data for all Alberta residents who have undergone cardiac catheterization and includes prospective ascertainment of comorbid conditions before each procedure. We linked patient data between the 2 databases for 2002 to 2013 using patient provincial health number. Temporal trends in sensitivity, specificity, positive predictive value, negative predictive value and Cohen kappa were calculated for both hypertension and diabetes in the Discharge Abstract Database. RESULTS: We matched 63 483 patients between the APPROACH database and the Discharge Abstract Database. The validity of the Discharge Abstract Database for hypertension and diabetes remained mostly consistent over time. Between 2002 and 2013, sensitivity, specificity, positive predictive value and negative predictive value ranged from 66% to 87% for hypertension and from 81% to 98% for diabetes; the corresponding kappa scores ranged from 0.50 to 0.62 and from 0.80 to 0.89. No significant differences in the validity of coding were found across age, sex or hospital location subgroups. INTERPRETATION: The validity of coding for hypertension and diabetes in the Discharge Abstract Database remained fairly consistent between 2002 and 2013. Our findings support the use of the Discharge Abstract Database for hypertension and diabetes surveillance in hospital settings. PMID- 28018878 TI - Regulatory approval time for hormonal contraception in Canada, the United States and the United Kingdom, 2000-2015: a retrospective data analysis. AB - BACKGROUND: Access to a wide range of contraceptive methods improves prevention of unintended pregnancy by ensuring the best method fit for each individual. We compared approval times of new hormonal contraceptives by Health Canada, the US Food and Drug Administration (FDA), and the UK Medicines and Healthcare Products Regulatory Agency (MHRA). METHODS: We obtained dates of applications to Health Canada, the FDA and the MHRA for contraceptive methods approved from January 2000 to January 2015. We used public data sources and direct correspondence, and excluded generic versions of previously approved drugs. The primary outcome of interest was median time to approval for novel hormonal contraceptives. Secondary outcomes included the median time to approval for all hormonal contraceptives and the number of approved hormonal contraceptives comparing countries studied, as well as the median time for approval of novel compared with nonnovel hormonal contraceptives within each country. RESULTS: During this period 16 contraceptives were approved in Canada, 26 in the US and 14 in the UK. Applications for novel contraceptives were initiated later in Canada, and time to approval was longer in Canada than in the US (p = 0.03). The median time to approval for all contraceptives in Canada was 529.5 (interquartile range [IQR] 420.8 to 784.0) days, compared with 396.0 (IQR 308.0 to 594.5) days in the US and 341.0 (IQR 244.8 to 512.2) days in the UK. No subdermal implant contraceptives are approved in Canada. INTERPRETATION: Canadian women wait longer for novel contraceptive methods and have fewer options. Canada could improve population health by addressing the regulatory barriers associated with the unmet need for contraception. Facilitation for approval of a contraceptive implant, and improvement to prolonged novel drug approval times, could support Canadians to plan and space their pregnancies. PMID- 28018879 TI - Cost evaluation of out-of-country care for patients with eating disorders in Ontario: a population-based study. AB - BACKGROUND: Eating disorders, specifically anorexia nervosa, bulimia nervosa and eating disorder not otherwise specified, represent a substantial burden to the health care system. Our goal was to estimate the economic burden of patients who received specialized inpatient care for an eating disorder out of country. METHOD: We conducted a cost-of-illness study evaluating health care costs among patients in Ontario who received specialized inpatient care for an eating disorder out of country from 2003 to 2011, from the public third-party payer perspective. Using linked administrative databases, we estimated net costs of eating disorders for 2 patient groups: those who received specialized inpatient care both out of country and in province (n = 160), and those who received specialized inpatient care out of country only (n = 126). RESULTS: Patients approved for specialized out-of-country inpatient care were mostly girls and young women from high-income, urban neighbourhoods. Total net costs varied annually and were higher for patients treated both out of country and in province (about $11 million before 2007, $6.5 million after) than for those treated out of country alone (about $5 million and $2 million, respectively). The main cost drivers were out-of-country care and physician services. INTERPRETATION: Costs associated with eating disorder care represent a substantial economic burden to the Ontario health care system. Given the high costs of out-of-country care, there may be opportunity to redirect these funds to increase capacity and expertise for eating disorder treatment within Ontario. PMID- 28018880 TI - Performance of a quantitative fecal immunochemical test in a colorectal cancer screening pilot program: a prospective cohort study. AB - BACKGROUND: British Columbia undertook a colorectal cancer screening pilot program in 3 communities. Our objective was to assess the performance of 2 specimen fecal immunochemical testing in the detection of colorectal neoplasms in this population-based screening program. METHODS: A prospective cohort of asymptomatic, average-risk people aged 50 to 74 years completed 2 quantitative fecal immunochemical tests every 2 years, with follow-up colonoscopy if the result of either test was positive. Participant demographics, fecal immunochemical test results, colonoscopy quality indicators and pathology results were recorded. Non-screen-detected colorectal cancer that developed in program participants was identified through review of data from the BC Cancer Registry. RESULTS: A total of 16 234 people completed a first round of fecal immunochemical testing, with a positivity rate of 8.6%; 5378 (86.0% of eligible participants) completed a second round before the end of the pilot program, with a positivity rate of 6.7%. Of the 1756 who had a positive test result, 1555 (88.6%) underwent colonoscopy. The detection rate of colorectal cancer was 3.5 per 1000 participants. The positive predictive value of the fecal immunochemical test was 4.9% (95% confidence interval [CI] 3.8%-6.0%) for colorectal cancer, 35.0% (95% CI 32.5%-37.2%) for high-risk polyps and 62.0% (95% CI 59.6%-64.4%) for all neoplasms. The number needed to screen was 283 to detect 1 cancer, 40 to detect 1 high-risk polyp and 22 to detect any neoplasm. INTERPRETATION: Screening every 2 years with a 2-specimen fecal immunochemical test surpassed the current benchmark for colorectal cancer detection in population-based screening. This study has implications for other jurisdictions planning colorectal cancer screening programs. PMID- 28018882 TI - Ontario primary care models: a descriptive study. AB - BACKGROUND: Between 2001 and 2006, the Ontario government introduced a menu of new primary care models, with elements such as patient enrolment and minimum group sizes, and various combinations of fee-for-service, capitation, pay-for performance and salary. From the statistical perspective of physicians, as opposed to patients, we looked at the distribution of physician characteristics, group size and patient visit patterns across models to describe primary care practice in Ontario. METHODS: Using administrative data for fiscal year 2010/11 containing information on physician characteristics, patient rostering status, patient visits and other practice information, we described similarities and differences across primary care models. RESULTS: Our sample included 11 626 family physicians. Compared with physicians in the new primary care models, physicians in fee-for-service models are much more likely to work part-time and many, particularly younger and female physicians, do not work in full-year full scope practices. Among the new primary care models, physicians in capitated models are slightly younger, are less likely to be an international medical graduate, work in smaller physician teams and do not practice in urban areas. On average, physicians saw and rostered 1888 patients. Although there is still substantial variation within each model, fee-for-service physicians saw the fewest patients; physicians in capitated models saw somewhat more, and those in the noncapitated models saw the most patients. INTERPRETATION: Practice and physician characteristics vary systematically across models. A high percentage of rostered patients see physicians outside the group with which they are rostered. Group-based primary care models may not have a large impact on group integration and continuity in the provision of primary care services. PMID- 28018881 TI - Evaluating alignment between Canadian Common Drug Review reimbursement recommendations and provincial drug plan listing decisions: an exploratory study. AB - BACKGROUND: The CADTH Common Drug Review was established in 2002 to prepare national health technology assessment reports to guide listing decisions for 18 participating drug plans. The aim of this study was to compare the nonmandatory recommendations from the Common Drug Review in Canada with the listing decisions of provincial payers to determine alignment. METHODS: We identified the recommendations issued by the Common Drug Review from Jan. 1, 2009, to Jan. 1, 2015, and compared these with the listing decisions of 3 provincial public payers (Alberta, British Columbia and Ontario) that participate in the Common Drug Review and the recommendations from Quebec. RESULTS: We identified 174 medicine indication pairs in CADTH Common Drug Review reports issued from Jan. 1, 2009, to Jan. 1, 2015; 110 of these met the inclusion criterion. Among the 110 medicine indication pairs, listing decisions were available for 95 in Alberta, 102 in Quebec, 104 in Ontario and 106 in BC. There was moderate to substantial agreement between provincial listing decisions and Common Drug Review recommendations: 74.5% (kappa = 0.47, 95% confidence interval [CI] 0.31-0.64) for Quebec, 78.8% (kappa = 0.56, 95% CI 0.41-0.72) for Ontario, 78.9% (kappa = 0.58, 95% CI 0.42 0.74) for Alberta and 81.1% (kappa = 0.62, 95% CI 0.47-0.77) for BC. INTERPRETATION: Our study showed moderate to substantial agreement between Common Drug Review recommendations and provincial listing decisions. Future studies can build on this research by evaluating the concordance between Common Drug Review recommendations and listing decisions of all participating federal, provincial and territorial drug plans. PMID- 28018883 TI - Determinants of alternate-level-of-care delayed discharge among acute care survivors of hypoxic-ischemic brain injury: a population-based cohort study. AB - BACKGROUND: Delayed discharge, captured as alternate-level-of-care days, represents inefficient use of high-demand acute care resources and results in potentially poorer patient outcomes. We performed a study to determine the extent of alternate-level-of-care days among patients who survived hypoxic-ischemic brain injury in inpatient hospital care in Ontario and to identify predictors of alternate-level-of-care use in this population. METHODS: A population-based cohort of acute care survivors of hypoxic-ischemic brain injury aged 20 years or more from 2002/03 through 2011/12 was identified. We used 2 case definitions, the more specific identifying patients with a most responsible diagnosis of "anoxic brain damage," and the more sensitive capturing additional likely causative conditions as the most responsible diagnosis. Multivariable zero-inflated negative binomial regression was used to estimate independent effects on the relative incidence of alternate-level-of-care days. RESULTS: We identified 491 patients using the specific case definition and 669 patients using the extended case definition. After deaths were excluded, 232 patients (47.2%) and 278 patients (41.6%), respectively, had at least 1 alternate-level-of-care day (median 20 and 19 d, respectively). In both cohorts, decreasing age, no special care unit hours and acute care episode earlier in the study period were predictive of increased alternate-level-of-care days relative to length of stay. Discharge disposition and psychiatric/behavioural comorbidity were most predictive of having any alternate-level-of-care days. INTERPRETATION: Patients with hypoxic-ischemic brain injury had a greater proportion of alternate-level-of care days than has been reported for patients with other types of acquired brain injury. This finding suggests that substantial barriers to appropriate discharge exist for this population. Predictors of increased alternate-level-of-care days were also shown to be unique. Further study of care deficits among patients with hypoxic-ischemic brain injury is warranted. PMID- 28018884 TI - Trends in prostate biopsy in Ontario, 1992-2014: a cohort study. AB - BACKGROUND: Prostate cancer is a substantial public health concern; however, in recent years, national guidelines have recommended against prostate cancer screening. We sought to determine if prostate biopsy incidence has changed over time in Ontario. We hypothesized that there has been a decrease in the incidence of prostate biopsy in recent years. METHODS: This cohort study used population based administrative databases from Ontario, Canada. We used a diagnostic code to identify if a patient received his first prostate biopsy between 1992 and 2012 (the last year for which records in the Ontario Cancer Registry were complete). Age-stratified and overall age-standardized incidences of prostate biopsy were determined. Changes over time in prostate biopsy incidence and the proportion of prostate biopsies that showed malignant disease were examined using negative binomial regression adjusting for patient age. RESULTS: We identified 231 266 Ontario men aged 40 years and older who received their first prostate biopsy between 1992 and 2014. Up to 2007, biopsy incidence increased in younger men, but decreased in older men. After 2007, biopsy incidence decreased in all age groups, with the age-standardized overall biopsy incidence dropping from 480 per 100 000 in 2007 to 250 per 100 000 in 2014. A total of 84 149 (39%) incident biopsies showed malignant disease. The proportion of biopsies classified as showing malignant disease increased during the study period, from 25.6% in 1992 to 49.2% in 2010, and then decreased in all age groups. INTERPRETATION: Previously increasing biopsy rates decreased significantly in recent years, suggesting that prostate cancer screening in Ontario may be changing. PMID- 28018885 TI - Lactobacillus probiotics in the prevention of diarrhea associated with Clostridium difficile: a systematic review and Bayesian hierarchical meta analysis. AB - BACKGROUND: Recent meta-analyses of the efficacy of probiotics for preventing diarrhea associated with Clostridium difficile have concluded there is a large effect favouring probiotics. We reexamined this evidence, which contradicts the results of a more recent large randomized controlled trial that found no benefit of Lactobacillus probiotics for preventing C. difficile-associated diarrhea. METHODS: We performed a systematic review of the efficacy of treatment with Lactobacillus probiotics for preventing nosocomial C. difficile-associated diarrhea in adults and carried out a meta-analysis using a Bayesian hierarchical model. We used credibility analysis and meta-regression to characterize the heterogeneity between studies. RESULTS: Ten studies met our inclusion criteria. The pooled risk ratio was highly statistically significant, at 0.25 (95% credible interval 0.08-0.47). However, the 95% prediction interval for the risk ratio in a future study, 0.02-1.34, was wider than the credible interval, owing to heterogeneity between studies. Furthermore, a credibility analysis showed that the strength of the evidence was weaker than the observed number of cases of C. difficile-associated diarrhea across studies would suggest. Meta-regression suggested that the beneficial effect of probiotics was more likely to be reported in studies with an increased risk of C. difficile-associated diarrhea in the control group, although this association was not statistically significant. INTERPRETATION: Accounting for between-study heterogeneity showed that there is considerable uncertainty regarding the apparently large efficacy estimate associated with Lactobacillus probiotic treatment in preventing C. difficile associated diarrhea. Most studies to date have been carried out in populations with a low risk of C. difficile-associated diarrhea, such that the evidence is inconclusive and inadequate to support a policy concerning routine use of probiotics in to prevent this condition. PMID- 28018886 TI - Correction: Using Canadian Primary Care Sentinel Surveillance Network data to examine depression in patients with a diagnosis of Parkinson disease: a retrospective cohort study. AB - [This corrects the article on p. E417 in vol. 4.]. PMID- 28018887 TI - Residents of highly walkable neighbourhoods in Canadian urban areas do substantially more physical activity: a cross-sectional analysis. AB - BACKGROUND: Research has shown that neighbourhood walkability is associated with small differences in physical activity; however, the health impacts of these small differences have been questioned. We examined the size of the association of walkability with accelerometer-measured physical activity in a large, national level Canadian population, and compared results to physical activity levels recommended in international guidelines. Our primary objective was to investigate the direction and size of the differences in physical activity that were related to walkability, and whether these differences depended on age. METHODS: Participants were included from among respondents to the 2007-2011 Canadian Health Measures Surveys who lived in urban areas and were aged 6-79 years. The Canadian Health Measures Surveys are ongoing cross-sectional surveys of a Canada wide population. Respondents were divided into quintiles based on Street Smart Walk Score(r) values of their census dissemination areas. For all respondents and age subgroups, we used covariate-adjusted generalized linear models to estimate differences between quintiles in accelerometer-measured moderate-to-vigorous physical activity (MVPA) and sedentary time. RESULTS: We included 7180 respondents. Differences in participant MVPA between highest and lowest Street Smart Walk Score quintiles were 3.2 (95% confidence interval [CI] -3.2 to 9.6) minutes/day for ages 6-11 years, 11.4 (95% CI 5.3 to 17.4) minutes/day for ages 12-17 years, 9.9 (95% CI 2.4 to 17.4) minutes/day for ages 18-29 years, 14.9 (95% CI 10.2 to 19.6) minutes/day for ages 30-44 years, 11.5 (95% CI 6.7 to 16.3) minutes/day for ages 45-64 years and 6.9 (95% CI 3.1 to 10.8) minutes/day for ages 65-79 years. There were no significant differences in sedentary time in any age group. INTERPRETATION: In all groups except the youngest, participants in the most walkable areas did significantly more MVPA than those in the least walkable areas. For several age groups, this difference was approximately one-half to two thirds of the amount recommended in guidelines for physical activity. Substantially higher MVPA levels suggest that residents of highly walkable areas may have greater health benefits. PMID- 28018888 TI - Health care for children with diabetes mellitus from low-income families in Ontario and California: a population-based cohort study. AB - BACKGROUND: Children with diabetes mellitus in low-income families have poor outcomes, but little is known as to how this relates to healthcare system structure. Our objective was to gain insight into how best to structure health systems to serve these children by describing their health care use in 2 health system models: a Canadian model, with an organized diabetes care network that includes generalists, and an American model, with targeted support services for children from low-income families. METHODS: We performed a population-based retrospective cohort study involving children aged 1-17 years with type 1 diabetes mellitus. We used administrative data from between 2009 and 2012 from the California Children's Services program and Ontario. We used Ontario Drug Benefit Program enrolment to identify children from low-income families. Proportions of children receiving 2 or more routine diabetes visits per year were compared using chi2 tests, and diabetes-complication hospital admission rates were compared using direct standardization. RESULTS: More California children from low-income families (n = 4922) received routine care for diabetes from pediatric endocrinologists (63.9% v. 26.9%, p < 0.001) and used insulin pumps (22.8% v. 16.4%, p < 0.001) than Ontario children (n = 2050).California children from low-income families were less likely than Ontario children to receive 2 visits for routine diabetes care per year (64.7% v. 75.7%, p < 0.001), and had slightly higher per-patient year hospital admission rates for diabetes complications (absolute differences 0.02, 95% confidence interval [CI] 0.02-0.02, for boys; 0.03, 95% CI 0.03-0.03, for girls). INTERPRETATION: Ontario children from low-income families received more routine diabetes care than did California children from low-income families. Both groups of children had clinically comparable rates of hospital admission for diabetes complications. Diabetes care networks that integrate generalists may play a role in improving access and outcomes for the growing population of children with diabetes. PMID- 28018889 TI - Systematic review of the accuracy of antibody tests used to screen asymptomatic adults for hepatitis C infection. AB - BACKGROUND: Several expert groups, including the United States Preventive Services Task Force and the Canadian Task Force on Preventive Health Care, have recently examined or are currently examining whether primary care physicians should screen asymptomatic adults for hepatitis C virus (HCV) infection. To inform decision-making on HCV screening, we performed a systematic review of the accuracy of antibody tests compared with other immunoassays and RNA detection for screening asymptomatic adults for HCV infection in Canada. METHODS: MEDLINE and Embase databases were searched from 1990 to 2016; resulting citations were uploaded into DistillerSR and independently screened by 2 reviewers. Original research studies, systematic reviews and meta-analyses were eligible for inclusion. At least 80% of the study population had to be asymptomatic, nonpregnant, treatment-naive adults with unknown liver enzyme values and unknown HCV status. Risk of bias was assessed with the use of the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) tool; the quality of the body of evidence was assessed by means of GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. RESULTS: Of 1537 articles identified, 81 underwent full-text review, and 9 studies met the inclusion criteria. Compared with RNA detection, the sensitivity of the third-generation enzyme-linked immunosorbent assay was variable (61.0%-81.8%), and its specificity was high (97.5%-99.7%). As expected, there were more false-positive results when comparing antibody tests to RNA detection than to other immunoassays. Our GRADE assessment suggested that there was a high concern for risk of bias, particularly verification bias, and substantial inconsistency between studies in terms of their design. INTERPRETATION: More research is needed to better characterize the accuracy of antibody tests used to screen for HCV infection in the general population. Jurisdictions that recently adopted birth cohort screening for HCV infection are encouraged to evaluate and report on the accuracy of HCV screening tests and screening benefits and harms. PROSPERO registration: no. CRD42016039710. PMID- 28018890 TI - Association between traumatic brain injury and incarceration: a population-based cohort study. AB - BACKGROUND: There is recent evidence to suggest that sustaining a traumatic brain injury (TBI) increases risk of criminal justice system involvement, including incarceration. The objective of this study was to explore the association between TBI and risk of incarceration among men and women in Ontario. METHODS: We identified a cohort of 1.418 million young adults (aged 18-28 yr) on July 1, 1997, living in Ontario, Canada, from administrative health records; they were followed to Dec. 31, 2011. History of TBI was obtained from emergency and hospital records, and incarceration history was obtained from the Correctional Service of Canada records. We estimated the hazard of incarceration using Cox proportional hazard models, adjusting for relevant sociodemographic characteristics and medical history. RESULTS: There were 3531 incarcerations over 18 297 508 person-years of follow-up. The incidence of incarceration was higher among participants with prior TBI compared with those without a prior TBI. In fully adjusted models, men and women who had sustained a TBI were about 2.5 times more likely to be incarcerated than men and women who had not sustained a TBI. INTERPRETATION: Traumatic brain injury was associated with an increased risk of incarceration among men and women in Ontario. Our research highlights the importance of designing primary, secondary and tertiary prevention strategies to mitigate risk of TBI and incarceration in the population. PMID- 28018891 TI - Cancer incidence attributable to the use of oral contraceptives and hormone therapy in Alberta in 2012. AB - BACKGROUND: Hormonal contraceptives and hormone replacement therapies are classified as carcinogenic to humans (group 1) by the International Agency for Research on Cancer. We sought to estimate the proportion and total number of cancers attributable to the use of oral contraceptives and hormone therapy in Alberta in 2012. METHODS: Population attributable risks were used to estimate the proportion of attributable cases for each associated cancer site. Relative risk estimates were obtained from the most relevant and recent epidemiologic literature. Prevalences of the use of oral contraceptives and hormone therapy in Alberta were collected from Alberta's Tomorrow Project. Specific cancer incidence data were obtained from the Alberta Cancer Registry for the year 2012. RESULTS: Overall, 6.3% of breast cancers (n = 135) diagnosed in Alberta in 2012 were estimated to be attributable to the use of oral contraceptives, and the exposure potentially prevented about 57.3% of endometrial cancers (n = 276) and 29.1% of ovarian cancers (n = 52). About 15.5% of breast cancers (n = 258) and 8.9% of ovarian cancers (n = 13) were estimated to be attributable to the use of hormone therapy, whereas 11.3% of endometrial cancers (n = 48) were possibly prevented by the exposure. INTERPRETATION: Based on our estimates, oral contraceptive use resulted in a net protective effect among the cancer sites studied, thus reducing the cancer burden in Alberta in 2012. The use of hormone therapy was estimated to increase the cancer burden in the province, therefore the risk and benefit of hormone therapy should be carefully considered before use. PMID- 28018892 TI - Cancer incidence attributable to insufficient fruit and vegetable consumption in Alberta in 2012. AB - BACKGROUND: Sufficient fruit and vegetable consumption (>= 5 servings/d) has been associated with a probable decreased risk for cancers of the oral cavity, pharynx, larynx, esophagus, stomach and lung (fruit only). The purpose of this study was to estimate the proportion and absolute number of cancer cases in Alberta in 2012 that were attributable to insufficient fruit and vegetable consumption. METHODS: The numbers and proportions of cancers attributable to insufficient fruit and vegetable consumption were estimated using the population attributable risk. Relative risks were obtained from international collaborative panels and peer-reviewed literature. Prevalence data for insufficient fruit and vegetable consumption in Alberta were obtained from the Canadian Community Health Survey (2003, 2004, 2005, 2007/08). Age-, site- and sex-specific cancer incidence data for 2012 were obtained from the Alberta Cancer Registry. RESULTS: The proportion of men consuming 5 or more servings of fruits and vegetables per day ranged from 25.9%-30.4% across age groups; the range among women was 46.8%-51.5% across age groups. The proportion of cancers attributable to insufficient fruit and vegetable consumption in Alberta was highest for esophageal cancer (40.0%) and lowest for lung cancer (3.3%). Overall, 290 cancer cases (1.8%) in Alberta in 2012 were attributable to insufficient fruit and vegetable consumption. INTERPRETATION: Almost 2% of cancers in Alberta can be attributed to insufficient fruit and vegetable consumption. A diet rich in fruits and vegetables has benefits for the prevention of cancer and other chronic diseases; thus, increasing the proportion of Albertans who meet cancer prevention guidelines for fruit and vegetable consumption is a priority. PMID- 28018893 TI - Cancer incidence attributable to red and processed meat consumption in Alberta in 2012. AB - BACKGROUND: Consumption of red and processed meats has been associated with an increased risk of colorectal cancer. The purpose of this study was to estimate the proportion and absolute number of cancers in Alberta in 2012 that could be attributed to the consumption of red and processed meat. METHODS: The number and proportion of colorectal cancers in Alberta that were attributable to red and processed meat consumption were estimated using population attributable risk. Relative risks were obtained from the World Cancer Research Fund's 2011 Continuous Update Project on Colorectal Cancer, and the prevalence of red and processed meat consumption was estimated using dietary data from Alberta's Tomorrow Project. Age- and sex-specific colorectal cancer incidence data for 2012 were obtained from the Alberta Cancer Registry. RESULTS: Among participants in Alberta's Tomorrow Project, 41%-61% of men and 14%-25% of women consumed more than 500 g of red and processed meat per week, which exceeds World Cancer Research Fund cancer prevention guidelines. For red meat consumption, population attributable risks for colorectal cancer were substantially higher for men (13.6% 17.9%) than for women (1.6%-2.1%). For processed meat consumption, the population attributable risks were also higher for men (3.2%-4.8%) than for women (1.5% 2.1%). Overall, about 12% of colorectal cancers, or 1.5% of all cancers, in Alberta in 2012 were attributable to the consumption of red and processed meat. INTERPRETATION: Red and processed meat consumption is estimated to acount for about 12% of colorectal cancers in Alberta. Decreasing its consumption has the potential to reduce to Alberta's cancer burden. PMID- 28018894 TI - Preassessment Interview Improves the Efficacy and Safety of Bowel Preparation for Colonoscopy. AB - Aim. To determine whether preassessment improves bowel preparation quality and prevents renal deterioration for chronic kidney disease (CKD) patients. Methods. Data was collected prospectively starting in January 2011 for 12 months. Patients were divided according to the presence or absence of preassessment and stratified to one of three risk groups based on patient's comorbidities and identified risk factors for poor bowel preparation; group 1 had no risk factors, group 2 had 1 risk factor, and group 3 patients had 2 or more risk factors. The association between preassessment and bowel preparation quality was analyzed using binary logistic regression. Results. 1840 colonoscopies were carried out during the period. Total number analyzed was 1704. 404 patients were preassessed. Preassessment patients had significantly better bowel preparation across all groups (OR 1.605; p = 0.002). Group 3 patients were 52% more likely to have good bowel preparation (p = 0.04) if they had been preassessed. Eighty-eight patients were identified with an eGFR < 60 mL/min. There was a significant difference in the eGFR percentage change between patients with preassessment and those without (p = 0.006). Conclusions. Face-to-face preassessment appears to improve the quality of bowel preparation and aids in minimizing the risk of renal injury in patients with CKD. PMID- 28018895 TI - Regional Differences in End-Diastolic Volumes between 3D Echo and CMR in HLHS Patients. AB - Ultrasound is commonly thought to underestimate ventricular volumes compared to magnetic resonance imaging (MRI), although the reason for this and the spatial distribution of the volume difference is not well understood. In this paper, we use landmark-based image registration to spatially align MRI and ultrasound images from patients with hypoplastic left heart syndrome and carry out a qualitative and quantitative spatial comparison of manual segmentations of the ventricular volume obtained from the respective modalities. In our experiments, we have found a trend showing volumes estimated from ultrasound to be smaller than those obtained from MRI (by approximately up to 20 ml), and that important contributors to this difference are the presence of artifacts such as shadows in the echo images and the different criteria to include or exclude image features as part of the ventricular volume. PMID- 28018896 TI - Factors Influencing Neurodevelopment after Cardiac Surgery during Infancy. AB - Short- and long-term neurodevelopmental (ND) disabilities with negative impact on psychosocial and academic performance, quality of life, and independence in adulthood are known to be the most common sequelae for surviving children after surgery for congenital heart disease (CHD). This article reviews influences and risk factors for ND impairment. For a long time, the search for independent risk factors was focused on the perioperative period and modalities of cardiopulmonary bypass (CPB). CPB operations to ensure intraoperative vital organ perfusion and oxygen supply with or without circulatory arrest or regional cerebral perfusion bear specific risks. Examples of such risks are embolization, deep hypothermia, flow rate, hemodilution, blood gas management, postoperative hyperthermia, systemic inflammatory response, and capillary leak syndrome. However, influences of these procedure-specific risk factors on ND outcome have not been found as strong as expected. Furthermore, modifications have not been found to support the effectiveness of the currently used neuroprotective strategies. Postoperative factors, such as need for extracorporal membrane oxygenation or assist device support and duration of hospital stay, significantly influence ND parameters. On the other hand, the so-called "innate," less modifiable patient-specific risk factors have been found to exert significant influences on ND outcomes. Examples are type and severity of CHD, genetic or syndromic abnormalities, as well as prematurity and low birth weight. Structural and hemodynamic characteristics of different CHDs are assumed to result in impaired brain growth and delayed maturation with respect to the white matter. Beginning in the fetal period, this so-called "encephalopathy of CHD" is suggested a major innate risk factor for pre , peri-, and postoperative additional hypoxic or ischemic brain injury and subsequent ND impairment. Furthermore, MRI studies on brain volume, structure, and function in adolescents have been found correlated with cognitive, motor, and executive dysfunctions. Finally, family and environmental factors independently moderate against ND outcomes. In conclusion, the different mediating factors may exert independent effects on ND and interactive influences. Implications for the future comprise modifying clinical risk factors, such as perioperative cerebral oxygen delivery, conducting brain MRI studies in correlation to ND outcomes, and extending psychosocial interventions leading to adequate resilience. PMID- 28018898 TI - Economic Costs Associated with Motorbike Accidents in Kathmandu, Nepal. AB - BACKGROUND: Road traffic accidents, considered as global tragedies, are in increasing trend; however, the safety situation is very severe in developing countries incurring substantial amount of human, economic, and social costs. Motorcycle crashes, the commonest form, occur mostly in economically active population. However, there is limited number of studies on economic burden of motorcycle crashes. This study aims to estimate the total cost and disability adjusted life years (DALYs) lost due to motorbike accidents among victims of Kathmandu Valley. MATERIALS AND METHODS: Retrospective cross-sectional study was conducted among the patients with a history of motorbike accidents within the past 3 to 12 months from the date of data collection. Interview was conducted using pro forma among 100 victims of accidents and their caregiver in case of death from November 15, 2014 to May 15, 2015. Cost estimation of motorbike accident was done based on human capital approach. Data collection tool was pretested, and collected data were analyzed using SPSS and Microsoft Excel. RESULTS: Males (79%) belonging to the economically productive age group shared the highest proportion among total accidents victims. Most common reason for accidents was reported to be poor road condition (41%). Indirect cost was found to be significantly higher than direct costs, highlighting its negative impact on economy of family and nation due to productivity loss. Total DALYs lost per person was found to be 490 years, and national estimation showed large burden of motorbike accidents due to huge DALY loss. CONCLUSION: For low-resource countries such as Nepal, high economic costs of motorbike accidents can pose additional burden to the fragile health system. These accidents can be prevented, and their consequences can be alleviated. There is an urgent need for reinforcement of appropriate interventions and legislation to decrease its magnitude and its associated grave economic consequences so as to nib this emerging epidemic in the bud. PMID- 28018897 TI - Patient-Centered Tablet Application for Improving Medication Adherence after a Drug-Eluting Stent. AB - BACKGROUND/AIMS: This study's objective was to evaluate a patient-centered educational electronic tablet application, "My Interventional Drug-Eluting Stent Educational App" (MyIDEA) to see if there was an increase in patient knowledge about dual antiplatelet therapy (DAPT) and medication possession ratio (MPR) compared to treatment as usual. METHODS: In a pilot project, 24 elderly (>=50 years old) research participants were recruited after a drug-eluting stent. Eleven were randomized to the control arm and 13 to the interventional arm. All the participants completed psychological and knowledge questionnaires. Adherence was assessed through MPR, which was calculated at 3 months for all participants who were scheduled for second and third follow-up visits. RESULTS: Relative to control, the interventional group had a 10% average increase in MPR. As compared to the interventional group, more patients in the control group had poor adherence (<80% MPR). The psychological data revealed a single imbalance in anxiety between the control and interventional groups. On average, interventional participants spent 21 min using MyIDEA. DISCUSSION: Consumer health informatics has enabled us to engage patients with their health data using novel methods. Consumer health technology needs to focus more on patient knowledge and engagement to improve long-term health. MyIDEA takes a unique approach in targeting DAPT from the onset. CONCLUSION: MyIDEA leverages patient-centered information with clinical care and the electronic health record highlighting the patients' role as a team member in their own health care. The patients think critically about adverse events and how to solve issues before leaving the hospital. PMID- 28018899 TI - Theoretical Investigation of Mono- and Di-Chloro-Substitient Effects on the Insulation and Greenhouse Properties of Octafluorocyclobutane. AB - Octafluorocyclobutane, c-C4F8, and its derivatives are regarded as promising replacements of insulation gaseous SF6, which are currently widely used in electric equipment but suffer greatly from its greenhouse effect. Based on the recent finding that the dielectric and thermodynamics properties of insulating gases are greatly dependent on the molecule's microscopic electronic and vibrational parameters, in this work, we use density functional theory (DFT) to study the molecular structures, electron affinities, and IR-active vibrational frequencies as well as thermodynamic properties for c-C4F8 and a series of mono-, di-substituted c-C4F8 compounds. It is shown that DFT calculation of perfluoro compounds is sensitive to the chosen functional. Although all chloro-substituted c-C4F8 molecules are found to have much larger electron affinities, only part of them have less IR intensity in the atmospheric IR "window" than c-C4F8. Such a study provides useful guideline for the pre-screening search for new insulation gases via electronic structure calculations. PMID- 28018900 TI - Redox Regulation of Heart Regeneration: An Evolutionary Tradeoff. AB - Heart failure is a costly and deadly disease, affecting over 23 million patients worldwide, half of which die within 5 years of diagnosis. The pathophysiological basis of heart failure is the inability of the adult heart to regenerate lost or damaged myocardium. Although limited myocyte turnover does occur in the adult heart, it is insufficient for restoration of contractile function (Nadal-Ginard, 2001; Laflamme et al., 2002; Quaini et al., 2002; Hsieh et al., 2007; Bergmann et al., 2009, 2012). In contrast to lower vertebrates (Poss et al., 2002; Poss, 2007; Jopling et al., 2010; Kikuchi et al., 2010; Chablais et al., 2011; Gonzalez Rosa et al., 2011; Heallen et al., 2011), adult mammalian heart cardiomyogenesis following injury is very limited (Nadal-Ginard, 2001; Laflamme et al., 2002; Quaini et al., 2002; Bergmann et al., 2009, 2012) and is insufficient to restore normal cardiac function. Studies in the late 90s elegantly mapped the DNA synthesis and cell cycle dynamics of the mammalian heart during development and following birth (Soonpaa et al., 1996; Soonpaa and Field, 1997, 1998), where they showed that DNA synthesis drops significantly around birth with low-level DNA synthesis few days after birth. Around P5 to P7, cardiomyocytes undergo a final round of DNA synthesis without cytokinesis, and the majority become binucleated and exit the cell cycle permanently. Therefore, due to the similarities between the immature mammalian heart and lower vertebrates (Poss, 2007; Walsh et al., 2010), it became important to determine whether they have similar regenerative abilities. Recently, we demonstrated that removal of up to 15% of the apex of the left ventricle of postnatal day 1 (P1) mice results in complete regeneration within 3 weeks without any measurable fibrosis and cardiac dysfunction (Porrello et al., 2011). This response is characterized by robust cardiomyocyte proliferation with gradual restoration of normal cardiac morphology. In addition to the histological evidence of proliferating myocytes, genetic fate-mapping studies confirmed that the majority of newly formed cardiomyocytes are derived from proliferation of preexisting cardiomyocytes (Porrello et al., 2011). More recently, we established an ischemic injury model where the left anterior descending coronary artery was ligated in P1 neonates (Porrello et al., 2013). The injury response was similar to the resection model, with robust cardiomyocyte proliferation throughout the myocardium, as well as restoration of normal morphology by 21 days. However, this regenerative capacity is lost by P7, after which injury results in the typical cardiomyocyte hypertrophy and scar-formation characteristic of the adult mammalian heart. Not surprisingly, the loss of this regenerative capacity coincides with binucleation and cell cycle exit of cardiomyocytes (Soonpaa et al., 1996; Walsh et al., 2010). An important approach toward a deeper understanding the loss of cardiac regenerative capacity in mammals is to first consider why , and not only how , this happens. Regeneration of the early postnatal heart following resection or ischemic infarction involves replacement of lost myocardium and vasculature with restoration of normal myocardial thickness and architecture, with long-term normalization of systolic function. Why would the heart permanently forego such a remarkable regenerative program shortly after birth? The answer may lie in within the fundamental principal of evolutionary tradeoff. PMID- 28018901 TI - Regulation of Store-Operated Ca2+ Entry by Septins. AB - The mechanism of store-operated Ca2+ entry (SOCE) brings extracellular Ca2+ into cells after depletion of intracellular Ca2+ stores. Regulation of Ca2+ homeostasis by SOCE helps control various intracellular signaling functions in both non-excitable and excitable cells. Whereas essential components of the SOCE pathway are well characterized, molecular mechanisms underlying regulation of this pathway need investigation. A class of proteins recently demonstrated as regulating SOCE is septins. These are filament-forming GTPases that assemble into higher order structures. One of their most studied cellular functions is as a molecular scaffold that creates diffusion barriers in membranes for a variety of cellular processes. Septins regulate SOCE in mammalian non-excitable cells and in Drosophila neurons. However, the molecular mechanism of SOCE-regulation by septins and the contribution of different subgroups of septins to SOCE-regulation remain to be understood. The regulation of SOCE is relevant in multiple cellular contexts as well as in diseases, such as the Severe Combined Immunodeficiency (SCID) syndrome and neurodegenerative syndromes like Alzheimer's, Spino Cerebellar Ataxias and Parkinson's. Moreover, Drosophila neurons, where loss of SOCE leads to flight deficits, are a possible cellular template for understanding the molecular basis of neuronal deficits associated with loss of either the Inositol-1,4,5-trisphosphate receptor (IP3R1), a key activator of neuronal SOCE or the Endoplasmic reticulum resident Ca2+ sensor STIM1 (Stromal Interaction Molecule) in mouse. This perspective summarizes our current understanding of septins as regulators of SOCE and discusses the implications for mammalian neuronal function. PMID- 28018902 TI - Focus on Nivolumab in NSCLC. AB - Immunotherapy is changing the treatment of non-small cell lung cancer (NSCLC). The PD-1 inhibitor nivolumab has demonstrated meaningful results in terms of efficacy with a good safety profile. The novel approach to treating NSCLC using immunotherapy still has unsolved questions and challenging issues. The main doubts regarding the optimal selection of the patient are the role of this drug in first line of treatment, the individualization of the correct methodology of radiologic assessment and efficacy analysis, the best management of immune mediated adverse events, and how to overcome the immunoresistance. The aim of this review is to analyze literature data on nivolumab in lung cancer with a focus on critical aspects related to the drug in terms of safety, the use in clinical practice, and possible placement in the treatment algorithm. PMID- 28018903 TI - Impact of Lymph Node Burden on Survival of High-risk Prostate Cancer Patients Following Radical Prostatectomy and Pelvic Lymph Node Dissection. AB - AIM: To determine the impact of the extent of lymph node invasion (LNI) on long term oncological outcomes after radical prostatectomy (RP). MATERIAL AND METHODS: In this retrospective study, we examined the data of 1,249 high-risk, non metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at eight different tertiary institutions. We fitted univariate and multivariate Cox models to assess independent predictors of cancer specific survival (CSS) and overall survival (OS). The number of positive lymph node (LN) was dichotomized according to the most informative cutoff predicting CSS. Kaplan-Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cutoff was chosen as a surrogate for a well performed PNLD. RESULTS: Mean age was 65 years (median: 66, IQR 60-70). Positive surgical margins were present in 53.7% (n = 671). Final Gleason score (GS) was 2-6 in 12.7% (n = 158), 7 in 52% (n = 649), and 8-10 in 35.4% (n = 442). The median number of LNs removed during PLND was 15 (IQR 12-17). Of all patients, 1,128 (90.3%) had 0-3 positive LNs, while 126 (9.7%) had >=4 positive LNs. Patients with 0-3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with >=4 positive LNs (87 vs. 50%; p < 0.0001). Similar results were obtained for OS, with a 72 vs. 37% (p < 0.0001) survival at 10 years for patients with 0-3 vs. >=4 positive LNs, respectively. At multivariate analysis, final GS of 8-10, salvage ADT therapy, and >=4 (vs. <4) positive LNs were predictors of worse CSS and OS. Pathological stage pT4 was an additional predictor of worse CSS. CONCLUSION: Four or more positive LNs, pathological stage pT4, and final GS of 8-10 represent independent predictors for worse CSS in patients with high-risk PCa. Primary tumor biology remains a strong driver of tumor progression and patients having >=4 positive LNs could be considered an enriched patient group in which novel treatment strategies should be studied. PMID- 28018904 TI - 3D Volumetric Modeling and Microvascular Reconstruction of Irradiated Lumbosacral Defects after Oncologic Resection. AB - BACKGROUND: Locoregional flaps are sufficient in most sacral reconstructions. However, large sacral defects due to malignancy necessitate a different reconstructive approach, with local flaps compromised by radiation and regional flaps inadequate for broad surface areas or substantial volume obliteration. In this report, we present our experience using free muscle transfer for volumetric reconstruction, in such cases, and demonstrate three-dimensional (3D) haptic models of the sacral defect to aid preoperative planning. METHODS: Five consecutive patients with irradiated sacral defects secondary to oncologic resections were included, surface area ranging from 143-600 cm2. Latissimus dorsi (LD)-based free flap sacral reconstruction was performed in each case, between 2005 and 2011. Where the superior gluteal artery was compromised, the subcostal artery (SA) was used as a recipient vessel. Microvascular technique, complications, and outcomes are reported. The use of volumetric analysis and 3D printing is also demonstrated, with imaging data converted to 3D images suitable for 3D printing with Osirix software (Pixmeo, Geneva, Switzerland). An office based, desktop 3D printer was used to print 3D models of sacral defects, used to demonstrate surface area and contour and produce a volumetric print of the dead space needed for flap obliteration. RESULTS: The clinical series of LD free flap reconstructions is presented, with successful transfer in all cases, and adequate soft-tissue cover and volume obliteration achieved. The original use of the SA as a recipient vessel was successfully achieved. All wounds healed uneventfully. 3D printing is also demonstrated as a useful tool for 3D evaluation of volume and dead space. CONCLUSION: Free flaps offer unique benefits in sacral reconstruction where local tissue is compromised by irradiation and tumor recurrence, and dead space requires accurate volumetric reconstruction. We describe for the first time the use of the SA as a recipient in free flap sacral reconstruction. 3D printing of haptic bio-models is a rapidly evolving field with a substantial role in preoperative planning. PMID- 28018905 TI - The Mutational Landscape of the Oncogenic MZF1 SCAN Domain in Cancer. AB - SCAN domains in zinc-finger transcription factors are crucial mediators of protein-protein interactions. Up to 240 SCAN-domain encoding genes have been identified throughout the human genome. These include cancer-related genes, such as the myeloid zinc finger 1 (MZF1), an oncogenic transcription factor involved in the progression of many solid cancers. The mechanisms by which SCAN homo- and heterodimers assemble and how they alter the transcriptional activity of zinc finger transcription factors in cancer and other diseases remain to be investigated. Here, we provide the first description of the conformational ensemble of the MZF1 SCAN domain cross-validated against NMR experimental data, which are probes of structure and dynamics on different timescales. We investigated the protein-protein interaction network of MZF1 and how it is perturbed in different cancer types by the analyses of high-throughput proteomics and RNASeq data. Collectively, we integrated many computational approaches, ranging from simple empirical energy functions to all-atom microsecond molecular dynamics simulations and network analyses to unravel the effects of cancer related substitutions in relation to MZF1 structure and interactions. PMID- 28018907 TI - The Use of the Ambulatory Arterial Stiffness Index in Patients Suspected of Secondary Hypertension. AB - The ambulatory arterial stiffness index (AASI) is a marker of arterial stiffness and is derived from ambulatory 24-h blood pressure registration. We studied whether the AASI could be used as a predictive factor for the presence of renal artery stenosis (RAS) in patients with a suspicion of secondary hypertension and as such as a diagnostic tool for RAS. We included 169 patients with difficult-to treat hypertension. They all underwent 24-h ambulatory blood pressure monitoring registration, imaging of the renal arteries, and cardiovascular risk measurement, including smoking, history, biometrics, blood pressure, renal function, lipids, and glucose metabolism. Performing univariate and multivariate analyses, we investigated if AASI and the other cardiovascular risk factors were related to the presence of RAS. Of the 169 patients (49% women), 31% had RAS. The mean AASI was 0.44 (0.16). The presence of RAS showed no significant correlation with AASI (r = 0.14, P = 0.06). Age (r = 0.19, P = 0.01), hypercholesterolemia (r = 0.26, P = 0.001), history of CVD (r = 0.22, P = 0.004), and creatinine clearance (r = 0.34, P < 0.001) all demonstrated a correlation with RAS. Although AASI is higher in patients with RAS, AASI does not independently predict the presence of RAS in hypertensive subjects. PMID- 28018906 TI - Chaperonopathies: Spotlight on Hereditary Motor Neuropathies. AB - Distal hereditary motor neuropathies (dHMN) are a group of rare hereditary neuromuscular disorders characterized by an atrophy that affects peroneal muscles in the absence of sensory symptoms. To date, 23 genes are thought to be responsible for dHMN, four of which encode chaperones: DNAJB2, which encodes a member of the HSP40/DNAJ co-chaperone family; and HSPB1, HSPB3, and HSPB8, encoding three members of the small heat shock protein family. While around 30 different mutations in HSPB1 have been identified, the remaining three genes are altered in many fewer cases. Indeed, a mutation of HSPB3 has only been described in one case, whereas a few cases have been reported carrying mutations in DNAJB2 and HSPB8, most of them caused by a founder c.352+1G>A mutation in DNAJB2 and by mutations affecting the K141 residue in the HSPB8 chaperone. Hence, their rare occurrence makes it difficult to understand the pathological mechanisms driven by such mutations in this neuropathy. Chaperones can assemble into multi-chaperone complexes that form an integrated chaperone network within the cell. Such complexes fulfill relevant roles in a variety of processes, such as the correct folding of newly synthesized proteins, in which chaperones escort them to precise cellular locations, and as a response to protein misfolding, which includes the degradation of proteins that fail to refold properly. Despite this range of functions, mutations in some of these chaperones lead to diseases with a similar clinical profile, suggesting common pathways. This review provides an overview of the genetics of those dHMNs that share a common disease mechanism and that are caused by mutations in four genes encoding chaperones: DNAJB2, HSPB1, HSPB3, and HSPB8. PMID- 28018908 TI - Partial Cranial Cruciate Ligament Tears Treated with Stem Cell and Platelet-Rich Plasma Combination Therapy in 36 Dogs: A Retrospective Study. AB - OBJECTIVE: To evaluate outcomes in 36 dogs with a partial cranial cruciate ligament (CCL) tear treated with autologous bone marrow aspirate concentrate (BMAC) or adipose-derived progenitor cells (ADPC) with platelet-rich plasma (PRP) combination. MATERIALS AND METHODS: Medical records of client-owned dogs diagnosed with an early partial (<=50%) tear of the craniomedial band of the CCL that was treated with BMAC-PRP or ADPC-PRP were reviewed from 2010 to 2015. Signalment, medical history, physical and orthopedic examination, objective temporospatial gait analyses, radiographs, day 0 and day 90 diagnostic arthroscopy findings, treatment, and outcome were among the data collected. A functional owner questionnaire, including the validated Helsinki chronic pain index (HCPI), was sent to owners whose dog was known to not have had a tibial plateau leveling osteotomy (TPLO). Statistical analysis was performed on data, where significance was established at p < 0.05. RESULTS: Stifle arthroscopy findings at 90 days posttreatment were available on 13 of the 36 dogs. In nine dogs, a fully intact CCL with marked neovascularization and a normal fiber pattern was found with all previous regions of disruption healed. One dog revealed significant improvement and received an additional injection. The remaining three dogs had a >50% CCL tear, and a TPLO was performed. Four additional dogs were known to have had a TPLO performed elsewhere. Baseline and day 90 posttreatment objective gait analyses were available on 11 of the 36 dogs. A significant difference was found between the treated limb total pressure index percent (TPI%) at day 0 and day 90 (p = 0.0124), and between the treated limb and contralateral limb TPI% at day 0 (p = 0.0003). No significant difference was found between the treated limb and contralateral limb TPI% at day 90 (p = 0.7466). Twelve questionnaires were returned, of which eight were performance/sporting dogs. Seven of the eight had returned to sport; the remaining dog had just begun a return to sport conditioning program 6 months posttreatment. All 12 respondents believed that their dog had an excellent or very good quality of life and rated their dog's procedural outcome as excellent or good. CONCLUSION: The use of BMAC-PRP and ADPC-PRP shows promise for the treatment of early partial CCL tears in dogs. Further studies are needed and should be randomized, blinded, and controlled. PMID- 28018910 TI - An Investigation of the Complexities of Successful and Unsuccessful Guide Dog Matching and Partnerships. AB - Matching a person who is blind or visually impaired with a guide dog is a process of finding the most suitable guide dog available for that individual. Not all guide dog partnerships are successful, and the consequences of an unsuccessful partnership may result in reduced mobility and quality of life for the handler (owner), and are costly in time and resources for guide dog training establishments. This study examined 50 peoples' partnerships with one or more dogs (118 pairings) to ascertain the outcome of the relationship. Forty-three of the 118 dogs were returned to the guide dog training establishment before reaching retirement age, with the majority (n = 40) being categorized as having dog-related issues. Most (n = 26) of these dogs' issues were classified as being behavioral in character, including work-related and non-work-related behavior, and 14 were due to physical causes (mainly poor health). Three dogs were returned due to matters relating to the handlers' behavior. More second dogs were returned than the handlers' first or third dogs, and dogs that had been previously used as a guide could be rematched successfully. Defining matching success is not clear cut. Not all dogs that were returned were considered by their handlers to have been mismatched, and not all dogs retained until retirement were thought to have been good matches, suggesting that some handlers were retaining what they considered to be a poorly matched dog. Almost all the handlers who regarded a dog as being mismatched conceded that some aspects of the match were good. For example, a dog deemed mismatched for poor working behavior may have shown good home and/or other social behaviors. The same principle was true for successful matches, where few handlers claimed to have had a perfect dog. It is hoped that these results may help the guide dog industry identify important aspects of the matching process, and/or be used to identify areas where a matching problem exists. PMID- 28018909 TI - A Review of Selected Genes with Known Effects on Performance and Health of Cattle. AB - There are genetic conditions that influence production in dairy and beef cattle. The objective of this review was to describe relevant genetic conditions that have been associated with productivity and health in cattle. Genes or genomic regions that have been identified as a candidate for the condition will be included, and the genetic basis of the condition will be defined. Genes and genetic conditions included in this review are bovine leukocyte adhesion deficiency, deficiency of the uridine monophosphate synthase, bovine chronic interstitial nephritis, horn development, myostatin, complex vertebral malformation, leptin, osteopetrosis, apoptosis peptide activating factor 1, chondrodysplastic dwarfism, caseins, calpastatin, umbilical hernia, lactoglobulin, citrullinemia, cholesterol deficiency, prions, thyroglobulin, diacylglycerol acyltransferase, syndactyly, maple syrup urine disease, slick hair, Factor XI deficiency, and MU-Calpain. This review is not meant to be comprehensive, and relevant information is provided to ascertain genetic markers associated with the conditions. PMID- 28018911 TI - A Quantitative Model to Estimate Drug Resistance in Pathogens. AB - Pneumocystis pneumonia (PCP) is an opportunistic infection that occurs in humans and other mammals with debilitated immune systems. These infections are caused by fungi in the genus Pneumocystis, which are not susceptible to standard antifungal agents. Despite decades of research and drug development, the primary treatment and prophylaxis for PCP remains a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) that targets two enzymes in folic acid biosynthesis, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), respectively. There is growing evidence of emerging resistance by Pneumocystis jirovecii (the species that infects humans) to TMP-SMX associated with mutations in the targeted enzymes. In the present study, we report the development of an accurate quantitative model to predict changes in the binding affinity of inhibitors (Ki, IC50) to the mutated proteins. The model is based on evolutionary information and amino acid covariance analysis. Predicted changes in binding affinity upon mutations highly correlate with the experimentally measured data. While trained on Pneumocystis jirovecii DHFR/TMP data, the model shows similar or better performance when evaluated on the resistance data for a different inhibitor of PjDFHR, another drug/target pair (PjDHPS/SMX) and another organism (Staphylococcus aureus DHFR/TMP). Therefore, we anticipate that the developed prediction model will be useful in the evaluation of possible resistance of the newly sequenced variants of the pathogen and can be extended to other drug targets and organisms. PMID- 28018912 TI - Recurrent rhinovirus detections in children following a rhinovirus-induced wheezing exacerbation: A retrospective study. AB - INTRODUCTION: It is unclear if children with a rhinovirus (RV)-induced wheezing exacerbation are more susceptible to viruses longitudinally, and whether a parental history of asthma and/or allergy impacts their susceptibility. The objective of this study was to determine if RV, RV-A and RV-C related wheezing exacerbations in children were associated with prior or subsequent viral detections and investigate the role of parental history of asthma and allergy. MATERIALS AND METHODS: Children presenting to hospital with acute wheeze were prospectively recruited and tested for respiratory viruses. Data on viruses detected in other respiratory samples (May 1997 to December 2012) were collected from hospital microbiology records and additional RV testing was performed on stored hospital respiratory samples (September 2009 to December 2012). A positive parental history was defined as either parent with self-reported asthma and/or allergy. RESULTS: At recruitment, RV was detected in 69.2% of samples from children with an acute wheezing episode (n=373, 0-16 years of age), with RV-C the most common virus (65.5%). Children with a history of parental asthma and/or allergy and RV at recruitment had a 14-fold increased incidence rate ratio (IRR) of subsequent RV detection (IRR 14.0, 95% CI 1.9-104.1; p=0.01) compared with children without RV at recruitment. Children without this parental history had a reduced incident rate ratio for samples assessed during this time (IRR 0.5, 95% CI 0.3-0.9; p=0.03). CONCLUSION: Children with a parental history of asthma and/or allergy may become more susceptible to recurrent symptomatic RV infections. PMID- 28018913 TI - Evolution of bopA Gene in Burkholderia: A Case of Convergent Evolution as a Mechanism for Bacterial Autophagy Evasion. AB - Autophagy is an important defense mechanism targeting intracellular bacteria to restrict their survival and growth. On the other hand, several intracellular pathogens have developed an antiautophagy mechanism to facilitate their own replication or intracellular survival. Up to now, no information about the origin or evolution of the antiautophagic genes in bacteria is available. BopA is an effector protein secreted by Burkholderia pseudomallei via the type three secretion system, and it has been shown to play a pivotal role in their escape from autophagy. The evolutionary origin of bopA was examined in this work. Sequence similarity searches for BopA showed that no homolog of BopA was detected in eukaryotes. However, eukaryotic linear motifs were detected in BopA. The phylogenetic tree of the BopA proteins in our analysis is congruent with the species phylogeny derived from housekeeping genes. Moreover, there was no obvious difference in GC content values of bopA gene and their respective genomes. Integrated information on the taxonomic distribution, phylogenetic relationships, and GC content of the bopA gene of Burkholderia revealed that this gene was acquired via convergent evolution, not from eukaryotic host through horizontal gene transfer (HGT) event. This work has, for the first time, characterized the evolutionary mechanism of bacterial evasion of autophagy. The results of this study clearly demonstrated the role of convergent evolution in the evolution of how bacteria evade autophagy. PMID- 28018915 TI - Ebola Virus Infection among Western Healthcare Workers Unable to Recall the Transmission Route. AB - Introduction. During the 2014-2016 West-African Ebola virus disease (EVD) outbreak, some HCWs from Western countries became infected despite proper equipment and training on EVD infection prevention and control (IPC) standards. Despite their high awareness toward EVD, some of them could not recall the transmission routes. We explored these incidents by recalling the stories of infected Western HCWs who had no known directly exposures to blood/bodily fluids from EVD patients. Methodology. We carried out conventional and unconventional literature searches through the web using the keyword "Ebola" looking for interviews and reports released by the infected HCWs and/or the healthcare organizations. Results. We identified fourteen HCWs, some infected outside West Africa and some even classified at low EVD risk. None of them recalled accidents, unintentional exposures, or any IPC violation. Infection transmission was thus inexplicable through the acknowledged transmission routes. Conclusions. We formulated two hypotheses: inapparent exposures to blood/bodily fluids or transmission due to asymptomatic/mildly symptomatic carriers. This study is in no way intended to be critical with the healthcare organizations which, thanks to their interventions, put an end to a large EVD outbreak that threatened the regional and world populations. PMID- 28018914 TI - Clinical Acceptability of the Internal Gap of CAD/CAM PD-AG Crowns Using Intraoral Digital Impressions. AB - The purpose of this study was to compare the internal gap between CAD/CAM palladium-silver crowns and cast gold crowns generated from intraoral digital versus conventional impressions and to determine the clinical acceptability. Nickel-chrome master dies were made from the prepared resin tooth with the conventional impression method (n = 40). For ICC (Intraoral, CAD/CAM) group, 10 intraoral digital impressions were made, and 10 CAD/CAM crowns of a PD-AG (palladium-silver) machinable alloy were generated. For IC (Intraoral, Cast) group, 10 gold crowns were cast from ten intraoral digital impressions. For CCC (Conventional, CAD/CAM) group, 10 CAD/CAM PD-AG crowns were made using the conventional impression method. For CC (Conventional, Cast) group, 10 gold crowns were fabricated from 10 conventional impressions. One hundred magnifications of the internal gaps of each crown were measured at 50 points with an optical microscope and these values were statistically analyzed using a two-way analysis of variance (alpha = 0.05). The internal gap of the intraoral digital impression group was significantly larger than in the conventional impression group (P < 0.05). No significant difference was observed between the CAD/CAM group and the cast group (P > 0.05). Within the limitations of this in vitro study, crowns from intraoral digital impressions showed larger internal gap values than crowns from conventional impressions. PMID- 28018916 TI - Tricholoma matsutake Aqueous Extract Induces Hepatocellular Carcinoma Cell Apoptosis via Caspase-Dependent Mitochondrial Pathway. AB - Tricholoma matsutake, one of widely accepted functional mushrooms, possesses various pharmacological activities, and its antitumor effect has become an important research point. Our study aims to evaluate the cytotoxicity activities of T. matsutake aqueous extract (TM) in HepG2 and SMMC-7721 cells. In in vitro experiments, TM strikingly reduced cell viability, promoted cell apoptosis, inhibited cell migration ability, induced excessive generation of ROS, and caused caspases cascade and mitochondrial membrane potential dissipation in hepatocellular carcinoma cells. In in vivo experiments, 14-day TM treatment strongly suppressed tumor growth in HepG2 and SMMC-7721-xenografted nude mice without influence on their body weights and liver function. Furthermore, TM increased the levels of cleaved poly-ADP-ribose polymerase (PARP), Bad, and Bax and reduced the expressions of B-cell lymphoma 2 (Bcl-2) in treated cells and tumor tissues. All aforementioned results suggest that caspase-dependent mitochondrial apoptotic pathways are involved in TM-mediated antihepatocellular carcinoma. PMID- 28018917 TI - Micronucleated Erythrocytes in Peripheral Blood from Neonate Rats Exposed by Breastfeeding to Cyclophosphamide, Colchicine, or Cytosine-Arabinoside. AB - Genotoxic exposure to chemical substances is common, and nursing mothers could transmit harmful substances or their metabolites to their offspring through breast milk. We explored the possibility of determining genotoxic effects in the erythrocytes of breastfeeding rat pups whose mothers received a genotoxic compound while nursing. Ten groups of female rats and five pups per dam were studied. The control group received sterile water, and the experimental groups received one of three different doses of cyclophosphamide, colchicine, or cytosine-arabinoside. Blood smears were prepared from samples taken from each dam and pup every 24 h for six days. There were increased numbers of micronucleated erythrocytes (MNEs) and micronucleated polychromatic erythrocytes (MNPCEs) in the samples from pups in the experimental groups (P < 0.02) and increased MNPCE frequencies in the samples from the dams (P < 0.05). These results demonstrate the vertical transmission of the genotoxic effect of the compounds tested. In conclusion, assessing MNEs in breastfeeding neonate rats to assess DNA damage may be a useful approach for identifying genotoxic compounds and/or cytotoxic effects. This strategy could help in screening for therapeutic approaches that are genotoxic during the lactation stage and these assessments might also be helpful for developing preventive strategies to counteract harmful effects. PMID- 28018918 TI - Role of BKCa in Stretch-Induced Relaxation of Colonic Smooth Muscle. AB - Stretch-induced relaxation has not been clearly identified in gastrointestinal tract. The present study is to explore the role of large conductance calcium activated potassium channels (BKCa) in stretch-induced relaxation of colon. The expression and currents of BKCa were detected and the basal muscle tone and contraction amplitude of colonic smooth muscle strips were measured. The expression of BKCa in colon is higher than other GI segments (P < 0.05). The density of BKCa currents was very high in colonic smooth muscle cells (SMCs). BKCa in rat colonic SMCs were sensitive to stretch. The relaxation response of colonic SM strips to stretch was attenuated by charybdotoxin (ChTX), a nonspecific BKCa blocker (P < 0.05). After blocking enteric nervous activities by tetrodotoxin (TTX), the stretch-induced relaxation did not change (P > 0.05). Still, ChTX and iberiotoxin (IbTX, a specific BKCa blocker) attenuated the relaxation of the colonic muscle strips enduring stretch (P < 0.05). These results suggest stretch-activation of BKCa in SMCs was involved in the stretch induced relaxation of colon. Our study highlights the role of mechanosensitive ion channels in SMCs in colon motility regulation and their physiological and pathophysiological significance is worth further study. PMID- 28018919 TI - The Emerging Role of MicroRNA-155 in Cardiovascular Diseases. AB - MicroRNAs have been demonstrated to be involved in human diseases, including cardiovascular diseases. Growing evidences suggest that microRNA-155, a typical multifunctional microRNA, plays a crucial role in hematopoietic lineage differentiation, immunity, inflammation, viral infections, and vascular remodeling, which is linked to cardiovascular diseases such as coronary artery disease, abdominal aortic aneurysm, heart failure, and diabetic heart disease. The effects of microRNA-155 in different cell types through different target genes result in different mechanisms in diseases. MicroRNA-155 has been intensively studied in atherosclerosis and coronary artery disease. Contradictory results of microRNA-155 either promoting or preventing the pathophysiological process of atherosclerosis illustrate the complexity of this pleiotropic molecule. Therefore, more comprehensive studies of the underlying mechanisms of microRNA-155 involvement in cardiovascular diseases are required. Furthermore, a recent clinical trial of Miravirsen targeting microRNA-122 sheds light on exploiting microRNA-155 as a novel target to develop effective therapeutic strategies for cardiovascular diseases in the near future. PMID- 28018920 TI - Delay between Onset of Symptoms and Seeking Physician Intervention Increases Risk of Diabetic Foot Complications: Results of a Cross-Sectional Population-Based Survey. AB - We present a post hoc analysis of 17,530 questionnaires collected as part of the 2012 screening for neuropathy using Norfolk Quality of Life tool in patients with diabetes in Romania, to assess the impact on foot complications of time between the onset of symptoms of diabetes/its complications and the physician visit. Odds ratios (ORs) for self-reporting neuropathy increased from 1.16 (95% CI: 1.07 1.25) in those who sought medical care in 1-6 months from symptoms of diabetes/its complications onset to 2.27 in those who sought medical care >2 years after symptoms onset. The ORs for having a history of foot ulcers were 1.43 (95% CI: 1.26-1.63) in those who sought medical care in 1-6 months and increased to 3.08 (95% CI: 2.59-3.66) in those who sought medical care after >2 years from symptoms of diabetes/its complications onset. The highest ORs for a history of gangrene (2.49 [95% CI: 1.90-3.26]) and amputations (2.18 [95% CI: 1.60-2.97]) were observed in those who sought medical care after >2 years following symptoms onset. In conclusion, we showed that waiting for >1 month after symptoms onset dramatically increases the risk of diabetic foot complications. These results show the need for accessible educational programs on diabetes and its chronic complications and the need to avoid delays in reporting. PMID- 28018921 TI - Low Serum Levels of Prealbumin, Retinol Binding Protein, and Retinol Are Frequent in Adult Type 1 Diabetic Patients. AB - Aim. To determine the serum prealbumin (PA), retinol binding protein (RBP), and retinol levels in adult patients with type 1 diabetes (T1D) and to analyze some factors related to those levels. Methods. A total of 93 patients (47 women) were studied. Age, gender, BMI, duration of diabetes, chronic complications, HbA1c, lipid profile, creatinine, albumin, PA, RBP, and retinol were recorded. High and low parameter groups were compared by Mann-Whitney U and chi2 tests. Correlation between parameters was analyzed by Spearman's test. Odds of low levels were analyzed by univariate logistic regression and included in the multivariate analysis when significant. Results. 49.5%, 48.4%, and 30.1% of patients displayed serum PA, RBP, and retinol levels below normal values, respectively. A high correlation (Rho > 0.8) between PA, RBP, and retinol serum levels was found. Patients presenting low levels of any of them were predominantly women, normal weighted, and with lower levels of triglycerides and serum creatinine. No differences in age, macrovascular complications, duration of diabetes, or HbA1c values were observed when comparing low and normal parameter groups. Conclusion. Low serum levels of PA, RBP, and retinol are frequent in T1D adult patients. This alteration is influenced by female sex and serum creatinine and triglyceride levels. PMID- 28018922 TI - Influence of the Expression of Inflammatory Markers on Kidney after Fetal Programming in an Experimental Model of Renal Failure. AB - Objective. To evaluate the expression of inflammatory markers in experimental renal failure after fetal programming. Methods. The offspring aged two and five months were divided into four groups: CC (control dams, control offspring); DC (diabetic dams, control offspring); CFA (control dams, folic acid offspring, 250 mg/Kg); and DFA (diabetic dams, folic acid offspring). Gene expression of inflammatory markers MCP-1, IL-1, NOS3, TGF-beta, TNF-alpha, and VEGF was evaluated by RT-PCR. Results. MCP-1 was increased in the CFA and DFA groups at two and five months of age, as well as in DC5 when compared to CC5. There was a higher expression of IL-1 in the CFA2, DFA2, and DC2 groups. There was a decrease in NOS3 and an increase in TNF-alpha in DFA5 in relation to CFA5. The gene expression of TGF-beta increased in cases that had received folic acid at two and five months, and VEGF decreased in the CFA5 and DFA5 groups. DC5 showed increased VEGF expression in comparison with CC5. Conclusions. Gestational diabetes mellitus and folic acid both change the expression of inflammatory markers, thus demonstrating that the exposure to harmful agents in adulthood has a more severe impact in cases which underwent fetal reprogramming. PMID- 28018923 TI - Spinal Epidural Abscess in Adults: A 10-Year Clinical Experience at a Tertiary Care Academic Medical Center. AB - Background. Delayed recognition of spinal epidural abscess (SEA) contributes to poor outcomes from this highly morbid and potentially lethal infection. We performed a case-control study in a regional, high-volume, tertiary care, academic medical center over the years 2005-2015 to assess the potential changing epidemiology, clinical and laboratory manifestations, and course of this disorder and to identify factors that might lead to early identification of SEA. Methods. Diagnostic billing codes consistent with SEA were used to identify inpatient admissions for abstraction. Subjects were categorized as cases or controls based on the results of spinal imaging studies. Characteristics were compared using Fisher's exact or Kruskal-Wallis tests. All P values were 2-sided with a critical threshold of <.05. Results. We identified 162 cases and 88 controls during the study period. The incidence of SEA increased from 2.5 to 8.0 per 10 000 admissions, a 3.3-fold change from 2005 to 2015 (P < .001 for the linear trend). Compared with controls, cases were significantly more likely to have experienced at least 1 previous healthcare visit or received antimicrobials within 30 days of admission; to have comorbidities of injection drug use, alcohol abuse, or obesity; and to manifest fever or rigors. Cases were also more likely to harbor coinfection at a noncontiguous site. When available, inflammatory markers were noted to be markedly elevated in cases. Focal neurologic deficits were seen with similar frequencies in both groups. Conclusions. Based on our analysis, it appears that selected factors noted at the time of clinical presentation may facilitate early recognition of SEA. PMID- 28018924 TI - H1N1-Induced Venous Thromboembolic Events? Results of a Single-Institution Case Series. AB - We describe the clinical and imaging characteristics of 7 cases with polymerase chain reaction-confirmed novel influenza A H1N1 virus (pH1N1) infection who developed venous thromboembolic events (VTEs) while being hospitalized for influenza pneumonia. Pulmonary embolism (PE) without deep vein thrombosis (DVT) was observed in 6 of 7 cases (85.7%); PE with underlying DVT was found in 1 patient (14.3%). PMID- 28018926 TI - Concurrent Systemic Chemoimmunotherapy and Sofosbuvir-Based Antiviral Treatment in a Hepatitis C Virus-Infected Patient With Diffuse Large B-Cell Lymphoma. AB - Hepatitis C virus (HCV) infection is associated with the development of non Hodgkin lymphomas. For aggressive lymphomas, such as diffuse large B-cell lymphoma (DLBCL), treatment of HCV infection is typically deferred in treatment naive patients until after completion of lymphoma therapy [1, 2]. We report a case of HCV-associated stage IV DLBCL successfully treated concurrently using chemoimmunotherapy and a sofosbuvir-based antiviral regimen. PMID- 28018925 TI - Parasite Clearance and Artemether Pharmacokinetics Parameters Over the Course of Artemether-Lumefantrine Treatment for Malaria in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Ugandan Children. AB - BACKGROUND: Artemisinins are primarily responsible for initial parasite clearance. Antimalarial pharmacokinetics (PK), human immunodeficiency virus (HIV) infection, and antiretroviral therapy have been shown to impact treatment outcomes, although their impact on early parasite clearance in children has not been well characterized. METHODS: Parasite clearance parameters were generated from twice-daily blood smears in HIV-infected and HIV-uninfected Ugandan children treated with artemether-lumefantrine (AL). Artemether and dihydroartemisinin (DHA) area-under-the-curve from 0-8 hours (AUC0-8hr) after the 1st AL dose was compared with AUC0-8hr after the last (6th) dose in a concurrently enrolled cohort. The association between post-1st dose artemisinin AUC0-8hr and parasite clearance was assessed. RESULTS: Parasite clearance was longer in HIV-infected versus HIV-uninfected children (median, 3.5 vs 2.8 hours; P = .003). Artemether AUC0-8hr was 3- to 4-fold lower after the 6th dose versus the 1st dose of AL in HIV-infected children on nevirapine- or lopinavir/ritionavir-based regimens and in HIV-uninfected children (P <= .002, 1st vs 6th-dose comparisons). Children on efavirenz exhibited combined post-1st dose artemether/DHA exposure that was significantly lower than those on lopinavir/ritonavir and HIV-uninfected children. Multiple regression analysis supported that the effect of artemether/DHA exposure on parasite clearance was significantly moderated by HIV status. CONCLUSIONS: Parasite clearance rates remain rapid in Uganda and were not found to associate with PK exposure. However, significant decreases in artemisinin PK with repeated dosing in nearly all children, coupled with small, but significant increase in parasite clearance half-life in those with HIV, may have important implications for AL efficacy, particularly because reports of artemisinin resistance are increasing. PMID- 28018927 TI - Meningococcal Disease in Patients With Human Immunodeficiency Virus Infection: A Review of Cases Reported Through Active Surveillance in the United States, 2000 2008. AB - BACKGROUND: Although human immunodeficiency virus (HIV) infection is an established risk factor for several bacterial infections, the association between HIV infection and meningococcal disease remains unclear. METHODS: Expanded chart reviews were completed on persons with meningococcal disease and HIV infection reported from 2000 through 2008 from 9 US sites participating in an active population-based surveillance system for meningococcal disease. The incidence of meningococcal disease among patients meeting Centers for Disease Control and Prevention acquired immune deficiency syndrome (AIDS) surveillance criteria was estimated using data from the National HIV Surveillance System for the participating sites. RESULTS: Thirty-three cases of meningococcal disease in individuals with HIV infection were reported from participating sites, representing 2.0% of all reported meningococcal disease cases. Most (75.8%) persons with HIV infection were adult males aged 25 to 64 years old. Among all meningococcal disease cases aged 25 to 64 years old, case fatality ratios were similar among HIV-infected and HIV-uninfected persons (13.3% vs 10.6%; P = .6). The cumulative, mean incidence of meningococcal disease among patients aged 25 to 64 years old with HIV infection ever classified as AIDS was 3.5 cases per 100000 person years (95% confidence interval [CI], 2.1-5.6), compared with 0.3 cases per 100000 person years (95% CI, 0.3-0.3) for persons of the same age group not reported to have AIDS (relative risk = 12.9; 95% CI, 7.9-20.9). CONCLUSIONS: Individuals with HIV infection meeting the AIDS surveillance case definition have a higher incidence of meningococcal disease compared with the general adult population. PMID- 28018928 TI - Autochthonous Transmission of Trypanosoma Cruzi in Southern California. AB - Trypanosoma cruzi usually infects humans via triatomine insects in Latin America. Vector-borne transmission in the United States is exceedingly rare. We describe (1) the first case of probable autochthonous transmission reported in California in more than 30 years and (2) the first ever reported case in the greater Los Angeles area. PMID- 28018929 TI - Antiretroviral Therapy as Prevention of ... Pneumococcal Infections? AB - BACKGROUND: Despite antiretroviral therapy, it is generally believed that the risk for pneumococcal infections (PnIs) is high among patients infected with human immunodeficiency virus (HIV). However, most studies in this field have been conducted before 2010, and the proportion of virologically suppressed patients has drastically increased in these latter years thanks to larger indications and more effective antiretroviral regimens. This study aimed to re-evaluate the current risk of PnI among adult patients infected with HIV. METHODS: The incidence of PnI was evaluated between 1996 and 2014 in 2 French regional hospitals. The 80 most recent cases of PnI (2000-2014) were retrospectively compared with 160 controls (HIV patients without PnI) to analyze the residual risk factors of PnI. RESULTS: Among a mean annual follow-up cohort of 1616 patients, 116 PnIs were observed over 18 years. The risk factors of PnI among patients infected with HIV were an uncontrolled HIV infection or "classic" risk factors of PnI shared by the general population such as addiction, renal or respiratory insufficiency, or hepatitis B or C coinfection. Pneumococcal vaccination coverage was low and poorly targeted, because only 5% of the cases had been previously vaccinated. The incidence of invasive PnIs among HIV patients with a nonvirologically suppressed infection or comorbidities was 12 times higher than that reported in the general population at the country level (107 vs 9/100000 patients), whereas the incidence among virologically suppressed HIV patients without comorbidities was lower (7.6/100000 patients). CONCLUSIONS: Human immunodeficiency virus infection no longer per se seems to be a significant risk factor for PnI, suggesting a step-down from a systematic to an "at-risk patient" targeted pneumococcal vaccination strategy. PMID- 28018930 TI - Intra-abdominal Infections: The Role of Anaerobes, Enterococci, Fungi, and Multidrug-Resistant Organisms. AB - BACKGROUND: Intra-abdominal infections (IAI) constitute a common reason for hospitalization. However, there is lack of standardization in empiric management of (1) anaerobes, (2) enterococci, (3) fungi, and (4) multidrug-resistant organisms (MDRO). The recommendation is to institute empiric coverage for some of these organisms in "high-risk community-acquired" or in "healthcare-associated" infections (HCAI), but exact definitions are not provided. METHODS: Epidemiological study of IAI was conducted at Assaf Harofeh Medical Center (May November 2013). Logistic and Cox regressions were used to analyze predictors and outcomes of IAI, respectively. The performances of established HCAI definitions to predict MDRO-IAI upon admission were calculated by receiver operating characteristic (ROC) curve analyses. RESULTS: After reviewing 8219 discharge notes, 253 consecutive patients were enrolled (43 [17%] children). There were 116 patients with appendicitis, 93 biliary infections, and 17 with diverticulitis. Cultures were obtained from 88 patients (35%), and 44 of them (50%) yielded a microbiologically confirmed IAI: 9% fungal, 11% enterococcal, 25% anaerobic, and 34% MDRO. Eighty percent of MDRO-IAIs were present upon admission, but the area under the ROC curve of predicting MDRO-IAI upon admission by the commonly used HCAI definitions were low (0.73 and 0.69). Independent predictors for MDRO-IAI were advanced age and active malignancy. CONCLUSIONS: Multidrug-resistant organism-IAIs are common, and empiric broad-spectrum coverage is important among elderly patients with active malignancy, even if the infection onset was outside the hospital setting, regardless of current HCAI definitions. Outcomes analyses suggest that empiric regimens should routinely contain antianaerobes (except for biliary IAI); however, empiric antienterococcal or antifungals regimens are seldom needed. PMID- 28018931 TI - Virologic Failure and Human Immunodeficiency Virus Drug Resistance in Rural Cameroon With Regard to the UNAIDS 90-90-90 Treatment Targets. AB - BACKGROUND: In rural Africa, data on virologic effectiveness of antiretroviral treatment (ART) are not sufficient to assess the gap with the UNAIDS 90-90-90 treatment targets. We investigated the prevalences of unsuppressed viral load and antiretroviral drug resistance and the profile of genotypic resistance mutations among patients routinely treated in rural Cameroon. METHODS: A cross-sectional study was performed in 2013-2014 among patients >=15 years and on first-line ART for >=6 months in a district hospital. Patients were offered free access to human immunodeficiency virus viral load testing. Genotypic drug resistance testing was done when the viral load was >1000 copies/mL. Multivariate logistic regression models were used to assess the relationship of unsuppressed viral load or antiretroviral drug resistance with sociodemographic and medical characteristics. RESULTS: Of 407 patients (women 74.9%, median age 41.8 years, median time on ART 29.2 months), 96 (23.6%; 95% confidence interval [CI], 19.5-28.0) had unsuppressed viral load and 74 (18.2%; 95% CI, 14.6-22.3) had antiretroviral drug resistance. The prevalences of unsuppressed viral load and resistance increased with time on ART, from 12.0% and 8.0% in the 6- to 12-month group to 31.3% and 27.1% in the >72-month group, respectively. All 74 patients with antiretroviral drug resistance were resistant to nonnucleoside reverse-transcriptase inhibitors, and 57 of them were also resistant to nucleoside reverse-transcriptase inhibitors. CONCLUSIONS: Our estimations were among the highest observed in the west and central African region. The proportion of patients with virologic failure should be divided at least by 2 to reach the UNAIDS 90-90-90 treatment targets. PMID- 28018932 TI - Staphylococcus epidermidis Protection Against Staphylococcus aureus Colonization in People Living With Human Immunodeficiency Virus in an Inner-City Outpatient Population: A Cross-Sectional Study. AB - BACKGROUND: People living with human immunodeficiency virus (PLWH) have been disproportionally affected by methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection, in particular by clones USA300 and USA500. However, the contribution of epidemiological, bacterial, and immunological risk factors to the excess of S aureus in PLWH remain incompletely understood. METHODS: In this cross-sectional study, we determined the prevalence and molecular epidemiology of S aureus colonization in 93 PLWH attending an urban human immunodeficiency virus (HIV) clinic. Participants completed a structured interview assessing demographic information and risk factors for MRSA. Swabs were obtained from the nose, throat, and groin and cultured for S aureus and Staphylococcus epidermidis. RESULTS: Most participants had well controlled HIV infection (89, 96% CD4 >200). Thirty-six (39%) individuals were colonized with S aureus at 1 or more body sites, including 6 (6%) with MRSA. Regular gym use was a risk factor for S aureus but not MRSA carriage. In contrast, S epidermidis was present in almost all individuals (n = 84, 90%), predominantly in the nares (n = 66, 71%). Using generalized estimating equation models, we observed that the odds of S aureus colonization were significantly and drastically reduced when S epidermidis was detected (P = .0001). After controlling for site, gender, and age, we identified that the odds of S aureus colonization were 80% less if S epidermidis was present (adjusted odds ratio, 0.20; 95% confidence interval, .09-.45; P < .0001). CONCLUSIONS: Taken together, we observed a lower prevalence of S aureus and MRSA colonization than has been previously reported in PLWH. In this cohort, colonization with S epidermidis was protective against S aureus colonization. PMID- 28018933 TI - Mindfulness as a Coping Strategy for Bias-Based School Victimization among Latina/o Sexual Minority Youth. AB - This study examined whether mindfulness strategies (e.g., acting non-judgmentally with awareness and attention to present events) were effective in mitigating the associations among school-based victimization related to ethnicity and sexual orientation, well-being (i.e., depressive symptoms and self-esteem), and grade point average (GPA). The U.S.-based sample included 236 Latina/o sexual minority students, ranging in age from 14 to 24 years (47% were enrolled in secondary schools, 53% in postsecondary schools). Results from structural equation modeling revealed that ethnicity-based school victimization was negatively associated with GPA but not well-being. However, sexual orientation-based victimization was not associated with well-being or GPA. Mindfulness was positively associated with well-being but not GPA. High levels of mindfulness coping were protective when the stressor was sexual orientation-based victimization but not ethnicity-based school victimization. These findings contribute to a growing literature documenting the unique school barriers experienced by Latina/o sexual minority youth and highlight the promising utility of mindfulness-based intervention strategies for coping with minority stress. PMID- 28018935 TI - Intraoperative intrinsic optical imaging of human somatosensory cortex during neurosurgical operations. AB - Intrinsic optical imaging as developed by Grinvald et al. is a powerful technique for monitoring neural function in the in vivo central nervous system. The advent of this dye-free imaging has also enabled us to monitor human brain function during neurosurgical operations. We briefly describe our own experience in functional mapping of the human somatosensory cortex, carried out using intraoperative optical imaging. The maps obtained demonstrate new additional evidence of a hierarchy for sensory response patterns in the human primary somatosensory cortex. PMID- 28018934 TI - Prefrontal hemodynamic mapping by functional near-infrared spectroscopy in response to thermal stimulations over three body sites. AB - Functional near-infrared spectroscopy (fNIRS) was used to examine hemodynamic responses in the prefrontal cortex (PFC) during noxious thermal pain, induced by thermal stimulations over three different body sites over the right forearm, right temporomandibular joint, and left forearm. Functional NIRS measurements were obtained from three groups of healthy volunteers, one group for each body region. Each group was subjected to both low-pain stimulation (LPS) and high-pain stimulation (HPS) by a [Formula: see text] thermode of a temperature-controlled thermal stimulator over the respective three body sites. Our results showed that HPS given at three sites induced significant increases ([Formula: see text]) in oxy-hemoglobin concentration ([Formula: see text]) in the PFC with similar temporal patterns in relatively spread PFC areas. In contrast, LPS did not cause any significant [Formula: see text] in the PFC of any subject group. Our observed PFC activations induced by acute HPS were generally consistent with previous reports by fMRI studies. The study also found a peculiar global trend of postpain deactivation in the PFC, which is attributed to global vasoconstriction due to acute nocuous pain. Overall, these results indicate that hemodynamic activities in PFC exhibit consistent temporal and spatial patterns in response to acute thermal stimulation given across all three body sites. PMID- 28018936 TI - Noise performance of low-dose CT: comparison between an energy integrating detector and a photon counting detector using a whole-body research photon counting CT scanner. AB - Photon counting detector (PCD)-based computed tomography (CT) is an emerging imaging technique. Compared to conventional energy integrating detector (EID) based CT, PCD-CT is able to exclude electronic noise that may severely impair image quality at low photon counts. This work focused on comparing the noise performance at low doses between the PCD and EID subsystems of a whole-body research PCD-CT scanner, both qualitatively and quantitatively. An anthropomorphic thorax phantom was scanned, and images of the shoulder portion were reconstructed. The images were visually and quantitatively compared between the two subsystems in terms of streak artifacts, an indicator of the impact of electronic noise. Furthermore, a torso-shaped water phantom was scanned using a range of tube currents. The product of the noise and the square root of the tube current was calculated, normalized, and compared between the EID and PCD subsystems. Visual assessment of the thorax phantom showed that electronic noise had a noticeably stronger degrading impact in the EID images than in the PCD images. The quantitative results indicated that in low-dose situations, electronic noise had a noticeable impact (up to a 5.8% increase in magnitude relative to quantum noise) on the EID images, but negligible impact on the PCD images. PMID- 28018937 TI - Shape complexes: the intersection of label orderings and star convexity constraints in continuous max-flow medical image segmentation. AB - Optimization-based segmentation approaches deriving from discrete graph-cuts and continuous max-flow have become increasingly nuanced, allowing for topological and geometric constraints on the resulting segmentation while retaining global optimality. However, these two considerations, topological and geometric, have yet to be combined in a unified manner. The concept of "shape complexes," which combine geodesic star convexity with extendable continuous max-flow solvers, is presented. These shape complexes allow more complicated shapes to be created through the use of multiple labels and super-labels, with geodesic star convexity governed by a topological ordering. These problems can be optimized using extendable continuous max-flow solvers. Previous approaches required computationally expensive coordinate system warping, which are ill-defined and ambiguous in the general case. These shape complexes are demonstrated in a set of synthetic images as well as vessel segmentation in ultrasound, valve segmentation in ultrasound, and atrial wall segmentation from contrast-enhanced CT. Shape complexes represent an extendable tool alongside other continuous max-flow methods that may be suitable for a wide range of medical image segmentation problems. PMID- 28018938 TI - Computer-aided diagnosis of retinopathy in retinal fundus images of preterm infants via quantification of vascular tortuosity. AB - Retinopathy of prematurity (ROP), a disorder of the retina occurring in preterm infants, is the leading cause of preventable childhood blindness. An active phase of ROP that requires treatment is associated with the presence of plus disease, which is diagnosed clinically in a qualitative manner by visual assessment of the existence of a certain level of increase in the thickness and tortuosity of retinal vessels. The present study performs computer-aided diagnosis (CAD) of plus disease via quantitative measurement of tortuosity in retinal fundus images of preterm infants. Digital image processing techniques were developed for the detection of retinal vessels and measurement of their tortuosity. The total lengths of abnormally tortuous vessels in each quadrant and the entire image were then computed. A minimum-length diagnostic-decision-making criterion was developed to assess the diagnostic sensitivity and specificity of the values obtained. The area ([Formula: see text]) under the receiver operating characteristic curve was used to assess the overall diagnostic accuracy of the methods. Using a set of 19 retinal fundus images of preterm infants with plus disease and 91 without plus disease, the proposed methods provided an overall diagnostic accuracy of [Formula: see text]. Using the total length of all abnormally tortuous vessel segments in an image, our techniques are capable of CAD of plus disease with high accuracy without the need for manual selection of vessels to analyze. The proposed methods may be used in a clinical or teleophthalmological setting. PMID- 28018939 TI - LUNGx Challenge for computerized lung nodule classification. AB - The purpose of this work is to describe the LUNGx Challenge for the computerized classification of lung nodules on diagnostic computed tomography (CT) scans as benign or malignant and report the performance of participants' computerized methods along with that of six radiologists who participated in an observer study performing the same Challenge task on the same dataset. The Challenge provided sets of calibration and testing scans, established a performance assessment process, and created an infrastructure for case dissemination and result submission. Ten groups applied their own methods to 73 lung nodules (37 benign and 36 malignant) that were selected to achieve approximate size matching between the two cohorts. Area under the receiver operating characteristic curve (AUC) values for these methods ranged from 0.50 to 0.68; only three methods performed statistically better than random guessing. The radiologists' AUC values ranged from 0.70 to 0.85; three radiologists performed statistically better than the best-performing computer method. The LUNGx Challenge compared the performance of computerized methods in the task of differentiating benign from malignant lung nodules on CT scans, placed in the context of the performance of radiologists on the same task. The continued public availability of the Challenge cases will provide a valuable resource for the medical imaging research community. PMID- 28018940 TI - Errata: Enhanced resolution pulse-echo imaging with stabilized pulses. AB - [This corrects the article DOI: 10.1117/1.JMI.3.2.027003.]. PMID- 28018941 TI - Modularized compact positron emission tomography detector for rapid system development. AB - We report the development of a modularized compact positron emission tomography (PET) detector that outputs serial streams of digital samples of PET event pulses via an Ethernet interface using the UDP/IP protocol to enable rapid configuration of a PET system by connecting multiple such detectors via a network switch to a computer. Presently, the detector is [Formula: see text] in extent (excluding I/O connectors) and contains an [Formula: see text] array of [Formula: see text] one to-one coupled lutetium-yttrium oxyorthosilicate/silicon photomultiplier pixels. It employs cross-wire and stripline readouts to merge the outputs of the 216 detector pixels to 24 channels. Signals at these channels are sampled using a built-in 24-ch, 4-level field programmable gate arrays-only multivoltage threshold digitizer. In the computer, software programs are implemented to analyze the digital samples to extract event information and to perform energy qualification and coincidence filtering. We have developed two such detectors. We show that all their pixels can be accurately discriminated and measure a crystal level energy resolution of 14.4% to 19.4% and a detector-level coincidence time resolution of 1.67 ns FWHM. Preliminary imaging results suggests that a PET system based on the detectors can achieve an image resolution of [Formula: see text]. PMID- 28018942 TI - Murine Leukemia Virus (MLV)-based Coronavirus Spike-pseudotyped Particle Production and Infection. AB - Viral pseudotyped particles (pp) are enveloped virus particles, typically derived from retroviruses or rhabdoviruses, that harbor heterologous envelope glycoproteins on their surface and a genome lacking essential genes. These synthetic viral particles are safer surrogates of native viruses and acquire the tropism and host entry pathway characteristics governed by the heterologous envelope glycoprotein used. They have proven to be very useful tools used in research with many applications, such as enabling the study of entry pathways of enveloped viruses and to generate effective gene-delivery vectors. The basis for their generation lies in the capacity of some viruses, such as murine leukemia virus (MLV), to incorporate envelope glycoproteins of other viruses into a pseudotyped virus particle. These can be engineered to contain reporter genes such as luciferase, enabling quantification of virus entry events upon pseudotyped particle infection with susceptible cells. Here, we detail a protocol enabling generation of MLV-based pseudotyped particles, using the Middle East respiratory syndrome coronavirus (MERS-CoV) spike (S) as an example of a heterologous envelope glycoprotein to be incorporated. We also describe how these particles are used to infect susceptible cells and to perform a quantitative infectivity readout by a luciferase assay. PMID- 28018944 TI - Finding NMO. PMID- 28018943 TI - Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro. AB - OBJECTIVE: To address the hypothesis that physiologic interactions between astrocytes and endothelial cells (EC) at the blood-brain barrier (BBB) are afflicted by pathogenic inflammatory signaling when astrocytes are exposed to aquaporin-4 (AQP4) antibodies present in the immunoglobulin G (IgG) fraction of serum from patients with neuromyelitis optica (NMO), referred to as NMO-IgG. METHODS: We established static and flow-based in vitro BBB models incorporating co-cultures of conditionally immortalized human brain microvascular endothelial cells and human astrocyte cell lines with or without AQP4 expression. RESULTS: In astrocyte-EC co-cultures, exposure of astrocytes to NMO-IgG decreased barrier function, induced CCL2 and CXCL8 expression by EC, and promoted leukocyte migration under flow, contingent on astrocyte expression of AQP4. NMO-IgG selectively induced interleukin (IL)-6 production by AQP4-positive astrocytes. When EC were exposed to IL-6, we observed decreased barrier function, increased CCL2 and CXCL8 expression, and enhanced leukocyte transmigration under flow. These effects were reversed after application of IL-6 neutralizing antibody. CONCLUSIONS: Our results indicate that NMO-IgG induces IL-6 production by AQP4 positive astrocytes and that IL-6 signaling to EC decreases barrier function, increases chemokine production, and enhances leukocyte transmigration under flow. PMID- 28018945 TI - Comprehensive population-based determination of pediatric multiple sclerosis health care costs. AB - OBJECTIVE: To determine the health care costs associated with pediatric multiple sclerosis (MS). METHODS: We performed a retrospective analysis of all patients with MS 18 years of age or younger who were diagnosed or treated between 2002 and 2012 in a population-based cohort. Demographics and health care costs were extracted from the Intermountain Healthcare Enterprise Data Warehouse. Patients were divided into high-cost (>84th percentile) and low-cost groups and differences in health care utilization between the groups were analyzed. RESULTS: Fifty-seven pediatric patients with MS were identified. Health care costs for the cohort totaled more than $1.5 million over the 10-year period, with the top 16th percentile of patients contributing nearly two-thirds. Outpatient visits represented the majority of health care encounters and expenditures, accounting for 83.1% of total costs. Costs per encounter were highest for inpatient stays, averaging $2,924 per stay. CONCLUSIONS: The burden of health care expenses for pediatric patients with MS is significant. Expenditures related to outpatient visits were the largest contributor to costs, but inpatient stays were the most costly per encounter. A small proportion of patients incurred the bulk of costs and spent significantly more time receiving care compared to the majority of patients. Avoidance of inpatient treatment and efficient outpatient management are potential areas for health care cost reduction and improvement in care. PMID- 28018947 TI - Random number datasets generated from statistical analysis of randomly sampled GSM recharge cards. AB - In this article, a random number of datasets was generated from random samples of used GSM (Global Systems for Mobile Communications) recharge cards. Statistical analyses were performed to refine the raw data to random number datasets arranged in table. A detailed description of the method and relevant tests of randomness were also discussed. PMID- 28018948 TI - Data on the NADPH-oxidase activity induced by WKYMVm and galectin-3 in bone marrow derived and exudated neutrophils isolated from four different mouse strains. AB - Neutrophils are the key players in inflammatory reactions and the release of superoxide through the NADPH-oxidase upon neutrophil activation contributes to bacterial clearance and surrounding tissue damage. Here we describe data on the mouse neutrophil NADPH-oxidase activation induced by the mouse formyl peptide receptor (Fpr) agonist WKYMVm and galectin-3. Neutrophils isolated from bone marrow, peritoneal exudated, and in vitro TNFalpha primed bone marrow neutrophils from four different laboratory strains (C57BL/6, DBA/1, BALB/c and NMRI) were used. Both Fpr agonist and galectin-3 activated neutrophils to release superoxide. No differences were observed in the amounts of superoxide released from neutrophils derived from four different strains. PMID- 28018946 TI - Multiple channels of visual time perception. AB - The proposal that the processing of visual time might rely on a network of distributed mechanisms that are vision-specific and timescale-specific stands in contrast to the classical view of time perception as the product of a single supramodal clock. Evidence showing that some of these mechanisms have a sensory component that can be locally adapted is at odds with another traditional assumption, namely that time is completely divorced from space. Recent evidence suggests that multiple timing mechanisms exist across and within sensory modalities and that they operate in various neural regions. The current review summarizes this evidence and frames it into the broader scope of models for time perception in the visual domain. PMID- 28018949 TI - Further intracellular proteins and signaling pathways regulated by angiotensin-(1 7) in human endothelial cells. AB - In 2016, Meinert et al. (doi: 10.1016/j.jprot.2015.09.020) published the first 25 proteins in a protein array regulated in Human Umbilical Vein Endothelial Cells (HUVEC) by the heptapeptide angiotensin (Ang)-(1-7) and the first 10 intracellular signaling cascades at different time points. This supporting data article shows further proteins and pathways stimulated by Ang-(1-7) in human endothelial cells at time points of 1 h, 3 h, 6 h, and 9 h. HUVECs were stimulated with Ang-(1-7), and regulated proteins were identified via antibody microarray. Bioinformatics software IPA was used for association of regulated proteins to metabolic pathways. PMID- 28018950 TI - Data on Rad51 amino acid sequences from higher and lower eukaryotic model organisms and parasites. AB - This paper contains data related to the research article titled "Characterization of the recombination activities of the Entamoeba histolytica Rad51 recombinase" (Kelso et al., in press) [1]. The known and putative amino acid sequence of Rad51, the central enzyme of homologous recombination, from nineteen different higher and lower eukaryotic organisms was analyzed. Here, we show amino acid conservation using a multiple sequence alignment, overall sequence identities using a percent identity matrix, and the evolutionary relationship between organisms using a neighbor-joining tree. PMID- 28018951 TI - Datasets for next-generation sequencing of DNA and RNA from urine and plasma of patients with prostate cancer. AB - Current prostate cancer (PCa) diagnostic tests suffer from insufficient sensitivity and specificity. Novel biomarkers that can be detected by minimally invasive methods are of a particular value. Here we provide two datasets. The first one is on the whole transcriptome profiling by RNA-seq of urine and plasma obtained from patients with PCa and benign prostatic hyperplasia (BPH). The second one represents targeted sequencing of DNA from urine and plasma of patients with PCa and BPH. Both datasets are available at NCBI Sequence Read Archive under Accession No. SRP093707 and No. SRP093842 respectively. PMID- 28018952 TI - Change in thermal transitions and water uptakes of poly(l-lactic acid) blends upon hydrolytic degradation. AB - This article reports experimental data related to the research article entitled "Poly(malic acid-co-l-lactide) as a Superb Degradation Accelerator for Poly(l lactic acid) at Physiological Conditions" (H.T. Oyama, D. Tanishima, S. Maekawa, 2016) [1]. Hydrolytic degradation of poly(l-lactic acid) (PLLA) blends with poly(aspartic acid-co-l-lactide) (PAL) and poly(malic acid-co-l-lactide) (PML) oligomers was investigated in a phosphate buffer solution at 40 degrees C. It was found in the differential scanning calorimetry measurements that upon hydrolysis the cold crystallization temperature (Tc ) and the melting temperature (Tm ) significantly shifted to lower temperature. Furthermore, the hydrolysis significantly promoted water sorption in both blends. PMID- 28018953 TI - High-resolution three-dimensional quantitative map of the macromolecular proton fraction distribution in the normal rat brain. AB - The presented dataset provides a normative high-resolution three-dimensional (3D) macromolecular proton fraction (MPF) map of the healthy rat brain in vivo and source images used for its reconstruction. The images were acquired using the protocol described elsewhere (Naumova, et al. High-resolution three-dimensional macromolecular proton fraction mapping for quantitative neuroanatomical imaging of the rodent brain in ultra-high magnetic fields. Neuroimage (2016) doi: 10.1016/j.neuroimage.2016.09.036). The map was reconstructed from three source images with different contrast weightings (proton density, T1, and magnetization transfer) using the single-point algorithm with a synthetic reference image. Source images were acquired from a living animal on an 11.7 T small animal MRI scanner with isotropic spatial resolution of 170 um3 and total acquisition time about 1.5 h. The 3D dataset can be used for multiple purposes including interactive viewing of rat brain anatomy, measurements of reference MPF values in various brain structures, and development of image processing techniques for the rodent brain segmentation. It also can serve as a gold standard image for implementation and optimization of rodent brain MRI protocols. PMID- 28018954 TI - Regression of metastatic, radiation/chemotherapy-resistant uterine serous carcinoma overexpressing HER2/neu with trastuzumab emtansine (TDM-1). AB - BACKGROUND: The management of uterine-serous-carcinoma (USC) no longer amenable to treatment with surgery, radiation and/or chemotherapy remains dismal. Alternative therapeutic options are desperately needed. CASE: We describe the case of a heavily pretreated 74-year-old patient with a recurrent USC overexpressing HER2/neu at 3 + level by IHC treated with the anti-HER2/neu antibody-drug-conjugate (ADC) trastuzumab-emtansine (TDM-1-Kadcyla Genentech/Roche). She experienced a remarkable clinical response to TDM-1 with a complete resolution of a large metastatic, radiation/chemotherapy resistant tumor deposit in her abdominal wall muscle confirmed by multiple CAT scans and a prolonged systemic control of her disease. CONCLUSION: TDM-1 may represent a novel treatment option for recurrent/metastatic HER2/neu-positive USC patients refractory to salvage-treatment. PMID- 28018955 TI - Wilms' tumor of the ovary. AB - Extrarenal Wilms' tumor of the ovary is a very rare tumor likely derived from embryonic mesonephros. We present the first reported case of a teratoid extrarenal Wilms' tumor of the ovary with a short review of the existing literature. In the case, a 26-year-old woman presented with back pain and was found to have a dermoid cyst; three years later, she presented again, now pregnant, with severe abdominal pain. She was diagnosed with an immature teratoma consisting of a Wilms' tumor (immature component) arising within a mature teratoma and treated exclusively with surgery and surveillance. The recovery from surgery was uneventful and the patient remains without evidence of disease with eleven months of follow-up. PMID- 28018956 TI - Reproductive counseling, contraception, and unplanned pregnancy in fertile women treated by gynecologic oncologists. AB - We sought to identify how gynecologic oncologists approach reproductive counseling for their fertile, reproductive age patients, and their experience with unplanned pregnancies. Members of the Society of Gynecologic Oncology (SGO) were surveyed electronically regarding consistency of counseling patterns of contraception and fertility concerns, most and least common contraceptive methods utilized, referral patterns, and incidence of unplanned pregnancy. Of the 1424 SGO members identified, 261 participated in the questionnaire, yielding a response rate of 18%. Eighty-two percent of respondents agreed unplanned pregnancy is a potential problem, but only 57% believed their patients understood unplanned pregnancy is possible during treatment. Half of respondents report "always" in terms of frequency that contraception is addressed among their high risk patients. After adjustment for gender, we found that the odds of reporting providing fertility counseling were nearly three times higher among attendings as compared to fellows [AOR = 2.72; 95% CI = (1.44, 5.12), three times higher in women as compared to men [AOR = 2.80; 95% CI = (1.46, 5.38)], as well as in individuals 50 + years as compared to those < 40 years old [AOR = 4.91; 95% CI = (2.05, 11.74)]. Ninety-six percent reported < 5 unplanned pregnancies, to their knowledge, in the previous five years of clinical practice. Most providers acknowledge that unplanned pregnancy is a potential risk in fertile gynecologic oncology patients, but only half believe their patients understand an unplanned pregnancy is possible. An opportunity exists to provide more directed counseling regarding fertility during and after cancer therapy, and to educate patients and providers regarding more reliable, long acting contraceptive methods. PMID- 28018957 TI - How can GPS technology help us better understand exposure to the food environment? A systematic review. AB - PURPOSE: Global Positioning Systems (GPS) are increasingly being used to objectively assess movement patterns of people related to health behaviours. However research detailing their application to the food environment is scarce. This systematic review examines the application of GPS in studies of exposure to food environments and their potential influences on health. METHODS: Based on an initial scoping exercise, published articles to be included in the systematic review were identified from four electronic databases and reference lists and were appraised and analysed, the final cut-off date for inclusion being January 2015. Included studies used GPS to identify location of individuals in relation to food outlets and link that to health or diet outcomes. They were appraised against a set of quality criteria. RESULTS: Six studies met the inclusion criteria, which were appraised to be of moderate quality. Newer studies had a higher quality score. Associations between observed mobility patterns in the food environment and diet related outcomes were equivocal. Findings agreed that traditional food exposure measures overestimate the importance of the home food environment. CONCLUSIONS: The use of GPS to measure exposure to the food environment is still in its infancy yet holds much potential. There are considerable variations and challenges in developing and standardising the methods used to assess exposure. PMID- 28018958 TI - The impact of housing payment problems on health status during economic recession: A comparative analysis of longitudinal EU SILC data of 27 European states, 2008-2010. AB - Although the recent Great Recession had its origins in the housing sector, the short-term health impact of the housing crisis is not well understood. We used longitudinal data to evaluate the impact of housing payment problems on health status among home-owners and renters in 27 European states. Multi-level and fixed effects models were applied to a retrospective cohort drawn from the EU Statistics on Income and Living Conditions survey of employed persons, comprising those without housing arrears in the base year 2008 and followed through to 2010 (n=45,457 persons, 136,371 person-years). Multi-variate models tested the impact of transitioning into housing payment arrears on self-reported health (0-worst to 4-best), adjusting for confounders including age, sex, baseline health, and individual fixed effects. Transitioning into housing arrears was associated with a significant deterioration in the health of renters (-0.09 units, 95% CI -0.05 to -0.13), but not owners (0.00, 95% CI -0.05 to 0.06), after adjusting for individual fixed effects. This effect was independent of and greater than the impact of job loss for the full sample (-0.05, 95% CI -0.002 to -0.09). The magnitude of this association varied across countries; the largest adverse associations were observed for renters in Belgium, Austria, and Italy. There was no observed protective association of differing categories of social protection or of the housing regulatory structure for renters. Women aged 30 and over who rented appeared to have worse self-reported health when transitioning into arrears than other groups. Renters also fared worse in those countries where house prices were escalating. We therefore find that housing payment problems are a significant risk factor for worse-self reported health in persons who are renting their homes. Future research is needed to understand potential sources of health resilience among renters, especially at a time when housing prices are rising in many European states. PMID- 28018959 TI - A qualitative systematic review of factors influencing parents' vaccination decision-making in the United Kingdom. AB - BACKGROUND: High uptake of vaccinations is crucial for disease prevention. Although overall uptake of childhood immunisations is high in the United Kingdom (UK), pockets of lower uptake remain. Novel systematic methods have not been employed when reviewing the qualitative literature examining parents' vaccination decisions. AIMS: We aimed to conduct a qualitative systematic review of studies in the UK to understand factors influencing parental decisions to vaccinate a child. METHODS: On 12/2/14 we searched PsycINFO, MEDLINE, CINAHL plus, Embase, Social Policy and Practice and Web of Science for studies using qualitative methods and reporting reasons why parents in the UK had or had not immunised their child. Participant quotes and authors' interpretations of qualitative data were extracted from the results of articles. Thematic synthesis was used to develop higher-order themes (conducted in 2015). RESULTS: 34 papers were included. Two types of decision-making had been adopted: non-deliberative and deliberative. With non-deliberative decisions parents felt they had no choice, were happy to comply and/or relied on social norms. Deliberative decisions involved weighing up the risks and benefits, considering others' advice/experiences and social judgement. Emotions affected deliberative decision making. Trust in information and vaccine stakeholders was integral to all decision-making. Practical issues affected those who intended to vaccinate. CONCLUSIONS: Parents adopted two different approaches to decision-making about childhood vaccinations. By understanding more about the mechanisms underpinning parents' vaccination behaviour, in collaboration with vaccine stakeholders, we can better design interventions to enhance informed uptake. PMID- 28018960 TI - Neighbourhood greenspace is associated with a slower decline in physical activity in older adults: A prospective cohort study. AB - Maintaining physical activity in later life is important for maintaining health and function. Activity outdoors, such as walking, jogging and cycling, may provide an accessible, sociable and practical solution, but maintaining outdoor mobility may be a challenge in later life. Providing green environments which are supportive of physical activity may facilitate this, yet research into how greenspace could be best used is inconclusive. This study evaluates the role of greenspace in protecting against decline in physical activity over time in older adults. Data from the European Prospective Investigation of Cancer Norfolk, UK, cohort 1993-2009 (N=15,672) was used. Linear regression modelling was used to examine the association between exposure to greenspace in the home neighbourhood and change in overall, recreational and outdoor physical activity measured in terms of metabolic equivalent cost (MET) in hours/week. Mediation analysis was conducted to assess if dog walking explained the relationship between greenspace and physical activity change. Models were adjusted for known and hypothesised confounders. People living in greener neighbourhoods experienced less of a decline in physical activity than those living in less green areas. Comparing change for those living in the greenest versus least green quartiles, participants showed a difference in overall physical activity of 4.21 MET hours/week (trend P=0.001), adjusted for baseline physical activity, age, sex, BMI, social class and marital status. This difference was 4.03 MET hours/week for recreational physical activity (trend P<0.001) and 1.28 MET hours/week for outdoor physical activity (trend P=0.007). Dog walking partially mediated the association between greenspace and physical activity change, by 22.6% for overall, 28.1% for recreational and 50.0% for outdoor physical activity (all P<0.001). Greenspace in the home neighbourhood may be protective against decline in physical activity among older people as they age. Dog walking is a potential mechanism in this relationship, and warrants further investigation as a way of maintaining physical activity in later life. PMID- 28018961 TI - Increasing inequality in age of death at shared levels of life expectancy: A comparative study of Scotland and England and Wales. AB - There is a strong negative correlation between increasing life expectancy and decreasing lifespan variation, a measure of inequality. Previous research suggests that countries achieving a high level of life expectancy later in time generally do so with lower lifespan variation than forerunner countries. This may be because they are able to capitalise on lessons already learnt. However, a few countries achieve a high level of life expectancy later in time with higher inequality. Scotland appears to be such a country and presents an interesting case study because it previously experienced lower inequality when reaching the same level of life expectancy as its closest comparator England and Wales. We calculated life expectancy and lifespan variation for Scotland and England and Wales for the years 1950 to 2012, comparing Scotland to England and Wales when it reached the same level of life expectancy later on in time, and assessed the difference in the level of lifespan variation. The lifespan variation difference between the two countries was then decomposed into age-specific components. Analysis was carried out for males and females separately. Since the 1950s Scotland has achieved the same level of life expectancy at least ten years later in time than England and Wales. Initially it did so with lower lifespan variation. Following the 1980s Scotland has been achieving the same level of life expectancy later in time than England and Wales and with higher inequality, particularly for males. Decomposition revealed that higher inequality is partly explained by lower older age mortality rates but primarily by higher premature adult age mortality rates when life expectancy is the same. Existing studies suggest that premature adult mortality rates are strongly associated with the social determinants of health and may be amenable to social and economic policies. So addressing these policy areas may have benefits for both inequality and population health in Scotland. PMID- 28018962 TI - Multiple health behaviours among mothers and partners in England: Clustering, social patterning and intra-couple concordance. AB - Research on multiple health behaviours is increasing but little is known about parental behaviours and how they covary. Our study investigates cigarette smoking, alcohol intake, fruit and vegetable (F&V) consumption and physical activity among mothers and co-resident partners in England. Using the UK Household Longitudinal Study, we examined (i) clustering of health behaviours using observed-expected ratios and latent class analysis (ii) socio-demographic correlates of the derived latent classes and (iii) intra-couple concordance of individual health behaviours and their latent classes. We identified five latent classes for mothers and partners: Never smoked drinkers (28% of mothers; 29% of partners), Abstainers (25%; 17%), Drinkers and ex-smokers (19%; 26%), Unhealthy low frequency drinkers (18%; 16%) and Unhealthiest behaviour group (11%; 12%). These had distinctive social profiles. Never smoked drinkers were more likely than those in other groups to be white and socially advantaged: married, older, and with higher educational qualifications and incomes. Abstainers were non smokers who never or occasionally drank, and were disproportionately drawn from ethnic minority groups and middle/lower income families. Drinkers and ex-smokers were the most physically active group and were more likely to be socially advantaged. Unhealthy low frequency drinkers were more likely to be disadvantaged and have a limiting long-standing illness. The Unhealthiest behaviour group had the highest proportion of smokers, heavy smokers and binge drinkers and the lowest F&V intake and physical activity levels. They were largely white and socially disadvantaged: younger, non-married and with lower educational levels. Mothers and their partners typically shared the same risk behaviours, and 44 per cent of partners and mothers belonged to the same latent class. Our findings point to the potential for a broadening of research and policy perspectives, from separate behaviours to combinations of behaviours, and from individuals to the domestic units and communities of which they are part. PMID- 28018963 TI - Uniporter substrate binding and transport: reformulating mechanistic questions. AB - Transporters are involved in material transport, signaling, and energy input in all living cells. One of the fundamental questions about transporters is concerned with the precise role of their substrate in driving the transport process. This is particularly important for uniporters, which must utilize the chemical potential of substrate as the only energy source driving the transport. Thus, uniporters present an excellent model for the understanding of how the difference in substrate concentration across the membrane is used as a driving force. Local conformational changes induced by substrate binding are widely considered as the main mechanism to drive the functional cycle of a transporter; in addition, reducing the energy barrier of the transition state has also been proposed to drive the transporter. However, both points of view require modification to allow consolidation with fundamental thermodynamic principles. Here, we discuss the relationship between thermodynamics and kinetics of uniporters. Substrate binding-induced reduction of the transition-state energy barrier accelerates the transport process in kinetic terms, while the chemical potential of the substrate drives the process thermodynamically. PMID- 28018964 TI - Structure determination of a human virus by the combination of cryo-EM and X-ray crystallography. AB - Virus 3D atomic structures provide insight into our understanding of viral life cycles and the development of antiviral drugs. X-ray crystallography and cryo-EM have been used to determine the atomic structure of viruses. However, limited availability of biological samples, biosafety issues due to virus infection, and sometimes inherent characteristics of viruses, pose difficulties on combining both methods in determining viral structures. These have made solving the high resolution structure of some medically important viruses very challenging. Here, we describe our recently employed protocols for determining the high-resolution structure of the virus-like particle of hepatitis E virus (HEV), a pathogen of viral hepatitis in human. These protocols include utilizing recombinant baculovirus system to generate sufficient amount of virus particles, single particle cryo-EM to get an intermediate resolution structure as a phasing model, and X-ray crystallography for final atomic structure determination. Our protocols have solved the hepatitis E virus structure to the resolution of 3.5 A. The combined methodology is generally applicable to other human infectious viruses. PMID- 28018966 TI - Crystal structures of MdfA complexed with acetylcholine and inhibitor reserpine. AB - The DHA12 family of transporters contains a number of prokaryotic and eukaryote membrane proteins. Some of these proteins share conserved sites intrinsic to substrate recognition, structural stabilization and conformational changes. For this study, we chose the MdfA transporter as a model DHA12 protein to study some general characteristics of the vesicular neurotransmitter transporters (VNTs), which all belong to the DHA12 family. Two crystal structures were produced for E. coli MdfA, one in complex with acetylcholine and the other with potential reserpine, which are substrate and inhibitor of VNTs, respectively. These structures show that the binding sites of these two molecules are different. The Ach-binding MfdA is mainly dependent on D34, while reserpine-binding site is more hydrophobic. Based on sequence alignment and homology modelling, we were able to provide mechanistic insights into the association between the inhibition and the conformational changes of these transporters. PMID- 28018965 TI - Regulation of metabolism by the Mediator complex. AB - The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals. PMID- 28018967 TI - Fast Pade Transform Accelerated CSI for Hyperpolarized MRS. AB - The fast Pade transform (FPT) is a method of spectral analysis that can be used to reconstruct nuclear magnetic resonance spectra from truncated free induction decay signals with superior robustness and spectral resolution compared with conventional Fourier analysis. The aim of this study is to show the utility of FPT in reducing of the scan time required for hyperpolarized 13C chemical shift imaging (CSI) without sacrificing the ability to resolve a full spectrum. Simulations, phantom, and in vivo hyperpolarized [1-13C] pyruvate CSI data were processed with FPT and compared with conventional analysis methods. FPT shows improved stability and spectral resolution on truncated data compared with the fast Fourier transform and shows results that are comparable to those of the model-based fitting methods, enabling a reduction in the needed acquisition time in 13C CSI experiments. Using FPT can reduce the readout length in the spectral dimension by 2-6 times in 13C CSI compared with conventional Fourier analysis without sacrificing the spectral resolution. This increased speed is crucial for 13C CSI because T1 relaxation considerably limits the available scan time. In addition, FPT can also yield direct quantification of metabolite concentration without the additional peak analysis required in conventional Fourier analysis. PMID- 28018968 TI - ATG16L1 governs placental infection risk and preterm birth in mice and women. AB - The placenta is a barrier against maternal-fetal transmission of pathogens. Placental infections can cause several adverse pregnancy outcomes, including preterm birth (PTB). Yet, we have limited knowledge regarding the mechanisms the placenta uses to control infections. Here, we show that autophagy, a cellular recycling pathway important for host defense against pathogens, and the autophagy gene Atg16L1 play a key role in placental defense and are negatively associated with PTB in pregnant women. First, we demonstrate that placentas from women who delivered preterm exhibit reduced autophagy activity and are associated with higher infection indicators. Second, we identify the cellular location of the autophagy activity as being in syncytial trophoblasts. Third, we demonstrate that higher levels of autophagy and ATG16L1 in human trophoblasts were associated with increased resistance to infection. Accordingly, loss of autophagy or ATG16L1 impaired trophoblast antibacterial defenses. Fourth, we show that Atg16l1 deficient mice gave birth prematurely upon an inflammatory stimulus and their placentas were significantly less able to withstand infection. Finally, global induction of autophagy in both mouse placentas and human trophoblasts increased infection resistance. Our study has significant implications for understanding the etiology of placental infections and prematurity and developing strategies to mitigate placental infection-induced PTB. PMID- 28018969 TI - HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver. AB - Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri sinusoidal fibrosis. Notably, this "maladaptive repair" phenotype was recapitulated in mice that lack S1P1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis. PMID- 28018971 TI - Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity. AB - Systemic sclerosis (SSc) is a rare autoimmune disease with the highest case fatality rate of all connective tissue diseases. Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by interclinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. There is an unmet critical need for an objective metric of SSc disease severity. Here, we performed an integrated, multicohort analysis of SSc transcriptome data across 7 datasets from 6 centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at 2 centers as a discovery cohort, we identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from 5 independent cohorts. Next, we defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in our study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, we showed that 4S allowed us to objectively monitor individual SSc patients over time, as (a) the change in 4S of a patient is significantly correlated with change in the mRSS, and (b) the change in 4S at 12 months of treatment could predict the change in mRSS at 24 months. Our results suggest that 4S could be used to distinguish treatment responders from nonresponders prior to mRSS change. Our results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification. PMID- 28018970 TI - Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells. AB - Heterogeneity of tumor cells and their microenvironment can affect outcome in cancer. Blockade of immune checkpoints (ICPs) expressed only on a subset of immune cells leads to durable responses in advanced melanoma. Tissue-resident memory T (TRM) cells have recently emerged as a distinct subset of memory T cells in nonlymphoid tissues. Here, we show that functional properties and expression of ICPs within tumor-infiltrating lymphocytes (TILs) differ from those of blood T cells. TILs secrete less IL-2, IFN-gamma, and TNF-alpha compared with circulating counterparts, and expression of VEGF correlated with reduced TIL infiltration. Within tumors, ICPs are particularly enriched within T cells with phenotype and genomic features of TRM cells and the CD16+ subset of myeloid cells. Concurrent T cell receptor (TCR) and tumor exome sequencing of individual metastases in the same patient revealed that interlesional diversity of TCRs exceeded differences in mutation/neoantigen load in tumor cells. These findings suggest that the TRM subset of TILs may be the major target of ICP blockade and illustrate interlesional diversity of tissue-resident TCRs within individual metastases, which did not equilibrate between metastases and may differentially affect the outcome of immune therapy at each site. PMID- 28018972 TI - Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. AB - Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3 methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARdelta in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion. PMID- 28018973 TI - Inactivation of ABL kinases suppresses non-small cell lung cancer metastasis. AB - Current therapies to treat non-small cell lung carcinoma (NSCLC) have proven ineffective owing to transient, variable, and incomplete responses. Here we show that ABL kinases, ABL1 and ABL2, promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses NSCLC metastasis to brain and bone, and other organs. ABL kinases are required for expression of prometastasis genes. Notably, ABL1 and ABL2 depletion impairs extravasation of lung adenocarcinoma cells into the lung parenchyma. We found that ABL-mediated activation of the TAZ and beta-catenin transcriptional coactivators is required for NSCLC metastasis. ABL kinases activate TAZ and beta catenin by decreasing their interaction with the beta-TrCP ubiquitin ligase, leading to increased protein stability. High-level expression of ABL1, ABL2, and a subset of ABL-dependent TAZ- and beta-catenin-target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature. PMID- 28018974 TI - Hypoxia sensing through beta-adrenergic receptors. AB - Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the beta-adrenergic receptor (beta-AR) and hypoxia responses, we hypothesized that the beta-AR mediates hypoxia sensing and is necessary for HIF-1alpha accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1alpha accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1alpha accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in beta-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1alpha accumulation, and inhibition of PKA did not blunt HIF-1alpha induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation-deficient beta-AR mutant in cells, blocked hypoxia-mediated HIF-1alpha accumulation. Mass spectrometry-based quantitative analyses revealed a hypoxia-mediated beta-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the beta-AR is fundamental to the molecular and physiological responses to hypoxia. PMID- 28018975 TI - Disease-modifying effects of orally bioavailable NF-kappaB inhibitors in dystrophin-deficient muscle. AB - Duchenne muscular dystrophy (DMD) is a devastating muscle disease characterized by progressive muscle deterioration and replacement with an aberrant fatty, fibrous matrix. Chronic upregulation of nuclear factor kappaB (NF-kappaB) is implicated as a driver of the dystrophic pathogenesis. Herein, 2 members of a novel class of NF-kappaB inhibitors, edasalonexent (formerly CAT-1004) and CAT 1041, were evaluated in both mdx mouse and golden retriever muscular dystrophy (GRMD) dog models of DMD. These orally bioavailable compounds consist of a polyunsaturated fatty acid conjugated to salicylic acid and potently suppress the pathogenic NF-kappaB subunit p65/RelA in vitro. In vivo, CAT-1041 effectively improved the phenotype of mdx mice undergoing voluntary wheel running, in terms of activity, muscle mass and function, damage, inflammation, fibrosis, and cardiac pathology. We identified significant increases in dysferlin as a possible contributor to the protective effect of CAT-1041 to sarcolemmal damage. Furthermore, CAT-1041 improved the more severe GRMD phenotype in a canine case study, where muscle mass and diaphragm function were maintained in a treated GRMD dog. These results demonstrate that NF-kappaB modulation by edasalonexent and CAT 1041 is effective in ameliorating the dystrophic process and these compounds are candidates for new treatments for DMD patients. PMID- 28018976 TI - Identifying the third dimension in 2D fluoroscopy to create 3D cardiac maps. AB - Three-dimensional cardiac mapping is important for optimal visualization of the heart during cardiac ablation for the treatment of certain arrhythmias. However, many hospitals and clinics worldwide cannot afford the high cost of the current mapping systems. We set out to determine if, using predefined algorithms, comparable 3D cardiac maps could be created by a new device that relies on data generated from single-plane fluoroscopy and patient recording and monitoring systems, without the need for costly equipment, infrastructure changes, or specialized catheters. The study included phantom and animal experiments to compare the prototype test device, Navik 3D, with the existing CARTO 3 System. The primary endpoint directly compared: (a) the 3D distance between the Navik 3D simulated ablation location and the back-projected ground truth location of the pacing and mapping catheter electrode, and (b) the same distance for CARTO. The study's primary objective was considered met if the 95% confidence lower limit was greater than 0.75% for the Navik 3D-CARTO difference between the 2 distances, or less than or equal to 2 mm. Study results showed that the Navik 3D performance was equivalent to the CARTO system, and that accurate 3D cardiac maps can be created using data from equipment that already exists in all electrophysiology labs. PMID- 28018978 TI - Clinical Practice Guideline for Management of Primary Aldosteronism: What is New in the 2016 Update? AB - Primary Aldosteronism is the single most common cause of secondary hypertension and is associated with increased target organ injury. The Endocrine Society has recently released the updated Clinical Practice Guideline for Primary Aldosteronism entitled "The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline". We review the updated Clinical Practice Guideline, highlighting the new recommendations and the implications that they may have in clinical practice. The recognition by the Endocrine Society's Task Force that Primary Aldosteronism is a public health issue and that the population at risk for screening should be significantly expanded will surely have an impact in the clinical practice which hopefully will translate in better detection, diagnosis and treatment of patients with Primary Aldosteronism. PMID- 28018977 TI - Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy. AB - Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFRbeta- and desmin+ pericytes, provides information about the response to epirubicin but not paclitaxel. Using 17 distinct patient-derived breast cancer xenografts, we demonstrate a cancer cell-derived influence on stromal Ang2 production and a cancer cell-defined control over tumor vasculature and perivascular heterogeneity. The aggressive features of tumors and their distinct response to therapies may thus emerge by the cancer cell-defined engagement of distinct and heterogeneous angiogenic programs. PMID- 28018979 TI - Increasing Access to Cost Effective Home-Based Rehabilitation for Rural Veteran Stroke Survivors. AB - INTRODUCTION: An estimated 750,000 Americans experience a stroke annually. Most stroke survivors require rehabilitation. Limited access to rehabilitation facilities has a pronounced burden on functional outcomes and quality of life. Robotic devices deliver reproducible therapy without the need for real-time human oversight. This study examined the efficacy of using home-based, telerobotic assisted devices (Hand and Foot Mentor: HM and FM) to improve functional ability and reduce depression symptoms, while improving access and cost savings associated with rehabilitation. METHODS: Twenty stroke survivors performed three months of home-based rehabilitation using a robotic device, while a therapist remotely monitored progress. Baseline and end of treatment function and depression symptoms were assessed. Satisfaction with the device and access to therapy were determined using qualitative surveys. Cost analysis was performed to compare home-based, robotic-assisted therapy to clinic-based physical therapy. RESULTS: Compared to baseline, significant improvement in upper extremity function (30.06%, p= 0.046), clinically significant benefits in gait speed (29.03%), moderate improvement in depressive symptoms (28.44%) and modest improvement in distance walked (30.2%) were observed. Participants indicated satisfaction with the device. Home-based robot therapy expanded access to post stroke rehabilitation for 35% of the people no longer receiving formal services and increased daily access for the remaining 65%, with a cost savings of $2,352 (64.97%) compared to clinic-based therapy. CONCLUSION: Stroke survivors made significant clinically meaningful improvements in the use of their impaired extremities using a robotic device in the home. Home-based, robotic therapy reduced costs, while expanding access to a rehabilitation modality for people who would not otherwise have received care. PMID- 28018980 TI - The LonDownS adult cognitive assessment to study cognitive abilities and decline in Down syndrome. AB - BACKGROUND: Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with an ultra-high risk of developing Alzheimer's disease. However, there is individual variability in the onset of clinical dementia and in baseline cognitive abilities prior to decline, particularly in memory, executive functioning, and motor coordination. The LonDownS Consortium aims to determine risk and protective factors for the development of dementia and factors relating to cognitive abilities in people with DS. Here we describe our cognitive test battery and related informant measures along with reporting data from our baseline cognitive and informant assessments. METHODS: We developed a cognitive test battery to assess general abilities, memory, executive function, and motor coordination abilities in adults with DS, with informant ratings of similar domains also collected, designed to allow for data on a broad range of participants. Participants (n=305) had a range of ages and abilities, and included adults with and without a clinical diagnosis of dementia. RESULTS: Results suggest the battery is suitable for the majority of adults with DS, although approximately half the adults with dementia were unable to undertake any cognitive task. Many test outcomes showed a range of scores with low floor and ceiling effects. Non-verbal age-adjusted IQ scores had lower floor effects than verbal IQ scores. Before the onset of any cognitive decline, females aged 16-35 showed better verbal abilities compared to males. We also identified clusters of cognitive test scores within our battery related to visuospatial memory, motor coordination, language abilities, and processing speed / sustained attention. CONCLUSIONS: Our further studies will use baseline and longitudinal assessments to explore factors influencing cognitive abilities and cognitive decline related to ageing and onset of dementia in adults with DS. PMID- 28018981 TI - Splice variant insertions in the C-terminus impairs YAP's transactivation domain. AB - The yes-associated protein (YAP) is a key effector of the mammalian Hippo signaling pathway. YAP has eight known alternately spliced isoforms and these are widely expressed across multiple tissues. Variable effects have been ascribed to different YAP isoforms by inducing their expression in cells, but whether these differences are due to variability in the transcriptional potency of individual YAP isoforms has not been addressed. Indeed a systematic comparison of the transcriptional potencies of YAP isoforms has not been done. To address this, using overexpression and transcriptional reporter analyses we investigated the transcriptional activities of several human YAP isoforms and determined the effects of the splice variant insertions within the transactivation domain on its transcriptional potency. Utilising full-length coding sequence constructs we determined that the number of WW domains and disruption of the leucine zipper motif within YAP's transactivation domain both contribute to transcriptional activity. Notably, disruption of YAP's leucine zipper had a greater effect on transcriptional activity than the absence of the second WW domain. Using GAL4-YAP transcriptional activation domain fusion proteins we found that disruption of the leucine zipper significantly decreased YAP's transcriptional activity in several cell lines. Our data indicates that expression of different YAP isoforms with varying transcriptional potencies may enable fine control of Hippo pathway signaling. Furthermore the specific isoform being utilised should be taken into consideration when interpreting published data or when designing experiments to ascribe YAP's function. PMID- 28018982 TI - PREVALANCE AND INFLUENCE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE ON STROKE OUTCOMES IN HOSPITALIZED STROKE PATIENTS. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and stroke are important causes of death. COPD patients are at higher risk of cerebral hypoxia and aspiration. Yet, relatively little is known about the prevalence of COPD among stroke patients or its impact on outcomes after an index stroke. We assess the prevalence of COPD among hospitalized stroke patients in a nationally representative sample and examine the effect of COPD with mortality risk in the hospital after a stroke. METHODS: Using the National Inpatient Sample, a nationally representative dataset of US hospital admissions between January 2004 and December 2009 (n=48,087,002), we assessed Crude and age-adjusted COPD prevalence among stroke patients and in-hospital mortality rates by COPD status. Independent associations of COPD with in-hospital mortality following stroke were evaluated using multivariable logistic regression. RESULTS: 11.71% (95% CI: 11.48 11.94%) of all adult patients hospitalized for stroke had COPD. The crude and age adjusted in-hospital mortality rates for these patients were 6.33% (95% CI: 6.14 6.53%) and 5.99% (95% CI: 4.05-7.94%), respectively. On multivariable analyses, COPD was modestly associated with overall stroke mortality (OR 1.03; 95% CI 1.01 1.06; p=0.018). The greater risks of mortality were seen among those with intracerebral hemorrhage (OR: 1.12; 95% CI 1.03-1.20; p=0.005) and ischemic stroke patients (OR 1.08; 95% CI 1.03-1.13, p=0.001). CONCLUSIONS: 12% of hospitalized stroke patients have COPD. The presence of COPD is independently associated with higher odds of dying during stroke. Prospective studies are needed to identify any modifiable risk factors contributing to this deleterious relationship. PMID- 28018983 TI - Corrigendum to "Threatening faces induce fear circuitry hypersynchrony in soldiers with post-traumatic stress disorder". AB - [This corrects the article DOI: 10.1016/j.heliyon.2015.e00063.]. PMID- 28018984 TI - Application of the WEPS and SWEEP models to non-agricultural disturbed lands. AB - Wind erosion not only affects agricultural productivity but also soil, air, and water quality. Dust and specifically particulate matter <=10 MUm (PM-10) has adverse effects on respiratory health and also reduces visibility along roadways, resulting in auto accidents. The Wind Erosion Prediction System (WEPS) was developed by the USDA-Agricultural Research Service to simulate wind erosion and provide for conservation planning on cultivated agricultural lands. A companion product, known as the Single-Event Wind Erosion Evaluation Program (SWEEP), has also been developed which consists of the stand-alone WEPS erosion submodel combined with a graphical interface to simulate soil loss from single (i.e., daily) wind storm events. In addition to agricultural lands, wind driven dust emissions also occur from other anthropogenic sources such as construction sites, mined and reclaimed areas, landfills, and other disturbed lands. Although developed for agricultural fields, WEPS and SWEEP are useful tools for simulating erosion by wind for non-agricultural lands where typical agricultural practices are not employed. On disturbed lands, WEPS can be applied for simulating long term (i.e., multi-year) erosion control strategies. SWEEP on the other hand was developed specifically for disturbed lands and can simulate potential soil loss for site- and date-specific planned surface conditions and control practices. This paper presents novel applications of WEPS and SWEEP for developing erosion control strategies on non-agricultural disturbed lands. Erosion control planning with WEPS and SWEEP using water and other dust suppressants, wind barriers, straw mulch, re-vegetation, and other management practices is demonstrated herein through the use of comparative simulation scenarios. The scenarios confirm the efficacy of the WEPS and SWEEP models as valuable tools for supporting the design of erosion control plans for disturbed lands that are not only cost-effective but also incorporate a science-based approach to risk assessment. PMID- 28018985 TI - Northern Chinese dental ages estimated from southern Chinese reference datasets closely correlate with chronological age. AB - While northern and southern Chinese are genetically correlated, there exists notable environmental differences in their living conditions. This study aimed to evaluate validity of the southern Chinese reference dataset for dental age estimation applied to northern Chinese. Dental panoramic tomographs of 437 northern Chinese aged 3 to 21 years were analysed. All the left maxillary and mandibular permanent teeth plus the 2 third molars on the right side were scored based on Demirjian's classification of tooth development stages. Mean and standard error of dental age were obtained for each tooth development stage, followed by random effect meta-analysis for mean dental age estimation. Validity of the method was examined through measures of agreement (95% limits of agreement, standard error of measurement, and Lin's concordance correlation coefficient) and measure of reliability (Intraclass correlation coefficient). On average, the estimated dental age overestimated chronological age by only around 1 month in both females and males. The Intraclass correlation coefficient values were 0.99 for both sexes, suggesting excellent reliability of the method. Reference dataset for dental age estimation developed on the basis of southern Chinese was applicable for use among the northern Chinese. PMID- 28018986 TI - A Roadmap for the Development of Applied Computational Psychiatry. AB - BACKGROUND: Computational psychiatry is a burgeoning field that utilizes mathematical approaches to investigate psychiatric disorders, derive quantitative predictions, and integrate data across multiple levels of description. Computational psychiatry has already led to many new insights into the neurobehavioral mechanisms that underlie several psychiatric disorders, but its usefulness from a clinical standpoint is only now starting to be considered. METHODS: Examples of computational psychiatry are highlighted, and a phase-based pipeline for the development of clinical computational-psychiatry applications is proposed, similar to the phase-based pipeline used in drug development. It is proposed that each phase has unique endpoints and deliverables, which will be important milestones to move tasks, procedures, computational models, and algorithms from the laboratory to clinical practice. RESULTS: Application of computational approaches should be tested on healthy volunteers in Phase I, transitioned to target populations in Phase IB and Phase IIA, and thoroughly evaluated using randomized clinical trials in Phase IIB and Phase III. Successful completion of these phases should be the basis of determining whether computational models are useful tools for prognosis, diagnosis, or treatment of psychiatric patients. CONCLUSIONS: A new type of infrastructure will be necessary to implement the proposed pipeline. This infrastructure should consist of groups of investigators with diverse backgrounds collaborating to make computational psychiatry relevant for the clinic. PMID- 28018987 TI - EEG slow waves in traumatic brain injury: Convergent findings in mouse and man. AB - OBJECTIVE: Evidence from previous studies suggests that greater sleep pressure, in the form of EEG-based slow waves, accumulates in specific brain regions that are more active during prior waking experience. We sought to quantify the number and coherence of EEG slow waves in subjects with mild traumatic brain injury (mTBI). METHODS: We developed a method to automatically detect individual slow waves in each EEG channel, and validated this method using simulated EEG data. We then used this method to quantify EEG-based slow waves during sleep and wake states in both mouse and human subjects with mTBI. A modified coherence index that accounts for information from multiple channels was calculated as a measure of slow wave synchrony. RESULTS: Brain-injured mice showed significantly higher theta:alpha amplitude ratios and significantly more slow waves during spontaneous wakefulness and during prolonged sleep deprivation, compared to sham-injured control mice. Human subjects with mTBI showed significantly higher theta:beta amplitude ratios and significantly more EEG slow waves while awake compared to age-matched control subjects. We then quantified the global coherence index of slow waves across several EEG channels in human subjects. Individuals with mTBI showed significantly less EEG global coherence compared to control subjects while awake, but not during sleep. EEG global coherence was significantly correlated with severity of post-concussive symptoms (as assessed by the Neurobehavioral Symptom Inventory scale). CONCLUSION AND IMPLICATIONS: Taken together, our data from both mouse and human studies suggest that EEG slow wave quantity and the global coherence index of slow waves may represent a sensitive marker for the diagnosis and prognosis of mTBI and post-concussive symptoms. PMID- 28018988 TI - GSK249320, A Monoclonal Antibody Against the Axon Outgrowth Inhibition Molecule Myelin-Associated Glycoprotein, Improves Outcome of Rodents with Experimental Stroke. AB - Myelin-associated glycoprotein (MAG) is an inhibitor of axon growth. MAG levels increase after stroke. GSK249320 is a monoclonal antibody that neutralizes MAG mediated inhibition and so may promote axon outgrowth and improve post-stroke outcomes. The current study tested the hypothesis that GSK249320 initiated 24 hours or 7 days after experimental stroke improves behavioural outcomes. Rats with right middle cerebral artery occlusion for 90 minutes were randomized to receive 6 weeks of intravenous (a) GSK249320 starting 24 hours post-stroke, (b) GSK249320 starting 7 days post-stroke, or (c) vehicle. Behavioral testing was performed over 7 weeks. Serial MRI demonstrated no differences in infarct volume across groups. Animals treated with GSK249320 24 hours post-stroke showed larger increases in Neuroscore (time X group, p = 0.0008) and staircase test (main effect of group, p = 0.0214) as compared to controls, but animals treated 7 days post-stroke showed no significant behavioral benefit. No significant results were found for the sticky tape or cylinder tests. A separate set of animals with experimental stroke received a single intravenous dose of GSK249320 or vehicle at 1 hour, 24 hours, 48 hours or 1 week post-stroke, and immunohistochemistry methods were used to measure GSK249320 distribution; GSK249320 was found in the ipsilesional hemisphere only, the extent of which increased with later times of injection. These data suggest that intravenous GSK249320 penetrates the lesion site and is associated with a small effect on functional outcomes when initiated 24 hours post-stroke and so support the translational potential of this monoclonal antibody as a restorative therapy for patients with stroke. PMID- 28018989 TI - The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. AB - By inducing DNA damage, radiotherapy both reduces tumor burden and enhances anti tumor immunity. Here, we will review the mechanisms by which radiation induces anti-tumor immune responses that can be augmented using immunotherapies to facilitate tumor regression. Radiotherapy increases inflammation in tumors by activating the NF-kappaB and the Type I interferon response pathways to induce expression of pro-inflammatory cytokines. This inflammation coupled with antigen release from irradiated cells facilitates dendritic cell maturation and cross presentation of tumor antigens to prime tumor-specific T cell responses. Radiation also sensitizes tumors to these T cell responses by enhancing T cell infiltration into tumors and the recognition of both malignant cancer cells and non-malignant stroma that present cognate antigen. Yet, these anti-tumor immune responses may be blunted by several mechanisms including regulatory T cells and checkpoint molecules that promote T cell tolerance and exhaustion. Consequently, the combination of immunotherapy using vaccines and/or checkpoint inhibitors with radiation is demonstrating early clinical potential. Overall, this review will provide a global view for how radiation and the immune system converge to target cancers and the early attempts to exploit this synergy in clinical practice. PMID- 28018990 TI - The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. AB - During chronic viral infections and in cancer, T cells become dysfunctional, a state known as T cell exhaustion. Although it is well recognized that memory CD8 T cells account for the persistence of CD8 T cell immunity after acute infection, how exhausted T cells persist remains less clear. Using chronic infection with lymphocytic choriomeningitis virus clone 13 and tumor samples, we demonstrate that CD8 T cells differentiate into a less exhausted TCF1high and a more exhausted TCF1low population. Virus-specific TCF1high CD8 T cells, which resemble T follicular helper (TFH) cells, persist and recall better than do TCF1low cells and act as progenitor cells to replenish TCF1low cells. We show that TCF1 is both necessary and sufficient to support this progenitor-like CD8 subset, whereas cell intrinsic type I interferon signaling suppresses their differentiation. Accordingly, cell-intrinsic TCF1 deficiency led to a loss of these progenitor CD8 T cells, sharp contraction of virus-specific T cells, and uncontrolled viremia. Mechanistically, TCF1 repressed several pro-exhaustion factors and induced Bcl6 in CD8 T cells, which promoted the progenitor fate. We propose that the TCF1-Bcl6 axis counteracts type I interferon to repress T cell exhaustion and maintain T cell stemness, which is critical for persistent antiviral CD8 T cell responses in chronic infection. These findings provide insight into the requirements for persistence of T cell immune responses in the face of exhaustion and suggest mechanisms by which effective T cell-mediated immunity may be enhanced during chronic infections and cancer. PMID- 28018991 TI - Patient-Clinician Communication: The Roadmap for HCI. AB - Effective communication between patients and their clinicians during clinical encounters has a positive impact on health outcomes. Technology has the potential to help transform this synchronous interaction, but researchers are still at early stages of developing interventions to assess and improve patient-clinician communication. In this workshop, we envision opening up a dialogue among researchers and clinicians who wish to discuss directions for future research in this domain. In particular, the workshop will focus on exploring how technologies available today, as well as projected for the future, can support the communication needs of clinicians and patients. PMID- 28018992 TI - Designing Inpatient Technology to Meet the Medication Information Needs of Cardiology Patients. AB - As patients are encouraged to become active participants in their own care, recent research has begun to explore the direct sharing of electronic health information with patients during hospital visits. The design of patient-facing views of clinical information is, however, a relatively recent line of inquiry. Research is needed to further understand guidelines for communicating specific types of information to hospital patients. In this work, we focus on cardiology patients' information needs related to their hospital medications. We assessed these needs to inform the design of interactive, electronic views of medication information for cardiology inpatients. We present results of in-situ interviews with 11 inpatients and 6 nurses in a cardiology step-down unit. Our findings suggest that cohesive trends in medication information needs exist across cardiology inpatients. We discuss interview results and their implications for the design of inpatient-facing information technology. We also discuss key ways in which electronic medication information, formatted for inpatient use, differs from that formatted for outpatient or transitional medication-management use. PMID- 28018993 TI - Sleep Duration, Sedentary Behaviors, and Physical Activity across Weight Status in Hispanic Toddlers' Participants of the WIC Program. AB - OBJECTIVE: To describe physical activity, sedentary behaviors and sleep duration in toddlers' participants of the WIC program in Puerto Rico and assess its association with excessive weight. METHODS: This was a cross-sectional analysis of data gathered in the follow-up visit (12 months later) of a longitudinal study among toddlers 12-36 months old participants of the WIC program. In this follow up visit, a Sleep, Sedentary Behaviors and Physical Activity Questionnaire was included. RESULTS: From the 213 eligible participants for the follow-up visit, 76 completed the follow-up visit. Most were girls (52.6%), with median age 21 months and most were categorized as healthy weight (76.3%). In general, toddlers spent a total median of 142 min/d in sedentary behaviors, 300 min/d in physical activities and 690 min/d sleeping. There was a higher duration of physical activities among overweight/obese compared to healthy weights (p<0.05) but similar duration of sedentary behaviors and sleep by weight status (p>0.05). There was a greater proportion of overweight/obese toddlers meeting the screen time recommendation (88.9%) compared to healthy weight toddlers (62.1%; p<0.05). Also, there was a significant positive age-adjusted correlation between time spent in unstructured physical activity (R=0.23, p<0.05) with weight-for-length z score. Infant weight status was not significantly correlated to parent's perception or knowledge of physical activity or sleep in toddlers (p>0.05). CONCLUSION: Most toddlers studied met the recommendations for duration of sleep, sedentary behaviors, and physical activity. Overweight/obese toddlers engage in more physical activities than those with a healthy weight status. These findings could be due to educational interventions by the WIC program to promote physical activities, as these toddlers are active WIC participants. PMID- 28018994 TI - Integrative Analysis of Cellular Morphometric Context Reveals Clinically Relevant Signatures in Lower Grade Glioma. AB - Integrative analysis based on quantitative representation of whole slide images (WSIs) in a large histology cohort may provide predictive models of clinical outcome. On one hand, the efficiency and effectiveness of such representation is hindered as a result of large technical variations (e.g., fixation, staining) and biological heterogeneities (e.g., cell type, cell state) that are always present in a large cohort. On the other hand, perceptual interpretation/validation of important multivariate phenotypic signatures are often difficult due to the loss of visual information during feature transformation in hyperspace. To address these issues, we propose a novel approach for integrative analysis based on cellular morphometric context, which is a robust representation of WSI, with the emphasis on tumor architecture and tumor heterogeneity, built upon cellular level morphometric features within the spatial pyramid matching (SPM) framework. The proposed approach is applied to The Cancer Genome Atlas (TCGA) lower grade glioma (LGG) cohort, where experimental results (i) reveal several clinically relevant cellular morphometric types, which enables both perceptual interpretation/validation and further investigation through gene set enrichment analysis; and (ii) indicate the significantly increased survival rates in one of the cellular morphometric context subtypes derived from the cellular morphometric context. PMID- 28018995 TI - Evaluating the Paper-to-Screen Translation of Participant-Aided Sociograms with High-Risk Participants. AB - While much social network data exists online, key network metrics for high-risk populations must still be captured through self-report. This practice has suffered from numerous limitations in workflow and response burden. However, advances in technology, network drawing libraries and databases are making interactive network drawing increasingly feasible. We describe the translation of an analog-based technique for capturing personal networks into a digital framework termed netCanvas that addresses many existing shortcomings such as: 1) complex data entry; 2) extensive interviewer intervention and field setup; 3) difficulties in data reuse; and 4) a lack of dynamic visualizations. We test this implementation within a health behavior study of a high-risk and difficult-to reach population. We provide a within-subjects comparison between paper and touchscreens. We assert that touchscreen-based social network capture is now a viable alternative for highly sensitive data and social network data entry tasks. PMID- 28018996 TI - Asymptomatic circulating T-cell clone cause renal polymorphic inflammatory fibrosis. AB - BACKGROUND: Renal complications of non-Hodgkin lymphoma encompass a wide spectrum of monoclonal Ig-related pathologies. Clonal circulating T cells can also be associated with non-renal autoimmune disorders induced by overproduction of specific patterns of cytokines or unbalanced lymphocytes sub-populations. METHODS: Immunophenotyping of circulating T cells and TCR gene restriction analysis using Biomed-2 protocol. NF-kappaB staining and mRNA quantification of inflammatory genes in HK-2 epithelial renal cells exposed to supernatants of peripheral blood mononuclear cells with clonal T-cell population. RESULTS: Here, we could identify a persistent clonal T-cell population, only characterized by in depth immunophenotyping of circulating lymphocytes and using multiplex PCR analysis of TCR gene rearrangements, in two patients with polymorphic inflammatory renal fibrosis of unknown origin. Using an in vitro approach, we could demonstrate that peripheral blood mononuclear cells including the clonal population can trigger a phenotype switch of epithelial renal cells from a quiescent state to a pro-inflammatory state characterized by NF-kappaB nuclear translocation and overexpression of inflammatory cytokine or chemokine. CONCLUSION: These preliminary data suggest that circulating T-cell clones may directly activate epithelial renal cells or promote a T-/B-cell population with autoimmune reactive properties against kidney cells, which, in the absence of overt renal lymphoma infiltration, lead to the subsequent inflammatory renal fibrotic phenotype. PMID- 28018998 TI - Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause. AB - In more than 50% of patients with a mild-to-moderate bleeding tendency, no underlying cause can be identified (bleeding of unknown cause, BUC). Data on parameters of fibrinolysis in BUC are scarce in the literature and reveal discrepant results. It was the aim of this study to investigate increased fibrinolysis as a possible mechanism of BUC. We included 270 patients (227 females, median age 44 years, 25-75th percentile 32-58) with BUC and 98 healthy controls (65 females, median age 47 years, 25-75thpercentile 39-55). Tissue plasminogen activator (tPA-) antigen and activity, plasminogen activator inhibitor type-1 (PAI-1), tPA-PAI-1 complexes, thrombin activatable fibrinolysis inhibitor (TAFI), alpha2-antiplasmin, and D-dimer were determined. While PAI-1 deficiency was equally frequent in patients with BUC and controls (91/270, 34%, and 33/98, 34%, p = 0.996), tPA activity levels were more often above the detection limit in patients than in controls (103/213, 48%, and 23/98, 23%, p < 0.0001). We found lower levels of tPA-PAI-1 complexes (6.86 (3.99-10.00) and 9.11 (7.17-13.12), p < 0.001) and higher activity of TAFI (18.61 (15.80-22.58) and 17.03 (14.02-20.02), p < 0.001) and alpha2-antiplasmin (102 (94-109) and 98 (90 106], p = 0.003) in patients compared to controls. Detectable tPA activity (OR 3.02, 95%CI 1.75-5.23, p < 0.0001), higher levels of TAFI (OR 2.57, 95%CI 1.48 4.46, p = 0.0008) and alpha2-antiplasmin (OR 1.03, 95%CI 1.01-1.05, p = 0.011), and lower levels of tPA-PAI-1 complexes (OR 0.90, 95%CI 0.86-0.95, p < 0.0001) were independently associated with BUC in sex-adjusted logistic regression analyses. We conclude that the fibrinolytic system can play an etiological role for bleeding in patients with BUC. PMID- 28018997 TI - An overview of geospatial methods used in unintentional injury epidemiology. AB - BACKGROUND: Injuries are a leading cause of death and disability around the world. Injury incidence is often associated with socio-economic and physical environmental factors. The application of geospatial methods has been recognised as important to gain greater understanding of the complex nature of injury and the associated diverse range of geographically-diverse risk factors. Therefore, the aim of this paper is to provide an overview of geospatial methods applied in unintentional injury epidemiological studies. METHODS: Nine electronic databases were searched for papers published in 2000-2015, inclusive. Included were papers reporting unintentional injuries using geospatial methods for one or more categories of spatial epidemiological methods (mapping; clustering/cluster detection; and ecological analysis). Results describe the included injury cause categories, types of data and details relating to the applied geospatial methods. RESULTS: From over 6,000 articles, 67 studies met all inclusion criteria. The major categories of injury data reported with geospatial methods were road traffic (n = 36), falls (n = 11), burns (n = 9), drowning (n = 4), and others (n = 7). Grouped by categories, mapping was the most frequently used method, with 62 (93%) studies applying this approach independently or in conjunction with other geospatial methods. Clustering/cluster detection methods were less common, applied in 27 (40%) studies. Three studies (4%) applied spatial regression methods (one study using a conditional autoregressive model and two studies using geographically weighted regression) to examine the relationship between injury incidence (drowning, road deaths) with aggregated data in relation to explanatory factors (socio-economic and environmental). CONCLUSION: The number of studies using geospatial methods to investigate unintentional injuries has increased over recent years. While the majority of studies have focused on road traffic injuries, other injury cause categories, particularly falls and burns, have also demonstrated the application of these methods. Geospatial investigations of injury have largely been limited to mapping of data to visualise spatial structures. Use of more sophisticated approaches will help to understand a broader range of spatial risk factors, which remain under-explored when using traditional epidemiological approaches. PMID- 28018999 TI - New approach to molecular characterization of Paramphistomum cervi and Carmyerius gregarius and comparative analyses with selected trematodes. AB - The two ruminant parasites, Paramphistomum cervi and Carmyerius gregarius, were collected from fresh-slaughtered native cattle at local abattoirs in Sadat district, Menoufia province and identified morphologically, then molecularly by sequencing the nucleotides of 18S ribosomal RNA gene (18S rRNA). The nucleotide sequences of the two isolates were 456 (P. cervi) and 401 bases for (C. gregarius). The data were used along with those of several other helminth species from the GenBank to identify these two species genetically. The nucleotide sequences were aligned using multiple sequence alignments of nucleotides by Clustal W 12.1 V and construct their relationship. Neighbor-joining analytical method was used showing sister relationship between C. gregarius from Sadat district and Gastrodiscoides hominis (EF027096) with relative identity of (98%) due to the presence of single nucleotides polymorphisms (SNPs) in the form of indels as nine nucleotides positions. But when clustering of P. cervi Sadat isolate with Paramphistomoidea sp. S4 isolate P5 (GU735643), this relationship shows complete identity (99%) between them. The homology and diversity was done using Bayesian analyses in MrBayes v3.1. This work will give a useful guide for other researchers for the molecular taxonomic position of Paramphistomatidae spp. in Sadat district among the different species around the world. PMID- 28019000 TI - Avian and simian malaria: do they have a cancer connection? AB - It has been claimed that infectious agents transmitted by mosquitoes (Diptera: Culicidae) may have a greater connection to cancer then hitherto supposed and that the immune system struggles to recognize and fight some of these infectious agents. One of the claims made is that there is a connection between human malaria and brain cancers in the USA. However, the USA declared itself free of human malaria in the last century, yet cancer incidences remain high, suggesting any overall cancer connection is slight. Two fundamental questions arise from the possible mosquito-cancer connection. Firstly, if mosquitoes are able to vector some pathogens and parasites linked with cancer pathogenesis, why has the fact not been discovered decades ago? Secondly, if there is a connection (other than in relation to Burkett's lymphoma), what is its extent? The answers may well lie with the various types of malarias known to exist. The discovery in humans of the simian malaria, caused by Plasmodium knowlesi, suggests that other forms of simian or even avian malaria may be capable of survival in humans, albeit at low levels of parasitemia, and humans may be a dead-end host. Other carcinogenic infectious agents transmitted by mosquitoes may also go undetected because either no one is looking for them, or they are looking in wrong anatomical locations and/or with inadequate tools. Research on false negative test results with respect to many infectious agents is sadly lacking, so its extent is unknown. However, electronic and other media provide numerous instances of patients failing to be diagnosed for both human malaria and Lyme's disease, to take just two examples. This review suggests that to shed light on a potential mosquito cancer connection, more research is required to establish whether other simian and avian forms of malaria play a part. If so, then they potentially provide unique markers for early cancer detection. PMID- 28019001 TI - Characteristics of road traffic accident casualties admitted to a tertiary care hospital in Sri Lanka. AB - The mortality and morbidity of road traffic accidents (RTA) is increasing in the South Asian region, including Sri Lanka. Therefore, the demographic factors, types of vehicles involved, and the severity of injuries sustained in RTA was studied. Age, gender, and details of the incident of all patients admitted to hospital following a RTA, between January 2007 and August 2012, were obtained by interview. Following a medico-legal examination, the type and severity of injuries was categorized as, non-grievous, grievous, endangering life or fatal in the ordinary course of nature. Of the 579 RTA casualties examined, 72% were males, 28% females, and 26% were in the 20-29 year age group. There were 44% passengers, 32% drivers, and 20% pedestrians. Of the 440 vehicle occupants, 37% were on motor cycles, 28% in three wheelers, 13% in dual purpose vehicles and 11% in buses. Of the 114 pedestrians, 33% had been struck by motor cycles, 19% by three-wheelers and 17% by dual purpose vehicles. There was at least one soft tissue injury in 84%, whilst 45% had one or more fractures. In 85% of bicycle riders, the injuries were grievous, endangering life or fatal in the ordinary course of nature. A high proportion of young adults sustained grievous injuries due to RTA. Almost two thirds of the casualties resulted from motorcycle or three wheeler accidents. Laws limiting the number of passengers carried, installation of side doors, mandatory use of seat belts in three wheelers, and protective garments for motorcyclists are recommended. PMID- 28019002 TI - Characterization of Yersinia species by protein profiling using automated microfluidic capillary electrophoresis. AB - Yersinia pestis is a biological agent of high risk to national security due to its ability to be easily disseminated and transmitted among humans. If Y. pestis was to be utilized in a deliberate disease outbreak it would be essential to rapidly and accurately identify the agent. Current identification methods for Yersinia species are limited by their reliance on cultivation, the time taken to achieve results and/or the use of protocols that are not amenable for field use. Faster identification methods are urgently required. Microfluidic capillary electrophoresis was used to identify seven Yersinia species based on their protein profiles. Further objectives included determining if Yersinia species could be detected in mixtures of milk products and Escherichia coli, determining if Yersinia could be detected in a blinded identification and reproducibility across two platforms. Two characteristic protein bands were detected at 50 kilodaltons (kDa) and between 50 and 75 kDa for the Yersinia species. Individual Yersinia species could be differentiated from one another and distinguished from E. coli, Bacillus anthracis Sterne strain and Dipel (containing Bacillus thuringiensis). Due to the high protein content of milk products Yersinia could not be detected when mixed with these but was detected when mixed with E. coli. Species were correctly identified with 96% success in blinded procedures using 12 individuals. Whilst protein profile patterns were reproducible across platforms there was some discrepancy in protein sizing. This study demonstrates that protein profiling using microfluidic capillary electrophoresis is able to rapidly and reproducibly identify and characterize Yersinia species. Results show this technique is a powerful front-line, rapid and broad range screening method capable of identifying and differentiating biological agents, hoax agents and environmental bacterial species. PMID- 28019003 TI - Validation of alternate light sources for detection of bruises in non-embalmed and embalmed cadavers. AB - Bruising is frequently documented in cases of violence for use as forensic evidence. However, bruises can be overlooked if they are not visible to the naked eye. Alternate light sources such as ultraviolet, narrow band, and infrared have been used in an attempt to reveal the presence of bruising that is not otherwise apparent. However, there is a significant gap in knowledge surrounding this technique as it has not been validated against histology to confirm that bruising is genuinely being enhanced. A recent study evaluated the ability of alternate light sources to enhance visibility of bruises using a pigskin model. However, histological confirmation of bruising in humans using these light sources has not yet been performed. In this study, embalmed and non-embalmed human cadavers were used. Bodies were surveyed with alternate light sources, and enhanced regions that were unapparent under white light were photographed with the alternate light sources and sampled for histological assessment. Immunohistochemical staining for the red blood cell surface protein glycophorin was used determine if the enhanced area was a bruise (defined by the presence of extravasated erythrocytes). Photographs of areas confirmed to be bruises were analyzed using the program Fiji to measure enhancement, which was defined as an increase in the measured transverse diameter. In the non-embalmed and the embalmed cadavers violet alternate light produced the greatest enhancement of histologically confirmed bruises, followed by blue (both p < 0.0001). Regions that were not confirmed as bruises also enhanced, indicating that light sources may not be specific. This suggests that the use of light sources to enhance the visibility of bruising should be undertaken with caution and further studies are required. PMID- 28019004 TI - Erratum to: Heavy metals relationship with water and size-fractionated sediments in rivers using canonical correlation analysis (CCA) case study, rivers of south western Caspian Sea. PMID- 28019005 TI - Quality of Working Life of cancer survivors: associations with health- and work related variables. AB - PURPOSE: This study aimed to (1) describe the Quality of Working Life (QWL) of cancer survivors and (2) explore associations between the QWL of cancer survivors and health- and work-related variables. METHODS: Employed and self-employed cancer survivors were recruited through hospitals and patient organizations. They completed the Quality of Working Life Questionnaire for Cancer Survivors (QWLQ CS) and health- and work-related variables in this cross-sectional study. The QWL scores of cancer survivors were described, and associations between QWL and health- and work-related variables were assessed. RESULTS: The QWLQ-CS was completed by 302 cancer survivors (28% male) with a mean age of 52 +/- 8 years. They were diagnosed between 0 and 10 years ago with various types of cancer, such as breast cancers, gastrointestinal cancers, urological cancers, and haematological cancers. The QWL mean score of cancer survivors was 75 +/- 12 (0 100). Cancer survivors had statistically significant lower QWL scores when they had been treated with chemotherapy or when they reported co-morbidity (p <= 0.05). Cancer survivors without managerial positions, with low incomes or physically demanding work, and who worked a proportion of their contract hours had statistically significantly lower QWL scores (p <= 0.05). CONCLUSIONS: This study described the QWL of cancer survivors and associations between QWL and health- and work-related variables. Based on these variables, it is possible to indicate groups of cancer survivors who need more attention and support regarding QWL and work continuation. PMID- 28019007 TI - Proposed revised nomenclature for transfusion-related acute lung injury. AB - A decade ago, definitions of "transfusion?related acute lung injury (TRALI)" and "possible TRALI" were standardized for research and clinical diagnosis. Since then, evidence has confirmed that TRALI is often due to transfusion of white blood cell antibodies to at-risk patients, and the term "TRALI, antibody mediated" is appropriate for such cases. Other TRALI cases are non-antibody mediated. Because specific, nonantibody transfusion factors have not yet been confirmed to cause TRALI in humans, the general term "TRALI, non-antibody mediated" is appropriate for such cases. In contrast, evidence is against possible TRALI being due to transfusion with the more likely cause of the acute respiratory distress syndrome (ARDS) being the alternative ARDS risk factor present in these patients. We propose to drop the misleading term "possible TRALI" and to rename this category of cases as "transfused ARDS." These nomenclature updates will more accurately categorize ARDS cases that develop after transfusion. PMID- 28019006 TI - Glucose and Intermediary Metabolism and Astrocyte-Neuron Interactions Following Neonatal Hypoxia-Ischemia in Rat. AB - Neonatal hypoxia-ischemia (HI) and the delayed injury cascade that follows involve excitotoxicity, oxidative stress and mitochondrial failure. The susceptibility to excitotoxicity of the neonatal brain may be related to the capacity of astrocytes for glutamate uptake. Furthermore, the neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance for limiting this kind of injury. Also, in the neonatal brain, neurons depend upon de novo synthesis of neurotransmitters via pyruvate carboxylase in astrocytes to increase neurotransmitter pools during normal brain development. Several recent publications describing intermediary brain metabolism following neonatal HI have yielded interesting results: (1) Following HI there is a prolonged depression of mitochondrial metabolism in agreement with emerging evidence of mitochondria as vulnerable targets in the delayed injury cascade. (2) Astrocytes, like neurons, are metabolically impaired following HI, and the degree of astrocytic malfunction may be an indicator of the outcome following hypoxic and hypoxic-ischemic brain injury. (3) Glutamate transfer from neurons to astrocytes is not increased following neonatal HI, which may imply that astrocytes fail to upregulate glutamate uptake in response to the massive glutamate release during HI, thus contributing to excitotoxicity. (4) In the neonatal brain, the activity of the PPP is reduced following HI, which may add to the susceptibility of the neonatal brain to oxidative stress. The present review aims to discuss the metabolic temporal alterations observed in the neonatal brain following HI. PMID- 28019008 TI - Enantiomeric resolution, stereochemical assignment and toxicity evaluation of TPA enantiomers. AB - Tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetic acid (TPA) is a critical intermediate in the synthesis of HIV protease inhibitors. A simple and efficient method for the separation and determination of TPA enantiomers was developed. The TPA was separated into its enantiomers with an enantiomeric purity of 99% using an HPLC system equipped with a Chiralpak OD-H column. Semi preparative HPLC enantioseparations were carried out for further enrichment of the enantiomers. The validity of this method was evaluated on the basis of its precision, accuracy, linearity and recovery. The method was observed to be suitable for the rapid separation and semi-preparation of TPA isomers. The separated enantiomers were identified by optical rotation and high-resolution electrospray ionization mass spectrometry. Furthermore, the stereochemical structures of the TPA enantiomers were definitively confirmed using a combination of experimental and calculated electronic circular dichroism spectra. The toxicity of the separated pure enantiomers against Oryzias melastigma was evaluated using the median lethal concentration (LC50 ) values. The results indicated that (S)-(-)-TPA is ~2.5 times more toxic than its enantiomorphism. PMID- 28019009 TI - Restrictive versus liberal red blood cell transfusion strategy after hip surgery: a decision model analysis of healthcare costs. AB - BACKGROUND: Red blood cell transfusion related to select surgical procedures accounts for approximately 2.8 million transfusions in the United States yearly and occurs commonly after hip fracture surgeries. Randomized controlled trials have demonstrated lack of clinical benefit with higher versus lower transfusion thresholds in postoperative hip fracture repair patients with cardiac disease or risk factors for cardiac disease. The economic implications of a higher versus lower hemoglobin (Hb) threshold have not yet been investigated. STUDY DESIGN AND METHODS: A decision tree analysis was constructed to estimate differences in healthcare costs and charges between a Hb transfusion threshold strategy of 8 g/dL versus 10 g/dL from the perspective of both Centers for Medicare and Medicaid Services (CMS) as well as hospitals. Secondary outcome measures included differences in transfusion-related adverse events. RESULTS: Among the 133,697 Medicare beneficiaries undergoing hip fracture repair in 2012, we estimated that 45,457 patients would be anemic and at risk for transfusion. CMS would save an estimated $11.3 million to $24.3 million in payments, while hospitals would reduce charges by an estimated $52.7 million to $93.6 million if the restrictive transfusion strategy were to be implemented nationally. Additionally, rates of transfusion-associated circulatory overload, transfusion-related acute lung injury, acute transfusion reactions, length of stay, and mortality would be reduced. CONCLUSIONS: This model suggests that the uniform adoption of a restrictive transfusion strategy among patients with cardiac disease and risk factors for cardiac disease undergoing hip fracture repair would result in significant reductions in clinically important outcomes with significant cost savings. PMID- 28019010 TI - Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End-Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects. AB - Two phase I open-label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end-stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of selumetinib 50 mg; those with ESRD received selumetinib before and after dialysis (with a between-treatment washout period of >=7 days). In the hepatic impairment study, subjects received varying single doses of selumetinib (20-50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child-Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax ) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose-normalized total selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child-Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound selumetinib exposure. In both studies, selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients. PMID- 28019011 TI - Prognostic value of biochemical variables for survival after surgery for metastatic bone disease of the extremities. AB - BACKGROUND AND OBJECTIVE: Prediction of survival in patients having surgery for metastatic bone disease in the extremities (MBDex) has been of interest in more than two decades. Hitherto no consensus on the value of biochemical variables has been achieved. Our purpose was (1) to investigate if standard biochemical variables have independent prognostic value for survival after surgery for MBDex and (2) to identify optimal prognostic cut off values for survival of biochemical variables. METHODS: In a consecutive cohort of 270 patients having surgery for MBDex, we measured preoperative biochemical variables: hemoglobin, alkaline phosphatase, C-reactive protein and absolute, neutrophil and lymphocyte count. ROC curve analyses were performed to identify optimal cut off levels. Independent prognostic factors for variables were addressed with multiple Cox regression analyses. RESULTS: Optimal cut off levels were identified as: hemoglobin 7.45 mmol/L, absolute lymphocyte count 8.5 * 109 /L, neutrophil 5.68 * 109 /L, lymphocyte 1.37 * 109 /L, C-reactive protein 22.5 mg/L, and alkaline phosphatase 129 U/L. Regression analyses found alkaline phosphatase (HR 2.49) and neutrophil count (HR 2.49) to be independent prognostic factors. CONCLUSIONS: We found neutrophil count and alkaline phosphatase to be independent prognostic variables in predicting survival in patients after surgery for MBDex. PMID- 28019012 TI - Improved planning of leukapheresis endpoint with customized prediction algorithm: minimizing collection days, volume of blood processed, procedure time, and citrate toxicity. AB - BACKGROUND: Increased emphasis on cost and productivity in apheresis centers calls for a proficient and predictable hematopoietic progenitor cell (HPC) collection. Therefore, the aim of this study was to determine the value of a customized predictive algorithm that estimates how many blood volumes are required to process for a targeted CD34 cell dose. STUDY DESIGN AND METHODS: Retrospective analysis was performed on 107 HPC collections completed on the Spectra Optia MNC from January 2013 to June 2014 in 51 patients and 12 donors. In December 2014, a prediction algorithm was implemented, designed from data acquired since January 2013, by linear regression of preapheresis CD34 cell counts (pre-CD34) versus collected CD34 cell dose per volume blood processed. RESULTS: CD34 collection efficiencies (CE2) of 51.9 +/- 1.7% (mean +/- SEM) and 57.5 +/- 3.0% were observed in autologous and allogeneic procedures, respectively. After implementation of the algorithm, the mean number of collections per patient declined from 1.97 to 1.5. Accordingly, the frequency of patients requiring single-day collections increased from 35% to 57%. All donors were collected in single procedures, although only 12.2 +/- 1.1 L blood was processed, including for National Marrow Donor Program collections. Cumulative procedure time, processed blood volume, product volume, infused anticoagulant volume, and symptomatic calcium administration decreased in patients, and overcollection was limited. CONCLUSION: A prediction algorithm can provide great value in the planning of leukapheresis, which may optimize resource utilization and capacity of the unit. In addition, predictability was facilitated by a proficient and consistent performance of the Spectra Optia MNC. PMID- 28019014 TI - Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. METHODS: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. RESULTS AND DISCUSSION: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1.811, 95% CI: 1.379-2.378), placebo (OR: 1.655: 95% CI: 1.029-2.661), nsNSAIDs (OR: 2.155, 95% CI: 1.146-4.053), and COXIBs (OR: 1.800, 95% CI: 1.217-2.662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0.583, 95% CI: 0.396-0.857) and (OR: 0.609, 95% CI: 0.375 0.989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1.488, 95% CI: 1.027-2.155) and (OR: 1.933, 95% CI: 1.052-3.549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0.603, 95% CI: 0.410-0.887), (OR: 0.517, 95% CI: 0.287-0.929), and (OR: 0.509, 95% CI: 0.280-0.925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1.612, 95% CI: 1.313-1.981), (OR: 1.572, 95% CI: 1.123-2.201) and (OR: 1.838, 95% CI: 1.323-2.554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0.805, 95% CI: 0.658 0.986) and (OR: 0.557, 95% CI: 0.404-0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. WHAT IS NEW AND CONCLUSION: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group. PMID- 28019013 TI - A cultural take on the links between religiosity, identity, and meaning in life in religious emerging adults. AB - Identity and meaning in life are core developmental assets in emerging adulthood. We analysed how religiosity is related to these intentional strivings in emerging adults enrolled in theological education, by depicting (1) identity strivings and meaning in life accounts in faith narratives (Study 1) and (2) links between personal identity and meaning in life profiles and religious beliefs, behaviours, and subjective experiences (Study 2). Both studies highlighted that a Foreclosed status, with high personal commitment and reduced exploration, was dominant in faith narratives and personal identity profiles. Also, in narratives meaning in life was reflected by a strong focus on presence of meaning through religious insights. Nonetheless, global meaning in life profiles indicated that many emerging adults were searching for a meaning in their lives, while reporting lower levels of presence of meaning. Identity Achievement and High Presence-High Search profiles were linked to the highest levels of subjective, behavioural, and cognitive religiosity. We highlighted the multidimensionality of identity and meaning in life strivings in emerging adults attending theological schools. We pointed out that even in a somewhat foreclosed cultural context (e.g., Romanian Christian Orthodox theological schools), religion represents a dynamic social and ideological context for self-development. Statement of contribution What is already known on this subject? Religious beliefs increase in emerging adults, doubled by decreases in religious behaviours, linked to an adherence to a more personal approach to religion. Religious youth are more committed to their faith and also explore identity and life meaning in relation to their religious strivings. Youth religious exemplars report close links between their religious faith and strivings for meaningful life goals. What does this study add? We investigated Christian Orthodox theology students, for whom religion is a normative dimension of personal and vocational development. A Foreclosed status, with high personal commitment and reduced exploration was dominant in faith narratives and in personal identity profiles. Many emerging adults were searching for a meaning in their lives, while at the same time reporting lower levels of presence of meaning. Identity Achievement and High Presence-High Search profiles were linked to higher levels of subjective, behavioural, and cognitive religiosity. PMID- 28019015 TI - Factors associated with oral health-related quality of life among safety-net clinic patients. AB - OBJECTIVES: Oral health-related quality of life (OHRQoL) is an important health indicator not only for individuals but also for oral health care providers to treat a person holistically. Previous studies focused on OHRQoL do not provide comprehensive knowledge regarding low-income patients in the United States, many of whom have chronic health conditions that can affect their oral health. The purpose of this study is to examine factors associated with OHRQoL among low income, uninsured patients of safety-net providers, which provide free or reduced fee medical and/or dental care to underserved populations. METHODS: Uninsured patients (N = 584) participated in a self-administered survey in May and June 2016 at a safety-net clinic in the United States serving a low-income uninsured population, which provides limited oral health care services. This study used cross-sectional design and a nonprobability sample. The dependent variable was OHRQoL measured using the Oral Health Impact Profile-14. Chi square tests, Analysis of Variance tests, and multiple regression were used for statistical analysis. RESULTS: Higher levels of dental care neglect and lower frequency of oral hygiene practice were associated with lower levels of OHRQoL (P < 0.01). Participants utilizing a diabetes clinic reported better OHRQoL than those who were not patients of a diabetes clinic (P < 0.05). US born English speakers had worse general health and OHRQoL compared to non-US born English speakers and Spanish speakers (P < 0.01). CONCLUSIONS: An intervention to remedy dental neglect is recommended to improve OHRQoL among uninsured safety-net patients. PMID- 28019016 TI - Talking with young children about concussions: an exploratory study. AB - BACKGROUND: Concussion education for children early in their participation in organized sport may help shape lasting attitudes about concussion safety. However, existing programming and research focus on older ages. METHODS: Qualitative interviews about concussions were conducted with twenty children between the ages of six and eight. Structural, descriptive and pattern coding were used to organize the transcribed interviews and identify emergent themes. RESULTS: Eighteen of the participants indicated that they had heard of the word concussion, with 12 describing the injury as related to the brain or head. The most frequently described mechanisms of injury were impacts to the head or falls, and symptoms tended to be somatic, such as generalized pain. The most frequently endorsed strategy to avoid sustaining a concussion was to 'follow the rules.' Multiple participants referenced parents as an informal source of information about concussions. CONCLUSIONS: While most participants demonstrated some awareness about concussions, there were clear knowledge gaps that can be addressed with developmentally appropriate concussion education programming. Consistent with their developmental stage, interventions targeted at children in this age range may be most successful if they use basic logic, concrete ideas, provide rules to be followed and engage parents in dissemination. PMID- 28019017 TI - Intelligent and automatic in vivo detection and quantification of transplanted cells in MRI. AB - PURPOSE: Magnetic resonance imaging (MRI)-based cell tracking has emerged as a useful tool for identifying the location of transplanted cells, and even their migration. Magnetically labeled cells appear as dark contrast in T2*-weighted MRI, with sensitivities of individual cells. One key hurdle to the widespread use of MRI-based cell tracking is the inability to determine the number of transplanted cells based on this contrast feature. In the case of single cell detection, manual enumeration of spots in three-dimensional (3D) MRI in principle is possible; however, it is a tedious and time-consuming task that is prone to subjectivity and inaccuracy on a large scale. This research presents the first comprehensive study on how a computer-based intelligent, automatic, and accurate cell quantification approach can be designed for spot detection in MRI scans. METHODS: Magnetically labeled mesenchymal stem cells (MSCs) were transplanted into rats using an intracardiac injection, accomplishing single cell seeding in the brain. T2*-weighted MRI of these rat brains were performed where labeled MSCs appeared as spots. Using machine learning and computer vision paradigms, approaches were designed to systematically explore the possibility of automatic detection of these spots in MRI. Experiments were validated against known in vitro scenarios. RESULTS: Using the proposed deep convolutional neural network (CNN) architecture, an in vivo accuracy up to 97.3% and in vitro accuracy of up to 99.8% was achieved for automated spot detection in MRI data. CONCLUSION: The proposed approach for automatic quantification of MRI-based cell tracking will facilitate the use of MRI in large-scale cell therapy studies. Magn Reson Med 78:1991-2002, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019018 TI - Contrast mechanisms associated with neuromelanin-MRI. AB - PURPOSE: To investigate the physical mechanisms associated with the contrast observed in neuromelanin MRI. METHODS: Phantoms having different concentrations of synthetic melanins with different degrees of iron loading were examined on a 3 Tesla scanner using relaxometry and quantitative magnetization transfer (MT). RESULTS: Concentration-dependent T1 and T2 shortening was most pronounced for the melanin pigment when combined with iron. Metal-free melanin had a negligible effect on the magnetization transfer spectra. On the contrary, the presence of iron-laden melanins resulted in a decreased magnetization transfer ratio. The presence of melanin or iron (or both) did not have a significant effect on the macromolecular content, represented by the pool size ratio. CONCLUSION: The primary mechanism underlying contrast in neuromelanin-MRI appears to be the T1 reduction associated with melanin-iron complexes. The macromolecular content is not significantly influenced by the presence of melanin with or without iron, and thus the MT is not directly affected. However, as T1 plays a role in determining the MT-weighted signal, the magnetization transfer ratio is reduced in the presence of melanin-iron complexes. Magn Reson Med 78:1790-1800, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019019 TI - Two Southern Ocean diatoms are more sensitive to ocean acidification and changes in irradiance than the prymnesiophyte Phaeocystis antarctica. AB - To better understand the impact of ocean acidification (OA) and changes in light availability on Southern Ocean phytoplankton physiology, we investigated the effects of pCO2 (380 and 800 uatm) in combination with low and high irradiance (20 or 50 and 200 umol photons m-2 s-1 ) on growth, particulate organic carbon (POC) fixation and photophysiology in the three ecologically relevant species Chaetoceros debilis, Fragilariopsis kerguelensis and Phaeocystis antarctica. Irrespective of the light scenario, neither growth nor POC per cell was stimulated by OA in any of the tested species and the two diatoms even displayed negative responses in growth (e.g. C. debilis) or POC content (e.g. F. kerguelensis) under OA in conjunction with high light. For both diatoms, also maximum quantum yields of photosystem II (Fv /Fm ) were decreased under these conditions, indicating lowered photochemical efficiencies. To counteract the negative effects by OA and high light, the two diatoms showed diverging photoacclimation strategies. While cellular chlorophyll a (Chl a) and fucoxanthin contents were enhanced in C. debilis to potentially maximize light absorption, F. kerguelensis exhibited reduced Chl a per cell, increased disconnection of antennae from photosystem II reaction centers and strongly lowered absolute electron transport rates (ETR). The decline in ETRs in F. kerguelensis might be explained in terms of different species-specific strategies for tuning the available flux of adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. Overall, our results revealed that P. antarctica was more tolerant to OA and changes in irradiance than the two diatoms, which may have important implications for biogeochemical cycling. PMID- 28019020 TI - Flow-suppressed hyperpolarized 13 C chemical shift imaging using velocity optimized bipolar gradient in mouse liver tumors at 9.4 T. AB - PURPOSE: To optimize and investigate the influence of bipolar gradients for flow suppression in metabolic quantification of hyperpolarized 13 C chemical shift imaging (CSI) of mouse liver at 9.4 T. METHODS: The trade-off between the amount of flow suppression using bipolar gradients and T2* effect from static spins was simulated. A free induction decay CSI sequence with alternations between the flow suppressed and non-flow-suppressed acquisitions for each repetition time was developed and was applied to liver tumor-bearing mice via injection of hyperpolarized [1-13 C] pyruvate. RESULTS: The in vivo results from flow suppression using the velocity-optimized bipolar gradient were comparable with the simulation results. The vascular signal was adequately suppressed and signal loss in stationary tissue was minimized. Application of the velocity-optimized bipolar gradient to tumor-bearing mice showed reduction in the vessel-derived pyruvate signal contamination, and the average lactate/pyruvate ratio increased by 0.095 (P < 0.05) in the tumor region after flow suppression. CONCLUSION: Optimization of the bipolar gradient is essential because of the short 13 C T2* and high signal in venous flow in the mouse liver. The proposed velocity optimized bipolar gradient can suppress the vascular signal, minimizing T2* related signal loss in stationary tissues at 9.4 T. Magn Reson Med 78:1674-1682, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019021 TI - Multiparametric estimation of brain hemodynamics with MR fingerprinting ASL. AB - PURPOSE: Assessment of brain hemodynamics without exogenous contrast agents is of increasing importance in clinical applications. This study aims to develop an MR perfusion technique that can provide noncontrast and multiparametric estimation of hemodynamic markers. METHODS: We devised an arterial spin labeling (ASL) method based on the principle of MR fingerprinting (MRF), referred to as MRF-ASL. By taking advantage of the rich information contained in MRF sequence, up to seven hemodynamic parameters can be estimated concomitantly. Feasibility demonstration, flip angle optimization, comparison with Look-Locker ASL, reproducibility test, sensitivity to hypercapnia challenge, and initial clinical application in an intracranial steno-occlusive process, Moyamoya disease, were performed to evaluate this technique. RESULTS: Magnetic resonance fingerprinting ASL provided estimation of up to seven parameters, including B1+, tissue T1 , cerebral blood flow (CBF), tissue bolus arrival time (BAT), pass-through arterial BAT, pass-through blood volume, and pass-through blood travel time. Coefficients of variation of the estimated parameters ranged from 0.2 to 9.6%. Hypercapnia resulted in an increase in CBF by 57.7%, and a decrease in BAT by 13.7 and 24.8% in tissue and vessels, respectively. Patients with Moyamoya disease showed diminished CBF and lengthened BAT that could not be detected with regular ASL. CONCLUSION: Magnetic resonance fingerprinting ASL is a promising technique for noncontrast, multiparametric perfusion assessment. Magn Reson Med 78:1812-1823, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019022 TI - Use of pattern recognition for unaliasing simultaneously acquired slices in simultaneous multislice MR fingerprinting. AB - PURPOSE: The purpose of this study is to accelerate an MR fingerprinting (MRF) acquisition by using a simultaneous multislice method. METHODS: A multiband radiofrequency (RF) pulse was designed to excite two slices with different flip angles and phases. The signals of two slices were driven to be as orthogonal as possible. The mixed and undersampled MRF signal was matched to two dictionaries to retrieve T1 and T2 maps of each slice. Quantitative results from the proposed method were validated with the gold-standard spin echo methods in a phantom. T1 and T2 maps of in vivo human brain from two simultaneously acquired slices were also compared to the results of fast imaging with steady-state precession based MRF method (MRF-FISP) with a single-band RF excitation. RESULTS: The phantom results showed that the simultaneous multislice imaging MRF-FISP method quantified the relaxation properties accurately compared to the gold-standard spin echo methods. T1 and T2 values of in vivo brain from the proposed method also matched the results from the normal MRF-FISP acquisition. CONCLUSION: T1 and T2 values can be quantified at a multiband acceleration factor of two using our proposed acquisition even in a single-channel receive coil. Further acceleration could be achieved by combining this method with parallel imaging or iterative reconstruction. Magn Reson Med 78:1870-1876, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019023 TI - Academic productivity of faculty associated with microsurgery fellowships. AB - BACKGROUND: The Hirsch index (h-index) is widely recognized as a reliable measure of academic productivity. While previous studies have applied the h-index to surgical disciplines, none have analyzed microsurgery faculty. This manuscript aims to examine the h-index of microsurgery fellowship faculty to categorize its applicability to microsurgeons as a determinant of academic output. METHODS: Faculty demographics and institution characteristics were obtained from the American Society of Reconstructive Microsurgery (ASRM) and official program websites. Faculty h-indices were calculated using the Scopus database (Elsevier, USA). Data was assessed using bivariate analysis and multiple linear regression models to determine the relationship between independent variables and total publications, career h-index and 5-year h-index (h5-index) of each faculty. RESULTS: A total of 139 faculties from 22 programs met inclusion criteria. The median faculty age was 44 (IQR 13) and 84.9% of faculty were male. Faculty size, number of years of fellowship existence, number of fellows, FACS memberships, number of free flaps annually, and academic appointment title were significantly associated with the total publications, h-index, and h5-index. Multivariable analysis based on the significant independent variables demonstrated that geographical region and faculty ranks were significantly associated with the h5 index. CONCLUSIONS: Variables associated with seniority (age, years of practice after fellowship, and academic appointment) were positively correlated with the h index. Given the increased use of bibliometrics in academic medicine, these results show that h-index is a viable tool that can be used to assess research productivity among academic microsurgeons. PMID- 28019024 TI - Nuclear paramagnetism-induced MR frequency shift and its implications for MR based magnetic susceptibility measurement. AB - PURPOSE: To investigate the 1 H spin contribution (0.004 parts per million (ppm)) to the water magnetic susceptibility and discuss its implications for high precision phase mapping and tissue susceptibility measurement. METHODS: Free induction decay (FID) signals were acquired at 3 Tesla (T) and 9.4T from thin square phantoms at a range of tip angles. The FID frequency shift was examined at a high resolution ( < 0.01 Hz) for different phantom orientations relative to the main magnetic field (B0 ). B0 maps on an axial and a coronal slice of a spherical phantom were obtained at 3T to examine the tip angle and orientation dependence at the 0.001 ppm level. RESULTS: A frequency shift of about 0.3 Hz was observed between tip angles of 10 degrees and 90 degrees when the thin phantom was normal to B0 at 3T, whereas the shift changed sign and was halved in magnitude when the phantom's face was parallel to B0 . At 9.4T, the effect size increased proportionately. The orientation-dependent frequency shift was also observed in the B0 map experiment. These observations agree with theoretical frequency shift due to longitudinal 1 H spin polarization. CONCLUSION: Magnetic susceptibility contribution from the nuclear paramagnetism should be taken into account in the interpretation of high-precision phase and susceptibility mapping in MRI. Magn Reson Med 77:848-854, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019025 TI - MTEP impedes the neuronal polarization and the activity of the Akt-NF-kappaB pathway in rat hippocampal neurons. AB - Metabotropic glutamate receptor 5 (mGluR5) is extensively involved in neural survival, differentiation, dendritic morphology, synaptic plasticity, and neural circuit formation. However, little is known about its role in neuronal polarization and axon outgrowth. In this study, we applied the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine sodium salt and antagonist 3-[(2-methyl-4 thaizolyl) ethynyl] pyridine (MTEP) of mGluR5 to the cultured hippocampal neurons to observe the neuronal polarization and axon outgrowth, and further explored the possible intracellular signal transduction pathway. The results demonstrated that MTEP administration significantly attenuates the proportion of polarized neurons and the length of the axon, indicated by SMI312 (an axon marker) and Tuj-1 (a marker of all the neurites) double-labeling immunofluorescence. Western blot analysis showed that MTEP administration also inhibited the activation of AKT and nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65, and decreased the phosphorylation of p65 as well. Furthermore, Akt inhibitor LY294002 treatment resulted in neuronal polarization delay and axon outgrowth retardation, while suppressing the phosphorylation and nuclear translocation of p65. We concluded that mGluR5 could regulate neuronal polarity and axon outgrowth during the morphological differentiation of rat developing neurons, and the intracellular signaling pathway of Akt-NF-kappaB might be involved in the action of mGluR5. (c) 2016 Wiley Periodicals, Inc. PMID- 28019026 TI - Psychedelics as Medicines: An Emerging New Paradigm. AB - Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5 HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network "resetting" after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched. PMID- 28019027 TI - Robustness of spatio-temporal regularization in perfusion MRI deconvolution: An application to acute ischemic stroke. AB - PURPOSE: The robustness of a recently introduced globally convergent deconvolution algorithm with temporal and edge-preserving spatial regularization for the deconvolution of dynamic susceptibility contrast perfusion magnetic resonance imaging is assessed in the context of ischemic stroke. THEORY AND METHODS: Ischemic tissues are not randomly distributed in the brain but form a spatially organized entity. The addition of a spatial regularization term allows to take into account this spatial organization contrarily to the sole temporal regularization approach which processes each voxel independently. The robustness of the spatial regularization in relation to shape variability, hemodynamic variability in tissues, noise in the magnetic resonance imaging apparatus, and uncertainty on the arterial input function selected for the deconvolution is addressed via an original in silico validation approach. RESULTS: The deconvolution algorithm proved robust to the different sources of variability, outperforming temporal Tikhonov regularization in most realistic conditions considered. The limiting factor is the proper estimation of the arterial input function. CONCLUSION: This study quantified the robustness of a spatio-temporal approach for dynamic susceptibility contrast-magnetic resonance imaging deconvolution via a new simulator. This simulator, now accessible online, is of wide applicability for the validation of any deconvolution algorithm. Magn Reson Med 78:1981-1990, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019028 TI - Noninvasive measurement of pressure gradient across a coronary stenosis using phase contrast (PC)-MRI: A feasibility study. AB - PURPOSE: To investigate the feasibility of blood pressure difference measurement, DeltaP, across the coronary artery using phase contrast (PC)-MRI for potential noninvasive assessment of the functional significance of coronary artery stenosis. METHODS: Three-directional velocities in the coronary arteries acquired using 2D-PC-MRI were used with the Navier-Stokes equations to derive DeltaP. Repeat phantom studies were performed to assess the reproducibility of flow velocity and DeltaP. DeltaP derived using PC-MRI (DeltaPMR ) and that obtained using pressure transducer (DeltaPPT ) were compared. Reproducibility of coronary flow velocity was assessed in healthy controls (n = 11). Patients with suspected coronary artery disease (n = 6) were studied to evaluate the feasibility of DeltaPMR measurement across a coronary stenosis. RESULTS: Phantom: Good overall reproducibility of flow velocity and DeltaP measurements and excellent correlation (DeltaPMR vs DeltaPPT ) was observed: intraclass correlation (ICC) of 0.95(Vz ), 0.72(Vx ), 0.73(Vy ), and 0.87(DeltaPMR ) and R2 = 0.94, respectively. Human: Good reproducibility of coronary flow velocity was observed: ICC of 0.94/0.95(Vz ), 0.76/0.74(Vx ), and 0.80/0.77(Vy ) at cardiac phase 1/2. Significant (p = 0.025) increase in DeltaPMR was observed in patients (6.40 +/- 4.43 mmHg) versus controls (0.70 +/- 0.57 mmHg). CONCLUSION: DeltaPMR in the coronary arteries is feasible. Upon further validation using the invasive measure, DeltaPMR has the potential for noninvasive assessment of coronary artery stenosis. Magn Reson Med 77:529-537, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019029 TI - HLA-DRB3*01:01 is a predictor of immunization against human platelet antigen-1a but not of the severity of fetal and neonatal alloimmune thrombocytopenia. AB - BACKGROUND: Most cases of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are caused by maternal alloantibodies against human platelet antigen-1a (HPA-1a). Alloimmunization mainly occurs in HPA-1a-negative mothers who are carriers of the HLA-DRB3*01:01 allele. Recently, it has been reported that the combined presence of HLA-DRB3*01:01 and HLA-DRB4*01:01P was associated with severity of FNAIT. We tested this hypothesis by analyzing a large cohort of cases and controls. STUDY DESIGN AND METHODS: In total, 101 mothers with a history of FNAIT caused by anti HPA-1a were investigated. HLA-DRB1, -DRB3, -DRB4, and -DRB5 genotypes were determined by Luminex technology. Haplotype frequencies were compared between cases and 100 controls. The platelet (PLT) counts of neonates and the incidence of intracranial hemorrhage (ICH) were compared between subgroups defined by genotype. RESULTS: Of the HPA-1a-immunized mothers, 98% (99/101) carried at least one copy of HLA-DRB3*01:01. Carriage of HLA-DRB3*01:01 was significantly associated with immune response to HPA-1a (odds ratio, 92.3; 95% confidence interval, 26.9-317.1; p = 1.34 * 10-12 ). No association between HLA-DRB3*01:01 and HLA-DRB4*01:01P alone or in combination with the PLT count of the newborns or the incidence of ICH was detected. CONCLUSION: In contrast to HLA-DRB4*01:01P, the inheritance of HLA-DRB3*01:01 is strongly associated with the propensity for mounting a humoral immune response against fetal HPA-1a antigen. Neither a homozygous nor a compound heterozygous gene dose predicts the severity of the disease. Testing for the presence of HLA-DRB3*01:01 might be very useful in counseling women at risk of FNAIT due to anti-HPA-1a. PMID- 28019030 TI - Histone deacetylase inhibitors suppress ABO transcription in vitro, leading to reduced expression of the antigens. AB - BACKGROUND: The ABO system is of fundamental importance in the fields of transfusion and transplantation and has apparent associations with certain diseases, including cardiovascular disorders. ABO expression is reduced in the late phase of erythroid differentiation in vitro, whereas histone deacetylase inhibitors (HDACIs) are known to promote cell differentiation. Therefore, whether or not HDACIs could reduce the amount of ABO transcripts and A or B antigens is an intriguing issue. STUDY DESIGN AND METHODS: Quantitative polymerase chain reactions were carried out for the ABO transcripts in erythroid-lineage K562 and epithelial-lineage KATOIII cells after incubation with HDACIs, such as sodium butyrate, panobinostat, vorinostat, and sodium valproate. Flow cytometric analysis was conducted to evaluate the amounts of antigen in KATOIII cells treated with panobinostat. Quantitative chromatin immunoprecipitation (ChIP) assays and luciferase assays were performed on both cell types to examine the mechanisms of ABO suppression. RESULTS: HDACIs reduced the ABO transcripts in both K562 and KATOIII cells, with panobinostat exerting the most significant effect. Flow cytometric analysis demonstrated a decrease in B-antigen expression on panobinostat-treated KATOIII cells. ChIP assays indicated that panobinostat altered the modification of histones in the transcriptional regulatory regions of ABO, and luciferase assays demonstrated reduced activity of these elements. CONCLUSION: ABO transcription seems to be regulated by an epigenetic mechanism. Panobinostat appears to suppress ABO transcription, reducing the amount of antigens on the surface of cultured cells. PMID- 28019031 TI - Pathogen inactivation by riboflavin and ultraviolet light illumination accelerates the red blood cell storage lesion and promotes eryptosis. AB - BACKGROUND: Pathogen reduction treatment using riboflavin and ultraviolet light illumination (Mirasol) effectively reduces the risk of transfusion-transmitted infections. This treatment is currently licensed for only platelets and plasma products, while its application to whole blood (WB) to generate pathogen inactivated red blood cells (RBCs) is under development. RBC storage lesion, constituting numerous morphologic and biochemical changes, influences RBC quality and limits shelf life. Stored RBCs further show enhanced susceptibility to RBC programmed cell death (eryptosis) characterized by increased cytosolic Ca2+ provoked membrane phosphatidylserine (PS) externalization. STUDY DESIGN AND METHODS: Using a "pool-and-split" approach, we examined multiple variables of RBC storage lesion and eryptosis in RBC units, derived from Mirasol-treated or untreated WB, after 4 to 42 days of storage, under blood bank conditions. RESULTS: In comparison to untreated RBC units, Mirasol treatment significantly altered membrane microvesiculation, supernatant hemoglobin, osmotic fragility, and intracellular adenosine triphosphate levels but did not influence membrane CD47 expression and 2,3-diphosphoglycerate levels. Mirasol-treated RBCs showed significantly higher PS exposure after 42, but not after not more than 21, days of storage, which was accompanied by enhanced cytosolic Ca2+ activity, ceramide abundance, and oxidative stress, but not p38 kinase activation. Mirasol treatment significantly augmented PS exposure, Ca2+ entry, and protein kinase C activation after energy depletion, a pathophysiologic cell stressor. Mirasol-treated RBCs were, however, more resistant to cell shrinkage. CONCLUSIONS: Prolonged storage of Mirasol-treated RBCs significantly increases the proportion of eryptotic RBCs, while even short-term storage enhances the susceptibility of RBCs to stress induced eryptosis, which could reduce posttransfusion RBC recovery in patients. PMID- 28019032 TI - Severe cardiac iron toxicity in two adults with sickle cell disease. AB - BACKGROUND: Use of chronic blood transfusions as a treatment modality in patients with blood disorders places them at risk for iron overload. Since patients with beta-thalassemia major (TM) are transfusion-dependent, most studies on iron overload and chelation have been conducted in this population. While available data suggest that compared to TM, patients with sickle cell disease (SCD) have a lower risk of extrahepatic iron overload, significant iron overload can develop. Further, previous studies have demonstrated a direct relationship between iron overload and morbidity and mortality rates in SCD. However, reports describing the outcome for patients with SCD and cardiac iron overload are rare. STUDY DESIGN AND METHODS: We performed a retrospective analysis and identified two SCD patients with cardiac iron overload. We provide detailed descriptions of both cases and their outcomes. RESULTS: Serum ferritin levels ranged between 17,000 and 19,000 MUg/L. Both had liver iron concentrations in excess of 35 mg of iron per gram of dried tissue as well as evidence of cardiac iron deposition on magnetic resonance imaging. One patient died of an arrhythmia and had evidence of severe multiorgan iron overload via autopsy. On the other hand, after appropriate therapy, a second patient had improvement in cardiac function. CONCLUSION: Improper treatment of iron overload in SCD can lead to a fatal outcome. Alternatively, iron overload may potentially be prevented or reversed with judicious use of blood transfusions and early use of chelation therapy, respectively. PMID- 28019033 TI - Evidence for the hERG Liability of Antihistamines, Antipsychotics, and Anti Infective Agents: A Systematic Literature Review From the ARITMO Project. AB - A systematic review was performed to categorize the hERG (human ether-a-go-go related gene) liability of antihistamines, antipsychotics, and anti-infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half-minimal inhibitory concentrations (IC50). A "hERG safety margin" was calculated from the IC50 divided by the peak human plasma concentration (free Cmax ). A margin below 30 defined hERG liability. Each drug was assigned an "uncertainty score" based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty-one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti-infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/Cmax data, or other patient/drug-specific factors that contribute to real-life TdP risk. PMID- 28019034 TI - Inactivation of Zika virus by solvent/detergent treatment of human plasma and other plasma-derived products and pasteurization of human serum albumin. AB - BACKGROUND: In 2016 the World Health Organization declared the mosquito-borne Zika virus (ZIKV) a "public health emergency of international concern." ZIKV is a blood-borne pathogen, which therefore causes concerns regarding the safety of human plasma-derived products due to potential contamination of the blood supply. This study investigated the effectiveness of viral inactivation steps used during the routine manufacturing of various plasma-derived products to reduce ZIKV infectivity. STUDY DESIGN AND METHODS: Human plasma and intermediates from the production of various plasma-derived products were spiked with ZIKV and subjected to virus inactivation using the identical techniques (either solvent/detergent [S/D] treatment or pasteurization) and conditions used for the actual production of the respective products. Samples were taken and the viral loads measured before and after inactivation. RESULTS: After S/D treatment of spiked intermediates of the plasma-derived products Octaplas(LG), Octagam, and Octanate, the viral loads were below the limit of detection in all cases. The mean log reduction factor (LRF) was at least 6.78 log for Octaplas(LG), at least 7.00 log for Octagam, and at least 6.18 log for Octanate after 60, 240, and 480 minutes of S/D treatment, respectively. For 25% human serum albumin (HSA), the mean LRF for ZIKV was at least 7.48 log after pasteurization at 60 degrees C for 120 minutes. CONCLUSION: These results demonstrate that the commonly used virus inactivation processes utilized during the production of human plasma and plasma-derived products, namely, S/D treatment or pasteurization, are effective for inactivation of ZIKV. PMID- 28019035 TI - Estimating and eliminating the excitation errors in bipolar gradient composite excitations caused by radiofrequency-gradient delay: Example of bipolar spokes pulses in parallel transmission. AB - PURPOSE: To eliminate a slice-position-dependent excitation error commonly observed in bipolar-gradient composite excitations such as spokes pulses in parallel transmission. THEORY AND METHODS: An undesired timing delay between subpulses in the composite pulse and their bipolar slice-selective gradient is hypothesized to cause the error. A mathematical model is presented here to relate this mismatch to an induced slice-position-dependent phase difference between the subpulses. A new navigator method is proposed to measure the timing mismatch and eliminate the error. This is demonstrated at 7 Tesla with flip-angle maps measured by a presaturation turbo-flash sequence and in vivo images acquired by a simultaneous multislice/echo-planar imaging (SMS-EPI) sequence. RESULTS: Error free flip-angle maps were obtained in two ways: 1) by correcting the time delay directly and 2) by applying the corresponding slice-position-dependent phase differences to the subpulses. This confirms the validity of the mathematical description. The radiofrequency (RF)-gradient delay measured by the navigator method was of 6.3 MUs, which agreed well with the estimate from flip-angle maps at different delay times. By applying the timing correction, accurately excited EPI images were acquired with bipolar dual-spokes SMS-2 excitations. CONCLUSION: An effective correction is proposed to mitigate slice-position-dependent errors in bipolar composite excitations caused by undesired RF-gradient timing delays. Magn Reson Med 78:1883-1890, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28019036 TI - Utility of newly developed short-type double-balloon endoscopy for endoscopic retrograde cholangiography in postoperative patients. AB - BACKGROUND AND AIM: The utility of conventional short-type double-balloon endoscopy (DBE) for pancreatobiliary disease in patients with postoperative anatomy had been widely acknowledged and accepted. However, some technical difficulties yet remained. In an attempt to solve these problems, the new short type DBE (N-short DBE) was uniquely designed for therapeutic endoscopic retrograde cholangiography (ERC) in postoperative patients. The aim of this study was to evaluate the usefulness of N-short DBE for ERC in postoperative patients. METHODS: From August 2015 to April 2016, ERC using N-short DBE (DB-ERC) was performed in 100 postoperative patients (112 procedures). We retrospectively studied the success rate of reaching the blind end, the median time to reach the blind end, the diagnostic success rate, the therapeutic success rate, the median time to complete ERC-related interventions, the overall success rate, the median time to complete DB-ERC, and adverse events. RESULTS: The success rate of reaching the blind end was 99.1%. The median time to reach the blind end was 10 min (interquartile range [IQR], 6-19 min). The diagnostic success rate was 98.2%. The therapeutic success rate was 100%. The median time to complete ERC-related interventions was 36 min (IQR, 22-62 min). The overall DB-ERC success rate was 97.3%. The median time to complete DB-ERC was 54 min (IQR, 37-73 min). The occurrence of adverse events was 2.7%. CONCLUSIONS: The N-short DBE for ERC in postoperative patients is useful and safe. DB-ERC is promising therapeutic modality in such patients and should be selected as the first-line policy. PMID- 28019037 TI - Effect of Dexamethasone on Resting Blood Lactate Concentrations in Horses. AB - BACKGROUND: Blood lactate concentration is a marker of tissue perfusion and helps guide therapeutic interventions in critically ill horses. In both humans and dogs, administration of corticosteroids can increase blood lactate concentration, leading to type B hyperlactatemia. This effect could be a consequence of the impact of corticosteroids on glucose metabolism. OBJECTIVES: To investigate the effects of daily IM dexamethasone administration on blood lactate and glucose concentrations in horses. ANIMALS: Nine healthy adult horses. METHODS: A randomized, blinded, controlled, cross-over study design was used. Horses were randomly assigned to 1 of 2 groups, either receiving 0.05 mg/kg of dexamethasone IM or an equivalent volume of saline, daily for 7 days. Blood was collected to determine lactate and glucose concentrations at baseline, 2 hours after the daily injections and 24 hours after the last injection. RESULTS: Dexamethasone treatment had a statistically significant effect on lactate (P = .006) and glucose (P = .033) concentrations. The least squares mean lactate concentration was 0.93 mmol/L (95% CI: 0.87-0.99) in the dexamethasone group compared to 0.71 mmol/L (95% CI: 0.70-0.73) for the saline group. A positive relationship between blood lactate and glucose concentrations was identified, with a 0.07 mmol/L (95% CI: 0.05-0.09) increase in lactate concentration per unit increase in glucose (P < .0001) concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Dexamethasone induces statistically significant increases in blood lactate and glucose concentrations in healthy horses. Awareness of the potential for corticosteroids to induce type B hyperlactatemia might be important in the management of critically ill horses receiving dexamethasone. PMID- 28019038 TI - Proteinuria in Apparently Healthy Elderly Dogs: Persistency and Comparison Between Free Catch and Cystocentesis Urine. AB - BACKGROUND: Up to 25% of elderly humans have proteinuria, often associated with underlying lesions. Data concerning the presence of proteinuria in elderly dogs is scarce. OBJECTIVES: To describe the presence and persistence of proteinuria and to compare urinary protein : creatinine ratio (UPC) between free catch and cystocentesis urine samples in apparently healthy elderly dogs. ANIMALS: Hundred apparently healthy elderly dogs. METHODS: Prospective study. Owners of 100 elderly dogs were asked to collect 2 free catch urine samples. Dogs were considered healthy based on owner's perception and an age chart, based on ideal bodyweight, was used to define dogs as senior or geriatric. UPC of urine collected by free catch and cystocentesis were compared. Overt proteinuria and borderline proteinuria were defined as UPC >0.5 and between 0.2 and 0.5, respectively, if examination of sediment did not explain proteinuria. Proteinuria was considered persistent if present at both sampling times. RESULTS: At baseline, 71 owners succeeded in collecting urine. Eleven percent of dogs had overt proteinuria, 14% were borderline proteinuric, and 75% nonproteinuric. Thirty-seven repeated urine samples, with a median time interval of 31 days (range 10-90), were available. Nineteen percent of dogs had a persistently increased UPC (>0.2), with persistent overt proteinuria present in 8%. A strong correlation (rho = 0.88) was found between UPC of urine collected by free catch and cystocentesis. CONCLUSIONS AND CLINICAL IMPORTANCE: As 19% of study dogs had persistent proteinuria, our findings emphasize that measurement of proteinuria should be part of geriatric health screening. For UPC in dogs, free catch urine provides a good alternative to cystocentesis. PMID- 28019039 TI - Integration of gene expression and methylation to unravel biological networks in glioblastoma patients. AB - The vast amount of heterogeneous omics data, encompassing a broad range of biomolecular information, requires novel methods of analysis, including those that integrate the available levels of information. In this work, we describe Regression2Net, a computational approach that is able to integrate gene expression and genomic or methylation data in two steps. First, penalized regressions are used to build Expression-Expression (EEnet) and Expression Genomic or Expression-Methylation (EMnet) networks. Second, network theory is used to highlight important communities of genes. When applying our approach, Regression2Net to gene expression and methylation profiles for individuals with glioblastoma multiforme, we identified, respectively, 284 and 447 potentially interesting genes in relation to glioblastoma pathology. These genes showed at least one connection in the integrated networks ANDnet and XORnet derived from aforementioned EEnet and EMnet networks. Although the edges in ANDnet occur in both EEnet and EMnet, the edges in XORnet occur in EMnet but not in EEnet. In depth biological analysis of connected genes in ANDnet and XORnet revealed genes that are related to energy metabolism, cell cycle control (AATF), immune system response, and several cancer types. Importantly, we observed significant overrepresentation of cancer-related pathways including glioma, especially in the XORnet network, suggesting a nonignorable role of methylation in glioblastoma multiforma. In the ANDnet, we furthermore identified potential glioma suppressor genes ACCN3 and ACCN4 linked to the NBPF1 neuroblastoma breakpoint family, as well as numerous ABC transporter genes (ABCA1, ABCB1) suggesting drug resistance of glioblastoma tumors. PMID- 28019040 TI - A small-sample multivariate kernel machine test for microbiome association studies. AB - High-throughput sequencing technologies have enabled large-scale studies of the role of the human microbiome in health conditions and diseases. Microbial community level association test, as a critical step to establish the connection between overall microbiome composition and an outcome of interest, has now been routinely performed in many studies. However, current microbiome association tests all focus on a single outcome. It has become increasingly common for a microbiome study to collect multiple, possibly related, outcomes to maximize the power of discovery. As these outcomes may share common mechanisms, jointly analyzing these outcomes can amplify the association signal and improve statistical power to detect potential associations. We propose the multivariate microbiome regression-based kernel association test (MMiRKAT) for testing association between multiple continuous outcomes and overall microbiome composition, where the kernel used in MMiRKAT is based on Bray-Curtis or UniFrac distance. MMiRKAT directly regresses all outcomes on the microbiome profiles via a semiparametric kernel machine regression framework, which allows for covariate adjustment and evaluates the association via a variance-component score test. Because most of the current microbiome studies have small sample sizes, a novel small-sample correction procedure is implemented in MMiRKAT to correct for the conservativeness of the association test when the sample size is small or moderate. The proposed method is assessed via simulation studies and an application to a real data set examining the association between host gene expression and mucosal microbiome composition. We demonstrate that MMiRKAT is more powerful than large sample based multivariate kernel association test, while controlling the type I error. A free implementation of MMiRKAT in R language is available at http://research.fhcrc.org/wu/en.html. PMID- 28019041 TI - Interindividual differences in the dynamics of the homeostatic process are trait like and distinct for sleep versus wakefulness. AB - The sleep homeostatic Process S reflects the build-up of sleep pressure during waking and its dissipation during sleep. Process S is modelled as a saturating exponential function during waking and a decreasing exponential function during sleep. Slow wave activity is a physiological marker for non-rapid eye movement (non-REM) sleep intensity and serves as an index of Process S. There is considerable interindividual variability in the sleep homeostatic responses to sleep and sleep deprivation. The aim of this study was to investigate whether interindividual differences in Process S are trait-like. Polysomnographic recordings of 8 nights (12-h sleep opportunities, 22:00-10:00 hours) interspersed with three 36-h periods of sustained wakefulness were performed in 11 healthy young adults. Empirical mean slow wave activity per non-REM sleep episode at episode mid-points were used for parameter estimation. Parameters of Process S were estimated using different combinations of consecutive sleep recordings, resulting in two to three sets of parameters per subject. Intraclass correlation coefficients were calculated to assess whether the parameters were stable across the study protocol and they showed trait-like variability among individuals. We found that the group-average time constants of the build-up and dissipation of Process S were 19.2 and 2.7 h, respectively. Intraclass correlation coefficients ranged from 0.48 to 0.56, which reflects moderate trait variability. The time constants of the build-up and dissipation varied independently among subjects, indicating two distinct traits. We conclude that interindividual differences in the parameters of the dynamics of the sleep homeostatic Process S are trait-like. PMID- 28019042 TI - Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios. AB - Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, affecting 1 in 700 live births. This malformation has a complex etiology where multiple genes and several environmental factors influence risk. At least a dozen different genes have been confirmed to be associated with risk of NSCL/P in previous studies. However, all the known genetic risk factors cannot fully explain the observed heritability of NSCL/P, and several authors have suggested gene-gene (G * G) interaction may be important in the etiology of this complex and heterogeneous malformation. We tested for G * G interactions using common single nucleotide polymorphic (SNP) markers from targeted sequencing in 13 regions identified by previous studies spanning 6.3 Mb of the genome in a study of 1,498 NSCL/P case-parent trios. We used the R-package trio to assess interactions between polymorphic markers in different genes, using a 1 degree of freedom (1df) test for screening, and a 4 degree of freedom (4df) test to assess statistical significance of epistatic interactions. To adjust for multiple comparisons, we performed permutation tests. The most significant interaction was observed between rs6029315 in MAFB and rs6681355 in IRF6 (4df P = 3.8 * 10-8 ) in case-parent trios of European ancestry, which remained significant after correcting for multiple comparisons. However, no significant interaction was detected in trios of Asian ancestry. PMID- 28019043 TI - Genomic and phenotypic evidence for an incomplete domestication of South American grain amaranth (Amaranthus caudatus). AB - The domestication syndrome comprises phenotypic changes that differentiate crops from their wild ancestors. We compared the genomic variation and phenotypic differentiation of the two putative domestication traits seed size and seed colour of the grain amaranth Amaranthus caudatus, which is an ancient crop of South America, and its two close wild relatives and putative ancestors A. hybridus and A. quitensis. Genotyping 119 accessions of the three species from the Andean region using genotyping by sequencing (GBS) resulted in 9485 SNPs that revealed a strong genetic differentiation of cultivated A. caudatus from its two relatives. A. quitensis and A. hybridus accessions did not cluster by their species assignment but formed mixed groups according to their geographic origin in Ecuador and Peru, respectively. A. caudatus had a higher genetic diversity than its close relatives and shared a high proportion of polymorphisms with their wild relatives consistent with the absence of a strong bottleneck or a high level of recent gene flow. Genome sizes and seed sizes were not significantly different between A. caudatus and its relatives, although a genetically distinct group of A. caudatus from Bolivia had significantly larger seeds. We conclude that despite a long history of human cultivation and selection for white grain colour, A. caudatus shows a weak genomic and phenotypic domestication syndrome and proposes that it is an incompletely domesticated crop species either because of weak selection or high levels of gene flow from its sympatric close undomesticated relatives that counteracted the fixation of key domestication traits. PMID- 28019044 TI - Severity of Nasal Inflammatory Disease Questionnaire for Canine Idiopathic Rhinitis Control: Instrument Development and Initial Validity Evidence. AB - BACKGROUND: Effective treatments are needed for idiopathic chronic rhinitis in dogs, but assessment of efficacy requires a practical, quantifiable method for assessing severity of disease. OBJECTIVES: To develop and perform initial validity and reliability testing of an owner-completed questionnaire for assessing clinical signs and dog and owner quality of life (QOL) in canine chronic rhinitis. ANIMALS: Twenty-two dogs with histopathologically confirmed chronic rhinitis and 72 healthy dogs. METHODS: In this prospective study, an online questionnaire was created based on literature review and feedback from veterinarians, veterinary internists with respiratory expertise, and owners of dogs with rhinitis. Owners of affected dogs completed the questionnaire twice, 1 week apart, to test reliability. Healthy dogs were assessed once. Data were analyzed using the Rasch Rating Scale Model, and results were interpreted using Messick's framework for evaluating construct validity evidence. RESULTS: Initial item generation resulted in 5 domains: nasal signs, paranasal signs, global rhinitis severity, and dog's and owner's QOL. A 25-item questionnaire was developed using 5-point Likert-type scales. No respondent found the questionnaire difficult to complete. Strong psychometric evidence was available to support the substantive, generalizability, content, and structural aspects of construct validity. Statistical differences were found between responses for affected and control dogs for all but 2 items. These items were eliminated, resulting in the 23-item Severity of Nasal Inflammatory Disease (SNIFLD) questionnaire. CONCLUSIONS AND CLINICAL IMPORTANCE: The SNIFLD questionnaire provides a mechanism for repeated assessments of disease severity in dogs with chronic rhinitis. PMID- 28019045 TI - Autonomic Modulation for the Treatment of Ventricular Arrhythmias: Therapeutic Use of Percutaneous Stellate Ganglion Blocks. AB - Ventricular tachycardia (VT), ventricular fibrillation (VF), and electrical storm are commonly encountered emergency conditions in cardiac and surgical intensive care units. In most cases, recurrent ventricular arrhythmias or electrical storm are associated with a heightened sympathetic tone. These arrhythmias can be difficult to treat and may be refractory to beta-blockade, antiarrhythmic therapy, sedation, and mechanical hemodynamic support. While monomorphic ventricular tachycardia and PVC-triggered polymorphic ventricular tachycardia may sometimes be amenable to successful ablation, some patients may be too critically ill to make such an approach feasible. We present 2 cases of minimally invasive stellate ganglion blocks for the treatment of electrical storm in patients with advanced heart failure on mechanical life support. These cases are part of a collaborative initiative at our institution to use percutaneous stellate ganglion block as an adjunctive intervention to achieve control of life-threatening ventricular arrhythmias. PMID- 28019046 TI - Evaluation of neonatal brain myelination using the T1- and T2-weighted MRI ratio. AB - PURPOSE: To validate the T1- and T2-weighted (T1w/T2w) MRI ratio technique in evaluating myelin in the neonatal brain. MATERIALS AND METHODS: T1w and T2w MR images of 10 term neonates with normal-appearing brain parenchyma were obtained from a single 1.5 Tesla MRI and retrospectively analyzed. T1w/T2w ratio images were created with a postprocessing pipeline and qualitatively compared with standard clinical sequences (T1w, T2w, and apparent diffusion coefficient [ADC]). Quantitative assessment was also performed to assess the ratio technique in detecting areas of known myelination (e.g., posterior limb of the internal capsule) and very low myelination (e.g., optic radiations) using linear regression analysis and the Michelson Contrast equation, a measure of luminance contrast intensity. RESULTS: The ratio image provided qualitative improvements in the ability to visualize regional variation in myelin content of neonates. Linear regression analysis demonstrated a significant inverse relationship between the ratio intensity values and ADC values in the posterior limb of the internal capsule and the optic radiations (R2 = 0.96 and P < 0.001). The Michelson Contrast equation showed that contrast differences between these two regions for the ratio images were 1.6 times higher than T1w, 2.6 times higher than T2w, and 1.8 times higher than ADC (all P < 0.001). Finally, the ratio improved visualization of the corticospinal tract, one of the earliest myelinated pathways. CONCLUSION: The T1w/T2w ratio accentuates contrast between myelinated and less myelinated structures and may enhance our diagnostic ability to detect myelination patterns in the neonatal brain. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage2 J. MAGN. RESON. IMAGING 2017;46:690-696. PMID- 28019047 TI - Neutrophil Gelatinase-Associated Lipocalin in Cats with Naturally Occurring Chronic Kidney Disease. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for the early prediction of renal damage and the progression of chronic kidney disease (CKD) in humans and dogs. HYPOTHESIS: Neutrophil gelatinase-associated lipocalin also may play a role in the progression of CKD in cats. ANIMALS: Eighty CKD and 18 control cats. METHODS: Cats were categorized into different stages according to the International Renal Interest Society (IRIS) staging system. Urine and plasma samples were collected and tested for NGAL concentrations using an in-house sandwich ELISA system and urinary NGAL (uNGAL)-to-creatinine ratio (UNCR) was determined. Cats in which serum creatinine concentration increased by >0.5 mg/dL from baseline within 30 days were defined as exhibiting progression. RESULTS: The urinary NGAL and UNCR of CKD cats were significantly higher than those of healthy cats (P < .05) and were highly correlated with serum creatinine concentration. The area under the receiver operating characteristic curve (AUROC) for uNGAL, when predicting the progression of CKD, was 0.71 and the best cutoff value was 2.06 ng/mL with a sensitivity of 76.9% and a specificity of 75%. The AUROC for UNCR when predicting the progression of CKD was 0.79 and the best cutoff value was 4.08 * 10-6 with a sensitivity of 76.9% and specificity of 79.2%. Cats with UNCR values higher than their cutoffs experienced significantly faster deterioration with a median of 19 days. CONCLUSIONS: Both urinary NGAL and UNCR are useful markers for the prediction of CKD progression in cats. PMID- 28019048 TI - Temporal and spatial changes in gene expression, metabolite accumulation and phytohormone content in rice seedlings grown under drought stress conditions. AB - In order to analyze the molecular mechanisms underlying the responses of plants to different levels of drought stress, we developed a soil matric potential (SMP) based irrigation system that precisely controls soil moisture. Using this system, rice seedlings were grown under three different drought levels, denoted Md1, Md2 and Md3, with SMP values set to -9.8, -31.0 and -309.9 kPa, respectively. Although the Md1 treatment did not alter the visible phenotype, the Md2 treatment caused stomatal closure and shoot growth retardation (SGR). The Md3 treatment markedly induced SGR, without inhibition of photosynthesis. More severe drought (Sds) treatment, under which irrigation was terminated, resulted in the wilting of leaves and inhibition of photosynthesis. Metabolome analysis revealed the accumulation of primary sugars under Md3 and Sds and of most amino acids under Sds. The starch content was increased under Md3 and decreased under Sds. Transcriptome data showed that the expression profiles of associated genes supported the observed changes in photosynthesis and metabolites, suggesting that the time lag from SGR to inhibition of photosynthesis might lead to the accumulation of photosynthates under Md3, which can be used as osmolytes under Sds. To gain further insight into the observed SGR, transcriptome and hormonome analyses were performed in specific tissues. The results showed specific decreases in indole-3-acetic acid (IAA) and cytokinin levels in Md2-, Md3- and Sds-treated shoot bases, though the expression levels of hormone metabolism related genes were not reflected in IAA and cytokinin contents. These observations suggest that drought stress affects the distribution or degradation of cytokinin and IAA molecules. PMID- 28019049 TI - Facial phenotype in obstructive sleep apnea-hypopnea syndrome: a systematic review and meta-analysis. AB - This systematic review and meta-analysis explores the association between facial phenotype and obstructive sleep apnea-hypopnea syndrome in adults. A comprehensive electronic (Medline via Ovid, Scopus, and Embase) database and reference search were undertaken in relation to imaging modalities for surface craniofacial assessments in subjects with sleep apnea. The outcome measures were surface facial dimensions, morphology and profile. The quality of studies was assessed and a meta-analysis conducted. The studies were weighted using the inverse variance method, and the random effects model was used to analyse data. This systematic review identified eight case-control studies. In five studies (906 participants), adults with sleep apnea showed increased weighted mean differences in neck circumference by 1.26 mm (P = 0.0001) with extensive heterogeneity between studies (I2 = 93%). Only two studies (467 participants) shared the following outcomes: mandible length, lower facial height, mandible width and anterior mandible height parameters. The pooled results demonstrated obstructive sleep apnea syndrome was associated with larger parameters than controls. In conclusion, the surface facial assessment was able to demonstrate some characteristic morphological features, facilitating a meta-analysis, in adults with obstructive sleep apnea-hypopnea syndrome. The strength of these findings, however, was limited by the heterogeneity of the studies precluding the identification of a clear phenotype. PMID- 28019050 TI - Electrocardiographic left ventricular hypertrophy predicts atrial fibrillation independent of left ventricular mass. AB - BACKGROUND: Although left ventricular hypertrophy (LVH) detected by electrocardiography (ECG-LVH) and echocardiography (echo-LVH) independently predict cardiovascular disease events, it is unclear if ECG-LVH and echo-LVH independently predict atrial fibrillation (AF). METHODS: This analysis included 4,904 participants (40% male; 85% white) from the Cardiovascular Health Study who were free of baseline AF and major intraventricular conduction delays. ECG-LVH was defined by Minnesota Code Classification from baseline ECG data. Echo-LVH was defined by sex-specific left ventricular mass values >95th sex-specific percentiles. Incident AF events were identified during the annual study ECGs and from hospitalization discharge data. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association of ECG-LVH and echo-LVH with incident AF, separately. RESULTS: ECG-LVH was detected in 224 (4.6%) participants and echo-LVH was present in 231 (4.7%) participants. Over a median follow-up of 11.9 years, a total of 1,430 AF events were detected. In a multivariable Cox model adjusted for age, sex, race, education, income, smoking, systolic blood pressure, diabetes, body mass index, total cholesterol, high density lipoprotein cholesterol, aspirin, antihypertensive medications, and cardiovascular disease, ECG-LVH (HR = 1.50; 95% CI = 1.18, 1.90) and echo-LVH (HR = 1.39; 95% CI = 1.09, 1.78) were independently associated with AF. When ECG-LVH (HR = 1.47, 95% CI = 1.16, 1.87) and echo-LVH (HR = 1.36, 1.07, 1.75) were included in the same model, both were predictive of incident AF. CONCLUSION: The association of ECG-LVH with AF is not dependent on left ventricular mass detected by echocardiography, suggesting that abnormalities in cardiac electrophysiology provide a distinct profile in the prediction of AF. PMID- 28019052 TI - Increased pollinator habitat enhances cacao fruit set and predator conservation. AB - The unique benefits of wild pollinators to the productivity of agricultural crops have become increasingly recognized in recent decades. However, declines in populations of wild pollinator species, largely driven by the conversion of natural habitat to agricultural land and broad-spectrum pesticide use often lead reductions in the provision of pollination services and crop production. With growing evidence that targeted pollinator conservation improves crop yield and/or quality, particularly for pollination specialist crops, efforts are increasing to substitute agriculturally intensive practices with those that alleviate some of the negative impacts of agriculture on pollinators and the pollination services they provide, in part through the provision of suitable pollinator habitat. Further, similarities between the responses of some pollinators and predators to habitat management suggest that efforts to conserve pollinators may also encourage predator densities. We evaluated the effects of one habitat management practice, the addition of cacao fruit husks to a monoculture cacao farm, on the provision of pollination services and the densities of two groups of entomophagous predators. We also evaluated the impacts of cacao fruit husk addition on pollen limitation, by crossing this habitat manipulation with pollen supplementation treatments. The addition of cacao fruit husks increased the number of fruits per tree and along with hand pollination treatments, increased final yields indicating a promotion of the pollination ecosystem service provided by the specialist pollinators, midges. We also found that cacao fruit husk addition increased the densities of two predator groups, spiders and skinks. Further, the conservation of these predators did not inhibit pollination through pollinator capture or deterrence. The findings show that, with moderate habitat management, both pollinator and predator conservation can be compatible goals within a highly specialized plant-pollinator system. The effectiveness of this habitat manipulation may be attributable to the increased availability of alternative habitat and food resources for both pollinators and predators. The results exemplify a win-win relationship between agricultural production and biological conservation, whereby agricultural practices to support vital pollinators and pollination services can increase production as well as support species conservation. PMID- 28019051 TI - REmote SUpervision to Decrease HospitaLization RaTe. Unified and integrated platform for data collected from devices manufactured by different companies: Design and rationale of the RESULT study. AB - The number of patients with heart failure implantable cardiac electronic devices (CIEDs) is growing. Hospitalization rate in this group is very high and generates enormous costs. To avoid the need for hospital treatment, optimized monitoring and follow-up is crucial. Remote monitoring (RM) has been widely put into practice in the management of CIEDs but it may be difficult due to the presence of differences in systems provided by device manufacturers and loss of gathered data in case of device reimplantation. Additionally, conclusions derived from studies about usefulness of RM in clinical practice apply to devices coming only from a single company. An integrated monitoring platform allows for more comprehensive data analysis and interpretation. Therefore, the primary objective of Remote Supervision to Decrease Hospitalization Rate (RESULT) study is to evaluate the impact of RM on the clinical status of patients with ICDs or CRT-Ds using an integrated platform. Six hundred consecutive patients with ICDs or CRT Ds implanted will be prospectively randomized to either a traditional or RM-based follow-up model. The primary clinical endpoint will be a composite of all-cause mortality or hospitalization for cardiovascular reasons within 12 months after randomization. The primary technical endpoint will be to construct and evaluate a unified and integrated platform for the data collected from RM devices manufactured by different companies. This manuscript describes the design and methodology of the prospective, randomized trial designed to determine whether remote monitoring using an integrated platform for different companies is safe, feasible, and efficacious (ClinicalTrials.gov Identifier: NCT02409225). PMID- 28019053 TI - Prestructural cartilage assessment using MRI. AB - : Cartilage loss is irreversible, and to date, no effective pharmacotherapies are available to protect or regenerate cartilage. Quantitative prestructural/compositional MR imaging techniques have been developed to characterize the cartilage matrix quality at a stage where abnormal findings are early and potentially reversible, allowing intervention to halt disease progression. The goal of this article is to critically review currently available technologies, present the basic concept behind these techniques, but also to investigate their suitability as imaging biomarkers including their validity, reproducibility, risk prediction and monitoring of therapy. Moreover, we highlighted important clinical applications. This review article focuses on the currently most relevant and clinically applicable technologies, such as T2 mapping, T2*, T1rho, delayed gadolinium enhanced MRI of cartilage (dGEMRIC), sodium imaging and glycosaminoglycan chemical exchange saturation transfer (gagCEST). To date, most information is available for T2 and T1rho mapping. dGEMRIC has also been used in multiple clinical studies, although it requires Gd contrast administration. Sodium imaging and gagCEST are promising technologies but are dependent on high field strength and sophisticated software and hardware. LEVEL OF EVIDENCE: 5 J. Magn. Reson. Imaging 2017;45:949-965. PMID- 28019054 TI - Interatrial block and interatrial septal thickness in patients with paroxysmal atrial fibrillation undergoing catheter ablation: Long-term follow-up study. AB - BACKGROUND: Interatrial block (IAB) is a strong predictor of recurrence of atrial fibrillation (AF). IAB is a conduction delay through the Bachman region, which is located in the upper region of the interatrial space. During IAB, the impulse travels from the right atrium to the interatrial septum (IAS) and coronary sinus to finally reach the left atrium in a caudocranial direction. No relation between the presence of IAB and IAS thickness has been established yet. OBJECTIVE: To determine whether a correlation exists between the degree of IAB and the thickness of the IAS and to determine whether IAS thickness predicts AF recurrence. METHODS: Sixty-two patients with diagnosis of paroxysmal AF undergoing catheter ablation were enrolled. IAB was defined as P-wave duration >=120 ms. IAS thickness was measured by cardiac computed tomography. RESULTS: Among 62 patients with paroxysmal AF, 45 patients (72%) were diagnosed with IAB. Advanced IAB was diagnosed in 24 patients (39%). Forty-seven patients were male. During a mean follow-up period of 49.8 +/- 22 months (range 12-60 months), 32 patients (51%) developed AF recurrence. IAS thickness was similar in patients with and without IAB (4.5 +/- 2.0 mm vs. 4.0 +/- 1.4 mm; p = .45) and did not predict AF. Left atrial size was significantly enlarged in patients with IAB (40.9 +/- 5.7 mm vs. 37.2 +/- 4.0 mm; p = .03). Advanced IAB predicted AF recurrence after the ablation (OR: 3.34, CI: 1.12-9.93; p = .03). CONCLUSIONS: IAS thickness was not significantly correlated to IAB and did not predict AF recurrence. IAB as previously demonstrated was an independent predictor of AF recurrence. PMID- 28019055 TI - Quality of life in patients with an idiopathic rapid eye movement sleep behaviour disorder in Korea. AB - There have been few quality of life studies in patients with idiopathic rapid eye movement sleep behaviour disorder. We compared the quality of life in idiopathic rapid eye movement sleep behaviour disorder patients to healthy controls, patients with hypertension, type 2 diabetes mellitus without complication and idiopathic restless legs syndrome. Sixty patients with idiopathic rapid eye movement sleep behaviour disorder (24 female; mean age: 61.43 +/- 8.99) were enrolled retrospectively. The diagnosis was established based on sleep history, overnight polysomnography, neurological examination and Mini-Mental State Examination to exclude secondary rapid eye movement sleep behavior disorder. All subjects completed questionnaires, including the Short Form 36-item Health Survey for quality of life. The total quality of life score in idiopathic rapid eye movement sleep behaviour disorder (70.63 +/- 20.83) was lower than in the healthy control group (83.38 +/- 7.96) but higher than in the hypertension (60.55 +/- 24.82), diabetes mellitus (62.42 +/- 19.37) and restless legs syndrome (61.77 +/- 19.25) groups. The total score of idiopathic rapid eye movement sleep behaviour disorder patients had a negative correlation with the Pittsburg Sleep Quality Index (r = -0.498, P < 0.001), Insomnia Severity Index (r = -0.645, P < 0.001) and the Beck Depression Inventory-2 (r = -0.694, P < 0.001). Multiple regression showed a negative correlation between the Short Form 36-item Health Survey score and the Insomnia Severity Index (beta = -1.100, P = 0.001) and Beck Depression Inventory-2 (beta = -1.038, P < 0.001). idiopathic rapid eye movement sleep behaviour disorder had a significant negative impact on quality of life, although this effect was less than that of other chronic disorders. This negative effect might be related to a depressive mood associated with the disease. PMID- 28019056 TI - The influence of collagen membrane and autogenous bone chips on bone augmentation in the anterior maxilla: a preclinical study. AB - OBJECTIVES: To evaluate the effect of a resorbable collagen membrane and autogenous bone chips combined with deproteinized bovine bone mineral (DBBM) on the healing of buccal dehiscence-type defects. MATERIAL AND METHODS: The second incisors and the first premolars were extracted in the maxilla of eight mongrels. Reduced diameter, bone-level implants were placed 5 weeks later. Standardized buccal dehiscence-type defects were created and grafted at implant surgery. According to an allocation algorithm, the graft composition of each of the four maxillary sites was DBBM + membrane (group D + M), autogenous bone chips + DBBM + membrane (group A + D + M), DBBM alone (group D) or autogenous bone chips + DBBM (group A + D). Four animals were sacrificed after 3 weeks of healing and four animals after 12 weeks. Histological and histomorphometric analyses were performed on oro-facial sections. RESULTS: The pattern of bone formation and resorption within the grafted area showed high variability among the same group and healing time. The histomorphometric analysis of the 3-week specimens showed a positive effect of autogenous bone chips on both implant osseointegration and bone formation into the grafted region (P < 0.05). The presence of the collagen membrane correlated with greater bone formation around the DBBM particles and greater bone formation in the grafted region after 12 weeks of healing (P < 0.05). The oro-facial width of the augmented region at the level of the implant shoulder was significantly reduced in cases where damage of the protection splints occurred in the first week of healing (P < 0.05). CONCLUSIONS: The addition of autogenous bone chips and the presence of the collagen membrane increased bone formation around DBBM particles. Wound protection from mechanical noxa during early healing may be critical for bone formation within the grafted area. PMID- 28019057 TI - A General Nickel-Catalyzed Method for C-H Bond Alkynylation of Heteroarenes Through Chelation Assistance. AB - A general nickel-catalyzed method for the alkynylation of heteroarenes through monodentate chelation assistance is described. Many heterocycles, including indoles, pyrroles, imidazoles, and pyrazole, efficiently coupled with (triisopropylsilyl)alkynyl bromide, and synthetically important functional groups, such as halides, ether, nitrile, and nitro, are tolerated. Synthetic applicability of this Ni-catalyzed method is demonstrated by the removal of the triisopropylsilyl group and further functionalization to triazolyl, benzofuranyl, and alkynyl arene derivatives. Preliminary mechanistic investigations of the alkynylation of indole suggest that the reaction proceeds through kinetically relevant C-H activation and follows a two-electron redox pathway. A catalytically relevant Ni species, namely, [(Phen)3 Ni]NiBr4 (PheN=1,10-phenanthroline), was isolated and structurally characterized. PMID- 28019058 TI - Cross-conjugated Trienamine Catalysis with alpha'-Alkylidene 2-Cyclohexenones: Application in beta,gamma-Regioselective Aza-Diels-Alder Reaction. AB - Endo-type cross-conjugated trienamines between highly congested alpha'-alkylidene 2-cyclohexenones and a chiral primary amine catalyst serve as HOMO-raised dienophiles in inverse-electron-demand aza-Diels-Alder cycloadditions with a number of 1-azadiene substrates. The reactions exhibit exclusive beta,gamma regioselectivity, and multifunctional products with high molecular complexity are efficiently constructed in excellent diastereo- and enantioselectivity (>19:1 d.r., up to 99 % ee). PMID- 28019060 TI - Development of a simple predictive model for decreased skeletal muscle mass in patients with compensated chronic liver disease. AB - AIM: To develop and validate a simple predictive model using easily obtained clinical parameters to predict decreased skeletal muscle mass (DSMM) in chronic liver disease (CLD) patients (n = 652). METHODS: Study subjects were divided into a training set (n = 326) and a validation set (n = 326). Decreased skeletal muscle mass was diagnosed based on skeletal muscle mass index measured by bioimpedance analysis. Variables significantly associated with DSMM were identified using univariate and multivariate analyses in the training set and used to construct a predictive formula. Receiver operating characteristic (ROC) curve analysis was carried out and the predictive model was validated in the validation set. Subgroup analyses were undertaken based on gender, age, or cirrhosis status of patients. RESULTS: Body mass index (BMI), age, serum albumin, and branched-chain amino acid to tyrosine ratio (BTR) were determined to be significant predictive factors for DSMM. A composite formula "BALB score" was constructed [-7.740 + (0.539 * BMI) + (-0.112 * age) + (1.358 * albumin) + ( 0.264 * BTR)]. The BALB score had the best predictive characteristics among all variables in both population sets (area under the ROC curve, 0.877-0.898). Patients with DSMM were stratified into three BALB score categories (>4, 0-4, and <0). Subgroup analyses also showed that BALB scoring was predictive of DSMM irrespective of gender, age, or cirrhosis status. The BALB score significantly correlated with psoas muscle index on computed tomography (rs = 0.6083 for men; rs = 0.6814 for women). CONCLUSION: The BALB scoring system based on routinely used clinical parameters offers a convenient and non-invasive method for predicting DSMM in compensated CLD patients with high accuracy. PMID- 28019059 TI - Impact of genotyping errors on statistical power of association tests in genomic analyses: A case study. AB - A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available. In this article, we investigate the impact of variant calling errors on the statistical power to identify associations between single nucleotides and disease, and on associations between multiple rare variants and disease. Both differential and nondifferential genotyping errors are considered. Our results show that the power of burden tests for rare variants is strongly influenced by the specificity in variant calling, but is rather robust with regard to sensitivity. By using the variant calling accuracies estimated from a substudy of a Cooperative Studies Program project conducted by the Department of Veterans Affairs, we show that the power of association tests is mostly retained with commonly adopted variant calling pipelines. An R package, GWAS.PC, is provided to accommodate power analysis that takes account of genotyping errors (http://zhaocenter.org/software/). PMID- 28019061 TI - Students' perceptions of a blended learning experience in dental education. AB - INTRODUCTION: "Flipped" instructional sequencing is a new instructional method where online instruction precedes the group meeting, allowing for more sophisticated learning through discussion and critical thinking during the in person class session; a novel approach studied in this research. PURPOSE: The purpose of this study was to document dental students' perceptions of flipped based blended learning and to apply a new method of displaying their perceptions based on Likert-scale data analysis using a network diagramming method known as an item correlation network diagram (ICND). In addition, this article aimed to encourage institutions or course directors to consider self-regulated learning and social constructivism as a theoretical framework when blended learning is incorporated in dental curricula. MATERIALS AND METHODS: Twenty (second year) dental students at a Northeastern Regional Dental School in the United States participated in this study. A Likert scale was administered before and after the learning experience to obtain evidence of their perceptions of its quality and educational merits. Item correlation network diagrams, based on the intercorrelations amongst the responses to the Likert-scale items, were constructed to display students' changes in perceptions before and after the learning experience. RESULTS: Students reported positive perceptions of the blended learning, and the ICND analysis of their responses before and after the learning experience provided insights into their social (group-based) cognition about the learning experience. The ICNDs are considered evidence of social or group-based cognition, because they are constructed from evidence obtained using intercorrelations of the total group responses to the Likert-scale items. CONCLUSIONS: The students positively received blended learning in dental education, and the ICND analyses demonstrated marked changes in their social cognition of the learning experience based on the pre- and post-Likert survey data. Self-regulated learning and social constructivism are encouraged as useful theoretical frameworks for a blended learning approach. PMID- 28019062 TI - Complete resolution of trichodysplasia spinulosa in a pediatric renal transplant patient: Case report and literature review. AB - TS of immunosuppression is a rare, disfiguring dermatologic condition caused by TS-associated polyomavirus in immunosuppressed patients. It is difficult to treat, with no clearly described approach to resolve the condition completely and safely. We report a child with a renal transplant who developed TS and was treated with significant reduction in immunosuppression and transient use of cidofovir cream. The combined approach, primarily with significant long-term reduction in immunosuppression guided by monitoring BK viremia in our patient, led to complete resolution of TS without recurrence or graft rejection by 5 years after transplant. This outcome was superior to all other reports of TS in children after transplantation. Closely monitoring for BK viremia, as a surrogate marker of over-immunosuppression, can guide adjustment in immunosuppressant medication to treat polyomavirus disease without developing the complication of graft rejection in a patient at significant risk. PMID- 28019063 TI - Interaction of transgenic and natural insect resistance mechanisms against Spodoptera littoralis in cotton. AB - BACKGROUND: Insect-resistant transgenic plants that express insecticidal Cry proteins from Bacillus thuringiensis (Bt) are grown on millions of hectares worldwide. While these proteins are efficient in controlling key lepidopteran pests, not all pests are affected and the development of resistance in target pests is always a concern. These shortcomings could be addressed by exploiting the natural insect resistance of cotton, especially inducible terpenoids such as gossypol. RESULTS: To assess the potential of gossypol in supplementing Cry proteins as a resistance trait, we conducted a range of feeding assays with Spodoptera littoralis using artificial diet with defined amounts of Cry proteins and gossypol. This was supplemented by assays with leaf discs of induced and uninduced non-Bt and Bt cotton (expressing Cry1Ac and Cry2Ab). Additionally, we quantified Cry proteins and cotton terpenoids to describe the interactions in planta. We found that gossypol can increase the efficacy of Cry proteins in artificial diet in an additive way. Induced production of gossypol and other cotton terpenoids, however, did not increase the efficacy of Bt cotton owing to the strong impact of the Bt trait. CONCLUSION: Cotton terpenoids may offer the chance to supplement the insect resistance of Bt cotton in cases were the pest is not strongly affected by the Cry proteins. (c) 2016 Society of Chemical Industry. PMID- 28019064 TI - Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus. AB - Liver-related diseases are the leading causes of death in patients with type 2 diabetes mellitus (T2DM) in Japan. Type 2 diabetes mellitus is closely associated with non-alcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma and hepatic failure. Non alcoholic steatohepatitis can be called "diabetic hepatopathy". There are no established pharmacotherapies for NAFLD/NASH patients with T2DM. Although metformin is established as the first-line therapy for T2DM, given its relative safety and beneficial effects on glycosylated hemoglobin, weight, and cardiovascular mortality, this agent is not recommended as specific therapy for NASH/NAFLD due to lack of clinical evidence. The effects of pioglitazone on NASH histology with T2DM have been extensively proved, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. In recent years, novel antidiabetic medications have been approved for T2DM, such as glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium/glucose cotransporter 2 inhibitors. A key clinical question for hepatologists is what kinds of antidiabetic medications are the most appropriate for the treatment of NAFLD accompanied by T2DM, to prevent progression of hepatic fibrosis resulting in HCC/liver-related mortality without increased risk of cardiovascular events. This review focuses on novel antidiabetic agents and future perspectives on the treatment of NAFLD/NASH with T2DM. PMID- 28019065 TI - Pregnancy outcomes in women with mechanical prosthetic heart valves: a prospective descriptive population based study using the United Kingdom Obstetric Surveillance System (UKOSS) data collection system. AB - OBJECTIVE: To describe the incidence of mechanical prosthetic heart valves (MPHV) in pregnancy in the UK; rates of maternal and fetal complications in this group of women, and whether these vary with the anticoagulation used during pregnancy. DESIGN: Prospective descriptive population-based study. SETTING: All consultant led maternity units in the UK. POPULATION: All women with an MPHV who were pregnant between 1 February 2013 and 31 January 2015. METHODS: Collection and analysis of anonymous data relating to pregnancy management and outcome, using the UKOSS notification and data collection system. MAIN OUTCOME MEASURES: Maternal death, serious maternal morbidity, poor fetal outcome. RESULTS: Data were obtained for 58 women giving an estimated incidence of 3.7 (95% CI 2.7-4.7) per 100 000 maternities. There were five maternal deaths (9%); a further 24 (41%) suffered serious maternal morbidity. There was a poor fetal outcome from 26 (47%) pregnancies. Only 16 (28%) women had a good maternal and good fetal outcome. Low molecular-weight heparin (LMWH) was used throughout pregnancy by 71% of women. Of these, 83% required rapid dose escalation in the first trimester. Monitoring regimens lacked consistency. CONCLUSIONS: This study has estimated the incidence of MPHV in pregnant women in the UK. It includes the largest cohort managed with LMWH throughout pregnancy reported to date. It demonstrates a high rate of maternal death, and serious maternal and fetal morbidity. Women with MPHVs, and their clinicians need to appreciate the significant maternal and fetal risks involved in pregnancy. Care should be concentrated in specialist centres. TWEETABLE ABSTRACT: High rates of poor maternal and fetal outcomes in pregnant women with mechanical prosthetic heart valves. PMID- 28019066 TI - Opioid analgesic use among patients presenting with acute abdominal pain and factors associated with surgical diagnoses. AB - BACKGROUND: The prevalence of chronic opioid use among non-cancer patients presenting with acute abdominal pain (AAP) is unknown. The aim was to characterize opioid use, constipation, diagnoses, and risk factors for surgical diagnoses among non-cancer patients presenting with AAP to an emergency department (ED). METHODS: We performed a retrospective, observational cohort study of all (n=16,121) adult patients (88% from MN, IA and WI) presenting during 2014 with AAP. We used electronic medical records, and focused on 2352 adults with AAP who underwent abdominal CT scan within 24 hours of presentation. We determined odds ratios of association with constipation and features predicting conditions that may require surgery (surgical diagnosis). KEY RESULTS: There were 2352 eligible patients; 18.8% were opioid users. Constipation was more frequent in opioid (35.1%) compared to non-opioid users [OR 2.88 (95% CI 2.28, 3.62)]. Prevalence of surgical diagnosis in the opioid and non-opioid users was 35.3% and 41.7% respectively (P=.019). By univariate analysis, age and neutrophil count independently predicted increased risk, and chronic opioid use decreased risk of surgical diagnosis. Internal validation of logistic models using a randomly selected validation subset (25% of entire cohort, 587/2352) showed receiver operating characteristic (ROC) curves for the validation and full cohorts were similar. CONCLUSIONS AND INFERENCES: Approximately 19% of adults presenting with AAP were opioid users; constipation is almost three times as likely in opioid users compared to non-opioid users presenting with AAP. Factors significantly associated with altered risk of surgical diagnoses were age, opioid use, and neutrophil count. PMID- 28019067 TI - Dental students' ability to locate emergency equipment-lessons learned from aviation. AB - PURPOSE: The purpose of this study was to evaluate the dental student's ability to locate medical emergency equipment/items at the University of Michigan School of Dentistry clinic. METHODS: A total of 138 second-year dental students (traditional group) participated in this study as part of a simulation-based medical emergencies rotation course held during the winter term of 2014 and 2015. Without prior training, students were tested on their ability to locate nine predetermined items on the clinic floor using a self-reported checklist. Six months later, a convenience sample of 18 students (novel group) from the same cohort were later trained on their location and retested individually. RESULTS: Of the 138 students tested, only 10.14% students could locate seven of the nine items when compared to 100% in the novel group. Only 5.07% of students in the traditional group could locate all items initially, compared with 72.22% students in the novel group. CONCLUSION: Whilst our students have lecture-based knowledge about medical emergencies, the results of our study identified a gap of knowledge of emergency equipment/item location amongst students. Therefore, an intervention performed with a similar group of second-year dental students supported that proper training may be used to achieve retention of knowledge. Based on our "novel group" results, we have incorporated targeted training in the dental curriculum that leads to students being better prepared in locating emergency equipment/items. This study suggests that other populations, such as faculty or staff, may also benefit from hands-on training. PMID- 28019069 TI - Use of finger-piece method for indocyanine green clearance test. AB - AIM: The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders. METHODS: Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter. RESULTS: Seventy-one patients (78.9%) had Child-Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values (r = 0.886, P < 0.001). Bland-Altman analysis showed good agreement between the two methods (mean difference, 0.012 +/- 0.018). The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values both in patients with Child-Pugh class A liver disease (r = 0.821, P < 0.001) and class B or C liver disease (r = 0.859, P < 0.001). CONCLUSION: The ICG FPM may be an alternative to the ICG BSM for liver function assessment. PMID- 28019068 TI - Using iron studies to predict HFE mutations in New Zealand: implications for laboratory testing. AB - BACKGROUND: The diagnosis of hereditary haemochromatosis (HH) is not straightforward because symptoms are often absent or non-specific. Biochemical markers of iron-overloading may be affected by other conditions. AIM: To measure the correlation between iron studies and HFE genotype to inform evidence-based recommendations for laboratory testing in New Zealand. METHODS: Results from 2388 patients genotyped for C282Y, H63D and S65C in Wellington, New Zealand from 2007 to 2013 were compared with their biochemical phenotype as quantified by serum ferritin (SF), transferrin saturation (TS), serum iron (SI) and serum transferrin (ST). The predictive power of these markers was evaluated by receiver operator characteristic (ROC) curve analysis, and if a statistically significant association for a variable was seen, sensitivity, specificity and predictive values were calculated. RESULTS: Test ordering patterns showed that 62% of HFE genotyping tests were ordered because of an elevated SF alone and only 11% of these had a C-reactive protein test to rule out an acute phase reaction. The association between SF and significant HFE genotypes SF was low. However, TS values >=45% predicted HH mutations with the highest sensitivity and specificity. A SF of >1000 ug/L was found in one at-risk patient (C282Y homozygote) who had a TS <45%. CONCLUSION: Our analysis highlights the need for clear guidelines for investigation of hyperferritinaemia and HH in New Zealand. Using our findings, we developed an evidence-based laboratory testing algorithm based on a TS >=45%, a SF >=1000 ug/L and/or a family history of HH which identified all C282Y homozygotes in this study. PMID- 28019070 TI - Why was resistance to shorter-acting pre-emergence herbicides slower to evolve? AB - BACKGROUND: Across several agricultural systems the evolution of herbicide resistance has occurred more rapidly to post-emergence than pre-emergence herbicides; however, the reasons for this are not clear. We used a new simulation model to investigate whether interactions between differences in order of application and weed cohorts affected could explain this historically observed difference between the herbicide groups. RESULTS: A 10 year delay in resistance evolution was predicted for a shorter-acting residual pre-emergence (cf. post emergence), when all other parameters were identical. Differences in order of application between pre- and post-emergence herbicides had minimal effect on rates of resistance evolution when similar weed cohorts were affected. CONCLUSION: This modelling suggested that the historically observed lower levels of resistance to pre-emergence herbicides are most likely to be due to the smaller number of weed cohorts affected by many pre-emergence herbicides. The lower number of weed cohorts affected by pre-emergence herbicides necessitated the use of additional, effective control measures, thereby reducing resistance evolution. This study highlights the advantages of applying multiple control measures to each weed cohort. (c) 2016 Society of Chemical Industry. PMID- 28019071 TI - The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy. AB - We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2 . After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2 , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P = .035), -0.08 (-12 to 0.29; P = .43) and 0.01 (-0.21 to 0.19; P = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P = .40) and 0.35 (0.05 0.65; P = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2 , suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated. PMID- 28019072 TI - Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: A 12-week, double blind randomized study (the GUARD Study). AB - AIMS: This multicentre, randomized, double-blind study investigated the efficacy and safety of gemigliptin in Korean type 2 diabetes mellitus (T2DM) patients with moderate to severe renal impairment (RI). METHODS: The study comprised a 12-week main part and a 40-week extension. We report here the results from the main part. In total, 132 patients were randomized to receive gemigliptin (n = 66) or placebo (n = 66). Changes in glycated haemoglobin (HbA1c; primary endpoint), other glycaemic control parameters (fasting plasma glucose, glycated albumin and fructosamine), lipid profiles, renal function parameters and safety profiles were evaluated. RESULTS: Baseline characteristics were comparable between the groups (mean HbA1c, 8.4% [68 mmol/mol]; age, 62.0 years; duration of type 2 diabetes, 16.3 years; estimated glomerular filtration rate, 33.3 mL/min/1.73 m2 ). At Week 12, the adjusted mean change +/- standard error in HbA1c with gemigliptin was 0.82% +/- 0.14% (-8.9 +/- 1.5 mmol/mol), whereas it was 0.38% +/- 0.14% (4.2 +/- 1.5 mmol/mol) with placebo (significant between-group difference, P < .001). Other glycaemic control parameters showed beneficial changes as well. Body weight change (gemigliptin, -0.3 kg; placebo, -0.2 kg) was not significant. In the gemigliptin group, the mean decrease in urinary albumin creatinine ratio (UACR) was significant, both in patients with microalbuminuria (-41.9 mg/g creatinine, P = .03) and macroalbuminuria (-528.9 mg/g creatinine, P < .001). Drug-related adverse events were similar with gemigliptin and placebo (15% and 12%, respectively). CONCLUSIONS: A 12-week treatment with gemigliptin improved glycaemic control and provided UACR reduction in T2DM patients with moderate to severe RI. Gemigliptin was well tolerated, with no additional risk of hypoglycaemia and change in body weight. PMID- 28019073 TI - Tuning the Electron-Transport and Electron-Accepting Abilities of Dyes through Introduction of Different pi-Conjugated Bridges and Acceptors for Dye-Sensitized Solar Cells. AB - A series of dyes, containing thiophene and thieno[3,2-b]thiophene as pi conjugated bridging units and six kinds of groups as electron acceptors, were designed for dye-sensitized solar cells (DSSCs). The ground- and excited-state properties of the designed dyes were investigated by using density functional theory (DFT) and time-dependent DFT, respectively. Moreover, the parameters affecting the short-circuit current density and open-circuit voltage were calculated to predict the photoelectrical performance of each dye. In addition, the charge difference density was presented through a three-dimensional (3D) real space analysis method to investigate the electron-injection mechanism in the complexes. Our results show that the longer conjugated bridge would inhibit the intramolecular charge transfer, thereby affecting the photoelectrical properties of DSSCs. Similarly, owing to the lowest chemical hardness, largest electron accepting ability, dipole moment (MUnormal ) and the change in the energy of the TiO2 conduction band (DeltaECB ), the dye with a (E)-3-(4 (benzo[c][1,2,5]thiadiazol-4-yl)phenyl)-2-cyanoacrylic acid (TCA) acceptor group would exhibit the most significant photoelectrical properties among the designed dyes. PMID- 28019075 TI - Surviving with trisomy 13: Provider and parent perspectives and the role of the pediatric palliative care program. AB - Trisomy 13 typically denotes an overall poor prognosis in the setting of multisystem anomalies. Through a provider and parent perspective, this case illustrates the benefit of hope, communication, and teamwork through the integration of a palliative care team in the care of a medically complex child with trisomy 13, resulting in enhance survival and perceived quality of life for patient and family. (c) 2016 Wiley Periodicals, Inc. PMID- 28019074 TI - Identification and detection of indoxacarb resistance mutations in the para sodium channel of the tomato leafminer, Tuta absoluta. AB - BACKGROUND: Indoxacarb is an important active ingredient extensively used for the control of Tuta absoluta, a major tomato pest, playing a particular role in insecticide resistance management schemes. RESULTS: Reduced susceptibility to indoxacarb was identified (1794-fold resistance) through toxicological bioassays in a field population from Greece and evolved rapidly to resistance after short laboratory selection. Combined bioassays with synergists and biochemical analysis suggested only a partial involvement of detoxification enzymes in the resistant phenotype. To investigate the role of target-site resistance, segment 6 of domain IV of the sodium channel in T. absoluta was cloned and the sequences compared between susceptible and indoxacarb-resistant T. absoluta insects. The presence of the F1845Y and the V1848I indoxacarb resistance mutations was detected and was strongly associated with the phenotype. These amino acid substitutions correspond to recently characterised indoxacarb resistance mutations in diamondback moth (Plutella xylostella). Robust and accurate PCR-RFLP assays were subsequently developed and successfully validated for detecting both indoxacarb resistance mutations in field T. absoluta populations. CONCLUSION: The identification of indoxacarb resistance mutations and the development of diagnostic tools will allow early detection of indoxacarb resistance, facilitating implementation of appropriate resistance management strategies, thus delaying the spread of resistance. (c) 2016 Society of Chemical Industry. PMID- 28019076 TI - Theoretical Evaluation of Terahertz Sources Generated From SnGa4 Q7 (Q=S, Se) as Infrared Nonlinear Optical Materials. AB - We theoretically evaluated the integrated knowledge that contributes to conversion efficiency, including the phonon, photon, and electron properties of infrared nonlinear optical materials such as SnGa4 Q7 (Q=S, Se), which are terahertz (THz) sources. Specifically, we developed a new formula to calculate the susceptibility of the difference frequency generation (DFG) optical process. By evaluating the characteristics of the materials themselves in the THz region, we found that a larger nonlinear susceptibility or a large figure of merit resulted in a large efficiency of the THz source by comparing the findings of SnGa4 Se7 and SnGa4 S7 under the same experimental conditions; furthermore, THz absorption was found to reduce the efficiency of the THz source for the two SnGa4 Q7 (Q=S, Se) materials. The efficiency of the THz source also depended on the experimental conditions. A large crystal size, strong pump intensity, and small THz wavelength resulted in better efficiency of the THz source based on the DFG process. The efficiency was found to be a comprehensive index to evaluate the THz source based on the DFG process. PMID- 28019077 TI - The adverse impact of the neonicotinoid seed treatment ban on crop protection in oilseed rape in the United Kingdom. AB - This paper describes the consequences of the ban on neonicotinoid seed treatments on pest management in oilseed rape. Since the ban was implemented in December 2013, there have been serious crop losses in 2014, 2015 and 2016 owing to cabbage stem flea beetles, Psylliodes chrysocephala, and aphids, Myzus persicae, which have developed resistance to the alternative pyrethroid sprays that were employed to control them. This has resulted in increased crop losses, decreased yields and a substantial decrease in the area grown, leading to fewer flowering crops available in the spring, especially in the eastern region of the United Kingdom. This is likely to have an adverse effect on bees locally. (c) 2016 Society of Chemical Industry. PMID- 28019078 TI - Target-site mutations conferring resistance to glyphosate in feathertop Rhodes grass (Chloris virgata) populations in Australia. AB - BACKGROUND: Chloris virgata is a warm-season, C4 , annual grass weed affecting field crops in northern Australia that has become an emerging weed in southern Australia. Four populations with suspected resistance to glyphosate were collected in South Australia, Queensland and New South Wales, Australia, and compared with one susceptible (S) population to confirm glyphosate resistance and elucidate possible mechanisms of resistance. RESULTS: Based on the rate of glyphosate required to kill 50% of treated plants (LD50 ), glyphosate resistance (GR) was confirmed in four populations of C. virgata (V12, V14.2, V14.16 and V15). GR plants were 2-9.7-fold more resistant and accumulated less shikimate after glyphosate treatment than S plants. GR and S plants did not differ in glyphosate absorption and translocation. Target-site EPSPS mutations corresponding to Pro-106-Leu (V14.2) and Pro-106-Ser (V15, V14.16 and V12) substitutions were found in GR populations. The population with Pro-106-Leu substitution was 2.9-4.9-fold more resistant than the three other populations with Pro-106-Ser substitution. CONCLUSION: This report confirms glyphosate resistance in C. virgata and shows that target-site EPSPS mutations confer resistance to glyphosate in this species. The evolution of glyphosate resistance in C. virgata highlights the need to identify alternative control tactics. (c) 2016 Society of Chemical Industry. PMID- 28019079 TI - Is cutis verticis Gyrata-Intellectual Disability syndrome an underdiagnosed condition? A case report and review of 62 cases. AB - Cutis Verticis Gyrata-Intellectual Disability (CVG-ID) syndrome is a rare neurocutaneous syndrome characterized by intellectual disability and scalp folds and furrows that are typically absent at birth and are first noticed after puberty. First reported in 1893, the syndrome was mainly identified in subjects living in psychiatric institutions, where it was found to have a prevalence of up to 11.4%. Most patients were reported in the literature during the first half of the 20th century. CVG-ID is now a less reported and possibly under-recognized syndrome. Here, we report a patient with CVG-ID that was diagnosed using the novel approach of magnetic resonance imaging and we conduct a systematic review of all patients reported in the last 60 years, discussing the core clinical features of this syndrome. (c) 2016 Wiley Periodicals, Inc. PMID- 28019080 TI - Breast and ovarian cancer referrals to the ACT Genetic Service: are we meeting guidelines? AB - BACKGROUND: The ACT Genetic Service at The Canberra Hospital evaluates the genetic risk of individuals for inherited diseases, and provides counselling and genetic testing where appropriate. AIM: To evaluate the current referral practice for patients with a personal and/or family history of breast and/or ovarian cancer, and to assess whether these referrals are made according to eviQ cancer referral guidelines. METHODS: A retrospective clinical audit of patients seen by the ACT Genetic Service for evaluation of genetic risk of breast and/or ovarian cancer between 1 January 2013 and 30 June 2015. Statistical analysis included Chi squared and Poisson distribution tests. RESULTS: Of the 711 patients referred during the 30-month period, 671 were seen by the service. The number of patients seen increased steadily over the time period, as did waiting times. The majority of referrals were made by general practitioners (403/711; 57%) and oncologists (172/711; 24%). Of note, 300 of 711 (42%) of all referrals made to the service during this time period did not meet eviQ referral guidelines. Patients who met guidelines for referral were more likely both to be offered genetic testing and to have a positive result. CONCLUSION: Demand on the ACT Genetic Service increased over the time period assessed. As a significant proportion of patients did not meet eviQ cancer referral guidelines, it is worth reviewing the referral process in order to optimise utility of this limited resource. PMID- 28019081 TI - DNA-based probes for flow cytometry analysis of endocytosis and recycling. AB - The internalization of proteins plays a key role in cell development, cell signaling and immunity. We have previously developed a specific hybridization internalization probe (SHIP) to quantitate the internalization of proteins and particles into cells. Herein, we extend the utility of SHIP to examine both the endocytosis and recycling of surface receptors using flow cytometry. SHIP was used to monitor endocytosis of membrane-bound transferrin receptor (TFR) and its soluble ligand transferrin (TF). SHIP enabled measurements of the proportion of surface molecules internalized, the internalization kinetics and the proportion and rate of internalized molecules that recycle to the cell surface with time. Using this method, we have demonstrated the internalization and recycling of holo TF and an antibody against the TFR behave differently. This assay therefore highlights the implications of receptor internalization and recycling, where the internalization of the receptor-antibody complex behaves differently to the receptor-ligand complex. In addition, we observe distinct internalization patterns for these molecules expressed by different subpopulations of primary cells. SHIP provides a convenient and high throughput technique for analysis of trafficking parameters for both cell surface receptors and their ligands. PMID- 28019083 TI - The long path towards implementation of clinical proteomics: Exemplified based on CKD273. AB - Clinical proteomics aims at the development and the implementation of novel biomarkers that demonstrate a clear clinical benefit in the management of diseases. However, though the attention in the field is increasing and multiple articles on biomarker research are published, clinical implementation of these biomarkers is scarce. In this paper, we aim towards identifying the hurdles on the path towards implementation, and present one successful approach, based on capillary electrophoresis coupled with mass spectrometry. A panel of biomarkers identified and assessed using this approach, termed CKD273, has recently received a Letter-of-Support from the US-Food and Drug Administration (FDA), and is now implemented in the (early) management of chronic kidney disease. Based on this experience in the process towards implementation of CKD273, issues associated with implementation and suggestions how to meet these challenges are given. PMID- 28019082 TI - Design, synthesis and pharmacophoric model building of new 3-alkoxymethyl/3 phenyl indole-2-carboxamides with potential antiproliferative activity. AB - Novel 3-alkoxymethyl/3-phenyl indole-2-carboxamide derivatives were synthesized and evaluated for their anticancer activity. Most of the tested compounds showed moderate to excellent activity against the tested cell lines (MCF7 and HCT116). 3 Phenyl substitution on indole with p-piperidinyl phenethyl 24a and p dimethylamino phenethyl 24c exhibited anticancer activity against MCF7 with IC50 of 0.13 and 0.14 MUm, respectively. Further mechanistic study of the most active compounds through their action on cell cycle showed disturbance in cell cycle progression and cell cycle arrest. For future development of this series of compounds, pharmacophore study was conducted which indicated that the enhancement of the activity could be achieved through the addition of acceptor or donating groups to the already-present indole nucleus. PMID- 28019084 TI - Heterogeneous activity causes a nonlinear increase in the group energy use of ant workers isolated from queen and brood. AB - Increasing evidence has shown that the energy use of ant colonies increases sublinearly with colony size so that large colonies consume less per capita energy than small colonies. It has been postulated that social environment (e.g., in the presence of queen and brood) is critical for the sublinear group energetics, and a few studies of ant workers isolated from queens and brood observed linear relationships between group energetics and size. In this paper, we hypothesize that the sublinear energetics arise from the heterogeneity of activity in ant groups, that is, large groups have relatively more inactive members than small groups. We further hypothesize that the energy use of ant worker groups that are allowed to move freely increases more slowly than the group size even if they are isolated from queen and brood. Previous studies only provided indirect evidence for these hypotheses due to technical difficulties. In this study, we applied the automated behavioral monitoring and respirometry simultaneously on isolated worker groups for long time periods, and analyzed the image with the state-of-the-art algorithms. Our results show that when activity was not confined, large groups had lower per capita energy use, a lower percentage of active members, and lower average walking speed than small groups; while locomotion was confined, however, the per capita energy use was a constant regardless of the group size. The quantitative analysis shows a direct link between variation in group energy use and the activity level of ant workers when isolated from queen and brood. PMID- 28019085 TI - Zinc-rich oysters as well as zinc-yeast- and astaxanthin-enriched food improved sleep efficiency and sleep onset in a randomized controlled trial of healthy individuals. AB - SCOPE: Zinc is an essential mineral that plays an important role in the body. We previously reported that orally feeding zinc-enriched yeast to mice induces nonrapid-eye-movement sleep. In addition, astaxanthin, an antioxidant abundant in seafood such as salmon and krill, is able to chelate minerals and may promote zinc absorption, which in return may also improve sleep. The purpose of our study was to examine the effect of zinc-rich and astaxanthin-containing food on sleep in humans. METHODS AND RESULTS: We conducted a randomized, double-blinded, placebo-controlled parallel group trial of 120 healthy subjects and recorded their night activity by actigraphy for 12 weeks. These subjects were divided into four groups: placebo, zinc-rich food, zinc-, and astaxanthin-rich food, and placebo supplemented with zinc-enriched yeast and astaxanthin oil. Compared with the placebo group, the zinc-rich food group efficiently decreased the time necessary to fall asleep and improved sleep efficiency, whereas the group that ingested zinc-enriched yeast and astaxanthin oil significantly improved the sleep onset latency. CONCLUSION: Actigraphic sleep monitoring demonstrated that eating zinc-rich food improved sleep onset latency as well as improved the sleep efficiency in healthy individuals. PMID- 28019086 TI - The risk of secondary cancer in nasopharyngeal carcinoma paediatric patients due to intensity modulated radiotherapy and mega-voltage cone beam computed tomography. AB - INTRODUCTION: There is a growing interest in the study of radiation-induced secondary cancer. The aim of this work is (i) to estimate the peripheral doses attributable to intensity modulated radiotherapy (IMRT) and mega-voltage cone beam computed tomography (MV-CBCT) for some organs at risk (OARs) which surround the target being treated (Nasopharynx) in paediatric patients. (ii) To estimate the risk of radiation-induced secondary cancers attributable to patient setup verification imaging dose using MV-CBCT for Nasopharyngeal Carcinoma (NPC) in paediatric patients and comparing it with that attributable to the therapeutic dose using IMRT. METHODS: Intensity modulated radiotherapy treatment planning of 10 NPC paediatric patients was carried out on KonRad release 2.2.23. The additional radiation doses to the patients attributable to MV-CBCT were calculated also using Xio Version 4.4. A paediatric phantom and thermoluminescent dosimeters (TLDs) were used to measure the patient doses attributable to IMRT. These doses were then compared with the calculated doses. The risk of induced secondary cancers attributable to IMRT and MV-CBCT was calculated and compared to each other. RESULTS: The absorbed doses (mean dose) for the OARs (Brain, Brain stem, spinal cord, thyroid, oesophagus, mandible, heart, optic nerve, lung and eye) were higher for the therapeutic dose than for the imaging dose used in the verification of patient position before and during the treatment. The risk of induced secondary cancers in thyroid, oesophagus and lung (the only organs from the OARs which have tabulated values for risk calculations) was higher for therapeutic dose (7.29 +/- 0.73%, 2.62 +/- 0.17% and 6.76 +/- 0.87%, respectively) than for verification imaging dose (0.14 +/- 0.00%, 0.06 +/- 0.00%, 0.10 +/- 0.03% respectively). CONCLUSION: The risk of secondary cancers attributable to verification imaging dose using MV-CBCT is very small compared to therapeutic dose using IMRT. Therefore, it is important to focus on the risk of secondary cancers attributable to therapeutic dose especially when using IMRT, where the produced leakage radiation is considerably high compared to some other techniques (such as conformal radiotherapy). PMID- 28019087 TI - Magnetic resonance imaging findings of central nervous system in lysosomal storage diseases: A pictorial review. AB - Lysosomal storage diseases (LSD) are a complex group of genetic disorders that are a result of inborn errors of metabolism. These errors result in a variety of metabolic dysfunction and build-up certain molecules within the tissues of the central nervous system (CNS). Although, they have discrete enzymatic deficiencies, symptomology and CNS imaging findings can overlap with each other, which can become challenging to radiologists. The purpose of this paper is to review the most common CNS imaging findings in LSD in order to familiarize the radiologist with their imaging findings and help narrow down the differential diagnosis. PMID- 28019088 TI - p16INK4a , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects. AB - The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport. PMID- 28019089 TI - Biomarker discovery by proteomics-based approaches for early detection and personalized medicine in colorectal cancer. AB - About one million people per year develop colorectal cancer (CRC) and approximately half of them die. The extent of the disease (i.e. local invasion at the time of diagnosis) is a key prognostic factor. The 5-year survival rate is almost 90% in the case of delimited CRC and 10% in the case of metastasized CRC. Hence, one of the great challenges in the battle against CRC is to improve early diagnosis strategies. Large-scale proteomic approaches are widely used in cancer research to search for novel biomarkers. Such biomarkers can help in improving the accuracy of the diagnosis and in the optimization of personalized therapy. Herein, we provide an overview of studies published in the last 5 years on CRC that led to the identification of protein biomarkers suitable for clinical application by using proteomic approaches. We discussed these findings according to biomarker application, including also the role of protein phosphorylation and cancer stem cells in biomarker discovery. Our review provides a cross section of scientific approaches and can furnish suggestions for future experimental strategies to be used as reference by scientists, clinicians and researchers interested in proteomics for biomarker discovery. PMID- 28019090 TI - Quantitative Characterization of the Exposure-Response Relationship for Cancer Immunotherapy: A Case Study of Nivolumab in Patients With Advanced Melanoma. AB - To inform the benefit-risk assessment of nivolumab in patients with advanced melanoma, analyses of efficacy and safety exposure-response (E-R) relationships were conducted with data from patients with advanced melanoma enrolled in two clinical studies (phase I and phase III) who received nivolumab 0.1-10.0 mg/kg every 2 weeks. E-R efficacy analyses were performed by relating the nivolumab time-averaged concentration after the first dose (Cavg1 ) to two endpoints: RECIST objective response (OR) and overall survival (OS). E-R safety analyses characterized the relationship between nivolumab Cavg1 and the hazard of all causality adverse events leading to discontinuation or death (AE-DC/D). Nivolumab exposure represented by Cavg1 was not a significant predictor of OR, OS, or the hazard of AE-DC/D. E-R efficacy and safety relationships were relatively flat over the exposure range. PMID- 28019091 TI - Model-Based Population Pharmacokinetic Analysis of Nivolumab in Patients With Solid Tumors. AB - Nivolumab is a fully human monoclonal antibody that inhibits programmed death-1 activation. The clinical pharmacology profile of nivolumab was analyzed by a population pharmacokinetics model that assessed covariate effects on nivolumab concentrations in 1,895 patients who received 0.3-10.0 mg/kg nivolumab in 11 clinical trials. Nivolumab pharmacokinetics is linear with a time-varying clearance. A full covariate model was developed to assess covariate effects on pharmacokinetic parameters. Nivolumab clearance and volume of distribution increase with body weight. The final model included the effects of baseline performance status (PS), baseline body weight, and baseline estimated glomerular filtration rate (eGFR), sex, and race on clearance, and effects of baseline body weight and sex on volume of distribution in the central compartment. Sex, PS, baseline eGFR, age, race, baseline lactate dehydrogenase, mild hepatic impairment, tumor type, tumor burden, and programmed death ligand-1 expression had a significant but not clinically relevant (<20%) effect on nivolumab clearance. PMID- 28019093 TI - Creatine and creatine forms intended for sports nutrition. AB - Creatine is a popular ergogenic supplement in sports nutrition. Yet, supplementation of creatine occasionally caused adverse effects such as gastrointestinal complaints, muscle cramps and an increase in body weight. Creatine monohydrate has already been evaluated by different competent authorities and several have come to the conclusion that a daily intake of 3 g creatine per person is unlikely to pose safety concerns, focusing on healthy adults with exclusion of pregnant and breastfeeding women. Possible vulnerable subgroups were also discussed in relation to the safety of creatine. The present review provides an up-to-date overview of the relevant information with special focus on human studies regarding the safety of creatine monohydrate and other marketed creatine forms, in particular creatine pyruvate, creatine citrate, creatine malate, creatine taurinate, creatine phosphate, creatine orotate, creatine ethyl ester, creatine pyroglutamate, creatine gluconate, and magnesium creatine chelate. Limited data are available with regard to the safety of the latter creatine forms. Considering an acceptable creatine intake of 3 g per day, most of the evaluated creatine forms are unlikely to pose safety concerns, however some safety concerns regarding a supplementary intake of creatine orotate, creatine phosphate, and magnesium creatine chelate are discussed here. PMID- 28019092 TI - Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children's Oncology Group. AB - PURPOSE: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. PATIENTS AND METHODS: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. RESULTS: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. CONCLUSIONS: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies. PMID- 28019094 TI - Open-pNovo: De Novo Peptide Sequencing with Thousands of Protein Modifications. AB - De novo peptide sequencing has improved remarkably, but sequencing full-length peptides with unexpected modifications is still a challenging problem. Here we present an open de novo sequencing tool, Open-pNovo, for de novo sequencing of peptides with arbitrary types of modifications. Although the search space increases by ~300 times, Open-pNovo is close to or even ~10-times faster than the other three proposed algorithms. Furthermore, considering top-1 candidates on three MS/MS data sets, Open-pNovo can recall over 90% of the results obtained by any one traditional algorithm and report 5-87% more peptides, including 14-250% more modified peptides. On a high-quality simulated data set, ~85% peptides with arbitrary modifications can be recalled by Open-pNovo, while hardly any results can be recalled by others. In summary, Open-pNovo is an excellent tool for open de novo sequencing and has great potential for discovering unexpected modifications in the real biological applications. PMID- 28019095 TI - Interface Energy Alignment of Atomic-Layer-Deposited VOx on Pentacene: an in Situ Photoelectron Spectroscopy Investigation. AB - Ultrathin atomic-layer-deposited (ALD) vanadium oxide (VOx) interlayer has recently been demonstrated for remarkably reducing the contact resistance in organic electronic devices (Adv. Funct. Mater. 2016, 26, 4456). Herein, we present an in situ photoelectron spectroscopy investigation (including X-ray and ultraviolet photoelectron spectroscopies) of ALD VOx grown on pentacene to understand the role of the ALD VOx interlayer for the improved contact resistance. The in situ photoelectron spectroscopy characterizations allow us to monitor the ALD growth process of VOx and trace the evolutions of the work function, pentacene HOMO level, and VOx defect states during the growth. The initial VOx growth is found to be partially delayed on pentacene in the first ~20 ALD cycles. The underneath pentacene layer is largely intact after ALD. The ALD VOx is found to contain a high density of defect states starting from 0.67 eV below the Fermi level, and the energy level of these defect states is in excellent alignment with the HOMO level of pentacene, which therefore allows these VOx defect states to provide an efficient hole-injection pathway at the contact interface. PMID- 28019096 TI - ZrO2/TiO2 Electron Collection Layer for Efficient Meso-Superstructured Hybrid Perovskite Solar Cells. AB - Since the first reports of efficient organic-inorganic perovskite solar cells in 2012, an explosion of research activity has emerged around the world, which has led to a rise in the power conversion efficiencies (PCEs) to over 20%. Despite the impressive efficiency, a key area of the device which remains suboptimal is the electron extraction layer and its interface with the photoactive perovskite. Here, we implement an electron collection "bilayer" composed of a thin layer of zirconia coated with titania, sitting upon the transparent conductive oxide fluorine-doped tin oxide (FTO). With this double collection layer we have reached up to 17.9% power conversion efficiency, delivering a stabilized power output (SPO) of 17.0%, measured under simulated AM 1.5 sunlight of 100 mW cm-2 irradiance. Finally, we propose a mechanism of the charge transfer processes within the fabricated architectures in order to explain the obtained performance of the devices. PMID- 28019097 TI - Multifunctional Self-Adhesive Fibrous Layered Matrix (FiLM) for Tissue Glues and Therapeutic Carriers. AB - Tissue adhesives, which inherently serve as wound sealants or as hemostatic agents, can be further augmented to acquire crucial functions as scaffolds, thereby accelerating wound healing or elevating the efficacy of tissue regeneration. Herein, multifunctional adherent fibrous matrices, acting as self adhesive scaffolds capable of cell/gene delivery, were devised by coaxially electrospinning poly(caprolactone) (PCL) and poly(vinylpyrrolidone) (PVP). Wrapping the building block PCL fibers with the adherent PVP layers formed film like fibrous matrices that could rapidly adhere to wet biological surfaces, referred to as fibrous layered matrix (FiLM) adhesives. The inclusion of ionic salts (i.e., dopamine hydrochloride) in the sheath layers generated spontaneously multilayered fibrous adhesives, whose partial layers could be manually peeled off, termed derivative FiLM (d-FiLM). In the context of scaffolds/tissue adhesives, both FiLM and d-FiLM demonstrated almost identical characteristics (i.e., sticky, mechanical, and performances as cell/gene carriers). Importantly, the single FiLM-process can yield multiple sets of d-FiLM by investing the same processing time, materials, and labor required to form a single conventional adhesive fibrous mat, thereby highlighting the economic aspects of the process. The FiLM/d-FiLM offer highly impacting contributions to many biomedical applications, especially in fields that require urgent aids (e.g., endoscopic surgeries, implantation in wet environments, severe wounds). PMID- 28019098 TI - Electrochemical Characterization and Catalytic Application of Gold-Supported Ferrocene-Containing Diblock Copolymer Thin Films in Ethanol Solution. AB - This paper reports the electrochemical behavior and catalytic property of electrode-supported thin films of polystyrene-block-poly(2-(acryloyloxy)ethyl ferrocenecarboxylate) (PS-b-PAEFc) in an ethanol (EtOH) solution. The electrochemical properties of PS-b-PAEFc films with different PAEFc volume fractions (fPAEFc = 0.47, 0.30, and 0.17) in 0.1 M ethanolic sodium hexafluorophosphate (NaPF6) were compared with those in an acetonitrile (MeCN) solution of 0.1 M tetrabutylammonium hexafluorophosphate. Pristine PS-b-PAEFc films did not afford significant faradaic currents in the EtOH solution because EtOH is a nonsolvent for both PS and PAEFc. However, the films could be rendered redox-active in the EtOH solution by applying potentials in the MeCN solution to induce the redox-associated incorporation of the supporting electrolytes into the films. Atomic force microscopy images verified the stability of PAEFc microdomains upon electrochemical measurements in these solutions. Cyclic voltammograms measured in the EtOH solution for PS-b-PAEFc with the larger fPAEFc were diffusion-controlled regardless of ellipsometric film thickness (23-152 nm) at relatively slow scan rates, in contrast to those in the MeCN solution that were controlled by surface-confined redox species. The electron propagation efficiency in the EtOH solution was significantly lower than that in the MeCN solution because of the poorer swelling of the films, which limited the migration of counterions and the collisional motions of the ferrocene moieties. PS-b-PAEFc films were applied as electrochemically responsive heterogeneous catalysts based on the ferrocenium moieties for Michael addition reaction between methyl vinyl ketone and ethyl 2-oxocyclopentanecarboxylate (E2OC) in 0.1 M NaPF6/EtOH. The catalytic activities of thin films were similar regardless of fPAEFc, suggesting that the catalytic reaction took place for the reactants that could penetrate through the film and reach PAEFc microdomains communicable with the underlying electrode. Interestingly, the permeability of PS-b-PAEFc films provided a means to control the reaction selectivity, as suggested by negligible reaction of E2OC with trans-4-phenyl-3-buten-2-one. PMID- 28019099 TI - Emissions of Selected Semivolatile Organic Chemicals from Forest and Savannah Fires. AB - The emission factors (EFs) for a broad range of semivolatile organic chemicals (SVOCs) from subtropical eucalypt forest and tropical savannah fires were determined for the first time from in situ investigations. Significantly higher (t test, P < 0.01) EFs (MUg kg-1 dry fuel, gas + particle-associated) for polycyclic aromatic hydrocarbons (?13 PAHs) were determined from the subtropical forest fire (7,000 +/- 170) compared to the tropical savannah fires (1,600 +/- 110), due to the approximately 60-fold higher EFs for 3-ring PAHs from the former. EF data for many PAHs from the eucalypt forest fire were comparable with those previously reported from pine and fir forest combustion events. EFs for other SVOCs including polychlorinated biphenyl (PCB), polychlorinated naphthalene (PCN), and polybrominated diphenyl ether (PBDE) congeners as well as some pesticides (e.g., permethrin) were determined from the subtropical eucalypt forest fire. The highest concentrations of total suspended particles, PAHs, PCBs, PCNs, and PBDEs, were typically observed in the flaming phase of combustion. However, concentrations of levoglucosan and some pesticides such as permethrin peaked during the smoldering phase. Along a transect (10-150-350 m) from the forest fire, concentration decrease for PCBs during flaming was faster compared to PAHs, while levoglucosan concentrations increased. PMID- 28019100 TI - Assessing the impact of autonomous motivation and psychological need satisfaction in explaining adherence to an exercise referral scheme. AB - Given the mixed findings concerning self-determination theory in explaining adherence to exercise referral schemes (ERS), the present study attempted to examine whether autonomous motivation and psychological need satisfaction could predict ERS adherence. Participants referred to an 8-week ERS completed self report measures grounded in self-determination theory and basic needs theory at baseline (N = 124), mid-scheme (N = 58), and at the end of the scheme (N = 40). Logistic regressions were used to analyse the data. Autonomous motivation measured at mid-scheme explained between 12 and 16% of the variance in ERS adherence. Autonomy, relatedness and competence measured at mid-scheme explained between 18 and 26% of the variance in ERS adherence. This model also explained between 18 and 25% when measured at the end of the scheme. The study found limited evidence for the role of autonomous motivation in explaining ERS adherence. Stronger support was found for the satisfaction of the three needs for autonomy, relatedness and competence in predicting ERS adherence. Future research should tap into the satisfaction of all three needs collectively to help foster ERS adherence. PMID- 28019101 TI - Subtypes and Risk Behaviors Among Incident HIV Cases in the Bangkok Men Who Have Sex with Men Cohort Study, Thailand, 2006-2014. AB - HIV-1 incidence and prevalence remain high among men who have sex with men (MSM), and transgender women (TGW), in Thailand. To examine the link between epidemiologic factors and HIV-1 subtype transmission among Thai MSM, we compared covariates of infection with HIV CRF01_AE and other HIV strains among participants in the Bangkok MSM Cohort Study (BMCS). The BMCS was an observational cohort study of Thai MSM and TGW with up to 60 months of follow-up at 4 monthly intervals. Participants underwent HIV/sexually transmitted infections testing and provided behavioral data at each visit. Infecting viral strain was characterized by gene sequencing and/or multiregion hybridization assay. We correlated behavioral/clinical variables with infecting strain using Cox proportional hazards. Among a total of 1372 HIV seronegative enrolled participants with 4,192 person-years of follow-up, we identified 215 seroconverters between April 2006 and December 2014, with 177 infected with CRF01_AE and 38 with non-CRF01_AE subtype. Age 18-21 years (adjusted hazard ratio [AHR] 2.2, 95% confidence interval [CI]: 1.4-3.5), age 22-29 (AHR 1.6, 95% CI: 1.1-2.3), living alone (AHR 1.5, 95% CI: 1.1-2.1), drug use (AHR 2.2, 95% CI: 1.4 3.5), intermittent condom use (AHR 1.7, 95% CI: 1.3-2.3), any receptive anal intercourse (AHR 1.7, 95% CI: 1.2-2.4), group sex (AHR 1.5, 95% CI: 1.1-2.2), anti-herpes simplex virus type 1 (AHR 1.5, 95% CI: 1.1-2.1), and Treponema pallidum antibody positivity (AHR 2.5, 95% CI: 1.4-4.4) were associated with CRF01_AE infection. Age 18-21 years (AHR 5.1, 95% CI: 1.6-16.5), age 22-29 (AHR 3.6, 95% CI: 1.3-10.4), drug use (AHR 3.1, 95% CI: 1.3-7.5), group sex (AHR 2.4, 95% CI: 1.1-5.0), and hepatitis B virus surface antigen (AHR 3.6, 95% CI: 1.3 10.2) were associated with non-CRF01_AE infection. We observed several significant biological and behavioral correlates of infection with CRF01_AE and other HIV strains among Thai MSM. Divergence in correlates by strain may indicate differences in HIV transmission epidemiology between CRF01_AE and other strains. These differences could reflect founder effects, transmission within networks distinguished by specific risk factors, and possibly biological differences between HIV strains. PMID- 28019102 TI - Arecoline aggravates hypothyroidism in metabolic stress in mice. AB - Millions of people consume betel nut for increased capacity of work. It contains arecoline which is highly toxic and has several untoward side effects on endocrine functions. In this article, the role of arecoline on thyroid function under metabolic stress was investigated in mice. Water or food-deprivation, each for 5 days, caused ultrastructural degeneration of thyro-follicular cells, evident from pycnotic nuclei, scanty rough endoplasmic reticulum and mitochondria followed by depletion of blood serum T3 and T4 levels with alteration of TSH level as compared with control. Thyroid activity was also suppressed ultrastructurally as well as at hormonal level after arecoline administration. Further, arecoline treatment in water deprivation or food deprivation stress also caused thyroid dysfunction beyond that of metabolic stress, as evident from further ultrastructural degeneration of thyrocytes and depletion of thyroid hormones in mice. The findings suggest that arecoline aggravates hypothyroid condition in metabolic stress in mice. PMID- 28019103 TI - Translation and validation of the King's Brief Interstitial Lung Disease (K-BILD) questionnaire in French, Italian, Swedish, and Dutch. AB - No disease-specific instruments exist in Dutch, French, Italian, and Swedish to measure health status in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). The King's Brief Interstitial Lung Disease (K BILD) is a 15-item validated questionnaire assessing health status in patients with ILD. The aim of this study was to translate and validate the K-BILD to French, Italian, Swedish, and Dutch versions. The K-BILD was translated following a forward-backward multistep procedure and tested in structured patient interviews. Subsequently, 195 outpatients with ILD were asked to complete K-BILD, St. George's Respiratory Questionnaire (SGRQ), and Euroqol EQ-5D-5L (EQ5D), twice, 2 weeks apart. Internal consistency, concurrent validity, and repeatability were determined. No major difficulties occurred in the translation processes. The K-BILD was considered comprehensible and relevant by patients. One hundred seventy-six patients (108 IPF and 68 other ILDs) completed the translated K-BILD. Internal consistency was good for all K-BILD modules (Cronbach's alpha 0.70-0.93). Concurrent validity of K-BILD was strong compared with SGRQ ( r = 0.86) and EQ5D ( r = 0.68), low with transfer capacity of the lung for carbon monoxide corrected for hemoglobin ( r = 0.33) and with forced vital capacity ( r = 0.35). The K-BILD and its domains were repeatable over 2 weeks; intraclass correlation coefficients were 0.86-0.93 ( n = 159). Known groups validity showed K-BILD was able to discriminate between patients based on severity of disease. K BILD's validity and reliability for patients with IPF was similar to that of other ILDs. The French, Italian, Swedish, and Dutch translated K-BILD questionnaires were well-received by patients and demonstrated excellent validity comparable to the original English K-BILD. PMID- 28019104 TI - Four new compounds from the rhizome of Aristolochia championii. AB - Three new flavonoid glycosides (1-3) and one new aristololactam N-glycoside (4) were isolated from the rhizome of Aristolochia championii. The structures of compounds 1-4 were elucidated on the basis of their spectroscopic data and chemical evidence (UV, IR, HR-ESI-MS, 1D and 2D NMR). Their structures were determined as 8-(5-formyl-2-furanmethyl)-isorhamentin 3-O-robinobioside (1), 8-(5 methyl-2-furanoyl)-isorhamentin 3-O-robinobioside (2), 8-formylisorhamentin 3-O robinobioside (3), and N-beta-D-glucopyranosylaristololactam V (4), respectively. PMID- 28019105 TI - Corrigendum. PMID- 28019106 TI - Geographic distributions of motor neuron disease mortality and well water use in U.S. counties. AB - OBJECTIVE: We recently reported that U.S. mortality rates for motor neuron disease (MND) at the level of the state are associated with well water use. However, data at the state level may not accurately reflect data at the individual level. We therefore examined the association between MND mortality and well water use utilizing data from smaller geographic units that may better reflect exposure and disease at the individual level. METHODS: We used data on age-adjusted MND mortality rates at the level of the county, obtained from the CDC, and corresponding data on the prevalence of well water use, obtained from the U.S. Geological Survey. Data were analyzed by multivariate linear regression and by Getis-Ord Gi*, a measure of spatial clustering. RESULTS: Age-adjusted mortality rates for MND in 923 U.S. counties were significantly correlated with the prevalence of well water (p < 0.0001). 'Hot spots' of MND mortality were significantly associated with 'hot spots' of well water use (p < 0.0005). CONCLUSIONS: These findings support the hypothesis that an agent present in well water plays an etiologic role in ALS. Further study of water use among individuals with ALS is warranted. PMID- 28019107 TI - Gross total resection rates of grade II/III intramedullary ependymomas using the surgical strategy of en-bloc resection without intra-operative neurophysiological monitoring. AB - INTRODUCTION: Grade II and III intramedullary ependymomas [IME] are circumscribed with a plane of cleavage that should facilitate high gross total resection rates (GTR). Gross total resection of grade II/III IME is superior to subtotal resection (STR) and radiotherapy (RTx) for progression-free and overall survival. We sought to compare our GTR with other series that have utilised standard intraoperative monitoring techniques and we explored factors that may influence rates of resection. MATERIALS AND METHODS: Database search and retrospective chart and radiological review of all grade II or III spinal ependymomas over a 10 year period from the senior authors practice. Comprehensive PubMed search to identify similar series that identified histology, McCormick Function scores (MCC) preoperatively and post-operatively, surgical strategy and use of intraoperative monitoring. Standard statistical analysis was performed. RESULTS: Seventeen patients were identified: 16 grade II and one grade 3. GTR was 94.12%. Factors that correlated with a decline in MCC were longitudinal extension of the tumour (p = 0.0238) and presentation with motor signs and symptoms (p = 0.0223). There was no statistical difference between preoperative factors that influence post-operative outcomes in the current study when compared with other published series. There was no statistical difference between preoperative and postoperative MCC scores between our series and other published series. DISCUSSION: The current series with a GTR of 94.12% compares favourably with other published series with GTRs of 55.8-84% with no significant difference in functional outcomes. Series with low GTRs should examine their operative strategy or false-positive alarm rates which may lead to higher STRs. This series should be viewed as a unique opportunity to benchmark GTRs of circumscribed intramedullary tumours. PMID- 28019108 TI - Two new compounds from the seeds of Vernonia anthelmintica. AB - Two new compounds, named benzoyl-vernovan (1) and 2-(4'-hydroxyphenyl)-6-methyl 4H-pyran-4-one (2), together with one biflavonoid (3), one aurone (4) and six flavonoids were isolated from the seeds of Vernonia anthelmintica. Their structures were elucidated by extensive spectroscopic analyses and comparison with published data, and their influence on melanin content in B16 melanoma cells were tested. 5 and 9 increased melanin content by 2.2% and 30.9% higher than positive control 8-methoxypsoralen. PMID- 28019109 TI - Efficacy of a novel iPod-based navigation system compared to traditional navigation system in total knee arthroplasty. AB - BACKGROUND: This prospective study aimed to verify the efficacy of a novel, hand held, iPod-based navigation system in comparison to traditional navigation system for total knee arthroplasty (TKA). METHODS: Limb alignment, tibial and distal femoral bone cut thickness and plane were recorded intraoperatively using both iPod-based and traditional navigation system in 36 knees undergoing primary TKAs. RESULTS: Intraoperatively, the iPod-based navigation system showed good to excellent correlation and reliability for tibial and distal femoral bone cut thickness, plane of the femoral cut and limb alignment when compared to the traditional navigation system. CONCLUSIONS: Despite its quick registration feature, the iPod-based system has an efficacy similar to traditional navigation system and is a positive step towards making navigation systems for TKA more compact, user-friendly, time and cost-effective. PMID- 28019110 TI - Severe Kaposi Sarcoma in an Urban Public Hospital. AB - The national incidence of epidemic Kaposi sarcoma (KS) has decreased dramatically since the availability of combined antiretroviral therapy. Despite national trends, we continue to see admissions for KS. Electronic medical records were queried to identify patients with HIV who were admitted with active KS between 2010 and 2013 and records were reviewed to determine patient characteristics and factors affecting survival. Data were collected from all hospital admissions until death or May 1, 2015. Kaplan-Meier survival analysis with log-rank tests were used to test for differences in survival and Cox proportional hazards models were used to assess the prognostic value of variables. Odds ratios were calculated to determine factors associated with death during hospital admissions. Forty-three patients were admitted 141 times, with 81 admissions specifically related to KS. The majority of patients were highly immunosuppressed when KS was diagnosed (median CD4 count: 11), and 68% had multiple organ involvement with KS. Comorbidities at diagnosis included hepatitis B (26%) and pneumocystis pneumonia (33%). Frequent reasons for admission included skin and soft tissue complaints (28.4%) and respiratory complaints (27.2%). The estimated median survival after KS diagnosis was 3.0 years. Lung involvement, liver involvement, poor performance status, and low CD4 T cell count (<50) were associated with lower survival. Lung infections were the only admission diagnoses significantly associated with an increased odds of death during admission (OR: 5.42, 95% CI: 1.04-28.24). KS in our population is associated with poor access to healthcare and management of HIV. Factors affecting survival, including CD4 count and pulmonary involvement of KS, are in accordance with previous studies. Pulmonary KS should therefore be considered early in AIDS patients presenting with respiratory complaints. Our study also demonstrated that respiratory infections are associated with significant morbidity in patients with KS. PMID- 28019111 TI - [Application of password manager software in health care]. AB - When using multiple IT systems, handling of passwords in a secure manner means a potential source of problem. The most frequent issues are choosing the appropriate length and complexity, and then remembering the strong passwords. Password manager software provides a good solution for this problem, while greatly increasing the security of sensitive medical data. This article introduces a password manager software and provides basic information of the application. It also discusses how to select a really secure password manager software and suggests a practical application to efficient, safe and comfortable use for health care. Orv. Hetil., 2016, 157(52), 2066-2073. PMID- 28019112 TI - [Indications, diagnoses and quality markers in upper and lower endoscopies in 2010 and 2011 at the 1st Department of Medicine, Semmelweis University, Budapest]. AB - INTRODUCTION AND AIM: The aim was to assess the incidence of endoscopic findings based on the indication of the procedures in upper/lower endoscopies, and measuring quality indicators of colonoscopies at the 1st Department of Medicine, Semmelweis University, Budapest. METHOD: Data of 2987 patients (male/female:1361/1626, mean age: 60.7 years(y), SD: 16.7y) between 01.01.2010 and 31.12.2011 were analyzed. Both inpatient and outpatient records were collected. RESULTS: Incidence of peptic ulcer disease, esophageal varices, gastric polyps and gastric cancer were 10.8%, 4.5%, 6.1%, 2.9% in upper endoscopies, respectively. In colonoscopies colorectal polyps, diverticulosis, colorectal cancer and IBD were found in 29.9%, 22.4%, 6.9%, 9.7%, respectively. In patients having upper endoscopy with GI bleeding indication, older age (p<0.001), male gender (p<0.001, OR: 1.64), acenocoumarol/heparin use (p<0,001, peptic ulcers and esophageal varices were more frequent (p<0.001, OR: 2.83 and p<0.001, OR: 2.79), while in colonoscopies colorectal cancer had higher incidence (p<0.001, OR:3.27). 81% of colonoscopies were complete. Causes of incomplete procedures were ineffective bowel preparation (38.2%), technical difficulties (25.1%) and strictures (20.5%). CONCLUSION: The endoscopic findings and quality indicators (adenoma detection rate, coecal intubation rate) were in line with that reported in published series. Orv. Hetil., 2016, 157(52), 2074-2081. PMID- 28019113 TI - [Analysis of death certificates in postmortem examination waivers]. AB - INTRODUCTION AND AIM: The practices of autopsies and waivers in three Hungarian counties subject to the same statutory framework in a 5-year interval have been examined, with special attention to cases of non-natural death. METHOD: The summary data included in the post mortem examination certificates, for the years between 2006 and 2010, in a breakdown according to counties, covering all cases of death were analysed. The work was assisted by a Java-based software programme. RESULTS: In terms of the waiving of autopsies, a comparison of the three counties revealed significant differences. The persons who issue waivers from the performance of autopsies also vary across the counties. In case of deaths caused by accidents, no autopsy was performed in 844 cases. Similar situation was found in case of various identified and non-identified injuries, which were entered as the direct cause of death in 28 cases, as well as road traffic accidents entered in 32 cases and the unidentified consequences of road traffic accidents, which we found in 26 cases. No autopsy was performed in 25 cases of deaths assumed to be suicides and in one homicide. CONCLUSIONS: The Hungarian laws follow the recommendation of the Committee of Ministers to Member States of the Council of Europe, and provide that in all cases where the death is due to non-natural causes or the possibility of non-natural causes is raised, an autopsy should be performed. In this given legal context it is unclear how autopsies in the cases of death due to homicides, suicides and accidents as detailed above could possibly be dispensed with. The purpose of this paper was to provide a baseline study on the current practice of certification. The findings could be used in the course of governmental reviews for the purpose of drawing up recommendations. Orv. Hetil., 2016, 157(52), 2082-2087. PMID- 28019114 TI - [Lipids and cerebrovascular disease - New therapeutic options in lowering LDL cholesterol]. AB - Stroke is the third most common cause of death worldwide following myocardial infaction and malignancies, furthermore, its functional outcome is the worst of all conditions. Cholesterol, especially LDL-cholesterol plays a key role in the formation of atherosclerotic plaques. It has been verified recently that escalating incidence and mortality of cerebrovascular diseases are proportional to increased levels of LDL-cholesterol. Statin therapy undeniably reduces the risk of stroke, however other methods for decreasing lipid levels have not been proved significantly effective. Preventive effect of high-dose statin treatment is without doubt, although administration of such high dosage might require special precautions for patients with prior intracerebral hemorrhage and it also risks development of incident diabetes. The recently published IMPROVE-IT study is the first to prove that the addition of ezetimibe as a non-statin type drug, to statin treatment contributes to further reduction of LDL-cholesterol. The combination treatment results in additional decrease in the incidence and mortality of cerebrovascular events, without any expansion in the number or adverse effects. These results confirm the importance of any further reduction of LDL-cholesterol levels. Achieving target values with statin-ezetimibe combination allows administration of low to moderate dose of statin, which decreases risks of adverse effects related to high-dose statin therapy. Orv. Hetil., 2016, 157(52), 2059-2065. PMID- 28019117 TI - Introductory paragraph. PMID- 28019115 TI - [The relation of healthcare system with magical thinking]. PMID- 28019118 TI - The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents. AB - INTRODUCTION: Cyclophosphamide (CP) is an alkylating antineoplastic agent with known toxicity to the male reproductive system. Areas covered: This review summarizes the known mechanisms by which CP exerts its toxic effects on the male reproductive system and the methods utilized to prevent such effects so that it could be further investigated and applied in clinical use. Keywords including ['Cyclophosphamide' AND 'male reproductive' OR' sperm toxicity' OR 'spermatotoxicity' OR 'infertility] were searched through Google Scholar, PubMed and Scopus databases based on PRISMA guidelines. After removing duplicates and irrelevant data, 76 papers were reviewed concerning the outcomes of treatment of male mice, rats, and humans with CP and the effects of co-administration of various natural and synthetic compounds on male reproductive system. Expert opinion: CP exerts its effect mainly by inducing oxidative stress and changing gene expression in spermatocytes variably during different stages of development. These effects could be either restored or prevented by the administration of compounds with antioxidant properties and those which target the biochemical alterations induced by CP. PMID- 28019120 TI - Standing the test of time: Reflecting on the relevance today of Levinson's Pet Oriented Child Psychotherapy. AB - Having the opportunity to re-read Pet-Oriented Child Psychotherapy was like visiting an old friend and reminiscing about times gone by all too fast. The re read allowed me an opportunity to conceptualize how many of Levinson's early tenets continue to be relevant today. As a trailblazer, Levinson made a discovery that drastically changed the way we view and understand the power of the human animal bond. PMID- 28019119 TI - Evaluation of Bacillus subtilis SPB1 biosurfactant effects on hyperglycemia, angiotensin I-converting enzyme (ACE) activity and kidney function in rats fed on high-fat-high-fructose diet. AB - This study investigated the protective and the curative effects of Bacillus subtilis SPB1 crude lipopeptide biosurfactant in alleviating induced obesity complications in rats fed on high-fat-high-fructose diet (HFFD). Male Wistar rats were divided into five groups with the following treatment schedule: normal diet fed rats (CD), HFFD-fed rats, HFFD-fed rats supplemented with SPB1 biosurfactant from the first day of the experiment (HFFD + Bios1), rats fed on HFFD receiving standard drug (HFFD + Torva), or SPB1 biosurfactant (HFFD + Bios2) during the last 4 weeks of the study. HFFD induced hyperglycemia, manifested by a significant (p < 0.001) increase (20%) in the levels of glucose and alpha-amylase activity in the plasma, when compared with CD. The administration of SPB1 biosurfactant to rats fed on HFFD reverted back normal blood glucose and alpha amylase activity levels. Also, the findings clearly showed that acute oral administration of SPB1 biosurfactant reduced significantly (34%) the peak of blood glucose concentration 60 min after glucose administration, as compared with untreated rats fed on HFFD. Furthermore, renal dysfunction indices such as creatinine and urea as well as the level of angiotensin I-converting enzyme (ACE) exhibited remarkable increases in serum of rats fed on HFFD by 28.35%, 46%, and 92%,. Interestingly, SPB1 lipopeptides treatments decreased the creatinine and urea levels significantly (p < 0.001) near normal values, as compared with that of the HFFD group, and also showed an improvement of the kidney cortex architecture. Moreover, SPB1 biosurfactant displayed a potent inhibition of ACE activity in vitro (CI50 value= 1.37 mg/mL) as well as in vivo in obese rats by 42% and 27.25% with HFFD + Bios1 and HFFD + Bios2 treatments, respectively, and comparatively with the HFFD group. Besides, SPB1 lipopeptides treatments improved some of serum electrolytes such as Na+, K+, Ca2+ , and Mg2+. The results showed that SPB1 lipopeptide biosurfactant presented useful hypoglycemic and antihypertensive properties, and was able to alleviate renal lipid deposition in rats fed on a hypercaloric diet. PMID- 28019121 TI - Personality, Emotional Qualities of Leisure, and Subjective Well-Being in the Elderly. AB - In this study, we examined personality traits of older adults and their emotional experiences associated with engaging in specific leisure activities. Older individuals (17 males, 32 females), ages ranging from 65 to 97 years (mean age 74), completed measures of Big Five personality traits, positive and negative affect, subjective well-being (SWB), independent functioning, and an emotion activity inventory. As expected, Extraversion, Agreeableness, Conscientiousness, and Openness to experience were related to positive affect, while Neuroticism was related to negative affect. Openness and Agreeableness were related to positive emotions experienced in social and cognitive domains, and Agreeableness was related to greater SWB, greater positive affect, and more positively experienced activities. Neuroticism was related to lower SWB and fewer positively experienced activities. These findings suggest that assessing the fit between personality and emotions experienced during activities should be considered when creating programs tailored to elderly individuals, with the goal of encouraging more active and rewarding lives. PMID- 28019122 TI - Sedative-Hypnotic Use Among Older Adults Participating in Anxiety Research. AB - Older adults are prescribed sedative-hypnotic medications at higher rates than younger adults. These are not recommended for older adults due to risk of sedation, cognitive impairment, and falls. Severe generalized anxiety disorder (GAD) is a possibly appropriate use of these medications in older people, but little is available on use of sedative-hypnotic medications among older adults with GAD. This study examined the frequency and predictors of sedative-hypnotic medication use among older adults screening positive for anxiety. 25.88% ( n = 125) of participants reported taking sedative-hypnotics over the past 3 months; 16.36% ( n = 79) reported taking benzodiazepines, and 12.22% ( n = 59) reported taking hypnotic sleep medications. Depressive symptoms were more strongly associated with sedative-hypnotic use than insomnia or worry. Major depressive disorder and posttraumatic stress disorder, but not GAD, predicted sedative hypnotic use. Other medications and treatments are more appropriate and efficacious for depression, anxiety, and insomnia in this population. PMID- 28019123 TI - Age Differences in the Effects of Mortality Salience on the Correspondence Bias. AB - According to terror management theory, awareness of death affects diverse aspects of human thought and behavior. Studies have shown that older and younger adults differ in how they respond to reminders of their mortality. The present study investigated one hypothesized explanation for these findings: Age-related differences in the tendency to make correspondent inferences. The correspondence bias was assessed in younger and older samples after death-related, negative, or neutral primes. Younger adults displayed increased correspondent inferences following mortality primes, whereas older adults' inferences were not affected by the reminder of death. As in prior research, age differences were evident in control conditions; however, age differences were eliminated in the death condition. Results support the existence of age-related differences in responses to mortality, with only younger adults displaying increased reliance on simplistic information structuring after a death reminder. PMID- 28019124 TI - Immediate and residual effects of low-dose nandrolone decanoate and treadmill training on adipose and reproductive tissues of male Wistar rats. AB - CONTEXT: Residual effects after nandrolone decanoate (ND) treatment are not reported. OBJECTIVE: Immediate and residual effects of low-dose ND and treadmill training were investigated. MATERIALS AND METHODS: Male rats were trained and/or ND-treated for four weeks and the assessments were made after this period or four weeks later. RESULTS: The groups did not differ in final plasma glucose or AUC of the ivGTT, but hyperinsulinemia was noticed in some trained/treated groups. Training with ND increased muscle mass and ND decreased the reproductive structures. Decreased fat with training was reversed by detraining. DISCUSSION: The anabolic action of ND on skeletal muscle was enhanced by training. Fat and lipid changes were more linked to training/detraining, but the effects of ND on the reproductive structures persisted after treatment. CONCLUSIONS: The effects of training on fat and muscle were not maintained after detraining, but low-dose ND had persistent effects on the reproductive structures. PMID- 28019125 TI - Auditory speed tasks as potential candidates for the study of cognitive ageing. AB - Speed of information processing is an important cognitive ability. It facilitates the efficient operation of higher order cognitive functions, such as reasoning, and is implicated in various models of cognitive decline. The present study considers the potential benefits of expanding the measurement of processing speed to include the auditory modality. It examines the reliability and factorial structure of a variety of auditory and visual speed tasks in a sample of N = 138 older adults aged between 51 and 82 years. Our findings demonstrate that auditory measures can be used to assess processing speed as indexed by existing widely used tests of this ability. Moreover, the inclusion of auditory tasks significantly increases the relationship between processing speed and general cognitive ability. This novel research provides strong evidence of the suitability of auditory speed tasks for the study of cognitive function in older people, and demonstrates the importance of expanding cognitive measurement to include alternate modalities. PMID- 28019126 TI - Mode of delivery among women admitted with polyhydramnios. AB - A retrospective matched case control study was conducted to examine the incidence of caesarean delivery (CD) among women admitted with polyhydramnios with and without a trial of labour compared to women with normal amniotic fluid index (AFI). Singleton pregnancies diagnosed with polyhydramnios upon admission to labour between 2003 and 2013 were included. A control group (normal AFI) matched at a ratio of 1:1 was randomly selected. Primary outcome was the incidence of CD. A total of 588 women were included. The overall incidence of CD was significantly higher among women with polyhydramnios (31.3%) compared to the controls (18.7%), (p < .001). The incidences of both non-labouring caesarean and intrapartum operative deliveries were significantly higher among women with polyhydramnios compared to the controls (p = .007 and p = .01, respectively). On a multiple logistic regression model, polyhydramnios was found to be an independent risk factor for delivery by a caesarean (p = .0015; OR 2.0; 95%CI 1.30-2.90). PMID- 28019127 TI - Astroglial transcriptome dysregulation in early disease of an ALS mutant SOD1 mouse model. AB - Astroglia are a morphologically diverse and highly abundant cell type in the CNS. Despite these obvious observations, astroglia still remain largely uncharacterized at the cellular and molecular level. In disease contexts such as amyotrophic lateral sclerosis (ALS), it has been widely shown that astroglia downregulate crucial physiological functions, become hypertrophied, reactive, and toxic to motor neurons. However, little is known about the astroglia-specific transcriptomic changes that occur during ALS disease progression, especially early in disease. To address this, we FACS-isolated pure astroglia from early and mid-symptomatic superoxide dismutase 1 (SOD1) G93A spinal cord and performed microarray sequencing, in hopes to uncover markers and pathways driving astroglia dysfunction in ALS. After extensive analyses, we uncovered genes selectively enriched and downregulated in both control and SOD1 astroglia at both disease points. In addition, we were able to identify genes and pathways differentially expressed that may have relevance with other neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, suggesting a common theme among astroglial dysfunction in neurodegenerative disease. In aggregate, this study sheds light on the common and unique themes of dysfunction that astroglia undergo during neurodegenerative disease progression and provides candidate targets for therapeutic approaches. PMID- 28019128 TI - Screening of potential biomarkers for prenatal diagnosis of trisomy 21. AB - We aimed to identify key genes located on chromosome 21 as potential biomarkers for prenatal diagnosis of trisomy 21 (Ts21). The microarray data of GSE48051, including 10 cultivated amniocyte samples with Ts21 and 9 controls with normal euploid constitution, was obtained from Gene Expression Omnibus database. The differentially expressed genes (DEGs) in cultivated amniocyte samples with Ts21 compared to normal controls were screened using limma package. Then, we performed GO enrichment analysis using DAVID and chromosomal location of DEGs based on the information of the University of California Santa Cruz (UCSC) Genome Browser Database. Finally, protein-protein interaction (PPI) network analysis was performed using STRING. Total 155 DEGs in cultivated amniocyte samples with Ts21 were identified, including 89 up- and 66 down-regulated DEGs. The over represented GO terms of DEGs were mainly related with apoptosis, programmed cell death and cell death. In total, 13 DEGs were located on chromosome 21, thereinto, only 6 DEGs were included into the PPI network, including superoxide dismutase 1 (SOD1), phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase (GART), downstream neighbour of SON (DONSON), ATP synthase, H + transporting, mitochondrial F1 complex, O subunit (ATP5O), chromatin assembly factor 1, subunit B (p60) (CHAF1B) and proteasome (prosome, macropain) assembly chaperone 1 (PSMG1). Our results suggest that SOD1, GART, DONSON, ATP5O, CHAF1B and PSMG1 may play important roles in the pathogenesis of Down syndrome and may serve as potential biomarkers for prenatal diagnosis of Ts21. PMID- 28019129 TI - Stroke and Hypertension in Children and Adolescents. AB - Hypertension is the single most important modifiable risk factor for adult stroke. Stroke mortality has significantly decreased over the last 5 decades; this decline has been mainly associated to improved blood pressure control. Though much less prevalent than in adults, stroke is an increasingly recognized cause of morbidity and mortality in children. Although hypertension has not been strongly identified as a risk factor in childhood stroke yet, there is preliminary evidence that suggests that elevated blood pressure may be associated with stroke in children. This review summarizes the literature that may link elevated blood pressure to the development of childhood ischemic and hemorrhagic stroke. The authors suggest that elevated blood pressure may be a significant risk factor that, alone or in combination with other multiple risk factors, leads to the development of stroke in childhood. It is therefore recommend that blood pressure be measured and assessed carefully in every child presenting with acute stroke. PMID- 28019130 TI - Eliciting societal preferences of reimbursement decision criteria for anti cancer drugs in South Korea. AB - INTRODUCTION: In order to look beyond the cost-effectiveness analysis, this study used a multi-criteria decision analysis (MCDA), which reflects societal values with regard to reimbursement decisions. This study aims to elicit societal preferences of the reimbursement decision criteria for anti cancer drugs from public and healthcare professionals. METHODS: Eight criteria were defined based on a literature review and focus group sessions: disease severity, disease population size, pediatrics targets, unmet needs, innovation, clinical benefits, cost-effectiveness, and budget impacts. Using quota sampling and purposive sampling, 300 participants from the Korean public and 30 healthcare professionals were selected for the survey. Preferences were elicited using an analytic hierarchy process. RESULTS: Both groups rated clinical benefits the highest, followed by cost-effectiveness and disease severity, but differed with regard to disease population size and unmet needs. Innovation was the least preferred criteria. CONCLUSIONS: Clinical benefits and other social values should be reflected appropriately with cost-effectiveness in healthcare coverage. MCDA can be used to assess decision priorities for complicated health policy decisions, including reimbursement decisions. It is a promising method for making logical and transparent drug reimbursement decisions that consider a broad range of factors, which are perceived as important by relevant stakeholders. PMID- 28019131 TI - Heutagogic approach to developing capable learners. AB - The twenty-first century higher education sector has come a long way after undergoing continuous metamorphosis from pedagogy to andragogy. Most of the educational approaches adopted in medical schools are directed towards developing more of competencies and less of capability, which is the ability to use competencies in novel contexts. Competencies alone are not sufficient to thrive in the present day work place as medical profession subsumes complex contexts; it is in this scenario that, medical educators are entrusted with the challenging task of developing "capable learners". In the heutagogical approach, learners are required to decide upon what to learn and how to learn and therefore the control of the learning process is on the learner and the role of the teacher becomes that of a navigator. This paper highlights the current higher educational practices based on heutagogy, considers its application in the context of Problem based learning and also discusses a few challenges in incorporating this approach in the existing undergraduate medical curriculum. The article proposes the use of social media in order to support learner autonomy, which in turn improves learners' cognitive engagement with content and tasks, thereby assisting the development of attributes associated with capability. PMID- 28019133 TI - The effects of IL-1A and IL-6 genes polymorphisms on gene expressions, hormonal and biochemical parameters in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a multifactorial disease characterised by chronic inflammation. We aimed to investigate an association between IL-1A and IL 6 gene polymorphisms and both hormonal/biochemical parameters and levels of IL-1A and IL-6. A total of 103 women diagnosed with PCOS according to ESHRE/ASRM criteria were investigated. The patients were divided into two groups as obese and non-obese. IL-1A and IL-6 genes polymorphisms as well as hormonal/biochemical parameters and levels of IL-1A and IL-6 were analysed in the same groups. Serum IL-1A and IL-6 levels were found to increase both in obese and non-obese groups. However, there was no association between IL-1A level and IL-1A polymorphism. A relationship was detected between H score, FSH, LH, total testosterone, HDL-C and TG levels and CG + GG genotypes of IL-6. Furthermore, an association was found between IL-6 levels and CC genotype of IL-6 in the obese PCOS patients. The abnormalities in hormonal/biochemical parameters detected in Turkish PCOS patients may be related with IL-6 gene polymorphism rather than IL-1A. PMID- 28019132 TI - Association of the polymorphism 12109g>A from the REN gene as a risk factor for preterm birth. AB - INTRODUCTION: Preterm birth is the most important cause of neonatal mortality and morbidity. It is a multifactorial disease with different etiologies, including genetic factors. Genetic variability is represented by single nucleotide polymorphisms (SNPs) in genes of proteins involved in the contractile activity. We determine the association between SNP 12109G> A in REN associated with preterm birth and premature rupture of membrane. MATERIALS AND METHODS: A study of cases ( N=112, 22-36 weeks of gestation; mean: 31, 95% confidence interval 30.7-32.2) and controls ( N=66; 38-40 weeks of gestation from the last menstrual period; mean: 39.8, 95% confidence interval 38.9-39.4) was performed. Genomic DNA was isolated in all patients from peripheral blood. The SNP 12109G> A ( Mbo I) in REN was typified by PCR-restriction fragment length polymorphism. RESULTS: A significant difference in the case group for the SNP 12109G>A was observed. The A allele was increased in women with preterm birth (81% cases vs. 15% control, p<0.0000004). There was also a significant difference between genotypes, mainly an excess of G/A heterozygotes in women with preterm birth (60% cases vs. 23% controls). The phenotype 12109G> A has odds ratio 6.62 (95% confidence interval 3.14-14.15), which means a high risk of preterm birth/premature rupture of membrane in presence of allele A, both in homozygotes and in heterozygotes. CONCLUSION: Allelic frequency of A of SNP 12109G>A was higher in women with preterm birth than in women with normal vaginal delivery and could be considered a risk factor. PMID- 28019134 TI - The sex of the foetus affects maternal blood glucose concentrations in overweight and obese pregnant women. AB - There is increasing evidence that the sex of the foetus may alter the maternal metabolic milieu during pregnancy. Following a randomized controlled trial of exercise in overweight and obese pregnant women, we assessed whether the sex of the foetus was associated with changes in maternal metabolism. Data were analysed on 74 randomized participants who completed the trial, including 38 mothers carrying males and 36 mothers carrying females. At 19 weeks of gestation, mothers carrying boys had higher blood glucose concentrations than those carrying girls (5.4 vs 4.9 mmol/l; p = .046). At 36 weeks of gestation, differences were more marked, with blood glucose concentrations 15% higher in mothers carrying females (5.7 vs 5.0 mmol/l; p = .004). In addition, mothers carrying girls had higher concentrations of hs-CRP across pregnancy (5.0 vs 3.6 mg/l; p = .029). Our findings provide further evidence that the sex of the foetus appears to influence maternal metabolism. PMID- 28019135 TI - Developing a competency framework for academic physicians. AB - BACKGROUND: There is a mismatch between the requirements of the multifaceted role of academic physicians and their education. Medical institutions use faculty development initiatives to support their junior academic physicians, however, these rarely revolve around academic physician competencies. The aim of this study was to identify these academic physician competencies and develop a competency framework customized to an organizational context. METHODS: The authors conducted semi-structured interviews and Critical Incident Technique with 25 academic physicians at a teaching medical center in the Middle East region inquiring about the behaviors of academic physicians in teaching, clinical, research, and administrative roles. RESULTS: Using content analysis, the authors identified 16 competencies: five "Supporting Competencies", common to all four roles of academic physicians, and 11 "Function-Specific Competencies", specific to the role being fulfilled. The developed framework shared similarities with frameworks reported in the literature but also had some distinctions. CONCLUSIONS: The framework developed represents a step towards closing the gap between the skills medical students are taught and the skills required of academic physicians. The model was customized to the context of the current organization and included a future orientation and addressed the literature calling for increasing focus on the administrative skills of academic physicians. PMID- 28019136 TI - Causes of resident lapses in professional conduct during the training: A qualitative study on the perspectives of residents. AB - BACKGROUND: The residency is a critical period for doctors to establish their professional identity and ethical standards, and yet during this time, residents are susceptible to engage in a diverse range of unprofessional behaviors. To prevent the misconduct of residents, it is critical to have a thorough understanding of the contributing factors or circumstances. METHODS: We conducted a qualitative study on 20 residents at one Korean university-affiliated tertiary hospital. During in-depth interviews, residents were asked to reveal their experiences or observations of misconduct, and describe their perceptions on the attributes of professional lapses. RESULTS: Diverse unethical and unprofessional behaviors were extracted from the transcripts and reported in a previous paper. In the current paper, the attributes that residents regarded as the causes of their unprofessional behaviors were identified within four categories: (1) inadequate systems within training hospitals; (2) lack of professionalism education; (3) strong hierarchical structure; and (4) poor character of individuals. The residents tended to perceive their misconduct as situation sensitive, and emphasized the importance of systematic and cultural changes. CONCLUSIONS: To enhance medical professionalism among residents, the results of this study suggest the need of systematic and structured training programs, adequate professionalism education with clear codes of conduct, and active monitoring and feedback systems. PMID- 28019137 TI - Oral pyogenic granuloma gravidarum: A case report describing a large bleeding lingual lesion. PMID- 28019138 TI - Age differences in perceptions of memory strategy effectiveness for recent and remote memory. AB - We examined whether young and older adults hold different beliefs about the effectiveness of memory strategies for specific types of memory tasks and whether memory strategies are perceived to be differentially effective for young, middle aged, and older targets. Participants rated the effectiveness of five memory strategies for 10 memory tasks at three target ages (20, 50, and 80 years old). Older adults did not strongly differentiate strategy effectiveness, viewing most strategies as similarly effective across memory tasks. Young adults held strategy specific beliefs, endorsing external aids and physical health as more effective than a positive attitude or internal strategies, without substantial differentiation based on task. We also found differences in anticipated strategy effectiveness for targets of different ages. Older adults described cognitive and physical health strategies as more effective for older than middle-aged targets, whereas young adults expected these strategies to be equally effective for middle aged and older target adults. PMID- 28019139 TI - Individual luteolysis post GnRH-agonist-trigger in GnRH-antagonist protocols. AB - Over the past few years, the use of Gonadotropin-releasing-hormone (GnRH)-agonist for final oocyte maturation in GnRH-antagonist-protocols in stimulated IVF/ICSI cycles has gained worldwide acceptance, as this approach reduces significantly the risk for development of ovarian hyperstimulation syndrome (OHSS). Final oocyte maturation with GnRH-agonist leads to sever luteolysis, which cannot be counterbalanced using standard luteal phase support with purely progesterone (P4) application and therefore administration of hCG or high doses of P4 is considered to be essential to prevent/counteract luteolysis. However, lately publications indicate, that luteolysis is not always complete after GnRH-agonist for trigger. This case-series evaluates the degree of luteolysis in high-responder-patients, who received GnRH-agonist for final oocyte maturation. Assessment of estradiol (E2)- and P4-levels 48 h after oocyte-pick-up (OPU) procedure demonstrate clearly, that luteolysis after GnRH-agonist trigger is individual-specific, even in high-responder patients with the same number of oocytes. Hence, individualization of luteal phase support with the focus on avoiding unnecessary administration of hCG, bearing the risk for development of OHSS, a new concept of luteal coasting needs to be developed, based on severity of luteolysis following luteal coasting. PMID- 28019140 TI - Cutaneous mucormycosis as result of insulin administration in an AML patient: Case report and review of the literature. AB - We present a case of cutaneous mucormycosis in a patient with several important risk factors precipitating disease, namely underlying acute myeloid leukaemia and poorly controlled secondary diabetes. Inoculation was most likely caused by repeated minor trauma (insulin injection) at the site of infection. Treatment consisted of surgical debridement and liposomal Amphotericin B (LAmB) during 71 days. Posaconazole had already been initiated prior to infection as primary antifungal prophylaxis but was discontinued during follow-up as susceptibility testing later revealed resistance to posaconazole. Additional treatment with caspofungin and G-CSF was associated because of poor initial result to treatment. Caspofungin was later continued as monotherapy when LAmB had to be interrupted because of renal toxicity. Treatment was completed after closure of the surgical site. The patient was successfully treated and remains infection free for one year after initial diagnosis. PMID- 28019141 TI - Drawing on healthcare professionals' ethnicity: lessons learned from a Danish community pharmacy intervention for ethnic minorities. AB - AIMS: To present and discuss implementation experiences regarding the involvement of community pharmacists with ethnic minority backgrounds in a medication review intervention for ethnic minority poly-pharmacy patients in Denmark. METHODS: Data sources include 1) reflection notes from an introductory seminar with pharmacists and the cross-disciplinary research team and 2) five individual interviews and one focus group interview with pharmacists. Data were thematically coded and synthesised to identify underlying rationales and challenges encountered when involving professionals with ethnic minority backgrounds in interventions for ethnic minorities. RESULTS: Informants perceived the need for interventions targeted at ethnic minority poly-pharmacy patients, and highlighted the potential of involving professionals with diverse ethnic backgrounds in such interventions. However, implementation created challenges, because the professional identity of the pharmacists reduced their options for serving as peers with the same ethnic background. Furthermore, issues related to organisational difficulties and overcoming language barriers in the intervention impacted on the potential of involving professionals with ethnic minority backgrounds. CONCLUSIONS: Involving healthcare professionals with ethnic minority backgrounds in encounters with ethnic minorities holds potential for the adaptation of services to ethnically diverse populations, thus improving access to and quality of care. However, it is important to ensure sufficient personal and organisational support and to acknowledge the delicate balance between simultaneously serving as a peer and as a professional. PMID- 28019142 TI - The association between hyperglycemia and the prognosis of acute spontaneous intracerebral hemorrhage. AB - OBJECTIVE: To evaluate the potential association between the plasma glucose levels and the 90-day prognosis in patients with spontaneous intracerebral hemorrhage (sICH). METHODS: Patients with a well-defined diagnosis of sICH admitted within 24 h of onset were included. Random plasma glucose at admission and fasting plasma glucose on the following day were measured. Hyperglycemia was defined as a random plasma glucose >=10 mmol/L or a fasting plasma glucose >=7 mmol/L. Neurological severity at admission was assessed using the National Institutes of Health Stroke Scale (NIHSS). Functional outcomes were evaluated using modified Rankin Score (mRS) at three months after onset. Potential correlations between plasma glucose levels and neurological severity or functional outcomes values were assessed on Spearman's correlation analysis. Multivariable logistic regression analyses were performed to identify whether there were independent risk factors for 90-day outcomes after sICH. RESULTS: 228 consecutive adult patients with a mean age of 62.4 +/- 12.9 years were prospectively enrolled. No significant association was observed between the random glucose levels (r = 0.108, p = 0.146) or fasting glucose levels (r = 0.116, p = 0.098) with functional outcomes at 90 days after discharge. However, hyperglycemia was associated with the neurological severity of sICH, both random glucose levels (r = 0.183, p = 0.009)and fasting glucose levels (r = 0.133, p = 0.045). On logistic regression analyses, age and NIHSS values at admission were independently associated with poor outcomes. CONCLUSION: Hyperglycemia was associated with neurological severity of sICH, but not with 90-day outcomes. PMID- 28019190 TI - Evolution of design considerations in complex craniofacial reconstruction using patient-specific implants. AB - Previously published evidence has established major clinical benefits from using computer-aided design, computer-aided manufacturing, and additive manufacturing to produce patient-specific devices. These include cutting guides, drilling guides, positioning guides, and implants. However, custom devices produced using these methods are still not in routine use, particularly by the UK National Health Service. Oft-cited reasons for this slow uptake include the following: a higher up-front cost than conventionally fabricated devices, material-choice uncertainty, and a lack of long-term follow-up due to their relatively recent introduction. This article identifies a further gap in current knowledge - that of design rules, or key specification considerations for complex computer-aided design/computer-aided manufacturing/additive manufacturing devices. This research begins to address the gap by combining a detailed review of the literature with first-hand experience of interdisciplinary collaboration on five craniofacial patient case studies. In each patient case, bony lesions in the orbito-temporal region were segmented, excised, and reconstructed in the virtual environment. Three cases translated these digital plans into theatre via polymer surgical guides. Four cases utilised additive manufacturing to fabricate titanium implants. One implant was machined from polyether ether ketone. From the literature, articles with relevant abstracts were analysed to extract design considerations. In all, 19 frequently recurring design considerations were extracted from previous publications. Nine new design considerations were extracted from the case studies - on the basis of subjective clinical evaluation. These were synthesised to produce a design considerations framework to assist clinicians with prescribing and design engineers with modelling. Promising avenues for further research are proposed. PMID- 28019191 TI - You suffer from what you eat: beware of raw, undercooked, spoiled, inadequately preserved fish. PMID- 28019192 TI - Lipid-lowering effect and changes in estimated cardiovascular risk after switching to a tenofovir-containing regimen for the treatment of HIV-infected patients. AB - Tenofovir could have a direct lipid-lowering effect. The aim of our retrospective study was to investigate changes in cardiovascular risk after switching from a tenofovir-sparing to a tenofovir-containing backbone. Lipid parameters and cardiovascular risk [calculated using 10-years Framingham Risk Score (FRS) and 5 years DAD Risk Score (DRS)] were analysed at baseline and after three months. 273 patients were enrolled. After switching, significant decreases in total cholesterol (TC) (-8.2mg/dl, p < 0.001), LDL (-8.7mg/dl, p < 0.001) and DRS (mean -0.26%, p < 0.001) were observed, while a reduction in FRS was only observed in patients with pre-switch high TC or medium-high (>10%) FRS. Pre-switch factors associated with DRS reduction were higher TC, abacavir, new generation protease inhibitors, while zidovudine predicted an increase of DRS. Our results suggest that the improvement of lipid parameters observed after switching to a tenofovir containing backbone could lead to a significant reduction in predicted cardiovascular risk, which became more evident in subjects with higher cardiovascular risk. PMID- 28019241 TI - A regenerative approach towards recovering the mechanical properties of degenerated intervertebral discs: Genipin and platelet-rich plasma therapies. AB - Degenerative disc disease, associated with discrete structural changes in the peripheral annulus and vertebral endplate, is one of the most common pathological triggers of acute and chronic low back pain, significantly depreciating an individual's quality of life and instigating huge socioeconomic costs. Novel emerging therapeutic techniques are hence of great interest to both research and clinical communities alike. Exogenous crosslinking, such as Genipin, and platelet rich plasma therapies have been recently demonstrated encouraging results for the repair and regeneration of degenerated discs, but there remains a knowledge gap regarding the quantitative degree of effectiveness and particular influence on the mechanical properties of the disc. This study aimed to investigate and quantify the material properties of intact (N = 8), trypsin-denatured (N = 8), Genipin-treated (N = 8), and platelet-rich plasma-treated (N = 8) discs in 32 porcine thoracic motion segments. A poroelastic finite element model was used to describe the mechanical properties during different treatments, while a meta model analytical approach was used in combination with ex vivo experiments to extract the poroelastic material properties. The results revealed that both Genipin and platelet-rich plasma are able to recover the mechanical properties of denatured discs, thereby affording promising therapeutic modalities. However, platelet-rich plasma-treated discs fared slightly, but not significantly, better than Genipin in terms of recovering the glycosaminoglycans content, an essential building block for healthy discs. In addition to investigating these particular degenerative disc disease therapies, this study provides a systematic methodology for quantifying the detailed poroelastic mechanical properties of intervertebral disc. PMID- 28019345 TI - Thoughts from an editor's desk. PMID- 28019344 TI - The boy in the intensive care unit. PMID- 28019636 TI - In Silico Design, Synthesis and Bioactivity of N-(2, 4-Dinitrophenyl)-3-oxo- 3 phenyl-N-(aryl) Phenyl Propanamide Derivatives as Breast Cancer Inhibitors. AB - BACKGROUND: Breast cancer is a systemic disease which has challenged physicians worldwide as it is the most predominant cancer in women often leading to fatality. One of the types of treatment is chemotherapy which includes targeted oral or intravenous cancer-killing drugs. Treatment options are often limited to surgery and/or chemotherapy. OBJECTIVE: The discovery and design of new small molecule estrogen inhibitors is necessitated in order to circumvent the problem of drug-induced resistance in chemotherapy resulting in disease relapse. Chemoinformatics facilitates the design, selection and synthesis of new drug candidates for breast cancer by providing efficient in silico techniques for prediction of favourable ADMET properties, and structural descriptors to profile druggability of a compound. METHOD: Several molecules selected from docking studies were synthesized and evaluated for their biological activities on the MCF 7 (human breast cancer) cell line. RESULTS: These estrogen inhibitors displayed good inhibitory activity with high selectivity and hence can be further progressed as drug candidates effective against breast cancer. CONCLUSION: It is for the first time that N-(2, 4-dinitrophenyl)-3-oxo-3-phenyl-N-(aryl) phenylpropanamide derivatives were reported to be biological active as potential breast cancer inhibitors. PMID- 28019637 TI - Recent Advances in Targeted Therapy for Glioma. AB - Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. PMID- 28019638 TI - The Extracellular Bacterial HtrA Proteins as Potential Therapeutic Targets and Vaccine Candidates. AB - BACKGROUND: An increasing resistance of bacteria to the commonly used antimicrobials forces to search for alternative or supportive ways to cure infections. Targeting virulence factors is one of such approaches. The bacterial HtrA proteins are strongly involved in virulence and the lack of functional HtrA in many cases impairs invasiveness of pathogens. HtrAs act by protecting the cells under stressful conditions as well as they take direct part in invasion of the host. The latter function is played predominantly by the recently identified extracellular fraction of HtrA. This review aims to evaluate HtrAs as therapeutic targets, including design of chemical inhibitors and vaccines. METHODS: We undertook a thorough search of bibliographic databases for peer-reviewed scientific literature. RESULTS: One hundred and sixty-four papers were included in the review. First, we briefly summarized key structural and functional properties of known HtrA proteins with the special focus on the extracellular HtrA fraction. Then we provided an overview of efforts and advancements to target HtrAs of pathogenic bacteria as a promising antimicrobial therapy. In some cases, encouraging results were obtained and application of HtrAspecific inhibitors protected tissues from damage and killed bacteria. Also promising reports concerning the use of HtrA as a protective antigen in several disease models have recently been published. CONCLUSION: The findings of this review suggest that the exported HtrA proteins are very attractive therapeutic targets due to their accessibility, significance in virulence and immunogenicity. However, further extensive studies are still needed to develop a safe antimicrobial treatment. PMID- 28019640 TI - Semantic Dementia: A Mini-Review. AB - At present there are about 47.5 million people having different types of dementia and by 2030 this number would reach 75.6 million. This obviously brings about a serious social and economic burden for people who take care for those with any kind of dementia. The purpose of this article is to explore only semantic dementia (SD), more specifically called semantic variant of primary progressive aphasia, as one of the forms of frontotemporal dementia (FTD) and provide the latest information on its diagnosis and treatment which play a significant role in the maintenance of quality of life of both patients and their caregivers. Especially unimpaired communication is one of the key factors in the relationship between the patients and their caregivers. The methods used for this mini review include a literature review of available sources found in the world's acknowledged databases such as Web of Science, PubMed, Springer and Scopus from 2000 to 2015; and a comparison and evaluation of the selected studies. The findings of this mini review show that FTD, respectively SD, is a serious neurodegenerative disorder which has fatal consequences for the affected patients. In addition, the findings also indicate that there are not many possibilities of pharmacological treatment for semantic dementia and therefore more attention should be paid to alternative, non-pharmacological approaches. Although semantic dementia is a relatively rare neurodegenerative disorder if compared with other types of dementia, it has an irreversible impact on patient's and his/her caregiver's life in terms of quality. PMID- 28019639 TI - Novobiocin Analogs as Potential Anticancer Agents. AB - BACKGROUND: The aminocoumarin antibiotic, novobiocin, is a natural product that inhibits DNA gyrase, a bacterial enzyme involved in cell division. METHOD: More recently, novobiocin was found to act also on eukaryotic cells by blocking the 90 kDa heat shock protein (Hsp90). Hsp90 is a molecular chaperone, critical for folding, stabilization and activation of many proteins, in particular oncoproteins responsible for cancer progression. As opposed to the geldanamycin and radicicol, the known inhibitors of Hsp90 that bind to the N-terminal region, the binding domain of novobiocin is localized in the C-terminal part of this protein. While the N-terminal inhibition also leads to the induction of some pro survival signals, C-terminal inhibitors in which prosurvival responses are avoided and client degradation is maintained can be developed as a new class of potential anticancer chemotherapeutics. Numerous novobiocin analogs have been designed in the search for more potent compounds and some of them exhibit significantly enhanced anti-proliferative activity versus the natural product, as evaluated by cellular efficacies against several cancer cell lines. CONCLUSION: This review describes structure-activity-relationships of novobiocin analogs and some biological data reported so far on the anticancer activity of these modified compounds. PMID- 28019641 TI - Green Synthesis and Molecular Docking of Thiazolyl-thiazole Derivatives as Potential Cytotoxic Agents. AB - METHOD: A series of novel thiazole derivatives were synthesized in a good yield via reaction of 2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)hydrazine carbothioamide with hydrazonoyl halides. The reaction was performed in the presence of DABCO as an organocatalyst in short reaction times, easy workup, good to excellent yields. The structure of the newly synthesized products was elucidated via elemental analysis, spectral data and alternative routes whenever possible. Ten compounds were evaluated for their anti-cancer activity against the colon carcinoma cell line (HCT-116). RESULTS & CONCLUSION: The results revealed that most of the tested compounds showed high or moderate anti-cancer activity. The molecular docking of five novel thiazolyl-thiazole derivatives was performed by the Molecular Operating Environment (MOE) program. PMID- 28019642 TI - Recent Updates in Melanocyte Function: The Use of Promising Bioactive Compounds for the Treatment of Hypopigmentary Disorders. AB - BACKGROUND: Skin pigmentation is a broadly appearing phenomenon in nature which plays an important task of determining the appearance and biology of all vertebrates including human beings. Skin color is a crucial attribute, determined by the synthesis of melanin pigment within melanocytes by the process of melanogenesis and is regulated by many extrinsic as well as intrinsic factors. Tyrosinase catalyzes the key step of melanogenesis, dysfunction of tyrosinase leads to reduce melanin production which results in severe clinical and aesthetical problems of hypopigmentation. Therefore, the regulation of melanin production is an important strategy in the treatment of abnormal skin pigmentation for cosmetic and medicinal purpose. METHOD: The present review covers the various aspects of mammalian melanocyte biology which will help in the identification of key regulators of melanogenesis from pharmaceutical and pharmacological point of view. Further sections of the review focus on the dysfunctions of melanogenic pathways, which result in severe clinical and aesthetical problems of hypopigmentation. CONCLUSION: We have also attempted to highlight the ability of available scientifically validated plant extracts to naturally enhance melanin synthesis in order to cure hypopigmentation. PMID- 28019643 TI - Sleep quality improves with endoscopic sinus surgery in patients with chronic rhinosinusitis and nasal polyposis. AB - BACKGROUND: Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) is a chronic disease that has a major impact on generic and disease-specific quality of life. Little is known about the influence of CRSwNP on sleep and what effect surgery for CRSwNP has on sleep quality. The aim of the study was to investigate sleep quality in patients with CRSwNP before and after endoscopic surgery. METHODOLOGY: Forty-two patients filled out four validated sleep questionnaires and one sino/nasal, disease specific quality of life questionnaire before surgery and three months later. A healthy control group filled out the same questionnaires at baseline and after three months. RESULTS: An impact on sleep patterns was found in all sleep questionnaires and surgery clearly improved the quality of sleep. The Sino-nasal outcome test sum score decreased from median 51,5 to 26,5. Epworth sleepiness scale showed a decline in score from score 7.5 to 6.0. Surgery also reduced the risk for obstructive sleep apnoea in 13 patients evaluated by the Berlin Questionnaire and Multivariable Apnea Prediction Index. CONCLUSIONS: Patients with CRSwNP had impaired sleep quality, daytime sleepiness, nasal patency, and risk for sleep apnea, all of which improved after corrective surgery. PMID- 28019644 TI - Allergic rhinitis severity can be assessed using a visual analogue scale in mild, moderate and severe. AB - BACKGROUND: Allergic rhinitis is a global healthcare problem due to its high prevalence, impact on individuals and socioeconomic burden for the nations. Allergic rhinitis severity evaluation is the key to a correct treatment, prevention of comorbidities and improving the quality of life of patients. This evaluation should be made with a simple, easy, fast but accurate and reliable methodology, both in a primary care and specialist setting. The visual analogue scale (VAS) meets all requirements to be the ideal tool to assess allergic rhinitis severity and has already been validated by using a single cut-off point, but this classification in two degrees of severity suffer from not allocating the patients uniformly and from giving a blind interval to classify the patients when the score is between 5 to 6 cm. METHODOLOGY: The main objective of our study is to describe the optimal cut-off points by using a VAS to discriminate between three degrees of allergic rhinitis severity (mild, moderate, and severe) following the ARIA modified severity criteria that has been previously validated. Sensitivity, specificity, positive and negative predictive values just like receiver operating characteristic curves were used to select the best cut-off values. RESULTS: In a cross-sectional multicentre study with 3,572 patients included we have found that VAS has a significant correlation with nasal symptom score and quality of life and that the best cut-off points to differentiate between mild, moderate an severe allergic rhinitis are a VAS score of 4 and 7, respectively. CONCLUSIONS: Allergic rhinitis severity could be assessed in three degrees by using VAS in a simple, easy, and accurate method. PMID- 28019646 TI - Do repetitive Valsalva maneuvers reduce glymphatic clearance? PMID- 28019645 TI - The Mini Alcohol Craving Experience Questionnaire: Development and Clinical Application. AB - BACKGROUND: Standardized alcohol craving scales are rarely used outside of research environments despite recognized clinical utility. Scale length is a key barrier to more widespread application. A brief measure of alcohol craving is needed to improve research and treatment of alcohol use disorders (AUDs). Grounded in the Elaborated Intrusion Theory of Desire, the Alcohol Craving Experience (ACE) Questionnaire comprises two 11-item self-report scales that assess past-week frequency and maximum strength of alcohol craving. This study aimed to create a brief version of the ACE while maintaining psychometric integrity and clinical utility. METHODS: Patients attending a university hospital alcohol and drug outpatient service for the treatment of AUD completed the ACE as part of a questionnaire battery. Three patient samples were utilized: 519 patients with pretreatment and outcome data, 228 patients with pretreatment data, and 66 patients who completed the ACE at treatment sessions 1 and 2. RESULTS: The Frequency scale of the ACE possessed greater clinical utility and predictive validity than the Strength scale. Revision of the Frequency measure produced a 5 item "Mini Alcohol Craving Experience" (MACE) Questionnaire. Satisfactory validity (construct, predictive, concurrent, convergent, and incremental) and reliability (internal and test-retest) were maintained. A 1 standard deviation increase in pretreatment MACE score was associated with a 54 percentage increase in the odds of patient lapse or dropout. CONCLUSIONS: The MACE provides a brief, theoretically, and psychometrically robust measure of alcohol craving suitable for use with AUD populations in time-limited clinical and research settings. PMID- 28019647 TI - A novel surrogate to identify anatomical changes during radiotherapy of head and neck cancer patients. AB - PURPOSE: To develop a novel method to monitor external anatomical changes in head and neck cancer patients in order to triage possible adaptive radiotherapy needs. METHODS: The presented approach aims to provide information on internal anatomical changes based on variations observed in external anatomy. Setup Cone Beam Computed Tomography (CBCT) images are processed to produce an accurate external contour of the patient's skin. After registering the CBCTs to the reference planning CT, the external contours from each CBCT are transferred to the initial - first week - CBCT. Contour radii, defined as the distances between an external contour and the isocenter projection in each CBCT slice, are calculated for each scan over the full 360 degrees. The changes in external anatomy are then quantified by the difference in radial distance between the external contours of any secondary CBCT relative to the initial CBCT. Finally, the radial difference is displayed in cylindrical coordinates as a 2D intensity map to highlight regions of interests with significant changes. Weekly CBCT scans from 15 head and neck patients were retrospectively analyzed to demonstrate the utility of this approach as a proof of principle. External changes suggested by the 2D radial difference map of an example patient after 23 fractions were then correlated with the changes in the gross tumor volumes and organs at risks. The resulting dosimetric effects were evaluated. An interactive standalone software application has been developed to facilitate the generation and the interpretation of the 2D intensity map. RESULTS: The 2D radial difference maps provided qualitative and quantitative information, such as the location and the magnitude of external contour changes and the rate at which these deviations occur. Out of the 15 patients, 10 presented clear evidence of general external volume shrinkage due to weight loss, and nine patients had at least one site of local shrinkage. Only two patients showed no signs of anatomical change during their entire treatment course. For the example patient, the mean (+/-sigma) radial difference was 6.7 (+/-3.0) mm for the left parotid and 7.3 (+/-2.5) mm for the right parotid. The mean dose to the left and right parotids increased from 20.1 Gy to 30 Gy and from 16.3 Gy to 29.6 Gy, respectively. CONCLUSION: This novel method provides an efficient tool to visualize 3D external anatomical changes on a single 2D map. It quickly pinpoints the location of differences in anatomy during the course of radiotherapy, which can help physicians determine if a treatment plan needs to be adapted. The interactive graphic user interface developed in this study will be evaluated in an adaptive radiotherapy workflow for head and neck patients in a future prospective trial. PMID- 28019648 TI - Reply. PMID- 28019649 TI - The relative accuracy of 4D dose accumulation for lung radiotherapy using rigid dose projection versus dose recalculation on every breathing phase. AB - PURPOSE: To investigate the accuracy of 4D dose accumulation using projection of dose calculated on the end-exhalation, mid-ventilation, or average intensity breathing phase CT scan, versus dose accumulation performed using full Monte Carlo dose recalculation on every breathing phase. METHODS: Radiotherapy plans for 10 patients with stage I-II lung cancer were analyzed. All patients had respiratory-correlated computed tomography (4D-CT) performed as part of an IRB approved research protocol. Stereotactic body radiotherapy (SBRT) plans were optimized using the dose calculated by a commercially available Monte Carlo algorithm on the end-exhalation 4D-CT phase. 4D dose accumulations using deformable registration were performed with a commercially available tool that projected the planned dose onto every breathing phase without recalculation, as well as with a Monte Carlo recalculation of the dose on all breathing phases. The 3D planned dose (3D-EX), the 3D dose calculated on the average intensity image (3D-AVE), and the 4D accumulations of the dose calculated on the end-exhalation phase CT (4D-PR-EX), the mid-ventilation phase CT (4D-PR-MID), and the average intensity image (4D-PR-AVE), respectively, were compared against the accumulation of the Monte Carlo dose recalculated on every phase. Plan evaluation metrics relating to target volumes and critical structures relevant for lung SBRT were analyzed. RESULTS: Plan evaluation metrics tabulated using 4D-PR-EX, 4D-PR-MID, and 4D-PR-AVE differed from those tabulated using Monte Carlo recalculation on every phase by an average of 0.14 +/- 0.70 Gy, -0.11 +/- 0.51 Gy, and 0.00 +/- 0.62 Gy, respectively. Plan evaluation metrics calculated from 3D-EX and 3D-AVE were acceptably accurate for target volumes and most critical structures, however, deviations of between 8 and 13 Gy were observed for the proximal bronchial trees of three patients. CONCLUSIONS: The accuracy of 4D dose accumulated by projecting the dose calculated on the end-exhale, mid-ventilation, and average intensity images has been presented for 10 lung cancer SRBT plans. These methods involving projection without recalculation may be sufficiently accurate compared to 4D dose accumulated from Monte Carlo recalculation on every phase, depending on institutional protocols. Projection of the dose calculated on the mid-ventilation scan was found to be statistically significantly more accurate than projection of the dose calculated on end-exhalation when considering target volume dose metrics. Use of 4D dose accumulation should be considered when evaluating normal tissue complication probabilities as well as in clinical situations where target volumes are directly inferior to mobile critical structures. PMID- 28019650 TI - Genomic analysis reveals frequent TRAF7 mutations in intraneural perineuriomas. AB - Intraneural perineuriomas are benign peripheral nerve sheath tumors that cause progressive debilitating focal extremity weakness. The etiology of perineuriomas is largely unknown. We utilized whole exome sequencing, copy number algorithm evaluation, and high-resolution whole genome microarray to investigate for a genetic causal link to intraneural perineuriomas. Ten of 16 (60%) tumor cases had mutations in the WD40 domain of TRAF7, the same location for causal mutations of meningiomas. Two additional perineurioma cases had large chromosomal abnormalities in multiple chromosomes, including chromosome 22q. This study identifies a common cause for intraneural perineuriomas and an unexpected shared pathogenesis with intracranial meningiomas. Ann Neurol 2017;81:316-321. PMID- 28019651 TI - Infratentorial superficial siderosis: Classification, diagnostic criteria, and rational investigation pathway. AB - Central nervous system infratentorial superficial siderosis (iSS) is increasingly detected by blood-sensitive magnetic resonance imaging (MRI) sequences. Despite this, there are no standardized diagnostic criteria, and the clinical radiological spectrum, causes, and optimum investigation strategy are not established. We reviewed clinical and radiological details of patients with iSS assessed at a specialist neurological center during 2004-2016 using predefined standardized radiological criteria. All imaging findings were rated blinded to clinical details. We identified 65 patients with iSS, whom we classified into 2 groups: type 1 (classical) and type 2 (secondary) iSS. Type 1 (classical) iSS included 48 patients without any potentially causal radiologically confirmed single spontaneous or traumatic intracranial hemorrhage, of whom 39 (83%) had hearing loss, ataxia, or myelopathy; type 2 (secondary) iSS included 17 patients with a potentially causal radiologically confirmed spontaneous or traumatic intracranial hemorrhage, of whom none had hearing loss, ataxia, or myelopathy. Of the patients with type 1 (classical) iSS, 40 (83%) had a potentially causal cranial or spinal dural abnormality, 5 (11%) had an alternative cause, and 3 (6%) had no cause identified. Intra-arterial digital subtraction angiography did not identify any underlying causal lesions for type 1 iSS. Type 1 (classical) iSS, defined using simple radiological criteria, is associated with a characteristic neurological syndrome. Rational investigation, including spinal MRI, nearly always reveals a potential cause, most often a dural abnormality. Catheter angiography appears to be unhelpful, suggesting that classical iSS is not associated with macrovascular arterial pathology. Recognition of type 1 (classical) iSS should allow timely diagnosis and early consideration of treatment. Ann Neurol 2017;81:333-343. PMID- 28019652 TI - Clinical Validation of Reduced Alcohol Consumption After Treatment for Alcohol Dependence Using the World Health Organization Risk Drinking Levels. AB - BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerable individual and societal costs. Abstinence from alcohol is the most widely accepted target of treatment for AUD, but it severely limits treatment options and could deter individuals who prefer to reduce their drinking from seeking treatment. Clinical validation of reduced alcohol consumption as the primary outcome of alcohol clinical trials is critical for expanding treatment options. One potentially useful measure of alcohol treatment outcome is a reduction in the World Health Organization (WHO, International Guide for Monitoring Alcohol Consumption and Related Harm. Geneva, Switzerland, 2000) risk levels of alcohol use (very high risk, high risk, moderate risk, and low risk). For example, a 2-shift reduction in WHO risk levels (e.g., high risk to low risk) has been used by the European Medicines Agency (2010, Guideline on the Development of Medicinal Products for the Treatment of Alcohol Dependence. UK) to evaluate nalmefene as a treatment for alcohol dependence (AD; Mann et al. 2013, Biol Psychiatry 73, 706-13). METHODS: The current study was a secondary data analysis of the COMBINE study (n = 1,383; Anton et al., ) to examine the association between reductions in WHO risk levels and reductions in alcohol-related consequences and mental health symptoms during and following treatment in patients with AD. RESULTS: Any reduction in WHO risk drinking level during treatment was associated with significantly fewer alcohol related consequences and improved mental health at the end of treatment and for up to 1 year posttreatment. A greater reduction in WHO risk drinking level predicted a greater reduction in consequences and greater improvements in mental health. CONCLUSIONS: Changes in WHO risk levels appear to be a valid end point for alcohol clinical trials. Based on the current findings, reductions in WHO risk drinking levels during treatment reflect meaningful reductions in alcohol related consequences and improved functioning. PMID- 28019653 TI - Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling. AB - Receptor tyrosine kinase (RTK) signaling controls key aspects of cellular differentiation, proliferation, survival, metabolism, and migration. Deregulated RTK signaling also underlies many cancers. Glycosphingolipids (GSL) are essential elements of the plasma membrane. By affecting clustering and activity of membrane receptors, GSL modulate signal transduction, including that mediated by the RTK. GSL are abundant in the nervous system, and glial development in Drosophila is emerging as a useful model for studying how GSL modulate RTK signaling. Drosophila has a simple GSL biosynthetic pathway, in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3-kinase (PI3K). However, to what extent this effect involves changes in upstream signaling events is unresolved. We show here that glial overgrowth in egh is strongly linked to increased activation of Insulin and fibroblast growth factor receptors (FGFR). Glial hypertrophy is phenocopied when overexpressing gain-of-function mutants of the Drosophila insulin receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of insulin and fibroblast growth factor receptors in Drosophila glia. PMID- 28019656 TI - [11 C]PBR-28 positron emission tomography in multiple sclerosis: Neuroinflammation or otherwise? PMID- 28019654 TI - Drinking, Alcohol Use Disorder, and Treatment Access and Utilization Among U.S. Racial/Ethnic Groups. AB - Data from approximately 140 articles and reports published since 2000 on drinking, alcohol use disorder (AUD), correlates of drinking and AUD, and treatment needs, access, and utilization were critically examined and summarized. Epidemiological evidence demonstrates alcohol-related disparities across U.S. racial/ethnic groups. American Indians/Alaska Natives generally drink more and are disproportionately affected by alcohol problems, having some of the highest rates for AUD. In contrast, Asian Americans are less affected. Differences across Whites, Blacks, and Hispanics are more nuanced. The diversity in drinking and problem rates that is observed across groups also exists within groups, particularly among Hispanics, Asian Americans, and American Indians/Alaska Natives. Research findings also suggest that acculturation to the United States and nativity affect drinking. Recent studies on ethnic drinking cultures uncover the possible influence that native countries' cultural norms around consumption still have on immigrants' alcohol use. The reasons for racial/ethnic disparities in drinking and AUD are complex and are associated with historically rooted patterns of racial discrimination and persistent socioeconomic disadvantage. This disadvantage is present at both individual and environmental levels. Finally, these data indicate that admission to alcohol treatment is also complex and is dependent on the presence and severity of alcohol problems but also on a variety of other factors. These include individuals' sociodemographic characteristics, the availability of appropriate services, factors that may trigger coercion into treatment by family, friends, employers, and the legal system, and the overall organization of the treatment system. More research is needed to understand facilitators and barriers to treatment to improve access to services and support. Additional directions for future research are discussed. PMID- 28019655 TI - Tumour-activated liver stromal cells regulate myeloid-derived suppressor cells accumulation in the liver. AB - Regulating mechanisms underlying hepatic myeloid-derived suppressor cell (MDSC) accumulation remain to be described. Here, we provide evidence for the involvement of tumour-activated liver stromal cells in the process of hepatic MDSCs migration and accumulation. Our data showed an elevated frequency of MDSCs in the liver of tumour-bearing mice. Moreover, tumour-activated liver stromal cells promote MDSC migration into the liver site. Further investigation indicated higher levels of cytokine and chemokine expression in liver stromal cells after exposure to the tumour-conditioned supernatant. Notably, the expression levels of proinflammatory factors, mainly including macrophage colony stimulating factor (M CSF), transforming growth factor-beta (TGF-beta), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor-1 (SDF-1), increased after treatment with tumour-conditioned supernatant, and blockade of MCP-1 or SDF-1 decreased the proportion of tumour infiltrated MDSCs in mice co-transplanted with liver stromal cells and tumour cells, but not in mice with only tumour cells injection. These findings demonstrate that tumour-activated liver stromal cells produce higher levels of chemokines and cytokines, which may contribute to MDSC accumulation into the liver site in patients with liver cancer. PMID- 28019658 TI - Reply. PMID- 28019657 TI - The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival. AB - OBJECTIVE: Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. METHODS: Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. RESULTS: MC1Re/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6 hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity. INTERPRETATION: Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395-406. PMID- 28019660 TI - High dose-per-pulse electron beam dosimetry: Usability and dose-rate independence of EBT3 Gafchromic films. AB - PURPOSE: The aim of this study was to assess the suitability of Gafchromic EBT3 films for reference dose measurements in the beam of a prototype high dose-per pulse linear accelerator (linac), capable of delivering electron beams with a mean dose-rate (Dm ) ranging from 0.07 to 3000 Gy/s and a dose-rate in pulse (Dp ) of up to 8 * 106 Gy/s. To do this, we evaluated the overall uncertainties in EBT3 film dosimetry as well as the energy and dose-rate dependence of their response. MATERIAL AND METHODS: Our dosimetric system was composed of EBT3 Gafchromic films in combination with a flatbed scanner and was calibrated against an ionization chamber traceable to primary standard. All sources of uncertainties in EBT3 dosimetry were carefully analyzed using irradiations at a clinical radiotherapy linac. Energy dependence was investigated with the same machine by acquiring and comparing calibration curves for three different beam energies (4, 8 and 12 MeV), for doses between 0.25 and 30 Gy. Dm dependence was studied at the clinical linac by changing the pulse repetition frequency (f) of the beam in order to vary Dm between 0.55 and 4.40 Gy/min, while Dp dependence was probed at the prototype machine for Dp ranging from 7 * 103 to 8 * 106 Gy/s. Dp dependence was first determined by studying the correlation between the dose measured by films and the charge of electrons measured at the exit of the machine by an induction torus. Furthermore, we compared doses from the films to independently calibrated thermo-luminescent dosimeters (TLD) that have been reported as being dose-rate independent up to such high dose-rates. RESULTS: We report that uncertainty below 4% (k = 2) can be achieved in the dose range between 3 and 17 Gy. Results also demonstrated that EBT3 films did not display any detectable energy dependence for electron beam energies between 4 and 12 MeV. No Dm dependence was found either. In addition, we obtained excellent consistency between films and TLDs over the entire Dp range attainable at the prototype linac confirming the absence of any dose-rate dependence within the investigated range (7 * 103 to 8 * 106 Gy/s). This aspect was further corroborated by the linear relationship between the dose-per-pulse (Dp ) measured by films and the charge per pulse (Cp ) measured at the prototype linac exit. CONCLUSION: Our study shows that the use of EBT3 Gafchromic films can be extended to reference dosimetry in pulsed electron beams with a very high dose rate. The measurement results are associated with an overall uncertainty below 4% (k = 2) and are dose-rate and energy independent. PMID- 28019659 TI - Na+ /H+ exchanger NHE1 and NHE2 have opposite effects on migration velocity in rat gastric surface cells. AB - Following superficial injury, neighbouring gastric epithelial cells close the wound by rapid cell migration, a process called epithelial restitution. Na+ /H+ exchange (NHE) inhibitors interfere with restitution, but the role of the different NHE isoforms expressed in gastric pit cells has remained elusive. The role of the basolaterally expressed NHE1 (Slc9a1) and the presumably apically expressed NHE2 (Slc9a2) in epithelial restitution was investigated in the nontransformed rat gastric surface cell line RGM1. Migration velocity was assessed by loading the cells with the fluorescent dye DiR and following closure of an experimental wound over time. Since RGM1 cells expressed very low NHE2 mRNA and have low transport activity, NHE2 was introduced by lentiviral gene transfer. In medium with pH 7.4, RGM1 cells displayed slow wound healing even in the absence of growth factors and independently of NHE activity. Growth factors accelerated wound healing in a partly NHE1-dependent fashion. Preincubation with acidic pH 7.1 stimulated restitution in a NHE1-dependent fashion. When pH 7.1 was maintained during the restitution period, migratory speed was reduced to ~10% of the speed at pH 7,4, and the residual restitution was further inhibited by NHE1 inhibition. Lentiviral NHE2 expression increased the steady-state pHi and reduced the restitution velocity after low pH preincubation, which was reversible by pharmacological NHE2 inhibition. The results demonstrate that in RGM1 cells, migratory velocity is increased by NHE1 activation, while NHE2 activity inhibit this process. A differential activation of NHE1 and NHE2 may therefore, play a role in the initiation and completion of the epithelial restitution process. PMID- 28019661 TI - KCNA2 mutations are rare in hereditary spastic paraplegia. PMID- 28019662 TI - Simvastatin is associated with decreased risk of Parkinson disease. PMID- 28019663 TI - Stereotactic radiosurgery planning of vestibular schwannomas: Is MRI at 3 Tesla geometrically accurate? AB - PURPOSE: MRI is a mandatory requirement to accurately plan Stereotactic Radiosurgery (SRS) for Vestibular Schwannomas. However, MRI may be distorted due not only to inhomogeneity of the static magnetic field and gradients but also due to susceptibility-induced effects, which are more prominent at higher magnetic fields. We assess geometrical distortions around air spaces and consider MRI protocol requirements for SRS planning at 3 T. METHODS: Hardware-related distortion and the effect of incorrect shimming were investigated with structured test objects. The magnetic field was mapped over the head on five volunteers to assess susceptibility-related distortion in the naso-oro-pharyngeal cavities (NOPC) and around the internal ear canal (IAC). RESULTS: Hardware-related geometric displacements were found to be less than 0.45 mm within the head volume, after distortion correction. Shimming errors can lead to displacements of up to 4 mm, but errors of this magnitude are unlikely to arise in practice. Susceptibility-related field inhomogeneity was under 3.4 ppm, 2.8 ppm, and 2.7 ppm for the head, NOPC region and IAC region, respectively. For the SRS planning protocol (890 Hz/pixel, approximately 1 mm3 isotropic), susceptibility-related displacements were less than 0.5 mm (head), and 0.4 mm (IAC and NOPC). Large displacements are possible in MRI examinations undertaken with lower receiver bandwidth values, commonly used in clinical MRI. Higher receiver bandwidth makes the protocol less vulnerable to sub-optimal shimming. The shimming volume and the CT-MR co-registration must be considered jointly. CONCLUSION: Geometric displacements can be kept under 1 mm in the vicinity of air spaces within the head at 3 T with appropriate setting of the receiver bandwidth, correct shimming and employing distortion correction. PMID- 28019664 TI - Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle. AB - Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24-96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and large-conductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions. PMID- 28019665 TI - The impact of left ventricular stretching in model cultivations with neonatal cardiomyocytes in a whole-heart bioreactor. AB - Here, we investigate the impact of integrated three-dimensional (3D) left ventricular (LV) stretching on myocardial maturation in a whole-heart bioreactor setting. Therefore, decellularized rat hearts were selectively repopulated with rodent neonatal cardiomyocytes (5 . 106 cells per heart) and cultured over 5 days. Continuous medium perfusion was maintained through the coronary artery system in a customized whole-heart bioreactor system with or without integrated biomechanical stimulation of LV. 3D repopulation effectiveness and cellular vitality were evaluated by repetitive metabolic WST-1 assays and 3D confocal microscopy analysis through fluorescent staining, also assessing cellular organization. Moreover, specific myocardial vitality was verified by detecting spontaneous electrophysiological activity using a multielectrode assay. Western blot analysis of cardiac myosin heavychain (MHC) and quantitative RT-PCR for Connexin 43 was used to analyze cardiomyocyte maturation. Decellularized whole heart constructs repopulated with neonatal cardiomyocytes (repopWHC) showed vital 3D cell populations throughout the repopulation sites within the LV with a significant increase in metabolic activity (326 +/- 113% for stimulated constructs vs. 162 +/- 32% for non-stimulated controls after 96 h of continuous cultivation as compared to their state 24 h after injection, directly prior to bioreactor cultivation). Further, bioreactor cultivation under integrated mechanical LV stimulation not only led to a higher degree of cellular organization and an increased MHC content, but also to a significant increase of Cx43 gene expression resulting in a regain of 60 +/- 19% of native neonatal hearts expression level in contrast to 20 +/- 9% for non-stimulated controls (P = 0.03). Therefore, our study suggests that the integration of LV stretching into whole-heart bioreactor cultivation may enhance cardiac maturation not only by promoting cellular organization but also through adaptive protein and gene expression with particular implications for the formation of the conductive apparatus. Further, this study emphasizes the importance of suitable bioprocessing strategies within sophisticated bioreactor systems as tools for customized stimulation and cultivation of tissue engineered tissues and organs. Biotechnol. Bioeng. 2017;114: 1107-1117. (c) 2016 Wiley Periodicals, Inc. PMID- 28019666 TI - Engineering the N-terminal end of CelA results in improved performance and growth of Caldicellulosiruptor bescii on crystalline cellulose. AB - CelA is the most abundant enzyme secreted by Caldicellulosiruptor bescii and has been shown to outperform mixtures of commercially available exo- and endoglucanases in vitro. CelA contains both a glycoside hydrolase family 9 endoglucanase and a glycoside hydrolase family 48 exoglucanase known to be synergistic in their activity, connected by three cellulose-binding domains via linker peptides. Here, repeated aspartate residues were introduced into the N terminal ends of CelA GH9 and GH48 domains to improve secretion efficiency and/or catalytic efficiency of CelA. Among several constructs, the highest activity on carboxymethylcellulose (CMC), 0.81 +/- 0.03 mg/mL was observed for the C. bescii strain containing CelA with 5-aspartate tag at the N-terminal end of GH9 domain an 82% increase over wild type CelA. In addition, expression of CelA with N terminal repeated aspartate residues in C. bescii results in a dramatic increase in its ability to grow on Avicel. Biotechnol. Bioeng. 2017;114: 945-950. (c) 2016 Wiley Periodicals, Inc. PMID- 28019667 TI - Isolation, identification, and characterization of cancer stem cells: A review. AB - Cancer stem cells (CSCs) or tumor-initiating cells (TICs) as a small subset of neoplastic cells are able to produce a tumor (tumorigenesis), maintain the population of tumorigenic cells (self-renewal), and generate the heterogeneous cells constructing the entire tumor (pluripotency). The research on stationary and circulating CSCs due to resistance to conventional therapies and inability in complete eradication of cancer is critical for developing novel therapeutic strategies for a more effective reduction in the risk of tumor metastasis and cancer recurrence. This review compiles information about different methods of detection and dissociation, side population, cellular markers, and establishment culture of CSCs, as well as characteristics of CSCs such as tumorigenicity, and signaling pathways associated with self-renewal and the capability of the same histological tumor regeneration in various cancers. PMID- 28019668 TI - Monosialyl Ganglioside GM3 Decreases Apolipoprotein B-100 Secretion in Liver Cells. AB - Some sialic acid-containing glycolipids are known to regulate development of atherosclerosis with accumulated plasma apolipoprotein B-100 (Apo-B)-containing lipoproteins, because Apo-B as an atherogenic apolipoprotein is assembled mainly in VLDL and LDL. Previously, we have elucidated that disialyl GD3 promotes the microsomal triglyceride transfer protein (MTP) gene expression and secretion of triglyceride (TG)-assembled ApoB, claiming the GD3 role in ApoB lipoprotein secretion in liver cells. In the synthetic pathway of gangliosides, GD3 is synthesized by addition of a sialic acid residue to GM3. Thus, there should be some regulatory links between GM3 and GD3. In this study, exogenous and endogenous monosialyl GM3 has been examined how GM3 plays a role in ApoB secretion in Chang liver cells in a view point of MTP and ApoB degradation in the same cells. The level of GM3 ganglioside in the GM3 synthase gene-transfected cells was increased in the cell extract, but not in the medium. In addition, GM3 synthase gene-transfected cells showed a diminished secretion of TG-enriched ApoB with a lower content of TG in the medium. Exogenous GM3 treatment for 24 h exerted a dose dependent inhibitory effect on ApoB secretion together with TG, while a liver-specific albumin was unchanged, indicating that GM3 effect is limited to ApoB secretion. GM3 decreased the mRNA level of MTP gene, too. ApoB protein assembly dysregulated by GM3 indicates the impaired ApoB secretion is caused by a proteasome-dependent pathway. Treatment with small interfering RNAs (siRNAs) decreased ApoB secretion, but GM3-specific antibody did not. These results indicate that plasma membrane associated GM3 inhibits ApoB secretion, lowers development of atherosclerosis by decreasing the secretion of TG-enriched ApoB containing lipoproteins, suggesting that GM3 is an inhibitor of ApoB and TG secretion in liver cells. J. Cell. Biochem. 118: 2168-2181, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28019669 TI - Transforming Growth Factor-beta1 Modulates the Expression of Syndecan-4 in Cultured Vascular Endothelial Cells in a Biphasic Manner. AB - Proteoglycans are macromolecules that consist of a core protein and one or more glycosaminoglycan side chains. Previously, we reported that transforming growth factor-beta1 (TGF-beta1 ) regulates the synthesis of a large heparan sulfate proteoglycan, perlecan, and a small leucine-rich dermatan sulfate proteoglycan, biglycan, in vascular endothelial cells depending on cell density. Recently, we found that TGF-beta1 first upregulates and then downregulates the expression of syndecan-4, a transmembrane heparan sulfate proteoglycan, via the TGF-beta receptor ALK5 in the cells. In order to identify the intracellular signal transduction pathway that mediates this modulation, bovine aortic endothelial cells were cultured and treated with TGF-beta1 . Involvement of the downstream signaling pathways of ALK5-the Smad and MAPK pathways-in syndecan-4 expression was examined using specific siRNAs and inhibitors. The data indicate that the Smad3-p38 MAPK pathway mediates the early upregulation of syndecan-4 by TGF-beta1 , whereas the late downregulation is mediated by the Smad2/3 pathway. Multiple modulations of proteoglycan synthesis may be involved in the regulation of vascular endothelial cell functions by TGF-beta1 . J. Cell. Biochem. 118: 2009 2017,2017. (c) 2016 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. PMID- 28019670 TI - Smoothened-antagonists reverse homogentisic acid-induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria. AB - Alkaptonuria (AKU) is an ultra-rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignaling and Hedgehog signaling pathways. Hedgehog signaling has been demonstrated to be activated in osteoarthritis (OA) and to drive cartilage degeneration in vivo. The numerous similarities between OA and AKU suggest that primary cilia Hedgehog signaling may also be altered in AKU. Thus, we characterized an AKU cellular model in which healthy chondrocytes were treated with HGA (66 uM) to replicate AKU cartilage pathology. We investigated the degree of activation of the Hedgehog signaling pathway and how treatment with inhibitors of the receptor Smoothened (Smo) influenced Hedgehog activation and primary cilia structure. The results obtained in this work provide a further step in the comprehension of the pathophysiological features of AKU, suggesting a potential therapeutic approach to modulate AKU cartilage degradation processes through manipulation of the Hedgehog pathway. PMID- 28019671 TI - A novel objective method for assessing high-contrast spatial resolution in CT based on the Rayleigh criterion. AB - PURPOSE: In China, most quality assessments (QAs) of the high-contrast resolution of medical computed tomography (CT) equipment is performed by subjective evaluation, which is simple but dependent on observer expertise. The purpose of this study was to compare the accuracy and degree of dispersion of evaluation results from observers with different expertise and to develop an objective, easily understandable new approach to minimize the error caused by the subjective nature of observer evaluation. The accuracy and reproducibility of this new approach was validated and compared using both subjective and objective evaluation methods. METHODS: This new objective evaluation method of high contrast resolution was based on measurements of CT phantom images. The intensity profile of the aluminum line pairs' (LPs') images was extracted and quantified following the Rayleigh criterion. The interpolation method was employed to improve the consistency of the middle profile lines of each LP group for application of the Rayleigh criterion. With the introduction of a normalized margin, the accuracy of the results increased to the decimal level. Five junior observers and three QA professionals evaluated the high-contrast resolution of three different CT scanners using the subjective method, modulation transfer function (MTF) method, and the new objective method, and the results were compared statistically. RESULTS: The experimental standard deviations ranged from 0.4 LP/cm to 0.55 LP/cm for subjective visual inspection. The uncertainty of the expert group's results was much lower than that of the volunteer group. The experimental standard deviations of the MTF evaluation, according to both the standard deviation (SD) and point spread function (PSF) methods, were within the intervals of (0.04-0.06) LP/cm and (0.08-0.16) LP/cm, whereas that of the proposed objective evaluation method was approximately 0.02 LP/cm. The experimental data indicated that the results of the new objective evaluation were in accordance with those of the expert group's subjective evaluation and the MTF evaluation. CONCLUSIONS: In this study, the subjective evaluation results from experienced observers showed relatively less uncertainty and more accuracy than those from inexperienced observers. Furthermore, a new objective evaluation approach that is easily understood, accurate, and reproducible was developed in this study. Results acquired using this new method were comparable with those of expert groups' subjective evaluation and MTF evaluation. Specialized QA software that integrates the steps implemented in the new method is being developed to enhance the convenience of the approach and assist observers in obtaining accurate and replicable assessment results. PMID- 28019672 TI - Serotonin transporter in Parkinson's disease: A meta-analysis of positron emission tomography studies. AB - Positron emission tomography (PET) is a powerful analytical tool for in vivo molecular imaging of the human brain. Over the past years, a number of PET studies imaging the serotonin transporter (SERT) have been used and provided evidence for the key role of serotonergic pathology in patients with Parkinson's disease (PD). Here, we review the role of SERT in the development of motor and nonmotor complications in patients with PD, and we performed a meta-analysis to identify the patterns of SERT pathology and the relevance to symptoms. Consistent SERT pathology in raphe nuclei, striatum, thalamus, and hypothalamus and associations with aging, PD progression, development of dyskinesias, and cognitive decline were observed. Ann Neurol 2017;81:171-180. PMID- 28019673 TI - Developing a successful global neurology program. PMID- 28019674 TI - Hairy and Enhancer of Split-Related With YRPW Motif-Like (HeyL) Is Dispensable for Bone Remodeling in Mice. AB - Notch induces Hairy Enhancer of Split (Hes)1 and Hes-related with YRPW motif (Hey) Hey1, Hey2 and Hey-like (HeyL) expression in osteoblasts, but it is not known whether any of these target genes mediates the effect of Notch in the skeleton. We demonstrated that Notch1 activation in osteoblasts/osteocytes induces Hes1, Hey1, Hey2, and HeyL, but HeyL was induced to a greater extent than other target genes. To characterize HeyL null mice for their skeletal phenotype, microcomputed tomography (uCT) and histomorphometric analysis of HeyL null and sex-matched littermate controls was performed. uCT demonstrated modest cancellous bone osteopenia in 1 month old male mice and normal microarchitecture in 3 month old male HeyL null mice. Female HeyL null mice were not different from controls at either 1 or 3 months of age. Bone histomorphometry did not demonstrate differences between HeyL null mice of either sex and littermate controls. In conclusion, HeyL null mice do not exhibit an obvious skeletal phenotype demonstrating that HeyL is dispensable for skeletal homeostasis. J. Cell. Biochem. 118: 1819-1826, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28019675 TI - Brusatol overcomes chemoresistance through inhibition of protein translation. AB - The NRF2 pathway activates a cell survival response when cells are exposed to xenobiotics or are under oxidative stress. Therapeutic activation of NRF2 can also be used prior to insult as a means of disease prevention. However, prolonged expression of NRF2 has been shown to protect cancer cells by inducing the metabolism and efflux of chemotherapeutics, leading to both intrinsic and acquired chemoresistance to cancer drugs. This effect has been termed the "dark side" of NRF2. In an effort to combat this chemoresistance, our group discovered the first NRF2 inhibitor, the natural product brusatol, however the mechanism of inhibition was previously unknown. In this report, we show that brusatol's mode of action is not through direct inhibition of the NRF2 pathway, but through the inhibition of both cap-dependent and cap-independent protein translation, which has an impact on many short-lived proteins, including NRF2. Therefore, there is still a need to develop a new generation of specific NRF2 inhibitors with limited toxicity and off-target effects that could be used as adjuvant therapies to sensitize cancers with high expression of NRF2. PMID- 28019677 TI - Chirality-specific lift forces of helix under shear flows: Helix perpendicular to shear plane. AB - Chiral objects in shear flow experience a chirality-specific lift force. Shear flows past helices in a low Reynolds number regime were studied using slender body theory. The chirality-specific lift forces in the vorticity direction experienced by helices are dominated by a set of helix geometry parameters: helix radius, pitch length, number of turns, and helix phase angle. Its analytical formula is given. The chirality-specific forces are the physical reasons for the chiral separation of helices in shear flow. Our results are well supported by the latest experimental observations. PMID- 28019676 TI - (S)Pinning down protein interactions by NMR. AB - Protein molecules are highly diverse communication platforms and their interaction repertoire stretches from atoms over small molecules such as sugars and lipids to macromolecules. An important route to understanding molecular communication is to quantitatively describe their interactions. These types of analyses determine the amounts and proportions of individual constituents that participate in a reaction as well as their rates of reactions and their thermodynamics. Although many different methods are available, there is currently no single method able to quantitatively capture and describe all types of protein reactions, which can span orders of magnitudes in affinities, reaction rates, and lifetimes of states. As the more versatile technique, solution NMR spectroscopy offers a remarkable catalogue of methods that can be successfully applied to the quantitative as well as qualitative descriptions of protein interactions. In this review we provide an easy-access approach to NMR for the non-NMR specialist and describe how and when solution state NMR spectroscopy is the method of choice for addressing protein ligand interaction. We describe very briefly the theoretical background and illustrate simple protein-ligand interactions as well as typical strategies for measuring binding constants using NMR spectroscopy. Finally, this review provides examples of caveats of the method as well as the options to improve the outcome of an NMR analysis of a protein interaction reaction. PMID- 28019678 TI - Post-Treatment Follow-Up of Screen-Detected Breast Cancer Patients: A National Survey from Italy. PMID- 28019679 TI - Inflammasome activation and innate immunity in Alzheimer's disease. AB - Activation of innate immunity and the assembly of microglial cells at sites of Alzheimer disease pathology has long been regarded as bystander phenomenon, which does not actively contribute to disease pathogenesis and progression. Recent data emerging from genetics, clinical imaging and animal experimentation point to an intimate and mutual interaction of innate immune mechanisms and neurodegenerative processes. NOD-like receptor (NLR) family, pyrin domain containing 3 and 1 inflammasomes, present in myeloid cells and neurons, respectively, represent key components of the innate immune reaction observed in Alzheimer patient brains. Inhibition of inflammasome activation just begins to prove beneficial and protective from cognitive deficits and neuronal death in cell culture and animal models of Alzheimer's disease, thereby opening a new avenue for therapeutic intervention. PMID- 28019680 TI - Modeling protein assemblies: Critical Assessment of Predicted Interactions (CAPRI) 15 years hence.: 6TH CAPRI evaluation meeting April 17-19 Tel-Aviv, Israel. PMID- 28019681 TI - Observations During paraHisian Entrainment. PMID- 28019682 TI - Assessment of Radio-Guided Occult Lesion Localization Associated with Sonography in Non-Palpable Breast Lesions. PMID- 28019683 TI - Effect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final Results of a 78-Week Randomized Clinical Trial. AB - We present final results of a study comparing teriparatide 20 MUg every day (QD) with risedronate 35 mg once per week (QW) started within 2 weeks after surgery for a pertrochanteric hip fracture. Patients with BMD T-score <= -2.0 and 25OHD >=9.2 ng/mL were randomized to receive 26-week double-dummy treatment plus calcium and vitamin D, followed by 52-week open-label treatment with the same assigned active drug. Primary endpoint was change from baseline in lumbar spine (LS) BMD at 78 weeks. Secondary and exploratory endpoints were change in BMD at the proximal femur, function, hip pain (Charnley score and 100 mm Visual Analog Scale [VAS]), quality of life (Short Form-36), radiology outcomes, and safety. Data were analyzed with mixed models for repeated measures (MMRM) and logistic regression. Totally, 224 patients were randomized; 171 (teriparatide: 86) contributed to the efficacy analyses (mean +/- SD age: 77 +/- 7.7 years, 77% females). Mean baseline LS, femoral neck (FN), and total hip (TH) T-scores were 2.16, -2.63, and -2.51, respectively. At 78 weeks, BMD increased significantly more with teriparatide compared to risedronate at the LS (+11.08% versus +6.45%; p < 0.001) and FN (+1.96% versus -1.19%; p = 0.003), with no significant between group difference in TH BMD. Timed up-and-go (TUG) test was significantly faster with teriparatide at 6, 12, 18, and 26 weeks (differences: -3.2 to -5.9 s; p = 0.045 for overall difference). Hip pain during TUG test by 100 mm VAS was significantly lower with teriparatide at 18 weeks (adjusted difference: -11.3 mm, p = 0.033; -10.0 and -9.3 mm at 12 and 26 weeks, respectively; p = 0.079 for overall difference). Other secondary and exploratory outcomes were not different. Teriparatide group showed two new hip fractures versus seven with risedronate (p = 0.171) and more frequent hypercalcemia and hyperuricemia. In conclusion, 78 week treatment with teriparatide showed significantly greater increases in LS and FN BMD, less pain, and a faster TUG test versus risedronate. (c) 2016 American Society for Bone and Mineral Research. PMID- 28019684 TI - Diaphyseal Femur Fractures in Osteogenesis Imperfecta: Characteristics and Relationship With Bisphosphonate Treatment. AB - Several recent case reports have suggested that bisphosphonate treatment in individuals with osteogenesis imperfecta (OI) is causally related to atypical femur fractures. However, it is not known whether atypical femur fractures are actually more frequent in patients who have received bisphosphonates. In the present study, we retrospectively analyzed 166 femur fractures in 119 children with a diagnosis of OI that had not undergone intramedullary rodding procedures. A total of 130 fractures in 90 patients occurred in femurs with preexisting deformities (age at fracture between 1 month and 19.9 years; 43 girls). Because deformities are a typical cause of fracture in OI, deformed femurs were excluded from the analysis of atypical fractures. However, it was noted that in deformed femurs a transverse fracture pattern (one of the criteria of atypical fractures) was associated with a moderate to severe OI phenotype and not related to bisphosphonate treatment. Of the 36 fractures that occurred in nondeformed femurs (30 individuals; age at fracture between 1 month and 17.4 years; 13 girls), 11 (in nine children) occurred during bisphosphonate treatment. Three of these fractures (27%) resembled atypical femur fractures. Among the 25 femur fractures (23 patients) that occurred in the absence of prior bisphosphonate treatment, 8 (22%) resembled atypical femur fractures. Logistic regression analysis showed that bisphosphonate treatment history was not associated with the occurrence of atypical fractures. In contrast, the presence of moderate to severe OI (defined as any OI type other than OI type I) was strongly associated with atypical femur fractures. Thus, we observed an atypical appearance in about a quarter of nondeformed femur fractures that occurred in children with OI. Such atypical femur fractures seemed to be related to the severity of OI rather than to bisphosphonate treatment history. (c) 2016 American Society for Bone and Mineral Research. PMID- 28019685 TI - Tauopathy with hippocampal 4-repeat tau immunoreactive spherical inclusions: a report of three cases. AB - Tauopathies are a major group of neurodegenerative proteinopathies characterized by the accumulation of abnormal and hyperphosphorylated tau proteins in the brain. Tau pathology is characterized as 3R (repeat) or 4R predominant or mixed 3R and 4R type. Here we report three cases lacking mutations in the microtubule associated protein tau (MAPT) gene with unusual tau pathology. The age at onset and duration of illness, respectively, were 63 and 20 years (male), 67 and 5 years (female) and 72 and 20 years (female). The clinical presentation was compatible with a diagnosis of progressive supranuclear palsy (PSP) in two subjects and with cognitive decline in all three subjects. Common neuropathological features included neuronal loss in the hippocampus and dentate gyrus associated with spherical basophilic Pick body-like inclusions showing 4R tau immunoreactivity, which was supported by the detection of predominantly 4R tau species by Western blot examination. In addition, accumulation of tau immunoreactive argyrophilic astrocytes in the hippocampus and amygdala and oligodendroglial coiled bodies in the hippocampal white matter were observed. These morphologies appeared in combination with Alzheimer disease-related pathology and subcortical tau pathology compatible with PSP. Together with a single case report in the literature, our observations on these three cases expand the spectrum of previously described tauopathies. We suggest that this tauopathy variant with hippocampal 4R tau immunoreactive spherical inclusions might contribute to the cognitive deficits in the patients reported here. The precise definition of the clinicopathological relevance of these unusual tau pathologies merits further study. PMID- 28019687 TI - Improving With Practice: A Neural Model of Mathematical Development. AB - The ability to improve in speed and accuracy as a result of repeating some task is an important hallmark of intelligent biological systems. Although gradual behavioral improvements from practice have been modeled in spiking neural networks, few such models have attempted to explain cognitive development of a task as complex as addition. In this work, we model the progression from a counting-based strategy for addition to a recall-based strategy. The model consists of two networks working in parallel: a slower basal ganglia loop and a faster cortical network. The slow network methodically computes the count from one digit given another, corresponding to the addition of two digits, whereas the fast network gradually "memorizes" the output from the slow network. The faster network eventually learns how to add the same digits that initially drove the behavior of the slower network. Performance of this model is demonstrated by simulating a fully spiking neural network that includes basal ganglia, thalamus, and various cortical areas. Consequently, the model incorporates various neuroanatomical data, in terms of brain areas used for calculation and makes psychologically testable predictions related to frequency of rehearsal. Furthermore, the model replicates developmental progression through addition strategies in terms of reaction times and accuracy, and naturally explains observed symptoms of dyscalculia. PMID- 28019686 TI - Dietary Inflammatory Index, Bone Mineral Density, and Risk of Fracture in Postmenopausal Women: Results From the Women's Health Initiative. AB - Previous studies suggest that bone loss and fracture risk are associated with higher inflammatory milieu, potentially modifiable by diet. The primary objective of this analysis was to evaluate the association of the dietary inflammatory index (DII), a measure of the inflammatory potential of diet, with risk of hip, lower-arm, and total fracture using longitudinal data from the Women's Health Initiative Observational Study and Clinical Trials. Secondarily, we evaluated changes in bone mineral density (BMD) and DII scores. DII scores were calculated from baseline food frequency questionnaires (FFQs) completed by 160,191 participants (mean age 63 years) without history of hip fracture at enrollment. Year 3 FFQs were used to calculate a DII change score. Fractures were reported at least annually; hip fractures were confirmed by medical records. Hazard ratios for fractures were computed using multivariable-adjusted Cox proportional hazard models, further stratified by age and race/ethnicity. Pairwise comparisons of changes in hip BMD, measured by dual-energy X-ray absorptiometry from baseline, year 3, and year 6 were analyzed by quartile (Q1 = least inflammatory diet) of baseline DII scores in a subgroup of women (n = 10,290). Mean DII score improved significantly over 3 years (p < 0.01), but change was not associated with fracture risk. Baseline DII score was only associated with hip fracture risk in younger white women (HR Q4,1.48; 95% CI, 1.09 to 2.01; p = 0.01). There were no significant associations among white women older than 63 years or other races/ethnicities. Women with the least inflammatory DII scores had less loss of hip BMD (p = 0.01) by year 6, despite lower baseline hip BMD, versus women with the most inflammatory DII scores. In conclusion, a less inflammatory dietary pattern was associated with less BMD loss in postmenopausal women. A more inflammatory diet was associated with increased hip fracture risk only in white women younger than 63 years. (c) 2016 American Society for Bone and Mineral Research. PMID- 28019688 TI - Cell culture media supplementation of infrequently used sugars for the targeted shifting of protein glycosylation profiles. AB - Mammalian cells in culture rely on sources of carbohydrates to supply the energy requirements for proliferation. In addition, carbohydrates provide a large source of the carbon supply for supporting various other metabolic activities, including the intermediates involved in the protein glycosylation pathway. Glucose and galactose, in particular, are commonly used sugars in culture media for these purposes. However, there exists a very large repertoire of other sugars in nature, and many that have been chemically synthesized. These sugars are particularly interesting because they can be utilized by cells in culture in distinct ways. In the present work it has been found that many infrequently used sugars, and the corresponding cellular response towards them as substrates, led to differences in the protein N-glycosylation profile of a recombinant glycoprotein. The selective media supplementation of raffinose, trehalose, turanose, palatinose, melezitose, psicose, lactose, lactulose, and mannose were found to be capable of redirecting N-glycan oligosaccharide profiles. Despite this shifting of protein glycosylation, there were no other adverse changes in culture performance, including both cell growth and cellular productivity over a wide range of supplemented sugar concentrations. The approach presented highlights a potential means towards both the targeted shifting of protein glycosylation profiles and ensuring recombinant protein comparability, which up to this point in time has remained under-appreciated for these under-utilized compounds. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:511-522, 2017. PMID- 28019689 TI - General solutions to decompose heterogeneous compositions using antibody afucosylation as a model system. AB - Methods involving the use of mathematical models of competitive ligand-receptor binding to characterize mixtures of ligands in terms of compositions and properties of the component ligands have been developed. The associated mathematical equations explicitly relate component ligand physical-chemical properties and mole fractions to measurable properties of the mixture including steady state binding activity, 1/Kd,apparent or equivalently 1/EC50, and kinetic rate constants kon,apparent and koff,apparent allowing: (1) component ligand physical property determination and (2) mixture property predictions. Additionally, mathematical equations accounting for combinatorial considerations associated with ligand assembly are used to compute ligand mole fractions. The utility of the methods developed is demonstrated using published experimental ligand-receptor binding data obtained from mixtures of afucosylated antibodies that bind FcgammaRIIIa (CD16a) to: (1) extract component ligand physical property information that has hitherto evaded researchers, (2) predict experimental observations, and (3) provide explanations for unresolved experimental observations. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:500-510, 2017. PMID- 28019690 TI - Structural analysis of oligomeric and protofibrillar Abeta amyloid pair structures considering F20L mutation effects using molecular dynamics simulations. AB - Abeta amyloid proteins are involved in neuro-degenerative diseases such as Alzheimer's, Parkinson's, and so forth. Because of its structurally stable feature under physiological conditions, Abeta amyloid protein disrupts the normal cell function. Because of these concerns, understanding the structural feature of Abeta amyloid protein in detail is crucial. There have been some efforts on lowering the structural stabilities of Abeta amyloid fibrils by decreasing the aromatic residues characteristic and hydrophobic effect. Yet, there is a lack of understanding of Abeta amyloid pair structures considering those effects. In this study, we provide the structural characteristics of wildtype (WT) and phenylalanine residue mutation to leucine (F20L) Abeta amyloid pair structures using molecular dynamics simulation in detail. We also considered the polymorphic feature of F20L and WT Abeta pair amyloids based on the facing beta-strand directions between the amyloid pairs. As a result, we were able to observe the varying effects of mutation, polymorphism, and protofibril lengths on the structural stability of pair amyloids. Furthermore, we have also found that opposite structural stability exists on a certain polymorphic Abeta pair amyloids depending on its oligomeric or protofibrillar state, which can be helpful for understanding the amyloid growth mechanism via repetitive fragmentation and elongation mechanism. Proteins 2017; 85:580-592. (c) 2016 Wiley Periodicals, Inc. PMID- 28019691 TI - Biofilm detection by wound blotting can predict slough development in pressure ulcers: A prospective observational study. AB - Bacteria have been found to form multicellular aggregates which have collectively been termed "biofilms." It is hypothesized that biofilm formation is a means to protect bacterial cells including protection form the immune response of humans. This protective mechanism is believed to explain persistent chronic wound infections. At times, the biofilms are abundant enough to see, and remove by simple wiping. However, recent evidence has shown that the removal of these visible portions are not sufficient, and that biofilms can continue to form even with daily wiping. In this work, we tested an approach to detect the biofilms which are present after clinically wiping or sharp wound debridement. Our method is based on a variation of impression cytology in which a nitrocellulose membrane was used to collect surface biofilm components, which were then differentially stained. In this prospective study, members of an interdisciplinary pressure ulcer team at a university hospital tested our method's ability to predict the generation of wound slough in the week that followed each blotting. A total of 70 blots collected from 23 pressure ulcers produced 27 wounds negative for staining and 43 positive. In the negative blots 55.6% were found to have decreased wound slough, while 81.4% with positive staining had either increase or unchanged wound slough generation. These results lead to an odds ratio of positive blotting cases of 9.37 (95% confidence intervals: 2.47-35.5, p = 0.001) for slough formation; suggesting that the changes in wound slough formation can be predicted clinically using a non-invasive wound blotting method. PMID- 28019692 TI - Postmenopausal Cutaneous Endometriosis: Mimicking Breast Metastasis. PMID- 28019694 TI - Taking care of teenagers, taking care of me: Profiling parental caregiving burden and activity restriction in a sample of Australian parents. AB - The current study extends the Activity Restriction Model of Depressed Affect by exploring the relationship between parental caregiving burden, activity restriction, and depressive symptoms. It investigated the mediating role of restriction in three types of activities (daily routine, personal control, and social) in the relationship between parental caregiving burden and carer depression. Respondents (n = 203, Meanage = 45.45 years, standard deviation = 7.81, females = 84.7%) were parent carers of a young person with mental illness and based in Australia. They completed a set of measures assessing caregiving burden, participation in daily routine, personal control and social activities, and depressive symptoms. A multiple mediation analysis revealed that restriction of daily routine, personal control, and social activities indirectly mediated the relationship between parental caregiving burden and parent carers' symptoms of depression. A latent profile analysis suggested an optimal three-profile solution. As predicted, profile membership distinguished parent carers on depressive symptoms ranging from normal to severe levels based on participation in the specific activities. Our results suggest a typology of parent carers perceiving differential levels of caregiving burden and activity restriction. Strategies addressing these specific areas provide preventative and promotion measures to optimize carer mental health and well-being. PMID- 28019693 TI - Relaxation of DNA supercoiling leads to increased invasion of epithelial cells and protein secretion by Campylobacter jejuni. AB - Invasion of intestinal epithelial cells by Campylobacter jejuni is a critical step during infection of the intestine by this important human pathogen. In this study we investigated the role played by DNA supercoiling in the regulation of invasion of epithelial cells and the mechanism by which this could be mediated. A significant correlation between more relaxed DNA supercoiling and an increased ability of C. jejuni strains to penetrate human epithelial cells was demonstrated. Directly inducing relaxation of DNA supercoiling in C. jejuni was shown to significantly increase invasion of epithelial cells. Mutants in the fibronectin binding proteins CadF and FlpA still displayed an increased invasion after treatment with novobiocin suggesting these proteins were not essential for the observed phenotype. However, a large increase in protein secretion from multiple C. jejuni strains upon relaxation of DNA supercoiling was demonstrated. This increase in protein secretion was not mediated by outer membrane vesicles and appeared to be dependent on an intact flagellar structure. This study identifies relaxation of DNA supercoiling as playing a key role in enhancing C. jejuni pathogenesis during infection of the human intestine and identifies proteins present in a specific invasion associated secretome induced by relaxation of DNA supercoiling. PMID- 28019695 TI - Determination of enantiomeric excess of nipecotic acid as 1-(7 nitrobenzo[c][1,2,5]oxadiazol-4-yl) derivatives. AB - For the enantiopure synthesis of novel chiral GABA uptake inhibitors, nipecotic acid (1) is an important key precursor. To characterize accurately the pharmacological activity of these interesting target compounds, the determination of the correct enantiomeric purity of nipecotic acid as the starting material is indispensable. In this report, a sensitive high-performance liquid chromatography (HPLC) based method for the separation and quantitation of both enantiomers of nipecotic acid as 1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl) derivatives (5) on a Chiralpak ID-3 column (Daicel, Illkirch, France) was established. UV/Vis detection at 490 nm was chosen to ensure a selective determination of even highly enantioenriched samples. Reliability was demonstrated by validation of specificity, linearity, lower limit of quantification (LLOQ), accuracy, and precision. By spiking highly enantiopure samples with small amounts of racemic rac-5, it was proven that the established HPLC method is able to detect even slight changes in enantiomeric excess (ee) values. Thus, accurate determination of ee values up to 99.87% ee for (R)-5 and 99.86% ee for (S)-5 over a linear concentration range of 1-1500 MUM for (R)-5 and of 1-1455 MUM for (S)-5 could be demonstrated. PMID- 28019696 TI - CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling. AB - We identified the neuroprotein collapsing response mediator protein-4 (CRMP4) as a noncanonical osteogenic factor that regulates the differentiation of mouse bone marrow skeletal stem cells (bone marrow stromal stem cells [mBMSCs]) into osteoblastic cells. CRMP4 is the only member of the CRMP1-CRMP5 family to be expressed by mBMSCs and in osteoprogenitors of both adult mouse and human bones. In vitro gain-of-function and loss-of-function of CRMP4 in murine stromal cells revealed its inhibitory effect on osteoblast differentiation. In addition, Crmp4 deficient mice (Crmp4-/- ) displayed a 40% increase in bone mass, increased mineral apposition rate, and bone formation rate, compared to wild-type controls. Increased bone mass in Crmp4-/- mice was associated with enhanced BMP2 signaling and BMP2-induced osteoblast differentiation in Crmp4-/- osteoblasts (OBs). Furthermore, Crmp4-/- OBs exhibited enhanced activation of RhoA/focal adhesion kinase (FAK) signaling that led to cytoskeletal changes with increased cell spreading. In addition, Crmp4-/- OBs exhibited increased cell proliferation that was mediated via inhibiting cyclin-dependent kinase inhibitor 1B, p27Kip1 and upregulating cyclin D1 expression which are targets of RhoA signaling pathway. Our findings identify CRMP4 as a novel negative regulator of osteoblast differentiation. (c) 2016 American Society for Bone and Mineral Research. PMID- 28019697 TI - Mixture toxicity of phostebupirim and cyfluthrin: Species-specific responses. AB - Currently, the potential impact of insecticide mixtures to nontarget organisms is largely unknown, and additional study is needed. The present study investigated the mixture toxicity of the organophosphate insecticide phostebupirim and the pyrethroid insecticide cyfluthrin using 4 nontarget species including Daphnia magna, Hyalella azteca, Pimephales promelas (fathead minnow), and Danio rerio (zebrafish). For each species, the toxicity of equipotent mixtures was compared with the expected toxicity estimated using the independent action (IA) and concentration addition (CA) models. Lethal and sublethal responses to D. magna and H. azteca were best described with the IA model. For both fish species, mixture toxicity was significantly higher than that estimated using either mixture model. The synergism noted in fish exposed to the combination of phostebupirim and cyfluthrin was confirmed by exposing P. promelas larvae to a nontoxic dose of phostebupirim and a range of toxic cyfluthrin concentrations, and vice versa. Sublethal and lethal concentrations to fish were up to 7 times lower for the mixture than in concurrently run individual compound exposures. Potential mechanisms for the synergistic responses found in fish are presented. Environ Toxicol Chem 2017;36:1947-1954. (c) 2016 SETAC. PMID- 28019698 TI - Novel product specificity toward erlose and panose exhibited by multisite engineered mutants of amylosucrase. AB - A computer-aided engineering approach recently enabled to deeply reshape the active site of N. polysaccharea amylosucrase for recognition of non-natural acceptor substrates. Libraries of variants were constructed and screened on sucrose allowing the identification of 17 mutants able to synthesize molecules from sole sucrose, which are not synthesized by the parental wild-type enzyme. Three of the isolated mutants as well as the new products synthesized were characterized in details. Mutants contain between 7 and 11 mutations in the active site and the new molecules were identified as being a sucrose derivative, named erlose (alpha-d-glucopyranosyl-(1->4)-alpha-d-glucopyranosyl-(1->2)-beta-d Fructose), and a new malto-oligosaccharide named panose (alpha-d-glucopyranosyl (1->6)-alpha-d-glucopyranosyl-(1->4)-alpha-d-Glucose). These product specificities were never reported for none of the amylosucrases characterized to date, nor their engineered variants. Optimization of the production of these trisaccharides of potential interest as sweeteners or prebiotic molecules was carried out. Molecular modelling studies were also performed to shed some light on the molecular factors involved in the novel product specificities of these amylosucrase variants. PMID- 28019699 TI - Conformational stability of the epidermal growth factor (EGF) receptor as influenced by glycosylation, dimerization and EGF hormone binding. AB - The epidermal growth factor receptor (EGFR) is an important transmembrane glycoprotein kinase involved the initiation or perpetuation of signal transduction cascades within cells. These processes occur after EGFR binds to a ligand [epidermal growth factor (EGF)], thus inducing its dimerization and tyrosine autophosphorylation. Previous publications have highlighted the importance of glycosylation and dimerization for promoting proper function of the receptor and conformation in membranes; however, the effects of these associations on the protein conformational stability have not yet been described. Molecular dynamics simulations were performed to characterize the conformational preferences of the monomeric and dimeric forms of the EGFR extracellular domain upon binding to EGF in the presence and absence of N-glycan moieties. Structural stability analyses revealed that EGF provides the most conformational stability to EGFR, followed by glycosylation and dimerization, respectively. The findings also support that EGF-EGFR binding takes place through a large-scale induced fitting mechanism. Proteins 2017; 85:561-570. (c) 2016 Wiley Periodicals, Inc. PMID- 28019701 TI - Current state and perspectives in modeling and control of human pluripotent stem cell expansion processes in stirred-tank bioreactors. AB - Implementation of model-based practices for process development, control, automation, standardization, and validation are important factors for therapeutic and industrial applications of human pluripotent stem cells. As robust cultivation strategies for pluripotent stem cell expansion and differentiation have yet to be determined, process development could be enhanced by application of mathematical models and advanced control systems to optimize growth conditions. Therefore, it is important to understand both the potential of possible applications and the apparent limitations of existing mathematical models to improve pluripotent stem cell cultivation technologies. In the present review, the authors focus on these issues as they apply to stem cell expansion processes. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:355-364, 2017. PMID- 28019700 TI - Assessment of Sex Differences in Fracture Risk Among Patients With Anorexia Nervosa: A Population-Based Cohort Study Using The Health Improvement Network. AB - Though previous studies have demonstrated an increased fracture risk in females with anorexia nervosa (AN), fracture risk in males is not well characterized. The objective of this study was to examine sex differences in fracture risk and site specific fracture incidence in AN. We performed a population-based retrospective cohort study using The Health Improvement Network (THIN; a large database of anonymized electronic medical records collected at primary care clinics throughout the United Kingdom). The median calendar year for the start of the observation period was 2004-2005. We identified 9239 females and 556 males <60 years of age with AN, and 97,889 randomly selected sex-, age-, and practice matched participants without eating disorders (92,329 females and 5560 males). Multivariable Cox regression was used to estimate the hazard ratio (HR) for incident fracture. Median age at start of observation was 29.8 years in females and 30.2 years in males. The HR for fracture associated with AN differed by sex and age (interaction p = 0.002). Females with AN had an increased fracture risk at all ages (HR, 1.59; 95% confidence interval [CI], 1.45 to 1.75). AN was associated with a higher risk of fracture among males >40 years of age (HR, 2.54; 95% CI, 1.32 to 4.90; p = 0.005) but not among males <=40 years. Females with AN had a higher risk of fracture at nearly all anatomic sites. The greatest excess fracture risk was noted at the hip/femur (HR, 5.59; 95% CI, 3.44 to 9.09) and pelvis (HR, 4.54; 95% CI, 2.42 to 8.50) in females and at the vertebrae (HR, 7.25; 95% CI, 1.21 to 43.45) for males with AN. AN was associated with higher incident fracture risk in females across all age groups and in males >40 years old. Sites of highest fracture risk include the hip/femur and pelvis in females and vertebrae in males with AN. (c) 2016 American Society for Bone and Mineral Research. PMID- 28019702 TI - Alkaline serine proteases from Helicoverpa armigera: potential candidates for industrial applications. AB - We characterized trypsin- and chymotrypsin-like serine alkaline proteases from cotton bollworm, Helicoverpa armigera, for their probable potential application as additives in various bio-formulations. Purification was achieved by using hydroxylapatite, DEAE sephadex and CM sephadex columns, which resulted in increased enzyme activity by 13.76- and 14.05-fold for trypsin and chymotrypsin, respectively. Michaelis-Menten constants (Km ) for substrates of trypsin and chymotrypsin, BApNA and SAAPFpNA, were found to be 1.25 and 0.085 mM, correspondingly. Fluorescent zymogram analysis indicated the presence of five trypsin bands with molecular masses of ~21, 25, 38, 40, and 66 kDa and two chymotrypsin bands with molecular masses of ~29 and 34 kDa in SDS-PAGE. The optimum pH was 10.0 and optimum temperature was 50 degrees C for proteolytic activity for the purified proteases. The proteases were inhibited by synthetic inhibitors such as PMSF, aprotonin, leupeptin, pefabloc, and antipain. TLCK and TPCK inhibited about 94 and 90% of trypsin and chymotrypsin activity, respectively, while EDTA, EGTA, E64, pepstatin, idoacetamide, and bestatin did not affect the enzymes. The purified enzymes exhibited high stability and compatibility with metal ions; oxidizing, reducing, and bleaching agents; organic solvents; and commercial detergents. Short life cycles, voracious feeding behavior, and production of multiple forms of proteases in the midgut with rapid catalytic activity and chemostability can serve H. armigera as an excellent alternative source of industrially important proteases for use as additives in stain removers, detergents, and other bio-formulations. Identification of enzymes with essential industrial properties from insect species could be a bioresource. PMID- 28019703 TI - Clinically relevant hydrogel-based on hyaluronic acid and platelet rich plasma as a carrier for mesenchymal stem cells: Rheological and biological characterization. AB - Intervertebral disc regeneration is quickly moving towards clinical applications. However, it is still missing an ideal injectable hydrogel to support mesenchymal stem cells (MSC) delivery. Herein, a new injectable hydrogel composed of platelet rich plasma (PRP) and hyaluronic acid (HA) blended with batroxobin (BTX) as gelling agent, was designed to generate a clinically relevant cell carrier for disc regeneration. PRP/HA/BTX blend was tested for rheological properties. Amplitude sweep, frequency sweep, and rotational measurements were performed and viscoelastic properties were evaluated. Human MSC encapsulated in PRP/HA/BTX hydrogel were cultured in both growing medium and medium with or without TGF beta1 up to day 21. The amount of glycosaminoglycan was evaluated. Quantitative gene expression evaluation for collagen type II, aggrecan, and Sox 9 was also performed. Rheological tests showed that the hydrogel jellifies in 15 min 20 degrees C and in 3 min at 37 degrees C. Biological test showed that MSCs cultured in the hydrogel maintain high cell viability and proliferation. Human MSC within the hydrogel cultured with or without TGF-beta1 showed significantly higher GAG production compared to control medium. Moreover, MSCs in the hydrogel underwent differentiation to chondrocyte-like cells with TGF-beta1, as shown by histology and gene expression analysis. This novel hydrogel improves viability and proliferation of MSCs supporting the differentiation process toward chondrocyte like cells. Rheology tests showed optimal gelation kinetics at room temperature for manipulation and faster gelation after transplantation (37 degrees C). The clinical availability of all components of the hydrogel will allow a rapid translation of this regenerative approach into the clinical scenario. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2109-2116, 2017. PMID- 28019704 TI - Isolation of the major chiral compounds from Bubonium graveolens essential oil by HPLC and absolute configuration determination by VCD. AB - The chirality issues in the essential oils (EOs) of leaves and flowers from Bubonium graveolens were addressed by chiral high-performance liquid chromatography (HPLC) with polarimetric detection and vibrational circular dichroism (VCD). The chemical compositions of the crude oils of three samples were established by gas chromatography / mass spectrometry (GC/MS). The well known cis-chrysanthenyl acetate (1), oxocyclonerolidol (2), and the recently disclosed cis-acetyloxychrysanthenyl acetate (3), the three major chiral compounds, were isolated by preparative HPLC. The naturally occurring oxocycloneroledol (2), mostly found in the leaf oil (49.4-55.6%), presents a (+) sign in the mobile phase during HPLC on a chiral stationary phase (CSP) with a Jasco polarimetric detection. The naturally occurring cis-chrysanthenyl acetate (1) and cis-acetyloxychrysanthenyl acetate (3), mostly found in the flower EO (35.9-74.9% and 10.0-34.3%, respectively), both present a (-) sign. HPLC on a CSP with polarimetric detection is an unprecedented approach to readily differentiate the flower and leaf EOs according to their chiral signature. The comparison of the experimental and calculated VCD spectra of pure isolated 1, 2, and 3 provided their absolute configuration as being (1S,5R,6S)-(-)-2,7,7 trimethylbicyclo[3.1.1]hept-2-en-6-yl acetate 1, (2R,6R)-(+)-6-ethenyl-2,6 dimethyl-2-(4-methylpent-3-en-1-yl)dihydro-2H-pyran-3(4H)-one) 2 and (1S,5R,6R,7S)-(-)-7-(acetyloxy)-2,6-dimethylbicyclo[3.1.1]hept-2-en-6-yl]methyl acetate 3. Compounds 1, 2, and 3 were already known in B. graveolens but this is the first report of the absolute configuration of (+)-2 and (-)-3. The VCD chiral signatures of the crude oils were also recorded. PMID- 28019705 TI - Empathic processes during nurse-consumer conflict situations in psychiatric inpatient units: A qualitative study. AB - Empathy is a central component of nurse-consumer relationships. In the present study, we investigated how empathy is developed and maintained when there is conflict between nurses and consumers, and the ways in which empathy can be used to achieve positive outcomes. Through semistructured interviews, mental health nurses (n = 13) and consumers in recovery (n = 7) reflected on a specific conflict situation where they had experienced empathy, as well as how empathy contributed more generally to working with nurses/consumers. Thematic analysis was used to analyse the data, utilizing a framework that conceptualizes empathy experiences as involving antecedents, processes, and outcomes. The central theme identified was 'my role as a nurse - the role of my nurse'. Within this theme, nurses focussed on how their role in managing risk and safety determined empathy experienced towards consumers; consumers saw the importance of nurse empathy both in conflict situations and for their general hospitalization experience. Empathy involved nurses trying to understand the consumer's perspective and feeling for the consumer, and was perceived by consumers to involve nurses 'being there'. Empathic relationships built on trust and rapport could withstand a conflict situation, with empathy a core component in consumer satisfaction regarding conflict resolution and care. Empathy allows the maintenance of therapeutic relationships during conflict, and influences the satisfaction of nurses and consumers, even in problematic situations. Nurse education and mentoring should focus on nurse self-reflection and building empathy skills in managing conflict. PMID- 28019706 TI - Acute sensitivity of the vernal pool fairy shrimp, Branchinecta lynchi (Anostraca; Branchinectidae), and surrogate species to 10 chemicals. AB - Vernal pool fairy shrimp, Branchinecta lynchi, (Branchiopoda; Anostraca) and other fairy shrimp species have been listed as threatened or endangered under the US Endangered Species Act. Because few data exist about the sensitivity of Branchinecta spp. to toxic effects of contaminants, it is difficult to determine whether they are adequately protected by water quality criteria. A series of acute (24-h) lethality/immobilization tests was conducted with 3 species of fairy shrimp (B. lynchi, Branchinecta lindahli, and Thamnocephalus platyurus) and 10 chemicals with varying modes of toxic action: ammonia, potassium, chloride, sulfate, chromium(VI), copper, nickel, zinc, alachlor, and metolachlor. The same chemicals were tested in 48-h tests with other branchiopods (the cladocerans Daphnia magna and Ceriodaphnia dubia) and an amphipod (Hyalella azteca), and in 96-h tests with snails (Physa gyrina and Lymnaea stagnalis). Median effect concentrations (EC50s) for B. lynchi were strongly correlated (r2 = 0.975) with EC50s for the commercially available fairy shrimp species T. platyurus for most chemicals tested. Comparison of EC50s for fairy shrimp and EC50s for invertebrate taxa tested concurrently and with other published toxicity data indicated that fairy shrimp were relatively sensitive to potassium and several trace metals compared with other invertebrate taxa, although cladocerans, amphipods, and mussels had similar broad toxicant sensitivity. Interspecies correlation estimation models for predicting toxicity to fairy shrimp from surrogate species indicated that models with cladocerans and freshwater mussels as surrogates produced the best predictions of the sensitivity of fairy shrimp to contaminants. The results of these studies indicate that fairy shrimp are relatively sensitive to a range of toxicants, but Endangered Species Act-listed fairy shrimp of the genus Branchinecta were not consistently more sensitive than other fairy shrimp taxa. Environ Toxicol Chem 2017;36:797-806. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28019707 TI - Weighted fitness theory: an approach to symbiotic communities. PMID- 28019708 TI - Revealing the inventory of type III effectors in Pantoea agglomerans gall-forming pathovars using draft genome sequences and a machine-learning approach. AB - Pantoea agglomerans, a widespread epiphytic bacterium, has evolved into a hypersensitive response and pathogenicity (hrp)-dependent and host-specific gall forming pathogen by the acquisition of a pathogenicity plasmid containing a type III secretion system (T3SS) and its effectors (T3Es). Pantoea agglomerans pv. betae (Pab) elicits galls on beet (Beta vulgaris) and gypsophila (Gypsophila paniculata), whereas P. agglomerans pv. gypsophilae (Pag) incites galls on gypsophila and a hypersensitive response (HR) on beet. Draft genome sequences were generated and employed in combination with a machine-learning approach and a translocation assay into beet roots to identify the pools of T3Es in the two pathovars. The genomes of the sequenced Pab4188 and Pag824-1 strains have a similar size (~5 MB) and GC content (~55%). Mutational analysis revealed that, in Pab4188, eight T3Es (HsvB, HsvG, PseB, DspA/E, HopAY1, HopX2, HopAF1 and HrpK) contribute to pathogenicity on beet and gypsophila. In Pag824-1, nine T3Es (HsvG, HsvB, PthG, DspA/E, HopAY1, HopD1, HopX2, HopAF1 and HrpK) contribute to pathogenicity on gypsophila, whereas the PthG effector triggers HR on beet. HsvB, HsvG, PthG and PseB appear to endow pathovar specificities to Pab and Pag, and no homologous T3Es were identified for these proteins in other phytopathogenic bacteria. Conversely, the remaining T3Es contribute to the virulence of both pathovars, and homologous T3Es were found in other phytopathogenic bacteria. Remarkably, HsvG and HsvB, which act as host-specific transcription factors, displayed the largest contribution to disease development. PMID- 28019709 TI - Exogenous induction of unphosphorylated PTEN reduces TGFbeta-induced extracellular matrix expressions in lung fibroblasts. AB - Transforming growth factor beta (TGFbeta) plays an important role in regulating aberrant extracellular matrix (ECM) production from alveolar/epithelial cells (AECs) and fibroblasts in pulmonary fibrosis. Although the tumor suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) can negatively control many TGFbeta-activated signaling pathways via the phosphatase activity, hyperactivation of the TGFbeta-related signaling pathways is often observed in fibrosis. Loss of PTEN expression might cause TGFbeta-induced ECM production. In addition, TGFbeta was recently shown to induce loss of PTEN enzymatic activity by phosphorylating the PTEN C-terminus. Therefore, we hypothesized that exogenous transfer of unphosphorylated PTEN (PTEN4A) might lead to reduce TGFbeta-induced ECM expression in not only epithelial cells but also fibroblasts. Adenovirus based exogenous PTEN4A induction successfully reduced TGFbeta-induced fibronectin expression and retained beta-catenin at the cell membrane in human epithelial cells. Exogenous unphosphorylated PTEN also attenuated TGFbeta-induced ECM production and inhibited TGFbeta-induced beta-catenin translocation in a human fibroblast cell line and in mouse primary isolated lung fibroblasts. Conversely, TGFbeta-induced alpha-smooth muscle actin expression did not seem to be inhibited in these fibroblasts. Our data suggest that exogenous administration of unphosphorylated PTEN might be a promising strategy to restore TGFbeta-induced loss of PTEN activity and reduce aberrant TGFbeta-induced ECM production from epithelial cells and fibroblasts in lung fibrosis as compared with wild-type PTEN induction. PMID- 28019710 TI - Mammalian cell culture monitoring using in situ spectroscopy: Is your method really optimised? AB - In recent years, as a result of the process analytical technology initiative of the US Food and Drug Administration, many different works have been carried out on direct and in situ monitoring of critical parameters for mammalian cell cultures by Raman spectroscopy and multivariate regression techniques. However, despite interesting results, it cannot be said that the proposed monitoring strategies, which will reduce errors of the regression models and thus confidence limits of the predictions, are really optimized. Hence, the aim of this article is to optimize some critical steps of spectroscopic acquisition and data treatment in order to reach a higher level of accuracy and robustness of bioprocess monitoring. In this way, we propose first an original strategy to assess the most suited Raman acquisition time for the processes involved. In a second part, we demonstrate the importance of the interbatch variability on the accuracy of the predictive models with a particular focus on the optical probes adjustment. Finally, we propose a methodology for the optimization of the spectral variables selection in order to decrease prediction errors of multivariate regressions. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:308-316, 2017. PMID- 28019711 TI - Acknowledging and incorporating mixed nutrition into aquatic protistan ecology, finally. PMID- 28019713 TI - Corrigendum. PMID- 28019712 TI - Inferior vena cava filters. AB - Use of inferior vena cava (IVC) filters has increased dramatically in recent decades, despite a lack of evidence that their use has impacted venous thromboembolism (VTE)-related mortality. This increased use appears to be primarily driven by the insertion of retrievable filters for prophylactic indications. A growing body of evidence, however, suggests that IVC filters are frequently associated with clinically important adverse events, prompting a closer look at their role. We sought to narratively review the current evidence on the efficacy and safety of IVC filter placements. Inferior vena cava filters remain the only treatment option for patients with an acute (within 2-4 weeks) proximal deep vein thrombosis (DVT) or pulmonary embolism and an absolute contraindication to anticoagulation. In such patients, anticoagulation should be resumed and IVC filters removed as soon as the contraindication has passed. For all other indications, there is insufficient evidence to support the use of IVC filters and high-quality trials are required. In patients where an IVC filter remains, regular follow-up to reassess removal and screen for filter-related complications should occur. PMID- 28019714 TI - A prospective study of the association between total sleep duration and incident hypertension. AB - The aim of this prospective study was to evaluate total sleep duration as a potential risk factor for the development of hypertension after a mean of 2.6 years of follow-up. The study participants comprised 1715 Korean adults aged 40 to 70 years. The participants were without hypertension at baseline (2005-2008) and during follow-up (2008-2011) to determine the incident cases of hypertension. Based on a self-reported questionnaire, the individuals were stratified according to total sleep duration (<6 hours, 6-7.9 hours, 8-9.9 hours, >=10 hours). Hypertension was defined according to the Eighth Joint National Committee (JNC 8) guidelines. After an average of 2.6 years of follow-up, 164 (9.56%) participants developed hypertension. In multivariate adjusted models, the odds ratio for new onset hypertension was 1.71 (95% confidence interval, 1.01-2.89) in participants with a short sleep duration (<6 hours) compared with those who reported 6 to 7.9 hours of sleep. Long sleep duration (more than 8 hours) did not have any significant difference on incident hypertension. Among middle-aged and elderly Korean adults, short sleepers were independently associated with a higher risk of developing hypertension. PMID- 28019715 TI - Experiences of mental health services for 'black' men with schizophrenia and a history of disengagement: A qualitative study. AB - Whilst mental disorders can be disabling they are also treatable, yet engagement with services is often poor and disengagement from treatment is a major concern for mental health nurses. Participants were service users typically perceived as the most disengaged from mental health services, yet they were willing to engage in the research interviews. The seven participants were all male with a diagnosis of schizophrenia, a history of disengagement from mental health services and described their ethnicity as 'black'. Participants were under the care of Assertive Outreach Teams and were recruited after the researcher was introduced to them by clinicians who were working with them. After ethical approval, in depth, semi-structured interviews were used to elicit the experiences of participants. Through interpretative phenomenological analysis, themes were developed. Interpretative Phenomenological analysis generated four themes: (i) "People just keep hounding me", (ii) Antipathy to Medication, (iii) Choice and the value of services, (iv) Stigmatisation and identity. By rigorously examining how service users with schizophrenia make sense of their experience of their relationship with mental health services, there is potential to give voice to the experiences of the recipients of mental health services. This study uncovered the complex nature of disengagement and in view of this there may never be a straightforward mechanism developed to engage all people with schizophrenia with mental health services. When the participants' experiences are considered in a broader social context it may be possible to reflect on how services can be adapted to facilitate better engagement. PMID- 28019716 TI - Assessment by airway ellipticity on cine-MRI to differentiate severe obstructive sleep apnea. AB - INTRODUCTION: The severity of obstructive sleep apnea (OSA) is assessed by the apnea-hypopnea index (AHI) determined from polysomnography (PSG). However, PSG requires a specialized facility with well-trained specialists and takes overnight. Therefore, simple tools, which could distinguish severe OSA, have been needed before performing PSG. OBJECTIVES: We propose the new index using cine-MRI as a screening test to differentiate severe OSA patients, who would need PSG and proper treatment. METHODS: Thirty-six patients with suspected OSA (mean age 54.6 y, mean AHI 52.6 events/h, 33 males) underwent airway cine-MRI at the fourth cervical vertebra level during 30 s of free breathing and PSG. The minimum airway ellipticity (AE) in 30 s duration was measured, and was defined as the severity of OSA. Patients were divided into severe OSA, not-severe OSA, and normal groups, according to PSG results. The comparison of AE between any two of the three groups was performed by Wilcoxon rank-sum test. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off of AE for identifying severe OSA patients. RESULTS: The minimum AE for severe OSA was significantly lower than that for not-severe OSA and normal (severe, 0.17 +/- 0.16; not severe, 0.31 +/- 0.17; normal, 0.38 +/- 0.19, P < .05). ROC analysis revealed that the optimal cutoff of the minimum AE 0.21 identified severe OSA patients, with an area under the curve of 0.75, 68% sensitivity, and 83% specificity. CONCLUSION: AE is a feasible quantitative index, and a promising screening test for detecting severe OSA patients. PMID- 28019717 TI - Reply. PMID- 28019718 TI - Excretions/secretions from medicinal larvae (Lucilia sericata) inhibit complement activation by two mechanisms. AB - Larvae of the blowfly Lucilia sericata facilitate wound healing by removing dead tissue and biofilms from non-healing and necrotic wounds. Another beneficial action of larvae and their excretions/secretions (ES) is down-regulation of excessive inflammation. As prolonged complement activation is key to excessive inflammation, the aim of this study was to elucidate the mechanisms underlying the anti-complement activities of ES. Results revealed that heat sensitive serine proteases in ES degrade multiple complement proteins in all steps of the three complement activation pathways. Importantly, C3a and C5a-major activators of inflammation-were also degraded by ES and pretreatment of these factors with ES completely blocked their ability to induce activation of human neutrophils. Pre exposure of the neutrophils to ES did not affect their responsiveness to C3a/C5a and fMLP, indicating that the receptors for these activators on neutrophils were not affected by ES. Surprisingly, heat and serine protease inhibitor pretreatment did not affect the ability of ES to inhibit C5b-9 complex formation despite degrading complement proteins, indicating a second complement-inhibiting molecule in ES. Heated ES was as effective as intact ES in inhibiting C3 deposition upon activation of the alternative pathway, but was significantly less effective in wells with a classical or lectin pathway-specific coating. Unfortunately, the molecules affecting the complement system could not be identified due to an insufficient database for L. sericata. Together, larval ES inhibit complement activation by two different mechanisms and down-regulate the C3a/C5a-mediated neutrophil activation. This attenuates the inflammatory process, which may facilitate wound healing. PMID- 28019719 TI - Identification and Enrichment of alpha-Glucosidase-Inhibiting Dihydrostilbene and Flavonoids from Glycyrrhiza uralensis Leaves. AB - To exploit Glycyrrhiza uralensis resources, we examined the bioactive constituents of G. uralensis leaves. Seven chemical components were isolated by repeat column chromatography, and using spectroscopic methods, their structures were determined to be a novel prenylated dihydrostilbene, alpha,alpha'-dihydro 3,5,3',4'-tetrahydroxy-2,5'-diprenylstilbene (1); a methylated flavonoid, quercetin-3-Me ether (4); and 5 prenylated flavonoids: 5'-prenylquercetin (3), 8 [(E)-3-hydroxymethyl-2-butenyl]eriodictyol (7), 6-prenyleriodictyol (5), 5' prenyleriodictyol (6), and 6-prenylquercetin-3-Me ether (2). Compounds 1-7 and their unprenylated counterparts, glycosides, and other related compounds (8-13) were quantitatively analyzed. Using a macroporous resin column, most of these compounds could be enriched in the 40% to 60% ethanol-eluted fractions. Compounds 1-7 showed strong radical scavenging activity toward DPPH, and most of them demonstrated greater inhibitory activity against alpha-glucosidase than their unprenylated counterparts. PMID- 28019720 TI - Solid- and solution-state nuclear magnetic resonance spectroscopic studies on antibody light chain amyloid formation and interactions with epigallocatechin gallate. PMID- 28019721 TI - The effect of deprivation on the developmental activities of adolescent rugby union players in Wales. AB - The developmental activities of rugby union players and their interaction with deprivation remain to be elucidated. Five-hundred and ninety elite junior rugby union players (14.8 +/- 0.5 years) were split into deprivation quintiles. These players subsequently completed a participant history questionnaire to record their involvement in rugby and other sports. Players accumulated 1987 +/- 1297 h in rugby between 6 and 15 years of age. During the mini rugby stage (6-10 years of age), players accumulated an average of 113 +/- 105, 89 +/- 69 and 43 +/- 19 h per year in rugby play, practice and competition, respectively. Moreover, 461 players engaged in an average of two other sports during the mini rugby stage. During the junior rugby stage (11-15 years of age), players accumulated 179 +/- 98, 115 +/- 90 and 64 +/- 26 h per year in rugby practice, play and competition, respectively, and 538 players took part in three other sports. Players who were more deprived accumulated less rugby hours and participated in fewer other sports, but age milestones were not different between deprivation quintiles. There were no differences within developmental activities in rugby between deprivation groups. PMID- 28019722 TI - Immunotherapeutic clearance of systemic amyloid deposits by antibodies to serum amyloid P component. PMID- 28019723 TI - Therapeutical potential of deregulated lysine methyltransferase SMYD3 as a safe target for novel anticancer agents. AB - INTRODUCTION: SET and MYND domain containing-3 (SMYD3) is a member of the lysine methyltransferase family of proteins, and plays an important role in the methylation of various histone and non-histone targets. Proper functioning of SMYD3 is very important for the target molecules to determine their different roles in chromatin remodeling, signal transduction and cell cycle control. Due to the abnormal expression of SMYD3 in tumors, it is projected as a prognostic marker in various solid cancers. Areas covered: Here we elaborate on the general information, structure and the pathological role of SMYD3 protein. We summarize the role of SMYD3-mediated protein interactions in oncology pathways, mutational effects and regulation of SMYD3 in specific types of cancer. The efficacy and mechanisms of action of currently available SMYD3 small molecule inhibitors are also addressed. Expert opinion: The findings analyzed herein demonstrate that aberrant levels of SMYD3 protein exert tumorigenic effects by altering the epigenetic regulation of target genes. The partial involvement of SMYD3 in some distinct pathways provides a vital opportunity in targeting cancer effectively with fewer side effects. Further, identification and co-targeting of synergistic oncogenic pathways is suggested, which could provide much more beneficial effects for the treatment of solid cancers. PMID- 28019724 TI - A comparison of methods to estimate anaerobic capacity: Accumulated oxygen deficit and W' during constant and all-out work-rate profiles. AB - This study investigated (i) whether the accumulated oxygen deficit (AOD) and curvature constant of the power-duration relationship (W') are different during constant work-rate to exhaustion (CWR) and 3-min all-out (3MT) tests and (ii) the relationship between AOD and W' during CWR and 3MT. Twenty-one male cyclists (age: 40 +/- 6 years; maximal oxygen uptake [VO2max]: 58 +/- 7 ml . kg-1 . min-1) completed preliminary tests to determine the VO2-power output relationship and VO2max. Subsequently, AOD and W' were determined as the difference between oxygen demand and oxygen uptake and work completed above critical power, respectively, in CWR and 3MT. There were no differences between tests for duration, work, or average power output (P >= 0.05). AOD was greater in the CWR test (4.18 +/- 0.95 vs. 3.68 +/- 0.98 L; P = 0.004), whereas W' was greater in 3MT (9.55 +/- 4.00 vs. 11.37 +/- 3.84 kJ; P = 0.010). AOD and W' were significantly correlated in both CWR (P < 0.001, r = 0.654) and 3MT (P < 0.001, r = 0.654). In conclusion, despite positive correlations between AOD and W' in CWR and 3MT, between-test differences in the magnitude of AOD and W', suggest that both measures have different underpinning mechanisms. PMID- 28019725 TI - The KCC3 cotransporter as a therapeutic target for peripheral neuropathy. PMID- 28019726 TI - Examining the relationships between challenge and threat cognitive appraisals and coaching behaviours in football coaches. AB - Previous research demonstrates that sports coaching is a stressful activity. This article investigates coaches' challenge and threat cognitive appraisals of stressful situations and their impact on coaching behaviour, using Blascovich and Mendes' (2000) biopsychosocial model as a theoretical framework. A cross sectional correlational design was utilised to examine the relationships between irrational beliefs (Shortened general attitude and belief scale), challenge and threat appraisals (Appraisal of life events scale), and coaching behaviours (Leadership scale for sports) of 105 professional football academy coaches. Findings reveal significant positive associations between challenge appraisals and social support, and between threat appraisals and autocratic behaviour, and a significant negative association between threat appraisals and positive feedback. Results also show that higher irrational beliefs are associated with greater threat, and lesser challenge cognitive appraisals. However, no associations were revealed between irrational beliefs and challenge cognitive appraisals. Additionally, findings demonstrate a positive relationship between age and training and instruction. Results suggest that practitioners should help coaches to appraise stressful situations as a challenge to promote positive coaching behaviours. PMID- 28019727 TI - Research methods in physical activity. PMID- 28024081 TI - Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich ataxia. AB - The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR edited successfully the GAA expansion in vitro and in vivo. Nevertheless, our results suggest the YG8sR as a better and more suitable model for the study of the CRISPR-Cas9 edition of the mutated frataxin gene. PMID- 28024082 TI - Evidence for the in vivo safety of insulated foamy viral vectors. AB - Retroviral vector-mediated stem cell gene therapy is a promising approach for the treatment of hematopoietic disorders. However, genotoxic side effects from integrated vector proviruses are a significant concern for the use of retroviral vectors in the clinic. Insulated foamy viral (FV) vectors are potentially safer retroviral vectors for hematopoietic stem cell gene therapy. We evaluated two newly identified human insulators, A1 and A2, for use in FV vectors. These insulators had moderate insulating capacity and higher titers than previously developed insulated FV vectors. The A1-insulated FV vector was chosen for comparison with the previously described 650cHS4-insulated FV vector in human cord blood CD34+ repopulating cells in an immunodeficient mouse model. To maximize the effects of the insulators on the safety of FV vectors, FV vectors containing a highly genotoxic spleen focus forming virus promoter were used to elicit differences in genotoxicity. In vivo, the A1-insulated FV vector showed an approximate 50% reduction in clonal dominance compared with either the 650cHS4 insulated or control FV vectors, although the transduction efficiency of the A1 insulated vector was higher. This data suggests that the A1-insulated FV vector is promising for future preclinical and clinical studies. PMID- 28024083 TI - Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. AB - Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo. PMID- 28024084 TI - Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11-q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642-two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)-activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pDeltaS-U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pDeltaS-U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS. PMID- 28024085 TI - On the Functional Role of Valve Interstitial Cell Stress Fibers: A Continuum Modeling Approach. AB - The function of the heart valve interstitial cells (VICs) is intimately connected to heart valve tissue remodeling and repair, as well as the onset and progression of valvular pathological processes. There is yet only very limited knowledge and extant models for the complex three-dimensional VIC internal stress-bearing structures, the associated cell-level biomechanical behaviors, and how they change under varying activation levels. Importantly, VICs are known to exist and function within the highly dynamic valve tissue environment, including very high physiological loading rates. Yet we have no knowledge on how these factors affect VIC function. To this end, we extended our previous VIC computational continuum mechanics model (Sakamoto, et al., 2016, "On Intrinsic Stress Fiber Contractile Forces in Semilunar Heart Valve Interstitial Cells Using a Continuum Mixture Model," J. Mech. Behav. Biomed. Mater., 54(244-258)). to incorporate realistic stress-fiber geometries, force-length relations (Hill model for active contraction), explicit alpha-smooth muscle actin (alpha-SMA) and F-actin expression levels, and strain rate. Novel micro-indentation measurements were then performed using cytochalasin D (CytoD), variable KCl molar concentrations, both alone and with transforming growth factor beta1 (TGF-beta1) (which emulates certain valvular pathological processes) to explore how alpha-SMA and F-actin expression levels influenced stress fiber responses under quasi-static and physiological loading rates. Simulation results indicated that both F-actin and alpha-SMA contributed substantially to stress fiber force generation, with the highest activation state (90 mM KCL + TGF-beta1) inducing the largest alpha-SMA levels and associated force generation. Validation was performed by comparisons to traction force microscopy studies, which showed very good agreement. Interestingly, only in the highest activation state was strain rate sensitivity observed, which was captured successfully in the simulations. These unique findings demonstrated that only VICs with high levels of alphaSMA expression exhibited significant viscoelastic effects. Implications of this study include greater insight into the functional role of alpha-SMA and F-actin in VIC stress fiber function, and the potential for strain rate-dependent effects in pathological states where high levels of alpha-SMA occur, which appear to be unique to the valvular cellular in vivo microenvironment. PMID- 28024086 TI - Leisure-Time Physical Activity Reduces Total and Cardiovascular Mortality and Cardiovascular Disease Incidence in Older Adults. AB - OBJECTIVES: To determine whether leisure-time physical activity (LTPA) is independently associated with all-cause and cardiovascular mortality and with incidence of cardiovascular disease (CVD) and stroke in older adults. DESIGN: Population-based cohort study (median follow-up 11.8 years). SETTING: Community, five Finnish provinces. PARTICIPANTS: Men and women aged 65 to 74 who participated in a baseline risk factor survey between 1997 and 2007 in Finland (N = 2,456). MEASUREMENTS: The study protocol included a self-administered questionnaire, health examination at the study site, and blood sample for laboratory analysis. LTPA was classified into three levels: low, moderate, high. Mortality data were obtained from the National Causes of Death Register and data on incident CVD (coronary heart disease, stroke) events from the National Hospital Discharge Register. RESULTS: Multifactorial-adjusted (age, area, study year, sex, smoking, body mass index, systolic blood pressure, serum cholesterol, education, marital status) risks of total mortality (moderate: hazard ratio (HR) = 0.61, 95% confidence interval (CI) = 0.50-0.74; high: HR = 0.47, 95% CI = 0.34 0.63, P for trend <.001), CVD mortality (moderate: HR = 0.46, 95% CI = 0.33-0.64; high: HR = 0.34, 95% CI = 0.20-0.59, P for trend <.001), and an incident CVD event (moderate HR = 0.69, 95% CI = 0.54-0.88; high: HR = 0.55, 95% CI = 0.38 0.79, P for trend <.001) were lower for those with moderate or high LTPA levels than for those with low LTPA levels. Further adjustment for self-reported inability to perform LTPA did not change the associations remarkably. CONCLUSIONS: Baseline LTPA reduces the risk of total and CVD mortality and incident CVD events in older adults independently of the major known CVD risk factors. The protective effect of LTPA is dose dependent. PMID- 28024087 TI - Response to Letter to the Editor: Aging and Statins. PMID- 28024088 TI - Age of Statin Therapy; Statin Therapy With Aging. PMID- 28024089 TI - Is Polypharmacy Associated with Frailty in Older People? Results From the ESTHER Cohort Study. AB - OBJECTIVES: To investigate the relationship between polypharmacy and frailty. DESIGN: Longitudinal, observational cohort study. SETTING: Saarland, Germany. PARTICIPANTS: 3,058 community-dwelling adults aged between 57 and 84 years. MEASUREMENTS: Frailty was assessed according to the frailty phenotype, described by Fried et al. Polypharmacy and hyperpolypharmacy were defined as the concomitant use of five or more and 10 or more drugs, respectively. We assessed associations between polypharmacy and prevalent and incident frailty within 3 years of follow-up by logistic regression models controlled for multiple potential confounders including comorbidity. Additionally, cubic splines were used to assess dose-response associations. RESULTS: Polypharmacy was reported in 39.1% (n = 1,194), and hyperpolypharmacy in 8.9% (n = 273) of participants. Prevalent frailty was present in 271 (8.9%) participants; 186 (9.3%) of 1,998 non frail participants with follow-up data became frail within 3 years. After adjustment, polypharmacy and hyperpolypharmacy were associated with prevalent frailty with adjusted odds ratios (95% confidence interval) of 2.30 (1.60-3.31) and 4.97 (2.97-8.32), respectively. Polypharmacy (odds ratio (OR) 1.51 (1.05 2.16)) and hyperpolypharmacy (OR 1.90 (1.10-3.28)) were also independent predictors of incident frailty. Furthermore, there was a moderate exposure response relationship between the number of medicines and prevalent as well as incident frailty. CONCLUSION: Our study showed that polypharmacy is associated with frailty. Further research should address the potential benefit of reducing of inappropriate polypharmacy and better pharmacotherapeutic management for preventing medication-associated frailty. PMID- 28024091 TI - Osteoporotic Fractures in Postmenopausal Women. PMID- 28024090 TI - Cost-Effectiveness of the 4 Pillars Practice Transformation Program to Improve Vaccination of Adults Aged 65 and Older. AB - OBJECTIVES: To estimate the cost-effectiveness of an intervention to increase pneumococcal, influenza, and pertussis-containing vaccine uptake in adults aged 65 and older in primary care practices. DESIGN: Markov decision analysis model, comparing the cost-effectiveness of the 4 Pillars Practice Transformation Program with no intervention. SETTING: Diverse primary care practices in two U.S. cities. PARTICIPANTS: Clinical trial participants aged 65 and older. MEASUREMENTS: Quality-adjusted life years (QALYs), public health outcomes, and costs. Vaccination rates and intervention costs were derived from a randomized controlled cluster trial. Other parameters were derived from the medical literature and Centers for Disease Control and Prevention data. All parameters were individually and simultaneously varied over their distributions. RESULTS: With the intervention program and extrapolating over 10 years, there would be approximately 60,920 fewer influenza cases, 2,031 fewer pertussis cases, and 13,842 fewer pneumococcal illnesses in adults aged 65 and older. Total per-person vaccination and illness costs with the intervention were $23.93 higher than without the intervention, with a concurrent increase in effectiveness of 0.0031 QALYs, or $7,635 per QALY gained. In sensitivity analyses, no individual parameter variation caused the intervention to cost more than $50,000 per QALY gained. CONCLUSIONS: Implementing an intervention based on the 4 Pillars Practice Transformation Program is a cost-effective undertaking in primary care practices for individuals aged 65 and older, with predicted public health benefits. PMID- 28024092 TI - Agreement and Predictive Validity Using Less-Conservative Foundation for the National Institutes of Health Sarcopenia Project Weakness Cutpoints. AB - OBJECTIVES: To derive lean mass cutpoints based on a less-conservative Foundation for the National Institutes of Health (FNIH) Sarcopenia Project Weakness cutpoint for grip strength (WeakI ) and to assess their agreement with European Working Group on Sarcopenia in Older People (EWGSOP) and prediction of incident slow walking and mortality. DESIGN: Longitudinal analysis. SETTING: Baltimore Longitudinal Study of Aging. PARTICIPANTS: Individuals aged 65 and older (287 men, 258 women) with 2 to 10 years of follow-up. MEASUREMENTS: Weakness was determined according to handgrip strength using a hand dynamometer, appendicular lean mass (ALM) using dual-energy X-ray absorptiometry, and walking speed according to 6-m usual pace walk speed. Analyses were performed using classification and regression tree analysis, Cohen's kappa, and Cox models. RESULTS: Cutpoints derived from WeakI for ALM (ALMI ) were less than 21.4 kg in men and less than 14.1 kg in women and for ALM adjusted for body mass index (ALM/BMII ) were less than 0.725 in men and less than 0.591 in women. Kappas with EWGSOP were 0.65 for men and 0.75 for women for ALMI and 0.34 for men and 0.47 for women for ALM/BMII . Men with WeakI + ALMI were twice as likely to develop slow walking as those not weak with normal ALMI (Hazard ratio (HR) = 2.44, 95% confidence interval (CI) = 1.02-5.82). Under EWGSOP, men with weakness and low RALM were almost 3 times as likely to develop slow walking as those not weak with normal RALM (HR = 2.91, 95% CI = 1.11-7.62). Neither approach predicted incident slow walking in women. CONCLUSION: The ALMI cutpoints agree with EWGSOP and predict slow walking in men. Future studies should explore sex differences in the relationship between body composition and physical function and the effect of change in muscle mass on muscle strength and physical function. PMID- 28024093 TI - Oral Hygiene in the Elderly with Different Degrees of Cognitive Impairment and Dementia. AB - The control of bacterial dental plaque through daily oral hygiene is essential to prevent oral diseases such as caries or periodontal disease, especially in at risk populations, including the elderly with mild cognitive impairment and dementia. The aim of this study was to determine the association between different levels of cognitive impairment and dementia in an elderly population and their capacity to maintain adequate oral hygiene. A case-control study (elderly with versus without mild cognitive impairment or dementia) was performed in Granada, Spain. Outcome variables were tooth/prosthesis-brushing frequency/day, bacterial plaque index, and gingival bleeding index. Statistical models were adjusted by age, sex, educational level, and tobacco and alcohol habits. The study included 240 cases and 324 controls. The final model, adjusted by age, sex, educational level, and tobacco and alcohol consumption, showed a significant association between degree of cognitive impairment and daily oral hygiene, accumulation of bacterial plaque, and gingival bleeding. In summary, deficient daily oral hygiene, evidenced by greater bacterial dental plaque accumulation and gingival inflammation, is independently associated with cognitive impairment, even at its earliest stage. PMID- 28024094 TI - Effect on surface character and mechanical property of unsintered hydroxyapatite/poly-l-lactic acid (uHA/PLLA) material by UV treatment. AB - Materials fabricated with unsintered hydroxyapatite/poly-l-lactic acid (uHA/PLLA) exhibit biological activity and biocompatibility, but are also hydrophobic. This hydrophobicity limits the ability of cells or tissues to adhere to the surface of the material and thereby prevents the materials from exhibiting effective biological activity. In this study, we examined the effects of ultraviolet (UV) treatment on the hydrophobicity of uHA/PLLA. We compared the contact angle, mechanical strength, cell attachment, and cell differentiation capacity between untreated uHA/PLLA and uHA/PLLA treated with UV light. The contact angle of UV treated uHA/PLLA was significantly reduced compared with that of untreated uHA/PLLA. However, there were no differences in mechanical strength between untreated uHA/PLLA and UV-treated uHA/PLLA. Notably, the ability of cells to adhere to UV-treated uHA/PLLA was significantly increased compared with that of untreated uHA/PLLA. Similarly, there were significant differences between UV treated uHA/PLLA and untreated uHA/PLLA in alkaline phosphatase assays. These findings demonstrated that UV irradiation of uHA/PLLA improved the surface hydrophilicity without changing the mechanical strength of the material; thus, UV treatment of uHA/PLLA may facilitate the use of this material in biomedical applications. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 191-200, 2018. PMID- 28024095 TI - Recent development of transcatheter closure of atrial septal defect and patent foramen ovale with occluders. AB - Atrial septal defect (ASD) and patent foramen ovale (PFO) are common clinical congenital heart defects. As an effective method for the treatment of ASD and PFO, transcatheter closure with occluders presents many advantages, including safety, ease of operation, minimal invasiveness, and reduced complications. This contribution reviews the various types of occluders currently used in clinical applications and under development, including non degradable occluders, partially degradable occluders, and totally degradable occluders. A number of case studies are described in detail. Comparison is made on the treatment outcomes using different occulders. Future development of transcatheter closure is discussed, in particular the use of totally degradable occluders. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 433-443, 2018. PMID- 28024096 TI - The prospective relationship between satisfaction with information and symptoms of depression and anxiety in breast cancer: A structural equation modeling analysis. AB - OBJECTIVE: Previous research has demonstrated associations between satisfaction with information and reduced emotional distress in cancer patients. However, as most studies were cross-sectional, the direction of this relationship remained unclear. We therefore aimed to test whether information satisfaction predicted subsequent depression and anxiety levels, and, reciprocally, depression and anxiety levels predicted subsequent information satisfaction, thus clarifying the direction of impact. METHODS: We performed a secondary analysis of a prospective cohort study with 436 female breast cancer patients (mean age 51 years). We measured information satisfaction with 2 self-developed items, symptoms of depression with the 2-item Patient Heath Questionnaire and symptoms of anxiety with the 2-item Generalized Anxiety Disorder Scale. We created 2 structural equation models, 1 for depression and 1 for anxiety, that examined the prediction of 1-year depression (or anxiety) levels by baseline information satisfaction and, in the same model, 1-year information satisfaction by baseline depression (or anxiety) levels (cross-lagged panel analysis). RESULTS: Baseline information satisfaction predicted 1-year levels of both depression (beta = -0.17, P < .01) and anxiety (beta = -0.13, P < .01), adjusting for the baseline scores of the outcome variables. Conversely, baseline levels of depression (beta = -0.12, P < .05) and anxiety (beta = -0.16, P < .01) predicted 1-year information satisfaction, adjusting for its baseline score. CONCLUSION: Our results suggest a bidirectional relationship between information satisfaction and symptoms of depression and anxiety. Thus, provision of information may reduce subsequent depression and anxiety, while reducing depression and anxiety levels may increase satisfaction with received information. Combining the provision of information with emotional support may be particularly beneficial. PMID- 28024097 TI - Immunoglobulin A: magic bullet or Trojan horse? AB - BACKGROUND: Neutrophils participate in the first line of defense by executing several killing mechanisms, including phagocytosis, degranulation and the release of neutrophil extracellular traps. Additionally, they can orchestrate the adaptive immune system by secreting cytokines and chemokines. Opsonization with antibodies aids in the recognition of pathogens, via binding to Fc receptors on the neutrophil surface. Immunoglobulin A (IgA) is the most abundant antibody at mucosal sites and has multiple functions in homeostasis and immunity. Neutrophils and IgA can interact via the IgA Fc receptor Fc?RI (CD89), leading to pro- or anti-inflammatory responses. AIMS: The aim of this review is to give a concise overview of the interplay between IgA, Fc?RI and neutrophils and to explore potential therapies for autoimmune diseases and cancer. RESULTS: Crosslinking of FcalphaRI by IgA-immune complexes yields potent neutrophil activation and pro inflammatory effector functions, including the recruitment of neutrophils. This can lead to neutrophil accumulation and tissue destruction during IgA autoantibody mediated diseases. Conversely, for cancer treatment, the myriad of powerful neutrophil effector functions after targeting FcalphaRI may contribute to effective immunotherapy. CONCLUSION: By interfering with or actively promoting the interaction between IgA and FcalphaRI, therapies for multiple maladies could be developed. PMID- 28024099 TI - Serum vaspin levels and carotid intima media thickness in pre dialysis patients. AB - BACKGROUND AND OBJECTIVE: Vaspin is a molecule belonging to adipokine family which is associated with insulin resistance and obesity in humans. Several studies have evaluated the serum levels of vaspin in various conditions including coronary artery disease and chronic hemodialysis patients. To our best knowledge, serum vaspin levels have not yet been studied in pre dialysis patients. Carotid intima-media thickness (CIMT) is a noninvasive procedure used to diagnose the extent of carotid atherosclerotic vascular disease. The objective of this study is to evaluate serum vaspin levels in pre dialysis patients and their relationships with glomerular filtration rate and CIMT levels. METHODS: A total of twenty-five pre dialysis patients (14 female and 11 male) and 22 healthy controls (8 female and 14 male) were included in the study. CIMT was measured through B-mode ultrasonography. RESULTS: Serum vaspin levels were significantly lower (p<0.05) and CIMT levels were significantly higher (p<0.001) in pre dialysis patients than in control subjects. Serum vaspin levels were found to be significantly correlated with glomerular filtration rate (r=0.42, p<0.001) and CIMT (r=-0.47, p<0.05) in pre dialysis patients. CONCLUSIONS: This is the first report to describe the correlation between serum vaspin levels and CIMT in pre dialysis patients. We concluded that serum vaspin levels were decreased in pre dialysis patients compared to the control subjects. In addition, serum vaspin levels were found to be significantly correlated with glomerular filtration rate and CIMT. This article is protected by copyright. All rights reserved. PMID- 28024098 TI - Helicobacter pylori serology testing is a useful diagnostic screening tool for symptomatic inner city children. AB - AIM: This study assessed the Helicobacter pylori (H. pylori) serum antibody test as a diagnostic screening tool in symptomatic inner city children. METHODS: This was a retrospective study of patients aged one to 18 years who were referred to our paediatric gastroenterology department from 2009 to 2013. We included all patients who had H. pylori serum antibodies and/or faecal antigens who underwent esophagogastroduodenoscopy (EGD) for histology, with or without a gastric tissue rapid urease test. RESULTS: A total of 395 patients had EGDs carried out to evaluate epigastric pain, heartburn and nausea or vomiting, and their overall socio-economic Z-score was -2.62. The histology was positive for H. pylori infection in 52 of 395 patients (13%), and epigastric pain was documented in 45 of these 52 patients (87%). Compared to histology, the serum H. pylori antibody test had a sensitivity of 88.4% and a specificity of 93.4%. The tissue rapid urease test and faecal antigen test had sensitivities of 89.3% and 55.6% and specificities of 89.9% and 98.9%, respectively. CONCLUSION: The serum H. pylori antibody test had high sensitivity and specificity, and it was a good diagnostic screening tool in our study. Epigastric pain was strongly associated with a current H. pylori infection in our population. PMID- 28024100 TI - Atmospheric CO2 mole fraction affects stand-scale carbon use efficiency of sunflower by stimulating respiration in light. AB - Plant carbon-use-efficiency (CUE), a key parameter in carbon cycle and plant growth models, quantifies the fraction of fixed carbon that is converted into net primary production rather than respired. CUE has not been directly measured, partly because of the difficulty of measuring respiration in light. Here, we explore if CUE is affected by atmospheric CO2 . Sunflower stands were grown at low (200 MUmol mol-1 ) or high CO2 (1000 MUmol mol-1 ) in controlled environment mesocosms. CUE of stands was measured by dynamic stand-scale 13 C labelling and partitioning of photosynthesis and respiration. At the same plant age, growth at high CO2 (compared with low CO2 ) led to 91% higher rates of apparent photosynthesis, 97% higher respiration in the dark, yet 143% higher respiration in light. Thus, CUE was significantly lower at high (0.65) than at low CO2 (0.71). Compartmental analysis of isotopic tracer kinetics demonstrated a greater commitment of carbon reserves in stand-scale respiratory metabolism at high CO2 . Two main processes contributed to the reduction of CUE at high CO2 : a reduced inhibition of leaf respiration by light and a diminished leaf mass ratio. This work highlights the relevance of measuring respiration in light and assessment of the CUE response to environment conditions. PMID- 28024101 TI - Thioesterase overexpression in Nicotiana benthamiana leaf increases the fatty acid flux into triacylgycerol. AB - Increasing the oil content of leafy biomass is emerging as a sustainable source of vegetable oil to meet global demand. Transient gene expression in leaf provides a reproducible platform to study the effect of transgenes on lipid biosynthesis. We first generated a transgenic Nicotiana benthamiana line containing high levels of triacylglycerol in the leaf tissue (31.4% by dry weight) by stably expressing WRI1, DGAT1 and OLEOSIN. We then used this line as a platform to test the effect of three Arabidopsis thaliana thioesterases (FATA1, FATA2 and FATB). Further increases in leaf oil content were observed with biochemical and lipid assays revealing an increase in the export of fatty acids from the chloroplast and a modification in the oil profile. PMID- 28024102 TI - Elevated ischaemia-associated lysyl oxidase activity in delayed graft failure 6 12 months after renal transplantation. AB - NEW FINDINGS: What is the central question of this study? What potential biochemical changes are associated with renal parenchyma 6-12 months after renal transplantation and delayed graft failure? What is the main finding and its importance? Tissue fibrosis, mediated by tissue ischaemia-induced induction of hypoxia-inducible factor-1alpha and fibronectin and consequent activation of lysyl oxidase, is a major underlying pathophysiological mechanism that contributes to delayed graft failure several months after renal transplantation. The present investigation was undertaken to evaluate the potential biochemical changes associated with renal parenchyma 6-12 months after renal transplantation and delayed graft failure. Serum concentrations of transforming growth factor beta in these subjects always remained elevated. In addition, examination of tissue from needle biopsies confirmed that there were consistent changes in the enzyme lysyl oxidase, which functions as an amine oxidase, modifies lysine residues on collagen and cross-links in a process of modulation of the extracellular matrix. Parenchymal levels of hypoxia-inducible factor-1alpha and fibronectin were elevated, as detected by Western blotting. These findings indicate an ongoing ischaemic insult, which might result from increased tissue fibrosis or, in some cases, might be additive with pre-existing pathophysiological factors that constrain proper renal haemodynamics. Thus, increased lysyl oxidase activity, which we assayed, is a potential unfavourable mechanism occurring in these kidneys that are undergoing failure and probably causes increased fibrosis within the organ and causes ischaemia, renovascular hypertension and a cascade leading to renal dysfunction and failure. PMID- 28024103 TI - Multiple-reaction monitoring for multiplex detection of three bacterial toxins using liquid chromatography-tandem mass spectrometry. AB - Clostridium perfringens epsilon toxin, staphylococcal enterotoxin B and shiga toxin are implicated in a number of diseases and food-borne intoxications and are considered potential agents for bioterrorism and warfare. Artificially generated aerosol is the likely mode of delivery of these for nefarious uses, potentially capable of causing mass destruction to human and animal health by inhalation of toxic bioaerosol. Multiplex and unambiguous detection of these agents is of paramount importance for emergency response in a biothreat scenario and for food safety. Multiple-reaction monitoring (MRM) assay for simultaneous monitoring of the three toxins is reported here using reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Three different peptides with two fragment ions each were considered for quantification and confirmation. One of the three MRM transitions from each toxin, which exhibited the best sensitivity, was selected for multiplexing of the assay. Simulating a biothreat scenario wherein the bioaerosol is collected in 10 ml of buffer, the multiplex assay was tested with blind samples with one or more of the three toxins even in the presence of interfering Escherichia coli lysate proteins. PMID- 28024104 TI - The Challenge: Assessment of risks posed by systemic insecticides to hymenopteran pollinators: New perception when we move from laboratory via (semi-)field to landscape scale testing? PMID- 28024106 TI - ET&C exceptional reviewers of 2016. PMID- 28024105 TI - Assessing and managing multiple risks in a changing world-The Roskilde recommendations. AB - Roskilde University (Denmark) hosted a November 2015 workshop, Environmental Risk Assessing and Managing Multiple Risks in a Changing World. This Focus article presents the consensus recommendations of 30 attendees from 9 countries regarding implementation of a common currency (ecosystem services) for holistic environmental risk assessment and management; improvements to risk assessment and management in a complex, human-modified, and changing world; appropriate development of protection goals in a 2-stage process; dealing with societal issues; risk-management information needs; conducting risk assessment of risk management; and development of adaptive and flexible regulatory systems. The authors encourage both cross-disciplinary and interdisciplinary approaches to address their 10 recommendations: 1) adopt ecosystem services as a common currency for risk assessment and management; 2) consider cumulative stressors (chemical and nonchemical) and determine which dominate to best manage and restore ecosystem services; 3) fully integrate risk managers and communities of interest into the risk-assessment process; 4) fully integrate risk assessors and communities of interest into the risk-management process; 5) consider socioeconomics and increased transparency in both risk assessment and risk management; 6) recognize the ethical rights of humans and ecosystems to an adequate level of protection; 7) determine relevant reference conditions and the proper ecological context for assessments in human-modified systems; 8) assess risks and benefits to humans and the ecosystem and consider unintended consequences of management actions; 9) avoid excessive conservatism or possible underprotection resulting from sole reliance on binary, numerical benchmarks; and 10) develop adaptive risk-management and regulatory goals based on ranges of uncertainty. Environ Toxicol Chem 2017;36:7-16. (c) 2016 SETAC. PMID- 28024107 TI - Corrigendum. PMID- 28024108 TI - A snapshot of cryo-EM. PMID- 28024109 TI - Financial Incompatibility and Paired Kidney Exchange: Walking a Tightrope or Blazing a Trail? PMID- 28024110 TI - The importance of EZH2 and MOC-31 expression in the differential diagnosis of benign and malignant effusions. AB - BACKGROUND: All malignant tumors may spread throughout the pleural, peritoneal, and pericardial cavities. The presence of tumor cells in serosal fluid is a poor prognostic indicator. It may be difficult to differentiate nuclear atypia of mesothelial cells due to injury of serosal surfaces from mesothelioma or malignant epithelial tumor cells. Epithelial and mesothelial immunohistochemical markers can be used in such conditions. The aim of this study was to evaluate the expression of two immunohistochemical markers (MOC-31 and EZH2) in serosal effusions. METHODS: The study included a total of 142 patients diagnosed with benign or malignant cytology between January 2012 and April 2014. MOC-31 and EZH2 were applied to the cell blocks of 53 patients with benign cytology and 89 patients with malignant cytology determined based on the clinical, radiological data, histopathology diagnosis, and clinical follow-up in the absence of any surgical material of the patient in the hospital archive system. RESULTS: None of the benign cases showed MOC-31 and EZH2 expression, although these markers were positive in 96 and 93% respectively of the malignant cases. CONCLUSION: In conclusion, it could be considered cost-effective to use a double immunohistochemical antibody kit for these two markers, MOC-31 membranous and EZH2 nuclear staining, in the diagnosis of malignant effusions. Diagn. Cytopathol. 2017;45:118-124. (c) 2016 Wiley Periodicals, Inc. PMID- 28024111 TI - Pleomorphic rhabdomyosarcoma arising in the anterior mediastinum: A case report with cytological features of imprint and liquid-based cytology specimens. AB - We herein report the cytological features of a very rare case of pleomorphic rhabdomyosarcoma arising in the anterior mediastinum on imprint and liquid-based cytology (LBC) specimens. A 58-year-old man had an approximately 10-cm tumor in the anterior mediastinum as shown on computed tomography. Thymectomy with complete resection of the left lung was performed. The fresh cut surface of the tumor was used to prepare imprint and LBC specimens. The imprint specimens showed four types of tumor cells dispersed on a background of hemorrhage, necrosis, and mucus. On the other hand, only two types of tumor cells (spindle-shaped and spiderweb cells) were scattered or present in clusters in the LBC specimens. Immunocytologically, both of these cell types were positive for desmin and myoglobin, negative for pan-keratin and epithelial membrane antigen. Cytological and immunocytological features are useful for the correct diagnosis of pleomorphic rhabdomyosarcoma, and LBC specimens show clearer results than do imprint specimens. Diagn. Cytopathol. 2017;45:333-338. (c) 2016 Wiley Periodicals, Inc. PMID- 28024112 TI - Left-Sided Living Kidney Donation Leads to Transiently Reduced Adrenocortical Responsiveness. AB - Living kidney donation is safe and established, but can lead to long-term complications such as chronic fatigue. Since the adrenal vein is usually transected during left-sided donor nephrectomy-which is not necessary on the right-we hypothesized that venous congestion might lead to an impairment of adrenal function, offering a possible explanation. In this prospective open label, monocentric cohort study, adrenal function was compared in left- and right sided living kidney donors. The primary endpoint was plasma cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation. Secondary endpoints included plasma renin and ACTH concentration as well as adrenal volume in response to donor nephrectomy. A total of 30 healthy donors-20 left- and 10 right sided donations-were included. On postoperative day 1, response to low-dose ACTH stimulation was intact, but significantly lower after left-sided donor nephrectomy. After 28 days, adrenal responsiveness to ACTH stimulation did not differ any longer. Magnetic resonance imaging volumetry showed no significant adrenal volume change over 4 weeks, neither after left- nor after right-sided nephrectomy. In conclusion, left-sided living kidney donation entails a transiently reduced adrenocortical responsiveness, which returns to baseline after 28 days. PMID- 28024113 TI - A novel and complex mechanism regulating PGC-1alpha4 expression. PMID- 28024114 TI - Evaluation of tubulin beta-3 as a novel senescence-associated gene in melanocytic malignant transformation. AB - Malignant melanoma might develop from melanocytic nevi in which the growth arrested state has been broken. We analyzed the gene expression of young and senescent human melanocytes in culture and compared the gene expression data with a dataset from nevi and melanomas. A concordant altered gene expression was identified in 84 genes when comparing the growth-arrested samples with proliferating samples. TUBB3, which encodes the microtubule protein tubulin beta 3, showed a decreased expression in senescent melanocytes and nevi and was selected for further studies. Depletion of tubulin beta-3 caused accumulation of cells in the G2/M phase and decreased proliferation and migration. Immunohistochemical assessment of tubulin beta-3 in benign lesions revealed strong staining in the superficial part of the intradermal components, which faded with depth. In contrast, primary melanomas exhibited staining without gradient in a disordered pattern and strong staining of the invasive front. Our results describe an approach to find clinically useful diagnostic biomarkers to more precisely identify cutaneous malignant melanoma and present tubulin beta-3 as a candidate marker. PMID- 28024115 TI - Mutation load in melanoma is affected by MC1R genotype. AB - Whole-genome sequencing of matched germline and tumour pairs in a well characterized cohort of melanoma patients allowed investigation of associations between melanoma body site, age at melanoma onset and MC1R variant status with overall mutation burden and specific base pair changes observed in the corresponding melanoma. We observed statistically significant associations between mutation burden in melanoma and body site, age at onset and MC1R genotype, for both ultraviolet radiation (UVR) signature changes (C>T and CC>TT) and non-UVR base pair substitutions, as well as with overall variant load. PMID- 28024116 TI - Mulberry cells in the thyroid: warthin-finkeldey-like cells in hashimoto thyroiditis-associated lymphoma. AB - Warthin-Finkeldey type giant cells were first described in autopsies performed on young children who died during the highly lethal measles epidemic in Palermo during the winter of 1908. The cells had 8-15 nuclei without identifiable cytoplasm within the germinal centers of lymphoid organs resembling megakaryocytes. We describe a case of Hashimoto thyroiditis with an enlarging substernal throid mass. The resection specimen contained many Warthin-Finkeldey Like Cells (WFLC) in an extranodal marginal zone lymphoma (MALT type) with focal transformation to diffuse large B-cell lymphoma. The WFLC showed nuclear features similar to those of neighboring follicular dendritic cells (FDCs), favoring the hypothesis that these cells might be the product of fusion of FDCs. This is supported by immunostaining results and the occurrence of similar cells in follicular dendritic cell sarcomas and in "dysplastic" FDCs in hyaline vascular type Castleman disease, a possible precursor of follicular dendritic cell tumors. Diagn. Cytopathol. 2017;45:212-216. (c) 2016 Wiley Periodicals, Inc. PMID- 28024117 TI - Quantitative validation of anti-PTBP1 antibody for diagnostic neuropathology use: Image analysis approach. AB - Traditional diagnostic neuropathology relies on subjective interpretation of visual data obtained from a brightfield microscopy. This approach causes high variability, unsatisfactory reproducibility, and inability for multiplexing even among experts. These problems may affect patient outcomes and confound clinical decision-making. Also, standard histological processing of pathological specimens leads to auto-fluorescence and other artifacts, a reason why fluorescent microscopy is not routinely implemented in diagnostic pathology. To overcome these problems, objective and quantitative methods are required to help neuropathologists in their clinical decision-making. Therefore, we propose a computerized image analysis method to validate anti-PTBP1 antibody for its potential use in diagnostic neuropathology. Images were obtained from standard neuropathological specimens stained with anti-PTBP1 antibody. First, the noise characteristics of the images were modeled and images are de-noised according to the noise model. Next, images are filtered with sigma-adaptive Gaussian filtering for normalization, and cell nuclei are detected and segmented with a k-means based deterministic approach. Experiments on 29 data sets from 3 cases of brain tumor and reactive gliosis show statistically significant differences between the number of positively stained nuclei in images stained with and without anti-PTBP1 antibody. The experimental analysis of specimens from 3 different brain tumor groups and 1 reactive gliosis group indicates the feasibility of using anti-PTBP1 antibody in diagnostic neuropathology, and computerized image analysis provides a systematic and quantitative approach to explore feasibility. PMID- 28024118 TI - Maternal-fetal cholesterol transport in the second half of mouse pregnancy does not involve LDL receptor-related protein 2. AB - AIM: LDL receptor-related protein type 2 (LRP2) is highly expressed on both yolk sac and placenta. Mutations in the corresponding gene are associated with severe birth defects in humans, known as Donnai-Barrow syndrome. We here characterized the contribution of LRP2 and maternal plasma cholesterol availability to maternal fetal cholesterol transport and fetal cholesterol levels in utero in mice. METHODS: Lrp2+/- mice were mated heterozygously to yield fetuses of all three genotypes. Half of the dams received a 0.5% probucol-enriched diet during gestation to decrease maternal HDL cholesterol. At E13.5, the dams received an injection of D7-labelled cholesterol and were provided with 1-13 C acetate supplemented drinking water. At E16.5, fetal tissues were collected and maternal cholesterol transport and fetal synthesis quantified by isotope enrichments in fetal tissues by GC-MS. RESULTS: The Lrp2 genotype did not influence maternal fetal cholesterol transport and fetal cholesterol. However, lowering of maternal plasma cholesterol levels by probucol significantly reduced maternal-fetal cholesterol transport. In the fetal liver, this was associated with increased cholesterol synthesis rates. No indications were found for an interaction between the Lrp2 genotype and maternal probucol treatment. CONCLUSION: Maternal-fetal cholesterol transport and endogenous fetal cholesterol synthesis depend on maternal cholesterol concentrations but do not involve LRP2 in the second half of murine pregnancy. Our results suggest that the mouse fetus can compensate for decreased maternal cholesterol levels. It remains a relevant question how the delicate system of cholesterol transport and synthesis is regulated in the human fetus and placenta. PMID- 28024119 TI - Accuracy of international ultrasound risk stratification systems in thyroid lesions cytologically classified as indeterminate. AB - BACKGROUND: Eminent international societies have published their thyroid ultrasound risk stratification system (US-RSS) to give a friendly tool for thyroidologists. In particular, American Thyroid Association (ATA), American Association Clinical Endocrinologists/American College of Endocrinologists and Associazione Medici Endocrinologi (AACE/ACE/AME), British Thyroid Association (BTA), and Thyroid Imaging Reporting and Data System (TIRADS) are often adopted for clinical practice. The reliability of these US-RSS has not been evaluated in discriminating cancers from benignancy in nodules with indeterminate FNA. METHODS: Indeterminate thyroid lesions were searched in our database and only those with histology were finally included. The matching of US and histologic data of nodule's location and size were verified. All US images and clips were re evaluated and nodules classified according to the above US-RSS. RESULTS: A series of 101 indeterminate lesions, diagnosed by FNA were included (mean size 2.4 cm) and a 21% of cancers was found at histology. When all lesions were classified by US-RSS, poor accuracy (up to 54%) and specificity (up to 19%) were recorded. Highest sensitivity (91%) and NPV (94%) was obtained by BTA. Of relevance, the rate of nodules with indeterminate US risk recorded by BTA was significantly lower than the other (P < 0.001). At nodule's size analysis, cancers had significantly higher estimated volume (P < 0.05). When we considered the size thresholds proposed by guidelines, ATA system reached the highest sensitivity in detecting cancers (95%). CONCLUSIONS: Even if international US-RSS have suboptimal accuracy in indeterminate thyroid nodules, high sensitivity can be obtained using ATA system with specific dimensional cut-offs. Diagn. Cytopathol. 2017;45:113-117. (c) 2016 Wiley Periodicals, Inc. PMID- 28024121 TI - Sodium Binding Sites and Permeation Mechanism in the NaChBac Channel: A Molecular Dynamics Study. AB - NaChBac was the first discovered bacterial sodium voltage-dependent channel, yet computational studies are still limited due to the lack of a crystal structure. In this work, a pore-only construct built using the NavMs template was investigated using unbiased molecular dynamics and metadynamics. The potential of mean force (PMF) from the unbiased run features four minima, three of which correspond to sites IN, CEN, and HFS discovered in NavAb. During the run, the selectivity filter (SF) is spontaneously occupied by two ions, and frequent access of a third one is often observed. In the innermost sites IN and CEN, Na+ is fully hydrated by six water molecules and occupies an on-axis position. In site HFS sodium interacts with a glutamate and a serine from the same subunit and is forced to adopt an off-axis placement. Metadynamics simulations biasing one and two ions show an energy barrier in the SF that prevents single-ion permeation. An analysis of the permeation mechanism was performed both computing minimum energy paths in the axial-axial PMF and through a combination of Markov state modeling and transition path theory. Both approaches reveal a knock-on mechanism involving at least two but possibly three ions. The currents predicted from the unbiased simulation using linear response theory are in excellent agreement with single-channel patch-clamp recordings. PMID- 28024120 TI - Ion channels, long QT syndrome and arrhythmogenesis in ageing. AB - Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Nav 1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Nav 1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration. PMID- 28024122 TI - Degradation and Microbial Uptake of C60 Fullerols in Contrasting Agricultural Soils. AB - The environmental fate of functionalized carbon nanomaterials (CNM) remains poorly understood. Using 13C-labeled nanomaterial we present the results of a study investigating the mineralization and microbial uptake of surface functionalized C60 (fullerols) in agricultural soils with contrasting properties. Soil microcosms rapidly mineralized fullerol C, as determined by 13C-content in the respired CO2, with higher fullerol mineralization in an organic, clay-rich soil versus a silty, low C soil (~56.3% vs ~30.9% fullerol C mineralized over 65 days). By tracking the enriched 13C from fullerol into microbial phospholipid fatty acids (PLFA) we also report, for the first time, the incorporation of nanomaterial-derived C into soil microbial biomass, primarily by fungi and Gram negative bacteria. While more fullerol C was incorporated into PLFA in the organic C-rich soil (0.77% vs 0.19% of PLFA C), this soil incorporated fullerol C into biomass less efficiently than the silty, low C soil (0.13% and 0.84% of assimilated fullerol C, respectively). These results demonstrate that, in contrast to pristine C60, surface functionalized C60 are unlikely to accumulate in surface soils and are readily mineralized by a range of soil microorganisms. PMID- 28024123 TI - Prevalence of weight loss attempts and behaviors used by individuals with psoriasis in the United States population. AB - OBJECTIVE: To examine weight loss behaviors of individuals with psoriasis in the American population and compare them to individuals without psoriasis. METHODS: An analysis of data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) was conducted. A total of 9174 Americans were included, with 232 self-reporting psoriasis. Measures included weight history and subjective physical activity, as well as the prevalence of weight loss attempts and weight loss behaviors over the past 12 months. RESULTS: Participants with psoriasis were no more likely to have attempted to lose weight than participants without psoriasis (46.3 vs. 38.2%, p = .161). Likewise, the proportion of participants with psoriasis desiring to weigh less was similar to those without psoriasis (67.4 vs. 61.9%; p = .277). Only 48.0% of participants with psoriasis employed exercise to lose weight, as compared to 62.4% without psoriasis (p = .027). Among participants that attempted to lose weight, only 16.1% with psoriasis engaged in vigorous recreational physical activity, as compared to 28% of individuals without psoriasis (p = .042). CONCLUSIONS: Participants self-reporting psoriasis were less likely to use exercise to lose weight. Clinicians should identify physical activity barriers among overweight/obese psoriasis patients, especially among those attempting to reduce weight. PMID- 28024124 TI - Developing therapies to treat hepatitis C infection in post-liver transplant recipients. AB - INTRODUCTION: Currently, hepatitis C virus (HCV) infection remains the most common indication for liver transplant in the United States (US) with almost universal HCV recurrence in the post-liver transplant setting. Previous interferon (IFN)-related efficacy and tolerability concerns about worsening liver function have limited treatment options for many patients with HCV-associated decompensated liver disease and post-liver transplant recipients. However, the last decade has seen a seen a radical shift in the management of HCV with multiple direct-acting antiviral (DAA) treatments that provide more effective, all-oral, IFN-free alternatives. Areas covered: This review will serve to highlight the various pharmacotherapies available to clinicians for patients with HCV recurrence post-liver transplant. A brief history of prior regimens is provided with evidence for newer treatments presented. Also detailed are updated guidelines from societal organizations. Finally, timing of HCV treatment is discussed as the decision to treat patients in a pre or post-liver transplant setting remains challenging. Expert opinion: While there are many potential available therapies for HCV recurrence in the post-liver transplant setting, daclatasvir/sofosbuvir and ledipasvir/sofosbuvir have been the most extensively studied. Newer, pangenotypic generation drugs require more evidence before routine utilization in post-liver transplant recipients. PMID- 28024125 TI - Recent progress on curcumin-based therapeutics: a patent review (2012-2016). Part I: Curcumin. AB - INTRODUCTION: curcumin is the main bioactive component contained in Curcuma Longa, largely employed in traditional medicine. Recently, beneficial properties, useful for prevention and treatment of several disorders, have been discovered for this compound. Peculiar structural feature is an alpha,beta-unsaturated carbonyl system essential for establishing contacts with critical cysteine residues of several targets. This distinctive mechanism of action imparts to the molecule the ability to affect a large number of targets, accounting for its pleiotropic behaviour and definition of "privileged structure". Areas covered: The objective of the review is an examination of the recent developments in the field of the anti-cancer applications of curcumin, together with formulation issues, considering the patent literature in the years 2012-2016. Expert opinion: The wide therapeutic efficacy of curcumin is related to synergistic interactions with several biological targets, along with the modulation of several signaling pathways. This peculiar behaviour could be useful in the treatment of multifactorial diseases such as cancer. Combination of curcumin with a first line antineoplastic drug proved to be a valuable strategy to obtain an amplified response with minimized side effects. Innovative curcumin formulations based on the nanotechnology approach allowed improving both bioavailability and therapeutic efficacy. PMID- 28024126 TI - Janus kinase (JAK) inhibitors for the treatment of skin and hair disorders: a review of literature. AB - Janus kinase family (JAKs) has recently attracted the attention of many researchers, and several JAK inhibitor drugs have been developed targeting different members of the JAK family. Tofacitinib and ruxolitinib are US FDA approved drugs in this family for rheumatoid arthritis and myeloproliferative diseases, respectively. Dysregulation of JAK/STAT pathway is also involved in many skin diseases, specifically inflammatory disorders. The JAK/STAT signaling pathway and its involvement in skin diseases are overviewed in this study. We also review clinical studies of JAK inhibitors in field of dermatology, including psoriasis, atopic dermatitis, alopecia areata and vitiligo. Although the available evidence shows promising results, it is still too early to draw a firm conclusion about the place of these drugs in dermatological treatment. PMID- 28024127 TI - Combined therapy in vulvar lichen sclerosus: does topical tretinoin improve the efficacy of mometasone furoate? AB - : Abstrract Purpose: To assess efficacy and safety profile of combining a potent corticosteroid with a retinoid in the treatment of vulvar lichen sclerosus (VLS). METHODS: We retrospectively compared 21 VLS patients treated with tretinoin (T) in short-contact therapy and mometasone furoate (MMF) (group A) and 20 treated with cold cream (CC) and MMF (group B) for 5 consecutive days/week for 12 weeks. The efficacy parameters were the response rate, the percentage of patients achieving an improvement from baseline of >=75% in subjective and objective scores and the mean reduction in subjective and objective scores. RESULTS: Thirteen patients (75.2%) were considered as responders in group A and 15 (78.9%) in group B; 50% and 61.1% of patients in group A and 100% and 63.1% in group B achieved an improvement of at least 75% in subjective and objective scores, respectively. The scheme combining MMF and CC was better tolerated than the combination of MMF and T. CONCLUSIONS: The combination with a topical retinoid did not enhance the effectiveness of a potent corticosteroid in the treatment of VLS. Either the scarce efficacy of the short-contact therapy regimen or a less favorable safety profile of such combination may account for these findings. PMID- 28024128 TI - [Pathogenesis, diagnosis and treatment of chronic obstructive pulmonary disease in the light of new research]. AB - Accurate number of patients with chronic obtructive pulmonary disease (COPD) is difficult to determine, both in Poland and in the world. Quoted estimates and fragmented with the research indicate that approx. 10% of the world's population may be burdened by this disease. As it turns out, COPD is recognized in 25-45% in non-smokers, suggesting a genetic link. This is confirmed by new data that indicates that further embodiments having genetic polymorphisms associated with the occurrence of the disease. It was further found that the allele GC-1F vitamin D were risk factor for development of COPD. It is emphasized that respiratory epithelial cells directly responsible for the response to inhaled agents. Attention was also drawn to the role of eosinophiles. It has been shown that in patients with COPD with the dominant of eosinophilic faction glucocorticoids work very efficiently, indicating the validity of the division to "responders" and "non-responders" for treatment. As a new biomarker for COPD is proposed irisin, released from skeletal myocytes, which is beneficial to exercise tolerance in patients with COPD. PMID- 28024129 TI - [The usefulness of complete blood count in predicting cardiac rehabilitation failure in post-NSTEMI patients]. AB - : ACS (acute coronary syndrome) NSTEMI is more prevalent than ACS STEMI. Within four years the mortality rate was twice higher in NSTEMI group than in the STEMI group. Studies have demonstrated that cardiac rehabilitation decreases the risk of all-cause mortality as well as the mortality related to cardiovascular events. AIM: The aim of the study was to evaluate with the use of an index of own design the prognostic value of the complete blood count (CBC) in predicting cardiac rehabilitation failure in post-NSTEMI patients. MATERIALS AND METHODS: The study comprised 116 post-NSTEMI patients, 81 men and 35 women, aged 64,12+/-11,29 years, admitted for cardiac rehabilitation to the Department of Internal Medicine and Cardiac Rehabilitation, MU in Lodz. On admission fasting blood cell count was performed, serum glucose and creatinine level was determined (GFR assessment). The following results were considered abnormal: glucose level >=100 mg/dl, GFR<60 ml/min/1.73m2, RBC < 4x106 MUl, WBC > 10x103/MUl, PLT < 150x103/MUl. Exercise test (cycloergometer) was performed twice in all patients - before and after the completion (4 weeks) of the II phase of the rehabilitation to assess its effects. RESULTS: Basing on logistic regression analysis and the results of individual odds ratio (OR) of the tested blood parameters, their prognostic impact on the risk of cardiac rehabilitation failure was determined. This risk was defined on the basis of patient's inability to tolerate any workload increment (0 Watt) between the initial and final result of the exercise test despite the applied cardiac rehabilitation program. The most statistically significant risk factors were selected as the result of logistic regression model building on the basis of which cardiac rehabilitation failure index was determined. Anemia and leucocytosis determined most significantly the failure of cardiac rehabilitation (respectively OR=2,77 and OR=2,36; p=0,01). They were used to construct a rehabilitation failure index with the values ranging from 0 to 2, where 0 - corresponds to absence of anemia and leucocytosis, 1 - corresponds to the occurrence of anemia or leucocytosis in post-NSTEMI patients and was associated with 2,65-fold increase of the risk of cardiac rehabilitation failure, 2 - corresponds to simultaneous occurrence of anemia and leucocytosis and was associated with 7,02-fold increase of the risk of cardiac rehabilitation failure. CONCLUSIONS: Complete blood count is useful in predicting cardiac rehabilitation failure. Anemia and leucocytosis are the most significant determinants of cardiac rehabilitation failure in post-NSTEMI patients. Cardiac rehabilitation failure index can be used for its individual programming. Then optimal rehabilitation effects can be obtained maintaining its safety in post-NSTEMI patients. PMID- 28024130 TI - [Estimation of cardiovascular risk in patients with metabolic syndrome]. AB - : Metabolic syndrome (MS) is a coexistence of metabolic risk factors affecting development of cardiovascular diseases. The SCORE system estimates fatal cardiovascular disease events over a ten-year period. AIM: The aim of the study was to estimate cardiovascular risk in patients with symptoms of MS. MATERIALS AND METHODS: The study included 268 patients with symptoms of MS according to International Diabetes Federation criteria (2005), 136 men and 132 women, mean age 59,62+/-9,21 years. The cardiovascular risk was estimated on based of pulse pressure and SCORE table in these patients. RESULTS: In subjects with MS the mean value of pulse pressure (pp) was 58,96+/-2,34 mmHg, increased values of pp was found in 33,21% subjects with MS. High and very high cardiovascular death risk occurred in 80,97% subjects with MS, significantly more often in men than women. CONCLUSIONS: In majority of patients with MS high cardiovascular risk was found. In every three subjects with MS high pulse pressure was stated. PMID- 28024131 TI - [Rating criteria for selection of an inhaler and instructing its use in patients with asthma and COPD]. AB - : The clinical efficacy of inhaled therapy in patients with asthma and COPD is dependent on the choice of inhaler and proper use of it. The need to instruct patients in the use of the recommended inhaler seems obvious, but in clinical practice is not always followed. AIM: The aim of the study was the comparative evaluation of the selection criteria and the method of instructing in operating the device in asthma and COPD patients. MATERIALS AND METHODS: The study was conducted in 80 patients with asthma and COPD in 9 European countries: France, Germany, Italy, Spain, Great Britain, Holland, Belgium, Denmark, Sweden. Patients (asthma / COPD) - 10 from each country - aged 18-65 years were diagnosed by a physician for asthma (2/3 patients) and COPD (1/3 patients) at least one year ago. The study involved using Symbicort Turbuhaler (8 patients in each country) or Seretide Accuhaler (2 in each country, 3 patients in the Netherlands). Evaluated the criteria for selecting the inhaler and the time and place of transfer of information technology inhalation. RESULTS: It has been shown that the main criterion for choosing an inhaler by a doctor was the construction of an inhaler and size of particles generated by it. More than 1/3 of the patients did not receive information about how to use the inhaler. In turn, granted briefing in most lasts less than 5 minutes. CONCLUSIONS: In the selection of the inhaler taken into account in the construction and the ability to generate particles of the expected size. Informing patients about how to use the inhaler it is considered marginal in most of the resorts in Europe. PMID- 28024132 TI - Isolated right ventricular takotsubo cardiomyopathy: a case report and literature review. AB - In about one quarter of patients with stress-induced takotsubo cardiomyopathy (TC) concomitant involvement of right ventricle (RV) can be observed. Opposite to this biventricular form of TC, isolated right ventricular takotsubo cardiomyopathy (RVTC) was described only in a few cases and so far has not been listed as a specific type of TC. The authors present a case of a 87-year-old demented female admitted with pneumonia in whom echocardiography revealed RV apical ballooning while the left ventricle function was quite normal. RV apical thrombus was also found. Initial ECG showed QR in V1, discrete ST elevation in V1 2 leads and low voltage of QRS complex in limb leads. There was only a slight increase in troponin I level but a marked BNP elevation. Despite treatment, the course of the disease ended in a fiasco. The authors compare the clinical picture of the patient presented with the data of the 6 remaining cases of isolated RVTC found in the literature. Routine echocardiographic evaluation of RV in different clinical situations which may trigger TC should show actual occurrence of isolated RVTC. PMID- 28024133 TI - Ranolazine in treatment of stable angina in woman with atrial fibrillation and intermittent left bundle branch block - a case report. AB - Stable angina is the most frequent manifestation of ischemic heart disease (IHD) in women as compared to men (65% versus 37%). IHD in women has more favorable clinical course because myocardial infarction develops twice as rare as in men. Coronary angiography of angina patients demonstrates normal coronary arteries more frequently in women than in men. Microvascular angina (MVA) is found to be a rather common form of stable IHD as that particular diagnosis is made later in 20 30% of patients who previously underwent coronary angiography. The disease occurs three times as often in women than in men irrespective of age. Most of these patients are in their perimenopausal age - 45-60 years. The major role in MVA development is considered to be decreased coronary flow reserve resulting from evident endothelial dysfunction of minor coronary arteries. MVA is characterized by great variability of its course and low response to conventional antianginal therapy, particularly in women. In view of this the problem of antianginal drugs which can be used in addition to standard therapy remains to be solved. Ranolazine is a new original antianginal medicine which improves left ventricular diastolic filling by selective inhibition of late Na-flow leading to more effective coronary vessels filling in diastole. The article presents the results of multicenter studies of ranolazine as to its effect on diastolic and systolic functions of the left ventricle, clinical manifestations of angina and heart failure as well as the data on antiarrhythmic action of ranolazine. This article describes the case of successful use of ranolazine as an additional anti-anginal medicine in the 46- year-old female patient diagnosed with microvascular angina. Before taking ranolazine, on the background of conventional treatment of coronary heart disease, the patient developed stable angina and persistent left bundle branch block, atrial fibrillation. After receiving ranolazine, 1000 mg per day for a month, Holter ECG monitoring showed not only significantly reduced number of strokes, the left bundle branch block and atrial fibrillation dissappeared as well. The results indicate a high efficiency of ranolazine as an antianginal, anti-ischemic and anti-arrythmic medicine. PMID- 28024134 TI - [Acute mastoiditis with retroauricular abscess - a report of two cases]. AB - Otogenic complications may occur as a result of both acute and chronic otitis media. The purpose of the diagnostic process and treatment of patients with otogenic complications is to identify and eliminate focal points of the infection. Due to general application of antibiotics, these complications are rarely observed. Retroauricular abscess may be the first symptom associated with the development of acute mastoiditis in patients with communication disturbances. Intravenous antibiotics and surgery have been successfully used for treatment in the two described cases. First case: 9 years old girl suffering from hydrocephalus, mental retardation. Retroauricular abscess occured as a result of the left ear acute otitis media. Second case: 17 years old girl with multiple congenital defects, mental retardation. Four surgery because of epidural abscess, meningitis, external auditory canal atresia, granulation and cholesteatoma during two years. Retroauricular abscess occured in the course of the right ear chronic otitis media. PMID- 28024135 TI - [Pancreatic cancer microenvironment]. AB - Pancreatic cancer remains one of the deadliest solid tumors in humans and an unsolved problem of today's medicine. Experimental studies reveal that the heterogeneous and complex pancreatic cancer microenvironment is responsible, not only for cancer growth, spread, development of metastases, but also for cancer recurrence and chemotherapy resistance. Chemotherapy affecting the cancer stroma is still under clinical and experimental research and remains hope for cure of pancreatic cancer. We present the cancer microenvironment characteristics and summary of experimental studies with use of agents affecting pancreatic cancer stroma. PMID- 28024136 TI - [New methods of uterine fibroids treatment]. AB - Uterine fibroids are the most common benign tumors of the uterus. Their main symptoms are prolonged menstrual bleeding, leading over time to a secondary anemia, bleeding and spotting between periods, pelvic pain and infertility. It is recognized that fibroids are the most common indication for surgery in gynecology. Currently radical surgical treatment of fibroids is abandon. Ulipristalu acetate is used in pharmacological treatment. This medicine reduces the growth of fibroids. New non-invasive technique is also MR-guided focused ultrasound surgery using thermal tissue destruction by focusing ultrasound beam. Ability to avoid the often crippling surgery makes conservative methods increasingly popular. PMID- 28024137 TI - [Secrets of the red-headed]. AB - Only 1-2% of people is red-headed but in the Russian Udmurt Republic or United Kingdom they can be met more often. A specific variant of MC1R gene (R allele) is responsible for the red hair. The gene encodes a receptor for melanocortins. These substances stimulate melanocytes to product melanin- a dye of the skin which is transported to keratinocytes. It protects a cellular nucleus from ultraviolet radiation. Melanin has two types: eumelanin which is dark brown or even black and red/orange pheomelanin. The second one is mostly observed in red headed which is caused by R allele. The DNA damage occurs more easily because of worse protecting ability of pheomelanin. Moreover this allele is connected with inefficient DNA repair. People with R allele have not only flaming red hairstyle but also very fair skin (often with freckles) and blue eyes. Unfortunately this phenotype is more exposed to harmful effects of UV rays. It means that too extensive exposition to solar light leads to sunburn and development of cancerous skin diseases with melanoma as the worst. R allele is a recessive variant of the gene so only in homozygous persons this characteristic phenotype is observed. Nevertheless blond- or auburn-haired carriers of this allele are also more prone to develop carcinomas. The red-headed also differ from the others in sensitivity to anaesthetics, what is shown by increased MAC. On the other hand these persons less often suffer from vitamin D deficiency. The aim of the article is to present facts and myths of red-headed. PMID- 28024138 TI - SET and MYND Domain-Containing Protein 3 (SMYD3) Polymorphism as a Risk Factor for Susceptibility and Poor Prognosis in Ovarian Cancer. AB - BACKGROUND We investigated the relationship of the polymorphisms of SET and MYND domain-containing protein 3 (SMYD3) with risk and prognosis of ovarian cancer. MATERIAL AND METHODS The polymerase chain reaction (PCR) amplification method was applied to detect the polymorphisms of variable number of tandem repeats (VNTR) in the SMYD3 gene promoter region for 156 patients with ovarian cancer (case group) and 174 healthy people (control group). Quantitative reverse transcription polymerase chain reaction and Western blot were applied to detect SMYD3 mRNA and protein expressions. RESULTS The frequencies of VNTR genotype 3/3 and allele genotype 3 in the case group were significantly higher than those in the control group, while the frequency of genotype 2/2 in the control group was significantly higher than that in case group (all P<0.05). The proportion of poorly differentiated patients carrying VNTR genotype 3/3 was significantly higher than the proportion of poorly differentiated patients carrying VNTR genotype 2/2+2/3, while the proportion of patients carrying genotype 3/3 with International Federation of Gynecology and Obstetrics (FIGO) stage III-IV disease was significantly higher than the proportion of patients carrying genotype 2/2 +2/3 with FIGO stage III-IV disease (all P<0.05). SMYD3 mRNA and protein expressions were higher in the patients carrying genotype 3/3 than they were in the patients with the 2/2+2/3 genotype (all P<0.05). The 5-year survival rate for patients carrying VNTR genotype 3/3 was significantly lower than that of patients carrying genotype 2/2+2/3, and Cox regression analysis showed that VNTR genotype 3/3 was an independent risk factor for ovarian cancer prognosis (all P<0.05). CONCLUSIONS VNTR genotype 3/3 of the SMYD3 gene was associated with the risk of ovarian cancer. The polymorphism of VNTR genotype could be recognized as an indicator for the poor prognosis of patients with ovarian cancer. PMID- 28024139 TI - Field trials and community trials: importance in public health. PMID- 28024140 TI - Do branched chain amino acids improve hepatic encephalopathy in cirrhosis? AB - There is controversy about the effectiveness of branched chain amino acids for treatment of hepatic encephalopathy. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews including 32 randomized controlled trials, of which 30 address the question of this article. We extracted results, combined the evidence using meta analysis and generated a summary of findings following the GRADE approach. We concluded branched chain amino acids might improve hepatic encephalopathy, but they probably lead to little or no effect on mortality. PMID- 28024141 TI - Harassment and discrimination in medical students. PMID- 28024142 TI - Scientific congresses of medical students in Latin America. PMID- 28024143 TI - Is electroconvulsive therapy during pregnancy safe? AB - Therapeutic options for psychiatric conditions are limited during pregnancy because many drugs are restricted or contraindicated. Electroconvulsive therapy constitutes an alternative, however there is controversy over its safety. Using the Epistemonikos database, which is maintained by searching multiple databases, we found five systematic reviews, including 81 studies overall describing case series or individual cases. Data were extracted from the identified reviews and summary tables of the results were prepared using the GRADE method. We concluded it is not clear what are the risks associated with electroconvulsive therapy during pregnancy because the certainty of the existing evidence is very low. Likewise, existing systematic reviews and international clinical guidelines differ in their conclusions and recommendations. PMID- 28024144 TI - Lack of broad functional differences in immunity in fully vaccinated vs. unvaccinated children. AB - BACKGROUND: Concerns have been raised that with an increase in the number of vaccines administered early in life, immune development could be altered, leading to either increased or decreased immune reactivity. METHODS: We investigated the impact of vaccination on immune status, contrasting the immune response to general, nonantigen-specific stimuli in a cohort of entirely unvaccinated vs. fully vaccinated children at 3-5 y of age. Innate immunity was assessed by quantifying bulk and cell-type-specific cytokine production in response to stimulation with pathogen associated microbial patterns. Adaptive immune status was characterized by assessing lymphocyte proliferation and cytokine production in response to generic T cell stimuli. RESULTS: Our investigations failed to reveal a broadly evident alteration of either innate or adaptive immunity in vaccinated children. Equivalently robust innate and adaptive responses to pathogen associated microbial patterns and generic T cell stimulants were observed in both groups. CONCLUSION: Although our sample size was small, our data suggest that standard childhood vaccinations do not lead to long-lasting gross alterations of the immune system. PMID- 28024145 TI - Calorie restriction prevents the development of insulin resistance and impaired lipid metabolism in gestational diabetes offspring. AB - BACKGROUND: Gestational diabetes mellitus (GDM) has long-lasting influence on offspring, which is associated with increased risks of insulin resistance, obesity, and type II diabetes mellitus. Calorie restriction (CR) is one of the most common and available nutritional interventions to prevent obesity and diabetes. We are trying to explore the effect of CR on GDM offspring. METHODS: The streptozotocin was used to stimulate C57BL/6J mice to develop GDM, a number of metabolic characteristics and related protein expressions were determined in GDM offspring that were fed ad-libitum or treated with calorie restriction. RESULTS: CR reduced body weight and glucose levels in GDM offspring. CR modulated the lipid metabolism by decreasing triglyceride and cholesterol levels in plasma. We also found that the effect of CR on insulin sensitivity may involve in signaling pathway through the regulations of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and protein kinase B (Akt). CONCLUSION: GDM is a high risk factor for GDM offspring to develop insulin resistance, while CR could ameliorate this adverse outcome. Moreover, the specific decrease in PTEN activation and increase in Akt phosphorylation in livers of GDM offspring with CR improved insulin sensitivity and lipid metabolism. PMID- 28024146 TI - Genome-wide mapping of autonomous promoter activity in human cells. AB - Previous methods to systematically characterize sequence-intrinsic activity of promoters have been limited by relatively low throughput and the length of the sequences that could be tested. Here we present 'survey of regulatory elements' (SuRE), a method that assays more than 108 DNA fragments, each 0.2-2 kb in size, for their ability to drive transcription autonomously. In SuRE, a plasmid library of random genomic fragments upstream of a 20-bp barcode is constructed, and decoded by paired-end sequencing. This library is used to transfect cells, and barcodes in transcribed RNA are quantified by high-throughput sequencing. When applied to the human genome, we achieve 55-fold genome coverage, allowing us to map autonomous promoter activity genome-wide in K562 cells. By computational modeling we delineate subregions within promoters that are relevant for their activity. We show that antisense promoter transcription is generally dependent on the sense core promoter sequences, and that most enhancers and several families of repetitive elements act as autonomous transcription initiation sites. PMID- 28024147 TI - Genome-wide assessment of sequence-intrinsic enhancer responsiveness at single base-pair resolution. AB - Gene expression is controlled by enhancers that activate transcription from the core promoters of their target genes. Although a key function of core promoters is to convert enhancer activities into gene transcription, whether and how strongly they activate transcription in response to enhancers has not been systematically assessed on a genome-wide level. Here we describe self transcribing active core promoter sequencing (STAP-seq), a method to determine the responsiveness of genomic sequences to enhancers, and apply it to the Drosophila melanogaster genome. We cloned candidate fragments at the position of the core promoter (also called minimal promoter) in reporter plasmids with or without a strong enhancer, transfected the resulting library into cells, and quantified the transcripts that initiated from each candidate for each setup by deep sequencing. In the presence of a single strong enhancer, the enhancer responsiveness of different sequences differs by several orders of magnitude, and different levels of responsiveness are associated with genes of different functions. We also identify sequence features that predict enhancer responsiveness and discuss how different core promoters are employed for the regulation of gene expression. PMID- 28024148 TI - Solution structure of discoidal high-density lipoprotein particles with a shortened apolipoprotein A-I. AB - High-density lipoprotein (HDL) particles are cholesterol and lipid transport containers. Mature HDL particles destined for the liver develop through the formation of intermediate discoidal HDL particles, which are the primary acceptors for cholesterol. Here we present the three-dimensional structure of reconstituted discoidal HDL (rdHDL) particles, using a shortened construct of human apolipoprotein A-I, determined from a combination of nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR) and transmission electron microscopy (TEM) data. The rdHDL particles feature a protein double belt surrounding a lipid bilayer patch in an antiparallel fashion. The integrity of this structure is maintained by up to 28 salt bridges and a zipper-like pattern of cation-pi interactions between helices 4 and 6. To accommodate a hydrophobic interior, a gross 'right-to-right' rotation of the helices after lipidation is necessary. The structure reflects the complexity required for a shuttling container to hold a fluid lipid or cholesterol interior at a protein:lipid ratio of 1:50. PMID- 28024149 TI - Crystal structure of the MOP flippase MurJ in an inward-facing conformation. AB - Peptidoglycan (PG) protects bacteria from osmotic lysis, and its biogenesis is a key antibiotic target. A central step in PG biosynthesis is flipping of the lipid linked PG precursor lipid II across the cytoplasmic membrane for subsequent incorporation into PG. MurJ, part of the multidrug/oligosaccharidyl lipid/polysaccharide (MOP) transporter superfamily, was recently shown to carry out this process. However, understanding of how MurJ flips lipid II, and of how MOP transporters operate in general, remains limited due to a lack of structural information. Here we present a crystal structure of MurJ from Thermosipho africanus in an inward-facing conformation at 2.0-A resolution. A hydrophobic groove is formed by two C-terminal transmembrane helices, which leads into a large central cavity that is mostly cationic. Our studies not only provide the first structural glimpse of MurJ but also suggest that alternating access is important for MurJ function, which may be applicable to other MOP superfamily transporters. PMID- 28024150 TI - Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol. AB - Controlled distribution of lipids across various cell membranes is crucial for cell homeostasis and regulation. We developed an imaging method that allows simultaneous in situ quantification of cholesterol in two leaflets of the plasma membrane (PM) using tunable orthogonal cholesterol sensors. Our imaging revealed marked transbilayer asymmetry of PM cholesterol (TAPMC) in various mammalian cells, with the concentration in the inner leaflet (IPM) being ~12-fold lower than that in the outer leaflet (OPM). The asymmetry was maintained by active transport of cholesterol from IPM to OPM and its chemical retention at OPM. Furthermore, the increase in the IPM cholesterol level was triggered in a stimulus-specific manner, allowing cholesterol to serve as a signaling lipid. We found excellent correlation between the IPM cholesterol level and cellular Wnt signaling activity, suggesting that TAPMC and stimulus-induced PM cholesterol redistribution are crucial for tight regulation of cellular processes under physiological conditions. PMID- 28024151 TI - beta2-adrenergic receptor control of endosomal PTH receptor signaling via Gbetagamma. AB - Cells express several G-protein-coupled receptors (GPCRs) at their surfaces, transmitting simultaneous extracellular hormonal and chemical signals into cells. A comprehensive understanding of mechanisms underlying the integrated signaling response induced by distinct GPCRs is thus required. Here we found that the beta2 adrenergic receptor, which induces a short cAMP response, prolongs nuclear cAMP and protein kinase A (PKA) activation by promoting endosomal cAMP production in parathyroid hormone (PTH) receptor signaling through the stimulatory action of G protein Gbetagamma subunits on adenylate cyclase type 2. PMID- 28024152 TI - Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. AB - Toll-like receptor (TLR) activation contributes to premalignant hematologic conditions, such as myelodysplastic syndromes (MDS). TRAF6, a TLR effector with ubiquitin (Ub) ligase activity, is overexpressed in MDS hematopoietic stem/progenitor cells (HSPCs). We found that TRAF6 overexpression in mouse HSPC results in impaired hematopoiesis and bone marrow failure. Using a global Ub screen, we identified hnRNPA1, an RNA-binding protein and auxiliary splicing factor, as a substrate of TRAF6. TRAF6 ubiquitination of hnRNPA1 regulated alternative splicing of Arhgap1, which resulted in activation of the GTP-binding Rho family protein Cdc42 and accounted for hematopoietic defects in TRAF6 expressing HSPCs. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS. PMID- 28024153 TI - HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3. AB - The mechanisms by which human immunodeficiency virus 1 (HIV-1) avoids immune surveillance by dendritic cells (DCs), and thereby prevents protective adaptive immune responses, remain poorly understood. Here we showed that HIV-1 actively arrested antiviral immune responses by DCs, which contributed to efficient HIV-1 replication in infected individuals. We identified the RNA helicase DDX3 as an HIV-1 sensor that bound abortive HIV-1 RNA after HIV-1 infection and induced DC maturation and type I interferon responses via the signaling adaptor MAVS. Notably, HIV-1 recognition by the C-type lectin receptor DC-SIGN activated the mitotic kinase PLK1, which suppressed signaling downstream of MAVS, thereby interfering with intrinsic host defense during HIV-1 infection. Finally, we showed that PLK1-mediated suppression of DDX3-MAVS signaling was a viral strategy that accelerated HIV-1 replication in infected individuals. PMID- 28024154 TI - Robust and scalable inference of population history from hundreds of unphased whole genomes. AB - It has recently been demonstrated that inference methods based on genealogical processes with recombination can uncover past population history in unprecedented detail. However, these methods scale poorly with sample size, limiting resolution in the recent past, and they require phased genomes, which contain switch errors that can catastrophically distort the inferred history. Here we present SMC++, a new statistical tool capable of analyzing orders of magnitude more samples than existing methods while requiring only unphased genomes (its results are independent of phasing). SMC++ can jointly infer population size histories and split times in diverged populations, and it employs a novel spline regularization scheme that greatly reduces estimation error. We apply SMC++ to analyze sequence data from over a thousand human genomes in Africa and Eurasia, hundreds of genomes from a Drosophila melanogaster population in Africa, and tens of genomes from zebra finch and long-tailed finch populations in Australia. PMID- 28024155 TI - A method for identifying genetic heterogeneity within phenotypically defined disease subgroups. AB - Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase specific antibody, driven generally by variants in known T1D-associated genomic regions. PMID- 28024156 TI - Designer vaccine nanodiscs for personalized cancer immunotherapy. AB - Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8alpha+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine. PMID- 28024157 TI - Hybrid metal-organic chalcogenide nanowires with electrically conductive inorganic core through diamondoid-directed assembly. AB - Controlling inorganic structure and dimensionality through structure-directing agents is a versatile approach for new materials synthesis that has been used extensively for metal-organic frameworks and coordination polymers. However, the lack of 'solid' inorganic cores requires charge transport through single-atom chains and/or organic groups, limiting their electronic properties. Here, we report that strongly interacting diamondoid structure-directing agents guide the growth of hybrid metal-organic chalcogenide nanowires with solid inorganic cores having three-atom cross-sections, representing the smallest possible nanowires. The strong van der Waals attraction between diamondoids overcomes steric repulsion leading to a cis configuration at the active growth front, enabling face-on addition of precursors for nanowire elongation. These nanowires have band like electronic properties, low effective carrier masses and three orders-of magnitude conductivity modulation by hole doping. This discovery highlights a previously unexplored regime of structure-directing agents compared with traditional surfactant, block copolymer or metal-organic framework linkers. PMID- 28024158 TI - Emotional brain states carry over and enhance future memory formation. AB - Emotional arousal can produce lasting, vivid memories for emotional experiences, but little is known about whether emotion can prospectively enhance memory formation for temporally distant information. One mechanism that may support prospective memory enhancements is the carry-over of emotional brain states that influence subsequent neutral experiences. Here we found that neutral stimuli encountered by human subjects 9-33 min after exposure to emotionally arousing stimuli had greater levels of recollection during delayed memory testing compared to those studied before emotional and after neutral stimulus exposure. Moreover, multiple measures of emotion-related brain activity showed evidence of reinstatement during subsequent periods of neutral stimulus encoding. Both slow neural fluctuations (low-frequency connectivity) and transient, stimulus-evoked activity predictive of trial-by-trial memory formation present during emotional encoding were reinstated during subsequent neutral encoding. These results indicate that neural measures of an emotional experience can persist in time and bias how new, unrelated information is encoded and recollected. PMID- 28024159 TI - Developmental broadening of inhibitory sensory maps. AB - Sensory maps are created by networks of neuronal responses that vary with their anatomical position, such that representations of the external world are systematically and topographically organized in the brain. Current understanding from studying excitatory maps is that maps are sculpted and refined throughout development and/or through sensory experience. Investigating the mouse olfactory bulb, where ongoing neurogenesis continually supplies new inhibitory granule cells into existing circuitry, we isolated the development of sensory maps formed by inhibitory networks. Using in vivo calcium imaging of odor responses, we compared functional responses of both maturing and established granule cells. We found that, in contrast to the refinement observed for excitatory maps, inhibitory sensory maps became broader with maturation. However, like excitatory maps, inhibitory sensory maps are sensitive to experience. These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps. PMID- 28024160 TI - RESA identifies mRNA-regulatory sequences at high resolution. AB - Gene expression is extensively regulated at the levels of mRNA stability, localization and translation. However, decoding functional RNA-regulatory features remains a limitation to understanding post-transcriptional regulation in vivo. Here, we developed RNA-element selection assay (RESA), a method that selects RNA elements on the basis of their activity in vivo and uses high throughput sequencing to provide a quantitative measurement of their regulatory functions at near-nucleotide resolution. We implemented RESA to identify sequence elements modulating mRNA stability during zebrafish embryogenesis. RESA provides a sensitive and quantitative measure of microRNA activity in vivo and also identifies novel regulatory sequences. To uncover specific sequence requirements within regulatory elements, we developed a bisulfite-mediated nucleotide conversion strategy for large-scale mutational analysis (RESA-bisulfite). Finally, we used the versatile RESA platform to map candidate protein-RNA interactions in vivo (RESA-CLIP). PMID- 28024161 TI - The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting. AB - The role of trabeculae carneae in modulating left ventricular (LV) diastolic compliance remains unclear. The objective of this study was to determine the contribution of trabeculae carneae to the LV diastolic compliance. LV pressure volume compliance curves were measured in six human heart explants from patients with LV hypertrophy at baseline and following trabecular cutting. The effect of trabecular cutting was also analyzed with finite-element model (FEM) simulations. Our results demonstrated that LV compliance improved after trabecular cutting (p < 0.001). Finite-element simulations further demonstrated that stiffer trabeculae reduce LV compliance further, and that the presence of trabeculae reduced the wall stress in the apex. In conclusion, we demonstrate that integrity of the LV and trabeculae is important to maintain LV stiffness and loss in trabeculae leads to more LV compliance. PMID- 28024162 TI - qNMR for profiling the production of fungal secondary metabolites. AB - Analysis of complex mixtures is a common challenge in natural products research. Quantitative nuclear magnetic resonance spectroscopy offers analysis of complex mixtures at early stages and with benefits that are orthogonal to more common methods of quantitation, including ultraviolet absorption spectroscopy and mass spectrometry. Several experiments were conducted to construct a methodology for use in analysis of extracts of fungal cultures. A broadly applicable method was sought for analysis of both pure and complex samples through use of an externally calibrated method. This method has the benefit of not contaminating valuable samples with the calibrant, and it passed scrutiny for line fitting and reproducibility. The method was implemented to measure the yield of griseofulvin and dechlorogriseofulvin from three fungal isolates. An isolate of Xylaria cubensis (coded MSX48662) was found to biosynthesize griseofulvin in the greatest yield, 149 +/- 8 mg per fermentation, and was selected for further supply experiments. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28024163 TI - A culturally adapted survivorship programme for Asian early stage breast cancer patients in Singapore: A randomized, controlled trial. AB - BACKGROUND: As cancer mortality rates improve in Singapore, there is an increasing need to improve the transition to posttreatment survivorship care. This study aimed to evaluate the effectiveness of a psychoeducation group (PEG) intervention program compared with usual care to reduce distress for physical symptom and psychological aspects in Asian breast cancer survivors who have completed adjuvant chemotherapy. METHODS: This was a randomized, controlled trial comprising 72 Asian early stage breast cancer survivors who were randomized into the PEG (n = 34) or the control (n = 38) arm. The participants in the PEG arm underwent a weekly multidisciplinary PEG program delivered in a group format over 3 weeks coupled with cultural adaptation. Both arms were assessed at baseline and 2 months after intervention using the Rotterdam Symptom Checklist, Beck Anxiety Inventory, and EORTC QLQ-C30. A satisfaction questionnaire was also conducted among those survivors who have participated in the PEG program. Effective sizes were calculated using Cohen d. RESULTS: The mean age +/- SD of all participants was 53.0 +/- 8.9 years, with the majority being Chinese (84.7%) and Malay (6.9%), and clinical characteristics were well balanced in both arms. Compared to the control arm, the PEG arm showed a significantly greater reduction in physical symptom distress (d = 0.76, P = .01) and fatigue (d = 0.49, P = .04). The 82.4% of the participants in the intervention group responded to the satisfaction questionnaire, and the majority (92.9%) agreed that the overall duration of the PEG intervention program was appropriate. CONCLUSIONS: A culturally adapted PEG program was effective in reducing physical symptom distress in Asian breast cancer survivors. (ClinicalTrials.gov: NCT02600299). PMID- 28024164 TI - No influence of CO2 on stable isotope analyses of soil waters with off-axis integrated cavity output spectroscopy (OA-ICOS). AB - RATIONALE: It was recently shown that the presence of CO2 affects the stable isotope (delta2 H and delta18 O values) analysis of water vapor via Wavelength Scanned Cavity Ring-Down Spectroscopy. Here, we test how much CO2 is emitted from soil samples and if the CO2 in the headspace influences the isotope analysis with the direct equilibration method by Off-Axis Integrated Cavity Output Spectroscopy (OA-ICOS). METHODS: The headspace above different amounts of sparkling water was sampled, and its stable isotopic composition (delta2 H and delta18 O values) and CO2 concentration were measured by direct equilibration and by gas chromatography, respectively. In addition, the headspace above soil samples was analyzed in the same way. Furthermore, the gravimetric water content and the loss on ignition were measured for the soil samples. RESULTS: The experiment with the sparkling water showed that CO2 does not influence the stable isotope analysis by OA-ICOS. CO2 was emitted from the soil samples and correlated with the isotopic fractionation signal, but no causal relationship between the two was determined. Instead, the fractionation signal in pore water isotopes can be explained by soil evaporation and the CO2 can be related to soil moisture and organic matter which both enhance microbial activity. CONCLUSIONS: We found, despite the high CO2 emissions from soil samples, no need for a post-correction of the pore water stable isotope analysis results, since there is no relation between CO2 concentrations and the stable isotope results of vapor samples obtained with OA ICOS. (c) 2016 The Authors. Rapid Communications in Mass Spectrometry Published by John Wiley & Sons Ltd. PMID- 28024165 TI - Evaluation of pit-and-fissure sealants placed with four different bonding protocols: a randomized clinical trial. AB - BACKGROUND: Application of adhesive after acid etching may increase the retention of pit-and-fissure sealants and improve clinical effectiveness. AIMS: To clinically evaluate the retention, marginal discoloration and caries incidence of pit-and-fissure sealants applied using four bonding protocols: conventional acid etching, etch-and-rinse adhesive, multimode universal adhesive and self-etch adhesive used after acid etching. DESIGN: In this split-mouth design study, the four adhesive protocols were randomly assigned to the four erupted, non-carious first permanent molars and involved 52 patients between 6 and 10 years of age. The sealants were evaluated at 3-, 6- and 12-month intervals. Statistical analysis was carried out using Friedman test and Kruskal-Wallis test. RESULTS: At 12 months, the retention rate was maximum in etch-and-rinse and universal adhesive groups (77.1%) followed by self-etch adhesive (58.3%) and conventional acid etching group (45.8%). Dental caries was observed only in one tooth, and marginal discoloration was found to be the highest in conventional group and least in etch-and-rinse group. CONCLUSIONS: Use of adhesives during pit-and fissure sealant application does not significantly enhance sealant retention nor decrease marginal discoloration. Etch-and-rinse adhesive is advantageous only at short term. PMID- 28024166 TI - East Asian perspective on the interaction between proton pump inhibitors and clopidogrel. AB - Both proton pump inhibitors (PPIs) and clopidogrel are widely prescribed in the Asia-Pacific population. PPIs are the mainstay therapeutic agents for prophylaxis against aspirin gastropathy and for acid-related disorders including gastroesophageal reflux disease. They are also co-prescribed with oral anticoagulant agents and with dual-antiplatelet therapy for the treatment and prevention of gastrointestinal bleeding. Clopidogrel belongs to the drug class of thienopyridines and is currently the most widely prescribed oral anticoagulant agent either alone or in combination with aspirin. Platelet inhibition by clopidogrel is prone to significant inter-individual variability and is believed to be affected by several factors such as genetics and drug-drug interactions. Since it was first reported in 2009, the potential for drug-drug interactions between PPIs and clopidogrel has remained headline news, and its significance in clinical practice is the subject of an ongoing debate. For East Asian patients in particular, the clinical relevance of the interaction between PPIs and clopidogrel remains unclear because of conflicting data, as well as underrepresentation of East Asian subjects in landmark trials. Increased CYP2C19 genetic polymorphisms in individuals from Asia-Pacific countries only fuel the confusion. Recent studies in East Asian cohorts suggests that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of newer PPIs with weaker affinity for the CYP2C19 isoenzyme, namely, pantoprazole, dexlansoprazole, and rabeprazole. This review aims to help clinicians choose the most appropriate PPI for co-prescription with clopidogrel in patients from Asia Pacific countries. PMID- 28024167 TI - A sensitive assay for urinary cocaine metabolite benzoylecgonine shows more positive results and longer half-lives than those using traditional cut-offs. AB - Cocaine is a common drug of abuse. To detect its use, a screening detection concentration for the cocaine metabolite benzoylecgonine is commonly set at 150 ng/mL and its confirmatory cut-off is set at 100 ng/mL. Studies have suggested that these cut-offs may be set too high, allowing some patients with this substance abuse problem to be missed or improperly monitored. With the advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology it is possible to reliably detect and quantify lower concentrations of its metabolite benzoylecgonine as part of a larger drug panel. One purpose of the study was to establish if there was a significant increase in detection of cocaine use with a ten-fold more sensitive cut-off. A very sensitive dilute and shoot assay for benzoylecgonine was developed with a lower limit of quantitation of 5 ng/mL. Validation of the 5 ng/mL cut-off was achieved by plotting all the positive cocaine observations as a frequency distribution on a logarithmic scale. The number of positive results with measurable concentrations below the typical industry 100 ng/mL cut-off level but above the high sensitivity 5 ng/mL cut-off level was observed to be 51.9% of the observed positives. The lower cut-off also allowed a re-evaluation of the window of detection after cessation of use. It was observed to be between 17 and 22 days. (c) 2016 Precision Diagnostics, LLC. Drug Testing and Analysis published by John Wiley & Sons, Ltd. PMID- 28024168 TI - Carbohydrate antigen 19-9 is significantly elevated in autosomal dominant polycystic kidney disease. AB - AIM: Liver cysts are the most common extrarenal manifestation in patients with autosomal dominant polycystic kidney disease (ADPKD). Carbohydrate antigen 19-9 (CA19-9) is generally used as a marker for biliopancreatic malignancies, although CA19-9 levels in patients with ADPKD are largely unknown. METHODS: A prospective observational study of 53 ADPKD patients and 83 non-ADPKD control subjects was performed. The serum levels of CA19-9 were studied to evaluate the association with clinical parameters and liver cysts. RESULTS: The serum CA19-9 levels were significantly higher in the ADPKD group than in the control group (32.9 U/mL vs. 9.8 U/mL, respectively, P < 0.001). The serum CA19-9 levels in the ADPKD group were positively correlated with the mean blood pressure (rho = 0.335, P < 0.05), gamma-glutamyl transferase (GTP) levels (rho = 0.541, P < 0.001), the largest cyst size (rho = 0.536, P < 0.001) and the liver cyst volume (rho = 0.682, P < 0.001). Multiple regression analyses showed that the gamma-GTP levels (P < 0.001) and the liver cyst volumes (P < 0.001) were independent predictors for serum CA19 9 levels. CONCLUSIONS: Serum CA19-9 levels are significantly elevated and appear to be dependent on the gamma-GTP levels and the volume of liver cysts in patients with ADPKD. Our findings indicate that the measurement of the baseline CA19-9 level in each patient with ADPKD may be useful for the interpretation of the value and the differential diagnosis of liver diseases, particularly the liver cyst infection. PMID- 28024169 TI - Evaluation of KIMS immunoassays on a cobas c 501 analyzer for drugs of abuse and ethyl glucuronide testing in urine for forensic abstinence control. AB - For the medico-psychological assessment (MPA) during driving licence re-granting in Germany, abstinence control including urine samples is required. In these programmes, even small amounts of markers for drug or alcohol abuse have to be detected. Thus, the concentrations of the target compounds are very low, and, in consequence, the sensitivity of the applied screening method has to be much higher than for clinical use. Modified drugs of abuse and ethyl glucuronide immunoassays on a Roche cobas c 501 analyzer were evaluated for precision, accuracy, onboard calibration stability, cross reactivity, sensitivity, and specificity using authentic urine samples. Precision (intra-day and inter-day relative standard deviation (RSD) and accuracy (bias) at three concentrations were 12% or lower for all parameters. The calibrations remained stable (deviations <25%) for at least 28 days for all assays except amphetamines (21 days). Satisfactory cross reactivity was determined for the relevant analytes and also for several new psychoactive substances (NPS). The sensitivity was 100% for all parameters except methadone metabolite EDDP (92%) and fully met the sensitivity criteria for MPA urine testing. The presented kinetic interaction of microparticles in a solution (KIMS) immunoassays on a cobas c 501 thus provide a new method to reliably detect drug or alcohol consumption in abstinence control programmes requiring high sensitivity. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28024170 TI - Reaction time profiles of adults' action prediction reveal two mindreading systems. AB - Human beings are able to quickly step into others' shoes to predict peoples' actions. There is little consensus over how this cognitive feat might be accomplished. We tested the hypotheses that an efficient, but inflexible, mindreading system gives rise to appropriate reaction time facilitation in a standard unexpected transfer task, but not in a task involving an identity component. We created a new behavioural paradigm where adults had to quickly select whether an actor would reach, or not reach, for an object based on the actor's false belief about the object's location. By manipulating the type of object we compared participants' responding behaviour when they did and did not have to take the actor's perspective into account. While the overall accuracy reflected a high level of flexible belief reasoning across both tasks, the pattern of response times across conditions revealed a limit in the processing scope of an efficient mindreading system. Thus, we show, for the first time, that there are indeed different profiles of reaction times for object-location scenarios and for object-identity scenarios. The results elevate growing evidence that adult humans have not one, but two mindreading systems for dealing with mental states that underlie action. PMID- 28024171 TI - Leaching and retention of dissolved metals in particulate loaded pervious concrete columns. AB - This study examined metal leaching and retention in pervious concrete with or without embedded particulate matter. Particulate matter was collected from an adjacent parking lot and from a nearby parking garage as examples of weathered and un-weathered particulate matter. Particle size distributions were similar, but metal content was 3-35-fold higher and organic matter content was 3-fold higher in the parking garage particulate matter compared to the parking lot particulate matter. Replicate columns were established with either no particulate added as the control, or 20 g of parking lot or parking garage particulate matter. Synthetic rainwater was passed through the columns at variable rainfall intensity or fixed intensity to assess leaching. Metals were leached at higher concentrations from the parking garage particulate amended column, but from all columns less than 1% of the metal mass leached. Rainfall intensity did not have a large effect on leached metal concentrations, only varying effluent by about 2 fold. Synthetic stormwater with elevated dissolved Cu, Zn, Cd and Pb concentrations was passed through the same columns and metal removal efficiencies were on the order of 85-95%, 30-95%, 60-90%, and 95+% for each metal, respectively. After loading the column with a year's worth of stormwater metal exposure, removal efficiencies in the no particulate and parking lot particulate amended columns decreased, while parking garage particulate amended columns performed similarly with a small drop in Cu and Pb removal efficiencies. Generally, columns with no particulate and parking lot particulate amendments performed similarly, suggesting the pervious concrete is responsible for the majority of the initial metal retention. The parking garage particulate amended columns retained more metals from stormwater, perhaps due to an increase in pH that promoted surface precipitation as hydroxides or carbonate species on the pervious concrete, or due to complexation in the higher concentrations of organic matter and iron oxides in the particulate matter. Overall, metal retention was aided by the presence of organic matter in the particulate matter, but the pervious concrete itself was more important than particulates for metal retention. A strategy to increase metal retention and removal from the environment could involve amending pervious concrete with mixtures of well defined sorbents to enhance metal retention. PMID- 28024172 TI - Biochar and flyash inoculated with plant growth promoting rhizobacteria act as potential biofertilizer for luxuriant growth and yield of tomato plant. AB - Overuse of agrochemical fertilizers alarmingly causes deterioration in soil health and soil-flora. Persistence of these agrochemicals exerts detrimental effects on environment, potentially inducing toxic effects on human health, thus pronouncing an urgent need for a safer substitute. The present study investigates the potential use of agricultural and industrial wastes as carrier materials, viz. biochar and flyash, respectively, for preparation of bioformulations (or biofertilizers) using two plant growth promoting rhizobacteria, Bacillus sp. strain A30 and Burkholderia sp. strain L2, and its effect on growth of Lycopersicon esculentum Mill. (tomato). The viability of strains was determined based on colony forming units (cfu) count of each bioformulation at an interval of 60 days for a period of 240 days. Seeds were coated with different carrier based bioformulations and pot experiment(s) were carried out to access its effects on plant growth parameters. Biochar based bioformulations showed higher cfu count and maximum viability for strain L2 (107 cfu g-1) at 240 days of storage. Maximum percentage of seed germination was also observed in biochar inoculated with strain L2. Significant (p < 0.05) increase in plant growth parameters (dry and fresh biomass, length, number of flowers) were ascertained from the pot experiment and amongst all bioformulations, biochar inoculated with strain L2 performed consistently thriving results for tomato yield. Furthermore, post-harvest study of this bioformulation treated soil improved physico-chemical properties and dehydrogenase activity as compared to pre-plantation soil status. Overall, we show that prepared biochar based bioformulation using Burkholderia sp. L2 as inoculum can tremendously enhance the productivity of tomato, soil fertility, and can also act as a sustainable substitute for chemical fertilizers. In addition, mixture of biochar and flyash inoculated with strain L2 also showed noteworthy results for the growth parameters and yield, and future studies are required to strengthen flyash utilization as carrier materials to resolve its disposal problem and waste management. PMID- 28024173 TI - Prioritising the placement of riparian vegetation to reduce flood risk and end-of catchment sediment yields: Important considerations in hydrologically-variable regions. AB - In perennial stream settings, there is abundant literature confirming that riparian vegetation affects flood hydrology by attenuating the flood wave, enhancing deposition and reducing bank erosion. In contrast, relatively little is known about the effectiveness of riparian vegetation during floods in hydrologically-variable regions. The dominant channel form in these settings is often referred to as a 'macrochannel' or compound channel-in-channel which displays multiple inundation surfaces where it is often difficult to identify the active channel bank and bank top. This study uses the inundation pattern of recent flood events in the Lockyer Valley of South East Queensland (SEQ), Australia to present a framework which specifically considers the interaction between inundation frequency and trapping potential on a range of inundation surfaces. Using hydrological modelling and a consistent definition of floodplains and within-channel features, it outlines five key priority areas for the placement of riparian vegetation to alleviate common flood problems within the catchment. The highest priority for the placement of riparian vegetation to ameliorate the effects of small-moderate floods is on within-channel benches. For out-of-macrochannel flows, riparian vegetation is most effective on genetic floodplains which occupy the largest spatial extent within the valley. In particular, it identifies the need for, and benefits of, revegetation in spill out zones (SOZ) which occur where upstream channel capacity is larger and flow is funnelled at high velocity onto the floodplain downstream. This study highlights the importance of understanding the key geomorphic processes occurring within a catchment and developing effective catchment management plans to suit these conditions. PMID- 28024174 TI - Biology meets physics: Reductionism and multi-scale modeling of morphogenesis. AB - A common reductionist assumption is that macro-scale behaviors can be described "bottom-up" if only sufficient details about lower-scale processes are available. The view that an "ideal" or "fundamental" physics would be sufficient to explain all macro-scale phenomena has been met with criticism from philosophers of biology. Specifically, scholars have pointed to the impossibility of deducing biological explanations from physical ones, and to the irreducible nature of distinctively biological processes such as gene regulation and evolution. This paper takes a step back in asking whether bottom-up modeling is feasible even when modeling simple physical systems across scales. By comparing examples of multi-scale modeling in physics and biology, we argue that the "tyranny of scales" problem presents a challenge to reductive explanations in both physics and biology. The problem refers to the scale-dependency of physical and biological behaviors that forces researchers to combine different models relying on different scale-specific mathematical strategies and boundary conditions. Analyzing the ways in which different models are combined in multi-scale modeling also has implications for the relation between physics and biology. Contrary to the assumption that physical science approaches provide reductive explanations in biology, we exemplify how inputs from physics often reveal the importance of macro-scale models and explanations. We illustrate this through an examination of the role of biomechanical modeling in developmental biology. In such contexts, the relation between models at different scales and from different disciplines is neither reductive nor completely autonomous, but interdependent. PMID- 28024175 TI - Two worlds apart: Determinants of height in late 18th century central Mexico. AB - Anthropometric literature on the American territories of the Hispanic monarchy before their independence is still scarce. We attempt to expand the field with a case study that includes some important novelties. Albeit our main source, the military records of the Censo de Revillagigedo (conducted in the early 1790s), has already been used, the sample size and the geographical scope are unprecedented: 19,390 males of four ethnicities (castizos, espanoles, mestizos, and mulatos) aged from 16 to 39 from 24 localities, including towns and villages scattered across central regions of the Viceroyalty of New Spain. We build a database that, complemented with information on resource endowments obtained from other sources, permits to analyze the determinants of height. Our results show the importance of spatial differences as well as the significance of ethnicity, occupation, rurality, age and resource endowments as determinants of height. Unprivileged mulatos are only 0.5cm shorter than, assumedly privileged, espanoles in the "first world" (El Bajio) and 1.3cm taller in the "second world" (Eastern Central Highlands). In turn, living in the "first world" implies being between nearly 1.5cm and 5cm taller than the inhabitants of the "second world". Our estimates of physical statures are placed within an international comparative context and offer a relatively "optimistic" picture. PMID- 28024176 TI - Talking after school: Parents' conversational styles and children's memory for a science lesson. AB - A scientist taught 40 4- to 6-year-old children an interactive science lesson at school. The same day, children talked about the lesson at home with a parent who was naive to the details of what had transpired at school. Six days later, a researcher interviewed children about objects, activities, and concepts that were part of the lesson. Aspects of parents' conversational style (e.g., open-ended memory questions, descriptive language) predicted how much information children provided in talking with them, which in turn predicted children's memory performance 6days later. The findings suggest that elaborative parent-child conversations at home could boost children's retention of academic information acquired at school even when parents have no specific knowledge of what children have experienced there. PMID- 28024177 TI - Children's understanding of additive concepts. AB - Most research on children's arithmetic concepts is based on one concept at a time, limiting the conclusions that can be made about how children's conceptual knowledge of arithmetic develops. This study examined six arithmetic concepts (identity, negation, commutativity, equivalence, inversion, and addition and subtraction associativity) in Grades 3, 4, and 5. Identity (a-0=a) and negation (a-a=0) were well understood, followed by moderate understanding of commutativity (a+b=b+a) and inversion (a+b-b=a), with weak understanding of equivalence (a+b+c=a+[b+c]) and associativity (a+b-c=[b-c]+a). Understanding increased across grade only for commutativity and equivalence. Four clusters were found: The Weak Concept cluster understood only identity and negation; the Two-Term Concept cluster also understood commutativity; the Inversion Concept cluster understood identity, negation, and inversion; and the Strong Concept cluster had the strongest understanding of all of the concepts. Grade 3 students tended to be in the Weak and Inversion Concept clusters, Grade 4 students were equally likely to be in any of the clusters, and Grade 5 students were most likely to be in the Two Term and Strong Concept clusters. The findings of this study highlight that conclusions about the development of arithmetic concepts are highly dependent on which concepts are being assessed and underscore the need for multiple concepts to be investigated at the same time. PMID- 28024178 TI - Sustained selective attention predicts flexible switching in preschoolers. AB - Stability and flexibility are fundamental to an intelligent cognitive system. Here, we examined the relationship between stability in selective attention and explicit control of flexible attention. Preschoolers were tested on the Dimension Preference (DP) task, which measures the stability of selective attention to an implicitly primed dimension, and the Dimension Change Card Sort (DCCS) task, which measures flexible attention switching between dimensions. Children who successfully switched on the DCCS task were more likely than those who perseverated to sustain attention to the primed dimension on the DP task across trials. We propose that perseverators have less stable attention and distribute their attention between dimensions, whereas switchers can successfully stabilize attention to individual dimensions and, thus, show more enduring priming effects. Flexible attention may emerge, in part, from implicit processes that stabilize attention even in tasks not requiring switching. PMID- 28024179 TI - Co-occurrence of autistic and schizotypal traits and its association with emotional and psychosocial function in Chinese college students. AB - Empirical findings suggest an overlap between autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD). Co-occurring autistic and positive schizotypal traits may have a moderating effect on behaviour and cognition. This study attempted to examine the co-occurrence rate of autistic and schizotypal traits in otherwise healthy college students and to test the moderating effect of co-occurring autistic and schizotypal traits on executive function, emotion processing and social function. Eight hundred and sixty-four participants took part in the present study. The results showed that the co-occurrence rate of autistic and schizotypal trait was 3.4% at baseline and 2.4% at one-year follow up. The interaction between autistic traits and schizotypal traits was associated with better executive functioning and social functioning but poorer emotional expression. PMID- 28024180 TI - Destination memory in schizophrenia: "Did I told Elvis Presley about the thief?" AB - Destination memory refers to the ability to remember to whom a piece of information was previously transmitted. Our paper assessed this ability in schizophrenia. Twenty-five patients with schizophrenia and 25 control participants told proverbs (e.g., "send a thief to catch a thief") to pictures of celebrities (e.g., Elvis Presley). Afterward, participants had to indicate to which celebrity they had previously said the proverbs. Participants also completed a binding task in which they were required to associate letters with their corresponding context (i.e., location). Analysis revealed worse destination memory and binding in patients with schizophrenia than in controls. In both populations, destination memory was significantly correlated with performances on the binding task. Our findings suggest difficulty in the ability to attribute information to its appropriate destination in schizophrenia. This difficulty may be related to compromise in binding separate cues together to form a coherent representation of an event in memory. PMID- 28024181 TI - Maternal and paternal personality profiles of adolescent suicide attempters. AB - Personality features have been correlated with suicidal behaviors in recent decades. Given its neurobiological background, Cloninger's model of personality, the Temperament and Character Inventory (TCI), may help to identify the maternal and paternal personality dimensions associated with adolescent suicide attempts. The present study is the first that specifically compares the temperament and character profiles of both mothers and fathers of the adolescent suicide attempters with a control group, by considering the influence of demographic and clinical factors. The study group comprised 117 parents of 71 adolescent suicide attempters and 119 parents of 71 age- and gender-matched adolescents without a suicide attempt included as a control group. The TCI and Brief Symptom Inventory (BSI) were applied to the parents in both groups. Logistic regression analysis, which was performed to adjust confounding factors, demonstrated significantly higher scores for harm avoidance among the mothers and lower scores of self directedness among the fathers of the adolescent suicide attempters. New psychotherapeutic modalities considering the high-risk parental personality traits would be beneficial to support parent-adolescent relationships and may have a preventative effect on adolescent suicide. PMID- 28024182 TI - CALR exon 9 mutations in idiopathic splanchnic vein thrombosis in an Australian cohort. PMID- 28024183 TI - Altered leukocyte distribution under hypercholesterolemia: A cross-sectional study in children with familial hypercholesterolemia. AB - BACKGROUND AND AIMS: Children with familial hypercholesterolemia (FH) have elevated LDL cholesterol from the first year of life, and represent a model of early-stage atherosclerosis. Data suggest that adults with FH have alterations in circulating monocyte subpopulations towards a more pro-inflammatory phenotype, but it is not known whether FH children have similar perturbations. In addition, there are no data on the distribution of lymphocyte subpopulations in FH children. The objective of the present study was to characterize the distributions of circulating monocyte and lymphocyte subpopulations in children with FH and healthy, normocholesterolemic children. METHODS: Using flow cytometry analysis, we analyzed whole blood B- and T-cell subpopulations and monocyte subpopulations in FH (n = 23) and healthy (n = 20) children. Moreover, we measured serum markers of leukocyte and endothelial cell activation using EIA. RESULTS: We found that FH children had monocytosis as well as a shift in the monocyte subpopulations. This shift was characterized by higher circulating pro inflammatory and non-classical monocytes, and lower levels of classical monocytes, and seemed to be present only in FH children with low HDL cholesterol (HDL-C, below 1.3 mmol/L). Additionally, monocytes expressing CD18 and serum E selectin were higher in FH children, in particular FH children with low HDL-C. CONCLUSIONS: FH children with low HDL-C had monocytosis as well as a shift in monocyte subpopulations towards a more pro-inflammatory phenotype. Our results suggest activation of monocytes at a very early stage of atherosclerosis in humans. PMID- 28024184 TI - Serpinb9 is a marker of antigen cross-presenting dendritic cells. AB - Serpinb9 (Sb9, also called Spi6) is an intracellular inhibitor of granzyme B (grB) that protects cytotoxic lymphocytes from grB-mediated death. In addition, Sb9 is also expressed in accessory immune cells, including dendritic cells (DCs), although its role is debated. Recently, we have demonstrated that Sb9 plays a grB independent role in cross-presentation of antigens by CD8+ DCs. Here, using a mouse line expressing green fluorescent protein knocked in under the control of the Sb9 promoter, we demonstrate that Sb9 expression is highest in those tissue resident and migratory DC subsets capable of cross-presentation. Further, we show that CD8+ DCs can be divided into two subsets based on Sb9 expression, and that only the subset expressing higher levels of Sb9 is capable of cross-presentation. These findings add support for role for Sb9 cross-presentation, and indicate that high Sb9 expression is a novel marker of cross-presentation capable DCs. PMID- 28024185 TI - In the loop: how chromatin topology links genome structure to function in mechanisms underlying learning and memory. AB - Different aspects of learning, memory, and cognition are regulated by epigenetic mechanisms such as covalent DNA modifications and histone post-translational modifications. More recently, the modulation of chromatin architecture and nuclear organization is emerging as a key factor in dynamic transcriptional regulation of the post-mitotic neuron. For instance, neuronal activity induces relocalization of gene loci to 'transcription factories', and specific enhancer promoter looping contacts allow for precise transcriptional regulation. Moreover, neuronal activity-dependent DNA double-strand break formation in the promoter of immediate early genes appears to overcome topological constraints on transcription. Together, these findings point to a critical role for genome topology in integrating dynamic environmental signals to define precise spatiotemporal gene expression programs supporting cognitive processes. PMID- 28024186 TI - Synthesis, characterization, DNA interactions and antiproliferative activity on glioblastoma of iminopyridine platinum(II) chelate complexes. AB - A series of iminopyridine platinum chelate compounds has been prepared and characterized by NMR spectroscopy and single-crystal X-ray diffraction. The complexes were evaluated in C6 tumoral cells as an in vitro model for glioblastoma multiforme. The DNA-binding properties of these complexes were studied by UV-Vis absorption and fluorescence spectroscopy and Density Functional Theory calculations were performed in an effort to rationalize the observed properties at the molecular level. The most promising drug candidate displayed a similar potency in inducing cell death to the clinically used reference compound and showed significant inhibition of glioblastoma cell proliferation. Moreover, this compound had a safer profile than cisplatin on non-tumoral cells. PMID- 28024187 TI - Synthesis, photophysical properties and structures of organotin-Schiff bases utilizing aromatic amino acid from the chiral pool and evaluation of the biological perspective of a triphenyltin compound. AB - Five new organotin(IV) complexes of compositions [Me2SnL1] (1), [Me2SnL2]n (2), [Me2SnL3] (3), [Ph3SnL1H]n (4) and [Ph3SnL3H] (5) (where L1=(2S)-2-((E)-((Z)-4 hydroxypent-3-en-2-ylidene)amino)-3-(1H-indol-3-yl)propanoate, L2=(2S)-(E)-2-((2 hydroxybenzylidene)amino)-3-(1H-indol-3-yl)propanoate and L3=(2S)-(E)-2-((1-(2 hydroxyphenyl)ethylidene)amino)-3-(1H-indol-3-yl)propanoate were synthesized and spectroscopically characterized. The crystal structures of 1-4 were determined. For the dimethyltin derivative 2, a polymeric chain structure was observed as a result of a long Sn???O contact involving the exocyclic carbonyl oxygen-atom from the tridentate ligand of a neighboring Sn-complex unit. The tin atom in this complex has a distorted octahedral coordination geometry, in which the long Sn-O bond is almost trans to the tridentate ligand nitrogen-atom. In contrast, the dimethyltin(IV) complexes 1 and 3 displayed discrete monomeric structures where the tin atom has distorted trigonal-bipyramidal geometry with the two coordinating L oxygen atoms defining the axial positions. On the other hand, 4 is a chain polymer in the solid state. The ligand-bridged Sn atoms adopt a trans Ph3SnO2 trigonal-bipyramidal configuration with equatorial phenyl groups. A carboxylato oxygen atom from one and the hydroxyl oxygen of the successive ligand in the chain occupy the axial positions. The solution structures were predicted by the use of 119Sn NMR chemical shifts. The photophysical properties of the complexes were investigated in the solid and in solution. The triphenyltin(IV) compound 4 was tested in detail ex vivo against A375 (human melanoma) cell line, exhibiting an IC50 value of 261nM to induce cell death as assessed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay without significant alteration of cytolysis as determined by lactate dehydrogenase (LDH) assay. Compound 4-mediated potent cell death was also determined by Live and Dead assay and caspase-mediated cleavage of poly-ADP ribose polymerase (PARP). Potent cell death activity was not observed in primary cells, like blood-derived peripheral mononuclear cells (PBMC). Compound 4 inhibited the diphenyl hexatriene (DPH) binding to cells and decreased the micro viscosity in a dose-dependent manner. Additionally, the ability of 4 and cyclodextrin (CD) to interact was determined by molecular modelling. PMID- 28024188 TI - Longitudinal patterns of marijuana use across ages 18-50 in a US national sample: A descriptive examination of predictors and health correlates of repeated measures latent class membership. AB - BACKGROUND: This descriptive study identified latent classes of longitudinal marijuana use from ages 18 through 50 among a national sample; examined covariate associations with class membership regarding use/non-use, use intensity, and use duration; and described associations between identified latent classes and age 50 health outcomes. METHODS: The study involved collection and primary analysis of data from 9831 individuals first surveyed as 12th graders in the national Monitoring the Future study and followed through modal age 50. Repeated measures latent class analysis was used to identify latent classes based on self-reported past 12-month marijuana use. RESULTS: Seven latent classes of marijuana use from ages 18 to 50 were identified including Non-users (44%), two classes characterized by shorter-term use patterns (totaling 28%), and four classes characterized by longer-term moderate or heavy use (totaling 28%). Use reduction appeared particularly likely during early and late 20s. Gender, parental education, alcohol/cigarette use, religious commitment, and marital status differentiated use/non-use, use intensity, and use duration after high school. In non-causal models controlling for covariates, longer-term marijuana use classes (where use extended into the late 20s or beyond) were associated with significantly higher odds of negative health outcomes at age 50. CONCLUSIONS: Approximately 28% of the national sample reported longer-term moderate/heavy marijuana use, which was associated with negative health outcomes at age 50. The early and late 20s may be especially important periods for marijuana use prevention and intervention efforts, which may be strengthened by recognition of characteristics that appear to have significant associations with persistent use. PMID- 28024189 TI - Highly efficient silica coated CuNi bimetallic nanocatalyst from reverse microemulsion. AB - Silica protected CuNi bimetallic nanoparticles (CuNi@SiO2) were successfully prepared by a modified co-reduction method. Typically, ammoniacal Cu(II) and Ni(II) were firstly dispersed and encapsulated inside silica by the method of reverse microemulsion. Then, ultra small CuO and NiO particles were in-situ formed during calcination under air. CuNi bimetallic nanoparticles were obtained by the co-reduction of CuO and NiO under H2 at high temperature. The composition and size of CuNi bimetallic nanoparticles was tuned simply by varying the concentration of precursor solutions. The samples were characterized by FT-IR, TEM, XPS, XRD and ICP-OES. The reduction of p-nitrophenol by NaBH4 was chosen as model reaction to evaluate the catalytic activity. The results indicate that CuNi bimetallic nanoparticles prepared by our method show size and composition dependent catalytic activity. The activation energy of Cu54Ni46@SiO2 for the same reaction was calculated as to be 16.6kJ/mol which was much lower than that of Cu@SiO2 (29.0kJ/mol) and Ni@SiO2 (39.5kJ/mol). PMID- 28024190 TI - Self-assembly of multi-hierarchically structured spongy mesoporous silica particles and mechanism of their formation. AB - Here we report on self-assembly of novel multi-hierarchically structured meso(nano)porous colloidal silica particles which have cylindrical pores of 4 6nm, overall size of ~10MUm and "cracks" of 50-200nm. These cracks make particles look like micro-sponges. The particles were prepared through a modified templated sol-gel self-assembly process. The mechanism of assembly of these particles is investigated. Using encapsulated fluorescent dye, we demonstrate that the spongy particles are advantageous to facilitate dye diffusion out of particles. This multi-hierarchically geometry of particles can be used to improve the particle design for multiple applications to control drug release, rate of catalysis, filtration, utilization of particles as hosts for functional molecules (e.g., enzymes), etc. PMID- 28024191 TI - On the driving forces for complexation of methyl orange with polycations. AB - HYPOTHESIS: Complexation between Methyl orange and polycations involves multiple interactions dictated by molecular structure, composition (D/P), pH and ionic strength. The effect of ionic strength is considered a generic effect. By step wise construction of complexes, we expect to gain insight in the nature of interactions and whether displacement by competing ions is a generic effect. EXPERIMENTS: We step-wise constructed complexes of methyl orange with two model polycations, whilst recording visible light spectra, size and electrophoretic mobility in buffered solution. MO organization was derived from discrete spectral changes, whereas complexes were described in terms of size and zeta-potential data. Spectral data were used to study the effect of competing ions, both potassium halides and polyanions, using a manual titration method. FINDINGS: Spectral and size data reveal a complex stoichiometry of D/P=2.2 and 4.6 for poly(ethylenimine hydrochloride)(PEI) and poly(di allyldimethyl amine hydrochloride) PDADMAC, respectively. Contrary to PEI-MO, the formation of PDADMAC-MO complexes is driven by hydrophobic rather than electrostatic interactions. Organization of PDADMAC-MO complexes also shows a strong dependency on the order of construction and polycation concentration. Displacement of MO by halides shows no effect of ion size for PEI, whereas Hofmeister series ordering was found for PDADMAC. The displacement by polyanions is shown to be charge stoichiometric. PMID- 28024192 TI - Next generation ultrasound platforms for theranostics. AB - Microbubbles are a well-established contrast agent which improves diagnostic ultrasound imaging. During the last decade research has focused on expanding their use to include molecular imaging, targeted therapy and imaging modalities other than ultrasound. However, bioadhesion of targeted microbubbles under physiological flow conditions is still difficult to achieve, the main challenge being connected to the poor stability of lipid microbubbles in the body's circulation system. In this article, we investigate the use of polymeric microbubbles based on a poly (vinyl alcohol) shell as an alternative to lipid microbubbles. In particular, we report on the development of microbubble shell modification, using mild reaction conditions, with the aim of designing a multifunctional platform to enable diagnosis and therapy. Superparamagnetic iron oxide nanoparticles and a near infrared fluorescent probe, indocyanine green, are coupled to the bubbles surface in order to support magnetic resonance and fluorescence imaging. Furthermore, anchoring cyclic arginyl-glycyl-aspartic acid (RGD) peptide, and cyclodextrin molecules, allows targeting and drug loading, respectively. Last but not least, shell topography is provided by atomic force microscopy. These applications and features, together with the high echogenicity of poly (vinyl alcohol) microbubbles, may offer a more stable alternative to lipid microbubbles for the development of a multimodal theranostic platform. PMID- 28024193 TI - Higher production of C-phycocyanin by nitrogen-free (diazotrophic) cultivation of Nostoc sp. NK and simplified extraction by dark-cold shock. AB - Nostoc sp. NK (KCTC 12772BP) was isolated and cultivated in a BG11 medium and a nitrate-free BG11 medium (BG110). To enhance C-phycocyanin (C-PC) content in the cells, different fluorescent lamps (white, plant, and red) were used as light sources for complementary chromatic adaptation (CCA). The maximum biomass productivity was 0.42g/L/d and 0.32g/L/d under BG11 and BG110 conditions, respectively. The maximum C-PC contents were 8.4% (w/w) under white lamps, 13.6% (w/w) under plant lamps, and 18% (w/w) under BG110 and the red light condition. The maximum C-PC productivity was 57.4mg/L/d in BG110 under the red lamp condition. These results indicate that a higher C-PC content could be obtained under a diazotrophic condition and a CCA reaction. The C-PC could be released naturally from cells without any extraction processes, when Nostoc sp. NK was cultivated in the BG110 medium with CO2 aeration and put in dark conditions at 5 degrees C. PMID- 28024194 TI - Co-composting of vegetable wastes and carton: Effect of carton composition and parameter variations. AB - The aim of the study was to investigate the effects of carton in the composting process of mixed vegetable wastes using an experimental composter of capacity 80L. Three different mixes were set-up (Mixes 1, 2 and 3) which consisted of vegetable wastes, 2.0kg paper and bulking agents, vegetable wastes, 1.5kg carton and bulking agents, vegetable wastes, 4.5kg carton and bulking agents, respectively. Temperature evolution, pH trends, moisture levels, respiration rates, percentage volatile solids and electrical conductivity were monitored for a period of 50days. The system remained under thermophilic conditions for a very short period due to the small size of the reactor. The three mixes did not exceed a temperature of 55 degrees C, where sanitization takes place by the destruction of pathogens. The highest peak of CO2 evolution was observed in Mix 2 indicating that maximum microbial degradation took place in that mix. PMID- 28024195 TI - The costs of production of alternative jet fuel: A harmonized stochastic assessment. AB - This study quantifies and compares the costs of production for six alternative jet fuel pathways using consistent financial and technical assumptions. Uncertainty was propagated through the analysis using Monte Carlo simulations. The six processes assessed were HEFA, advanced fermentation, Fischer-Tropsch, aqueous phase processing, hydrothermal liquefaction, and fast pyrolysis. The results indicate that none of the six processes would be profitable in the absence of government incentives, with HEFA using yellow grease, HEFA using tallow, and FT revealing the lowest mean jet fuel prices at $0.91/liter ($0.66/liter-$1.24/liter), $1.06/liter ($0.79/liter-$1.42/liter), and $1.15/liter ($0.95/liter-$1.39/liter), respectively. This study also quantifies plant performance in the United States with a Renewable Fuel Standard policy analysis. Results indicate that some pathways could achieve positive NPV with relatively high likelihood under existing policy supports, with HEFA and FPH revealing the highest probability of positive NPV at 94.9% and 99.7%, respectively, in the best case scenario. PMID- 28024196 TI - Dissolution and fractionation of nut shells in ionic liquids. AB - The aim of this work was to study the dissolution of raw peanut and chestnut shells in ionic liquids. Dissolution of raw biomass up to 7wt% was achieved under optimized operatory conditions. Quantification of polysaccharides dissolved through quantitative 13Cq NMR revealed extractions of the cellulosic material to ionic liquids as high as 87%. Regeneration experiments using an antisolvent mixture allowed to recover the cellulosic material and the ionic liquid. The overall mass balance presented very low loss rates (<8%), recoveries of 75% and 95% of cellulosic material from peanut and chestnut shells, respectively, and the recovery of more than 95% of the ionic liquid in both cases. These results show the high potential of using nut shells and ionic liquids for biorefining purposes. Moreover, high recovery of ionic liquids favors the process from an economical point of view. PMID- 28024197 TI - Building 'blue': An eco-engineering framework for foreshore developments. AB - Urbanisation in terrestrial systems has driven architects, planners, ecologists and engineers to collaborate on the design and creation of more sustainable structures. Examples include the development of 'green infrastructure' and the introduction of wildlife corridors that mitigate urban stressors and provide positive ecological outcomes. In contrast, efforts to minimise the impacts of urban developments in marine environments have been far more restricted in their extent and scope, and have often overlooked the ecological role of the built environment as potential habitat. Urban foreshore developments, i.e. those built on the interface of intertidal and/or subtidal zones, have the potential to incorporate clear multi-functional outcomes, by supporting novel ecosystems. We present a step-by-step eco-engineering framework for 'building blue' that will allow coastal managers to facilitate planning and construction of sustainable foreshore developments. Adopting such an approach will incorporate ecological principles, thereby mitigating some of the environmental impacts, creating more resilient urban infrastructure and environments, and maximising benefits to the multiple stakeholders and users of marine urban waterfronts. PMID- 28024198 TI - An evaluation of laparoscopic hysterectomy alone versus in combination with laparoscopic myomectomy for patients with uterine fibroids. AB - OBJECTIVE: The purpose of this study was to compare surgical outcomes following conventional laparoscopic hysterectomy (LH) (C-LH) versus the combination method of LH plus laparoscopic myomectomy (LM) (LH+LM) for the treatment of large uterine fibroids. STUDY DESIGN: This study was performed in 56 patients (uterine weights >=500g) who underwent either C-LH or LH+LM performed by the same surgeon between May 2010 and May 2016. LH+LM was performed when C-LH was problematic because of poor visibility and/or mobility due to uterine fibroids. RESULTS: The C-LH and LH+LM groups consisted of 27 (48%) and 29 (52%) patients, respectively. The clinical characteristics of patients differed significantly only in the median sizes of the dominant fibroid. The sizes of the dominant fibroid in the C LH and LH+LM groups were 9.5cm and 10.7cm (P=0.04), respectively. Regarding the surgical outcomes for the C-LH and LH+LM groups, the median uterine weights were 558g and 737g (P=0.03), respectively, the median operating times were 156min and 173min (P=0.23), respectively, and the median intraoperative blood losses were 150g and 300g (P=0.0004), respectively. In all patients, LH was performed without conversion to laparotomy and there were no cases of bladder, ureteral, or gastrointestinal tract injury. There were no postoperative complications of Clavien-Dindo scale>=III in either group. CONCLUSIONS: When C-LH cannot be performed because of large uterine fibroids that cause poor visibility and/or mobility, LH+LM may allow the procedure to be successfully completed without conversion to laparotomy. However, the latter approach increases the risk for intraoperative blood loss. PMID- 28024199 TI - Physical and mental health comorbidities of epilepsy: Population-based cross sectional analysis of 1.5 million people in Scotland. AB - PURPOSE: To measure the prevalence of physical and mental health comorbidities in people with epilepsy in a large population cohort, and to examine the prevalence of depression accounting for other physical comorbidity. METHODS: Population based, cross-sectional descriptive epidemiology analysis of primary care electronic records for 1,510,742 people aged 14+ years, examining the prevalence of 39 comorbidities. RESULTS: 12,720 people with epilepsy were identified (prevalence 8.4/1000 population, 95% CI 8.3-8.5). Physical and mental health comorbidity was more common with epilepsy (mean of an additional 1.02 physical conditions difference, 95% CI 0.99-1.06). 69.9% of people with epilepsy had one or more comorbid health conditions and 18.6% had four or more, compared to 46.9% and 9.0% of people without epilepsy. Depression was present in 16.3% of people with epilepsy compared to 9.5% of those without (adjusted OR 1.57, 95% CI 1.49 1.65). The prevalence of comorbid depression in epilepsy increased as the number of physical comorbidities increased (OR 5.82, 95% CI 4.90-6.91 for 4+ physical comorbidities vs none) and with increasing deprivation, similar to the patterns observed in other common physical conditions. CONCLUSION: People with epilepsy have higher rates of both physical and mental health comorbidity than people without even after adjustment for age, gender and levels of deprivation. Depression is more common than in the general population but the prevalence is similar to other physical health conditions, and is strongly associated with the total burden of physical conditions. This study highlights the complexity in caring for people with epilepsy. PMID- 28024200 TI - Nanosystem composed with MSNs, gadolinium, liposome and cytotoxic peptides for tumor theranostics. AB - A dual-functional delivery system, based on mesoporous silica nanoparticles (MSNs) with the integration of Magnetic Resonance (MR) imaging and therapeutic peptide delivery, is reported in this paper. A lipid bilayer is attached onto the surface of the nanoparticles, following the doping of Gadolinium (Gd), a paramagnetic lanthanide ion. The liposome-coated GdMSNs exhibit improved colloidal stability, better biocompatibility and more efficient cellular uptake. The Gd renders the nano carrier a potential T1 contrast agent, confirmed by the MR imaging. A pro-apoptotic peptide, KLA (HGGKLAKLAKKLAKLAK), is encapsulated into the GdMSNs-LP and enters into the cells successfully to induce mitochondrial swelling and apoptosis, while it is nontoxic outside the cells. The synthesis procedure is convenient and free of toxic organic reagents. The nanosystem we construct may contribute to a promising theranostic platform for therapeutic peptide delivery in cancer treatment. PMID- 28024201 TI - Halloysite nanotubes with immobilized silver nanoparticles for anti-bacterial application. AB - Halloysite nanotubes (HNTs) with immobilized silver (Ag) nanoparticles (NPs) were prepared by methods of wet chemistry and were characterized by using the transmission electron microscopy, x-ray diffraction, optical spectroscopy and experiments with E. coli bacteria in-vitro. It was found that Ag NPs with almost perfect crystalline structure and sizes from ~9nm were mainly attached over the external surface of HNTs. The optical absorption measurement revealed a broad plasmonic resonance in the region of 400-600nm for HNTs with Ag NPs. The later samples exhibit bactericidal effect, which is more pronounced under illumination. A role of the plasmonic excitation of Ag NPs for their bioactive properties is discussed. The obtained results show that Ag NPs-decorated HNTs are promising agents for the antibacterial treatment. PMID- 28024202 TI - Microcontact imprinted quartz crystal microbalance nanosensor for protein C recognition. AB - Detection of protein C (PC) in human serum was performed by quartz crystal microbalance (QCM) based on molecular imprinting technique (MIP). The high resolution and mass-sensitive QCM based sensor was integrated with high sensitivity and selectivity of the MIP technique. The PC microcontact imprinted (PC-MUCIP) nanofilm was prepared on the glass surface. Then, the PC-MUCIP/QCM sensor was prepared with 2-hydroxyethyl methacrylate (HEMA), ethylene glycol dimethacrylate (EGDMA) and N-methacryloyl l-histidine methylester (MAH) as the functional monomer with copper(II) ions. The polymerization was performed under UV light (100W and 365nm) for 20-25min under nitrogen atmosphere. The characterization studies of QCM sensor were done by observation using atomic force microscopy (AFM), contact angle measurements, ellipsometry and fourier transform infrared spectroscopy (FTIR). Detection of PC was investigated in a concentration range of 0.1-30MUg/mL. Selectivity of PC-MUCIP and PC non imprinted/QCM (PC-non-MUCIP) sensors for PC determination was investigated by using proteins namely hemoglobin (Hb), human serum albumin (HSA) and fibrinogen solutions. QCM sensor was also used for detection of PC molecules in aqueous solutions and human plasma. The detection limit was determined as 0.01MUg/mL for PC analysis. The PC-MUCIP/QCM sensor was used for five consecutive adsorption desorption cycles. According to the results, the PC-MUCIP/QCM sensor had obtained high selectivity and sensitivity for detection of PC molecules. PMID- 28024203 TI - Constructing a publically available distracted driving database and research tool. AB - BACKGROUND: The goal of the current work was to create a publicly available visualization tool of distracted driving research, the purpose of which is to allow the public and other stakeholders to empirically inform questions of their choice that may bear on policy discussions. METHODS: Fifty years of distracted driving research was used to design a comprehensive database of studies that evaluated the effects of distraction on driving performance. Distraction sources (e.g., texting, talking, visual distraction) and performance measures were defined, and the sample of studies were evaluated and categorized by their measures. RESULTS: The final product yielded 342 studies using various methodologies. Across all measures, 1297 found distractions degraded driving performance, 54 found distraction improved driving performance, and 257 found distraction had no effect on driving performance. An analysis of the most common phone distractions (texting and talking) showed that texting almost always results in degraded performance. Aggregate data reveal no difference in performance decrements for hand-held or hands-free phones even though single studies of those variables vary in their outcomes. CONCLUSIONS: This project illustrates how scientific research can be made publically available for use by a diverse audience of stakeholders. An important result of this project is that data aggregated along a simple set of characteristics such as whether or not performance is decreased, improved or not affected, can reveal trends in the data that are less clear from any individual study. PMID- 28024204 TI - A 2D-g-C3N4 nanosheet as an eco-friendly adsorbent for various environmental pollutants in water. AB - A novel graphitic carbon nitride (g-C3N4) nanosheet adsorbent with a large surface area, remarkable hydrophilicity and high adsorption capacity, was presented for the removal of cadmium ions (Cd2+) and methylene blue (MB) from aqueous solution. Adsorption measurements were conducted systematically to study the influences of the contact time, initial concentrations of Cd2+ and MB, temperature, and pH value. The maximum adsorption capacities of g-C3N4 towards Cd2+ and MB were 94.4 and 42.1 mg g-1, respectively, at 318.5 K when the initial concentrations of Cd2+ and MB were 200 and 20 mg L-1, respectively. The adsorption kinetics fit a pseudo-second-order model. The high adsorption performance of the g-C3N4 adsorbent can be attributed to the multiple adsorption sites on g-C3N4, including the pi-pi conjugate interactions and electrostatic attractions with pollutants in water. In addition, it is significant to achieve high adsorption performance of g-C3N4 nanosheets by efficiently exposing the adsorption sites by adjusting the microstructure surface properties and dispersity in solution. PMID- 28024205 TI - Exogenous substances regulate silkworm fat body protein synthesis through MAPK and PI3K/Akt signaling pathways. AB - Insect fat body is an important intermediate metabolic organ that plays an important role in protein metabolism and detoxification. In order to study the effects of TiO2 NPs and phoxim on fat body protein synthesis through MAPK and PI3K/Akt signaling pathways in silkworms, we determined the effects of TiO2 NPs and phoxim, alone and in combination, on fat body protein content of silkworms, analyzed the gene expression profile of the fat body, and verified the expression of characteristic genes. We found that TiO2 NPs and phoxim alone increased the total protein content of the fat body, and up-regulated MAPK and PI3K/Akt signaling pathway genes. TiO2 NPs up-regulated the expression of two growth and development-related genes-insulin-like peptide and neuropeptide receptor B-by 5.17 and 3.89-fold, respectively. Phoxim up-regulated the expression of detoxification genes-P450, GST, and CarE2. Pretreatment with TiO2 NPs could reduce phoxim-increased total protein content and up-regulated MAPK and PI3K/Akt signaling pathway genes and detoxification genes; the activities of detoxification enzymes were consistent with the gene expression pattern. Our results showed that MAPK and PI3K/Akt signaling pathways both regulate fat body protein synthesis in silkworms, but the target proteins induced to express were different under different inducing factors. Our finding may provide a reference for investigating the mechanism of protein synthesis regulation through MAPK and PI3K/Akt signaling pathways. PMID- 28024206 TI - Bioaccumulation of Hg, Cd and Pb by Fucus vesiculosus in single and multi-metal contamination scenarios and its effect on growth rate. AB - Results of 7-days exposure to metals, using environmentally realistic conditions, evidenced the high potential of living Fucus vesiculosus to remove Pb, Hg and Cd from contaminated salt waters. For different contamination scenarios (single- and multi-contamination), ca 450 mg L-1 (dry weight), enable to reduce the concentrations of Pb in 65%, of Hg in 95% and of Cd between 25 and 76%. Overall, bioconcentration factors ranged from 600 to 2300. Elovich kinetic model described very well the bioaccumulation of Pb and Cd over time, while pseudo-second-order model adjusted better to experimental data regarding Hg. F. vesiculosus showed different affinity toward studied metals, following the sequence order: Hg > Pb > Cd. Analysis of metal content in the macroalgae after bioaccumulation, proved that all metal removed from solution was bound to the biomass. Depuration experiments reveled no significant loss of metal back to solution. Exposure to contaminants only adversely affected the organism's growth for the highest concentrations of Cd and Pb. Findings are an important contribute for the development of remediation biotechnologies for confined saline waters contaminated with trace metal contaminants, more efficient and with lower costs than the traditional treatment methods. PMID- 28024207 TI - Oriented growth of poly(m-phenylenediamine) on Calotropis gigantea fiber for rapid adsorption of ciprofloxacin. AB - A facile polymerization of m-phenylenediamine (mPD) in methanol/water (50:50, v/v) was performed via conventional chemical oxidative method by using Calotropis gigantea fiber (CGF) as the natural biotemplate. The as-prepared CGF oriented poly(m-phenylenediamine) (PmPD), i.e. CGF-O-PmPD, exhibits a well defined fiber oriented morphology. The presence of PmPD layer enables CGF-O-PmPD to present roughen surface with N-rich functional groups that can show high performance for the adsorption of ciprofloxacin. The variables affecting the adsorption capacity were systematically investigated, including contact time, initial concentration, initial pH, ion strength, and so forth. The experimental data reveal that with increasing the amount of mPD from 0.2, 0.5 to 2.0 g, the adsorption capacity for ciprofloxacin shows a monotonic decrease, while the adsorption kinetics show a monotonic increase, with the adsorption percentage from >50%, >60% to >70% within 10 s, demonstrating its superfast adsorption kinetics for ciprofloxacin. In addition, an increasing adsorption capacity is observed over the pH range studied, with the adsorption capacity from 0.73 to 6.7 mg g-1 at pH 2.0 to 64.9 77.3 mg g-1 at pH 10.0. After five adsorption-desorption cycles, the adsorption capacity of CGF-O-PmPD for ciprofloxacin shows no significant decrease, indicating its excellent reusability and potential application in treating antibiotic-containing wastewater. PMID- 28024208 TI - Adsorption behavior of levulinic acid onto microporous hyper-cross-linked polymers in aqueous solution: Equilibrium, thermodynamic, kinetic simulation and fixed-bed column studies. AB - The recovery of levulinic acid (LA) from aqueous solution and actual biomass hydrolysate by a microporous hyper-cross-linked polymer, SY-01, was investigated for the first time under batch and fixed-bed column conditions. The results showed that the optimum pH should be in the acidic range (pH < 3.0) without adjusting the pH. In the single-component system equilibrium study, the Langmuir isotherm model fits the LA adsorption onto SY-01 resin better than the Freundlich isotherm model, indicating that LA adsorption onto SY-01 resin under the concentration range studied is a monolayer homogeneous adsorption process. The maximum adsorption capacity of LA onto SY-01 resin decreased with increasing temperature, ranging from 103.74 to 95.70 mg/g. The obtained thermodynamic parameters suggested that the adsorption of LA on SY-01 was spontaneous (DeltaG0< 3.788 kJ/mol), and exothermic (DeltaH0 = -11.764 kJ/mol). For kinetic study, the adsorption of LA onto SY-01 resin at various operating conditions follows the pore diffusion model and the intraparticle diffusion is the rate-limiting step for the adsorption of LA onto SY-01 resin. The effective pore diffusivity was dependent upon temperature, but independent of initial LA concentration, and were 3.306 * 10-10, 5.274 * 10-10 and 7.707 * 10-10 m2/s at 298, 318 and 338 K, respectively. In desorption process, the recovery efficiency of LA from SY-01 resin was 99.39%, and LA concentration in the eluent was raised 2.97-fold. In conclusion, our results show that the SY-01 resin has potential application in product recovery of LA from biomass hydrolysate. PMID- 28024209 TI - Influence and interaction of iron and cadmium on photosynthesis and antioxidative enzymes in two rice cultivars. AB - In this study, a soil pot experiment was conducted to investigate the changes in photosynthesis and antioxidative enzymes in two rice varieties (Shendao 6 and Shennong 265) supplied with iron (Fe), cadmium (Cd), and Fe and Cd together. The concentrations of Fe and Cd in the soil were 0, 1.0 g Fe.kg-1 and 0, 2.0 mg Cd.kg 1, respectively. Photosynthetic indices and antioxidative enzyme activities were recorded at different rice growth stages. At the early stage, Cd showed a transient stimulatory effect on the photosynthetic rate of Shennong 265. For Shendao 6, however, Cd showed a transient stimulatory effect on photosynthetic rate, intercellular CO2 concentration, stomatal conductance and transpiration efficiency. In addition, the results show that Cd can also enhance the superoxide dismutase (SOD) and peroxidase (POD) activities, but reduce the malondialdehyde (MDA) and soluble protein contents in the two rice cultivars. Subsequently, Cd starts to inhibit photosynthesis and SOD activity until the ripening stage, causing the lowest photosynthetic rate and SOD activity at this stage. In contrast, Fe alleviates the Cd-induced changes at earlier or later growth stage. Notably at the later growth stage, the results show that the interaction between Fe and Cd increases the SOD and catalase (CAT) activities, while decreasing the lipid peroxidation and promoting photosynthesis. As a result, it ultimately increases the biomass. The results from this study suggest that Fe (as Fe fertilizer) is a promising alternative for agricultural use to enhance the plant development and, simultaneously, to reduce Cd toxicity in extensively polluted soils. PMID- 28024210 TI - Microplastics in the surface sediments from the Beijiang River littoral zone: Composition, abundance, surface textures and interaction with heavy metals. AB - While large quantities of studies on microplastics in the marine environment have been widely carried out, few were available in the freshwater environment. The occurrence and characteristics, including composition, abundance, surface texture and interaction with heavy metals, of microplastics in the surface sediments from Beijiang River littoral zone were investigated. The concentrations of microplastics ranged from 178 +/- 69 to 544 +/- 107 items/kg sediment. SEM images illustrated that pits, fractures, flakes and adhering particles were the common patterns of degradation. Chemical weathering of microplastics was also observed and confirmed by MU-FTIR. EDS spectra displayed difference in the elemental types of metals on the different surface sites of individual microplastic, indicating that some metals carried by microplastics were not inherent but were derived from the environment. The content of metals (Ni, Cd, Pb, Cu, Zn and Ti) in microplastics after ultrasonic cleaning has been analyzed by ICP-MS. Based on data from the long-term sorption of metals by microplastics and a comparison of metal burden between microplastics, macroplastics and fresh plastic products, we suggested that the majority of heavy metals carried by microplastics were derived from inherent load. PMID- 28024211 TI - Conservative approach to Hepatic Portal Venous Gas: A case report. AB - INTRODUCTION: Hepatic Portal Venous Gas (HPVG), a rare condition in which gas accumulates in the portal venous circulation, is often associated with a significant underlying pathology, such as Crohn's disease, ulcerative colitis, diverticulitis, pancreatitis, sepsis, intra-abdominal abscess, endoscopic procedures, mesenteric ischemia, abdominal trauma. PRESENTATION OF CASE: Here we report a case of HPVG in an 82-year-old patient who underwent a left colectomy for stenosing tumor of the descending colon. The patient was treated conservatively, and his symptoms resolved. Follow-up computed tomography (CT) scan showed complete resolution of HPVG. DISCUSSION: The mechanism underlying the passage of the gas from the intestine into the mesenteric, then portal, venous system is not fully understood. Historically, this condition has been related to acute intestinal ischemia, as a consequence of a bacterial translocation through a wall defect. CONCLUSION: This case underscores the role of conservative management, highlighting how the severity of the prognosis of HPVG should be related to the underlying pathology, and not influenced by the presence of HPVG itself. PMID- 28024212 TI - Thymoma in middle mediastinum that induced tracheal compression-Case report and literature review. AB - BACKGROUND: A thymoma, an epithelial neoplasm of the thymus, mainly occurs in the anterior mediastinum, while few are seen in the middle mediastinum. CASE PRESENTATION: An 83-year-old male was referred for an incidental mass in the middle mediastinum. He had severe dementia and denied symptoms. Our follow-up computed tomography (CT) examinations had revealed the progress of tracheal compression along with tumor enlargement for 2 years. At 85 years old, we performed a thymomectomy via a median sternotomy to avoid complete trachea obstruction. The pathological diagnosis was WHO type A thymoma, Masaoka stage II. One year after surgery, the patient was free of disease. DISCUSSION: Thymomas occurring in the middle mediastinum are rare. In our review of 13 such cases, none were Masaoka stage III or IV, while the majority (9/13, 69.2%) were WHO type A or AB. CONCLUSION: We encountered a thymoma in the middle mediastinum that showed enlargement over a 2-year period, inducing severe tracheal compression. Thymomas can occur widely in pharyngeal pouch-derived locations and should be considered in differential diagnosis of a middle mediastinum tumor. PMID- 28024213 TI - Long-sleeve-working-port assisted laparoscopic pancreaticoduodenectomy-A new technique in laparoscopic surgery. AB - INTRODUCTION: Advances in technology and instruments have made laparoscopic pancreaticoduodenectomy (LPD) feasible. Unfortunately, this operation is technically very challenging and it is not widely accepted by laparoscopic surgeons. PRESENTATION OF CASE: A 59-year-old woman underwent LPD using a newly invented long-sleeve-working-port (LSWP) for a mucinous cystadenoma of the head of pancreas. This case report describes this port and its use on this patient. DISCUSSION: LSWP is a new invention to facilitate difficult laparoscopic operations. Through this LSWP, ordinary instruments used in open surgery can be used to overcome the limitation encountered in conventional laparoscopic surgery. CONCULSION: LSWP made complex laparoscopic surgery less complex. PMID- 28024214 TI - A bimodal tomographic reconstruction technique combining EDS-STEM and HAADF-STEM. AB - A three-dimensional (3D) chemical characterization of nanomaterials can be obtained using tomography based on high angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) or energy dispersive X-ray spectroscopy (EDS) STEM. These two complementary techniques have both advantages and disadvantages. The Z-contrast images have good image quality but lack robustness in the compositional analysis, while the elemental maps give more element specific information, but at a low signal-to-noise ratio and a longer exposure time. Our aim is to combine these two types of complementary information in one single tomographic reconstruction process. Therefore, an imaging model is proposed combining both HAADF-STEM and EDS-STEM. Based on this model, the elemental distributions can be reconstructed using both types of information simultaneously during the reconstruction process. The performance of the new technique is evaluated using simulated data and real experimental data. The results demonstrate that combining two imaging modalities leads to tomographic reconstructions with suppressed noise and enhanced contrast. PMID- 28024215 TI - Antidepressant sales and regional variations of suicide mortality in Germany. AB - Suicides account for over one million deaths per year worldwide with depression among the most important risk factors. Epidemiological research into the relationship between antidepressant utilization and suicide mortality has shown heterogeneous and contradictory results. Different methodological approaches and limitations could at least partially explain varying results. This is the first study assessing the association of suicide mortality and antidepressant sales across Germany using complex statistical approaches in order to control for possible confounding factors including spatial dependency of data. German suicide counts were analyzed on a district level (n = 402) utilizing ecological Poisson regressions within a hierarchical Bayesian framework. Due to significant spatial effects between adjacent districts spatial models were calculated in addition to a baseline non-spatial model. Models were adjusted for several confounders including socioeconomic variables, quality of psychosocial care, and depression prevalence. Separate analyses were performed for Eastern and Western Germany and for different classes of antidepressants (SSRIs and TCAs). Overall antidepressant sales were significantly negatively associated with suicide mortality in the non spatial baseline model, while after adjusting for spatially structured and unstructured effects the association turned out to be insignificant. In sub analyses, analogue results were found for SSRIs and TCAs separately. Suicide risk shows a distinct heterogeneous pattern with a pronounced relative risk in Southeast Germany. In conclusion, the results reflect the heterogeneous findings of previous studies on the association between suicide mortality and antidepressant sales and point to the complexity of this hypothesized link. Furthermore, the findings support tailored suicide preventive efforts within high risk areas. PMID- 28024216 TI - Toxicity, accumulation, and trophic transfer of chemically and biologically synthesized nano zero valent iron in a two species freshwater food chain. AB - The impact of bio-remediation agent nZVI on environment is still inadequately understood, especially on aquatic food web. The study presented here has therefore considered both chemical (CS) and biological (BS) synthetic origins of nZVI and their effects on both algae and daphnia. The study is unique in its attempt to explore the possibility of trophic transfer from algae to its immediate higher niche (daphnia as the model). An equal weightage of the effects of both CS and BS nZVI on algae and daphnia has been explored here; hence it allows us to compare the capping of nZVI on toxicity. To examine the causes of observed lethality- ROS generation, effects on the activity of oxidative enzymes, membrane damage and biouptake of nZVI was analysed. The overall outcome of CS and BS nZVI on lethality was significantly different in algae and daphnia, where daphnia demonstrated relatively higher sensitivity against CS nZVI. Algae demonstrated considerable differences in CS and BS nZVI toxicity only at higher concentration. This study did not show a probable biomagnification and trophic transfer from algae to daphnia under the experimental conditions even at the highest exposure concentration. The study instigates the importance of trophic transfer to understand the possible biomagnification of nZVI among organisms of different trophic levels and eventually the consequences on environment. PMID- 28024217 TI - Optimized procedures for manganese-52: Production, separation and radiolabeling. AB - Pressed chromium-powder cyclotron targets were irradiated with 16MeV protons, producing 52Mn with average yields of 6.2+/-0.8MBq/uAh. Separation by solid-phase anion exchange from ethanol-HCl mixtures recovered 94.3+/-1.7% of 52Mn and reduced the chromium content by a factor of 2.2+/-0.4*105. An additional AG 1-X8 column was used to remove copper, iron, cobalt and zinc impurities from the prepared 52Mn in 8M HCl. The macrocyclic chelator DOTA was rapidly radiolabeled with 52Mn in aq. ammonium acetate (pH 7.5R.T.) with a radiochemical yield >99% within 1min and was stable for >2 days in bovine serum. The improved separation and purification methodology facilitates the use of 52Mn in basic science and preclinical investigations. PMID- 28024218 TI - Estimation of coastal residence time of submarine groundwater discharge using radium progenies. AB - A methodology based on gamma-spectrometry measurements of untreated coastal water samples is proposed for the direct estimation of coastal residence time of submarine discharged groundwater. The method was applied to a submarine spring at Stoupa Bay covering all seasons. The estimated residence time exhibited an annual mean of 4.6+/-1.7 d. An additional measurement using the in situ underwater gamma spectrometry technique was performed, in the same site. The in situ method yielded a value of 2.8+/-0.2 d that was found consistent with the corresponding value derived using the developed lab-based method (3.4+/-2.0 d) for the same period. PMID- 28024219 TI - A strategy for translational epilepsy research. PMID- 28024220 TI - Perceptions and experiences of interventions to prevent postnatal depression. A systematic review and qualitative evidence synthesis. AB - BACKGROUND: More women experience depressive symptoms antenatally than postnatally. Supporting women through the antenatal period is recognised as important in mitigating negative outcomes and in preventing postnatal depression (PND). A systematic review was conducted which aimed to provide a detailed service user and service provider perspective on the uptake, acceptability, and perception of harms of antenatal interventions and postnatal interventions for preventing PND. METHODS: A comprehensive literature search was conducted in 12 major bibliographic databases in November 2012 and updated in December 2014. Studies were included if they contained qualitative evidence on the perspectives and attitudes of pregnant women and postnatal women who had taken part in, or healthcare professionals (HCPs) involved in delivering, preventive interventions for PND. RESULTS: Twenty-two studies were included. Support and empowerment through education were identified as particularly helpful to women as intervention components, across all intervention types. Implications for accessing the service, understanding the remit of the service and women's preferences for group and individual care also emerged. LIMITATIONS: The majority of the included studies were of moderate or low quality, which may result in a lack of rich data consistently across all studies, limiting to some degree interpretations that can be made. CONCLUSION: The synthesis demonstrated important considerations for devising new interventions or adapting existing interventions. Specifically, it is important that individual or group interventions are carefully tailored to women's needs or preferences and women are aware of the remit of the HCPs role to ensure they feel able to access the support required. PMID- 28024221 TI - The association between depression and mortality - a comparison of survey- and register-based measures of depression. AB - BACKGROUND: A number of studies have associated depression with a high mortality risk. However, in surveys, depression is often measured by self-reports in selected sub-samples, while register studies have been based on hospital diagnosis or purchase of antidepressants. We examined how different survey- and register-based measures of depression were associated with 7-year mortality in a cohort of middle-aged Danish men. METHODS: The study was based on 10,517 men born in 1953. Depression was assessed through hospital diagnosis for the period from 1969 to 2004 and by self-reported information on depression, use of antidepressants and the Major Depression Inventory (MDI) from a survey in 2004, in which 58.8% (n=6292) of the men participated. Information on mortality and cause of death was retrieved from registers for the period between 2004 and 2011. RESULTS: Depression diagnosis from hospital registers as well as self-reported depression, use of antidepressants and having a high MDI-score were significantly associated with mortality from all, natural and unnatural causes. The associations were of a similar magnitude for the register-based measure of depression and for the survey-based measures reflecting past depression, but the strongest association was found for current depression as assessed by the MDI score. LIMITATIONS: The study population consists almost exclusively of white men and the findings may not be generalizable to female populations or other races and ethnicities. CONCLUSIONS: Physicians should be aware of male patients with a history of depression from hospital records or self-reported as they have higher mortality risk years after their first symptom. PMID- 28024222 TI - Effects of prenatal childbirth education for partners of pregnant women on paternal postnatal mental health and couple relationship: A systematic review. AB - BACKGROUND: Partner education during pregnancy may be able to prevent postnatal mental health problems, and support expectant fathers in their transition to parenthood. The aim of this systematic review is to investigate the effects of prenatal childbirth education among partners of pregnant women, particularly regarding paternal postnatal mental health and couple relationship. METHODS: We searched Medline, CINAHL, EMBASE, PsycINFO, ERIC, and CENTRAL using terms such as "partners of pregnant women," "education," and "prenatal support." Searches were limited to randomized trials. RESULTS: We included 11 trials out of 13 reports that addressed the following topics: childbirth preparation, couple relationship, infants and parenting, postpartum psychosocial issues, and housework sharing. Overall risk of bias was low or unclear. Study outcomes, including parents' mental health (e.g., anxiety, depression, distress), couple relationship, parents' transition adjustment and parenting stress, and parents' satisfaction with their experience of childbirth and prenatal childbirth education programs were reported. LIMITATIONS: The studies included in this review were very diverse regarding intervention intensity and content, outcome types, measurement tools, and outcome timing. This impeded evaluation of the interventions' effectiveness. CONCLUSION: No sufficient evidence was identified that prenatal childbirth education for partners of pregnant women protects against paternal postnatal depression and couple relationship; however, paternal postnatal mental health is important to maternal and perinatal healthcare. The results of this review suggest that further research and intervention are required to provide partners of pregnant women with evidence-based information and support whole families during the perinatal period. PMID- 28024223 TI - Relationships between self-reported childhood traumatic experiences, attachment style, neuroticism and features of borderline personality disorders in patients with mood disorders. AB - BACKGROUND: Co-occurring borderline personality disorder (BPD) features have a marked impact on treatment of patients with mood disorders. Overall, high neuroticism, childhood traumatic experiences (TEs) and insecure attachment are plausible aetiological factors for BPD. However, their relationship with BPD features specifically among patients with mood disorders remains unclear. We investigated these relationships among unipolar and bipolar mood disorder patients. METHODS: As part of the Helsinki University Psychiatric Consortium study, the McLean Screening Instrument (MSI), the Experiences in Close Relationships-Revised (ECR-R), the Short Five (S5) and the Trauma and Distress Scale (TADS) were filled in by patients with mood disorders (n=282) in psychiatric care. Correlation coefficients between total scores of scales and their dimensions were estimated, and multivariate regression (MRA) and mediation analyses were conducted. RESULTS: Spearman's correlations were strong (rho=0.58; p<0.001) between total scores of MSI and S5 Neuroticism and moderate (rho=0.42; p<0.001) between MSI and TADS as well as between MSI and ECR-R Attachment Anxiety. In MRA, young age, S5 Neuroticism and TADS predicted scores of MSI (p<0.001). ECR-R Attachment Anxiety mediated 33% (CI=17-53%) of the relationships between TADS and MSI. LIMITATIONS: Cross-sectional questionnaire study. CONCLUSIONS: We found moderately strong correlations between self-reported BPD features and concurrent high neuroticism, reported childhood traumatic experiences and Attachment Anxiety also among patients with mood disorders. Independent predictors for BPD features include young age, frequency of childhood traumatic experiences and high neuroticism. Insecure attachment may partially mediate the relationship between childhood traumatic experiences and borderline features among mood disorder patients. PMID- 28024224 TI - Facial emotion recognition, theory of mind and the role of facial mimicry in depression. AB - BACKGROUND: This study examined whether acutely (aMDD) and remitted depressed patients (rMDD) show deficits in the two aspects of social cognition - facial emotion recognition (FER) and reasoning - when using ecologically valid material. Furthermore, we examined whether reduced facial mimicry mediates the association between depressive symptoms and FER, and whether FER deficits and reasoning deficits are associated. METHOD: In 42 aMDD, 43 rMDD, and 39 healthy controls (HC) FER was assessed using stimuli from the Amsterdam Dynamic Facial Expression Set, reasoning by the Movie for the Assessment of Social Cognition. Furthermore, the activity of Zygomaticus Major and Corrugator supercilii were recorded. RESULTS: aMDD recognized happy faces less accurately, were less confident recognizing happiness and anger and found it more difficult to recognize happiness, anger and fear than HC. rMDD were less confident recognizing anger and found it more difficult to recognize happiness, anger and fear than HC. Reduced mimicry did not explain FER deficits. aMDD but not rMDD showed impaired reasoning. LIMITATIONS: The stimulus material was comparably easy to decode. Therefore, it is possible that the FER deficits of aMDD and rMDD patients are more pronounced than demonstrated in this study. CONCLUSIONS: aMDD show deficits in FER and reasoning, whereas rMDD only show mild impairments in the recognition of emotional expressions. There must be other processes - besides mimicry - that serve the accurate recognition of emotional facial expressions. PMID- 28024225 TI - Evolutionary dynamic of antigenic residues on influenza B hemagglutinin. AB - Hemagglutinin (HA) of seasonal influenza virus evolves under positive selection pressure exerted by host immunity. It was previously shown that antigenic drift in different influenza B sublineages during different time periods distributed unevenly among different epitopes, and that more recent viruses up to 2007 might have their antigenic drift more focused on certain epitope. We further analyzed whether more recent influenza B viruses up to 2016 followed that same pattern of antigenic evolution. By using Shannon entropy and relative entropy to characterize HA antigenic epitopes, the most recent viruses of both Victoria and Yamagata lineages had residues with high relative entropy located most frequently on the 120-loop region. In addition to residues in the known epitopes, possible antigenic residues were also identified outside of the known epitope regions. The data provide an insight into the antigenic evolution of current influenza B viruses and expand our knowledge on their antigenic sites. PMID- 28024226 TI - PCB concentrations in women based on breastfeeding history: NHANES 2001-2004. AB - Data from the 2001-2004 National Health and Nutrition Examination Survey (NHANES) were used to evaluate serum concentrations of polychlorinated biphenyls (PCBs) in women of reproductive age, with or without a history of breastfeeding. Analytical data for PCBs 138, 153, and 180 were used along with responses to the NHANES Reproductive Health questions: [Have you] breastfed any of your children? " and "[What] number of children [have been] breastfed [for] at least 1 month? " PCB concentrations were found to be significantly lower among 15-44 year old women who had a history of breastfeeding compared to those who had not breastfed any of their children. Based on data for 474 women, ages 15-44 years, mean serum PCB 138, 153, and 180 concentrations were 16.4, 21.4, and 14.3ng/g lipid for women who have a history of breastfeeding, and 24.0, 30.0, and 21.4ng/g lipid for women who have not breastfed, respectively. These results were weighted using the 2001 2004 sample weights provided by NHANES to represent over 27 million U.S. women. PCB concentrations were also lower among women who had breastfed multiple children. Mean serum PCB 138, 153, and 180 concentrations were 11.8, 15.2, and 10.1ng/g lipid, respectively, for women 35-44 years who had breastfed six children and 22.7, 31.9, and 22.5ng/g lipid, respectively, for women 35-44 years who had breastfed only one child. The results tend to support the long-standing hypothesis that depuration of PCBs may occur via breastfeeding. PMID- 28024227 TI - The role of outdoor fungi on asthma hospital admissions in children and adolescents: A 5-year time stratified case-crossover analysis. AB - BACKGROUND: Some fungal spores can trigger asthma exacerbation but knowledge of which outdoor fungal spores contribute to asthma hospitalisation is limited. OBJECTIVES: To examine the role of outdoor fungal spores in child and adolescent asthma hospitalisations. METHODS: We conducted a bi-directional time-stratified case-crossover study of child and adolescent asthma hospitalisations over 5 years. Conditional logistic regression assessed the role of 20 fungi taxa (Same day [L0] and lagged [L1-3]) adjusted for maximum temperature, humidity and grass pollen. Strata specific effects were explored if there was evidence of effect modification by age, sex, air pollutants or grass pollen. Non-linear effects examined with Generalized Additive Models. RESULTS: Of 2098 children hospitalised for asthma, 60% were boys; mean age was 5.5+/-3.7 years. Fungal spore counts peaked during warm months. Regression models found weak associations with Coprinus [L0,L1: OR=1.03, 1.01-1.06], Periconia [L0: OR=1.03, 1.001-1.07] and Chaetomium [L2: OR=1.08, 1.0-1.2]. Sex appeared to act as an effect modifier with girls having stronger associations with Cladosporium, Coprinus and total fungi. Older adolescent (14-18 years) hospitalisation was significantly associated with Coprinus and Ustilago/smuts. Air pollutants and grass pollen did not appear to act as effect modifiers. Non-linearity was not detected. CONCLUSION: There may be associations between some outdoor fungal spores and asthma hospitalisations. Further research needed to explore whether these findings can be replicated; and examine whether fungal sensitisation and/or human rhinovirus infections are associated with stronger effects. If findings are replicated, then the need to develop predictive models for fungal spore distribution and levels may become more important. PMID- 28024228 TI - Vector-field statistics for the analysis of time varying clinical gait data. AB - BACKGROUND: In clinical settings, the time varying analysis of gait data relies heavily on the experience of the individual(s) assessing these biological signals. Though three dimensional kinematics are recognised as time varying waveforms (1D), exploratory statistical analysis of these data are commonly carried out with multiple discrete or 0D dependent variables. In the absence of an a priori 0D hypothesis, clinicians are at risk of making type I and II errors in their analyis of time varying gait signatures in the event statistics are used in concert with prefered subjective clinical assesment methods. The aim of this communication was to determine if vector field waveform statistics were capable of providing quantitative corroboration to practically significant differences in time varying gait signatures as determined by two clinically trained gait experts. METHODS: The case study was a left hemiplegic Cerebral Palsy (GMFCS I) gait patient following a botulinum toxin (BoNT-A) injection to their left gastrocnemius muscle. FINDINGS: When comparing subjective clinical gait assessments between two testers, they were in agreement with each other for 61% of the joint degrees of freedom and phases of motion analysed. For tester 1 and tester 2, they were in agreement with the vector-field analysis for 78% and 53% of the kinematic variables analysed. When the subjective analyses of tester 1 and tester 2 were pooled together and then compared to the vector-field analysis, they were in agreement for 83% of the time varying kinematic variables analysed. INTERPRETATION: These outcomes demonstrate that in principle, vector-field statistics corroborates with what a team of clinical gait experts would classify as practically meaningful pre- versus post time varying kinematic differences. The potential for vector-field statistics to be used as a useful clinical tool for the objective analysis of time varying clinical gait data is established. Future research is recommended to assess the usefulness of vector-field analyses during the clinical decision making process. PMID- 28024229 TI - Use of social network analysis in maternity care to identify the profession most suited for case manager role. AB - OBJECTIVE: To improve Dutch maternity care, professionals start working in interdisciplinary patient-centred networks, which includes the patients as a member. The introduction of the case manager is expected to work positively on both the individual and the network level. However, case management is new in Dutch maternity care. The present study aims to define the profession that would be most suitable to fulfil the role of case manager. DESIGN: The maternal care network in the Nijmegen region was determined by using Social Network Analysis (SNA). SNA is a quantitative methodology that measures and analyses patient related connections between different professionals working in a network. To identify the case manager we focused on the position, reach, and connections in the network of the maternal care professionals. SETTING: Maternity healthcare professionals in a single region of the Netherlands with an average of 4,500 births/year. PARTICIPANTS: The participants were 214 individual healthcare workers from eight different professions. MEASUREMENTS AND FINDINGS: The total network showed 3948 connections between 214 maternity healthcare professionals with a density of 0.08. Each profession had some central individuals in the network. The 52 community-based midwives were responsible for 51% of all measured connections. The youth health doctors and nurses were mostly situated on the periphery and less connected. The betweenness centrality had the highest score in obstetricians and community-based midwives. Only the community-based midwives had connections with all other groups of professions. Almost all professionals in the network could reach other professionals in two steps. PMID- 28024230 TI - In silico study of porphyrin-anthraquinone hybrids as CDK2 inhibitor. AB - Cyclin-Dependent Kinases (CDKs) are known to play crucial roles in controlling cell cycle progression of eukaryotic cell and inhibition of their activity has long been considered as potential strategy in anti-cancer drug research. In the present work, a series of porphyrin-anthraquinone hybrids bearing meso substituents, i.e. either pyridine or pyrazole rings were designed and computationally evaluated for their Cyclin Dependent Kinase-2 (CDK2) inhibitory activity using molecular docking, molecular dynamics simulation, and binding free energy calculation. The molecular docking simulation revealed that all six porphyrin hybrids were able to bind to ATP-binding site of CDK2 and interacted with key residues constituted the active cavity of CDK2, while molecular dynamics simulation indicated that all porphyrins bound to CDK2 were stable for 6ns. The binding free energies predicted by MM-PBSA method showed that most compounds exhibited higher affinity than that of native ligand (4-anilinoquinazoline, DTQ) and the affinity of mono-H2PyP-AQ was about three times better than that of DTQ, indicating its potential to be advanced as a new CDK2 inhibitor. PMID- 28024231 TI - Fabrication of injectable high strength hydrogel based on 4-arm star PEG for cartilage tissue engineering. AB - Hydrogels prepared from poly(ethylene glycol) (PEG) are widely applied in tissue engineering, especially those derived from a combination of functional multi-arm star PEG and linear crosslinker, with an expectation to form a structurally ideal network. However, the poor mechanical strength still renders their further applications. Here we examined the relationship between the dynamics of the pre gel solution and the mechanical property of the resultant hydrogel in a system consisting of 4-arm star PEG functionalized with vinyl sulfone and short dithiol crosslinker. A method to prepare mechanically strong hydrogel for cartilage tissue engineering is proposed. It is found that when gelation takes place at the overlap concentration, at which a slow relaxation mode just appears in dynamic light scattering (DLS), the resultant hydrogel has a local maximum compressive strength ~20 MPa, while still keeps ultralow mass concentration and Young's modulus. Chondrocyte-laden hydrogel constructed under this condition was transplanted into the subcutaneous pocket and an osteochondral defect model in SCID mice. The in vivo results show that chondrocytes can proliferate and maintain their phenotypes in the hydrogel, with the production of abundant extracellular matrix (ECM) components, formation of typical chondrocyte lacunae structure and increase in Young's modulus over 12 weeks, as indicated by histological, immunohistochemistry, gene expression analyses and mechanical test. Moreover, newly formed hyaline cartilage was observed to be integrated with the host articular cartilage tissue in the defects injected with chondrocytes/hydrogel constructs. The results suggest that this hydrogel is a promising candidate scaffold for cartilage tissue engineering. PMID- 28024232 TI - Genetically engineered and self-assembled oncolytic protein nanoparticles for targeted cancer therapy. AB - The integration of a targeted delivery with a tumour-selective agent has been considered an ideal platform for achieving high therapeutic efficacy and negligible side effects in cancer therapy. Here, we present engineered protein nanoparticles comprising a tumour-selective oncolytic protein and a targeting moiety as a new format for the targeted cancer therapy. Apoptin from chicken anaemia virus (CAV) was used as a tumour-selective apoptotic protein. An EGFR specific repebody, which is composed of LRR (Leucine-rich repeat) modules, was employed to play a dual role as a tumour-targeting moiety and a fusion partner for producing apoptin nanoparticles in E. coli, respectively. The repebody was genetically fused to apoptin, and the resulting fusion protein was shown to self assemble into supramolecular repebody-apoptin nanoparticles with high homogeneity and stability as a soluble form when expressed in E. coli. The repebody-apoptin nanoparticles showed a remarkable anti-tumour activity with negligible side effects in xenograft mice through a cooperative action of the two protein components with distinct functional roles. The repebody-apoptin nanoparticles can be developed as a systemic injectable and tumour-selective therapeutic protein for targeted cancer treatment. PMID- 28024233 TI - A critical review of social and health inequalities in the nursing curriculum. AB - CONTEXT: Social and health inequalities are a reality around the world and one of the most important challenges in the current age. Nurse educators can respond to these challenges by incorporating curricular components to identify and intervene in social and health inequalities. OBJECTIVE: To examine how social and health inequalities have been addressed in the nursing curriculum. DESIGN: Informed by the work of Paulo Freire, a critical literature review was performed to examine how social and health inequalities have been addressed in the nursing curriculum. DATA SOURCES AND REVIEW METHODS: In July 2015, we searched for articles published from 2000 to 2015 in ERIC, CINAHL, Web of Science, Scielo, MEDLINE and LILACS databases. Main search terms included "disparity" or "inequality" and "curriculum" and "nursing." We included studies published in academic journals in English, Portuguese and Spanish. RESULTS: A total of 20 articles were included in this review. Most of the articles (15) were from the United States and described educational experiences in implementing courses in nursing undergraduate curricula. Limited experiences with graduate nursing education were identified. Social and health inequalities were approached in these articles through elements such as social justice, cultural competence, cultural safety, and advocacy. A concern to reduce social and health disparities was noted. We identified three major themes in the articles included in this review: 1) elements in the curricula that can contribute to reducing social and health inequalities; 2) educational and research strategies used to address the theme of inequalities; 3) a focus on socially vulnerable populations to increase awareness on social and health inequalities. CONCLUSION: Findings suggest that nursing education initiatives align with the recommendations from the World Health Organization to address disparities. There is also a need to identify existing conceptual and practical content on inequalities in the nursing curriculum through future research. PMID- 28024234 TI - The hidden curriculum in near-peer learning: An exploratory qualitative study. AB - BACKGROUND: Near-peer learning involving students from the same course, but at different levels, has gained prominence in health professional education over recent years. At the authors' university, nursing and paramedic students engage in near-peer learning in clinical skills laboratories where junior students learn specific skills from senior students. Our observations indicated that beyond the skills teaching, unintended learning occurred repeatedly. OBJECTIVES: The aim of this study was to examine near-peer learner and teacher experiences of participating in near-peer learning and to explore students' engagement beyond the skill being learnt. METHODS: Separate focus group interviews were conducted with groups of peer learners and peer teachers from nursing and paramedics following near-peer teaching and learning sessions. In total, 26 students participated in one of four audio-recorded focus groups. RESULTS: Data were analysed thematically. A range of unintended learning experiences became evident, indicating the operation of hidden curriculum additional to that intended within the formal curriculum. Four main areas emerged and were focussed on junior students: identifying with their peers, the course and related expectations, clinical placements and managing difficult situations. CONCLUSIONS: Near-peer learning and teaching has been reported as having a range of positive outcomes, particularly for those engaged in the teaching. However, this study has highlighted that can also provide a range of benefits unique to junior students. More research is warranted to further examine this phenomena and ways to harness and extend such learning opportunities, as well as the nature of social and cognitive congruence. PMID- 28024235 TI - Implications of terminal oxidase function in regulation of salicylic acid on soybean seedling photosynthetic performance under water stress. AB - The aim of this study is to investigate whether exogenous application of salicylic acid (SA) could modulate the photosynthetic capacity of soybean seedlings in water stress tolerance, and to clarify the potential functions of terminal oxidase (plastid terminal oxidase (PTOX) and alternative oxidase (AOX)) in SA' s regulation on photosynthesis. The effects of SA and water stress on gas exchange, pigment contents, chlorophyll fluorescence, enzymes (guaiacol peroxidase (POD; EC 1.11.1.7), superoxide dismutase (SOD; EC 1.15.1.1), catalase (CAT; EC 1.11.1.6), ascorbate peroxidase (APX; EC 1.11.1.11) and NADP-malate dehydrogenase (NADP-MDH; EC1.1.1.82)) activity and transcript levels of PTOX, AOX1, AOX2a, AOX2b were examined in a hydroponic cultivation system. Results indicate that water stress significantly decreased the photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (E), pigment contents (Chla + b, Chla/b, Car), maximum quantum yield of PSIIphotochemistry (Fv/Fm), efficiency of excitation capture of open PSIIcenter (Fv'/Fm'), quantum efficiency of PSIIphotochemistry (PhiPSII), photochemical quenching (qP), and increased malondialdehyde (MDA) content and the activity of all the enzymes. SA pretreatment led to significant decreases in Ci and MDA content, and increases in Pn, Gs, E, pigment contents, Fv/Fm, Fv'/Fm', PhiPSII, qP, and the activity of all the enzymes. SA treatment and water stress alone significantly up-regulated the expression of PTOX, AOX1 and AOX2b. SA pretreatment further increased the transcript levels of PTOX and AOX2b of soybean seedling under water stress. These results indicate that SA application alleviates the water stress-induced decrease in photosynthesis may mainly through maintaining a lower reactive oxygen species (ROS) level, a greater PSIIefficiency, and an enhanced alternative respiration and chlororespiration. PTOX and AOX may play important roles in SA-mediated resistance to water stress. PMID- 28024236 TI - Cerebral blood flow and its connectivity features of auditory verbal hallucinations in schizophrenia: A perfusion study. AB - The goal of the study was to investigate cerebral blood flow (CBF) and its connectivity (an across-subject covariance measure) patterns of schizophrenia (SZ) patients with auditory verbal hallucinations (AVHs). A total of demographically matched 25 SZ patients with AVHs, 25 without AVHs, and 25 healthy controls (HCs) underwent resting state perfusion imaging using a pulsed arterial spin labeling sequence. CBF and its connectivity were analyzed and then CBF topological properties were calculated. AVHs patients exhibited decreased CBF in the bilateral superior and middle frontal gyri and postcentral gyri, and right supplementary motor area compared with SZ patients without AVHs. SZ patients without AVHs showed reduced CBF in the left middle frontal gyrus relative to HCs. Moreover, AVHs groups showed distinct connectivity pattern, an intermediate level between HCs and patients without AVHs in the global efficiency. Our study demonstrates aberrant CBF in the brain regions associated with inner speech monitoring and language processing in SZ patients with AVHs. The complex network measures showed by CBF-derived functional connectivity indicate dysconnectivity between different functional units within the network of AVHs in SZ. Our findings might shed light on the neural underpinnings behind AVHs in this devastating disease at the level of CBF and its connectivity. PMID- 28024237 TI - Concurrent beta-thalassaemia trait and Southeast Asian ovalocytosis associated with clinically significant iron loading. PMID- 28024238 TI - Forensic application of phylogenetic analyses - Exploration of suspected HIV-1 transmission case. AB - Transmission of human immunodeficiency virus (HIV) between individuals may have important legal implications and therefore may come to require forensic investigation based upon phylogenetic analysis. In criminal trials results of phylogenetic analyses have been used as evidence of responsibility for HIV transmission. In Serbia, as in many countries worldwide, exposure and deliberate transmission of HIV are criminalized. We present the results of applying state of the art phylogenetic analyses, based on pol and env genetic sequences, in exploration of suspected HIV transmission among three subjects: a man and two women, with presumed assumption of transmission direction from one woman to a man. Phylogenetic methods included relevant neighbor-joining (NJ), maximum likelihood (ML) and Bayesian methods of phylogenetic trees reconstruction and hypothesis testing, that has been shown to be the most sensitive for the reconstruction of epidemiological links mostly from sexually infected individuals. End-point limiting-dilution PCR (EPLD-PCR) assay, generating the minimum of 10 sequences per genetic region per subject, was performed to assess HIV quasispecies distribution and to explore the direction of HIV transmission between three subjects. Phylogenetic analysis revealed that the viral sequences from the three subjects were more genetically related to each other than to other strains circulating in the same area with the similar epidemiological profile, forming strongly supported transmission chain, which could be in favour of a priori hypothesis of one of the women infecting the man. However, in the EPLD based phylogenetic trees for both pol and env genetic region, viral sequences of one subject (man) were paraphyletic to those of two other subjects (women), implying the direction of transmission opposite to the a priori assumption. The dated tree in our analysis confirmed the clustering pattern of query sequences. Still, in the context of unsampled sequences and inherent limitations of the applied methods, we cannot unambiguously prove that HIV-1 transmission occurred directly between two individuals. Further exploration of the known and suspected transmission cases is needed in order to define methodologies and establish their reliability. PMID- 28024239 TI - Hospitals as complex adaptive systems: A case study of factors influencing priority setting practices at the hospital level in Kenya. AB - There is a dearth of literature on priority setting and resource allocation (PSRA) practices in hospitals, particularly in low and middle income countries (LMICs). Using a case study approach, we examined PSRA practices in 2 public hospitals in coastal Kenya. We collected data through a combination of in-depth interviews of national level policy makers, hospital managers, and frontline practitioners in the case study hospitals (n = 72), review of documents such as hospital plans and budgets, minutes of meetings and accounting records, and non participant observations of PSRA practices in case study hospitals over a period of 7 months. In this paper, we apply complex adaptive system (CAS) theory to examine the factors that influence PSRA practices. We found that PSRA practices in the case hospitals were influenced by, 1) inadequate financing level and poorly designed financing arrangements, 2) limited hospital autonomy and decision space, and 3) inadequate management and leadership capacity in the hospital. The case study hospitals exhibited properties of complex adaptive systems (CASs) that exist in a dynamic state with multiple interacting agents. Weaknesses in system 'hardware' (resource scarcity) and 'software' (including PSRA guidelines that reduced hospitals decision space, and poor leadership skills) led to the emergence of undesired properties. The capacity of hospitals to set priorities should be improved across these interacting aspects of the hospital organizational system. Interventions should however recognize that hospitals are CAS. Rather than rectifying isolated aspects of the system, they should endeavor to create conditions for productive emergence. PMID- 28024240 TI - Governance of global health research consortia: Sharing sovereignty and resources within Future Health Systems. AB - Global health research partnerships are increasingly taking the form of consortia that conduct programs of research in low and middle-income countries (LMICs). An ethical framework has been developed that describes how the governance of consortia comprised of institutions from high-income countries and LMICs should be structured to promote health equity. It encompasses initial guidance for sharing sovereignty in consortia decision-making and sharing consortia resources. This paper describes a first effort to examine whether and how consortia can uphold that guidance. Case study research was undertaken with the Future Health Systems consortium, performs research to improve health service delivery for the poor in Bangladesh, China, India, and Uganda. Data were thematically analysed and revealed that proposed ethical requirements for sharing sovereignty and sharing resources are largely upheld by Future Health Systems. Facilitating factors included having a decentralised governance model, LMIC partners with good research capacity, and firm budgets. Higher labour costs in the US and UK and the funder's policy of allocating funds to consortia on a reimbursement basis prevented full alignment with guidance on sharing resources. The lessons described in this paper can assist other consortia to more systematically link their governance policy and practice to the promotion of health equity. PMID- 28024241 TI - What caused the 2012 dengue outbreak in Pucallpa, Peru? A socio-ecological autopsy. AB - Dengue is highly endemic in Peru, with increases in transmission particularly since vector re-infestation of the country in the 1980s. Pucallpa, the second largest city in the Peruvian Amazon, experienced a large outbreak in 2012 that caused more than 10,000 cases and 13 deaths. To date, there has been limited research on dengue in the Peruvian Amazon outside of Iquitos, and no published review or critical analysis of the 2012 Pucallpa dengue outbreak. This study describes the incidence, surveillance, and control of dengue in Ucayali to understand the factors that contributed to the 2012 Pucallpa outbreak. We employed a socio-ecological autopsy approach to consider distal and proximal contributing factors, drawing on existing literature and interviews with key personnel involved in dengue control, surveillance and treatment in Ucayali. Spatio-temporal analysis showed that relative risk of dengue was higher in the northern districts of Calleria (RR = 2.18), Manantay (RR = 1.49) and Yarinacocha (RR = 1.25) compared to all other districts between 2004 and 2014. The seasonal occurrence of the 2012 outbreak is consistent with typical seasonal patterns for dengue incidence in the region. Our assessment suggests that the outbreak was proximally triggered by the introduction of a new virus serotype (DENV-2 Asian/America) to the region. Increased travel, rapid urbanization, and inadequate water management facilitated the potential for virus spread and transmission, both within Pucallpa and regionally. These triggers occurred within the context of failures in surveillance and control programming, including underfunded and ad hoc vector control. These findings have implications for future prevention and control of dengue in Ucayali as new diseases such as chikungunya and Zika threaten the region. PMID- 28024242 TI - Aneugenicity and clastogenicity in freshwater fish Oreochromis niloticus exposed to incipient safe concentration of tannery effluent. AB - Conventional effluent bioassays mostly rely on overt responses or endpoints such as apical and Darwinian fitness. Beyond the empirical observation, laboratory toxicity testing needs to rely on effective detection of prognostic biomarkers such as genotoxicity. Indeed, characterization of tannery effluent requires slotting in of genotoxic responses in whole effluent toxicity testing procedures. Hence, the prime objective of the present experimental investigation is to apply the technique of biological assay as a tool of toxicity testing to evaluate the induction of micronuclei (MN) in peripheral erythrocytes, and exfoliated cells of gill and kidney of O.niloticus exposed to Maximum tolerable concentrations (MTCs) of composite Modjo tannery effluent (CMTE) and to compare the sensitivity of each cells origin to the induction of MN. After 72h of exposure, cellular aberrations were detected using MN and nuclear abnormality (NA) tests. The induction of MN was significantly higher in exposed groups (P<0.05) when compared to the control group; moreover the tissue specific MN response was in the order, gill cells>peripheral erythrocyte>kidney. Total NA was found to increase significantly (P<0.05), when compared to the non-exposed group. NA was also further ramified as blebbed (BL), bi-nucleated (BN), lobbed (LB) and notched (NT) abnormalities. The result of each endpoint measured has demonstrated that at a concentration of total chromium (0.1, 0.73 and 1.27mg/L), a perceptible amount cellular aberration was measured, further implicating somber treat of genotoxicity to fishes, if exposed to water contaminated with tannery effluent. This further highlight that conventional effluent monitoring alone cannot reveal the effects expressed at cellular and genetic levels further demanding the incorporation of effluent bioassays in risk assessment and risk management/abatement programs. PMID- 28024243 TI - Extinction, emission, and scattering spectroscopy of 5-50 nm citrate-coated gold nanoparticles: An argument for curvature effects on aggregation. AB - The interaction of macromolecules with gold nanoparticles (GNPs) is of interest in the emerging field of biomedical and environmental detection devices. However, the physicochemical properties, including spectra, of GNPs in aqueous solution in the absence of metal-macromolecular interactions must first be considered before their activity in biological and environmental systems can be understood. The specific objective of this research was to experimentally illuminate the role of nanoparticle core size on the spectral (simultaneous consideration of extinction, emission, and scattering) versus aggregation behaviors of citrate-coated GNPs (CT GNPs). It is difficult to find in the literature systematic simultaneous presentation of scattering, emission, and extinction spectra, including the UV range, and thus the present work will aid those who would use such particles for spectroscopic related separations or sensors. The spectroscopic behavior of CT GNPs with different core sizes (5, 10, 30, and 50nm) was studied in ultra-pure water at pH6.0-6.5 employing UV-visible extinction, excitation-emission matrix (EEM), resonance Rayleigh scattering, and dynamic light scattering (DLS) spectroscopies. The CT-GNP-5 and CT-GNP-10 samples aggregated, absorbed light, and emitted light. In contrast, the CT-GNP-30 and CT-GNP-50 samples did not aggregate and did not emit light, but scattered light intensely. Multimodal peaks were observed in the intensity-based DLS spectra of CT-GNP-5 and CT-GNP-10 samples. Monomodal peaks in the volume-based DLS spectra overestimated particle diameters by 60% and 30% for the CT-GNP-5 and CT-GNP-10 samples, respectively, but underestimated diameters by 10% and 4% for the CT-GNP-30 and CT-GNP-50 samples. The volume-based DLS spectra indicated that dimer and trimer aggregates contributed most to the overall volume of particles in the 5- and 10-nm CT-GNPs, whereas the CT-GNP-30 and CT-GNP-50 samples did not aggregate. Here, we discuss the potential influence that differences in preparation, ionic strength, zeta potential, and conformation of adsorbed citrate anions (due to surface curvature of corona) may exert on the aggregation and spectral observations in these data. In particular, the severe surface curvature of the 5- and 10-nm GNP corona may affect the efficiency of the di-/tribasic citrate compatiblizer molecule to shield the core from interactions with light and from GNP-GNP homoaggregation. PMID- 28024244 TI - Effect of Zinc oxide nanoparticle on Fluorescence Resonance Energy transfer between Fluorescein and Rhodamine 6G. AB - Fluorescence Resonance Energy Transfer between two dyes Fluorescein and Rhodamine 6G were investigated in solution in the presence and absence of Zinc oxide nanoparticle. Zinc oxide nanostructure is used as the fluorescence enhancing agent for the present study since donor (Fluorescein) fluorescence increase significantly in presence of nanoparticle. Accordingly, the energy transfer efficiency in the presence of nanoparticle increases. The maximum efficiency was 69% for acceptor (Rhodamine 6G) concentration of 0.75*10-5M. The energy transfer efficiency was found to be pH sensitive and it varies from 4.15% to 90.00% in mixed dye solution for a change in pH from 1.5 to 10.0. With proper calibration it is possible to use the present system under investigation to sense pH which is better with respect to our previous reported results [Spectrochim. Acta Part A. 149 (2015) 143-149] as it can sense a wide range of pH and with better sensitivity. PMID- 28024245 TI - Phenazine-based colorimetric and fluorescent sensor for the selective detection of cyanides based on supramolecular self-assembly in aqueous solution. AB - Taking advantages of both the well-known phenazine structure and the mechanism of the supramolecular self-assembly and deprotonation process, the fluorescent and colorimetric sensor (ZL) was designed and synthesized, behaving as a circulation utilization (above 10 times) receptor for selective detection of cyanide anion (CN-) in aqueous media. Upon the addition of CN-, the sensor displayed obvious color changes from yellow to jacinth by naked eyes and the fluorescence immediately quenched (<10s). With respect to other common anions, the sensor possessed high selectivity and sensitivity (0.05MUM) for cyanide anions. In addition, the test strips of ZL were fabricated, which could serve as practical colorimetric and fluorescent sensor for "in-the-field" measurements. PMID- 28024246 TI - A new unsymmetrical azine derivative based on coumarin group as dual-modal sensor for CN- and fluorescent "OFF-ON" for Zn2. AB - A simple chemosensor YS based on coumarin group was designed and synthesized. Its structure was determined by single crystal X-ray diffraction analysis. In the presence of cyanide the sensor showed an immediate visible change in color from colorless to pale yellow by naked-eyes and produced a strong blue fluorescence rapidly in DMSO/H2O (3:7, v/v). The detection limit on fluorescence response of the sensor to CN- is down to 1.69*10-7M. In addition YS could show fluorescence turn-on response rapidly for Zn2+ over other metals ions such as Fe3+, Hg2+, Ag+, Ca2+, Cu2+, Co2+, Ni2+, Cd2+, Pb2+, Cr3+ and Mg2+ in aqueous solutions. Notably, this sensor served as a molecular switch, which was controlled by Zn2+ and EDTA cyclically. Test strips based on YS were fabricated, which could act as a convenient and efficient CN- and Zn2+ test kit. This chemosensor could achieve the detection of two ions, which need not depend on two different sensors. PMID- 28024247 TI - Noncovalent interactions from electron density topology and solvent effects on spectral properties of Schiff bases. AB - Two Schiff bases were prepared by the condensation of o-allyl substituted 2,4 dihydroxy acetophenone with 1,2-diaminopropane (L1) and ethanediamine (L2) and characterized by elemental analysis, and ESI-MS, IR, UV-Vis, 1H and 13C NMR spectral techniques. The effect of solvents with respect to different polarities on UV-Vis and emission spectra of L1 and L2 was investigated at room temperature show that the compounds exist in keto and enol forms in solution and may be attributed to the intramolecular proton transfer in the ground state. The solute solvent interactions, change in dipole moment and solvatochromic properties of the compounds were studied based on the solvent polarity parameters. For L1 and L2, the ground and excited state electronic structure calculations were carried out by DFT and TD-DFT at B3LYP/6-311G (d,p) level, respectively. The IR, NMR and electronic absorption spectra computed were compared with the experimental observations. The intramolecular charge transfer within the molecule is evidenced from the HOMO and LUMO energy levels and surface analysis. The noncovalent interactions like hydrogen bonding and van der Waals interactions were identified from the molecular geometry and electron localization function. These interactions in molecules have been studied by using reduced density gradient and graphed by Multiwfn. PMID- 28024248 TI - Energy transfer at heterogeneous protein-protein interfaces to investigate the molecular behaviour in the crowding environment. AB - Investigation of the behaviour of proteins in crowded environments is crucial for understanding the role of proteins in biological environments. In this study, the behaviour of bovine serum albumin (BSA) in crowded (highly concentrated) environments was investigated using time-resolved fluorescence spectroscopy as a model system. By using energy transfer as a molecular ruler, the crowding effect was clearly observed in the time resolved spectra. In addition, by using both time resolved anisotropy measurement and Raman spectroscopy, more detail insights from conformational and dynamic points of view were described. Consequently, it was revealed that in the highly concentrated solution, most of the BSA molecules are in the fast-reversible oligomeric state and the association at the "hard" and "soft" interfaces between protein surfaces occurred in a highly crowded environment with the aid of a charge-charge and short-range attractive interface. From both the conformational and dynamic aspects, the detail spectroscopic understanding of the behaviour of BSA in the crowding environment was obtained. PMID- 28024249 TI - Temperature assisted radiative and non-radiative recombination mechanisms in sillimanite (Al2SiO5) mineral. AB - Temperature assisted luminescence in sillimanite (Al2SiO5) mineral was studied using thermoluminescence (TL). TL characteristics were studied in un-annealed and different annealed samples. Analysis showed that in the un-annealed sample, there was four electron trapping sites at depths ~0.56, 0.87, 1.08, 1.32eV and a hole trapping site at depth ~3.63eV from the conduction band acting as a recombination center. Further analysis on the annealed samples showed that the 0.56eV trapping site was a pressure induced surface trap and it disappeared after annealing. However, the other trapping and recombination sites were found to be stable under thermal treatment. Due to this trap distribution, three partially overlapping glow peaks were observed. The glow peaks were found to be affected by thermal quenching. The thermal quenching parameters were evaluated from the composite glow curves by using Computerized Resolved Peak (CRP) technique. The activation energies for thermal quenching (W) estimated from the three peaks were found to be ~0.69+/-0.05, 0.92+/-0.06 and 1.15+/-0.03eV respectively and the pre exponential factors (C) were ~1.12*108, 2.65*1010 and 9.23*1011 respectively. Based on the analysis, a band model was proposed and the whole radiative and non radiative recombination mechanisms were discussed. PMID- 28024250 TI - A novel combined approach of diffuse reflectance UV-Vis-NIR spectroscopy and multivariate analysis for non-destructive examination of blue ballpoint pen inks in forensic application. AB - The present research is focused on the analysis of writing inks using destructive UV-Vis spectroscopy (dissolution of ink by the solvent) and non-destructive diffuse reflectance UV-Vis-NIR spectroscopy along with Chemometrics. Fifty seven samples of blue ballpoint pen inks were analyzed under optimum conditions to determine the differences in spectral features of inks among same and different manufacturers. Normalization was performed on the spectroscopic data before chemometric analysis. Principal Component Analysis (PCA) and K-mean cluster analysis were used on the data to ascertain whether the blue ballpoint pen inks could be differentiated by their UV-Vis/UV-Vis NIR spectra. The discriminating power is calculated by qualitative analysis by the visual comparison of the spectra (absorbance peaks), produced by the destructive and non-destructive methods. In the latter two methods, the pairwise comparison is made by incorporating the clustering method. It is found that chemometric method provides better discriminating power (98.72% and 99.46%, in destructive and non destructive, respectively) in comparison to the qualitative analysis (69.67%). PMID- 28024251 TI - Synthesis, structure, spectral properties and DFT quantum chemical calculations of 4-aminoazobenzene dyes. Effect of intramolecular hydrogen bonding on photoisomerization. AB - In this paper three different "push-pull" 4-aminoazobenzene dyes have been synthesized in order to characterize their photochromic behavior in different solvents. The molecular geometry was optimized by DFT/B3LYP functional combined with the standard 6-31+G(d,p) basis set for trans (E) and cis (Z) isomers and the energy levels of HOMO and LUMO frontier orbitals were computed using IEFPCM solvation in CHCl3 and DMF. The calculated results were compared to the experimental optical band gap and HOMO values of cyclic voltammetry. The intramolecular six-membered hydrogen bond was formed in both isomers of the synthesized dyes. The thermodynamic parameters such as total electronic energy E (RB3LYP), enthalpy H298 (sum of electronic and thermal enthalpies), free Gibbs energy G298 (sum of electronic and thermal free Gibbs energies) and dipole moment MU were computed for trans (E) and cis (Z) isomers in order to estimate the DeltaEtrans->cis, DeltaMUtrans->cis, DeltaHtrans->cis, DeltaGtrans->cis and DeltaStrans->cis values. The NBO analysis was performed in order to understand the intramolecular charge transfer and energy of resonance stabilization. The solvatochromic shift was evaluated by UV-VIS spectroscopy in CHCl3 (nonpolar), EtOH (polar protic) and DMF (polar aprotic) solvents to determine the electron withdrawing and donating properties of the substituents on electron transitions energy. Through the increasing solvent polarity a strong bathochromic shift is observed. The photoisomerization experiments have been performed in two solvents CHCl3 (nonpolar) and DMF (polar aprotic) by UV light irradiation with lambda=365nm at equal concentrations and time of illuminations. The electronic spectra were computed by TD-DFT after geometry optimization using IEFPCM solvation in CHCl3 and DMF. The degree of photoisomerization was calculated for the three azo chromophores in both solvents. By using first derivative of the UV VIS spectra it was possible to resolve the overlapped electron transitions absorption bands. The existing intramolecular hydrogen bond in the azo chromophores was discussed in relation to the isomerization mechanisms and relative stability of the cis (Z) isomers. PMID- 28024252 TI - A series of stilbazolium salts with A-pi-A model and their third-order nonlinear optical response in the near-IR region. AB - A series of water-soluble stilbazolium salts with A-pi-A (A: Acceptor) model have been synthesized and fully characterized. The results obtained from absorption spectra and TD-DFT computational studies show that there is a relative strong intramolecular charge transfer (ICT) transition from pyridine unit to pyridine cation of the stilbazolium salts. Furthermore, it is found that the three stilbazolium salts (T1, T2, T3) show the strong two-photon absorption (2PA) response in the near-infrared (IR) region by Z-scan technique using femtosecond laser. And the stilbazolium salt T3 shows the largest two-photon absorption cross section and third-order nonlinear optical (NLO) coefficient chi(3) at 730nm, indicating the different terminal substituent group of the pyridinium plays a vital role in third-order NLO behavior. PMID- 28024253 TI - Language use statistics and prototypical grapheme colours predict synaesthetes' and non-synaesthetes' word-colour associations. AB - Synaesthesia is the neuropsychological phenomenon in which individuals experience unusual sensory associations, such as experiencing particular colours in response to particular words. While it was once thought the particular pairings between stimuli were arbitrary and idiosyncratic to particular synaesthetes, there is now growing evidence for a systematic psycholinguistic basis to the associations. Here we sought to assess the explanatory value of quantifiable lexical association measures (via latent semantic analysis; LSA) in the pairings observed between words and colours in synaesthesia. To test this, we had synaesthetes report the particular colours they experienced in response to given concept words, and found that language association between the concept and colour words provided highly reliable predictors of the reported pairings. These results provide convergent evidence for a psycholinguistic basis to synaesthesia, but in a novel way, showing that exposure to particular patterns of associations in language can predict the formation of particular synaesthetic lexical-colour associations. Consistent with previous research, the prototypical synaesthetic colour for the first letter of the word also played a role in shaping the colour for the whole word, and this effect also interacted with language association, such that the effect of the colour for the first letter was stronger as the association between the concept word and the colour word in language increased. Moreover, when a group of non-synaesthetes were asked what colours they associated with the concept words, they produced very similar reports to the synaesthetes that were predicted by both language association and prototypical synaesthetic colour for the first letter of the word. This points to a shared linguistic experience generating the associations for both groups. PMID- 28024254 TI - Relation between temporal perception and inhibitory control in the Go/No-Go task. AB - This research was designed to replicate and extend findings concerning bidirectional interference between concurrent timing and inhibition tasks reported previously. Subjects performed serial temporal production and Go/No-Go (GNG) tasks under single-task and dual-task conditions in two experiments. The degree of inhibitory control required in the GNG tasks was manipulated by varying the proportion of go and no-go stimuli (experiment 1) and by instructing subjects to devote different amounts of attention to the dual tasks (experiment 2). The dual-task conditions in both experiments showed a pattern of mutual interference in which each task interfered with the other. In experiment 1, concurrent timing interfered more strongly with performance on a high inhibitory-demand GNG task compared with a low inhibitory-demand GNG task. In experiment 2, concurrent timing and GNG performance displayed a reciprocity effect in which greater attentiveness to one task improved performance for that task but diminished performance for the other task, and vice versa. These results support the view that temporal processing and inhibitory control depend upon a common pool of attentional resources, and point to the GNG task as a reliable research tool for investigators studying the role of attentional processes in time perception. PMID- 28024255 TI - Dual-route imitation in preschool children. AB - Imitation can be realized via two different routes: a direct route that translates visual input into motor output when gestures are meaningless or unknown, and a semantic route for known/meaningful gestures. Young infants show imitative behaviours compatible with the direct route, but little is known about the development of the semantic route, studied here for the first time. The present study examined preschool children (3-5years of age) imitating gestures that could be transitive or intransitive, and meaningful or meaningless. Both routes for imitation were already present by three years of age, and children were more accurate at imitating meaningful-intransitive gestures than meaningless intransitive ones; the reverse pattern was found for transitive gestures. Children preferred to use their dominant hand even if they had to anatomically imitate the model to do this, showing that a preference for specular imitation is not exclusive at these ages. PMID- 28024256 TI - MU-ViP: Customized virtual phantom for quantitative magnetic resonance micro imaging at high magnetic field. AB - The applications of Magnetic Resonance micro-Imaging (MRMUI) cover nowadays a wide range of fields. However few of them present quantitative measurements when the sample of interest changes over time or in case of a long acquisition time. In this domain, two challenges have to be overcome: the introduction of a phantom as a reference signal and the guarantee that this signal is stable over the experiment duration while some conditions such as temperature and/or the moisture are varied. The aim of the present study was to implement a dedicated experimental set-up to generate a virtual phantom (ViP) signal in a vertical-bore 11.7 T NMR spectrometer, equipped with a micro-imaging probe. This study shows that the generation of a micro-imaging-dedicated ViP (MU-ViP) signal is of great benefit for on-line quality control of the spectrometer performance during acquisition in the case of real-time experiments. Thus, MUViP represents a step towards improvement of the magnetic resonance signal quantification in small samples. PMID- 28024257 TI - Evaluation of sandstone surface relaxivity using laser-induced breakdown spectroscopy. AB - Nuclear magnetic resonance (NMR) relaxometry is a common technique used to assess the pore size of fluid-filled porous materials in a wide variety of fields. However, the NMR signal itself only provides a relative distribution of pore size. To calculate an absolute pore size distribution from the NMR data, the material's surface relaxivity needs to be known. Here, a method is presented using laser-induced breakdown spectroscopy (LIBS) to evaluate surface relaxivity in sandstones. NMR transverse and longitudinal relaxation was measured on a set of sandstone samples and the surface relaxivity was calculated from the pore size distribution determined with MICP measurements. Using multivariate analysis, it was determined that the LIBS data can predict with good accuracy the longitudinal (R2~0.84) and transverse (R2~0.79) surface relaxivity. Analysis of the regression coefficients shows significant influence from several elements. Some of these are elements previously established to have an effect on surface relaxivity, such as iron and manganese, while others are not commonly associated with surface relaxivity, such as cobalt and titanium. Furthermore, LIBS provides advantages compared to current methods to calibrate surface relaxivity in terms of speed, portability, and sample size requirements. While this paper focuses on geological samples, the method could potentially be expanded to other types of porous materials. PMID- 28024258 TI - Phase incremented echo train acquisition applied to magnetic resonance pore imaging. AB - Efficient phase cycling schemes remain a challenge for NMR techniques if the pulse sequences involve a large number of rf-pulses. Especially complex is the Carr Purcell Meiboom Gill (CPMG) pulse sequence where the number of rf-pulses can range from hundreds to several thousands. Our recent implementation of Magnetic Resonance Pore Imaging (MRPI) is based on a CPMG rf-pulse sequence in order to refocus the effect of internal gradients inherent in porous media. While the spin dynamics for spin-1/2 systems in CPMG like experiments are well understood it is still not straight forward to separate the desired pathway from the spectrum of unwanted coherence pathways. In this contribution we apply Phase Incremented Echo Train Acquisition (PIETA) to MRPI. We show how PIETA offers a convenient way to implement a working phase cycling scheme and how it allows one to gain deeper insights into the amplitudes of undesired pathways. PMID- 28024259 TI - A novel method for the determination of chemical purity and assay of menaquinone 7. Comparison with the methods from the official USP monograph. AB - An HPLC method with UV detection and separation with the use of a C30 reversed phase analytical column for the determination of chemical purity and assay of menaquinone-7 (MK7) in one chromatographic run was developed. The method is superior to the methods published in the USP Monograph in terms of selectivity, sensitivity and accuracy, as well as time, solvent and sample consumption. The developed methodology was applied to MK7 samples of active pharmaceutical ingredient (API) purity, MK7 samples of lower quality and crude MK7 samples before purification. The comparison of the results revealed that the use of USP methodology could lead to serious overestimation (up to a few percent) of both purity and MK7 assay in menaquinone-7 samples. PMID- 28024260 TI - Structure and pharmaceutical formulation development of a new long-acting recombinant human insulin analog studied by NMR and MS. AB - A monomer structure of a novel human insulin analog A22S-B3K-B31R (SK3R) has been characterized by NMR in water/acetonitrile solution and compared with the structure of human insulin (HIS) established in the same medium. The composition of the oligomer ensemble for neat insulins in water was qualitatively assessed by monitoring, derived from NMR experiment, translational diffusion coefficient Dix10-10m2s-1, whose value is a population averaged of individual coefficients for species in oligomeric ensemble. Nanospray ESI/MS experiment was used to establish the masses of oligomers in pharmaceutical formulation of the SK3R insulin. The pharmacodynamic data were established and compared to insulin glargine characterized by the same profile of action in diabetics. The oligomerization process of insulin during development of pharmaceutical formulation with routinely used excipients has been studied using translation diffusion coefficient Dix10-10m2s-1 established in water solution. These properties were compared with those of human insulin (HIS) which is a standard reference for novel recombinant insulins. PMID- 28024261 TI - Simultaneous HPLC assay for pretomanid (PA-824), moxifloxacin and pyrazinamide in an inhaler formulation for drug-resistant tuberculosis. AB - A simple and sensitive reversed phase HPLC method has been developed for the simultaneous quantitation of pretomanid (PA-824), moxifloxacin and pyrazinamide in a combination spray-dried powder formulation for inhalation, without any use of an internal standard. Good resolution of the analytes was achieved on a Luna C18 (2), 150*4.6mm, 5MUm, 100A column using gradient elution with a mobile phase containing methanol and triethylamine phosphate buffer (pH 2.5) at a flow rate of 1.0mL/min in a total run time of 25min. Pyrazinamide, moxifloxacin and pretomanid (PA-824) were detected at wavelengths (retention times) of 269nm (3.80min), 296nm (7.94min) and 330nm (17.46min), respectively. The assay was linear for all analytes in the concentration range 2.5-100MUg/mL (correlation coefficients >0.999) with LODs and LLOQs (MUg/mL) of pretomanid (PA-824) 0.51 and 1.56, moxifloxacin 0.06 and 0.19 and pyrazinamide 0.35 and 1.06, respectively. Recoveries of the three drugs were 99.6-106.8% with intra- and inter-day precisions (as relative standard deviation) of <7%. The method was successfully applied to an evaluation of content uniformity and freedom from interference by l leucine of a spray-dried combination powder for inhalation. PMID- 28024262 TI - Levothyroxine sodium revisited: A wholistic structural elucidation approach of new impurities via HPLC-HRMS/MS, on-line H/D exchange, NMR spectroscopy and chemical synthesis. AB - The structural elucidation of unknown pharmaceutical impurities plays an important role in the quality control of newly developed and well-established active pharmaceutical ingredients (APIs). The United States Pharmacopeia (USP) monograph for the API Levothyroxine Sodium, a synthetic thyroid hormone, features two high pressure liquid chromatography (HPLC) methods using UV-VIS absorption detection to determine organic impurities in the drug substance. The impurity profile of the first USP method ("Procedure 1") has already been extensively studied, however for the second method ("Procedure 2"), which exhibits a significantly different impurity profile, no wholistic structural elucidation of impurities has been performed yet. Applying minor modifications to the chromatographic parameters of USP "Procedure 2" and using various comprehensive structural elucidation methods such as high resolution tandem mass spectrometry with on-line hydrogen-deuterium (H/D) exchange or two-dimensional nuclear magnetic resonance spectroscopy (NMR) we gained new insights about the complex impurity profile of the synthetic thyroid hormone. This resulted in the characterization of 24 compounds previously unknown to literature and the introduction of two new classes of Levothyroxine Sodium impurities. Five novel compounds were unambiguously identified via isolation or synthesis of reference substances and subsequent NMR spectroscopic investigation. Additionally, Collision-Induced Dissociation (CID)-type fragmentation of identified major impurities as well as neutral loss fragmentation patterns of many characterized impurities were discussed. PMID- 28024263 TI - Improved survival for patients with de novo metastatic prostate cancer in the last 20 years. AB - INTRODUCTION: During recent years, several new life-prolonging therapeutic options have been introduced for patients with metastatic prostate cancer (mPCa). The aim of the present study was to evaluate the changes in the survival of patients diagnosed with mPCa prior to and in the early period of the implementation of these new agents. PATIENTS AND METHODS: The study population consisted of 207 men diagnosed in 1997 and 316 men diagnosed in the period 2007 2013 with de novo mPCa and managed with initial endocrine therapy. Men were followed for overall survival and PCa-specific survival. RESULTS: At the time of diagnosis, men diagnosed in the period 2007-2013 had less co-morbidity, lower prostrate-specific antigen levels and lower clinical tumour categories than men diagnosed in 1997. A significantly higher proportion of men diagnosed in 1997 were managed with surgical castration (57% versus 9%). Only one patient diagnosed in 1997 received second-line therapy compared with 81 men (26%) diagnosed in the period 2007-2013. The median overall survival was significantly longer for men diagnosed between 2007 and 2013 compared with men diagnosed in 1997 (39.4 months versus 24.2 months, p < 0.0001). Likewise, the cumulative incidence of PCa specific death was higher among men diagnosed in 1997 compared with men diagnosed between 2007 and 2013, with 5-year cumulative incidences of 72% and 47%, respectively (p < 0.0001). CONCLUSION: Survival in men diagnosed with metastatic PCa has improved significantly over time. The improved survival can in part be explained by lead-time bias, but also by the introduction of new life-prolonging treatments. PMID- 28024264 TI - Fracture after gastrectomy for gastric cancer: A long-term follow-up observational study. AB - AIM: Gastrectomy is a known risk factor for decreased bone mass. We aimed to evaluate the cumulative incidence and predictive factors of fracture in gastric cancer patients who underwent gastrectomy. METHOD: We retrospectively reviewed the records of 1687 patients who underwent gastrectomy for gastric cancer at our hospital between September 1991 and December 2008. The exclusion criteria were stage IV gastric cancer, history of cancer recurrence, medical conditions that cause osteoporosis and high-energy injury. Fractures at sites considered to be associated with osteoporosis were diagnosed radiologically. RESULTS: In total, our analysis included the records of 1131 patients. The incidence of postgastrectomy fracture was 42.1 cases per 1000 person-years. Fractures typically occurred within 3.7 +/- 0.5 years postoperatively. The cumulative incidence of fracture was 9.1%, 19.7%, and 37.3% by postoperative year 2, 4, and 6, respectively. During the following years, the cumulative incidence increased slowly, up to a final 40.6%. Multivariate analysis showed that older age (hazard ratio, 1.03; 95% confidence interval, 1.01-1.04) and smoking (hazard ratio, 1.35; 95% confidence interval, 1.05-1.73) were significantly associated with fracture, whereas sex, body mass index, percent weight loss, diabetes mellitus, tumour stage, and type of gastrectomy were not. CONCLUSION: The cumulative incidence of fracture is high in gastric cancer patients who have undergone gastrectomy, and fracture rate is higher during the early postoperative period. Old age and smoking are independent risk factors for postgastrectomy fracture in these patients. More detailed postoperative surveillance and pharmacological intervention should be considered to prevent fracture. PMID- 28024265 TI - Structural distress screening and supportive care for patients with lung cancer on systemic therapy: A randomised controlled trial. AB - INTRODUCTION: Gaining regular insight into the nature and severity of distress by a psychosocial nurse coupled with referral to psychosocial and/or paramedical healthcare provider(s) is an experimental supportive care approach. We sought to examine the effects of this approach on quality of life (QoL), patient's mood and satisfaction, end-of-life care and survival in patients with lung cancer. METHODS: Patients with newly diagnosed or recurrent lung cancer starting systemic therapy were randomly assigned to receive usual care or the experimental approach. Patients were followed up at 1, 7, 13 and 25 weeks after randomisation with the EORTC-QLQ-C30, the European Quality of Life-5D, the Hospital Anxiety and Depression Scale and the Patient Satisfaction Questionnaire-III. Primary outcome was the mean change in the EORTC-QLQ-C30 global QoL-score between 1 and 25 weeks. RESULTS: A total of 223 patients were randomised of whom 111 (50%) completed all four assessments (44% in the usual care group versus 55% in the experimental group). No significant difference was found in the mean change global QoL-score ( 2.4, 95% CI: 12.1-7.2; P = 0.61), nor in the other patient-reported outcomes. Fewer patients in the experimental group received chemotherapy shortly before the end-of-life, and median survival was comparable (10.3 versus 10.1 months, P = 0.62). Of the 112 dropouts, 33 died and 79 discontinued participation for other reasons. CONCLUSIONS: This supportive care approach neither improved QoL nor other patient-reported outcomes in patients with lung cancer. However, it reduced the use of chemotherapy shortly before the end of life. Possibly, (late) side effects of systemic therapy may have obscured effects of our intervention on QoL. CLINICAL TRIAL REGISTRATION: NTR3540. PMID- 28024266 TI - The risk of being depressed is significantly higher in cancer patients than in the general population: Prevalence and severity of depressive symptoms across major cancer types. AB - BACKGROUND: Depression is a common co-morbidity of cancer that has a detrimental effect on quality of life, treatment adherence and potentially survival. We conducted an epidemiological multi-center study including a population-based random comparison sample and estimated the prevalence of depressive symptoms by cancer site, thereby identifying cancer patients with the highest prevalence of depression. PATIENTS AND METHODS: We included 4020 adult cancer inpatients and outpatients from five distinct regions across Germany in a proportional stratified random sample based on the nationwide cancer incidence and a comparison group consisting of 5018 participants. Both groups reported depressive symptoms by filling in the Patient Health Questionnaire (PHQ-9). In multivariate analyses adjusted for age and sex, we calculated the odds of being depressed. RESULTS: Out of 5818 eligible patients, 69% participated (51% women, mean age = 58 years). We estimated that one in four cancer patients (24%) is depressed (PHQ 9 >= 10). The odds of being depressed among cancer patients were more than five times higher than in the general population (OR, 5.4; 95% CI, 4.6-6.2). Patients with pancreatic (M = 8.0, SD = 5.0), thyroid (M = 7.8, SD = 6.3) and brain tumours (M = 7.6, SD = 4.9) showed the highest prevalence, whereas patients with prostate cancer (M = 4.3, SD = 3.8) and malignant melanoma (M = 5.3, SD = 4.3) had the lowest levels of depressive symptoms. CONCLUSION: Our results help clinicians identify cancer patients in need of psychosocial support when navigating in the growing survivor population. PMID- 28024267 TI - Sexual homicide: Brief review of the literature and case report involving rape, genital mutilation and human arson. AB - The objective of the current paper is to report a new case of sexual murder involving human arson and summarize the literature on the phenomenon of sexual homicide. The present case study is unprecedented in Greece and a rarity in international literature due to the fact that the victim suffered genital mutilation and incineration while still alive. The evaluation consisted of 176 articles; 53 were reviewed by the authors. The results revealed sparse, but significant, research findings. The authors discuss the limitations regarding research, incidence of the phenomenon, crime-scene patterns, offender characteristics (killing methods, motive inferences, sociodemographic data, classifications, psychopathology, modus operandi), and victim selection. The incidence of the phenomenon is unclear (1-4%) due to non-standardized criteria. It is an expression of displaced anger or sexual sadism and/or a way to elude detection (ancillary benefit). Most offenders (in their first kill) and victims were in their late 20s to early 30s and belong to Caucasian populations. Personal weapons were commonly used against women, strangulation is the prevalent killing method against children, and firearms against men. Most of the sexual homicide perpetrators are non-psychotic at the time of the attack, but experience personality pathology, primitive defenses, pathological object relations, and withdrawal into fantasy in order to deal with social isolation. PMID- 28024268 TI - Validation of autonomic and endocrine reactivity to a laboratory stressor in young children. AB - The validation of laboratory paradigms that reliably induce a stress response [including hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) activation], is critical for understanding how children's stress-response systems support emotional and cognitive function. Early childhood research to date is markedly limited, given the difficulty in establishing paradigms that reliably induce a cortisol response. Furthermore, research to date has not included a control condition or examined concurrent ANS reactivity. We addressed these limitations by characterizing the extent to which a modified matching task stressor paradigm induces HPA and ANS activation, beyond a closely matched control condition. Modifications include an unfamiliar and unfriendly assessor to increase the stressful nature of the task. Results validate the matching task as a laboratory stressor, with significant differences in HPA and ANS responsivity between conditions. The Stressor group exhibited a cortisol increase post stressor, while the Control group was stable over time. Children in both conditions exhibited reduced parasympathetic activity to the first-half of the task, but in the second-half, only children in the Stressor condition, who were experiencing exaggerated signals of failure, exhibited further parasympathetic decline. The Stressor condition induced higher sympathetic activity (versus Control) throughout the task, with exaggerated second-half differences. Within the Stressor condition, responsivity was convergent across systems, with greater cortisol reactivity correlated with the magnitude of parasympathetic withdrawal and sympathetic engagement. Future research employing the matching task will facilitate understanding the role of HPA and ANS function in development. PMID- 28024269 TI - Aromatase changes in depression: A postmortem and animal experimental study. AB - A hyperactive hypothalamo-pituitary-adrenal (HPA) axis is a prominent feature in depression. It has been shown that androgens inhibit HPA activity and that estrogens stimulate it. We have therefore investigated, in human postmortem hypothalamus, whether depression features an increase in aromatase, which is the rate-limiting enzyme for the conversion of androgens to estrogens. In addition, we have tested the effect of an aromatase inhibitor on depression-like symptoms in a frequently used animal model for depression. At first, aromatase immunoreactivity (ir) was quantified in the central part of the hypothalamic paraventricular nucleus (PVN) of 10 major depressive disorder (MDD) patients and 10 well-matched control subjects. Subsequently an animal experimental study was performed using the chronic unpredictable mild stress (CUMS) rats as depression model. The effect of administration of 1,4,6-androstatriene-3,17-dione (ATD), an aromatase inhibitor, was investigated by silastic capsule implantation. In the postmortem study, the amount of PVN aromatase-ir decreased significantly in the MDD group compared to the controls (P=0.029). In the animal study, ATD was found to cause significantly increased testosterone (T) levels, both in plasma and in the hypothalamus. However, ATD administration did not show significant effects on the depression-like behaviors or plasma corticosterone levels in CUMS rats. Based on our observations in human postmortem material and the animal experiment, we have to conclude that alterations in aromatase in adulthood do not seem to play a major role in the pathogenesis of the symptoms of depression. PMID- 28024270 TI - The stress hormone cortisol blocks perceptual learning in humans. AB - Cortisol, the primary glucocorticoid (GC) in humans, influences neuronal excitability and plasticity by acting on mineralocorticoid and glucocorticoid receptors. Cellular studies demonstrated that elevated GC levels affect neuronal plasticity, for example through a reduction of hippocampal long-term potentiation (LTP). At the behavioural level, after treatment with GCs, numerous studies have reported impaired hippocampal function, such as impaired memory retrieval. In contrast, relatively little is known about the impact of GCs on cortical plasticity and perceptual learning in adult humans. Therefore, in this study, we explored the impact of elevated GC levels on human perceptual learning. To this aim, we used a training-independent learning approach, where lasting changes in human perception can be induced by applying passive repetitive sensory stimulation (rss), the timing of which was determined from cellular LTP studies. In our placebo-controlled double-blind study, we used tactile LTP-like stimulation to induce improvements in tactile acuity (spatial two-point discrimination). Our results show that a single administration of hydrocortisone (30mg) completely blocked rss-induced changes in two-point discrimination. In contrast, the placebo group showed the expected rss-induced increase in two-point discrimination of over 14%. Our data demonstrate that high GC levels inhibit rss induced perceptual learning. We suggest that the suppression of LTP, as previously reported in cellular studies, may explain the perceptual learning impairments observed here. PMID- 28024271 TI - The impact of the severity of early life stress on diurnal cortisol: The role of puberty. AB - Researchers have documented dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in children and adolescents who experienced early life stress (ELS). The precise nature of this dysregulation, however, has been difficult to discern. In fact, both elevated and blunted patterns of diurnal cortisol regulation have been reported in children and adolescents exposed to greater ELS, including both reduced and heightened cortisol levels and change in cortisol across the day. These divergent findings may be due to developmental changes in the relation between ELS and HPA-axis functioning. The present study was designed to examine the role of puberty in the impact of the severity of ELS on the regulation of diurnal cortisol. Boys and girls (N=145) ages 9-13 years recruited from lower risk communities completed an interview about their ELS experiences and at-home collection of diurnal cortisol. ELS experiences were objectively coded for severity, and children's level of pubertal development was measured using Tanner Staging. Multi-level piecewise mixed-effects models tested the effects of ELS severity and pubertal stage on cortisol levels at waking, the cortisol awakening response (CAR), and the daytime cortisol slope. While we found no significant interactive effects of pubertal stage and ELS severity on cortisol levels at waking or the daytime cortisol slope, findings indicated that pubertal stage interacted with ELS severity to predict the cortisol awakening response (CAR). Specifically, in earlier puberty, higher ELS was associated with a blunted CAR compared to lower ELS; in contrast, in later puberty, higher ELS was associated with a heightened CAR compared to lower ELS. Differences in the relation between ELS severity and the CAR were uniquely determined by puberty, and not by age. By considering and examining the role of puberty, the current study provides a developmental explanation for previous divergent findings of both blunted and heightened patterns of diurnal cortisol following ELS. These results indicate that careful attention should be given to children's pubertal status before drawing conclusions concerning the nature of diurnal cortisol dysregulation. PMID- 28024272 TI - Effects of the combination of metyrapone and oxazepam on cocaine-induced increases in corticosterone in the medial prefrontal cortex and nucleus accumbens. AB - We have previously demonstrated that a combination of drugs (i.e., metyrapone and oxazepam) known to attenuate HPA-axis activity effectively decreases cocaine self administration and cue reactivity in rats. However, we did not find changes in plasma corticosterone that matched the behavioral effects we observed, indicating that a different mechanism of action must be involved. Therefore, we hypothesized that the combination of metyrapone and oxazepam attenuates cocaine taking and seeking by decreasing cocaine-induced increases in corticosterone in the brain. Male rats were implanted with guide cannulae targeting the medial prefrontal cortex or nucleus accumbens. After the rats recovered from surgery, the microdialysis session was conducted. Rats were housed in the experimental chamber and the dialysis probes inserted into the guide cannulae the night before the session. The following day, dialysate samples were collected over a five-hour session. Baseline samples were collected for the first two hours, every 20min. Samples were then collected following administration of cocaine (15mg/kg, ip). Before injections of cocaine, rats were pretreated with either vehicle or the combination of metyrapone (50mg/kg, ip) and oxazepam (10mg/kg, ip). The administration of cocaine resulted in an increase in corticosterone in the medial prefrontal cortex following vehicle pretreatment, which was not observed in the nucleus accumbens. This cocaine-induced increase in corticosterone was attenuated by metyrapone/oxazepam. Reducing cocaine-induced increases in corticosterone in the medial prefrontal cortex might represent a novel mechanism through which the combination of metyrapone/oxazepam produces its behavioral effects. PMID- 28024273 TI - OXTR polymorphism in depression and completed suicide-A study on a large population sample. AB - In the light of contradictory results concerning OXTR polymorphism rs53576 and depression, we decided to verify the potential association between the two on 1) a large, ethnically homogenous sample of 1185 individuals who completed the Beck Depression Inventory (BDI), as well as on 2) a sample of 763 suicide victims. In the population sample, AA males showed significantly lower BDI scores (p=0.005, pcor=0.030). Exploratory analyses suggested that this effect was limited to a subgroup within 0-9 BDI score range (p=0.0007, U-Mann Whitney test), whereas no main effect on depressive symptoms (BDI>9) was found. In the suicide sample no association with rs53576 genotype was present. Exploratory analyses in suicides revealed higher blood alcohol concentration (BAC) among AA than GG/GA males (p=0.014, U-Mann Whitney test). Our results show that the OXTR rs53576 variant modulates the mood in male individuals and may positively correlate with alcohol intake among male suicides, but is not associated with suicide or depression. The study adds to the growing knowledge on rs53576 genotype characteristics. PMID- 28024274 TI - Heterogeneity in HPA axis dysregulation and serotonergic vulnerability to depression. AB - Variability in the serotonin transporter (5-HTTLPR) gene can influence the risk of depression associated with adversity, as well as cortisol stress reactivity, although not consistently. No study has examined the impact of both a stressful environment and corticotropic-axis dysfunction on depression, as a function of 5 HTTLPR. This population-based study included 334 subjects aged 65 and older. Depression was measured at both diagnostic (major depression according to DSM-IV) and symptomatic (subthreshold depression) levels of caseness, in addition to 5 HTTLPR and rs25531 genotyping and diurnal cortisol measures. For participants with the SS genotype, higher morning cortisol levels were associated with a 4 fold increased risk of depression. Among LL participants, both evening cortisol levels and recent stressful events increased depression risk, although only the latter remained significant after multivariable adjustment. Conversely, SL individuals appeared somewhat resilient to depression in terms of cortisol and recent stress. These findings indicate that 5-HTTLPR genetic variability appears to influence the association between stress-related factors and late-life depression, although the gene-environment interactions failed to reach statistical significance levels. Participants homozygous for the short allele appeared to have a cortisol-related neuroendocrine vulnerability to depression, while long allele homozygotes were more reactive to stressful events in terms of depression risk. PMID- 28024275 TI - Stress disrupts the reconsolidation of fear memories in men. AB - Reconsolidation is a post-retrieval process of restabilization of the memory trace. Previous findings from our group suggest that cortisol, a glucocorticoid hormone secreted in response to stress, enhances the reconsolidation of fear memories in healthy men. Cortisol effect was found to be very specific, enhancing only the fear memory that was reactivated (i.e. retrieved), but not the non reactivated memory. In the current study we aimed to investigate the effects of psychosocial stress, a more ecologically valid intervention, on fear memory reconsolidation in men. Using a similar design, we expected stress induction to have comparable effects to those of cortisol intake. During the three testing days, the participants went through (1) fear acquisition, (2) stress induction and memory reactivation (or the corresponding control conditions), (3) fear extinction, reinstatement and reinstatement test. Salivary cortisol, blood pressure measures and subjective ratings confirmed the success of the stress induction. Skin conductance response, serving as a measure of conditioned fear, confirmed acquisition, fear retrieval, and extinction in all groups. In the three control groups (where either reactivation, stress, or both components were missing) reinstatement effects were seen as expected. Yet in contrast to the hypothesis, the target group (i.e. combining reactivation and stress) showed no reinstatement to any of the stimuli. Stress induction is thus suggested to have a general impairing effect on the reconsolidation of fear memories. The unique characteristic of the stress response and experience compared to a pharmacological intervention are proposed as possible explanations to the findings. This disruptive effect of stress on fear memory reconsolidation may have potential therapeutic implications. PMID- 28024276 TI - Effect of lifestyle interventions on glucose regulation among adults without impaired glucose tolerance or diabetes: A systematic review and meta-analysis. AB - This study systematically assessed the effectiveness of lifestyle interventions on glycemic indicators among adults (?18years) without IGT or diabetes. Randomized controlled trials using physical activity (PA), diet (D), or their combined strategies (PA+D) with follow-up ?12months were systematically searched from multiple electronic-databases between inception and May 4, 2016. Outcome measures included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin (FI), homeostasis model assessment-estimated insulin resistance (HOMA-IR), and bodyweight. Included studies were divided into low-range (FPG <5.5mmol/L or HbA1c <5.5%) and high-range (FPG ?5.5mmol/L or HbA1c ?5.5%) groups according to baseline glycemic levels. Seventy-nine studies met inclusion criteria. Random-effect models demonstrated that compared with usual care, lifestyle interventions achieved significant reductions in FPG (-0.14mmol/L [95%CI, -0.19, -0.10]), HbA1c (-0.06% [-0.09, -0.03]), FI (%change: -15.18% [ 20.01, -10.35]), HOMA-IR (%change: -22.82% [-29.14, -16.51]), and bodyweight (%change: -3.99% [-4.69, -3.29]). The same effect sizes in FPG reduction (0.07) appeared among both low-range and high-range groups. Similar effects were observed among all groups regardless of lengths of follow-up. D and PA+D interventions had larger effects on glucose reduction than PA alone. Lifestyle interventions significantly improved FPG, HbA1c, FI, HOMA-IR, and bodyweight among adults without IGT or diabetes, and might reduce progression of hyperglycemia to type 2 diabetes mellitus. PMID- 28024277 TI - QT prolongation caused by insulin-induced hypoglycaemia - An interventional study in 119 individuals. AB - AIMS: Hypoglycaemia is associated with increased risk of cardiovascular events and mortality in patients with diabetes, but the extent and mechanisms of this link are ill defined. We here prospectively studied cardiac repolarization abnormalities during insulin-induced hypoglycaemia in humans. METHODS: 119 individuals (69 males, age 47.5+/-13.4years, range 18-82years) were assessed during hypoglycaemia after the injection of 0.1-0.25units/kg human insulin. Corrected QT intervals (QTc) and QT dispersion (QTd) were calculated from serially recorded twelve lead electrocardiograms, and plasma glucose and other endocrine markers were studied. RESULTS: QTc increased from 415.1+/-21.9ms (mean+/-standard deviation) at baseline to 444.9+/-26.5ms during hypoglycaemia (plasma glucose nadir, 1.6+/-0.5mmol/L, p=0.001), accompanied by an increase of QTd from 45.0+/-22.7ms to 64.1+/-40.0ms (p<0.001). Hypoglycaemia-induced abnormal QTc prolongation (defined as ?460ms in females and ?450ms in males) occurred in 17% (9/54) of females and 26% (17/65) of males. 97 of 119 of individuals (82%) developed transient hypokalaemia (K+ ?3.6mmol/L), and plasma epinephrine increased from 220.4+/-169.5pmol/L at baseline to 2945.6+/-2421.4pmol/L during hypoglycaemia. Baseline QTc, but not age or gender, was a significant predictor of hypoglycaemia-induced QTc prolongation (p=0.001). CONCLUSIONS: Insulin-induced hypoglycaemia frequently causes abnormal QT prolongation and is associated with hypokalaemia and sympathoadrenal activation, thereby increasing the potential risk for ventricular arrhythmias, particularly in individuals with pre-existing high normal QTc. PMID- 28024278 TI - Recycled-tire pyrolytic carbon made functional: A high-arsenite [As(III)] uptake material PyrC350(r). AB - A novel material, PyrC350(r), has been developed from pyrolytic-tire char (PyrC), as an efficient low-cost Arsenite [As(III)] adsorbent from water. PyrC350(r) achieves 31mgg-1 As(III) uptake, that remains unaltered at pH=4-8.5. A theoretical Surface Complexation Model has been developed that explains the adsorption mechanism, showing that in situ formed Fe3C, ZnS particles act cooperatively with the carbon matrix for As(III) adsorption. Addressing the key issue of cost-effectiveness, we provide a comparison of As(III)-uptake effectiveness in conjunction with a cost analysis, showing that PyrC350(r) stands in the top of [effectiveness/cost] vs. existing carbon-based, low-cost materials. PMID- 28024279 TI - A review of the literature - The use of interactive puppet simulation in nursing education and children's healthcare. AB - The use of puppets in health care is emerging as a mode of simulation that combines elements of engaging with the child through play whilst at the same time providing education. This review examines the impact when nurses use play therapy or puppets as a simulation modality in nursing education and in the clinical paediatric nursing environment. Electronic search was conducted using CINAHL, PubMed, Scopus, Web of Science and PsycINFO data bases, between 1980 and January 2015 with the combinations of play therapy; puppetry; nursing education; nursing; simulation; health professionals and puppets. Twelve articles were identified that highlight the use of puppet simulation in the education of nursing students and children in the healthcare environment. Puppet modelling and puppet simulation is predominantly adopted in the areas of health education and specifically diabetes education. Identified gaps in the use of puppet simulation in nursing, nurse education and puppet simulation as a three-way communication process; thus identifying the need for further research on puppet simulation and its application and benefits in nursing and nurse education. PMID- 28024280 TI - Comparative effect of berberine and its derivative 8-cetylberberine on attenuating atherosclerosis in ApoE-/- mice. AB - Berberine (BBR), one of the main bioactive compounds in Rhizoma coptidis, has multiple pharmacological activities. It has been reported that 8-cetylberberine (8-BBR-C16) has increased anti-microbial property in vivo and a higher bioavailability in hamsters. Therefore, in the present study, we used apolipoprotein E-deficient mice (ApoE-/-) as an atherosclerosis model to investigate the anti-atherosclerosis effects of 8-BBR-C16. After 12weeks of treatment, the atherosclerotic plaque area of the aorta, serum lipid profile, the plasma redox state and the expression of inflammatory cytokines in ApoE-/- mice were determined. Both BBR and 8-BBR-C16 significantly decreased the atherosclerotic plaque area by suppressing inflammatory and oxidative markers in ApoE-/- mice. Treatment with BBR or 8-BBR-C16, decreased serum levels of IL-1beta and TNF-alpha as well as mRNA levels of NF-kappaBp65, i-NOS, ICAM-1, IL-6 in the aorta. In addition, the expression of NF-kappaB p65 protein decreased in the nucleus, whereas IkappaBalpha levels increased in the cytosol. The anti inflammatory and anti-oxidative effect of BBR and 8-BBR-C16 attributed to inhibition of the translocation of NF-kappaB to the nucleus. Since the dosage of BBR used was 10 fold higher than that of 8-cetylberberine, we conclude that 8-BBR C16 is more efficient in treating atherosclerosis in ApoE-/- mice. PMID- 28024281 TI - Photodynamic therapy mediated by acai oil (Euterpe oleracea Martius) in nanoemulsion: A potential treatment for melanoma. AB - Melanoma is the most aggressive and lethal form of skin cancer, responsible for >80% of deaths. Standard treatments for late-stage melanoma usually present poor results, leading to life-threatening side effects and low overall survival. Thus, it is necessary to rethink treatment strategies and design new tools for the treatment of this disease. On that ground, we hereby report the use of acai oil in nanoemulsion (NanoA) as a novel photosensitizer for photodynamic therapy (PDT) used to treat melanoma in in vitro and in vivo experimental models. NIH/3T3 normal cells and B16F10 melanoma cell lines were treated with PDT and presented 85% cell death for melanoma cells, while maintaining high viability in normal cells. Flow cytometry indicated that cell death occurred by late apoptosis/necrosis. Tumor bearing C57BL/6 mice treated five times with PDT using acai oil in nanoemulsion showed tumor volume reduction of 82% in comparison to control/tumor group. Necrotic tissue per tumor area reached its highest value in PDT-treated mice, supporting PDT efficacy. Overall, acai oil in nanoemulsion was an effective photosensitizer, representing a promising source of new photosensitizing molecules for PDT treatment of melanoma, a tumor with an inherent tendency to be refractory for this type of therapy. PMID- 28024282 TI - 460nm visible light irradiation eradicates MRSA via inducing prophage activation. AB - A growing number of researches demonstrate that light with a wavelength between 400 and 500nm, namely blue light (BL), has exhibited antibacterial effects on methicillin-resistant Staphylococcus aureus (MRSA) and other microbes. However, there is insufficient evidence to show that BL kills MRSA inside biofilm and the mechanisms underlying the antibacterial effects remain unclear. Here we demonstrate that BL irradiation with 460nm effectively eliminated both planktonic and biofilm MRSA in a dose-dependent manner by utilizing a planktonic MRSA or MRSA biofilm model. Furthermore, using a animal model of skin wound infections with MRSA, we found that 460nm BL showed a therapeutic effect on MRSA infected wounds in mice with significant killing of MRSA, better survival and wound healing. Moreover, RNA sequencing was used to analyze differential gene expressions in MRSA genome after BL irradiation. Our data showed that about one third of up-regulated genes were phage-related. Using phage inhibitor GS-11P, increased prophage activation in MRSA cells induced by BL irradiation was blocked and phage particles were observed. The results indicate that blue visible light irradiation with 460nm is a novel tool for eliminating both planktonic and biofilm MRSA. Prophage activation may be involved in the process. This study may provide a new perspective to understand the antibacterial mechanism by BL. PMID- 28024283 TI - Bactericidal laser ablation of carbon dots: An in vitro study on wild-type and antibiotic-resistant Staphylococcus aureus. AB - Suspensions of Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) were irradiated with a 808-nm diode laser in the presence of different concentrations of carbon dots (C-dots). The effects of laser irradiation and C-dots on the bactericidal activity were separately investigated. The results indicated that without laser irradiation, C-dots caused to a significant cease in the colony formation of both wild and methicillin-resistance types of S. aureus in a concentration-dependent manner. On the other hand, the bactericidal effect of C-dots was accelerated upon laser irradiation. Mechanistic studies revealed that formation of reactive oxygen species and protein leakage, which occurred in the presence of C-dots, were greatly accelerated by laser irradiation. Moreover, field emission scanning electron microscopy (FESEM) images showed morphological changes in the bacterial surfaces in the presence of C-dots upon laser irradiations, while almost no changes in the bacteria morphology were observed in the presence of C-dots alone. Outer membrane damage was a synergism result of laser irradiation and presence of C-dots. PMID- 28024284 TI - Chemiluminescence cloth-based glucose test sensors (CCGTSs): A new class of chemiluminescence glucose sensors. AB - Chemiluminescence (CL) has been widely applied in many fields, but it is rarely used in a very simple, economical but effective way. In this work, for the first time, the CL cloth-based glucose test sensors (CCGTSs) are developed as a new class of CL glucose sensors, with no need for complicated, expensive device fabrication and peripheral equipment. When integrated with desirable hydrophobic barrier in the flow channel and gravity/capillary flow induced by a difference in height between the loading zone and the detection zone, a single cloth-based device can perform the whole CL process involving two steps of enzyme reactions. The wax screen-printing approach is used to fabricate ultra-cheap CCGTSs, the glucose detection involves the enzymatic oxidation of glucose to gluconic acid and H2O2 followed by the horseradish peroxidase (HRP)-catalyzed oxidation of luminol by H2O2, and the emitted CL signals are heightened with p-iodophenol (PIP) and imaged using an inexpensive, portable CCD camera. Under optimized conditions, glucose can be determined over the range of 0.1-100mM, with a detection limit of 0.0948mM and an analysis time of less than 5.5min. Finally, the applicability and validity of the CCGTSs are demonstrated for the measurement of glucose in clinical urine and serum samples. Thus, the proposed sensors could provide great promise in applications in many areas, and may facilitate the achievement of point-of-care testing. PMID- 28024285 TI - A potentiometric non-enzymatic glucose sensor using a molecularly imprinted layer bonded on a conducting polymer. AB - A non-enzymatic potentiometric glucose sensor for the determination of glucose in the micomolar level in saliva was developed based on a molecularly imprinted polymer (MIP) binding on a conducting polymer layer. A MIP containing acrylamide, and aminophenyl boronic acid, as a host molecule to glucose, was immobilized on benzoic acid-functionalized poly(terthiophene) (pTBA) by the amide bond formation onto a gold nanoparticles deposited-screen printed carbon electrode (pTBA/AuNPs/SPCE). Aromatic boronic acid was incorporated into the MIP layer to stably capture glucose and create a potentiometric signal through the changed pKa value of polymer film by the formation of boronate anion-glucose complex with generation of H+ ions by the cis-diol reaction. Reversible binding and extraction of glucose on the sensor surface was observed using a quartz crystal microbalance. Each layer of the sensor probe was characterized by cyclic voltammetry, electrochemical impedance spectroscopy, X-ray photoelectron spectroscopy, and atomic force microscopy. The potentiometric response at the optimized conditions exhibited a wide linear dynamic range of 3.2*10-7 to 1.0*10 3M, with a detection limit of 1.9 (+/-0.15)*10-7M. The sensor probe revealed an excellent selectivity and sensitivity for glucose compared to other saccharides. In addition, the reliability of the proposed glucose sensor was evaluated in physiological fluid samples of saliva and finger prick blood. PMID- 28024286 TI - Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia. AB - Ammonia-induced mitochondrial dysfunction and energy crisis is known as a critical consequence of hepatic encephalopathy (HE). Hence, mitochondria are potential targets of therapy in HE. The current investigation was designed to evaluate the role of taurine treatment on the brain and liver mitochondrial function in a rat model of hepatic encephalopathy and hyperammonemia. The animals received thioacetamide (400mg/kg, i.p, for three consecutive days at 24-h intervals) as a model of acute liver failure and hyperammonemia. Several biochemical parameters were investigated in the serum, while the animals' cognitive function and locomotor activity were monitored. Mitochondria was isolated from the rats' brain and liver and several indices were assessed in isolated mitochondria. Liver failure led to cognitive dysfunction and impairment in locomotor activity in the rats. Plasma and brain ammonia was high and serum markers of liver injury were drastically elevated in the thioacetamide-treated group. An assessment of brain and liver mitochondrial function in the thioacetamide-treated animals revealed an inhibition of succinate dehydrogenase activity (SDA), collapsed mitochondrial membrane potential, mitochondrial swelling, and increased reactive oxygen species (ROS). Furthermore, a significant decrease in mitochondrial ATP was detected in the brain and liver mitochondria isolated from thioacetamide-treated animals. Taurine treatment (250, 500, and 1000mg/kg) decreased mitochondrial swelling, ROS, and LPO. Moreover, the administration of this amino acid restored brain and liver mitochondrial ATP. These data suggest taurine to be a potential protective agent with therapeutic capability against hepatic encephalopathy and hyperammonemia-induced mitochondrial dysfunction and energy crisis. PMID- 28024287 TI - Tetramethylpyrazine attenuates carbon tetrachloride-caused liver injury and fibrogenesis and reduces hepatic angiogenesis in rats. AB - Liver fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with abnormalities of angiogenesis in the liver. Capillarization of liver sinusoidal endothelial cell (LSEC) is the pivotal event during liver angiogenesis. In the current study, we sought to investigate the effect of tetramethylpyrazine (TMP) on carbon tetrachloride (CCl4)-induced liver injury and fibrosis in rats, and to further examine the molecular mechanisms of TMP-induced anti-angiogenic effect. We found that TMP significantly ameliorated histopathological feature of liver fibrosis characterized by decreased collagen deposition, hepatocyte apoptosis, and expression of biochemical indicators, such as aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Moreover, TMP appeared to play an essential role in controlling pathological angiogenesis. In addition, TMP attenuated angiogenesis by downregulation of vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGF-R2), platelet-derived growth factor-BB (PDGF-BB), and platelet-derived growth factor-beta receptor (PDGF-betaR), four important factors transmitting pro-angiogenic pathways. Besides, TMP inhibited LSEC capillarization in CCl4-induced liver fibrotic model with the morphological features of increasing sinusoidal fenestrae. Importantly, we found that disruption of angiogenesis is required for TMP to inhibit hepatocyte apoptosis in rats. Treatment with TMP significantly inhibited the expression of Bax, and up regulated Bcl-2 expression. Interestingly, treatment with angiogenesis-inducer AngII dramatically eliminated the effect of TMP on Bax/Bcl-2 axis. Overall, these results provide novel perspectives to reveal the protective effect of TMP on liver, opening up the possibility of using TMP based anti-angiogenic drugs for the liver diseases. PMID- 28024288 TI - Asiaticoside protects cochlear hair cells from high glucose-induced oxidative stress via suppressing AGEs/RAGE/NF-kappaB pathway. AB - Asiaticoside (AC) has been known to have anti-oxidative activity, however, the effect of AC on the progression of high glucose-induced hearing loss has not been studied. This study aims to analyze the effect of AC on cochlear hair cells under the treatment of high glucose in vitro and the hearing function in vivo. The results of MTT showed that high glucose decreased the activity of HEI-OC1 cells, but AC increased the activity of HEI-OC1 cells compared with high glucose group. The results of flow cytometry showed that AC decreased the degree of apoptosis induced by high levels of glucose. The results of DCFH-DA staining showed that AC inhibited the ROS production induced by high glucose levels. The results of JC-1 staining showed that AC inhibited the mitochondrial depolarization induced by high glucose levels. Furthermore, AC decreased the threshold, and protected inner and outer hair cells from damage in rats with hearing loss induced by diabetes mellitus. Moreover, AC decreased the activity of MDA, but, increased the activity of SOD, CAT and GSH-Px in vivo. AC also decreased the expression of AGEs, RAGE and NF-kappaB p65. Collectively, these results suggest that AC protects cochlear hair cells from high glucose-induced injury by increasing anti-oxidative activity and suppressing the AGEs/RAGE/NF-kappaB pathway. PMID- 28024289 TI - Protective abilities of pyridoxine in experimental oxidative stress settings in vivo and in vitro. AB - BACKGROUND: Pyridoxine (Pr, B6) or its active form pyridoxal phosphate (PLP, B6) deficiency promotes oxidative lipid peroxidation and exacerbates the oxidative stress. From the other hand, by our previous experiments we proved that B6 is able strongly inhibit Xanthine Oxidase (XO) activity, which is an enzyme responsible for the formation of uric acid and hydrogen peroxide. METHODS: Cells were cultured by Mattson M. method and treated with 3%% hydrogen peroxide. Before and after treatment we added allopurinol as well as B6 into the cell culture media. Hydrogen peroxide after limited craniotomy was injected into the brain parenchyma in accordance to the following coordinates from bregma: 2mm lateral to midline, 3mm anterior to the coronal suture, and 2mm below the surface of the skull. Blood Brain Barrier (BBB) disruption was evaluated spectrophotometrically (lambda=550nm). RESULTS: were evidencing - B6 as well as allourinol are protective against oxidative stress and support cells maintenance in the culture, protect them from death. In in vivo studies animals treated with pyridoxine and allopurnol from days 1-6 and 1-12 (p<0.035) had less damaged BBB in comparison with the control group. CONCLUSION: Antioxidative abilities via XO inhibition of B6 are proposed. PMID- 28024290 TI - NFAT1 promotes cell motility through MMP-3 in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors and the prognosis of patients remains poor. Increasing evidence suggests that nuclear factor of activated T cell (NFAT1) plays an important role in the development and progression of cancers. Herein, we show that NFAT1 was overexpressed in human ESCC, which was significantly associated with advanced tumor stage and lymph node metastasis. Functional studies found that NFAT1 silencing could suppress cell migration and invasion through MMP-3. The data therefore suggest that NFAT1 plays an important adverse role in the development and progression of ESCC, implicating possible application in clinics as a biomarker and a potential new therapeutic target. PMID- 28024291 TI - Novel transferrin modified and doxorubicin loaded Pluronic 85/lipid-polymeric nanoparticles for the treatment of leukemia: In vitro and in vivo therapeutic effect evaluation. AB - PURPOSE: Childhood leukemia is a common malignant disease in children. Doxorubicin (DOX) was widely used for the treatment of leukemia. However, severe toxic side effects and drug resistance are the major limitations of DOX. Nanocarriers offer the opportunity to overcome these drawbacks, there are many attempts to enhance the activity of DOX against drug resistance. This study aimed to develop a novel transferrin (Tf) modified and doxorubicin (DOX) loaded Pluronic 85/lipid-polymeric nanoparticles for the treatment of leukemia. METHODS: In this study, a novel targeted ligand: transferrin-polyethylene glycol-oleic acid (Tf-PEG-OA) was synthesized. Tf modified and DOX loaded Pluronic 85/lipid polymeric nanoparticles (Tf-DOX P85/LPNs) were prepared via the self-assembly of PLGA, P85, stearic acid and Tf-PEG-OA using the nanoprecipitation method. The physicochemical properties of LPNs were characterized. In vitro and in vivo anti tumor efficacy of LPNs was evaluated in human promyelocytic leukemia cell line (HL-60 cells) and DOX resistance HL-60 cell line (HL-60/DOX cells) including the relevant animal models. RESULTS: Tf-DOX P85/LPNs displayed strong anti-tumor ability on both HL-60 cells and HL-60/DOX cells than other formulations used as contrast. Also, in HL-60/DOX bearing animal models, Tf-DOX P85/LPNs exhibited the highest efficiency as well as the lowest systemic toxicity. CONCLUSION: The results indicated that Tf P85/LPNs is a promising platform to enhance efficacy, reduce toxicity and overcome drug resistance of DOX for the treatment of leukemia. PMID- 28024292 TI - Adjuvant effect of Asparagus racemosus Willd. derived saponins in antibody production, allergic response and pro-inflammatory cytokine modulation. AB - The study manifests the immunoadjuvant potential of saponin rich fraction from Asparagus racemosus in terms of cellular and humoral immune response that can be exploited against microbial infections. Asparagus racemosus (AR) has been attributed as an adaptogen and rasayana in traditional medication systems for enhancing the host defence mechanism. Spectrophotometric and HPTLC analysis ensured the presence of saponins. The saponin rich fractions were tested for immunoadjuvant property in ovalbumin immunised mice for the humoral response, quantified in terms of prolonged antibody production upto a duration of 56days. Proinflammatory cytokines (IL-6 and TNF) were estimated for the cellular immune response in LPS stimulated primary murine macrophages. The safety evaluation in terms of cytotoxicity and allergic response has also been evaluated through in vitro (MTT) and in-vivo (IgE) respectively. ARS significantly inhibited the pro inflammatory cytokines, in LPS stimulated murine macrophages with no intrinsic cytotoxicity. The significant increase in IgG production infers the utility of ARS for prolonged humoral response. Further, the antigen specific response of IL 12 at early stage and IgE titres also suggests the generation of cellular immune response and low allergic reaction respectively, as compared to conventional adjuvants. IL-6 and TNF fluctuations in LPS stimulated and non-stimulated macrophages along with IgG and IL-12 also confirmed the Th1/Th2 modulating effect of ARS. The study indicates potential effect of ARS as an adjuvant for the stimulation of cellular immune response in addition to generating a sustained adaptive response without any adverse effects paving way for further validation with pathogenic organisms. PMID- 28024293 TI - Modulation of the lipid profile and insulin levels of streptozotocin induced diabetic rats by ethanol extract of Cnidoscolus aconitifolius leaves and some fractions: Effect on the oral glucose tolerance of normoglycemic rats. AB - BACKGROUND: No study to date has investigated the effect of different polar solvent extracts from Cnidoscolus aconitifolius leaves on glycemic control as used in folk medicine. Hence this study which investigated the effect of ethanol extract and fractions of C. aconitifolius leaves on body weights, relative organ weights, serum levels of glucose, lipid profiles and insulin in streptozotocin induced diabetic rats and on oral glucose tolerance of normoglycemic rats. METHODS: The ethanol extract was partitioned using methanol, hexane and chloroform to obtain different fractions. RESULTS: The ethanol extract, fractions or glibenclamide demonstrated hypoglycemic/therapeutic actions as seen from the reduction of serum glucose but increase in serum insulin and body weights of the diabetic rats at the end of experimentation following their administration, unlike the diabetic control that had significant alteration of these parameters with respect to the normal control. Whereas the diabetic control had significant increase in pancreatic weights with no alteration in the heart weights, the ethanol extract, fractions or glibenclamide had no effect on these organs. The ethanol extract, methanol fractions or glibenclamide showed better hypoglycemic actions than the n-hexane or chloroform fractions at the doses used and results obtained were corroborated by histology. Furthermore, the ethanol extract, n hexane (at 250mg/kg) and methanol fractions or glibenclamide improved glucose tolerance in glucose loaded normal rats. The methanol fraction (500mg/kg) demonstrated anti-hypercholesterolemic, anti-hypertriglyceridemic and insulin modulatory properties in a manner akin to glibenclamide. Acute toxicity study revealed the non toxicity of the plant CONCLUSION: The study justifies the use of polar solvent extracts of this plant in the management of diabetes mellitus. PMID- 28024294 TI - Celecoxib administration reduced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ injury in septic rats. AB - BACKGROUND: The cyclooxygenase (COX)-2 overexpression is associated with vascular injury and multiple organ failure in sepsis. However, constitutive COX-1 and basal COX-2 expressions have physiological effects. We aimed to investigate the effects of partial and selective COX-2 inhibition without affecting constitutive COX-1 and basal COX-2 activities by celecoxib on mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries, and survival in septic rats accomplished by cecal ligation and puncture (CLP). METHODS: Wistar rats were allocated into Sham, CLP, Sham+celecoxib, CLP+celecoxib subgroups. 2h after Sham and CLP operations, celecoxib (0.5mg/kg) or vehicle (saline; 1mL/kg) was administered orally to rats. 18h after drug administrations, MABF and responses of isolated aortic rings to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological examinations. Furthermore, survival rate was monitored throughout 96h. RESULTS: Celecoxib ameliorated mesenteric hypoperfusion and partially improved aortic dysfunction induced by CLP. Survival rate was%0 at 49th h in CLP group, but in CLP+celecoxib group it was 42.8% at the end of 96h. Serum AST, ALT, LDH, BUN, Cr and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) levels were increased in CLP group that were prevented by celecoxib. The decreases in liver and spleen glutathione levels and the increases in liver, lung, spleen and kidney malondialdehyde levels in CLP group were blocked by celecoxib. The histopathological protective effects of celecoxib on organ injury due to CLP were also observed. CONCLUSIONS: Celecoxib has protective effects on sepsis due to its preservative effects on mesenteric perfusion, aortic function and its anti-inflammatory and antioxidative effects. PMID- 28024295 TI - Characterization of two novel FANCG mutations in Indian Fanconi anemia patients. AB - FA is a rare recessive genetic disorder with autosomal or X-linked mode of inheritance and is associated with 19 different FA complementation groups. We have studied three patients clinically diagnosed as FA. All three patients showed a high frequency chromosomal breakage in MMC induced blood cultures and FANCD2 non-monoubiquitination by western blotting. The molecular analysis using direct sequencing revealed two novel mutations in FANCG; 2 novel mutations c.1143+5G>C and c.883dupG, and a reported mutation c.1471_1473delAAAinsG. We have for the first time modeled FANCG protein with fold based template search using pGenthreader which revealed sequence fold identical to super helical TPR domain of O linked GLCNAC transferase and have studied the impact of mutations on the function and structure of FANCG. All three mutations are potential pathogenic molecular changes which can affect FANCG interactions required for FA pathway, homologous recombination repairs and unhooking step of the ICL repair process. PMID- 28024296 TI - mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. AB - Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide 'small regulatory polypeptide of amino acid response' (SPAR). We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile. PMID- 28024297 TI - Variable chromatin structure revealed by in situ spatially correlated DNA cleavage mapping. AB - Chromatin structure at the length scale encompassing local nucleosome-nucleosome interactions is thought to play a crucial role in regulating transcription and access to DNA. However, this secondary structure of chromatin remains poorly understood compared with the primary structure of single nucleosomes or the tertiary structure of long-range looping interactions. Here we report the first genome-wide map of chromatin conformation in human cells at the 1-3 nucleosome (50-500 bp) scale, obtained using ionizing radiation-induced spatially correlated cleavage of DNA with sequencing (RICC-seq) to identify DNA-DNA contacts that are spatially proximal. Unbiased analysis of RICC-seq signal reveals regional enrichment of DNA fragments characteristic of alternating rather than adjacent nucleosome interactions in tri-nucleosome units, particularly in H3K9me3-marked heterochromatin. We infer differences in the likelihood of nucleosome-nucleosome contacts among open chromatin, H3K27me3-marked, and H3K9me3-marked repressed chromatin regions. After calibrating RICC-seq signal to three-dimensional distances, we show that compact two-start helical fibre structures with stacked alternating nucleosomes are consistent with RICC-seq fragmentation patterns from H3K9me3-marked chromatin, while non-compact structures and solenoid structures are consistent with open chromatin. Our data support a model of chromatin architecture in intact interphase nuclei consistent with variable longitudinal compaction of two-start helical fibres. PMID- 28024298 TI - Genome sequence and genetic diversity of European ash trees. AB - Ash trees (genus Fraxinus, family Oleaceae) are widespread throughout the Northern Hemisphere, but are being devastated in Europe by the fungus Hymenoscyphus fraxineus, causing ash dieback, and in North America by the herbivorous beetle Agrilus planipennis. Here we sequence the genome of a low heterozygosity Fraxinus excelsior tree from Gloucestershire, UK, annotating 38,852 protein-coding genes of which 25% appear ash specific when compared with the genomes of ten other plant species. Analyses of paralogous genes suggest a whole-genome duplication shared with olive (Olea europaea, Oleaceae). We also re sequence 37 F. excelsior trees from Europe, finding evidence for apparent long term decline in effective population size. Using our reference sequence, we re analyse association transcriptomic data, yielding improved markers for reduced susceptibility to ash dieback. Surveys of these markers in British populations suggest that reduced susceptibility to ash dieback may be more widespread in Great Britain than in Denmark. We also present evidence that susceptibility of trees to H. fraxineus is associated with their iridoid glycoside levels. This rapid, integrated, multidisciplinary research response to an emerging health threat in a non-model organism opens the way for mitigation of the epidemic. PMID- 28024300 TI - Genetic variants regulating expression levels and isoform diversity during embryogenesis. AB - Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues. However, the extent and types of genetic variation impacting embryonic gene expression, and their interactions with developmental programs, remain largely unknown. Here we assessed the effect of genetic variation on transcriptional (expression levels) and post-transcriptional (3' RNA processing) regulation across multiple stages of metazoan development, using 80 inbred Drosophila wild isolates, identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila, we obtain near base-pair resolution, resolving causal mutations in developmental enhancers, validated transcription factor-binding sites and RNA motifs. This fine-grain mapping uncovered extensive allelic interactions within enhancers that have opposite effects, thereby buffering their impact on enhancer activity. QTL affecting 3' RNA processing identify new functional motifs leading to transcript isoform diversity and changes in the lengths of 3' untranslated regions. These results highlight how developmental stage influences the effects of genetic variation and uncover multiple mechanisms that regulate and buffer expression variation during embryogenesis. PMID- 28024301 TI - Issues Surrounding Age-Adjusted d-Dimer Cutoffs That Practicing Physicians Need to Know When Evaluating Patients With Suspected Pulmonary Embolism. PMID- 28024299 TI - The role of fatty acid beta-oxidation in lymphangiogenesis. AB - Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC specific loss of CPT1A, a rate-controlling enzyme in fatty acid beta-oxidation, impairs lymphatic development. LECs use fatty acid beta-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid beta-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo. PMID- 28024302 TI - Readmission Rates After Passage of the Hospital Readmissions Reduction Program: A Pre-Post Analysis. AB - Background: Whether hospitals with the highest risk-standardized readmission rates (RSRRs) subsequently experienced the greatest improvement after passage of the Medicare Hospital Readmissions Reduction Program (HRRP) is unknown. Objective: To evaluate whether passage of the HRRP was followed by acceleration in improvement in 30-day RSRRs after hospitalizations for acute myocardial infarction (AMI), congestive heart failure (CHF), or pneumonia and whether the lowest-performing hospitals had faster acceleration in improvement after passage of the law than hospitals that were already performing well. Design: Pre-post analysis stratified by hospital performance groups. Setting: U.S. acute care hospitals. Patients: 15 170 008 Medicare patients discharged alive from 2000 to 2013. Intervention: Passage of the HRRP. Measurements: 30-day readmission rates after hospitalization for AMI, CHF, or pneumonia for hospitals in the highest performance (0% penalty), average-performance (>0% and <0.50% penalty), low performance (>=0.50% and <0.99% penalty), and lowest-performance (>=0.99% penalty) groups. Results: Of 2868 hospitals serving 1 109 530 Medicare discharges annually, 30.1% were highest performers, 44.0% were average performers, 16.8% were low performers, and 9.0% were lowest performers. After controlling for prelaw trends, an additional 67.6 (95% CI, 66.6 to 68.4), 74.8 (CI, 74.0 to 75.4), 85.4 (CI, 84.0 to 86.8), and 95.1 (CI, 92.6 to 97.5) readmissions per 10 000 discharges were found to have been averted per year in the highest-, average , low-, and lowest-performance groups, respectively, after passage of the law. Limitation: Inability to distinguish between improvement caused by the magnitude of the penalty or by different levels of health improvement in different patient populations. Conclusion: After passage of the HRRP, 30-day RSRRs for myocardial infarction, heart failure, and pneumonia decreased more rapidly than before the law's passage. Improvement was most marked for hospitals with the lowest prelaw performance. Primary Funding Source: National Institutes of Health. PMID- 28024303 TI - Depression in Women with Recurrent Miscarriages - an Exploratory Study. AB - Objective To assess depression, domestic violence and the use of substances in women with recurrent miscarriages. Methods The Abuse Assessment Screen (AAS), the Edinburgh Postnatal Depression Scale (EPDS) and the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) were used to assess violence, depression and the use of substances among women with recurrent miscarriages. The population corresponded to patients receiving prenatal care from June to August 2014. Multiple logistic regression was used to assess the multivariable relationship between depression and sociodemographic, psychosocial and medical characteristics (p < 0,10). Results The prevalence of depression was of 41.3% (95% confidence interval [CI] = 28.3-55.7%). One third of the pregnant women (32.6%) reported emotional or physical violence, and 13% were classified as abusing or addicted to tobacco according to ASSIST. History of psychiatric diseases was associated with depression (p = 0.005). Violence during life demonstrated a modest association (p = 0.073) with depression, as well as the number of miscarriages (p = 0.071). Conclusion Depression is a frequent disease among pregnant women with recurrent miscarriages. The results of this investigation suggest that a systematic assessment of depression and its associated conditions, such as domestic violence and the use of substances, should be part of the prenatal follow-up visits for women with recurrent miscarriages. PMID- 28024304 TI - Nasal Unit Transplantation: A Cadaveric Anatomical Feasibility Study. AB - Background The science and technical acumen in the field of vascularized composite allotransplantation has progressed rapidly over the past 15 years, and transplantation of specialized units of the face, such as the nose, appears possible. No study to date has evaluated the technical feasibility of isolated nasal unit transplantation (NUT). In this study, we explore the anatomy and technical specifics of NUT. Methods In this study, four fresh cadaver heads were studied. Bilateral vascular pedicle dissections were performed in each cadaver. The facial artery was cannulated and injected with food dye under physiologic pressure in two cadavers, and with lead oxide mixture in two cadavers to evaluate perfusion territories supplied by each vascular pedicle. Results The facial artery and vein were found to be adequate pedicles for NUT. Divergent courses of the vein and artery were consistently identified, which made for a bulky pedicle with necessary inclusion of large amounts of subcutaneous tissue. In all cases, the artery remained superficial, while the vein coursed in a deeper plane, and demonstrated consistent anastomoses with the superior transverse orbital arcade. While zinc oxide injection of the facial artery demonstrated filling of the nasal vasculature across the midline, dye perfusion studies suggested that unilateral arterial inflow may be insufficient to perfuse contralateral NUT components. Discrepancies in these two studies underscore the limitations of nondynamic assessment of nutritive perfusion. Conclusion NUT based on the facial artery and facial vein is technically feasible. Angiosome evaluation suggests that bilateral pedicle anastomoses may be required to ensure optimal perfusion. PMID- 28024305 TI - Lower Extremity Reconstruction with Free Gracilis Flaps. AB - Background There have been significant advancements in lower extremity reconstruction over the last several decades, and the plastic surgeon's armamentarium has grown to include free muscle and fasciocutaneous flaps along with local perforator and propeller flaps. While we have found a use for a variety of techniques for lower extremity reconstruction, the free gracilis has been our workhorse flap due to the ease of harvest, reliability, and low donor site morbidity. Methods This is a retrospective review of a single surgeon's series of free gracilis flaps utilized for lower extremity reconstruction. Demographic information, comorbidities, outcomes, and secondary procedures were analyzed. Results We identified 24 free gracilis flaps. The duration from injury to free flap coverage was <= 7 days in 6 patients, 8-30 days in 11 patients, 31 90 days in 4 patients, and > 90 days in 3 patients. There were 22 (92%) successful flaps and an overall limb salvage rate of 92%. There was one partial flap loss. Two flaps underwent incision and drainage in the operating room for infection. Two patients developed donor site hematomas. Four patients underwent secondary procedures for contouring. Our subset of pediatric patients had 100% flap survival and no secondary procedures at a mean 30-month follow-up. Conclusion This study demonstrates the utility of the free gracilis flap in reconstruction of small- to medium-sized defects of the lower extremity. This flap has a high success rate and a low donor site morbidity. Atrophy of the denervated muscle over time allows for good shoe fit, often obviating the need for secondary contouring procedures. PMID- 28024306 TI - A Canine Arthroscopic Anterior Cruciate Ligament Reconstruction Model for Study of Synthetic Augmentation of Tendon Allografts. AB - Novel graft types, fixation methods, and means for augmenting anterior cruciate ligament (ACL) reconstructions require preclinical validation prior to safe and effective clinical application. The objective of this study was to describe and validate a translational canine model for all-inside arthroscopic complete ACL reconstruction using a quadriceps tendon allograft with internal brace (QTIB). With institutional approval, adult research hounds underwent complete transection of the native ACL followed by all-inside ACL reconstruction using the novel QTIB construct with suspensory fixation (n = 10). Contralateral knees were used as nonoperated controls (n = 10). Dogs were assessed over a 6-month period using functional, diagnostic imaging, gross, biomechanical, and histologic outcome measures required for preclinical animal models. Study results suggest that the novel QTIB construct used for complete ACL reconstruction can provide sustained knee stability and function without the development of premature osteoarthritis in a rigorous and valid preclinical model. The unique configuration of the QTIB construct-the combination of a tendon allograft with a synthetic suture tape internal brace-allowed for an effective biologic-synthetic load-sharing ACL construct. It prevented early failure, allowed for direct, four-zone graft-to bone healing, and functional graft remodeling while avoiding problems noted with use of all-synthetic grafts. PMID- 28024307 TI - Ethics in Child Health: Principles and Cases in Neurodisability. PMID- 28024308 TI - Middle Cerebellar Peduncles T2-Hyperintense Signal in Fazio-Londe Syndrome. PMID- 28024310 TI - Horizontal Gaze Palsy in Two Brothers with Compound Heterozygous ROBO3 Gene Mutations. PMID- 28024309 TI - Stroke as Initial Manifestation of Adenosine Deaminase 2 Deficiency. AB - Deficiency of adenosine deaminase 2 (ADA2) due to homozygous or compound heterozygous mutations in the cat eye syndrome chromosome region, candidate 1 (CECR1) gene causes an autoimmune phenotype with systemic vasculitis affecting the skin, inner organs, and the central nervous system. Typically, stroke has been reported to follow systemic inflammatory disease and predominantly affects posterior and central brain areas. Here, we describe one of the rare patients in whom acute mesencephalic stroke preceded systemic inflammation and presented as initial clinical symptom. Symptoms typical for ADA2 deficiency such as fever, livedo racemosa, abdominal colics, arthralgias, and Raynaud phenomenon were observed later. Moreover, angiography of cerebral arteries did not reveal typical vasculitic findings supporting the hypothesis that alternative mechanism of vascular occlusion might have caused the stroke. ADA2 deficiency should be considered in patients with childhood stroke despite the absence of systemic inflammation and cerebral vasculitis. PMID- 28024311 TI - Lost in translation: The search for an in vitro screen for spermatogenic toxicity. AB - The last two decades have seen an increasing search for in vitro models that can replace the use of animals for safety testing. We adapted the methods from a recent nonquantitative report of spermatogenesis occurring in ex vivo mouse testis explants and tried to develop them into a screening assay. The model consisted of small pieces of neonatal mouse testis (testis "chunks"), explanted and placed on pillars of agarose or chamber inserts, and cultured at the air liquid interface. A peripheral torus-shaped zone in these explants would often contain tubules showing spermatogenesis, while the middle of each chunk was often necrotic, depending on the thickness of the tissue. The endpoint was histology: what proportion of tubules in the "permissive torus" actually contained healthy pachytene spermatocytes or spermatids? Extensive statistical modeling revealed that a useful predictive model required more than 60% of these tubules to show spermatogenesis. Separately, the logistics of running this as a predictive assay require that the controls consistently produce >= 60% tubules with pachytenes and round spermatids, and achieving this level of spermatogenesis reliably and consistently every week proved ultimately not possible. Extensive trials with various media additions and amendments proved incapable of maintaining the frequency of spermatogenic tubules at consistently >= 60%. Congruent with Schooler's "decline effect"; generally, the more often we ran these cultures, the worse the performance became. We hope that future efforts in this area may use our experience as a starting point on the way to a fully productive in vitro model of spermatogenesis. PMID- 28024312 TI - Factors That Distinguish High-Performing Accountable Care Organizations in the Medicare Shared Savings Program. AB - OBJECTIVE: To identify factors that promote the effective performance of accountable care organizations (ACOs) in the Medicare Shared Savings Program. DATA SOURCES/STUDY SETTING: Data come from a convenience sample of 16 Medicare Shared Savings ACOs that were organized around large physician groups. We use claims data from the Center for Medicaid and Medicare Services and data from 60 interviews at three high-performing and three low-performing ACOs. STUDY DESIGN: Explanatory sequential design, using qualitative data to account for patterns observed in quantitative assessment of ACO performance. DATA COLLECTION METHODS: A total of 16 ACOs were first rank-ordered on measures of cost and quality of care; we then selected three high and three low performers for site visits; interview data were content-analyzed. PRINCIPAL FINDINGS: Results identify several factors that distinguish high- from low-performing ACOs: (1) collaboration with hospitals; (2) effective physician group practice prior to ACO engagement; (3) trusted, long-standing physician leaders focused on improving performance; (4) sophisticated use of information systems; (5) effective feedback to physicians; and (6) embedded care coordinators. CONCLUSIONS: Shorter interventions can improve ACO performance-use of embedded care coordinators and local, regional health information systems; timely feedback of performance data. However, longer term interventions are needed to promote physician-hospital collaboration and skills of physician leaders. CMS and other stakeholders need realistic timelines for ACO performance. PMID- 28024313 TI - Utilisation of home-based physician, nurse and personal support worker services within a palliative care programme in Ontario, Canada: trends over 2005-2015. AB - With health system restructuring in Canada and a general preference by care recipients and their families to receive palliative care at home, attention to home-based palliative care continues to increase. A multidisciplinary team of health professionals is the most common delivery model for home-based palliative care in Canada. However, little is known about the changing temporal trends in the propensity and intensity of home-based palliative care. The purpose of this study was to assess the propensity to use home-based palliative care services, and once used, the intensity of that use for three main service categories: physician visits, nurse visits and care by personal support workers (PSWs) over the last decade. Three prospective cohort data sets were used to track changes in service use over the period 2005 to 2015. Service use for each category was assessed using a two-part model, and a Heckit regression was performed to assess the presence of selectivity bias. Service propensity was modelled using multivariate logistic regression analysis and service intensity was modelled using log-transformed ordinary least squares regression analysis. Both the propensity and intensity to use home-based physician visits and PSWs increased over the last decade, while service propensity and the intensity of nurse visits decreased. Meanwhile, there was a general tendency for service propensity and intensity to increase as the end of life approached. These findings demonstrate temporal changes towards increased use of home-based palliative care, and a shift to substitute care away from nursing to less expensive forms of care, specifically PSWs. These findings may provide a general idea of the types of services that are used more intensely and require more resources from multidisciplinary teams, as increased use of home-based palliative care has placed dramatic pressures on the budgets of local home and community care organisations. PMID- 28024314 TI - Modeling Health Care Spending Growth of Older Adults. AB - OBJECTIVE: To forecast out-of-pocket health care spending among older adults. Long-term forecasts allow policy makers to explore potential impacts of policy scenarios, but existing microsimulations do not incorporate details of supplemental insurance coverage and income effects on health care spending. DATA SOURCES: Dynamic microsimulation calibrated to survey and administrative data. STUDY DESIGN: We augment Urban Institute's Dynamic Simulation of Income Model (DYNASIM) with modules that incorporate demand responses and economic equilibria, with dynamics driven by exogenous technological change. A lengthy technical appendix provides details of the microsimulation model and economic assumptions for readers interested in applying these techniques. PRINCIPAL FINDINGS: The model projects total out-of-pocket spending (point of care plus premiums) as a share of income for adults aged 65 and older. People with lower incomes and poor health fare worse, despite protections of Medicaid. Spending rises 40 percent from 2012 to 2035 (from 10 to 14 percent of income) for the median beneficiary, but it increases from 5 to 25 percent of income for low-income beneficiaries and from 23 to 29 percent for the near poor who are in fair/poor health. CONCLUSIONS: Despite Medicare coverage, near-poor seniors will face out-of-pocket spending that would render them, in practical terms, underinsured. PMID- 28024315 TI - Patient, Physician, and Health-System Factors Influencing the Quality of Antidepressant and Sedative Prescribing for Older, Community-Dwelling Adults. AB - OBJECTIVE: To identify determinants of potentially inappropriate (PI) antidepressant and anxiolytic/sedative prescribing for older, community-dwelling adults. DATA SOURCES/STUDY SETTING: Office visits from the 2010 National Ambulatory Medical Care Survey. STUDY DESIGN: A cross-sectional study measuring associations between various patient and physician factors and prescribing of PI antidepressants, and PI sedatives among elderly, using Beers 2012/2015 criteria, a clinical decision model, and multivariate logistic regressions. DATA COLLECTION: Visits by older adults (>=65 years) involving medications were extracted to identify visits with antidepressants and sedatives. PRINCIPAL FINDINGS: Black race, asthma, depression, osteoporosis, payment type, consultation time, and computer systems with prescribing support were associated with reduced odds of PI antidepressant prescribing among users. Income, chronic renal failure, diabetes, and obesity were associated with reduced odds of PI sedative prescribing. Female sex, white race, depression, increasing number of medications, and physician specialty were associated with increased odds of PI sedative prescribing. CONCLUSIONS: Various patient and health-system factors influence the quality of antidepressant and sedative prescribing for older community-dwelling adults. Longer consultations and the use of computer systems with prescribing support may minimize potentially inappropriate antidepressant prescribing. As medication numbers increase, exposure to PI sedatives is more likely, requiring medication review and monitoring. PMID- 28024316 TI - Cavin-2 Functions as a Suppressive Regulator in TNF-induced Mesenchymal Stromal Cell Inflammation and Angiogenic Phenotypes. AB - Tumour necrosis factor (TNF)-alpha activation of mesenchymal stromal cells (MSC) enhances their tumour-suppressive properties and tumour-homing ability. The molecular actors involved are unknown. We found that TNF induced MSC migration and tubulogenesis which correlated with a dose-dependent increase in Cavin-1 and Cavin-3 transcript levels. TNF triggered cyclooxygenase (COX)-2 expression, whereas specific siRNA-mediated gene silencing of Cavin-2 resulted in an amplified COX-2 expression, tubulogenesis, and migratory response partially due to a rapid and sustained increase in NF-kappaB phosphorylation status. Our results highlight a suppressive role for the caveolar component Cavin-2 in the angiogenic and inflammatory regulation of TNF-activated MSC. PMID- 28024317 TI - Induction of Nestin Early Expression as a Hallmark for Mesenchymal Stem Cells Expression of PDX-1 as a Pre-disposing Factor for Their Conversion into Insulin Producing Cells. AB - Diabetes constitutes a worldwide epidemic that affects all ethnic groups. Cell therapy is one of the best alternatives of treatment, by providing an effective way to regenerate insulin-producing cells lost during the course of the disease, but many issues remain to be solved. Several groups have been working in the development of a protocol capable of differentiating Mesenchymal Stem Cells (MSCs) into physiologically sound Insulin Producing Cells (IPCs). In order to obtain a simple, fast and direct method, we propose in this manuscript the induction of MSCs to express NESTIN in a short time period (2 h), proceeded by incubation in a low glucose induced medium (24 h) and lastly by incubation in a high glucose medium. Samples from cell cultures incubated in high glucose medium from 12 to 168 h were obtained to detect the expression of INSULIN-1, INSULIN -2, PDX-1 and GLUT-2 genes. Induced cells were exposed to a glucose challenge, in order to assess the production of insulin. This method allowed us to obtain cells expressing PDX-1, which resembles a progenitor insulin-producing cell. PMID- 28024318 TI - Empirical Method To Accurately Determine Peptide-Averaged Protection Factors from Hydrogen Exchange MS Data. AB - Amide hydrogen exchange experiments measured by mass spectrometry have become commonplace to study protein structural dynamics; however, the underdetermined nature of these measurements render extraction of exchange rates unreliable at the level of individual peptides. This prevents orthogonal verification of results and severely limits interpretation of the data. This work describes an easy-to-implement empirical method to determine the change in an observed rate constant or the average change in multiple rate constants as compared to some reference condition. This allows direct empirical computation of the average protection factor (PF) for peptides in isolation requiring no knowledge of actual rate constants themselves. Benchmarking the method by comparison of average peptide PFs with site-resolved NMR-derived PFs demonstrates high reliability and accuracy. This empirical method provides the first universally reliable strategy for recovering subglobal structural physics from individual peptides and, in doing so, standardizes the hydrogen exchange experiments measured by bottom-up mass spectrometry (HX MS), simplifies interpretation, and facilitates clear communication of the results. PMID- 28024319 TI - Tomography of a Probe Potential Using Atomic Sensors on Graphene. AB - Our ability to access and explore the quantum world has been greatly advanced by the power of atomic manipulation and local spectroscopy with scanning tunneling and atomic force microscopes, where the key technique is the use of atomically sharp probe tips to interact with an underlying substrate. Here we employ atomic manipulation to modify and quantify the interaction between the probe and the system under study that can strongly affect any measurement in low charge density systems, such as graphene. We transfer Co atoms from a graphene surface onto a probe tip to change and control the probe's physical structure, enabling us to modify the induced potential at a graphene surface. We utilize single Co atoms on a graphene field-effect device as atomic scale sensors to quantitatively map the modified potential exerted by the scanning probe over the whole relevant spatial and energy range. PMID- 28024320 TI - Three-Dimensional Fin-Structured Semiconducting Carbon Nanotube Network Transistor. AB - Three-dimensional (3-D) fin-structured carbon nanotube field-effect transistors (CNT-FETs) with purified 99.9% semiconducting CNTs were demonstrated on a large scale 8 in. silicon wafer. The fabricated 3-D CNT-FETs take advantage of the 3-D geometry and exhibit enhanced electrostatic gate controllability and superior charge transport. A trigated structure surrounding the randomly networked single walled CNT channel was formed on a fin-like 3-D silicon frame, and as a result, the effective packing density increased to almost 600 CNTs/MUm. Additionally, highly sensitive controllability of the threshold voltage (VTH) was achieved using a thin back gate oxide in the same silicon frame to control power consumption and enhance performance. Our results are expected to broaden the design margin of CNT-based circuit architectures for versatile applications. The proposed 3-D CNT-FETs can potentially provide a desirable alternative to silicon based nanoelectronics and a blueprint for furthering the practical use of emerging low-dimensional materials other than CNTs. PMID- 28024321 TI - Strain-Gradient Modulated Exciton Emission in Bent ZnO Wires Probed by Cathodoluminescence. AB - Photoelectrical properties of semiconductor nanostructures are expected to be improved significantly by strain engineering. Besides the local strain, the strain gradient is promising to tune the luminescence properties by modifying the crystal symmetry. Here, we report the investigation of strain-gradient induced symmetry-breaking effect on excitonic states in pure bending ZnO microwires by high spatial-resolved cathodoluminescence at low temperature of 80 K. In addition to the local-strain induced light emission peak shift, the bound exciton emission photon energy shows an extraordinary jump of ~16.6 meV at a high strain-gradient of 1.22% MUm-1, which is ascribed to the strain gradient induced symmetry breaking. Such a symmetry-breaking lifts the energy degeneracy of the electronic band structures, which significantly modifies the electron-hole interactions and the fine structures of the bound exciton states. These results provide a further understanding of the strain gradient effect on the excitonic states and possess a potential for the applications in optoelectronic devices. PMID- 28024322 TI - Enhanced Luminescence Performance of Quantum Wells by Coupling Piezo-Phototronic with Plasmonic Effects. AB - With a promising prospect of light-emitting diodes as an attractive alternative to conventional light sources, remaining challenges still cannot be addressed owing to their limited efficiency. Among the continued scientific efforts, significant improvement on the emission efficiency has been achieved via either piezo-phototronic effect-based strain modulation or resonant excitation of plasmons in metallic nanostructures. Here, we present the investigation on the coupling process between piezo-phototronic effect and localized surface plasmonic resonance for enhancing the photoluminescence of InGaN/GaN quantum wells coated with Ag nanoparticles. The underlying physical mechanism of experimental results originates from tuning plasmonic resonance controlled by the shift of emission wavelength via piezo-phototronic effect, and it is further confirmed with the support of theoretical calculations. As a result, our research provides an approach to the integration of plasmonics with piezo-phototronic effect and brings widespread applications to high-efficiency artificial lighting, on-chip integrated plasmonic circuits, subwavelength optical communication, and micro optoelectronic mechanical systems. PMID- 28024323 TI - Self-Assembled Active Plasmonic Waveguide with a Peptide-Based Thermomechanical Switch. AB - Nanoscale plasmonic waveguides composed of metallic nanoparticles are capable of guiding electromagnetic energy below the optical diffraction limit. Signal feed in and readout typically require the utilization of electronic effects or near field optical techniques, whereas for their fabrication mainly lithographic methods are employed. Here we developed a switchable plasmonic waveguide assembled from gold nanoparticles (AuNPs) on a DNA origami structure that facilitates a simple spectroscopic excitation and readout. The waveguide is specifically excited at one end by a fluorescent dye, and energy transfer is detected at the other end via the fluorescence of a second dye. The transfer distance is beyond the multicolor FRET range and below the Abbe limit. The transmittance of the waveguide can also be reversibly switched by changing the position of a AuNP within the waveguide, which is tethered to the origami platform by a thermoresponsive peptide. High-yield fabrication of the plasmonic waveguides in bulk was achieved using silica particles as solid supports. Our findings enable bulk solution applications for plasmonic waveguides as light focusing and light-polarizing elements below the diffraction limit. PMID- 28024324 TI - High-Efficiency Nanowire Solar Cells with Omnidirectionally Enhanced Absorption Due to Self-Aligned Indium-Tin-Oxide Mie Scatterers. AB - Photovoltaic cells based on arrays of semiconductor nanowires promise efficiencies comparable or even better than their planar counterparts with much less material. One reason for the high efficiencies is their large absorption cross section, but until recently the photocurrent has been limited to less than 70% of the theoretical maximum. Here we enhance the absorption in indium phosphide (InP) nanowire solar cells by employing broadband forward scattering of self-aligned nanoparticles on top of the transparent top contact layer. This results in a nanowire solar cell with a photovoltaic conversion efficiency of 17.8% and a short-circuit current of 29.3 mA/cm2 under 1 sun illumination, which is the highest reported so far for nanowire solar cells and among the highest reported for III-V solar cells. We also measure the angle-dependent photocurrent, using time-reversed Fourier microscopy, and demonstrate a broadband and omnidirectional absorption enhancement for unpolarized light up to 60 degrees with a wavelength average of 12% due to Mie scattering. These results unambiguously demonstrate the potential of semiconductor nanowires as nanostructures for the next generation of photovoltaic devices. PMID- 28024325 TI - A High-Capacity and Long-Cycle-Life Lithium-Ion Battery Anode Architecture: Silver Nanoparticle-Decorated SnO2/NiO Nanotubes. AB - The combination of high-capacity and long-term cyclability has always been regarded as the first priority for next generation anode materials in lithium-ion batteries (LIBs). To meet these requirements, the Ag nanoparticle decorated mesoporous SnO2/NiO nanotube (m-SNT) anodes were synthesized via an electrospinning process, followed by fast ramping rate calcination and subsequent chemical reduction in this work. The one-dimensional porous hollow structure effectively alleviates a large volume expansion during cycling as well as provides a short lithium-ion duffusion length. Furthermore, metallic nickel (Ni) nanoparticles converted from the NiO nanograins during the lithiation process reversibly decompose Li2O during delithiation process, which significantly improves the reversible capacity of the m-SNT anodes. In addition, Ag nanoparticles uniformly decorated on the m-SNT via a simple chemical reduction process significantly improve rate capability and also contribute to long-term cyclability. The m-SNT@Ag anodes exhibited excellent cycling stability without obvious capacity fading after 500 cycles with a high capacity of 826 mAh g-1 at a high current density of 1000 mA g-1. Furthermore, even at a very high current density of 5000 mA g-1, the charge-specific capacity remained as high as 721 mAh g-1, corresponding to 60% of its initial capacity at a current density of 100 mA g-1. PMID- 28024326 TI - Surpassing the Exciton Diffusion Limit in Single-Walled Carbon Nanotube Sensitized Solar Cells. AB - Semiconducting single-walled carbon nanotube (s-SWNT) light sensitized devices, such as infrared photodetectors and solar cells, have recently been widely reported. Despite their excellent individual electrical properties, efficient carrier transport from one carbon nanotube to another remains a fundamental challenge. Specifically, photovoltaic devices with active layers made from s SWNTs have suffered from low efficiencies caused by three main challenges: the overwhelming presence of high-bandgap polymers in the films, the weak bandgap offset between the LUMO of the s-SWNTs and the acceptor C60, and the limited exciton diffusion length from one SWNT to another of around 5 nm that limits the carrier extraction efficiency. Herein, we employ a combination of processing and device architecture design strategies to address each of these transport challenges and fabricate photovoltaic devices with s-SWNT films well beyond the exciton diffusion limit of 5 nm. While our solution processing method minimizes the presence of undesired polymers in our active films, our interfacial designs led to a significant increase in current generation with the addition of a highly doped C60 layer (n-doped C60), resulting in increased carrier separation efficiency from the s-SWNTs films. We create a dense interconnected nanoporous mesh of s-SWNTs using solution shearing and infiltrate it with the acceptor C60. Thus, our final engineered bulk heterojunction allows carriers from deep within to be extracted by the C60 registering a 10-fold improvement in performance from our preliminary structures. PMID- 28024327 TI - Simple Synthesis of Nanocrystalline Tin Sulfide/N-Doped Reduced Graphene Oxide Composites as Lithium Ion Battery Anodes. AB - Composites of nitrogen-doped reduced graphene oxide (NRGO) and nanocrystalline tin sulfides were synthesized, and their performance as lithium ion battery anodes was evaluated. Following the first cycle the composite consisted of Li2S/LixSn/NRGO. The conductive NRGO cushions the stress associated with the expansion of lithiation of Sn, and the noncycling Li2S increases the residual Coulombic capacity of the cycled anode because (a) Sn domains in the composite formed of unsupported SnS2 expand only by 63% while those in the composite formed of unsupported SnS expand by 91% and (b) Li percolates rapidly at the boundary between the Li2S and LixSn nanodomains. The best cycling SnS2/NRGO-derived composite retained a specific capacity of 562 mAh g-1 at the 200th cycle at 0.2 A g-1 rate. PMID- 28024328 TI - High-Capacitance Mechanism for Ti3C2Tx MXene by in Situ Electrochemical Raman Spectroscopy Investigation. AB - MXenes represent an emerging family of conductive two-dimensional materials. Their representative, Ti3C2Tx, has been recognized as an outstanding member in the field of electrochemical energy storage. However, an in-depth understanding of fundamental processes responsible for the superior capacitance of Ti3C2Tx MXene in acidic electrolytes is lacking. Here, to understand the mechanism of capacitance in Ti3C2Tx MXene, we studied electrochemically the charge/discharge processes of Ti3C2Tx electrodes in sulfate ion-containing aqueous electrolytes with three different cations, coupled with in situ Raman spectroscopy. It is demonstrated that hydronium in the H2SO4 electrolyte bonds with the terminal O in the negative electrode upon discharging while debonding occurs upon charging. Correspondingly, the reversible bonding/debonding changes the valence state of Ti element in the MXene, giving rise to the pseudocapacitance in the acidic electrolyte. In stark contrast, only electric double layer capacitance is recognized in the other electrolytes of (NH4)2SO4 or MgSO4. The charge storage ways also differ: ion exchange dominates in H2SO4, while counterion adsorption in the rest. Hydronium that is characterized by smaller hydration radius and less charge is the most mobile among the three cations, facilitating it more kinetically accommodated on the deep adsorption sites between the MXene layers. The two key factors, i.e., surface functional group-involved bonding/debonding induced pseudocapacitance, and ion exchange-featured charge storage, simultaneously contribute to the superior capacitance of Ti3C2Tx MXene in acidic electrolytes. PMID- 28024329 TI - (n,m) Assignments of Metallic Single-Walled Carbon Nanotubes by Raman Spectroscopy: The Importance of Electronic Raman Scattering. AB - In this work, we report an accurate and convenient method that can be used to assign the chirality of all metallic single-walled carbon nanotubes (M-SWNTs). This method is designed based on the electronic Raman scattering (ERS) features, which are resonantly enhanced at the corresponding excitonic transition energies (Mii+ and Mii-). Using this method, we are able to accurately determine the electronic property Mii with the resolution of a vibrational Raman spectroscopy (~0.3 meV), which is significantly higher than that of the electronic spectroscopies (~3 meV). We use the Mii splitting value, which is found insensitive to environmental changes, as a universal criteria for (n,m) assignments in various environments. As an illustrative example, simply using a commercialized Raman spectrometer with two laser lines (1.959 and 2.330 eV), we are able to unambiguously assign 18 metallic chiralities with M11 in the 1.6-2.3 eV range in our samples. This method provides an accurate database of Mii's in a similar way as photoluminescence excitation spectroscopy does for Sii's. It can facilitate further systematic studies on the properties of M-SWNTs with defined chirality. PMID- 28024330 TI - Reversible Plasmonic Circular Dichroism via Hybrid Supramolecular Gelation of Achiral Gold Nanorods. AB - The fabrication of chiroptical plasmonic nanomaterials such as chiral plasmonic gold nanorods (GNRs) has been attracting great interest. Generally, in order to realize the plasmonic circular dichroism (PCD) from achiral GNRs, it is necessary to partially replace the surface-coated cetyltrimethylammonium bromide with chiral molecules. Here, we present a supramolecular approach to generate and modulate the PCD of GNRs through the hybrid gelation of GNRs with an amphiphilic chiral dendron gelator. Upon gelation, the PCD could be produced and further regulated depending on the ratio of the dendrons to GNRs. It was revealed that the wrapping of the self-assembled nanofibers around the GNRs is crucial for generating the PCD. Furthermore, the hybrid gel underwent a thermotriggered gel sol and sol-gel transformation, during which the PCD can disappear (solution) and reappear (gel), respectively, and such process can be repeated many times. In addition, the hybrid gel could also undergo shrinkage upon addition of a slight amount of Mg2+ ions, during which the PCD disappeared also. Thus, through the gel formation and subsequent metal ion- or temperature-triggered phase transition, PCD can be reversibly modulated. The results not only clarified the generation mechanism of PCD from the achiral GNRs without the chiral modification on the surface but also offered a simple and efficient way to modulate the PCD. PMID- 28024331 TI - Formation of Silicene Nanosheets on Graphite. AB - The extraordinary properties of graphene have spurred huge interest in the experimental realization of a two-dimensional honeycomb lattice of silicon, namely, silicene. However, its synthesis on supporting substrates remains a challenging issue. Recently, strong doubts against the possibility of synthesizing silicene on metallic substrates have been brought forward because of the non-negligible interaction between silicon and metal atoms. To solve the growth problems, we directly deposited silicon on a chemically inert graphite substrate at room temperature. Based on atomic force microscopy, scanning tunneling microscopy, and ab initio molecular dynamics simulations, we reveal the growth of silicon nanosheets where the substrate-silicon interaction is minimized. Scanning tunneling microscopy measurements clearly display the atomically resolved unit cell and the small buckling of the silicene honeycomb structure. Similar to the carbon atoms in graphene, each of the silicon atoms has three nearest and six second nearest neighbors, thus demonstrating its dominant sp2 configuration. Our scanning tunneling spectroscopy investigations confirm the metallic character of the deposited silicene, in excellent agreement with our band structure calculations that also exhibit the presence of a Dirac cone. PMID- 28024332 TI - Structure and Growth of Hexagonal Boron Nitride on Ir(111). AB - Using the X-ray standing wave method, scanning tunneling microscopy, low energy electron diffraction, and density functional theory, we precisely determine the lateral and vertical structure of hexagonal boron nitride on Ir(111). The moire superstructure leads to a periodic arrangement of strongly chemisorbed valleys in an otherwise rather flat, weakly physisorbed plane. The best commensurate approximation of the moire unit cell is (12 * 12) boron nitride cells resting on (11 * 11) substrate cells, which is at variance with several earlier studies. We uncover the existence of two fundamentally different mechanisms of layer formation for hexagonal boron nitride, namely, nucleation and growth as opposed to network formation without nucleation. The different pathways are linked to different distributions of rotational domains, and the latter enables selection of a single orientation only. PMID- 28024333 TI - Interplay of Chemical and Electronic Structure on the Single-Molecule Level in 2D Polymerization. AB - Single layers of covalently linked organic materials in the form of two dimensional (2D) polymers constitute structures complementary to inorganic 2D materials. The electronic properties of 2D polymers may be manipulated through a deliberate choice of the organic precursors. Here we address the changes in electronic structure-from precursor molecule to oligomer-by scanning tunneling spectroscopy and ultraviolet photoelectron spectroscopy. For this purpose, we introduce the polymerization reaction of 1,3,5-tris(4-carboxyphenyl)benzene via decarboxylation on Cu(111), which is thoroughly characterized by scanning tunneling microscopy, X-ray photoelectron spectroscopy, and density functional theory calculations. We present a comprehensive study of a contamination-free on surface coupling scheme and study how dehydrogenation, decarboxylation, and polymerization affect the electronic structure on the molecular level. PMID- 28024334 TI - Functionalized Nano-MoS2 with Peroxidase Catalytic and Near-Infrared Photothermal Activities for Safe and Synergetic Wound Antibacterial Applications. AB - We have developed a biocompatible antibacterial system based on polyethylene glycol functionalized molybdenum disulfide nanoflowers (PEG-MoS2 NFs). The PEG MoS2 NFs have high near-infrared (NIR) absorption and peroxidase-like activity, which can efficiently catalyze decomposition of low concentration of H2O2 to generate hydroxyl radicals (.OH). The conversion of H2O2 into .OH can avoid the toxicity of high concentration of H2O2 and the .OH has higher antibacterial activity, making resistant bacteria more vulnerable and wounds more easily cured. The PEG-MoS2 NFs combine the catalysis with NIR photothermal effect, providing a rapid and effective killing outcome in vitro for Gram-negative ampicillin resistant Escherichia coli (Ampr E. coli) and Gram-positive endospore-forming Bacillus subtilis (B. subtilis) as compared to catalytic treatment or photothermal therapy (PTT) alone. Wound healing results indicate that the synergy antibacterial system could be conveniently used for wound disinfection in vivo. Interestingly, glutathione (GSH) oxidation can be accelerated due to the 808 nm irradiation induced hyperthermia at the presence of PEG-MoS2 NFs proved by X-ray near-edge absorption spectra and X-ray spectroscopy. The accelerated GSH oxidation can result in bacterial death more easily. A mechanism based on .OH enhanced PTT is proposed to explain the antibacterial process. PMID- 28024335 TI - Nanoimprinted Perovskite Nanograting Photodetector with Improved Efficiency. AB - Recently, organolead halide-based perovskites have emerged as promising materials for optoelectronic applications, particularly for photovoltaics, photodetectors, and lasing, with low cost and high performance. Meanwhile, nanoscale photodetectors have attracted tremendous attention toward realizing miniaturized optoelectronic systems, as they offer high sensitivity, ultrafast response, and the capability to detect beyond the diffraction limit. Here we report high performance nanoscale-patterned perovskite photodetectors implemented by nanoimprint lithography (NIL). The spin-coated lead methylammonium triiodide perovskite shows improved crystallinity and optical properties after NIL. The nanoimprinted metal-semiconductor-metal photodetectors demonstrate significantly improved performance compared to the nonimprinted conventional thin-film devices. The effects of NIL pattern geometries on the optoelectronic characteristics were studied, and the nanograting pattern based photodetectors demonstrated the best performance, showing approximately 35 times improvement on responsivity and 7 times improvement on on/off ratio compared with the nonimprinted devices. The high performance of NIL-nanograting photodetectors likely results from high crystallinity and favored nanostructure morphology, which contribute to higher mobility, longer diffusion length, and better photon absorption. Our results have demonstrated that the NIL is a cost-effective method to fabricate high performance perovskite nanoscale optoelectronic devices, which may be suitable for manufacturing of high-density perovskite nanophotodetector arrays and to provide integration with state-of-the-art electronic circuits. PMID- 28024336 TI - Fully Packaged Blue Energy Harvester by Hybridizing a Rolling Triboelectric Nanogenerator and an Electromagnetic Generator. AB - Ocean energy, in theory, is an enormous clean and renewable energy resource that can generate electric power much more than that required to power the entire globe without adding any pollution to the atmosphere. However, owing to a lack of effective technology, such blue energy is almost unexplored to meet the energy requirement of human society. In this work, a fully packaged hybrid nanogenerator consisting of a rolling triboelectric nanogenerator (R-TENG) and an electromagnetic generator (EMG) is developed to harvest water motion energy. The outstanding output performance of the R-TENG (45 cm3 in volume and 28.3 g in weight) in the low-frequency range (<1.8 Hz) complements the ineffective output of EMG (337 cm3 in volume and 311.8 g in weight) in the same range and thus enables the hybrid nanogenerator to deliver valuable outputs in a broad range of operation frequencies. Therefore, the hybrid nanogenerator can maximize the energy conversion efficiency and broaden the operating frequency simultaneously. In terms of charging capacitors, this hybrid nanogenerator provides not only high voltage and consistent charging from the TENG component but also fast charging speed from the EMG component. The practical application of the hybrid nanogenerator is also demonstrated to power light-emitting diodes by harvesting energy from stimulated tidal flow. The high robustness of the R-TENG is also validated based on the stable electrical output after continuous rolling motion. Therefore, the hybrid R-TENG and EMG device renders an effective and sustainable approach toward large-scale blue energy harvesting in a broad frequency range. PMID- 28024337 TI - Universal Readers Based on Hydrogen Bonding or pi-pi Stacking for Identification of DNA Nucleotides in Electron Tunnel Junctions. AB - A reader molecule, which recognizes all the naturally occurring nucleobases in an electron tunnel junction, is required for sequencing DNA by a recognition tunneling (RT) technique, referred to as a universal reader. In the present study, we have designed a series of heterocyclic carboxamides based on hydrogen bonding and a large-sized pyrene ring based on a pi-pi stacking interaction as universal reader candidates. Each of these compounds was synthesized to bear a thiolated linker for attachment to metal electrodes and examined for their interactions with naturally occurring DNA nucleosides and nucleotides by 1H NMR, ESI-MS, computational calculations, and surface plasmon resonance. RT measurements were carried out in a scanning tunnel microscope. All of these molecules generated electrical signals with DNA nucleotides in tunneling junctions under physiological conditions (phosphate buffered aqueous solution, pH 7.4). Using a support vector machine as a tool for data analysis, we found that these candidates distinguished among naturally occurring DNA nucleotides with the accuracy of pyrene (by pi-pi stacking interactions) > azole carboxamides (by hydrogen-bonding interactions). In addition, the pyrene reader operated efficiently in a larger tunnel junction. However, the azole carboxamide could read abasic (AP) monophosphate, a product from spontaneous base hydrolysis or an intermediate of base excision repair. Thus, we envision that sequencing DNA using both pi-pi stacking and hydrogen-bonding-based universal readers in parallel should generate more comprehensive genome sequences than sequencing based on either reader molecule alone. PMID- 28024338 TI - Ultrasmall Biocompatible Bi2Se3 Nanodots for Multimodal Imaging-Guided Synergistic Radiophotothermal Therapy against Cancer. AB - Sub-3 nm ultrasmall Bi2Se3 nanodots stabilized with bovine serum albumin were successfully synthesized through a reaction of hydroxyethylthioselenide with bismuth chloride in aqueous solution under ambient conditions. These nanodots exhibit a high photothermal conversion efficiency (eta = 50.7%) due to their strong broad absorbance in the near-infrared (NIR) window and serve as a nanotheranostic agent for photoacoustic imaging and photothermal cancer therapy. In addition, they also display radioenhancement with a ratio of 6% due to their sensitivity to X-rays, which makes them a potential sensitizer for radiotherapy. These nanodots were also labled with radioactive 99mTc for quantification of their biodistribution by single-photon-emission computed tomography (SPECT)/computed tomography (CT) imaging. Our work demonstrates the potential of ultrasmall Bi2Se3 nanodots in multimodal imaging-guided synergetic radiophotothermal therapy of cancer. PMID- 28024339 TI - Using Gold Nanoparticles To Disrupt the Tumor Microenvironment: An Emerging Therapeutic Strategy. AB - Gold nanoparticles have received much attention recently as carriers for anticancer drugs and therapeutic oligonucleotides, but little research has investigated their potential to act as stand-alone therapeutics. Previous studies interrogating their short- and long-term systemic toxicity have found that although gold nanoparticles accumulate within and clear slowly from the liver and spleen, they do not appear to exert toxic effects in these organs. Interestingly, gold nanoparticles innately exhibit the ability to modulate the tumor microenvironment specifically by interfering with crosstalk between tumor cells and stromal cells. In this issue of ACS Nano, Mukherjee and colleagues demonstrate that bare gold nanoparticles can disturb crosstalk between pancreatic stellate cells and pancreatic cancer cells by modulating the cellular secretome to reduce the growth of desmoplastic tissue and inhibit tumor growth. In this Perspective, we highlight opportunities for anticancer targeting within the tumor microenvironment and discuss gold nanoparticles as potential mediators of microenvironment-targeted therapy. PMID- 28024340 TI - Superhydrophobic Cones for Continuous Collection and Directional Transportation of CO2 Microbubbles in CO2 Supersaturated Solutions. AB - Microbubbles are tiny bubbles with diameters below 50 MUm. Because of their minute buoyant force, the microbubbles stagnate in aqueous media for a long time, and they sometimes cause serious damage. Most traditional methods chosen for elimination of gas bubbles utilize buoyancy forces including chemical methods and physical methods, and they only have a minor effect on microbubbles. Several approaches have been developed to collect and transport microbubbles in aqueous media. However, the realization of innovative strategies to directly collect and transport microbubbles in aqueous media remains a big challenge. In nature, both spider silk and cactus spines take advantage of their conical-shaped surface to yield the gradient of Laplace pressure and surface free energy for collecting fog droplets from the environment. Inspired by this, we introduce here the gradient of Laplace pressure and surface free energy to the interface of superhydrophobic copper cones (SCCs), which can continuously collect and directionally transport CO2 microbubbles (from tip side to base side) in CO2-supersaturated solution. A gas layer was formed when the microbubbles encounter the SCCs. This offers a channel for microbubble directional transportation. The efficiency of microbubble transport is significantly affected by the apex angle of SCCs and the carbon dioxide concentration. The former provides different gradients of Laplace pressure as the driving force. The latter represents the capacity, which offers the quantity of CO2 microbubbles for collection and transportation. We believe that this approach provides a simple and valid way to remove microbubbles. PMID- 28024341 TI - Direct Chemical-Vapor-Deposition-Fabricated, Large-Scale Graphene Glass with High Carrier Mobility and Uniformity for Touch Panel Applications. AB - In this work, we report the transfer-free measurement of carrier dynamics and transport of direct chemical vapor deposition (CVD) grown graphene on glass with the aid of ultrafast transient absorption microscopy (TAM) and demonstrate the use of such graphene glass for high-performance touch panel applications. The 4.5 in.-sized graphene glass was produced by an optimized CVD procedure, which can readily serve as transparent conducting electrode (TCE) without further treatment. The graphene glass exhibited an intriguing optical transmittance and electrical conductance concurrently, presenting a sheet resistance of 370-510 Omega.sq-1 at a transmittance of 82%, much improved from our previous achievements. Moreover, direct measurement of graphene carrier dynamics and transport by TAM revealed the similar biexponential decay behavior to that of CVD graphene grown on Cu, along with a carrier mobility as high as 4820 cm2.V-1.s-1. Such large-area, highly uniform, transparent conducting graphene glass was assembled to integrate resistive touch panels that demonstrated a high device performance. Briefly, this work aims to present the great feasibility of good quality graphene glass toward scalable and practical TCE applications. PMID- 28024342 TI - Mo2C Nanoparticles Dispersed on Hierarchical Carbon Microflowers for Efficient Electrocatalytic Hydrogen Evolution. AB - The development of nonprecious metal based electrocatalysts for hydrogen evolution reaction (HER) has received increasing attention over recent years. Previous studies have established Mo2C as a promising candidate. Nevertheless, its preparation requires high reaction temperature, which more than often causes particle sintering and results in low surface areas. In this study, we show supporting Mo2C nanoparticles on the three-dimensional scaffold as a possible solution to this challenge and develop a facile two-step preparation method for ~3 nm Mo2C nanoparticles uniformly dispersed on carbon microflowers (Mo2C/NCF) via the self-polymerization of dopamine. The resulting hybrid material possesses large surface areas and a fully open and accessible structure with hierarchical order at different levels. MoO42- was found to play an important role in inducing the formation of this morphology presumably via its strong chelating interaction with the catechol groups of dopamine. Our electrochemical evaluation demonstrates that Mo2C/NCF exhibits excellent HER electrocatalytic performance with low onset overpotentials, small Tafel slopes, and excellent cycling stability in both acidic and alkaline solutions. PMID- 28024343 TI - Comment on "Electrum, the Gold-Silver Alloy, from the Bulk Scale to the Nanoscale: Synthesis, Properties, and Segregation Rules". PMID- 28024344 TI - Modifying the Size of Ultrasound-Induced Liquid-Phase Exfoliated Graphene: From Nanosheets to Nanodots. AB - Ultrasound-induced liquid-phase exfoliation (UILPE) is an established method to produce single- (SLG) and few-layer (FLG) graphene nanosheets starting from graphite as a precursor. In this paper we investigate the effect of the ultrasonication power in the UILPE process carried out in either N-methyl-2 pyrrolidone (NMP) or ortho-dichlorobenzene (o-DCB). Our experimental results reveal that while the SLGs/FLGs concentration of the NMP dispersions is independent of the power of the ultrasonic bath during the UILPE process, in o DCB it decreases as the ultrasonication power increases. Moreover, the ultrasonication power has a strong influence on the lateral size of the exfoliated SLGs/FLGs nanosheets in o-DCB. In particular, when UILPE is carried out at ~600 W, we obtain dispersions composed of graphene nanosheets with a lateral size of 180 nm, whereas at higher power (~1000 W) we produce graphene nanodots (GNDs) with an average diameter of ~17 nm. The latter nanostructures exhibit a strong and almost excitation-independent photoluminescence emission in the UV/deep-blue region of the electromagnetic spectrum arising from the GNDs' intrinsic states and a less intense (and strongly excitation wavelength dependent) emission in the green/red region attributed to defect states. Notably, we also observe visible emission with near-infrared excitation at 850 and 900 nm, a fingerprint of the presence of up-conversion processes. Overall, our results highlight the crucial importance of the solvent choice for the UILPE process, which under controlled experimental conditions allows the fine-tuning of the morphological properties, such as lateral size and thickness, of the graphene nanosheets toward the realization of luminescent GNDs. PMID- 28024345 TI - Bound Layers "Cloak" Nanoparticles in Strongly Interacting Polymer Nanocomposites. AB - Polymer-nanoparticle (NP) interfacial interactions are expected to strongly influence the properties of nanocomposites, but surprisingly, experiments often report small or no changes in the glass transition temperature, Tg. To understand this paradoxical situation, we simulate nanocomposites over a broad range of polymer-NP interaction strengths, epsilon. When epsilon is stronger than the polymer-polymer interaction, a distinct relaxation that is slower than the main alpha-relaxation emerges, arising from an adsorbed "bound" polymer layer near the NP surface. This bound layer "cloaks" the NPs, so that the dynamics of the matrix polymer are largely unaffected. Consequently, Tg defined from the temperature dependence of the routinely measured thermodynamics or the polymer matrix relaxation is nearly independent of epsilon, in accord with many experiments. Apparently, quasi-thermodynamic measurements do not reliably reflect dynamical changes in the bound layer, which alter the overall composite dynamics. These findings clarify the relation between quasi-thermodynamic Tg measurements and nanocomposite dynamics, and should also apply to thin polymer films. PMID- 28024346 TI - Multifunctional Silicon Optoelectronics Integrated with Plasmonic Scattering Color. AB - Plasmonic scattering from metallic nanoparticles has been used for centuries to create the colorful appearance of stained glass. Besides their use as passive spectral filtering components, multifunctional optoelectronic applications can be achieved by integrating the nanoscatters with semiconductors that generate electricity using the complementary spectral components of plasmonic colors. To suppress the usual degradation of both efficiency and the gamut of plasmonic scattering coloration in highly asymmetric index configurations like a silicon host, aluminum nanodisks on indium tin oxide (ITO) coated silicon were experimentally studied and demonstrated color sorting in the full visible range along with photocurrent generation. Interestingly, the photocurrents were found to be comparable to the reference devices with only antireflection coatings in spite of the power loss for coloration. Detailed investigation shows that ITO serves as both the impedance matching layer for promoting the backward scattering and schottky contact with silicon, and moreover, plasmonic nanoscatters efficiently harvest the complement spectrum components for charge generation. The present approach combines the capacities of nanoscale color sorting and photoelectric converting at a negligible cost of efficiency, thus providing a broad flexibility of being utilized in various optoelectronic applications including self-powered display, filter-free imaging, and colorful photovoltaics. PMID- 28024347 TI - Fano Transparency in Rounded Nanocube Dimers Induced by Gap Plasmon Coupling. AB - Homodimers of noble metal nanocubes form model plasmonic systems where the localized plasmon resonances sustained by each particle not only hybridize but also coexist with excitations of a different nature: surface plasmon polaritons confined within the Fabry-Perot cavity delimited by facing cube surfaces (i.e., gap plasmons). Destructive interference in the strong coupling between one of these highly localized modes and the highly radiating longitudinal dipolar plasmon of the dimer is responsible for the formation of a Fano resonance profile and the opening of a spectral window of anomalous transparency for the exciting light. We report on the clear experimental evidence of this effect in the case of 50 nm silver and 160 nm gold nanocube dimers studied by spatial modulation spectroscopy at the single particle level. A numerical study based on a plasmon mode analysis leads us to unambiguously identify the main cavity mode involved in this process and especially the major role played by its symmetry. The Fano depletion dip is red-shifted when the gap size is decreasing. It is also blue shifted and all the more pronounced that the cube edge rounding is large. Combining nanopatch antenna and plasmon hybridization descriptions, we quantify the key role of the face-to-face distance and the cube edge morphology on the spectral profile of the transparency dip. PMID- 28024349 TI - Following DNA Compaction During the Cell Cycle by X-ray Nanodiffraction. AB - X-ray imaging of intact biological cells is emerging as a complementary method to visible light or electron microscopy. Owing to the high penetration depth and small wavelength of X-rays, it is possible to resolve subcellular structures at a resolution of a few nanometers. Here, we apply scanning X-ray nanodiffraction in combination with time-lapse bright-field microscopy to nuclei of 3T3 fibroblasts and thus relate the observed structures to specific phases in the cell division cycle. We scan the sample at a step size of 250 nm and analyze the individual diffraction patterns according to a generalized Porod's law. Thus, we obtain information on the aggregation state of the nuclear DNA at a real space resolution on the order of the step size and in parallel structural information on the order of few nanometers. We are able to distinguish nucleoli, heterochromatin, and euchromatin in the nuclei and follow the compaction and decompaction during the cell division cycle. PMID- 28024348 TI - Polydopamine-Enabled Approach toward Tailored Plasmonic Nanogapped Nanoparticles: From Nanogap Engineering to Multifunctionality. AB - We present a platform strategy that offers diverse flexibility in tailoring the structure and properties of core-shell plasmonic nanoparticles with built-in nanogaps. Our results have demonstrated that polydopamine serves multiple concerted functions as a nanoscale spacer to afford controllable nanogap sizes, a redox-active coating to promote metal shell growth, and a reactive scaffold to exclusively lock molecular probes inside the nanogap for surface-enhanced Raman scattering (SERS). More interestingly, the universal adhesion of polydopamine on diverse colloidal substrates allows for customized synthesis of multishell plasmonic nanogapped nanoparticles (NNPs) and multifunctional hybrid NNPs containing different cores (i.e., magnetic nanoparticles), which are not readily accessible by conventional methods. Internally coupled plasmonic NNPs with broadly tunable spectroscopic properties, highly active SERS, and multifunctionality hold great promise for emerging fields, such as sensing, optoelectronics, and theranostics, as demonstrated by the ultrasensitive SERS detection and efficient photothermal killing of food-borne pathogens here. PMID- 28024350 TI - Some Like It Flat: Decoupled h-BN Monolayer Substrates for Aligned Graphene Growth. AB - On the path to functional graphene electronics, suitable templates for chemical vapor deposition (CVD) growth of high-mobility graphene are of great interest. Among various substrates, hexagonal boron nitride (h-BN) has established itself as one of the most promising candidates. The nanomesh, a h-BN monolayer grown on the Rh(111) surface where the lattice mismatch of h-BN and rhodium leads to a characteristic corrugation of h-BN, offers an interesting graphene/h-BN interface, different from flat graphene/h-BN systems hitherto studied. In this report, we describe a two-step CVD process for graphene formation on h-BN/Rh(111) at millibar pressures and describe the influence of the surface texture on the CVD process. During a first exposure to the 3-pentanone precursor, carbon atoms are incorporated in the rhodium subsurface, which leads to decoupling of the h-BN layer from the Rh(111) surface. This is reflected in the electronic band structure, where the corrugation-induced splitting of the h-BN bands vanishes. In a second 3-pentanone exposure, a graphene layer is formed on the flat h-BN layer, evidenced by the appearance of the characteristic linear dispersion of its pi band. The graphene layer grows incommensurate and highly oriented. The formation of graphene/h-BN on rhodium opens the door to scalable production of well-aligned heterostacks since single-crystalline thin-film Rh substrates are available in large dimensions. PMID- 28024351 TI - Understanding the Kinetics of Protein-Nanoparticle Corona Formation. AB - When a pristine nanoparticle (NP) encounters a biological fluid, biomolecules spontaneously form adsorption layers around the NP, called "protein corona". The corona composition depends on the time-dependent environmental conditions and determines the NP's fate within living organisms. Understanding how the corona evolves is fundamental in nanotoxicology as well as medical applications. However, the process of corona formation is challenging due to the large number of molecules involved and to the large span of relevant time scales ranging from 100 MUs, hard to probe in experiments, to hours, out of reach of all-atoms simulations. Here we combine experiments, simulations, and theory to study (i) the corona kinetics (over 10-3-103 s) and (ii) its final composition for silica NPs in a model plasma made of three blood proteins (human serum albumin, transferrin, and fibrinogen). When computer simulations are calibrated by experimental protein-NP binding affinities measured in single-protein solutions, the theoretical model correctly reproduces competitive protein replacement as proven by independent experiments. When we change the order of administration of the three proteins, we observe a memory effect in the final corona composition that we can explain within our model. Our combined experimental and computational approach is a step toward the development of systematic prediction and control of protein-NP corona composition based on a hierarchy of equilibrium protein binding constants. PMID- 28024352 TI - Improved Lithium Ionic Conductivity in Composite Polymer Electrolytes with Oxide Ion Conducting Nanowires. AB - Solid Li-ion electrolytes used in all-solid-state lithium-ion batteries (LIBs) are being considered to replace conventional liquid electrolytes that have leakage, flammability, and poor chemical stability issues, which represents one major challenge and opportunity for next-generation high-energy-density batteries. However, the low mobility of lithium ions in solid electrolytes limits their practical applications. Here, we report a solid composite polymer electrolyte with Y2O3-doped ZrO2 (YSZ) nanowires that are enriched with positive charged oxygen vacancies. The morphologies and ionic conductivities have been studied systemically according to concentration of Y2O3 dopant in the nanowires. In comparison to the conventional filler-free electrolyte with a conductivity of 3.62 * 10-7 S cm-1, the composite polymer electrolytes with the YSZ nanowires show much higher ionic conductivity. It indicates that incorporation of 7 mol % of Y2O3-doped ZrO2 nanowires results in the highest ionic conductivity of 1.07 * 10-5 S cm-1 at 30 degrees C. This conductivity enhancement originates from the positive-charged oxygen vacancies on the surfaces of the nanowires that could associate with anions and then release more Li ions. Our work demonstrates a composite polymer electrolyte with oxygen-ion conductive nanowires that could address the challenges of all-solid-state LIBs. PMID- 28024353 TI - Revealing the Conformational Dynamics in a Single-Molecule Junction by Site- and Angle-Resolved Dynamic Probe Method. AB - Single-molecule junctions have been extensively studied because of their high potential for future nanoscale device applications as well as their importance in basic studies for molecular science and technology. However, since the bonding sites at an electrode and the molecular tilt angles, for example, cannot be determined experimentally, analyses have been performed assuming the structures of such interactive key factors, with uncertainties and inconsistencies remaining in the proposed mechanisms. We have developed a methodology that enables the probing of conformational dynamics in single-molecule junctions simultaneously with the direct characterization of molecular bonding sites and tilt angles. This technique has revealed the elemental processes in single-molecule junctions, which have not been clarified using conventional methods. The mechanisms of the molecular dynamics in 1,4-benzenedithiol and 4,4'-bipyridine single-molecule junctions, which, for example, produce binary conductance switching of different types, were clearly discriminated and comprehensively explained. PMID- 28024354 TI - Nanoscience and Nanotechnology Impacting Diverse Fields of Science, Engineering, and Medicine. PMID- 28024355 TI - Hexagonal Boron Nitride/Au Substrate for Manipulating Surface Plasmon and Enhancing Capability of Surface-Enhanced Raman Spectroscopy. AB - We report on an insulating two-dimensional material, hexagonal boron nitride (h BN), which can be used as an effective wrapping layer for surface-enhanced Raman spectroscopy (SERS) substrates. This material exhibits outstanding characteristics such as its crystallinity, impermeability, and thermal conductance. Improved SERS sensitivity is confirmed for Au substrates wrapped with h-BN, the mechanism of which is investigated via h-BN thickness-dependent experiments combined with theoretical simulations. The investigations reveal that a stronger electromagnetic field can be generated at the narrowed gap of the h-BN surface, which results in higher Raman sensitivity. Moreover, the h-BN-wrapped Au substrate shows extraordinary stability against photothermal and oxidative damages. We also describe its capability to detect specific chemicals that are difficult to analyze using conventional SERS substrates. We believe that this concept of using an h-BN insulating layer to protect metallic or plasmonic materials will be widely used not only in the field of SERS but also in the broader study of plasmonic and optoelectronic devices. PMID- 28024356 TI - Ultrasound-Triggered Nitric Oxide Release Platform Based on Energy Transformation for Targeted Inhibition of Pancreatic Tumor. AB - Inspired by considerable application potential in various diseases, nitric oxide (NO) has gained increasing attention. Nevertheless, current NO release scaffolds suffer from some inevitable drawbacks, for example, high toxicity for NO donor byproducts, poor specificity, shallow penetration depth, and strong ionizing irradiation for triggers, all of which remain obstacles to clinical application. Herein, an ultrasound-triggered NO on-demand release system is constructed using natural l-arginine as NO donor and local ultrasound as trigger. The focused ultrasound can activate H2O2 to generate more oxygen-contained species (ROS) of stronger oxidation ability than H2O2 for oxidizing LA via the energy transformation from ultrasound mechanical energy to chemical energy, and thus produce more NO for ultimately suppressing the highly aggressive and lethal Panc 1 tumor. Moreover, a blood vessel-intercellular matrix-cell "relay" targeting strategy has been established and relying on it, over 7-fold higher retention of such NO release system in a subcutaneous xenograft mouse model of Panc-1 is obtained, which consequently results in a more evident inhibitory effect and a prolonged survival rate (80% +/- 5% improvement in 60-day survival). PMID- 28024357 TI - Controllable CO Release Following Near-Infrared Light-Induced Cleavage of Iron Carbonyl Derivatized Prussian Blue Nanoparticles for CO-Assisted Synergistic Treatment. AB - Carbon monoxide (CO) causes the dysfunction of mitochondria to induce the apoptosis of cancer cells giving a promising choice as an emerging treatment. The currently reported CO-based complexes still suffer from many limitations. Synthesis of CO-release carriers in the manner of on-demand control is highly anticipated. In this study, we present a near-infrared (NIR) light-responsive CO delivery nanocarrier, a PEGylated iron carbonyl derivatized Prussian blue (PB) nanoparticle (NP). Taking the structural characteristic containing Fe3+-N=C-Fe2+ unit, the -CN- served as the active sites for the coordination of iron carbonyl, while the surface Fe sites chelated with the amine-functionalized polyethylene glycol (NH2-PEG6000-NH2) to yield PEGylated PB NPs carrying CO. The control of light intensity and exposure period is important to release the amount of CO as well as to deliver the hyperthermia effect. The combination therapy including CO and photothermal treatments displayed a synergistic effect against cancer cells. Importantly, the release of CO is inert in the blood circulation without NIR irradiation. The blood oxygen saturation measured by the pulse oximeter and the HCO3, tCO2, and pH values analyzed by the blood assay revealed the steady status from the mice studies, showing no acute CO poisoning. PMID- 28024358 TI - Pronounced Fano Resonance in Single Gold Split Nanodisks with 15 nm Split Gaps for Intensive Second Harmonic Generation. AB - Single metallic nanostructures supporting strong Fano resonances allow more compact nanophotonics integration and easier geometrical control in practical applications such as enhanced spectroscopy and sensing. In this work, we designed a class of plasmonic split nanodisks that show pronounced Fano resonance comparable to that observed in widely studied plasmonic oligomer clusters. Using our recently developed "sketch and peel" electron-beam lithography, split nanodisks with varied diameter and split length were fabricated over a large area with high uniformity. Transmission spectroscopy measurements demonstrated that the fabricated structures with 15 nm split gap exhibit disk diameter and split length controlled Fano resonances in the near-infrared region, showing excellent agreement with simulation results. Together with the plasmon hybridization theory, in-depth full-wave analyses elucidated that the Fano resonances observed in the split nanodisks were induced by mode interference between the bright antibonding dipole mode of split disks and the subradiant mode supported by the narrow split gap. With the giant near-field enhancement enabled by the intensive Fano resonance at the tiny split gap, strong wavelength-dependent second harmonic generation was observed under near-infrared excitation. Our work demonstrated that single split nanodisks could serve as important building blocks for plasmonic and nanophotonic applications including sensing and nonlinear optics. PMID- 28024359 TI - Vibrational Properties of a Two-Dimensional Silica Kagome Lattice. AB - Kagome lattices are structures possessing fascinating magnetic and vibrational properties, but in spite of a large body of theoretical work, experimental realizations and investigations of their dynamics are scarce. Using a combination of Raman spectroscopy and density functional theory calculations, we study the vibrational properties of two-dimensional silica (2D-SiO2), which has a kagome lattice structure. We identify the signatures of crystalline and amorphous 2D SiO2 structures in Raman spectra and show that, at finite temperatures, the stability of 2D-SiO2 lattice is strongly influenced by phonon-phonon interaction. Our results not only provide insights into the vibrational properties of 2D-SiO2 and kagome lattices in general but also suggest a quick nondestructive method to detect 2D-SiO2. PMID- 28024360 TI - Large-Scale Automated Production of Highly Ordered Ultralong Hydroxyapatite Nanowires and Construction of Various Fire-Resistant Flexible Ordered Architectures. AB - Practical applications of nanostructured materials have been largely limited by the difficulties in controllable and scaled-up synthesis, large-sized highly ordered self-assembly, and macroscopic processing of nanostructures. Hydroxyapatite (HAP), the major inorganic component of human bone and tooth, is an important biomaterial with high biocompatibility, bioactivity, and high thermal stability. Large-sized highly ordered HAP nanostructures are of great significance for applications in various fields and for understanding the formation mechanisms of bone and tooth. However, the synthesis of large-sized highly ordered HAP nanostructures remains a great challenge, especially for the preparation of large-sized highly ordered ultralong HAP nanowires because ultralong HAP nanowires are easily tangled and aggregated. Herein, we report our three main research findings: (1) the large-scale synthesis of highly flexible ultralong HAP nanowires with lengths up to >100 MUm and aspect ratios up to >10000; (2) the demonstration of a strategy for the rapid automated production of highly flexible, fire-resistant, large-sized, self-assembled highly ordered ultralong HAP nanowires (SHOUHNs) at room temperature; and (3) the successful construction of various flexible fire-resistant HAP ordered architectures using the SHOUHNs, such as high-strength highly flexible nanostructured ropes (nanoropes), highly flexible textiles, and 3-D printed well-defined highly ordered patterns. The SHOUHNs are successively formed from the nanoscale to the microscale then to the macroscale, and the ordering direction of the ordered HAP structure is controllable. These ordered HAP architectures made from the SHOUHNs, such as highly flexible textiles, may be engineered into advanced functional products for applications in various fields, for example, fireproof clothing. PMID- 28024361 TI - Monitoring Dynamic Cellular Redox Homeostasis Using Fluorescence-Switchable Graphene Quantum Dots. AB - Monitoring cellular redox homeostasis is critical to the understanding of many physiological functions ranging from immune reactions to metabolism, as well as to the understanding of pathological development ranging from tumorigenesis to aging. Nevertheless, there is currently a lack of appropriate probes for this ambition, which should be reversibly, sensitively, and promptly responsive to a wide range of physiological oxidants and reductants. In this work, a redox sensitive fluorescence-switchable probe is designed based on graphene quantum dots (GQDs) functionalized with a chelated redox Fe2+/Fe3+ couple. The underlying mechanism is investigated and discussed. The high sensitivity and fast response are attributable to the fact that the GQD's photoluminescence is highly sensitive to photon-induced electron transfer because of its ultrasmall size and associated prominent quantum confinement effect. Also taking advantages of GQDs' excellent photostability, biocompatibility, and readiness for cell uptake, our reversibly tunable fluorescence probe is employed to monitor in real time the triggered dynamic change of the intracellular redox state. This addition to the limited arsenal of available redox probes shall be useful to the still poorly understood redox biology, as well as for monitoring environment or chemical processes involving redox reactions. PMID- 28024362 TI - Controlled Sub-Nanometer Epitope Spacing in a Three-Dimensional Self-Assembled Peptide Hydrogel. AB - Cells in the body use a variety of mechanisms to ensure the specificity and efficacy of signal transduction. One way that this is achieved is through tight spatial control over the position of different proteins, signaling sequences, and biomolecules within and around cells. For instance, the extracellular matrix protein fibronectin presents RGDS and PHSRN sequences that synergistically bind the alpha5beta1 integrin when separated by 3.2 nm but are unable to bind when this distance is >5.5 nm.1 Building biomaterials to controllably space different epitopes with subnanometer accuracy in a three-dimensional (3D) hydrogel is challenging. Here, we synthesized peptides that self-assemble into nanofiber hydrogels utilizing the beta-sheet motif, which has a known regular spacing along the peptide backbone. By modifying specific locations along the peptide, we are able to controllably space different epitopes with subnanometer accuracy at distances from 0.7 nm to over 6 nm, which is within the size range of many protein clusters. Endothelial cells encapsulated within hydrogels displaying RGDS and PHSRN in the native 3.2 nm spacing showed a significant upregulation in the expression of the alpha 5 integrin subunit compared to those in hydrogels with a 6.2 nm spacing, demonstrating the physiological relevance of the spacing. Furthermore, after 24 h the cells in hydrogels with the 3.2 nm spacing appeared to be more spread with increased staining for the alpha5beta1 integrin. This self assembling peptide system can controllably space multiple epitopes with subnanometer accuracy, demonstrating an exciting platform to study the effects of ligand density and location on cells within a synthetic 3D environment. PMID- 28024363 TI - Hierarchical Metal Oxide Topographies Replicated from Highly Textured Graphene Oxide by Intercalation Templating. AB - Confined assembly in the intersheet gallery spaces of two-dimensional (2D) materials is an emerging templating route for creation of ultrathin material architectures. Here, we demonstrate a general synthetic route for transcribing complex wrinkled and crumpled topographies in graphene oxide (GO) films into textured metal oxides. Intercalation of hydrated metal ions into textured GO multilayer films followed by dehydration, thermal decomposition, and air oxidation produces Zn, Al, Mn, and Cu oxide films with high-fidelity replication of the original GO textures, including "multi-generational", multiscale textures that have been recently achieved through extreme graphene compression. The textured metal oxides are shown to consist of nanosheet-like aggregates of interconnected particles, whose mobility, attachment, and sintering are guided by the 2D template. This intercalation templating approach has broad applicability for the creation of complex, textured films and provides a bridging technology that can transcribe the wide variety of textures already realized in graphene into insulating and semiconducting materials. These textured metal oxide films exhibit enhanced electrochemical and photocatalytic performance over planar films and show potential as high-activity electrodes for energy storage, catalysis, and biosensing. PMID- 28024364 TI - From Metal-Organic Framework to Li2S@C-Co-N Nanoporous Architecture: A High Capacity Cathode for Lithium-Sulfur Batteries. AB - Owing to the high theoretical specific capacity (1166 mAh g-1), lithium sulfide (Li2S) has been considered as a promising cathode material for Li-S batteries. However, the polysulfide dissolution and low electronic conductivity of Li2S limit its further application in next-generation Li-S batteries. In this report, a nanoporous Li2S@C-Co-N cathode is synthesized by liquid infiltration evaporation of ultrafine Li2S nanoparticles into graphitic carbon co-doped with cobalt and nitrogen (C-Co-N) derived from metal-organic frameworks. The obtained Li2S@C-Co-N architecture remarkably immobilizes Li2S within the cathode structure through physical and chemical molecular interactions. Owing to the synergistic interactions between C-Co-N and Li2S nanoparticles, the Li2S@C-Co-N composite delivers a reversible capacity of 1155.3 (99.1% of theoretical value) at the initial cycle and 929.6 mAh g-1 after 300 cycles, with nearly 100% Coulombic efficiency and a capacity fading of 0.06% per cycle. It exhibits excellent rate capacities of 950.6, 898.8, and 604.1 mAh g-1 at 1C, 2C, and 4C, respectively. Such a cathode structure is promising for practical applications in high performance Li-S batteries. PMID- 28024365 TI - Spatially Controlled Nucleation of Single-Crystal Graphene on Cu Assisted by Stacked Ni. AB - In spite of recent progress of graphene growth using chemical vapor deposition, it is still a challenge to precisely control the nucleation site of graphene for the development of wafer-scale single-crystal graphene. In addition, the postgrowth patterning used for device fabrication deteriorates the quality of graphene. Herein we demonstrate the site-selective nucleation of single-crystal graphene on Cu foil based on spatial control of the local CH4 concentration by a perforated Ni foil. The catalytically active Ni foil acts as a CH4 modulator, resulting in millimeter-scale single-crystal grains at desired positions. The perforated Ni foil also allows to synthesize patterned graphene without any postgrowth processing. Furthermore, the uniformity of monolayer graphene is significantly improved when a plain Ni foil is placed below the Cu. Our findings offer a facile and effective way to control the nucleation of high-quality graphene, meeting the requirements of industrial processing. PMID- 28024367 TI - Fully Printed Stretchable Thin-Film Transistors and Integrated Logic Circuits. AB - This paper reports intrinsically stretchable thin-film transistors (TFTs) and integrated logic circuits directly printed on elastomeric polydimethylsiloxane (PDMS) substrates. The printed devices utilize carbon nanotubes and a type of hybrid gate dielectric comprising PDMS and barium titanate (BaTiO3) nanoparticles. The BaTiO3/PDMS composite simultaneously provides high dielectric constant, superior stretchability, low leakage, as well as good printability and compatibility with the elastomeric substrate. Both TFTs and logic circuits can be stretched beyond 50% strain along either channel length or channel width directions for thousands of cycles while showing no significant degradation in electrical performance. This work may offer an entry into more sophisticated stretchable electronic systems with monolithically integrated sensors, actuators, and displays, fabricated by scalable and low-cost methods for real life applications. PMID- 28024366 TI - Identification and Optimization of Carbon Radicals on Hydrated Graphene Oxide for Ubiquitous Antibacterial Coatings. AB - While the antibacterial properties of graphene oxide (GO) have been demonstrated across a spectrum of bacteria, the critical role of functional groups is unclear. To address this important issue, we utilized reduction and hydration methods to establish a GO library with different oxidation, hydroxyl, and carbon radical (*C) levels that can be used to study the impact on antibacterial activity. Using antibiotic-resistant bacteria as a test platform, we found that the *C density is most proximately associated with bacterial killing. Accordingly, hydrated GO (hGO), with the highest *C density, had the strongest antibacterial effects through membrane binding and induction of lipid peroxidation. To explore its potential applications, we demonstrated that coating of catheter and glass surfaces with hGO is capable of killing drug-resistant bacteria. In summary, *C is the principle surface moiety that can be utilized for clinical applications of GO-based antibacterial coatings. PMID- 28024368 TI - Breaking Degeneracy of Tautomerization-Metastability from Days to Seconds. AB - We present a detailed study of the tautomerization, that is, the switching of hydrogen protons, between different sites in the molecular frame of phthalocyanine (H2Pc) on a Ag(111) substrate by means of scanning tunneling microscopy (STM) and STM-based pump-and-sample techniques. Our data reveal that the symmetry mismatch between the substrate and the molecular frame lifts the energetic degeneracy of the two H2Pc tautomers. Their energy difference is so large that only one tautomer can be found in the ground state. Tip-induced tautomerization was triggered at sufficiently high bias voltages. The excited metastable H2Pc tautomer was found to exhibit a lifetime of at least several days, as derived from the fact that the molecule did not change back to the ground state within experimentally accessible time scales as long as noninvasive tunneling parameters were used to probe the state of the molecule. By the controlled removal of a hydrogen proton from the molecule, a four-level system was created. Pump-and-sample experiments reveal that the lifetime of the metastable positions amounts to seconds only. Current- and bias-dependent studies indicate that the presence of the STM tip modifies the potential barrier, thereby allowing for a controlled tuning of the metastable tautomer's lifetime. PMID- 28024369 TI - Dilution-Induced Formation of Hybrid Perovskite Nanoplatelets. AB - Perovskite nanocrystals (NCs) are an important extension to the fascinating field of hybrid halide perovskites. Showing significantly enhanced photoluminescence (PL) efficiency and emission wavelengths tunable through halide content and size, they hold great promise for light-emitting applications. Despite the rapid advancement in this field, the physical nature and size-dependent excitonic properties have not been well investigated due to the challenges associated with their preparation. Herein we report the spontaneous formation of highly luminescent, quasi-2D organic-inorganic hybrid perovskite nanoplatelets (NPls) upon dilution of a dispersion of bulk-like NCs. The fragmentation of the large NCs is attributed to osmotic swelling induced by the added solvent. An excess of organic ligands in the solvent quickly passivates the newly formed surfaces, stabilizing the NPls in the process. The thickness of the NPls can be controlled both by the dilution level and by the ligand concentration. Such colloidal NPls and their thin films were found to be extremely stable under continuous UV light irradiation. Full tunability of the NPl emission wavelength is achieved by varying the halide ion used (bromide, iodide). Additionally, time-resolved PL measurements reveal an increasing radiative decay rate with decreasing thickness of the NPls, likely due to an increasing exciton binding energy. Similarly, measurements on iodide-containing NPls show a transformation from biexponential to monoexponential PL decay with decreasing thickness, likely due to an increasing fraction of excitonic recombination. This interesting phenomenon of change in fluorescence upon dilution is a result of the intricate nature of the perovskite material itself and is uncommon in inorganic materials. Our findings enable the synthesis of halide perovskite NCs with high quantum efficiency and good stability as well as a tuning of both their optical and morphological properties. PMID- 28024370 TI - Encapsulation of Homogeneous Catalysts in Porous Polymer Nanocapsules Produces Fast-Acting Selective Nanoreactors. AB - Nanoreactors were created by entrapping homogeneous catalysts in hollow nanocapsules with 200 nm diameter and semipermeable nanometer-thin shells. The capsules were produced by the polymerization of hydrophobic monomers in the hydrophobic interior of the bilayers of self-assembled surfactant vesicles. Controlled nanopores in the shells of nanocapsules ensured long-term retention of the catalysts coupled with the rapid flow of substrates and products in and out of nanocapsules. The study evaluated the effect of encapsulation on the catalytic activity and stability of five different catalysts. Comparison of kinetics of five diverse reactions performed in five different solvents revealed the same reaction rates for free and encapsulated catalysts. Identical reaction kinetics confirmed that placement of catalysts in the homogeneous interior of polymer nanocapsules did not compromise catalytic efficiency. Encapsulated organometallic catalysts showed no loss of metal ions from nanocapsules suggesting stabilization of the complexes was provided by nanocapsules. Controlled permeability of the shells of nanocapsules enabled size-selective catalytic reactions. PMID- 28024371 TI - High-Performance Flexible Thermoelectric Power Generator Using Laser Multiscanning Lift-Off Process. AB - Flexible thermoelectric generators (f-TEGs) are emerging as a semipermanent power source for self-powered sensors, which is an important area of research for next generation smart network monitoring systems in the Internet-of-things era. We report in this paper a f-TEG produced by a screen-printing technique (SPT) and a laser multiscanning (LMS) lift-off process. A screen-printed TEG was fabricated on a SiO2/a-Si/quartz substrate via the SPT process, and the LMS process completely separated the rigid quartz substrate from the original TEG by selective reaction of the XeCl excimer laser with the exfoliation layer (a-Si). Using these techniques, we fabricate a prototype f-TEG composed of an array of 72 TE couples that exhibits high flexibility at various bending radii, together with excellent output performance (4.78 mW/cm2 and 20.8 mW/g at DeltaT = 25 degrees C). There is no significant change in the device performance even under repeated bending of 8000 cycles. PMID- 28024372 TI - Internal Hydration Properties of Single Bacterial Endospores Probed by Electrostatic Force Microscopy. AB - We show that the internal hydration properties of single Bacillus cereus endospores in air under different relative humidity (RH) conditions can be determined through the measurement of its electric permittivity by means of quantitative electrostatic force microscopy (EFM). We show that an increase in the RH from 0% to 80% induces a large increase in the equivalent homogeneous relative electric permittivity of the bacterial endospores, from ~4 up to ~17, accompanied only by a small increase in the endospore height, of just a few nanometers. These results correlate the increase of the moisture content of the endospore with the corresponding increase of environmental RH. Three-dimensional finite element numerical calculations, which include the internal structure of the endospores, indicate that the moisture is mainly accumulated in the external layers of the endospore, hence preserving the core of the endospore at low hydration levels. This mechanism is different from what we observe for vegetative bacterial cells of the same species, in which the cell wall at high humid atmospheric conditions is not able to preserve the cytoplasmic region at low hydration levels. These results show the potential of quantitative EFM under environmental humidity control to study the hygroscopic properties of small-scale biological (and nonbiological) entities and to determine its internal hydration state. A better understanding of nanohygroscopic properties can be of relevance in the study of essential biological processes and in the design of bionanotechnological applications. PMID- 28024373 TI - Toward Cavity Quantum Electrodynamics with Hybrid Photon Gap-Plasmon States. AB - Combining localized surface plasmons (LSPs) and diffractive surface waves (DSWs) in metallic nanoparticle gratings leads to the emergence of collective hybrid plasmonic-photonic modes known as surface lattice resonances (SLRs). These show reduced losses and therefore a higher Q factor with respect to pure LSPs, at the price of larger volumes. Thus, they can constitute a flexible and efficient platform for light-matter interaction. However, it remains an open question if there is, in terms of the Q/V ratio, a sizable gain with respect to the uncoupled LSPs or DSWs. This is a fundamental point to shed light upon if such modes want to be exploited, for instance, for cavity quantum electrodynamic effects. Here, using aluminum nanoparticle square gratings with unit cells consisting of narrow gap disk dimers-a geometry featuring a very small modal volume-we demonstrate that an enhancement of the Q/V ratio with respect to the pure LSP and DSW is obtained for SLRs with a well-defined degree of plasmon hybridization. Simultaneously, we report a 5* increase of the Q/V ratio for the gap-coupled LSP with respect to that of the single nanoparticle. These outcomes are experimentally probed against the Rabi splitting, resulting from the coupling between the SLR and a J-aggregated molecular dye, showing an increase of 80% with respect to the DSW-like SLR sustained by the disk LSP of the dimer. The results of this work open the way toward more efficient applications for the exploitation of excitonic nonlinearities in hybrid plasmonic platforms. PMID- 28024374 TI - Symmetry-Driven Band Gap Engineering in Hydrogen Functionalized Graphene. AB - Band gap engineering in hydrogen functionalized graphene is demonstrated by changing the symmetry of the functionalization structures. Small differences in hydrogen adsorbate binding energies on graphene on Ir(111) allow tailoring of highly periodic functionalization structures favoring one distinct region of the moire supercell. Scanning tunneling microscopy and X-ray photoelectron spectroscopy measurements show that a highly periodic hydrogen functionalized graphene sheet can thus be prepared by controlling the sample temperature (Ts) during hydrogen functionalization. At deposition temperatures of Ts = 645 K and above, hydrogen adsorbs exclusively on the HCP regions of the graphene/Ir(111) moire structure. This finding is rationalized in terms of a slight preference for hydrogen clusters in the HCP regions over the FCC regions, as found by density functional theory calculations. Angle-resolved photoemission spectroscopy measurements demonstrate that the preferential functionalization of just one region of the moire supercell results in a band gap opening with very limited associated band broadening. Thus, hydrogenation at elevated sample temperatures provides a pathway to efficient band gap engineering in graphene via the selective functionalization of specific regions of the moire structure. PMID- 28024375 TI - Rapid Focused Ion Beam Milling Based Fabrication of Plasmonic Nanoparticles and Assemblies via "Sketch and Peel" Strategy. AB - Focused ion beam (FIB) milling is a versatile maskless and resistless patterning technique and has been widely used for the fabrication of inverse plasmonic structures such as nanoholes and nanoslits for various applications. However, due to its subtractive milling nature, it is an impractical method to fabricate isolated plasmonic nanoparticles and assemblies which are more commonly adopted in applications. In this work, we propose and demonstrate an approach to reliably and rapidly define plasmonic nanoparticles and their assemblies using FIB milling via a simple "sketch and peel" strategy. Systematic experimental investigations and mechanism studies reveal that the high reliability of this fabrication approach is enabled by a conformally formed sidewall coating due to the ion milling-induced redeposition. Particularly, we demonstrated that this strategy is also applicable to the state-of-the-art helium ion beam milling technology, with which high-fidelity plasmonic dimers with tiny gaps could be directly and rapidly prototyped. Because the proposed approach enables rapid and reliable patterning of arbitrary plasmonic nanostructures that are not feasible to fabricate via conventional FIB milling process, our work provides the FIB milling technology an additional nanopatterning capability and thus could greatly increase its popularity for utilization in fundamental research and device prototyping. PMID- 28024376 TI - Activated Carbon Textile via Chemistry of Metal Extraction for Supercapacitors. AB - Carbothermic reduction in the chemistry of metal extraction (MO(s) + C(s) -> M(s) + CO(g)) using carbon as a sacrificial agent has been used to smelt metals from diverse oxide ores since ancient times. Here, we paid attention to another aspect of the carbothermic reduction to prepare an activated carbon textile for high rate-performance supercapacitors. On the basis of thermodynamic reducibility of metal oxides reported by Ellingham, we employed not carbon, but metal oxide as a sacrificial agent in order to prepare an activated carbon textile. We conformally coated ZnO on a bare cotton textile using atomic layer deposition, followed by pyrolysis at high temperature (C(s) + ZnO(s) -> C'(s) + Zn(g) + CO(g)). We figured out that it leads to concurrent carbonization and activation in a chemical as well as mechanical way. Particularly, the combined effects of mechanical buckling and fracture that occurred between ZnO and cotton turned out to play an important role in carbonizing and activating the cotton textile, thereby significantly increasing surface area (nearly 10 times) compared with the cotton textile prepared without ZnO. The carbon textiles prepared by carbothermic reduction showed impressive combination properties of high power and energy densities (over 20-fold increase) together with high cyclic stability. PMID- 28024377 TI - Kinetics of T3-DNA Ligase-Catalyzed Phosphodiester Bond Formation Measured Using the alpha-Hemolysin Nanopore. AB - The latch region of the wild-type alpha-hemolysin (alpha-HL) protein channel can be used to distinguish single base modifications in double-stranded DNA (dsDNA) via ion channel measurements upon electrophoretic capture of dsDNA in the vestibule of alpha-HL. Herein, we investigated the use of the latch region to detect a nick in the phosphodiester DNA backbone. The presence of a nick in the phosphodiester backbone of one strand of the duplex results in a significant increase in both the blockade current and noise level relative to the intact duplex. Differentiation between the nicked and intact duplexes based on blockade current or noise, with near baseline resolution, allows real-time monitoring of the rate of T3-DNA ligase-catalyzed phosphodiester bond formation. Under low ionic strength conditions containing divalent cations and a molecular crowding agent (75 mg mL-1 PEG), the rate of enzyme-catalyzed reaction in the bulk solution was continuously monitored by electrophoretically capturing reaction substrate or product dsDNA in the alpha-HL protein channel vestibule. Enzyme kinetic results obtained from the nanopore experiments match those from gel electrophoresis under the same reaction conditions, indicating the alpha-HL nanopore measurement provides a viable approach for monitoring enzymatic DNA repair activity. PMID- 28024378 TI - A Flexible Integrated System Containing a Microsupercapacitor, a Photodetector, and a Wireless Charging Coil. AB - Nowadays, the integrated systems on a plane substrate containing energy harvesting, energy storing, and working units are strongly desired with the fast development of wearable and portable devices. Here, a simple, low cost, and scalable strategy involving ink printing and electrochemical deposition is proposed to fabricate a flexible integrated system on a plane substrate containing an all-solid-state asymmetric microsupercapacitor (MSC), a photoconduct-type photodetector of perovskite nanowires (NWs), and a wireless charging coil. In the asymmetric MSCs, MnO2-PPy and V2O5-PANI composites are used as positive and negative electrodes, respectively. Typical values of energy density in the range of 15-20 mWh cm-3 at power densities of 0.3-2.5 W cm-3 with an operation potential window of 1.6 V are achieved. In the system, the wireless charging coil receives energy from a wireless power transmitter, which then can be stored in the MSC to drive the photoconductive detector of perovskite NWs in sequence. The designed integrated system exhibits a stable photocurrent response comparable with the detector driven by an external power source. This research provides an important routine to fabricate integrated systems. PMID- 28024379 TI - Coupling-Enhanced Broadband Mid-infrared Light Absorption in Graphene Plasmonic Nanostructures. AB - Plasmons in graphene nanostructures show great promise for mid-infrared applications ranging from a few to tens of microns. However, mid-infrared plasmonic resonances in graphene nanostructures are usually weak and narrow banded, limiting their potential in light manipulation and detection. Here, we investigate the coupling among graphene plasmonic nanostructures and further show that, by engineering the coupling, enhancement of light-graphene interaction strength and broadening of spectral width can be achieved simultaneously. Leveraging the concept of coupling, we demonstrate a hybrid two-layer graphene nanoribbon array which shows 5-7% extinction within the entire 8-14 MUm (~700 1250 cm-1) wavelength range, covering one of the important atmosphere "infrared transmission windows". Such coupled hybrid graphene plasmonic nanostructures may find applications in infrared sensing and free-space communications. PMID- 28024380 TI - Redox-Activated Light-Up Nanomicelle for Precise Imaging-Guided Cancer Therapy and Real-Time Pharmacokinetic Monitoring. AB - Simultaneous tumor imaging, therapy, and pharmacokinetic monitoring can offer a safe and effective strategy for cancer therapy. This work describes the design of a fluorescence light-up nanomicelle that can afford precise imaging-guided drug delivery and pharmacokinetic monitoring in a real-time fashion for cancer chemotherapy. The nanomicelle, which contains a boron dipyrromethene based fluorescent probe as the hydrophobic core and a redox-triggered detachable poly(ethylene glycol) (PEG) shell, can accumulate at the tumor site via enhanced permeation and retention effect. The PEG detachment induced by tumoral and intracellular glutathione can destabilize the nanomicelle, leading to fluorescence light up and simultaneous drug release. Importantly, the fluorescence intensities generated by the nanomicelles in different organs are well-correlated with released drug concentrations in both temporal and spatial manners, suggesting its precise role for imaging-guided drug delivery and pharmacokinetic monitoring in vivo. The tumor growth can be effectively inhibited by the docetaxel-loaded nanomicelle formulation, and the nanomicelles are monitored to be excreted via hepatobiliary routes. This nanomicelle for precise imaging-guided chemotherapy provides a safe and robust theranostic strategy for the evaluation of cancer nanomedicine. PMID- 28024381 TI - Enabling Prussian Blue with Tunable Localized Surface Plasmon Resonances: Simultaneously Enhanced Dual-Mode Imaging and Tumor Photothermal Therapy. AB - Prussian blue (PB) has been used as a photothermal conversion agent to generate heat to induce localized damage to tumor. However, its therapeutic efficiency is far from satisfactory. One of the major obstacles is that the maximum NIR absorption peak of PB within 690-720 nm cannot be optimized near the wavelength of the laser to enhance its therapeutic efficiency. Herein, we report that the integration of Gd3+ into PB nanocrystals (GPB NCs) enables PB with tunable localized surface plasmon resonances (LSPRs) from 710 to 910 nm, achieving the maximum NIR peak near the wavelength of the laser. Concurrently, the efficiency of dual-mode imaging including photoacoustic imaging and magnetic resonance imaging has been greatly improved. These enhancements in dual-mode imaging and photothermal therapy enable PB with low nanomaterial dose and laser flux. Additionally, it is found that GPB NCs show the capability of not only acting as a chemical probe with tunable sensitivity but also scavenging reactive oxygen species. The integration of functional ions into a photothermal conversion agent is an efficient strategy to improve the synergy of nanoagent, enchancing tumor theranostic efficiency. PMID- 28024382 TI - Gold-Nanoclustered Hyaluronan Nano-Assemblies for Photothermally Maneuvered Photodynamic Tumor Ablation. AB - Optically active nanomaterials have shown great promise as a nanomedicine platform for photothermal or photodynamic cancer therapies. Herein, we report a gold-nanoclustered hyaluronan nanoassembly (GNc-HyNA) for photothermally boosted photodynamic tumor ablation. Unlike other supramolecular gold constructs based on gold nanoparticle building blocks, this system utilizes the nanoassembly of amphiphilic hyaluronan conjugates as a drug carrier for a hydrophobic photodynamic therapy agent verteporfin, a polymeric reducing agent, and an organic nanoscaffold upon which gold can grow. Gold nanoclusters were selectively installed on the outer shell of the hyaluronan nanoassembly, forming a gold shell. Given the dual protection effect by the hyaluronan self-assembly as well as by the inorganic gold shell, verteporfin-encapsulated GNc-HyNA (Vp-GNc-HyNA) exhibited outstanding stability in the bloodstream. Interestingly, the fluorescence and photodynamic properties of Vp-GNc-HyNA were considerably quenched due to the gold nanoclusters covering the surface of the nanoassemblies; however, photothermal activation by 808 nm laser irradiation induced a significant increase in temperature, which empowered the PDT effect of Vp-GNc HyNA. Furthermore, fluorescence and photodynamic effects were recovered far more rapidly in cancer cells due to certain intracellular enzymes, particularly hyaluronidases and glutathione. Vp-GNc-HyNA exerted a great potential to treat tumors both in vitro and in vivo. Tumors were completely ablated with a 100% survival rate and complete skin regeneration over the 50 days following Vp-GNc HyNA treatment in an orthotopic breast tumor model. Our results suggest that photothermally boosted photodynamic therapy using Vp-GNc-HyNA can offer a potent therapeutic means to eradicate tumors. PMID- 28024383 TI - Response to "Comment on 'Electrum, the Gold-Silver Alloy, from the Bulk Scale to the Nanoscale: Synthesis, Properties, and Segregation Rules'". PMID- 28024384 TI - From Au-Thiolate Chains to Thioether Sierpinski Triangles: The Versatile Surface Chemistry of 1,3,5-Tris(4-mercaptophenyl)benzene on Au(111). AB - Self-assembly of 1,3,5-tris(4-mercaptophenyl)benzene (TMB), a 3-fold symmetric, thiol-functionalized aromatic molecule, was studied on Au(111) with the aim of realizing extended Au-thiolate-linked molecular architectures. The focus lay on resolving thermally activated structural and chemical changes by a combination of microscopy and spectroscopy. Thus, scanning tunneling microscopy (STM) provided submolecularly resolved structural information, while the chemical state of sulfur was assessed by X-ray photoelectron spectroscopy (XPS). Directly after room-temperature deposition, only less well ordered structures were observed. Mild annealing promoted the first structural transition into ordered molecular chains, partly organized in homochiral molecular braids. Further annealing led to self-similar Sierpinski triangles, while annealing at even higher temperatures again resulted in mostly disordered structures. Both the irregular aggregates observed at room temperature and the chains were identified as metal-organic assemblies, whereby two out of the three intermolecular binding motifs are energetically equivalent according to density functional theory (DFT) simulations. The emergence of Sierpinski triangles is driven by a chemical transformation, i.e., the conversion of coordinative Au-thiolate to covalent thioether linkages, and can be further understood by Monte Carlo simulations. The great structural variance of TMB on Au(111) can on one hand be explained by the energetic equivalence of two binding motifs. On the other hand, the unexpected chemical transition even enhances the structural variance and results in thiol derived covalent molecular architectures. PMID- 28024385 TI - Controlling Stiction in Nano-Electro-Mechanical Systems Using Liquid Crystals. AB - Stiction is one of the major reliability issues limiting practical application of nano-electro-mechanical systems (NEMS), an emerging device technology that exploits mechanical movements on the scale of an integrated electronic circuit. We report on a discovery that stiction can be eliminated by infiltrating NEMS with nematic liquid crystals. We demonstrate this experimentally using a NEMS based tunable photonic metamaterial, where reliable switching of optical response was achieved for the entire range of nanoscopic structural displacements admitted by the metamaterial design. Being a more straightforward and easy-to-implement alternative to the existing antistiction solutions, our approach also introduces an active mechanism of stiction control, which enables toggling between stiction free and the usual (stiction-limited) regimes of NEMS operation. It is expected to greatly expand the functionality of electro-mechanical devices and enable the development of adaptive and smart nanosystems. PMID- 28024386 TI - Origin of Contact Resistance at Ferromagnetic Metal-Graphene Interfaces. AB - Edge contact geometries are thought to yield ultralow contact resistances in most nonferromagnetic metal-graphene interfaces, owing to their large metal-graphene coupling strengths. Here, we examine the contact resistance of edge- versus surface-contacted ferromagnetic metal-graphene interfaces (i.e., nickel- and cobalt-graphene interfaces) using both single-layer and few-layer graphene. Good qualitative agreement is obtained between theory and experiment. In particular, in both theory and experiment, we observe that the contact resistance of edge contacted ferromagnetic metal-graphene interfaces is much lower than that of surface-contacted ones, for all devices studied and especially for the single layer graphene systems. We show that this difference in resistance is not due to differences in the metal-graphene coupling strength, which we quantify using Hamiltonian matrix elements. Instead, the larger contact resistance in surface contacts results from spin filtering at the interface, in contrast to the edge contacted case where both spins are transmitted. Temperature-dependent resistance measurements beyond the Curie temperature TC show that the spin degree of freedom is indeed important for the experimentally measured contact resistance. These results show that it is possible to induce a large change in contact resistance by changing the temperature in the vicinity of TC. PMID- 28024387 TI - Exploring the Angstrom Excursion of Au Nanoparticles Excited away from a Metal Surface by an Impulsive Acoustic Perturbation. AB - We report the anharmonic angstrom dynamics of self-assembled Au nanoparticles (Au:NPs) away from a nickel surface on top of which they are coupled by their near-field interaction. The deformation and the oscillatory excursion away from the surface are induced by picosecond acoustic pulses and probed at the surface plasmon resonance with femtosecond laser pulses. The overall dynamics are due to an efficient transfer of translational momentum from the Ni surface to the Au:NPs, therefore avoiding usual thermal effects and energy redistribution among the electronic states. Two modes are clearly revealed by the oscillatory shift of the Au:NPs surface plasmon resonance-the quadrupole deformation mode due to the transient ellipsoid shape and the excursion mode when the Au:NPs bounce away from the surface. We find that, contrary to the quadrupole mode, the excursion mode is sensitive to the distance between Au:NPs and Ni. Importantly, the excursion dynamics display a nonsinusoidal motion that cannot be explained by a standard harmonic potential model. A detailed modeling of the dynamics using a Hamaker type Lennard-Jones potential between two media is performed, showing that each Au:NPs coherently evolves in a nearly one-dimensional anharmonic potential with a total excursion of ~1 A. This excursion induces a shift of the surface plasmon resonance detectable because of the strong near-field interaction. This general method of observing the spatiotemporal dynamics with angstrom and picosecond resolutions can be directly transposed to many nanostructures or biosystems to reveal the interaction and contact mechanism with their surrounding medium while remaining in their fundamental electronic states. PMID- 28024389 TI - Tribotronic Transistor Array as an Active Tactile Sensing System. AB - Large-scale tactile sensor arrays are of great importance in flexible electronics, human-robot interaction, and medical monitoring. In this paper, a flexible 10 * 10 tribotronic transistor array (TTA) is developed as an active tactile sensing system by incorporating field-effect transistor units and triboelectric nanogenerators into a polyimide substrate. The drain-source current of each tribotronic transistor can be individually modulated by the corresponding external contact, which has induced a local electrostatic potential to act as the conventional gate voltage. By scaling down the pixel size from 5 * 5 to 0.5 * 0.5 mm2, the sensitivities of single pixels are systematically investigated. The pixels of the TTA show excellent durability, independence, and synchronicity, which are suitable for applications in real-time tactile sensing, motion monitoring, and spatial mapping. The integrated tribotronics provides an unconventional route to realize an active tactile sensing system, with prospective applications in wearable electronics, human-machine interfaces, fingerprint identification, and so on. PMID- 28024390 TI - Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins. AB - Recent developments in the modification of methionine and other thioether containing residues in peptides, polypeptides, and proteins are reviewed. Properties and potential applications of the resulting functionalized products are also discussed. While much of this work is focused on natural Met residues, modifications at other side-chain residues have also emerged as new thioether containing amino acids have been incorporated into peptidic materials. Functional modification of thioether-containing amino acids has many advantages and is a complementary methodology to the widely utilized methods for modification at cysteine residues. PMID- 28024391 TI - Silo-Stored Pistachios at Varying Humidity Levels Produce Distinct Volatile Biomarkers. AB - Fungal-contaminated tissues are known to produce volatile profiles that are different from uncontaminated tissues. Fungi require certain water activity levels before growth can occur. For nonxerophilic fungi, a water activity of 0.85 is typical for growth, and for extreme xerophilic fungi, the water activity can be as low as 0.64. Recent investigations with stored pistachios (kernels in shell, no hull tissue) at varying relative humidities showed differences among the collected volatile profiles at the tested humidities (ambient, 63, 75, and 84%). Water activities of the kernel and shell were also measured. Results showed significant changes in volatile profiles as a function of water activity of the corresponding pistachio tissue with measured water activity levels at or below that of what is considered extreme xerophilic activities. Because fungal growth, including mycotoxigenic fungi, is dependent upon water activity, the detected volatile profiles could be used for early detection of fungal presence. Multivariate analysis of the volatile data demonstrated significant differences among the volatile profiles at the tested relative humidity levels, and several volatiles were identified as biomarkers of increased humidity and likely fungal development. PMID- 28024392 TI - Insights into the Key Compounds of Durian (Durio zibethinus L. 'Monthong') Pulp Odor by Odorant Quantitation and Aroma Simulation Experiments. AB - Sixteen compounds, previously identified as potent odorants by application of an aroma extract dilution analysis and the gas chromatography-olfactometry analysis of static headspace samples, were quantitated in the pulp of durians, variety Monthong, and odor activity values (OAVs) were calculated by dividing the concentrations obtained by the odor thresholds of the compounds in water. In combination with data recently reported for hydrogen sulfide and short-chain alkanethiols, OAVs > 1 were obtained for 19 compounds, among which ethyl (2S)-2 methylbutanoate (fruity; OAV 1700000), ethanethiol (rotten onion; OAV 480000), and 1-(ethylsulfanyl)ethane-1-thiol (roasted onion; OAV 250000) were the most potent, followed by methanethiol (rotten, cabbage; OAV 45000), ethane-1,1-dithiol (sulfury, durian; OAV 23000), and ethyl 2-methylpropanoate (fruity; OAV 22000). Aroma simulation and omission experiments revealed that the overall odor of durian pulp could be mimicked by only two compounds, namely, ethyl (2S)-2 methylbutanoate and 1-(ethylsulfanyl)ethane-1-thiol, when combined in their natural concentrations. PMID- 28024393 TI - Boron Precursor-Dependent Evolution of Differently Emitting Carbon Dots. AB - Attention has been directed toward electron-deficient boron doping in carbon dots (CDs) with the expectation of revealing new photophysical aspects in accordance with varying amounts of boron content. It has been emphatically shown that boron uptake in CDs varies with different boron precursors evolving altered emissive CDs. Boron doping in CDs causes definite surface defect due to the generation of electron-deficient states. Modified hydrothermal treatment of a mixture of ascorbic acid (AA) and different boron precursor compounds (borax/boric acid/sodium borate/sodium borohydride) produces different kinds of boron-doped CDs (BCDs). These BCDs (<6 nm) differ in size, emission maxima (~15 nm), and fluorescence intensity but carry unchanged excitation maxima (365 nm). These differences are related to the nature of boron precursor compounds. The most fluorescing BCD (quantum yield ~ 5%) is identified from the borax-mediated reaction and is used for the detection of Fe(III) on a nanomolar level in water via the fluorescence "Turn Off" phenomenon. Again, Fe(III)-infested CD solution regains its lost fluorescence, with AA paving the way for nanomolar level AA detection from the same pot. The proposed method has been tactfully made interference free for the quantitative measure of Fe(III) and AA in real samples. Furthermore, new photophysical properties of the CDs with variable boron contents supplement information that is hitherto unknown. Theoretical calculations also justify the observed optical behavior of the as-synthesized BCDs. The calculations describe the variable amount of boron doping-related huge charge polarization within the carbon surface, leading to the formation of surface defects. Thus, subsequent electronic transition-related red shift in the absorption spectrum authenticates experimental findings. PMID- 28024394 TI - Broadband Emission in Two-Dimensional Hybrid Perovskites: The Role of Structural Deformation. AB - Only a selected group of two-dimensional (2D) lead-halide perovskites shows a peculiar broad-band photoluminescence. Here we show that the structural distortions of the perovskite lattice can determine the defectivity of the material by modulating the defect formation energies. By selecting and comparing two archetype systems, namely, (NBT)2PbI4 and (EDBE)PbI4 perovskites (NBT = n butylammonium and EDBE = 2,2-(ethylenedioxy)bis(ethylammonium)), we find that only the latter, subject to larger deformation of the Pb-X bond length and X-Pb-X bond angles, sees the formation of VF color centers whose radiative decay ultimately leads to broadened PL. These findings highlight the importance of structural engineering to control the optoelectronic properties of this class of soft materials. PMID- 28024395 TI - Metalloporphyrin-Encapsulated Biodegradable Nanosystems for Highly Efficient Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy. AB - Traditional photodynamic therapy (PDT) suffers from the critical issues of low tissue-penetrating depth of light and potential phototoxicity, which are expected to be solved by developing new dynamic therapy-based therapeutic modalities such as sonodynamic therapy (SDT). In this work, we report on the design/fabrication of a high-performance multifunctional nanoparticulate sonosensitizer for efficient in vivo magnetic resonance imaging (MRI)-guided SDT against cancer. The developed approach takes the structural and compositional features of mesoporous organosilica-based nanosystems for the fabrication of sonosensitizers with intriguing theranostic performance. The well-defined mesoporosity facilitates the high loading of organic sonosensitizers (protoporphyrin, PpIX) and further chelating of paramagnetic transitional metal Mn ions based on metalloporphyrin chemistry (MnPpIX). The mesoporous structure of large surface area also maximizes the accessibility of water molecules to the encapsulated paramagnetic Mn ions, endowing the composite sonosensitizers with markedly high MRI performance (r1 = 9.43 mM-1 s-2) for SDT guidance and monitoring. Importantly, the developed multifunctional sonosensitizers (HMONs-MnPpIX-PEG) with controllable biodegradation behavior and high biocompatibility show distinctively high SDT efficiency for inducing the cancer-cell death in vitro and suppressing the tumor growth in vivo. This report provides a paradigm that nanotechnology-enhanced SDT based on elaborately designed high-performance multifunctional sonosensitizers will pave a new way for efficient cancer treatment by fully taking the advantages (noninvasiveness, convenience, cost-effectiveness, etc.) of ultrasound therapy and quickly developing nanomedicine. PMID- 28024396 TI - Tuning the Surface Chirality of Adsorbed Gly-Pro Dipeptide/Cu(110) by Changing Its Chemical Form via Electrospray Deposition. AB - By changing the ultrahigh vacuum (UHV) deposition method, classical sublimation versus electrospray ionization, one can tune the chemistry of a chiral dipeptide molecule (Gly-Pro, GP), when adsorbed on a Cu(110) surface, from anionic to zwitterionic. This chemical shift will influence the adsorption mode of the dipeptide, either in a three-point fashion in the case of anionic GP molecules with a strong interaction among the copper surface, both O atoms of the carboxylate moiety, and the nitrogen atoms, or in the case of zwitterions GP, the adsorption mode relies on the sole interaction of one carboxylate oxygen atom. These different anchoring modes strongly modify the expression of surface 2D chirality and the supramolecular assemblies with two very distinct unit cells. PMID- 28024397 TI - MayaChemTools: An Open Source Package for Computational Drug Discovery. AB - MayaChemTools is a growing collection of Perl scripts, modules, and classes to support a variety of computational drug discovery needs, such as manipulation and analysis of data, generation of two-dimensional (2D) fingerprints, similarity searching, and calculation of physicochemical properties. MayaChemTools provides command line scripts for the following tasks: manipulation and analysis of data in SD, CSV/TSV, sequence/alignments, and PDB files; calculation of a key set of physicochemical properties, such as molecular weight, hydrogen bond donors and acceptors, logP, and topological polar surface area; generation of 2D fingerprints corresponding to atom neighborhoods, atom types, E-state indices, extended connectivity, MACCS keys, path lengths, topological atom pairs, topological atom triplets, topological atom torsions, topological pharmacophore atom pairs, and topological pharmacophore atom triplets; similarity searching and calculation of similarity matrices using available 2D fingerprints; listing properties of elements in the periodic table, amino acids, and nucleic acids; and exporting data from relational databases. An extensive set of modules and classes are also available for custom development. MayaChemTools is freely available online at www.MayaChemTools.org , under the terms of the GNU LGPL, as published by the Free Software Foundation. PMID- 28024398 TI - What's What: The (Nearly) Definitive Guide to Reaction Role Assignment. AB - When analyzing chemical reactions it is essential to know which molecules are actively involved in the reaction and which educts will form the product molecules. Assigning reaction roles, like reactant, reagent, or product, to the molecules of a chemical reaction might be a trivial problem for hand-curated reaction schemes but it is more difficult to automate, an essential step when handling large amounts of reaction data. Here, we describe a new fingerprint based and data-driven approach to assign reaction roles which is also applicable to rather unbalanced and noisy reaction schemes. Given a set of molecules involved and knowing the product(s) of a reaction we assign the most probable reactants and sort out the remaining reagents. Our approach was validated using two different data sets: one hand-curated data set comprising about 680 diverse reactions extracted from patents which span more than 200 different reaction types and include up to 18 different reactants. A second set consists of 50 000 randomly picked reactions from US patents. The results of the second data set were compared to results obtained using two different atom-to-atom mapping algorithms. For both data sets our method assigns the reaction roles correctly for the vast majority of the reactions, achieving an accuracy of 88% and 97% respectively. The median time needed, about 8 ms, indicates that the algorithm is fast enough to be applied to large collections. The new method is available as part of the RDKit toolkit and the data sets and Jupyter notebooks used for evaluation of the new method are available in the Supporting Information of this publication. PMID- 28024399 TI - Plasma Protein Binding of Anisomelic Acid: Spectroscopy and Molecular Dynamic Simulations. AB - Anisomelic acid (AA) is a macrocyclic cembranolide compound extracted from Anisomeles herbal species. Recently, we have shown that AA possesses both anticancer and antiviral activity. However, to date, the plasma protein binding properties of AA are unknown. Here, we describe the molecular interactions of AA with two serum proteins, human serum albumin (HSA) and bovine serum albumin (BSA), adopting multiple physicochemical methods. Besides, molecular docking and dynamics simulations were performed to predict the interaction mode and the dynamic behavior of AA with HSA and BSA. The experimental results revealed that hydrophobic forces play a significant part in the interaction of AA to HSA and BSA. The outcomes of the principal components analysis (PCA) of the poses based on root-mean-squared distances showed less variation in AA-HSA, opposed to what is seen for BSA-AA. Furthermore, binding free energies estimated for AA-HSA and AA-BSA complexes at different temperatures (298, 303, 308, and 313 K) based on molecular mechanics-generalized Born surface area (MMGBSA) approaches were well correlated with our experimental results. PMID- 28024400 TI - Cheminformatics Modeling of Adverse Drug Responses by Clinically Relevant Mutants of Human Androgen Receptor. AB - The human androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of prostate cancer (PCa). Many forms of castration-resistant prostate cancer (CRPC) still rely on the AR for survival. Currently used antiandrogens face clinical limitations as drug resistance develops in patients over time since they all target the mutation prone androgen binding site (ABS), where gain-of-function mutations eventually convert antagonists into agonists. With a significant number of reported distinct mutations located across the ABS, it is imperative to develop a prognostic platform which would equip clinicians with prior knowledge and actionable strategies if cases of previously unreported AR mutations are encountered. The goal of this study is to develop a theoretical approach that can predict such previously unreported AR mutants in response to current treatment options for PCa. The expected drug response by these mutants has been modeled using cheminformatics methodology. The corresponding QSAR pipeline has been created, which extracts key protein-ligand interactions and quantifies them by 4D molecular descriptors. The developed models reported with an accuracy reaching 90% and enable prediction of activation of AR mutants by its native ligand as well as assess whether known antiandrogens will act on them as agonists or antagonists. As a result, a previously uncharacterized mutant, T878G, has been predicted to be activated by the latest antiandrogen enzalutamide, and the corresponding experimental evaluation confirmed this prediction. Overall, the developed cheminformatics pipeline provides useful insights toward understanding the changing genomic landscape of advanced PCa. PMID- 28024401 TI - Beyond Rotatable Bond Counts: Capturing 3D Conformational Flexibility in a Single Descriptor. AB - A new molecular descriptor, nConf20, based on chemical connectivity, is presented which captures the accessible conformational space of a molecule. Currently the best available two-dimensional descriptors for quantifying the flexibility of a particular molecule are the rotatable bond count (RBC) and the Kier flexibility index. We present a descriptor which captures this information by sampling the conformational space of a molecule using the RDKit conformer generator. Flexibility has previously been identified as a key feature in determining whether a molecule is likely to crystallize or not. For this application, nConf20 significantly outperforms previously reported single-variable classifiers and also assists rule-based analysis of black-box machine learning classification algorithms. PMID- 28024402 TI - Relative Binding Free Energy Calculations Applied to Protein Homology Models. AB - A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters). Recent advances in sampling methods and force fields coupled with vast increases in computational resources have made FEP a viable technology to drive hit-to-lead and lead optimization, allowing for more efficient cycles of medicinal chemistry and the possibility to explore much larger chemical spaces. However, previous FEP applications have focused on systems with high-resolution crystal structures of the target as starting points something that is not always available in drug discovery projects. As such, the ability to apply FEP on homology models would greatly expand the domain of applicability of FEP in drug discovery. In this work we apply a particular implementation of FEP, called FEP+, on congeneric ligand series binding to four diverse targets: a kinase (Tyk2), an epigenetic bromodomain (BRD4), a transmembrane GPCR (A2A), and a protein-protein interaction interface (BCL-2 family protein MCL-1). We apply FEP+ using both crystal structures and homology models as starting points and find that the performance using homology models is generally on a par with the results when using crystal structures. The robustness of the calculations to structural variations in the input models can likely be attributed to the conformational sampling in the molecular dynamics simulations, which allows the modeled receptor to adapt to the "real" conformation for each ligand in the series. This work exemplifies the advantages of using all-atom simulation methods with full system flexibility and offers promise for the general application of FEP to homology models, although additional validation studies should be performed to further understand the limitations of the method and the scenarios where FEP will work best. PMID- 28024404 TI - A Novel Scaffold for Developing Specific or Broad-Spectrum Chitinase Inhibitors. AB - Chitinases play important roles in pathogen invasion, arthropod molting, plant defense, and human inflammation. Inhibition of the activity of a typical chitinase by small molecules is of significance in drug development and biological research. On the basis of a recent reported crystal structure of OfChtI, the insect chitinase derived from the pest Ostrinia furnacalis, we computationally identified 17 compounds from a library of over 4 million chemicals by two rounds virtual screening. Among these, three compounds from one chemical class inhibited the activity of OfChtI with single-digit-micromolar IC50 values, and one compound from another chemical class exhibited a broad inhibitory activity not only toward OfChtI but also toward bacterial, fungal, and human chitinases. A new scaffold was discovered, and a structure-inhibitory activity relationship was proposed. This work may provide a novel starting point for the development of specific or broad-spectrum chitinase inhibitors. PMID- 28024403 TI - Genetic Algorithm Managed Peptide Mutant Screening: Optimizing Peptide Ligands for Targeted Receptor Binding. AB - This study demonstrates the utility of genetic algorithms to search exceptionally large and otherwise intractable mutant libraries for sequences with optimal binding affinities for target receptors. The Genetic Algorithm Managed Peptide Mutant Screening (GAMPMS) program was used to search an alpha-conotoxin (alpha CTx) MII mutant library of approximately 41 billion possible peptide sequences for those exhibiting the greatest binding affinity for the alpha3beta2-nicotinic acetylcholine receptor (nAChR) isoform. A series of top resulting peptide ligands with high sequence homology was obtained, with each mutant having an estimated DeltaGbind approximately double that of the potent native alpha-CTx MII ligand. A consensus sequence from the top GAMPMS results was subjected to more rigorous binding free energy calculations by molecular dynamics and compared to alpha-CTx MII and other related variants for binding with alpha3beta2-nAChR. In this study, the efficiency of GAMPMS to substantially reduce the sample population size through evolutionary selection criteria to produce ligands with higher predicted binding affinity is demonstrated. PMID- 28024405 TI - Boosting Docking-Based Virtual Screening with Deep Learning. AB - In this work, we propose a deep learning approach to improve docking-based virtual screening. The deep neural network that is introduced, DeepVS, uses the output of a docking program and learns how to extract relevant features from basic data such as atom and residues types obtained from protein-ligand complexes. Our approach introduces the use of atom and amino acid embeddings and implements an effective way of creating distributed vector representations of protein-ligand complexes by modeling the compound as a set of atom contexts that is further processed by a convolutional layer. One of the main advantages of the proposed method is that it does not require feature engineering. We evaluate DeepVS on the Directory of Useful Decoys (DUD), using the output of two docking programs: Autodock Vina1.1.2 and Dock 6.6. Using a strict evaluation with leave one-out cross-validation, DeepVS outperforms the docking programs, with regard to both AUC ROC and enrichment factor. Moreover, using the output of Autodock Vina1.1.2, DeepVS achieves an AUC ROC of 0.81, which, to the best of our knowledge, is the best AUC reported so far for virtual screening using the 40 receptors from the DUD. PMID- 28024406 TI - The Effect of Conformational Flexibility on Binding Free Energy Estimation between Kinases and Their Inhibitors. AB - Accurate prediction of binding affinities of drug candidates to their targets remains challenging because of protein flexibility in solution. Conformational flexibility of the ATP-binding site in the CDK2 and ERK2 kinases was identified using molecular dynamics simulations. The binding free energy (DeltaG) of twenty four ATP-competitive inhibitors toward these kinases was assessed using an alchemical free energy perturbation method, MP-CAFEE. However, large calculation errors of 2-3 kcal/mol were observed using this method, where the free energy simulation starts from a single equilibrated conformation. Here, we developed a new DeltaG computation method, where the starting structure was set to multiconformations to cover flexibility. The calculation accuracy was successfully improved, especially for larger molecular size compounds, leading to reliable prediction of a broader range of drug candidates. The present study demonstrates that conformational flexibility of interactions between a compound and the glycine-rich loop in the kinases is a key factor in DeltaG estimation. PMID- 28024407 TI - Discovering Novel and Diverse Iron-Chelators in Silico. AB - Specific iron chelation is a validated strategy in anticancer drug discovery. However, only a few chemical classes (4-5 categories) have been reported to date. We discovered in silico five new structurally diverse iron-chelators by screening through models based on previously known chelators. To encompass a larger chemical space and propose newer scaffolds, we used our iterative stochastic elimination (ISE) algorithm for model building and subsequent virtual screening (VS). The ISE models were developed by training a data set of 130 reported iron chelators. The developed models are statistically significant with area under the receiver operating curve greater than 0.9. The models were used to screen the Enamine chemical database of ~1.8 million molecules. The top ranked 650 molecules were reduced to 50 diverse structures, and a few others were eliminated due to the presence of reactive groups. Finally, 34 molecules were purchased and tested in vitro. Five compounds were identified with significant iron-chelation activity in Cal-G assay. Intracellular iron-chelation study revealed one compound as equivalent in potency to the iron chelating "gold standards" deferoxamine and deferiprone. The amount of discovered positives (5 out of 34) is expected by the realistic enrichment factor of the model. PMID- 28024408 TI - Sexual Regret. AB - The current study sought to answer three key questions about explaining the emotion of regret in the domain of casual sex: Are sex differences in sexual regret robust or attenuated in a highly egalitarian culture? What proximate psychological variables might explain sex differences in sexual regret? And what accounts for within-sex variation in experiences of sexual regret about casual sex. We conducted a study of 263 Norwegian students (ages 19-37) who reported how much they regretted having either engaged in, or passed up, their most recent casual sexual experience. Sex differences in sexual regret are not attenuated in this sexually egalitarian culture. The study revealed sex differences in worries about pregnancy, STIs, and reputation; however, these predictors did not succeed in accounting for the sex differences in regret engaging in casual sex. Sexual gratification and socio-sexual orientation both predicted the sex differences in casual sex regret. In contrast, only socio-sexual orientation attenuated the sex difference in regret passing up casual sex. Predictors of within-sex variation in casual sexual regret included worry about sexual reputation, experienced gratification during the encounter, and socio-sexual orientation. Discussion focuses on implications for the psychological design features of this relatively neglected emotion. PMID- 28024409 TI - Exercise Self-Efficacy Scale: Validation of the Arabic Version Among Jordanians With Chronic Diseases. AB - This study assessed the psychometric properties of the Arabic version of Exercise Self-Efficacy scale (ESE-A) among Jordanian outpatients with a variety of chronic diseases using descriptive cross-sectional design. Participants' scores of ESE-A significantly correlated with their reported weekly exercise frequency ( r = .23, p< .001), duration ( r = .31, p< .001), and evaluation of their physical exercise ( r = .39, p< .001). The construct validity was tested using exploratory factor analysis, which retained all items, and the scree plot showed one meaningful factor with an eigenvalue of 10.38 and an explained variance of 57.7%. Furthermore, Cronbach's alpha was .89 and split-half coefficient was .83 indicating that the ESE-A is a reliable scale. The ESE-A was found to be a robust measure to evaluate exercise self-efficacy among Arabic patients with chronic diseases. Arabic researchers interested in exercise self-efficacy are invited to utilize the ESE-A in their studies to confirm its psychometric properties. PMID- 28024410 TI - The Effects of Acupressure on Meridian Energy as well as Nausea and Vomiting in Lung Cancer Patients Receiving Chemotherapy. AB - Nausea and vomiting are the most common side effects of antineoplastic chemotherapy. However, only a small number of studies have been conducted in Taiwan to determine the efficacy of acupressure in treating these side effects in cancer patients receiving chemotherapy. In this quasi-experimental study, we aimed to explore the effects of acupressure on meridian energy as well as nausea and vomiting in 70 lung cancer patients receiving chemotherapy. Patients were assigned to the experimental or control group based on order of hospital admission. The experimental group received acupressure on "Neiguan (PC6)" and "Gongsun (SP4)" points, and the control group received sham acupoint patches on "Houxi (SI3)" point. The results showed that the mean meridian energy in the experimental group after acupressure was significantly higher than in the control group ( F = 28.71, p < .001). The experimental group had significantly less nausea ( p < .001) and vomiting ( p = .006) during the delayed phase than the control group. In conclusion, acupressure significantly increased the mean meridian energy and effectively decreased the severity of nausea and vomiting in lung cancer patients undergoing chemotherapy. We recommend that clinical nurses provide acupressure as an intervention to relieve nausea and vomiting in patients receiving chemotherapy. PMID- 28024411 TI - The Impact of Inclusion in a Quality Indicators Program on Anticoagulant Treatment in Atrial Fibrillation. PMID- 28024412 TI - Self-disclosure of HIV status, disclosure counseling, and retention in HIV care in Cameroon. AB - Poor retention in care is common among HIV-positive adults in sub-Saharan Africa settings and remains a key barrier to HIV management. We quantify the associations of disclosure of HIV status and referral to disclosure counseling with successful retention in care using data from three Cameroon clinics participating in the Phase 1 International epidemiologic Databases to Evaluate AIDS Central Africa cohort. Of 1646 patients newly initiating antiretroviral therapy between January 2008 and January 2011, 43% were retained in care following treatment initiation. Self-disclosure of HIV status to at least one person prior to treatment initiation was associated with a minimal increase in the likelihood of being retained in care (risk ratio [RR] = 1.14; 95% confidence interval (CI): 0.94, 1.38). However, referral to disclosure counseling was associated with a moderate increase in retention (RR = 1.37; 95% CI: 1.21, 1.55) and was not significantly modified by prior disclosure status (p = .3). Our results suggest that while self-disclosure may not significantly improve retention among patients receiving care at these Cameroon sites, counseling services may play an important role regardless of prior disclosure status. PMID- 28024413 TI - Ferulic acid induces proliferation and differentiation of rat osteoblasts in vitro through cGMP/PKGII/ENaC signaling. AB - Ferulic acid (FA) is an active component of the traditional Chinese herb Angelica sinensis. Numerous health benefits have been attributed to FA, but few studies have investigated the effects of FA on osteoblasts (Obs). Our work studied the effects of FA on proliferation, differentiation, and mineralization of rat calvarial Obs and examined the signaling pathways involved. Cell proliferation and differentiation were evaluated by Cell Counting Kit-8 (CCK-8) and alkaline phosphatase (ALP) assay kit, respectively. Cyclic guanosine monophosphate (cGMP) dependent protein kinase II (PKGII) expression was silenced by small interfering RNA (siRNA). The mRNA expression was investigated by semi-quantitative PCR. FA (40-2560 MUM) promoted Ob proliferation and differentiation; at 40-640 MUM, FA stimulated calcified nodule formation and increased the expression of osteogenic genes encoding osteopontin and collagen-l. FA (40-2560 MUM) increased cGMP levels in Obs and upregulated the expression of PKGII, EnaCalpha, and ENaCgamma mRNAs. Downregulated ENaCalpha mRNA expression in Obs transfected with the siRNA for PKGII was reversed when FA was introduced into Obs. These results demonstrated that FA promoted proliferation, differentiation, and mineralization of Obs in vitro, and enhanced osteogenic genes expression partly through the cGMP-PKGII ENaC signaling pathway. PMID- 28024414 TI - Defining Service and Education in Pediatrics. AB - Program directors (PDs) and trainees are often queried regarding the balance of service and education during pediatric residency training. We aimed to use qualitative methods to learn how pediatric residents and PDs define service and education and to identify activities that exemplify these concepts. Focus groups of pediatric residents and PDs were performed and the data qualitatively analyzed. Thematic analysis revealed 4 themes from focus group data: (1) misalignment of the perceived definition of service; (2) agreement about the definition of education; (3) overlapping perceptions of the value of service to training; and (4) additional suggestions for improved integration of education and service. Pediatric residents hold positive definitions of service and believe that service adds value to their education. Importantly, the discovery of heterogeneous definitions of service between pediatric residents and PDs warrants further investigation and may have ramifications for Accreditation Council for Graduate Medical Education and those responsible for residency curricula. PMID- 28024415 TI - 15N allocation into wheat grains (Triticum aestivum L.) influenced by sowing rate and water supply at flowering under a Mediterranean climate. AB - This study examined the effects of a reduced wheat sowing rate (250 vs. 500 grains m-2) on grain yield, uptake of 15N into grains, and the incorporation into gluten and non-gluten proteins of wheat under field conditions in the Aegean region. A single 15N application was applied at stem elongation, at flowering, or at both developmental stages. Each 15N treatment included either additional water supply, or no additional water supply at flowering. Sowing rate (either 250 or 500 grains m-2) had no impact on grain yield. Grain yield increased with additional water supply, but at the expense of protein quality, because of a decrease in the protein content of gluten. The 15N content of the gluten and non gluten proteins at grain maturity was not different among cultivars. 15N applied at both stem elongation and flowering was found in comparable amounts in grains and protein fractions, irrespective of sowing rate. PMID- 28024416 TI - An Evolutionary Perspective on Mate Rejection. AB - We argue that mate rejection and ex-partner relationships are important, multifaceted topics that have been underresearched in social and evolutionary psychology. Mate rejection and relationship dissolution are ubiquitous and form integral parts of the human experience. Both also carry with them potential risks and benefits to our fitness and survival. Hence, we expect that mate rejection would have given rise to evolved behavioral and psychological adaptations. Herein, we outline some of the many unanswered questions in evolutionary psychology on these topics, at each step presenting novel hypotheses about how men and women should behave when rejecting a mate or potential mate or in response to rejection. We intend these hypotheses and suggestions for future research to be used as a basis for enriching our understanding of human mating from an evolutionary perspective. PMID- 28024417 TI - Neighborhood and Parental Influences on Diet and Physical Activity Behaviors in Young Low-Income Pediatric Patients. AB - This study explores the relationship between neighborhood characteristics and caregiver preferences for establishing diet and physical activity behaviors among low-income African American and Hispanic young children (2-5 years). Primary caregivers of young children were recruited from 2 urban pediatric clinics to participate in focus groups (n = 33). Thematic analysis of transcripts identified 3 themes: neighborhood constraints on desired behaviors, caregivers' strategies in response to neighborhoods, and caregivers' sense of agency in the face of neighborhood constraints. This study elucidates the dynamic relationship between neighborhoods and caregiver preferences, their interrelated impacts on establishment of diet and physical activity behaviors among young children, and the important role of caregiver agency in establishing behaviors among young children. To effectively address obesity disparities among young children, primary care behavioral interventions must leverage and support such resilient caregiver responses to neighborhood constraints in order to optimally address racial/ethnic and socioeconomic disparities in obesity among young children. PMID- 28024418 TI - Financial Care for Older Adults With Dementia. AB - This article describes an examination of the sociodemographic characteristics of adult children, particularly Baby Boomer caregivers, who provide financial care to older parents with dementia. The sample including 1,011adult children dementia caregivers aged 50 to 64 years is selected from a nationally representative sample in the 2010 Health and Retirement Study. Exact logistic regression revealed that race, provision of financial assistance to caregiver children, and the number of their children are significantly associated with financial caregiving of parents. Non-White caregivers are more likely to provide financial care to their parents or parents-in-law with dementia; those who have more children and provide financial assistance to their children are less likely to provide financial care to parents with dementia. The current findings present valuable new information on the sociodemographic characteristics of adult children who provide financial assistance to parents with dementia and inform research, programs, and services on dementia caregiving. PMID- 28024419 TI - People with dementia, contributing to learning and teaching in higher education: Innovative practice. AB - Patients and service users have a well-established role in teaching and learning on professional qualifying programmes such as such as social work and nursing. However, the role of people with dementia in contributing to educational initiatives at higher educational level remains under explored. Four people with dementia were recruited as Expert by Lived Experience Tutors for the Foundation Degree in Dementia Studies at a University in the United Kingdom. They met students regularly to support their learning. We were interested in researching whether and how this enhanced the ability of students to enable people to live well with dementia. However, we also discovered that the initiative gave insight into psychosocial aspects of dementia, and a new opportunity to explore personhood, co-production and social citizenship. That is the focus of this article. PMID- 28024420 TI - Assessing the Correlation Between Physical Activity and Quality of Life in Advanced Lung Cancer. AB - BACKGROUND AND OBJECTIVE: Increasing physical activity (PA) is safe and beneficial in lung cancer (LC) patients. Advanced-stage LC patients are under studied and have worse symptoms and quality of life (QoL). We evaluated the feasibility of monitoring step count in advanced LC as well as potential correlations between PA and QoL. METHODS: This is a prospective, observational study of 39 consecutive patients with advanced-stage LC. Daily step count over 1 week (via Fitbit Zip), QoL, dyspnea, and depression scores were collected. Spearman rank testing was used to assess correlations. Correlation coefficients (rho) >0.3 or <-0.3 (more and less correlated, respectively) were considered potentially clinically significant. RESULTS: Most (83%) of the patients were interested in participating, and 67% of those enrolled were adherent with the device. Of those using the device (n = 30), the average daily step count was 4877 (range = 504-12 118) steps/d. Higher average daily step count correlated with higher QoL (rho = 0.46), physical (rho = 0.61), role (rho = 0.48), and emotional functioning (rho = 0.40) scores as well as lower depression (rho = -0.40), dyspnea (rho = -0.54), and pain (rho = -0.37) scores. CONCLUSION: Remote PA monitoring (Fitbit Zip) is feasible in advanced-stage LC patients. Interest in participating in this PA study was high with comparable adherence to other PA studies. In those utilizing the device, higher step count correlates with higher QoL as well as lower dyspnea, pain, and depression scores. PA monitoring with wearable devices in advanced-stage LC deserves further study. PMID- 28024421 TI - Subjective taste to polyethylene glycol is associated with efficacy of right colon preparation. AB - AIM: A prospective observational trial with preparations using polyethylene glycol (PEG) to compare patient compliance and adverse events according to individual subjective taste. METHODS: A total of 299 outpatients (mean +/- standard deviation [SD] 56.5 +/- 13.8 years, 172 males) were recruited for our study. We assessed the efficacy of bowel preparation, subjective taste to their regimens, compliance and adverse events during the preparation. RESULTS: We achieved adequate preparation in 267 (89.3%). A total of 124 patients (41.5%) had 'unacceptable taste' to their regimens. The patients with acceptable taste had better compliance than the patients with unacceptable taste (p = .009). The patients with unacceptable taste had more frequent adverse events such as nausea, vomiting and abdominal bloating than the patients with acceptable taste (all p < .001, Table 2). Patients with unacceptable taste (16.1%) had more frequent inadequate preparation in overall colon than patients with acceptable taste (6.9%, p = .011). There was a significant difference in the efficacy of preparation of right colon between the two groups (p = .004). CONCLUSION: Subjective taste to PEG is associated with efficacy of right colon preparation. In addition, subjective taste to PEG is associated with compliance and adverse events. PMID- 28024422 TI - No homology means there can be no analyses; a comment on Jose & Harikrishnan. PMID- 28024423 TI - Molecular phylogenetic study on few morphotypes of a patellogastropod Cellana karachiensis from northern Arabian Sea reveals unexpected genetic diversity. AB - A group of limpets, Cellana karachiensis, exhibiting phenotypic plasticity were examined from Gujarat coastline India, using molecular phylogeny. Previous examination of the COI genes established the presence of three different haplotypes X, Y and Z, while present study showed three more haplotypes X1, X2 and Z1. Thus, a total of six COI gene haplotypes, having 99.23% to 99.85% sequence similarity, were observed with variations at six sites. Bayesian phylogenetic analysis shows divergence of lineages X-Y, X1-X2 and Z-Z1. Careful observation of nucleotide alterations showed a nonrandom mutation with more A<->G and C<->T transitions between closely related species of the genus Cellana. A stretch of 17 base pair, within COI region, was marked as region with high degree of variability between species of Cellana. Results suggest that this could be the beginning of speciation, with partial or complete reproductive barrier or these are already distinct species in different stages of evolution. PMID- 28024425 TI - Acknowledgements to Referees. PMID- 28024424 TI - The Relationship Between Health-Related Quality of Life and Survival in Metastatic Colorectal Cancer Patients Treated With Korean Medicine. AB - OBJECTIVES: This study aimed to identify the relationship between health-related quality of life (HRQoL) measured by the Functional Assessment Cancer Therapy General (FACT-G) and survival in metastatic colorectal cancer (mCRC) patients. METHODS: The clinical characteristics and FACT-G scores were retrospectively reviewed in mCRC patients who visited the Cancer Center of Korean Medicine. The overall survival (OS) was calculated and compared using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were performed based on clinical characteristics and FACT-G scores. To identify significant differences in answer frequency, chi2 tests and Fisher's exact tests were used. RESULTS: A total of 58 patients were reviewed. The proportion of patients who had an Eastern Cooperative Oncology Group-Performance Status >= 2 was 43.1%, multiple distant metastatic sites was 77.6%, liver metastases was 43.1%, been previously treated was 89.7%, and received more than the second-line chemotherapy was 75.5%. The mean total FACT-G score was 65.3 (median 65.6). The median OS was 7 months. There was no significant difference in OS between the 2 groups divided by the median values of FACT-G total and subscores. In univariate analyses, functional well-being (FWB) score had a significant impact on survival. In multivariate analyses, presence of liver metastasis, FACT-G total score, and FWB score were significant prognostic predictors of survival. No statistically different answer frequency was observed for any question regarding FWB. CONCLUSIONS: This study found that FACT-G total and FWB scores were potential prognostic factors for predicting OS in relapsed or refractory mCRC patients treated with Korean Medicine. PMID- 28024426 TI - Across-subject calibration of an instrumented glove to measure hand movement for clinical purposes. AB - Motion capture of all degrees of freedom of the hand collected during performance of daily living activities remains challenging. Instrumented gloves are an attractive option because of their higher ease of use. However, subject-specific calibration of gloves is lengthy and has limitations for individuals with disabilities. Here, a calibration procedure is presented, consisting in the recording of just a simple hand position so as to allow capture of the kinematics of 16 hand joints during daily life activities even in case of severe injured hands. 'across-subject gains' were obtained by averaging the gains obtained from a detailed subject-specific calibration involving 44 registrations that was repeated three times on multiple days to 6 subjects. In additional 4 subjects, joint angles that resulted from applying the 'across-subject calibration' or the subject-specific calibration were compared. Global errors associated with the 'across-subject calibration' relative to the detailed, subject-specific protocol were small (bias: 0.49 degrees ; precision: 4.45 degrees ) and comparable to those that resulted from repeating the detailed protocol with the same subject on multiple days (0.36 degrees ; 3.50 degrees ). Furthermore, in one subject, performance of the 'across-subject calibration' was directly compared to another fast calibration method, expressed relative to a videogrammetric protocol as a gold-standard, yielding better results. PMID- 28024427 TI - Twelve tips on how to establish a new undergraduate firm on a critical care unit. AB - BACKGROUND: Little is known about undergraduate teaching in critical care unit (CrCU) and many undergraduate curricula lack placements in CrCU. AIMS: To describe how our CrCU succeeded in developing a novel placement for Year 3 undergraduate medical students. METHODS: Particular emphasis was placed on a robust timetable incorporating a variety of activities, a dedicated and thorough induction, and a mix of teaching methods such as formal and informal, consultant led, and skills. Services allied to CrCU were also utilized. RESULTS: Our new firm has exceeded all expectations and, based on student feedback, received the "Firm of the Year" award for several years in succession. It now serves as a model of undergraduate teaching in our hospital. CONCLUSIONS: Educationalists and intensivists should work together to unlock the full potential of this rich learning environment. Professional societies in critical care medicine should take the opportunity to develop more interest in undergraduate medical education. PMID- 28024428 TI - Population structure and genetic diversity of Indian Major Carp, Labeo rohita (Hamilton, 1822) from three phylo-geographically isolated riverine ecosystems of India as revealed by mtDNA cytochrome b region sequences. AB - The population structure and genetic diversity of Rohu (Labeo rohita Hamilton, 1822) was studied by analysis of the partial sequences of mitochondrial DNA cytochrome b region. We examined 133 samples collected from six locations in three geographically isolated rivers of India. Analysis of 11 haplotypes showed low haplotype diversity (0.00150), nucleotide diversity (pi) (0.02884) and low heterogeneity value (0.00374). Analysis of molecular variance (AMOVA) revealed the genetic diversity of L. rohita within population is very high than between the populations. The Fst scores (-0.07479 to 0.07022) were the indication of low genetic structure of L. rohita populations of three rivers of India. Conspicuously, Farakka-Bharuch population pair Fst score of 0.0000, although the sampling sites are from different rivers. The phylogenetic reconstruction of unique haplotypes revealed sharing of a single central haplotype (Hap_1) by all the six populations with a point mutations ranging from 1-25 nucleotides. PMID- 28024429 TI - Top 10 undergraduate medical students had not all attended lectures. PMID- 28024430 TI - History teaches everything. PMID- 28024431 TI - How patient educators help students to learn: An exploratory study. AB - INTRODUCTION: Benefits of the active involvement of patients in educating health professionals are well-recognized but little is known about how patient educators facilitate student learning. METHOD: This exploratory qualitative study investigated the teaching practices and experiences that prepared patient educators for their roles in a longitudinal interprofessional Health Mentors program. Semi-structured interviews were conducted with eleven experienced health mentors. Responses were coded and analyzed for themes related to teaching goals, methods, and prior experiences. RESULTS: Mentors used a rich variety of teaching methods to teach patient-centeredness and interprofessionalism, categorized as: telling my story, stimulating reflection, sharing perspectives, and problem solving. As educators they drew on a variety of prior experiences with teaching, facilitation or public speaking and long-term interactions with the health-care system. CONCLUSIONS: Patient educators use diverse teaching methods, drawing on both individualistic and social perspectives on learning. A peer-support model of training and support would help maintain the authenticity of patients as educators. The study highlights inadequacies of current learning theories to explain how patients help students learn. PMID- 28024432 TI - Students generate items for an online formative assessment: Is it motivating? AB - BACKGROUND: A reported problem with e-learning is sustaining students' motivation. We propose a framework explaining to what extent an e-learning task is motivating. This framework includes students' perceived Value of the task, Competence in executing the task, Autonomy over how to carry out the task, and Relatedness. METHODS: To test this framework, students generated items in an online environment and answered questions developed by their fellow students. Motivation was measured by analyzing engagement with the task, with an open-ended questionnaire about engagement, and with the motivated strategies for learning questionnaire (MSLQ). RESULTS: Students developed 59 questions and answered 1776 times on the questions. Differences between students who did or did not engage in the task are explained by the degree of self-regulation, time management, and effort regulation students report. There was a significant relationship between student engagement and achievement after controlling for previous academic achievement. CONCLUSIONS: This study proposes a way of explaining the motivational value of an e-learning task by looking at students' perceived competence, autonomy, value of the task, and relatedness. Student-generated items are considered of high task value, and help to perceive relatedness between students. With the right instruction, students feel competent to engage in the task. PMID- 28024433 TI - Medical education research: The realm of the rich. PMID- 28024434 TI - Twelve tips on writing a discussion case that facilitates teaching and engages learners. AB - The authors share twelve practical tips on writing a case that engages learners in active learning and discussion. They first advise that, during the initial preparation of the case, authors should (1) identify the case goals and objectives, and (2) identify the level of the learners. When writing the case, authors should (3) use active and colorful language; (4) use patients' own descriptions rather than medical language; (5) allow the learners to interpret data themselves; (6) allow for natural discovery rather than presenting information chronologically; and (7) be realistic about interruptions in patient care. In addition, case authors should pay attention to methods that enhance discussion by (8) creating barriers to diagnostic or treatment options; (9) promoting questions and discussion over answers; (10) using cues to assure discussion flow and knowledge exploration; and (11) omitting details or inserting informational distractors. Finally, well-crafted questions are essential during the case presentation to engage learners in higher-order thinking; and to (12) stimulate curiosity and reflection. PMID- 28024435 TI - An OSCE with very limited resources: Is it possible? PMID- 28024436 TI - International consensus statement on the assessment of interprofessional learning outcomes. AB - Regulatory frameworks around the world mandate that health and social care professional education programs graduate practitioners who have the competence and capability to practice effectively in interprofessional collaborative teams. Academic institutions are responding by offering interprofessional education (IPE); however, there is as yet no consensus regarding optimal strategies for the assessment of interprofessional learning (IPL). The Program Committee for the 17th Ottawa Conference in Perth, Australia in March, 2016, invited IPE champions to debate and discuss the current status of the assessment of IPL. A draft statement from this workshop was further discussed at the global All Together Better Health VIII conference in Oxford, UK in September, 2016. The outcomes of these deliberations and a final round of electronic consultation informed the work of a core group of international IPE leaders to develop this document. The consensus statement we present here is the result of the synthesized views of experts and global colleagues. It outlines the challenges and difficulties but endorses a set of desired learning outcome categories and methods of assessment that can be adapted to individual contexts and resources. The points of consensus focus on pre-qualification (pre-licensure) health professional students but may be transferable into post-qualification arenas. PMID- 28024437 TI - High-throughput thermal stability assessment of DNA hairpins based on high resolution melting. AB - On the basis of high-resolution melting, a high-throughput approach to measure melting temperatures (Tms) of short DNA hairpins was developed. With this method, Tms of thousands of triloop, tetraloop, and pentaloop hairpins involving various loop sequences and various closing base pairs (cbp) were obtained in hours. The stability of triloop hairpins decreased with the change of cbp (5'-3') in the order of c-g > g-c > t-a >= a-t, showing that the cbp of 5'-Pyr-Pur-3' (Pyr = pyrimidine, Pur = purine) contributed more stability than 5'-Pur-Pyr-3'. For tetraloop hairpins, GNNA, GNAB, and CNNG (N = A, G, C, or T; B = G, C, or T) were found to be highly stable irrespective of the cbp type. TNNA was also stable in both g-c and a-t families, while CGNA only in the c-g family. Pentaloop hairpins of cTGNAGg, cGNYNAg (Y = T or C) and cCGNNAg were exceptionally stable motifs. In most cases, pyrimidine-rich loops were more favorable to stabilize the whole structure than purine-rich ones. The present approach showed a good performance in assessing the thermal stability of large amounts of DNA hairpins comprehensively. These data are useful to understand the sequence dependence of the stability of DNA secondary structures and promising to improve the structure simulation by consummating basic databases. PMID- 28024438 TI - To participate or not participate in unprofessional behavior - Is that the question? AB - INTRODUCTION: Medical education provides students with abundant learning opportunities, each of which is embodied with messages concerning what is expected from students. This paper analyses students? exposure to instances of unprofessional behavior, investigating whether they judge such behavior to be unprofessional and whether they also participate in unprofessional behavior. METHODS: The survey developed in the Pritzker School of Medicine at the University of Chicago was the basis of this questionnaire that was answered by 276 students from two medical schools in Brazil and Portugal. RESULTS: Unprofessional behavior was observed frequently by students in both universities, and the mean participation rates were similar (26% and 27%). Forty-five percent of students? participation in unprofessional behavior was explained by academic year, prior observation, and judgment. DISCUSSION: The results indicate that once students have observed, participated in or misjudged unprofessional behavior, they tend to participate in and misjudge such behavior. The frequency with which students judged behaviors they had observed or participated in as ?borderline? or unprofessional could mean that they are experiencing moral distress. CONCLUSION: Proper discussion of unprofessional behavior should foster a broad debate to encourage empowered students, faculties, and physicians to co-create a more professional environment for patient care. PMID- 28024439 TI - Impact of sociodemographic characteristics of applicants in multiple mini interviews. AB - BACKGROUND: Multiple mini-interviews (MMI) are commonly used for medical school admission. This study aimed to assess if sociodemographic characteristics are associated with MMI performance, and how they may act as barriers or enablers to communication in MMI. METHODS: This mixed-method study combined data from a sociodemographic questionnaire, MMI scores, semi-structured interviews and focus groups with applicants and assessors. Quantitative and qualitative data were analyzed using multiple linear regression and a thematic framework analysis. RESULTS: 1099 applicants responded to the questionnaire. A regression model (R2 = 0.086) demonstrated that being age 25-29 (beta = 0.11, p = 0.001), female and a French-speaker (beta = 0.22, p = 0.003) were associated with better MMI scores. Having an Asian-born parent was associated with a lower score (beta = -0.12, p < 0.001). Candidates reporting a higher family income had higher MMI scores. In the qualitative data, participants discussed how maturity and financial support improved life experiences, how language could act as a barrier, and how ethnocultural differences could lead to misunderstandings. CONCLUSION: Age, gender, ethnicity, socioeconomic status and language seem to be associated with applicants' MMI scores because of perceived differences in communications skills and life experiences. Monitoring this association may provide guidance to improve fairness of MMI stations. PMID- 28024440 TI - Moment-to-moment changes in feeling moved match changes in closeness, tears, goosebumps, and warmth: time series analyses. AB - Feeling moved or touched can be accompanied by tears, goosebumps, and sensations of warmth in the centre of the chest. The experience has been described frequently, but psychological science knows little about it. We propose that labelling one's feeling as being moved or touched is a component of a social relational emotion that we term kama muta (its Sanskrit label). We hypothesise that it is caused by appraising an intensification of communal sharing relations. Here, we test this by investigating people's moment-to-moment reports of feeling moved and touched while watching six short videos. We compare these to six other sets of participants' moment-to-moment responses watching the same videos: respectively, judgements of closeness (indexing communal sharing), reports of weeping, goosebumps, warmth in the centre of the chest, happiness, and sadness. Our eighth time series is expert ratings of communal sharing. Time series analyses show strong and consistent cross-correlations of feeling moved and touched and closeness with each other and with each of the three physiological variables and expert-rated communal sharing - but distinctiveness from happiness and sadness. These results support our model. PMID- 28024441 TI - The effects of telehealth use for post-acute rehabilitation patient outcomes. AB - Introduction Previous research has shown that home telehealth services can reduce hospitalisations and emergency department visits and improve clinical outcomes among older adults with chronic conditions. However, there is a lack of research on the impact of telehealth (TH) use on patient outcomes in post-acute rehabilitation settings. The current study examined the effects of TH for post acute rehabilitation patient outcomes (i.e. discharge setting and change in functional independence) when controlling for other factors (e.g. cognitive functioning). Methods For this retrospective study, electronic medical records (EMRs) of 294 patients who were discharged from a post-acute rehabilitation unit at a skilled nursing facility were reviewed. Only patients with an admitting condition of a circulatory disease based on ICD-9 classification were included. Main EMR data extracted included use of TH, cognitive functioning, admission and discharge functional independence, and discharge setting (returning home vs. returning to acute care/re-hospitalisation). Results Results from a regression analysis showed that although TH use was unrelated to post-acute rehabilitation care transition, it was significantly related to change in functional independence. Patients who used TH during their stay had significantly more improvement in functional independence from admission to discharge when compared to those who did not use TH. Discussion Findings indicate that TH use during post acute rehabilitation has the potential to improve patient physical functioning. PMID- 28024442 TI - Validity of the Model for Assessment of Telemedicine: A Delphi study. AB - Introduction In 2009, the Model for Assessment of Telemedicine (MAST) was developed within the MethoTelemed project as a framework for description of the effectiveness of telemedicine applications. The goal was for the assessments to be used as basis for decision-making in healthcare systems. Since then, MAST has been used in many European telemedicine studies and is now the most widely used model for assessment of telemedicine. The aim of this study was to assess the face validity of MAST. Methods A modified Delphi process was carried out and included a workshop with a sample of healthcare decision makers. A total of 56 decision makers and experts in telemedicine were invited and 19 persons participated in the two Delphi rounds. Thirteen hospitals or regional health authorities from 12 European countries and six research organisations were represented in the final sample. The participants were asked to assess the importance of the different domains and topics in MAST on a 0-3 Likert scale. Results All respondents completed the two rounds. Based on the answers, the face validity of all MAST domains was confirmed, since all domains were considered moderately or highly important by more than 80% of the respondents. Discussion Even though the study confirmed the validity of MAST, a number of supplements and improvements regarding study design and data collection were suggested. When considering the results it should be noticed that the sample size was small and larger studies are needed to confirm the results. PMID- 28024444 TI - Contextual Effects in Judgments of Taste Intensity: No Assimilation, Sometimes Contrast. AB - Judgments of taste intensity often show contextual contrast but not assimilation, even though both effects of stimulus context appear in other sense modalities, such as hearing. Four experiments used a paradigm that shifts the stimulus context within a test session in order to seek evidence of assimilation in judgments of the taste intensity of sucrose and, for comparison, the loudness of 500-Hz tones. Experiment 1 found no assimilation in taste using three response scales, magnitude estimation, labeled magnitude, and visual analog, but did find evidence of contrast. Experiments 2 and 3 found no clear evidence of either assimilation or contrast in taste, but found consistent evidence of assimilation in loudness. Experiment 4 found no assimilation in loudness, however, when the intervals between successive stimuli increased from about 6 to 30 s in order to match the interval used with sucrose in Experiments 1 to 3. Taken together, these findings suggest that the assimilation found in intensity judgments in other sensory modalities may not appear in taste perception because of the slower rates presenting of taste stimuli. PMID- 28024445 TI - Role of structural water for prediction of cation binding sites in apoproteins. AB - Structures of many metal-binding proteins are often obtained without structural cations in their apoprotein forms. Missing cation coordinates are usually updated from structural templates constructed from many holoprotein structures. Such templates usually do not include structural water, the important contributor to the ion binding energy. Structural templates are also inconvenient for taking into account structural modifications around the binding site at apo-/holo- transitions. An approach based upon statistical potentials readily takes into account structural modifications associated with binding as well as contribution of structural water molecules. Here, we construct a set of statistical potentials for Mg2+, Ca2+, and Zn2+ contacting with protein atoms of a different type or structural water oxygens. Each type of the cations tends to form tight contacts with protein atoms of specific types. Structural water contributes relatively more into the binding pseudo-energy of Mg2+ and Ca2+ than of Zn2+. We have developed PIONCA (Protein-Ion Calculator), a fast CUDA GPGPU-based algorithm that predicts ion-binding sites in apoproteins. Comparative tests demonstrate that PIONCA outperforms most of the tools based on structural templates or docking. Our software can be also used for locating bound cations in holoprotein structures with missing cation heteroatoms. PIONCA is equipped with an interactive web interface based upon JSmol. PMID- 28024446 TI - Mental health in a conflict area: Migration, economic stress and religiosity in the three southernmost provinces of Thailand. AB - AIM: Three southern provinces of Thailand, Pattani, Yala and Narathiwat, have been involved in a long period of unrest due to differences between the population in the provinces and the Thai government with regard to language, culture and governance. The objectives of this article are to examine the effects of everyday stressors due to the conflict, including economic stress and migration, as well as the effect of religiosity on the reporting of psychiatric symptoms among adults in the three provinces. METHODS: Data were drawn from a survey conducted in 2014. The survey included a probability sample of 2,053 Muslim adults aged 18-59 years.Mental health was assessed using World Health Organization's (WHO) Self-Reporting Questionnaire (SRQ) of 20 questions. Multilevel models were estimated to examine the influence of economic stress due to the conflict, as well as community and individual aspects of migration and religion on mental health. RESULTS: The data showed that migration from the household and the community and the economic effects of the unrest were associated with reporting of more psychiatric symptoms among adults in the southern provinces. Religion was related to reporting of fewer psychiatric symptoms at the individual and the community levels. CONCLUSION: The study documented increased reporting of psychiatric symptoms among persons reporting perceived household economic stress due to the conflict and the migration of family members. PMID- 28024447 TI - Detecting and correcting for publication bias in meta-analysis - A truncated normal distribution approach. AB - Publication bias can significantly limit the validity of meta-analysis when trying to draw conclusion about a research question from independent studies. Most research on detection and correction for publication bias in meta-analysis focus mainly on funnel plot-based methodologies or selection models. In this paper, we formulate publication bias as a truncated distribution problem, and propose new parametric solutions. We develop methodologies of estimating the underlying overall effect size and the severity of publication bias. We distinguish the two major situations, in which publication bias may be induced by: (1) small effect size or (2) large p-value. We consider both fixed and random effects models, and derive estimators for the overall mean and the truncation proportion. These estimators will be obtained using maximum likelihood estimation and method of moments under fixed- and random-effects models, respectively. We carried out extensive simulation studies to evaluate the performance of our methodology, and to compare with the non-parametric Trim and Fill method based on funnel plot. We find that our methods based on truncated normal distribution perform consistently well, both in detecting and correcting publication bias under various situations. PMID- 28024449 TI - Effects of different force fields on the structural character of alpha synuclein beta-hairpin peptide (35-56) in aqueous environment. AB - The hallmark of Parkinson's disease (PD) is the intracellular protein aggregation forming Lewy Bodies (LB) and Lewy neuritis which comprise mostly of a protein, alpha synuclein (alpha-syn). Molecular dynamics (MD) simulation methods can augment experimental techniques to understand misfolding and aggregation pathways with atomistic resolution. The quality of MD simulations for proteins and peptides depends greatly on the accuracy of empirical force fields. The aim of this work is to investigate the effects of different force fields on the structural character of beta hairpin fragment of alpha-syn (residues 35-56) peptide in aqueous solution. Six independent MD simulations are done in explicit solvent using, AMBER03, AMBER99SB, GROMOS96 43A1, GROMOS96 53A6, OPLS-AA, and CHARMM27 force fields with CMAP corrections. The performance of each force field is assessed from several structural parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), formation of beta-turn, the stability of folded beta-hairpin structure, and the favourable conformations obtained for different force fields. In this study, CMAP correction of CHARMM27 force field is found to overestimate the helical conformation, while GROMOS96 53A6 is found to most successfully capture the conformational dynamics of alpha-syn beta-hairpin fragment as elicited from NMR. PMID- 28024448 TI - Effects of pentachlorophenol and dichlorodiphenyltrichloroethane on secretion of interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) from human immune cells. AB - Pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) are pesticides that have been widely used and significantly contaminate the environment. Both are found in human blood and have been shown to alter the lytic and binding function of human natural killer (NK) cells. Interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) are pro-inflammatory cytokines, which regulate immune responsiveness to pathogens and tumors. Their levels require very tight control to prevent loss of immune competence or excessive inflammation. Here, we examined the capacity of PCP and DDT to alter the secretion of these critical pro-inflammatory cytokines from increasingly reconstituted (more complex) preparations of human immune cells which included NK cells, monocyte depleted (MD) peripheral blood mononuclear cells (PBMCs) (a preparation that is predominantly lymphocytes) and PBMCs (a preparation containing lymphocytes and monocytes). Results indicated that exposure to PCP decreased IFNgamma secretion at the highest exposures (2.5 and 5 MUM) and increased IFNgamma secretion at lower concentrations. These effects were seen irrespective of the complexity of the cell preparation. PCP at 2.5 and 5 MUM generally decreased TNFalpha secretion from NK cells, but had inconsistent effects in MD-PBMCs and PBMCs. Exposure of each of the immune cell preparations to DDT caused increase in IFNgamma secretion. DDT (2.5 MUM) increased TNFalpha secretion from MD-PBMCs after either 24 h or 48 h of exposure. The mechanism of PCP-induced increase in IFNgamma secretion appears to involve the p38 mitogen activated protein kinase (MAPK) pathway, based on loss of PCP stimulated increase when this pathway was inhibited. PMID- 28024450 TI - Age estimation for the genus Cymbidium (Orchidaceae: Epidendroideae) with implementation of fossil data calibration using molecular markers (ITS2 & matK) and phylogeographic inference from ancestral area reconstruction. AB - Intercontinental dislocations between tropical regions harboring two-thirds of the flowering plants have always drawn attention from taxonomists and biogeographers. One such family belonging to angiosperms is Orchidaceae with an herbaceous habit and high species diversity in the tropics. Here, we investigate the evolutionary and biogeographical history of the genus Cymbidium, which represents a monophyletic subfamily (Epidendroideae) of the orchids and comprises 50 odd species that are distinctly distributed in tropical to temperate regions. Much is not known about correlations among the level of CAM activity (one of the photosynthetic pathways often regarded as an adaptation to water stress in land plants), habitat, life forms, and phylogenetic relationships of orchids from an evolutionary perspective. A relatively well-resolved and highly supported phylogeny for Cymbidium orchids is reconstructed based on sequence analysis of ITS2 and matK regions from the chloroplast DNA available in public repositories viz. GenBank at NCBI. This study examines a genus level analysis by integrating different molecular matrices to existing fossil data on orchids in a molecular Bayesian relaxed clock employed in BEAST and assessed divergence times for the genus Cymbidium with a focus on evolutionary history of photosynthetic characters. Our study has enabled age estimations (45Ma) as well as ancestral area reconstruction for the genus Cymbidium using BEAST by addition of previously analyzed two internal calibration points. PMID- 28024451 TI - Weathering in soil increases nanoparticle CuO bioaccumulation within a terrestrial food chain. AB - This study evaluates the bioaccumulation of unweathered (U) and weathered (W) CuO in NP, bulk and ionic form (0-400 mg/kg) by lettuce exposed for 70 d in soil co contaminated with field incurred chlordane. To evaluate CuO trophic transfer, leaves were fed to crickets (Acheta domestica) for 15 d, followed by insect feeding to lizards (Anolis carolinensis). Upon weathering, the root Cu content of the NP treatment increased 214% (327 +/- 59.1 mg/kg) over unaged treatment. Cu root content decreased in bulk and ionic treatments from 70-130 mg/kg to 13-26 mg/kg upon aging in soil. Micro X-ray fluorescence (MU-XRF) analysis of W-NP exposed roots showed a homogenous distribution of Cu (and Ca) in the tissues. Additionally, micro X-ray absorption near-edge (MU-XANES) analysis of W-NP exposed roots showed near complete transformation of CuO to Cu (I)-sulfur and oxide complexes in the tissues, whereas in unweathered treatment, most root Cu remained as CuO. The expression level of nine genes involved in Cu transport shows that the mechanisms of CuO NPs (and bulk) response/accumulation are different than ionic Cu. The chlordane accumulation by lettuce upon co-exposure to CuO NPs significantly increased upon weathering. Conversely, bulk and ionic exposures decreased pesticide accumulation by plant upon weathering. The Cu cricket fecal content from U-NP-exposed insects was significantly greater than the bulk or ion treatments, suggesting a higher initial NP accumulation followed by significantly greater elimination during depuration. In the lizard, Cu content in the intestine, body and head did not differ as a function of weathering. This study demonstrates that CuO NPs may undergo transformation processes in soil upon weathering that subsequently impact NPs availability in terrestrial food chains. PMID- 28024452 TI - Positive predictive value of ELISpot in BAL and pleural fluid from patients with suspected pulmonary tuberculosis. AB - BACKGROUND: The aim of this study was to evaluate the positive predictive value (PPV) of ELISpot in bronchoalveolar lavage (BAL) and pleural fluid for the diagnosis of active tuberculosis (TB) in real-life clinical practice, together with the added value of a cut-off >1.0 for the ratio between the extra sanguineous and systemic interferon-gamma responses in positive samples. METHODS: A retrospective, single-centre study was performed. Patients with positive ELISpot in BAL and pleural fluid were included. RESULTS: The PPV for TB in patients with positive ELISpot in BAL (n = 40) was 64.9%, which increased to 82.6% for the ESAT-6 panel and 71.4% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the BAL and blood interferon-gamma responses. In patients with positive ELISpot in pleural fluid (n = 16), the PPV for TB was 85.7%, which increased to 91.7% for the ESAT-6 panel and 92.3% for the CFP-10 panel after the introduction of a cut-off >1.0 for the ratio between the pleural fluid and blood interferon-gamma responses. CONCLUSIONS: This report describes the PPV of ELISpot in BAL and pleural fluid for the diagnosis of active TB in real-life clinical practice. The results indicate the possibility of an increase of the PPV using a cut-off >1.0 for the ratio between the extra sanguineous and systemic interferon-gamma responses. Further studies are needed to underline this ratio-approach and to evaluate the full diagnostic accuracy of ELISpot in extra-sanguineous fluids like BAL and pleural fluid. PMID- 28024453 TI - Family Structure, Child Living Arrangement and Mothers' Self-rated Health in Sweden-A Cross-Sectional Study. AB - Alternate living, i.e. children living 50-50 with their parents following separation is emerging as a new family form. This study is the first to differentiate separated mothers with sole/main custody from mothers with alternately living children, analysing health outcomes and using a sample representative of the population. The association between the self-rated health (SRH) of mothers and different family structures are examined. Parental cooperation is included in the analyses as a potential mediator. Data on 755 mothers from the 2010 Swedish Level of Living Survey were analyzed by multivariate logistic regression. Single mothers with sole/main custody reported poorer SRH than couple mothers in intact families while the difference was not significant for single mothers with children living alternately and mothers in stepfamilies. Controlling for potential confounders, probabilities for poor SRH for single mothers were reduced. The excess risk among mothers with sole/main custody may be due to poorer socioeconomic conditions. Employment was significantly more common among mothers with alternate living and an important explanatory factor for their better health compared to single mothers with sole/main custody. Adjusting for parental cooperation lowered the increased probability for poor SRH among single mothers with sole/main custody compared to single mothers with alternate living. PMID- 28024454 TI - Awareness and Perceptions of Type 2 Diabetes Risk Factors, Preventability, and Complications Among College Students in Visakhapatnam, India. AB - In India, often referred to as the "diabetes capital of the world," it is imperative to establish the level of knowledge among Asian Indians of Type 2 Diabetes (DM2) in order to plan effective public health programs aimed at prevention of DM2. Using an original survey of 983 college students in Visakhapatnam, Andhra Pradesh, we evaluated individuals' knowledge of DM2 including prevalence, risk factors, and prevention. To date, there are only a few studies that look at awareness of diabetes on the community level, and no previous studies have involved sampling college students. Our findings show that although awareness of diabetes is high, only half of the students sampled were aware that DM2 could be prevented and 60% were unaware that little or no exercise was a risk factor. The results suggest that diabetes awareness programs are needed among the college age population in India to prevent DM2. PMID- 28024455 TI - The Neisseria meningitidis lpxL1 mutant induces less tissue factor expression and activity in primary human monocytes and monocyte-derived microvesicles than the wild type meningococcus. AB - Neisseria meningitidis (N. meningitidis) may cause sepsis and meningitis. N. meningitidis with a mutated lpxL1 gene has five, instead of six, acyl chains in the lipid A moiety. Compared with patients infected with the wild type (wt) meningococcus, patients infected with the lpxL1 mutant have a mild meningococcal disease with less systemic inflammation and less coagulopathy. Circulating tissue factor (TF), the main initiator of coagulation, has a central role in the development of coagulation disturbances during sepsis. To study how TF was influenced by the lpxL1 mutant, human primary monocytes and whole blood were incubated with the lpxL1 mutant or the wt meningococcus (H44/76). Monocyte and microvesicle (MV)-associated TF expression and TF-dependent thrombin generation were measured. In both purified monocytes and whole blood, our data show that the lpxL1 mutant is a weaker inducer of monocyte and MV-associated TF compared with the wt. Our data indicate that low levels of circulating TF may contribute to the reduced coagulopathy reported in patients infected with lpxL1 mutants. PMID- 28024456 TI - Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation. AB - Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) has been shown to disrupt endothelium-dependent arteriolar dilation in the peripheral microcirculation. The molecular mechanisms behind these arteriolar disruptions have yet to be fully elucidated. The secreted matricellular matrix protein thrombospondin-1 (TSP-1) is capable of moderating arteriolar vasodilation by inhibiting soluble guanylate cyclase activity. We hypothesized that TSP-1 may be a link between nanomaterial exposure and observed peripheral microvascular dysfunction. To test this hypothesis, wild-type C57B6J (WT) and TSP-1 knockout (KO) mice were exposed via lung aspiration to 50 MUg MWCNT or a Sham dispersion medium control. Following exposure (24 h), arteriolar characteristics and reactivity were measured in the gluteus maximus muscle using intravital microscopy (IVM) coupled with microiontophoretic delivery of acetylcholine (ACh) or sodium nitroprusside (SNP). In WT mice exposed to MWCNT, skeletal muscle TSP-1 protein increased > fivefold compared to Sham exposed, and exhibited a 39% and 47% decrease in endothelium-dependent and -independent vasodilation, respectively. In contrast, TSP-1 protein was not increased following MWCNT exposure in KO mice and exhibited no loss in dilatory capacity. Microvascular leukocyte-endothelium interactions were measured by assessing leukocyte adhesion and rolling activity in third order venules. The WT + MWCNT group demonstrated 223% higher leukocyte rolling compared to the WT + Sham controls. TSP-1 KO animals exposed to MWCNT showed no differences from the WT + Sham control. These data provide evidence that TSP-1 is likely a central mediator of the systemic microvascular dysfunction that follows pulmonary MWCNT exposure. PMID- 28024457 TI - Haemorrhagic enteritis of turkeys - current knowledge. AB - Haemorrhagic enteritis virus (HEV), an adenovirus associated with acute haemorrhagic gastro-intestinal disease of 6-11-week old turkeys predominantly hampers both humoral and cellular immunity. Affected birds are more prone to secondary complications (e.g. colibacillosis and clostridiosis) and failure to mount an effective vaccine-induced immune response. HEV belongs to the new genus Siadenovirus. Feco-oral transmission is the main route of entry of the virus and it mainly colonizes bursa, intestine and spleen. Both naturally occurring virulent and avirulent strains of HEVs are serologically indistinguishable. Recent findings revealed that ORF1, E3 and fib genes are the key factors affecting virulence. The adoption of suitable diagnostic tools, proper vaccination and biosecurity measures have restrained the occurrence of disease epidemics. For diagnostic purposes, the best source of HEV is either intestinal contents or samples from spleen. For rapid detection highly sensitive and specific tests such as quantitative real-time PCR based on Taq man probe has been designed. Avirulent strains of HEV or MSDV can be effectively used as live vaccines. Novel vaccines include recombinant hexon protein-based subunit vaccines or recombinant virus-vectored vaccines using fowl poxvirus (FPV) expressing the native hexon of HEV. Notably, subunit vaccines and recombinant virus vectored vaccines altogether offer high protection against challenge or field viruses. Herein, we converse a comprehensive analysis of the HEV genetics, disease pathobiology, advancements in diagnosis and vaccination along with appropriate prevention and control strategies. PMID- 28024458 TI - Advanced Chronic Venous Insufficiency. AB - INTRODUCTION: Intervention for advanced chronic venous insufficiency is considered an appropriate standard of care. However, outcomes vary among patients who present in advanced clinical stages of disease. The main objectives of this study were to determine whether racial disparity exists at initial presentation and response to intervention. METHODS: A retrospective database was created to include all radiofrequency ablation procedures performed by a single surgeon from January 14, 2009, through May 25, 2011. Demographics, clinical traits, race, procedure, and outcomes were analyzed. Stepwise model selection reduced candidate baseline factors to a final parsimonious model, which was analyzed using analysis of variance. RESULTS: The database consisted of 300 patients with a predominant female (n = 215, 85%) base and 85 (15%) males, with a mean age distribution of 53 years. The mean body mass index was 30.2. Racial distribution revealed Asian (n = 9, 3.3%), Pacific Islander (n = 1, 0.4%), African American (n = 37, 13.6%), and Caucasian (CAU, n = 225, 82.7%). African Americans presented with more advanced clinical stages than the CAU group-C2: African American 21.6%, CAU 36.7%; C4: African American 35%, CAU 24.3%; and C6: African American 35.1%, CAU 7.5%. African Americans demonstrated a higher preoperative venous clinical severity score (VCSS) than their CAU counterparts. Postprocedural decrease in VCSS score was lower in African Americans than their CAU counterparts. CONCLUSION: African American patients present with more advanced venous insufficiency than CAUs. Postprocedural analysis reveals not only slower ulcer healing times but also higher ulcer recurrence rates. PMID- 28024459 TI - Post-acute hospital healthcare services for people with mild stroke: a scoping review. AB - BACKGROUND: People with mild stroke comprise a significant proportion of the overall stroke population. Previously this population has been viewed as having limited impairments, receiving minimal services following hospital discharge. Recent findings demonstrate that the implications of mild stroke are more significant than originally comprehended, warranting further services. OBJECTIVES: To identify the evidence-base regarding services for people with mild stroke, post-acute hospital discharge, that target secondary prevention and/or changes following stroke. METHODS: Scoping review utilizing the five-stage framework proposed by Arksey and O'Malley, with revisions by Levac, Colquhuon, and O'Brien. Framework stages included: identification of a research question and relevant studies, study selection, charting of data, and collating, summarizing, and reporting. A critical appraisal using the Downs and Black Checklist was added to determine methodological quality of studies. The search strategy used six databases: Pubmed, Embase, PsycINFO, CINAHL, OTseeker, and Scopus, alongside a hand-search. Three researchers were involved in article selection and two in critical appraisal. RESULTS: Twelve articles met inclusion criteria from 589 identified. A number of study methodologies were used to assess services, with varying methodological qualities. Studies were located within two major regions in the world. Five main approaches to service provision were identified: telehealth, exercise and education, Comprehensive Cardiac Rehabilitation, one-off visits and care-plan development, and community group programs. The majority of programs focused on secondary prevention and were aimed at an impairment level, with a mix of findings observed. CONCLUSION: Further development and assessment of services is warranted. Incorporation of the entire transition period, and research that is mild stroke and location-specific is advised. Attention to maximizing participation in daily life, secondary prevention, emotional well being, and careful reporting is needed. PMID- 28024460 TI - Fungal treatment of humic-rich industrial wastewater: application of white rot fungi in remediation of food-processing wastewater. AB - This paper presents the results of fungal treatment of a real industrial wastewater (WW), providing insight into the main mechanisms involved and clarifying some ambiguities and uncertainties in the previous reports. In this regard, the mycoremediation potentials of four strains of white rot fungi (WRF): Phanerochaete chrysosporium, Trametes versicolor, Pleurotus ostreatus and Pleurotus pulmonarius were tested to remove humic acids (HA) from a real humic rich industrial treated WW of a food-processing plant. The HA removal was assessed by color measurement and size-exclusion chromatography (SEC) analysis. T. versicolor showed the best decolorization efficiency of 90% and yielded more than 45% degradation of HA, which was the highest among the tested fungal strains. The nitrogen limitation was studied and results showed that it affected the fungal extracellular laccase and manganese peroxidase (MnP) activities. The results of the SEC analysis revealed that the mechanism of HA removal by WRF involves degradation of large HA molecules to smaller molecules, conversion of HA to fulvic acid-like molecules and also biosorption of HA by fungal mycelia. The effect of HS on the growth of WRF was investigated and results showed that the inhibition or stimulation of growth differs among the fungal strains. PMID- 28024461 TI - Clinical coaching: Evolving the apprenticeship model for modern housestaff. AB - Feedback is one of the core components of teaching in the clinical setting. Traditionally, this activity has emphasized observations made by senior physicians and delivered to medical trainees. However, the optimal approach to feedback remains uncertain, and the literature abounds with trainee-perceived inadequacies in feedback content, quality, and impact. Moreover, given the multiplicity of demands on trainees and their physician mentors, we propose that medical trainees themselves-specifically, medical residents-are poised to serve as unique adjunct effectors of feedback. We propose a model of "clinical coaching" for residents as teachers, with emphasis on the active roles of both the feedback "giver" and "recipient". We define "clinical coaching" as "a helping longitudinal relationship between coach and apprentice that provides continuing feedback on and assistance with improving performance." Here, "coach" is the more experienced trainee (e.g. supervising resident), and "apprentice" is the less experienced trainee (e.g. intern or medical student). By working to better recognize and prepare residents for this vital role, we propose to encourage efforts to optimize the structure, execution, and impact of feedback in the contemporary climate of medical education. PMID- 28024462 TI - Predicting the Perceptual Consequences of Hidden Hearing Loss. AB - Recent physiological studies in several rodent species have revealed that permanent damage can occur to the auditory system after exposure to a noise that produces only a temporary shift in absolute thresholds. The damage has been found to occur in the synapses between the cochlea's inner hair cells and the auditory nerve, effectively severing part of the connection between the ear and the brain. This synaptopathy has been termed hidden hearing loss because its effects are not thought to be revealed in standard clinical, behavioral, or physiological measures of absolute threshold. It is currently unknown whether humans suffer from similar deficits after noise exposure. Even if synaptopathy occurs in humans, it remains unclear what the perceptual consequences might be or how they should best be measured. Here, we apply a simple theoretical model, taken from signal detection theory, to provide some predictions for what perceptual effects could be expected for a given loss of synapses. Predictions are made for a number of basic perceptual tasks, including tone detection in quiet and in noise, frequency discrimination, level discrimination, and binaural lateralization. The model's predictions are in line with the empirical observations that a 50% loss of synapses leads to changes in threshold that are too small to be reliably measured. Overall, the model provides a simple initial quantitative framework for understanding and predicting the perceptual effects of synaptopathy in humans. PMID- 28024463 TI - In silico Evidence for Binding of Pentacyclic Triterpenoids to Keap1-Nrf2 Protein Protein Binding Site. AB - AIM AND OBJECTIVE: Kelch like ECH-associated protein 1 (Keap1) and Nuclear factor E2 related factor 2 (Nrf2) binding is a key step in the ubiquitination and degradation of Nrf2. The compounds inhibiting this binding exert antioxidant actions. Naturally occurring pentacyclic triterpenoids (PTs) and their synthetic derivatives are projected as activators of Nrf2 signalling. The 16-mer Nrf2 peptide binding site on Keap-1 (PDB: 2 FLU) is proposed to be the prospective target where pentacyclic triterpenoid may exert protein-protein interaction. MATERIAL AND METHOD: In the present study, seventy seven PTs of natural and synthetic origin are screened for Nrf2 stimulatory activity using online PASS (Prediction of Activity Spectrum of Substances) software followed by in silico molecular docking against 16-mer Nrf2 peptide binding site on Keap-1. This virtual screening reveals that Nrf2 stimulatory PTs dock on the 16-mer peptide binding site on Keap-1 and may exert their biological activities by interfering with the Keap-1 and Nrf2 binding. RESULTS: In the present study shows that the small molecules like PT's bind to keap 1 pocket where the 16 mer peptide of Neh2 domain of Nrf2. High docking score of -10.53, -9.08, -8.36, -7.94, -7.49 and 7.18 is shown by glycyrrhizin, asiatic acid, medecassic acid, barrigenic acid, rotundic acid, ursolic acid, respectively. CONCLUSION: The identified hits such as asiatic acid and medecassic acid represent a very promising starting point for the development of potent Nrf2 stimulator. The natural PTs are more promising than the most potent synthetic derivatives of oleanolic acid like CDDO, CDDO methyl and CDDOimidazol. PMID- 28024464 TI - MSD-MAP: A Network-Based Systems Biology Platform for Predicting Disease Metabolite Links. AB - BACKGROUND: Cancer-associated metabolites result from cell-wide mechanisms of dysregulation. The field of metabolomics has sought to identify these aberrant metabolites as disease biomarkers, clues to understanding disease mechanisms, or even as therapeutic agents. OBJECTIVE: This study was undertaken to reliably predict metabolites associated with colorectal, esophageal, and prostate cancers. Metabolite and disease biological action networks were compared in a computational platform called MSD-MAP (Multi Scale Disease-Metabolite Association Platform). METHODS: Using differential gene expression analysis with patient based RNAseq data from The Cancer Genome Atlas, genes up- or down-regulated in cancer compared to normal tissue were identified. Relational databases were used to map biological entities including pathways, functions, and interacting proteins, to those differential disease genes. Similar relational maps were built for metabolites, stemming from known and in silico predicted metabolite-protein associations. The hypergeometric test was used to find statistically significant relationships between disease and metabolite biological signatures at each tier, and metabolites were assessed for multi-scale association with each cancer. Metabolite networks were also directly associated with various other diseases using a disease functional perturbation database. RESULTS: Our platform recapitulated metabolite-disease links that have been empirically verified in the scientific literature, with network-based mapping of jointly-associated biological activity also matching known disease mechanisms. This was true for colorectal, esophageal, and prostate cancers, using metabolite action networks stemming from both predicted and known functional protein associations. CONCLUSION: By employing systems biology concepts, MSD-MAP reliably predicted known cancermetabolite links, and may serve as a predictive tool to streamline conventional metabolomic profiling methodologies. PMID- 28024465 TI - [FLT3-ITD Mutation in Newly Diagnosed Patients with Acute Promyelocytic Leukemia]. AB - OBJECTIVE: To evaluate the influence of FLT3-ITD mutation on long term survival of newly diagnosed patients with acute promyelocytic leukemia (APL). METHODS: Long term survival of 170 newly diagnosed APL patients was retrospective analyzed. Mutation rate of FLT3-ITD was assayed, and its influence on disease free survival(DFS) or overall survival (OS) was analyzed. RESULTS: The mutation rate of FLT3-ITD in newly diagnosed patients with APL was 14.1%. WBC count at diagnosis was higer in FLT3-ITD positive group than that in negative group, and the mutation rate of FLT3-ITD was highest in high risk group. Induction death rate in FLT3-ITD positive and negative group were 12.5% and 2.9%, respectively (P=0.031). Complete remission(CR) rate in 2 groups were 83.3% and 97.1%(P=0.004). The 5-year OS rates in 2 groups were 87.5+/-6.8% and 90.6+/-2.6% (P=0.740). The 5 year DFS in 2 groups were 82.8+/-9.1% and 83.6+/-3.4%(P=0.928). CONCLUSION: FLT3 ITD mutation is related with high peripheral white blood cell count in APL, the APL with FLT3-ITD mutation has higher induction death rate and lower CR rate than those in that without FLT3-ITD mutation, but FLT3-ITD mutation did not affect on long term DFS and OS. PMID- 28024466 TI - [Role of NF-kappaB inhibitor in Acute Myeloid Leukemia]. AB - OBJECTIVE: To investigate the role of NF-kappaB inhibitor in occurence and development of AML. METHODS: AML and normal bone marrow samples were collected from 8 AML patients and 8 normal persons. The expression of NF-kappaB signaling pathway genes was detected by NF-kappaB PCR array. Then, AML mouse model was constructed to test the role of NF-kappaB inhibitor in AML. RESULTS: The NF kappaB signal pathway was activated in AML patients. The up-regulated genes, EDARADD, TNFSF14, could activate the NF-kappaB signal pathway, IL6 could regulate the inflammatory signal. The down-regulated genes, TNFRSF 10B, TNFRSF1A, could lead to cell apoptosis. the AML mouse model was constructed successfully. Then administration of NF-kappaB inhibitor reduced the inhibition of leukemia niche to the normal hematopoietic stem cells (HSCs), promoted the HSC to enter into cell cycle. CONCLUSION: The NF-kappaB signal pathway is activated in AML cells. AML mouse model is constructed successfully. NF-kappaB inhibitor has a potential to treat AML and promotes the HSC to enrter into cell cycle. PMID- 28024467 TI - [Features of Immunophenotypes and Characteristics of Molecular Biology and Cellular Genetics of AML Patients with CD4 and CD7 Expression]. AB - OBJECTIVE: To explore the features of immunophenotypes and the characteristics of molecular biology and cellular genetics of AML patients with CD7 and CD4 expression. METHODS: The immunophenotypical markers of AML cells were detected by multiple parameter flow cytometry; the expression of WT1, MDK, ETO, PML-RaRa and BCR-ABL were detected by RT-PCR; and cellular features were analyzed by R-band in 304 patients. The patients were divided into three groups according to their immunophenotypes: AML with CD7 expression (CD7 group), AML with CD4 expression(CD4 group) and AML without CD7 and CD4 expression (common AML group). RESULTS: The expression rate and level of HLA-DR in CD7 group were higher than those in the common AML group, and the expression rate of CD33 and CD34 was higher than that in the other two groups. The expression rate and level of CD15, CD64 in the CD4 group were higher than those in the other 2 groups, and the expression rate and level of CD33 were higher than those in the common AML group. WT1 expression in the CD7 group was lower than that in the common AML group. PML RaRa was not detected in the CD7 group. AML with co-expression of CD4 or CD7 showed more normal karyotype. (15;17) was not found in AML with CD7 expression. CONCLUSION: AML cells with CD7 expression originate from precursor cells and are blocked in the early phase of hematological development; AML cells with CD4 expression originate from more mature stage of hematological devevelopment and with CD33, CD64 and CD15 high expression; AML cells with CD7 and CD4 expression are characterized by no-specific change of cellular genetics. According to the expression level and intesity of CD4 and CD7, and together with other specific lineage markers, the MRD in AML patients can be quantitatively detected. PMID- 28024468 TI - [Expression and Activity Regulation of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia Cells]. AB - OBJECTIVE: To investigate the expression and activity regulation of indoleamine 2,3-dioxygenase(IDO) in acute myeloid leukemia cells. METHODS: Expression of IDO and TLR9 in HL-60 and K562 cells cocultured with or without IFN-gamma,Talpha1,IFN gamma+Talpha1 and chloroquine were determined by reverse transcription-polymerase chain reaction(RT-PCR). Then, the IDO activity in HL-60 and K562 cells cocultured with or without IFN-gamma,Talpha1,IFN-gamma+ Talpha1 was assayed by coomassie brilliant blue staining and modified colorimetric method. RESULTS: Both IDO and TLR9 mRNA were expressed in HL-60 and K562 cells; IFN-gamma increased the expression and activity of IDO in a concentration-dependent manner; Talpha1 decreased the expression and activity of IDO in a concentration-dependent manner; the up-regulation of IFN-gamma on IDO induced expression and activity had been weakened by Talpha1(P<0.01); Chloroquine had no effect on the expression of IDO. The expression of TLR9 in HL-60 cells and K562 cells cocultured with IFN gamma,Talpha1,IFN-gamma+Talpha1 and chloroquine was not significantly changed. CONCLUSION: IDO can be expressed in acute myeloid leukemia cells and possesses the activity. IDO may play an important role in immune tolerance induced by leukemia cells, and become a new predictor of AML prognosis. Talpha1 decreases the expression and activity of IDO, which can weaken the induction of IFN-gamma on IDO expression and activity, thus Talpha1 as an immune modulator may be a new agent for AML immunotherapy. PMID- 28024469 TI - [Role of Non-classical NF-kappaB Signaling Pathway in B Acute Lymphoblastic Leukemia]. AB - OBJECTIVE: To study the role of non-classical NF-kappaB signaling pathway in B acute lymphoblastic leukemia (B-ALL). METHODS: The bone marrow samples from 48 patients with B-ALL were collected from March 2015 to March 2016. The real-time quantitative RT-PCR was used for determing mRNA expression levels of NF-kappaB family members; the NF-kappaB DNA binding activity in B-ALL cell nucleus was analyzed by ELISA; the apoptosis rate of B-ALL cells alone or co-cultured with bone marrow stromal cells (hBMSC) was determined by flow cytometry. RESULTS: Relative expression level of mRNA for NF-kappaB family members, including the Rel A, Rel B, P50 and P52 in ALL-B group was statistically significantly higher than that in normal control group (P<0.05). The clinical characteristics of B-ALL patients with different NF-kappaB activity were not significantly different (P> 0.05); after B-ALL cells cultured alone or co-cultured, the apoptosis rate of Rel A+ / Rel B- group was statistically significantly higher than that in Rel A+ / Rel B+ group (P<0.05); the apoptosis rate of B-ALL cells cultured alone or co cultured with hBMSC was significantly different. CONCLUSION: Non-classical NF kappaB signal marked by Rel B can be used as a new target for B-ALL treatment. PMID- 28024470 TI - [Establishment of Human Chronic Lymphocytic Leukemia Model in the BALB/c Nude Mice by Using MEC-1 and HG3 Cell Lines]. AB - OBJECTIVE: To explore the the optimal condition for establishing immune deficiency mouse(BALB/c) model with CLL via subcutaneous inoculation of human chronic lymphocytic leukemia (CLL) cells at different inoculative locations and different cell concentrations. METHODS: Firstly, Two CLL cell lines (MEC-1-GFP and HG3-GFP)with the green fluorescent protein (GFP) were established by lentivirus system respectively, and then the MEC-1-GFP cells (5*107/ml) were inoculated into forelimb, hindlimb and abdomen to observe the tumorigenesis. Secondly, the MEC-1-GFP and HG3-GFP cells with same density (5*107/ml) were inoculated into forelimb to compare the time and rate of tumor formation. Thirdly, the MEC-1-GFP cells (1*107/ml) and HG3-GFP cells (5*107/ml) were inoculated into forelimb to compare the time and rate of tumor formation at different inoculative density. After observation for 5 weeks, the peripheral blood was collected and treated with EDTA and erythrocytolysin, then the of GFP positive cells were detected by flow cytomety. Meanwhile, the tumor-bearing mice were killed, and the tumors were isolated and cut into slices for histopathological examination. RESULTS: MEC-1-GFP and HG3-GFP cell lines were successfully established, and after inocutation of MEC-1-GFP cells with 5*107/ml the xenograt tumors were formated in forelimb, hindlimb and abdomen of mice, especially in the forelimb with a higher tumorigenic rate. In addition, the inoculation of same density of MEC-1-GFP and HG3-GFP cells (5*107/ml) also resulted in xenograft in forelimb, and the tumorigenic rate reached to 80% after 5 weeks. Moreover, the inocutation of MEC-1-GFP and HG3-GFP cells with 1*107 and 5*107/ml respectively also effectively resulted to xenograft tumor in forelimb. The flow cytometry showed that there was no MEC-1-GFP and HG3-GFP cells in peripheral blood, while histopathological examination demonstrated CLL cell metastasis towards peritoneal cavity. CONCLUSION: The BALB/c nude mouse model is successfully established by subcutaneous injection of MEC-1-GFP and HG3-GFP cells. This model is a useful tool to explore the pathogenic mechanism. PMID- 28024471 TI - [Combination of Homoharringtonine with Arsenic Trioxide Induces Apoptosis of Human Acute Myeloid Leukemia Cell Line U937]. AB - OBJECTIVE: To investigate the effects and mechanisms of the combination of homoharringtonine (HHT) with arsenic trioxide(As2O3) on human myeloid cell line U937 in vitro. METHODS: MTT method was used to determine the antiproliferating effect of different concentrations of HHT, As2O3 and their combination on U937 cells; the flow cytometry with Annexin-V-FITC/PI double staining was used to determine the apoptosis-induced effect of HHT and As2O3 alone or their combination; Western blot method was used to detect the protein expression of P AktSer473,P-AktThr308,BCL-XL, BID,MCL-1,P-MCL-1 and so on. RESULTS: HHT and As2O3 could significantly inhibit proliferation of U937 cells and induce their apoptosis. The combination of these 2 drugs could significantly enhance the early apoptosis of U937 cells. After combination of these 2 drugs was used, the protein expressions of P-AktSer473,P-AktThr308,MCL-1,P-MCL-1 and BCL-XL were obviously down-regulated, but the expression of BID protein did not change. CONCLUSION: The combination treatment of HHT and As2O3 can synergistically inhibit the growth of U937 cells through inhibition of PI3K/Akt signal way and MCL-1 protein. PMID- 28024472 TI - [Effect of BRD4 Inhibitor GSK525762A on Proliferation and Apoptosis of SUP-B15 Cells In Vitro and Its Possible Mechanism]. AB - OBJECTIVE: To investigate the effect of BRD4 inhibitor GSK525762A on the proliferation and apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells and its mechanism. METHODS: SUP-B15 cells were treated with different concentration of GSK525762A, the proliferation inhibition curve was assayed and plotted by CCK-8 method, the cell viability and apoptosis were detected by flow cytometry with Annexin V and 7-AAD staining. The transcripts of anti-apoptotic genes C-MYC, CDK6 and BCL-2 were detected by real time PCR. RESULTS: GSK525762A could inhibit significantly SUP-B15 cell proliteration in dose-and time-dependent manner; GSK525762A treatment could induce apoptosis of SUP-B15 cells. The levels of C-MYC,CDK6 and BCL-2 mRNA transcripts in SUP-B15 cells were reduced in GSK525762A-treated group. CONCLUSION: The GSK525762A can remarkably inhibit proliferation and induce apoptosis of SUP-B15 cells. The down-regulation of apoptosis-related genes C MYC,CDK6 and BCL-2 may be involved in the process of apoptosis. PMID- 28024473 TI - [Effects of Simvastatin on Expression of Multidrug Resistance Gene and Protein of SHI-1 Cells]. AB - OBJECTIVE: To investigate the effects of simvastatin(SIM) and serum free medium(SFM) on the expression of multidrug resistance gene(MDR1) and protein of SHI-1 cells. METHODS: Trypan blue exclusion assay was used to detect the proliferation level and viability of SHI-1 cells after treatment with SIM and culture in SFM; The multi-drug resistant protein p-gp was measured by flow cytometry after culture in SFM for 1 to 3 days and treatment with various concentration of simvastatin. The effect of SFM culture and SIM treatment on the expression of MDR1 trascript was detected by qPCR; ELISA was used to measure the change of cellular cholesterol after culture in SIM and SFM. Chemosensitivity assay was performed after treatment with SIM for SHI-1 cells. RESULTS: Compared with control group, the growth of SHI-1 cells cultured in SFM decreased in a time dependent manner. The growth-inhibitory effect was markedly increased when SHI-1 cells were treated with SIM and SFM. The mRNA level of MDR1 gene decreased after SIM treatment or/and culture in SFM. P-gp protein was downregulated in SHI-1 cells cultured in SFM or/and treated with SIM. The cellular cholesterol level increased when the cells were cultured in SFM. Total cellular cholesterol level decreased in SHI-1 cells treated with SIM and cultured in SFM. Chemosensitivity assays found that pre-treatment with SIM could increase the cytotoxicity of DNR to SHI-1 cells. CONCLUSION: Culture with SIM and SFM can downregulate the expression of MDR1 gene and p-gp protein in SHI-1 cells. SIM also can enhance the chemotherapeutic sensitivity of SHI-1 cells. PMID- 28024474 TI - [hnRNP K Contributes to Adriamycin Resistance in Acute Myeloid Leukemia through Regulating Autophagy]. AB - OBJECTIVE: To explore the role of heterogeneous nuclear ribonucleoprotein(hnRNP) K regulating autophagy in the drug resistance of acute myeloid leukemia, so as to provide a new molecular marker for treatment of leukemia. METHODS: The relationship between the expression level of hnRNP K and the drug resistance of myeloid leukemia was verified by fluorescence quantitative PCR; the expression of autophagy related protein LC3I/ II was detected by Western blot after the hnRNP K was modulated by RNA interference technology; the sensitivity of leukemia cells to doxorubicin was analyzed before and after the expression of hnRNP K were modulatd. RESULTS: The expression of hnRNP K and LC3I/II significantly increased in bone marrow nonremission patients and in drug resistant cell line, however, the expression of LC3I/ II decreased when the expression of hnRNP K were reduced, while the sensitivity of cells to adriamycin could be recovered. CONCLUSION: hnRNP K may be involved in the formation of adriamycin resistance in acute myeloid leukemia by regulating autophagy. PMID- 28024475 TI - [Effect of WT1 Gene High Expression and CD34+ and Auer+ on Prognosis of Acute Myeloid Leukemia]. AB - OBJECTIVE: To explore the clinical significance of WT1 expression level in patient with AML non-M3,understand the biological characteristics of Auer+ and CD34+ AML and its effects on first induced remission rate and prognosis. METHODS: The RQ-PCR was used to detect the WT1 expression levels in 92 patients suffering AML non-M3; the relationship between the CR1 and OS was analysed and the differences of CR1 and OS in AML with Auer+ and Auer-,CD34+ and CD34- were compared. RESULTS: AML with WT1 high expression level at first visit had quite lower CR1 (P<0.05). AML with CD34+ had quite lower CR1 (P<0.05). Compared with Auer- patients, CR1 of Auer+ CML patients was higher (P<0.05), the OS of AML patients with WT1 high expression level was lower than that of the AML patients with low expression level of WT1, and with significant differences (P<0.05), the OS of AML patients with CD34+ was lower than that of AML patients with CD34-, and with significant differences (P<0.05). There was no obvious difference in OS between the AML patients with Auer+ and Auer-. CONCLUSION: High expression level of WT1 and CD34+ in AML patients suggests the poor prognosis. The Auer positive only relats with CR1, and does not relate with OS. PMID- 28024476 TI - [Clinical Characteristics and Prognosis of 21 Cases of Acute Lymphoblastic Leukemia with Central Nervous System Leukemia]. AB - OBJECTIVE: To investigate the clinical characteristics, therapeutic efficacy survival and prognosis of patients with adult acute lymphoblastic leukemia (ALL) accompanied by central nervous system leukemia (CNSL). METHODS: The clinical and cerebrospinal fluid (CSF) features, diagnosis and treatment, therapeutic efficacy and survival rate of 21 cases of acute lymphoblastic leukemia (ALL) with central nervous system involvement (CNSL) were analyzed retrospectively. RESULTS: Out of 21 cases, 10 cases were B cell acute lymphoblastic leukemia(B-ALL), 6 cases were T cells acute lymphoblastic(T-ALL), 4 cases were determined as no clear typing, 1 case was Burkitt lymphoma/leukemia, 7 patients had CNSL at the time of diagnosis, and 14 patients were showed CNS relapse. Clinical manifestations included headache, facial paralysis, limb weakness and blurred vision, etc. Their median follow-up time was 19(6-40) months,from them 10 cases died, 7 cases survived, 4 cases were lost to follow up. Patients had CNSL at the time of diagnosis, their peripheral blood LDH>=600 U/L or not achieving complete remission (CR) after 1 course of treatment with poor prognosis, and the difference is significant (P< 0.05). Radiotherapy and allogeneic stem cell transplantation (allo-HSCT) could improve the patient's survival. Multivariate analysis showed that the LDH and allo-HSCT was significantly correlated with survival time (P=0.048, P=0.013). CONCLUSION: There are no specific clinical manifestations, CSF features and imaging manifestations of ALL accompanied by CNSL, and the diagnosis of CSF is needed to find the leukemia cells in CSF. The factors for poor prognosis include LDH>=600 U/L, no CR of patients after 1 course of treatment, existence of CNSL at the diagnosis. ALL patients with CNSL have a poor prognosis. Intrathecal injection combined with systemic chemotherapy, radiation therapy and allo-HSCT after CR is the feasible and effective treatment regimen. PMID- 28024477 TI - [A Retrospective Study of Ph Negative Adolescent and Young Adults with Acute B Lymphoblastic Leukemia in Two Centers]. AB - OBJECTIVE: To analyze the therapeutic efficacy of different consolidation therapies after induction remission on Ph negative adolescent and young adults with acute B lymphoblastic leukemia, and to explore the effect of different risk factors on prognosis. METHODS: The treatment and efficacy of 80 Ph negative B-ALL in patients of 16-39 years old in the Hematology Department of 301(65 cases) and 309(15 cases) hospital from 1999 to 2016 are retrospectively analyzed. The patients received combined induction chemotherapy of 4 or 5 chemotherapeutic drugs (VDCLP/ VDLP/ DOLP/ IOLP). After remission patients received consolidation protocols of 3-5 cycls, and then received allo-HSCT or haploidentical HSCT. The median follow-up time was 29 (6-153) months. RESULTS: HSCT was carried out after CR1. The 5-year OS and EFS of allo-HSCT group(n=29) was (73+/-16)% and (67+/ 17)%, respectively, while those of haploidentical-HSCT group(n=20) were (53+/ 22)% and (53+/-22)%, respectively, and those of pediatric-inspired protocols(n=31) was (63+/-17)% and (50+/-18)%, respectively. The difference between OS and EFS in 3 group was not statistically significant(P>0.05). The re remission rate of recurrent patients was (50+/-23)%. On the one side, the cumulative incidence of TRM of pediatric-inspired protocol was better than that of HSCT (P<0.05). On the other side, the cummulative incidence of relapse (CIR) of pediatric-inspired protocol was poorer than that of HSCT, yet without significant difference (P>0.05). The median remission time of CR2 in patients was 14(2-36) months. Univariate and multivariate analysis were performed in 65 patients, and showed an abnormal result of CD13 or CD33 positive, CD22 negative, indicating a poor prognosis(P<0.05). CONCLUSION: In the adolescent and young adult patients with Ph- B-ALL treated by pediatric-inspired protocols, the survival time is similar with that in allo-HSCT group. However, more prospective clinical studies of random control test(RCT) should be carried out. PMID- 28024478 TI - [Comparison of Ex Vivo Expanded and Highly Purified NK Cell-Mediated Cytotoxicity Detected by 3 Different Staining Methods of Flow Cytometry]. AB - OBJECTIVE: To compare the cytotoxicity of ex vivo expanded NK cells detected by flow cytometry with 3 different staining methods. METHODS: NK cells were collected from peripheral blood on the 17th day after culture. The cultured cells were divided into 3 groups: group A , B, and C. The cells in group A were stained with CFSE/Annectin-V/7-AAD; the cells in group B were stained with Annectin-V/PI, and the cells in group C cells were stained with CFSE/PI. The E:T ratios in 3 groups were 10:1, 20:1 and 40:1, respectively, the K562 cells were incubated with NK cells for 4 hrs. RESULTS: The purity of NK cells(CD3-CD56+) reached to (16.34+/-10.51)% on day 0 and to (83.63+/-10.63)% on the day 17 after incubation(P<0.05); the cytotoxicity of group A was significantly higher than thay of group B at different E:T ratio (P<0.05). The cytotoxicities in A, B, C groups at E:T ratio=10:1 were (36.56+/-3.69)%, (10.85+/-2.09)% and (22.35+/ 2.71)% respectively; the cytotoxicities in A, B, C groups at E:T ratio=9:1 were (47.83+/-5.52)%, (39.07+/-5.55)% and (29.61+/-4.81)%; the cytotoxicities in A, B, C groups at E:T ratio=40:1 were (67.7+/-4.77)%, (51.51+/-4.43)% and (44.12+/ 5.62)% respectively. Meanwhile, the cytotoxicity in group A was significantly higher than that in group C at different E:T ratio (P<0.05), the percentage of cytotoxicity was (36.56+/-3.69)% vs (10.85+/-2.09)%, (47.83+/-5.52)% vs (29.61+/ 4.81)%, (67.7+/-4.77)% vs (44.12+/-5.62)%, respectively. CONCLUSION: CFSE/Annectin-V/7-AAD is able to clearly show human NK cell cytotoxicity against human tumors. Moreover, this staining technique also allows to distinguish different stages of cytotoxic killing as early and late apoptotic phase. PMID- 28024479 TI - [Construction of Eukaryotic Expression Vector of siRNA Specific for BCR/ABL Fusion Gene and Its Effects on K562 Cells]. AB - OBJECTIVE: To construct eukaryotic expression vector of siRNA specific for BCR/ABL and to investigate the effect of recombinant plasmid on BCR/ABL and P210 protein expression in K562 cells. METHODS: siRNA(small interfering RNA)was designed according to the Tuschl's principle of Ai-based medicine, and was converted into cDNA coding expression of shRNA(small hairpin RNAs)of siRNA for BCR/ABL fusion gene. The cDNA was synthesized and inserted into plasmid pTER. The pTER117 and pTER363 of recombinant plasmid being eukaryotic expression vector was controlled by the H1 promoter of RNA polymerase III, and identified by the restriction map and the sequence analysis. The recombinant plasmid did not only have the screening resisting antibiotics, its expression but also are induced by tetracycline (tet). After steadily transfection into K562 cells by Lipofectamine, their positive mono-cell clones being resistant to Zeocin were isolated. TaqMan real-time quantitative RT-PCR (RQ-PCR) and Western blot respectively detected expression of BCR/ABL mRNA and P210 protein. Trypaum blue dying was used to analyze the proliferation of K562 cells. Cell apoptosis was observed by flow cytometer. RESULTS: the recombinant plasmid was steadily transfected into K562 cells by Lipofectamine 2000, Their positive mono-cell clones being resistant to Zeocin were isolated. The proliferation of K562 cells were remarkably inhibited by the recombinant plasmid induced gene expression by tetracycline. Tetracycline induced its expression for 48 h and 72 h. pTER117, pTER363 decreased the mRNA level of BCR/ABL 90%, 82% and 91.5%, 84%, respectively, P210 protein were almost measured in K562 cells. FCM analysis showed that the recombinant plasmid induced apoptosis in K562 cells, the apoptosis rate were respectively 34.4%, 58.1% in K562 cells treated by pTER117 for 48 h and 72 h, apoptosis rate were 31.8%, 54.6% by pTER363, but the control groups did not show these effects on K562 cells. CONCLUSION: The siRNA eukaryotic expression vector against BCR/ABL mRNA has been successfully conctructed,and effectively inhibits the expression of BCR/ABL in K562 cells, inhibite cell growth and induce cell apoptosis. PMID- 28024480 TI - [Clinical Analysis of Priming Regimen for Treatment of Acute Myeloid Leukemia (Non-APL) Patients Aged over 70 Years]. AB - OBJECTIVE: To explore the therapeutic efficacy for patients aged over 70 years with acute myeloid leukemia(non-APL). METHODS: Clinical data of 19 acute myeloid leukemia patients aged over 70 years admitted in our hospital from March 2006 to April 2016 years were analyzed retrospectively. Among them 15 patients received priming regimen and 4 patients received best supportive treatment. The overall survival time between patients with priming regimen and patients with best supportine treatment was compared by Kaplan-Meier analysis. The prognostic factors were evaluated by using multivariate analysis. Out of the 19 patients, 9 were males and 10 were females, with median age of 75 years (70-84). RESULTS: After 2 cycles of induction chemotherapy, the complete response rate was (7/15)46.6% and overall response rate was (11/15) 73%. Significant longer median survival time was observed in priming regimen group, compared with that in best supportive treatment group (11 months vs 2 months)(chi2=17.077, P<0.001). The patients were well tolerant to side-effect of chemotherapy. Multivariate analysis showed that only receiving induction chemotherapy or not was the independent prognostic factor of the survival time(P<0.05), while the sex, age, ECOG index, CD34, HLA-DR, WBC count and ratio of blast cells in bone marrow were factor affecting the prognosis. CONCLUSION: The priming regimen may be practicable and effective for the treatment of patients with acute myeloid leukemia aged over 70 years (non-APL) and prolong the survival time of these patients. PMID- 28024481 TI - [Effect of Human Umbilical Cord-derived Mesenchymal Stem Cells on Proliferation and Differentiation of Leukemia Cells]. AB - OBJECTIVE: To investigate the effect of human umbilical cord-derived mesenchymal stem cells(HUC-MSC) on the proliferation and differentiation of NB4 treated with all-trans retinoid acid (ATRA) and its underlining mechanisms . METHODS: Human umbilical cord mesenchymal stem cells were isolated from umbilical cord of newborns. Co-culture system was established by HUC-MSC and NB4 in vitro. The experiment was divided into 4 groups: NB4 group (NB4 cells alone) , NM group (NB4 cells co-cultured with HUC-MSC) , NA group (NB4 cells treated with ATRA) , NMA group (NB4 cells co-cultured with HUC-MSC and treated with ATRA) . NB4 cells were counted by a microscopy, NB4 proliferation was monitored by CCK-8 assay, NB4 differentiation was assessed by Wright ' s staining and nitroblue tetrazolium reduction test. IL-6 levels in the culture supernatant of different groups were tested by ELISA kit. Quantitative PCR was used to detect the transcription level of CDKN1A, CCND1 and Survivin. RESULTS: NB4 and HUC-MSC in the co-culturing systems were in good condition with a slight repression of NB4 proliferation by HUC-MSC. HUC-MSC could collaborate with ATRA to induce significant NB4 differentiation. Consistent with this finding, IL-6 expression levels of co cultured groups were remarkably higher than that in any other groups or the group of HUC-MSC alone. The quantitative PCR analysis showed that the levels of CDKN1A and CCND1 mRNA expression were increased or decreased respectively in the co cultured groups. CONCLUSION: HUC-MSC co-culture can reduce proliferation but promote the differentiation of NB4 cells, suggesting that this effect may be closely related with the secretion of IL-6 which can affect the expression of some factors in vitro. PMID- 28024482 TI - [Effects of Homoharringtonine Combined with Imatinib on K562 Cell Apoptosis and BCL6 expression]. AB - OBJECTIVE: To explore the effects of homoharringtonine (HHT) alone or combined with imatinib (IM) on K562 cell proliferation and apoptosis, as well as the mRNA and protein expression of BCL6. METHODS: The CCK-8 was used to detect the inhibitory effect of drugs on cell growth, the flow cytometry was used to detect the cell apoptosis. The expression of BCL6 protein was assayed by Western blot, and BCL6 mRNA expression was detected by RT-PCR. RESULTS: HHT alone displayed a proliferation inhibition effect with dose- dependent manner, and induced apotosis; after combination of HHT and IM drugs, both the inhibitory rate and the apoptosis rate were significantly increased compared with the drug alone(P<0.05). Western blot showed that the expression of BCL6 protein was down-regulated after being treated with HHT, however, the BCL6 protein was up-regulated after being treated with IM . The effect of drug combination showed that BCL6 protein significantly down-regulated(P<0.05 ). The expression of BCL6 mRNA was decreased both in the treatment of HHT or IM alone when compared with control. And the effect of drug combination showed that BCL6 mRNA expression was more significantly down-regulated(P<0.05 ). CONCLUSION: HHT can inhibit the K562 cell proliferation and induce apoptosis of K562 cells. Combination of IM with HHT shows a significant synergistic effect, the mechanism may be associated with down regulation of BCL6. PMID- 28024483 TI - [Analysis of Therapy and Efficacy after Remission of Acute Myeloid Leukemia]. AB - OBJECTIVE: To investigate the therapy and efficacy after remission of patients with acute myeloid leukemia (AML). METHODS: The clinical data of 110 patients diagnosed as AML treated from 2008 to 2013 were analyzed retrospectively. According to different consolidation therapy regimens, the patients were divided into 4 groups:1 ID-Ara-C group, 2 ID-Ara-C group, 3-4 ID-Ara-C group, allogeneic hematopoietic stem cell transplantation (allo-HSCT) group. The disease-free survival (DFS) and overall survival (OS) were analyzed retrospectovely. RESULTS: 110 patients were completely remittend by 1-2 couses. The median follow-up time was 26.8 months, 35 cases relapsed and 58 cases died, the median DFS and OS were 20.5 and 26.8 months. The 3-year DFS of 1, 2, 3-4 ID-Ara-C and allo-HSCT groups were 0%, 36.1%, 37.5% and 67.9% respectively. The 5-year DFS of 1, 2, 3-4 ID-Ara C and allo-HSCT groups were 0%, 30.1%, 37.5% and 63.0%. The 3-year OS rates of 1, 2 ID-Ara-C groups, 3-4 ID-Ara-C group and allo-HSCT group were 24.0%, 36.0%, 58.3% and 67.8%. The 5-year OS of 1, 2 ID-Ara-C grous, 3-4 ID-Ara-C and allo-HSCT group were 24.0%, 36.0%, 58.3% and 67.8% respectively. The 5-year OS rates of 1 ID-Ara-C group, 2 ID-Ara-C group, 3-4 ID-Ara-C group were 0%,30.0%,35.0% and 62.9% respectively. The multifactor analysis indicated that the courses of ID-Ara C and allo-HSCT were independent risk factors for DFS and OS. CONCLUSION: >=2 ID Ara-C regimen may be used as one regimen of consolidation therapy for patients with AML after remission. PMID- 28024484 TI - [Effects of Arsenic Trioxide on K562 Cell Proliferation and Its Mechanisms]. AB - OBJECTIVE: To investigate the effects of arsenic trioxide (As2O3) on K562 cell proliferation by regulating cell cycle protein D1 and cyclin-dependent kinase inhibitor p27kip1. METHODS: MTT was used to detect the effect of As2O3 on K562 cell proliferation, so as to screen out the appropriate drug concentration. Furthermore, the K562 cell apoptosis was observed by microscopy. The expression of CyclinD1 and p27kip1 in K562 cells treated with As2O3 was analyzed by reverse transcription-polymerase chain reaction(RT-PCR), immunohistochemistry and Western blot. RESULTS: As2O3 could inhibit the proliferation of K562 cells in a dose- and time- dependent manner (r= 0.967). And the apoptosis cell number in As2O3 group was significantly higher than that in the control group(P<0.05). As2O3 could markedly inhibit the expression of CyclinD1 in K562 cells(P<0.05), but the expression of P27kip1 was not significantly changed after As2O3 treatment. CONCLUSIONS: As2O3 can induce K562 cell apoptosis and inhibit K562 cell proliferation by regulating the expression of CyclinD1. PMID- 28024485 TI - [Therapeutic Efficacy of VICP+L-ASP/TKI on Adult Patients with B-ALL]. AB - OBJECTIVE: To evaluate the therapeutic efficacy of VICP+L-ASP/TKI on adult patients with B-ALL and to explore the influence factors. METHODS: Forty-one adult B-ALL patients treated with VICP+L-ASP/TKI from August 2008 to June 2014 were following-up. The complete remission(CR) rate, toxicity, overall survival(OS) and event free survival(EFS) after induction treatment were analyzed, the therapeutic outcome of patients between different risk stratification subgroups was compared, the influence of standardized consolidatory and maintaining treatment as well as allogeneic hematopoietic stem cell transplantation(allo-HSCT) on survival time was analyzed. RESULTS: The early death not occurred in 41 patients with B-ALL including 37 cases with CR; the CR rate of 1 course treatment was 90.2%. The follow-up time lasted to March 17, 2015, the median follow-up time was 25(9-79) months; the 1 year OS rate was 75.3%, the EFS rate was 58.3%. Analysis of risk factors showed that the initial WBC count over 30*109/L, LDH over 250 U/L and minimal residual disease(MRD) over 10-4 after treatment were poor prognostic factors. After remission, the standardized consolidatory treatment or allo-HSCT according to the "2012 China adult ALL diagnosis and treatment expert consensus" could improve long-term survival, 3 years OS rate was 73.8% and 61.5% respectively, 3 years EFS were 63.5% and 65.7% respectively. The main toxic and side effects were hematologic reactions, the hematologic adverse reaction of IV grade was observed in 97.6%(40/41) during induction treatment. CONCLUSION: Induction chemotherapy based on VICP+L-ASP/TKI and standardized consolidatory after remission according to the "2012 China adult acute lymphoblastic leukemia diagnosis and treatment expert consensus" can improve the therapeutic efficacy. The allo-HSCT should be actively performed for B-ALL paients with high risk(elevated initial WBC count and LDH level); at some time, the regularly monitoring MRD and adjusting therapeutic protocol according to monitoring result can promote the prognosis of adult B-ALL patients. PMID- 28024486 TI - [Analysis of Clinical Feature and Treatment Outcome of Patients with Renal Diffuse Large B Cell Lymphoma]. AB - OBJECTIVE: To analyse the clinical feature and treatment outcome of patients with renal diffuse large B cell lymphoma(DLBCL). METHODS: The clinical data of 24 patients with renal DLBCL were collected and retrospectively analysed, the clinical features, laboratorial data, survival and prognostic factors were analysed. RESULTS: In our center, the incidence of renal DLBCL was 5.3% in all DLBCL patients, 3 cases were primary renal DLBCL and 21 cases were secondary renal DLBCL, the median age was 52.5 years, 21(87.5%) patients belonged to III and IV stage, 20 (83.3%) patients had high-intermediate and high risk by IPI, 50% patients had more than 3 extranodal organs involvement, and the higher proliferation index(KI-67>=80%) was present in 75.0% of patients. The overall response rate(ORR) for the whole group was 66.7%, the complete response(CR) rate was 37.5%, the 3y,5-year progression-free survival(PFS) rate was 49.5% and 49.5%, the 3y,5-year overall survival rate was 66.0% and 49.5% respectively. Rituximab could improve the survival of patients, the 3-year PFS rate was 71.4% vs 30.0%. High-dose chemotherapy was superior to CHOP-like regimens, 3-year PFS was 75% vs 41.3%, and hematopoietic stem cell transplantation improved prognosis of patients. Clinical stage, IPI score, the level of WBC, LDH and albumin, the existence of renal failure and coagulopathy, the numbers of extranodal organs involvement, initial treatment outcome and the level of KI-67 were prognosis related factors for overall survival. CONCLUSION: Renal DLBCL often occures in eldly men with lower incidence and poor prognosis, its clinical and pathological features are highly aggressive. Rituximab and high-dose chemotherapy can improve the survival of patients, and HSCT can further improve the survival and reduce the recurrence of patients. PMID- 28024487 TI - [Clinical Efficacy of Autologous Hematopoietic Stem Cell Transplantation Using Tumor-ablative Conditioning Regimen for Patients with Refractory/Relapsed Non Hodgkin's Lymphoma]. AB - OBJECTIVE: To investigate the safety and effectiveness of autologous hematopoietic stem cell transplantation (auto-HSCT) using tumor-ablative conditioning regiment for patients with refractory/relapsed non-Hodgkin's lymphoma. METHODS: The clinical data of 16 patients with refractory/relapsed non Hodgkin's lymphoma received above-mentioned therapeutic regimen from January 2013 to July 2015 was analyzed retrospectively, and conditioning-related toxicity, engraftment, infection, relapse and survival rate were evaluated. RESULTS: No conditioning-related organs' failure and mortality were found. Only 1 patient had not been engrafted, and the engraftment rate was 93.7%. The incidence of serious infection was 31.2%. The median follow-up was 20.5(1-30) months, and 3 patients died, out of them 2 patients died of relapse. Two year overall survival (OS) , disease-free survival (DFS) and relapse rates were 80.2%, 74.5% and 20.6% respectively. CONCLUSION: Auto-HSCT using tumor-ablative conditioning regimen is safe and effective for patients with refractory/relapsed non-Hodgkin's lymphoma, and it possess a certain effect for reducing disease relapse after transplantation. PMID- 28024488 TI - [Clinical Analysis of Adoptive Immunotherapy after Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation in B Lymphocyte Malignant Lymphoma]. AB - OBJECTIVE: To investigate the efficacy of autologous peripheral blood hematopoietic stem cell transplantation(auto-PBHSCT) combined with adoptive immunotherapy for patients with B lymphocyte malignant lymphoma(ML). METHODS: A total of 110 cases of ML treated with adoptive immunotherapy after auto-PBHSCT from January 2000 to December 2009 were enrolled in adoptive immunotherapy group (treated group), while 74 cases of ML treated without adoptive immunotherapy after auto-PBHSCT from January 1995 to December 1999 were used as control group. The efficacy of 2 groups were analyzed and compared, 110 case of ML in treated group included 78 cases of non-Hodgkin's lymphoma(NHL), 32 cases of Hodgkin's lymphoma(HL),74 cases of ML in control group included 52 NHL and 22 HL. All of the patients were treated sequentially with chemotherapy regimens for 6 courses. After that, all the patients received auto-PBHSCT. After hematopoietic reconstruction, the patients in treated group were given 6 courses of adoptive immunotherapy(rhIL-2 100 WU/day for 10 days monthly for each course), while the patients in control group were not given immunotherapy. All the patients were followed-up for more than 5 years. RESULTS: There was one patient in each group, who died of liver failure and cerebral hemorrhage respectively within 3 and 2 months, and all the other patients achieved hematopoietic reconstruction. Following-up for 1, 3, 5 years, the disease-free survival (DFS) rate in treated group was 97.3%,93.6%,87.3% while 91.9%, 73.0%, 64.9% in control group. Following up for 3 and 5 years, there was very significant difference in DFS between 2 groups(P<0.01). The 1,3 and 5 year DFS rate of patients in stage I/II and III/IV in the treated group were 100%,100%,91.7% and 96.5%,91.9%,86.0% respectively while DFS of control group was 100%, 93.3%, 86.7% and 89.8%, 67.8%, 59.3%, there was a significant difference in 3 and 5 years DFS of III/IV stage patients between 2 groups (P<0.01). The 1,3 and 5 year DFS rate of HL patients were 100%, 93.8%,84.4% in treated group and 100%,72.7%,59.1% in control group respectively. There was significant difference in 3 and 5 years DFS of HL between 2 groups (P<0.05). The 1,3 and 5 year DFS rate of stage I/II HL patients were 100%,100%,88.9% in treated group and 100%,100%,80.0% in control group. The 1,3 and 5 year DFS of HL patients in stage III/IV was 100%,91.3%,82.6% and 94.1%,64.7%,52.9% respectively. There was significant difference in 3 and 5 years DFS of III/IV stage of HL patients between 2 groups (P<0.05). The 1,3 and 5 year DFS rate of NHL patients is 96.2%, 93.6%,88.5% in treated group and 90.4%,73.1%,65.4% in control group respectively. There was a significant difference in 3 and 5 years DFS of NHL between 2 groups(P<0.01). The 1,3 and 5 year DFS rate of stage I/II NHL patients was 100%, 100%, 93.3.9% in treated group and 100%, 90%, 90.0% in control group, respectively. The 1,3 and 5 year DFS of NHL patients in stage III/IV is 95.2%, 92.1%,87.3% and 88.1%,69.0%, 59.5% respectively. There was significant difference in 3 and 5 years DFS of III/IV stage NHL patients between 2 groups (P<0.05). CONCLUSION: Therapeutic efficacy is satisfactory for the patients of B lymphocyte ML treated with adoptive immunotherapy after auto-PBHSCT, especially benefited the patients of stage III/IV significantly. PMID- 28024489 TI - [Divergence Analysis of Hepatitis Virus Infection between Aggressive and Indolent B Cell Non-Hodgkin's Lymphoma]. AB - OBJECTIVE: To investigate the prevalence rate of hepatitis B virus(HBV)and hepatitis C virus(HCV)between aggressive and indolent B cell non-Hodgkin's lymphoma (B-NHL), and to compare the different infection rate of Hepatifis Virus between the 2 groups. METHODS: Integrated clinical information of 733 newly diagnosed indolent B-NHL patients and 148 aggressive B-NHL patients from January 1994 to January 2014 was retrospectively analyzed. The difference of hepatitis virus infection was compared between the 2 groups. RESULTS: The positive rate of HCV-Ab was 1.8% in 881 newly diagnosed B-NHL patients. The HCV prevalence was 1.9% and 1.35% in the indolent and aggressive B-NHL group respecitvely. Compared with general population, the HCV positive rate was significantly higher in the whole B-NHL group and the indolent group(1.8% vs 0.4%,1.9% vs 1.4%)(P<0.01), while it was not significantly different in the aggressive group (1.35% vs 0.4%)(P=0.068). The positive rate of HCV-Ab was not significantly different between the indolent and the aggressive group (1.9% vs 1.35%)(P=0.639). The HBs Ag positive rate in the whole B-NHL group was 9.0%, which was significantly higher than that in the general population (9.0% vs 7.2%)(P<0.05). The positive rate of HBs-Ag in the indolent and aggressive B-NHL group was 7.9% and 14.2%, respectively. It was significantly higher in the aggressive group than that in the indolent one (14.2% vs 7.2%)(P<0.01). Compared with the general population, the aggressive group had significantly higher prevalence rate of HBV. However, it was not significantly different between the indolent group and the general population (7.9% vs 7.2%)(P>0.05).In the aggressive B-NHL group,the co-expression of HBs-Ag,HBe-Ag and anti-HBc-Ab was 4.4%, which was higher than that in the indolent one (4.7% vs 1.2%)(P<0.01). However, compared with the indolent group, the co-expression of HBs-Ag, anti-HBe-Ab and anti-HBc-Ab was not significantly different in the aggressive group (5.5% vs 6.1%)(P>0.05). CONCLUSION: The HCV is more relevant with indolent B-NHL, the HBV has more relevance with the aggressive patients. PMID- 28024490 TI - [Allogeneic Hematopoietic Stem Cell Transplantation for Treatment of T Cell Lymphoblastic Lymphoma - Clinical observation of 10 Cases]. AB - OBJECTIVE: To analyze the result of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treatment of patients with T cell Lymphoblastic lymphoma(T-LBL). METHODS: The engraftment, graft versus host disease (GVHD), infection, relapse and survival of 10 T-LBL patients received allo-HSCT was observed. The clinical outcome of allo-HSCT for T-LBL patients was analyzed. RESULTS: The median age of patients was 25 years old, 10 (6 males and 4 females) T-LBL patients received allo-HSCT including 3 from HLA-matched unrelated donors, 3 from HLA-matched sibling donors, 2 from HLA haploidentical sibling donors, and 2 from haploidentical related donors. The clinical staging showed that 1 case was in stage III and 8 cases were in stage IV. The bone marrow was involved in 7 patients. All the 10 patients achieved engraftment, and the median times of neutrophil and platelet engraftment were 11 (10-19) days and 12(7-19) days, respectively. Acute GVHD occurred in 5 patients and chronic GVHD occured in 1 patient. After the median follow-up of 26 months (11-51 months), 3 patients died, out of them 1 died from relapse after transplantation, 1 from infection and 1 from GVHD. The relapse, overall survival, and disease-free survival rate were 10%, 70%, 70%,respectively. And the estimated overall survival rate was 66.7%. CONCLUSION: T-LBL has high rate of relapse and poor prognosis. The allo-HSCT can improve the survival of patients with T-LBL, and is an effective method for treatment of T-LBL patients. PMID- 28024492 TI - [Analysis of Indicators Related with Cell Proliferation and Apoptosis in the Patients with B Cell Non-Hodgkin's Lymphoma]. AB - OBJECTIVE: To analyze the indicators related with cell proliferation and apoptosis in patients with B cell non-Hodgkin's lymphoma(B-NHL). METHODS: Seventy two cases of B-NHL and 50 cases of reactive hyperplasia of lymph nodes were entrolled in the experimental group and control group respectively. The expression levels of proliferating cell nuclear antigen(PCNA), X-linked inhibitor of apoptosis(XIAP) and B cell lymphoma leukemia-2(BCL-2) in paraffin-embedded tissue samples of 2 groups were detected by immuno-histochemistry staining, and their ralationship with pathologic factors was analyzed. RESULTS: The positive cell rates of PCNA, XIAP and BCL-2 in experiment group were significantly higher than those in control group (P<0.05); the positive cell rate of PCNA in B-NHL patients at III-IV stage was higher than that in B-NHL patients at I-II stage(P<0.05), however, the positive cell rates of XIAP and BCL-2 in B-NHL patients with different pathologic factors were not significantly different(P>0.05). The progression-free survival(PES) time in PCNA low positive expression group was longer than that in PCNA high positive expression group(P<0.05), but the PFS time between B-NHL patients with XIAP positive and negative expression was not significantly different(P>0.05); the PFS time also was not significantly different between B-NHL patients with BCL-2 positive and negative expression(P>0.05). CONCLUSION: All the PCNA, XIAP and BCL-2 participate in the pathngenesis of B-NHL, among them the positive level of PCNA obviously influences the clinical staging of B-NHL. PMID- 28024491 TI - [Children's NK/T Cell Lymphoma-Associated Hemophagocytic Syndrome: Clinical Analysis of 6 Cases]. AB - OBJECTIVE: To study the clinical features, treatment and prognosis of patients with NK/T cell lymphoma-associated hemophagocytic syndrome(NK/T-LAHPS). METHODS: Retrospective analysis was used to explore the clinical data of 6 children with NK/T-LAHPS who were admitted in Department of Pediatric Hematology of Fujian Medical University Union Hospital from July 2012 to June 2016. The 6 patients included 4 boys and 2 girls, with a median age of 4 years(range 1.75 to 11). In 4 patients the hemophagocytic syndrome(HPS) occurred as the main primary manifestations of underlying lymphoma, in the other 2 patients HPS occurred during lymphoma progression. The clinical manifestations included persistent fever(6/6), hepatomegaly(6/6), splenomegaly(6/6) and pancytopenia(6/6). Laboratory data indicated that the level of ferritin(2179-15000 ng/ml) , LDH(608 3899 IU/L) and EBV-DNA(>105 copies/ml ) was elevated obviously. The other common clinical features of NK/T-LAHPS were hypoproteinemia(6/6), hepatic dysfunction(5/6), hypofibrinogenimia(5/6), hypertriglyceridemia(3) and hemophagocytosis in bone marrow(5/6). RESULTS: After being treated according to the HLH-2004 protocol combined with supported therapy for 1 or 2 weeks, all the patients achieved a clinical response, and the laboratory indicators of HPS were improved. The combined chemotherapy of SMILE was given to 4 patients timely, among them 2 patients achieved complete remission(CR) and long term survival, 1 patient achieved partial remission(PR) and died of relapse after drug withdrawal and 1 patient died of aggravated lymphoma. The other 2 patients did not receive chemotherapy in time, HPS relapsed quickly, because of the progression of lymphoma, and all died of severe hepatic dysfunction and coagulopathy. CONCLUSION: The NK/T-LAHPS is an invariably fatal disease with poor prognosis, and typically occurrs at the advanced stage or the terminal phase of the disease. HLH-2004- based protocol in combination with comprehensive therapy is hopeful for the patients with NK/T-LAHPS, which may delay the disease progression and provide opportunities for the treatment of primary disease. Once the laboratory indicators of HPS are improved, it is important to treat lymphoma timely with the combined chemotherapy of SMILE, which is significant for improving the prognosis. PMID- 28024493 TI - [Clinicopathological Features of Primary Central Nervous System Lymphoma and Their Influence on Prognosis of Desease]. AB - OBJECTIVE: To study the clinical features of of patients with primary central nervous system lymphoma(PCNSL) and their influence on prognosis. METHODS: Forty two cases of PCNSL hospitallized in our hospital from January 2012 to December 2015 were selected, and the laboratory analysis, imaging examination, bone marrow analysis and pathological examination all were performed, 26 cases were treated by lumbar puncture combined with intrathecal injection of drugs (Ara C, dexamethason and methotrexate), 8 cases were treated by methotrexate combined with rituximab, 8 cases voluntanly abandon treatment after being diagnosed as PCNSL. RESULTS: Headache accrued in 12 cases, diplopia in 2 cases, dizziness in 6 cases, limb weakness in 10 cases, amnesia in 2 cases, inhibited speech in 4 cases.Out of 42 patients 4 cases of peripheral T cell lymphoma, 38 cases of B cell lymphoma; 30 cases of multiple lesions, 12 cases of solitary lesions, 8 cases of corpus callosum, 8 cases of thalamus, 8 cases of frontal lobe, parietal lobe, temporal lobe, thalamus and other lesions, 2 cases of hydrocephalus, 2 cases of cerebral hemorrhage; and the patients HIV were negative. 8 cases erythrocyte sedimentation rate were faster, IgG, IgE and IgM levels increased to varying degrees in 42 cases, and the blood routine, liver function and blood coagulation examinations showed normal; There was no significant difference in the influence of the lumbar injection, methotrexate dose, radiation therapy, and hematopoietic stem cell transplantation on survival time(P>0.05); but there was significant difference in the influence of rituximab and number of lesions on survival time (P<0.05); there were significant differences in the effects of age and protein content in cerebrospinal fluid on therapeutic effecacy(P<0.05). CONCLUSION: There is no significant difference in the imaging examination and clinical manifestation between PCNSL and other intracranial tumors. The lumbar puncture is an effective way to identify, the age, cerebrospinal fluid protein and the number of lesions are the adverse factors influencing the prognosis. PMID- 28024494 TI - [PET-CT Manifestation and Clinical Analysis of Waldenstrom Macroglobulinemia]. AB - OBJECTIVE: To investigate the PET-CT manifestation and clinical features of patients with Waldenstrom macroglobulinemia(WM) . METHODS: The clinical features, laboratorial examination results and PET-CT manifestation of 12 patients with WM were analyzed retrospectively. RESULTS: The average age of 12 patients with WM was 63.5 years old, the most common incipient symptoms were fatigue and hyperviscosity syndrome. The median SUVmax of bone marrow was 4.9 (range of 2.1 to 21.9), with diffusely increased 18F-FDG uptake in all the patients. In 6 patients, the median SUVmax of splenomegaly and lymphadenectasis was 3.2 (range of 2.3 to 5.2) and 5.2 (range of 3.6 to 11.2), respectively. The SUVmax of bone marrow, splenomegaly and lymphadenectasis did not related with white blood cell count, hemoglobin level, blood platelet count, beta2- microglobulin level and serum monoclonal IgM of such patients, respectively (both P>0.5). In univariate analysis, serum monoclonal IgM and the SUVmax of lymphadenectasis were found to be the prognostic factors (both P<0.5). CONCLUSION: The 18F-FDG PET-CT feature of Waldenstrom macroglobulinemia has some characteristics which are helpful for setting up the clinical therapeutic schedule. PMID- 28024495 TI - [Mechanism of Regulating BAFF Signaling Pathway by Act1 in B Cell Lymphoma]. AB - OBJECTIVE: To explore the mechanism of regulating B cell-activating factor (BAFF) signalling pathway by NF-kappaB activator 1 (Act1) in B cell lymphoma so as to provide a new thinking for treatment of B cell lymphoma. METHODS: The human B cell lymphoma cell lines including Raji, Daudi and BALL-1 were cultured, when the cells were in logarithmic phase, the RNA was extracted, and the Act1 was amplified by RT-PCR; and pTT5-Act1 expression plasmid was constructed and was transfected into cells; the Act1 was silenced by using Act1 mRNA; the NF-kappaB signaling pathway protein was detected by Western blot. RESULTS: After silence or overexpression of Act1, the proliferation levels of Raji, Daudi and BALL-1 cells were up- or down-regulated, respectively. Overexpression and silence of Act1 could down-or up-regulate BAFF-R expression level, furthermore could inhibit or activate of NF-kappaB signalling pahway, respectively. CONCLUSION: Among 3 above mentioned B cell lymphoma cell lines, Act1 plays negative regulating role, indicating that the Act1 may be a promising therapeutic target for treating B cell lymphoma. PMID- 28024496 TI - [Construction of Lentiviral Vector Over-Expressing MEG3 and Its Effect on XG-7 Cell Apoptosis]. AB - OBJECTIVE: To construct a recombinant lentiviral expression vectors carrying MEG3 and to evaluate its effects on XG-7 cell apoptosis. METHODS: A full-length genomic fragment of human MEG3 was cloned from the pcDNA3.0-MEG3 packaging plasmid and was amplified by PCR. New restriction sites were introduced to be blunted with T4 DNA Ligase. The sequence of the amplified segments was sub-cloned into lentivirus expression vector pCDH-EF1-MCS-T2A-copGFP.The recombined lentiviral expression vector was transfected into 293T cells. FACS was used to detect the effect of MEG3 on XG-7 cell apoptosis after being infected by optimized MOI. RESULTS: The recombined lentiviral expression vector pCDH-EF1-MEG3 copGFP was constructed successfully. The results showed that pCDH-EF1-MEG3-copGFP could increase the mRNA expression of MEG3 dramatically, its transfection efficiency was more than 90%. The apoptosis rate in XG-7 cells (26.8+/-2.8%) was very significantly higher than that of the control group (P<0.01). CONCLUSION: The recombined lentiviral LncRNA expression vector targeting MEG3, pCDH-EF1-MEG3 copGFP, has been successfully constructed, the pCDH-EF1-MEG3-copGFP can induce the cell apoptosis in human myeloma cell lines. This study set up a basis to further explore the relationship between human myeloma cells and LncRNA-MEG3 gene. PMID- 28024497 TI - [Effect of G Protein-coupled Receptor Kinase 6 on Proliferation and Apoptosis of Multiple Myeloma Cells and Its Mechanisms]. AB - OBJECTIVE: To study the effect of G protein-coupled receptor kinase 6(GRK6) on proliferation and apoptosis of multiple myeloma(MM) cells and its mechanisms. METHODS: The samples were collected from MM patients and healthy people for study in vivo. The plasma cells isolated from multiple myeloma patients, as well as U266 and NCI H929 myeloma cell lines were used for study in vitro. Western blot and quantitative real-time PCR were used to evaluate the protein and mRNA of expression of GRK6 in multiple myeloma, cell proliferation and apoptosis were tested by BrdU and Annexin V-FITC/PI assays. RESULTS: The protein and mRNA expression of GRK6 in multiple myeloma was higher than those in control group, and the expression level of GRK6 in stage I of MM was higher than that in control group, while the expression level of GRK6 in stage II was higher than that in stage I, but lower than that in stage III (P<0.05). U266 and MM cells showed high sensitivity to CX-4945, except NCI H929. GRK6 expression level in U266, NCI H929 and MM cells treated with siRNA and CX-4945, significantly decreased as compared with those cells treated by CX-4945 alone. Cell proliferations of U266, NCI H92 and MM groups treated with CX-4945 were (58.25+/-18.24)%, (64.32+/-20.03)% and (45.42+/-25.01)% respectively, moreover, their apoptotic rates were (62.82+/ 53.21)%, (43.25+/-47.05)% and (85.67+/-40.32)% respectively. CONCLUSION: The expression level of GRK6 in multiple myeloma increases, and GRK6 inhibitor CX 4945 inhibits proliferation and promotes apoptosis of myeloma cells; GRK6 regulates Rac1 and involves in the proliferation and apoptosis pathway of multiple myeloma cells. PMID- 28024498 TI - [Reactivated Expression of MicroRNA-124 in Patients with Myelodysplastic Syndromes after Demethylating Therapy]. AB - OBJECTIVE: To explore the role of microRNA-124(miR-124) in the pathogenesis of myelodysplastic syndromes(MDS) through detecting the expression level of miR-124 in bone marrow mononuclear cells(MNC) of MDS patients before and after demethylating therapy with decitabine. METHODS: The expression levels of miR-124 in the MNC of 35 MDS patients and 10 healthy donors were detected with stem-loop quantitative real time polymerase chain reaction assay. RESULTS: The expression level of miR-124 was lower in MDS patients than that in healthy donors. The difference was not statistically significant between patients with low-risk MDS subtypes (RA and RCMD) and control, but statistically significant between patients with high-risk MDS subtypes (RAEB1, RAEB2 and CMML) and control. This study also proved that expression of miR-124 was reactivated in 7 out of 18 MDS patients after treatment with low dose decitabine. CONCLUSION: The hypermethylation and silencing of miR-124 may be an important factor in the clonal transformation of MDS cells. PMID- 28024499 TI - [Clinical Efficacy of Haploidentical Allo-HSCT of Reduced Intensity Preconditioning Combined with Induced Immune Tolerance after Transplantation for Severe Aplastic Anemia]. AB - OBJECTIVE: To investigate the efficacy and safety of haploidentical allo-HSCT in combination of reduced intensity preconditioning combined with cyclophosphamid (CTX)-induced immune tolerance after transplanitation for treatment of severe aplastic anemia (SAA). METHODS: A total of 15 patients with SAA received the haploidentical allo-HSCT of reduced intensity preconditioning combined with CTX induced immune tolerance after transplartation in the General hospital of Beijing military command of chinese PLA from June 2012 to December 2014. The reduced intensity preconditioning regimen consisted of CTX, fludarabine, busulfex and amti-lymphocyte immunoglobin; the immune tolerance was induced with CTX (50 mg/kg.d) on day 3 after transplantation; the HSC donors were father and mother of patients. The GVHD was prevented by inmunosuppression consisted of cyclosporine A(CsA), methotrexate and tacrolimus. The aduvese reaction and disease-free survival (DFS) were observed in all the patients. RESULTS: All the SAA patients achieved hematopoietic reconstitution with 100% donor hematopoiesis, and all the T lymphocyte subsets increased. Out of 15 patients, 3 cases died of complication, and the DFS rate was 80% with a median follow-up of 19.8 month (6-36 months). CONCLUSION: The haploidentical allo-HSCT of reduced intensity preconditioning combined with CTX-induced immune tolerance after transplantation is safet and effective for SAA patients, that may be applied to clinical therapy. PMID- 28024500 TI - [Hematopoietic Reconstitution and Prognosis of HLA Matched and Haploidentical Hematopoietic Stem Cell Transplantation Using Modified FC/ATG Conditioning for Treatment of Severe Aplastic Anemia]. AB - OBJECTIVE: To analyse the feasibility and compare differences between hematopoietic reconstitution and prognosis of patients with severe aplastic anemia(SAA) after matched sibling donor (MSD) or haploidentical family donor (HFD) hematopoietic stem cell transplantation (HSCT) using the modified FC/ATG conditioning. METHODS: The clinical data of 56 patients with SAA who received HSCT in First Affiliated Hospital of Chinese PLA General Hospital from January 2011 to June 2016 were analyzed retrospectively. The hematopoietic reconstitution, graft verus host disease (GVHD), transplantation related toxicity (TRT) and prognosis after transplantation were compared. Furthermore, the modifed conditioning FC/ATG included low-dose cyclophosphamide (total dose 100 mg/kg), infustion of third-party donor-derived mesenchymal stem cells. RESULTS: All 56 patients with MSD-HSCT or HFD-HSCT achieved hematopoietic reconstitution. Among them, not only the recovery of neutrophils and platelets, but also the incidences of III-IV aGVHD, extensive cGVHD and TRT were not significantly different (the P value were 0.58, 0.61, 0.73, 0.73 and 0.67, respectively). After following-up for 32(2-66) months, 48 patients alive well, the 1-year overall survival rates were 86% in HFD-HSCT group and 89% in MSD-HSCT group, respectively (P=0.58). CONCLUSION: After HSCT using the modifed FC/ATG conditioning, patients with SAA achieved stable engraftment, low toxicity, mild GVHD and excellent outcomes. Furthermore, the HFD-HSCT achieved comparable outcomes to MSD-HSCT and may be served as an alternate therapy for patients with SAA. PMID- 28024501 TI - [Effect of Rabbit Anti-human Thymocyte Immunoglobulin Combined with Cyclosporin A on Severe Aplastic Anemia]. AB - OBJECTIVE: To study the efficacy and safety of anti-human thymocyte immunoglobulin(ATG-F) combined with cyclosporin A(CsA) on patients with severe aplastic anemia (SSA), so as to provide support for clinical work. METHODS: From January 2010 to December 2015, 78 patients with SAA admitted in our hospital were divided into 2 groups: ATG-F+CsA group(40 cases) and ATG-F group(38 cases). After treatment for 6 months, the effective rate, side reaction rate and time of effect initiation were compared between 2 groups. The follow-up results were compared between 2 groups. RESULTS: The effective rate and side reaction rate in ATG-F+CsA group were 100.00% and 32.50% respectively, those in ATG-F group were 94.74% and 44.74% respectively and without statistical significant difference(P>0.05). In ATG-F+CsA group, the time of effect initiation in cured patients, remission and obvious inprovement were (44.9+/-15.4) d, (68.8+/-15.9) d and (85.4+/-17.6) d; in ATG-F group, patients with those were (59.6+/-11.5) d, (94.7+/-17.8) d and (119.8+/-21.4) d respectively, the difference showed statistical significance(P<0.05). The follow-up results were not statistically significantly different between 2 groups(P>0.05). CONCLUSION: ATG-F combined with CsA can shorten the time of effect initiation, and demonstrates reliable safety. PMID- 28024502 TI - [Value of Analyzing Hemoglobin A2 by ROC Curve for Screening Thalassemia]. AB - OBJECTIVE: To investigate the value of hemoglobin A2(HbA2) for screening thalassemia. METHODS: A total of 2 000 adults' peripheral blood samples from Guangdong Women and Children Hospital from June 2013 to January 2014 were collected. The hemoglobin A2 (HbA2) level was analyzed by the full automatic capillary electrophoresis technique, and the genotypes of thalassemia were detected. RESULTS: The optimal cutoff values of HbA2 for screening silent alpha thalassemia, alpha-thalassemia trait, intermedia alpha-thalassemia and beta thalassemia trait were 2.85%, 2.65%, 2.25% and 3.45%, respectively; the areas under receiver operator characteristic (ROC) curve were 0.709, 0.839, 0.979 and 0.997 respectively; the sensitivities were 0.481, 0.721, 0.953 and 0.994, and the specificities were 0.846, 0.837, 0.929 and 0.969 respectively. CONCLUSION: The optimal cutoff values of HbA2 for screening different type of thalassemia based on our laboratory data are established by using ROC curve. According to the area under ROC curve, a satisfactory accuracy for screening intermedia alpha thalassemia and beta-thalassemia trait can be achieved by detecting hemoglobin A2 level. PMID- 28024503 TI - [Role and Significance of T Help Cells 17 in Pathogenesis of Idiopathic Thrombocytopenic Purpura]. AB - OBJECTIVE: To investigate the role and significance of T help cells 17(Th17) in pathogenesis of idiopathic thrombocytopenic purpura (ITP). METHODS: Peripheral blood samples from ITP patients and normal controls were examined for Th17 cell proportion by flow cytometry (FCM). Expression of IL-17, IL-23, IL-6 and TGF beta1 in hematoplasma was detected by ELISA. The mRNA expression level of IL-17 and RORgammat in peripheral blood mononuclear cells (PBMNC) from patients with ITP and normal controls were measured by RT-PCR technique, and expression levels of pSTAT3 and RORgammat proteins were analyzed by Western-blot. RESULTS: Th17 cells in peripheral blood from patients with ITP was greatly increased when compared with normal control group (P<0.05). Expressions of IL-17, IL-23, IL-6 and TGF-beta1 in hematoplasma of ITP patients were all significantly higher than those in normal control group (all P<0.01). mRNA expression levels of IL-17 and RORgammat in PBMNC from patients with ITP were much higher than those in normal controls (P<0.05). Protein expressions of pSTAT3 and RORgammat in PBMNC of ITP patients were greatly increased as compared with those in control (P<0.05). CONCLUSION: Th17 cell subgroup may play a role in incidence and development of ITP, which may participate in the pathogenesis of ITP by increasing Th17 cell proportion and altering the expression level of Th17-related cytokines as well as regulatory and transcriptional factors. PMID- 28024504 TI - [Significance of Plasma HMGB1, IFN-gamma, IL-4 and TLR4 Expression on CD4+T Cell Surface in Patients with Immune Thrombocytopenia]. AB - OBJECTIVE: To investigate the effects of plasma HMGB1, IFN-gamma, IL-4 and CD4+T cell surface TLR4 expression on the immune thrombocytopenia(ITP). METHODS: Twenty five patients diagnosed as ITP in our hospital from October 2014 to October 2015, and 20 healthy persons as controls were selected. The ELISA was used to detect the plasma levels of HMGB1, IFN-gamma and IL-4 in 2 groups; the flow cytometry was used to detect the expression level of TLR4 on the surface of CD4+ cells. The relatienship between different parameters was analyzed. RESULTS: Before treatment, the plasma HMGB1 level in ITP group was significantly higher than that in control group (t=4.259, P<0.01), while after treatment it significantly decreased and close to level in control group (t=1.267, P>0.05). The plasma IFN gamma level detected in ITP group before and after treatment was not significantly different from level in control group (P>0.05), while the IL-4 level in ITP group before treatment was significantly lower than that in control grup (t=2.107, P<0.05), but the IL-4 level in ITP group after treatment was significantly higher than that in control group (t=2.107, P<0.05). The plasma IFN gamma/IL-4 ratio in ITP group before treatment was significantly higher than that in control group (t=5.436, P<0.01), but it obviously decreased and was slightly lower than that in control group after treatment. The expression level of TLR4 in ITP group before and after treatment was all significantly lower than that in control group (P<0.01). The HMGB1 level in ITP group was directly proportional to the CD3+ content (r=0.824, P<0.01), however it not significantly related with CD4+ content (r=0.074, P>0.05), but than the HMGB1 level in ITP group was directly proportional to CD8+ content (r=0.844, P<0.01) and to IL-4 content (r=0.784, P<0.01), and was inversely proportional to IFN-gamma level(r= 0.814,P<0.01),and also was inversely proportional to IFN-gamma /IL-4 ratio(r= 0.887,P<0.01),and directly proportional to TLR4 expression level(r=0.772,P<0.01). CONCLUSION: The HMGB1 and TLR4 expression levels in ITP patients are higher, and clinical therapy can relieve the disease by targetly control in HMGB1 and TLR4 expression. PMID- 28024505 TI - [Comparison of Therapeutic Efficacy for Neonatal ABO Hemolytic Disease Treated with Intravenous Immunoglobin G by Different Modes of Administration]. AB - OBJECTIVE: To compare the therapeutic efficacy of patients with neonatal ABO hemolytic disease treated with introvenous immunoglobin G (IVIG) by different modes of administration. METHODS: Ninety-three in patients with neonatal ABO hemolytic disease treated in our hospital were divided into group A (31 cases), B(31 cases) and C (31 cases). Based on basic treatment, the patients in group A were treated by a single high dose of IVIG (1 g/kg), patients in group B were treated by multiple low-dose of IVIG (0.5 g/kg), and the patients in group C treated by placebo without IVIG used as controls. The phototherapy time, jaundice time in 3 groups were observed; the total bilirubin levels in 3 groups were compared before and after treatment; the incidence of anemia, the rate of blood transfusion and the occurrence of bilirubin encephalopathy were compared after treatment between 3 groups. RESULTS: The phototherapy time, jaundice time in group A were statistically significantly shorter than those in the group B and C (P<0.05), but there was not statistical significantly difference between group B and C(P>0.05). Before treatment, serum TBIL level in 3 groups was not significantly different (P>0.05); and after treatment for 24 h and 48 h, the serum TBIL levels in group A were significantly lower than that in group B and C (P<0.05); after treatment for 72 h, the serum TBIL level in group A was all lower than 34.2 umol/L; before treatment, Hb levels in 3 groups were not significantly different (P>0.05); Hb level in group A was significantly higher than that in group B and C after treatment for 24 h, 48 h and 72 h (P<0.05). The incidence of anemia in group A after treatment was significantly lower than that in group B and C, and that in group B significantly lower than that in group C(P<0.05). The rate of blood transfusion in group A was significantly lower than that in the group B and C (P<0.05); the rate of blood transfusion was not statistically significantly different between group B and C(P>0.05). CONCLUSION: The single high dose of IVIG infusion can effectively reduce the serum TBIL level, shorten treatment time and reduce the incidence of anemia and blood transfusion, so the therapeutic efficacy is significantly improved. PMID- 28024506 TI - [Clinical Significance of the Balanceshift of Th1 and Th2 Type Cytokines in Patients with Primary Immune Thrombocytopenic Purpura Detected by Cytometric Bead Array]. AB - OBJECTIVE: To investigate the levels of Th1/Th2 cytokines in peripheral blood of patients with primary immune thrombocytopenic purpura(ITP) before and after treatment and their clinical significance. METHODS: Ninety-eight cases of ITP were treated with glucocorticoid(GC), then were divided into 2 groups: effectively treated group and uneffectively treated group according to efficacy of treatment, 40 healthy persons confirmed by health examination were selected and enrolled in control group. The levels of Th1 cytokines(IFN-gamma,TNFalpha,IL 2) and Th2 cytokines(IL-4,IL-5,IL-10) were detected by cytometric bead array before and at 4 weeks, 3 and 6 months after treatment and the relationship among detected indexes was analyzed. RESULTS: Before treatment with glucocorticoid, the levels of Th1 type cytokines were in 98 patients with ITP were higher and the levels of Th2 type cytokines were lower, compared with the healthy controls(P<0.05). The IL-2/IL-4 ratio was significantly higher than that of healthy controls(P<0.05). After treatment, the levels of Th1 type cytokines in effectively treated group were significantly decreased and the levels of Th2 type cytokines were significantly increased, compared with level before treatment(P<0.05). The IL-2/IL-4 ratio was significantly decreased after treatment for 6 months, compared with that before treatment(1.05+/-0.43 vs 2.53+/ 0.72)(P<0.05), but the level of Th1 or Th2 type cytokines did not obviously changed. CONCLUSION: Peripheral blood Th1 and Th2 cells express abnormally in ITP patients, ITP is a Th1 dominated disease; the change of IL-2/IL-4 ratio before and after treatment correlated with the prognosis of ITP patients, displaying clinical significance for ITP individual therapy. PMID- 28024507 TI - [Correlation of Thrombosis and Prothrombotic State with Coagulation Factor V Gene Polymorphism and APCR. HHcy]. AB - OBJECTIVE: To investigate the correlation of patients with thrombosis or prothrombotic status with hyperhomocysteinemia (HHcy), activated protein C resistance(APCR) and gene polymorphism of coagulation factor V. METHODS: Three hundred healthy voluteers were selected as controls, 223 cases of thrombosis (80 cases of cerebral infarction of CT, the MI of 82 cases of myocardial infarction, venous thrombosis of VTE 61 cases), 270 cases of patients with prothrombotic state (76 cases of pregnancy disease of PIH, 62 cases of chronic obstructive pulmonary disease (COPD), 60 cases of diabetes(DM) and 72 cases of cancer) were enrolled in this study. The plasma APCR and hyperhomocysteinemia were detected by APTT coagulation method and cycling enzyme method respectively, and restriction fragment length polymorphism(RFLP) were was used to detect the gene polymorphism of FV G1691-A, G1091-C and A1090-G in the patient and control groups. RESULTS: APCR positive rate was 62.29% and 7.33%, and the positive hyperhomocysteinemia accounted for 68.42% and 10.00% respectively in the group of the patients with venous thrombosis and the normal control group. 3 cases of heterozygous FV gene mutations were found in the APCR-positive patients with venous thrombosis. CONCLUSION: HHcy possitive rate of patients with venous thrombosis is signiticantly higher than that in control, the HHcy is one of the important causes resulting in thrombosis, the patients with venous thrombosis have proved to be with APCR, and the possitive APCR may be related with the coagulation factor V gene polymorphism. PMID- 28024508 TI - [Reconstruction of Humanized Bone Marrow Niche in Immunodeficiency Mouse]. AB - OBJECTIVE: To reconstruct a human bone marrow niche in immunodeficiency mouse (NOD/SCID) so as to provide a model for observing the effect of abnormal BM niche on the occurence and development of leukemia. METHODS: Human platelet lysate(HPL) was obtained by repeated freezing and thawing of concentrated platelet. Bone marrow-derived mesenchymal stem cells were cultured in alpha-minimal essential medium (alpha-MEM) containing 10% HPL or 10% FBS. The morphology, cell phenotype, multilineage differentiation potential in vitro and proliferation capacity between the mesenchymal stem cells cultured with HPL or FBS were compared. The human bone marrow formation capacity of HPL-cultured MSC was observed. The MSC was seeded on beta-TCP scaffolds for 12h, then the MSC-coated scaffold were implanted in a subcutaneous pocket on the dorsum of NOD/SCID mice. After 8-12 week, the scaffolds were harvested from the mice, then fixed, paraffin-embedded and stained for HE. RESULTS: Whether cultured in the presence of HPL or FBS, the MSC all displayed a spindle-shaped fibroblast-like morphology; the flow cytometry analysis revealed no obvious differences in cell immunophenotype in this 2 groups; they all have the ability to differentiate towards osteoblasts, adipocytes, and chondrocytes in vitro. However, the mesenchymal stem cells cultivated with HPL-contained medium showed stronger proliferation capacity and higher activity to differentiate towards osteoblasts. Mesenchymal stem cells cultivated with HPL still have in vivo bone-forming capacity. CONCLUSION: HPL cultured MSC have stronger proliferation capacity and potential of differentiate towards osteoblasts, HPL-cultured MSC also can reconstruct humanized bone marrow niche in murine host. PMID- 28024509 TI - [Effects of Different Culture Systems on the Hematopoietic Differentiation Ability of iPS Cells]. AB - OBJECTIVE: To investigate the in vitro effects of different culture systems on hematopoietic differentiation ability of induced pluripotent stem (iPS) cells. METHOD: Two culture systems including E8 and mTESR(freeder-free medium), and the classical ES culture medium were chosen for culture of iPS cells. The iPS cells maintaining in above mentioning culcure systems were co-cultured with OP9 cells(murine bone marrow stromal cells) in vitro to be induced to differentiate into hematopoietic stem/progenitor cells. Flow cytometry and real-time quantitative PCR were used to detect the expression of specific hematopoietic markers and the effects of different culture systems on the differentiation of iPS in vitro. RESULT: iPS cultured in the 3 selected medium could be differentiated into hematopoietic stem cells. Efficiency of hematopoietic differentiation was up to 28.4% in classical ES culture system, which was significantly higher than that in E8 and mTESR system. CONCLUSION: Under the co culture with OP9, iPS can differentiate into hematopoietic stem/progenitor cells, which shows higher efficiency when iPS maintained in the ES medium. PMID- 28024510 TI - [Effect of Different Hemapheresis Procedures on Components of Hematopoietic Stem Cells Collected from Healthy Donors]. AB - OBJECTIVE: To investigate the effects of different hemapheresis procedures on the components of hematopoietic stem cells(HSCs) collected from helathy donors. METHODS: twelve donors were underwent stem cell collection from January 2015 to August 2016, and the stem cells were randomly colleted by AutoPBSC procedure of COBE spectra and MNC procedure of the Spectra Optia blood cell separator, the mononuclear cells, CD34+ cells, granulocytes, lymphocytes and platelets in the collections were compared. RESULTS: The circulating blood volume, the acquisition time and dosage of anticoagulants were not significantly different between two procedures. The volume and the mononuclear cell count collected by AutoPBSC procedure were lower than those by the MNC procedure, while the CD34+ cell count by AutoPBSC procedure was higher than that by the MNC procedure. More lymphocytes and platelets were collected by AutoPBSC procedure as compared with that by the MNC procedure (P<0.05). CONCLUSION: Compared with MNC procedure of the Spectra Optia blood cell separator, the number of collected stem cells, lymphocytes and platelets are higher by using AutoPBSC procedure of the COBE spectra blood cell separator. PMID- 28024511 TI - [Clinico-pathologic Characteristics of Adult Patients with Atypical Infectious Mononucleosis]. AB - OBJECTIVE: To investigate the clinicopathologic characteristics of adult patients with atypical infectious mononucleosis(IM). METHODS: From January 2003 to December 2013, a total of 5 cases of atypical IM misdiagnosed as lymphoma were selected, and the clinico-pathological characteristics and efficacy of treatment were analyzed. Biopsy of lymph node or tonsil was performed to evaluate the possibility of lymphoma. Peripheral blood EBV antibody and EBV-DNA were examined by ELISA and real-time fluorescence quantitative PCR, respectively. RESULTS: All the cases were considered as lymphoma on the basis of morphological features in initial evaluation before relapse. These features included a florid immunoblastic proliferation, distortion of the underlying nodal or tonsillar architecture and the presence of necrosis. The immunophenotypic features, EBV encoded RNA (EBER) in situ hybridization and the gene rearrangement of immunoglobulin or T cell receptor may be helpful for the distinction of atypical IM from lymphoma. CONCLUSION: IM as EBV-related lymphoproliferative process shows marked clinical and histological diversity. Atypical case of IM may mimic many different type of lymphoma in clinical and pathologic features, and the misdiagnosis should be avoided by using molecular and pathological examination. PMID- 28024512 TI - [Arginase Level in Apheresis Leukocyte-Reduced Platelets Stored for Different Time]. AB - OBJECTIVE: To explore the effect of storage time on arginase level and possible source of arginase in apheresis leukocyte-reduced platelets(ALR-Plt). METHODS: The arginase level and myeloperoxidase(MPO) levels in ALR-Plt and control plasma were detected by ELISA. The relationship between arginase level and MPO level in ALR-Plt was analyzed by correlation analysis. RESULTS: There was no significant difference of arginase level between ALR-Plt stored less than 3 days and control plasma. However, arginase level in ALR-Plt stored over 3 days was significantly higher than that in ALR-Plt stored less than 3 days and control plasma(P<0.05). There was no significant difference of MPO level in ALR-Plt stored for different times, but the MPO level in ALR-Plt stored for different time was lower than that in control plasma. Correlation analysis showed that arginase level positively correlated with MPO level in ALR-Plt of different storage time (r=0.58). CONCLUSION: The arginase level in ALR-Plt stored over 3 days increase significantly. The main possible source of arginase in ALR-Plt is the residual white blood cells, especially neutrophils. PMID- 28024513 TI - [A New Goal for Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: Treatment-free Remission -Review]. AB - Tyrosine kinase inhibitor (TKI) therapy significantly improved the prognosis and outcome of patients with chronic myeloid leukemia(CML). Long-term therapy of TKI drugs was often accompanied with financial burden and the rise of chronic adverse effects. At present, the treatment-free remission (TFR) has been gradually regarded as the new ultimate aim to the patients with long-term CML. In clinical trials, the patients with the therapy of imatinib stopping TKI treatment after acquired deep molecular reaction still maintained remission. Here, the research progress on discontinuation of TKI therapy and how to better grasp the safety of drug withdrawal strategy are reviewed. However, the radical cure of CML needs more further research. PMID- 28024514 TI - [Advances of CRBN in Immunomodulatory Drugs for Multiple Myeloma-Review]. AB - Multiple myeloma is a plasma cell malignant clone proliferation diseases and has been remained incurable. In the resent years, the widespread application of immunomodulatory drugs (IMiD) have made a great progress in the treatment of multiple myeloma, greatly improved the complete remission rate and prolonged the overall survival of MM patients. According to recent researches, CRBN (cereblon) plays an important role in mediating anti-myeloma effects of IMiD, and its expression correlated with the effect of IMiD treatment and the prognosis of multiple myeloma. The discovery of CRBN not only deepened the understanding the molecular pharmacological mechanisms of IMiD, but also provide new insights into the novel therapeutic targets and therapeutic strategies for myeloma. This review focuses on the research advances of effectiveness and related mechanisms of CRBN and IMiD for MM, the concrete problems discussing in this review are discover of CRBN, therapeutic effect of CRBN and IMiD, mechnism of CRBN in IMiD treatment for MM, and so on. PMID- 28024515 TI - [Disorders of Ribosomal Proteins and Related Hematologic Diseases -Review]. AB - Ribosomal proteins are key elements of protein synthesis machinery, ribosome. Besides the essential role in ribosome assembly and protein synthesis, there are lots of extraribosomal functions for ribosomal proteins, ranging from regulating cell proliferation and apoptosis to mediating DNA repair, cellular development and differentiation. Based on the typical features of hematologic system, the ribosomal proteins are related with many hematologic diseases, such as Diamond Blackfan anemia, 5q- syndrome. In this review, the recent research progress on extraribosomal functions and related hematologic diseases are summarised. PMID- 28024516 TI - [Progress of Experimental Research on Differentiation of Muscle-Derived Stem Cells into Haematopoietic Lineages in Vitro -Review]. AB - Muscle-derived stem cells (MDSC) are a population of multipotent stem cells in the muscular tissue. It provide an excellent prospect of hemopathy treatment due to their superiorities, such as rich sources, convenient material resource and a high survival rate after transplantation and so on. However, there are great differences in sampling, separation, purification, and proliferation when MDSC were cultured in vitro. In addition, the proliferation conditions of the MDSC in vitro are yet unclear. The related regulatory mechanisms, which MDSC transformed into haematopoietic cells, need to be investigated. In this article, the experimental researches on the differentiation of MDSC into haematopoietic lineages are reviewed, the concrete problems discussed in this review are culture of MDSC in vitro, identification of MDSC, proleferation of MDSC, differention of MDSC in to hematopoietic lineages and so on. PMID- 28024517 TI - [Role of Bone Marrow Mesenchymal Stem Cells in Resistance of Chronic Myeloid Leukemia to Tyrosine Kinase Inhibitors -Review]. AB - Chronic myeloid leukemia (CML) is a disease originated from malignant hematopoietic stem cell disorder. In CML, mesenchymal stem cells(MSC) have been changed in the bone marrow microenvironment, which can protect the leukemia cells from apoptosis induced by tyrosine kinase inhibitors (TKI) and lead to the resistance to TKI by the secretion of soluble factors, involvement in cell-cell adhesion, and so on. This review mainly focuses on the changes of the bone marrow mesenchymal stem cells in CML, as well as the role and mechanism of MSC in the CML resistance of TKI. The concrete probrems dicussing in this review are role of MSC in bone marrow microenviroment, characteristics of MSC in CML, the related mechanisms of MSC in drug resistance and so on. PMID- 28024518 TI - [Role of Autophagy in Acute Lymphoblastic Leukemia -Review]. AB - Autophagy is an evolutionarily highly conservative lysosomal degradative process and closely associates with pathogenesis, process, treatment, drug resistance and relapse of acute lymphoblastic leukemia (ALL). Whether the autophagy displays resistance to chemotherapy or a tumor suppressor in ALL, it mainly depends on the context of autophagy in the cells. Understanding the different role of autophagy in different conditions for ALL, determing the autophagy signaling pathways and targeting combination with autophagy revulsants or inhibitors were significant for the therapy of ALL, particularly for the treatment of refractory/relapsed ALL patients. This review summarizes the role of autophagy in pathogenesis, developmant, drug resistance and treatment of ALL, providing some theoretical guidance of new drugs targeting autophagy for ALL therapy. PMID- 28024519 TI - [Mechanism of A New DOT1L Inhibitor EPZ-5676 and Its Research Progress -Review]. AB - Leukemia carring translocation at the 11q23 locus is referred to MLL-rearranged (MLL-r) leukemia, and the occurrence of this genetic lesion is associated with a poor prognosis. The most common translocation chromosomes are chromosomes 4,9 and 10. Recently MLL protein was found to interact with DOT1L (DOT1-like) protein, which can promote leukemogenesis. A new DOT1L inhibitor EPZ-5676 can selectively inhibit proliferation, promote apoptosis and differentiation, which was also found to act synergistically with anti-AML (acute myeloid leukemia) and anti-ALL (acute lymphoblastic leukemia) drugs. EPZ-5676 can also induce sustained regression in a rat xenograft model of MLL-rearranged leukemia. Now the novel drug is in phase I of clinical trail. The results suggest that the EPZ-5676 is promising. In this article, the mechanism of EPZ-5676 and its research progress are reviwed. PMID- 28024520 TI - Molecular identification of Azospirillum spp.: Limitations of 16S rRNA and qualities of rpoD as genetic markers. AB - Since their discovery, plant-growth promoting rhizobacteria from the genus Azospirillum have been subjected to intensive research due to their biotechnological potential as crop inoculants. Phylogenetic analysis of Azospirillum spp. is carried out by 16S rRNA sequencing almost exclusively, but inconsistencies and low confidence often arise when working with close species. In this work, it was observed that these difficulties might be explained by a high number of rRNA operons with considerable inter-genic variability within Azospirillum genomes. To search for alternative genetic markers from a list of housekeeping genes, the correlation between pairwise gene and whole-genome similarities was examined. Due to its good performance, rpoD was selected for further analyses. Genus-specific primers for the PCR-amplification and sequencing of rpoD from Azospirillum spp. were designed and tested on 16 type strains of different species. The sequences obtained were used for inferring a phylogenetic tree of the genus, which was in turn used as a reference to successfully identify a collection of 31 azospirilla isolated from many different locations of Argentine. In addition, several strains that might represent novel species were detected. The results indicate that the sequencing of rpoD is a suitable alternative method for a confident molecular identification in Azospirillum spp. PMID- 28024521 TI - A novel interpretation of the Fractional Inhibitory Concentration Index: The case Origanum vulgare L. and Leptospermum scoparium J. R. et G. Forst essential oils against Staphylococcus aureus strains. AB - Origanum vulgare (oregano) and Leptospermum scoparium (manuka) were traditionally employed as natural remedies for infected wounds and skin injuries where Staphylococcus aureus is mainly involved. The first aim of this study was to investigate oregano and manuka essential oils (EOs) chemical compositions and evaluate their antibacterial activity (MIC, Minimum Inhibitory Concentration) against fourteen S. aureus wild strains. The second aim was to evaluate the antibacterial activities of oregano and manuka EOs mixed in different combination (FIC, Fractional Inhibitory Concentration) with an improved chequerboard technique. This allowed to avoid the usual uncertainty in the determination of MIC and FIC values and to obtain a more precise interpretation of FIC indexes (FICIs). Moreover, FICIs were discussed on the basis of a novel interpretation method to evaluate the synergistic/antagonistic effect of EOs mixtures. The most representative compounds in oregano EO were Carvacrol (65.93%), p-Cymene (9.33%) and gamma-Terpinene (5.25%), while in manuka EO were Leptospermone (31.65%), cis Calamenene (15.93%) and Flavesone (6.92%). EOs presented MIC values ranging from 1:2048 to 1:4096 v/v and FIC values ranging from 0.125 to 1. According to our interpretation, a synergistic effect (34.68%), a commutative effect (15.32%) and an indifferent effect (50.00%) and no antagonistic effect were observed. Conversely, according to two previously proposed FICI interpretation models, 1.80% synergistic effect could be observed and, respectively, 98.20% indifferent effect or 48.20% additive effect and 50.00% indifferent effect. As practical results, oregano and manuka EOs may be an effective alternative to chemotherapic drugs in staphylococcal infections and useful tools to enhance food security. PMID- 28024522 TI - Brevibacillin, a cationic lipopeptide that binds to lipoteichoic acid and subsequently disrupts cytoplasmic membrane of Staphylococcus aureus. AB - Brevibacillin is a newly-discovered antimicrobial lipopeptide produced by Brevibacillus laterosporus OSY-I1. It is active against Gram-positive bacteria, including antibiotic resistant strains. This research was initiated to investigate the mechanism of action of brevibacillin against an indicator strain, Staphylococcus aureus ATCC 6538. Results of the study proved that brevibacillin binds to lipoteichoic acid (LTA) on cell wall before interacting with cell membrane. Additionally, brevibacillin disrupts S. aureus cytoplasmic membrane by increasing its permeability, depolarization and potassium leakage. Therefore, cytoplasmic membrane serves as a major target for brevibacillin. Despite the presence of multiple sites on S. aureus cell envelope, scanning electron microscope observation didn't reveal evidence of cell lysis or any morphological defects in cells treated with brevibacillin. Based on the results of this study, we propose that the electrostatic interaction between the cationic brevibacillin and the anionic LTA helped the accumulation of the antimicrobial agent at cell surface; this was followed by translocation of the lipopeptide to the cytoplasmic membrane and disrupting its vital functions. PMID- 28024523 TI - Zeolite food supplementation reduces abundance of enterobacteria. AB - According to the World Health Organisation, antibiotics are rapidly losing potency in every country of the world. Poultry are currently perceived as a major source of pathogens and antimicrobial resistance. There is an urgent need for new and natural ways to control pathogens in poultry and humans alike. Porous, cation rich, aluminosilicate minerals, zeolites can be used as a feed additive in poultry rations, demonstrating multiple productivity benefits. Next generation sequencing of the 16S rRNA marker gene was used to phylogenetically characterize the fecal microbiota and thus investigate the ability and dose dependency of zeolite in terms of anti-pathogenic effects. A natural zeolite was used as a feed additive in laying hens at 1, 2, and 4% w/w for a 23 week period. At the end of this period cloacal swabs were collected to sample faecal microbial communities. A significant reduction in carriage of bacteria within the phylum Proteobacteria, especially in members of the pathogen-rich family Enterobacteriaceae, was noted across all three concentrations of zeolite. Zeolite supplementation of feed resulted in a reduction in the carriage of a number of poultry pathogens without disturbing beneficial bacteria. This effect was, in some phylotypes, correlated with the zeolite concentration. This result is relevant to zeolite feeding in other animal production systems, and for human pathogenesis. PMID- 28024525 TI - Gut content microbiota of introduced bigheaded carps (Hypophthalmichthys spp.) inhabiting the largest shallow lake in Central Europe. AB - Studying the microbiota in the alimentary tract of bigheaded carps (Hypophthalmichthys spp.) gained special interest recently, as these types of investigations on non-native fish species may lead to a better understanding of their ecological role and feeding habits in an invaded habitat. For microbiological examinations, bigheaded carp gut contents and water column samples from Lake Balaton (Hungary) were collected from spring to autumn in 2013. Denaturing Gradient Gel Electrophoresis (DGGE) and pyrosequencing of the 16S rRNA gene were performed to reveal the composition. According to the DGGE patterns, bacterial communities of water samples separated clearly from that of the intestines. Moreover, the bacterial communities in the foreguts and hindguts were also strikingly dissimilar. Based on pyrosequencing, both foregut and hindgut samples were predominated by the fermentative genus Cetobacterium (Fusobacteria). The presence of some phytoplankton taxa and the high relative abundance of cellulose-degrading bacteria in the guts suggest that intestinal microbes may have an important role in digesting algae and making them utilizable for bigheaded carps that lack cellulase enzyme. In turn, the complete absence of typical heterotrophic freshwater bacteria in all studied sections of the intestines indicated that bacterioplankton probably has a negligible role in the nutrition of bigheaded carps. PMID- 28024524 TI - Diversity of free-Living nitrogen fixing Streptomyces in soils of the badlands of South Dakota. AB - Biological Nitrogen Fixation is critical for ecosystem productivity. Select members of Bacteria and Archaea express a nitrogenase enzyme complex that reduces atmospheric nitrogen to ammonia. Several nitrogen fixing bacteria form symbiotic associations with plants, but free-living diazotrophs also contribute a substantial amount of nitrogen to ecosystems. The aim of this study was to isolate and characterize free-living diazotrophs in arid lands of South Dakota Badlands. Samples were obtained from sod tables and the surrounding base in spring and fall. Diazotrophs were isolated on solid nitrogen free medium (NFM) under hypoxic conditions, and their16S rRNA and nifH genes sequenced. nifH was also amplified directly from soil DNA extracts. The 16S rRNA gene data indicated a diversity of putative free-living diazotrophs across 4 phyla (Actinomycetes, Proteobacteria, Bacteroidetes, and Firmicutes), but ~50% of these clustered with Streptomyces. These Streptomyces isolates grew in liquid NFM in an ammonia depleted environment. Only 5 of these yielded a nifH gene product using the PolF/PolR primer set. Four of these aligned with nifH of the cyanobacteria Scytonema and Nostoc, and the other one aligned with nifH of Bradyrhizobium. Six selected Streptomyces isolates, three of which were nifH positive by PCR, all indicated 15N2 incorporation, providing strong support of nitrogen fixation. All nifH amplicons from soil DNA extract resembled Cyanobacteria. This is the first known report of diazotrophic Streptomyces, other than the thermophilic, autotrophic S. thermoautotrophicus. nifH genes of these Streptomyces were related to those from Cyanobacteria. It is possible that the cyanobacteria-like nifH amplicons obtained from soil DNA were associated with Streptomyces. PMID- 28024526 TI - Overexpression of Rv2788 increases mycobacterium stresses survival. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis-one of the most devastating infectious diseases, is a successful intracellular pathogen capable of surviving diverse stresses. Unveiling the molecular mechanisms governing this superior adaptation will inspire better control measures against tuberculosis. To define the role of Rv2788, a manganese-dependent transcriptional repressor, M.smegmatis was used as the host strain for heterologous expression Rv2788. Rv2788 can significantly change the colony morphology and fatty acids and permeability of cell wall, enhance the growth of the recombinants and resistance to diverse stresses, such as hydrogen peroxide (H2O2), diamide exposure, surface stress, acidic condition, multiple antibiotics treatment including chloramphenicol, vancomycin and amikacin. The dysregulation of the target genes of Rv2788, such as whiB1 and lexA, might underpin such phenotypes. The results implicate important roles of Rv2788 in the survival of Mycobacterium under stresses, and might represent ideal novel antibiotics target candidate. PMID- 28024527 TI - In-silico prediction of dual function of DksA like hypothetical protein in V. cholerae O395 genome. AB - Cholera, an acute infection of the small intestine, is caused by Vibrio cholerae. The present study identified a hypothetical protein in V. cholerae O395, which was predicted to be acquired through horizontal gene transfer the origin of which was found to be from a phage. Its expression was further confirmed by RT-PCR. Homology based 3D model of the hypothetical protein indicated DksA like homologue. Protein binding site of 3D-model revealed a deep cleft which may influence the dimer formation and interaction with ds-DNA molecule. Also, canonical function of direct interaction with RNA polymerase (RNAP) holoenzyme in complex with ppGpp suggests its dual role in the pathogenesis of cholera. PMID- 28024528 TI - TPP riboswitch characterization in Alishewanella tabrizica and Alishewanella aestuarii and comparison with other TPP riboswitches. AB - Riboswitches are located in non-coding areas of mRNAs and act as sensors of cellular small molecules, regulating gene expression in response to ligand binding. The TPP riboswitch is the most widespread riboswitch occurring in all three domains of life. However, it has been rarely characterized in environmental bacteria other than Escherichia coli and Bacillus subtilis. In this study, TPP riboswitches located in the 5' UTR of thiC operon from Alishewanella tabrizica and Alishewanella aestuarii were identified and characterized. Moreover, affinity analysis of TPP binding to the TPP aptamer domains originated from A. tabrizica, A. aestuarii, E.coli, and B. subtilis were studied and compared using In-line probing and Surface Plasmon Resonance (SPR). TPP binding to the studied RNAs from A. tabrizica and A. aestuarii caused distinctive changes of the In-line cleavage pattern, demonstrating them as functional TPP riboswitches. With dissociation constant of 2-4nM (depending on the method utilized), the affinity of TPP binding was highest in A. tabrizica, followed by the motifs sourced from A. aestuarii, E. coli, and B. subtilis. The observed variation in their TPP-binding affinity might be associated with adaptation to the different environments of the studied bacteria. PMID- 28024529 TI - Fungicidal effect of thymoquinone involves generation of oxidative stress in Candida glabrata. AB - The antifungal effect of thymoquinone, a component of black seed essential oil, has been studied on different types of fungi. Its mechanism of action as an antifungal has not been described yet. This study demonstrates the fungicidal effect of thymoquinone on different Candida species with particular emphasis on C. glabrata planktonic cells and biofilms. Since cell death was induced via the generation of oxidative stress as evidenced by the abrogation of thymoquinone toxicity in cells incubated with antioxidants, a part of thymoquinone's mechanism of action includes a direct involvement as a pro-oxidant. This was further confirmed by measuring the generation of reactive oxygen species, glutathione level reduction and decrease in mitochondrial membrane potential. The oxidative stress caused by thymoquinone was confirmed to be the cause of death and not a result of cell death. PMID- 28024530 TI - Editorial. PMID- 28024531 TI - Presence of nano-sized chitosan-layered silicate composites protects against toxicity induced by lead ions. AB - Protecting cells from toxicosis even apoptosis induced by a variety of toxic heavy metals stimulus has drawn more and more attentions. This study was designed to elucidate whether chitosan-organic rectorite (CS-OREC) composites exhibited any protective effects on altered oxidative stress parameter in PC12 cells exposed to lead ions (Pb2+). The cells were exposed to Pb2+ either alone or in combination with CS-OREC composites for designated time to evaluate the efficacy of the composites on Pb2+-induced toxicity. The MTT assay results showed that the cell viability of PC12 was remarkably decreased when exposed to Pb2+, but significantly retained after adding CS-OREC composites compared to that of the control. The beneficial effect of CS-OREC composites on cytotoxicity was related, at least in part, to its ability to protect against apoptosis in PC12 cells exposed to 50MUM Pb2+. Their protective effect was also associated with the inhibitory effect on Pb2+-induced activation of Bax/Bcl-2, P-38, and caspase-3 pathways, while was independent on JNK pathway. PMID- 28024532 TI - "Aerogels of enzymatically oxidized galactomannans from leguminous plants: Versatile delivery systems of antimicrobial peptides and enzymes". AB - We describe aerogels obtained by laccase/TEMPO-oxidation and lyophilization of galactomannans (GM) from fenugreek, sesbania and guar. Enzymatic oxidation of GM in aqueous solution caused viscosity increase up to fifteen-fold, generating structured, elastic, stable hydrogels, presumably due to establishment of hemiacetalic bonds between newly formed carbonyl groups and free hydroxyl groups. Upon lyophilization, water-insoluble aerogels were obtained, whose mechanical properties and porosity were investigated. Active principles were absorbed into the aerogels from aqueous solutions and, following rinsing, blotting, re lyophilization, were released in an appropriate medium. The release of the antibiotic polymyxin B was tested against six different Gram-negative bacterial strains, of the antimicrobial peptide nisin against two Gram-positive and of the muraminidase lysozyme against one anaerobic strain. Protease and lipase release in solution from "enzyme loaded" aerogels was monitored by the increase in enzymatic activity. These biomaterials could represent new versatile, biocompatible "delivery systems" of actives for biomedical and industrial applications. PMID- 28024533 TI - Using chitosan nanoparticles as drug carriers for the development of a silver sulfadiazine wound dressing. AB - Burn wounds environment favors the growth of micro-organisms causing delay in wound healing. The traditional treatment with antimicrobial creams offer inaccurate doses. In the present study, a dressing coated with silver sulfadiazine (SSD) loaded chitosan nanoparticles (CSNPs) for the controlled release of SSD into burn wound to control bacterial growth was investigated. CSNPs were formulated with different concentrations of chitosan and CM-beta-CD and loaded with SSD complexed in 1:1 molar ratio with CM-beta-CD, CSNPs were assessed for their particle size, polydispersity index, morphology and association efficiency. The formula showing the best characteristics was selected for the preparation of SSD loaded CSNPs wound dressing through a padding process with/without the use of cross-linker. The dressing was characterized for its physical properties, in addition, FTIR, X-ray, SEM and in vitro release were used for characterization. The dressing was proven effective for the inhibition of the growth of Gram positive and Gram negative bacteria as well as candida on an infected wound. PMID- 28024534 TI - Amylopectin small chain glucans form structure fingerprint that determines botanical origin of starch. AB - Starch granule size, shape and structure of amylopectin are species specific and influence starch properties and end-use of starch. Amylopectin glucan chain structure was used to predict the starch botanical sources. Mathematical probability for accumulation of small glucan chains DP 6-10 reveal exponential fit curve with maximum R2 in smallest granule size starches (Chlamydomonas, quinoa, buckwheat). Cereal and cassava showed R2 of 0.81-0.96 while in pulses and tubers it was less than 0.7. The amylopectin small glucan chains form a unique 'finger print region' that identified starch botanical source. Differential amylopectin chain length distribution (APCLD) graphs between DP 6-80 of all species from Chlamydomonas starch distinguished five structural groups that clustered the 31 analyzed starches into four major patterns. APCLD analyses of amylopectin combined with characteristic pattern of small linear DP (6-9) glucan chains predicted the starch botanical source. PMID- 28024535 TI - Molecular structure of quinoa starch. AB - Quinoa starch has very small granules with unique properties. However, the molecular structure of quinoa starch remains largely unknown. In this study, composition and amylopectin molecular structure of 9 quinoa starch samples were characterised by chromatographic techniques. In particular, the amylopectin internal molecular structure, represented by phi, beta-limit dextrins (LDs), was explored. Great variations in the composition and molecular structures were recorded among samples. Compared with other amylopectins, quinoa amylopectin showed a high ratio of short chain to long chains (mean:14.6) and a high percentage of fingerprint A-chains (Afp) (mean:10.4%). The average chain length, external chain length, and internal chain length of quinoa amylopectin were 16.6, 10.6, and 5.00 glucosyl residues, respectively. Pearson correlation and principal component analysis revealed some inherent correlations among structural parameters and a similarity of different samples. Overall, quinoa amylopectins are structurally similar to that from starches with A-type polymorph such as oat and amaranth starches. PMID- 28024536 TI - Nanocellulose based asymmetric composite membrane for the multiple functions in cell encapsulation. AB - We describe the nanocomposite membrane for cell encapsulation using nanocelluose hydrogels. One of the surfaces of bacterial cellulose (BC) pellicles was coated with collagen to enhance cell adhesion and the opposite side of the BC pellicles was coated with alginate to protect transplanted cells from immune rejection by the reduced pore size of the composite membrane. The morphology of nanocomposite membrane was observed by scanning electron microscopy and the permeability of the membrane was estimated by the release test using different molecular weights of polymer solution. The nanocomposite membrane was permeable to small molecules but impermeable to large molecules such as IgG antibodies inferring the potential use in cell implantation. In addition, the BC-based nanocomposite membrane showed a superior mechanical property due to the incorporation of compared with alginate membranes. The cells attached efficiently to the surface of BC composite membranes with a high level of cell viability as well as bioactivity. Cells grown on the BC composite membrane kit released dopamine freely to the medium through the membrane, which showed that the BC composite membrane would be a promising cell encapsulation material in implantation. PMID- 28024537 TI - CMC stabilized nano silver synthesis, characterization and its antibacterial and synergistic effect with broad spectrum antibiotics. AB - In the present study silver nanoparticles were synthesized by reduction of AgNO3 using aqueous CMC solution, which acts as both reducing and capping agent. The formation of AgNO3 nanoparticles was observed visually by color change and these nanoparticles were characterized through UV-vis spectroscopy, FTIR, XRD, SEM, EDS and AFM. The FTIR peaks observed to be ranging from 3300 to 605cm-1. The AFM image clearly showed the surface morphology of well dispersed nanoparticles. SEM image illustrates the nanoparticles with spherical shape. The crystalline nature of the particles was assured by XRD analysis. The antimicrobial activity of nanoparticles was tested against human bacterial pathogens (Bacillus cereus, Staphylococcus aureus, S. epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhimurium &Vibrio vulnificus). The bacterial growth was highly inhibited by the nanoparticles. The synergistic effect of nanoparticles in combination with selected broad spectrum antibiotics against the tested bacteria determined strong growth inhibitory activity. PMID- 28024538 TI - Estimation of cellulose crystallinity of sugarcane biomass using near infrared spectroscopy and multivariate analysis methods. AB - A method for estimation of sugarcane (Saccharum spp.) biomass crystallinity using near infrared spectroscopy (NIR) and partial least squares regression (PLS) as an alternative to the standard method using X-ray diffractometry (XRD) is proposed. Crystallinity was obtained using XRD from sugarcane bagasse. NIR spectra were obtained of the same material. PLS models were built using the NIR and crystallinity values. Cellulose crystallinity ranged from 50 to 81%. Two variable selection algorithms were applied to improve the predictive ability of models, i.e. (a) Ordered Predictors Selection (OPS) and (b) Genetic Algorithm. The best model, obtained with the OPS algorithm, presented values of correlation coefficient of prediction, root mean squared error of prediction and ratio of performance deviation equals to 0.92, 3.01 and 1.71, respectively. A scatter matrix among lignin, alpha-cellulose, hemicellulose, ash and crystallinity was built that showed that there was no correlation among these properties for the samples studied. PMID- 28024539 TI - An improved approach for evaluating the semicrystalline lamellae of starch granules by synchrotron SAXS. AB - A fitting method combined with a linear correlation function was developed as an improved approach for the SAXS analysis of the semicrystalline lamellae of starch granules. Using a power-law function with two Gaussian plus Lorentz functions, the SAXS pattern was resolved into sub-patterns of the net lamellar peak and the power-law scattering plus scattering background (PL+B). The ratio of the net lamellar peak area (Apeak) to the total scattering area (Atotal) was proposed equal to the proportion of the lamellae within the starch granule (PSL). Along with this fitting method, we obtained a better profile of linear correlation function, with the elimination of the interference of non-lamellar amorphous starch (i.e., amorphous growth rings). Then, we could accurately calculate the lamellar parameters, e.g., PSL, the thicknesses of semicrystalline (d), crystalline (dc) and amorphous (da) lamellae, and the volume fraction (phic) of crystalline lamellae within semicrystalline lamellae. Quantitative analysis revealed that PSL was positively correlated with the crystallinity (Xc) of starch. It was confirmed that the distribution of lamellar thickness was more important than the starch botanical origin in affecting the validity of the developed fitting method. We also proposed a criterion to test the validity of the proposed method. Specifically, the total SAXS pattern should be mostly tangent to the profile of PL+B at a high q tail (close to 0.2A-1). PMID- 28024540 TI - Extraction and characterization of pectins from primary cell walls of edible acai (Euterpe oleraceae) berries, fruits of a monocotyledon palm. AB - Acai berries (Euterpe oleracea) are greatly consumed in Brazil and exported to other countries as a nutritional supplement, due to health benefits attributed to its consumption. However, the complete chemical structure of bioactive polysaccharides was not fully elucidated yet. In this work, we characterize pectic polysaccharides from acai berries through monosaccharide composition, HPSEC, methylation and 13C and 1H/13C HSQC-DEPT-NMR analyses. A highly methoxylated homogalacturonan with a DM of 88% and Mw of 22kDa together with small amounts of a mannoglucan were found. Moreover, a type II arabinogalactan (Mw=45kDa) containing a backbone with high portions of 6-O-linked and 3,6-O linked Galp chains rather than 3-O-linked Galp was also isolated and structurally characterized. The type II arabinogalactan was found as a side chain of a type I rhamnogalacturonan. These findings contribute to correlate the fine chemical structure with the previously reported action of acai polysaccharides on innate immune response. Moreover, from the taxonomic point of view, the results bring new information about polysaccharide composition of primary cell walls of palms (Arecaceae), that despite being commelinid monocots, have a distinct cell wall composition. PMID- 28024541 TI - Natural cellulose fiber derived hollow-tubular-oriented polydopamine: In-situ formation of Ag nanoparticles for reduction of 4-nitrophenol. AB - A facile method was reported to achieve hollow-tubular-oriented polydopamine (HTO PDA) layer using natural kapok fiber (KF) as the bio-template without any pretreatments by altering hydrophobic fiber into hydrophilic one. Subsequently, the HTO-PDA can be utilized for direct in-situ deposition of Ag nanoparticles (NPs). The structures of pristine fiber and HTO-PDA, as well as the resulting Ag NPs attached HTO-PDA (Ag@HTO-PDA) were well characterized by means of scanning electron microscopy (SEM) coupled energy dispersion spectrum (EDS), x-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and Fourier transform infrared (FTIR) spectroscopy. Due to the presence of relatively uniform Ag NPs attached onto PDA layer, Ag@KF-HTO-PDA shows stable catalytic ability towards the reduction of 4-nitrophenol into its amino derivative. Further, this method was used for facile fabrication of Calotropis gigantea fiber derived, surface-functionalized material. The experimental data demonstrated also its excellent catalytic efficiency towards 4 nitrophenol reduction. PMID- 28024542 TI - Guar gum oleate-graft-poly(methacrylic acid) hydrogel as a colon-specific controlled drug delivery carrier. AB - A novel type of ethylene glycol dimethacrylate (EGDMA) cross-linked guar gum oleate-graft-poly(methacrylic acid) (GGO-g-PMAc) hydrogel was prepared as a pH responsive controlled release carrier for colon-specific drug delivery. The structure of GGO-g-PMAc hydrogel was characterized by FT-IR, 1H NMR and X-ray diffraction (XRD) analysis. The swelling degree of the GGO-g-PMAc hydrogel at pH 7.4 was found to be higher than that at pH 1.2. The drug release studies performed in pH 7.4 and 1.2 buffer solutions at 37 degrees C revealed that the rate and amount of drug released from the GGO-g-PMAc hydrogel at pH 7.4 were higher than that at pH 1.2. The MTT assay revealed that there is no noticeable cytotoxicity of GGO-g-PMAc hydrogel at the concentration range of 0-100MUg/ml against the mouse mesenchymal stem cell line (C3H10T1/2). These results suggested that GGO-g-PMAc hydrogel can be a prospective pH-sensitive carrier for colon targeted drug delivery. PMID- 28024543 TI - Characterization of a bioactive polysaccharide from Ganoderma atrum: Re elucidation of the fine structure. AB - The fine structure in terms of backbone and branch chain features of a bioactive polysaccharide from Ganoderma atrum (PSG-1) was re-elucidated systematically using high performance anion-exchange chromatography (HPAEC), methylation and GLC MS analysis, and 1D & 2D NMR spectroscopy. Monosaccharide composition analysis revealed that PSG-1-F0.2 fraction mainly consisted of glucose (73.8%) and glucuronic acid (15.3%), with small amount of mannose (5.7%) and galactose (5.2%). Based on methylation, multistep partial acid hydrolysis and NMR study, were proposed to substitute at the O-6 position of beta-(1->3)-glucan. The small amount of mannose and galactose residues were considered to be from the other fraction in PSG which was very difficult to be separated from PSG-1-F0.2. This revised structure as an acidic beta-(1->3, 1->6)-glucan is considered to be more accurate than the previous proposal of PSG-1. PMID- 28024544 TI - Design of starch-formate compound fibers as encapsulation platform for biotherapeutics. AB - Effective encapsulation and protection of biotherapeutics using a bio-based carrier, preferably issued from renewable resources, remains a challenge. Herein, we demonstrate application of coaxial electrospinning to fabric starch-based core sheath compound fibers as a bacterial cells' carrier. Starch-formate is employed as an encapsulation agent, while the fiber core is made of glycerol, serving as a cell suspension medium. SEM microscopy reveals a distinct core-sheath morphology of the starch-formate/glycerol (SFG) compound fibers with mean diameters of 4.13+/-1.05MUm. Calorimetric and thermomechanical analyses and FTIR spectroscopy show a progressive interaction between the starch-formate and the glycerol with time, pronounced with temperature increase. SFG fibers with encapsulated Lactobacillus paracasei are proved stable with retained bacterial viability when stored at 4 degrees C and room temperature for up to 21days. SFG fibers present a potential biotherapeutic products' encapsulation platform, guaranteeing the stability at refrigerated and ambient storage conditions, as determined in this study. PMID- 28024545 TI - Biodegradation of cotton and cotton/polyester fabrics impregnated with Ag/TiO2 nanoparticles in soil. AB - This study discusses the biodegradation behavior of cotton and cotton/PET fabrics impregnated with Ag/TiO2 nanoparticles in soil. Biodegradation behavior was evaluated by standard test method ASTM 5988-03 based on determination of percentage conversions of carbon content to CO2 as well as by soil burial test and enzymatic hydrolysis with cellulase where the extent of biodegradation was estimated by the calculation of fabric weight loss. The morphological and chemical changes of fibers during biodegradation process were analyzed by SEM and FTIR spectroscopy, respectively. The results obtained by all applied methods suggested that Ag/TiO2 nanoparticles hindered the biodegradation of investigated cotton and cotton/PET fabrics. Soil burial test indicated faster biodegradation of the impregnated blend compared to impregnated cotton fabric which is attributed to smaller amount of fabricated Ag nanoparticles on the blend proved by AAS measurement. Similar trend was established by enzymatic hydrolysis of cotton fibers. Severe damage of cotton fibers in both fabrics due to biodegradation process was confirmed by SEM. However, the cotton fiber damage occurred to a lesser extent in the samples that were impregnated with Ag/TiO2 nanoparticles. PET fibers remained intact which was also indicated by FTIR analysis. PMID- 28024546 TI - New insights into the action of bacterial chondroitinase AC I and hyaluronidase on hyaluronic acid. AB - Hyaluronic acid (HA), a glycosaminoglycan, is a linear polysaccharide with negative charge, composed of a repeating disaccharide unit [->4)-beta-d glucopyranosyluronic acid (1->3)-beta-d- N-acetyl-d-glucoaminopyranose (1->]n ([ >4) GlcA (1->3) GlcNAc 1->]n). It is widely used in different applications based on its physicochemical properties associated with its molecular weight. Enzymatic digestion by polysaccharides lyases is one of the most important ways to decrease the molecular weight of HA. Thus, it is important to understand the action patterns of lyases acting on HA. In this study, the action patterns of two common lyases, Flavobacterial chondroitinase AC I and Streptomyces hyaluronidase, were investigated by analyzing HA oligosaccharide digestion products. HA oligosaccharides having an odd-number of saccharide residues were observed in the products of both lyases, but their distributions were quite different. Chondroitinase AC acted more efficiently at the beta 1-4 glycosidic bond linking GlcNAc and GlcA. Oligosaccharides, having an even number of saccharide residues, and with an unsaturated uronic acid (4-deoxy-alpha-l-threo-hex-4 enepyranosyluronic acid, ?UA) residue at their non-reducing end represent the major product. A minor amount of oligosaccharides having an odd number of saccharide residues resulted from the irregular terminal residues of HA substrate chains. Hyaluronidase showed a more complicated product mixture. Its minimum recognition and digestion domain is HA heptasaccharide and it could cleave both beta 1-4 and beta 1-3 glycosidic linkages. The HA oligosaccharides, generated with a 2-acetamido-2,3-di-deoxy-beta-d-erythro-hex-2-enopyranose (?HexNAc) at the non-reducing end, are believed to be unstable and undergo breakdown immediately after their generation, and the oligosaccharides with ?UA residue at the non reducing end are formed. Thus, oligosaccharides having both an even and odd number saccharide residues with a ?UA residue at their non-reducing ends, represent the major products of hyaluronidase acting on HA. PMID- 28024547 TI - Metrics of rhamnogalacturonan I with beta-(1->4)-linked galactan side chains and structural basis for its self-aggregation. AB - Within the family of plant cell wall polysaccharides rhamnogalacturonans I are the most diverse and structurally complex members. In present study we characterize the 3-dimensional structures and dynamic features of the constituents of RG-I along MD trajectories. It is demonstrated that extended threefold helical structure of the rhamnogalacturonan linear backbone is the most energetically favorable motif. Branching helps to stabilize a conformer of the backbone twisted along 1->2 glycosidic linkage triggering the orientation of long side chains without altering the extended overall backbone chain conformation. Formation of anti-parallel pairing of the beta-galactan side chains allows us to suggest a novel mode of non-covalent cross-linking in pectins. Studied structural elements are organized to report the first attempt to characterize 3D structure of RG-I focusing on the special case of flax tertiary cell wall and elucidate the structural basis underlying the formation of RG-I self-associates and functional role of RG-I in planta. PMID- 28024548 TI - Canadian Cardiovascular Society/Canadian Cardiovascular Critical Care Society/Canadian Association of Interventional Cardiology Position Statement on the Optimal Care of the Postarrest Patient. AB - Out of hospital cardiac arrest (OHCA) is associated with a low rate of survival to hospital discharge and high rates of neurological morbidity among survivors. Programmatic efforts to institute and integrate OHCA best care practices from the bystander response through to the in-hospital phase have been associated with improved patient outcomes. This Canadian Cardiovascular Society position statement was developed to provide comprehensive yet practical recommendations to guide the in-hospital care of OHCA patients. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system recommendations have been generated. Recommendations on initial care delivery on the basis of presenting rhythm, appropriate use of targeted temperature management, postarrest angiography, and revascularization in the initial phase of care of the OHCA patient are detailed within this statement. In addition, further description of best practices on sedation, use of neuromuscular blockade, oxygenation targets, hemodynamic monitoring, and blood product transfusion triggers in the critical care environment are contained in this document. Last, discussion of optimal care systems for the OHCA patient is provided. These guidelines aim to serve as a practical guide to optimize the in-hospital care of survivors of cardiac arrest and encourage the adoption of "best practice" protocols and treatment pathways. Emphasis is placed on integrating these aspects of in-hospital care as part of a postarrest "care bundle." It is hoped that this position statement can assist all medical professionals who treat survivors of cardiac arrest. PMID- 28024549 TI - Temporary Mechanical Circulatory Support in Cardiac Critical Care: A State of the Art Review and Algorithm for Device Selection. AB - With more than 60 years of continuous development and improvement, a variety of temporary mechanical circulatory support (MCS) devices and implantation strategies exist, each with unique advantages and disadvantages. A thorough understanding of each available device is essential for optimizing patient outcomes in a fiscally responsible manner. In this state of the art review we examine the entire range of commonly available peripheral and centrally cannulated temporary MCS devices, including intra-aortic balloon pumps, the Impella (Abiomed, Danvers, MA) family of microaxial pumps, the TandemHeart (CardiacAssist Inc, Pittsburg, PA) pump and percutaneous cannulas, centrally cannulated centrifugal pumps such as the CentriMag (Thoratec Corp, Pleasanton, CA/St Jude Medical, St Paul, MN/Abbott Laboratories, Abbott Park, IL) and Rotaflow (Maquet Holding BV & Co KG, Rastatt Germany), and extracorporeal membrane oxygenation. Several factors need detailed consideration when contemplating MCS in any given patient, mandating a balanced, algorithmic approach for these sick patients. In this review we describe our approach to MCS, and emphasize the need for multidisciplinary input to consider patient-related, logistical, and institutional factors. Evidence is summarized and referenced where available, but because of the lack of high-quality evidence, current best practice is described. Future directions for investigation are discussed, which will better define patient and device selection, and optimize MCS-specific patient care protocols. PMID- 28024550 TI - Simulation as a Tool to Ensure Competency and Quality of Care in the Cardiac Critical Care Unit. AB - Cardiac critical care units are high-risk clinical environments. Medical emergencies are frequent and require the intervention of a cohesive, efficient, and well trained interprofessional team. In modern clinical practice there is increased emphasis on safety but also increased lack of acceptance of medical errors and as a consequence, increased litigation. In the past decade, simulation based learning has arisen as an effective and safe means to learn and practice acute care setting skills. It has been used and studied in different contexts including procedural skills training, crisis resource management and team training, patient and family member communication skills, and health care system quality improvement. Simulation-based education is a relatively recent teaching strategy and evidence of its efficacy continues to grow. Nevertheless, many influential medical societies are now promoting a simulation-based approach for cardiovascular training and continuing medical education. In this article we review the simulation literature in the intensive care unit and evaluate its integration in coronary care units and postoperative cardiovascular intensive care units. We also provide resources for educators and clinicians who wish to implement simulation workshops in these settings. PMID- 28024551 TI - End-of-Life Issues in Cardiac Critical Care: The Option of Organ Donation. AB - Despite important advances in the care of postcardiac arrest patients, severe brain injury remains one of the major causes of death in the cardiac intensive care unit. Neurological prognostication after cardiac arrest has evolved significantly since the introduction of therapeutic hypothermia. It now relies on a multimodal approach and a minimal observation period of 72 hours is usually advocated. However, when brain injury is severe and the prognosis considered dismal, patients become eligible for organ donation. Patients with severe anoxic encephalopathy might evolve toward brain death and be candidates for donation after brain death. In the presence of severe brain injury without brain death criteria, when withdrawal of life-sustaining therapy is considered, patients might be eligible for donation after cardiocirculatory death. The diagnosis of brain death, the differences between donation after brain death and donation after cardiocirculatory death, family approach, and donor management in the intensive care unit are discussed. Because these are increasingly encountered situations in the cardiac intensive care unit, it is essential that physicians involved in cardiac critical care be familiar with these concepts. PMID- 28024552 TI - The Swan-Ganz Catheter Remains a Critically Important Component of Monitoring in Cardiovascular Critical Care. AB - Few inventions in modern medicine have generated as passionate and extended debate as the pulmonary artery catheter (PAC). Since its introduction in 1970, the PAC remains an indispensable monitor in cardiovascular critical care. Despite attempts to develop less invasive alternatives, the PAC remains unequaled as a single monitoring device capable of measuring physiological derangement in most components of the circulation, in the awake or sedated patient, with real-time feedback on the efficacy of an intervention. In reviewing the literature, we contend that the PAC remains the "gold standard" for hemodynamic monitoring of critically ill cardiac patients. PMID- 28024553 TI - Sustained Performance of a "Physicianless" System of Automated Prehospital STEMI Diagnosis and Catheterization Laboratory Activation. AB - BACKGROUND: Treatment times for primary percutaneous coronary intervention frequently exceed the recommended maximum delay. Automated "physicianless" systems of prehospital cardiac catheterization laboratory (CCL) activation show promise, but have been met with resistance over concerns regarding the potential for false positive and inappropriate activations (IAs). METHODS: From 2010 to 2015, first responders performed electrocardiograms (ECGs) in the field for all patients with a complaint of chest pain or dyspnea. An automated machine diagnosis of "acute myocardial infarction" resulted in immediate CCL activation and direct transfer without transmission or human reinterpretation of the ECG prior to patient arrival. Any activation resulting from a nondiagnostic ECG (no ST-elevation) was deemed an IA, whereas activations resulting from ECG's compatible with ST-elevation myocardial infarction but without angiographic evidence of a coronary event were deemed false positive. In 2012, the referral algorithm was modified to exclude supraventricular tachycardia and left bundle branch block. RESULTS: There were 155 activations in the early cohort (2010-2012; prior to algorithm modification) and 313 in the late cohort (2012-2015). Algorithm modification resulted in a 42% relative decrease in the rate of IAs (12% vs 7%; P < 0.01) without a significant effect on treatment delay. CONCLUSIONS: A combination of prehospital automated ST-elevation myocardial infarction diagnosis and "physicianless" CCL activation is safe and effective in improving treatment delay and these results are sustainable over time. The performance of the referral algorithm in terms of IA and false positive is at least on par with systems that ensure real-time human oversight. PMID- 28024554 TI - Moving Beyond SHOCK: New Paradigms in the Management of Acute Myocardial Infarction Complicated by Cardiogenic Shock. AB - The current management of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with a high rate of mortality, despite widespread regional implementation of rapid transfer to percutaneous coronary intervention-capable centres for prompt infarct-related artery reperfusion. The limited clinical effectiveness of early revascularization in patients with AMI-CS might be secondary to the extent of coronary artery disease in these patients and the risk of incomplete revascularization, as well as the lower probability of achieving successful reperfusion compared with acute myocardial infarction without hemodynamic instability. Also, the severity of end organ injury is a critical determinant of outcome. We review adjunctive therapies to early revascularization in AMI-CS, specifically with a focus on the role of short-term mechanical circulatory support. In selected patients with AMI-CS, there might be a benefit associated with early institution of mechanical circulatory support before revascularization. PMID- 28024555 TI - Innovative Approaches to Arrhythmic Storm: The Growing Role of Interventional Procedures. AB - Arrhythmic or electrical storm (AES) is a clinical condition characterized by 3 or more sustained ventricular arrhythmia episodes leading to appropriate device therapy in a 24-hour period and is associated with very high mortality. The clinical presentation is dramatic, and the management remains challenging. Although pharmacologic treatment and sedation are still part of the initial treatment, newer approaches that include ablation (endocardial, epicardial, or alternative procedures), sympathetic blockade (pharmacologic or by interventional sympathetic denervation), and mechanical hemodynamic support are used increasingly in this setting. In this article we review the current technologies at our disposal clinically to treat AES. PMID- 28024556 TI - Current and Future Status of Extracorporeal Cardiopulmonary Resuscitation for In Hospital Cardiac Arrest. AB - Numerous series, propensity-matched trials, and meta-analyses suggest that appropriate use of extracorporeal cardiopulmonary resuscitation (E-CPR) for in hospital cardiac arrest (IHCA) can be lifesaving. Even with an antecedent cardiopulmonary resuscitation (CPR) duration in excess of 45 minutes, 30-day survival with favourable neurologic outcome using E-CPR is approximately 35%-45%. Survival may be related to age, duration of CPR, or etiology. Associated complications include sepsis, renal failure, limb and neurologic complications, hemorrhage, and thrombosis. However, methodological biases-including small sample size, selection bias, publication bias, and inability to control for confounders in these series prevent definitive conclusions. As such, the 2015 American Heart Association Advanced Cardiac Life Support guidelines update recommended E-CPR as a Level of Evidence IIb recommendation in appropriate cases. The absence of high quality evidence presents an opportunity for clinician/scientists to generate practice-defining data through collaborative investigation and prospective trials. A multidisciplinary dialogue is required to standardize the field and promote multicentre investigation of E-CPR with data sharing and the development of a foundation for high-quality trials. The objectives of this review are to (1) provide an overview of the strengths and limitations of currently available studies investigating the use of E-CPR in patients with IHCA and highlight knowledge gaps; (2) create a framework for the standardization of terminology, clinical practice, data collection, and investigation of E-CPR for patients with IHCA that will help ensure congruence in future work in this area; and (3) propose suggestions to guide future research by the cardiovascular community to advance this important field. PMID- 28024557 TI - Acute Right Ventricle Failure in the Intensive Care Unit: Assessment and Management. AB - Caring for the critically ill patient with acute right ventricle (RV) failure is a diagnostic and management challenge. A thorough understanding of normal RV anatomy and physiology is essential to manage RV failure. Despite the fact that the RV is essentially a volume chamber that ejects into a low-pressure system, the left ventricle contributes significantly to RV function through maintenance of the transseptal gradient (TSG). Preserving systemic mean arterial pressure maintains the TSG and RV perfusion. Various pathological states cause acute RV failure by decreasing the TSG and RV perfusion and/or increasing pulmonary vascular resistance. Early diagnosis prevents rapid progression of RV failure due to the "double hit phenomenon," which is acute intra-abdominal multiple organ system failure as a result of a reduced blood pressure and elevated central venous pressure. Management includes hemodynamic support and reversal of the precipitating cause through optimizing RV rate and rhythm, determining ideal RV filling pressure, reducing RV afterload through nonpharmacologic and pharmacological means, and selecting the appropriate RV inotrope or mechanical support. PMID- 28024558 TI - Detection, Prevention, and Management of Delirium in the Critically Ill Cardiac Patient and Patients Who Undergo Cardiac Procedures. AB - Delirium is an acute change in cognitive functioning, characterized by inattention and associated with alterations in awareness and fluctuation in arousal, disorganized thinking, or altered level that preferentially affects older adult patients. In the acutely ill cardiac patient, the incidence of delirium has been reported as high as 73%, depending on the type and sensitivity of delirium assessment. Cardiac patients with delirium experience higher rates of in-hospital and longer-term mortality and are at risk for progressive cognitive impairment, loss of functional independence, and increased hospitalization costs. As such, delirium represents an undesirable outcome in cardiac patients. Care improvements such as identifying risk of delirium at time of admission or in the preoperative setting; training cardiologist, surgeons, anaesthesiologists and nurses to screen for delirium; implementing delirium prevention programs; and developing standardized delirium treatment protocols might reduce the incidence of delirium and its associated morbidity. PMID- 28024559 TI - Retraction notice to "Piceatannol Suppresses endotoxin-induced ocular inflammation in Rats" [International Immunopharmacology 17/2 (2013) 439 - 446]. PMID- 28024560 TI - When should a time at risk start in efficacy malaria vaccine trials? PMID- 28024561 TI - Efficacy of the GMZ2 malaria vaccine in African children. PMID- 28024562 TI - Efficacy and safety of an inactivated vaccine against Salmonid alphavirus (family Togaviridae) [Vaccine 30 (2012) 5688-5694]. PMID- 28024563 TI - Response to request for Corrigendum to "Efficacy and safety of an inactivated vaccine against Salmonid alphavirus (family Togaviridae)". [Vaccine 30(38) (2012) 5688-5694]. PMID- 28024564 TI - Green reduction of graphene oxide using alanine. AB - There remains a real need for the easy, eco-friendly and scalable preparation method of graphene due to various potential applications. Chemical reduction is the most versatile method for the large scale production of graphene. Here we report the operating conditions for a one-step, economical and green synthesis method for the reduction of graphene oxide using a biomolecule (alanine). Graphene oxide was produced by the oxidation and exfoliation of natural graphite flake with strong oxidants using Hummers method (Hummers and Offeman, 1958), but the method was revised in our laboratory to set up a safe and environmentally friendly route. The reduction of graphene oxide was investigated using alanine at various operating conditions in order to set up optimum conditions (treatment time, temperature and concentration of the reagent). Samples have been characterized by using UV-Visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, Raman spectroscopy and X-ray diffraction analysis. PMID- 28024565 TI - Enhanced adhesion and proliferation of human umbilical vein endothelial cells on conductive PANI-PCL fiber scaffold by electrical stimulation. AB - Recently, electrically conductive biomaterial scaffolds have shown great potential in tissue regeneration. Herein, we reported an electrically conductive polyaniline (PANI) coated poly(epsilon-caprolactone) (PCL) electrospun micron fiber scaffold for the enhanced attachment and proliferation of human umbilical vein endothelial cells (HUVECs) under electrical stimulation conditions. After the O2 plasma treatment toward PCL electrospun fiber, PANI could be polymerized onto their surfaces successfully. The obtained PANI-PCL fibers were characterized by SEM observations, FT-IR spectra, XPS analysis, and water contact angle measurement. The mechanical tests indicated that the fibers could satisfy the practical vascular scaffold requirements. The conductivity of the PANI-PCL fibers was 6.71*10-3S/cm which could provide a conductive in-vitro platform to study the effect of electrical stimulation on HUVECs proliferation. When PANI-coated PCL fibers were compared with PCL fibers, HUVECs exhibited highly enhanced adhesion and viability, especially under electrical stimulation (ES) of 200, 300, and 400mV/cm. Proliferation of HUVECs on PANI-PCL fibers was strongly dependent on electrical stimulation intensity. The results showed new insights into conductive scaffolds for vascular tissue engineering. PMID- 28024566 TI - Electrospun polyurethane membranes for Tissue Engineering applications. AB - Tissue Engineering proposes, among other things, tissue regeneration using scaffolds integrated with biological molecules, growth factors or cells for such regeneration. In this research, polyurethane membranes were prepared using the electrospinning technique in order to obtain membranes to be applied in Tissue Engineering, such as epithelial, drug delivery or cardiac applications. The influence of fibers on the structure and morphology of the membranes was studied using scanning electron microscopy (SEM), the structure was evaluated by Fourier transform infrared spectroscopy (FT-IR), and the thermal stability was analyzed by thermogravimetry analysis (TGA). In vitro cells attachment and proliferation was investigated by SEM, and in vitro cell viability was studied by 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays and Live/Dead(r) assays. It was found that the membranes present an homogeneous morphology, high porosity, high surface area/volume ratio, it was also observed a random fiber network. The thermal analysis showed that the membrane degradation started at 254 degrees C. In vitro evaluation of fibroblasts cells showed that fibroblasts spread over the membrane surface after 24, 48 and 72h of culture. This study supports the investigation of electrospun polyurethane membranes as biocompatible scaffolds for Tissue Engineering applications and provides some guidelines for improved biomaterials with desired properties. PMID- 28024567 TI - Sugar-sensitive dendrimer films as a sacrificial layer for the preparation of freestanding multilayer films. AB - Multilayer thin films composed of poly(vinyl alcohol) (PVA) and phenylboronic acid-bearing poly(amidoamine) dendrimer (PBA-PAMAM) were used as a sacrificial layer for constructing freestanding polyelectrolyte films consisting of poly(styrenesulfonate) (PSS) and poly(allylamine hydrochloride) (PAH). Freestanding (PSS/PAH)15 films were successfully released from substrate by exposing composite (PVA/PBA-PAMAM)n/(PSS/PAH)15 films (n=5 and 10) to sorbitol solutions under mild conditions at pH7.0-9.0. The film release was accelerated in solutions of higher sorbitol concentrations at pH9.0 as well as in solutions with lower concentration of NaCl. The results were rationalized based on the scission of boronate ester bonds between PBA-PAMAM and PVA in the (PVA/PBA-PAMAM)n layer due to a competitive binding of sorbitol to PBA-PAMAM. PMID- 28024568 TI - Study and evaluation of nucleolin-targeted delivery of magnetic PLGA-PEG nanospheres loaded with doxorubicin to C6 glioma cells compared with low nucleolin-expressing L929 cells. AB - Magnetic nanoparticulate systems based on polymeric materials such as poly (lactic-co-glycolic acid) (PLGA1) are being studied for their potential applications in targeted therapy and imaging of malignant tumors. In the current study, superparamagnetic iron oxide nanocrystals (SPIONs2) and doxorubicin (Dox3) were entrapped in the PLGA-based nanoparticles via a modified multiple emulsion solvent evaporation method. Furthermore, SPIO/Dox-NPs4 were conjugated to anti nucleolin AS1411 aptamer (Apt5) and their targeting ability was investigated in high nucleolin-expressing C6 glioma cells compared to low nucleolin-expressing L929 cells. The NPs exhibited a narrow size distribution with mean diameter of ~170nm and an appropriate SPION content (~18% of total polymer weight) with a sufficient saturation magnetization value of 5.9emu/g which is suitable for imaging objectives. They manifested an increased Dox release at pH5.5 compared to pH7.4, with initial burst release (within 24h) followed by sustained release of Dox for 36days. The Apt conjugation to NPs enhanced cellular uptake of Dox in C6 glioma cells compared to L929 cells. Similarly, the Apt-NPs increased the cytotoxicity effect of Dox compared with NPs and Dox solution (f-Dox) alone. In conclusion, the Apt-NPs were found to be a promising delivery system for therapeutic and diagnostic purposes. PMID- 28024569 TI - Strontium hydroxyapatite/chitosan nanohybrid scaffolds with enhanced osteoinductivity for bone tissue engineering. AB - For the clinical application of bone tissue engineering with the combination of biomaterials and mesenchymal stem cells (MSCs), bone scaffolds should possess excellent biocompatibility and osteoinductivity to accelerate the repair of bone defects. Herein, strontium hydroxyapatite [SrHAP, Ca10-xSrx(PO4)6(OH)2]/chitosan (CS) nanohybrid scaffolds were fabricated by a freeze-drying method. The SrHAP nanocrystals with the different x values of 0, 1, 5 and 10 are abbreviated to HAP, Sr1HAP, Sr5HAP and Sr10HAP, respectively. With increasing x values from 0 to 10, the crystal cell volumes and axial lengths of SrHAP become gradually large because of the greater ion radius of Sr2+ than Ca2+, while the crystal sizes of SrHAP decrease from 70.4nm to 46.7nm. The SrHAP/CS nanohybrid scaffolds exhibits three-dimensional (3D) interconnected macropores with pore sizes of 100-400MUm, and the SrHAP nanocrystals are uniformly dispersed within the scaffolds. In vitro cell experiments reveal that all the HAP/CS, Sr1HAP/CS, Sr5HAP/CS and Sr10HAP/CS nanohybrid scaffolds possess excellent cytocompatibility with the favorable adhesion, spreading and proliferation of human bone marrow mesenchymal stem cells (hBMSCs). The Sr5HAP nanocrystals in the scaffolds do not affect the adhesion, spreading of hBMSCs, but they contribute remarkably to cell proliferation and osteogenic differentiation. As compared with the HAP/CS nanohybrid scaffold, the released Sr2+ ions from the SrHAP/CS nanohybrid scaffolds enhance alkaline phosphatase (ALP) activity, extracellular matrix (ECM) mineralization and osteogenic-related COL-1 and ALP expression levels. Especially, the Sr5HAP/CS nanohybrid scaffolds exhibit the best osteoinductivity among four groups because of the synergetic effect between Ca2+ and Sr2+ ions. Hence, the Sr5HAP/CS nanohybrid scaffolds with excellent cytocompatibility and osteogenic property have promising application for bone tissue engineering. PMID- 28024570 TI - Visualization of silver-decorated poly (DL-lactide-co-glycolide) nanoparticles and their efficacy against Staphylococcus epidermidis. AB - Understanding of self-protection activity of the bacteria and interaction with drug substances has significant importance for designing of effective drug delivery system for treatment of biofilm infections. Recently silver nanoparticle has attracted attention as antibacterial substance for drug delivery system because of its high antibacterial activity. Here, efflux of silver nanoparticles obtained from within the prepared silver-decorated poly (DL-lactide-co-glycolide) (Ag PLGA) nanoparticles derived from Staphylococcus epidermidis bacterial cell was successfully visualized using scanning transmission electron microscopy (STEM). We also revealed the interaction between prepared Ag PLGA nanoparticles and the bacterial cells at the nanoscale level using field emission scanning electron microscopy and STEM, after a pretreatment process by an ionic liquid. This finding is significant to understand a fundamental function of S. epidermidis bacterial cells, which is not explored previously. The results suggest that Ag PLGA nanoparticles could demonstrate high efficacy against biofilm infections. PMID- 28024571 TI - Ocular biocompatibility of gelatin microcarriers functionalized with oxidized hyaluronic acid. AB - Given that the presence of aldehyde groups on the oxidized sugar residues may pose toxicity concerns, it is necessary to examine the safety of gelatin microcarriers (GMC) functionalized with oxidized hyaluronic acid (oHA) for potential ophthalmic applications. In this study, the ocular biocompatibility of biopolymer microcarriers was investigated in vitro using primary rabbit corneal cell cultures and in vivo using the anterior chamber of the rabbit eye model. Our results showed that different types of corneal cells including epithelial, stromal, and endothelial cells remain viable and actively proliferate following 2 and 4days of exposure to test materials. In addition, similar interleukin-6 gene expression levels and comet tail lengths were seen in the presence and absence of biopolymer microcarriers, suggesting no cellular inflammation and genotoxicity. After 7 and 14days of intracameral injection in the rabbit eyes, both the GMC samples and their counterparts functionalized with oHA were well tolerated in the ocular anterior chamber as demonstrated by slit-lamp biomicroscopy. Clinical observations including specular microscopic examinations, corneal topography, and corneal thickness measurements also showed that the rabbits bearing biopolymer microcarriers exhibit no signs of corneal edema and astigmatism as well as endothelial damage, indicating the absence of tissue response. It is concluded that the GMC materials functionalized with oHA (oxidation level: 10.4+/-0.9%) are compatible toward corneal cells and ocular anterior segment tissues at a concentration of 10mg/ml. The information about the effect of coupling of aldehyde-functionalized HA to gelatin on in vitro and in vivo biocompatibility of biopolymer composites can be used as further development of corneal stromal cell microcarriers for tissue engineering applications. PMID- 28024572 TI - Topical hydrogel matrix loaded with Simvastatin microparticles for enhanced wound healing activity. AB - A prolonged release drug delivery system was developed by loading Simvastatin chitosan microparticles into poly vinyl alcohol (PVA) hydrogels for enhanced wound healing efficiency. The microparticles prepared by ionic gelation method with varying composition of chitosan and surfactants (Tween 80/Pluronic F-127) were optimized for entrapment efficiency, morphology and drug-polymer interactions. Microparticles prepared with 0.3% between 80 and 0.5:5 chitosan: drug ratio showed maximum entrapment efficiency of 82% with spherical morphology and mild interaction between drug and chitosan. 5% PVA solutions loaded with pure drug and drug loaded microparticles at three different doses (2.5mg, 5mg and 10mg equivalent of drug) were chemically cross linked using gluteraldehyde and HCl. The formulated hydrogels were optimized for swelling, in vitro release behavior and in vivo wound healing effect. Hydrogels containing 2.5mg equivalent dose of Simvastatin microparticles exhibited maximum cumulative percentage drug release of 92% (n=3) at the end of 7days. The in vitro drug release data was supported by the higher swelling index of the low dose hydrogels. The in vivo wound healing study was performed using Wistar rats (n=30, 5 groups with 6 animals in each group) for the formulated hydrogels (at 3 doses) and compared with the untreated animals and the positive control group treated with conventional topical Simvastatin ointment (1%). The wound healing effect was comparable to the in vitro results, wherein the animals treated with low dose hydrogels (replaced every 7days) exhibited considerable reduction in the wound area compared to medium and high dose hydrogels. Statistically significant difference (P<0.05) was observed in the wound area of the animals treated with low dose hydrogels compared to 1% ointment and untreated animals, as estimated by two-way ANOVA. The histopathology images of the different groups of animals also displayed the comparative changes in the wound healing process. Hence, the incorporation of Simvastatin-chitosan microparticles in PVA hydrogels has demonstrated significant wound healing efficiency at optimum dose. PMID- 28024573 TI - L-dopa co-drugs in nanostructured lipid carriers: A comparative study. AB - This paper describes the production and characterization of nanostructured lipid carriers (NLC) containing four different levodopa (LD) co-drugs (PD), named PDA (3,4-diacetyloxy-LD-caffeic acid co-drug), PDB (lipoic acid-dopamine co-drug), PDC (lipoic acid-3,4-diacetoxy-dopamine co-drug), and PDD (dimeric LD co-drug containing an alkyl linker), with therapeutic potential in Parkinson's disease. These co-drugs were produced with the aim of prolonging the pharmacological activity of LD, enhancing its absorption and protecting it from metabolism. These compounds were characterized by very low water solubility that limits their systemic administration. To improve the solubility of these LDPD, NLC were considered. The obtained NLC showed acceptable particle size and a good stability up to two months from preparation. Cryo-TEM morphological characterization revealed no substantial differences between unloaded and co-drug loaded NLC. In vitro studies showed that the LDPD loaded NLC provided a controlled drug release. Moreover, the enhancement of LDPD stability on the hydrolysis catalysed by foetal calf serum (FCS) esterases or in the presence of lipases was evaluated as compared to a labrasol solution. In presence of esterases PDA-NLC and PDD-NLC showed half-lives higher >3-fold as compared to the corresponding aqueous micellar solution. In the case of PDB-NLC it was found that the stability exceeds the 19h. It can be concluded that NLC represent good strategies to encapsulate lipophilic LD co-drugs, although further studies aimed to deeply evaluate anti parkinsonian effects in vivo have to be carried on. PMID- 28024574 TI - miRNA-218-loaded carboxymethyl chitosan - Tocopherol nanoparticle to suppress the proliferation of gastrointestinal stromal tumor growth. AB - Gastrointestinal stromal tumors (GIST) are one of the most common forms of mesenchymal cancers of the gastrointestinal tract. Although chemotherapeutic drugs inhibited the proliferation of GIST, however, sizable proportion of people developed resistance and therefore difficult to treat. In the present study, O carboxymethyl chitosan (OCMC)-tocopherol polymer conjugate was synthesized and formulated into stable polymeric nanoparticles. The main aim of present study was to increase the therapeutic efficacy of miR-218 in GIST. The mean size of nanoparticles was ~110nm with a spherical shape. The miR-218 NP has been shown inhibit the cell proliferation and exhibited a superior cell apoptosis. The miR 218 NP inhibited the cell invasion and promoted the apoptosis of GIST cancer cells. In the present study, we have successfully showed that KIT1 is the target gene of miR-218 as shown by the luciferase reporter assay. These findings collectively suggest the miR-218 loaded nanoparticle by virtue of effective transfection could act as a tumor suppressor miRNA in the treatment of GIST. PMID- 28024575 TI - Effect of Mg content on the thermal stability and mechanical behaviour of PLLA/Mg composites processed by hot extrusion. AB - In the field of bioabsorbable composites for biomedical applications, extrusion has been employed as a method to prepare homogeneous blends of polymeric matrices with bioactive ceramic fillers. In this work, the suitability of processing poly l-lactic acid/Magnesium (PLLA/Mg) composites by hot extrusion has been assessed by a systematic characterization of PLLA/Mg composites containing different amounts of Mg particles up to 7wt%. The results show that extrusion causes a reduction of almost 20% in the viscosity average molecular weight of PLLA, which further decreases with increasing Mg content. Extrusion gave always rise to a homogeneous distribution of Mg particles within the PLLA matrix. This composite processing was not compromised by the degradation of the polymeric matrix because the processing temperature was always below the onset degradation temperature. In the processing conditions employed in the present work, degradation of the composite slightly increases as more Mg is added up to 5wt%, but is very high at 7wt%. This was also evident from the mechanical behaviour, so that Mg particles improved the stiffness and compression strength of neat PLLA until 5wt% of Mg content, which dropped drastically when the material had 7wt% of Mg. The filler strengthening factor decreases with the increment in Mg content. In order to obtain an optimised contribution of Mg particles, a balance between thermal degradation and mechanical resistance of PLLA must be achieved. PMID- 28024576 TI - Resveratrol-loaded folic acid-grafted dextran stearate submicron particles exhibits enhanced antitumor efficacy in non-small cell lung cancers. AB - In this study, we have aimed to prepare folic acid-conjugated dextran stearate (DF) polymeric micelles to target resveratrol in lung cancers. The polymeric micelle was nanosized and exhibited a controlled drug release pattern. The resveratrol (RSV)-loaded dextran stearate (RSV-DF) micelles exhibited an enhanced cellular uptake in A549 cells due to the folic acid-based receptor interactions. We have demonstrated that RSV-DF polymeric micelles retain the cytotoxic and metabolic effects of RSV on A549 cancer cells with potencies similar to that of the free compound. Furthermore, RSV-DF showed an enhanced cellular apoptosis of cancer cells compared to that of free RSV. We have found that apoptosis induced by RSV-DF was associated with the higher expression of p53, caspase-3, and BAX than the free RSV. The higher level of BAX and caspase-3 further indicates the involvement of mitochondria-dependent apoptosis in the anticancer efficacy of formulations. Based on these results, it can be concluded that natural compound like RSV could be an interesting prospect to treat lung cancers and the fact that folic acid-conjugated dextran stearate could be a potential carrier to deliver the drug in the cancer cells. PMID- 28024577 TI - Novel urethane-based polymer for dental applications with decreased monomer leaching. AB - The aim of this study was to synthesize and characterize new multifunctional urethane-methacrylate monomers to be used as the organic matrix in restorative dental composites, and evaluate the main physical-chemical properties of the resulting material. Bis-GMA (bisphenol-A-diglycidylmethacrylate) and GDMA (glycerol dimethacrylate) were modified by reacting the hydroxyl groups with isocyanate groups of urethane-methacrylate precursors to result in the new monomeric systems U-(bis-GMA)-Mod and U-(GDMA)-Mod, U=Urethane and Mod=Modified. The modifications were characterized by FTIR and 1H NMR. The final monomeric synthesized system was used to prepare dental resins and composites. The physical chemical properties were evaluated and compared with those of bis-GMA composites with varying filler contents or unfilled resins. U-(bis-GMA)-Mod and U-(GDMA)-Mod can be used to prepare dental restorative composites, with some foreseeable advantages compared with bis-GMA composites. One significant advantage is that these composites have the potential to be less toxic, once they presented a reduction of 50% in leaching of unreacted monomers extracted by solvent. PMID- 28024578 TI - A novel tantalum-containing bioglass. Part I. Structure and solubility. AB - Bioglasses are employed for surgical augmentation in a range of hard tissue applications. Tantalum is a bioactive and biocompatible transition metal that has been used as an orthopedic medical device. It has a range of biological and physical properties that make its incorporation into ionic form into bioactive glass systems promising for various clinical applications. The work herein reports the characterization and properties of novel tantalum-containing glasses. A series of glasses based on the system 48SiO2-(36-X)ZnO-6CaO-8SrO-2P2O5-XTa2O5 with X varying from 0mol% (TA0) to 0.5mol% (TA2) were synthesized. The addition of small amounts of Ta2O5 did not cause crystallization of the glasses but increasing Ta2O5 content at the expense of ZnO was found to result in an increased number of bridging oxygens (BOs). This, along with the data recorded by differential thermal analysis (DTA) and magic angle spinning-nuclear magnetic resonance (MAS-NMR), confirms that Ta acts as a glass former in this series. Solubility experiments showed that minor changes in the glass structure caused by Ta incorporation (0.5mol%) exhibited greater cumulative % weight loss, pH values and cumulative Zn2+ and Sr2+ ion concentration over a period of 30days of maturation, when compared to Ta2O5-free glasses. The results presented in this article confirm that replacing ZnO with Ta2O5 in silicate glasses results in the formation of stronger bonds within the glass network without any adverse effects on the solubility of the glasses prepared from them. PMID- 28024579 TI - Keratose/poly (vinyl alcohol) blended nanofibers: Fabrication and biocompatibility assessment. AB - Increasing interest in using keratin-based materials for biomedical application has prompted the development of keratin/PVA nanofibers. To date, several kinds of keratins (including wool, feather, and human hair reductive keratins)/PVA blended nanofibers have been fabricated but limited to the in vitro studies. However, few studies focused on the in vivo biocompatibility test of keratin/PVA nanofibers. Herein, the keratose (oxidative keratin)/PVA nanofiber, a novel type of keratin/PVA nanofiber, was fabricated with an electrospinning technique. The obtained nanofibers possess uniform fibrous structure, suitable hydrophilicity and mechanical properties, which could be affected by the mass ratio of keratose to PVA. Furthermore, the biocompatibility tests of keratose/PVA nanofibers have been performed by subcutaneous implantation into SD rats. H&E staining and Masson's trichrome staining revealed that the implants were highly compatible with body tissue, and no acute toxic effects as well as no tissue damage were observed. The implants were fully degraded within four weeks. Beyond this, the analysis of proinflammatory cytokines in rat serum indicated that the implants induced normal immune response and had no immunogenicity. These results demonstrate that keratose/PVA nanofibers have the potential for biomedical applications due to the favorable biocompatibility and biodegradability. PMID- 28024580 TI - Strong and tough nanofibrous hydrogel composites based on biomimetic principles. AB - Mechanically robust hydrogels are required for many tissue engineering applications to serve as cell-supporting structures. Unlike natural tissues, the majority of existing tough hydrogels lack ordered microstructures organized to withstand specific loading conditions. In this work, electrospun gelatin nanofibres, mimicking the collagen network in native tissues, are used to strengthen and resist crack propagation in brittle alginate hydrogels. Aligned nanofibre reinforcement enhances the tensile strength of the hydrogels by up to two orders of magnitude. The nanofibres can be arranged as multilayer laminates with varying orientations, which increases the toughness by two orders of magnitude compared with the unreinforced hydrogel. This work demonstrates a two part strategy of fibre reinforcement and composite lamination in manufacturing strong and tough hydrogels with flexible microstructures to suit different mechanical and biomedical requirements. PMID- 28024581 TI - Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals. AB - To overcome the toxicity of excipient or blank nanoparticles for drug delivery nano-system, the surface modified paclitaxel nanocrystals (PTX-NC) have been developed. PTX-NCs were prepared by nano-precipitation method. The surface of PTX NCs were modified by grafting with apo-transferrin (Tf) or hyaluronic acid (HA). The physical properties of PTX-NCs were evaluated by field emission scanning electron microscope (FE-SEM), zeta-sizer, zeta-potential, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectrometry. In vitro drug release study was performed in phosphate buffered saline (PBS) with or without 0.5% (w/v) Tween 80 for 24h. Cellular uptake was studied at time intervals of 0.5, 1, and 2h in MCF-7 cells, and cell growth inhibition study was performed for 24h using MCF-7 cells (cancer cells), and HaCaT cells (normal cells). Three different types of PTX-NCs with a mean size of 236.0+/-100.6nm (PTX NC), 302.0+/-152.0nm (Tf-PTX-NC) and 339+/-180.6nm (HA-PTX-NC) were successfully prepared. The drug release profiles showed 29.1%/6.9% (PTX (pure)), 40.7%/23.9% (PTX-NC), 50.5%/25.1% (Tf-PTX-NC) and 46.8/24.8% (HA-PTX-NC) in PBS with/without 0.5% (w/v) Tween 80 for 24h, respectively. As per the results, the drug release of PTX-NCs showed the faster release as compared to that of PTX (pure). Surface modified PTX-NCs exhibited higher values for cell permeability than unmodified PTX-NC in the cellular uptake study. Surface modified PTX-NCs inhibited the cell growth approximately to 60% in MCF-7 cells, however effect of surface modified PTX-NCs on normal cell line was lower than the PTX-NC and PTX (pure). In conclusion, biological macromolecules (Tf or HA) surface modified PTX-NC enhanced the cellular uptake and the cell growth inhibition. PMID- 28024582 TI - Evaluation of poly(lactic-co-glycolic acid) and poly(dl-lactide-co-epsilon caprolactone) electrospun fibers for the treatment of HSV-2 infection. AB - More diverse multipurpose prevention technologies are urgently needed to provide localized, topical pre-exposure prophylaxis against sexually transmitted infections (STIs). In this work, we established the foundation for a multipurpose platform, in the form of polymeric electrospun fibers (EFs), to physicochemically treat herpes simplex virus 2 (HSV-2) infection. To initiate this study, we fabricated different formulations of poly(lactic-co-glycolic acid) (PLGA) and poly(dl-lactide-co-epsilon-caprolactone) (PLCL) EFs that encapsulate Acyclovir (ACV), to treat HSV-2 infection in vitro. Our goals were to assess the release and efficacy differences provided by these two different biodegradable polymers, and to determine how differing concentrations of ACV affected fiber efficacy against HSV-2 infection and the safety of each platform in vitro. Each formulation of PLGA and PLCL EFs exhibited high encapsulation efficiency of ACV, sustained-delivery of ACV through one month, and in vitro biocompatibility at the highest doses of EFs tested. Additionally, all EF formulations provided complete and efficacious protection against HSV-2 infection in vitro, regardless of the timeframe of collected fiber eluates tested. This work demonstrates the potential for PLGA and PLCL EFs as delivery platforms against HSV-2, and indicates that these delivery vehicles may be expanded upon to provide protection against other sexually transmitted infections. PMID- 28024583 TI - Reconciling in vivo and in vitro kinetics of the polymorphic transformation in zirconia-toughened alumina for hip joints: I. Phenomenology. AB - Exploitation of the toughening effect induced by polymorphic phase transformation of zirconia in zirconia-toughened alumina (ZTA) requires the composite being properly designed and carefully manufactured. A sound algorithm for predicting phase stability along with strict control over manufacturing steps are required in order to prevent possible in vivo surface degradation or implant fracture. This paper is the first in a series of three monographs, which aim at: (i) statistically comparing the in vitro/in vivo phenomenology of surface metastability for currently marketed ZTA femoral heads; (ii) refining pre existing theoretical models for predicting in vivo zirconia phase metastability via the use of accelerated in vitro ageing experiments; and, (iii) providing a rationale for the mechanism(s) involved with the observed in vivo surface metastability. This initial paper of a series of three, which specifically deals with item (i), shows discrepancies between the levels of polymorphic phase transformation detected in ZTA retrievals and in vitro predictions, and attempts a phenomenological analysis of the reasons behind such discrepancies. Moreover, marked inhomogeneities are also found among as-manufactured components through different years of production. The phenomenology of retrievals' data suggests key roles for both the presence of metallic stain and the initial value of monoclinic volume fraction. PMID- 28024584 TI - A comparative study on the synthesis mechanism, bioactivity and mechanical properties of three silicate bioceramics. AB - In the present study three akermanite (Ca2MgSi2O7), diopside (CaMgSi2O6) and baghdadite (Ca3ZrSi2O9) applicable bioceramics were synthesized via a sol-gel based method. The combination of sol-gel method and the raw materials used in this study presents a new route for the synthesis of the mentioned bioceramics. By the use of thermal analysis, the mechanisms occurred during the synthesis of these bioceramics were investigated. The differences in the structural density and their relation with the degradation rate and mechanical properties of all three ceramics were studied. In vitro bioactivity and apatite formation mechanisms of the samples soaked in the simulated body fluid were considered. The results showed that baghdadite as a Zr-containing material has a more dense structure in comparison with the other ceramics, which leads to a lower degradation rate and also lower bioactivity. There were also main differences between akermanite and diopside as Mg-containing ceramics. Diopside showed a structure with lower porosity content compared to the akermanite samples which resulted in the lower degradation rate and higher compressive strength. PMID- 28024585 TI - Simple and rapid mercury ion selective electrode based on 1-undecanethiol assembled Au substrate and its recognition mechanism. AB - A simple and rapid mercury ion selective electrode based on 1-undecanethiol (1 UDT) assembled Au substrate (Au/1-UDT) has been well constructed. 1-UDT was for the purpose of generating self-assembled monolayer on gold surface to recognize Hg2+ in aqueous solution, which had a working concentration range of 1.0*10-8 1.0*10-4molL-1, with a Nernst response slope of 28.83+/-0.4mV/-pC, a detection limit of 4.5*10-9molL-1, and a good selectivity over the other tested cations. Also, the Au/1-UDT possessed good reproducibility, stability, and short response time. The recovery obtained for the determination of mercury ion in practical tremella samples was in the range of 99.8-103.4%. Combined electrochemical analysis and X-ray photoelectron spectroscopy (XPS) with quantum chemical computation, the probable recognition mechanism of the electrode for selective recognition of Hg2+ has been investigated. The covalent bond formed between mercury and sulfur is stronger than the one between gold and sulfur and thus prevents the adsorption of 1-UDT molecules on the gold surface. The quantum chemical computation with density functional theory further demonstrates that the strong interaction between the mercury atom and the sulfur atom on the gold surface leads to the gold sulfur bond ruptured and the gold mercury metallophilic interaction. PMID- 28024586 TI - Microstructural control of modular peptide release from microporous biphasic calcium phosphate. AB - Drug release from tissue scaffolds is commonly controlled by using coatings and carriers, as well as by varying the binding affinity of molecules being released. This paper considers modulating synthetic peptide incorporation and release through the use of interconnected microporosity in biphasic calcium phosphate (BCP) and identifies the microstructural characteristics important to the release using experiments and a model of relative diffusivity. First, the release of three modular peptides designed to include an osteocalcin-inspired binding sequence based on bone morphogenic protein-2 (BMP-2) was compared and one was selected for further study. Next, the incorporation and release of the peptide from four types of substrates were compared: non-microporous (NMP) substrates had no microporosity; microporous (MP) substrates were either 50% microporous with 5MUm pores (50/5), 60% microporous with 5MUm pores (60/5), or 50% microporous with 50MUm pores (50/50). Results showed that MP substrates incorporated significantly more peptide than NMP ones, but that the three different microporous substrates all incorporated the same total amount of peptide. NMP had a markedly lower release rate compared to each of three of the MP samples, though the initial burst release was the highest. The initial release and the release rate for the 60/5 samples were different from the 50/50, though they were not statistically different from the 50/5. The model indicated that the pore interconnection to pore size ratio, affecting the constriction between pores, had the greatest influence on the calculated relative diffusivity. While the model was consistent with the trends observed experimentally, the quantitative experimental results suggested that to attain an appreciable difference in release characteristics, both pore size and pore fraction should be changed for this system. These results contribute to rational scaffold design by showing that microstructure, specifically microporosity, can be used to modulate drug release. PMID- 28024587 TI - Novel approach towards aligned PCL-Collagen nanofibrous constructs from a benign solvent system. AB - Under several conditions such as severe trauma skeletal muscle lack the ability to reorganize and the loss of muscle function is inevitable. The application of tissue engineered constructs is a promising approach in regenerative therapies for damaged muscular tissue. Therefore, the development of highly aligned scaffolds based on polycaprolactone (PCL) has been studied extensively. Nanofiber scaffolds containing collagen have mostly been fabricated via electrospinning using highly corrosive 1,1,1,3,3,3 hexafluoro-2-propanol (HFIP) so far. In this study, aligned Polycaprolactone-Collagen (PCL-Coll) biocomposite nanofibers were fabricated via electrospinning using environmentally benign diluted acetic acid (AcOH) as solvent. Furthermore, ultrasonic treatment was introduced to enhance the intrinsically weak solubility of PCL in AcOH. AcOH was diluted to an ideal concentration for electrospinning of 90%. The final solutions were spun at various conditions and collected with different collector setups in order to determine ideal processing conditions for the fabrication of highly aligned nanofibers. PMID- 28024588 TI - Surface analysis and shear bond strength of zirconia on resin cements after non thermal plasma treatment and/or primer application for metallic alloys. AB - There is no established protocol for bonding zirconia (Y-TZP) with resin cements. Non-thermal plasma (NTP) may be an alternative for the clinical problems related to adhesion. The purpose of the present study was to characterize the surface of Y-TZP exposed to methane (CH4) NTP or coated with a layer of primer for metal alloys and the association between the two methods and to evaluate the effect of NTP treatment on bond strength between Y-TZP and two resin cements. A total of 235 Y-TZP discs (8*2mm) were distributed into five groups: Co (no surface treatment), Pr (primer), NTP (methane plasma), Pr+NTP and NTP+Pr. The effect of the treatment type on the surface free energy, morphology, topography and chemical composition of the Y-TZP discs was investigated. The discs were cemented to composite resin substrates using Panavia F2.0 or RelyX U200. Shear bond strength (n=10) analyses were performed (1mm/min) before and after thermocycling (5-55 degrees C, 2000cycles) on the bonded specimens. The data were analyzed with one and three-way ANOVAs and Bonferroni tests (alpha=0.05). NTP reduced the surface energy and roughness of the Y-TZP discs. SEM-EDS and XPS analyses showed the presence of the organic thin film, which significantly improved the bond strength results when Rely X U200 was used, whereas the primer treatment was more effective with Panavia F2.0. Thermocycling significantly reduced the bond strength results of the NTP and Pr+NTP groups cemented with Rely X U200 and the Pr and NTP+Pr groups cemented with Panavia F2.0. Nonthermal plasma improves the bond strength between Rely X U200 and Y-TZP and also seems to have water resistant behavior, whereas Panavia F2.0 showed better results when associated with primer. PMID- 28024589 TI - Temperature-responsive PLLA/PNIPAM nanofibers for switchable release. AB - Smart antimicrobial materials with on-demand drug release are highly desired for biomedical applications. Herein, we report about temperature-responsive poly(N isopropylacrylamide) (PNIPAM) nanospheres doped with crystal violet (CV) and incorporated into the poly-l-lactide (PLLA) nanofibers. The nanofibers were prepared by electrospinning, using different initial polymers ratios. The morphology of the nanofibers and polymers distribution in the nanofibers were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The interaction between PNIPAM and PLLA in the nanofibers was studied by Fourier transform infrared spectroscopy (FTIR) and its effect on the PNIPAM phase transition was also investigated. It was shown that by the changing of the environmental temperature across the lower critical solution temperature (LCST) of PNIPAM, the switchable wettability and controlled CV release can be achieved. The temperature-dependent release kinetics of CV from polymer nanofibers was investigated by ultraviolet-visible spectroscopy (UV-Vis). The temperature responsive release of antibacterial CV was also tested for triggering of antibacterial activity, which was examined on Staphylococcus epidermidis (S. epidermidis) and Escherichia coli (E. coli). Thus, the proposed material is promising value for controllable drug-release. PMID- 28024590 TI - A novel electrochemical platform based on carbon nanofibers and tri-metallic nanoparticles of gold, nickel and cobalt for the quantification of ethyl paraben. AB - A composite of carbon nanofibers (CNFs) and tri-metallic nanoparticles of gold, cobalt and nickel were used for the preparation of a novel voltammetric platform. The proposed voltammetric platform was utilized for quantifying ethyl paraben (EPB) in pharmaceutical and cosmetic products. The electrode layers were characterized by utilizing X-ray diffraction method (XRD) and Fourier transform infrared spectroscopy (FTIR). The electrode system, (Au-Ni-Co)NPs-CNFs/GCE, exhibited high catalytic activity and enhanced the electrochemical behaviour of EPB compared with several other electrodes. The proposed composite layer based electrode produced a well-defined oxidation peak at 0.760V. The determination of EPB was carried out by square wave voltammetry (SWV). The electrode produced a linear plot with a concentration range from 1.0*10-9 to 1.0*10-7M at (Au-Ni Co)NPs-CNFs/GCE. The composite material enabled a detection limit of 3.5*10-10M for EPB. Good reproducibility, high precision and excellent accuracy for EPB were obtained at (Au-Ni-Co)NPs-CNFs/GCE. The composite layer based platform was successfully applied for the quantification of EPB in pharmaceutical and cosmetic products. The sensitive quantification of EPB is of great importance for the public health care. Furthermore, data show that EPB binds to DNA via intercalation with a binding constant of 2.51(+/-0.40)*104. PMID- 28024591 TI - Modulation of electrostatic interactions to improve controlled drug delivery from nanogels. AB - The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device. PMID- 28024592 TI - Bi-layered constructs of poly(glycerol-sebacate)-beta-tricalcium phosphate for bone-soft tissue interface applications. AB - This study aims to establish a facile protocol for the preparation of a bi layered poly(glycerol-sebacate) (PGS)/beta-tricalcium phosphate (beta-TCP) construct and to investigate its potential for bone-soft tissue engineering applications. The layered structure was prepared by distributing the ceramic particles within a prepolymer synthesized in a microwave reactor followed by a cross-linking of the final construct in vacuum (<10mbar). The vacuum stage led to the separation of cross-linked elastomer (top) and ceramic (bottom) phases. Results showed that addition of beta-TCP particles to the elastomer matrix after the polymerization led to an increase in compression strength (up to 14+/ 2.3MPa). Tensile strength (sigma), Young's modulus (E), and elongation at break (%) values were calculated as 0.29+/-0.03MPa and 0.21+/-0.03; 0.38+/-0.02 and 1.95+/-0.4; and 240+/-50% and 24+/-2% for PGS and PGS/beta-TCP bi-layered constructs, respectively. Morphology was characterized by using Scanning Electron Microscopy (SEM) and micro-computed tomography (MU-CT). Tomography data revealed an open porosity of 35% for the construct, mostly contributed from the ceramic phase since the elastomer side has no pore. Homogeneous beta-TCP distribution within the elastomeric structure was observed. Cell culture studies confirmed biocompatibility with poor elastomer-side and good bone-side cell attachment. In a further study to investigate the osteogenic properties, the construct were loaded with BMP-2 and/or TGF-beta1. The PGS/beta-TCP bi-layered constructs with improved mechanical and biological properties have the potential to be used in bone-soft tissue interface applications where soft tissue penetration is a problem. PMID- 28024593 TI - Poly(epsilon-caprolactone) (PCL) hybrid sheets containing polymeric micelles: Effects of inner structures on the material properties of the sheets. AB - In the present paper, we clarify the effects that the composition of three types of sheets-the PCL sheet, the PCL-BC (PCL-block copolymer composite) sheet, and the PCL-PM (PCL-polymeric micelle composite) sheet-can have on (1) the sheets' inner structure, (2) the dispersity of hydrophilic compounds in the sheets, (3) the sheets' mechanical properties, and (4) the sheets' degradability. Our results show that (1) the PCL-PM sheet can disperse hydrophilic compounds uniformly, (2) the molecular state (free or micellar) of a co-existing compound (PEG-b-PCL block copolymers) affects the strength and the inner structures of the sheets, whereas the presence of a co-existing compound affects the flexibility of the sheets, and (3) according to our degradation experiment, hard-to-handle PCL having extremely low hydrolysis could serve as materials with a controllable surface morphology by the effective use of co-existing compounds. The results obtained in this paper show that the PCL-CM sheet, with its uniformly dispersed polymeric micelles providing hydrophilic spaces, could be an effective biomaterial platform for incorporating hydrophilic polymers. PMID- 28024594 TI - An injectable poly(caprolactone trifumarate-gelatin microparticles) (PCLTF-GMPs) scaffold for irregular bone defects: Physical and mechanical characteristics. AB - Recently, a modified form of a three-dimension (3D) porous poly(caprolactone trifumarate) (PCLTF) scaffold has been produced using a fabrication technique that involves gelatin microparticles porogen leaching. This poly(caprolactone trifumarate-gelatin microparticles) (PCLTF-GMPs) scaffold has been shown to be biocompatible, more flowable clinically, and has a shorter degradation time as compared to its existing predecessors. In this report, a detailed characterization of this new scaffold was performed by testing its cytocompatibility, analyzing the surface topography, and understanding its thermal, physical and mechanical properties. The result showed that the PCLTF GMPs has no critical cytotoxic effect. To confirm improvement, the surface properties were compared against the older version of PCLTF fabricated using salt porogen leaching. This PCLTF-GMPs scaffold showed no significant difference (unpaired t-test; p>0.05) in mechanical properties before and after gelatin leaching. However, it is mechanically weaker when compared to its predecessors. It has a high biodegradability rate of 16weeks. The pore size produced ranges from 40 to 300MUm, and the RMS roughness is 613.7+/-236.9nm. These characteristics are condusive for osteoblast in-growth, as observed by the extension of filopodia across the macropores. Overall, this newly produced material has good thermal, physical and mechanical properties that complements its biocompatibility and ease of use. PMID- 28024595 TI - Amine bridges grafted mesoporous silica, as a prolonged/controlled drug release system for the enhanced therapeutic effect of short life drugs. AB - Hybrid mesoporous silica SBA-15, with surface incorporated cross-linked long hydrophobic organic bridges was synthesized using stepwise synthesis. The synthesized materials were characterized by elemental analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, nitrogen adsorption, X rays diffraction, thermogravimetry and scanning and transmission electron microscopy. The functionalized material showed highly ordered mesoporous network with a surface area of 629.0m2g-1. The incorporation of long hydrophobic amine chains on silica surface resulted in high drug loading capacity (21% Mass/Mass) and prolonged release of ibuprofen up till 75.5h. The preliminary investigations suggests that the synthesized materials could be proposed as controlled release devices to prolong the therapeutic effect of short life drugs such as ibuprofen to increase its efficacy and to reduce frequent dosage. PMID- 28024596 TI - Laminated electrospun nHA/PHB-composite scaffolds mimicking bone extracellular matrix for bone tissue engineering. AB - Electrospinning is an effective means to generate nano- to micro-scale polymer fibers resembling native extracellular matrix for tissue engineering. However, a major problem of electrospun materials is that limited pore size and porosity may prevent adequate cellular infiltration and tissue ingrowth. In this study, we first prepared thin layers of hydroxyapatite nanoparticle (nHA)/poly hydroxybutyrate (PHB) via electrospinning. We then laminated the nHA/PHB thin layers to obtain a scaffold for cell seeding and bone tissue engineering. The results demonstrated that the laminated scaffold possessed optimized cell-loading capacity. Bone marrow mesenchymal stem cells (MSCs) exhibited better adherence, proliferation and osteogenic phenotypes on nHA/PHB scaffolds than on PHB scaffolds. Thereafter, we seeded MSCs onto nHA/PHB scaffolds to fabricate bone grafts. Histological observation showed osteoid tissue formation throughout the scaffold, with most of the scaffold absorbed in the specimens 2months after implantation, and blood vessels ingrowth into the graft could be observed in the graft. We concluded that electrospun and laminated nanoscaled biocomposite scaffolds hold great therapeutic potential for bone regeneration. PMID- 28024597 TI - Preparation of PEGylated polymeric nanoprobes with aggregation-induced emission feature through the combination of chain transfer free radical polymerization and multicomponent reaction: Self-assembly, characterization and biological imaging applications. AB - Self-assembly of amphiphilic luminescent copolymers is a general route to fabricate fluorescent polymeric microparticles (FPMs). In this work, the FPMs with aggregation-induced emission (AIE) feature were fabricated via the combination of the chain transfer free radical polymerization and "one-pot" multicomponent reaction, which conjugated the aldehyde-containing AIE active dye AIE (CHO-An-CHO) and amino-terminated hydrophilic polymer (ATPPEGMA) using mercaptoacetic acid (MTA) as the "lock" molecule. The structure, chemical compositions, optical properties as well as biological properties of the PPEGMA An-PPEGMA FPMs were characterized and investigated by means of a series of techniques and experiments in detail. We demonstrated the final copolymers showed amphiphilic properties, strong yellow fluorescence and high water dispersibility. Biological evaluation suggested that PPEGMA-An-PPEGMA FPMs possess low cytotoxicity and can be used for cell imaging. More importantly, many other AIE active FPMs are expected to be fabricated using the similar strategy because of the good substrate and monomer applicability of the multicomponent reaction and chain transfer living radical polymerization. Therefore, we could conclude that the strategy described in this work should be of great interest for fabrication of multifunctional AIE active nanoprobes for biomedical applications. PMID- 28024598 TI - Design and characterization of 3D hybrid collagen matrixes as a dermal substitute in skin tissue engineering. AB - The highly interconnected porous dressing material was fabricated with the utilization of novel collagen (COL-SPG) for the efficient healing of the wound. Herein, we report the fabrication of 3D collagen impregnated with bioactive extract (COL-SPG-CPE) to get rid of infection at the wound site. The resultant 3D collagen matrix was characterized physiochemically using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and mechanical property. The dressing substrate possesses the high swelling ability, increase in the porosity, in vitro enzymatic degradability and antibacterial property. The in vitro biocompatibility and fluorescence activity of the collagen scaffold against both NIH 3T3 fibroblast and Human keratinocyte (HaCaT) cell lines assisted in excellent cell adhesion and proliferation over the collagen matrix. Furthermore, the in vivo evaluation of the COL-SPG-CPE 3D sponge exhibited with enhanced collagen synthesis and aids in faster reepithelialization. However, the rate of wound healing was influenced by the expression of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and transforming growth factor (TGF beta) growth factors promotes the collagen synthesis, thereby increases the healing efficiency. Based on the results, COL-SPG-CPE has a potential ability in the remodeling of the wound with the 3D collagen as wound dressing material. PMID- 28024599 TI - Ca-P bioactive coating prepared by combining microwave-hydrothermal and supersonic atmospheric plasma spraying methods. AB - Ca-P based coatings on carbon/carbon composite (C/C) were manufactured via a combined method comprising of microwave-hydrothermal (MH) and supersonic atmospheric plasma spraying (SAPS) techniques. However, a weak mutual interaction between the coating and C/C substrate has been a critical issue for a long time. Herein, we reported a new method for shear strength enhancement without compromising the osteoconductivity and osteoproductivity. Results showed that the inner layer has a strong mechanical interlocking with C/C substrate and the failure mode of outer layer changed from the coating cohesion (within the coating) to adhesive (at the coating/substrate interface) fracture. The shear strength between Ca-P bioactive coating-C/C substrate by MH/SAPS was significantly improved as compared to that prepared by SAPS. The Ca-P bioactive coating exhibited a good bioactivity as evidenced by the formation of a uniform carbonate-apatite layer formed on coating after immersing into stimulated body fluid for a specified period of time. PMID- 28024600 TI - Chondrogenic differentiation of ATDC5-cells under the influence of Mg and Mg alloy degradation. AB - Biodegradable magnesium (Mg)-based materials are a potential alternative to permanent implants for application in children. Nevertheless effects of those materials on growth plate cartilage and chondrogenesis have not been previously evaluated. In vitro differentiation of ATDC5 cells was evaluated under the influence of pure Mg (PMg), Mg with 10wt% of gadolinium (Mg-10Gd) and Mg with 2wt% of silver (Mg-2Ag) degradation products (extracts) and direct cell culture on the materials. Gene expression showed an inhibitory effect on ATDC5 mineralization with the three extracts and a chondrogenic potential of Mg-10Gd. Cells cultured in Mg-10Gd and Mg-2Ag extracts showed the same proliferation and morphology than cells cultured in growth conditions. Mg-10Gd induced an increase in production of ECM and a bigger cell size, similar to the effects found with differentiation conditions. An increased metabolic activity was observed in cells cultured under the influence of Mg-10Gd extracts, indicated by an acidic pH during most of the culture period. After 7days of culture on the materials, ATDC5 growth, distribution and ECM synthesis were higher on Mg-10Gd samples, followed by Mg-2Ag and PMg, which was influenced by the homogeneity and composition of the degradation layer. This study confirmed the tolerance of ATDC5 cells to Mg-based materials and a chondrogenic effect of Mg-10Gd. Further studies in vitro and in vivo are necessary to evaluate cell reactions to those materials, as well as the effects on bone growth and the biocompatibility of the alloying system in the body. PMID- 28024601 TI - Fabrication of calcite blocks from gypsum blocks by compositional transformation based on dissolution-precipitation reactions in sodium carbonate solution. AB - Calcium carbonate (CaCO3) has been used as a bone substitute, and is a precursor for carbonate apatite, which is also a promising bone substitute. However, limited studies have been reported on the fabrication of artificial calcite blocks. In the present study, cylindrical calcite blocks (phi6*3mm) were fabricated by compositional transformation based on dissolution-precipitation reactions using different calcium sulfate blocks as a precursor. In the dissolution-precipitation reactions, both CaSO4.2H2O and CaSO4 transformed into calcite, a polymorph of CaCO3, while maintaining their macroscopic structure when immersed in 1mol/L Na2CO3 solution at 80 degrees C for 1week. The diametral tensile strengths of the calcite blocks formed using CaSO4.2H2O and CaSO4 were 1.0+/-0.3 and 2.3+/-0.7MPa, respectively. The fabrication of calcite blocks using CaSO4.2H2O and CaSO4 proposed in this investigation may be a useful method to produce calcite blocks because of the self-setting ability and high temperature stability of gypsum precursors. PMID- 28024602 TI - Functionalized silk fibroin dressing with topical bioactive insulin release for accelerated chronic wound healing. AB - The healing of chronic wounds remains a key challenge in regenerative medicine. To promote wound healing, a bioactive wound dressing is required. In this study, a functionalized silk fibroin dressing with topical bioactive insulin release was prepared for the treatment of chronic wounds. For this purpose, insulin encapsulated silk fibroin (SF) microparticles were prepared by coaxial electrospraying of aqueous SF solution under mild processing conditions. Insulin was successfully encapsulated in the inner layer of SF microparticles, providing a sustained insulin release for up to 28days. It was found that the insulin released from the microparticles could maintain original molecular conformation. Moreover, the cell migration assay based on human keratinocyte and endothelial cells confirmed that the insulin released from SF microparticles retained its native bioactivity. Furthermore, the insulin-encapsulated microparticles were loaded into a SF sponge, functioned as a bioactive wound dressing, and the in vivo therapeutic effect of the sponge dressing was evaluated on dorsal full thickness wounds of diabetic Sprague-Dawley rats. The results showed that an insulin-functionalized SF dressing accelerated wound closure, collagen deposition and vascularization, thus, significantly promoting wound healing. The insulin functionalized SF dressing provides new treatment options for chronic wounds. PMID- 28024603 TI - Physicochemical characterization of in situ drug-polymer nanocomplex formed between zwitterionic drug and ionomeric material in aqueous solution. AB - Biocompatible polymeric materials with the potential to form functional structures, in association with different therapeutic molecules, in physiological media, represent a great potential for biological and pharmaceutical applications. Therefore, here the formation of a nano-complex between a synthetic cationic polymer and model drug (ampicillin trihydrate) was studied. The formed complex was characterized by size and zeta potential measurements, using dynamic light scattering and capillary electrophoresis. Moreover, the chemical and thermodynamically stability of these complexes were studied. The ionomeric material, here referred as EuCl, was obtained by equimolar reaction between Eudragit E and HCl. The structural characterization was carried out by potentiometric titration, FTIR spectroscopy, and DSC. The effect of pH, time, polymer concentration and ampicillin/polymer molar ratio over the hydrodynamic diameter and zeta potential were established. The results show that EuCl ionomer in aqueous media presents two different populations of nanoparticles; one of this tends to form flocculated aggregates in high pH and concentrations, by acquiring different conformations in solution by changing from a compact to an extended conformation. Moreover, the formation of an in situ interfacial polymer-drug complex was demonstrated, this could slightly reduce the hydrolytic degradation of the drug while affecting its solubility, mainly under acidic conditions. PMID- 28024604 TI - Direct one-pot synthesis of glutathione capped hydrophilic FePt-CdS nanoprobe for efficient bimodal imaging application. AB - One-pot synthesis methods for development of hydrophilic imaging nanoprobes have advantages over multi-pot methods due to their simple procedures, less probability for degradation of efficiency, superior control over growth and morphology, cost effectiveness, improved scope for scale-up synthesis etc. Here, we present a novel one-pot facile synthesis of hydrophilic colloidal bimodal nanoprobe (FePt-CdS) prepared through a seed-mediated nucleation and growth technique. In this facile synthesis of complex nanostructure, glutathione (GSH) was used as the capping agent to render biocompatibility and dispersibility. The microstructure, surface, optical, magnetic, biocompatibility, relaxivity and imaging property of the developed nanoprobe have been studied. The microstructural characterizations reveal average size of the particle as ~9-11nm with bleb shaped morphology. Spectroscopic characterization depicts the development of GSH capped CdS QDs on FePt, surface functionalities and their stability. The magnetic measurements confirm the superparamagnetic property in the developed bimodal nanoprobe. In addition, the GSH capping imparts excellent biocompatibility, water dispersibility, and fluorescence property to the probe. In RAW 264.7 macrophage cells, the bimodal nanoprobes exhibit intense green and red fluorescence. The magnetic resonance imaging (MRI) and fluorescence imaging (FI) study depict high transverse relaxivity and visible range fluorescent property in the synthesized FePt-CdS nanoprobe. Hence, the developed bimodal nanoprobe can be used as a potential candidate in simultaneous FI and MR imaging. PMID- 28024605 TI - Effects of extraction solvents on photoluminescent properties of eysenhardtia polystachia and their potential usage as biomarker. AB - Currently, nanomaterials had been used for several applications; one of them is as bio-markers. These nanomaterials contain fluorescent compounds as effective indicators for imaging and other applications in Biotechnology. In previous studies, we proposed a functionalized nanomaterial-based biomarker from silica and Eysenhardtia Polystachia, a medicinal tree known in Mexico as "palo azul" (Kidneywood). Our previous results showed the feasibility of the nanomaterial obtained as bio-marker. In this article, our purpose is to evaluate the effects of extraction solvents on fluorescence of that biomarker. The photoluminescence (PL) effect was evaluated at different pH (4, 7.4 and 8); four extraction solvents, ethanol, methanol, methanol-ethanol and methanol-ethanol-water were evaluated. A molecular dynamics simulation was performed to recognize molecular interaction between the compounds of the extracts with solvent molecules and to investigate the solvent molecules effect on photoluminescence spectra. The results were also compared with rhodamine 6G and we found that, at physiological pH (7.4), the fluorescent-coated silica nanoparticles obtained were also stable. We found that extraction solvents could be used for obtaining different nanomaterials for specific applications, and also found the best extraction solvent for obtaining EP nanomaterials for health care applications, specifically for imaging techniques. PMID- 28024606 TI - Fabrication of graphene/titanium carbide nanorod arrays for chemical sensor application. AB - Vertically stacked graphene nanosheet/titanium carbide nanorod array/titanium (graphene/TiC nanorod array) wires were fabricated using a direct current arc plasma jet chemical vapor deposition (DC arc plasma jet CVD) method. The graphene/TiC nanorod arrays were characterized by scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction spectroscopy. The TiO2 nanotube array was reduced to the TiC nanorod array, and using those TiC nanorods as nucleation sites, the vertical graphene layer was formed on the TiC nanorod surface. The multi-target response mechanisms of the graphene/TiC nanorod array were investigated for ascorbic acid (AA), dopamine (DA), uric acid (UA), and hydrochlorothiazide (HCTZ). The vertically stacked graphene sheets facilitated the electron transfer and reactant transport with a unique porous surface, high surface area, and high electron transport network of CVD graphene sheets. The TiC nanorod array facilitated the electron transfer and firmly held the graphene layer. Thus, the graphene/TiC nanorod arrays could simultaneously respond to trace biomarkers and antihypertensive drugs. PMID- 28024607 TI - Robust formulation for the design of tissue engineering scaffolds: A comprehensive study on structural anisotropy, viscoelasticity and degradation of 3D scaffolds fabricated with customized desktop robot based rapid prototyping (DRBRP) system. AB - This study investigates the scaffolds' structural anisotropy (i.e. the effect of loading direction), viscoelasticity (i.e. the effect of cross head speed or strain rate), and the influence of simulated physiological environment (PBS solution at 37 degrees C) on the mechanical properties. Besides, the in vitro degradation study has also been performed that evaluates the effect of variation in material and lay-down pattern on the scaffolds' degradation kinetics in terms of mass loss, and change in morphological and mechanical properties. Porous three dimensional (3D) scaffolds of polycarprolactone (PCL) and polycarprolactone polyethylene glycol (PCL-PEG) were developed by laying down the microfilaments directionally layer-by-layer using an in-house built computer-controlled extrusion and deposition process, called desktop robot based rapid prototyping (DRBRP) system. The loading direction, strain rate and physiological environment directly influenced the mechanical properties of the scaffolds. In vitro degradation study demonstrated that both PCL and PCL-PEG scaffolds realized homogeneous hydrolytic degradation via surface erosion resulting in a consistent and predictable mass loss. The linear mass loss caused uniform and linear increase in porosity that accordingly led to the decrease in mechanical properties. The synthetic polymer had the potential to modulate hydrophilicity and/or degradability and consequently, the biomechanical properties of the scaffolds by varying the polymer constituents. PMID- 28024609 TI - Mesenchymal stem cell-laden hybrid scaffold for regenerating subacute tympanic membrane perforation. AB - Tympanic membrane (TM) perforation is one of the most common otology complications. To date, there has not been reported TM regeneration using bioprinted scaffold. The purpose of this study was to evaluate the efficacy and feasibility of bioprinted polycaprolactone/collagen/alginate-mesenchymal stem cell (PCAMSC) scaffolds for the regeneration of subacute TM perforation. Sprague Dawley rats were used in an animal model of subacute TM perforation. In the experimental group (n=7), bioprinted 3D PCAMSC scaffold was placed on the perforation. The control group (n=7) were treated with polycaprolactone/collagen/alginate (PCA) scaffold. Healing time, acoustic mechanical properties, and morphological analysis were performed by otoendoscopy, auditory brainstem response (ABR), single-point laser doppler vibrometer (LDV), optical coherence tomography (OCT), and light microscopic evaluation. The closure of the TM perforation was achieved in 100% of the experimental group vs. 72% of the control group, and this difference was statistically significant (p<0.05). The ABR threshold at all frequencies of the experimental group was recovered to the normal level compared to the control group. TM vibration velocity in the experimental group recovered similar to the normal control level. The difference are very small and they are not statistically significant below 1kHz (p=0.074). By OCT and light microscopic examination, regenerated TM of the experimental group showed thickened fibrous and mucosal layer. In contrast, the control group showed well regenerated but less thickened than experimental group. From these results, the cell-laden PCAMSC scaffold offers a significant advantage in the TM regeneration in a rat subacute TM perforation model. It may offer attractive opportunities in the conservative clinical treatment. PMID- 28024608 TI - Self-aggregation of cationically modified poly(epsilon-caprolactone)2-co poly(ethylene glycol) copolymers: Effect of cationic grafting ligand and poly(epsilon-caprolactone) chain length. AB - Cationic copolymers have been attractive to investigate due to their potential to complexation with anionic drugs and expected to use in the pharmaceutical application. In this study, the modified poly(epsilon-caprolactone)2-co poly(ethylene glycol) copolymers (P(CL)2-PEG) were successfully synthesized by click reaction. The amount of small molecular cationic ligand, propargyltrimethyl ammonium iodide, was varied and grafted onto various mole ratios of P(CL) to PEG. The effects of P(CL) chain length and amount of the grafting cationic ligand on physicochemical properties of polymers and particles were studied. The number average molecular weights of the copolymers grafted with cationic ligand were found ranging between 10,000 and 23,000g/mol as investigated by NMR. From DSC study, the results showed that the grafting ligand affected thermal behaviors of the copolymers by increasing the glass transition temperature and decreasing the melting temperature of the copolymers. Furthermore, these cationic copolymers could self-aggregate with their critical aggregation concentration depending on mole ratios of hydrophilic to hydrophobic portions. The particles containing higher amounts of the cationic ligand tended to aggregate in both acidic and basic pH environment and at high salt concentration. Additionally, particle size, size distribution (PdI), and morphology of self-assembling particles varied depending on P(CL) chain length and the amount of the grafting cationic ligand. The synthesized cationic copolymer showed a capability to encapsulate a high negatively charged drug, enoxaparin, with an encapsulation efficiency of 87%. After drug incorporation, the particles substantially changed in size, shape, PdI, and zeta potential to become more suitable for drug delivery. These cationic copolymers with flexible properties will be the candidate for further development as carriers for the delivery of negatively charged drugs. PMID- 28024610 TI - Alkalescent nanotube films on a titanium-based implant: A novel approach to enhance biocompatibility. AB - The interfacial pH value has a marked effect on cell viability because the pro mineralization activity of osteoblasts increases at alkaline extracellular pH, whereas the pro-resorptive activity of osteoclasts increases under more acidic conditions. To obtain the more favorable alkaline interface, we developed a novel nanotube layer that was incorporated with magnesium oxide on a titanium implant substrate (MgO/NT/Ti) via ethylenediamine tetraacetic acid (EDTA) chelation. This facile immersion-annealing process successfully created a homogeneous magnesium oxide layer with sustained release kinetics and superior hydrophilicity according to the surface characterization and microenvironment measurement. The titania nanotubes on the substrate with an anatase phase exhibited a lower passivation current and a more positive corrosion potential compared with pure titanium, which guaranteed a reasonable corrosion resistance, even when it was wrapped with a magnesium oxide layer. In vitro cell cultures showed that MgO/NT/Ti significantly increased cell proliferation and alkaline phosphatase (ALP) activity. The resulting alkalescent microenvironment created by the MgO layer encouraged the cells to spread into polygonal shapes, accelerated the differentiation stage to osteoblast and induced a higher expression of vinculin. In summary, the incorporated alkalescent microenvironment of MgO/NT/Ti provided a viable approach to stimulate cell proliferation, adhesion, and differentiation and to improve the implant osseointegration. PMID- 28024611 TI - Facile microwave-assisted synthesis of Te-doped hydroxyapatite nanorods and nanosheets and their characterizations for bone cement applications. AB - In this work, the authors have fabricated the nanorods and nanosheets of pure and Te-doped HAp with different Te concentrations (0.04, 0.08, 0.16, 0.24wt%) by microwave-assisted technique at low temperature. The crystallite size, degree of crystallinity and lattice parameters are calculated. FE-SEM study confirms that the fabricated nanostructures are nanorods of diameter about 10nm in undoped and at low concentration of Te doping. However, at and higher concentration, it becomes nanosheets of about 5nm thickness. X-ray diffraction, FT-IR and FT-Raman studies shows that the prepared products are of HAp and Te has been successfully incorporated. From EDX the Ca/P molar ratio of the pure HAp is about 1.740, while this ratio for 0.04, 0.08, 0.16, 0.24 wt% Te doped is about 1.53, 1.678, 1.724, 1.792, respectively. Crystallite size was found to be increased with Te doping from 15nm to 62nm. The value of dielectric constant is found to be enhanced at higher concentrations of Te. The values of linear absorption coefficient were also determined and show that the prepared material with Te doping is more absorbable than pure and will be highly applicable in radiation detection applications. Furthermore, the antimicrobial potential of pure and Te doped HAp was examined against some Gram- negative and positive bacteria and fungi by agar disk diffusion method. The results demonstrated that the antimicrobial activity of Te doped HAp is stronger than that of pure HAp where it exhibited the highest activity against Bacillus subtilis>Candida albicans>Shigella dysenteriae. PMID- 28024612 TI - Fabrication of a three-dimensional beta-tricalcium-phosphate/gelatin containing chitosan-based nanoparticles for sustained release of bone morphogenetic protein 2: Implication for bone tissue engineering. AB - Fabrication of an ideal scaffold having proper composition, physical structure and able to have sustained release of growth factors still is challenging for bone tissue engineering. Current study aimed to design an appropriate three dimensional (3-D) scaffold with suitable physical characteristics, including proper compressive strength, degradation rate, porosity, and able to sustained release of bone morphogenetic protein-2 (BMP2), for bone tissue engineering. A highly porous 3-D beta-tricalcium phosphate (beta-TCP) scaffolds, inside of which two perpendicular canals were created, was fabricated using foam-casting technique. Then, scaffolds were coated with gelatin layer. Next, BMP2-loaded chitosan (CS) nanoparticles were dispersed into collagen hydrogel and filled into the scaffold canals. Physical characteristics of fabricated constructs were evaluated. Moreover, the capability of given construct for bone regeneration has been evaluated in vitro in interaction with human buccal fat pad-derived stem cells (hBFPSCs). The results showed that gelatin-coated TCP scaffold with rhBMP2 delivery system not only could act as a mechanically and biologically compatible framework, but also act as an osteoinductive graft by sustained delivering of rhBMP2 in a therapeutic window for differentiation of hBFPSCs towards the osteoblast lineage. The proposed scaffold model can be suggested for delivering of cells and other growth factors such as vascular endothelial growth factor (VEGF), alone or in combination, for future investigations. PMID- 28024613 TI - Polymer based microspheres of aceclofenac as sustained release parenterals for prolonged anti-inflammatory effect. AB - Poly(lactic-co-glycolic acid) (PLGA) (75:25) and polycaprolactone (PCL) microspheres were fabricated for prolonged release of aceclofenac by parenteral administration. Microspheres encapsulating aceclofenac were designed to release the drug at controlled rate for around one month. Biodegradable microspheres were prepared by solvent emulsification evaporation method in different polymer:drug ratios (1:1, 2:1 and 3:1). After drug loading, PLGA and PCL microspheres showed a controlled size distribution with an average size of 11.75MUm and 3.81MUm respectively and entrapment efficiency in the range of 90+/-0.72% to 91.06+/ 4.01% with PLGA and 83.01+/-2.13% to 90.4+/-2.11% with PCL. Scanning electron microscopy has confirmed good spherical structures of microspheres. The percent yield of biodegradable polymeric microspheres ranged between 30.95+/-10.14% to 92.84+/-3.15% and 47.33+/-4.72% to 80+/-3.60% for PLGA and PCL microspheres respectively. PLGA microspheres followed Higuchi release pattern while Korsmeyer Peppas explained the release pattern of PCL microspheres. Stability studies of microspheres were also carried out by storing the preparations at 2-8 degrees C for 30, 60 and 90days and evaluating them for entrapment efficiency, residual drug content and polymer drug compatability. In-vivo studies showed significant anti-inflammatory activity of microspheres upto 48hours using the carrageenan induced rat paw oedema model. PMID- 28024615 TI - Surface characterization and antibacterial response of silver nanowire arrays supported on laser-treated polyethylene naphthalate. AB - Polymeric biomaterials with antibacterial effects are requisite materials in the fight against hospital-acquired infections. An effective way for constructing a second generation of antibacterials is to exploit the synergic effect of (i) patterning of polymeric materials by a laser, and (ii) deposition of noble metals in their nanostructured forms. With this approach, we prepared highly-ordered periodic structures (ripples) on polyethylene naphthalate (PEN). Subsequent deposition of Ag under the glancing angle of 70 degrees resulted in the formation of self-organized, fully separated Ag nanowire (Ag NW) arrays homogenously distributed on PEN surface. Surface properties of these samples were characterized by AFM and XPS. Vacuum evaporation of Ag at the glancing angle geometry of 70 degrees caused that Ag NWs were formed predominantly from one side of the ripples, near to the top of the ridges. The release of Ag+ ions into physiological solution was studied by ICP-MS. The results of antibacterial tests predetermine these novel structures as promising materials able to fight against a broad spectrum of microorganisms, however, their observed cytotoxicity warns about their applications in the contact with living tissues. PMID- 28024614 TI - Anomalous dissolution behavior of celecoxib in PVP/Isomalt solid dispersions prepared using spray drier. AB - Celecoxib is a COX II inhibitor NSAID which is used for joint pains, rheumatoid arthritis and osteoarthritis, however due to its poor water solubility it shows very low oral bioavailability. Using solid dispersion formulations is one of the most promising strategies to increase solubility of poorly water soluble drugs. The purpose of this study is dissolution enhancement of celecoxib by preparation of solid dispersions via spray drying technique using PVP and Isomalt as hydrophilic carriers. Different ratios of celecoxib, Isomalt and PVP K30 (7:3:0, 5:5:0, 3:7:0, 1:9:0 and 3:5:2, 3:2:5) were prepared from 2% hydroalcoholic solutions (70:30 ethanol:water) using spray drier. Particle size analyzing, saturation solubility, SEM, DSC, FT-IR, XRPD and dissolution studies in 0.25% SDS and 0.04M Na3HPO4 mediums were performed. Stability of samples was also studied after a week and a month storage at 75% humidity condition. The results showed that the saturation solubility of celecoxib in solid dispersion samples is 20-30 folds higher than raw celecoxib. Similar results have been shown for dissolution studies. Solid state analyses showed glass solution state of celecoxib in PVP/Isomalt matrixes. FTIR studies exhibited the formation of hydrogen bonding between celecoxib and PVP in these samples. Spray dried celecoxib (amorphous celecoxib) without usage of carrier showed lower dissolution rate compare to its crystalline state (in 0.25% SDS dissolution medium) whilst these results is vise versa in Na3PO4 dissolution medium. Interestingly almost all samples exhibited higher dissolution rate (in 0.25% SDS) after storage in 75% humidity. XRPD analysis demonstrated the crystallization of amorphous celecoxib after 1month storage. In general using PVP K30 and Isomalt as hydrophilic carriers could increase solubility and dissolution rate of celecoxib in solid dispersion formulations. PMID- 28024616 TI - Development and characterization of a novel porous small intestine submucosa hydroxyapatite scaffold for bone regeneration. AB - The fabricated small intestine submucosa (SIS) - hydroxyapatite (HAp) sponges can act as biomimetic scaffolds to be utilized in tissue engineering and regeneration. Here we developed SIS-HAp sponges and investigated their mechanical, physical and chemical characteristics using scanning electron microscopy, Fourier transformed infrared spectroscopy, uniaxial compression, porosity, and swelling testing techniques. The results demonstrated mechanical properties superior to comparable bone substitutes fabricated with similar methods. SIS-HAp scaffolds possess an interconnected macroporosity, similar to that of trabecular bone, hence presenting a novel biomaterial that may serve as a superior bone substitute and tissue scaffold. PMID- 28024617 TI - Development, characterization and biocompatibility of chondroitin sulfate/poly(vinyl alcohol)/bovine bone powder porous biocomposite. AB - Chondroitin sulfate (ChS), a sulfated glycosaminoglycan, poly(vinyl alcohol) (PVA) and bovine bone powder (BBP) were blended to form a novel eco-friendly biocomposite through cyclic freeze-thawing under mild conditions. The systematic investigation reveals that the content of BBP has a remarkable effect on the pore size, porosity, mechanical and liquid uptake properties and biodegradability. At 10wt.% BBP the biocomposite exhibited enhanced mechanical properties and biodegradability rate as compared to the pristine sample. Further, different properties of the biocomposite can be tailored according to the content of BBP. In vitro assays showed that ChS/PVA-BBP does not exert cytotoxicity against healthy cells. In vivo and ex vivo experiments revealed that ChS/PVA-BBP biocomposites are biocompatibility materials without exert pro-inflammatory responses. The biocomposite was completely biodegraded and bioresorbed after 15days of treatment. Taken together, BBP is a low-cost source of hydroxyapatite and collagen, which are insurance. All these results suggest that the biocomposite designed in this study is a promising biomaterial for potential skin tissue engineering. PMID- 28024618 TI - Comparison between PCL/hydroxyapatite (HA) and PCL/halloysite nanotube (HNT) composite scaffolds prepared by co-extrusion and gas foaming. AB - In this work, three-dimensional poly(caprolactone) (PCL) tissue engineering scaffolds were prepared by co-extrusion and gas foaming. Biocompatible hydroxyapatite (HA) and halloysite nanotubes (HNT) were added to the polymer matrix to enhance the mechanical properties and bioactivity of the composite scaffolds. The effects of HA and HNT on the rheological behavior, microstructure, and mechanical properties of the composite scaffolds were systematically compared. It was found that the HNT improved viscosity more significantly than HA, and reduced the pore size of scaffolds, while the mechanical performance of PCL/HNT scaffolds was higher than PCL/HA scaffolds with the same filler content. Human mesenchymal stem cells (hMSCs) were used as the cell model to compare the biological properties of two composite scaffolds. The results demonstrated that cells could survive on all scaffolds, and showed a more flourishing living state on the composite scaffolds. The cell differentiation for 5% HA and 1% HNT scaffolds were significantly higher than other scaffolds, while the differentiation of 5% HNT scaffolds was lower than that of 1% HNT scaffolds mainly because of the reduced pore size and pore interconnectivity. Therefore, this study suggested that, with proper filler content and control of microstructure through processing, HNT could be a suitable substitute for HA for bone tissue engineering to reduce the cost and improve mechanical performance. PMID- 28024619 TI - Microstructure and mechanical properties of a newly developed low Young's modulus Ti-15Zr-5Cr-2Al biomedical alloy. AB - The Ti-15Zr-5Cr-2Al alloy has been developed and various heat treatments have been investigated to develop new biomedical materials. It is found that the heat treatment conditions strongly affect the phase constitutions and mechanical properties. The as-cast specimen is comprised of beta phase and a small fraction of alpha phase, which is attributed to the suppression of omega phase caused by adding Al. A high yield strength of 1148+/-36MPa and moderate Young's modulus of 96+/-3GPa are obtained in the as-cast specimen. Besides the beta phase and alpha phase, omega phase is also detected in the air cooled and liquid nitrogen quenched specimens, which increases the Young's modulus and lowers the ductility. In contrast, only beta phase is detected after ice water quenching. The ice water quenched specimen exhibits a good combination of mechanical properties with a high microhardness of 302+/-10HV, a large plastic strain of 23+/-2%, a low Young's modulus of 58+/-4GPa, a moderate yield strength of 625+/-32MPa and a high compressive strength of 1880+/-59MPa. Moreover, the elastic energies of the ice water quenched specimen (3.22MJ/m3) and as-cast specimen (6.86MJ/m3) are higher than that of c.p. Ti (1.25MJ/m3). These results demonstrate that as-cast and ice water quenched Ti-15Zr-5Cr-2Al alloys with a superior combination of mechanical properties are potential materials for biomedical applications. PMID- 28024620 TI - Chitosan/banana peel powder nanocomposites for wound dressing application: Preparation and characterization. AB - Wound infection is a serious infection has been spread worldwide. In order to provide fast aid treatments for such infection, banana peels have been incorporated within chitosan as wound dressing. Banana was collected from Egyptian markets peeled and the dried peels were grounded to powder, Incorporated as nano fillers within chitosan matrix with different concentrations (0, 2, 5 and 10wt%). Glycerol was added as plasticizer and crosslinker to the membranes. The banana peel powder (BPP) particle shape and size were determined using Transmission Electron Microscope (TEM), The homogeneity and distribution of BPP in the membranes were investigated through Scanning Electron Microscope (SEM). The interaction between BPP and chitosan was characterized by Fourier Transform Infrared (FTIR). The dielectric properties of chitosan and BPP-chitosan membranes studied via dielectric constant, dielectric loss and conductivity measurements over a frequency range 100Hz up to 100kHz. The curves relating epsilon" and the applied frequency are broad enough reflecting more than one relaxation process. These processes may be attributed to the relaxation processes of the main chain and its related motions. The higher values of epsilon" at low frequency range may be a combination of the losses due to the electrical conductivity and the interfacial polarization process called "Maxwell Wagner Sillers" effect. By increasing BPP content in the sample a pronounced shift towards lower frequency was noticed. This shift may be due to some sort of polymer/filler interaction which causes an increase in the relaxed units and consequently the relaxation time. The addition of BPP decreases the swelling degree of chitosan matrix. The antimicrobial properties of the membranes were done against Gram positive, Gram negative bacteria and yeast. The results showed that chitosan/BPP membranes have a synergistic action with the highest activity at 10wt%. Moreover, Candida albicans was the most sensitive strain recorded for these membranes. PMID- 28024621 TI - A novel fluorescence probe based on triphenylamine Schiff base for bioimaging and responding to pH and Fe3. AB - A novel fluorescence probe 1 based on triphenylamine was synthesized and characterized by NMR, IR, high resolution mass spectrometry and elemental analysis. Its fluorescence was quenched when pH below 2. There was a linear relationship between the fluorescence intensity and pH value ranged from 2 to 7. And its fluorescence emission was reversibility in acidic and alkaline solution. Furthermore, it exhibited remarkable selectivity and high sensitivity to Fe3+ and was able to detect Fe3+ in aqueous solution with low detection limit of 0.511MUM. Job plot showed that the binding stoichiometry of 1 with Fe3+ was 1:1. Further observations of 1H NMR titration suggested that coordination interaction between Fe3+ and nitrogen atom on CN bond promoted the intramolecular charge transfer (ICT) or energy transfer process causing fluorescence quenching. Additionally, 1 was also able to be applied for detecting Fe3+ in living cell and bioimaging. PMID- 28024622 TI - Synthesis of a novel thermo/pH sensitive nanogel based on salep modified graphene oxide for drug release. AB - Nanogels (NGs) are three-dimensional water soluble cross-linked hydrogel materials in the nanoscale size range with a high loading capacity for guest molecules and act as drug carrier systems. In the present work, a new type of thermo/pH sensitive NG comprising salep modified graphene oxide (SMGO) with branched N-isopropylacrylamide (NIPAM) and acrylic acid (AA) was prepared. The SMGO/P(NIPAM-co-AA) NGs exhibited nanoporous structure and spherical particles with diameters about 82nm as characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The samples were also characterized by Fourier transform infrared spectroscopy (FT IR) and thermo gravimetric analysis (TGA) to further confirm about the formation of NGs. Doxorubicin (DOX) loaded SMGO/P(NIPAM-co-AA) NGs showed thermo/pH dependent releasing behavior: slow drug release at neutral pH and lower temperature but increased significantly in acidic pH and higher temperature, without any burst release. In addition, the NGs exhibited no effect on the cell viability in the tested concentration range up to 410MUg/mL and drug release systems enhanced toxicity to HeLa cells when compared to the equivalent dose of the free drug. Overall, our results put forth NGs as potential candidates in the development of a new nanocarrier for anti-cancer drug delivery. PMID- 28024623 TI - Role of magnesium oxide and strontium oxide as modifiers in silicate-based bioactive glasses: Effects on thermal behaviour, mechanical properties and in vitro bioactivity. AB - The composition of a CaO-rich silicate bioglass (BG_Ca-Mix, in mol%: 2.3 Na2O; 2.3 K2O; 45.6 CaO; 2.6 P2O5; 47.2 SiO2) was modified by replacing a fixed 10mol% of CaO with MgO or SrO or fifty-fifty MgO-SrO. The thermal behaviour of the modified glasses was accurately evaluated via differential thermal analysis (DTA), heating microscopy and direct sintering tests. The presence of MgO and/or SrO didn't interfere with the thermal stability of the parent glass, since all the new glasses remained completely amorphous after sintering (treatment performed at 753 degrees C for the glass with MgO; at 750 degrees C with SrO; at 759 degrees C with MgO and SrO). The sintered samples achieved good mechanical properties, with a Young's modulus ranging between 57.9+/-6.7 for the MgO-SrO modified composition and 112.6+/-8.0GPa for the MgO-modified one. If immersed in a simulated body fluid (SBF), the modified glasses after sintering retained the strong apatite forming ability of the parent glass, in spite of the presence of MgO and/or SrO. Moreover, the sintered glasses, tested with MLO-Y4 osteocytes by means of a multi-parametrical approach, showed a good bioactivity in vitro, since neither the glasses nor their extracts caused any negative effect on cell viability or any inhibition on cell growth. The best results were achieved by the MgO-modified glasses, both BGMIX_Mg and BGMIX_MgSr, which were able to exert a strong stimulating effect on the cell growth, thus confirming the beneficial effect of MgO on the glass bioactivity. PMID- 28024624 TI - Fabrication of hydroxyapatite thin films on polyetheretherketone substrates using a sputtering technique. AB - Hydroxyapatite (HA) thin films were coated on a polyetheretherketone (PEEK) substrate using a sputtering technique. A thin titanium (Ti) intermediate layer was formed between the HA and the PEEK surface to improve adhesion of the HA film to the PEEK substrate. The coated films were recrystallized using a hydrothermal treatment to reduce the dissolution of the HA film. The films were then characterized by X-ray diffractometry (XRD), scanning electron microscopy (SEM), and a UV-Vis spectrophotometer. A pull-out test was performed to measure the film to-substrate adhesion strength, and an immersion test was performed in ultra-pure water. In the XRD patterns of the sputtered film with the Ti intermediate layer on the PEEK substrate, small HA peaks and large Ti peaks were observed. After the hydrothermal treatment, the intensity of the HA peaks increased. The transmittance of the HA films with 5 and 10nm Ti intermediate layers was >79% and 68%, respectively, in the visible light wavelength region (400-700nm) after the hydrothermal treatment. The adhesion strength of the hydrothermally treated HA films increased with decreasing thickness of the Ti intermediate layer, and the strength reached 2.7MPa with the 5-nm-thick Ti intermediate layer. In the immersion test, the HA film with a 5-nm-thick Ti intermediate layer without hydrothermal treatment exhibited a released Ti concentration of 42.0+/-2.4ppb. After hydrothermal treatment, the released Ti concentration decreased to 17.3+/ 1.1ppb. PMID- 28024625 TI - Development of simple and sensitive hydrogel based colorimetric sensor array for the real-time quantification of gaseous ammonia. AB - A real-time colorimetric sensor array (CSA) offers the advantages of diversity and accuracy for the quantification of multiple analytes; however, traditional sensors require a complex fabrication process. Therefore, to take full advantage of this sensing platform, we have developed a simple CSA system composed of a polymer, a reducing agent, and different pH indicators. Distinctive color response patterns were classified by extracting the hidden information, (i.e., red, green, and blue (RGB) values) from the indicators. This triple-channel sensing platform is further applied for statistical analysis, to quantify different concentrations of ammonia and other analytes. The sensor array showed a limit of detection of 0.3ppm, which is well below the diagnostic criteria for ammonia concentration in the breath of healthy individuals and of patients with end-stage renal disease. As this sensor would be able to quantify gaseous ammonia in the breath, it is relevant to the point-of-care diagnosis of patients with renal diseases. PMID- 28024626 TI - Self-assembly of aromatic alpha-amino acids into amyloid inspired nano/micro scaled architects. AB - In the pursuit for design of novel bio inspired materials, aromatic alpha-amino acids (phenylalanine, tyrosine, tryptophan and histidine) have been investigated for the generation of well-ordered self-assembled architects such as fibrils, rods, ribbons and twisted nanosheets in varying solvent systems. These nano/micro scaled architects were thoroughly characterized using FE-SEM, confocal microscopy, optical microscopy, 1H NMR, FTIR, XRD and TGA. These self-assembled architects were histologically stained with Congo red and thioflavin T dyes for investigation of amyloid morphology which revealed that the deposited state of ordered assemblies exhibit specific characteristic of amyloid deposits. The self assembly of aromatic amino acids was observed to be driven by non-covalent forces such as pi-pi stacking, van der Waals and electrostatic interaction. PMID- 28024627 TI - Fretting corrosion behavior of nitinol spinal rods in conjunction with titanium pedicle screws. AB - Untypical corrosion damage including erosions combined with the build-up of titanium oxide as a corrosion product on the surface of explanted Nitinol spinal rods in the areas where it was in contact with titanium pedicle screw head is reported. It was suggested that Nitinol rods might have inferior fretting corrosion resistance compared with that made of titanium or CoCr. Fretting corrosion of Nitinol spinal rods with titanium (Ti6Al4V) pedicle screws were tested in-vitro by conducting a series of potentiostatic measurements of the peak to-peak values of fretting corrosion current under bending in a 10% solution of calf serum in PBS. The test included Nitinol rods locked in titanium pedicle screws of different designs. Performance of commercially available titanium (Ti6Al4V) and CoCr spinal rods was also investigated for a comparison. Corrosion damage observed after the in-vitro tests was studied using SEM and EDAX analysis and was compared with patterns on Nitinol rods retrieved 12months after initial surgery. Metal ions level was measured in the test media after in-vitro experiments and in the blood and tissues of the patients who had the rods explanted. The results of this study revealed that Nitinol spinal rods locked in Ti pedicle screws are susceptible to fretting corrosion demonstrating higher fretting corrosion current compared with commercially used Ti6Al4V and CoCr rods. On the surface of Nitinol rods after in-vitro tests and on those retrieved from the patients similar corrosion patterns were observed. Improved resistance to fretting corrosion was observed with Nitinol rods in the in-vitro tests where pedicle screws were used with a stiffer locking mechanism. Since the development of the localized corrosion damage might increase the risk of premature fatigue failure of the rods and result in leaching of Ni ions, it is concluded that Nitinol rods should not be used in conjunction with Ti pedicle screws without special protection especially where the design provides a high degree of mobility to the rods. PMID- 28024628 TI - Polypropyleneimine and polyamidoamine dendrimer mediated enhanced solubilization of bortezomib: Comparison and evaluation of mechanistic aspects by thermodynamics and molecular simulations. AB - Bortezomib (BTZ) is the first proteasome inhibitor approved by the US-FDA is majorly used for the treatment of newly diagnosed and relapsed multiple myeloma including mantle cell lymphoma. BTZ is hydrophobic in nature and is a major cause for its minimal presence as marketed formulations. The present study reports the design, development and characterization of dendrimer based formulation for the improved solubility and effectivity of bortezomib. The study also equally focuses on the mechanistic elucidation of solubilization by two types of dendrimers i.e. fourth generation of poly (amidoamine) dendrimers (G4-PAMAM-NH2) and fifth generation of poly (propylene) imine dendrimers (G5-PPI-NH2). It was observed that aqueous solubility of BTZ was concentration and pH dependent. At 2mM G5-PPI NH2 concentration, the fold increase in bortezomib solubility was 1152.63 times in water, while approximately 3426.69 folds increase in solubility was observed at pH10.0, respectively (p<0.05). The solubility of the drug was increased to a greater extent with G5-PPI-NH2 dendrimers because it has more hydrophobic interior than G4-PAMAM-NH2 dendrimers. The release of BTZ from G5-PPI-NH2 complex was comparatively slower than G4-PAMAM-NH2. The thermodynamic treatment of data proved that dendrimer drug complexes were stable at all pH with values of DeltaG always negative. The experimental findings were also proven by molecular simulation studies and by calculating RMSD and intermolecular hydrogen bonding through Schrodinger software. It was concluded that PPI dendrimers were able to solubilize the drug more effectively than PAMAM dendrimers through electrostatic interactions. PMID- 28024629 TI - Low-temperature thermal reduction of suspended graphene oxide film for electrical sensing of DNA-hybridization. AB - A reduced graphene oxide (RGO) based capacitive real time bio-sensor was presented. Suspended graphene oxide (GO) film was assembled electrophoretically between the source and drain electrodes of a transistor and then reduced by annealing in hydrogen/nitrogen forming gas to optimize the surface functional groups and conductivity. The resonance frequency of the transmission coefficient (S21) of the transistor was observed to shift with deoxyribonucleic acid (DNA) hybridization, with a detecting limit of ~5nM. The advantages of the bio-sensing approach include low-noise frequency output, solution based real time detection and capable of on-chip integration. PMID- 28024630 TI - Kinetics of deposition and stability of pyrocatechol -FeIII coordinated films. AB - Metal coordination between polyphenols and metal cations like Fe3+ allows to produce conformal homogeneous and robust coatings on a vast variety of materials. The deposition kinetics and the stability of the obtained films are however only poorly investigated. In the present article it is shown that rough, granular but pinhole free coatings up to 50nm in thickness can be obtained in a one pot manner using pyrocatechol (Pyr)/Fe3+ mixtures at different stoichiometries (with Fe3+/Pyr ratios equal to 0.55 or 1.10) provided the deposition time is extended up to 24h. More importantly, we show that these films are dissolved upon oxidation of Pyr in cyclic voltammetry experiments. When the films deposited during short durations are rinsed with buffer and subsequently re-exposed to Pyr containing solution, they undergo partial dissolution most probably through a ligand exchange process. Such a dissolution process does not occur anymore in the same conditions, when the deposition time is increased above 5h. All Pyr-Fe3+ based films can be stabilized by a post-deposition of a polyelectrolyte multilayer film based on the alternated adsorption of poly(allylamine hydrochloride) and the sodium salt of poly(styrene sulfonate). The deposition of 5 bilayers of these polyelectrolytes allows suppressing the dissolution of Pyr Fe3+ based films produced for short deposition times. PMID- 28024631 TI - Gold nanoparticle-filled biodegradable photopolymer scaffolds induced muscle remodeling: in vitro and in vivo findings. AB - Therapeutic stem cell transplantation bears the promise of new directions in organ and tissue replacement, but a number of its difficulties and perils are also well known. Our goal was to develop a method of transplantation by which the transplanted cells remain confined to the transplantation site and induce favorable processes. With the help of mask-projection excimer laser stereolithography, 3D hybrid nanoscaffolds were fabricated from biodegradable, photocurable PPF:DEF resin with incorporated gold nanoparticles (Au NPs). The scaffolds were tested in vitro and in vivo in order to find out about their biocompatibility and fitness for our purposes. In vitro, macrophages and mouse autologous adipose stem cells (ASCs) were seeded over the hybrid scaffolds and non-hybrid (with Au NPs) scaffolds for 4days. The hybrid nanocomposite greater stem cell dispension and stem cell adhesion than PPF scaffolds without Au NPs, but such a difference was not seen in the case of macrophages. In vivo, stem cells, scaffoldings and scaffoldings covered in stem cells were transplanted under the back skin of mice. After 14days, blood samples were taken and the affected skin area was excised. Cytokine and chemokine profiling did not indicate elevated immunomediators in the sera of experimental animals. Interestingly, the autologous-stem-cell-seeded hybrid nanocomposite scaffold induced muscle tissue regeneration after experimental wound generation in vivo. We could not observe such stem cell-induced tissue regeneration when no scaffolding was used. We conclude that PPF:DEF resin nanoscaffolds with incorporated gold nanoparticles offer a safe and efficient alternative for the enhancement of local tissue remodeling. The results also support the idea that adipose derived stem cells are an optimal cell type for the purposes of regenerative musculoskeletal tissue engineering. PMID- 28024632 TI - Preliminary study on the corrosion resistance, antibacterial activity and cytotoxicity of selective-laser-melted Ti6Al4V-xCu alloys. AB - In this study, a series of Cu-bearing Ti6Al4V-xCu (x=0, 2, 4, 6wt%) alloys (shorten by Ti6Al4V, 2C, 4C, and 6C, respectively.) with antibacterial function were successfully fabricated by selective laser melting (SLM) technology with mixed spherical powders of Cu and Ti6Al4V for the first time. In order to systematically investigate the effects of Cu content on the microstructure, phase constitution, corrosion resistance, antibacterial properties and cytotoxicity of SLMed Ti6Al4V-xCu alloys, experiments including XRD, SEM-EDS, electrochemical measurements, antibacterial tests and cytotoxicity tests were conducted with comparison to SLMed Ti6Al4V alloy (Ti6Al4V). Microstructural observations revealed that Cu had completely fused into the Ti6Al4V alloy, and presented in the form of Ti2Cu phase at ambient temperature. With Cu content increase, the density of the alloy gradually decreased, and micropores were obviously found in the alloy. Electrochemical measurements showed that corrosion resistance of Cu bearing alloys were stronger than Cu-free alloy. Antibacterial tests demonstrated that 4C and 6C alloys presented strong and stable antibacterial property against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) compared to the Ti6Al4V and 2C alloy. In addition, similar to the Ti6Al4V alloy, the Cu-bearing alloys also exerted good cytocompatibility to the Bone Marrow Stromal Cells (BMSCs) from Sprague Dawley (SD) rats. Based on those results, the preliminary study verified that it was feasible to fabricated antibacterial Ti6Al4V-xCu alloys direct by SLM processing mixed commercial Ti6Al4V and Cu powder. PMID- 28024633 TI - Novel impedimetric dopamine biosensor based on boronic acid functional polythiophene modified electrodes. AB - In this study we report a new, simple and first impedimetric biosensor based on 3 Thienyl boronic acid for dopamine detection. Biosensor electrode preparation is 1min long by simple electro-polymerization of 3-Thienyl boronic acid and copolymer Thiophene P(TBA0.50Th0.50). Strong interaction between dopamine and thin layer of boronic acid has provided bio-sensing electrode high selectivity and stability, linear range of 7.8 to 125MUM, and detection limit of 0.3MUM. Characterization and optimization studies were conducted using electrochemical impedance spectroscopy (EIS) and cyclic voltammogram (CV). In order to test reliability of proposed biosensor real sample application study has been conducted using non-diluted human urine and it has been found that biosensor selectivity and recovery is excellent. As well P(TBA0.50Th0.50) based electrode and dopamine interaction has been proven by single frequency impedance measurements. Biosensors acquired good reproducibility, stability, selectivity and very low interference. PMID- 28024634 TI - Biocompatibility of sol-gel hydroxyapatite-titania composite and bilayer coatings. AB - Titania-Hydroxyapatite (TiO2/HAP) reinforced coatings are proposed to enhance the bioactivity and corrosion resistance of 316L stainless steel (316L SS). Herein, spin- and dip-coating sol-gel processes were investigated to construct two kinds of coatings: TiO2/HAP composite and TiO2/HAP bilayer. Physicochemical characterization highlighted the bioactivity response of the TiO2/HAP composite once incubated in physiological conditions for 7days whereas the TiO2/HAP bilayer showed instability and dissolution. Biological analysis revealed a failure in human stem cells adhesion on TiO2/HAP bilayer whereas on TiO2/HAP composite the presence of polygonal shaped cells, possessing good behaviour attested a good biocompatibility of the composite coating. Finally, TiO2/HAP composite with hardness up to 0.6GPa and elastic modulus up to 18GPa, showed an increased corrosion resistance of 316L SS. In conclusion, the user-friendly sol-gel processes led to bioactive TiO2/HAP composite buildup suitable for biomedical applications. PMID- 28024635 TI - The rational designed graphene oxide-Fe2O3 composites with low cytotoxicity. AB - Novel two-dimensional materials with a layered structure are of special interest for a variety of promising applications. In current research, the nanostructured graphene oxide-Fe2O3 composite (GO-Fe2O3) was firstly obtained via a carefully elaborated approach of vacuum freeze-drying. The scanning electron microscopy (SEM) and transmission electron microscope (TEM) images revealed that alpha-Fe2O3 nanoparticles loaded well on the surfaces of graphene. A series of characterization were performed to further elucidate the as-obtained nanomaterial's physicochemical properties. These results suggested the current route could be further extended to obtain the other kinds of two-dimensional materials based composites. For the sake of extending the potential application of herein achieved graphene composites, its cytotoxicity assessment on HeLa cells was systematically investigated. CCK-8 assay in HeLa cells treated by GO-Fe2O3 showed dose- (1-100MUg/ml) and time- (24-48h) dependent cytotoxicity, which was comparable to that of GO. The excess generation of intracellular reactive oxygen species (ROS) induced by these nanomaterials was responsible for the cytotoxicity. TEM analysis vividly illustrated GO-Fe2O3 internalized by HeLa cells in endomembrane compartments such as lysosomes, and degraded through autophagic pathway. The detrimental biological consequence accompanied by cell internalization was limited. Based on the above results, it expected to render useful information for the development of new and popular strategies to design graphene-based composites, as well as deep insights into the mechanism of graphene-based composites cytotoxicity for further potential application. PMID- 28024636 TI - Spectroscopic and TDDFT investigation on highly selective fluorogenic chemosensor and construction of molecular logic gates. AB - 1,5-Bis(2-fluorene)thiocarbohydrazone (FBTC) was designed and synthesized for selective sensing of fluoride and copper ions. The binding constants of FBTC towards fluoride and copper ions have been calculated using the Benesi-Hildebrand equation, and FBTC has more binding affinity towards copper ion than fluoride ion. The 1H NMR and 13C NMR titration studies strongly support the deprotonation was taken from the N-H protons followed by the formation of hydrogen bond via N H...F. To understand the fluoride ion sensing mechanism, theoretical investigation had been carried out using the density functional theory and time dependent density functional theory. The theoretical data well reproduced the experimental results. The deprotonation process has a moderate transition barrier (481.55kcal/mol). The calculated DeltaE and DeltaG values (-253.92 and 192.41kcal/mol respectively) suggest the feasibility of sensing process. The potential energy curves give the optimized structures of FBTC-F complex in the ground state and excited state, which states the proton transition occurs at the excited state. The excited state proton transition mechanism was further confirmed with natural bond orbital analysis. The reversibility of the sensor was monitored by the alternate addition of F- and Cu2+ ions, which was explained with "Read-Erase-Write-Read" behaviour. The multi-ion detection of sensor used to construct the molecular logic gate, such as AND, OR, NOR and INHIBITION logic gates. PMID- 28024637 TI - Effect of Ca/P ratio on the structural and corrosion properties of biomimetic CaP coatings on ZK60 magnesium alloy. AB - Magnesium and its alloys have attracted much attention as metallic biodegradable implants for their excellent biocompatibility and mechanical properties. However, magnesium has a poor corrosion resistance, causing its rapid degrading in vivo via an electrochemical reaction, which has become a major obstacle to their applications in implants. In this work, CaP coating was successfully coated on the ZK60 magnesium alloys by a simple hydrothermal deposition method. The mechanisms of the hydrothermal reactions of CaP coatings on Mg substrate are described in details. The effect of Ca/P ratio in the hydrothermal solution on the phase composition, microstructure and biodegradation properties of CaP coatings on ZK60 alloys was investigated by varying the Ca/P ratio from 0.83 to 4.18. The morphology of the CaP coating changed significantly with the Ca/P ratio. Biodegradation behavior of the CaP coating magnesium was characterized by anodic polarization and immersion tests in a simulated body fluid. It is revealed that the corrosion resistance of ZK60 magnesium alloy was greatly improved with the biomimetic CaP coatings, and the ZK60 alloy with CaP coating deposited at Ca/P ratio of 1.67 has the best corrosion resistance, which indicates that the CaP coatings are promising for improving the biodegradation properties of Mg based orthopedic implants and devices. PMID- 28024638 TI - Sulfonated chitosan and dopamine based coatings for metallic implants in contact with blood. AB - Thrombosis and calcification constitute the main clinical problems when blood interacting devices are implanted in the body. Coatings with thin polymer layers represent an acknowledged strategy to modulate interactions between the material surface and the blood environment. To ensure the implant success, at short-term the coating should limit platelets adhesion and delay the clot formation, and at long-term it should delay the calcification process. Sulfonated chitosan, if compared to native chitosan, shows the unique ability to reduce proteins adsorption, decrease thrombogenic properties and limit calcification. In this work, stainless steel surfaces, commonly used for cardiovascular applications, were coated with sulfonated chitosan, by using dopamine and PEG as anchors, and the effect of these grafted surfaces on platelet adhesion, clot formation as well as on calcification were investigated. Surface characterization techniques evidenced that the coating formation was successful, and the sulfonated chitosan grafted sample exhibited a higher roughness and hydrophilicity, if compared to native chitosan one. Moreover, sulfonated surface limited platelet activation and the process of clot formation, thus confirming its high biological performances in blood. Calcium deposits were also lower on the sulfonated chitosan sample compared to the chitosan one, thus showing that calcification was minimal in presence of sulfonate groups. In conclusion, this sulfonated-modified surface has potential to be as blood-interacting material. PMID- 28024639 TI - Soluble telmisartan bearing poly (ethylene glycol) conjugated chitosan nanoparticles augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in human cervical cancer cells. AB - Soluble telmisartan and telmisartan were loaded in to poly (ethylene-glycol) grafted chitosan nanoparticles (S-TEL-PEG-CNPs and TEL-PEG-CNPs) for targeting cervical cancer through non-invasive, intravaginal route. The mean particle size of S-TEL-PEG-CNPs was measured to be 23.4+/-5.9-nm significantly (P<0.05) higher than 16.2+/-3.2-nm of TEL-PEG-CNPs. In contrast, the zeta-potential (-21.5+/-4.6 mV) of S-TEL-PEG-CNPs was insignificantly (P>0.05) different from -23.8+/-3.7-mV of TEL-PEG-CNPs. In addition, S-TEL-PEG-CNPs exhibited higher percent mucoadhesiveness (40.2%) in comparison (P<0.05) to 31.4% of TEL-PEG-CNPs, although it was lower than CNPs (100%). S-TEL-PEG-CNPs displayed significantly (P<0.01) higher dissolution of drug, 92.5% in comparison to 31.6% from TEL-PEG CNPs up to 24h. Furthermore, S-TEL-PEG-CNPs exhibited superior cytotoxicity, apoptosis and cellular uptake, analyzed in human cervical cancer, HeLa cells. The IC50 of S-TEL-PEG-CNPs was measured to be 22.3-MUM significantly (P<0.05) lower than 40.1-MUM of TEL-PEG-CNPs. S-TEL-PEG-CNPs induced higher extent of apoptosis (P<0.05) in HeLa cells as compared to TEL-PEG-CNPs, owing to higher diffusion of drug across biological membrane. Finally, quantitative and qualitative cellular uptake assay confirmed the greater endocytosis of S-TEL-PEG-CNPs in HeLa cells due to diffusion, amorphization, hydrophilicity, and submicron size particularly, below 100nm. In conclusion, S-TEL-PEG-CNPs warrant further in vivo tumour regression study to scale up the technology for clinical translation. PMID- 28024640 TI - Graphene oxide directed in-situ synthesis of Prussian blue for non-enzymatic sensing of hydrogen peroxide released from macrophages. AB - A novel electrochemical non-enzymatic hydrogen peroxide (H2O2) sensor has been developed based on Prussian blue (PB) and electrochemically reduced graphene oxide (ERGO). The GO was covalently modified on glassy carbon electrode (GCE), and utilized as a directing platform for in-situ synthesis of electroactive PB. Then the GO was electrochemically treated to reduction form to improve the effective surface area and electroactivity of the sensing interface. The fabrication process was characterized by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX) and atomic force microscopy (AFM). The results showed that the rich oxygen containing groups play a crucial role for the successful synthesis of PB, and the obtained PB layer on the covalently immobilized GO has good stability. Electrochemical sensing assay showed that the modified electrode had tremendous electrocatalytic property for the reduction of H2O2. The steady-state current response increased linearly with H2O2 concentrations from 5MUM to 1mM with a fast response time (less than 3s). The detection limit was estimated to be 0.8MUM. When the sensor was applied for determination of H2O2 released from living cells of macrophages, satisfactory results were achieved. PMID- 28024641 TI - Poly (amido amine) and nano-calcium phosphate bonding agent to remineralize tooth dentin in cyclic artificial saliva/lactic acid. AB - The objectives of this study were to develop a novel method to remineralize dentin lesions, and investigate the remineralization effects of poly (amido amine) (PAMAM) dendrimer plus a bonding agent with nanoparticles of amorphous calcium phosphate (NACP) in a cyclic artificial saliva/lactic acid environment for the first time. Dentin lesions were produced via phosphoric acid. Four groups were tested: (1) dentin control, (2) dentin with PAMAM, (3) dentin with NACP bonding agent, and (4) dentin with PAMAM plus NACP bonding agent. Specimens were treated with cyclic artificial saliva/lactic acid. The remineralized dentin was examined using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), hardness and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). NACP bonding agent yielded a dentin shear bond strength similar to commercial controls (Prime & Bond NT, Dentsply; Scotchbond Multi purpose, 3M) (p>0.1). Increasing NACP in bonding agent from 0 to 40% did not affect bond strength. NACP bonding agent neutralized the acid and released Ca ions with concentrations of 4 to 20mmol/L, and P ions of 2 to 9mmol/L. PAMAM or NACP bonding agent alone achieved slight remineralization. The PAMAM+NACP group achieved the greatest dentin remineralization p<0.05). At 20days, PAMAM+NACP increased the hardness of pre-demineralized dentin to reach the normal dentin hardness (p>0.1). In conclusion, superior remineralization of PAMAM+NACP bonding agent was demonstrated for the first time. PAMAM+NACP bonding agent induced dentin remineralization under acid challenge, when conventional remineralization methods such as PAMAM alone did not work well. The novel PAMAM+NACP bonding agent method is promising to improve the longevity of resin-dentin bonds, inhibit caries, and protect teeth. PMID- 28024642 TI - A theranostic prodrug based on FRET for real-time drug release monitoring in response to biothiols. AB - The clinical applications of tradition prodrug are restricted to a certain extent due to its some defects such as side effects, low selectivity and single function. Herein, we designed a theranostic strategy based on the fluorescence resonance energy transfer (FRET) mechanism. The theranostic prodrug was constructed with an anticancer drug camptothecin (CPT), a cleavable linker based on disulfide bonds (SS) and a fluorophore naphthalimide derivative (NAP). For this drug delivery and reporting system (NAP-SS-CPT), FRET occurs between CPT (energy donor) and NAP (energy receptor); and upon cellular uptake by GSH overexpressing cancer cells, disulfide bonds could be successfully cleaved by the high concentration of GSH, and FRET process was interrupted to achieve dual fluorescence response and specifically release of CPT. The drug delivery system features some favorable properties, like excellent pH-stability, high selectivity and cytotoxicity towards GSH-overexpressing cells and relatively lower cytotoxicity towards normal cells. Fluorescence analysis reveals that NAP-SS-CPT shows a ratiometric fluorescence signal under excitation at 400nm for quantitative detection of GSH. Intracellular fluorescence imaging studies indicate that the prodrug can be efficiently internalized in HeLa cells and used for real-time monitoring of drug release. Moreover, MTT and flow cytometry assay indicate that NAP-SS-CPT exhibits high pro-apoptotic effect for cancer cells. This strategy may provide a new approach for cancer diagnosis and therapy. PMID- 28024643 TI - Facile and innovative method for bioglass surface modification: Optimization studies. AB - In this work it is presented a facile and novel method for modification of bioglass surface based on (Camolten salt bath2+|Naglass+) ion exchange by immersion in molten salt bath. This method allows changing selectively the chemical composition of a surface layer of glass, creating a new and more reactive bioglass in a shell that surrounds the unchanged bulk of the original BG45S5 bioglass (core-shell type system). The modified bioglass conserves the non crystalline structure of BG45S5 bioglass and presents a significant increase of surface reactivity in comparison with BG45S5. Melt-derived bioactive glasses BG45S5 with the nominal composition of 46.1mol% SiO2, 24.4mol% Na2O, 26.9mol% CaO, and 2.6mol% P2O5 have been subjected to ion exchange at 480 degrees C in molten mixture of Ca(NO3)2 and NaNO3 with molar ratio of 70:30 for different time periods ranging from 0 to 60min. The optimization studies by using XRF and XRD showed that ion exchange time of 30min is enough to achieve higher changes on the glass surface without alters its non-crystalline structure. The chemical composition, morphology and structure of BG45S5 and bioglass with modified surface were studied by using several analytical techniques. FTIR and O1s XPS results showed that the modification of glass surface favors the formation of Si ONBO groups at the expense of SiOBOSi bonds. 29Si MAS-NMR studies showed that the connectivity of SiQn species decreases from cross-linked SiQ3 units to chain-like SiQ2 units and finally to depolymerized SiQ1 and SiQ0 units after ion exchange. This result is consistent with the chemical model based on the enrichment with calcium ions of the bioglass surface such that the excess of positive charges is balanced by depolymerization of silicate network. The pH changes in the early steps of reaction of bioactive glasses BG45S5 and BG45Ca30, in deionized water or solutions buffered with HEPES were investigated. BG45Ca30 bioactive glass exhibited a significant increase in the pH during the early steps of the reaction compared to BG45S5. PMID- 28024645 TI - Graphene oxide based nanohybrid proton exchange membranes for fuel cell applications: An overview. AB - In the context of many applications, such as polymer composites, energy-related materials, sensors, 'paper'-like materials, field-effect transistors (FET), and biomedical applications, chemically modified graphene was broadly studied during the last decade, due to its excellent electrical, mechanical, and thermal properties. The presence of reactive oxygen functional groups in the grapheme oxide (GO) responsible for chemical functionalization makes it a good candidate for diversified applications. The main objectives for developing a GO based nanohybrid proton exchange membrane (PEM) include: improved self-humidification (water retention ability), reduced fuel crossover (electro-osmotic drag), improved stabilities (mechanical, thermal, and chemical), enhanced proton conductivity, and processability for the preparation of membrane-electrode assembly. Research carried on this topic may be divided into protocols for covalent grafting of functional groups on GO matrix, preparation of free-standing PEM or choice of suitable polymer matrix, covalent or hydrogen bonding between GO and polymer matrix etc. Herein, we present a brief literature survey on GO based nano-hybrid PEM for fuel cell applications. Different protocols were adopted to produce functionalized GO based materials and prepare their free-standing film or disperse these materials in various polymer matrices with suitable interactions. This review article critically discussed the suitability of these PEMs for fuel cell applications in terms of the dependency of the intrinsic properties of nanohybrid PEMs. Potential applications of these nanohybrid PEMs, and current challenges are also provided along with future guidelines for developing GO based nanohybrid PEMs as promising materials for fuel cell applications. PMID- 28024646 TI - Reply. PMID- 28024644 TI - Impact of macromolecular crowding on structure and properties of pepsin and trypsin. AB - The change of conformation of pepsin and trypsin in absence and presence of a high molecular crowding agent has been characterized using dynamic light scattering (DLS). Structural properties were investigated as a function of chemical denaturant concentrations, the guanidine hydrochloride (GdmCl). The results showed that Ficoll 400, macromolecular crowding, has a strong effect on the chemical denaturation process of these two proteins. The changes of measured hydrodynamic radius are attributed to the enhancement effect of the crowder agent due to the excluded volume effects. The data proved that the large size of a macromolecular crowder plays a crucial role on the conformation of a protein in its unfolded states. The values of interactions Parameter kd of complex particles and a number of proteins npr attached on the Ficoll 400 measured in different GdmCl concentrations. The effect of aging on the structure of complex are studied by small angle light scattering (SALS). PMID- 28024647 TI - Long-term Outcomes of Aflibercept Treatment for Neovascular Age-related Macular Degeneration in a Clinical Setting. PMID- 28024648 TI - Extent of Lymphadenectomy Is Associated With Improved Overall Survival After Esophagectomy With or Without Induction Therapy. AB - BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend sampling 15 or more lymph nodes during esophagectomy. The proportion of patients meeting this guideline is unknown, as is its influence on overall survival (OS). METHODS: Univariate analysis and logistic regression were performed to identify variables associated with sampling 15 or more lymph nodes among patients undergoing esophagectomy in the National Cancer Data Base (NCDB). The NCCN guideline was evaluated in Cox proportional hazards modeling, along with alternative lymph node thresholds. Positive to examined node (PEN) ratios were calculated, and OS was compared using Kaplan-Meier analysis. RESULTS: From 2006 to 2012, only 6,961 of 18,777 (37.1%) patients undergoing esophagectomy had sampling of 15 or more lymph nodes. Variables associated with sampling 15 or more lymph nodes included income greater than or equal to $38,000, procedure performed in an academic facility, and increasing clinical T and N stages. Induction therapy was associated with a decreased likelihood of 15 or more lymph nodes being sampled. The largest decrease in mortality hazard in patients undergoing upfront esophagectomy was detected when 25 lymph nodes or more were sampled (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67-0.89; p < 0.001), whereas for patients undergoing induction therapy, sampling of 10 or 15 or more lymph nodes was associated with optimal survival benefit (HR, 0.81; 95% CI, 0.74 0.90; p < 0.001). PEN ratios of 0 to 0.10 were associated with maximum survival benefit among all patients undergoing esophagectomy. For patients with a PEN ratio of 0, increases in OS were detected with higher lymph node sampling (85.3 months for sampling of 20 or more lymph nodes versus 52.0 months for sampling 1-9 lymph nodes; p < 0.001). CONCLUSIONS: For patients undergoing upfront esophagectomy, there may be an increased survival benefit for examining 20 to 25 lymph nodes, which is higher than current recommendations. However, only a minority of patients are meeting current guidelines. PMID- 28024649 TI - Management Strategy for Patients With Chronic Subclavian Vein Thrombosis. AB - We performed a systematic review to determine best practice for the management of patients with chronic or subacute subclavian vein thrombosis. This condition is best managed with surgical excision of the first rib followed by long-term anticoagulation. Interventional techniques aimed at restoring patency are ineffective beyond 2 weeks postthrombosis. Additional therapeutic options should be made based on the severity of symptoms as well as vein status. Patients with milder symptoms are given decompression surgery followed by anticoagulation whereas patients with more severe symptoms are considered for either a jugular vein transposition or saphenous patch based on the vein characteristics. PMID- 28024650 TI - Recoarctation After Norwood I Procedure for Hypoplastic Left Heart Syndrome: Impact of Patch Material. AB - BACKGROUND: The development of recoarctation after the Norwood I procedure is a known complication in patients with hypoplastic left heart syndrome (HLHS). METHODS: We reviewed data on 194 consecutive patients with HLHS who underwent the Norwood I procedure between 2000 and 2015. All patients who survived until the second stage of the procedure were included. Recoarctation was defined by the need for intervention, either catheter based or surgical. The aim of our study was to determine if the patch material used for the initial arch reconstruction had an influence on the development of recoarctation. RESULTS: The study population consisted of 145 patients. The patch material used for aortic arch reconstruction was either a homograft (n = 87), autologous pericardium (n = 23), equine pericardium (n = 28), or other material (n = 7). Recoarctation was documented in 27 patients (18%) at a median time of 4.3 months (range, 1 to 28 months) after completion of Norwood I. Freedom from recoarctation was 85% +/- 4%, 86% +/- 7%, and 30% +/- 22% at 2 years for homograft, autologous pericardium, and equine pericardium, respectively. Thirty-six percent of patients with equine pericardium exhibited recoarctation, significantly more than homograft patch (p < 0.01) or autologous pericardium (p = 0.002). Treatment for recoarctation was percutaneous balloon angioplasty in 19 patients, stent implantation in 3, and operative enlargement of the aortic arch in 5. On univariate analysis, arch reconstruction with equine pericardium was the only risk factor for recoarctation (hazard ratio, 6.0; 95% confidence interval, 2.6-14; p < 0.01). CONCLUSIONS: The patch material used for reconstruction of the aortic arch in HLHS influences the rate of recoarctation following the Norwood I procedure. Equine pericardium cannot be recommended. PMID- 28024651 TI - Dedicated mass-casualty incident hospitals: An overview. AB - INTRODUCTION: Hospitals worldwide are preparing for mass casualty incidents (MCIs). The Major Incident Hospital in the Netherlands was constructed 25 years ago as a dedicated hospital for situations wherein a sudden increase in medical surge capacity is mandated to handle an MCI. Over the years, more initiatives of dedicated MCIs have arisen. Herein, we compared the MCI facilities from three countries considering the reasons for construction and the functionality. METHODS: Three dedicated mass casualty hospitals and one hospital with a largely fortified structure were compared. The centres were located in the Netherlands, Italy, and Israel. Between August 2015 and January 2016, structured interviews were conducted with representatives of the hospitals' medical operations. The interviews focussed on general information regarding the need for MCI preparedness and scenarios that require preparation, reasons for construction, hospital missions, and the experiences gained including training. RESULTS: All dedicated MCI hospitals had a common policy wherein they sought to create normal work circumstances for the medical staff by using similar equipment and resources as in normal hospitals. The MCI hospitals' designs differed substantially, as determined by the threats faced by the country. In Europe, these hospitals are designed as a solution to surge capacity and function as buffer hospitals offering readily available, short term, additional medical capacity to the local health care system. Israel faces constant threat from long-term conflicts; during the 2006 war, several hospitals suffered direct missile impacts. Therefore, Israeli MCI hospitals are designed to be fortified structures offering shelter against both conventional and non-conventional warfare and intended as a long term solution during siege situations. CONCLUSION: Several dedicated MCI hospitals are presently being constructed. During construction, the local circumstances should be taken into account to determine the functionality for both short-term solutions for surge capacity and as fortified structures to withstand under-siege situations. PMID- 28024652 TI - Patient engagement in research: Are we really worse than orthopaedics? PMID- 28024653 TI - Comparison of 2015 Medicare relative value units for gender-specific procedures: Gynecologic and gynecologic-oncologic versus urologic CPT coding. Has time healed gender-worth? AB - BACKGROUND: In 1992, Congress implemented a relative value unit (RVU) payment system to set reimbursement for all procedures covered by Medicare. In 1997, data supported that a significant gender bias existed in reimbursement for gynecologic compared to urologic procedures. The present study was performed to compare work and total RVU's for gender specific procedures effective January 2015 and to evaluate if time has healed the gender-based RVU worth. METHODS: Using the 2015 CPT codes, we compared work and total RVU's for 50 pairs of gender specific procedures. We also evaluated 2015 procedure related provider compensation. The groups were matched so that the procedures were anatomically similar. We also compared 2015 to 1997 RVU and fee schedules. RESULTS: Evaluation of work RVU's for the paired procedures revealed that in 36 cases (72%), male vs female procedures had a higher wRVU and tRVU. For total fee/reimbursement, 42 (84%) male based procedures were compensated at a higher rate than the paired female procedures. On average, male specific surgeries were reimbursed at an amount that was 27.67% higher for male procedures than for female-specific surgeries. Female procedure based work RVU's have increased minimally from 1997 to 2015. CONCLUSION: Time and effort have trended towards resolution of some gender related procedure worth discrepancies but there are still significant RVU and compensation differences that should be further reviewed and modified as surgical time and effort highly correlate. PMID- 28024654 TI - Coronary Computed Tomography Angiography-Derived Plaque Quantification in Patients With Acute Coronary Syndrome. AB - This study investigated the discriminatory value of quantitative atherosclerotic plaque markers derived from coronary computed tomography angiography (cCTA) in patients with first acute coronary syndrome (ACS) compared with patients with stable coronary artery disease (CAD). Forty patients (56.9 +/- 9.3 years, 55% men) admitted with their first ACS and Framingham risk score-matched controls with stable CAD were retrospectively analyzed. All patients had undergone cCTA followed by invasive coronary angiography. Total plaque volume, calcified and noncalcified plaque volumes, plaque burden (in %), remodeling index, lesion length, presence of napkin-ring sign, segment involvement score, and segment stenosis score were derived from cCTA and compared between both groups on a per lesion and per-patient level. Patients with ACS showed a significant higher number of obstructive CAD and higher values for segment stenosis score, segment involvement score, noncalcified plaque volume, lesion length, and remodeling index than the stable angina group (all p <0.05). On a per-lesion level, culprit lesions had significantly higher values for plaque burden, total plaque volume, noncalcified plaque volume, remodeling index, lesion length, and prevalence of napkin-ring sign in comparison to nonculprit lesions (all p <0.05). On receiver operating characteristics (ROC) analysis, a stepwise model demonstrated incremental discriminatory power for identifying ACS both per-patient (area under the curve 0.92, p <0.0001) as well as per-lesion (area under the curve 0.88, p <0.0001). cCTA-derived culprit plaque markers show discriminatory value both on a per-patient and per-lesion level. A combination of markers added to the Framingham risk score yields the greatest discriminatory ability. PMID- 28024655 TI - Prevalence by Computed Tomographic Angiography of Coronary Plaques in South Asian and White Patients With Type 2 Diabetes Mellitus at Low and High Risk Using Four Cardiovascular Risk Scores (UKPDS, FRS, ASCVD, and JBS3). AB - The aim of this study was to explore the association between various cardiovascular (CV) risk scores and coronary atherosclerotic burden on coronary computed tomography angiography (CTA) in South Asians with type 2 diabetes mellitus and matched whites. Asymptomatic type 2 diabetic South Asians and whites were matched for age, gender, body mass index, hypertension, and hypercholesterolemia. Ten-year CV risk was estimated using different risk scores (United Kingdom Prospective Diabetes Study [UKPDS], Framingham Risk Score [FRS], AtheroSclerotic CardioVascular Disease [ASCVD], and Joint British Societies for the prevention of CVD [JBS3]) and categorized into low- and high-risk groups. The presence of coronary artery calcium (CAC) and obstructive coronary artery disease (CAD; >=50% stenosis) was assessed using coronary CTA. Finally, the relation between coronary atherosclerosis on CTA and the low- and high-risk groups was compared. UKPDS, FRS, and ASCVD showed no differences in estimated CV risk between 159 South Asians and 159 matched whites. JBS3 showed a significant greater absolute CV risk in South Asians (18.4% vs 14.2%, p <0.01). Higher presence of CAC score >0 (69% vs 55%, p <0.05) and obstructive CAD (39% vs 27%, p <0.05) was observed in South Asians. South Asians categorized as high risk, using UKPDS, FRS, and ASCVD, showed more CAC and CAD compared than whites. JBS3 showed no differences. In conclusion, asymptomatic South Asians with type 2 diabetes mellitus more frequently showed CAC and obstructive CAD than matched whites in the population categorized as high-risk patients using UKPDS, FRS, and ASCVD as risk estimators. However, JBS3 seems to correlate best to CAC and CAD in both ethnicity groups compared with the other risk scores. PMID- 28024657 TI - Repeat the Electrocardiogram! AB - A 71-year-old diabetic woman with intermittent chest pain and left bundle branch block was admitted to the hospital for further assessment. A repeat electrocardiogram showed new anterior T-wave inversions concordant with the QRS complexes. Thus, she had myocardial ischemia, and coronary arteriography revealed left main and triple vessel coronary disease. She went for urgent coronary artery bypass operation. PMID- 28024656 TI - Validation of Bleeding Classifications in Coronary Artery Bypass Grafting. AB - Perioperative bleeding is a determinant of poor outcome in patients undergoing coronary artery bypass grafting (CABG), but there is a lack of adequate stratification of its severity. The ability of the European registry of Coronary Artery Bypass Grafting (E-CABG), Universal Definition of Perioperative Bleeding (UDPB), Study of Platelet Inhibition and Patient Outcomes (PLATO), Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7), Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE), and SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation (STEEPLE) bleeding classifications to predict early mortality, stroke, acute kidney injury (AKI) stage 3, and deep sternal wound infection/mediastinitis was investigated in 3,730 patients from the prospective, multicentre E-CABG registry. Increasing grades of the E-CABG, UDPB, PLATO, and CURRENT-OASIS 7 classifications were associated with increasing risks of early mortality, had similar receiver-operating characteristic area under the curves (>0.7), and were predictive also when adjusted for EuroSCORE II. The E CABG and UDPB classifications had satisfactory area under the curves (>0.6) in predicting stroke, AKI stage 3, and deep sternal wound infection/mediastinitis even when adjusted for EuroSCORE II. The PLATO and CURRENT-OASIS 7 classifications had similar predictive ability for stroke and AKI stage 3 as confirmed by multivariate analysis adjusted for EuroSCORE II but showed inferior ability in predicting severe wound infection compared to the E-CABG and UDPB classifications. The STEEPLE and ESSENCE classifications had a poor ability of predicting all these adverse events. Decision curve analysis showed a benefit of the E-CABG bleeding classification over the other classifications in predicting all adverse events. In conclusion, the E-CABG, UDPB, PLATO, and CURRENT-OASIS 7 bleeding classifications have a satisfactory ability in predicting adverse events after CABG. Decision curve analysis showed that the E-CABG bleeding classification had the best predictive performance. PMID- 28024658 TI - The association between socioeconomic status and health-related quality of life among Polish postmenopausal women from urban and rural communities. AB - In recent years, more scholarly attention has been paid to a growing range of geographic characteristics as antecedents of inequalities in women's health and well-being. The purpose of this study was to evaluate differences in health related quality of life between rural and urban Polish postmenopausal women. Using a data set from a reproductive health preventive screening of 660 postmenopausal women aged 48-60 years, inhabitants of Wielkopolska and Lublin provinces, the association of place of residence, socioeconomic status and lifestyle factors with health-related quality of life (the SF-36 instrument) was evaluated using ANCOVA models and multiple logistic regression analysis with backward elimination steps. A consistent rural-to-urban gradient was found in all indices of physical health functioning and well-being but not in vitality, social functioning, emotional role and mental health scales with women in large cities being likely to enjoy the highest and those in villages the lowest quality of life. The rural-urban disparities in health-related quality of life were mediated by women's socioeconomic status. The likelihood of worse physical and mental functioning and well-being was 2-3 times greater for the low socioeconomic status rural women than their counterparts from more affluent urban areas. The educational attainment and employment status were the most powerful independent risk factors for health-related quality of life in both rural and urban women. Better understanding of the role of socioeconomic status that acts as a mediator in the association between area of residence and health-related quality of life may be useful in developing public health policies on health inequalities among women at midlife. PMID- 28024659 TI - Diagnosis of Complex Pulley Ruptures Using Ultrasound in Cadaver Models. AB - Pulley ruptures are common in climbing athletes. The purposes of this study were to determine the specific positioning of each pulley with regards to the joint, and to evaluate the ultrasound diagnostics of various pulley rupture combinations. For this, 34 cadaver fingers were analyzed via ultrasound, the results of which were compared to anatomic measurements. Different pulley ruptures were then simulated and evaluated using ultrasound in standardized dynamic forced flexion. Visualization of the A2 and A4 pulleys was achieved 100% of the time, while the A3 pulley was visible in 74% of cases. Similarly, injuries to the A2 and A4 pulleys were readily observable, while A3 pulley injuries were more challenging to identify (sensitivity of 0.2 for singular A3 pulley, 0.5 for A2/A4 pulley and 0.33 for A3/A4 pulley ruptures). Receiver operating characteristic analysis was used to evaluate the optimal tendon-bone distance for pulley rupture diagnosis, a threshold which was determined to be 1.9 mm for A2 pulley ruptures and 1.85 for A4 pulley ruptures. This study was the first to carry out a cadaver ultrasound examination of a wide variety of pulley ruptures. Ultrasound is a highly accurate tool for visualizing the A2 and A4 pulleys in a cadaver model. This method of pathology diagnosis was determined to be suitable for injuries to the A2 and A4 pulleys, but inadequate for A3 pulley injuries. PMID- 28024660 TI - A Novel Approach to Detecting Postpartum Hemorrhage Using Contrast-Enhanced Ultrasound. AB - The aim of this study was to estimate the efficacy of contrast-enhanced ultrasound (CEUS) in detecting postpartum hemorrhage (PPH) after cesarean section. This is the first study of CEUS in obstetric hemorrhage. A total of 37 patients, operated at Nagoya University Hospital, underwent CEUS. We evaluated the findings of CEUS, which were qualitatively defined as positive when pooling or leakage of contrast agent was observed in the uterine cavity, by measuring the amount of bleeding during the first 4 h after cesarean section. The time intensity curve patterns of leaked contrast agents were also analyzed for quantitative prediction of the amount of blood loss. Significant differences between the excessive hemorrhage (N = 7) and non-excessive hemorrhage groups (N = 30) were noted in the occurrence of positive CEUS (p = 0.011). Additionally, mean postpartum blood loss markedly increased in patients with a positive CEUS (p = 0.002). From a quantitative perspective, the time until leakage of contrast agents was detected correlated with the amount of bleeding, but the other characteristics of the time-intensity curve pattern did not provide valuable information. In conclusion, CEUS, which enables bedside assessment and rapid diagnosis, is a promising strategy for the detection of PPH. PMID- 28024661 TI - The suspicious relation between syncope and echocardiographic abnormalities. PMID- 28024662 TI - Quantifying the competing relationship between adduction range of motion and baseplate micromotion with lateralization of reverse total shoulder arthroplasty. AB - Lateralizing the center of rotation (COR) of reverse total shoulder arthroplasty (rTSA) could improve functional outcomes and mitigate scapular notching, a commonly occurring complication of the procedure. However, resulting increases in torque at the bone-implant interface may negatively affect initial fixation of the glenoid-side component, especially if only two fixation screws can be placed. Shoulder-specific finite element (FE) models of four fresh-frozen cadaveric shoulders were constructed. Scapular geometry and material property distributions were derived from CT data. Generic baseplates with two and four fixation screws were virtually implanted, after which superiorly-oriented shear loads, accompanied by a compressive load, were applied incrementally further from the glenoid surface to simulate lateralization of the COR. Relationships between lateralization, adduction range of motion (ROM), the number of fixation screws and micromotion of the baseplate (initial implant fixation) were characterized. Lateralization significantly increases micromotion (p=0.015) and adduction ROM (p=0.001). Using two, versus four, baseplate fixation screws significantly increases micromotion (p=0.008). The effect of lateralization and the number of screws on adduction ROM and baseplate fixation is variable on a shoulder-specific basis. Trade-offs exist between functional outcomes, namely adduction ROM, and initial implant fixation and the negative effect of lateralization on implant fixation is amplified when only two fixation screws are used. The possibility of lateralizing the COR in order to improve functional outcomes of the procedure should be considered on a patient-specific basis accounting for factors such as availability and quality of bone stock. PMID- 28024663 TI - T4 Syndrome: A Scoping Review of the Literature. AB - OBJECTIVE: The purpose of this scoping review was to identify any available evidence regarding T4 syndrome. METHODS: Databases were searched from inception through October 2015 and included PubMed, CINAHL, PEDro, Google Scholar, Osteomed DR; Index to Chiropractic Literature, PROSPERO, and Chiroaccess. All studies with information about T4 syndrome that were published in a peer-reviewed journal or textbook were included. The information was organized in the format of the International Classification of Functioning, Disability, and Health. Studies were ranked using Sackett's levels of evidence. RESULTS: Eight articles met the inclusion criteria. Studied areas included theoretical pathophysiology and symptom etiology, diagnosis, symptoms, treatment, and outcomes of T4 syndrome. The methodological quality of included studies was low. CONCLUSION: T4 syndrome is a diagnosis of exclusion that appears to be rare. It has been treated conservatively in the literature using mobilization and exercise. There is no high-quality evidence published about T4 syndrome, and we caution clinicians when considering it as a primary means to determine patient care. PMID- 28024664 TI - Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study. AB - BACKGROUND/PURPOSE: Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential drawbacks following long-term use of opioids. METHODS: An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. RESULTS: For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ~50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients (9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine. CONCLUSION: This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose. PMID- 28024665 TI - When, Where, and How to Use Ultrasonography in Patients With Chronic Obstructive Pulmonar Disease. PMID- 28024666 TI - Strongyloides Stercoralis Infection With a Diffuse Miliary Pattern. PMID- 28024667 TI - Aspergillus Fumigatus Empyema. PMID- 28024668 TI - Potential risks of maternal administration of Mucophylline on the pups of albino rats during lactation. AB - The present study was undertaken to evaluate the potential risks of the mucolytic and broncholytic drug, Theophylline derivatives (Mucophylline) maternally administered on the pups. The nursing rats orally administered from 1st postpartum day (PPD) to 21th PPD with two different doses 30.83mg/kg (low dose) and 66.61mg/kg (Human equivalent dose (HED)). On the 21th PPD, the postnatal developmental signs, skeletal malformation and the histopathology of neonatal liver, kidney and brain were examined. Our results showed that Mucophylline induced a significant reduction in the neonatal weight and length, delayed, weak and incomplete ossification, wavy ribs and the neonatal liver revealed histopathological changes, pyknotic hepatocytes, cytoplasmic vacuolization, dilated sinusoid and necrotic area. Kidney revealed alternation changes, enlargement of the glomerulus, renal tubules degeneration and lymphatic infiltration. Brain (cerebral cortex and cerebellum) showed neurodegenerative changes, vacuolization of neuropil, congested and dilated blood vessel and dark stain neurons. Our results showed that the activities of non-enzymatic (GSH) and enzymatic (GST, CAT) antioxidants were insignificantly decrease in both neonatal brain and liver tissues of rats administered with 30.83mg/kg and 61.66mg/kg of Mucophylline and insignificant increase in MDA levels in both neonatal brain and liver tissues. However, significant reduction (P<=0.05) in the content of GR was recorded in neonatal brain tissue of rats administered with 30.83mg/kg and 61.66mg/kg of Mucophylline during lactation period in comparison with control. These support and proof the potential risks of the maternal administration of Mucophylline on pups. PMID- 28024669 TI - The 'Antibiotic Apocalypse' - Scaremongering or Scientific Reporting? AB - Antimicrobial resistance is dominating scientific media. We are warned of an impending 'antibiotic apocalypse', where mankind faces its biggest threat, untreatable microbes. However, the world is not ending. Scientists are responding to the threat; new knowledge and chemotherapeutics are being created to safeguard our future. The future is bright, not gloomy. PMID- 28024670 TI - Sexuality and older people: a neglected issue. PMID- 28024671 TI - Reform of abortion law in Uruguay: context, process and lessons learned. AB - In October 2012, a new law was approved in Uruguay that allows abortion on demand during the first 12 weeks of pregnancy, 14 weeks in the case of rape, and without a time limit when the woman's health is at risk or in the case of foetal anomalies. This paper analyses this legal reform. It is based on 27 individual and group interviews with key informants, and on review of primary documents and the literature. The factors explaining the reform include: secular values in society, favourable public opinion, a persistent feminist movement, effective coalition building, particular party politics, and a vocal public health sector. The content of the new law reflects the tensions between a feminist perspective of women's rights and public health arguments that stop short of fully recognizing women's autonomy. The Uruguayan reform shows that, even in Latin America, abortion can be addressed politically without electoral cost to the parties that promote it. On the other hand, the prevailing public health rationale and conditionalities built into the law during the negotiation process resulted in a law that cannot be interpreted as a full recognition of women's rights, but rather as a modified protectionist approach that circumscribes women's autonomy. PMID- 28024673 TI - Health status and years of sexually active life among older men and women in South Africa. AB - Little is known about sexual activity in old age, particularly in Africa. The objective of this paper is to estimate years of sexually active life for older men and women, and examine the association between sexual activity and self-rated health status. Data were extracted from two large cross sectional HIV household surveys conducted in 2005 and 2012 in South Africa. The Sullivan method was used to estimate sexually active life expectancy, whilst logistic regression was used to assess associations with sexual activity. Sexually active life expectancy was higher among men across all the age groups in both surveys. At age 50, the sexually active life expectancy for men was double that for women - 2005 (12.6 vs. 5.9 years), 2012 (12.7 vs. 7.2 years). Self-rated health was significantly associated with sexual activity in men (adjusted Odds Ratio (aOR) 1.56; 95% CI 1.11-2.19; p<0.001). Among older women, moderate exercise was associated with being sexual active, while HIV infection was significantly associated with reduced sexual activity. The presence of chronic conditions was also significantly associated with reduced sexual activity among men. The results confirm that older adults are sexually active, and that factors associated with sexual activity are different for men and women. HIV among women and chronic conditions among men are areas of intervention to improve sexual activity in older people. PMID- 28024672 TI - Factors associated with caesarean sections in Phnom Penh, Cambodia. AB - C-sections are an increasingly performed medical practice which can save lives but may also lead to major complications. Through a mixed methods study conducted in 2015 in Cambodia, we aimed to analyze the reasons for requesting a c-section and to explore factors that are associated with c-sections. 60% of the women in the cohort who gave birth by c-section reported having requested it. Through 31 in-depth interviews, we determined the reasons given by women for requesting a c section before and during labour. Before labour, reasons for requesting a c section were: choosing the delivery date; bringing luck and joy to the family; protecting the genitals, and the belief that c-section is safer for the mother and for the baby. Reasons given during labour were fear, pain, and having no more energy. We also observed two major factors driving the women's request for a c section: family support for requesting a c-section, and the over-usage of ultrasound examinations. Our multivariate analysis of the interviews of 143 women before and after delivery showed that having a previous c-section, delivering in a private facility, being older than median at the time of sexual debut, residing outside of Phnom Penh and having the delivery costs covered by the family were all factors independently and significantly associated with a higher chance of c section delivery. We conclude that women are not well informed to give consent for c-delivery, and that their request is often affected by false belief and poor knowledge. PMID- 28024674 TI - Acknowledging sexual bereavement: a path out of disenfranchised grief. AB - Despite increasing awareness of the importance of sexuality for older adults, research and popular literature rarely acknowledge what we term "sexual bereavement" - mourning the loss of sexual intimacy when predeceased. The reluctance to acknowledge sexual bereavement may create "disenfranchised grief" leaving the bereaved unsupported in coping with this aspect of mourning. This preliminary study focuses on women in the United States and sought to determine whether they anticipate missing sex if predeceased, whether they would want to talk about this loss, and identified factors associated with communicating about sexual bereavement. Findings from our survey of 104 women, 55 years and older, most of whom were heterosexual, revealed that a large majority (72%) anticipates missing sex with their partner and 67% would want to initiate a discussion about this. An even higher percentage would want friends to initiate the topic. Yet, 57% of participants report it would not occur to them to initiate a discussion with a widowed friend about the friend's loss. Disenfranchised grief can have negative emotional and physical consequences. This paper suggests a role for friends and professionals in addressing this neglected issue. PMID- 28024675 TI - Socio-cultural influences upon knowledge of sexually transmitted infections: a qualitative study with heterosexual middle-aged adults in Scotland. AB - There has been a recent global increase in sexually transmitted infections (STIs) including HIV among adults aged over 45. Limited evidence exists regarding middle aged adults' knowledge of STIs other than HIV. This qualitative study sought to understand middle-aged adults' knowledge of STIs within a socio-cultural context. Individual interviews, based on a life-course approach, were conducted with 31 recently sexually active heterosexual men and women. Participants were aged between 45 and 65 and of mixed relationship status (14 were single, 17 in a relationship). Thematic analysis identified four key findings, including: "engagement with STI-related knowledge"; "general knowledge of STIs"; "learning about STIs from children"; and "limited application of knowledge". The findings allow insight into a neglected area, and indicate that socio-cultural factors influence middle-aged adults' STI-related knowledge acquisition throughout the life course. These are important implications for the prevention of STIs, particularly in addressing the on-going stigmatisation of STIs in older age groups. PMID- 28024676 TI - Ageing and healthy sexuality among women living with HIV. AB - Populations around the world are rapidly ageing and effective treatment for HIV means women living with HIV (WLHIV) can live longer, healthier lives. HIV testing and screening programmes and safer sex initiatives often exclude older sexually active WLHIV. Systematically reviewing the literature to inform World Health Organization guidelines on the sexual and reproductive health and rights (SRHR) of WLHIV, identified four studies examining healthy sexuality among older WLHIV. In Uganda, WLHIV reported lower rates of sexual activity and rated sex as less important than men. In the United States, HIV stigma, disclosure, and body image concerns, among other issues, were described as inhibiting relationship formation and safer sexual practices. Sexual activity declined similarly over time for all women, including for WLHIV who reported more protected sex, while a significant minority of WLHIV reported unprotected sex. A single intervention, the "ROADMAP" intervention, demonstrated significant increases in HIV knowledge and decreases in HIV stigma and high risk sexual behaviour. WLHIV face ageist discrimination and other barriers to remaining sexually active and maintaining healthy sexual relationships, including challenges procuring condoms and seeking advice on safe sex practices, reduced ability to negotiate safer sex, physical and social changes associated with menopause, and sexual health challenges due to disability and comorbidities. Normative guidance does not adequately address the SRHR of older WLHIV, and while this systematic review highlights the paucity of data, it also calls for additional research and attention to this important area. PMID- 28024677 TI - Sexual health and older adults: suggestions for social science research. AB - The body of evidence on older adults' sexual health is beginning to grow. However, it remains an under-researched area particularly within the social sciences. This viewpoint outlines four considerations for those who carry out social science research in this area: 1. defining the age category "older adults"; 2. being clear about the types of sex under research; 3. capturing a range of diverse voices; and 4. considering the use of qualitative research methods to explore the topic in depth. These suggestions are aimed at helping researchers to avoid some of the pitfalls of research in this area, as well as improving the evidence base in order to advance recognition of the issues and drive change in service provision. PMID- 28024678 TI - Inequality, Zika epidemics, and the lack of reproductive rights in Latin America. AB - It is well-documented that structural economic inequalities in Latin America are expressed through and reinforce existing gender gaps. This article aims to look at the relationship between structural inequalities and reproductive health in the case of the Zika epidemic. The consequences of the epidemic will continue to affect the same women whose access to comprehensive reproductive health services, including safe abortion, is restricted at best. PMID- 28024679 TI - Gender norms as health harms: reclaiming a life course perspective on sexual and reproductive health and rights. AB - Despite their demographic significance and the lifetime impact of gender disparities on their health and rights, women considered older than reproductive age are excluded from most investments in global public health. While development policies linking human rights with access to sexual and reproductive healthcare have yielded progress towards improving the status of women and girls, older women have not benefited from these initiatives. Yet as women grow older, they experience a range of health conditions rooted in their reproductive biology - from ageing with fistula, to cervical and breast cancers. Current approaches to global women's health ignore these serious conditions, harming older women through the perpetuation of gender norms that construe women's health through a narrow reproductive lens. Meanwhile, older women are generally absent from global ageing discourse, which lacks a gender perspective, creating a dual invisibility as the field of global women's health presumes ageing women are accounted for. Reclaiming the sexual rights framework suggested by the International Conference on Population and Development and the Beijing Platform for Action, we call for the revision of global health policies to incorporate a life course approach to women's health as a matter of human rights. PMID- 28024680 TI - Politics, policies, pronatalism, and practice: availability and accessibility of abortion and reproductive health services in Turkey. AB - Turkey has maintained liberal contraception and abortion policies since the 1980s. In 2012, the government proposed to restrict abortion; a bill limiting abortion was later drafted but never passed into law. Since the proposed restriction, women have reported difficulty accessing abortion services across Turkey. We aimed to better understand the current availability of abortion and reproductive health services in Istanbul and explore whether access to services has changed since 2012. In 2015, we completed 14 in-depth interviews with women and 11 semi-structured interviews with key informants. We transcribed all interviews and completed content and thematic analyses of the data. Key informants had good knowledge about the political discourse and the current abortion law. In contrast, women were familiar with the political discourse but had mixed information about the current status of abortion and were unsure about the legality of their own abortions. There was consensus that access to services has become more limited in the last five years due to the political climate, thus advocacy to prioritize reproductive health services, and abortion care in particular, in the public health system are needed. PMID- 28024681 TI - "Girls need to behave like girls you know": the complexities of applying a gender justice goal within sexuality education in South African schools. AB - Sexuality education, as a component within the Life Orientation (LO) programme in South African schools, is intended to provide young people with knowledge and skills to make informed choices about their sexuality, their own health and that of others. Key to the programme are outcomes relating to power, power relations and gender. In this paper, we apply a critical gender lens to explore the ways in which the teaching of sexuality education engages with larger goals of gender justice. The paper draws from a number of ethnographic studies conducted at 12 South African schools. We focus here on the data collected from focus group discussions with learners, and semi-structured interviews with individual learners, principals and Life Orientation (LO) teachers. The paper highlights the complexities of having gender justice as a central goal of LO sexuality education. Teaching sexuality education is reported to contradict dominant community values and norms. Although some principals and school authorities support gender equity and problematize hegemonic masculinities, learners experience sexuality education as upholding normative gender roles and male power, rather than challenging it. Teachers rely heavily on cautionary messages that put more responsibility for reproductive health on female learners, and use didactic, authoritative pedagogical techniques, which do not acknowledge young people's experience nor facilitate their sexual agency. These complexities need to be foregrounded and worked with systematically if the goal of gender justice within LO is to be realised. PMID- 28024682 TI - Coming of age? Women's sexual and reproductive health after twenty-one years of democracy in South Africa. AB - This paper is a sequel to a 2004 article that reviewed South Africa's introduction of new sexual and reproductive health (SRH) and rights laws, policies and programmes, a decade into democracy. Similarly to the previous article, this paper focuses on key areas of women's SRH: contraception and fertility, abortion, maternal health, HIV, cervical and breast cancer and sexual violence. In the last decade, South Africa has retained and expanded its sexual and reproductive health and rights (SRHR) policies in the areas of abortion, contraception, youth and HIV treatment (with the largest antiretroviral treatment programme in the world). These are positive examples within the SRHR policy arena. These improvements include fewer unsafe abortions, AIDS deaths and vertical HIV transmission, as well as the public provision of a human papillomavirus vaccine to prevent cervical cancer. However, persistent socio economic inequities and gender inequality continue to profoundly affect South African women's SRHR. The state shows mixed success over the past two decades in advancing measurable SRH social justice outcomes, and in confronting and ameliorating social norms that undermine SRHR. PMID- 28024683 TI - How can a state control swallowing? The home use of abortion pills in Ireland. AB - Evidence suggests that there is widespread home use of abortion pills in Ireland and that ending a pregnancy in this way is potentially safer than the alternatives available to many women. This paper argues that there is a strong case for women with unwanted pregnancies to be offered truthful and objective information regarding the use of abortion pills by trusted local professionals and, further, that this is possible within existing law. A move in this direction would not, however, negate the need for legal reform to address the fundamental moral incoherence of a law that treats women who terminate pregnancies within Ireland as criminals but those who travel to access services overseas as victims in need of support. In support of these arguments, the paper draws on both library research and a small number of interviews with government officials, service providers and activists. PMID- 28024684 TI - Non-pathogenic pemphigus foliaceus (PF) IgG acts synergistically with a directly pathogenic PF IgG to increase blistering by p38MAPK-dependent desmoglein 1 clustering. AB - BACKGROUND: Pemphigus foliaceus (PF) is an autoimmune blistering disease caused by autoantibodies (Abs) against desmoglein 1 (Dsg1). PF sera contain polyclonal Abs which are heterogeneous mixture of both pathogenic and non-pathogenic Abs, as shown by isolation of monoclonal Abs (mAbs). OBJECTIVE: To investigate how pathogenic and non-pathogenic anti-Dsg1 Abs contribute to blister formation in PF. METHODS: Using organ-cultured human skin, we compared the effect of a single pathogenic anti-Dsg1 IgG mAb, a single non-pathogenic anti-Dsg1 IgG mAb, and their mixture on blister formation as analyzed by histology, subcellular localization of IgG deposits and desmosomal proteins by confocal microscopy, and desmosomal structure by electron microscopy. In addition, we measured keratinocyte adhesion by an in vitro dissociation assay. RESULTS: 24h after injection, a single pathogenic anti-Dsg1 IgG caused a subcorneal blister with IgG and Dsg1 localized linearly on the cell surface of keratinocytes. A single non pathogenic anti-Dsg1 IgG bound linearly on the keratinocytes but did not induce blisters. A pathogenic and a non-pathogenic IgG mAb injected together caused an aberrant granular pattern of IgG and Dsg1 in the lower epidermis with blister formation in the superficial epidermis. Electron microscopy demonstrated that the mixture of mAbs shortened desmosomal lengths more than a single mAb in the basal and spinous layers. Furthermore, although Dsg1 clustering required both cross linking of Dsg1 molecules by the non-pathogenic IgG plus a pathogenic antibody, the latter could be in the form of a monovalent single chain variable fragment, suggesting that loss of trans-interaction of Dsg1 is required for clustering. Finally, a p38MAPK inhibitor blocked Dsg1 clustering. When pathogenic strength was measured by the dissociation assay, a mixture of pathogenic and non pathogenic IgG mAbs disrupted keratinocyte adhesion more than a single pathogenic mAb. This pathogenic effect was only partially suppressed by the p38MAPK inhibitor. CONCLUSION: These findings indicate that a polyclonal mixture of anti Dsg1 IgG antibodies enhances pathogenic activity for blister formation associated with p38MAPK-dependent Dsg1 clustering and that not only pathogenic antibodies but also non-pathogenic antibodies coordinately contribute to blister formation in PF. PMID- 28024685 TI - Decreases in 15-lipoxygenase metabolites in Olmsted syndrome model rats. AB - BACKGROUND: Olmsted syndrome (OS) is a congenital dermatosis characterized by palmoplantar keratoderma and periorificial keratotic plaque. TRPV3 (transient receptor potential vanilloid subtype 3) encodes a thermosensitive Ca2+ channel and is the causative gene of OS. However, the molecular mechanism that causes the pathological development of OS is unclear. OBJECTIVE: We aimed to investigate the molecular mechanisms underlying OS pathology from the perspective of lipid metabolism. METHODS: Comprehensive lipidomics and microarray analyses were conducted on tissue samples from a non-lesional skin area of OS model rats (Ht rats) and from wild type (WT) rats as the control. RESULTS: Infiltration of leukocytes such as eosinophils and neutrophils and an increase in the fibrotic region were detected in the unaffected skin area of Ht rats compared with the WT rats. Among about 600 lipid species examined, the levels of 15-lipoxygenase (LOX) metabolites, the precursors of anti-inflammatory and pro-resolving lipid mediators, and dihydroceramides decreased by >=16-fold in Ht rats compared with WT rats. Consistent with the decreases in the 15-LOX metabolites, expression levels of the genes that encode the 15-LOXs, Alox15 and Alox15b, were largely reduced. Conversely, increased expression levels were detected of Il36b, Ccl20, Cxcl1, and Cxcl2, which encode cytokines/chemokines, and S100a8 and S100a9, which encode the Ca2+ binding proteins that are implicated in epidermal proliferation. CONCLUSION: The pro-inflammatory state in the unaffected skin of Ht rats caused by decreases in 15-LOX metabolites and increases in cytokines/chemokines may contribute to the pathogenesis of OS. PMID- 28024686 TI - Selecting optimal columns for clarithromycin impurity analysis according to the quantitative relationship of hydrophobic subtraction model. AB - Hydrophobic subtraction model (HSM) is widely applied to select columns of equivalent or different selectivity compared with a reference column, but its application in identifying optimal columns for specific separations of real samples is rare. In this work, a column selection method was proposed by firstly directly correlating separation selectivity of different pairs of solutes to column parameters based on the quantitative relationship of HSM and then selecting the optimal columns according to the predicted selectivity in consideration of the total separation of all critical pairs of solutes. Three critical pairs of solutes in clarithromycin impurity analysis were evaluated as examples. Starting with the analysis of clarithromycin impurities on 15 columns with different selectivities, ten optimal columns were finally identified for clarithromycin impurity analysis from the HSM column characterization database containing nearly 600 columns and two of them were validated with satisfactory separations for all critical peak pairs. The proposed methodology was also compared to the traditional column selection procedure based on calculations of scalar measures of the Euclidean distance between chromatographic columns. Results showed that our method provides an effective way to find the desired columns that may be overlooked by the traditional column selection due to selection of an inappropriate reference column or overestimation of column similarity, such as Fs introduced in HSM. PMID- 28024687 TI - Thoughts on the U.S. Food and Drug Administration (FDA) Draft Guidance on Low Sexual Desire and Arousal. PMID- 28024688 TI - In Memoriam: Jean Fourcroy-Behr, MD, PhD, MPH, 1930 - 2016. PMID- 28024689 TI - ALK-Testing in non-small cell lung cancer (NSCLC): Immunohistochemistry (IHC) and/or fluorescence in-situ Hybridisation (FISH)?: Statement of the Germany Society for Pathology (DGP) and the Working Group Thoracic Oncology (AIO) of the German Cancer Society e.V. (Stellungnahme der Deutschen Gesellschaft fur Pathologie und der AG Thorakale Onkologie der Arbeitsgemeinschaft Onkologie/Deutsche Krebsgesellschaft e.V.). AB - The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as ALK tyrosine kinase inhibitors lead to improved progression free survival and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify eligible patients in a timely fashion. While FISH techniques are commonly used to detect this translocation, the broad implementation of this type of ALK testing into routine diagnostics is not optimal due to technical, structural and financial reasons. Immunohistochemical techniques to screen for EML4-ALK translocations may therefore play an important role in the near future. This consensus paper provides recommendations for the test algorithm and quality of the respective test approaches, which are discussed in the light of the current literature. PMID- 28024690 TI - Trends in stereotactic body radiation therapy for stage I small cell lung cancer. AB - OBJECTIVES: We aimed to report trends in stereotactic body radiation therapy (SBRT) utilization, dose prescriptions, and chemotherapy administration for stage I small cell lung cancer (SCLC) in the United States. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to identify patients with cT1-2 N0 SCLC treated with SBRT between 2004 and 2013. Trends in SBRT use and dose prescription were analyzed over time. Multivariable logistic regression was used to determine factors associated with the administration of chemotherapy with SBRT. The Kaplan Meier method was used to estimate overall survival. RESULTS: Of 9265 patients with clinical stage I SCLC who were examined for initial treatment allocation, 285 were treated with SBRT and represented the subject of the primary analysis. SBRT utilization increased from 2004 (0.4% of all stage I patients diagnosed that year) to 2013 (6.4%). During this same time period, definitive surgical management also increased from 14.9% of all patients in 2004 to 28.5% in 2013. The median SBRT biologically effective dose (BED10) was 112.5Gy (range, 72-290) and only 33 out of 285 (11.6%) received a BED10<100Gy. Nearly half of all patients (130/285, 45.6%) received chemotherapy, with 42.7% of those patients receiving their chemotherapy prior to SBRT. On multivariable logistic regression, only age<75 (the median) vs. >=75years (OR 4.97, 95% CI 2.96-8.35, p<0.001) and year of diagnosis 2004-2008 vs. 2009-2013 (OR 2.58, 95% CI 1.27-5.26, p=0.009) were predictive of chemotherapy use with SBRT. After median follow up of 45 months, the median survival was 23.5 months. CONCLUSIONS: Our findings suggest that SBRT utilization for stage I SCLC has increased between 2004 and 2013, highlighting the need for additional research to validate the feasibility of this management approach for inoperable patients. PMID- 28024691 TI - Detection of ALK rearrangements in 4002 Russian patients: The utility of different diagnostic approaches. AB - BACKGROUND: Clinical guidelines highly recommended the detection of potentially targetable genetic aberrations such as anaplastic lymphoma kinase (ALK) rearrangements in patients with non-small cell lung cancer (NSCLC). Few methods, such as the ALK break apart FISH assay and IHC for ALK protein, are approved for routine diagnostics. However, some challenges exist in selecting the most reliable, robust and cost-effective algorithm, especially for large-scale screening of NSCLC patients. MATERIALS AND METHODS: A total of 4002 FFPE samples from Russian patients with NSCLC were tested for ALK rearrangement using two algorithms: FISH testing only (2334 samples) and IHC screening supported by FISH in positive or equivocal cases (1546 samples). Cross validation of the methods was performed blindly in 122 specimens. All discrepant IHC/FISH cases were examined for unbalanced 5'/3'-end ALK expression and variant-specific RT PCR. RESULTS: The sensitivity and specificity of IHC compared to FISH was 100% and 99%, respectively, therefore initial IHC screening was strongly supported. The prevalence of ALK rearrangements was estimated to be 7.8% and 6.6% for the FISH and IHC/FISH groups, respectively, with significant correlations for female gender, non-smoking status and age below 60. The use of FISH after IHC screening revealed 10 additional positive cases among equivocal samples (13.4%). Seven IHC/FISH cases (0.5% of the total group) characterized as discordant were reevaluated, and four were reclassified as truly discrepant. The PCR-based investigation revealed chimeric transcripts in IHC-/FISH+ and IHC+/FISH borderline samples, while no transcript was found in two IHC+/FISH- cases. CONCLUSION: These results reveal the utility of the two-step testing algorithm for the evaluation of potentially complicated cases with preanalytic defects, providing additional information for IHC equivocal cases without a significant increase in cost. The evaluation of discrepant cases appears to be necessary to better understand ALK biology and should be included in the routine testing algorithm. PMID- 28024692 TI - Synchronous occurrence of squamous-cell carcinoma "transformation" and EGFR exon 20 S768I mutation as a novel mechanism of resistance in EGFR-mutated lung adenocarcinoma. AB - The occurrence of secondary EGFR mutation T790M in exon 20 and histologic "transformation" are common mechanisms underlying resistance to EGFR first- or second-generation tyrosine kinase inhibitors (TKI). We describe here on a hitherto unreported mechanism of EGFR TKI resistance synchronously combining squamous-cell carcinoma change and occurrence of the EGFR exon 20 S768I secondary mutation in a 43 year-old woman with stage IV adenocarcinoma harbouring EGFR exon 21 L858R mutation. After 8 months of response to gefitinib, the patient experienced EGFR TKI resistance and died of leptomeningeal neoplastic dissemination. PMID- 28024693 TI - The race to target MET exon 14 skipping alterations in non-small cell lung cancer: The Why, the How, the Who, the Unknown, and the Inevitable. AB - A number of small molecule tyrosine kinase inhibitors (TKIs) have now been approved for the treatment of non-small cell lung cancers (NSCLC), including those targeted against epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1. Despite a wealth of agents developed to target the receptor tyrosine kinase, MET, clinical outcomes have as yet been disappointing, leading to pessimism about the role of MET in the pathogenesis of NSCLC. However, in recent years, there has been a renewed interest in MET exon 14 alterations as potential drivers of lung cancer. MET exon 14 alterations, which result in increased MET protein levels due to disrupted ubiquitin-mediated degradation, occur at a prevalence of around 3% in adenocarcinomas and around 2% in other lung neoplasms, making them attractive targets for the treatment of lung cancer. At least five MET-targeted TKIs, including crizotinib, cabozantinib, capmatinib, tepotinib, and glesatinib, are being investigated clinically for patients with MET exon 14 altered-NSCLC. A further two compounds have shown activity in preclinical models. In this article, we review the current clinical and preclinical data available for these TKIs, along with a number of other potential therapeutic options, including antibodies and immunotherapy. A number of questions remain unanswered regarding the future of MET TKIs, but unfortunately, the development of resistance to targeted therapies is inevitable. Resistance is expected to arise as a result of receptor tyrosine kinase mutation or from upregulation of MET ligand expression; potential strategies to overcome resistance are proposed. PMID- 28024694 TI - The diagnostic performance of routinely acquired and reported computed tomography imaging in patients presenting with suspected pleural malignancy. AB - OBJECTIVES: Contrast-enhanced computed tomography (CT) provides essential cross sectional imaging data in patients with suspected pleural malignancy (PM). The performance of CT in routine practice may be lower than in previously reported research. We assessed this relative to 'real-life' factors including use of early arterial-phase contrast enhancement (by CT pulmonary angiography (CTPA)) and non specialist radiology reporting. MATERIALS AND METHODS: Routinely acquired and reported CT scans in patients recruited to the DIAPHRAGM study (a prospective, multi-centre observational study of mesothelioma biomarkers) between January 2014 and April 2016 were retrospectively reviewed. CT reports were classified as malignant if they included specific terms e.g. "suspicious of malignancy", "stage M1a" and benign if others were used e.g. "indeterminate", "no cause identified". All patients followed a standard diagnostic algorithm. The diagnostic performance of CT (overall and based on the above factors) was assessed using 2*2 Contingency Tables. RESULTS: 30/345 (9%) eligible patients were excluded (non-contrast (n=13) or non-contiguous CT (n=4), incomplete follow-up (n=13)). 195/315 (62%) patients studied had PM; 90% were cyto-histologically confirmed. 172/315 (55%) presented as an acute admission, of whom 31/172 (18%) had CTPA. Overall, CT sensitivity was 58% (95% CI 51-65%); specificity was 80% (95% CI 72-87%). Sensitivity of CTPA (performed in 31/315 (10%)) was lower (27% (95% CI 9-53%)) than venous-phase CT (61% (95% CI 53-68%) p=0.0056). Sensitivity of specialist thoracic radiologist reporting was higher (68% (95% CI 55-79%)) than non-specialist reporting (53% (95% CI 44-62%) p=0.0488). Specificity was not significantly different. CONCLUSION: The diagnostic performance of CT in routine clinical practice is insufficient to exclude or confirm PM. A benign CT report should not dissuade pleural sampling where the presence of primary or secondary pleural malignancy would alter management. Sensitivity is lower with non-thoracic radiology reporting and particularly low using CTPA. PMID- 28024695 TI - Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis. AB - OBJECTIVES: Compared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients. MATERIALS AND METHODS: Using tissue microarrays comprising 270 consecutive cases of lung adenocarcinoma, we evaluated tumor B7-H3 expression by immunohistochemistry. We examined the prognostic association between B7-H3 expression levels and smoking history, using Cox proportional hazards regression analysis and the log-rank test. Additionally, we used logistic regression analysis to examine the correlations between B7-H3 expression levels and clinicopathological/molecular features of lung adenocarcinoma. RESULTS: The association of B7-H3 expression with survival differed by smoking history (Pinteraction=0.014); high B7-H3 expression was associated with decreased lung cancer-specific survival in moderate/heavy-smoking patients (smoking index [SI]>=400) (hazard ratio [HR]=3.07, 95% confidence interval [CI]=1.74-5.49, P=0.0001; log-rank: P<0.0001), but not in non/light-smoking patients (SI<400) (HR=1.14, 95% CI=0.63-1.96, P=0.64; log-rank: P=0.64). Interestingly, in moderate/heavy-smoking patients, high B7-H3 expression was associated with decreased survival in stage I cancer (log-rank; P=0.0005), whereas it showed no significant difference of survival in stage II-IV cancer (P=0.37). High B7-H3 expression was associated with smokers (univariable odds ratio [OR]=2.63, 95% CI=1.51-4.65; P=0.0005) and independently associated with EGFR wild-type status (multivariable OR=2.80, 95% CI=1.38-5.84; P=0.0042). CONCLUSIONS: We demonstrated that the prognostic association of B7-H3 expression indeed differed according to smoking history. Our study also showed the significant association of high B7-H3 expression with EGFR wild-type and smoking patients, indicating the potential effectiveness of anti-B7-H3 therapy for EGFR wild-type or smokers' lung adenocarcinoma. PMID- 28024696 TI - PIK3CA mutations as prognostic factor in squamous cell lung carcinoma. AB - OBJECTIVES: Mutation in the PIK3CA gene is reported frequent in squamous cell carcinomas of the lung, but its potential prognostic role is still obscure. We have studied the prognostic importance of PIK3CA mutations as well as the relation to other markers in a large number of early stage lung cancers of squamous carcinoma subtype. PATIENTS AND METHODS: Tumour tissue was obtained from 308 consecutively operated lung cancer patients with squamous cell carcinoma in the period 2003-2013. DNA was isolated according to standard procedures, and mutation analysis was done with either the SnapShot method and/or using PIK3CA specific primers in the Cobas system. PD-L1-expression was analysed with immunohistochemistry After thorough follow-up (median 67.6 months), overall survival and time to relapse was calculated. RESULTS: Tumour tissue from 102 females and 206 males were analysed. 167 (54.2%) were in stage I, 96 (31.2%) in stage II and 45 (14.6%) in stage III. PIK3CA mutation was found in 35 (11.4%) patients, most frequently in exon 20. There were no differences in sex, stage or smoking behaviour between mutated and non-mutated cases. Patients with PIK3CA mutations had a significantly longer overall survival (p=0.042) and time to relapse (p=0.030) than non-mutated cases, and the difference in time to relapse was also retained in stage I-cases (p=0.044). PD-L1-expression was less frequent among mutated cases. CONCLUSION: Our results indicate that PIK3CA mutations may confer a survival advantage in early stage squamous cell lung cancers, but further work is needed to confirm this finding. PMID- 28024697 TI - Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat. AB - OBJECTIVES: To investigate and elucidate the mechanism for the potentiation of cisplatin anticancer activity by belinostat in platinum (Pt)-resistant lung cancer cells. MATERIALS AND METHODS: Combination of cisplatin and belinostat was investigated in two pairs of parental and cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines. The Pt-resistant cell models exhibited overexpression of the efflux transporter ABCC2 and enhanced DNA repair capacity. Cellular accumulation of cisplatin and extent of DNA platination were measured by inductively coupled plasma optical emission spectrometer. Expression of Pt transporters and DNA repair gene were determined by quantitative real-time PCR. Inhibition of ABCC2 transport activity was examined by flow cytometric assay. Regulation of ABCC2 at the promoter level was studied by chromatin immunoprecipitation assay. RESULTS AND CONCLUSION: In Pt-resistant lung cancer cells, belinostat apparently circumvent the resistance through inhibition of both ABCC2 and DNA repair-mediated mechanisms. The combination of belinostat and cisplatin were found to display synergistic cytotoxic effect in cisplatin resistant lung cancer cell lines when the two drugs were added concomitantly or when belinostat was given before cisplatin. Upon the concomitant administration of belinostat, cellular accumulation of cisplatin and formation of DNA-Pt adducts were found to be increased whereas expression levels of the efflux transporter ABCC2 and the DNA repair gene ERCC1 were inhibited in Pt-resistant cells. Belinostat-mediated downregulation of ABCC2 was associated with an increase association of a transcriptional repressor (negative cofactor 2) but reduced association of a transcriptional activator (TFIIB) to the ABCC2 promoter. The data advocates the use of belinostat as a novel drug resistance reversal agent for use in combination cancer chemotherapeutic regimens. PMID- 28024698 TI - Interpreting survival data from clinical trials of surgery versus stereotactic body radiation therapy in operable Stage I non-small cell lung cancer patients. AB - OBJECTIVES: To identify the variability of short- and long-term survival outcomes among closed Phase III randomized controlled trials with small sample sizes comparing SBRT (stereotactic body radiation therapy) and surgical resection in operable clinical Stage I non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Clinical Stage I NSCLC patients who underwent surgery at our institution meeting the inclusion/exclusion criteria for STARS (Randomized Study to Compare CyberKnife to Surgical Resection in Stage I Non-small Cell Lung Cancer), ROSEL (Trial of Either Surgery or Stereotactic Radiotherapy for Early Stage (IA) Lung Cancer), or both were identified. Bootstrapping analysis provided 10,000 iterations to depict 30-day mortality and three-year overall survival (OS) in cohorts of 16 patients (to simulate the STARS surgical arm), 27 patients (to simulate the pooled surgical arms of STARS and ROSEL), and 515 (to simulate the goal accrual for the surgical arm of STARS). RESULTS: From 2000 to 2012, 749/873 (86%) of clinical Stage I NSCLC patients who underwent resection were eligible for STARS only, ROSEL only, or both studies. When patients eligible for STARS only were repeatedly sampled with a cohort size of 16, the 3-year OS rates ranged from 27 to 100%, and 30-day mortality varied from 0 to 25%. When patients eligible for ROSEL or for both STARS and ROSEL underwent bootstrapping with n=27, the 3-year OS ranged from 46 to 100%, while 30-day mortality varied from 0 to 15%. Finally, when patients eligible for STARS were repeatedly sampled in groups of 515, 3-year OS narrowed to 70-85%, with 30-day mortality varying from 0 to 4%. CONCLUSION: Short- and long-term survival outcomes from trials with small sample sizes are extremely variable and unreliable for extrapolation. PMID- 28024699 TI - Temporal patterns of care and outcomes of non-small cell lung cancer patients in the United States diagnosed in 1996, 2005, and 2010. AB - INTRODUCTION: Lung cancer remains a common and deadly cancer in the United States. This study evaluated factors associated with stage-specific cancer therapy and survival focusing on temporal trends and sociodemographic disparities. METHODS: A random sample (n=3,318) of non-small cell lung cancer (NSCLC) patients diagnosed in 1996, 2005 and 2010, and reported to the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program was analyzed. Logistic regression was utilized to identify factors associated with receipt of surgery among stage I/II patients and chemotherapy among stage IIIB/IV patients. Cox proportional hazard regression was utilized to assess factors associated with all-cause mortality, stratified by stage. RESULTS: Surgery among stage I/II patients decreased non-significantly overtime (1996: 78.8%; 2010: 68.5%; p=0.18), whereas receipt of chemotherapy among stage IIIB/IV patients increased significantly overtime (1996: 36.1%; 2010: 51.2%; p<0.01). Receipt of surgery (70-79 and >=80 vs. <70: Odds Ratio(OR):0.31; 95% Confidence Interval (CI): 0.16-0.63 and OR:0.04; 95% CI: 0.02-0.10, respectively) and chemotherapy (>=80 vs. <70: OR: 0.26; 95% CI:0.15-0.45) was less likely among older patients. Median survival improved non-significantly among stage I/II patients from 51 to 64 months (p=0.75) and significantly among IIIB/IV patients from 4 to 5 months (p<0.01). CONCLUSION: Treatment disparities were observed in both stage groups, notably among older patients. Among stage I/II patients, survival did not change significantly possibly due to stable surgery utilization. Among stage IIIB/IV patients, although the use of chemotherapy increased and survival improved, the one-month increase in median survival highlights the need for addition research. PMID- 28024700 TI - Defining outcomes of patients with clinical stage I small cell lung cancer upstaged at surgery. AB - BACKGROUND: A proportion of patients with clinical stage I small cell lung cancer (SCLC) will be upstaged following surgical resection. The existing data regarding the management of upstaged SCLC patients and guidelines for their treatment remains sparse. The primary objective was to describe the impact of pathologic upstaging following surgical resection. METHODS: The National Cancer Database was queried for patients with clinical stage I SCLC (cT1-2a,N0,M0) who underwent resection with curative intent followed by adjuvant therapy, excluding patients who underwent surgery alone. Clinical and pathologic T, N, and M staging were compared to identify patients that were upstaged. RESULTS: Four-hundred and seventy-seven patients were identified with clinical stage I SCLC. Pathologic upstaging occurred in 25% (117). Of those upstaged, 30% (35) were due to a higher pathologic T descriptor and 81% (95) were due to the presence of nodal disease. Overall 5-year survival was significantly worse for upstaged patients compared with those patients who remained a pathologically stage I (36% vs 52%, p<0.001). Among patients with positive lymph node involvement, adjuvant chemotherapy and radiation therapy was associated a significantly improved 5-year survival compared to adjuvant chemotherapy alone (20% vs 55%, respectively, p<0.01). The use of adjuvant chemotherapy and radiation therapy in patients with nodal disease after surgical resection was an independent predictor of improved survival (HR 0.36, 95% CI 0.18-0.73, p<0.01). CONCLUSIONS: Pathologic upstaging is common after surgical resection of stage I SCLC, and is associated with significantly inferior survival. These data provide evidence that recommend the use of adjuvant chemotherapy and radiation therapy in the setting of nodal upstaging after resection of clinical stage I SCLC patients. PMID- 28024701 TI - A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population. AB - INTRODUCTION: Recurrent somatic splice-site alterations at MET exon 14 (METDelta14), which result in exon skipping and MET proto-oncogene, receptor tyrosine kinase (MET) activation, have been characterised. However, their demographic features and clinical outcomes in East Asian lung cancer patients have yet to be determined. METHODS: A one-step reverse transcription-polymerase chain reaction (RT-PCR), using RNA samples from 850 East Asian lung cancer patients, was performed in order to detect METDelta14 and five other major driver mutations, including those in the EGFR, KRAS, ALK, HER2, and ROS1 genes. Immunohistochemistry (IHC) was used to confirm the overexpression of MET in patients harbouring the METDelta14 mutation. We analysed the demographic data and clinical outcomes of METDelta14 mutation positive lung cancer patients and compared them to those of METDelta14 mutation negative lung cancer patients. RESULTS: In total, 27 lung adenocarcinoma (ADC) patients and 1 squamous cell carcinoma patient with the METDelta14 mutation were identified. The overall incidence was 3.3% for lung cancer and 4.0% for lung ADC. IHC demonstrated that the majority of lung cancer patients harboring a METDelta14 mutation exhibited a strong cytoplasmic expression of MET. METDelta14 mutation positive patients were generally quite elderly individuals. Stage IV METDelta14 mutation positive lung cancer patients receiving no specific anti-MET therapy were observed to have a similar overall survival (OS) compared to patients in the all negative group (P>0.05). In the multivariate analysis, mutation status was found not to be a major risk factor for OS in lung cancer patients without appropriate tyrosine kinase inhibitors treatment. CONCLUSIONS: The OS of METDelta14 mutation positive lung cancer patients is comparable to that of the major driver gene mutation negative lung cancer patients. PMID- 28024702 TI - Development of a prediction model for a severe reaction in cow's milk challenges. PMID- 28024703 TI - A new molecular paradigm in mycosis fungoides and Sezary syndrome. AB - Mycosis Fungoides (MF) and Sezary Syndrome (SS) are clonal proliferations of mature T-cells manifesting as lymphoproliferative disorders in which the neoplastic cells show a strong propensity for skin-homing. While the predominant site of presentation in MF is the skin, the peripheral blood carries a significant tumor burden in Sezary Syndrome such that it resembles a "leukemic" disease. While the genetic basis of these diseases has been studied using different approaches in the previous years, recent genome-wide studies employing massively parallel sequencing techniques now offer new insights into the molecular pathogenesis of these diseases. In this chapter, we discuss the recent findings elucidating the genomic landscape of MF and SS. The pathways targeted by mutational alterations are discussed and a model for understanding the pathogenesis of these diseases is proposed. It is anticipated that prognostic stratification and therapeutic targeting based on mutational signatures will be achieved in the near future based on the improved understanding of the molecular pathogenesis of these diseases. PMID- 28024704 TI - Protocadherins and the Social Brain. PMID- 28024705 TI - Common Variation in the GTF2I Gene: A Promising Neurogenetic Mechanism for Affiliative Drive and Social Anxiety. PMID- 28024706 TI - Neurochemicals Drawing the Line Between Love and Hate. PMID- 28024707 TI - Oxytocin and the Social Brain. PMID- 28024708 TI - Fearing the Mother's Virus: The Lasting Consequences of Prenatal Immune Activation on the Epigenome and Brain Function. PMID- 28024709 TI - Thalamic deep brain stimulation as rescue therapy for tremor following bilateral radiosurgery. PMID- 28024710 TI - Basal ganglia calcification in a case of PKAN. PMID- 28024711 TI - [Progressive hematoma in anterior neck after endovascular treatment of middle cerebral artery aneurysm]. AB - BACKGROUND: Cervical hematomas can lead to airway compromise, a life threatening condition, regardless of the cause. The following case is the first presentation of cervical hematoma as a complication of endovascular treatment of middle cerebral artery aneurysm. CASE REPORT: A 49 year-old woman was scheduled for stent placement under general anesthesia for middle cerebral artery aneurysm. Few days before intervention, acetyl salicylic acid and clopidogrel treatment was started. Following standard monitoring and anesthesia induction, the patient's trachea was intubated with a 7.5mm endotracheal tube and the procedure was completed without any complications. Three hours later, dyspnea developed and physical examination revealed progressive swelling and stiffness in the neck. Endotracheal intubation was performed with a 6mm diameter uncuffed tube with the aid of sedation. The vocal cords were completely closed due to compression. There was no leak around the endotracheal tube. The rapidly performed computerized tomography scans showed an enormous hematoma around the neck and extravasation of contrast medium through superior thyroid artery. After coil embolization of superior thyroid artery, she was taken to the intensive care unit as intubated and sedated. Surgical exploration of the hematoma was not recommended by the surgeons, because she was on clopidogrel. After two days, the patient's trachea was extubated safely ensuring that the swelling was sufficiently ceased and leak detected around the endotracheal tube. CONCLUSIONS: Securing the airway rapidly by endotracheal intubation is the most crucial point in the management of cervical hematomas. Diagnostic and therapeutic procedures should be performed only afterwards. PMID- 28024712 TI - Factors related to attrition from trauma-focused cognitive behavioral therapy. AB - Attrition from child trauma-focused treatments such as Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) is common; yet, the factors of children who prematurely terminate are unknown. The aim of the current study was to identify risk factors for attrition from TF-CBT. One hundred and twenty-two children (ages 3-18; M=9.97, SD=3.56; 67.2% females; 50.8% Caucasian) who received TF-CBT were included in the study. Demographic and family variables, characteristics of the trauma, and caregiver- and child-reported pretreatment symptoms levels were assessed in relation to two operational definitions of attrition: 1) clinician rated dropout, and 2) whether the child received an adequate dose of treatment (i.e., 12 or more sessions). Several demographic factors, number of traumatic events, and children's caregiver-rated pretreatment symptoms were related to clinician-rated dropout. Fewer factors were associated with the adequate dose definition. Child Protective Services involvement, complex trauma exposure, and child-reported pretreatment trauma symptoms were unrelated to either attrition definition. Demographics, trauma characteristics, and level of caregiver-reported symptoms may help to identify clients at risk for premature termination from TF CBT. Clinical and research implications for different operational definitions and suggestions for future work will be presented. PMID- 28024713 TI - Guaranteed cost consensus protocol design for linear multi-agent systems with sampled-data information: An input delay approach. AB - To investigate the energy consumption involved in a sampled-data consensus process, the problem of guaranteed cost consensus for sampled-data linear multi agent systems is considered. By using an input delay approach, an equivalent system is constructed to convert the guaranteed cost consensus problem to a guaranteed cost stabilization problem. A sufficient condition for guaranteed cost consensus is given in terms of linear matrix inequalities (LMIs), based on a refined time-dependent Lyapunov functional analysis. Reduced-order protocol design methodologies are proposed, with further discussions on determining sub optimal protocol gain and enlarging allowable sampling interval bound made as a complement. Simulation results illustrate the effectiveness of the theoretical results. PMID- 28024714 TI - Reply to Sorscher S. PMID- 28024716 TI - Reply to: Respiratory acidosis in obese gynecologic patients undergoing laparoscopic surgery independently of the type of ventilation. PMID- 28024715 TI - Incidence of postoperative nausea and vomiting following gynecological laparoscopy: A comparison of standard anesthetic technique and propofol infusion. AB - OBJECTIVE: To determine the safety, efficacy, and feasibility of propofol-based anesthesia in gynecological laparoscopies in reducing incidences of postoperative nausea and vomiting compared to a standard anesthesia using thiopentone/isoflurane. DESIGN: Randomized single-blind (for anesthesia techniques used) and double-blind (for postoperative assessment) controlled trial. SETTING: Operation theater, postanesthesia recovery room, teaching hospital. PATIENTS: Sixty ASA (American Society of Anesthesiologists) I and II female patients (aged 20-60 years) scheduled for gynecological laparoscopy were included in the study. INTERVENTIONS: Patients in Group A received standard anesthesia with thiopentone for induction and maintenance with isoflurane fentanyl, and those in Group B received propofol for induction and maintenance along with fentanyl. All patients received nitrous oxide, vecuronium, and neostigmine/glycopyrrolate. No patient received elective preemptive antiemetic, but patients did receive it after more than one episode of vomiting. MEASUREMENTS: Assessment for incidence of postoperative nausea and vomiting as well as other recovery parameters were carried out over a period of 24 hours. MAIN RESULTS: Six patients (20%) in Group A and seven patients (23.3%) in Group B experienced nausea. Two patients (6.66%) in Group B had vomiting versus 12 (40%) in Group A (p<0.05). Overall, the incidence of emesis was 60% and 30% in Groups A and B, respectively (p<0.05). All patients in Group B had significantly faster recovery compared with those in Group A. No patient had any overt cardiorespiratory complications. CONCLUSION: Propofol-based anesthesia was associated with significantly less postoperative vomiting and faster recovery compared to standard anesthesia in patients undergoing gynecological laparoscopy. PMID- 28024717 TI - Respiratory acidosis in obese gynecological patients undergoing laparoscopic surgery independently of the type of ventilation. PMID- 28024718 TI - Patterns of dysphagia and acute toxicities in patients with head and neck cancer undergoing helical IMRT+/-concurrent chemotherapy. AB - BACKGROUND: There is limited prospective data reporting the extent of treatment related toxicities associated with helical Intensity Modulated Radiotherapy (H IMRT) for head and neck cancer (HNC). The study aim was to investigate severity, peak incidence and recovery patterns of dysphagia and related toxicities in patients undergoing H-IMRT+/-chemotherapy to examine when patients are experiencing symptoms requiring supportive clinical care. METHODS: Prospective study of 212 patients undergoing H-IMRT. Dysphagia and associated acute toxicities were monitored weekly during treatment and at weeks 2, 4 and 12 post treatment using the CTCAE v4, Functional Oral Intake Score and National Dysphagia Diet Descriptors. RESULTS: 75% experienced Grade 2-3 dysphagia. Over 70% had grade 2-3 dysguesia, xerostomia, and thick saliva, and >50% experienced grade 2-3 pharyngeal mucositis, oral mucositis, and nausea. 13% patients declined to NBM requiring complete enteral nutrition, 25% required enteral nutrition but maintained some form of oral intake. Symptoms peaked in final week of treatment, consistently improving thereafter, with the majority better than baseline by 12 weeks post-treatment. Concurrent chemotherapy at least doubles the odds of experiencing most symptoms excepting xerostomia, taste and fluid level. CONCLUSION: Despite advancements in radiation techniques, results confirm a high proportion of HNC patients experience dysphagia and related toxicities requiring supportive care during H-IMRT. Patients receiving H-IMRT alone experience a lower incidence of symptoms compared with those receiving concurrent chemotherapy. The data confirms the ongoing need for active on treatment monitoring with implications for the timing and intensity of patient support services. PMID- 28024719 TI - Prognostic impact of adjuvant chemotherapy in high-risk nasopharyngeal carcinoma patients. AB - OBJECTIVES: To investigate the prognostic impact of adjuvant chemotherapy (AdjCT) in patients with high-risk nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: A total 403 NPC patients with at least one of the following criteria (1) neck node>6cm; (2) supraclavicular node metastasis; (3) skull base destruction/intracranial invasion plus multiple nodes metastasis; or (4) multiple neck nodes metastasis with one of nodal size>4cm were retrospectively reviewed. All patients finished curative radiotherapy+/-neoadjuvant/concurrent chemotherapy. Post-radiation AdjCT consisted of tegafur-uracil (two capsules twice daily) for 12months. We analyzed the treatment outcome between patients with (n=154) and without (n=249) AdjCT. RESULTS: Baseline patient characteristics at diagnosis (age, gender, pathological type, performance status, T classification, N-classification, and overall stage) were comparable in both arms. After a median follow-up of 72months for surviving patients, 31.8% (49/154) and 42.2% (105/249) in patients with and without AdjCT developed tumor relapse respectively (P=0.0377). AdjCT improved both overall survival (HR 1.89, 95% CI 1.37-2.61, P=0.0001) and progression-free survival (HR 1.42, 95% CI 1.03-1.96, P=0.0322). There were significant reduction in distant failures (P=0.0016) but not in local (P=0.8587) or regional (P=0.8997) recurrences for patients who received AdjCT. CONCLUSION: AdjCT can reduce distant failure and improve overall survival in high-risk NPC patients after curative radiotherapy+/ neoadjuvant/concurrent chemotherapy. PMID- 28024720 TI - Healthy life expectancy of oral squamous cell carcinoma patients aged 75years and older. AB - OBJECTIVES: Healthy life expectancy, an extension of the concept of life expectancy, is a summary measure of population health that takes into account the mortality and morbidity of a population. The aim of the present study was to retrospectively analyze the self-reliance survival times of oral squamous cell carcinoma (OSCC) patients. MATERIALS AND METHODS: One hundred and twelve patients aged 75years or older with primary OSCC were included and examined at Shinshu University Hospital. To investigate healthy life expectancy, OSCC patients older than 75years were divided into 3 groups: 75-79, 80-84, and older than 85years. The Kaplan-Meier method was used to estimate the median times of healthy life expectancy. The Log-rank test was used to test significant differences between actual curves. RESULTS: The median self-reliance survival times of patients aged 75-79, 80-84, and older than 85years were 5.7, 1.6, and 1.4years, respectively. Most patients with early stage cancers underwent curative treatments and showed a health expectancy of more than 5years. In patients with advanced cancers, health expectancy was poor (less than one year), except among patients aged 75-79years who underwent standard treatments. CONCLUSIONS: It seems that in patients with advanced cancers, health expectancy was poor (less than 1year), except among patients aged 75-79years who underwent standard treatments. In elderly patients, healthy life expectancy (self-reliance survival time) may be one of the measures of patient prognosis as well as overall survival times. PMID- 28024721 TI - Functional and cognitive impairment, social environment, frailty and adverse health outcomes in older patients with head and neck cancer, a systematic review. AB - OBJECTIVES: Older head and neck cancer patients are at increased risk for adverse health outcomes, but little is known about which geriatric assessment associates with poor outcome. The aim is to study the association of functional or cognitive impairment, social environment and frailty with adverse health outcomes in patients with head and neck cancer. METHODS: Four libraries were searched for studies reporting on an association of functional or cognitive impairment, social environment and frailty with adverse outcomes in head and neck cancer patients. RESULTS: Of 4158 identified citations, 31 articles were included. The mean age was ?60years in twelve studies (39%). Geriatric conditions were prevalent: between 40 and 50% of the included participants were functional impaired, around 50% had depressive symptoms, and around 40% did not have a partner. Functional impairment was assessed in 18 studies, two studies reported on a cognitive test, eight studies examined mood and social status was depicted by 14 studies. None of the included studies addressed frailty or objectively measured physical capacity such as hand grip strength, gait speed or balance tests. In 64% of the reported associations, a decline in functional or cognitive impairment, mood or social environment was associated with adverse outcomes. CONCLUSION: Functional and cognitive impairment, depressive symptoms and social isolation are highly prevalent in head and neck cancer patients and associate with high risk of adverse health outcomes. In the future, these measurements may guide decision making and customize treatments, but more research is needed to further improve and firmly establish clinical usability. PMID- 28024722 TI - The role of HPV on the risk of second primary neoplasia in patients with oropharyngeal carcinoma. AB - OBJECTIVES: It has been reported that patients with HPV-positive oropharyngeal cancer (OPC) have a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor. MATERIALS AND METHODS: We included 412 OPC patients treated at our center from 1991 to 2014 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. RESULTS: Fifty-one (12.4%) out of 412 OPCs included in the study were HPV related. Five-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 57.0% and 89.0% (P<0.001), respectively. Corresponding estimates for 10-year SPN-free survival were 35.2% versus 78.5% (P<0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates where 62.0% versus 97.6% (P<0.001) and 42.2% versus 97.6%, (P<0.001), for 5-year and 10 year survival rates, respectively. HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. CONCLUSION: HPV-related OPC patients have a significant lower risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption. PMID- 28024723 TI - The prevalence and risk factors associated with osteoradionecrosis of the jaw in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT): The Memorial Sloan Kettering Cancer Center experience. AB - OBJECTIVE: To determine the prevalence and correlation of various risk factors [radiation dose, periodontal status, alcohol and smoking] to the development of osteoradionecrosis (ORN). PATIENTS AND METHODS: The records of 1023 patients treated with IMRT for oral cavity cancer (OCC) and oropharyngeal cancer (OPC) between 2004 and 2013 were retrospectively reviewed to identify patients who developed ORN. Fisher exact tests were used to analyze patient characteristics between ORN patients with OCC and OPC. Paired Wilcoxon tests were used to compare the dose volumes to the ORN and contralateral non-ORN sites. To evaluate an association between ORN and risk factors, a case-control comparison was performed. One to 2 ORN-free patients were selected to match each ORN patient by gender, tumor site and size. General estimation equations models were used to compare the risk factors in ORN cases and matched controls. RESULTS: 44 (4.3%) patients developed ORN during a median follow-up time of 52.5months. In 82% of patients, ORN occurred spontaneously. Patients with OPC are prone to develop ORN earlier compared to patients with OCC (P=0.03). OPC patients received a higher Dmax compared to OCC patients (P=0.01). In the matched case-control analysis the significant risk factors on univariate analysis were poor periodontal status, history of alcohol use and radiation dose (P=0.03, 0.002 and 0.009, respectively) and on multivariate analysis were alcohol use and radiation dose (P=0.004 and 0.026, respectively). CONCLUSION: In our study, higher radiation dose, poor periodontal status and alcohol use are significantly related to the risk of developing ORN. PMID- 28024724 TI - A PPAR gamma agonist protects against oral mucositis induced by irradiation in a murine model. AB - BACKGROUND: Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR gamma agonist rosiglitazone is of interest in prevention and therapy of radiation-induced toxicities. We aimed to evaluate the radioprotective effect of rosiglitazone in a mouse model of radiation-induced oral mucositis. MATERIAL AND METHODS: Oral mucositis was obtained by irradiation of the oral region of C57BL/6J mice, pretreated or not with rosiglitazone. Mucositis was assessed by macroscopic scoring, histology and molecular analysis. Tumor xenograft was obtained by s.c. injection of Hep-2 cells in CD1 mice. Tumor volume was measured twice a week to evaluate effect of rosiglitazone alone and combined with radiotherapy. RESULTS: Irradiated mice showed typical features of oral mucositis, such as oedema and reddening, reaching the peak of damage after 12 15days. Rosiglitazone markedly reduced visible signs of mucositis and significantly reduced the peak. Histological analysis showed the presence of an inflammatory cell infiltrate after irradiation; the association with rosiglitazone noticeably reduced infiltration. Rosiglitazone significantly inhibited radiation-induced tnfalpha, Il-6 and Il-1beta gene expression. Rosiglitazone controlled the increase of TGF-beta and NF-kB p65 subunit proteins induced by irradiation, and enhanced the expression of catalase. Irradiation and rosiglitazone significantly reduced tumor volume as compared to control. Rosiglitazone did not protect tumor from the therapeutic effect of radiation. CONCLUSION: Rosiglitazone exerted a protective action on normal tissues in radiation-induced mucositis. Moreover, it showed antineoplastic properties on head-neck carcinoma xenograft model and selective protection of normal tissues. Thus, PPAR gamma agonists should be further investigated as radioprotective agents in head and neck cancer. PMID- 28024725 TI - Adherence to the World Cancer Research Fund/American Institute for Cancer Research recommendations and head and neck cancers risk. AB - OBJECTIVES: The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) have proposed eight recommendations for cancer prevention, related to body fatness, diet, and physical activity. Our aim is to evaluate the role of adherence to these recommendations on head and neck cancers risk. MATERIALS AND METHODS: We obtained an overall score including seven of the WCRF/AICR recommendations, and examined its relationship with head and neck cancers risk in two Italian case-control studies including 946 patients with oral cavity and pharyngeal (OCP) cancer and 2492 controls, and 689 patients with laryngeal cancer and 1605 controls. RESULTS: Higher adherence to WCRF/AICR recommendations was associated to a reduced risk of OCP cancer (odds ratio, OR=0.45, 95% confidence interval, CI: 0.33-0.62 for a score of 4-<5, and OR=0.32, 95% CI: 0.22-0.49 for a score of ?5 as compared to <3). The ORs for laryngeal cancer were 0.68 (95% CI: 0.50-0.92) for a score of 3-<4, 0.39 (95% CI: 0.28 0.55) for a score of 4-<5, and 0.24 (95% CI: 0.15-0.38) for a score of ?5. CONCLUSION: Our study indicates that high adherence to the WCRF/AICR recommendations for cancer prevention is associated with a substantially decreased risk of head and neck cancers. PMID- 28024726 TI - Defining the boundaries and expanding the utility of head and neck cancer patient derived xenografts. AB - BACKGROUND: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system. METHODS: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1. First and last passaged PDXs were compared via a paired t-test to examine for the stability of protein expression across passages. We performed a similar comparison of the mutational profile of the patient tumor and resulting xenografts using a targeted sequencing approach. RESULTS: No patient/tumor characteristics influenced PDX take rate and the 24-h time delay from tumor excision to xenograft implantation did not affect PDX establishment, growth or histology. There was no significant difference in biomarker expression between the first and last passaged PDXs for EGFR, pEGFR, pAkt, and ERCC1. For pERK there was a significant difference (p=0.002), but further analysis demonstrated this only arose in three of 15 PDXs. Targeted sequencing revealed striking stability of passenger and likely driver mutations from patient to xenograft. CONCLUSIONS: The stability of protein expression across PDX passages will hopefully allow greater investigation of predictive biomarkers in order to identify ones for further pre-clinical and clinical investigation. PMID- 28024727 TI - Refining the definition of mandibular osteoradionecrosis in clinical trials: The cancer research UK HOPON trial (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis). AB - INTRODUCTION: Mandibular osteoradionecrosis (ORN) is a common and serious complication of head and neck radiotherapy for which there is little reliable evidence for prevention or treatment. The diagnosis and classification of ORN have been inconsistently and imprecisely defined, even in clinical trials. METHODS: A systematic review of diagnosis and classifications of ORN with specific focus on clinical trials is presented. The most suitable classification was evaluated for consistency using blinded independent review of outcome data (clinical photographs and radiographs) in the HOPON trial. RESULTS: Of 16 ORN classifications found, only one (Notani) appeared suitable as an endpoint in clinical trials. Clinical records of 217 timepoints were analysed amongst 94 randomised patients in the HOPON trial. The only inconsistency in classification arose where minor bone spicules (MBS) were apparent, which occurred in 19% of patients. Some trial investigators judged MBS as clinically unimportant and not reflecting ORN, others classified as ORN based on rigid definitions in common clinical use. When MBS was added as a distinct category to the Notani classification this ambiguity was resolved and agreement between observers was achieved. DISCUSSION: Most definitions and clinical classifications are based on retrospective case series and may be unsuitable for prospective interventional trials of ORN prevention or treatment. When ORN is used as a primary or secondary outcome in prospective clinical trials, the use of Notani classification with the additional category of MBS is recommended as it avoids subjectivity and enhances reliability and consistency of reporting. PMID- 28024728 TI - Laryngeal tumours and radiotherapy dose to the cricopharyngeus are predictive of death from aspiration pneumonia. AB - OBJECTIVES: Aspiration pneumonia is an under-reported treatment sequelae following radiotherapy for head and neck cancer (HNC) patients. This study aims to investigate its incidence and risk factors in this population. MATERIALS AND METHODS: A retrospective review of all HNC patients that had received radiotherapy or chemo radiotherapy with radical intent at a single institution was undertaken (n=206). Dose delivered to the pharyngeal constrictors, base of tongue and cricopharyngeus was calculated and compared between those patients who had died from aspiration pneumonia and those who are alive or had died from other causes. RESULTS: In a cohort of 206 patients, the median time of follow up was 3.5years (IQR 1.8-4.9years). The cause of death was known in 80 and one of the leading causes of non-cancer related mortality was aspiration pneumonia (n=12) equating to an annual incidence of 0.016. Patients with a tumour located in the larynx had a higher risk of death compared to other sites (p=0.005). The mean cricopharyngeal dose was significantly higher in those patients who died of aspiration pneumonia (p=0.023) compared to those who were still alive or had died from other causes. In a multivariate regression analysis, maximum cricopharyngeal dose is a significant predictor of death from aspiration pneumonia. CONCLUSION: Dose to the cricopharyngeus and tumours located within the larynx is associated with an increased mortality due to aspiration pneumonia. Clinical awareness of high risk groups and more studies into causative nature are needed. PMID- 28024729 TI - [Solitary primary splenic lymphangioma]. PMID- 28024730 TI - [Efficiency of laparoscopic vs endoscopic management in cholelithiasis and choledocholithiasis. Is there any difference?] AB - BACKGROUND: Concomitant cholelithiasis and choledocholithiasis is a disease where incidence increases with age and can have serious complications such as pancreatitis, cholangitis and liver abscesses, but its management is controversial, because there are minimally invasive laparoscopic and endoscopic surgical procedures. OBJECTIVE: To compare the efficiency in the management of cholelithiasis and choledocholithiasis with laparoscopic cholecystectomy with common bile duct exploration vs cholangiopancreatography endoscopic retrograde+laparoscopic cholecystectomy. MATERIAL AND METHOD: Retrospective analysis of a five year observational, cross sectional multicenter study of patients with cholelithiasis and concomitant high risk of choledocholithiasis who were divided into two groups and the efficiency of both procedures was compared. Group 1 underwent laparoscopic cholecystectomy with common bile duct exploration and group 2 underwent cholangiopancreatography endoscopic retrograde+laparoscopic cholecystectomy. RESULTS: 40 patients, 20 were included in each group, we found p=0.10 in terms of operating time; when we compared hospital days we found p=0.63; the success of stone extraction by study group we obtained was p=0.15; the complications presented by group was p=0.1 and the number of hospitalizations by group was p <= 0.05 demonstrating statistical significance. CONCLUSIONS: Both approaches have the same efficiency in the management of cholelithiasis and choledocholithiasis in terms of operating time, success in extracting stone, days of hospitalization, postoperative complications and conversion to open surgery. However the laparoscopic approach is favourable because it reduces the number of surgical anaesthetic events and the number of hospital admissions. PMID- 28024731 TI - Olive oil polyphenols: A quantitative method by high-performance liquid chromatography-diode-array detection for their determination and the assessment of the related health claim. AB - In order to assess if an extra virgin olive oil (EVOO) can be acknowledged with the health claim related to olive oil polyphenols (Reg. EU n.432/2012), a new method to quantify these species in EVOO, by means of liquid-liquid extraction followed by HPLC-DAD/MS/MS of the hydroalcoholic extract, has been developed and validated. Different extraction procedures, different types of reverse-phase analytical columns (Synergi Polar, Spherisorb ODS2 and Kinetex) and eluents have been tested. The chromatographic column Synergi Polar (250*4.6mm, 4MUm), never used before in this kind of application, provided the best results, with water and methanol/isopropanol (9/1) as eluents. The method allows the quantification of the phenolic alcohols tyrosol and hydroxytyrosol, the phenolic acids vanillic, p-coumaric and ferulic acids, secoiridoids derivatives, the lignans, pinoresinol and acetoxypinoresinol and the flavonoids luteolin and apigenin. The new method has been applied to 20 commercial EVOOs belonging to two different price range categories (3.78-5.80 euros/L and 9.5-25.80 euros/L) and 5 olive oils. The obtained results highlight that acetoxypinoresinol, ferulic acid, vanillic acid and the total non secoiridoid phenolic substances resulted to be significantly higher in HEVOOs than in LEVOOs (P=0.0026, 0.0217, 0.0092, 0.0003 respectively). For most of the samples analysed there is excellent agreement between the results obtained by applying the HPLC method adopted by the International Olive Council and the results obtained by applying the presented HPLC method. Results obtained by HPLC methods have been also compared with the ones obtained by the colorimetric Folin-Ciocalteu method. PMID- 28024732 TI - MRI-guided laser interstitial thermal therapy for treatment of medically refractory non-lesional mesial temporal lobe epilepsy: Outcomes, complications, and current limitations: A review. AB - There is a new focus on minimally invasive treatments for medically refractory mesial temporal lobe epilepsy (MTLE). MRI-guided laser interstitial thermal therapy (MRgLITT) is one such minimally invasive procedure, which utilizes MRI guidance and real-time feedback to ablate an epileptogenic focus. A total of 38 patients presenting exclusively with MTLE and no other lesions (including neoplasia), who underwent MRgLITT were reviewed. We evaluated a number of outcome measures, including seizure freedom, neuropsychological performance, complications, and other considerations. Eighteen (53%) had an Engel class I outcome, 10 patients had repeat procedures/operations, and 12 post-procedural complications occurred. Follow-up time ranged from 6 to 38.5months. There was a decreased length of procedure time, hospitalization time, and analgesic requirement when compared to open surgery. In cases of well-localized MTLE this procedure may offer similar (albeit slightly lower) rates of seizure freedom versus traditional surgery. MRgLITT may be an alternative treatment option for high risk surgical patients and, more importantly, could increase referrals for surgery in patients with medically refractory MTLE. However, data is limited and long-term outcomes have not been evaluated. Further investigation is required to understand the potential of this minimally invasive technique for MTLE. PMID- 28024733 TI - Racial disparities in anaplastic oligodendroglioma: An analysis on 1643 patients. AB - The objective of our study is to determine the influence of race on overall survival (OS) for anaplastic oligodendroglioma (AO). Data were extracted from the National Cancer Data Base (NCDB). Chi-square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 1643 patients with AO were identified. 1386 (84.3%) were White, 83 (5.0%) Black, 133 (8.1%) Hispanic, and 41 (2.5%) were Asian. White and Black patients were significantly older than Hispanic and Asian patients (49.3% vs. 49.4% vs. 33.1% vs. 39.0%, p=0.003). Black patients were significantly less likely to be insured than White patients (12.8 vs. 7.2%, p<0.001) and significantly more likely to have lower income than other races (p<0.001). A trend towards higher comorbidity burden and lower rate of gross total resection was seen in Black patients. Black patients had significantly worse five-year OS compared to White, Hispanic, and Asian patients (40.3% vs. 52.3% vs. 67.8% vs. 67.7%, p=0.028). Of those who received adjuvant chemoRT, Black patients still had significantly worse OS compared to White patients (p=0.021). On multivariate analysis, Black race, older age at diagnosis, and not receiving adjuvant chemoradiotherapy were independent prognostic factors for worse OS in anaplastic oligodendroglioma. Future studies are warranted to help determine predictors for unfavorable molecular status, ways to optimize management of comorbidities, and interventions to help ensure adequate access to medical care for all patients to better care for those who may be at more risk for poorer outcome. PMID- 28024735 TI - Metabolic Syndrome, Gastric Cancer Mortality and Competing Risk Survival Analysis. PMID- 28024736 TI - [Elevated serum aldosterone levels in dialysis patients: Are we underusing renin angiotensin-aldosterone system blockers?] AB - : Serum aldosteronelevels (SA) are a marker of cardiovascular (CV) risk in the general population. OBJECTIVE: To analyze SA levels in dialysis patients and its relationship with characteristics of dialysis; comorbidity; blood pressure and the use of blocking renin-angiotensin-aldosterone system agents (BSRAA). METHODS: We determined SA in 102 patients: 81 on hemodialysis (HD) and 21 on peritoneal dialysis. Mean age 71.4+/-12 years; 54.9% male; 29.4% diabetics. Mean time on dialysis 59.3+/-67 months. In 44 HD patients plasma renin activity (PRA) was measured. RESULTS: Mean SA was 72.6+/-114.9ng/dl (normal range 1.17-23.6ng/dl). A total of 57.8% of patients had above normal levels which were not related to dialysis characteristics or comorbidity. Only 21% of patients with heart failure and 19.2% with ischemic heart disease used BSRAA. A number of 25 patients treated with BSRAA had significantly lower levels of SA. There was an inverse correlation between AS and systolic blood pressure (SBP), and direct with PRA. The logistic regression analysis conducted to find SA levels above the median associated factors showed that SBP was the only independent risk variable in the overall population (OR 0.97; P=.022); in the 44 patients in whom PRA was determined this was the only independent risk factor (OR 2.24; P=.012). CONCLUSIONS: A high percentage of dialysis patients have elevated levels of SA that are associated to diminished SBP and activated PRA and not to dialysis characteristics. In patients with a history of heart disease we underuse BSRAA. PMID- 28024734 TI - Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma. AB - In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85alpha/Akt pathway and NFkappaB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFkappaB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma. PMID- 28024737 TI - Testicular ectopia: Why does it happen and what do we do? AB - BACKGROUND/AIM: Testicular ectopia is rare, but the large range of anatomical locations described in the literature has spawned an abundance of possible theories to explain etiology. However, as the anatomical characteristics of normal testicular descent have only been elucidated recently, many of the theories of testicular ectopia do not incorporate this new perspective. In this study we aimed to determine what was in the literature about ectopic testis since 1980, and then try to explain the different anatomical variants in the light of current knowledge about testicular descent. METHODS: A literature search was performed and all articles in English published since 1980 about testicular ectopia using several key words were identified. RESULTS: A total of 271 articles in English were found, of which 31 addressed the pathophysiology and are the primary focus of this study. Case reports and reviews described perineal ectopia (*4), transverse testicular ectopia (*11), and abdominal ectopia (*2), along with 3 reviews/case reports addressing diagnosis and management. A range of proposed causes were found, including obstructed 'third inguinal ring' at neck of scrotum, abnormal CGRP function, aberrant distal gubernacular attachment, mechanical hindrance from retained Mullerian ducts, defective gubernacular formation or disruption of the gubernacular attachment to the testis. CONCLUSION: After reviewing the proposed theories, we propose a unifying theory, based on current knowledge of testicular descent, where testicular ectopia can be explained by a) anomalous attachment of the gubernaculum to the anterior abdominal wall during transabdominal descent, or b) aberrant migration of the gubernaculum during the inguinoscrotal phase of testicular descent. PMID- 28024738 TI - Recent epidemiology of Streptococcus pneumoniae in nasopharynxes of Korean children with acute otitis media. AB - BACKGROUND: This prospective study was performed to evaluate serotype distribution, multilocus sequence typing, and antibiotic susceptibility of Streptococcus pneumoniae identified in Korean children with acute otitis media (AOM) after the introduction of a 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: Nasopharyngeal aspirates were collected from children diagnosed with AOM in seven hospitals in Korea. The bacteria identified in these samples and the serotypes, sequence types (STs), and antibiotic susceptibilities of S. pneumoniae isolates were evaluated. RESULTS: A total of 390 children were enrolled, and bacteria were identified in 376 (96.4%) children. S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were identified in 155 (39.7%), 127 (32.6%) and 86 (22.1%) children, respectively. Serotype 19A (22.4%) was the most common S. pneumoniae serotype, with serogroups 11 (14.7%) and 15 (13.5%) following. ST320 (23.5%) was the most common ST; ST166 (17.0%) and ST83 (8.5%) followed. The overall susceptibility rates of S. pneumoniae to oral penicillin V and amoxicillin/clavulanate were 2.6% and 53.2%, respectively. The susceptibility rate to cefditoren was 91.0%; however, the rates for other cephalosporins were less than 10.0%. Compared with other serogroups, S. pneumoniae serogroups 19, 11, and 15 showed significantly lower susceptibility rates to all the antibiotics tested. CONCLUSION: S. pneumoniae serotype 19A, serogroups 11 and 15 were the major nasopharyngeal-colonizing bacteria in Korean children with AOM after the introduction of PCV7. These relatively prevalent serotype/serogroups showed lower antibiotic susceptibility rates. PMID- 28024739 TI - Pneumococcal biliary tract infections - How rare are they? AB - Pneumococcal biliary tract infections (PBTIs) were reported as rare due to the bacterium's bile solubility. The purpose of this study was to determine the occurrence and clinical characteristics of PBTIs. A retrospective case series review was conducted from January 2006 to August 2014 at a tertiary referral university hospital in Japan. Patients with a blood or bile culture positive for Streptococcus pneumoniae diagnosed with definite cholangitis or cholecystitis according to Tokyo Guideline 2013 were enrolled in this study. Data on clinical information, treatments, and outcomes were collected. During 104 months, 48 cases of positive blood cultures and 13 cases of positive bile cultures were recorded, and after excluding 43 and 5 of these, respectively, a total of 10 patients were diagnosed with PBTI. Most patients (9/10) had biliary tract problems and biliary devices in place. PBTIs were not rare; conversely, they were a relatively common cause of pneumococcal bacteremia in this center treating a high volume of biliary tract illnesses. PMID- 28024740 TI - Impact of procalcitonin-guided therapy for hospitalized community-acquired pneumonia on reducing antibiotic consumption and costs in Japan. AB - BACKGROUND AND OBJECTIVE: This study aimed to investigate the usefulness of procalcitonin-guided therapy in hospitalized community-acquired pneumonia patients to reduce antibiotic duration and costs without worsening prognosis. METHODS: 352 hospitalized community-acquired pneumonia patients in an observational cohort study in which procalcitonin was measured three times serially, on admission (Day 1) and 2-3 days (Day 3) and 6-8 days (Day 7) after admission, between October 2010 and February 2016 were reviewed retrospectively. Antibiotics could be stopped if Day 7 procalcitonin was <0.25 ng mL-1 or <=10% of the higher value of procalcitonin on Day 1 or 3. Antibiotic duration and costs and recurrence and mortality rates were evaluated in mild to moderate or severe pneumonia by theoretical procalcitonin guidance for community-acquired pneumonia treatment. RESULTS: Using theoretical procalcitonin guidance, antibiotic duration could be reduced from 12.6 to 8.6 days (P < 0.001), while costs could be reduced from 45,833 to 38,952 yen (P = 0.005). Among the patients in whom theoretical procalcitonin guidance could be adopted, recurrence rates (5.6% vs. 8.1%, P = 0.15) and mortality rates (0% vs. 5.1%, P = 0.07) did not worsen between the group having the same antibiotic durations as with theoretical procalcitonin guidance in actual practice (N = 71) and the group having durations more than 2 days longer in actual practice than in theoretical procalcitonin guidance (N = 198). There was no significant difference in pneumonia severity using A-DROP, CURB-65, and PSI between two groups. CONCLUSIONS: Procalcitonin-guided therapy may be useful in hospitalized community-acquired pneumonia patients to reduce antibiotic duration and costs without worsening the prognosis. PMID- 28024741 TI - Characterization of PBDEs and novel brominated flame retardants in seawater near a coastal mariculture area of the Bohai Sea, China. AB - The concentrations and distributions of PBDEs and novel brominated flame retardants (NBFRs) in dissolved phase of surface seawater near a coastal mariculture area of the Bohai Sea were investigated. The total concentrations of PBDE and NBFRs were in the range of 15.4-65.5 and 2.12-13.6ng/L, respectively. The highest concentration was discovered in the water near an anchorage ground, whereas concentrations in water samples from offshore cage-culture area were not elevated. Relatively high concentrations of BDE28, 99, and 100 were discovered in the medium range of distance from shore, where is the path of tidal or coastal current. This suggested that inputs from ships or through tidal current rather than mariculture activities may be the main sources of BFRs in this area. BDE209, BDE47, hexabromobenzene (HBB), and 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) were the most abundant BFR congeners. Relatively high proportions of these BFRs may originate from discharge of wastewater nearby or degradation from higher brominated PBDEs. No correlations were found between BFR concentrations and water dissolved organic carbon, suggesting that concentrations and distributions of BFRs in this area were source-dependent. The relatively high concentrations in this study emphasized the importance of monitoring and managing BFR contaminations in mariculture areas of China. PMID- 28024742 TI - Influence of porewater sulfide on methylmercury production and partitioning in sulfate-impacted lake sediments. AB - In low-sulfate and sulfate-limited freshwater sediments, sulfate loading increases the production of methylmercury (MeHg), a potent and bioaccumulative neurotoxin. Sulfate loading to anoxic sediments leads to sulfide production that can inhibit mercury methylation, but this has not been commonly observed in freshwater lakes and wetlands. In this study, sediments were collected from sulfate-impacted, neutral pH, surface water bodies located downstream from ongoing and historic mining activities to examine how chronic sulfate loading produces porewater sulfide, and influences MeHg production and transport. Sediments were collected over two years, during several seasons from lakes with a wide range of overlying water sulfate concentration. Samples were characterized for in-situ solid phase and porewater MeHg, Hg methylation potentials via incubations with enriched stable Hg isotopes, and sulfur, carbon, and iron content and speciation. Porewater sulfide reflected historic sulfur loading and was strongly related to the extractable iron content of sediment. Overall, methylation potentials were consistent with the accumulation of MeHg on the solid phase, but both methylation potentials and MeHg were significantly lower at chronically sulfate-impacted sites with a low solid-phase Fe:S ratio. At these heavily sulfate-impacted sites that also contained elevated porewater sulfide, both MeHg production and partitioning are influenced: Hg methylation potentials and sediment MeHg concentrations are lower, but occasionally porewater MeHg concentrations in sediment are elevated, particularly in the spring. The dual role of sulfide as a ligand for inorganic mercury (decreasing bioavailability) and methylmercury (increasing partitioning into porewater) means that elucidating the role of iron and sulfur loads as they define porewater sulfide is key to understanding sulfate's influence on MeHg production and partitioning in sulfate impacted freshwater sediment. PMID- 28024744 TI - Is an ecosystem services-based approach developed for setting specific protection goals for plant protection products applicable to other chemicals? AB - Clearly defined protection goals specifying what to protect, where and when, are required for designing scientifically sound risk assessments and effective risk management of chemicals. Environmental protection goals specified in EU legislation are defined in general terms, resulting in uncertainty in how to achieve them. In 2010, the European Food Safety Authority (EFSA) published a framework to identify more specific protection goals based on ecosystem services potentially affected by plant protection products. But how applicable is this framework to chemicals with different emission scenarios and receptor ecosystems? Four case studies used to address this question were: (i) oil refinery waste water exposure in estuarine environments; (ii) oil dispersant exposure in aquatic environments; (iii) down the drain chemicals exposure in a wide range of ecosystems (terrestrial and aquatic); (iv) persistent organic pollutant exposure in remote (pristine) Arctic environments. A four-step process was followed to identify ecosystems and services potentially impacted by chemical emissions and to define specific protection goals. Case studies demonstrated that, in principle, the ecosystem services concept and the EFSA framework can be applied to derive specific protection goals for a broad range of chemical exposure scenarios. By identifying key habitats and ecosystem services of concern, the approach offers the potential for greater spatial and temporal resolution, together with increased environmental relevance, in chemical risk assessments. With modifications including improved clarity on terminology/definitions and further development/refinement of the key concepts, we believe the principles of the EFSA framework could provide a methodical approach to the identification and prioritization of ecosystems, ecosystem services and the service providing units that are most at risk from chemical exposure. PMID- 28024745 TI - Assessment of ambient background concentrations of elements in soil using combined survey and open-source data. AB - Understanding ambient background concentrations in soil, at a local scale, is an essential part of environmental risk assessment. Where high resolution geochemical soil surveys have not been undertaken, soil data from alternative sources, such as environmental site assessment reports, can be used to support an understanding of ambient background conditions. Concentrations of metals/metalloids (As, Mn, Ni, Pb and Zn) were extracted from open-source environmental site assessment reports, for soils derived from the Newer Volcanics basalt, of Melbourne, Victoria, Australia. A manual screening method was applied to remove samples that were indicated to be contaminated by point sources and hence not representative of ambient background conditions. The manual screening approach was validated by comparison to data from a targeted background soil survey. Statistical methods for exclusion of contaminated samples from background soil datasets were compared to the manual screening method. The statistical methods tested included the Median plus Two Median Absolute Deviations, the upper whisker of a normal and log transformed Tukey boxplot, the point of inflection on a cumulative frequency plot and the 95th percentile. We have demonstrated that where anomalous sample results cannot be screened using site information, the Median plus Two Median Absolute Deviations is a conservative method for derivation of ambient background upper concentration limits (i.e. expected maximums). The upper whisker of a boxplot and the point of inflection on a cumulative frequency plot, were also considered adequate methods for deriving ambient background upper concentration limits, where the percentage of contaminated samples is <25%. Median ambient background concentrations of metals/metalloids in the Newer Volcanic soils of Melbourne were comparable to ambient background concentrations in Europe and the United States, except for Ni, which was naturally enriched in the basalt-derived soils of Melbourne. PMID- 28024743 TI - Human exposure to organic arsenic species from seafood. AB - Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be non-toxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge. PMID- 28024746 TI - Citizen science-based water quality monitoring: Constructing a large database to characterize the impacts of combined sewer overflow in New York City. AB - To protect recreational water users from waterborne pathogen exposure, it is crucial that waterways are monitored for the presence of harmful bacteria. In NYC, a citizen science campaign is monitoring waterways impacted by inputs of storm water and untreated sewage during periods of rainfall. However, the spatial and temporal scales over which the monitoring program can sample are constrained by cost and time, thus hindering the construction of databases that benefit both scientists and citizens. In this study, we first illustrate the scientific value of a citizen scientist monitoring campaign by using the data collected through the campaign to characterize the seasonal variability of sampled bacterial concentration as well as its response to antecedent rainfall. Second, we examine the efficacy of the HyServe Compact Dry ETC method, a lower cost and time efficient alternative to the EPA-approved IDEXX Enterolert method for fecal indicator monitoring, through a paired sample comparison of IDEXX and HyServe (total of 424 paired samples). The HyServe and IDEXX methods return the same result for over 80% of the samples with regard to whether a water sample is above or below the EPA's recreational water quality criteria for a single sample of 110 enterococci per 100mL. The HyServe method classified as unsafe 90% of the 119 water samples that were classified as having unsafe enterococci concentrations by the more established IDEXX method. This study seeks to encourage other scientists to engage with citizen scientist communities and to also pursue the development of cost- and time-efficient methodologies to sample environmental variables that are not easily collected or analyzed in an automated manner. PMID- 28024747 TI - Greenhouse gas footprint and the carbon flow associated with different solid waste management strategy for urban metabolism in Bangladesh. AB - Greenhouse gas (GHG) emissions from municipal solid waste (MSW) and associated climate change consequences are gripping attention globally, while MSW management as a vital subsystem of urban metabolism significantly influences the urban carbon cycles. This study evaluates the GHG emissions and carbon flow of existing and proposed MSW management in Bangladesh through scenario analysis, including landfill with landfill gas (LFG) recovery, waste to energy (WtE), and material recovery facility (MRF). The analysis indicates that, scenario H2 and H5 emitted net GHGs -152.20kg CO2 eq. and -140.32kg CO2 eq., respectively, in comparison with 420.88kg CO2 eq. of scenario H1 for managing per ton of wastes during the reference year 2015. The annual horizontal carbon flux of the waste input was 319Gg and 158Gg during 2015 in Dhaka and Chittagong, respectively. An integrated strategy of managing the wastes in the urban areas of Bangladesh involving WtE incineration plant and LFG recovery to generate electricity as well as MRF could reverse back 209.46Gg carbon and 422.29Gg carbon to the Chittagong and Dhaka urban system, respectively. This study provides valuable insights for the MSW policy framework and revamp of existing MSW management practices with regards to reduction of GHGs emissions from the waste sector in Bangladesh. PMID- 28024748 TI - Realistic pesticide exposure through water and food amplifies long-term effects in a Limnephilid caddisfly. AB - Pesticides are increasingly recognized as relevant stressors in stream ecosystems. Stream biota is exposed to pesticides with low water solubility, e.g. pyrethroid insecticides, via water, habitat, and food. However, long-term effects of simultaneous exposure pathways are unknown. In this context, we conducted a microcosm experiment with the caddisfly Anabolia nervosa exposing the larvae to the pyrethroid insecticide esfenvalerate (EFV) at 0.1 and 1.0MUgL-1 via (i) water, (ii) food or a (iii) combination of water and food. Combined exposure through water and food significantly reduced emergence by 60% and significantly postponed emergence timing at the highest EFV level, whereas none of the single phase exposures showed significant effects. Moreover, our study revealed that successfully emerged females from the highest biphasic treatment level were characterised by altered composition of storage lipids indicative of reduced energy reserves. Consequently, a realistic test scenario that represents simultaneous exposure of organisms and their food may reveal substantially increased long term effects of pyrethroids when compared with current ecological risk assessment applying only single phase exposure. We recommend that relevant concurrent exposure routes of pesticides should be considered in order to derive realistic regulatory acceptable concentrations of pesticides. PMID- 28024749 TI - Influence of the vegetative cover on the fate of trace metals in retention systems simulating roadside infiltration swales. AB - Large-scale outdoor mesocosms were designed and co-contaminated with metals (Cd, Pb, Zn) and organic compounds to better understand the complex functioning of urban roadside swale environments. Infiltration systems were planted with macrophytes (P. arundinaceae, J. effusus and I. pseudacorus) or grassed, and natural or spiked target metals were monitored over two years. In the non-spiked mesocosms, atmospheric metal inputs were slightly higher than outputs, leading to low metal accumulation in topsoils and to very low outflow water contamination (<0.7% of the initial metal stock). In the spiked infiltration systems that simulated point pollution through water inflow, transfer of the initial stock of metals to the deeper soil layers was quite low and outflow water contamination was very low (<0.6% of the initial stock). The main metal output from these systems occurred in the first days of their installation because of the high metal solubility in water and insufficient plant cover at that time. The infiltration systems stabilized after a few weeks, probably because of stronger sorption to soil aggregates, and because of plant root development. Mephytoextraction in plant roots was more efficient in mesocosms planted with P. arundinacea and grass. Metal phytoextraction in plant aerial parts was also better for grass and P. arundinacea, when considering metal standing stocks instead of their concentration in plants. J. effusus was a good metal accumulator, but its low aboveground biomass development was less favorable to metal removal through harvesting. PMID- 28024750 TI - Rainfall-runoff of anthropogenic waste indicators from agricultural fields applied with municipal biosolids. AB - The presence of anthropogenic contaminants such as antimicrobials, flame retardants, and plasticizers in runoff from agricultural fields applied with municipal biosolids may pose a potential threat to the environment. This study assesses the potential for rainfall-induced runoff of 69 anthropogenic waste indicators (AWIs), widely found in household and industrial products, from biosolids amended field plots. The agricultural field containing the test plots was treated with biosolids for the first time immediately prior to this study. AWIs present in soil and biosolids were isolated by continuous liquid-liquid extraction and analyzed by full-scan gas chromatography/mass spectrometry. Results for 18 AWIs were not evaluated due to their presence in field blank QC samples, and another 34 did not have sufficient detection frequency in samples to analyze trends in data. A total of 17 AWIs, including 4-nonylphenol, triclosan, and tris(2-butoxyethyl)phosphate, were present in runoff with acceptable data quality and frequency for subsequent interpretation. Runoff samples were collected 5days prior to and 1, 9, and 35days after biosolids application. Of the 17 AWIs considered, 14 were not detected in pre-application samples, or their concentrations were much smaller than in the sample collected one day after application. A range of trends was observed for individual AWI concentrations (typically from 0.1 to 10MUg/L) over the course of the study, depending on the combination of partitioning and degradation mechanisms affecting each compound most strongly. Overall, these results indicate that rainfall can mobilize anthropogenic contaminants from biosolids-amended agricultural fields, directly to surface waters and redistribute them to terrestrial sites away from the point of application via runoff. For 14 of 17 compounds examined, the potential for runoff remobilization during rainstorms persists even after three 100-year rainstorm-equivalent simulations and the passage of a month. PMID- 28024751 TI - Assessing the environmental impacts of freshwater thermal pollution from global power generation in LCA. AB - Freshwater heat emissions from power plants with once-through cooling systems constitute one of many environmental pressures related to the thermoelectric power industry. The objective of this work was to obtain high resolution, operational characterization factors (CF) for the impact of heat emissions on ecosystem quality, and carry out a comprehensive, spatially, temporally and technologically differentiated damage-based environmental assessment of global freshwater thermal pollution. The aggregation of CFs on a watershed level results in 12.5% lower annual impacts globally and even smaller differences for the most crucial watersheds and months, so watershed level CFs are recommended when the exact emission site within the basin is unknown. Long-range impacts account for almost 90% of the total global impacts. The Great Lakes, several Mississippi subbasins, the Danube, and the Yangtze are among the most thermally impacted watersheds globally, receiving heat emissions from predominantly coal-fuelled and nuclear power plants. Globally, over 80% of the global annual impacts come from power plants constructed during or before the 1980s. While the impact-weighted mean age of the power plants in the Mississippi ranges from 38 to 51years, in Chinese watersheds including the Yangtze, the equivalent range is only 15 to 22years, reflecting a stark contrast in thermal pollution mitigation approaches. With relatively high shares of total capacity from power plants with once-through freshwater cooling, and tracing a large part of the Danube, 1kWh of net electricity mix is the most impactful in Hungary, Bulgaria and Serbia. Monthly CFs are provided on a grid cell level and on a watershed level for use in Life Cycle Assessment. The impacts per generating unit are also provided, as part of our effort to make available a global dataset of thermoelectric power plant emissions and impacts. PMID- 28024752 TI - Nationwide reconnaissance of contaminants of emerging concern in source and treated drinking waters of the United States. AB - When chemical or microbial contaminants are assessed for potential effect or possible regulation in ambient and drinking waters, a critical first step is determining if the contaminants occur and if they are at concentrations that may cause human or ecological health concerns. To this end, source and treated drinking water samples from 29 drinking water treatment plants (DWTPs) were analyzed as part of a two-phase study to determine whether chemical and microbial constituents, many of which are considered contaminants of emerging concern, were detectable in the waters. Of the 84 chemicals monitored in the 9 Phase I DWTPs, 27 were detected at least once in the source water, and 21 were detected at least once in treated drinking water. In Phase II, which was a broader and more comprehensive assessment, 247 chemical and microbial analytes were measured in 25 DWTPs, with 148 detected at least once in the source water, and 121 detected at least once in the treated drinking water. The frequency of detection was often related to the analyte's contaminant class, as pharmaceuticals and anthropogenic waste indicators tended to be infrequently detected and more easily removed during treatment, while per and polyfluoroalkyl substances and inorganic constituents were both more frequently detected and, overall, more resistant to treatment. The data collected as part of this project will be used to help inform evaluation of unregulated contaminants in surface water, groundwater, and drinking water. PMID- 28024753 TI - Local and regional contributions to fine particulate matter in Beijing during heavy haze episodes. AB - In order to alleviate extreme haze pollution, understanding the origin of fine particulate matter (PM2.5) is crucial. In this study, we applied Particulate Matter Source Apportionment Technology (PSAT) in CAMx (Comprehensive Air Quality Model with Extensions) to quantify the impacts of emissions from different regions on PM2.5 concentrations in Beijing for haze episodes during January 6-23, 2013. Emission inventory was developed by Tsinghua University. Evolution of local and Regional contributions during local and non-local dominated haze episodes were discussed, separately. In the meanwhile, average contribution of other every city in Jing-Jin-Ji region to PM2.5 concentrations larger than 75MUgm-3 in Beijing urban for each range of local contribution percent was analyzed. The results indicate that local emissions contributed 83.6% of PM2.5 at the urban center of Beijing, while regional transport from surrounding cities and parts of Shandong, Henan and Anhui provinces contributed 9.4%; long-range transport contributed the remaining 7.0% mainly from areas >750km away to the south of Beijing during this study period. Compared to non-local-dominated haze episodes, local-dominated heavy haze episodes in Beijing were easily resulted from unfavorable meteorological conditions with much lower PBL and wind velocity. Furthermore, local contribution is more easily to cause a sharp increase or sharp reduction of PM2.5 concentration in central Beijing, reflecting that Beijing local has much stronger potential to form extremely heavy haze episodes. The results indicated that controlling local emissions is a much more important measure to alleviate the extreme haze episodes in Beijing, like that on the night of Jan 12, 2013. Furthermore, emission control in Jing-Jin-Ji region, especially in Tangshan, Tianjin, Baoding, Langfang, Shijiazhuang and Cangzhou, as well as Henan and Shandong province, are important to reduce the PM2.5 concentrations and the occurrence of haze episodes in Beijing. PMID- 28024754 TI - MIPs-graphene nanoplatelets-MWCNTs modified glassy carbon electrode for the determination of cardiac troponin I. AB - An electrochemical sensor with high selectivity in addition to sensitivity was developed for the determination of cardiac troponin I (cTnI), based on the modification of cTnI imprinted polymer film on a glassy carbon electrode (GCE). The sensor was fabricated by layer-by-layer assembled graphene nanoplatelets (GS), multiwalled carbon nanotubes (MWCNTs), chitosan (CS), glutaraldehyde (GA) composites, which can increase the electronic transfer rate and the active surface area to capture a larger number of antigenic proteins. MWCNTs/GS based imprinted polymers (MIPs/MWCNTs/GS) were synthesized by means of methacrylic acid (MAA) as the monomer, ethylene glycol dimethacrylate (EGDMA) as the cross linker alpha,alpha'-azobisisobutyronitrile (AIBN) as the initiator and cTnI as the template. In comparison with conventional methods, the proposed electrochemical sensor is highly sensitive for cTnI, providing a better linear response range from 0.005 to 60 ng cm-3 and a lower limit of detection (LOD) of 0.0008 ng cm-3 under optimal experimental conditions. In addition, the electrochemical sensor exhibited good specificity, acceptable reproducibility and stability. Moreover, satisfactory results were obtained in real human serum samples, indicating that the developed method has the potential to find application in clinical detection of cTnI as an alternative approach. PMID- 28024755 TI - Characterization of charge variants of a monoclonal antibody using weak anion exchange chromatography at subunit levels. AB - An efficient strategy to characterize recombinant monoclonal antibody charge variants was established using weak anion exchange chromatography, LC-MS and IdeS digestion to allow subunit level characterization. Significantly higher resolution was achieved at subunit levels by weak anion exchange chromatography and LC-MS. In addition, subunit analysis localized potential modifications to either F(ab')2 or Fc fragments to facilitate further characterization. Peptide mapping of fractions from various charge variants after IdeS digestion identified aspartate isomerization, asparagine deamidation and glycation as the modifications. Although, aspartate isomerization does not generate net charge difference directly, it does generate antibody basic species. Antibodies with either isoaspartate or aspartate from deamidation showed different retention times by chromatography. Even more interestingly, the antibody contained succinimide as the isomerization intermediate, which though more basic compared to aspartate, eluted off the weak anion exchange column as an acidic species. The results demonstrated not only the utility of subunit level characterization but also the unpredictable chromatographic behavior of antibody charge variants. PMID- 28024756 TI - Tools to assess risk of bias in systematic reviews of nursing intervention in China: Global implications of the findings. AB - BACKGROUND: The number of systematic reviews (SRs) of nursing interventions is increasing in China. Authors of such studies are encouraged to use a risk of bias tool for assessing individual studies. Therefore, it is important to know how these tools have been applied in SRs in Chinese nursing. PURPOSE: The purpose of the study is to examine risk of bias tools used by Chinese nursing researchers to assess the quality of individual studies included in SRs of nursing interventions. METHODS: We searched the Chinese Biomedical Literature Database, Chinese Journal Full-Text Database, Chinese Academic Journal Full-Text Database, and Wanfang Database. Each relevant review found was subjected to quality assessment, data synthesis, and comprehensively described. DISCUSSION: Two hundred eight SRs were identified, most (94.7%) of which used the words "systematic review" or "meta-analysis" in their titles. Most used quality assessment rather than risk of bias as their major method to gauge quality; 7.6% reported on six domains of the Cochrane risk of bias tool. Only four provided a risk of bias graph/summary figure. CONCLUSIONS: Many SRs of nursing interventions are published in Chinese journals, and their assessment of risk of bias is usually either lacking or incomplete, potentially producing misleading results. This may also be the case in other countries. Assessment of risk of bias in SRs is a requisite. Authors who systematically review nursing literature should follow the latest Cochrane Collaboration Handbook. PMID- 28024757 TI - Expression of Inflammatory Cytokines and Chemokines in Replanted Permanent Teeth with External Root Resorption. AB - INTRODUCTION: The progressive forms of inflammatory external root resorption (IERR) and replacement external root resorption (RERR) are serious complications and the main causes of tooth loss after replantation. This study aimed to investigate the expression pattern of inflammatory molecules in extracted human teeth presenting with external root resorption (ERR) after replantation. METHODS: Root fragments from 22 teeth showing IERR and 20 teeth with RERR were triturated using a homogenizer to extract inflammatory molecules. Interleukin-1beta (IL 1beta), IL-1Ra, transforming growth factor beta, IL-8/CXCL8, CCL2, CCL3, and CCL5 were measured using double-ligand enzyme-linked immunosorbent assay, and IL-2, IL 4, IL-6, IL-10, tumor necrosis factor alpha, interferon gamma, and IL-17A detection was performed using the multiplex Th1/Th2/Th17 Cytometric Bead Array kit (BD Biosciences, San Jose, CA). Cytokine and chemokine concentrations were compared in the RERR and IERR groups corrected by patients' age at the moment of extraction, survival time after replantation, and index of ERR, adopting a generalized estimation equation model. RESULTS: The IERR group showed higher levels of tumor necrosis factor alpha than the RERR group, even after correction for the index of ERR (P < .05). IL-1Ra levels were higher in the IERR group for moderate cases but higher in the RERR group for severe cases (P < .05). IL-4 concentration became higher with the increase of patients' age in the RERR group but did not vary in the IERR group (P < .05). CCL2 levels decreased with the increase of the patients' age at the moment of extraction irrespective of the type or index of ERR (P < .05). CONCLUSIONS: The present results showed differences in the immunologic profile of IERR and RERR that may be relevant to understanding the biological mechanisms underlying ERR. PMID- 28024758 TI - Cone-beam Computed Tomography Uses in Clinical Endodontics: Observer Variability in Detecting Periapical Lesions. AB - INTRODUCTION: The accurate interpretation of a cone-beam computed tomographic (CBCT) volume is critical in identifying the presence of disease correctly and consistently. The aim of this clinical study was to determine the effect of experience level on the detection of periapical lesions in CBCT volumes. METHODS: CBCT volumes of 22 maxillary molars were interpreted by 3 endodontic faculty, 3 endodontic residents, and 3 dental students. These groups were compared with the consensus opinion of 2 experienced oral and maxillofacial radiologists. The observers determined the presence or absence of apical radiolucencies for each root using a 5-point Likert scale. RESULTS: Compared with the radiologists, the average weighted kappa value for endodontic faculty was 0.49, for endodontic residents it was 0.35 and for dental students it was 0.32. Intrarater reliability for each group showed endodontic faculty having the highest average weighted kappa value of 0.68 followed by endodontic residents (0.48) and dental students (0.28). CONCLUSIONS: Clinicians' experience level appears to be correlated with their ability to correctly diagnose periapical disease in CBCT volumes. In addition, experience leads to better inter-rater reliability. In neither of these 2 categories was agreement found to be excellent, suggesting that more can be done to improve the CBCT interpretation skills of clinicians at various levels of experience. PMID- 28024760 TI - Longitudinal vs retrospective studies. PMID- 28024759 TI - Rethinking American Board of Orthodontics Certification: A paradigm shift. PMID- 28024761 TI - Displacement and stress distribution by different bone-borne palatal expanders with facemask: A 3-dimensional finite element analysis. AB - INTRODUCTION: The purpose of this study was to analyze displacement and stress distribution in the maxilla during maxillary expansion followed by protraction using bone-borne and conventional tooth-borne palatal expanders and a facemask via 3-dimensional finite element analysis. METHODS: A finite element model of an adolescent skull was created, and 4 different types of appliances were integrated into it: facemask (type A); facemask with paramedian bone-borne expander (type B), facemask with palatal-slope bone-borne expander (type C), and facemask with conventional expander (type D). Expansion of 0.25 mm followed by 500 g of force per side was applied. RESULTS: Type A showed anterior displacement of the dentition combined with downward displacement of posterior teeth and upward displacement of anterior teeth. The combination of protraction and expansion in type D showed the greatest anterior displacement. In types B and C, the expansion forces resulted in posterior displacement decreasing the net displacement of the combination. Stresses concentrated around the miniscrews in types B and C. In types A and D, stresses concentrated at the first premolar and first molar. Type B had the highest stresses followed by type C and then D. CONCLUSIONS: The conventional tooth-borne expander (type D) enhanced the effect of maxillary protraction. Facemask alone (type A) resulted in more anterior displacement of the maxilla than the combination of facemask and bone-borne expanders (types B and C). The clinician should be aware of the initial stresses and movements from different expanders with facemask found in this study and confirm the movements in future clinical Class III studies. PMID- 28024762 TI - Correction. PMID- 28024763 TI - Authors' response. PMID- 28024764 TI - Precision of manual landmark identification between as-received and oriented volume-rendered cone-beam computed tomography images. AB - INTRODUCTION: The objective of this study was to evaluate the effect of the orientation of cone-beam computed tomography (CBCT) images on the precision and reliability of 3-dimensional cephalometric landmark identification. METHODS: Ten CBCT scans were used for manual landmark identification. Volume-rendered images were oriented by aligning the Frankfort horizontal and transorbital planes horizontally, and the midsagittal plane vertically. A total of 20 CBCT images (10 as-received and 10 oriented) were anonymized, and 3 random sets were generated for manual landmark plotting by 3 expert orthodontists. Twenty-five landmarks were identified for plotting on each anonymized image independently. Hence, a total of 60 images were marked by the orthodontists. After landmark plotting, the randomized samples were decoded and regrouped into as-received and oriented data sets for analysis and comparison. Means and standard deviations of the x-, y-, and z-axis coordinates were calculated for each landmark to measure the central tendency. Intraclass correlation coefficients were calculated to analyze the interobserver reliability of landmark plotting in the 3 axes in both situations. Paired t tests were applied on the mean Euclidean distance computed separately for each landmark to evaluate the effect of 3-dimensional image orientation. RESULTS: Interobserver reliability (intraclass correlation coefficient, >0.9) was excellent for all 25 landmarks for the x-, y-, and z-axes on both before and after orientation of the images. Paired t test results showed insignificant differences for the orientation of volume-rendered images for all landmarks except 3: R1 left (P = 0.0138), sella (P = 0.0490), and frontozygomatic left (P = 0.0493). Also midline structures such as Bolton and nasion were plotted more consistently or precisely than bilateral structures. CONCLUSIONS: Orientation of the CBCT image does not enhance the precision of landmark plotting if each landmark is defined properly on multiplanar reconstruction slices and rendered images, and the clinician has sufficient training. The consistency of landmark identification is influenced by their anatomic locations on the midline, bilateral, and curved structures. PMID- 28024766 TI - Effects of a magnetic palatal expansion appliance with reactivation system: An animal experiment. AB - INTRODUCTION: The purpose of this study was to evaluate the effects of a newly designed magnetic palatal expansion appliance with a reactivation system. METHODS: A magnetic palatal expansion appliance was designed based on the repulsion forces of neodymium-iron-boron magnets combined with a reactivation system. Eighteen prepubertal male beagle dogs were assigned randomly to the magnetic expansion (ME) group, the mechanical screw expansion (SE) group, or the control group. Two pairs of nonmagnetic metal bone marker implants were inserted into palatal bone bilaterally 3 mm lateral to the midpalatal suture and in line with the first and fourth premolars, respectively, in each dog. The 6 animals in each group received (1) newly designed magnetic expanders, (2) jackscrew expanders, or (3) no expansion appliance. Expansion was stopped after 4 weeks when 6 mm of activation was achieved in the 2 treated groups. Three-dimensional evaluations of dental and skeletal effects were performed with cone-beam computed tomography. Histologic examinations were conducted using light microscopy to observe morphologic changes in the midpalatal suture after hematoxylin and eosin staining. RESULTS: The absolute transversal changes of both treated groups before and after expansion were significantly greater than those in the control group in all parameters (P <0.001). The differences of the distances of bilateral canines in the ME group were significantly greater than in the SE group (1.04 +/- 0.16 mm; P <0.001); the differences of the distances between implants adjacent to the first premolars (0.77 +/- 0.06 mm; P <0.001) and the distances between implants adjacent to the fourth premolars (0.37 +/- 0.06 mm; P <0.001) in the SE group were significantly greater than in the ME group. Histologic observations of the palatal sutures in the ME and SE groups, when compared with the control group, showed widening of the sutures and many fibroblasts in an active, proliferative state. Counts of osteoblasts were increased in both expansion groups. Counts of osteoclasts were increased in the SE group. CONCLUSIONS: Both appliances expanded the maxilla effectively and induced processes of bone remodeling of the midpalatal sutures during expansion. The new magnetic palatal expansion appliances produced a smaller skeletal effect and a greater dental effect than did the mechanical screw palatal expansion appliances. PMID- 28024767 TI - Who and where? PMID- 28024768 TI - Influence of quality of life, self-perception, and self-esteem on orthodontic treatment need. AB - INTRODUCTION: In this study, we aimed to assess the relationship between normative and perceived orthodontic treatment need associated with quality of life, self-esteem, and self-perception. METHODS: The sample included 248 schoolchildren aged 12 years. The normative aspect of orthodontic treatment was assessed by the Dental Health Component and the Aesthetic Component of the Index of Orthodontic Treatment Need. The subjects were further evaluated for their oral health-related quality of life, self-esteem, and self-perception of oral esthetics. The Aesthetic Component of the Index of Orthodontic Treatment Need was considered as the response variable, and generalized linear models estimated by the GENMOD procedure (release 9.3, 2010; SAS Institute, Cary, NC). Model 1 was estimated with only the intercept, providing the basis for evaluating the reduction in variance in the other models studied; then the variables were tested sequentially, considering P <=0.05 as the criterion for remaining in the model. RESULTS: In the model, self-perception and self-esteem were statistically significant in relation to the perceived need for treatment. The normative need was significantly associated with the outcome variable and was not influenced by independent variables. CONCLUSIONS: The normative need for orthodontics treatment was not overestimated by the perceived need, and the perceived need was not influenced by sex and the impact on quality of life. PMID- 28024769 TI - Transverse dental compensation in relation to sagittal and transverse skeletal discrepancies in skeletal Class III patients. AB - INTRODUCTION: The purposes of this study were to compare the buccolingual inclinations of the posterior teeth in skeletal Class III patients with and without facial asymmetry with those of skeletal Class I patients and to investigate their relationships with sagittal and transverse skeletal discrepancies. METHODS: Sixty-three skeletal Class III adult patients were divided into 2 groups according to the degree of menton deviation: a symmetry group with deviation less than 2 mm (n = 30), and an asymmetry group with deviation greater than 4 mm (n = 33). The control group comprised 25 skeletal Class I patients. The buccolingual inclinations of the posterior teeth measured on cone-beam computed tomography images were compared among the 3 groups, and regression analysis was performed to investigate the relationships between the inclinations and the sagittal and transverse skeletal discrepancies. RESULTS: The symmetry group showed greater buccal inclinations of the maxillary posterior teeth and lingual inclinations of the mandibular second molars than did the control, and this was correlated with the ANB angles. The deviated sides in the asymmetry group showed the greatest transverse dental compensation, which was correlated with menton deviation, whereas the nondeviated sides showed no significant transverse dental compensation. CONCLUSIONS: Transverse dental compensation is closely related to sagittal and transverse skeletal discrepancy in skeletal Class III patients. PMID- 28024770 TI - Indirect vs direct bonding of mandibular fixed retainers in orthodontic patients: Comparison of retainer failures and posttreatment stability. A 2-year follow-up of a single-center randomized controlled trial. AB - INTRODUCTION: The objectives of this 2-arm parallel trial were to compare the numbers of failures of mandibular fixed retainers bonded with indirect and direct methods and to investigate the posttreatment changes 2 years after placement. METHODS: Sixty-four consecutive patients from the postgraduate orthodontic clinic of the University of Geneva in Switzerland were randomly allocated to either an indirect or a traditional direct bonding procedure of a mandibular fixed retainer at the end of their orthodontic treatment (T0). Eligibility criteria were the presence of the 4 mandibular incisors and the 2 mandibular canines, and no active caries, restorations, fractures, or periodontal disease of these teeth. The patients were randomized in blocks of 4 (using an online randomization service) with allocation concealment secured by contacting the sequence generator for assignment. The patients were recalled 12 months and 24 months (T3) after retainer bonding. The main outcome was any first-time failure of retainers (ie, at least 1 composite pad debonded or fractured); unexpected posttreatment changes of the mandibular incisors and canines were a secondary outcome. Impressions and lateral cephalograms were taken at T0 and T3: changes in mandibular intercanine and interpremolar distances and mandibular incisor inclination were assessed. Blinding was applicable for outcome assessment only. The chi-square test and Cox regression were used to compare the survival rates of the retainers bonded with direct and indirect methods. Paired t tests were used to assess differences in intercanine and interpremolar distances and mandibular incisor inclination at T0 and T3. Significance was set at P <0.05. RESULTS: Sixty-four patients were randomized in a 1:1 ratio. One patient dropped out at baseline, and 3 patients did not reach the T3 recall. In 24 of 60 (40%) patients, the fixed retainer failed within 2 years: 13 of 30 (43%) in the indirect bonding group and 11 of 30 (37%) in the direct bonding group (log-rank test, P = 0.64). The hazard ratio was 1.26 (95% confidence interval, 0.56-2.81; P = 0.58). Bond failures occurred mainly during the first year. There were no clinically significant changes in mandibular intercanine distance, interpremolar distance, and incisor inclination between T0 and T3, or between groups. In 5 patients (17%), all in the direct bonding group, unexpected posttreatment changes, systematically consisting in a lingual inclination of the mandibular left canine, were observed. In 1 patient (3%), the change was considered clinically severe. No other serious harm was observed. CONCLUSIONS: There was no difference in the risks of failure between mandibular retainers bonded with direct and indirect methods. Bonded retainers are effective in maintaining intercanine and interpremolar distances. There seem to be fewer unexpected posttreatment changes with retainers bonded with the indirect compared with the direct method. REGISTRATION: The trial was not registered. PROTOCOL: The protocol was not published before trial commencement. FUNDING: No funding or conflict of interest to be declared. PMID- 28024771 TI - Cephalometric landmark identification consistency between undergraduate dental students and orthodontic residents in 3-dimensional rendered cone-beam computed tomography images: A preliminary study. AB - INTRODUCTION: The aim of this study was to compare 3-dimensional landmark consistency and precision in skeletal structures in groups with different levels of experience with 2-dimensional cephalometrics. METHODS: Sixteen observers, all undergraduate or graduate students, were divided into 4 groups with different levels of experience in 2-dimensional landmarking and no previous experience in 3 dimensions. Group 1 consisted of 4 third-year dental students with no experience in cephalometric landmarking. Groups 2, 3, and 4 consisted of first-, second-, and third-year graduate students, with increasing levels of experience. The participants located 18 landmarks in 12 surface models of cone-beam computed tomography scans of patients on 3 separate occasions. The average of all examiners locating each landmark was defined as the centroid. The mean of the distances of each located point to the centroid of that landmark was used as the mean consistency (MC), and the standard deviation (SD) was used as the precision. Analysis of variance and post hoc Tukey comparisons between groups were done. RESULTS: The MC and SD values across landmarks, patients, and examiners were 1.03 +/- 1.14 mm. The MC and SD were 0.89 +/- 0.83 mm for group 1 with no experience, 1.02 +/- 0.95 mm for group 2, 1.17 +/- 1.60 mm for group 3, and 1.05 +/- 1.00 mm for group 4. Significant differences were found among the groups. CONCLUSIONS: Comparing the observer groups studied, the undergraduate dental school students without previous experience in bidimensional cephalometrics obtained the best values in volumetric landmark location. Graduate students with increasing amounts of experience did not perform as well. These results and conclusions should be interpreted with caution because the number of subjects in each group was small. PMID- 28024772 TI - Effects of casein phosphopeptide-amorphous calcium phosphate application after interproximal stripping on enamel surface: An in-vivo study. AB - INTRODUCTION: The aim of this study was to investigate the effects of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) application after interproximal stripping on enamel surface structures in vivo. METHODS: Fifteen patients with a mean age of 15.8 years participated in this study. For each patient, the extraction of 4 first premolars was part of the orthodontic treatment plan. The patients were randomly divided into 5 groups of 3 patients. With the exception of group 1, the mesial and distal surfaces of all first premolars were stripped with a stripping disc (Komet; Gebr Brasseler, Lemgo, Germany) under air cooling and then polished with Sof-Lex polishing discs (3M Dental Products, St Paul, Minn). In group 1, no stripping was performed, and the teeth were removed immediately. In group 2, the teeth were removed immediately after the stripping. In group 3, the stripped teeth were extracted after exposure to oral conditions for 3 months. In groups 4 and 5, CPP-ACP (Recaldent Tooth Mousse; GC Europe, Leuven, Belgium) or fluoride varnish (Bifluoride 12; Voco, Cuxhaven, Germany) was applied to the stripped surfaces for 3 months, respectively, before the teeth were extracted. Surface roughness and microhardness values were evaluated with 1-way analysis of variance and Tukey HSD tests. RESULTS: The CPP-ACP and the fluoride varnish applications increased the surface roughness and microhardness values that had been decreased by stripping. No statistically significant differences were found between groups 3, 4, and 5 for microhardness or between groups 4 and 5 for surface roughness (P > 0.5). CONCLUSIONS: The saliva and saliva plus remineralizing agents (fluoride varnish and CPP-ACP) increased the microhardness and surface roughness values of stripped enamel surfaces that had been decreased by stripping. PMID- 28024774 TI - Three-dimensional virtual-surgery simulation-assisted asymmetric bilateral mandibular distraction osteogenesis for a patient with bilateral condylar fractures. AB - INTRODUCTION: Our objective was to report a patient treated with 3-dimensional virtual-surgery simulation-assisted asymmetric bilateral mandibular distraction osteogenesis. METHODS: A boy (age, 9.5 years) had mandibular hypoplasia and facial asymmetry, induced by bilateral condylar fractures at 4 years of age. The asymmetric bilateral mandibular distraction osteogenesis was planned to correct facial asymmetry and mandibular hypoplasia. The 3-dimensional virtual-surgery simulation results were 11 mm of horizontal distraction on the right side and 4.5 mm of horizontal and 18 mm of vertical distraction on the left side of the mandible. Bilateral ramus osteotomies were performed, and intraoral unidirectional distraction devices were inserted. After a 6-day latency period, distraction was performed at 1 mm per day, followed by a 5-month consolidation period. Transarch and interarch elastics and an acrylic plate were used during distraction and consolidation. Total treatment time was 30 months. RESULTS: Satisfactory outcomes were obtained (achievement ratios between postconsolidation results and simulated results: gonial angle, 106% and 103.9%; mandibular body length, 94.2% and 89.9%; ramus height, 104.1% and 94.5% [values of the right and left sides, respectively]). The chin-point deviation and the transverse cant of the maxillary occlusal plane were significantly improved (10.1 mm to 3.3 mm; -6.8 degrees to -4.4 degrees ). At 53 months of follow-up, the Class I molar relationship was well maintained. The transverse cant of the maxillary occlusal plane was slightly improved to -3.7 degrees during pubertal growth. CONCLUSIONS: Three-dimensional virtual-surgery simulation can help clinicians to determine the optimal vector and amount of distraction with high accuracy in complex cases requiring simultaneous correction of a hypoplastic mandible and facial asymmetry. PMID- 28024773 TI - Comprehensive treatment approach for condylar hyperplasia and mandibular crowding with custom lingual braces and 2-jaw surgery. AB - We report on the successful treatment of a 32-year-old woman with condylar hyperplasia and severe mandibular crowding. In addition, her maxilla was canted to the right, her mandibular midline and chin point deviated to the left, and her maxillary canines were missing. The treatment plan included (1) aligning and leveling the teeth in both arches, (2) correcting overbite and overjet, (3) performing LeFort I osteotomy and bilateral split osteotomies, and (4) correcting the malocclusion postsurgically. The orthodontic treatment was performed with custom lingual braces and clear brackets, and virtual surgical planning techniques were used to plan the orthognathic surgery. The condylar hyperplasia and the mandibular crowding were corrected. At the end of treatment, the patient's face appeared symmetrical. The results suggest that esthetic and functional results can be achieved with the cooperation of 2 specialties and the use of state-of-the-art technology. PMID- 28024775 TI - Bone resorption under chin implants: The orthodontist's role in its diagnosis and management. AB - Alloplastic chin implants have been a valuable treatment modality for the correction of microgenia. Their use has provided satisfactory esthetic results by improving facial balance. However, bone resorption under these implants can occur. Case reports of 4 patients with the incidental radiographic finding of the presence of chin implants are presented. All 4 subjects had lateral cephalograms and panoramic x-rays taken as part of their orthodontic evaluation. One had a normal mandibular symphyseal contour, and 3 had bone resorption under the implants. One subject had severe resorption. In addition to panoramic and cephalometric x-rays, the subject with severe resorption also had magnetic resonance imaging and computerized tomography as part of the evaluation workup. PMID- 28024776 TI - Comparison of reconstructed rapid prototyping models produced by 3-dimensional printing and conventional stone models with different degrees of crowding. AB - INTRODUCTION: Rapid prototyping models can be reconstructed from stereolithographic digital study model data to produce hard-copy casts. In this study, we aimed to compare agreement and accuracy of measurements made with rapid prototyping and stone models for different degrees of crowding. METHODS: The Z Printer 450 (3D Systems, Rock Hill, SC) reprinted 10 sets of models for each category of crowding (mild, moderate, and severe) scanned using a structured light scanner (Maestro 3D, AGE Solutions, Pisa, Italy). Stone and RP models were measured using digital calipers for tooth sizes in the mesiodistal, buccolingual, and crown height planes and for arch dimension measurements. Bland-Altman and paired t test analyses were used to assess agreement and accuracy. Clinical significance was set at +/-0.50 mm. RESULTS: Bland-Altman analysis showed the mean bias of measurements between the models to be within +/-0.15 mm (SD, +/-0.40 mm), but the 95% limits of agreement exceeded the cutoff point of +/-0.50 mm (lower range, -0.81 to -0.41 mm; upper range, 0.34 to 0.76 mm). Paired t tests showed statistically significant differences for all planes in all categories of crowding except for crown height in the moderate crowding group and arch dimensions in the mild and moderate crowding groups. CONCLUSIONS: The rapid prototyping models were not clinically comparable with conventional stone models regardless of the degree of crowding. PMID- 28024777 TI - Teleorthodontics. PMID- 28024778 TI - Matched analysis for paired binary data (McNemar test). PMID- 28024780 TI - What are the limits of microimplant-assisted palatal expanders? PMID- 28024779 TI - Early orthodontic treatment for Class III malocclusion: A systematic review and meta-analysis. AB - INTRODUCTION: Class III malocclusion affects between 5% and 15% of our population. The 2 most common dilemmas surrounding Class III treatment are the timing of treatment and the type of appliance. A number of appliances have been used to correct a Class III skeletal discrepancy, but there is little evidence available on their effectiveness in the long term. Similarly, early treatment of Class III malocclusion has been practiced with increasing interest. However, there has been no solid evidence on the benefits in the long term. The aim of this systematic review was to evaluate the effectiveness of orthodontic/orthopedic methods used in the early treatment of Class III malocclusion in the short and long terms. METHODS: Several sources were used to identify all relevant studies independently of language. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase (Ovid), and MEDLINE (Ovid) were searched to June 2016. The selection criteria included randomized controlled trials (RCTs) and prospective controlled clinical trials (CCTs) of children between the ages of 7 and 12 years on early treatment with any type of orthodontic/orthopedic appliance compared with another appliance to correct Class III malocclusion or with an untreated control group. The primary outcome measure was correction of reverse overjet, and the secondary outcomes included skeletal changes, soft tissue changes, quality of life, patient compliance, adverse effect, Peer Assessment Rating score, and treatment time. The search results were screened for inclusion, and the data extracted by 2 independent authors. The data were analyzed using software (version 5.1, Review Manager; The Nordic Cochrane Centre, The Cochrane Collaboration; Copenhagen, Denmark). The mean differences with 95% confidence intervals were expressed for the continuous data. Random effects were carried out with high levels of clinical or statistical heterogeneity and fixed affects when the heterogeneity was low. RESULTS: Fifteen studies, 9 RCTs and 6 CCTs, were included in this review. In the RCT group, only 3 of 9 studies were assessed at low risk of bias, and the others were at high or unclear risk of bias. All 6 CCT studies were classified as high risk of bias. Three RCTs involving 141 participants looked at the comparison between protraction facemask and untreated control. The results for reverse overjet (mean difference, 2.5 mm; 95% CI, 1.21-3.79; P = 0.0001) and ANB angle (mean difference, 3.90 degrees ; 95% CI, 3.54-4.25; P <0.0001) were statistically significant favoring the facemask group. All CCTs demonstrated a statistically significant benefit in favor of the use of each appliance. However, the studies had high risk of bias. CONCLUSIONS: There is a moderate amount of evidence to show that early treatment with a facemask results in positive improvement for both skeletal and dental effects in the short term. However, there was lack of evidence on long-term benefits. There is some evidence with regard to the chincup, tandem traction bow appliance, and removable mandibular retractor, but the studies had a high risk of bias. Further high-quality, long-term studies are required to evaluate the early treatment effects for Class III malocclusion patients. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024252. PMID- 28024781 TI - Authors' response. PMID- 28024782 TI - Effect of piezocision on root resorption associated with orthodontic force: A microcomputed tomography study. AB - INTRODUCTION: The purpose of this study was to investigate the effect of piezocision on orthodontically induced inflammatory root resorption. METHODS: Fourteen patients were included in this split-mouth study; 1 side was assigned to piezocision, and the other side served as the control. Vertical corticotomy cuts of 4 to 5 mm in length were performed on either side of each piezocision premolar, and 150-g buccal tipping forces were applied to the premolars. After 4 weeks, the maxillary first premolars were extracted and scanned with microcomputed tomography. RESULTS: There was a significantly greater total amount of root resorption seen on the piezocision sides when compared with the control sides (P = 0.029). The piezocision procedure resulted in a 44% average increase in root resorption. In 5 patients, there was noticeable piezocision-related iatrogenic root damage. When that was combined with the orthodontic root resorption found on the piezocision-treated teeth, there was a statistically significant 110% average increase in volumetric root loss when compared with the control side (P = 0.005). CONCLUSIONS: The piezocision procedure that initiates the regional acceleratory phenomenon may increase the iatrogenic root resorption when used in conjunction with orthodontic forces. Piezocision applied close to the roots may cause iatrogenic damage to the neighboring roots and should be used carefully. PMID- 28024783 TI - Three-dimensional imaging for indirect-direct bonding could expose patients to unnecessary radiation. PMID- 28024784 TI - Assessing the feasibility of yttria-stabilized zirconia in novel designs as mandibular anterior fixed lingual retention after orthodontic treatment. AB - INTRODUCTION: The purpose of this study is to explore the feasibility of yttria stabilized zirconia (Y-TZP) in fixed lingual retention as an alternative to stainless steel. METHODS: Exploratory Y-TZP specimens were milled to establish design parameters. Next, the specimens were milled according to ASTM standard C1161-13 and subjected to 4-point flexural tests to determine material properties. Finite element analysis was used to evaluate 9 novel cross-sectional designs, which were compared with stainless steel wire. Each design was analyzed under loading conditions to determine von Mises and bond stresses. The most promising design was fabricated to assess the accuracy and precision of current CAD/CAM milling technology. RESULTS: The superior design had a 1.0 * 0.5 mm semielliptical cross-section and was shown to be fabricated reliably. Overall, the milling indicated a maximum percent standard deviation of 9.3 and maximum percent error of 13.5 with a cost of $30 per specimen. CONCLUSIONS: Y-TZP can be reliably milled to dimensions comparable with currently available metallic retainer wires. Further research is necessary to determine the success of the bonding protocol and the clinical longevity of Y-TZP fixed retainers. Advanced technology is necessary to connect the intraoral scan to an esthetic and patient specific Y-TZP fixed retainer. PMID- 28024785 TI - Authors' response. PMID- 28024786 TI - Ethical considerations of 3-dimensional imaging. PMID- 28024787 TI - Cone-beam computed tomographic evaluation of the long-term effects of orthodontic retainers on marginal bone levels. AB - INTRODUCTION: Fixed retainers are widely used after orthodontic treatment, sometimes for extended periods, despite insufficient knowledge of their possible long-term adverse effects on the periodontium. The aim of this study was to evaluate whether bonded orthodontic retainers have an adverse long-term effect on the marginal bone levels of the mandibular front teeth. METHODS: The study included 62 consecutive patients in 3 groups: (1) patients who underwent orthodontic treatment and wore a fixed retainer for 10 years, (2) patients who underwent orthodontic treatment but did not have a fixed retainer, and (3) untreated controls. The marginal bone levels were measured by cone-beam computed tomography 10 years after treatment. Additionally, multivariate data analysis was used to analyze possible correlations between the marginal bone levels at 10 years and the variables obtained from the study casts and profile radiographs. RESULTS: The results demonstrated a significantly lower marginal bone level on the buccal side of the mandibular front teeth in the orthodontically treated patients compared with the orthodontically untreated group. There was no difference in the marginal bone levels between the retainer group and the no retainer group. Multivariate analysis indicated that a low marginal bone level was correlated with a basal open vertical relationship, posterior rotation of the mandible, pretreatment of the incisor protrusion, and extraction therapy. CONCLUSIONS: Within the limits of this research design, the long-term retention phase in general does not seem to cause any adverse effects on the marginal bone levels after 10 years. PMID- 28024788 TI - Authors' response. PMID- 28024789 TI - Quantitative evaluation of maxillary alveolar cortical bone thickness and density using computed tomography imaging. AB - INTRODUCTION: Primary stability is essential to the success of orthodontic mini implants (OMIs) and heavily depends on the mechanical retention between OMIs and their supporting bone. Alveolar cortical bone commonly serves as the supporting bone for OMIs during treatment. The purposes of this study were to characterize alveolar cortical bone thickness and density in the maxilla and to explore patient factors that may significantly affect these bone properties. METHODS: Sixty medical computed tomography scans of the maxilla were analyzed from a selected sample of patients seen at the Radiology Department of Boston Children's Hospital. Interradicular alveolar bone thickness and density were measured at 2, 4, 6, and 8 mm from the buccal and palatal alveolar bone crests using the Synapse 3D software (version 4.1; FUJIFILM Medical Systems USA, Stamford, Conn). Analyses were conducted with STATA /1C (version 12.0 for Windows; StataCorp, College Station, Tex) using multivariate mixed-effects regression models and paired t tests. RESULTS: Mean age and body mass index of the study sample were 17.88 years and 22.94 kg/m2, respectively. Cortical bone density and thickness significantly increased from the coronal (2 mm) to the apical (8 mm) regions of the alveolar bone (P <0.05). At 8 mm from the alveolar crest, interradicular buccal cortical bone was thickest (1 mm) and densest (1395 Hounsfield units) between the first and second molars. On the palatal side, the thickest bone (1.15 mm) was found between the canine and first premolar; it was similarly densest (1406 Hounsfield units) between the first premolar and canine, and between the first premolar and second premolar interradicular bones. On average, palatal cortical bone was thicker and denser compared with buccal; this difference was statistically significant (P <0.01) in the anterior and middle maxilla, with the anterior maxillary region showing the greatest difference. Female subjects have significantly denser bone compared with male subjects; however, sex is not significantly associated with bone thickness. Body mass index and age are positively associated with bone thickness and density. Radiologic absence of bone was more commonly seen in the anterior maxilla. CONCLUSIONS: Alveolar bone properties vary in the maxilla in patterns that could guide clinicians in selecting sites best suited for placement of OMIs. PMID- 28024790 TI - The paradox of 1-phase vs 2-phase orthodontic treatment. PMID- 28024791 TI - Author's response. PMID- 28024792 TI - Effects of local platelet-rich plasma injection on the rate of orthodontic tooth movement in a rat model: A histomorphometric study. AB - INTRODUCTION: The aims of this study were to determine the effects of different concentrations of platelet-rich plasma (PRP) on alveolar bone density and orthodontic tooth movement. METHODS: Seventy-six rats were divided into 2 groups: a moderate concentration PRP injection group (n = 38) and a high concentration PRP injection group (n = 38). In each group, 5 time points were studied: 3, 7, 14, 21, and 60 days. Before orthodontic mesialization of the maxillary first molars, moderate and high concentrations of PRP were injected on the right sides of the molar buccal sulcus, and the left sides served as the controls. Tooth movements were measured on 3-dimensional digital models. Alveolar bone volume density and osteoclastic activity in the first molar intraradicular areas were evaluated by histomorphometric analysis. RESULTS: Alveolar bone density was decreased in the experimental groups compared with the control groups (P = 0.0001) at 3, 7, 14, and 21 days. On day 3, osteoclastic activity of the experimental groups was higher than that of the controls (P = 0.044, P = 0.0001). On day 21, the amounts of tooth movement in the high-concentration experimental group were 1.7 times greater than in the high-concentration control group and 1.4 times greater than in the moderate-concentration experimental group (P = 0.001). On day 60, alveolar bone density increased to the original levels in all groups. CONCLUSIONS: Injection of both moderate and high concentrations of PRP may accelerate orthodontic tooth movement by decreasing alveolar bone density on paradental tissues by enhancing osteoclastic activity in a transient way. PMID- 28024793 TI - Recombinant Interferon Alpha-2b is a High-Affinity Antigen for Type 1 Diabetes Autoantibodies. AB - OBJECTIVES: Type 1 diabetes results from T-cell-mediated destruction of the beta cells of the pancreas and is associated with several autoimmune phenomena. Many studies have suggested the involvement of interferon alpha (IFN alpha) in the development of type 1 diabetes, but the exact mechanism remains unclear. In this study, the binding of type 1 diabetes antibodies with recombinant interferon alpha-2b (hrIFN alpha-2b), their gene (cIFN alpha-2b gene) and commercially available interferon alpha-2b (IFN alpha-2b) were assessed. Furthermore, we also sought to use anti-hrIFN alpha-2b antibodies as a probe for the estimation of plasma IFN alpha in patients with type 1 diabetes. METHODS: The binding specificity of antibodies was analyzed by direct binding, inhibition ELISA and quantitative precipitin titration in 45 patients with type 1 diabetes and 30 control subjects. Competition ELISA was also used to estimate INF alpha in the serum of patients with type 1 diabetes. RESULTS: Antibodies from type 1 diabetes sera, purified in a protein A-agarose matrix, exhibited greater recognition of hrIFN alpha-2b than IFN alpha-2b (p<0.05) and cIFN alpha-2b gene (p<0.001). The relative affinity of type 1 diabetes antibodies for the hrIFN alpha-2b, IFN alpha 2b and cIFN alpha-2b genes was found to be 1.34*10-7, 1.28*10-6 and 1.13*10-6, respectively. The concentration of plasma INF alpha evaluated by induced antibodies was found to be significantly higher than in controls (p<0.05). CONCLUSIONS: High binding of hrIFN alpha-2b with IgG from patients with type 1 diabetes might suggest involvement of hrIFN alpha-2b in type 1 diabetes, especially as an antigenic agent. Anti-hrIFN alpha-2b antibodies were shown to be good probes for estimation of plasma INF alpha in patients with type 1 diabetes. PMID- 28024794 TI - Does Resveratrol Improve Insulin Signalling in HepG2 Cells? AB - OBJECTIVES: Diabetes mellitus is a common metabolic disorder with high global prevalence. It is characterized by a decrease in insulin secretion or a decrease in insulin sensitivity or both. The aim of the present study was to investigate the effects of resveratrol treatment on the expression of the genes involved in insulin signalling cascade, such as Forkhead box protein O1 (FoxO1), 3 phosphoinositide-dependent protein kinase 1 (PDPK1) and mammalian target of rapamycin (mTOR). METHODS: HepG2 cells were cultured in serum-free medium with high concentrations of glucose and insulin and then were treated with resveratrol (5, 10 and 20 uM) for 24 and 48 hours. Complementary deoxyribonucleic acids (cDNAs) were synthesized followed by RNA extraction. Real-time quantitative reverse transcription polymerase chain reaction was used to analyze the expression of FoxO1, PDPK1 and mTOR. RESULTS: Resveratrol increased the expression of PDPK1, mTOR and FoxO1. No significant difference was seen among differing dosages of resveratrol, but treatments for 48 hours exerted the greatest effectiveness. CONCLUSIONS: Our results were consistent with other studies showing the beneficial effects of resveratrol on diabetes. However, considering the effects of resveratrol in increasing FoxO1 and gluconeogenic gene expression, long-term usage of resveratrol should be investigated in greater depth in future studies. PMID- 28024795 TI - Response to comment: An objective assessment of halitosis in children with adenoid vegetation during the pre- and postoperative periods. PMID- 28024797 TI - Border controls: Lipids control proteins and proteins control lipids. PMID- 28024796 TI - Mechanisms of epidermal growth factor receptor signaling as characterized by patterned ligand activation and mutational analysis. AB - The cell surface receptor for epidermal growth factor (EGFR), a receptor tyrosine kinase, is a key player in normal cell growth and proliferation. Mutations in this receptor often lead to oncological transformation and other pathologies. Because of its representation of the receptor tyrosine kinase family and its important role in health and disease, a broad range of studies have been carried out in many laboratories to investigate the structural basis for transmembrane receptor activation and the resulting assembly of cytosolic signaling components. This review highlights two approaches our laboratory has taken to gain more detailed information about both aspects: Surface patterned ligands to examine recruitment of the signaling machinery, and mutational analysis to examine the regulatory role of EGFR's juxtamembrane segment. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova. PMID- 28024798 TI - Zonisamide attenuates lactacystin-induced parkinsonism in mice without affecting system xc. AB - Zonisamide (ZNS), an anticonvulsant drug exhibiting symptomatic effects in Parkinson's disease (PD), was recently reported to exert neuroprotection in rodent models. One of the proposed neuroprotective mechanisms involves increased protein expression of xCT, the specific subunit of the cystine/glutamate antiporter system xc-, inducing glutathione (GSH) synthesis. Here, we investigated the outcome of ZNS treatment in a mouse model of PD based on intranigral proteasome inhibition, and whether the observed effects would be mediated by system xc-. The proteasome inhibitor lactacystin (LAC) was administered intranigrally to male C57BL/6J mice receiving repeated intraperitoneal injections of either ZNS 30mgkg-1 or vehicle. Drug administration was initiated three days prior to stereotaxic LAC injection and was maintained until six days post-surgery. One week after lesion, mice were behaviorally assessed and investigated in terms of nigrostriatal neurodegeneration and molecular changes at the level of the basal ganglia, including expression levels of xCT. ZNS reduced the loss of nigral dopaminergic neurons following LAC injection and the degree of sensorimotor impairment. ZNS failed, however, to modulate xCT expression in basal ganglia of lesioned mice. In a separate set of experiments, the impact of ZNS treatment on system xc- was investigated in control conditions in vivo as well as in vitro. Similarly, ZNS did not influence xCT or glutathione levels in naive male C57BL/6J mice, nor did it alter system xc activity or glutathione content in vitro. Taken together, these results demonstrate that ZNS treatment provides neuroprotection and behavioral improvement in a PD mouse model based on proteasome inhibition via system xc- independent mechanisms. PMID- 28024799 TI - Assessment of older patients with cancer: Edmonton Frail Scale (EFS) as a predictor of adverse outcomes in older patients undergoing radiotherapy. AB - OBJECTIVE: In this study we evaluate the usefulness of the Edmonton Frail Scale (EFS) in predicting which older patients are at risk of developing serious toxicities during radiotherapy. MATERIALS AND METHODS: This prospective study was carried out over an 18month period. Our primary aim was to examine the Edmonton Frail Scale (EFS) as a predictor of toxicity in patients over 70years undergoing radical radiotherapy for any malignant diagnosis. RESULTS: 63 patients were recruited: 29% experienced grade 3 or greater toxicities, with very few having multiple grade 3 or greater toxicities. The majority of patients experienced multiple grade 1 or 2 toxicities. Patients were often admitted: either electively due to geographical reasons, or due to toxicities. All patients completed their courses of radiotherapy. All grade 3 or 4 toxicities occurred within five radiotherapy sites; upper GI, gynaecological, lung, prostate and head & neck. There was no statistical correlation between EFS score and the presence of grade 3 or 4 toxicities. CONCLUSION: This study showed that neither EFS score, age nor ECOG performance status were predictive of radiotherapy toxicity, breaks in treatment or hospital admissions. Patients with oesophageal cancer, gynaecological cancers and lung cancer had a high rate of toxicity and hospital admission, which may highlight the need for additional patient support in these groups. Whilst comprehensive geriatric assessment is recommended, further research is needed to conclude if the frail elderly patient is at greater risk of toxicities from radiotherapy, and which geriatric assessment tool may be the most helpful. PMID- 28024801 TI - Erratum to 'The durability of a hydroxyapatite paste used in decreasing the permeability of hypersensitive dentin' [J. Dent. 51 (2016) 1-7]. PMID- 28024800 TI - Dietary Assessment in the MetaCardis Study: Development and Relative Validity of an Online Food Frequency Questionnaire. AB - BACKGROUND: The European study MetaCardis aims to investigate the role of the gut microbiota in health and cardiometabolic diseases in France, Germany, and Denmark. To evaluate long-term diet-disease relationships, a food frequency questionnaire (FFQ) was found to be the most relevant dietary assessment method for the MetaCardis study. OBJECTIVE: The objectives of this study were to describe the development of three semiquantitative online FFQs used in the MetaCardis study-one FFQ per country-and to assess the relative validity of the French MetaCardis FFQ. DESIGN: The layout and format of the MetaCardis FFQ was based on the European Prospective Investigation of Cancer (EPIC)-Norfolk FFQ and the content was based on relevant European FFQs. Portion size and nutrient composition were derived from national food consumption surveys and food composition databases. To assess the validity of the French MetaCardis FFQ, a cross-sectional study design was utilized. PARTICIPANTS/SETTING: The validation study included 324 adults recruited between September 2013 and June 2015 from different hospitals in Paris, France. MAIN OUTCOME MEASURES: Food intakes were measured with both the French MetaCardis FFQ and 3 consecutive self-administered web-based 24-hour dietary recalls (DRs). STATISTICAL ANALYSES PERFORMED: Several measures of validity of the French MetaCardis FFQ were evaluated: estimations of food groups, energy, and nutrient intakes from the DRs and the FFQ, Spearman and Pearson correlations, cross-classification, and Bland-Altman analyses. RESULTS: The French MetaCardis FFQ tended to report higher food, energy, and nutrient intakes compared with the DRs. Mean correlation coefficient was 0.429 for food, 0.460 for energy, 0.544 for macronutrients, 0.640 for alcohol, and 0.503 for micronutrient intakes. Almost half of participants (44.4%) were correctly classified within tertiles of consumption, whereas 12.9% were misclassified in the opposite tertile. Performance of the FFQ was relatively similar after stratification by sex. CONCLUSIONS: The French MetaCardis FFQ was found to have an acceptable level of validity and may be a useful instrument to rank individuals based on their food and nutrient intakes. PMID- 28024802 TI - Transitions at the International Journal of Drug Policy. PMID- 28024803 TI - My time with the International Journal of Drug Policy. PMID- 28024804 TI - Hidden renal disease in the elderly is not longer buried after 10 years of follow up. PMID- 28024805 TI - Review: Placental mitochondrial function and structure in gestational disorders. AB - The aetiology of many gestational disorders is still unknown. However, insufficient trans-placental nutrient and oxygen transfer due to abnormal placentation is characteristic of several pathologies, and may alter the function of placental mitochondria. Mitochondria are multifunctional organelles that respond to a wide range of stimuli - such as physiological changes in cellular energy demands or various pathologies - by reshaping via fusion or fission, increasing/decreasing in number, altering oxidative phosphorylation, and signalling cellular functions such as apoptosis. Mitochondrial function is integral to tissue functions including energy production, metabolism, and regulation of various cellular responses including response to oxidative stress. This review details the functions of placental mitochondria and investigates mitochondrial function and structure in gestational disorders including preeclampsia, intrauterine growth restriction, diabetes mellitus, and obesity. Placental mitochondrial dysfunction may be critical in a range of gestational disorders which have important implications for maternal and fetal/offspring health. PMID- 28024806 TI - "Consensus guidelines for the surgical treatment of infective endocarditis": The surgeon must lead the team. PMID- 28024807 TI - Someday, a scientific dream will become reality. PMID- 28024808 TI - Total and free cortisol responses and their relation to outcomes after cardiopulmonary bypass in infants. AB - BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction may be partially responsible for the hemodynamic instability experienced by infants after cardiopulmonary bypass (CPB). We report the full spectrum of the HPA response surrounding CPB for infant congenital cardiac surgery. METHODS: We enrolled 84 infants who received 1 mg/kg of dexamethasone before initiation of CPB. Total cortisol (TC), free cortisol (FC), adrenocorticotropic hormone (ACTH), and corticosteroid-binding globulin (CBG) were measured at 3 time points: immediately before CPB (TP1), on intensive care unit arrival (TP2), and at 24 hours after surgery (TP3). A 1-MUg ACTH stimulation test was performed at each time point to evaluate adrenal responsiveness. RESULTS: Sixty-eight infants completed all study procedures. Levels of TC, FC, CBG, and ACTH decreased significantly between the preoperative and 24-hour postoperative measurements. There were no significant associations between preoperative FC responses and clinical outcomes after adjusting for weight and Risk-Adjusted Scores for Congenital Heart Surgery. Infants with subnormal TC responses to ACTH stimulation (<9 MUg/dL) at TP2 had greater fluid requirements (P < .001) and greater chest tube output (P < .001) during the first 24 hours, as well as longer length of stay (LOS) (P = .007). Except for LOS, these differences persisted for infants with subnormal stimulation tests at TP3. CONCLUSIONS: We observed a significant decline in all aspects of the HPA axis throughout the first 24 hours after infant CPB. TC and FC levels were not associated with clinical outcomes. Subnormal (Delta <9 MUg/dL) TC response to cosyntropin stimulation during the postoperative period was associated with increased fluid resuscitation and greater LOS. PMID- 28024809 TI - Immobilization of metals in contaminated soils using natural polymer-based stabilizers. AB - Three low-cost natural polymer materials, namely, lignin (Ln), carboxymethyl cellulose, and sodium alginate, were used for soil amendment to immobilize lead and cadmium in two contaminated soil samples collected from a mining area in Nanjing, China. The remediation effects of the aforementioned natural polymers were evaluated by toxicity characteristic leaching procedure (TCLP) and sequential extractions. The stabilizers could lower the bioavailability of Pb and Cd in the contaminated soils, and the amount of the exchangeable forms of the aforementioned two metals were reduced evidently. TCLP results showed that the leaching concentrations of Pb and Cd were decreased by 5.46%-71.1% and 4.25% 49.6%, respectively, in the treated soils. The contents of the organic forms of the two metals both increased with the increase in stabilizer dose on the basis of the redistribution of metal forms by sequential extractions. These findings were due to the fact that the abundant oxygen-containing groups on the polymeric amendments were effective in chelating and immobilizing Pb and Cd, which have been further confirmed from the metal adsorptions in aqueous solutions. Moreover, Ln achieved the greatest effect among the three polymers under study because of the former's distinct three-dimensional molecular structure, showing the preferential immobilization of Pb over Cd in soils also. Thus, the above mentioned natural polymers hold great application potentials for reducing metal ion entry into the food chain at a field scale. PMID- 28024810 TI - Transplacental transfer of polycyclic aromatic hydrocarbons in paired samples of maternal serum, umbilical cord serum, and placenta in Shanghai, China. AB - Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is a high-priority public health concern. However, maternal to fetal transplacental transfer of PAHs has not been systematically studied. To investigate the transplacental transfer of PAHs from mother to fetus and determine the influence of lipophilicity (octanol-water partition coefficient, KOW) on transfer process, in the present study, we measured the concentrations of 15 PAHs in 95 paired maternal and umbilical cord serum, and placenta samples (in total 285 samples) collected in Shanghai, China. The average concentration of total PAHs was the highest in maternal serums (1290 ng g-1 lipid), followed by umbilical cord serums (1150 ng g 1 lipid). The value was the lowest in placenta samples (673 ng g-1 lipid). Low molecular weight PAHs were the predominant compounds in the three matrices. Increases in fish and meat consumption did not lead to increases in maternal PAH levels, and no obvious gender differences in umbilical cord serums were observed. The widespread presence of PAHs in umbilical cord serums indicated the occurrence of transplacental transfer. The ratios of PAH concentrations in umbilical cord serum to those in maternal serum (F/M) and the concentrations in placenta to those in maternal serum (P/M) of paired samples were analyzed to characterize the transfer process of individual PAHs. Most F/M ratios on lipid basis were close to one (range: 0.79 to 1.36), which suggested that passive diffusion may control the transplacental transfer of PAHs from maternal serum to the fetal circulation. The P/M and F/M values calculated on lipid basis showed that PAHs with lower KOW were more likely to transfer from mother to fetus via the placenta. PMID- 28024811 TI - Revealing the complex effects of salinity on copper toxicity in an estuarine clam Potamocorbula laevis with a toxicokinetic-toxicodynamic model. AB - The effects of salinity on metal toxicity are complex: not only affecting metal bioaccumulation, but also altering the physiology and sensitivity of organisms. In this study, we used a toxicokinetic-toxicodynamic (TK-TD) model to separate and quantify the dual effects of salinity on copper (Cu) toxicity in a euryhaline clam Potamocorbula laevis. The toxicokinetics of Cu was determined using the stable isotope 65Cu as a tracer at concentrations (10-500 MUg L-1) realistic to contaminated environments and at salinities ranging from 5 to 30. At low Cu concentrations (ca. 10 MUg L-1), Cu bioaccumulation decreased monotonically with salinity, and the uptake rate constant (ku, 0.546 L g-1 h-1 to 0.213 L g-1 h-1) fitted well with an empirical equation, ku = 1/(1.35 + 0.116.Salinity), by treating salinity as a pseudo-competitor. The median lethal concentrations (LC50s) of Cu were 269, 224, and 192 MUg L-1 at salinity 5, 15, and 30, respectively. At high Cu concentrations (ca. 500 MUg L-1), elevating salinity were much less effective in decreasing Cu bioaccumulation; whereas Cu toxicity increased with salinity. The increased toxicity could be explained by the increases in Cu killing rates (kks), which were estimated to be 0.44-2.08 mg MUg 1 h-1 and were presumably due to the osmotic stress caused by the deviation from the optimal salinity of the clams. The other toxicodynamic parameter, internal threshold concentration (CIT), ranged from 79 to 133 MUg-1 g-1 and showed no clear trend with salinity. PMID- 28024812 TI - Occurrence of Chlorotriazine herbicides and their transformation products in arable soils. AB - Chlorotriazine herbicides (CTs) are widely used pest control chemicals. In contrast to groundwater contamination, little attention has been given to the circumstances of residue formation of parent compounds and transformation products in soils. Seventy-five cultivated floodplain topsoils in the Czech Republic were sampled in early spring of 2015, corresponding to a minimum of six months (current-use terbuthylazine, TBA) and a up to a decade (banned atrazine, AT and simazine, SIM) after the last herbicide application. Soil residues of parent compounds and nine transformation products were quantified via multiple residue analysis using liquid chromatography - tandem mass spectrometry of acetonitrile partitioning extracts (QuEChERS). Using principal component analysis (PCA), their relation to soil chemistry, crops and environmental parameters was determined. Of the parent compounds, only TBA was present in more than one sample. In contrast, at least one CT transformation product, particularly hydroxylated CTs, was detected in 89% of the sites, or 54% for banned triazines. Deethylated and bi-dealkylated SIM or AT residues were not detectable. PCA suggests the formation and/or retention of CT hydroxy-metabolite residues to be related to low soil pH, and a direct relation between TBA and soil organic carbon, and between deethyl-TBA and clay or Ca contents, respectively, the latter pointing towards distinct sorption mechanisms. The low historic application of simazine contrasted by the high abundance of its residues, and the co-occurrence with AT residues suggests the post-ban application of AT and SIM banned triazines as a permitted impurity of TBA formulations as a recent, secondary source. The present data indicate that topsoils do not contain abundant extractable residues of banned parent chlorotriazines, and are thus likely not the current source for related ground- and surface water contamination. In contrast, topsoils might pose a long-term source of TBA and CT transformation products for ground and surface water contamination. PMID- 28024813 TI - Perfluoroalkyl substances and thyroid hormones in cord blood. AB - BACKGROUND: Perfluoroalkyl substances (PFASs) are pollutants that tend to accumulate in the environment and organisms. The animal and human studies to date have focused on thyroid function, but the results are inconsistent. METHODS: A sample of 118 mother-infant pairs was obtained from the Taiwan Birth Panel Study (TBPS). Cord blood PFASs levels were evaluated using the Waters ACQUITY UPLC system coupled with a Waters Quattro Premier XE triple quadrupole mass spectrometer, and cord blood thyroid hormones were assessed using a Roche Analytics E170 modular analyser (Roche Diagnostics, Mannheim, Germany). PFASs concentrations were analysed in the final models to examine the associations between cord blood PFASs levels and thyroid hormone concentrations. RESULTS: The cord blood perfluorooctane sulfonate (PFOS) concentration was negatively associated with the cord blood thyroxine (T4) concentration [per ln unit: adjusted beta (95% confidence interval, CI) = -0.458(-0.916, -0.001)]. Moreover, the level of cord blood thyroid stimulating hormone (TSH) was positively associated with the cord blood PFOS concentration [per ln unit: adjusted beta (95% confidence interval, CI) = 0.346(0.101, 0.592)]. The sex stratified effects of PFOS on T4 were suggestive of differential effects in high-exposure groups compared with low-exposure group in boys. CONCLUSIONS: We found that cord blood thyroid hormone levels are affected by PFASs, with a negative association between T4 and PFOS and a positive association between TSH and PFOS. The causal associations of thyroid hormones and PFASs require further exploration. PMID- 28024814 TI - Cumulative risk assessment of phthalates associated with birth outcomes in pregnant Chinese women: A prospective cohort study. AB - A prospective cohort study of a Chinese population of mother-neonate pairs (n = 3103) was conducted to investigate the relationship between the cumulative hazard index (HI) of combined diethyl phthalate (DEP), dibutyl phthalate (DBP), dibenzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) exposure and birth outcomes. The estimated HI for phthalates was based on phthalate metabolite concentrations in urine collected between 5th and 14th gestational weeks. The median HI values according to the European Food Safety Authority tolerable daily intake (HITDI) and U.S. Environmental Protection Agency reference dose (HIRfD) were 0.358 and 0.187, respectively. A total of 16.3% and 1.9% of the women exhibited HITDI and HIRfD exceeding the value of one, respectively. In unadjusted models, the categories (low < P25, median P25-P50, high > P75) of HITDI were associated with decreased birth weight (beta = -26.34 g, p = 0.021) and head circumference (beta = -0.09 cm, p = 0.029), whereas those for HIRfD were negatively associated with birth weight (beta = -31.74 g, p = 0.005), birth length (beta = -0.11 cm, p = 0.032), head circumference (beta = -0.13 cm, p = 0.003) and chest circumference (beta = -0.10 cm, p = 0.021) in all neonates. Adjustment for potential confounders revealed that HIRfD was inversely associated with head circumference (beta = -0.10 cm, p = 0.020). Stratification by gender indicated that HIRfD was associated with decreased birth length (beta = -0.17 cm, p = 0.041) in infant boys and HITDI was associated with decreased birth weight (beta = -33.12 g, p = 0.036) and head circumference (beta = -0.13 cm, p = 0.027) in girls. This is the first study on the cumulative risk assessment of phthalate exposures in pregnant Chinese women. We found that the HI values of multiple phthalate co-exposure were sex-specifically related to birth outcomes. PMID- 28024815 TI - Fit of pressed crowns fabricated from two CAD-CAM wax pattern process plans: A comparative in vitro study. AB - STATEMENT OF PROBLEM: Subtractive and additive computer-aided design and computer aided manufacturing (CAD-CAM) wax pattern processing are 2 methods of fabricating a pressed ceramic crown. Whether a subtractive milled wax pattern or a pattern from the micro-stereolithography additive process produces lithium disilicate crowns with better marginal and internal fit is unclear. MATERIALS AND METHODS: Ten silicone impressions were made for a prepared canine tooth. Each die received 2 lithium disilicate (IPS e.max) copings, 1 from milled wax blocks and 1 from additive wax. The replica technique was used to measure the fit by scanning electron microscopy at *80 magnification. Collected data were analyzed using the paired Student t test for the marginal and internal fit. For the occlusal fit, the difference in scores did not follow a normal distribution, and the Wilcoxon signed rank test was used (alpha=.05). RESULTS: The mean marginal, axial, and occlusal fit showed no significant differences when the 2 CAD-CAM manufacturing processes were compared (P>.05). For the marginal fit, the mean (+/-SD) values were 105.1 MUm +/-39.6 with the milled process and 126.2 MUm +/-25.2 for the additive process. The mean values were 98.1 MUm +/-26.1 for the axial fit in the milled process and 106.8 MUm +/-21.2 in the additive process. For the occlusal fit, median values (interquartile interval) were 199.0 MUm (141.5 to 269.9) for subtractive manufacturing and 257.2 MUm (171.6 to 266.0) for micro-SLA manufacturing. CONCLUSIONS: No significant difference was found between the fit of the 2 techniques. The mean values of axial and occlusal median values were 10 and 5 to 6 times greater than machine's nominal values. PMID- 28024816 TI - Zirconia changes after grinding and regeneration firing. AB - STATEMENT OF PROBLEM: Despite improvements in computer-aided design and computer aided manufacturing (CAD-CAM) systems, grinding during either laboratory procedures or clinical adjustments is often needed to modify the shape of 3 mol(%) yttria-tetragonal zirconia polycrystal (3Y-TZP) restorations. However, the best way to achieve adjustment is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the microstructural and crystallographic phase changes, flexural strength, and Weibull modulus of a 3Y-TZP zirconia after grinding with or without water cooling and regeneration firing. MATERIAL AND METHODS: Ninety six bar-shaped specimens were obtained and divided as follows: as-sintered, control; as-sintered with regeneration firing; grinding without water cooling; grinding and regeneration firing with water cooling; and grinding and regeneration firing. Grinding (0.3 mm) was performed with a 150-MUm diamond rotary instrument in a high-speed handpiece. For regeneration firing, the specimens were annealed at 1000 degrees C for 30 minutes. The crystalline phases were evaluated by using x-ray powder diffraction. A 4-point bending test was conducted (10 kN; 0.5 mm/min). The Weibull modulus was used to analyze strength reliability. The microstructure was analyzed by scanning electron microscopy. Data from the flexural strength test were evaluated using the Kruskal-Wallis and Dunn tests (alpha=.05). RESULTS: Tetragonal-to-monoclinic phase transformation was identified in the ground specimens; R regeneration firing groups showed only the tetragonal phase. The median flexural strength of as-sintered specimens was 642.0; 699.3 MPa for as-sintered specimens with regeneration firing; 770.1 MPa for grinding and water-cooled specimens; 727.3 MPa for specimens produced using water-cooled grinding and regeneration firing; 859.9 MPa for those produced by grinding; and 764.6 for those produced by grinding and regeneration firing; with statistically higher values for the ground groups. The regenerative firing did not affect the flexural strength. Weibull modulus values ranged from 5.3 to 12.4. The SEM images showed semicircular cracks after grinding. CONCLUSIONS: Adjustments by grinding in 3Y-TZP frameworks should be performed with water cooling, and regeneration firing should be undertaken to obtain a more reliable material. PMID- 28024817 TI - Interrater and intrarater reliability of FDI criteria applied to photographs of posterior tooth-colored restorations. AB - STATEMENT OF PROBLEM: Since 2007, the FDI World Dental Federation (FDI) criteria have been used for the clinical evaluation of dental restorations. However, the reliability of the FDI criteria has not been sufficiently addressed. PURPOSE: The purpose of this study was to assess and compare the interrater and intrarater reliability of the FDI criteria by evaluating posterior tooth-colored restorations photographically. MATERIAL AND METHODS: A total of 160 clinical photographs of posterior tooth-colored restorations were evaluated independently by 5 raters with 9 of the FDI criteria suitable for photographic evaluation. The raters recorded the score of each restoration by using 5 grades, and the score was dichotomized into the clinical evaluation scores. After 1 month, 2 of the raters reevaluated the same set of 160 photographs in random order. To estimate the interrater reliability among the 5 raters, the proportion of agreement was calculated, and the Fleiss multirater kappa statistic was used. For the intrarater reliability, the proportion of agreement was calculated, and the Cohen standard kappa statistic was used for each of the 2 raters. RESULTS: The interrater proportion of agreement was 0.41 to 0.57, and the kappa value was 0.09 to 0.39. Overall, the intrarater reliability was higher than the interrater reliability, and rater 1 demonstrated higher intrarater reliability than rater 2. The proportion of agreement and kappa values increased when the 5 scores were dichotomized. The reliability was relatively lower for the esthetic properties compared with the functional or biological properties. CONCLUSIONS: Within the limitations of this study, the FDI criteria presented slight to fair interrater reliability and fair to excellent intrarater reliability in the photographic evaluation of posterior tooth-colored restorations. The reliability was improved by simplifying the evaluation scores. PMID- 28024818 TI - Effect of production method on surface roughness, marginal and internal fit, and retention of cobalt-chromium single crowns. AB - STATEMENT OF PROBLEM: New production methods have been developed for metal ceramic restorations. Different production methods may show different surface roughness and fit, which may affect retention and long-term success. PURPOSE: The purpose of this in vitro study was to examine 3 different production methods with regard to surface roughness, marginal and internal fit, and retention of cobalt chromium alloy single-crown copings. MATERIAL AND METHODS: A master abutment of a premolar mandibular tooth preparation with 4-mm height and a 0.6-mm deep 120 degree chamfer finish line with a 12-degree angle of convergence was replicated in die stone and scanned. Thirty-six cobalt-chromium alloy copings were produced using 3 different production techniques. Twelve copings were produced by laser sintering, 12 by milling, and 12 by milled wax/lost wax. The surface microstructure of 2 copings in each group was analyzed using interferometry. The remaining 10 copings in each group were used to evaluate marginal and internal fit by using an impression material replica method, and retention was evaluated by using a uniaxial tensile force pull-off test. The copings from each test group were cemented with zinc phosphate cement onto resin abutments. Statistical analyses of differences in marginal and internal fit were performed using 1-way ANOVA and the Mann-Whitney U test. Differences in surface topography were analyzed with the Kruskal-Wallis and Mann-Whitney U tests for nonparametric data. Differences in retentive values were analyzed using the Mann-Whitney U test for nonparametric data (all alpha=.05). RESULTS: Differences in surface microstructure were seen. The laser-sintered copings showed increased surface roughness compared with milled and milled wax/lost wax copings. Differences in marginal and internal fit were noted. Laser-sintered showed significantly smaller spaces between coping and abutment than milled wax/lost wax copings (P=.003). At the margins, laser-sintered copings showed significantly smaller spaces than either the milled wax/lost wax group (P=.002) or the milled group (P=.002). At the chamfer, laser-sintered copings showed significantly smaller spaces than milled wax/lost wax copings (P=.005). At the center of the axial walls, laser sintered copings showed significantly smaller spaces than those in the milled wax/lost wax (P=.004) and milled copings (P=.005). No significant differences were noted between milled and milled wax/lost wax copings (P>.05). No significant differences were detected regarding retentive forces in the pull-off tests (P>.05). CONCLUSIONS: Laser-sintered Co-Cr crown copings showed increased surface roughness and better internal and marginal fit than copings produced by milling or milled wax/lost wax technique. However, the crown pull-off tests did not reveal any significant differences. PMID- 28024819 TI - Randomized controlled within-subject evaluation of digital and conventional workflows for the fabrication of lithium disilicate single crowns. Part II: CAD CAM versus conventional laboratory procedures. AB - STATEMENT OF PROBLEM: Clinical studies are needed to evaluate the entire digital and conventional workflows in prosthetic dentistry. PURPOSE: The purpose of the second part of this clinical study was to compare the laboratory production time for tooth-supported single crowns made with 4 different digital workflows and 1 conventional workflow and to compare these crowns clinically. MATERIAL AND METHODS: For each of 10 participants, a monolithic crown was fabricated in lithium disilicate-reinforced glass ceramic (IPS e.max CAD). The computer-aided design and computer-aided manufacturing (CAD-CAM) systems were Lava C.O.S. CAD software and centralized CAM (group L), Cares CAD software and centralized CAM (group iT), Cerec Connect CAD software and lab side CAM (group CiL), and Cerec Connect CAD software with centralized CAM (group CiD). The conventional fabrication (group K) included a wax pattern of the crown and heat pressing according to the lost-wax technique (IPS e.max Press). The time for the fabrication of the casts and the crowns was recorded. Subsequently, the crowns were clinically evaluated and the corresponding treatment times were recorded. The Paired Wilcoxon test with the Bonferroni correction was applied to detect differences among treatment groups (alpha=.05). RESULTS: The total mean (+/ standard deviation) active working time for the dental technician was 88 +/-6 minutes in group L, 74 +/-12 minutes in group iT, 74 +/-5 minutes in group CiL, 92 +/-8 minutes in group CiD, and 148 +/-11 minutes in group K. The dental technician spent significantly more working time for the conventional workflow than for the digital workflows (P<.001). No statistically significant differences were found between group L and group CiD or between group iT and group CiL. No statistical differences in time for the clinical evaluation were found among groups, indicating similar outcomes (P>.05). CONCLUSIONS: Irrespective of the CAD CAM system, the overall laboratory working time for a digital workflow was significantly shorter than for the conventional workflow, since the dental technician needed less active working time. PMID- 28024820 TI - Simplified fabrication of an implant-supported framework with luted abutment cylinders. AB - A technique is described to generate a framework for an implant-supported fixed complete denture. The main advantage of the described technique is the low production cost of a framework that has high strength, passive fit, and distinct retentive structures for each denture tooth. PMID- 28024821 TI - Machinability of CAD-CAM materials. AB - STATEMENT OF PROBLEM: Although new materials are available for computer-aided design and computer-aided manufacturing (CAD-CAM) fabrication, limited information is available regarding their machinability. The depth of penetration of a milling tool into a material during a timed milling cycle may indicate its machinability. PURPOSE: The purpose of this in vitro study was to compare the tool penetration rate for 2 polymer-containing CAD-CAM materials (Lava Ultimate and Enamic) and 2 ceramic-based CAD-CAM materials (e.max CAD and Celtra Duo). MATERIAL AND METHODS: The materials were sectioned into 4-mm-thick specimens (n=5/material) and polished with 320-grit SiC paper. Each specimen was loaded into a custom milling apparatus. The apparatus pushed the specimens against a milling tool (E4D Tapered 2016000) rotating at 40 000 RPM with a constant force of 0.98 N. After a 6-minute timed milling cycle, the length of each milling cut was measured with image analysis software under a digital light microscope. Representative specimens and milling tools were examined with scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy. RESULTS: The penetration rate of Lava Ultimate (3.21 +/-0.46 mm/min) and Enamic (2.53 +/-0.57 mm/min) was significantly greater than that of e.max CAD (1.12 +/-0.32 mm/min) or Celtra Duo (0.80 +/-0.21 mm/min) materials. SEM observations showed little tool damage, regardless of material type. Residual material was found on the tools used with polymer-containing materials, and wear of the embedding medium was seen on the tools used with the ceramic-based materials. Edge chipping was noted on cuts made in the ceramic-based materials. CONCLUSIONS: Lava Ultimate and Enamic have greater machinability and less edge chipping than e.max CAD and Celtra Duo. PMID- 28024822 TI - Evaluation of the accuracy of 7 digital scanners: An in vitro analysis based on 3 dimensional comparisons. AB - STATEMENT OF PROBLEM: As digital impressions become more common and more digital impression systems are released onto the market, it is essential to systematically and objectively evaluate their accuracy. PURPOSE: The purpose of this in vitro study was to evaluate and compare the trueness and precision of 6 intraoral scanners and 1 laboratory scanner in both sextant and complete-arch scenarios. Furthermore, time of scanning was evaluated and correlated with trueness and precision. MATERIAL AND METHODS: A custom complete-arch model was fabricated with a refractive index similar to that of tooth structure. Seven digital impression systems were used to scan the custom model for both posterior sextant and complete arch scenarios. Analysis was performed using 3-dimensional metrology software to measure discrepancies between the master model and experimental casts. RESULTS: Of the intraoral scanners, the Planscan was found to have the best trueness and precision while the 3Shape Trios was found to have the poorest for sextant scanning (P<.001). The order of trueness for complete arch scanning was as follows: 3Shape D800 >iTero >3Shape TRIOS 3 >Carestream 3500 >Planscan >CEREC Omnicam >CEREC Bluecam. The order of precision for complete-arch scanning was as follows: CS3500 >iTero >3Shape D800 >3Shape TRIOS 3 >CEREC Omnicam >Planscan >CEREC Bluecam. For the secondary outcome evaluating the effect time has on trueness and precision, the complete- arch scan time was highly correlated with both trueness (r=0.771) and precision (r=0.771). CONCLUSIONS: For sextant scanning, the Planscan was found to be the most precise and true scanner. For complete-arch scanning, the 3Shape Trios was found to have the best balance of speed and accuracy. PMID- 28024823 TI - Panoramic radiographs made before complete removable dental prostheses fabrication: A retrospective study of clinical significance. AB - STATEMENT OF PROBLEM: The value of digital panoramic radiographs to screen for problems before fabricating conventional complete dentures is unclear. PURPOSE: The purpose of this retrospective study was to examine the influence of pretreatment digital panoramic radiographs on the clinical management of patients receiving complete removable dental prostheses. MATERIAL AND METHODS: The clinical records, including panoramic radiographs, of 169 patients seeking new complete removable dental prostheses over a 6-year period were interpreted independently by both a prosthodontist and an oral and maxillofacial radiologist to identify radiographic findings that influenced clinical patient management. A 95% confidence interval and an observed proportion of agreement were used to interpret the results. RESULTS: Sixty percent of the 169 radiographs examined had 1 or more abnormal or positive radiographic findings; however, only 6 (<4%) of 165 abnormalities detected influenced patient management, and 3 of them were identified during the clinical examination. CONCLUSIONS: Pretreatment digital panoramic radiographs revealed very few abnormalities that influenced the treatment of patients requiring complete removable dental prostheses. Furthermore, the digital images in this study revealed positive findings at a rate similar to those found in studies assessing analog radiographs, reinforcing current guidelines that recommend against radiographic screening of patients who seek new complete removable dental prostheses. PMID- 28024824 TI - A technique for fabrication of cranial prostheses using high-temperature vulcanizing silicone material. AB - Cranioplasty is performed with various alloplastic implant materials, each having advantages and drawbacks. High-temperature vulcanizing silicone is used to fabricate cranioplasty implants because of certain beneficial properties. Silicone cranial implants lead to better adaptation with the bone adjacent to the cranial defect than acrylic resin and metal cranial prostheses. This article describes a technique for fabricating cranial implant prostheses using high temperature vulcanizing silicone material. PMID- 28024825 TI - Automated Diabetic Retinopathy Image Assessment Software: Diagnostic Accuracy and Cost-Effectiveness Compared with Human Graders. AB - OBJECTIVE: With the increasing prevalence of diabetes, annual screening for diabetic retinopathy (DR) by expert human grading of retinal images is challenging. Automated DR image assessment systems (ARIAS) may provide clinically effective and cost-effective detection of retinopathy. We aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders. DESIGN: Observational measurement comparison study of human graders following a national screening program for DR versus ARIAS. PARTICIPANTS: Retinal images from 20 258 consecutive patients attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013. METHODS: Retinal images were manually graded following a standard national protocol for DR screening and were processed by 3 ARIAS: iGradingM, Retmarker, and EyeArt. Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration. MAIN OUTCOME MEASURES: Screening performance (sensitivity, false positive rate) and diagnostic accuracy (95% confidence intervals of screening performance measures) were determined. Economic analysis estimated the cost per appropriate screening outcome. RESULTS: Sensitivity point estimates (95% confidence intervals) of the ARIAS were as follows: EyeArt 94.7% (94.2%-95.2%) for any retinopathy, 93.8% (92.9%-94.6%) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative, or proliferative), 99.6% (97.0%-99.9%) for proliferative retinopathy; Retmarker 73.0% (72.0 %-74.0%) for any retinopathy, 85.0% (83.6%-86.2%) for referable retinopathy, 97.9% (94.9% 99.1%) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading both as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost effective. CONCLUSIONS: Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders and had sufficient specificity to make them cost-effective alternatives to manual grading alone. ARIAS have the potential to reduce costs in developed-world health care economies and to aid delivery of DR screening in developing or remote health care settings. PMID- 28024826 TI - Predictors of Discordance between Symptoms and Signs in Dry Eye Disease. AB - PURPOSE: To investigate predictors of discordance between symptoms and signs in dry eye disease (DED). DESIGN: Cross-sectional association study. PARTICIPANTS: A total of 648 patients with dry eye from the Groningen LOngitudinal Sicca StudY (GLOSSY), a tertiary dry eye clinic patient cohort from the Netherlands. METHODS: Patient symptoms were assessed using the Ocular Surface Disease Index (OSDI) questionnaire. Dry eye signs were assessed by tear osmolarity, Schirmer test, tear breakup time, corneal and conjunctival staining, and meibomian gland dysfunction, all in both eyes, and a composite dry eye signs severity score was calculated from these 6 tests for each patient. Linear regression analysis was used to test the association of discordance between symptoms and signs with a wide range of independent variables (demographic and environmental variables, systemic diseases, ocular traits, and medications). MAIN OUTCOME MEASURES: Predictors of discordance between symptoms and signs in DED, defined by the difference between the rank score of the OSDI and the rank score of the dry eye signs severity score. RESULTS: Of the 648 subjects in this cohort, 536 (82.7%) were female and the mean age was 55.8 years (standard deviation, 15.6 years). Significant predictors of greater symptoms than signs were the presence of a chronic pain syndrome, atopic diseases, a known allergy, the use of antihistamines (all P < 0.001), depression (P = 0.003), osteoarthritis (P = 0.008), and the use of antidepressants (P = 0.02). Predictors of lesser symptoms than signs were increased age (P < 0.001) and the presence of Sjogren's disease (P < 0.001) (primary Sjogren's disease, P < 0.001) more than secondary Sjogren's disease (P = 0.08), and graft-versus-host disease (P = 0.04). Furthermore, greater symptoms compared with signs were highly associated with lower self perceived health (P < 0.001). CONCLUSIONS: This large clinical study has shown that discordance between symptoms and signs in DED is an indicator of self perceived health. The study found important predictors of greater symptoms to signs but also predictors of lesser symptoms to signs. Awareness of these predictors is helpful in assessing patients with dry eye in clinical practice. PMID- 28024827 TI - Evaluation of peripheral auditory pathways and brainstem in obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea causes changes in normal sleep architecture, fragmenting it chronically with intermittent hypoxia, leading to serious health consequences in the long term. It is believed that the occurrence of respiratory events during sleep, such as apnea and hypopnea, can impair the transmission of nerve impulses along the auditory pathway that are highly dependent on the supply of oxygen. However, this association is not well established in the literature. OBJECTIVE: To compare the evaluation of peripheral auditory pathway and brainstem among individuals with and without obstructive sleep apnea. METHODS: The sample consisted of 38 adult males, mean age of 35.8 (+/-7.2), divided into four groups matched for age and Body Mass Index. The groups were classified based on polysomnography in: control (n=10), mild obstructive sleep apnea (n=11) moderate obstructive sleep apnea (n=8) and severe obstructive sleep apnea (n=9). All study subjects denied a history of risk for hearing loss and underwent audiometry, tympanometry, acoustic reflex and Brainstem Auditory Evoked Response. Statistical analyses were performed using three-factor ANOVA, 2-factor ANOVA, chi-square test, and Fisher's exact test. The significance level for all tests was 5%. RESULTS: There was no difference between the groups for hearing thresholds, tympanometry and evaluated Brainstem Auditory Evoked Response parameters. An association was observed between the presence of obstructive sleep apnea and changes in absolute latency of wave V (p=0.03). There was an association between moderate obstructive sleep apnea and change of the latency of wave V (p=0.01). CONCLUSION: The presence of obstructive sleep apnea is associated with changes in nerve conduction of acoustic stimuli in the auditory pathway in the brainstem. The increase in obstructive sleep apnea severity does not promote worsening of responses assessed by audiometry, tympanometry and Brainstem Auditory Evoked Response. PMID- 28024829 TI - Implication of homocysteine in diabetes and impact of folate and vitamin B12 in diabetic population. AB - Diabetes mellitus is an acutely debilitating ailment affecting a large population of the world. At present, over 415 million people around the world including 7 million people in Pakistan suffering from diabetes. Homocysteine is an amino acid that is inversely related to vitamin B12 and folate, and raised level of homocysteine is implicated in many adverse health conditions. In this study, the potential role of homocysteine in diabetes and the epidemiology of hyperhomocysteinaemia, and vitamin B12 and folate deficiency is reviewed along with the impact of folate and vitamin B12 in regulation of homocysteine level. Deficiency of vitamin B12 and folate is rare in developed countries and the countries which adopted fortification programs, but deficiency of these vitamins is found to be highly prevalent in developing world, particularly in Pakistan. Several studies have found an association of high homocysteine levels and diabetes, but a few studies found contrary results. Hence, further epidemiological studies are recommended for homocysteine involvement in diabetes and vitamin B12 and folate deficiency, so that an urgent action can be taken to control the hyperhomocysteinaemia and consequently the ever increasing burden of disease and specifically diabetes. PMID- 28024830 TI - Relationship between metabolic syndrome and its components with bone densitometry in postmenopausal women. AB - BACKGROUND: Prevention of osteoporosis and bone fracture and the relationship between metabolic syndrome and bone density are controversial issues. THE AIM OF THIS STUDY: The aim of this study was to evaluate the association between metabolic syndrome and its components with bone mineral density in post menopausal women referred for bone mineral density (BMD) test. METHODS: A total of 143 postmenopausal women with at least one year of menopause experience participated in this cross-sectional study. Demographic and anthropometric characteristics for all participants were collected. Also, biochemical parameters including fasting blood sugar, Cholesterol (HDL and LDL), triglyceride were measured. Association between the components of metabolic syndrome and bone densitometry were analyzed by statistical methods. RESULTS: In this study, 72% of participants did not have metabolic syndrome. Among them, 43.4% and 28.7% had osteoporosis and normal density, respectively. Of remaining participants with metabolic syndrome, 12.6% and 15.4% had osteoporosis and normal density, respectively. Among the metabolic syndrome components, waist circumference, HDL cholesterol, and waist to hip ratio were significantly associated with bone mass (P<0.05). Osteoporotic women had lower waist circumference and waist to hip ratio and higher HDL than women without osteoporosis. On the other hand, women with metabolic syndrome did not have significant differences than women without metabolic syndrome in terms of lumbar and femoral neck density (P>0.05). CONCLUSION: Results from this study showed that metabolic syndrome and its components did not induce bone mass loss. The discrepancies of the studies in this area call for more large scale studies in population so as to prevent women problems in this area. PMID- 28024828 TI - Gene and environment interaction: Is the differential susceptibility hypothesis relevant for obesity? AB - The differential susceptibility model states that a given genetic variant is associated with an increased risk of pathology in negative environments but greater than average resilience in enriched ones. While this theory was first implemented in psychiatric-genetic research, it may also help us to unravel the complex ways that genes and environments interact to influence feeding behavior and obesity. We reviewed evidence on gene vs. environment interactions that influence obesity development, aiming to support the applicability of the differential susceptibility model for this condition, and propose that various environmental "layers" relevant for human development should be considered when bearing the differential susceptibility model in mind. Mother-child relationship, socioeconomic status and individual's response are important modifiers of BMI and food intake when interacting with gene variants, "for better and for worse". While only a few studies to date have investigated obesity outcomes using this approach, we propose that the differential susceptibility hypothesis is in fact highly applicable to the study of genetic and environmental influences on feeding behavior and obesity risk. PMID- 28024831 TI - Impact of a comprehensive intervention to families with teenage sons with overweight and obesity in a primary care setting: A case report. AB - BACKGROUND: Overweight and obesity in adolescence is a public health problem and a risk factor for chronic noncommunicable diseases. To prevent further diseases, preventive interventions are needed, including educational programmes, addressed in a primary care setting, that include the whole family. The objective of this study was to evaluate the impact of a comprehensive intervention, targeting families with teenage sons with overweight and obesity, in the lifestyle, cardiovascular risk factors and metabolic syndrome in a primary care setting. METHODS: A pre-post intervention study was conducted. Twelve families with teenage sons between 10 and 14 years were enrolled; all the families were affiliated to the IMSS (Insituto Mexicano del Seguro Social). The comprehensive strategy was applied for 6 months (educational sessions for self-care, physical activity and nutritional counselling). The following measurements were performed before and after the intervention: the FANTASTIC lifestyle survey was applied. Clinical, anthropometric and biochemical assessments were performed. The changes in life style and cardiovascular risk factors were analyzed with Student's t-test or Mann-Whitney U test. RESULTS: The lifestyle was improved after the intervention in the domains of family and friends, nutrition and alcohol intake (p<0.05). Body mass index, waist circumference and diastolic blood pressure and fasting glucose decreased significantly. CHDL increased (p<0.05). Metabolic syndrome improved (p<0.05). CONCLUSIONS: Our comprehensive intervention for the families in a primary care setting, improved their lifestyle, decreased cardiovascular risk factors and decreased the metabolic syndrome. PMID- 28024832 TI - Increased waist circumference is the main driver for the development of the metabolic syndrome in South African Asian Indians. AB - : There is no current evidence available on the prevalence of metabolic syndrome (MetS) in South African Asian Indians, who are at high risk for cardiovascular disease. The aim of our study was to determine the prevalence of the MetS in this group, between males and females, as well as in the different age-groups, using the harmonised criteria and determined the main components driving the development of MetS. DESIGN AND METHODS: This cross-sectional study recruited randomly selected community participants between the ages of 15 and 65 years, in the community of Phoenix, in KwaZulu-Natal. All subjects had anthropometric variables and blood pressure measured, as well as blood drawn for blood glucose and lipids after overnight fasting. The MetS was determined using the harmonised criteria. RESULTS: There were 1378 subjects sampled, mean age 45.5+/-13years and 1001 (72.6%) women. The age standardised prevalence for MetS was 39.9% and significantly higher (p<0.001) in women (49.9% versus 35.0% in men). The MetS was identified in 6.9% of young adults (15-24 years), with a four-fold increase in the 25-34year olds, and 60.1% in the 55-64year old group. Clustering of MetS components was present in all age-groups, but increased with advancing age. The independent contributors to the MetS were increased waist circumference, raised triglycerides and obesity. This study highlights the high prevalence of MetS in this ethnic group and the emergence of MetS in our younger subjects. Urgent population-based awareness campaigns, focussing on correcting unhealthy lifestyle behaviours should begin in childhood. PMID- 28024833 TI - [Guillain-Barre syndrome complicating Shigella flexneri infection]. PMID- 28024834 TI - [Verrucous tumor]. PMID- 28024835 TI - Leukocytosis and neutrophilia predicts outcome in anal cancer. AB - OBJECTIVE: Leukocytosis and neutrophilia could be the tip of the iceberg in the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a cohort of patients treated with definitive chemoradiation for anal squamous cell carcinoma (SCC). MATERIALS & METHODS: Clinical records from all consecutive patients treated in a single institution between 2006 and 2016 with curative-intent radiotherapy were retrospectively analyzed. Leukocytosis and neutrophilia, defined as leukocyte or neutrophil count over 10,000 and 7500/mm3, respectively, were studied in terms of overall survival (OS), progression (PFS), locoregional (LFS) and distant (DFS)-free survival. RESULTS: We identified 103 non-metastatic HIV-negative patients, with concurrent chemotherapy use in 78%. Twelve and 8% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year OS and PFS were 88% and 67%, respectively. In univariate analysis, both leukocytosis and neutrophilia were strongly associated with inferior OS, PFS, LFS and DFS (p<0.01). In multivariate analysis, leukocytosis and neutrophilia remained strongly associated with patient outcome (p<0.01), independently from tumor T and N-stage. Anemia was an independent predictor of worse OS and PFS, while chemoradiation overall treatment time below 50days improved PFS. CONCLUSION: Leukocytosis and neutrophilia are strong prognostic factors for OS, PFS, LFS and DFS in anal cancer treated with chemoradiation. These biomarkers could help identify patients with higher risk of tumor relapse that require treatment intensification. PMID- 28024837 TI - Ultrasound and microbubble enhanced treatment of inoperable pancreatic cancer. PMID- 28024836 TI - Effects of testosterone on mean arterial pressure and aquaporin (AQP)-1, 2, 3, 4, 6 and 7 expressions in the kidney of orchidectomized, adult male Sprague-Dawley rats. AB - : We hypothesized that higher blood pressure in males than females could be due to testosterone effects on aquaporin (AQP) expression in kidneys. METHODS: Orchidectomized adult male Sprague-Dawley (SD) rats received seven days subcutaneous testosterone treatment (125 MUg/kg/day or 250 MUg/kg/day), with or without flutamide or finasteride. Following completion of treatment, MAP was determined in rats under anaesthesia via carotid artery cannulation. In another cohort of rats, kidneys were removed following sacrifice and AQP-1, 2, 3, 4, 6 and 7 protein and mRNA levels were determined by Western blotting and Real-time PCR respectively. Distribution of AQP subunits' protein in the nephrons were visualized by immunofluorescence. RESULTS: Testosterone caused MAP, AQP-1, 2, 4, 6 and 7 protein and mRNA levels in kidneys to increase while AQP-3 protein and mRNA levels in kidneys to decrease (p < 0.05). AQP-1 and 7 were found to be distributed in the proximal convoluted tubule (PCT) while AQP-2, 3, 4 and 6 were found to be distributed in the collecting ducts (CD). Effects of testosterone were antagonized by flutamide and finasteride. CONCLUSIONS: Elevated expression of AQP-1, 2, 4, 6 and 7 under testosterone influence in kidneys could lead to increase H2O reabsorption which eventually lead to increase in blood pressure. PMID- 28024838 TI - Special issue on "Biofluid mechanics of multitude pathways: From cellular to organ". PMID- 28024839 TI - Pink1/Parkin-mediated mitophagy play a protective role in cisplatin induced renal tubular epithelial cells injury. AB - Cisplatin often causes acute kidney injury (AKI) in the treatment of a wide variety of malignancies. Mitochondrial dysfunction is one of the main reasons for cisplatin nephrotoxicity. Previous study showed that Pink1 and Parkin play central roles in regulating the mitophagy, which is a key protective mechanism by specifically eliminating dysfunctional or damaged mitochondria. However, the mechanisms that modulate mitophagy in cisplatin induced nephrotoxicity remain to be elucidated. The purpose of this study was to investigate the effects of Pink1/Parkin pathway in mitophagy, mitochondrial dysfunction and renal proximal tubular cells injury during cisplatin treatment. In cultured human renal proximal tubular cells, we found that knockdown of Pink1/Parkin induced the aggravation of mitochondrial function, leading to the increase of cell injury through inhibition of mitophagy. Additionally, the overexpression of Pink1/Parkin protected against cisplatin-induced mitochondrial dysfunction and cell injury by promoting mitophagy. Our results provide clear evidence that Pink1/Parkin-dependent mitophagy has identified potential targets for the treatment of cisplatin-induced AKI. PMID- 28024840 TI - Intrafamilial phenotypic variability in Andersen-Tawil syndrome: A diagnostic challenge in a potentially treatable condition. AB - Andersen-Tawil syndrome (ATS) is a rare autosomal dominant channelopathy characterized by periodic paralysis, cardiac dysrhythmias, and distinct facial and skeletal characteristics, that may be variably present in the affected members. Mutations in the KCNJ2 and KCNJ5 gene have been associated with this disorder. We describe a family in which several members presented with different ATS phenotypes. The proband, a 4-year-old boy, presented with recurrent episodes of muscle weakness from an early age; two siblings suffered cardiac arrhythmia but had never experienced episodes of paralysis; their mother reported occasional muscle pain after exercise and unspecified cardiac arrhythmias. The analysis of KCNJ2 gene in the proband disclosed the presence of a pathogenic mutation (p.R218W), that was subsequently confirmed in the other affected subjects. Our results underline the possible intrafamilial phenotypic variability, ranging from full clinical triad to exclusive cardiac or muscular involvement, representing a diagnostic challenge that may also delay adequate management. There are still limited data on the treatment of ATS; in our patient there was clinical improvement with dichlorphenamide. PMID- 28024841 TI - A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype. AB - In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics. Molecular dynamics simulations comparing wild type and mutant Nav1.4 showed that threonine substitution hindered D4S4 mobility in response to membrane depolarization, consistent with effects of the mutation on channel inactivation. The fixed myopathy is likely to be associated to gain-of-function leading to sodium accumulation, regional edema, T tubular swelling and mitochondrial stress. A possible contribution of the loss-of function features towards myotonia and myopathy is discussed. PMID- 28024843 TI - Comparison of organochlorine and PAHs residues in terns eggs from two natural protected areas in the Gulf of Mexico. AB - Persistent organic pollutants (POPs) are dispersed all over the world while polycyclic aromatic hydrocarbons (PAHs) are released into the environment from pyrogenic and petrogenic sources and are not very mobile or persistent. The aim of this study was to identify POPs and PAHs from eggs of Least and Sooty Terns nesting in two protected marine areas with different anthropogenic impacts in the southern Gulf of Mexico. SigmaHCHs were higher in Terminos in 2010 and higher in Alacranes in 2011. SigmaDienes and SigmaDDTs were higher in 2011 in both study sites. SigmaEndosulfan was higher in Terminos than in Alacranes in both years. SigmaDienes, SigmaDDT and SigmaHeptachlor were the highest in both species both years. Acenaphtylene and Fluoranthene were higher in Terminos while Pyrene was higher in Alacranes. No differences were present within species between years. In 2011 PAHs in eggs could have reflected the BP oil spill input. PMID- 28024842 TI - Congenital myasthenic syndrome in Israel: Genetic and clinical characterization. AB - The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected. PMID- 28024844 TI - Correlation of florbetaben PET imaging and the amyloid peptide Abeta42 in cerebrospinal fluid. AB - Today, the use of biomarkers such as amyloid-specific positron emission tomography (PET) tracers and information derived from cerebrospinal fluid (CSF) can support the diagnosis of Alzheimer's disease (AD) as an indicator for the presence of amyloid pathology. We here show that the PET signal of the 18F labelled tracer florbetaben (NeuraCeqTM), that binds to amyloid-beta plaques, inversely correlates with CSF levels of Abeta42, another biomarker for AD. Results from the two biomarkers were concordant in 35 out of 38 subjects. In 7 AD subjects (20%) at least one biomarker was inconsistent with the clinical diagnosis. This confirms known limitations of the clinical AD diagnosis and highlights the potential of biomarker-assisted diagnosis to improve accuracy. PMID- 28024846 TI - 9th Congress of the Associazione Italiana di Fisica Medica, Perugia 25-28 February 2016, "Continuity and evolution in medical physics". PMID- 28024845 TI - Switching between internally and externally focused attention in obsessive compulsive disorder: Abnormal visual cortex activation and connectivity. AB - Obsessive-compulsive disorder (OCD) is characterized by excessive absorption with internally-generated distressing thoughts and urges, with difficulty incorporating external information running counter to their fears and concerns. In the present study, we experimentally probed this core feature of OCD through the use of a novel attention switching task that investigates transitions between internally focused (IF) and externally focused (EF) attentional states. Eighteen OCD patients and 18 controls imagined positive and negative personal event scenarios (IF state) or performed a color-word Stroop task (EF state). The IF/EF states were followed by a target detection (TD) task requiring responses to external stimuli. Compared to controls, OCD patients made significantly more errors and showed reduced activation of superior and inferior occipital cortex, thalamus, and putamen during TD following negative IF, with the inferior occipital hypoactivation being significantly greater for TD following negative IF compared to TD following the other conditions. Patients showed stronger functional connectivity between the inferior occipital region and dorsomedial prefrontal cortex. These findings point to an OCD-related impairment in the visual processing of external stimuli specifically when they follow a period of negative internal focus, and suggest that future treatments may wish to target the transition between attentional states. PMID- 28024847 TI - Dark-Field Imaging: Recent developments and potential clinical applications. AB - This paper describes an X-ray phase contrast imaging technique using analyzer based optics called X-ray Dark-Field Imaging that has been under development for the past 10years. We describe the theory behind XDFI, the X-ray optics required for implementing it in practice, and algorithms used for 2D, 2.5D, and 3D image reconstruction. The XDFI optical chain consists of an asymmetrically cut, Bragg type monochromator-collimator that provides a planar monochromatic X-ray beam, a positioning stage for the specimens, a Laue-case angle analyzer, and one or two cameras to capture the dark and bright field images. We demonstrate the soft tissue discrimination capabilities of XDFI by reconstructing images with absorption and phase contrast. By using a variety of specimens such as breast tissue with cancer, joints with articular cartilage, ex-vivo human eye specimen, and others, we show that refraction-based contrast derived from XDFI is more effective in characterizing anatomical features, articular pathology, and neoplastic disease than conventional absorption-based images. For example, XDFI of breast tissue can discriminate between the normal and diseased terminal duct lobular unit, and between invasive and in-situ cancer. The final section of this paper is devoted to potential future developments to enable clinical and histo pathological applications of this technique. PMID- 28024848 TI - Neutron shielding for a new projected proton therapy facility: A Geant4 simulation study. AB - In this work, we used the Monte Carlo-based Geant4 simulation toolkit to calculate the ambient dose equivalents due to the secondary neutron field produced in a new projected proton therapy facility. In particular the facility geometry was modeled in Geant4 based on the CAD design. Proton beams were originated with an energy of 250MeV in the gantry rooms with different angles with respect to the patient; a fixed 250MeV proton beam was also modeled. The ambient dose equivalent was calculated in several locations of interest inside and outside the facility, for different scenarios. The simulation results were compared qualitatively to previous work on an existing facility bearing some similarities with the design under study, showing that the ambient dose equivalent ranges obtained are reasonable. The ambient dose equivalents, calculated by means of the Geant4 simulation, were compared to the Australian regulatory limits and showed that the new facility will not pose health risks for the public or staff, with a maximum equivalent dose rate equal to 7.9mSv/y in the control rooms and maze exit areas and 1.3.10-1mSv/y close to the walls, outside the facility, under very conservative assumptions. This work represents the first neutron shielding verification analysis of a new projected proton therapy facility and, as such, it may serve as a new source of comparison and validation for the international community, besides confirming the viability of the project from a radioprotection point of view. PMID- 28024849 TI - Diminished force production and mitochondrial respiratory deficits are strain dependent myopathies of subacute limb ischemia. AB - OBJECTIVE: Reduced skeletal muscle mitochondrial function might be a contributing mechanism to the myopathy and activity based limitations that typically plague patients with peripheral arterial disease (PAD). We hypothesized that mitochondrial dysfunction, myofiber atrophy, and muscle contractile deficits are inherently determined by the genetic background of regenerating ischemic mouse skeletal muscle, similar to how patient genetics affect the distribution of disease severity with clinical PAD. METHODS: Genetically ischemia protected (C57BL/6) and susceptible (BALB/c) mice underwent either unilateral subacute hind limb ischemia (SLI) or myotoxic injury (cardiotoxin) for 28 days. Limbs were monitored for blood flow and tissue oxygen saturation and tissue was collected for the assessment of histology, muscle contractile force, gene expression, mitochondrial content, and respiratory function. RESULTS: Despite similar tissue O2 saturation and mitochondrial content between strains, BALB/c mice suffered persistent ischemic myofiber atrophy (55.3% of C57BL/6) and muscle contractile deficits (approximately 25% of C57BL/6 across multiple stimulation frequencies). SLI also reduced BALB/c mitochondrial respiratory capacity, assessed in either isolated mitochondria (58.3% of C57BL/6 at SLI on day (d)7, 59.1% of C57BL/6 at SLI d28 across multiple conditions) or permeabilized myofibers (38.9% of C57BL/6 at SLI d7; 76.2% of C57BL/6 at SLI d28 across multiple conditions). SLI also resulted in decreased calcium retention capacity (56.0% of C57BL/6) in BALB/c mitochondria. Nonischemic cardiotoxin injury revealed similar recovery of myofiber area, contractile force, mitochondrial respiratory capacity, and calcium retention between strains. CONCLUSIONS: Ischemia-susceptible BALB/c mice suffered persistent muscle atrophy, impaired muscle function, and mitochondrial respiratory deficits during SLI. Interestingly, parental strain susceptibility to myopathy appears specific to regenerative insults including an ischemic component. Our findings indicate that the functional deficits that plague PAD patients could include mitochondrial respiratory deficits genetically inherent to the regenerating muscle myofibers. PMID- 28024850 TI - Volume of subclinical embolic infarct correlates to long-term cognitive changes after carotid revascularization. AB - OBJECTIVE: Carotid intervention is safe and effective in stroke prevention in appropriately selected patients. Despite minimal neurologic complications, procedure-related subclinical microemboli are common and their cognitive effects are largely unknown. In this prospective longitudinal study, we sought to determine long-term cognitive effects of embolic infarcts. METHODS: The study recruited 119 patients including 46% symptomatic patients who underwent carotid revascularization. Neuropsychological testing was administered preoperatively and at 1 month, 6 months, and 12 months postoperatively. Rey Auditory Verbal Learning Test (RAVLT) was the primary cognitive measure with parallel forms to avoid practice effect. All patients also received 3T brain magnetic resonance imaging with a diffusion-weighted imaging (DWI) sequence preoperatively and within 48 hours postoperatively to identify procedure-related new embolic lesions. Each DWI lesion was manually traced and input into a neuroimaging program to define volume. Embolic infarct volumes were correlated with cognitive measures. Regression models were used to identify relationships between infarct volumes and cognitive measures. RESULTS: A total of 587 DWI lesions were identified on 3T magnetic resonance imaging in 81.7% of carotid artery stenting (CAS) and 36.4% of carotid endarterectomy patients with a total volume of 29,327 mm3. Among them, 54 DWI lesions were found in carotid endarterectomy patients and 533 in the CAS patients. Four patients had transient postoperative neurologic symptoms and one had a stroke. CAS was an independent predictor of embolic infarction (odds ratio, 6.6 [2.1-20.4]; P < .01) and infarct volume (P = .004). Diabetes and contralateral carotid severe stenosis or occlusion had a trend of positive association with infarct volume, whereas systolic blood pressure >=140 mm Hg had a negative association (P = .1, .09, and .1, respectively). There was a trend of improved RAVLT scores overall after carotid revascularization. Significantly higher infarct volumes were observed among those with RAVLT decline. Within the CAS cohort, infarct volume was negatively correlated with short- and long-term RAVLT changes (P < .05). CONCLUSIONS: Cognitive assessment of procedure-related subclinical microemboli is challenging. Volumes of embolic infarct correlate with long-term cognitive changes, suggesting that microembolization should be considered a surrogate measure for carotid disease management. PMID- 28024851 TI - Deficiency of gammadeltaT cells protects against abdominal aortic aneurysms by regulating phosphoinositide 3-kinase/AKT signaling. AB - OBJECTIVE: It is known that T lymphocytes are activated in human abdominal aortic aneurysms (AAAs). gammadeltaT cells, as a subset of T cells, play a role in many inflammation-related diseases. However, whether gammadeltaT cells participate in the formation of AAA remains unknown. In this study, we explored the role of gammadeltaT cells in AAA lesions. METHODS AND RESULTS: Using the porcine pancreatic elastase-induced AAA model, we found that knock out of gammadeltaT cells significantly attenuated AAA formation. To elucidate how gammadeltaT cells contribute to AAA, microarray analysis was performed, which found that the phosphoinositide 3-kinase/AKT signaling pathway was activated in elastase perfused gammadeltaT knockout (gammadeltaT KO) mice. By studying differentially expressed genes involved in phosphoinositide 3-kinase signaling, we found that proliferation-related genes (Sos1, Mtor, Myc) were upregulated whereas apoptosis related genes (Pten, Bcl1, Bad) were downregulated in elastase-perfused gammadeltaT KO mice. Furthermore, histopathologic analysis showed increased PCNA+ and decreased TUNEL+ cells in elastase-perfused gammadeltaT KO mice compared with wild-type mice. In addition, inflammatory cytokines including interleukin-1beta, Mcp-1, and tumor necrosis factor-alpha were downregulated in the aneurysm tissues of elastase-perfused gammadeltaT KO mice. CONCLUSIONS: These data reveal a pathogenic role of gammadeltaT cells in the experimental AAA model, likely through mechanisms regulating cell proliferation and mediating inflammatory response. Thus, targeting of gammadeltaT cells may offer a potential therapeutic method for aortic aneurysms. PMID- 28024852 TI - A model for choosing an automated ultraviolet-C disinfection system and building a case for the C-suite: Two case reports. AB - Environmental disinfection has become the new frontier in the ongoing battle to reduce the risk of health care-associated infections. Evidence demonstrating the persistent contamination of environmental surfaces despite traditional cleaning and disinfection methods has led to the widespread acceptance that there is both a need for reassessing traditional cleaning protocols and for using secondary disinfection technologies. Ultraviolet-C (UV-C) disinfection is one type of no touch technology shown to be a successful adjunct to manual cleaning in reducing environmental bioburden. The dilemma for the infection preventionist, however, is how to choose the system best suited for their facility among the many UV-C surface disinfection delivery systems available and how to build a case for acquisition to present to the hospital administration/C-suite. This article proposes an approach to these dilemmas based in part on the experience of 2 health care networks. PMID- 28024853 TI - Inferior Vena Cava Compression as a Novel Maneuver to Detect Patent Foramen Ovale: A Transesophageal Echocardiographic Study. AB - BACKGROUND: The Valsalva maneuver, the most sensitive test for patent foramen ovale (PFO) detection, is difficult during transesophageal echocardiography (TEE), especially after sedation. The aim of this study was to compare PFO detection effectiveness between inferior vena cava (IVC) compression and the Valsalva maneuver. METHODS: A total of 293 patients with paroxysmal atrial fibrillation undergoing TEE before initial atrial fibrillation ablation were prospectively enrolled. Agitated saline was injected in 290 patients under three conditions: Valsalva maneuver under conscious sedation, at rest, and IVC compression under deep sedation. Three patients with newly diagnosed atrial septal defects on TEE were excluded. The IVC compression maneuver consisted of manual compression 5 cm to the right of the epigastric region and depressed the abdominal wall by 5 cm for 30 sec and compression release immediately before right atrial opacification with microbubbles by agitated intravenous saline. RESULTS: The overall PFO detection rate was better with IVC compression (57 PFOs [19.7%]) than at rest (15 patients [5.2%]) (P < .0001) or with the Valsalva maneuver (37 patients [12.8%]) (P = .024). There were no significant differences in PFO detection between IVC compression and the Valsalva maneuver (IVC compression, 43 patients [22.5%]; Valsalva maneuver, 35 patients [18.3%]; P = .31), even in patients who could perform the Valsalva maneuver effectively (n = 191). CONCLUSIONS: IVC compression is feasible and effective for detecting PFO and is not inferior to the Valsalva maneuver. In particular, IVC compression could be an alternative diagnostic method for PFO using TEE when the Valsalva maneuver cannot be performed under deep sedation. PMID- 28024854 TI - How efficacious are vaccines against bovine respiratory syncytial virus in cattle? AB - Bovine respiratory syncytial virus (BRSV) is a paramyxovirus that is the major cause of pneumonia in calves. Vaccines for this important pathogen have been available since the late 1970's. This review is a critical assessment of the literature including, experimental challenge studies and field trials, that address the efficacy of commonly used vaccines to control respiratory disease caused by BRSV. PMID- 28024855 TI - Current limitations in control of viral arthritis and tenosynovitis caused by avian reoviruses in commercial poultry. AB - Avian reoviruses are the causative agent of viral arthritis/tenosynovitis in chickens and turkeys. Clinical signs of disease include swelling of the hock joints accompanied by lesions in the gastrocnemius and digital flexor tendons causing lameness in addition to hydropericardium. The economic impact is significant as it results in poor weight gain, increased feed conversion ratios and condemnations at the processing plant. Vaccination with both live attenuated and inactivated oil emulsion vaccines have been used successfully for decades to control the disease. Current commercial vaccine strains belong to the same serotype and are antigenically and serologically distinct from circulating variant field viruses isolated from clinical cases of tenosynovitis. Since 2012, there has been a dramatic increase in the number of clinical cases of tenosynovitis in commercial poultry and commercial vaccines are unable to provide adequate levels of protection against disease. Producers have elected to use custom inactivated vaccines in the absence of any commercially available homologous vaccines. Identification and selection of field isolates for use in autogenous vaccines can be difficult especially when multiple reoviruses are co circulating among flocks. In addition, field data suggests that in some cases the custom vaccines are providing adequate protection against disease but as new genetic variants emerge, new vaccines are needed. PMID- 28024856 TI - Newcastle disease vaccines-A solved problem or a continuous challenge? AB - Newcastle disease (ND) has been defined by the World Organisation for Animal Health as infection of poultry with virulent strains of Newcastle disease virus (NDV). Lesions affecting the neurological, gastrointestinal, respiratory, and reproductive systems are most often observed. The control of ND must include strict biosecurity that prevents virulent NDV from contacting poultry, and also proper administration of efficacious vaccines. When administered correctly to healthy birds, ND vaccines formulated with NDV of low virulence or viral-vectored vaccines that express the NDV fusion protein are able to prevent clinical disease and mortality in chickens upon infection with virulent NDV. Live and inactivated vaccines have been widely used since the 1950's. Recombinant and antigenically matched vaccines have been adopted recently in some countries, and many other vaccine approaches have been only evaluated experimentally. Despite decades of research and development towards formulation of an optimal ND vaccine, improvements are still needed. Impediments to prevent outbreaks include uneven vaccine application when using mass administration techniques in larger commercial settings, the difficulties associated with vaccinating free-roaming, multi-age birds of village flocks, and difficulties maintaining the cold chain to preserve the thermo-labile antigens in the vaccines. Incomplete or improper immunization often results in the disease and death of poultry after infection with virulent NDV. Another cause of decreased vaccine efficacy is the existence of antibodies (including maternal) in birds, which can neutralize the vaccine and thereby reduce the effectiveness of ND vaccines. In this review, a historical perspective, summary of the current situation for ND and NDV strains, and a review of traditional and experimental ND vaccines are presented. PMID- 28024857 TI - Calpain inhibition decreases inflammatory protein expression in vessel walls in a model of chronic myocardial ischemia. AB - BACKGROUND: Emerging data suggest a link between calpain activation and the enhanced inflammatory response of the cardiovascular system. We hypothesize that calpain activation associates with altered inflammatory protein expression in correlation with the proinflammatory profile of the myocardium. Our pig hypercholesterolemic model with chronic myocardial ischemia was treated with calpain inhibitors to establish their potential to improve cardiac function. METHODS: Yorkshire swine, fed a high cholesterol diet for 4 weeks then underwent placement of an ameroid constrictor on the left circumflex artery. Two weeks later, animals received either no drug (high-cholesterol control group, n = 8), a low dose of calpain inhibitors (0.12 mg/kg, n = 9), or a high dose of calpain inhibitors (0.25 mg/kg; n = 8). The high-cholesterol diet and calpain inhibitors were continued for 5 weeks, after which the pig was euthanized. The left ventricular myocardial tissue (ischemic and nonischemic) was harvested and analyzed for inflammatory protein expression. Data were statistically analyzed via the Kruskal-Wallis and Dunn post hoc test. RESULTS: Calpain inhibitor treatment coincides with increased expression of IKB-alpha and decreased expression of macrophages, NFkB, IL-1, and tumor necrosis factor (TNF)-alpha in the ischemic myocardial tissue as compared with the control group. An NFkB array revealed decreased expression of IRF5, JNK1/2, JNK2, CD18, NFkB p65, c-Rel, Sharpin, TNF R1, TNF R2, and DR5 in the ischemic myocardium of the group treated with a high dose of calpain inhibitors compared with the control. CONCLUSION: Calpain activation in metabolic syndrome is a potential contributor to cardiac dysfunction in metabolic disorders with ischemic background. We suggest that calpain inhibition downregulates NFkB signaling in the vessel walls, which might be useful for improving myocardial blood flow in ischemic conditions. PMID- 28024858 TI - Costs of Clostridium difficile infection in pediatric operations: A propensity score-matching analysis. AB - BACKGROUND: The purpose of this analysis was to assess the burden of Clostridium difficile infection in the hospitalized pediatric surgical population and to characterize its influence on the costs of care. METHODS: There were 313,664 patients age 1-18 years who underwent a general thoracic or abdominal procedure in the Kids' Inpatient Database during 2003, 2006, 2009, and 2012. Logistic regression was used to model factors associated with the development of C difficile infection. A propensity score-matching analysis was performed to evaluate the influence of C difficile infection on mortality, duration of stay, and costs in similar patient cohorts. Population weights were used to estimate the national excess burden of C difficile infection on these outcomes. RESULTS: The overall prevalence of C difficile infection in the sampled cohort was 0.30%, with an increasing trend of C difficile infection over time in non-children's hospitals (P < .001). C difficile infection was associated with younger age, nonelective procedures, increasing comorbidities, and urban teaching hospital status (P < .001). An estimated 1,438 children developed C difficile infection after operation. After propensity score matching, the mean excess duration of stay and costs attributable to C difficile infection were 5.8 days and $12,801 (P < .001), accounting for 8,295 days spent in the hospital and $18.4 million (2012 USD) in spending annually. CONCLUSION: C difficile infection is a relatively uncommon but costly complication after pediatric operative procedures. Given the increasing trend of C difficile infection among hospitalized surgical patients, there is substantial opportunity for reduction of inpatient burden and associated costs in this potentially preventable nosocomial infection. PMID- 28024859 TI - Bi-directional associations of electronic and combustible cigarette use onset patterns with depressive symptoms in adolescents. AB - Whether well-documented patterns of mental health comorbidity with adolescent combustible cigarette use extend to e-cigarette use is unclear. Demonstrating associations between e-cigarette and combustible cigarette use with mental health symptomatology across adolescence may be important for promoting accurate perceptions of populations at risk for and potential consequences of tobacco product use. Adolescents (N=2460; mean age at baseline=14.1; 53.4% female; 44.1% Hispanic) who had never previously used combustible or e-cigarettes were assessed at baseline, and 6- and 12-month follow-ups in Los Angeles, CA (2013-2014). Logistic regression was used to examine associations between baseline depressive symptoms and onset of e-cigarette and cigarette single product and dual use at follow-ups. Latent growth modeling was used to examine associations between sustained use of either product (vs. non-use) and changes in depressive symptoms over 12-months. Higher baseline depressive symptoms predicted subsequent onset of cigarette (OR=1.024, 95% C.I.=1.009-1.055), e-cigarette (OR=1.015, C.I.=1.003 1.023), and dual use of both products (OR=1.021, C.I.=1.003-1.043). Sustained use of e-cigarettes over the 12-month observation (vs. non-use) was associated with a greater rate of increase in depressive symptoms over time (b=1.272, SE=0.513, p=0.01). Among those who sustained use of e-cigarettes, higher frequency of use was associated with higher depressive symptoms at the final follow-up (B=1.611, p=0.04). A bi-directional association of depressive symptoms with e-cigarette use onset across mid adolescence was observed. Further research on the causal nature, etiological underpinnings, and intervention implications of mental health and tobacco product use comorbidity is warranted. PMID- 28024860 TI - How hearing about harmful chemicals affects smokers' interest in dual use of cigarettes and e-cigarettes. AB - Substantial harm could result from concurrent cigarette and e-cigarette use (i.e., dual use) were it to undermine smoking cessation. Perceptions of chemical exposure and resulting harms may influence dual use. We conducted a probability based phone survey of 1164 U.S. adult cigarette smokers in 2014-2015 and analyzed results in 2016. In a between-subjects experiment, smokers heard a hypothetical scenario in which cigarettes and e-cigarettes had the same amount of harmful chemicals or cigarettes had more chemicals than e-cigarettes (10* more, 100* more, or chemicals were present only in cigarettes). Smokers indicated how the scenario would change their interest in dual use and perceived health harms. Few smokers (7%) who heard that the products have the same amount of chemicals were interested in initiating or increasing dual use. However, more smokers were interested when told that cigarettes have 10* more chemicals than e-cigarettes (31%), 100* more chemicals than e-cigarettes (32%), or chemicals were present only in cigarettes (43%) (all p<.001). Individuals told that cigarettes have more chemicals were more likely than those in the "same amount" scenario to perceive that cigarettes would be more harmful than e-cigarettes (79% vs. 41%, OR=5.41, 95% CI=4.08-7.17). These harm perceptions partially explained the relationship between chemical scenario and dual use interest. Smokers associated higher chemical amounts in cigarettes versus e-cigarettes with greater health harms from cigarettes and thus expressed increased interest in dual use. The findings suggest that disclosing amounts of chemicals in cigarette smoke and e-cigarette aerosol could unintentionally encourage dual use. PMID- 28024861 TI - Use of global positioning system for physical activity research in youth: ESPACOS Adolescentes, Brazil. AB - The built environment is an important factor associated with physical activity and sedentary behavior (SB) during adolescence. This study presents the methods for objective assessment of context-specific moderate to vigorous physical activity (MVPA) and SB, as well as describes results from the first project using such methodology in adolescents from a developing country. An initial sample of 381 adolescents was recruited from 32 census tracts in Curitiba, Brazil (2013); 80 had their homes geocoded and wore accelerometer and GPS devices for seven days. Four domains were defined as important contexts: home, school, transport and leisure. The majority of participants (n=80) were boys (46; 57.5%), with a normal BMI (52; 65.0%) and a mean age (SD) of 14.5 (5.5) years. Adolescents spent most of their time at home, engaging in SB. Overall, the largest proportion of MVPA was while in transport (17.1% of time spent in this context) and SB while in leisure (188.6min per day). Participants engaged in MVPA for a median of 28.7 (IQR 18.2-43.2) and 17.9 (IQR 9.2-32.1) minutes during week and weekend days, respectively. Participants spent most of their day in the leisure and home domains. The use of Geographic Information System (GIS), Global Positioning System (GPS) and accelerometer data allowed objective identification of the amount of time spent in MVPA and SB in four different domains. Though the combination of objective measures is still an emerging methodology, this is a promising and feasible approach to understanding interactions between people and their environments in developing countries. PMID- 28024862 TI - Perceived urban neighborhood environment for physical activity of older adults in Seoul, Korea: A multimethod qualitative study. AB - This study assessed the attributes of a perceived urban neighborhood environment for the physical activity (PA) of older adults by applying a qualitative multimethod approach to collect both descriptive and spatial information. Conducted in a northern community of Seoul, Korea, from April 2014 to November 2015, data collection methods included 90 walking tours by researchers, 46 face to-face, semi-structured interviews combined with qualitative mapping with senior residents aged 65+, 19 guided tours with the interviewees, and 3 focus groups with 12 community service providers. Thematic analysis and pattern finding were performed on the data. Walking was the main type of PA of the older adults. Nine attributes of perceived neighborhood environment for PA were identified under three themes: daily living (everyday life activities, mobility, social opportunities, diverse destinations); the multidimensionality of accessibility (physical, economic, psychosocial), and attractiveness and pleasantness (maintenance, aesthetics). The subcategories of the attributes included proximity, access to public transportation, walkability, cost-worthiness, low or no cost, familiarity, sense of welcoming, sociocultural appropriateness, fair access, order and upkeep, safety, openness, cleanliness, and interestingness. Strategies to generate more movement and activities in the everyday routine of the elderly should be a core task for health promotion and neighborhood design. A strategic application of multiple qualitative methods can create an opportunity to build contextual understanding and to generate ideas in interactions with the community. PMID- 28024863 TI - Targeting physical activity interventions for adults: When should intervention occur? AB - Understanding demographic differences in transitions across physical activity (PA) levels is important for informing PA-promoting interventions, yet few studies have examined these transitions in contemporary multi-ethnic adult populations. We estimated age-, race/ethnicity-, and sex-specific 1-year net transition probabilities (NTPs) for National Health and Nutrition Examination Survey (2007-2012, n=11,556) and Hispanic Community Health Study/Study of Latinos (2008-2011, n=15,585) adult participants using novel Markov-type state transition models developed for cross-sectional data. Among populations with ideal PA (>=150min/week; ranging from 56% (non-Hispanic black females) to 88% (non Hispanic white males) at age 20), NTPs to intermediate PA (>0-<149min/week) generally increased with age, particularly for non-Hispanic black females for whom a net 0.0% (95% confidence interval (CI): 0.0, 0.2) transitioned from ideal to intermediate PA at age 20; by age 70, the NTP rose to 3.6% (95% CI: 2.3, 4.8). Heterogeneity in intermediate to poor (0min/week) PA NTPs also was observed, with NTPs peaking at age 20 for Hispanic/Latino males and females [age 20 NTP=3.7% (95% CI: 2.0, 5.5) for females and 5.0% (1.2, 8.7) for males], but increasing throughout adulthood for non-Hispanic blacks and whites [e.g. age 70 NTP=7.8% (95% CI: 6.1, 9.6%) for black females and 8.1% (4.7, 11.6) for black males]. Demographic differences in PA net transitions across adulthood justify further development of tailored interventions. However, innovative efforts may be required for populations in which large proportions have already transitioned from ideal PA by early adulthood. PMID- 28024864 TI - Appointment-keeping behaviors and procedure day are associated with colonoscopy attendance in a patient navigator population. AB - BACKGROUND: Patient navigator programs (PNP) have been shown to improve colonoscopy completion with demonstrated cost-effectiveness. Despite additional resources available to these patients, many still do not attend their colonoscopies. The aim of this study was to determine factors associated with colonoscopy attendance amongst patients in whom logistical barriers to attendance have been minimized through enrollment in a PNP. METHODS: Retrospective case control study of patients enrolled in a PNP for colonoscopy performed at a tertiary endoscopy center from 2009 to 2014. Cases were defined as patients who did not attend their first scheduled colonoscopy after PNP enrollment. Age- and gender-matched controls completed their first scheduled colonoscopy after PNP enrollment. RESULTS: 514 subjects (257 cases, mean age 57.1years, 36.6% males) were included. Patients who attended their colonoscopy were less likely to be Spanish-speaking (64.6% vs 78.2%, p=0.0003) and uninsured (0.4% vs 3.9%, p=0.006). Attendance rates were significantly lower for screening colonoscopies compared to an indication of surveillance or diagnostic (45.5% vs 65.3%, p<0.0001). Fewer patients attended colonoscopies scheduled on Monday (39.2% vs 52.1%, p=0.04) and in December (10.7% vs 52.3%, p<0.0001). On multivariate analysis, poor appointment-keeping behaviors, including a prior missed colonoscopy (OR 0.20, 95% CI 0.10-0.39) or missed office visit (OR 0.44, 95% CI 0.26-0.73) and procedures scheduled on Mondays (OR 0.51, 95% CI 0.27-0.94) were negatively associated with attendance. CONCLUSIONS: Appointment-keeping behaviors, in addition to insurance-status, language-barriers and medical comorbidities, influence colonoscopy attendance in a PNP population. Patients scheduled for colonoscopies on Mondays or in December may require more resources to ensure attendance. PMID- 28024865 TI - Taxonomy for colorectal cancer screening promotion: Lessons from recent randomized controlled trials. AB - OBJECTIVE: To derive a taxonomy for colorectal cancer screening that advances Randomized Controlled Trials (RCTs) and screening uptake. DESIGN: Detailed publication review, multiple interviews with principal investigators (PIs) and collaboration with PIs as co-authors produced a CRCS intervention taxonomy. Semi structured interview questions with PIs (Drs. Inadomi, Myers, Green, Gupta, Jerant and Ritvo) yielded details about trial conduct. Interview comparisons led to an iterative process informing serial interviews until a consensus was obtained on final taxonomy structure. RESULTS: These taxonomy headings (Engagement Sponsor, Population Targeted, Alternative Screening Tests, Delivery Methods, and Support for Test Performance (EPADS)) were used to compare studies. Exemplary insights emphasized: 1) direct test delivery to patients; 2) linguistic ethnic matching of staff to minority subjects; and 3) authorization of navigators to schedule or refer for colonoscopies and/or distribute stool blood tests during screening promotion. CONCLUSION: PIs of key RCTs (2012-2015) derived a CRCS taxonomy useful in detailed examination of CRCS promotion and design of future RCTs. PMID- 28024866 TI - Saccharomyces boulardii probiotic-associated fungemia: questioning the safety of this preventive probiotic's use. AB - We report a case of fungemia in an immunocompetent patient after administration of probiotic containing Saccharomyces boulardii. We demonstrated the strain relatedness of the yeast from the probiotic capsule and the yeast causing fungal infection using genomic and proteomic typing methods. Our study questions the safety of this preventative biotherapy. PMID- 28024867 TI - Enterococcus spp. in a single blood culture: bacteremia or contamination? AB - We retrospectively evaluated adult cases with Enterococcus spp. in 1 blood culture (BC) (1/1/2010-12/31/2015; n=294) and stratified them into bacteremia or contamination. Contamination frequency was similar in community versus hospital onset, E. faecalis versus E. faecium, and number of BC drawn per day. Contamination predictors were vancomycin-resistance, ampicillin-resistance, commensal organism copresence, and nonurinary/abdominal sources. PMID- 28024869 TI - Expression of heat shock proteins (HSPs) in Aedes aegypti (L) and Aedes albopictus (Skuse) (Diptera: Culicidae) larvae in response to thermal stress. AB - Climatic changes are responsible, to a certain extent for the occurrence and spread of arboviral pathogens world over. Temperature is one of the important abiotic factors influencing the physiological processes of mosquitoes. Several genes of heat shock protein (HSP) families are known to be expressed in mosquitoes, which aid in overcoming stress induced by elevated temperature. In order to understand expression of HSP family genes in the Andaman population of Aedes aegypti and Aedes albopictus, we used quantitative real-time polymerase chain reaction (qPCR) to examine expression levels of HSPs in response to thermal stress under laboratory and in actual field conditions. HSP genes AeaHsp26, AeaHsp83 and AeaHsc70 were examined by comparing relative transcript expression levels at 31 degrees C, 33 degrees C, 34 degrees C, 37 degrees C and 39 degrees C respectively. Enhanced up-regulation of HSPs was evident in third instar larvae of Ae. aegypti with rise in water temperatures (31 degrees C, 33 degrees C, 34 degrees C) in the containers in the nature and thermally stressed (37 degrees C and 39 degrees C) in laboratory conditions. In Ae. albopictus up-regulation of HSPs was observed in field conditions at 34 degrees C only and when thermally treated at 37 degrees C, while down regulation was evident in larvae subjected to thermal stress in laboratory at 39 degrees C. Data on expression levels revealed that larvae of Ae. aegypti was tolerant to thermal stress, while Ae. albopictus larvae was sensitive to heat shock treatment. Statistical analysis indicated that AeaHsp83 genes were significantly up-regulated in Ae. aegypti larvae after 360min exposure to high temperature (39 degrees C). The difference in expression levels of AeaHsp26, AeaHsc70 and AeaHsp83 genes in Ae. albopictus larvae was statistically significant between different exposure temperatures. All of these genes were significantly up-regulated at 37 degrees C. These results indicate that AeaHsp26, AeaHsc70 and AeaHsp83 are important markers of stress and perhaps function as proteins conferring protection and enhance survival of the Andaman population of both the Aedine species. Biological implications of these findings could impact the vector competencies. PMID- 28024868 TI - Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer. AB - Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer. PMID- 28024870 TI - Arthroscopic-Assisted Latissimus Dorsi Tendon Transfer for Massive, Irreparable Rotator Cuff Tears: Technique and Short-Term Follow-Up of Patients With Pseudoparalysis. AB - PURPOSE: To describe a modified technique for arthroscopic-assisted transfer of the latissimus dorsi tendon in a selected group of patients with irreparable rotator cuff tears and pseudoparalysis and to evaluate its short-term results. METHODS: Fifteen patients with irreparable rotator cuff tears and pseudoparalysis treated by arthroscopic-assisted latissimus dorsi tendon transfer were included. The mean patient age was 61.53 +/- 6.24 years (range, 52-71 years). Patients were assessed with physical examination, University of California Los Angeles (UCLA) Score and Constant-Murley score, as well as visual analog scale score at a mean follow-up of 26.4 +/- 2.58 months (range, 24-31 months). RESULTS: At final follow up, mean UCLA score increased to 27.47 +/- 6.31 compared with the preoperative UCLA score of 6.53 +/- 2.1 (P < .001). Constant-Murley score was 21 +/- 7.41 and 59.73 +/- 13.62 (P < .001), visual analog scale pain score was 7.47 +/- 1.06 and 2.47 +/- 0.91 (P < .001), active forward flexion was 58 degrees +/- 21.11 degrees and 130 degrees +/- 30.05 degrees (P < .001), active abduction was 51 degrees +/- 21.64 degrees and 129.67 degrees +/- 25.45 degrees (P < .001), and active external rotation was 13.33 degrees +/- 21.68 degrees and 32 degrees +/- 18.03 degrees (P < .001) preoperatively and postoperatively, respectively. Mean acromiohumeral distance was 3.13 +/- 1.40 mm preoperatively, whereas it was 5.67 +/- 1.67 mm postoperatively (P < .001). No significant complications requiring a revision surgery was observed during the final follow-up. CONCLUSIONS: The modified technique of arthroscopic-assisted transfer of the latissimus dorsi tendon is a feasible, minimally invasive option for the surgical treatment of irreparable rotator cuff tears in a subset of patients with pseudoparalysis. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28024871 TI - Balancing selection on allorecognition genes in the colonial ascidian Botryllus schlosseri. AB - Allorecognition is the capability of an organism to recognize its own or related tissues. The colonial ascidian Botryllus schlosseri, which comprises five genetically distinct and divergent species (Clades A-E), contains two adjacent genes that control allorecognition: fuhcsec and fuhctm. These genes have been characterized extensively in Clade A and are highly polymorphic. Using alleles from 10 populations across the range of Clade A, we investigated the type and strength of selection maintaining this variation. Both fuhc genes exhibit higher within-population variation and lower population differentiation measures (FST) than neutral loci. The fuhc genes contain a substantial number of codons with >95% posterior probability of dN/dS > 1. fuhcsec and fuhctm also have polymorphisms shared between Clade A and Clade E that were present prior to speciation (trans-species polymorphisms). These results provide robust evidence that the fuhc genes are evolving under balancing selection. PMID- 28024872 TI - Molecular and functional characterization of pigeon (Columba livia) tumor necrosis factor receptor-associated factor 3. AB - Tumor necrosis factor receptor-associated factor 3 (TRAF3) plays a key antiviral role by promoting type I interferon production. We cloned the pigeon TRAF3 gene (PiTRAF3) according to its predicted mRNA sequence to investigate its function. The 1704-bp full-length open reading frame encodes a 567-amino acid protein. One Ring finger, two TRAF-type Zinc fingers, one Coiled coil, and one MATH domain were inferred. RT-PCR showed that PiTRAF3 was expressed in all tissues, with relatively weak expression in the heart and liver. In HEK293T cells, over expression of wild-type, ?Ring, ?Zinc finger, and ?Coiled coil PiTRAF3, but not a ?MATH form, significantly increased IFN-beta promoter activity. Zinc finger and Coiled coil domains were essential for NF-kappaB activation. In chicken HD11 cells, PiTRAF3 increased IFN-beta promoter activity and four domains were all contributing. R848 stimulation of pigeon peripheral blood mononuclear cells and splenocytes significantly increased expression of PiTRAF3 and the inflammatory cytokine genes CCL5, IL-8, and IL-10. These data demonstrate TRAF3's innate immune function and improve understanding of its involvement in poultry antiviral defense. PMID- 28024873 TI - Conceptual Design of Future Children's Hospitals in Europe: The Role of Caregivers in Transferring New Concepts from Theory into Practice. PMID- 28024874 TI - Dental and Temporomandibular Joint Pathology of the California Mountain Lion (Puma concolor couguar). AB - Skulls from 91 California mountain lions (Puma concolor couguar) were examined macroscopically and radiographically. The majority of the skulls were from young adult animals (57.1%). The skull specimens were from 42 male (46.1%) and 34 female (37.4%) animals, while the gender was unknown for the remainder. The majority (94.5%) of teeth were present for examination. Only 11 teeth were identified as absent congenitally; five of these teeth were maxillary first molar teeth and three were maxillary second premolar teeth. Abnormal tooth morphology was identified in 3.5% of teeth. The most common abnormality in tooth form was abnormally large crowns of the maxillary first molar teeth. Teeth with an abnormal number of roots were uncommon (n = 21). Ninety-one teeth were found to have an abnormal number of roots, most often two-rooted maxillary first molar teeth instead of the expected one root. The most prevalent dental lesions found in the California mountain lion were attrition/abrasion (93.4%), tooth fractures (80.2%) and periodontitis (38.5%). Less common dental lesions were tooth resorption (n = 32 teeth) and endodontal disease (n = 29 teeth). PMID- 28024875 TI - Comparative characterization of mesenchymal stromal cells from multiple abdominal adipose tissues and enrichment of angiogenic ability via CD146 molecule. AB - BACKGROUND: There are various types of adipose tissue in the human body, and their morphology is known to be closely related to cell function and metabolism. However, the functional differences among the mesenchymal stromal cells (MSCs) of different abdominal adipose tissues have not been clearly elucidated. METHODS: MSCs were isolated from different abdominal adipose tissues according to their regional distribution and included superficial subcutaneous, deep subcutaneous, omentum, mesentery and retroperitoneal MSCs. The immunophenotype, proliferative ability and angiogenic function of these MSCs were compared based on flow cytometry analysis, CCK-8 proliferation, in vitro differentiation, tubule formation and in vivo plug assay. RESULTS: The plastic adherence, cell morphology and general immunophenotype are similar among the MSCs. However, subcutaneous adipose tissue-derived MSCs have a faster growth rate and a higher level of CD146 expression than the other MSCs. Moreover, according to the fluorescence-activated cell sorting (FACS) enrichment procedure, the expression level of CD146 is positively related to the growth rate and angiogenic capability of MSCs. DISCUSSION: MSCs in adipose tissue showed slightly different characteristics depending on their location of origin, and they possessed different angiogenic abilities that were mediated by the expression of CD146. This study provides evidence that subcutaneous adipose tissue is the most appropriate source of MSCs for therapeutic cell transplantation in vascular disease. PMID- 28024876 TI - Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenlandische Dachsbracke dog. AB - Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenlandische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenlandische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenlandische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenlandische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases. The deletion follows recessive inheritance since the dam and a healthy male littermate of Case 1 were tested as heterozygous carriers. This is the first detailed description of CLN8 gene associated NCL in Alpenlandische Dachsbracke dogs and thus provides a novel canine CLN8 model for this lysosomal storage disease. The presence of ceroid lipofuscin in extracerebral tissues may help to confirm the diagnosis of NCL in vivo, especially in new dog breeds where the underlying mutation is not known. PMID- 28024877 TI - Neonatal ovarian cysts: ultrasound assessment and differential diagnosis. AB - Ovarian cysts are the most common abdominal cysts in female fetuses and newborn girls. Ultrasonography is the imaging technique of choice for diagnosing ovarian cysts because it makes it possible to differentiate them from other cystic lesions. Although most neonatal ovarian cysts regress in the first few months after birth, complications can occur during gestation or after birth. The manifestations of ovarian cysts on ultrasonography will depend on the complications. The management is controversial, although the current trend favors watchful waiting. We describe the different presentations of neonatal ovarian cysts with their complications and their patterns of findings on ultrasonography. We also discuss the differential diagnosis with other cystic abdominal lesions, and finally we discuss the therapeutic management of neonatal ovarian cysts. PMID- 28024878 TI - Congenital anomalies of the pulmonary arteries: spectrum of findings on computed tomography. AB - OBJECTIVE: Congenital anomalies of the pulmonary arteries are uncommon. They can occur in isolation or in association with congenital heart defects. Isolated congenital anomalies remain undiscovered until they are reported as incidental findings on imaging tests, usually not until adolescence. We review the embryological development and normal anatomy of the pulmonary arteries as well as the spectrum of computed tomography findings for various congenital anomalies: unilateral interruption of the pulmonary artery, anomalous origin of the left pulmonary artery (pulmonary artery sling), idiopathic aneurysm of the pulmonary artery, and other anomalies associated with congenital heart defects. CONCLUSION: Congenital anomalies of the pulmonary arteries represent a diagnostic challenge for clinicians and radiologists. Computed tomography is useful for their diagnosis, and general radiologists need to be familiar with their imaging appearance because they are often discovered incidentally. PMID- 28024879 TI - Dynamic representations of visual space for perception and action. AB - The division of labor in visual processing between two anatomically relatively separate cortical pathways, a ventral and a dorsal stream, has been hotly debated in the last decades. One influential model is the What & How pathway model, suggesting that the separation is along ventral perception versus dorsal action, although the degree of functional separation between the two streams is controversial. An implication of this model is that perception and memory-guided movements are highly sensitive to visual contextual illusions, whereas visually guided movements are largely immune to them. Here, we summarize our recent behavioral and imaging data obtained in single and double saccade paradigms that test this proposal, with a focus on the role of time in visuomotor processing and updating. We describe results showing that presentation time of the illusion affects both saccade amplitude and perceptual judgments in a similar way. We also discuss behavioral findings showing that visuomotor updating is affected by illusory context. Complementary neuroimaging data suggest a neural correlate of these findings in dorsal stream areas. Taken together, these results are suggestive of a dynamic, common visual representation that drives both perception and action, or - at least - that there is no absolute functional specialization of the two visual processing streams. PMID- 28024881 TI - Scientific Autobiography. PMID- 28024882 TI - DHA-enriched fish oil upregulates cyclin-dependent kinase inhibitor 2A (P16INK) expression and downregulates telomerase activity without modulating effects of PPARgamma Pro12Ala polymorphism in type 2 diabetic patients: A randomized, double blind, placebo-controlled clinical trial. AB - OBJECTIVE: The present study investigated the effects of docosahexaenoic acid (DHA)-enriched fish oil supplement on telomerase activity, mRNA expression of P16INK, IL-6, and TNF-alpha considering Pro12Ala polymorphism in the PPARgamma gene. METHODS/DESIGN: In this double-blind randomized controlled trial, 72 PPARgamma Pro12Ala polymorphism genotyped type 2 diabetic patients aged 30-70 years were randomly assigned to receive 2.4 gr of DHA-enriched fish oil or a placebo for 8 weeks. Genotyping of the Pro12Ala polymorphism in the PPARgamma gene was assessed using polymerase chain reaction-restriction length polymorphism (PCR-RFLP), telomerase activity in the peripheral blood mononuclear cell (PBMC) was measured using PCR-ELISA based on the telomeric repeat amplification protocol (TRAP), and changes in the mRNA expression of P16, IL-6, and TNF-alpha were measured using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the DHA group, telomerase activity was decreased (p = 0.001) during the intervention. In addition, between-group comparisons showed significant differences in the changes in telomerase activity (p = 0.003) and P16 mRNA expression (p = 0.028) and non-significant differences in TNF-alpha and IL-6 mRNA expression. The gene*DHA interaction could not affect changes in P16, IL-6, or TNF-alpha mRNA expression or in telomerase activity in PBMC. DISCUSSION: Short-time DHA-enriched fish oil supplementation caused increased levels of P16 expression and a decline in telomerase activity compared with the control group without modulating the effects of Pro12Ala polymorphism on the PPARgamma gene. Because of the positive correlation between P16 activity and cellular senescence, the possibility of senescence stimulation by DHA is proposed. PMID- 28024880 TI - Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight. AB - Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase expressing transgenic mice. Adult male and female mice, with conditional ablation of the Vgf gene in embryonic neurons had significantly reduced body weight, increased energy expenditure, and were resistant to diet-induced obesity. Conditional forebrain postnatal ablation of VGF in male mice, primarily in adult excitatory neurons, had no measurable effect on body weight nor on energy expenditure, but led to a modest increase in adiposity, partially overlapping the effect of AAV-Cre-mediated targeted ablation of VGF in the adult ventromedial hypothalamus and arcuate nucleus of floxed Vgf mice (Foglesong et al., 2016), and also consistent with results of icv delivery of the VGF-derived peptide TLQP-21 to adult mice, which resulted in increased energy expenditure and reduced adiposity (Bartolomucci et al., 2006). Because the lean, hypermetabolic phenotype of germline VGF knockout mice is to a great extent recapitulated in Syn-Cre+/ ,Vgfflpflox/flpflox mice, we conclude that the metabolic profile of germline VGF knockout mice is largely the result of VGF ablation in embryonic CNS neurons, rather than peripheral endocrine and/or neuroendocrine cells, and that in forebrain structures such as hypothalamus, VGF and/or VGF-derived peptides play uniquely different roles in the developing and adult nervous system. PMID- 28024883 TI - Health and social determinants and outcomes of home cooking: A systematic review of observational studies. AB - Many dietary interventions assume a positive influence of home cooking on diet, health and social outcomes, but evidence remains inconsistent. We aimed to systematically review health and social determinants and outcomes of home cooking. Given the absence of a widely accepted, established definition, we defined home cooking as the actions required for preparing hot or cold foods at home, including combining, mixing and often heating ingredients. Nineteen electronic databases were searched for relevant literature. Peer-reviewed studies in English were included if they focussed mainly on home cooking, and presented post 19th century observational or qualitative data on participants from high/very high human development index countries. Interventional study designs, which have previously been reviewed, were excluded. Themes were summarised using narrative synthesis. From 13,341 unique records, 38 studies - primarily cross sectional in design - met the inclusion criteria. A conceptual model was developed, mapping determinants of home cooking to layers of influence including non-modifiable, individual, community and cultural factors. Key determinants included female gender, greater time availability and employment, close personal relationships, and culture and ethnic background. Putative outcomes were mostly at an individual level and focused on potential dietary benefits. Findings show that determinants of home cooking are more complex than simply possessing cooking skills, and that potential positive associations between cooking, diet and health require further confirmation. Current evidence is limited by reliance on cross sectional studies and authors' conceptualisation of determinants and outcomes. PMID- 28024884 TI - Consumers' perceptions of food risks: A snapshot of the Italian Triveneto area. AB - This study investigated the food risk perceptions of people living in the Triveneto area (Northeast Italy), a territory characterized by a particular interest in the production of quality foodstuffs, to determine what aspects people associate with food risk and to understand what beliefs underlie these perceptions. Four focus groups were conducted in the major towns of the target area (N = 45). A semi-structured interview was used that focused on beliefs about food risks, the use of information and media sources in relation to food risk, and the behaviours adopted when eating outside the home. A homogeneous view of food risk emerged among the respondents, and a common definition of risky food was identified. The concept of risk was in opposition to the quality and controllability of food, which emerged as major strategies to cope with food risks. Quality was linked to freshness and local origin, whereas controllability reflected a direct (e.g., checking labels, having a relationship with the vendor, cultivating one's own vegetable garden) or indirect (e.g., control guarantees provided by suppliers and the government) means to check the safety and quality of food. Although people seemed quite informed about food risks, a common sense of impotence with regard to one's own protection prevailed, together with a fatalistic sense of incomplete control over risk. The results identified food concerns for consumers living in this specific territory and might represent a starting point for public health authorities to increase compliance with responsible behaviours for risk mitigation and to define successful food policies for this area. PMID- 28024885 TI - Heterotopic Ossification in Primary Total Hip Arthroplasty Using the Direct Anterior vs Direct Lateral Approach. AB - BACKGROUND: The formation and severity of heterotopic ossification (HO) may be influenced by type of surgical approach. Our hypothesis was that because of differences in soft tissue dissection, differences exist in HO formation in primary total hip arthroplasty using direct anterior (DA) vs direct lateral (DL) approach. METHODS: A total of 1482 consecutive patients with DL (736) or DA (746) approach and similar perioperative care protocol during 2009-2011 were retrospectively studied. No patient received prophylactic radiotherapy. Preoperative and 6-month postoperative radiographs were reviewed based on Brooker classification. RESULTS: The incidence of overall HO was higher in DL (36.1%) vs DA group (19.4%, P < .001) but high-grade HO (Brooker >=3) was not significantly different among the groups (3.9% for DL and 3.0% for DA groups). No patient required further surgery for HO resection. CONCLUSION: The type of approach (DA vs DL) did not seem to have a major influence on the short-term incidence of high grade HO based on this radiographic analysis. PMID- 28024886 TI - Letter to the Editor on "The Impact of Imaging Modality on the Measurement of Coronal Plane Alignment After Total Knee Arthroplasty". PMID- 28024887 TI - 5-Substituted-benzylsulfanyl-thiophene-2-sulfonamides with effective carbonic anhydrase inhibitory activity: Solution and crystallographic investigations. AB - A series of 5-substituted-benzylsulfanyl-thiophene-2-sulfonamides was prepared by reacting 5-bromo-thiophene-2-sulfonamide with 5-substituted-benzyl mercaptans. The new compounds were investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The cytosolic human (h) isoforms hCA I was poorly inhibited by the new sulfonamides (KIs in the range of 683-4250nM), whereas hCA II, and the transmembrane, tumor associated isoforms hCA IX and XII were effectively inhibited in the subnanomolar-nanomolar range. A high resolution X-ray crystal structure of the adduct of hCA II with one of the new sulfonamides allowed us to rationalize the excellent inhibitory activity of these heterocyclic sulfonamides. PMID- 28024888 TI - Optimization of magnetic retention in the gastrointestinal tract: Enhanced bioavailability of poorly permeable drug. AB - Oral administration of low permeable drugs remains a challenge as they do not cross biological membrane efficiently and therefore exhibit a poor bioavailability. Herein, the effect of magnetic retention on the circulation and bioavailability of magnetic beads in the gastrointestinal tract in the presence of an external magnetic field is evaluated. Retention efficiency is imaged using magnetic resonance and near infrared techniques. The effect on bioavailability is then evaluated in a pharmacokinetic study. Iron oxide nanoparticles, the drug (dipeptidyl peptidase-IV inhibitor) and a fluorophore (Alexa Fluor-750) are co encapsulated in chitosan-alginate core-shell beads. Retention of these beads is induced by the presence of an external permanent magnet on the abdomen of rats. After single administration of magnetic beads containing 20mg/kg of drug to fasted rats, a 2.5-fold increase in drug's bioavailability is observed in the presence of an external magnetic field, significantly higher than the same dose administered to rats without the field or for the drug in aqueous solution. Retention of the magnetic carriers in the presence of an external magnet proves to accumulate these carriers in a specific localization of the intestine leading to a significant improve in the drug's bioavailability. PMID- 28024889 TI - Towards prostate cancer gene therapy: Development of a chlorotoxin-targeted nanovector for toxic (melittin) gene delivery. AB - Prostate cancer is the second leading cause of death due to cancer in men. Owing to shortcomings in the current treatments, other therapies are being considered. Toxic gene delivery is one of the most effective methods for cancer therapy. Cationic polymers are able to form stable nanoparticles via interaction with nucleic acids electrostatically. Branched polyethylenimine that contains amine groups has notable buffering capacity and the ability to escape from endosome through the proton sponge effect. However, the cytotoxicity of this polymer is high, and modification is one of the applicable strategies to overcome this problem. In this study, PEI was targeted with chlorotoxin (CTX) via N succinimidyl 3-(2-pyridyldithio) propionate (SPDP) cross-linker. CTX can bind specifically to matrix metalloproteinase-2 that is overexpressed in certain cancers. Melittin as the major component of bee venom has been reported to have anti-cancer activity. This was thus selected to deliver to PC3 cell line. Flow cytometry analysis revealed that transfection efficiency of targeted nanoparticles is significantly higher compared to non-targeted nanoparticles. Targeted nanoparticles carrying the melittin gene also decreased cell viability of PC3 cells significantly while no toxic effects were observed on NIH3T3 cell line. Therefore, CTX-targeted nanoparticles carrying the melittin gene could serve as an appropriate gene delivery system for prostate and other MMP-2 positive cancer cells. PMID- 28024890 TI - Assessment of cell viability and permeation enhancement in presence of lipid based self-emulsifying drug delivery systems using Caco-2 cell model: Polysorbate 80 as the surfactant. AB - PURPOSE: Lipid-based self-emulsifying drug delivery systems (SEDDS) are commonly used for solubilizing and enhancing oral bioavailability of poorly water-soluble drugs. However, their effects on viability of intestine epithelial cells and influence on membrane permeation are poorly understood. The present study was undertaken for safety assessment of lipid-based formulations containing medium chain fatty acid esters as lipids and polysorbate 80 as the surfactant using the Caco-2 in vitro model. Any possible paracellular permeation enhancement through Caco-2 monolayers by the nontoxic formulations was also investigated. METHODS: Mixtures of monoglyceride (Capmul MCM EP or 708G) or propylene glycol monoester (Capmul PG-8 NF) of medium chain fatty acids with polysorbate 80, with and without the incorporation of a medium-chain triglyceride (Captex 355), were prepared. After suitable dilution with aqueous culture medium, the formulations were incubated with a series of Caco-2 cultures of different maturity. Cell viability and membrane integrity were assessed. Any effects of nontoxic formulations on the transport of the fluorescent dye, Lucifer yellow, through Caco-2 monolayers were also determined. RESULTS: Formulations containing 1:1 ratios of monoglyceride or propylene glycol monoester to triglyceride (30% polysorbate 80, 35% monoglyceride or monoester and 35% triglyceride) were best tolerated by Caco-2 cells. Increased maturity obtained through longer culture durations rendered Caco-2 cells greater tolerance towards lipid-based formulations, and maximum tolerance to lipid-based formulations was observed with Caco-2 monolayers after being cultured for 21-23days. Furthermore, extent of cell membrane rupture caused by lipid-surfactant mixtures correlated positively with levels of cytotoxicity, suggesting a potential underlying mechanism. Permeation studies using Caco-2 monolayer model revealed that certain formulations significantly enhanced paracellular transport activities. CONCLUSIONS: Lipid based SEDDS containing mixtures of monoglyceride (or monoester) and triglyceride of medium chain fatty acids formed fine microemulsions and were significantly less toxic than other formulations. Fully differentiated Caco-2 monolayer was more resistant to lipid-surfactant mixtures than less mature cultures. Certain formulations were also capable of enhancing paracellular permeation. PMID- 28024892 TI - Classifying the additional morbidities of Gaucher disease. PMID- 28024891 TI - Transdural herniated lumbar disc disease with muscle patch for closure of durotomy - A Brief review of literature. AB - PURPOSE: Intradural migration of disc (IDMD) is a rare clinical entity accounting for 0.27-0.33% of all herniated disc diseases. Flimsy or dense adhesion between the ventral dural surface and the opposing posterior longitudinal ligament (PLL) is the principal pathology for intradural migrated disc. The most commonly affected lumbar segments are L4-5 (55%), L3-4 (16%), L5-S1 (10%) and less commonly L2L3 and L1L2. No imaging feature is characteristic and the management protocol of durotomy via an endoscopic method is unclear. METHODS: An L5S1 disc disease was operated by endoscopic method. Difficulty in separating the dural sac from PLL, dense adhesions prompting sharp dissection at this location and a calcified disc are the earliest evidence of intradural migration. MRI features of an intradural location are loss of continuity of posterior longitudinal ligament, beak-like appearance also known as "Hawk-beak sign", peripheral enhancement around an intradural disc, fluid-filled intradural cyst. Magnification either by Microscope or Endoscope is of importance when dissecting the intradural disc so as to avoid the nerve root injury. Liberal use of fibrin glue and augmentation with muscle patch was performed. RESULTS: Ambulated by 48h and discharged by 5th day. Two and 9 months follow up showed no evidence of pseudomeningocoele. CONCLUSION: Autologous muscle patch with fibrin glue for dural rent closure is a simple and effective method which can be performed by endoscopic or minimally invasive approaches. Suturing the dura, being a tedious and cumbersome procedure can be avoided. PMID- 28024893 TI - Left upper lobar torsion after video-assisted thoracoscopic lower lobectomy. PMID- 28024894 TI - Layer-by-layer assembly surface modified microbial biomass for enhancing biorecovery of secondary gold. AB - Enhancement of the biosorption capacity for gold is highly desirable for the biorecovery of secondary gold resources. In this study, polyethylenimine (PEI) was grafted on Shewanella haliotis surface through layer-by-layer assembly approach so as to improve the biosorption capacity of Au(III). Results showed that the relative contribution of amino group to the biosorption of Au(III) was the largest one (about 44%). After successful grafting 1, 2 and 3-layer PEI on the surface of biomass, the biosorption capacity significantly enhanced from 143.8mg/g to 597.1, 559.1, and 536.8mg/g, respectively. Interestingly, the biomass modified with 1-layer PEI exhibited 4.2 times higher biosorption capacity than the untreated control. When 1-layer modified biomass was subjected to optimizing the various conditions by response surface methodology, the theoretical maximum adsorption capacity could reach up to 727.3mg/g. All findings demonstrated that PEI modified S. haliotis was effective for enhancing gold biorecovery. PMID- 28024895 TI - Catalytic pyrolysis characteristics of scrap printed circuit boards by TG-FTIR. AB - In the present work, pyrolysis and catalytic pyrolysis of waste printed circuit boards (WPCBs) was carried out in the coupling of Thermo Gravimetric Analysis and Fourier Transform Infrared Spectroscopy (TG-FTIR) under nitrogen atmosphere. The reaction temperature was increased from 30 to 700 degrees C, while the heating rates were varied from 10 to 40 degrees C/min. Experimental results show that the effect of catalyst on the WPCBs particles pyrolysis was significance. Compared with another two combustion-supporting agents (MgO, CaO), the whole pyrolysis process was optimized when the catalyst ZSM-5 was added into the WPCBs particles. The distributed activation energy model (DAEM) was used to analyze the kinetic parameters of the WPCBs pyrolysis. It was found that values of frequency factor (k0) changed with different activation energy (E) values during pyrolysis process. The activation energy values range from 129.15 to 280.53kJ/mol, and the frequency factor values range from 9.02*1010 to 4.21*1022s-1. The generated major products for the catalytic pyrolysis of WPCBs were H2, CO2, CO, H2O, phenols and aromatics. PMID- 28024896 TI - Mercury recovery from mercury-containing wastes using a vacuum thermal desorption system. AB - Mercury (Hg)-containing waste from various industrial facilities is commonly treated by incineration or stabilization/solidification and retained in a landfill at a managed site. However, when highly concentrated Hg waste is treated using these methods, Hg is released into the atmosphere and soil environment. To eliminate these risks, Hg recovery technology using thermal treatment has been developed and commercialized to recover Hg from Hg-containing waste for safe disposal. Therefore, we developed Hg recovery equipment to treat Hg-containing waste under a vacuum of 6.67kPa (abs) at 400 degrees C and recover the Hg. In addition, the dust generated from the waste was separated by controlling the temperature of the dust filtration unit to 230 degrees C. Additionally, water and Hg vapors were condensed in a condensation unit. The Hg removal rate after waste treatment was 96.75%, and the Hg recovery rate as elemental Hg was 75.23%. PMID- 28024897 TI - Optimization of the anaerobic co-digestion of pasteurized slaughterhouse waste, pig slurry and glycerine. AB - The feasibility of co-digestion of blends of two different animal by-products (pig manure and pasteurized slaughterhouse waste) and recovered glycerine was studied in mesophilic conditions. Experiments were performed in a lab-scale CSTR along 490days, with a hydraulic retention time of 21-33days and with a step-wise increased organic loading rate, by adding and/or changing the wastes ratio, from 0.8 to 3.2kgCODm-3d-1. The best methane production rate (0.64Nm3CH4m-3d-1) represented an increment of 2.9-fold the initial one (0.22Nm3CH4m-3d-1 with pig manure solely). It was attained with a ternary mixture composed, in terms of inlet volatile solids, by 35% pig slurry, 47% pasteurized slaughterhouse waste and 18% glycerine. This blend was obtained through a stepwise C/N adjustment: this strategy led to a more balanced biodegradation due to unstressed bacterial populations through the performance, showed by the VFA-related indicators. Besides this, an improved methane yield (+153%) and an organic matter removal efficiency (+83%), regarding the digestion of solely pig slurry, were attained when the C/N ratio was adjusted to 10.3. PMID- 28024898 TI - Reducing nitrogen loss and phytotoxicity during beer vinasse composting with biochar addition. AB - The aim of this study was to investigate the feasibility of composting of beer vinasse generated from brewing industry, the effect of biochar amendment on beer vinasse composting was also evaluated based on the changes of different physicochemical parameters, phytotoxicity and final compost quality. Four different treatments were performed of beer vinasse with biochar addition at 0, 5%, 10%, 15% (w/w dry basis). The final product obtained from beer vinasse composting was phytotoxicity-free (GI: 120.8%), mature (C/N: 19.88, NH4+-N: 295.0mg/kg, DOC: 9.76g/kg) and nutrient-rich (especially for P: 1.92%) compost except high N loss (60.76%), which had the potential to be as soil amendment or fertilizer. Biochar addition contributed to decomposition of DOC indicating higher microbial activity and attain phytotoxicity-free standard rapidly. N loss significantly reduced by 27% with biochar at 15% addition. And 15% biochar addition ensured all parameters, which was involved in composts quality, to attain the mature standard. Therefore, it was suggested that biochar addition at 15% was optimal. PMID- 28024899 TI - Characterization, quantification and management of China's municipal solid waste in spatiotemporal distributions: A review. AB - Municipal Solid Waste (MSW) is a heterogeneous waste stream, which is harmful for human health and the ecological environment if it is not well managed. Based on results from different authors by analyzing the generation, physical components and management of MSW from different cities, this paper presents an overview of the temporal trends and spatial variation characterization of MSW generation and its physical components in China. Total MSW generation has increased from 31,320 thousand tons in 1980 to 178,602 thousand tons in 2014, and MSW generation per capita has also increased from 448.3g to 653.2g. The distribution of MSW generation is mostly concentrated in the coastal southeastern region, as well as large point sources of more than 200 thousand tons per year are mostly distributed in Jiangsu, Zhejiang, Shandong, Hebei and Guangdong provinces. The review shows that the largest proportion of food waste, plastics and paper is 61.2% (54.2-65.9%, 95% CI), 9.8% (7.2-14.0%, 95% CI), 9.6% (6.7-12.3%, 95% CI), respectively, in 2014; the best estimates of other waste were as follows: 3.1% textile, 2.1% glass, 1.1% metal, 1.8% wood and grass, 1.3% rubber and leather, 1.8% ceramic, 2.5% ash, 1.2% hazardous waste, and 4.5% miscellaneous. To better manage China's MSW, several possible and appropriate solutions (e.g., concentrating on key regions, intensifying source separation, promoting green lifestyle, and establishing specialized regulations and policies) should be adopted, which might facilitate the application of China's 13th Five, and identify gaps in our knowledge of MSW management subject. PMID- 28024900 TI - What is the Best Pain Management During Gastric Tube Insertion for Infants Aged 0 12months: A Systematic Review. AB - PROBLEM: Synthesized evidence on the effectiveness of pain management for nasogastric tube (NGT) and orogastric tube (OGT) insertions in infants is lacking. This paper is a systematic review of the effectiveness of pain management for gastric tube (GT) insertion in infants. ELIGIBILITY CRITERIA: Randomized control trial (RCT) or quasi-experimental studies published up to April 2016, on pain management strategies during GT insertions (either NGT or OGT) in infants up to 12months of age. Databases searched included seven English databases and three Chinese databases. RESULTS: Six English studies out of 1236 screened met the eligibility criteria and were included in the review. Two studied OGT insertion and four studies focused on NGT insertion. All six studies evaluated oral sweet solutions (24%-30% sucrose and 25% glucose) compared to placebo (water) or no treatment and all focused on newborn infants. Data from four studies which used the Premature Infant Pain Profile (PIPP) were pooled for meta-analysis. Results showed a significant reduction in PIPP scores during or immediately after the procedure for sweet solution interventions (MD=-2.18, 95% CI (-3.86, -0.51), P=0.01), compared to no intervention or placebo. CONCLUSIONS: Small volumes of oral sweet solutions reduce pain during GT insertion procedure in newborn infants. IMPLICATIONS: Oral sweet solutions can be recommended before GT insertion for newborns in clinical practice. Further studies determining the effect of sweet solution beyond the newborn period, different concentrations of sweet solution and comparison with other pain management strategies are warranted. Systematic review registration number: CRD42016038535. http://www.crd.york.ac.uk/prospero/. PMID- 28024901 TI - Cyclin-dependent kinase 5 contributes to endoplasmic reticulum stress induced podocyte apoptosis via promoting MEKK1 phosphorylation at Ser280 in diabetic nephropathy. AB - Endoplasmic reticulum (ER) stress has been reported to be associated with podocyte apoptosis in diabetic nephropathy, but the mechanism of ER signaling in podocyte apoptosis hasn't been fully understood. Our previous studies have demonstrated that Cyclin-dependent kinase 5 (Cdk5) was associated with podocyte apoptosis in diabetic nephropathy. The present study was designed to examine whether and how Cdk5 activity plays a role in ER stress induced podocyte apoptosis in diabetic nephropathy. The results showed that along with induction of Cdk5 and apoptosis, GRP78 and its two sensors as well as CHOP and cleaved caspase-12 were induced in high glucose treated podocytes. These responses were attenuated by treated salubrinal. The ER stress inducer, tunicamycin, also up regulated the kinase activity and protein expression of Cdk5 in podocytes accompanied with the increasing of GRP78. On the other hand, Cdk5 phosphorylates MEKK1 at Ser280 in tunicamycin treated podocytes, and together, they increase the JNK phosphorylation. Moreover, disruption of this pathway can decrease the podocyte apoptosis induced by tunicamycin. Therefore, our study proved that Cdk5 may play an important role in ER stress induced podocyte apoptosis through MEKK1/JNK pathway in diabetic nephropathy. PMID- 28024902 TI - Chromosomes Orchestrate Their Own Liberation: Nuclear Envelope Disassembly. AB - The mammalian nuclear division cycle is coordinated with nuclear envelope breakdown (NEBD), in which the entire nuclear envelope (NE) is dissolved to allow chromosomes to access their segregation vehicle, the spindle. In other eukaryotes, complete NEBD is replaced by localized disassembly or remodeling of the NE. Although the molecular mechanisms controlling NE disassembly are incompletely understood, coordinated cycles of modification of specific NE components drive breakdown. Here, we review the current state of knowledge regarding NE disassembly and argue for a role of chromosome-NE contacts in triggering initiation of NE disassembly and thereby, cell division. PMID- 28024903 TI - Cloning, localization, and physiological effects of sulfakinin in the kissing bug, Rhodnius prolixus. AB - Sulfakinins (SKs) are a family of multifunctional neuropeptides that have been shown to have myotropic activity on muscles of the digestive system and to function as feeding satiety factors. Here, we confirm via cloning the presence of two sulfakinins (Rhopr-SK-1 and Rhopr-SK-2) in Rhodnius prolixus. Reverse transcriptase quantitative PCR demonstrates that the Rhopr-SK transcript is highly expressed in the central nervous system (CNS) of unfed fifth-instar R. prolixus. Fluorescent in situ hybridization shows transcript expression only in neurons in the brain. Immunohistochemical staining of SK-like peptides was observed in the same neurons in the brain and in processes extending throughout the CNS, as well as over the posterior midgut and anterior hindgut. Rhopr-SK-1 (sulfated form) induces contractions of the hindgut in a dose-dependent manner. Injection Rhopr-SK-1 (sulfated form) significantly decreases the overall weight of the blood meal consumed, suggesting SK's role as a satiety factor in R. prolixus. PMID- 28024905 TI - Good science. PMID- 28024904 TI - Early-life mortality risks in opposite-sex and same-sex twins: a Danish cohort study of the twin testosterone transfer hypothesis. AB - PURPOSE: To investigate the twin testosterone transfer (TTT) hypothesis by comparing early-life mortality risks of opposite-sex (OS) and same-sex (SS) twins during the first 15 years of life. METHODS: We performed a population-based cohort study to compare mortality in OS and SS twins. We included 68,629 live born Danish twins from 1973 to 2009 identified through the Danish Twin Registry and performed piecewise stratified Cox regression and log-binomial regression. RESULTS: Among 1933 deaths, we found significantly higher mortality for twin boys than for twin girls. For both sexes, OS twins had lower mortality than SS twins; the difference persisted for the first year of life for boys and for the first week of life for girls. CONCLUSIONS: Although the mortality risk for OS boys was in the expected direction according to the TTT hypothesis, the results for OS girls pointed in the opposite direction, providing no clear evidence for the TTT hypothesis. PMID- 28024906 TI - Iatrogenic gastric emphysema. PMID- 28024907 TI - Clinical information systems: An opportunity to measure value, investigate and innovate from the real world. PMID- 28024908 TI - HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats. AB - Clinical and experimental studies suggest that voltage-gated sodium channels (VGSCs) play a key role in the pathogenesis of neuropathic pain and that blocking agents against these channels can be potentially therapeutic. In the current study, we investigated whether a novel compound, (-)-2-Amino-1-(4-((4 chlorophenyl)(phenyl)methyl)piperazin-1-yl)-propan-1-one(HYP-17), binds to VGSCs and evaluated its inhibitory effect on Na+ currents of the rat dorsal root ganglia (DRG) sensory neurons and its analgesic effect on inflammatory and neuropathic pain. HYP-17 (10MUM) reduced both the tetrodotoxin-sensitive (TTX-S) and the TTX-resistant (TTX-R) currents in DRG sensory neurons. However, neither the voltage-dependent activation curves nor the steady-state inactivation curves for TTX-S and TTX-R currents were changed by HYP-17. In rats injected with 5% formalin under the plantar surface of the hind paw, HYP-17 (10MUg) significantly reduced both the early and late phase spontaneous pain behaviors. Systemic injection with HYP-17 (60mg/kg, i.p.) also significantly relieved the mechanical, cold, and warm allodynia induced by rat tail nerve injury. Furthermore, HYP-17 (60mg/kg, i.p.) significantly relieved the central neuropathic pain induced by spinal cord injury (SCI), and inhibited c-Fos expression in lumbar (L) 4-L5 spinal segments. Electrophysiological study showed that HYP-17 significantly attenuated the hyper-responsiveness of lumbar dorsal horn neurons. In addition, HYP-17 significantly reduced the levels of pp38MAPK and p-JNK in microglia and astrocytes, respectively, in the L4-L5 spinal dorsal horn. Therefore, our results indicate that HYP-17 has potential analgesic activities against nociceptive, inflammatory and neuropathic pain. PMID- 28024909 TI - Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats. AB - Clinicians administer subanesthetic intravenous (IV) ketamine infusions for treatment of refractory depression, chronic pain, and post-traumatic stress disorder in humans. However, ketamine is administered via the subcutaneous (SC) or intraperitoneal (IP) routes to rodents in most pre-clinical research, which may limit translational application. The present study characterized the dose response of a subanesthetic IV ketamine bolus (2 and 5mg/kg) and 1-h infusion (5, 10, and 20mg/kg/h) on dissociative stereotypy, locomotion, sensorimotor gating, and thermal nociception in male Sprague-Dawley rats. The secondary aim was to measure ketamine and norketamine plasma concentrations following IV ketamine bolus at 1, 20, and 50min and at the conclusion of the 1-h infusion using liquid chromatography/mass spectrometry. The results showed that ketamine bolus and infusions produced dose-dependent dissociative stereotypy. Bolus (2 and 5mg/kg) and 20mg/kg/h infusion increased locomotor activity while 5mg/kg/h infusion decreased locomotor activity. Both 10 and 20mg/kg/h infusions reduced the acoustic startle reflex, while 5mg/kg bolus and 20mg/kg/h infusion impaired pre pulse inhibition. Ketamine 5mg/kg bolus and the 10 and 20mg/kg/h infusions induced significant and prolonged antinociception to the hotplate test. Plasma concentrations of ketamine decreased quickly after bolus while norketamine levels increased from 1 to 20min and plateaued from 20 to 50min. The peak ketamine plasma concentrations [ng/ml] were similar between 5mg/kg bolus [4100] vs. 20mg/kg/h infusion [3900], and 2mg/kg bolus [1700] vs. 10mg/kg/h infusion [1500]. These results support the findings from previous ketamine injection studies and further validate the feasibility of administering subanesthetic doses of IV ketamine infusion to rats for neuropharmacological studies. PMID- 28024910 TI - The effect of potassium supplementation on blood pressure in hypertensive subjects: A systematic review and meta-analysis. AB - BACKGROUND: Several intervention studies have investigated the relation between potassium intake and blood-pressure, particularly in hypertensive subjects. However, uncertainties still exist about the existence and the amount of such an effect, and about the role of some potential effect-modifiers, including the baseline potassium intake and geographical area. METHODS: We carried out a systematic review of the evidence concerning such relation in hypertensive subjects, performing a meta-analysis and a meta-regression of RCT with selective and validated long-term (>=4weeks) potassium supplementation. We also implemented 'unconventional' search strategies in order to identify all potentially interesting studies. RESULTS: Overall, potassium supplementation decreased systolic blood pressure of 4.48mmHg (95% CI 3.07-5.90) and diastolic blood pressure of 2.96mmHg (1.10-4.82). There was little evidence of dose-response relation between blood-pressure decrease and potassium supplementation, as assessed through total achieved potassium intake in the intervention groups, difference in achieved potassium intake, and study duration. However, lower (<90mmol/day) potassium intake at baseline was associated with a higher blood pressure lowering effect, as were higher sodium intake (particularly >=4g/day), higher sodium-to-potassium ratio and the absence of any anti-hypertensive drug treatment. Trials conducted in Southern Europe showed the highest blood-pressure lowering effect compared with the remaining regions. CONCLUSIONS: Potassium supplementation in hypertensives was generally associated with decreased blood pressure, particularly in high sodium consumers, subjects not on hypertensive drug treatment, and those in the lowest category of potassium intake. An adequate dietary intake of potassium, in the order of 90mmol/day, should be achieved for blood pressure control. PMID- 28024911 TI - Strike while the iron is hot; early invasive treatment in patients with non-ST elevation acute coronary syndrome. PMID- 28024912 TI - Early diagnosis and outcome prediction of neonatal hypoxic-ischemic encephalopathy with color Doppler ultrasound. AB - PURPOSE: To describe the ultrasound presentation of the brain and cerebral hemodynamics in neonates with hypoxic-ischemic encephalopathy (HIE) by comparison with control subjects. MATERIAL AND METHODS: During June 2012 to April 2013, full term neonates who had clinical evidence of HIE were enrolled. Healthy newborns without HIE were used as a control group. Cerebral parenchyma, size of lateral ventricles and hemodynamic parameters of cerebral arteries were studied using two dimensional duplex and color Doppler ultrasound. Neonates with moderate and severe HIE were followed-up with ultrasound for at least 3 months. RESULTS: A total of 158 consecutive neonates (82 boys and 76 girls), including 54 with mild HIE, 60 with moderate HIE and 44 with severe HIE were included. One hundred and twenty healthy newborns were randomly selected as a control group. Abnormal ultrasound findings of brain parenchyma were found in 25/54 (46.3%) neonates with mild HIE whereas they were found in 58/60 (96.7%) neonates with moderate HIE and 44/44 (100%) neonates with severe HIE. Almost all neonates with severe HIE had decreased cerebral artery blood flow velocity and increased resistance index of cerebral arteries. Of the 104 neonates with moderate or severe HIE, follow-up ultrasound examination revealed cystic parenchymal lesions in 12/104 (11.5%), progressive ventricular dilatation and brain atrophy in 12/104 (11.5%), mild ventricular dilatation in 15/104 (14.4%) and leukoencephalomalacia in 2/104 (1.9%) neonates. CONCLUSION: Ultrasound features such as the size of lateral ventricles, altered brain parenchymal echogenicity and cerebral blood flow parameters are useful for the early diagnosis of HIE and help predict outcome. PMID- 28024913 TI - Anxiety sensitivity explains associations between anxious arousal symptoms and smoking abstinence expectancies, perceived barriers to cessation, and problems experienced during past quit attempts among low-income smokers. AB - Disproportionately more smokers report low-income and mental health problems relative to non-smokers. Low-income smokers may use smoking to alleviate negative emotional states resulting from exposure to multiple stressors. Yet, little work has been devoted to elucidating mechanisms that may explain the association between negative emotional states and smoking-related processes among low-income smokers. The present study sought to address this gap by examining anxiety sensitivity, a transdiagnostic factor related to both anxiety and smoking, as a potential mediator for the influence of anxiety symptoms on smoking-related processes, including threat-related smoking abstinence expectancies (somatic symptoms and harmful consequences), perceived barriers for cessation, and problems experienced during past quit attempts. Participants included treatment seeking daily cigarette smokers (n=101; 68.3% male; Mage=47.1; SD=10.2). Results indicated that anxiety symptoms exerted a significant indirect effect through anxiety sensitivity for threat-related smoking abstinence expectancies (somatic symptoms and harmful consequences), perceived barriers for cessation, and problems experienced during past quit attempts. The present results provide empirical support that anxiety sensitivity may be an underlying mechanism that partially explains the relation between anxiety symptoms and smoking processes among low-income treatment-seeking smokers. Findings broaden current theoretical understanding of pathways through which anxiety symptoms contribute to maladaptive smoking processes and cognitions among socioeconomically disadvantaged smokers. PMID- 28024914 TI - Topical and cutaneous delivery using nanosystems. AB - The goal of topical and cutaneous delivery is to deliver therapeutic and other substances to a desired target site in the skin at appropriate doses to achieve a safe and efficacious outcome. Normally, however, when the stratum corneum is intact and the skin barrier is uncompromised, this is limited to molecules that are relatively lipophilic, small and uncharged, thereby excluding many potentially useful therapeutic peptides, proteins, vaccines, gene fragments or drug-carrying particles. In this review we will describe how nanosystems are being increasingly exploited for topical and cutaneous delivery, particularly for these previously difficult substances. This is also being driven by the development of novel technologies, which include minimally invasive delivery systems and more precise fabrication techniques. While there is a vast array of nanosystems under development and many undergoing advanced clinical trials, relatively few have achieved full translation to clinical practice. This slow uptake may be due, in part, to the need for a rigorous demonstration of safety in these new nanotechnologies. Some of the safety aspects associated with nanosystems will be considered in this review. PMID- 28024915 TI - How do megakaryocytic microparticles target and deliver cargo to alter the fate of hematopoietic stem cells? AB - Megakaryocytic microparticles (MkMPs), the most abundant MPs in circulation, can induce the differentiation of hematopoietic stem and progenitor cells (HSPCs) into functional megakaryocytes. This MkMP capability could be explored for applications in transfusion medicine but also for delivery of nucleic acids and other molecules to HSPCs for targeted molecular therapy. Understanding how MkMPs target, deliver cargo and alter the fate of HSPCs is important for exploring such applications. We show that MkMPs, which are distinct from Mk exosomes (MkExos), target HSPCs with high specificity since they have no effect on other ontologically or physiologically related cells, namely mesenchymal stem cells, endothelial cells or granulocytes. The outcome is also specific: only cells of the megakaryocytic lineage are generated. Observation of intact fluorescently tagged MkMPs inside HSPCs demonstrates endocytosis as one mechanism of cargo delivery. Fluorescent labeling and scanning electron microscopy (SEM) imaging show that direct fusion of MkMPs into HSPCs is also engaged in cargo delivery. SEM imaging detailed the membrane-fusion process in four stages leading to full adsorption of MkMPs into HSPCs. Furthermore, macropinocytosis and lipid raft mediated were shown here as mechanisms of MkMP uptake by HSPC. In contrast, the ontologically related platelet-derived MPs (PMPs) cannot be taken up by HSPCs although they bind to and induce HSPC aggregation. We show that platelet-like thrombin activation is apparently responsible for the different biological effects of MkMPs versus PMPs on HSPCs. We show that HSPC uropods are the preferential site for MkMP binding, and that CD54 (ICAM-1), CD11b, CD18 and CD43, localized on HSPC uropods, are involved in MkMP binding to HSPCs. Finally, we show that MkMP RNA is largely responsible for HSPC programming into Mk differentiation. PMID- 28024917 TI - Transposition of the great arteries: Rationale for tailored preoperative management. AB - As preoperative morbi-mortality remains significant, care of newborns with transposition of the great arteries is still challenging. In this review of the literature, we discuss the different treatments that could improve the patient's condition into the preoperative period. Instead of a standardized management, we advocate personalized care of these neonates. Considering the deleterious effects of hypoxia, special attention is given to the use of non-invasive technologies to assess oxygenation of the tissues. As a prolonged preoperative time with low cerebral oxygenation is associated with cerebral injuries, distinguishing neonates who should undergo early surgery from those who could wait longer is crucial and requires full expertise in the management of neonatal congenital heart disease. Finally, to treat these newborns as soon as possible, we support a planned delivery policy for foetuses with transposition of the great arteries. PMID- 28024916 TI - Drug-free macromolecular therapeutics: Impact of structure on induction of apoptosis in Raji B cells. AB - Recently, we developed a new paradigm in macromolecular therapeutics that avoids the use of low molecular weight drugs. The activity of the "drug-free macromolecular therapeutics" is based on the biorecognition of complementary motifs at cell surface resulting in receptor crosslinking and apoptosis induction. The system is composed of two nanoconjugates: (1) a single-stranded morpholino oligonucleotide (MORF1) attached to an anti-CD20 Fab' fragment (Fab' MORF1); (2) multiple copies of complementary oligonucleotide MORF2 grafted to a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) - P-(MORF2)x. The two conjugates crosslink CD20 antigens via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells and induce apoptosis. Preclinical studies in a murine model of human non-Hodgkin's lymphoma showed cancer cells eradication and long term survivors. The aim of this study was to determine the relationship between the detailed structure of the nanoconjugates and apoptosis induction in Raji cells to allow system optimization. The factors studied include the length of the MORF sequence, the valence of P-(MORF2)x (varying x), molecular weight of P (MORF2)x, incorporation of a miniPEG spacer between Fab' and MORF1 and between polymer backbone and pendant MORF2, and comparison of two Fab' fragments, one from 1F5 antibody (Fab'1F5), the other from Rituximab (Fab'RTX). The results of apoptosis induction in human Burkitt's B-cell non-Hodgkin's lymphoma (NHL) Raji cells as determined using three apoptotic assays (Annexin V, Caspase 3, and TUNEL) indicated that: a) An improvement of apoptotic activity was observed for a 28 base pair MORF sequence when compared to MORFs composed of 20 and 25 base pairs. The differences depended on type of assay, concentration and exposure schedule (consecutive vs. premixed). b) The higher the valence of P-(MORF2)x the higher the levels of apoptosis. c) Higher molecular weight of P-(MORF2)x induced higher levels of apoptosis. d) A miniPEG8 spacer was effective in enhancing apoptotic levels in contrast to a miniPEG2 spacer. e) There was not a statistically significant difference when comparing Fab'1F5-MORF1 with Fab'RTX MORF1. PMID- 28024918 TI - T Cell Repertoire Diversity Is Decreased in Type 1 Diabetes Patients. AB - Type 1 diabetes mellitus (T1D) is an immune-mediated disease. The autoreactive T cells in T1D patients attack and destroy their own pancreatic cells. In order to systematically investigate the potential autoreactive T cell receptors (TCRs), we used a high-throughput immune repertoire sequencing technique to profile the spectrum of TCRs in individual T1D patients and controls. We sequenced the T cell repertoire of nine T1D patients, four type 2 diabetes (T2D) patients, and six nondiabetic controls. The diversity of the T cell repertoire in T1D patients was significantly decreased in comparison with T2D patients (P=7.0E-08 for CD4+ T cells, P=1.4E-04 for CD8+ T cells) and nondiabetic controls (P=2.7E-09 for CD4+ T cells, P=7.6E-06 for CD8+ T cells). Moreover, T1D patients had significantly more highly-expanded T cell clones than T2D patients (P=5.2E-06 for CD4+ T cells, P=1.9E-07 for CD8+ T cells) and nondiabetic controls (P=1.7E-07 for CD4+ T cells, P=3.3E-03 for CD8+ T cells). Furthermore, we identified a group of highly expanded T cell receptor clones that are shared by more than two T1D patients. Although further validation in larger cohorts is needed, our data suggest that T cell receptor diversity measurements may become a valuable tool in investigating diabetes, such as using the diversity as an index to distinguish different types of diabetes. PMID- 28024919 TI - Effect of gap detection threshold on consistency of speech in children with speech sound disorder. AB - BACKGROUND AND AIMS: The present study examined the relationship between gap detection threshold and speech error consistency in children with speech sound disorder. METHODS AND PROCEDURES: The participants were children five to six years of age who were categorized into three groups of typical speech, consistent speech disorder (CSD) and inconsistent speech disorder (ISD).The phonetic gap detection threshold test was used for this study, which is a valid test comprised six syllables with inter-stimulus intervals between 20-300ms. The participants were asked to listen to the recorded stimuli three times and indicate whether they heard one or two sounds. OUTCOMES AND RESULTS: There was no significant difference between the typical and CSD groups (p=0.55), but there were significant differences in performance between the ISD and CSD groups and the ISD and typical groups (p=0.00). The ISD group discriminated between speech sounds at a higher threshold. CONCLUSIONS AND IMPLICATIONS: Children with inconsistent speech errors could not distinguish speech sounds during time-limited phonetic discrimination. It is suggested that inconsistency in speech is a representation of inconsistency in auditory perception, which causes by high gap detection threshold. PMID- 28024920 TI - Hepatic Adenomas in Adolescents and Young Women with Endometriosis Treated with Norethindrone Acetate. AB - BACKGROUND: Endometriosis-ectopic implantation of endometrial-like tissue-affects 10% of female adolescents and adults. First-line treatment includes progesterone only (such as norethindrone acetate [NET-A]) or combined estrogen/progestin oral contraceptive pills. Estrogen-containing contraceptives confer increased risk of hepatic adenomas, whereas the association with NET-A is very rarely reported. CASE: Three adolescents with stage I to II endometriosis managed with NET-A (up to 15 mg/d for 28-78 months) were diagnosed with hepatic adenomas at ages 17-22 years. They previously received estrogen-containing medications, which were stopped 24 months or longer before diagnosis of hepatic adenoma. SUMMARY AND CONCLUSION: NET-A in a dose greater than 10 mg/d might be associated with increased risk for hepatic adenomas, likely due to peripheral conversion to ethinyl estradiol. Use of NET-A might not be advisable in patients with known hepatic adenomas. PMID- 28024921 TI - Applicability and limitations of sex assessment based on foramen magnum. AB - Sex assessment of skeletal remains in the context of forensic investigation is one of the most important components when constructing biological profile of the deceased individual since it helps to significantly narrow down the number of potential victims. Therefore, the number of methods suitable to estimate sex should be as wide as possible, especially for cases of highly fragmented remains. This paper offers a classification method for sexing human remains based on an area around foramen magnum and tests other similar discriminatory functions published elsewhere on an independent sample from the circummediterranean region. We provide discriminant and logistic regression functions for several sets of variable combinations derived from head CT images. None of the functions performs reliably enough to be used in the forensic context. The same holds true for other discriminatory functions published in the literature. For most of the functions, the failure rate (its inability to successfully assign sex of an unknown individual) reaches 100%. Thus, despite the fact that foramen magnum is sexually dimorphic in most populations, its use in sexing cranial remains in the forensic context should be limited only to cases in which we know population affinity of unknown skeletal remains and can provide referential data from the same population to estimate sex. PMID- 28024922 TI - Estimation of left ventricular assist device pre-load using pump flow waveform analysis. PMID- 28024923 TI - WITHDRAWN: Management and follow-up of the male with Lower Urinary Tract Symptoms secondary to Benign Prostate Hyperplasia. PMID- 28024924 TI - Recognition of Propionibacterium acnes by human TLR2 heterodimers. AB - Propionibacterium acnes has been considered as a crucial contributor to the pathogenesis of acne vulgaris. The interaction between P. acnes and the host is mainly mediated by Toll like receptor (TLR) 2 recognition. TLR2 homodimers recognize P. acnes in mice, but here we describe the prerequisite of TLR2/1 and TLR2/6 heterodimers in human cells for P. acnes recognition. P. acnes-induced NF kappaB and AP-1activation observed in HEK hTLR2-transfected but not control cells confirmed the specificity of TLR2 recognition. The activation was blocked by neutralizing antibodies against TLR2, TLR1 and TLR6, as well as the TLR2 antagonist CU-CPT22, which showed no selectivity towards human TLR2 heterodimers. The combination of anti-TLR1 and anti-TLR6 antibodies completely abrogated activation by P. acnes. In primary human keratinocytes, P. acnes-increased NF kappaB phosphorylation was inhibited by anti-TLR6 and anti-TLR2 antibodies. Furthermore, P. acnes-induced inflammatory responses were impaired by anti-TLR2 neutralizing antibodies and fully blocked by CU-CPT22. Our study suggests species specific recognition of P. acnes by TLR2 heterodimers which can be exploited therapeutically by small molecules targeting TLR2 for the control of inflammatory responses. PMID- 28024925 TI - The evolution of diastolic function during liver transplantation. AB - INTRODUCTION: The peroperative management of liver transplantation is still associated with many cardiocirculatory complications in which diastolic dysfunction may play a contributive role. Transoesophageal echocardiography is a monitoring device commonly used in liver transplantation allowing diastolic function assessment. METHODS: We prospectively analysed the peroperative transoesophageal echocardiography recordings of 40 patients undergoing liver transplantation in order to describe changes in diastolic function at different steps of the surgery. The diastolic function marker we used was the lateral mitral annulus motion (E' wave velocity) obtained by tissue-Doppler imaging. In addition, we also studied the left ventricular filling pressure indices and systolic function. RESULTS: As a whole, there was no global change in E' wave velocity throughout the surgery. However, 11 patients (27.5%) presented a decrease in E' wave velocity up to 15% that identified an occurrence of diastolic function alteration. In this group, other peroperative data were not different from other patients (amount of bleeding, fluid administration or vasopressive support). Conversely, this group experienced lower preoperative E' wave velocity values (9cm.s-1 versus 12cm.s-1, P=0.05) and an increased incidence of postoperative cardiorespiratory complications (OR=6 [1-56], P=0.02). Considering all patients, 18 patients had an E' wave velocity under 10cm.s-1 at unclamping, characterizing a diastolic dysfunction according to the usual criteria. This dysfunction was not associated with cardiorespiratory complications. CONCLUSION: This work investigated peroperative systematic echocardiographic evaluation of diastolic function during liver transplantation. Diastolic dysfunction occurs frequently during liver transplantation and could lead to postoperative cardiorespiratory complications. PMID- 28024926 TI - Durable Response to Combination of Dabrafenib and Trametinib in BRAF V600E Mutated Non-small-cell Lung Cancer. PMID- 28024928 TI - Molecular Profiling and Survival of Completely Resected Primary Pulmonary Neuroendocrine Carcinoma. AB - BACKGROUND: Currently, molecular profiles and prognosis of primary pulmonary neuroendocrine carcinoma (PNC) are poorly elucidated. The present study was designed to evaluate genomic abnormalities and survival in patients with primary PNC. METHODS: Completely resected PNC samples were collected from Zhejiang Cancer Hospital during the period of 2008 to 2015. Nine driver genes, including 6 mutations (EGFR, KRAS, NRAS, PIK3CA, BRAF, and HER2) and 3 fusions (ALK, ROS1, and RET), were evaluated by reverse transcription-polymerase chain reaction (RT PCR). Survival analysis was conducted by the Kaplan-Meier method. RESULTS: A total of 108 patients with pathologically confirmed PNC were enrolled. The types were pulmonary large-cell neuroendocrine carcinoma (PLCNC, n = 52), small-cell lung cancer (SCLC, n = 44), and carcinoid (n = 12). Twelve patients (11.1%) harbored genomic aberrations. The most frequent gene abnormalities in decreasing order were PIK3CA (n = 5, 4.6%), EGFR (n = 3, 2.8%), KRAS (n = 2, 1.9%), ALK (n = 1, 0.9%), and RET (n = 1, 0.9%). No ROS1, BRAF, NRAS, or HER2 mutation was detected. The frequencies of gene aberrations were 15.4%, 6.8%, and 8.3% in PLCNC, SCLC, and carcinoid, respectively. Survival differences existed among PLCNC, SCLC, and carcinoid groups (37.0 vs. 34.0 vs. not reached, P = .035); however, no difference existed between PLCNC and SCLC groups (P = .606). CONCLUSIONS: Genomic abnormality is rare in patients with PNC and it is the most frequently observed in PLCNC. PMID- 28024927 TI - Utilization Patterns and Trends in Epidermal Growth Factor Receptor (EGFR) Mutation Testing Among Patients With Newly Diagnosed Metastatic Lung Cancer. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR)-targeted therapy significantly improves outcomes among patients with non-small-cell lung cancer (NSCLC) whose tumors harbor sensitizing mutations. Patterns of EGFR testing have not been well-documented. The objective of this population-based study is to assess the testing pattern on a national scale. PATIENTS AND METHODS: Using MarketScan 2012 to 2014 data, we identified 5842 patients newly diagnosed with metastatic lung cancer from January 2013 to June 2014 and assessed their EGFR mutation testing pattern in the 6 months after diagnosis. We further examined the testing rate among patients who received the EGFR inhibitor erlotinib. Because histology information is not available in this database, we also conducted a subgroup analysis of EGFR testing among patients who were treated with bevacizumab or pemetrexed, who are likely to have non-squamous NSCLC. Multivariable logistic regression was performed to ascertain factors associated with EGFR testing. RESULTS: Of 5842 patients with metastatic lung cancer, 1039 (18%) had claims for EGFR testing within 6 months of diagnosis, and 283 (5%) received erlotinib. The testing rate among patients who received erlotinib was 42%. Within a subgroup of 1685 patients treated with bevacizumab or pemetrexed, 616 (37%) underwent EGFR testing. Multivariable logistic regression showed that younger patients, female patients, patients with fewer comorbidities, and patients living in the West region were more likely to receive EGFR testing. CONCLUSION: This population-based study demonstrates low EGFR testing rates among advanced lung cancer patients in 2013 and 2014. PMID- 28024929 TI - Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma. AB - A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental glomerulosclerosis. Surprisingly, the biopsy specimen revealed diffuse glomerular deposition of amyloid that was proved to be derived from the calcitonin hormone (Acal), produced by the medullary thyroid carcinoma. This amyloid was also present in an abdominal fat pad biopsy. Although local ACal deposition is a characteristic feature of medullary thyroid carcinoma, the systemic amyloidosis involving the kidney that is presented in this case report has not to our knowledge been described previously and may be the result of long-term high plasma calcitonin levels. Our case illustrates that systemic calcitonin amyloidosis should be considered in the differential diagnosis of proteinuria in patients with medullary thyroid carcinoma. PMID- 28024930 TI - Urine Fibrosis Markers and Risk of Allograft Failure in Kidney Transplant Recipients: A Case-Cohort Ancillary Study of the FAVORIT Trial. AB - BACKGROUND: Kidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown. STUDY DESIGN: Case cohort study. SETTING & PARTICIPANTS: The FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257). PREDICTOR: Using spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine alpha1-microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide). OUTCOME: Death censored allograft failure. RESULTS: In models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure. LIMITATIONS: We lack kidney biopsy data, BK titers, and HLA antibody status. CONCLUSIONS: Urine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR. PMID- 28024932 TI - Corrigendum to "Oral microbiome, periodontitis and risk of head and neck cancer" [Oral Oncol. 53 (2016) 17-19]. PMID- 28024931 TI - A Randomized, Single-Blind, Crossover Trial of Recovery Time in High-Flux Hemodialysis and Hemodiafiltration. AB - BACKGROUND: The choice between hemodiafiltration (HDF) or high-flux hemodialysis (HD) to treat end-stage kidney disease remains a matter of debate. The duration of recovery time after treatment has been associated with mortality, affects quality of life, and may therefore be important in informing patient choice. We aimed to establish whether recovery time is influenced by treatment with HDF or HD. STUDY DESIGN: Randomized patient-blinded crossover trial. SETTINGS & PARTICIPANTS: 100 patients with end-stage kidney disease were enrolled from 2 satellite dialysis units in Glasgow, United Kingdom. INTERVENTION: 8 weeks of HD followed by 8 weeks of online postdilution HDF or vice versa. OUTCOMES: Posttreatment recovery time, symptomatic hypotension events, dialysis circuit clotting events, and biochemical parameters. MEASUREMENTS: Patient-reported recovery time in minutes, incidence of adverse events during treatments, hematology and biochemistry results, quality-of-life questionnaire. RESULTS: There was no overall difference in recovery time between treatments (medians for HDF vs HD of 47.5 [IQR, 0-240] vs 30 [IQR, 0-210] minutes, respectively; P=0.9). During HDF treatment, there were significant increases in rates of symptomatic hypotension (8.0% in HDF vs 5.3% in HD; relative risk [RR], 1.52; 95% CI, 1.2 1.9; P<0.001) and intradialytic tendency to clotting (1.8% in HDF vs 0.7% in HD; RR, 2.7; 95% CI, 1.5-5.0; P=0.002). Serum albumin level was significantly lower during HDF (3.2 vs 3.3g/dL; P<0.001). Health-related quality-of-life scores were equivalent. LIMITATIONS: Single center; mean achieved HDF convection volume, 20.6L. CONCLUSIONS: Patients blinded to whether they were receiving HD or HDF in a randomized controlled crossover study reported similar posttreatment recovery times and health-related quality-of-life scores. PMID- 28024933 TI - A Preoperative Multimarker Approach to Evaluate Acute Kidney Injury After Cardiac Surgery. AB - OBJECTIVE: To investigate whether a multimarker strategy combining preoperative biomarkers representing distinct pathophysiologic pathways enhances preoperative risk assessment of acute kidney injury after cardiac surgery (CSA-AKI) and increases knowledge of underlying pathogenesis. DESIGN: Prospective, cohort study. SETTING: Single-center tertiary referral hospital. PARTICIPANTS: The study comprised 1,015 adults undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: CSA-AKI was defined as>=50% increase in serum creatinine concentration, absolute increase>=26 umol/L, or new requirement for dialysis. Preoperative and perioperative information until hospital discharge was recorded. Preoperative plasma levels of C-reactive protein, terminal complement complex, neopterin, lactoferrin, N-terminal pro-brain natriuretic peptide, and cystatin C were determined using enzyme immunoassays. Biomarkers were selected based on causal hypotheses of underlying mechanisms and were related to inflammatory, hemodynamic, or renal signaling pathways. MEASUREMENTS AND MAIN RESULTS: One hundred patients (9.9%) developed CSA-AKI. Higher baseline plasma concentrations of neopterin and N-terminal pro-brain natriuretic peptide were associated independently with CSA-AKI (p = 0.04 and p<0.001, respectively). Lower baseline plasma lactoferrin concentrations were observed in patients with CSA-AKI (p = 0.05). Compared with clinical risk assessment, addition of these biomarkers provided a slight, but significant, increment in predictive utility (area under the curve 0.81-0.83, likelihood ratio test p<0.001). A net of 12% of patients were reclassified correctly, and improved prediction was demonstrated, especially in patients with intermediate risk (56% correct reclassification). CONCLUSIONS: Preoperative hemodynamic, renal, and immunologic function play central roles in the pathogenesis of CSA-AKI. These findings add evidence to the potential of a multimarker approach to improve preoperative prediction of CSA-AKI. PMID- 28024934 TI - Response: assessing ooplasm maturity. PMID- 28024935 TI - Influence of iodide ingestion on nitrate metabolism and blood pressure following short-term dietary nitrate supplementation in healthy normotensive adults. AB - Uptake of inorganic nitrate (NO3-) into the salivary circulation is a rate limiting step for dietary NO3- metabolism in mammals. It has been suggested that salivary NO3- uptake occurs in competition with inorganic iodide (I-). Therefore, this study tested the hypothesis that I- supplementation would interfere with NO3 metabolism and blunt blood pressure reductions after dietary NO3- supplementation. Nine healthy adults (4 male, mean +/- SD, age 20 +/- 1 yr) reported to the laboratory for initial baseline assessment (control) and following six day supplementation periods with 140 mL.day-1 NO3--rich beetroot juice (8.4 mmol NO3-.day-1) and 198 mg potassium gluconate.day-1 (nitrate), and 140 mL.day-1 NO3--rich beetroot juice and 450 MUg potassium iodide.day-1 (nitrate + iodide) in a randomized, cross-over experiment. Salivary [I-] was higher in the nitrate + iodide compared to the control and NIT trials (P < 0.05). Salivary and plasma [NO3-] and [NO2-] were higher in the nitrate and nitrate + iodide trials compared to the control trial (P < 0.05). Plasma [NO3-] was higher (474 +/- 127 vs. 438 +/- 117 MUM) and the salivary-plasma [NO3-] ratio was lower (14 +/- 6 vs. 20 +/- 6 MUM), indicative of a lower salivary NO3- uptake, in the nitrate + iodide trial compared to the nitrate trial (P < 0.05). Plasma and salivary [NO2-] were not different between the nitrate and nitrate + iodide trials (P > 0.05). Systolic blood pressure was lower than control (112 +/- 13 mmHg) in the nitrate (106 +/- 13 mmHg) and nitrate + iodide (106 +/- 11 mmHg) trials (P < 0.05), with no differences between the nitrate and nitrate + iodide trials (P > 0.05). In conclusion, co-ingesting NO3- and I- perturbed salivary NO3- uptake, but the increase in salivary and plasma [NO2-] and the lowering of blood pressure were similar compared to NO3- ingestion alone. Therefore, increased dietary I- intake, which is recommended in several countries worldwide as an initiative to offset hypothyroidism, does not appear to compromise the blood pressure reduction afforded by increased dietary NO3- intake. PMID- 28024936 TI - Nanotoxicity of cobalt induced by oxidant generation and glutathione depletion in MCF-7 cells. AB - There are very few studies regarding the biological activity of cobalt-based nanoparticles (NPs) and, therefore, the possible mechanism behind the biological response of cobalt NPs has not been fully explored. The present study was designed to explore the potential mechanisms of the cytotoxicity of cobalt NPs in human breast cancer (MCF-7) cells. The shape and size of cobalt NPs were characterized by scanning and transmission electron microscopy (SEM and TEM). The crystallinity of NPs was determined by X-ray diffraction (XRD). The dissolution of NPs was measured in phosphate-buffered saline (PBS) and culture media by atomic absorption spectroscopy (AAS). Cytotoxicity parameters, such as [3-(4,5 dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), neutral red uptake (NRU), and lactate dehydrogenase (LDH) release suggested that cobalt NPs were toxic to MCF-7 cells in a dose-dependent manner (50-200MUg/ml). Cobalt NPs also significantly induced reactive oxygen species (ROS) generation, lipid peroxidation (LPO), mitochondrial outer membrane potential loss (MOMP), and activity of caspase-3 enzymes in MCF-7 cells. Moreover, cobalt NPs decreased intracellular antioxidant glutathione (GSH) molecules. The exogenous supply of antioxidant N-acetyl cysteine in cobalt NP-treated cells restored the cellular GSH level and prevented cytotoxicity that was also confirmed by microscopy. Similarly, the addition of buthionine-[S, R]-sulfoximine, which interferes with GSH biosynthesis, potentiated cobalt NP-mediated toxicity. Our data suggested that low solubility cobalt NPs could exert toxicity in MCF-7 cells mainly through cobalt NP dissolution to Co2+. PMID- 28024937 TI - Curative brachytherapy for prostate cancer in African-Caribbean patients: A retrospective analysis of 370 consecutive cases. AB - PURPOSE: Prostate cancer is the most frequent malignancy in African-Caribbean men, a population sharing common genetic traits with African-American (AA) but presenting also genomic and epidemiologic specificities. Despite socioeconomic disparities with French mainland, all patients were treated within the French state-financed equal-access health care system. In this study, we report biochemical outcomes of patients treated by brachytherapy in our department from 2005 to 2014 in an African-Caribbean population. METHODS AND MATERIALS: Three hundred seventy consecutive patients receiving 125I brachytherapy as a curative treatment for early-stage (localized) disease between 2005 and 2014 were recorded. Selected patients presented with low-risk disease: initial prostate specific antigen (PSA) <10 ng/mL, clinical stage <= T2c, and Gleason score <7. Patients with intermediate risk of recurrence were also included on a case-to case basis with prostate-specific antigen <15 or Gleason score 7 (3 + 4). Biochemical failure free-survival was defined according to the American Society for Radiation Oncology nadir+2 definition. RESULTS: The 3-year and 5-year biochemical failure free-survival for the entire cohort were 98.3% and 91.6%, respectively. For patients with low- and intermediate-risk disease, the 5-year BBFS rates were 92.1% and 90.8%, respectively. In univariate and multivariate analyses, only Gleason score (<7 vs. 7; p = 0.030 vs. p < 0.05) was a significant predictor of biochemical failure. The overall rate of late and acute Grade 2 or higher genitourinary toxicity was 12.6% and 10.3%. CONCLUSIONS: In this large single-center series, brachytherapy achieved excellent rates of medium term biochemical control in both low and selected intermediate-risk localized prostate cancer in African-Caribbean patients. Brachytherapy seems to be an excellent choice of treatment, with excellent outcomes and limited morbidity for African-Caribbean populations. PMID- 28024938 TI - Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing. AB - Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T>C, c.321+1G>A) were present in multiple, unrelated patients. Functional analysis of recombinantly expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321+1G>A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines. PMID- 28024939 TI - RAGE deficiency alleviates aortic valve calcification in ApoE-/- mice via the inhibition of endoplasmic reticulum stress. AB - Receptor for advanced glycation end products (RAGE) and endoplasmic reticulum (ER) stress have been shown to be involved in calcific aortic valve disease (CAVD). However, the association between RAGE and ER stress remains unknown in the pathogenesis of CAVD. The current study aims to test the hypothesis that RAGE deficiency alleviates aortic valve calcification via the inhibition of ER stress. Up-regulation of RAGE and ER stress markers in calcified human aortic valves were confirmed by immunoblotting. Aortic valve calcification was evaluated in atherosclerotic prone ApoE-/- mice or in mice with dual deficiencies of ApoE and RAGE (ApoE-/-RAGE-/-) fed with high cholesterol diet for 24weeks. Echocardiography and histological examination show that genetic deficiency of RAGE attenuates aortic valve calcification in ApoE-/- mice. Meanwhile, RAGE deficiency inhibited the osteogenic signaling and ER stress activation as well as suppressed macrophage infiltration in vivo. Cultured human aortic valve interstitial cells (AVICs) were treated with high molecular group box 1 protein (HMGB1) as in vitro model. We found that HMGB1 induced osteoblastic differentiation and calcification through RAGE/ER stress. Furthermore, Sox9 up regulation and intranuclear translocation mediated the pro-osteogenic effect of HMGB1 on AVICs. RAGE or ER stress knockdown reduced the up-regulation of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in human AVICs exposed to HMGB1.These novel findings demonstrate that RAGE deficiency protects against aortic valve calcification in high cholesterol diet fed ApoE-/- mice via inhibition of ER stress. HMGB1 induces AVIC osteoblastic differentiation and calcification through RAGE/ER stress/Sox9 pathway. PMID- 28024940 TI - A new flavonoid glycoside (APG) isolated from Clematis tangutica attenuates myocardial ischemia/reperfusion injury via activating PKCepsilon signaling. AB - Clematis tangutica has been shown to be beneficial for the heart; however, the mechanism of this effectremains unknown. Apigenin-7-O-beta-D-(-6"-p-coumaroyl) glucopyranoside (APG) is a new flavonoid glycoside isolated from Clematis tangutica. This study investigates the effects of APG on myocardial ischemia/reperfusion (IR) injury (IRI). An IRI model of primary myocardial cells and mice was used in this study. Compared with the IR group, APG preconditioning is protective against IRI in primary myocardial cells and in mice hearts in a dose-dependent manner. The cardioprotective mechanisms of APG may involve a significant PKCepsilon translocation into the mitochondria and an activation of the Nrf2/HO-1 pathway, which respectively suppressesmitochondrial oxidative stress and inhibits apoptosis. In addition, PKCepsilon-targeted siRNA and a PKCepsilon specialized inhibitor (epsilon-V1-2) were used to inhibit PKCepsilon expression and activity. The inhibition of PKCepsilon reversed the cardioprotective effect of APG, with an inhibition of Nrf2/HO-1 activation and increased mitochondrial oxidative stress and cardiomyocyte apoptosis. In conclusion, PKCepsilon activation plays an important role in the cardioprotective effects of APG. PKCepsilon activation induced by APG preconditioning reduces mitochondrial oxidative stress and promotes Nrf2/HO-1-mediated anti-apoptosis signaling. PMID- 28024942 TI - Uncomplicated Pregnancy in a Patient Treated With Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. AB - Pregnancy in women with hypertrophic cardiomyopathy (HCM) is associated with a slightly increased risk of maternal morbidity and mortality, as well as a higher risk of premature births. One of the risk factors complicating pregnancies in HCM is left ventricular outflow tract obstruction (LVOTO). We report a case of a symptomatic patient with HCM and LVOTO who was treated with alcohol septal ablation and then had an uncomplicated pregnancy. PMID- 28024941 TI - Orthostatic Hypotension After Continuous-Flow Left Ventricular Assist Device Implantation in a Patient With Longstanding Diabetes Mellitus. AB - A continuous-flow left ventricular assist device (CF-LVAD) benefits patients with advanced heart failure as a bridge to cardiac transplantation. However, unanticipated complications may occur. We report a patient with end-stage heart failure and longstanding diabetes who experienced functionally debilitating orthostatic hypotension from autonomic insufficiency after CF-LVAD implantation. This case demonstrates a role for comprehensive autonomic function testing in the workup of orthostatic hypotension after LVAD implantation. PMID- 28024943 TI - Effects of ovarian ablation or suppression in premenopausal breast cancer: A meta analysis of randomized controlled trials. AB - BACKGROUND: The effect of ovarian ablation or suppression (OAS) in premenopausal women with breast cancer is controversial. The overall survival (OS), disease free survival (DFS) and adverse event of OAS versus no OAS were compared. METHODS: A literature review of EMBASE, Web of Science, PUBMED, and Cochrane Library was conducted. The hazard ratio (HR) and 95% confidence interval (CI) for OS and DFS, as well as risk ratio (RR) and 95% CI for adverse events were evaluated. I-squared statistic (I2) represents heterogeneity. RESULTS: Twenty nine studies with a total of 21,249 women were included. In premenopausal women aged 40 years or younger, there were significant differences in OS (HR 0.78, 95% CI: 0.66-0.94, P=0.008, I2 = 0%) and DFS (HR 0.84, 95% CI: 0.73-0.97, P=0.02, I2 = 0%) between OAS and no OAS. In advanced stage breast cancer, a significant difference was found in OS (HR 0.76, 95% CI: 0.60-0.96, P=0.02, I2 = 0%). Patients treated with OAS had more chances to have hot flushes (RR 1.91, 95% CI: 1.62-2.26, P < 0.01, I2 = 0%) and vaginal dryness (RR 1.19, 95% CI: 1.08-1.31, P=0.0003, I2 = 0%). No significant difference in depression (RR 1.28, 95% CI: 0.94-1.74, P=0.12, I2 = 0%). CONCLUSIONS: The study shows that OAS plays a beneficial role in premenopausal women aged 40 years or younger and advanced stage breast cancer. However, OAS is associated with increase in hot flushes and vaginal dryness. PMID- 28024944 TI - Impact of sarcopenia on outcome in patients with esophageal resection following neoadjuvant chemotherapy for esophageal cancer. AB - BACKGROUND: Nutritional status and body composition parameters such as sarcopenia are important risk factors for impaired outcome in patients with esophageal cancer. This study was conducted to evaluate the effect of sarcopenia on long term outcome after esophageal resection following neoadjuvant treatment. METHODS: Skeletal muscle index (SMI) and body composition parameters were measured in patients receiving neoadjuvant treatment for locally advanced esophageal cancer. Endpoints included relapse-free survival (RFS) and overall survival (OS). RESULTS: The study included 130 patients. Sarcopenia was found in 80 patients (61.5%). Patients with squamous-cell cancer (SCC) showed a decreased median SMI of 48 (range 28.4-60.8) cm/m2 compared with that of patients with adenocarcinoma (AC) of 52 (range 34.4-74.2) cm/m2, P < 0.001. The presence of sarcopenia had a significant impact on patient outcome: HR 1.69 (1.04-2.75), P = 0.036. Median OS was 20.5 (7.36-33.64) versus 52.1 (13.55-90.65) months in sarcopenic and non sarcopenic patients, respectively. Sarcopenia was identified as an independent risk factor: HR 1.72 (1.049-2.83), P = 0.032. CONCLUSION: Our data provide evidence that sarcopenia impacts long-term outcome after esophageal resection in patients who have undergone neoadjuvant therapy. Assessment of the body composition parameter can be a reasonable part of patient selection and may influence treatment methods. PMID- 28024945 TI - MC37, a new mono-carbonyl curcumin analog, induces G2/M cell cycle arrest and mitochondria-mediated apoptosis in human colorectal cancer cells. AB - (E)-1-(3'-fluoro-[1,1'-biphenyl-3-yl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1 one) (MC37), a novel mono-carbonyl curcumin analog, was previously synthesized in our laboratory as a nuclear factor kappa B (NF-kappaB) inhibitor with excellent cytotoxicity against several cancer cell lines. In this study, our further investigations showed that the potent growth inhibitory activity of MC37 in human colorectal cancer cells was associated with the arrest of cell cycle progression and the induction of apoptosis. As a multi-targeted agent, MC37 inhibited the intracellular microtubule assembly, altered the expression of cyclin-dependent kinase 1 (CDK1), and ultimately induced G2/M cell cycle arrest. Moreover, MC37 collapsed the mitochondrial membrane potential (MMP), increased the Bax/Bcl-2 ratio, activated the caspase-9/3 cascade, and finally led to cancer cells apoptosis, suggesting that the mitochondrial-mediated apoptotic pathway was involved in MC37-induced apoptosis. In conclusion, these observations demonstrated that mono-carbonyl curcumin analogs would serve as multi-targeted lead for promising anti-colorectal cancer agent development. PMID- 28024946 TI - Short- and Mid-Term Outcomes after Endoscopic Transanal or Laparoscopic Transabdominal Total Mesorectal Excision for Low Rectal Cancer: A Single Institutional Case-Control Study. AB - BACKGROUND: Transabdominal laparoscopic proctectomy (LAP) for rectal cancer was associated with postoperative recovery improvement. Early studies showed favorable short-term results of endoscopic transanal proctectomy (ETAP), with low conversion rates to open procedures. We aimed to compare efficacy, morbidity, and functional outcomes of ETAP to standard LAP for low rectal cancer. STUDY DESIGN: From 2008 to 2013, 72 consecutive patients received proctectomy and coloanal manual anastomosis for low rectal adenocarcinoma. Thirty-four patients had transanal endoscopic proctectomy, and 38 patients underwent the standard laparoscopic procedure. RESULTS: When compared with the LAP group, the ETAP group demonstrated a lower conversion rate to open procedures (23.7% vs 2.9%, respectively; p = 0.015), shorter in-hospital stays (9 vs 8 days, respectively; p = 0.04), and a lower readmission rate (13.2% vs 0%; p = 0.03). Overall postoperative morbidity rates for the LAP and the ETAP groups (36.8% vs 32.4%, respectively; p = 0.69) and functional results (Kirwan score 1/2, 73.7% vs 73.5%, respectively; p = 0.85) were comparable; additionally, we found similar oncologic quality criteria (R1 resection 10.5% vs 5.9%, respectively; p = 0.68; grade 3 mesorectal integrity 52.6% vs 55.9%, respectively; p = 0.66). Disease-free survival of 24 months (Kaplan-Meier estimation) was comparable in the 2 groups: 86% in the ETAP group vs 88% in the LAP group; p = 0.91. At the date of last follow-up, 91.2% of ETAP patients and 92.1% of LAP patients were free of stoma. CONCLUSIONS: The endoscopic transanal approach could facilitate mesorectal excision and improve short-term outcomes without impairing the oncologic quality of the resection or mid-term functional and oncologic results. PMID- 28024947 TI - Clinical Genomic Profiling of a Diverse Array of Oncology Specimens at a Large Academic Cancer Center: Identification of Targetable Variants and Experience with Reimbursement. AB - Large cancer panels are being increasingly used in the practice of precision medicine to generate genomic profiles of tumors with the goal of identifying targetable variants and guiding eligibility for clinical trials. To facilitate identification of mutations in a broad range of solid and hematological malignancies, a 467-gene oncology panel (Columbia Combined Cancer Panel) was developed in collaboration with pathologists and oncologists and is currently available and in use for clinical diagnostics. Herein, we share our experience with this testing in an academic medical center. Of 255 submitted specimens, which encompassed a diverse range of tumor types, we were able to successfully sequence 92%. The Columbia Combined Cancer Panel assay led to the detection of a targetable variant in 48.7% of cases. However, although we show good clinical performance and diagnostic yield, third-party reimbursement has been poor. Reimbursement from government and third-party payers using the 81455 Current Procedural Terminology code was at 19.4% of billed costs, and 55% of cases were rejected on first submission. Likely contributing factors to this low level of reimbursement are the delays in valuation of the 81455 Current Procedural Terminology code and in establishing national or local coverage determinations. In the absence of additional demonstrations of clinical utility and improved patient outcomes, we expect the reimbursement environment will continue to limit the availability of this testing more broadly. PMID- 28024949 TI - Acute Myeloid Leukemia After Radium-223 Therapy: Case Report. PMID- 28024948 TI - Successful Treatment of Metastatic Upper Tract Urothelial Carcinoma With Vemurafenib: Case Report. PMID- 28024950 TI - Detection and Clinical Significance of Circulating Tumor Cells in Patients Undergoing Radical Cystectomy for Urothelial Bladder Cancer. AB - INTRODUCTION: Estimation of prognosis is patients undergoing radical cystectomy is often unreliable, as occult disease remains undetected by conventional diagnostic tools. The purpose of this study was to evaluate the feasibility and the clinical significance of a polymerase chain reaction assay to detect cytokeratin 7 (CK7) mRNA expression in peripheral blood cells of patients undergoing radical cystectomy for clinically nonmetastatic bladder cancer. PATIENTS AND METHODS: From 2005 to 2009, 59 patients undergoing radical cystectomy and pelvic lymph node dissection were prospectively investigated. Peripheral blood was collected prior to surgery, and a nested polymerase chain reaction assay was developed to identify patients with circulating cells expressing CK7 mRNA. Preoperative, histopathologic data and clinical outcome were compared with CK7 findings. RESULTS: CK7 expression was detected in 23 (38.9%) of 59 patients and correlated to T stage and lymph node status. After a median follow-up of 42 months, 29 patients experienced a recurrence, whereas 36 died. The presence of CK7-positive cells was significantly associated with an increased risk for recurrence and decreased survival as compared with patients who were CK7 negative (P < .001 and P < .001, respectively; hazard ratios of 8.77 and 5.2 for recurrence and overall death, respectively). The detection of CK7-positive cells was an independent predictor of recurrence and death in a multivariable analysis. CONCLUSION: The detection of CK7 mRNA in the circulating cells of patients undergoing radical cystectomy for urothelial cancer identifies those with significantly increased risk of cancer recurrence and death. PMID- 28024951 TI - Role of Molecular Profiling in Diagnosis of Papillary Renal-cell Cancer Presenting as Cancer of Unknown Primary Site. PMID- 28024952 TI - Real-time dynamic modelling for the design of a cluster-randomized phase 3 Ebola vaccine trial in Sierra Leone. AB - BACKGROUND: Declining incidence and spatial heterogeneity complicated the design of phase 3 Ebola vaccine trials during the tail of the 2013-16 Ebola virus disease (EVD) epidemic in West Africa. Mathematical models can provide forecasts of expected incidence through time and can account for both vaccine efficacy in participants and effectiveness in populations. Determining expected disease incidence was critical to calculating power and determining trial sample size. METHODS: In real-time, we fitted, forecasted, and simulated a proposed phase 3 cluster-randomized vaccine trial for a prime-boost EVD vaccine in three candidate regions in Sierra Leone. The aim was to forecast trial feasibility in these areas through time and guide study design planning. RESULTS: EVD incidence was highly variable during the epidemic, especially in the declining phase. Delays in trial start date were expected to greatly reduce the ability to discern an effect, particularly as a trial with an effective vaccine would cause the epidemic to go extinct more quickly in the vaccine arm. Real-time updates of the model allowed decision-makers to determine how trial feasibility changed with time. CONCLUSIONS: This analysis was useful for vaccine trial planning because we simulated effectiveness as well as efficacy, which is possible with a dynamic transmission model. It contributed to decisions on choice of trial location and feasibility of the trial. Transmission models should be utilised as early as possible in the design process to provide mechanistic estimates of expected incidence, with which decisions about sample size, location, timing, and feasibility can be determined. PMID- 28024953 TI - Immune protection conferred by recombinant MRLC (myosin regulatory light chain) antigen in TiterMax Gold(r) adjuvant against experimental fasciolosis in rats. AB - Protection against experimental fasciolosis in rats immunized with recombinant myosin regulatory light chain (MRLC) in TiterMax Gold(r) adjuvant was assessed. The experimental trial consisted of four groups of 15 animals; group 1 was unimmunized and infected, group 2 was immunized with MRLC in adjuvant and infected, group 3 was infected and immunized with adjuvant only and group 4 was unimmunized and uninfected. Immunization with MRLC in TiterMax Gold(r) adjuvant (group 2) induced a reduction in fluke burdens of 51.0% (p<0.001) when compared with the adjuvant control group, and 61.5% (p<0.001) when compared with the unimmunized infected controls. There was a reduction in fecal egg output in group 2 of 44.8% and 37.3% compared with group 1 and group 3, respectively; although this difference was not statistically significant. Measurement of cytokine levels revealed higher levels of TNF-alpha and IL-2 as well as lower levels of IL-4 in group 2 during the chronic stage of infection (p<0.05), along with higher levels of IFN-gamma during early stages of infection (p<0.05). These results suggest a mixed Th1/Th2 phenotype immune response; however predominance of Th1 cytokines was observed. Levels of anti-MRLC serum IgG in group 2 were significantly higher than controls at the time of euthanasia (p<0.05). This is the first report of immunization with recombinant MRLC in rats, demonstrating that this antigen significantly reduces fluke burdens, increases the Th1 immune response and encourages further studies to improve the vaccine's efficacy. PMID- 28024954 TI - Primary care physicians' perspective on financial issues and adult immunization in the Era of the Affordable Care Act. AB - BACKGROUND: Financial barriers to adult vaccination are poorly understood. Our objectives were to assess among general internists (GIM) and family physicians (FP) shortly after Affordable Care Act (ACA) implementation: (1) proportion of adult patients deferring or refusing vaccines because of cost and frequency of physicians not recommending vaccines for financial reasons; (2) satisfaction with reimbursement for vaccine purchase and administration by payer type; (3) knowledge of Medicare coverage of vaccines; and (4) awareness of vaccine-specific provisions of the ACA. METHODS: We administered an Internet and mail survey from June to October 2013 to national networks of 438 GIMs and 401 FPs. RESULTS: Response rates were 72% (317/438) for GIM and 59% (236/401) for FP. Among physicians who routinely recommended vaccines, up to 24% of GIM and 30% of FP reported adult patients defer or refuse certain vaccines for financial reasons most of the time. Physicians reported not recommending vaccines because they thought the patient's insurance would not cover it (35%) or the patient could be vaccinated more affordably elsewhere (38%). Among physicians who saw patients with this insurance, dissatisfaction ('very dissatisfied') was highest for payments received from Medicaid (16% vaccine purchase, 14% vaccine administration) and Medicare Part B (11% vaccine purchase, 11% vaccine administration). Depending on the vaccine, 36-71% reported not knowing how Medicare covered the vaccine. Thirty-seven percent were 'not at all aware' and 19% were 'a little aware' of vaccine-specific provisions of the ACA. CONCLUSIONS: Patients are refusing and physicians are not recommending adult vaccinations for financial reasons. Increased knowledge of private and public insurance coverage for adult vaccinations might position physicians to be more likely to recommend vaccines and better enable them to refer patients to other vaccine providers when a particular vaccine or vaccines are not offered in the practice. PMID- 28024955 TI - Pregnancy as a risk factor for severe outcomes from influenza virus infection: A systematic review and meta-analysis of observational studies. AB - BACKGROUND: Pregnancy is considered to be an important risk factor for severe complications following influenza virus infection. As a consequence, WHO recommendations prioritize pregnant women over other risk groups for influenza vaccination. However, the risk associated with pregnancy has not been systematically quantified. PURPOSE: Systematic review and meta-analysis of observational studies that reported on pregnancy as a risk factor for severe outcomes from influenza virus infection. DATA SOURCE: MEDLINE, EMBASE, CINAHL, and CENTRAL up to April 2014. DATA SELECTION: Studies reporting on outcomes in pregnant women with influenza in comparison to non-pregnant patients with influenza. Outcomes included community-acquired pneumonia, hospitalization, admission to intensive care units (ICU), ventilatory support, and death. DATA EXTRACTION: Two reviewers conducted independent screening and data extraction. A random effects model was used to obtain risk estimates. Ecological studies were summarized descriptively. DATA SYNTHESIS: A total of 142 non-ecological and 10 ecological studies were included. The majority of studies (n=136, 95.8%) were conducted during the 2009 influenza A (pH1N1) pandemic. There was a higher risk for hospitalization in pregnant versus non-pregnant patients infected with influenza (odds ratio [OR] 2.44, 95% CI 1.22-4.87), but no significant difference in mortality (OR 1.04, 95% CI 0.81-1.33) or other outcomes. Ecologic studies confirmed the association between hospitalization risk and pregnancy and 4 of 7 studies reported higher mortality rates in pregnant women. LIMITATIONS: No studies were identified in which follow-up began prior to contact with the healthcare system and lack of adjustment for confounding factors. CONCLUSIONS: We found that influenza during pregnancy resulted in a higher risk of hospital admission than influenza infection in non-pregnant individuals, but that the risk of mortality following influenza was similar in both pregnant and non-pregnant individuals. PMID- 28024956 TI - Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: A systematic review and meta-analysis. AB - BACKGROUND: In the elderly, traditional influenza inactivated vaccines are often only modestly immunogenic, owing to immunosenescence. Given that adjuvantation is a means of enhancing the immune response, the trivalent inactivated vaccine adjuvanted with MF59 (MF59-TIV) was specifically designed to overcome this problem. Considering that, for ethical reasons, the absolute effectiveness of an influenza vaccine in the elderly cannot be demonstrated in placebo-controlled studies, the present study aimed to assess the effectiveness of MF59-TIV in preventing influenza-related outcomes in the elderly. METHODS: We conducted a systematic review of observational studies aimed at evaluating the effectiveness of MF59-TIV against influenza-related outcomes. Results of single studies were pooled whenever possible. RESULTS: Of the 1993 papers screened, 11 (6 case control, 3 cohort and 2 prospective case-control) studies were identified. Hospitalization due to pneumonia/influenza and laboratory-confirmed influenza were reported in more than one study, while other outcomes (influenza-like illness, cardio- and cerebrovascular accidents) were investigated only by one study each. Pooled analysis of four case-control studies showed an adjusted MF59 TIV effectiveness of 51% (95% CI: 39-61%) against hospitalizations for pneumonia/influenza among community-dwelling seniors. Pooled results of the adjusted vaccine effectiveness against laboratory-confirmed influenza were also high (60.1%), although the 95% CI passed through zero (-1.3 to 84.3%). Other single community-based studies showed very high effectiveness of MF59-TIV in preventing hospitalizations for acute coronary [87% (95% CI: 35-97%)] and cerebrovascular [93% (95% CI: 52-99%)] events. MF59-TIV proved highly effective [94% (95% CI: 47-100%] in reducing influenza-like illness among institutionalized elderly. Furthermore, MF59-TIV displayed greater efficacy than non-adjuvanted vaccines in preventing hospitalizations due to pneumonia/influenza [adjusted risk ratio 0.75 (95% CI: 0.57-0.98)] and laboratory-confirmed influenza [adjusted odds ratio 0.37 (0.14-0.96)]. CONCLUSIONS: Our results suggest that MF59-TIV is effective in reducing several influenza-related outcomes among the elderly, especially hospitalizations due to influenza-related complications. PMID- 28024957 TI - Writing a scientific paper-A brief guide for new investigators. AB - When applying for funding, researchers must demonstrate their productivity. For most funding organizations, a key measure of productivity is the number of papers published. The road to publication is rarely straightforward; few journals provide practical guidance to researchers who are struggling to publish their data. Here, we outline the sections of a research paper and describe practical steps in each part of the publication process as an aid to newer authors. PMID- 28024958 TI - Outer membrane vesicles harboring modified lipid A moiety augment the efficacy of an influenza vaccine exhibiting reduced endotoxicity in a mouse model. AB - Influenza is an acute respiratory disease and a major health problem worldwide. Since mucosal immunity plays a critical role in protection against influenza virus infection, mucosal immunization is considered a promising vaccination route. However, except for live-attenuated vaccines, there are no effective killed or recombinant mucosal influenza vaccines to date. Outer membrane vesicles (OMVs) are nano-sized vesicles produced by gram-negative bacteria, and contain various bacterial components capable of stimulating the immune system of the host. We generated an OMV with low endotoxicity (fmOMV) by modifying the structure of the lipid A moiety of lipopolysaccharide and investigated its effect as an intranasal vaccine adjuvant in an influenza vaccine model. In this model, fmOMV exhibited reduced toll-like receptor 4-stimulating activity and attenuated endotoxicity compared to that of native OMV. Intranasal injection of the vaccine antigen with fmOMV significantly increased systemic antibody and T cell responses, mucosal IgA levels, and the frequency of lung-resident influenza specific T cells. In addition, the number of antigen-bearing CD103+ dendritic cells in the mediastinal lymph nodes was significantly increased after fmOMV co administration. Notably, the mice co-immunized with fmOMV showed a significantly higher protection rate against challenge with a lethal dose of homologous or heterologous influenza viruses without adverse effects. These results show the potential of fmOMV as an effective mucosal adjuvant for intranasal vaccines. PMID- 28024959 TI - Clinicopathologic, immunophenotyping and cytogenetic analysis of Sweet syndrome in Egyptian patients with acute myeloid leukemia. AB - BACKGROUND: Sweet syndrome (SS) is an uncommon dermatologic disorder that could be associated with hematologic malignancies. OBJECTIVE: To describe the clinicopathologic, immunophenotyping and cytogenetic characteristics of SS in Egyptian patients with acute myeloid leukemia (AML). METHODS: The study was conducted during the period from April 2011 to March 2015. For each patient, a clinical evaluation and histological assessment of cutaneous lesions were recorded. Diagnostic investigations, immunophenotyping and cytogenetic features of leukemia were analyzed. Therapeutic monitoring and follow up of both diseases were registered. RESULTS: The study included 13 patients (7 males and 6 females) with a mean age of 44.4+/-17.49years. Fever was recorded in 10 cases and most of the lesions (61.5%) appeared during the post remission period. Clinically, the lesions were more frequently located on the extremities (61.5%), presented as solitary lesion (53.8%) and mostly tender (69.2%). Atypical presentations were observed in 5 cases and included ulcerative lesion, indurated mass and a gangrenous mass. Histological assessment revealed two patterns of inflammatory reactions described as classic (dermal) form (38.5%) and deep (subcutaneous) form (61.5%). Laboratory investigations showed leukocytosis in 61.5%, neutropenia in 38.5%, anaemia in 92.3%, and thrombocytopenia in 84.6%. Bone marrow aspiration and biopsy showed suppressed trilineage hematopoesis in 84.6% and blast cell count >50% in 69.2%. The common subtypes of AML included M2 and M4 (23.1% for each). Cytogenetic studies revealed genetic abnormalities in 69.2% of cases. Most of the cases (76.9%) showed a poor response to oral prednisolone but responded well to alternative therapies, including dapsone, colchicine and cyclosporine. CONCLUSION: Sweet syndrome associated with AML may show atypical clinical forms that have an aggressive course and is mostly associated with subcutaneous involvement. Although chemotherapy of AML may play a significant role in the development of SS, the exact mechanism remains unclear. The disease is considered a steroid refractory and genetic abnormalities may have a role in altering the classic nature of the disease. PMID- 28024960 TI - Detecting congenital hypothyroidism with newborn screening: the relevance of thyroid-stimulating hormone cutoff values. AB - OBJECTIVES: To assess the prevalence of congenital hypothyroidism and the ability of various neonatal thyroid-stimulating hormone (TSHneo) cutoff values to detect this disease. METHODS: This cohort study was based on the retrospective collection of information available from the Reference Service for Newborn Screening database for all live births from January 1, 2010, to December 31, 2012, assessed using the Newborn Screening Program of a Brazilian state, Brazil. The infants were divided into two groups: I - Control: infants with normal newborn screening tests and II - Study: infants with congenital hypothyroidism. Analysis included comparing the TSHneo levels from both groups. A receiver operating characteristic (ROC) curve was constructed to assess the TSHneo cutoff values. RESULTS: Using a TSHneo cutoff value of 5.0MUIU/mL, 50 out of 111,705 screened infants had diagnosis of congenital hypothyroidism (prevalence 1:2234 live births). The ROC curve showed that TSHneo value of 5.03MUIU/mL had 100% sensitivity and the greatest associated specificity (93.7%). The area under the curve was 0.9898 (p<0.0001). CONCLUSIONS: The ROC curve confirmed that the TSHneo cutoff value of 5.0MUIU/mL adopted by the Newborn Screening Program of a Brazilian state was the most appropriate for detecting congenital hypothyroidism and most likely explains the high prevalence that was found. PMID- 28024961 TI - Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: Rationale for and design of the randomized, double-blind PARALLEL-HF study. AB - BACKGROUND: The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan. METHODS AND DESIGN: This is a multicenter, randomized, double-blind, parallel-group, active controlled study of 220 Japanese HFrEF patients. Eligibility criteria include a diagnosis of chronic HF (New York Heart Association Class II-IV) and reduced ejection fraction (left ventricular ejection fraction <=35%) and increased plasma concentrations of natriuretic peptides [N terminal pro B-type natriuretic peptide (NT-proBNP) >=600pg/mL, or NT-proBNP >=400pg/mL for those who had a hospitalization for HF within the last 12 months] at the screening visit. The study consists of three phases: (i) screening, (ii) single-blind active LCZ696 run-in, and (iii) double-blind randomized treatment. Patients tolerating LCZ696 50mg bid during the treatment run-in are randomized (1:1) to receive LCZ696 100mg bid or enalapril 5mg bid for 4 weeks followed by up titration to target doses of LCZ696 200mg bid or enalapril 10mg bid in a double blind manner. The primary outcome is the composite of cardiovascular death or HF hospitalization and the study is an event-driven trial. CONCLUSIONS: The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study and aims to assess the efficacy and safety of LCZ696 in Japanese HFrEF patients. PMID- 28024962 TI - Department of Error. PMID- 28024963 TI - Variability in neural excitability and plasticity induction in the human cortex: A brain stimulation study. AB - BACKGROUND: The potential of non-invasive brain stimulation (NIBS) for both probing human neuroplasticity and the induction of functionally relevant neuroplastic change has received significant interest. However, at present the utility of NIBS is limited due to high response variability. One reason for this response variability is that NIBS targets a diffuse cortical population and the net outcome to stimulation depends on the relative levels of excitability in each population. There is evidence that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) as assessed by transcranial magnetic stimulation (TMS) is useful in predicting NIBS response. OBJECTIVE: Here we examined whether an additional marker of cortical excitability, MEP amplitude variability, could provide additional insights into response variability following application of the continuous theta burst stimulation (cTBS) NIBS protocol. Additionally we investigated whether I-wave recruitment was associated with MEP variability. METHODS: Thirty-four healthy subjects (15 male, aged 18-35 years) participated in two experiments. Experiment 1 investigated baseline MEP variability and cTBS response. Experiment 2 determined if I-wave recruitment was associated with MEP variability. RESULTS: Data show that both baseline MEP variability and late I-wave recruitment are associated with cTBS response, but were independent of each other; together, these variables predict 31% of the variability in cTBS response. CONCLUSIONS: This study provides insight into the physiological mechanisms underpinning NIBS plasticity responses and may facilitate development of more reliable NIBS protocols. PMID- 28024964 TI - Re: Hofner et al.: Low Serum Testosterone Level Predisposes to Artificial Urinary Sphincter Cuff Erosion (Urology 2016;97:245-249). PMID- 28024965 TI - Efficacy of Cranberry in Preventing Recurrent Urinary Tract Infections: Have We Learned Anything New?: Commentary on: Effect of Cranberry Capsules on Bacteriuria Plus Pyuria Among Older Women in Nursing Homes: A Randomized Clinical Trial. PMID- 28024966 TI - Office-based Ultrasound-guided Renal Core Biopsy Is Safe and Efficacious in the Management of Small Renal Masses. AB - OBJECTIVE: To evaluate the safety and efficacy of ultrasound (US)-guided percutaneous renal mass biopsy (RMB) performed in the office setting by urologists. MATERIALS AND METHODS: This is a retrospective study involving patients who underwent office-based US-guided percutaneous RMB between April 2010 and October 2015. Baseline vital signs and US were performed prior to the procedure. Patients were then observed for 1 hour after the procedure and repeat vital signs and US were performed. Hemodynamically stable patients who did not develop hematoma were discharged. RESULTS: In 108 patients, 70 (64.8%) were male, median age was 69.5 years, and median mass size was 3.3 cm (interquartile range: 2.5-4.6). Biopsy yield was as follows: 72 (66.7%) had renal cell carcinoma, 14 (13.0%) had benign renal parenchyma, 11 (10.2%) had oncocytoma, 6 (5.6%) had angiomyolipoma, 2 (1.9%) had lymphoma, and 3 (2.8%) had other disease. The initial nondiagnostic rate was 14 of 108 (13.0%). There were 28 of 108 (25.9%) patients observed whereas 79 of 108 (73.2%) received surgery or ablative therapy. Final pathology was concordant with biopsy results in 66 of 68 (97.1%) cases. Three patients experienced a grade I Clavien-Dindo surgical complication, all of which were managed conservatively. CONCLUSION: Office-based US-guided RMB is safe and efficacious in the management of appropriately selected SRM. It potentially offers improved dynamic characterization of solid renal mass, greater convenience to patients, as well as cost savings. Further studies are needed to evaluate this promising technique. PMID- 28024967 TI - Extent of Baseline Prostate Atrophy Is Associated With Lower Incidence of Low- and High-grade Prostate Cancer on Repeat Biopsy. AB - OBJECTIVE: To evaluate whether baseline prostate atrophy (PA) extent is associated with prostate cancer (PCa) incidence at 2-year repeat prostate biopsy in a clinical trial with systematic biopsies. MATERIALS AND METHODS: We performed a retrospective analysis of 3165 men 50-75 years old with prostate-specific antigen between 2.5 and 10 ng/mL and a prior negative biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events trial who underwent a 2-year repeat biopsy. PA extent was defined as the percentage of cores with atrophic changes. The association of baseline PA with positive 2-year biopsies was evaluated with logistic regression in uni- and multivariable analysis, controlling for baseline covariates. RESULTS: PA involving none, 1%-25%, 26%-50%, 51%-75%, and >75% of the baseline cores was observed in 966 of 3165 (30.5%), 1189 of 3165 (37.6%), 677 of 3165 (21.4%), 209 of 3165(6.6%), and 124 of 3165 (3.9%) cases, respectively. More extensive PA was associated with older age, lower prostate-specific antigen, larger prostate volume, and higher prevalence of acute and chronic inflammations (all P < .05). Compared to subjects without PA, those with 1%-25%, 26%-50%, 51% 75%, and >75% core involvement had an odds ratio for PCa of 0.65 (95% confidence interval [CI] = 0.52-0.81), 0.60 (95% CI = 0.46-0.78), 0.56 (95% CI = 0.37-0.86), and 0.35 (95% CI = 0.19-0.67), respectively. In multivariable analysis, the extent of PA was independently associated with lower PCa risk (P < .001). More extensive PA was associated with lower incidence of low-grade (Gleason 2-6) and high-grade (Gleason 7-10) PCa. CONCLUSION: The extent of baseline PA is independently associated with lower PCa risk in a dose-dependent fashion. PMID- 28024968 TI - Assessing the Variability in Insurance Coverage Transparency for Male Sexual Health Conditions in the United States. AB - OBJECTIVE: To determine the degree of transparency of health insurance policies regarding coverage of male sexual health conditions, we examined the publicly available policy coverage documents of the largest U.S. medical insurance plans. METHODS: We selected 2 index patients across the male sexual health spectrum: (1) a phosphodiesterase type 5 refractory erectile dysfunction (ED) patient requiring intracavernosal injection therapy or penile prosthesis and (2) a 50-year-old male patient with laboratory-confirmed, symptomatic hypogonadism requiring testosterone replacement therapy as defined by endocrine society criteria. We researched the policy documents regarding coverage for standard therapies. We used breast reconstruction after mastectomy as a control. RESULTS: We queried the publicly available policy statements for 84 of the largest health-care plans in the United States. Whereas breast reconstruction policies are publicly available for 94% of the plans examined, policies of only 39% of the plans for advanced ED treatment options and 62% for hypogonadism are publicly available. Of the plans that had publicly accessible data for ED coverage, 85% viewed penile prosthesis and intracavernosal injection as medically necessary, whereas 91% viewed androgen replacement as medically necessary for our index patient. CONCLUSION: There is a lack of transparency among medical insurers regarding coverage of ED and hypogonadism in stark contrast to reconstructive breast surgery. PMID- 28024969 TI - Ultrasound Guidance Reduces Percutaneous Nephrolithotomy Cost Compared to Fluoroscopy. AB - OBJECTIVE: To examine the cost factors associated with ultrasound and fluoroscopic guidance for percutaneous nephrolithotomy (PCNL) and to determine which method can be performed at a lower cost per case. METHODS: A cost comparison study was performed utilizing clinical data from a prospectively maintained research database. We included the most recent 33 consecutive ultrasound-guided PCNL cases in 2016 and the most recent 40 consecutive fluoroscopy-guided PCNL cases before the operative surgeon transitioned to ultrasound guidance in May 2014. The total operative time and clinical outcomes were examined. Costs were extracted from the institution accounting systems and given a uniform multiplier to protect institutional financial reporting confidentiality. Comparisons were made using the Student t test and the chi squared test. RESULTS: After excluding outliers, 71 PCNL procedures were included in the analysis. Demographic data and stone characteristics were not different between ultrasound-guided and fluoroscopy-guided groups. However, the mean operative time for ultrasound-guided PCNL was significantly shorter (99.8 +/- 27.0 vs 144.9 +/- 55.1 minutes, P < .05). When capital equipment costs were included, the mean total cost per case of ultrasound-guided PCNL was approximately 30% less than fluoroscopy-guided PCNL (simulated costs with a uniform multiplier; $5258.90 +/- 957.12 vs $7508.60 +/- 1163.83, P < .05). Postoperative clinical outcomes were comparable between the 2 groups. CONCLUSION: When capital costs are included, ultrasound-guided PCNL can produce comparable clinical outcomes to fluoroscopy-guided procedures at a lower cost to the institution. Shorter operative time drives significant savings with the adoption of ultrasound guidance, which may be magnified with increasing case volume. Using ultrasound imaging during PCNL may be more cost-effective compared to fluoroscopy and warrants further study. PMID- 28024970 TI - Unilateral Nasal Congestion and Headache: Renal Cell Carcinoma Metastasis to the Sinuses. PMID- 28024971 TI - In commemoration of completion of the genetic code, and in memory of Prof. Brian Clark. AB - While we celebrate the 20th anniversary of the complete decoding of the genetic code, we should also commemorate Prof. Brian Clark for his remarkable contributions to this historic landmark in life sciences, as well as to the global collaboration on sciences. As an international citizen and a great scientist, Prof. Brian Clark will live for ever in the hearts of all his friends and students. PMID- 28024972 TI - Efficacy and Complications of Endoscopic Skull Base Surgery for Giant Pituitary Adenomas. AB - OBJECTIVE: We report surgical results and complications of endoscopic endonasal skull base surgery for giant pituitary adenomas. METHODS: This study included 34 pituitary adenomas >40 mm treated by endoscopic endonasal skull base surgery between 2002 and 2015. Removal rates, symptoms, and complications were analyzed by direction of tumor extension. RESULTS: Average tumor size was 45.5 mm. Near total resection was achieved in 16 of 34 (47.1%) cases. Near-total resection was achieved significantly more often in anterior extension types and round tumor in superior extension types compared with multiple extension types. The average residual amount in 18 partial resection cases was 30.2% of preoperative volume, with no significant difference between groups. Regrowth after partial resection occurred in 8 cases, but repeated surgery or stereotactic radiotherapy controlled tumor growth and improved symptoms. Postoperative improvement of visual field deficits was achieved in 23 of 25 (92.0%) cases. Postoperative complications included visual deterioration (n = 1), cerebrospinal fluid leakage (n = 2), and cerebral infarction secondary to perforator injury (n = 2). Symptomatic intratumoral hemorrhage occurred in 1 multiple extension type. CONCLUSIONS: Endoscopic endonasal skull base surgery enables less invasive and safer removal of various extension types of giant pituitary adenomas. Preservation of visual function is essential. Two-stage surgery or partial resection with additional treatments is possible without complications if a sufficient amount of resection is performed. In cases in which insufficient resection may be expected, alternative treatment, including combined-simultaneous resection, should be considered. PMID- 28024973 TI - Is Intravenous Tissue Plasminogen Activator Still Relevant for Mechanical Embolectomy Stroke Candidates? PMID- 28024974 TI - Dual-Image Videoangiography During Intracranial Microvascular Surgery. AB - OBJECTIVE: Indocyanine green videoangiography (ICG-VA) is a valuable tool to assess vessel and aneurysm patency during neurovascular surgical procedures. However, ICG-VA highlights vascular structures, which appear white over a black background. Anatomic relationships are sometimes difficult to understand at first glance. Dual-image videoangiography (DIVA) enables simultaneous visualization of light and near-infrared fluorescence images of ICG-VA. METHODS: The DIVA system was mounted on an OPMI Pentero Flow 800 intraoperative microscope. DIVA was used during microsurgical procedures on 5 patients who were operated for aneurysm clipping and superficial temporal artery-middle cerebral artery bypass. RESULTS: DIVA provides real-time simultaneous visualization of aneurysm and vessels and surrounding structures including brain, nerves, and surgical clips. Although visual contrast between vessels and background is higher with standard black-and white imaging, DIVA makes it easier to understand anatomic relationships between intracranial structures. DIVA also provides better vision of the depth of field. CONCLUSIONS: DIVA has the potential to become a widely used intraoperative tool to check patency of intracranial vessels. It should be considered as an adjunct to standard ICG-VA for better understanding of vascular anatomy in relation to surrounding structures and can have an impact on decision making during surgery. PMID- 28024975 TI - Trump, Obamacare, and the Market for "Lemons" Paradigm: Current Perspectives on the Future of U.S. Health Care. PMID- 28024976 TI - Neurologic Functional Outcomes of Decompressive Hemicraniectomy Versus Conventional Treatment for Malignant Middle Cerebral Artery Infarction: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The aims of this study were to evaluate decompressive hemicraniectomy (DHC) versus conventional treatment (CT) for patients with malignant middle cerebral artery (MCA) infarction and to investigate the impact of age and surgical timing on neurologic function and mortality. METHODS: We searched English and Chinese databases for randomized controlled trials or observational studies published before August 2016. Outcomes included good functional outcome (GFO), mortality, and National Institutes of Health Stroke Scale and Barthel index scores. RESULTS: This meta-analysis included 25 studies (1727 patients). There were statistically significant differences between DHC and CT groups in terms of GFO (P < 0.0001), mortality (P < 0.00001), and National Institutes of Health Stroke Scale and Barthel index scores (P < 0.0001) at different follow-up points. Significant differences were observed between the groups in survival with moderately severe disability (P < 0.00001); no differences were observed in survival with severe disability. In the subgroup analysis, in the DHC group, GFO was less in patients >60 years old (9.65%) versus <=60 years old (38.94%); more patients >60 years old had moderately severe or severe disability (55.27%) compared with patients <=60 years old (44.21%). CONCLUSIONS: DHC could significantly improve GFO and reduces mortality of patients of all ages with malignant MCA infarction compared with CT, without increasing the number of patients surviving with severe disability. However, patients in the DHC group more frequently had moderately severe disability. Patients >60 years old with malignant MCA infarction had a higher risk of surviving with moderately severe or severe disability and less GFO. PMID- 28024977 TI - External Ventricular Drain-Related Infection in Spontaneous Intracerebral Hemorrhage. AB - OBJECTIVE: We aimed to analyze infection rates in patients with spontaneous intracranial hemorrhage who underwent surgical external ventricular drain (EVD) placement. METHODS: This prospective study included 94 consecutive patients who required an EVD for spontaneous intracranial hemorrhage at the Neurosurgery Department of Hospital Cristo Redentor, Porto Alegre, Rio Grande do Sul, Brazil. RESULTS: The mean duration of EVD use was 7 days. Overall sample mortality was 45%, and overall infection rate was 36%. Patients who had an EVD in place >10 days had higher odds of infection than patients who had an EVD in place <=10 days (odds ratio = 3.1, 95% confidence interval, 1.1-8.7). Culture positivity rate was 5.3%. CONCLUSIONS: Our findings suggest that EVD infection is a very common complication, occurring in 36.2% of cases. We adopted ventriculitis as the standard diagnosis, as advocated by the U.S. Centers for Disease Control and Prevention. Considering the high lethality associated with intracranial hemorrhage, use of a more aggressive treatment protocol for this patient population might improve morbidity and mortality rates. PMID- 28024978 TI - Pilocytic Astrocytoma of Fornix Mimicking a Colloid Cyst: Report of 2 Cases and Review of the Literature. AB - BACKGROUND: Colloid cyst is a gelatin-containing cyst in the brain almost always found in the third ventricle. The specific shape and location of these cysts, a round well-delineated mass in the rostral part of the third ventricle adjacent to the foramen of Monro, on imaging are the main findings for diagnosis. Several masses of the third ventricle masquerading colloid cysts on images have been reported. Based on different surgical approaches, preoperative misdiagnosis of colloid cyst may have great impact on prognosis. METHODS: We report 2 cases that presented with severe headache and hydrocephalus, and their preoperative images were highly indicative of colloid cyst. RESULTS: Histopathologic investigations after tumor resection showed pilocytic astrocytoma of fornix in both cases. CONCLUSIONS: Fifteen cases of colloid cyst misdiagnosis with other masses have been reported thus far; among them, 2 cases were pilocytic astrocytoma. In this study we report 2 other cases. Furthermore, we discuss additional clues helping to differentiate pilocytic astrocytoma from colloid cyst on images. PMID- 28024979 TI - Viewing the effects of species loss in complex ecological networks. AB - Species loss is becoming a major threat to ecosystems. An urgent task in ecology is to predict the consequence of species loss which requires an extending of our traditional study of the topology of network structure to the population dynamic analyses in complex food webs. Here, via numerical simulations of the model combining structural networks with nonlinear bioenergetic models of population dynamics, we analyzed the secondary effects of species removal on biomass distribution and population stability, as well as the factors influencing these effects. We found that the biomass of target species, the nutrient supply, and the trophic level of target species were the three most significant determiners for the effects of species loss. Species loss had large negative effect on the biomass of the species with small biomass or intermediate trophic levels, especially in infertile environment. The population stability of the species with large biomass or low trophic level is easily to be influenced especially in nutrient-rich environment. Our findings indicate the species which are easily to be affected by species loss in food webs, which may help ecologists to outline a better conservation policy. PMID- 28024980 TI - Validation of novel cost-effective antimicrobial gradient strips for the determination of carbapenem susceptibility in Enterobacteriaceae. AB - OBJECTIVES: The aim of this study was to validate the use of LML antimicrobial gradient strips for quantitative determination of carbapenem susceptibility in Enterobacteriaceae. METHODS: A total of 95 non-redundant Enterobacteriaceae strains isolated during 2012-2014 were used for this validation study. Initially, LML antimicrobial gradient strips were validated for their performance in comparison with the agar dilution method. The test strip was then validated in comparison with broth microdilution (BMD) and Etest with 24 selected strains using the same inocula and other laboratory parameters. RESULTS: The LML strip showed 83%, 68% and 86% essential agreement (within +/-1 log2 dilution) with the reference methods of agar dilution, BMD and Etest, respectively; furthermore, essential agreement was >90% within +/-2 log2 dilution. Categorical agreement was >=87% with all reference methods according to Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. However, the meropenem strip requires performance improvements to fulfil US Food and Drug Administration (FDA) and International Organization for Standardization (ISO) requirements for an antimicrobial susceptibility test device. CONCLUSIONS: In LML antimicrobial gradient strip minimum inhibitory concentrations (MICs) were comparable with Etest MICs and it might serve as a reasonable, cost-effective alternative to Etest for quantitative determination of carbapenem susceptibility in Enterobacteriaceae. PMID- 28024981 TI - The new Korean action plan for containment of antimicrobial resistance. AB - BACKGROUND: The Korean national action plan on antimicrobial resistance (AMR) was established on 11 August 2016 by the Korean Ministry of Health and Welfare. METHODS AND RESULTS: This article briefly describes the current status of AMR in Korea and introduces six objectives of the action plan, including the prudent use of antimicrobial medicines, prevention of the spread of AMR, strengthening surveillance programmes, awareness improvement, strengthening research and development, and enhancement of international collaboration. CONCLUSIONS: Integrated multisectoral principles are applied to fight AMR more effectively. This 5-year national AMR action plan will be the cornerstone of public health in Korea. PMID- 28024982 TI - Monte Carlo optimization of shielding for novel industrial free release measurement facility. AB - Monte Carlo (MC) simulations were done for the optimization of shielding configuration of a novel industrial radionuclide-specific pre-selection free release measurement facility. The shielding is made from unique bricks of concrete with very low specific activity of natural radionuclides. The final configuration was selected as a compromise between shielding volume and the simulated 1461keV full-energy peak detector count rates of natural 40K. PMID- 28024983 TI - Stringent control of FLP recombinase in Escherichia coli. AB - Site specific recombinases are invaluable tools in molecular biology, and are emerging as powerful recorders of cellular events in synthetic biology. We have developed a stringently controlled FLP recombinase system in Escherichia coli using an arabinose inducible promoter combined with a weak ribosome binding site. PMID- 28024984 TI - Enhancing yields of low and single copy number plasmid DNAs from Escherichia coli cells. AB - Many plasmids used for gene cloning and heterologous protein expression in Escherichia coli cells are low copy number or single copy number plasmids. The extraction of these types of plasmids from small bacterial cell cultures produces low DNA yields. In this study, we have quantitated yields of low copy and single copy number plasmid DNAs after growth of cells in four widely used broths (SB, SOC, TB, and 2xYT) and compared results to those obtained with LB, the most common E. coli cell growth medium. TB (terrific broth) consistently generated the greatest amount of plasmid DNA, in agreement with its ability to produce higher cell titers. The superiority of TB was primarily due to its high levels of yeast extract (24g/L) and was independent of glycerol, a unique component of this broth. Interestingly, simply preparing LB with similarly high levels of yeast extract (LB24 broth) resulted in plasmid yields that were equivalent to those of TB. By contrast, increasing ampicillin concentration to enhance plasmid retention did not improve plasmid DNA recovery. These experiments demonstrate that yields of low and single copy number plasmid DNAs from minipreps can be strongly enhanced using simple and inexpensive media. PMID- 28024985 TI - Adverse events of self-expandable esophageal metallic stents in patients with long-term survival from advanced malignant disease. AB - BACKGROUND AND AIMS: Self-expandable metallic stents are considered the best palliative treatment of dysphagia for patients with advanced esophageal cancer. Adverse events (AEs) are a major concern, especially in patients with better prognosis and longer survival. The present study aimed to evaluate the AEs of patients who survived longer than 6 months with esophageal stents in place. METHODS: This is a retrospective analysis of a prospectively collected database including all patients submitted to esophageal stent placement for the palliation of malignant diseases during the period from February 2009 to February 2014 at a tertiary care academic center who had stents longer than 6 months. RESULTS: Sixty three patients were included. Mean follow-up was 10.7 months. Clinical success was achieved in all patients, and the median stent patency was 7.1 months. AEs occurred in 40 patients (63.5%), totaling 62 AEs (mean, 1.5 AEs per patient). Endoscopic management of AEs was successful in 84.5% of cases, with a mean of 1.6 reinterventions per patient. The univariate analysis revealed that performance status, age, and post-stent radiotherapy presented a trend to higher risk of AEs. The multivariate analysis revealed that only performance status was associated with AEs (P = .025; hazard ratio, 4.1). CONCLUSIONS: AEs are common in patients with long-term esophageal stenting for malignancy. However, AEs were not related to higher mortality rate, and most AEs could be successfully managed by endoscopy. Only performance status was a risk factor for AEs. Our data suggest that metallic stenting is a valid option for the treatment of malignant esophageal conditions, even when survival longer than 6 months is expected. PMID- 28024986 TI - Natural history of diminutive and small colorectal polyps: a systematic literature review. AB - BACKGROUND AND AIMS: Diminutive (1-5 mm) and small (6-9 mm) polyps comprise 90% of detected lesions during colonoscopy and rarely contain advanced histology or colorectal cancer (CRC). Routine removal of these lesions results in a significant burden to colonoscopy programs. At the same time, the risk for progression of these polyps to CRC is unclear. We performed a systematic review to explore the natural history of diminutive and small colorectal polyps. METHODS: We searched MEDLINE and EMBASE for studies investigating the natural history of colorectal polyps. Studies were considered eligible when they assessed patients with 1- to 9-mm polyps that were not treated with polypectomy and that underwent follow-up. We excluded studies in patients with inflammatory bowel disease, polyposis syndromes, and previously diagnosed CRC. We independently extracted study characteristics and evaluated CRC and advanced adenoma (size >= 10 mm, containing high-grade dysplasia or villous features) as outcome parameters. RESULTS: Of 8775 retrieved studies, 9 studies with 721 patients were included that prospectively evaluated the evolution of 1- to 9-mm polyps. In 7 studies the average duration of observation was 2 to 3 years. There was only 1 study in which 1 small polyp might have progressed to cancer. Of 1034 adenomas sized 1 to 9 mm in those studies, 6% progressed to advanced adenomas over time. CONCLUSIONS: Based on this systematic review, it appears that some 1- to 9-mm adenomas progress to advanced adenomas within 2 to 3 years. No information on long-term CRC transition rates was found. Defining the biologic significance of these polyps is needed to balance between benefits and harm of polypectomy. (PROSPERO database registration number: CRD42016036577.). PMID- 28024987 TI - Effects of high-intensity training on cardiovascular risk factors in premenopausal and postmenopausal women. AB - BACKGROUND: Menopause is associated with increased risk of cardiovascular disease and the causal factors have been proposed to be the loss of estrogen and the subsequent alterations of the hormonal milieu. However, which factors contribute to the deterioration of cardiometabolic health in postmenopausal women is debated as the menopausal transition is also associated with increased age and fat mass. Furthermore, indications of reduced cardiometabolic adaptations to exercise in postmenopausal women add to the adverse health profile. OBJECTIVE: We sought to evaluate risk factors for type 2 diabetes and cardiovascular disease in late premenopausal and early postmenopausal women, matched by age and body composition, and investigate the effect of high-intensity training. STUDY DESIGN: A 3-month high-intensity aerobic training intervention, involving healthy, nonobese, late premenopausal (n = 40) and early postmenopausal (n = 39) women was conducted and anthropometrics, body composition, blood pressure, lipid profile, glucose tolerance, and maximal oxygen consumption were determined at baseline and after the intervention. RESULTS: At baseline, the groups matched in anthropometrics and body composition, and only differed by 4.2 years in age (mean [95% confidence limits] 49.2 [48.5-49.9] vs 53.4 [52.4-54.4] years). Time since last menstrual period for the postmenopausal women was (mean [95% confidence limits] 3.1 [2.6-3.7] years). Hormonal levels (estrogen, follicle stimulation hormone, luteinizing hormone) confirmed menopausal status. At baseline the postmenopausal women had higher total cholesterol (P < .001), low-density lipoprotein-cholesterol (P < .05), and high-density lipoprotein-cholesterol (P < .001) than the premenopausal women. The training intervention reduced body weight (P < .01), waist circumference (P < .01), and improved body composition by increasing lean body mass (P < .001) and decreasing fat mass (P < .001) similarly in both groups. Moreover, training resulted in lower diastolic blood pressure (P < .05), resting heart rate (P < .001), total cholesterol (P < .01), low-density lipoprotein-cholesterol (P < .01), total cholesterol/high-density lipoprotein cholesterol index (P < .01), and improved plasma insulin concentration during the oral glucose tolerance test (P < .05) in both groups. CONCLUSION: Cardiovascular risk factors are similar in late premenopausal and early postmenopausal women, matched by age and body composition, with the exception that postmenopausal women have higher high- and low-density lipoprotein-cholesterol levels. A 3-month intervention of high-intensity aerobic training reduces risk factors for type 2 diabetes and cardiovascular disease to a similar extent in late premenopausal and early postmenopausal women. PMID- 28024988 TI - Delayed villous maturation in term placentas exposed to opioid maintenance therapy: a retrospective cohort study. AB - BACKGROUND: Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy. OBJECTIVE: This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone. STUDY DESIGN: This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n = 86) or methadone (n = 268) versus women without opioid use disorder (n = 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone. RESULTS: Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20 2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52-3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64 3.31). Results were similar after accounting for smoking. CONCLUSION: Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone). PMID- 28024989 TI - Reducing health disparities by removing cost, access, and knowledge barriers. AB - BACKGROUND: While the rate of unintended pregnancy has declined in the United States in recent years, unintended pregnancy among teens in the United States is the highest among industrialized nations, and disproportionately affects minority teens. OBJECTIVE: Our objective of this secondary analysis was to estimate the risk of unintended pregnancy for both Black and White teens age 15-19 years when barriers to access, cost, and knowledge are removed. Our hypothesis was that the Black-White disparities would be reduced when access, education, and cost barriers are removed. STUDY DESIGN: We performed an analysis of the Contraceptive CHOICE Project database. CHOICE is a longitudinal cohort study of 9256 sexually active girls and women ages 14-45 years in the St Louis, MO, region from 2007 through 2013. Two measures of disparities were used to analyze teenage pregnancy rates and pregnancy risk from 2008 through 2013 among teens ages 15-19 years. These rates were then compared to the rates of pregnancy among all sexually active teens in the United States during the years 2008, 2009, 2010, and 2011. We estimated an absolute measure (rate difference) and a relative measure (rate ratio) to examine Black-White disparities in the rates of unintended pregnancy. RESULTS: While national rates of unintended pregnancy are decreasing, racial disparities in these rates persist. The Black-White rate difference dropped from 158.5 per 1000 in 2008 to 120.1 per 1000 in 2011; however, the relative ratio disparity decreased only from 2.6-2.5, suggesting that Black sexually active teens in the United States have 2.5 times the rate of unintended pregnancy as White teenagers. In the CHOICE Project, there was a decreasing trend in racial disparities in unintended pregnancy rates among sexually active teens (age 15-19 years): 2008 through 2009 (rate difference, 18.2; rate ratio, 3.7), 2010 through 2011 (rate difference, 4.3; rate ratio, 1.2), and 2012 through 2013 (rate difference, -1.5; rate ratio, 1.0). CONCLUSION: When barriers to cost, access, and knowledge were removed, such as in the Contraceptive CHOICE Project, Black White disparities in unintended pregnancy rates among sexually active teens were reduced on both absolute and relative scales. The rate of unintended pregnancy was almost equal between Black and White teens compared to large Black-White disparities on the national level. PMID- 28024990 TI - Molecular approaches for the analysis of airborne pollen: A case study of Juniperus pollen. AB - BACKGROUND: Pollen monitoring is a common and vital tool in the field of allergy, creating awareness in pollen sensitive individuals. Traditionally, pollen monitoring has been based on conventional microscopic counting techniques that are labor intensive and limited in the identification to the genus or family level. Molecular techniques provide an alternative approach that is less labor intensive and enable identification of any species by its genetic fingerprint. OBJECTIVE: To use quantitative polymerase chain reaction (qPCR) to evaluate pollen concentrations in air samples. METHODS: Juniperus pollen was selected as our model because of the importance of this pollen in the southcentral United States. We analyzed 105 air samples collected with a Burkard spore trap from 2013 to 2015 using species-specific primers and probes. To evaluate the feasibility of a molecular approach, we used duplicate air samples that allowed us to compare results from classical identification based on light microscopy with our qPCR results. RESULTS: Pollen concentrations from the qPCR data were significantly correlated with concentrations determined through light microscopy (R = 0.902, P < .001). We also confirmed an overlap in the pollination seasons between Juniperus ashei and Juniperus pinchotii and between J ashei and Juniperus virginiana. CONCLUSION: We found that this method correctly identified different Juniperus species present in mixed air samples in the southcentral United States, an accomplishment that cannot be achieved using microscopic identification. We conclude that the qPCR method is more accurate and sensitive than current pollen monitoring techniques and, therefore, has the potential to be used in various pollen monitoring stations. PMID- 28024991 TI - Acute renal dysfunction caused by nonsucrose intravenous immunoglobulin in common variable immunodeficiency. PMID- 28024992 TI - Spironolactone. AB - Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com). PMID- 28024993 TI - PC-FACS. AB - PC-FACS(FastArticleCriticalSummaries for Clinicians inPalliativeCare) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at pc facs@aahpm.org. PMID- 28024994 TI - Teaching the Art of Difficult Family Conversations. AB - CONTEXT: Difficult family conversations are a challenge for even the most seasoned clinicians. Teaching the skills of successful communication between providers, family members, and patients is a vital component of medical education. However, traditional teaching methods using didactics and expert role modeling are often inadequate. OBJECTIVES: The train-the-educator workshop aimed to teach educators how to create and conduct workshops on facilitating difficult family conversations that target their own learners' needs. METHODS: This three hour workshop included instruction on scenario writing and on the use of standardized actors as patients and family members. Workshop leaders presented examples of commonly encountered clinical scenarios where difficult information is discussed. The session used experiential teaching techniques. Outcomes were measured by qualitative discussions and a questionnaire to demonstrate communication skills learned from the sessions. RESULTS: The workshop was well received by participants who consisted of educators attending the annual meeting of the Pediatric Academic Societies in May 2016. Evaluations revealed that 92% of participants agreed or strongly agreed that the workshop achieved the learning objectives. All participants believed that the workshop increased their knowledge, competency, and skills in teaching and facilitation as an educator, with 86% of participants planning to apply the skills toward curriculum development. The major themes that participants learned centered on facilitation skills as an educator and techniques on how to communicate during challenging family meetings (86% of comments). CONCLUSION: This train-the-educator workshop addresses a critical need in both palliative care and general medicine by enhancing the educators' skills in designing and implementing a curriculum on communication skills of health care providers using experiential techniques with formative feedback. The authors hope that by outlining the implementation of this three-hour interactive format, future educators will adapt and use this workshop as it works best for their learners. PMID- 28024995 TI - Synergistic interaction between amyloid and tau predicts the progression to dementia. AB - INTRODUCTION: Recent literature proposes that amyloid beta (Abeta) and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia. METHODS: We stratified 314 mild cognitive impairment individuals using [18F]florbetapir positron emission tomography Abeta imaging and cerebrospinal fluid p-tau. Regression and voxel based logistic regression models with interaction terms evaluated 2-year changes in cognition and clinical status as a function of baseline biomarkers. RESULTS: We found that the synergism between [18F]florbetapir and p-tau, rather than their additive effects, was associated with the cognitive decline and progression to AD. Furthermore, voxel-based analysis revealed that temporal and inferior parietal were the regions where the synergism determined an increased likelihood of developing AD. DISCUSSION: Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between Abeta and p-tau proteins. PMID- 28024996 TI - Meta-Analysis of Prevalence of Erectile Dysfunction in Mainland China: Evidence Based on Epidemiological Surveys. AB - INTRODUCTION: The epidemiologic characteristics of erectile dysfunction (ED) in mainland China remain incompletely understood. AIM: To evaluate the overall prevalence and determine the severity of ED in mainland China. METHODS: An extensive database search was performed of PubMed, Embase, the Chinese National Knowledge Infrastructure (CNKI) database, the WanFang database, the Chinese Biological Medical Literature (CBM) database, and the Chongqing VIP using the following terms: erectile dysfunction, prevalence, epidemiology, epidemiological, and China. Study quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Data were pooled for the random-effects model. Sensitivity analyses were conducted to assess potential bias. MAIN OUTCOME MEASURES: All survey studies reporting on the prevalence of ED in mainland China were included. Data extraction was performed independently by two of the authors, and conflicts were resolved by another author. RESULTS: Of 2,155 retrieved articles, 25 were included in this meta-analysis with a total of 48,254 participants. The pooled prevalence of ED in men was 49.69% (95% CI = 39.29-60.10). The occurrence rates of ED in age groups younger than 30, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and at least 70 years were 20.86%, 25.30%, 40.48%, 60.12%, 79.10%, and 93.72%, respectively. The severity-specific prevalences of mild, moderate, and severe ED were 32.54%, 9.86%, and 13.97%, respectively. Moreover, the prevalences reported by different diagnostic methods were 14.19% for self-reports, 44.60% for the Chinese Index of Erectile Function, and 49.91% for the International Index of Erectile Function-5. The prevalence map based on a geographic information system showed an unequal geographic distribution. CONCLUSION: ED is highly prevalent in mainland China, and its prevalence increases with age. More high-quality surveys on ED with larger samples throughout mainland China are needed to confirm these findings. PMID- 28024997 TI - Androgen Receptor (AR) Gene (CAG)n and (GGN)n Length Polymorphisms and Symptoms in Young Males With Long-Lasting Adverse Effects After Finasteride Use Against Androgenic Alopecia. AB - INTRODUCTION: Long-term adverse symptoms of men who used oral finasteride against androgenic alopecia have been recently described as post-finasteride syndrome (PFS). AIM: To determine whether (CAG)n-rs4045402 and (GGN)n-rs3138869 polymorphisms in the androgen receptor (AR) gene are implicated in PFS. METHODS: AR polymorphisms were studied according to PFS symptoms in 66 white participants (31.8% Italian, 28.8% American, and 39.4% other). MAIN OUTCOME MEASURES: Symptoms were investigated by an ad hoc 100-item questionnaire and the Arizona Sexual Experience Scale and Aging Male Symptom Scale (AMS). (CAG)n and (GGN)n repeats were categorized as short ([CAG]9-19, [GGN]<23), medium ([CAG]20-24, [GGN]23), or long ([CAG]25-37, [GGN]>23). RESULTS: Median age was 32 years, duration of finasteride use was 360 days, and time from finasteride discontinuation was 1,053 days. We observed several frequency differences in symptoms according to (CAG)n and (GGN)n repeat numbers. Three AMS items were worse for medium (GGN)23 than for long (GGN)>23 carriers and one item was worse for short (GGN)<23 carriers. The AMS item for decrease in sexual desire or libido was worse for short (CAG)9-19 carriers than for medium (CAG)20-24 carriers. Through the ad hoc questionnaire, significant findings in (CAG)n and/or (GGN)n repeats were obtained for penile discomfort, loss of scrotal sensitivity, scrotal discomfort, less pubic hair, loss of perceived perineal fullness, increased sperm density, involuntary muscle spasms, loss of muscle tone, increased weight (>2 kg), increased skin dryness, and onset of symptoms after finasteride use. CONCLUSION: This study showed that short and/or long (CAG)n and (GGN)n repeats had different frequencies according to symptoms reported by patients with PFS, likely reflecting the vast array of genes modulated by the AR. This study showed a U-curvilinear profile of (CAG)n repeats for skin dryness symptoms, where the two extremes exhibited a worse condition than medium repeats. Further studies are necessary to investigate the PFS pathophysiology using a precision medicine approach. PMID- 28024999 TI - Diversity and endemicity in the scorpion fauna of Vietnam. A preliminary synopsis. AB - A faunistic inventory is proposed for the known Vietnamese scorpion species. The aim of this contribution is to bring an up-to-date checklist of all known species in Vietnam, prior to a more detailed study of the Vietnamese fauna to be performed by one of the authors (T.-H.T.) in the context of the preparation of a doctoral degree. Final taxonomic decisions should be taken at the end of the doctoral dissertation. PMID- 28024998 TI - Development and validation of a cell-based fluorescent method for measuring antibody affinity. AB - Monoclonal antibodies have become essential tools for diagnostic and therapeutic purposes. Antibody affinity is one of the critical factors influencing the therapeutic success of tumor-targeting antibodies. Therefore, developing an accurate and reliable method for determining antibody affinity is crucial. In this study, we describe a fluorescent cell-based immunosorbent assay that can accurately measure antibody affinity (KD) in the nanomolar range. This method involves the addition of fluorescently labeled antibodies to antigen-positive and antigen-negative cell lines fixed on 96-well plates. The fluorescent signals from nonspecific binding to negative control cell lines is subtracted from the specific binding to the antigen-positive cell lines. The KD values obtained by this method were comparable with values obtained by the flow cytometry and radioactive (I125) scatchard assay. Our results demonstrate that this modified cell-based fluorescent method allows for a convenient and efficient identification of therapeutically relevant leads. PMID- 28025000 TI - Determination of water-soluble and fat-soluble vitamins in tears and blood serum of infants and parents by liquid chromatography/mass spectrometry. AB - Tears serve as a viable diagnostic fluid with advantages including less invasive sample to collect and less complex to prepare for analysis. Several water-soluble and fat-soluble vitamins were detected and quantified in human tears and compared with blood serum levels. Samples from 15 family pairs, each pair consisting of a four-month-old infant and one parent were analyzed; vitamin concentrations were compared between tears and blood serum for individual subjects, between infants and parents, and against self-reported dietary intakes. Water-soluble vitamins B1, B2, B3 (nicotinamide), B5, B9 and fat-soluble vitamin E (alpha-tocopherol) were routinely detected in tears and blood serum while fat-soluble vitamin A (retinol) was detected only in blood serum. Water-soluble vitamin concentrations measured in tears and blood serum of single subjects were comparable, while higher concentrations were measured in infants compared to their parents. Fat soluble vitamin E concentrations were lower in tears than blood serum with no significant difference between infants and parents. Serum vitamin A concentrations were higher in parents than infants. Population trends were compiled and quantified using a cross correlation factor. Strong positive correlations were found between tear and blood serum concentrations of vitamin E from infants and parents and vitamin B3 concentrations from parents, while slight positive correlations were detected for infants B3 and parents B1 and B2 concentrations. Correlations between infants and parents were found for the concentrations of B1, B2, B3, and E in tears, and the concentrations of B2, A, and E in blood serum. Stronger vitamin concentration correlations were found between infants and parents for the breast-fed infants, while no significant difference was observed between breast-fed and bottle-fed infants. This work is the first to demonstrate simultaneous vitamin A, B, and E detection and to quantify correlations between vitamin concentrations in tears and blood serum. Our results suggest that tears are a viable biofluid to monitor nutritional health because they sufficiently mirror blood serum data and may enhance the speed of deficiency diagnoses. PMID- 28025001 TI - A molecular phylogeny of Dichocarpum (Ranunculaceae): Implications for eastern Asian biogeography. AB - East Asia is characterized by high levels of species diversity and endemism. However, the biogeographical patterns and processes underlying the distribution of biodiversity within the area are still poorly known. In this study, we used plastid (matK, trnL-F, and trnH-psbA) and nuclear (ITS) DNA sequences to investigate the historical biogeography of Dichocarpum (Ranunculaceae), an eastern Asian endemic genus throughout warm-temperate and subtropical forests of the area. Phylogenetic analyses strongly support Dichocarpum as monophyletic, which contains two major clades. Clade I corresponds to section Hutchinsonia, and clade II includes sections Dichocarpum and Fargesia. Section Dichocarpum and its subsections Dalzielia and Dichocarpum are not recognized as monophyletic. Our results suggest that the most recent common ancestor of Dichocarpum occurred in central China and Japan in the earliest Early Miocene, and thus support an ancient vicariance event between Japan and China. Within mainland China, three migrations at the species level were hypothesized to explain the expansion of Dichocarpum from central China to southeastern Yunnan, Hengduan mountains, and eastern Himalaya. These migration events occurred in the Late Miocene to Early Pliocene, which may be associated with the uplift of the southeastern Qinghai Tibetan Plateau and accordingly the expansion of subtropical forests in China around that period. A migration or dispersal from central China to Taiwan was inferred in the Early Pleistocene, which supports the close floristic affinity between Taiwan and mainland China. This study contributes to our knowledge on the historical biogeography of plants in eastern Asia. PMID- 28025002 TI - Sulfonamide inhibition profile of the gamma-carbonic anhydrase identified in the genome of the pathogenic bacterium Burkholderia pseudomallei the etiological agent responsible of melioidosis. AB - A new gamma-carbonic anhydrase (CA, EC 4.1.1.1) was cloned and characterized kinetically in the genome of the bacterial pathogen Burkholderia pseudomallei, the etiological agent of melioidosis, an endemic disease of tropical and sub tropical regions of the world. The catalytic activity of this new enzyme, BpsCAgamma, is significant with a kcat of 5.3*105s-1 and kcat/Km of 2.5*107M-1*s 1 for the physiologic CO2 hydration reaction. The inhibition constant value for this enzyme for 39 sulfonamide inhibitors was obtained. Acetazolamide, benzolamide and metanilamide were the most effective (KIs of 149-653nM) inhibitors of BpsCAgamma activity, whereas other sulfonamides/sulfamates such as ethoxzolamide, topiramate, sulpiride, indisulam, sulthiame and saccharin were active in the micromolar range (KIs of 1.27-9.56MUM). As Burkholderia pseudomallei is resistant to many classical antibiotics, identifying compounds that interfere with crucial enzymes in the B. pseudomallei life cycle may lead to antibiotics with novel mechanisms of action. PMID- 28025003 TI - Chemical synthesis and biological evaluation of omega-hydroxy polyunsaturated fatty acids. AB - omega-Hydroxy polyunsaturated fatty acids (PUFAs), natural metabolites from arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were prepared via convergent synthesis approach using two key steps: Cu mediated CC bond formation to construct methylene skipped poly-ynes and a partial alkyne hydrogenation where the presence of excess 2-methyl-2-butene as an additive that is proven to be critical for the success of partial reduction of the poly-ynes to the corresponding cis-alkenes without over-hydrogenation. The potential biological function of omega-hydroxy PUFAs in pain was evaluated in naive rats. Following intraplantar injection, 20-hydroxyeicosatetraenoic acid (20 HETE, omega-hydroxy ARA) generated an acute decrease in paw withdrawal thresholds in a mechanical nociceptive assay indicating pain, but no change was observed from rats which received either 20-hydroxyeicosapentaenoic acid (20-HEPE, omega hydroxy EPA) or 22-hydroxydocosahexaenoic acid (22-HDoHE, omega-hydroxy DHA). We also found that both 20-HEPE and 22-HDoHE are more potent than 20-HETE to activate murine transient receptor potential vanilloid receptor1 (mTRPV1). PMID- 28025004 TI - Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK). AB - Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26pmol/mg protein. PMID- 28025005 TI - Macroscopic and Histologic Analysis of Vessel Wall Reaction After Mechanochemical Endovenous Ablation Using the ClariVein OC Device in an Animal Model. AB - OBJECTIVE/BACKGROUND: Mechanochemical endovenous ablation (MOCA) has been developed as a tumescentless technique to ablate saphenous veins and to avoid heat induced complications and post-procedural pain. The mechanism of action of MOCA is poorly understood. The present experiments were conducted to determine the effect of MOCA on vein wall injury and sclerosis in an animal model. METHODS: A total of 36 lateral saphenous veins (LSVs) were treated in 18 goats according to the human protocol. Veins from nine goats were evaluated 45 min after the procedure, while in the remaining nine, the treated veins were evaluated 6 weeks later. All treated veins were divided equally over three treatment groups: (i) MOCA, (ii) mechanical ablation without the sclerosant, and (iii) liquid sclerotherapy alone. The histological effects of treatment on the vein wall were systematically evaluated. RESULTS: The average diameter of the LSV was 4.0 +/- 0.5 mm. Technical success was achieved in all but one LSV (35/36; 97%), with a median procedure time of 14 min (range 9-22 min). In the acute group, histological examination showed that mechanical ablation (alone or MOCA) induced severe injury to the endothelium in 82% but no damage to other layers of the vein wall. Mechanical ablation led to vasoconstriction. After 6 weeks follow-up, four of six MOCA treated veins were occluded. The occluded segments consisted mainly of fibrotic lesions probably evolved from organised thrombus. No occlusions were observed after sclerotherapy or mechanical treatment alone. No major complications occurred during procedures or follow-up. CONCLUSION: MOCA is associated with an increased occlusion rate compared with its separated components of mechanical ablation or sclerotherapy. The occlusion consists of cellular fibrotic material likely to be evolved from organised thrombus with fibrotic alterations to the surrounding media and adventitia. This study underlines the hypothesis that the additive use of MOCA increases the effectiveness of sclerosants alone by inducing endothelial damage and probably vasoconstriction. PMID- 28025006 TI - Empathy, Schmempathy: Response to Zaki. PMID- 28025009 TI - Peri-operative care for patients undergoing lymphaticovenular anastomosis: A systematic review. AB - BACKGROUND: Lymphaticovenular anastomosis (LVA) is a supermicrosurgical procedure that involves the anastomosis of a functional lymphatic channel to a venule. Although peri-operative care might be an important contributor to the success of this technique, evidence about optimal peri-operative care seems limited. This review aims to summarize the peri-operative methods used by authors reporting on LVA. METHODS: A systematic search of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Peri-operative care used by authors was summarized and listed in a pre-defined form. Studies were also graded on quality of evidence by the GRADE system and a lymphedema surgery-specific system. RESULTS: In total, 22 studies were identified describing peri-operative measures. Although most authors were sparse in their description of peri-operative management, most recommended initiation of conventional compression therapy at 1-4 weeks after surgery. Prophylactic antibiotics, elevation of the affected limb, bandaging, low molecular-weight heparin, prostaglandin E1, and manual pressure therapy were also described. The quality of evidence of the included studies was low on average. CONCLUSION: Although supermicrosurgical LVAs are gaining in popularity, there are no high-quality prospective trials evaluating these new techniques and the description of peri-operative management is scarce. Of the available studies, a peri-operative management consisting of prophylactic antibiotics, elevation of the affected limb during night and hospital stay, and compression therapy 4 weeks post-surgery for 6 months seems to be preferred. Future studies should describe a detailed peri-operative protocol to allow for a better comparison between study results and to determine optimal peri-operative recommendations. PMID- 28025008 TI - Prolonged thoracic epidural analgesia for chest tube pain during pregnancy. PMID- 28025010 TI - The impact of resource quality on the evolution of virulence in spatially heterogeneous environments. AB - Understanding the drivers of parasite evolution and in particular disease virulence remains a major focus of evolutionary theory. Here, we examine the role of resource quality and in particular spatial environmental heterogeneity in the distribution of these resources on the evolution of virulence. There may be direct effects of resources on host susceptibility and pathogenicity alongside effects on reproduction that indirectly impact host-parasite population dynamics. Therefore, we assume that high resource quality may lead to both increased host reproduction and/or increased disease resistance. In completely mixed populations there is no effect of resource quality on the outcome of disease evolution. However, when there are local interactions higher resource quality generally selects for higher virulence/transmission for both linear and saturating transmission-virulence trade-off assumptions. The exception is that in castrators (i.e., infected hosts have no reproduction), higher virulence is selected for both low and high resource qualities at mixed local and global infection. Heterogeneity in the distribution of environment resources only has an effect on the outcome in castrators where random distributions generally select for higher virulence. Overall, our results further underline the importance of considering spatial structure in order to understand evolutionary processes. PMID- 28025007 TI - Brain Rhythms of Pain. AB - Pain is an integrative phenomenon that results from dynamic interactions between sensory and contextual (i.e., cognitive, emotional, and motivational) processes. In the brain the experience of pain is associated with neuronal oscillations and synchrony at different frequencies. However, an overarching framework for the significance of oscillations for pain remains lacking. Recent concepts relate oscillations at different frequencies to the routing of information flow in the brain and the signaling of predictions and prediction errors. The application of these concepts to pain promises insights into how flexible routing of information flow coordinates diverse processes that merge into the experience of pain. Such insights might have implications for the understanding and treatment of chronic pain. PMID- 28025011 TI - Influence of raltegravir intensification on viral load and 2-LTR dynamics in HIV patients on suppressive antiretroviral therapy. AB - Antiretroviral therapy can suppress HIV-1 plasma viral load to below the detection limit but cannot eradicate the virus. Whether residual ongoing viral replication persists during suppressive therapy remains unclear. A few clinical studies showed that treatment intensification with an additional drug led to a lower viral load or an increase in 2-LTR (long terminal repeat), a marker for ongoing viral replication. However, some other studies found no change in the viral load and 2-LTR. In this paper, we developed multi-stage models to evaluate the influence of treatment intensification with the integrase inhibitor raltegravir on viral load and 2-LTR dynamics in HIV patients under suppressive therapy. We analyzed one model and obtained the local and global stability of the steady states. The model and its variation predict that raltegravir intensification induces a very minor decrease in the viral load and a minor increase in 2-LTR. We also compared modeling prediction with the 2-LTR data in a raltegravir intensification study. To achieve the 2-LTR increase observed in some patients, the level of viral replication needs to be substantially high, which is inconsistent with the sustained viral suppression in patients during treatment intensification. These modeling results, together with the theoretical estimate of the upper bound of the 2-LTR increase, suggest that treatment intensification with raltegravir has a minor effect on the plasma viremia and 2-LTR in patients under suppressive therapy. Other treatment strategies have to be developed for the cure or functional control of the infection. PMID- 28025012 TI - Catabolism of C1 inhibitor influences the response to replacement therapy in hereditary angioedema. PMID- 28025013 TI - Eosinophilic esophagitis and colonic mucosal eosinophilia in Netherton syndrome. PMID- 28025014 TI - An unusual imported case of diphyllobothriosis in Mexico. PMID- 28025015 TI - Developmental trajectories of event related potentials related to working memory. AB - Working memory is an important cognitive function, and it is crucial to better understand its neurophysiological mechanisms. The developmental trajectories of the Event Related Potentials related to this important function have hardly been studied. However, these ERPs may provide some clues about the individual state of maturation, as has been demonstrated for anatomical brain images. The present study aims to determine the behavioral and neurophysiological development of Working Memory (WM) processes. For this purpose, 170 subjects with ages ranging from 6 to 26 years performed a visual Delayed Match-to-Sample task (DMTS). The RTs, total errors, and Event Related Potentials (ERPs) in the phases of encoding, retention, and matching were obtained. Results revealed a decrease in the amplitude of ERPs with age, paralleled by improved performance on the DMTS task (i.e., shorter RTs and fewer errors). None of these variables were affected by gender. To determine whether memory performance was influenced by the individual pattern of maturation beyond age, the amplitude of the different ERP components was correlated with RT and errors on the WM task after removing the effect of age. Frontal N2 and posterior P1 and the Late Positive Component were the only ERPs that presented significant correlations with behavioral errors. Behavioral performance was predicted by age and by the scores on the first component extracted from Principal Component Analysis (PCA) of the ERPs. Age (under 17 years old) explained 85.04% and the PCA component explained 14.96% of the variance explained by the bivariate model predicting behavioral errors (1/age + scores of 1st PCA component). From the age of 17 on, the principal PCA component ceases to be an independent component predicting error performance. The results suggest that the individual maturation of ERP components seems to be of particular importance in controlling behavioral errors in WM, as measured by the DMTS. PMID- 28025016 TI - Negative induced mood influences word production: An event-related potentials study with a covert picture naming task. AB - The present event-related potentials (ERPs) study investigated the effects of mood on phonological encoding processes involved in word generation. For this purpose, negative, positive and neutral affective states were induced in participants during three different recording sessions using short film clips. After the mood induction procedure, participants performed a covert picture naming task in which they searched letters. The negative compared to the neutral mood condition elicited more negative amplitudes in a component peaking around 290ms. Furthermore, results from source localization analyses suggested that this activity was potentially generated in the left prefrontal cortex. In contrast, no differences were found in the comparison between positive and neutral moods. Overall, current data suggest that processes involved in the retrieval of phonological information during speech generation are impaired when participants are in a negative mood. The mechanisms underlying these effects were discussed in relation to linguistic and attentional processes, as well as in terms of the use of heuristics. PMID- 28025017 TI - Automatic numerical-spatial association in synaesthesia: An fMRI investigation. AB - A horizontal mental number line (MNL) is used to describe how quantities are represented across space. In humans, the neural correlates associated with such a representation are found in different areas of the posterior parietal cortex, especially, the intraparietal sulcus (IPS). In a phenomenon known as number-space synaesthesia, individuals visualise numbers in specific spatial locations. The experience of a MNL for number-space synaesthetes is explicit, idiosyncratic, and highly stable over time. It remains an open question whether the mechanisms underlying numerical-spatial association are shared by synaesthetes and nonsynaesthetes. We address the neural correlates of number-space association by examining the brain response in a number-space synaestheste (MkM) whose MNL differs dramatically in its ordinality and direction from that of a control group. MkM and 15 nonsynaesthetes compared the physical size of two numbers, while ignoring their numerical value, during an event-related functional magnetic resonance imaging session (fMRI). Two factors were analysed: the numerical distance effect (NDE; e.g., 2-4 small distance vs. 1-6 large distance), and the size congruity effect (e.g., 2-8 congruent vs. 2-8 incongruent). Only for MkM, the NDE elicited significant activity in the left and right IPS, supramarginal gyrus (bilateral), and in the left angular gyrus. These results strongly support the role of the parietal cortex in the automatic coding of space and quantity in number-space synaesthesia, even when numerical values are task-irrelevant. PMID- 28025018 TI - Pharmacy provision of sexual and reproductive health commodities to young people: a systematic literature review and synthesis of the evidence. AB - BACKGROUND: We conducted a systematic review of peer-reviewed literature on youth access to, use of and quality of care of sexual and reproductive health (SRH) commodities through pharmacies. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, we searched for publications from 2000 to 2016. To be eligible for inclusion, articles had to address the experiences of young people (aged 25 years and below) accessing SRH commodities (e.g., contraception, abortifacients) via pharmacies. The heterogeneity of the studies precluded meta-analysis - instead, we conducted thematic analysis. RESULTS: A total of 2842 titles were screened, and 49 met the inclusion criteria. Most (n=43) were from high-income countries, and 33 examined emergency hormonal contraception provision. Seventeen focused on experiences of pharmacy personnel in provision, while 28 assessed client experiences. Pharmacy provision of SRH commodities was appealing to and utilized by youth. Increasing access to SRH commodities for youth did not correspond to increases in risky sexual behavior. Both pharmacists and youth had reservations about the ease of access and its impact on sexual behaviors. In settings where regulations allowing pharmacy access were established, some pharmacy personnel created barriers to access or refused access entirely. DISCUSSION: With training and support, pharmacy personnel can serve as critical SRH resources to young people. Further research is needed to better understand how to capitalize on the potential of pharmacy provision of SRH commodities to young people without sacrificing qualities which make pharmacies so appealing to young people in the first place. PMID- 28025019 TI - Time-dependent interacting effects of caffeine, diazepam, and ethanol on zebrafish behaviour. AB - Zebrafish have become a popular animal model for behavioural pharmacology due to their small size, rapid development, and amenability to high throughput behavioural drug screens. Furthermore, water-soluble compounds can be administered via immersion of the fish in the drug solution, which provides a non invasive drug delivery method. Numerous studies have demonstrated stimulant effects of alcohol. Diazepam and caffeine, on the other hand have been found to have inhibitory effect on locomotor activity in zebrafish. However, the time dependent changes induced by these psychoactive drugs are rarely reported, and potential drug interactions have not been examined in zebrafish, despite the translational relevance of this question. In the current study, we examine time- and dose-dependent changes in zebrafish following exposure to caffeine, diazepam, and ethanol quantifying four different behavioural parameters over a 30min recording session. We subsequently analyze potential drug-drug interactions by co administering the three drugs in different combinations. Our time-course and dose response analyses for each of the three drugs represent so far the most detailed studies available serving as a foundation for future psychopharmacology experiments with zebrafish. Furthermore, we report significant interactions between the three drugs corroborating findings obtained with rodent models as well as in humans, providing translational relevance for the zebrafish model. PMID- 28025020 TI - Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine. AB - The serotonin 1B receptor (5-HT1B) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants. PMID- 28025021 TI - Inflammatory pain-related traits of sensory DRG neurons innervating the hip joints. AB - BACKGROUND: Hip pain is transmitted to the dorsal horn of the spinal cord via the dorsal root ganglion (DRG), which contains two types of neurons with differential sensitivity to neurotrophic factors. If either type predominantly innervates the hip joint, it may represent a good target for hip joint pain treatment. METHODS: Inflammation was induced in the left hip joint of rats (n = 10) by using complete Freund's adjuvant. Fluoro-Gold (FG) was applied to the hip joint after 7 days, and T12-L6 DRGs were double-stained for calcitonin gene-related peptide (CGRP) and isolection-IB4 1 week later. RESULTS: FG-labeled neurons in the control group were distributed throughout the left DRG from T13 to L5, primarily in L2 to L4, and CGRP-positive neurons were significantly more frequent than IB4-binding neurons. In the inflammatory group, FG-labeled neurons were similarly distributed, primarily at L3 and L4, and CGRP-positive neurons were significantly more frequent than IB4-binding neurons. The percentage of CGRP-positive neurons was significantly greater in the inflammatory group (P < 0.05). CONCLUSIONS: Most small neurons innervating the hip joint express CGRP. Furthermore, hip joint inflammation caused an increase in CGRP-positive neurons, but not in IB4-binding neurons. Our results suggest that CGRP-expressing nerve growth factor-dependent neurons are primarily responsible for hip joint pain and may represent therapeutic targets. PMID- 28025022 TI - The Japanese version of the STarT Back Tool predicts 6-month clinical outcomes of low back pain. AB - BACKGROUND: The STarT Back Tool classifies patients into low-, medium-, or high risk groups according to risk for chronic low back pain. The Japanese version of the STarT Back Tool (STarT-J) has been translated and psychometrically validated. The present analysis investigated the predictive ability of the STarT-J. METHODS: Baseline data were collected through an online survey conducted with Japanese patients with low back pain. Long-term outcomes were assessed in a 6-month follow up survey. Clinical outcomes at 6 months were evaluated with a pain numerical rating scale, the Roland-Morris Disability Questionnaire, and the EuroQol 5 Dimension. Differences in these scores among the three STarT-J risk groups were analyzed. Participants' perceived changes in low back pain and overall health status were examined to determine associations between the chronicity of low back pain at 6 months and STarT-J risk groups. RESULTS: Data of 1228 volunteers who responded to the baseline and follow-up surveys were included in this analysis. Mean +/- standard deviation (SD) scores for the pain numerical rating scale and the Roland-Morris Disability Questionnaire were highest in the high-risk group (5.6 +/- 1.9 and 9.6 +/- 7.5) and lowest in the low-risk group (3.9 +/- 1.6 and 2.1 +/- 3.5). Mean +/- SD EuroQol 5 Dimension index scores were lowest in the high-risk group (0.66 +/- 0.20) and highest in the low-risk group (0.86 +/- 0.14). A small percentage of high-risk patients (5.3%) perceived improvement in low back pain at the 6-month follow-up. CONCLUSIONS: The STarT-J predicted 6 month pain and disability outcomes. The STarT-J is an easy-to-use tool to screen for patients who are more likely to have chronic low back pain, and may be useful to initiate stratified care in primary care settings. PMID- 28025023 TI - Correlation between preoperative physical signs and functional outcomes after laminoplasty for ossification of the posterior longitudinal ligament. AB - BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) can cause myelopathy that is often managed surgically. Knowledge of predictors of surgical outcomes can provide decision support to surgeons. The aims of this study were to investigate the relationships between preoperative physical signs and postoperative functional outcomes in patients with OPLL and to clarify whether physical signs could predict functional outcomes. METHODS: Fifty-five patients with OPLL who had undergone cervical laminoplasty were included in this study. Six physical signs including hyperreflexia, Babinski sign, sensory disturbance, grip strength, 10-s grip and release test, and bladder dysfunction, and four other factors including age, duration of symptoms, history of minor trauma and preoperative Japanese Orthopaedic Association (JOA) score were investigated as potential predictive prognostic factors using both univariate and multivariate analyses. RESULTS: The mean recovery rate of JOA score was 62.5 +/- 32.5%. The neurological recovery rate was negatively associated with age (P = 0.002), the duration of symptoms (P = 0.002) and Babinski sign (P = 0.007), whereas it was positively correlated with grip strength (P = 0.011). Multiple logistic regression analyses revealed that age (Odds ratio: 0.89, 95% CI: 0.81-0.99) and Babinski sign (Odds ratio: 0.18, 95% CI: 0.04-0.89) were factors associated with functional outcomes. CONCLUSIONS: Satisfactory functional outcomes could be expected for patients who are young and do not exhibit the Babinski sign, showing that the Babinski sign could be useful as an indicator of the window of opportunity for achieving satisfactory functional outcomes. PMID- 28025024 TI - Cervical sagittal alignment in adolescent idiopathic scoliosis patients (Lenke type 1-6). AB - OBJECTIVE: We collected the radiographic and clinical data of 129 AIS patients (Lenke type 1-6) to analyze the characteristics of cervical sagittal alignment in adolescent idiopathic scoliosis patients and the correlations between cervical sagittal alignment and global sagittal alignment, and clinical symptoms. METHODS: 129 patients with AIS and 48 adolescent volunteers were included in this study. The angles of the main thoracic curve, proximal thoracic curve, thoracolumbar curve, lumbar curve, C2-7 Cobb angle, T5-12 Cobb angle, L1-5 Cobb angle, pelvic incidence, pelvic tilt, sacrum slop, C2-7 sagittal vertical axis, C7-S1 sagittal vertical axis, and T1 pelvic angle were included in radiographic measurements. In addition, a 10-cm Visual Analogue Score was used to assess neck pain. Pearson correlation coefficients and t-test were used for statistical analysis. RESULTS: In the AIS group, C2-7 Cobb angle increased significantly compared with the control group, and it was significantly correlated with T5-12 Cobb angle and L1-5 Cobb angle. There was no significant correlation between C2-7 Cobb angle and coronal curvature in each Lenke type of patients. In the C2-7 SVA >= 3 cm group, C2-7 Cobb angle was related to T5-12 Cobb angle, L1-5 Cobb angle, pelvic incidence, and sacrum slop. In the cervical kyphosis group, T5-12 Cobb angle was significantly lower than that of the C2-7 Cobb angle >=0 group. The C2-7 Cobb angle in the group with T5-12 Cobb angle >30 degrees increased significantly compared with that in the group with T5-12 Cobb angle <=30 degrees . The Visual Analogue Score of neck pain of the cervical imbalance group was significantly higher than that of the cervical balance group. CONCLUSIONS: The cervical sagittal alignment in AIS patients was related with thoracic kyphosis and lumbar lordosis, especially with thoracic kyphosis, but not with the coronal angle of thoracic and lumbar spine, and pelvic parameters. PMID- 28025025 TI - A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy. AB - AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group ( 0.075mmol/L); no patients developed hyperkalemia. CONCLUSION: When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN. PMID- 28025026 TI - Hyperdynamic Right Heart Function in Graves' Hyperthyroidism Measured by Echocardiography Normalises on Restoration of Euthyroidism. AB - BACKGROUND: Graves' hyperthyroidism commonly causes tachycardia and may result in pulmonary hypertension and high output cardiac failure. There is limited information regarding the effect of treatment on cardiac function measured using modern echocardiographic techniques. METHODS: Eight individuals with Graves' hyperthyroidism, aged 22-64 years, underwent comprehensive transthoracic echocardiography at three time points: before treatment, two weeks after commencement of carbimazole, and at six months or more when euthyroid. Exercise capacity was assessed using the 6-minute-walk-distance (6MWT), and quality of life was assessed by Medical Outcome Study 36-item Short-Form Health Status Survey. RESULTS: All individuals were rendered euthyroid by final assessment. At presentation, there was evidence of hyperdynamic right ventricular function as measured by peak systolic velocity of the free wall of the tricuspid annulus, tricuspid annular plane systolic excursion and right ventricular ejection fraction, which normalised after resolution of thyrotoxicosis. Baseline heart rate correlated significantly with severity of the thyrotoxicosis for either free T4 (r = 0.91, p=0.01) or free T3 (r=0.94, p=0.001). No individual had measurable pulmonary hypertension. Cardiac output was significantly lower in the euthyroid compared to the thyrotoxic state (p=0.03). A higher baseline TSH-receptor antibody titre corresponded to a greater improvement in exercise capacity (r=0.76, p<0.05) and physical quality of life (r=0.73, p<0.05) on resolution of the hyperthyroidism. CONCLUSION: Graves' hyperthyroidism causes increased cardiac output and a hyperdynamic right ventricle which normalise on restoration of the euthyroid state. PMID- 28025027 TI - Catheter-directed thrombolysis and pharmacomechanical thrombectomy improve midterm outcome in acute iliofemoral deep vein thrombosis. AB - BACKGROUND: Aggressive and early thrombus removal strategy has been widely used as a treatment for iliofemoral deep vein thrombosis (DVT). We compared the long tem venous outcome, including postthrombotic syndrome (PTS), in patients undergoing catheter-directed thrombolysis (CDT) and pharmacomechanical thrombectomy (PMT). METHODS: From January 2009 to December 2013, 61 patients with acute proximal DVT were enrolled in this prospective study. Thirty-one patients underwent CDT and 30 patients underwent PMT, and each patient was followed for at least 2 years after treatment. Observations included venous outflow resistance, venous insufficiency, thrombus score (TS), severity of PTS, and surgical complications. RESULTS: Venous outflow obstruction was similar in the CDT and PMT groups (32.3% vs. 30.0%, p = 0.695), and venous insufficiency of each group was 38.7% and 30.0% (p = 0.774), respectively. The TS at 24 months of each group showed no significant difference (0.90 vs. 0.70, p = 0.526). The mean Villalta scale scores of the CDT and PMT groups were 3.13 and 1.87, respectively (p = 0.042). Patients without PTS had significantly lower TS since 1 week postoperatively (1.59 vs. 4.60, p < 0.001). The severity of PTS was highly correlated with the TS, rate of thrombolysis, and severity of obstruction, and was moderately correlated with the venous registry index and reflux severity. CONCLUSION: CDT and PMT have similar venous outcomes in patients with acute iliofemoral DVT, although PTS is less severe following PMT than after CDT. We propose that early and thorough removal of thrombus, using either CDT or PMT, is beneficial to prevent PTS. PMID- 28025028 TI - IFCC approved HPLC reference measurement procedure for the alcohol consumption biomarker carbohydrate-deficient transferrin (CDT): Its validation and use. AB - Carbohydrate-deficient transferrin (CDT) is used as a biomarker of sustained high alcohol consumption. The currently available measurement procedures for CDT are based on various analytical techniques (HPLC, capillary electrophoresis, nephelometry), some differing in the definition of the analyte and using different reference intervals and cut-off values. The Working Group on Standardization of CDT (WG-CDT), initiated by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), has validated an HPLC candidate reference measurement procedure (cRMP) for CDT (% disialotransferrin to total transferrin based on peak areas), demonstrating that it is suitable as a reference measurement procedure (RMP) for CDT. Presented is a detailed description of the cRMP and its calibration. Practical aspects on how to treat genetic variant and so-called di-tri bridge samples are described. Results of method performance characteristics, as demanded by ISO 15189 and ISO 15193, are given, as well as the reference interval and measurement uncertainty and how to deal with that in routine use. The correlation of the cRMP with commercial CDT procedures and the performance of the cRMP in a network of laboratories are also presented. The performance of the CDT cRMP in combination with previously developed commutable calibrators allows for standardization of the currently available commercial measurement procedures for CDT. The cRMP has recently been approved by the IFCC and will be from now on be known as the IFCC-RMP for CDT, while CDT results standardized according to this RMP should be indicated as CDTIFCC. PMID- 28025029 TI - Neutropenia is independently associated with sub-therapeutic serum concentration of vancomycin. AB - BACKGROUND: We aimed to identify the impact of the presence of neutropenia on serum vancomycin concentration (SVC). METHODS: A retrospective study was conducted from January 2005 to December 2015. The study population was comprised of adult patients who were performed serum concentration of vancomycin. Patients with renal failure or using non-conventional dosages of vancomycin were excluded. RESULTS: A total of 1307 adult patients were included in this study, of whom 163 (12.4%) were neutropenic. Patients with neutropenia presented significantly lower SVCs than non-neutropenic patients (P<0.0001). Multiple linear regressions showed significant association between neutropenia and trough SVC (beta coefficients, 2.351; P=0.004). Multiple logistic regression analysis also revealed a significant association between sub-therapeutic vancomycin concentrations (trough SVC values<10mg/l) and neutropenia (odds ratio, 1.75, P=0.029) CONCLUSIONS: The presence of neutropenia is significantly associated with low SVC, even after adjusting for other variables. Therefore, neutropenic patients had a higher risk of sub-therapeutic SVC compared with non-neutropenic patients. We recommended that vancomycin therapy should be monitored with TDM-guided optimization of dosage and intervals, especially in neutropenic patients. PMID- 28025030 TI - Apelin/APJ system: A novel promising therapy target for pathological angiogenesis. AB - Apelin is the endogenous ligand of the G protein-coupled receptor APJ. Both Apelin and APJ receptor are widely distributed in various tissues such as heart, brain, limbs, retina and liver. Recent research indicates that the Apelin/APJ system plays an important role in pathological angiogenesis which is a progress of new blood branches developing from preexisting vessels via sprouting. In this paper, we review the important role of the Apelin/APJ system in pathological angiogenesis. The Apelin/APJ system promotes angiogenesis in myocardial infarction, ischemic stroke, critical limb ischemia, tumor, retinal angiogenesis diseases, cirrhosis, obesity, diabetes and other related diseases. Furthermore, we illustrate the detailed mechanism of pathological angiogenesis induced by the Apelin/APJ system. In conclusion, the Apelin/APJ system would be a promising therapeutic target for angiogenesis-related diseases. PMID- 28025031 TI - Triclosan/triclocarban levels in maternal and umbilical blood samples and their association with fetal malformation. AB - Triclosan (TCS) and triclocarban (TCC) are widely used as antimicrobial compounds in consumer products. TCS and TCC are frequently found in waste water and sewage. In this study, we investigate the potential impact of exposure to triclosan (TCS) and triclocarban (TCC) on fetal abnormalities. We measured TCS and TCC levels in maternal and umbilical cord blood samples from 39 pregnant women diagnosed with fetal or post-birth abnormalities at Beijing Obstetrics and Gynecology Hospital. 52 pregnant women who gave birth to healthy neonates during the same period of time were included as controls. Applying ultra-performance liquid chromatography tandem mass spectrometry, TCS and TCC concentrations were measured in maternal and fetal sera. Significantly increased levels of TCS were detected in maternal sera from mothers with abnormal births. Similar levels of TCS or TCC were found in maternal and cord sera in control group. The concentrations of TCS or TCC in maternal sera correlated with those in umbilical cord sera (r=0.649, P<0.01). These observations suggest that maternal blood test could be a useful assay for detecting fetal exposure to TCS and TCC, and high exposure to TCS may be potentially associated with increased risk for fetal malformations. PMID- 28025033 TI - Using comparative biology to understand how aging affects mitochondrial metabolism. AB - Lifespan varies considerably among even closely related species, as exemplified by rodents and primates. Despite these disparities in lifespan, most studies have focused on intra-specific aging pathologies, primarily within a select few systems. While mice have provided much insight into aging biology, it is unclear if such a short-lived species lack defences against senescence that may have evolved in related longevous species. Many age-related diseases have been linked to mitochondrial dysfunction that are measured by decreased energy generation, structural damage to cellular components, and even cell death. Post translational modifications (PTMs) orchestrate many of the pathways associated with cellular metabolism, and are thought to be a key regulator in biological senescence. We propose hyperacylation as one such modification that may be implicated in numerous mitochondrial impairments affecting energy metabolism. PMID- 28025032 TI - The metabolic syndrome and chronic kidney disease. AB - The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including insulin resistance (IR), dyslipidemia, and hypertension, which may also foster development of chronic kidney disease. The mechanisms of MetS-induced kidney disease are not fully understood. The purpose of this review is to summarize recent discoveries regarding the impact of MetS on the kidney, particularly on the renal microvasculature and cellular mitochondria. Fundamental manifestations of MetS include IR and adipose tissue expansion, the latter promoting chronic inflammation and oxidative stress that exacerbate IR. Those in turn can elicit various kidney injurious events through endothelial dysfunction, activation of the renin-angiotensin-aldosterone system, and adipokine imbalance. Inflammation and IR are also major contributors to microvascular remodeling and podocyte injury. Hence, these events may result in hypertension, albuminuria, and parenchymal damage. In addition, dyslipidemia and excessive nutrient availability may impair mitochondrial function and thereby promote progression of kidney cell damage. Elucidation of the link between MetS and kidney injury may help develop preventative measures and possibly novel therapeutic targets to alleviate and avert development of renal manifestations. PMID- 28025034 TI - CCL2/CCR2 signaling pathway in glioblastoma multiforme. AB - Glioblastoma multiform (GBM) is described as one of the most frequent primary brain tumors. These types of malignancies constitute only 15% of all primary brain tumors. Despite, extensive developments on effective therapeutic methods during the 20th century as well as the first decade of the present century (21st), the median survival rate for patients suffering from GBM is only approximately 15 months, even in response to multi-modal therapy. numerous types of reticuloendothelial system cells such as macrophages and microglial cells occupied within both GBM and also normal surrounding tissues. These immune cells acquire an otherwise activated phenotype with potent tumor-tropic functions that contribute to the glioma growth and invasion. The CC chemokine, CCL2 (previously named MCP-1) is of the most important CC chemokines family member involving in regulation of oriented migration and penetrative infiltration of mainly reticuloendothelial system cells specifically monocyte/macrophage phenotypes. Fundamental parts are played by CCL2 and its related receptor (the CCR2) in brain tumors and obviously in migration of monocytes from the bloodstream through the vascular endothelium. Therefore, CCL2/CCR2 axis is required for the routine immunological surveillance of tissues, in accordance with response to inflammation. Briefly, in this review, we have tried our best to collect the latest, straightened and summarize literature reports exist within data base regarding the interaction between microglia/macrophages and CCL2/CCR2 axis in GBM. We aimed to discuss potential application of this chemokine/receptor interaction axis for the expansion of future anti-glioma therapies as well. PMID- 28025035 TI - Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. AB - BACKGROUND: Neuronal dysfunction caused by neuroinflammation triggered by the stimulation of matrix metalloproteinases and the subsequent release of pro inflammatory cytokines, as a result of oxidative stress and mitochondrial dysfunction, is one of the probable mechanisms involved in the pathogenesis of autism spectrum disorders (ASD). The aim of the present study was to explore the ameliorative potential of resveratrol on neuroinflammation in the experimental paradigm of neuroinflammatory model of ASD in rats. METHOD: 1M Propanoic acid (PPA) (4 MUl) was infused over 10 min into the anterior portion of the lateral ventricle to induce ASD like symptoms in rats. Resveratrol (5, 10 and 15 mg/kg) was administered starting from the 2nd day of the surgery and continued upto 28th day. Rats were tested for various behavioural paradigms such as social interaction, stereotypy, locomotor activity, anxiety, novelty, depression, spatial learning, memory, repetitive and pervasive behaviour between the 7th day and 28th day. In addition, biochemical tests for oxidative stress, mitochondrial complexes, TNF-alpha and MMP-9 were also assessed. RESULTS: Treatment with resveratrol for four weeks restored, significantly and dose dependently, all the neurological, sensory, behavioural, biochemical and molecular deficits in PPA induced autistic phenotype in rats. CONCLUSION: The major finding of the study is that resveratrol restored the core and associated symptoms of autistic phenotype by suppressing oxidative-nitrosative stress, mitochondrial dysfunction, TNF-alpha and MMP-9 expression in PPA induced ASD in rats. Therefore, resveratrol might serve as an adjunct potential therapeutic agent for amelioration of neurobehavioural and biochemical deficits associated with autism spectrum disorders. PMID- 28025036 TI - Decreased eicosapentaenoic acid levels in acne vulgaris reveals the presence of a proinflammatory state. AB - This study aimed to determine circulating levels of polyunsaturated fatty acids (PUFAs), secretory phospholipase A2 (sPLA2), lipoprotein lipase (LPL) and measure circulating protein levels of angiopoietin-like protein 3 (ANGPTL3), ANGPTL4, cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in patients with acne vulgaris. Serum from 21 control subjects and 31 acne vulgaris patients were evaluated for levels of arachidonic acid (AA, C20:4n- 6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3). PUFA levels were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Lipid profile, routine biochemical and hormone parameters were assayed by standard kit methods Serum EPA levels were significantly decreased while AA/EPA and DGLA/EPA ratio were significantly increased in acne vulgaris patients compared to controls. Serum levels of AA, DGLA and DHA showed no significant difference while activity of sPLA2 and LPL were significantly increased in acne vulgaris compared to controls. Results of this study reveal the presence of a proinflammatory state in acne vulgaris as shown by significantly decreased serum EPA levels and increased activity of sPLA2, AA/EPA and DGLA/EPA ratio. Increased LPL activity in the serum of acne vulgaris patients can be protective through its anti-dyslipidemic actions. This is the first study reporting altered EPA levels and increased sPLA2 activity in acne vulgaris and supports the use of omega-3 fatty acids as adjuvant treatment for acne patients. PMID- 28025038 TI - Incidence and Risk of Cardiac Events in Patients With Previously Treated Multiple Myeloma Versus Matched Patients Without Multiple Myeloma: An Observational, Retrospective, Cohort Study. AB - BACKGROUND: Multiple myeloma (MM) patients have age-, disease-, and treatment related risk factors for cardiac events. MATERIALS AND METHODS: We analyzed the 2006 to 2011 MarketScan database to determine whether the risk of cardiac events is greater in MM patients than in non-MM patients. Included were 1723 MM patients treated with corticosteroids and >= 3 drugs (bortezomib, immunomodulatory derivatives, and alkylating agents or anthracyclines). The index date (ID) was the date on which the 3-drug exposure criterion was met. Also included were 8615 age- and gender-matched non-MM patients (5:1). The distribution of non-MM patients' IDs matched that of the MM patients' IDs. Baseline was 6 months before the ID. The follow-up duration was from the ID to study end (ie, 2011 or end of enrollment or prescription drug coverage). Hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for baseline variables when the univariate analyses showed a 10% difference. RESULTS: The median duration of observation was 9 months (range, 0-60 months) for MM patients and 19 months (range, 0-66 months) for non MM patients. The risk of any cardiac event (HR, 2.2; 95% CI, 1.9-2.5), dysrhythmia (HR, 4.1; 95% CI, 3.5-4.8), congestive heart failure (HR, 2.9; 95% CI, 2.2-3.7), cardiomyopathy (HR, 2.6; 95% CI, 1.8-3.8), and conduction disorders (HR, 1.7; 95% CI, 1.2-2.5) was significantly greater for MM than for non-MM patients. The incidence of hypertensive or arterial events and ischemic heart disease was similar between the 2 groups. CONCLUSION: The present study provides the first known comparison of cardiac event risk in patients with MM versus age- and gender-matched patients without MM. The cardiac event risk was greater in MM patients with >= 3 previous drugs for any cardiac event, dysrhythmias, congestive heart failure, cardiomyopathy, and conduction disorders compared with patients without MM. PMID- 28025039 TI - Computation Resources for Molecular Biology: Special Issue 2017. PMID- 28025037 TI - Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis. AB - BACKGROUND: Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic. METHODS: Test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modeling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump. RESULTS: Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV1 (L) increased 0.8% during a 4-week period of inhaled tobramycin and an additional 6.4% during a subsequent 4-week period of inhaled aztreonam (P<0.005). CFQ-R respiratory symptom score decreased 1.8 points during inhaled tobramycin and increased 8.3 points during subsequent inhaled aztreonam (P<0.001). A smaller number of trial participants not using azithromycin had similar improvement in lung function and quality of life scores during inhaled tobramycin and inhaled aztreonam. In vitro, azithromycin selectively reduced the bactericidal effects tobramycin in cultures of clinical strains of P. aeruginosa, while up regulating antibiotic resistance through MexXY efflux. CONCLUSIONS: Azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients. PMID- 28025040 TI - Acetylcholine released from T cells regulates intracellular Ca2+, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor. AB - AIMS: T lymphocytes synthesize acetylcholine (ACh) and express muscarinic and nicotinic ACh receptors (mAChR and nAChR, respectively) responsible for increases in the intracellular Ca2+ concentration ([Ca2+]i). Our aim in the present study was to assess whether autocrine ACh released from T lymphocytes regulates their physiological functions. MAIN METHODS: MOLT-3 human leukemic cell line and murine splenocytes were loaded with fura-2 to monitor [Ca2+]i changes in the absence or presence of several AChR antagonists, including mecamylamine, methyllycaconitine and scopolamine. Real-time PCR and ELISA were performed to measure interleukin-2 (IL-2) mRNA and protein levels. KEY FINDINGS: T lymphocytes constitutively produce sufficient amounts of ACh to elicit autocrine changes in [Ca2+]i. These autocrine ACh-evoked [Ca2+]i transients were mediated by nAChRs and then influx of extracellular Ca2+. Mecamylamine, a nAChR inhibitor, suppressed not only these [Ca2+]i transients, but also IL-2 release and T cell proliferation. SIGNIFICANCE: Here, we confirmed that T lymphocytes utilize ACh as a tool to interact with each other and that autocrine ACh-activated nAChRs are involved in cytokine release and cell proliferation. These findings suggest the possibility that nAChR agonists and antagonists and smoking are able to modulate immune function, which in turn suggests the therapeutic potential of immune activation or suppression using nAChR agonists or antagonists. PMID- 28025041 TI - Effect of LPS treatment on tyrosine hydroxylase expression and Parkinson-like behaviors. AB - Puberty is a critical period of development during which the brain undergoes reorganizing and remodeling. Exposure to stress during this period is thought to interfere with normal brain development and increase susceptibility to mental illnesses. In female mice, pubertal exposure to lipopolysaccharide (LPS), a bacterial endotoxin, has been shown to alter sexual, anxiety-like, and depression like behaviors and cognition in an enduring manner. However, the mechanisms underlying these effects remain unknown. The present study examined age and sex difference in tyrosine hydroxylase (TH) expression and dopamine-dependent and Parkinson-like behaviors following LPS treatment. The results show that LPS treatment during adulthood causes an enduring increase in TH expression in many of the brain regions examined. In contrast, there is no change in TH expression following LPS treatment during puberty. However, pubertal LPS treatment induces enduring behavioral deficits in tests of Parkinson-like behaviors, more so in male than in female mice. These results suggest that the low levels of TH following exposure to pubertal immune challenge may predispose mice to Parkinson like behavior. These findings add to our understanding of stress and immune responses during puberty and their impact on mental health later in life. PMID- 28025043 TI - MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-alpha pathway in intracerebral hemorrhage. AB - Microglia mediated inflammation contributes to intracerebral hemorrhage (ICH) induced secondary injury. Activated microglia has dual functions as pro inflammatory (M1) and anti-inflammatory (M2) factors in brain injury and repair. MiR-124 is a potent anti-inflammatory agent which affects microglia after brain injury. However, the potential of modulating the M1/M2 polarization of microglia after ICH has not been reported. In this experiment, we detected the effect of miR-124 on the M1/M2 polarization state. In addition, the ability miR-124 to subsequently impacted neurological deficit and cerebral water content of ICH mice were studied. Furthermore, the relationship between miR-124 and C/EBP-alpha target was detected. We found that miR-124 significantly increased in M2 polarized microglia. Transduction of miR-124 mimics decreased proinflammatory cytokine levels. A coculture model of microglia and neuron indicated that M2 polarized microglia protected neuron damage. Furthermore, miR-124 banded to the 3 untranslated region of C/EBP-alpha and downregulated its protein levels. In vivo, infusion of miR-124 decreased brain levels of C/EBP-alpha and significantly reduced brain injury in ICH mice. Thus, miR-124 ameliorated ICH-induced inflammatory injury by modulating microglia polarization toward the M2 phenotype via C/EBP-alpha. MiR-124 regulatory mechanisms also might represent new therapeutic strategy in ICH. PMID- 28025042 TI - Quercetin ameliorates chronic unpredicted stress-mediated memory dysfunction in male Swiss albino mice by attenuating insulin resistance and elevating hippocampal GLUT4 levels independent of insulin receptor expression. AB - Chronic stress is associated with impaired neuronal functioning, altered insulin signaling, and behavioral dysfunction. Quercetin has shown neuroprotective and antidiabetic effects, besides modulating cognition and insulin signaling. Therefore, in the present study, we explored whether or not quercetin ameliorates stress-mediated cognitive dysfunction and explored the underlying mechanism. Swiss albino male mice were subjected to an array of unpredicted stressors for 21days, during which 30mg/kg quercetin treatment was given orally. The effect of chronic unpredicted stress (CUS) and quercetin treatment on cognition were evaluated using novel object recognition (NOR) and Morris water maze (MWM) tests. Hippocampal neuronal integrity was observed by histopathological examination. Blood glucose, serum corticosterone, and insulin levels were measured by commercial kits and insulin resistance was evaluated in terms of HOMA-IR index. Hippocampal insulin signaling was determined by immunofluorescence staining. CUS induced significant cognitive dysfunction (NOR and MWM) and severely damaged hippocampal neurons, especially in the CA3 region. Quercetin treatment alleviated memory dysfunction and rescued neurons from CUS-mediated damage. Fasting blood glucose, serum corticosterone, and serum insulin were significantly elevated in stressed animals, besides, having significantly higher HOMA-IR index, suggesting the development of insulin resistance. Quercetin treatment alleviated insulin resistance and attenuated altered biochemical parameters. CUS markedly down regulated insulin signaling in CA3 region and quercetin treatment improved neuronal GLUT4 expression, which seemed to be independent of insulin and insulin receptor levels. These results suggest that intact insulin functioning in the hippocampus is essential for cognitive functions and quercetin improves CUS mediated cognitive dysfunction by modulating hippocampal insulin signaling. PMID- 28025044 TI - A dual-label time-resolved fluorescence immunoassay (TRFIA) for screening of Coronary atherosclerosis based on simultaneous detection of Lp-PLA2 and HsCRP. AB - Atherosclerosis is the underlying cause of most coronary events. The conventional method for coronary atherosclerosis detection is morphological examination or coronary arterionyraphy. These methods are complex and time-consuming. In this study a two-step dual-label TRFIA was developed for the simultaneous detection of Lp-PLA2 and hsCRP in a single run. The performance of this assay was first evaluated using clinical serum samples, and then compared with commercialized kits. The sensitivity of this assay for Lp-PLA2 detection was 1ng/mL (dynamic range, 0-1000U/L), and the sensitivity for hsCRP detection was 1mg/L (dynamic range, 1-1000mg/L). High correlation coefficients (R) were obtained between the present dual-label TRFIA and commercially available kits(R=0.99 for LP-PLA2 and hsCRP). The present dual-label TRFIA has high sensitivity, specificity, and accuracy in clinical sample analysis. It is a good alternative to the single label diagnostic methods. PMID- 28025045 TI - A novel role for Nhp6 proteins in histone gene regulation in Saccharomyces cerevisiae. AB - Maintaining a stable and balanced histone pool is of paramount importance for genome stability and fine regulation of DNA replication and transcription. This involves a complex regulatory machinery, exploiting transcription factors as well as histone chaperones, chromatin remodelers and modifiers. The functional details of this machinery are as yet unclear. Previous studies report histone decrease in mammalian and yeast HMGB family mutants. In this study we find that Nhp6 proteins, the S. cerevisiae HMGB1 homologues, control histone gene expression by affecting nucleosome stability at regulative regions of the histone clusters. In addition, we observe that histone gene overexpression in the nhp6ab mutant is accompanied by downregulated translation, which in turn is responsible for the histone decrease phenotype. Our observations allow us to incorporate Nhp6 proteins into the large group of chromatin factors that tightly regulate histone gene expression. PMID- 28025047 TI - Refractive changes following corrective surgery for thyroid-related orbitopathy. AB - Thyroid-related orbitopathy (TRO) is a common and recognizable manifestation of Graves' disease, caused by an increase in orbital fat volume, increased extraocular muscle diameter, and fibrosis. Together, within the bony confines of the orbit, these changes might alter the shape and position of the globe, potentially inducing refractive shifts. These refractive changes may then be affected by corrective surgical interventions for TRO such as orbital decompression and strabismus surgery. We studied refractive changes in patients with TRO who underwent strabismus surgery with or without orbital decompression. Manifest refraction was performed preoperatively and postoperatively in 33 patients who met inclusion criteria. Statistically significant postoperative refractive changes were found for cylinder, axis, and spherical equivalent. PMID- 28025046 TI - CaMKII is a nodal signal for multiple programmed cell death pathways in heart. AB - Sustained Ca2+/calmodulin-dependent kinase II (CaMKII) activation plays a central role in the pathogenesis of a variety of cardiac diseases. Emerging evidence suggests CaMKII evoked programmed cell death, including apoptosis and necroptosis, is one of the key underlying mechanisms for the detrimental effect of sustained CaMKII activation. CaMKII integrates beta-adrenergic, Gq coupled receptor, reactive oxygen species (ROS), hyperglycemia, and pro-death cytokine signaling to elicit myocardial apoptosis by intrinsic and extrinsic pathways. New evidence demonstrates CaMKII is also a key mediator of receptor interacting serine/threonine kinase 3 (RIP3)-induced myocardial necroptosis. The role of CaMKII in cell death is dependent upon subcellular localization and varies across isoforms and splice variants. While CaMKII is now an extensively validated nodal signal for promoting cardiac myocyte death, the upstream and downstream pathways and targets remain incompletely understood, demanding further investigation. PMID- 28025048 TI - Tropoelastin inhibits intimal hyperplasia of mouse bioresorbable arterial vascular grafts. AB - : Neointimal hyperplasia, which results from the activation, proliferation and migration of vascular smooth muscle cells (SMCs), is a detrimental condition for vascular stents or vascular grafts that leads to stenosis. Preventing neointimal hyperplasia of vascular grafts is critically important for the success of arterial vascular grafts. We hypothesized that tropoelastin seeding onto the luminal surface of the graft would prevent neointimal hyperplasia through suppressing neointimal smooth muscle cell proliferation. In this study, we investigated the efficacy of tropoelastin seeding in preventing neointimal hyperplasia of bioresorbable arterial vascular grafts. Poly (glycolic acid) (PGA) fiber mesh coated with poly (l-lactic-co-epsilon-caprolactone) (PLCL) scaffolds reinforced by poly (l-lactic acid) (PLA) nano-fibers were prepared as bioresorbable arterial grafts. Tropoelastin was then seeded onto the luminal surface of the grafts. Tropoelastin significantly reduced the thickness of the intimal layer. This effect was mainly due to a substantial reduction the number of cells that stained positive for SMC (alpha-SMA) and PCNA in the vessel walls. Mature elastin and collagen type I and III were unchanged with tropoelastin treatment. This study demonstrates that tropoelastin seeding is beneficial in preventing SMC proliferation and neointimal hyperplasia in bioresorbable arterial vascular grafts. STATEMENT OF SIGNIFICANCE: Small resorbable vascular grafts can block due to the over-proliferation of smooth muscle cells in neointimal hyperplasia. We show here that the proliferation of these cells is restricted in this type of graft. This is achieved with a simple dip, non-covalent coating of tropoelastin. It is in principle amendable to other grafts and is therefore an attractive process. This study is particularly significant because: (1) it shows that smooth muscle cell proliferation can be reduced while still accommodating the growth of endothelial cells, (2) small vascular grafts with an internal diameter of less than 1mm are amenable to this process, and (3) this process works for resorbable grafts. PMID- 28025049 TI - Polylysine-modified polyethylenimine (PEI-PLL) mediated VEGF gene delivery protects dopaminergic neurons in cell culture and in rat models of Parkinson's Disease (PD). AB - : Parkinson's Disease (PD) is a chronic neurodegenerative disorder characterized by motor deficits which result from the progressive loss of dopaminergic neurons. Gene therapy using growth factors such as VEGF seems to be a viable approach for potential therapeutic treatment of PD. In this study, we utilized a novel non viral gene carrier designated as PEI-PLL synthesized by our laboratory to deliver VEGF gene to study its effect by using both cell culture as well as animal models of PD. For cell culture experiments, we utilized 6-hydroxydopamine (6-OHDA) mediated cell death model of MN9D cells following transfection with either a control plasmid or VEGF expressing plasmid. As compared to control transfected cells, PEI-PLL mediated VEGF gene delivery to MN9D cells resulted in increased cell viability, increase in the number of Tyrosine hydroxylase (TH) positive cells and decreased apoptosis following 6-OHDA insult. Next, we studied the therapeutic potential of PEI-PLL mediated VEGF gene delivery in SNPc by using unilateral 6-OHDA Medial forebrain bundle (MFB) lesion model of PD in rats. VEGF administration prevented the loss of motor functions induced by 6-OHDA as determined by behavior analysis. Similarly, VEGF inhibited the 6-OHDA mediated loss of DA neurons in Substantia Nigra Pars Compacta (SNPc) as well as DA nerve fibers in striatum as determined by TH immunostaining. In addition, PEI-PLL mediated VEGF gene delivery also prevented apoptosis and microglial activation in PD rat models. Together, these results clearly demonstrated the beneficial effects of PEI-PLL mediated VEGF gene delivery on dopaminergic system in both cell culture and animal models of PD. STATEMENT OF SIGNIFICANCE: In this report, we exploited the potential of PEI-PLL to deliver VEGF gene for the potential therapeutic treatment of PD by using both cell culture and animal models of PD. To the best of our knowledge, this is the first report describing the use of novel polymeric gene carriers for the delivery of VEGF gene to DA neurons with improved transfection efficiency. Finally, the study will lead to a significant advancement in the field of non-viral PD gene therapy treatment. PMID- 28025050 TI - Hometown size affects the processing of naturalistic face variability. AB - Face exposure during development determines adults' abilities to recognize faces and the information they use to process them. Individual differences in the face categories represented in the visual environment can lead to category-specific deficits for recognizing faces that are atypical of observer's experience (e.g. the other-race effect). But what happens when observers have limited opportunities to learn about faces in general? In previous work, we found that observers from depopulated areas have poorer face recognition performance than observers from larger communities, suggesting that impoverished face experience limits face processing broadly. Here, we further investigate this phenomenon by examining how hometown size impacts the ability to assess appearance variability in natural images of faces and bodies. We asked individuals from small and large communities to complete (1) an unconstrained card-sorting task designed to test observers' ability to categorize within-person and between-person appearance variability properly, and (2) the Cambridge Face Memory Test. For both tasks, we examined the direct comparison between groups as well as the relationship between CFMT scores and sorting performance as a function of face experience. We find that small-town observers perform more poorly on the CFMT, but exhibit both better and worse performance than large-town observers on different aspects of the card-sorting task. Further, we also examine the relationship between CFMT performance and card-sorting errors. Our results suggest that individual differences in lifetime face exposure induce important variation in face processing abilities. PMID- 28025052 TI - Holding visual attention for 400millionyears: A model of tectum and torus longitudinalis in teleost fishes. AB - Only ray-finned fishes possess a torus longitudinalis (TL), a paired, elongated body attached to the medial margins of the optic tectum. Its granule cells project large numbers of fine fibers running laterally over adjacent tectum, synapsing excitatorily on the spiny dendrites of pyramidal cells. Sustained TL activity is evoked visuotopically by dark stimuli; TL bursting is a corollary discharge of saccadic eye movements. To suggest a function for this ancient structure, neural network models were constructed to show that: (1) pyramidal cells could form an attentional locus, selecting one out of several moving objects to track, but rapid image shifts caused by saccades disrupt tracking; (2) TL could supply both the pre-saccade position of a locus, and the shift predicted from a saccade so as to prime pyramidal dendrites at the target location, ensuring the locus stays with the attended object; (3) that the specific pattern of synaptic connections required for such predictive priming could be learned by an unsupervised rule; (4) temporal and spatial filtering of visual pattern input to TL allows learning from a complex scene. The principles thus evinced could apply to trans-saccadic attention and visual stability in other species. PMID- 28025051 TI - Variations in normal color vision. VI. Factors underlying individual differences in hue scaling and their implications for models of color appearance. AB - Observers with normal color vision vary widely in their judgments of color appearance, such as the specific spectral stimuli they perceive as pure or unique hues. We examined the basis of these individual differences by using factor analysis to examine the variations in hue-scaling functions from both new and previously published data. Observers reported the perceived proportion of red, green, blue or yellow in chromatic stimuli sampling angles at fixed intervals within the LM and S cone-opponent plane. These proportions were converted to hue angles in a perceptual-opponent space defined by red vs. green and blue vs. yellow axes. Factors were then extracted from the correlation matrix using PCA and Varimax rotation. These analyses revealed that inter-observer differences depend on seven or more narrowly-tuned factors. Moreover, although the task required observers to decompose the stimuli into four primary colors, there was no evidence for factors corresponding to these four primaries, or for opponent relationships between primaries. Perceptions of "redness" in orange, red, and purple, for instance, involved separate factors rather than one shared process for red. This pattern was compared to factor analyses of Monte Carlo simulations of the individual differences in scaling predicted by variations in standard opponent mechanisms, such as their spectral tuning or relative sensitivity. The observed factor pattern is inconsistent with these models and thus with conventional accounts of color appearance based on the Hering primaries. Instead, our analysis points to a perceptual representation of color in terms of multiple mechanisms or decision rules that each influence the perception of only a relatively narrow range of hues, potentially consistent with a population code for color suggested by cortical physiology. PMID- 28025053 TI - Lightness perception for matte and glossy complex shapes. AB - Humans are able to estimate the reflective properties of the surface (albedo) of an object despite the large variability in the reflected light due to shading, illumination and specular reflection. Here we first used a physically based rendering simulation to study how different statistics (i.e. percentiles) based on the luminance distributions of matte and glossy objects predict the overall surface albedo. We found that the brightest parts of matte surfaces are good predictors of the surface albedo. As expected, the brightest parts led to poor performance in glossy surfaces. We then asked human observers to sort four (2 matte and 2 glossy) objects in a virtual scene in terms of their albedo. The brightest parts of matte surfaces highly correlated with human judgments, whereas in glossy surfaces, the highest correlation was achieved by percentiles within the darker half of the objects' luminance distributions. Furthermore, glossy surfaces tend to appear darker than matte ones, and observers are less precise in judging their lightness. We then manipulated different bands of the virtual objects' luminance distributions separately for glossy and matte surfaces. Modulating the brightest parts of the luminance distributions of the glossy surfaces had a limited impact on lightness perception, whereas it clearly influenced the perceived lightness of the matte objects. Our results demonstrate that human observers effectively ignore specular reflections while evaluating the lightness of glossy objects, which results in a bias to perceive glossy objects as darker. PMID- 28025054 TI - Visual sensitivity and spatial resolution of the planktivorous fish, Atherinomorus forskalii (Atherinidae; Ruppell, 1838), to a polarized grating. AB - Polarized light detection has been documented in only a small number of fish species. The benefit of polarization vision for fish is not fully understood, nor is the transduction mechanism that underlies it. Past studies proposed that one possible advantage of polarization vision is that it enhances the contrast of zooplankton targets by breaking their transparency. Here, we used an optomotor apparatus to test the responses of the planktivorous Hardyhead silverside fish Atherinomorus forskalii (Atherinidae) to vertical unpolarized (intensity) and polarized gratings. We also tested and compared the spatial and temporal resolutions of A. forskalii in the intensity and polarization domains. A. forskalii responded to the polarization pattern, but only under illumination that included ultraviolet-blue (lambda>380nm) wavelengths. The spatial resolution of A. forskalii was measured as a minimum separable angle of 0.57 degrees (a 1-mm prey viewed from 100-mm distance). The temporal resolution to unpolarized vs. polarized gratings was constant, at 33 and 10Hz respectively at most of the stripe widths tested. At the smallest stripe width tested (1mm=the minimal separable angle), which correlates with the size of prey typically consumed by these fish, the temporal resolution to the polarized grating increased to 42Hz. We conclude that A. forskalii is polarization sensitive, may use polarization vision to improve detection of its planktonic prey, and that polarization may be perceived by the fish via a separate visual pathway than intensity. PMID- 28025055 TI - Changes in the distribution of sustained attention alter the perceived structure of visual space. AB - Visual spatial attention is a critical process that allows for the selection and enhanced processing of relevant objects and locations. While studies have shown attentional modulations of perceived location and the representation of distance information across multiple objects, there remains disagreement regarding what influence spatial attention has on the underlying structure of visual space. The present study utilized a method of magnitude estimation in which participants must judge the location of briefly presented targets within the boundaries of their individual visual fields in the absence of any other objects or boundaries. Spatial uncertainty of target locations was used to assess perceived locations across distributed and focused attention conditions without the use of external stimuli, such as visual cues. Across two experiments we tested locations along the cardinal and 45 degrees oblique axes. We demonstrate that focusing attention within a region of space can expand the perceived size of visual space; even in cases where doing so makes performance less accurate. Moreover, the results of the present studies show that when fixation is actively maintained, focusing attention along a visual axis leads to an asymmetrical stretching of visual space that is predominantly focused across the central half of the visual field, consistent with an expansive gradient along the focus of voluntary attention. These results demonstrate that focusing sustained attention peripherally during active fixation leads to an asymmetrical expansion of visual space within the central visual field. PMID- 28025056 TI - Nonmalignant Pleural Effusions: A Prospective Study of 356 Consecutive Unselected Patients. AB - BACKGROUND: Pleural effusion secondary to a nonmalignant cause can represent significant morbidity and mortality. Nonmalignant pleural effusion (NMPE) is common, with congestive heart failure representing the leading cause. Despite this, there are limited data on mortality risk and associated prognostic factors. METHODS: We recruited 782 consecutive patients presenting to a pleural service between March 2008 and March 2015 with an undiagnosed pleural effusion. Further analysis was conducted in 356 patients with NMPE. Pleural biochemical analysis, cytologic analysis, thoracic ultrasonography, and chest radiography were performed. Echocardiography, CT imaging, radiologically guided biopsy, and medical thoracoscopy were undertaken as clinically indicated. Patients were followed for a minimum duration of 12 months, with the final diagnosis decided through independent review by two respiratory consultants. RESULTS: Of the 782 patients, 356 were diagnosed with NMPE (46%). These patients had a mean age of 68 years (SD, 17 years) with 69% of them being men. Patients with cardiac, renal, and hepatic failure had 1-year mortality rates of 50%, 46%, and 25%, respectively. Bilateral effusions (hazard ratio [HR], 3.55; 95% CI, 2.22-5.68) and transudative effusions (HR, 2.78; 95% CI, 1.81-4.28) were associated with a worse prognosis in patients with NMPE, with a 57% and 43% 1-year mortality rate, respectively. CONCLUSIONS: This is the largest prospectively collected series in patients with NMPE, demonstrating that cases secondary to organ dysfunction have extremely high 1-year mortality. In addition, the presence of bilateral and transudative effusions is an indicator of increased mortality. Clinicians should be aware of these poor prognostic features and guide management accordingly. PMID- 28025057 TI - A generalization of Kingman's model of selection and mutation and the Lenski experiment. AB - Kingman's model of selection and mutation studies the limit type value distribution in an asexual population of discrete generations and infinite size undergoing selection and mutation. This paper generalizes the model to analyze the long-term evolution of Escherichia. coli in Lenski experiment. Weak assumptions for fitness functions are proposed and the mutation mechanism is the same as in Kingman's model. General macroscopic epistasis are designable through fitness functions. Convergence to the unique limit type distribution is obtained. PMID- 28025058 TI - Moderate doses of commercial preparations of Ginkgo biloba do not alter markers of liver function but moderate alcohol intake does: A new approach to identify and quantify biomarkers of 'adverse effects' of dietary supplements. AB - : It is difficult to determine if certain dietary supplements are safe for human consumption. Extracts of leaves of Ginkgo biloba trees are dietary supplements used for various purported therapeutic benefits. However, recent studies reported they increased risk of liver cancer in rodents. Therefore, this study assessed the association between ginkgo consumption and liver function using NHANES 2001 2012 data (N = 29,684). Since alcohol is known to adversely affect liver function, association of its consumption with liver function was also assessed. Alcohol and ginkgo extract intake of adult consumers and clinical markers of liver function (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin) were examined. Moderate consumers of alcohol (0.80 +/- 0.02 drinks/day) had higher levels of aspartate aminotransferase and gamma glutamyl transferase than non-consumers (P < 0.001). There was no difference (P > 0.01) in levels of markers of liver function in 616 ginkgo consumers (65.1 +/- 4.4 mg/day intake) compared to non-consumers. While moderate alcohol consumption was associated with changes in markers of liver function, ginkgo intake as typically consumed by U.S. adults was not associated with these markers. Biomarkers measured by NHANES may be useful to examine potential adverse effects of dietary supplements for which insufficient human adverse event and toxicity data are available. TRIAL REGISTRATION NUMBER: Not applicable, as this is secondary analysis of publicly released observational data (NHANES 2001-2012). PMID- 28025060 TI - Liver sinusoidal endothelial cell cross-priming is supported by CD4 T cell derived IL-2. AB - BACKGROUND & AIMS: Liver sinusoidal endothelial cells (LSECs) are prominent liver resident antigen (cross-)presenting cells. LSEC cross-priming of naive CD8 T cells does not require CD4 T cell help in contrast to priming by dendritic cells (DC) but leads to the formation of memory T cells that is preceded by transient Granzyme B (GzmB) expression. Here we provide evidence for a so far unrecognized CD4 T helper cell function in LSEC-induced CD8 T cell activation. METHODS: Naive CD8 T cells and differentiated T helper 1 (Th1) cells were stimulated by antigen presenting LSEC, and GzmB expression in CD8 T cells was determined by flow cytometry. To identify molecular pathways mediating this GzmB expression, mechanistic proof-of-concept experiments were conducted using stimulatory anti CD3 antibody together with Hyper-IL-6. RESULTS: We demonstrate that LSECs simultaneously function in antigen co-presentation to CD8 and CD4 T cells. Such co-presentation revealed a function of Th1 cells to increase GzmB expression in CD8 T cells after LSEC but not DC cross-priming. IL-2 released from Th1 cells was required but not sufficient for rapid GzmB induction in CD8 T cells. T cell receptor together with IL-6 trans-signaling was necessary for IL-2 to mediate rapid GzmB induction. CONCLUSIONS: Our findings indicate that LSECs can serve as a platform to facilitate CD4-CD8 T cell crosstalk enhancing the immune function of LSECs to cross-prime CD8 T cells. IL-6 trans-signaling-mediated responsiveness for IL-2 inducing sustained GzmB expression in CD8 T cells reveals unique mechanisms of CD4 T cell help and CD8 T cell differentiation through liver resident antigen-presenting cells. LAY SUMMARY: Our findings demonstrate that LSEC co-present antigen to CD8 and CD4 T cells and thereby enable CD4 T cell help for LSEC-priming of CD8 T cells. This CD4 T cell help selectively enhances the rapid upregulation of GzmB and effector function of LSEC-primed CD8 T cells thereby enhancing functional differentiation towards CD8 effector T cells. PMID- 28025061 TI - Understanding Resident Performance, Mindfulness, and Communication in Critical Care Rotations. AB - OBJECTIVE: Evidence from the medical literature suggests that surgical trainees can benefit from mindful practices. Surgical educators are challenged with the need to address resident core competencies, some of which may be facilitated by higher levels of mindfulness. This study explores whether mindful residents perform better than their peers as members of the health care team. DESIGN: This study employed a multiphase, multimethod design to assess resident mindfulness, communication, and clinical performance. SETTING: Academic, tertiary medical center. PARTICIPANTS: Residents (N = 51) working in an intensive care unit. In phase I, medical residents completed a self-report survey of mindfulness, communication, emotional affect, and clinical decision-making. In phase II, resident performance was assessed using independent ratings of mindfulness and clinical decision-making by attending physicians and registered nurses. RESULTS: In phase 1, a significant positive relationship was found between resident performance and mindfulness, positive affect (PA), and communication. In phase 2, attending physicians/registered nurses' perceptions of residents' mindfulness were positively correlated with communication and inversely related to negative affect (NA). The top quartile of residents for performance and mindfulness had the lowest NA. Higher-rated residents underestimated their performance/mindfulness, whereas those in the lowest quartile overestimated these factors. CONCLUSIONS: This study offers a number of implications for medical resident education. First, mindfulness was perceived to be a significant contributor to self-assessments of competency and performance. Second, both PA and NA were important to mindfulness and performance. Third, communication was associated with resident performance, mindfulness, and PA. These implications suggest that individual characteristics of mindfulness, communication, and affect, all potentially modifiable, influence care quality and safety. To improve low performers, surgical educators could screen and identify residents with inaccurate self-assessments. Residents open to feedback will improve faster and develop awareness toward situations and interactions with patients, colleagues, attending physicians, and staff. PMID- 28025059 TI - MicroRNA-206 prevents hepatosteatosis and hyperglycemia by facilitating insulin signaling and impairing lipogenesis. AB - BACKGROUND & AIMS: The paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce lipids, has been central to the pathophysiology of hepatosteatosis and hyperglycemia. Our study was designed to investigate the mechanism(s) by which microRNA-206 alleviates the pathogenesis of hepatosteatosis and hyperglycemia. METHODS: Dietary obese mice induced by a high fat diet were used to study the role of microRNA-206 in the pathogenesis of hepatosteatosis and hyperglycemia. A mini-circle vector was used to deliver microRNA-206 into the livers of mice. RESULTS: Lipid accumulation impaired biogenesis of microRNA-206 in fatty livers of dietary obese mice and human hepatocytes (p<0.01). Delivery of microRNA-206 into the livers of dietary obese mice resulted in the strong therapeutic effects on hepatosteatosis and hyperglycemia. Mechanistically, miR-206 interacted with the 3' untranslated region of PTPN1 (protein tyrosine phosphatase, non-receptor type 1) and induced its degradation. By inhibiting PTPN1 expression, microRNA-206 facilitated insulin signaling by promoting phosphorylation of INSR (insulin receptor) and impaired hepatic lipogenesis by inhibiting Srebp1c transcription. By simultaneously modulating lipogenesis and insulin signaling, microRNA-206 reduced lipid (p=0.006) and glucose (p=0.018) production in human hepatocytes and livers of dietary obese mice (p<0.001 and p<0.01 respectively). Re-introduction of Ptpn1 into livers offset the inhibitory effects of microRNA-206, indicating that PTPN1 mediates the inhibitory effects of microRNA-206 on both hepatosteatosis and hyperglycemia. CONCLUSIONS: MicroRNA-206 is a potent inhibitor of lipid and glucose production by simultaneously facilitating insulin signaling and impairing hepatic lipogenesis. Our findings potentially provide a novel therapeutic agent for both hepatosteatosis and hyperglycemia. LAY SUMMARY: The epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complications, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). However, there are no effective treatments because the mechanisms underlying both disorders are not well described. We identified microRNA-206 as a novel and effective inhibitor for both glucose and lipid production in liver and potentially provide a unique therapeutic drug for both hepatosteatosis and hyperglycemia. PMID- 28025062 TI - A Randomized Controlled Trial to Compare e-Feedback Versus "Standard" Face-to Face Verbal Feedback to Improve the Acquisition of Procedural Skill. AB - BACKGROUND: Constructive feedback plays an important role in learning during surgical training. Standard feedback is usually given verbally following direct observation of the procedure by a trained assessor. However, such feedback requires the physical presence of expert faculty members who are usually busy and time-constrained by clinical commitments. We aim to evaluate electronic feedback (e-feedback) after video observation of surgical suturing in comparison with standard face-to-face verbal feedback. METHODS: A prospective, blinded, randomized controlled trial comparing e-feedback with standard verbal feedback was carried out in February 2015 using a validated pro formas for assessment. The study participants were 38 undergraduate medical students from the University of Sheffield, UK. They were recorded on video performing the procedural skill, completed a self-evaluation form, and received e-feedback on the same day (group 1); observed directly by an assessor, invited to provide verbal self-reflection, and then received standard verbal feedback (group 2). In both groups, the feedback was provided after performing the procedure. The participants returned 2 days later and performed the same skill again. Poststudy questionnaire was used to assess the acceptability of each feedback among the participants. RESULTS: Overall, 19 students in group 1 and 18 students in group 2 completed the study. Although there was a significant improvement in the overall mean score on the second performance of the task for all participants (first performance mean 11.59, second performance mean 15.95; p <= 0.0001), there was no difference in the overall mean improvement score between group 1 and group 2 (4.74 and 3.94, respectively; p = 0.49). The mean overall scores for the e-feedback group at baseline recorded by 2 independent investigators showed good agreement (mean overall scores of 12.84 and 11.89; Cronbach alpha = 0.86). Poststudy questionnaire demonstrated that both e-feedback and standard verbal feedback achieved high mean Likert grades as recorded by the participants (4.42 [range: 2 5] and 4.71 [range: 4-5], respectively; p = 0.274). CONCLUSION: e-Feedback after watching a video recording appears to be acceptable and is not quantitatively different than standard feedback in improving suturing skills among novice trainees. Video assessment of procedural skills is reliable. PMID- 28025063 TI - Was it me? - Filling the interval between action and effects increases agency but not sensory attenuation. AB - Sensory stimuli resulting from one's own actions are perceptually attenuated compared to identical but externally produced stimuli. This may enable the organism to discriminate between self-produced events and externally produced events, suggesting a strong link between sensory attenuation and a subjective sense of agency. To investigate this supposed link, we compared the influence of filled and unfilled action-effect delays on both, judgements of agency for self produced sounds and attenuation of the event-related potential (ERP). In line with previous findings, judgments of agency differed between both delay conditions with higher ratings for filled than for unfilled delays. Sensory attenuation, however, was not influenced by filling the delay. These findings indicate a partial dissociation of the two phenomena. PMID- 28025064 TI - Effects of Nuclear Factor-E2-related factor 2/Heme Oxygenase 1 on splanchnic hemodynamics in experimental cirrhosis with portal hypertension. AB - OBJECTIVE: We explored the effects of Nuclear Factor-E2-related factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1) on splanchnic hemodynamics in portal hypertensive rats. METHODS: Experimental cirrhosis with portal hypertension was induced by intraperitoneal injection of carbon tetrachloride. The expression of proteins was examined by immunoblotting. Hemodynamic studies were performed by radioactive microspheres. The vascular perfusion system was used to measure the contractile response of mesentery arterioles in rats. RESULTS: Nrf2 expression in the nucleus and HO-1 expression in cytoplasm was significantly enhanced in portal hypertensive rats. Portal pressure, as well as regional blood flow, increased significantly in portal hypertension and can be blocked by tin protoporphyrin IX. The expression of endogenous nitric oxide synthase and vascular endothelial growth factors increased significantly compared to normal rats, while HO-1 inhibition decreased the expression of these proteins significantly. The contractile response of mesenteric arteries decreased in portal hypertension, but can be partially recovered through tin protoporphyrin IX treatment. CONCLUSIONS: The expression of Nrf2/HO-1 increased in mesenteric arteries of portal hypertensive rats, which was related to oxidative stress. HO-1was involved in increased portal pressure and anomaly splanchnic hemodynamics in portal hypertensive rats. PMID- 28025065 TI - Trends in U.S. Cardiovascular Care: 2016 Report From 4 ACC National Cardiovascular Data Registries. AB - Cardiovascular disease is a leading cause of death and disability in the United States. National programs, such as the National Cardiovascular Data Registry, facilitate assessments of the quality of care and outcomes for broad populations of patients with cardiovascular disease. This report provides data for 2014 from 4 National Cardiovascular Data Registry hospital quality programs: 1) CathPCI (Diagnostic Catheterization and Percutaneous Coronary Intervention) for coronary angiography and percutaneous coronary intervention (667,424 procedures performed in 1,612 hospitals); 2) ICD Registry for implantable cardioverter-defibrillators (158,649 procedures performed in 1,715 hospitals); 3) ACTION-GWTG (Acute Coronary Treatment and Intervention Outcomes Network-Get With The Guidelines) for acute coronary syndromes (182,903 patients admitted to 907 hospitals); and 4) IMPACT (Improving Pediatric and Adult Congenital Treatment) for cardiac catheterization and intervention for pediatric and adult congenital heart disease (20,169 procedures in 76 hospitals). The report provides perspectives on the demographic and clinical characteristics of enrolled patients, characteristics of participating centers, and selected measures of processes and outcomes of care in these programs. PMID- 28025066 TI - Executive Summary: Trends in U.S. Cardiovascular Care: 2016 Report From 4 ACC National Cardiovascular Data Registries. PMID- 28025067 TI - Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats. AB - The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. PMID- 28025068 TI - Transcription of four Rhopalosiphum padi (L.) heat shock protein genes and their responses to heat stress and insecticide exposure. AB - The bird cherry-oat aphid, Rhopalosiphum padi (L.), a worldwide destructive pest, is more heat tolerant than other wheat aphids, and it has developed resistance to different insecticides. Heat shock proteins (HSPs) play an important role in coping with environmental stresses. To investigate Hsp transcriptional responses to heat and insecticide stress, four full-length Hsp genes from R. padi (RpHsp60, RpHsc70, RpHsp70-1, and RpHsp70-2) were cloned. Four RpHsps were expressed during all R. padi developmental stages, but at varying levels. The mRNA levels of RpHsps were increased under thermal stress and reached maximal induction at a lower temperature (36 degrees C) in the alate morph than in the apterous morph (37 degrees C or 38 degrees C). RpHsp expressions under heat stress suggest that RpHsp70-1 and RpHsp70-2 are inducible in both apterous and alate morphs, RpHsc70 is only heat-inducible in apterous morph, and RpHsp60 exhibits poor sensitivity to heat stress. The pretreatment at 37 degrees C significantly increase both the survival rate and the RpHsps expression level of R. padi at subsequent lethal temperature. Under exposure to two sublethal concentrations (LC10 and LC30) of beta-cypermethrin, both RpHsp70-1 and RpHsp70-2 expressions were induced and reached a maximum 24h after exposure. In contrast, expression of RpHsp60 was not induced by either sublethal concentration of beta-cypermethrin. Moreover, the responses of RpHsp70-1 and RpHsp70-2 to heat shock were more sensitive than those to beta-cypermethrin. These results suggest that induction of RpHsp expression is related to thermal tolerance, and that RpHsp70-1 and RpHsp70-2 are the primary genes involved in the response to both heat and pesticide stress. PMID- 28025069 TI - Does reactivation trigger episodic memory change? A meta-analysis. AB - According to the reconsolidation hypothesis, long-term memories return to a plastic state upon their reactivation, leaving them vulnerable to interference effects and requiring re-storage processes or else these memories might be permanently lost. The present study used a meta-analytic approach to critically evaluate the evidence for reactivation-induced changes in human episodic memory. Results indicated that reactivation makes episodic memories susceptible to physiological and behavioral interference. When applied shortly after reactivation, interference manipulations altered the amount of information that could be retrieved from the original learning event. This effect was more pronounced for remote memories and memories of narrative structure. Additionally, new learning following reactivation reliably increased the number of intrusions from new information into the original memory. These findings support a dynamic view of long-term memory by showing that memories can be changed long after they were acquired. PMID- 28025070 TI - A recombinant vesicular stomatitis virus encoding CCR5-tropic HIV-1 receptors targets HIV-1-infected cells and controls HIV-1 infection. AB - Anti-retroviral therapy is useful to treat human immunodeficiency virus type 1 (HIV-1)-infected individuals, but has some major problems, such as the generation of multidrug-resistant viruses. To develop a novel supplemental or alternative therapeutic for CCR5-tropic (R5) HIV-1 infection, we generated a recombinant vesicular stomatitis virus (rVSV) in which the gene encoding its envelope glycoprotein (G) was replaced with the genes encoding R5 HIV-1 receptors (human CD4 and CCR5), designated VSVDeltaG-CC5. Our present data demonstrate that this rVSV specifically infects cells that are transiently expressing R5 HIV-1 envelope glycoproteins, but does not infect those expressing CXCR4-tropic HIV-1 envelope glycoproteins. Notably, after a CD4+CCR5+ T cell line or primary cells initially infected with R5 HIV-1 were inoculated with G-complemented VSVDeltaG-CC5, the rVSV significantly reduced the number of HIV-1-infected cells, probably through direct targeting of the rVSV and VSV-mediated cytolysis and/or through syncytium formation- or cell-cell fusion-dependent killing, and markedly inhibited HIV-1 production. Furthermore, G-complemented VSVDeltaG-CC5 also efficiently inhibited HIV-1 infection in R5 HIV-1-infected humanized immunodeficient mice. Taken together, our findings indicate that a cytolytic rVSV that targets and eliminates R5 HIV-1-infected cells potentially has therapeutic value for controlling R5 HIV 1 infection. PMID- 28025071 TI - Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls. AB - : Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. METHODS: FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial statistic was used to obtain measures of white matter integrity (fractional anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with 35 directions. Patients were also studied for fMRI through a moral valence decision task were subjects had to decide whether morally tuned stimuli were positive or negative. RESULTS: The percentage of circulating Th17 (CCR6+CXCR3negCCR4+CCR10neg) cells correlated positively with higher fractional anisotropy in fiber tracts contributing to the functional integrity of the brain both in patients and healthy controls, while the frequency of circulating T regulatory (CD4+CD25+FOXP3+) cells correlated positively with higher radial and mean diffusivity in patients. The frequency of circulating T regulatory cells also correlated to lower neuronal responses to negative versus positive morally tuned stimuli in the right dorsolateral prefrontal cortex of patients. Th1 cells correlated negatively with white matter integrity in several tracts (healthy controls), while the cells showed a positive correlation to the levels of pro inflammatory cytokines (patients). CONCLUSION: This study shows a new putative role for Th17 cells. Th17 cells are not only playing a role in inducing autoimmunity and auto-inflammation, but might also play a counter intuitive anabolic role in the maintenance of the functional and structural integrity of the brain. PMID- 28025072 TI - Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation. AB - Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgf-phospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with three molar ratios of Mgf and Phospholipon 90G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10 fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line studies indicated insignificant cytotoxicity, and P-gp efflux, while bi directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-a-vis Mgf solution. In a nutshell, the promising results observed from the present research work signify enhanced biopharmaceutical attributes of the novel PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf. PMID- 28025073 TI - Nano- and Microstructured model carrier surfaces to alter dry powder inhaler performance. AB - The present study investigates the effect of different carrier surface modifications on the aerosolisation performance and on the effective carrier payload of interactive blends for inhalation. Two different active pharmaceutical ingredients (APIs) were used: Formoterol fumarate dihydrate (FF) and budesonide (BUD). Blends were prepared with glass beads as model carriers which have been subjected to mechanical surface modifications in order to introduce surface roughness via treatment with hydrofluoric acid (HF) and/or milling with tungsten carbide (TC). As far as effective carrier payload, in this study expressed as true surface coverage (TSC), is concerned, surface modification had varying effects on blends containing BUD or FF. Aerodynamic characterisation in vitro showed a significant decrease in respirable fraction for glass beads treated with HF (40.2-50.1%), due to the presence of clefts and cavities, where drug particles were sheltered during inhalation. In contrast, grinding with TC leads to surface roughness on a nano scale, ultimately increasing aerodynamic performance up to 20.0-38.1%. These findings are true for both APIs, regardless of their chemical properties. PMID- 28025074 TI - The evaluation of physical properties of injection molded systems based on poly(ethylene oxide) (PEO). AB - The effect of product design parameters on the formation and properties of an injection molded solid dosage form consisting of poly(ethylene oxide)s (PEO) and two different active pharmaceutical ingredients (APIs) was studied. The product design parameters explored were melting temperature and the duration of melting, API loading degree and the molecular weight (Mw) of PEO. The solid form composition of the model APIs, theophylline and carbamazepine, was of specific interest, and its possible impact on the in vitro drug release behavior. Mw of PEO had the greatest impact on the release rate of both APIs. High Mw resulted in slower API release rate. Process temperature had two-fold effect with PEO 300,000g/mol. Firstly, higher process temperature transformed the crystalline part of the polymer into metastable folded form (more folded crystalline regions) and less into the more stable extended form (more extended crystalline regions), which lead to enhanced theophylline release rate. Secondly, the higher process temperature seemed to induce carbamazepine polymorphic transformation from p monoclinic form III (carbamazepine (M)) into trigonal form II (carbamazepine (T)). The results indicated that the actual content of carbamazepine (T) affected drug release behavior more than the magnitude of transformation. PMID- 28025075 TI - Influence of particle properties on powder bulk behaviour and processability. AB - Understanding interparticle interactions in powder systems is crucial to pharmaceutical powder processing. Nevertheless, there remains a great challenge in identifying the key factors affecting interparticle interactions. Factors affecting interparticle interactions can be classified in three different broad categories: powder properties, environmental conditions, and powder processing methods and parameters. Although, each of these three categories listed is known to affect interparticle interactions, the challenge remains in developing a mechanistic understanding on how combination of these three categories affect interparticle interactions. This review focuses on the recent advances on understanding the effect of powder properties, particularly particle properties, its effect on interparticle interactions and ultimately on powder bulk behaviour. Furthermore, this review also highlights how particle properties are affected by the particle processing route and parameters. Recent advances in developing a particle processing route to prepare particles with desired properties allowing desired interparticle interaction to deliver favoured powder bulk behaviour are also discussed. Perspectives for the development of potential particle processing approaches to control interparticle interaction are presented. PMID- 28025076 TI - Unusual extramedullary hematopoietic neoplasms in lymph nodes. AB - Myeloid, plasma cell, and lymphoblastic neoplasms are expected findings in bone marrow but are much less commonly diagnosed as primary processes in lymph nodes. The objective of this review is to aid pathologists in recognizing common hematopoietic neoplasms in the unusual setting of initial presentation in lymph nodes. Review of historical background and evolution of testing strategies is presented to improve understanding of the need for accurate diagnosis and classification using current nomenclature. The review is based on peer-reviewed literature and the personal experience of the authors. The University of Minnesota Medical Center, Fairview provides lymph node diagnostic consultation services for its busy oncology and therapeutic hematopoietic cell transplant divisions serving patients from around the globe. Although readily recognizable when they present in bone marrow, myeloid leukemia in the form of myeloid sarcoma, plasmacytoma, and lymphoblastic lymphoma can create diagnostic and classification challenges when they present as primary lymph node pathologies. Use of all diagnostic tools may be necessary to ensure accurate and reproducible diagnoses. PMID- 28025077 TI - CD45 is a more sensitive marker than CD3 to diagnose lymphocytic myocarditis in the endomyocardium. AB - To diagnose lymphocytic myocarditis (LM), immunohistopathological examination of endomyocardial biopsies (EMBs) is used with a cutoff value of at least 14 leukocytes per mm2, composed of CD3- and CD68-positive cells. We hypothesized that a more common leukocyte marker, CD45, instead of CD3 could increase the diagnostic sensitivity. Hearts of mice with acute viral myocarditis (n = 9) and of controls (n = 7) and the EMB sampling area of the left ventricular posterior wall (LVPW) obtained from autopsied hearts of patients diagnosed with LM (n = 18) and controls (n = 6) were stained with anti-CD68, anti-CD3, and anti-CD45. When applying the threshold of at least 14 leukocytes per mm2, 33% of the mice would be diagnosed with LM with the use of CD3+CD68 and 89% with the use of CD45+CD68. In the EMB sampling area of autopsied hearts, using the cutoff value of at least 14 leukocytes per mm2, CD3+CD68 could only confirm 17% of the diagnosis of LM, whereas CD45+CD68 could confirm 50% of the LM cases. Moreover, we compared inflammation in the EMB sampling area of the LVPW to the remaining myocardium of the LVPW and observed a significant increase of CD45+CD68 cells per mm2 in patients with LM. In conclusion, the use of the common leukocyte marker CD45 increases the sensitivity of the diagnosis of LM. Furthermore, the inflammatory infiltrate in the EMB sampling area is significantly increased compared with the remaining LVPW, indicating that the sampling area constitutes the highest chance for histological diagnosis of LM. PMID- 28025078 TI - Analysis of KRAS, NRAS, PIK3CA, and BRAF mutational profile in poorly differentiated clusters of KRAS-mutated colon cancer. AB - Recently, a grading system based on the counting of poorly differentiated clusters (PDCs) of neoplastic cells was shown to be a strong predictor of nodal metastases and negative prognosis in colon cancer (CC). In this study, we assessed and compared the mutational status of KRAS, NRAS, and PIK3CA in PDCs and corresponding main tumor tissue of 25 CCs with KRAS mutations. For each tumor, PDC and main tumor tissue were distinctly analyzed by using laser microdissection and mass spectrometry. In 3 CCs, the main tumor tissue had also PIK3CA mutations (C420R: 1; E545K: 1; H1047R: 1), and in 1, it showed NRAS mutation (codon 12). In 20 cases, PDCs had the same biomolecular profile as the main tumor, but in 5, they had different biomolecular profiles. In detail, PDCs had KRAS wild type in 2 cases and additional PIK3CA mutations (E542K: 1; H1047Y: 1; E545Q: 1) in 3. All 3 cases with additional PIK3CA mutations in PDCs had nodal metastases, high pathological TNM stage, and lymphatic invasion. In 1 of 3 cases, additional PIK3CA mutation detected in PDC, but not in the main tumor, was also found in the corresponding nodal metastases. Our findings show for the first time that heterogeneous biomolecular profile previously observed in CC may depend on different histologic aspects of the lesion. Because PDCs may represent the tumor cells with the highest potential to metastatize, their molecular status may be relevant for the prediction of response to targeted therapies. PMID- 28025079 TI - betaIII-tubulin overexpression is linked to aggressive tumor features and genetic instability in urinary bladder cancer. AB - Development of genetic instability is a hallmark of tumor progression. Type III beta-tubulin (TUBB3) is a component of microtubules involved in chromosome segregation. Its overexpression has been linked to adverse features of urinary bladder cancer. To investigate the role of TUBB3 for development of genetic instability, we compared TUBB3 expression with histopathological features and surrogate markers of genetic instability and tumor aggressiveness; copy number changes of HER2, TOP2A, CCND1, RAF1, and FGFR1; nuclear accumulation of p53, and cell proliferation in a tissue microarray (TMA) with more than 700 bladder cancers. TUBB3 expression was linked to high-grade and advanced-stage cancers (P<.0001), rapid cell proliferation (P<.0001), presence of multiple gene copy number alterations (P=.0008), and nuclear accumulation of p53 (P=.0008). Strong TUBB3 staining was found in 43% of urothelial cancers harboring copy number alterations as compared with 28% of genetically stable cancers, and in 50% of p53 positive cancers as compared with 30% of p53-negative tumors. The fraction of tumors with concomitant TUBB3 and p53 positivity increased with tumor stage and grade: 2% in pTaG1-2, 11% in pTaG3, 17% in pT1G2, 23% in pT1G3, and 32% in pT2-4 cancers (P<.0001). Importantly, strong TUBB3 overexpression was detectable in about 20% of low-grade, noninvasive cancers. In summary, our study demonstrates that TUBB3 overexpression is linked to an aggressive subtype of urinary bladder cancers, which is characterized by increased genetic instability, p53 alterations, and rapid cell proliferation. Detection of TUBB3 overexpression in genetically stable, low-grade, and noninvasive bladder cancers may be clinically useful to identify patients requiring particular close monitoring. PMID- 28025080 TI - Expression of mTORC1/2-related proteins in primary and brain metastatic lung adenocarcinoma. AB - Brain metastases (BMs) are common complications of adenocarcinomas (ADCs) of the lung and are associated with a poor prognosis. Although an increasing amount of data indicates that dysregulated activity of mammalian target of rapamycin (mTOR) can influence the metastatic potential of various tumors, the role of mTOR complexes in the development of BMs from ADCs of the lung is largely unknown. To estimate mTOR activity, we studied the expression of mTOR-related proteins (mTORC1: p-mTOR, p-S6; mTORC2: p-mTOR, Rictor) in primary (n=67) and brain metastatic (n=67) lung ADCs, including 15 paired tissue samples, using immunohistochemistry and tissue microarrays. Correlation with clinicopathological parameters was also analyzed. Increased p-mTOR, p-S6, and Rictor expressions were observed in 34%, 33%, and 37% of primary ADCs and in 79%, 70%, and 66% of BMs, respectively. Expression of these markers was significantly higher in BMs as compared with primary carcinomas (P<.0001, P<.0001, P<.001). Rictor expression was significantly higher in primary ADCs of the paired cases with BMs as compared with primary ADCs without BMs (67% versus 28%; P<.01). No other statistically significant correlations were found between mTOR activity and clinicopathological parameters. The increased mTORC1/C2 activity in a subset of pulmonary ADCs and the higher incidence of increased mTORC1/C2 activity in BMs suggest that the immunohistochemistry panel for characterizing mTOR activity and its potential predictive and prognostic role warrants further investigations. PMID- 28025081 TI - Biochemical characterization of TyrA enzymes from Ignicoccus hospitalis and Haemophilus influenzae: A comparative study of the bifunctional and monofunctional dehydrogenase forms. AB - Biosynthesis of l-tyrosine (l-Tyr) is directed by the interplay of two enzymes. Chorismate mutase (CM) catalyzes the rearrangement of chorismate to prephenate, which is then converted to hydroxyphenylpyruvate by prephenate dehydrogenase (PD). This work reports the first characterization of the independently expressed PD domain of bifunctional CM-PD from the crenarchaeon Ignicoccus hospitalis and the first functional studies of both full-length CM-PD and the PD domain from the bacterium Haemophilus influenzae. All proteins were hexa-histidine tagged, expressed in Escherichia coli and purified. Expression and purification of I. hospitalis CM-PD generated a degradation product identified as a PD fragment lacking the protein's first 80 residues, Delta80CM-PD. A comparable stable PD domain could also be generated by limited tryptic digestion of this bifunctional enzyme. Thus, Delta80CM-PD constructs were prepared in both organisms. CM-PD and Delta80CM-PD from both organisms were dimeric and displayed the predicted enzymatic activities and thermal stabilities in accord with their hyperthermophilic and mesophilic origins. In contrast with H. influenzae PD activity which was NAD+-specific and displayed >75% inhibition with 50MUM l-Tyr, I. hospitalis PD demonstrated dual cofactor specificity with a preference for NADP+ and an insensitivity to l-Tyr. These properties are consistent with a model of the I. hospitalis PD domain based on the previously reported structure of the H. influenzae homolog. Our results highlight the similarities and differences between the archaeal and bacterial TyrA proteins and reveal that the PD activity of both prokaryotes can be successfully mapped to a functionally independent unit. PMID- 28025082 TI - Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization. AB - BACKGROUND: Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. METHODS: Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations. RESULTS: Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed. CONCLUSIONS: Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. GENERAL SIGNIFICANCE: The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 28025083 TI - G-quadruplexes in human promoters: A challenge for therapeutic applications. AB - BACKGROUND: G-rich sequences undergo unique structural equilibria to form G quadruplexes (G4) both in vitro and in cell systems. Several pathologies emerged to be directly related to G4 occurrence at defined genomic portions. Additionally, G-rich sequences are significantly represented around transcription start sites (TSS) thus leading to the hypothesis of a gene regulatory function for G4. Thus, the tuning of G4 formation has been proposed as a new powerful tool to regulate gene expression to treat related pathologies. However, up-to date this approach did not provide any new really efficient treatment. SCOPE OF REVIEW: Here, we summarize the most recent advances on the correlation between the structural features of G4 in human promoters and the role these systems physiologically exert. In particular we focus on the effect of G4 localization among cell compartments and along the promoters in correlation with protein interaction networks and epigenetic state. Finally the intrinsic structural features of G4 at promoters are discussed to unveil the contribution of different G4 structural modules in this complex architecture. MAJOR CONCLUSIONS: It emerges that G4s play several roles in the intriguing and complex mechanism of gene expression, being able to produce opposite effects on the same target. This reflects the occurrence of a highly variegate network of several components working simultaneously. GENERAL SIGNIFICANCE: The resulting picture is still fuzzy but some points of strength are definitely emerging, which prompts all of us to strengthen our efforts in view of a selective control of gene expression through G4 modulation. This article is part of a Special Issue entitled "G quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. PMID- 28025084 TI - A profiling study of a newly developed HCVcc strain PR63cc's sensitivity to direct-acting antivirals. AB - The development of direct-acting antivirals (DAAs) has significantly improved hepatitis C virus (HCV) treatment. However, drug resistance remains a potential concern in the real-world DAA-based therapies. We previously developed a novel full-length genotype 2a HCVcc clone PR63cc directly from clinical isolates. Here in this study, we compared the sensitivity of PR63cc and JFH1 to 12 different DAAs most of which are either already in clinical use or in the late clinical development phase. For NS5B inhibitors, PR63cc and JFH1 displayed comparable sensitivity to nucleoside/nucleotide analogues sofosbuvir and 2'-C methyladenosine, while PR63cc was 4-fold more sensitive than JFH1 to nesbuvir, a non-nucleoside inhibitor. Interestingly, PR63cc and JFH1 were both completely resistant to dasabuvir which efficiently inhibited the replication of genotype 1b HCV replicon. For NS5A inhibitors, while PR63cc was as sensitive as JFH1 to ombitasvir and velpatasvir, it was much more resistant than JFH1 to daclatasvir and ledipasvir, which was mainly due to methionine at amino acid residue 31 of NS5A. For NS3 inhibitors, PR63cc was generally less sensitive than JFH1 to simeprevir, grazoprevir, asunaprevir and paritaprevir. Serine at residue 67 of NS3 was identified to be a resistance-associated variant (RAV) for asunaprevir. Finally, we showed that PR63cc was more resistant than JFH1 to the asunaprevir/daclatasvir combination treatment. In summary, our study systemically analyzed the DAA sensitivity of a new HCVcc strain and identified critical RAVs. These results are not only important for monitoring the emergence of drug resistant mutations of current DAA therapies, but also valuable for developing next-generation DAAs. PMID- 28025085 TI - Modelling viral infections using zebrafish: Innate immune response and antiviral research. AB - Zebrafish possess a highly developed immune system that is remarkably similar to the human one. Therefore, it is expected that the majority of the signalling pathways and molecules involved in the immune response of mammals exist and behave similarly in fish. The innate antiviral response depends on the recognition of viral components by host cells. Pattern recognition receptors initiate antimicrobial defence mechanisms via several well-conserved signalling pathways. In this paper, we review current knowledge of the antiviral innate immune response in zebrafish by considering the main molecules that have been characterized and the infection models used for the in vivo study of the antiviral innate immune response. We next summarize published studies in which larval and adult zebrafish were used to study viral diseases of fish, then provide a similar review of studies of human viral diseases in zebrafish and experience with antiviral drug screening in this model organism. PMID- 28025086 TI - Exercise training on skill-related physical fitness in adolescents with intellectual disability: A systematic review and meta-analysis. AB - BACKGROUND: Skill-related fitness (SRF) is a component of physical fitness related to sports or occupational performance. Adolescents with intellectual disability (ID) can take advantage of SRF for enhancing work performance and enjoying participation with peers in leisure activities. However, few studies have examined the benefits of exercise on SRF in adolescents with ID. OBJECTIVE: This study synthesized the results from the reviewed studies and determined whether exercise training improves SRF in adolescents with ID. METHODS: We searched ten electronic databases and used the Physiotherapy Evidence Database (PEDro) scale to assess the methodological quality of included studies. This study pooled quantitative data where possible in statistical meta-analyses and expressed the effect sizes (ESs) as Cohen's d and converted it to Hedges's g. Eighteen studies met inclusion criteria for systematic review, of which 14 for further meta-analyses. RESULTS: Nine meta-analyses were conducted in this study. The results supported positive exercise training effects on agility, power, RT, and speed, but not balance (Hedges's g range -1.465-0.760) in adolescents with ID. CONCLUSIONS: We found only a limited number of studies exhibiting high quality evidence and were being included in the meta-analyses. Therefore, the results of our systematic review and meta-analyses should be interpreted with caution. PMID- 28025087 TI - Comparing women with and without disabilities in five-site "Healthy Weight" interventions for lesbian/bisexual women over 40. AB - BACKGROUND: Lesbian/bisexual women with physical disabilities (LBPD) are an under studied population. OBJECTIVES: This study compared LBPD to LB women without physical disabilities as defined by the Americans with Disabilities Act on socio demographic variables, health characteristics, and quality of life, physical activity, weight, and nutrition outcomes following a health intervention. METHODS: Data came from the Healthy Weight in Lesbian and Bisexual Women Study (HWLB) where 376 LB women were recruited into five geographically dispersed interventions. Baseline data were examined to compare women with and without physical disabilities as defined by the ADA, and pre/post intervention data were analyzed for differences in treatment outcomes including quality of life, physical activity, nutrition, and body size. RESULTS: Compared to women without disability, LBPD were more likely to be bisexual or another sexual identity than lesbian, single, report poor or fair health status, postmenopausal, and had a higher body mass index and waist circumference to height ratio. LBPD women were less likely to work and to drink heavily, and reported reduced physical and mental health quality of life. In spite of these differences, after the intervention, LBPD had similar outcomes to women without disabilities on most measures, and were more likely to show improvements in physical quality of life and consumption of fruits/vegetables. CONCLUSIONS: Although different from women without disabilities on many socio-demographic and health variables at baseline, the study suggests that LBPD have similar outcomes to women without disabilities, or may even do better, in group health interventions. PMID- 28025088 TI - Health and participation problems in older adults with long-term disability. AB - BACKGROUND: More attention and understanding of the health and participation problems of adults with early and later onset disabilities in the Netherlands is needed. OBJECTIVE: To explore health/participation problems and unmet needs in adults aged >=40 years with long-term disabilities and their relationship with the time of onset. METHODS: Participants were recruited in the Netherlands through newsletters and social media to participate in a web-based questionnaire. The questionnaire assessed background characteristics, (change in) health/participation problems, and unmet needs. Spearman's rho was used to examine the relationships with time of onset. RESULTS: Of the 163 survey respondents, 42% acquired their disability before age 25 years and reported fatigue (77%), walking problems (66%), and pain (59%). In 21% of the respondents with early-onset disability fatigue, pain and depressive feelings co-occurred. Early-onset disability correlated with joint deformities, pain and anxiety. Participation problems included loss of income and fewer social activities. Early onset correlated with the need for more information about diagnosis and prognosis. CONCLUSIONS: People aged over 40 years with long-term disability have significant and increasing health and participation problems. Adults with early onset disability are more likely to have health or participation problems than adults with late-onset disability. Early identification is needed for preventive care and access to specialized services that focus on improving and maintaining physical symptoms, energy management, and participation. PMID- 28025089 TI - Histone deacetylase 5 modulates the effects of social adversity in early life on cocaine-induced behavior. AB - Psychostimulants induce stable changes in neural plasticity and behavior in a transcription-dependent manner. Further, stable cellular changes require transcription that is regulated by epigenetic mechanisms that alter chromatin structure, such as histone acetylation. This mechanism is typically catalyzed by enzymes with histone acetyltransferase or histone deacetylase (HDAC) activity. Class IIa HDACs are notable for their high expression in important regions of the brain reward circuitry and their neural activity-dependent shuttling in and out of the cell nucleus. In particular, HDAC5 has an important modulatory function in cocaine-induced behaviors and social defeat stress-induced effects. Although a mutation in HDAC5 has been shown to cause hypersensitive responses to chronic cocaine use whether this response worsens during chronic early life stress has not been examined yet. In this study, we exposed mouse pups to two different early life stress paradigms (social isolation, ESI, and social threat, EST) to determine whether the heterozygous null mutation in HDAC5 (HDAC5+/-) moderated the effects of exposure to stress in early life on adult cocaine-induced conditioned place preference (CPP). Notably, HDAC5+/- mice that had been exposed to ESI were more susceptible to developing cocaine-induced CPP and more resistant to extinguishing this behavior. The same effect was not observed for HDAC5+/- mice experiencing EST, suggesting that only ESI induces behavioral changes by acting precisely through HDAC5-related biological pathways. Finally, an analysis of c-Fos expression performed to discover the neurobiological substrates that mediated this phenotype, identified the dorsolateral striatum as an important structure that mediates the interaction between HDAC5 mutation and ESI. Our data demonstrate that decreased HDAC5 function is able to exacerbate the long-term behavioral effects of adverse rearing environment in mouse. PMID- 28025090 TI - Temporal organization: A novel mechanism of hormonal control of male-typical sexual behavior in vertebrates. AB - In vertebrates, male-typical sexual behavior (MSB) is largely controlled by gonadal androgens, however, the mechanism of this control is believed to vary among species. During immediate activation MSB is tightly correlated with circulating levels of androgens, while the organization of MSB by a hormonal event at a specific developmental period, early in ontogeny or during puberty, has been postulated in other lineages. Here, we put forward an alternative concept of "temporal organization". Under temporal organization longer exposure to circulating androgens is needed for the onset of MSB, which can continue for a long time after the levels of these hormones drop. We tested this concept through long-term monitoring of MSB in females and castrated males of the leopard gecko (Eublepharis macularius) in response to experimental changes in testosterone levels. Several weeks of elevated testosterone levels were needed for the full expression of MSB in both treatment groups and MSB diminished only slowly and gradually after the supplementation of exogenous testosterone ended. Moreover, despite receiving the same application of the hormone both the progressive onset and the cessation of MSB were significantly slower in experimental females than in castrated males. We suggest that the concept of temporal organization of MSB can parsimoniously explain several earlier discrepancies and debatable conclusions on the apparent variability in the hormonal control of MSB in vertebrates, which were based on behavioral testing at a few subjectively selected time points. We conclude that long-term and continuous behavioral testing after hormonal manipulations is needed to understand the regulation of MSB in vertebrates. PMID- 28025091 TI - Stereopsis in end-stage renal disease (ESRD). AB - We investigated an effect of end-stage renal disease (ESRD) on the visual system by measuring the ability of 21 patients to perceive depth in the random dot stereograms and circles of the Randot Test. To control for other factors which might influence performance on the tests of stereopsis, patients were compared with healthy controls matched for age, years of education, IQ, and general cognitive ability. Vernier acuity (thought to reflect mainly central processing) and Landolt acuity (more sensitive to retinal and optical abnormalities) were also measured, but the study did not include a formal ophthalmological examination. All controls could perceive depth in random dot stereograms, whereas 9/21 patients could not. Patients who could perceive depth had worse stereoacuity than did their matched controls. The patient group as a whole had worse Vernier and Landolt acuities than the controls. The stereoblind patient subgroup had similar Vernier acuity to the stereoscopic subgroup, but worse Landolt acuity, and was more likely to have peripheral vascular disease. We conclude that ESRD had affected structures both within the eye, and within the visual brain. However, the similarity of Vernier acuity and difference of Landolt acuity in the stereoblind and stereoscopic patient subgroups suggest that the differences in stereoscopic ability arise from abnormalities in the eyes rather than in the brain. PMID- 28025092 TI - Sex and the stimulus-movement effect: Differences in acquisition of autoshaped responding in cynomolgus monkeys. AB - The stimulus-movement effect refers to the phenomenon in which stimulus discrimination or acquisition of a response is facilitated by moving stimuli as opposed to stationary stimuli. The effect has been found in monkeys, rats, and humans, but the experiments conducted did not provide adequate female representation to investigate potential sex differences. The current experiment analyzed acquisition of stimulus touching in a progressive series of classical conditioning procedures in cynomolgus monkeys (Macaca fascicularis) as a function of sex and stimulus movement. Classical conditioning tasks arrange two or more stimuli in relation to each other with different temporal and predictive relations. Autoshaping procedures overlay operant contingencies onto a classical conditioning stimulus arrangement. In the present case, a neutral stimulus (a small gray square displayed on a touchscreen) functioned as the conditional stimulus and a food pellet functioned as the unconditional stimulus. Although touching is not required to produce food, with repeated stimulus pairings subjects eventually touch the stimulus. Across conditions of increasing stimulus correlation and temporal contiguity, male monkeys acquired the response faster with a moving stimulus. In contrast, females acquired the response faster with a stationary stimulus. These results demonstrate that the stimulus-movement effect may be differentially affected by sex and indicate that additional experiments with females are needed to determine how sex interacts with behavioral phenomena discovered and elaborated almost exclusively using males. PMID- 28025093 TI - Varenicline improves motor and cognitive deficits and decreases depressive-like behaviour in late-stage YAC128 mice. AB - OBJECTIVE: Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease. METHOD: The performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively. RESULTS: Chronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival. INTERPRETATION: Our findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease. PMID- 28025094 TI - Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain. AB - Serotonergic mechanisms play a central role in migraine pathology. However, the region-specific effects of serotonin (5-HT) mediated via multiple types of receptors in the nociceptive system are poorly understood. Using extracellular and patch-clamp recordings, we studied the action of 5-HT on the excitability of peripheral and central terminals of trigeminal afferents. 5-HT evoked long lasting TTX-sensitive firing in the peripheral terminals of meningeal afferents, the origin site of migraine pain. Cluster analysis revealed that in majority of nociceptive fibers 5-HT induced either transient or persistent spiking activity with prevailing delta and theta rhythms. The 5-HT3-receptor antagonist MDL-72222 or 5-HT1B/D-receptor antagonist GR127935 largely reduced, but their combination completely prevented the excitatory pro-nociceptive action of 5-HT. The 5-HT3 agonist mCPBG activated spikes in MDL-72222-dependent manner but the 5HT-1 receptor agonist sumatriptan did not affect the nociceptive firing. 5-HT also triggered peripheral CGRP release in meninges, which was blocked by MDL-72222.5 HT evoked fast membrane currents and Ca2+ transients in a fraction of trigeminal neurons. Immunohistochemistry showed expression of 5-HT3A receptors in fibers innervating meninges. Endogenous release of 5-HT from degranulated mast cells increased nociceptive firing. Low pH but not histamine strongly activated firing. 5-HT reduced monosynaptic inputs from trigeminal Adelta- and C-afferents to the upper cervical lamina I neurons and this effect was blocked by MDL-72222. Consistent with central inhibitory effect, 5-HT reduced CGRP release in the brainstem slices. In conclusion, 5-HT evokes powerful pro-nociceptive peripheral and anti-nociceptive central effects in trigeminal system transmitting migraine pain. PMID- 28025095 TI - A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder. AB - Deficits in fear extinction learning are hypothesized to underlie the development of posttraumatic stress disorder (PTSD). Such deficits may, in part, be due to genetic and epigenetic variation in the stress related gene FKBP5. Conversely, altering FKBP5 epigenetic responses during memory consolidation may rescue extinction deficits making it a target for acute intervention to prevent the development of PTSD. Study 1 (Humans) examines if FKBP5 single nucleotide polymorphisms (SNPs) and PTSD symptom domains (re-experiencing, avoidance/numbing, hyperarousal) are associated with abnormal fear extinction phenotypes identified using latent growth mixture modeling (LGMM). Study 2 (Mice) tests if increasing doses of dexamethasone administered prior to extinction alters Fkbp5 mRNA production in the amygdala after extinction and recall and prevents the development of abnormal extinction phenotypes. In humans, abnormal extinction was associated with the TT homozygous genotype of FKBP5 SNPs RS9470080 and RS1360780, and hyperarousal symptoms. In mice, dexamethasone 300 MUg/kg was associated with increased amygdala Fkbp5 mRNA following extinction and robust extinction learning while lower doses were not associated with amygdala Fkbp5 mRNA or differences in extinction learning. Further, mice that extinguished on dexamethasone 300 MUg/kg maintained low levels of freezing behavior during recall training while mRNA levels were no longer elevated. Together, findings indicate that FKBP5 confers risk for fear extinction deficits. However, this risk may be ameliorated by increasing fkbp5 mRNA expression in the amygdala during memory consolidation making this mechanism a plausible point of acute intervention to prevent the development of PTSD. PMID- 28025097 TI - Complete mitochondrial genomes of Gnathostoma nipponicum and Gnathostoma sp., and their comparison with other Gnathostoma species. AB - Gnathostomiasis is a foodborne zoonotic parasitosis caused by Gnathostoma nematodes. It has caused significant public problems worldwide, but its molecular biology is limited. The purpose of this study was to decode the complete mitochondrial (mt) genomes of Gnathostoma nipponicum and Gnathostoma sp., and compare their mt sequences with other Gnathostoma species. The complete mt genome sequences were amplified by long-range PCR and determined by subsequent primer walking. The complete mt genomes of G. nipponicum and Gnathostoma sp. were 14,093bp and 14,391bp, respectively. Both of the two mt genomes contain 12 protein-coding genes (PCGs), 2 ribosomal RNA genes and 22 transfer RNA genes. The gene order and transcription direction are the same as G. spinigerum and G. doloresi. The sequence difference across the entire mt genomes varied from 14.4% to 18.2% between G. nipponicum, Gnathostoma sp., G. spinigerum and G. doloresi of Japan and China isolates. Phylogenetic analyses by Bayesian inference (BI) using concatenated amino acid sequences of 12 PCGs showed that G. nipponicum and Gnathostoma sp. are two distinctive species of Gnathostoma, and G. nipponicum are more closely related to Gnathostoma sp. than to G. spinigerum. The mtDNA datasets provide abundant resources of novel markers, which can be used for the studies of molecular epidemiology and diagnosis of Gnathostoma spp. PMID- 28025096 TI - Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, alpha-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints. AB - We have previously demonstrated that enalapril, alpha-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, alpha-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, alpha-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes. PMID- 28025098 TI - Novel hantavirus identified in European bat species Nyctalus noctula. AB - Hantaviruses are emerging RNA viruses that cause human diseases predominantly in Asia, Europe, and the Americas. Besides rodents, insectivores and bats serve as hantavirus reservoirs. We report the detection and genome characterization of a novel bat-borne hantavirus isolated from insectivorous common noctule bat. The newfound virus was tentatively named as Brno virus. PMID- 28025099 TI - Evaluation of anti-cholinesterase, antibacterial and cytotoxic activities of green synthesized silver nanoparticles using from Millettia pinnata flower extract. AB - The aim of this study is to develop an easy and eco-friendly method for the synthesis of Ag-NPs using extracts from the medicinal plant, Millettia pinnata flower extract and investigate the effects of Ag-NPs on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), antibacterial and cytotoxicity activity. UV Vis peak at 438 nm confirmed the Ag-NPs absorbance. The SEM analysis results confirmed the presence of spherical shaped Ag-NPs by a huge disparity in the particle size distribution with an average size of 49 +/- 0.9 nm. TEM images revealed the formation of Ag-NPs with spherical shape and sizes in the range between 16 and 38 nm. The Ag-NPs showed an excellent inhibitory efficacy against AChE and BChE. The highest antibacterial activity was found against Escherichia coli (20.25 +/- 0.91 mm). These nanoparticles showed the cytotoxic effects against brine shrimp (artemia saliana) nauplii with a LD50 value of 33.92. PMID- 28025100 TI - ARF6, induced by mutant Kras, promotes proliferation and Warburg effect in pancreatic cancer. AB - Though significant progress has been made in the availability of diagnostic techniques and treatment strategies, pancreatic cancer remains a disease of high mortality rates. Therefore, there is an urgent need for a better understanding of the molecular mechanisms that governs the oncogenesis and metastasis process of pancreatic cancer. In our study, by using the Cancer Genome Atlas (TCGA) dataset analysis, we demonstrated that the small guanosine triphosphatase (GTPase) ADP ribosylation factor 6 (ARF6) serves as a biomarker for predicting prognosis of pancreatic cancer. In vitro studies demonstrated that silencing ARF6 expression reduced cell proliferation and attenuated the Warburg effect. Moreover, we observed that ARF6 was a downstream target of Kras/ERK signaling pathway, and the strong correlation of expression between Kras and ARF6 in the TCGA dataset further confirmed this observation. Taken together, our novel findings suggest ARF6, a target of mutant Kras, may promote pancreatic cancer development by enhancing the Warburg effect. PMID- 28025101 TI - Soluble guanylate cyclase stimulators increase sensitivity to cisplatin in head and neck squamous cell carcinoma cells. AB - Head and neck squamous cell carcinoma (HNSCC) is an aggressive and often fatal disease. Cisplatin is the most common chemotherapeutic drug in the treatment of HNSCC, but intrinsic and acquired resistance are frequent, and severe side effects occur at high doses. The second messenger cyclic GMP (cGMP) is produced by soluble guanylate cyclase (sGC). We previously reported that activation of the cGMP signaling cascade caused apoptosis in HNSCC cells, while others found that this pathway enhances cisplatin efficacy in some cell types. Here we found that sGC stimulators reduced HNSCC cell viability synergistically with cisplatin, and enhanced apoptosis by cisplatin. Moreover, the sGC stimulators effectively reduced viability in cells with acquired cisplatin resistance, and were synergistic with cisplatin. The sGC stimulator BAY 41-2272 reduced expression of the survival proteins EGFR and beta-catenin, and increased pro-apoptotic Bax, suggesting a potential mechanism for the anti-tumorigenic effects of these drugs. The sGC stimulator Riociguat is FDA-approved to treat pulmonary hypertension, and others are being studied for therapeutic use in several diseases. These drugs could provide valuable addition or alternative to cisplatin in the treatment of HNSCC. PMID- 28025102 TI - Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy. AB - Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a synthetic somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein loaded liposomes (DNL) were prepared and they were further decorated with the synthetic and stable analogue of somatostatin (SST-DNL). Fabricated liposomes were nano-size in range and biocompatible. SST-DNL displayed significantly better anti-tumor efficacy as compared to free Diacerein (DN) and DNL in breast cancer models. Enhanced apoptosis in breast cancer cells was detected in SST-DNL treated groups as monitored by cell cycle analysis and changes in expression level of apoptotic/anti-apoptotic proteins Bcl-2, Bax, cleaved Caspase 3 and PARP. SST-DNL more effectively inhibited the oncogenic IL-6/IL-6R/STAT3/MAPK/Akt signalling pathways as compared to DN or DNL in cancer cells. In addition, SST-DNL effectively suppressed angiogenesis and cancer cell invasion. In vivo tumor growth in a MDA-MB-231 mouse xenograft model was significantly suppressed following SST-DNL treatment. In xenograft model, immunohistochemistry of Ki-67 and CD-31 indicated that SST-DNL improved the anti-proliferative and anti angiogenic impacts of Diacerein. In vivo pharmacokinetic studies in rats showed enhanced circulation time in the DNL or SST-DNL treated groups as compared to free DN. Considering all of these findings, we conclude that SST-DNL provides a novel strategy with better efficacy for breast cancer therapy. PMID- 28025103 TI - Polymer-coated nanoparticles: Carrier platforms for hydrophobic water- and air sensitive metallo-organic compounds. AB - Many of the relevant compounds for anticancer therapy are metal-based compounds (metallodrugs), being platinum-based drugs such as cisplatin, carboplatin (Paraplatin(r)), and oxaliplatin (Eloxatin(r)) the most widely used. Despite this, their application is limited by issues such as cell-acquired platinum resistance and manifold side effects following systemic delivery. Thus, the development of new metal-based compounds is highly needed. The catalytic properties of a variety of metal-based compounds are nowadays very well known, which opens new opportunities to take advantage of them inside living cells or organisms. However, many of these compounds are hydrophobic and thus not soluble in aqueous solution, as they lack stability against water or oxygen presence. Thus, versatile platforms capable of enhancing the features of these compounds in aqueous solutions are of importance in the development of new drugs. Surface engineered nanoparticles may render metallodrugs with good colloidal stability in water and in complex media containing high salt concentration and/or proteins. Herein, polymer coated nanoparticles are proposed as a platform to link insoluble and water/oxygen sensitive drugs. The linkage of insoluble and oxygen sensitive tin clusters to nanoparticles is presented, aiming to enhance both, the solubility and the stability of these compounds in water, which may be an alternative approach in the development of metal-based drugs. The formation of the cluster-nanoparticle system was confirmed via inductively coupled plasma mass spectrometry experiments. The catalytic activity and the stability of the cluster in water were studied through the reduction of methylene blue. Results demonstrate that in fact the tin clusters could be transferred into aqueous solution and retained their catalytic activity. PMID- 28025104 TI - Adrenoceptors promote glucose uptake into adipocytes and muscle by an insulin independent signaling pathway involving mechanistic target of rapamycin complex 2. AB - Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from beta-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of GLUT4 transporters to the cell surface. This process is complex, involving signaling proteins including the mechanistic (or mammalian) target of rapamycin (mTOR) and Akt that intersect with multiple pathways controlling cell survival, growth and proliferation. mTOR exists in two forms, mTOR complex 1 (mTORC1), and mTOR complex 2 (mTORC2). mTORC1 has been intensively studied, acting as a key regulator of protein and lipid synthesis that integrates cellular nutrient availability and energy balance. Studies on mTORC2 have focused largely on its capacity to activate Akt by phosphorylation at Ser473, however recent findings demonstrate a novel role for mTORC2 in cellular glucose uptake. For example, agonists acting at beta2-adrenoceptors (ARs) in skeletal muscle or beta3 ARs in brown adipose tissue increase glucose uptake in vitro and in vivo via mechanisms dependent on mTORC2 but not Akt. In this review, we will focus on the signaling pathways downstream of beta-ARs that promote glucose uptake in skeletal muscle and brown adipocytes, and will highlight how the insulin and adrenergic pathways converge and interact in these cells. The identification of insulin independent mechanisms that promote glucose uptake should facilitate novel treatment strategies for metabolic disease. PMID- 28025105 TI - Some personal thoughts on the Australasian Society of Clinical and Experimental Pharmacologists in the 1980s. AB - There were a number of highly significant events regarding ASCEP in the 1980s: a tour of China by ASCEP pharmacologists; the Sydney IUPHAR Congress; and the initiation of the Australasian Visitor to the BPS scheme. ASCEP appointed a professional secretariat, established an investment portfolio, and initiated Special Interest Groups. The Society entered the 1990s welcoming toxicologists into the new ASCEPT. PMID- 28025106 TI - Effect of lysosomotropic molecules on cellular homeostasis. AB - Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities. PMID- 28025108 TI - Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in liver of SD rats and L02 cells via PPARgamma. AB - Di-(2-ethylhexyl)-phthalate (DEHP), a ubiquitous industrial pollutant in our daily life, has been reported to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies previously. Recently, it has been reported to be an endocrine disrupter and ligand to peroxisome proliferator activated receptor, which could influence the homeostasis of liver metabolic systems and contribute to the development of type-2 diabetes. However, the potential mechanisms are not known yet. This study was designed to solve these problems with male SD rats and normal human hepatocyte line, L02 cells, exposed to DEHP for toxicological experiments. Adult male SD rats were divided into four groups, normal group fed with regular diets and three DEHP-treated groups (dissolved in olive oil at doses of 0.05, 5 and 500mg/kg body weight, respectively, once daily through gastric intubations for 15weeks). L02 cells were divided into 6 groups, normal group with 5, 10, 25, 50, and 100MUmol/l DEHP groups. DEHP-exposed rats exhibited significant liver damage, glucose tolerance, and insulin tolerance along with reduced expression of insulin receptor and GLUT4 proteins in the liver tissues. The results of in vitro experiments could determine that the DEHP-induced activation of peroxisome proliferator activated receptor gamma (PPARgamma) played a key role in the production of oxidative stress and down-regulated expression of insulin receptor and GLUT4 proteins in L02 cells. This conclusion could be supported by the results of in vitro experiments, in which the cells were exposed to DEHP with GW9662 (PPARgamma inhibitor). In general, these results highlight the key role of PPARgamma in the process of insulin resistance induced by DEHP. PMID- 28025107 TI - Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms. AB - BACKGROUND: Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. AIM: This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). METHODS: Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC+5-FU, SEC+apigenin, SEC+ 5-FU+apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. RESULTS: 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. IN CONCLUSION: The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice. PMID- 28025109 TI - DEET potentiates the development and persistence of anticholinesterase dependent chronic pain signs in a rat model of Gulf War Illness pain. AB - Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400mg/kg; 50% topical) to an exposure protocol of permethrin (2.6mg/kg; topical), chlorpyrifos (CP; 120mg/kg), and pyridostigmine bromide (PB;13mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (Nutter et al., 2015). Rats underwent behavioral testing before, during and after a 4week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted to assess the influence of acute DEET (10-100MUM) on muscle and vascular nociceptor Kv7, KDR, Nav1.8 and Nav1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5-12weeks post-exposure and persisted through weeks 21-24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor Kv7, KDR, Nav1.8 or Nav1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of Kv7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role. PMID- 28025110 TI - Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and increased urinary 8-nitroguanine in arsenic-exposed newborns and children. AB - Early-life exposure to arsenic increases risk of developing a variety of non malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10-100MUM) and long-term low doses (0.5-1MUM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life. PMID- 28025111 TI - Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma. AB - Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2'-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%-12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with >=12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies. PMID- 28025112 TI - Digestomics: an emerging strategy for comprehensive analysis of protein catabolism. AB - When cells mobilize nutrients from protein, they generate a fingerprint of peptide fragments that reflects the net action of proteases and the identities of the affected proteins. Analyzing these mixtures falls into a grey area between proteomics and metabolomics that is poorly served by existing technology. Herein, we describe an emerging digestomics strategy that bridges this gap and allows mixtures of proteolytic fragments to be quantitatively mapped with an amino acid level of resolution. We describe recent successes using this technique, including a case where digestomics provided the link between hemoglobin digestion by the malaria parasite and the world-wide distribution of chloroquine resistance. We highlight other areas of microbiology and cancer research that are well-suited to this emerging technology. PMID- 28025114 TI - Differences in hippocampal serotonergic activity in a mouse single prolonged stress paradigm impact discriminant fear acquisition and retention. AB - A mouse model of traumatic stress provided insight into a mechanism of individual differences in conditioned fear responding. Hippocampal serotonergic activity (metabolic turnover) was associated with increased behavioral freezing during fear acquisition in a portion of trauma-exposed subjects. These subjects later displayed enhanced fear to the neutral cue during retention. An inability to discriminate fear responses may underlie dysfunctional fear memories in a sub population of individuals with Posttraumatic Stress Disorder, with contributions from the hippocampal serotonin system. PMID- 28025113 TI - Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter. AB - Recovery from injuries to the central nervous system, including spinal cord injury, is constrained in part by the intrinsically low ability of many CNS neurons to mount an effective regenerative growth response. To improve outcomes, it is essential to understand and ultimately reverse these neuron-intrinsic constraints. Genetic manipulation of key transcription factors (TFs), which act to orchestrate production of multiple regeneration-associated genes, has emerged as a promising strategy. It is likely that no single TF will be sufficient to fully restore neuron-intrinsic growth potential, and that multiple, functionally interacting factors will be needed. An extensive literature, mostly from non neural cell types, has identified potential mechanisms by which TFs can functionally synergize. Here we examine four potential mechanisms of TF/TF interaction; physical interaction, transcriptional cross-regulation, signaling based cross regulation, and co-occupancy of regulatory DNA. For each mechanism, we consider how existing knowledge can be used to guide the discovery and effective use of TF combinations in the context of regenerative neuroscience. This mechanistic insight into TF interactions is needed to accelerate the design of effective TF-based interventions to relieve neuron-intrinsic constraints to regeneration and to foster recovery from CNS injury. PMID- 28025115 TI - Neuroprotective effect of hypobaric hypoxic postconditioning is accompanied by dna protection and lipid peroxidation changes in rat hippocampus. AB - The present study was performed to explore the effect of severe hypobaric hypoxia (180Torr, 3h) and severe hypoxia followed by hypoxic postconditioning (360Torr, 2h, 3 episodes) on DNA fragmentation and dynamics of lipid peroxidation products in rat hippocampus. The severe hypoxia induced intense DNA fragmentation in the hippocampus. A persistent decrease of thiobarbituric acid reactive substances in the hippocampus was also detected in response to severe hypoxia while the levels of Schiff bases did not significantly change. The postconditioning prevented severe hypoxia-induced DNA fragmentation, returned the levels of thiobarbituric acid reactive substances to the baseline and decreased the levels of Schiff bases. These findings indicate that the neuroprotective effect of hypoxic postconditioning on hippocampal neurons detected as suppression of hypoxia induced DNA fragmentation is accompanied by the changes in lipid peroxidation processes. PMID- 28025116 TI - Perceived timing of a postural perturbation. AB - Falling down is a common event that threatens the survival of an organism. Simple, yet sophisticated neural mechanisms allow for rapid detection of a fall as well as the generation of compensatory reflexes designed to prevent a fall. Fall awareness and preventative alerting devices could potentially mitigate the likelihood of a fall, however, relatively little is known about the perceived timing of a fall. Common anecdotal reports suggest that humans often describe distortions in their perception of time with very little recollection of what occurred during the fall. Previous research has also found that the vestibular system is perceptually slow compared to the other senses (45-160ms delay), indicating that vestibular stimuli must occur prior to other sensory stimuli in order for it to be perceived as synchronous. Here we examine whether fall perception is similarly slow. Participants made temporal order judgments identifying whether fall or sound onset came first to measure the point of subjective simultaneity. Results show that fall perception is slow, where the onset of a perturbation has to precede an auditory stimulus by ~44 ms to appear coincident with the fall. We suggest that the central nervous system's rapid detection and response capabilities are restricted to reflexive behaviour, with conscious awareness of a fall being prioritized less. The additional lead times for detecting perturbation onset constrain possible fall detection and alert systems that have been proposed to inform a user to prevent falls and may also help explain the increased likelihood for fall incidence in the elderly. PMID- 28025117 TI - A Pivotal Role of Cell Wall in Cadmium Accumulation in the Crassulaceae hyperaccumulator Sedum plumbizincicola. PMID- 28025118 TI - Detection of Echinococcus granulosus and Echinococcus ortleppi in Bhutan. AB - In this pilot study, fecal samples were collected from community dogs around slaughterhouses and from the city of Thimphu (n=138) as well as from carnivores in the forest area around a farm in Bhutan (n=28). Samples were analyzed microscopically for the presence of taeniid eggs by the floatation and sieving method. Further molecular analyses of 20 samples of community dogs positive for taeniid eggs confirmed 10 Echinococcus granulosus sensu lato and one Taenia hydatigena case. From 14 environmental fecal samples from the forest area positive for taeniid eggs, one contained E. granulosus s.l., six T. hydatigena and one Taenia taeniaeformis DNA. In the remaining samples considered positive for taeniid eggs, no molecular confirmation could be achieved. Additionally, Echinococcus cysts were collected from locally slaughtered cattle and imported cattle organs. Seven Echinococcus cysts (one fertile) from the local animals and 35 (four fertile) from imported cattle organs were confirmed as E. granulosus (G1 3) by PCR/sequencing. One Echinococcus cyst each from a local animal and from an imported cattle organ (both fertile) were confirmed to be Echinococcus ortleppi (G5). Sterile Echinococcus cysts were also collected from local yaks (n=10), and all revealed to be E. granulosus (G1-G3). Hospital records of cystic echinococcosis in humans and the presence of Echinococcus spp. in dogs and ungulates indicate the existence of local transmission for both E. ortleppi and E. granulosus in Bhutan. PMID- 28025119 TI - Thaulin-1: The first antimicrobial peptide isolated from the skin of a Patagonian frog Pleurodema thaul (Anura: Leptodactylidae: Leiuperinae) with activity against Escherichia coli. AB - Patagonia's biodiversity has been explored from many points of view, however, skin secretions of native amphibians have not been evaluated for antimicrobial peptide research until now. In this sense, Pleurodema thaul is the first amphibian specie to be studied from this large region of South America. Analysis of cDNA-encoding peptide in skin samples allowed identification of four new antimicrobial peptides. The predicted mature peptides were synthesized and all of them showed weak or null antimicrobial activity against Klebsiella pneumoniae, Staphylococcus aureus and Escherichia coli with the exception of thaulin-1, a cationic 26-residue linear, amphipathic, Gly- and Leu-rich peptide with moderate antimicrobial activity against E. coli (MIC of 24.7MUM). AFM and SPR studies suggested a preferential interaction between these peptides and bacterial membranes. Cytotoxicity assays showed that thaulin peptides had minimal effects at MIC concentrations towards human and animal cells. These are the first peptides described for amphibians of the Pleurodema genus. These findings highlight the potential of the Patagonian region's unexplored biodiversity as a source for new molecule discovery. PMID- 28025120 TI - Comparative systems toxicology analysis of cigarette smoke and aerosol from a candidate modified risk tobacco product in organotypic human gingival epithelial cultures: A 3-day repeated exposure study. AB - Smoking is one of the major lifestyle-related risk factors for periodontal diseases. Modified risk tobacco products (MRTP) offer a promising alternative in the harm reduction strategy for adult smokers unable to quit. Using a systems toxicology approach, we investigated and compared the exposure effects of a reference cigarette (3R4F) and a heat-not-burn technology-based candidate MRTP, the Tobacco Heating System (THS) 2.2. Human gingival epithelial organotypic cultures were repeatedly exposed (3 days) for 28 min at two matching concentrations of cigarette smoke (CS) or THS2.2 aerosol. Results showed only minor histopathological alterations and minimal cytotoxicity upon THS2.2 aerosol exposure compared to CS (1% for THS2.2 aerosol vs. 30% for CS, at the high concentration). Among the 14 proinflammatory mediators analyzed, only 5 exhibited significant alterations with THS2.2 exposure compared with 11 upon CS exposure. Transcriptomic and metabolomic analysis indicated a general reduction of the impact in THS2.2 aerosol-exposed samples with respect to CS (~79% lower biological impact for the high THS2.2 aerosol concentration compared to CS, and 13 metabolites significantly perturbed for THS2.2 vs. 181 for CS). This study indicates that exposure to THS2.2 aerosol had a lower impact on the pathophysiology of human gingival organotypic cultures than CS. PMID- 28025121 TI - Tris (1, 3-dichloro-2-propyl) phosphate induces apoptosis and autophagy in SH SY5Y cells: Involvement of ROS-mediated AMPK/mTOR/ULK1 pathways. AB - Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. We hypothesized that the neurotoxicity might occur via the induction of the apoptosis and autophagy pathways. In the present study, we investigated TDCIPP induced apoptotic death and autophagy in SH-SY5Y cells. Treatment with TDCIPP induced increased reactive oxygen species (ROS) generation and cell apoptosis, as well as autophagy. The autophagy inhibitor 3-methyladenine (3-MA) markedly decreased the expression of the autophagy marker beclin-1, microtubule-associated protein light chain 3-II (LC3II), p62/sequestosome 1 (SQSTM1) degradation, and promoted apoptosis. Conversely, the autophagy inducer rapamycin (Rapa) alleviated TDCIPP-induced apoptosis and markedly increased the expression of the autophagy markers. Pretreatment with N-acetyl cysteine (NAC) eliminated the increased ROS generation, resulting in increased cell viability. For further examination of the signaling pathways involved in TDCIPP-induced autophagy, compound C, a pharmacological inhibitor of adenosine monophosphate activated protein kinase (AMPK) was used. Western blotting showed that compound C markedly reduced the expression of phospho-AMPK (p-AMPK) and phospho-Unc-51-like kinase 1 (p-ULK1), increased phospho-mammalian target of rapamycin (p-mTOR) expression, and decreased beclin-1 and LC3II expression. These results suggested that the AMPK/mTOR/ULK1 signaling pathway was involved in TDCIPP-induced autophagy. The antioxidant NAC antagonized TDCIPP-induced activation of AMPK and autophagy. Taken together, our findings provide the first evidence that TDCIPP promotes apoptosis and autophagy simultaneously and that this process involves the ROS mediated AMPK/mTOR/ULK1 pathways. Lastly, the induction of autophagy is a protective mechanism against TDCIPP-induced apoptosis. PMID- 28025122 TI - Protective effect of rutaecarpine against t-BHP-induced hepatotoxicity by upregulating antioxidant enzymes via the CaMKII-Akt and Nrf2/ARE pathways. AB - Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, has been shown to have cytoprotective potential, but the molecular mechanism underlying this activity remains unclear. Our study was designed to investigate the cytoprotective effect of rutaecarpine against tert butyl hydroperoxide (t-BHP) and to elucidate its action mechanism of action of rutaecarpine in a cultured HepG2 cell line and in mouse liver. Rutaecarpine decreased t-BHP-induced reactive oxygen species (ROS) production, cytotoxicity, and apoptosis in HepG2 cells. Pretreatment with rutaecarpine prior to the injection of t-BHP significantly prevented the increase in serum levels of AST, ALT, and lipid peroxidation in mice liver. It increased the transcriptional activity of NF-E2-related factor 2 (Nrf2) as well as the products of the Nrf2 target genes hemeoxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate cysteine ligase (GCL). Moreover, rutaecarpine also enhanced the phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase-II (CaMKII). The pharmaceutical inhibitors, such as KN-93 (CaMKII inhibitor) and LY294002 (Akt inhibitor) suppressed rutaecarpine-induced HO-1 expression and cytoprotection. Our findings identify the CaMKII-PI3K/Akt-Nrf2 cascade as an antioxidant pathway mediating rutaecarpine signaling and leading to HO-1 expression in hepatocytes. PMID- 28025123 TI - Structured DAG oil ameliorates renal injury in streptozotocin-induced diabetic rats through inhibition of NF-kappaB and activation of Nrf2 pathway. AB - Accumulating evidence suggested that inflammatory processes are involved in the development of diabetic nephropathy (DN). Here, we have tested the hypothesis that Caprylic Acid (Cy)-diacylglycerol (DAG) oil (Cy-DAG), a novel structurally formulated lipid with high nutritional value, ameliorated DN in streptozotocin (STZ)-induced diabetic rats through the anti-inflammatory mechanisms. Basic hematological, biochemical parameters, immunoblotting, immunofluorescence and flow cytometry analysis were performed to observe the anti-inflammatory potential of Cy-DAG oil. The data revealed that STZ significantly increased the renal oxidative stress markers and decreased the levels of renal enzymatic and non enzymatic antioxidants. Moreover, renal nitric oxide (NO), tissue necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) were also increased in the renal tissue of STZ-treated rats. Further, DAG oil pretreatment produced a significant improvement in renal antioxidant status, reduced the lipid peroxidation and the levels of inflammatory markers in STZ-treated kidney. Similarly, results of protein expression showed that DAG oil pretreatment normalized the renal expression of Nrf2/Keap1 and its downstream regulatory proteins in STZ-treated condition. Immunohistochemical observations provided further evidence that DAG oil effectively protected the kidney from STZ-mediated oxidative damage. These results suggested that the DAG oil ameliorated STZ-induced oxidative renal injury by the activation of AKT/Nrf2/HO-1 pathway and the inhibition of ROS/MAPK/NF kappaB pathway. PMID- 28025124 TI - Major triterpenoids in Chinese hawthorn "Crataegus pinnatifida" and their effects on cell proliferation and apoptosis induction in MDA-MB-231 cancer cells. AB - The cytotoxicity and antiproliferative effect of phytochemicals presenting in the fruits of Chinese hawthorn (Crataegus pinnatifida) were evaluated. Shanlihong (Crataegus pinnatifida Bge. var. major N.E.Br.) variety possessed significant levels of flavonoids and triterpenoids, and showed potent antiproliferative effect against HepG2, MCF-7 and MDA-MB- 231 human cancer cells lines. Triterpenoids-enriched fraction (S9) prepared by Semi-preparative HPLC, and its predominant ingredient ursolic acid (UA) demonstrated remarkably antiproliferative activities for all the tested cancer cell lines. DNA flow cytometric analysis showed that S9 fraction and UA significantly induced G1 arrest in MDA-MB-231 cells in a dose-dependent manner. Western blotting analysis revealed that S9 fraction and UA significantly induced PCNA, CDK4, and Cyclin D1 downregulation in MDA-MB-231 cells, followed by p21Waf1/Cip1 up-regulation. Additionally, flow cytometer and DNA ladder assays indicated that S9 fraction and UA significantly induced MDA-MB-231 cells apoptosis. Mitochondrial death pathway was involved in this apoptosis as significantly induced caspase-9 and caspase-3 activation. These results suggested that triterpenoids-enriched fraction and UA exhibited antiproliferative activity through the cell cycle arrest and apoptosis induction, and was majorly responsible for the potent anticancer activity of Chinese hawthorn. PMID- 28025125 TI - Production, purification and immunogenicity of recombinant Ebola virus proteins - A comparison of Freund's adjuvant and adjuvant system 03. AB - There is an urgent need for Ebola virus (EBOV) proteins, EBOV-specific antibodies and recombinant antigens to be used in diagnostics and as potential vaccine candidates. Our objective was to produce and purify recombinant proteins for immunological assays and for the production of polyclonal EBOV specific antibodies. In addition, a limited comparison of the adjuvant effects of Freund's complete adjuvant (FCA) and adjuvant system 03 (AS03) was carried out. Recombinant EBOV GST-VP24, -VP30, -VP35, -VP40 and -NP were produced in E. coli and purified with affinity chromatography followed by preparative gel electrophoresis. Recombinant EBOV GP-His was produced in Sf9 insect cells and purified by preparative gel electrophoresis. To compare the adjuvant effect of FCA and AS03, 12 rabbits were immunized four times with one of the six recombinant EBOV proteins using FCA or AS03. In addition, three guinea pigs were immunized with EBOV VP24 using FCA. With the exception of sera from two rabbits immunized with GST-VP24, the antisera against all other EBOV proteins showed very high and specific antibody responses after three to four immunizations. The adjuvant effect of AS03 was comparable to that of FCA. The produced antibodies recognized the corresponding EBOV proteins in wild type EBOV-infected cells. PMID- 28025126 TI - Digital technology to enable aging in place. AB - Aging, both of individuals and populations, presents challenges and opportunities. The multitude of morbidities and disabilities that are a too common component of aging represent significant challenges to individuals, their families and to healthcare systems. Aging in place is the ability to safely and comfortably maintain an independent and high quality of life in one's own home and community and is a highly desirable goal of most individuals with the additional benefit of significantly impacting the impending enormous healthcare burden. In order to make this possible, new care models that take advantage of novel technologies for tracking important physiologic and safety parameters need to be developed and implemented. By thoughtfully doing so, it can be possible to seamlessly provide preventative interventions when and as needed, detect the earliest signs of aggravation of chronic conditions, or identify and respond to any emergency situations, such as falls or cardiac arrest. In contrast to current approaches, caring for elderly individuals in their homes based on a digital technology infrastructure could be effective and cost-saving. In this review, we provide an overview of the characteristics of potential digital solutions applicable to creative aging along with the existing evidence supporting their ability to improve care, increase quality of life, and substantially decrease the emotional and financial costs associated with aging. PMID- 28025127 TI - Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Abeta) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggests that both type 1 and type 2 diabetes are risk factors for AD-related dementia and several clinical studies have demonstrated that AD patients show alterations in peripheral glucose regulation characterized by insulin resistance (hyperinsulinemia) or hypoinsulinemia. Whether animal models of AD exhibit a pre-diabetic phenotype without additional dietary or experimental manipulation is unclear however, with contradictory data available. Further, most studies have not examined the time course of potential pre-diabetic changes relative to AD pathogenesis and cognitive decline. Thus, in this study we tested the hypothesis that a pre-diabetic phenotype (peripheral metabolic dysregulation) exists in the APP/PS1 transgenic model of AD under normal conditions and precedes AD-related pathology. Specifically, we examined glucose tolerance in male APP/PS1 mice on a C57BL/6J congenic background at 2, 4-6 and 8 9months of age by assessing fasting glucose levels, glucose tolerance, plasma insulin levels and insulin sensitivity as well as the development of pathological characteristics of AD and verified that our APP/PS1 mice develop cognitive impairment. Here we show that APP/PS1 mice, compared to wild-type controls, exhibit a significant impairment in glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT) and a trend for increased fasting plasma insulin concentrations as early as 2months of age, while extracellular Abeta1-42 deposition occurs later and cognitive decline exists at 8-9months of age. Moreover, APP/PS1 mice did not respond as well to exogenous insulin as the wild type controls during an intraperitoneal insulin tolerance test (ipITT). Taken together, these data reveal that male APP/PS1 mice on a C57BL/6J congenic background exhibit a pre-diabetic phenotype prior to the development of AD-like pathology and that this metabolic deficit persists when they exhibit neuropathology and cognitive decline. This raises the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis. PMID- 28025128 TI - Potential pitfalls when denoising resting state fMRI data using nuisance regression. AB - In resting state fMRI, it is necessary to remove signal variance associated with noise sources, leaving cleaned fMRI time-series that more accurately reflect the underlying intrinsic brain fluctuations of interest. This is commonly achieved through nuisance regression, in which the fit is calculated of a noise model of head motion and physiological processes to the fMRI data in a General Linear Model, and the "cleaned" residuals of this fit are used in further analysis. We examine the statistical assumptions and requirements of the General Linear Model, and whether these are met during nuisance regression of resting state fMRI data. Using toy examples and real data we show how pre-whitening, temporal filtering and temporal shifting of regressors impact model fit. Based on our own observations, existing literature, and statistical theory, we make the following recommendations when employing nuisance regression: pre-whitening should be applied to achieve valid statistical inference of the noise model fit parameters; temporal filtering should be incorporated into the noise model to best account for changes in degrees of freedom; temporal shifting of regressors, although merited, should be achieved via optimisation and validation of a single temporal shift. We encourage all readers to make simple, practical changes to their fMRI denoising pipeline, and to regularly assess the appropriateness of the noise model used. By negotiating the potential pitfalls described in this paper, and by clearly reporting the details of nuisance regression in future manuscripts, we hope that the field will achieve more accurate and precise noise models for cleaning the resting state fMRI time-series. PMID- 28025130 TI - High and ultra-high resolution metabolite mapping of the human brain using 1H FID MRSI at 9.4T. AB - Magnetic resonance spectroscopic imaging (MRSI) is a promising technique for mapping the spatial distribution of multiple metabolites in the human brain. These metabolite maps can be used as a diagnostic tool to gain insight into several biochemical processes and diseases in the brain. In comparison to lower field strengths, MRSI at ultra-high field strengths benefits from a higher signal to noise ratio (SNR) as well as higher chemical shift dispersion, and hence spectral resolution. This study combines the benefits of an ultra-high field magnet with the advantages of an ultra-short TE and TR single-slice FID-MRSI sequence (such as negligible J-evolution and loss of SNR due to T2 relaxation effects) and presents the first metabolite maps acquired at 9.4T in the healthy human brain at both high (voxel size of 97.6uL) and ultra-high (voxel size of 24.4uL) spatial resolutions in a scan time of 11 and 46min respectively. In comparison to lower field strengths, more anatomically-detailed maps with higher SNR from a larger number of metabolites are shown. A total of 12 metabolites including glutamate (Glu), glutamine (Gln), N-acetyl-aspartyl-glutamate (NAAG), Gamma-aminobutyric acid (GABA) and glutathione (GSH) are reliably mapped. Comprehensive description of the methodology behind these maps is provided. PMID- 28025129 TI - Myelin volume fraction imaging with MRI. AB - MRI is a valuable tool to assess myelin during development and demyelinating disease processes. While multiexponential T2 and quantitative magnetization transfer measures correlate with myelin content, neither provides the total myelin volume fraction. In many cases correlative measures are adequate; but to assess microstructure of myelin, (e.g. calculate the g-ratio using MRI), an accurate measure of myelin volume fraction is imperative. Using a volumetric model of white matter, we relate MRI measures of myelin to absolute measures of myelin volume fraction and compare them to quantitative histology. We assess our approach in control mice along with two models of hypomyelination and one model of hypermyelination and find strong agreement between MRI and histology amongst models. This work investigates the sensitivities of MRI myelin measures to changes in axon geometry and displays promise for estimating g-ratio from MRI. PMID- 28025131 TI - Glutamatergic stimulation of the left dentate gyrus abolishes depressive-like behaviors in a rat learned helplessness paradigm. AB - BACKGROUND: Episodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual's coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). METHODS: We used a learned helplessness paradigm-a well-established model of MDD-to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. RESULTS: After exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. CONCLUSION: Increased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress. PMID- 28025132 TI - Differences in characteristics between J-wave syndrome patients. PMID- 28025133 TI - Carbapenems and febrile neutropenia - author's reply. PMID- 28025134 TI - Carbapenems and febrile neutropenia. PMID- 28025135 TI - Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer. AB - Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4+ T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti inflammatory cytokines IL-10 and TNF-alpha. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy. PMID- 28025136 TI - CD3+CD56+ natural killer T cell activity in children with different forms of juvenile idiopathic arthritis and the influence of etanercept treatment on polyarticular subgroup. AB - Juvenile idiopathic arthritis (JIA) has three major onset types with widely varying clinical features. We assessed the natural killer T (NKT) cell function in patients with different JIA subtypes, and found systemic patients exhibited lower NKT cell counts, perforin and granzyme B expression, while the pauciarticular and polyarticular patients displayed higher perforin and granzyme B expression as compared with the controls. The synovial fluid had more NKT cells with higher levels of perforin, granzyme B, and tumour necrosis factor (TNF) alpha than peripheral cells. The polyarticular patients that responded to etanercept had lower NKT cell counts, intracellular perforin, granzyme B and the mean fluorescence intensity of TNF-alpha than the patients that did not respond. Treatment with etanercept reduced the granzyme B and perforin, interferon (IFN) gamma and TNF-alpha expression in NKT cells in the responsive group. Therefore, a higher NKT cell function may indicate a decreased response to etanercept in polyarticular patients. PMID- 28025137 TI - Nongenomic effects of 1alpha,25-dihydroxyvitamin D3 on cartilage formation deduced from comparisons between Cyp27b1 and Vdr knockout mice. AB - The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1alpha,25D3), plays an important role in the maintenance of calcium (Ca) homeostasis, bone formation, and cell proliferation and differentiation via nuclear vitamin D receptor (VDR). It is formed by the hydroxylation of vitamin D at the 1alpha position by 25 hydroxyvitamin D 1alpha-hydroxylase (CYP27B1) in the kidney. However, Cyp27b1-/- mice, deficient in CYP27B1, and VDR-deficient mice (Vdr-/-) have not been extensively examined, particularly in a comparative framework. To clarify the physiological significance of 1alpha,25D3 and VDR, we produced Cyp27b1-/- mice and compared their phenotypes with those of Vdr-/- mice. Cyp27b1-/- mice exhibited hypocalcemia, growth defects, and skeletogenesis dysfunction, similar to Vdr-/- mice. However, unlike Cyp27b1-/- mice, Vdr-/- mice developed alopecia. Cyp27b1-/- mice exhibited cartilage mass formation and had difficulty walking on hindlimbs. Furthermore, a phenotypic analysis was performed on Cyp27b1-/- mice provided a high Ca diet to correct for the Ca metabolic abnormality. In addition, the effects of 1alpha,25D3 that are not mediated by Ca metabolic regulatory activity were investigated. Even when the blood Ca concentration was corrected, abnormalities in growth and cartilage tissue formation did not improve in Cyp27b1 /- mice. These results suggested that 1alpha,25D3 directly controls chondrocyte proliferation and differentiation. Using Cyp27b1-/- mice produced in this study, we can analyze the physiological effects of novel vitamin D derivatives in the absence of endogenous 1alpha,25D3. Accordingly, this study provides a useful animal model for the development of novel vitamin D formulations that are effective for the treatment and prevention of osteoporosis. PMID- 28025138 TI - Functional analysis of HSPA1A and HSPA8 in parturition. AB - Many factors are involved in parturition, such as apoptosis, inflammatory mediators, and hormones. Previous studies indicated that HSP70 directly or indirectly regulates apoptosis, inflammatory immune response and hormone stimulus. To gain new insights into molecular mechanism underlying HSP70 for regulating parturition, we overexpressed and knocked down two representative members of HSP70 (HSPA1A and HSPA8) through transfection of their recombinant plasmid and si-RNA separately in WISH (human amniotic epithelial) cells. The expression changes of several pathways' marker genes were investigated by Western blotting and quantitative real-time PCR (qRT-PCR). Results showed extreme expression changes in the genes of IL-8 and ESR2. HSP70 was found to stimulate estrogen response by regulating ESR2 through ERK1/2 after treating WISH cells with the special phosphorylation inhibitor of ERK1/2 and analyzing the changes of E2 concentration by ELISA. HSP70 was also observed to contribute to preterm birth after administering the special inhibitor of HSP70-PFT-MU with LPS-induced preterm birth mouse model. Overall, HSP70 induces parturition through stimulating immune inflammatory and estrogen response. The balanced HSP70 expression could ensure a smooth parturition, while the imbalanced expression may cause a pathological state like preterm. PMID- 28025139 TI - The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation. AB - Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation. To explore factors contributing to generation of AR-V7 mRNA, we conducted a focused RNA interference screen in AR-V7-positive JDCaP-hr cells using an shRNA library targeting spliceosome-related genes. This screen identified DDX39B as a regulator of AR-V7 mRNA expression. Simultaneous knockdown of DDX39B and its paralog DDX39A drastically and selectively downregulated AR-V7 mRNA expression in multiple AR-V7 positive prostate cancer cell lines. DDX39B was upregulated in relapsed JDCaP xenografts expressing AR splice variants, suggesting its role in expression of AR splice variants. Taken together, our findings offer insight into the mechanisms of AR splice variant generation and identify DDX39 as a potential drug target for the treatment of AR splice variant-positive prostate cancer. PMID- 28025140 TI - Protease-activated receptor 2 exacerbates adenine-induced renal tubulointerstitial injury in mice. AB - Hypercoagulability is associated with chronic kidney disease (CKD). Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade are known to activate protease-activated receptor 2 (PAR2), and to cause inflammation and tissue injury. Although PAR2 is highly expressed in the kidney, it is unclear whether PAR2 plays a pathogenic role in CKD. To test this, we fed the mice lacking Par2 (F2rl1-/-) and wild type (F2rl1+/+) mice with adenine diet to induce tubulointerstitial injury, a hallmark of CKD. Adenine-treated mice showed severe renal dysfunction, tubular atrophy, and fibrosis. Fibrin deposition and the expression of tissue factor and PARs markedly increased in their kidneys. Lack of Par2 attenuated renal histological damage and reduced the expression levels of genes related to inflammation, fibrosis, and oxidative stress. Our data indicate that PAR2 is critically important in the pathogenesis of adenine-induced tubular injury. PAR2 antagonists under development could be useful to treat and prevent CKD. PMID- 28025141 TI - MafB is required for development of the hindbrain choroid plexus. AB - The choroid plexus (ChP) is a non-neural epithelial tissue that produces cerebrospinal fluid (CSF). The ChP differentiates from the roof plate, a dorsal midline structure of the neural tube. However, molecular mechanisms underlying ChP development are poorly understood compared to neural development. MafB is a bZip transcription factor that is known to be expressed in the roof plate. Here we investigated the role of MafB in embryonic development of the hindbrain ChP (hChP) using Mafb-deficient mice. Immunohistochemical analyses revealed that MafB is expressed in the roof plate and early hChP epithelial cells but its expression disappears at a later embryonic stage. We also found that the Mafb-deficient hChP exhibits delayed differentiation and results in hypoplasia compared to the wild type hChP. Furthermore, the Mafb-deficient hChP exhibits increased apoptotic cell death and decreased proliferating cells at E12.5, an early stage of hChP development. Collectively, our findings reveal that MafB play an important role in promoting hChP development during embryogenesis. PMID- 28025142 TI - Characterization of goat inner cell mass derived cells in double kinase inhibition condition. AB - The identification of small molecular inhibitors, which were reported to promote the derivation of mouse and human embryonic stem cells (ESCs), provides a potential strategy for the derivation of domesticated ungulate ESCs. In present study, goat inner cell mass (ICM) derived cells in the double inhibition (2i) condition, in which, mitogen-activated protein kinase kinase (MAP2K) and glycogen synthase kinase 3 (GSK3) were inhibited by PD0325901 and BIO respectively, were characterized. The results showed that goat ICM derived cells in 2i medium adding leukaemia inhibitor factor (LIF) possessed a mouse ES-like morphology. But these cells had much compromised proliferation capacity, resulting in difficulty in expansion. In 2i alone medium, goat ICM derived cells possessed primate ES-like morphology. These cells expressed pluripotent markers and could differentiate into derivatives of three germ layers in vitro. However, these cells could not be proliferated in long-term (persisted for 15 passages) because of spontaneously neural differentiation. Additionally, goat ICM derived cells could be inducing differentiated into neural lineage in vitro. Although goat ESCs could not be established in PD0325901 and BIO alone medium, this derivation condition provides a useful research system to find signaling molecular those regulate early embryonic development and pluripotency in goat. PMID- 28025143 TI - Rapid PD-L1 detection in tumors with PET using a highly specific peptide. AB - Molecular imaging can report on the status of the tumor immune microenvironment and guide immunotherapeutic strategies to enhance the efficacy of immune modulation therapies. Imaging agents that can rapidly report on targets of immunomodulatory therapies are few. The programmed death ligand 1 (PD-L1) is an immune checkpoint protein over-expressed in several cancers and contributes to tumor immune suppression. Tumor PD-L1 expression is indicative of tumor response to PD-1 and PD-L1 targeted therapies. Herein, we report a highly specific peptide based positron emission tomography (PET) imaging agent for PD-L1. We assessed the binding modes of the peptide WL12 to PD-L1 by docking studies, developed a copper 64 labeled WL12 ([64Cu]WL12), and performed its evaluation in vitro, and in vivo by PET imaging, biodistribution and blocking studies. Our results show that [64Cu]WL12 can be used to detect tumor PD-L1 expression specifically and soon after injection of the radiotracer, to fit within the standard clinical workflow of imaging within 60 min of administration. PMID- 28025144 TI - Bio-active molecules modified surfaces enhanced mesenchymal stem cell adhesion and proliferation. AB - Surface modification of the substrate as a component of in vitro cell culture and tissue engineering, using bio-active molecules including extracellular matrix (ECM) proteins or peptides derived ECM proteins can modulate the surface properties and thereby induce the desired signaling pathways in cells. The aim of this study was to evaluate the behavior of human bone marrow mesenchymal stem cells (hBM-MSCs) on glass substrates modified with fibronectin (Fn), collagen (Coll), RGD peptides (RGD) and designed peptide (R-pept) as bio-active molecules. The glass coverslips were coated with fibronectin, collagen, RGD peptide and R peptide. Bone marrow mesenchymal stem cells were cultured on different substrates and the adhesion behavior in early incubation times was investigated using scanning electron microscopy (SEM) and confocal microscopy. The MTT assay was performed to evaluate the effect of different bio-active molecules on MSCs proliferation rate during 24 and 72 h. Formation of filopodia and focal adhesion (FA) complexes, two steps of cell adhesion process, were observed in MSCs cultured on bio-active molecules modified coverslips, specifically in Fn coated and R-pept coated groups. SEM image showed well adhesion pattern for MSCs cultured on Fn and R-pept after 2 h incubation, while the shape of cells cultured on Coll and RGD substrates indicated that they might experience stress condition in early hours of culture. Investigation of adhesion behavior, as well as proliferation pattern, suggests R-peptide as a promising bio-active molecule to be used for surface modification of substrate in supporting and inducing cell adhesion and proliferation. PMID- 28025145 TI - Direct transcriptional activation of BT genes by NLP transcription factors is a key component of the nitrate response in Arabidopsis. AB - Nitrate modulates growth and development, functioning as a nutrient signal in plants. Although many changes in physiological processes in response to nitrate have been well characterized as nitrate responses, the molecular mechanisms underlying the nitrate response are not yet fully understood. Here, we show that NLP transcription factors, which are key regulators of the nitrate response, directly activate the nitrate-inducible expression of BT1 and BT2 encoding putative scaffold proteins with a plant-specific domain structure in Arabidopsis. Interestingly, the 35S promoter-driven expression of BT2 partially rescued growth inhibition caused by reductions in NLP activity in Arabidopsis. Furthermore, simultaneous disruption of BT1 and BT2 affected nitrate-dependent lateral root development. These results suggest that direct activation of BT1 and BT2 by NLP transcriptional activators is a key component of the molecular mechanism underlying the nitrate response in Arabidopsis. PMID- 28025146 TI - Attachment of a 'molecular spring' restores drug-stimulated ATPase activity to P glycoprotein lacking both Q loop glutamines. AB - P-glycoprotein (P-gp) is an ABC (ATP-Binding Cassette) drug pump that is clinically important because it confers multidrug resistance. Drugs bind at the interface between the transmembrane domains to activate ATPase activity at the two nucleotide-binding domains (NBDs). Drug transport involves ATP-dependent conformational changes between inward- (open, NBDs far apart) and outward-facing (closed, NBDs close together) conformations. Recently, it was reported that the conserved glutamines residues (Gln475 in NBD1 and Gln1118 in NBD2) in the Q loops of P-gp when mutated to alanine completely inhibited the drug-stimulated ATPase activity. It is unknown why the glutamine residues (Gln475 and Gln1118) in the Q loops of the NBDs of P-gp are required for drug-stimulated ATPase activity. Here we show that introduction of these mutations into the L175C/N820C mutant (L175C/N820C/Q475A/Q1118A) also abolished drug-stimulated ATPase activity. The ATPase activity was restored however, when the L175C/N820C/Q475A/Q1118A mutant was cross-linked with a flexible disulfide cross-linker. These results suggest that both Q-loop glutamines are not required for ATP hydrolysis and they might function as part of a spring-like mechanism in facilitating the open (inactive) to closed (active) conformational change during ATP hydrolysis. The molecular spring-like action of the Q-loop glutamines during drug-stimulated ATPase activity is likely mimicked by the attachment of the flexible cross-linker. PMID- 28025147 TI - The significant effect of chronic intermittent hypoxia on prostaglandin D2 biosynthesis in rat brain. AB - Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). Excessive daytime sleepiness (EDS) is one of severe complications frequently associated with OSA. Lipocalin-type prostaglandin synthase (L-PGDS) is potentially responsible for the production of prostaglandin D2 (PGD2) which is an endogenous sleep inducer. To date, whether the content of PGD2 and PGDS is related to intermittent hypoxia has never been reported. The aim of this study was to compare the content of PGD2 and L-PGDS in rats' brains with and without intermittent hypoxia. Adult male Wistar rats (n = 48; 8-10 weeks) were averagely divided into two groups. One was control group, and the other group was exposed to IH (12 h/day for 6 weeks). In each group there are four time points including 0, 2, 4 and 6 weeks, and six rats were killed and studied at each time-point. At the end of 0, 2, 4 and 6 weeks, the concentrations of PGD2 in brains were measured by LC-MS/MS. In addition, the expressions of L-PGDS protein and mRNA in brains were investigated by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The results showed the concentrations of PGD2 in CIH rat brains were higher than those in control groups from the second week. At the end of 6 weeks, the concentrations of PGD2 in CIH and control groups were 11.1 and 5.9 ng/g, respectively. The levels of L-PGDS protein and mRNA followed the same trend during the whole 6 weeks. The results will provide a new idea to explore that patients with OSA are always accompanied by excessive daytime sleepiness. PMID- 28025149 TI - Substrate stiffness promotes latent TGF-beta1 activation in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) was usually coupled with increased stiffness of the extracellular matrix (ECM) and elevated level of transforming growth factor beta1 (TGF-beta1). However, the mechanism by which substrate rigidity modulated TGF-beta1 signaling transduction remained unknown. This paper investigated the molecular mechanism of how matrix stiffness regulating TGF-beta1 signaling in HCC cells. By means of stiffness tunable collagen I-coated polyacrylamide (PA) gels, we found that the expressions of beta1 integrin, p-FAK Y397 and p-Smad2 upregulated on stiffer gels as well as the content of TGF-beta1 in culture media of HCC cells, which were inhibited by RGD blocking peptides, Y-27632 (ROCK inhibitor) or Blebbistatin (myosin II inhibitor). Cellular traction force was also significantly higher when plated on stiffer substrates but dramatically decreased after treatment with Y-27632 or Blebbistatin. Furthermore, the upregulation of p-Smad2 in the HCC cells on stiffer PA gels induced by exogenetic latent TGF-beta1 was downregulated in the presence of RGD peptides. The nuclear translocation of Smad2 induced by latent TGF-beta1 was inhibited by Y-27632 or Blebbistatin. Our results suggested that the extracellular matrix stiffness regulated latent TGF-beta1 activation by cytoskeletal tension in HCC cells, showing that matrix stiffness was a key regulator involving the TGF-beta1 activity in HCC cells. The current study presented a mechanism of how hepatocirrhosis developed into liver cancer. PMID- 28025148 TI - Circadian clock and steroidogenic-related gene expression profiles in mouse Leydig cells following dexamethasone stimulation. AB - Previous studies have shown that circadian clock genes are expressed in mammalian testes; however, it remains unclear if the expression patterns of these genes are cyclic. Furthermore, it is unknown whether Leydig cells, the primary androgen secreting cells in the testis, play a role in the rhythmicity of circadian clock and steroidogenic-related gene transcription. Here, we examine the circadian clock of mouse Leydig cells, and the link to steroidogenic-related gene transcription. We confirm, via sampling over a full circadian time (CT) period, a lack of circadian rhythmicity in mouse testes in comparison with the robust gene expression cycling of circadian clock genes in mouse livers. Immunofluorescence imaging of mouse testes collected at CT0 and CT12 show that the BMAL1 protein is exclusively expressed in mouse Leydig cells, and clearly linked to the circadian oscillation. Furthermore, dexamethasone treatment synchronized the expression of several of these canonical circadian clock and steroidogenic-related genes. Bioinformatic analyses revealed the presence of several circadian clock-related sequence motifs in the promoters of these steroidogenic-related genes. Our results suggest mouse Leydig cells may contain a functional circadian oscillator and the circadian clockwork in mouse Leydig cells regulates steroidogenic-related gene transcription by binding to the E-box, RORE, and D-box motifs in their promoters. However, additional research is required to determine the specific molecular mechanisms involved. PMID- 28025150 TI - Bioconvection induced by bacterial chemotaxis in a capillary assay. AB - Bacterial chemotaxis allows cells to swim toward a more favorable environment. Capillary assays are a major method for exploring bacterial responses to attractive and repellent chemicals, but the accumulation process obtained using a capillary containing chemicals has not been investigated fully. In this study, we quantitatively analyzed the response of Salmonella cells to serine as an attractant diffusing from a capillary placed in a cell suspension. Video microscopy showed that cells gradually accumulated near the tip of the capillary and thereafter directed flows were generated. Flow analysis using microspheres as tracers showed that the flow comprised millimeter-scale convection, which originated at the point source where serine was supplied by the capillary. The generation of convection was attributable to cell accumulation and gravitational force, thereby suggesting that it is a variant of bioconvection. We recorded the time courses of the changes in cell numbers and the convection flow speed at different positions near the capillary, which showed that the number of cells increased initially until an almost saturated level, and the convection flow speed then accelerated as the cell accumulation area increased in size. This result indicates that cell accumulation at the stimulation source and enlargement of the accumulation area were essential for generating the convection. PMID- 28025151 TI - Normative 3D acetabular orientation measurements by the low-dose EOS imaging system in 102 asymptomatic subjects in standing position: Analyses by side, gender, pelvic incidence and reproducibility. AB - BACKGROUND: Three-dimensional (3D) acetabular orientation is a fundamental topic in orthopedic surgery. Computed tomography (CT) allows 3D measurement of native acetabular orientation, but with a substantial radiation dose. The EOS imaging system was developed to perform this kind of evaluation, but has not been validated in this indication with specific attention to the acetabulum. We therefore performed a prospective study using EOS to assess: (1) the reproducibility of the 3D acetabulum orientation measures; (2) normative asymptomatic acetabular morphology in standing position, according to side and gender; and (3) the relationship between acetabular anteversion and pelvic incidence. HYPOTHESIS: The low-dose EOS imaging system is a reproducible method for measuring 3D acetabular orientation in standing position. PATIENTS AND METHODS: In a previous prospective study of spine sagittal balance, 165 asymptomatic volunteers were examined on whole-body EOS biplanar X-ray; 102 had appropriate images for pelvic and acetabular analysis, with an equal sex-ratio (53 female, 49 male). These EOS images were reviewed using sterEOS 3D software, allowing automatic measurement of acetabular parameters (anteversion and inclination) and pelvic parameters (pelvic incidence, pelvic tilt and sacral slope) in an anatomical (anterior pelvic plane: APP) and a functional reference plane (patient vertical plane: PVP). RESULTS: Both intra- and inter-observer analysis showed good agreement (ICC>0.90); Bland-Altman plot distributions were good. Acetabular anatomical anteversion and inclination relative to APP (AAAPP and AIAPP, respectively) were significantly greater in women than in men, with no effect of side (right AAA: women 21.3 degrees +/-3.4 degrees vs. men 16.1 degrees +/-3.3 degrees (P<0001); right AIAPP: women 55.3 degrees +/-3.7 degrees vs. men 52.5 degrees +/-3.0 degrees (P<0001); left AAAPP: women 20.9 degrees +/ 3.5 degrees vs. men 15.6 degrees +/-4.0 degrees (P<0001); left AIAPP: women 54.6 degrees +/-3.5 degrees vs. men 52.7 degrees +/-2.8 degrees (P=0003)). The same differences between men and women were observed when measurements were related to PVP. Pelvic incidence subgroup (<44 degrees ; 44-62 degrees ; >62 degrees ) correlated significantly with functional acetabular orientation in standing position: PVP functional anteversion decreased by 5 degrees relative to APP anteversion with incidence <44 degrees , was equal to APP with incidence 44 62 degrees , and or was greater by 4 degrees relative to APP with incidence >62 degrees . DISCUSSION: The use of a 3D sterEOS software prototype version for 3D reconstruction of the native acetabulum from standard EOS X-ray was shown to be a reliable and reproducible method. This innovative method enabled the reference values of 3D acetabular orientation in standing position to be measured for the first time. The results reinforced the concept of hip-spine relationships, and involved very low radiation dose. LEVEL OF EVIDENCE: IV prospective study without control group. PMID- 28025152 TI - Efficacy of nighttime brace in preventing progression of idiopathic scoliosis of less than 25 degrees . AB - INTRODUCTION: The objective of the present study was to assess, at skeletal maturity, the efficacy of non-operative treatment by isolated nighttime brace in the prevention of progression of progressive idiopathic scoliosis of less than 25 degrees . HYPOTHESIS: Isolated nighttime brace treatment is effective in the prevention of progression of mild progressive idiopathic scoliosis (Cobb<25 degrees ). MATERIAL AND METHODS: A single-center retrospective study included 142 patients managed by nighttime brace for progressive idiopathic scoliosis with Cobb angle<25 degrees , with assessment at skeletal maturity. Mean Cobb angle at start of treatment was 15.5 degrees (range, 10-25 degrees ). Mean values for Cobb angle and sagittal parameters before treatment and at skeletal maturity were compared on Student t-test. Change in Cobb angle over time was also analyzed. RESULTS: Mean Cobb angle at skeletal maturity was 16.3 degrees , showing significant increase over baseline (15.5 degrees ; P=0.04), although the difference was less than the uncertainty of measurement (+/-6 degrees ). In baseline Risser 0 or 1, mean change in Cobb angle at skeletal maturity (16.2 degrees ) was not significant (P=0.1). Cobb angle diminished in 26 cases (18%), increased in 24 (17%) and was unchanged in 92 (65%). CONCLUSION: The present study confirmed the efficacy of non-operative treatment by nighttime brace in mild progressive idiopathic scoliosis (<25 degrees ) in a large majority of cases. A nighttime brace thus seems to be an effective option for the treatment of adolescent scoliosis, ensuring a safe curve of around 20 degrees . LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 28025153 TI - Direct observation of the crystallographic relationship between interlamellar membranes and aragonite tablets in bivalve nacre. AB - Nacre is one of the most attractive models for understanding the fundamental principles of biomineralization and for designing bio-inspired materials due to its simple structure but with unusual mechanical properties. It is made up of lamellae of aragonite tablets bonded together by the organic interlamellar membranes (ILMs), of which the latter occupy less than 5wt% of nacre. For a long time, previous authors failed to directly observe the crystallographic relationship between the ILM and aragonite tablet in bivalve shells. Here, using high resolution transmission electron microscope (HRTEM), we investigate the interfacial structure of the domed tablets that coexist with the flat ones in green mussels. We directly observed that the ILMs are oriented with the underlying tablets and connected with the latter via a superlattice region. The finding advances our current knowledge of nacre biomineralization and may help to design novel nacre-like materials. PMID- 28025155 TI - Should Patients Receiving Antiplatelet Agents Undergo Platelet Transfusion for Acute Gastrointestinal Bleeding? PMID- 28025154 TI - Increasing Number of Passes Beyond 4 Does Not Increase Sensitivity of Detection of Pancreatic Malignancy by Endoscopic Ultrasound-Guided Fine-Needle Aspiration. AB - BACKGROUND & AIMS: It is not clear exactly how many passes are required to determine whether pancreatic masses are malignant using endoscopic ultrasound guided fine-needle aspiration (EUS-FNA). We aimed to define the per-pass diagnostic yield of EUS-FNA for establishing the malignancy of a pancreatic mass, and identify factors associated with detection of malignancies. METHODS: In a prospective study, 239 patients with solid pancreatic masses were randomly assigned to groups that underwent EUS-FNA, with the number of passes determined by an on-site cytopathology evaluation or set at 7 passes, at 3 tertiary referral centers. A final diagnosis of pancreatic malignancy was made based on findings from cytology, surgery, or a follow-up evaluation at least 1 year after EUS-FNA. The cumulative sensitivity of detection of malignancy by EUS-FNA was calculated after each pass; in the primary analysis, lesions categorized as malignant or suspicious were considered as positive findings. RESULTS: Pancreatic malignancies were found in 202 patients (84.5% of the study population). EUS-FNA detected malignancies with 96% sensitivity (95% confidence interval [CI], 92%-98%); 4 passes of EUS-FNA detected malignancies with 92% sensitivity (95% CI, 87%-95%). Tumor size greater than 2 cm was the only variable associated with positive results from cytology analysis (odds ratio, 7.8; 95% CI, 1.9-31.6). In masses larger than 2 cm, 4 passes of EUS-FNA detected malignancies with 93% sensitivity (95% CI, 89%-96%) and in masses <=2 cm, 6 passes was associated with 82% sensitivity (95% CI, 61%-93%). Sensitivity of detection did not increase with increasing number of passes. CONCLUSIONS: In a prospective study, we found 4 passes of EUS-FNA to be sufficient to detect malignant pancreatic masses; increasing the number of passes did not increase the sensitivity of detection. Tumor size greater than 2 cm was associated with malignancy, and a greater number of passes may be required to evaluate masses 2 cm or less. ClinicalTrials.gov number, NCT01386931. PMID- 28025156 TI - A Modern Magnetic Implant for Gastroesophageal Reflux Disease. AB - A magnetic implant for the treatment of gastroesophageal reflux disease (GERD) was Food and Drug Administration-approved in 2012 and has been extensively evaluated. The device is a ring of magnets that are placed around the gastroesophageal junction, augmenting the native lower esophageal sphincter and preventing reflux yet preserving lower esophageal sphincter physiologic function and allowing belching and vomiting. Magnetic force is advantageous, being permanent and precise, and forces between magnets decrease with esophageal displacement. Multiple patient cohorts have been studied using the magnetic device, and trials establish consistent, long-term improvement in pH data, GERD symptom scores, and proton-pump inhibitor use. A 5-year Food and Drug Administration trial demonstrated that most patients achieved normal pH scores, 85% stopped proton-pump inhibitors, and GERD health-related quality of life symptom scores improved from 27 to 4 at 5 years. Seven studies have compared magnetic augmentation with laparoscopic Nissen fundoplication and demonstrated that the magnetic device achieved comparable efficacy with regard to proton-pump inhibitor cessation, GERD symptom score improvement, and heartburn and regurgitation scores. However, to date there have been no randomized, controlled trials comparing the 2 techniques, and the study cohorts are not necessarily comparable regarding hiatal hernia size, severity of reflux, body mass index scores, or esophagitis scores. Dysphagia incidence was similar in both groups. Reoperation rates and safety profiles were also comparable, but the magnetic device demonstrated significant beneficial differences in allowing belching and vomiting. The magnetic device is safe, with the main adverse event being dysphagia with an approximate 3%-5% chronic incidence. Device removals in clinical trials have been between 0% and 7% and were uneventful. There have been no erosions, perforations, or infections in FDA clinical trials; erosions have rarely been noted in practice. Magnetic augmentation of the lower esophageal sphincter is a safe and effective operation for GERD, and should be considered a surgical option for those seeking a fundic-sparing operation, particularly those with parameters consistent with study cohorts. Additional randomized, controlled trials are underway. PMID- 28025157 TI - Reply. PMID- 28025158 TI - Characterization and function analysis of interleukin-1 receptor-associated kinase-1 (IRAK-1) from Fenneropenaeus penicillatus. AB - The interleukin-1 receptor-associated kinase-1 (IRAK-1) is an important adapter protein which links downstream of MyD88, and involved in the complex composed of MyD88 and TRAF6 to activate TLRs signaling pathway. In this study, an IRAK-1 homolog (FpIRAK-1) was cloned from the red tail shrimp Fenneropenaeus penicillatus. The ORF of FpIRAK-1 consisted of 2874 bp encoding a protein of 957 amino acids which contains a death domain (DD) and a catalytic domain of serine/threonine kinases (STKc). Homology analysis revealed that the predicted amino acid sequence of FpIRAK-1 shared 71% similarities with IRAK-1 of Litopenaeus vannamei. Real-time RT-PCR indicated that FpIRAK-1 was constitutively expressed in various tissues of F. penicillatus. The expression level of FpIRAK-1 mRNA was significantly up-regulated and then decreased gradually after white spot syndrome virus (WSSV) and Vibrio alginolyticus challenge. Gene knockdown of FpIRAK-1 enhanced the sensitivity of shrimps to WSSV and V. alginolyticus challenge, suggesting FpIRAK-1 could play a positive role against bacterial and viral pathogens. In conclusion, the results of this study provide some insights into the function of FpIRAK-1 in activating Toll signaling pathway and the host defense against invading pathogens. PMID- 28025159 TI - Anti-apoptotic genes Bcl-2 and Bcl-xL overexpression can block iridovirus serine/threonine kinase-induced Bax/mitochondria-mediated cell death in GF-1 cells. AB - Although serine/threonine (ST) kinase is known to induce host cell death in GF-1 cells, it remains unclear how ST kinase induces mitochondrial function loss. In the present study, we addressed the issue of mitochondrial function loss by determining whether the Bcl-2 family members Bcl-2 and Bcl-xL can prevent ST kinase-induced cell death activity via interacting with the pro-apoptotic gene Bax. Grouper fin cells (GF-1) carrying EGFP-Bal-xL and EGFP-Bcl-2 fused genes were selected, established in cell culture, and used to examine the involvement of Bcl-2 and Bcl-xL overexpression in protection of GF-1 cells from the effects of the giant sea perch iridovirus (GSIV) ST kinase gene. Using the TUNEL assay, we found that EGFP-Bcl-2 and EGFP-Bcl-xL reduced GSIV ST kinase-induced apoptosis to 20% all at 24 h and 48 h post-transfection (pt). Also, Bcl-2 and Bcl-xL substantially reduced the percentage of cells with GSIV ST kinase-induced loss of mitochondrial membrane potential (Deltapsips) at 24 and 48 hpt, respectively, and this reduction correlated with a 30% and 50% enhancement of host cell viability at 24 and 48 hpt as compared with vector control. Moreover, analysis of the effect of Bcl-2 and Bcl-xL interaction with Bax targeted to mitochondria during ST kinase expression at 48 hpt found that Bcl-2 and Bcl-xL also interacted with Bax to block cytochrome c release. Finally, Bcl-2 and Bcl-xL overexpression caused blockage of ST kinase function at 48 hpt, which was correlated with preventing caspase-9 and -3 cleavage and activation, thereby blocking downstream death signaling events. Taken together, our results suggest that the ST kinase induced Bax/mitochondria-mediated cell death pathway can be blocked by the interaction of Bcl-2 and Bcl-xL with Bax to inhibit cytochrome c release during MMP loss. This rescue activity also correlated with inhibition of caspase-9 and 3 activation, thereby enhancing cell viability. PMID- 28025160 TI - Characterisation of arginase paralogues in salmonids and their modulation by immune stimulation/ infection. AB - In this study we show that four arginase isoforms (arg1a, arg1b, arg2a, arg2b) exist in rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar). We have characterised these molecules in terms of a) sequence analysis, b) constitutive expression in different tissues, and modulated expression following c) stimulation of head kidney macrophages in vitro, or d) vaccination/infection with Yersinia ruckeri and e) parasite infection (AGD caused by Paramoeba perurans and PKD caused by Tetracapsuloides bryosalmonae). Synteny analysis suggested that these arginase genes are paralogues likely from the Ss4R duplication event, and amino acid identity/similarity analyses showed that the proteins are relatively well conserved across species. In rainbow trout constitutive expression of one or both paralogues was seen in most tissues but different constitutive expression patterns were observed for the different isoforms. Stimulation of rainbow trout head kidney macrophages with PAMPs and cytokines also revealed isoform specific responses and kinetics, with arg1a being particularly highly modulated by the PAMPs and pro-inflammatory cytokines. In contrast the type II arginase paralogues were induced by rIl-4/13, albeit to a lesser degree. Vaccination and infection with Y. ruckeri also revealed isoform specific responses, with variation in tissue expression level and kinetics. Lastly, the impact of parasite infection was studied, where down regulation of arg1a and arg1b was seen in two different models (AGD in salmon and PKD in trout) and of arg2a in AGD. The differential responses seen are discussed in the context of markers of type II responses in fish and paralogue subfunctionalization. PMID- 28025161 TI - Association of weekend effect with early mortality in severe sepsis patients over time. AB - BACKGROUND: The aim of this study is to investigate the "weekend effect" and early mortality of patients with severe sepsis. METHODS: Using the Taiwanese National Healthcare Insurance Research Database, all patients who were hospitalized for the first time with an episode of severe sepsis between January 2000 and December 2011 were identified and the short-term mortality of patients admitted on weekdays was compared to those admitted on weekends. The primary endpoint was 7-day mortality. The secondary endpoints were 14 and 28-day mortality. RESULTS: A total of 398,043 patients were identified to have had the diagnosis of severe sepsis. Compared with patients admitted on weekends, patients admitted on weekdays had a lower 7-day mortality rate (adjusted odds ratio [OR] 0.89, 95% confidential interval [CI] 0.87-0.91), 14-day mortality rate (adjusted OR 0.92, 95% CI 0.90-0.93), and 28-day mortality rate (adjusted OR 0.97, 95% CI 0.95-0.98). This "weekend effect" was maintained every year throughout the 11 year study period. CONCLUSIONS: Patients with severe sepsis are more likely to die in the hospital if they were admitted on weekends than if they were admitted on weekdays. PMID- 28025162 TI - Antioxidant and acetylcholinesterase inhibitory activities in vitro of different fraction of Huperzia squarrosa (Forst.) Trevis extract and attenuation of scopolamine-induced cognitive impairment in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huperzia squarrosa (Forst.) Trevis is used in traditional medicine for improving memory deficits. Alkaloids, triterpenoids, flavonoids are main bioactive compounds of Huperzia squarrosa (Forst.) Trevis. AIM OF THE STUDY: This study aimed to investigate the antioxidant, AChE inhibitory activities in vitro of differents fraction of Huperzia squarrosa (Forst.) Trevis extract and neuroprotective effects of EtOAc fraction on scopolamine-induced cognitive impairment in mice. MATERIALS AND METHODS: Antioxidant activity was measured by DPPH assay. AChE inhibitory effect in vitro and detail kinetic inhibition mechanism was evaluated by Ellman's assay. For in vivo assay, mice were administrated orally EtOAc fraction (150 and 300mg/kg) for fourteen days, and injected scopolamine at a dose of 1mg/kg intraperitoneally for four days to induce memory injured. The memory behaviors were evaluated using the Morris water maze. ACh levels were measured in brain tissue. Superoxide dismutase (SOD), glutathione peroxidase (GPx) activities, malondialdehyde and protein thiol groups were also evaluated in the brains. RESULTS: Our data also demonstrated that EtOAc fraction had the strongest antioxidant with an IC50 value of 9.35+/ 1.68ug/mL and AChE inhibitory activity with an IC50 value of 23.44+/-3.14MUg/mL in a concentration-dependent manner. Kinetic inhibition analysis indicated that EtOAc fraction was mixed inhibition type with Ki (representing the affinity of the enzyme and inhibitor) was 34.75+/-1.42ug/mL. Scopolamine significantly increased the escape latency time, reduced the crossings number, and swimming time in the target quadrant, while EtOAc fraction reversed these scopolamine induced effects. EtOAc fraction significantly increased levels of acetylcholine in the brain. EtOAc fraction also significantly decreased oxidative stress in mice. CONCLUSION: Our data suggest that EtOAc fraction of Huperzia squarrosa extract exhibited a strong neuroprotective effect on cognitive impairment, and may be a potential candidate for the treatment of Alzheimer. PMID- 28025163 TI - Use of medicinal plants by health professionals in Mexico. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of medicinal plants in Mexico has been documented since pre-Hispanic times. Nevertheless, the level of use of medicinal plants by health professionals in Mexico remains to be explored. AIM OF THE STUDY: To evaluate the use, acceptance and prescription of medicinal plants by health professionals in 9 of the states of Mexico. MATERIALS AND METHODS: Direct and indirect interviews, regarding the use and acceptance of medicinal plants, with health professionals (n=1614), including nurses, physicians, pharmacists, and odontologists from nine states in Mexico were performed from January 2015 to July 2016. The interviews were analyzed with the factor the informant consensus (FIC). RESULTS: The information obtained indicated that 46% of those interviewed feel patients should not use medicinal plants as an alternative therapy. Moreover, 54% of health professionals, and 49% of the physicians have used medicinal plants as an alternative therapy for several diseases. Twenty eight percent of health professionals, and 26% of the physicians, have recommended or prescribed medicinal plants to their patients, whereas 73% of health professionals were in agreement with receiving academic information regarding the use and prescription of medicinal plants. A total of 77 plant species used for medicinal purposes, belonging to 40 botanical families were reported by the interviewed. The results of the FIC showed that the categories of diseases of the digestive system (FIC=0.901) and diseases of the respiratory system (FIC=0.898) had the greatest agreement. CONCLUSIONS: This study shows that medicinal plants are used for primary health care in Mexico by health professionals. PMID- 28025164 TI - Grilling enhances antidiarrheal activity of Terminalia bellerica Roxb. fruits. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia bellerica Roxb. fruits are rich in a variety of biologically active ingredients. Tharu and Buksa tribes of Udham Singh Nagar, Uttarakhand, India use grilled fruits of Terminalia bellerica as an effective cure for diarrhea AIM OF THE STUDY: We validated the ethnobotanical claim by comparing the antidiarrheal effect of grilled fruits (GF) with dried fruits (DF). MATERIALS AND METHODS: The 50% ethanolic extracts of GF and DF were successively fractionated; the antioxidant and bacterial inhibition activity were studied using DPPH free radical scavenging, anti-lipid peroxidation and broth dilution method respectively. Difference in metabolites of ethyl acetate fractions of GF and DF was analyzed using GC-MS, gallic acid content was determined through HPTLC. Further the in-vivo antidiarrheal effect of ethyl acetate fractions of DF and GF was studied on castor oil induced diarrhea model. RESULTS: The ethyl acetate fractions showed potential DPPH free radical scavenging (IC50 11.13ug/ml in DF and 8.56ug/ml in GF), anti-lipid peroxidation and antibacterial activity. The non-targeted metabolic profiling showed higher content of tartaric acid, valeric acid, gallic acid, succinic acid, oxalic acid, malonic acid, malic acid, 1,2,3 trisbenzene, uridine and 11-eicosenoic acid in GF. The HPTLC results indicated that gallic acid content was 2.8 (+/-0.14) and 4.92 (+/-0.28) mg/g while ellagic acid content was 4.7 (+/-0.32) and 4.45 (+/ 0.45) mg/g dry powder in DF and GF respectively. According to in vivo antidiarrheal activity DF and GF (100mg/kg oral) inhibited diarrhea by 41.87% and 71.72% respectively. CONCLUSION: Grilling significantly altered the levels of metabolites in T. bellerica fruits which could be responsible for its increased therapeutic potential. PMID- 28025165 TI - Searching molecular structure databases using tandem MS data: are we there yet? AB - Untargeted metabolomics experiments usually rely on tandem mass spectrometry (MS/MS) to identify the thousands of compounds in a complex sample. Spectral libraries used for identification are incomplete, and many metabolites remain unknown. There has been a recent development to replace spectral libraries by molecular structure databases when searching the MS/MS data of the unknown compound. Several tools have been developed for this task, including CFM-ID, MetFrag, MAGMa(+), FingerID and CSI:FingerID. These methods are already helpful for everyday metabolomics; with further advances, these methods can become indispensable tools for tomorrow's metabolomics. Here, I discuss several questions related to this task, such as: Why not wait for spectral libraries to grow sufficiently? Why evaluate methods outside their 'comfort zone'? Should we use prior information such as citation frequencies? And, ultimately: are we there yet? PMID- 28025166 TI - Considerations when choosing a genetic model organism for metabolomics studies. AB - Model organisms are important in many areas of chemical biology. In metabolomics, model organisms can provide excellent samples for methods development as well as the foundation of comparative phylometabolomics, which will become possible as metabolomics applications expand. Comparative studies of conserved and unique metabolic pathways will help in the annotation of metabolites as well as provide important new targets of investigation in biology and biomedicine. However, most chemical biologists are not familiar with genetics, which needs to be considered when choosing a model organism. In this review we summarize the strengths and weaknesses of several genetic systems, including natural isolates, recombinant inbred lines, and genetic mutations. We also discuss methods to detect targets of selection on the metabolome. PMID- 28025167 TI - Force-dependent breaching of the basement membrane. AB - Clinically, non-invasive carcinomas are confined to the epithelial side of the basement membrane and are classified as benign, whereas invasive cancers invade through the basement membrane and thereby acquire the potential to metastasize. Recent findings suggest that, in addition to protease-mediated degradation and chemotaxis-stimulated migration, basement membrane invasion by malignant cells is significantly influenced by the stiffness of the associated interstitial extracellular matrix and the contractility of the tumor cells that is dictated in part by their oncogenic genotype. In this review, we highlight recent findings that illustrate unifying molecular mechanisms whereby these physical cues contribute to tissue fibrosis and malignancy in three epithelial organs: breast, pancreas, and liver. We also discuss the clinical implications of these findings and the biological properties and clinical challenges linked to the unique biology of each of these organs. PMID- 28025169 TI - Evaluation of in vitro toxicity of polymeric micelles to human endothelial cells under different conditions. AB - Polymeric micelles have been extensively studied in the area of antitumor therapy, and more recently explored as nanocarriers for atherosclerosis. These applications of polymeric micelles in biomedicine will increase their contact with human blood vessels. However, few studies have considered the interactions between polymeric micelles and endothelial cells, especially in a complex system. This study used human umbilical vein endothelial cells (HUVECs) as an in vitro model for endothelial cells to investigate the toxic effects of methoxy poly(ethylene glycol)-poly(d,l-lactide) (MPEG-PLA) based micelles. In addition, an endoplasmic reticulum stress inducer thapsigargin (TG), and a pro-atherogenic stimulus palmitate (PA), were used to co-expose HUVECs to further mimic the responses of diseased endothelial cells to micelle exposure. Overall, up to 200 MUg/mL micelles did not significantly induce cytotoxicity, reactive oxygen species (ROS), release of inflammatory mediators in terms of interleukin 6 (IL 6), IL-8 and soluble vascular cell adhesion molecule 1 (sVCAM-1), or adhesion of THP-1 monocytes to HUVECs. TG and PA significantly induced cytotoxicity and THP-1 adhesion as well as modestly promoted the release of IL-6, but did not affect ROS or release of sVCAM-1 and IL-8. Co-exposure of micelles did not significantly enhance the effects of TG and PA to HUVECs, and ANOVA analysis indicated no interaction between concentrations of micelles and the presence of TG/PA. Taken together, these data indicated that micelles are not toxic to HUVECs under different conditions in vitro. PMID- 28025168 TI - Inversion of substrate stereoselectivity of horse liver alcohol dehydrogenase by substitutions of Ser-48 and Phe-93. AB - The substrate specificities of alcohol dehydrogenases (ADH) are of continuing interest for understanding the physiological functions of these enzymes. Ser-48 and Phe-93 have been identified as important residues in the substrate binding sites of ADHs, but more comprehensive structural and kinetic studies are required. The S48T substitution in horse ADH1E has small effects on kinetic constants and catalytic efficiency (V/Km) with ethanol, but decreases activity with benzyl alcohol and affinity for 2,2,2-trifluoroethanol (TFE) and 2,3,4,5,6 pentafluorobenzyl alcohol (PFB). Nevertheless, atomic resolution crystal structures of the S48T enzyme complexed with NAD+ and TFE or PFB are very similar to the structures for the wild-type enzyme. (The S48A substitution greatly diminishes catalytic activity.) The F93A substitution significantly decreases catalytic efficiency (V/Km) for ethanol and acetaldehyde while increasing activity for larger secondary alcohols and the enantioselectivity for the R isomer relative to the S-isomer of 2-alcohols. The doubly substituted S48T/F93A enzyme has kinetic constants for primary and secondary alcohols similar to those for the F93A enzyme, but the effect of the S48T substitution is to decrease V/Km for (S)-2-alcohols without changing V/Km for (R)-2-alcohols. Thus, the S48T/F93A substitutions invert the enantioselectivity for alcohol oxidation, increasing the R/S ratio by 10, 590, and 200-fold for 2-butanol, 2-octanol, and sec-phenethyl alcohol, respectively. Transient kinetic studies and simulations of the ordered bi bi mechanism for the oxidation of the 2-butanols by the S48T/F93A ADH show that the rate of hydride transfer is increased about 7-fold for both isomers (relative to wild-type enzyme) and that the inversion of enantioselectivity is due to more productive binding for (R)-2-butanol than for (S)-2-butanol in the ternary complex. Molecular modeling suggests that both of the sec-phenethyl alcohols could bind to the enzyme and that dynamics must affect the rates of catalysis. PMID- 28025170 TI - Instability of C154Y variant of aldo-keto reductase 1C3. AB - Aldo-keto reductase (AKR) 1C3 is a cytosolic enzyme that metabolizes steroids, prostaglandins, toxic aldehydes and drugs. Recently, some nonsynonymous single nucleotide polymorphisms of AKR1C3 have been suggested to impact steroid and drug metabolism. In this study, we examined the effects of C154Y and L159V variants of AKR1C3 on stability and function of the enzyme. Both variants had been detected in patients with the neurodegenerative disease amyotrophic lateral sclerosis. Recombinant wild-type (WT), C154Y and L159V enzymes were similar in specific activity, but C154Y displayed much lower thermostability than WT and L159V. C154Y was inactivated by 10-min incubation at >25 degrees C, and about 90% of its activity was lost at 40 degrees C. Differential scanning fluorimetry revealed that Tm (thermal denaturation midpoint) of C154Y was lower than that of WT. In order to study the cause of thermosensitivity of C154Y, we prepared C154F and C154S mutant AKR1C3s. Like C154Y, C154F was highly sensitive to thermal inactivation, whereas C154S showed almost the same thermostability as WT. The C154F and C154Y variants induced secondary and tertiary structural changes in AKR1C3 at 40 degrees C as reflected by their altered circular dichroism and 8 anilinonaphthalene-1-sulfonate fluorescence characteristics. These results suggest that the replacement of C154 with a residue possessing a bulky aromatic side-chain impairs the folding of the alpha-helix containing C154 and its neighboring secondary structures, leading to low thermostability of AKR1C3. AKR1C3 metabolizes cytotoxic 4-oxo-2-nonenal into a less toxic metabolite, and overexpression of WT in HEK293 cells alleviated the 4-oxo-2-nonenal-induced cytotoxicity. In contrast, the overexpression of C154Y in the cells did not show such a significant protective effect, suggesting that C154Y is unstable in cells. PMID- 28025171 TI - Editorial. PMID- 28025172 TI - CRISPR/Cas9 system-mediated impairment of synaptobrevin/VAMP function in postmitotic hippocampal neurons. AB - BACKGROUND: The use of the CRISPR/Cas9 system is becoming widespread, however current studies have predominantly focused on dividing cells. It is currently unknown if CRISPR/Cas9 can be used in a postmitotic setting to examine non-cell autonomous/presynaptic phenotypes in the resulting genetically heterogeneous cell population. NEW METHOD: A single CRISPR/Cas9 lentivirus was used to transfect a high percentage of primary cultured neurons and target synaptobrevin 2 (Syb2, also called VAMP2). RESULTS: Primary hippocampal cultures infected with the Syb2 targeting virus displayed dramatic reductions in Syb2 protein and immunocytochemical staining. In many boutons Syb2 was completely undetected. These cultures recapitulated the known functional phenotypes of Syb2 knockout neurons, which are non-cell autonomous and presynaptic in origin, indicating that Syb2 was knocked out in a large fraction of neurons. COMPARISON WITH EXISTING METHOD(S): Previous methods used multiple viruses or sparse transfection methods and only examined cell autonomous or postsynaptic phenotypes. The current method demonstrates that the CRISPR/Cas9 system can be used to alter network dynamics by removing or lowering the target gene from a majority of cells in the culture. CONCLUSIONS: A combination of CRISPR/Cas9 system and single high efficiency lentivirus infection can be used to examine non-cell autonomous and presynaptic phenotypes in postmitotic neurons. PMID- 28025173 TI - Does music therapy enhance behavioral and cognitive function in elderly dementia patients? A systematic review and meta-analysis. AB - Demographic aging is a worldwide phenomenon, cognitive and behavioral impairment is becoming global burden of nerve damage. However, the effect of pharmacological treatment is not satisfying. Therefore, we analyzed the efficacy of music therapy in elderly dementia patients, and if so, whether music therapy can be used as first-line non-pharmacological treatment. A comprehensive literature search was performed on PubMed, EMbase and the Cochrane Library from inception to September 2016. A total of 34 studies (42 analyses, 1757 subjects) were included; all of them had an acceptable quality based on the PEDro and CASP scale scores. Studies based on any type of dementia patient were combined and analyzed by subgroup. The standardized mean difference was -0.42 (-0.74 to -0.11) for disruptive behavior and 0.20 (-0.09 to 0.49) for cognitive function as primary outcomes in random effect models using controls as the comparator; the secondary outcomes were depressive score, anxiety and quality of life. No evidence of publication bias was found based on Begg's and Egger's test. The meta-analysis confirmed that the baseline differences between the two groups were balanced. Subgroup analyses showed that disease sub-type, intervention method, comparator, subject location, trial design, trial period and outcome measure instrument made little difference in outcomes. The meta-regression may have identified the causes of heterogeneity as the intervention method, comparator and trial design. Music therapy was effective when patients received interactive therapy with a compared group. There was positive evidence to support the use of music therapy to treat disruptive behavior and anxiety; there were positive trends supporting the use of music therapy for the treatment of cognitive function, depression and quality of life. This study is registered with PROSPERO, number CRD42016036153. PMID- 28025174 TI - Biomarkers associated with sedentary behaviour in older adults: A systematic review. AB - OBJECTIVE: Pathomechanisms of sedentary behaviour (SB) are unclear. We conducted a systematic review to investigate the associations between SB and various biomarkers in older adults. METHODS: Electronic databases were searched (MEDLINE, EMBASE, CINAHL, AMED) up to July 2015 to identify studies with objective or subjective measures of SB, sample size >=50, mean age >=60years and accelerometer wear time >=3days. Methodological quality was appraised with the CASP tool. The protocol was pre-specified (PROSPERO CRD42015023731). RESULTS: 12701 abstracts were retrieved, 275 full text articles further explored, from which 249 were excluded. In the final sample (26 articles) a total of 63 biomarkers were detected. Most investigated markers were: body mass index (BMI, n=15), waist circumference (WC, n=15), blood pressure (n=11), triglycerides (n=12) and high density lipoprotein (HDL, n=15). Some inflammation markers were identified such as interleukin-6, C-reactive protein or tumor necrosis factor alpha. There was a lack of renal, muscle or bone biomarkers. Randomized controlled trials found a positive correlation for SB with BMI, neck circumference, fat mass, HbA1C, cholesterol and insulin levels, cohort studies additionally for WC, leptin, C peptide, ApoA1 and Low density lipoprotein and a negative correlation for HDL. CONCLUSION: Most studied biomarkers associated with SB were of cardiovascular or metabolic origin. There is a suggestion of a negative impact of SB on biomarkers but still a paucity of high quality investigations exist. Longitudinal studies with objectively measured SB are needed to further elucidate the pathophysiological pathways and possible associations of unexplored biomarkers. PMID- 28025175 TI - Vitamin D deficiency and the pathogenesis of Crohn's disease. AB - Vitamin D has emerged as a key regulator of innate immune responses to pathogen threat. The hormonal form of vitamin D signals through a nuclear receptor transcription factor and regulates gene transcription. Several papers have shown that vitamin D signaling is active both upstream and downstream of pattern recognition receptors, vanguards of innate immune responses. Crohn's disease (CD) is a relapsing-recurring inflammatory bowel disease (IBD) that arises from dysregulated intestinal innate immunity. Indeed, genetic studies have identified several CD susceptibility markers linked to mechanisms of innate immune responses to infection. Interest in links between vitamin D deficiency and CD has grown substantially, particularly in the last five years. While a number of studies have consistently revealed an association between CD and vitamin D deficiency, recent experimental work has uncovered a compelling mechanistic basis for the contribution of vitamin D deficiency to the pathogenesis of the disease. Moreover, a number of intervention trials have provided generally solid evidence that robust vitamin D supplementation may be of therapeutic benefit to patients with CD. This review summarizes these laboratory and clinical findings. PMID- 28025176 TI - Beyond proneural: emerging functions and regulations of proneural proteins. AB - Proneural proteins, which include Ascl1, Atoh1 and Neurogenins epiniere in vertebrates and Achaete-Scute proteins and Atonal in Drosophila, are expressed in the developing nervous system throughout the animal kingdom and have an essential and well-characterised role in specifying the neural identity of progenitors. New properties and additional roles of these factors have emerged in recent years, including the regulation of stem cell proliferation and the capacity to reprogram many types of cells into neurons. This review will focus on these recent findings. The review will also discuss the mechanisms that allow proneural proteins to induce the transcription of their target genes in different chromatin contexts and the phosphorylation events and other post-transcriptional mechanisms that regulate the proneural proteins themselves. PMID- 28025177 TI - Family and sexual life in people with epilepsy. AB - Having epilepsy is much more than having seizures. Epilepsy can have a severe negative effect on quality of life, affecting social relationships, academic achievement, housing, employment, and the ability to live and function independently. We undertook a cross-sectional study in a tertiary epilepsy center in Lithuania, aiming to assess the influence of epilepsy and aspects relating to epilepsy (employment, stigma, anxiety) on patients and their families, and to estimate their quality of family life and sexual functioning. We asked patients to complete a questionnaire about their socio-demographic situation, their seizure types and antiepileptic medications, and their quality of family and sexual life. Our results confirmed that epilepsy seriously influences family life. One third of our patients are lonely and half are childless. Epilepsy leads to difficulty in finding a job, especially for men, and unemployment affects their status in the family. People with epilepsy are uncomfortable interacting with those of the opposite sex and tend to conceal their medical condition from their partner. One third have sexual dysfunction, yet only a quarter of them seek professional help. There is a clear need to improve self-confidence and to reduce social stigma in people with epilepsy, and to encourage them to discuss their problems with specialists. PMID- 28025178 TI - MTGIpick allows robust identification of genomic islands from a single genome. AB - Genomic islands (GIs) that are associated with microbial adaptations and carry sequence patterns different from that of the host are sporadically distributed among closely related species. This bias can dominate the signal of interest in GI detection. However, variations still exist among the segments of the host, although no uniform standard exists regarding the best methods of discriminating GIs from the rest of the genome in terms of compositional bias. In the present work, we proposed a robust software, MTGIpick, which used regions with pattern bias showing multiscale difference levels to identify GIs from the host. MTGIpick can identify GIs from a single genome without annotated information of genomes or prior knowledge from other data sets. When real biological data were used, MTGIpick demonstrated better performance than existing methods, as well as revealed potential GIs with accurate sizes missed by existing methods because of a uniform standard. Software and supplementary are freely available at http://bioinfo.zstu.edu.cn/MTGI or https://github.com/bioinfo0706/MTGIpick. PMID- 28025179 TI - Measuring the diversity of the human microbiota with targeted next-generation sequencing. AB - The human microbiota is a complex ecological community of commensal, symbiotic and pathogenic microorganisms harboured by the human body. Next-generation sequencing (NGS) technologies, in particular targeted amplicon sequencing of the 16S ribosomal RNA gene (16S-seq), are enabling the identification and quantification of human-resident microorganisms at unprecedented resolution, providing novel insights into the role of the microbiota in health and disease. Once microbial abundances are quantified through NGS data analysis, diversity indices provide valuable mathematical tools to describe the ecological complexity of a single sample or to detect species differences between samples. However, diversity is not a determined physical quantity for which a consensus definition and unit of measure have been established, and several diversity indices are currently available. Furthermore, they were originally developed for macroecology and their robustness to the possible bias introduced by sequencing has not been characterized so far. To assist the reader with the selection and interpretation of diversity measures, we review a panel of broadly used indices, describing their mathematical formulations, purposes and properties, and characterize their behaviour and criticalities in dependence of the data features using simulated data as ground truth. In addition, we make available an R package, DiversitySeq, which implements in a unified framework the full panel of diversity indices and a simulator of 16S-seq data, and thus represents a valuable resource for the analysis of diversity from NGS count data and for the benchmarking of computational methods for 16S-seq. PMID- 28025180 TI - Survival trees for left-truncated and right-censored data, with application to time-varying covariate data. AB - Tree methods (recursive partitioning) are a popular class of nonparametric methods for analyzing data. One extension of the basic tree methodology is the survival tree, which applies recursive partitioning to censored survival data. There are several existing survival tree methods in the literature, which are mainly designed for right-censored data. We propose two new survival trees for left-truncated and right-censored (LTRC) data, which can be seen as a generalization of the traditional survival tree for right-censored data. Further, we show that such trees can be used to analyze survival data with time-varying covariates, essentially building a time-varying covariates survival tree. Implementation of the methods is easy, and simulations and real data analysis results show that the proposed methods work well for LTRC data and survival data with time-varying covariates, respectively. PMID- 28025181 TI - A rigorous statistical framework for spatio-temporal pollution prediction and estimation of its long-term impact on health. AB - In the United Kingdom, air pollution is linked to around 40000 premature deaths each year, but estimating its health effects is challenging in a spatio-temporal study. The challenges include spatial misalignment between the pollution and disease data; uncertainty in the estimated pollution surface; and complex residual spatio-temporal autocorrelation in the disease data. This article develops a two-stage model that addresses these issues. The first stage is a spatio-temporal fusion model linking modeled and measured pollution data, while the second stage links these predictions to the disease data. The methodology is motivated by a new five-year study investigating the effects of multiple pollutants on respiratory hospitalizations in England between 2007 and 2011, using pollution and disease data relating to local and unitary authorities on a monthly time scale. PMID- 28025182 TI - Incorporating social contact data in spatio-temporal models for infectious disease spread. AB - Routine public health surveillance of notifiable infectious diseases gives rise to weekly counts of reported cases-possibly stratified by region and/or age group. We investigate how an age-structured social contact matrix can be incorporated into a spatio-temporal endemic-epidemic model for infectious disease counts. To illustrate the approach, we analyze the spread of norovirus gastroenteritis over six age groups within the 12 districts of Berlin, 2011-2015, using contact data from the POLYMOD study. The proposed age-structured model outperforms alternative scenarios with homogeneous or no mixing between age groups. An extended contact model suggests a power transformation of the survey based contact matrix toward more within-group transmission. PMID- 28025184 TI - Hot stuff: a rare diagnosis of a mitral valve mass confirmed on cardiac fludeoxyglucose positron emission tomography. PMID- 28025183 TI - Inequality in treatment benefits: Can we determine if a new treatment benefits the many or the few? AB - In many randomized controlled trials, the primary analysis focuses on the average treatment effect and does not address whether treatment benefits are widespread or limited to a select few. This problem affects many disease areas, since it stems from how randomized trials, often the gold standard for evaluating treatments, are designed and analyzed. Our goal is to learn about the fraction who benefit from a new treatment using randomized trial data. We consider the case where the outcome is ordinal, with binary outcomes as a special case. In general, the fraction who benefit is non-identifiable, and the best that can be obtained are sharp lower and upper bounds. Our contributions include (i) proving the plug-in estimator of the bounds can be inconsistent if support restrictions are made on the joint distribution of the potential outcomes; (ii) developing the first consistent estimator for this case; and (iii) applying this estimator to a randomized trial of a medical treatment to determine whether the estimates can be informative. Our estimator is computed using linear programming, allowing fast implementation. R code is provided. PMID- 28025185 TI - Pheochromocytoma triggers takotsubo syndrome complicated by cerebral and peripheral embolic events. PMID- 28025186 TI - Oesophageal fistula-related pneumopericardium secondary to radiochemotherapy. PMID- 28025187 TI - Percutaneous repair of ascending aorta pseudoaneurysm and aortopulmonary fistula with two Amplatzer septal occluder devices. PMID- 28025188 TI - Unusual presentation of a left atrial tumour prolapsing beyond the aortic valve. PMID- 28025190 TI - Acute heart failure caused by mechanical valve leaflet dislodgment at the mitral position. PMID- 28025189 TI - Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. AB - Aims: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted. PMID- 28025191 TI - Fractional flow reserve to guide and to assess coronary artery bypass grafting. AB - The aim of this review is to highlight the role of invasive functional evaluation in patients in whom coronary artery bypass graft (CABG) is indicated, and to examine the clinical evidence available in favour of fractional flow reserve (FFR) adoption in these patients, outline appropriate use, as well as point out potential pitfalls. FFR after CABG will also be reviewed, highlighting its correct interpretation and adoption when applied to both native coronary arteries and bypass grafts. Practice European guidelines support the use of FFR to complement coronary angiography with the highest degree of recommendation (Class IA) for the assessment of coronary stenosis before undertaking myocardial revascularization when previous non-invasive functional evaluation is unavailable or not conclusive. As a result, FFR has been adopted in routine clinical practice to guide clinicians decision as to whether or not perform a revascularization. Of note, due to the increasing confidence of the interventional cardiologists, FFR guidance is also being implemented to indicate or guide CABG. This is in anticipation of supportive clear-cut evidence, since recommendations for FFR adoption were based on randomized clinical trials investigating percutaneous coronary intervention (PCI) strategies in which patients with typical indications for CABG were excluded (e.g. left main disease, valvular disease, and coronary anatomy unsuitable for PCI). Based on the critical appraisal of the literature, FFR can play an important role in risk stratification and determining management strategy of patients either before or after CABG. PMID- 28025193 TI - How to RESPOND to the quest to increase the effectiveness of cardiac resynchronization therapy? PMID- 28025192 TI - Percutaneous repair of right ventricular perforation with Amplatzer septal defect occlusion device. PMID- 28025194 TI - Corrigendum. PMID- 28025195 TI - Corrigendum. PMID- 28025196 TI - Corrigendum. PMID- 28025197 TI - A novel approach based on KATZ measure to predict associations of human microbiota with non-infectious diseases. AB - Motivation: Accumulating clinical observations have indicated that microbes living in the human body are closely associated with a wide range of human noninfectious diseases, which provides promising insights into the complex disease mechanism understanding. Predicting microbe-disease associations could not only boost human disease diagnostic and prognostic, but also improve the new drug development. However, little efforts have been attempted to understand and predict human microbe-disease associations on a large scale until now. Results: In this work, we constructed a microbe-human disease association network and further developed a novel computational model of KATZ measure for Human Microbe Disease Association prediction (KATZHMDA) based on the assumption that functionally similar microbes tend to have similar interaction and non interaction patterns with noninfectious diseases, and vice versa. To our knowledge, KATZHMDA is the first tool for microbe-disease association prediction. The reliable prediction performance could be attributed to the use of KATZ measurement, and the introduction of Gaussian interaction profile kernel similarity for microbes and diseases. LOOCV and k-fold cross validation were implemented to evaluate the effectiveness of this novel computational model based on known microbe-disease associations obtained from HMDAD database. As a result, KATZHMDA achieved reliable performance with average AUCs of 0.8130 +/- 0.0054, 0.8301 +/- 0.0033 and 0.8382 in 2-fold and 5-fold cross validation and LOOCV framework, respectively. It is anticipated that KATZHMDA could be used to obtain more novel microbes associated with important noninfectious human diseases and therefore benefit drug discovery and human medical improvement. Availability and Implementation: Matlab codes and dataset explored in this work are available at http://dwz.cn/4oX5mS . Contacts: xingchen@amss.ac.cn or zhuhongyou@gmail.com or wangxuesongcumt@163.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025198 TI - DACE: a scalable DP-means algorithm for clustering extremely large sequence data. AB - Motivation: Advancements in next-generation sequencing technology have produced large amounts of reads at low cost in a short time. In metagenomics, 16S and 18S rRNA gene have been widely used as marker genes to profile diversity of microorganisms in environmental samples. Through clustering of sequencing reads we can determine both number of OTUs and their relative abundance. In many applications, clustering of very large sequencing data with high efficiency and accuracy is essential for downstream analysis. Results: Here, we report a scalable D irichlet Process Means (DP-means) a lgorithm for c lustering e xtremely large sequencing data, termed . With an efficient random projection partition strategy for parallel clustering, DACE can cluster billions of sequences within a couple of hours. Experimental results show that DACE runs between 6 and 80 times faster than state-of-the-art programs, while maintaining overall better clustering accuracy. Using 80 cores, DACE clustered the Lake Taihu 16S rRNA gene sequencing data (~316M reads, 30 GB) in 25 min, and the Ocean TARA Eukaryotic 18S rRNA gene sequencing data (~500M reads, 88 GB) into ~100 000 clusters within an hour. When applied to the IGC gene catalogs in human gut microbiome (~10M genes), DACE produced 9.8M clusters with 52K redundant genes in 1.5 hours of running time. Availability and Implementation: DACE is available at https://github.com/tinglab/DACE . Contacts: tingchen@mail.tsinghua.edu.cn or ningchen@mail.tsinghua.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025199 TI - Computational prediction of species-specific malonylation sites via enhanced characteristic strategy. AB - Motivation: Protein malonylation is a novel post-translational modification (PTM) which orchestrates a variety of biological processes. Annotation of malonylation in proteomics is the first-crucial step to decipher its physiological roles which are implicated in the pathological processes. Comparing with the expensive and laborious experimental research, computational prediction can provide an accurate and effective approach to the identification of many types of PTMs sites. However, there is still no online predictor for lysine malonylation. Results: By searching from literature and database, a well-prepared up-to-data benchmark datasets were collected in multiple organisms. Data analyses demonstrated that different organisms were preferentially involved in different biological processes and pathways. Meanwhile, unique sequence preferences were observed for each organism. Thus, a novel malonylation site online prediction tool, called MaloPred, which can predict malonylation for three species, was developed by integrating various informative features and via an enhanced feature strategy. On the independent test datasets, AUC (area under the receiver operating characteristic curves) scores are obtained as 0.755, 0.827 and 0.871 for Escherichia coli ( E.coli ), Mus musculus ( M.musculus ) and Homo sapiens ( H.sapiens ), respectively. The satisfying results suggest that MaloPred can provide more instructive guidance for further experimental investigation of protein malonylation. Availability and Implementation: http://bioinfo.ncu.edu.cn/MaloPred.aspx . Contact: jdqiu@ncu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025200 TI - Falco: a quick and flexible single-cell RNA-seq processing framework on the cloud. AB - Summary: Single-cell RNA-seq (scRNA-seq) is increasingly used in a range of biomedical studies. Nonetheless, current RNA-seq analysis tools are not specifically designed to efficiently process scRNA-seq data due to their limited scalability. Here we introduce Falco, a cloud-based framework to enable paralellization of existing RNA-seq processing pipelines using big data technologies of Apache Hadoop and Apache Spark for performing massively parallel analysis of large scale transcriptomic data. Using two public scRNA-seq datasets and two popular RNA-seq alignment/feature quantification pipelines, we show that the same processing pipeline runs 2.6-145.4 times faster using Falco than running on a highly optimized standalone computer. Falco also allows users to utilize low cost spot instances of Amazon Web Services, providing a ~65% reduction in cost of analysis. Availability and Implementation: Falco is available via a GNU General Public License at https://github.com/VCCRI/Falco/. Contact: j.ho@victorchang.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025201 TI - tranSMART-XNAT Connector tranSMART-XNAT connector-image selection based on clinical phenotypes and genetic profiles. AB - Motivation: TranSMART has a wide range of functionalities for translational research and a large user community, but it does not support imaging data. In this context, imaging data typically includes 2D or 3D sets of magnitude data and metadata information. Imaging data may summarise complex feature descriptions in a less biased fashion than user defined plain texts and numeric numbers. Imaging data also is contextualised by other data sets and may be analysed jointly with other data that can explain features or their variation. Results: Here we describe the tranSMART-XNAT Connector we have developed. This connector consists of components for data capture, organisation and analysis. Data capture is responsible for imaging capture either from PACS system or directly from an MRI scanner, or from raw data files. Data are organised in a similar fashion as tranSMART and are stored in a format that allows direct analysis within tranSMART. The connector enables selection and download of DICOM images and associated resources using subjects' clinical phenotypic and genotypic criteria. Availability and Implementation: tranSMART-XNAT connector is written in Java/Groovy/Grails. It is maintained and available for download at https://github.com/sh107/transmart-xnat-connector.git. Contact: sijin@ebi.ac.uk. PMID- 28025202 TI - Calypso: a user-friendly web-server for mining and visualizing microbiome environment interactions. AB - : Calypso is an easy-to-use online software suite that allows non-expert users to mine, interpret and compare taxonomic information from metagenomic or 16S rDNA datasets. Calypso has a focus on multivariate statistical approaches that can identify complex environment-microbiome associations. The software enables quantitative visualizations, statistical testing, multivariate analysis, supervised learning, factor analysis, multivariable regression, network analysis and diversity estimates. Comprehensive help pages, tutorials and videos are provided via a wiki page. Availability and Implementation: The web-interface is accessible via http://cgenome.net/calypso/ . The software is programmed in Java, PERL and R and the source code is available from Zenodo ( https://zenodo.org/record/50931 ). The software is freely available for non commercial users. Contact: l.krause@uq.edu.au. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025203 TI - Accelerating Bayesian inference for evolutionary biology models. AB - Motivation: Bayesian inference is widely used nowadays and relies largely on Markov chain Monte Carlo (MCMC) methods. Evolutionary biology has greatly benefited from the developments of MCMC methods, but the design of more complex and realistic models and the ever growing availability of novel data is pushing the limits of the current use of these methods. Results: We present a parallel Metropolis-Hastings (M-H) framework built with a novel combination of enhancements aimed towards parameter-rich and complex models. We show on a parameter-rich macroevolutionary model increases of the sampling speed up to 35 times with 32 processors when compared to a sequential M-H process. More importantly, our framework achieves up to a twentyfold faster convergence to estimate the posterior probability of phylogenetic trees using 32 processors when compared to the well-known software MrBayes for Bayesian inference of phylogenetic trees. Availability and Implementation: https://bitbucket.org/XavMeyer/hogan. Contact: nicolas.salamin@unil.ch. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025204 TI - Novel probabilistic models of spatial genetic ancestry with applications to stratification correction in genome-wide association studies. AB - Motivation: Genetic variation in human populations is influenced by geographic ancestry due to spatial locality in historical mating and migration patterns. Spatial population structure in genetic datasets has been traditionally analyzed using either model-free algorithms, such as principal components analysis (PCA) and multidimensional scaling, or using explicit spatial probabilistic models of allele frequency evolution. We develop a general probabilistic model and an associated inference algorithm that unify the model-based and data-driven approaches to visualizing and inferring population structure. Our spatial inference algorithm can also be effectively applied to the problem of population stratification in genome-wide association studies (GWAS), where hidden population structure can create fictitious associations when population ancestry is correlated with both the genotype and the trait. Results: Our algorithm Geographic Ancestry Positioning (GAP) relates local genetic distances between samples to their spatial distances, and can be used for visually discerning population structure as well as accurately inferring the spatial origin of individuals on a two-dimensional continuum. On both simulated and several real datasets from diverse human populations, GAP exhibits substantially lower error in reconstructing spatial ancestry coordinates compared to PCA. We also develop an association test that uses the ancestry coordinates inferred by GAP to accurately account for ancestry-induced correlations in GWAS. Based on simulations and analysis of a dataset of 10 metabolic traits measured in a Northern Finland cohort, which is known to exhibit significant population structure, we find that our method has superior power to current approaches. Availability and Implementation: Our software is available at https://github.com/anand-bhaskar/gap . Contacts: abhaskar@stanford.edu or ajavanma@usc.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28025206 TI - Dr Robert O. Bonow. PMID- 28025205 TI - Update on interventional cardiology: outcome according to stent type and implantation technique. PMID- 28025207 TI - The role of the ESC in education. PMID- 28025208 TI - The ESC cardiologists of tomorrow. PMID- 28025210 TI - The Russian National Congress of cardiology 2016. PMID- 28025211 TI - Male GPs are less likely to assess cardiovascular risk in female patients. PMID- 28025209 TI - The Andreas Gruntzig lecture at European Society of Cardiology congress 2016. PMID- 28025212 TI - Matthias Nahrendorf MD new International Associate Editor for European Heart Journal. PMID- 28025213 TI - Non-vitamin-K oral anticoagulants and laboratory testing: now and in the future: Views from a workshop at the European Medicines Agency (EMA). AB - In contrast to vitamin K antagonists, no routine coagulation monitoring is required in patients taking non-vitamin-K oral anticoagulants (NOACs). However, dosing must take into account factors such as patient age, renal function, and accompanying haemorrhagic risk. There has been considerable debate about when laboratory measurement might be appropriate and which tests should be used. A workshop at the European Medicines Agency recently discussed the evidence about laboratory measurement from formal studies, clinical experience, and the multiple perspectives on NOAC treatment, and considered how our knowledge might be further enhanced. PMID- 28025214 TI - New ESC/EACTS Guidelines for the management of atrial fibrillation. PMID- 28025215 TI - Congestive heart failure: more common as well as an important cardiovascular outcome. PMID- 28025216 TI - Hydroxychloroquine for the prevention of recurrent cardiovascular events in myocardial infarction patients: rationale and design of the OXI trial. AB - Background: Inflammation of the arterial wall plays a central role in the pathogenesis of atherosclerosis. Among patients with rheumatic diseases, anti rheumatic medication reduces the incidence of cardiovascular (CV) diseases, but only few studies have addressed their cardioprotective effects on patients with no rheumatic diseases. Hydroxychloroquine (HCQ) is an anti-rheumatic drug commonly used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol levels and the risk of type II diabetes, and has also anti-platelet effects. Design: The OXI trial is an event-driven trial that will randomize 2500 patients hospitalized for myocardial infarction (MI). Participants will receive active HCQ or placebo for at least 12 months, and until 350 CV events are confirmed. The primary trial endpoint is the composite of death, MI, hospitalization for unstable angina, urgent percutaneous coronary intervention, and urgent coronary artery bypass grafting. Secondary trial endpoints are the primary end point plus stroke, the effect of HCQ treatment on lipids, on the incidence of Type 2 diabetes, on the level of haemoglobin A1c, and on inflammatory parameters. A 6 months placebo-controlled safety pilot trial with 200 patients is currently ongoing to assess the safety of HCQ in the setting of MI. Summary: The OXI trial will determine whether treatment with HCQ, as compared with placebo, will reduce recurrent CV events among MI patients. If positive, then the OXI trial would provide an entirely novel multitarget approach for the secondary prevention of atherosclerotic cardiovascular diseases (ACVD). PMID- 28025217 TI - Visit-to-visit blood pressure variability: an epiphenomenon or a risk for the progression of carotid artery remodelling? PMID- 28025218 TI - Non-steroidal anti-inflammatory drug use is associated with increased risk of out of-hospital cardiac arrest: a nationwide case-time-control study. AB - Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been associated with increased cardiovascular risk. Nonetheless, it remains unknown whether use of NSAIDs is associated with out-of-hospital cardiac arrest (OHCA). Methods and results: From the nationwide Danish Cardiac Arrest Registry, all persons with OHCA during 2001-10 were identified. NSAID use 30 days before OHCA was categorized as follows: diclofenac, naproxen, ibuprofen, rofecoxib, celecoxib, and other. Risk of OHCA associated with use of NSAIDs was analysed by conditional logistic regression in case-time-control models matching four controls on sex and age per case to account for variation in drug utilization over time. We identified 28 947 persons with OHCA of whom 3376 were treated with an NSAID up to 30 days before OHCA. Ibuprofen and diclofenac were the most commonly used NSAIDs and represented 51.0% and 21.8% of total NSAID use, respectively. Use of diclofenac (odds ratio [OR], 1.50 [95% confidence interval (CI) 1.23-1.82]) and ibuprofen [OR, 1.31 (95% CI 1.14-1.51)] was associated with a significantly increased risk of OHCA. Use of naproxen [OR, 1.29 (95% CI 0.77 2.16)], celecoxib [OR, 1.13 (95% CI 0.74-1.70)], and rofecoxib (OR, 1.28 [95% CI 0.74-1.70)] was not significantly associated with increased risk of OHCA; however, these groups were characterized by few events. Conclusion: Use of non selective NSAIDs was associated with an increased early risk of OHCA. The result was driven by an increased risk of OHCA in ibuprofen and diclofenac users. PMID- 28025219 TI - Tillage Reduces Survival of Grape Berry Moth (Lepidoptera: Tortricidae), via Burial Rather Than Mechanical Injury. AB - The grape berry moth, Paralobesia viteana (Clemens), is a key pest of vineyards in eastern North America that overwinters as pupae in leaf litter on the vineyard floor. This presents an opportunity for tillage to disturb and bury the pupae, providing a potential nonchemical approach to control of this pest. Using a Lilleston-style rotary cultivator, we determined the distribution of pupae within the soil profile after single tillage passes, measured the type and severity of damage inflicted on pupae, and investigated how these effects on pupae influenced their survival. Survivorship of pupae recovered from the vineyard immediately after tillage and held until emergence was not significantly different from those recovered from an untilled control area, indicating little effect of mechanical damage on this pest. However, a single pass of the tillage implement buried three quarters of pupae under at least 1 cm of soil. A laboratory experiment to recreate these conditions resulted in significant increase in mortality when pupae were buried in more than 1 cm of sand. We conclude that 1) interference with adult emergence of diapausing pupae via burial is the primary mechanism by which tillage controls grape berry moth, and 2) efforts to optimize the impact of tillage on grape berry moth populations should focus on maximizing the number of pupae buried. We discuss the potential integration of tillage into different vineyard management systems to enhance pest management. PMID- 28025220 TI - Intraguild Predation Among Three Common Coccinellids (Coleoptera: Coccinellidae) in China: Detection Using DNA-Based Gut-Content Analysis. AB - The ubiquity of intraguild predation (IGP) has been widely recognized for predatory coccinellids (Coleoptera: Coccinellidae). In Chinese agroecosystems, three species (Coccinella septempunctata L., Harmonia axyridis (Pallas), and Propylea japonica (Thunberg)) are particularly common, but there is little information of interactions occurring between them. In no-choice laboratory feeding trials, differential directional predation was observed between species: C. septempunctata preyed on eggs of P. japonica more than H. axyridis and H. axyridis consumed eggs of C. septempunctata and P. japonica equally, whereas P. japonica had a very low predation rate on eggs of the other two species. In choice trials, C. septempunctata and P. japonica larvae preyed less on H. axyridis eggs than those of P. japonica and C. septempunctata, respectively, contrasting with H. axyridis larvae, which showed similar preference for both species. Species-specific primers were developed for each coccinellid and used to determine the relative frequency of prey consumption in the field. Prior to field based analysis, primer specificity was confirmed and consumption of prey elicited a positive reaction success, and detection time varied between different predator prey combinations. Predators were then collected from cotton agroecosystems and, interestingly, no DNA of C. septempunctata was found in P. japonica, but all other predator-prey combinations yielded positive documentation of IGP in the field, with the greatest rate of 9% of C. septempunctata testing positive for H. axyridis DNA. This study confirmed the frequency of IGP among three common coccinellids in Chinese agroecosystems and the likelihood for interference to the biological control services provided by these important natural enemies. PMID- 28025221 TI - Bacteria Associated With Piezodorus guildinii (Hemiptera: Pentatomidae), With Special Reference to Those Transmitted by Feeding. AB - The redbanded stink bug, Piezodorus guildinii (Westwood) (Hemiptera: Heteroptera: Pentatomidae), is a rapidly growing pest damaging southern US agriculture. Pentatomid stink bugs are known to vector bacterial, fungal, and viral plant diseases. However, bacteria associated with redbanded stink bugs and their vector potential have not yet been assessed. In this study, we 1) cultured and identified bacteria transmitted by feeding of redbanded stink bug and 2) described bacteria from guts of redbanded stink bug individuals using next generation sequencing of 16S rRNA genes. Nineteen bacteria transmitted by feeding of redbanded stink bug on soybean agar were isolated and identified via Sanger sequencing of near full length 16S RNA genes. The transmitted bacteria belonged to at least a dozen species in eight genera and included potential plant pathogens (Phaseolibacter flectens), plant beneficials (Bacillus atropheus), and possible insect beneficials (Acinetobacter sp. and Citrobacter farmeri). A total of 284,448 reads were captured from Illumina MiSeq sequencing of the uncultured gut bacteria community. Fifty-one putative bacteria species (74% of the estimated total species richness) were identified via matches to NCBI databases. The bacteria metagenome contained potential plant and insect pathogens (Erwinia persicina, E. rhaponici, Brenneria nigrifluens, Ralstonia picketti, and Serratia marcescens) and beneficials (Pantoea dispersa, Klebsiella oxytoca, Clostridium butyricum, and Citrobacter farmeri). PMID- 28025222 TI - Mechanisms Underlying the Nonconsumptive Effects of Parasitoid Wasps on Aphids. AB - Natural enemies need not consume herbivores to suppress herbivore populations. Behavioral interactions can adversely impact herbivore fitness from reduced time feeding, investment in defense, or injury from failed attacks. The importance of such "nonconsumptive effects" for herbivore suppression may vary across species based on the specificity and intensity of the herbivore defensive response. In a series of manipulative studies, we quantified the nature and consequences of nonconsumptive interactions between two parasitoid wasps, Aphidius ervi Haliday and Aphidius colemani Viereck, on two aphid species, pea aphids (Acyrthosiphon pisum (Harris)) and green peach aphids (Myzus persicae (Sulzer)). Both wasps successfully parasitize green peach aphids, but only A. ervi parasitizes pea aphids. We observed A. ervi antennating and stinging pea aphids and documented a decrease in pea aphid longevity in response to stinging even when the aphid survived the interaction and no mummy formed. The primary defensive tactic of pea aphids in response to either wasp species was dropping from the host plant. Both wasp species antennated and stung green peach aphids, but they elicited unique defensive behaviors. Green peach aphids kicked or emitted cornicle secretions in response to A. colemani but spent more time off the plant in the presence of A. ervi. Green peach aphid longevity and fecundity were not affected by wasp stings when the aphid survived and no mummy formed. Our study demonstrates the complexity of behavioral interactions between parasitoids and their potential hosts and contributes to a mechanistic understanding of variation in the nonconsumptive suppression of herbivore populations. PMID- 28025223 TI - Substantial Mortality of Cabbage Looper (Lepidoptera: Noctuidae) From Predators in Urban Agriculture Is not Influenced by Scale of Production or Variation in Local and Landscape-Level Factors. AB - As Midwestern (United States) cities experience population decline, there is growing interest in converting underutilized vacant spaces to agricultural production. Urban agriculture varies in area and scope, yet most growers use similar cultivation practices such as avoiding chemical control of crop pests. For community gardens and farms that sell produce commercially, effective pest suppression by natural enemies is important for both societal, economic, and marketing reasons. To gauge the amount of prey suppression at 28 urban food production sites, we measured removal of sentinel eggs and larvae of the cabbage looper Trichoplusia ni (Hubner), a caterpillar pest that defoliates Brassica. We investigated how landscape and local factors, such as scale of production, influence cabbage looper mortality caused by predators. Predators removed 50% of eggs and 25% of larvae over a 3-d period. Landscape factors did not predict mortality rates, and the amount of loss and damage to sentinel prey were similar across sites that differed in scale (residential gardens, community gardens, and farms). To confirm that removal of sentinel items was likely caused by natural enemies, we set up a laboratory assay that measured predation of cabbage looper eggs and larvae by several predators occurring in urban gardens. Lady beetles caused the highest mortality rates, suggesting their potential value for biocontrol; spiders and pirate bugs also consumed both eggs and larvae at high rates. Our results suggest that urban growers benefit from high consumption rates of cabbage looper eggs and larvae by arthropod predators. PMID- 28025224 TI - Bacteria and Hoverflies (Diptera: Syrphidae) in Tree Hollows From the Iberian Mediterranean Forest. AB - Saproxylic insect communities inhabiting tree hollows in Mediterranean forests depend on a combination of physical characteristics and interactions occurring between community member species. Despite the need to preserve these organisms, little is known about their interrelationships, in particular those relationships between saproxylic insects and microbiota occurring in these microhabitats. In tree hollows of Quercus rotundifolia Lamark that hold water and contain dead leaves, abundant microbial populations can be found. Developing on them are the larvae of Mallota dusmeti Andreu, 1926 (Diptera: Syrphidae), a vulnerable species (IUCN category: Marcos-Garcia and Quinto 2011). This study provides the first data on the microbiota living inside the gut of the larvae of M. dusmeti, as well as the microbiota in the hollow where these larvae develop. Bacteria were identified by amplification and partial sequencing of the V1-V3 regions and the complete nucleotide sequence of 16S rRNA genes. We found eight species of bacteria living in tree hollows and three species in the gut of M. dusmeti larvae: Bacillus cereus, Bacillus toyonensis, and Lysinibacillus sphaericus. The filter-feeding mechanism characteristic of M. dusmeti larvae is selective in enabling ingestion of bacteria only above 2.1 um in diameter. PMID- 28025225 TI - The Effect of Temperature and Host Plant Resistance on Population Growth of the Soybean Aphid Biotype 1 (Hemiptera: Aphididae). AB - A laboratory experiment was conducted to evaluate direct and indirect effects of temperature on demographic traits and population growth of biotype 1 of the soybean aphid, Aphis glycines Matsumura. Our objectives were to better understand how temperature influences the expression of host plant resistance, quantify the individual and interactive effects of plant resistance and temperature on soybean aphid population growth, and generate thermal constants for predicting temperature-dependent development on both susceptible and resistant soybeans. To assess indirect (plant-mediated) effects, soybean aphids were reared under a range of temperatures (15-30 degrees C) on soybean seedlings from a line expressing a Rag1 gene for resistance, and life history traits were quantified and compared to those obtained for soybean aphids on a susceptible soybean line. Direct effects of temperature were obtained by comparing relative differences in the magnitude of life-history traits among temperatures on susceptible soybeans. We predicted that temperature and host plant resistance would have a combined, but asymmetrical, effect on soybean aphid fitness and population growth. Results showed that temperature and plant resistance influenced preimaginal development and survival, progeny produced, and adult longevity. There also appeared to be a complex interaction between temperature and plant resistance for survival and developmental rate. Evidence suggested that the level of plant resistance increased at higher, but not lower, temperature. Soybean aphids required about the same number of degree-days to develop on resistant and susceptible plants. Our results will be useful for making predictions of soybean aphid population growth on resistant plants under different seasonal temperatures. PMID- 28025226 TI - Response of Pemphigus betae (Hemiptera: Aphididae) and Beneficial Epigeal Arthropod Communities to Sugarbeet Plant Density and Seed-Applied Insecticide in Western Nebraska. AB - This study investigated the impact of a neonicotinoid seed-applied insecticide (Poncho Beta) and two plant densities (86,487 and 61,776 plants per hectare) on the sugarbeet root aphid (Pemphigus betae Doane), beneficial epigeal arthropods, and selected crop yield parameters in sugarbeet (Beta vulgaris L. var. vulgaris). Ground beetles and centipedes were the most commonly collected taxa during 2012 and 2013, respectively. Centipede, spider, and rove beetle activity densities were not affected by the seed-applied insecticide, whereas plant density had a marginal effect on centipede activity density during 2012. Ground beetle species richness, diversity, and evenness were also not impacted by the seed treatments. However, during 2013, ground beetle activity density was significantly higher in plots planted with untreated sugarbeet seeds due to the abundance of Bembidion quadrimaculatum oppositum Say. Sugarbeet root aphid populations were significantly higher in the untreated plots during both years. In 2012, sugarbeet tonnage and sugar yield were higher under the low plant density treatment, while higher sugar content was recorded from the seed-applied insecticide plots (2013). Seed-applied neonicotinoids and plant density had little impact on beneficial epigeal arthropod activity density. Seed treatment did result in decreased root aphid populations; however, these reductions were not sufficient to be considered as an adequate control. This limited aphid control likely contributed to inconsistent effects on yield parameters. PMID- 28025227 TI - Rectal cancer restaging using 3D CUBE vs. 2D T2-weighted technique after neoadjuvant therapy: a diagnostic study. AB - OBJECTIVE: This study aimed to compare the accuracy of rectal cancer restaging after neoadjuvant therapy with 3D CUBE sequence with 2D T2-weighted fast spin echo (FSE) sequence. METHODS: This retrospective study comprised 72 patients with rectal cancer confirmed by colonoscopy and biopsy. After neoadjuvant therapy, all patients underwent pelvic magnetic resonance imaging (MRI) examination at 1.5T MRI sequences including a single coronal 3D CUBE T2-weighted FSE sequence with 1.4 mm thickness and a 2D T2-weighted FSE sequence in the sagittal, coronal and axial planes with 5 mm thickness. The total acquisition time of the two sequences was recorded. Results were compared with postsurgical pathology (gold standard). The diagnostic accuracy was evaluated; and receiver operating characteristic (ROC) curves and the area under the curves (AUC) were calculated. RESULTS: The T category staging accuracy of 3D T2WI and 2D T2WI was 81.9% and 72.2%, respectively, for reviewer 1 and 86.1% and 75.0% for reviewer 2. The AUC of 3D was higher than that of 2D (0.878 vs. 0.783 for reader 1 and 0.905 vs. 0.796 for reader 2; both P < 0.05) when judging whether the tumor broke through the muscle layer. There was no significant difference between 3D and 2D in judging whether lymph nodes were malignant (AUC 0.719 vs. 0.698 for reader 1 and 0.740 vs. 0.698 for reader 2; both P > 0.05). There were no significant differences in the visibility of the rectal wall layer, tumor lesion and the overall image quality (all P > 0.05). Compared with 2D sequences, the 3D sequence had shorter acquisition time and higher signal intensity ratio (both P < 0.05). CONCLUSION: 3D CUBE T2-weighted sequences offer better diagnostic accuracy in rectal cancer restaging after neoadjuvant therapy when compared with 2D T2-weighted FSE sequences; it has a shorter scanning time and more versatility of orientation reconstruction. PMID- 28025228 TI - Sex Reassignment Surgery and Enhancement. AB - Sex reassignment surgery is a therapy for gender dysphoria (gender identity disorder) standardly provided only upon a psychiatric authorization. Transgender scholars criticize this practice as unjustified medicalization and stigmatization of transsexual people. By demanding that sex reassignment surgery is not classified as therapy, they imply it should be classified as some kind of a biomedical enhancement. It is argued in this article that this reclassification is empirically and morally implausible because sex reassignment surgery is incompatible with two major views of enhancement. It is incompatible with the nontherapeutic view because it does not improve or augment, above average, any physical or mental trait or function. It is incompatible with the welfarist view because this view, contrary to the transgender scholars's demands, is compelled to retain the standard practice of providing sex reassignment surgery in order to ensure the optimal balance between its availability, beneficence, and possible harmfulness. PMID- 28025229 TI - Malpractice, Criminality, and Medical Regulation: Reforming the Role of the GMC in Fitness to Practise Panels. AB - A recent Law Commission Review emphasised that medical fitness to practise panels (also called medical practitioners tribunals) are an important legal mechanism for ensuring that public trust in medical regulation is maintained when a complaint is made against a doctor. This article examines trends over time in panel outcomes to identify their effectiveness in ensuring public protection. Although a rise in complaints, and a change from the criminal to civil standard of proof, has not led to more doctors being struck off the medical register, increasingly action is being taken to provide advice, issue warnings, and agree rehabilitative forms of action with doctors. It is argued that these trends are congruent with the broader adoption of a risk-based approach to professional regulation. Legal reforms to maintain public trust must ensure that the shift towards risk-averse forms of professional accountability do not sacrifice public safety and due process for the sake of political pragmatic exigency. PMID- 28025230 TI - Mechanisms for Hepatobiliary Toxicity in Rats Treated with an Antagonist of Melanin Concentrating Hormone Receptor 1 (MCHR1). AB - The objective of this work was to investigate the mechanisms of hepatobiliary toxicity caused by thienopyrimidone MCHR1 antagonists using BMS-773174 as a tool molecule. Co-administration of the pan CYP inhibitor 1-aminobenzotriazole with BMS-773174 prevented hepatobiliary damage, and direct delivery of the diol metabolite BMS-769750 caused hepatobiliary toxicity, identifying the diol and possibly its downstream hydroxyacid (BMS-800754) metabolite as the toxic species. Rat liver gene expression revealed treatment-related changes in hepatic transporters and induction of oval cell-specific genes including deleted malignant tumor 1 (Dmbt1). The metabolites did not alter hepatic transporter activities, suggesting that transporter-mediated cholestasis was not involved. Because injury to biliary epithelium can result in adaptive hyperplasia, rat biliary epithelial cells (BECs) were isolated and exposed to the oxidative metabolites. BMS-769750 was cytotoxic to BECs, but not rat hepatocytes, suggesting a role of the diol in biliary epithelial injury. BMS-800754 was cytotoxic to rat hepatocytes therefore its contribution to hepatocyte injury in rats is a possibility. Induction of Dmbt1 in rat BECs was investigated because of its role in hepatic progenitor cell differentiation/proliferation during injury. Dmbt1 mRNA was induced by BMS-769750, but not BMS-800754 in BECs; this induction and cellular injury was confirmed with diol metabolites formed by other compounds with the same hepatobiliary liability. In conclusion, hepatobiliary injury by thienopyrimidinone MCHR1 antagonists was driven through a CYP-mediated bioactivation pathway. Induction of Dmbt1 mRNA coupled with cellular injury suggests that injury of biliary epithelium may be the first step toward an adaptive proliferative response causing BDH by these compounds. PMID- 28025231 TI - Cardiac resynchronization therapy by multipoint pacing improves response of left ventricular mechanics and fluid dynamics: a three-dimensional and particle image velocimetry echo study. AB - Aims: To characterize the effect of multipoint pacing (MPP) compared to biventricular pacing (BiV) on left ventricle (LV) mechanics and intraventricular fluid dynamics by three-dimensional echocardiography (3DE) and echocardiographic particle imaging velocimetry (Echo-PIV). Methods and results: In 11 consecutive patients [8 men; median age 65 years (57-75)] receiving cardiac resynchronization therapy (CRT) with a quadripolar LV lead (Quartet,St.Jude Medical,Inc.), 3DE and Echo-PIV data were collected for each pacing configuration (CRT-OFF, BiV, and MPP) at follow-up after 6 months. 3DE data included LV volumes, LV ejection fraction (LVEF), strain, and systolic dyssynchrony index (SDI). Echo-PIV was used to evaluate the directional distribution of global blood flow momentum, ranging from zero, when flow force is predominantly along the base-apex direction, up to 90 degrees when it becomes transversal. MPP resulted in significant reduction in end-diastolic and end-systolic volumes compared with both CRT-OFF (P = 0.02; P = 0.008, respectively) and BiV (P = 0.04; P = 0.03, respectively). LVEF and cardiac output were significant superior in MPP compared with CRT-OFF, but similar between MPP and BiV. Statistical significant differences when comparing global longitudinal and circumferential strain and SDI with MPP vs. CRT-OFF were observed (P = 0.008; P = 0.008; P = 0.01, respectively). There was also a trend towards improvement in strain between BiV and MPP that did not reach statistical significance. MPP reflected into a significant reduction of the deviation of global blood flow momentum compared with both CRT-OFF and BiV (P = 0.002) indicating a systematic increase of longitudinal alignment from the base-apex orientation of the haemodynamic forces. Conclusion: These preliminary results suggest that MPP resulted in significant improvement of LV mechanics and fluid dynamics compared with BiV. However, larger studies are needed to confirm this hypothesis. PMID- 28025232 TI - Three-dimensional printing in vitro simulation of percutaneous pulmonary valve implantation in large right ventricular outflow tract. PMID- 28025233 TI - Nonrandomized Trial of Feasibility and Acceptability of Strategies for Promotion of Soapy Water as a Handwashing Agent in Rural Bangladesh. AB - We conducted a nonrandomized trial of strategies to promote soapy water for handwashing in rural Bangladesh and measured uptake. We enrolled households with children < 3 years for three progressively intensive study arms: promotion of soapy water (N = 120), soapy water promotion plus handwashing stations (N = 103), and soapy water promotion, stations plus detergent refills (N = 90); we also enrolled control households (N = 72). Our handwashing stations included tap fitted buckets and soapy water bottles. Community promoters visited households and held community meetings to demonstrate soapy water preparation and promote handwashing at key times. Field workers measured uptake 4 months later. In-depth interviews and focus group discussions assessed factors associated with uptake. More households had soapy water at the handwashing place in progressively intensive arms: 18% (promotion), 60% (promotion plus station), and 71% (promotion, station with refills). Compared with the promotion-only arm, more households that received stations had soapy water at the primary handwashing station (44%, P <= 0.001; 71%, P < 0.001 with station plus detergent refill). Qualitative findings highlighted several dimensions that affected use: contextual (shared courtyard), psychosocial (perceived value), and technology dimensions (ease of use, convenience). Soapy water may increase habitual handwashing by addressing barriers of cost and availability of handwashing agents near water sources. Further research should inform optimal strategies to scale-up soapy water as a handwashing agent to study health impact. PMID- 28025234 TI - Disparities in Aesthetic Procedures Performed by Plastic Surgery Residents. AB - Background: Operative experience in aesthetic surgery is an important issue affecting plastic surgery residents. Objectives: This study addresses the variability of aesthetic surgery experience during plastic surgery residency. Methods: National operative case logs of chief residents in independent/combined and integrated plastic surgery residency programs were analyzed (2011-2015). Fold differences between the bottom and top 10th percentiles of residents were calculated for each aesthetic procedure category and training model. The number of residents not achieving case minimums was also calculated. Results: Case logs of 818 plastic surgery residents were analyzed. There was marked variability in craniofacial (range, 6.0-15.0), breast (range, 2.4-5.9), trunk/extremity (range, 3.0-16.0), and miscellaneous (range, 2.7-22.0) procedure categories. In 2015, the bottom 10th percentile of integrated and independent/combined residents did not achieve case minimums for botulinum toxin and dermal fillers. Case minimums were achieved for the other aesthetic procedure categories for all graduating years. Conclusions: Significant variability persists for many aesthetic procedure categories during plastic surgery residency training. Greater efforts may be needed to improve the aesthetic surgery experience of plastic surgery residents. PMID- 28025235 TI - Commentary on: Disparities in Aesthetic Procedures Performed by Plastic Surgery Residents. PMID- 28025236 TI - OTX2 Defines a Subgroup of Atypical Teratoid Rhabdoid Tumors With Close Relationship to Choroid Plexus Tumors. AB - Atypical teratoid rhabdoid tumors (ATRT) are highly malignant brain tumors of early childhood that have been regarded as a homogenous entity characterized by inactivation of the SMARCB1/INI1 or SMARCA4/BRG1 genes as the only characteristic alteration. Recent studies suggest that similar to other embryonal tumors ATRT can also be divided into subgroups based on their mRNA or methylation profiles. Using microarray-based expression analysis of 12 patient ATRT specimens we demonstrated the existence of 2 subgroups of ATRT. One subgroup is characterized by high expression of OTX2, encoding a transcription factor involved in brain development. OTX2 expression was verified by immunohistochemistry and might function as a novel therapeutic target for this fatal tumor. High expression of OTX2 as well as expression of Kir7.1/KCNJ13, TRPM3 and ENPP2, which have all previously been linked to either choroid plexus epithelium or choroid plexus tumors (CPTs), suggests a close histogenetic relation of this subgroup to CPTs. PMID- 28025237 TI - Responsible Innovation in Children's Surgical Care. AB - Advances in medical care may occur when a change in practice incorporates a new treatment or methodology. In surgery, this may involve the translation of a completely novel concept into a new procedure or device or the adaptation of existing treatment approaches or technology to a new clinical application. Regardless of the specifics, innovation should have, as its primary goal, the enhancement of care leading to improved outcomes from the patient's perspective. This policy statement examines innovation as it pertains to surgical care, focusing on some of the definitions that help differentiate applied innovation or innovative therapy from research. The ethical challenges and the potential for conflict of interest for surgeons or institutions seeking to offer innovative surgical therapy are examined. The importance of engaging patients and families as "innovation partners" to ensure complete transparency of expectations from the patient's and provider's perspectives is also examined, with specific emphasis on cultural competence and mutually respectful approaches. A framework for identifying, evaluating, and safely implementing innovative surgical therapy in children is provided. PMID- 28025238 TI - Racial Disparities in Medicaid Asthma Hospitalizations. AB - BACKGROUND AND OBJECTIVES: Black children with asthma comprise one-third of all asthma patients in Medicaid. With increasing Medicaid coverage, it has become especially important to monitor Medicaid for differences in hospital practice and patient outcomes by race. METHODS: A multivariate matched cohort design, studying 11 079 matched pairs of children in Medicaid (black versus white matched pairs from inside the same state) admitted for asthma between January 1, 2009 and November 30, 2010 in 33 states contributing adequate Medicaid Analytic eXtract claims. RESULTS: Ten-day revisit rates were 3.8% in black patients versus 4.2% in white patients (P = .12); 30-day revisit and readmission rates were also not significantly different by race (10.5% in black patients versus 10.8% in white patients; P = .49). Length of stay (LOS) was also similar; both groups had a median stay of 2.0 days, with a slightly lower percentage of black patients exceeding their own state's median LOS (30.2% in black patients versus 31.8% in white patients; P = .01). The mean paired difference in LOS was 0.00 days (95% confidence interval, -0.08 to 0.08). However, ICU use was higher in black patients than white patients (22.2% versus 17.5%; P < .001). After adjusting for multiple testing, only 4 states were found to differ significantly, but only in ICU use, where blacks had higher rates of use. CONCLUSIONS: For closely matched black and white patients, racial disparities concerning asthma admission outcomes and style of practice are small and generally nonsignificant, except for ICU use, where we observed higher rates in black patients. PMID- 28025239 TI - Off-Label Use of Medical Devices in Children. AB - Despite widespread therapeutic needs, the majority of medical and surgical devices used in children do not have approval or clearance from the Food and Drug Administration (FDA) for use in pediatric populations. The clinical need for devices to diagnose and treat diseases or conditions occurring in children has led to the widespread and necessary practice in pediatric medicine and surgery of using approved devices for "off-label" or "physician-directed" applications that are not included in FDA-approved labeling. This practice is common and often appropriate, even with the highest-risk (class III) devices. The legal and regulatory framework used by the FDA for devices is complex, and economic or market barriers to medical and surgical device development for children are significant. Given the need for pediatric medical and surgical devices and the challenges to pediatric device development, off-label use is a necessary and appropriate part of care. In addition, because of the relatively uncommon nature of pediatric conditions, FDA clearance or approval often requires other regulatory pathways (eg, Humanitarian Device Exemption), which can cause confusion among pediatricians and payers about whether a specific use, even of an approved device, is considered experimental. This policy statement describes the appropriateness of off-label use of devices in children; the use of devices approved or cleared through the FDA regulatory processes, including through the Humanitarian Device Exemption; and the important need to increase pediatric device labeling information for all devices and especially those that pose the highest risk to children. PMID- 28025240 TI - Safety of Quadrivalent Meningococcal Conjugate Vaccine in 11- to 21-Year-Olds. AB - BACKGROUND: Meningococcal conjugate vaccination is recommended in the United States. This study evaluates the safety of quadrivalent meningococcal conjugate vaccine in a cohort aged 11 to 21 years. METHODS: This cohort study with self controlled case-series analysis was conducted at Kaiser Permanente Southern California. Individuals receiving MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, during September 30, 2011 to June 30, 2013, were included. Twenty-six prespecified events of interest (EOIs), including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric, and pediatric infectious disease EOIs, were identified through electronic health records 1 year after vaccination. Of these, 16 were reviewed by case review committees. Specific risk and comparison windows after vaccination were predefined for each EOI. The relative incidence (RI) and 95% confidence intervals (CIs) were estimated through conditional Poisson regression models, adjusted for seasonality. RESULTS: This study included 48 899 vaccinated individuals. No cases were observed in the risk window for 14 of 26 EOIs. The RI for Bell's palsy, a case review committee reviewed EOI, was statistically significant (adjusted RI: 2.9, 95% CI: 1.1-7.5). Stratified analyses demonstrated an increased risk for Bell's palsy in subjects receiving concomitant vaccines (RI = 5.0, 95% CI = 1.4-17.8), and no increased risk for those without concomitant vaccine (RI = 1.1, 95% CI = 0.2-5.5). CONCLUSIONS: We observed a temporal association between occurrence of Bell's palsy and receipt of MenACWY-CRM concomitantly with other vaccines. The association needs further investigation as it could be due to chance, concomitant vaccination, or underlying medical history predisposing to Bell's palsy. PMID- 28025241 TI - Clinical Tools to Assess Asthma Control in Children. AB - Asthma affects an estimated 7 million children and causes significant health care and disease burden. The most recent iteration of the National Heart, Lung and Blood Institute asthma guidelines, the Expert Panel Report 3, emphasizes the assessment and monitoring of asthma control in the management of asthma. Asthma control refers to the degree to which the manifestations of asthma are minimized by therapeutic interventions and the goals of therapy are met. Although assessment of asthma severity is used to guide initiation of therapy, monitoring of asthma control helps determine whether therapy should be maintained or adjusted. The nuances of estimation of asthma control include understanding concepts of current impairment and future risk and incorporating their measurement into clinical practice. Impairment is assessed on the basis of frequency and intensity of symptoms, variations in lung function, and limitations of daily activities. "Risk" refers to the likelihood of exacerbations, progressive loss of lung function, or adverse effects from medications. Currently available ambulatory tools to measure asthma control range are subjective measures, such as patient-reported composite asthma control score instruments or objective measures of lung function, airway hyperreactivity, and biomarkers. Because asthma control exhibits short- and long-term variability, health care providers need to be vigilant regarding the fluctuations in the factors that can create discordance between subjective and objective assessment of asthma control. Familiarity with the properties, application, and relative value of these measures will enable health care providers to choose the optimal set of measures that will adhere to national standards of care and ensure delivery of high quality care customized to their patients. PMID- 28025242 TI - A New Era in Quality Measurement: The Development and Application of Quality Measures. AB - Quality measures are used for a variety of purposes in health care, including clinical care improvement, regulation, accreditation, public reporting, surveillance, and maintenance of certification. Most quality measures are 1 of 3 types: structure, process, or outcome. Health care quality measures should address the domains of quality across the continuum of care and reflect patient and family experience. Measure development for pediatric health care has a number of important challenges, including gaps in the evidence base; the fact that measures for most conditions must be age-specific; the long, resource-intensive development process; and the national focus on measure development for adult conditions. Numerous national organizations focus on the development and application of quality measures, including the Pediatric Quality Measures Program, which is focused solely on the development and implementation of pediatric-specific measures. Once a quality measure is developed for use in national measurement programs, the organization that develops and/or "stewards" the measure may submit the measure or set of measures for endorsement, which is recognition of the scientific soundness, usability, and relevance of the measure. Quality measures must then be disseminated and applied to improve care. Although pediatric health care providers and child health care institutions alike must continually balance time and resources needed to address multiple reporting requirements, quality measurement is an important tool for advancing high-quality and safe health care for children. This policy statement provides an overview of quality measurement and describes the opportunities for pediatric health care providers to apply quality measures to improve clinical quality and performance in the delivery of pediatric health care services. PMID- 28025243 TI - Instrument-Based Vision Screening in Children. PMID- 28025244 TI - Shining the Light on Parity and Disparity in Childhood Asthma Care. PMID- 28025245 TI - Predicting the Distribution of Phlebotomus papatasi (Diptera: Psychodidae), the Primary Vector of Zoonotic Cutaneous Leishmaniasis, in Golestan Province of Iran Using Ecological Niche Modeling: Comparison of MaxEnt and GARP Models. AB - Zoonotic cutaneous leishmaniasis (ZCL) is a prevalent vector-borne disease in the Golestan province of Iran, with Phlebotomus papatasi (Scopoli, 1786) serving as the main vector. The aim of this study was to model the probability of presence of this species in the study area, and to determine the underlying factors affecting its distribution. Three villages were selected from each county of the province and visited monthly for investigating ZCL. Sticky paper traps were used for collecting the sand flies to determine the species present. The presence of Ph. papatasi was modeled using genetic algorithm for rule-set production (GARP) and maximum entropy (MaxEnt) techniques. Both models showed the central and northern parts of the province with lowland areas were more vulnerable to Ph. papatasi propagation, in comparison with the southern parts with mountainous and forest areas. The area under curve (AUC) of MaxEnt model for the training points was calculated as 0.90, indicating excellent performance of the model in predicting Ph. papatasi distribution. Jackknife test showed that the factors with the greatest influence in vector distribution were slope, vegetation cover, annual mean temperature, and altitude. By using ecological niche models, it is possible to identify areas with higher probability of presence of Ph. papatasi, which guides public health policy makers for planning better vector control interventions. PMID- 28025246 TI - Mosquito Species (Diptera: Culicidae) Persistence and Synchrony Across an Urban Altitudinal Gradient. AB - Patterns of mosquito spatial persistence and temporal presence, as well as synchrony, i.e., the degree of concerted fluctuations in abundance, have been scarcely studied at finely grained spatial scales and over altitudinal gradients. Here, we present a spatial persistence, temporal presence, and synchrony analysis of four common mosquito species across the altitudinal gradient of Mt. Konpira in Nagasaki, Japan. We found that Aedes albopictus (Skuse) was more frequently found at the mountain base. In contrast, Aedes japonicus (Theobald) and Aedes flavopictus Yamada were common higher in the mountain, while Armigeres subalbatus (Coquillet) was uniformly present across the mountain, yet less frequently than the other species during the studied period. Our analysis showed that these spatial heterogeneities were associated with differences in landscape and microclimatic elements of Mt. Konpira. Temporally we found that presence across sampling locations was mainly synchronous across the four species and positively associated with rainfall and temperature. With the exception of Ae albopictus, where no significant synchrony was observed, mosquito species mainly showed flat synchrony profiles in Mt. Konpira when looking at the geographic (2-D) distance between their sampling locations. By contrast, when synchrony was studied across altitude, it was observed that Ae. flavopictus tracked the temperature synchrony pattern, decreasing its synchrony with the separation in altitude between sampling locations. Finally, our results suggest that differences in mosquito species persistence, temporal presence, and synchrony might be useful to understand the entomological risk of vector-borne disease transmission in urban landscapes. PMID- 28025247 TI - Prevalence of Escherichia coli O157:H7 From House Flies (Diptera: Muscidae) and Dairy Samples in North Central Florida1. AB - La deteccion de Escherichia coli O157:H7 en las lecherias es importante para mejorar la seguridad de los productos lacteos, y se ha llevado a cabo principalmente mediante el aislamiento de las bacterias a partir de las muestras de estiercol. Sin embargo, los componentes biliares presentes en el estiercol complica la identificacion genetica utilizando la tecnica del PCR, y el aislamiento microbiologico se dificulta por la presencia de bacterias competidoras que comparten caracteristicas microbiologicas similares. El aislamiento de E. coli O157:H7 a partir de la mosca domestica evita las dificultades asociadas con el estiercol del ganado. El aislamiento de patogenos a partir de las moscas domesticas proporciona informacion adicional sobre el potencial impacto epidemiologico de la dispersion de la mosca domestica en la distribucion de patogenos, ya que las moscas domesticas se dispersan desde las lecherias donde la E. coli O157:H7 existe en forma endemica en el ganado. En este estudio, se encontro que las moscas domesticas son 2,6 veces mas sensibles para la deteccion de E. coli O157:H7 en las lecherias. Las moscas son mas faciles de capturar y manejar que el estiercol, y deberian ser utilizadas en cualquier ensayo para detectar E. coli O157:H7 en las lecherias y otros establecimientos. PMID- 28025248 TI - Larval Habitat Substrates Could Affect the Biology and Vectorial Capacity of Culex quinquefasciatus (Diptera: Culicidae). AB - Culex quinquefasciatus Say is an important disease vector throughout much of the world. Experiments were conducted to determine the effects of different larval habitat substrates on the fitness and biting efficiency of Cx. quinquefasciatus adults. Our findings indicate that the development time (egg to adult) of larvae reared in irrigation water was 8.63 d while that of larvae reared in distilled water was 17.10 d (Effect size = 0.95). However, the rate of adult emergence was similar for all the tested treatments. Furthermore, the mean weight of an egg raft varied between larval habitats: distilled water (1.83 mg), rainfall water (1.25 mg), irrigation water (1.52 mg), and sewerage water (2.52 mg) (Effect size = 0.91). But, the fecundity (eggs per female) and hatchability (%) were statistically similar in all the rearing mediums (Effect size = 0.79). Longevity of females in all the tested populations did not differ significantly (Effect size = 0.91). The mean relative growth rates of larvae reared in tap water (0.80) and distilled water (0.86) habitats were lower than growth rates in all other rearing habitats (Effect size = 0.96). The intrinsic rate of natural increase in tap water (0.27) and irrigation water (0.35) was significantly higher than that in distilled water (0.09) and sewerage water (0.16) (Effect size = 0.84). Adults reared in rain water had the highest biting efficiency among all the tested populations. These results provide useful information for the management of Cx. quinquefasciatus. PMID- 28025249 TI - Glucosylglycerate metabolism, bioversatility and mycobacterial survival. AB - Despite the progressive decline in tuberculosis mortality, strains resistant to our dated antibiotics remain a global threat, as are the emerging nontuberculous mycobacteria, ubiquitous in natural and human environments. This pressing situation boosted by debilitated immune systems, chronic illness and the aged population calls for efficient strategies to fight these successful organisms, and identifying pathways critical for their survival is a crucial step towards this goal. In this context, the glycoside glucosylglycerate (GG) has been implicated in the adaptation of mycobacteria to nitrogen starvation and to thermal stress, and the key gene for GG synthesis has been considered essential for Mycobacterium tuberculosis growth. The many organisms we now know to have genes for GG metabolism opened new exciting avenues of research into its functions, hinting for example at hypothetical roles as an inter-cellular messenger among bacteria and in microbe-plant interactions, or at key roles in the global nitrogen cycle beyond what cyanobacteria and mycobacteria have taught us so far. Indeed, the insights into GG biology gained over the last decade have changed the perception of GG from a rare polysaccharide constituent to a widespread molecule with multiple functions and biosynthetic origins. It is now possible to build upon this knowledge and further explore its physiological importance in both pathogenic and environmentally relevant microorganisms. In particular, the vital roles of GG and of its important derivative the mycobacterial methylglucose lipopolysaccharide (MGLP) discussed here are now evident, making their metabolic links attractive targets for the development of new urgently needed antimycobacterial therapies. PMID- 28025250 TI - Glycosylation of MUC1 influences the binding of a therapeutic antibody by altering the conformational equilibrium of the antigen. AB - In cancer cells, the glycoprotein Mucin 1 (MUC1) undergoes abnormal, truncated glycosylation. The truncated glycosylation exposes cryptic peptide epitopes that can be recognized by antibodies. Since these immunogenic regions are cancer specific, they represent ideal targets for therapeutic antibodies. We investigated the role of tumor-specific glycosylation on antigen recognition by the therapeutic antibody AR20.5. We explored the affinity of AR20.5 to a synthetic cancer-specific MUC1 glycopeptide and peptide. The antibody bound to the glycopeptide with an order of magnitude stronger affinity than the naked peptide. Given these results, we postulated that AR20.5 must specifically bind the carbohydrate as well as the peptide. Using X-ray crystallography, we examined this hypothesis by determining the structure of AR20.5 in complex with both peptide and glycopeptide. Surprisingly, the structure revealed that the carbohydrate did not form any specific polar contacts with the antibody. The high affinity of AR20.5 for the glycopeptide and the lack of specific binding contacts support a hypothesis that glycosylation of MUC1 stabilizes an extended bioactive conformation of the peptide recognized by the antibody. Since high affinity binding of AR20.5 to the MUC1 glycopeptide may not driven by specific antibody antigen contacts, but rather evidence suggests that glycosylation alters the conformational equilibrium of the antigen, which allows the antibody to select the correct conformation. This study suggests a novel mechanism of antibody antigen interaction and also suggests that glycosylation of MUC1 is important for the generation of high affinity therapeutic antibodies. PMID- 28025251 TI - Non-reducing end labeling of heparan sulfate via click chemistry and a high throughput ELISA assay for heparanase. AB - Heparan sulfate (HS) is a linear polysaccharide found in the extracellular matrix (ECM) and on the cell membrane. It plays numerous roles in cellular events, including cell growth, migration and differentiation through binding to various growth factors, cytokines and other ECM proteins. Heparanase (HPSE) is an endoglycosidase that cleaves HS in the ECM and cell membrane. By degrading HS, HPSE not only alters the integrity of the ECM but also releases growth factors and angiogenic factors bound to HS chains, therefore, changes various cellular activities, including cell mobility that is critical for cancer metastasis. Accordingly, HPSE is an ideal drug target for cancer therapeutics. Here, we describe a method for non-reducing end labeling of HS via click chemistry (CC), and further use it in a novel HPSE assay. HS chains on a recombinant human syndecan-4 are first labeled at their non-reducing ends with GlcNAz using dimeric HS polymerase EXT1/EXT2. The labeled sample is then biotinylated through CC, immobilized on a multi-well plate and detected with ELISA. HPSE digestion of the biotinylated sample removes the label and, therefore, reduces the signal in ELISA assay. Non-reducing end labeling avoids the interference in an HPSE reaction caused by any internal labeling of HS. The assay is very sensitive with only 2.5 ng of labeled syndecan-4 needed in each reaction. The assay is also highly reproducible with a Z' > 0.6. Overall, this new method is suitable for high throughput drug screening on HPSE. PMID- 28025252 TI - Various sulfated carbohydrate tumor marker candidates identified by focused glycomic analyses. AB - Glycomic analysis focused on sulfated O-glycans was performed to identify novel serum carbohydrate tumor markers. Sulfated glycans were enriched by alpha neuraminidase digestion of pyridylaminated glycans prepared from sera, followed by anion exchange chromatography. Sulfated O-glycan profiles were constructed by two types of high performance liquid chromatography separation. Comparison of the profiles from 20 healthy controls with those of 11 gastric and 9 pancreatic cancer patients identified 14 marker candidates. The structures of these candidates were precisely analyzed using various methods including enzymatic digestion and mass spectrometry. The candidates comprised 9 core1 and 5 core2 glycans. All these candidates were monosulfated, and 11 were also mono- or difucosylated, and included various determinants such as 6-sulfo type2 lactosamine, 6-sulfo Lewis X, 6-sulfo Lewis Y, 3'-sulfo type1 lactosamine and 3' sulfo Lewis A. Furthermore, among the core1 glycans, five candidates displayed a type1 and type2 lactosamine hybrid backbone. The levels of these candidate glycans in the sera from all 40 subjects were quantified using a selected reaction monitoring assay. These analyses revealed: (i) the levels of all candidates were elevated in sera of at least one or more patients; (ii) core1 candidates having type1-type2 hybrid backbones with 6-sulfo Lewis X, 6-sulfo type2 lactosamine or 3'-sulfo Lewis A were elevated in sera of variety of patients; and (iii) levels of the candidates varied widely among patients, suggesting analysis of multiple candidates will be an effective means of screening various cancers. To fully evaluate the clinical utility of these candidates, a further verification study is required. PMID- 28025254 TI - Shaping the Output of Lumbar Flexor Motoneurons by Sacral Neuronal Networks. AB - : The ability to improve motor function in spinal cord injury patients by reactivating spinal central pattern generators (CPGs) requires the elucidation of neurons and pathways involved in activation and modulation of spinal networks in accessible experimental models. Previously we reported on adrenoceptor-dependent sacral control of lumbar flexor motoneuron firing in newborn rats. The current work focuses on clarification of the circuitry and connectivity involved in this unique modulation and its potential use. Using surgical manipulations of the spinal gray and white matter, electrophysiological recordings, and confocal microscopy mapping, we found that methoxamine (METH) activation of sacral networks within the ventral aspect of S2 segments was sufficient to produce alternating rhythmic bursting (0.15-1 Hz) in lumbar flexor motoneurons. This lumbar rhythm depended on continuity of the ventral funiculus (VF) along the S2 L2 segments. Interrupting the VF abolished the rhythm and replaced it by slow unstable bursting. Calcium imaging of S1-S2 neurons, back-labeled via the VF, revealed that ~40% responded to METH, mostly by rhythmic firing. All uncrossed projecting METH responders and ~70% of crossed projecting METH responders fired with the concurrent ipsilateral motor output, while the rest (~30%) fired with the contralateral motor output. We suggest that METH-activated sacral CPGs excite ventral clusters of sacral VF neurons to deliver the ascending drive required for direct rhythmic activation of lumbar flexor motoneurons. The capacity of noradrenergic-activated sacral CPGs to modulate the activity of lumbar networks via sacral VF neurons provides a novel way to recruit rostral lumbar motoneurons and modulate the output required to execute various motor behaviors. SIGNIFICANCE STATEMENT: Spinal central pattern generators (CPGs) produce the rhythmic output required for coordinating stepping and stabilizing the body axis during movements. Electrical stimulation and exogenous drugs can reactivate the spinal CPGs and improve the motor function in the absence of descending supraspinal control. Since the body-stabilizing sacral networks can activate and modulate the limb-moving lumbar circuitry, it is important to clarify the functional organization of sacral and lumbar networks and their linking pathways. Here we decipher the ascending circuitry linking adrenoceptor-activated sacral CPGs and lumbar flexor motoneurons, thereby providing novel insights into mechanisms by which sacral circuitry recruits lumbar flexors, and enhances the motor output during lumbar afferent-induced locomotor rhythms. Moreover, our findings might help to improve drug/electrical stimulation-based therapy to accelerate locomotor based rehabilitation. PMID- 28025253 TI - Visual Population Receptive Fields in People with Schizophrenia Have Reduced Inhibitory Surrounds. AB - People with schizophrenia (SZ) experience abnormal visual perception on a range of visual tasks, which have been linked to abnormal synaptic transmission and an imbalance between cortical excitation and inhibition. However, differences in the underlying architecture of visual cortex neurons, which might explain these visual anomalies, have yet to be reported in vivo Here, we probed the neural basis of these deficits using fMRI and population receptive field (pRF) mapping to infer properties of visually responsive neurons in people with SZ. We employed a difference-of-Gaussian model to capture the center-surround configuration of the pRF, providing critical information about the spatial scale of the pRFs inhibitory surround. Our analysis reveals that SZ is associated with reduced pRF size in early retinotopic visual cortex, as well as a reduction in size and depth of the inhibitory surround in V1, V2, and V4. We consider how reduced inhibition might explain the diverse range of visual deficits reported in SZ.SIGNIFICANCE STATEMENT People with schizophrenia (SZ) experience abnormal perception on a range of visual tasks, which has been linked to abnormal synaptic transmission and an imbalance between cortical excitation/inhibition. However, associated differences in the functional architecture of visual cortex neurons have yet to be reported in vivo We used fMRI and population receptive field (pRF) mapping to demonstrate that the fine-grained functional architecture of visual cortex in people with SZ differs from unaffected controls. SZ is associated with reduced pRF size in early retinotopic visual cortex largely due to reduced inhibitory surrounds. An imbalance between cortical excitation and inhibition could drive such a change in the center-surround pRF configuration and ultimately explain the range of visual deficits experienced in SZ. PMID- 28025256 TI - Commentary: Mendelian randomization-inspired causal inference in the absence of genetic data. AB - Studying the long-term causal effects of alcohol drinking is notoriously difficult. Epidemiological studies that use conventional analytical approaches are likely to be confounded and affected by reporting/recall bias and reverse causality, specifically in the form of the sick quitter effect (individuals quitting or never starting to consume alcohol due to underlying ill health).1 Decades of observational data showing J-shaped relationships of alcohol with risk of disease and in particular cardiovascular disease,2 fuelled by confirmation bias, have resulted in alcohol policies such that individuals are recommended to drink in moderation, due to putative cardioprotective effects. Critically, randomized controlled trials (RCTs) to investigate the long-term effects of alcohol drinking are not feasible for reasons including lack of suitable and ethical interventions and extended duration (and hence cost and likely high loss to follow-up). PMID- 28025255 TI - Representations of Pitch and Timbre Variation in Human Auditory Cortex. AB - : Pitch and timbre are two primary dimensions of auditory perception, but how they are represented in the human brain remains a matter of contention. Some animal studies of auditory cortical processing have suggested modular processing, with different brain regions preferentially coding for pitch or timbre, whereas other studies have suggested a distributed code for different attributes across the same population of neurons. This study tested whether variations in pitch and timbre elicit activity in distinct regions of the human temporal lobes. Listeners were presented with sequences of sounds that varied in either fundamental frequency (eliciting changes in pitch) or spectral centroid (eliciting changes in brightness, an important attribute of timbre), with the degree of pitch or timbre variation in each sequence parametrically manipulated. The BOLD responses from auditory cortex increased with increasing sequence variance along each perceptual dimension. The spatial extent, region, and laterality of the cortical regions most responsive to variations in pitch or timbre at the univariate level of analysis were largely overlapping. However, patterns of activation in response to pitch or timbre variations were discriminable in most subjects at an individual level using multivoxel pattern analysis, suggesting a distributed coding of the two dimensions bilaterally in human auditory cortex. SIGNIFICANCE STATEMENT: Pitch and timbre are two crucial aspects of auditory perception. Pitch governs our perception of musical melodies and harmonies, and conveys both prosodic and (in tone languages) lexical information in speech. Brightness-an aspect of timbre or sound quality-allows us to distinguish different musical instruments and speech sounds. Frequency-mapping studies have revealed tonotopic organization in primary auditory cortex, but the use of pure tones or noise bands has precluded the possibility of dissociating pitch from brightness. Our results suggest a distributed code, with no clear anatomical distinctions between auditory cortical regions responsive to changes in either pitch or timbre, but also reveal a population code that can differentiate between changes in either dimension within the same cortical regions. PMID- 28025257 TI - An introduction to multiplicity issues in clinical trials: the what, why, when and how. AB - In clinical trials it is not uncommon to face a multiple testing problem which can have an impact on both type I and type II error rates, leading to inappropriate interpretation of trial results. Multiplicity issues may need to be considered at the design, analysis and interpretation stages of a trial. The proportion of trial reports not adequately correcting for multiple testing remains substantial. The purpose of this article is to provide an introduction to multiple testing issues in clinical trials, and to reduce confusion around the need for multiplicity adjustments. We use a tutorial, question-and-answer approach to address the key issues of why, when and how to consider multiplicity adjustments in trials. We summarize the relevant circumstances under which multiplicity adjustments ought to be considered, as well as options for carrying out multiplicity adjustments in terms of trial design factors including Population, Intervention/Comparison, Outcome, Time frame and Analysis (PICOTA). Results are presented in an easy-to-use table and flow diagrams. Confusion about multiplicity issues can be reduced or avoided by considering the potential impact of multiplicity on type I and II errors and, if necessary pre-specifying statistical approaches to either avoid or adjust for multiplicity in the trial protocol or analysis plan. PMID- 28025258 TI - The causes of human variability. PMID- 28025259 TI - Defining the relationship between atherosclerotic plaque, ischaemia, and risk-the story unfolds. PMID- 28025261 TI - The whole is more than the sum of its parts-Aristotle. PMID- 28025260 TI - Coronary sinus endocarditis due to tricuspid regurgitation jet lesion. PMID- 28025262 TI - 3D printing of normal and pathologic tricuspid valves from transthoracic 3D echocardiography data sets. AB - Aims: To explore the feasibility of using transthoracic 3D echocardiography (3DTTE) data to generate 3D patient-specific models of tricuspid valve (TV). Methods and Results: Multi-beat 3D data sets of the TV (32 vol/s) were acquired in five subjects with various TV morphologies from the apical approach and analysed offline with custom-made software. Coordinates representing the annulus and the leaflets were imported into MeshLab (Visual Computing Lab ISTICNR) to develop solid models to be converted to stereolithographic file format and 3D print. Measurements of the TV annulus antero-posterior (AP) and medio-lateral (ML) diameters, perimeter (P), and TV tenting height (H) and volume (V) obtained from the 3D echo data set were compared with those performed on the 3D models using a caliper, a syringe and a millimeter tape. Antero-posterior (4.2 +/- 0.2 cm vs. 4.2 +/- 0 cm), ML (3.7 +/- 0.2 cm vs. 3.6 +/- 0.1 cm), P (12.6 +/- 0.2 cm vs. 12.7 +/- 0.1 cm), H (11.2 +/- 2.1 mm vs. 10.8 +/- 2.1 mm) and V (3.0 +/- 0.6 ml vs. 2.8 +/- 1.4 ml) were similar (P = NS for all) when measured on the 3D data set and the printed model. The two sets of measurements were highly correlated (r = 0.991). The mean absolute error (2D - 3D) for AP, ML, P and tenting H was 0.7 +/- 0.3 mm, indicating accuracy of the 3D model of <1 mm. Conclusion: Three dimensional printing of the TV from 3DTTE data is feasible with highly conserved fidelity. This technique has the potential for rapid integration into clinical practice to assist with decision-making, surgical planning, and teaching. PMID- 28025264 TI - EACVI HIT initiative: discussion with the seniors. Highlights from EuroCMR 2016. PMID- 28025263 TI - Quantitative plaque features from coronary computed tomography angiography to identify regional ischemia by myocardial perfusion imaging. AB - Aims: We aimed to investigate whether quantitative plaque features measured from coronary CT angiography (CCTA) predict ischemia by myocardial perfusion SPECT imaging (MPI). Methods and Results: Hundred and eighty-four consecutive patients (63% males) with suspected-coronary artery disease, undergoing hybrid CCTA, and attenuation corrected solid state 99mTc stress/rest MPI and single vessel ischemia were considered. Quantitative analysis of CCTA derived non-calcified plaque (NCP), low-density NCP [< 30 Hounsfield Units (HU)] (LDNCP), calcified and total plaque burdens (%, normalized to vessel volume), maximum diameter stenosis and contrast density difference (CD, maximum difference in HU/lumen area within lesion). Normal thresholds for plaque features were defined as 95th percentile thresholds, from 40% of vessels with non-ischemic MPI regions. These vessels were excluded from further analysis. Regional ischemia (>= 2%) was quantified from MPI. All plaque features were higher in arteries corresponding to ischemia (P < 0.003 for all). In multi-variable analysis, abnormal NCP burden [odds ratio (OR) 2.6], LDNCP burden (OR 3.9), and CD (OR 2.7) were significantly associated with ischemia, whereas stenosis >= 50% was not (P = 0.14). In a subset of vessels with >= 50% stenosis, LDNCP burden (OR 4.3, P = 0.008) and CD (OR 3.7, P = 0.029) were associated with ischemia. In subsets of vessels with stenosis 30-69% and >= 70%, abnormal LDNCP burden (OR 6.4, P = 0.006) and CD (OR 7.3, P = 0.02) were associated with ischemia. Conclusions: Quantitative plaque features obtained from CCTA, LDNCP, and CD, are associated with ischemia by MPI independent of stenosis. LDNCP burden and CD are associated with ischemia in stenosis 30-69% and >= 70%, respectively. PMID- 28025265 TI - Affection of the cardiovascular system by IgG4-related disease. PMID- 28025266 TI - An unexpected cause of recurrent myocardial infarction. PMID- 28025267 TI - Coronary artery aneurysms detected by computed tomography coronary angiography. AB - Aims: Coronary artery aneurysms (CAAs) are incidentally revealed by coronary angiography and consist in a localized dilation of a coronary artery. Although invasive coronary angiography (ICA) is the gold standard imaging technique, it can lead to the underestimation of CAAs diameter in presence of parietal thrombi. Computed tomography coronary angiography (CTCA) is a very sensitive tool in CAAs detection and provides a clear visualization of coronary lumen highlighting intraluminal thrombi. Methods and results: We retrospectively reviewed 390 CTCA performed at our institution, 9 patients (6 men, 3 women) resulted affected by CAAs and represented the aneurysmal group (A group). Matched controls were identified among the non-aneurysmal patients with healthy coronaries to CTCA (NAH group). Clinical variables and imaging findings were compared and correlated. CAAs prevalence in our population was 2.31%. 15 CAAs were detected, mainly on the right coronary artery (RCA) (9 aneurysms) followed by the left anterior descending coronary artery (LAD) (three aneurysms) and the left circumflex coronary artery (CX) (three aneurysms). In six patients (66.7%) CTCA displayed an aneurysmal thrombosis and in 5 patients (55.5%) CAAs were associated to coronary artery stenoses. A statistically significant difference was found between the diameters of coronary vessels measured in healthy segments in A and NAH group. Conclusions: CTCA has led to a non-invasive estimation of CAAs prevalence and characterization of aneurysmal features and coronary anatomy. Overcoming ICA limitations, CTCA has provided a fine analysis of the aneurysms, also in presence of intraluminal thrombi. PMID- 28025268 TI - Hypertrophic cardiomyopathy with aortic dilation: a novel observation. AB - Aims: Our goal was to identify the prevalence of aortic dilation in patients with hypertrophic cardiomyopathy (HCM), the most prevalent (0.2%) heritable, genetic cardiovascular disease. Aortic dilation also represents a spectrum of familial inheritance. However, data regarding the prevalence of aortic dilation in HCM patients is lacking. Methods and results: This is an observational retrospective study of all patients referred to our HCM centre. Aortic dilation was defined based on recent American Society of Echocardiography and European Association of Cardiovascular Imaging published guidelines. Of the 201 HCM patients seen between Jan. 1, 2011 and March 31, 2014, 18 (9.0%) met the definition of aortic dilation. Mean age was 56.3 +/- 9.3 years, 77.8% were male, mean ascending aorta diameter was 4.0 +/- 0.4 cm in males and 3.8 +/- 0.2 cm in females, mean sinuses of Valsalva diameter was 4.2 +/- 0.2 cm in males and 3.8 +/- 0.4 cm in females, and 13 (72.2%) had left ventricular outflow tract obstruction. HCM patients with dilated aorta were more likely males, less likely hypertensive and had larger left ventricle diameter and more aortic valve regurgitation; remaining characteristics were similar. Conclusion: We report a novel observation with 9.0% prevalance of dilated aorta in HCM patients. Further studies are needed to help define the genetic and pathophysiologic basis as well as the clinical implications of this association in a larger group of HCM patients. PMID- 28025269 TI - Neoplastic non-bacterial endocarditis of the aortic valve. PMID- 28025271 TI - No Evidence That Protein Noise-Induced Epigenetic Epistasis Constrains Gene Expression Evolution. AB - Changes in gene expression can affect phenotypes and therefore both its level and stochastic variability are frequently under selection. It has recently been proposed that epistatic interactions influence gene expression evolution: gene pairs where simultaneous knockout is more deleterious than expected should evolve reduced expression noise to avoid concurrent low expression of both proteins. In apparent support, yeast genes with many epistatic partners have low expression variation both among isogenic individuals and between species. However, the specific predictions and basic assumptions of this verbal model remain untested. Using bioinformatics analysis, we first demonstrate that the model's predictions are unsupported by available large-scale data. Based on quantitative biochemical modeling, we then show that epistasis between expression reductions (epigenetic epistasis) is not expected to aggravate the fitness cost of stochastic expression, which is in sharp contrast to the verbal argument. This nonintuitive result can be readily explained by the typical diminishing return of fitness on gene activity and by the fact that expression noise not only decreases but also increases the abundance of proteins. Overall, we conclude that stochastic variation in epistatic partners is unlikely to drive noise minimization or constrain gene expression divergence on a genomic scale. PMID- 28025270 TI - Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites. AB - Multiple kelch13 alleles conferring artemisinin resistance (ART-R) are currently spreading through Southeast Asian malaria parasite populations, providing a unique opportunity to observe an ongoing soft selective sweep, investigate why resistance alleles have evolved multiple times and determine fundamental population genetic parameters for Plasmodium We sequenced kelch13 (n = 1,876), genotyped 75 flanking SNPs, and measured clearance rate (n = 3,552) in parasite infections from Western Thailand (2001-2014). We describe 32 independent coding mutations including common mutations outside the kelch13 propeller associated with significant reductions in clearance rate. Mutations were first observed in 2003 and rose to 90% by 2014, consistent with a selection coefficient of ~0.079. ART-R allele diversity rose until 2012 and then dropped as one allele (C580Y) spread to high frequency. The frequency with which adaptive alleles arise is determined by the rate of mutation and the population size. Two factors drive this soft sweep: (1) multiple kelch13 amino-acid mutations confer resistance providing a large mutational target-we estimate the target is 87-163 bp. (2) The population mutation parameter (Theta = 2NeMU) can be estimated from the frequency distribution of ART-R alleles and is ~5.69, suggesting that short term effective population size is 88 thousand to 1.2 million. This is 52-705 times greater than Ne estimated from fluctuation in allele frequencies, suggesting that we have previously underestimated the capacity for adaptive evolution in Plasmodium Our central conclusions are that retrospective studies may underestimate the complexity of selective events and the Ne relevant for adaptation for malaria is considerably higher than previously estimated. PMID- 28025272 TI - Variation in Mutational Robustness between Different Proteins and the Predictability of Fitness Effects. AB - Random mutations in genes from disparate protein classes may have different distributions of fitness effects (DFEs) depending on different structural, functional, and evolutionary constraints. We measured the fitness effects of 156 single mutations in the genes encoding AraC (transcription factor), AraD (enzyme), and AraE (transporter) used for bacterial growth on l-arabinose. Despite their different molecular functions these genes all had bimodal DFEs with most mutations either being neutral or strongly deleterious, providing a general expectation for the DFE. This contrasts with the unimodal DFEs previously obtained for ribosomal protein genes where most mutations were slightly deleterious. Based on theoretical considerations, we suggest that the 33-fold higher average mutational robustness of ribosomal proteins is due to stronger selection for reduced costs of translational and transcriptional errors. Whereas the large majority of synonymous mutations were deleterious for ribosomal proteins genes, no fitness effects could be detected for the AraCDE genes. Four mutations in AraC and AraE increased fitness, suggesting that slightly advantageous mutations make up a significant fraction of the DFE, but that they often escape detection due to the limited sensitivity of commonly used fitness assays. We show that the fitness effects of amino acid substitutions can be predicted based on evolutionary conservation, but those weakly deleterious mutations are less reliably detected. This suggests that large-effect mutations and the fraction of highly deleterious mutations can be computationally predicted, but that experiments are required to characterize the DFE close to neutrality, where many mutations ultimately fixed in a population will occur. PMID- 28025274 TI - Mitochondrial Phylogenomics Resolves the Global Spread of Higher Termites, Ecosystem Engineers of the Tropics. AB - The higher termites (Termitidae) are keystone species and ecosystem engineers. They have exceptional biomass and play important roles in decomposition of dead plant matter, in soil manipulation, and as the primary food for many animals, especially in the tropics. Higher termites are most diverse in rainforests, with estimated origins in the late Eocene (~54 Ma), postdating the breakup of Pangaea and Gondwana when most continents became separated. Since termites are poor fliers, their origin and spread across the globe requires alternative explanation. Here, we show that higher termites originated 42-54 Ma in Africa and subsequently underwent at least 24 dispersal events between the continents in two main periods. Using phylogenetic analyses of mitochondrial genomes from 415 species, including all higher termite taxonomic and feeding groups, we inferred 10 dispersal events to South America and Asia 35-23 Ma, coinciding with the sharp decrease in global temperature, sea level, and rainforest cover in the Oligocene. After global temperatures increased, 23-5 Ma, there was only one more dispersal to South America but 11 to Asia and Australia, and one dispersal back to Africa. Most of these dispersal events were transoceanic and might have occurred via floating logs. The spread of higher termites across oceans was helped by the novel ecological opportunities brought about by environmental and ecosystem change, and led termites to become one of the few insect groups with specialized mammal predators. This has parallels with modern invasive species that have been able to thrive in human-impacted ecosystems. PMID- 28025273 TI - Transmission between Archaic and Modern Human Ancestors during the Evolution of the Oncogenic Human Papillomavirus 16. AB - Every human suffers through life a number of papillomaviruses (PVs) infections, most of them asymptomatic. A notable exception are persistent infections by Human papillomavirus 16 (HPV16), the most oncogenic infectious agent for humans and responsible for most infection-driven anogenital cancers. Oncogenic potential is not homogeneous among HPV16 lineages, and genetic variation within HPV16 exhibits some geographic structure. However, an in-depth analysis of the HPV16 evolutionary history was still wanting. We have analyzed extant HPV16 diversity and compared the evolutionary and phylogeographical patterns of humans and of HPV16. We show that codivergence with modern humans explains at most 30% of the present viral geographical distribution. The most explanatory scenario suggests that ancestral HPV16 already infected ancestral human populations and that viral lineages co-diverged with the hosts in parallel with the split between archaic Neanderthal-Denisovans and ancestral modern human populations, generating the ancestral HPV16A and HPV16BCD viral lineages, respectively. We propose that after out-of-Africa migration of modern human ancestors, sexual transmission between human populations introduced HPV16A into modern human ancestor populations. We hypothesize that differential coevolution of HPV16 lineages with different but closely related ancestral human populations and subsequent host-switch events in parallel with introgression of archaic alleles into the genomes of modern human ancestors may be largely responsible for the present-day differential prevalence and association with cancers for HPV16 variants. PMID- 28025275 TI - miRNAs in Ancient Tissue Specimens of the Tyrolean Iceman. AB - The analysis of nucleic acids in ancient samples is largely limited to DNA. Small noncoding RNAs (microRNAs) are known to be evolutionary conserved and stable. To gain knowledge on miRNAs measured from ancient samples, we profiled microRNAs in cryoconserved mummies. First, we established the approach on a World War One warrior, the "Kaiserjager", which has been preserved for almost one century. Then, we profiled seven ancient tissue specimens including skeletal muscle, stomach mucosa, stomach content and two corpus organ tissues of the 5,300-year old copper age mummy Iceman and compared these profiles to the presence of organ specific miRNAs in modern tissues. Our analyses suggest the presence of specific miRNAs in the different Iceman's tissues. Of 1,066 analyzed human miRNAs, 31 were discovered across all biopsies and 87 miRNAs were detected only in a single sample. To check for potential microbiological contaminations, all miRNAs detected in Iceman samples and not present in ancient samples were mapped to 14,582 bacterial and viral genomes. We detected few hits (3.9% of miRNAs compared with 3.6% of miRNAs). Interestingly, the miRNAs with higher abundance across all ancient tissues were significantly enriched for Guanine (P value of 10-13) and Cytosine (P value of 10-7). The same pattern was observed for modern tissues. Comparing miRNAs measured from ancient organs to modern tissue patterns highlighted significant similarities, e.g., for miRNAs present in the muscle. Our first comprehensive analysis of microRNAs in ancient human tissues indicates that these stable molecules can be detected in tissue specimens after 5,300 years. PMID- 28025276 TI - IMGui-A Desktop GUI Application for Isolation with Migration Analyses. AB - The Isolation with Migration (IM) programs (e.g., IMa2) have been utilized extensively by evolutionary biologists for model-based inference of demographic parameters including effective population sizes, migration rates, and divergence times. Here, we describe a graphical user interface for the latest IM program. IMGui provides a comprehensive set of tools for performing demographic analyses, tracking progress of runs, and visualizing results. Developed using node. js and the Electron framework, IMGui is an application that runs on any desktop operating system, and is available for download at https://github.com/jaredgk/IMgui-electron-packages. PMID- 28025277 TI - Uniparental Inheritance Promotes Adaptive Evolution in Cytoplasmic Genomes. AB - Eukaryotes carry numerous asexual cytoplasmic genomes (mitochondria and plastids). Lacking recombination, asexual genomes should theoretically suffer from impaired adaptive evolution. Yet, empirical evidence indicates that cytoplasmic genomes experience higher levels of adaptive evolution than predicted by theory. In this study, we use a computational model to show that the unique biology of cytoplasmic genomes-specifically their organization into host cells and their uniparental (maternal) inheritance-enable them to undergo effective adaptive evolution. Uniparental inheritance of cytoplasmic genomes decreases competition between different beneficial substitutions (clonal interference), promoting the accumulation of beneficial substitutions. Uniparental inheritance also facilitates selection against deleterious cytoplasmic substitutions, slowing Muller's ratchet. In addition, uniparental inheritance generally reduces genetic hitchhiking of deleterious substitutions during selective sweeps. Overall, uniparental inheritance promotes adaptive evolution by increasing the level of beneficial substitutions relative to deleterious substitutions. When we assume that cytoplasmic genome inheritance is biparental, decreasing the number of genomes transmitted during gametogenesis (bottleneck) aids adaptive evolution. Nevertheless, adaptive evolution is always more efficient when inheritance is uniparental. Our findings explain empirical observations that cytoplasmic genomes despite their asexual mode of reproduction-can readily undergo adaptive evolution. PMID- 28025278 TI - Mitogenomic Phylogeny, Diversification, and Biogeography of South American Spiny Rats. AB - Echimyidae is one of the most speciose and ecologically diverse rodent families in the world, occupying a wide range of habitats in the Neotropics. However, a resolved phylogeny at the genus-level is still lacking for these 22 genera of South American spiny rats, including the coypu (Myocastorinae), and 5 genera of West Indian hutias (Capromyidae) relatives. Here, we used Illumina shotgun sequencing to assemble 38 new complete mitogenomes, establishing Echimyidae, and Capromyidae as the first major rodent families to be completely sequenced at the genus-level for their mitochondrial DNA. Combining mitogenomes and nuclear exons, we inferred a robust phylogenetic framework that reveals several newly supported nodes as well as the tempo of the higher level diversification of these rodents. Incorporating the full generic diversity of extant echimyids leads us to propose a new higher level classification of two subfamilies: Euryzygomatomyinae and Echimyinae. Of note, the enigmatic Carterodon displays fast-evolving mitochondrial and nuclear sequences, with a long branch that destabilizes the deepest divergences of the echimyid tree, thereby challenging the sister-group relationship between Capromyidae and Euryzygomatomyinae. Biogeographical analyses involving higher level taxa show that several vicariant and dispersal events impacted the evolutionary history of echimyids. The diversification history of Echimyidae seems to have been influenced by two major historical factors, namely (1) recurrent connections between Atlantic and Amazonian Forests and (2) the Northern uplift of the Andes. PMID- 28025279 TI - Evolution of DNA Methylation across Insects. AB - DNA methylation contributes to gene and transcriptional regulation in eukaryotes, and therefore has been hypothesized to facilitate the evolution of plastic traits such as sociality in insects. However, DNA methylation is sparsely studied in insects. Therefore, we documented patterns of DNA methylation across a wide diversity of insects. We predicted that underlying enzymatic machinery is concordant with patterns of DNA methylation. Finally, given the suggestion that DNA methylation facilitated social evolution in Hymenoptera, we tested the hypothesis that the DNA methylation system will be associated with presence/absence of sociality among other insect orders. We found DNA methylation to be widespread, detected in all orders examined except Diptera (flies). Whole genome bisulfite sequencing showed that orders differed in levels of DNA methylation. Hymenopteran (ants, bees, wasps and sawflies) had some of the lowest levels, including several potential losses. Blattodea (cockroaches and termites) show all possible patterns, including a potential loss of DNA methylation in a eusocial species whereas solitary species had the highest levels. Species with DNA methylation do not always possess the typical enzymatic machinery. We identified a gene duplication event in the maintenance DNA methyltransferase 1 (DNMT1) that is shared by some Hymenoptera, and paralogs have experienced divergent, nonneutral evolution. This diversity and nonneutral evolution of underlying machinery suggests alternative DNA methylation pathways may exist. Phylogenetically corrected comparisons revealed no evidence that supports evolutionary association between sociality and DNA methylation. Future functional studies will be required to advance our understanding of DNA methylation in insects. PMID- 28025281 TI - Meta-analysis of Driving Cessation and Dementia: Does Sex Matter? AB - Objectives: The number of drivers with dementia is expected to increase over the coming decades. Because dementia is associated with a higher risk of crashes, driving cessation becomes inevitable as the disease progresses, but many people with dementia resist stopping to drive. This meta-analysis examines whether there are sex differences in the prevalence and incidence of driving cessation among drivers with dementia and compares the pattern of sex differences in drivers with dementia to those without dementia. Method: MEDLINE, PsycINFO, Scopus, and CINAHL were searched in July 2015 for observational studies of sex differences in driving cessation. Meta-analyses were performed using a random-effects model. Results: Twenty studies provided data on sex differences in driving cessation in older adults with or without dementia. Driving cessation was significantly more prevalent in women with dementia than men (odds ratio [OR] = 2.11, 95% confidence interval [CI] = 1.50-2.98), and the same pattern was found in women without dementia (OR = 2.74, 95% CI = 1.85-4.06). Discussion: Our findings suggest that the patterns of driving cessation differ between men and women with dementia, and this may have implications for sex-specific approaches designed to support drivers with dementia both before and after driving cessation. PMID- 28025280 TI - What Accounts for the Relationship Between Internet Use and Suicidal Ideation of Korean Older Adults? A Mediation Analysis. AB - Objectives: This study sought to examine the relationship between Internet use and suicidal ideation in Korean older adults and the mediating roles of social relationships and depressive symptoms. Method: A nationally representative sample of older adults aged 50 or older (N = 6,306), from four waves of the Korean Welfare Panel Study, was used in the analyses. All analyses were conducted using generalized estimation equations, and the mediation effects of social relationship satisfaction and depression in the relationship between Internet use and suicidal ideation were calculated using the product-of-coefficients approach. Results: Internet use was linked with lower levels of suicidal ideation directly and indirectly via the protective effects of Internet use on lowering depression, which was partially mediated by the positive influence Internet use has on older adults' social relationship satisfaction. Discussion: The results support previous theories about the relationship between social relationships, depression, and suicidal behavior and prior results about how the Internet might confer mental and social health benefits to older adults. This suggests that the Internet is an important social and health activity that contributes to lowering suicidal ideation in older adults. PMID- 28025282 TI - Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles. AB - Objectives: Apolipoprotein E (APOE) E4 and Clusterin (CLU) C alleles are risk factors for Alzheimer's disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Method: Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). Results: For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Discussion: Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied. PMID- 28025283 TI - Costs and Cost-Effectiveness of Plasmodium vivax Control. AB - The continued success of efforts to reduce the global malaria burden will require sustained funding for interventions specifically targeting Plasmodium vivax The optimal use of limited financial resources necessitates cost and cost effectiveness analyses of strategies for diagnosing and treating P. vivax and vector control tools. Herein, we review the existing published evidence on the costs and cost-effectiveness of interventions for controlling P. vivax, identifying nine studies focused on diagnosis and treatment and seven studies focused on vector control. Although many of the results from the much more extensive P. falciparum literature can be applied to P. vivax, it is not always possible to extrapolate results from P. falciparum-specific cost-effectiveness analyses. Notably, there is a need for additional studies to evaluate the potential cost-effectiveness of radical cure with primaquine for the prevention of P. vivax relapses with glucose-6-phosphate dehydrogenase testing. PMID- 28025284 TI - Flower development of Goniorrhachis marginata reveals new insights into the evolution of the florally diverse detarioid legumes. AB - BACKGROUND AND AIMS: The study of floral morphology and ontogeny and the re investigation of existing data help to uncover potential synapomorphic characters and foster our understanding of phylogenetic relationships that rely primarily on molecular analyses. Goniorrhachis marginata is a monotypic caesalpinioid legume (Leguminosae) that shows some interesting floral features, such as a long hypanthium and regular Rosaceae-like flowers. We studied the ontogeny and morphology of the flowers in detail and present our results in a broad phylogenetic context. METHODS: Flower buds were collected in the field, fixed in 70 % ethanol and investigated using scanning electron microscopy. Older buds in spirit were carefully opened to investigate the direction of style bending. Characters of the style from 131 taxa from the main legume lineages were analysed and mapped on a Bayesian molecular phylogeny. KEY RESULTS: The tetramerous calyx is the result of complete loss of one sepal. The formation of the radially symmetrical corolla starts in a typical caesalpinioid pattern with the adaxial petal innermost (ascending aestivation). The young style bends in the abaxial direction, which is a character found exclusively in all studied detarioid legumes and therefore a newly described synapomorphy for the clade. CONCLUSIONS: We show that investigation of unstudied taxa and reinvestigation of published data can uncover new, previously overlooked and important characters. Curvature of the style can be detected in young buds with a hand lens and therefore is an important character for field botanists. Our study reveals the importance of including poorly studied and/or phylogenetically enigmatic taxa in molecular phylogenies and in detailed morphological and ontogenetic analyses. PMID- 28025285 TI - Elymus repens biomass allocation and acquisition as affected by light and nutrient supply and companion crop competition. AB - BACKGROUND AND AIMS: Competitive crops are a central component of resource efficient weed control, especially for problematic perennial weeds such as Elymus repens Competition not only reduces total weed biomass, but denial of resources can also change the allocation pattern - potentially away from the underground storage organs that make perennial weeds difficult to control. Thus, the competition mode of crops may be an important component in the design of resource efficient cropping systems. Our aim was to determine how competition from companion crops with different modes of competition affect E. repens biomass acquisition and allocation and discuss that in relation to how E. repens responds to different levels of light and nutrient supply. METHODS: Greenhouse experiments were conducted with E. repens growing in interspecific competition with increasing density of perennial ryegrass or red clover, or growing at three levels of both light and nutrient supply. KEY RESULTS: Elymus repens total biomass decreased with increasing biomass of the companion crop and the rate of decrease was higher with red clover than with perennial ryegrass, particularly for E. repens rhizome biomass. A reduced nutrient supply shifted E. repens allocation towards below-ground biomass while a reduced light supply shifted it towards shoot biomass. Red clover caused no change in E. repens allocation pattern, while ryegrass mostly shifted the allocation towards below-ground biomass, but the change was not correlated with ryegrass biomass. CONCLUSIONS: The companion crop mode of competition influences both the suppression rate of E. repens biomass acquisition and the likelihood of shifts in E. repens biomass allocation. PMID- 28025286 TI - Photosynthetic induction and its diffusional, carboxylation and electron transport processes as affected by CO2 partial pressure, temperature, air humidity and blue irradiance. AB - BACKGROUND AND AIMS: Plants depend on photosynthesis for growth. In nature, factors such as temperature, humidity, CO2 partial pressure, and spectrum and intensity of irradiance often fluctuate. Whereas irradiance intensity is most influential and has been studied in detail, understanding of interactions with other factors is lacking. METHODS: We tested how photosynthetic induction after dark-light transitions was affected by CO2 partial pressure (20, 40, 80 Pa), leaf temperatures (15.5, 22.8, 30.5 degrees C), leaf-to-air vapour pressure deficits (VPDleaf-air; 0.5, 0.8, 1.6, 2.3 kPa) and blue irradiance (0-20 %) in tomato leaves (Solanum lycopersicum). KEY RESULTS: Rates of photosynthetic induction strongly increased with CO2 partial pressure, due to increased apparent Rubisco activation rates and reduced diffusional limitations. High leaf temperature produced slightly higher induction rates, and increased intrinsic water use efficiency and diffusional limitation. High VPDleaf-air slowed down induction rates and apparent Rubisco activation and (at 2.3 kPa) induced damped stomatal oscillations. Blue irradiance had no effect. Slower apparent Rubisco activation in elevated VPDleaf-air may be explained by low leaf internal CO2 partial pressure at the beginning of induction. CONCLUSIONS: The environmental factors CO2 partial pressure, temperature and VPDleaf-air had significant impacts on rates of photosynthetic induction, as well as on underlying diffusional, carboxylation and electron transport processes. Furthermore, maximizing Rubisco activation rates would increase photosynthesis by at most 6-8 % in ambient CO2 partial pressure (across temperatures and humidities), while maximizing rates of stomatal opening would increase photosynthesis by at most 1-3 %. PMID- 28025287 TI - Do floral and niche shifts favour the establishment and persistence of newly arisen polyploids? A case study in an Alpine primrose. AB - BACKGROUND AND AIMS: Polyploidization plays a key role in plant evolution. Despite the generally accepted 'minority-cytotype exclusion' theory, the specific mechanisms leading to successful establishment and persistence of new polyploids remain controversial. The majority of newly formed polyploids do not become established, because they are less common, have fewer potential mates or may not be able to compete successfully with co-occurring progenitors at lower ploidy levels. Changes in floral traits and ecological niches have been proposed as important mechanisms to overcome this initial frequency-dependent disadvantage. The aim of this study was to determine whether dodecaploids of the heterostylous P. marginata differ from their hexaploid progenitors in P. marginata and P. allionii for selected floral traits and ecological preferences that might be involved in establishment and persistence, providing a possible explanation for the origin of polyploidized populations. METHODS: Floral morphological traits and ecological niche preferences among dodecaploids and their hexaploid progenitors in P. marginata and P. allionii ,: all restricted to the south-western Alps, were quantified and compared KEY RESULTS: Differences in floral traits were detected between dodecaploids and their closest relatives, but such differences might be too weak to counter the strength of minority cytotype disadvantage and are unlikely to enable the coexistence of different cytotypes. Furthermore, the results suggest the preservation of full distyly and no transition to selfing in dodecaploids. Finally, dodecaploids occur almost exclusively in environments that are predicted to be suitable also for their closest hexaploid relatives. CONCLUSIONS: In light of the results, P. marginata dodecaploids have probably been able to establish and persist by occupying geographical areas not yet filled by their closest relatives without significant evolution in their climatic and pollination niches. Dispersal limitation and minority-cytotype exclusion probably maintain their current range disjunct from those of its close relatives. PMID- 28025289 TI - Geraniales flowers revisited: evolutionary trends in floral nectaries. AB - BACKGROUND AND AIMS: The detailed relationships in Geraniales in their current circumscription have only recently been clarified. The disparate floral morphologies and especially the nectaries of the corresponding group have consequently not previously been studied in a phylogenetic context. METHODS: The present study investigates floral and especially nectary morphology and structure for representatives of 12 of the 13 currently accepted genera in the five families of the Geraniales. Flowers were studied using light microscopy and scanning electron microscopy. KEY RESULTS: The data demonstrate the derivation of even the most disparate floral morphologies from a basic pentamerous and pentacyclic organization, with an obdiplostemonous androecium and receptacular nectaries associated with the antesepalous stamens. Divergent morphologies are explained by modifications of merosity (tetramerous flowers), symmetry (several transitions to zygomorphic flowers) and elaboration of the nectaries into variously shaped outgrowths and appendages, especially in Francoaceae. The divergent development of nectar glands ultimately leads to either a reduction in their number (to one in some Geraniaceae and Melianthaceae) or their total loss (some Vivianiaceae). CONCLUSIONS: Floral morphology of the Geraniales shows a high degree of similarity, despite the variation in overall floral appearance and nectary morphology. A hypothesis on the transformation of the nectaries within the Geraniales is presented. PMID- 28025288 TI - Characterization of CYCLOIDEA-like genes in Proteaceae, a basal eudicot family with multiple shifts in floral symmetry. AB - BACKGROUND AND AIMS: The basal eudicot family Proteaceae (approx. 1700 species) shows considerable variation in floral symmetry but has received little attention in studies of evolutionary development at the genetic level. A framework for understanding the shifts in floral symmetry in Proteaceae is provided by reconstructing ancestral states on an upated phylogeny of the family, and homologues of CYCLOIDEA (CYC), a key gene for the control of floral symmetry in both monocots and eudicots, are characterized. METHODS: Perianth symmetry transitions were reconstructed on a new species-level tree using parsimony and maximum likelihood. CYC-like genes in 35 species (31 genera) of Proteaceae were sequenced and their phylogeny was reconstructed. Shifts in selection pressure following gene duplication were investigated using nested branch-site models of sequence evolution. Expression patterns of CYC homologues were characterized in three species of Grevillea with different types of floral symmetry. KEY RESULTS: Zygomorphy has evolved 10-18 times independently in Proteaceae from actinomorphic ancestors, with at least four reversals to actinomorphy. A single duplication of CYC-like genes occurred prior to the diversification of Proteaceae, with putative loss or divergence of the ProtCYC1 paralogue in more than half of the species sampled. No shifts in selection pressure were detected in the branches subtending the two ProtCYC paralogues. However, the amino acid sequence preceding the TCP domain is strongly divergent in Grevillea ProtCYC1 compared with other species. ProtCYC genes were expressed in developing flowers of both actinomorphic and zygomorphic Grevillea species, with late asymmetric expression in the perianth of the latter. CONCLUSION: Proteaceae is a remarkable family in terms of the number of transitions in floral symmetry. Furthermore, although CYC-like genes in Grevillea have unusual sequence characteristics, they display patterns of expression that make them good candidates for playing a role in the establishment of floral symmetry. PMID- 28025290 TI - Large- and small-scale environmental factors drive distributions of cool-adapted plants in karstic microrefugia. AB - BACKGROUND AND AIMS: Dolines are small- to large-sized bowl-shaped depressions of karst surfaces. They may constitute important microrefugia, as thermal inversion often maintains cooler conditions within them. This study aimed to identify the effects of large- (macroclimate) and small-scale (slope aspect and vegetation type) environmental factors on cool-adapted plants in karst dolines of East Central Europe. We also evaluated the potential of these dolines to be microrefugia that mitigate the effects of climate change on cool-adapted plants in both forest and grassland ecosystems. METHODS: We compared surveys of plant species composition that were made between 2007 and 2015 in 21 dolines distributed across four mountain ranges (sites) in Hungary and Romania. We examined the effects of environmental factors on the distribution and number of cool-adapted plants on three scales: (1) regional (all sites); (2) within sites and; (3) within dolines. Generalized linear models and non-parametric tests were used for the analyses. KEY RESULTS: Macroclimate, vegetation type and aspect were all significant predictors of the diversity of cool-adapted plants. More cool adapted plants were recorded in the coolest site, with only few found in the warmest site. At the warmest site, the distribution of cool-adapted plants was restricted to the deepest parts of dolines. Within sites of intermediate temperature and humidity, the effect of vegetation type and aspect on the diversity of cool-adapted plants was often significant, with more taxa being found in grasslands (versus forests) and on north-facing slopes (versus south facing slopes). CONCLUSIONS: There is large variation in the number and spatial distribution of cool-adapted plants in karst dolines, which is related to large- and small-scale environmental factors. Both macro- and microrefugia are therefore likely to play important roles in facilitating the persistence of cool-adapted plants under global warming. PMID- 28025291 TI - Evolution of genome size and genomic GC content in carnivorous holokinetics (Droseraceae). AB - BACKGROUND AND AIMS: Studies in the carnivorous family Lentibulariaceae in the last years resulted in the discovery of the smallest plant genomes and an unusual pattern of genomic GC content evolution. However, scarcity of genomic data in other carnivorous clades still prevents a generalization of the observed patterns. Here the aim was to fill this gap by mapping genome evolution in the second largest carnivorous family, Droseraceae, where this evolution may be affected by chromosomal holokinetism in Drosera METHODS: The genome size and genomic GC content of 71 Droseraceae species were measured by flow cytometry. A dated phylogeny was constructed, and the evolution of both genomic parameters and their relationship to species climatic niches were tested using phylogeny-based statistics. KEY RESULTS: The 2C genome size of Droseraceae varied between 488 and 10 927 Mbp, and the GC content ranged between 37.1 and 44.7 %. The genome sizes and genomic GC content of carnivorous and holocentric species did not differ from those of their non-carnivorous and monocentric relatives. The genomic GC content positively correlated with genome size and annual temperature fluctuations. The genome size and chromosome numbers were inversely correlated in the Australian clade of Drosera CONCLUSIONS: Our results indicate that neither carnivory (nutrient scarcity) nor the holokinetism have a prominent effect on size and DNA base composition of Droseraceae genomes. However, the holokinetic drive seems to affect karyotype evolution in one of the major clades of Drosera Our survey confirmed that the evolution of GC content is tightly connected with the evolution of genome size and also with environmental conditions. PMID- 28025292 TI - Comparative seed germination and seedling development of the ghost orchid, Dendrophylax lindenii (Orchidaceae), and molecular identification of its mycorrhizal fungus from South Florida. AB - BACKGROUND AND AIMS: The endangered leafless ghost orchid, Dendrophylax lindenii, one of the most renowned orchids in the world, is difficult to grow under artificial conditions. Published information on asymbiotic and symbiotic (co culture with a mycobiont) seed germination, seedling anatomy and developmental morphology of this leafless orchid is completely lacking. This information is critical for the development of efficient procedures for ghost orchid production for successful reintroduction. METHODS: Ghost orchid seedling early development stages were morphologically and anatomically defined to compare germination, embryo and protocorm maturation and seedling development during asymbiotic and symbiotic culture with one of two mycorrhizal strains (Dlin-379 and Dlin-394) isolated from ghost orchid roots in situ KEY RESULTS: Seeds symbiotically germinated at higher rates when cultured with fungal strain Dlin-394 than with strain Dlin-379 or asymbiotically on P723 medium during a 10-week culture period. Fungal pelotons were observed in protocorm cells co-cultured with strain Dlin-394 but not Dlin-379. Some 2-year-old seedlings produced multinode inflorescences in vitro Production of keikis from inflorescence nodes indicated the capacity for clonal production in the ghost orchid. CONCLUSIONS: Ghost orchid embryo and seedling development were characterized into seven stages. Fungal strain Dlin-394 was confirmed as a possible ghost orchid germination mycobiont, which significantly promoted seed germination and seedling development. Internal transcribed spacer sequencing data confirmed that Dlin-394 belongs within the genus Ceratobasidium These results offer the opportunity to examine the benefits of using a mycobiont to enhance in vitro germination and possibly ex vitro acclimatization and sustainability following outplanting. PMID- 28025293 TI - An Innovative Air-Oxygen Blender for Continuous Positive Airway Pressure Support in Resource-Poor Locations: A Feasibility Study. AB - Objectives: The objectives of this study are (i) to evaluate the feasibility of using an inexpensive air pump to maintain reliable oxygen concentration in a continuous positive airway pressure (CPAP) system and (ii) to evaluate whether an inexpensive air pump can maintain infant 02 sats >90%. Methods: This prospective study, which included 19 babies in pilot phase and 90 during extension phase, was conducted at a neonatal intensive care unit in a resource-poor academic medical center in India. The intervention involved introduction of an air pump in the CPAP delivery system. Outcome measures were oxygen concentration in the air oxygen blend and oxygen saturation of the study babies. Results: Oxygen concentration at the outlets ranged between 56 and 70% and in the blend between 42 and 51%. Oxygen saturation ranged between 90 and 97%. Conclusion: A simple and inexpensive air pump can work as a safe and effective oxygen blender. PMID- 28025294 TI - Investigation of nucleation processes during dynamic recrystallization of ice using cryo-EBSD. AB - Nucleation mechanisms occurring during dynamic recrystallization play a crucial role in the evolution of microstructures and textures during high temperature deformation. In polycrystalline ice, the strong viscoplastic anisotropy induces high strain heterogeneities between grains which control the recrystallization mechanisms. Here, we study the nucleation mechanisms occurring during creep tests performed on polycrystalline columnar ice at high temperature and stress (T=-5 degrees C;sigma=0.5 MPa) by post-mortem analyses of deformation microstructures using cryogenic electron backscatter diffraction. The columnar geometry of the samples enables discrimination of the nuclei from the initial grains. Various nucleation mechanisms are deduced from the analysis of the nuclei relations with the dislocation sub-structures within grains and at grain boundaries. Tilt sub grain boundaries and kink bands are the main structures responsible for development of polygonization and mosaic sub-structures. Nucleation by bulging at serrated grain boundaries is also an efficient nucleation mechanism near the grain boundaries where strain incompatibilities are high. Observation of nuclei with orientations not related to the 'parent' ones suggests the possibility of 'spontaneous' nucleation driven by the relaxation of the dislocation-related internal stress field. The complexity of the nucleation mechanisms observed here emphasizes the impact of stress and strain heterogeneities on dynamic recrystallization mechanisms.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025295 TI - Dynamic recrystallization during deformation of polycrystalline ice: insights from numerical simulations. AB - The flow of glaciers and polar ice sheets is controlled by the highly anisotropic rheology of ice crystals that have hexagonal symmetry (ice lh). To improve our knowledge of ice sheet dynamics, it is necessary to understand how dynamic recrystallization (DRX) controls ice microstructures and rheology at different boundary conditions that range from pure shear flattening at the top to simple shear near the base of the sheets. We present a series of two-dimensional numerical simulations that couple ice deformation with DRX of various intensities, paying special attention to the effect of boundary conditions. The simulations show how similar orientations of c-axis maxima with respect to the finite deformation direction develop regardless of the amount of DRX and applied boundary conditions. In pure shear this direction is parallel to the maximum compressional stress, while it rotates towards the shear direction in simple shear. This leads to strain hardening and increased activity of non-basal slip systems in pure shear and to strain softening in simple shear. Therefore, it is expected that ice is effectively weaker in the lower parts of the ice sheets than in the upper parts. Strain-rate localization occurs in all simulations, especially in simple shear cases. Recrystallization suppresses localization, which necessitates the activation of hard, non-basal slip systems.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025296 TI - Physical analysis of an Antarctic ice core-towards an integration of micro- and macrodynamics of polar ice. AB - Microstructures from deep ice cores reflect the dynamic conditions of the drill location as well as the thermodynamic history of the drill site and catchment area in great detail. Ice core parameters (crystal lattice-preferred orientation (LPO), grain size, grain shape), mesostructures (visual stratigraphy) as well as borehole deformation were measured in a deep ice core drilled at Kohnen Station, Dronning Maud Land (DML), Antarctica. These observations are used to characterize the local dynamic setting and its rheological as well as microstructural effects at the EDML ice core drilling site (European Project for Ice Coring in Antarctica in DML). The results suggest a division of the core into five distinct sections, interpreted as the effects of changing deformation boundary conditions from triaxial deformation with horizontal extension to bedrock-parallel shear. Region 1 (uppermost approx. 450 m depth) with still small macroscopic strain is dominated by compression of bubbles and strong strain and recrystallization localization. Region 2 (approx. 450-1700 m depth) shows a girdle-type LPO with the girdle plane being perpendicular to grain elongations, which indicates triaxial deformation with dominating horizontal extension. In this region (approx. 1000 m depth), the first subtle traces of shear deformation are observed in the shape-preferred orientation (SPO) by inclination of the grain elongation. Region 3 (approx. 1700-2030 m depth) represents a transitional regime between triaxial deformation and dominance of shear, which becomes apparent in the progression of the girdle to a single maximum LPO and increasing obliqueness of grain elongations. The fully developed single maximum LPO in region 4 (approx. 2030-2385 m depth) is an indicator of shear dominance. Region 5 (below approx. 2385 m depth) is marked by signs of strong shear, such as strong SPO values of grain elongation and strong kink folding of visual layers. The details of structural observations are compared with results from a numerical ice sheet model (PISM, isotropic) for comparison of strain rate trends predicted from the large-scale geometry of the ice sheet and borehole logging data. This comparison confirms the segmentation into these depth regions and in turn provides a wider view of the ice sheet.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025297 TI - Temperature dependence of ice-on-rock friction at realistic glacier conditions. AB - Using a new biaxial friction apparatus, we conducted experiments of ice-on-rock friction in order to better understand basal sliding of glaciers and ice streams. A series of velocity-stepping and slide-hold-slide tests were conducted to measure friction and healing at temperatures between -20 degrees C and melting. Experimental conditions in this study are comparable to subglacial temperatures, sliding rates and effective pressures of Antarctic ice streams and other glaciers, with load-point velocities ranging from 0.5 to 100 um s-1 and normal stress sigman = 100 kPa. In this range of conditions, temperature dependences of both steady-state friction and frictional healing are considerable. The friction increases linearly with decreasing temperature (temperature weakening) from MU = 0.52 at -20 degrees C to MU = 0.02 at melting. Frictional healing increases and velocity dependence shifts from velocity-strengthening to velocity-weakening behaviour with decreasing temperature. Our results indicate that the strength and stability of glaciers and ice streams may change considerably over the range of temperatures typically found at the ice-bed interface.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025298 TI - The effect of rock particles and D2O replacement on the flow behaviour of ice. AB - Ice-rock mixtures are found in a range of natural terrestrial and planetary environments. To understand how flow processes occur in these environments, laboratory-derived properties can be extrapolated to natural conditions through flow laws. Here, deformation experiments have been carried out on polycrystalline samples of pure ice, ice-rock and D2O-ice-rock mixtures at temperatures of 263, 253 and 233 K, confining pressure of 0 and 48 MPa, rock fraction of 0-50 vol.% and strain-rates of 5 * 10-7 to 5 * 10-5 s-1 Both the presence of rock particles and replacement of H2O by D2O increase bulk strength. Calculated flow law parameters for ice and H2O-ice-rock are similar to literature values at equivalent conditions, except for the value of the rock fraction exponent, here found to be 1. D2O samples are 1.8 times stronger than H2O samples, probably due to the higher mass of deuterons when compared with protons. A gradual transition between dislocation creep and grain-size-sensitive deformation at the lowest strain-rates in ice and ice-rock samples is suggested. These results demonstrate that flow laws can be found to describe ice-rock behaviour, and should be used in modelling of natural processes, but that further work is required to constrain parameters and mechanisms for the observed strength enhancement.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025299 TI - The influence of closed brine pockets and permeable brine channels on the thermo elastic properties of saline ice. AB - A model of the thermo-elastic behaviour of saline ice is formulated, and model solutions describing thermo-elastic waves (TEW) propagating into a half-space of the ice are investigated. The model is based on a proposal that saline ice is a matrix, which encompasses both closed brine pockets and permeable channels filled with brine. Experiments on the thermal expansion of saline ice samples, and on TEW in saline ice, have been performed in the cold laboratories of the University Centre in Svalbard and in University College London. The experimental data are compared with theoretical conclusions. The experimental data support our hypothesis that the brine in saline ice is divided between closed pockets and open, permeable channels.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025300 TI - Linking scales in sea ice mechanics. AB - Mechanics plays a key role in the evolution of the sea ice cover through its control on drift, on momentum and thermal energy exchanges between the polar oceans and the atmosphere along cracks and faults, and on ice thickness distribution through opening and ridging processes. At the local scale, a significant variability of the mechanical strength is associated with the microstructural heterogeneity of saline ice, however characterized by a small correlation length, below the ice thickness scale. Conversely, the sea ice mechanical fields (velocity, strain and stress) are characterized by long-ranged (more than 1000 km) and long-lasting (approx. few months) correlations. The associated space and time scaling laws are the signature of the brittle character of sea ice mechanics, with deformation resulting from a multi-scale accumulation of episodic fracturing and faulting events. To translate the short-range correlated disorder on strength into long-range-correlated mechanical fields, several key ingredients are identified: long-ranged elastic interactions, slow driving conditions, a slow viscous-like relaxation of elastic stresses and a restoring/healing mechanism. These ingredients constrained the development of a new continuum mechanics modelling framework for the sea ice cover, called Maxwell elasto-brittle. Idealized simulations without advection demonstrate that this rheological framework reproduces the main characteristics of sea ice mechanics, including anisotropy, spatial localization and intermittency, as well as the associated scaling laws.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025301 TI - Recrystallization and damage of ice in winter sports. AB - Ice samples, after sliding against a steel runner, show evidence of recrystallization and microcracking under the runner, as well as macroscopic cracking throughout the ice. The experiments that produced these ice samples are designed to be analogous to sliding in the winter sport of skeleton. Changes in the ice fabric are shown using thick and thin sections under both diffuse and polarized light. Ice drag is estimated as 40-50% of total energy dissipation in a skeleton run. The experimental results are compared with visual inspections of skeleton tracks, and to similar behaviour in rocks during sliding on earthquake faults. The results presented may be useful to athletes and designers of winter sports equipment.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025302 TI - Micromechanics of sea ice frictional slip from test basin scale experiments. AB - We have conducted a series of high-resolution friction experiments on large floating saline ice floes in an environmental test basin. In these experiments, a central ice floe was pushed between two other floes, sliding along two interfacial faults. The frictional motion was predominantly stick-slip. Shear stresses, normal stresses, local strains and slip displacement were measured along the sliding faults, and acoustic emissions were monitored. High-resolution measurements during a single stick-slip cycle at several positions along the fault allowed us to identify two phases of frictional slip: a nucleation phase, where a nucleation zone begins to slip before the rest of the fault, and a propagation phase when the entire fault is slipping. This is slip-weakening behaviour. We have therefore characterized what we consider to be a key deformation mechanism in Arctic Ocean dynamics. In order to understand the micromechanics of sea ice friction, we have employed a theoretical constitutive relation (i.e. an equation for shear stress in terms of temperature, normal load, acceleration, velocity and slip displacement) derived from the physics of asperity-asperity contact and sliding (Hatton et al. 2009 Phil. Mag. 89, 2771 2799 (doi:10.1080/14786430903113769)). We find that our experimental data conform reasonably with this frictional law once slip weakening is introduced. We find that the constitutive relation follows Archard's law rather than Amontons' law, with [Formula: see text] (where tau is the shear stress and sigman is the normal stress) and n = 26/27, with a fractal asperity distribution, where the frictional shear stress, tau = ffractal Tmlws, where ffractal is the fractal asperity height distribution, Tml is the shear strength for frictional melting and lubrication and ws is the slip weakening. We can therefore deduce that the interfacial faults failed in shear for these experimental conditions through processes of brittle failure of asperities in shear, and, at higher velocities, through frictional heating, localized surface melting and hydrodynamic lubrication.This article is part of the themed issue 'Microdynamics of ice'. PMID- 28025303 TI - Microdynamics of ice. PMID- 28025304 TI - Ice microstructures and microdynamics. PMID- 28025305 TI - Dispersal of Amblyseius swirskii (Acari: Phytoseiidae) on High-Tunnel Bell Peppers in Presence or Absence of Polyphagotarsonemus latus (Acari: Tarsonemidae). AB - Amblyseius swirskiiAthias-Henriot (Acari: Phytoseiidae) is a predatory mite used to control thrips (Thysanoptera), whiteflies (Bemisia tabaci Genn., Hemiptera: Aleyrodidae), and broad mites (BMs) (Polyphagotarsonemus latus Banks, Acari: Tarsonemidae). Dispersal of A. swirskii, using the ornamental pepper "Explosive Ember" as a banker plant was evaluated for control of BMs in high-tunnel peppers. Open-canopy plants (5 weeks old) versus closed-canopy plants (10-weeks old) were used to evaluate the effect of plant connectedness in A. swirskii dispersal, in the presence (two females per plant) and absence of BMs. Plots consisted of a single central banker plant and four bell peppers extending linearly north and south. Sets of all treatments were destructively sampled 1, 4, and 7 days after releasing A. swirskii Within 24 h, A. swirskii dispersed four plants away from the banker plants (1 m), regardless of the state of the canopy. Canopy connectedness did increase the presence of A. swirskii on the crop plants. Predatory mite numbers on closed-canopy treatments doubled within the 7-day sampling period, whereas no significant increase was observed on open-canopy treatments. The presence of BMs had no significant effect on the movement of A. swirskii The results suggest further experiments with A. swirskii and banker plants for control of BMs is warranted. PMID- 28025306 TI - Risks and Benefits of Mucosal Healing With Combined Immunosuppression in Paediatric Crohn's Disease: A Complex Topic That Needs Careful Evaluation. PMID- 28025307 TI - Five-year Safety Data From ENCORE, a European Observational Safety Registry for Adults With Crohn's Disease Treated With Infliximab [Remicade(r)] or Conventional Therapy. AB - Background and Aims: The ENCORE registry aimed at comparing the long-term safety of Crohn's disease [CD] treatment with infliximab [Remicade(r)] and with conventional therapies in real-world clinical practice. Methods: The 5-year, prospective, observational ENCORE registry followed patients with CD in nine European countries, who received treatment with infliximab, conventional therapies, or switched to infliximab from conventional therapy. Adverse events [AEs] in pre-specified categories and serious AEs were recorded at least every 6 months of the 5-year observation period. Frequency of events was evaluated, and multivariable analyses using follow-up time [Cox proportion hazards model] and exposure time [Poisson regression] were used to identify risk factors for time to AEs in pre-specified categories. Results: Patients who received infliximab [N = 1541], conventional therapies [N = 1121], or switched to infliximab [N = 298] were followed for medians of 60.4, 55.6, and 42.5 months, respectively. Infliximab median exposure was 18.7 and 19.3 months in the infliximab and switched-to-infliximab groups, respectively. In time-to-event Cox proportion hazards [PH] analyses adjusting for confounders, infliximab [vs conventional therapy] was associated with serious infections (hazard ratio [HR] = 1.64, 95% confidence interval [CI]: 1.17, 2.31] and haematological conditions [HR = 2.91, CI: 1.51, 5.59], and not associated with lymphoproliferative disorders/malignancy [HR = 1.44, CI: 0.86, 2.42] or death [HR = 1.22, CI: 0.63, 2.36]. Prednisone use was associated with higher mortality [HR = 3.58, CI: 1.49, 8.61]. In exposure adjusted Poisson regression analyses, infliximab was associated with lower mortality (risk ratio [[RR] 0.39, CI: 0.17, 0.88]). Conclusions: Data from 5-year safety follow-up of patients with CD in the ENCORE registry demonstrate that infliximab [Remicade(r)] exposure is associated with increased risk of serious infections and haematological conditions, whereas mortality may be decreased. PMID- 28025308 TI - 2,5-Dimethyl-Celecoxib Extends Drosophila Life Span via a Mechanism That Requires Insulin and Target of Rapamycin Signaling. AB - The search for antiaging drugs is a key component of gerontology research. A few drugs with positive effects on life span in model organisms have been found. Here, we report that 2,5-dimethyl-celecoxib, a derivative of the anti inflammatory drug celecoxib, can extend Drosophila life span and delay aging by a mechanism involving insulin signaling and target of rapamycin signaling. Importantly, its positive effects were apparent when the treatment window was restricted to the beginning of life or the later half. 2,5-Dimethyl-celecoxib induced longevity was also associated with improvements in physical activity, intestinal integrity, and increased autophagy. In addition, 2,5-dimethyl celecoxib exhibited protective effects against several kinds of stress such as starvation and heat. The generally positive effects of 2,5-dimethyl-celecoxib on both health and life span, combined with its mode of action via evolutionarily conserved signaling pathways, indicate that it has the potential to become an effective antiaging drug. PMID- 28025309 TI - Safety and efficacy of prophylactic negative pressure wound therapy following open saphenous vein harvest in cardiac surgery: a feasibility study. AB - Objectives: Surgical site complications following great saphenous vein (GSV) harvest presents a significant risk of morbidity. Negative pressure wound therapy (NPWT) has shown promise in the treatment and prophylaxis of open wounds and surgical incisions but has not been studied following GSV harvest. We performed a feasibility study examining the use of NPWT following GSV harvest for coronary bypass surgery. Methods: Sixty-four patients were recruited in this single centre, single-blind, randomized controlled trial. The primary endpoint assessed feasibility by examining rates of device complication and malfunction. Secondary endpoints included rates of surgical site infection, lower leg complications, discharge date, and quality of life at discharge and 6 weeks. NPWT was delivered using the Prevena NPWT device. Results: There were no complications associated with NPWT which required intervention aside from discontinuation. NPWT was tolerated in 91% (30/33) of patients for the duration of treatment with an average of 4.8 days (+/-1.45 days). Device malfunction which required discontinuation was 6% (2/33) and involved a malfunctioning pressure sensor and did not affect patient care or present safety concerns. One patient had allergic contact dermatitis to the adhesive and had the device removed. NPWT patients had an earlier date of discharge (6 vs 10 days, P = 0.008), increased ability for self-care ( P = 0.0234) and quality of life ( P = 0.039) at initial assessment, and increased mobility at initial and follow-up assessment ( P = 0.0117 and 0.0123). Conclusions: The use of NPWT following GSV harvest is safe, well tolerated and improves postoperative recovery with prolonged impact on mobility at 6 weeks. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01698372 ; registration number: NCT01698372. PMID- 28025310 TI - Sarcomatoid carcinoma of the lung: a rare histological subtype of non-small cell lung cancer with a poor prognosis even at earlier tumour stages. AB - Objectives: Pulmonary sarcomatoid carcinoma (PSC) is a rare histological subtype of non-small cell lung cancer and comprises a diagnostically and therapeutically challenging group of tumours. We explored the clinicopathological features and prognostic factors of this tumour. Methods: We conducted a retrospective study of all patients who were treated for PSC in the Department of Thoracic Surgery between May 2005 and December 2014. Primary outcomes of interest were patient survival and prognostic factors. Results: A total of 58 patients were treated for sarcomatoid carcinoma within the described period and 46 patients underwent surgical resection with curative intent. The mean follow-up period was 30 months. Of the operated patients, 21.7% had pathological stage I disease, and 78.3% had more advanced disease. There were 25 carcinosarcomas, 10 pleomorphic carcinomas, 7 spindle cell carcinomas, 3 giant cell carcinomas and 1 pulmonary blastoma. Overall 5-year survival of the operated patients was 28.7%. A total of 28 patients experienced recurrence and died cancer-related. Our analysis revealed that tumour size, gender, histological entity, lymphatic vessel invasion (L1) and vascular invasion (V1) did not influence survival. There was a trend for decreased survival in older patients (>65 years). Conclusions: Surgical treatment can achieve satisfactory results with low perioperative mortality, but the overall prognosis even with multimodality concepts and in earlier tumour stages is worse compared to other types of non-small cell lung cancer. PMID- 28025311 TI - Operative results of the anterolateral thoracotomy with partial sternotomy approach for chronic-type B aortic dissection involving the aortic arch. AB - Objectives: There are various treatment strategies for chronic-type B aortic dissection involving the aortic arch. Our aim was to review our surgical experience in the anterolateral thoracotomy with the partial sternotomy approach for chronic-type B aortic dissection involving the aortic arch. Methods: From January 2000 to October 2015, 39 patients underwent the single-stage open surgery for chronic-type B aortic dissection involving the aortic arch using the anterolateral thoracotomy with partial sternotomy approach. Results: Among the 39 patients, 32 were men (82.1%; mean age at surgery, 61.3 +/- 11.9 years), with a mean dissecting aortic aneurysm diameter of 50.21 +/- 12.20 mm; 28 patients (71.8%) had patent false lumens of the descending aorta. The median interval from dissection occurrence until surgery was 34.05 +/- 52.34 months. Twenty-one patients underwent descending aortic replacement plus total aortic arch replacement and 18 underwent descending aortic replacement (plus partial aortic arch replacement). Overall in-hospital mortality and postoperative stroke rates were 5.1% (2 patients) and 10.3% (4 patients), respectively. Survival rates at 1, 3 and 5 years were 94.7%, 94.7% and 90.2%, respectively. Aortic event-free rates at 1, 3 and 5 years were 90.9%, 90.9% and 80.2%, respectively. Conclusions: The anterolateral thoracotomy with partial sternotomy approach is a useful surgical procedure with acceptable outcomes for chronic-type B aortic dissection cases involving the aortic arch, when aortic remodelling using thoracic endovascular aortic repair cannot be performed. PMID- 28025312 TI - Performance of the Labcor Dokimos Plus pericardial aortic prosthesis: a single centre experience. AB - Objectives: In patients with a small aortic annulus, aortic valve replacement (AVR) is frequently associated with high residual pressure gradients. Supra annular pericardial aortic prostheses are gaining popularity due to the increased effective orifice areas (EOA) and resulting lower gradients. This study reports the clinical and echocardiographic results following implantation of the new supra-annular pericardial aortic prosthesis Dokimos Plus (Labcor, Belo Horizonte, Brazil). Methods: Between October 2013 and July 2015, 137 patients (41% women, mean age: 74 years) underwent supra-annular AVR with or without concomitant procedures using the Dokimos Plus prosthesis in our department. Transthoracic echocardiography was performed pre- and postoperatively on all patients to assess haemodynamic parameters (gradients, acceleration time [AT], Doppler velocity indices [DVIs] and indexed EOA [EOAI]) and to detect paravalvular leakage (PVL). Data were collected retrospectively from our hospital databases. Methods: Patients were grouped by prosthesis size: Most patients received 23-mm (57.6%), followed by 21-mm (19%), 25-mm (15.4%) and 27-mm (8%) prostheses. The mean EOAI in all groups was 1.1 +/- 0.26 cm 2 /m 2 . Pressure gradients were low in all groups (mean: 8.9 +/- 4.4 mmHg; peak: 18.8 +/- 6.8 mmHg); AT and DVI were in the normal range according to American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations (mean AT 73.3 +/- 29 ms; mean DVI 0.5 +/- 0.2). One patient had severe PVL and one presented with central regurgitation, both requiring re-intervention. The mortality rate was 5.1% ( n = 7); none of the cases was associated with valve insufficiency. Conclusions: The Dokimos prosthesis showed a satisfactory overall performance, presenting low gradients and DVIs as well as high EOAI. Further investigations are needed to analyse the cases of regurgitation and monitor long-term performance. PMID- 28025313 TI - Stability and Hopf bifurcation analysis for the hypothalamic-pituitary-adrenal axis model with memory. AB - This article generalizes the existing minimal model of the hypothalamic-pituitary adrenal (HPA) axis in a realistic way, by including memory terms: distributed time delays, on one hand and fractional-order derivatives, on the other hand. The existence of a unique equilibrium point of the mathematical models is proved and a local stability analysis is undertaken for the system with general distributed delays. A thorough bifurcation analysis for the distributed delay model with several types of delay kernels is provided. Numerical simulations are carried out for the distributed delays models and for the fractional-order model with discrete delays, which substantiate the theoretical findings. It is shown that these models are able to capture the vital mechanisms of the HPA system. PMID- 28025314 TI - Cucumber Lure Trapping of Zeugodacus cucurbitae (Diptera: Tephritidae) in Hawaii and Taiwan: Longevity and Nontargets Captures. AB - The melon fly, Zeugodacus cucurbitae (Coquillett), is a serious pest of tropical horticulture, causing damage to cucurbits, tree fruits, and fruiting vegetables. Melon flies are especially attractive to freshly sliced cucumber, and this has led to the identification of a nine-compound kairomone lure that can be used to trap both female and male flies. In this study, a seven-compound lure, containing (Z)-6-nonenal, (Z)-6-nonen-1-ol, 1-octen-3-ol, (E,Z)-2,6-nonadienal, (E)-2 nonenal, hexanal, and 1-hexanol, was formulated into PVC plugs (100 or 300 mg/plug) for field testing in wet traps. In Hawaii, 100 mg of the seven-compound cucumber lure, loaded in either plugs or glass capillaries, attracted more flies than traps containing Solulys protein over a 9-wk period. However, both cucumber lure formulations showed marked declines in the number of flies trapped after 3 wk. Similar results were obtained during a 6-wk field trial using 100 mg cucumber lure plugs in Taiwan. Increasing the cucumber lure loading rate to 300 mg/lure increased the effective trapping life of the attractant during a second 9-wk field trial conducted in Hawaii. The synthetic cucumber lure showed female-biased sex ratios in trap captures in the Taiwanese and second Hawaiian field trials. Protein lures captures were female-biased in all three field trials. Wet traps in Hawaii containing the cucumber lure were found to capture 25-30 nontarget insects/trap/week, less than half that captured with Solulys. Captured nontarget insects represented 37 families in 10 orders. The most common families caught were Ceratopogonidae (~9 flies/trap) and Gryllidae (~7 crickets/trap). PMID- 28025315 TI - alpha2-COP is involved in early secretory traffic in Arabidopsis and is required for plant growth. AB - COP (coat protein) I-coated vesicles mediate intra-Golgi transport and retrograde transport from the Golgi to the endoplasmic reticulum. These vesicles form through the action of the small GTPase ADP-ribosylation factor 1 (ARF1) and the COPI heptameric protein complex (coatomer), which consists of seven subunits (alpha-, beta-, beta'-, gamma-, delta-, epsilon- and zeta-COP). In contrast to mammals and yeast, several isoforms for coatomer subunits, with the exception of gamma and delta, have been identified in Arabidopsis. To understand the role of COPI proteins in plant biology, we have identified and characterized a loss-of function mutant of alpha2-COP, an Arabidopsis alpha-COP isoform. The alpha2-cop mutant displayed defects in plant growth, including small rosettes, stems and roots and mislocalization of p24delta5, a protein of the p24 family containing a C-terminal dilysine motif involved in COPI binding. The alpha2-cop mutant also exhibited abnormal morphology of the Golgi apparatus. Global expression analysis of the alpha2-cop mutant revealed altered expression of plant cell wall associated genes. In addition, a strong upregulation of SEC31A, which encodes a subunit of the COPII coat, was observed in the alpha2-cop mutant; this also occurs in a mutant of a gene upstream of COPI assembly, GNL1, which encodes an ARF-guanine nucleotide exchange factor (GEF). These findings suggest that loss of alpha2-COP affects the expression of secretory pathway genes. PMID- 28025316 TI - Despite phylogenetic effects, C3-C4 lineages bridge the ecological gap to C4 photosynthesis. AB - C4 photosynthesis is a physiological innovation involving several anatomical and biochemical components that emerged recurrently in flowering plants. This complex trait evolved via a series of physiological intermediates, broadly termed 'C3 C4', which have been widely studied to understand C4 origins. While this research program has focused on biochemistry, physiology, and anatomy, the ecology of these intermediates remains largely unexplored. Here, we use global occurrence data and local habitat descriptions to characterize the niches of multiple C3-C4 lineages, as well as their close C3 and C4 relatives. While C3-C4 taxa tend to occur in warm climates, their abiotic niches are spread along other dimensions, making it impossible to define a universal C3-C4 niche. Phylogeny-based comparisons suggest that, despite shifts associated with photosynthetic types, the precipitation component of the C3-C4 niche is particularly lineage specific, being highly correlated with that of closely related C3 and C4 taxa. Our large scale analyses suggest that C3-C4 lineages converged toward warm habitats, which may have facilitated the transition to C4 photosynthesis, effectively bridging the ecological gap between C3 and C4 plants. The intermediates retained some precipitation aspects of their C3 ancestors' habitat, and likely transmitted them to their C4 descendants, contributing to the diversity among C4 lineages seen today. PMID- 28025317 TI - Macro optical projection tomography for large scale 3D imaging of plant structures and gene activity. AB - Optical projection tomography (OPT) is a well-established method for visualising gene activity in plants and animals. However, a limitation of conventional OPT is that the specimen upper size limit precludes its application to larger structures. To address this problem we constructed a macro version called Macro OPT (M-OPT). We apply M-OPT to 3D live imaging of gene activity in growing whole plants and to visualise structural morphology in large optically cleared plant and insect specimens up to 60 mm tall and 45 mm deep. We also show how M-OPT can be used to image gene expression domains in 3D within fixed tissue and to visualise gene activity in 3D in clones of growing young whole Arabidopsis plants. A further application of M-OPT is to visualise plant-insect interactions. Thus M-OPT provides an effective 3D imaging platform that allows the study of gene activity, internal plant structures and plant-insect interactions at a macroscopic scale. PMID- 28025318 TI - Alternative splicing in tomato pollen in response to heat stress. AB - Alternative splicing (AS) is a key control mechanism influencing signal response cascades in different developmental stages and under stress conditions. In this study, we examined heat stress (HS)-induced AS in the heat sensitive pollen tissue of two tomato cultivars. To obtain the entire spectrum of HS-related AS, samples taken directly after HS and after recovery were combined and analysed by RNA-seq. For nearly 9,200 genes per cultivar, we observed at least one AS event under HS. In comparison to control, for one cultivar we observed 76% more genes with intron retention (IR) or exon skipping (ES) under HS. Furthermore, 2,343 genes had at least one transcript with IR or ES accumulated under HS in both cultivars. These genes are involved in biological processes like protein folding, gene expression and heat response. Transcriptome assembly of these genes revealed that most of the alternative spliced transcripts possess truncated coding sequences resulting in partial or total loss of functional domains. Moreover, 141 HS specific and 22 HS repressed transcripts were identified. Further on, we propose AS as layer of stress response regulating constitutively expressed genes under HS by isoform abundance. PMID- 28025319 TI - Molecular cytogenetic characterization of chromosome site-specific repetitive sequences in the Arctic lamprey (Lethenteron camtschaticum, Petromyzontidae). AB - All extant lamprey karyotypes are characterized by almost all dot-shaped microchromosomes. To understand the molecular basis of chromosome structure in lampreys, we performed chromosome C-banding and silver staining and chromosome mapping of the 18S-28S and 5S ribosomal RNA (rRNA) genes and telomeric TTAGGG repeats in the Arctic lamprey (Lethenteron camtschaticum). In addition, we cloned chromosome site-specific repetitive DNA sequences and characterized them by nucleotide sequencing, chromosome in situ hybridization, and filter hybridization. Three types of repetitive sequences were detected; a 200-bp AT rich repetitive sequence, LCA-EcoRIa that co-localized with the 18S-28S rRNA gene clusters of 3 chromosomal pairs; a 364-bp AT-rich LCA-EcoRIb sequence that showed homology to the EcoRI sequence family from the sea lamprey (Petromyzon marinus), which contains short repeats as centromeric motifs; and a GC-rich 702-bp LCA-ApaI sequence that was distributed on nearly all chromosomes and showed significant homology with the integrase-coding region of a Ty3/Gypsy family long terminal repeat (LTR) retrotransposon. All three repetitive sequences are highly conserved within the Petromyzontidae or within Petromyzontidae and Mordaciidae. Molecular cytogenetic characterization of these site-specific repeats showed that they may be correlated with programed genome rearrangement (LCA-EcoRIa), centromere structure and function (LCA-EcoRIb), and site-specific amplification of LTR retroelements through homogenization between non-homologous chromosomes (LCA ApaI). PMID- 28025320 TI - Does donor proliferation in development aid for health affect health service delivery and population health? Cross-country regression analysis from 1995 to 2010. AB - Background: Previous literature suggests that increasing numbers of development aid donors can reduce aid effectiveness but this has not been tested in the health sector, which has experienced substantial recent growth in aid volume and number of donors. Methods: Based on annual data for 1995-2010 on 139 low- and middle-income countries that received health sector aid from donors reporting to the OECD's Creditor Reporting System, the study used two-step system generalized method of moments regression models to test whether the number of health aid donors and an index of health aid donor fragmentation affect health services (measured by DTP3 immunization rate) or health outcomes (measured by infant mortality rate) for three subsectors of health aid. Results: For total health aid and for the general and basic health aid subsector, controlling for economic and political conditions, increases in the number of donors were associated with increases in DTP3 immunization rate and reductions in infant mortality while increases in the donor fragmentation index were associated with decreases in DTP3 immunization rate and increases in infant mortality, though none of these relationships were statistically significant. For the population and reproductive health aid subsector, a one percent increase in the number of donors was associated with a 0.23 percent decrease in DTP3 immunization ( P < 0.01) while a one percent increase in donor fragmentation was associated with a 0.54 percent increase in DTP3 immunization rate ( P < 0.01); associations with infant mortality rates for this subsector were similar to those for total health aid. Conclusion: The results do not provide clear evidence in support of the hypothesis that donor proliferation negatively impacts development results in the health sector. Aid effectiveness policy prescriptions should distinguish responses to donor proliferation versus donor fragmentation and be adapted to specific subsectors of health aid. PMID- 28025321 TI - National income inequality and ineffective health insurance in 35 low- and middle income countries. AB - Global health policy efforts to improve health and reduce financial burden of disease in low- and middle-income countries (LMIC) has fuelled interest in expanding access to health insurance coverage to all, a movement known as Universal Health Coverage (UHC). Ineffective insurance is a measure of failure to achieve the intended outcomes of health insurance among those who nominally have insurance. This study aimed to evaluate the relation between national-level income inequality and the prevalence of ineffective insurance. We used Standardized World Income Inequality Database (SWIID) Gini coefficients for 35 LMICs and World Health Survey (WHS) data about insurance from 2002 to 2004 to fit multivariable regression models of the prevalence of ineffective insurance on national Gini coefficients, adjusting for GDP per capita. Greater inequality predicted higher prevalence of ineffective insurance. When stratifying by individual-level covariates, higher inequality was associated with greater ineffective insurance among sub-groups traditionally considered more privileged: youth, men, higher education, urban residence and the wealthiest quintile. Stratifying by World Bank country income classification, higher inequality was associated with ineffective insurance among upper-middle income countries but not low- or lower-middle income countries. We hypothesize that these associations may be due to the imprint of underlying social inequalities as countries approach decreasing marginal returns on improved health insurance by income. Our findings suggest that beyond national income, income inequality may predict differences in the quality of insurance, with implications for efforts to achieve UHC. PMID- 28025322 TI - Corrigendum. PMID- 28025323 TI - Role of emerging private hospitals in a post-Soviet mixed health system: a mixed methods comparative study of private and public hospital inpatient care in Mongolia. AB - Background: The collapse of the Soviet Union in 1990 severely impacted the health sector in Mongolia. Limited public funding for the post-Soviet model public system and a rapid growth of poorly regulated private providers have been pressing issues for a government seeking to re-establish universal health coverage. However, the evidence available on the role of private providers that would inform sector management is very limited. This study analyses the current contribution of private hospitals in Mongolia for the improvement of accessibility of health care and efficiency. Methods: We used mixed research methods. A descriptive analysis of nationally representative hospital admission records from 2013 was followed by semi-structured interviews that were carried out with purposively selected key informants (N = 45), representing the main actors in Mongolia's mixed health system. Results: Private-for-profit hospitals are concentrated in urban areas, where their financial model is most viable. The result is the duplication of private and public inpatient services, both in terms of their geographical location and the range of services delivered. The combination of persistent inpatient-oriented care and perverse financial incentives that privilege admission over outpatient management, have created unnecessary health costs. The engagement of the private sector to improve population health outcomes is constrained by a series of issues of governance, regulation and financing and the failure of the state to manage the private sector as an integral part of its health system planning. Discussions/Conclusion: For a mixed system like in Mongolia, a comprehensive policy and plan which defines the complementary role of private providers to optimize private public service mix is critical in the early stages of the private sector development. It further supports the importance of a system perspective that combines regulation and incentives in consistent policy, rather than an isolated approach to provide regulation. PMID- 28025324 TI - Defining pharmaceutical systems strengthening: concepts to enable measurement. AB - Pharmaceutical products are indispensable for improving health outcomes. An extensive body of work on access to and use of medicines has resulted in an assortment of tools measuring various elements of pharmaceutical systems. Until now however, there has been little attempt to conceptualize a pharmaceutical system as an entity and define its strengthening in a way that allows for measuring systems strengthening. The narrow focus of available tools limits their value in ascertaining which interventions result in stronger, more resilient systems. We sought to address this shortcoming by revisiting the current definitions, frameworks and assessment tools related to pharmaceutical systems. We conducted a comprehensive literature review and consulted with select pharmaceutical experts. On the basis of our review, we propose that a pharmaceutical system consists of all structures, people, resources, processes, and their interactions within the broader health system that aim to ensure equitable and timely access to safe, effective, quality pharmaceutical products and related services that promote their appropriate and cost-effective use to improve health outcomes. We further propose that pharmaceutical systems strengthening is the process of identifying and implementing strategies and actions that achieve coordinated and sustainable improvements in the critical components of a pharmaceutical system to make it more responsive and resilient and to enhance its performance for achieving better health outcomes. Finally, we established that, in addition to system performance and resilience, seven components of the pharmaceutical system are critical for measuring pharmaceutical systems strengthening: pharmaceutical products and related services; policy, laws and governance; regulatory systems; innovation, research and development, manufacturing, and trade; financing; human resources; and information. This work adds clarity to the concept of pharmaceutical systems and their strengthening by proposing holistic definitions on the basis of systems thinking. It provides a practical starting point for measuring the progress of pharmaceutical systems strengthening. PMID- 28025325 TI - Developing a decision support system to link health technology assessment (HTA) reports to the health system policies in Iran. AB - The recent increase of 'Health Technology Assessment' (HTA)-related activities in Iran has necessitated the clarification of policy-making process based on the HTA reports. This study aimed to develop a Decision Support System (DSS) in order to adopt evidence-informed policies regarding health technologies in Iran. The study can be classified as Health Policy and Systems Research. A core panel of seven experts conducted two separate reviews of relevant literature for: 1- Determining the potential technology-related policies. 2- Listing the criteria influencing those policy decisions. The policies and criteria were separately discussed and subsequently rated for appropriateness and necessity during two expert meetings in 2013. In the next step, The 'Discrete Choice Experiment' (DCE) method was employed to develop the DSS for the final technology-related policies. Accordingly, the core panel members independently rated the appropriateness of each policy for 30 virtual technologies based on the random values assigned to all the criteria for each technology. The obtained data for each policy were separately analysed using stepwise regression model, resulting in a minimal set of independent and statistically significant criteria contributing in the experts' judgments about the appropriateness of that policy. The obtained regression coefficients were used as the relative weights of the different levels of the final criteria of any policy statement, shaping the decision support scoring tool for each policy. The study has outlined 64 policy decisions under 7 macro policy areas concerning a health technology. Also, 34 criteria used for making those policy decisions have been organized within a portfolio. DCE, using stepwise regression, resulted in 64 scoring tools shaping the DSS for all HTA related policies. Both the results and methodology of the study may serve as a guide for policy makers (researchers), particularly in low and middle income countries, in developing decision aids for their own context-specific HTA-related policies. PMID- 28025326 TI - Dysfunction of cGMP signalling in photoreceptors by a macular dystrophy-related mutation in the calcium sensor GCAP1. AB - Macular dystrophy leads to progressive loss of central vision and shows symptoms similar to age-related macular degeneration. Genetic screening of patients diagnosed with macular dystrophy disclosed a novel mutation in the GUCA1A gene, namely a c.526C > T substitution leading to the amino acid substitution p.L176F in the guanylate cyclase-activating protein 1 (GCAP1). The same variant was found in three families showing an autosomal dominant mode of inheritance. For a full functional characterization of the L176F mutant we expressed and purified the mutant protein and measured key parameters of its activating properties, its Ca2+/Mg2+-binding, and its Ca2+-induced conformational changes in comparison to the wildtype protein. The mutant was less sensitive to changes in free Ca2+, resulting in a constitutively active form under physiological Ca2+-concentration, showed significantly higher activation rates than the wildtype (90-fold versus 20 fold) and interacted with an higher apparent affinity with its target guanylate cyclase. However, direct Ca2+-binding of the mutant was nearly similar to the wildtype; binding of Mg2+ occurred with higher affinity. We performed molecular dynamics simulations for comparing the Ca2+-saturated inhibiting state of GCAP1 with the Mg2+-bound activating states. The L176F mutant exhibited significantly lower flexibility, when three Ca2+ or two Mg2+ were bound forming probably the structural basis for the modified GCAP1 function. PMID- 28025327 TI - FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination. AB - The Myocyte Enhancer Factor 2 (MEF2) transcription factors suppress an excitatory synapse number by promoting degradation of the synaptic scaffold protein, postsynaptic density protein 95 (PSD-95), a process that is deficient in the mouse model of Fragile X Syndrome, Fmr1 KO. How MEF2 activation results in PSD-95 degradation and why this is defective in Fmr1 KO neurons is unknown. Here we report that MEF2 induces a Protein phosphatase 2A (PP2A)-mediated dephosphorylation of murine double minute-2 (Mdm2), the ubiquitin E3 ligase for PSD-95, which results in nuclear export and synaptic accumulation of Mdm2 as well as PSD-95 degradation and synapse elimination. In Fmr1 KO neurons, Mdm2 is hyperphosphorylated, nuclear localized basally, and unaffected by MEF2 activation, which our data suggest due to an enhanced interaction with Eukaryotic Elongation Factor 1alpha (EF1alpha), whose protein levels are elevated in Fmr1 KO. Expression of a dephosphomimetic of Mdm2 rescues PSD-95 ubiquitination, degradation and synapse elimination in Fmr1 KO neurons. This work reveals detailed mechanisms of synapse elimination in health and a developmental brain disorder. PMID- 28025328 TI - Mutations in BOREALIN cause thyroid dysgenesis. AB - Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN p.R114W. These studies open new avenues in the genetics of TD in humans. PMID- 28025330 TI - Serum calcium and risk of migraine: a Mendelian randomization study. AB - Migraine affects ~14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co heritability analysis, and a two-sample Mendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising >1 million patient entries. Genetic co heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 * 10-13), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 * 10-3). Second, we observed co-heritability (rg = 0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31-2.46, P = 2.5 * 10-4), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biological mechanism, pathways, and clinical implication for risk management. PMID- 28025331 TI - Detailed analysis of inversions predicted between two human genomes: errors, real polymorphisms, and their origin and population distribution. AB - The growing catalogue of structural variants in humans often overlooks inversions as one of the most difficult types of variation to study, even though they affect phenotypic traits in diverse organisms. Here, we have analysed in detail 90 inversions predicted from the comparison of two independently assembled human genomes: the reference genome (NCBI36/HG18) and HuRef. Surprisingly, we found that two thirds of these predictions (62) represent errors either in assembly comparison or in one of the assemblies, including 27 misassembled regions in HG18. Next, we validated 22 of the remaining 28 potential polymorphic inversions using different PCR techniques and characterized their breakpoints and ancestral state. In addition, we determined experimentally the derived allele frequency in Europeans for 17 inversions (DAF = 0.01-0.80), as well as the distribution in 14 worldwide populations for 12 of them based on the 1000 Genomes Project data. Among the validated inversions, nine have inverted repeats (IRs) at their breakpoints, and two show nucleotide variation patterns consistent with a recurrent origin. Conversely, inversions without IRs have a unique origin and almost all of them show deletions or insertions at the breakpoints in the derived allele mediated by microhomology sequences, which highlights the importance of mechanisms like FoSTeS/MMBIR in the generation of complex rearrangements in the human genome. Finally, we found several inversions located within genes and at least one candidate to be positively selected in Africa. Thus, our study emphasizes the importance of careful analysis and validation of large-scale genomic predictions to extract reliable biological conclusions. PMID- 28025332 TI - Transgenic TBK1 mice have features of normal tension glaucoma. AB - Duplication of the TBK1 gene is associated with 1-2% of normal tension glaucoma, a common cause of vision loss and blindness that occurs without grossly abnormal intraocular pressure. We generated a transgenic mouse that has one copy of the human TBK1 gene (native promoter and gene structure) incorporated into the mouse genome (Tg-TBK1). Expression of the TBK1 transgene in the retinae of these mice was demonstrated by real-time PCR. Using immunohistochemistry TBK1 protein was predominantly localized to the ganglion cell layer of the retina, the cell type most affected by glaucoma. More intense TBK1 labelling was detected in the retinal ganglion cells (RGCs) of Tg-TBK1 mice than in wild-type littermates. Tg TBK1 mice exhibit the cardinal sign of glaucoma, a progressive loss of RGCs. Hemizygous Tg-TBK1 mice (with one TBK1 transgene per genome) had a 13% loss of RGCs by 18 months of age (P = 1.5 * 10-8). Homozygous Tg-TBK1 mice had 7.6% fewer RGCs than hemizygous Tg-TBK1 mice and 20% fewer RGCs than wild-type mice (P = 1.9 * 10-5) at 6 months of age. No difference in intraocular pressures was detected between Tg-TBK1 mice and wild-type littermates as they aged (P > 0.05). Tg-TBK1 mice with extra doses of the TBK1 gene recapitulate the phenotype of normal tension glaucoma in human patients with a TBK1 gene duplication. Together, these studies confirm the pathogenicity of the TBK1 gene duplication in human glaucoma and suggest that excess production of TBK1 kinase may have a role in the pathology of glaucoma. PMID- 28025329 TI - Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations. AB - To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 * 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications. PMID- 28025333 TI - Modulation of bilirubin neurotoxicity by the Abcb1 transporter in the Ugt1-/- lethal mouse model of neonatal hyperbilirubinemia. AB - Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown.To this end, we mated Abcb1a/b-/- and Abcc1-/- strains with Ugt1-/- mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1-/- mice survived after temporary phototherapy, all Abcb1a/b-/-/Ugt1-/- mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important.In the cerebellum of Ugt1-/- mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response.We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity. PMID- 28025334 TI - Minimizing proteome redundancy in the UniProt Knowledgebase. AB - Advances in high-throughput sequencing have led to an unprecedented growth in genome sequences being submitted to biological databases. In particular, the sequencing of large numbers of nearly identical bacterial genomes during infection outbreaks and for other large-scale studies has resulted in a high level of redundancy in nucleotide databases and consequently in the UniProt Knowledgebase (UniProtKB). Redundancy negatively impacts on database searches by causing slower searches, an increase in statistical bias and cumbersome result analysis. The redundancy combined with the large data volume increases the computational costs for most reuses of UniProtKB data. All of this poses challenges for effective discovery in this wealth of data. With the continuing development of sequencing technologies, it is clear that finding ways to minimize redundancy is crucial to maintaining UniProt's essential contribution to data interpretation by our users. We have developed a methodology to identify and remove highly redundant proteomes from UniProtKB. The procedure identifies redundant proteomes by performing pairwise alignments of sets of sequences for pairs of proteomes and subsequently, applies graph theory to find dominating sets that provide a set of non-redundant proteomes with a minimal loss of information. This method was implemented for bacteria in mid-2015, resulting in a removal of 50 million proteins in UniProtKB. With every new release, this procedure is used to filter new incoming proteomes, resulting in a more scalable and scientifically valuable growth of UniProtKB.Database URL: http://www.uniprot.org/proteomes/. PMID- 28025335 TI - CaspNeuroD: a knowledgebase of predicted caspase cleavage sites in human proteins related to neurodegenerative diseases. AB - BACKGROUND: A variety of neurodegenerative diseases (NDs) have been associated with deregulated caspase activation that leads to neuronal death. Caspases appear to be involved in the molecular pathology of NDs by directly cleaving important proteins. For instance, several proteins involved in Alzheimer's disease, including beta-amyloid precursor protein (APP) and presenilins, are known to be cleaved by caspases. Therefore, cell death pathway may play a central role in many neurological diseases, and targeting the important proteins that control the cell survival and death may potentially represent a therapeutic approach for chronic neurodegenerative disorders. FINDINGS: We developed CaspNeuroD, a relational database of in silico predicted caspase cleavage sites in human proteins associated with NDs. The prediction has been done on collection of 249 human proteins reported in clinical studies of NDs using the recently published CaspDB Random Forest machine-learning model. This database could be used for identifying new caspase substrates and further our understanding of the caspase mediated substrate cleavage in NDs. CONCLUSION: Our database provides information about potential caspase cleavage sites in a verified set of human proteins involved in NDs. It provides also information about the conservation of cleavage positions in corresponding orthologs, and information about the positions of single nucleotide polymorphisms and posttranslational modifications (PTMs) that may modulate the caspase cleavage efficiency.Database URL: caspdb.sanfordburnham.org/caspneurod.php. PMID- 28025336 TI - Construction of antimicrobial peptide-drug combination networks from scientific literature based on a semi-automated curation workflow. AB - Considerable research efforts are being invested in the development of novel antimicrobial therapies effective against the growing number of multi-drug resistant pathogens. Notably, the combination of different agents is increasingly explored as means to exploit and improve individual agent actions while minimizing microorganism resistance. Although there are several databases on antimicrobial agents, scientific literature is the primary source of information on experimental antimicrobial combination testing. This work presents a semi automated database curation workflow that supports the mining of scientific literature and enables the reconstruction of recently documented antimicrobial combinations. Currently, the database contains data on antimicrobial combinations that have been experimentally tested against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans, which are prominent pathogenic organisms and are well-known for their wide and growing resistance to conventional antimicrobials. Researchers are able to explore the experimental results for a single organism or across organisms. Likewise, researchers may look into indirect network associations and identify new potential combinations to be tested. The database is available without charges.Database URL: http://sing.ei.uvigo.es/antimicrobialCombination/. PMID- 28025337 TI - On-the-fly selection of cell-specific enhancers, genes, miRNAs and proteins across the human body using SlideBase. AB - Genomics consortia have produced large datasets profiling the expression of genes, micro-RNAs, enhancers and more across human tissues or cells. There is a need for intuitive tools to select subsets of such data that is the most relevant for specific studies. To this end, we present SlideBase, a web tool which offers a new way of selecting genes, promoters, enhancers and microRNAs that are preferentially expressed/used in a specified set of cells/tissues, based on the use of interactive sliders. With the help of sliders, SlideBase enables users to define custom expression thresholds for individual cell types/tissues, producing sets of genes, enhancers etc. which satisfy these constraints. Changes in slider settings result in simultaneous changes in the selected sets, updated in real time. SlideBase is linked to major databases from genomics consortia, including FANTOM, GTEx, The Human Protein Atlas and BioGPS.Database URL: http://slidebase.binf.ku.dk. PMID- 28025338 TI - TBro: visualization and management of de novo transcriptomes. AB - RNA sequencing (RNA-seq) has become a powerful tool to understand molecular mechanisms and/or developmental programs. It provides a fast, reliable and cost effective method to access sets of expressed elements in a qualitative and quantitative manner. Especially for non-model organisms and in absence of a reference genome, RNA-seq data is used to reconstruct and quantify transcriptomes at the same time. Even SNPs, InDels, and alternative splicing events are predicted directly from the data without having a reference genome at hand. A key challenge, especially for non-computational personnal, is the management of the resulting datasets, consisting of different data types and formats. Here, we present TBro, a flexible de novo transcriptome browser, tackling this challenge. TBro aggregates sequences, their annotation, expression levels as well as differential testing results. It provides an easy-to-use interface to mine the aggregated data and generate publication-ready visualizations. Additionally, it supports users with an intuitive cart system, that helps collecting and analysing biological meaningful sets of transcripts. TBro's modular architecture allows easy extension of its functionalities in the future. Especially, the integration of new data types such as proteomic quantifications or array-based gene expression data is straightforward. Thus, TBro is a fully featured yet flexible transcriptome browser that supports approaching complex biological questions and enhances collaboration of numerous researchers. DATABASE URL: : tbro.carnivorom.com. PMID- 28025339 TI - iMITEdb: the genome-wide landscape of miniature inverted-repeat transposable elements in insects. AB - Miniature inverted-repeat transposable elements (MITEs) have attracted much attention due to their widespread occurrence and high copy numbers in eukaryotic genomes. However, the systematic knowledge about MITEs in insects and other animals is still lacking. In this study, we identified 6012 MITE families from 98 insect species genomes. Comparison of these MITEs with known MITEs in the NCBI non-redundant database and Repbase showed that 5701(~95%) of 6012 MITE families are novel. The abundance of MITEs varies drastically among different insect species, and significantly correlates with genome size. In general, larger genomes contain more MITEs than small genomes. Furthermore, all identified MITEs were included in a newly constructed database (iMITEdb) (http://gene.cqu.edu.cn/iMITEdb/), which has functions such as browse, search, BLAST and download. Overall, our results not only provide insight on insect MITEs but will also improve assembly and annotation of insect genomes. More importantly, the results presented in this study will promote studies of MITEs function, evolution and application in insects. DATABASE URL: http://gene.cqu.edu.cn/iMITEdb/. PMID- 28025340 TI - Crowd-sourcing and author submission as alternatives to professional curation. AB - Can we decrease the costs of database curation by crowd-sourcing curation work or by offloading curation to publication authors? This perspective considers the significant experience accumulated by the bioinformatics community with these two alternatives to professional curation in the last 20 years; that experience should be carefully considered when formulating new strategies for biological databases. The vast weight of empirical evidence to date suggests that crowd sourced curation is not a successful model for biological databases. Multiple approaches to crowd-sourced curation have been attempted by multiple groups, and extremely low participation rates by 'the crowd' are the overwhelming outcome. The author-curation model shows more promise for boosting curator efficiency. However, its limitations include that the quality of author-submitted annotations is uncertain, the response rate is low (but significant), and to date author curation has involved relatively simple forms of annotation involving one or a few types of data. Furthermore, shifting curation to authors may simply redistribute costs rather than decreasing costs; author curation may in fact increase costs because of the overhead involved in having every curating author learn what professional curators know: curation conventions, curation software and curation procedures. PMID- 28025341 TI - Can we replace curation with information extraction software? AB - Can we use programs for automated or semi-automated information extraction from scientific texts as practical alternatives to professional curation? I show that error rates of current information extraction programs are too high to replace professional curation today. Furthermore, current IEP programs extract single narrow slivers of information, such as individual protein interactions; they cannot extract the large breadth of information extracted by professional curators for databases such as EcoCyc. They also cannot arbitrate among conflicting statements in the literature as curators can. Therefore, funding agencies should not hobble the curation efforts of existing databases on the assumption that a problem that has stymied Artificial Intelligence researchers for more than 60 years will be solved tomorrow. Semi-automated extraction techniques appear to have significantly more potential based on a review of recent tools that enhance curator productivity. But a full cost-benefit analysis for these tools is lacking. Without such analysis it is possible to expend significant effort developing information-extraction tools that automate small parts of the overall curation workflow without achieving a significant decrease in curation costs.Database URL. PMID- 28025342 TI - RiceATM: a platform for identifying the association between rice agronomic traits and miRNA expression. AB - MicroRNAs (miRNAs) are known to play critical roles in plant development and stress-response regulation, and they frequently display multi-targeting characteristics. The control of defined rice phenotypes occurs through multiple genes; however, evidence demonstrating the relationship between agronomic traits and miRNA expression profiles is lacking. In this study, we investigated eight yield-related traits in 187 local rice cultivars and profiled the expression levels of 193 miRNAs in these cultivars using microarray analyses. By integrating the miRBase database, the rice annotation project database, and the miRanda and psRNATarget web servers, we constructed a database (RiceATM) that can be employed to investigate the association between rice agronomic traits and miRNA expression. The functions of this platform include phenotype selection, sample grouping, microarray data pretreatment, statistical analysis and target gene predictions. To demonstrate the utility of RiceATM, we used the database to identify four miRNAs associated with the heading date and validated their expression trends in the cultivars with early or late heading date by real-time PCR. RiceATM is a useful tool for researchers seeking to characterize the role of certain miRNAs for a specific phenotype and discover potential biomarkers for breeding or functional studies.Database URL: http://syslab3.nchu.edu.tw/rice/. PMID- 28025343 TI - Reefgenomics.Org - a repository for marine genomics data. AB - Over the last decade, technological advancements have substantially decreased the cost and time of obtaining large amounts of sequencing data. Paired with the exponentially increased computing power, individual labs are now able to sequence genomes or transcriptomes to investigate biological questions of interest. This has led to a significant increase in available sequence data. Although the bulk of data published in articles are stored in public sequence databases, very often, only raw sequencing data are available; miscellaneous data such as assembled transcriptomes, genome annotations etc. are not easily obtainable through the same means. Here, we introduce our website (http://reefgenomics.org) that aims to centralize genomic and transcriptomic data from marine organisms. Besides providing convenient means to download sequences, we provide (where applicable) a genome browser to explore available genomic features, and a BLAST interface to search through the hosted sequences. Through the interface, multiple datasets can be queried simultaneously, allowing for the retrieval of matching sequences from organisms of interest. The minimalistic, no-frills interface reduces visual clutter, making it convenient for end-users to search and explore processed sequence data. DATABASE URL: http://reefgenomics.org. PMID- 28025344 TI - GeneBase 1.1: a tool to summarize data from NCBI gene datasets and its application to an update of human gene statistics. AB - We release GeneBase 1.1, a local tool with a graphical interface useful for parsing, structuring and indexing data from the National Center for Biotechnology Information (NCBI) Gene data bank. Compared to its predecessor GeneBase (1.0), GeneBase 1.1 now allows dynamic calculation and summarization in terms of median, mean, standard deviation and total for many quantitative parameters associated with genes, gene transcripts and gene features (exons, introns, coding sequences, untranslated regions). GeneBase 1.1 thus offers the opportunity to perform analyses of the main gene structure parameters also following the search for any set of genes with the desired characteristics, allowing unique functionalities not provided by the NCBI Gene itself. In order to show the potential of our tool for local parsing, structuring and dynamic summarizing of publicly available databases for data retrieval, analysis and testing of biological hypotheses, we provide as a sample application a revised set of statistics for human nuclear genes, gene transcripts and gene features. In contrast with previous estimations strongly underestimating the length of human genes, a 'mean' human protein-coding gene is 67 kbp long, has eleven 309 bp long exons and ten 6355 bp long introns. Median, mean and extreme values are provided for many other features offering an updated reference source for human genome studies, data useful to set parameters for bioinformatic tools and interesting clues to the biomedical meaning of the gene features themselves.Database URL: http://apollo11.isto.unibo.it/software/. PMID- 28025345 TI - Large-scale inference of gene function through phylogenetic annotation of Gene Ontology terms: case study of the apoptosis and autophagy cellular processes. AB - We previously reported a paradigm for large-scale phylogenomic analysis of gene families that takes advantage of the large corpus of experimentally supported Gene Ontology (GO) annotations. This 'GO Phylogenetic Annotation' approach integrates GO annotations from evolutionarily related genes across ~100 different organisms in the context of a gene family tree, in which curators build an explicit model of the evolution of gene functions. GO Phylogenetic Annotation models the gain and loss of functions in a gene family tree, which is used to infer the functions of uncharacterized (or incompletely characterized) gene products, even for human proteins that are relatively well studied. Here, we report our results from applying this paradigm to two well-characterized cellular processes, apoptosis and autophagy. This revealed several important observations with respect to GO annotations and how they can be used for function inference. Notably, we applied only a small fraction of the experimentally supported GO annotations to infer function in other family members. The majority of other annotations describe indirect effects, phenotypes or results from high throughput experiments. In addition, we show here how feedback from phylogenetic annotation leads to significant improvements in the PANTHER trees, the GO annotations and GO itself. Thus GO phylogenetic annotation both increases the quantity and improves the accuracy of the GO annotations provided to the research community. We expect these phylogenetically based annotations to be of broad use in gene enrichment analysis as well as other applications of GO annotations.Database URL: http://amigo.geneontology.org/amigo. PMID- 28025346 TI - The importance of digitized biocollections as a source of trait data and a new VertNet resource. AB - For vast areas of the globe and large parts of the tree of life, data needed to inform trait diversity is incomplete. Such trait data, when fully assembled, however, form the link between the evolutionary history of organisms, their assembly into communities, and the nature and functioning of ecosystems. Recent efforts to close data gaps have focused on collating trait-by-species databases, which only provide species-level, aggregated value ranges for traits of interest and often lack the direct observations on which those ranges are based. Perhaps under-appreciated is that digitized biocollection records collectively contain a vast trove of trait data measured directly from individuals, but this content remains hidden and highly heterogeneous, impeding discoverability and use. We developed and deployed a suite of openly accessible software tools in order to collate a full set of trait descriptions and extract two key traits, body length and mass, from >18 million specimen records in VertNet, a global biodiversity data publisher and aggregator. We tested success rate of these tools against hand checked validation data sets and characterized quality and quantity. A post processing toolkit was developed to standardize and harmonize data sets, and to integrate this improved content into VertNet for broadest reuse. The result of this work was to add more than 1.5 million harmonized measurements on vertebrate body mass and length directly to specimen records. Rates of false positives and negatives for extracted data were extremely low. We also created new tools for filtering, querying, and assembling this research-ready vertebrate trait content for view and download. Our work has yielded a novel database and platform for harmonized trait content that will grow as tools introduced here become part of publication workflows. We close by noting how this effort extends to new communities already developing similar digitized content.Database URL: http://portal.vertnet.org/search?advanced=1. PMID- 28025347 TI - HEDD: the human epigenetic drug database. AB - Epigenetic drugs are chemical compounds that target disordered post-translational modification of histone proteins and DNA through enzymes, and the recognition of these changes by adaptor proteins. Epigenetic drug-related experimental data such as gene expression probed by high-throughput sequencing, co-crystal structure probed by X-RAY diffraction and binding constants probed by bio-assay have become widely available. The mining and integration of multiple kinds of data can be beneficial to drug discovery and drug repurposing. HEMD and other epigenetic databases store comprehensively epigenetic data where users can acquire segmental information of epigenetic drugs. However, some data types such as high-throughput datasets are not provide by these databases and they do not support flexible queries for epigenetic drug-related experimental data. Therefore, in reference to HEMD and other epigenetic databases, we developed a relatively comprehensive database for human epigenetic drugs. The human epigenetic drug database (HEDD) focuses on the storage and integration of epigenetic drug datasets obtained from laboratory experiments and manually curated information. The latest release of HEDD incorporates five kinds of datasets: (i) drug, (ii) target, (iii) disease, (vi) high-throughput and (v) complex. In order to facilitate data extraction, flexible search options were built in HEDD, which allowed an unlimited condition query for specific kinds of datasets using drug names, diseases and experiment types.Database URL: http://hedds.org/. PMID- 28025348 TI - Pressing needs of biomedical text mining in biocuration and beyond: opportunities and challenges. AB - Text mining in the biomedical sciences is rapidly transitioning from small-scale evaluation to large-scale application. In this article, we argue that text-mining technologies have become essential tools in real-world biomedical research. We describe four large scale applications of text mining, as showcased during a recent panel discussion at the BioCreative V Challenge Workshop. We draw on these applications as case studies to characterize common requirements for successfully applying text-mining techniques to practical biocuration needs. We note that system 'accuracy' remains a challenge and identify several additional common difficulties and potential research directions including (i) the 'scalability' issue due to the increasing need of mining information from millions of full-text articles, (ii) the 'interoperability' issue of integrating various text-mining systems into existing curation workflows and (iii) the 'reusability' issue on the difficulty of applying trained systems to text genres that are not seen previously during development. We then describe related efforts within the text mining community, with a special focus on the BioCreative series of challenge workshops. We believe that focusing on the near-term challenges identified in this work will amplify the opportunities afforded by the continued adoption of text-mining tools. Finally, in order to sustain the curation ecosystem and have text-mining systems adopted for practical benefits, we call for increased collaboration between text-mining researchers and various stakeholders, including researchers, publishers and biocurators. PMID- 28025349 TI - viruSITE-integrated database for viral genomics. AB - Viruses are the most abundant biological entities and the reservoir of most of the genetic diversity in the Earth's biosphere. Viral genomes are very diverse, generally short in length and compared to other organisms carry only few genes. viruSITE is a novel database which brings together high-value information compiled from various resources. viruSITE covers the whole universe of viruses and focuses on viral genomes, genes and proteins. The database contains information on virus taxonomy, host range, genome features, sequential relatedness as well as the properties and functions of viral genes and proteins. All entries in the database are linked to numerous information resources. The above-mentioned features make viruSITE a comprehensive knowledge hub in the field of viral genomics.The web interface of the database was designed so as to offer an easy-to-navigate, intuitive and user-friendly environment. It provides sophisticated text searching and a taxonomy-based browsing system. viruSITE also allows for an alternative approach based on sequence search. A proprietary genome browser generates a graphical representation of viral genomes. In addition to retrieving and visualising data, users can perform comparative genomics analyses using a variety of tools.Database URL: http://www.virusite.org/. PMID- 28025350 TI - "Care" Without Compassion-The Eighth Social Sin? PMID- 28025351 TI - Immediate Adverse Events in Interventional Pain Procedures: A Multi-Institutional Study. AB - SETTING: Interventional procedures directed toward sources of pain in the axial and appendicular musculoskeletal system are performed with increasing frequency. Despite the presence of evidence-based guidelines for such procedures, there are wide variations in practice. Case reports of serious complications such as spinal cord infarction or infection from spine injections lack appropriate context and create a misleading view of the risks of appropriately performed interventional pain procedures. OBJECTIVE: To evaluate adverse event rate for interventional spine procedures performed at three academic interventional spine practices. METHODS: Quality assurance databases at three academic interventional pain management practices that utilize evidence-based guidelines [1] were interrogated for immediate complications from interventional pain procedures. Review of the electronic medical record verified or refuted the occurrence of a complication. Same-day emergency department transfers or visits were also identified by a records search. RESULTS: Immediate complication data were available for 26,061 consecutive procedures. A radiology practice performed 19,170 epidural steroid (primarily transforaminal), facet, sacroiliac, and trigger point injections (2006 2013). A physiatry practice performed 6,190 spine interventions (2004-2009). A second physiatry practice performed 701 spine procedures (2009-2010). There were no major complications (permanent neurologic deficit or clinically significant bleeding [e.g., epidural hematoma]) with any procedure. Overall complication rate was 1.9% (493/26,061). Vasovagal reactions were the most frequent event (1.1%). Nineteen patients (<0.1%) were transferred to emergency departments for: allergic reactions, chest pain, symptomatic hypertension, and a vasovagal reaction. CONCLUSION: This study demonstrates that interventional pain procedures are safely performed with extremely low immediate adverse event rates when evidence based guidelines are observed. PMID- 28025352 TI - Chronic Whiplash Associated Disorders (WAD): Responses to Nerve Blocks of Cervical Zygapophyseal Joints. AB - OBJECTIVE: This study explores the prevalence of facet joint pain in chronic Whiplash Associated Disorder (WAD). DESIGN: Forty-seven patients with chronic WAD were scheduled for medial branch blocks of the cervical spine. METHODS: The patient's localization of the pain together with established pain maps guided to the first level of zygapophyseal joint to be tested. The joint was anesthetized by injecting bupivacaine (0.5 ml; 5 mg/ml) to the medial branches of the cervical dorsal rami above and below the joint. If a positive response was noted, the schedule continued with a double-blinded sequence with a placebo (saline) and bupivacaine. If a negative response was noted, other joint levels were anesthetized until all joints from C2 to C7 were tested. The responses were assessed using a visual analog scale (VAS) in a predefined protocol.The study was carried through with a definition of a positive response to a diagnostic block as a VAS decrease >=50% compared with baseline during a minimum of 3 hours after the block. All other responses were regarded as negative. The data were also analyzed using a definition of a positive response as a VAS decrease >=80%, and figures from this analysis are presented as the main result of the study. RESULTS: The study yielded 29% true positive responders, 60% non-responders, and 11% placebo responders. CONCLUSIONS: A substantial amount of patients with chronic WAD have their persistent pain emanating from cervical zygapophyseal joints. PMID- 28025353 TI - Imaging Determinants of Clinical Effectiveness of Lumbar Transforaminal Epidural Steroid Injections. AB - OBJECTIVE: To examine associations between imaging characteristics of compressive lesions and patient outcomes after lumbar transforaminal epidural steroid injections (TFESIs) stratified by steroid formulation (solution versus suspension). DESIGN/SUBJECTS: Retrospective observational study, academic radiology practice. A 516-patient sample was selected from 2,634 consecutive patients receiving lumbar TFESI for radicular pain. METHODS: The advanced imaging study(s) preceding sampled TFESI were reviewed. Compressive lesions were described by a) nature of the lesion [disc herniation, fixed stenosis, synovial cyst, epidural fibrosis, no lesion] b) degree of neural compression [4 part scale], and c) presence of a tandem lesion. Associations between 2-month categorical outcomes (responder rates for pain, functional recovery) and imaging characteristics, stratified by steroid formulation, were examined with chi squared tests of categorical outcomes and multivariable logistic regression models. RESULTS: Disc herniation patients had more responders for functional recovery than patients with fixed lesions (54% versus 38%, P = 0.01). Patients with fixed lesions receiving steroid solution (dexamethasone) had more responders for pain relief, with a similar trend for functional recovery, than patients receiving suspensions (59% versus 40%, P = 0.01). Outcomes for patients with fixed lesions treated with dexamethasone were not statistically different from those for disc herniation patients. Patients with single compressive lesions had more responders than those with tandem lesions (55% versus 41%, P = 0.03). CONCLUSION: In the entire sample, outcomes for disc herniations were more favorable than for fixed lesions. However, fixed lesions treated with dexamethasone had outcomes indistinguishable from disc herniations. Single lesions had better outcomes than tandem lesions. PMID- 28025354 TI - The Effectiveness and Risks of Non-Image-Guided Lumbar Interlaminar Epidural Steroid Injections: A Systematic Review with Comprehensive Analysis of the Published Data. AB - OBJECTIVE: To determine the effectiveness and risks of non-image-guided lumbar interlaminar epidural steroid injections. DESIGN: Systematic review. INTERVENTIONS: Three reviewers with formal training and certification in evidence based medicine searched the literature on non-image-guided lumbar interlaminar epidural steroid injections. A larger team of seven reviewers independently assessed the methodology of studies found and appraised the quality of the evidence presented. OUTCOME MEASURES: The primary outcome assessed was pain relief. Other outcomes such as functional improvement, reduction in surgery rate, decreased use of opioids, and complications were noted, if reported. The evidence was appraised in accordance with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system of evaluating evidence. RESULTS: The searches yielded 92 primary publications addressing non-image-guided lumbar interlaminar epidural steroid injections. The evidence supporting the effectiveness of these injections for pain relief and functional improvement in patients with lumbar radicular pain due to disc herniation or neurogenic claudication secondary to lumbar spinal stenosis is limited. This procedure may provide short-term benefit in the first 3-6 weeks. The small number of case reports on significant risks suggests these injections are relatively safe. In accordance with GRADE, the quality of evidence is very low. CONCLUSIONS: In patients with lumbar radicular pain secondary to disc herniation or neurogenic claudication due to spinal stenosis, non-image-guided lumbar interlaminar epidural steroid injections appear to have clinical effectiveness limited to short-term pain relief. Therefore, in a contemporary medical practice, these procedures should be restricted to the rare settings where fluoroscopy is not available. PMID- 28025355 TI - Does a Brief Educational Session Produce Positive Change for Individuals Waiting for Tertiary Chronic Pain Services? AB - OBJECTIVES: To examine: 1) whether a single brief pre-clinic educational session improved the well-being and quality of life of individuals entering the wait-list for a tertiary chronic pain (CP) service; and 2) the impact of waiting for services on these outcomes. METHODS: Participants were 346 adults, with basic English skills and non-urgent triage codes, who were recruited on referral to a tertiary Australian metropolitan CP unit. Participants were randomized across two conditions: "treatment as usual" (normal wait-list) and "experimental" (normal wait-list plus a 3-hour CP educational session). The educational session encouraged self-management and life engagement despite pain. Multiple outcomes (pain acceptance, pain-related interference, psychological distress, health care utilization [frequency, types], quality of life, health knowledge/beliefs), as well as pain severity and symptom exaggeration, were assessed at intake and again at 2 weeks and 6 months post-educational session (or equivalent for the wait-list group). RESULTS: Satisfaction with the educational session was moderate-to-high, but attendance was not associated with improved outcomes. At 2 weeks, all study participants reported significant improvements in pain acceptance (willingness, overall acceptance), health care utilization (frequency) and quality of life (physical), which were maintained/enhanced at 6 months. Use of psychological and physical therapies increased significantly by 6 months. There was no functional deterioration while wait-listed. CONCLUSIONS: Attending a brief pre-clinic education session did not improve function. There was no deterioration in wait listed participants who agreed to be involved in research and who completed study measures at 2 and 6 months, but referral was associated with short-term functional improvements. This is the first study to link positive change with referral to, rather than treatment by, a tertiary CP service. PMID- 28025356 TI - Graded Activity for Older Adults with Chronic Low Back Pain: Program Development and Mixed Methods Feasibility Cohort Study. AB - BACKGROUND: Persistent pain is highly prevalent in older adults and can lead to functional limitations in activities of daily living, and to psychosocial distress. There is a lack of established active therapy programs, especially for older adults with chronic pain. OBJECTIVES: To develop a graded activity program and to evaluate its feasibility within a pilot study. DESIGN: Phase I/phase II trial of a complex intervention. A mixed methods design was chosen to evaluate the feasibility, acceptability, and preliminary evidence of effectiveness. SUBJECTS AND SETTING: Several experts participated in the program development. Sixteen community-dwelling older adults (73.9 +/- 5.9 years on average) with chronic low back pain and three primary care physical therapists attempted the program. METHODS: Guided semi-structured interviews were conducted with all patients and therapists and used a content-analytic approach. Measurements of self-rated functional status (HFAQ), average pain (NRS), falls self-efficacy (FES I), and catastrophizing and avoidance beliefs (CAS-D 65+) were applied at baseline and after the intervention. RESULTS: The interviews revealed high acceptance, satisfaction, and practicality. Besides improvements in function and pain, patients mentioned more positive attitudes towards pain, activity, and self confidence. There was a clinically relevant increase in physical function by 20.3%, a decrease in pain intensity, and a reduction in catastrophizing and avoidance behavior. CONCLUSION: This graded activity program demonstrated feasibility and high acceptance in aged individuals and therapists. Future studies with larger samples must confirm effectiveness. The principles also appear applicable to other chronic pain conditions. The program could easily be implemented in routine primary care. PMID- 28025357 TI - Deconstructing Chronic Low Back Pain in the Older Adult-Step-by-Step Evidence and Expert-Based Recommendations for Evaluation and Treatment: Part XII: Leg Length Discrepancy. AB - OBJECTIVE: To present the last in a 12-part series designed to deconstruct chronic low back pain (CLBP) in older adults. This article focuses on leg length discrepancy (LLD) and presents an algorithm outlining approaches to diagnosis and management of LLD in older adults, along with a representative clinical case. METHODS : Using a modified Delphi approach, the LLD evaluation and treatment algorithm was developed by a multidisciplinary expert panel representing expertise in physical therapy, geriatric medicine, and physical medicine and rehabilitation. The materials were subsequently refined through an iterative process of input from a primary care provider panel comprised of VA and non-VA providers. The clinical case was taken from one of the authors. RESULTS : We present an algorithm and illustrative clinical case to help guide the care of older adults with LLD, which can be an important contributor to CLBP. Firstline assessment includes referral to physical therapy or orthopedics, depending on the context of the LLD. A variety of nonsurgical interventions may ensue depending on the etiology of the LLD, including shoe inserts, customized shoes, manual therapy, or a combination. CONCLUSIONS : To promote a patient-centered approach, providers should consider evaluating for leg length discrepancy when treating older adults with CLBP to help diminish pain and disability. PMID- 28025358 TI - Deconstructing Chronic Low Back Pain in Older Adults: Summary Recommendations. PMID- 28025359 TI - How Do Patients with Chronic Pain Benefit from a Peer-Supported Pain Self Management Intervention? A Qualitative Investigation. AB - OBJECTIVE: Peer support is a novel and under-studied approach to the management of chronic pain. This study's purpose was to uncover the elements of a peer supported self-management intervention that are perceived by participants as essential to achieving positive changes. DESIGN: Qualitative, semi-structured interviews. METHODS: Veterans and veteran peer coaches who participated in a pilot study of peer support Improving Pain using Peer-Reinforced Self-Management Strategies (IMPPRESS, NCT01748227) took part in qualitative semi-structured interviews after completing the 4-month intervention. Questions were designed to facilitate understanding of how participants experienced the intervention. An immersion/crystallization approach was used to analyze data. RESULTS: All 26 peer coaches and patients who completed the intervention were interviewed. Qualitative analysis revealed three elements of IMPPRESS that peer coaches and patients believed conferred benefit: 1) making interpersonal connections; 2) providing/receiving encouragement and support; and 3) facilitating the use of pain self-management strategies. CONCLUSIONS: Peer support represents a promising approach to chronic pain management that merits further study. The current study helps to identify intervention elements perceived by participants to be important in achieving positive results. Understanding how peer support may benefit patients is essential to optimize the effectiveness of peer support interventions and increase the implementation potential of peer-supported pain self-management into clinical practice. PMID- 28025360 TI - Patterns of Cerebral Blood Flow Modulation During Painful Stimulation in Fibromyalgia: A Transcranial Doppler Sonography Study. AB - OBJECTIVE: This study analyzed the temporal dynamics of cerebral blood flow (CBF) modulations, during painful stimulation in fibromyalgia syndrome (FMS), using functional transcranial Doppler sonography. METHOD: Blood flow velocities were recorded bilaterally in the anterior (ACA) and middle (MCA) cerebral arteries of 24 FMS patients and 20 healthy individuals during exposure to painful pressure stimulation. Participants were presented with two stimulation blocks: a) fixed pressure (2.4 kg) and b) stimulation pressure, individually calibrated to produce equal subjective and moderate pain intensity in all participants. RESULTS: A complex pattern of CBF modulations arose, comprising four main components: an anticipatory increase before stimulation onset, an early increase, a transient decrease to baseline or below, and a final increase. Group differences were observed in all components. The anticipatory component only arose in FMS patients, specifically in the ACA. Patients exhibited a greater early CBF increase under the fixed pressure condition, predominantly in the right ACA. A stronger CBF decrease after the early component was observed in patients during the equal pain condition, in the ACA and MCA. Significant associations were found between clinical pain severity and CBF responses in the MCA. CONCLUSIONS: The results demonstrate that acute pain processing is associated with a complex pattern of CBF modulation, where FMS patients exhibited alterations in all phases of the response. The aberrances may be ascribed to psychophysiological phenomena, including central nervous nociceptive sensitization and protective-defensive reflex mechanisms. The anticipatory CBF response in patients may relate to various cognitive, emotional, and behavioral mechanisms involved in pain chronification. PMID- 28025361 TI - Drug Overdose: Differing Risk Models for Women and Men among Opioid Users with Non-Cancer Pain. AB - OBJECTIVE: To examine risk factors for drug overdose by sex reflecting differing patterns of opioid and other drug use. DESIGN: National privately insured cohort. SUBJECTS: 206,869 subjects filling >=2 opioid prescriptions from January 2009 through July 2012. METHODS: Sex-specific prediction models for future drug overdose developed and validated using variables measured within 6 months after starting opioids: demographics, substance use, comorbidities, opioid dose, and psychoactive drugs. Logistic regression and split-sample validation were used. RESULTS: Area under the receiver operating curves (AUCs) for both sex-specific risk models (0.80) were higher (P < 0.001) than for daily opioid dose alone. Risk factors for drug overdose were similar by sex but effects differed. For both sexes, substance use was the strongest predictor but the adjusted odds ratio (AOR) [95% CI] was 5.95 [4.33, 8.06] for women vs. 4.69 [3.24, 6.68] for men. AORs for daily opioid dose rose monotonically in men to 2.42 [1.76, 3.28] for high vs. low dose but were non-monotonic in women with 1.79 [1.35, 2.35] for high dose. AOR for 1-60 days of antidepressants vs. none was significant only in men (1.98 [1.32, 2.9]). AOR for benzodiazepine use was higher in men than women (2.75 vs 2.35, respectively). Zolpidem use was significant only in women. AUCs for sex specific models were lower for the opposite sex and significantly lower for the men's model in the women's derivation dataset. CONCLUSIONS: These models reveal similar risk factors by sex for drug overdose in opioid users but significant differences in effects that, if validated in other cohorts, may inform differing risk management strategies. PMID- 28025362 TI - Development and Preliminary Evaluation of an Integrated Cognitive-Behavior Treatment for Chronic Pain and Substance Use Disorder in Patients with the Hepatitis C Virus. AB - OBJECTIVE: Individuals with the hepatitis C virus (HCV) have high rates of both chronic pain and substance use disorder (SUD). Despite high comorbidity, there are limited data available on effective methods of treatment for co-occurring chronic pain and SUD. In this study, we sought to develop and conduct preliminary testing of an integrated cognitive-behavior therapy (CBT) for chronic pain and SUD in patients with HCV. DESIGN: Descriptive, including pretreatment, posttreatment, and follow-up testing. SETTING AND PATIENTS: Outpatient clinic as part of one VA Medical Center. PARTICIPANTS: Veterans with chronic pain, SUD, and HCV. INTERVENTION: Eight-session integrated group CBT for chronic pain and SUD in patients with HCV. METHODS: Participants completed standardized measures of pain, function, depression severity, and alcohol and substance use at baseline, post treatment, and 3-month follow-up. RESULTS: Generalized estimating equations identified improvements in pain interference, reducing cravings for alcohol and other substances, and decreasing past-month alcohol and substance use. The proportion of participants who met diagnostic criteria for current SUD demonstrated a four-fold decrease over the course of the study from 24% at baseline to 15% at post-treatment and 6% at 3-month follow-up. On response to a global impression of change, 94% of participants noted improvement from baseline. CONCLUSIONS: Results from this pilot study suggest that a customized CBT for patients with both chronic pain and SUD (CBT-cp.sud) may be beneficial in improving important pain and addiction-related outcomes in patients with HCV. Larger scale investigations of this intervention appear warranted. PMID- 28025363 TI - National Action Plan for Adverse Drug Event Prevention: Recommendations for Safer Outpatient Opioid Use. AB - INTRODUCTION: Adverse drug events (ADEs) have been highlighted as a major patient safety and public health challenge by the National Action Plan for Adverse Drug Event Prevention (ADE Action Plan), which was released by the Office of Disease Prevention and Health Promotion (ODPHP) in August 2014. The ADE Action Plan focuses on surveillance, evidence-based prevention, incentives, and oversights, additional research needs as well as possible measures and metrics to track progress of ADE prevention within three drug classes: anticoagulants, diabetes agents, and opioids.Objectives and Recommendations. With outpatient opioid prescriptions being a great concern among many healthcare providers, this article focuses on recommendations from the ADE Action Plan to help guide safer opioid use in healthcare delivery settings. Its aim is to discuss current federal methods in place to prevent opioid ADEs while also providing evidence to encourage providers and hospitals to innovate new systems and practices to increase prevention. PMID- 28025364 TI - "Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models. AB - OBJECTIVE: "Placebo effects" in analgesic medication trials for chronic pain are pervasive; however, little is known regarding mechanisms or factors that may influence the presence or magnitude of these effects. Our objective is to consider elements of the placebo response in the context of two pain models using a "single-blind placebo lead-in" design (SBPLI). METHODS: As part of two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. We examined whether gender and/or diagnosis affected placebo responses as observed in changes in patient self reported pain, depressive and pain anxiety symptoms. We also evaluated the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance). RESULTS: VAS Pain Intensity (Now) values decreased significantly during the SBPLI for the sample as a whole, but the effects appeared stronger among LBP subjects. CES-D short form values (depressive symptoms) did not decrease significantly during the SBPLI for the sample as a whole, but some placebo effects appeared to emerge for women in the KOA group. PASS values (pain anxiety symptoms) decreased significantly, albeit mildly, during the SBPLI for the sample as a whole.Stair Climb (time) revealed no significant SBPLI effects. Bend Forward to Floor (ROM) increased significantly at the end of the SBPLI period for the sample as a whole, but the effects appeared stronger among KOA subjects. Sit to Stand Repetitions increased during the SBPLI for the sample as a whole. Treadmill Distance did not change significantly from Visit 1 to Visit 2; however, a significant Sex difference for the KOA group was found such that women showed greater Treadmill Distance at Visit 2. CONCLUSION: Placebo effects emerged across psychometric and performance-based measures, indicating the pervasiveness of this phenomenon. In this design, diagnostic and (to a lesser extent) gender categories differentials were observed during the placebo period. The SBPLI design may prove not only a robust method in studying the placebo phenomena, but also as a design element to mitigate some aspects of the placebo response in clinical trials. PMID- 28025365 TI - Spinal Cord Stimulation Provides Pain Relief with Improved Psychosocial Function: Results from EMP3OWER. AB - OBJECTIVE: The EMP3OWERTM study evaluated spinal cord stimulation (SCS) safety and efficacy and the associated changes in psychosocial and functional outcomes. METHODS: Upon informed consent and IRB approval, 620 eligible subjects were enrolled prior to SCS trial evaluation and were assessed at baseline, 3, 6 and 12 months post-implant. Patient-reported pain relief (PRP), numerical rating scale (NRS), satisfaction, quality of life (QOL), and pain disability index (PDI) were assessed at all follow-up visits while the pain catastrophizing scale (PCS), short form-36 (SF-36), short form-McGill pain questionnaire version 2 (SF-MPQ-2), and the state-trait anxiety inventory (STAI) were assessed at the 6- and 12-month follow-up visits. Device and/or procedure-related adverse events were also recorded and reported. Subjects reporting a PRP >= 50% were considered responders. Repeated measures analysis of variance (RMANOVA) examined the changes across time for all continuous measures. RESULTS: A total of 401 (71%) subjects received a permanent implant. Mean (+/-SD) patient-reported pain relief was 59.3% (+/-26.2), 59.2% (+/-28.9), and 58.2% (+/-32.0) at 3, 6, and 12 months, respectively. A majority of enrolled subjects were responders at 3 (75.5%), 6 (74.7%), and 12 months (69.7%). RMANOVA revealed a statistically significant change for NRS, PCS, PDI, SF-36, SF-MPQ-2, and STAI scores. At 3 months, the majority of subjects (85.7%) were either very satisfied or satisfied with their device, with similar results at 6 and 12 months. At 3 months, the majority of subjects (73.3%) reported greatly improved or improved QOL with similar results at 6 and 12 months. CONCLUSIONS: Spinal cord stimulation provided pain relief and significant improvement of patient psychological and functional outcome measures. PMID- 28025366 TI - High-Frequency Spinal Cord Stimulation for Chronic Pain: Pre-Clinical Overview and Systematic Review of Controlled Trials. AB - OBJECTIVE: To assess the evidence base for high-frequency spinal cord stimulation (HFSCS). HFSCS has the potential to provide paresthesia-free pain relief for patients with chronic pain, in contrast to conventional spinal cord stimulation, which produces distracting and potentially unpleasant paresthesias. DESIGN: A systematic review following standard methodological guidelines (Prospero #CRD42015029215). METHODS: We searched PubMed to March 14, 2016 without language restriction and hand-checked reference lists. Two authors independently performed study selection, bias evaluations, and data extraction. The pre-clinical review selected studies focusing on the mechanism and non-human experience with HFSCS. Clinically, any prospective study of adults using HFSCS (>= 1000 Hz) was included. RESULTS: Pre-clinical studies have characterized many aspects underlying the mechanism of HFSCS. For the clinical systematic review, eight trials (236 participants randomized or 160 followed prospectively) met inclusion criteria. All trials of HFSCS focused on patients with chronic low back pain with one exception, which included patients with chronic migraine. All but one trial documented funding by industry. Performance bias due to unmasked participants, physicians, and outcome assessors limited the quality of all but one study. CONCLUSIONS: Significant growth in the preclinical and clinical evidence base for HFSCS suggests that HFSCS may differ from conventional SCS in mechanism of action and efficacy of treatment, respectively. Addressing current knowledge gaps in clinical evidence will require standardization in trial reporting and leveraging the paresthesia-free characteristic of HFSCS to enable masking in high-quality randomized controlled trials. PMID- 28025367 TI - Phenotypic Variation in Complex Regional Pain Syndrome: Comparison Between Presentation in Knee Alone or in Ankle/Foot. AB - OBJECTIVE: To compare the phenotypes of patients with complex regional pain syndrome (CRPS) of the knee to those with CRPS of the ankle/foot. SETTING: A retrospective study. SUBJECTS: Patients with CRPS of the knee and patients with CRPS of the ankle/foot. METHODS: We used electronic patient databases to identify patients with CRPS of the knee and patients with CRPS of the ankle/foot. The following variables were recorded: age, gender, duration of complaints, initial injury, and symptoms and signs. Frequency distributions and statistical significant differences between the groups were determined. RESULTS: Included were 50 patients with CRPS of the knee and 64 patients with CRPS of the ankle/foot. These patients were all diagnosed with CRPS according to the criteria used at the time of diagnosis. No significant differences were found in demographic characteristics. A few symptoms and signs appeared to be proportionally more prevalent in patients with CRPS of the ankle/foot. However, patients with CRPS of the knee suffered significantly longer from the disease than patients with CRPS of the ankle/foot. CONCLUSIONS: Some signs and symptoms appeared to be statistically significantly more prevalent in CRPS of the ankle/foot than in CRPS confined to the knee. We conclude that the phenotypes of CRPS confined to the knee and CRPS of the ankle/foot are comparable, but not identical. This can be a reason why CRPS in patients with pain of the knee, that is disproportionate to the initial trauma, is sometimes not recognized. PMID- 28025368 TI - Analysis of Common Single Nucleotide Polymorphisms in Complex Regional Pain Syndrome: Genome Wide Association Study Approach and Pooled DNA Strategy. AB - OBJECTIVE: The objective of this study was to use a genome-wide association (GWAS) approach and pooled DNA strategy to search for new genomic loci associated with complex regional pain syndrome (CRPS). DESIGN: The study cohort consisted of 230 patients with established diagnosis of CRPS. The control group consisted of 230 age- and gender-matched subjects without chronic pain. We tested the association of common single nucleotide polymorphisms (SNPs), genotyped using a high-density microarray platform, with CRPS phenotype. This was followed by individual genotyping of the most significant SNPs identified in the microarray genomic scan, in both original discovery (N = 115) and independent verification (N = 115) groups of patients with CRPS, as well as in the appropriate matched control subjects. RESULTS: The results of our study provide no support for the initial hypothesis of the existence of an association between any investigated genomic targets (including GWAS for all genomic loci available on the microarray, and focused scan of the HLA locus on chromosome 6) and CRPS phenotype. CONCLUSIONS: Despite the fact that we interrogated about 83% of all of common SNPs in the human genome, we did not find evidence that any of the investigated common SNPs may be associated with CRPS phenotype. PMID- 28025369 TI - Incidence of Complex Regional Pain Syndrome I Following Foot and Ankle Fractures Using the Budapest Criteria. AB - OBJECTIVE : Fractures are a well-recognized inciting event in the development of complex regional pain syndrome. This study aimed to prospectively determine the incidence of complex regional pain syndrome following foot and ankle fractures. METHODS : A prospective study was conducted of patients presenting to two metropolitan hospitals with plain radiograph diagnosis of fractures to the foot or ankle. Patients were initially screened by phone 3 months after injury using the validated International Association for the Study of Pain Budapest criteria. Patients who fulfilled the screening criteria were then physically examined by a pain specialist to assess clinical signs as part of the Budapest criteria. RESULTS : A total of 306 consecutive eligible patients were included. One hundred and ten patients reported at least one symptom of complex regional pain syndrome; however, only three fulfilled the minimum requirements to necessitate clinical review. Of these three, only one patient fulfilled the combination of symptom and sign criteria for a positive diagnosis according to the validated Budapest criteria. The incidence of complex regional pain syndrome following foot and ankle fracture in this study was 0.3%. CONCLUSION : Although many patients may experience vasomotor, sensory, and sudomotor disturbance following a fracture to the foot and ankle, the observed incidence of complex regional pain syndrome using a prospectively collected validated criteria is significantly lower than previously published. PMID- 28025370 TI - Prognosis After Surgical Treatment of Trigeminal Neuropathy with a PGA-c Tube: Report of 10 Cases. AB - OBJECTIVE: Although surgery using a polyglycolic acid-collagen (PGA-c) tube is effective for peripheral nerve injury-induced chronic hand pain, it has not been applied to trigeminal nerve lesions because of the difficult approach. We used a PGA-c tube during surgery for trigeminal neuropathy and evaluated its prognosis based on the outcomes. DESIGN: Case report. SETTING AND PATIENTS: In the dental anesthesia division of a university hospital, 11 patients with severe dysesthesia underwent surgical repair of a damaged lingual nerve (LN) or inferior alveolar nerve (IAN). One patient was lost to follow-up. Changes in quantitative sensory testing (QST) and the presence of dysesthesia as a treatment outcome were compared preoperatively and postoperatively in 10 patients. Two surgical treatments, bridging or encircling peripheral nerves, were applied. Bridging of both stumps was selected when neurotmesis was detected or the nerve was lacerated during surgery (N = 4). Otherwise, a longitudinal PGA-c tube was used to encircle the lesion (N = 6). Outcomes were evaluated 2 months to 8 years postoperatively. RESULTS: Both methods improved the patients' condition based on QST results (brush stroke perception, mechanical touch threshold, sensitivity to cold/hot stimuli). Preoperative allodynia or dysesthesia was resolved in six patients and greatly reduced in four. Two patients (one with inflammation-induced pain, one with implant-related pain) developed prolonged postoperative allodynia requiring pain-relief medication. CONCLUSIONS: Use of a PGA-c tube for surgical treatment of intractable pain due to LN or IAN neuropathy helps alleviate sensory impairment. The possibility of new dysesthesias emerging postoperatively, however, should be noted. PMID- 28025371 TI - Prevalence of Myofascial Pain Syndrome in Chronic Non-Specific Neck Pain: A Population-Based Cross-Sectional Descriptive Study. AB - BACKGROUND: Chronic non-specific neck pain is a frequent complaint. It is a recognized medical and socioeconomic problem and a frequent cause of job absenteeism. In recent years, case reports about myofascial pain syndrome (MPS) are emerging among patients suffering from pain. MPS is a regional pain syndrome characterized by myofascial trigger points (MTrP) in palpable taut bands of skeletal muscle that refer pain to a distance, and that can cause distant motor and autonomic effects. OBJECTIVE: To assess the prevalence of active and latent MTrPs in subjects suffering from chronic non-specific neck pain. DESIGN: A population-based cross-sectional descriptive study was carried out from January 2012 to December 2014. SETTING: Three primary healthcare centers in Alcala de Henares, Madrid (Spain). SUBJECTS: Two hundred and twenty-four participants diagnosed by their family doctor with chronic non-specific neck pain. METHODS: Participants were examined by a physical therapist to determine the presence of MPS. Pain descriptions from the subjects and pain body diagrams guided the physical examination. The subjects were not given any information concerning MPS or other muscle pain syndromes. RESULTS: All participants presented with MPS. MTrPs of the trapezius muscles were the most prevalent, in 93.75% of the participants. The most prevalent active MTrPs were located right (82.1%) and left (79%) in the nearly-horizontal fibers of the upper trapezius muscle. Furthermore, active MTrPs in the levator scapulae, multifidi, and splenius cervicis muscles reached a prevalence of 82.14%, 77.68%, and 62.5%, respectively. CONCLUSIONS: MPS is a common source of pain in subjects presenting chronic non-specific neck pain. PMID- 28025372 TI - A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator Controlled Phase III Trials of Multiple-Dose Injectable HPbetaCD-Diclofenac in Subjects with Acute Postoperative Pain. AB - OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPbetaCD-diclofenac when given for <= 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPbetaCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPbetaCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPbetaCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPbetaCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPbetaCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPbetaCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population. PMID- 28025373 TI - Trends in Opioid Analgesic Use in Encounters Involving Physician Trainees in U.S. Emergency Departments. AB - BACKGROUND: Opioid analgesic use has increased dramatically in emergency departments (EDs), but the relative contribution of physician trainees has not been explored. We assessed trends in opioid utilization focusing on ED encounters where a physician trainee was involved. METHODS: We studied ED visits from the National Hospital Ambulatory Medical Care Survey, 2001-2011. Adult ED visits in which an opioid was administered in the ED or prescribed at discharge were stratified by whether or not there was trainee involvement. Trends in use over time for five common opioids (codeine, hydrocodone, hydromorphone, morphine, oxycodone) were tested using survey-weighted logistic regression. RESULTS: From 2001-02 to 2009-11, the proportion of ED visits where an opioid analgesic was used increased 31.5% from 21.9% (95% CI: 20.3-23.6) of visits to 28.8% (95% CI: 27.5-30.1). Trainee involvement in ED visits was stable, with 9.3% (95% CI: 7.7 11.3) seen by a trainee in 2001-02 vs. 10.2% (95% CI: 8.1-12.7) in 2010-11. Opioid use in visits with trainee involvement did not change significantly over time relative to visits without a trainee (increase of 36.8% compared to 31.2% without trainees, P = 0.652). Trends in opioid utilization for trainee visits paralleled non-trainee visits. Hydromorphone had the greatest relative increase in use for all providers. Adjusted for patient- and hospital-level factors, the probability of receiving opioids when a trainee was involved increased to a greater extent than among non-trainee visits (30.9% vs. 24.0%). CONCLUSION: Opioid utilization patterns for visits involving trainees reflect similar trends in attending practice, and highlights the more liberal opioid prescribing climate over time. PMID- 28025374 TI - Effect of Local Anesthetic Concentration (0.2% vs 0.1% Ropivacaine) on Pulmonary Function, and Analgesia After Ultrasound-Guided Interscalene Brachial Plexus Block: A Randomized Controlled Study. AB - OBJECTIVE: This study aims to assess diaphragmatic excursion and measure pulmonary functions as measures of the degree to which the phrenic nerve is blocked after ISB with two different concentrations of ropivacaine: 0.2% and 0.1%. DESIGN: Randomized, double-blinded study. SETTING AND PATIENTS: Ambulatory surgical facility. SUBJECTS: Fifty patients undergoing shoulder arthroscopy for rotator cuff repair. METHODS: Patients were randomized to receive ultrasound guided ISB with 20 mL of either 0.2% or 0.1% ropivacaine. Diaphragmatic excursion was measured using M-mode ultrasound. Pulmonary functions were assessed by portable spirometer. Additional outcome data included oxygen saturation in post anesthesia care unit (PACU), pain scores, quality of recovery scores (QOR), and opioid consumption over 72 hour period after surgery. RESULTS: Forced vital capacity (FVC) was significantly reduced 30 minutes after block placement and in PACU in the 0.2% group when compared with the 0.1% group (P = 0.04, P = 0.03, respectively). Forced expiratory volume (FEV1) was also significantly decreased in the 0.2% group in PACU when compared with the 0.1% group (P = 0.04). There were no significant differences in pain scores, length of stay, and total opioid consumption in PACU. Patients who received 0.2% ropivacaine had a longer block duration (18 vs 11.9 hours, P = 0.04) and used less opioid in the 72 hours after surgery (55 mg vs 102 mg codeine equivalents, P = 0.02), when they were compared to their counterparts who received 0.1% for their block. CONCLUSION: 0.1% ropivacaine may impair pulmonary function less than 0.2% ropivacaine. The clinical significance of these differences needs to be further studied. PMID- 28025376 TI - Local and Generalized Endogenous Pain Modulation in Healthy Men: Effects of Exercise and Exercise-Induced Muscle Damage. AB - : Isometric exercise has been shown to activate endogenous pain inhibitory pathways in healthy adults, but not in some clinical pain populations. OBJECTIVE: Exercise-induced muscle damage (EIMD) and the associated delayed-onset muscle soreness (DOMS) are a model for studying clinical pain; thus, our purpose was to examine the effects of isometric exercise on pressure pain threshold (PPT) in the presence and absence of DOMS. METHODS: Data were collected on 23 males (22.8 +/- 2.5 yrs). PPT was assessed in the right (exercising) and left (resting) quadriceps prior to, every 30 seconds during, and 2 and 15 minutes following an isometric contraction of the right quadriceps at 25% of maximal voluntary contraction (MVC) held until fatigue. Unilateral eccentric exercise was performed to induce DOMS in the exercising leg and testing was repeated 48 hours later. RESULTS: DOMS increased (P < 0.001) and resting PPT decreased (P = 0.03) following EIMD. PPTs were elevated during exercise in the exercising (P <= 0.002) and resting (P <= 0.002) quadriceps but did not differ between the control and EIMD conditions in either leg (P <= 0.61). PPT remained elevated 2 and 15 minutes postexercise (P < 0.05) in the exercised quadriceps in both conditions, but values returned to baseline at 2 (P = 0.91) and 15 minutes (P = 0.28) postisometric exercise in the resting quadriceps. CONCLUSIONS: Unlike clinical pain, DOMS had no effect on the PPT response during exercise in either the exercising or resting quadriceps. The fact that exercise altered PPT in both quadriceps during exercise suggests a generalized pain inhibitory mechanism was activated. However, the restriction of postexercise effects to the exercised limb suggests localized inhibitory mechanism(s) were activated after exercise. PMID- 28025375 TI - Intrathecal Therapy for Cancer-Related Pain. AB - OBJECTIVE: The increasing incidence of cancer survivorship has shifted treatment of cancer-related pain from short-term analgesia to long-term chronic pain management. As a result, alternatives to oral analgesics, such as intrathecal therapy, may be beneficial for patients with cancer-related pain. The authors review the use of intrathecal therapy in the management of cancer-related pain. METHODS: The Medline database was searched for English-language articles that included "ziconotide" or "morphine" AND ("cancer" OR "malignant") AND "intrathecal" in title or abstract. Available abstracts from scientific congresses in the areas of neuromodulation and oncology were also reviewed. RESULTS: Intrathecal therapy provides pain relief with reduced systemic concerns in patients with cancer-related pain. Patients should undergo multidisciplinary evaluation and, in most cases, drug trialing before intrathecal pump implantation. Morphine, an opioid ( MU: -opioid receptor antagonist), and ziconotide, a nonopioid (selective N-type calcium channel inhibitor), are both approved for intrathecal analgesia; however, tolerance and safety concerns may deter the use of intrathecal morphine. Ziconotide has also shown efficacy for reduction of cancer-related pain; however, proper dosing and titration must be used to prevent adverse events. There is little information available on use of intrathecal therapies specifically in cancer survivors. CONCLUSIONS: Treatment of cancer-related pain has shifted toward chronic pain management strategies, especially among cancer survivors. Intrathecal therapy provides an alternate route of administration of chronic pain medications (e.g., morphine and ziconotide) for cancer patients with and without active disease, although additional research is needed to support effectiveness in cancer survivors. PMID- 28025377 TI - Cervical Myelitis Presenting as Occipital Neuralgia. PMID- 28025378 TI - Ultrasonographic Imaging of a Pancoast Tumor Presenting with Breakthrough Pain and Not Visualized by Plane Radiograph. PMID- 28025379 TI - Comment on "Perforator-Guided Drug Injection in the Treatment of Abdominal Wall Pain". PMID- 28025380 TI - Ultrasound of Small Nerves and Perforator-Guided Treatment of ACNES. PMID- 28025382 TI - Mortality reduction by post-dilution online-haemodiafiltration: a cause-specific analysis. AB - Background: From an individual participant data (IPD) meta-analysis from four randomized controlled trials comparing haemodialysis (HD) with post-dilution online-haemodiafiltration (ol-HDF), previously it appeared that HDF decreases all cause mortality by 14% (95% confidence interval 25; 1) and fatal cardiovascular disease (CVD) by 23% (39; 3). Significant differences were not found for fatal infections and sudden death. So far, it is unclear, however, whether the reduced mortality risk of HDF is only due to a decrease in CVD events and if so, which CVD in particular is prevented, if compared with HD. Methods: The IPD base was used for the present study. Hazard ratios and 95% confidence intervals for cause specific mortality overall and in thirds of the convection volume were calculated using the Cox proportional hazard regression models. Annualized mortality and numbers needed to treat (NNT) were calculated as well. Results: Besides 554 patients dying from CVD, fatal infections and sudden death, 215 participants died from 'other causes', such as withdrawal from treatment and malignancies. In this group, the mortality risk was comparable between HD and ol-HDF patients, both overall and in thirds of the convection volume. Subdivision of CVD mortality in fatal cardiac, non-cardiac and unclassified CVD showed that ol-HDF was only associated with a lower risk of cardiac casualties [0.64 (0.61; 0.90)]. Annual mortality rates also suggest that the reduction in CVD death is mainly due to a decrease in cardiac fatalities, including both ischaemic heart disease and congestion. Overall, 32 and 75 patients, respectively, need to be treated by high volume HDF (HV-HDF) to prevent one all-cause and one CVD death, respectively, per year. Conclusion: The beneficial effect of ol-HDF on all-cause and CVD mortality appears to be mainly due to a reduction in fatal cardiac events, including ischaemic heart disease as well as congestion. In HV-HDF, the NNT to prevent one CVD death is 75 per year. PMID- 28025384 TI - Renal effects of immune checkpoint inhibitors. AB - Recent advances in immune checkpoint inhibitor (ICPI) development have led to major improvements in oncology patient outcomes. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are two essential immune checkpoint receptors. Ipilimumab and tremelimumab (anti-CTLA-4-blocking antibodies) and pembrolizumab and nivolumab (antibodies targeting PD-1 receptors) have already been approved by US Food and Drug Administration in several malignancies. Two different forms of ICPI-induced renal damage have been identified, including acute (granulomatous) tubulointerstitial nephritis and immune complex glomerulonephritis. The observed acute renal damage can be reversed upon ICPI drug discontinuation and renal function can recover back to normal following the introduction of systemic corticosteroid treatment. Any delay in treating this complication could result in definitive and irreversible renal injury. PMID- 28025383 TI - Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation. AB - Background: The variability of tacrolimus blood levels has been shown to be associated with inferior graft survival. However, the effect of variability during the early post-transplantation period has not been evaluated. We sought to evaluate the association between time-weighted variability in the early post transplantation period and graft survival. We also explored the interaction between drug level variability and exposure to inadequate drug levels. Methods: This retrospective cohort study included all patients who underwent kidney transplantation in the Rabin Medical Center and were treated with tacrolimus. Time-weighted coefficient of variability (TWCV) was defined as time-weighted standard deviation divided by the mean drug level. Univariate and multivariate Cox proportional hazard model was used with the primary outcome of patients and graft survival. Results: The study population included 803 patients who underwent kidney transplantation between 1 January 2000 and 29 September 2013. The high tertile of TWCV of tacrolimus blood levels was associated with reduced graft survival by univariate and multivariate analyses [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.14-2.53, P = 0.01 and HR 1.74, 95% CI 1.14-2.63, P = 0.01, respectively]. The interaction between high TWCV and exposure to inadequately low drug levels was significantly associated with reduced survival (P = 0.004), while the interaction between TWCV and high drug blood levels was not. One hundred and thirty patients (16.2%) had the combination of high TWCV and exposure to low drug values (<5 ng/mL). These patients had reduced graft survival by univariate and multivariate analyses (HR 2.42, 95% CI 1.57-3.74, P < 0.001 and HR 2.6, 95% CI 1.65-4.11, P < 0.001, respectively). Conclusions: The combination of high TWCV and exposure to low drug levels might identify high-risk patients in the early post-transplantation period. PMID- 28025385 TI - Prognostic value of bone- and vascular-derived molecular biomarkers in hemodialysis and renal transplant patients: a systematic review and meta analysis. AB - Background: Patients undergoing hemodialysis and kidney graft recipients are high risk populations for cardiovascular and all-cause mortality. Fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), RANK ligand, osteopontin (OPN), Klotho protein and bone morphogenetic protein-7 (BMP-7) are bone- and vascular-derived molecular biomarkers that have been shown to be associated with cardiovascular surrogate end points; however, currently available data on the prognostic value of these biomarkers is inconsistent. The aim of the present study was to conduct a systematic review and meta-analysis in order to summarize the available evidence on the association of molecular biomarkers with mortality in individuals undergoing hemodialysis and renal transplant patients. Methods: Two databases (MEDLINE and Embase) were systematically searched. Studies were eligible if the association of biomarker and mortality was reported as time-to-event data [hazard Ratio (HR)] or as effect size with a fixed time of follow-up [odds Ratio (OR)]. Abstracted HRs were converted onto a standard scale of effect and combined using a random effects model. Results: From a total of 1170 studies identified in initial searches, 21 met the inclusion criteria. In hemodialysis patients, comparing the lower third with the upper third of baseline FGF23 distribution, pooled HRs (95% confidence intervals) were 1.94 (1.47, 2.56) for all-cause mortality and 2.4 (1.64, 3.51) for cardiovascular mortality. For the same comparison of baseline OPG distribution, pooled HRs were 1.8 (0.95, 3.39) for all cause mortality and 2.53 (1.29, 4.94) for cardiovascular mortality. Reported risk estimates of RANK ligand, OPN, Klotho protein and BMP-7 were not suitable for pooling; however, only Klotho protein was significantly related to mortality. For kidney graft recipients, four studies that investigated the relationship of FGF23 and OPG with mortality were identified, all of which reported a significant association. Conclusions: In hemodialysis patients, FGF23 is a predictor of all cause and cardiovascular mortality, whereas the predictive value of OPG is restricted to cardiovascular mortality. Further studies are needed in order to gain insight into the prognostic value of these biomarkers in renal transplant recipients. PMID- 28025387 TI - The challenge of adequate imaging surveillance in primary central nervous system lymphoma. PMID- 28025386 TI - Tweak up-regulates endothelin-1 system in mouse and human endothelial cells. AB - AIM: To analyse the ability of TWEAK to modify the endothelin system, particularly endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1), studying the intracellular mechanisms implied. TNF-like weak inducer of apoptosis (TWEAK) is a member of TNF superfamily; it has different biological functions such as inflammation, angiogenesis, proliferation, and apoptosis. TWEAK and fibroblast growth-factor-inducible 14 are expressed in different cell types, including endothelial and smooth muscle cells. Despite their presence in endothelial cells, the effect of TWEAK on endothelial function is incompletely defined. METHODS AND RESULTS: In cells, TWEAK induced protein (Western blot) and mRNA (quantitative polymerase chain reaction) expression of ECE-1. Results were related to transcriptional changes, as ECE-1 promoter activity (transfection assays) was also increased. Transfections with serial deletions of ECE-1 promoter suggest a potential role for AP-1 and NFkB, which were confirmed by electrophoretic mobility shift assays. When AP-1 or NFkB activations were inhibited by specific inhibitors of AP-1, PD-98059 (Erk1/2 inhibitor), or SP 600125 (JNK inhibitor), and also with an inhibitor of NFKB and PDTC, TWEAK effect was partially blocked in both cases, suggesting that both transcription factors are implied in ECE-1 regulation. Moreover, the endothelial changes induced by TWEAK were also tested in vivo, using 3-month-old male CD-1 mice treated with TWEAK 10 ug/kg body weight for 24 h, finding similar effects, a rise in ET-1 production (enzyme-linked immunosorbent assay), and ECE-1 expression in aorta and lung tissues. Mice showed slight hypertension after 4 h of treatment, which disappeared at 24 h. CONCLUSIONS: In pathological situations such as chronic inflammation, TWEAK could be more harmful through this effect at endothelial level. Pharmacological blockade of this cytokine could prevent the haemodynamic and structural changes related to an increased ET-1 synthesis. PMID- 28025388 TI - Nosema ceranae Winter Control: Study of the Effectiveness of Different Fumagillin Treatments and Consequences on the Strength of Honey Bee (Hymenoptera: Apidae) Colonies. AB - Overview: In Uruguay, colonies of honey bees moving to Eucalyptus grandis plantation in autumn habitually become infected with the microsporidian Nosema ceranae , a parasite that attacks the digestive system of bees. Beekeepers attributed to N. ceranae depopulation of the colonies that often occurs at the end of the blooming period, and many use the antibiotic fumagillin to reduce the level of infection. The aim of this study was to compare the effectiveness of four different fumagillin treatments and determine how this antibiotic affects the strength of the colonies during the winter season. The colonies treated with fumagillin in July showed less spore load at the end of applications, being the most effective the following treatments: the four applications sprayed over bees of 30 mg of fumagillin in 100 ml of sugar syrup 1:1, and four applications of 90 mg of fumagillin in 250 ml of sugar syrup 1:1 using a feeder. However, 2 month after the treatment applications, the colonies treated with fumagillin were the same size as the untreated colonies. In September, the colonies treated and not treated with fumagillin did not differ in colony strength (adult bee population and brood area) or spores abundance. Our study demonstrates that fumagillin treatment temporarily decreased the spore load of N. ceranae , but this was not reflected in either the size of the colonies or the probability of surviving the winter regardless of the dose or the administration strategy applied. Given the results obtained, we suggest to not perform the pharmacological treatment under the conditions described in the experiment. Resumen: En Uruguay las colonias de abejas meliferas que se trasladan a las forestaciones de Eucalyptus grandis en otono indefectiblemente se infectan con el microsporido Nosema ceranae , parasito que ataca el sistema digestivo de las abejas. Los apicultores atribuyen a N. ceranae el despoblamiento de las colonias que ocurre con frecuencia al terminar el periodo de floracion y muchos emplean el antibiotico fumagilina para reducir el nivel de infeccion. El objetivo de este estudio fue comparar la eficacia de cuatro tratamientos diferentes con fumagilina y determinar como incide en la fortaleza de las colonias durante la invernada. Las colonias tratadas con fumagilina en julio presentaron una menor carga de esporas al terminar las aplicaciones, siendo los tratamientos mas eficaces el de 4 aplicaciones mediante asperjado sobre las abejas de 30 mg de fumagilina en 100 ml de jarabe de azucar 1:1, y el de 4 aplicaciones de 90 mg de fumagilina en 250 ml de jarabe de azucar 1:1 utilizando un alimentador. Sin embargo, durante el periodo de experimentacion, las colonias tratadas con antibiotico presentaron igual tamano que las colonias no tratadas. En setiembre, las colonias tratadas y no tratadas con fumagilina no se diferenciaron en la intensidad de infeccion ni en su tamano. En las condiciones en que se realizo el estudio, la aplicacion de fumagilina disminuyo temporalmente la carga de esporas de N. ceranae pero esto no se reflejo en el tamano de las colonias ni en la probabilidad de sobrevivir el invierno. PMID- 28025389 TI - Direct Multiplex PCR (dmPCR) for the Identification of Six Phlebotomine Sand Fly Species (Diptera: Psychodidae), Including Major Leishmania Vectors of the Mediterranean. AB - Sand flies (Diptera: Psychodidae, subfamily Phlebotominae) are hematophagous insects that are known to transmit several anthroponotic and zoonotic diseases. Reliable identification of sand flies at species level is crucial for their surveillance, the detection and spread of their pathogens, and the implementation of targeted pest control strategies. Here, we designed a novel, time-saving, cost effective and easy-to-apply molecular methodology, which avoids sequencing, for the identification of the following six Eastern Mediterranean sand fly species: Phebotomus perfiliewi Parrot, Phebotomus simici Theodor, Phebotomus tobbi Adler and Theodor, Phebotomus papatasi Scopoli, Sergentomyia dentata Sinton, and Sergentomyia minuta Theodor. This methodology, which is a multiplex PCR assay using one common and six diagnostic primers, is based on species-specific single nucleotide polymorphisms of the nuclear 18S rRNA gene. Amplification products were easily and reliably separated in agarose gel yielding one single clear band of diagnostic size for each species. Further, we verified its successful application on tissue samples that were immersed directly to the PCR mix, skipping DNA extraction. The direct multiplex PCR can be completed in < 3 h, including all operating procedures, and costing no more than a simple PCR. The applicability of this methodology in the detection of hybrids is an additional considerable benefit. PMID- 28025390 TI - Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients. AB - The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities. PMID- 28025391 TI - Salt-mediated two-site ligand binding by the cocaine-binding aptamer. AB - Multisite ligand binding by proteins is commonly utilized in the regulation of biological systems and exploited in a range of biochemical technologies. Aptamers, although widely utilized in many rationally designed biochemical systems, are rarely capable of multisite ligand binding. The cocaine-binding aptamer is often used for studying and developing sensor and aptamer-based technologies. Here, we use isothermal titration calorimetry (ITC) and NMR spectroscopy to demonstrate that the cocaine-binding aptamer switches from one site to two-site ligand binding, dependent on NaCl concentration. The high affinity site functions at all buffer conditions studied, the low-affinity site only at low NaCl concentrations. ITC experiments show the two ligand-binding sites operate independently of one another with different affinities and enthalpies. NMR spectroscopy shows the second binding site is located in stem 2 near the three-way junction. This ability to control ligand binding at the second site by adjusting the concentration of NaCl is rare among aptamers and may prove a useful in biotechnology applications. This work also demonstrates that in vitro selected biomolecules can have functions as complex as those found in nature. PMID- 28025392 TI - INO80 represses osmostress induced gene expression by resetting promoter proximal nucleosomes. AB - The conserved INO80 chromatin remodeling complex is involved in regulation of DNA damage repair, replication and transcription. It is commonly recruited to the transcription start region and contributes to the establishment of promoter proximal nucleosomes. We find a substantial influence of INO80 on nucleosome dynamics and gene expression during stress induced transcription. Transcription induced by osmotic stress leads to genome-wide remodeling of promoter proximal nucleosomes. INO80 function is required for timely return of evicted nucleosomes to the 5? end of induced genes. Reduced INO80 function in Arp8-deficient cells leads to correlated prolonged transcription and nucleosome eviction. INO80 and the related complex SWR1 regulate incorporation of the H2A.Z isoform at promoter proximal nucleosomes. However, H2A.Z seems not to influence osmotic stress induced gene regulation. Furthermore, we show that high rates of transcription promote INO80 recruitment to promoter regions, suggesting a connection between active transcription and promoter proximal nucleosome remodeling. In addition, we find that absence of INO80 enhances bidirectional promoter activity at highly induced genes and expression of a number of stress induced transcripts. We suggest that INO80 has a direct repressive role via promoter proximal nucleosome remodeling to limit high levels of transcription in yeast. PMID- 28025396 TI - Identification of aberrant white matter bundles entering the inferior cerebellar peduncle. PMID- 28025393 TI - Peroxiredoxins prevent oxidative stress during human sperm capacitation. AB - STUDY QUESTION: Do peroxiredoxins (PRDXs) control reactive oxygen species (ROS) levels during human sperm capacitation? SUMMARY ANSWER: PRDXs are necessary to control the levels of ROS generated during capacitation allowing spermatozoa to achieve fertilizing ability. WHAT IS KNOWN ALREADY: Sperm capacitation is an oxidative event that requires low and controlled amounts of ROS to trigger phosphorylation events. PRDXs are antioxidant enzymes that not only act as scavengers but also control ROS action in somatic cells. Spermatozoa from infertile men have lower levels of PRDXs (particularly of PRDX6), which are thiol oxidized and therefore inactive. STUDY DESIGN, SIZE, DURATION: Semen samples were obtained from a cohort of 20 healthy nonsmoker volunteers aged 22-30 years old over a period of 1 year. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Sperm from healthy donors was capacitated with fetal cord serum ultrafiltrate (FCSu) in the absence or presence of thiostrepton (TSP), inhibitor of 2-Cys PRDXs or 1 Hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol lithium (MJ33), inhibitor of calcium independent-phospholipase A2 (Ca2+-iPLA2) activity of PRDX6, added at different times of incubation. Capacitation was also induced by the dibutyryl cAMP+3-isobuty1-1-methylxanthine system. Sperm viability and motility were determined by the hypo-osmotic swelling test and computer-assisted semen analysis system, respectively. Capacitation was determined by the ability of spermatozoa to undergo the acrosome reaction triggered by lysophosphatidylcholine. Percentages of acrosome reaction were obtained using the FITC-conjugated Pisum sativum agglutinin assay. Phosphorylation of tyrosine residues and of protein kinase A (PKA) substrates were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblotting with specific antibodies. Actin polymerization was determined by phalloidin labeling. MAIN RESULTS AND THE ROLE OF CHANCE: TSP and MJ33 prevented sperm capacitation and its associated actin polymerization in spermatozoa incubated with 10% FCSu (capacitation inducer) compared to non-capacitated controls (P < 0.05) without altering sperm viability. PKA substrates and tyrosine phosphorylations were prevented in FCSu-treated spermatozoa in a differential fashion depending on the type and the time of addition of the inhibitor used compared to non-capacitated controls (P < 0.05). TSP and MJ33 promoted an increase of lipid peroxidation in spermatozoa (P < 0.01) and these levels were higher in those spermatozoa incubated with the inhibitors and FCSu compared to those capacitated spermatozoa incubated without the inhibitors (P < 0.0001). Inhibition of 2-Cys PRDXs by TSP generated an oxidative stress in spermatozoa, affecting their viability compared to controls (P < 0.05). This oxidative stress was prevented by nuclephile D penicillamine (PEN). MJ33 also promoted an increase of lipid peroxidation and impaired sperm viability compared to non-treated controls (P < 0.05) but its effect was not circumvented by PEN, suggesting that not only peroxidase but also Ca2+-iPLA2 activity of PRDX6 are necessary to guarantee viability in human spermatozoa. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: We focused on the global effect of PRDXs inhibitors on human sperm capacitation and in two of its associated phosphorylation events. Thus, other phosphorylation events and mechanisms necessary for capacitation may also be affected. WIDER IMPLICATIONS OF THE FINDINGS: PRDXs are the major antioxidant system in ejaculated spermatozoa and are necessary to allow spermatozoon to achieve fertilizing ability (capacitation and acrosome reaction). STUDY FUNDING/COMPETING INTEREST(S): This research was supported by Canadian Institutes of Health Research (MOP 133661) and the Fonds de Recherche en Sante Quebec (FRSQS #22151) to C.O. The authors have nothing to disclose. PMID- 28025397 TI - Lingual epilepsia partialis continua in neurocysticercosis. PMID- 28025399 TI - Letter re: Autism and epilepsy: A population-based nationwide cohort study. PMID- 28025400 TI - Author response: Autism and epilepsy: A population-based nationwide cohort study. PMID- 28025401 TI - Letter re: CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism. PMID- 28025402 TI - Author response: CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism. PMID- 28025403 TI - Child Neurology: Sjogren-Larsson syndrome. PMID- 28025404 TI - Journal Club: Pregnancy outcome following maternal exposure to pregabalin may call for concern. PMID- 28025405 TI - Teaching Video NeuroImages: Minimal anomalies of dorsal midbrain syndrome (Parinaud syndrome). PMID- 28025406 TI - Teaching Video NeuroImages: Purposeless groaning in progressive supranuclear palsy. PMID- 28025407 TI - Altered S-nitrosylation of p53 is responsible for impaired antioxidant response in skeletal muscle during aging. AB - p53 transcriptional activity has been proposed to regulate both homeostasis and sarcopenia of skeletal muscle during aging. However, the exact molecular function of p53 remains to be clearly defined. We demonstrated a requirement of nuclear p53 S-nitrosylation in inducing a nitric oxide/PGC-1alpha-mediated antioxidant pathway in skeletal muscle. Importantly, mutant form of p53-DNA binding domain (C124S) did not undergo nuclear S-nitrosylation and failed in inducing the expression of antioxidant genes (i.e. SOD2 and GCLC). Moreover, we found that during aging the nuclear S-nitrosylation of p53 significantly declines in gastrocnemius/soleus leading to an impairment of redox homeostasis of skeletal muscle. We suggested that decreased level of nuclear neuronal nitric oxide synthase (nNOS)/Syntrophin complex, which we observed during aging, could be responsible for impaired nuclear S-nitrosylation. Taken together, our data indicate that altered S-nitrosylation of p53 during aging could be a contributing factor of sarcopenia condition and of other skeletal muscle pathologies associated with oxidative/nitrosative stress. PMID- 28025408 TI - A case of anti aquapolin-4 antibody positive myelitis with hyperhidrosis, following herpes zoster. AB - We report an acute myelitis in a 53-year-old woman that occurred in 7 days after the diagnosis of Th5-6 herpes zoster. Clinical examination revealed hyperhidrosis of left side of her face, neck, arm and upper chest. She also had muscle weakness of her left leg and sensory impairment for light touch and temperature in her chest and legs. Spinal cord MRI demonstrated a longitudinal T2-hyperintense lesion extending from Th1 to 7. In the axial imaging, the lesion dominantly located in the left side gray matter. Hyperhidrosis, weakness and sensory impairment were improved after intravenous therapy with acyclovir and methylprednisolone. VZV (varicella zoster virus) IgG index of the cerebrospinal fluid was high and serological anti aquaporin-4 antibodies were positive at the time of the admission. This case had both characteristics of VZV myelitis and neuromyelitis optica spectrum disorder. Myelitis relapsed 19 months after the first attack. We believe that sympathetic hyper reactivity due to thoracic spinal cord lesion was responsible for the hyperhidrosis in our patient. PMID- 28025409 TI - A case of acute autonomic and sensory neuropathy (AASN) with antibody against a mixture of galactocerebroside and phospholipids. AB - A 62-year-old woman presented with paresthesia of limbs, gait disturbance, urinary retention and constipation following upper respiratory infection. Neurological examination revealed gait disturbance due to loss of position sense in her extremities with intact muscle power, and autonomic failure represented by orthostatic hypotension, constipation and autonomic bladder. Cerebrospinal fluid analysis showed normal cell counts with elevated protein levels. Nerve conduction study showed sensory nerve impairment with almost normal motor nerve conduction in her upper and lower extremities. Sympathetic skin response of both hands was unresponsive, indicating autonomic nervous dysfunction. We diagnosed her as having acute autonomic and sensory neuropathy (AASN) and treated her with intravenous immunoglobulin, which ameliorated her symptoms enabling her to walk without any assistance at the time of discharge. Screening tests of serum autoantibodies revealed positivity of antibody against a mixture of galactocerebroside (Gal-Cer) and phospholipids. According to previous literature, no specific antibodies have been identified in AASN. This case, therefore, suggests a possible role of anti-Gal-Cer antibody in the pathogenesis of AASN. PMID- 28025410 TI - A case of internal carotid thrombus associated with brain infarction. AB - A 49-year-old man was transferred to our hospital with chief complaint of global aphasia and weakness of right upper and lower limbs. Brain MRI showed ultra-acute cerebral infarction in left anterior cerebral artery and middle cerebral artery territory and MRA showed occlusion of A2 and M2. Although t-PA was administrated intravenously, symptoms didn't improve and giant internal carotid thrombus (size 6 * 7 * 17 mm) was recognized at left internal carotid artery by carotid ultrasonography. After started anticoagulant therapy, thrombus was miniaturized gradually and finally disappeared. Anticoagulant therapy is effective to internal carotid thrombus and carotid ultrasonography is useful to confirm the effectiveness. We suggest that clinicians should enforce anticoagulant therapy for the first choice to internal carotid thrombus. PMID- 28025411 TI - A case of anti-neurofascin 155 antibody-positive combined central and peripheral demyelination successfully treated with plasma exchange. AB - A 21-year-old man was admitted to our hospital in June 2015. He felt paresthesia of toes in April 2015, which had been spreading upward, and he became difficult to walk in June. Nerve conduction study showed peripheral demyelinating neuropathy that met the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), and the cerebrospinal fluid (CSF) examination revealed the remarkably increased protein level. In addition, magnetic resonance imaging of his brain showed a few plaques in white matter, so he was finally diagnosed with combined central and peripheral demyelination (CCPD). Moreover, anti-neurofascin155 (NF155) antibodies assayed in his serum and CSF turned out to be positive. Although he was treated with intravenous immunoglobulin and intravenous methylprednisolone, his symptoms were not ameliorated. However, plasma exchange therapy was apparently effective, and the titer of anti-NF155 antibody was reduced. Recently, the number of case reports of CIDP with CNS lesions has gradually been increasing, while the information about the diagnosis and the treatment responses are not enough. Thus, we reported our case with CCPD who was successfully treated with plasma exchange. PMID- 28025413 TI - ADULT ANAPHYLAXIS. PMID- 28025414 TI - ASTHMA DEATH. PMID- 28025412 TI - Effects of 17beta-estradiol on leptin signaling in anterior pituitary of ovariectomized rats. AB - Leptin is secreted predominantly by adipocytes and exerts its role mainly by interaction with the long form of leptin receptor (LEPR_V2). It has been identified that LEPR_V2 is widely distributed in various tissues, including the anterior pituitary. Cross-talk between leptin and estrogens has been indentified. Estrogen is known to modulate the tissue-specific expression of LEPR_V2 and leptin in ovariectomized (OVX) rats, a model of postmenopausal condition. Our previous data showed that 17beta-estradiol (E2) up-regulated the expression of LEPR_V2 protein and mRNA in rat dorsal root ganglion (DRG) in an estrogen receptor alpha (ERalpha)-dependent manner. But it is still unclear whether estrogen can regulate leptin signalling in the pituitary of OVX rats. In the present study, we found that ovariectomy decreased the expressions of LEPR_V2. Administration of E2 increased the expressions of LEPR_V2 in a dose-dependent manner. In addition, E2 improved LEPR_V2, STAT3, and SOCS3 protein levels in OVX rats. The effects of exogenous E2 were attenuated by ICI 182,780, a specific estrogen receptors antagonist. However, E2 did not change the Lepr_v1, a type of short form of leptin receptor (LEPR), or leptin mRNA levels. Thus, E2 plays a crucial role in regulating pituitary sensitivity to leptin in OVX rats. Our findings implied that exogenous E2 had potential roles in modification of the function of pituitary in postmenopausal women. PMID- 28025415 TI - JAPANESE PEDIATRIC GUIDELINE FOR FOOD ALLERGY 2016 HOW TO PREVENT COMPLETE AVOIDANCE? PMID- 28025416 TI - STRATEGIES FOR PREVENTING ALLERGIC DISEASES: FOR THE NEXT GENERATIONS. PMID- 28025418 TI - ? PMID- 28025417 TI - INTERLEUKIN-33 IN ALLERGIC DISEASES. PMID- 28025419 TI - ? PMID- 28025421 TI - ? PMID- 28025420 TI - IL-25. PMID- 28025422 TI - Diagnosis of poor safety culture as a major shortcoming in OHSAS 18001-certified companies. AB - The evaluation of safety performance in occupational health and safety assessment series (OHSAS) 18001-certified companies provides useful information about the quality of the management system. A certified organization should employ an adequate level of safety management and a positive safety culture to achieve a satisfactory safety performance. The present study conducted in six manufacturing companies: three OHSAS 18001-certified, and three non-certified to assess occupational health and safety (OHS) as well as OHSAS 18001 practices. The certified companies had a better OHS practices compared with the non-certified companies. The certified companies slightly differed in OHS and OHSAS 18001 practices and one of the certified companies had the highest activity rates for both practices. The results indicated that the implemented management systems have not developed and been maintained appropriately in the certified companies. The in-depth analysis of the collected evidence revealed shortcomings in safety culture improvement in the certified companies. This study highlights the importance of safety culture to continuously improve the quality of OHSAS 18001 and to properly perform OHS/OHSAS 18001 practices in the certified companies. PMID- 28025423 TI - Cross-sectional associations between daily rest periods during weekdays and psychological distress, non-restorative sleep, fatigue, and work performance among information technology workers. AB - A daily rest period (DRP; rest taken from daily work during a 24 h period), is essential to work recovery. This study examined DRPs' distribution and association with health outcomes among information technology workers recruited from an internet panel (N=1,811). Participants completed a web questionnaire examining psychological distress as a primary outcome, along with non-restorative sleep, fatigue (stress reaction), and work performance. Logistic regression analysis showed elevated psychological distress when DRP was <12 h (OR: 2.54; 95% CI: 1.47-4.42) and <11 h (OR: 2.48, 95% CI: 1.17-5.26), although the 95% CI included 1 after adjusting for age, sex, and working and commuting hours. After the above adjustment, similar associations were found with non-restorative sleep and fatigue, but not work performance, when DRP was <12 h. These findings constitute the first analysis of a dose-response relationship between DRP and subjective health outcomes among white-collar workers. PMID- 28025424 TI - Morphological features of coronary plaques in WHHLMI rabbits (Oryctolagus cuniculus), an animal model for familial hypercholesterolemia. AB - In order to examine their suitability for studies on coronary atherosclerosis, we evaluated the features of coronary atherosclerotic plaques in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, a spontaneous animal model for coronary atherosclerosis and myocardial infarction. Coronary segments of the hearts of 187 WHHLMI rabbits (10-29 months old) were sectioned serially and stained histopathologically and immunohistologically. Progression of coronary lesions was prominent in rabbits that had died suddenly. The degree of coronary lesions of females was higher than that of males. Various types of atherosclerotic lesions were observed in the coronary arteries, such as plaques with a large lipid core covered by a thin fibrous cap, fatty streaks, early and advanced fibroatheromas, fibrous lesions, and advanced lesions with calcium accumulation and the vasa vasorum. In rabbits that had died suddenly, the frequencies of fibroatheromas or advanced lesions were higher than those of rabbits euthanized. Matrix metalloproteinase (MMP)-positive macrophages were detected in gaps among endothelial cells at the plaque surface, beneath the fibrous cap of thin-capped fibroatheromas, and at the bottom of the intimal plaques in which the tunica media was attenuated. Immunohistological results suggest that MMP-positive macrophages are involved in the initiation, progression, and destabilization of coronary plaques, in addition to vascular remodeling, even in WHHLMI rabbits. In conclusion, coronary lesions in WHHLMI rabbits resemble human atherosclerotic lesions, and thus, the WHHLMI rabbit is a suitable animal model for studies on human coronary plaques. PMID- 28025425 TI - Virus and Host Events in Squamous Carcinogenesis. AB - Our group investigates early and late stages in the development of squamous cell carcinomas (SCCs), in order to identify new approaches to diagnosis and therapy. The principal themes are:1. Transcriptional deregulation of high-risk human papillomavirus (HRHPV)We study mechanisms of HRHPV transcriptional deregulation and competitive cell selection during SCC progression, focussing on the causes and effects of integration of HPV16 into the host genome. We showed that HPV16 integration does not necessarily lead to a competitive growth advantage or increased levels of virus oncogenes. Selection of individual cells is determined through multiple layers of epigenetic regulation of the integrated virus genome. We are currently studying whether the epigenetic landscape of integrated HPV16 reflects that of the host genome at the integration site and/or sites of long range chromatin interactions of the virus DNA. This work may ultimately identify targets for epigenetic therapies in SCCs containing integrated HRHPV.2. The oncostatin-M receptor (OSMR) in metastasisThe cell-surface oncostatin-M receptor (OSMR) has emerged as an exciting therapeutic target in SCCs. Both copy number gain and over-expression of OSMR have a strong adverse prognostic effect in SCCs. Carcinoma cells that over-expressed OSMR were more sensitive to the major ligand OSM, which induced multiple pro-malignant effects, including epithelial mesenchymal transition, increased metastasis and the ability to induce pro malignant changes in cells from the tumour microenvironment (TME). We are now studying the effectiveness of OSM:OSMR blockade on the growth and metastasis of SCC cells in vivo, as well as effects on the TME in immunocompetent hosts.(Presented at the 1923th Meeting, August 10, 2016). PMID- 28025426 TI - Life and Medical Ethics in Pediatric Neurosurgery. AB - Ethical issues in the field of pediatric neurosurgery, including prenatal diagnosis, palliative care for children with an intractable serious disease, and medical neglect, are discussed. An important role of medicine is to offer every possible treatment to a patient. However, it also is the responsibility of medicine to be conscious of its limitations, and to help parents love and respect a child who suffers from an incurable disease. When dealing with cases of medical neglect and palliative care for an incurable disease, it is critical to diagnose the child's condition accurately and evaluate the outcome. However, to treat or not to treat also depends on the medical resources and social-economic status of the community, the parents' religion and philosophy, the policies of the institutions involved, and the limits of medical science. Moral dilemmas will continue to be addressed as medical progress yields treatments for untreatable diseases in the future. PMID- 28025427 TI - The role of TERT-CLPTM1L SNPs, hTERT expression and telomere length in the pathogenesis of oral squamous cell carcinoma. AB - The aim of this study was to assess TERT-CLPTM1L single-nucleotide polymorphisms (SNPs) (rs402710 C/T in the CLPTM1L gene; rs2736100 A/C and rs2736098 G/A in the TERT gene) as risk factors for development of oral squamous cell carcinoma (OSCC), and to investigate the relationship between the analyzed polymorphisms, relative telomere length (RTL), telomerase expression and clinicopathologic characteristics of OSCC in a Serbian population. Paraffin-embedded tumor samples and buccal swabs from cancer-free controls were genotyped using PCR-RFLP, while tumor RTL values and telomerase expression were estimated by real-time PCR and immunohistochemistry, respectively. CLPTM1L rs402710 and TERT rs2736100 polymorphisms were associated with a significantly increased risk of OSCC, and TERT rs2736098 with a significantly decreased risk. No significant association was found between TERT-CLPTM1L polymorphisms, tumor RTL values, telomerase expression, and clinicopathologic features, although a trend towards longer telomeres was evident in telomerase-positive samples and less advanced tumors. Kaplan-Meier survival analysis showed that patients with longer telomeres in their tumors had significantly better overall survival than patients with shorter telomeres. Our research seems to provide strong evidence for an association between CLPTM1L rs402710C/T and TERT rs2736100A/C SNPs and the risk of OSSC, and suggests that higher tumor RTL values and positive hTERT expression may be applicable as early prognostic markers.(J Oral Sci 58, 449-458, 2016). PMID- 28025428 TI - Expression of p73 and TRAIL in odontogenic cysts and tumors. AB - Odontogenic tumors are a group of lesions arising from the odontogenic apparatus. Although the mechanism of oncogenesis and tumor progression in these lesions remains unknown, certain proteins, such as those involved in apoptosis, seem to be involved in the differentiation and proliferation of odontogenic epithelial cells. The aim of this study was to analyze the expression of p73 and TNF-related apoptosis-inducing ligand (TRAIL) in odontogenic tumors and cysts, and to clarify changes in the expression of these proteins. Immunohistochemical analysis was performed on 21 ameloblastomas, 15 keratocystic odontogenic tumors and 15 dentigerous cysts. We carried out quantitative assessment of p73 and TRAIL expression by determining the percentages of positive cells on a continuous scale. Five cases of orthokeratinized odontogenic cyst were also examined. The percentages of cells immunohistochemically positive for p73 were 52.6 +/- 25.4% in ameloblastomas, 76.0 +/- 13.1% in keratocystic odontogenic tumors, and 26.7 +/ 30.7% in odontogenic cysts, whereas the corresponding figures for TRAIL were 57.6 +/- 16.1%, 8.9 +/- 10.0%, and 1.5 +/- 0.5%, respectively. Imbalance of the apoptosis pathway, with dysregulation of p73 and TRAIL, seems to play a role in the oncogenesis of odontogenic tumors.(J Oral Sci 58, 459-464, 2016). PMID- 28025429 TI - The levels of visceral adipose tissue-derived serpin, omentin-1 and tumor necrosis factor-alpha in the gingival crevicular fluid of obese patients following periodontal therapy. AB - The aim of this clinical study was to determine levels of visceral adipose tissue derived serpin (vaspin), omentin-1, and tumor necrosis factor-alpha (TNF-alpha) in the gingival crevicular fluid (GCF) of obese and non-obese periodontitis patients following nonsurgical periodontal therapy. Seventy-six subjects were separated into four groups according to periodontal and anthropometric measurements: a periodontal-healthy group, a chronic periodontitis (CP) group, a periodontal-healthy with obesity group, and a CP with obesity group. Nonsurgical periodontal treatment was administered to periodontitis patients. Before treatment and at 6 weeks after treatment, GCF samples were analyzed and clinical periodontal parameters were examined. Enzyme-linked immunosorbent assays were used to measure the levels of vaspin, omentin-1, and TNF-alpha. Obese and non obese CP patients displayed higher levels of vaspin and TNF-alpha (P < 0.008), which declined following treatment (P < 0.025), and lower omentin levels (P < 0.008), which increased after treatment (P < 0.025). There was a negative correlation between the total amount of vaspin and omentin-1 in all groups. Obese and non-obese patients had opposing levels of vaspin and omentin-1 in the GCF; therefore, these may represent diagnostic and prognostic indicators of periodontal disease and therapeutic outcome.(J Oral Sci 58, 465-473, 2016). PMID- 28025430 TI - The relationship between the clinical features of idiopathic burning mouth syndrome and self-perceived quality of life. AB - In this descriptive study, we investigated the relationship between the clinical characteristics of idiopathic burning mouth syndrome (iBMS) and the quality of life. Eighteen iBMS patients were interviewed about their experience with pain, oral-associated complaints, cognitive status, and self-perceived quality of life using the French versions of the Hospital Anxiety and Depression Scale (HADS) and the Global Oral Health Assessment Index (GOHAI). The Spearman coefficient was used to analyze correlations. The level of significance was fixed at P < 0.05. The majority of patients described the association of oral burning sensations with other oral complaints, including dry mouth (77.8%), tactile abnormalities (66.7%), thermal abnormalities (44.5%), and taste disturbances (38.9%). HAD anxiety scores were higher than 10 in 38.8% of iBMS patients and HAD-depression scores were higher than 10 in 33.3% of patients. A significant correlation was found between the number of associated complaints and HAD-depression scores. The mean GOHAI-add score was 37.9 +/- 9.6 (mean +/- SD), and 94.5% of iBMS patients had a score lower than 50. GOHAI-add scores strongly correlated with pain intensity, which was calculated using a visual analog scale and duration of pain. Our findings indicate a strong correlation between iBMS-related pain and self perceived oral health-related quality of life. In addition, a correlation was observed between iBMS-associated oral complaints and cognitive status.(J Oral Sci 58, 475-481, 2016). PMID- 28025431 TI - Correlation between oral health-related quality of life and clinical dysfunction index in patients with temporomandibular joint osteoarthritis. AB - We evaluated the correlation between oral health-related quality of life (OHRQoL) and the Helkimo clinical dysfunction index (HDI) in patients with temporomandibular joint osteoarthritis (TMJ OA). Clinical data and scores for the Chinese version of the 14-item Oral Health Impact Profile (OHIP-C14) were recorded and analyzed for 541 patients with TMJ OA. Each patient was assigned an HDI score of 1 to 25, which was used to classify severity into three categories. OHRQoL was assessed by using OHIP-C14 score, which ranged from 0 to 56. Both HDI score and severity were significantly correlated with total OHIP-C14 score (P < 0.001 for both comparisons). The scores for all HDI domains except function impairment (P = 0.205) were significantly correlated with OHIP-C14 score. The scores for all seven OHIP-C14 domains were significantly correlated with HDI score and severity. Several correlations between OHIP-C14 domains and HDI domain scores were significant. HDI score and severity were correlated with OHIP-C14 score in TMJ OA patients. As compared with function-related domains, pain-related HDI domains were more strongly inversely related to OHRQoL.(J Oral Sci 58, 483 490, 2016). PMID- 28025432 TI - Visfatin levels in gingival crevicular fluid and serum before and after non surgical treatment for periodontal diseases. AB - The purpose of this study was to evaluate visfatin levels at different stages of periodontal disease and in healthy tissues. In addition, the effect of non surgical periodontal therapy on visfatin levels in gingival crevicular fluid and serum was investigated. Forty-five patients were divided into three groups based on clinical and radiographical findings. Group 1 comprised periodontally healthy individuals (n = 15); group 2 comprised patients with gingivitis (n = 15); and group 3 was composed of patients with generalized chronic periodontitis (n = 15). Gingival crevicular fluid and serum samples were collected before treatment and at 1, 3, and 6 months after treatment. Visfatin levels were measured by enzyme linked immunosorbent assays. Gingival crevicular fluid and serum visfatin levels were higher in patients with chronic periodontitis than those with gingivitis or healthy controls (P < 0.016). In addition, visfatin levels were higher in the gingivitis group than in healthy controls (P < 0.016). Non-surgical periodontal treatment resulted in a significant reduction in gingival crevicular fluid and serum visfatin levels. Furthermore, visfatin levels increased with inflammation and decreased following periodontal treatment. Our findings suggest that visfatin is an inflammatory biomarker of periodontal disease.(J Oral Sci 58, 491-499, 2016). PMID- 28025433 TI - Three-dimensional changes in the temporomandibular joint after maxillary protraction in children with skeletal Class III malocclusion. AB - We evaluated 3-dimensional changes in the temporomandibular joints of children with skeletal Class III malocclusion and maxillary deficiency after facemask therapy for maxillary protraction. Eighteen children with anterior crossbite and a Class III molar relationship underwent facemask therapy for maxillary protraction, after which they exhibited positive overjet and a Class II molar relationship. Three-dimensional cone-beam computed tomography images of the patients were obtained before (T1) and after (T2) facemask protraction, and the 3 dimensional coordinates of the anatomical landmarks in T1 and T2 images were compared. After facemask therapy, the mandibular condyles of the patients were displaced outside, upward, and backward. Additionally, the anterior and posterior walls of the glenoid fossa had negative values for anteroposterior change. Three dimensional analysis of the temporomandibular joint showed that facemask therapy resulted in bone apposition (to the anterior wall) and bone resorption (of the posterior wall) in the glenoid fossa. This bone remodeling resulted in upward and backward displacement of the condyle.(J Oral Sci 58, 501-508, 2016). PMID- 28025434 TI - IL-1beta, TNF-alpha, and IL-6 levels in gingival fluid and serum of patients with ischemic stroke. AB - It has been documented that an increase of immune cells in periodontitis may stimulate the process of atherosclerosis and lead to ischemic stroke. The aim of this study was to investigate whether there is any significant difference in serum and gingival crevicular fluid (GCF) cytokine concentrations between patients with early ischemic stroke (IS) and a control group. Eighty-six patients were consecutively enrolled for this study, 50 with ischemic stroke and 36 as a control group with no previous stroke. Only dentulous patients were included. In each patient, GCF was collected from the deepest periodontal pocket. Blood serum samples were also taken from all subjects. The collected material was analyzed for cytokine concentrations using the cytometric bead array technique. Cerebral ischemia was found to be correlated with higher serum levels of IL-1beta (13.01 +/- 13.87 vs. 7.83 +/- 2.11) and IL-6 (15.82 +/- 16.64 vs. 6.64 +/- 2.5) compared to the control group. The levels of IL-1, IL-6 and TNF-alpha in GCF were higher in patients with ischemic stroke but the difference was not significant. In conclusion, ischemic stroke was found to be associated with higher levels of IL 1beta and IL-6 in serum. The cytokine concentrations in GCF did not appear to be directly correlated with those in serum in patients with ischemic stroke.(J Oral Sci 58, 509-513, 2016). PMID- 28025435 TI - A prospective study of factors associated with orthodontic mini-implant survival. AB - The orthodontic mini-implant (MI) is a widely used anchorage device in orthodontic treatment. This prospective study analyzed MI survival and factors associated with MI survival in 139 patients (114 females and 25 males; average age, 25.7 years; age range, 12-56 years) who had received orthodontic treatment with MIs. Survival analysis and Kaplan-Meier curves were used to identify clinical variables associated with MI survival. For the 254 MIs investigated, the overall success rate was 85.8%, and the 1-year cumulative survival rate was 81.6%. MI survival was significantly associated with patient age and MI size. Notably, MI survival was significantly longer in patients aged 20-30 years than in older patients. The Cox proportional-hazards model revealed a 5% increase in failure risk for every 1-year increase in age among participants older than 30 years. Additionally, MI failure risk was inversely associated with MI length. MIs are generally reliable anchorage devices for orthodontic treatment but should be used with caution in older patients, due to the higher rate of failure in that population. Another important factor in MI survival is implant size. Future studies should attempt to clarify associations between MI survival and clinical variables.(J Oral Sci 58, 515-521, 2016). PMID- 28025436 TI - The clinical and systemic effects of periodontal treatment in diabetic and non diabetic obese patients. AB - The purpose of the present study was to evaluate the response to periodontal management in obese individuals with poorly controlled diabetes mellitus (DM) and obese individuals without DM. Changes in clinical and biochemical parameters were also investigated. Seventeen obese patients with poorly controlled DM and 14 obese non-DM patients with generalized chronic periodontitis were enrolled. The anthropometric measurements, periodontal parameters, and serum levels of lipid (triglyceride, high-density lipoprotein cholesterol, total cholesterol, low density lipoprotein cholesterol) and glucose (fasting plasma glucose [FPG], insulin, insulin resistance [IR], hemoglobin [Hb]A1c) metabolism, pro inflammatory mediators (high-sensitivity C-reactive protein, tumor necrosis factor-alpha [TNF-alpha] and Pentraxim-3), and interleukin-6 were measured before and at 3 months, and 6 months after full-mouth scaling and root planing (FM-SRP) together with full-mouth disinfection (FMD). A significant reduction in TNF-alpha (P < 0.001) values was observed in both groups following periodontal healing. However, significant changes in FPG (P < 0.05), HbA1C (P < 0.05), and the homeostasis model assessment of IR (HOMA-IR; P < 0.05) were only observed after 3 months in the DM group. Our findings suggest that obesity with or without DM does not seem to be a modifying factor for the clinical outcome of FM-SRP and FMD.(J Oral Sci 58, 523-531, 2016). PMID- 28025437 TI - Diverse calcification patterns of ameloblastic fibro-odontoma on radiographic examination. AB - The occurrence of ameloblastic fibro-odontoma (AFO) in the oral region is unusual and accounts for 1-3% of all odontogenic tumors. AFO presents mixed radiopaque patterns within the lesion with diverse findings; therefore, it is important to compare this tumor with other odontogenic tumors that radiographically present with calcified bodies. Herein, we observed the calcification patterns within the lesion in seven AFO cases (five males, two females; mean age, 8.3 years; age range, 4-13 years). Periapical and panoramic radiographs were obtained from all seven cases. Five cases underwent conventional computed tomography (CT) scanning, and one underwent cone beam CT. Classification of the calcifications primarily involved the following two characteristics on the X-rays: appearance and location of the lesions. All seven cases were located in the molar regions of the mandible in association with impacted teeth. The calcification patterns of these AFOs were mixed or inhomogeneous within the lesion with various findings, including complex odontoma-like calcifications. However, the patterns differed between panoramic radiography and CT in some cases. The radiolucent lesions in AFO demonstrated varying calcification patterns and were associated with impacted teeth on the CT images.(J Oral Sci 58, 533-537, 2016). PMID- 28025438 TI - Effect of frequency on the fatigue strength of dentin bonds. AB - This study aimed to investigate the effect of frequency on shear fatigue strength (SFS). The SFS of a resin composite bonded to dentin was determined using three self-etch adhesive systems: G-aenial Bond, Scotchbond Universal, and Optibond XTR. The staircase method of fatigue testing was used to determine the SFS at frequencies of 5, 10, and 20 Hz for 50,000 cycles. The failed bonding sites observed were classified based on the type of bond failure as follows: adhesive failure, cohesive failure in composite, cohesive failure in dentin, or mixed failure (partially adhesive, partially cohesive). A modified t-test with Bonferroni correction was used to analyze the SFS data, and a complex chi-square test was used to analyze the fracture modes. The SFS of OX was significantly greater than that of GB at both 5 and 10 Hz. However, no significant differences in SFS were found among the three frequencies (5, 10, and 20 Hz) in the three self-etch adhesive systems. Furthermore, no significant differences in bond failure mode were observed among the three frequency rates in all the three adhesives used.(J Oral Sci 58, 539-546, 2016). PMID- 28025439 TI - Human soluble receptor for advanced glycation end products and tumor necrosis factor-alpha as gingival crevicular fluid and serum markers of inflammation in chronic periodontitis and type 2 diabetes. AB - The present study aimed to evaluate the levels of soluble receptor for advanced glycation end products (sRAGE) and tumor necrosis factor-alpha (TNF-alpha) in serum and gingival crevicular fluid (GCF) in chronic periodontitis (CP) patients with and without type 2 diabetes mellitus (T2DM). A total of 70 subjects were divided into four groups: group 1 (n = 15; subjects with healthy periodontium); group 2 (n = 20; CP patients); group 3 (n = 20; CP patients with T2DM); and group 4 (n = 15; CP patients without T2DM). The serum and GCF levels of human sRAGE and TNF-alpha were assessed using enzyme-linked immunosorbent assay and correlated with clinical parameters, including probing depth, gingival index and clinical attachment level. Both sRAGE and TNF-alpha levels varied with the inflammatory state of the patient; the highest levels of sRAGE were seen in group 1, whereas the lowest levels in group 3 (P < 0.05). Conversely, TNF-alpha levels were found to be the highest in group 3 and lowest in group 1 (P < 0.05). Thus, human sRAGE and TNF-alpha can be considered as possible GCF and serum markers of inflammatory activity in CP and T2DM.(J Oral Sci 58, 547-553, 2016). PMID- 28025440 TI - Toll-like receptor 4 polymorphism is associated with increased susceptibility to chronic obstructive pulmonary disease in Han Chinese patients with chronic periodontitis. AB - The aim of the present study was to evaluate the association of single nucleotide polymorphisms (SNPs) in toll-like receptor 4 (TLR4) with chronic obstructive pulmonary disease (COPD) in Han Chinese patients with chronic periodontitis (CP). Six candidate SNPs of TLR4-rs10759930, rs10983755, rs11536879, rs1927907, rs11536889 and rs7873784-and 18 haplotype-tagging SNPs (tagSNPs) were genotyped in 339 patients with chronic periodontitis only (CP group), and 373 CP patients with COPD (CP with COPD group). The genotype distribution and allele frequencies of TLR4 rs1927907 among the CP (AA: 26, 8.5%, AG: 109, 35.5%, GG: 172, 56.0%) and CP with COPD (AA: 41, 12.0%, AG: 143, 41.7%, GG: 159, 46.4%) groups were significantly different (P = 0.039). After adjusting for age, sex, smoking status, and oral hygiene habits, CP patients carrying the AG polymorphism in TLR4 rs1927907 were found to be more susceptible to concomitant COPD than those carrying the GG genotype (P = 0.005, OR = 1.94, 95% CI for OR: 1.22-3.03). In conclusion, TLR4 gene polymorphism plays a role in the common pathophysiology of CP and COPD, indicating that CP patients with TLR4 gene rs1927907 polymorphism may be more susceptible to COPD.(J Oral Sci 58, 555-560, 2016). PMID- 28025441 TI - Effects of auxiliary device use on smear layer removal. AB - This study evaluated the effects of different auxiliary irrigation devices on smear layer removal with a chelating solution (QMix). Fifty single-rooted permanent human teeth were shaped with a sequence of nickel-titanium instruments. A 2% chlorhexidine gel was used as a chemical auxiliary substance during preparation. Samples were assigned to five groups (n = 10 each) according to final irrigation protocol, namely, distilled water (control group), QMix 1 min, QMix + passive ultrasonic irrigation (PUI), QMix + plastic endodontic finishing file (EC), and QMix 3 min. Teeth were prepared and evaluated by scanning electron microscopy, and three photomicrographs (magnification, 1,000*) were obtained for each root third. Two blinded and precalibrated evaluators analyzed and scored the images, and the data were statistically analyzed by the Kruskal-Wallis and Dunn tests (P < 0.05). Groups were ranked according to the extent of smear layer removal. The total area of the root canal walls and apical root thirds was calculated, and the groups ranked PUI > EC = QMix 3 min > QMix 1 min > control. QMix 1 min was effective for smear layer removal only when used with auxiliary devices, and QMix + passive ultrasonic irrigation yielded the best results, particularly for the apical third.(J Oral Sci 58, 561-567, 2016). PMID- 28025442 TI - Clinical efficacy of a 1% Matricaria chamomile L. mouthwash and 0.12% chlorhexidine for gingivitis control in patients undergoing orthodontic treatment with fixed appliances. AB - This pilot study evaluated the clinical efficacy of a mouthwash containing 1% Matricaria chamomilla L. (MTC) extract in reducing gingival inflammation and plaque formation in patients undergoing orthodontic treatment with fixed appliances. This randomized, double-blind, placebo-controlled study enrolled a total of 30 males and females (age, 10-40 years) with fixed orthodontic appliances and a minimum of 20 natural teeth. The participants were allocated to three groups (n = 10 each) and asked to rinse with 15 mL of a placebo, 0.12% chlorhexidine (CHX), or 1% MTC mouthwash, immediately after brushing for 1 min, in the morning and evening, for 15 days. Data (mean +/- SD) on visible plaque index (VPI) and gingival bleeding index (GBI) were recorded on days 1 and 15. The placebo group exhibited increases in VPI and GBI (10.2% and 23.1%, respectively) from day 1 to day 15. As compared with placebo, VPI and GBI significantly decreased in the MTC group (-25.6% and -29.9%, respectively) and the CHX group ( 39.9% and -32.0%, respectively). In summary, MTC reduced biofilm accumulation and gingival bleeding in patients with gingivitis, probably because of its antimicrobial and anti-inflammatory activities.(J Oral Sci 58, 569-574, 2016). PMID- 28025443 TI - Direct and indirect antibacterial effects of various concentrations of triple antibiotic pastes loaded in a methylcellulose system. AB - We investigated the direct and indirect (residual) antibacterial effects of various concentrations of triple antibiotic paste (TAP) loaded into a methylcellulose system. Enterococcus faecalis (E. faecalis) was grown on sterilized dentin blocks (n = 60) and treated with clinically used TAP (1,000 mg/mL), low concentrations of methylcellulose-based TAP (100, 10, and 1 mg/mL), placebo paste, or 1.5% NaOCl (n = 10). The pastes were then removed, and biofilm disruption assays were performed. Additional dentin blocks (n = 120) were pretreated with the same experimental groups (n = 20). The pastes were rinsed off, and the samples were immersed independently in phosphate-buffered saline for 2 and 4 weeks (n = 10). E.faecalis was then grown on the dentin blocks, and biofilm disruption assays were performed. Fisher's Exact and Wilcoxon rank sum tests were used for statistical analyses. With regard to direct antibacterial effects, all treatment groups demonstrated complete eradication of biofilms in comparison to placebo paste, while 10 mg/mL of TAP or higher provided substantial residual antibacterial effects. However, dentin treated with 1 mg/mL of TAP or 1.5% NaOCl did not provide substantial residual antibacterial effects. Dentin pretreated with 10 mg/mL of TAP or higher exhibited extended residual antibacterial effects and can thus be used during endodontic regeneration.(J Oral Sci 58, 575-582, 2016). PMID- 28025444 TI - Histological evaluation of three techniques for caries removal. AB - A number of concepts and devices have been proposed for caries removal. Among these, the Er:YAG laser is a potential alternative to conventional mechanical treatment. This study compared the effectiveness of the Er:YAG laser with that of low-speed rotary instruments for removal of carious tissue in 26 extracted human molars and premolars with severe decay (i.e., large occlusal or proximal decay but no pulpal contact). The teeth were divided into three groups of eight teeth, and two teeth were used as controls. After sectioning all the teeth through the center of the carious lesion before excavation, each group was randomly assigned to three groups-Er:YAG laser versus tungsten bur, Er:YAG laser versus polymer bur, and polymer bur versus tungsten bur-to evaluate the efficacy of the three techniques. The time required for carious treatment of each half was recorded, and samples were then histologically examined. Mean duration of caries removal did not significantly differ in relation to the technique used. Histological analysis of tooth halves treated with the Er:YAG laser revealed a regular 5-um thick stained layer that appeared to be denatured collagen. A smear layer was often detectable in halves treated with carbide burs. A superficial disorganized layer, which was found to be affected dentin, was observed in halves treated with polymer burs. The present findings indicate that the three techniques were clinically and histologically effective in removing the infected dentin layer.(J Oral Sci 58, 583-589, 2016). PMID- 28025445 TI - Hypertension is a characteristic complication of X-linked hypophosphatemia. AB - X-linked hypophosphatemia (XLH) is a group of rare disorders caused by defective proximal tubular reabsorption of phosphate. Mutations in the PHEX gene are responsible for the majority of cases. There are very few reports of long-term complications of XLH other than skeletal and dental diseases. The aim of this study was to identify the phenotypic presentation of XLH during adulthood including complications other than skeletal and dental diseases. The clinical and biochemical phenotype of 22 adult patients with a PHEX gene mutation were examined retrospectively from their medical records. 6 patients had hypertension. The average age of hypertension onset was 29.0 years. Secondary hyperparathyroidism preceded the development of hypertension in 5 patients. 1 patient developed tertiary hyperparathyroidism. 15 patients had nephrocalcinosis. 2 patients had chronic renal dysfunction. Patients with hypertension had a significantly lower eGFR (p=0.010) compared to patients without hypertension. No significant difference was found in any other parameters. To examine the genotype phenotype correlation, 10 adult males were chosen for analysis. No significant genotype-phenotype correlation analysis was revealed in any of the complications. However, there was a possibility that the age at nephrocalcinosis onset was younger in the non-missense mutation group than in the missense mutation group (p=0.063). This study corroborated the view that early-onset hypertension could be one of the characteristic complications seen in XLH patients. Considering the limited number of our patients, further study is necessary to address a potential cause of hypertension. XLH patients require careful lifelong treatment. PMID- 28025446 TI - History and development of The Journal of Toxicological Sciences. AB - The Journal of Toxicological Sciences, published by The Japanese Society of Toxicology (JSOT), is an international scientific journal covering the entire field of toxicology. This article reviews the history of The Journal of Toxicological Sciences as well as actions taken by the Editorial Committee to improve the journal and the results of these initiatives. PMID- 28025447 TI - Platinum-Based Adjuvant Chemotherapy for Stage II and Stage III Squamous Cell Carcinoma of the Lung. AB - INTRODUCTION: The efficacy of platinum-based adjuvant chemotherapy (PBAC) for pathological stage II and stage III squamous cell carcinoma (SCC) of the lung was analyzed retrospectively. MATERIALS AND METHODS: The prognoses of 94 patients with stage II and stage III SCC with or without PBAC (more than three courses of cisplatin-, carboplatin-, and nedaplatin-based adjuvant chemotherapy) were compared. RESULTS: The mean observation period was 46.1 months. PBAC was not administered for the following reasons: 39 (55.7%) patients had comorbidities, 25 (35.7%) were older than 75 years, 19 (27.1%) patients underwent surgery before the approval of PBAC, and 3 (4.3%) patients could not continue PBAC (<=2 cycles) because of adverse events. PBAC patients (n = 24) were significantly younger than non-PBAC patients (n = 70; 66.3 vs 69.6 years old, respectively; p = 0.043). Disease-free survival (DFS) did not differ between PBAC and non-PBAC patients (55.0% and 67.1%, respectively; p = 0.266). PBAC patients tended to have worse overall survival (OS) than non-PBAC patients (56.1% and 70.2%, respectively; p = 0.138). PBAC was not prognostic for OS (hazard ratio (HR), 2.11; 95% confidence interval (CI), 0.82%-5.40%; p = 0.120). CONCLUSION: PBAC did not improve the prognoses of patients with pathological stage II or stage III SCC in the single institution experience. PMID- 28025448 TI - Cholesterol Levels of Six Fractionated Serum Lipoproteins and its Relevance to Coronary Heart Disease Risk Scores. AB - AIM: Evaluation of serum lipoprotein profiles including triglyceride (TG)-rich lipoprotein, that is, intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL), and chylomicron (CM) remnant is important to manage coronary heart disease (CHD) risk. The purpose of this study was to investigate CHD or cardiovascular disease (CVD) risk scores with cholesterol levels of six fractionated lipoprotein classes {high-density lipoprotein [HDL], low-density lipoprotein [LDL], IDL, VLDL, CM including CM remnant, and lipoprotein (a) [Lp (a)]} in Japanese healthy men. METHODS: The present study enrolled 161 healthy men without any medications. Lipoprotein profiles (fractionated lipoprotein cholesterol levels) were measured by anion-exchange high-performance liquid chromatography (AEX-HPLC) method and were compared with age, estimated glomerular filtration rate (eGFR), and three risk scores, that is, NIPPON DATA, Hisayama risk predicting model, and Suita score. RESULTS: Levels of LDL-cholesterol (C), VLDL-C, and CM-C significantly differed with age, while values of HDL-C, IDL-C, and Lp(a)-C were not different. The eGFR inversely correlated with LDL-C, IDL-C, VLDL-C, and CM-C. In a stepwise multiple logistic regression analysis, VLDL-C only correlated independently with eGFR. Three risk scores significantly correlated with CM-C. CONCLUSIONS: These results suggested that VLDL-C concentration contributes to an increased risk at early stages of renal dysfunction, and CM-C may serve as a marker for estimating CHD risk in Japanese healthy men. PMID- 28025449 TI - Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells. AB - Metformin is the first-line anti-hyperglycemic drugs commonly used to treat type 2 diabetes. Recent studies have shown that metformin can enhance bone formation through induction of endothelial nitric oxide synthase (eNOS). Human chorionic villous mesenchymal stem cells (CV-MSCs) are promising candidates for regenerative medicine. The present study aimed to investigate the effects of metformin on the osteogenic and adipocytic differentiation of human CV-MSCs, and to elucidate the underlying mechanism. CV-MSCs, prepared from human term placentae, were cultured with different concentrations of metformin. Treatment for 72 hours with 0.05 mM metformin had no noticeable effect on the proliferation of CV-MSCs. Consequently, CV-MSCs were cultured for seven or 14 days in the osteogenic medium supplemented with 0.05 mM metformin. Treatment for seven days with metformin increased the expression levels of osteogenic protein mRNAs, including alkaline phosphatase, runt-related transcription factor 2, and osteopontin. Metformin also enhanced the mineralization of CV-MSCs. Furthermore, metformin induced the expression of eNOS in CV-MSCs during osteogenic differentiation. By contrast, when CV-MSCs were cultured for 14 days in the adipogenic medium, 0.05 mM metformin inhibited the expression of adipogenic protein mRNAs, including proliferators-activated receptor-gamma and CCAAT/enhancer binding protein-alpha. The lipid droplet accumulation was also reduced on 28 days after metformin treatment. These findings indicate that metformin can enhance osteogenic differentiation of CV-MSCs and reduce adipocyte formation. The effect of metformin on osteogenic differentiation of CV-MSCs may be associated with eNOS expression. Our findings will highlight the therapeutic potential of metformin in osteoporosis and bone fracture. PMID- 28025450 TI - Application of fiber tractography and diffusion tensor imaging to evaluate spinal cord diseases in dogs. AB - Fiber tractography is a technique capable of depicting the three-dimensional structure and connectivity of nerve fibers using serial magnetic resonance diffusion tensor imaging (DTI). To establish fiber tractography and DTI methods in veterinary clinical medicine, we evaluated fiber tractography and DTI parameters: apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values, in various spinal cord diseases. Spinal cord DTI was examined in 28 dogs with spinal cord diseases. The ADC and FA values were measured at lesion sites and cranial normal sites on spinal cords, and both values of lesion sites were compared with normal sites. In thoracolumbar intervertebral disk herniation (IVDH) cases, depending on their neurologic grades, fiber tractography indicated rupture of fiber trajectories, loss of neuronal bundles and disorder of fiber directions. In these cases, the average ADC values at lesion sites significantly decreased compared with normal sites (P=0.016). In the progressive myelomalacia case, the average ADC and FA values of hyperintense swollen regions in T2WI decreased compared to both values in other disease cases. Finally, in the meningioma case, the continuity of fiber trajectories improved after the administration of an anticancer agent. This study suggests that fiber tractography and DTI are useful in the diagnosis and prognosis of veterinary spinal cord diseases. PMID- 28025451 TI - What Has Been Done in Japan and Other Countries about Trans Fatty Acids? PMID- 28025452 TI - Development and Evaluation of Event-Specific Quantitative PCR Method for Genetically Modified Soybean MON87701. AB - A real-time PCR-based analytical method was developed for the event-specific quantification of a genetically modified (GM) soybean event, MON87701. First, a standard plasmid for MON87701 quantification was constructed. The conversion factor (Cf) required to calculate the amount of genetically modified organism (GMO) was experimentally determined for a real-time PCR instrument. The determined Cf for the real-time PCR instrument was 1.24. For the evaluation of the developed method, a blind test was carried out in an inter-laboratory trial. The trueness and precision were evaluated as the bias and reproducibility of relative standard deviation (RSDr), respectively. The determined biases and the RSDr values were less than 30 and 13%, respectively, at all evaluated concentrations. The limit of quantitation of the method was 0.5%, and the developed method would thus be applicable for practical analyses for the detection and quantification of MON87701. PMID- 28025453 TI - Preparation of a Ammonia-Treated Lac Dye and Structure Elucidation of Its Main Component. AB - Lac dye and cochineal extract contain laccaic acids and carminic acid as the main pigments, respectively. Both laccaic acids and carminic acid are anthraquinone derivatives. 4-Aminocarminic acid (acid-stable carmine), an illegal colorant, has been detected in several processed foods. 4-Aminocarminic acid is obtained by heating cochineal extract (carminic acid) in ammonia solution. We attempted to prepare ammonia-treated lac dye and to identify the structures of the main pigment components. Ammonia-treated lac dye showed acid stability similar to that of 4-aminocarminic acid. The structures of the main pigments in ammonia-treated lac dye were analyzed using LC/MS. One of the main pigments was isolated and identified as 4-aminolaccaic acid C using various NMR techniques, including 2D INADEQUATE. These results indicated that ammonia-treatment of lac dye results in the generation of 4-aminolaccaic acids. PMID- 28025454 TI - Determination of Diphenylamine in Agricultural Products by HPLC-FL. AB - A method for the determination of diphenylamine in agricultural products was developed. Diphenylamine was extracted with acetonitrile from a sample under an acidic condition, passed through a C18 cartridge column, re-extracted with n hexane, cleaned up on a PSA cartridge column, determined by HPLC with fluorescence detector and confirmed by liquid chromatography with tandem mass spectrometry. Average recoveries (n=5) from brown rice, corn, soybeans, potato, cabbage, eggplant, spinach, orange, apple and green tea were in the range from 76.7 to 94.9%, and the relative standard deviations were from 0.6 to 5.8% at concentrations equal to the maximum residue limits (MRLs). The quantification limits were 0.01 mg/kg, which is the uniform limit in the positive list system for agricultural chemical residues in food in Japan. PMID- 28025455 TI - Analysis of Acidic Tar Dyes in High Protein Food: Effect of pH of Column Loading Solution for Clean-Up. AB - The effect of pH of the clean-up process in the analysis of 11 permitted tar dyes in high protein food was investigated by using a handmade polyamide column (PA column) and Oasis HLB. Boiled fish paste spiked with the 11 dyes was extracted with appropriate solvents and the pH of the extract was adjusted to 3.0-7.0 in increments of 0.5, followed by clean-up with the PA column. At pH 3.0-5.5, precipitate formed in the extract clogged the column, and the recoveries of R3, R104 and R105 were 26-68%. At pH 6.0-7.0, clogging was not observed and the recoveries of the 3 dyes were somewhat higher, at 38-79%. The recoveries of other dyes were more than 80% at pH 3.0-7.0. With Oasis HLB, column loading was conducted at pH 11.0, and the recoveries of the 3 dyes improved to 70-83%. In conclusion, all 11 dyes could be cleaned-up with the PA column and Oasis HLB and the recoveries exceeded 70%. PMID- 28025456 TI - Survey of Allergenic Substances in Foods in Chiba Prefecture (Fiscal Years 2004 2014). AB - We surveyed the presence of allergenic substances such as egg, milk, wheat, buckwheat, peanut, shrimp and crab in foods produced or distributed in Chiba Prefecture during the fiscal years 2004-2014. Six hundred and ninety-five samples that did not display the target allergenic substances were screened by using ELISA. Three percent of the samples (21/695 samples) were found to be positive. Wheat had the highest positivity rate of 9.7% (10/103 samples). Among the samples tested, advisory labeling was displayed in the case of 109 samples. Among these samples, 77.1%(84/109 samples) contained less than 1.0 MUg/g of the specified allergen. Out of the 21 samples that tested positive in the screening-test, 16 did not display the advisory labeling. PMID- 28025457 TI - Interlaboratory Study on Caprolactam Test for Food-Contact Nylon Products. AB - The Japanese Food Sanitation Law sets a limit on the migration level of caprolactam for food-contacting nylon products. Here, we carried out an interlaboratory study in twenty laboratories to evaluate the performance of the official GC-FID test method and a GC-MS method as an alternative test method to the official method. Each laboratory quantified caprolactam in three test solutions in 20% ethanol as blind duplicates using GC-FID or GC-MS. The official method (GC-FID with absolute calibration) gave trueness, repeatability (RSDr) and reproducibility (RSDr) values of 96-97%, 3.3-5.4% and 4.0-6.7%, respectively. These values met the target criteria (trueness: 80-110%, RSDr: 10%, RSDr: 25%). The performance of the method was further improved by the introduction of heptalactam as an internal standard. As for GC-MS method, some values of the RSDr exceeded 10% when absolute calibration was used. However, when an internal standard was introduced, the trueness, RSDr and RSDr of GC-MS method were all acceptable at 94-96%, 2.0-4.4% and 7.0-9.4%, respectively. Therefore, GC-MS with an internal standard is available as an alternative test method to the official method. PMID- 28025458 TI - Adverse effects of maternal exposure to bisphenol F on the anxiety- and depression-like behavior of offspring. AB - Bisphenol A (BPA), a well-known endocrine disruptor, is metabolized and eliminated rapidly from the body in adult animals. However, many authors have reported that perinatal BPA exposure alters development of the brain, reproductive system and behavior in the next generation. Recently, BPA substitutes, especially bisphenol F (BPF), have been used because of concerns about the influence of BPA on children, although the actual effects on the next generation are unknown. In this study, we observed behavioral adverse effects of the offspring of mice exposed to BPA or BPF in fetal period. Female C57BL/6 mice were given oral BPA or BPF (0 or 10 mg/kg body weight) daily from gestational day 11.5 to 18.5. The open field test, the elevated plus maze test and the forced swim test were performed at postnatal week 10. BPF exposure altered offspring behavior significantly, resulting in increases in anxiety and depressive state. The influence of BPF was stronger than that of BPA. We demonstrated novel evidence that BPF influences the behavior of offspring. PMID- 28025459 TI - TGP attenuates endoplasmic reticulum stress and regulates the expression of thioredoxin-interacting protein in the kidneys of diabetic rats. AB - Recent evidence suggests that the endoplasmic reticulum stress (ERS)-thioredoxin interacting protein (TXNIP)-inflammation chain contributes to diabetic renal injury. The aim of the current study was to investigate whether total glucosides of peony (TGP) could inhibit ERS and attenuate up-regulation of TXNIP in the kidneys of rats with streptozotocin-induced diabetes. TGP was orally administered daily at a dose of 50, 100, or 200 mg/kg for 8 weeks. The expression of glucose regulated protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (p-PERK), phosphor- eukaryotic translation initiation factor 2alpha (p-eIF2alpha), C/EBP homologous protein (CHOP), and TXNIP was assessed. Results indicated that TGP significantly decreased diabetes-induced albuminuria and it acted by down regulating activation of the ERS-TXNIP-inflammation chain in the kidneys of diabetic rats. These findings indicate that renoprotection from TGP in diabetic rats possibly contributed to inhibition of ERS and decreased expression of TXNIP. These findings also offer a new perspective from which to study the molecular mechanisms of diabetic nephropathy and prevent its progression. PMID- 28025460 TI - Riser Pattern Is a Novel Predictor of Adverse Events in Heart Failure Patients With Preserved Ejection Fraction. AB - BACKGROUND: The cardiovascular prognosis of heart failure with preserved ejection fraction (HFpEF) has been shown to be similar to that of heart failure with reduced ejection fraction (HFrEF). It is unknown which factors predict cardiovascular outcome in HFpEF. We tested the hypothesis that the abnormal pattern of circadian blood pressure (BP) rhythm known as the riser BP pattern is associated with adverse outcomes in HFpEF.Methods and Results:We performed a prospective, observational cohort study of hospitalized HF patients who underwent ambulatory BP monitoring (ABPM). Five hundred and sixteen hospitalized HF patients (age, 69+/-13 years; male, n=321 [62%]; female, n=195 [38%]) were followed up for a median 20.9 months. The composite outcome consisting of all cause mortality and cardiovascular events was observed in 220 patients. On Kaplan Meier analysis, the riser BP pattern subgroup had a significantly higher incidence of the composite outcome than the other subgroups of HFpEF patients (HR, 3.01; 95% CI: 1.54-6.08, P<0.01), but not the HFrEF patients. CONCLUSIONS: The riser BP pattern was found to be a novel predictor of cardiovascular outcome in HFpEF patients. PMID- 28025461 TI - Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy. AB - BACKGROUND: The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dtmax) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patient's prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM).Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I-II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2alpha) were observed exclusively in the patients exhibiting a BiF pattern. CONCLUSIONS: The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease. PMID- 28025462 TI - Empagliflozin and Cardiovascular Outcomes in Asian Patients With Type 2 Diabetes and Established Cardiovascular Disease - Results From EMPA-REG OUTCOME(r). AB - BACKGROUND: In the EMPA-REG OUTCOME(r)trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular (CV) events (3 point MACE: composite of CV death, non-fatal myocardial infarction, or non-fatal stroke) by 14%, CV death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in patients with type 2 diabetes (T2DM) and established CV disease. We investigated the effects of empagliflozin in patients of Asian race.Methods and Results:Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Of 7,020 patients treated, 1,517 (21.6%) were of Asian race. The reduction in 3-point MACE in Asian patients was consistent with the overall population: 3-point MACE occurred in 79/1,006 patients (7.9%) in the pooled empagliflozin group vs. 58/511 patients (11.4%) in the placebo group (hazard ratio: 0.68 [95% confidence interval: 0.48-0.95], P value for treatment by race interaction (Asian, White, Black/African-American): 0.0872). The effects of empagliflozin on the components of MACE, all-cause mortality, and heart failure outcomes in Asian patients were consistent with the overall population (P-values for interaction by race >0.05). The adverse event profile of empagliflozin in Asian patients was similar to the overall trial population. CONCLUSIONS: Reductions in the risk of CV outcomes and mortality with empagliflozin in Asian patients with T2DM and established CV disease were consistent with the overall trial population. PMID- 28025463 TI - Value of 3-Dimensional Speckle Tracking Echocardiography in the Prediction of Microvascular Obstruction and Left Ventricular Remodeling in Patients With ST Elevation Myocardial Infarction. AB - BACKGROUND: In patients with myocardial infarction (MI), microvascular obstruction (MVO) determined by cardiac magnetic resonance imaging (CMR) is associated with left ventricular (LV) remodeling and worse prognosis.Methods and Results:In 71 patients with ST-segment elevation MI (STEMI) treated by primary percutaneous coronary intervention (PCI), speckle tracking echocardiography (STE) and CMR were performed early after PCI. All patients underwent CMR at 6 months after hospital discharge to assess the occurrence of LV remodeling. The values of 3-dimensional (3D)-circumferential strain (CS), area change ratio (ACR), and 2 dimensional (2D)-CS were significantly different for the transmural extent of infarct, whereas the values of 3D- and 2D- longitudinal strain (LS) were not significantly different. In transmural infarct segments, the values of 3D-CS and ACR were significantly lower in segments with MVO than in those without MVO. At 6 month follow-up, LV remodeling was observed in 22 patients. In multivariable logistic regression models, global 3D-CS and ACR were significant determinants of LV remodeling rather than the number of MVO segments. CONCLUSIONS: Regional 3D-CS and ACR reflected the transmural extent of infarct and were significantly associated with the presence of MVO. In addition, global 3D-CS and ACR were preferable to the extent of MVO in the prediction of LV remodeling. PMID- 28025464 TI - Tricuspid Valve Replacement vs. Repair in Severe Tricuspid Regurgitation. AB - BACKGROUND: The aim of this study was to compare early and late outcomes of tricuspid valve replacement (TVR) and tricuspid valve repair (TVr) for severe tricuspid regurgitation (TR).Methods and Results:From 1994 to 2012, 360 patients (mean age, 58+/-13 years) with severe TR underwent TVR (n=97, 27%) or TVr (n=263, 73%). Among them, 282 patients (78%) had initial rheumatic etiology, and 307 patients (85%) had preoperative atrial fibrillation. The TVR group had higher total bilirubin, higher baseline central venous pressure, and higher incidence of previous cardiac operation. There was no difference in early mortality (TVR:TVr, 3.1%:3.4%, P=0.877). Ten-year overall survival (TVR:TVr, 72%:70%, P=0.532) and 10 year freedom from cardiac death (TVR:TVr, 76%:77%, P=0.715) were not significantly different between groups. After applying stabilized inverse probability of treatment weighting methods, there were still no significant differences in early mortality (P=0.293), overall survival (P=0.649) or freedom from cardiac death (P=0.870). Higher NYHA functional class, total bilirubin (>2 mg/dL), initial central venous pressure, and cardiopulmonary bypass time were independent predictors of early mortality. Older age, LV dysfunction (EF <40%), and hemoglobin <10 g/dL were independent predictors of late cardiac mortality. CONCLUSIONS: Compared with TVr, TVR had acceptable early and late outcomes in patients with severe TR. TVR can be considered as a valid option with acceptable clinical outcomes in patients who are not suitable candidates for TVr. PMID- 28025465 TI - Myocardial Regeneration for Humans - Modifying Biology and Manipulating Evolution. AB - Cardiovascular disease remains the leading cause of death worldwide and developing novel therapies to treat and cure the disease remains a high priority in the healthcare research community. Adult stem cells were successful in entering numerous clinical trials over the past 15 years in attempts to regenerate the heart. First-generation adult stem cell therapies for myocardial regeneration were highly promising in small animal models but realized benefits in humans were far more modest. Consequently, second-generation therapeutic approaches in early implementation phases have focused on enhancing cellular properties with higher survival and regenerative potential. Genetic programming dictates cellular fate, so understanding genetic composition and responses at the gene level to influence the outcome of the cell is essential for successful outcomes in regenerative medicine. Genetic editing is at the forefront of scientific innovation and as basic scientific research continues to expand upon understanding eukaryotic regenerative themes, a clearer vision of the possible future therapeutic approaches can be realized. Ultimately, enhancing biology and manipulating evolutional selection of cellular properties will be critical to achieving clinically relevant and biologically meaningful cardiac regeneration. PMID- 28025466 TI - Deterioration of epithelium mediated mechanisms in diabetic-antigen sensitized airways of guinea pigs. AB - BACKGROUND: The onset of diabetes causes disruption of respiratory epithelial mediators. The present study investigates whether diabetes modifies the epithelium mediated bronchial responses in hyper-reactive airway smooth muscle (ASM) primarily through nitric oxide (NO), cyclooxygenase (COX), and epithelium derived hyperpolarizing factor (EpDHF) pathways. METHODS: Experimental model of guinea pigs having hyper-reactive airways with or without diabetes were developed. The responses of tracheal rings to cumulative concentrations of acetylcholine (ACh) and isoproterenol (IP) in the presence and absence of epithelium and before and after incubation with NO, K+ATP and COX inhibitors, N (omega)-Nitro-L-arginine methyl ester (L-NAME; 100 MUM), glybenclamide (10 MUM) and indomethacin (100 MUM) were assessed. RESULTS: In diabetic guinea pigs with hyper-reactive airways, a decrease in ACh induced bronchoconstriction was observed after epithelium removal and after incubation with L-NAME/indomethacin, suggesting damage to NO/COX pathways. Hyper-reactivity did not alter the response of trachea to ACh but affected the response to IP which was further reduced in hyper-reactive animals with diabetes. The ASM response to IP after glybenclamide treatment did not alter in hyper-reactive guinea pigs and diabetic guinea pigs with hyper-reactive airways, suggesting damage to the EpDHF pathway. Treatment with indomethacin reduced IP response in the hyper-reactive model, and did not produce any change in diabetic model with hyper-reactive airways, indicating further disruption of the COX pathway. CONCLUSION: EpDHF pathway is damaged in hyper-reactive guinea pigs and in diabetic guinea pigs with hyper-reactive airways. Diabetes further aggravates the NO and COX mediated pathways in diabetic guinea pigs with hyper-reactive airways. PMID- 28025467 TI - Mechanical Thrombectomy Using the Trevo ProVue in 50 Consecutive Patients with Anterior Circulation Stroke: A Single-Center Experience after Approval of the Stent Retriever in Japan. AB - Mechanical thrombectomy using the stent retriever has been proven to be effective for select patients with acute ischemic stroke. We evaluated our early experience using the device after its approval in 2014 in Japan, with a special emphasis on the occlusion site. Fifty consecutive endovascular revascularization procedures for treating anterior acute large vessel occlusion were performed using the Trevo ProVue as the first-line device at our institute between April 2015 and March 2016. Focusing on the involvement of the M1-M2 bifurcation with deployment or retrieval of the stent retriever, we regarded the middle cerebral artery M1 mid portion as the boundary and divided the cases into proximal (n = 26) and distal (n = 24) groups. We assessed the overall clinical outcome and compared the outcome between the two groups. Among 50 patients (median age, 80 years; National Institutes of Health Stroke Scale score (NIHSS) score, 20), successful (modified Thrombolysis in Cerebral Infarction score (TICI) 2b or 3) or complete revascularization (TICI 3) was achieved in 41 patients (82%; 88% in the proximal group vs 75% in the distal group, P = 0.28) and in 27 patients (54%; 73% vs 33%, P = 0.01), respectively. Symptomatic intracranial hemorrhage occurred in three patients (6%; 4% vs 8%, P = 0.60). A good outcome (mRS score 0 to 2) was obtained in 25 patients at 90 days (50%; 54% vs 46%, P = 0.78). Mechanical thrombectomy using the Trevo ProVue was safe and effective in patients with acute cerebral artery occlusion, especially for proximal occlusions. The efficacy of the procedure for distal occlusions was somewhat inferior to those for proximal occlusions, which might be resolved by next generation devices. PMID- 28025468 TI - Evaluation of Fetal Thyroid with 3D Gradient Echo T1-weighted MR Imaging. AB - PURPOSE: The characteristics of fetal thyroid on magnetic resonance (MR) imaging, including normal thyroid and disorders other than goiter have not been fully evaluated. Our aim was to assess fetal thyroid using three dimensional (3D) gradient echo (GRE) T1-weighted MR imaging and to examine the usefulness of this modality. MATERIALS AND METHODS: The study included 27 3D GRE T1-weighted images from 26 fetuses. The largest possible region of interest (ROI) within the thyroid at the slice level depicting the thyroid was manually defined and three circular ROIs on neck muscle were manually defined on the image slices showing the highest signal intensity (SI) of the thyroid. Maximum and mean thyroid-to-muscle SI ratios (SIRs) were then calculated as SIR = maximum or mean thyroid SI/muscle SI. RESULTS: The thyroid could not be identified in two cases. Fetal thyroid function was normal in 17 cases, and there were 7 cases of hypothyroidism (6 transient and 1 thyroid dysgenesis). There was no linear relationship between mean and maximum SIR and gestational age. The mean and maximum SIR in the cases of normal fetal thyroid were 1.85 +/- 0.20 and 2.61 +/- 0.39, and the mean and maximum SIR in fetal hypothyroidism were 1.58 +/- 0.20 and 2.13 +/- 0.37. Mean (P = 0.0088) and maximum (P = 0.0221) SIR values were significantly different between euthyroid and hypothyroid fetuses. CONCLUSION: Thyroid SIR measurement provided useful information regarding fetal thyroid function. PMID- 28025469 TI - MR Spectroscopy in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids and Asymptomatic Carriers of Colony-stimulating Factor 1 Receptor Mutation. AB - PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare neurodegenerative disorder with various clinical presentations. Mutation of the colony-stimulating factor 1 receptor (CSF1R) gene is considered to be a cause of this autosomal dominant disorder. The purpose of this study was to report magnetic resonance spectroscopy (MRS) findings in patients with HDLS and asymptomatic carriers and to clarify the use of MRS in this disease. MATERIALS AND METHODS: In this retrospective, institutional review board-approved study, we included four consecutive patients, genetically diagnosed with HDLS, and two asymptomatic carriers after acquiring informed consent. We performed single-voxel MRS of the left centrum semiovale on a 3-T clinical scanner. We also included a sex-matched normal dataset. We quantified N-acetylaspartate (NAA), creatine, choline-containing compounds (Cho), glutamine, glutamate (Glu), myo-inositol (Ins), glutathione, lactate (Lac), and gamma-amino butyric acid using LCModel. We performed statistical analysis, and P value <0.05 was considered significant. RESULTS: In HDLS cases, MRS revealed decreased NAA and Glu concentrations, which probably reflected neuronal damage and/or loss, and a subsequent reduction of neurotransmitters. A patient with HDLS also had increased Cho and Ins concentrations, indicating gliosis, and increased Cho concentration was also observed in an asymptomatic carrier. This suggests that metabolic changes had already occurred in an asymptomatic state. CONCLUSION: We demonstrated changes in metabolite concentrations not only in patients with HDLS but also in asymptomatic CSF1R mutation carriers. Our study indicates that MRS is a potentially useful tool for the analysis of metabolic and pathophysiological findings of HDLS, even during the early stages of disease. PMID- 28025470 TI - Virologists are "Symbionts" in Microbial Ecology. PMID- 28025471 TI - [New Colonoscopy Devices to Improve Colon Neoplasm Detection]. AB - Early detection and removal of adenomatous polyps can prevent the development of colorectal cancer. However, it is fairly common-up to 20%-for polyps to be undetected in a colonoscopy due to poor visualization of the proximal aspect of colonic folds and anatomical flexures. To overcome these limitations, many new endoscopes and accessories have been developed. A wide-angle colonoscopy did not improve the detection of adenoma compared with the standard colonoscopy. An extra wide angle and Retroview colonoscopies showed a significantly lower miss rate of polyps in the colon model. However, clinical trials are mandatory in the future. The recently introduced full spectrum endoscopy system showed a significantly higher adenoma detection rate than the standard forward-viewing colonoscopy. In accessories, The cap-assisted colonoscopy showed only a marginal or no benefit on the detection of polyps and adenomas. In contrast, a colonoscopy with Endocuff, EndoRings, and G-eye have showed significantly lower adenoma miss rates. The Third Eye, which provides additional retrograde viewing, has revealed a significant improvement in the detection of adenoma and polyp. However, the Third Eye Retroscope was limited by its deployment through the working channel of the scope. Recently, the Third Eye Panoramic cap, which was designed to overcome the limitation of the Third Eye Retroscope, was introduced. In the future, this would be needed to evaluate the effectiveness, efficiency and safety for these new colonoscopies and accessories. PMID- 28025472 TI - [Molecular Classification of Colorectal Cancers and Clinical Application]. AB - The molecular genetics of colorectal cancers (CRCs) is among the best understood of common human cancers. It is difficult to predict the prognosis and/or to predict chemoresponding in CRC patients. At present, prognosis is based predominantly on the tumor stage and pathological examination of the disease. Molecular classification of CRCs, based on genomics and transcriptomics, proposed that CRCs can be classified into at least three-to-six subtypes, depending on the gene expression pattern, and groups of marker genes representing to each subtype have also been reported. Gene expression-based subtyping is now widely accepted as a relevant source of disease stratification. We reviewed the previous studies on CRC subtyping, international consortium dedicated to large-scale data sharing and analytics recently established four consensus molecular subtypes with distinguishing features. Predictive markers identified in these studies are under investigation and large-scale clinical evaluations of molecular markers are currently in progress. PMID- 28025473 TI - [Target Therapy in Unresectable or Metastatic Colorectal Cancer]. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Korea. Despite recent developments in the treatment of CRC, the median overall survival time in patients with metastatic CRC is less than 30 months. The biologic agents that target the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have proven clinical benefits in the treatment of patient with metastatic CRC. Anti-EGFR agents, including cetuximab and panitumumab, as well as anti-VEGF agents, including bevacizumab, aflibercept, ramucirumab, and regorafenib have been shown to extend survival in combination with cytotoxic chemotherapy. In particular, the addition of anti-EGFR agents has demonstrated significant efficacy in patients with the RAS wild-type metastatic CRC. In the future, building a personalized treatment strategy, according to the clinical characteristics and biologic features of patients with unresectable or metastatic CRC, will be necessary. In this review, we summarized the mechanisms of target therapy, the results of main clinical trials, and the guideline of clinical practice in patients with unresectable or metastatic CRC. PMID- 28025474 TI - Mediastinal Tuberculous Lymphadenitis Diagnosed by Endosonographic Fine Needle Aspiration. AB - Isolated mediastinal tuberculous lymphadenitis is clinically rare. Its clinical presentation may mimic an esophageal submucosal tumor by extrinsic compression. A 26-year-old woman was referred to our hospital for an esophageal subepithelial tumor. A 15*10 mm sized subepithelial lesion was found 30 cm from the upper incisors on esophagogastroduodenoscopy. We diagnosed the lesion as a submucosal tumor, and performed endoscopic ultrasonography-guided fine needle aspiration for a pathologic diagnosis. The histologic examination revealed granulomatous inflammation consistent with tuberculosis. We suggest that the use of endoscopic ultrasonography and fine needle aspiration may be helpful in making an early diagnosis and planning for an optimal treatment. PMID- 28025475 TI - [A Case of Tenofovir-associated Fanconi Syndrome in Patient with Chronic Hepatitis B]. AB - Tenofovir disoproxil fumarate (TDF) is one of the most widely used treatment options for human immunodeficiency virus (HIV) and HBV infections. Despite its efficacy and safety, some cases of nephrotoxicity have been reported in the treatment of HIV patients. Even more recently, very few cases of Fanconi syndrome associated with tenofovir therapy in HBV monoinfection have been reported. Herein, we report a case of a 47-year-old male with an HBV monoinfection, who developed Fanconi syndrome and a secondary osteomalacia with multiple bone pain. After TDF withdrawal and supplementation of calcitriol, his renal function was reverted. Although the overall risk of TDF-associated nephrotoxicity is very low, both glomerular and tubular function should be monitored in patients undergoing TDF treatment. PMID- 28025476 TI - A Case of Hepatocellular Carcinoma Presenting as a Gingival Mass. AB - Oral metastatic tumor, which is uncommon and represents less than 1% of malignant oral neoplasms, usually arises from a primary mucosal or cutaneous cancer located in the head and neck regions. Metastasis of hepatocellular carcinoma (HCC) to the oral cavity, especially to gingiva, is extremely rare. A 50-year-old man, who was a chronic alcoholic and hepatitis B virus carrier, presented with abdominal distension and weight loss for the past 3 months. Three-phased contrast-enhanced abdominal CT revealed numerous conglomerated masses in the liver, suggesting huge HCCs arising in the background of liver cirrhosis with a large amount of ascites. He complained of recurrent profuse bleeding from the left upper gingival mass. A facial CT revealed an oral cavity mass destructing the left maxillary alveolar process and hard palate, which was diagnosed as metastatic HCC by an incisional biopsy. Herein, we report a case of metastatic HCC to the gingiva. PMID- 28025477 TI - Duodenal Loop Obstruction as an Unusual Cause of Acute Pancreatitis: A Case Series. AB - Duodenal loop obstruction is an unusual cause of acute pancreatitis. Increased intraluminal pressure hinders pancreatic flow, causing dilatation of the pancreatic duct and inducing acute pancreatitis. We experienced three cases of acute pancreatitis that resulted from duodenal loop obstruction after (1) an esophagectomy with gastric pull-up procedure for esophageal cancer, (2) a gastrectomy with Billroth I reconstruction for gastric cancer, and (3) a gastrojejunostomy for abdominal trauma. An abdominal CT scan revealed a distended duodenal loop, dilated pancreatic duct, and inflamed pancreas with fluid collection. Acute pancreatitis with duodenal loop obstruction was diagnosed by abdominal pain, elevated serum amylase/lipase, and abdominal CT findings. Immediate decompression with a nasogastric tube was performed, and all patients showed improvement within one week after admission. Each patient was followed up for more than two years without recurrence. Our findings suggest the usefulness of nasogastric tube decompression as the first line of treatment for acute pancreatitis related to duodenal loop obstruction. PMID- 28025478 TI - CD11c+ CD8+ T Cells Reduce Renal Fibrosis Following Ureteric Obstruction by Inducing Fibroblast Apoptosis. AB - Tubulointerstitial fibrosis is a common consequence of various kidney diseases that lead to end-stage renal failure, and lymphocyte infiltration plays an important role in renal fibrosis. We previously found that depletion of cluster of differentiation 8+ (CD8+) T cells increases renal fibrosis following ureteric obstruction, and interferon-gamma (IFN-gamma)-expressing CD8+ T cells contribute to this process. CD8+ T cells are cytotoxic T cells; however, whether their cytotoxic effect reduces fibrosis remains unknown. This study showed that CD8+ T cells isolated from obstructed kidney showed mRNA expression of the cytotoxicity related genes perforin 1, granzyme A, granzyme B, and FAS ligand; additionally, CD8 knockout significantly reduced the expression levels of these genes in obstructed kidney. Infiltrated CD8+ T cells were distributed around fibroblasts, and they are associated with fibroblast apoptosis in obstructed kidney. Moreover, CD11c+ CD8+ T cells expressed higher levels of the cytotoxicity-related genes than CD11c- CD8+ T cells, and infiltrated CD11c+ CD8+ T cells in obstructed kidney could induce fibroblast death in vitro. Results indicated that induction of fibroblast apoptosis partly contributed to the effect of CD8+ T cells on reduction of renal fibrosis. Given that inflammatory cells are involved in fibrosis, our results suggest that kidney fibrosis is a multifactorial process involving different arms of the immune system. PMID- 28025479 TI - Housing of Cull Sows in the Hours before Transport to the Abattoir-An Initial Description of Sow Behaviour While Waiting in a Transfer Vehicle. AB - In modern pig production, sows are transported by road to abattoirs. For reasons of biosecurity, commercial trucks may have limited access to farms. According to Danish regulations, sows can be kept in stationary transfer vehicles away from the farm for up to two hours before being loaded onto the commercial truck. We aimed to describe the behaviour of sows in transfer vehicles. This preliminary, exploratory study included data from 11 loads from a total of six Danish sow herds. Selection of animals to be slaughtered was done by the farmers. Clinical registrations were made before collection of the sows, after which they (in groups of 7-13) were mixed and moved to the transfer vehicle (median stocking density: 1.2 sow/m2), and driven a short distance to a public road. The duration of the stays in the transfer vehicles before being loaded onto the commercial trucks ranged from 6-59 min. During this period, the median frequency of aggressive interactions per load was 18 (range: 4-65), whereas the median frequency of lying per load was 1 (range: 0-23). The duration of the stay correlated positively with the frequency of aggressive interactions (rs = 0.89; n = 11; p < 0.001) and with the frequency of lying (rs = 0.62; n = 11; p < 0.05). Frequency of aggressive interactions correlated positively with the temperature inside the transfer vehicle (rs = 0.89; n = 7; p < 0.001). These preliminary results are the first to describe the behaviour of cull sows during waiting in transfer vehicles, and may suggest that this period can be challenging for sow welfare, especially for longer stays and during hot days. PMID- 28025480 TI - Measurement and Geometric Modelling of Human Spine Posture for Medical Rehabilitation Purposes Using a Wearable Monitoring System Based on Inertial Sensors. AB - This paper presents a mathematical model that can be used to virtually reconstruct the posture of the human spine. By using orientation angles from a wearable monitoring system based on inertial sensors, the model calculates and represents the curvature of the spine. Several hypotheses are taken into consideration to increase the model precision. An estimation of the postures that can be calculated is also presented. A non-invasive solution to identify the human back shape can help reducing the time needed for medical rehabilitation sessions. Moreover, it prevents future problems caused by poor posture. PMID- 28025481 TI - A Unified Framework for Street-View Panorama Stitching. AB - In this paper, we propose a unified framework to generate a pleasant and high quality street-view panorama by stitching multiple panoramic images captured from the cameras mounted on the mobile platform. Our proposed framework is comprised of four major steps: image warping, color correction, optimal seam line detection and image blending. Since the input images are captured without a precisely common projection center from the scenes with the depth differences with respect to the cameras to different extents, such images cannot be precisely aligned in geometry. Therefore, an efficient image warping method based on the dense optical flow field is proposed to greatly suppress the influence of large geometric misalignment at first. Then, to lessen the influence of photometric inconsistencies caused by the illumination variations and different exposure settings, we propose an efficient color correction algorithm via matching extreme points of histograms to greatly decrease color differences between warped images. After that, the optimal seam lines between adjacent input images are detected via the graph cut energy minimization framework. At last, the Laplacian pyramid blending algorithm is applied to further eliminate the stitching artifacts along the optimal seam lines. Experimental results on a large set of challenging street view panoramic images captured form the real world illustrate that the proposed system is capable of creating high-quality panoramas. PMID- 28025482 TI - Implication of the Receptor Tyrosine Kinase AXL in Head and Neck Cancer Progression. AB - Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested in clinical trials for patients suffering from non-small cell lung cancer or acute myeloid leukemia. Our study investigates AXL expression during HNSCC progression and its use as a potential therapeutic target in HNSCC. AXL protein expression was determined in a HNSCC cohort (n = 364) using immunohistochemical staining. For functional validation, AXL was either overexpressed or inhibited with BGB324 in HNSCC cell lines to assess proliferation, migration and invasion. We found AXL protein expression increasing during tumor progression with highest expression levels in recurrent tumors. In HNSCC cell lines in vitro, AXL overexpression increased migration as well as invasion. Both properties could be reduced through treatment with BGB324. In contrast, proliferation was neither affected by AXL overexpression nor by inhibition with BGB324. Our patient-derived data and in vitro results show that, in HNSCC, AXL is important for the progression to more advanced tumor stages. Moreover, they suggest that AXL could be a target for precision medicine approaches in this dismal tumor entity. PMID- 28025483 TI - Graphene-Based Long-Period Fiber Grating Surface Plasmon Resonance Sensor for High-Sensitivity Gas Sensing. AB - A graphene-based long-period fiber grating (LPFG) surface plasmon resonance (SPR) sensor is proposed. A monolayer of graphene is coated onto the Ag film surface of the LPFG SPR sensor, which increases the intensity of the evanescent field on the surface of the fiber and thereby enhances the interaction between the SPR wave and molecules. Such features significantly improve the sensitivity of the sensor. The experimental results demonstrate that the sensitivity of the graphene-based LPFG SPR sensor can reach 0.344 nm%-1 for methane, which is improved 2.96 and 1.31 times with respect to the traditional LPFG sensor and Ag-coated LPFG SPR sensor, respectively. Meanwhile, the graphene-based LPFG SPR sensor exhibits excellent response characteristics and repeatability. Such a SPR sensing scheme offers a promising platform to achieve high sensitivity for gas-sensing applications. PMID- 28025484 TI - Cross View Gait Recognition Using Joint-Direct Linear Discriminant Analysis. AB - This paper proposes a view-invariant gait recognition framework that employs a unique view invariant model that profits from the dimensionality reduction provided by Direct Linear Discriminant Analysis (DLDA). The framework, which employs gait energy images (GEIs), creates a single joint model that accurately classifies GEIs captured at different angles. Moreover, the proposed framework also helps to reduce the under-sampling problem (USP) that usually appears when the number of training samples is much smaller than the dimension of the feature space. Evaluation experiments compare the proposed framework's computational complexity and recognition accuracy against those of other view-invariant methods. Results show improvements in both computational complexity and recognition accuracy. PMID- 28025485 TI - Overexpression of AmRosea1 Gene Confers Drought and Salt Tolerance in Rice. AB - Ectopic expression of the MYB transcription factor of AmROSEA1 from Antirrhinum majus has been reported to change anthocyanin and other metabolites in several species. In this study, we found that overexpression of AmRosea1 significantly improved the tolerance of transgenic rice to drought and salinity stresses. Transcriptome analysis revealed that a considerable number of stress-related genes were affected by exogenous AmRosea1 during both drought and salinity stress treatments. These affected genes are involved in stress signal transduction, the hormone signal pathway, ion homeostasis and the enzymes that remove peroxides. This work suggests that the AmRosea1 gene is a potential candidate for genetic engineering of crops. PMID- 28025486 TI - Implicating Cryptic and Novel Anophelines as Malaria Vectors in Africa. AB - Entomological indices and bionomic descriptions of malaria vectors are essential to accurately describe and understand malaria transmission and for the design and evaluation of appropriate control interventions. In order to correctly assign spatio-temporal distributions, behaviors and responses to interventions to particular anopheline species, identification of mosquitoes must be accurately made. This paper reviews the current methods and their limitations in correctly identifying anopheline mosquitoes in sub-Saharan Africa, and highlights the importance of molecular methods to discriminate cryptic species and identify lesser known anophelines. The increasing number of reports of Plasmodium infections in assumed "minor", non-vector, and cryptic and novel species is reviewed. Their importance in terms of evading current control and elimination strategies and therefore maintaining malaria transmission is emphasized. PMID- 28025487 TI - Indoxyl Sulfate as a Mediator Involved in Dysregulation of Pulmonary Aquaporin-5 in Acute Lung Injury Caused by Acute Kidney Injury. AB - High mortality of acute kidney injury (AKI) is associated with acute lung injury (ALI), which is a typical complication of AKI. Although it is suggested that dysregulation of lung salt and water channels following AKI plays a pivotal role in ALI, the mechanism of its dysregulation has not been elucidated. Here, we examined the involvement of a typical oxidative stress-inducing uremic toxin, indoxyl sulfate (IS), in the dysregulation of the pulmonary predominant water channel, aquaporin 5 (AQP-5), in bilateral nephrectomy (BNx)-induced AKI model rats. BNx evoked AKI with the increases in serum creatinine (SCr), blood urea nitrogen (BUN) and serum IS levels and exhibited thickening of interstitial tissue in the lung. Administration of AST-120, clinically-used oral spherical adsorptive carbon beads, resulted in a significant decrease in serum IS level and thickening of interstitial tissue, which was accompanied with the decreases in IS accumulation in various tissues, especially lung. Interestingly, a significant decrease in AQP-5 expression of lung was observed in BNx rats. Moreover, the BNx induced decrease in pulmonary AQP-5 protein expression was markedly restored by oral administration of AST-120. These results suggest that BNx-induced AKI causes dysregulation of pulmonary AQP-5 expression, in which IS could play a toxico physiological role as a mediator involved in renopulmonary crosstalk. PMID- 28025488 TI - Toxicity and Physiological Actions of Carbonic Anhydrase Inhibitors to Aedes aegypti and Drosophila melanogaster. AB - The physiological role of carbonic anhydrases in pH and ion regulation is crucial to insect survival. We examined the toxic and neurophysiological effects of five carbonic anhydrase inhibitors (CAIs) against Aedes aegypti. The 24 h larvicidal toxicities followed this rank order of potency: dichlorphenamide > methazolamide > acetazolamide = brinzolamide = dorzolamide. Larvicidal activity increased modestly in longer exposures, and affected larvae showed attenuated responses to probing without overt tremors, hyperexcitation, or convulsions. Acetazolamide and dichlorphenamide were toxic to adults when applied topically, but were of low potency and had an incomplete effect (<50% at 300 ng/mosquito) even after injection. Dichlorphenamide was also the most toxic compound when fed to adult mosquitoes, and they displayed loss of posture and occasionally prolonged fluttering of the wings. Co-exposure with 500 ng of the synergist piperonyl butoxide (PBO) increased the toxicity of dichlorphenamide ca. two-fold in feeding assays, indicating that low toxicity was not related to oxidative metabolism. Dichlorphenamide showed mild depolarizing and nerve discharge actions on insect neuromuscular and central nervous systems, respectively. These effects were increased in low buffer salines, indicating they were apparently related to loss of pH control in these tissues. Overall, sulfonamides displayed weak insecticidal properties on Aedes aegypti and are weak lead compounds. PMID- 28025489 TI - The Effects of Ascorbate, N-Acetylcysteine, and Resveratrol on Fibroblasts from Patients with Mitochondrial Disorders. AB - Reactive oxygen species (ROS) are assumed to be implicated in the pathogenesis of inborn mitochondrial diseases affecting oxidative phosphorylation (OXPHOS). In the current study, we characterized the effects of three small molecules with antioxidant properties (N-acetylcysteine, ascorbate, and resveratrol) on ROS production and several OXPHOS parameters (growth in glucose free medium, ATP production, mitochondrial content and membrane potential (MMP)), in primary fibroblasts derived from seven patients with different molecularly defined and undefined mitochondrial diseases. N-acetylcysteine appeared to be the most beneficial compound, reducing ROS while increasing growth and ATP production in some patients' cells. Ascorbate showed a variable positive or negative effect on ROS, ATP production, and mitochondrial content, while incubation with resveratrol disclosed either no effect or detrimental effect on ATP production and MMP in some cells. The individual responses highlight the importance of investigating multiple parameters in addition to ROS to obtain a more balanced view of the overall effect on OXPHOS when evaluating antioxidant treatment options for mitochondrial diseases. PMID- 28025490 TI - A Model of Health for Family Caregivers of Elders. AB - : Family members who provide care to their loved ones experience changes in their own health. The caregiver health model (CGHM) is a new model that identifies health holistically and identifies four determinant(s) that contribute to the health status of the family caregiver. The purpose is to introduce the CGHM: Hypothesis 1: the determinants of health in the CGHM contribute to the health of the Caregiver, Hypothesis 2: the determinants of health contribute to changes in the caregivers' health at 8 and 16 weeks, and Hypothesis 3: a change in health occurs from baseline to 8 and 16 weeks. METHODS: A descriptive, longitudinal design used three data collection points and five survey instruments. Community recruitment (N = 90) occurred through word of mouth and newspapers. Inclusion criteria consisted of being a family caregiver, living in a rural residence, and providing care to elders with necessary activities of daily living (ADLs) and/or instrumental ADLs (IADLs). Following a participant generated phone call to provide consent, caregivers received an initial study packet, additional packets were sent upon return of the previous packet. Analysis for the three hypotheses included multiple backwards stepwise linear regression, generalized estimating equations (GEE), and analysis of variance (ANOVA) alpha = 0.05. RESULTS: A significant decrease in mental (p < 0.01) but not physical health at 8 weeks (p = 0.38) and 16 weeks (p = 0.29) occurred over time. Two determinants displayed significant (p < 0.05 or less) changes in mental and/or physical health at one or more time points. Study limitations include caregiver entry at varying times and self-report of elder nursing needs and medical conditions. CONCLUSIONS: Findings support two of the four determinants contributing to caregiver health. PMID- 28025493 TI - Analysis to Estimate Genetic Variations in the Idarubicin-Resistant Derivative MOLT-3. AB - Gene alterations are a well-established mechanism leading to drug resistance in acute leukemia cells. A full understanding of the mechanisms of drug resistance in these cells will facilitate more effective chemotherapy. In this study, we investigated the mechanism(s) of drug resistance in the human acute leukemia cell line MOLT-3 and its idarubicin-resistant derivative MOLT-3/IDR through complete mitochondrial and nuclear DNA analyses. We identified genetic differences between these two cell lines. The ND3 mutation site (p.Thr61Ile) in the mitochondrial DNA sequence was unique to MOLT-3/IDR cells. Moreover, we identified five candidate genes harboring genetic alterations, including GALNT2, via CGH array analysis. Sequencing of the GALNT2 exon revealed a G1716K mutation present within the stop codon in MOLT-3/IDR cells but absent from MOLT-3 cells. This mutation led to an additional 18 amino acids in the protein encoded by GALNT2. Using real-time PCR, we determined an expression value for this gene of 0.35. Protein structure predictions confirmed a structural change in GALNT2 in MOLT-3/IDR cells that corresponded to the site of the mutation. We speculate that this mutation may be related to idarubicin resistance. PMID- 28025492 TI - Cofilin-1 and Other ADF/Cofilin Superfamily Members in Human Malignant Cells. AB - Identification of actin-depolymerizing factor homology (ADF-H) domains in the structures of several related proteins led first to the formation of the ADF/cofilin family, which then expanded to the ADF/cofilin superfamily. This superfamily includes the well-studied cofilin-1 (Cfl-1) and about a dozen different human proteins that interact directly or indirectly with the actin cytoskeleton, provide its remodeling, and alter cell motility. According to some data, Cfl-1 is contained in various human malignant cells (HMCs) and is involved in the formation of malignant properties, including invasiveness, metastatic potential, and resistance to chemotherapeutic drugs. The presence of other ADF/cofilin superfamily proteins in HMCs and their involvement in the regulation of cell motility were discovered with the use of various OMICS technologies. In our review, we discuss the results of the study of Cfl-1 and other ADF/cofilin superfamily proteins, which may be of interest for solving different problems of molecular oncology, as well as for the prospects of further investigations of these proteins in HMCs. PMID- 28025491 TI - Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines. AB - Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. A high caloric intake combined with a sedentary lifestyle is the leading cause of these conditions. Whole-body insulin resistance and its improvement are the result of the combined actions of each insulin-sensitive organ. Among the fundamental molecular mechanisms by which each organ is able to communicate and engage in cross-talk are cytokines or peptides which stem from secretory organs. Recently, it was reported that several cytokines or peptides are secreted from muscle (myokines), adipose tissue (adipokines) and liver (hepatokines) in response to certain nutrition and/or physical activity conditions. Cytokines exert autocrine, paracrine or endocrine effects for the maintenance of energy homeostasis. The present review is focused on the relationship and cross-talk amongst muscle, adipose tissue and the liver as secretory organs in metabolic diseases. PMID- 28025494 TI - Effect of Elderberry (Sambucus nigra L.) Extract Supplementation in STZ-Induced Diabetic Rats Fed with a High-Fat Diet. AB - Elderberry (Sambucus nigra L.) lipophilic and polar extract dietary supplementation effects were evaluated according to diabetes management indices, using an in vivo model. A research pipeline was constructed, that ranged from extract preparation, partial chemical characterization and toxicity evaluation, to examining the elderberry extract dietary supplementation effects on biofluid and tissues. Extracts toxicity was screened using an Aliivibrio fischeri bioluminescence model. A concentration of up to 60 mg/L was selected, and rat doses for oral supplementation were computed applying the interspecies correlation between A. fischeri and rats. Wistar type 2 diabetic rats, induced by streptozotocin (STZ), were fed a high-fat diet and supplemented for 4 weeks at doses of 190 and 350 mg/kg body weight/day of lipophilic and polar extract, respectively. As far as we know, lipophilic elderberry extract supplementation was assessed for the first time, while polar extract was administrated at higher doses and for a shorter period compared to previous studies, aiming to evaluate subacute supplementation effects. The polar extract modulated glucose metabolism by correcting hyperglycemia, while the lipophilic extract lowered insulin secretion. Both extracts lowered insulin resistance, without remarkable alterations to hematological indices, sera lipids and sera and tissular trace element homeostasis. In conclusion, elderberries are a potential source of bioactive compounds for formulations to be used as co-adjuvants in diabetes management. PMID- 28025495 TI - CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor gamma Ligands. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) ligands are important therapeutic drugs for the treatment of type 2 diabetes, obesity and cardiovascular diseases. In particular, partial agonists and non-agonists are interesting targets to reduce glucose levels, presenting few side effects in comparison to full agonists. In this work, we present a set of CHARMM-based parameters of a molecular mechanics force field for two PPARgamma ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPARgamma partial agonist that has been shown to promote the "browning" of white adipose tissue. SR1664 is the precursor of the PPARgamma non-agonist class of ligands that activates PPARgamma in a non-classical manner. Here, we use quantum chemical calculations consistent with the CHARMM protocol to obtain bonded and non-bonded parameters, including partial atomic charges and effective torsion potentials for both molecules. The newly parameterized models were evaluated by examining the behavior of GQ16 and SR1664 free in water and bound to the ligand binding pocket of PPARgamma using molecular dynamics simulations. The potential parameters derived here are readily transferable to a variety of pharmaceutical compounds and similar PPARgamma ligands. PMID- 28025496 TI - Plant MicroRNAs-Novel Players in Natural Medicine? AB - MicroRNAs (miRNAs) represent a class of small non-coding RNAs that act as efficient gene expression regulators and thus play many important roles in living organisms. Due to their involvement in several known human pathological and pathogenic states, miRNA molecules have become an important issue in medicine and gained the attention of scientists from the pharmaceutical industry. In recent few years, a growing number of studies have provided evidence that miRNAs may be transferred from one species to another and regulate gene expression in the recipients' cells. The most intriguing results revealed that stable miRNAs derived from food plants may enter the mammals' circulatory system and, after reaching the target, inhibit the production of specific mammalian protein. Part of the scientific community has perceived this as an attractive hypothesis that may provide a foundation for novel therapeutic approaches. In turn, others are convinced about the "false positive" effect of performed experiments from which the mentioned results were achieved. In this article, we review the recent literature that provides evidence (from both fronts) of dietary, plant miRNA uptake and functionality in various consumers. Additionally, we discuss possible miRNA transport mechanisms from plant food sources to human cells. PMID- 28025497 TI - Mechanisms Governing DDK Regulation of the Initiation of DNA Replication. AB - The budding yeast Dbf4-dependent kinase (DDK) complex-comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)-is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also a target of the radiation sensitive 53 (Rad53) checkpoint kinase in response to replication stress. Numerous investigations have determined mechanistic details, including the regions of Mcm2, Mcm4, and Mcm6 phosphorylated by DDK, and a number of DDK docking sites. Similarly, the way in which the Rad53 forkhead-associated 1 (FHA1) domain binds to DDK-involving both canonical and non-canonical interactions-has been elucidated. Recent work has revealed mutual promotion of DDK and synthetic lethal with dpb11-1 3 (Sld3) roles. While DDK phosphorylation of Mcm2-7 subunits facilitates their interaction with Sld3 at origins, Sld3 in turn stimulates DDK phosphorylation of Mcm2. Details of a mutually antagonistic relationship between DDK and Rap1-interacting factor 1 (Rif1) have also recently come to light. While Rif1 is able to reverse DDK-mediated Mcm2-7 complex phosphorylation by targeting the protein phosphatase glycogen 7 (Glc7) to origins, there is evidence to suggest that DDK can counteract this activity by binding to and phosphorylating Rif1. PMID- 28025498 TI - Calcium-Mediated Control of Polydopamine Film Oxidation and Iron Chelation. AB - The facile preparation of conformal polydopamine (PDA) films on broad classes of materials has prompted extensive research into a wide variety of potential applications for PDA. The constituent molecular species in PDA exhibit diverse chemical moieties, and therefore highly variable properties of PDA-based devices may evolve with post-processing conditions. Here we report the use of redox inactive cations for oxidative post-processing of deposited PDA films. PDA films incubated in alkaline CaCl2 solutions exhibit accelerated oxidative evolution in a dose-dependent manner. PDA films incubated in CaCl2 solutions exhibit 53% of the oxidative charge transfer compared to pristine PDA films. Carboxylic acid groups generated from the oxidation process lower the isoelectric point of PDA films from pH = 4.0 +/- 0.2 to pH = 3.1 +/- 0.3. PDA films exposed to CaCl2 solutions during post-processing also enhance Fe2+/Fe3+ chelation compared to pristine PDA films. These data illustrate that the molecular heterogeneity and non-equilibrium character of as-deposited PDA films afford control over the final composition by choosing post-processing conditions, but also demands forethought into how the performance of PDA-incorporated devices may change over time in salt solutions. PMID- 28025499 TI - Patterns of Apoptosis and Proliferation throughout the Biennial Reproductive Cycle of Viviparous Female Typhlonectes compressicauda (Amphibia, Gymnophiona). AB - Typhlonectes compressicauda is an aquatic gymnophionan amphibian living in South America. Its breeding cycle is linked to seasons, characterized by a regular alternation of rainy and dry seasons. During a complex biennial cycle, the female genital tract undergoes a series of alternations of increasing and decreasing, governed by equilibrium of proliferation and apoptotic phenomena. Immunohistochemical methods were used to visualize cell proliferation with the detection of Ki67 antibody, a protein present in proliferative cells; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Apostain were performed to detect apoptotic cells on sections of ovaries and oviducts. In ovaries, both phenomena affect the germinal nests and follicles according to the cycle period. In the oviduct, the balance was in favor of proliferation during preparation for reproduction, and in favor of apoptosis when genital ducts regress. Apoptosis and proliferation are narrowly implicated in the remodeling of the genital tract and they are accompanied by the differentiation of tissues according to the phase of the breeding cycle. These variations permit the capture of oocytes at ovulation, always at the same period, and the parturition after 6-7 months of gestation, at a period in which the newborns live with their mother, protected in burrows in the mud. During the intervening year of sexual inactivity, the female reconstitutes body reserves. PMID- 28025500 TI - Glucocorticoids Protect Neonatal Rat Brain in Model of Hypoxic-Ischemic Encephalopathy (HIE). AB - Hypoxic-ischemic encephalopathy (HIE) resulting from asphyxia in the peripartum period is the most common cause of neonatal brain damage and can result in significant neurologic sequelae, including cerebral palsy. Currently therapeutic hypothermia is the only accepted treatment in addition to supportive care for infants with HIE, however, many additional neuroprotective therapies have been investigated. Of these, glucocorticoids have previously been shown to have neuroprotective effects. HIE is also frequently compounded by infectious inflammatory processes (sepsis) and as such, the infants may be more amenable to treatment with an anti-inflammatory agent. Thus, the present study investigated dexamethasone and hydrocortisone treatment given after hypoxic-ischemic (HI) insult in neonatal rats via intracerebroventricular (ICV) injection and intranasal administration. In addition, we examined the effects of hydrocortisone treatment in HIE after lipopolysaccharide (LPS) sensitization in a model of HIE and sepsis. We found that dexamethasone significantly reduced rat brain infarction size when given after HI treatment via ICV injection; however it did not demonstrate any neuroprotective effects when given intranasally. Hydrocortisone after HI insult also significantly reduced brain infarction size when given via ICV injection; and the intranasal administration showed to be protective of brain injury in male rats at a dose of 300 ug. LPS sensitization did significantly increase the brain infarction size compared to controls, and hydrocortisone treatment after LPS sensitization showed a significant decrease in brain infarction size when given via ICV injection, as well as intranasal administration in both genders at a dose of 300 ug. To conclude, these results show that glucocorticoids have significant neuroprotective effects when given after HI injury and that these effects may be even more pronounced when given in circumstances of additional inflammatory injury, such as neonatal sepsis. PMID- 28025501 TI - Ameliorating Effects of Bacillus subtilis ANSB060 on Growth Performance, Antioxidant Functions, and Aflatoxin Residues in Ducks Fed Diets Contaminated with Aflatoxins. AB - Bacillus subtilis ANSB060 isolated from fish gut is very effective in detoxifying aflatoxins in feed and feed ingredients. The purpose of this research was to investigate the effects of B. subtilis ANSB060 on growth performance, body antioxidant functions, and aflatoxin residues in ducks fed moldy maize naturally contaminated with aflatoxins. A total of 1500 18-d-old male Cherry Valley ducks with similar body weight were randomly assigned to five treatments with six replicates of 50 ducks per repeat. The experiment design consisted of five dietary treatments labeled as C0 (basal diet containing 60% normal maize), M0 (basal diet containing 60% moldy maize contaminated with aflatoxins substituted for normal maize), M500, M1000, and M2000 (M0 +500, 1000 or 2000 g/t aflatoxin biodegradation preparation mainly consisted of B. subtilis ANSB060). The results showed that ducks fed 22.44 +/- 2.46 MUg/kg of AFB1 (M0) exhibited a decreasing tendency in average daily gain (ADG) and total superoxide dismutase (T-SOD) activity in serum, and T-SOD and glutathione peroxidase (GSH-Px) activities in the liver significantly decreased along with the appearance of AFB1 and AFM1 compared with those in Group C0. The supplementation of B. subtilis ANSB060 into aflatoxin-contaminated diets increased the ADG of ducks (p > 0.05), significantly improved antioxidant enzyme activities, and reduced aflatoxin accumulation in duck liver. In conclusion, Bacillus subtilis ANSB060 in diets showed an ameliorating effect to duck aflatoxicosis and may be a promising feed additive. PMID- 28025502 TI - Role of p38alpha/beta MAP Kinase in Cell Susceptibility to Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B. AB - Lethal Toxin from Clostridium sordellii (TcsL), which is casually involved in the toxic shock syndrome and in gas gangrene, enters its target cells by receptor mediated endocytosis. Inside the cell, TcsL mono-O-glucosylates and thereby inactivates Rac/Cdc42 and Ras subtype GTPases, resulting in actin reorganization and an activation of p38 MAP kinase. While a role of p38 MAP kinase in TcsL induced cell death is well established, data on a role of p38 MAP kinase in TcsL induced actin reorganization are not available. In this study, TcsL-induced Rac/Cdc42 glucosylation and actin reorganization are differentially analyzed in p38alpha-/- MSCV empty vector MEFs and the corresponding cell line with reconstituted p38alpha expression (p38alpha-/- MSCV p38alpha MEFs). Genetic deletion of p38alpha results in reduced susceptibility of cells to TcsL-induced Rac/Cdc42 glucosylation and actin reorganization. Furthermore, SB203580, a pyridinyl imidazole inhibitor of p38alpha/beta MAP kinase, also protects cells from TcsL-induced effects in both p38-/- MSCV empty vector MEFs and in p38alpha-/ MSCV p38alpha MEFs, suggesting that inhibition of p38beta contributes to the protective effect of SB203580. In contrast, the effects of the related C. difficile Toxin B are responsive neither to SB203580 treatment nor to p38alpha deletion. In conclusion, the protective effects of SB203580 and of p38alpha deletion are likely not based on inhibition of the toxins' glucosyltransferase activity rather than on inhibited endocytic uptake of specifically TcsL into target cells. PMID- 28025503 TI - Associations of Maternal Dietary Patterns during Pregnancy with Offspring Adiposity from Birth Until 54 Months of Age. AB - Most studies linking maternal diet with offspring adiposity have focused on single nutrients or foods, but a dietary pattern approach is more representative of the overall diet. We thus aimed to investigate the relations between maternal dietary patterns and offspring adiposity in a multi-ethnic Asian mother-offspring cohort in Singapore. We derived maternal dietary patterns using maternal dietary intake information at 26-28 weeks of gestation, of which associations with offspring body mass index (BMI), abdominal circumference (AC), subscapular skinfold (SS), and triceps skinfold (TS) were assessed using longitudinal data analysis (linear mixed effects (LME)) and multiple linear regression at ages 0, 3, 6, 9, 12, 15, 18, 24, 36, 48, and 54 months. Three dietary patterns were derived: (1) vegetables-fruit-and-white rice (VFR); (2) seafood-and-noodles (SfN); and (3) pasta-cheese-and-bread (PCB). In the LME model adjusting for potential confounders, each standard deviation (SD) increase in maternal VFR pattern score was associated with 0.09 mm lower offspring TS. Individual time point analysis additionally revealed that higher VFR score was generally associated with lower postnatal offspring BMI z-score, TS, SS, and sum of skinfolds (SS + TS) at ages 18 months and older. Maternal adherence to a dietary pattern characterized by higher intakes of fruit and vegetables and lower intakes of fast food was associated with lower offspring adiposity. PMID- 28025505 TI - Chitosan-Based Nano-Embedded Microparticles: Impact of Nanogel Composition on Physicochemical Properties. AB - Chitosan-based nanogels have been widely applied as drug delivery vehicles. Spray drying of said nanogels allows for the preparation of dry powder nano-embedded microparticles. In this work, chitosan-based nanogels composed of chitosan, alginate, and/or sodium tri-penta phosphate were investigated, particularly with respect to the impact of composition on the resulting physicochemical properties. Different compositions were obtained as nanogels with sizes ranging from 203 to 561 nm. The addition of alginate and exclusion of sodium tri-penta phosphate led to an increase in nanogel size. The nanogels were subsequently spray-dried to form nano-embedded microparticles with trehalose or mannitol as matrix excipient. The microparticles of different composition were mostly spherical with a smooth surface and a mass median aerodynamic diameter of 6-10 um. Superior redispersibility was observed for microparticles containing amorphous trehalose. This study demonstrates the potential of nano-embedded microparticles for stabilization and delivery of nanogel-based delivery systems. PMID- 28025506 TI - Fatty Acids in Membranes as Homeostatic, Metabolic and Nutritional Biomarkers: Recent Advancements in Analytics and Diagnostics. AB - Fatty acids, as structural components of membranes and inflammation/anti inflammatory mediators, have well-known protective and regulatory effects. They are studied as biomarkers of pathological conditions, as well as saturated and unsaturated hydrophobic moieties in membrane phospholipids that contribute to homeostasis and physiological functions. Lifestyle, nutrition, metabolism and stress-with an excess of radical and oxidative processes-cause fatty acid changes that are examined in the human body using blood lipids. Fatty acid-based membrane lipidomics represents a powerful diagnostic tool for assessing the quantity and quality of fatty acid constituents and also for the follow-up of the membrane fatty acid remodeling that is associated with different physiological and pathological conditions. This review focuses on fatty acid biomarkers with two examples of recent lipidomic research and health applications: (i) monounsaturated fatty acids and the analytical challenge offered by hexadecenoic fatty acids (C16:1); and (ii) the cohort of 10 fatty acids in phospholipids of red blood cell membranes and its connections to metabolic and nutritional status in healthy and diseased subjects. PMID- 28025507 TI - Effects of Operating Temperature on Droplet Casting of Flexible Polymer/Multi Walled Carbon Nanotube Composite Gas Sensors. AB - This study examined the performance of a flexible polymer/multi-walled carbon nanotube (MWCNT) composite sensor array as a function of operating temperature. The response magnitudes of a cost-effective flexible gas sensor array equipped with a heater were measured with respect to five different operating temperatures (room temperature, 40 degrees C, 50 degrees C, 60 degrees C, and 70 degrees C) via impedance spectrum measurement and sensing response experiments. The selected polymers that were droplet cast to coat a MWCNT conductive layer to form two-layer polymer/MWCNT composite sensing films included ethyl cellulose (EC), polyethylene oxide (PEO), and polyvinylpyrrolidone (PVP). Electrical characterization of impedance, sensing response magnitude, and scanning electron microscope (SEM) morphology of each type of polymer/MWCNT composite film was performed at different operating temperatures. With respect to ethanol, the response magnitude of the sensor decreased with increasing operating temperatures. The results indicated that the higher operating temperature could reduce the response and influence the sensitivity of the polymer/MWCNT gas sensor array. The morphology of polymer/MWCNT composite films revealed that there were changes in the porous film after volatile organic compound (VOC) testing. PMID- 28025504 TI - Reverse Genetics Approaches for the Development of Influenza Vaccines. AB - Influenza viruses cause annual seasonal epidemics and occasional pandemics of human respiratory disease. Influenza virus infections represent a serious public health and economic problem, which are most effectively prevented through vaccination. However, influenza viruses undergo continual antigenic variation, which requires either the annual reformulation of seasonal influenza vaccines or the rapid generation of vaccines against potential pandemic virus strains. The segmented nature of influenza virus allows for the reassortment between two or more viruses within a co-infected cell, and this characteristic has also been harnessed in the laboratory to generate reassortant viruses for their use as either inactivated or live-attenuated influenza vaccines. With the implementation of plasmid-based reverse genetics techniques, it is now possible to engineer recombinant influenza viruses entirely from full-length complementary DNA copies of the viral genome by transfection of susceptible cells. These reverse genetics systems have provided investigators with novel and powerful approaches to answer important questions about the biology of influenza viruses, including the function of viral proteins, their interaction with cellular host factors and the mechanisms of influenza virus transmission and pathogenesis. In addition, reverse genetics techniques have allowed the generation of recombinant influenza viruses, providing a powerful technology to develop both inactivated and live-attenuated influenza vaccines. In this review, we will summarize the current knowledge of state-of-the-art, plasmid-based, influenza reverse genetics approaches and their implementation to provide rapid, convenient, safe and more effective influenza inactivated or live-attenuated vaccines. PMID- 28025508 TI - Selection of Shear Horizontal Wave Transducers for Robotic Nondestructive Inspection in Harsh Environments. AB - Harsh environments and confined spaces require that nondestructive inspections be conducted with robotic systems. Ultrasonic guided waves are well suited for robotic systems because they can provide efficient volumetric coverage when inspecting for various types of damage, including cracks and corrosion. Shear horizontal guided waves are especially well suited for robotic inspection because they are sensitive to cracks oriented perpendicular or parallel to the wave propagation direction and can be generated with electromagnetic acoustic transducers (EMATs) and magnetostrictive transducers (MSTs). Both types of transducers are investigated for crack detection in a stainless steel plate. The MSTs require the robot to apply a compressive normal force that creates frictional force coupling. However, the coupling is observed to be very dependent upon surface roughness and surface debris. The EMATs are coupled through the Lorentz force and are thus noncontact, although they depend on the lift off between transducer and substrate. After comparing advantages and disadvantages of each transducer for robotic inspection the EMATs are selected for application to canisters that store used nuclear fuel. PMID- 28025509 TI - A High-Throughput RNA Extraction for Sprouted Single-Seed Barley (Hordeum vulgare L.) Rich in Polysaccharides. AB - Germinated seed from cereal crops including barley (Hordeum vulgare L.) is an important tissue to extract RNA and analyze expression levels of genes that control aspects of germination. These tissues are rich in polysaccharides and most methods for RNA extraction are not suitable to handle the excess polysaccharides. Here, we compare the current methods for RNA extraction applicable to germinated barley tissue. We found that although some of these standard methods produced high-quality RNA, the process of extraction was drastically slow, mostly because the frozen seed tissue powder from liquid N2 grinding became recalcitrant to buffer mixing. Our suggested modifications to the protocols removed the need for liquid N2 grinding and significantly increased the output efficiency of RNA extraction. Our modified protocol has applications in other cereal tissues rich in polysaccharides, including oat. PMID- 28025510 TI - Energy and Quality Evaluation for Compressive Sensing of Fetal Electrocardiogram Signals. AB - This manuscript addresses the problem of non-invasive fetal Electrocardiogram (ECG) signal acquisition with low power/low complexity sensors. A sensor architecture using the Compressive Sensing (CS) paradigm is compared to a standard compression scheme using wavelets in terms of energy consumption vs. reconstruction quality, and, more importantly, vs. performance of fetal heart beat detection in the reconstructed signals. We show in this paper that a CS scheme based on reconstruction with an over-complete dictionary has similar reconstruction quality to one based on wavelet compression. We also consider, as a more important figure of merit, the accuracy of fetal beat detection after reconstruction as a function of the sensor power consumption. Experimental results with an actual implementation in a commercial device show that CS allows significant reduction of energy consumption in the sensor node, and that the detection performance is comparable to that obtained from original signals for compression ratios up to about 75%. PMID- 28025512 TI - Characteristics of the Fiber Laser Sensor System Based on Etched-Bragg Grating Sensing Probe for Determination of the Low Nitrate Concentration in Water. AB - The necessity of environmental protection has stimulated the development of many kinds of methods allowing the determination of different pollutants in the natural environment, including methods for determining nitrate in source water. In this paper, the characteristics of an etched fiber Bragg grating (e-FBG) sensing probe-which integrated in fiber laser structure-are studied by numerical simulation and experiment. The proposed sensor is demonstrated for determination of the low nitrate concentration in a water environment. Experimental results show that this sensor could determine nitrate in water samples at a low concentration range of 0-80 ppm with good repeatability, rapid response, and average sensitivity of 3.5 * 10-3 nm/ppm with the detection limit of 3 ppm. The e FBG sensing probe integrated in fiber laser demonstrates many advantages, such as a high resolution for wavelength shift identification, high optical signal-to noise ratio (OSNR of 40 dB), narrow bandwidth of 0.02 nm that enhanced accuracy and precision of wavelength peak measurement, and capability for optical remote sensing. The obtained results suggested that the proposed e-FBG sensor has a large potential for the determination of low nitrate concentrations in water in outdoor field work. PMID- 28025511 TI - Immunological Roles of Elevated Plasma Levels of Matricellular Proteins in Japanese Patients with Pulmonary Tuberculosis. AB - Elevated matricellular proteins (MCPs), including osteopontin (OPN) and galectin 9 (Gal-9), were observed in the plasma of patients with Manila-type tuberculosis (TB) previously. Here, we quantified plasma OPN, Gal-9, and soluble CD44 (sCD44) by enzyme-linked immunosorbent assay (ELISA), and another 29 cytokines by Luminex assay in 36 patients with pulmonary TB, six subjects with latent tuberculosis (LTBI), and 19 healthy controls (HCs) from Japan for a better understanding of the roles of MCPs in TB. All TB subjects showed positive results of enzyme-linked immunospot assays (ELISPOTs). Spoligotyping showed that 20 out of 36 Mycobacterium tuberculosis (MTB) strains belong to the Beijing type. The levels of OPN, Gal-9, and sCD44 were higher in TB (positivity of 61.1%, 66.7%, and 63.9%, respectively) than in the HCs. Positive correlations between OPN and Gal 9, between OPN and sCD44, and negative correlation between OPN and ESAT-6-ELISPOT response, between chest X-ray severity score of cavitary TB and ESAT-6-ELISPOT response were observed. Instead of OPN, Gal-9, and sCD44, cytokines G-CSF, GM CSF, IFN-alpha, IFN-gamma, IL-12p70, and IL-1RA levels were higher in Beijing MTB infected patients. These findings suggest immunoregulatory, rather than inflammatory, effect of MCPs and can advance the understanding of the roles of MCPs in the context of TB pathology. PMID- 28025513 TI - New Stable Cu(I) Catalyst Supported on Weakly Acidic Polyacrylate Resin for Green C-N Coupling: Synthesis of N-(Pyridin-4-yl)benzene Amines and N,N-Bis(pyridine-4 yl)benzene Amines. AB - A method for preparation of a new stable Cu(I) catalyst supported on weakly acidic polyacrylate resin without additional stabilizing ligands is described. A simple and efficient methodology for Ullmann Cu(I) catalyzed C-N cross coupling reactions using this original catalyst is reported. Coupling reactions of 4 chloropyridinium chloride with anilines containing electron donating (EDG) or electron withdrawing (EWG) groups, naphthalen-2-amine and piperazine, respectively, are successfully demonstrated. PMID- 28025514 TI - Visualizing the Heterogeneity of Effects in the Analysis of Associations of Multiple Myeloma with Glyphosate Use. Comments on Sorahan, T. Multiple Myeloma and Glyphosate Use: A Re-Analysis of US Agricultural Health Study (AHS) Data. Int. J. Environ. Res. Public Health 2015, 12, 1548-1559. AB - We address a methodological issue of the evaluation of the difference in effects in epidemiological studies that may arise, for example, from stratum-specific analyses or differences in analytical decisions during data analysis. We propose a new simulation-based method to quantify the plausible extent of such heterogeneity, rather than testing a hypothesis about its existence. We examine the contribution of the method to the debate surrounding risk of multiple myeloma and glyphosate use and propose that its application contributes to a more balanced weighting of evidence. PMID- 28025515 TI - Visualising and Thinking and Interpreting. Response to the Burstyn and De Roos Comments on Sorahan, T. Multiple Myeloma and Glyphosate Use: A Re-Analysis of US Agricultural Health Study (AHS) Data. Int. J. Environ. Res. Public Health 2015, 12, 1548-1559. AB - n/a. PMID- 28025516 TI - Motivations and Limitations Associated with Vaping among People with Mental Illness: A Qualitative Analysis of Reddit Discussions. AB - This study aims to understand the nature and significance of online lay discussions about e-cigarettes and mental illness. We systematically searched the website Reddit.com using keywords related to e-cigarettes and mental illness. We coded relevant posts into themes under the framework of motivations for and limitations of vaping for people with mental illness. The thematic analysis included 3263 comments from 133 discussion threads. Six themes were classified as motivations to vape for people with mental illness: Self-medication; Quitting smoking; Freedom and control; Hobby; Social connectedness; and Motivation from caregivers and online communities. The limitations of vaping included: Unsatisfactory substitute for cigarettes and psychiatric medicines; Drug interactions; Nicotine addiction; Risks of e-liquid; Practical difficulties and Cost. People with mental illness; and their carers; use online discussion boards like Reddit to discuss the benefits and limitations of e-cigarettes for people with mental illness. Both positive and negative views exist. Media platforms like Reddit may shape the opinions of stakeholders and generate lay expertise about contentious health topics such as e-cigarettes. These findings have implications for policy and practice concerning assisting smokers with mental illness to reduce their health risk through switching to e-cigarettes. PMID- 28025517 TI - Prospective Cohort Study to Elucidate the Correlation between Occupational Stress and Hypertension Risk in Oil Workers from Kelamayi City in the Xinjiang Uygur Autonomous Region of China. AB - The purpose of this study was to assess the major risk factors for hypertension in oil workers, and investigate the effect of occupational stress on the incidence of hypertension after controlling for other risk factors. A prospective cohort approach was used following enrollment of 1354 oil workers. The occupational stress experienced by oil workers was higher than for the general population in China. By the end of the cohort study, 231 new cases of hypertension among the oil workers had been diagnosed. The cumulative incidence of hypertension was 17.06%. There were 44, 112, and 75 workers who developed hypertension in the low, intermediate, and high occupational stress groups, which represented a 12.0%, 15.6%, and 20.3% cumulative incidence, respectively (chi square value = 9.812, p < 0.01). Multivariate Cox proportional hazard model analysis showed that type of work, cigarette smoking, excess body weight, and obesity were risk factors for hypertension (p < 0.05). After risk factors such as type of work, cigarette smoking, alcohol consumption, and body mass index (BMI) were controlled, the hypertension risk (hazard ratio, HR) in the high occupational stress group was 1.549 (1.072-2.236) compared to the low exposure group, and 2.337 (1.191-4.585) in female subjects. Our study indicated that an increase in occupational stress was associated with an increased risk of hypertension after other factors were adjusted. PMID- 28025518 TI - Ecosystem Health Assessment at County-Scale Using the Pressure-State-Response Framework on the Loess Plateau, China. AB - Assessing ecosystem health is helpful to determine reasonable eco-environmental restoration and resource management strategies. Based on a pressure-state response (PSR) framework, a set of comprehensive indicators including natural, social and economic aspects was proposed and applied for assessing the ecosystem health of Yuanzhou County, Loess Plateau, Ningxia Province, China. The basic data used to calculate the values of the assessment indicators include Landsat TM image and socio-economic data, and remote sensing (RS) and the geographic information system (GIS) were used to process image data. The results showed that the ecosystem health conditions of most townships in Yuanzhou County were at the moderately healthy level, three townships were at the healthy level, and only two townships were at the unhelathy level; the areas (percentage) at the unhealthy, moderately healthy and healthy levels were 443.91 km2 (12.66%), 2438.75 km2 (69.54%) and 624.50 km2 (17.81%), respectively. The results could provide useful information for local residents and the government to take measures to improve the health conditions of their township ecosystem. PMID- 28025520 TI - Plastoglobule-Targeting Competence of a Putative Transit Peptide Sequence from Rice Phytoene Synthase 2 in Plastids. AB - Plastoglobules (PGs) are thylakoid membrane microdomains within plastids that are known as specialized locations of carotenogenesis. Three rice phytoene synthase proteins (OsPSYs) involved in carotenoid biosynthesis have been identified. Here, the N-terminal 80-amino-acid portion of OsPSY2 (PTp) was demonstrated to be a chloroplast-targeting peptide by displaying cytosolic localization of OsPSY2(DeltaPTp):mCherry in rice protoplast, in contrast to chloroplast localization of OsPSY2:mCherry in a punctate pattern. The peptide sequence of a PTp was predicted to harbor two transmembrane domains eligible for a putative PG targeting signal. To assess and enhance the PG-targeting ability of PTp, the original PTp DNA sequence (PTp) was modified to a synthetic DNA sequence (stPTp), which had 84.4% similarity to the original sequence. The motivation of this modification was to reduce the GC ratio from 75% to 65% and to disentangle the hairpin loop structures of PTp. These two DNA sequences were fused to the sequence of the synthetic green fluorescent protein (sGFP) and drove GFP expression with different efficiencies. In particular, the RNA and protein levels of stPTp-sGFP were slightly improved to 1.4-fold and 1.3-fold more than those of sGFP, respectively. The green fluorescent signals of their mature proteins were all observed as speckle-like patterns with slightly blurred stromal signals in chloroplasts. These discrete green speckles of PTp-sGFP and stPTp-sGFP corresponded exactly to the red fluorescent signal displayed by OsPSY2:mCherry in both etiolated and greening protoplasts and it is presumed to correspond to distinct PGs. In conclusion, we identified PTp as a transit peptide sequence facilitating preferential translocation of foreign proteins to PGs, and developed an improved PTp sequence, a stPTp, which is expected to be very useful for applications in plant biotechnologies requiring precise micro-compartmental localization in plastids. PMID- 28025519 TI - Development and Structural Modification of BACE1 Inhibitors. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder which usually occurs in the elderly. The accumulation of beta-amyloid and the formation of neurofibrillary tangles are considered as the main pathogenies of AD. Research suggests that beta-secretase 1 (BACE1) plays an important role in the formation of beta-amyloid. Discovery of new BACE1 inhibitors has become a significant method to slow down the progression of AD or even cure this kind of disease. This review summarizes the different types and the structural modification of these new BACE1 inhibitors. PMID- 28025521 TI - Exposure to Indoor Particulate Matter Worsens the Symptoms and Acute Exacerbations in Chronic Obstructive Pulmonary Disease Patients of Southwestern Taiwan: A Pilot Study. AB - Ambient particulate matter (PM) can trigger adverse reactions in the respiratory system, but less is known about the effect of indoor PM. In this longitudinal study, we investigated the relationships between indoor PM and clinical parameters in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Indoor air quality (PM2.5 and PM10 levels) was monitored in the patients' bedroom, kitchen, living room, and front door at baseline and every two months for one year. At each home visit, the patients were asked to complete spirometry and questionnaire testing. Exacerbations were assessed by chart review and questionnaires during home visits. Generalized estimating equation (GEE) analysis (n = 83) showed that the level of wheezing was significantly higher in patients whose living room and kitchen had abnormal (higher than ambient air quality standards in Taiwan) PM2.5 and PM10 levels. Patients who lived in houses with abnormal outdoor PM2.5 levels had higher COPD Assessment Test scores (physical domain), and those who lived in houses with abnormal PM10 levels in the living room and kitchen had higher London Chest Activity of Daily Living scores. Increased PM levels were associated with worse respiratory symptoms and increased risk of exacerbation in patients with moderate to very severe COPD. PMID- 28025522 TI - Residential Proximity to Major Roadways and Risk of Type 2 Diabetes Mellitus: A Meta-Analysis. AB - Research indicates that higher levels of traffic-related pollution exposure increase the risk of diabetes, but the association between road proximity and diabetes risk remains unclear. To assess and quantify the association between residential proximity to major roadways and type 2 diabetes, a systematic review and meta-analysis was performed. Embase, Medline, and Web of Science were searched for eligible studies. Using a random-effects meta-analysis, the summary relative risks (RRs) were calculated. Bayesian meta-analysis was also performed. Eight studies (6 cohort and 2 cross-sectional) with 158,576 participants were finally included. The summary unadjusted RR for type 2 diabetes associated with residential proximity to major roadways was 1.24 (95% confidence interval [CI]: 1.07-1.44, p = 0.001, I2 = 48.1%). The summary adjusted RR of type 2 diabetes associated with residential proximity to major roadways was 1.12 (95% CI: 1.03 1.22, p = 0.01, I2 = 17.9%). After excluding two cross-sectional studies, the summary results suggested that residential proximity to major roadways could increase type 2 diabetes risk (Adjusted RR = 1.13; 95% CI: 1.02-1.27, p = 0.025, I2 = 36.6%). Bayesian meta-analysis showed that the unadjusted RR and adjusted RR of type 2 diabetes associated with residential proximity to major roadways were 1.22 (95% credibility interval: 1.06-1.55) and 1.13 (95% credibility interval: 1.01-1.31), respectively. The meta-analysis suggested that residential proximity to major roadways could significantly increase risk of type 2 diabetes, and it is an independent risk factor of type 2 diabetes. More well-designed studies are needed to further strengthen the evidence. PMID- 28025523 TI - Development of a UPLC-TQ/MS Approach for the Determination of Eleven Bioactive Components in Haizao Yuhu Decoction Plus-Minus Haizao and Gancao Drug Combination after Oral Administration in a Rat Model of Hypothyroidism. AB - Haizao Yuhu Decoction (HYD) has been used for approximately 500 years and is well known in Traditional Chinese Medicine for its efficacy in the treatment of thyroid-related diseases. In this study, a rapid liquid chromatography-tandem mass spectrometry method was developed for the determination of liquiritin, naringin, hesperidin, peimine, liquiritigenin, glycyrrhizic acid, bergapten, nobiletin, osthole, and glycyrrhetinic acid in rat plasma to investigate the pharmacokinetic profile of different HYD prescriptions in a rat model of hypothyroidism. The differences in pharmacokinetic parameters among the groups were compared by Student's t-test. The pharmacokinetic profile of liquiritin, naringin, hesperidin, peimine, liquiritigenin, glycyrrhizic acid, bergapten, nobiletin, osthole, and glycyrrhetinic acid showed significant differences between Haizao and Gancao anti-drug combination and other herbs in HYD. These results may contribute to the rational clinical use of HYD and reveal the compatibility profile of the Haizao and Gancao anti-drug combination. PMID- 28025524 TI - A Multi-Sensor Fusion MAV State Estimation from Long-Range Stereo, IMU, GPS and Barometric Sensors. AB - State estimation is the most critical capability for MAV (Micro-Aerial Vehicle) localization, autonomous obstacle avoidance, robust flight control and 3D environmental mapping. There are three main challenges for MAV state estimation: (1) it can deal with aggressive 6 DOF (Degree Of Freedom) motion; (2) it should be robust to intermittent GPS (Global Positioning System) (even GPS-denied) situations; (3) it should work well both for low- and high-altitude flight. In this paper, we present a state estimation technique by fusing long-range stereo visual odometry, GPS, barometric and IMU (Inertial Measurement Unit) measurements. The new estimation system has two main parts, a stochastic cloning EKF (Extended Kalman Filter) estimator that loosely fuses both absolute state measurements (GPS, barometer) and the relative state measurements (IMU, visual odometry), and is derived and discussed in detail. A long-range stereo visual odometry is proposed for high-altitude MAV odometry calculation by using both multi-view stereo triangulation and a multi-view stereo inverse depth filter. The odometry takes the EKF information (IMU integral) for robust camera pose tracking and image feature matching, and the stereo odometry output serves as the relative measurements for the update of the state estimation. Experimental results on a benchmark dataset and our real flight dataset show the effectiveness of the proposed state estimation system, especially for the aggressive, intermittent GPS and high-altitude MAV flight. PMID- 28025525 TI - Object-Based Paddy Rice Mapping Using HJ-1A/B Data and Temporal Features Extracted from Time Series MODIS NDVI Data. AB - Accurate and timely mapping of paddy rice is vital for food security and environmental sustainability. This study evaluates the utility of temporal features extracted from coarse resolution data for object-based paddy rice classification of fine resolution data. The coarse resolution vegetation index data is first fused with the fine resolution data to generate the time series fine resolution data. Temporal features are extracted from the fused data and added with the multi-spectral data to improve the classification accuracy. Temporal features provided the crop growth information, while multi-spectral data provided the pattern variation of paddy rice. The achieved overall classification accuracy and kappa coefficient were 84.37% and 0.68, respectively. The results indicate that the use of temporal features improved the overall classification accuracy of a single-date multi-spectral image by 18.75% from 65.62% to 84.37%. The minimum sensitivity (MS) of the paddy rice classification has also been improved. The comparison showed that the mapped paddy area was analogous to the agricultural statistics at the district level. This work also highlighted the importance of feature selection to achieve higher classification accuracies. These results demonstrate the potential of the combined use of temporal and spectral features for accurate paddy rice classification. PMID- 28025527 TI - Purification and Characterization of a New Alginate Lyase from Marine Bacterium Vibrio sp. SY08. AB - Unsaturated alginate disaccharides (UADs), enzymatically derived from the degradation of alginate polymers, are considered powerful antioxidants. In this study, a new high UAD-producing alginate lyase, AlySY08, has been purified from the marine bacterium Vibrio sp. SY08. AlySY08, with a molecular weight of about 33 kDa and a specific activity of 1070.2 U/mg, showed the highest activity at 40 degrees C in phosphate buffer at pH 7.6. The enzyme was stable over a broad pH range (6.0-9.0) and retained about 75% activity after incubation at 40 degrees C for 2 h. Moreover, the enzyme was active in the absence of salt ions and its activity was enhanced by the addition of NaCl and KCl. AlySY08 resulted in an endo-type alginate lyase that degrades both polyM and polyG blocks, yielding UADs as the main product (81.4% of total products). All these features made AlySY08 a promising candidate for industrial applications in the production of antioxidants from alginate polysaccharides. PMID- 28025526 TI - Regulation and Function of Cdt1; A Key Factor in Cell Proliferation and Genome Stability. AB - Successful cell proliferation requires efficient and precise genome duplication followed by accurate chromosome segregation. The Cdc10-dependent transcript 1 protein (Cdt1) is required for the first step in DNA replication, and in human cells Cdt1 is also required during mitosis. Tight cell cycle controls over Cdt1 abundance and activity are critical to normal development and genome stability. We review here recent advances in elucidating Cdt1 molecular functions in both origin licensing and kinetochore-microtubule attachment, and we describe the current understanding of human Cdt1 regulation. PMID- 28025528 TI - Elevated Plasma Vitamin B12 Concentrations Are Independent Predictors of In Hospital Mortality in Adult Patients at Nutritional Risk. AB - Background: Elevated plasma vitamin B12 concentrations were identified as predictors of mortality in patients with oncologic, hepatic and renal diseases, and in elderly and critically ill medical patients. The association between vitamin B12 concentrations and in-hospital mortality in adult patients at nutritional risk has not been assessed. Methods: In this five-year prospective study, we investigated whether high vitamin B12 concentrations (>1000 pg/mL) are associated with in-hospital mortality in 1373 not-bed-ridden adult patients at nutritional risk (Nutrition Risk Index <97.5), admitted to medical and surgical departments. Results: Three hundred and ninety-six (28.8%) patients presented vitamin B12 > 1000 pg/mL. Two hundred and four patients died in the hospital (14.9%). The adjusted odds ratio of in-hospital mortality in patients with high vitamin B12 was 2.20 (95% CI, 1.56-3.08; p < 0.001); it was independent of age, gender, body mass index, six-month previous unintentional weight loss, admission ward, presence of malignancy, renal function, C-reactive protein and prealbumin. Patients with high vitamin B12 also had a longer length of stay (LOS) than those with normal concentrations (median 25 days, (IQR 15-41) versus 23 days (IQR 14 36); p = 0.014), and elevated vitamin B12 was an independent predictor of LOS (p = 0.027). Conclusions: An independent association between elevated vitamin B12 concentrations, mortality and LOS was found in our sample of hospitalized adult patients at nutritional risk. Although the underlying mechanisms are still unknown and any cause-effect relation cannot be inferred, clinicians should be aware of the potential negative impact of high vitamin B12 concentrations in hospitalized patients at nutritional risk and avoid inappropriate vitamin supplementation. PMID- 28025530 TI - High Performance CMOS Light Detector with Dark Current Suppression in Variable Temperature Systems. AB - This paper presents a dark current suppression technique for a light detector in a variable-temperature system. The light detector architecture comprises a photodiode for sensing the ambient light, a dark current diode for conducting dark current suppression, and a current subtractor that is embedded in the current amplifier with enhanced dark current cancellation. The measured dark current of the proposed light detector is lower than that of the epichlorohydrin photoresistor or cadmium sulphide photoresistor. This is advantageous in variable temperature systems, especially for those with many infrared light-emitting diodes. Experimental results indicate that the maximum dark current of the proposed current amplifier is approximately 135 nA at 125 degrees C, a near zero dark current is achieved at temperatures lower than 50 degrees C, and dark current and temperature exhibit an exponential relation at temperatures higher than 50 degrees C. The dark current of the proposed light detector is lower than 9.23 nA and the linearity is approximately 1.15 MUA/lux at an external resistance RSS = 10 kOmega and environmental temperatures from 25 degrees C to 85 degrees C. PMID- 28025529 TI - Anticonvulsant Effects of Fractions Isolated from Dinoponera quadriceps (Kempt) Ant Venom (Formicidae: Ponerinae). AB - Natural products, sources of new pharmacological substances, have large chemical diversity and architectural complexity. In this context, some toxins obtained from invertebrate venoms have anticonvulsant effects. Epilepsy is a neurological disorder that affects about 65 million people worldwide, and approximately 30% of cases are resistant to pharmacological treatment. Previous studies from our group show that the denatured venom of the ant Dinoponera quadriceps (Kempt) protects mice against bicuculline (BIC)-induced seizures and death. The aim of this study was to investigate the anticonvulsant activity of compounds isolated from D. quadriceps venom against seizures induced by BIC in mice. Crude venom was fractionated by high-performance liquid chromatography (HPLC) resulting in six fractions referred to as DqTx1-DqTx6. A liquid chromatography-mass spectrometry (LC/MS) analysis revealed a major 431 Da compound in fractions DqTx1 and DqTx2. Fractions DqTx3 and DqTx4 showed a compound of 2451 Da and DqTx5 revealed a 2436 Da compound. Furthermore, the DqTx6 fraction exhibited a major component with a molecular weight of 13,196 Da. Each fraction (1 mg/mL) was microinjected into the lateral ventricle of mice, and the animals were observed in an open field. We did not observe behavioral alterations when the fractions were given alone. Conversely, when the fractions were microinjected 20 min prior to the administration of BIC (21.6 nM), DqTx1, DqTx4, and DqTx6 fractions increased the latency for onset of tonic-clonic seizures. Moreover, all fractions, except DqTx5, increased latency to death. The more relevant result was obtained with the DqTx6 fraction, which protected 62.5% of the animals against tonic-clonic seizures. Furthermore, this fraction protected 100% of the animals from seizure episodes followed by death. Taken together, these findings indicate that compounds from ant venom might be a potential source of new anticonvulsants molecules. PMID- 28025531 TI - Small UAS-Based Wind Feature Identification System Part 1: Integration and Validation. AB - This paper presents a system for identification of wind features, such as gusts and wind shear. These are of particular interest in the context of energy efficient navigation of Small Unmanned Aerial Systems (UAS). The proposed system generates real-time wind vector estimates and a novel algorithm to generate wind field predictions. Estimations are based on the integration of an off-the-shelf navigation system and airspeed readings in a so-called direct approach. Wind predictions use atmospheric models to characterize the wind field with different statistical analyses. During the prediction stage, the system is able to incorporate, in a big-data approach, wind measurements from previous flights in order to enhance the approximations. Wind estimates are classified and fitted into a Weibull probability density function. A Genetic Algorithm (GA) is utilized to determine the shaping and scale parameters of the distribution, which are employed to determine the most probable wind speed at a certain position. The system uses this information to characterize a wind shear or a discrete gust and also utilizes a Gaussian Process regression to characterize continuous gusts. The knowledge of the wind features is crucial for computing energy-efficient trajectories with low cost and payload. Therefore, the system provides a solution that does not require any additional sensors. The system architecture presents a modular decentralized approach, in which the main parts of the system are separated in modules and the exchange of information is managed by a communication handler to enhance upgradeability and maintainability. Validation is done providing preliminary results of both simulations and Software-In-The Loop testing. Telemetry data collected from real flights, performed in the Seville Metropolitan Area in Andalusia (Spain), was used for testing. Results show that wind estimation and predictions can be calculated at 1 Hz and a wind map can be updated at 0.4 Hz . Predictions show a convergence time with a 95% confidence interval of approximately 30 s . PMID- 28025532 TI - Plasmonic Fiber Optic Refractometric Sensors: From Conventional Architectures to Recent Design Trends. AB - Surface Plasmon Resonance (SPR) fiber sensor research has grown since the first demonstration over 20 year ago into a rich and diverse field with a wide range of optical fiber architectures, plasmonic coatings, and excitation and interrogation methods. Yet, the large diversity of SPR fiber sensor designs has made it difficult to understand the advantages of each approach. Here, we review SPR fiber sensor architectures, covering the latest developments from optical fiber geometries to plasmonic coatings. By developing a systematic approach to fiber based SPR designs, we identify and discuss future research opportunities based on a performance comparison of the different approaches for sensing applications. PMID- 28025533 TI - Pyran Rings Containing Polyketides from Penicillium raistrickii. AB - Five new pyran rings containing polyketides, penicipyrans A-E (1-5), together with the known pestapyrone A (6), were isolated from the saline soil-derived Penicillium raistrickii. Their structures were determined by interpretation of NMR and HRESIMS data. The absolute configurations of compounds 4 and 5 were established by the modified Mosher's method and single-crystal X-ray diffraction analysis, respectively. These compounds possessed high structural diversity including two alpha-pyrones (1, 2), three isocoumarins (3, 4, 6), and one dihydropyran derivative (5). Among them, Compound 5 exhibited cytotoxicity against HL-60 and K562 cell lines with IC50 values of 4.4 and 8.5 MUM, respectively. PMID- 28025534 TI - A Novel Controller Design for the Next Generation Space Electrostatic Accelerometer Based on Disturbance Observation and Rejection. AB - The state-of-the-art accelerometer technology has been widely applied in space missions. The performance of the next generation accelerometer in future geodesic satellites is pushed to 8 * 10 - 13 m / s 2 / H z 1 / 2 , which is close to the hardware fundamental limit. According to the instrument noise budget, the geodesic test mass must be kept in the center of the accelerometer within the bounds of 56 pm / Hz 1 / 2 by the feedback controller. The unprecedented control requirements and necessity for the integration of calibration functions calls for a new type of control scheme with more flexibility and robustness. A novel digital controller design for the next generation electrostatic accelerometers based on disturbance observation and rejection with the well-studied Embedded Model Control (EMC) methodology is presented. The parameters are optimized automatically using a non-smooth optimization toolbox and setting a weighted H infinity norm as the target. The precise frequency performance requirement of the accelerometer is well met during the batch auto-tuning, and a series of controllers for multiple working modes is generated. Simulation results show that the novel controller could obtain not only better disturbance rejection performance than the traditional Proportional Integral Derivative (PID) controllers, but also new instrument functions, including: easier tuning procedure, separation of measurement and control bandwidth and smooth control parameter switching. PMID- 28025535 TI - Special Issue: New Approaches to Counteract Drug Resistance in Cancer. AB - n/a. PMID- 28025536 TI - Simultaneous Moisture Content and Mass Flow Measurements in Wood Chip Flows Using Coupled Dielectric and Impact Sensors. AB - An 8-electrode capacitance tomography (ECT) sensor was built and used to measure moisture content (MC) and mass flow of pine chip flows. The device was capable of directly measuring total water quantity in a sample but was sensitive to both dry matter and moisture, and therefore required a second measurement of mass flow to calculate MC. Two means of calculating the mass flow were used: the first being an impact sensor to measure total mass flow, and the second a volumetric approach based on measuring total area occupied by wood in images generated using the capacitance sensor's tomographic mode. Tests were made on 109 groups of wood chips ranging in moisture content from 14% to 120% (dry basis) and wet weight of 280 to 1100 g. Sixty groups were randomly selected as a calibration set, and the remaining were used for validation of the sensor's performance. For the combined capacitance/force transducer system, root mean square errors of prediction (RMSEP) for wet mass flow and moisture content were 13.42% and 16.61%, respectively. RMSEP using the combined volumetric mass flow/capacitance sensor for dry mass flow and moisture content were 22.89% and 24.16%, respectively. Either of the approaches was concluded to be feasible for prediction of moisture content in pine chip flows, but combining the impact and capacitance sensors was easier to implement. In situations where flows could not be impeded, however, the tomographic approach would likely be more useful. PMID- 28025537 TI - Which Diet-Related Behaviors in Childhood Influence a Healthier Dietary Pattern? From the Ewha Birth and Growth Cohort. AB - This study was performed to examine how childhood dietary patterns change over the short term and which changes in diet-related behaviors influence later changes in individual dietary patterns. Using food frequency questionnaire data obtained from children at 7 and 9 years of age from the Ewha Birth and Growth Cohort, we examined dietary patterns by principal component analysis. We calculated the individual changes in dietary pattern scores. Changes in dietary habits such as eating a variety of food over two years were defined as "increased", "stable", or "decreased". The dietary patterns, termed "healthy intake", "animal food intake", and "snack intake", were similar at 7 and 9 years of age. These patterns explained 32.3% and 39.1% of total variation at the ages of 7 and 9 years, respectively. The tracking coefficient of snack intake had the highest coefficient (gamma = 0.53) and that of animal food intake had the lowest (gamma = 0.21). Intra-individual stability in dietary habits ranged from 0.23 to 0.47, based on the sex-adjusted weighted kappa values. Of the various behavioral factors, eating breakfast every day was most common in the "stable" group (83.1%), whereas consuming milk or dairy products every day was the least common (49.0%). Moreover, changes in behavior that improved the consumption of milk or dairy products or encouraged the consumption of vegetables with every meal had favorable effects on changes in healthy dietary pattern scores over two years. However, those with worsened habits, such as less food variety and more than two portions of fried or stir-fried food every week, had unfavorable effects on changes in healthy dietary pattern scores. Our results suggest that diet-related behaviors can change, even over a short period, and these changes can affect changes in dietary pattern. PMID- 28025538 TI - The Impact of Health Literacy Status on the Comparative Validity and Sensitivity of an Interactive Multimedia Beverage Intake Questionnaire. AB - Self-reported dietary assessment methods can be challenging to validate, and reporting errors for those with lower health literacy (HL) may be augmented. Interactive multimedia (IMM) based questionnaires could help overcome these limitations. The objectives of this investigation are to assess the comparative validity and sensitivity to change of an IMM beverage intake questionnaire (IMM BEVQ) as compared to dietary recalls and determine the impact of HL. Adults completed three 24-h dietary recalls and the IMM-BEVQ at baseline and after a six month intervention targeting either sugar-sweetened beverages (SSB) or physical activity. Correlations and paired-samples t-tests are presented. For validity (n = 273), intake of SSB (mean difference = 10.6 fl oz) and total beverage consumption (mean difference = 16.0 fl oz) were significantly different (p <= 0.001) at baseline between the IMM-BEVQ and dietary recalls for all participants. However, the differences in intake were generally greater in low HL participants than in adequate HL participants. For sensitivity (n = 162), change in SSB intake (mean difference = 7.2 fl oz) was significantly different (p <= 0.01) between pre /post-IMM-BEVQ and pre-/post-dietary recalls, but not total beverage intake (mean difference = 7.6 fl oz) for all participants. Changes in SSB and total beverage intake were not significantly different for those with adequate HL. The IMM-BEVQ is a valid dietary assessment tool that is as responsive to detecting changes in beverage intake as dietary recalls. However, adults with lower HL may need additional guidance when completing the IMM-BEVQ. PMID- 28025539 TI - Group vs. Individual Treatment for Acute Insomnia: A Pilot Study Evaluating a "One-Shot" Treatment Strategy. AB - BACKGROUND: Despite undeniable evidence for the efficacy and effectiveness of Cognitive Behaviour Therapy for Insomnia (CBT-I), the potential for its widespread dissemination and implementation has yet to be realised. A suggested reason for this is that traditional CBT-I is considered too burdensome for deployment, in its current form, within the context of where it would be most beneficial-Primary Care. One strategy, aimed to address this, has been to develop briefer versions of CBT-I, whilst another has been to deliver CBT-I in a group format. An alternative has been to attempt to address insomnia during its acute phase with a view to circumventing its progression to chronic insomnia. The aim of the present study was to compare a brief version of CBT-I (one-shot) when delivered individually or in groups to those with acute insomnia. METHOD: Twenty eight individuals with acute insomnia (i.e., meeting full DSM-5 criteria for insomnia disorder for less than three months) self-assigned to either a group or individual treatment arm. Treatment consisted of a single one-hour session accompanied by a self-help pamphlet. Subjects completed measures of insomnia severity, anxiety and depression pre-treatment and at one-month post-treatment. Additionally, daily sleep diaries were compared between pre-treatment and at the one-month follow up. RESULTS: There were no significant between group differences in treatment outcome on any sleep or mood measures although those in the group treatment arm were less adherent than those who received individual treatment. Furthermore, the combined (group and individual treatment arms) pre-post test effect size on insomnia symptoms, using the Insomnia Severity Index, was large (d = 2.27). DISCUSSION: It appears that group treatment is as efficacious as individual treatment within the context of a "one shot" intervention for individuals with acute insomnia. The results are discussed with a view to integrating one-shot CBT-I in Primary Care. PMID- 28025540 TI - Nanostructured Tip-Shaped Biosensors: Application of Six Sigma Approach for Enhanced Manufacturing. AB - Nanostructured tip-shaped biosensors have drawn attention for biomolecule detection as they are promising for highly sensitive and specific detection of a target analyte. Using a nanostructured tip, the sensitivity is increased to identify individual molecules because of the high aspect ratio structure. Various detection methods, such as electrochemistry, fluorescence microcopy, and Raman spectroscopy, have been attempted to enhance the sensitivity and the specificity. Due to the confined path of electrons, electrochemical measurement using a nanotip enables the detection of single molecules. When an electric field is combined with capillary action and fluid flow, target molecules can be effectively concentrated onto a nanotip surface for detection. To enhance the concentration efficacy, a dendritic nanotip rather than a single tip could be used to detect target analytes, such as nanoparticles, cells, and DNA. However, reproducible fabrication with relation to specific detection remains a challenge due to the instability of a manufacturing method, resulting in inconsistent shape. In this paper, nanostructured biosensors are reviewed with our experimental results using dendritic nanotips for sequence specific detection of DNA. By the aid of the Six Sigma approach, the fabrication yield of dendritic nanotips increases from 20.0% to 86.6%. Using the nanotips, DNA is concentrated and detected in a sequence specific way with the detection limit equivalent to 1000 CFU/mL. The pros and cons of a nanotip biosensor are evaluated in conjunction with future prospects. PMID- 28025541 TI - miR-203 and miR-320 Regulate Bone Morphogenetic Protein-2-Induced Osteoblast Differentiation by Targeting Distal-Less Homeobox 5 (Dlx5). AB - MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17-24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP 2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism. PMID- 28025542 TI - Impact of Spinal Manipulation on Cortical Drive to Upper and Lower Limb Muscles. AB - This study investigates whether spinal manipulation leads to changes in motor control by measuring the recruitment pattern of motor units in both an upper and lower limb muscle and to see whether such changes may at least in part occur at the cortical level by recording movement related cortical potential (MRCP) amplitudes. In experiment one, transcranial magnetic stimulation input-output (TMS I/O) curves for an upper limb muscle (abductor pollicus brevis; APB) were recorded, along with F waves before and after either spinal manipulation or a control intervention for the same subjects on two different days. During two separate days, lower limb TMS I/O curves and MRCPs were recorded from tibialis anterior muscle (TA) pre and post spinal manipulation. Dependent measures were compared with repeated measures analysis of variance, with p set at 0.05. Spinal manipulation resulted in a 54.5% +/- 93.1% increase in maximum motor evoked potential (MEPmax) for APB and a 44.6% +/- 69.6% increase in MEPmax for TA. For the MRCP data following spinal manipulation there were significant difference for amplitude of early bereitschafts-potential (EBP), late bereitschafts potential (LBP) and also for peak negativity (PN). The results of this study show that spinal manipulation leads to changes in cortical excitability, as measured by significantly larger MEPmax for TMS induced input-output curves for both an upper and lower limb muscle, and with larger amplitudes of MRCP component post manipulation. No changes in spinal measures (i.e., F wave amplitudes or persistence) were observed, and no changes were shown following the control condition. These results are consistent with previous findings that have suggested increases in strength following spinal manipulation were due to descending cortical drive and could not be explained by changes at the level of the spinal cord. Spinal manipulation may therefore be indicated for the patients who have lost tonus of their muscle and/or are recovering from muscle degrading dysfunctions such as stroke or orthopaedic operations and/or may also be of interest to sports performers. These findings should be followed up in the relevant populations. PMID- 28025543 TI - RNA Editing and Its Molecular Mechanism in Plant Organelles. AB - RNA editing by cytidine (C) to uridine (U) conversions is widespread in plant mitochondria and chloroplasts. In some plant taxa, "reverse" U-to-C editing also occurs. However, to date, no instance of RNA editing has yet been reported in green algae and the complex thalloid liverworts. RNA editing may have evolved in early land plants 450 million years ago. However, in some plant species, including the liverwort, Marchantia polymorpha, editing may have been lost during evolution. Most RNA editing events can restore the evolutionarily conserved amino acid residues in mRNAs or create translation start and stop codons. Therefore, RNA editing is an essential process to maintain genetic information at the RNA level. Individual RNA editing sites are recognized by plant-specific pentatricopeptide repeat (PPR) proteins that are encoded in the nuclear genome. These PPR proteins are characterized by repeat elements that bind specifically to RNA sequences upstream of target editing sites. In flowering plants, non-PPR proteins also participate in multiple RNA editing events as auxiliary factors. C to-U editing can be explained by cytidine deamination. The proteins discovered to date are important factors for RNA editing but a bona fide RNA editing enzyme has yet to be identified. PMID- 28025544 TI - Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases. AB - Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways primarily interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases. PMID- 28025545 TI - The Pathogenetic Effect of Natural and Bacterial Toxins on Atopic Dermatitis. AB - Atopic dermatitis (AD) is a common allergic skin disease that is associated with chronic, recurrent eczematous and pruritic lesions at the flexural folds caused by interacting factors related to environmental and immune system changes. AD results in dry skin, and immunoglobulin E-mediated allergic reactions to foods and environmental allergens. While steroids and anti-histamines temporarily relieve the symptoms of AD, the possibility of side effects from pharmacological interventions remains. Despite intensive research, the underlying mechanisms for AD have not been clarified. A study of Staphylococcus aureus (S. aureus) established the role of its toxins in the pathogenesis of AD. Approximately 90% of patients with AD experience S. aureus colonization and up to 50%-60% of the colonizing S. aureus is toxin-producing. Any damage to the protective skin barrier allows for the entry of invading allergens and pathogens that further drive the pathogenesis of AD. Some natural toxins (or their components) that have therapeutic effects on AD have been studied. In addition, recent studies on inflammasomes as one component of the innate immune system have been carried out. Additionally, studies on the close relationship between the activation of inflammasomes and toxins in AD have been reported. This review highlights the literature that discusses the pathogenesis of AD, the role of toxins in AD, and the positive and negative effects of toxins on AD. Lastly, suggestions are made regarding the role of inflammasomes in AD. PMID- 28025546 TI - The Use and Interpretation of Sodium Concentrations in Casual (Spot) Urine Collections for Population Surveillance and Partitioning of Dietary Iodine Intake Sources. AB - In 2013, the World Health Organization (WHO) called for joint surveillance of population salt and iodine intakes using urinary analysis. 24-h urine collection is considered the gold standard for salt intake assessment, but there is an emerging consensus that casual urine sampling can provide comparable information for population-level surveillance. Our review covers the use of the urinary sodium concentration (UNaC) and the urinary iodine concentration (UIC) from casual urine samples to estimate salt intakes and to partition the sources of iodine intakes. We reviewed literature on 24-h urinary sodium excretion (UNaE) and UNaC and documented the use of UNaC for national salt intake monitoring. We combined information from our review of urinary sodium with evidence on urinary iodine to assess the appropriateness of partitioning methods currently being adapted for cross-sectional survey analyses. At least nine countries are using casual urine collection for surveillance of population salt intakes; all these countries used single samples. Time trend analyses indicate that single UNaC can be used for monitoring changes in mean salt intakes. However; single UNaC suffers the same limitation as single UNaE; i.e., an estimate of the proportion excess salt intake can be biased due to high individual variability. There is evidence, albeit limited, that repeat UNaC sampling has good agreement at the population level with repeat UNaE collections; thus permitting an unbiased estimate of the proportion of excess salt intake. High variability of UIC and UNaC in single urine samples may also bias the estimates of dietary iodine intake sources. Our review concludes that repeated collection, in a sub-sample of individuals, of casual UNaC data would provide an immediate practical approach for routine monitoring of salt intake, because it overcomes the bias in estimates of excess salt intake. Thus we recommend more survey research to expand the evidence-base on predicted-UNaE from repeat casual UNaC sampling. We also conclude that the methodology for partitioning the sources of iodine intake based on the combination of UIC and UNaC measurements in casual urine samples can be improved by repeat collections of casual data; which helps to reduce regression dilution bias. We recommend more survey research to determine the effect of regression dilution bias and circadian rhythms on the partitioning of dietary iodine intake sources. PMID- 28025547 TI - A Review of Analytical Techniques and Their Application in Disease Diagnosis in Breathomics and Salivaomics Research. AB - The application of metabolomics to biological samples has been a key focus in systems biology research, which is aimed at the development of rapid diagnostic methods and the creation of personalized medicine. More recently, there has been a strong focus towards this approach applied to non-invasively acquired samples, such as saliva and exhaled breath. The analysis of these biological samples, in conjunction with other sample types and traditional diagnostic tests, has resulted in faster and more reliable characterization of a range of health disorders and diseases. As the sampling process involved in collecting exhaled breath and saliva is non-intrusive as well as comparatively low-cost and uses a series of widely accepted methods, it provides researchers with easy access to the metabolites secreted by the human body. Owing to its accuracy and rapid nature, metabolomic analysis of saliva and breath (known as salivaomics and breathomics, respectively) is a rapidly growing field and has shown potential to be effective in detecting and diagnosing the early stages of numerous diseases and infections in preclinical studies. This review discusses the various collection and analyses methods currently applied in two of the least used non invasive sample types in metabolomics, specifically their application in salivaomics and breathomics research. Some of the salient research completed in this field to date is also assessed and discussed in order to provide a basis to advocate their use and possible future scientific directions. PMID- 28025548 TI - Improvement of Intestinal Immune Cell Function by Lactic Acid Bacteria for Dairy Products. AB - Lactic acid bacteria (LAB) form a major component of gut microbiota and are often used as probiotics for fermented foods, such as yoghurt. In this study, we aimed to evaluate immunomodulatory activity of LAB, especially that of Lactobacillus bulgaricus ME-552 (ME552) and Streptococcus thermophilus ME-553 (ME553). In vivo/in vitro assay was performed in order to investigate their effects on T cell function. After oral administration of ME553 to C57BL/6 mice, the amount of both interferon gamma (IFN-gamma) and interleukin 17 (IL-17) produced by cluster of differentiation (CD) 4+ T cells from Peyer's patches (PPs) were significantly enhanced. On the other hand, ME552 only up-regulated the production of IL-17 from PP cells. The extent of induction for IFN-gamma production differed between ME552 and ME553. These results suggest that LAB modulate T cell effector functions and mucosal immunity. PMID- 28025549 TI - A Spatial Control for Correct Timing of Gene Expression during the Escherichia coli Cell Cycle. AB - Temporal transcriptions of genes are achieved by different mechanisms such as dynamic interaction of activator and repressor proteins with promoters, and accumulation and/or degradation of key regulators as a function of cell cycle. We find that the TorR protein localizes to the old poles of the Escherichia coli cells, forming a functional focus. The TorR focus co-localizes with the nucleoid in a cell-cycle-dependent manner, and consequently regulates transcription of a number of genes. Formation of one TorR focus at the old poles of cells requires interaction with the MreB and DnaK proteins, and ATP, suggesting that TorR delivery requires cytoskeleton organization and ATP. Further, absence of the protein-protein interactions and ATP leads to loss in function of TorR as a transcription factor. We propose a mechanism for timing of cell-cycle-dependent gene transcription, where a transcription factor interacts with its target genes during a specific period of the cell cycle by limiting its own spatial distribution. PMID- 28025550 TI - Targeted Metabolomic Analysis of Polyphenols with Antioxidant Activity in Sour Guava (Psidium friedrichsthalianum Nied.) Fruit. AB - Psidium is a genus of tropical bushes belonging to the Myrtaceae family distributed in Central and South America. The polar extract of Psidium friedrichsthalianum Nied. was partitioned with ethyl ether, ethyl acetate, and n butanol, and the total phenolic content and antioxidant activity were measured by Folin-Ciocalteu and ABTS assays, respectively. The ethyl acetate fraction exhibited both the highest phenolic content and antioxidant activity. Due to the complexity of this fraction, an analytical method for the comprehensive profiling of phenolic compounds was done by UPLC-ESI/QqQ in MRM (multiple reaction monitoring) mode. In this targeted analysis, 22 phenolic compounds were identified, among which several hydroxybenzoic, phenylacetic, and hydroxycinnamic acid derivatives were found. This is the first time that (+)-catechin, procyanidin B1, procyanidin B2, and (-)-epicatechin have been reported as constituents of sour guava. A fractionation by exclusion size, C18-column chromatography, and preparative RRLC (rapid resolution liquid chromatography) allowed us to confirm the presence of ellagic acid and isomeric procyanidins B, well-known bioactive compounds. The content of phenolic compounds in this fruit shows its potential for the development of functional foods. PMID- 28025551 TI - Special Issue "Recent Synthetic Aspects on the Chemistry of Nitro, Nitroso and Amino Compounds". AB - Nitrogen-containing molecules are key scaffolds that are widely applied in organic synthesis as precursors of highly functionalized materials, and are also investigated for their biological activities. This Special Issue collects seven innovative contributions which expand our knowledge of the chemistry of nitro compounds, amines, diazonium salts, and peptides, and that provide a good overview about their main reactivities. PMID- 28025552 TI - Solvation Dynamics of CO2(g) by Monoethanolamine at the Gas-Liquid Interface: A Molecular Mechanics Approach. AB - A classical force field approach was used to characterize the solvation dynamics of high-density CO2(g) by monoethanolamine (MEA) at the air-liquid interface. Intra- and intermolecular CO2 and MEA potentials were parameterized according to the energetics calculated at the MP2 and BLYP-D2 levels of theory. The thermodynamic properties of CO2 and MEA, such as heat capacity and melting point, were consistently predicted using this classical potential. An approximate interfacial simulation for CO2(g)/MEA(l) was performed to monitor the depletion of the CO2(g) phase, which was influenced by amino and hydroxyl groups of MEA. There are more intramolecular hydrogen bond interactions notably identified in the interfacial simulation than the case of bulk MEA(l) simulation. The hydroxyl group of MEA was found to more actively approach CO2 and overpower the amino group to interact with CO2 at the air-liquid interface. With artificially reducing the dipole moment of the hydroxyl group, CO2-amino group interaction was enhanced and suppressed CO2(g) depletion. The hydroxyl group of MEA was concluded to play dual but contradictory roles for CO2 capture. PMID- 28025553 TI - Special Issue "Saffron (Crocus sativus, L.): Omics and Other Techniques in Authenticity, Quality, and Bioactivity Studies". AB - n/a. PMID- 28025554 TI - Antioxidant Activities and Chemical Constituents of Flavonoids from the Flower of Paeonia ostii. AB - Paeonia ostii is a traditional medicinal plant popularly used in China. This study intended to evaluate the antioxidant properties and the chemical components of the flavonoid-rich extracts from the flowers of P. ostii. The results showed that the flavonoid-rich extracts from the flowers of P. ostii had strong scavenging capacities on 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS), hydroxyls, superoxide anions, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals in a dose-dependent manner. Five flavonoids, dihydrokaempferol (1), apigenin-7-O-beta-d-glucoside (2), apigenin-7-O-beta-d-neohesperidoside (3), kaempferol-7-O-beta-d-glucopyranoside (4), and kaempferol-3-O-beta-d glucopyranosyl-7-O-beta-d-glucopyranoside (5), were isolated from the flavonoid rich extracts of the flowers of P. ostii. High-performance liquid chromatography (HPLC) analysis revealed that compounds 3 and 4 were abundant in the P. ostii flower and in flavonoid-rich extracts. The main components of the flower of P. ostii are flavonoids. The high antioxidant activity of the flavonoid-rich extracts may be attributed to the high content of flavonoids. The five isolated flavonoids were the primary antioxidant ingredients, and may play important roles in the strong antioxidant activities of this flower. Based on the obtained results, the flower of P. ostii could be a potential source of natural antioxidants in food and pharmaceutical applications. PMID- 28025555 TI - Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage. AB - Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high hydrophilicity. The therapeutic effect of GA on OA could be improved if certain structural modifications were made to increase its hydrophobicity. In this study, a novel sulfonamido-based gallate was synthesized by bonding sulfonamide with GA, and its biological evaluations on OA were investigated. Results show that 5-[4-(Pyrimidin-2 ylsulfamoylphenyl)]-carbamoyl-benzene-1,2,3-triyl triacetate (HAMDC) was able to reverse the effects induced by Interleukin-1 (IL-1) stimulation, and it also had a great effect on chondro-protection via promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as well as enhancing synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Furthermore, a docking study showed that HAMDC fits into the core of the active site of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5), which provides an explanation for its activity and selectivity. PMID- 28025556 TI - Detection of Campylobacter jejuni in Lizard Faeces from Central Australia Using Quantitative PCR. AB - Worldwide, Campylobacter is a significant cause of gastrointestinal illness. It is predominately considered a foodborne pathogen, with human exposure via non food transmission routes generally overlooked. Current literature has been exploring environmental reservoirs of campylobacteriosis including potential wildlife reservoirs. Given the close proximity between lizards and human habitats in Central Australia, this study examined the presence of Campylobacter jejuni from lizard faeces collected from this region. Of the 51 samples collected, 17 (33%) (this included 14/46 (30%) wild and 3/5 (60%) captive lizard samples) were positive for C. jejuni using quantitative PCR (qPCR). This was the first study to investigate the presence of C. jejuni in Australian lizards. This has public health implications regarding the risk of campylobacteriosis from handling of pet reptiles and through cross-contamination or contact with wild lizard faeces. Additionally this has implication for horizontal transmission via lizards of C. jejuni to food production farms. Further research is needed on this environmental reservoir and potential transmission routes to reduce the risk to public health. PMID- 28025557 TI - A Study of Personal Health Record User's Behavioral Model Based on the PMT and UTAUT Integrative Perspective. AB - The personal health record (PHR) is a system that enables borderless medical care services by combining technological innovation and human consideration. This study explored factors affecting the adoption of PHR from technical, medical, and social perspectives according to the Protection Motivation Theory (PMT) and Unified Theory of Acceptance and Use of Technology (UTAUT) model. A survey using a structured questionnaire was subsequently conducted, which produced the following results: (1) The PMT and UTAUT were effective at predicting PHR usage behaviors; (2) Perceived ease-of-use was the most decisive factor influencing the use of PHR, followed by self-efficacy and perceived usefulness; and (3) Behavioral intention for PHR was significantly and positively correlated with usage behavior. From the obtained results, this study recommends that health authorities and medical institutions promote self-efficacy in the use of PHR to improve the levels of behavioral intention and usage behavior among the people. Additionally, medical care institutions are recommended to promote health management and preventive healthcare concepts to help improve public acceptance of the PHR system as a means to self-manage their health. Finally, community centers, medical institutions, and health authorities are urged to work together to enhance public medical knowledge and pool resources for the PHR system, both of which are essential for improving the popularity of the PHR, public quality of life, and the effectiveness of health management. PMID- 28025558 TI - Empirical Analysis and Modeling of Stop-Line Crossing Time and Speed at Signalized Intersections. AB - In China, a flashing green (FG) indication of 3 s followed by a yellow (Y) indication of 3 s is commonly applied to end the green phase at signalized intersections. Stop-line crossing behavior of drivers during such a phase transition period significantly influences safety performance of signalized intersections. The objective of this study is thus to empirically analyze and model drivers' stop-line crossing time and speed in response to the specific phase transition period of FG and Y. High-resolution trajectories for 1465 vehicles were collected at three rural high-speed intersections with a speed limit of 80 km/h and two urban intersections with a speed limit of 50 km/h in Shanghai. With the vehicle trajectory data, statistical analyses were performed to look into the general characteristics of stop-line crossing time and speed at the two types of intersections. A multinomial logit model and a multiple linear regression model were then developed to predict the stop-line crossing patterns and speeds respectively. It was found that the percentage of stop-line crossings during the Y interval is remarkably higher and the stop-line crossing time is approximately 0.7 s longer at the urban intersections, as compared with the rural intersections. In addition, approaching speed and distance to the stop-line at the onset of FG as well as area type significantly affect the percentages of stop line crossings during the FG and Y intervals. Vehicle type and stop-line crossing pattern were found to significantly influence the stop-line crossing speed, in addition to the above factors. The red-light-running seems to occur more frequently at the large intersections with a long cycle length. PMID- 28025559 TI - Cancer's Achilles' Heel: Apoptosis and Necroptosis to the Rescue. AB - Apoptosis, and the more recently discovered necroptosis, are two avenues of programmed cell death. Cancer cells survive by evading these two programs, driven by oncogenes and tumor suppressor genes. While traditional therapy using small molecular inhibitors and chemotherapy are continuously being utilized, a new and exciting approach is actively underway by identifying and using synergistic relationship between driver and rescue genes in a cancer cell. Through these synthetic lethal relationships, we are gaining tremendous insights into tumor vulnerabilities and specific molecular avenues for induction of programmed cell death. In this review, we briefly discuss the two cell death processes and cite examples of such synergistic manipulations for therapeutic purposes. PMID- 28025560 TI - Use of Electronic Nicotine Delivery Systems among Adults with Mental Health Conditions, 2015. AB - Adults with mental health conditions (MHC) are especially likely to smoke and experience tobacco-related health disparities. Individuals with MHC may also use electronic nicotine delivery devices (ENDS) at disproportionately high rates. However, there is a relative dearth of knowledge regarding ENDS use among individuals with MHC. In a large representative sample of U.S. adults (n = 6051), associations between self-reported MHC diagnoses and ENDS use and susceptibility were examined, stratified by smoking status. Participants with MHC were approximately 1.5 times more likely to have used ENDS in their lifetime and almost twice as likely to currently use ENDS as those without MHC. MHC status was most strongly linked to higher ENDS use among former smokers, and former smokers with MHC were more likely to report using ENDS during past smoking quit attempts than those without MHC. Among participants who had not tried ENDS, former smokers with MHC were especially susceptible to future ENDS use. The potential advantage of ENDS for cessation purposes should be balanced with the risk of attracting former smokers with MHC to ENDS. PMID- 28025561 TI - Synthesis, Characterization, and Bactericidal Evaluation of Chitosan/Guanidine Functionalized Graphene Oxide Composites. AB - In response to the wide spread of microbial contamination induced by bacterial pathogens, the development of novel materials with excellent antibacterial activity is of great interest. In this study, novel antibacterial chitosan (CS) and polyhexamethylene guanidine hydrochloride (PHGC) dual-polymer-functionalized graphene oxide (GO) (GO-CS-PHGC) composites were designed and easily fabricated. The as-prepared materials were characterized by Fourier transform infrared (FTIR), X-ray photoelectron spectrometer (XPS), field emission scanning electron microscopy (FE-SEM), transmission electron microscope (TEM), thermogravimetric analysis (TGA) and Raman spectroscopy. Their antibacterial capability towards bacterial strains was also studied by incubating both Gram-negative bacteria and Gram-positive bacteria in their presence. More significantly, the synergistic antibacterial action of the three components was assayed, and the findings implied that the as-prepared GO-CS-PHGC shows enhanced antibacterial activity when compared to its single components (GO, CS, PHGC or CS-PHGC) and the mixture of individual components. Not only Gram-negative bacteria but also Gram-positive bacteria are greatly inhibited by GO-CS-PHGC composites. The minimum inhibitory concentration (MIC) value of GO-CS-PHGC against E. coli was 32 MUg/mL. With the powerful antibacterial activity as well as its low cost and facile preparation, GO-CS-PHGC has potential applications as a novel antibacterial agent in a wide range of biomedical uses. PMID- 28025562 TI - Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer's disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Abeta), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 MUM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Abeta generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3beta, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3beta axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Abeta production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD. PMID- 28025563 TI - Novel Structural Approaches to Study GPCR Regulation. AB - BACKGROUND: Upon natural agonist or pharmacological stimulation, G protein coupled receptors (GPCRs) are subjected to posttranslational modifications, such as phosphorylation and ubiquitination. These posttranslational modifications allow protein-protein interactions that turn off and/or switch receptor signaling as well as trigger receptor internalization, recycling or degradation, among other responses. Characterization of these processes is essential to unravel the function and regulation of GPCR. METHODS: In silico analysis and methods such as mass spectrometry have emerged as novel powerful tools. Both approaches have allowed proteomic studies to detect not only GPCR posttranslational modifications and receptor association with other signaling macromolecules but also to assess receptor conformational dynamics after ligand (agonist/antagonist) association. RESULTS: this review aims to provide insights into some of these methodologies and to highlight how their use is enhancing our comprehension of GPCR function. We present an overview using data from different laboratories (including our own), particularly focusing on free fatty acid receptor 4 (FFA4) (previously known as GPR120) and alpha1A- and alpha1D-adrenergic receptors. From our perspective, these studies contribute to the understanding of GPCR regulation and will help to design better therapeutic agents. PMID- 28025564 TI - Versatile Flexible Graphene Multielectrode Arrays. AB - Graphene is a promising material possessing features relevant to bioelectronics applications. Graphene microelectrodes (GMEAs), which are fabricated in a dense array on a flexible polyimide substrate, were investigated in this work for their performance via electrical impedance spectroscopy. Biocompatibility and suitability of the GMEAs for extracellular recordings were tested by measuring electrical activities from acute heart tissue and cardiac muscle cells. The recordings show encouraging signal-to-noise ratios of 65 +/- 15 for heart tissue recordings and 20 +/- 10 for HL-1 cells. Considering the low noise and excellent robustness of the devices, the sensor arrays are suitable for diverse and biologically relevant applications. PMID- 28025565 TI - A Machine Learning Approach to Pedestrian Detection for Autonomous Vehicles Using High-Definition 3D Range Data. AB - This article describes an automated sensor-based system to detect pedestrians in an autonomous vehicle application. Although the vehicle is equipped with a broad set of sensors, the article focuses on the processing of the information generated by a Velodyne HDL-64E LIDAR sensor. The cloud of points generated by the sensor (more than 1 million points per revolution) is processed to detect pedestrians, by selecting cubic shapes and applying machine vision and machine learning algorithms to the XY, XZ, and YZ projections of the points contained in the cube. The work relates an exhaustive analysis of the performance of three different machine learning algorithms: k-Nearest Neighbours (kNN), Naive Bayes classifier (NBC), and Support Vector Machine (SVM). These algorithms have been trained with 1931 samples. The final performance of the method, measured a real traffic scenery, which contained 16 pedestrians and 469 samples of non pedestrians, shows sensitivity (81.2%), accuracy (96.2%) and specificity (96.8%). PMID- 28025567 TI - An Efficient Wireless Recharging Mechanism for Achieving Perpetual Lifetime of Wireless Sensor Networks. AB - Energy recharging has received much attention in recent years. Several recharging mechanisms were proposed for achieving perpetual lifetime of a given Wireless Sensor Network (WSN). However, most of them require a mobile recharger to visit each sensor and then perform the recharging task, which increases the length of the recharging path. Another common weakness of these works is the requirement for the mobile recharger to stop at the location of each sensor. As a result, it is impossible for recharger to move with a constant speed, leading to inefficient movement. To improve the recharging efficiency, this paper takes "recharging while moving" into consideration when constructing the recharging path. We propose a Recharging Path Construction (RPC) mechanism, which enables the mobile recharger to recharge all sensors using a constant speed, aiming to minimize the length of recharging path and improve the recharging efficiency while achieving the requirement of perpetual network lifetime of a given WSN. Performance studies reveal that the proposed RPC outperforms existing proposals in terms of path length and energy utilization index, as well as visiting cycle. PMID- 28025566 TI - A Circuit-Based Neural Network with Hybrid Learning of Backpropagation and Random Weight Change Algorithms. AB - A hybrid learning method of a software-based backpropagation learning and a hardware-based RWC learning is proposed for the development of circuit-based neural networks. The backpropagation is known as one of the most efficient learning algorithms. A weak point is that its hardware implementation is extremely difficult. The RWC algorithm, which is very easy to implement with respect to its hardware circuits, takes too many iterations for learning. The proposed learning algorithm is a hybrid one of these two. The main learning is performed with a software version of the BP algorithm, firstly, and then, learned weights are transplanted on a hardware version of a neural circuit. At the time of the weight transplantation, a significant amount of output error would occur due to the characteristic difference between the software and the hardware. In the proposed method, such error is reduced via a complementary learning of the RWC algorithm, which is implemented in a simple hardware. The usefulness of the proposed hybrid learning system is verified via simulations upon several classical learning problems. PMID- 28025568 TI - A Formal Methodology to Design and Deploy Dependable Wireless Sensor Networks. AB - Wireless Sensor Networks (WSNs) are being increasingly adopted in critical applications, where verifying the correct operation of sensor nodes is a major concern. Undesired events may undermine the mission of the WSNs. Hence, their effects need to be properly assessed before deployment, to obtain a good level of expected performance; and during the operation, in order to avoid dangerous unexpected results. In this paper, we propose a methodology that aims at assessing and improving the dependability level of WSNs by means of an event based formal verification technique. The methodology includes a process to guide designers towards the realization of a dependable WSN and a tool ("ADVISES") to simplify its adoption. The tool is applicable to homogeneous WSNs with static routing topologies. It allows the automatic generation of formal specifications used to check correctness properties and evaluate dependability metrics at design time and at runtime for WSNs where an acceptable percentage of faults can be defined. During the runtime, we can check the behavior of the WSN accordingly to the results obtained at design time and we can detect sudden and unexpected failures, in order to trigger recovery procedures. The effectiveness of the methodology is shown in the context of two case studies, as proof-of-concept, aiming to illustrate how the tool is helpful to drive design choices and to check the correctness properties of the WSN at runtime. Although the method scales up to very large WSNs, the applicability of the methodology may be compromised by the state space explosion of the reasoning model, which must be faced by partitioning large topologies into sub-topologies. PMID- 28025569 TI - Robust Functionalization of Large Microelectrode Arrays by Using Pulsed Potentiostatic Deposition. AB - Surface modification of microelectrodes is a central step in the development of microsensors and microsensor arrays. Here, we present an electrodeposition scheme based on voltage pulses. Key features of this method are uniformity in the deposited electrode coatings, flexibility in the overall deposition area, i.e., the sizes and number of the electrodes to be coated, and precise control of the surface texture. Deposition and characterization of four different materials are demonstrated, including layers of high-surface-area platinum, gold, conducting polymer poly(ethylenedioxythiophene), also known as PEDOT, and the non-conducting polymer poly(phenylenediamine), also known as PPD. The depositions were conducted using a fully integrated complementary metal-oxide-semiconductor (CMOS) chip with an array of 1024 microelectrodes. The pulsed potentiostatic deposition scheme is particularly suitable for functionalization of individual electrodes or electrode subsets of large integrated microelectrode arrays: the required deposition waveforms are readily available in an integrated system, the same deposition parameters can be used to functionalize the surface of either single electrodes or large arrays of thousands of electrodes, and the deposition method proved to be robust and reproducible for all materials tested. PMID- 28025570 TI - Optical Gas Sensing of Ammonia and Amines Based on Protonated Porphyrin/TiO2 Composite Thin Films. AB - Open porous and transparent microcolumnar structures of TiO2 prepared by physical vapour deposition in glancing angle configuration (GLAD-PVD) have been used as host matrices for two different fluorescent cationic porphyrins, 5-(N-methyl 4 pyridyl)-10,15,20-triphenyl porphine chloride (MMPyP) and meso-tetra (N-methyl 4 pyridyl) porphine tetrachloride (TMPyP). The porphyrins have been anchored by electrostatic interactions to the microcolumns by self-assembly through the dip coating method. These porphyrin/TiO2 composites have been used as gas sensors for ammonia and amines through previous protonation of the porphyrin with HCl followed by subsequent exposure to the basic analyte. UV-vis absorption, emission, and time-resolved spectroscopies have been used to confirm the protonation-deprotonation of the two porphyrins and to follow their spectral changes in the presence of the analytes. The monocationic porphyrin has been found to be more sensible (up to 10 times) than its tetracationic counterpart. This result has been attributed to the different anchoring arrangements of the two porphyrins to the TiO2 surface and their different states of aggregation within the film. Finally, there was an observed decrease of the emission fluorescence intensity in consecutive cycles of exposure and recovery due to the formation of ammonium chloride inside the film. PMID- 28025571 TI - Finite Element Analysis of Single Cell Stiffness Measurements Using PZT Integrated Buckling Nanoneedles. AB - This paper proposes a new technique for real-time single cell stiffness measurement using lead zirconate titanate (PZT)-integrated buckling nanoneedles. The PZT and the buckling part of the nanoneedle have been modelled and validated using the ABAQUS software. The two parts are integrated together to function as a single unit. After calibration, the stiffness, Young's modulus, Poisson's ratio and sensitivity of the PZT-integrated buckling nanoneedle have been determined to be 0.7100 N.m-1, 123.4700 GPa, 0.3000 and 0.0693 V.m.N-1, respectively. Three Saccharomyces cerevisiae cells have been modelled and validated based on compression tests. The average global stiffness and Young's modulus of the cells are determined to be 10.8867 +/- 0.0094 N.m-1 and 110.7033 +/- 0.0081 MPa, respectively. The nanoneedle and the cell have been assembled to measure the local stiffness of the single Saccharomyces cerevisiae cells The local stiffness, Young's modulus and PZT output voltage of the three different size Saccharomyces cerevisiae have been determined at different environmental conditions. We investigated that, at low temperature the stiffness value is low to adapt to the change in the environmental condition. As a result, Saccharomyces cerevisiae becomes vulnerable to viral and bacterial attacks. Therefore, the proposed technique will serve as a quick and accurate process to diagnose diseases at early stage in a cell for effective treatment. PMID- 28025572 TI - Influence of miR-155 on Cell Apoptosis in Rats with Ischemic Stroke: Role of the Ras Homolog Enriched in Brain (Rheb)/mTOR Pathway. AB - BACKGROUND We designed and carried out this study to examine the role of miR-155 and the Rheb/mTOR pathway in ischemic stroke. We also investigated how these two elements interact with each other and contribute to injuries resulting from ischemic stroke. MATERIAL AND METHODS We used both a middle cerebral artery occlusion rat model in vivo and an oxygen-glucose deprivation cell model in vitro to simulate the onset of ischemic stroke. miR-155 mimics, miR-155 inhibitors, and Rheb siRNA were transfected to alter the expression of miR-155 and Rheb. Infarct sizes were measured using magnetic resonance imaging (MRI) and triphenyltetrazolium chloride (TTC) staining; cell apoptosis rates were calculated using Annexin V-FITC/PI staining and flow cytometry. Levels of miR 155, Rheb, mTOR, and S6K were examined by RT-PCR, immunofluorescence, and western blot. We performed a luciferase activity assay so that the association between miR-155 and Rheb could be fully assessed. RESULTS We demonstrated that miR-155 bound the 3'-UTR of Rheb and suppressed Rheb expression. As suggested by animal models, significant cerebral infarct volumes and cell apoptosis were induced by increased expression of miR-155 and decreased expression of Rheb, mTOR, and p-S6K (P<0.05). miR-155 inhibitors exhibited protective effects on ischemic stroke, including down-regulation of infarction size in cerebral tissues in vivo and reduced apoptosis of BV2 cells in vitro with increased expression of Rheb, mTOR and p-S6K (P<0.05). These protective effects could be substantially antagonized by the transfection of Rheb siRNA (P<0.05). CONCLUSIONS Inhibition of miR-155 may play protective roles in ischemic stroke by phosphorylating S6K through the Rheb/mTOR pathway. PMID- 28025573 TI - Diagnosis and Treatment of Pythium Insidiosum Corneal Ulcer in a Chinese Child: A Case Report and Literature Review. AB - BACKGROUND Pythium insidiosum keratitis is a rare but sight-threatening disease with a high morbidity rate. It can be misdiagnosed as fungal keratitis in clinic settings. We report a case of severe Pythium insidiosum keratitis in a Chinese child, treated with combined approaches. CASE REPORT A 7-year-old boy from Hainan province in the south of China developed a suppurative corneal ulcer after being in a forest. A mass of hyphae was detected by confocal imaging in vivo, fungal smear test, and histochemical examination. Treatment with Natamycin, fluconazole, and Voriconazole for 1 month was unsuccessful, and a penetrating keratoplasty with anterior vitrectomy was performed. The infection reappeared 1 day after surgery, immediately after which anterior chamber irrigation with 0.02% Fluconazole and amphotericin B solution was performed. Finally, the globe was saved and there was no further recurrent infection. A cultured mycelial organism, which was hard to identify by biomorphology, was confirmed by PCR to be Pythium insidiosum. The zoospores were observed in water environments. The imaging characteristics of P. insidiosum in confocal microscopy are described herein. CONCLUSIONS This is the first case of Pythium insidiosum keratitis reported in China. It can be misdiagnosed as fungal keratitis in the clinic. Improving the awareness of clinicians, promoting early diagnosis, and a multidisciplinary approach, especially early surgery, improve the prognosis. PMID- 28025574 TI - Intervention-related increases in preoperative physical activity are maintained 6 months after Bariatric surgery: results from the bari-active trial. AB - Higher preoperative physical activity (PA) strongly predicts higher post operative PA in bariatric surgery (BS) patients, providing rationale for preoperative PA interventions (PAIs). However, whether PAI-related increases can be maintained post-operatively has not been examined. This study compared PA changes across pre- (baseline, post-intervention) and post-operative (6-month follow up) periods in participants randomized to 6 weeks of preoperative PAI or standard care control (SC). Of 75 participants initially randomized, 36 (PAI n=22; SC n=14) underwent BS. Changes in daily bout-related (?10-min bouts) moderate-to-vigorous PA (MVPA) and steps were assessed via the SenseWear Armband monitor. PAI received weekly counseling to increase walking exercise. Retention (86%) at post-operative follow up was similar between groups. Intent-to-treat analyses showed that PAI vs SC had greater increases across time (baseline, post intervention, follow up) in bout-related MVPA minutes/day (4.3+/-5.1, 26.3+/ 21.3, 28.7+/-26.3 vs 10.4+/-22.9, 11.4+/-16.0, 18.5+/-28.2; P=0.013) and steps/day (5163+/-2901, 7950+/-3286, 7870+/-3936 vs 5163+/-2901, 5601+/-3368, 5087+/-2603; P<0.001). PAI differed from SC on bout-related MVPA at post intervention (P=0.016; d=0.91), but not follow up (P=0.15; d=0.41), and steps at post-intervention (P=0.031; d=0.78) and follow up (P=0.024; d=0.84). PAI participants maintained preoperative PA increases post-operatively. Findings support preoperative PAIs and research to test whether PA changes can be sustained and influence surgical outcomes beyond the initial post-operative period. PMID- 28025575 TI - Patterned feeding induces neuroendocrine, behavioral and genetic changes that promote palatable food intake. AB - BACKGROUND: Selection of a healthy diet is the cornerstone for treating obesity and metabolic disease. Unfortunately, the majority of diets fail leading to weight regain and in some cases, pathological feeding behavior. We hypothesize that alternating bouts of caloric overconsumption and caloric restriction, behavioral manifestations of dieting induce neuroendocrine, behavioral and genetic changes that promote future bouts of palatable food intake. METHODS: To test this hypothesis, we subjected male Long-Evans rats to a high-fat diet (HFD) feeding paradigm that induced a pattern of caloric overconsumption and caloric restriction. Under these conditions we measured operant responding for sucrose, pre-meal ghrelin secretion, the effects of peripheral ghrelin blockade on patterned feeding, HFD intake in an aversive environment and mRNA expression of the ghrelin receptor, orexin, orexin-1 and 2 receptors, and FTO in the medial prefrontal cortex, lateral hypothalamus and ventral tegmental area. RESULTS: Rats subjected to this feeding regimen displayed increased ghrelin levels prior to HFD exposure and blockade of this response attenuated patterned feeding behavior. In addition, patterned feeding promoted enhanced motivation for sucrose, diminished extinction of this response and increased HFD intake in an aversive environment. The neuroendocrine and behavioral changes correlated with increased hypothalamic expression of the ghrelin receptor and FTO. CONCLUSION: Collectively, these data indicate that patterns of feeding that include caloric overconsumption and caloric restriction induce neuroendocrine and neurobiological changes that signify an enhanced drive for palatable food. PMID- 28025576 TI - Determination of the half-life of circulating leptin in the mouse. AB - BACKGROUND: The adipokine hormone, leptin, is a major component of body weight homeostasis. Numerous studies have been performed administering recombinant mouse leptin as an experimental reagent; however, the half-life of circulating leptin following exogenous administration of recombinant mouse leptin has not been carefully evaluated. METHODS: Exogenous leptin was administered (3 mg leptin per kg body weight) to 10-week-old fasted non-obese male mice and plasma was serially collected at seven time points; plasma leptin concentration was measured by enzyme-linked immunosorbent assay at each time point to estimate the circulating half-life of mouse leptin. RESULTS: Under the physiological circumstances tested, the half-life of mouse leptin was 40.2 (+/-2.2) min. Circulating leptin concentrations up to 1 h following exogenous leptin administration were 170-fold higher than endogenous levels at fasting. CONCLUSIONS: The half-life of mouse leptin was determined to be 40.2 min. These results should be useful in planning and interpreting experiments employing exogenous leptin. The unphysiological elevations in circulating leptin resulting from widely used dosing regimens for exogenous leptin are likely to confound inferences regarding some aspects of the hormone's clinical biology. PMID- 28025577 TI - Impact of perinatal exposure to high-fat diet and stress on responses to nutritional challenges, food-motivated behaviour and mesolimbic dopamine function. AB - BACKGROUND/OBJECTIVES: Energy-dense food exposure and stress during development have been suggested to contribute to obesity and metabolic disorders later in life. Although these factors are frequently associated, the effects of their combination have not yet been investigated. In this study, using an animal model, we examined the long-term impact of maternal high-fat diet (HFD) and early-life stress (ELS) on energy homoeostasis control and food motivation. METHODS: Body weight growth under HFD, adipose tissue, body weight control in response to fasting and refeeding, food-motivated behaviour and mesolimbic dopamine function were examined in adult male offspring exposed to maternal HFD (during gestation and lactation) and/or ELS (maternal separation 3 h per day from postnatal day 2 to 14). RESULTS: Maternal HFD or ELS alone had no significant effect on offspring body weight; however, the combination of these factors exacerbated body weight gain when animals were exposed to HFD after weaning. There are no other significant combinatory effects of these perinatal events. In contrast, independently of the maternal diet, ELS disrupted body weight control during a fasting-refeeding procedure, increased adipose tissue mass and altered lipid metabolism. Finally, maternal HFD and ELS both resulted in exacerbated food motivated behaviour and blunted dopamine release in the nucleus accumbens during palatable food consumption. CONCLUSIONS: We report a synergistic effect of perinatal HFD exposure and stress on the susceptibility to gain weight under HFD. However, ELS has a stronger impact than maternal HFD exposure on energy homoeostasis and food motivation in adult offspring. Altogether, our results suggest a programming effect of stress and nutrition supporting the hypothesis of the developmental origin of health and disease. PMID- 28025578 TI - BMI loci and longitudinal BMI from adolescence to young adulthood in an ethnically diverse cohort. AB - OBJECTIVE: The association of obesity susceptibility variants with change in body mass index (BMI) across the life course is not well understood. SUBJECTS: In ancestry-stratified models of 5962 European American (EA), 2080 African American (AA) and 1582 Hispanic American (HA) individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined associations between 34 obesity single-nucleotide polymorphisms (SNPs) with per year change in BMI, measured by the slope from a growth-curve analysis of two or more BMI measurements between adolescence and young adulthood. For SNPs nominally associated with BMI change (P<0.05), we interrogated age differences within data collection Wave and time differences between age categories that overlapped between Waves. RESULTS: We found SNPs in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 were significantly associated (P<0.0015~0.05/34) with BMI change in EA and the ancestry-combined meta-analysis. rs9939609 in FTO met genome-wide significance at P<5e-08 in the EA and ancestry-combined analysis, respectively [Beta(se)=0.025(0.004);Beta(se)=0.021(0.003)]. No SNPs were significant after Bonferroni correction in AA or HA, although five SNPs in AA and four SNPs in HA were nominally significant (P<0.05). In EA and the ancestry-combined meta analysis, rs3817334 near MTCH2 showed larger effects in younger respondents, whereas rs987237 near TFAP2B, showed larger effects in older respondents across all Waves. Differences in effect estimates across time for MTCH2 and TFAP2B are suggestive of either era or cohort effects. CONCLUSION: The observed association between variants in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 with change in BMI from adolescence to young adulthood suggest that the genetic effect of BMI loci varies over time in a complex manner, highlighting the importance of investigating loci influencing obesity risk across the life course. PMID- 28025579 TI - Associations of childhood and adult obesity with left ventricular structure and function. AB - BACKGROUND: Overweight and obesity are associated with left ventricular (LV) dysfunction. We sought whether echocardiographic evidence of abnormal adult cardiac structure and function was related to childhood or adult adiposity. METHODS: This study included 159 healthy individuals aged 7-15 years and followed until age 36-45 years. Anthropometric measurements were performed both at baseline and follow-up. Cardiac structure (indexed left atrial volume (LAVi), left ventricular mass (LVMi)) and LV function (global longitudinal strain (GLS), mitral e') were assessed using standard echocardiography at follow-up. Conventional cutoffs were used to define abnormal LAVi, LVMi, GLS and mitral annular e'. RESULTS: Childhood body mass index (BMI) was correlated with LVMi (r=0.25, P=0.002), and child waist circumference was correlated with LVMi (r=0.18, P=0.03) and LAVi (r=0.20, P=0.01), but neither were correlated with GLS. One s.d. (by age and sex) increase in childhood BMI was associated with LV hypertrophy (relative risk: 2.04 (95% confidence interval (CI): 1.09, 3.78)) and LA enlargement (relative risk: 1.81 (95% CI: 1.02, 3.21)) independent of adult BMI, but the association was not observed with impaired GLS or mitral e'. Cardiac functional measures were more impaired in those who had normal BMI as child, but had high BMI in adulthood (P<0.03), and not different in those who were overweight or obese as a child and remained so in adulthood (P>0.33). CONCLUSIONS: Childhood adiposity is independently associated with structural cardiac disturbances (LVMi and LAVi). However, functional alterations (GLS and mitral e') were more frequently associated with adult overweight or obesity, independent of childhood adiposity. PMID- 28025580 TI - PKM2 and other key regulators of Warburg effect positively correlate with CD147 (EMMPRIN) gene expression and predict survival in multiple myeloma. PMID- 28025581 TI - PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias. AB - It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network. PMID- 28025582 TI - Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. AB - The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ?CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk. PMID- 28025583 TI - A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. AB - B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3E (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM. PMID- 28025585 TI - Biparental care is predominant and beneficial to parents in the burying beetle Nicrophorus orbicollis (Coleoptera: Silphidae). AB - Parenting strategies can be flexible within a species, and may have varying fitness effects. Understanding this flexibility and its fitness consequences is important for understanding why parenting strategies evolve. Here, we investigate the fitness consequences of flexible parenting in the burying beetle Nicrophorus orbicollis, a species known for its advanced provisioning behaviour of regurgitated vertebrate carrion to offspring by both sexes. We show that even when a parent is freely allowed to abandon the carcass at any point in time, biparental post-hatching care is the most common pattern of care adopted in N. orbicollis. Furthermore, two parents together raised more offspring than single parents of either sex, showing that the presence of the male can directly influences parental fitness even in the absence of competitors. This contrasts with studies in other species of burying beetle, where biparental families do not differ in offspring number. This may explain why biparental care is more common in N. orbicollis than in other burying beetles. We suggest how fitness benefits of two parents may play a role in the evolution and maintenance of flexible biparental care in N. orbicollis. PMID- 28025584 TI - Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma. AB - Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10-5 with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 * 10-11; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 * 10-8). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated. PMID- 28025586 TI - Mapping paddy rice planting area in northeastern Asia with Landsat 8 images, phenology-based algorithm and Google Earth Engine. AB - Area and spatial distribution information of paddy rice are important for understanding of food security, water use, greenhouse gas emission, and disease transmission. Due to climatic warming and increasing food demand, paddy rice has been expanding rapidly in high latitude areas in the last decade, particularly in northeastern (NE) Asia. Current knowledge about paddy rice fields in these cold regions is limited. The phenology- and pixel-based paddy rice mapping (PPPM) algorithm, which identifies the flooding signals in the rice transplanting phase, has been effectively applied in tropical areas, but has not been tested at large scale of cold regions yet. Despite the effects from more snow/ice, paddy rice mapping in high latitude areas is assumed to be more encouraging due to less clouds, lower cropping intensity, and more observations from Landsat sidelaps. Moreover, the enhanced temporal and geographic coverage from Landsat 8 provides an opportunity to acquire phenology information and map paddy rice. This study evaluated the potential of Landsat 8 images on annual paddy rice mapping in NE Asia which was dominated by single cropping system, including Japan, North Korea, South Korea, and NE China. The cloud computing approach was used to process all the available Landsat 8 imagery in 2014 (143 path/rows, ~3290 scenes) with the Google Earth Engine (GEE) platform. The results indicated that the Landsat 8, GEE, and improved PPPM algorithm can effectively support the yearly mapping of paddy rice in NE Asia. The resultant paddy rice map has a high accuracy with the producer (user) accuracy of 73% (92%), based on the validation using very high resolution images and intensive field photos. Geographic characteristics of paddy rice distribution were analyzed from aspects of country, elevation, latitude, and climate. The resultant 30-m paddy rice map is expected to provide unprecedented details about the area, spatial distribution, and landscape pattern of paddy rice fields in NE Asia, which will contribute to food security assessment, water resource management, estimation of greenhouse gas emissions, and disease control. PMID- 28025587 TI - Panel Conditioning in the General Social Survey. AB - Does participation in one wave of a survey have an effect on respondents' answers to questions in subsequent waves? In this article, we investigate the presence and magnitude of "panel conditioning" effects in one of the most frequently used data sets in the social sciences: the General Social Survey (GSS). Using longitudinal records from the 2006, 2008, and 2010 surveys, we find evidence that at least some GSS items suffer from this form of bias. To rule out the possibility of contamination due to selective attrition and/or unobserved heterogeneity, we strategically exploit a series of between-person comparisons across time-in-survey groups. This methodology, which can be implemented whenever researchers have access to at least three waves of rotating panel data, is described in some detail so as to facilitate future applications in data sets with similar design elements. PMID- 28025588 TI - Exporting an Inherently Harmful Product: The Marketing of Virginia Slims Cigarettes in the United States, Japan, and Korea. AB - Ethical issues surrounding the marketing and trade of controversial products such as tobacco require a better understanding. Virginia Slims, an exclusively women's cigarette brand first launched in 1968 in the USA, was introduced during the mid 1980s to major Asian markets, such as Japan and Korea, dominated by male smokers. By reviewing internal corporate documents, made public from litigation, we examine the marketing strategies used by Philip Morris as they entered new markets such as Japan and Korea and consider the extent that the company attempted to appeal to women in markets where comparatively few women were smokers. The case study of Virginia Slims reveals that the classification of "vulnerable" consumers is variable depending on culture, tobacco firms display responsive efforts and strategies when operating within a "mature" market, and cultural values played a role in informing Philip Morris' strategic decision to embrace an adaptive marketing approach, particularly when entering the Korean market. Finally, moral questions are raised with tobacco being identified as a priority product for export and international trade agreements being used by corporations, governments, or trade partners in efforts to undermine domestic public health policies. PMID- 28025589 TI - Bilingualism and Phonological Awareness: Re-examining Theories of Cross-Language Transfer and Structural Sensitivity. AB - The purpose of this study was to examine the relationship between bilingualism and phonological awareness by re-evaluating structural sensitivity theory and expanding cross-language transfer theory. The study was conducted with three groups of 1st and 2nd graders matched in age, SES and non-verbal IQ: a) monolingual English-speaking children from a general education program, b) native Japanese-speaking children from a Japanese-English two-way immersion bilingual program and c) native English-speaking children from the same bilingual program. An odd-man-out task that took into account the phonological and orthographical contrasts between English and Japanese was developed to assess onset awareness. The results showed that the bilingual children outperformed their monolingual peers in processing onsets that are shared between the two languages, which provided empirical support for the first hypothesis derived from structural sensitivity theory and highlighted the importance of contextual variability in bilingual metalinguistic processing. The second hypothesis derived from structural sensitivity theory, which predicated that bilingual advantage would be more evident in processing novel stimuli, was not confirmed in the present study. The absence of the predicted group difference may be attributed to the disparity in the extent of novelty of the stimuli and the difference in the comparability of participants' degrees of bilingualism between the present study and previous research. Finally, expanding existing research, results from this study showed that cross-language transfer can occur at a phonetic featural level. Future research and theoretical implications were discussed. PMID- 28025591 TI - Stepping Toward Making Less More for Concerning Anxiety in Children and Adolescents. PMID- 28025590 TI - Nicotinic Acetylcholine Receptors as Targets for Tobacco Cessation Therapeutics: Cutting-Edge Methodologies to Understand Receptor Assembly and Trafficking. AB - Tobacco dependence is a chronic relapsing disorder and nicotine, the primary alkaloid in tobacco, acts at nicotinic receptors to stimulate dopamine release in brain, which is responsible for the reinforcing properties of nicotine, leading to addiction. Although the majority of tobacco users express the desire to quit, only a small percentage of those attempting to quit are successful using the currently available pharmacotherapies. Nicotine upregulates the number of specific nicotinic receptors on the neuronal cell surface. An increase in receptor trafficking or preferential stoichiometric assembly of receptor subunits involves changes in assembly, endoplasmic reticulum export, vesicle transport, decreased degradation, desensitization, enhanced maturation of functional pentamers, and pharmacological chaperoning. Understanding these changes on a mechanistic level is important to the development of nicotinic receptors as drug targets. For this reason, cutting-edge methodologies are being developed and employed to pinpoint distinct changes in localization, assembly, export, vesicle trafficking, and stoichiometry in order to further understand the physiology of these receptors and to evaluate the action of novel therapeutics for smoking cessation. PMID- 28025592 TI - Mortality Related Risk Factors in High-Risk Pulmonary Embolism in the ICU. AB - Introduction. We sought to identify possible risk factors associated with mortality in patients with high-risk pulmonary embolism (PE) after intensive care unit (ICU) admission. Patients and Methods. PE patients, diagnosed with computer tomography pulmonary angiography, were included from two ICUs and were categorized into groups: group 1 high-risk patients and group 2 intermediate/low risk patients. Results. Fifty-six patients were included. Of them, 41 (73.2%) were group 1 and 15 (26.7%) were group 2. When compared to group 2, need for vasopressor therapy (0 vs 68.3%; p < 0.001) and need for invasive mechanical ventilation (6.7 vs 36.6%; p = 0.043) were more frequent in group 1. The treatment of choice for group 1 was thrombolytic therapy in 29 (70.7%) and anticoagulation in 12 (29.3%) patients. ICU mortality for group 1 was 31.7% (n = 13). In multivariate logistic regression analysis, APACHE II score >18 (OR 42.47 95% CI 1.50-1201.1), invasive mechanical ventilation (OR 30.10 95% CI 1.96 463.31), and thrombolytic therapy (OR 0.03 95% CI 0.01-0.98) were found as independent predictors of mortality. Conclusion. In high-risk PE, admission APACHE II score and need for invasive mechanical ventilation may predict death in ICU. Thrombolytic therapy seems to be beneficial in these patients. PMID- 28025593 TI - Tobacco Use and Its Health Effects among Professional Athletes in Qatar. AB - The objective of the study was to determine the effects of tobacco use on selected markers of health and lung function in professional athletes. A total of 108 male professional athletes participated in the study from ten ball game teams in the same sport league in Qatar (age = 26.4 +/- 5.1 yrs, height = 190.6 +/- 11.9 cm, and weight = 91.5 +/- 16.4 kg). The athletes have been playing professionally for about 6.3 years on average. In addition to demographic and tobacco use status, the following clinical variables were measured: resting blood pressure, heart rate, FVC, FEV1 sec, and PEF. The prevalence of tobacco use among the athletes was 27.7%. The FVC, FVC%, and FEV1% were significantly lower among the smokers compared to the nonsmokers (p = 0.003, 0.044, and 0.001, resp.). There were no significant differences between cigarettes smokers and nonsmokers in BP, HR, FEV1, FEV1/FVC, PEF, and PEF%. Similarly, those who smoked shisha had lower FEV1% values as compared to those who did not smoke shisha (p = 0.001). The decrease of FEV1 and FVC among smokers compared to nonsmokers is similar to what has been reported in the literature about other populations. PMID- 28025594 TI - A Longitudinal Study of Cultural Adaptation among Mexican and Dominican Immigrant Women. AB - The present longitudinal study examined cultural adaptation (i.e., acculturation and enculturation) and its correlates in a sample of 189 Mexican and Dominican immigrant women. Acculturation and enculturation were measured within the domains of language competence, identity and cultural knowledge at two time points over a one-year period. Across groups and domains, cultural adaptation was generally stable over time; only American cultural knowledge showed change, and only for MA women. Several correlates of cultural adaptation were identified. For Mexican women, living in poverty and in immigrant-dense neighborhoods was associated with lower acculturation. For Dominican women, age at immigration was the most robust correlate and was associated with more acculturation and less enculturation, though poverty and neighborhood characteristics emerged as significant for Dominican women too. Findings are consistent with the notion of cultural adaptation as a complex construct that is influenced by cultural context as well as individual immigrant characteristics. PMID- 28025595 TI - Transcript Polymorphism Rates in Soybean Seed Tissue Are Increased in a Single Transformant of Glycine max. AB - Transgenic crops have been utilized for decades to enhance agriculture and more recently have been applied as bioreactors for manufacturing pharmaceuticals. Recently, we investigated the gene expression profiles of several in-house transgenic soybean events, finding one transformant group to be consistently different from our controls. In the present study, we examined polymorphisms and sequence variations in the exomes of the same transgenic soybean events. We found that the previously dissimilar soybean line also exhibited markedly increased levels of polymorphisms within mRNA transcripts from seed tissue, many of which are classified as gene expression modifiers. The results from this work will direct future investigations to examine novel SNPs controlling traits of great interest for breeding and improving transgenic soybean crops. Further, this study marks the first work to investigate SNP rates in transgenic soybean seed tissues and demonstrates that while transgenesis may induce abundant unanticipated changes in gene expression and nucleotide variation, phenotypes and overall health of the plants examined remained unaltered. PMID- 28025596 TI - Corrigendum to "Extraction of HCV-RNA from Plasma Samples: Development towards Semiautomation". AB - [This corrects the article DOI: 10.1155/2015/367801.]. PMID- 28025597 TI - Clinical Profiles of Dengue Infection during an Outbreak in Northern India. AB - Introduction. Dengue fever is an arboviral disease, which is transmitted by mosquito vector and presents as varied clinical spectrum of dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS), and expanded dengue syndrome (EDS) with atypical presentations, thus posing a diagnostic dilemma. Unless we are aware of these presentations, diagnosis as well as early initiation of treatment becomes difficult. We studied the various clinical presentations of dengue infection during an outbreak of disease in 2015. Materials and Methods. A total of 115 confirmed cases of dengue infection from Department of Medicine of Deen Dayal Upadhyay Hospital, New Delhi, were enrolled in this observational study. Results. The common signs and symptoms of dengue infection were fever, headache, body ache, backache, retro-orbital pain, bleeding manifestations, and rash in 100%, 87%, 86%, 58%, 41%, 21%, and 21%, respectively. Nonspecific or warning signs and symptoms included vomiting, weakness, abdominal pain, breathlessness, vertigo, sweating, and syncope. Other possible signs and symptoms of coinfections, comorbidities, or complications included diarrhea, sore throat, and neurological manifestations. There were seven patients with coinfections and four with comorbidities. The final diagnosis of these patients was DF (73%), DHF (16.5%), DSS (1.7%), and EDS (4.3%). Among EDS patients, the atypical presentations included encephalopathy, lateral rectus nerve palsy, acalculous cholecystitis, and myocarditis. Four patients required ICU care and there was no death in this study. Conclusion. Knowledge of atypical presentations is a must for early diagnosis and timely intervention to prevent life-threatening complications. PMID- 28025598 TI - Estimating Access to Drinking Water Supply, Sanitation, and Hygiene Facilities in Wolaita Sodo Town, Southern Ethiopia, in Reference to National Coverage. AB - Introduction. The coverage of sanitation and access to safe drinking water in Ethiopia especially in Wolaita Sodo town are not well studied. Therefore, the main objective of this study was estimating access to drinking water supply, sanitation, and hygiene facilities in Wolaita Sodo town, southern Ethiopia, in reference to national coverage. Methods. A community based cross-sectional study design method was employed in the study in 588 households of Wolaita Sodo town inhabitants. Face-to-face interview to household owners, in-depth interview to key informants, reviewing secondary data, and observational check lists were used to collect data. Districts were selected using simple random sampling techniques, while systematic random sampling technique was applied to select households. Data was analyzed using Epi Info version 3.5.4 and SPSS version 16 statistical software. Bivariate and multivariable logistic regression analysis were carried out. Results. The community has access to improved water supply which was estimated to be 67.9%. The main water sources of the town were tap water within the yard, which was estimated to be 44.7%, and tap water in the community was 40.0% followed by private protected well which was 14.5%. Ninety-one percent of the households had at least one type of latrine in their homes. The most common type of latrine available to households was pit latrine with superstructure which was estimated to be 75.9% followed by a pit without superstructure, 21.3%, and more than half of the respondents had hand washing facilities in their compound. Occupational status, educational status, and training on water, sanitation, and hygiene related topics were significantly associated with use of improved water source, improved sanitation, and hygiene facilities. Conclusion. In order to address the demand of the town, additional water, sanitation, and hygiene programs are required. PMID- 28025599 TI - Disparity Implications of Proposed 2015 Medicare Eligibility Criteria for Medication Therapy Management Services. AB - OBJECTIVES: Previous studies found that racial and ethnic minorities may be less likely than non-Hispanic Whites (Whites) to meet existing Medicare medication therapy management (MTM) eligibility criteria. To address these issues, the Centers for Medicare & Medicaid Services (CMS) proposed alternative Medicare MTM eligibility criteria for 2015. Due to opposition to other Part D reforms proposed simultaneously by various stakeholders, CMS rescinded all proposed reforms. This study was conducted to determine whether non-Hispanic Blacks (Blacks) and Hispanics have lower likelihood of meeting the proposed 2015 Medicare MTM eligibility criteria. METHODS: This retrospective observational analysis used Medical Expenditure Panel Survey data (2010-2011). The final study sample was comprised of 2,721 Whites (weighted to 37,185,896), 917 Blacks (weighted to 4,665,644), and 538 Hispanics (weighted to 3,532,882). Chi-square tests were used to examine racial and ethnic disparities in meeting proposed 2015 MTM eligibility criteria and each component of proposed 2015 MTM eligibility criteria. In multivariate analysis, a logistic regression model was used to control for population socio-demographic and health-related characteristics. KEY FINDINGS: Compared to Whites with a proportion of MTM eligibility of 58.82%, the eligible proportion was 57.09% (P=0.20) for Blacks, and 48.97% (P<0.0001) for Hispanics, respectively. According to multivariate logistic regression, odds ratios of meeting MTM eligibility for Blacks and Hispanics compared to Whites were 0.74 (95% Confidence Internal [CI] = 0.62-0.88) and 0.53 (95% CI=0.43-0.67), respectively. CONCLUSIONS: The proposed 2015 MTM eligibility criteria would not eliminate racial and ethnic disparities in MTM eligibility. Alternative MTM eligibility criteria should be devised. PMID- 28025600 TI - Tobacco Cessation in Economically Disadvantaged Dominican Republic Communities: Who are the Ex-Users? AB - INTRODUCTION: Tobacco use and harm continue to increase in low- and middle income countries (LMICs) globally. Smoking cessation is the most effective means of reducing morbidity and mortality from tobacco use. Increasing the prevalence of ex-users is an indicator of population cessation. AIMS: This study provides the first examination of factors associated with ex-tobacco use status in the Dominican Republic (DR), a LMIC in the Latin America and Caribbean region. METHODS: Baseline surveillance was conducted for 1177 randomly selected households in 7 economically disadvantaged DR communities (total N=2680 adult household members). RESULTS: Ex-user prevalence was 10.6% (1.0%-18.5% across communities), 14.8% were current users (9.1-20.4), and quit ratios were 41.7% (9.7%-52.7%). Among ever-users, females (OR 2.02, 95% CI 1.41, 2.90), older adults (45-64: OR 1.75, 95% CI 1.12, 2.74; 65+: OR 2.09, 95% CI 1.29, 3.39), and those who could read/write (OR 1.64, 95% CI 1.08, 2.50), had health conditions (OR 1.63, 95% CI 1.11, 2.41), and lived with ex-users (OR 1.70, 95% CI 1.12, 2.58) were over 60% to two times as likely to be ex-users. Those from remote communities (OR 0.52, 95% CI 0.36, 0.74), using chewed tobacco (OR 0.14, 95% CI 0.04, 0.48) and living with tobacco users (OR 0.55, 95% CI 0.37, 0.81) were less likely to be ex-users. CONCLUSIONS: Ex-user prevalence and quit ratios were lower than for high income countries. Implementing broad tobacco control measures, combined with clinically targeting vulnerable groups, may increase tobacco cessation to most effectively reduce this public health crisis. PMID- 28025601 TI - Implementation of study results in guidelines and adherence to guidelines in clinical practice. AB - Guidelines were introduced in hospital- and practice-based otorhinolaryngology in the 1990ies, and have been undergoing further development ever since. There are currently 20 guidelines on file at the German Society of Oto-Rhino-Laryngology, Head & Neck Surgery. The society has cooperated in further 34 guidelines. The quality of the guidelines has been continuously improved by concrete specifications put forward by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V., AWMF). Since increasing digitalization has made access to scientific publications quicker and simpler, relevant study results can be incorporated in guidelines more easily today than in the analog world. S2e and S3 guidelines must be based on a formal literature search with subsequent evaluation of the evidence. The consensus procedure for S2k guidelines is also regulated. However, the implementation of guidelines in routine medical practice must still be considered inadequate, and there is still a considerable need for improvement in adherence to these guidelines. PMID- 28025602 TI - Evidence and evidence gaps of medical treatment of non-tumorous diseases of the head and neck. AB - Unfortunately, the treatment of numerous otolaryngological diseases often lacks of evidence base because appropriate studies are missing. Whereas sufficient high quality trials exist for the specific immunotherapy of allergic rhinitis and in a limited measure also for the angiotensin-converting enzyme inhibitor induced angioedema, the evidence for Meniere's disease or for pharmacotherapy of postoperative laryngeal edema is rather poor. This contribution will discuss the trial situation and evidence of the respective diseases. PMID- 28025603 TI - Evidence and evidence gaps of laryngeal cancer surgery. AB - Surgical treatment of laryngeal cancer has been established for decades. In addition to total laryngectomy, which was first performed in 1873, a large number or organ preservation surgical techniques, like open partial laryngectomy, transoral laser microsurgery, and transoral robotic surgery have been developed. Studies on laryngeal cancer surgery are mainly retrospective case series and cohort studies. The evolution of chemoradiation protocols and their analysis in prospective randomized trials have led to an increasing acceptance of non surgical treatment procedures. In addition to an improvement of prognosis, in recent years the preservation of function and maintenance of life quality after primary therapy of laryngeal cancer has increasingly become the focus of therapy planning. Significant late toxicity after chemoradiation has been identified as an important issue. This leads to a reassessment of surgical concepts and initiation of studies on laryngeal cancer surgery which was additionally stimulated by the advent of transoral robotic surgery in the US. Improving the evidence base of laryngeal cancer surgery by successful establishment of surgical trials should be the future goal. PMID- 28025605 TI - Evidence and evidence gaps in the treatment of Eustachian tube dysfunction and otitis media. AB - Evidence-based medicine is an approach to medical treatment intended to optimize patient-oriented decision-making on the basis of empirically proven effectiveness. For this purpose, a classification system has been established to categorize studies - and hence therapy options - in respect of associated evidence according to defined criteria. The Eustachian tube connects the nasopharynx with the middle ear cavity. Its key function is to ensure middle ear ventilation. Compromised ventilation results in inflammatory middle ear disorders. Numerous evidence-based therapy options are available for the treatment of impaired middle ear ventilation and otitis media, the main therapeutic approach being antibiotic treatment. More recent procedures such as balloon dilation of the Eustachian tube have also shown initial success but must undergo further evaluation with regard to evidence. There is, as yet, no evidence for some of the other long-established procedures. Owing to the multitude of variables, the classification of evidence levels for various treatment approaches calls for highly diversified assessment. Numerous evidence-based studies are therefore necessary in order to evaluate the evidence pertaining to existing and future therapy solutions for impaired middle ear ventilation and otitis media. If this need is addressed, a wealth of implications can be expected for therapeutic approaches in the years to come. PMID- 28025607 TI - Tonsillectomy remains a questionable option for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). AB - Background: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a disease attributed to children with obsessive compulsive disorders (OCD) or tic disorders associated with streptococcal infections. Because otolaryngologists examine a large number of pediatric patients with recurrent streptococcal infections, tonsillectomy (TE) is a common option of therapy. This study was conducted to evaluate the efficacy of TE in patients presenting with verified PANDAS. Material and methods: A PubMed review was performed using search terms "tonsillectomy" and "PANDAS", "OCD", "compulsive" "pediatric autoimmune", "chorea" and "tic" limited by publication date of January 1, 1995, to July 31, 2015. Reviews without patients were not included in the review. Results: Nine papers matched our search criteria, including 6 case reports with 8 patients and 3 case series. Most case reports were in favor of TE, but this was by far not supported by the findings in the case series. The follow-up ranged from 2 to 36 months in case reports and from 24 to 36 in case series. Conclusion: Establishing the diagnosis of PANDAS is complicated because of underlying comorbidities in the field of neurology psychiatry and the lack of a reliable biomarker. The positive outcome after TE as reported in case studies may be influenced by the postoperative medication and is not supported by the results of large-scale studies. In the light of the considerable postoperative morbidity rate, it appears wise to indicate TE for PANDAS only in supervised clinical studies. PMID- 28025604 TI - Evidence and evidence gaps in tinnitus therapy. AB - A nearly endless number of procedures has been tried and in particular sold for the treatment of tinnitus, unfortunately they have not been evaluated appropriately in an evidence-based way. A causal therapy, omitting the tinnitus still does not exist, actually it cannot exist because of the various mechanisms of its origin. However or perhaps because of that, medical interventions appear and reappear like fashion trends that can never be proven by stable and reliable treatment success. This contribution will discuss and acknowledge all current therapeutic procedures and the existing or non-existing evidence will be assessed. Beside external evidence, the term of evidence also encompasses the internal evidence, i.e. the experience of the treating physician and the patient's needs shall be included. While there is no evidence for nearly all direct procedures that intend modulating or stimulating either the cochlea or specific cervical regions such as the auditory cortex, there are therapeutic procedures that are acknowledged in clinical practice and have achieved at least a certain degree of evidence and generate measurable effect sizes. Those are in particular habituation therapy and psychotherapeutic measures, especially if they are combined with concrete measures for improved audio perception (hearing aids, CI, hearing therapies). PMID- 28025606 TI - Evidence and evidence gaps in therapies of nasal obstruction and rhinosinusitis. AB - Therapeutic decisions in otorhinolaryngology are based on clinical experience, surgical skills, and scientific evidence. Recently, evidence-based therapies have gained increased attention and importance due to their potential to improve the individual patient's treatment and their potential at the same time to reduce treatment costs. In clinical practice, it is almost impossible to stay ahead of the increasing mass of literature and on the other hand critically assess the presented data. A solid scientific and statistical knowledge as well as a significant amount of spare time are required to detect systematic bias and other errors in study designs, also with respect to assessing whether or not a study should be part of an individual therapeutic decision. Meta-analyses, reviews, and clinical guidelines are, therefore, of increasing importance for evidence-based therapy in clinical practice. This review is an update of the availability of external evidence for the treatment of nasal obstruction and rhinosinusitis. It becomes evident that both groups of diseases differ significantly in the availability of external evidence. Furthermore, it becomes obvious that surgical treatment options are normally based on evidence of significantly lower quality than medical treatment options. PMID- 28025608 TI - Specified data for tonsil surgery in Germany. AB - Background: Tonsillectomy rates vary considerably among different states, regions, and times. This study was conducted to identify the prevalence of "chronic" tonsillitis, peritonsillar abscess, hypertrophy of the tonsils with and without adenoids in absolute and relative numbers in an 80 million people nation. Moreover, the number and rates of different surgical procedures to resolve either "chronic" tonsillitis, peritonsillar abscess, or upper airway obstruction due to (adeno)tonsillar hypertrophy over several years was evaluated in this study (tonsillectomy, adenotonsillectomy, tonsillotomy, abscess tonsillectomy, transoral incision and drainage). Finally, the post-tonsillectomy hemorrhage rate was calculated and analyzed in relation to age and gender. Material and methods: Calculations were based on data as published by the Federal Institute of Statistics or on request, if needed. The latest data were provided for 2013. Results: The total number of the aforementioned diseases (stratified by ICD-10) decreased from 142,574 (in 2000) to 87,624 in 2013 (38.5%). Tonsillectomy, with or without adenoidectomy, was performed in a total of 833,896 patients between 2006 and 2013 in Germany. The yearly number decreased continually from 120,993 in 2006 to 84,332 procedures in 2013 (30.3%). The most significant decrease was registered in patients younger than 20 years of age for this time period: 70.92 per 10,000 in 2010 to 58.68 per 10,000 in 2013. If all age groups were included, the rate decreased from 13.34 per 10,000 to 10.90 per 10,000. In contrast, an increasing number of tonsillotomies was observed between 2007 (4,659 procedures) and 2013 (11,493). The cumulated number of procedures was 59,049. A constant number of 15,000 cases with peritonsillar abscess were diagnosed per year in Germany (19 patients per 100,000). The prevalence increased significantly at an age of 15 years and there was a preponderance of female patients below that age. Compared to the transoral incision and drainage, a 2.8-fold greater number of abscess tonsillectomies were performed annually. Post-tonsillectomy hemorrhage was experienced in 5.98% of all patients after 245,721 procedures in 2010 and 2013 (all indications, except tonsillotomy). Bleeding complications had occurred less frequently in female patients (5.06% vs. 7.02%). Finally, a considerable increase of post-tonsillectomy hemorrhage in patients older than 10 years of age was registered in male patients only. Conclusion: Chronic tonsillitis was less frequently diagnosed and surgically treated in terms of tonsillectomy (with or without adenoidectomy), particularly in female patients. In contrast, the number of tonsillotomies increased continually, particularly in male patients. Peritonsillar abscess was diagnosed and surgically treated in a constant number of patients in the yearly comparison. Most of these patients were scheduled for abscess tonsillectomy, and only a 2.8-fold smaller number for transoral incision and drainage. Independent from the indication for surgery, post-tonsillectomy hemorrhage was clearly associated with male gender and age (>10 years). The study reveals a dramatic change mandating further surveillance in insurance companies and authorities in the national health system of an 80 million people nation. (Tab. 1). PMID- 28025611 TI - Evidence and evidence gaps - an introduction. AB - Background: Medical treatment requires the implementation of existing evidence in the decision making process in order to be able to find the best possible diagnostic, therapeutic or prognostic measure for the individual patient based on the physician's own expertise. Clinical trials form the evidence base and ideally, their results are assembled, analyzed, summarized, and made available in systematic review articles. Beside planning, conducting, and evaluating clinical trials in conformity with GCP (good clinical practice), it is essential that all results of conducted studies are publicly available in order to avoid publication bias. This includes also the public registration of planned and cancelled trials. History: During the last 25 years, evidence-based medicine became increasingly important in medical care and research. It is closely associated with the names of Archibald Cochrane and David Sackett. About 15 years ago, the Deutsche Cochrane Zentrum (Cochrane Germany) and the Deutsche Netzwerk Evidenzbasierte Medizin e.V. (German Network for Evidence-based Medicine, DNEbM) were founded in Germany. In the International Cochrane Collaboration, clinicians and methodologists come together on an interdisciplinary level to further develop methods of evidence-based medicine and to discuss the topics of evidence generation and processing as well as knowledge transfer. Problem: Evidence is particularly important for physicians in the process of decision making, however, at the same time it is the base of a scientific proof of benefit for the patient and finally for the payers in health care. The closure of evidence gaps requires enormously high staff and financial resources, significant organizational efforts, and it is only successful when clinical and methodical expertise as well as specific knowledge in the field of clinical research are included. On the other hand, the knowledge has to be transferred into practice. For this purpose, practice guidelines, meetings, databases, information portals with processed evidence as well as specific journals and finally teaching are appropriate vehicles. One problem is the multitude of information so that knowledge gaps may affect the clinical routine despite actually existing evidence. Generally, it still takes several years until new knowledge is implemented in daily routine. Tasks: The German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (Deutsche Gesellschaft fur Hals-, Nasen- und Ohren-Heilkunde, Kopf- und Hals Chirurgie e.V., DGHNOKHC) and the Professional Association of Otolaryngologists (Deutscher Berufsverband der HNO-Arzte e.V., BVHNO) have fundamental interest in supporting their members in generating, processing, and providing evidence as well as accompanying knowledge transfer. It encompasses the fields of diagnostics, therapy, and prognosis in the same way as prevention and applies to medicinal products as well as to medical devices or surgical procedures. The base for this is the regular assessment of evidence gaps, also in the area of established procedures, that has to be followed by a prioritization of research questions and the subsequent initiation of clinical research. In addition, large trials verifying therapies and diagnostics, for example in the context of daily conditions after approval, can only be conducted combining all resources in the ENT community. Method, results, and outlook: Together, the executive committees of the DGHNOKHC and the BVHNO founded the German Study Center of Oto-Rhino Laryngology, Head and Neck Surgery (Deutsches Studienzentrum fur Hals-, Nasen- und Ohren-Heilkunde, Kopf- und Hals-Chirurgie, DSZ-HNO). First projects have been initiated, among those a clinical trial on the therapy of sudden hearing loss supported by the BMBF and a survey on evidence gaps in oto-rhino-laryngology. It seems to be both reasonable and feasible to make available methodological expertise via such an infrastructure of a study center for physicians in hospitals and private practices in order to support clinical research and to implement the principles of evidence-based medicine in daily routine. PMID- 28025610 TI - Evidence gaps in ENT surgery - a qualitative survey. AB - Introduction: As in other disciplines, the burgeoning knowledge in ENT medicine long ago surpassed our ability to adequately absorb it and maintain a proper overview. This can give rise to actual or assumed evidence gaps that can impede the progress of the discipline and evidence-based treatment of patients. Clinics and medical practices also hold to traditional doctrines that shape day-to-day medicine, without these schools being challenged based on evidence. Methods: Between February and June 2015, 160 ENT clinics, including 34 university hospitals, and 2,670 ENT practices took part in a two-arm online survey on existing or perceived evidentiary gaps in ENT medicine using a previously developed questionnaire. The survey used for half of the participants was open in form; the other half were given a closed survey with systematics of the field for orientation. The survey was augmented with additional data such as the number of publications and focus areas in the clinics and the age and type of practice of the established physicians. Results: The return rate from the clinics was 39.7%; the return rate of the closed surveys was 29.3%. Of the physicians in medical practice, 14.6% responded to the closed and 18.6% to the open survey. There were no major differences between the two forms of survey. Otological and oncological issues comprised approximately 30% of the list of answers from clinics. Corresponding questions were formulated regarding the current diagnostic and therapeutic problems, such as with stage-related tumor treatment or implantable hearing aids. Diagnostic procedures, e.g., special new procedures in audiology and vestibulogy, dominated the surveys from the practices. However clinics and practices alike cited marginal areas of the discipline that are of daily relevance. Discussion: The cited evidence gaps then needed to be verified or refuted and clarified based on research of the literature as to whether the existing evidence actually reached healthcare providers in the form of guidelines, publications, conferences, or continuing training for application in daily practice. Other steps would include prioritizing future research, evidence mapping, deciding on further systematic reviews, and targeted studies in conjunction with procuring third-party funding and in cooperation with patient associations. The knowledge thus gained should ultimately be transferred in improved form for application in daily clinical practice. Ten questions of key importance each needed to be formulated for the hospitals and practices. PMID- 28025612 TI - ERF, a new candidate gene in craniosynostosis may regulate osteogenesis. PMID- 28025613 TI - Factors that predict nonunion of tibial shaft fractures. PMID- 28025614 TI - Nonunion in surgically repaired tibial fractures predictable at 3 months. PMID- 28025615 TI - ErbB3 emerges as an exciting therapeutic target in osteosarcoma. PMID- 28025616 TI - Combination teriparatide and denosumab more effective than either therapy alone. PMID- 28025617 TI - Denosumab, cancer treatment and risk of osteonecrosis of the jaw. PMID- 28025618 TI - AB3-Loaded and Tumor-Targeted Unimolecular Micelles for Medullary Thyroid Cancer Treatment. AB - Medullary thyroid cancer (MTC) is often resistant to standard therapies, emphasizing the need for the development of other treatments. A new histone deacetylase inhibitor, AB3, can effectively inhibit MTC cell proliferation in vitro. However, its poor aqueous solubility and stability, fast clearance, and lack of tumor targeting ability limit its in vivo application. Therefore, multifunctional unimolecular micelles were developed for targeted delivery of AB3 for MTC therapy. The unimolecular micelles exhibited a spherical core-shell structure, uniform size distribution, and excellent stability. AB3 was encapsulated into the hydrophobic core of the unimolecular micelles, thus significantly enhancing its aqueous solubility and stability. KE108, a somatostatin analog possessing high affinity to all five subtypes of SSTR, was used as an MTC-targeting ligand. In vitro cellular uptake analyses demonstrated that the KE108 exhibited superior targeting ability in MTC cells compared to octreotide, the first clinically used somatostatin analog. Moreover, the AB3 loaded and KE108-conjugated unimolecular micelles exhibited the best efficacy in suppressing MTC cell growth and tumor marker expression in vitro. Furthermore, AB3-loaded, KE108-conjugated micelles demonstrated the best anticancer efficacy in vivo without any apparent systemic toxicity, thereby offering a promising approach for targeted MTC therapy. PMID- 28025619 TI - Posterior Segment Intraocular Foreign Body: Extraction Surgical Techniques, Timing, and Indications for Vitrectomy. AB - Ocular penetrating injury with Intraocular Foreign Body (IOFB) is a common form of ocular injury. Several techniques to remove IOFB have been reported by different authors. The aim of this publication is to review different timing and surgical techniques related to the extraction of IOFB. Material and Methods. A PubMed search on "Extraction of Intraocular Foreign Body," "Timing for Surgery Intraocular Foreign Body," and "Surgical Technique Intraocular Foreign Body" was made. Results. Potential advantages of immediate and delayed IOFB removal have been reported with different results. Several techniques to remove IOFB have been reported by different authors with good results. Conclusion. The most important factor at the time to perform IOFB extraction is the experience of the surgeon. PMID- 28025609 TI - Indications for tonsillectomy stratified by the level of evidence. AB - Background: One of the most significant clinical trials, demonstrating the efficacy of tonsillectomy (TE) for recurrent throat infection in severely affected children, was published in 1984. This systematic review was undertaken to compile various indications for TE as suggested in the literature after 1984 and to stratify the papers according to the current concept of evidence-based medicine. Material and methods: A systematic Medline research was performed using the key word of "tonsillectomy" in combination with different filters such as "systematic reviews", "meta-analysis", "English", "German", and "from 1984/01/01 to 2015/05/31". Further research was performed in the Cochrane Database of Systematic Reviews, National Guideline Clearinghouse, Guidelines International Network and BMJ Clinical Evidence using the same key word. Finally, data from the "Trip Database" were researched for "tonsillectomy" and "indication" and "from: 1984 to: 2015" in combination with either "systematic review" or "meta-analysis" or "metaanalysis". Results: A total of 237 papers were retrieved but only 57 matched our inclusion criteria covering the following topics: peritonsillar abscess (3), guidelines (5), otitis media with effusion (5), psoriasis (3), PFAPA syndrome (6), evidence-based indications (5), renal diseases (7), sleep-related breathing disorders (11), and tonsillitis/pharyngitis (12), respectively. Conclusions: 1) The literature suggests, that TE is not indicated to treat otitis media with effusion. 2) It has been shown, that the PFAPA syndrome is self limiting and responds well to steroid administration, at least in a considerable amount of children. The indication for TE therefore appears to be imbalanced but further research is required to clarify the value of surgery. 3) Abscesstonsillectomy as a routine is not justified and indicated only for cases not responding to other measures of treatment, evident complications, or with a significant history of tonsillitis. In particular, interval-tonsillectomy is not justified as a routine. 4) TE, with or without adenoidectomy, is efficacious to resolve sleep-related breathing disorders resulting from (adeno)tonsillar hypertrophy in children. However, the benefit is reduced by co-morbidities, such as obesity, and further research is required to identify prognostic factors for this subgroup of patients. Further research is indicated to clarify selection criteria not only for this subpopulation that may benefit from less invasive procedures such as tonsillotomy in the long-term. 5) Further trials are also indicated to evaluate the efficacy of TE on the clinical course in children with psoriasis guttata as well as on psoriasis vulgaris in adults, not responding to first-line therapy. 6) Conflicting results were reported concerning the role of TE in the concert to treat Ig-A nephropathy, mandating further clinical research. 7) Most importantly, randomized-controlled clinical trials with an adequate long term follow-up are desirable to clarify the benefit of TE in patients with recurrent episodes of tonsillitis, with or without pharyngitis. Factors like age, spontaneous healing rate and postoperative quality of life have to be included when comparing TE with antibiotic therapy. PMID- 28025620 TI - A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family. AB - Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T 0.05). An increase in osteocalcin was observed 48 h after exercise (P < 0.05), which did not differ between exercise groups. C-terminal telopeptide of type 1 collagen was not affected by exercise. Blood lactate concentration increased during exercise for FG15 (0.6 +/- 0.2 to 3.4 +/- 1.2 mM) and FG60 (0.6 +/- 0.2 to 3.3 +/- 2.0 mM), but not for VIB (0.6 +/- 0.2 to 0.8 +/- 0.4 mM) (P < 0.05). Plasma creatine kinase increased by 55 +/- 63% and 137 +/- 119% 48 h after FG15 and FG60 (P < 0.05), but not after VIB (26 +/- 54%, NS). In contrast to the minor elevation in osteocalcin in response to a single session of vibration exercise, both short and longer durations of small sided football acutely increased plasma P1NP, osteocalcin, and creatine kinase. This may contribute to favorable effects of chronic training on musculoskeletal health. PMID- 28025641 TI - iTRAQ-Based Proteomics Identification of Serum Biomarkers of Two Chronic Hepatitis B Subtypes Diagnosed by Traditional Chinese Medicine. AB - Background. Chronic infection with hepatitis B virus (HBV) is a leading cause of cirrhosis and hepatocellular carcinoma. By traditional Chinese medicine (TCM) pattern classification, damp heat stasis in the middle-jiao (DHSM) and liver Qi stagnation and spleen deficiency (LSSD) are two most common subtypes of CHB. Results. In this study, we employed iTRAQ proteomics technology to identify potential serum protein biomarkers in 30 LSSD-CHB and 30 DHSM-CHB patients. Of the total 842 detected proteins, 273 and 345 were differentially expressed in LSSD-CHB and DHSM-CHB patients compared to healthy controls, respectively. LSSD CHB and DHSM-CHB shared 142 upregulated and 84 downregulated proteins, of which several proteins have been reported to be candidate biomarkers, including immunoglobulin (Ig) related proteins, complement components, apolipoproteins, heat shock proteins, insulin-like growth factor binding protein, and alpha-2 macroglobulin. In addition, we identified that proteins might be potential biomarkers to distinguish LSSD-CHB from DHSM-CHB, such as A0A0A0MS51_HUMAN (gelsolin), PON3_HUMAN, Q96K68_HUMAN, and TRPM8_HUMAN that were differentially expressed exclusively in LSSD-CHB patients and A0A087WT59_HUMAN (transthyretin), ITIH1_HUMAN, TSP1_HUMAN, CO5_HUMAN, and ALBU_HUMAN that were differentially expressed specifically in DHSM-CHB patients. Conclusion. This is the first time to report serum proteins in CHB subtype patients. Our findings provide potential biomarkers can be used for LSSD-CHB and DHSM-CHB. PMID- 28025643 TI - Transferrin Impacts Bacillus thuringiensis Biofilm Levels. AB - The present study examined the impact of transferrin on Bacillus thuringiensis biofilms. Three commercial strains, an environmental strain (33679), the type strain (10792), and an isolate from a diseased insect (700872), were cultured in iron restricted minimal medium. All strains produced biofilm when grown in vinyl plates at 30 degrees C. B. thuringiensis 33679 had a biofilm biomass more than twice the concentration exhibited by the other strains. The addition of transferrin resulted in slightly increased growth yields for 2 of the 3 strains tested, including 33679. In contrast, the addition of 50 MUg/mL of transferrin resulted in an 80% decrease in biofilm levels for strain 33679. When the growth temperature was increased to 37 degrees C, the addition of 50 MUg/mL of transferrin increased culture turbidity for only strain 33679. Biofilm levels were again decreased in strain 33679 at 37 degrees C. Growth of B. thuringiensis cultures in polystyrene resulted in a decrease in overall growth yields at 30 degrees C, with biofilm levels significantly decreased for 33679 in the presence of transferrin. These findings demonstrate that transferrin impacts biofilm formation in select strains of B. thuringiensis. Identification of these differences in biofilm regulation may be beneficial in elucidating potential virulence mechanisms among the differing strains. PMID- 28025644 TI - TNFalpha Affects Ciliary Beat Response to Increased Viscosity in Human Pediatric Airway Epithelium. AB - In airway epithelium, mucociliary clearance (MCC) velocity depends on the ciliary beat frequency (CBF), and it is affected by mucus viscoelastic properties. Local inflammation induces secretion of cytokines (TNFalpha) that can alter mucus viscosity; however airway ciliated cells have an autoregulatory mechanism to prevent the collapse of CBF in response to increase in mucus viscosity, mechanism that is associated with an increment in intracellular Ca+2 level ([Ca2+]i). We studied the effect of TNFalpha on the autoregulatory mechanism that regulates CBF in response to increased viscosity using dextran solutions, in ciliated cells cultured from human pediatric epithelial adenoid tissue. Cultures were treated with TNFalpha, before and after the viscous load was changed. TNFalpha treatment produced a significantly larger decrease in CBF in cultures exposed to dextran. Furthermore, an increment in [Ca2+]i was observed, which was significantly larger after TNFalpha treatment. In conclusion, although TNFalpha has deleterious effects on ciliated cells in response to maintaining CBF after increasing viscous loading, it has a positive effect, since increasing [Ca2+]i may prevent the MCC collapse. These findings suggest that augmented levels of TNFalpha associated with an inflammatory response of the nasopharyngeal epithelium may have dual effects that contribute to maintaining the effectiveness of MCC in the upper airways. PMID- 28025645 TI - Clinical and Laboratory Features of Acute Porphyria: A Study of 36 Subjects in a Chinese Tertiary Referral Center. AB - Porphyria is a group of eight metabolic disorders characterized by defects in heme biosynthesis. The presentation of porphyria is highly variable, and the symptoms are nonspecific, which accounts in part for delays in establishing a diagnosis. In this study, we report the characteristics of 36 Chinese acute porphyria patients. Most of them were female (33/36), and the median age was 25.3 years (range 18-45 years). The most frequent presenting symptom was abdominal pain (32/36). Hyponatremia was the most common electrolyte abnormality (29/36), and the serum sodium concentration was significantly negatively correlated with convulsion (p = 0.00). Genetic testing provided a precise diagnosis of the patients. Genetic analysis of the porphobilinogen deaminase (PBGD) gene was performed for 10 subjects. Of them, 9 were found to harbor a mutation in the PBGD gene, proving a diagnosis of acute intermittent porphyria, and, in 1 case, a novel Cys209Term mutation was found. PMID- 28025646 TI - Ketorolac Tromethamine Spray Prevents Postendotracheal-Intubation-Induced Sore Throat after General Anesthesia. AB - Background. Postoperative sore throat is one of the major complaints of general anesthesia in the postanesthesia care unit. This prospective study investigated the preventive effect of ketorolac tromethamine spray in postendotracheal intubation-induced sore throat after general anesthesia. Methods. Surgical patients undergoing general anesthesia with endotracheal intubation were recruited from a medical center. Patients were randomly assigned to group K (treated with 5% ketorolac tromethamine spray) or group D (treated with distilled water spray). Before intubation, each endotracheal tube was sprayed with the appropriate solution by physicians over the 20 cm length of the cuff. Each group comprised 95 patients fitting the inclusion and exclusion criteria for whom complete data sets were collected. The intensity of the sore throat was measured at 1, 3, 6, and 24 h after surgery, and data were compared. Results. The two groups had similar characteristics. Postoperative sore throat was significantly less frequent in group K than in group D (p < 0.001) and the pain intensity was significantly lower in group K than in group D at each time point (all p < 0.001). Conclusions. This study demonstrated that preanesthesia 5% ketorolac tromethamine spray could effectively decrease postendotracheal-intubation-induced sore throat in patients undergoing general anesthesia. PMID- 28025647 TI - Corrigendum to "The Effects of Cytokines in Adipose Stem Cell-Conditioned Medium on the Migration and Proliferation of Skin Fibroblasts In Vitro". AB - [This corrects the article DOI: 10.1155/2013/578479.]. PMID- 28025648 TI - Functional Assessment of the Hautmann Ileal Neobladder with Chimney Modification Using Uroflowmetry and a Questionnaire. AB - Urinary diversion reconstruction is essential after radical cystectomy and neobladder reconstruction is accepted as a fine option. This study included 51 patients, who underwent radical cystectomy with orthotopic neobladder reconstruction by a Hautmann ileal neobladder with chimney modification from 2006 to 2014. Functional outcomes were evaluated using a questionnaire and uroflowmetry. Perioperative complications were analyzed retrospectively. The mean follow-up period was 36.1 months. Eighty-six percent of patients voided without clean intermittent catheterization (CIC) assistance. CIC was used 1-2x per day or every time they voided in 8% and 6% of patients, respectively, and 71% of patients were continent. The percentages of patients who used 1, 2, 3-4, and >=5 pads per day were 15%, 6%, 2%, and 6%, respectively. Daytime and nighttime continence were achieved in 86% and 69% of patients, respectively. Daily mucus leakage was reported in 69% of patients. The mean maximum neobladder capacity, voided volume, postvoid residual volume, and maximum flow rate were 413.2 mL, 370.6 mL, 43.7 mL, and 20.8 mL/s, respectively. Eighteen early and 5 late complications developed in 13 and 5 patients, respectively. Reoperations were needed in 7 patients. The Hautmann ileal neobladder with chimney modification provided satisfactory results regarding functional outcomes. PMID- 28025649 TI - Biochemical Characterization, Thermal Stability, and Partial Sequence of a Novel Exo-Polygalacturonase from the Thermophilic Fungus Rhizomucor pusillus A13.36 Obtained by Submerged Cultivation. AB - This work reports the production of an exo-polygalacturonase (exo-PG) by Rhizomucor pusillus A13.36 in submerged cultivation (SmC) in a shaker at 45 degrees C for 96 h. A single pectinase was found and purified in order to analyze its thermal stability, by salt precipitation and hydrophobic interaction chromatography. The pectinase has an estimated Mw of approximately 43.5-47 kDa and optimum pH of 4.0 but is stable in pH ranging from 3.5 to 9.5 and has an optimum temperature of 61 degrees C. It presents thermal stability between 30 and 60 degrees C, has 70% activation in the presence of Ca2+, and was tested using citrus pectin with a degree of methyl esterification (DE) of 26%. Ea(d) for irreversible denaturation was 125.5 kJ/mol with positive variations of entropy and enthalpy for that and DeltaG(d) values were around 50 kJ/mol. The hydrolysis of polygalacturonate was analyzed by capillary electrophoresis which displayed a pattern of sequential hydrolysis (exo). The partial identification of the primary sequence was done by MS MALDI-TOF and a comparison with data banks showed the highest identity of the sequenced fragments of exo-PG from R. pusillus with an exo-pectinase from Aspergillus fumigatus. Pectin hydrolysis showed a sigmoidal curve for the Michaelis-Menten plot. PMID- 28025650 TI - Corrigendum to "Cytotoxic Effect of Ethanol Extract of Microalga, Chaetoceros calcitrans, and Its Mechanisms in Inducing Apoptosis in Human Breast Cancer Cell Line". AB - [This corrects the article DOI: 10.1155/2013/783690.]. PMID- 28025651 TI - Delphinidin-Rich Maqui Berry Extract (Delphinol(r)) Lowers Fasting and Postprandial Glycemia and Insulinemia in Prediabetic Individuals during Oral Glucose Tolerance Tests. AB - Delphinidin anthocyanins have previously been associated with the inhibition of glucose absorption. Blood glucose lowering effects have been ascribed to maqui berry (Aristotelia chilensis) extracts in humans after boiled rice consumption. In this study, we aimed to explore whether a standardized delphinidin-rich extract from maqui berry (Delphinol) affects glucose metabolism in prediabetic humans based on glycemia and insulinemia curves obtained from an oral glucose tolerance test (OGTT) after a challenge with pure glucose. Volunteers underwent four consecutive OGTTs with at least one week washout period, in which different doses of Delphinol were administered one hour before glucose intake. Delphinol significantly and dose-dependently lowered basal glycemia and insulinemia. Lower doses delayed postprandial glycemic and insulinemic peaks, while higher doses reversed this tendency. Glycemia peaks were dose-dependently lowered, while insulinemia peaks were higher for the lowest dose and lower for other doses. The total glucose available in blood was unaffected by treatments, while the total insulin availability was increased by low doses and decreased by the highest dose. Taken together, these open exploratory results suggest that Delphinol could be acting through three possible mechanisms: by inhibition of intestinal glucose transporters, by an incretin-mediated effect, or by improving insulin sensitivity. PMID- 28025652 TI - What Type of Communication during Conflict is Beneficial for Intimate Relationships? AB - What constitutes effective communication during conflict? Answering this question requires (a) clarifying whether communication expresses opposition versus cooperation and is direct versus indirect, (b) assessing the mechanisms through which communication effects relationships, and (c) identifying the contextual factors that determine the impact of communication. Recent research incorporating these components illustrates that direct opposition is beneficial when serious problems need to be addressed and partners are able to change, but can be harmful when partners are not confident or secure enough to be responsive. In contrast, cooperative communication involving affection and validation can be harmful when serious problems need to changed, but may be beneficial when problems are minor, cannot be changed, or involve partners whose defensiveness curtails problem solving. PMID- 28025654 TI - Subjective and objective heterogeneity scores for differentiating small renal masses using contrast-enhanced CT. AB - PURPOSE: The aim of this study was to assess the effect of denoising on objective heterogeneity scores and its diagnostic capability for the diagnosis of angiomyolipoma (AML) and renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 158 resected renal masses <=4 cm [98 clear cell (cc) RCCs, 36 papillary (pap)-RCCs, and 24 AMLs] from 139 patients were evaluated. A representative contrast-enhanced computed tomography (CT) image for each mass was selected by a genitourinary radiologist. A largest possible region of interest was drawn on each mass by the radiologist, from which three objective heterogeneity indices were calculated: standard deviation (SD), entropy (Ent), and uniformity (Uni). Objective heterogeneity indices were also calculated after images were processed with a denoising algorithm (non-local means) at three strengths: weak, medium, and strong. Two genitourinary radiologists also subjectively scored each mass independently using a three-point scale (1-3; with 1 the least and 3 the most heterogeneous), which were added to represent the final subjective heterogeneity score of each mass. Heterogeneity scores were compared among mass types, and area under the ROC curve (AUC) was calculated. RESULTS: For all heterogeneity indices, cc-RCC was significantly more heterogeneous than pap-RCC and AML (p < 0.001), but no significant difference was found between pap-RCC and AML (p > 0.01). For cc RCC and pap-RCC differentiation, AUCs were 0.91, 0.81, 0.78, and 0.78 for the subjective score, SD, Ent, and Uni, respectively, using original images. The corresponding AUC values were 0.84, 0.74, 0.79, and 0.80 for differentiation of AML and cc-RCC. Noise reduction at weak setting improves AUC values by 0.03, 0.05, and 0.05 for SD, entropy, and uniformity for differentiation of cc-RCC from pap-RCC. Further increase of filtering strength did not improve AUC values. For differentiation of AML vs. cc-RCC, the AUC values stayed relatively flat using the noise reduction technique at different strengths for all three indices. CONCLUSIONS: Both subjective and objective heterogeneity indices can differentiate cc-RCC from pap-RCC and AML. Noise reduction improved differentiation of cc-RCC from pap-RCC, but not differentiation of AML from cc RCC. PMID- 28025653 TI - Designing Biomaterials for 3D Printing. AB - Three-dimensional (3D) printing is becoming an increasingly common technique to fabricate scaffolds and devices for tissue engineering applications. This is due to the potential of 3D printing to provide patient-specific designs, high structural complexity, rapid on-demand fabrication at a low-cost. One of the major bottlenecks that limits the widespread acceptance of 3D printing in biomanufacturing is the lack of diversity in "biomaterial inks". Printability of a biomaterial is determined by the printing technique. Although a wide range of biomaterial inks including polymers, ceramics, hydrogels and composites have been developed, the field is still struggling with processing of these materials into self-supporting devices with tunable mechanics, degradation, and bioactivity. This review aims to highlight the past and recent advances in biomaterial ink development and design considerations moving forward. A brief overview of 3D printing technologies focusing on ink design parameters is also included. PMID- 28025656 TI - A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism (Niccolini and Politis, 2016) : Reply to Jean-Claude Baron Letter to Editor. PMID- 28025655 TI - Targets and probes for non-invasive imaging of beta-cells. AB - beta-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic beta-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of beta-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by beta-cells that excessively secrete insulin, like for instance beta-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting beta-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of beta-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications. PMID- 28025657 TI - miR-200a controls hepatic stellate cell activation and fibrosis via SIRT1/Notch1 signal pathway. AB - OBJECTIVES: miR-200a has been established as a key regulator of HSC activation processes in liver fibrosis. Epigenetic silencing of miR-200a contributing to SIRT1 over-expression has been discussed in breast cancer; however, whether miR 200a controls SIRT1 gene expression in hepatic fibrosis is still unknown. METHODS AND MATERIALS: We analyzed miR-200a regulation of SIRT1 expression in CCl4 induced liver fibrosis and TGF-beta1-mediated activation of HSC. miR-200a, SIRT1, alpha-SMA, Col1A1, Notch1 and NICD expression were estimated by Western blotting, qRT-PCR and Immunohistochemistry. HSCs were transfected with miR-200a mimic, miR 200a inhibitor and SIRT1-RNAi. Luciferase reporter assays further confirmed the interaction between miR-200a and the SIRT1 mRNA 3'-UTR. Cell proliferation ability was assessed by MTT and cell cycle. RESULTS: We found that treatment activated HSC with miR-200a mimics, restored miR-200a expression and reduced SIRT1 levels. Conversely, treatment activated HSC with miR-200a inhibitors, decreased miR-200a expression and up-regulated SIRT1 levels. Restoration of miR 200a or the knockdown of SIRT1 prevented HSC activation and proliferation. We have established the SIRT1 transcript as subject to regulation by miR-200a, through miR-200a targeting of SIRT1 3'-UTR. Finally, HSC transfected with SIRT1 siRNA increased the levels of Notch1 protein and mRNA expression. CONCLUSIONS: Our study demonstrated that miR-200a regulates SIRT1/Notch1 expression during HSC activation and fibrosis. PMID- 28025658 TI - Microorganisms: Good or Evil, MIRRI Provides Biosecurity Awareness. AB - The life-science community is a key stakeholder in the effort to ensure that the advances in biotechnology are not misused. Unfortunately, to date, the engagement of life scientists with issues of biosecurity has been limited. Microorganisms have been harnessed for the benefit of humankind but in the wrong hands could be used in direct or indirect acts against humans, livestock, crops, food, water infrastructure and other economically valuable entities. The Microbial Resources Research Infrastructure in its preparatory phase has addressed the topic implementing a code of conduct as part of its programme of prevention of malicious use and continues to work with the international community to raise awareness of best practice to avoid misuse of microorganisms. Biosecurity has become a major concern for several countries creating numerous activities to put in place counter measures, risk assessment, legislation and emergency response. The goal is to implement measures to protect us against malicious use of microorganisms, their products, information and technology transfer. Through this paper, we wish to discuss some of the activities that are underway, mention key educational tools and provide scientists with information on addressing biosecurity issues. PMID- 28025659 TI - Results of primary total hip replacement with first generation Bousquet dual mobility socket with more than twenty five years follow up. About a series of two hundred and twelve hips. AB - PURPOSE: The aim of our study was to evaluate long-term survival and dislocation rate of this concept. METHODS: It was a retrospective study, on 212 hips using a Bousquet dual mobility Novae(r) tripodal socket (SERF). Mean follow-up was 25.3 years (95 to 372 months). Mean age at the time of the surgery was 53 years. RESULTS: Pre-operative mean Harris and PMA scores were respectively 54.14 and 11.2. Their respective last follow-up counterparts were 83.6 and 16.9; 25 year follow-up cup survival rate was 90.6%. No dislocation occurred, 45 hips were revised (including 17 cup aseptic loosenings, ten intra prosthetic dislocations, nine liner changes, seven stem failures, two sepsis). CONCLUSION: Dual mobility socket global long term survival rate was comparable to similar cemented or uncemented series. The absence of dislocations proved the interest of dual mobility concept in hip stability. Implant improvements might widen DM socket indication. PMID- 28025661 TI - Erratum to: Increasing the synthesis of bioactive abietane diterpenes in Salvia sclarea hairy roots by elicited transcriptional reprogramming. PMID- 28025660 TI - Low amplitude rhythmic contraction frequency in human detrusor strips correlates with phasic intravesical pressure waves. AB - PURPOSE: Low amplitude rhythmic contractions (LARC) occur in detrusor smooth muscle and may play a role in storage disorders such as overactive bladder and detrusor overactivity. The purpose of this study was to determine whether LARC frequencies identified in vitro from strips of human urinary bladder tissue correlate with in vivo LARC frequencies, visualized as phasic intravesical pressure (p ves) waves during urodynamics (UD). METHODS: After IRB approval, fresh strips of human urinary bladder were obtained from patients. LARC was recorded with tissue strips at low tension (<2 g) and analyzed by fast Fourier transform (FFT) to identify LARC signal frequencies. Blinded UD tracings were retrospectively reviewed for signs of LARC on the p ves tracing during filling and were analyzed via FFT. RESULTS: Distinct LARC frequencies were identified in 100% of tissue strips (n = 9) obtained with a mean frequency of 1.97 +/- 0.47 cycles/min (33 +/- 8 mHz). Out of 100 consecutive UD studies reviewed, 35 visually displayed phasic p ves waves. In 12/35 (34%), real p ves signals were present that were independent of abdominal activity. Average UD LARC frequency was 2.34 +/- 0.36 cycles/min (39 +/- 6 mHz) which was similar to tissue LARC frequencies (p = 0.50). A majority (83%) of the UD cohort with LARC signals also demonstrated detrusor overactivity. CONCLUSIONS: During UD, a subset of patients displayed phasic p ves waves with a distinct rhythmic frequency similar to the in vitro LARC frequency quantified in human urinary bladder tissue strips. Further refinements of this technique may help identify subsets of individuals with LARC mediated storage disorders. PMID- 28025662 TI - The effect of a Live-high Train-high exercise regimen on behavioural temperature regulation. AB - PURPOSE: Acute hypoxia alters the threshold for sensation of cutaneous thermal stimuli. We hypothesised that hypoxia-induced alterations in cutaneous temperature sensation may lead to modulation of the perception of temperature, ultimately influencing behavioural thermoregulation and that the magnitude of this effect could be influenced by daily physical training. METHODS: Fourteen men were confined 10 days to a normobaric hypoxic environment (PIO2 = 88.2 +/- 0.6 mmHg, corresponding to 4175 m elevation). Subjects were randomly assigned to a non-exercising (Live-high, LH, N = 6), or exercising group (Live-high Train-high, LH-TH, N = 8) comprised of 1-h bouts of cycle ergometry, twice daily, at a work rate equivalent to 50% hypoxic peak power output. A subset of subjects (N = 5) also completed a control trial under normoxic conditions. The thermal comfort zone (TCZ) was determined in normoxia, and during hypoxic confinement days 2 (HC2) and 10 (HC10) in both groups using a water-perfused suit in which water temperature was regulated by the subjects within a range, they deemed thermally comfortable. Mean skin temperature and proximal-distal temperature gradients (two sites: forearm-fingertip, calf-toe) were recorded each minute throughout the 60 min protocol. RESULTS: The average width of the TCZ did not differ between the control group (9.0 +/- 6.9 degrees C), and the LH and LH-TH groups on days HC2 (7.2 +/- 4.2 degrees C) and HC10 (10.2 +/- 7.5 degrees C) of the hypoxic exposure (p = 0.256). [Formula: see text] was marginally higher on HC2 (35.9 +/- 1.0 degrees C) compared to control (34.9 +/- 0.8 degrees C, p = 0.040), but not on HC10 (35.6 +/- 1.0 degrees C), reflecting the responses of hand perfusion. CONCLUSION: There was a little systematic effect of hypoxia or exercise training on TCZ magnitude or boundary temperatures. PMID- 28025663 TI - Conservative management of osteoporotic vertebral fractures: an update. AB - PURPOSE: Adequate conservative management of osteoporotic vertebral fractures remains important in an aging population. METHODS: We performed a research of multiple databases and present important studies in this narrative review. RESULTS: The pertinent literature remains scarce and of mixed quality. However, trends are shown to support early mobilization, less rigid bracing and pharmaceutical secondary prevention. CONCLUSION: There is insufficient data to recommend the optimal conservative management for osteoporotic vertebral fractures. As such high-quality studies need to be conducted to establish a solid course of action. PMID- 28025664 TI - Characterization of the neurological diseases associated with Mycoplasma pneumoniae infection and anti-glycolipid antibodies. AB - Mycoplasma pneumoniae infection often causes various neurological complications of both the central nervous system (CNS) and the peripheral nervous system. We retrospectively investigated the IgM and IgG antibodies to nine glycolipids [GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, and Gal-C (galactocerebroside)] and clinical features in neurological diseases associated with M. pneumoniae infection diagnosed in multiple hospitals throughout Japan between September 2010 and March 2012. Of the 46 patients with neurological diseases associated with M. pneumoniae infection, 27 were diagnosed with Guillain-Barre syndrome (GBS), 2 with Fisher syndrome (FS), 16 with CNS diseases, and 1 with both GBS and CNS disease. Anti-Gal-C IgM and IgG antibodies were most frequently detected (23/46, 50%). Patients with CNS diseases were younger than patients with GBS or FS, and IgM antibodies to Gal-C were more frequently detected in the patients with CNS diseases (41%) than in those with GBS or FS (13%). Of the nine patients who were positive for anti-Gal-C IgM antibody but lacked IgG antibody, we found the class switch of anti-Gal-C antibody from IgM to IgG in two patients. The IgG antibodies appeared during their recovery phase, and the IgG belonged to the IgG1 subclass. Anti-Gal-C antibodies are closely associated with neurological diseases after M. pneumoniae infection. Particularly, anti-Gal-C IgM antibody is more frequently detected in younger patients affected with CNS involvement. The class-switch from IgM to IgG sometimes occurs in anti-Gal-C antibodies. PMID- 28025665 TI - MDS clinical diagnostic criteria for Parkinson's disease in China. AB - The Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (MDS-PD Criteria) was introduced by the Movement Disorder Society in 2015 for research purposes. However, its use for clinical diagnosis of Parkinson disease still needs further revision. This study compares the UK-Criteria versus MDS-PD Criteria in the clinical diagnosis of Parkinson disease referred to the China-Japan Friendship Hospital of Beijing, China. To compare the MDS-PD Criteria with the UK-Criteria and discuss the feasibility of the clinical application of MDS-PD Criteria as a general guide to clinical diagnosis of PD in Chinese PD patients. 150 patients of neurology clinic of China-Japan Friendship Hospital of Beijing were recruited in our research. They were divided into three groups: UK Criteria group, MDS-PD Criteria group and a combined group of UK and MDS-PD Criteria. Clinical history was collected while physical and auxiliary examinations were done by a trained neurologist according to the corresponding criteria. An interrater reliability analysis using the Kappa statistic claimed substantial agreement (kappa = 0.626) between the MDS-PD Criteria and the UK Criteria. The differences between the diagnostic results of these two criteria were statistically significant by paired Chi-square test (p = 0.000). It was found that levodopa-induced dyskinesia had a good positive predictive value, while early bulbar impairment and inspiratory dysfunction presented a negative predictive value. The MDS-PD Criteria emphasize the importance of non-motor symptoms, keeping the motor symptoms as the core for the clinical diagnosis of PD, and establish categories of diagnosis features and levels of certainty which are more complete and organized to be used and replicated by non specialized physicians to evaluated patients with Parkinsonism. The higher sensitivity of MDS PD Criteria compared with UK-Criteria is worth being widely used in clinical work. PMID- 28025668 TI - Ericoid Roots and Mycospheres Govern Plant-Specific Bacterial Communities in Boreal Forest Humus. AB - In this study, the bacterial populations of roots and mycospheres of the boreal pine forest ericoid plants, heather (Calluna vulgaris), bilberry (Vaccinium myrtillus), and lingonberry (Vaccinium vitis-idaea), were studied by qPCR and next-generation sequencing (NGS). All bacterial communities of mycosphere soils differed from soils uncolonized by mycorrhizal mycelia. Colonization by mycorrhizal hyphae increased the total number of bacterial 16S ribosomal DNA (rDNA) gene copies in the humus but decreased the number of different bacterial operational taxonomic units (OTUs). Nevertheless, ericoid roots and mycospheres supported numerous OTUs not present in uncolonized humus. Bacterial communities in bilberry mycospheres were surprisingly similar to those in pine mycospheres but not to bacterial communities in heather and lingonberry mycospheres. In contrast, bacterial communities of ericoid roots were more similar to each other than to those of pine roots. In all sample types, the relative abundances of bacterial sequences belonging to Alphaproteobacteria and Acidobacteria were higher than the sequences belonging to other classes. Soil samples contained more Actinobacteria, Deltaproteobacteria, Opitutae, and Planctomycetia, whereas Armatimonadia, Betaproteobacteria, Gammaproteobacteria, and Sphingobacteriia were more common to roots. All mycosphere soils and roots harbored bacteria unique to that particular habitat. Our study suggests that the habitation by ericoid plants increases the overall bacterial diversity of boreal forest soils. PMID- 28025669 TI - Bronchoconstriction Induces Structural and Functional Airway Alterations in Non sensitized Rats. AB - The impact of mechanical forces on pathogenesis of airway remodeling and the functional consequences in asthma remains to be fully established. In the present study, we investigated the effect of repeated bronchoconstriction induced by methacholine (MCh) on airway remodeling and airway hyperresponsiveness (AHR) in rats with or without sensitization to an external allergen. We provide evidence that repeated bronchoconstriction, using MCh, alone induces airway inflammation and remodeling as well as AHR in non-allergen-sensitized rats. Also, we found that the airways are structurally and functionally altered by bronchoconstriction induced by either allergen or MCh in allergen-sensitized animals. This finding provides a new animal model for the development of airway remodeling and AHR in mammals and can be used for studying the complex reciprocal relationship between bronchoconstriction and airway inflammation. Further studies on presented animal models are required to clarify the exact mechanisms underlying airway remodeling due to bronchoconstriction and the functional consequences. PMID- 28025670 TI - Ovarian borderline tumors in the 2014 WHO classification: evolving concepts and diagnostic criteria. AB - Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Since BOT were first identified >40 years ago, they have inspired controversies disproportionate to their incidence. This review discusses diagnostic criteria for the histologic subtypes of BOT, highlighting areas of diagnostic challenges, ongoing controversies, and changes in terminology implemented by the recent 2014 WHO Classification of Tumours of the Female Genital Organs. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. Serous borderline tumors (SBT) share molecular and genetic alterations with low-grade serous carcinomas and can present at higher stages with peritoneal implants and/or lymph node involvement, which validates their borderline malignant potential. All other (non-serous) subtypes of BOT commonly present at stage I confined to the ovary(ies) and are associated with overall survival approaching that of the general population. An important change in the WHO 2014 classification is the new terminology of non-invasive implants associated with SBT, as any invasive foci (previously called "invasive implants") are now in line with their biological behavior considered peritoneal low-grade serous carcinoma (LGSC). The controversy regarding the terminology of non-serous borderline tumors, called by some pathologists "atypical proliferative tumor" in view of their largely benign behavior, has not been resolved. The concepts of intraepithelial carcinoma and microinvasion may evolve in further studies, as their presence appears to have no prognostic impact and is subject to considerable inter-observer variability. PMID- 28025671 TI - Retinoic acid maintains human skeletal muscle progenitor cells in an immature state. AB - Muscle satellite cells are resistant to cytotoxic agents, and they express several genes that confer resistance to stress, thus allowing efficient dystrophic muscle regeneration after transplantation. However, once they are activated, this capacity to resist to aggressive agents is diminished resulting in massive death of transplanted cells. Although cell immaturity represents a survival advantage, the signalling pathways involved in the control of the immature state remain to be explored. Here, we show that incubation of human myoblasts with retinoic acid impairs skeletal muscle differentiation through activation of the retinoic-acid receptor family of nuclear receptor. Conversely, pharmacologic or genetic inactivation of endogenous retinoic-acid receptors improved myoblast differentiation. Retinoic acid inhibits the expression of early and late muscle differentiation markers and enhances the expression of myogenic specification genes, such as PAX7 and PAX3. These results suggest that the retinoic-acid-signalling pathway might maintain myoblasts in an undifferentiated/immature stage. To determine the relevance of these observations, we characterised the retinoic-acid-signalling pathways in freshly isolated satellite cells in mice and in siMYOD immature human myoblasts. Our analysis reveals that the immature state of muscle progenitors is correlated with high expression of several genes of the retinoic-acid-signalling pathway both in mice and in human. Taken together, our data provide evidences for an important role of the retinoic-acid-signalling pathway in the regulation of the immature state of muscle progenitors. PMID- 28025673 TI - Wet fractionation of the succulent halophyte Salicornia sinus-persica, with the aim of low input (water saving) biorefining into bioethanol. AB - In this study Salicornia sinus-persica, a succulent halophyte was assessed for its potential to be used as a feedstock for bioethanol production. For such succulent, salty, green biomasses, direct fractionation and fermentation allow for water preservation in the process. Fresh biomass of S. sinus-persica was collected and split into two fractions by wet fractionation; liquid (juice) and solid (pulp). Sugar contents were found to be 1.0-1.5% for the juice fraction and 50% (w/w) for the fresh pulp. Direct fermentation of the juice using Saccharomyces cerevisiae showed no salt inhibition of the yeast and ethanol yields of ~70% were achieved. A pretreatment study was carried out for the pulp fraction applying mild hydrothermal pretreatment. Cellulose convertibility was found to be significantly higher for severity factors above 2.00, and the highest ethanol yield (76.91 +/- 3.03%) was found at process severity of 3.06 (170 degrees C, 10 min). PMID- 28025672 TI - Reverse transendothelial cell migration in inflammation: to help or to hinder? AB - The endothelium provides a strong barrier separating circulating blood from tissue. It also provides a significant challenge for immune cells in the bloodstream to access potential sites of infection. To mount an effective immune response, leukocytes traverse the endothelial layer in a process known as transendothelial migration. Decades of work have allowed dissection of the mechanisms through which immune cells gain access into peripheral tissues, and subsequently to inflammatory foci. However, an often under-appreciated or potentially ignored question is whether transmigrated leukocytes can leave these inflammatory sites, and perhaps even return across the endothelium and re-enter circulation. Although evidence has existed to support "reverse" transendothelial migration for a number of years, it is only recently that mechanisms associated with this process have been described. Here we review the evidence that supports both reverse transendothelial migration and reverse interstitial migration within tissues, with particular emphasis on some of the more recent studies that finally hint at potential mechanisms. Additionally, we postulate the biological significance of retrograde migration, and whether it serves as an additional mechanism to limit pathology, or provides a basis for the dissemination of systemic inflammation. PMID- 28025674 TI - Localization of RNS2 ribonuclease to the vacuole is required for its role in cellular homeostasis. AB - MAIN CONCLUSION: Localization of the RNase RNS2 to the vacuole via a C-terminal targeting signal is essential for its function in rRNA degradation and homeostasis. RNase T2 ribonucleases are highly conserved enzymes present in the genomes of nearly all eukaryotes and many microorganisms. Their constitutive expression in different tissues and cell types of many organisms suggests a housekeeping role in RNA homeostasis. The Arabidopsis thaliana class II RNase T2, RNS2, is encoded by a single gene and functions in rRNA degradation. Loss of RNS2 results in RNA accumulation and constitutive activation of autophagy, possibly as a compensatory mechanism. While the majority of RNase T2 enzymes is secreted, RNS2 is located within the vacuole and in the endoplasmic reticulum (ER), possibly within ER bodies. As RNS2 has a neutral pH optimum, and the endomembrane organelles are connected by vesicle transport, the site within the endomembrane system at which RNS2 functions is unclear. Here we demonstrate that localization to the vacuole is essential for the physiological function of RNS2. A mutant allele of RNS2, rns2-1, results in production of an active RNS2 RNase but with a mutation that removes a putative C-terminal vacuolar targeting signal. The mutant protein is, therefore, secreted from the cell. This results in a constitutive autophagy phenotype similar to that observed in rns2 null mutants. These findings illustrate that the intracellular retention of RNS2 and localization within the vacuole are critical for its cellular function. PMID- 28025675 TI - Direct isolation of a functional violaxanthin cycle domain from thylakoid membranes of higher plants. AB - MAIN CONCLUSION: A special domain of the thylakoid membrane of higher plants has been isolated which carries out the de-epoxidation of the xanthophyll cycle pigment violaxanthin to zeaxanthin. Recent models indicate that in the chloroplast of higher plants, the violaxanthin (V) cycle takes place within specialized domains in the thylakoid membrane. Here, we describe a new procedure to directly isolate such a domain in functional state. The procedure consists of a thylakoid membrane isolation at a pH value of 5.2 which realizes the binding of the enzyme V de-epoxidase (VDE) to the membrane throughout the preparation process. Isolated thylakoid membranes are then solubilized with the very mild detergent n-dodecyl alpha-D-maltoside and the pigment-protein complexes are separated by sucrose gradient ultracentrifugation. The upper main fraction of the sucrose gradient represents a V cycle domain which consists of the major light harvesting complex of photosystem II (LHCII), a special lipid composition with an enrichment of the galactolipid monogalactosyldiacylglycerol (MGDG) and the VDE. The domain is isolated in functional state as evidenced by the ability to convert the LHCII-associated V to zeaxanthin. The direct isolation of a V cycle domain proves the most important hypotheses concerning the de-epoxidation reaction in intact thylakoid membranes. It shows that the VDE binds to the thylakoid membrane at low pH values of the thylakoid lumen, that it binds to membrane regions enriched in LHCII, and that the domain contains high amounts of MGDG. The last point is in line with the importance of the galactolipid for V solubilisation and, by providing inverted hexagonal lipid structures, for VDE activity. PMID- 28025676 TI - The effects of training on tactile enumeration. AB - Subitizing is a fast and accurate process of enumerating small quantities. Whether subitizing carried out in the tactile modality is under debate. We previously found a moderately increasing RT slope from one to four stimuli and a large decrease in RT for five stimuli when using one hand. Yet, a high error rate was observed, making it difficult to determine if the RT pattern found was indeed subitizing. To increase accuracy, we carried out training of the tactile enumeration task using one hand for 6 days. We compared performance in the trained and additional non-trained tasks between two groups-the 6-day training group (6DT) and the non-trained controls (C)-after three periods (1 week, 1 and 6 months after the training of the 6DT group ended). Results showed an increase in accuracy rates for both groups but a decrease in RT for the 6DT group only for the trained task. This RT improvement was present even after 6 months. Importantly, the RT slope of one-hand enumeration did not change after training, showing a moderately increased slope up to four stimuli and a decrease for five stimuli. Our study shows the training long-term effect on tactile enumeration and emphasizes the embodiment of finger counting on enumeration. Two possible enumeration processes are discussed-accelerated counting and subitizing-both based on spatial cues and pattern recognition of familiarized finger-counting patterns. PMID- 28025677 TI - PCSK9 inhibition: the dawn of a new age in cholesterol lowering? AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating enzyme of hepatic origin that plays a key role in LDL receptor turnover. Genetic studies have confirmed that individuals with gain-of-function PCSK9 mutations have increased PCSK9 activity, elevated LDL-cholesterol levels and a severe form of familial hypercholesterolaemia. Those with variants leading to reduced PCSK9 have lower LDL-cholesterol levels and a reduced risk of coronary heart disease, and this has led to the development of various strategies aimed at reducing circulating PCSK9. Monoclonal antibodies to PCSK9, given every 2-4 weeks by subcutaneous injection, have been shown to reduce LDL-cholesterol by 50-60% compared with placebo in individuals with and without diabetes. PCSK9 inhibition also reduces lipoprotein(a), an atherogenic lipid particle, by around 20-30%. Major cardiovascular outcome trials for two agents, evolocumab and alirocumab, are expected to report from 2017. These trials involve over 45,000 participants and are likely to include about 15,000 individuals with diabetes. PCSK9-binding adnectins have been employed as an alternative method of removing circulating PCSK9. Small interfering RNA targeting messenger RNA for PCSK9, which acts by reducing hepatic production of PCSK9, is also under investigation. These agents may only need to be given by subcutaneous injection once every 4-6 months. Ongoing trials will determine whether anti-PCSK9 antibody therapy safely reduces cardiovascular risk, although high cost may limit its use. Development of PCSK9 lowering technologies cheaper than monoclonal antibodies will be necessary for large numbers of individuals to benefit from this approach to lowering cholesterol. PMID- 28025678 TI - Enlightening the mechanisms of POP recurrence after LeFort colpocleisis. Case report and review. AB - INTRODUCTION AND HYPOTHESIS: Obliterative procedures for the treatment of pelvic organ prolapse have been reported to have a recurrence rate up to 10%. We present (1) a case report of a patient with prolapse after LeFort colpocleisis and how it was managed in our department, and (2) a review of the literature regarding the types of recurrence after LeFort colpocleisis, their rate and their treatment. METHODS: A 77-year-old woman was treated in our department for recurrence of prolapse through the right lateral channel 6 months after LeFort colpocleisis. A systematic review of the literature up to 2016 was performed through MEDLINE, Web of Science and the Cochrane Library. RESULTS: The patient underwent a modified repeat colpocleisis and 6 months later was doing well with no signs of recurrence. We found 28 eligible studies including 1,810 patients, and the rate of recurrence after LeFort colpocleisis was 4.2% (76/1,810) leaving the majority of patients very satisfied. Information about the management of recurrence of prolapse after LeFort colpocleisis was provided in 17 studies including 33 patients with a 60-month follow-up. It appears that there are three major categories of recurrent prolapse after LeFort partial colpocleisis: (1) patients with a total breakdown of colpocleisis (57.6%), (2) patients with "channel prolapse" (15.2%), and (3) patients with prolapse at sites not involved in the primary partial colpocleisis (27.3%). The most frequent treatments were total colpocleisis/colpectomy (27.3%), perineorrhaphy and posterior repair (9.1%) and hysterectomy (9.1%). Almost 50% of these patients opted not to have surgical treatment. CONCLUSIONS: The rate of prolapse recurrence after LeFort colpocleisis is estimated to be 4.2%. The management of recurrences after LeFort colpocleisis depends on the time and type of recurrence. The repeat modified LeFort colpocleisis is a viable option in patients with channel prolapse; if no uterus exists, colpectomy appears to be the best option. PMID- 28025679 TI - Vascular anatomical relationships of the retropubic space and the sacrospinous ligament, using three-dimensional imaging. AB - INTRODUCTION AND HYPOTHESIS: Pelvic anatomy is complex and intimate knowledge of variabilities in anatomical relationships is critical for surgeons to safely perform surgical procedures. Three-dimensional Imaging provides the opportunity to analyze undisturbed anatomical relationships. The authors hypothesized that three-dimensional models created from pelvic computed tomography angiograms could be used to obtain vascular anatomical measurements, and that the measurements obtained from three-dimensional models would be similar to those from cadaver studies. METHODS: We included all pelvic computed tomography angiograms that were acquired in female patients older than 18 years at our institution within the previous 5 years. Three-dimensional models were created using the Invivo5 software based on the Digital Imaging and Communications in Medicine files. Structures of interest were virtually dissected and measured replicating previous cadaver studies. Statistical analysis of demographics and measurements was performed. RESULTS: The final analysis included 87 studies. The average age of the subjects was 66.9 years and their average BMI was 26.1 kg/m2. Of the 87 subjects, 12.6% had a history of hysterectomy, 2.3% a history of a continence procedure, and 1.1% a history of a prolapse procedure. The range of distance between the ischial spine and the pudendal artery was 3-17 mm. The closest vessels to the lower edge of the symphysis pubis were the obturator vessels. The aberrant corona mortis vessel was present in 27.9% of the subjects. Prior hysterectomy was associated with changes in the measurements of the obturator arteries with minimal changes in other measurements. CONCLUSIONS: Our results indicate that this technology provides similar measurements to those found in previous unembalmed cadaver studies. This technology offers a great opportunity to study anatomical relationships in a native undisturbed state. PMID- 28025680 TI - Impact of surgery on quality of life of women with obstetrical fistula: a qualitative study in Burkina Faso. AB - INTRODUCTION AND HYPOTHESIS: Obstetric fistula, caused by traumatic delivery and patient lack of access to obstetric care, is an important public health concern in developing countries, particularly in Sub-Saharan Africa. This research focuses on the experience of women living with obstetric fistula in Burkina Faso as well as their reintegration into community after surgery. METHODS: This project was funded by the Meres du Monde en Sante (MMS) Foundation and conducted in collaboration with the Boromo Hospital. A qualitative approach based on grounded theory and using the principles of participative action research (PAR) was used with semidirected interviews prior to surgery and follow-up interviews 1 2 years after surgery directly in the women's village of origin. Thirty-nine participants were recruited between 2012 and 2015. RESULTS: The results point to circumstances leading to obstetric fistula development: poverty, gender inequality in terms of decision making, healthcare-system deficiencies, and lack of services for referral and treatment of this condition. Our results reinforce the knowledge about the social and psychological repercussions of fistula by exploring the concepts of gossips, shame and self-exclusion as powerful mechanisms of exclusion, but they also show that social support was conserved for several women through their journey with this disease. There was complete social rehabilitation within the community after surgery; however, persistent barriers in term of anxiety regarding obstetric future and economic insecurity were present. CONCLUSIONS: Early recruitment for surgery and prevention are the main objectives when attempting to reduce the impact of obstetric fistula and facilitate patient reintegration. Improvements in local and governmental public health policies are required. PMID- 28025681 TI - Dynamic assessment of sling function on transperineal ultrasound: does it correlate with outcomes 1 year following surgery? AB - INTRODUCTION AND HYPOTHESIS: To correlate dynamic assessment of sling function using 2D and 3D transperineal ultrasound with outcomes following transobturator sling surgery. METHODS: This is an unmatched case-control study of 100 patients who underwent transobturator sling surgery at our center between 2009 and 2012. Group A (n = 50) patients had successful outcomes and group B (n = 50) patients had suboptimal outcomes 1 year following surgery. The patients underwent 2D dynamic and 3D transperineal ultrasound. The two groups were compared with regard to the deformability of the sling on Valsalva, the concordance of urethral movement with the sling, and location of the sling. RESULTS: When compared with group B, group A had a significantly greater number of patients in whom the sling deformed at Valsalva (flat at rest, curving into a c-shape at Valsalva), the urethral movement was concordant with the sling and the sling had a midurethral location (p < 0.0001). In all 17 patients in group B in whom the urethra moved in a concordant manner with the sling (34%), the sling did not deform on Valsalva maneuver and was located proximally. In all 15 patients in group A in whom the sling remained either flat or curved (30%), the urethra moved concordant with the sling and the sling was in midurethral location. CONCLUSIONS: On 2D and 3D transperineal ultrasound, the best outcomes following transobturator sling surgery are associated with concordance of urethral movement with the sling, midurethral location, and deformability of the sling on dynamic assessment. PMID- 28025682 TI - Impact of subsequent birth and delivery mode for women with previous OASIS: systematic review and meta-analysis. AB - INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injuries (OASIS) are serious complications of vaginal birth. In a pregnancy following OASIS women may be keen to avoid an elective caesarean section, yet cautious about pursuing another vaginal birth that may result in further damage to the pelvic floor and possible long-term anal incontinence. This review aimed to evaluate the impact of subsequent birth and its mode on anal incontinence (AI) and/or quality of life (QoL), for women with previous OASIS. METHODS: Searches of MEDLINE, EMBASE, CINAHL, and AMED from inception to February 2016 were undertaken with selection criteria of any study evaluating the effect of a subsequent birth on AI and/or QoL in women with previous OASIS. Where possible, data were extracted to populate 2 * 2 tables and allow meta-analysis relating to the impact of subsequent birth on AI and/or QoL. RESULTS: Twenty-seven non-randomised studies were included. Meta-analysis of 14 studies (977 women) did not demonstrate any significant associations between AI in women with previous OASIS and subsequent birth or its mode. Impact on QoL was reported in 12 studies (912 women); however, difference in outcome reporting precluded data meta-analysis. CONCLUSIONS: Comparisons of outcomes and effective synthesis were limited by sample size, quality and heterogeneity of the studies included. Consequently, the optimal mode of delivery for women with previous OASIS is still not known and better data are needed. PMID- 28025683 TI - Why do we argue about route of hysterectomy? A call for dialogue. PMID- 28025684 TI - Utility of anterior vaginal wall length measurement in vaginal reconstructive surgery. AB - INTRODUCTION AND HYPOTHESIS: The pelvic organ prolapse quantification system (POP Q) is the most commonly used method to quantify the extent of pelvic organ prolapse. However, it does not include assessment of anterior vaginal wall length (AVL). The objectives of this study were to characterize AVL and distance to the sacrospinous ligament (SSL), and to examine associations between total vaginal length (TVL), AVL, body mass index (BMI) and age. METHODS: This was a retrospective chart review of 139 patients with cervix in situ presenting during an 8-month period for initial evaluation to the University of Rochester Medical Center Urogynecology practice. AVL, TVL and distance to the SSL were measured in addition to POP-Q measurements. Age, height, BMI, presenting complaint and prolapse stage were obtained from medical records. Simple linear regression was used to assess the relationship between TVL and AVL. Multivariate regression was used to test independent variables. RESULTS: The mean +/- SD TVL, AVL and distance to the SSL were 9.4 +/- 1.2 cm, 7.4 +/- 0.9 cm and 7.2 +/- 0.9 cm, respectively. All three measurements approached a normal distribution. TVL decreased slightly with age. No association was found between vaginal length and BMI or parity. CONCLUSIONS: AVL is a useful measurement that may aid in surgical decision-making. Providers should consider using AVL when planning sacrospinous hysteropexy. PMID- 28025685 TI - Comparison of pelvic floor muscle strength in nulliparous women and those with normal vaginal delivery and cesarean section. AB - INTRODUCTION AND HYPOTHESIS: Weakness of the pelvic floor is quite common among women, and may occur following childbirth. The aim of this study was to compare pelvic floor muscle strength in women of reproductive age who were nulliparous or who had a cesarean section or normal vaginal delivery. METHODS: In this cross sectional study, 341 women including 96 nulliparous women, 73 women with a history of normal vaginal delivery with and without episiotomy, and 172 women with a history of elective or emergency cesarean section were recruited randomly from public health centers in Ahvaz, Iran. Data were collected using a sociodemographic questionnaire and a checklist was used to record weight, height, body mass index, and pelvic floor muscle strength. Pelvic floor muscle strength was measured with the woman in the lithotomy position using a Peritron 9300 V perineometer. Data were analyzed using one-way analysis of variance, the least significant difference test and the chi-squared test. RESULTS: The nulliparous women had the highest mean pelvic muscle strength (55.62 +/- 15.86 cm H2O). Women who had vaginal delivery with episiotomy had the lowest pelvic muscle strength (32.71 +/- 14 cm H2O). In nulliparous women pelvic floor muscle strength was higher than in women who had normal vaginal delivery with episiotomy (p < 0.001), but was not significantly different from that in women with normal vaginal delivery without episiotomy or in women with cesarean section (elective or emergency, p = 0.245). CONCLUSIONS: Nulliparous women had the highest pelvic floor muscle strength and there was no significant difference in pelvic floor muscle strength between women with normal vaginal delivery and those with cesarean section. PMID- 28025686 TI - Contasure-needleless(r) compared with Monarc(r) for the treatment of stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: For the treatment of stress urinary incontinence (SUI), various retropubic and transobturator techniques have demonstrated high cure rates. Single-incision tapes, such as Contasure-Needleless(r) (C-NDL), have demonstrated similar cure rates to the inside-out transobturator sling (TVT O(r)). The aim of this study was to analyse if C-NDL(r) is equally as effective as an outside-in transobturator sling (Monarc(r)) for the treatment of SUI. METHODS: We carried out a prospective, single-centre, randomised trial. The results were analysed for a non-inferiority test with a minimum postoperative follow-up of 12 months. The objective and subjective cure rates were evaluated by a stress test and a postoperative Sandvik Severity Index respectively. Patient satisfaction and operative complications were registered. The cure was defined by a negative stress test and SSI 0. RESULTS: A total of 187 patients were included, 89 and 98 undergoing C-NDL(r) and Monarc(r) respectively. Epidemiological and clinical data did not show and significant differences between both groups except a high prevalence of women who smoke (15.7% C-NDL(r) vs 6.1% Monarc(r), p 0.03). The negative stress test was negative in 72 patients (80.9%) in C-NDL(r) compared with 85 (88.5%) in Monarc(r) (p 0.082). The SSI was 0 in 47 (66.2%) for C-NDL(r) and 61 (70.1%) for the Monarc(r) group (p 0.01). There were 14 (16.1%) and 8 (8.3%) dissatisfied patients for the C-NDL(r) and Monarc(r) groups respectively (p 0.068). The rate of complications was similar in both groups. CONCLUSIONS: According to the non-inferiority test, C-NDL(r) is not inferior to Monarc(r) (post-surgical SSI test), but it is inferior in the comparison of a negative stress test and patient satisfaction. PMID- 28025688 TI - Mercury Concentrations in Tuna (Thunnus albacares and Thunnus obesus) from the Brazilian Equatorial Atlantic Ocean. AB - Average total Hg concentrations measured in muscle of two species of tuna (Thunnus obesus and T. albacares) captured in the Brazilian Equatorial Atlantic Ocean varied from 95 to 1748 ng.g-1 wet weight in T. obesus and 48 to 500 ng.g-1 wet weight in T. albacares. Higher concentrations in T. obesus are probably related to foraging on deep water carnivorous fish. Smaller individuals of both species showed the lowest concentrations, but a significant positive relationship between fish weight and length and Hg concentrations was found for T. obesus, but not for T. albacares. Largest individuals (>30 kg) of T. obesus showed Hg concentrations >=1000 ng.g-1, surpassing the legal limits for human consumption, although the average concentration for this species was much lower (545 ng.g-1). Concentrations in T. albacares from the Brazilian Equatorial were lower than those found in the African and in the North Atlantic. No comparison could be made for T. obesus due to few studies for this species in the Atlantic Ocean. PMID- 28025687 TI - Characterisation of the DAACS Family Escherichia coli Glutamate/Aspartate-Proton Symporter GltP Using Computational, Chemical, Biochemical and Biophysical Methods. AB - Escherichia coli glutamate/aspartate-proton symporter GltP is a member of the Dicarboxylate/Amino Acid:Cation Symporter family of secondary active transport proteins. A range of computational, chemical, biochemical and biophysical methods characterised evolutionary relationships, structural features, substrate binding affinities and transport kinetics of wild-type and mutant forms of GltP. Sequence alignments and phylogenetic analysis revealed close homologies of GltP with human glutamate transporters involved in neurotransmission, neutral amino acid transporters and with the archaeal aspartate transporter GltPh. Topology predictions and comparisons with the crystal structure of GltPh were consistent with eight transmembrane-spanning alpha-helices and two hairpin re-entrant loops in GltP. Amplified expression of recombinant GltP with C-terminal affinity tags was achieved at 10% of total membrane protein in E. coli and purification to homogeneity with a yield of 0.8 mg/litre. Binding of substrates to GltP in native inner membranes and to purified protein solubilised in detergent was observed and quantified using solid-state NMR and fluorescence spectroscopy, respectively. A homology model of GltP docked with L-glutamate identified a putative binding site and residues predicted to interact with substrate. Sequence alignments identified further highly conserved residues predicted to have essential roles in GltP function. Residues were investigated by measuring transport activities, kinetics and response to thiol-specific reagents in 42 site-specific mutants compared with cysteine-less GltP (C256A) having an apparent affinity of initial rate transport (K m) for 3H-L-glutamate of 22.6 +/- 5.5 MUM in energised E. coli cells. This confirmed GltP residues involved in substrate binding and transport, especially in transmembrane helices VII and VIII. PMID- 28025689 TI - Single Low-Dose Ionizing Radiation Induces Genotoxicity in Adult Zebrafish and its Non-Irradiated Progeny. AB - This study investigated to what extent a single exposure to low doses of ionizing radiation can induce genotoxic damage in irradiated adult zebrafish (Danio rerio) and its non-irradiated F1 progeny. Four groups of adult zebrafish were irradiated with a single dose of X-rays at 0 (control), 100, 500 and 1000 mGy, respectively, and couples of each group were allowed to reproduce following irradiation. Blood of parental fish and whole-body offspring were analysed by the comet assay for detection of DNA damage. The level of DNA damage in irradiated parental fish increased in a radiation dose-dependent manner at day 1 post-irradiation, but returned to the control level thereafter. The level of DNA damage in the progeny was directly correlated with the parental irradiation dose. Results highlight the genotoxic risk of a single exposure to low-dose ionizing radiation in irradiated individuals and also in its non-irradiated progeny. PMID- 28025690 TI - Gender discrimination, educational attainment, and illicit drug use among U.S. women. AB - PURPOSE: While gender inequality has been a topic of concern for decades, little is known about the relationship between gender discrimination and illicit drug use. Further, whether this association varies by education level is unknown. METHODS: Among 19,209 women participants in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (2004-2005), we used logistic regression to test the association between gender discrimination (measured with four items from the Experiences of Discrimination instrument) and three outcomes: past-year illicit drug use, frequent drug use, and drug use disorders. We then tested whether associations differed by education level. RESULTS: Gender discrimination was reported by 9% of women and was associated with past-year drug use [adjusted odds ratio (aOR) = 2.67; 95% confidence interval (CI) 2.17-3.29], frequent drug use (aOR = 2.82; CI 1.99-4.00), and past-year drug use disorders (aOR = 3.15; CI 2.16-4.61). All specific domains of gender discrimination (on the job, in public, with institutions, being called a sexist name) were associated with all drug use outcomes. The association between gender discrimination and past-year drug use was stronger among women with less than a high school education (aOR = 6.33; CI 3.38-11.85) compared to those with more education (aOR = 2.45; CI 1.97-3.04; p interaction < 0.01). CONCLUSIONS: Gender discrimination is consistently and strongly associated with illicit drug use and drug use disorders among U.S. women, with significantly higher odds for drug use among women with less than a high school education. Future research should examine whether explicitly addressing distress from discrimination could benefit women in drug treatment, especially among clients with lower educational attainment. PMID- 28025691 TI - Masculinity and suicidal thinking. AB - PURPOSE: Males feature prominently in suicide statistics, but relatively little work has been done to date to explore whether endorsement of dominant masculinity norms heightens the risk of or is protective against suicidal thinking. This paper aimed to further knowledge in this area. METHODS: We used baseline data from 13,884 men (aged 18-55) in the Australian Longitudinal Study on Male Health (Ten to Men) cohort. These men filled in self-complete questionnaires in 2013/14 which covered a range of topics, including conformity to dominant masculinity norms and suicidal thinking. We conducted logistic regression analyses to estimate the strength of association between these two variables. RESULTS: After controlling for other key predictors of suicidal thinking, one characteristic of dominant masculinity-self-reliance-stood out as a risk factor for suicidal thinking (AOR 1.33; 95% CI 1.25-1.42). CONCLUSIONS: It suggests that one particular element of dominant masculinity-being self-reliant-may place men at increased risk of suicidal thinking. This finding resonates with current theories of how suicidal thinking develops and leads to action. It also has implications for the full gamut of suicide prevention approaches that target males in clinical settings and in the general population, and for our broader society. Further work is needed, however, to confirm the direction of the relationship between self reliance and suicidality, and to unpack the means through which self-reliance may exert an influence. PMID- 28025692 TI - Age-related differences in inhibitory control and memory updating in boys with Asperger syndrome. AB - Deficits in specific executive domains are highly prevalent in autism spectrum disorder; however, age-related improvements in executive functions (reflecting prefrontal maturational changes) have been reported even in individuals diagnosed with autism. The current study examined two components of cognitive flexibility (inhibition of prepotent responses and memory monitoring/updating) by using a random-motor-generation task (MPT) in a group of 23 boys with Asperger syndrome (AS) and 23 matched healthy controls. We found poorer inhibition and more repetitive responses in younger AS children solely, but comparable memory monitoring/updating skills across groups. Overall, our findings correspond well with previous studies and reveal that even in AS specific EFs may improve with age and, thus, call for a more differentiated view of executive (dys) function profiles in children diagnosed with AS. Tests such as the random-motor-generation task may help to disentangle more specific processes of executive deficits in autism spectrum disorder as compared to the more classical tests. PMID- 28025693 TI - Laparoscopic versus open inguinal hernia repair in children <=3: a randomized controlled trial. AB - PURPOSE: Laparoscopy is being increasingly applied to pediatric inguinal hernia repair. In younger children, however, open repair remains preferred due to concerns related to anesthesia and technical challenges. We sought to assess outcomes after laparoscopic and open inguinal hernia repair in children less than or equal to 3 years. METHODS: A prospective, single-blind, parallel group randomized controlled trial was conducted at three clinical sites. Children <=3 years of age with reducible unilateral or bilateral inguinal hernias were randomized to laparoscopic herniorrhaphy (LH) or open herniorrhaphy (OH). The primary outcome was the number of acetaminophen doses. Secondary outcomes included operative time, complications, and parent/caregiver satisfaction scores. RESULTS: Forty-one patients were randomized to unilateral OH (n = 10), unilateral LH (n = 17), bilateral OH (n = 5) and bilateral LH (n = 9). Acetaminophen doses, LOS, complications, and parent/caregiver scores did not differ among groups. Laparoscopic unilateral hernia repair demonstrated shorter operative time, a consistent finding for overall laparoscopic repair in univariate (p = 0.003) and multivariate (p = 0.010) analysis. No cases of testicular atrophy were documented at 2 (SD = 2.7) years. CONCLUSION: Children <=3 years of age in our cohort safely underwent LH with similar pain scores, complications, and recurrence as OH. Parents and caregivers report high satisfaction with both techniques. PMID- 28025694 TI - Low vitamin D deficiency in Irish toddlers despite northerly latitude and a high prevalence of inadequate intakes. AB - PURPOSE: While reports of inadequate vitamin D intakes among young children are widespread, data on the prevalence of vitamin D deficiency are inconsistent. We aimed to quantify vitamin D intake and serum 25-hydroxyvitamin D [25(OH)D] concentrations in children aged 2 years in the prospective Cork BASELINE Birth Cohort Study. METHODS: Serum 25(OH)D was analysed using UPLC-MS/MS in 741 children living in Cork, Ireland (51 degrees N). Two-day weighed food diaries were collected in 467 children, and 294 provided both a blood sample and a food diary. RESULTS: Mean (SD) 25(OH)D concentrations were 63.4 (20.4) nmol/L [winter: 54.5 (19.9), summer: 71.2 (17.5)]. The prevalence of vitamin D deficiency (<30 nmol/L) was 4.6, and 26.7% were <50 nmol/L [45.2% during winter (November-April) and 10.4% in summer (May-October)]. With a mean (SD) vitamin D intake of 3.5 (3.1) ug/day, 96% had intakes below 10 ug/day, the current IOM estimated average requirement and the SACN safe intake value for this age group. After adjustment for season, vitamin D intake (ug/day) was associated with higher 25(OH)D concentrations [adjusted estimate (95% CI) 2.5 (1.9, 3.1) nmol/L]. Children who did not consume vitamin D-fortified foods or supplements had very low vitamin D intakes (1.2 (0.9) ug/day), and during winter, 12 and 77% were <30 and <50 nmol/L, respectively, compared with 6 and 44% of fortified food consumers. CONCLUSION: There was a high prevalence of low vitamin D status during winter, especially among children who did not consume fortified foods or nutritional supplements. Our data indicate the need for dietary strategies to increase vitamin D intakes in this age group. This report provides further evidence that DRVs for vitamin D should be based on experimental data in specific population groups and indicates the need for dose-response RCTs in young children. PMID- 28025695 TI - Efficacy of everolimus-eluting stent implantation in patients with small coronary arteries (<=2.5 mm): outcomes of 3-year clinical follow-up. AB - Previous studies have demonstrated that patients with small coronary artery lesions are at increased risk for late cardiac events after percutaneous coronary intervention. It remains uncertain whether second-generation drug-eluting stents have an advantage over first-generation drug-eluting stents in patients with small vessel lesions. Our aim was to compare in the 3-year clinical impact between second-generation everolimus-eluting stents (EES) and first-generation sirolimus-eluting stents (SES) in small vessel lesions. Four-hundred forty-four patients with small vessel lesions defined as reference diameter <2.5 mm were treated with EES (237 patients, 265 lesions) or SES (207 patients, 220 lesions) and completed 3-year follow-up. We compared the major adverse clinical events (MACE) between the two groups. EES had no significant impact on the MACE rate compared with SES (4.6 vs. 7.2%, p = 0.14). No significant differences were observed in the individual components of cardiac death (1.7 vs. 1.9%, p = 0.78), myocardial infarction (1.3 vs. 3.4%, p = 0.12), and ischemia-driven target lesion revascularization (2.3 vs. 4.6%, p = 0.13) in EES and SES, respectively. Stent thrombosis, however, was significantly less in the EES group than in the SES group (0.7 vs. 3.4%, HR: 0.53, 95% CI 0.38-0.88, p < 0.05). EES implantation did not significantly impact 3-year MACE rates compared to SES implantation in small vessel lesions. A significant reduction in the overall rate of stent thrombosis was observed in recipients of EES. While the SES group showed increasing rates of late and very late thrombosis, the EES group did not. EES offers a safe and effective treatment for small vessel lesions. PMID- 28025697 TI - Metabolic heat production by human and animal populations in cities. AB - Anthropogenic heating from building energy use, vehicle fuel consumption, and human metabolism is a key term in the urban energy budget equation. Heating from human metabolism, however, is often excluded from urban energy budgets because it is widely observed to be negligible. Few reports for low-latitude cities are available to support this observation, and no reports exist on the contribution of domestic animals to urban heat budgets. To provide a more comprehensive view of metabolic heating in cities, we quantified all terms of the anthropogenic heat budget at metropolitan scale for the world's 26 largest cities, using a top-down statistical approach. Results show that metabolic heat release from human populations in mid-latitude cities (e.g. London, Tokyo, New York) accounts for 4 8% of annual anthropogenic heating, compared to 10-45% in high-density tropical cities (e.g. Cairo, Dhaka, Kolkata). Heat release from animal populations amounts to <1% of anthropogenic heating in all cities. Heat flux density from human and animal metabolism combined is highest in Mumbai-the world's most densely populated megacity-at 6.5 W m-2, surpassing heat production by electricity use in buildings (5.8 W m-2) and fuel combustion in vehicles (3.9 W m-2). These findings, along with recent output from global climate models, suggest that in the world's largest and most crowded cities, heat emissions from human metabolism alone can force measurable change in mean annual temperature at regional scale. PMID- 28025698 TI - Is it possible to prevent recurrent vulvovaginitis? The role of Lactobacillus plantarum I1001 (CECT7504). PMID- 28025696 TI - Influence of vitamin D signaling on hormone receptor status and HER2 expression in breast cancer. AB - PURPOSE: Breast cancer is a significant global public health issue. It is the leading cause of death among women around the world, with an incidence increasing annually. In recent years, there has been more and more information in the literature regarding a protective role of vitamin D in cancer. Increasingly preclinical and clinical studies suggest that vitamin D optimal levels can reduce the risk of breast cancer development and regulate cancer-related pathways. METHOD: In this review, we focus on the importance of vitamin D in breast cancers, discussing especially the influence of vitamin D signaling on estrogen receptor and human epidermal growth factor receptor 2 (HER2), two major biomarkers of breast cancer today. CONCLUSION: We discuss the possibility of actual and future targeted therapeutic approaches for vitamin D signaling in breast cancer. PMID- 28025699 TI - Surveillance of Gram-negative bacteria: impact of variation in current European laboratory reporting practice on apparent multidrug resistance prevalence in paediatric bloodstream isolates. AB - This study evaluates whether estimated multidrug resistance (MDR) levels are dependent on the design of the surveillance system when using routine microbiological data. We used antimicrobial resistance data from the Antibiotic Resistance and Prescribing in European Children (ARPEC) project. The MDR status of bloodstream isolates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was defined using European Centre for Disease Prevention and Control (ECDC)-endorsed standardised algorithms (non-susceptible to at least one agent in three or more antibiotic classes). Assessment of MDR status was based on specified combinations of antibiotic classes reportable as part of routine surveillance activities. The agreement between MDR status and resistance to specific pathogen-antibiotic class combinations (PACCs) was assessed. Based on all available antibiotic susceptibility testing, the proportion of MDR isolates was 31% for E. coli, 30% for K. pneumoniae and 28% for P. aeruginosa isolates. These proportions fell to 9, 14 and 25%, respectively, when based only on classes collected by current ECDC surveillance methods. Resistance percentages for specific PACCs were lower compared with MDR percentages, except for P. aeruginosa. Accordingly, MDR detection based on these had low sensitivity for E. coli (2-41%) and K. pneumoniae (21-85%). Estimates of MDR percentages for Gram negative bacteria are strongly influenced by the antibiotic classes reported. When a complete set of results requested by the algorithm is not available, inclusion of classes frequently tested as part of routine clinical care greatly improves the detection of MDR. Resistance to individual PACCs should not be considered reflective of MDR percentages in Enterobacteriaceae. PMID- 28025700 TI - Use of the effluent from biogas production for cultivation of Spirulina. AB - The effluent from the biogas process was tested as a nutrient source during cultivation of the protein-rich and edible microalgae Spirulina (Arthrospira platensis) and compared with conventional Spirulina medium. Equal biomass production was observed until late exponential phase and no significant differences could be observed between the treatments in protein amount, amino acid composition, and total lipid concentration. The concentration of the pigment phycocyanin differed significantly between Spirulina medium and the effluent based medium (63.3 +/- 11.7 and 86.2 +/- 1.9 mg g-1, respectively). Slightly higher concentrations of saturated fatty acids, mainly palmitic acid, were observed in the biomass produced in Spirulina medium than in that produced in the effluent-based medium. In the biomass produced in the effluent-based medium, the cadmium concentration was 0.07 +/- 0.05 mg kg-1 of dry weight, whereas it was below the detection limit in the biomass produced in Spirulina medium. There is a need to identify new food and feed resources and a possible future scenario is to integrate Spirulina production into the biogas plant for protein production as it contains more than 60% of protein on dry weight basis. In that scenario, it is important to control heavy metal concentrations in the biogas slurry fed to Spirulina. PMID- 28025701 TI - Flux control-based design of furfural-resistance strains of Saccharomyces cerevisiae for lignocellulosic biorefinery. AB - We have previously developed a dynamic flux balance analysis of Saccharomyces cerevisiae for elucidation of genome-wide flux response to furfural perturbation (Unrean and Franzen, Biotechnol J 10(8):1248-1258, 2015). Herein, the dynamic flux distributions were analyzed by flux control analysis to identify target overexpressed genes for improved yeast robustness against furfural. The flux control coefficient (FCC) identified overexpressing isocitrate dehydrogenase (IDH1), a rate-controlling flux for ethanol fermentation, and dicarboxylate carrier (DIC1), a limiting flux for cell growth, as keys of furfural-resistance phenotype. Consistent with the model prediction, strain characterization showed 1.2- and 2.0-fold improvement in ethanol synthesis and furfural detoxification rates, respectively, by IDH1 overexpressed mutant compared to the control. DIC1 overexpressed mutant grew at 1.3-fold faster and reduced furfural at 1.4-fold faster than the control under the furfural challenge. This study hence demonstrated the FCC-based approach as an effective tool for guiding the design of robust yeast strains. PMID- 28025702 TI - Characteristics of gastric cancer in negative test of serum anti-Helicobacter pylori antibody and pepsinogen test: a multicenter study. AB - BACKGROUND AND AIM: The serological risk prediction system combines the pepsinogen test and anti-Helicobacter pylori (H. pylori) antibody determination. In this system, chronic atrophic gastritis (CAG) is diagnosed using the pepsinogen test. Patients who are H. pylori negative and pepsinogen negative are classified into group A, are assumed to be H. pylori uninfected, and are at an extremely low risk for gastric cancer. However, gastric cancers are detected in this group. The aim of this study is to clarify the clinicopathological status of group A patients with gastric cancer. METHODS: A total of 109 gastric cancer patients classified as group A were enrolled in a multicenter study. Group A patients were divided into two subgroups: group AN (H. pylori uninfected) and group AP (H. pylori infected). They were compared to 183 H. pylori-infected gastric cancer patients who were not in group A. RESULTS: Of the 109 patients, only 7 were classified as group AN; the other 102 were classified as group AP. The clinicopathological features of group AP included older age, predominantly differentiated type cancer, endoscopically visualized CAG, and pepsinogen (PG) I/II ratio lower than that of group AN. In group AN, the depressed type was dominant, and the PG I/II ratio was higher than in those gastric cancer patients who were infected with H. pylori. CONCLUSION: Patients in group AP had CAG, and their gastric cancers were similar to those of H. pylori-eradicated patients. Concerning the recent ABC classification system, advanced decision criteria should be proposed to decrease the false-negative evaluation of gastric cancer risk. PMID- 28025704 TI - Pulmonary vascular remodeling in pulmonary hypertension. AB - Pulmonary vascular remodeling is the key structural alteration in pulmonary hypertension and involves changes in the intima, media and adventitia, often with the interplay of inflammatory cells. This review examines the pathology of these changes and highlights some of the pathogenetic mechanisms that underlie the remodeling process. PMID- 28025703 TI - The biology of the ABCA3 lipid transporter in lung health and disease. AB - The lipid transporter, ATP-binding cassette class A3 (ABCA3), is a highly conserved multi-membrane-spanning protein that plays a critical role in the regulation of pulmonary surfactant homeostasis. Mutations in ABCA3 have been increasingly recognized as one of the causes of inherited pulmonary diseases. These monogenic disorders produce familial lung abnormalities with pathological presentations ranging from neonatal surfactant-deficiency-induced respiratory failure to childhood or adult diffuse parenchymal lung diseases for which specific treatment modalities remain limited. More than 200 ABCA3 mutations have been reported to date with approximately three quarters of patients presenting as compound heterozygotes. Recent advances in our understanding of the molecular basis underlying normal ABCA3 biosynthesis and processing and of the mechanisms of alveolar epithelial cell dysregulation caused by the expression of its mutant forms are beginning to emerge. These insights and the role of environmental factors and modifier genes are discussed in the context of the considerable variability in disease presentation observed in patients with identical ABCA3 gene mutations. Moreover, the opportunities afforded by an enhanced understanding of ABCA3 biology for targeted therapeutic strategies are addressed. PMID- 28025705 TI - Prevalence and predictors of positive screening for postpartum depression in minority parturients in the South Bronx. AB - It is reported that the rates of perinatal depressive disorders are high in ethnic minority groups from non-English speaking countries. However, very few studies have compared the prevalence of positive screening for postpartum depression (PPD) in minority communities living in an inner city. The goal of this study is to determine the prevalence and the predictors of positive screening for postpartum depression in minority parturients in the South Bronx. The study is a chart review of 314 minority parturients, Black or Hispanic, screened for postpartum depression using the Edinburgh Postnatal Depression Scale (EPDS) tool. The overall prevalence of a positive EPDS screen among Black and Hispanic women was similar, 24.04 and 18.75%, respectively. The Black immigrant cohort had comparable positive screens with 23.81 as African Americans. Hispanic women born in the USA had the least prevalence of positive screens, 7.14%, and those who moved from the Dominican Republic and Puerto Rico had a prevalence of 17.24% of positive screens. The women who immigrated from Mexico, Central America, or South America had the highest prevalence of positive screens for PPD, 32.26%. As to the socioeconomic status (SES), there was a significant increase of 27.04 vs. 13.95% (P < 0.019) in positive screens for PPD for the unemployed mothers. Overall, Black and Hispanic parturients had similar rates of positive screens for PPD. Among the Hispanic women, immigrants had higher rates of positive screens, with those from Mexico, Central, and South America as the highest. The hospital experience did not affect the rates of positive screens. Neither did the SES with one exception; those unemployed had the higher rates of positive screens. PMID- 28025706 TI - Does social environment influence learning ability in a family-living lizard? AB - Early developmental environment can have profound effects on individual physiology, behaviour, and learning. In birds and mammals, social isolation during development is known to negatively affect learning ability; yet in other taxa, like reptiles, the effect of social isolation during development on learning ability is unknown. We investigated how social environment affects learning ability in the family-living tree skink (Egernia striolata). We hypothesized that early social environment shapes cognitive development in skinks and predicted that skinks raised in social isolation would have reduced learning ability compared to skinks raised socially. Offspring were separated at birth into two rearing treatments: (1) raised alone or (2) in a pair. After 1 year, we quantified spatial learning ability of skinks in these rearing treatments (N = 14 solitary, 14 social). We found no effect of rearing treatment on learning ability. The number of skinks to successfully learn the task, the number of trials taken to learn the task, the latency to perform the task, and the number of errors in each trial did not differ between isolated and socially reared skinks. Our results were unexpected, yet the facultative nature of this species' social system may result in a reduced effect of social isolation on behaviour when compared to species with obligate sociality. Overall, our findings do not provide evidence that social environment affects development of spatial learning ability in this family-living lizard. PMID- 28025707 TI - Phenotypic plasticity in the common garden snail: big guts and heavier mucus glands compete in snails faced with the dual challenge of poor diet and coarse substrate. AB - Phenotypic plasticity allows animals to manage environmental challenges. Studies aimed at quantifying plasticity often focus on one challenge, such as diet, and one organ system, such the gastrointestinal tract, but this approach may not adequately reflect how plasticity could buffer multiple challenges. Thus, we investigated the outcomes of a dual challenge experiment that fed land snails either a high-fibre (low quality) or a low-fibre (high quality) diet, and simultaneously exercised them daily over 1.2 m on either a smooth surface of polyvinyl chloride (PVC) or a rough sandpaper. By the end of 20 days, snails fed the poor quality diet had a longer crop and oesophagus and a heavier intestine and rectum than those offered a low-fibre diet. Additionally, high-fibre fed snails had a smaller spermoviduct and oviduct. When also exercised on sandpaper, high-fibre fed snails had a smaller digestive gland, a main energy store, than those exercised on PVC. All snails exercised on sandpaper had a heavier pedal mucus gland, used a loping gait and used less mucus than those on PVC plastic, but there was no difference in the average speed of snails on either surface, supporting the conclusion that loping is a mucus conserving gait. Notably, snails faced with both a diet and substrate challenge had a smaller kidney, which could directly effect fecundity. This demonstrates that our dual challenge approach has potential for evaluating the costs and limits of the plasticity necessary to fully appreciate the evolutionary significance of plasticity in snails and other species. PMID- 28025708 TI - LBet 88: a new device for outpatient treatment of selected grade III hemorrhoids. PMID- 28025709 TI - EORTC QLQ-COMU26: a questionnaire for the assessment of communication between patients and professionals. Phase III of the module development in ten countries. AB - PURPOSE: Communication between patients and professionals is one major aspect of the support offered to cancer patients. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group (QLG) has developed a cancer-specific instrument for the measurement of different issues related to the communication between cancer patients and their health care professionals. METHODS: Questionnaire development followed the EORTC QLG Module Development Guidelines. A provisional questionnaire was pre-tested (phase III) in a multicenter study within ten countries from five cultural areas (Northern and South Europe, UK, Poland and Taiwan). Patients from seven subgroups (before, during and after treatment, for localized and advanced disease each, plus palliative patients) were recruited. Structured interviews were conducted. Qualitative and quantitative analyses have been performed. RESULTS: One hundred forty patients were interviewed. Nine items were deleted and one shortened. Patients' comments had a key role in item selection. No item was deleted due to just quantitative criteria. Consistency was observed in patients' answers across cultural areas. The revised version of the module EORTC QLQ-COMU26 has 26 items, organized in 6 scales and 4 individual items. CONCLUSIONS: The EORTC COMU26 questionnaire can be used in daily clinical practice and research, in various patient groups from different cultures. The next step will be an international field test with a large heterogeneous group of cancer patients. PMID- 28025710 TI - Clinical and subclinical bovine leukemia virus infection in a dairy cattle herd in Zambia. AB - Bovine leukemia virus (BLV) causes enzootic bovine leucosis (EBL) and is responsible for substantial economic losses in cattle globally. However, information in Africa on the disease is limited. Here, based on clinical, hematological, pathological and molecular analyses, two clinical cases of EBL were confirmed in a dairy cattle herd in Zambia. In contrast, proviral DNA was detected by PCR in five apparently healthy cows from the same herd, suggesting subclinical BLV infection. Phylogenetic analysis of the env gene showed that the identified BLV clustered with Eurasian genotype 4 strains. This is the first report of confirmed EBL in Zambia. PMID- 28025711 TI - Differential expression of miRNAs and associated gene targets in grapevine leafroll-associated virus 3-infected plants. AB - MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs (sRNA) that play an essential role in the regulation of target mRNAs expressed during plant development and in response to stress. MicroRNA expression profiling has helped to identify miRNAs that regulate a range of processes, including the plant's defence response to pathogens. In this study, differential miRNA expression in own-rooted Vitis vinifera cv. Cabernet Sauvignon plants infected with grapevine leafroll-associated virus 3 was investigated with microarrays and next-generation sequencing (NGS) of sRNA and mRNA. These high-throughput approaches identified several differentially expressed miRNAs. Four miRNAs, identified by both approaches, were validated by stemloop RT-PCRs. Three of the predicted targets of the differentially expressed miRNAs were also differentially expressed in the transcriptome data of infected plants, and were validated by RT-qPCR. Identification of these miRNAs and their targets can lead to a better understanding of host-pathogen interactions involved in grapevine leafroll disease and the identification of possible targets for virus resistance. PMID- 28025712 TI - A cluster of coxsackievirus A21 associated acute respiratory illness: the evidence of efficient transmission of CVA21. AB - In March 2016, a cluster of unexplained respiratory illnesses was reported by the acute respiratory infections (ARI) surveillance system of Guangdong Province, China. Twenty-three high school students and one teacher from the four neighboring classes were admitted to a hospital. CVA21 was found in eight of fourteen patients. Phylogenetic analysis suggested that the CVA21 outbreak was most likely caused by transmission of the virus from person to person. This is the first report of an ARI outbreak caused by CVA21, which suggests that CVA21 has the potential to be transmitted efficiently from person to person and should be closely monitored by clinicians and public health agencies. PMID- 28025713 TI - Cyclic ADP-ribose as an endogenous inhibitor of the mTOR pathway downstream of dopamine receptors in the mouse striatum. AB - The role of cyclic ADP-ribose (cADPR) as a second messenger and modulator of the mTOR pathway downstream of dopamine (DA) receptors and/or CD38 was re-examined in the mouse. ADP-ribosyl activity was low in the membranes of neonates, but DA stimulated it via both D1- and D2-like receptors. ADP-ribosyl cyclase activity increased significantly during development in association with increased expression of CD38. The cADPR binding proteins, FKBP12 and FKBP12.6, were expressed in the adult mouse striatum. The ratio of phosphorylated to non phosphorylated S6 kinase (S6K) in whole mouse striatum homogenates decreased after incubation of adult mouse striatum with extracellular cADPR for 5 min. This effect of cADPR was much weaker in MPTP-treated Parkinson's disease model mice. The inhibitory effects of cADPR and rapamycin were identical. These data suggest that cADPR is an endogenous inhibitor of the mTOR signaling pathway downstream of DA receptors in the mouse striatum and that cADPR plays a certain role in the brain in psychiatric and neurodegenerative diseases. PMID- 28025714 TI - Bone marrow mesenchymal stem cell transplantation improves radiation-induced heart injury through DNA damage repair in rat model. AB - Radiotherapy is an effective form of therapy for most thoracic malignant tumors. However, myocardial injury resulting from the high doses of radiation is a severe complication. Here we aimed to study the possibility of reducing radiation induced myocardial injury with mesenchymal stem cell (MSC) transplantation. We used MSCs extracted from bone marrow (BMSCs) to transplant via the tail vein into a radiation-induced heart injury (RIHI) rat model. The rats were divided into six groups: a Sham group, an IRR (irradiation) group, and four IRR + BMSCs transplantation groups obtained at different time points. After irradiation, BMSC transplantation significantly enhanced the cardiac function in rats. By analyzing the expression of PPAR-alpha, PPAR-gamma, TGF-beta, IL-6, and IL-8, we found that BMSC transplantation alleviated radiation-induced myocardial fibrosis and decreased the inflammatory reaction. Furthermore, we found that expression of gamma-H2AX, XRCC4, DNA ligase4, and TP53BP1, which are associated with DNA repair, was up-regulated, along with increased secretion of growth factors SDF-1, CXCR4, VEGF, and IGF in rat myocardium in the IRR + BMSCs transplantation groups compared with the IRR group. Thus, BMSC transplantation has the potential to improve RIHI via DNA repair and be a new therapeutic approach for patients with myocardial injury. PMID- 28025716 TI - Factors contributing to delays in diagnosis of breast cancers in Ghana, West Africa. AB - BACKGROUND: Late diagnoses and poor prognoses of breast cancer are common throughout Africa. METHODS: To identify responsible factors, we utilized data from a population-based case-control study involving 1184 women with breast malignancies conducted in three hospitals in Accra and Kumasi, Ghana. Interviews focused on potential breast cancer risk factors as well as factors that might contribute to presentation delays. We calculated odds ratios (OR) and 95% confidence intervals (CI) comparing malignances with biopsy masses larger than 5 cm. (62.4% of the 1027 cases with measurable lesions) to smaller lesions. RESULTS: In multivariate analyses, strong predictors of larger masses were limited education (OR 1.96, 95% CI 1.32-2.90 =senior secondary school), being separated/divorced or widowed (1.75, 1.18-2.60 and 2.25, 1.43 3.55, respectively, vs. currently married), delay in care seeking after onset of symptoms (2.64, 1.77-3.95 for >=12 vs. <=2 months), care having initially been sought from someone other than a doctor/nurse (1.86, 0.85-4.09), and frequent use of herbal medications/treatment (1.51, 0.95-2.43 for >=3x/day usage vs. none). Particularly high risks associated with these factors were found among less educated women; for example, women with less than junior secondary schooling who delayed seeking care for breast symptoms for 6 months or longer were at nearly 4 times the risk of more educated women who promptly sought assistance. CONCLUSIONS: Our findings suggest that additional communication, particularly among less educated women, could promote earlier breast cancer diagnoses. Involvement of individuals other than medical practitioners, including traditional healers, may be helpful in this process. PMID- 28025717 TI - Functioning in patients with schizophrenia: a systematic review of the literature using the International Classification of Functioning, Disability and Health (ICF) as a reference. AB - PURPOSE: To identify and quantify the main concepts included in published studies focusing on individuals with schizophrenia using the International Classification of Functioning, Disability and Health (ICF). METHODS: Searches (limited to those published from 2008 to 2012) were performed in MEDLINE, PsycINFO and CINAHL. Included studies described participants with schizophrenia, were original articles and included only subjects who were at least 18 years of age at study entry. All concepts underlying the measures and the text of the articles were extracted, and they were linked to ICF categories using standardized rules. RESULTS: From the 3584 abstracts retrieved, 348 were randomly selected, and of these, 206 studies met the inclusion criteria. A total of 17,141 concepts were extracted, 84.8% of which could be linked to 491 ICF categories: 222 (45.21%) of the categories referred to Body Functions, 29 (5.91%) to Body Structures, 186 (37.88%) to Activities and Participation and 54 (11%) to Environmental Factors. Seventy second-level categories were reported in at least 5% of all studies: 30 of these categories referred to Body Functions, 2 to Body Structures, 34 to Activities and Participation and 4 to Environmental Factors. CONCLUSION: The study has allowed us to identify and quantify the main concepts included in studies focusing on people with schizophrenia using the ICF. The majority of the concepts refer to Body Functions and Activities and Participation, rather than to Body Structures and Environmental Factors. PMID- 28025718 TI - Conformational changes during human P2X7 receptor activation examined by structural modelling and cysteine-based cross-linking studies. AB - The P2X7 receptor (P2X7R) is important in mediating a range of physiological functions and pathologies associated with tissue damage and inflammation and represents an attractive therapeutic target. However, in terms of their structure function relationships, the mammalian P2X7Rs remain poorly characterised compared to some of their other P2XR counterparts. In this study, combining cysteine-based cross-linking and whole-cell patch-clamp recording, we examined six pairs of residues (A44/I331, D48/I331, I58/F311, S60/L320, I75/P177 and K81/V304) located in different parts of the extracellular and transmembrane domains of the human P2X7R. These residues are predicted to undergo substantial movement during the transition of the receptor ion channel from the closed to the open state, predictions which are made based on structural homology models generated from the crystal structures of the zebrafish P2X4R. Our results provide evidence that among the six pairs of cysteine mutants, D48C/I133C and K81C/V304C formed disulphide bonds that impaired the channel gating to support the notion that such conformational changes, particularly those in the outer ends of the transmembrane domains, are critical for human P2X7R activation. PMID- 28025715 TI - Alzheimer's disease: experimental models and reality. AB - Experimental models of Alzheimer's disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the formation of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies would help enhance the success of therapy translation from preclinical studies to patients. In this review, we summarize the pathological features and limitations of the major experimental models of AD, including transgenic mice, transgenic rats, various physiological models of sporadic AD and in vitro human cell culture models. PMID- 28025720 TI - Reliability of drug-induced sedation endoscopy: a methodological issue. PMID- 28025719 TI - Cabergoline in acromegaly. AB - Acromegaly, a rare disease due to growth hormone (GH) hypersecretion by a pituitary adenoma, is associated with severe comorbidity and premature death if not adequately treated. The usual first-line treatment is surgery. Various drugs, including somatostatin receptor ligands, dopamine agonists and GH receptor antagonists, are now available for use if surgery fails to suppress GH/IGF-I hypersecretion. Cabergoline, now the preferred dopamine agonist for treating hyperprolactinemia, is also used off-label for treating acromegaly. Cabergoline monotherapy is reported to normalize IGF-I levels in more than one-third of patients with acromegaly. When a somatostatin receptor ligand proves ineffective, cabergoline add-on therapy normalizes the IGF-I level in 40-50% of patients. Finally, when combined with the GH receptor antagonist pegvisomant in patients with mild uncontrolled disease, cabergoline helps to achieve normal IGF-I levels while avoiding the need for high-dose pegvisomant. Cabergoline is also inexpensive and well tolerated; in particular, it does not appear to promote heart valve disease. PMID- 28025721 TI - Family Relations and Psychopathology: Examining Depressive and Bulimic Symptomatology. AB - Despite early theories suggesting that family dysfunction (FD) may cause disordered eating, FD has been linked with other disorders and is a non-specific risk factor for disordered eating. We examined one potential model of the way FD relates to disordered eating, drawing on research that identified depression as a risk factor for bulimia. We examined whether depression symptoms (DEPs) partially mediated the relationship between family cohesion (as a measure of FD) and bulimic symptoms (BNs) using a sample of 215 never-married college women under age 20. Perceptions that one's family was less cohesive (or more disengaged) was associated with increased DEPs and BNs. Moreover, DEPs partially mediated the influence of cohesion on BNs through a significant indirect effect. Both family systems in general and treatment of mood difficulties may be important considerations in the prevention of disordered eating, and prevention efforts that include family relationships should be experimentally explored. PMID- 28025722 TI - Quantified coronary frequency domain optical coherence tomography signal analysis for the evaluation of erythrocyte-rich thrombus: ex-vivo validation study. AB - Previous study has demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in myocardial infarction. The aim of this study is to investigate the utility of quantified frequency domain optical coherence tomography (FD-OCT) signal analysis in evaluating the erythrocyte-rich thrombus with ex-vivo materials. We evaluated 54 specimens of coronary artery thrombus obtained by thrombectomy catheter from 8 patients who underwent primary percutaneous coronary intervention. The thrombi were immersed in saline immediately after thrombectomy and FD-OCT image acquisition was performed ex vivo. Quantitative analysis for all contiguous frames was performed by the dedicated automated software (OCT system software, Light Lab Inc.). For the maximum thrombus area, mean signal intensity (MSI) and normalized standard deviation of signal (NSD) was evaluated. All thrombi were stained using double staining of phosphotungstic acid-hematoxylin and eosin to enable automatic extraction of erythrocyte from fibrin. Computer-assisted analysis was performed using dedicated image processing software (WinROOF, Mitani Corp., Tokyo, Japan) for color identification of the erythrocyte area. Erythrocyte-rich thrombus, defined as % erythrocyte [(erythrocyte area/total thrombus area) * 100] >= 10%, showed significantly lower MSI [4.39 +/- 0.24 vs. 4.74 +/- 0.35, p = 0.002] than that of <10%. The cut-off point for prediction of erythrocyte-rich thrombus was defined as MSI <= 4.56, sensitivity: 87.5%, specificity: 82.9%, area under the curve: 0.836, respectively). The present ex-vivo study suggested the utility of quantified FD-OCT signal analysis on the detection of erythrocyte-rich thrombus. PMID- 28025723 TI - Polyneuropathy with demyelinating changes in Churg-Strauss syndrome: an unusual association. PMID- 28025724 TI - Safety and Efficacy of Anti-Amyloid-beta Immunotherapy in Alzheimer's Disease: A Systematic Review and Meta-Analysis. AB - Immunotherapeutics targeting amyloid-beta (Abeta) have had mixed results in clinical trials. The present study aims to evaluate the safety and clinical efficacy of immunotherapeutic agents targeting Abeta in Alzheimer's disease. Randomised controlled trials of at least two weeks duration were included in the review. Fourteen randomised controlled trials (n = 5554) were identified in a systematic search of eight electronic databases. Upon pooling of data, there was no increased risk of any adverse event, serious adverse events, or death with the exception of a near fivefold increase in amyloid-related imaging abnormalities (ARIA; OR 4.79, 95% CI 1.24-18.55; p = 0.02). Of the cognitive indicators, the Mini-Mental State Examination (MMSE) showed a small statistically significant improvement (diff in means =0.44; p = 0.02), while the others (ADAS-cog, ADCS ADL, and CDR-sb) showed no change. Therefore, immunotherapeutic agents have been relatively well tolerated, with some promise for cognitive improvements if the occurrence of ARIA can be mitigated. PMID- 28025725 TI - Theory-Based Interventions to Improve Medication Adherence in Older Adults Prescribed Polypharmacy: A Systematic Review. AB - BACKGROUND: Previous interventions have shown limited success in improving medication adherence in older adults, and this may be due to the lack of a theoretical underpinning. OBJECTIVE: This review sought to determine the effectiveness of theory-based interventions aimed at improving medication adherence in older adults prescribed polypharmacy and to explore the extent to which psychological theory informed their development. DATA SOURCES: Eight electronic databases were searched from inception to March 2015, and extensive hand-searching was conducted. ELIGIBILITY CRITERIA: Interventions delivered to older adults (populations with a mean/median age of >=65 years) prescribed polypharmacy (four or more regular oral/non-oral medicines) were eligible. Studies had to report an underpinning theory and measure at least one adherence and one clinical/humanistic outcome. REVIEW METHODS: Data were extracted independently by two reviewers and included details of intervention content, delivery, providers, participants, outcomes and theories used. The theory coding scheme (TCS) was used to assess the extent of theory use. RESULTS: Five studies cited theory as the basis for intervention development (social cognitive theory, health belief model, transtheoretical model, self-regulation model). The extent of theory use and intervention effectiveness in terms of adherence and clinical/humanistic outcomes varied across studies. No study made optimal use of theory as recommended in the TCS. CONCLUSIONS: The heterogeneity observed and inclusion of pilot designs mean conclusions regarding effectiveness of theory based interventions targeting older adults prescribed polypharmacy could not be drawn. Further primary research involving theory as a central component of intervention development is required. The review findings will help inform the design of future theory-based adherence interventions. PMID- 28025726 TI - Management of HCV infection in the penitentiary setting in the direct-acting antivirals era: practical recommendations from an expert panel. AB - BACKGROUND: The prevalence of HCV infection is higher among prisoners than in the general population. The introduction of HCV direct-acting antivirals (DAA) holds the potential to improve clinical outcomes also in inmates. However, treatment of hepatitis C in inmates has to face several clinical and logistical issues which are peculiar of prison environment. Recommendations on the management of HCV infection specific for the penitentiary setting in the DAA era remain scant. The Italian Society for Penitentiary Medicine and Healthcare has, therefore, issued these recommendations, to provide clinicians with a guide for the comprehensive management of HCV infection in the restriction setting, taking into account its peculiar characteristics. RESULTS: Dedicated diagnostic and treatment procedures should be established in each prison. In particular, the use of DAAs appears crucial to provide patients with an effective therapeutic option, able to overcome the limitations of IFN-based regimens with a short period of treatment. DAA treatment should be initiated as soon as possible in all eligible subjects with the aim to cure the patient, as well as to limit the transmission of HCV infection both inside the penitentiary system and to the free community, once the inmates ends his/her release. Importantly, efforts should be made to open a discussion with regulatory bodies, to define specific regulations aimed to guarantee wide access to effective therapies of all eligible patients, to optimize the management of and the adherence to the HCV treatment, and to ensure the therapeutic continuity after discharge from prison. PMID- 28025727 TI - Efficacy of Switching from Infliximab to Subcutaneous Golimumab in Patients with Rheumatoid Arthritis to Control Disease Activity or Adverse Events. AB - BACKGROUND: Some rheumatoid arthritis (RA) patients initially respond to treatment with infliximab (IFX), but subsequently their responsiveness decreases. OBJECTIVES: Our objective was to evaluate the efficacy and safety of switching from IFX to subcutaneous golimumab (GLM-SC) in RA patients. METHODS: Thirty-three patients who had been treated for a mean 4.4 years with IFX (3-6 mg/kg/8 weeks) were switched to GLM-SC to control disease activity or adverse events. The patients with low disease activity (LDA) or remission were divided into two groups: the LDA group and the LDA every 8 weeks (q8w) group, which included patients with LDA or remission who switched to GLM therapy with 50 mg at 4- and 8 week intervals, respectively. The moderate disease activity (MDA) group included patients with MDA who switched to GLM therapy with 50 mg at 4-week intervals. Effects of the IFX to GLM-SC switch were evaluated at weeks 12, 24, and 52 after switching. RESULTS: The mean disease activity score 28-ESR and -C-reactive protein values in the LDA and LDAq8w groups were maintained from baseline throughout the 52-week treatment period. The mean disease activity score 28 values at 12, 24, and 52 weeks in the MDA group were improved significantly compared with baseline. Treatment discontinuations due to adverse events occurred in one patient in the MDA group, and no serious adverse events occurred during the observation period in the LDA group or the LDAq8w group. The GLM continuation rates at 52 weeks were 100% in the LDA and LDAq8w groups and 83.3% in the MDA group. Thus, GLM-SC treatment regimens were effective in controlling disease activity and improving the clinical response related to adverse events caused by IFX. CONCLUSION: The clinical efficacy of GLM-SC was sustained or improved in patients who switched from IFX without serious safety concerns. PMID- 28025728 TI - Semiautomatic classification of acetabular shape from three-dimensional ultrasound for diagnosis of infant hip dysplasia using geometric features. AB - PURPOSE: Developmental dysplasia of the hip (DDH) is a congenital deformity which in severe cases leads to hip dislocation and in milder cases to premature osteoarthritis. Image-aided diagnosis of DDH is partly based on Graf classification which quantifies the acetabular shape seen at two-dimensional ultrasound (2DUS), which leads to high inter-scan variance. 3D ultrasound (3DUS) is a promising alternative for more reliable DDH diagnosis. However, manual quantification of acetabular shape from 3DUS is cumbersome. METHODS: Here, we (1) propose a semiautomated segmentation algorithm to delineate 3D acetabular surface models from 3DUS using graph search; (2) propose a fully automated method to classify acetabular shape based on a random forest (RF) classifier using features derived from 3D acetabular surface models; and (3) test diagnostic accuracy on a dataset of 79 3DUS infant hip recordings (36 normal, 16 borderline, 27 dysplastic based on orthopedic surgeon assessment) in 42 patients. For each 3DUS, we performed semiautomated segmentation to produce 3D acetabular surface models and then calculated geometric features including the automatic [Formula: see text]lpha (AA), acetabular contact angle (ACA), kurtosis (K), skewness (S) and convexity (C). Mean values of features obtained from surface models were used as inputs to train a RF classifier. RESULTS: Surface models were generated rapidly (user time 46.2 s) via semiautomated segmentation and visually closely correlated with actual acetabular contours (RMS error 1.39 +/- 0.7 mm). A paired nonparametric u test on of feature values in each category showed statistically significant variation (p < 0.001) for AA, ACA and convexity. The RF classifier was 100 % specific and 97.2 % sensitive in classifying normal versus dysplastic hips and yielded true positive rates of 94.4, 62.5 and 89.9 % for normal, borderline and dysplastic hips. CONCLUSIONS: The proposed technique reduces the subjectivity of image-aided DDH diagnosis and could be useful in clinical practice. PMID- 28025729 TI - Impact of elevated temperatures on specific leaf weight, stomatal density, photosynthesis and chlorophyll fluorescence in soybean. AB - High-temperature stress is a major environmental stress and there are limited studies elucidating its impact on soybean (Glycine max L. Merril.). The objectives of present study were to quantify the effect of high temperature on changes in leaf thickness, number of stomata on adaxial and abaxial leaf surfaces, gas exchange, chlorophyll fluorescence parameters and seed yield in soybean. Twelve soybean genotypes were grown at day/night temperatures of 30/22, 34/24, 38/26 and 42/28 degrees C with an average temperature of 26, 29, 32 and 35 degrees C, respectively, under greenhouse conditions. One set was also grown under ambient temperature conditions where crop season average maximum, minimum and mean temperatures were 28.0, 22.4 and 25.2 degrees C, respectively. Significant negative effect of temperature was observed on specific leaf weight (SLW) and leaf thickness. Rate of photosynthesis, stomatal conductance and water use efficiency declined as the growing temperatures increased; whereas, intercellular CO2 and transpiration rate were increased. With the increase in temperature chlorophyll fluorescence parameters such as Fv/Fm, qP and PhiPSII declined while there was increase in qN. Number of stomata on both abaxial and adaxial surface of leaf increased significantly with increase in temperatures. The rate of photosynthesis, PhiPSII, qP and SPAD values were positively associated with leaf thickness and SLW. This indicated that reduction in photosynthesis and associated parameters appears to be due to structural changes observed at higher temperatures. The average seed yield was maximum (13.2 g/pl) in plants grown under ambient temperature condition and declined by 8, 14, 51 and 65% as the temperature was increased to 30/22, 34/24, 38/26 and 42/28 degrees C, respectively. PMID- 28025730 TI - Automated Facial Recognition of Computed Tomography-Derived Facial Images: Patient Privacy Implications. AB - The recognizability of facial images extracted from publically available medical scans raises patient privacy concerns. This study examined how accurately facial images extracted from computed tomography (CT) scans are objectively matched with corresponding photographs of the scanned individuals. The test subjects were 128 adult Americans ranging in age from 18 to 60 years, representing both sexes and three self-identified population (ancestral descent) groups (African, European, and Hispanic). Using facial recognition software, the 2D images of the extracted facial models were compared for matches against five differently sized photo galleries. Depending on the scanning protocol and gallery size, in 6-61 % of the cases, a correct life photo match for a CT-derived facial image was the top ranked image in the generated candidate lists, even when blind searching in excess of 100,000 images. In 31-91 % of the cases, a correct match was located within the top 50 images. Few significant differences (p > 0.05) in match rates were observed between the sexes or across the three age cohorts. Highly significant differences (p < 0.01) were, however, observed across the three ancestral cohorts and between the two CT scanning protocols. Results suggest that the probability of a match between a facial image extracted from a medical scan and a photograph of the individual is moderately high. The facial image data inherent in commonly employed medical imaging modalities may need to consider a potentially identifiable form of "comparable" facial imagery and protected as such under patient privacy legislation. PMID- 28025731 TI - Development and Evaluation of a Semi-automated Segmentation Tool and a Modified Ellipsoid Formula for Volumetric Analysis of the Kidney in Non-contrast T2 Weighted MR Images. AB - Volumetric analysis of the kidney parenchyma provides additional information for the detection and monitoring of various renal diseases. Therefore the purposes of the study were to develop and evaluate a semi-automated segmentation tool and a modified ellipsoid formula for volumetric analysis of the kidney in non-contrast T2-weighted magnetic resonance (MR)-images. Three readers performed semi automated segmentation of the total kidney volume (TKV) in axial, non-contrast enhanced T2-weighted MR-images of 24 healthy volunteers (48 kidneys) twice. A semi-automated threshold-based segmentation tool was developed to segment the kidney parenchyma. Furthermore, the three readers measured renal dimensions (length, width, depth) and applied different formulas to calculate the TKV. Manual segmentation served as a reference volume. Volumes of the different methods were compared and time required was recorded. There was no significant difference between the semi-automatically and manually segmented TKV (p = 0.31). The difference in mean volumes was 0.3 ml (95% confidence interval (CI), -10.1 to 10.7 ml). Semi-automated segmentation was significantly faster than manual segmentation, with a mean difference = 188 s (220 vs. 408 s); p < 0.05. Volumes did not differ significantly comparing the results of different readers. Calculation of TKV with a modified ellipsoid formula (ellipsoid volume * 0.85) did not differ significantly from the reference volume; however, the mean error was three times higher (difference of mean volumes -0.1 ml; CI -31.1 to 30.9 ml; p = 0.95). Applying the modified ellipsoid formula was the fastest way to get an estimation of the renal volume (41 s). Semi-automated segmentation and volumetric analysis of the kidney in native T2-weighted MR data delivers accurate and reproducible results and was significantly faster than manual segmentation. Applying a modified ellipsoid formula quickly provides an accurate kidney volume. PMID- 28025732 TI - Liver Ultrasound Image Segmentation Using Region-Difference Filters. AB - In this paper, region-difference filters for the segmentation of liver ultrasound (US) images are proposed. Region-difference filters evaluate maximum difference of the average of two regions of the window around the center pixel. Implementing the filters on the whole image gives region-difference image. This image is then converted into binary image and morphologically operated for segmenting the desired lesion from the ultrasound image. The proposed method is compared with the maximum a posteriori-Markov random field (MAP-MRF), Chan-Vese active contour method (CV-ACM), and active contour region-scalable fitting energy (RSFE) methods. MATLAB code available online for the RSFE method is used for comparison whereas MAP-MRF and CV-ACM methods are coded in MATLAB by authors. Since no comparison is available on common database for the performance of the three methods, therefore, performance comparison of the three methods and proposed method was done on liver US images obtained from PGIMER, Chandigarh, India and from online resource. A radiologist blindly analyzed segmentation results of the 4 methods implemented on 56 images and had selected the segmentation result obtained from the proposed method as best for 46 test US images. For the remaining 10 US images, the proposed method performance was very near to the other three segmentation methods. The proposed segmentation method obtained the overall accuracy of 99.32% in comparison to the overall accuracy of 85.9, 98.71, and 68.21% obtained by MAP-MRF, CV-ACM, and RSFE methods, respectively. Computational time taken by the proposed method is 5.05 s compared to the time of 26.44, 24.82, and 28.36 s taken by MAP-MRF, CV-ACM, and RSFE methods, respectively. PMID- 28025733 TI - Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases. AB - INTRODUCTION: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. OBJECTIVE: We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients. METHODS: A large, multi-database, population based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000-2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]). RESULTS: We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [ORadj] 3.22, 95% CI 2.57-4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest ORadj of 1.86 (95% CI 1.08 3.21) for amoxicillin to the highest ORadj of 24.16 (95% CI 11.78-49.54) for cotrimoxazole (i.e. sulphamethoxazole/trimethoprim) and 26.70 (95% CI 12.09 58.96) for ceftriaxone. Sensitivity analyses confirm the associations for ceftriaxone, cotrimoxazole, and clarithromycin. CONCLUSION: Antibiotic-induced liver injury in children is heterogeneous across the use of individual antibiotics. When prescribing ceftriaxone, cotrimoxazole and clarithromycin in children, paediatricians should definitely be aware of their potential risk of liver injury, even if for short periods. PMID- 28025734 TI - Reaching Key Populations: PrEP Uptake in an Urban Health Care System in the Bronx, New York. AB - Pre-exposure prophylaxis (PrEP) has been established as an effective HIV prevention tool, but real world studies are limited. To inform dissemination efforts, we sought to describe individuals prescribed PrEP in the largest health care system in the Bronx, New York, an urban region with a high burden of HIV. We used a clinical database and chart review to identify individuals prescribed PrEP between 2011 and 2015 (n = 108). A majority were Black and Hispanic, half were men who have sex with men, and nearly a third were cisgender women who have sex with men. Primary care settings were the most common site of PrEP prescription and PrEP prescription rates increased over time. Despite reaching a diverse patient population, PrEP prescribing rates were low, underscoring the urgent need for PrEP scale-up. PMID- 28025736 TI - Drug use Discrimination Predicts Formation of High-Risk Social Networks: Examining Social Pathways of Discrimination. AB - Experiences of discrimination, or social marginalization and ostracism, may lead to the formation of social networks characterized by inequality. For example, those who experience discrimination may be more likely to develop drug use and sexual partnerships with others who are at increased risk for HIV compared to those without experiences of discrimination. This is critical as engaging in risk behaviors with others who are more likely to be HIV positive can increase one's risk of HIV. We used log-binomial regression models to examine the relationship between drug use, racial and incarceration discrimination with changes in the composition of one's risk network among 502 persons who use drugs. We examined both absolute and proportional changes with respect to sex partners, drug use partners, and injecting partners, after accounting for individual risk behaviors. At baseline, participants were predominately male (70%), black or Latino (91%), un-married (85%), and used crack (64%). Among those followed-up (67%), having experienced discrimination due to drug use was significantly related to increases in the absolute number of sex networks and drug networks over time. No types of discrimination were related to changes in the proportion of high-risk network members. Discrimination may increase one's risk of HIV acquisition by leading them to preferentially form risk relationships with higher-risk individuals, thereby perpetuating racial and ethnic inequities in HIV. Future social network studies and behavioral interventions should consider whether social discrimination plays a role in HIV transmission. PMID- 28025735 TI - Examining the Acceptability of mHealth Technology in HIV Prevention Among High Risk Drug Users in Treatment. AB - Despite promising trends of the efficacy of mobile health (mHealth) based strategies to a broad range of health conditions, very few if any studies have been done in terms of the examining the use of mHealth in HIV prevention efforts among people who use drugs in treatment. Thus, the goal of this study was to gain insight into the real-world acceptance of mHealth approaches among high-risk people who use drugs in treatment. A convenience sample of 400 HIV-negative drug users, who reported drug- and/or sex-related risk behaviors, were recruited from a methadone clinic in New Haven, Connecticut. Participants completed standardized assessments of drug- and sex-related risk behaviors, neurocognitive impairment (NCI), and measures of communication technology access and utilization, and mHealth acceptance. We found a high prevalence of current ownership and use of mobile technologies, such as cell phone (91.5%) including smartphone (63.5%). Participants used mobile technologies to communicate mostly through phone calls (M = 4.25, SD = 1.24), followed by text messages (M = 4.21, SD = 1.29). Participants expressed interest in using mHealth for medication reminders (72.3%), receive information about HIV (65.8%), and to assess drug-related (72.3%) and sex-related behaviors (64.8%). Furthermore, participants who were neurocognitively impaired were more likely to use cell phone without internet and show considerable interest in using mHealth as compared to those without NCI. The findings from this study provide empirical evidence that mHealth-based programs, specifically cell phone text messaging-based health programs, may be acceptable to this high-risk population. PMID- 28025737 TI - Substance Use and Sexual Risk Behavior Among Black South African Men Who Have Sex With Men: The Moderating Effects of Reasons for Drinking and Safer Sex Intentions. AB - Research studies suggest an association between substance use and sexual risk behavior, but are not completely consistent. The moderating effects of other psychosocial factors might help explain these inconsistencies. The current study therefore assessed whether substance use is associated with sexual risk behavior, and whether this relationship is modified by expectancies about the effects of alcohol, reasons for consuming alcohol, or intentions to engage in safe sex. A cross-sectional survey was conducted among 480 black South African men who have sex with men recruited using respondent-driven sampling. In multivariable analyses, the effect of alcohol use on unprotected receptive anal intercourse (URAI) was modified by drinking to enhance social interaction (R2 change = 0.03, p < 0.01). The effect of drug use on URAI was modified by safe sex intentions (R2 change = 0.03, p < 0.001). Alcohol use was positively associated with URAI only among those who drink to enhance social interaction (beta = 0.08, p < 0.05). Drug use was positively associated with URAI only among those with high safe sex intentions (beta = 0.30, p < 0.001). Our findings suggest that efforts to minimize the impact of substance use on HIV risk behavior should target men who drink to enhance social interaction and men who intend to engage in safer sex. Efforts made to increase safer sex intentions as a way to reduce HIV risk behavior should additionally consider the effects of substance use. PMID- 28025738 TI - Community-Based Accompaniment and the Impact of Distance for HIV Patients Newly Initiated on Antiretroviral Therapy: Early Outcomes and Clinic Visit Adherence in Rural Rwanda. AB - Community-based accompaniment (CBA) has been associated with improved antiretroviral therapy (ART) patient outcomes in Rwanda. In contrast, distance has generally been associated with poor outcomes. However, impact of distance on outcomes under the CBA model is unknown. This retrospective cohort study included 537 adults initiated on ART in 2012 in two rural districts in Rwanda. The primary outcomes at 6 months after ART initiation included overall program status, missed a visit and missed three consecutive visits. The associations between cost surface distance (straight-line distance adjusted for surface features) and outcomes were assessed using logistic regression, controlling for potential confounders. Died/lost-to-follow-up and missed three consecutive visits were not associated with distance. Patients within 0-1 km cost surface distance were significantly more likely to miss a visit, potentially due to stigma of attending clinic within one's community. These results suggest that CBA may mediate the impact of long distances on outcomes. PMID- 28025739 TI - Parastomal hernia following cystectomy and ileal conduit urinary diversion: a systematic review. AB - PURPOSE: The natural history of development of Parastomal hernia (PH) following cystectomy and ileal conduit diversion is poorly understood. The aim of this study was to systematically review the frequency and risk factors of PH following ileal conduit diversion. METHODS: A systematic review of literature was performed and the Cochrane, EMBASE and PubMed databases were searched from 1st January 1985 to 30th April 2016. All articles reporting occurrence of PH following cystectomy and ileal conduit diversion were analysed. The primary outcome measure was the frequency of development of PH. Secondary outcome measures were risk factors for PH development, complications of PH, frequency of PH repair and recurrence of PH. RESULTS: Twelve articles of the 63 originally identified were analysed. Sample sizes ranged from 36 to 1057 patients with a pooled total of 3170 undergoing ileal conduit surgery. Age at the time of surgery ranged from 31 to 92 years. Of the 3170 patients who underwent ileal conduit surgery, 529 patients (17.1%) developed a PH based on either clinical examination or cross sectional imaging. Female gender, high BMI, low preoperative albumin and previous laparotomy were significantly associated with the development of PH in two studies. Repair of PH was offered to 8-75% of patients. The rate of recurrence following repair of PH was reported to range from 27 to 50%. CONCLUSION: A PH is frequent following cystectomy and ileal conduit urinary diversion. The diagnosis of a PH depends upon duration of clinical follow-up and the use of cross-sectional imaging. The recurrence rates following the repair of a PH remain substantial. PMID- 28025740 TI - Long-term follow-up of laparoscopic total extraperitoneal (TEP) repair in inguinal hernia without mesh fixation. AB - PURPOSE: From the current evidence, non-fixation of the mesh (NMF) in laparoscopic total extraperitoneal (TEP) repair appears to be a safe alternative for inguinal hernia patients in the short term. This study aims to demonstrate that NMF is as effective in the long term by following up a large number of patients with a mean follow-up of 6 years. The primary outcomes are chronic pain and recurrence rate. METHODS: A thorough review of medical records was conducted from a prospectively maintained database of 538 patients who underwent a laparoscopic TEP inguinal hernia repair by a single surgeon working in Sydney from the year 2005 to 2010. Patient demographics, perioperative outcomes, and postoperative complications were extracted from this database. All these patients were then interviewed using a modified questionnaire based on Franneby et al. [10]. RESULT: 538 patients had TEP repair between 2005 and 2010. Out of this 11 were excluded as tacks were used for fixation of mesh. Out of the 649 repairs done on 527 patients during this period, 463 hernia repairs in 387 patients could be followed up with a mean follow-up of 6 years and 4 months. The mean age of patients was 63 years. Overall, there were seven (1.5%) recurrences, and the incidence of chronic pain was 1%, however 2.9% patients in total complained of pain. CONCLUSION: This is the only study in literature having a long-term follow up of more than 5 years for the patients having inguinal hernia repair by TEP technique without mesh fixation. It demonstrates that fixation of mesh with tacks or glue is unnecessary for TEP repair of inguinal hernia. PMID- 28025741 TI - Prospective study evaluating the impact of severity of chronic pain on quality of life after inguinal hernioplasty. AB - PURPOSE: The definition of chronic pain after inguinal hernioplasty and the methods of its assessment vary a great deal, which make it complicated to conduct meta-analyses. The primary aim of the present prospective study was to evaluate at which pain severity degree the quality-of-life scores will be reduced. METHOD: A prospective study of patients operated for inguinal hernia was conducted. A pain questionnaire and a quality-of-life (QoL) questionnaire were completed. RESULTS: Altogether, 370 patients were investigated and included in analysis. Of them, 33.8% experienced pain during different activities. Compared to the non pain response group, significantly lower QoL scores for the Bodily pain domain were reported by patients who gave 1, 2, or 3 positive responses to the pain questionnaire. Patients with no pain as well as patients who gave 1 positive response to the pain questionnaire and whose VAS score was <=20 had similar QoL scores for all domains. Patients who gave 1 positive response to the pain questionnaire and whose VAS score was >20, and patients who gave two or more positive responses to the pain questionnaire, showed significantly lower QoL scores in most of the domains compared with the non-pain group. When the patients who gave 1 positive response to the pain questionnaire and whose VAS score was <=20 were excluded from the group of patients with pain, the rate of chronic pain was 19.7%. Considering the above result, the reduction in the rate of chronic pain from 33.8 to 19.7% was statistically significant. CONCLUSION: Pain scores 20 mm or less on the VAS (0 to 100 mm) have no impact on the patients' quality of life. Uniform assessment methods of chronic pain should be developed to improve the quality of research. PMID- 28025742 TI - Loss-of-function of PTPR gamma and zeta, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice. AB - RATIONALE: The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. OBJECTIVE: Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG -/- , PTPRZ -/- , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. RESULTS: The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ -/- mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO. CONCLUSION: PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy. PMID- 28025743 TI - Relationship between organochlorine pesticides and stress indicators in hawksbill sea turtle (Eretmochelys imbricata) nesting at Punta Xen (Campeche), Southern Gulf of Mexico. AB - Data on the impact of environmental pollution on the homeostasis of sea turtles remains scarce, particularly in the Southern Gulf of Mexico. As many municipalities along the coastline of the Yucatan Peninsula do not rely on a waste treatment plant, these organisms could be particularly vulnerable. We searched for relationships between the presence of organochlorine pesticides (OCP) and the level of several oxidative and pollutant stress indicators of the hawksbill sea turtle (Eretmochelys imbricata) during the 2010 nesting season at Punta Xen (Campeche, Mexico). Of the 30 sampled sea turtles, endosulfans, aldrin related (aldrin, endrin, dieldrin, endrin ketone, endrin aldehyde) and dichlorodiphenyldichloroethylene (DDT) families were detected in 17, 21 and 26, respectively. Significant correlation existed between the size of sea turtles with the concentration of methoxychlor, cholinesterase activity in plasma and heptachlors family, and catalase activity and hexachlorohexane family. Cholinesterase activity in washed erythrocytes and lipid peroxidation were positively correlated with glutathione reductase activity. Antioxidant enzyme actions seem adequate as no lipids damages were correlated with any OCPs. Future studies are necessary to evaluate the effect of OCPs on males of the area due to the significant detection of methoxychlor, which target endocrine functioning and increases its concentration with sea turtles size. PMID- 28025745 TI - MicroRNA-98 Suppress Warburg Effect by Targeting HK2 in Colon Cancer Cells. AB - BACKGROUND: Warburg effect is a hallmark of cancer cells. Accumulating evidence suggests that microRNAs (miRs) could regulate such metabolic reprograming. Aberrant expression of miR-98 has been observed in many types of cancers. However, its functions and significance in colon cancer remain largely elusive. AIMS: To investigate miR-98 expression and the biological functions in colon cancer progression. METHODS: miR-98 expression levels were determined by quantitative RT-PCR in 215 cases of colon cancer samples. miR-98 mimic or inhibitor was used to test the biological functions in SW480 and HCT116 cells, followed by cell proliferation assay, lactate production, glucose uptake, and cellular ATP levels assay and extracellular acidification rates measurement. Western blot and luciferase assay were used to identify the target of miR-98. RESULTS: miR-98 was significantly down-regulated in colon cancer tissues compared to adjacent colon tissues and acted as a suppressor for Warburg effect in cancer cells. miR-98 inhibited glycolysis by directly targeting hexokinase 2, or HK2, illustrating a novel pathway to mediate Warburg effect of cancer cells. In vitro experiments further indicated that HK2 was involved in miR-98-mediated suppression of glucose uptake, lactate production, and cell proliferation. In addition, we detected HK2 expression in colon cancer tissues and found that the expressions of miR-98 and HK2 were negatively correlated. CONCLUSION: miR-98 acts as tumor suppressor gene and inhibits Warburg effect in colon cancer cells, which provided potential targets for clinical treatments. PMID- 28025744 TI - Soluble Syndecan-1: A Novel Biomarker of Small Bowel Mucosal Damage in Children with Celiac Disease. AB - BACKGROUND: Syndecan-1 (SDC1) is essential for maintaining normal epithelial barrier. Shedding of SDC1 ectodomain, reflected by serum soluble syndecan-1 (SSDC1) levels, is regulated by inflammation. Increased intestinal permeability plays a central role in celiac disease (CD). The association between SSDC1 levels and mucosal damage in CD has not been evaluated. AIMS: To evaluate serum SSDC1 levels in children with CD and to determine its relationship with histological grading classified by modified Marsh criteria. METHODS: This is a cross sectional, pilot study, in which serum SSDC1 was analyzed by ELISA in a cohort of 49 untreated children with CD and 15 children with nonspecific abdominal pain (AP). CD was diagnosed based on positive celiac serology and small intestinal biopsy. SSDC1 levels at the time of biopsy were correlated with Marsh grading. Controls were defined by AP, negative celiac serology, normal upper endoscopy, and small intestinal biopsies. RESULTS: SSDC1 levels were significantly higher in CD patients compared to AP controls (116.2 +/- 161 vs. 41.3 +/- 17.5 ng/ml, respectively, p < 0.01). SSDC1 levels were significantly higher in patients with Marsh 3c lesion compared to AP controls (170.6 +/- 201 vs. 41.3 +/- 17.5 ng/ml, respectively, p < 0.05). SSDC1 concentrations displayed a significant correlation with mucosal damage defined by Marsh (r = 0.39, p < 0.05). CONCLUSION: This is the first study demonstrating elevated levels of serum SSDC1 in children with CD. Our results suggest that SSDC1 is a potentially novel marker of intestinal mucosal damage in patients with CD. Its applicability as a surrogate biomarker in CD remains to be determined. PMID- 28025746 TI - Gender-Specific Differences in Baseline, Peak, and Delta Serum Creatinine: The NACSELD Experience. AB - BACKGROUND: Women have lower serum creatinine values than men for similar renal function. AIMS: We aimed to determine the differential effect of baseline, peak, and delta creatinine between genders on outcomes in infected hospitalized cirrhotic patients. METHODS: North American Consortium for the Study of End-Stage Liver Disease is a 15-center consortium of tertiary care hepatology centers prospectively enrolling infected cirrhotic inpatients. Baseline, peak, and delta creatinine during hospitalization were compared between genders, and their impact on overall survival, transplant-free survival, probability of transplantation, and need for renal replacement therapy (RRT) was analyzed. RESULTS: In total, 532 patients with cirrhosis (males = 59% median admission MELD = 20) had significantly lower median baseline (1.07 vs. 1.30 mg/dL, p < 0.0001) and peak creatinine (1.47 vs. 1.59 mg/dL, p = 0.024) in women than men during hospitalization for an infection, but both genders had similar delta creatinine levels (0.30 vs. 0.30 mg/dL, p = 0.957). Thirty-day mortality was similar between genders. RRT was not used more often in women (19 vs. 12%, p = 0.050), and women were 1.8 times more likely than men to receive RRT at the same creatinine (p = 0.028). Both peak and delta creatinine significantly predicted 6-month overall and transplant-free survival (p < 0.0001), but the probability of liver transplantation was affected by the interaction between gender and both peak and delta creatinine. CONCLUSIONS: Infected hospitalized cirrhotic women are significantly more likely than men to receive RRT at similar creatinine levels. Gender-specific differences in baseline, peak, and delta creatinine need further investigation to determine whether women need acute kidney injury treatment at lower creatinine thresholds than men. PMID- 28025747 TI - Enduring Value of Thiopurines for Inflammatory Bowel Disease Therapy. PMID- 28025749 TI - Farewell to a Friend. PMID- 28025750 TI - Validity and Reliability of the 8-Item Work Limitations Questionnaire. AB - Purpose To evaluate factorial validity, scale reliability, test-retest reliability, convergent validity, and discriminant validity of the 8-item Work Limitations Questionnaire (WLQ) among employees from a public university system. Methods A secondary analysis using de-identified data from employees who completed an annual Health Assessment between the years 2009-2015 tested research aims. Confirmatory factor analysis (CFA) (n = 10,165) tested the latent structure of the 8-item WLQ. Scale reliability was determined using a CFA-based approach while test-retest reliability was determined using the intraclass correlation coefficient. Convergent/discriminant validity was tested by evaluating relations between the 8-item WLQ with health/performance variables for convergent validity (health-related work performance, number of chronic conditions, and general health) and demographic variables for discriminant validity (gender and institution type). Results A 1-factor model with three correlated residuals demonstrated excellent model fit (CFI = 0.99, TLI = 0.99, RMSEA = 0.03, and SRMR = 0.01). The scale reliability was acceptable (0.69, 95% CI 0.68-0.70) and the test-retest reliability was very good (ICC = 0.78). Low-to-moderate associations were observed between the 8-item WLQ and the health/performance variables while weak associations were observed between the demographic variables. Conclusions The 8-item WLQ demonstrated sufficient reliability and validity among employees from a public university system. Results suggest the 8-item WLQ is a usable alternative for studies when the more comprehensive 25-item WLQ is not available. PMID- 28025751 TI - Influence of continuously evolving transcatheter aortic valve implantation technology on cerebral oxygenation. AB - This study assessed the influence of the evolution in Transcatheter Aortic Valve Implantation technology on cerebral oxygenation. Cerebral oxygenation was measured continuously with Near-Infrared Spectroscopy and compared retrospectively between balloon-expandable, self-expandable and differential deployment valves which were implanted in 12 (34%), 17 (49%) and 6 patients (17%), respectively. Left and right SctO2 values were averaged at four time points and used for analysis (i.e. at baseline, balloon-aortic valvuloplasty, valve deployment, and at the end of the procedure). During balloon-aortic valvuloplasty and valve deployment, cerebral oxygenation decreased in patients treated with balloon or self-expandable valves (balloon-expandable: p = 0.003 and p = 0.002; self-expandable: p < 0.001 and p = 0.003, respectively). The incidence of cerebral desaturations below 80% of baseline was significantly larger in patients treated with balloon-expandable valves (p = 0.001). In contrast, patients who received differential deployment valves never experienced a cerebral desaturation below 80% of baseline. Furthermore, both the incidence and duration below a cerebral oxygenation of 55% was significantly different between balloon and self-expandable valves (p = 0.038 and p = 0.018, respectively). This study demonstrated that Transcatheter Aortic Valve Implantation procedures are associated with significant cerebral desaturations, especially during balloon aortic valvuloplasty and valve deployment. Moreover, our results showed that latest innovations in Transcatheter Aortic Valve Implantation technology beneficially influenced the adequacy of cerebral perfusion. PMID- 28025752 TI - Sound level analysis in endotracheal tube obstruction in spontaneous breathing and mechanical ventilation-an animal model study. AB - Endotracheal tube (ETT) obstruction, either complete or partial, is a serious life threatening complication in intubated patients. Therefore, implementing a practical method to diagnose this condition is vital. Alteration in respiratory sound signals caused by ETT occlusion can be used for early detection of obstruction. This study is aimed to assess changes in respiratory sound signals after creation of different types of tubal obstruction in an animal model experiment. Artificial internal obstructions were created in three different sizes and three different locations by stitching pieces of smaller tubes in ETTs with internal diameter of 8 mm. A microphone was used to record respiratory sounds during both spontaneous breathing and mechanical ventilation in seven anesthetized dogs. The sound intensity levels produced by different grades and degrees of obstructions were measured and compared with those in non-obstructed tubes. During spontaneous breathing, significant decrease in sound intensity level was detected even with the lowest grades of obstruction (p = 0.003, 0.001, and 0.002, proximal, middle and distal obstructions, respectively). However, in mechanical ventilation, significant decrease in sound intensity was observed only in distal tubal obstruction (p = 0.037). The difference among levels of sound intensity produced by different obstruction locations of occlusion was not statistically significant (p >= 0.090). Data analysis revealed that sound intensity level decreased significantly when the degree of obstruction increased. In addition, this change in sound level was not related to the location of obstruction. The decrease in sound intensity changes can be used to detect ETT obstruction. However, further studies are needed for clinical application. PMID- 28025753 TI - 'Gushing Out Blood': Defloration and Menstruation in Memoirs of a Woman of Pleasure. AB - John Cleland's 1740s pornographic novel, Memoirs of a Woman of Pleasure repeatedly depicts and eroticises the act of defloration. As such it is a revealing illustration of what Ivan Bloch termed the 'defloration mania' of the eighteenth century. This article maps narrative events on to contemporary medical depictions of first intercourse to show the ways that the theories and ideas presented in medical and pseudo-medical texts transferred into erotic fiction and demonstrates how in some instances the bloody defloration scenes can be read as being sex during menstruation, an act which was culturally forbidden at this time. PMID- 28025748 TI - Patient-derived xenograft (PDX) models in basic and translational breast cancer research. AB - Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research. PMID- 28025754 TI - Introduction: Caregiving, Kinship, and the Making of Stories. PMID- 28025755 TI - Parent ADHD and Evidence-Based Treatment for Their Children: Review and Directions for Future Research. AB - One fourth to one half of parents of children with attention deficit/hyperactivity disorder (ADHD) have ADHD themselves, complicating delivery of evidence-based child behavioral and pharmacological treatments. In this article, we review the literature examining the relation between parent ADHD and outcomes following behavioral and pharmacological treatments for children with ADHD. We also review research that has incorporated treatment of parent ADHD (either alone or in combination with child treatment) with the goal of improving parenting and child outcomes. Finally, we offer recommendations for future research on the relation between parent ADHD and evidence-based treatment outcomes for their children, with the purpose of advancing the science and informing clinical care of these families. PMID- 28025756 TI - The Longitudinal Relation between Daily Hassles and Depressive Symptoms among Unaccompanied Refugees in Norway. AB - The aim of the present longitudinal study is to understand the longitudinal relation between depressive symptoms and daily hassles (i.e., general and acculturation hassles) in a high-risk population of unaccompanied refugees. We investigated the validity of three stress-mental health models: the stress exposure model, the stress generation model, and the reciprocal model. Data were collected from 918 unaccompanied refugees in Norway in three waves. Of the initial sample, the majority (82.1%) were male (M age = 19.01 years, SD = 2.54 years). The data were analyzed with auto-regressive cross-lagged modeling and latent growth curve modeling. The results supported the stress exposure model for the relation between depressive symptoms and acculturation hassles, indicating that acculturation hassles predicted the subsequent levels of depressive symptoms rather than vice versa. On the other hand, the reciprocal model was supported for the relation between depressive symptoms and general hassles indicating a bidirectional, mutual relation. Unconditional latent growth models further showed that depression level remained unchanged over time, while levels of acculturation and general hassles decreased. The implications for clinical practice and immigration policy are discussed. PMID- 28025757 TI - Evidence of a Prototheca Zopfii Genotype 2 Disseminated Infection in a Dog with Cutaneous Lesions. AB - Protothecosis is a disease caused by saprophyte aerobic unicellular algae belonging to the genus Prototheca. In dogs, it mainly occurs as a disseminated form, with initial clinical manifestations often referable to the gastrointestinal tract, followed by typical ocular and neurological signs. So far, Prototheca zopfii genotype 2 infection has been reported in severe forms of disseminated protothecosis, while in dogs has never been associated with cutaneous forms. In this study, we describe a case of Prototheca zopfii genotype 2 infection in a dog characterized by nodular and ulcerative dermatitis and with evidence of dissemination. In December 2015, a 5-year-old unneutered male English Setter dog was presented with a 4-month history of footpads ulcerations and multifocal nodular lesions (3-5 cm diameter) on both front limbs. Cytological examination of the aspirated fluid collected from all nodules revealed the presence of sporangic forms compatible with Prototheca spp. organisms. Suspected Prototheca spp. colonies were isolated from the aspirated fluid and identified as Prototheca zopfii genotype 2 by molecular methods. Few days after the visit, the patient developed serious neurological and ocular signs, and the owners elected humane euthanasia. To the authors' knowledge, this case could represent the first report of a disseminated Prototheca zopfii genotype 2 infection associated with cutaneous lesions in a dog. This study underlines the importance of considering Prototheca zopfii genotype 2 infection in the differential etiological diagnosis of nodular and ulcerative dermatitis in dogs. PMID- 28025758 TI - Cutaneous Exophiala oligosperma Infection in a Patient with Bullous Pemphigoid with a Review of the Literature. AB - Phaeohyphomycosis is an infection caused by a heterogeneous group of melanized fungi. Human infections due to members of genus Exophiala are rare but may occur at any part of the body. We herein report a case of an 85-year-old male with a history of bullous pemphigoid who presented with a chronic, non-healing wound on his right dorsal hand for a month. Direct microscopy of a pus sample from the base of the ulcer revealed strands of pigmented, moniliform hyphae. The isolate was identified as E. oligosperma based on morphological characters and sequencing of the rDNA internal transcribed spacers (ITS) and partial beta-tubulin gene. The patient received a three-month course of oral itraconazole with no recurrence. PMID- 28025759 TI - Religiosity: Its Impact on Coping Styles Among Women Undergoing Fertility Treatment. AB - The Israeli worldview places great significance on childbearing. This could create emotional and ethical difficulties for women coping with fertility issues in addition to their treatments. This study examined the relations between coping strategies and level of religiosity in 159 women undergoing infertility treatment. Statistically significant relations were found between the problem solving coping style and religious observance (p < 0.01) and religious beliefs (p < 0.05). An inverse correlation was found between the emotional coping style and religious beliefs (p < 0.001). Health professionals should recognize the patient's coping styles and understand the patient's religious belief system as part of an ongoing fertility treatment. PMID- 28025760 TI - Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth. AB - Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using small interfering RNA (siRNA) resulted in significant (p < 0.05) inhibition of CHLA-9 and TC-32 cell growth as assessed by CellTiter-Glo assay kit. TA or Mit treatment caused dose/time-dependent inhibition of cell viability, and this inhibition was correlated with a decrease in Sp1 and survivin protein levels in ES cells. Quantitative PCR results showed that Mit treatment decreased the mRNA expression of both survivin and Sp1, whereas TA diminished only survivin but not Sp1. Proteasome inhibitor restored TA-induced inhibition of Sp1 protein expression suggesting that TA might cause proteasome-dependent degradation. Gel shift assay using ES cell nuclear extract and biotinylated Sp1 consensus oligonucleotides confirmed that both TA and Mit decreased DNA-binding activity of Sp1. These results demonstrate that both Mit and TA reduce expression of Sp1 and survivin, disrupt Sp1 DNA-binding and inhibit ES cell proliferation. This investigation suggests that targeting Sp1 and survivin could be an effective strategy for inhibiting ES cell growth. PMID- 28025761 TI - NPR1-dependent salicylic acid signaling inhibits Agrobacterium-mediated transient expression in Arabidopsis. PMID- 28025762 TI - Mammography rates after the 2009 revision to the United States Preventive Services Task Force breast cancer screening recommendation. AB - BACKGROUND: In 2009, the United States Preventive Services Task Force (USPSTF) recommended against routine mammography screening for women aged 40-49 years. This revised recommendation was widely criticized and has sparked off intense debate. The objectives of this study are to examine the impact of the revised recommendation on the proportion of women receiving mammograms and how the effect varied by age. METHODS: We identified women who had continuous health insurance coverage and who did not have breast cancer between 2008 and 2011 in the Truven Health MarketScan Commercial Claims Databases using mammogram procedure codes. Using women aged 50-59 years as a control group, we used a differences-in differences approach to estimate the impact of the revised recommendation on the proportion of women ages 40-49 years who received at least one mammogram. We also compared the age-specific changes in the proportion of women ages 35-59 years who were screened before and after the release of the revised recommendation. RESULTS: The proportion of women screened among the 40-49 and 50-59 age groups were 58.5 and 62.5%, respectively, between 2008 and 2009, and 56.9 and 62.0%, respectively, between 2010 and 2011. After 2009, the proportion of women screened declined by 1.2 percentage point among women aged 40-49 years (P < 0.01). The proportion of women screened decreased for all ages, and decreases were larger among women closer to the 40-year threshold. CONCLUSIONS: The 2009 USPSTF breast cancer recommendation was followed by a small reduction in the proportion of insured women aged 40-49 years who were screened. Reductions were larger among women at the younger end of the age range, who presumably had less prior experience with mammography than women nearing 50. PMID- 28025763 TI - Helicobacter pylori infection is an independent risk factor for colonic adenomatous neoplasms. AB - PURPOSE: Helicobacter pylori infection is considered to have a positive association with colorectal neoplasms. In this study, we evaluated the association between H. pylori infection and colorectal adenomas, based on the characteristics of these adenomas in Korea, where the prevalence of H. pylori infection is high and the incidence of colorectal cancer continues to increase. METHODS: The study cohort consisted of 4,466 subjects who underwent colonoscopy and esophagogastroduodenoscopy during screening (1,245 colorectal adenomas vs. 3,221 polyp-free controls). We compared the rate of H. pylori infection between patients with adenoma and polyp-free control cases, using multivariable logistic regression analysis. RESULTS: The overall rate of positive H. pylori infection was higher in adenoma cases than in polyp-free control cases (55.0 vs. 48.5%, p < 0.001). The odds ratio (OR) of positive H. pylori infection in patients with adenoma compared to polyp-free controls was 1.28 (95% CI 1.11-1.47). The positive association of H. pylori infection with colorectal adenomas was more prominent in advanced adenomas (OR 1.84, 95% CI 1.25-2.70) and multiple adenomas (OR 1.72, 95% CI 1.26-2.35). Based on the location of these adenomas, the OR was significant only in patients with colonic adenomas (OR 1.31, 95% CI 1.13-1.52) and not in those with rectal adenoma (OR 0.85, 95% CI 0.58-1.24). CONCLUSION: Helicobacter pylori infection is an independent risk factor for colonic adenomas, especially in cases of advanced or multiple adenomas, but not for rectal adenomas. PMID- 28025764 TI - A prospective study of reproductive factors and exogenous hormone use in relation to ovarian cancer risk among Black women. AB - PURPOSE: Extensive data in White women have linked oral contraceptive use, tubal ligation, and parity to reduced risk of ovarian cancer; results on postmenopausal female hormone use are mixed. Few studies, all of which are case-control studies, have been undertaken among Black women. The aim of the present study was to prospectively assess associations of reproductive factors and exogenous hormones with ovarian cancer among Black women. METHODS: During follow-up from 1995 to 2013 in the Black Women's Health Study, a prospective cohort study, 115 incident cases of ovarian cancer were identified. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the relation of the factors of interest to risk of ovarian cancer, with control for covariates. RESULT: Oral contraceptive use was inversely associated with ovarian cancer risk: The HR for >=10 years of use relative to <1 year was 0.50 (95% CI 0.30-0.98). For postmenopausal female hormone use, the HRs for ever use of estrogen with progestin and of estrogen alone were 1.37 (0.73-2.55) and 1.66 (0.90-3.07), respectively. The HRs for parity and tubal ligation were below 1.0, but were not statistically significant. CONCLUSION: Overall, the findings indicate that the relation of reproductive factors and exogenous hormone use to risk of ovarian cancer is similar among Black and White women. The results on estrogen-only supplements and estrogen with progestin supplements add to evidence from Whites, indicating that use of hormone supplements may be associated with increased risk of ovarian cancer. PMID- 28025765 TI - Incidence of malignant mesothelioma in Germany 2009-2013. AB - PURPOSE: The malignant mesothelioma is a rare malignancy and mainly caused by occupational exposure to asbestos. German cancer registries are providing a national database to investigate temporal and regional patterns of mesothelioma incidence. These may be of interest for healthcare planning and for surveillance programs aiming at the formerly exposed workforce. METHODS: We analyzed population-based incidence data of malignant mesothelioma by site, type, sex, age, as well as district and state of patient's residence. Age-standardized incidence rates (AIRs40+) were calculated according to the European standard population truncated to the age of 40 years and older. We present rates at national, state, and district level and trends of incidence of northern states of Germany. RESULTS: In total, 7,547 malignant mesotheliomas were reported to German cancer registries diagnosed between 2009 and 2013-90% located to the pleura. On average, 1,198 men and 312 women were affected each year. We estimated AIR40+ of 4.77 in 100,000 German men and 0.98 in 100,000 German women. Regional clusters were predominantly located to the seaports of West Germany. The highest regional AIR40+ was 20 per 100,000 men. Corresponding rates in northeast Germany were between 2 and 4 per 100,000 men. CONCLUSION: Regional clusters of high incidence indicate districts with former shipyards and steel industry, but predominantly in the western part of Germany. The West-to-East difference corresponds to patterns of mortality. Twenty years after banning asbestos in Germany, Bremen and Hamburg are presenting the highest mesothelioma incidence but show steadily decreasing trends. PMID- 28025766 TI - Safety of cardioversion in atrial fibrillation lasting less than 48 h without post-procedural anticoagulation in patients at low cardioembolic risk. AB - Currently, there is no unified consensus on short-term anticoagulation after cardioversion of atrial fibrillation lasting less than 48 h in low-cardioembolic risk patients. The aim of this study is to evaluate the rate of transient ischemic attacks, stroke and death in this subset of patients after cardioversion without post-procedural anticoagulation. In a prospective observational study, patients with recent-onset AF undergoing cardioversion attempts in the Emergency Department were evaluated over the past 3 years. Inclusion criteria were conversion to sinus rhythm, low thromboembolic risk defined by a CHA2DS2VASc score of 0-1 points for males (0-2 points for females aged over 65 years), and hospital discharge without anticoagulant treatment. Patients with severe valvular heart disease, underlying systemic causes of AF, and those discharged with anticoagulant therapy were excluded. The main outcomes measured were TIA, stroke and death at thirty days' follow-up after discharge. During the study period, 218 successful cardioversions, obtained both electrically and pharmacologically, were performed on 157 patients. One hundred and eleven patients were males (71%), the mean age was 55.2 years (+/-standard deviation 10.7), 99 patients (63%) reported a CHA2DS2VASc score of 0, and the remaining 58 (37%) had a risk profile of 1 point. Of these, latter 8 were females (5%) older than 65 years (risk score 2 points). At the thirty days outcome, none of the 150 enrolled patients who completed a follow-up visit has reported TIA or stroke, nor died, in the overall 211 successful cardioversions evaluated. In our study, the rate of thromboembolic events after cardioversion of recent-onset AF of less than 48 h duration, in patients with a 0-1 CHA2DS2VASc risk profile (females 0-2), appeared to be extremely low even in absence of post-procedural anticoagulation. These findings seem to confirm data from previous studies, and suggest that routine post procedural short-term anticoagulation may be considered as an overtreatment in this very low-risk subset of patients. PMID- 28025768 TI - Capsule Commentary on Mueller et al., Attitudes Toward Naloxone Prescribing in Clinical Settings: A Qualitative Study of Patients Prescribed High Dose Opioids for Chronic Non-Cancer Pain. PMID- 28025767 TI - Residential Neighborhood Amenities and Physical Activity Among U.S. Children with Special Health Care Needs. AB - Objectives Children with special health care needs (SHCN) have or are at elevated risk for chronic physical, developmental, behavioral or emotional conditions and therefore require specialized health care services. This study examines the relationship between residential neighborhood amenities and physical activity among U.S. children with SHCN. Methods A nationally representative sample of 113,767 children aged 6-17 years was taken from National Survey of Children's Health (NSCH) 2007-2008 and 2011-2012. Residential neighborhood amenities were defined by parent-reported presence or absence of sidewalks, parks/playgrounds, and recreation center. Physical activity was measured by parent-reported number of physically active days (0-7), defined as 20 min or longer during the past week. Negative binomial regressions were performed to estimate the associations between residential neighborhood amenities and physical activity among U.S. children with and without SHCN, adjusting for various neighborhood (detracting condition and safety) and individual characteristics and NSCH sampling design. Results Approximately 23% of young children aged 6-11 years and adolescents aged 12-17 years had SHCN. Number of weekly physically active days was both 4.8 among young children with and without SHCN, and 3.7 and 4.1 among adolescents with and without SHCN, respectively. Among young children with SHCN, neighborhood availability of a recreation center was associated with increased weekly physically active days by 0.23; whereas among young children without SHCN, number of weekly physically active days was not associated with the availability of any amenity. Among adolescents with SHCN, neighborhood availability of parks/playgrounds was associated with increased weekly physically active days by 0.33, whereas neighborhood availability of sidewalks was associated with reduced weekly physically active days by 0.21. Conversely, among adolescents without SHCN, neighborhood availability of a recreation center was associated with increased weekly physically active days by 0.22. Conclusions for Practice Vulnerable health status and high dependence on health care may prevent children with SHCN from being physically active. Provision of adequate amenities in residential neighborhoods could be essential in promoting physical activity and preventing obesity among children/adolescents with SHCN. PMID- 28025769 TI - Capsule Commentary on Velez et al., "It's Been an Experience, a Life Learning Experience": A Qualitative Study of Hospitalized Patients with Substance Use Disorders. PMID- 28025770 TI - Molecular-genetic and clinicopathological prognostic factors in patients with gliomas showing total 1p19q loss: gain of chromosome 19p and histological grade III negatively correlate with patient's prognosis. AB - Although 1p19q codeleted gliomas are the most favorable molecular subgroup of lower-grade gliomas, there are cases with early recurrence or short survival. The objective of this study was to elucidate molecular-genetic and clinicopathological prognostic factors in patients with gliomas showing total 1p19q loss. The study included 57 consecutive patients with codeleted gliomas who were operated at Keio University Hospital between 1990 and 2010. These patients were assessed for chromosomal copy number aberrations, promoter methylation status of the O6-methylguanine-DNA methyltransferase gene (MGMT), and demographic and clinicopathological prognostic factors in diffuse gliomas. No significant difference was observed in the overall survival (OS) of the patients with respect to age (>=40 years vs. <40 years), degree of resection, maximum tumor diameter (>=5 cm vs. <5 cm), histological subtype, and MGMT promoter methylation status. Gain of chromosome 19p and grade III histology were associated with shorter OS (P = 0.019, 0.061, respectively). Gain of 19p and histological grade III might be negative prognostic factors for the patients with gliomas showing total 1p19q loss. Further investigation is warranted to confirm these notions. PMID- 28025771 TI - Early Experience with Laparoscopic Frey Procedure for Chronic Pancreatitis: a Case Series and Review of Literature. AB - The Frey procedure has been demonstrated to be an effective surgical technique to treat patients with painful large duct chronic pancreatitis. More commonly reported as an open procedure, we report our experience with a minimally invasive approach to the Frey procedure. Four consecutive patients underwent a laparoscopic Frey procedure at our institution from January 2012 to July 2015. We herein report our technique and describe short- and medium-term outcomes. The median age was 40 years old. The median duration of pancreatic pain prior to surgery was 12 years. Median operative time and intraoperative blood loss was 130 min (100-160 min) and 60 mL (50-100 mL), respectively. The median length of stay was 7 days (3-40 days) and median follow-up was 26 months (12-30 months). There was one major postoperative complication requiring reoperation. Within 6 months, in all four patients, frequency of pain and analgesic requirement reduced significantly. Two patients appeared to have resolution of pancreatic exocrine insufficiency. The Frey procedure is possible laparoscopically with acceptable short- and medium-term outcomes in well-selected patients. PMID- 28025772 TI - Laparoscopically Assisted Proximal Gastrectomy with Esophagogastrostomy Using a Novel "Open-Door" Technique : LAPG with Novel Reconstruction. AB - Laparoscopy-assisted proximal gastrectomy (LAPG) with esophagogastrostomy using a novel "open-door" technique was introduced recently, with the aim of preventing gastroesophageal reflux. However, quantitate assessment of gastroesophageal reflux after this surgery has not been performed till date. The aims of the current study were to investigate the safety and feasibility of this operation and to elucidate the postoperative reflux status. Twenty consecutive patients (18 men) with (y)cStage I gastric cancer in the upper third of the stomach who underwent LAPG at Kitasato University Hospital from May 2015 through September 2016 were retrospectively reviewed. We performed 24-h impedance-pH monitoring 3 months after surgery for the first eight patients and analyzed the postoperative reflux status. Median operation time was 333 min, while median anastomotic time was 81 min. None of the 20 patients experienced anastomotic leakage while two patients experienced anastomotic stricture requiring endoscopic balloon dilatation. No patient experienced heartburn without antacid drugs. During the 24 h impedance-pH monitoring, all but one patient had normal gastroesophageal acid reflux with the acid percent time of <1.1% and reflux percent time of <1.4%. One patient with marginally abnormal postoperative gastroesophageal reflux had a normal DeMeester score of 3.0. Our results showed that esophagogastrostomy using the "open-door" technique is a safe and feasible procedure for LAPG. The degree of gastroesophageal reflux was acceptable using this technique. Randomized controlled trials with long-term follow-ups are required to confirm that this technique would be superior to the others. PMID- 28025773 TI - Bone Mineral Density in Celiac Disease. AB - OBJECTIVES: To study bone mineral density (BMD) and standard serum biochemical indices among newly diagnosed and already diagnosed cases of Celiac Disease (CD) on gluten free diet for at least one year. METHODS: This hospital based analytic, observational study was done at a tertiary care centre, from April 2013 through June 2014. Thirty six children (20 females) with untreated CD at diagnosis (Group A) and 36 age and sex matched children on gluten-free diet for at least one year (Group B) were studied. Serum measurements of biochemical bone health indices and BMD, assessed by dual X-ray absorptiometry, were obtained. RESULTS: BMD Z-score was significantly low in newly diagnosed celiac patients. Patients on gluten free diet had higher BMD Z-score as compared to newly diagnosed patients (-2.02 vs. 0.65 respectively, p < 0.001). BMD Z-score was high in GI symptom patients as compared to non-GI symptom patients (-0.46+/-0.89 vs. - 0.88 = +/-0.94) in Group B. In female patients BMD Z-score was comparatively low as compared to male patients in both groups but difference was not significant. In Group A the mean serum calcium level was lower than the patients in Group B (8.72 + 0.73 vs. 9.34 + 0.65, p < 0.001). S. calcium levels were not correlated with bone mineral density (BMD) in both groups (P value >0.05). CONCLUSIONS: Children with CD are at risk for reduced BMD. Strict gluten-free diet significantly improves bone mineralization. Early diagnosis and treatment of celiac disease during childhood may protect CD patients from osteoporosis. PMID- 28025774 TI - "They Treat you a Different Way:" Public Insurance, Stigma, and the Challenge to Quality Health Care. AB - Under the Affordable Care Act, Medicaid Expansion programs are extending Medicaid eligibility and increasing access to care. However, stigma associated with public insurance coverage may importantly affect the nature and content of the health care beneficiaries receive. In this paper, we examine the health care stigma experiences described by a group of low-income public insurance beneficiaries. They perceive stigma as manifest in poor quality care and negative interpersonal interactions in the health care setting. Using an intersectional approach, we found that the stigma of public insurance was compounded with other sources of stigma including socioeconomic status, race, gender, and illness status. Experiences of stigma had important implications for how subjects evaluated the quality of care, their decisions impacting continuity of care, and their reported ability to access health care. We argue that stigma challenges the quality of care provided under public insurance and is thus a public health issue that should be addressed in Medicaid policy. PMID- 28025775 TI - Systemic Treatment of Adult Atopic Dermatitis: A Review. AB - Atopic dermatitis (AD) is a common chronic inflammatory skin disease that predominantly affects children. However, it can persist in adulthood and/or start at older ages. Due to its chronic nature and frequently occurring relapses, AD has a substantial effect on patients' quality of life, often requiring long-term systemic treatment, especially in adult patients, who are more frequently refractory to adequate topical treatment with mid- to high-potent corticosteroids and/or calcineurin inhibitors. Therefore, treatment with systemic therapies is often needed to take control of the disease, prevent exacerbations and improve quality of life. However, data regarding systemic treatment effectiveness and long-term safety in adult patients with AD are insufficient. Indeed, standardized international guidelines are lacking, and the treatment approach widely differs among diverse countries. This review focuses on the use of systemic treatments in adult AD patients analyzing published literature. PMID- 28025776 TI - Expression, Polyubiquitination, and Therapeutic Potential of Recombinant E6E7 from HPV16 Antigens Fused to Ubiquitin. AB - Ubiquitin-proteasome system plays an essential role in the immune response due to its involvement in the antigen generation and presentation to CD8+ T cells. Hereby, ubiquitin fused to antigens has been explored as an immunotherapeutic strategy that requires the activation of cytotoxic T lymphocytes. Here we propose to apply this ubiquitin fusion approach to a recombinant vaccine against human papillomavirus 16-infected cells. E6E7 multi-epitope antigen was fused genetically at its N- or C-terminal end to ubiquitin and expressed in Escherichia coli as inclusion bodies. The antigens were solubilized using urea and purified by nickel affinity chromatography in denatured condition. Fusion of ubiquitin to E6E7 resulted in marked polyubiquitination in vitro mainly when fused to the E6E7 N-terminal. When tested in a therapeutic scenario, the fusion of ubiquitin to E6E7 reinforced the anti-tumor protection and increased the E6/E7-specific cellular immune responses. Present results encourage the investigation of the adjuvant potential of the ubiquitin fusion to recombinant vaccines requiring CD8+ T cells. PMID- 28025777 TI - Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases. AB - Neurodevelopmental biology, coupled with the application of advanced histological, imaging, molecular, cellular, biochemical, and genetic approaches, has provided new insights into these intricate genetic, cellular, and molecular events. During telencephalic development, specific neural progenitor cells (NPCs) proliferate, differentiate into numerous cell types, migrate to their apposite positions, and form an integrated circuitry. Critical disturbance to this dynamic process via genetic and environmental risk can cause neurological disorders and disability. The phosphatidylinositol-3-OH kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling cascade contributes to mediate various cellular processes, including cell proliferation and growth, and nutrient uptake. In light of its critical function, dysregulation of this node has been regarded as a root cause of several neurodevelopmental diseases, such as megalencephaly ("big brain"), microcephaly ("small brain"), autism spectrum disorders, intellectual disability, schizophrenia, and epilepsy. In this review, particular emphasis will be given to the PI3K-Akt-mTOR signaling pathway and their paramount importance in neurodevelopment of the cerebral neocortex, because of its critical roles in complex cognition, emotional regulation, language, and behaviors. PMID- 28025778 TI - Role of Mast Cells in the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. AB - Multiple sclerosis (MS) is a neurological autoimmune disorder of the central nervous system (CNS), characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. The hallmark of the disease is the demyelinated plaque, a hypocellular area characterized by formation of astrocytic scars and infiltration of mononuclear cells. Recent studies have revealed that both innate and adaptive immune cells contribute to the pathogenesis of MS and its experimental autoimmune encephalomyelitis (EAE) model. Here, we review the current understanding of the role of mast cells in the pathogenesis of MS and EAE. Mast cells may act at the early stage that promote demyelination through interactions among mast cells, neurons, and other immune cells to mediate neuroinflammation. Studies from EAE model suggest that mast cells regulate adaptive autoimmune responses, present myelin antigens to T cells, disrupt the blood-brain barrier, and permit the entry of inflammatory cells and mediators into the CNS. Depletion or limiting mast cells could be a new promising therapeutic target for MS and EAE. PMID- 28025779 TI - Correlation of Ki-67 Proliferative Antigen Expression and Tumor Response to Induction Chemotherapy Containing Cell Cycle-Specific Agents in Head and Neck Squamous Cell Carcinoma. AB - Determine if highly proliferative head and neck squamous cell carcinomas, assessed by pretreatment Ki-67 expression, respond more robustly to induction chemotherapy (IC) that is selectively toxic to cycling cells. Retrospective analysis of 59 patients treated with IC and chemoradiation. IC included either nab-paclitaxel, cisplatin, 5-FU and cetuximab (APF-C, n = 27) or docetaxel, cisplatin, 5-FU +/- cetuximab (TPF+/-C, n = 32). Ki-67 expression was assessed by immunohistochemistry. Tumor response (complete/partial/stable/progressive) at the primary site after two IC cycles was evaluated by visual examination in all patients. In the APF-C sub-group, tumor response (primary site and neck nodes) after two IC cycles was evaluated by computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT. Ki-67 expression (median 66%, range: 16-97) did not differ across the tumor response categories assessed by visual examination (p = 0.95), CT (p = 0.30), or FDG-PET/CT (p = 0.65). Median decrease in summed SUVmax of measured lesions was 71.6% (range: 8.3 100%). The Pearson correlation coefficient between Ki-67 expression and the percent decrease in summed SUVmax was 0.48 (p = 0.02). Ki-67 expression was not different between those with or without a relapse (median: 60 and 71%, p = 0.10). In multivariate regression analysis (MVA) controlling for p16 positive oropharyngeal SCC status and smoking status, Ki-67 expression was not significantly associated with tumor response by visual examination (coefficient estimate -0.002, standard error 0.010, p = 0.84), CT (coefficient estimate 0.007, standard error 0.011, p = 0.54), FDG-PET/CT (coefficient estimate 0.006, standard error 0.008, p = 0.51), the percent decrease in summed SUVmax (coefficient estimate 0.389, standard error 0.222, p = 0.09), or relapse events (OR = 1.02(95%CI:0.99-1.05), p = 0.28). No significant relationships were found in MVA between pretreatment Ki-67 expression and tumor response to IC or to relapse. PMID- 28025781 TI - Bronchial artery embolization for the treatment of haemoptysis in pulmonary hypertension. AB - PURPOSE: To test the efficacy of bronchial artery embolization (BAE) to treat haemoptysis in pulmonary hypertension (PH). METHODS: 33 patients were treated by BAE for haemoptysis associated with PH (PH group = 21) or non-associated with PH (control group = 12). The details of procedure, outcome, and rate of relapse were compared between the two groups. Within the PH group, the comparison was operated between subjects with congenital heart disease-associated pulmonary artery hypertension (CHD-APAH subgroup = 12) and non-CHD (non-CHD-APAH subgroup = 9). RESULTS: The rate of relapse at 30 and 90-days was similar between the PH group and control group. BAE in the PH group was more challenging (median 2 arteries embolized per procedure) compared to the control group (median 1 artery embolized per procedure; p = 0.001). Bleeding arteries were more heterogeneous in the PH group, while a single right bronchial artery was the only clinical finding in 66.7% of controls (p = 0.001). Within the PH group, the CHD subgroup showed higher survival rate compared to the non-CHD-APAH group (p = 0.007). CONCLUSION: BAE is effective and safe for the treatment of haemoptysis in PH, yet more challenging than other conditions. In PH-associated haemoptysis, BAE provides higher survival rate for subjects with PH associated with CHD. PMID- 28025780 TI - Exosomes in Parkinson's Disease. AB - Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found in all kinds of biological fluids and tissues, including the central nervous system (CNS). The proposed functions of these vesicles include roles in cell-cell signaling, removal of cellular debris, and transfer of pathogens between cells. Many studies have revealed that exosomes derived from the CNS occur in the cerebrospinal fluid and peripheral body fluids, and their contents are altered during disease, making them an appealing target for biomarker development in Parkinson's disease (PD). Exosomes have been shown to spread toxic alpha-synuclein (alphasyn) between cells and induce apoptosis, which suggests a key mechanism underlying the spread of alphasyn aggregates in the brain and the acceleration of pathology in PD. However, potential neuroprotective roles of exosomes in PD have also been reported. On the treatment side, as drug delivery vehicles, exosomes have been used to deliver small interfering RNAs and catalase to the brain, and have shown clear therapeutic effects in a mouse model of PD. These features of exosomes in PD make them extremely interesting from the point of view of developing novel diagnostic and therapeutic approaches. PMID- 28025782 TI - A new shielding calculation method for X-ray computed tomography regarding scattered radiation. AB - The goal of this study is to develop a more appropriate shielding calculation method for computed tomography (CT) in comparison with the Japanese conventional (JC) method and the National Council on Radiation Protection and Measurements (NCRP)-dose length product (DLP) method. Scattered dose distributions were measured in a CT room with 18 scanners (16 scanners in the case of the JC method) for one week during routine clinical use. The radiation doses were calculated for the same period using the JC and NCRP-DLP methods. The mean (NCRP-DLP-calculated dose)/(measured dose) ratios in each direction ranged from 1.7 +/- 0.6 to 55 +/- 24 (mean +/- standard deviation). The NCRP-DLP method underestimated the dose at 3.4% in fewer shielding directions without the gantry and a subject, and the minimum (NCRP-DLP-calculated dose)/(measured dose) ratio was 0.6. The reduction factors were 0.036 +/- 0.014 and 0.24 +/- 0.061 for the gantry and couch directions, respectively. The (JC-calculated dose)/(measured dose) ratios ranged from 11 +/- 8.7 to 404 +/- 340. The air kerma scatter factor kappa is expected to be twice as high as that calculated with the NCRP-DLP method and the reduction factors are expected to be 0.1 and 0.4 for the gantry and couch directions, respectively. We, therefore, propose a more appropriate method, the Japanese-DLP method, which resolves the issues of possible underestimation of the scattered radiation and overestimation of the reduction factors in the gantry and couch directions. PMID- 28025783 TI - Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease. AB - INTRODUCTION: Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase which was approved by the United States Federal Drug Administration in 2014 for the treatment of relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Drug-induced injury of the gastrointestinal tract is a relatively frequent but usually under-recognized disease entity. CASE PRESENTATION: We report the case of a 56-year-old male with a history of relapsed follicular lymphoma status post allogenic bone marrow transplant who developed severe diarrhea with a skin eruption mimicking graft versus-host disease (GVHD) 6 months after starting idelalisib. He underwent a colonoscopy demonstrating a grossly normal-appearing colon and terminal ileum. Biopsies taken during the procedure revealed mild active ileitis, colitis, and proctitis with frequent epithelial apoptosis, and focal intra-epithelial lymphocytosis. Skin biopsies revealed sub-acute spongiotic dermatitis suggestive of either contact dermatitis or an eczematous drug reaction. Symptoms were attributed to idelalisib given their resolution with withdrawal of the drug in conjunction with the skin and colonic biopsies. CONCLUSION: High clinical suspicion and awareness of the histological features of idelalisib-associated colitis is important to distinguish it from potential mimickers such as GVHD and infectious colitis. PMID- 28025784 TI - Multi-scale detection of rate changes in spike trains with weak dependencies. AB - The statistical analysis of neuronal spike trains by models of point processes often relies on the assumption of constant process parameters. However, it is a well-known problem that the parameters of empirical spike trains can be highly variable, such as for example the firing rate. In order to test the null hypothesis of a constant rate and to estimate the change points, a Multiple Filter Test (MFT) and a corresponding algorithm (MFA) have been proposed that can be applied under the assumption of independent inter spike intervals (ISIs). As empirical spike trains often show weak dependencies in the correlation structure of ISIs, we extend the MFT here to point processes associated with short range dependencies. By specifically estimating serial dependencies in the test statistic, we show that the new MFT can be applied to a variety of empirical firing patterns, including positive and negative serial correlations as well as tonic and bursty firing. The new MFT is applied to a data set of empirical spike trains with serial correlations, and simulations show improved performance against methods that assume independence. In case of positive correlations, our new MFT is necessary to reduce the number of false positives, which can be highly enhanced when falsely assuming independence. For the frequent case of negative correlations, the new MFT shows an improved detection probability of change points and thus, also a higher potential of signal extraction from noisy spike trains. PMID- 28025785 TI - Significance of OCT1 Expression in Acute Myeloid Leukemia. AB - Organic cation transporter 1 (OCT1) is one of the membrane proteins in the large solute carrier (SLC) family. It participates in the transport of organic cations, i.e. nutrients, neurotransmitters, metabolites or drugs in an electrogenic manner and translocate various cationic cytostatics. Knowledge concerning the expression of drug transporters in tumor cells may help to develop cytotoxic agents that are targeted to specific tumors. OCT1 expression and its relationship to the proliferation of cancer cells, development of metastases and resistance to chemotherapy has been observed in solid tumors. There is no data concerning the significance of OCT1 expression in the clinical course and treatment results in acute myeloid leukemia (AML). The objective of the study was firstly to evaluate OCT1 mRNA expression in patients with newly diagnosed de novo AML, and secondly to compare the obtained results to the healthy control group as well as analyze them according to leukemia subtypes, CD34 expression, cytogenetic and molecular factors and treatment results. 101 patients with AML, excluding the subtype classified as M3 by French-American-British (FAB) criteria, were analyzed. The control group consisted of 26 healthy individuals. The evaluated material was bone marrow (BM). Real-time quantitative polymerase chain reaction (RQ-PCR) was used in the study as a method of evaluating OCT1 mRNA expression. The study showed a statistically significant lower expression of OCT1 mRNA in patients with AML in comparison to the control group. The level of OCT1 mRNA expression was lowest for CD34+ leukemia. No significant correlation between OCT1 mRNA expression and cytogenetic and molecular factors was observed. A significant influence of OCT1 mRNA expression on the clinical outcome of the disease was observed: patients with lower expression had higher chances of achieving complete remission (CR) and longer overall survival (OS). PMID- 28025786 TI - EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer. AB - Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising. PMID- 28025787 TI - Lodging stress in cereal-effects and management: an overview. AB - Uncertainty in climatic and weather conditions may result in lodging. Lodging is a most chronic constraint, which is causing tremendous yield reduction in crop plants; therefore, better understanding to control lodging-induced adversities or to enhance lodging resistance in cereals is imperative. In this review, we presented a contemporary synthesis of the existing data regarding the effects of lodging on growth and yield of cereals. Moreover, we highlighted key factors which trigger the detrimental effects of lodging in cereals. Numerous morphological, anatomical, and biochemical traits in plants that can influence lodging risk have also been discussed. These traits showed significant correlation with lodging resistance in cereals. At end, we tried to link our hypothetical concepts with previous evidences and provided a comprehensive summary of all the possible management approaches that can be used to further control lodging effects on cereals. The selection of a management option though is based on cereal type and genotype; nonetheless, different agronomic approaches including seeding rate, sowing time, tillage system, crop rotation, and fertilizer application help in reducing lodging risk in cereals. PMID- 28025788 TI - Benzo(a)pyrene degradation and microbial community responses in composted soil. AB - Benzo(a)pyrene degradation was compared in soil that was either composted, incubated at a constant temperature of 22 degrees C, or incubated under a temperature regime typical of a composting process. After 84 days, significantly more (61%) benzo(a)pyrene was removed from composted soil compared to soils incubated at a constant temperature (29%) or at composting temperatures (46%). Molecular fingerprinting approaches indicated that in composted soils, bacterial community changes were driven by both temperature and organic amendment, while fungal community changes were primarily driven by temperature. Next-generation sequencing data revealed that the bacterial community in composted soil was dominated by Actinobacteria (order Actinomycetales), Firmicutes (class Bacilli), and Proteobacteria (classes Gammaproteobacteria and Alphaproteobacteria), regardless of whether benzo(a)pyrene was present or not. The relative abundance of unclassified Actinomycetales (Actinobacteria) was significantly higher in composted soil when degradation was occurring, indicating a potential role for these organisms in benzo(a)pyrene metabolism. This study provides baseline data for employing straw-based composting strategies for the removal of high molecular weight PAHs from soil and contributes to the knowledge of how microbial communities respond to incubation conditions and pollutant degradation. PMID- 28025789 TI - Nutrient leaching, soil pH and changes in microbial community increase with time in lead-contaminated boreal forest soil at a shooting range area. AB - Despite the known toxicity of lead (Pb), Pb pellets are widely used at shotgun shooting ranges over the world. However, the impacts of Pb on soil nutrients and soil microbes, playing a crucial role in nutrient cycling, are poorly understood. Furthermore, it is unknown whether these impacts change with time after the cessation of shooting. To shed light on these issues, three study sites in the same coniferous forest in a shooting range area were studied: an uncontaminated control site and an active and an abandoned shooting range, both sharing a similar Pb pellet load in the soil, but the latter with a 20-year longer contamination history. Soil pH and nitrate concentration increased, whilst soil phosphate concentration and fungal phospholipid fatty acid (PLFA) decreased due to Pb contamination. Our results imply that shooting-derived Pb can influence soil nutrients and microbes not only directly but also indirectly by increasing soil pH. However, these mechanisms cannot be differentiated here. Many of the Pb induced changes were most pronounced at the abandoned range, and nutrient leaching was increased only at that site. These results suggest that Pb disturbs the structure and functions of the soil system and impairs a crucial ecosystem service, the ability to retain nutrients. Furthermore, the risks of shooting derived Pb to the environment increase with time. PMID- 28025790 TI - Bentonite supplementation can improve performance and fermentation parameters of chronic lead-exposed lambs. AB - Two experiments were conducted to investigate the effect of supplemental bentonite on performance, blood, and fermentation characteristics in Zandi lambs. In experiment 1, 20 Zandi male lambs (initial BW, 17.5 +/- 1.6 kg and 110 +/- 5 days old) were randomly assigned into four groups of five animals in each. The experimental treatments were (1) control (no Pb and bentonite), (2) 15 mg/kg DM Pb as Pb acetate and no bentonite, (3) 15 mg/kg DM Pb as Pb acetate and 1.5% bentonite, and (4) 15 mg/kg DM Pb as Pb acetate and 3% bentonite. The dietary treatments had no significant effect on dry matter intake of experimental lambs. Feed required per unit of weight gain was more (P < 0.05) in lead-exposed lambs in group 2 compared to the control and bentonite supplemented groups. Serum glucose, urea nitrogen, cholesterol, HDL, and LDL concentrations was similar among the treatments. In experiment 2, an in vitro gas production technique was used to evaluate the effects of bentonite supplementation on the gas production parameters of lead-polluted diets. The rate and amount of gas production was higher for bentonite supplemented groups (P < 0.01). Asymptotic gas production (b), metabolizable energy, and concentration of short chain fatty acids were lower (P < 0.05) for lead-polluted non-supplemented diet (group 2) as compared to the bentonite supplemented and control groups. It was concluded that bentonite supplementation favorably modified ruminal fermentation pattern and improved feed conversion ratio in growing lead-exposed lambs. PMID- 28025791 TI - High resolution melt curve analysis based on methylation status for human semen identification. AB - A high resolution melt curve assay to differentiate semen from blood, saliva, urine, and vaginal fluid based on methylation status at the Dapper Isoform 1 (DACT1) gene was developed. Stains made from blood, saliva, urine, semen, and vaginal fluid were obtained from volunteers and DNA was isolated using either organic extraction (saliva, urine, and vaginal fluid) or Chelex(r) 100 extraction (blood and semen). Extracts were then subjected to bisulfite modification in order to convert unmethylated cytosines to uracil, consequently creating sequences whose amplicons have melt curves that vary depending on their initial methylation status. When primers designed to amplify the promoter region of the DACT1 gene were used, DNA from semen samples was distinguishable from other fluids by a having a statistically significant lower melting temperature. The assay was found to be sperm-significant since semen from a vasectomized man produced a melting temperature similar to the non-semen body fluids. Blood and semen stains stored up to 5 months and tested at various intervals showed little variation in melt temperature indicating the methylation status was stable during the course of the study. The assay is a more viable method for forensic science practice than most molecular-based methods for body fluid stain identification since it is time efficient and utilizes instrumentation common to forensic biology laboratories. In addition, the assay is advantageous over traditional presumptive chemical methods for body fluid identification since results are confirmatory and the assay offers the possibility of multiplexing which may test for multiple body fluids simultaneously. PMID- 28025792 TI - Two extraordinary autoerotic fatalities. PMID- 28025793 TI - Allogenic cultivated limbal stem cell transplantation versus cadaveric keratolimbal allograft in ocular surface disorder: 1-year outcome. AB - PURPOSE: To compare the outcome of allogenic ex vivo cultivated limbal stem cell transplantation (LSCT) versus cadaveric keratolimbal allograft in patients with limbal stem cell deficiency (LSCD). METHODS: In this prospective interventional study from Army Hospital Research and Referral in New Delhi, 50 eyes of 40 patients with ocular surface disorder having LSCD underwent either cultivated LSCT (group 1: 25 eyes of 20 patients) or keratolimbal allograft transplantation (group 2: 25 eyes of 20 patients). The outcome measures were gain of two or more lines of best-corrected visual acuity (BCVA), absence of conjunctival vascularization over cornea, corneal neovascularization regression, regression of visually significant corneal opacity (iris details poorly visible), Schirmer's 1 >=10 s, tear break-up time (TBUT) >=10 s, and absence of fluorescein staining. RESULTS: At 1 year of follow-up, both groups experienced significant improvement in all outcome measures, but there was no significant difference between both groups in improvement of two or more lines of BCVA (P = 0.841), absence of conjunctival vascularization over cornea (P = 0.812), corneal neovascularization (P = 0.074), visually significant corneal opacity (P = 0.075), Schirmer's 1 >=10 s (P = 0.814), TBUT >=10 s (P = 0.382), or absence of fluorescein stain (P = 1.00). CONCLUSION: Both allogenic ex vivo cultivated LSCT and cadaveric keratolimbal allograft transplantation are comparable in terms of visual gain and ocular surface restoration. PMID- 28025794 TI - Alterations in corneal epithelial thickness in patients with congenital myogenic eyelid ptosis. AB - PURPOSE: To evaluate whether the corneal epithelial thickness (CET) maps obtained by optical coherence tomography (OCT) of the congenital myogenic eyelid ptosis differ from controls. METHODS: CET maps of 13 patients with congenital myogenic eyelid ptosis (m/f = 9/4; mean age 20.5 +/- 7.5) and randomly selected one eye of 13 controls (m/f = 7/6; mean age 21.5 +/- 6.5) were investigated. Three pachymetry scans of each eye were performed by OCT (RTVue-XR, Optovue Inc., USA), and the scan with the highest signal strength index was selected for the analysis. RESULTS: In ptosis group: Minimum corneal epithelial thickness was thinner (p = 0.029), standard deviation of thickness was higher (p = 0.039), the negative of min-max values were higher (p = 0.007). This difference was originating from the significant thinness of the superior sectors (S, SN, ST) of the corneal epithelium than the inferior counterparts (I, IT, IN) (p = 0.001, p = 0.017, p = 0.002), respectively. There was no difference regarding total corneal thickness measurements. CONCLUSIONS: The mechanic effects of ptotic eyelid to the ocular surface may reshape the corneal epithelium, which can be objectively detected by OCT. PMID- 28025795 TI - Possible role of HIWI2 in modulating tight junction proteins in retinal pigment epithelial cells through Akt signaling pathway. AB - PIWI subfamily of proteins is shown to be primarily expressed in germline cells. They maintain the genomic integrity by silencing the transposable elements. Although the role of PIWI proteins in germ cells has been documented, their presence and function in somatic cells remains unclear. Intriguingly, we detected all four members of PIWI-like proteins in human ocular tissues and somatic cell lines. When HIWI2 was knocked down in retinal pigment epithelial cells, the typical honeycomb morphology was affected. Further analysis showed that the expression of tight junction (TJ) proteins, CLDN1, and TJP1 were altered in HIWI2 knockdown. Moreover, confocal imaging revealed disrupted TJP1 assembly at the TJ. Previous studies report the role of GSK3beta in regulating TJ proteins. Accordingly, phospho-kinase proteome profiler array indicated increased phosphorylation of Akt and GSK3alpha/beta in HIWI2 knockdown, suggesting that HIWI2 might affect TJ proteins through Akt-GSK3alpha/beta signaling axis. Moreover, treating the HIWI2 knockdown cells with wortmannin increased the levels of TJP1 and CLDN1. Taken together, our study demonstrates the presence of PIWI like proteins in somatic cells and the possible role of HIWI2 in preserving the functional integrity of epithelial cells probably by modulating the phosphorylation status of Akt. PMID- 28025796 TI - IFN-gamma regulates xanthine oxidase-mediated iNOS-independent oxidative stress in maneb- and paraquat-treated rat polymorphonuclear leukocytes. AB - Maneb (MB) and paraquat (PQ) provoke oxidative stress-mediated cell damage. Role of xanthine oxidase (XO) in oxidative stress and its association with nitric oxide (NO)/NO synthase (NOS) have been widely reported. While inducible NOS (iNOS) is implicated in MB+PQ-induced toxicity in rat polymorphonuclear leukocytes (PMNs), role of XO and its alliance with iNOS have not yet been established. The study investigated the role of XO in MB+PQ-induced oxidative stress in rat PMNs and its regulation by iNOS and inflammatory cytokines. MB+PQ augmented reactive oxygen species (ROS), superoxide, nitro-tyrosine, lipid peroxidation (LPO), and nitrite levels along with the catalytic activity of iNOS, superoxide dismutase (SOD), and XO. XO inhibitor, allopurinol (AP), alleviated MB+PQ-induced changes except nitrite content and iNOS activity. Conversely, an iNOS inhibitor, aminoguanidine, mitigated MB+PQ-induced LPO, nitrite, iNOS, and nitro-tyrosine levels; however, no change was observed in ROS, SOD, and XO. Nuclear factor-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), tumor necrosis factor-alpha (TNF-alpha) inhibitor, pentoxyfylline, and an anti inflammatory agent, dexamethasone, attenuated MB+PQ-induced increase in XO, superoxide, and ROS with parallel reduction in the expression of interferon-gamma (IFN-gamma), TNF-alpha, and interleukin-1beta (IL-1beta) in rat PMNs. Exogenous IFN-gamma, TNF-alpha, and IL-1beta enhanced superoxide, ROS, and XO in the PMNs of control and MB+PQ-treated rats; however, IFN- gamma was found to be the most potent inducer. Moreover, AP ameliorated cytokine-induced free radical generation and restored XO activity towards normalcy. The results thus demonstrate that XO mediates oxidative stress in MB+PQ-treated rat PMNs via iNOS-independent but cytokine (predominantly IFN-gamma)-dependent mechanism. PMID- 28025797 TI - Inhibition of cell survival and proliferation by nimbolide in human androgen independent prostate cancer (PC-3) cells: involvement of the PI3K/Akt pathway. AB - Prostate cancer is most common malignancy among men in the world. PI3K-Akt signaling appears to be critical to prostate cancer cell proliferation and survival. Our earlier study reveals that nimbolide (2 uM) prevents cell survival via IGF signaling pathway through PI3K/Akt and induces apoptosis in PC-3 cell line. Akt mediates the phosphorylation and activation of mTOR that plays a critical role in the regulation of protein translation and synthesis, angiogenesis, and cell cycle progression. The present study was aimed to investigate the effect of nimbolide on tPI3K, tAkt, pAkt, tmTOR, GSK3beta, pGSK3beta, PCNA, c-Myc, Cyclin D1, and Survivin protein levels by western blot analysis. Apoptosis was visualized by Ao/EtBr dual staining (20*), and protein expression of PCNA by immunocytochemistry was performed. Molecular docking was performed to understand the possible interaction between nimbolide and Akt, PCNA, and Cyclin D1. Nimbolide altered the PI3K-Akt-mediated cell survival and proliferative molecules. Thus, nimbolide exerted anticancer effects in vitro by representing the PI3K-Akt-mTOR pathway in PC-3 cells. Thereby, it acts as a potent anticancer drug for prostate cancer. PMID- 28025798 TI - Comparison of Glutamate Turnover in Nerve Terminals and Brain Tissue During [1,6 13C2]Glucose Metabolism in Anesthetized Rats. AB - The 13C turnover of neurotransmitter amino acids (glutamate, GABA and aspartate) were determined from extracts of forebrain nerve terminals and brain homogenate, and fronto-parietal cortex from anesthetized rats undergoing timed infusions of [1,6-13C2]glucose or [2-13C]acetate. Nerve terminal 13C fractional labeling of glutamate and aspartate was lower than those in whole cortical tissue at all times measured (up to 120 min), suggesting either the presence of a constant dilution flux from an unlabeled substrate or an unlabeled (effectively non communicating on the measurement timescale) glutamate pool in the nerve terminals. Half times of 13C labeling from [1,6-13C2]glucose, as estimated by least squares exponential fitting to the time course data, were longer for nerve terminals (GluC4, 21.8 min; GABAC2 21.0 min) compared to cortical tissue (GluC4, 12.4 min; GABAC2, 14.5 min), except for AspC3, which was similar (26.5 vs. 27.0 min). The slower turnover of glutamate in the nerve terminals (but not GABA) compared to the cortex may reflect selective effects of anesthesia on activity dependent glucose use, which might be more pronounced in the terminals. The 13C labeling ratio for glutamate-C4 from [2-13C]acetate over that of 13C-glucose was twice as large in nerve terminals compared to cortex, suggesting that astroglial glutamine under the 13C glucose infusion was the likely source of much of the nerve terminal dilution. The net replenishment of most of the nerve terminal amino acid pools occurs directly via trafficking of astroglial glutamine. PMID- 28025799 TI - Upregulated Expression of TRIM32 Is Involved in Schwann Cell Differentiation, Migration and Neurite Outgrowth After Sciatic Nerve Crush. AB - Tripartite motif containing 32 (TRIM32), a member of the tripartite motif (TRIM) family, plays an indispensable role in myoblast proliferation. It also regulates neuron and skeletal muscle stem cell differentiation. Although it is of great importance, we know little about the roles of TRIM32 during peripheral nervous system injury. Here, we examined the dynamic changes of TRIM32 in acute sciatic nerve crush (SNC) model. After crush, TRIM32 rapidly increased and reached the climax at 1 week but then gradually declined to the normal level at 4 weeks post injury. Meanwhile, we observed similar changes of Oct-6. What is more, we found co-localization of TRIM32 with S100 and Oct-6 in 1-week-injured tissues using double immunofluorescent staining. In further vitro experiments, enhancive expression of TRIM32 was detected during the process of cyclic adenosine monophosphate (cAMP)-induced Schwann cell differentiation and nerve growth factor (NGF)-induced PC12 cell neurite outgrowth. More interestingly, specific si-TRIM32 transfected RSC96 cells exhibited obvious reduction in the ability of migration. Taken together, we inferred that upregulated TRIM32 was not only involved in the differentiation and migration of Schwann cells but the neurite elongation after SNC. PMID- 28025800 TI - Intrathecal Delivery of ssAAV9-DAO Extends Survival in SOD1G93A ALS Mice. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset, irreversible neurodegenerative disease that leads to progressive paralysis and inevitable death 3-5 years after diagnosis. The mechanisms underlying this process remain unknown, but new evidence indicates that accumulating levels of D-serine result from the downregulation of D-amino acid oxidase (DAO) and that this is a novel mechanism that leads to motoneuronal death in ALS via N-methyl-D-aspartate receptor-mediated cell toxicity. Here, we explored a new therapeutic approach to ALS by overexpressing DAO in the lumbar region of the mouse spinal cord using a single stranded adeno-associated virus serotype 9 (ssAAV9) vector. A single intrathecal injection of ssAAV9-DAO was made in SOD1G93A mice, a well-established mouse model of ALS. Treatment resulted in moderate expression of exogenous DAO in motorneurons in the lumbar spinal cord, reduced immunoreactivity of D-serine, alleviated motoneuronal loss and glial activation, and extended survival. The potential mechanisms underlying these effects were associated with the down regulation of NF-kappaB and the restoration of the phosphorylation of Akt. In conclusion, administering ssAAV9-DAO may be an effective complementary approach to gene therapy to extend lifespans in symptomatic ALS. PMID- 28025801 TI - Chromium tolerance, oxidative stress response, morphological characteristics, and FTIR studies of phytopathogenic fungus Sclerotium rolfsii. AB - Sclerotium rolfsii is one of the most destructive fungal plant pathogens that can infect over 500 plants and can adapt to diverse environmental conditions. The present research work was carried out to evaluate the impact of both hexa- and trivalent chromium (Cr) on growth, morphology, enzymatic characteristics, and metal accumulation in S. rolfsii under laboratory conditions. Experiments were performed in both malt extract broth and agar growth medium amended with six different concentrations (10, 20, 40, 60, 80, and 100 ppm) of each Cr(III) and Cr(VI) ions inoculated with fungus and incubated for 6-7 days at 25 +/- 3 degrees C. In broth medium, the total protein content was declined and activities of antioxidant enzymes were increased with an increase in metal concentrations. Lower concentrations (10 ppm) of the metal ions stimulated the growth of fungus and higher concentrations (60-100) inhibited it. The Fourier transform infrared spectroscopy (FTIR) assessment showed hydroxyl, carboxyl, and amine groups as major metal binding sites. In agar medium, tolerance index was decreased up to 0.56 at 10-80 ppm of Cr(III) and up to 0.62 at 10-60 ppm of Cr(VI). Considerable modifications were observed in hyphal and sclerotial morphology with an increase in concentration of metal ions. The current study concluded that interference of Cr with growth and physiological process of S. rolfsii could affect its infection level on its host plant. This study provides important information regarding cultivation of susceptible plant varieties in Cr-polluted soil as evidenced by pathogen growth up to 50 ppm of Cr(III) and Cr(VI) ions. PMID- 28025802 TI - The effect of tissue surface modification with collagenase and addition of TGF beta3 on the healing potential of meniscal tears repaired with tissue glues in vitro. AB - The aim of the current in vitro study was to investigate if tissue surface modification with collagenase and addition of the TGF-beta3 can increase the number of cells present in meniscus tears repaired with the use of newly developed tissue adhesives based on isocyanate-terminated block copolymers. Cylindrical explants were harvested from the inner part of bovine menisci. To simulate a full-thickness tear, the central core of the explants was removed and glued back into the defect, with or without incubation in collagenase solution prior to gluing. The repair constructs were then cultured with or without addition of TGF-beta3, and assessed for their histological appearance. The histological staining of the constructs confirmed that both developed adhesives were not cytotoxic. After 28 days, meniscus cells were present in direct contact with the glues. The addition of TGF-beta3 to the culture medium resulted in the presence of cells that formed a sheath inside the simulated tear and in increased cell numbers at the edges of annulus of the explants. In the group in which the tissue was incubated in collagenase and cultured in medium containing TGF-beta3, thicker layers of cells were observed. These results suggest that repairing the torn meniscus with tissue adhesives after pre-treatment of the tissue with collagenase and stimulation with TGF-beta3 is a very promising treatment method, especially when treating the inner avascular part of the meniscus. Nevertheless, longer-term in vitro and in vivo studies are needed to confirm the beneficial effects of this combination therapy. PMID- 28025803 TI - Metabolic Transition of Milk Lactose Synthesis and Up-regulation by AKT1 in Sows from Late Pregnancy to Lactation. AB - Lactose plays a crucial role in controlling milk volume by inducing water toward into the mammary secretory vesicles from the mammary epithelial cell cytoplasm, thereby maintaining osmolality. In current study, we determined the expression of several lactose synthesis related genes, including glucose transporters (glucose transporter 1, glucose transporter 8, sodium-glucose cotransporter 1, sodium glucose cotransporter 3, and sodium-glucose cotransporter 5), lactose synthases (alpha-lactalbumin and beta1,4-galactosyltransferase), and hexokinases (hexokinase-1 and hexokinase-2) in sow mammary gland tissue at day 17 before delivery, on the 1st day of lactation and at peak lactation. The data showed that glucose transporter 1 was the dominant glucose transporter within sow mammary gland and that expression of each glucose transporter 1, sodium-glucose cotransporter 1, hexokinase-1, hexokinase-2, alpha-lactalbumin, and beta1,4 galactosyltransferase were increased (p < 0.05) when the sows transited from late pregnancy to peak lactation. AKT1 over-expressed mammary epithelial cells were then constructed, and the results indicated that AKT1 increases (p < 0.01) the expression of hexokinase-1 and glucose transporter 1. In summary, lactose synthesis was significantly elevated with the increase of milk production and AKT1 could positively regulate lactose synthesis. PMID- 28025804 TI - Investigating Executive Working Memory and Phonological Short-Term Memory in Relation to Fluency and Self-Repair Behavior in L2 Speech. AB - This paper reports the findings of a study investigating the relationship of executive working memory (WM) and phonological short-term memory (PSTM) to fluency and self-repair behavior during an unrehearsed oral task performed by second language (L2) speakers of English at two levels of proficiency, elementary and lower intermediate. Correlational analyses revealed a negative relationship between executive WM and number of pauses in the lower intermediate L2 speakers. However, no reliable association was found in our sample between executive WM or PSTM and self-repair behavior in terms of either frequency or type of self repair. Taken together, our findings suggest that while executive WM may enhance performance at the conceptualization and formulation stages of the speech production process, self-repair behavior in L2 speakers may depend on factors other than working memory. PMID- 28025805 TI - Meaningful Words and Non-Words Repetitive Articulatory Rate (Oral Diadochokinesis) in Persian Speaking Children. AB - Repetitive articulatory rate or Oral Diadochokinesis (oral-DDK) shows a guideline for appraisal and diagnosis of subjects with oral-motor disorder. Traditionally, meaningless words repetition has been utilized in this task and preschool children have challenges with them. Therefore, we aimed to determine some meaningful words in order to test oral-DDK in Persian speaking preschool children. Participants were 142 normally developing children, (age range 4-6 years), who were asked to produce /motaeka, golabi/ as two meaningful Persian words and /pa-ta-ka/ as non-word in conventional oral-DDK task. We compared the time taken for 10-times fast repetitions of two meaningful Persian words and the tri-syllabic nonsense word /pa-ta-ka/. Praat software was used to calculate the average time that subjects took to produce the target items. In 4-5 year old children, [Formula: see text] of time taken for 10-times repetitions of /pa-ta ka, motaeka, golabi/ were [Formula: see text], and [Formula: see text] seconds respectively, and in 5-6 year old children were [Formula: see text], and [Formula: see text] seconds respectively. Findings showed that the main effect of type of words on oral diadochokinesis was significant ([Formula: see text]). Children repeated meaningful words /motaeka, golabi/ faster than the non-word /pa ta-ka/. Sex and age factors had no effect on time taken for repetition of oral DDK test. It is suggested that Speech Therapists can use meaningful words to facilitate oral-DDK test for children. PMID- 28025806 TI - The first detection of potentially toxic Microcystis strains in two Middle Atlas Mountains natural lakes (Morocco). AB - Aguelmam Azizgza (LAZ) and Dayet Afourgah (DAF) are two Moroccan natural lakes located in a humid hydrographic basin of the Middle Atlas Mountains. Both are considered important reservoirs of plant and animal biodiversity. In addition, they are extensively used for recreational and fishing activities and as a water source for irrigation of agricultural crops. Recurrent cyanobacteria scum episodes in the two water bodies have been reported, Microcystis being the main genus in the scums. Here, we report on the toxic potential of three Microcystis aeruginosa strains isolated from those lakes: Mic LAZ and Mic B7 from LAZ and Mic DAF isolated from DAF. The toxic potential was checked by their microcystin (MC) content and the presence of mcy genes involved in MC synthesis. The identification and quantification of MC variants were performed by high performance liquid chromatography-photo-diode array. The detection of mcy genes was achieved by whole-cell multiplex PCR that allowed the simultaneous amplification of DNA sequences corresponding to specific mcy regions. MC content of cultured cells, as MC-LR equivalents per gram cell biomass, was slightly higher in Mic LAZ (ca. 860) than in Mic B7 (ca. 700) and Mic DAF (ca. 690). Four MC variants were identified in the three isolates: MC-WR, MC-RR, MC-DM-WR, and MC YR. The presence of toxic Microcystis strains in the two studied lakes may be regarded as an environmental and health hazard, especially during periods of bloom proliferation. It would be recommended the use of two complementary techniques, as those utilized herein (HPLC and mcy detection) to alert on highly probable toxicity of such lakes. PMID- 28025807 TI - Risk factors and prevalence of dental fluorosis and dental caries in school children of North India. AB - The aim of the study was to assess the prevalence of dental fluorosis, dental caries, and associated risk factors in the school children of district Fatehgarh Sahib, Punjab, India, using a cross-sectional study design. Oral health status of children aged between 8 and 15 years was assessed using World Health Organization (WHO) 2013 criteria. Dental fluorosis was assessed using Dean's index, and dental caries were recorded using decayed, missing, filled/decayed, extracted, filled (DMF/def) indices. Four hundred school children were examined, of which 207 were in the 8-11-year-old group and 193 were in the 12-15-year-old group. The overall prevalence of dental fluorosis was 4.1%, which might be linked to a high concentration of fluoride in drinking water at certain locations of rural Punjab. The prevalence of dental caries was 36.5% with a mean DMF score of 0.3 and def score of 0.6. Risk factors for dental caries include oral hygiene behavior and sugar consumption patterns. The study highlights the need to increase awareness about the oral health and hygiene among the school children in India. PMID- 28025808 TI - Backbone resonance assignments of monomeric SOD1 in dilute and crowded environments. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to movement disorders. In motor neurons of ALS patients, intracellular aggregates of superoxide dismutase 1 (SOD1) have often been observed. To elucidate the aggregation mechanism, it is important to analyze the folding equilibrium of SOD1 between folded and aggregation-prone unfolded states. However, in most cases, this folding equilibrium has been studied in dilute solution even though the aggregate formation occurs in a highly crowded intracellular environment. Indeed, a recent study reported that the folding stability of SOD1 decreased in an environment containing protein crowder molecules. To understand such a destabilization effect due to protein crowders, it is necessary to obtain more precise structural information on SOD1 in the presence of protein crowders. Here, we report the 1H, 13C, and 15N backbone resonance assignments of monomeric SOD1 in the absence and presence of the protein crowder lysozyme. The chemical shift differences caused by addition of lysozyme suggest that SOD1 associated with lysozyme via negatively charged surfaces. Based on the assigned chemical shifts, the presence of lysozyme has a limited influence on the secondary structure of SOD1. We anticipate that our assignments will provide an important basis for elucidation of the crowding induced folding destabilization of SOD1. PMID- 28025809 TI - The Human Orexin/Hypocretin Receptor Crystal Structures. AB - The human orexin/hypocretin receptors (hOX1R and hOX2R) are G protein-coupled receptors (GPCRs) that mediate the diverse functions of the orexin/hypocretin neuropeptides. Orexins/hypocretins produced by neurons in the lateral hypothalamus stimulate their cognate GPCRs in multiple regions of the central nervous system to control sleep and arousal, circadian rhythms, metabolism, reward pathways, and other behaviors. Dysfunction of orexin/hypocretin signaling is associated with human disease, and the receptors are active targets in a number of therapeutic areas. To better understand the molecular mechanism of the orexin/hypocretin neuropeptides, high-resolution three-dimensional structures of hOX1R and hOX2R are critical. We have solved high-resolution crystal structures of both human orexin/hypocretin receptors bound to high-affinity antagonists. These atomic structures have elucidated how different small molecule antagonists bind with high potency and selectivity, and have also provided clues as to how the native ligands may associate with their receptors. The orexin/hypocretin receptor coordinates, now available to the broader academic and drug discovery community, will facilitate rational design of new therapeutics that modulate orexin/hypocretin signaling in humans. PMID- 28025810 TI - Application of a Combined Approach to Identify New Psychoactive Street Drugs and Decipher Their Mechanisms at Monoamine Transporters. AB - Psychoactive compounds can cause acute and long-term health problems and lead to addiction. In addition to well-studied and legally controlled compounds like cocaine, new psychoactive substances (NPS) are appearing in street drug markets as replacement strategies and legal alternatives. NPS are effectively marketed as "designer drugs" or "research chemicals" without any knowledge of their underlying pharmacological mode of action and their potential toxicological effects and obviously devoid of any registration process. As of 2016, the knowledge of structure-activity relationships for most NPS is scarce, and predicting detailed pharmacological activity of newly emerging drugs is a challenging task. Therefore, it is important to combine different approaches and employ biological test systems that are superior to mere chemical analysis in recognizing novel and potentially harmful street drugs. In this chapter, we provide a detailed description of techniques to decipher the molecular mechanism of action of NPS that target the high-affinity transporters for dopamine, norepinephrine, and serotonin. In addition, this chapter provides insights into a combined approach to identify and characterize new psychoactive street drugs of unknown content in a collaboration with the Austrian prevention project "checkit!." PMID- 28025811 TI - Neurocognition in PTSD: Treatment Insights and Implications. AB - Post-traumatic stress disorder (PTSD) is classified as a traumatic stress-related condition and is most often discussed in terms of emotional dysfunction. However, given that cognitive and emotional processes are intricately intertwined, implemented by overlapping brain networks, and effectively integrated in at least some of the same regions (e.g., prefrontal cortex, for a review, see Crocker et al. 2013), an abundance of literature now highlights the key role that cognitive functioning plays in both the development and maintenance (or exacerbation) of PTSD symptoms (Aupperle et al. 2012a; Verfaellie et al. 2012). Findings from this body of work detail objective impairment in neuropsychological function in those with PTSD (Brandes et al. 2002; Hayes et al. 2012a; Koenen et al. 2001). Yet despite the impact of neurocognition on PTSD treatment engagement and success (e.g., Haaland et al. 2016; Nijdam et al. 2015) and conversely, the role of PTSD treatment in normalizing cognitive dysfunction, a much smaller literature exists on neurocognitive changes following treatment for PTSD. Even aside from its role in treatment, cognitive functioning in PTSD has significant implications for daily functioning for individuals with this disorder, as cognition is predictive of school achievement, obtaining and maintaining employment, job advancement, maintaining relationships, greater wealth, and better health and quality of life (e.g., Diamond and Ling 2016). PMID- 28025812 TI - The Anatomy and Physiology of Eyeblink Classical Conditioning. AB - This chapter reviews the past research toward identifying the brain circuit and its computation underlying the associative memory in eyeblink classical conditioning. In the standard delay eyeblink conditioning paradigm, the conditioned stimulus (CS) and eyeblink-eliciting unconditioned stimulus (US) converge in the cerebellar cortex and interpositus nucleus (IPN) through the pontine nuclei and inferior olivary nucleus. Repeated pairings of CS and US modify synaptic weights in the cerebellar cortex and IPN, enabling IPN neurons to activate the red nucleus and generate the conditioned response (CR). In a variant of the standard paradigm, trace eyeblink conditioning, the CS and US are separated by a brief stimulus-free trace interval. Acquisition in trace eyeblink conditioning depends on several forebrain regions, including the hippocampus and medial prefrontal cortex as well as the cerebellar-brainstem circuit. Details of computations taking place in these regions remain unclear; however, recent evidence supports a view that the forebrain encodes a temporal sequence of the CS, trace interval, and US in a specific environmental context and signals the cerebellar-brainstem circuit to execute the CR when the US is likely to occur. Together, delay eyeblink conditioning represents one of the most successful cases of understanding the neural substrates of long-term memory in mammals, while trace eyeblink conditioning demonstrates its utility for uncovering detailed computations in the whole brain network underlying long-term memory. PMID- 28025813 TI - The Sensory Neocortex and Associative Memory. AB - Most behaviors in mammals are directly or indirectly guided by prior experience and therefore depend on the ability of our brains to form memories. The ability to form an association between an initially possibly neutral sensory stimulus and its behavioral relevance is essential for our ability to navigate in a changing environment. The formation of a memory is a complex process involving many areas of the brain. In this chapter we review classic and recent work that has shed light on the specific contribution of sensory cortical areas to the formation of associative memories. We discuss synaptic and circuit mechanisms that mediate plastic adaptations of functional properties in individual neurons as well as larger neuronal populations forming topographically organized representations. Furthermore, we describe commonly used behavioral paradigms that are used to study the mechanisms of memory formation. We focus on the auditory modality that is receiving increasing attention for the study of associative memory in rodent model systems. We argue that sensory cortical areas may play an important role for the memory-dependent categorical recognition of previously encountered sensory stimuli. PMID- 28025814 TI - Phenomenology, Structure, and Dynamic of Psychedelic States. AB - Classic serotonergic hallucinogens or psychedelics produce an altered states of consciousness (ASC) that is characterized by profound alterations in sensory perception, mood, thought including the perception of reality, and the sense of self. Over the past years, there has been considerable progress in the search for invariant and common features of psychedelic states. In the first part of this review, we outline contemporary approaches to characterize the structure of ASCs by means of three primary etiology-independent dimensions including oceanic boundlessness, anxious ego-dissolution, and visionary restructuralization as well as by 11 lower-order factors, all of which can be reliably measured by the altered state of consciousness questionnaire (APZ-OAV). The second part sheds light on the dynamic nature of psychedelic experiences. Frequently, psychedelic subjects progress through different stages over time and levels of changes along a perception-hallucination continuum of increasing arousal and ego-dissolution. We then review in detail the acute effects of psychedelics on sensory perception, emotion, cognition, creativity, and time perception along with possible neural mechanisms underlying them. The next part of this review outlines the influence of non-pharmacological factors (predictors) on the acute psychedelic experience, such as demographics, genetics, personality, mood, and setting, and also discusses some long-term effects succeeding the acute experience. The last part presents some recent concepts and models attempting to understand different facets of psychedelic states of consciousness from a neuroscientific perspective. PMID- 28025815 TI - Capecitabine-Induced Severe Toxicity Secondary to DPD Deficiency and Successful Treatment with Low Dose 5-Fluorouracil. PMID- 28025816 TI - The Comparison of the Advantages of Neoadjuvant Chemoradiotherapy versus Postoperative Chemoradiotherapy: Outcomes in Esophageal Cancer Patients. AB - BACKGROUND AND OBJECTIVES: Esophageal cancer is the eighth most common type of cancer worldwide. For the treatment of which, surgical intervention alone or with neoadjuvant chemoradiotherapy or chemotherapy is recommended. In this study, we aimed to compare the benefits of neoadjuvant chemoradiotherapy versus postoperative chemoradiotherapy. PATIENTS AND METHODS: We collected data regarding 325 patients admitted for esophageal cancer to Qaem Hospital, Mashhad, Iran, during 2006-2016. The participants were divided into two groups of neoadjuvant and postoperative adjuvant therapies. Chi-square, McNemar, Kaplan Mayer, and multivariate regression tests were performed using SPSS. RESULTS: Gender, age, stage of the disease, tumor grade and location, disease histopathology, and the recurrence showed no significant differences between the two groups (P ? 0.05), but there was a significant association between the two types of treatment in terms of postoperative complications (P = 0.03). We followed up 147 patients postoperatively and found no significant differences between the groups (P ? 0.05). CONCLUSION: No conclusion can be drawn on whether there are any advantages in adjuvant chemoradiotherapy over neoadjuvant approaches. Further confirmatory trials, particularly randomized trials, are necessary before any recommendations can be made. PMID- 28025818 TI - Need for knowledge translation to improve tumor marker application. PMID- 28025817 TI - Cost Effectiveness of Metal Stents in Relieving Obstructive Jaundice in Patients with Pancreatic Cancer. AB - BACKGROUND: ASGE and ESGE guidelines recommend endoscopic metal stent placement for pancreatic carcinoma patients with biliary obstruction, and whose estimated life expectancy is greater than 6 months. Because median overall survival (OS) of metastatic pancreatic adenocarcinoma until recently has been less than 6 months, plastic biliary stents were preferentially placed rather than metal due to the greater upfront cost of the latter. Recent advances in the treatment of metastatic pancreatic cancer have extended median OS beyond the 6-month range. Given this improvement in OS, we performed a cost-effectiveness analysis of initial metal biliary versus plastic stent placement in metastatic pancreatic cancer patients with biliary obstruction. METHODS: A Markov model was developed to predict lifetime costs, quality-adjusted life years (QALYs), and cost effectiveness of metal compared with plastic stents. Adult patients entered the model with locally advanced cancer and underwent endoscopic retrograde cholangiopancreatography (ERCP) with placement of metal or plastic stents. A targeted literature search was conducted to identify published sources, which were used to estimate clinical, cost, utility, and event rate inputs to the model. Results were estimated from the third-party payer perspective in 2012 US dollars per QALY. One-way and probabilistic sensitivity analyses were conducted to assess the impact on model outcomes resulting from uncertainty among inputs. RESULTS: Our analysis found that initial placement of metal stents was more cost effective than plastic biliary stents with lower overall costs due to lower restenting rates while at the same time associated with a better quality of life. Based on model projections, placement of metal stents could save approximately $1450 per patient over a lifetime, while simultaneously improving quality of life. These findings were robust in sensitivity analyses. CONCLUSIONS: Placement of metal biliary stents at initial onset of obstructive jaundice in adult patients with metastatic pancreatic carcinoma with an expected OS greater than 6 months was found to be a more cost-effective strategy than plastic stents. These results reinforce guidelines' suggestions for metal stent placement. PMID- 28025819 TI - Circulating tumor markers: a guide to their appropriate clinical use | Comparative summary of recommendations from clinical practice guidelines (PART 1) PMID- 28025820 TI - Adductor canal blocks: changing practice patterns and associated quality profile. AB - BACKGROUND: Femoral nerve blocks have been the gold standard approach for post operative analgesia following total knee arthroplasty; however, the adductor canal block has recently gained popularity due to less block-induced motor weakness. The primary aim of this time-series analysis was to identify whether regional anesthesia practice changes have occurred for total knee arthroplasty. Our secondary aim was to assess for possible associated changes in safety and quality. METHODS: Using a 20-member clinical registry, we examined the practice patterns and safety around the performance of adductor canal blocks for all total knee arthroplasties between 18 July 2011 to 9 October 2015. To obtain more information about changes in quality associated with this practice transition, we analyzed clinical outcomes data surrounding all primary total knee arthroplasties from the largest contributing institution. RESULTS: A total of 6921 blocks were performed for 4822 primary and revision total knee arthroplasties (TKAs). Across the registry, adductor canal block utilization for TKA increased. This was not associated with any increase in immediate or recovery room-related complications. When analyzing unilateral primary TKAs from the largest surgical volume center (n = 766), there were no statistically significant changes in numeric rating scale scores (5.4 to 4.6, P value = 0.004), length of stay (3.0 to 2.8 days, P value = 0.3), or 30-day hospital re-evaluations for pain (2.8-4.9%, P value = 0.1). CONCLUSION: There was a large increase in the utilization of adductor canal blockade for TKAs among participating registry members. This change in practice was not associated with significant changes in safety or quality. PMID- 28025821 TI - Identifying patients at risk of acute symptomatic seizure after ischemic stroke. AB - BACKGROUND: Contributors to post-stroke seizure research have advocated the need for prospective studies of acute symptomatic seizures after stroke. Identification of the patient at risk of seizure and the impact of the event on outcome is a prerequisite for this kind of research. The aim of this study was to identify risk factors, make an outline for a risk score, and look at consequences of seizure on short-time clinical outcomes. METHODS: This registry-based study included patients with ischemic stroke admitted between 2007 and 2013. We identified variables associated with the presence of acute symptomatic seizures and made a risk score. Clinical outcome measures were modified Rankin scale, National Institute of Health Stroke Scale (NIHSS), and death at discharge or at day seven. RESULTS: A total of 2598 ischemic stroke patients were included, 66 experiencing seizure within seven days of stroke. We found diabetes mellitus, NIHSS on admission, and cortical lesion to be associated with the risk of seizure. The risk score had a sensitivity of 58%, specificity of 85%, and a positive predictive value of 9% with a three-point cutoff. We found a negative effect of seizure on survival in mild-to-moderate strokes after adjusting for infections and stroke severity. CONCLUSIONS: Because of low incidence and the lack of specific risk factors, acute symptomatic seizure after ischemic stroke is hard to predict. The negative effect of seizure on stroke outcome is uncertain, and more thorough studies are needed because of possible subtle or non-overt seizures. PMID- 28025822 TI - The experience of the International Consortium on Acute Promyelocytic Leukemia in monitoring minimal residual disease in acute promyelocytic leukaemia. PMID- 28025823 TI - HLA Alleles are Genetic Markers for Susceptibility and Resistance towards Leprosy in a Mexican Mestizo Population. AB - Despite the use of multidrug therapy, leprosy remains endemic in some countries. The association of several human leucocyte antigen (HLA) alleles and gene polymorphisms with leprosy has been demonstrated in many populations, but the major immune contributors associated to the spectrum of leprosy have not been defined yet. In this study, genotyping of HLA-A, -B, -DR, and -DQ alleles was performed in leprosy patients (n = 113) and control subjects (n = 117) from the region with the highest incidence for the disease in Mexico. The odds of developing leprosy and lepromatous subtype were 2.12- and 2.74-fold higher in carriers of HLA-A*28, and 2.48- and 4.14-fold higher for leprosy and dimorphic subtype in carriers of DQB1*06. Interestingly, DQB1*07 was overrepresented in healthy individuals, compared to patients with leprosy (OR = 0.08) and the lepromatous subtype (OR = 0.06). These results suggest that HLA-A*28 is a marker for predisposition to leprosy and the lepromatous subtype and DQB1*06 to leprosy and the dimorphic subtype, while DQB1*07 might be a resistance marker in this Mestizo population. PMID- 28025825 TI - Ultrastructural analysis of sequential cyprinid herpesvirus 3 morphogenesis in vitro. AB - Cyprinid herpesvirus 3 (CyHV-3) is an alloherpesvirus, and it is the aetiological agent of koi herpesvirus disease. Although the complex morphogenic stages of the replication cycle of CyHV-3 were shown to resemble that of other members of the Herpesvirales, detailed analysis of the sequence and timing of these events was not definitively determined. This study describes these features through a time course using cyprinid cell cultures (KF-1 and CCB) infected with CyHV-3 (KHV isolate, H361) and analysed by transmission electron microscopy. Rapid viral entry was noted, with high levels of intracellular virus within 1-4 h post infection (hpi). Intranuclear capsid assembly, paracrystalline array formation and primary envelopment of capsids occurred within 4 hpi. Between 1 and 3 days post-infection (dpi), intracytoplasmic secondary envelopment occurred, as well as budding of infectious virions at the plasma membrane. At 5-7 dpi, the cytoplasm contained cytopathic vacuoles, enveloped virions within vesicles, and abundant non-enveloped capsids; also there was frequent nuclear deformation. Several morphological features are suggestive of inefficient viral assembly, with production of non-infectious particles, particularly in KF-1 cells. The timing of this alloherpesvirus morphogenesis is similar to other members of the Herpesvirales, but there may be possible implications of using different cell lines for CyHV-3 propagation. PMID- 28025824 TI - Four-week cold acclimation in adult humans shifts uncoupling thermogenesis from skeletal muscles to brown adipose tissue. AB - KEY POINTS: Muscle-derived thermogenesis during acute cold exposure in humans consists of a combination of cold-induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold-induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography-determined muscle activity and whole-body heat production following cold acclimation suggests a maintenance of ATPase-dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure. ABSTRACT: We previously showed that 4 weeks of daily cold exposure in humans can increase brown adipose tissue (BAT) volume by 45% and oxidative metabolism by 182%. Surprisingly, we did not find a reciprocal reduction in shivering intensity when exposed to a mild cold (18 degrees C). The present study aimed to determine whether changes in skeletal muscle oxidative metabolism or shivering activity could account for these unexpected findings. Nine men participated in a 4 week cold acclimation intervention (10 degrees C water circulating in liquid-conditioned suit, 2 h day-1 , 5 days week-1 ). Shivering intensity and pattern were measured continuously during controlled cold exposure (150 min at 4 degrees C) before and after the acclimation. Muscle biopsies from the m. vastus lateralis were obtained to measure oxygen consumption rate and proton leak of permeabilized muscle fibres. Cold acclimation elicited a modest 21% (P < 0.05) decrease in whole-body and m. vastus lateralis shivering intensity. Furthermore, cold acclimation abolished the acute cold-induced increase in proton leak. Although daily cold exposure did not change the fibre composition of the m. vastus lateralis, fibre composition was a strong predictor of the shivering pattern evoked during acute cold. We conclude that muscle derived thermogenesis during acute cold exposure in humans is not only limited to shivering, but also includes cold-induced increases in proton leak. The efficiency of muscle oxidative phosphorylation improves with cold acclimation, suggesting that reduced muscle thermogenesis occurs through decreased proton leak, in addition to decreased shivering intensity as BAT capacity and activity increase. These changes occur with no net difference in whole-body thermogenesis. PMID- 28025826 TI - Concurrent use of continuous and pulsatile flow Ventricular Assist Device on a fontan patient: A simulation study. AB - The aim of this work is to develop and test a lumped parameter model of the cardiovascular system to simulate the concurrent use of pulsatile (PVAD) and continuous flow (CVAD) ventricular assist device (VAD) on Fontan patients. Echocardiographic and hemodynamic data of five Fontan patients were retrospectively collected and used to simulate the patients' baseline hemodynamics. Then, for each patient, the following assistance modality was simulated for the cavopulmonary and the single ventricle (SV): (a) CVAD for cavopulmonary assistance (RCF) and PVAD assisting the SV (LCF) (RPF + LCF), (b) CVAD assisting SV and PVAD for cavopulmonary assistance (LPF + RCF). The numerical model can well reproduce patients' baseline. The cardiac output increases more importantly in the LCF + RPF configuration (35 vs. 8%). Ventricular volume decreases more evidently in the configuration LCF + RPF (28 vs. 6%), atrial pressure decreases in the LCF + RPF modality (10%), while it slightly increases in the RCF + LPF modality. The pulmonary arterial pressure slightly decreases (increases) in the configuration RCF + LPF (LCF + RPF). Ventricular external work increases in both configurations because of the total increment of the cardiac output. However, artero-ventricular coupling improves in both configurations: RCF + LPF-14%, LCF + RPF-41%. The pulsatility index decreases (increases) by 8% (13.8%) in the configuration LCF + RPF (RCF + LPF). A model could permit us to simulate extreme physiological conditions of the implantation of both CF and PF VAD on the Fontan patient and could permit to choose the proper VAD on the base of patients' condition. The configuration LCF + RPF seems to maximize the hemodynamic benefits. PMID- 28025827 TI - The ecology of a continental evolutionary radiation: Is the radiation of sigmodontine rodents adaptive? AB - Evolutionary radiations on continents are less well-understood and appreciated than those occurring on islands. The extent of ecological influence on species divergence can be evaluated to determine whether a radiation was ultimately the outcome of divergent natural selection or else arose mainly by nonecological divergence. Here, we used phylogenetic comparative methods to test distinct hypotheses corresponding to adaptive and nonadaptive evolutionary scenarios for the morphological evolution of sigmodontine rodents. Results showed that ecological variables (diet and life-mode) explain little of the shape and size variation of sigmodontine skulls and mandibles. A Brownian model with varying rates for insectivory versus all other diets was the most likely evolutionary model. The insectivorous sigmodontines have a faster rate of morphological evolution than mice feeding on other diets, possibly due to stronger selection for features that aid insectivory. We also demonstrate that rapid early-lineage diversification is not accompanied by high morphological divergence among subclades, contrasting with island results. The geographic size of continents permits spatial segregation to a greater extent than on islands, allowing for allopatric distributions and escape from interspecific competition. We suggest that continental radiations of rodents are likely to produce a pattern of high species diversification coupled with a low degree of phenotypic specialization. PMID- 28025828 TI - Prognostic parameters and outcome after re-irradiation for progressive glioblastoma. AB - OBJECTIVES: In progressive glioblastoma, salvage treatment remains unstandardized, response is highly variable, and detailed analysis of individual approaches is mandatory. Re-irradiation is an established option in the therapy of progressive glioblastoma. Thus, we analysed outcome and prognostic parameters of patients with re-irradiated glioblastoma treated at our institution since 1998. MATERIALS AND METHODS: In a total of 51 patients, clinical and treatment parameters were collected and analysed retrospectively. Re-irradiation protocols included radiosurgery, hypofractionated radiotherapy or normofractionated radiotherapy. Outcome was analysed regarding prognostic factors in this highly selected cohort. RESULTS: Median overall survival after primary diagnosis was 28.8 months. Patients re-irradiated with single-dose stereotactic radiosurgery or hypofractionated regimes showed a superior overall survival after primary diagnosis compared to normofractionated treatment. Positive prognostic factors included a smaller gross tumour volume and younger age. A methylated MGMT promoter approached statistical significance as a positive factor regarding overall survival after re-irradiation. Further well-known prognostic factors as extension of the initial resection and the concomitance of temozolomide with the initial radiation treatment only appeared relevant in a subgroup of four long term survivors. CONCLUSIONS: The favourable results regarding overall survival are probably due to patient selection for re-irradiation. If technically feasible, stereotactic radiosurgery or hypofractionated regimes should be preferred. In this highly selected re-irradiation cohort, only some of the well known prognostic factors of the primary tumour setting were found to influence overall survival significantly. In contrast, also some patients presenting with unfavourable predictive parameters showed an encouraging course of disease and thus should not be excluded from re-irradiation. PMID- 28025829 TI - A bibliographic exploration of nursing's scope of practice. AB - AIM: To conduct a bibliographic analysis of the indexed literature relating to scope of practice in nursing so as to identify underlying patterns in journal publication, volume of scholarly work over time, countries of origin, central contributors, academic affiliation and the major dimension of the studies conducted. METHODS: A systematic search of the Scopus database provided data that was then extracted and utilized to undertake a bibliometric analysis of published work relating to scope of practice. In addition to identification of aggregated metrics relating to the most frequently occurring journals and most cited authors, a co-word analysis was conducted. RESULTS: A total of 2730 articles with the term Scope of Practice in the Title, Abstract or Keywords were identified. Co word analysis revealed five major themes - Changing Regulatory Environment; Health Care Drivers; Competence & Role Implementation; Policy Context; and Role Evolution & Role Differentiation. CONCLUSIONS AND POLICY IMPLICATIONS: From a policy perspective, we conclude that bibliographic analysis of the indexed literature is a useful technique that can augment our understanding of key regulatory issues such as scope of practice. However, the overemphasis on advanced practice in the scope of practice literature coupled with the increased interest in task shifting to support-personnel as governments pursue the goal of universal health coverage may leave nursing inadequately prepared to inform any evidence-based policy change. PMID- 28025830 TI - The Hispanic and Latino dentist workforce in the United States. AB - OBJECTIVES: The purpose of this paper is to describe the Hispanic/Latino (H/L) dentist workforce, their general practice patterns, and their contributions to oral health care for H/L and underserved patients. METHODS: A national sample survey of underrepresented minority dentists was conducted in 2012 and received a 35.4 percent response rate for self-reported H/L dentists. Data were weighted for selection and response bias to be nationally representative. A workforce profile of H/L dentists was created using descriptive and multivariable statistics and published data. RESULTS: Among all H/L dentists (weighted n = 5,748), 31.9 percent self-identify their origin as Mexican, 13.4 percent as Puerto Rican, 13.0 percent as Cuban, and 41.7 percent as another H/L group. The largest share of H/L dentists are male, married, and have children under age 18. Fifty percent of H/L dentists are foreign-born and 25 percent are foreign-trained. H/L dentists report higher than average educational debt, with those completing International Dentist Programs reporting the highest debt load. Sixty-nine percent of clinically active H/L dentists own their own practices, and 85 percent speak Spanish in their practice. Among clinical H/L dentists, 7 percent work in safety-net settings, 40 percent primarily treat underserved populations, and, on average, 42 percent of their patient population is H/L. CONCLUSIONS: H/L dental providers are underrepresented in the dentist population, and those that are in practice shoulder a disproportionate share of dental care for minority and underserved communities. Improving the workforce diversity of dental providers is a critical part of strategy to address the high burden of dental disease in the H/L population. PMID- 28025831 TI - New Daily Persistent Headache Caused by a Multinodular Goiter and Headaches Associated With Thyroid Disease. AB - A 33-year-old female is presented with the first case to our knowledge of new daily persistent headache (NDPH) with a large right benign non-toxic multinodular goiter causing carotid and vertebral compression with complete resolution of the headache immediately after thyroidectomy. Although this may be quite rare, hypothyroidism or hyperthyroidism causing NDPH, migraine, or an exacerbation of pre-existing migraine is not. Clinicians should consider routinely obtaining serum thyroid-stimulating hormone (TSH) and free T4 in patients with new onset frequent headaches or an exacerbation of prior primary headaches. PMID- 28025832 TI - Characterizing the sympatholytic role of endothelial-dependent vasodilator signalling during handgrip exercise. PMID- 28025833 TI - Inhibition of CHK1 and WEE1 as a new therapeutic approach in diffuse large B cell lymphomas with MYC deregulation. PMID- 28025834 TI - Chinese children's early knowledge about writing. AB - Much research on literacy development has focused on learners of alphabetic writing systems. Researchers have hypothesized that children learn about the formal characteristics of writing before they learn about the relations between units of writing and units of speech. We tested this hypothesis by examining young Chinese children's understanding of writing. Mandarin-speaking 2- to 5-year olds completed a graphic task, which tapped their knowledge about the formal characteristics of writing, and a phonological task, which tapped their knowledge about the correspondence between Chinese characters and syllables. The 3- to 5 year-olds performed better on the graphic task than the phonological task, indicating that learning how writing appears visually begins earlier than learning that writing corresponds to linguistic units, even in a writing system in which written units correspond to syllables. Statement of contribution What is already known on this subject? Learning about writing's visual form, how it looks, is an important part of emergent literacy. Knowledge of how writing symbolizes linguistic units may emerge later. What does this study add? We test the hypothesis that Chinese children learn about writing's visual form earlier than its symbolic nature. Chinese 3- to 5- year-olds know more about visual features than character-syllable links. Results show learning of the visual appearance of a notation system is developmentally precocious. PMID- 28025835 TI - Bedside Tunneled Dialysis Catheter Removal-A Lesson Learned From Nephrology Trainees. AB - Semi-permanent dual-lumen tunneled (or tunneled-cuffed) hemodialysis catheters (TDC) are increasingly utilized during renal replacement therapy, while awaiting permanent access maturation or renal recovery. Although there is a wealth of literature focused on placement, infection prevention, and maintenance of catheter patency, circumstances and indications for TDC removal are less well understood. Timely removal of these catheters is an important management decision, with the length of TDC duration representing the largest cumulative risk factor for catheter-associated blood stream infections. Waiting for assistance from surgical or radiological services-which may not be available in all hospitals-may result in delays in services and potential harm to the patients. Imparting and maintaining procedural skills to remove infected TDC may be very valuable for training programs in clinical nephrology. In this article the current literature on bedside TDC removal, including potential anticipated complications during removal, are reviewed. To date, the authors have documented successful implementation of bedside TDC removal in training programs from two different settings, including both in- and outpatients and with trainee involvement. In summary, training general nephrologists for bedside TDC removal will afford immediate removal of infected hardware in ill patients and avoid potential delays in outpatient setting. PMID- 28025836 TI - STAT3 mutations are not sufficient to induce large granular lymphocytic leukaemia in mice. PMID- 28025837 TI - Ketamine Infusions for Treatment Refractory Headache. AB - BACKGROUND: Management of chronic migraine (CM) or new daily persistent headache (NDPH) in those who require aggressive outpatient and inpatient treatment is challenging. Ketamine has been suggested as a new treatment for this intractable population. METHODS: This is a retrospective review of 77 patients who underwent administration of intravenous, subanesthetic ketamine for CM or NDPH. All patients had previously failed aggressive outpatient and inpatient treatments. Records were reviewed for patients treated between January 2006 and December 2014. RESULTS: The mean headache pain rating using a 0-10 pain scale was an average of 7.1 at admission and 3.8 on discharge (P < .0001). The majority (55/77, 71.4%) of patients were classified as acute responders defined as at least 2-point improvement in headache pain at discharge. Some (15/77, 27.3%) acute responders maintained this benefit at their follow-up office visit but sustained response did not achieve statistical significance. The mean length of infusion was 4.8 days. Most patients tolerated ketamine well. A number of adverse events were observed, but very few were serious. CONCLUSIONS: Subanesthetic ketamine infusions may be beneficial in individuals with CM or NDPH who have failed other aggressive treatments. Controlled trials may confirm this, and further studies may be useful in elucidating more robust benefit in a less refractory patient population. PMID- 28025838 TI - Hodgkin lymphoma: is there really a need for interim and end-of-treatment FDG-PET evaluations? PMID- 28025839 TI - Biological and structural effects of the conjugation of an antimicrobial decapeptide with saturated, unsaturated, methoxylated and branched fatty acids. AB - The increasing bacterial resistance against conventional antibiotics has led to the search for new antimicrobial drugs with different modes of action. Cationic antimicrobial peptides (AMPs) and lipopeptides are promising candidates to treat infections because they act on bacterial membranes causing rapid destruction of sensitive bacteria. In this study, a decapeptide named A2 (IKQVKKLFKK) was conjugated at the N-terminus with saturated, unsaturated, methoxylated and methyl -branched fatty acids of different chain lengths (C8 - C20), the antimicrobial and structural properties of the lipopeptides being then investigated. The attachment of the fatty acid chain significantly improved the antimicrobial activity of A2 against bacteria, and so, endowed it with moderated antifungal activity against yeast strains belonging to genus Candida. Lipopeptides containing hydrocarbon chain lengths between C8 and C14 were the best antibacterial compounds (MIC = 0.7 to 5.8 MUM), while the most active compounds against yeast were A2 conjugated with methoxylated and enoic fatty acids (11.1 to 83.3 MUM). The improvement in antimicrobial activity was mainly related to the amphipathic secondary structure adopted by A2 lipopeptides in the presence of vesicles that mimic bacterial membranes. Peptide conjugation with long hydrocarbon chains (C12 or more), regardless of their structure, significantly increased toxicity towards eukaryotic cells, resulting in a loss of selectivity. These findings suggest that A2-derived lipopeptides are potential good candidates for the treatment of infectious diseases caused by bacteria and opportunistic pathogenic yeast belonging to genus Candida. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28025840 TI - Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients. AB - BACKGROUND: Real-life long-term data on infliximab treatment in ulcerative colitis are limited. AIM: To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined. METHODS: A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age >=18 years, ambulatory treated, steroid dependent or intolerant and/or immunomodulator refractory or intolerant. RESULTS: Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10 17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy. CONCLUSIONS: Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy. PMID- 28025841 TI - Regulation of diapause in carnivores. AB - Embryonic diapause is an evolutionary strategy to ensure that offspring are born when maternal and environmental conditions are optimal for survival. In many species of carnivores, obligate embryonic diapause occurs in every gestation. In mustelids, the regulation of diapause and reactivation is influenced by photoperiod, which then acts to regulate the secretion of pituitary prolactin. Prolactin in turn regulates ovarian steroid function. Reciprocal embryo transplant studies indicate that this state of embryonic arrest is conferred by uterine conditions and is presumed to be due to a lack of specific factors necessary for continued development. Studies of global gene expression in the mink (Neovison vison) revealed reduced expression of a cluster of genes that regulate the abundance of polyamines in the uterus during diapause, including the rate-limiting enzyme in polyamine production, ornithine decarboxylase (ODC). In addition, in this species, in vivo inhibition of the conversion of ornithine to the polyamine, putrescine, induces a reversible arrest in embryonic development and an arrest in both trophoblast and inner cell mass proliferation in vitro. Putrescine, at 0.5, 2 and 1,000 MUM concentrations induced reactivation of mink embryos in culture, indicated by an increase in embryo volume, observed within five days. Further, prolactin induces ODC1 expression in the uterus, thereby regulating uterine polyamine levels. These results indicate that pituitary prolactin acts on ovarian and uterine targets to terminate embryonic diapause. In summary, our findings suggest that the polyamines, with synthesis under the control of pituitary prolactin, are the uterine factor whose absence is responsible for embryonic diapause in mustelid carnivores. PMID- 28025842 TI - A review of safe-staffing models and their applicability to care homes. AB - Presently, there are a range of evidence-based staffing tools that have been used to inform nursing, midwifery and health care capacity. These tools are designed to be used with professional judgement and include frameworks such as Rhys Hearn, the National Services Scotland Care Home Staffing Project, a variety of Royal College of Nursing Tool Kits including the Older People in Hospital's tool and the only National Institute of Clinical Excellence approved safe-staffing tool, Shelford's Safer Nursing Tool. These safe-staffing tools are used to score a patient's or resident's level of dependency across a number of domains, for example a patient/resident's ability to wash, dress, mobilise or fulfil their own elimination needs. While these tools have been beneficial with regards to informing staff levels there are a number of limitations that are important to highlight. Succinctly, most are not readily applicable to care home settings nor do they focus on more person-centred aspects of care. PMID- 28025843 TI - 10 kHz High-Frequency Spinal Cord Stimulation for Chronic Axial Low Back Pain in Patients With No History of Spinal Surgery: A Preliminary, Prospective, Open Label and Proof-of-Concept Study. AB - OBJECTIVE: To explore the effectiveness of 10 kHz high frequency spinal cord stimulation (HF10 therapy) treatment of chronic low back pain in patients who have not had spinal surgery. METHODS: Patients with chronic low back pain without prior spinal surgery were evaluated by a team of spine surgeons to rule out any spinal pathology amenable to surgical interventions and by a multidisciplinary pain team to confirm eligibility for the study. After a successful (>50% back pain reduction) trial of HF10 therapy, enrolled subjects underwent permanent system implantation and were followed-up one year post-implant. RESULTS: About 95% of the enrolled subjects (20/21) received the permanent system. At 12 months post-implant, both back pain VAS score and ODI were significantly reduced compared with baseline values (by 73% and 48%, respectively); an estimated quality-adjusted life year gain of 0.47 and a reduction in opioid use by 64% was observed. Four more patients among those unable to work at baseline due to back pain were employed at 12 months post-implant. There were no serious adverse events. CONCLUSION: HF10 therapy may provide significant back pain relief, reduction in disability, improvement quality of life, and reduction in opioid use in chronic low back pain not resulting from spinal surgery. PMID- 28025844 TI - Cross-Sectional Study Evaluating Skin, Hair, Nail, and Bone Disease in Patients with Focal Dermal Hypoplasia. AB - Focal dermal hypoplasia (FDH) is an X-linked dominant disease characterized by dermal thinning and fat herniation with other ectodermal and mesodermal abnormalities. There is limited literature regarding the symptomatology and progression of skin, hair, and nail disease. The risk of bone fragility has not been explored either. This cross-sectional survey-based study explored these gaps in knowledge and provides direction for future avenues of research in FDH. PMID- 28025845 TI - Managing support for newly qualified practitioners: lessons learnt from one health care region in the UK. AB - AIM: The study mapped the support provided for newly qualified practitioners across Kent, Surrey and Sussex. BACKGROUND: Newly qualified practitioners require support and guidance to facilitate their transition from student to their new role as qualified practitioner. Professional bodies advocate that programmes be provided but the type and intensity of that support is variable. METHODS: Telephone interviews were conducted with 24 people delivering support for newly qualified practitioners across professions in 13 different health care trusts. Documents (n = 41) related to support programmes were analysed. Two case study site visits and a knowledge exchange conference of 45 delegates completed the data collection. Data were analysed using the constant comparative method of analysis. RESULTS: Support for newly qualified practitioners was largely idiosyncratic to profession and Trust. Evidence emerged of a conceptual shift from basic competency acquisition toward a corporate induction programme. CONCLUSIONS: Interdisciplinary programmes can provide generic transitional support, but the newly qualified practitioners favoured skill acquisition to help them to be effective in their new role. Measuring the impact of newly qualified practitioner support on patient outcome and the practitioner is required. IMPLICATIONS FOR NURSING MANAGEMENT: A career pathway for those who support newly qualified practitioners and one that includes specific preparation for the role is proposed. PMID- 28025846 TI - Prolactin and growth hormone immunoactivity in canine mammary adenomas and adenocarcinomas. AB - It is now widely accepted in human medicine that prolactin (PRL) and growth hormone (GH) function in the mammary gland in an autocrine and paracrine manner in tumour formation. The aim of this study was to compare PRL and GH immunoactivity in canine mammary tumours submitted for histopathologic evaluation. Formalin-fixed specimens from spontaneously occurring mammary adenomas and adenocarcinomas from 24 female client-owned dogs were used. Information pertaining to the reproductive status of the patient at the time of mammary tumour diagnosis was obtained from each of the submitting veterinarians. Tissues were paraffin-embedded and sectioned (5 MUm) onto charged slides. All slides were deparaffinized and rehydrated. Endogenous peroxidase activity was inactivated with 3% H2 O2, and non-specific binding was blocked. Polyclonal rabbit antihuman PRL (DAKO A0569) and GH antibody (DAKO A0570) were applied at a 1:250 and 1:200 dilutions, respectively. A universal rabbit negative control (DAKO N1699) was used. Slides were then reacted with anti-rabbit horseradish peroxidase followed by Nova Red Peroxidase substrate. Slides were counter-stained with haematoxylin, dehydrated and mounted. Tumour type and reproductive status at time of tumour diagnosis were compared individually between tumours that were negative or positive for PRL and GH using a two-tailed analysis of variance. Significance was defined as p < .05. There was no significant relationship between tumour type and PRL and GH presence. In addition, reproductive status at the time of tumour removal was found to be not significant. These results vary from previous reports in canine mammary tumours and warrant further investigation. PMID- 28025847 TI - Metabolic remodeling triggered by salivation and diabetes in major salivary glands. AB - The metabolic profile of major salivary glands was evaluated by 13 C nuclear magnetic resonance isotopomer analysis (13 C NMR-IA) following the infusion of [U 13 C]glucose in order to define the true metabolic character of submandibular (SM) and parotid (PA) glands at rest and during salivary stimulation, and to determine the metabolic remodeling driven by diabetes. In healthy conditions, the SM gland is characterized at rest by a glycolytic metabolic profile and extensive pyruvate cycling. On the contrary, the PA gland, although also dominated by glycolysis, also possesses significant Krebs' cycle activity and does not sustain extensive pyruvate cycling. Under stimulation, both glands increase their glycolytic and Krebs' cycle fluxes, but the metabolic coupling between the two pathways is further compromised to account for the much increased biosynthetic anaplerotic fluxes. In diabetes, the responsiveness of the PA gland to a salivary stimulus is seriously hindered, mostly as a result of the incapacity to burst glycolytic activity and also an inability to improve the Krebs' cycle flux to compensate. The Krebs' cycle activity in the SM gland is also consistently compromised, but the glycolytic flux in this gland is more resilient. This diabetes-induced metabolic remodeling in SM and PA salivary glands illustrates the metabolic need to sustain adequate saliva production, and identifies glycolytic and oxidative pathways as key players in the metabolic dynamism of salivary glands. PMID- 28025848 TI - The influence of Anglo-American theoretical models on the evolution of the nursing discipline in Spain. AB - In Spain, the introduction of the new Diploma in Nursing in 1977 saw the role of nurses shifting from that of medical assistants with technical skills to being independent members of the healthcare team with specific responsibility for providing professional nursing care. Here, we analyse the evolution of the nursing profession in Spain following the transfer of nurse education to universities, doing so through interviews with the first generation of academic tutors. This was a qualitative study using the method of analytic induction and based on the principles of grounded theory. Participants were selected by means of theoretical sampling and then underwent in-depth interviews. Steps were taken to ensure the credibility, transferability, dependability and confirmability of data. The main conclusion of the analysis is that there is a gap between a theoretical framework borrowed from the Anglo-American context and a nursing practice that, in Spain, has traditionally prioritised the application of technical procedures, a role akin to that of a medical assistant. It is argued that a key factor underlying the way in which nursing in Spain has evolved in recent decades is the lack of conceptual clarity regarding what the role of the professional nurse might actually entail in practice. PMID- 28025849 TI - Tropical rat mite (Ornithonyssus bacoti) infestation in pet Syrian hamsters (Mesocricetus auratus) and their owner. PMID- 28025850 TI - Estimating latent trends in multivariate longitudinal data via Parafac2 with functional and structural constraints. AB - Longitudinal data are inherently multimode in the sense that such data are often collected across multiple modes of variation, for example, time * variables * subjects. In many longitudinal studies, multiple variables are collected to measure some latent construct(s) of interest. In such cases, the goal is to understand temporal trends in the latent variables, as well as individual differences in the trends. Multimode component analysis models provide a powerful framework for discovering latent trends in longitudinal data. However, classic implementations of multimode models do not take into consideration functional information (i.e., the temporal sequence of the collected data) or structural information (i.e., which variables load onto which latent factors) about the study design. In this paper, we reveal how functional and structural constraints can be imposed in multimode models (Parafac and Parafac2) in order to elucidate trends in longitudinal data. As a motivating example, we consider a longitudinal study on per capita alcohol consumption trends conducted from 1970 to 2013 by the U.S. National Institute on Alcohol Abuse and Alcoholism. We demonstrate how functional and structural information about the study design can be incorporated into the Parafac and Parafac2 alternating least squares algorithms to understand temporal and regional trends in three latent constructs: beer consumption, spirits consumption, and wine consumption. Our results reveal that Americans consume more than the recommended amount of alcohol, and total alcohol consumption trends show no signs of decreasing in the last decade. PMID- 28025851 TI - Long-term effects of GnRH agonists on fertility and behaviour. AB - This review aimed to summarize the present knowledge about the effects of GnRH agonist slow-release implants (GnRH A-SRI) on fertility and behaviour in male and female dogs and cats with special focus on deslorelin. Following an initial stimulation of gonadotropin and testosterone secretion possibly associated with an improved semen quality, GnRH A-SRI induce long-term depression of fertility in male dogs and cats with, however, a large individual variation in onset and duration of efficacy especially in cats. The GnRH A-SRI furthermore interfere with testosterone-dependent/affected behaviour; a significant positive effect in reducing sexual behaviour and libido, hypersexuality, intermale dominance and excessive territorial urine marking has been described. Rates of improvement of the respective behaviour are comparable to those after surgical castration, making GnRH A-SRI a valuable option to predict castration-related effects on behaviour and to identify animals where surgical castration will not be beneficial. No effect has been seen in reducing aggression towards humans indicating the need for behavioural therapy to control this problem. Effects on spermatogenesis, steroidogenesis and behaviour have by now been shown to be fully reversible. Knowledge in females is more limited, and particularly, the initial induction of a possibly fertile oestrus and individual variation in duration of efficacy remain problems in bitches and queens treated for suppression of fertility. However, long-term suppression of oestrous cycle and fertility seems to be possible with induced effects shown to be reversible including restoration of normal fertility after the end of efficacy/GNRH A-SRI removal. PMID- 28025852 TI - Multiple confidence intervals for selected parameters adjusted for the false coverage rate in monotone dose-response microarray experiments. AB - Benjamini and Yekutieli () introduced the concept of the false coverage-statement rate (FCR) to account for selection when the confidence intervals (CIs) are constructed only for the selected parameters. Dose-response analysis in dose response microarray experiments is conducted only for genes having monotone dose response relationship, which is a selection problem. In this paper, we consider multiple CIs for the mean gene expression difference between the highest dose and control in monotone dose-response microarray experiments for selected parameters adjusted for the FCR. A simulation study is conducted to study the performance of the method proposed. The method is applied to a real dose-response microarray experiment with 16, 998 genes for illustration. PMID- 28025853 TI - Rifampicin treatment of canine pyoderma due to multidrug-resistant meticillin resistant staphylococci: a retrospective study of 32 cases. AB - BACKGROUND: Rifampicin has received increased interest in veterinary dermatology because of its activity against multidrug-resistant meticillin-resistant staphylococci (MRS). There is limited knowledge about the efficacy and safety of rifampicin in dogs. HYPOTHESIS/OBJECTIVE: To provide information on response to treatment and adverse effects in dogs treated with rifampicin for multidrug resistant MRS pyoderma. ANIMALS: Thirty two dogs treated with rifampicin for rifampicin-susceptible multidrug-resistant MRS pyoderma. METHODS: Retrospective review of medical records, including alanine aminotransferase (ALT) and alkaline phosphatase (ALP) serum activity levels and total bilirubin concentrations, obtained before and throughout the treatment, was performed. RESULTS: Oral rifampicin as sole systemic antimicrobial therapy (median dose 5 mg/kg twice daily) was effective in 71.88% of cases. Topical antimicrobials were used in most cases. Median duration of rifampicin treatment was five weeks for superficial pyoderma and four weeks for deep pyoderma. Gastrointestinal signs were reported in 15% of treated dogs. Statistically significant increases of ALT (P = 0.045) and ALP (P = 0.0002) values after 3-4 weeks of treatment was observed. The median increase was equal to 0.3 and *1.5 the upper limit of the reference ranges for ALT and ALP, respectively. CONCLUSIONS/CLINICAL IMPORTANCE: Oral rifampicin combined with topical antimicrobials can be considered an effective therapeutic option for canine superficial and deep pyoderma caused by rifampicin-susceptible multidrug-resistant MRS. Liver enzyme induction might be the most important cause of ALT and ALP increase associated with rifampicin therapy in dogs. PMID- 28025854 TI - Changes in acetylation of lysine 5 on histone H4 in canine oocytes following in vitro maturation. AB - Post-translational modifications of histones, such as acetylation, are involved in regulating chromatin remodelling and gene expression. Proper in vitro maturation (IVM) of canine oocytes, for many reasons, is up to now inefficient. This study aimed to evaluate the post-translational histone H4 acetylation at lysine 5 (H4K5) in immature and post-IVM canine oocytes. Oocyte nuclear stage was assessed using Hoechst 33342 staining. Acetylation patterns were determined by indirect immunofluorescence staining of immature and post-IVM oocytes, using an antibody against the acetylated lysine 5 residue on histone 4 (H4K5ac). The experiment was repeated four times, with a total of 7-17 oocytes evaluated per stage. Immunofluorescence signal was quantified using the NIHimagej software. Data were expressed as a percentage of the average fluorescence intensity of the specific antibody over the intensity of DNA, as determined by Hoescht staining. H4K5ac displayed a significantly higher acetylated pattern in immature oocytes (0.97 +/- 0.08) when compared to post-IVM oocytes at different nuclear stages. There was a decrease in the fluorescence level of the matured oocytes with the progression of meiosis (GVBD: 0.47 +/- 0.06 and MI/MII: 0.35 +/- 0.04). Similarly to other domestic species, we hypothesized that post-translational modification of histone acetylation takes place during meiosis of in vitro matured canine oocytes. However, it remains to be investigated whether these changes occur during in vivo maturation. PMID- 28025855 TI - A critical analysis of scales to measure the attitude of nurses toward spiritual care and the frequency of spiritual nursing care activities. AB - Quantitative studies have assessed nurses' attitudes toward and frequency of spiritual care [SC] and which factors are of influence on this attitude and frequency. However, we had doubts about the construct validity of the scales used in these studies. Our objective was to evaluate scales measuring nursing SC. Articles about the development and psychometric evaluation of SC scales have been identified, using, Web of Science, and CINAHL, and evaluated with respect to the psychometric properties and item content of the scales. Item content was evaluated by each of the five authors with respect to the following questions: Does the item (1) reflect a general opinion about SC instead of a personal willingness to offer SC; (2) reflect general psychosocial care instead of specific SC; (3) focus solely on religious care; (4) contain the words 'spiritual' (care/needs/health/strengths, etc.); and (5) contain multiple propositions, or have an unclear meaning? We found eight scales. Psychometric analysis of these scales was often meager and the items of all but one scale suffered from two or more of the five problems described above. This leads us to conclude that many quantitative results in this area are based on findings with questionable scales. Suggestions for improvements are provided. PMID- 28025856 TI - Exploring psychiatric comorbidities and their effects on quality of life in patients with temporal lobe epilepsy and juvenile myoclonic epilepsy. AB - AIM: The relation of epilepsy with psychiatric disorders is of great interest to researchers due to its behavioral, social, and cognitive outcomes. In this study, we explored psychiatric comorbidity and its effects on quality of life (QOL) in patients with mesial temporal lobe epilepsy (MTLE) and juvenile myoclonic epilepsy (JME). METHODS: Thirty patients with MTLE, 30 patients with JME, and 30 healthy controls underwent the Structured Clinical Interview for DSM-IV (SCID-I) to diagnose psychiatric disorders. None of the subjects had previously undergone psychiatric examination. The Quality of Life in Epilepsy Inventory-89 (QOLIE-89) was used to assess QOL. We compared psychiatric comorbidity among groups and evaluated its effects on QOL. RESULTS: We detected comorbid psychiatric disorders in 37% of patients with JME and in 57% of patients with MTLE. Comorbid psychiatric disorders were less frequent in healthy controls compared to the patient groups (P = 0.029). Comparing demographic and clinical features of patients with JME and MTLE and their mean QOL scores, there was no statistical difference. Furthermore, we compared QOLIE scores between patients with and without psychiatric comorbidity. JME patients with mood disorders had lower scores on the Attention/Concentration subscale (P = 0.013). MTLE patients with a psychotic disorder had lower scores on the Social Isolation, Energy, and Fatigue subscales (P = 0.045). Patients with somatoform disorders had higher Pain scores (P = 0.04). CONCLUSION: Our study suggests that comorbid psychiatric disorders negatively affect patients' QOL regardless of seizure syndrome. Comorbid psychiatric conditions should be determined to increase QOL in patients with epilepsy. PMID- 28025857 TI - Use of the Monte Carlo Method for OECD Principles-Guided QSAR Modeling of SIRT1 Inhibitors. AB - SIRT1 inhibitors offer therapeutic potential for the treatment of a number of diseases including cancer and human immunodeficiency virus infection. A diverse series of 45 compounds with reported SIRT1 inhibitory activity has been employed for the development of quantitative structure-activity relationship (QSAR) models using the Monte Carlo optimization method. This method makes use of simplified molecular input line entry system notation of the molecular structure. The QSAR models were built up according to OECD principles. Three subsets of three splits were examined and validated by respective external sets. All the three described models have good statistical quality. The best model has the following statistical characteristics: R2 = 0.8350, Q2test = 0.7491 for the test set and R2 = 0.9655, Q2ext = 0.9261 for the validation set. In the mechanistic interpretation, structural attributes responsible for the endpoint increase and decrease are defined. Further, the design of some prospective SIRT1 inhibitors is also presented on the basis of these structural attributes. PMID- 28025858 TI - The New Rich and Their Unplanned Births: Stratified Reproduction under China's Birth-planning Policy. AB - This article explores the creation and ramifications of a stratified reproductive system under China's state control of reproduction. Within this system, an emerging group of "new rich" are able to circumvent birth regulations and have unplanned births because of their financial capabilities and social networks. While China's birth-planning policy is meant to be enforced equally for all couples, the unequal access to wealth and bureaucratic power as a result of China's widening social polarization has created disparate reproductive rights and experiences. This article identifies three ways in which reproductive privileges are created. It further explores how a stratified reproductive system under state population control reinforces social polarization. While many socially marginalized couples are unable to register their unplanned children for citizenship status and social benefits, the new rich are able to legitimate their births and transfer their privilege and status to their children, thus reproducing a new generation of elites. PMID- 28025859 TI - Negotiations of Blame and Care among HIV-positive Mothers and Daughters in South Africa's Eastern Cape. AB - Research delineates two epidemiological categories among HIV-positive adolescents: those who contract the virus sexually and those who inherit it as infants. In this article, we are interested in how tacit inferences about adolescents' mode of infection contribute to their experiences of HIV-related blame, and their ability to achieve care, in their intimate, everyday settings. The analysis arises from ethnographic research with 23 HIV-positive adolescents living in South Africa's Eastern Cape. From these, we draw particularly on the narratives of four HIV-positive teenage girls and their HIV-positive mothers. The article explores the social stakes entailed in ascriptions of adolescents' mode of infection, particularly in terms of how blame was allocated between mothers and daughters. It further considers how these families have sought to negotiate repudiation and thereby sustain intergenerational care. The article furthers limited research on the life projects and dilemmas of this HIV-positive adolescent cohort. PMID- 28025860 TI - Musculoskeletal decline and mortality: prospective data from the Geelong Osteoporosis Study. AB - BACKGROUND: We aimed to examine the relationship between musculoskeletal deterioration and all-cause mortality in a cohort of women studied prospectively over a decade. METHODS: A cohort of 750 women aged 50-94 years was followed for a decade after femoral neck bone mineral density (BMD) and appendicular lean mass (ALM) were measured using dual energy X-ray absorptiometry, in conjunction with comorbidities, health behaviour data, and other clinical measures. The outcome was all-cause mortality identified from the Australian National Deaths Index. Using Cox proportional hazards models and age as the time variable, mortality risks were estimated according to BMD groups (ideal-BMD, osteopenia, and osteoporosis) and ALM groups (T-scores > -1.0 high, -2.0 to -1.0 medium, <-2.0 low). RESULTS: During 6712 person years of follow-up, there were 190 deaths, the proportions increasing with diminishing BMD: 10.7% (23/215) ideal-BMD, 23.5% (89/378) osteopenia, 49.7% (78/157) osteoporosis; and with diminishing ALM: 17.0% (59/345) high, 26.2% (79/301) medium, 50.0% (52/104) low. In multivariable models adjusted for smoking, polypharmacy, and mobility, compared with those with ideal BMD, mortality risk was greater for those with osteopenia [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.11-2.81] and osteoporosis (HR 2.61, 95%CI 1.60-4.24). Similarly, compared with those with high ALM, adjusted mortality risk was greater for medium ALM (HR 1.36, 95%CI 0.97-1.91) and low ALM (HR 1.65, 95%CI 1.11-2.45). When BMD and ALM groups were tested together in the model, BMD remained a predictor of mortality (HR 1.74, 95%CI 1.09-2.78; HR 2.82, 95%CI 1.70 4.70; respectively), and low ALM had borderline significance (HR 1.52, 95%CI 1.00 2.31), which was further attenuated after adjusting for smoking, polypharmacy, and mobility. CONCLUSIONS: Poor musculoskeletal health increased the risk for mortality independent of age. This appears to be driven mainly by a decline in bone mass. Low lean mass independently exacerbated mortality risk, and this appeared to operate through poor health exposures. PMID- 28025861 TI - Neurocognitive profile of euthymic Japanese patients with bipolar disorder. AB - AIM: Neurocognitive impairment is one of the core symptoms of bipolar disorder (BD). The MATRICS Cognitive Consensus Battery (MCCB) is a potential consensus assessment tool to evaluate cognitive function in patients with BD. Here, we report on cognitive deficits evaluated using the MCCB Japanese version (MCCB-J) in euthymic Japanese patients with BD, and compare them with scores in previous studies. METHODS: We compared neurocognitive function in 25 patients with euthymic BD and 53 healthy controls (HC). Additionally, we searched all available databases for studies that have evaluated cognitive function in BD using the MCCB, and conducted a meta-analysis. RESULTS: Canonical discriminant analysis revealed significant differences in MCCB-J domain scores between BD and HC. Patients with BD performed significantly worse on visual learning, social cognition, speed of processing, and MCCB composite scores. Our meta-analysis revealed that patients with BD performed worse than HC, as reflected by MCCB composite scores and scores on all seven cognitive domains. However, there are differences in the cognitive deficits identified in previous studies compared with our participants, particularly social cognition. CONCLUSION: As reported in previous studies, neurocognitive deficits were observed in Japanese euthymic BD patients assessed using the MCCB-J. Further study is needed to clarify whether differences in social cognition between this study and previous studies are a result of coping mechanisms for social settings in Japanese populations. PMID- 28025862 TI - Maternal plasma cholesterol and duration of pregnancy: A prospective cohort study in Ghana. AB - Low plasma cholesterol may be associated with preterm birth; however, results are mixed and limited primarily to high-income countries. Our objective was to determine whether maternal plasma lipid concentrations are associated with pregnancy duration. We performed a nested cohort (n = 320) study of pregnant Ghanaian women enrolled in a randomized controlled trial. Total cholesterol, high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and triglyceride concentrations were analyzed in plasma at <=20and 36 weeks gestation as continuous variables and also categorized into low, referent, or high (<10th, 10th-90th, >90th percentile). At <=20 weeks, plasma lipid concentrations were not associated with pregnancy duration. At 36 weeks, total cholesterol and triglyceride concentrations were not associated with pregnancy duration. Higher HDL-C at 36 weeks was associated with a longer pregnancy duration (adjusted beta coefficient +/- standard error: 0.05 +/- 0.02 days mg-1 /dL, p = .02); pregnancy duration was 5.9 +/- 2.0 (mean +/- standard error) days shorter among women with low HDL-C compared with the referent group (10th-90th percentile) (p = .02) and 8.6 +/- 2.6 days shorter when compared with the high HDL-C group (p = .003). Pregnancy duration was 4.9 +/- 2.1 days longer among women with low low-density lipoprotein cholesterol at 36 weeks gestation when compared with the referent group (p = .051). Our data suggest that low HDL-C in the third trimester of pregnancy is associated with a shorter duration of pregnancy in this study population but do not support the hypothesis that low total cholesterol is associated with a shorter pregnancy duration. PMID- 28025864 TI - Immunoadsorption as a Long-Term Therapy in Recurrent Focal Segmental Glomerulosclerosis After Renal Transplantation. PMID- 28025863 TI - Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15. AB - BACKGROUND: The cancer-anorexia-cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour-derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour-derived macrophage inhibitory cytokine-1 (MIC-1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC 1 in mice. METHODS: Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC-1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response. RESULTS: In tumour bearing sham-operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer-induced anorexia or body weight loss. Tumour-bearing rats had substantially increased MIC-1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake. CONCLUSIONS: These findings demonstrate the importance of the AP in the mediation of cancer-dependent anorexia and body weight loss and support a pathological role of MIC-1 as a tumour-derived factor mediating CACS, possibly via an AP-dependent action. PMID- 28025865 TI - Health staff understanding, application, and interpretation of growth charts in Nigeria. AB - We aimed to compare plotting accuracy and interpretation of weight gain patterns in average and small infants on road-to-health (RTH) and the new World Health Organization (WHO) growth charts in Enugu, Nigeria. Child health staff plotted standard weights on both formats. Twelve plotted charts were created, permutating three different weight trajectories (fast, steady, and slow) ending at two attained weights (average and small), with each plotted on both chart formats. Respondents were shown four of these charts and asked to describe the weight gain pattern shown and what action this pattern would prompt. There were 222 respondents, of whom 78% were hospital based; 54% were nurses, 32% medical doctors, and 13% nutritionists. Plotting accuracy was good on both the WHO and RTH charts, but rating of weight gain was generally poor. On the RTH chart, slow weight gain was correctly recognized in only 19% average and 35% small infants, and responses were not significantly associated with the pattern shown. On the WHO charts, slow weight gain was correctly recognized in 40% average and 65% small infants (p = .002 and <.001), but they were also more likely to rate small children with normal growth as slow weight gain. In a logistic regression model, final weight predicted a slow weight gain rating more strongly (OR = 2.4; 1.8 3.2) than an actual slow weight gain pattern (OR 1.8; 1.1-1.6). Health staff seemed unable to recognize slow weight gain and were influenced more by current weight than actual weight gain pattern, though the new WHO format improved recognition. PMID- 28025866 TI - Proliferative characteristics of Philadelphia-negative myeloproliferative neoplasms - clinical implications. AB - INTRODUCTION: Philadelphia-negative myeloproliferative neoplasms (Ph- MPN) are characterized by overproduction of one or more blood cell lines. METHODS: We studied the proliferative characteristics of 91 patients with de novo Ph- MPN. Colony-forming cells (CFC) and endogenous colonies (EC), from bone marrow (BM) and/or peripheral blood (PB), were analyzed by colony assay based on methylcellulose. The level of circulating CD34+ cells was determined by flow cytometry. RESULTS: The total number of PB CFC in primary myelofibrosis (PMF) was increased compared to the control sample (P < 0.01) and essential thrombocythemia (ET) (P < 0.05). The highest number of BM and PB EC was observed in polycythemia vera (PV) (P < 0.01). Increased levels of CD34+ cells characterized early prefibrotic (57%) and advanced-fibrotic PMF (90%) as compared to PV (34%) and ET (32%) (P < 0.01). In the whole Ph- MPN group, the total number of PB CFC (P < 0.01), PB EC (P < 0.05), and CD34+ cells (P < 0.01) correlated with the degree of BM fibrosis. Higher levels of circulating CD34+ cells in PMF correlated with the total number of PB EC (P < 0.05) and degree of BM fibrosis (P < 0.01). CONCLUSIONS: Exploration of the PB proliferative characteristics of Ph- MPN on diagnosis may be helpful in revealing early-prefibrotic PMF. Monitoring the levels of circulating CD34+ cells may provide a sensitive indicator of fibrotic evolution in PV and PMF. PMID- 28025868 TI - Metabolic responses to exercise on land and in water following glucose ingestion. AB - Although aerobic exercise after a meal decreases postprandial blood glucose, the differences in glucose response between land and aquatic exercise are unclear. Thus, we examined the effect of different modes of exercise with same energy expenditure following glucose ingestion on carbohydrate metabolism. Ten healthy sedentary men (age, 22 +/- 1 years) participated in this study. All subjects performed each of three exercise modes (cycling, walking and aquatic exercise) for 30 min after ingestion of a 75-g glucose solution with 1-2 weeks between trials. The exercise intensity was set at 40% of the maximum oxygen uptake that occurred during cycling. The velocity during walking and the target heart rate during aquatic exercise were predetermined in a pretest. The plasma glucose concentration at 30 min after exercise was significantly lower with aquatic exercise compared to that with cycling and walking (P<0.05). However, there were no significant differences among the three exercise modes in respiratory exchange ratio. On the other hand, serum free fatty acid concentration with aquatic exercise was significantly higher at 120 min after exercise compared with that after walking (P<0.05). These results suggest that aquatic exercise reduces postprandial blood glucose compared with both cycling and walking with the same energy expenditure. Aquatic exercise shows potential as an exercise prescription to prevent postprandial hyperglycaemia. PMID- 28025869 TI - Obituary - In Memoriam Per Brandtzaeg. PMID- 28025870 TI - The 2016 Nobel Prize in Physiology or Medicine. PMID- 28025867 TI - Brain natriuretic peptide usefulness in very elderly dyspnoeic patients: the BED study. AB - AIMS: To evaluate the interest of brain natriuretic peptide (BNP) for heart failure (HF) diagnosis in very old patients. METHODS AND RESULTS: A total of 383 patients aged 80 years or older, hospitalized in geriatrics care for dyspnoea, had a BNP measurement at the acute phase. Independent cardiologists blinded to BNP values classified the patients into cardiac vs. respiratory aetiology according to the European Society of Cardiology guidelines. Mean (SD) age was 88.5 (5.4) years, 66% (n = 254) of patients were women, 62% (n = 238) had cardiac dyspnoea and 38% (n = 145) had respiratory dyspnoea. The BNP levels were significantly higher in the cardiac group (median = 385.5 ng/L, interquartile range = 174.0-842.0) than in the respiratory group (median = 172.0 ng/L, interquartile range = 70.8-428.0; P < 0.001). On its own, BNP showed poor discriminative ability [area under the curve (AUC) = 0.68; 95% confidence interval (CI) 0.62-0.73] for the diagnostic. In multivariate analysis, BNP remained independently associated with the cardiac aetiology after full adjustment (odds ratio 1 log increase = 1.87; 95% CI 1.28-2.74), but did not improve the discrimination between the cardiac and the respiratory aetiologies (DeltaAUC = 0.013, P = 0.16). In addition, although adding BNP to the other predictive covariates yielded a significant continuous NRI of 57.8% (95% CI 31.2 83.5%), the mean changes in individual predicted probabilities were too low (<3%) to be clinically relevant. CONCLUSION: In this population of very old patients with acute dyspnoea, despite being independently associated with the cardiac aetiology, BNP was not useful for better discriminating cardiac vs. respiratory origin. PMID- 28025871 TI - Editorial - Per Brandtzaeg In Memoriam. PMID- 28025873 TI - An emerging paradox: Toward a better understanding of the potential benefits and adversity of microbe exposures in the indoor environment. PMID- 28025872 TI - Lamivudine therapy during the second vs the third trimester for preventing transmission of chronic hepatitis B. AB - There are little data on the timing of initiating lamivudine therapy for preventing transmission of hepatitis B in highly viremic mothers. Between May 2008 and January 2015, we retrospectively enrolled mothers with HBV DNA >6 log10 copies/mL who received lamivudine during pregnancy, and we compared them to untreated mothers. The primary measurement was the vertical transmission rate. The secondary outcomes were the mothers' and infants' safety. Among 249 consecutive mothers enrolled, 66 and 94 received lamivudine during the second and third trimesters, respectively, and 89 were untreated. At delivery, maternal mean HBV DNA levels were significantly lower in mothers who received lamivudine (4.45 log10; vs 7.16 log10 copies/mL; P<.001). Lamivudine treatment was well tolerated. However, early treatment during the second trimester did not significantly increase the percentage of mothers achieving HBV DNA levels of <6 log10 copies/mL compared to those treated during the third trimester (98.5% vs 94.7%; P=.40). At the age of 28 weeks, the vertical transmission rates were significantly lower in the lamivudine-treated mothers vs in the untreated mothers (0% [0/160] vs 5.62% [5/89]; P<.001), but the rates were similar when comparing the two subgroups treated with lamivudine (0% [0/66] vs 0% [0/94], P>.05). The birth defect rates and mothers' and infants' adverse events were similar among the groups. Lamivudine treatment initiated in the second or third trimester for mothers with HBV DNA levels below 9 log10 copies/mL was equally safe and effective in preventing vertical transmission. Thus, lamivudine should be deferred until the third trimester to minimize foetal exposure and drug resistance. PMID- 28025874 TI - Fifty volumes of scholarship on eating disorders. PMID- 28025875 TI - Benefit of extending the dosing interval of long-acting antipsychotic injections on schizophrenics with extrapyramidal symptoms. PMID- 28025876 TI - Novel deletion mutation of HLA-B*40:02 gene in acquired aplastic anemia. AB - Despite prevalence of clonal evolution in patients with aplastic anemia (AA), somatic mutation of human leukocyte antigen (HLA) gene is rarely reported. Herein, we reported a case of acquired AA (aAA) harboring a new four-base-pair deletion mutation within exon 4 of HLA-B*40:02 leading to frameshift and premature stop codon. The HLA-B*40:02 mutant allele was detected in the patient's peripheral blood sample not in patient's buccal epithelial cells. The patient received allogenic hematopoietic stem cell transplantation (HSCT) from HLA matched sibling donor. On day 30 after HSCT, the mutant HLA allele was not detected by high-resolution sequence-based HLA typing. Serial chimerism analyses showed mixed chimeric status indicative of coexisting donor and recipient hematopoietic cells. Our data could provide additional support in view of pathophysiology of aAA that somatic mutation of HLA-B*40:02 allele is one of the possible origin of clonal escape to evade immune attack in patient with aAA. PMID- 28025877 TI - New insights into the understanding of MHC associations with immune-mediated disorders. AB - Recent advances in technologies such as high density array-based genotyping, DNA and RNA deep sequencing, expression quantitative-trait loci mapping, epigenome analyses, and new computational strategies, have introduced drastic shifts into our understanding of major histocompatibility complex (MHC) association with immune-mediated diseases. Here, we review the most exciting findings in this field. We show how the fine characterization of structural features and expression levels of MHC alleles, posttranslational or environmental modifications of HLA-bound peptides, and epistatic interactions with non-HLA genes, has made it possible not only to provide mechanistic explanations for MHC associations with immune-mediated diseases but also to help choose relevant therapeutic targets. PMID- 28025878 TI - Intra- and interday reproducibility of high-flow-mediated constriction response in young adults. AB - BACKGROUND: Previously, we have demonstrated that high-flow-mediated constriction (H-FMC) of the brachial artery has been shown to negatively affect flow-mediated dilation (FMD). However, the reproducibility of an H-FMC response is unknown. OBJECTIVE: The aim of this study was to determine the intra- and interday reproducibility of H-FMC in young adults. METHODS: Thirty young adults (15 male, 15 female; 24 +/- 3 years) were assessed for H-FMC reproducibility via high resolution ultrasound imaging of the brachial artery during and after forearm occlusion of a normal FMD procedure. Two vascular assessments were conducted for all participants during two separate visits with a minimum of 7 days in between. H-FMC was characterized as the greatest 10-s average constriction occurring after 3-s postocclusion compared to baseline brachial artery diameter and considered present if the percent change was <-0.1%. RESULTS: Of the 120 total vascular assessments performed in this study, 98 of the assessments (80.3%) displayed an H FMC. H-FMC diameter was not statistically different for intraday comparisons for visit 1 (P = 0.39) or visit 2 (P = 0.55) or interday comparisons between the first (P = 0.61) or second (P = 0.10) assessments. H-FMC percentage was also not statistically different for intra-day comparison for visit 1 (P = 0.94) or visit 2 (P = 0.15) or interday comparisons between the first (P = 0.63) or second (P = 0.16) assessments. CONCLUSION: These data are supportive of H-FMC being reproducible in young adults and included in future FMD studies. The impact of H FMC on future CVD risk and development warrants evaluation. PMID- 28025879 TI - Primary Sclerosing Cholangitis PMID- 28025880 TI - Durable, Transparent, and Hot Liquid Repelling Superamphiphobic Coatings from Polysiloxane-Modified Multiwalled Carbon Nanotubes. AB - Although encouraging progress in the field of superamphiphobic coatings has been obtained, the superamphiphobic coatings with high durability, transparency, and repellency to hot liquids are very rare. Here, durable, transparent, and hot liquid-repelling superamphiphobic coatings were successfully prepared using polysiloxane-modified multiwalled carbon nanotubes (MWCNTs@POS) as the templates. The hydrolytic condensation of n-hexadecyltrimethoxysilane (HDTMS) and tetraethoxysilane on the surface of MWCNTs formed MWCNTs@POS, which are highly dispersible in toluene. The superamphiphobic coatings were prepared by spray coating the homogeneous suspension of MWCNTs@POS in toluene onto glass slides, calcination in air to form the silica nanotubes (SNTs), and then modification with 1H,1H,2H,2H-perfluorodecyltrichlorosilane in dry toluene. The changes in the surface microstructure, surface chemical composition, and wettability were characterized by various techniques such as scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy. It was found that the microstructures of the SNTs have great influences on superamphiphobicity and transparency of the coatings and can be regulated by the concentration of HDTMS and the diameter of MWCNTs. The SNTs with tunable wall thickness and diameter could be obtained using the method. The superamphiphobic coatings showed high contact angles and low sliding angles for various cool and hot liquids of different surface tensions. The superamphiphobic coatings also exhibited high transparency and comprehensive durability. PMID- 28025881 TI - Probing the Role of Glycol Chain Lengths in pi-Donor-Acceptor [2]Pseudorotaxanes Based on Monopyrrolo-Tetrathiafulvalene and Cyclobis(paraquat-p-phenylene). AB - We have investigated and quantified the role that the glycol chain length has on the strength of the noncovalent bonding interactions taking place between cyclobis(paraquat-p-phenylene) (CBPQT4+) and five different monopyrrolo tetrathiafulvalene (MPTTF) derivatives that only differ in the length of the N substituted glycol chain. The MPTTF derivatives were used to form [2]pseudorotaxanes by mixing them with CBPQT4+. The binding constants (Ka) associated with the complexation process leading to the formation of the [2]pseudorotaxanes were obtained using the UV-vis-NIR dilution method and the [2]pseudorotaxanes were characterized structurally using 1H NMR spectroscopy. These experimental investigations clearly indicate that the glycol chains provide additional stability to the [2]pseudorotaxanes findings that were further supported by density functional theory (DFT) studies. The DFT calculated superstructure of the [2]pseudorotaxane 3?CBPQT4+ reveal that [C-H...O] hydrogen bonding interactions between the acidic alpha-H protons in CBPQT4+ and the oxygen atoms present in the glycol chain can take place on the exterior of the [2]pseudorotaxane. However, the length of the glycol chain is of paramount importance and the present studies show that the first and second oxygen atom in the [2]pseudorotaxanes 2-5?CBPQT4+ are engaged in [C-H...O] hydrogen bonding interactions with CBPQT4+, whereas the third and fourth oxygen atoms are not. PMID- 28025882 TI - Characterization of the Key Aroma Compounds in Chinese Vidal Icewine by Gas Chromatography-Olfactometry, Quantitative Measurements, Aroma Recombination, and Omission Tests. AB - The key aroma compounds of Chinese Vidal icewine were characterized by means of gas chromatography-olfactometry (GC-O) coupled with mass spectrometry (MS) on polar and nonpolar columns, and their flavor dilution (FD) factors were determined by aroma extract dilution analysis (AEDA). A total of 59 odor-active aroma compounds in three ranks of Vidal icewines were identified, and 28 odorants (FD >= 9) were further quantitated for aroma reconstitution and omission tests. beta-Damascenone showed the highest FD value of 2187 in all icewines. Methional and furaneol were first observed as important odorants in Vidal icewine. Aroma recombination experiments revealed a good similarity containing the 28 important aromas. Omission tests corroborated the significant contribution of beta damascenone and the entire group of esters. Besides, 4-hydroxy-2,5-dimethyl-3(2H) furanone (furaneol) and 3-(methylthio)-1-propanal (methional) also had significant effects on icewine character, especially on apricot, caramel, and tropical fruit characteristics. PMID- 28025883 TI - Self-Assembling Halloysite Nanotubes into Concentric Ring Patterns in a Sphere-on Flat Geometry. AB - Highly ordered and concentric ring patterns consisting of halloysite nanotubes (HNTs) with hierarchical cholesteric architectures are prepared by evaporation induced self-assembly in a sphere-on-flat geometry. The structure and properties of HNTs are investigated. HNTs show a perfect tubular morphology on the nanoscale with high dispersion stability in water. Upon drying the HNTs aqueous suspension in a sphere-on-flat confined space, regular concentric HNTs rings are formed on the substrate via a self-assembly process. The widths of the inner and outer rings and the spacing between the adjacent rings increase with an increase in the concentration of the HNTs suspension. The highly ordered and concentric HNTs rings show a pronounced Maltese cross-like pattern under crossed polarizers, which suggests the formation of hierarchical cholesteric architectures. Scanning electron microscopy and atomic force microscopy observations show a disclination alignment of HNTs in the ring strips, especially with a high concentration of the HNTs suspension. The patterned rough surfaces of the HNTs show low cytotoxicity and can be used as a cell-supporting scaffold. The HNTs rings can guide the growth and orientation of C2C12 myoblast cells perpendicular to the rings. This work provides a simple, repeatable, mild, and high-efficiency method for obtaining HNTs with hierarchical architectures, which show potential for a large variety of applications, for example, in vascular grafts and skin regeneration. PMID- 28025884 TI - A Well-Defined Silicon Nanocone-Carbon Structure for Demonstrating Exclusive Influences of Carbon Coating on Silicon Anode of Lithium-Ion Batteries. AB - Nanotechnology and carbon coating have been applied to silicon anodes to achieve excellent lithium-ion batteries, but the exclusive influence of carbon coating on solid-electrolyte interphase (SEI) formation is difficult to exhibit distinctly because of the impurity and morphological irregularity of most nanostructured anodes. Here, we design a silicon nanocone-carbon (SNC-C) composite structure as a model anode to demonstrate the significant influences of carbon coating on SEI formation and electrochemical performance, unaffectedly as a result of pure electrode component and distinctly due to regular nanocone morphology. As demonstrated by morphological and elemental analysis, compared to the SNC electrode, the SNC-C electrode maintains a thinner SEI layer (~10 nm) and more stable structure during cycling as well as longer cycle life (>725 cycles), higher Coulombic efficiency (>99%), and lower electrode polarization. This well defined structure clearly shows the interface stability attributed to carbon coating and is promising in fundamental research of the silicon anode. PMID- 28025885 TI - Comparison of MoS2, WS2, and Graphene Oxide for DNA Adsorption and Sensing. AB - Interfacing DNA with two-dimensional (2D) materials has been intensely researched for various analytical and biomedical applications. Most of these studies have been performed on graphene oxide (GO) and two metal dichalcogenides, molybdenum disulfide (MoS2) and tungsten disulfide (WS2); all of them can all adsorb single stranded DNA. However, they use different surface forces for adsorption based on their chemical structures. In this work, fluorescently labeled DNA oligonucleotides were used and their adsorption capacities and kinetics were studied as a function of ionic strength, DNA length, and sequence. Desorption of DNA from these surfaces was also measured. DNA is more easily desorbed from GO by various denaturing agents, whereas surfactants yield more desorption from MoS2 and WS2. Our results are consistent with the fact that DNA can be adsorbed by GO via pi-pi stacking and hydrogen bonding, and MoS2 and WS2 mainly use van der Waals force for adsorption. Finally, fluorescent DNA probes were adsorbed by these 2D materials for detecting complementary DNA. For this assay, GO gave the highest sensitivity, whereas they all showed a similar detection limit. This study has enhanced our fundamental understanding of DNA adsorption by two important types of 2D materials and is useful for further rational optimization of their analytical and biomedical applications. PMID- 28025886 TI - Comparative Analysis of the Rats' Gut Microbiota Composition in Animals with Different Ginsenosides Metabolizing Activity. AB - Following oral intake of Panax ginseng, major ginsenosides are metabolized to deglycosylated ginsenosides by gut microbiota before absorption into the blood. As the composition of gut microbiota varies between individuals, metabolic activities are significantly different. We selected 6 rats with low efficiency metabolism (LEM) and 6 rats with high efficiency metabolism (HEM) from 60 rats following oral administration of Panax ginseng extract, and analyzed their gut microbiota composition using Illumina HiSeq sequencing of the 16S rRNA gene. The components of gut microbiota between the LEM and HEM groups were significantly different. Between the 2 groups, S24-7, Alcaligenaceae, and Erysipelotrichaceae occupied most OTUs of the HEM group, which was notably higher than the LEM group. Furthermore, we isolated Bifidobacterium animalis GM1 that could convert the ginsenoside Rb1 to Rd. The result implies that these specific intestinal bacteria may dominate the metabolism of Panax ginseng. PMID- 28025887 TI - Influence of Cross-Linkers on the in Vitro Chondrogenesis of Mesenchymal Stem Cells in Hyaluronic Acid Hydrogels. AB - This study aims to investigate the effect of the structures of cross-linkers on the in vitro chondrogenic differentiation of bone mesenchymal stem cells (BMSCs) in hyaluronic acid (HA)-based hydrogels. The hydrogels were prepared by the covalent cross-linking of methacrylated HA with different types of thiol-tailored molecules, including dithiothreitol (DTT), 4-arm poly(ethylene glycol) (PEG), and multiarm polyamidoamine (PAMAM) dendrimer using thiol-ene "click" chemistry. The microstructure, mechanical properties, diffusivity, and degradation rates of the resultant hydrogels were controlled by the structural feature of different cross linkers. BMSCs were then encapsulated in the resulting hydrogels and cultured in chondrogenic conditions. Overall, chondrogenic differentiation was highly enhanced in the PEG-cross-linked HA hydrogels, as measured by glycosaminoglycan (GAG) and collagen accumulation. The physical properties of hydrogels, especially the mechanical property and microarchitecture, were resulted from the structures of different cross-linkers, which subsequently modulated the fate of BMSC differentiation. PMID- 28025888 TI - Analysis of the Xyloglucan Endotransglucosylase/Hydrolase Gene Family during Apple Fruit Ripening and Softening. AB - Ethylene and xyloglucan endotransglucosylase/hydrolase (XTH) genes were important for fruit ripening and softening in 'Taishanzaoxia' apple. In this study, we found it was ACS1-1/-1 homozygotes in 'Taishanzaoxia' apple, which determined the higher transcription activity of ACS1. XTH1, XTH3, XTH4, XTH5, and XTH9 were mainly involved in the early fruit softening independent of ethylene, while XTH2, XTH6, XTH7, XTH8, XTH10, and XTH11 were predominantly involved in the late fruit softening dependent on ethylene. Overexpression of XTH2 and XTH10 in tomato resulted in the elevated expression of genes involved in ethylene biosynthesis (ACS2, ACO1), signal transduction (ERF2), and fruit softening (XTHs, PG2A, Cel2, and TBG4). In summary, the burst of ethylene in 'Taishanzaoxia' apple was predominantly determined by ACS1-1/-1 genotype, and the differential expression of XTH genes dependent on and independent of ethylene played critical roles in the fruit ripening and softening. XTH2 and XTH10 may act as a signal switch in the feedback regulation of ethylene signaling and fruit softening. PMID- 28025889 TI - Detailed Study of BSA Adsorption on Micro- and Nanocrystalline Diamond/beta-SiC Composite Gradient Films by Time-Resolved Fluorescence Microscopy. AB - The adsorption of bovine serum albumin (BSA) on micro- and nanocrystalline diamond/beta-SiC composite films synthesized using the hot filament chemical vapor deposition (HFCVD) technique has been investigated by confocal fluorescence lifetime imaging microscopy. BSA labeled with fluorescein isothiocyanate (FITC) was employed as a probe. The BSAFITC conjugate was found to preferentially adsorb on both O-/OH-terminated microcrystalline and nanocrystalline diamond compared to the OH-terminated beta-SiC, resulting in an increasing amount of BSA adsorbed to the gradient surfaces with an increasing diamond/beta-SiC ratio. The different strength of adsorption (>30 times for diamond with a grain size of 570 nm) coincides with different surface energy parameters and differing conformational changes upon adsorption. Fluorescence data of the adsorbed BSAFITC on the gradient film with different diamond coverage show a four-exponential decay with decay times of 3.71, 2.54, 0.66, and 0.13 ns for a grain size of 570 nm. The different decay times are attributed to the fluorescence of thiourea fluorescein residuals of linked FITC distributed in BSA with different dye-dye and dye surface distances. The longest decay time was found to correlate linearly with the diamond grain size. The fluorescence of BSAFITC undergoes external dynamic fluorescence quenching on the diamond surface by H- and/or sp2-defects and/or by amorphous carbon or graphite phases. An acceleration of the internal fluorescence concentration quenching in BSAFITC because of structural changes of albumin due to adsorption, is concluded to be a secondary contributor. These results suggest that the micro- and nanocrystalline diamond/beta-SiC composite gradient films can be utilized to spatially control protein adsorption and diamond crystallite size, which facilitates systematic studies at these interesting (bio)interfaces. PMID- 28025890 TI - Enhanced Microwave Absorption Performance of Coated Carbon Nanotubes by Optimizing the Fe3O4 Nanocoating Structure. AB - It is well accepted that the microwave absorption performance (MAP) of carbon nanotubes (CNTs) can be enhanced via coating magnetic nanoparticles on their surfaces. However, it is still unclear if the magnetic coating structure has a significant influence on the microwave absorption behavior. In this work, nano Fe3O4 compact-coated CNTs (FCCs) and Fe3O4 loose-coated CNTs (FLCs) are prepared using a simple solvothermal method. The MAP of the Fe3O4-coated CNTs is shown to be adjustable via controlling the Fe3O4 nanocoating structure. The results reveal that the overall MAP of coated CNTs strongly depends on the magnetic coating structure. In addition, the FCCs show a much better MAP than the FLCs. It is shown that the microwave absorption difference between the FLCs and FCCs is due to the disparate complementarities between the dielectric loss and the magnetic loss, which are related to the coverage density of Fe3O4 nanoparticles on the surfaces of CNTs. For FCCs, the mass ratio of CNTs to Fe3+ is then optimized to maximize the effective complementarities between the dielectric loss and the magnetic loss. Finally, a comparison is made with the literature on Fe3O4-carbon based composites. The FCCs at the optimized CNT to Fe3+ ratio in the present work show the most effective specific RLmin (28.7 dB.mm-1) and the widest effective bandwidth (RL < -10 dB) (8.3 GHz). The excellent MAP of the as-prepared FCC sample is demonstrated to result from the consequent dielectric relaxation process and the improved magnetic loss. Consequently, the structure-property relationship revealed is significant for the design and preparation of CNT-based materials with effective microwave absorption. PMID- 28025892 TI - Tandem Peptide Based on Structural Modification of Poly-Arginine for Enhancing Tumor Targeting Efficiency and Therapeutic Effect. AB - The nonselectivity of cell penetrating peptides had greatly limited the application in systemic administration. By conjugating a dGR motif to the C terminal of octa-arginine, the formed tandem peptide R8-dGR had been proved to specifically recognize both integrin alphavbeta3 and neuropilin-1 receptors. However, the positive charge of poly-arginine would still inevitably lead to rapid clearance in the circulation system. Therefore, in this study, we tried to reduce the positive charge of poly-arginine by decreasing the number of arginine, to thus achieve improved tumor targeting efficiency. We had designed several different Rx-dGR peptides (x = 4, 6, and 8) modified liposomes and investigated their tumor targeting and penetrating properties both in vitro and in vivo. Among all the liposomes, R6-dGR modified liposomes exhibited a long circulation time similar to that of PEGylated liposomes while they retained strong penetrating ability into both tumor cells and tumor tissues, and thus had displayed the most superior tumor targeting efficiency. Then, paclitaxel and indocyanine green coloaded liposomes were prepared, and R6-dGR modified coloaded liposomes also exhibited enhanced antitumor effect on C6 xenograft tumor bearing mice. Therefore, we suggest R6-dGR as a potential tumor targeting ligand with both strong penetrating ability and improved pharmacokinetic behavior, which could be further used for efficient antitumor therapy. PMID- 28025891 TI - Spatially Resolved Ferroelectric Domain-Switching-Controlled Magnetism in Co40Fe40B20/Pb(Mg1/3Nb2/3)0.7Ti0.3O3 Multiferroic Heterostructure. AB - Intrinsic spatial inhomogeneity or phase separation in cuprates, manganites, etc., related to electronic and/or magnetic properties, has attracted much attention due to its significance in fundamental physics and applications. Here we use scanning Kerr microscopy and scanning electron microscopy with polarization analysis with in situ electric fields to reveal the existence of intrinsic spatial inhomogeneity of the magnetic response to an electric field on a mesoscale with the coexistence of looplike (nonvolatile) and butterfly-like (volatile) behaviors in Co40Fe40B20/Pb(Mg1/3Nb2/3)0.7Ti0.3O3 ferromagnetic/ferroelectric (FM/FE) multiferroic heterostructures. Both the experimental results and micromagnetic simulations suggest that these two behaviors come from the 109 degrees and the 71 degrees /180 degrees FE domain switching, respectively, which have a spatial distribution. This FE domain switching-controlled magnetism is significant for understanding the nature of FM/FE coupling on the mesoscale and provides a path for designing magnetoelectric devices through domain engineering. PMID- 28025893 TI - Isoflavones from Maclura pomifera: structural elucidation and in silico evaluation of their interaction with PDE5. AB - While osajin and pomiferin are known for their anticancer, antibacterial and antidiabetic properties, scandenone and auriculasin have been proposed as anti inflammatory and antinociceptive agents. Curiously, these two couples of molecules are, from a chemical point of view, structural isomers which can all be extracted from Maclura pomifera. Although previous works described, separately, the isolation in reasonable amounts of the sole osajin/pomiferin couple or of scandenone/auriculasin, we report the extraction and characterization using direct spectral and chromatographical comparison of the four compounds. 2D NMR allowed to unambiguously assign the correct structures to the isomers. The compounds were screened in silico against PDE5 and their interaction pattern with the protein was compared with that of icarisid II, a natural PDE5 inhibitor. PMID- 28025894 TI - Imagining uses for things: Teaching "useful knowledge" in the early eighteenth century. AB - There has been an explosion of interest in "innovation-oriented knowledge" and utility in early modern knowledge economies. Despite this, a healthy skepticism surrounding the category of "useful knowledge" persists, at least in part because of its association with intentional concealment. Helpful in many ways, this skepticism has fostered a tendency to overlook a variety of efforts to teach "useful knowledge" in the period: efforts that were anchored in engagement with the real and involved the cultivation of an ability to direct the powers of the imagination. Indeed, for some the imagination served as a faculty central to an epistemology of use. This article takes as its example a handbook written by an early political economist (c. 1700) who endeavored to teach readers how to imagine uses for things they observed in collections while traveling so they would be better prepared to participate in a new, transnational culture of innovation. PMID- 28025895 TI - Advanced diagnostic plan applied to the Royal Villa in Naples. AB - To achieve adequate restoration project, the moment of choice of the type of intervention is a very delicate phase that necessarily involves a thorough understanding of the asset in all its aspects, as the location, the history, the architecture, the state of preservation, the pathologies causing the degradation, the degradation in itself, the analysis of constituent materials. The set of all that can be investigated on a product (cultural), to obtaining important information for subsequent maintenance, conservation and/or restoration actions, is what is called a diagnostic plan. In this case it was applied directly on a monument of national importance: the Royal Villa in Naples (today the Municipal Villa). The analysis were performed in situ and in the laboratory (SEM-EDS) on samples taken directly at the Villa, which allowed the creation of a series of analytical cards, containing digital data, required for the selection of expense future of intervention. PMID- 28025896 TI - Challenges in Implementation of the New Accreditation System. AB - Despite major changes in US Graduate Medical Education, from Core Competencies (2002) to the Next Accreditation System (2012), few studies have evaluated the role of the Residency Coordinator in program accreditation. This role may be especially challenging in child neurology, which involves separate, accredited child and adult neurology residencies. The present study of Child Neurology Program Coordinators evaluated workforce factors and first-year implementation of new training requirements. The response rate was 65% (48/74). Concerning workforce features included high turnover, unpaid overtime, inconsistent job titles, limited career paths, inadequate training, and nonacademic supervision. Programs' average implementation of 14 new accreditation items averaged 7.5 (standard deviation 2.5). This survey demonstrated that greater Next Accreditation System implementation is linked to increased coordinator experience, supervision within Graduate Medical Education, and greater administrative support for the coordinator role. Changes in these areas could improve future compliance of US child neurology programs with Graduate Medical Education accreditation requirements. PMID- 28025897 TI - New insights on geographical/ecological populations within Coilia nasus (Clupeiformes: Engraulidae) based on mitochondrial DNA and microsatellites. AB - The Coilia nasus is an important fish species, which is of commercial values in China. In order to manage the fisheries resources and the development of sustainable fishing strategies to protect this species, 11 microsatellite loci polymorphisms and mtDNA COI sequences were used to examine the genetic diversity of C. nasus in Japan and China. In total, the 40 COI haplotypes and 93 microsatellite alleles were detected. The mtDNA phylogeny did not support population grouping, but the distribution patterns of mtDNA haplotypes and the results of STRUCTURE analysis based on microsatellite indicated a degree of genetic isolation in this species. Our study suggested that the lack of a population genetic structure might result in its amphidromous life cycle, and the geographical distance and habitat fragments might cause isolated populations. Thus, the sampling populations of C. nasus in Japan and China could be divided as four geographical/ecological populations. PMID- 28025898 TI - Antioxidant and antimicrobial properties of traditional green and purple "Napoletano" basil cultivars (Ocimum basilicum L.) from Campania region (Italy). AB - The present study is the first effort to a comprehensive evaluation of the antioxidant and antimicrobial activities of 'Napoletano' green and purple basil (Ocimum basilicum L.) varieties. The results obtained revealed that the basil sample extracts were characterised by a generally higher polyphenolic concentration than those reported elsewhere for other more conventional and geographically different basil varieties. Napoletano purple basil revealed higher radical-scavenging and ferric-reducing capacities than the green one probably due to its relevant anthocyanin content. As regards the antimicrobial properties, both basil varieties exhibited activity against a broad spectrum of food-borne and human pathogenic micro-organisms, revealing not only a moderate to high natural preserving capacity, but also potentially beneficial influence on human health. Results indicated Napoletano green and purple basils as a good source of antioxidants of potential nutraceutical interest. PMID- 28025899 TI - Molecular phylogeny of four ascidian species inferred from mitochondrial Cytochrome Oxidase subunit I (COI) sequence. AB - Ascidians is a crucial group for the studies of deuterostome evolution and the origin of chordates, yet little molecular work has been done to determine the evolutionary relationships and largely unexplored beyond a few species. The phylogenetic analysis are presented for four different species of solitary ascidians, Ascidia virginea, Ascidiella aspersa, Clavelina oblonga and Aplidium fuscum, obtained from Great Nicobar Biosphere reserve (GNBR). Mitochondrial Cytochrome Oxidase subunit 1(COI) gene was amplified and the genetic diversity at the phylogenic level was measured. Bar-coded sequences were extracted with BLAST format from NCBI and the genetic diversity of the submitted sequences were compared with the related ascidian species. Maximum divergences measured among the four species were as follows: Ascidia virginea (96%), Ascidiella aspersa (96%), Clavelina oblonga (94%) and Aplidium fuscum (97%). This is the first report of molecular phylogeny of ascidians from Great Nicobar Biosphere Reserve, Andaman and Nicobar Islands. From this study, we found some stable clades on the evolutionary relationships among these ascidian species that may prompt a reevaluation of some morphological characters. PMID- 28025901 TI - The bottom of the universe: Flat earth science in the Age of Encounter. AB - This essay challenges the dominance of the spherical earth model in fifteenth- and early-sixteenth-century Western European thought. It examines parallel strains of Latin and vernacular writing that cast doubt on the existence of the southern hemisphere. Three factors shaped the alternate accounts of the earth as a plane and disk put forward by these sources: (1) the unsettling effects of maritime expansion on scientific thought; (2) the revival of interest in early Christian criticism of the spherical earth; and (3) a rigid empirical stance toward entities too large to observe in their entirety, including the earth. Criticism of the spherical earth model faded in the decades after Magellan's crew returned from circuiting the earth in 1522. PMID- 28025900 TI - Phytochemical and biological evaluation of Salvia apiana. AB - Salvia apiana (white sage, Lamiaceae family) plant is native to southern California and parts of Mexico. Some Native American tribes local to this region consider S. apiana to be sacred and burn the leaves as incense for purification ceremonies. The plant has been used to treat sore throats, coughs, chest colds, upper respiratory infections and poison oak rashes. The aqueous ethanolic extract of S. apiana showed moderate CB1 activity (58.3% displacement). Chromatographic purification of the ethanolic extract on silica gel column led to isolation of nine compounds: rosmadial (I), carnosol (II), 16-hydroxycarnosol (III), sageone (IV), cirsimaritin (V), salvigenin (VI), oleanolic acid (VII), 3beta,28-dihydroxy urs-12-ene (VIII), and ursolic acid (IX). The structures of the isolated compounds were determined by their 1D, 2D NMR and MS spectral data. All the fractions and isolated compounds were tested for cannabinoid and opioid receptor binding. PMID- 28025902 TI - What can science and technology studies learn from art and design? Reflections on 'Synthetic Aesthetics'. AB - In this paper we reflect on a project called 'Synthetic Aesthetics', which brought together synthetic biologists with artists and designers in paired exchanges. We - the STS researchers on the project - were quickly struck by the similarities between our objectives and those of the artists and designers. We shared interests in forging new collaborations with synthetic biologists, 'opening up' the science by exploring implicit assumptions, and interrogating dominant research agendas. But there were also differences between us, the most important being that the artists and designers made tangible artefacts, which had an immediacy and an ability to travel, and which seemed to allow different types of discussions from those initiated by our academic texts. The artists and designers also appeared to have the freedom to be more playful, challenging and perhaps subversive in their interactions with synthetic biology. In this paper we reflect on what we learned from working with the artists and designers on the project, and we argue that engaging more closely with art and design can enrich STS work by enabling an emergent form of critique. PMID- 28025903 TI - Antibacterial coating on in-line suction respiratory catheter to inhibit the bacterial biofilm formation using renewable cardanyl methacrylate copolymer. AB - Health-care materials associated with infections are very common in hospital admitted patients. There are generally infected by contact with the catheter or other multipurpose devices which are contacted with microbes. The respiratory infections associated with the pathogens having strong biofilm forming ability on catheter surface, causes life-threatening in every year. Therefore, a catheter coating material is of great interest which inhibits the biofilm formation of pathogens on a catheter to prevent respiratory infections. In this study, we synthesized cardanol containing copolymers as antimicrobial healthcare material via radical polymerization of cardanyl methacrylate (CMA) with styrene (St) monomer in presence of free radical initiator. The rate of polymerization was drastically reduced with the increase of feeding CMA monomer in copolymer. The thermal and mechanical properties were found to increase with incorporation of cardanol moiety in brittle and hard polystyrene. This soft copolymer was grafted onto polyvinyl chloride respiratory catheter which showed high antibacterial activity, inhibit the biofilm formation and also prevent bacterial adhesion. Therefore, the developed coating material on respiratory catheter surface is effective way to control the respiratory catheter-associated nosocomial infections. PMID- 28025904 TI - Intracochlear Pressure Changes due to 2 Electrode Types: An Artificial Model Experiment. AB - Objective To preserve residual hearing in cochlear implant surgery, the electrode design has been refined, and an atraumatic insertion has become one aspect of cochlear implant research. Previous studies have described the effect of insertion speed and opening of the round window membrane on intracochlear pressure changes. The aim of our current study was to observe intracochlear pressure changes due to different cochlear implant electrodes in an artificial cochlear model with stable surrounding factors. Study Design Prospective controlled study. Setting Tertiary referral center. Subjects and Methods The experiments were performed in an artificial cochlear model with a pressure sensor in the apical area. With straight and perimodiolar electrode arrays, 5 insertions with the same insertion speed and 5 insertions over the same time were performed. Results With the perimodiolar high-volume electrode, significantly greater intracochlear fluid pressure changes were observed than with the straight electrode. Compared with the straight electrode, the perimodiolar electrode induces significantly higher pressure peaks (1.12 +/- 0.15 vs 0.86 +/- 0.05 mm Hg, P = .006) and significantly higher amplitudes (0.38 +/- 0.07 vs 0.09 +/- 0.07 mm Hg, P < .001). Conclusion The reliable preservation of residual hearing is an important multifactorial challenge in modern cochlear implant surgery. Insertion speed, handling, and electrode design are known to influence the preservation of residual hearing. In our artificial model experiments, we could prove objectively that the volume of the electrodes has a significant influence on the intracochlear pressure changes during cochlear implantation. PMID- 28025905 TI - Otolaryngology Education: Recent Trends in Publication. AB - Objectives (1) Evaluate peer-reviewed publications regarding education in otolaryngology since 2000. (2) Analyze publication trends as compared with overall otolaryngology publications. Study Design Bibliometric analysis. Setting Academic medical center. Subjects and Methods A search for articles regarding education in otolaryngology from 2000 to 2015 was performed with MEDLINE and EMBASE databases, yielding 1220 articles; 362 relevant publications were categorized by topic, subspecialty, subject, article type, and funding source. Impact factors for each journal by year were obtained, and trends of each category over time were analyzed. These were then compared with publication numbers and impact factors for all otolaryngology journals. Results From 2000 to 2015, publications in otolaryngology education increased more rapidly than the field of otolaryngology overall. The most published topics included operative skills training, surgical simulation, and professionalism/career development. Recently there has been a decline in publications related to residency administration and duty hours relative to other topics. Only 12.2% of publications reported a funding source, and only 12.2% of studies were controlled. Conclusion Recent trends in otolaryngology literature reflect an increasing focus on education; however, this work is underfunded and often lacks high-quality evidence. PMID- 28025906 TI - Accuracy of Mobile-Based Audiometry in the Evaluation of Hearing Loss in Quiet and Noisy Environments. AB - Objectives (1) To compare the accuracy of 2 previously validated mobile-based hearing tests in determining pure tone thresholds and screening for hearing loss. (2) To determine the accuracy of mobile audiometry in noisy environments through noise reduction strategies. Study Design Prospective clinical study. Setting Tertiary hospital. Subjects and Methods Thirty-three adults with or without hearing loss were tested (mean age, 49.7 years; women, 42.4%). Air conduction thresholds measured as pure tone average and at individual frequencies were assessed by conventional audiogram and by 2 audiometric applications (consumer and professional) on a tablet device. Mobile audiometry was performed in a quiet sound booth and in a noisy sound booth (50 dB of background noise) through active and passive noise reduction strategies. Results On average, 91.1% (95% confidence interval [95% CI], 89.1%-93.2%) and 95.8% (95% CI, 93.5%-97.1%) of the threshold values obtained in a quiet sound booth with the consumer and professional applications, respectively, were within 10 dB of the corresponding audiogram thresholds, as compared with 86.5% (95% CI, 82.6%-88.5%) and 91.3% (95% CI, 88.5% 92.8%) in a noisy sound booth through noise cancellation. When screening for at least moderate hearing loss (pure tone average >40 dB HL), the consumer application showed a sensitivity and specificity of 87.5% and 95.9%, respectively, and the professional application, 100% and 95.9%. Overall, patients preferred mobile audiometry over conventional audiograms. Conclusion Mobile audiometry can correctly estimate pure tone thresholds and screen for moderate hearing loss. Noise reduction strategies in mobile audiometry provide a portable effective solution for hearing assessments outside clinical settings. PMID- 28025907 TI - Synopsis of spine surgery: third edition. PMID- 28025908 TI - Atlas of Anatomy, third edition. PMID- 28025910 TI - Science, ethnography, art. PMID- 28025909 TI - Habituating field scientists. AB - This article explores the sensory dimensions of scientific field research in the only region in the world where free-ranging bonobos ( Pan paniscus) can be studied in their natural environment; the equatorial rainforest of the Democratic Republic of Congo. If, as sensory anthropologists have argued, the senses are developed, grown and honed in a given cultural and environmental milieu, how is it that field scientists come to dwell among familiarity in a world which is, at first, unfamiliar? This article builds upon previous anthropological and philosophical engagements with habituation that have critically examined primatologists' attempts to become 'neutral objects in the environment' in order to habituate wild apes to their presence. It does so by tracing the somatic modes of attention developed by European and North American researchers as they follow bonobos in these forests. The argument is that as environments, beings and their elements become familiar, they do not become 'neutral', but rather, suffused with meaning. PMID- 28025911 TI - At home in the postcolony: Ecology, empire and domesticity at the Lamto field station, Ivory Coast. AB - This article is a history of the field station Lamto, in Ivory Coast, which was created by French ecologists in 1962, after independence. It retraces the origins, the logics and the contradictions of an extraordinarily ambitious scientific project, which aimed at the systematic, holistic, quantitative and multi-disciplinary description of a unit of African nature - the savannah ecosystem. It explores how knowledge-making was articulated with work hierarchies and postcolonial politics, lifestyles, values and affects. It reconstitutes the political ecology of a research station in ecology, following in its residences, laboratories and open-air experiments the co-production of domesticity, nature, science and (post-)colonial situations. PMID- 28025912 TI - Of spheres and squares: Can Sloterdijk help us rethink the architecture of climate science? AB - This article explores how different visions and values of science translate into different architectural shapes. I bring Peter Sloterdijk's 'spherology' to bear on my ethnographic fieldwork at the NEEM ice core base in Greenland, a significant node in the global infrastructure of climate science. I argue that the visual form of the geodesic dome of the camp materializes specific values and visions of this branch of paleoclimate science, which I elaborate vis-a-vis the pragmatic claims of the scientists/designers and the particular architectural history of Danish ice core drilling in Greenland. I argue that this aesthetic history articulates with Buckminster Fuller's ideas of a 'new nature' and 'scalar connections' encapsulated in his geodesic form. Second, I argue that the aesthetic production of space in the camp replicates the modern distinction between science and society, in so far as the lab space is rectangular and the recreational space is spherical. Third, I argue that NEEM scientists and Sloterdijk are essentially engaged in a common project: the scientists work hard to align air bubbles in the cores with atmospheric fluctuations in the hemisphere on the evidentiary terrain of ice, and Sloterdijk attempts to connect micro-uteri with macro-uteri in an attempt to fundamentally rethink space. Fuller's notion of 'Spaceship Earth', appropriated by Sloterdijk in his thinking about anthropogenic climate change, lends itself well to capturing the scalar alignments and the isolated NEEM base - on a mission to save planet Earth. In conclusion, I argue that Sloterdijk's spherology may serve as a point of departure for rethinking the aesthetic grammar of the architecture of science. PMID- 28025913 TI - A home for science: The life and times of Tropical and Polar field stations. AB - A 'halfway house' between the generic, purified space of the laboratory and the varied and particular spaces of the field, the field station is a controlled yet uncontained setting from which nature can be accessed and anchored. As living quarters for visiting scientists, field stations are also enmeshed in the routine and rhythms of everyday domestic life, and in longer cycles of habitation, wear, and repair. This introduction considers the empirical and conceptual significance of Polar and Tropical field stations as homes for scientific work and scientific lives. The field station's extra-territorial yet intimate character affects the credibility and circulation of knowledge along science's frontiers. The challenge of making a home in the (non-temperate) field and the mundane experiences of expatriation and appropriation establish particular political dynamics of knowledge-making in these locations. They bring into focus the imaginaries of nature and science that drive transnational research and put into relief the aesthetic and affective dimensions of work and life in these distant homes for science. All these themes are pursued and amplified in a different medium by the artists who contributed to our research and are also featured in this special issue. PMID- 28025914 TI - Higher and colder: The success and failure of boundaries in high altitude and Antarctic research stations. AB - This article offers a series of case studies of field stations and field laboratories based at high altitudes in the Alps, Himalayas and Antarctica, which have been used by Western scientists (largely physiologists and physicists) from circa 1820 to present. It rejects the common frame for work on such spaces that polarizes a set of generalizations about practices undertaken in 'the field' versus 'the laboratory'. Field sites are revealed as places that can be used to highlight common and crucial features of modern experimental science that are exposed by, but not uniquely the properties of, fieldwork. This includes heterogeneity of population and practice, diverse afterlives, the manner in which spaces of science construct individual and group expertise, and the extensive support and funding structures needed for modern scientific work. PMID- 28025915 TI - Field station as stage: Re-enacting scientific work and life in Amani, Tanzania. AB - Located high in Tanzania's Usambara Mountains, Amani Hill Station has been a site of progressive scientific endeavours for over a century, pushing the boundaries of botanical, zoological and medical knowledge, and providing expertise for imperial expansion, colonial welfare, national progress and international development efforts. The station's heyday was from the 1950s to the 1970s, a period of global disease eradication campaigns and the 'Africanization' of science. Today, Amani lies in a state of suspended motion. Officially part of a national network of medical research stations, its buildings and vegetation are only minimally maintained, and although some staff report for duty, scientific work has ceased. Neither ruin nor time capsule, Amani has become a quiet site of remains and material traces. This article examines the methodological potentials of re-enactment - on-site performances of past research practices - to engage ethnographically with the distinct temporalities and affective registers of life at the station. The heuristic power of re-enactment resides in its anachronicity, the tensions it introduces between immediacy and theatricality, authenticity and artifice, fidelity and futility. We suggest that re-enacting early post-colonial science as events unfolding in the present disrupts straightforward narratives about the promises and shortfalls of scientific progress, raising provocative questions about the sentiments and stakes of research in 'the tropics'. PMID- 28025916 TI - The hospital and the hospital: Infrastructure, human tissue, labour and the scientific production of relational value. AB - How does science make a home for itself in a public hospital? This article explores how scientists working in 'resource poor' contexts of global health negotiate relationships with their hosts, in this case the doctors, nurses and patients who already inhabit a provincial-level hospital. Taking its lead from recent works on science, ethics and development, this article seeks to 'provincialize the laboratory' by focussing on the scientific tropics as a space of productive encounter and engagement. A view from the hospital reveals the tenuous process of 'setting up' a place for science, in a world that does not immediately recognize its value. The article examines the material exchanges of infrastructure, bodily tissues and labour that enable one young scientist to establish a scientific life for himself. The success of those transactions, it argues, ultimately derives from their objectification of scientific vulnerability and their enactment of relationships of mutual recognition. As opposed to asking how scientific knowledge is produced in the tropics, the view from the hospital challenges us to focus on the establishment of relationships between scientists and their hosts as a productive endeavour in its own right. PMID- 28025917 TI - Science as national belonging: The construction of Svalbard as a Norwegian space. AB - This article examines how science has been employed to establish, maintain, and contest senses of belonging on Svalbard, an Arctic archipelago administered by Norway since 1925 under an international treaty. Our central argument is that the process of constructing Svalbard as a space belonging to Norway has long been intertwined with the processes of describing and representing the archipelago and that participating in those processes has also permitted other states to articulate their own narratives of belonging - on Svalbard in particular and in the Arctic more generally. We deploy the concept of belonging to capture a sense of legitimate presence and stakeholdership that we do not believe can be adequately captured by narrow concepts of sovereignty. Norway's historic and current use of science validates (and even naturalizes) its rule over Svalbard. At the same time, other states use science on Svalbard to articulate geopolitical scripts that portray them as stakeholders in an Arctic that is of transregional relevance due to the effects of climate change. PMID- 28025918 TI - Outcomes of Upper Airway Stimulation for Obstructive Sleep Apnea in a Multicenter German Postmarket Study. AB - Objective Selective stimulation of the hypoglossal nerve is a new surgical therapy for obstructive sleep apnea, with proven efficacy in well-designed clinical trials. The aim of the study is to obtain additional safety and efficacy data on the use of selective upper airway stimulation during daily clinical routine. Study Design Prospective single-arm study. Setting Three tertiary hospitals in Germany (Munich, Mannheim, Lubeck). Subjects and Methods A multicenter prospective single-arm study under a common implant and follow-up protocol took place in 3 German centers (Mannheim, Munich, Lubeck). Every patient who received an implant of selective upper airway stimulation was included in this trial (apnea-hypopnea index >=15/h and <=65/h and body mass index <35 kg/m2). Before and 6 months after surgery, a 2-night home sleep test was performed. Data regarding the safety and efficacy were collected. Results From July 2014 through October 2015, 60 patients were included. Every subject reported improvement in sleep and daytime symptoms. The average usage time of the system was 42.9 +/- 11.9 h/wk. The median apnea-hypopnea index was significantly reduced at 6 months from 28.6/h to 8.3/h. No patient required surgical revision of the implanted system. Conclusion Selective upper airway stimulation is a safe and effective therapy for patients with obstructive sleep apnea and represents a powerful option for its surgical treatment. PMID- 28025919 TI - AMCP Partnership Forum: Enabling the Exchange of Clinical and Economic Information Pre-FDA Approval. AB - : Current federal laws and FDA regulations have significantly restricted the sharing of clinical and health economic information on biopharmaceuticals that have yet to receive FDA approval. Over the past several years, organizations that make health care coverage decisions, including those that set copayments, premiums, and formulary placement, have expressed a need for receiving this information before approval, as long as appropriate safeguards exist to prevent this information from reaching unintended entities. Population health decision makers have indicated that waiting until FDA approval is often too late for the critical planning, budgeting, and forecasting associated with health benefit design, especially given the recent influx of high-cost medications and scrutiny for better evaluation and preparation. Recognizing that securities laws restrict the disclosure of nonpublic information and may need to be amended, permissible early dissemination would allow population health decision makers to incorporate clinical and economic information for pipeline drugs or expanded indications into financial forecasting for the following year's plan. Access to this information is needed 12-18 months before FDA approval when organizations are deciding on terms of coverage and budgetary assumptions for state health insurance rate filings, Medicare and Medicaid bids, contracts with health care purchasers, and other financial arrangements. The need for exchange of clinical economic information before FDA approval was first introduced at a previous Academy of Managed Care (AMCP) forum in March 2016, which addressed section 114 of the Food and Drug Administration Modernization Act and the communication of such information after FDA approval. To address preapproval information specifically, AMCP convened a Partnership Forum on September 13-14, 2016. This forum included a diverse group of stakeholders representing managed care, the biopharmaceutical industry, providers, patients, health economists, academia, and others. The multistakeholder group represented the key professionals and entities affected by the federal laws and FDA regulations that restrict the sharing of preapproval information and the collective credibility necessary for proposing this new communication process. Forum participants primarily focused on 6 items of discussion: (1) creating and defining new terms for how biopharmaceutical manufacturers may provide clinical and economic information 12-18 months before FDA approval; (2) defining the clinical and scientific standards that this information should meet; (3) determining which entities should have access to this information and the value to each; (4) the format and process by which this information should be disseminated; (5) developing definitions for existing terms referenced in current laws, regulations, or guidance documents that would need to be modernized to align with the identified new term; and (6) providing safeguards to prevent this information from reaching unintended entities. Forum participants selected "preapproval information exchange" (PIE) as the correct term to describe this proposed new communication process and to be inclusive of data from pivotal phase III clinical trials, pharmaco-economic data, and patient-reported outcomes, as well as other relevant items, including anticipated indications, place in therapy, and routes of administration. Stakeholders agreed that PIE should be truthful, non-misleading, and include a broad range of information to meet the needs of population health decision makers and health care technology evolution. Recipients of PIE would be limited to population health decision makers who need this information for coverage decisions. The format and process for PIE disseminated should allow for a bidirectional exchange between manufacturers and population health decision makers but should not be proscribed in legislation. Furthermore, new legislative language may be beneficial, since PIE is a novel category of information. New legislation could provide a safe harbor and clarity that PIE does not violate preapproval promotion and the Federal Food, Drug, and Cosmetic Act and its regulations. DISCLOSURES: The AMCP Partnership Forum on Enabling the Exchange of Clinical and Economic Data Pre-FDA Approval and the development of this proceedings document were supported by AbbVie, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Celgene, Intarcia Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Merck, National Pharmaceutical Council, Novo Nordisk, Pfizer, Pharmaceutical Research and Manufacturers of America, Precision for Value, Sanofi, Takeda Pharmaceuticals, U.S.A., and Xcenda. All sponsors participated in the forum and in revising and approving the manuscript. PMID- 28025920 TI - Impact of Overactive Bladder Step Therapy Policies on Medication Utilization and Expenditures Among Treated Medicare Members. AB - BACKGROUND: The impact of formulary management strategies on utilization and expenditures in overactive bladder (OAB) treatment has not been extensively investigated. In 2013, step therapy (ST) policies for 2 branded OAB treatments, mirabegron and fesoterodine, were removed from Humana Medicare Advantage Prescription Drug (MAPD) plans and Medicare prescription drug plans (PDP), allowing for an examination of the effect of ST policies on OAB medication use patterns and costs. OBJECTIVE: To assess the impact of removal of formulary restriction policies for mirabegron and fesoterodine on medication utilization patterns and costs associated with OAB treatment in Medicare patients. METHODS: A retrospective cross-sectional study design was utilized. Subjects included individuals enrolled in Humana MAPD plans or PDPs, aged >= 65 years, with >= 1 prescription for an OAB medication in 2013. Patient demographic characteristics, OAB medication utilization, and pharmacy cost trends in 2013 were described. OAB medication use was calculated as the number of 30-day-supply equivalent medication claims and reported as a percentage of the total number of 30-day supply equivalent claims across all OAB products. OAB medication expenditures were calculated as a percentage of the sum of pharmacy costs for OAB medications and reported separately for each month and drug during 2013. Temporal trends of OAB medication utilization and expenditures in 2013 were calculated using ordinary least squares regression. RESULTS: Of 194,511 patients, trends in utilization of OAB medications indicated that on average, there was a statistically significant monthly increase in utilization of mirabegron (regression coefficient [B] = 274; P < 0.001; 95% CI: 218, 330), fesoterodine (B = 167; P < 0.001; 95% CI = 129, 205), oxybutynin extended release (ER; B = 357; P = 0.011; 95% CI = 99, 614), and trospium ER (B = 33; P = 0.001; 95% CI = 17, 50) and statistically significant decreases in utilization of solifenacin (B = -202; P = 0.048; 95% CI = -402, -2), tolterodine ER (B = -287; P = 0.002; 95% CI = 437, -137), darifenacin (B = -94; P < 0.001; 95% CI = -128, -61), and trospium immediate release (IR; B = -22; P = 0.001; 95% CI = -32, -12). Total OAB medication expenditures significantly increased an average of 0.12% for each month during the course of 2013 (B = 0.12; P = 0.026; 95% CI = 0.017, -0.223). While monthly oxybutynin IR utilization did not change significantly throughout 2013 (B = 228; P = 0.169; 95% CI = -114, -570), it demonstrated the largest average monthly expenditure increase (B = 0.082; P < 0.001; 95% CI = 0.056, 0.108). When removing oxybutynin IR costs from the total OAB medication costs, the trend in total OAB medication average monthly expenditures was not significant (B = 0.038; P = 0.365; 95% CI = -0.051, -0.126). An over 4-fold per unit-cost increase for oxybutynin IR was noted. CONCLUSIONS: Utilization of 2 branded OAB products increased in the months after ST removal with minimal cost impact. One of the possible reasons total OAB expenditures increased may have been due to the increased cost of the largest-volume generic product, oxybutynin IR. DISCLOSURES: This research was funded by Astellas Pharma Global Development and was conducted as part of the Astellas-Humana Research Collaboration. Ng, Kristy, Schermer, and Bradt are employees of Astellas. Astellas manufactures mirabegron (Myrbetriq) and solifenacin (VESIcare). Abbass, Caplan, Collins, and Suehs are employees of Comprehensive Health Insights, a subsidiary of Humana, which received funding from Astellas for this study. Suehs owns stock in Humana. Chan is an employee of Humana Pharmacy Solutions. Portions of this study were presented as a poster at Academy of Managed Care Pharmacy Nexus 2015; October 26 29, 2015; Orlando, Florida. Study concept and design were contributed by Ng, Chan, Suehs, and Abbass, along with Collins. Abbass took the lead in data collection, along with Collins and with assistance from Caplan, Chan, and Suehs. Data interpretation was provided by Kristy and Bradt, along with Abbass, Caplan, Ng, Suehs, Collins, and Chan. The manuscript was written primarily by Caplan, along with Schermer, Suehs, and Abbass, and revised by Caplan, Schermer, and Ng, along with the other authors. PMID- 28025921 TI - Improving Clinical Decision Support in Pharmacy: Toward the Perfect DUR Alert. AB - : The cornerstone of every health care profession is decision making. Historically, the decisions made by pharmacists have focused on ensuring the accuracy and physical integrity of the pharmaceutical product delivered to the patient in strict compliance with the prescriber's order. As the role of the pharmacist evolved over the past half century, the focus of decision making progressively shifted from a product-centric orientation to optimizing the interaction that occurs between the pharmaceutical product and the patient. Toward that end, prospective drug utilization review (pro-DUR) represents, perhaps, the quintessential expression of the pharmacist's contemporary clinical role. Fueled by evolving practice standards, innovations in information technology, and legal mandates such as The Omnibus Budget Reconciliation Act of 1990, computer-assisted pro-DUR systems have become a ubiquitous component of pharmacy practice. While these data-driven clinical decision support systems have clearly demonstrated their ability to improve the quality and safety of medication delivery and use, they have yet to fully achieve their promised potential. Doing so will require recognition of continuing shortcomings and a shared commitment by all stakeholders to develop and adhere to best practice guidelines that will better ensure that alerts received by practitioners are valid, interpretable, clinically significant, and actionable. DISCLOSURES: The authors received no funding for this article. Rupp discloses consultancy fees from Surescripts unrelated to this manuscript. Both authors contributed equally to concept, analysis, and manuscript preparation. PMID- 28025922 TI - Comprehensive Medication Reviews in Long-term Care Facilities: History of Process Implementation and 2015 Results. AB - BACKGROUND: Since 2013, Part D sponsors have been required to offer comprehensive medication reviews (CMRs) to all beneficiaries enrolled in their medication therapy management (MTM) programs at least annually, including those in long-term care (LTC) settings. Since that time, MTM providers have found that accessing and completing CMRs with beneficiaries is frequently prohibitively complex, since the process often requires a live, face-to-face interactive interview where the beneficiary resides. However, with the migration of the CMR completion rate from a star ratings display measure to an active measure, coupled with the new CMR completion rate cutpoints for 2016, accessing this population for CMR completion has heightened importance. PROGRAM DESCRIPTION: Our proprietary consultant pharmacist (CP) software was programmed in 2012 to produce a cover letter, medication action plan, and personal medication list per CMS standardized format specifications. Using this system, CPs were trained to perform and document CMRs and the interactive interviews. MTM-eligible Part D beneficiaries, identified by several contracted clients as residing in LTC serviced by Omnicare, were provided CMRs and summaries written in CMS standardized format by CPs. Residents with cognitive impairment were identified using 3 data elements in the Minimum Data Set (MDS). OBSERVATIONS: In 2015, 7,935 MTM-eligible beneficiaries were identified as receiving medications from an Omnicare pharmacy. After excluding those who were disenrolled by their prescription drug plans, discharged from the LTC facility, or resided in a LTC facility no longer serviced by Omnicare, 5,593 residents were available for CMR completion. Of these, only 3% refused the CMR offer, and 5,392 CMRs (96%) were completed successfully. Thirty-nine percent of residents had cognitive impairment per MDS assessments; in those instances, CMRs were conducted with someone other than the beneficiary. Based on the CMRs and interactive interviews, 7,527 drug therapy problem recommendations were made to prescribers, about 50% of which resulted in an alteration in therapy, including reductions in polypharmacy and high-risk medications. IMPLICATIONS: The CMR process and written summary in CMS standardized format works effectively for residents in LTC when performed by CPs in the facility, as evidenced by high completion rates and drug therapy problem identification/resolution. Part D plans should further consider using CPs to conduct CMRs in LTC settings. DISCLOSURES: No outside funding supported this research. All authors are employees of Omnicare, a CVS Health Company, and are stockholders of CVS Health. O'Shea and Zarowitz have received research funding (unrelated to the submitted work) from Acadia, AstraZeneca, and Sunovion. The abstract for this article was presented as a research poster at the Academy of Managed Care and Specialty Pharmacy 2016 Annual Meeting; April 21, 2016; San Francisco, California. Study concept and design were contributed by O'Shea and Zarowitz, along with Erwin. O'Shea collected the data, and data interpretation was performed primarily by O'Shea, along with Zarowitz and Erwin. The manuscript was written by O'Shea, along with Zarowitz, and revised primarily by Zarowitz, along with O'Shea and Erwin. PMID- 28025923 TI - Progression to Uncontrolled Severe Asthma: A Novel Risk Equation. AB - BACKGROUND: Recently published asthma guidelines by the European Respiratory Society and the American Thoracic Society (ERS-ATS) define severe disease based on medication use and control level. These guidelines also emphasize that asthma severity involves certain biomarker phenotypes, one of them being eosinophilic phenotype. The quantification of the influence of eosinophil level toward predicting disease severity can help decision makers manage therapy better earlier. OBJECTIVE: To develop a risk-scoring algorithm to identify patients at greater risk of developing uncontrolled severe asthma as defined by ERS-ATS guidelines. METHODS: Data on asthma patients were extracted from the EMRClaims + database from January 2004 to July 2011. Patients with continuous enrollment 12 months before and after the date of the first encounter with a diagnosis of asthma (index date) with at least 1 blood eosinophil test result in the 12 months after the index date, but before the development of uncontrolled severe asthma or the study end date, were included. Uncontrolled severe asthma was defined as the first date on which all criteria of the ERS-ATS definition were first satisfied in the 12 months after the index date. Age (>= 50 years vs. < 50 years), race, and sex were measured at index, and the Charlson Comorbidity Index (CCI) score (> 0 vs. 0) was measured in the pre-index period. Elevated eosinophil level was defined as a test result with >= 400 cells/uL. The study cohort was randomly split 50-50 into derivation and validation samples. Cox proportional hazards regression was used to develop the risk score for uncontrolled severe asthma using the derivation cohort with independent variables of eosinophil level, age, sex, race, and CCI. A bootstrapping procedure was used to generate 1,000 samples from the derivation cohort. Variables significant in >= 50% of the samples were retained in the final regression model. A risk score was then calculated based on the coefficient estimates of the final model. C-statistic was used to test the model's discrimination power. RESULTS: The study included 2,405 patients, 147 (6%) of whom developed uncontrolled severe asthma. Higher eosinophil level and CCI score > 0 were significantly and independently associated with an increased risk of uncontrolled severe asthma in the derivation cohort (HR = 1.90, 95% CI = 1.17-3.08 and HR = 2.00, 95% CI = 1.28-3.13, respectively); findings were similar in the validation cohort. Total risk score was categorized as 0, 2, and 4. All models showed good C-statistics (0.79-0.80), indicating favorable model discrimination. There was a significantly greater number of patients with uncontrolled severe asthma in the risk score segments of 2 and 4 compared with 0 (each P < 0.0001). CONCLUSIONS: A risk stratification tool using peripheral eosinophil counts and CCI can be used to predict the development of uncontrolled severe asthma. DISCLOSURES: This study was funded by Teva Pharmaceuticals. eMAX Health Systems was a consultant to Teva Pharmaceuticals for this study and received payment from Teva Pharmaceuticals for work on this study. Casciano and Dotiwala are employed by eMAX Health Systems. Krishnan, Li, and Martin received payment from eMAX Health Systems for work on this study. Small was employed by Teva Pharmaceuticals at the time of this study. Study concept and design were contributed primarily by Casciano, Krishnan, Small, and Martin, along with Li and Dotiwala. Dotiwala, Casciano, Small, and Li collected the data, along with Martin and Li and Krishnan. Data interpretation was provided by Martin, Casciano, and Li, with assistance from the other authors. The manuscript was written by Li, Casciano, Dotiwala, and Small, with assistance from the other authors, and revised by Dotiwala, Small, Li, and Martin, with assistance from Krishnan and Casciano. PMID- 28025924 TI - Improving Comprehensive Medication Review Acceptance by Using a Standardized Recruitment Script: A Randomized Control Trial. AB - BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) require prescription drug plan sponsors to offer a comprehensive medication review (CMR) annually to eligible beneficiaries through the plans' Medication Therapy Management Programs (MTMPs). In 2011, the Pharmacy Quality Alliance endorsed the CMR completion rate as a quality measure for MTMPs, and CMS has adopted the measure into the 2016 CMS star ratings. CMS star ratings are used to describe the quality of plans to assist Medicare plan enrollees in choosing a plan and to determine quality bonus payments for Medicare Advantage plans. Star ratings are measured on a scale of 1 to 5, with 5 being the highest possible rating for an individual measure. Currently, the majority of plans score 2 stars or less on the CMR completion rate measure. OBJECTIVE: To demonstrate the effectiveness of a standardized CMR recruitment script emphasizing the benefits of the service to increase acceptance of CMR offers among beneficiaries of a Medicare prescription drug plan. METHODS: A CMR recruitment script, shaped by the Health Belief Model, was developed based on a previous pilot study. The original script described the CMR service but did not emphasize key benefits or barriers from the beneficiary perspective. The updated script aimed to enhance beneficiary understanding of the CMR service, explain the benefits from the beneficiary perspective, and address potential barriers to accepting the service. The updated script was tested during the 2012 MTMP enrollment in a randomized controlled experiment, using the original script as the control. The CMR service was offered to MTMP members via phone calls by live call agents who spoke with members who answered, using 1 of the 2 scripts. Both scripts asked members if they were willing to have a pharmacist call them back and perform a CMR at a later date. Two call attempts were made to all eligible beneficiaries. If contact was not made after 2 unsuccessful outreach attempts, a computer-generated voicemail message was left, and an informational letter regarding the MTMP and CMR was subsequently mailed. CMR acceptance rates, defined as the proportion of beneficiaries who spoke with a call agent and agreed to participate in the CMR service, divided by the total number of beneficiaries contacted who confirmed their membership with the Part D plan, were compared between those exposed to the original script and those exposed to the updated script. Multivariate logistic regression was employed to examine factors that may have influenced members' decisions regarding the offer to participate in CMRs. RESULTS: There were 105,701 beneficiaries in the first quarter of the MTMP 2012 enrollment who were eligible for the MTM service. Approximately 10% of eligible beneficiaries answered the live calls and listened to the scripts. On average, members who responded to calls were aged 68.9 years, prescribed 10.5 chronic medications, and had 6 different chronic conditions. Among members who answered the calls, 52.9% were exposed to the original script, and 47.1% heard the updated script. For the updated script, 48.2% of the members accepted the offer to be subsequently contacted by a pharmacist to complete the CMR, whereas 38.1% of members exposed to the original script agreed to the CMR offer. Logistic regression results indicated that members who received the updated script were 1.58 (95% CI = 1.45-1.72) times more likely to accept the CMR offer compared with those who received the original script. Among other factors, increased number of chronic medications (OR = 1.038, 95% CI = 1.020-1.057), increased number of disease conditions (OR = 1.039, 95% CI = 1.014-1.064), and previous involvement in the MTMP were positively associated with acceptance of the CMR offer. CONCLUSIONS: The updated script outperformed the original script in promoting member willingess to participate in a CMR by describing key components and emphasizing benefits of participation. CMR engagement remains a challenge for Medicare plan sponsors. This study demonstrates that to overcome common hurdles to CMR engagement, sponsors should seek strategies to educate members regarding MTM programs and the benefits and components of a CMR. DISCLOSURES: No outside funding supported this study. Research for this study was conducted while Liu was a postdoctoral fellow at the University of Florida. Liu is currently an employee of the U.S. Food and Drug Administration (FDA). The views expressed here are those of the authors and not necessarily those of the FDA. Yang reports receiving a research fellowship funded by WellCare Health Plans at the time of this study. The authors report no other potential conflicts of interest. Study concept and design were primarily contributed by Yang, Segal, and Miguel, along with Hall, Liu, and Ballew. Miguel, Liu, Yang, Ballew, and Hall collected the data, which were analysed and interpreted primarily by Liu, along with Yang and Segal and assisted by the other authors. The manuscript was written primarily by Miguel, Hall, and Garret, along with Liu, Yang, and Ballew, and revised by Ballew, Segal, Hall, and Miguel, along with Liu and Yang. PMID- 28025925 TI - Contemporary Trends in Oral Antiplatelet Agent Use in Patients Treated with Percutaneous Coronary Intervention for Acute Coronary Syndrome. AB - BACKGROUND: Recent trials demonstrated the efficacy of prasugrel and ticagrelor compared with clopidogrel in the reduction of cardiovascular complications in patients with acute coronary syndrome (ACS). However, it is unclear how use of the 3 antiplatelet medications has changed in commercially insured patients since the advent of the new agents. OBJECTIVES: To (a) describe the adoption of prasugrel and ticagrelor in patients who received percutaneous coronary intervention (PCI) for the onset of ACS and (b) explore patient factors associated with the selection of the drug to provide insight into utilization patterns of these antiplatelet agents. METHODS: Patients who received a new dispensing of an antiplatelet agent following a hospitalization for a PCI administered for ACS were identified from insurance claims between 2009 and 2013. Demographics and comorbid conditions were determined based on a 6-month period before the ACS event. Longitudinal trends in antiplatelet agent selection were illustrated using descriptive statistics segmented by month and quarter. Using logistic regressions with stepwise model selection, factors associated with use of the newer medications, as well as with the selection between ticagrelor and prasugrel, were identified. RESULTS: The analysis included 66,335 subjects. The use of clopidogrel decreased from 100% to roughly 65% of total antiplatelet agent use by the end of 2011 and leveled off thereafter. The introduction of ticagrelor in 2011 coincided with a drop in prasugrel initiation from 35%-18% by December 2013. The use of new agents as opposed to use of clopidogrel was associated with younger age (< 65 years), male gender, and a diagnosis of ST-elevation myocardial infarction. In addition, conditions increasing mortality and risk of cardiovascular complication were associated with higher odds of using clopidogrel. The odds of using ticagrelor over prasugrel increased with older age and history of a cerebrovascular event. CONCLUSIONS: In 2013, clopidogrel remained the most prescribed agent. Meanwhile, ticagrelor had gradually replaced a substantial portion of prasugrel initiation. Further investigation into outcomes associated with the newer agents, as well as reasons behind the conservative use of the antiplatelet agents, is warranted. DISCLOSURES: No funding was received for the conduct of this study. DiDomenico received an honorarium from Amgen for the preparation of a heart failure drug monograph for Pharmacy Practice News and was a co-investigator on funded research for the Patient-Centered Outcomes Research Institute. DiDomenico also serves as an advisory board member for a heart failure program at Otsuka America Pharmaceuticals and as an advisory board member at Novartis Pharmaceuticals. Touchette has received unrestricted grant funding from Cardinal Health and Sunovion Pharmaceuticals and has also served as a consultant to and director of the American College of Clinical Pharmacy Practice-Based Research Network on a study funded by Pfizer. None of the authors of this study are involved in financial or personal relationships with agencies, institutions, or organizations that inappropriately influenced the statistical analysis plan or interpretation of the results. Study concept and design were contributed by Kim, Lee, Touchette, and Walton, with assistance from DiDomenico and Ardati. Kim and Lee collected the data, and data interpretation was performed by Lee, DiDomenico, and Ardati, along with Kim and Walton and assisted by Touchette. The manuscript was written by Kim and Walton, with assistance from the other authors, and revised by Kim, Walton, and Lee, with assistance from the other authors. PMID- 28025926 TI - Clinical and Economic Burden of Elevated Blood Eosinophils in Patients With and Without Uncontrolled Asthma. AB - BACKGROUND: The European Respiratory Society and American Thoracic Society (ERS/ATS) published guidelines in 2014 for the evaluation and treatment of asthma. These guidelines draw attention to management of patients with asthma that remains uncontrolled despite therapy. One phenotypic characteristic of therapy-resistant asthma is eosinophil elevation. It is important to better understand the burden of care gaps in this patient subgroup in order to support improved treatment strategies in the future. OBJECTIVE: To quantify the economic burden of asthma patients with and without peripheral blood eosinophil elevation. METHODS: A retrospective cohort study was conducted using data from patients aged 12 years or older with a diagnosis of asthma using electronic health records of over 2 million patients between 2004-2010. Patients with a diagnosis of chronic obstructive pulmonary disease, Churg Strauss syndrome/Wegener's granulomatosis, eosinophilia, cystic/pulmonary fibrosis, allergic bronchopulmonary aspergillosis, or lung cancer in the 12-month period before the date of asthma diagnosis were excluded. Patients with asthma were followed for 12 months after their initial asthma diagnosis to identify those with controlled versus uncontrolled asthma based on ERS/ATS criteria. Patients with at least 1 peripheral blood eosinophil test result of >= 400 cells/uL were classified as those with elevated eosinophils. Total annual paid-claim cost was compared by eosinophil levels within the controlled and uncontrolled asthma subgroups. Costs were adjusted to 2015 U.S. dollars. Patients were stratified by control level, and generalized linear modeling regressions were used to assess the magnitude of increase in cost of the elevated eosinophil group. RESULTS: A total of 2,701 patients were included in the study, of which 17% had uncontrolled asthma and 21% had elevated eosinophils. The mean total annual cost of patients with uncontrolled asthma was more than 2 times the cost of those with controlled asthma ($18,341 vs. $8,670, P < 0.001). Patients with uncontrolled asthma in the elevated eosinophil group had almost double the total cost ($28,644 vs. $14,188, P = 0.008) compared with those with blood eosinophil levels in a normal range. Similarly, patients classified as those with controlled asthma in the elevated eosinophil group had almost twice the average costs as those without elevated eosinophils ($14,754 vs. $7,203, P < 0.001). Uncontrolled asthma with elevated eosinophils had 4 times greater hospital admissions and over 4 times higher total costs than controlled asthma without elevated eosinophils. Among patients with uncontrolled asthma, patients with elevated eosinophils had a 53% increase in mean cost ($17,723 vs. $11,581, P < 0.001) compared with patients without elevated eosinophils. Among patients with controlled asthma, patients with elevated eosinophils had a 62% increase in mean cost ($8,897 vs. $5,486, P < 0.001) compared with patients without elevated eosinophils. CONCLUSIONS: Elevated peripheral blood eosinophil level is associated with higher cost irrespective of disease control status. DISCLOSURES: This study was funded by Teva Pharmaceuticals. Dotiwala and Casciano report consulting and writing fees from Teva Pharmaceuticals for work on this study. Sun is an employee and stockholder of Teva Pharmaceuticals. Li reports consulting fees from eMAX Health. All authors contributed to study design. Dotiwala took the lead in data collection, along with the other authors, and data interpretation was performed primarily by Krishnan, Sun, and Li, along with Casciano and Dotiwala. The manuscript was written by Casciano, Dotiwala, and Li, along with Sun and Krishnan, and revised by Casciano, Dotiwala, Sun, and Li, with assistance from Krishnan. PMID- 28025927 TI - The Effect of Medicare Part D on Prescription Drug Spending and Health Care Use: 6 Years of Follow-up, 2007-2012. AB - BACKGROUND: Previous studies have shown that Medicare Part D was associated with a reduction in out-of-pocket expenditures for Medicare beneficiaries during the early years of its implementation (2006 and 2007). However, a question remains regarding the effect of Part D on out-of-pocket expenditures in the longer term. OBJECTIVE: To evaluate the effects of Part D on prescription drug expenditures and certain health care use for a longer time period using a large, nationally representative sample of Medicare beneficiaries. METHODS: Using Medical Expenditure Panel Survey (MEPS) data from 2000 through 2005 (pre-Part D period) and from 2007 through 2012 (Part D era), this study identified a cohort of elderly Medicare beneficiaries (treatment group) and a near-elderly non-Medicare population (control group). A difference-in-differences analysis was conducted to estimate the effect of Part D on prescription medication use and expenditures and outpatient visits. Propensity score weights and sampling weights were applied to obtain unbiased effect estimates accounting for complex survey designs. RESULTS: A total of 26,585 elderly Medicare beneficiaries and 20,688 near-elderly non Medicare beneficiaries were identified. The introduction of Part D was associated with an adjusted average reduction of $105 in annual out-of-pocket spending on prescription drugs during the post-Part D period (2007 through 2012). The reduction in annual out-of-pocket spending ranged from $49 to $152 during the post-Part D period. No significant increase was found in total prescription expenditures or prescription medication use following the introduction of Part D nor were there significant changes in outpatient visits. CONCLUSIONS: A continued reduction of Part D out-of-pocket drug expenditures was found each year from 2007 to 2012. DISCLOSURES: No funding has been received to conduct this study or prepare this manuscript. The authors have no conflicts of interest to declare. Study concept and design were primarily contributed by Park with assistance from Jung. Both authors contributed equally to data analysis and interpretation. The manuscript was written primarily by Park, with assistance from Jung, and revised primarily by Jung. PMID- 28025928 TI - Effectiveness of the Dader Method for Pharmaceutical Care on Patients with Bipolar I Disorder: Results from the EMDADER-TAB Study. AB - BACKGROUND: Bipolar I disorder (BD-I) is a chronic illness characterized by relapses alternating with periods of remission. Pharmacists can contribute to improved health outcomes in these patients through pharmaceutical care in association with a multidisciplinary health team; however, more evidence derived from randomized controlled trials (RCTs) is needed to demonstrate the effect of pharmaceutical care on patients with BD-I. OBJECTIVE: To assess the effectiveness of a pharmaceutical intervention using the Dader Method on patients with BD-I, measured by the decrease in the number of hospitalizations, emergency service consultations, and unscheduled outpatient visits from baseline through 1 year of follow-up. METHODS: This study is based on the EMDADER-TAB trial, which was an RCT designed to compare pharmaceutical care with the usual care given to outpatients with BD-I in a psychiatric clinic. The main outcome was the use of health care services, using Kaplan-Meier methods and Cox regression. The trial protocol was registered in ClinicalTrials.gov (Identifier NCT01750255). RESULTS: 92 patients were included in the EMDADER-TAB study: 43 pharmaceutical care patients (intervention group) and 49 usual care patients (control group). At baseline, no significant differences in demographic and clinical characteristics were found across the 2 groups. After 1 year of follow-up, the risk of hospitalizations and emergencies was higher for the control group than for the intervention group (HR = 9.03, P = 0.042; HR = 3.38, P = 0.034, respectively); however, the risk of unscheduled outpatient visits was higher for the intervention group (HR = 4.18, P = 0.028). There was no "placebo" treatment, and patients in the control group might have produced positive outcomes and reduced the magnitude of differences compared with the intervention group. CONCLUSIONS: Compared with usual care, pharmaceutical care significantly reduced hospitalizations and emergency service consultations by outpatients with BD-I. DISCLOSURES: This study received funding from the Universidad de Antioquia, Committee for Development Research and Sustainability Program, CODI, (2013-2014 and 2014-2015). Humax Pharmaceutical provided support for the initial development of the EMDADER-TAB trial without commercial interest in the outcomes derived from the trial. Salazar-Ospina reports grants from Credito Beca Francisco Jose de Caldas Scholarship for Doctoral Programs (528), which also contributed to the support of this study. Gonzalez-Avendano is an employee of Humax Pharmaceutical. The other authors have nothing to disclose. Study concept and design were contributed by Benjumea, Faus, and Rodriguez, along with Salazar-Ospina and Amariles. Salazar-Ospina took the lead in data collection, assisted by Gonzalez Avendano, and data interpretation was performed by Salazar-Ospina, Hincapie Garcia, and Gonzalez-Avendano. The manuscript was written primarily by Salazar Ospina, with assistance from Amariles and Gonzalez-Avendano, and revised by all the authors. PMID- 28025929 TI - Hemophilia Management via Data Collection and Reporting: Initial Findings from the Comprehensive Care Sustainability Collaborative. AB - BACKGROUND: Despite being a rare disorder, hemophilia represents a significant driver of health care resource utilization and requires expert hematologic and multidisciplinary services to achieve optimal outcomes. Since their inception nearly 40 years ago, hemophilia treatment centers (HTCs) have served as centers of excellence in providing the intensive care and ancillary services necessary for this unique patient base; however, the full capabilities of these centers may be underused in the current framework of managed care, largely because of a lack of communication and information shared between payers and HTC stakeholders. PROGRAM DESCRIPTION: In an effort to enact tangible change toward improving the quality of care for bleeding disorders, the National Hemophilia Foundation developed an ongoing initiative among 18 leading clinicians and managed care decision makers called the Comprehensive Care Sustainability Collaborative (CCSC). The primary aim of the CCSC is to develop a framework for quality improvement pilot programs that can be replicated across the United States between payers and HTCs to facilitate cost-effective hemophilia management by integrating the HTC comprehensive care model. OBSERVATIONS: After CCSC committee members shared perspectives on care delivery, quality, and value, actionable data points were reviewed at length in order to develop meaningful metrics to facilitate information sharing between HTC and payer stakeholders. The following pragmatic measures will be reported by HTCs and payers via a series of pilot programs (reporting group is indicated in brackets): (a) patient classification by diagnosis (type, severity, and inhibitor status) [HTC]; (b) total cost of clotting factor [payer]; (c) prescribed factor dose/dispensed dose/patient weight (+/- range) [payer and HTC]; (d) emergency department visits/hospitalizations [payer and HTC]; (e) home infusion of clotting factor (%) [HTC]; (f) total cost per patient [payer]; and (g) patient contacts (e.g., clinic visits, follow-ups, telemedicine, and e-mail) [HTC]. IMPLICATIONS: Routine information sharing between HTCs and payer stakeholders is paramount to improving the quality and reducing the cost of hemophilia care, and the CCSC initiative provides a unique forum for such dialogue. Over the course of several consensus meetings, the CCSC has rigorously developed a set of quality improvement and cost management metrics. These metrics will be used in a first-of-its-kind series of pilot projects that are anticipated to forge innovative collaboration between payers and HTCs so as to improve outcomes in the management of bleeding disorders. DISCLOSURES: The preparation of this article was funded as part of the Comprehensive Care Sustainability Collaborative (CCSC) initiative, which is jointly sponsored by the National Hemophilia Foundation (NHF) and Impact Education, LLC, and supported via a charitable donation from Shire. Tarantino and Pindolia are members of the CCSC and were part of the NHF CCSC group that developed the metrics included in this article. Both authors received honorariums from the NHF for content development and expert review of the manuscript. Both authors contributed equally to the concept and design of this article and to analysis and manuscript preparation. PMID- 28025930 TI - Cost-Effectiveness of Treatment Sequences of Chemotherapies and Targeted Biologics for Elderly Metastatic Colorectal Cancer Patients. AB - BACKGROUND: Treatment patterns for metastatic colorectal cancer (mCRC) patients have changed considerably over the last decade with the introduction of new chemotherapies and targeted biologics. These treatments are often administered in various sequences with limited evidence regarding their cost-effectiveness. OBJECTIVE: To conduct a pharmacoeconomic evaluation of commonly administered treatment sequences among elderly mCRC patients. METHODS: A probabilistic discrete event simulation model assuming Weibull distribution was developed to evaluate the cost-effectiveness of the following common treatment sequences: (a) first-line oxaliplatin/irinotecan followed by second-line oxaliplatin/irinotecan + bevacizumab (OI-OIB); (b) first-line oxaliplatin/irinotecan + bevacizumab followed by second-line oxaliplatin/irinotecan + bevacizumab (OIB-OIB); (c) OI OIB followed by a third-line targeted biologic (OI-OIB-TB); and (d) OIB-OIB followed by a third-line targeted biologic (OIB-OIB-TB). Input parameters for the model were primarily obtained from the Surveillance, Epidemiology, and End Results-Medicare linked dataset for incident mCRC patients aged 65 years and older diagnosed from January 2004 through December 2009. A probabilistic sensitivity analysis was performed to account for parameter uncertainty. Costs (2014 U.S. dollars) and effectiveness were discounted at an annual rate of 3%. RESULTS: In the base case analyses, at the willingness-to-pay (WTP) threshold of $100,000/quality-adjusted life-year (QALY) gained, the treatment sequence OIB-OIB (vs. OI-OIB) was not cost-effective with an incremental cost-effectiveness ratio (ICER) per patient of $119,007/QALY; OI-OIB-TB (vs. OIB-OIB) was dominated; and OIB-OIB-TB (vs. OIB-OIB) was not cost-effective with an ICER of $405,857/QALY. Results similar to the base case analysis were obtained assuming log-normal distribution. Cost-effectiveness acceptability curves derived from a probabilistic sensitivity analysis showed that at a WTP of $100,000/QALY gained, sequence OI-OIB was 34% cost-effective, followed by OIB-OIB (31%), OI-OIB-TB (20%), and OIB-OIB-TB (15%). CONCLUSIONS: Overall, survival increases marginally with the addition of targeted biologics, such as bevacizumab, at first line and third line at substantial costs. Treatment sequences with bevacizumab at first line and targeted biologics at third line may not be cost-effective at the commonly used threshold of $100,000/QALY gained, but a marginal decrease in the cost of bevacizumab may make treatment sequences with first-line bevacizumab cost effective. Future economic evaluations should validate the study results using parameters from ongoing clinical trials. DISCLOSURES: This study was supported in part by a grant from the Agency for Healthcare Research and Quality (R01 HS018956) and in part by a grant from the Cancer Prevention and Research Institute of Texas (RP130051), which were obtained by Du. The authors report no conflicts of interest. Study concept and design were primarily contributed by Parikh, along with the other authors. All authors participated in data collection, and Parikh took the lead in data interpretation and analysis, along with Lairson and Morgan, with assistance from Du. The manuscript was written primarily by Parikh, along with Lairson, Morgan, and Du, and revised by Parikh. PMID- 28025931 TI - A Review of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient Outcomes in the United States. AB - : Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subgroups of pulmonary hypertension and are considered rare diseases. Understanding how endpoints of clinical trials (and patient registry studies) of patients with PAH and CTEPH are associated with patient outcomes is important in order to address the concerns of patients, health care providers, decision makers, and payers. The purpose of this review was to examine how endpoints used in clinical trials and patient registry studies are associated with outcomes of patients with PAH and CTEPH. A PubMed literature search was conducted to retrieve published studies, including randomized phase III clinical trials and observational studies, from years 2000 to May 2015 that evaluated the associations between change in 6-minute walking distance (6MWD), 6MWD thresholds, change in World Health Organization functional class (WHO-FC), and time to clinical worsening with outcomes of patients with PAH and CTEPH. Based on this review of published literature, a reduction in 6MWD as a criterion for PAH worsening, a deterioration in WHO-FC, and delay in the time to clinical worsening are clinically meaningful trial endpoints and are associated with outcomes of patients with PAH and CTEPH. Utilization and standardization of these endpoints will be useful for comparing interventions of clinical trials and therapies. Hospitalizations are frequent among patients with PAH and CTEPH, and total health care costs are high. From a U.S. payer perspective, clinical worsening is an important composite endpoint in that it includes hospitalization, which can be transformed into a preventative cost value associated with efficacious treatment of patients with PAH and CTEPH. In view of the greater number of medications available to treat PAH, the introduction of the first approved therapy to treat CTEPH, and the increasing use of combination pharmacotherapy, reliable prognostic markers of treatment responsiveness are important to help guide appropriate management. As new clinical trials and observational studies are conducted, it will be important to maintain universal endpoints so that health care providers, decision makers, and payers can better understand the value of targeted pharmacotherapies and combination therapies for the treatment of patients with PAH and CTEPH. DISCLOSURES: Sponsorship for this review and article processing charges were funded by Bayer HealthCare Pharmaceuticals. Divers and Platt are employees of Bayer HealthCare Pharmaceuticals. Wang is an employee of Bayer HealthCare Pharmaceuticals and owns stock in the company. Lin and Lingohr-Smith are employees of Novosys Health, which received research funds from Bayer HealthCare Pharmaceuticals in connection with conducting this review and developing this manuscript. Mathai is a consultant to Bayer HealthCare Pharmaceuticals and also reports consulting fees from Actelion and Gilead. Study concept and design were contributed by Divers, Platt, Lin, and Mathai. Lin and Lingohr-Smith collected the data, and data interpretation was performed by Divers, Platt, Wang, and Matthai. The manuscript was written primarily by Lingohr Smith, with assistance from the other authors, and revised by Divers, Platt, Wang, and Mathai. PMID- 28025933 TI - Editorial: School food provided for free. PMID- 28025932 TI - Thyroid Surgery in a Resource-Limited Setting. AB - Objective The present study reviews a series of patients who underwent thyroid surgery in Eldoret, Kenya, to demonstrate the feasibility of conducting long-term (>1 year) outcomes research in a resource-limited setting, impact on the quality of life of the recipient population, and inform future humanitarian collaborations. Study Design Case series with chart review. Setting Tertiary public referral hospital in Eldoret, Kenya. Subjects and Methods Twenty-one patients were enrolled during the study period. A retrospective chart review was performed for all adult patients who underwent thyroid surgery during humanitarian trips (2010-2015). Patients were contacted by mobile telephone. Medical history and physical examination, including laryngoscopy, were performed, and the SF-36 was administered (a quality-of-life questionnaire). Laboratory measurements of thyroid function and neck ultrasound were obtained. Results The mean follow-up was 33.6 +/- 20.2 months after surgery: 37.5% of subtotal thyroidectomy patients and 15.4% of lobectomy patients were hypothyroid postoperatively according to serologic studies. There were no cases of goiter recurrence or malignancy. All patients reported postoperative symptomatic improvement and collectively showed positive pre- and postoperative score differences on the SF-36. Conclusion Although limited by a small sample size and the retrospective nature, our study demonstrates the feasibility of long-term surgical and quality-of-life outcomes research in a resource-limited setting. The low complication rates suggest minimal adverse effects of performing surgery in this context. Despite a considerable rate of postoperative hypothyroidism, it is in accordance with prior studies and emphasizes the need for individualized, longitudinal, and multidisciplinary care. Quality-of-life score improvements suggest benefit to the recipient population. PMID- 28025934 TI - Drug Repurposing in Anticancer Reagent Development. AB - BACKGROUND: Cancer is a complex disease and a huge threat to human health. The prognosis for some cancer types such as breast cancer has improved dramatically over the past 50 years due to rapid development of surgery, chemotherapy and radiotherapy technologies. However, for many patients bearing unresectable cancers, the prognosis remained poor. For this reason, there is always high demand for newer and better therapeutic reagents in cancer field. But the development of anticancer drugs is risky, lengthy and costly. Not many new anticancer reagents come into market every year. OBJECTIVE: This review focuses on the latest progress of chemotherapy drug repurposing in cancer research. CONCLUSION: It is clear from the review of that drug repurposing is faster and cheaper than conventional drug development process. The anticancer efficacy of numerous non-cancer drugs are being tested now. However, not many of them have obtained enough evidence to go into clinical trials for cancer treatment. How to filter the right candidate and narrow the gap between bench and bed remains a hurdle for both conventional and repurposing drug development. PMID- 28025935 TI - Developmental Phases of Anticancer Screening Models. AB - The development of new screening models for cancer therapy is indispensable for the improvement of cancer treatment, and for the creation of alternative possibilities in the field of chemotherapy. Screening models are routinely used to reduce the cost and resources involved in anticancer drug development. The value of any screening model will ultimately be ascertained by its ability to reliably predict the clinical response. Traditional in vivo screening models have been replaced with cell-based screening assays, and these cell-based models are under constant development to better mimic in vivo conditions. In this review, the developmental phases of anticancer screening models are discussed and exemplified, including the two-dimensional, threedimensional, cancer stem cell, and non-mammalian screening models. In addition, the use of new virtual screening tools as a model for anticancer drug development is highlighted. PMID- 28025937 TI - DNA Methylation is Correlated with Pluripotency of Stem Cells. AB - BACKGROUND: Pluripotency of stem cells is an important scientific issue and is attracting great interest for the broader community, especially for regenerative medicine field. Pluripotent stem cells (PSCs) in mammalians are defined as naive- and primed-states according to their cellular, molecular, epigenetic and functional states. OBJECTIVE: Understand the correlation between DNA methylation and pluripotency of stem cells. METHOD: Based on published papers, we discussed the DNA methylation and corresponding functions for embryonic stem cells. We also summarized the correlation between DNA methylation and naive state maintenance, and outlook future emphasis of DNA methylation for primate naive PSCs. RESULTS AND CONCLUSION: DNA methylation is closely associated with cell reprogramming, functional remodeling and cell differentiation of PSCs. The pluripotency and naive characteristics of PSCs are closely associated with cell DNA methylation. However, the mechanisms, which are involved in methylation modifications of naive ground, are still one of the important scientific issues for primate naive PSCs because of lack of widely accepted culture condition. PMID- 28025936 TI - Current Status of Leukemia Cytotherapy - Exploitation with Immune Cells. AB - With the development of chemotherapy and hematopoietic stem cell transplantation (HSCT), the prognosis of leukemia patients has been improved greatly in the past few decades. However, relapsed and refractory leukemia is still the major cause of mortality in leukemia patients. Besides, advancing age, poor performance status and severe co-morbidities limit the applicability of cytotoxic chemotherapy in certain groups of leukemia patients. Novel agents including nucleoside analogs, kinase inhibitors targeting oncoproteins and monoclonal antibodies are under investigation for the management of leukemia. Nevertheless, the outcome remains disappointing. Since immune system plays an important role in eradicating tumor cells, a lot of studies have been conducted in the administration of cytotherapy of immune cells as an alternative method when chemotherapy and transplantation fail to cure the disease, including usage of natural killer (NK) cells, cytokine-induced killer (CIK) cells, donor lymphocyte infusion (DLI), chimeric antigen receptor (CAR)-modified T cells, dendritic cell (DC)-based vaccine and antigen-specific cytotoxic T lymphocytes (CTL). Due to overexpression of several leukemia associated antigens (LAA), leukemic cells are potentially suitable for cellular therapy approach. Here we review the recent literature regarding the different types of cytotherapy against leukemia, and talk about both efficacy and adverse effects related to the strategy. PMID- 28025939 TI - Serotonin Selective Reuptake Inhibitors (SSRIs) and Female Sexual Dysfunction (FSD): Hypothesis on its Association and Options of Treatment. AB - Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter- playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potential confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies. The exact mechanism of FSD-induced SSRIs is unknown. It has been postulated that although SSRIs may modulate other neurotransmitter system such as nitric oxide (NO), noradrenergic and dopamine in inducing FSD. In the present review, we highlight current evidence regarding potential mechanism of SSRIs in causing FSD, which include low sexual desire (low libido), arousal difficulties (lack of lubrication), and anorgasmia. The specific association of FSD to SSRI use, has not been ellucidated. The relationship is dose-dependent, and may vary among the groups with respect to mechanism of serotonin and dopamine reuptake, induction of release of prolactin from the pituitary gland, anticholinergic side-effects, inhibition of NO synthesis and emotional-memory circuit encryption for sexual experiences. Various interventional strategies exist regarding the treatment of SSRI-induced FSD and this includes tolerance, titration dosage, substitution to another antidepressant drug and psychotherapy. There is a need of better understanding of SSRIs-induced FSD for better treatment outcome. PMID- 28025938 TI - Trypanothione Reductase and Superoxide Dismutase as Current Drug Targets for Trypanosoma cruzi: An Overview of Compounds with Activity against Chagas Disease. AB - It has been over a century since Carlos Chagas discovered the Trypanosoma cruzi (T. cruzi) as the causative agent of Chagas disease (CD), a neglected tropical disease with several socioeconomic, epidemiological and human health repercussions. Currently, there are only two commercialized drugs to treat CD in acute phase, nifurtimox and benznidazol, with several adverse side effects. Thus, new orally available and safe drugs for this parasitic infection are urgently required. One strategy of great importance in new drug discovery programmes is based on the search of molecules enabling to interfere with enzymes involved in T. cruzi metabolism. This review will focus on two of the most promising targets for the therapy of CD: trypanothione reductase (TR) and the iron-containing superoxide dismutase (Fe- SOD), which protect the parasite against oxidative damage by reactive oxygen species. A brief comparison of the function, mechanism of action and the active sites between T. cruzi TR and Fe-SOD with their analogues enzymes in human, glutathione reductase (GR) and the corresponding SODs, will be discussed. This review will also summarize the recent development and structure-activity relationships of novel compounds reported for their ability to selectively inhibit these targets, aiming to define molecular bases in the search for new effective treatment of CD. PMID- 28025940 TI - A Mini Review on the Chemistry and Neuroprotective Effects of Silymarin. AB - BACKGROUND: The plant milk thistle and silymarin has been traditionally used as a natural remedy for the treatment of various ailments including neurological disorders such as Alzheimer's and Parkinson's disease and cerebral ischemia for over 2000 years. OBJECTIVE: In this article we review the neuroprotective effects of silymarin against various neurological dysfunctions. RESULTS: The neuroprotective effects conferred by silymarin include modulation of various antioxidant mechanisms, and several kinases involved in cell signaling pathways, inhibition of the inflammatory response generated during neurodegeneration, neurotropic effects, regulation of neurotransmitters and inhibition of apoptosis. The ease of availability, comparative low cost and safety profile provide additional advantages for the use of this compound as a potent drug with immense clinical benefit. However, there is a growing need for improvements in the bioavailability of silymarin and related products, and more consistent and reliable human trials are required to accurately validate the neuroprotective efficacy of this natural compound. CONCLUSION: The promising outcomes of the studies mentioned in this review provide renewed insight into the clinical relevance of silymarin in a variety of neurodegenerative disorders where neuroinflammation and oxidative stress are pathologically relevant to disease progression. PMID- 28025941 TI - Bone: A Fertile Soil for Cancer Metastasis. AB - Bone is one of the most common and most dangerous sites for metastatic growth across cancer types, and bone metastasis remains incurable. Unfortunately, the processes by which cancers preferentially metastasize to bone are still not well understood. In this review, we summarize the morphological features, physical properties, and cell signaling events that make bone a unique site for metastasis and bone remodeling. The signaling crosstalk between the tumor cells and bone cells begins a vicious cycle - a self-sustaining feedback loop between the tumor cells and the bone microenvironment composed of osteoclasts, osteoblasts, other bone marrow cells, bone matrix, and vasculature to support both tumor growth and bone destruction. Through this crosstalk, bone provides a fertile microenvironment that can harbor dormant tumor cells, sometimes for long periods, and support their growth by releasing cytokines as the bone matrix is destroyed, similar to providing nutrients for a seed to germinate in soil. However, few models exist to study the late stages of bone colonization by metastatic tumor cells. We describe some of the current methodologies used to study bone metastasis, highlighting the limitations of these methods and alternative future strategies to be used to study bone metastasis. While in vivo animal and patient studies may provide the gold standard for studying metastasis, ex vivo models can be used as an alternative to enable more controlled experiments designed to study the late stages of bone metastasis. PMID- 28025942 TI - Nano-medicine Improving the Bioavailability of Small Molecules for the Prevention of Neurodegenerative Diseases. AB - Neurodegenerative diseases, including Parkinson's and Alzheimer's, are a heterogeneous group of brain disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous system. It is thought that the number of people affected by these pathologies will increase in future decades, particularly in the more economically developed countries, where the populations are experiencing a demographic shift towards older ages. For many of these pathologies, and in particular for Alzheimer's disease, no effective treatments are available, and the consequent economic and social costs are very high. Scientific progress in recent decades has provided a better understanding of the genetic and biological mechanisms responsible for these neurodegenerative diseases, and offers the hope for new therapeutic approaches in the near future. Meanwhile, the lack of effective therapies for these diseases has caused researchers to focus attention on the powerful opportunity of prevention, seen on the one hand as a series of healthcare measures and patient behaviors, and on the other hand as treatments exploiting several molecules or compounds with the potential to slow down the appearance of the first signs of pathology or even to prevent these diseases. Among these, curcumin, flavonoids, such as quercetin, Gingko biloba, and folic acid have attracted the attention of scientists, and ways are being explored to increase their effectiveness and bioavailability in the site of action. Most molecules suffer from problems of solubility, or bioavailability, or the ability to cross the blood brain barrier, and one solution to this limitation being explored is nanomedicine. Polymeric nanoparticles, as well as liposomes, and functionalized nanosystems may overcome several bioavailability limits of active molecules and increase their effectiveness in the brain. This review offers an overview of small molecules that may prove effective in preventing neurodegenerative diseases, and describes the strategies in nanomedicine that are being studied to improve their bioavailability. PMID- 28025943 TI - Phenolic Compounds as Nutraceuticals or Functional Food Ingredients. AB - BACKGROUND: Nowadays, the functional foods represent one the most promising, interesting and innovative areas in the food industry. Various components are being added to foods in order to render them functional. METHODS: One example of these components are plant naturally occurring phenolic compounds, which are associated with a high antioxidant capacity and thus with benefits in relation to human health. RESULTS: However, despite the huge number of scientific studies and patents on this topic and their natural presence in foods, namely in the ones from plant origin, there are still few marketable products enriched with these compounds. The commercialization of this type of functional products needs to go through various regulations, proving that they are safe and present the ascribed health benefits, conquering the target audience. In this review the growing interest of industry and consumers' appetence for functional foods and nutraceuticals is highlighted, focusing especially on phenolic compounds. CONCLUSION: Although several published works show the multitude of bioactive properties of these compounds, ensuring their use as bioactive ingredients in food, they present inherent stability issues needing to be solved. However, considerable research is presently ongoing to overcome this problem, making viable the development of new products to be launched in the market. PMID- 28025944 TI - Targeting Nanomedicine to Brain Tumors: Latest Progress and Achievements. AB - Targeting nanomedicine to brain tumors is hampered by the heterogeneity of brain tumors and the blood brain barrier. These represent the main reasons of unsuccessful treatments. Nanomedicine based approaches hold promise for improved brain tissue distribution of drugs and delivery of combination therapies. In this review, we describe the recent advancements and latest achievements in the use of nanocarriers, virus and cell-derived nanoparticles for targeted therapy of brain tumors. We provide successful examples of nanomedicine based approaches for direct targeting of receptors expressed in brain tumor cells or modulation of pathways involved in cell survival as well as approaches for indirect targeting of cells in the tumor stroma and immunotherapies. Although the field is at its infancy, clinical trials involving nanomedicine based approaches for brain tumors are ongoing and many others will start in the near future. PMID- 28025945 TI - Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury. AB - BACKGROUND: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. METHODS: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. RESULTS: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM-treated groups displayed significant EMG activity accompanied by locomotor-like characteristics that is with rhythmic and bilaterally alternating bursts. CONCLUSION: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI. PMID- 28025946 TI - Proteolytic Cleavage of Polyglutamine Disease-Causing Proteins: Revisiting the Toxic Fragment Hypothesis. AB - Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded, these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of deleterious protein fragments. This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning fragment detection and the mechanisms of fragment toxicity. Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins. Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further investigation. Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances toxicity in disease associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim. PMID- 28025947 TI - Genetics in the Clinical Decision of Antiplatelet Treatment. AB - BACKGROUND: Coronary artery disease remains the leading cause of death globally. Dual antiplatelet treatment with aspirin and aP2Y12 receptor significantly reduces thrombotic events. However, antiplatelet drug response displays considerable interindividual variability. METHODS: Genetic factors account for up to 70% of impaired drug response. A number of genes encoding proteins involved in the pharmacokinetic pathway have been found to alter drug response. RESULTS: According to most studies, CYP2C19 gene is the strongest genetic determinant. The novel antiplatelet agents prasugrel and ticagrelor, seem to overcome genetic restrictions but in expense of increased bleeding rates. Achieving a balance between adequate platelet inhibition and bleeding complications is challenging. CONCLUSION: Genetic screening may provide valuable guidance towards an efficient antiplatelet treatment. However, the lack of randomized controls trials testing the effect of a genotype-guided therapy, forbids the implementation of genetic testing into clinical practice. PMID- 28025948 TI - Perspectives of In Vivo Bioluminescence Imaging: Application to Basic and Translational Neuroscience. AB - BACKGROUND: In vivo bioluminescence imaging has been used extensively for screening assays and for qualitative determination of localization of cells, in particular in cancer studies. OBJECTIVE: In this review we show the potential of this noninvasive molecular imaging modality to investigate gene activity, dynamic processes, and translational disease processes, all under true in vivo conditions with the specific focus on brain. RESULTS: We demonstrate a range of applications of bioluminescence imaging in basic and translational neuroscience. Here, emphasis is on the contribution of bioluminescence imaging of the brain to the elucidation of cellular and genetic mechanisms, understanding of dynamic processes, and to the discussion of disease characterization and therapeutic strategies. PMID- 28025949 TI - Targeted Nanoparticles for the Treatment of Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) has a dramatic impact on society. The therapeutic targets are located in the central nervous system (CNS), which limits the efficacy of drugs systemically administered: the blood-brain barrier (BBB) selectively allows the permeation of just a few kinds of molecules from the systemic circulation to the CNS. On the other hand, local administration routes to CNS are highly invasive. METHODS: In this article, we have reviewed therapeutic approaches against AD, which are based on nanoparticles targeted to the brain and to the pathological hallmarks of the disease. The existing literature has been classified according to the AD feature that is addressed. RESULTS: Nanoparticles have been used for the targeted delivery of drugs aiming to reduce the AD symptoms or to reverse the course of the disease. For this task the multivalency of nanoparticles has allowed their functionalization with several kinds of targeting groups, to cross the BBB and to target the place of treatment. With this approach an increased drug bioavailability has been achieved in the CNS using intravenous administration in place of more invasive administration routes. Additionally, nanoparticles have also been used in the development of vaccines and therapeutic formulations for intranasal administration. CONCLUSION: Targeted nanoparticles have been proved useful to enhance the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted nanoparticles for combined therapies. PMID- 28025950 TI - Age differences in the use of serving size information on food labels: numeracy or attention? AB - OBJECTIVE: The ability to use serving size information on food labels is important for managing age-related chronic conditions such as diabetes, obesity and cancer. Past research suggests that older adults are at risk for failing to accurately use this portion of the food label due to numeracy skills. However, the extent to which older adults pay attention to serving size information on packages is unclear. We compared the effects of numeracy and attention on age differences in accurate use of serving size information while individuals evaluated product healthfulness. DESIGN: Accuracy and attention were assessed across two tasks in which participants compared nutrition labels of two products to determine which was more healthful if they were to consume the entire package. Participants' eye movements were monitored as a measure of attention while they compared two products presented side-by-side on a computer screen. Numeracy as well as food label habits and nutrition knowledge were assessed using questionnaires. SETTING: Sacramento area, California, USA, 2013-2014. SUBJECTS: Stratified sample of 358 adults, aged 20-78 years. RESULTS: Accuracy declined with age among those older adults who paid less attention to serving size information. Although numeracy, nutrition knowledge and self-reported food label use supported accuracy, these factors did not influence age differences in accuracy. CONCLUSIONS: The data suggest that older adults are less accurate than younger adults in their use of serving size information. Age differences appear to be more related to lack of attention to serving size information than to numeracy skills. PMID- 28025951 TI - Optimizing Inpatient Urine Culture Ordering Practices Using the Electronic Medical Record: A Pilot Study. AB - A prospective quasi-experimental before-and-after study of an electronic medical record-anchored intervention of embedded education on appropriate urine culture indications and indication selection reduced the number of urine cultures ordered for catheterized patients at an academic medical center. This intervention could be a component of CAUTI-reduction bundles. Infect Control Hosp Epidemiol 2017;38:486-488. PMID- 28025952 TI - Development and validation of the Palliative Care Knowledge Scale (PaCKS). AB - OBJECTIVE: The purpose of this study was to develop a reliable and valid scale that broadly measures knowledge about palliative care among non-healthcare professionals. METHOD: An initial item pool of 38 true/false questions was developed based on extensive qualitative and quantitative pilot research. The preliminary items were tested with a community sample of 614 adults aged 18-89 years as well as 30 palliative care professionals. The factor structure, reliability, stability, internal consistency, and validity of the 13-item Palliative Care Knowledge Scale (PaCKS) were assessed. RESULTS: The results of our study indicate that the PaCKS meets or exceeds the standards for psychometric scale development. SIGNIFICANCE OF RESULTS: Prior to this study, there were no psychometrically evaluated scales with which to assess knowledge of palliative care. Our study developed the PaCKS, which is valid for assessing knowledge about palliative services in the general population. With the successful development of this instrument, new research exploring how knowledge about palliative care influences access and utilization of the service is possible. Prior research in palliative care access and utilization has not assessed knowledge of palliative care, though many studies have suggested that knowledge deficits contribute to underutilization of these services. Creating a scale that measures knowledge about palliative care is a critical first step toward understanding and combating potential barriers to access and utilization of this life-improving service. PMID- 28025953 TI - Development and validation of a nutrition knowledge questionnaire for a Canadian population. AB - OBJECTIVE: The present study aimed to develop and validate a nutrition knowledge questionnaire in a sample of French Canadians from the province of Quebec, taking into account dietary guidelines. DESIGN: A thirty-eight-item questionnaire was developed by the research team and evaluated for content validity by an expert panel, and then administered to respondents. Face validity and construct validity were measured in a pre-test. Exploratory factor analysis and covariance structure analysis were performed to verify the structure of the questionnaire and identify problematic items. Internal consistency and test-retest reliability were evaluated through a validation study. SETTING: Online survey. SUBJECTS: Six nutrition and psychology experts, fifteen registered dietitians (RD) and 180 lay people participated. RESULTS: Content validity evaluation resulted in the removal of two items and reformulation of one item. Following face validity, one item was reformulated. Construct validity was found to be adequate, with higher scores for RD v. non-RD (21.5 (sd 2.1) v. 15.7 (sd 3.0) out of 24, P<0.001). Exploratory factor analysis revealed that the questionnaire contained only one factor. Covariance structure analysis led to removal of sixteen items. Internal consistency for the overall questionnaire was adequate (Cronbach's alpha=0.73). Assessment of test-retest reliability resulted in significant associations for the total knowledge score (r=0.59, P<0.001). CONCLUSIONS: This nutrition knowledge questionnaire was found to be a suitable instrument which can be used to measure levels of nutrition knowledge in a Canadian population. It could also serve as a model for the development of similar instruments in other populations. PMID- 28025954 TI - Anti-inflammatory effects of an oxylipin-containing lyophilised biomass from a microalga in a murine recurrent colitis model. AB - Diet and nutritional factors have emerged as possible interventions for inflammatory bowel diseases (IBD), which are characterised by chronic uncontrolled inflammation of the intestinal mucosa. Microalgal species are a promising source of n-3 PUFA and derived oxylipins, which are lipid mediators with a key role in the resolution of inflammation. The aim of the present study was to investigate the effects of an oxylipin-containing lyophilised biomass from Chlamydomonas debaryana on a recurrent 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis mice model. Moderate chronic inflammation of the colon was induced in BALB/c mice by weekly intracolonic instillations of low dose of TNBS. Administration of the lyophilised microalgal biomass started 2 weeks before colitis induction and was continued throughout colitis development. Mice were killed 48 h after the last TNBS challenge. Oral administration of the microalgal biomass reduced TNBS-induced intestinal inflammation, evidenced by an inhibition of body weight loss, an improvement in colon morphology and a decrease in pro inflammatory cytokines TNF-alpha, IL-1beta, IL-6 and IL-17. This product also down-regulated colonic expressions of inducible nitric oxide, cyclo-oxygenase 2 and NF-kappaB, as well as increased PPAR-gamma. In addition, lyophilised microalgal biomass up-regulated the expressions of the antioxidant transcription factor nuclear factor E2-related factor 2 and the target gene heme oxygenase 1. This study describes for the first time the prophylactic effects of an oxylipin containing lyophilised microalgae biomass from C. debaryana in the acute phase of a recurrent TNBS-induced colitis model in mice. These findings suggest the potential use of this microalga, or derived oxylipins, as a nutraceutical in the treatment of IBD. PMID- 28025955 TI - Attention allocation to facial expressions of emotion among persons with Williams and Down syndromes. AB - Individuals with Williams syndrome and those with Down syndrome are both characterized by heightened social interest, although the manifestation is not always similar. Using a dot-probe task, we examined one possible source of difference: allocation of attention to facial expressions of emotion. Thirteen individuals with Williams syndrome (mean age = 19.2 years, range = 10-28.6), 20 with Down syndrome (mean age = 18.8 years, range = 12.1-26.3), and 19 typically developing children participated. The groups were matched for mental age (mean = 5.8 years). None of the groups displayed a bias to angry faces. The participants with Williams syndrome showed a selective bias toward happy faces, whereas the participants with Down syndrome behaved similarly to the typically developing participants with no such bias. Homogeneity in the direction of bias was markedly highest in the Williams syndrome group whose bias appeared to result from enhanced attention capture. They appeared to rapidly and selectively allocate attention toward positive facial expressions. The complexity of social approach behavior and the need to explore other aspects of cognition that may be implicated in this behavior in both syndromes is discussed. PMID- 28025957 TI - Correlation between pharmacokinetics of tacrolimus and pharmacodynamics on NFAT regulated gene expression in stable kidney transplant recipients?. AB - Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (Ctrough) and peak concentrations (Cpeak) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (Etrough) and at peak levels (Epeak) were determined by qRT PCR. The pharmacodynamic concentration producing the half-maximum effect (CE50) and the Hill coefficient (H) were estimated from Etrough and from Epeak. Ten stable kidney transplant recipients on triple immunosuppression with prednisolone, mycophenolate, and tacrolimus were analyzed. Median age was 58 years, median time since transplant was 84 months, and median serum creatinine was 249 umol/L. The immunosuppressive effect on NFAT-regulated genes at trough concentrations was 38% (Etrough), and the effect at peak concentrations was 59% (Epeak) of maximum immunosuppression (Emax). The pharmacodynamic parameters of the action of tacrolimus were estimated with the Hill coefficient H at 1.5 and the CE50 at 6.7 ng/mL. Accordingly, the pharmacodynamic threshold concentration was estimated at 0.9 ng/mL and the ceiling concentration at 48 ng/mL, indicating a wide span between target trough and peak levels. The low Hill coefficient indicates concentration-dependent pharmacodynamics of tacrolimus on NFAT transcripts. Therefore, the extension of the administration interval to 24 hours is not likely to jeopardize the immunosuppressive effect of the prolonged-release tacrolimus preparations. ?. PMID- 28025956 TI - Effects of a community-based nutrition promotion programme on child feeding and hygiene practices among caregivers in rural Eastern Ethiopia. AB - OBJECTIVE: To evaluate the effectiveness of a community-based participatory nutrition promotion (CPNP) programme involving a 2-week group nutrition session in improving child feeding and hygiene practices among caregivers. DESIGN: Cluster randomized trial. In the intervention area (six clusters), the CPNP programme was added to the context of government nutrition programmes; the control area (six clusters) received the government programme only. Child feeding practices were assessed every 3 months using a 24 h dietary recall questionnaire, and hand washing with soap was assessed every 6 months, over a period of 12 months. Feeding and hygiene measures at each visit were scored and the scores summed up for the entire follow-up period. SETTING: Habro and Melka Bello districts, Ethiopia. SUBJECTS: Randomly selected mothers with a child aged 6-12 months (n 1790). RESULTS: A total of 1199 mothers, 629 in the control and 570 in the intervention areas, were assessed at all visits and included in the analysis. Mothers in the intervention area showed higher scores than those in the control area regarding meal frequency (difference: 1.04, 95 % CI 0.35, 1.73), composite feeding score_1 (difference: 1.25, 95 % CI 0.37, 2.13; a summing score of currently breast-feeding, meal frequency and dietary diversity) and composite feeding score_2 (difference: 1.40, 95 % CI 0.49, 2.32; a summing score of meal frequency and dietary diversity). However, there were no differences in the scores of breast-feeding, dietary diversity and hand washing between the two areas (all P>0.05). CONCLUSIONS: The CPNP programme was effective in improving some child feeding behaviours in rural Eastern Ethiopia. PMID- 28025958 TI - Localization of ectopic fibroblast growth factor 23 production in tumor-induced osteomalacia using selective venous samplings. PMID- 28025959 TI - Hypokalemia associated with acute colonic pseudo-obstruction in an ESRD patient. AB - Ogilvie's syndrome, or acute colonic pseudo-obstruction, is characterized by massive dilation of the colon without mechanical obstruction. Water and electrolytes often can be sequestered in the dilated intestinal loops resulting in profuse and watery diarrhea as well as hypokalemia. We report an anuric, end stage renal disease (ESRD) patient undergoing peritoneal dialysis (PD) who developed acute colonic pseudo-obstruction causing a prolonged hospitalization. He also developed severe hypokalemia with a serum potassium (K+) as low as 2.4 mEq/L and required 180 - 240 mEq of potassium chloride per day for more than a month to correct it. While PD K+ losses often contribute to hypokalemia, the PD K+ loss was estimated to be only 39 mEq/day. Therefore, PD could only contribute modestly to the recalcitrant hypokalemia observed during the episode of pseudo obstruction. It has been shown, however, that patients with colonic pseudo obstruction have enhanced colonic K+ secretion. In addition, experimental studies in patients with chronic kidney disease (CKD) have demonstrated that colonic K+ excretion can be up to 3 times greater than in individuals with normal renal function. This increase may involve an upregulation of the large conductance K+ channel (maxi-K), also known as the BK channel, in the apical border of the colonocytes. We suggest that ESRD may have placed our patient at a greater risk of developing hypokalemia as his colon may have already adapted to secrete more K+. Clinicians should be aware of this extrarenal K+ wasting etiology in patients with colonic pseudo-obstruction, particularly in those with CKD where such a severe K+ deficit is not anticipated and, therefore, may inhibit more rigorous K+ replacement. PMID- 28025960 TI - Metastatic spread of systemic neoplasms to central nervous system tumors: review of the literature and case presentation of esophageal carcinoma metastatic to meningioma. AB - Metastatic spread of a systemic neoplasm to a central nervous system malignancy is a rare but well-documented phenomenon. Over 100 case reports of tumor-to-tumor spread involving the central nervous system have been described since the first report in 1930. Overwhelmingly, intracranial meningioma represents the most common recipient tumor, while breast and lung are the first and second most common donor malignancies, respectively. The propensity for meningiomas to harbor metastatic lesions has been attributed to cell-to-cell adhesion molecules, favorable metabolic environment as well as hormonal and mechanical factors. We distinguish the concepts of true "tumor-to-tumor metastasis" and "tumor collision" and discuss potential non-invasive diagnostic modalities that may aid in preoperatively identifying intracranial lesions harboring distal metastasis. We present the first incidence, to our knowledge, of metastatic esophageal carcinoma spread to intracranial meningioma.?. PMID- 28025961 TI - Prevalence of aspirin resistance in patients with type II diabetes: a descriptive analytical study?. AB - BACKGROUND: Aspirin resistance is one of the most important factors for arterial thrombotic events in diabetic patients. This study aimed to evaluate aspirin resistance in diabetic patients. METHODS: In this cross-sectional study, 180 patients who received 80 mg of aspirin daily for at least 10 days were studied, and their urinary 11-DH-TXB2 was measured. Those with 11-dehydro-thromboxane B2 above 1,500 pg/mg creatinine were considered aspirin resistant. Data with significance level of 5% were analyzed in SPSS-16. RESULTS: The mean +/- SD of patient age was 60.22 +/- 9.59 years and 50% (n = 90) were male. BMI was normal in 29.4% of the patients (n = 53), the others were overweight or obese. Aspirin resistance was observed in 33 (18%) patients. The relationship between aspirin resistance and gender, age, and BMI was not significant (p > 0.05). CONCLUSIONS: There is a high prevalence of aspirin resistance in diabetic patients and given that such patients are at risk of arterial thrombotic events, evaluation of aspirin resistance is suggested for those at a high risk of cardiovascular events or recurring events despite the use of aspirin.?. PMID- 28025962 TI - The cost savings of newer oral anticoagulants in atrial fibrillation-related stroke prevention?. AB - BACKGROUND: Newer oral anticoagulants (NOACs) are considered as better alternatives compared to warfarin for stroke prevention in atrial fibrillation (AF) in terms of clinical effectiveness although the drug acquisition cost is more substantial. AIM: This study determined the direct stroke costs based on inpatient hospitalization in a subgroup of the National Health Service (NHS) Grampian, Scotland, stroke patients, to evaluate the differences in costs related to AF stroke, and to ascertain whether the use of NOACs within this study population would produce greater cost savings. METHODS: Hospitalization records over 5 years involving 3,601 stroke patients were analyzed. Direct costs were based on the costs of inpatient length of stay per day. The potential cost savings if AF patients had been on NOACs were estimated using efficacy data from a landmark clinical trial involving rivaroxaban. RESULTS: Out of the total stroke cases, 29.5% of total stroke cases were secondary to AF, and these cases were more severe with longer hospitalizations. Only 254 patients (39.4%) with confirmed AF were anticoagulated with warfarin prior to admission. AF patients incurred higher median costs (L4,719 (interquartile range (IQR) L1,815 - L12,452) compared to non-AF patients (L3,267 (IQR L1,175 - L11,368)), although the association was statistically insignificant. The use of NOACs in AF-related patients with ischemic strokes would potentially prevent more strokes (leading to 58 fewer cases in comparison to warfarin), resulting in 17.1% in total cost reduction. CONCLUSION: AF stroke patients incurred higher total direct costs compared to non-AF cases. However, more cost savings were evident with NOACs, due to more strokes being prevented through the use of NOACs compared to warfarin.?. PMID- 28025963 TI - Association between pioglitazone use and the risk of bladder cancer among subjects with diabetes mellitus: a dose-response meta-analysis?. AB - PURPOSE: Previous epidemiological studies reported inconsistent results regarding the association between pioglitazone use and the risk of bladder cancer (BC). We conducted a dose-response meta-analysis to assess this association. METHODS: PUBMED and EMBASE databases were searched through August 2015. Pooled results derived from a random-effects model, and the dose-response analyses were conducted for the association between cumulative dose or duration of pioglitazone use and BC risk. RESULTS: 14 studies were included. After comparing "ever use" with "never use" of pioglitazone, an increased risk of BC (HR = 1.16, 95% CI = 1.06 to 1.25) was present, and there was no significant heterogeneity between studies (P for heterogeneity = 0.54, I2 = 0.0%). Every 12 months increase (HR = 1.16, 95% CI = 1.03 - 1.30) or 10 g increase (HR = 1.05, 95% CI = 1.02 - 1.09) in pioglitazone use was marginally associated with elevated BC risk. The evidence of linear relationships was found for the cumulative dose of pioglitazone and BC risk, and a nonlinear curve for association between the duration of pioglitazone use and the risk of BC was revealed. Subgroup analyses revealed that an increased risk of BC for pioglitazone use was observed in European male subjects with more than 12 months of pioglitazone use and in the "multivariate adjusted" group. CONCLUSIONS: Pioglitazone use among subjects with diabetes mellitus increases BC risk mildly. More studies are needed to investigate the association between the cumulative dose of pioglitazone use and BC risk.?. PMID- 28025964 TI - Bioequivalence of two formulations of pregabalin 150-mg capsules under fasting conditions in healthy male subjects?. AB - BACKGROUND: Pregabalin binds to the alpha2delta auxiliary subunit of voltage gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems and modulate calcium-dependent neurotransmitter release. Pregabalin is indicated for the treatment of peripheral and central neuropathic pain, partial seizures with or without secondary generalization, and treatment of generalized anxiety disorder (GAD). OBJECTIVE: The purpose of this study was to assess the bioequivalence of two different formulations of pregabalin 150-mg capsules in healthy Korean male subjects under fasting conditions. METHODS: This bioequivalence study was based on an open-label, single dose, randomized, 2-period, 2-sequence crossover design with a washout period of 7 days. Blood samples for pharmacokinetic (PK) evaluation were collected up to 24 hours postdose. Plasma concentrations of pregabalin were determined using a validated LC-MS/MS method. PK parameters were determined using noncompartmental analysis. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of log-transformed Cmax and AUClast values met the bioequivalence criteria specified by Korean regulatory guidelines (90% CI 0.8 - 1.25). RESULTS: The extent of exposure in terms of AUClast amounted to 26,018.3 - 3,580.8 ug*h/L for the test formulation and 25,680.2 +/- 3,083.6 ug*h/L for the reference formulation. Cmax reached values of 4,782.7 +/- 1,124.2 ug/L and 4,654.0 +/- 911.4 ug/L for the test product and reference product, respectively. The geometric mean ratio and 90% CIs of the test product to the reference product were 1.0132 (0.9862 - 1.0351) for AUClast and 1.0153 (0.9351 - 1.1044) for Cmax, which were well within the range necessary to establish bioequivalence (90% CI 0.8 - 1.25). CONCLUSIONS: The bioequivalence between test and reference formulations under fasting conditions was confirmed both in terms of the rate and extent of absorption.?. PMID- 28025965 TI - Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment?. AB - OBJECTIVE: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment. METHODS: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC. Safety and tolerability were assessed throughout the study. RESULTS: On average, area under the plasma concentration vs. time curves (AUC) for nifedipine increased 93% and 253% in mild and moderate hepatic impairment, while maximum plasma concentrations (Cmax) increased 64% and 171%, respectively. AUC values for candesartan increased 19% and 92%, while Cmax values increased 3% and 11%, respectively. In subjects with or without liver impairment, adverse event rates were similar and consistent with the known side-effect profiles of nifedipine GITS and candesartan as monotherapies. CONCLUSIONS: Careful monitoring, and, if necessary, dose adjustment according to response and tolerability may be required for nifedipine GITS/candesartan FDC in patients with mild and moderate hepatic impairment.?. PMID- 28025966 TI - A single and multiple postprandial dose study investigating the pharmacokinetics and pharmacodynamics of edoxaban in healthy Chinese volunteers?. AB - AIMS: This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of once-daily postprandial doses of edoxaban 60 mg in healthy Chinese subjects. METHODS: 6 male and 6 female healthy Chinese volunteers, aged 18 - 45 years, were enrolled into this open-label, phase-I trial. Subjects received single oral doses of edoxaban 60 mg after a meal, followed by successive once-daily doses for 7 days. Serial blood samples were taken pre- and postdose to measure plasma concentrations of edoxaban and its major active metabolite D21-2393 as well as prothrombin time (PT) and activated partialprothrombin time (aPTT). Safety was assessed throughout the study. RESULTS: Eoxaban was quickly absorbed after dosing. The resultant maximum and total exposure of edoxaban after single postprandial dose were similar to those after the same dose in fasting condition, but tmax was about half an hour longer. Meanwhile, the exposure of D21 2393 and the metabolite-over-parent ratio were both lower vs. the fasting condition, suggesting involvement of food on D21-2393 formation. Steady state was attained after two successive daily doses. The PK parameters of edoxaban with multiple postprandial doses were comparable to those observed in Caucasian and Japanese volunteers. Similarly, the PD profiles and the concentration-response relationship of edoxaban were not changed with repeated doses. Minor bleeding was the most commonly reported adverse event during the study. CONCLUSION: Once daily postprandial doses of edoxaban 60 mg was safe and well tolerated in healthy Chinese volunteers. The PK and PD characteristics of edoxaban were comparable among Chinese, Caucasian, and Japanese subjects.?. PMID- 28025967 TI - A single dose, randomized, open-label, cross-over bioequivalence study of sildenafil citrate tablets in healthy Chinese volunteers?. AB - OBJECTIVE: The present study was designed to evaluate the bioequivalence of a newly developed sildenafil citrate tablet 50 mg (Jinge(r), Test) and a marketed counterpart (Viagra(r), 100 mg, Reference) in healthy adult male Chinese volunteers. METHODS: This single-dose, randomized, open-label, four period, and two-treatment self-crossover study included two parts: fasting and postprandial studies. In each part of the study, the subjects were randomly assigned to receive test or reference products (100 mg sildenafil) in a 1 : 1 ratio, and then received the alternative products, following a 1-week washout period. Plasma sildenafil concentrations were analyzed by liquid chromatography tandem mass spectrometry. Tolerability was assessed during the entire study period. RESULTS: 32 healthy volunteers (aged 19 - 30) were enrolled in the study; 31 volunteers completed the fasting study, while 32 volunteers completed the postprandial study. The test formulation was bioequivalent to the marketed formulation as the 90% CIs for the ratio of geometric means of Cmax (fasting: 98.79 - 119.61%; fed: 94.47 - 119.65%), AUClast (fasting: 98.70 - 109.71%; fed: 96.39 - 112.89%), and AUCinfinity (fasting: 98.45 - 108.87%; fed: 96.36 - 112.74%) were within equivalence limits (80 - 125%) under both fasting and postprandial conditions. When sildenafil was given with high-fat meals, mean Cmax was reduced by 23%, and median tmax ranged from 0.75 to 1.50 hours (p <= 0.05). However, both AUClast and AUCinfinity were comparable between fasting and postprandial conditions. No serious adverse events were found among the subjects. CONCLUSIONS: This study confirmed that test and reference sildenafil citrate tablets were bioequivalent under fasting and postprandial conditions.?. PMID- 28025968 TI - Risk of dementia in German patients treated with antidepressants in general or psychiatric practices?. AB - AIMS: To study the impact of the use of antidepressants on dementia in German patients with depression treated in general (GPs) or psychiatric practices (PPs). METHODS: Patients with a first-time documentation of depression with known severity level between 2010 and 2013 (index date) were identified by 1,126 general practitioners and 176 psychiatrists in the IMS Disease Analyzer database. We included patients between the ages of 60 and 80 years who had not previously received prescriptions for antidepressant drugs and had not been diagnosed with all-cause dementia prior to or on the index date. The main outcome of the study was the risk of dementia depending on antidepressant therapy. Cox proportional hazards models (dependent variable: incident dementia) were used to adjust for confounders and to estimate the effect of antidepressant therapy. RESULTS: A total of 22,838 patients treated in GPs and 33,112 patients treated in PPs were included in this study. Of those, 9,570, 30,321, and 16,059 individuals suffered from mild, moderate, and severe depression, respectively. Antidepressant drug use was associated with a decreased risk of dementia in patients affected by moderate (HR = 0.86, 95% CI: 0.77 - 0.95) or severe depression (HR = 0.83, 95% CI: 0.73 - 0.94). CONCLUSION: The use of antidepressants decreased dementia risk in patients with moderate or severe depression.?. PMID- 28025969 TI - Quantitative analysis of valsartan by two-dimensional liquid chromatography (2D HPLC) and its application in a bioequivalence study in Chinese volunteers?. AB - PURPOSE: To develop a sensitive, two-dimensional liquid chromatography (2D-LC) method for determination of valsartan, applied to investigate bioequivalence of two valsartan tablets in Chinese volunteers under fasting condition. METHODS: A full automatic 2D-HPLC system was used to quantify valsartan in human plasma. The analytes were extracted by protein precipitation, using telmisartan as internal standard. The analytical method was applied in a randomized, crossover bioequivalence study of valsartan tablets; the study enrolled 18 Chinese volunteers (12 were men and 6 were women). The subjects received a single 160-mg dose of test or reference preparation with 7-days of washout under fasting state. Plasma samples were collected, pharmacokinetic parameters were obtained and the bioequivalence was evaluated. RESULTS: The calibration range was 9.2 - 4213.8 ng*mL-1. Inter- and intraprecision was less than 7.0%, and accuracies ranged from 99.5 to 103.8%. The extraction recovery for valsartan varied between 89.3 and 97.8%, and the stability in all conditions was excellent. The 90% CI of AUC0 >36h and Cmax were 96.5 - 109.4% and 94.2 - 108.6%, respectively. The relative bioavailability was 103.9 +/- 15.7%. No gender difference was observed in pharmacokinetic parameters. CONCLUSIONS: A sensitive 2D-HPLC method was established for the estimation of valsartan in human plasma and successfully applied in a bioequivalence study of valsartan, which suggests that these two formulations can be assumed to be bioequivalent.?. PMID- 28025970 TI - Impact of VKORC1 gene polymorphisms on warfarin maintenance dosage: A novel systematic review and meta-analysis of 53 studies. AB - OBJECTIVE: To analyze the correlation between VKORC1 gene polymorphisms and warfarin maintenance dosage, as well as the correlation of dosage of warfarin with age and ethnicity. METHODS: We retrieved related studies published between January 2000 and March 2016 from PubMed, Embase, the Cochrane Library, Web of Science, VIP, CNKI, and Wan Fang data. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and crosscheck data. Then, RevMan5.3 software was used to perform a meta-analysis. RESULTS: 53 studies were included in the meta-analysis. The most prevalent genotypes were -1639 AA, 1173 TT, and 3730 GG in both Asian and Caucasians, but the distribution frequencies of all three were higher in Asians than in Caucasians. The meta-analysis showed that compared with homozygous VKORC1 1639 AA carriers, carriers of type GA, GG, and G (GA + GG) required 45% (95% confidence interval (CI) 42 - 49), 77% (95% CI 70 - 84), and 51% (95% CI 47 - 55) higher warfarin doses, respectively. Carriers of type CC, TC, and C (CC + TC) required 83% (95% CI 73 - 92), 26% (95% CI 23 - 29), and 53% (95% CI 44 - 62) higher warfarin doses, respectively, compared to homozygous VKORC1 1173 TT carriers. Carriers of type AA, GA, and A (AA + GA) required 40% (95% CI 29 - 51), 25% (95% CI 17 - 33), and 33% (95% CI 21 - 45) higher warfarin doses, respectively, compared to carriers of the homozygous VKORC1 3730 GG polymorphism (all p < 0.05). Subgroup analysis showed that Asian patients aged <= 60 years carrying 1173 CC, TC, and C genotypes required 28%, 39%, and 22% higher warfarin doses, respectively, compared with patients aged > 60 years. Caucasian patients aged > 60 years carrying -1639 GA, GG and G genotypes needed 24%, 39%, and 37% lower warfarin doses, respectively, compared with patients aged <= 60 years. These differences were statistically significant (p < 0.05). CONCLUSIONS: Our study showed that the relationship between VKORC1 gene polymorphisms and warfarin maintenance dose differs between individuals, and that individuals with different ages and ethnicities require different doses of warfarin. Caucasians carriers of genotype -1639 GG, G and 1173 CC, TC, C required a higher mean daily warfarin doses compared with Asian patients. Therefore, in order to achieve optimal treatment and lowest risk, VKORC1 gene polymorphism detection is suggested.?. PMID- 28025971 TI - [Primary and Secondary Prevention of Hip Fragility Fracture in Teruel Health Sector, Aragon, Spain]. AB - OBJECTIVE: Osteoporosis should be prevented, diagnosed and treated, preferably before the fragility fracture occurs. The objective was to analyze primary and secondary interventions carried out in individuals diagnosed with femur fragility fracture at Teruel in 2014. METHODS: Descriptive retrospective study. Variables assessed were sex, age, main health district, place of residence, basal functional situation, diagnosis on osteoporosis, hip or vertebral fracture, loss of height, use of FRAX tool, treatment on discharge, survival and cause of exitus. Student's t-test and ANOVA were used for quantitative variables by categories and regression for linear relationships. RESULTS: 148 patients were included. 123 were women median age was 87 years, 123 (76,4%) were women, 27,4% of the patients were totally or severely dependent for activities of daily living and 33% of them were living in a nursing home. There was a previous history of hip fracture in 10,1%, and one or more vertebral fractures in 10,1%. FRAX(r) tool was not used in any case. 12,2% of patients had been treated with calcium prior to fracture, 11,5% with vitamin D, and 6,8% of them with antiosteoporotic drugs. Only 52,7% were treated for secondary prevention after discharge. At the end of follow-up, 25,7% of hip fractured patients had died. Median survivorship of deceased patients was 64,5 days. 42,3% of exitus were caused by cardiovascular disease, 23,1% by infection and 11,5% by neoplasms. CONCLUSIONS: Primary pharmacologic prevention and assessment of osteoporosis or risk of fracture are unfrequent in our health district.. Although pharmacologic treatment is prescribed more frequently in Teruel than in other areas after a hip or vertebral fracture, additional measures should be taken in order to improve fragility fracture prevention. PMID- 28025972 TI - [Spanish Network for the Study of Paediatric Tuberculosis. At the forefront of Europe]. PMID- 28025973 TI - Lateral Habenula Involvement in Impulsive Cocaine Seeking. AB - The lateral habenula (LHb) is a brain structure receiving inputs from limbic forebrain areas and innervating major midbrain monoaminergic nuclei. Evidence indicates LHb involvement in sleep control, reward-based decision making, avoidance of punishment, and responses to stress. Additional work has established that the LHb mediates negative feedback in response to aversive events. As a hallmark of drug addiction is the inability to limit drug use despite negative consequences, we hypothesize that LHb dysfunction may have a role in the lack of control over drug seeking. Here we examine the effects of LHb inactivation in control over drug seeking in several cocaine self-administration (SA) paradigms in rats. We find that inhibition of the LHb with GABAergic agonists did not alter cocaine SA under progressive ratio or seeking/taking chained reinforcement schedules, or during punishment-induced suppression of cocaine-reinforced responding. In contrast, LHb inhibition increased cocaine seeking when the drug was not available in rats trained to discriminate its presence using an environmental cue. This effect of LHb inhibition was selective for cocaine, as it did not impair responding for sucrose reinforcement. The effect of LHb injection of GABA agonists was mimicked by intra-LHb muscarinic cholinergic (mACh) antagonist injection, and activation of mACh receptors excited a majority of LHb neurons in in vitro electrophysiology experiments. These results indicate that the LHb participates in the suppression of impulsive responding for cocaine through the activation of a cholinergic circuit, and they suggest that LHb dysfunction may contribute to impaired impulse control associated with drug addiction. PMID- 28025974 TI - Social Status in Monkeys: Effects of Social Confrontation on Brain Function and Cocaine Self-Administration. AB - Individual differences in response to social stress and environmental enrichment may contribute to variability in response to behavioral and pharmacological treatments for drug addiction. In monkeys, social status influences the reinforcing effects of cocaine and the effects of some drugs on cocaine self administration. In this study, we used male cynomolgus macaques (n=15) living in established social groups to examine the effects of social confrontation on the reinforcing effects of cocaine using a food-drug choice procedure. On the test day, a dominant or subordinate monkey was removed from his homecage and placed into another social pen; 30 min later he was studied in a cocaine-food choice paradigm. For the group, following social confrontation, sensitivity to cocaine reinforcement was significantly greater in subordinate monkeys compared with dominant animals. Examining individual-subject data revealed that for the majority of monkeys (9/15), serving as an intruder in another social group affected cocaine self-administration and these effects were dependent on the social rank of the monkey. For subordinate monkeys, sensitivity to the reinforcing effects of cocaine increased while sensitivity decreased in dominant monkeys. To investigate potential mechanisms mediating these effects, brain glucose metabolism was studied in a subset of monkeys (n=8) using [18F]fluorodeoxyglucose ([18F]FDG) with positron emission tomography. Dominant and subordinate monkeys displayed distinctly different patterns of brain glucose metabolism in their homecage, including areas associated with vigilance and stress/anxiety, respectively, and during social confrontation. These data demonstrate that, depending on an individual's social status, the same social experience can have divergent effects on brain function and cocaine self administration. These phenotypic differences in response to social conditions support a personalized treatment approach to cocaine addiction. PMID- 28025975 TI - Incubation of Methamphetamine but not Heroin Craving After Voluntary Abstinence in Male and Female Rats. AB - We recently introduced an animal model of incubation of methamphetamine craving after choice-based voluntary abstinence in male rats. Here we studied the generality of this phenomenon to (1) female rats, and (2) male and female rats with a history of heroin self-administration. We first trained rats to self administer palatable food pellets for 6 days (6 h per day) for either methamphetamine (0.1 mg/kg/infusion) or heroin (0.1 mg/kg/infusion) for 12 days (6 h/day). We then assessed relapse to drug seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent either voluntary abstinence (achieved via a discrete choice procedure between drug and palatable food; 20 trials/day) or home-cage forced abstinence. We found no sex differences in methamphetamine self-administration or in the strong preference for the palatable food over methamphetamine during the choice-based voluntary abstinence. In both sexes, methamphetamine seeking in the relapse tests was higher after 21 days of either voluntary or forced abstinence than after 1 day (incubation of methamphetamine craving). We also found no sex differences in heroin self-administration or the strong preference for the palatable food over heroin during the choice-based voluntary abstinence. However, male and female rats with a history of heroin self-administration showed incubation of heroin craving after forced but not voluntary abstinence. Our results show that incubation of methamphetamine craving after voluntary abstinence generalizes to female rats. Unexpectedly, prolonged voluntary abstinence prevented the emergence of incubation of heroin craving in both sexes. PMID- 28025977 TI - Origins of rice cytoplasmic male sterility genes. AB - Cytoplasmic male sterility (CMS) factors have long been known in some wild plants, and also in some domesticated species, where they are used to produce plants to be used as maternal parents, for example to breed hybrids that display hybrid vigor. Their origins have been mystifying, and now a study recently published in Cell Research helps understand how one widely-used rice CMS factor evolved. PMID- 28025976 TI - Dendritic cell-based immunotherapy. AB - Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity. PMID- 28025980 TI - Cracking the mnemonic code. PMID- 28025979 TI - Driving gene-engineered T cell immunotherapy of cancer. AB - Chimeric antigen receptor (CAR) gene-engineered T cell therapy holds the potential to make a meaningful difference in the lives of patients with terminal cancers. For decades, cancer therapy was based on biophysical parameters, with surgical resection to debulk, followed by radiation and chemotherapy to target the rapidly growing tumor cells, while mostly sparing quiescent normal tissues. One breakthrough occurred with allogeneic bone-marrow transplant for patients with leukemia, which provided a sometimes curative therapy. The field of adoptive cell therapy for solid tumors was established with the discovery that tumor infiltrating lymphocytes could be expanded and used to treat and even cure patients with metastatic melanoma. Tumor-specific T-cell receptors (TCRs) were identified and engineered into patient peripheral blood lymphocytes, which were also found to treat tumors. However, these were limited by patient HLA restriction. Close behind came generation of CAR, combining the exquisite recognition of an antibody with the effector function of a T cell. The advent of CD19-targeted CARs for treating patients with multiple forms of advanced B-cell malignancies met with great success, with up to 95% response rates. Applying CAR treatment to solid tumors, however, has just begun, but already certain factors have been made clear: the tumor target is of utmost importance for clinicians to do no harm; and solid tumors respond differently to CAR therapy compared with hematologic ones. Here we review the state of clinical gene-engineered T cell immunotherapy, its successes, challenges, and future. PMID- 28025981 TI - Brake and gas pedals in motor cortex. PMID- 28025982 TI - Correlations demystified. PMID- 28025978 TI - Immune targets and neoantigens for cancer immunotherapy and precision medicine. AB - Harnessing the immune system to eradicate malignant cells is becoming a most powerful new approach to cancer therapy. FDA approval of the immunotherapy-based drugs, sipuleucel-T (Provenge), ipilimumab (Yervoy, anti-CTLA-4), and more recently, the programmed cell death (PD)-1 antibody (pembrolizumab, Keytruda), for the treatment of multiple types of cancer has greatly advanced research and clinical studies in the field of cancer immunotherapy. Furthermore, recent clinical trials, using NY-ESO-1-specific T cell receptor (TCR) or CD19-chimeric antigen receptor (CAR), have shown promising clinical results for patients with metastatic cancer. Current success of cancer immunotherapy is built upon the work of cancer antigens and co-inhibitory signaling molecules identified 20 years ago. Among the large numbers of target antigens, CD19 is the best target for CAR T cell therapy for blood cancer, but CAR-engineered T cell immunotherapy does not yet work in solid cancer. NY-ESO-1 is one of the best targets for TCR-based immunotherapy in solid cancer. Despite the great success of checkpoint blockade therapy, more than 50% of cancer patients fail to respond to blockade therapy. The advent of new technologies such as next-generation sequencing has enhanced our ability to search for new immune targets in onco-immunology and accelerated the development of immunotherapy with potentially broader coverage of cancer patients. In this review, we will discuss the recent progresses of cancer immunotherapy and novel strategies in the identification of new immune targets and mutation-derived antigens (neoantigens) for cancer immunotherapy and immunoprecision medicine. PMID- 28025983 TI - Grid cells' need for speed. PMID- 28025984 TI - Fast-acting neurons that suppress appetite. PMID- 28025985 TI - Quality of life after primary septorhinoplasty in deviated- and non-deviated nose measured with ROE, FROI-17 and SF-36. AB - BACKGROUND: Quality of life measurements are gaining in importance. The present study was conducted with the aim to compare patient satisfaction after septorhinoplasty according to their preoperative nasal deformity. METHODS: The patients completed two disease-specific questionnaires before their surgery: the Functional Rhinoplasty Outcome Inventory (FROI-17), the Rhinoplasty Outcome Evaluation (ROE) and as a general instrument, the Short Form 36 Health Survey (SF 36). The second measurement was taken during an outpatient examination 12 months after their primary septorhinoplasty. Patients were grouped in nasal axis deviation (NAD), nasal hump deformity (NHD) and NAD plus NHD. Additionally the patients with preoperative NAD and NAD+NHD were combined as deviated nose and compared to the non-deviation group. RESULTS: One hundred and two patients (51 male and 51 female) underwent primary septorhinoplasty. The ROE- and the FROI-17 overall score including all three subgroups showed significant postoperative improvements. Regarding the SF-36, the postoperative score improved significantly only in two scales (role-functioning physical and mental health). Looking at the the different QoL questionnaires, there were significant postoperative differences in regards to deviated versus non-deviated nose in the FROI-17 overall- and FROI-17 subscores (nasal and general symptoms) and in three scales of the SF-36 (vitality, social functioning, role-functioning emotional), showing a greater postoperative satisfaction in the deviated-nose patient. CONCLUSION: Patients with and without nasal deviation showed improved QoL after their surgery, as measured with the ROE, the FROI-17 and the SF-36. The patients with a nasal deviation showed a significantly better outcome, as measured with the FROI 17, in comparison with the non-deviated group. PMID- 28025986 TI - Responsiveness and reliability of the Sinus Control Test in chronic rhinosinusitis. AB - BACKGROUND: The Sinus Control Test (SCT) is a patient-reported questionnaire designed to help physicians identify sub-optimally controlled chronic rhinosinusitis (CRS). This study measures responsiveness to surgery and reliability of the SCT. METHODOLOGY: Adults meeting diagnostic criteria for CRS were recruited from rhinology clinics at a tertiary academic institution. To measure responsiveness, the SCT was administered at baseline and at least 3 months after surgery to 62 CRS patients. To measure reliability, the SCT was administered at two clinical encounters a maximum of 14 days apart to 22 CRS patients. RESULTS: Total SCT scores significantly improved from baseline to post operative follow-up, and the distribution of patients with total SCT scores falling into the uncontrolled, partially controlled, and controlled categories before and after surgery were significantly different in the direction of improvement. The SCT met minimum standards for reliability and internal consistency as measured by: test-retest reliability coefficient, intra-class correlation coefficients, and item-total correlations. Cronbach alpha; values with each item deleted were lower than the overall Cronbach alpha. The SCT captures the full range of disease control as measured by floor and ceiling effects. CONCLUSION: The SCT is responsive to surgical intervention and a reliable tool to monitor changes in CRS control levels. PMID- 28025987 TI - Toll-like receptor activation by sino-nasal mucus in chronic rhinosinusitis. AB - BACKGROUND: The sino-nasal disease chronic rhinosinusitis (CRS) is primarily an inflammatory condition that manifests in several ways. However, the aetiology of this complex disease is poorly understood. The aim of this study was to explore the association between toll-like receptor (TLR) activation, host immune response and sino-nasal mucus in healthy and diseased patients. METHODS: The activation of TLR2/1 and TLR4 by sino-nasal mucus from 26 CRS patients and 10 healthy controls was measured. In addition, 7 inflammatory cytokines, bacterial community composition and bacterial abundance within the sino-nasal mucus were measured using molecular and diagnostic tools. RESULTS: TLR activity was observed in 9/36 samples, including 2 healthy controls. There was a strong, positive correlation between members of the Gammaproteobacteria (Haemophilus, Enterobacter, Pseudomonas) and TLR2/1 and TLR4 activity. Bacterial abundance and cytokine (tumour necrosis factor) abundance were also positively correlated with TLR activity. CONCLUSIONS: These findings suggest that a small proportion (20-30%) of individuals in each sub-group are more predisposed to TLR activity, which may be related to bacterial composition, diversity and abundance in the sinuses. PMID- 28025988 TI - Charge-based precipitation of extracellular vesicles. AB - Vesicular-mediated communication between cells appears critical in many biological processes. Extracellular vesicles (EVs) released from healthy and diseased cells are involved in a network of exchange of biologically active molecules. Since EVs present in biological fluids carry the signature of the cell of origin, they are potential biomarkers for ongoing physiological or pathological processes. Despite the knowledge on EV biology accrued in recent years, techniques of EV purification remain a challenge and all the described methods have some advantages and disadvantages. In the present study, we described a method based on charge precipitation of EVs from biological fluids and from cell supernatants in comparison with the differential ultracentrifugation, which is considered the gold standard for EV purification. The analysis of zeta-potential revealed that EVs have a negative charge that allows the interaction with a positively charged molecule, such as protamine. Protamine was shown to induce EV precipitation from serum and saliva and from cell culture media without the need for ultracentrifugation. EV resuspension was facilitated when protamine (P) precipitation was performed in the presence of PEG 35,000 Da (P/PEG precipitation). The recovery of precipitated EVs evaluated by NanoSight analysis was more efficient than that obtained by ultracentrifugation. By electron microscopy the size of EVs was similar after both methods were used, and the expression of CD63, CD9 and CD81 exosomal markers in the P/PEG precipitated EVs indicated an enrichment in exosomes. The RNA recovery of P/PEG precipitated EVs was similar to that of EVs isolated by ultracentrifugation. In addition, P/PEG-precipitated EVs retained the biological activity in vitro as observed by the induction of wound closure by keratinocytes and of proliferation of tubular epithelial cells. In conclusion, charge-based precipitation of EVs has the merit of simplicity and avoids the requirement of expensive equipments and may be used for the efficient isolation of EVs from small biological samples. PMID- 28025990 TI - Focal cortical dysplasia: Molecular disturbances and clinicopathological classification (Review). AB - Focal cortical dysplasia (FCD) is one of the most important causes of drug resistant epilepsy in paediatric patients, particularly in those below the age of 3. Even though over 40 years have passed since the first description of the entity by Taylor, the exact mechanisms causing these cortical abnormalities remain unelucidated. In this review, we summarise the current knowledge on clinical and histopathological aspects, taking into account the new classification system proposed by the International League Against Epilepsy. We focus on the clinicopathological associations and differences in post-surgical outcome among FCD subtypes, in particular isolated FCD vs. FCD associated with principal lesions, which have not been summarised to date. We also recapitulate genetic studies, pointing to the possible mechanisms of the cortical dysregulation and drug resistance, and summarise novel factors which may contribute to epileptogenesis in FCD. Furthermore, we compare FCD type IIB (FCDIIB) with brain tumours found in a neurocutaneous disorder, tuberous sclerosis, as we evaluate the hypothesis that FCD IIB may be a local form of this disease. PMID- 28025989 TI - MicroRNA-142-3p inhibits hypoxia/reoxygenation-induced apoptosis and fibrosis of cardiomyocytes by targeting high mobility group box 1. AB - Myocardial ischemia/reperfusion (I/R) injury may cause the apoptosis of cardiomyocytes as well as cardiac fibrosis, which is characterized as the transdifferentiation of fibroblasts to myofibroblasts and collagen deposition. MicroRNAs (miRNAs or miRs) have been demonstrated to be involved in myocardial I/R injury. However, the underlying molecular mechanism remains largely unclear. In the present study, mouse cardiomyocyte M6200 cells were treated with hypoxia/reoxygenation (H/R). Our data indicated that H/R treatment led to cell apoptosis, the increased expression of fibrosis-related proteins, namely collagen I, II, III, and fibronectin, as well as the downregulation of miR-142-3p in M6200 cells. Overexpression of miR-142-3p suppressed the H/R-induced apoptosis and fibrosis of M6200 cells. Bioinformatics analysis and a Dual-Luciferase reporter assay further identified high mobility group box 1 (HMGB1) as a direct target gene of miR-142-3p, and miR-142-3p negatively regulated the protein level of HMGB1 in M6200 cells. Furthermore, knockdown of HMGB1 enhanced cell proliferation whereas it inhibited the apoptosis and fibrosis of M6200 cells. In addition, TGF beta1/Smad3 signaling was suggested to be involved in the miR-142-3p/HMGB1 mediated apoptosis and fibrosis of M6200 cells treated with H/R. Taken together, the findings of the present study demonstrate that miR-142-3p inhibits H/R induced apoptosis and fibrosis of cardiomyocytes, partly at least, by the direct inhibition of HMGB1 expression. Therefore, these findings have increased our understanding of the pathogenesis of H/R-induced myocardial injury. PMID- 28025991 TI - Early cellular responses of BMSCs genetically modified with bFGF/BMP2 co-cultured with ligament fibroblasts in a three-dimensional model in vitro. AB - Currently, a number of strategies including the implantation of bone marrow derived mesenchymal stem cells (BMSCs) and growth factors have been developed to regenerate the tendon-to-bone interface after performing anterior cruciate ligament reconstruction. However, the mechanisms behind the interactions of the implanted BMSCs and tendon cells remain to be elucidated. The aim of this study was to evaluate the early cellular responses of BMSCs genetically modified with basic growth factor growth factor (bFGF)/bone morphogenic protein 2 (BMP2) and ligament fibroblasts in a three-dimensional co-culture model. BMSCs and ligament fibroblasts were both isolated from male Wistar rats. The BMSCs were then transfected with an adenoviral vector carrying bFGF or BMP2. The transfected BMSCs and ligament fibroblasts both encapsulated in alginate beads were co cultured for 6 days in three-dimensional model. On days 0, 3 and 6, cell proliferation was assayed. On day 6, the expression of several tendon-bone related markers was evaluated. In the co-culture system, bFGF and BMP2 were highly expressed at the mRNA and protein level. During the process, bFGF significantly promoted cell proliferation, as well as the expression of scleraxis (SCX) and collagen (COL) type I (COL1) in the BMSCs; however, it markedly decreased the expression of phenotype markers in the ligament fibroblasts, including COL1 and COL3. BMP2 markedly increased the expression of alkaline phosphatase and osteocalcin in the BMSCs and ligament fibroblasts, whereas it had no obvious effect on cell proliferation and collagen synthesis in the ligament fibroblasts. The combination of bFGF and BMP2 resulted in the similarly enhanced proliferation of BMSCs and ligament fibroblasts as observed with bFGF alone; however, this combination more potently promoted osteogenic differentiation than did BMP2 alone. The findings of our study demonstrate the superiority of the combined use of growth factors in inducing osteogenic differentiation and provide a theoretical foundation for the regeneration of the tendon-to-bone interface. PMID- 28025993 TI - Anti-inflammatory effect of tricin isolated from Alopecurus aequalis Sobol. on the LPS-induced inflammatory response in RAW 264.7 cells. AB - The aim of this study was to identify major anti-inflammatory compounds in Alopecurus aequalis Sobol. (A. aequalis). The ethanol extract and the hexane-, dichloromethane-, ethyl acetate- and n-butanol-soluble fractions derived from A. aequalis were evaluated in order to determine their inhibitory effects on nitric oxide (NO) production in RAW 264.7 cells stimulated with lipopolysaccharide (LPS). The ethanol extract decreased NO production in a dose-dependent manner without any evidence of cytotoxicity at a concentration range of 0-200 ug/ml. The ethyl acetate soluble fraction was the most potent among the four soluble fractions. A compound was isolated by reversed-phase high-performance liquid chromatography from the ethyl acetate soluble fraction and this was identified to be tricin. Tricin inhibited the LPS-induced NO production in a dose-dependent manner without any evidence of cytotoxity at a concentration range of 1-100 ug/ml. Tricin also inhibited the LPS-induced production of prostaglandin E2. Western blot analysis indicated that tricin decreased the LPS-induced increase in the protein levels of inducible NO synthase and cyclooxygenase. In addition, tricin suppressed the production of intracellular reactive oxygen species in the LPS-stimulated RAW 264.7 cells, as measured by flow cytometry. Taken together, our results clearly indicate that tricin is a major functional anti-inflammatory compound which can be isolated from A. aequalis extracts. PMID- 28025992 TI - miR-124 promotes the neuronal differentiation of mouse inner ear neural stem cells. AB - MicroRNAs (miRNAs or miRs) act as key regulators in neuronal development, synaptic morphogenesis and plasticity. However, their role in the neuronal differentiation of inner ear neural stem cells (NSCs) remains unclear. In this study, 6 miRNAs were selected and their expression patterns during the neuronal differentiation of inner ear NSCs were examined by RT-qPCR. We demonstrated that the culture of spiral ganglion stem cells present in the inner ears of newborn mice gave rise to neurons in vitro. The expression patterns of miR-124, miR-132, miR-134, miR-20a, miR-17-5p and miR-30a-5p were examined during a 14-day neuronal differentiation period. We found that miR-124 promoted the neuronal differentiation of and neurite outgrowth in mouse inner ear NSCs, and that the changes in the expression of tropomyosin receptor kinase B (TrkB) and cell division control protein 42 homolog (Cdc42) during inner ear NSC differentiation were associated with miR-124 expression. Our findings indicate that miR-124 plays a role in the neuronal differentiation of inner ear NSCs. This finding may lead to the development of novel strategies for restoring hearing in neurodegenerative diseases. PMID- 28025995 TI - Prediction of key genes and miRNAs responsible for loss of muscle force in patients during an acute exacerbation of chronic obstructive pulmonary disease. AB - The present study aimed to identify genes and microRNAs (miRNAs or miRs) that were abnormally expressed in the vastus lateralis muscle of patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The gene expression profile of GSE10828 was downloaded from the Gene Expression Omnibus database, and this dataset was comprised of 4 samples from patients with AECOPD and 5 samples from patients with stable COPD. Differentially expressed genes (DEGs) were screened using the Limma package in R. A protein-protein interaction (PPI) network of DEGs was built based on the STRING database. Module analysis of the PPI network was performed using the ClusterONE plugin and functional analysis of DEGs was conducted using DAVID. Additionally, key miRNAs were enriched using gene set enrichment analysis (GSEA) software and a miR-gene regulatory network was constructed using Cytoscape software. In total, 166 up- and 129 downregulated DEGs associated with muscle weakness in AECOPD were screened. Among them, NCL, GOT1, TMOD1, TSPO, SOD2, NCL and PA2G4 were observed in the modules consisting of upregulated or downregulated genes. The upregulated DEGs in modules (including KLF6 and XRCC5) were enriched in GO terms associated with immune system development, whereas the downregulated DEGs were enriched in GO terms associated with cell death and muscle contraction. Additionally, 39 key AECOPD-related miRNAs were also predicted, including miR-1, miR-9 and miR-23a, miR-16 and miR 15a. In conclusion, DEGs (NCL, GOT1, SOD2, KLF6, XRCC5, TSPO and TMOD1) and miRNAs (such as miR-1, miR-9 and miR-23a) may be associated with the loss of muscle force in patients during an acute exacerbation of COPD which also may act as therapeutic targets in the treatment of AECOPD. PMID- 28025996 TI - Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice. AB - Hepatocellular carcinoma (HCC) represents approximately 85% of all primary liver cancer cases. Non-alcoholic fatty liver disease (NAFLD) is one of the risk factors for HCC. NAFLD occurs in patients with components of metabolic syndrome, such as type 2 diabetes mellitus, obesity, hypertension and hyperlipidemia. Therefore, hyperlipidemia also represents a patient population at risk for HCC that can readily be identified. Rosuvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, has exhibited a more potent affinity for the active site of HMG-CoA reductase than other statins. In addition, the hepatic uptake of rosuvastatin in rats has been found to be more selective and efficient than that with other drugs. Furthermore, the cytoprotective effects of rosuvastatin against ischemic injury have been clearly reported. Thus, in this study, we aimed to determine the role of rosuvastatin as a preventive drug in HCC associated with NAFLD. STAM mice, which developed HCC from NAFLD by being fed a high-fat diet (HFD), were divided into a group in which a HFD was given to the mice for 15 weeks (n=8) and another in which a HFD supplemented with 0.00125% rosuvastatin was given to the mice for 15 weeks (n=8). Rosuvastatin inhibited the development of hepatic tumors in the mice with NAFLD induced by a specific diet both macroscopically and histologically. Rosuvastatin significantly decreased the expression levels of pro-inflammatry cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and transforming growth factor (TGF)-beta1. Tumor aggressiveness is mediated by angiogenic factors. Therefore, we examined the hepatic mRNA expression of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF). The hepatic expression of these factors significantly decreased in the rousvastin-fed mice. Our results thus suggest rosuvastatin that prevents carcinogenesis and improves the hepatic background. Our data suggest that rosuvastatin has potential for use as a preventive drug for the development of HCC associated with NAFLD in mice. PMID- 28025994 TI - The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain. AB - Bone cancer pain (BCP) is one of the most difficult and intractable tasks for pain management, which is associated with spinal 'neuron-astrocytic' activation. The activation of the c-Jun N-terminal kinase (JNK)/chemokine (C-C motif) ligand (CCL2) signaling pathway has been reported to be critical for neuropathic pain. Rolipram (ROL), a selective phosphodiesterase 4 inhibitor, possesses potent anti inflammatory and anti-nociceptive activities. The present study aimed to investigate whether the intrathecal administration of ROL has an analgesic effect on BCP in rats, and to assess whether the inhibition of spinal JNK/CCL2 pathway and astrocytic activation are involved in the analgesic effects of ROL. The analgesic effects of ROL were evaluated using the Von Frey and Hargreaves tests. Immunofluorescence staining was used to determine the number of c-Fos immunoreactive neurons, and the expression of spinal astrocytes and microglial activation on day 14 after tumor cell inoculation. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of pro-inflammatory cytokines [interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha] and chemokines (CCL2), and western blot analysis was then used to examine the spinal phosphodiesterase 4 (PDE4), ionized calcium binding adapter molecule-1 (IBA-1) and JNK levels on day 14 after tumor cell inoculation. The results revealed that ROL exerted a short-term analgesic effect in a dose-dependent manner, and consecutive daily injections of ROL exerted continuous analgesic effects. In addition, spinal 'neuron-astrocytic' activation was suppressed and was associated with the downregulation of spinal IL-1beta, IL-6 and TNF-alpha expression, and the inhibition of PDE4B and JNK levels in the spine was also observed. In addition, the level of CCL2 was decreased in the rats with BCP. The JNK inhibitor, SP600125, decreased CCL2 expression and attenuated pain behavior. Following co-treatment with ROL and SP600125, no significant increases in thermal hyperalgesia and CCL2 expression were observed compared with the ROL group. Thus, our findings suggest that the analgesic effects of ROL in BCP are mainly mediated through the inhibition of 'neuron-astrocytic' activation, which occurs via the suppression of spinal JNK/CCL2 signaling. PMID- 28025997 TI - A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1. AB - Since checkpoint kinase 1 (Chk1) is an essential factor for cell viability following DNA damage, the inhibition of Chk1 has been a major focus of pharmaceutical development to enhance the sensitivity of tumor cells to chemo- and radiotherapy that damage DNA. However, due to the off-target effects of conventional Chk1-targeting strategies and the toxicity of Chk1 inhibitors, alternative strategies are required to target Chk1. To facilitate such efforts, in this study, we identified a specific Chk1-binding 12-mer peptide from the screening of a phage display library and characterized the peptide in terms of cellular cytotoxicity, and in terms of its effect on Chk1 activity and sensitivity to genotoxic agents. This peptide, named N-terminal Chk1-binding peptide (Chk1-NP), bound the kinase domain of Chk1. Simulation of the binding revealed that the very N-terminus of the Chk1 kinase domain is the potential peptide binding site. Of note, the polyarginine-mediated internalization of Chk1 NP redistributed nuclear Chk1 with a prominent decrease in the nucleus in the absence of DNA damage. Treatment with Chk1-NP peptide alone decreased the viability of p53-defective HeLa cells, but not that of p53-functional NCI-H460 cells under normal conditions. The treatment of HeLa or NCI-H460 cells with the peptide significantly enhanced radiation sensitivity following ionizing radiation (IR) with a greater enhancement observed in HeLa cells. Moreover, the IR-induced destabilization of Chk1 was aggravated by treatment with Chk1-NP. Therefore, the decreased nuclear localization and protein levels of Chk1 seem to be responsible for the enhanced cancer cell killing following combined treatment with IR and Chk1-NP. The approach using the specific Chk1-binding peptide may facilitate the mechanistic understanding and potential modulation of Chk1 activities and may provide a novel rationale for the development of specific Chk1-targeting agents. PMID- 28025998 TI - In vitro screening of radioprotective properties in the novel glucosylated flavonoids. AB - Novel glucosyl flavonoids are developed by the addition of glucose to naturally occurring flavonoids. Flavonoids are known antioxidants that possess radioprotective properties. In order to investigate the radioprotective properties of novel glucosyl flavonoids, in vitro DNA double-strand breaks (DSBs) analysis was carried out. In the present study, Quercetin, Naringenin, and Hesperetin groups of flavonoids included in the natural and novel glucosyl 13 flavonoids were investigated. Flavonoids were mixed with Lambda DNA, and subsequently exposed to gamma-rays. Furthermore, DNA DSB yields were visualized by gel electrophoresis. Quercetin derivatives displayed reduced DNA DSB formation at 10 uM. At a high concentration, the majority of flavonoids displayed radioprotective properties as a reduction of DSB yields. Suppression of DSB formation was confirmed via the molecular combing assay for Quercetin, and three monoglucosyl flavonoids. Glucosylation showed positive effects for radioprotection and monoglucosyl-Rutin showed superior radioprotective properties when compared to monoglucosyl-Naringin and Hesperidin. In addition, Quercetin derivatives had greater total antioxidant capacities and DPPH radical scavenging ability than other flavonoid groups. Since Quercetin, Isoquercetin, and Rutin display poor water solubility, monoglucosyl-Rutin, maltooligosyl-Isoquercetin, and maltooligosyl-Rutin may be better radioprotective agents and easily bioavailable with increased water solubility. PMID- 28025999 TI - miR-200a-3p promotes the proliferation of human esophageal cancer cells by post transcriptionally regulating cytoplasmic collapsin response mediator protein-1. AB - The dysregulation of cytoplasmic collapsin response mediator protein 1 (CRMP1) has been reported in lung cancer, medulloblastoma and esophageal cancer. However, the role of CRMP1 and its regulatory mechanisms in esophageal cancer remain unclear. In this study, we demonstrated that CRMP1 expression was downregulated in esophageal cancer tissues and that there were differences in its expression levels in different esophageal cancer cell lines. We found that CRMP1 overexpression inhibited the proliferation of esophageal cancer cells, whereas the silencing of CRMP1 promoted cell proliferation. We performed an analysis of potential microRNA (miRNA or miR) target sites using a commonly used prediction algorithm (TargetScan). The algorithm predicted that miR-200a-3p targets the 3' untranslated region (3'UTR) of CRMP1. Further experiments confirmed this prediction. In addition, we found that miR-200a-3p promoted the proliferation of esophageal cancer cells. Thus, our findings indicate that miR-200a-3p promotes the proliferation of human esophageal cancer cells by post-transcriptionally regulating CRMP1. PMID- 28026000 TI - Low-magnitude, high-frequency vibration promotes the adhesion and the osteogenic differentiation of bone marrow-derived mesenchymal stem cells cultured on a hydroxyapatite-coated surface: The direct role of Wnt/beta-catenin signaling pathway activation. AB - The positive effect of low-magnitude, high-frequency (LMHF) vibration on implant osseointegration has been demonstrated; however, the underlying cellular and molecular mechanisms remain unknown. The aim of this study was to explore the effect of LMHF vibration on the adhesion and the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) cultured on hydroxyapatite (HA)-coated surfaces in an in vitro model as well as to elucidate the molecular mechanism responsible for the effects of LMHF vibration on osteogenesis. LMHF vibration resulted in the increased expression of fibronectin, which was measured by immunostaining and RT-qPCR. Stimulation of BMSCs by LMHF vibration resulted in the rearrangement of the actin cytoskeleton with more prominent F-actin. Moreover, the expression of beta1 integrin, vinculin and paxillin was notably increased following LMHF stimulation. Scanning electron microscope observations revealed that there were higher cell numbers and more extracellular matrix attached to the HA-coated surface in the LMHF group. Alkaline phosphatase activity as well as the expression of osteogenic-specific genes, namely Runx2, osterix, collagen I and osteocalcin, were significantly elevated in the LMHF group. In addition, the protein expression of Wnt10B, beta-catenin, Runx2 and osterix was increased following exposure to LMHF vibration. Taken together, the findings of this study indicate that LMHF vibration promotes the adhesion and the osteogenic differentiation of BMSCs on HA-coated surfaces in vitro, and LMHF vibration may directly induce osteogenesis by activating the Wnt/beta-catenin signaling pathway. These data suggest that LMHF vibration enhances the osseointegration of bone to a HA-coated implant, and provide a scientific foundation for improving bone-implant osseointegration through the application of LMHF vibration. PMID- 28026001 TI - Expression of glycine receptors and gephyrin in rat medial vestibular nuclei and flocculi following unilateral labyrinthectomy. AB - The medial vestibular nucleus (MVN) and the cerebellar flocculus have been known to be the key areas involved in vestibular compensation (VC) following unilateral labyrinthectomy (UL). In this study, we examined the role of gephyrin and glycine receptor (GlyR) in VC using Sprague-Dawley rats, in an aim to gain deeper insight into the mechanisms responsible for VC. The expression of the alpha1 and beta subunits of GlyR and gephyrin was immunohistochemically localized in rat MVN and flocculi. The mRNA and protein expression of GlyR (alpha1 and beta subunits) and gephyrin was quantitatively determined by RT-qPCR and western blot analysis at 8 h, and at 1, 3 and 7 days following UL. It was found that in the ipsilateral MVN, the mRNA and protein expression of the beta subunit of GlyR was significantly increased in comparison to the sham-operated (P<0.01) rats, and in comparison to the contralateral side (P<0.01) at 8 h following UL. In the ipsilateral flocculi, GlyR beta protein expression was significantly elevated (P<0.01 for all), as compared to the sham-operated rats at 8 h, and at 1 and 3 days and to the contralateral side 8 h, 1 and 3 days following UL. No significant differences were observed in the mRNA and protein expression of GlyR alpha1 and gephyrin in the MVN or flocculi between the two sides (ipsilateral and contralateral) in the UL group, and between the sham-operated group and the UL group at any time point. The findings of our study thus suggest that GlyR plays a major role in the recovery of the resting discharge of the deafferented MVN neurons in the central vestibular system. PMID- 28026002 TI - MicroRNA-33b suppresses the proliferation and metastasis of hepatocellular carcinoma cells through the inhibition of Sal-like protein 4 expression. AB - MicroRNAs (miRNAs or miRs) have been found to participate in the development and malignant progression of human cancers by negatively mediating the expression of their target genes. Recently, miR-33b has been reported to be involved in multiple types of human cancer, including hepatocellular carcinoma (HCC). However, the underlying regulatory mechanisms of miR-33b in HCC cell growth and metastasis remain largely unclear. In the present study, RT-qPCR revealed that miR-33b was significantly downregulated in HCC tissues compared to their matched adjacent normal tissues. Moreover, the miR-33b level was significantly lower in advanced-stage HCC (stages T3-T4) compared to early-stage HCC (stages T1-T2). Furthermore, it was also downregulated in the HCC cell lines, LH86, HepG2, LMH and PLHC-1, when compared with the THLE-3 normal human liver cells. We further demonstrated that the overexpression of miR-33b led to a significant decrease in the proliferation, migration and invasion of HepG2 and LH86 cells. Luciferase reporter assay identified Sal-like protein 4 (SALL4) as a target gene of miR-33b, and its protein expression was negatively regulated by miR-33b in HepG2 and LH86 cells. Moreover, the restoration of SALL4 expression markedly reversed the inhibitory effect of miR-33b overexpression on the proliferation, migration and invasion of HepG2 and LH86 cells, indicating that SALL4 is involved in miR-33b mediated malignant phenotypes of HCC cells. Furthermore, we found that SALL4 was significantly upregulated in HCC tissues compared to their matched adjacent normal tissues, and its increased expression was significantly associated with the advanced malignancy of HCC. Moreover, SALL4 was also upregulated in HCC cell lines compared to the THLE-3 normal human liver cells. Finally, we found that the SALL4 expression inversely correlated with the miR-33b level in HCC tissues. On the whole, the findings of our study demonstrate that miR-33b suppresses the proliferation and metastasis of HCC cells through the inhibition of SALL4 expression. Therefore, miR-33b/SALL4 may become a potential therapeutic target for the treatment of HCC. PMID- 28026003 TI - Quercetin promotes the apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis by upregulating lncRNA MALAT1. AB - Rheumatoid arthritis (RA) is a chronic autoimmune joint disease and fibroblast like synoviocytes (FLS) are the resident mesenchymal cells of synovial joints. Quercetin is a dietary antioxidant. In this study, we aimed to explore the mechanisms responsible for the quercetin-induced apoptosis of FLS from patients with RA (termed RAFLS). RAFLS viability was determined following treatent of the cells with or without quercetin using the Cell Counting kit-8 (CCK-8) assay. The apoptosis of the RAFLS was analyzed using the Annexin V-fluorescein isothiocyanate (FITC) apoptosis detection kit I. The results revealed that RAFLS viability decreased and apoptosis increased in following treatment with quercetin. The differentially expressed long non-coding RNAs (lncRNAs) were screened and marked by PCR array following treatment with quercetin. The expression levels of the screened lncRNAs were then determined and compared in the cells treated with or without quercetin by quantitative PCR. The lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was finally selected. Small interfering RNA (siRNA) was then used to knock down the expression of MALAT1 in order to determine the role of MALAT1 in the quercetin induced apoptosis of RAFLS. The results revealed that the knockdown of MALAT1 inhibited RAFLS apoptosis. At the same time, the expression of caspase-3 and caspase-9 was significantly decreased in the cells in which MALAT1 was knocked down. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway was activated; this activation is known to be associated with enhanced cell proliferation and decreased apoptosis. The findings of our study indicate that quercetin promotes RAFLS apoptosis by upregulating lncRNA MALAT1, and that MALAT1 induces apoptosis by inhibiting the activation of the PI3K/AKT pathway. PMID- 28026004 TI - Ethanol enhances thymocyte apoptosis and autophagy in macrophages of rat thymi. AB - Tingible body macrophages (TBMs) play essential roles in the phagocytosis of apoptotic lymphocytes, specifically under exposure to various stressors. Although excessive ethanol consumption may enhance thymocyte apoptosis, reports investigating the autophagic response of the thymus to ethanol toxicity are still lacking. We investigated apoptosis and autophagy in thymi of an animal model of binge ethanol exposure. Adult male Wistar rats were injected intraperitoneally either with 5 g/kg ethanol or phosphate buffer saline (for the control group) and sacrificed 0, 3, 6 and 24 hours after injection. Light and transmission electron microscopy (TEM) studies revealed enhanced formation of TBMs phagocytosing many apoptotic thymocytes in the thymic cortex of the ethanol-treated rats (ETRs), and this formation was particularly marked at 24 h. The macrophages showed signs of activation under TEM and immunofluorescence double labeling with RM4 (a macrophage marker) and iNOS. Additionally, in comparison to the control group, autophagy was enhanced in ETR thymic TBMs as evidenced ultrastructurally by accumulation of autophagic vacuoles, immunohistochemical increases in LC3 puncta, Western blot analysis of the latter protein, and colocalization of LC3 and RM4 in immunofluorescence double labeling. Immunoelectron microscopy also revealed LC3 labeled autophagic vacuoles and apoptotic cell phagosomes in ETR TBMs, suggesting the possibility of LC3-related phagocytosis. This was confirmed by enhanced colocalization of LC3 with lysosomal cathepsins in double labeling. These results indicate that enhanced autophagy in ETR thymic TBMs is not only a cytoprotective mechanism but could also be involved in the clearance of apoptotic thymocytes, thus preventing autoimmune reactions and suppressing inflammatory response. PMID- 28026005 TI - Conformational properties and aggregation of homo-oligomeric beta3 (R)-valine peptides in organic solvents. AB - The conformational characteristics of protected homo-oligomeric Boc-[beta3 (R)Val]n -OMe, n = 1, 2, 3, 4, 6, 9, and 12 have been investigated in organic solvents using nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) absorption spectroscopy and circular dichroism (CD) methods. The detailed 1 H NMR analysis of Boc-[beta3 (R)Val]12 -OMe reveals that the peptide aggregates extensively in CDCl3 , but is disaggregated in 20%, (v/v) dimethyl sulfoxide (DMSO) in CDCl3 and in CD3 OH. Limited assignment of the N-terminus NH groups, together with solvent dependence of NH chemical shifts and temperature coefficients provides evidence for 14-helix conformation in the 12-residue peptide. FTIR analysis in CHCl3 establishes that the onset of folding and aggregation, as evidenced by NH stretching bands at 3375 cm-1 (intramolecular) and 3285 cm-1 (intermolecular), begins at the level of the tetrapeptide. The observed CD bands, 214 nm (negative) and 198 nm (positive), support 14-helix formation in the 9 and 12 residue sequences. The folding and aggregation tendencies of homo-oligomeric alpha-, beta-, and gamma- residues is compared in the model peptides Boc-[omegaVal]n -NHMe, omega = alpha, beta, and gamma and n = 1, 2, and 3. Analysis of the FTIR spectra in CHCl3 , establish that the tendency to aggregate at the di and tripeptide level follows the order beta > alpha~gamma, while the tendency to fold follows the order gamma > beta > alpha. PMID- 28026006 TI - Extended EEG and non-convulsive status epilepticus: Benefit over routine EEG? AB - OBJECTIVE: EEG monitoring is increasingly used in critically ill patients, but impact on clinical outcome remains unclear. We aimed to investigate the benefit of repeated extended EEG in the prognosis of patients with non-convulsive status epilepticus (SE). MATERIALS & METHODS: We retrospectively collected 29 consecutive patients with non-convulsive SE without coma, who underwent repeated extended EEG between 2013 and 2015. We compared these patients with an historical age-matched group of 58 patients managed between 2011 and 2013 with routine EEG only. We excluded patients treated with therapeutic coma for SE treatment. Outcome at hospital discharge was categorized as return to baseline conditions, new disability, and death. RESULTS: Severity of SE was similar in the two groups, with similar proportion of potential fatal etiologies (58% in the extended EEG group vs 60%, P=.529), similar STESS scores (median was three in both groups, P=.714), and comparable acute hospitalization duration (median of 15 vs 11 days, P=.131). The extended EEG group received slightly more anti-epileptic drugs (median was three in both groups, P=.026). Distribution of the outcome categories at hospital discharge was similar (P=.129). CONCLUSIONS: Extended EEG used for the management of non-convulsive status epilepticus does not seem to improve clinical outcome, but is associated with a higher number of prescribed anti epileptic drugs. The benefit of continuous EEG monitoring in non-convulsive SE without coma SE should be addressed through a randomized trial. PMID- 28026007 TI - Growth characteristics of the intracellular pathogen, Piscirickettsia salmonis, in tissue culture and cell-free media. AB - Piscirickettsia salmonis is an intracellular bacterium that was first isolated and identified in fish cells. Several types of cell lines have been explored for their ability to provide the bacterium with a host cell to replicate in. Tissue culture has been used for growth and cultivation for nearly two decades, until the facultative nature of P. salmonis was confirmed upon the development of blood and cysteine-based agar. Since then, research has continued to drive the creation of novel agar and broth formulations in order to improve the efficacy of cultivation of P. salmonis. Until now, the techniques and components used for growth have not been thoroughly discussed. In this review, the methods and formulations for growth of P. salmonis in tissue culture and cell-free media will be examined. PMID- 28026008 TI - Cyprinid herpesvirus 3 as a potential biological control agent for carp (Cyprinus carpio) in Australia: susceptibility of non-target species. AB - Carp (Cyprinus carpio L.) is a pest species in Australian waterways, and cyprinid herpesvirus 3 (CyHV-3) is being considered as a potential biological control (biocontrol) agent. An important consideration for any such agent is its target specificity. In this study, the susceptibility to CyHV-3 of a range of non-target species (NTS) was tested. The NTS were as follows: 13 native Australian, and one introduced, fish species; a lamprey species; a crustacean; two native amphibian species (tadpole and mature stages); two native reptilian species; chickens; and laboratory mice. Animals were exposed to 100-1000 times the approximate minimum amount of CyHV-3 required to cause disease in carp by intraperitoneal and/or bath challenge, and then examined clinically each day over the course of 28 days post challenge. There were no clinical signs, mortalities or histological evidence consistent with a viral infection in a wide taxonomic range of NTS. Furthermore, there was no molecular evidence of infection with CyHV-3, and, in particular, all RT-PCRs for viral mRNA were negative. As a consequence, the results encourage further investigation of CyHV-3 as a potential biocontrol agent that is specific for carp. PMID- 28026009 TI - Transcriptomic profiling of platelet senescence and platelet extracellular vesicles. AB - BACKGROUND: Platelets (PLTs) are derived from megakaryocytes during PLT shedding. Senescent or activated PLTs are expanded in vascular and neurological diseases and release PLT extracellular vesicles (PL-EVs). A systematic analysis of regular messenger RNA (mRNA) and small RNA composition in PLTs and PL-EVs during in vitro PLT senescence has not yet been published. STUDY DESIGN AND METHODS: We isolated PLTs, total PL-EVs, and PL-EV subsets on Days 0 and 5 from human stored donor platelet concentrates. Isolated mRNA species and microRNA (miRNA) species were analyzed by microarrays and deep sequencing. Correlation of mRNA and miRNA species (miR) and miRNA target analyses were performed using bioinformatics. RESULTS: During in vitro PLT senescence, residual PLT mRNA species were decreased and partially converted to miRNA species. Residual mRNAs included encoded genes relevant for atherosclerosis, inflammation (matrix metallopeptidase 14 [MMP-14], granulin [GRN], angiopoietin like 2 [ANGPTL2]), and neurotransmission (dopamine receptor 2 [DRD2], gamma-aminobutyric acid type A receptor rho3 [GABRR3]). Compared with senescent PLTs, PL-EVs have up-regulated their miRNA species involved in "diabesity" and in vascular and metabolic disease (miR-144-3p, miR 486-5p, miR-142-5p, miR-451a, miR-25-3p, miR-145-5p, and let-7f-5p). The 100 highest expressed PL-EV miRNA species determined by microarrays were compared with the 100 highest expressed PL-EV miRNA species detected by deep sequencing. This approach resulted in 66 overlaps. The regulated miRNAs (assessed by both methods) were related to neurological disorders, including targets for Alzheimer's disease (e.g., beta-site amyloid precursor protein APP-cleaving enzyme 1 [BACE1], translocase of outer mitochondrial membrane 40 homolog [TOMM40], neuron navigator 3 [NAV3]). CONCLUSION: During in vitro senescence, PLTs degrade large RNA species. Concomitantly, they up-regulate a distinct set of known small RNA species involved in atherosclerosis, inflammation, and neurodegeneration. PL-EVs enrich miRNA species, likely supporting the role of PLTs and PL-EVs in vascular homeostasis and as carriers of neurodegenerative disease-related miRNA cargo. PMID- 28026010 TI - Temperature and light conditions at different latitudes affect sensory quality of broccoli florets (Brassica oleracea L. var. italica). AB - BACKGROUND: Broccoli (Brassica oleracea L. var. italica) is a popular vegetable grown at a wide range of latitudes. Plants were grown in 2009-2011 in pots with standardized soil, irrigation and nutrient supply under natural temperature and light conditions at four locations (42-70 degrees N). A descriptive sensory analysis of broccoli florets was performed by a trained panel to examine any differences along the latitudinal gradient for 30 attributes within appearance, odour, taste/flavour and texture. RESULTS: Average results over three summer seasons in Germany, southern Norway and northern Norway showed that the northernmost location with low temperatures and long days had highest scores for bud coarseness and uniform colour, while broccoli from the German location, with high temperatures and shorter days, had highest intensity of colour hue, whiteness, bitter taste, cabbage flavour, stale flavour and watery flavour. Results from two autumn seasons at the fourth location (42 degrees N, Spain), with low temperatures and short days, tended toward results from the two northernmost locations, with an exception for most texture attributes. CONCLUSION: Results clearly demonstrate that temperature and light conditions related to latitude and season affect the sensory quality of broccoli florets. Results may be used in marketing special quality regional or seasonal products. (c) 2016 Society of Chemical Industry. PMID- 28026011 TI - Community integration outcomes of people with spinal cord injury and multiple matched controls: A pilot study. AB - BACKGROUND/AIM: Australia's National Disability Insurance Scheme (NDIS) is designed to influence home, social and economic participation for Scheme participants. Given the major disability reform underway, this pilot study aimed to: (i) examine community integration outcomes of people with spinal cord injury (SCI); (ii) compare findings with multiple matched controls and (iii) consider findings within the context of Australia's NDIS. METHODS: Setting: Victoria, Australia. DESIGN: Matched analysis (people with and without SCI). INSTRUMENTATION: Community Integration Questionnaire (CIQ). PARTICIPANTS: n = 40 adults with SCI (M age = 52.8 years; 61% male; 77% traumatic SCI). ANALYSES: Matched analyses from each SCI subject aged <70 years (n = 31) with four CIQ normative data subjects (from n = 1927) was undertaken, with key demographic variables matched (age range, gender, living location and living situation). Risk of low CIQ score as a function of SCI was also examined using conditional Poisson regression. RESULTS: With key demographic variables held constant, small to medium effect sizes were found in favour of the normative sample, with statistically significant differences in home (rho = 0.003) and productivity integration (rho = 0.02). Relative risk of low home integration was significant in the SCI cohort (conditional RR (95% CI) = 3.1 (1.5-6.3), rho = 0.001). Relative risk of low CIQ total, social integration and productivity scores did not reach significance. CONCLUSION: This cohort of SCI participants was less integrated into home and productive occupations than matched norms, holding implications for planning and allocation of supports to influence outcomes within an NDIS. Further research is necessary to understand community integration outcomes in larger matched samples. PMID- 28026012 TI - Phosphorus reduces the zinc concentration in cereals pot-grown on calcareous Vertisols from southern Spain. AB - BACKGROUND: Zinc deficiency, a major problem in crops grown on soils low in available Zn, is even more important in phosphorus-rich soils. This work aimed to elucidate the effects of soil P and Zn levels, and of fertilizer application, on yield and Zn concentration in cereal grains. RESULTS: Wheat and barley were successively pot-grown on 20 calcareous Vertisols low in available Zn and ranging widely in available P. Grain yield in the plants grown on the native soils was positively correlated with Olsen P but not with diethylenetriaminepentaacetic acid (DTPA)-extractable Zn except for wheat on P-rich soils. Grain Zn concentration was negatively correlated with Olsen P. Grain Zn uptake differed little among soils. Application of P to the soils increased grain yield insignificantly and P concentration significantly; however, it reduced grain Zn concentration (particularly at low Olsen P values). Applying Zn alone only increased grain Zn concentration, whereas applying P and Zn in combination increased yield and grain Zn concentration at low and high Olsen P values, respectively. CONCLUSION: Applying P alone to plants grown on calcareous Vertisols low in available P and Zn may in practice reduce grain Zn concentrations while not increasing grain yield significantly. (c) 2016 Society of Chemical Industry. PMID- 28026013 TI - Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics. AB - Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women). Subjects with hepatic impairment were required to have chronic, stable hepatic impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-infinity , 0.93 (0.74-1.18) for AUC0-24 h , 0.90 (0.66-1.24) for Cmax , and 0.99 (0.74-1.33) for C24 h . Geometric mean apparent terminal t1/2 was ~18 hours for both groups, whereas median Tmax was 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that moderate hepatic impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and moderate hepatic impairment. PMID- 28026014 TI - Characterization of the nociceptive effect of carrageenan: Masseter versus gastrocnemius. AB - INTRODUCTION: To better understand the pathophysiology of chronic muscle pain, there are multiple animal models that mimic different acute/chronic pain conditions, such as carrageenan injection. Our previous studies demonstrated differences between muscles of different innervation in acute pain. In this study we characterized the effect of carrageenan in 2 muscles: masseter (trigeminal innervation) and gastrocnemius (spinal innervation). METHODS: Carrageenan (3%, 6%, and 9%) was injected into the masseter and gastrocnemius of rats. Mechanical, heat, and chemical nociceptive thresholds were measured for 14 days. RESULTS: Carrageenan did not induce mechanical allodynia or thermal hypersensitivity in either muscle. Instead, it induced a short-lasting mechanical hyperalgesia, greater in the masseter than in the gastrocnemius. CONCLUSION: Carrageenan injected into the masseter and gastrocnemius induces a short-lasting hyperalgesia. These results could indicate a higher susceptibility of orofacial muscles to this type of insult and, consequently, a difference between trigeminal and spinal innervation. Muscle Nerve 56: 804-813, 2017. PMID- 28026015 TI - Design and validation of a RT-qPCR procedure for diagnosis and quantification of most types of infectious pancreatic necrosis virus using a single pair of degenerated primers. AB - Infectious pancreatic necrosis virus (IPNV) is an important virus which affects the salmonid aquaculture industry worldwide; therefore, it is important to develop rapid and reliable methods of diagnosis to detect the disease at early stages. Nowadays, RT-qPCR is replacing other methods because it provides additional information on the viral load, which is important to have a better understanding of the virus replication level and of the stage of the infection and its risk level. The main problem stems from the high diversity of this virus, which can compromise the reliability of the diagnosis. In this study, we have designed an RT-qPCR procedure for diagnosis and quantification of IPNV based on a single pair of primers targeted to segment B. The procedure has been validated, in vitro and in vivo, testing two different types of standards against seven reference strains and 23 field isolates from different types. The procedure is reliable for the detection of any type, with a detection limit of 31 TCID50 mL-1 , 50 pfu mL-1 or 66 RNA copies mL-1 , depending on the standard. All the standard curves showed high reliability (R2 > 0.95). The results support the high reliability of this new procedure for the diagnosis and quantification of IPNV. PMID- 28026016 TI - Design, synthesis, and biological evaluation of cyclic peptidotriazoles derived from BPC194 as novel agents for plant protection. AB - The search for novel antimicrobial agents to be used for plant protection has prompted us to design analogues incorporating non-natural amino acids. Herein, we designed and synthesized cyclic peptidotriazoles derived from the lead antimicrobial cyclic peptide c(Lys-Lys-Leu3 -Lys-Lys5 -Phe-Lys-Lys-Leu-Gln) (BPC194). In particular, Leu3 and Lys5 were replaced by a triazolyl alanine, a triazolyl norleucine or a triazolyl lysine. These peptides were screened for their antibacterial activity against Xanthomonas axonopodis pv. vesicatoria, Erwinia amylovora, and Pseudomonas syringae pv. syringae, for their hemolysis and for their phytotoxicity. Results showed that the type of triazolyl amino acid and the substituent present at the triazole influenced the antibacterial and hemolytic activities. Moreover, the position of this residue was also crucial for the hemolysis. The lead compounds BPC548 and BPC550 exhibited high antibacterial activity (MIC of 3.1 to 25 MUM), low hemolysis (19 and 26% at 375 MUM, respectively) and low phytotoxicity. Therefore, these analogues could be used as new leads for the development of effective agents to control pathogenic bacteria responsible for plant diseases of economic importance. PMID- 28026017 TI - Chemical characterization and in vitro colonic fermentation of grape pomace extracts. AB - BACKGROUND: Currently, there is growing interest in extracts derived from winery by-products because of their beneficial health properties, which are associated with the presence of bioactive compounds. In this paper, we have carried out the chemical characterization and in vitro colonic fermentation of four grape pomace (GP) extracts rich in polyphenols and dietary fibre. RESULT: Firstly, phenolic and dietary fibre composition of the GP extracts was determined. The highest individual phenolic concentrations corresponded to gallic and ellagic acids, followed by catechins and flavonols. The non-digestible fibre fraction ranged from 66% to 83% of the GP extracts, which indicated that they mainly contained non-digestible cell wall components. Secondly, when GP extracts were subjected to fermentation by faecal microbiota, a total of 16 bacterial phenolic metabolites were found in the fermented samples, confirming that polyphenols contained in the GP extracts were metabolized to different active metabolites by microbiota. In addition, the GP extracts tended to promote the growth of intestinal microbiota, although it was only significant for the Enterococcus group. CONCLUSION: These findings, together with other information available in the literature, support the high added value of products obtained from winery by-products. (c) 2016 Society of Chemical Industry. PMID- 28026018 TI - A preliminary investigation into the morphology of oral papillae and denticles of blue sharks (Prionace glauca) with inferences about its functional significance across life stages. AB - Sensory organs in elasmobranchs (sharks, skates, rays) detect and respond to a different set of biotic and/or abiotic stimuli, through sight, smell, taste, hearing, mechanoreception and electroreception. Although gustation is crucial for survival and essential for growth, mobility, and maintenance of neural activity and the proper functioning of the immune system, comparatively little is known about this sensory system in elasmobranchs. Here we present a preliminary investigation into the structural and dimensional characteristics of the oral papillae and denticles found in the oropharyngeal cavity of the blue shark (Prionace glauca) during embryonic development through adulthood. Samples were obtained from the dorsal and ventral surface of the oropharyngeal cavity collected from embryos at different development stages as well as from adults. Our results suggest that development of papillae occurs early in ontogeny, before the formation of the oral denticles. The diameter of oral papillae gradually increases during development, starting from 25 MUm in stage I embryos, to 110 MUm in stage IV embryos and 272-300 MUm in adults. Embryos exhibit papillae at early developmental stages, suggesting that these structures may be important during early in life. The highest density of papillae was observed in the maxillary and mandibular valve regions, possibly related to the ability to identify, capture and process prey. The oral denticles were observed only in the final embryonic stage as well as in adults. Accordingly, we suggest that oral denticles likely aid in ram ventilation (through reducing the hydrodynamic drag), to protect papillae from injury during prey consumption and assist in the retention and consumption of prey (through adhesion), since these processes are only necessary after birth. PMID- 28026019 TI - Activating the AKT2-nuclear factor-kappaB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-kappaB (NF-kappaB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-kappaB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28026020 TI - Low pHo boosts burst firing and catecholamine release by blocking TASK-1 and BK channels while preserving Cav1 channels in mouse chromaffin cells. AB - KEY POINTS: Mouse chromaffin cells (MCCs) generate spontaneous burst-firing that causes large increases of Ca2+ -dependent catecholamine release, and is thus a key mechanism for regulating the functions of MCCs. With the aim to uncover a physiological role for burst-firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pHo ) from 7.4 to 6.6 induces cell depolarizations of 10-15 mV that generate bursts of ~330 ms at 1-2 Hz and a 7.4 fold increase of cumulative catecholamine-release. Burst-firing originates from the inhibition of the pH-sensitive TASK-1-channels and a 60% reduction of BK channel conductance at pHo 6.6. Blockers of the two channels (A1899 and paxilline) mimic the effects of pHo 6.6, and this is reverted by the Cav1 channel blocker nifedipine. MCCs act as pH-sensors. At low pHo , they depolarize, undergo burst-firing and increase catecholamine-secretion, generating an effective physiological response that may compensate for the acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue. ABSTRACT: Mouse chromaffin cells (MCCs) generate action potential (AP) firing that regulates the Ca2+ -dependent release of catecholamines (CAs). Recent findings indicate that MCCs possess a variety of spontaneous firing modes that span from the common 'tonic-irregular' to the less frequent 'burst' firing. This latter is evident in a small fraction of MCCs but occurs regularly when Nav1.3/1.7 channels are made less available or when the Slo1beta2-subunit responsible for BK channel inactivation is deleted. Burst firing causes large increases of Ca2+ -entry and potentiates CA release by ~3.5-fold and thus may be a key mechanism for regulating MCC function. With the aim to uncover a physiological role for burst firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pHo ) from 7.4 to 7.0 and 6.6 induces cell depolarizations of 10-15 mV that generate repeated bursts. Bursts at pHo 6.6 lasted ~330 ms, occurred at 1-2 Hz and caused an ~7-fold increase of CA cumulative release. Burst firing originates from the inhibition of the pH-sensitive TASK-1/TASK-3 channels and from a 40% BK channel conductance reduction at pHo 7.0. The same pHo had little or no effect on Nav, Cav, Kv and SK channels that support AP firing in MCCs. Burst firing of pHo 6.6 could be mimicked by mixtures of the TASK-1 blocker A1899 (300 nm) and BK blocker paxilline (300 nm) and could be prevented by blocking L-type channels by adding 3 MUm nifedipine. Mixtures of the two blockers raised cumulative CA-secretion even more than low pHo (~12-fold), showing that the action of protons on vesicle release is mainly a result of the ionic conductance changes that increase Ca2+ -entry during bursts. Our data provide direct evidence suggesting that MCCs respond to low pHo with sustained depolarization, burst firing and enhanced CA-secretion, thus mimicking the physiological response of CCs to acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue. PMID- 28026021 TI - Identification of a novel FUT1 allele with two mutations in a Chinese para-Bombay individual. AB - BACKGROUND: The para-Bombay phenotype often results from a silenced beta-D galactoside 2-alpha-fucosyltransferase 1 (FUT1) gene (h/h) but an active FUT2 (Se/Se or Se/se) gene. We identified a para-Bombay phenotype with two novel mutations in the FUT1 gene and homozygous mutated FUT2 (se357, 385 /se357, 385 ) genes. STUDY DESIGN AND METHODS: Red blood cell phenotype was detected by using a standard serologic technique. The entire coding regions of the FUT1 and FUT2 genes were amplified and direct sequenced using genomic DNA. RESULTS: No ABH substance was detected on the surface of the proband's red blood cells. Anti-A, anti-B, and anti-H were identified in serum. Genetic studies indicated that the proband's ABO genotyping was A102/O01 and that the FUT2 phenotype was se357, 385 /se357,385 . The sample was homozygous for two FUT1 mutations: c.958insG and c.961G > A. CONCLUSION: Two novel FUT1 mutations have been identified in the proband's FUT1 gene. The insertion mutation in the FUT1 that caused a shift of the open reading frame and formed a termination codon early at Amino Acid Position 334 may be the main reason for H deficiency in this case. PMID- 28026022 TI - Protective responses of intestinal mucous cells in a range of fish-helminth systems. AB - Histopathological, immunofluorescence and ultrastructural studies were conducted on the intestines of four fish species infected with different taxa of enteric helminths. Brown trout (Salmo trutta trutta), eel (Anguilla anguilla) and tench (Tinca tinca) obtained from Lake Piediluco (central Italy) were examined. Brown trout and eel were infected with two species of acanthocephalans, and tench was parasitized with a tapeworm species. In addition to the above site, specimens of chub (Squalius cephalus) and brown trout infected with an acanthocephalan were examined from the River Brenta (north Italy). Moreover, eels were examined from a brackish water, Comacchio lagoons (north Italy), where one digenean species was the predominant enteric worm. All the helminths species induced a similar response, the hyperplasia of the intestinal mucous cells, particularly of those secreting acid mucins. Local endocrine signals seemed to affect the production and secretion of mucus in the parasitized fish, as worms often were surrounded by an adherent mucus layer or blanket. This is the first quantitative report of enteric worm effects on the density of various mucous cell types and on the mucus composition in intestine of infected/uninfected conspecifics. We provide a global comparison between the several fish-helminth systems examined. PMID- 28026023 TI - Effects of long-term ethanol consumption and Aldh1b1 depletion on intestinal tumourigenesis in mice. AB - Ethanol and its metabolite acetaldehyde have been classified as carcinogens for the upper aerodigestive tract, liver, breast, and colorectum. Whereas mechanisms related to oxidative stress and Cyp2e1 induction seem to prevail in the liver, and acetaldehyde has been proposed to play a crucial role in the upper aerodigestive tract, pathological mechanisms in the colorectum have not yet been clarified. Moreover, all evidence for a pro-carcinogenic role of ethanol in colorectal cancer is derived from correlations observed in epidemiological studies or from rodent studies with additional carcinogen application or tumour suppressor gene inactivation. In the current study, wild-type mice and mice with depletion of aldehyde dehydrogenase 1b1 (Aldh1b1), an enzyme which has been proposed to play an important role in acetaldehyde detoxification in the intestines, received ethanol in drinking water for 1 year. Long-term ethanol consumption led to intestinal tumour development in wild-type and Aldh1b1 depleted mice, but no intestinal tumours were observed in water-treated controls. Moreover, a significant increase in DNA damage was detected in the large intestinal epithelium of ethanol-treated mice of both genotypes compared with the respective water-treated groups, along with increased proliferation of the small and large intestinal epithelium. Aldh1b1 depletion led to increased plasma acetaldehyde levels in ethanol-treated mice, to a significant aggravation of ethanol-induced intestinal hyperproliferation, and to more advanced features of intestinal tumours, but it did not affect intestinal tumour incidence. These data indicate that ethanol consumption can initiate intestinal tumourigenesis without any additional carcinogen treatment or tumour suppressor gene inactivation, and we provide evidence for a role of Aldh1b1 in protection of the intestines from ethanol-induced damage, as well as for both carcinogenic and tumour-promoting functions of acetaldehyde, including increased progression of ethanol-induced tumours. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28026024 TI - Loss of dual-specificity phosphatase-2 promotes angiogenesis and metastasis via up-regulation of interleukin-8 in colon cancer. AB - Dual-specificity phosphatase 2 (DUSP2) is a negative regulator of mitogen activated protein kinases. Our previous study showed that DUSP2 expression is down-regulated in many human cancers and loss of DUSP2 promotes cancer progression; however, the underlying mechanism remains largely uncharacterized. Herein, we found that loss of DUSP2 induces angiogenesis, while forced expression of DUSP2 inhibits microvessel formation in xenografted mouse tumours. Genome-wide screening of expression profiles, and meta-analysis of clinical data, identified that the level of interleukin-8 (IL-8) correlated negatively with that of DUSP2, suggesting that it may be a downstream target of DUSP2. Molecular characterization revealed that DUSP2 inversely regulates IL-8 expression, mediated by ERK1/2 and C/EBPalpha-dependent transcriptional regulation. Further study showed that hypoxia-induced IL-8 expression in cancer cells is also mediated via down-regulation of DUSP2. Treatment with the IL-8 receptor inhibitor reparixin or knockdown of IL-8 in cancer cells abolished angiogenesis induced by loss of DUSP2. Functionally, knockdown of DUSP2 enhanced tumour growth and metastasis, which were abolished by treatment with reparixin or knockdown of IL-8 in an orthotopic mouse model. Taken together, our results demonstrate that hypoxia inhibits DUSP2 expression in colon cancer, leading to up-regulation of IL 8, which facilitates angiogenesis and tumour metastasis. Our findings suggest that blocking hypoxia-DUSP2-IL-8 signalling may be a plausible approach for therapeutic intervention in cancer. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28026025 TI - Impact of diabetes on mortality in peripheral artery disease: a meta-analysis. AB - BACKGROUND: There are accumulating studies showing the association between diabetes and all-cause mortality in peripheral vascular disease. However, the results in these studies are conflicting regarding the impact of diabetes on outcome. HYPOTHESIS: Diabetes is associated with increased risk of mortality in peripheral artery disease. METHODS: Using MEDLINE and Scopus, we searched for studies published before January 2016. Additionally, studies were identified by manual search of references of original articles or review studies on this topic. Of the 1072 initially identified records, 21 studies with 15,857 patients were included in the final analysis. RESULTS: Diabetes was associated with a statistically significant increased risk of all-cause mortality (odds ratio: 1.89, 95% confidence interval: 1.51-2.35, P < 0.001), without detected publication bias (Egger bias = 0.75, P = 0.631). The stronger effect on outcome was obtained in patients with critical limb ischemia (odds ratio: 2.38, 95% confidence interval: 1.22-4.63, P < 0.001) as the most severe form of peripheral vascular disease. CONCLUSIONS: Diabetes is associated with an increased risk of mortality in peripheral vascular disease, and the effect is even more pronounced in patients with critical limb ischemia. PMID- 28026026 TI - MAMs are attractive targets for bacterial repurposing of the host cell: MAM functions might be key for undermining an infected cell. AB - Pathogenic bacteria frequently target the endoplasmic reticulum (ER) and mitochondria in order to exploit host functions. ER-mitochondria inter-organelle communication is topologically sub-compartmentalized at mitochondria-associated ER membranes (MAMs). MAMs are specific membranous microdomains with unique regulatory functions such as lipid synthesis and trafficking, calcium homeostasis, mitochondrial morphology, inflammasome activation, autophagosome formation, and apoptosis. These important cellular processes are all modulated by pathogens to subvert host functions and promote infection, thus it is tempting to assume that pathogenic bacteria target MAMs to subvert these different pathways in their hosts. First lines of evidence that support this hypothesis come from Legionella pneumophila. This intracellular bacterium secretes an effector that exhibits sphingosine-1 phosphate lyase activity (LpSpl) that seems to target MAMs to modulate the autophagy response to infection. Here we thus propose the concept that MAMs could be targeted by pathogenic bacteria to undermine key host cellular processes. PMID- 28026027 TI - The contemporary value of peak creatine kinase-MB after ST-segment elevation myocardial infarction above other clinical and angiographic characteristics in predicting infarct size, left ventricular ejection fraction, and mortality. AB - BACKGROUND: Complex multimarker approaches to predict outcome after ST-elevation myocardial infarction (STEMI) have only considered a single baseline sample, while neglecting easily obtainable peak creatine kinase and creatine kinase-MB (CK-MB) values during hospitalization. METHODS: We studied 476 patients undergoing primary percutaneous coronary intervention for STEMI and cardiac magnetic resonance imaging (CMRI) at 4-6 months after STEMI. We determined the association with cardiac biomarkers (peak CK-MB, peak troponin T, N-terminal pro brain natriuretic peptide), clinical and angiographic characteristics with infarct size, and LVEF, followed by association with mortality in 1120 STEMI patients. RESULTS: Peak CK-MB was the strongest predictor for infarct size (P<0.001, R 2 =0.60) and LVEF (P<0.001, R 2 =0.40). The additional value of clinical and angiographic characteristics was limited. The optimal peak CK-MB cutpoints, for differentiation among small (<10% of the left ventricle), moderate (>=10%-<30%), and large infarct size (>=30%), were 210 U/L and 380 U/L, respectively. These cutpoints were associated with 90-day mortality; the hazard ratio for moderate infarct was 2.99 (95% confidence interval [CI]: 1.51-5.93, P=0.002) and for large infarct 6.53 (95% CI: 3.63-11.76, P<0.001). CONCLUSIONS: Classical peak CK-MB measured during hospitalization for STEMI was superior to other clinical and angiographic characteristics in predicting CMRI-defined infarct size and LVEF, and should be included and validated in future multimarker studies. Peak CK-MB cutpoints differentiated among infarct size categories and were associated with increased 90-day mortality risk. PMID- 28026028 TI - Chromatin priming elements establish immunological memory in T cells without activating transcription: T cell memory is maintained by DNA elements which stably prime inducible genes without activating steady state transcription. AB - We have identified a simple epigenetic mechanism underlying the establishment and maintenance of immunological memory in T cells. By studying the transcriptional regulation of inducible genes we found that a single cycle of activation of inducible factors is sufficient to initiate stable binding of pre-existing transcription factors to thousands of newly activated distal regulatory elements within inducible genes. These events lead to the creation of islands of active chromatin encompassing nearby enhancers, thereby supporting the accelerated activation of inducible genes, without changing steady state levels of transcription in memory T cells. These studies also highlighted the need for more sophisticated definitions of gene regulatory elements. The chromatin priming elements defined here are distinct from classical enhancers because they function by maintaining chromatin accessibility rather than directly activating transcription. We propose that these priming elements are members of a wider class of genomic elements that support correct developmentally regulated gene expression. PMID- 28026029 TI - Anti-LGI1 encephalitis is associated with unique HLA subtypes. AB - OBJECTIVE: Autoimmune encephalitis (AE), represented by anti-leucine-rich glioma inactivated 1 (anti-LGI1) and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes. METHODS: We compared the HLA genotypes of 11 anti-LGI1 and 17 anti-NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans. RESULTS: Anti-LGI1 encephalitis was associated with the DRB1*07:01-DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship. INTERPRETATION: This finding suggests that most anti-LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183-192. PMID- 28026030 TI - Evaluation of left ventricular diastolic function profile in patients with pulmonary hypertension due to heart failure with preserved ejection fraction. AB - BACKGROUND: Echocardiography plays an important role in the diagnostic work up of heart failure with preserved ejection fraction (HFpEF). We sought to determine the left ventricular (LV) diastolic profile by echocardiography in patients diagnosed with pulmonary hypertension (PH) due to PH-HFpEF. HYPOTHESIS: The study of LV diastolic function by echocardiography has limitations in patients with HFpEF and PH, and certain LV diastolic determinations convey a worse prognosis. METHODS: We included patients with postcapillary PH and diagnosis of PH-HFpEF. Investigators reviewed Doppler echocardiograms completed within 3 months of the diagnostic right heart catheterization. RESULTS: We included 149 patients with a mean +/- standard deviation age of 63 +/- 14 years; 58% were women. LV diastolic function profile was determined as normal (41%), grade I (34%), and grade II and grade III (25%). Pulmonary artery pressure and pulmonary vascular resistance were higher and cardiac output lower in patients with LV diastolic dysfunction profile; however, pulmonary artery wedge pressure was not significantly different among grades of LV diastolic function. Although there was an association between the presence of LV diastolic dysfunction profile and long-term survival (P = 0.03), it disappeared when adjusting for age and gender. Right ventricular (RV) dysfunction, paradoxical septal motion, and higher RV systolic pressure remained the only variables significantly associated with poor survival. CONCLUSIONS: The profile of LV diastolic dysfunction by conventional echocardiography is highly variable in patients with PH-HFpEF and has no significant impact on long-term survival. A more severe RV function and higher right ventricle systolic pressure were associated with worse survival. PMID- 28026032 TI - The major histocompatibility complex and antibody-mediated limbic encephalitis. PMID- 28026031 TI - Patterns and predictors of lipid-lowering therapy in patients with atherosclerotic cardiovascular disease and/or diabetes mellitus in 2014: Insights from a large US managed-care population. AB - BACKGROUND: Lowering low-density lipoprotein cholesterol with statins reduces risk of cardiovascular events. We examined patterns and predictors of filled prescriptions for lipid-lowering therapy (LLT) in subgroups of patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes mellitus (DM). HYPOTHESIS: Statin treatment remains underutilized across subgroups of high CV risk patients. METHODS: Patients in the Optum Research Database with these criteria were included: age >=20 years, 2 years continuous enrollment, and ASCVD and/or DM. Patients were hierarchically classified by the presence of recent acute coronary syndrome, other coronary heart disease, ischemic stroke, peripheral arterial disease (PAD), or only DM. Predictors of filled LLT regimens were examined using multinomial logistic regression. RESULTS: A total of 1 055 932 individuals met all inclusion criteria. Evidence by point-in-time analysis of filled (not only written) statin prescriptions was 45% for the overall cohort. By subgroups, this was 62%, 52%, 43%, 36%, and 40% for recent acute coronary syndrome, other coronary heart disease, ischemic stroke, PAD, and only DM, respectively. Predictors of higher rates of any statin regimen included age 50 to 69 years, male sex, absence of comorbidities, and filled prescriptions of other standard-of-care therapies. CONCLUSIONS: In 2014, only 49% of patients with ASCVD and 40% with only DM had evidence for a filled statin prescription. Those with indications of ischemic stroke, PAD, and DM were less likely to receive statins than those with coronary conditions. Other characteristics such as advanced age, female sex, and noncardiac conditions predicted less statin utilization, thereby representing good targets for quality improvement. PMID- 28026033 TI - Complete type of pachydermoperiostosis with a novel mutation c.510G>A of the SLCO2A1 gene. PMID- 28026034 TI - Case of lupus erythematosus panniculitis triggered by human papillomavirus quadrivalent vaccine injection. PMID- 28026035 TI - Clinical features of Korean patients with rhinophyma. AB - Rhinophyma results from hyperplasia of the sebaceous glands and connective tissue. Clinical features in Asian rhinophyma patients are largely underreported. In this study, we aimed to evaluate the clinical features of rhinophyma in Korean patients. We reviewed clinical photos and medical records of 39 Korean patients diagnosed with rhinophyma and assessed the severity and clinical course by using the classical National Rosacea Society index. The male : female ratio was 6.8:1, and over 90% of the patients were older than 40 years. The mild-grade rhinophyma was the most dominant (46.1%), followed by the moderate (41.0%) and severe (12.8%) grades. Disease progression to severe grade occurred over an average of 8.2 years. Furthermore, 70% of all cases revealed lesion distribution limited to the nose. As disease severity progressed to higher grades, the extent of nasal involvement increased (Pearson correlation coefficient, 0.685). Rhinophyma is a slowly progressing disease showing male predominance unrelated to specific trigger factors. In many cases, this disease often exclusively affects the nose in Asian patients. PMID- 28026036 TI - The re-emerging arboviral threat: Hidden enemies: The emergence of obscure arboviral diseases, and the potential use of Wolbachia in their control. AB - Mayaro, Oropouche, and O'Nyong-Nyong share many traits with more prominent arboviruses, like dengue and yellow fever, chikungunya, and Zika. These include severe clinical symptoms, multiple animal hosts, and widespread vector species living in close proximity to human habitats, all of which constitute significant risk factors for more frequent outbreaks in the future, greatly increasing the potential of these hidden enemies to follow Zika and become the next wave of global arboviral threats. Critically, the current dearth of knowledge on these arboviruses might impede the success of future control efforts, including the potential application of Wolbachia pipientis. This bacterium inherently possesses broad anti-pathogen properties and a means of genetic drive that allows it to eliminate or replace target vector populations. We conclude that control of obscure arboviruses with Wolbachia might be possible, but successful implementation will be critically dependent on the ability to transinfect key vector species. PMID- 28026037 TI - Relative contributions of testosterone deficiency and metabolism syndrome at the risk of reduced quality of life: A cross-sectional study among Chinese mid-aged and elderly men. AB - Testosterone deficiency and metabolism syndrome (MetS) are universal among ageing males, and they have been suggested responsible for poorer quality of life (QoL). We aimed to evaluate the relative contributions of reproductive hormones and components of MetS at the risk of reduced QoL among Chinese mid-aged and elderly men. A cross-sectional study recruited 2,364 males aged 40-79 years, and 2,165 was included for analysis eventually. The Chinese version of ageing male symptoms scale, 36-item Short Form and Beck Depression Inventory were applied to assess QoL. Bivariate correlation analysis and multiple linear regression analysis were used to assess the relative contributions of reproductive hormones and components of MetS at the risk of reduced QoL. Testosterone deficiency and MetS contributed to poorer QoL, of which higher fasting blood glucose made the primary contribution, lower total testosterone mainly contributed to poorer physical functioning. PMID- 28026038 TI - Cutaneous adverse reaction of mogamulizumab, an anti-CC chemokine receptor 4 monoclonal antibody: Shared histopathological features with thymoma-associated multi-organ autoimmunity. PMID- 28026039 TI - Positive correlation of vanilloid receptor subtype1 and prostaglandin E2 expression with pain in leiomyomas. AB - Cutaneous leiomyomas are benign smooth muscle tumors that are occasionally painful. The mechanism of pain related to leiomyoma is not fully understood. To investigate the possible involvement of algoneic factors in pain from cutaneous leiomyomas. We present a case of cutaneous leiomyoma with severe, diffused pain in a large area and collected 10 more specimens of cutaneous leiomyoma with or without pain in patient histories. We immunohistochemiacally examined the expression of algoneic factors: serotonin, histamin, Substance P, PGE2, BDKRB2, VR1 and CGRP. We compared the pain area and expression of algoneic factors to reveal possible correlations. We describe here a patient with a cutaneous leiomyoma 1-cm in diameter, which caused severe pain diffused throughout an area of 20-cm around the tumor. The pain completely resolved after surgical excision of the leiomyoma. We observed that the leiomyoma cells expressed CGRP, PGE2 and VR1 in this case. We found a positive correlation between VR1 and PGE2 expression in the leiomyoma cells and areas with pain around the tumors among 11 specimens in total. VR1 and PGE2 might be key algogenic substances in painful leiomyoma. PMID- 28026040 TI - Forces positioning the mitotic spindle: Theories, and now experiments. AB - The position of the spindle determines the position of the cleavage plane, and is thus crucial for cell division. Although spindle positioning has been extensively studied, the underlying forces ultimately responsible for moving the spindle remain poorly understood. A recent pioneering study by Garzon-Coral et al. uses magnetic tweezers to perform the first direct measurements of the forces involved in positioning the mitotic spindle. Combining this with molecular perturbations and geometrical effects, they use their data to argue that the forces that keep the spindle in its proper position for cell division arise from astral microtubules growing and pushing against the cell's cortex. Here, we review these ground-breaking experiments, the various biomechanical models for spindle positioning that they seek to differentiate, and discuss new questions raised by these measurements. PMID- 28026043 TI - THE EARLY HOME ENVIRONMENT OF LATINO BOYS AND THEIR PEERS: A DEVELOPMENTAL PERSPECTIVE. AB - Using a sample (N = 5,200) drawn from the Early Childhood Longitudinal Study Birth Cohort, we examined Latino boys' developmental profiles and their early home experiences from 9 months to kindergarten entry in comparison to their peers Latina girls and White boys. We also examined how children's early home experiences related to outcomes at kindergarten entry and whether these varied by gender and ethnicity. Controlling for socioeconomic indicators, the largest mean group differences were between Latino and White boys, beginning at 24 months and persisting at kindergarten entry. There were modest differences between Latino boys and Latina girls on some outcomes, with boys showing an early and persistent advantage in math and girls showing a persistent advantage in social skills. Household resources and maternal and paternal investments in literacy activities were the strongest predictors of children's preacademic skills at kindergarten entry. Our model did not vary by gender or ethnicity, suggesting that the ingredients for learning are the same for all children. PMID- 28026042 TI - EARLY CHILDHOOD PREDICTORS OF LOW-INCOME BOYS' PATHWAYS TO ANTISOCIAL BEHAVIOR IN CHILDHOOD, ADOLESCENCE, AND EARLY ADULTHOOD. AB - Guided by a bridging model of pathways leading to low-income boys' early starting and persistent trajectories of antisocial behavior, the current article reviews evidence supporting the model from early childhood through early adulthood. Using primarily a cohort of 310 low-income boys of families recruited from Women, Infants, and Children Nutrition Supplement centers in a large metropolitan area followed from infancy to early adulthood and a smaller cohort of boys and girls followed through early childhood, we provide evidence supporting the critical role of parenting, maternal depression, and other proximal family risk factors in early childhood that are prospectively linked to trajectories of parent-reported conduct problems in early and middle childhood, youth-reported antisocial behavior during adolescence and early adulthood, and court-reported violent offending in adolescence. The findings are discussed in terms of the need to identify at-risk boys in early childhood and methods and platforms for engaging families in healthcare settings not previously used to implement preventive mental health services. PMID- 28026041 TI - Emerging therapies and challenges in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368. PMID- 28026044 TI - Expression of programmed cell death-1 and its ligand B7 homolog 1 in peripheral blood lymphocytes from patients with peripartum cardiomyopathy. AB - BACKGROUND: Immune response has been postulated to play a prominent role in the pathogenesis of peripartum cardiomyopathy (PPCM). Given the importance of programmed death (PD)-1 and its ligand B7 homologue 1 (B7-H1) costimulatory molecules as an immune regulatory pathway, this study aimed to investigate the effect of PD-1 and B7-H1 expression on immune response in peripheral blood lymphocytes from the patients with PPCM. HYPOTHESIS: PD-1 and B7-H1 may be involved in modulating immune response in PPCM. METHODS: Peripheral blood lymphocytes were obtained from PPCM and pregnancy-matched healthy women. PD-1 and B7-H1 expression were determined using fluorescence quantitative reverse transcription-polymerase chain reactions (RT-PCR) and Western blot. The presence of serum interferon (IFN)-gamma and interleukin (IL)-4 were determined with enzyme-linked immunosorbent assay. RESULTS: The levels of pro-brain natriuretic peptide and IFN-gamma were markedly elevated, whereas the levels of left ventricular ejection fraction and IL-4 were significantly reduced in PPCM patients compared to controls. Additionally, both RT-PCR and Western blot revealed that the levels of PD-1 and B7-H1 expression were decreased significantly in PPCM patients compared with controls. A significant positive correlation was observed between PD-1 and B7-H1 expression. Furthermore, PD-1 and B7-H1 expression showed significant negative correlation with IFN-gamma, as well as positive correlation with IL-4. Therefore, decreased expression of PD-1 and B7 H1 led to a dysregulating immune response such that cellular immunity linked to T helper (Th)1 cells was predominant over humoral immunity linked to Th2 cells in PPCM. CONCLUSIONS: This study provided the first findings that PD-1 and B7-H1 expression were decreased, which might impair functional regulation of negative costimulation on immune response that may work in the etiopathogenesis of PPCM. PMID- 28026045 TI - Differentiating regressed melanoma from regressed lichenoid keratosis. AB - BACKGROUND: Distinguishing regressed lichen planus-like keratosis (LPLK) from regressed melanoma can be difficult on histopathologic examination, potentially resulting in mismanagement of patients. OBJECTIVE: We aimed to identify histopathologic features by which regressed melanoma can be differentiated from regressed LPLK. METHODS: Twenty actively inflamed LPLK, 12 LPLK with regression and 15 melanomas with regression were compared and evaluated by hematoxylin and eosin staining as well as Melan-A, microphthalmia transcription factor (MiTF) and cytokeratin (AE1/AE3) immunostaining. RESULTS: (1) A total of 40% of regressed melanomas showed complete or near complete loss of melanocytes within the epidermis with Melan-A and MiTF immunostaining, while 8% of regressed LPLK exhibited this finding. (2) Necrotic keratinocytes were seen in the epidermis in 33% regressed melanomas as opposed to all of the regressed LPLK. (3) A dense infiltrate of melanophages in the papillary dermis was seen in 40% of regressed melanomas, a feature not seen in regressed LPLK. CONCLUSIONS: In summary, our findings suggest that a complete or near complete loss of melanocytes within the epidermis strongly favors a regressed melanoma over a regressed LPLK. In addition, necrotic epidermal keratinocytes and the presence of a dense band-like distribution of dermal melanophages can be helpful in differentiating these lesions. PMID- 28026046 TI - Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4. AB - Leucine-rich glioma-inactivated1 (LGI1) encephalitis is an antibody-associated inflammation of the limbic area. An autoimmune etiology is suspected but not yet proven. We performed human leukocyte antigen (HLA) analysis in 25 nontumor anti LGI1 patients and discovered a remarkably strong HLA association. HLA-DR7 was present in 88% compared to 19.6% in healthy controls (p = 4.1 * 10-11 ). HLA-DRB4 was present in all patients and in 46.5% controls (p = 1.19 * 10-7 ). These findings support the autoimmune hypothesis. An exploratory analysis was performed in a small group of 4 tumor-LGI1 patients. The strong HLA association seems not applicable in these patients. Therefore, the absence of HLA-DR7 or HLA-DRB4 could raise tumor suspicion in anti-LGI1 patients. Ann Neurol 2017;81:193-198. PMID- 28026047 TI - RF-EMF exposure at 1800 MHz did not elicit DNA damage or abnormal cellular behaviors in different neurogenic cells. AB - Despite many years of studies, the debate on genotoxic effects of radiofrequency electromagnetic fields (RF-EMF) continues. To systematically evaluate genotoxicity of RF-EMF, this study examined effects of RF-EMF on DNA damage and cellular behavior in different neurogenic cells. Neurogenic A172, U251, and SH SY5Y cells were intermittently (5 min on/10 min off) exposed to 1800 MHz RF-EMF at an average specific absorption rate (SAR) of 4.0 W/kg for 1, 6, or 24 h. DNA damage was evaluated by quantification of gammaH2AX foci, an early marker of DNA double-strand breaks. Cell cycle progression, cell proliferation, and cell viability were examined by flow cytometry, hemocytometer, and cell counting kit-8 assay, respectively. Results showed that exposure to RF-EMF at an SAR of 4.0 W/kg neither significantly induced gammaH2AX foci formation in A172, U251, or SH-SY5Y cells, nor resulted in abnormal cell cycle progression, cell proliferation, or cell viability. Furthermore, prolonged incubation of these cells for up to 48 h after exposure did not significantly affect cellular behavior. Our data suggest that 1800 MHz RF-EMF exposure at 4.0 W/kg is unlikely to elicit DNA damage or abnormal cellular behaviors in neurogenic cells. Bioelectromagnetics. 38:175-185, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026048 TI - Consideration of different heating lengths of needles with induction heating and resistance system: A novel design of needle module for thermal ablation. AB - Thermal ablation using alternating electromagnetic fields is a promising method to treat tissues including tumors. With this approach, an electromagnetic field is generated around an induction coil, which is supplied with high frequency current from a power source. Any electrically conducting object, which is placed in the electromagnetic field, is then heated due to eddy currents. Basic principles underlying this novel thermotherapy needle system are internal induction and resistance heating. This presents a new design of a standard gauge 18 percutaneous trans-hepatic cholangiography needle module combined with a compact power source. Three needle modules containing coils of different lengths were used to locally heat up different volumes of tissues in in vitro experiments on pig livers. Temperature on the inside surface of the needle was controlled and monitored through a K-type thermocouple. By using this needle module system, no two-section or ferromagnetic nanoparticle-coated needles were required; the system worked well with the SUS-304 stainless-steel needle. Successful results were demonstrated in the in vitro experiments on pig livers with different heating lengths of 10, 20, and 30 mm needles. With low power sources, needles could be heated up to a high temperature. The novel design of the needle module incorporated with a high frequency power source was thus shown to be a promising technology for tissue ablation. Bioelectromagnetics.38:220-226, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026049 TI - Assessment of polarization dependence of body shadow effect on dosimetry measurements in 2.4 GHz band. PMID- 28026050 TI - Case of late-onset erythropoietic protoporphyria with myelodysplastic syndrome who has homozygous IVS3-48C polymorphism in the ferrochelatase gene. AB - We report the case of a 42-year-old man with a 5-year history of myelodysplastic syndrome and photosensitivity who had developed painful erythema and blisters on sun-exposed sites. Histological examination of a mildly lichenified lesion on the dorsal finger revealed extensive deposits of a hyaline-like, periodic acid-Schiff positive material around superficial dermal blood vessels. Laboratory tests showed elevated erythrocyte protoporphyrin and normal urinary porphyrins, suggesting a diagnosis of erythropoietic protoporphyria. Late-onset erythropoietic protoporphyria is rare and is usually associated with an acquired somatic mutation of the ferrochelatase gene secondary to a hematological malignancy such as myelodysplastic syndrome. DNA analysis revealed that our patient has the homozygous IVS3-48C polymorphism that is a low-expression variant of wild-type ferrochelatase allele. PMID- 28026051 TI - The effects of electromagnetic fields on B16-BL6 cells are dependent on their spatial and temporal character. AB - Exposure to low intensity, low frequency electromagnetic fields (EMF) has effects on several biological systems. Spatiotemporal characteristics of these EMFs are critical. The effect of several complex EMF patterns on the proliferation of B16 BL6 mouse melanoma cells was tested. Exposure to one of these patterns, the Thomas-EMF, inhibited cell proliferation and promoted calcium uptake. The Thomas EMF is coded from a digital-to-analog file comprised of 849 points, which provides power to solenoids and can be set to alter timing, intensity, and duration of variable EMF. Setting the point duration to 3 ms generated a time varying EMF pattern which began at 25 Hz and slowed to 6 Hz over a 2.5 s repeat. Exposing B16-BL6 cells to Thomas-EMF set to 3 ms for 1 h/day inhibited cell proliferation by 40% after 5 days, while setting the point duration to 1, 2, 4, or 5 ms had no effect on cell proliferation. Similarly, exposing cells to Thomas EMF set to 3 ms promoted a three-fold increase in calcium uptake after 1 h, while the other timings had no effect. Exposure to Thomas-EMF for as short as 15 min/day slowed cell proliferation, but exposure for 1 h/day was optimal. This corresponded to the effect on calcium uptake where uptake was detected after 15 min exposure and was maximal by 1 h of treatment. Studies show that the specific spatiotemporal character of EMF is critical in mediating their biological activities. Bioelectromagnetics. 38:165-174, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026052 TI - tRNA biology in the omics era: Stress signalling dynamics and cancer progression. AB - Recent years have seen a burst in the number of studies investigating tRNA biology. With the transition from a gene-centred to a genome-centred perspective, tRNAs and other RNA polymerase III transcripts surfaced as active regulators of normal cell physiology and disease. Novel strategies removing some of the hurdles that prevent quantitative tRNA profiling revealed that the differential exploitation of the tRNA pool critically affects the ability of the cell to balance protein homeostasis during normal and stress conditions. Furthermore, growing evidence indicates that the adaptation of tRNA synthesis to cellular dynamics can influence translation and mRNA stability to drive carcinogenesis and other pathological disorders. This review explores the contribution given by genomics, transcriptomics and epitranscriptomics to the discovery of emerging tRNA functions, and gives insights into some of the technical challenges that still limit our understanding of the RNA polymerase III transcriptional machinery. PMID- 28026053 TI - Nanoarchitectured Design of Porous Materials and Nanocomposites from Metal Organic Frameworks. AB - The emergence of metal-organic frameworks (MOFs) as a new class of crystalline porous materials is attracting considerable attention in many fields such as catalysis, energy storage and conversion, sensors, and environmental remediation due to their controllable composition, structure and pore size. MOFs are versatile precursors for the preparation of various forms of nanomaterials as well as new multifunctional nanocomposites/hybrids, which exhibit superior functional properties compared to the individual components assembling the composites. This review provides an overview of recent developments achieved in the fabrication of porous MOF-derived nanostructures including carbons, metal oxides, metal chalcogenides (metal sulfides and selenides), metal carbides, metal phosphides and their composites. Finally, the challenges and future trends and prospects associated with the development of MOF-derived nanomaterials are also examined. PMID- 28026054 TI - Ruthenium-Ruthenium-Bonded [Bis{corrolato-ruthenium(III)}]n (n=0, +1, -1) Complexes: Model Compounds for the Photosynthetic Special Pair. AB - We present herein the synthesis of three new bis(corrolato-ruthenium(III)) complexes containing unsupported Ru-Ru bonds and their characterization in different redox states. The 1 H NMR spectra of the bis(corrolato-ruthenium(III)) complexes displayed "normal" chemical shifts and the compounds proved to be EPR silent. Crystallographic characterization of the dimers indicated Ru-Ru distances of 2.175 A, consistent with a triple bond between the two ruthenium centers. All of the synthesized complexes undergo two successive reversible oxidations and a single reversible reduction. A combination of UV/Vis/NIR/EPR spectroelectrochemical studies and DFT calculations established the redox state distributions in these ruthenium-ruthenium-bonded dimers. Whereas reduction of the dimers is metal-based and leads to metal-metal-bonded mixed-valent RuII RuIII species, one-electron oxidation largely retains the RuIII -RuIII situation with the generation of metal-bound corrolato radicals. The present study thus concerns the first UV/Vis/NIR/EPR spectroelectrochemical characterization and DFT calculations of ruthenium-ruthenium-bonded rotationally ordered corrole dimers. The mean plane separation between the two corrole units in these dimers is around 3.543 A, which is in close agreement to that in the "special pair" in chlorophyll. Oxidation of these ruthenium-ruthenium-bonded dimers gives rise to two new electronic absorption bands in the NIR region (similar to those of the special pair), which have apparently not been mentioned/observed in earlier reports on ruthenium-ruthenium-bonded corrole dimers. These bands mainly originate from inter-corrole transitions. PMID- 28026055 TI - Fertility preservation counselling in Dutch Oncology Practice: Are nurses ready to assist physicians? AB - Cancer and its treatments may result in impaired fertility, which could cause long-term distress to cancer survivors. For eligible patients, fertility preservation (FP) is available to secure future reproductive potential. Many physicians, however, feel inhibited about discussing FP. Oncology nurses may serve as an initiator for discussing the subject and provide additional support. Our aim was to investigate their knowledge about FP, the way they apply this, and possible barriers to discussing FP with patients of reproductive age. A questionnaire was administered via mail, Internet and the Dutch Oncology Nursing Congress. Four hundred and twenty-one oncology nurses participated, a third of whom (31.1%) had "sufficient" knowledge of FP. Twenty-eight per cent of participants reported that they "never/hardly ever" discussed FP; 32.2% "almost always/always." FP discussions were more frequently performed by graduate nurses, academic nurses, experienced nurses and nurses with sufficient knowledge. Reasons for not discussing FP were a "lack of knowledge" (25.2%), "poor prognosis" (16.4%) and "lack of time" (10.5%). In conclusion, several obstacles may result in FP not being routinely discussed, specifically a lack of knowledge. Yet nurses feel responsible for addressing the issue, indicating that assistance with FP discussions should be encouraged. Educational training about FP is recommended. PMID- 28026056 TI - Atomically and Electronically Coupled Pt and CoO Hybrid Nanocatalysts for Enhanced Electrocatalytic Performance. AB - Atomically and electronically coupled Pt and CoO hybrid nanocatalysts are fabricated for electrocatalytic oxygen reduction reaction. The atomic coupling between the Pt and the CoO endows precise control of the atomic interface between the Pt and the CoO, which directly results in electron donation from the CoO to the Pt, and thus favorable tuning of the electronic structure of the Pt. PMID- 28026057 TI - Functioning of people with colorectal cancer during chemotherapy. Demographic and clinical determinants of quality of life of patients with colorectal cancer receiving chemotherapy. Pilot study. AB - Cancer of the colon is one of the most common malignant tumours in both genders. Thanks to the development of diagnostic techniques, lesions can be detected early fostering full patient's recovery. The aim of this study was to investigate factors affecting quality of life of patients with colorectal cancer (CRC) during chemotherapy. The research tool was a questionnaire of our own design that allows collecting demographic and clinical data and Functional Assessment of Cancer Therapy Scale-Colorectal (FACT-C). The study included 90 patients. The analysis confirmed the difference between Social-Family Well-Being (SWB) and Emotional Well-Being (EWB) and in the overall assessment of quality of life and age. Taking into account the presence of stoma, a statistically significant difference was found only in the Colorectal Cancer Subscale (CCS p = .01321). Regarding the number of cycles of chemotherapy, a statistically significant difference was shown in the overall evaluation (p = .0459) and the SWB (p = .0463) area. In patients with CRC in the general assessment of quality of life, which is at a medium level, non-modifiable factors like age and gender play a minor role when compared with the group of variables related to the process and treatment of the disease. PMID- 28026058 TI - Reversibly Photoswitchable Supramolecular Assembly and Its Application as a Photoerasable Fluorescent Ink. AB - A photoswitchable supramolecular assembly can efficiently and reversibly switch on/off the luminescence of the [Ru(bpy)3]2+ center upon irradiation by light with different wavelengths in solution and the solid state. The assembly possesses reversible photoisomerization and a high Forster resonance energy transfer efficiency, and when used as an ink it can be reversibly and repeatedly erased and recovered by altering the wavelength of irradiation light. PMID- 28026059 TI - Highly Reversible and Durable Na Storage in Niobium Pentoxide through Optimizing Structure, Composition, and Nanoarchitecture. AB - Amorphous, hydrogenated, and self-ordered nanoporous Nb2 O5 films serve as an excellent binder-free electrode for sodium batteries, affording a high and sustainable capacity delivery and robust high-rate capability. This collaborative material engineering of structural order (amorphization), composition (hydrogenation), and architecture (ordered nanopore) opens up new possibilities to develop an energy storage solution that is more accessible, sustainable, and producible. PMID- 28026060 TI - Alkene Metalates as Hydrogenation Catalysts. AB - First-row transition-metal complexes hold great potential as catalysts for hydrogenations and related reductive reactions. Homo- and heteroleptic arene/alkene metalates(1-) (M=Co, Fe) are a structurally distinct catalyst class with good activities in hydrogenations of alkenes and alkynes. The first syntheses of the heteroleptic cobaltates [K([18]crown-6)][Co(eta4 -cod)(eta2 styrene)2 ] (5) and [K([18]crown-6)][Co(eta4 -dct)(eta4 -cod)] (6), and the homoleptic complex [K(thf)2 ][Co(eta4 -dct)2 ] (7; dct=dibenzo[a,e]cyclooctatetraene, cod=1,5-cyclooctadiene), are reported. For comparison, two cyclopentadienylferrates(1-) were synthesized according to literature procedures. The isolated and fully characterized monoanionic complexes were competent precatalysts in alkene hydrogenations under mild conditions (2 bar H2 , r.t., THF). Mechanistic studies by NMR spectroscopy, ESI mass spectrometry, and poisoning experiments documented the operation of a homogeneous mechanism, which was initiated by facile redox-neutral pi-ligand exchange with the substrates followed by H2 activation. The substrate scope of the investigated precatalysts was also extended to polar substrates (ketones and imines). PMID- 28026061 TI - Detection of smoke-induced pulmonary lesions by hyperpolarized 129 Xe diffusion kurtosis imaging in rat models. AB - PURPOSE: To demonstrate that hyperpolarized (HP) xenon diffusion kurtosis imaging (DKI) is able to detect smoke-induced pulmonary lesions in rat models. METHODS: Multi-b DKI with hyperpolarized xenon was used for the first time in five smoke exposed rats and five healthy rats. Additionally, DKI with b values of up to 80 s/cm2 were used in two healthy rats to probe the critical b value (a limit beyond which the DKI cannot describe the non-Gaussian diffusion). RESULTS: The mean apparent diffusion coefficient (Dapp ) and diffusion kurtosis (Kapp ) extracted by the DKI model revealed significant changes in the smoke-exposed rats compared with those in the control group (P = 0.027 and 0.039, respectively), exhibiting strong correlations with mean linear intercept (Lm ) from the histology. Although the maximum b value was increased to 80 s/cm2 , the DKI could still describe the non-Gaussian diffusion (R2 > 0.97). CONCLUSION: DKI with hyperpolarized xenon exhibited sensitivity in the detection of pulmonary lesions induced by smoke, including moderate emphysema and small airway diseases. The critical b value was rarely exceeded in DKI of the lungs due to the limited gradient strength of the MRI scanner used in our study. Magn Reson Med 78:1891-1899, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 28026062 TI - Addressing recent docking challenges: A hybrid strategy to integrate template based and free protein-protein docking. AB - Protein-protein docking is an important computational tool for predicting protein protein interactions. With the rapid development of proteomics projects, more and more experimental binding information ranging from mutagenesis data to three dimensional structures of protein complexes are becoming available. Therefore, how to appropriately incorporate the biological information into traditional ab initio docking has been an important issue and challenge in the field of protein protein docking. To address these challenges, we have developed a Hybrid DOCKing protocol of template-based and template-free approaches, referred to as HDOCK. The basic procedure of HDOCK is to model the structures of individual components based on the template complex by a template-based method if a template is available; otherwise, the component structures will be modeled based on monomer proteins by regular homology modeling. Then, the complex structure of the component models is predicted by traditional protein-protein docking. With the HDOCK protocol, we have participated in the CPARI experiment for rounds 28-35. Out of the 25 CASP-CAPRI targets for oligomer modeling, our HDOCK protocol predicted correct models for 16 targets, ranking one of the top algorithms in this challenge. Our docking method also made correct predictions on other CAPRI challenges such as protein-peptide binding for 6 out of 8 targets and water predictions for 2 out of 2 targets. The advantage of our hybrid docking approach over pure template-based docking was further confirmed by a comparative evaluation on 20 CASP-CAPRI targets. Proteins 2017; 85:497-512. (c) 2016 Wiley Periodicals, Inc. PMID- 28026063 TI - Materials with Giant Mechanocaloric Effects: Cooling by Strength. AB - The search for materials with large caloric effects has become a major challenge in material science due to their potential in developing near room-temperature solid-state cooling devices, which are both efficient and clean, and that can successfully replace present refrigeration technologies. There are three main families of caloric materials: magnetocaloric, electrocaloric, and mechanocaloric. While magnetocaloric and electrocaloric materials have been studied intensively in the last few decades, mechanocaloric materials are only very recently receiving a great deal of attention. The mechanocaloric effect refers to the reversible thermal response of a solid when subjected to an external mechanical field, and encompasses both the elastocaloric effect, corresponding to a uniaxial force, and the barocaloric effect, which corresponds to the response to hydrostatic pressure. Here, the state of the art in giant mechanocaloric effects is reviewed and a critical analysis of the thermodynamic quantities that characterize the major families of barocaloric and elastocaloric materials is provided. Finally perspectives for further development in this area are given. PMID- 28026064 TI - Paramagnetic Properties of Metal-Free Boron-Doped Graphene Quantum Dots and Their Application for Safe Magnetic Resonance Imaging. AB - A boron-doped graphene quantum dot (B-GQD) as a metal-free multimodal contrast agent (CA) for safe magnetic resonance imaging and fluorescence imaging is reported. In vivo T1 -weighted magnetic resonance images show that B-GQDs induce significant contrast enhancement on the heart, liver, spleen, and kidney, and sustain for more than 1 h, about 10 times longer than Gd-based CAs currently used in clinic. PMID- 28026065 TI - A Mixed-Extractor Strategy for Efficient Sorting of Semiconducting Single-Walled Carbon Nanotubes. AB - A general strategy for sorting semiconducting single-walled carbon nanotubes (s SWNTs) with high efficiency using a mixed-extractor is reported. When the two extractors have a sufficient difference in binding energy with s-SWNTs, and skeleton flexibility, the mixture shows enhanced yield for sorting s-SWNTs. The strategy could be effective when applied to increase the sorting yield of other selective dispersion systems. PMID- 28026066 TI - Programmable Kiri-Kirigami Metamaterials. AB - Programmable kirigami metamaterials with controllable local tilting orientations on demand through prescribed notches are constructed through a new approach of kiri-kirgami, and their actuation of pore opening via both mechanical stretching and temperature, along with their potential application as skins for energy saving buildings, is discussed. PMID- 28026067 TI - Fuel-Free Synthetic Micro-/Nanomachines. AB - Inspired by the swimming of natural microorganisms, synthetic micro /nanomachines, which convert energy into movement, are able to mimic the function of these amazing natural systems and help humanity by completing environmental and biological tasks. While offering autonomous propulsion, conventional micro /nanomachines usually rely on the decomposition of external chemical fuels (e.g., H2 O2 ), which greatly hinders their applications in biologically relevant media. Recent developments have resulted in various micro-/nanomotors that can be powered by biocompatible fuels. Fuel-free synthetic micro-/nanomotors, which can move without external chemical fuels, represent another attractive solution for practical applications owing to their biocompatibility and sustainability. Here, recent developments on fuel-free micro-/nanomotors (powered by various external stimuli such as light, magnetic, electric, or ultrasonic fields) are summarized, ranging from fabrication to propulsion mechanisms. The applications of these fuel free micro-/nanomotors are also discussed, including nanopatterning, targeted drug/gene delivery, cell manipulation, and precision nanosurgery. With continuous innovation, future autonomous, intelligent and multifunctional fuel-free micro /nanomachines are expected to have a profound impact upon diverse biomedical applications, providing unlimited opportunities beyond one's imagination. PMID- 28026068 TI - Predictors of breast self-examination performance among Jordanian university female students. AB - Breast cancer is considered one of the main types of cancer among female worldwide and in Jordan also. Early detection of it will improve the prognosis and decrease the mortality rate also. Thus, this study was conducted to assess the predictors of breast self-examination performance among Jordanian university female students. Across-sectional design was utilised in this study. A sample of 100 participants was completed the study survey (The Champion's Health Belief Model Scale). The main results or regression analysis showed that confidence (beta = .71, p < .0001) and perceived barriers (beta = -.061, p = .0004) were significant predictors of breast self-examination performance. In summary, other variables of Health belief model were found not be significant indicators of BSE performance in this study. However, the HBM is considered a valid framework to assess the predictors of breast self-examination knowledge, attitude, beliefs and barriers among Jordanian college female students. PMID- 28026069 TI - Written information material and availability of sexual health care for men experiencing sexual dysfunction after prostate cancer treatment: An evaluation of Dutch urology and radiotherapy departments. AB - Objective was to investigate content of written information material and availability of sexual health care for men experiencing sexual dysfunction (SD) after prostate cancer treatment. A cross-sectional survey was conducted among Dutch urology and radiotherapy departments to evaluate information materials and availability of sexual health care. Out of 71 eligible departments, 34 urology and 15 radiotherapy departments participated in the survey (response rate 69.0%). Fifty-nine brochures corresponding to 31 urology and 11 radiotherapy departments were analysed. In 88.1% of collected information material, sexual health was mentioned. Regarding extensiveness, 20.4% of the brochures contained extensive information, 50.8% moderate amount of information and 28.8% contained little or no information. Urology departments provided pre-treatment nurse consultations more often than radiotherapy departments. Sexual counselling was more frequently provided by urology departments. Urology departments were more aware of adequate referral possibilities. Information material provided by Dutch urology and radiotherapy departments does not address treatment-related SD routinely. Sexual health care is not available everywhere for men experiencing SD. Applying a standard regarding content of sexual health in information material is recommended as well as improved awareness of referral possibilities and enhanced provision of pre-treatment nurse consultations for men experiencing SD after prostate cancer treatment. PMID- 28026070 TI - Cancer-related pain management: A review of knowledge and attitudes of healthcare professionals. AB - Cancer-related pain (CRP) is common and many patients continue to experience pain in spite of advances in pain management modalities. The lack of knowledge, inadequate assessment of CRP and/or organisational factors, such as lack of time due to heavy workload, can be a barrier to effective pain management of healthcare professionals. The purpose was to examine the evidence with regard to the knowledge and attitudes towards practice of healthcare professionals in relation to CRP management. A search of the literature (1999-2015) was conducted searching databases and journals including CINAHL, MEDLINE, PsycINFO, PubMed, Science Direct and Wiley-Blackwell. The initial search revealed a total of 99 articles and following removal of those that did not meet the inclusion criteria, 19 articles were included in the final review. Recognition of the widespread under treatment of CRP has prompted recent corrective efforts in terms of education from healthcare professionals, however, there is a continuing deficit in healthcare professionals' knowledge with regard to CRP management and indicated that healthcare professionals still have negative attitudes that hinder the delivery of quality care to patients suffering from CRP. Further research on how and where education on this topic should be delivered is required. PMID- 28026071 TI - The association between physical activity and mortality among patients undergoing maintenance hemodialysis. AB - The aim of this study was to assess whether physical activity can predict mortality in patients undergoing maintenance hemodialysis (MHD). This observational study enrolled 317 patients undergoing MHD from Shanxi Provincial People Hospital and the Second Affiliated Hospital of Xi'an Medical University from February to June 2012. Physical activity was measured by using the Human Activity Profile (HAP) and the Stanford 7-day Physical Activity Recall Questionnaire (PAR). Exercise or not, maximal activity score (MAS), adjusted activity score (AAS), light physical activities, moderate physical activities, and the PAR value were significantly associated with mortality among patients undergoing MHD. The patients with higher scores of maximal activity score (MAS), adjusted activity score (AAS), and PAR value; more hours of the light physical activities; and moderate physical activities have the lower mortality. Through multivariate Cox regression analysis, adjusting for age, MAS, PAR value, and light physical activities can predict the mortality among patients undergoing MHD (P < .05), and the relative risk values were 0.44, 0.69, and 0.66, respectively. Baseline physical activities are independent predictors of mortality in patients undergoing hemodialysis. PMID- 28026072 TI - Activation of KLF1 Enhances the Differentiation and Maturation of Red Blood Cells from Human Pluripotent Stem Cells. AB - Blood transfusion is widely used in the clinic but the source of red blood cells (RBCs) is dependent on donors, procedures are susceptible to transfusion transmitted infections and complications can arise from immunological incompatibility. Clinically-compatible and scalable protocols that allow the production of RBCs from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have been described but progress to translation has been hampered by poor maturation and fragility of the resultant cells. Genetic programming using transcription factors has been used to drive lineage determination and differentiation so we used this approach to assess whether exogenous expression of the Erythroid Kruppel-like factor 1 (EKLF/KLF1) could augment the differentiation and stability of iPSC-derived RBCs. To activate KLF1 at defined time points during later stages of the differentiation process and to avoid transgene silencing that is commonly observed in differentiating pluripotent stem cells, we targeted a tamoxifen-inducible KLF1-ERT2 expression cassette into the AAVS1 locus. Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation. Continued culture resulted the appearance of more enucleated cells when KLF1 was activated which is possibly due to their more robust morphology. Globin profiling indicated that these conditions produced embryonic-like erythroid cells. This study demonstrates the successful use of an inducible genetic programing strategy that could be applied to the production of many other cell lineages from human induced pluripotent stem cells with the integration of programming factors into the AAVS1 locus providing a safer and more reproducible route to the clinic. Stem Cells 2017;35:886-897. PMID- 28026073 TI - Use of the UKHCDO Database for a postmarketing surveillance study of different doses of recombinant factor VIIa in haemophilia. AB - INTRODUCTION: Recombinant factor VIIa (rFVIIa) is recommended in Europe at standard (3 * 90 MUg kg-1 ) or high (1 * 270 MUg kg-1 ) doses. When granting the license for the high dose, the European Medicines Agency (EMA) requested postmarketing surveillance for thrombosis. This was conducted by the United Kingdom National Haemophilia Database (NHD) on behalf of Novo Nordisk and the EMA. AIM: To assess the use and safety of rFVIIa utilizing prospective data collected by the NHD (1 January 2008 to 30 June 2011). RESULTS: Data were obtained from 67 haemophilia A/B patients with inhibitors treated for 1057 bleeds and 31 acquired haemophilia patients treated for 70 bleeds. Initial rFVIIa dose was categorized post hoc as low (<90 MUg kg-1 ), intermediate (>=90-<180 MUg kg-1 ) or high (>=180-<270 or >=270 MUg kg-1 ). For haemophilia A/B, high and lower initial rFVIIa dose was used for 38.4% and 51.4% of episodes, respectively, while for acquired haemophilia, the values were 11.4% and 77.1% respectively. Median initial doses were higher for haemophilia A/B (146.3 MUg kg-1 ) than acquired haemophilia (90.5 MUg kg-1 ). A single administration of rFVIIa was the most frequently used regimen for haemophilia A/B, in contrast with standard recommendations and previous reports. For acquired haemophilia, most episodes were treated with multiple doses. No adverse drug reactions or thromboembolic events were reported for any rFVIIa dose. CONCLUSION: The novel use of a national database for postmarketing surveillance has demonstrated acceptable safety for all recommended doses of rFVIIa. PMID- 28026074 TI - Measurement properties of the Haem-A-QoL in haemophilia clinical trials. AB - INTRODUCTION: Patients with haemophilia on long-acting prophylactic treatment may experience an improvement in health-related quality of life (HRQoL) through reductions in breakthrough bleeds and associated complications, including long term joint damage, compared with episodic treatment. AIM: This analysis examined clinical trial data to understand the psychometric characteristics (reliability, validity and sensitivity to change over time) of the Haem-A-QoL Questionnaire in adult males with haemophilia. METHODS: Two recent, multinational, Phase 3 clinical trials of new, long-acting factor concentrates (A-LONG: rFVIIIFc; B LONG: rFIXFc) assessed HRQoL in adolescent and adult males with severe haemophilia A or B respectively. The adults' baseline assessments, via the 46 item Haem-A-QoL Questionnaire, and change over time at the 6-month assessment were used in the psychometric analyses. RESULTS: Internal consistency reliability was adequate (Cronbach's alpha > 0.70) for nine of the 10 Haem-A-QoL domains and for 'Total Score' in both trials at baseline (A-LONG, n = 133; B-LONG, n = 73). At baseline, several Haem-A-QoL domains and 'Total Score' demonstrated known groups and convergent validity when compared with other trial measures, including the EQ-5D (items and total scores) and joint impairment. Change score correlations (baseline to 28 weeks) between the EQ-5D and the Haem-A-QoL 'Total Score', and 'Physical Health' and 'Feelings' domains were moderate in magnitude (?r? >= 0.33; P < 0.03), demonstrating sensitivity to change for these outcome measures in A-LONG. CONCLUSION: These psychometric analyses provide evidence of the reliability, validity and ability to detect change of the Haem-A-QoL to assess the HRQoL of adult males with severe haemophilia A and B in longitudinal clinical trials. PMID- 28026075 TI - Elucidation of the Dexter-Type Energy Transfer in DNA by Thymine-Thymine Dimer Formation Using Photosensitizers as Artificial Nucleosides. AB - C-nucleosides of 4-methylbenzophenone, 4-methoxybenzophenone, and 2' methoxyacetophenone were synthetically incorporated as internal photosensitizers into DNA double strands. This structurally new approach makes it possible to study the distance dependence of thymidine dimer formation because the site of photoinduced triplet energy transfer injection is clearly defined. The counterstrands to these modified strands lacked the phosphodiester bond between the two adjacent thymidines that are supposed to react with each other. Their dimerization could be evidenced by gel electrophoresis because the covalent connection by cyclobutane formation between the two thymidines changes the mobility. A shallow exponential distance dependence for the formation of thymidine dimers over up to 10 A-T base pairs was observed that agrees with a Dexter-type triplet-triplet energy transfer mechanism. Concomitantly, a significant amount of photoinduced DNA crosslinking was observed. PMID- 28026076 TI - Ethical issues with colorectal cancer screening-a systematic review. AB - RATIONALE, AIMS, AND OBJECTIVES: Colorectal cancer (CRC) screening is widely recommended and implemented. However, sometimes CRC screening is not implemented despite good evidence, and some types of CRC screening are implemented despite lack of evidence. The objective of this article is to expose and elucidate relevant ethical issues in the literature on CRC screening that are important for open and transparent deliberation on CRC screening. METHODS: An axiological question-based method is used for exposing and elucidating ethical issues relevant in HTA. A literature search in MEDLINE, Embase, PsycINFO, PubMed Bioethics subset, ISI Web of Knowledge, Bioethics Literature Database (BELIT), Ethics in Medicine (ETHMED), SIBIL Base dati di bioetica, LEWI Bibliographic Database on Ethics in the Sciences and Humanities, and EUROETHICS identified 870 references of which 114 were found relevant according to title and abstract. The content of the included papers were subject to ethical analysis to highlight the ethical issues, concerns, and arguments. RESULTS: A wide range of important ethical issues were identified. The main benefits are reduced relative CRC mortality rate, and potentially incidence rate, but there is no evidence of reduced absolute mortality rate. Potential harms are bleeding, perforation, false test results, overdetection, overdiagnosis, overtreatment (including unnecessary removal of polyps), and (rarely) death. Other important issues are related to autonomy and informed choice equity, justice, medicalization, and expanding disease. CONCLUSION: A series of important ethical issues have been identified and need to be addressed in open and transparent deliberation on CRC screening. PMID- 28026077 TI - 2,4,6-Tri(hydroxy)-1,3,5-triphosphinine, P3 C3 (OH)3 : The Phosphorus Analogue of Cyanuric Acid. AB - Cyanuric acid (C3 H3 N3 O3 ) is widely used as cross-linker in basic polymers (often in combination with other crosslinking agents like melamine) but also finds application in more sophisticated materials such as in supramolecular assemblies and molecular sheets. The unknown phosphorus analogue of cyanuric acid, P3 C3 (OH)3 , may become an equally useful building block for phosphorus based polymers or materials which have unique properties. Herein we describe a straightforward synthesis of 2,4,6-tri(hydroxy)-1,3,5-triphosphinine and its derivatives P3 C3 (OR)3 which have been applied as strong pi-acceptor eta6 ligands in piano stool Mo(CO)3 complexes. PMID- 28026078 TI - Screening for cervical carcinoma in HIV-infected women: Analysis of main risk factors for cervical cytologic abnormalities. AB - AIM: The aim of this study was to identify potential predictive factors for cervical disease in women with HIV and to evaluate adherence during follow-up to cervical cancer screening. METHODS: In order to identify the independent role of factors associated with the presence of a cervical abnormality, all of the variables showing in univariate analyses a potential association with the outcome variable (presence of cervical abnormalities) were entered into a multivariate logistic regression model, along with age at first visit to our center, and age at diagnosis. RESULTS: A total of 540 HIV-positive women who received screening for cervical cancer during the first year after their first visit to our center were included in the analysis; 423 (78.3%) had normal cytology and 117 (21.7%) had cytological abnormalities, classified as follows: 21 atypical squamous cells of undetermined significance (17.9%); 51 low-grade squamous intraepithelial lesions (43.6%); 41 high-grade squamous intraepithelial lesions (35.0%); and four cervical cancers (3.4%). In our study, women with more than two previous pregnancies were significantly associated with a lower risk of cervical cytological abnormalities compared to the other women. Women with CD4+ levels of 200-499/mm3 had a higher risk of developing cervical cytological abnormalities compared to those with a CD4+ level > 500/ mm3 . CONCLUSION: In summary, management of HIV-positive women must be modeled on HIV-clinical status, CD4+ cell count, drug regimen, and adherence to follow-up, relying on the cooperation of highly qualified professionals. In HIV-positive women, an adequate screening and follow-up allows for a reduced occurrence of advanced cervical disease and prevents recourse to invalidating surgical interventions. PMID- 28026079 TI - Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3-Fluorinated and All-Carbon Quaternary Oxindoles. AB - Synthetically versatile 3,3-disubstituted fluorooxindoles exhibiting vicinal chirality centers were obtained in high yields and with excellent enantio-, diastereo-, and regioselectivity through catalytic asymmetric fluoroenolate alkylation with allylic acetates. The reaction proceeds under mild conditions and can be scaled up without compromising the asymmetric induction. The unique synthetic usefulness of the products is highlighted by the incorporation of additional functionalities and the formation of 3-fluorinated oxindoles exhibiting an array of four adjacent centers of chirality. A new C-F bond functionalization path that provides unprecedented possibilities for the stereoselective generation of a chiral quaternary carbon center in the alkaloid scaffold is introduced. PMID- 28026080 TI - Transcriptomic gene profiling of porcine muscle tissue depending on histological properties. AB - In pig, the histological profile of muscle tissue, especially the proportion of individual fiber types, is one of the main factors affecting meat quality properties. In the present research, RNA sequencing (RNA-seq) by using next generation sequencing method was applied to estimate the whole gene expression profile of Longissimus lumborum muscle of pigs (Large White breed) differing in the percentage of two fiber types (slow-twitch (type I) fibers and fast-twitch glycolytic (type IIB) fibers). The RNA-seq approach allowed us to identify 355 differentially expressed genes (DEGs) indicated as significant (false discovery rate-adjusted P < 0.05) using three types of software: DESeq2, edgeR and baySeq. Detected genes and pathways deregulated in muscle depending on tissue microstructure were associated with: metabolic processes - 158 genes; cellular processes - 122; biological regulation - 62; localization - 51; and 35 genes with developmental processes. The DEGs were included in: PI3K-Akt; FoxO and MAPK signaling pathways, regulation of actin cytoskeleton, lysine degradation and insulin signaling pathway as well as mTOR and Hippo signaling pathways. These results highlight the mainly metabolic pathways related to glucose metabolism and contraction processes of muscle cells. Detection of genes involved in variation of fiber-type distribution will be useful in understanding of the genetic factors affecting muscle structure, metabolic process and indirectly, meat quality traits. PMID- 28026081 TI - Distinct complexes of yeast Snx4 family SNX-BARs mediate retrograde trafficking of Snc1 and Atg27. AB - The yeast SNX4 sub-family of sorting nexin containing a Bin-Amphiphysin-Rvs domain (SNX-BAR) proteins, Snx4/Atg24, Snx41 and Atg20/Snx42, are required for endocytic recycling and selective autophagy. Here, we show that Snx4 forms 2 functionally distinct heterodimers: Snx4-Atg20 and Snx4-Snx41. Each heterodimer coats an endosome-derived tubule that mediates retrograde sorting of distinct cargo; the v-SNARE, Snc1, is a cargo of the Snx4-Atg20 pathway, and Snx4-Snx41 mediates retrograde sorting of Atg27, an integral membrane protein implicated in selective autophagy. Live cell imaging of individual endosomes shows that Snx4 and the Vps5-Vps17 retromer SNX-BAR heterodimer operate concurrently on a maturing endosome. Consistent with this, the yeast dynamin family protein, Vps1, which was previously shown to promote fission of retromer-coated tubules, promotes fission of Snx4-Atg20 coated tubules. The results indicate that the yeast SNX-BAR proteins coat 3 distinct types of endosome-derived carriers that mediate endosome-to-Golgi retrograde trafficking. PMID- 28026083 TI - New oral targeted therapies for metastatic breast cancer disrupt the traditional patients' management-A healthcare providers' view. AB - Although a cure still cannot be expected for metastatic breast cancer, thanks to progressive advances in treatments, life expectancy has been increasing over the past 15 years. This study aims to present the impact on the organisation of patients' management of newly released oral targeted therapies dedicated to metastatic breast cancer and the obstacles to their diffusion. Our work is based on the analysis of 40 semi-structured interviews, conducted with oncology healthcare professionals in three regions of France (2015-2016). It shows three main results. First, the prescription of an oral targeted therapy requires greater collaboration between healthcare professionals than traditional intravenous oncology drugs, which may be challenging. Second, there remain many barriers to the dissemination of oral targeted therapies. Third, taking an oral targeted therapy keeps the patient away from the hospital facility and asks for a strong therapeutic alliance. The management of oral targeted therapies is time consuming for medical oncologists and disrupts the traditional care pathway. The multiplication of actors involved in patients' management reinforces the slowdown in the deployment and acceptance of therapeutic innovations. More players equal a higher risk of slowdown. Questioning and re-designing hospital organisation and management modalities towards this type of care are critical. PMID- 28026082 TI - Hox genes in the adult skeleton: Novel functions beyond embryonic development. AB - Hox genes encode evolutionarily conserved transcription factors that control skeletal patterning in the developing embryo. They are expressed in regionally restricted domains and function to regulate the morphology of specific vertebral and long bone elements. Recent work has provided evidence that Hox genes continue to be regionally expressed in adult tissues. Fibroblasts cultured from adult tissues show broadly maintained Hox gene expression patterns. In the adult skeleton, Hox genes are expressed in progenitor-enriched populations of mesenchymal stem/stromal cells (MSCs), and genetic loss-of-function analyses have provided evidence that Hox genes function during the fracture healing process. This review will highlight our current understanding of Hox expression in the adult animal and its function in skeletal regeneration. Developmental Dynamics 246:310-317, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026084 TI - A Cocatalytic Effect between Meldrum's Acid and Benzoxazine Compounds in Preparation of High Performance Thermosetting Resins. AB - In this work, a cocatalytic effect between Meldrum's acid (MA) and benzoxazine (Bz) compounds has been explored to build up a self-promoting curing system. Consequently, the MA/Bz reactive blend exhibits a relatively low reaction temperature compared to the required temperatures for the cross-linking reactions of the pure MA and Bz components. This feature is attractive for energy-saving processing issues. Moreover, the thermosetting resins based on the MA/Bz reactive blends have been prepared. The MA component can generate additional free volume in the resulting resins, so as to trap air in the resin matrix and consequently to bring low dielectric constants to the resins. The MA-containing agent is an effective modifier for benzoxazine resins to reduce their dielectric constants. PMID- 28026085 TI - Health Insurance Costs and Employee Compensation: Evidence from the National Compensation Survey. AB - This paper examines the relationship between rising health insurance costs and employee compensation. I estimate the extent to which total compensation decreases with a rise in health insurance costs and decompose these changes in compensation into adjustments in wages, non-health fringe benefits, and employee contributions to health insurance premiums. I examine this relationship using the National Compensation Survey, a panel dataset on compensation and health insurance for a sample of establishments across the USA. I find that total hourly compensation reduces by $0.52 for each dollar increase in health insurance costs. This reduction in total compensation is primarily in the form of higher employee premium contributions, and there is no evidence of a change in wages and non health fringe benefits. These findings show that workers are absorbing at least part of the increase in health insurance costs through lower compensation and highlight the importance of examining total compensation, and not just wages, when examining the relationship between health insurance costs and employee compensation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28026086 TI - Identification of serum protein markers for early diagnosis of pregnancy in buffalo. AB - Improper or delayed pregnancy diagnosis has significant impact over animal production, particularly in buffaloes which inherently suffer from several reproductive inefficiencies. Thus the present study has undertaken to identify serum protein markers pertaining to early pregnancy diagnosis in buffaloes. Serum samples were collected from 10 pregnant Murrah Buffalo heifers at weekly intervals from days 0-35 post-artificial insemination and from 12 inseminated non pregnant cyclic buffalo heifers on days 0, 7, 14 and 21. Two-dimensional gel electrophoresis and densitometric analysis revealed the presence of five protein spots showing average density fold change of >=4 during early pregnancy. Mass spectrometry analysis identified these up-regulated proteins as anti-testosterone antibody light chain, apolipoprotein A-II precursor, serum amyloid A, cytokeratin type II, component IV isoform 1, which are have established roles in embryogenesis, but over-expression of the fifth identified protein immunoglobulin lambda light chain in pregnancy has been elucidated as a novel finding in the current study. Further, with bioinformatics analysis, potential antigenic B-cell epitopes were predicted for all these five proteins. An antibody cocktail-based approach involving antibodies against all these five up-regulated entire proteins or their epitopes could be developed for early detection of pregnancy in buffaloes. (c) 2016 Japanese Society of Animal Science. PMID- 28026087 TI - Oral contraceptive therapy reduces serum relaxin-2 in elite female athletes. AB - AIM: Recent investigations have demonstrated that athletes with high relaxin-2 levels have a high risk of anterior cruciate ligament injuries, while athletes taking oral contraceptives (OC) have low relaxin-2 levels. It has not yet been clarified whether taking OC reduces relaxin-2 levels. The purpose of this study was to investigate changes in relaxin-2 levels in athletes taking OC. METHODS: Levels of relaxin-2, estradiol, progesterone, luteinizing hormone and follicle stimulating hormone were measured in serum samples (n = 183) from 106 elite female athletes. Five athletes with serum relaxin-2 concentrations > 6 pg/mL during the luteal phase were recruited to assess the effect of OC therapy. RESULTS: Serum relaxin-2 concentrations were significantly higher during the luteal phase (n = 57) than in the follicular phase (n = 72), or in athletes on OC therapy (n = 10) (P < 0.001, P < 0.001 and P < 0.05, respectively). In the luteal phase, 36.8% (21/57) of the athletes had relaxin levels > 6 pg/mL. In 23 athletes, serum relaxin-2 concentrations were measured during both the follicular and luteal phases, revealing that relaxin-2 levels were significantly higher in the luteal phase compared with the follicular phase. In 5 out of 23 athletes, serum relaxin-2 concentrations were > 6 pg/mL in the luteal phase and during the second cycle of OC therapy, relaxin-2 concentrations decreased dramatically to below the detection limit (0.26 pg/mL). CONCLUSIONS: High serum relaxin-2 concentrations were only detected during the luteal phase. In athletes with high relaxin-2 concentrations during the luteal phase, OC therapy decreased serum relaxin-2 levels. PMID- 28026088 TI - The checking methods before medication administration: A perspective from a Joint Commission International-accredited academic medical center hospital in China. PMID- 28026089 TI - Synonymous Somatic Variants in Human Cancer Are Not Infamous: A Plea for Full Disclosure in Databases and Publications. AB - Single-nucleotide variants (SNVs) are the most frequent genetic changes found in human cancer. Most driver alterations are missense and nonsense variants localized in the coding region of cancer genes. Unbiased cancer genome sequencing shows that synonymous SNVs (sSNVs) can be found clustered in the coding regions of several cancer oncogenes or tumor suppressor genes suggesting purifying selection. sSNVs are currently underestimated, as they are usually discarded during analysis. Furthermore, several public databases do not display sSNVs, which can lead to analytical bias and the false assumption that this mutational event is uncommon. Recent progress in our understanding of the deleterious consequences of these sSNVs for RNA stability and protein translation shows that they can act as strong drivers of cancer, as demonstrated for several cancer genes such as TP53 or BCL2L12. It is therefore essential that sSNVs be properly reported and analyzed in order to provide an accurate picture of the genetic landscape of the cancer genome. PMID- 28026090 TI - The Mesenchymal Precursor Cell Marker Antibody STRO-1 Binds to Cell Surface Heat Shock Cognate 70. AB - Since its discovery more than 25 years ago, the STRO-1 antibody has played a fundamental role in defining the hierarchical nature of mesenchymal precursor cells (MPC) and their progeny. STRO-1 antibody binding remains a hallmark of immature pluripotent MPC. Despite the significance of STRO-1 in the MPC field, the identity of the antigen has remained elusive. Using a combination of two dimensional gel electrophoresis, coupled with Western blotting and Tandem mass spectroscopy, we have identified the STRO-1 antigen as heat shock cognate 70 (HSC70;HSPA8). STRO-1 binds to immune-precipitated HSC70 and siRNA-mediated knock down of HSPA8 reduced STRO-1 binding. STRO-1 surface binding does not correlate with HSC70 expression and sequestration of cholesterol reduces STRO-1 surface binding, suggesting that the plasma membrane lipid composition may be an important determinant in the presentation of HSC70 on the cell surface. HSC70 is present on the surface of STRO-1+ but not STRO-1- cell lines as assessed by cell surface biotinylation and recombinant HSC70 blocks STRO-1 binding to the cell surface. The STRO-1 epitope on HSC70 was mapped to the ATPase domain using a series of deletion mutants in combination with peptide arrays. Deletion of the first four amino acids of the consensus epitope negated STRO-1 binding. Notably, in addition to HSC70, STRO-1 cross-reacts with heat shock protein 70 (HSP70), however all the clonogenic cell activity is restricted to the STRO-1BRIGHT /HSP70 fraction. These results provide important insight into the properties that define multipotent MPC and provide the impetus to explore the role of cell surface HSC70 in MPC biology. Stem Cells 2017;35:940-951. PMID- 28026091 TI - Rhodium-Catalyzed Asymmetric Synthesis of beta-Branched Amides. AB - A general asymmetric route for the one-step synthesis of chiral beta-branched amides is reported through the highly enantioselective isomerization of allylamines, followed by enamine exchange, and subsequent oxidation. The enamine exchange allows for a rapid and modular synthesis of various amides, including challenging beta-diaryl and beta-cyclic. PMID- 28026092 TI - Dipolar Relaxation Dynamics at the Active Site of an ATPase Regulated by Membrane Lateral Pressure. AB - The active transport of ions across biological membranes requires their hydration shell to interact with the interior of membrane proteins. However, the influence of the external lipid phase on internal dielectric dynamics is hard to access by experiment. Using the octahelical transmembrane architecture of the copper transporting P1B -type ATPase from Legionella pneumophila as a model structure, we have established the site-specific labeling of internal cysteines with a polarity-sensitive fluorophore. This enabled dipolar relaxation studies in a solubilized form of the protein and in its lipid-embedded state in nanodiscs. Time-dependent fluorescence shifts revealed the site-specific hydration and dipole mobility around the conserved ion-binding motif. The spatial distribution of both features is shaped significantly and independently of each other by membrane lateral pressure. PMID- 28026093 TI - Cyanobacterial harmful algal blooms are a biological disturbance to Western Lake Erie bacterial communities. AB - Human activities are causing a global proliferation of cyanobacterial harmful algal blooms (CHABs), yet we have limited understanding of how these events affect freshwater bacterial communities. Using weekly data from western Lake Erie in 2014, we investigated how the cyanobacterial community varied over space and time, and whether the bloom affected non-cyanobacterial (nc-bacterial) diversity and composition. Cyanobacterial community composition fluctuated dynamically during the bloom, but was dominated by Microcystis and Synechococcus OTUs. The bloom's progression revealed potential impacts to nc-bacterial diversity. Nc bacterial evenness displayed linear, unimodal, or no response to algal pigment levels, depending on the taxonomic group. In addition, the bloom coincided with a large shift in nc-bacterial community composition. These shifts could be partitioned into components predicted by pH, chlorophyll a, temperature, and water mass movements. Actinobacteria OTUs showed particularly strong correlations to bloom dynamics. AcI-C OTUs became more abundant, while acI-A and acI-B OTUs declined during the bloom, providing evidence of niche partitioning at the sub clade level. Thus, our observations in western Lake Erie support a link between CHABs and disturbances to bacterial community diversity and composition. Additionally, the short recovery of many taxa after the bloom indicates that bacterial communities may exhibit resilience to CHABs. PMID- 28026094 TI - Phenotypic characteristics of aged CD4+ CD28null T lymphocytes are determined by changes in the whole-genome DNA methylation pattern. AB - Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4+ lymphocytes (CD28null T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28null T cells and its CD28+ counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB, TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1, CD27, and IL 1R) are demethylated in CD28null T cells, while 136 de novo-methylated genes matched defects in the TCR signaling pathway (e.g. ITK, TXK, CD3G, and LCK). TCR landscape analysis confirmed that CD28null T cells have an oligo/monoclonal expansion over the polyclonal background of CD28+ T cells, but feature a Vbeta family repertoire specific to each individual. We reported that CD28null T cells show a preactivation state characterized by a higher level of expression of inflammasome-related genes that leads to the release of IL-1beta when activated. Overall, our results demonstrate that CD28null T cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging. PMID- 28026095 TI - Pulsed electromagnetic field at different stages of knee osteoarthritis in rats induced by low-dose monosodium iodoacetate: Effect on subchondral trabecular bone microarchitecture and cartilage degradation. AB - The aim of the study was to investigate the efficacy of pre-emptive, early, and delayed pulsed electromagnetic field (PEMF) treatment on cartilage and subchondral trabecular bone in knee osteoarthritis (OA) rats induced by low-dose monosodium iodoacetate (MIA). Seventy-five 12-week-old male Sprague-Dawley rats were assigned to five groups: OA (n = 30), pre-emptive PEMF (n = 10), early PEMF (n = 10), delayed PEMF (n = 10), and control (n = 15). Osteoarthritis was induced by injecting 0.2 mg MIA in rat's right knee joint. Control rats received a single sterile saline injection in the right knee. Male rats received pre-emptive (n = 10, day 0-end of week 4), early (n = 10, end of week 4-end of week 8), or delayed (n = 10, end of week 8-end of week 12) PEMF treatment (75 Hz, 1.6 mT). After 4, 8, and 12 weeks, rats were sacrificed at each time point and right knees were harvested. After sacrifice, micro-computed tomography, histology, and biomarker analyses were performed. We found pre-emptive PEMF treatment preserved subchondral trabecular bone microarchitecture and prevented subchondral bone loss in MIA-induced OA rat model. Early and delayed PEMF treatment maintained subchondral trabeculae. PEMF treatment increased bone and cartilage formation, and decreased bone and cartilage resorption. Pre-emptive and early PEMF treatment had moderate effects on cartilage degradation. Time point of treatment initiation is crucial for treating OA. PEMF might become a potential biophysical treatment modality for osteoarthritis. Bioelectromagnetics. 38:227-238, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026096 TI - Interarm blood pressure differences predict target organ damage in type 2 diabetes. AB - Patients with type 2 diabetes mellitus are at high risk for atherosclerotic disease, and proper blood pressure measurement is mandatory. The authors examined the prevalence of an interarm difference (IAD) in blood pressure and its association with cardiovascular risk factors and organ damage (nephropathy, retinopathy, left ventricular hypertrophy, and vascular damage) in a large diabetic population. A total of 800 consecutive patients with type 2 diabetes mellitus were evaluated with an automated simultaneous bilateral device (men: 422 [52.8%]; mean age: 68.1+/-12.2 years). Diabetic patients with systolic IAD >=5 and systolic IAD >=10 mm Hg showed an increased risk of having vascular damage (adjusted odds ratios: 1.73 and 2.49, respectively) and higher pulse pressure. IAD is highly prevalent in patients with diabetes, is associated with vascular damage, even for IAD >=5 mm Hg, and should be accurately obtained to avoid underdiagnosis and undertreatment of hypertension. PMID- 28026097 TI - Barley susceptibility factor RACB modulates transcript levels of signalling protein genes in compatible interaction with Blumeria graminis f.sp. hordei. AB - RHO (rat sarcoma homologue) GTPases (guanosine triphosphatases) are regulators of downstream transcriptional responses of eukaryotes to intracellular and extracellular stimuli. For plants, little is known about the function of Rho-like GTPases [called RACs (rat sarcoma-related C botulinum substrate) or ROPs (RHO of plants)] in transcriptional reprogramming of cells. However, in plant hormone response and innate immunity, RAC/ROP proteins influence gene expression patterns. The barley RAC/ROP RACB is required for full susceptibility of barley to the powdery mildew fungus Blumeria graminis f.sp. hordei (Bgh). We compared the transcriptomes of barley plants either silenced for RACB or over-expressing constitutively activated RACB with and without inoculation with Bgh. This revealed a large overlap of the barley transcriptome during the early response to Bgh and during the over-expression of constitutively activated RACB. Global pathway analyses and stringent analyses of differentially expressed genes suggested that RACB influences, amongst others, the expression of signalling receptor kinases. Transient induced gene silencing of RACB-regulated signalling genes (a leucine-rich repeat protein, a leucine-rich repeat receptor-like kinase and an S-domain SD1-receptor-like kinase) suggested that they might be involved in RACB-modulated susceptibility to powdery mildew. We discuss the function of RACB in regulating the transcriptional responses of susceptible barley to Bgh. PMID- 28026098 TI - Risk factors for preeclampsia in infertile Chinese women with polycystic ovary syndrome: A prospective cohort study. AB - To explore preconception risk factors for preeclampsia (PE) in women with polycystic ovary syndrome (PCOS), a prospective cohort study was conducted in 92 infertile Chinese women with PCOS who had a singleton pregnancy by ovulation induction and were followed up for 6 weeks after delivery. The patients underwent assessment of physical, endocrine, and metabolic features before ovulation induction. Fifteen (16.3%) patients were diagnosed with PE. Logistic regression analysis showed that preconception sex hormone-binding globulin (SHBG), insulin level at 120 minutes, and body mass index were three independent risk factors for PE (odds ratio [OR], 0.981; 95% confidence interval [CI], 0.964-0.998 [P=.027]; OR, 1.011; 95% CI, 1.000-1.021 [P=.048]; and OR, 1.249; 95% CI, 0.992-1.572 [P=.059], respectively). Receiver operator characteristic analysis indicated the risk value of prepregnancy SHBG, insulin level at 120 minutes, and body mass index (area under the curve=.788, .686, and .697, respectively). Preconception low SHBG levels, overweight/obesity, and hyperinsulinism might be correlated with the subsequent development of PE in patients with PCOS. PMID- 28026099 TI - Synthesis and crystal structure of a highly selective colorimetric and fluorometric sensor for hydrogen sulfide. AB - A novel Cu(II) complex chemosensor for hydrogen sulfide with azo as the colorimetric group has been synthesized. The complex and ligand crystals were obtained and the molecular structures were characterized by X-ray diffraction and Electrospray ionization High resolution mass spectrometer (ESI-HRMS). The photophysical and recognition properties were examined. The complex can recognize S2- , with an obvious color change from yellow to red based on a copper ion complex displacement mechanism. By contrast, no obvious changes were observed in the presence of other anions (AcO- , H2 PO4- , F- , Cl- , Br- and I- ). We present a simple, easily prepared, yet efficient, inorganic reaction-based sensor for the detection of S2- . The complex should have many chemical and analytical applications in the sensing of hydrogen sulfide. PMID- 28026100 TI - Uptake-release dynamics of the inorganic and organic carbon pool mediated by planktonic prokaryotes in the deep Mediterranean Sea. AB - Understanding the ecosystem functioning in the dark portion of the ocean is a challenge that microbial ecologists are still facing. Due to the large volume, the global deep Ocean plays a central role in the regulation of climate, possibly buffering the rise of atmospheric carbon dioxide if processes of CO2 fixation compensate for respiration. We investigated the rates of several prokaryotic activities (dissolved and particulate primary production, heterotrophic carbon production and respiration) in meso- and bathypelagic waters of the Mediterranean Sea, covering all sub-basins. Chemosynthesis was the main process for C uptake. The rates of organic C (OC) excretion (or viral-induced cell lysis) inferred from the dissolved primary production measurements were noteworthy, being comparable to particulate primary production, and possibly contributing to the formation of non-sinking particulate organic matter. Inorganic C fixation rates were significantly higher than those reported for other deep-sea systems, probably as a consequence of the persistently higher temperature of dark Mediterranean waters or to phylogenetically diverse communities involved in the process. Primary production was negatively correlated with dissolved organic carbon concentration and showed an inverse pattern to heterotrophic carbon production, indicating a niche partitioning between heterotrophs and autotrophs. In sum, the deep Mediterranean Sea harbors active autotrophic communities able to fix inorganic carbon faster than the heterotrophic carbon production rates. PMID- 28026101 TI - Single-Molecule Force Spectroscopy Trajectories of a Single Protein and Its Polyproteins Are Equivalent: A Direct Experimental Validation Based on A Small Protein NuG2. AB - Single-molecule force spectroscopy (SMFS) has become a powerful tool in investigating the mechanical unfolding/folding of proteins at the single-molecule level. Polyproteins made of tandem identical repeats have been widely used in atomic force microscopy (AFM)-based SMFS studies, where polyproteins not only serve as fingerprints to identify single-molecule stretching events, but may also improve statistics of data collection. However, the inherent assumption of such experiments is that all the domains in the polyprotein are equivalent and one SMFS trajectory of stretching a polyprotein made of n domains is equivalent to n trajectories of stretching a single domain. Such an assumption has not been validated experimentally. Using a small protein NuG2 and its polyprotein (NuG2)4 as model systems, here we use optical trapping (OT) to directly validate this assumption. Our results show that OT experiments on NuG2 and (NuG2)4 lead to identical parameters describing the unfolding and folding kinetics of NuG2, demonstrating that indeed stretching a polyprotein of NuG2 is equivalent to stretching single NuG2 in force spectroscopy experiments and thus validating the use of polyproteins in SMFS experiments. PMID- 28026102 TI - Enzymes Beat Chemists in the Formation of an Unnatural Bond. AB - A fundamental difference? A heme protein known to catalyze electron transfers was engineered into an enzyme that catalyzes the formation of C-Si bonds with >99 % ee. The new enzyme uses diazoesters as carbene donors for the insertion of various silanes into the Si-H bond. This is the first reported organosilicon producing enzyme. PMID- 28026104 TI - Service and infrastructure needs to support recovery programmes for Indigenous community mental health consumers. AB - Mental health is a major concern in Indigenous communities, as Indigenous people experience poorer health outcomes generally, and poorer social and emotional well being throughout their lives, compared to non-Indigenous populations. Interviews were conducted with 20 mental health workers from a housing assistance programme for Indigenous clients with mental illness. Service and infrastructure needs identified to support clients were classified under the following overarching theme 'supports along the road to recovery'. Subthemes were: (i) It is OK to seek help; (ii) linking in to the local community; (iii) trusting the workers; and (iv) help with goal setting and having activities that support their achievement. This paper highlights the importance of targeted housing and accommodation support programmes for Indigenous people to prevent homelessness, and the essential services and infrastructure required to support Indigenous clients' mental health needs. These insights may inform service review, workforce development, and further research. PMID- 28026103 TI - Artificial microRNAs and synthetic trans-acting small interfering RNAs interfere with viroid infection. AB - Artificial microRNAs (amiRNAs) and synthetic trans-acting small interfering RNAs (syn-tasiRNAs) are two classes of artificial small RNAs (sRNAs) engineered to silence endogenous transcripts as well as viral RNAs in plants. Here, we explore the possibility of using amiRNAs and syn-tasiRNAs to specifically interfere with infections by viroids, small (250-400-nucleotide) non-coding circular RNAs with compact secondary structure infecting a wide range of plant species. The combined use of recent high-throughput methods for artificial sRNA construct generation and the Potato spindle tuber viroid (PSTVd)-Nicotiana benthamiana pathosystem allowed for the simple and time-effective screening of multiple artificial sRNAs targeting sites distributed along PSTVd RNAs of (+) or (-) polarity. The majority of amiRNAs were highly active in agroinfiltrated leaves when co-expressed with an infectious PSTVd transcript, as were syn-tasiRNAs derived from a construct including the five most effective amiRNA sequences. A comparative analysis showed that the effects of the most effective amiRNA and of the syn-tasiRNAs were similar in agroinfiltrated leaves, as well as in upper non-agroinfiltrated leaves in which PSTVd accumulation was significantly delayed. These results suggest that amiRNAs and syn-tasiRNAs can be used effectively to control viroid infections in plants. PMID- 28026105 TI - Challenges in intergenerational caregiving for frail older people: A multiple case study. AB - Families in Taiwan are considered central in caring for frail older people. However, rapid social changes are reshaping Taiwanese family values and structures. In this study, we explored the challenges of intergenerational families in caring for frail older people in Taiwan. Using a multiple-case study, 32 participants representing 12 families comprising three or more generations participated in individual, semistructured interviews. A grounded theory technique was used for the data analysis. Four themes emerged in the findings: intergenerational and intragenerational disharmony, restrictions in the physical environment, financial caregiving burdens, and lack of support from the healthcare system. The findings can help raise awareness of filial caregiving obligations of aging family members that have shifted from a parent-child dyad to being shared across multiple generations in Taiwan. Intergenerational caregiving for frail older people has become a challenge for policies aimed at keeping the aging population in the community. PMID- 28026106 TI - Recovery concept in a Norwegian setting to be examined by the assertive community treatment model and mixed methods. AB - Recovery is a crucial concept in the mental health field. The research of recovery is split into the categories of personal, social and clinical recovery. The purpose of this study was to explore the fragmented concept of recovery in light of assertive community treatment (ACT) in Norway. The study has a mixed methods design with a pragmatic approach. The Questionnaire about the Process of Recovery and open-ended questions posed to 70 participants from 12 ACT teams in Norway, gathered by the "Users interview users" method, are combined with interviews or focus groups with eight of these participants. Surprisingly those under a community treatment order (CTO) report the highest degree of personal recovery. The qualitative material shows that the service users interpreted the concept of recovery differently than researchers and professionals. The ACT service users highlighted three important elements: flexible treatment, medication and access to a car. They emphasized the necessity for basic needs to be met in order to experience a meaningful recovery process, and these basic needs may be of even greater importance to those under CTOs. Their experiences should imply a greater emphasis on securing basic needs such as secure housing, sounder finances and access to the normal benefits offered by society. PMID- 28026107 TI - A hierarchical task analysis of shoulder arthroscopy for a virtual arthroscopic tear diagnosis and evaluation platform (VATDEP). AB - BACKGROUND: Shoulder arthroscopy is a minimally invasive surgical procedure for diagnosis and treatment of a shoulder pathology. The procedure is performed with a fiber optic camera, called arthroscope, and instruments inserted through very tiny incisions made around the shoulder. The confined shoulder space, unintuitive camera orientation and constrained instrument motions complicates the procedure. Therefore, surgical competence in arthroscopy entails extensive training especially for psychomotor skills development. Conventional arthroscopy training methods such as mannequins, cadavers or apprenticeship model have limited use attributed to their low-fidelity in realism, cost inefficiency or incurring high risk. However, virtual reality (VR) based surgical simulators offer a realistic, low cost, risk-free training and assessment platform where the trainees can repeatedly perform arthroscopy and receive quantitative feedback on their performances. Therefore, we are developing a VR based shoulder arthroscopy simulation specifically for the rotator cuff ailments that can quantify the surgery performance. Development of such a VR simulation requires a through task analysis that describes the steps and goals of the procedure, comprehensive metrics for quantitative and objective skills and surgical technique assessment. METHODS: We analyzed shoulder arthroscopic rotator cuff surgeries and created a hierarchical task tree. We introduced a novel surgery metrics to reduce the subjectivity of the existing grading metrics and performed video analysis of 14 surgery recordings in the operating room (OR). We also analyzed our video analysis results with respect to the existing proposed metrics in the literature. RESULTS: We used Pearson's correlation tests to find any correlations among the task times, scores and surgery specific information. We determined strong positive correlation between cleaning time vs difficulty in tying suture, cleaning time vs difficulty in passing suture, cleaning time vs scar tissue size, difficulty passing vs difficulty in tying suture, total time and difficulty of the surgery. CONCLUSION: We have established a hierarchical task analysis and analyzed our performance metrics. We will further use our metrics in our VR simulator for quantitative assessment. PMID- 28026108 TI - Outcomes utilizing imported liver grafts for recipients with hepatocellular carcinoma. AB - Liver transplantation (LT) offers the best chance of survival in selected patients with hepatocellular carcinoma (HCC). Wait-list mortality or dropout due to tumor progression can be significant, and therefore, timely transplantation is critical. Liver grafts discarded by outside organ procurement organizations are a potential source of grafts for low Model for End-Stage Liver Disease tumor patients. The primary aim of this study was to assess the disease-free and overall survival of patients with HCC transplanted with imported liver grafts (ILGs). Review of all patients transplanted for HCC between June 2005 and December 2014 was performed. Data on demographics, survival, and HCC recurrence were analyzed. During this time period, 59 out of 190 (31%) recipients with HCC received ILG. Of these 59 grafts, 54 were imported from within the region and 5 were from national offers (outside the region). The mean cold ischemia time for local liver grafts (LLGs) was 4.1 +/- 1.5 hours versus 5.1 +/- 1.4 hours for ILG (P < 0.001). The 1-, 3-, and 5-year patient survival was 90%, 85%, and 83% and 85%, 80%, and 79% for LLG and ILG (P = 0.08), respectively. The observed disease recurrence rate for both LLG and ILG recipients was equivalent. The median wait list time for HCC recipients was 43 days (range, 2-1167 days). In conclusion, with careful graft assessment, the use of ILGs results in comparable outcomes following LT and no increased risk of HCC recurrence. Use of ILGs maximizes the donor pool and results in a higher rate of transplantation for HCC recipients. Liver Transplantation 23 299-304 2017 AASLD. PMID- 28026109 TI - Soft Elastomers with Ionic Liquid-Filled Cavities as Strain Isolating Substrates for Wearable Electronics. AB - Managing the mechanical mismatch between hard semiconductor components and soft biological tissues represents a key challenge in the development of advanced forms of wearable electronic devices. An ultralow modulus material or a liquid that surrounds the electronics and resides in a thin elastomeric shell provides a strain-isolation effect that enhances not only the wearability but also the range of stretchability in suitably designed devices. The results presented here build on these concepts by (1) replacing traditional liquids explored in the past, which have some nonnegligible vapor pressure and finite permeability through the encapsulating elastomers, with ionic liquids to eliminate any possibility for leakage or evaporation, and (2) positioning the liquid between the electronics and the skin, within an enclosed, elastomeric microfluidic space, but not in direct contact with the active elements of the system, to avoid any negative consequences on electronic performance. Combined experimental and theoretical results establish the strain-isolating effects of this system, and the considerations that dictate mechanical collapse of the fluid-filled cavity. Examples in skin-mounted wearable include wireless sensors for measuring temperature and wired systems for recording mechano-acoustic responses. PMID- 28026110 TI - Reversal of direct oral anticoagulants for liver transplantation in cirrhosis: A step forward. PMID- 28026111 TI - Biomedical Applications of Metal-Encapsulated Fullerene Nanoparticles. AB - The carbonaceous nanomaterials known as metallofullerenes have attracted considerable attention due to their attractive properties. The robust nature of the "Trojan Horse" fullerene cage provides an important structural component, which isolates the metal cluster from the bioenvironment. The large carbon surface area is ideally suited for multiple exo-functionalization approaches to modify the hydrophobic cage for a more hydrophilic bioenvironment. Additionally, peptides and other agents are readily covalently attached to this nanoprobe for targeting applications. The recent progress in developing metallofullerenes for next-generation biomedical applications is described. Of special interest are magnetic resonance imaging (MRI) contrast agents. Several recent studies reported cumulative gadolinium deposition in the brain and bones of individuals using commercial clinical MRI contrast agents. Gadolinium-based metallofullerenes provide 2-3 orders of magnitude improvement in MRI relaxivity and potentially lower clinical levels of toxic Gd3+ ions deposited. Other potential biomedical applications are also reviewed herein. PMID- 28026112 TI - Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells. AB - Pharmacological modulation of autophagy has been referred to as a promising therapeutic strategy for cancer. Matrine, a main alkaloid extracted from Sophora flavescens Ait, has antitumour activity against acute myelocytic leukaemia (AML). Whether autophagy is involved in antileukaemia activity of matrine remains unobvious. In this study, we demonstrated that matrine inhibited cell viability and colony formation via inducing apoptosis and autophagy in AML cell lines HL 60, THP-1 and C1498 as well as primary AML cells. Matrine promoted caspase-3 and PARP cleavage dose-dependently. Matrine up-regulated the level of LC3-II and down regulated the level of SQSTM1/p62 in a dose-dependent way, indicating that autophagy should be implicated in anti-AML effect of matrine. Furthermore, the autophagy inhibitor bafilomycin A1 relieved the cytotoxicity of matrine by blocking the autophagic flux, while the autophagy promoter rapamycin enhanced the cytotoxicity of matrine. Additionally, matrine inhibited the phosphorylation of Akt, mTOR and their downstream substrates p70S6K and 4EBP1, which led to the occurrence of autophagy. In vivo study demonstrated that autophagy was involved in antileukaemia effect of matrine in C57BL/6 mice bearing murine AML cell line C1498, and the survival curves showed that mice did benefit from treatment with matrine. Collectively, our findings indicate that matrine exerts antitumour effect through apoptosis and autophagy, and the latter one might be a potential therapeutic strategy for AML. PMID- 28026113 TI - Prognostic evaluation by oxygenation with positive end-expiratory pressure in acute exacerbation of idiopathic pulmonary fibrosis: A retrospective cohort study. AB - INTRODUCTION: Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (IPF), which shares some common pathological features with acute respiratory distress syndrome (ARDS). The new definition of ARDS requires positive end-expiratory pressure (PEEP) to assess gas exchange and has better predictive validity for short-term mortality compared with the previous definition. OBJECTIVES: The aim of this study was to evaluate the prognostic utility of oxygenation with PEEP in AE-IPF. METHODS: We performed a retrospective cohort study using the data of AE-IPF patients between 2007 and 2015. At the time of diagnosis, PaO2 /FiO2 was evaluated before and 30 minutes after PEEP. We evaluated the prognostic utility of PaO2 /FiO2 with PEEP after including other candidate prognostic factors. Considering the definition of ARDS, patients with AE-IPF were classified into a severe group (PaO2 /FiO2 <= 300 with PEEP) and a non-severe group (PaO2 /FiO2 > 300 with PEEP). RESULTS: We identified 62 consecutive patients with AE-IPF. All patients were treated with mechanical ventilation on the first day. The median PaO2 /FiO2 before and 30 minutes after PEEP was significantly increased (237.5-425.5, P < .001). In multivariate Cox proportional analysis, Krebs von den Lungen-6 (KL-6) (HR 1.239; 95%CI 1.050 1.461; P = .011), D-dimer (HR 1.039; 95%CI 1.015-1.064; P = .001), % neutrophils in bronchoalveolar lavage fluid (HR 1.015; 95%CI 1.003-1.027; P = .017), and being in the severe group (HR 3.233; 95%CI 1.503-6.957; P = .003) had significant impacts on survival up to 90 days. CONCLUSION: Evaluation of oxygenation with PEEP may provide useful information for predicting short-term mortality in patients with AE-IPF. PMID- 28026114 TI - Self-Templated Formation of Uniform F-CuO Hollow Octahedra for Lithium Ion Batteries. AB - Novel F-CuO and FeOOH hollow octahedra are developed through a facile structure evolution reaction. The formation of interior voids within the hierarchical octahedra is motivated by the Cl- ions based etching, under a precise control over reaction agents and conditions. Owing to the synergistic effect of unique structural features and favorable composition, the hollow octahedra exhibit superior lithium-storage properties. PMID- 28026116 TI - Hyperpolarized 13 C-Acetate-to-acetylcarnitine imaging: Correction of acetate transport into mitochondria. PMID- 28026115 TI - Immune Cell-Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery. AB - Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell-mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer-specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP-PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti-BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP-PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP-PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell-cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The "self-powered" immune cell-mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies. PMID- 28026117 TI - Molecular elements of pheromone detection in the female moth, Heliothis virescens. AB - Pheromones play pivotal roles in the reproductive behavior of moths, most prominently for the mate finding of male moths. Accordingly, the molecular basis for the detection of female-released pheromones by male moths has been studied in great detail. In contrast, little is known about how females can detect pheromone components released by themselves or by conspecifics. In this study, we assessed the antenna of female Heliothis virescens for elements of pheromone detection. In accordance with previous findings that female antennae respond to the sex pheromone component (Z)-9-tetradecenal, we identified olfactory sensory neurons that express its cognate receptor, the receptor type HR6. All HR6 cells coexpressed the "sensory neuron membrane protein 1" (SNMP1) and were associated with supporting cells expressing the pheromone-binding proteins PBP1 and PBP2. These features are reminiscent to male antennae and point to congruent mechanisms for pheromone detection in the two sexes. Further analysis of the SNMP1 expressing cells revealed a higher number in females compared to males. Moreover, in females, the SNMP1 neurons were arranged in clusters, which project their dendrites into a common sensillum, whereas in males there were only solitary SNMP1-neurons and only 1 per sensillum. Not all SNMP1 positive cells in female antennae expressed HR6 but instead the putative pheromone receptors HR11 and HR18, respectively. Neurons expressing 1 of the 3 receptor types were assigned to different sensilla. Together the data indicate that on the antenna of females, sensory neurons in a subset of sensilla trichodea are equipped with molecular elements, which render them responsive to pheromones. PMID- 28026118 TI - Mounier-Kuhn syndrome (tracheobronchomegaly): An analysis of eleven cases. AB - BACKGROUND AND AIM: Mounier-Kuhn syndrome (MKS) is a congenital disorder characterized by tracheobronchomegaly resulting from the absence of elastic fibers in the trachea and main bronchi or atrophy and thinning of the smooth muscle layer. In this syndrome, dead space associated with tracheobronchomegaly increases and discharge of secretions decreases because of ineffective coughing. The most common complications are recurrent lower respiratory tract infections and bronchiectasis. We examined the clinical characteristics, radiological features, and related complications of patients with MKS. METHODS: The cases were obtained between September 2007 and November 2015. Computed tomography scans of the chest were used to diagnose tracheobronchomegaly. RESULTS: All cases (a total of 11) were males with a mean age of 63 +/- 13 (range, 38-80) years. The mean diameter of the trachea was 31.53 +/- 2.99 mm; the mean transverse diameter was 31.69 +/- 3.10 mm and the mean sagittal diameter was 31.36 +/- 3.01 mm. Complaints at the time of presentation included chronic cough, purulent sputum, dyspnea, and hemoptysis. There were recurrent pulmonary infections in seven cases, bronchiectasis in six, and tracheal diverticulum in four at the time of diagnosis. CONCLUSIONS: In this article, 11 cases with various rarely seen complications are presented and evaluated in the light of current literature. We recommend that if chronic cough, recurrent pulmonary infections, and bronchiectasis seen in a patient, MKS should be kept in mind. PMID- 28026119 TI - Bench evaluation of commercially available and newly developed interfaces for mouthpiece ventilation. AB - INTRODUCTION: Mouthpiece ventilation represents a valuable treatment for patients needing daytime non-invasive ventilation. This modality is however underused, in part because of limitations in the available equipment. OBJECTIVE: To develop a new flexible and moldable mouthpiece, aiming to address some of the issues of the currently available interfaces. METHODS: We compared two commercially available and the newly developed mouthpieces in a bench test using four life-support home ventilators and three settings per ventilator. RESULTS: The three interfaces showed marked differences in their resistive characteristics. In the volume controlled setting (VC-CMV) with 500 mL tidal volume (VT ), the delivered VT , ranged between 459 +/- 7 mL (-8%) and 501 +/- 4 mL (+0.2%), according to the used ventilator. In the VC-CMV setting with VT 1000 mL, one of the ventilators did not assure the set VT with the new mouthpiece, because of the high-pressure limitation. In the pressure-controlled setting (PC-CMV at 20 cmH2 O), the effective pressure differed between the tested interfaces according to their resistance, resulting in a decrease in the delivered VT . CONCLUSIONS: They found measurable differences in the ventilation's performances comparing the interfaces for mouthpiece ventilation, which seem to have a minor clinical relevance in the most settings, but should be systematically checked. They validated in-vitro the newly developed mouthpiece with respect to the ventilation performances; a clinical study is needed to investigate the potential advantages we expect from the new mouthpiece. PMID- 28026120 TI - Reply. PMID- 28026121 TI - Circulating exosomal microRNA-96 promotes cell proliferation, migration and drug resistance by targeting LMO7. AB - Detection and treatment of lung cancer still remain a clinical challenge. This study aims to validate exosomal microRNA-96 (miR-96) as a serum biomarker for lung cancer and understand the underlying mechanism in lung cancer progression. MiR-96 expressions in normal and lung cancer patients were characterized by qPCR analysis. Changes in cell viability, migration and cisplatin resistance were monitored after incubation with isolated miR-96-containing exosomes, anti-miR-96 and anti-miR negative control (anti-miR-NC) transfections. Dual-luciferase reporter assay was used to study interaction between miR-96 and LIM-domain only protein 7 (LMO7). Changes induced by miR-96 transfection and LMO7 overexpression were also evaluated. MiR-96 expression was positively correlated with high-grade and metastatic lung cancers. While anti-miR-96 transfection exhibited a tumour suppressing function, exosomes isolated from H1299 enhanced cell viability, migration and cisplatin resistance. Potential miR-96 binding sites were found within the 3'-UTR of wild-type LMO7 gene, but not of mutant LMO7 gene. LMO7 expression was inversely correlated with lung cancer grades, and LMO7 overexpression reversed promoting effect of miR-96. We have identified exosomal miR-96 as a serum biomarker of malignant lung cancer. MiR-96 promotes lung cancer progression by targeting LMO7. The miR-96-LMO7 axis may be a therapeutic target for lung cancer patients, and new diagnostic or therapeutic strategies could be developed by targeting the miR-96-LMO7 axis. PMID- 28026122 TI - The Electrochemical Response of Single Crystalline Copper Nanowires to Atmospheric Air and Aqueous Solution. AB - In this paper, single crystalline copper nanowires (CuNWs) have been electrochemically grown through anodic aluminum oxide template. The environmental stability of the as-obtained CuNWs in both 40% relative humidity (RH) atmosphere and 0.1 m NaOH aqueous solution has been subsequently studied. In 40% RH atmosphere, a uniform compact Cu2 O layer is formed as a function of exposure time following the logarithmic law and epitaxially covers the CuNW surfaces. It is also found that the oxide layers on CuNWs are sequentially grown when subjected to the cyclic voltammetry measurement in 0.1 m NaOH solution. An epitaxially homogeneous Cu2 O layer is initially formed over the surface of the CuNW substrates by solid-state reaction (SSR). Subsequently, the conversion of Cu2 O into epitaxial CuO based on the SSR takes place with the increase of applied potential. This CuO layer is partially dissolved in the solution forming Cu(OH)2 , which then redeposited on the CuNW surfaces (i.e., dissolution redeposition (DR) process) giving rise to a mixed polycrystalline CuO/Cu(OH)2 layer. The further increase of applied potential allows the complete oxidation of Cu2 O into CuO to form a dual-layer structure (i.e., CuO inner layer and Cu(OH)2 outer layer) with random orientations through an enhanced DR process. PMID- 28026123 TI - Liposomal Spherical Nucleic Acids for Regulating Long Noncoding RNAs in the Nucleus. AB - Emerging evidence indicates that long noncoding RNAs (lncRNAs) are actively involved in a number of developmental and tumorigenic processes. Here, the authors describe the first successful use of spherical nucleic acids as an effective nanoparticle platform for regulating lncRNAs in cells; specifically, for the targeted knockdown of the nuclear-retained metastasis associated lung adenocarcinoma transcript 1 (Malat1), a key oncogenic lncRNA involved in metastasis of several cancers. Utilizing the liposomal spherical nucleic acid (LSNA) constructs, the authors first explored the delivery of antisense oligonucleotides to the nucleus. A dose-dependent inhibition of Malat1 upon LSNA treatment as well as the consequent up-regulation of tumor suppressor messenger RNA associated with Malat1 knockdown are shown. These findings reveal the biologic and therapeutic potential of a LSNA-based antisense strategy in targeting disease-associated, nuclear-retained lncRNAs. PMID- 28026124 TI - Cobalt-Nickel Layered Double Hydroxides Modified on TiO2 Nanotube Arrays for Highly Efficient and Stable PEC Water Splitting. AB - TiO2 -based photoanodes have attracted extensive attention worldwide for photoelectrochemical (PEC) water splitting, but these materials still suffer from poor electron-hole separation and low photoconversion efficiency. Here, the high PEC water splitting activity and long-term stability against photocorrosion of well-aligned hierarchical TiO2 @CoNi-layered double hydroxides nanotube arrays (TiO2 @CoNi-LDHs NTAs) are reported. The typical TiO2 @CoNi-LDHs NTAs exhibits enhancing photocurrent density of 4.4 mA cm-2 at a potential of 1.23 V (vs reversible hydrogen electrode) under AM 1.5G simulated sunlight (100 mW cm-2 ), 3.3 times higher than that of the pristine TiO2 sample. Moreover, this hierarchical electrode displays excellent stability against photocorrosion with initial activity loss no more than 1.0% even after 10 h irradiation in Na2 SO4 electrolyte solution (pH 6.8), much competitive to those reported TiO2 -based photoelectrodes. This work may offer a combinatorial synthesis strategy for the preparation of hierarchical architectures with high PEC performances. PMID- 28026125 TI - Effects of temperature on fitness costs in chlorpyrifos-resistant brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae). AB - Insecticide resistance is inevitable if an insecticide is widely used to control insect pests. Fortunately, the resistance-associated fitness costs often give chances to manage resistances. In most cases, the fitness cost in resistant insects is often evaluated under laboratory conditions for insect development, which limits its practical application in pest control in the field. In a laboratory population R9 with 253-fold resistance to chlorpyrifos after nine generation selection with chlorpyrifos, the relative fitness was only 0.206 under laboratory conditions (25 degrees C, humidity 70%-80% and 16 h light/8 h dark photoperiod), when compared to S9, a susceptible counterpart (resistance ratio = 2.25-fold) from the same origin as R9 but without any selection with insecticides. Temperatures varied the resistance-associated fitness costs, with enhanced costs at high temperatures and reduced costs at low temperatures, such as 0.174 at 32 degrees C and 0.527 at 18 degrees C. The copulation rate and fecundity were two key factors for the reduced costs at low temperatures. Another finding was that R9 individuals needed much more time to recover from heat shock than that of S9, but R9 and S9 individuals were similarly sensitive to cold shock. The low fitness cost at low temperatures would increase the overwintering population, which might further increase risks of rapid development and widespread distribution of chlorpyrifos resistance in Nilaparvata lugens. PMID- 28026126 TI - Recapitulating the Micromechanical Behavior of Tension and Shear in a Biomimetic Hydrogel for Controlling Tenocyte Response. AB - A fiber composite system is presented which recapitulates the fiber-composite like nature of tissues and generates similar modes of shear and tension. The shear/tension ratio can be customized during composite manufacture and incorporates viable cells. The system is a valuable tool for mechanotransduction research, providing a platform with physiologically relevant conditions for investigating cell behavior in different tissue types. PMID- 28026127 TI - Well-differentiated bronchial neuroendocrine tumors: Clinical management and outcomes in 105 patients. AB - INTRODUCTION: Bronchial neuroendocrine tumors (NETs) are rare tumors representing approximately 20%-30% of all neuroendocrine tumors and 2%-3% of all adult lung cancers. Here, they present a large case series of well-differentiated bronchial NETs with the aim of investigating the behavior of these tumors and long-term outcomes. METHODS: A retrospective review was performed of 105 patients with bronchial NETs managed in a tertiary referral center in the period between January 1998 and January 2012. RESULTS: Bronchial NETs are commoner in females and the commonest presenting symptoms were cough (13.9%) and dyspnoea (11.6%). OctreoscanTM and Gallium-68 DOTATATE PET were found to have similar diagnostic sensitivity and FDG PET was more sensitive for higher-grade tumors. Over a median follow-up period of 35.5 months mortality rate was 5.7%. The 5-year survival was 76% and the 10-year survival was 62%. Female patients survived longer but this difference was not statistically significant (P = .59). Older age greater than 50 years (P = .027), higher levels of Chromogranin A (CgA) (P = .034), first-line treatment with surgery (P = .005), ki67 over 10% (P = .037), and tumor stage (P = .036) but not tumor grade (P = .22), were significantly associated with survival. DISCUSSION: Several factors have been identified which are independently associated with survival including CgA levels greater than 100 pmol/L, tumor stage, age greater than 50, ki67 over 10% and having surgery as first-line treatment. There was no difference in survival between typical and atypical carcinoids. PMID- 28026128 TI - ETS transcription factor ETV2/ER71/Etsrp in hematopoietic and vascular development, injury, and regeneration. AB - The major goal in regenerative medicine is to repair and restore injured, diseased or aged tissue function, thereby promoting general health. As such, the field of regenerative medicine has great translational potential in undertaking many of the health concerns and needs that we currently face. In particular, hematopoietic and vascular systems supply oxygen and nutrients and thus play critical roles in tissue development and tissue regeneration. Additionally, tissue vasculature serves as a tissue stem cell niche and thus contributes to tissue homeostasis. Notably, hematopoietic and vascular systems are sensitive to injury and subject to regeneration. As such, successful hematopoietic and vascular regeneration is prerequisite for efficient tissue repair and organismal survival and health. Recent studies have established that the interplay among the ETS transcription factor ETV2, vascular endothelial growth factor, and its receptor VEGFR2/FLK1 is essential for hematopoietic and vascular development. Emerging studies also support the role of these three factors and possible interplay in hematopoietic and vascular regeneration. Comprehensive understanding of the molecular mechanisms involved in the regulation and function of these three factors may lead to more effective approaches in promoting tissue repair and regeneration. Developmental Dynamics 246:318-327, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026129 TI - Light-Enhancing Plasmonic-Nanopore Biosensor for Superior Single-Molecule Detection. AB - A stacked plasmonic nanowell-nanopore biosensor strongly suppresses the background fluorescence from the bulk and yields net more than tenfold enhancement of the fluorescence intensity. The device offers extremely high signal-to-background (S/B) ratio for single-molecule detection at ultralow excitation laser intensities, while maintaining extremely high temporal bandwidth for single-DNA sensing. PMID- 28026130 TI - Efficacy and safety of a VWF/FVIII concentrate (wilate(r) ) in inherited von Willebrand disease patients undergoing surgical procedures. AB - INTRODUCTION: Surgical procedures in von Willebrand disease (VWD) patients may require prophylactic treatment with exogenous von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding. Wilate(r) is a plasma-derived, double virus-inactivated, highly purified, freeze-dried VWF/FVIII concentrate, containing both factors in a physiological activity ratio of 1:1. AIM: To investigate the efficacy and safety of wilate(r) in maintaining haemostasis in VWD patients undergoing surgical procedures. METHODS: This prospective, open-label multinational clinical study documents 28 individuals who underwent 30 surgical procedures managed with wilate(r) . Twenty-one patients had VWD Type 3, and 21 surgeries were major. Efficacy was assessed intra- and postoperatively by the surgeon and investigator, respectively, and adjudicated by an Independent Data Monitoring Committee, using an objective scale based on blood loss, transfusion requirements and postoperative bleeding and oozing. Treatment success (primary endpoint) was determined using a composite assessment algorithm and was formally assessed. RESULTS: Surgical prophylaxis with wilate(r) was successful in 29 of 30 procedures. The overall rate of success was 96.7% (98.75% CI: 0.784, 1.000). All 21 surgeries in patients with VWD Type 3 were managed successfully. There was no accumulation of VWF or FVIII after multiple dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed. CONCLUSIONS: Wilate(r) demonstrated effective prevention and treatment of bleeding in inherited VWD patients undergoing surgery, with no clinically significant safety concerns. PMID- 28026132 TI - Late treatment effects following bone marrow transplant: Efficacy of implementing international guidelines. AB - An increasing cohort of haematopoietic cell transplantation (HCT) survivors has raised awareness of long-term and late effects. Updated recommendations for HCT late effects screening were published in 2012 [Majhail et al. Biology of Blood and Marrow Transplantation, 18 (2012):348]. We aimed to assess the clinical efficacy of a dedicated screening clinic to identify problems in HCT survivors using the international guidelines. Clinic letters and test results of the first 59 consecutive patients attending the screening clinic were evaluated. 30 females and 29 males (mean age of 49 years, range 22-74) were included. The mean time since transplant was 6 years (0.5-18). 49/65 transplants were allogeneic. Primary indications for HCT were myeloid (56%), lymphoid (37%), solid tumour (5%) and auto-immune diseases (2%). 134 complications were reported (mean 2, range 0-8), with 114 documented further actions/referrals. The most commonly reported concerns were pain 18/59 (31%), fatigue 14/59 (24%), sexual function 14/59 (24%) and sleep disturbance 11/59 (19%). Second primary malignancies were recorded in five cases. Implementation and audit of the international late effect screening guidelines confirm the need for systematic long-term physical and psychological screening and care, thus ensuring timely and efficient identification of problems and the opportunity to minimise morbidity effects and optimise health. PMID- 28026131 TI - Sphingosine-1-Phosphate Receptor-3 Supports Hematopoietic Stem and Progenitor Cell Residence Within the Bone Marrow Niche. AB - Hematopoietic stem and progenitor cells (HSPCs) egress from bone marrow (BM) during homeostasis and at increased rates during stress; however, the mechanisms regulating their trafficking remain incompletely understood. Here we describe a novel role for lipid receptor, sphingosine-1-phosphate receptor 3 (S1PR3), in HSPC residence within the BM niche. HSPCs expressed increased levels of S1PR3 compared to differentiated BM cells. Pharmacological antagonism or knockout (KO) of S1PR3 mobilized HSPCs into blood circulation, suggesting that S1PR3 influences niche localization. S1PR3 antagonism suppressed BM and plasma SDF-1, enabling HSPCs to migrate toward S1P-rich plasma. Mobilization synergized with AMD3100 mediated antagonism of CXCR4, which tethers HSPCs in the niche, and recovered homing deficits of AMD3100-treated grafts. S1PR3 antagonism combined with AMD3100 improved re-engraftment and survival in lethally irradiated recipients. Our studies indicate that S1PR3 and CXCR4 signaling cooperate to maintain HSPCs within the niche under homeostasis. These results highlight an important role for S1PR3 in HSPC niche occupancy and trafficking that can be harnessed for both rapid clinical stem cell mobilization and re-engraftment strategies, as well as the opportunity to design novel therapeutics for control of recruitment, homing, and localization through bioactive lipid signaling. Stem Cells 2017;35:1040-1052. PMID- 28026133 TI - Role of increased mean platelet volume (MPV) and decreased MPV/platelet count ratio as poor prognostic factors in lung cancer. AB - OBJECTIVES: In this study, they investigated whether mean thrombocyte volume (MPV) and MPV/platelet count ratio have a prognostic significance in advanced NSCLC or not. METHODS: A total of 496 NSCLC patients at stage IIIB/IV and did not meet exclusion criteria were included in the study. The demographic features (age, gender, smoking habit), clinical characteristics (performance status, weight loss, disease stage, first-line treatment regimen), laboratory tests (levels of hemoglobin, lactate dehydrogenase and calcium as well as MPV, MPV/platelet count ratio and counts of white blood cell, platelet), and histological features (histologic type, tumor grade) were recorded. RESULTS: The MPV levels of all patients were determined as 10.2 {plus minus} 3.4 (range, 6.4 14.1 fL). With ROC curve analysis, the MPV/PC ratio was associated with a sensitivity of 67.8% and a specificity of 84.8% at a cutoff value of 0.47424 for presence of brain metastasis at the time of diagnosis. Univariate analysis showed that OS was significantly shorter in the group with an increased MPV level than in the other group (median OS time 6.8 months vs. 11.5 months, log-rank, P = .032). Multivariate analysis confirmed that an increased MPV level was an independent poor prognostic factor for OS (HR: 1.704, 95% CI: 1.274-3.415, P = .014). CONCLUSIONS: Unlike results of previous studies, the study showed that increased MPV was an important prognostic factor in patients with NSCLC. Hence, an increased MPV level may be used as a prognostic biomarker to estimate for poor overall survival in patients with NSCLC. PMID- 28026134 TI - Chiral Nanoparticle as a New Efficient Antimicrobial Nanoagent. AB - d-type functionalized nanoparticles (NPs) can bind to MurD ligase with high affinity and inhibit its peptidoglycan synthetic enzyme activity, and finally cause bacterial killing. In contrast, its L-type counterpart displays a negligible effect, indicating that the chiral structure of the functionalized NPs plays an essential role in their binding interaction with MurD and therefore the antibacterial activity. PMID- 28026135 TI - Protective effects of trans-caryophyllene on maintaining osteoblast function. AB - Age-related osteoblast dysfunction is the main cause of age-related bone loss. Trans-caryophyllene (TC) is an important constituent of the essential oils derived from several species of medicinal plants. In this study, we investigated the effects of TC on osteoblast function in osteoblastic MC3T3-E1 cells. The results indicate that TC caused a significant elevation in collagen content, alkaline phosphatase activity, osteocalcin production, and mineralization, which are the four markers that account for the various stages of osteoblastic differentiation. In addition, pretreatment with TC prior to antimycin A exposure significantly reduced antimycin A-induced cell damage by attenuating cell death, preventing the release of reactive oxygen species and impeding osteoblast dysfunction. TC has been shown to be an agonist of the cannabinoid type 2 receptor (CB2R), and the effects of TC on osteocalcin secretion and matrix mineralization were abolished in MC3T3E1 cells transfected with CB2R siRNA. Our findings that TC promotes the formation of a mineralized extracellular matrix help to elucidate the role of CB2 signaling in the formation of bone and the maintenance of normal bone mass. (c) 2016 IUBMB Life, 69(1):22-29, 2017. PMID- 28026136 TI - Erratum for: Identification of arginine and its "Downstream" molecules as potential markers of breast cancer, IUBMB life, 10.1002/Iub.1557, 68(10): 817 822. PMID- 28026139 TI - Technology, health care and person centeredness: Beyond Utopia and Dystopia. Thinking the future. PMID- 28026138 TI - Towards a molecular architecture of the centrosome in Toxoplasma gondii. AB - Toxoplasma gondii is the causative agent of toxoplasmosis. The pathogenicity of this unicellular parasite is tightly linked to its ability to efficiently proliferate within its host. Tachyzoites, the fast dividing form of the parasite, divide by endodyogeny. This process involves a single round of DNA replication, closed nuclear mitosis, and assembly of two daughter cells within a mother. The successful completion of endodyogeny relies on the temporal and spatial coordination of a plethora of simultaneous events. It has been shown that the Toxoplasma centrosome serves as signaling hub which nucleates spindle microtubules during mitosis and organizes the scaffolding of daughter cells components during cytokinesis. In addition, the centrosome is essential for inheriting both the apicoplast (a chloroplast-like organelle) and the Golgi apparatus. A growing body of evidence supports the notion that the T. gondii centrosome diverges in protein composition, structure and organization from its counterparts in higher eukaryotes making it an attractive source of potentially druggable targets. Here, we summarize the current knowledge on T. gondii centrosomal proteins and extend the putative centrosomal protein repertoire by in silico identification of mammalian centrosomal protein orthologs. We propose a working model for the organization and architecture of the centrosome in Toxoplasma parasites. Experimental validation of our proposed model will uncover how each predicted protein translates into the biology of centrosome, cytokinesis, karyokinesis, and organelle inheritance in Toxoplasma parasites. PMID- 28026140 TI - IPONS conference report 2015. PMID- 28026137 TI - The "right" way is not always popular: comparison of surgeons' perceptions during laparoscopic cholecystectomy for acute cholecystitis among experts from Japan, Korea and Taiwan. AB - BACKGROUND: Generally, surgeons' perceptions of surgical safety are based on experience and institutional policy. Our recent pilot survey demonstrated that the acceptable duration of surgery and criteria for open conversion during laparoscopic cholecystectomy (LC) vary among workplaces. METHODS: A web-based survey was distributed to 554 expert LC surgeons in Japan, Korea, and Taiwan. The questionnaire covered LC experience, safety measures and recognition of landmarks, decision-making regarding conversion to open/partial cholecystectomy and the implications of this decision. Overall responses were compared among nations, and then stratified by LC experience level (lifetime cases 200-499, 500 999, and >=1,000). RESULTS: The response rate was 92.6% (513/554); 67 surgeons with <=199 LCs were excluded, and responses from 446 surgeons were analyzed. We observed significant differences among nations on almost all questions. Differences that remained after stratification by LC experience were on questions related to acceptable duration of surgery, adoption rates of intraoperative cholangiography, the "critical view of safety" technique, identification of Rouviere's sulcus, recognition of the SS-Inner layer theory, and intraoperative judgment to abandon conventional LC. CONCLUSIONS: Even among experts, surgeons' perceptions during LC are workplace-dependent. A novel grading system of surgical difficulty and standardized LC procedures are paramount to generate high-level evidence. PMID- 28026141 TI - In vitro fermentative capacity of swine large intestine: comparison between native Lantang and commercial Duroc breeds. AB - Native Lantang and commercial Duroc pigs were used as animal models to evaluate the differences existing in dietary fiber utilization ability between breeds. Animals were fed the same diet from weaning (4 weeks) to 4 months of age. Neutral detergent fiber (NDF) from wheat bran (as substrate) and fecal samples from the two breeds (as inoculum) were used in an in vitro gas production trial. Results showed that cumulative and maximum gas productions were higher in inocula from Lantang than those from the Duroc breed (P < 0.05). The degradation capacity of NDF for microbiome from Lantang fecal samples were significantly higher compared to Duroc (P < 0.01). The total quantity of short-chain fatty acids and its constituents from the fermentation liquors were different between breeds, suggesting that the dynamic characteristics of fermentation differed between the two breeds. The PCR denaturing gradient gel electrophoresis fingerprint and cluster analysis demonstrated that microbial communities of the two breeds were separated into two clusters and the bacterial community structure of large intestine among the two breed of pigs was different. Our results concluded that Lantang had higher dietary fiber degradation capacity than Duroc pigs, and the higher degradation capacity for the former breed was due to differences in the inherent microbial community in their respective large intestines. PMID- 28026142 TI - Thinking families: A study of the characteristics of the workforce that delivers family-focussed practice. AB - Parenting with mental illness is not uncommon and is often associated with a range of challenges for parents, children, and the family unit. Family-focussed practice involves the provision of services to the wider family system, including children. While family-focussed practice is important to consumers and their families, adult mental health practitioners do not routinely discuss parenting or children with their clients, nor work closely with the whole family. In the present study, we aimed to examine the characteristics of practitioners from Australian adult mental health services associated with family-focussed practices. Characteristics included sex, years of experience, location, and previous training in child and family-focussed practice. A total of 307 adult mental health practitioners from Victoria, Australia, responded to the Family Focused Mental Health Practice Questionnaire and a series of demographic items. The results indicated that particular practitioner characteristics predicted the delivery of family-focussed practice. Practitioner experience, sex, working in a rural location, and previous family- or child-related training were found to be important in the provision of family-focussed practice. More experienced, female, rurally-located, and well-trained practitioners undertake most family-focussed practice. These results suggest that training in family-focussed practice needs to be promoted, with considerations made for differing needs according to the characteristics of the adult mental health practitioner. PMID- 28026143 TI - Umpolung Addition of Aldehydes to Aryl Imines. AB - One of the classical ways to synthesize amines involves the coupling of carbonyl compounds and imines, either through enolate chemistry or acyl-based carbanion equivalents. We herein report an alternative strategy that is based on the use of aldehydes as alkyl carbanion equivalents in a reductive coupling with aryl imines. A wide array of secondary amines can be synthesized in moderate to high yields. This reaction is mediated by hydrazine and catalyzed by ruthenium(II) complexes, and it tolerates various functional groups, such as esters, amides, and nitriles. PMID- 28026144 TI - Deciduoid mesothelioma of the thorax: A comprehensive review of the scientific literature. AB - OBJECTIVE: Deciduoid mesothelioma is a rare variant of malignant epithelioid mesothelioma. It often involves the peritoneum, but also thoracic cases have been reported. The aim of the present review is to describe the demographic, clinical, radiological, and pathological features of such a rare variant of thoracic mesothelioma, and the state of the art regarding the therapeutic approaches currently available. DATA SOURCE: English-language articles published from 1985 to June 2016, and related to thoracic deciduoid mesothelioma cases were retrieved using the Pubmed database. STUDY SELECTION: The search terms were "mesothelioma," "thoracic mesothelioma," "epithelial mesothelioma," "pleural mesothelioma," and "deciduoid mesothelioma." RESULTS: Forty-four cases included in 16 articles, published in the period under investigation, were analyzed in detail. CONCLUSIONS: The mean age of the patients was 63 years, and the male to female ratio 1.7:1. Approximately 58% had exposure to asbestos, and 73% had a smoking history; familiarity was rarely reported. The most common anatomical site of origin was the right pleura, and the most frequent clinical manifestations were chest pain, dyspnea, cough, and weight loss. Thoracic X-ray and computed tomography were the imaging techniques most employed for diagnosis and surgical planning. The pathological diagnosis was obtained by examination of surgical or biopsy specimens in most cases. The best treatment strategy of deciduoid mesothelioma is a matter of debate; nevertheless a multidisciplinary approach is currently the best option for the choice of the adequate therapeutic scheme. PMID- 28026146 TI - Profiling the extended phenotype of plant pathogens: Challenges in Bacterial Molecular Plant Pathology. AB - One of the most fundamental questions in plant pathology is what determines whether a pathogen grows within a plant? This question is frequently studied in terms of the role of elicitors and pathogenicity factors in the triggering or overcoming of host defences. However, this focus fails to address the basic question of how the environment in host tissues acts to support or restrict pathogen growth. Efforts to understand this aspect of host-pathogen interactions are commonly confounded by several issues, including the complexity of the plant environment, the artificial nature of many experimental infection systems and the fact that the physiological properties of a pathogen growing in association with a plant can be very different from the properties of the pathogen in culture. It is also important to recognize that the phenotype and evolution of pathogen and host are inextricably linked through their interactions, such that the environment experienced by a pathogen within a host, and its phenotype within the host, is a product of both its interaction with its host and its evolutionary history, including its co-evolution with host plants. As the phenotypic properties of a pathogen within a host cannot be defined in isolation from the host, it may be appropriate to think of pathogens as having an 'extended phenotype' that is the product of their genotype, host interactions and population structure within the host environment. This article reflects on the challenge of defining and studying this extended phenotype, in relation to the questions posed below, and considers how knowledge of the phenotype of pathogens in the host environment could be used to improve disease control. What determines whether a pathogen grows within a plant? What aspects of pathogen biology should be considered in describing the extended phenotype of a pathogen within a host? How can we study the extended phenotype in ways that provide insights into the phenotypic properties of pathogens during natural infections? PMID- 28026145 TI - The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo. AB - Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20-40 years) and are classified as seminoma or non seminoma. TGCTs are commonly treated by orchiectomy and chemo- or radiotherapy. However, a subset of metastatic non-seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumour therapy, which interferes with the function of 'bromodomain and extraterminal (BET)' proteins. JQ1-treated TGCT cell lines display up-regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down-regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma-like TCam-2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs. PMID- 28026147 TI - Development of a Novel Immobilization Method by Using Microgels to Keep Enzyme in Hydrated Microenvironment in Porous Hydrophobic Membranes. AB - Using colloidal polyacrylamide (PAAm) microgels as carriers, a novel strategy for covalent immobilization of enzymes maintained in hydrated microenvironment on/in a macroporous surface-functionalized hydrophobic polyvinylidene fluoride (PVDF) membrane is developed. The PAAm microgels are synthesized by inverse miniemulsion polymerization, and first the parameters are investigated which are suited to obtain particles in the desired size range, 100-200 nm, with narrow size distribution. Amino functions are then imparted to the microgels applying the Hofmann reaction. The modification is confirmed by Fourier-transform infrared spectroscopy analysis, ninhydrin test, and elemental analysis. In addition, functionalized microgels are characterized by dynamic light scattering. The amino functionalized PAAm microgels are then immobilized on pre-modified PVDF membrane having aldehyde functionalities on the surface. Afterward, unreacted aldehyde groups still present on the membrane where quenched by ethanolamine and the enzyme lipase from Candida rugosa (LCR) is subsequently immobilized on the microgels loaded PVDF membrane via glutaraldehyde cross-linking, exploiting the free amino groups on immobilized microgels. Catalytic efficiency of LCR immobilized by this strategy is evaluated using para-nitrophenyl palmitate as substrate and compared with LCR directly immobilized on PVDF membrane without microgels. Results show that LCR immobilized by means of microgels exhibits better performance with a 2.3-fold higher specific biocatalytic activity. PMID- 28026148 TI - Manipulating Electrical and Fluidic Access in Integrated Nanopore-Microfluidic Arrays Using Microvalves. AB - On-chip microvalves regulate electrical and fluidic access to an array of nanopores integrated within microfluidic networks. This configuration allows for on-chip sequestration of biomolecular samples in various flow channels and analysis by independent nanopores. PMID- 28026149 TI - Arctigenin protects against neuronal hearing loss by promoting neural stem cell survival and differentiation. AB - Neuronal hearing loss has become a prevalent health problem. This study focused on the function of arctigenin (ARC) in promoting survival and neuronal differentiation of mouse cochlear neural stem cells (NSCs), and its protection against gentamicin (GMC) induced neuronal hearing loss. Mouse cochlea was used to isolate NSCs, which were subsequently cultured in vitro. The effects of ARC on NSC survival, neurosphere formation, differentiation of NSCs, neurite outgrowth, and neural excitability in neuronal network in vitro were examined. Mechanotransduction ability demonstrated by intact cochlea, auditory brainstem response (ABR), and distortion product optoacoustic emissions (DPOAE) amplitude in mice were measured to evaluate effects of ARC on GMC-induced neuronal hearing loss. ARC increased survival, neurosphere formation, neuron differentiation of NSCs in mouse cochlear in vitro. ARC also promoted the outgrowth of neurites, as well as neural excitability of the NSC-differentiated neuron culture. Additionally, ARC rescued mechanotransduction capacity, restored the threshold shifts of ABR and DPOAE in our GMC ototoxicity murine model. This study supports the potential therapeutic role of ARC in promoting both NSCs proliferation and differentiation in vitro to functional neurons, thus supporting its protective function in the therapeutic treatment of neuropathic hearing loss in vivo. PMID- 28026150 TI - Worm-Shape Pt Nanocrystals Grown on Nitrogen-Doped Low-Defect Graphene Sheets: Highly Efficient Electrocatalysts for Methanol Oxidation Reaction. AB - Although direct methanol fuel cell offers high energy use efficiency and low pollution emission, the lack of suitable electrode materials poses a great challenge to its commercial application. Herein, a facile and scalable approach is developed to fabricate a hybrid electrocatalyst consisting of strongly coupled worm-shape Pt nanocrystals and nitrogen-doped low-defect graphene (N-LDG) sheets. Interestingly, it is found that the formation of Pt nanoworms (NWs) is induced by the N atoms in the high-quality carbon matrix, which also allows the integration of their respective structural advantages and leads to a strong synergetic coupling effect. As a result, the obtained Pt NW/N-LDG catalyst exhibits an extremely high mass activity of 1283.1 mA mg-1 toward methanol oxidation reaction, accompanied by reliable long-term stability and good antipoisoning ability, which are dramatically enhanced as compared with conventional Pt nanoparticle catalysts dispersed on undoped LDG, reduced graphene oxide, and commercial carbon black supports. PMID- 28026151 TI - Controlled Deposition and Performance Optimization of Perovskite Solar Cells Using Ultrasonic Spray-Coating of Photoactive Layers. AB - This study investigated a new film-deposition technique, ultrasonic spray coating, for use in the production of a photoactive layer of perovskite solar cells. Stable atomization and facile fabrication of perovskite thin films by ultrasonic spray-coating were achieved in a one-step method through manipulating the ink formulation (e.g., solution concentration, precursor composition, and mixing solvent ratio) and the drying kinetics (e.g., post-annealing temperature). The performance of the perovskite solar cells was mainly influenced by the intrinsic film morphology and crystalline orientation of the deposited perovskite layer. By suitable optimization of the spreading and drying conditions of the ink, ultrasonic spray-coated perovskite photovoltaic devices were obtained with a maximum power conversion efficiency of 11.30 %, a fill factor of 73.6 %, a short circuit current of 19.7 mA cm-1 , and an open-circuit voltage of 0.78 V, respectively. Notably, the average power efficiency reached above 10 %, attributed to the large flower-like perovskite crystal with orientation along the (1 1 2)/(2 0 0) and (2 2 4)/(4 0 0) directions. Thus, the ultrasonic spray coating method for perovskite photoactive layers, combining advantages of good photovoltaic performance results and benefits from cost and processing, has the potential for large-scale commercial production. PMID- 28026152 TI - Harnessing Three Dimensional Anatomy of Graphene Foam to Induce Superior Damping in Hierarchical Polyimide Nanostructures. AB - Graphene foam-based hierarchical polyimide composites with nanoengineered interface are fabricated in this study. Damping behavior of graphene foam is probed for the first time. Multiscale mechanisms contribute to highly impressive damping in graphene foam. Rippling, spring-like interlayer van der Waals interactions and flexing of graphene foam branches are believed to be responsible for damping at the intrinsic, interlayer and anatomical scales, respectively. Merely 1.5 wt% graphene foam addition to the polyimide matrix leads to as high as ~300% improvement in loss tangent. Graphene nanoplatelets are employed to improve polymer-foam interfacial adhesion by arresting polymer shrinkage during imidization and pi-pi interactions between nanoplatelets and foam walls. As a result, damping behavior is further improved due to effective stress transfer from the polymer matrix to the foam. Thermo-oxidative stability of these nanocomposites is investigated by exposing the specimens to glass transition temperature of the polyimide (~400 degrees C). The composites are found to retain their damping characteristics even after being subjected to such extreme temperature, attesting their suitability in high temperature structural applications. Their unique hierarchical nanostructure provides colossal opportunity to engineer and program material properties. PMID- 28026153 TI - Clinical and hemodynamic characteristics of pulmonary hypertension associated with interstitial lung disease in China. AB - BACKGROUND: Pulmonary hypertension (PH) is an important complication of interstitial lung disease (ILD). The aim of the present study was to investigate characteristics and prognosis of ILD associated PH in a predominantly Chinese patient cohort. METHODS: Consecutive patients with ILD associated PH, confirmed by right heart catheterization at shanghai pulmonary hospital were included in the study. Characteristics at baseline and during follow-up, as well as survival, were analyzed. RESULTS: This observational study was conducted in 26 patients with a mean age of 60.0 +/- 12.2 y old. The 6-min walking distance was 335.0 +/- 190.9 m. The mean pulmonary arterial pressure (PAP) was 42.9 +/- 10.9 mmHg, cardiac output was 4.4 +/- 1.0 L/min, and pulmonary vascular resistance (PVR) was 8.6 +/- 4.1 Wood Units. The mean PAP was >=35 mmHg in 69.2% of cases. There were no difference in lung function parameters between ILD with PH and ILD without PH. The overall survival rate was 92% at 1 y, 82% at 3 y, and 62% at 5 y. PVR was the only variable significantly associated with death. CONCLUSIONS: Severe hemodynamic impairment along with PH can occur in patients with ILD. These patients have more severely impaired exercise capacity and cardiac function than ILD patients without PH. PVR was the only prognostic factor identified in this group of patients. PMID- 28026154 TI - Surface Topography and Mechanical Strain Promote Keratocyte Phenotype and Extracellular Matrix Formation in a Biomimetic 3D Corneal Model. AB - The optimal functionality of the native corneal stroma is mainly dependent on the well-ordered arrangement of extracellular matrix (ECM) and the pressurized structure. In order to develop an in vitro corneal model, it is crucial to mimic the in vivo microenvironment of the cornea. In this study, the influence of surface topography and mechanical strain on keratocyte phenotype and ECM formation within a biomimetic 3D corneal model is studied. By modifying the surface topography of materials, it is found that patterned silk fibroin film with 600 grooves mm-1 optimally supports cell alignment and ECM arrangement. Furthermore, treatment with 3% dome-shaped mechanical strain, which resembles the shape and mechanics of native cornea, significantly enhances the expression of keratocyte markers as compared to flat-shaped strain. Accordingly, a biomimetic 3D corneal model, in the form of a collagen-modified, silk fibroin-patterned construct subjected to 3% dome-shaped strain, is created. Compared to traditional 2D cultures, it supports a significantly higher expression of keratocyte and ECM markers, and in conclusion better maintains keratocyte phenotype, alignment, and fusiform cell shape. Therefore, the novel biomimetic 3D corneal model developed in this study serves as a useful in vitro 3D culture model to improve current 2D cultures for corneal studies. PMID- 28026155 TI - Corrigendum. PMID- 28026156 TI - Corrigendum. PMID- 28026158 TI - Incorrect Value in Table 2 in the Article by Inciarte-Mundo et al (Arthritis Care Res [Hoboken], July 2016). PMID- 28026157 TI - From Content to Collaboration. AB - Looking back, looking forward: Editor Theresa Kueckmann looks back to the journal's highlights of 2016 and forward to exciting new developments in 2017. PMID- 28026159 TI - Ratiometric Fluorescent Silicon Quantum Dots-Ce6 Complex Probe for the Live Cell Imaging of Highly Reactive Oxygen Species. AB - The monitoring of reactive oxygen species (ROS) in living cells remains challenging because of the complexity, short half-life, and autofluorescence of biological samples. In this work, we designed a ratiometric fluorescent probe for the detection and imaging of ROS, which was constructed from silicon quantum dots (Si QDs) with chlorin e6 (Ce6) through electrostatic attraction and showed well resolved dual fluorescence emission signals (490 and 660 nm). Sensitive and selective biosensing of hydroxyl radical (*OH) was demonstrated on the basis of fluorescence quenching of the Si QDs and Ce6 as an internal reference to avoid environmental interference, with a detection limit of ~0.97 MUM. The endogenous release of *OH was also monitored and imaged in living cells. PMID- 28026160 TI - Mussel-Inspired Polydopamine Functionalized Plasmonic Nanocomposites for Single Particle Catalysis. AB - Polydopamine functionalized plasmonic nanocomposites with well-distributed catalytically active small gold nanoislands around large gold core were fabricated without using any chemical reductant or surfactant. The optical properties, surface molecular structures, and ensemble catalytic activity of the gold nanocomposites were investigated by time-of-flight secondary ion mass spectrometry and UV-vis spectroscopy, respectively. Moreover, the considerable catalytic activity of the nanocomposites toward 4-nitrophenol reduction was real time monitored by dark-field spectroscopy techniques at the single-nanoparticle level avoiding averaging effects in bulk systems. According to the obtained plasmonic signals from individual nanocomposites, the electron charging and discharging rates for these nanocomposites during the catalytic process were calculated. Our results offer new insights into the design and synthesis of plasmonic nanocomposites for future catalytic applications as well as a further mechanistic understanding of the electron transfer during the catalytic process at the single-nanoparticle level. PMID- 28026161 TI - 3D Reticular Li1.2Ni0.2Mn0.6O2 Cathode Material for Lithium-Ion Batteries. AB - In this study, a hard-templating route was developed to synthesize a 3D reticular Li1.2Ni0.2Mn0.6O2 cathode material using ordered mesoporous silica as the hard template. The synthesized 3D reticular Li1.2Ni0.2Mn0.6O2 microparticles consisted of two interlaced 3D nanonetworks and a mesopore channel system. When used as the cathode material in a lithium-ion battery, the as-synthesized 3D reticular Li1.2Ni0.2Mn0.6O2 exhibited remarkably enhanced electrochemical performance, namely, superior rate capability and better cycling stability than those of its bulk counterpart. Specifically, a high discharge capacity of 195.6 mA h g-1 at 1 C with 95.6% capacity retention after 50 cycles was achieved with the 3D reticular Li1.2Ni0.2Mn0.6O2. A high discharge capacity of 135.7 mA h g-1 even at a high current of 1000 mA g-1 was also obtained. This excellent electrochemical performance of the 3D reticular Li1.2Ni0.2Mn0.6O2 is attributed to its designed structure, which provided nanoscale lithium pathways, large specific surface area, good thermal and mechanical stability, and easy access to the material center. PMID- 28026163 TI - Enhanced Electrochemical and Photocatalytic Performance of Core-Shell CuS@Carbon Quantum Dots@Carbon Hollow Nanospheres. AB - A controlled structural morphology, high specific surface area, large void space, and excellent biocompatibility are typical favorable properties in electrochemical energy storage and photocatalytic studies; however, a complete understanding about this essential topic still remains a great challenge. Herein, we have developed a new type of functionalized carbon hollow-structured nanospheres based on core-shell copper sulfide@carbon quantum dots (CQDs)@carbon hollow nanosphere (CHNS) architecture. This CuS@CQDs@C HNS is accomplished by a simple, scalable, in situ single-step hydrothermal method to produce the material that can be employed as an electrode for electrochemical energy storage and photocatalytic applications. Impressively, the CuS@CQDs@C HNS nanostructure delivers exceptional electrochemical energy storage characteristics with high specific capacitance (618 F g-1 at a current density of 1 A g-1) and an excellent rate capability with an extraordinary capacitance (462 F g-1 at current density of 20 A g-1) and long cycle life (95% capacitance retention after 4000 cycles). Further, the proposed photocatalyst exhibited superior photocatalytic activity under solar light due to the efficient electron transfer, which was revealed by photoluminescence studies. Such superior electrochemical and photocatalytic performance can be ascribed to the mutual contribution of CuS, CQDs, and CHNS and unique core-shell architecture. These results exhibit that the core-shell CuS@CQDs@C HNS nanostructure is one of the potential candidates for supercapacitors and photocatalytic applications. PMID- 28026162 TI - hBfl-1/hNOXA Interaction Studies Provide New Insights on the Role of Bfl-1 in Cancer Cell Resistance and for the Design of Novel Anticancer Agents. AB - Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members of the antiapoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding to conserved alpha-helical regions, named BH3 domains, of pro apoptotic proteins such as Bim, tBid, Bad, or NOXA. Five antiapoptotic proteins have been identified that interact with various selectivity with BH3 containing pro-apoptotic counterparts. Cancer cells present various and variable levels of these proteins, making the design of effective apoptosis based therapeutics challenging. Recently, BH3 profiling was introduced as a method to classify cancer cells based on their ability to resist apoptosis following exposure to selected BH3 peptides. However, these studies were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences. While the majority of these interactions are conserved between mice and humans, we found surprisingly that human NOXA binds to human Bfl-1 potently and covalently via conserved Cys residues, with over 2 orders of magnitude increased affinity over hMcl-1. Our data suggest that some assumptions of the original BH3 profiling need to be revisited and that perhaps further targeting efforts should be redirected toward Bfl-1, for which no suitable specific inhibitors or pharmacological tools have been reported. In this regard, we also describe the initial design and characterizations of novel covalent BH3-based agents that potently target Bfl-1. These molecules could provide a novel platform on which to design effective Bfl-1 targeting therapeutics. PMID- 28026164 TI - Correction to Chemistry and Structure of Graphene Oxide via Direct Imaging. PMID- 28026165 TI - Long-Lasting Nb2O5-Based Nanocomposite Materials for Li-Ion Storage. AB - Advanced nanostructured hybrid materials can help us overcome the electrochemical performance limitations of current energy storage devices. In this study, three dimensional porous carbon nanowebs (3D-CNWs) with numerous included orthorhombic Nb2O5 (T-Nb2O5) nanoparticles were fabricated using a microbe-derived nanostructure. The 3D-CNW/T-Nb2O5 nanocomposites showed an exceptionally stable long-term cycling performance over 70 000 cycles, a high reversible capacity of ~125 mA h g-1, and fast Li-ion storage kinetics in a coin-type two-electrode system using Li metal. In addition, energy storage devices based on the above nanocomposites achieved a high specific energy of ~80 W h kg-1 together with a high specific power of ~5300 W kg-1 and outstanding cycling performance with ~80% capacitance retention after 35 000 cycles. PMID- 28026166 TI - Correction to "Self-Assembled, Nanostructured, Tunable Metamaterials via Spinodal Decomposition". PMID- 28026167 TI - Heat Capacity Changes for Transition-State Analogue Binding and Catalysis with Human 5'-Methylthioadenosine Phosphorylase. AB - Human 5'-methylthioadenosine phosphorylase (MTAP) catalyzes the phosphorolysis of 5'-methylthioadenosine (MTA). Its action regulates cellular MTA and links polyamine synthesis to S-adenosylmethionine (AdoMet) salvage. Transition state analogues with picomolar dissociation constants bind to MTAP in an entropically driven process at physiological temperatures, suggesting increased hydrophobic character or dynamic structure for the complexes. Inhibitor binding exhibits a negative heat capacity change (-DeltaCp), and thus the changes in enthalpy and entropy upon binding are strongly temperature-dependent. The DeltaCp of inhibitor binding by isothermal titration calorimetry does not follow conventional trends and is contrary to that expected from the hydrophobic effect. Thus, ligands of increasing hydrophobicity bind with increasing values of DeltaCp. Crystal structures of MTAP complexed to transition-state analogues MT-DADMe-ImmA, BT DADMe-ImmA, PrT-ImmA, and a substrate analogue, MT-tubercidin, reveal similar active site contacts and overall protein structural parameters, despite large differences in DeltaCp for binding. In addition, DeltaCp values are not correlated with Kd values. Temperature dependence of presteady state kinetics revealed the chemical step for the MTAP reaction to have a negative heat capacity for transition state formation (-DeltaCp?). A comparison of the DeltaCp? for MTAP presteady state chemistry and DeltaCp for inhibitor binding revealed those transition-state analogues most structurally and thermodynamically similar to the transition state. Molecular dynamics simulations of MTAP apoenzyme and complexes with MT-DADMe-ImmA and MT-tubercidin show small, but increased dynamic motion in the inhibited complexes. Variable temperature CD spectroscopy studies for MTAP inhibitor complexes indicate remarkable protein thermal stability (to Tm = 99 degrees C) in complexes with transition-state analogues. PMID- 28026168 TI - Synthetic Models of Quasi-Stable Amyloid beta40 Oligomers with Significant Neurotoxicity. AB - The formation of soluble oligomers of amyloid beta42 and 40 (Abeta42, Abeta40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Abeta42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Abeta42, Abeta40 dimers can also contribute to AD progression because of the more abundance of Abeta40 monomer in biological fluids. Here, we describe the synthesis and characterization of three dimer models of the toxic conformation constrained E22P-Abeta40 using l,l-2,6-diaminopimeric acid (DAP) or l,l-2,8-diaminoazelaic acid (DAZ) linker at position 30, which is incorporated into the intermolecular parallel beta-sheet region, and DAP at position 38 in the C-terminal hydrophobic core. E22P-A30DAP-Abeta40 dimer (1) and E22P-A30DAZ Abeta40 dimer (2) existed mainly in oligomeric states even after 2 weeks incubation without forming fibrils, unlike the corresponding monomer. Their neurotoxicity toward SH-SY5Y neuroblastoma cells was very weak. In contrast, E22P G38DAP-Abeta40 dimer (3) formed beta-sheet-rich oligomeric aggregates, and exhibited more potent neurotoxicity than the corresponding monomer. Ion mobility mass spectrometry suggested that high molecular-weight oligomers (12-24-mer) of 3 form, but not for 1 and 2 after 4 h incubation. These findings indicate that formation of the hydrophobic core at the C-terminus, rather than intermolecular parallel beta-sheet, triggers the formation of toxic Abeta oligomers. Compound 3 may be a suitable model for studying the etiology of Alzheimer's disease. PMID- 28026169 TI - Efficient CO Oxidation by 50-Facet Cu2O Nanocrystals Coated with CuO Nanoparticles. AB - As carbon monoxide oxidation is widely used for various chemical processes (such as methanol synthesis and water-gas shift reactions H2O + CO ? CO2 + H2) as well as in industry, it is essential to develop highly energy efficient, inexpensive, and eco-friendly catalysts for CO oxidation. Here we report green synthesis of ~10 nm sized CuO nanoparticles (NPs) aggregated on ~400 nm sized 50-facet Cu2O polyhedral nanocrystals. This CuO-NPs/50-facet Cu2O shows remarkable CO oxidation reactivity with very high specific CO oxidation activity (4.5 MUmolCO m-2 s-1 at 130 degrees C) and near-complete 99.5% CO conversion efficiency at ~175 degrees C. This outstanding catalytic performance by CuO NPs over the pristine multifaceted Cu2O nanocrystals is attributed to the surface oxygen defects present in CuO NPs which facilitate binding of CO and O2 on their surfaces. This new material opens up new possibilities of replacing the usage of expensive CO oxidation materials. PMID- 28026170 TI - Pattern-Directed Ordering of Spin-Dewetted Liquid Crystal Micro- or Nanodroplets as Pixelated Light Reflectors and Locomotives. AB - Chemical pattern directed spin-dewetting of a macroscopic droplet composed of a dilute organic solution of liquid crystal (LC) formed an ordered array of micro- and nanoscale LC droplets. Controlled evaporation of the spin-dewetted droplets through vacuum drying could further miniaturize the size to the level of ~90 nm. The size, periodicity, and spacing of these mesoscale droplets could be tuned with the variations in the initial loading of LC in the organic solution, the strength of the centripetal force on the droplet, and the duration of the evaporation. A simple theoretical model was developed to predict the spacing between the spin-dewetted droplets. The patterned LC droplets showed a reversible phase transition from nematic to isotropic and vice versa with the periodic exposure of a solvent vapor and its removal. A similar phase transition behavior was also observed with the periodic increase or reduction of temperature, suggesting their usefulness as vapor or temperature sensors. Interestingly, when the spin-dewetted droplets were confined between a pair of electrodes and an external electric field was applied, the droplets situated at the hydrophobic patches showed light-reflecting properties under the polarization microscopy highlighting their importance in the development of micro- or nanoscale LC displays. The digitized LC droplets, which were stationary otherwise, showed dielectrophoretic locomotion under the guidance of the external electric field beyond a threshold intensity of the field. Remarkably, the motion of these droplets could be restricted to the hydrophilic zones, which were confined between the hydrophobic patches of the chemically patterned surface. The findings could significantly contribute in the development of futuristic vapor or temperature sensors, light reflectors, and self-propellers using the micro- or nanoscale digitized LC droplets. PMID- 28026171 TI - Correction to "Bottlebrush Polymer Synthesis by Ring-Opening Metathesis Polymerization: The Significance of the Anchor Group". PMID- 28026172 TI - Reactions of Boron-Derived Radicals with Nucleophiles. AB - Reactions of phenanthrenedione- and pyrenedione-derived borocyclic radicals, CnH8O2B(C6F5)2* (n = 14 (1), 16 (3)), with a variety of nucleophiles have been studied. Reaction of 1 with P(t-Bu)3 affords the zwitterion 3-(t Bu)3PC14H7O2B(C6F5)2 (5) in addition to the salt [HP(t-Bu)3][C14H8O2B(C6F5)2] (6). In contrast, the reaction of 1 with PPh3 proceeds to give two regioisomeric zwitterions, 1-(Ph3P)C14H7O2B(C6F5)2 (7a) and 3-(Ph3P)C14H7O2B(C6F5)2 (7b), as well as the related boronic ester C14H8O2B(C6F5) (2). In a similar fashion, 3 reacted with PPh3 to give 3-(Ph3P)C16H7O2B(C6F5)2 (8a), 1-(Ph3P)C16H7O2B(C6F5)2 (8b), and boronic ester C16H8O2B(C6F5) (4). Reactions of secondary phosphines Ph2PH and tBu2PH with 3 yield 3-(R2PH)C16H7O2B(C6F5)2 (R = Ph (9), t-Bu (10)). The reaction of 1 with N-heterocyclic carbene IMes afforded 3 (IMes)C14H7O2B(C6F5)2 (11) and [IMesH][C14H8O2B(C6F5)2] (12), while the reactions with quinuclidine and DMAP afforded the species 3-(C7H13N)C14H7O2B(C6F5)2 (13) and [H(NC7H13)2][C14H8O2B(C6F5)2] (14), and the salt [9,10 (DMAP)2C14H8O2B(C6F5)2][C14H8O2B(C6F5)2] (15), respectively. These products have been fully characterized, and the mechanism for the formation of these products is considered in the light of DFT calculations. PMID- 28026173 TI - Strong Localization of Anionic Electrons at Interlayer for Electrical and Magnetic Anisotropy in Two-Dimensional Y2C Electride. AB - We have synthesized a single crystalline Y2C electride of centimeter-scale by floating-zone method and successfully characterized its anisotropic electrical and magnetic properties. In-plane resistivity upturn at low temperature together with anisotropic behavior of negative magnetoresistance is ascribed to the stronger suppression of spin fluctuation along in-plane than that along the c axis, verifying the existence of magnetic moments preferred for the c-axis. A superior magnetic moment along the c-axis to that along the in-plane direction strongly demonstrates the anisotropic magnetism of Y2C electride containing a magnetically easy axis. It is clarified from the theoretical calculations that the anisotropic nature of the Y2C electride originates from strongly localized anionic electrons with an inherent magnetic anisotropy in the interlayer spaces. PMID- 28026175 TI - Ceylonins A-F, Spongian Diterpene Derivatives That Inhibit RANKL-Induced Formation of Multinuclear Osteoclasts, from the Marine Sponge Spongia ceylonensis. AB - Six new spongian diterpene derivatives, ceylonins A-F (1-6), were isolated from the Indonesian marine sponge Spongia ceylonensis along with spongia-13(16),14 dien-19-oic acid (7). They contained three additional carbons in ring D to supply an ether-bridged bicyclic ring system. Their structures were elucidated by analyzing NMR spectroscopic data and calculated ECD spectra in comparison to experimental ECD spectra. The bicyclic ring system may be derived from the major metabolite 7 and a C3 unit (an acrylic acid equivalent) through an intermolecular Diels-Alder reaction, which was experimentally supported by the formation of 1-6 from 7 and acrylic acid. The inhibitory effects of the isolated compounds on the RANKL-induced formation of multinuclear osteoclasts in RAW264 macrophages were examined. PMID- 28026174 TI - Comprehensive Analysis of Tiamulin Metabolites in Various Species of Farm Animals Using Ultra-High-Performance Liquid Chromatography Coupled to Quadrupole/Time-of Flight. AB - Tiamulin is an antimicrobial widely used in veterinary practice to treat dysentery and pneumonia in pigs and poultry. However, knowledge about the metabolism of tiamulin is very limited in farm animals. To better understand the biotransformation of tiamulin, in the present study, in vitro and in vivo metabolites of tiamulin in rats, chickens, swine, goats, and cows were identified and elucidated using ultra-high performance liquid chromatography coupled to quadrupole/time-of-flight. As a result, a total of 26 metabolites of tiamulin, identified in vitro and in vivo, and majority of metabolites were revealed for the first time. In all farm animals, tiamulin undergoes phase I metabolic routes of hydroxylation in the mutilin part (the ring system), S-oxidation and N deethylation on side chain, and no phase II metabolite was detected. Among these, 2beta- and 8alpha-hydroxylation and N-deethylation were the main metabolic pathways of tiamulin in farm animals. In addition, we have put forward that 8a hydroxy-tiamulin and 8a-hydroxy-N-deethyl-tiamulin could be hydroxylated into 8a hydroxy-mutilin, the marker residue of tiamulin in swine. Furthermore, a significant interspecies difference was observed on the metabolism of tiamulin among various farm animals. The possible marker residues for tiamulin in swine were 8alpha-hydroxy-tiamulin, N-deethyl-tiamulin, and 8alpha-hydroxy-N-deethyl tiamulin, which were consistent with the hypothesis proposed by the European Agency for the Evaluation of Medicinal Products. However, results in present study indicated that three metabolites (2beta-hydroxy-tiamulin, N-deethyl tiamulin, and 2beta-hydroxy-N-deethyl-tiamulin) of tiamulin in chickens had larger yields, which implied that 2beta-hydroxy-mutilin or N-deethyl-tiamulin was more likely to be regarded as the potential marker residue of tiamulin in chickens. PMID- 28026176 TI - The Synthesis of Certain Phomentrioloxin A Analogues and Their Evaluation as Herbicidal Agents. AB - A series of 28 analogues of the phytotoxic geranylcyclohexentriol (-) phomentrioloxin A (1) has been synthesized through cross-couplings of various enantiomerically pure haloconduritols or certain deoxygenated derivatives with either terminal alkynes or borylated alkenes. Some of these analogues display modest herbicidal activities, and physiological profiling studies suggest that analogue 4 inhibits photosystem II in isolated thylakoids in vitro. PMID- 28026177 TI - Influence of Anion Delocalization on Electron Transfer in a Covalent Porphyrin Donor-Perylenediimide Dimer Acceptor System. AB - Photodriven electron transfer from a donor excited state to an assembly of electronically coupled acceptors has been proposed to enhance charge transfer efficiency in functional organic electronic materials. However, the circumstances under which this may occur are difficult to investigate in a controlled manner in disordered donor-acceptor materials. Here we investigate the effects of anion delocalization on electron transfer using zinc meso-tetraphenylporphyrin (ZnTPP) as a donor and a perylene-3,4:9,10-bis(dicarboximide) dimer as the acceptor (PDI2). The PDI units of the dimer are positioned in a cofacial orientation relative to one another by attachment of the imide group of each PDI to the 4- and 5-positions of a xanthene spacer. Furthermore, the distal imide group of one PDI is linked to the para-position of one ZnTPP phenyl group to yield ZnTPP-PDI2. The data for the dimer are compared to two different ZnTPP-PDI monomer reference systems designed to probe electron transfer to each of the individual PDI molecules comprising PDI2. The electron transfer rate from the ZnTPP lowest excited singlet state to PDI2 is increased by 50% relative to that in ZnTPP-PDI, when the data are corrected for the statistics of having two electron acceptors. Femtosecond transient IR absorption spectroscopy provides evidence that the observed enhancement in charge separation results from electron transfer producing a delocalized PDI2 anion. PMID- 28026178 TI - Catalytic Mechanism of Peptidoglycan Deacetylase: A Computational Study. AB - Bacterial peptidoglycan deacetylase enzymes are potentially important targets for the design of new drugs. In pathogenic bacteria, they modify cell-wall peptidoglycan by removing the acetyl group, which makes the bacteria more resistant to the host's immune response and other forms of attack, such as degradation by lysozyme. In this study, we have investigated the mechanism of reaction of acetyl removal from a model substrate, the N-acetylglucosamine/N acetylmuramic acid dimer, by peptidogylcan deacetylase from Helicobacter pylori. For this, we employed a range of computational approaches, including molecular docking, Poisson-Boltzmann electrostatic pKa calculations, molecular dynamics simulations, and hybrid quantum chemical/molecular mechanical potential calculations, in conjunction with reaction-path-finding algorithms. The active site of this enzyme is in a region of highly negative electrostatic potential and contains a zinc dication with a bound water molecule. In the docked enzyme substrate complex, our pKa calculations indicate that in the most stable protonation states of the active site the zinc-bound water molecule is in its hydroxide form and that the adjacent histidine residue, His247, is doubly protonated. In addition, there are one or two excess protons, with the neighboring aspartate residues, Asp12 and/or Asp199, being protonated. Overall, we find five classes of feasible reaction mechanisms, with the favored mechanism depending heavily on the protonation state of the active site. In the major one excess-proton form, the mechanism with the lowest barrier (84 kJ mol-1) involves an initial protonation of the substrate nitrogen, followed by nucleophilic attack of the zinc-bound hydroxide and rupture of the substrate's carbon-nitrogen bond. However, in the minor two-excess-proton form, four mechanisms are almost equienergetic (83-86 kJ mol-1), comprising both those that start with nitrogen protonation and those in which nucleophilic attack by hydroxide occurs first. PMID- 28026179 TI - Frozen Rotation of the Ammonium Group Observed for the First Time in Liquid-Phase NMR Spectra. AB - Hindered rotation of the -NH3+ group in a sterically crowded molecular environment was frozen on the NMR time scale. These effects were observed for solutions of 1,2,3,4-tetrabromotriptycyl-9-ammonium tetrafluoroborate in tetrahydrofuran with and without excess of HBF4. In the absence of acid, the hindered rotation is accompanied by a number of other effects originating in part from practically nonremovable traces of water in the solvent. Because of these additional effects, an effective rate constant of the hindered rotation could be evaluated at only one temperature for the neutral solution of the salt. For one of the acidified samples, which was prepared with special precautions against moisture, these complications are practically nonexistent at low and intermediate temperatures. For the latter sample, the Arrhenius parameters of the hindered rotation could be determined from the rotation rates evaluated in the range 194 226 K. PMID- 28026180 TI - Computational Design of Experiment Unveils the Conformational Reaction Coordinate of GH125 alpha-Mannosidases. AB - Conformational analysis of enzyme-catalyzed mannoside hydrolysis has revealed two predominant conformational itineraries through B2,5 or 3H4 transition-state (TS) conformations. A prominent unassigned catalytic itinerary is that of exo-1,6 alpha-mannosidases belonging to CAZy family 125. A published complex of Clostridium perfringens GH125 enzyme with a nonhydrolyzable 1,6-alpha thiomannoside substrate mimic bound across the active site revealed an undistorted 4C1 conformation and provided no insight into the catalytic pathway of this enzyme. We show through a purely computational approach (QM/MM metadynamics) that sulfur-for-oxygen substitution in the glycosidic linkage fundamentally alters the energetically accessible conformational space of a thiomannoside when bound within the GH125 active site. Modeling of the conformational free energy landscape (FEL) of a thioglycoside strongly favors a mechanistically uninformative 4C1 conformation within the GH125 enzyme active site, but the FEL of corresponding O-glycoside substrate reveals a preference for a Michaelis complex in an OS2 conformation (consistent with catalysis through a B2,5 TS). This prediction was tested experimentally by determination of the 3D X ray structure of the pseudo-Michaelis complex of an inactive (D220N) variant of C. perfringens GH125 enzyme in complex with 1,6-alpha-mannobiose. This complex revealed unambiguous distortion of the -1 subsite mannoside to an OS2 conformation, matching that predicted by theory and supporting an OS2 -> B2,5 -> 1S5 conformational itinerary for GH125 alpha-mannosidases. This work highlights the power of the QM/MM approach and identified shortcomings in the use of nonhydrolyzable substrate analogues for conformational analysis of enzyme-bound species. PMID- 28026181 TI - Five-State Rotary Nanoswitch. AB - In our quest to develop artificial multistate devices, we synthesized the nanomechanical switch 1 that is characterized by a tetrahedral core equipped with four pending arms. The rotary arm with its azaterpyridine terminal is intramolecularly coordinated to a zinc(II) porphyrin station that is the terminus of another arm in 1. The two other arms carry identical sterically shielded phenanthroline stations. The 2-fold alternate addition of a copper(I) ion and [1,10]-phenanthroline (1 equiv each) results in the formation of five different switching states (State I-> State II-> State III-> State IV-> State V -> State I), which force the toggling arm to move back and forth between the zinc(II) porphyrin and phenanthroline stations separated by a distance of 25 A. All switching states constitute clean single species, except for State III, and thus are fully characterized by spectroscopic methods and elemental analysis. Finally, the initial state of nanoswitch was reset by addition of cyclam for complete removal of the copper(I) ions. PMID- 28026182 TI - Directing Energy Transfer in Panchromatic Platinum Complexes for Dual Vis-Near-IR or Dual Visible Emission from sigma-Bonded BODIPY Dyes. AB - We report on the platinum complexes trans-Pt(BODIPY)(8-ethynyl-BODIPY)(PEt3)2 (EtBPtB) and trans-Pt(BODIPY)(4-ethynyl-1,8-naphthalimide)(PR3)2 (R = Et, EtNIPtB 1; R = Ph, EtNIPtB-2), which all contain two different dye ligands that are connected to the platinum atom by a direct sigma bond. The molecular structures of all complexes were established by X-ray crystallography and show that the different dye ligands are in either a coplanar or an orthogonal arrangement. pi stacking and several CH...F and short CH...pi interactions involving protons at the phosphine substituents lead to interesting packing motifs in the crystal. The complexes feature several strong absorptions (epsilon = 3.2 * 105-5.5 * 105 M-1 cm-1) that cover the regime from 350 to 480 nm (EtNIPtB-1 and EtNIPtB-2) or from 350 to 580 nm (EtBPtB). Besides the typical absorption bands of both kinds of attached dyes, they also feature an intense band near 400-420 nm, which is assigned by time-dependent density functional theory calculations to a higher energy transition within the ethynyl-BODIPY (EtB) ligand or to charge transfer between the BODIPY (B) and naphthalimide (NI) chromophores. All complexes show dual fluorescence and phosphorescence emission from either the B (EtNIPtB-1 and EtNIPtB-2) or EtB (EtBPtB) ligand with a maximum phosphorescence quantum yield of 41% for EtNIPtB-1. The latter seems to be the highest reported value for room temperature phosphorescence from a BODIPY dye. The complete quenching of the emission from the chromophore absorbing at the higher energy and the appearance of the corresponding absorption bands in the fluorescence and phosphorescence excitation spectra indicate complete and rapid energy transfer to the chromophore with the lower-energy excited state, i.e., EtNI -> B in EtNIPtB-1 and EtNIPtB-2 and B -> EtB in EtBPtB. The latter process was further investigated by transient absorption spectroscopy, indicating that energy transfer is complete within 0.6 ns. EtNIPtB-1 catalyzes the photooxidation of 1,5-dihydroxynaphthalene with photogenerated 1O2 to Juglone at a much faster rate than methylene blue but with only modest quantum yields of 37% and with the onset of photodegradation after 60 min. PMID- 28026183 TI - Enantioselective 2-Alkylation of 3-Substituted Indoles with Dual Chiral Lewis Acid/Hydrogen-Bond-Mediated Catalyst. AB - A chiral-at-metal bis-cyclometalated iridium complex combines electrophile activation via metal coordination with nucleophile activation through hydrogen bond formation. This new bifunctional chiral Lewis acid/hydrogen-bond-mediated catalyst permits the challenging enantioselective 2-alkylation of 3-substituted indoles with alpha,beta-unsaturated 2-acyl imidazoles in up to 99% yield and with up to 98% enantiomeric excess at a catalyst loading of 2 mol %. As an application, the straightforward synthesis of a chiral pyrrolo[1,2-a]indole is demonstrated. PMID- 28026184 TI - Enhanced Structural Stability of Nickel-Cobalt Hydroxide via Intrinsic Pillar Effect of Metaborate for High-Power and Long-Life Supercapacitor Electrodes. AB - Layered alpha-Ni(OH)2 and its derivative bimetallic hydroxides (e.g., alpha (Ni/Co)(OH)2) have attracted much attention due to their high specific capacitance, although their insufficient cycling stability has blocked their wide application in various technologies. In this work, we demonstrate that the cycling performance of alpha-(Ni/Co)(OH)2 can be obviously enhanced via the intrinsic pillar effect of metaborate. Combining the high porosity feature of the metaborate stabilized alpha-(Ni/Co)(OH)2 and the improved electronic conductivity offered by graphene substrate, the average capacitance fading rate of the metaborate stabilized alpha-(Ni/Co)(OH)2 is only ~0.0017% per cycle within 10 000 cycles at the current density of 5 A g-1. The rate performance is excellent over a wide temperature range from -20 to 40 degrees C. We believe that the enhancements should mainly be ascribed to the excellent structural stability offered by the metaborate pillars, and the detailed mechanism is discussed. PMID- 28026185 TI - Pd-Catalyzed Dimethylation of Tyrosine-Derived Picolinamide for Synthesis of (S) N-Boc-2,6-dimethyltyrosine and Its Analogues. AB - A short and efficient synthesis of (S)-N-Boc-2,6-dimethyltyrosine utilizing palladium-catalyzed directed C-H functionalization is described. This represents the first general method for the ortho-dimethylation of tyrosine derivatives and offers a practical approach for preparing this synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible alpha-chiral centers. PMID- 28026186 TI - The Use of Graphene and Its Derivatives for Liquid-Phase Transmission Electron Microscopy of Radiation-Sensitive Specimens. AB - One of the key challenges facing liquid-phase transmission electron microscopy (TEM) of biological specimens has been the damaging effects of electron beam irradiation. The strongly ionizing electron beam is known to induce radiolysis of surrounding water molecules, leading to the formation of reactive radical species. In this study, we employ DNA-assembled Au nanoparticle superlattices (DNA-AuNP superlattices) as a model system to demonstrate that graphene and its derivatives can be used to mitigate electron beam-induced damage. We can image DNA-AuNP superlattices in their native saline environment when the liquid cell window material is graphene, but not when it is silicon nitride. In the latter case, initial dissociation of assembled AuNPs was followed by their random aggregation and etching. Using graphene-coated silicon nitride windows, we were able to replicate the observation of stable DNA-AuNP superlattices achieved with graphene liquid cells. We then carried out a correlative Raman spectroscopy and TEM study to compare the effect of electron beam irradiation on graphene with and without the presence of water and found that graphene reacts with the products of water radiolysis. We attribute the protective effect of graphene to its ability to efficiently scavenge reactive radical species, especially the hydroxyl radicals which are known to cause DNA strand breaks. We confirmed this by showing that stable DNA-AuNP assemblies can be imaged in silicon nitride liquid cells when graphene oxide and graphene quantum dots, which have also recently been reported as efficient radical scavengers, are added directly to the solution. We anticipate that our study will open up more opportunities for studying biological specimens using liquid-phase TEM with the use of graphene and its derivatives as biocompatible radical scavengers to alleviate the effects of radiation damage. PMID- 28026187 TI - Structure and Thermochemistry of Perrhenate Sodalite and Mixed Guest Perrhenate/Pertechnetate Sodalite. AB - Treatment and immobilization of technetium-99 (99Tc) contained in reprocessed nuclear waste and present in contaminated subsurface systems represents a major environmental challenge. One potential approach to managing this highly mobile and long-lived radionuclide is immobilization into micro- and meso-porous crystalline solids, specifically sodalite. We synthesized and characterized the structure of perrhenate sodalite, Na8[AlSiO4]6(ReO4)2, and the structure of a mixed guest perrhenate/pertechnetate sodalite, Na8[AlSiO4]6(ReO4)2-x(TcO4)x. Perrhenate was used as a chemical analogue for pertechnetate. Bulk analyses of each solid confirm a cubic sodalite-type structure (P43n, No. 218 space group) with rhenium and technetium in the 7+ oxidation state. High-resolution nanometer scale characterization measurements provide first-of-a-kind evidence that the ReO4- anions are distributed in a periodic array in the sample, nanoscale clustering is not observed, and the ReO4- anion occupies the center of the sodalite beta-cage in Na8[AlSiO4]6(ReO4)2. We also demonstrate, for the first time, that the TcO4- anion can be incorporated into the sodalite structure. Lastly, thermochemistry measurements for the perrhenate sodalite were used to estimate the thermochemistry of pertechnetate sodalite based on a relationship between ionic potential and the enthalpy and Gibbs free energy of formation for previously measured oxyanion-bearing feldspathoid phases. The results collected in this study suggest that micro- and mesoporous crystalline solids maybe viable candidates for the treatment and immobilization of 99Tc present in reprocessed nuclear waste streams and contaminated subsurface environments. PMID- 28026188 TI - Editorial. AB - Developmental Psychology (DP) has long been in the forefront of shaping the field of life span developmental science by advancing theory, research design, and statistical methodology and applying these to timely topics. My overarching goal as editor is to ensure that DP continues to play a leading role in charting the future of developmental science research by maintaining the highest theoretical and methodological standards and to further extend our reach by continuing to encourage international and multidisciplinary researchers to submit manuscripts. My comments in this editorial are not meant to be viewed as an endorsement of any specific topic, theoretical perspective, or methodological/statistical modeling technique, and we do not propose to change the journal's broad mission, which is to publish "articles that significantly advance knowledge and theory about development across the life span." Rather, my comments reflect my views of the field of life span developmental science and where it is headed, informed by my own research since the early 1980s and, more recently, by my 6 years as an Associate Editor and my year as incoming Editor of DP. Based on these experiences, I want to share a few examples of what I have observed in terms of specific emerging timely content areas, as well as methodological design characteristics, that appear to be on the forefront of developmental science (PsycINFO Database Record PMID- 28026189 TI - Infants prospectively control reaching based on the difficulty of future actions: To what extent can infants' multiple-step actions be explained by Fitts' law? AB - Prospective motor control, a key element of action planning, is the ability to adjust one's actions with respect to task demands and action goals in an anticipatory manner. The current study investigates whether 14-month-olds can prospectively control their reaching actions based on the difficulty of the subsequent action. We used a reach-to-place task, with difficulty of the placing action varied by goal size and goal distance. To target prospective motor control, we determined the kinematics of the prior reaching movements using a motion-tracking system. Peak velocity of the first movement unit of the reach served as indicator for prospective motor control. Both difficulty aspects (goal size and goal distance) affected prior reaching, suggesting that both these aspects of the subsequent action have an impact on the prior action. The smaller the goal size and the longer the distance to the goal, the slower infants were in the beginning of their reach toward the object. Additionally, we modeled movement times of both reaching and placing actions using a formulation of Fitts' law (as in heading). The model was significant for placement and reaching movement times. These findings suggest that 14-month-olds can plan their future actions and prospectively control their related movements with respect to future task difficulties. (PsycINFO Database Record PMID- 28026190 TI - Why are faces denser in the visual experiences of younger than older infants? AB - Recent evidence from studies using head cameras suggests that the frequency of faces directly in front of infants declines over the first year and a half of life, a result that has implications for the development of and evolutionary constraints on face processing. Two experiments tested 2 opposing hypotheses about this observed age-related decline in the frequency of faces in infant views. By the people-input hypothesis, there are more faces in view for younger infants because people are more often physically in front of younger than older infants. This hypothesis predicts that not just faces but views of other body parts will decline with age. By the face-input hypothesis, the decline is strictly about faces, not people or other body parts in general. Two experiments, 1 using a time-sampling method (84 infants, 3 to 24 months in age) and the other analyses of head camera images (36 infants, 1 to 24 months) provide strong support for the face-input hypothesis. The results suggest developmental constraints on the environment that ensure faces are prevalent early in development. (PsycINFO Database Record PMID- 28026191 TI - Maternal postnatal depression and anxiety and their association with child emotional negativity and behavior problems at two years. AB - Postnatal maternal depression is associated with poorer child emotional and behavioral functioning, but it is unclear whether this occurs following brief episodes or only with persistent depression. Little research has examined the relation between postnatal anxiety and child outcomes. The present study examined the role of postnatal major depressive disorder (MDD) and generalized anxiety disorder (GAD) symptom chronicity on children's emotional and behavioral functioning at 24 months. Following postnatal screening mothers (n = 296) were identified as having MDD, GAD, MDD and GAD, or no disorder at 3 months postnatal; the average age was 32.3 (SD = 5.0), 91.9% self-identified as Caucasian, and 62.2% were married. Maternal disorder symptom severity was assessed by questionnaires and structured interview at 3, 6, 10, 14, and 24 months postpartum. At 24 months, child emotional negativity and behavior were assessed using questionnaires and by direct observation. Latent trait-state-occasion modeling was used to represent maternal disorder symptom chronicity; both stable trait and time-specific occasion portions of maternal symptomatology were examined in relation to child outcomes. Only the stable trait portion of maternal MDD and GAD symptom severity were related to maternal report of child behavior problems and higher levels of emotional negativity. Persistent maternal MDD, but not GAD, symptom severity was related to higher levels of child emotional negativity as measured observationally. These data suggest that children's behavior problems and emotional negativity are adversely affected by persistent maternal depression, and possibly anxiety. This has implications for interventions to prevent negative effects of postnatal psychopathology on children. (PsycINFO Database Record PMID- 28026192 TI - The fulfillment of others' needs elevates children's body posture. AB - Much is known about young children's helping behavior, but little is known about the underlying motivations and emotions involved. In 2 studies we found that 2 year-old children showed positive emotions of similar magnitude-as measured by changes in their postural elevation using depth sensor imaging technology-after they achieved a goal for themselves and after they helped another person achieve her goal. Conversely, children's posture decreased in elevation when their actions did not result in a positive outcome. These results suggest that for young children, working for themselves and helping others are similarly rewarding. (PsycINFO Database Record PMID- 28026193 TI - Mexican-origin youth's risk behavior from adolescence to young adulthood: The role of familism values. AB - Engagement in risk behavior has implications for individuals' academic achievement, health, and well-being, yet there is a paucity of developmental research on the role of culturally relevant strengths in individual and family differences in risk behavior involvement among ethnic minority youth. In this study, we used a longitudinal cohort-sequential design to chart intraindividual trajectories of risk behavior and test variation by gender and familism values in 492 youth from 12 to 22 years of age. Participants were older and younger siblings from 246 Mexican-origin families who reported on their risk behaviors in interviews spaced over 8 years. Multilevel cohort-sequential growth models revealed that youth reported an increase in risk behavior from 12 to 18 years of age, and then a decline to age 22. Male youth reported greater overall levels and a steeper increase in risk behavior from ages 12 to 18, compared to female youth. For familism values, on occasions when youth reported higher levels, they also reported lower levels of risk behavior (i.e., within-person effect). For sibling dyads characterized by higher average levels of familism values, youth reported lower average levels of risk behavior (i.e., between-family effect). Findings provide unique insights into risk behavior from adolescence to young adulthood among Mexican-origin youth. (PsycINFO Database Record PMID- 28026194 TI - Predicting reading and mathematics from neural activity for feedback learning. AB - Although many studies use feedback learning paradigms to study the process of learning in laboratory settings, little is known about their relevance for real world learning settings such as school. In a large developmental sample (N = 228, 8-25 years), we investigated whether performance and neural activity during a feedback learning task predicted reading and mathematics performance 2 years later. The results indicated that feedback learning performance predicted both reading and mathematics performance. Activity during feedback learning in left superior dorsolateral prefrontal cortex (DLPFC) predicted reading performance, whereas activity in presupplementary motor area/anterior cingulate cortex (pre SMA/ACC) predicted mathematical performance. Moreover, left superior DLPFC and pre-SMA/ACC activity predicted unique variance in reading and mathematics ability over behavioral testing of feedback learning performance alone. These results provide valuable insights into the relationship between laboratory-based learning tasks and learning in school settings, and the value of neural assessments for prediction of school performance over behavioral testing alone. (PsycINFO Database Record PMID- 28026195 TI - Age differences in negative emotional responses to daily stressors depend on time since event. AB - Research on age differences in the experience of negative emotional states have produced inconsistent results, particularly when emotion is examined in the context of daily stress. Strength and vulnerability integration (SAVI; Charles, 2010) theory postulates that age differences in emotional states are contingent upon whether a stressor occurred, and whether sufficient time has passed since the stressor to allow older adults to benefit from theorized strengths. The present study uses an ecological momentary assessment design to examine how timing of daily stressors relates to age differences in negative emotional responses. Participants (N = 199, aged 25-65) completed mobile surveys up to 5 times daily for 14 days. They reported current mood and stressor exposure, as well as how long ago the stressor occurred. As expected, no age differences were observed in current negative affect (NA) for stressors which occurred in the previous 0-10 min. As predicted, older age was associated with less of a stressor related increase in NA when a greater time had passed (i.e., 10 min to 2.5 hours) since stressor exposure. Consistent with previous results, there were no age differences in the effects of more distal stressors that occurred 2.5 to 5 hr ago, although NA remained significantly elevated. The present findings are consistent with SAVI's predictions and advance understanding age differences in the time course relating everyday stressors to emotional responses. (PsycINFO Database Record PMID- 28026196 TI - Unresolved loss, a risk factor for offspring, predicts event-related potential responses to death-related imagery. AB - This study investigates whether individual differences in attachment status can be detected by electrophysiological responses to loss-themed pictures. The Adult Attachment Interview (AAI) was used to identify discourse/reasoning lapses during the discussion of loss experiences via death that place speakers in the Unresolved/disorganized AAI category. In parents, Unresolved AAI status has been associated with Disorganized infant Strange Situation response, a known risk factor for psychopathology (e.g., internalizing/externalizing/dissociation). This association has been related to anomalous frightening (FR) parental behavior in the infant's presence, behavior presumed to be instigated by vulnerability to trauma-related fright. Here, psychophysiological methods were utilized to examine whether Unresolved AAI status could be detected in brain responses to subtle/symbolic reminders of loss. One year after AAI administration, 31 undergraduate women who had experienced loss (16 Unresolved) underwent continuous electroencephalogram (EEG) recording during a picture-viewing, valence-rating task. Picture onset-locked event-related potentials (ERPs) revealed millisecond responses to 4 picture categories: pleasant people, pleasant nature, cemetery (symbolic death), and gruesome death (dead or dying people). Participants' valence ratings did not differ between groups across picture categories. However, the N2 ERP, implicated in detecting stimulus salience, was selectively greater in Unresolved participants viewing cemetery scenes; it was in fact as high as the N2 for gruesome death images observed throughout the sample. Additionally, Unresolved participants exhibited a right-hemispheric P3 asymmetry across picture categories, suggestive of continuously heightened vigilance/arousal. Together, these results suggest that Unresolved AAI status is associated with greater neurophysiological sensitivity to subtle reminders of loss that may disrupt ongoing mental function. (PsycINFO Database Record PMID- 28026197 TI - What paint can tell us: A fractal analysis of neurological changes in seven artists. AB - OBJECTIVE: The notion that artistic capability increases with dementia is both novel and largely unsupported by available literature. Recent research has suggested an emergence of artistic capabilities to be a by-product of involuntary behaviour seen with dementia, as opposed to a progression in original thinking (de Souza, et al., 2010). A far more complementary explanation comes from Hannemann (2006), who suggests that art offers an outlet for dementia patients to refine and sharpen their cognitive abilities. As dementia severely impedes linguistic skills, non-verbal therapeutic methods such as painting can permit dementia patients to express themselves in a way not possible verbally. Fractal analysis has been used to determine the authenticity of major works of art. Taylor et al., (1999) found that through a fractal analysis of Jackson Pollock's paintings it was possible to distinguish authentic works from a large collection of fakes, demonstrating that when artists paint they instill within their work their own pattern of unique fractal behaviour. Can age-indexed variations in the fractal dimension of the works of artists anticipate specific cognitive deteriorations? METHOD: To answer this question we analysed age-related variations in the fractal dimension of a large corpus of digital images (n = 2092) of work created by seven notable artists who experienced both normal ageing and neurodegenerative disorders. RESULTS: The results of our analysis showed that patterns of change in the fractal dimension of the paintings differentiated artists who suffered neurological deterioration from those of normal aging controls. CONCLUSIONS: These findings are of importance for two reasons. Our work adds to studies that demonstrate that fractal analysis has the potential to determine the provenance of paintings. Secondly, our work suggests that may be possible to identify a-typical changes in the structure of an artist's work; changes that may be early indicators of the onset of neurological deterioration. (PsycINFO Database Record PMID- 28026198 TI - The importance of a second opinion in the diagnosis of Barrett's esophagus: a "real life" study. AB - BACKGROUND: Barrett's esophagus is a precancerous lesion, and its identification with the early detection of dysplasia is of paramount importance to prevent adenocarcinoma onset. However, there is still debate on the correct pathological identification of Barrett's esophagus (and of associated dysplasia), and most studies have been conducted in an experimental setting. AIMS: To assess previous uncertain diagnoses of Barrett's (with and without dysplasia) via a second opinion of an expert pathologist in a real life setting. PATIENTS AND METHODS: Histological sections of 32 suspected Barrett's patients from ten general Pathology units were centralized into one single unit in which an expert pathologist reviewed the slides blindly. RESULTS: Overall, in 78% of cases there was diagnostic discordance; in particular, in 64% of cases the presence of low grade dysplasia was not confirmed. Of interest, 28% of cases with the original diagnosis were reclassified as non-Barrett's. CONCLUSIONS: The pathological diagnosis of Barrett's esophagus, especially with regard to the presence of dysplasia, is still misinterpreted, particularly in the setting of general Pathology units. Thus, a second opinion from an experienced pathologist may help in the interpretation of the results and in starting appropriate follow-up programs. PMID- 28026199 TI - Clinical status, quality of life, and work productivity in Crohn's disease patients after one year of treatment with adalimumab. AB - OBJECTIVE: Clinical trials have shown the efficacy of adalimumab in Crohn's disease, but the outcome in regular practice remains unknown. The aim of the study was to examine clinical status, quality of life, and work productivity of Crohn's disease patients receiving adalimumab for one year in the context of usual clinical practice. MATERIAL AND METHODS: This was a prospective, observational study with a one-year follow-up. After baseline, Crohn's disease patients were evaluated at 1, 3, 6, 9, and 12 months after starting treatment with adalimumab. Outcome variables included: clinical status (measured with CDAI), quality of life (measured with EuroQoL-5D and IBDQ), and work productivity (measured with WPAI questionnaire). These outcome variables were compared using the Student's t test or Wilcoxon test for paired comparison data according to the data distribution. Statistical significance was set at two-sided p < 0.05. RESULTS: The sample was composed of 126 patients (age [mean] 39.1 +/- [standard deviation] 13.8 years; 51% male). Significant changes were observed during the follow-up period: CDAI decreased from [median] 194 ([25-75 percentiles] 121-269) to 48.2 (10.1-122.0) (p < 0.05); the EuroQoL-5D increased from 0.735 (0.633 0.790) to 0.797 (0.726-1.000) (p < 0.05); the EuroQoL-5D visual analogue scale increased from 50.0 (40-70) to 80.0 (60-90); (p < 0.05) and the IBDQ increased from 56.7 (51.6-61.5) to 67.5 (60.1-73.6) (p < 0.05). The total work productivity impact decreased from 53% to 24% (p < 0.05). CONCLUSIONS: In regular practice, adalimumab is clinically effective in the treatment of Crohn's disease patients and results in a significant improvement in quality of life and work productivity. PMID- 28026200 TI - What is the real-life maintenance mesalazine dose in ulcerative colitis? AB - OBJECTIVE: To describe how mesalazine (MSZ) is used in our practice in ulcerative colitis (UC), at what dose, and the success rate (regarding adherence to therapy). METHODS: Observational, transversal study, including all patients with UC and with MSZ maintenance therapy seen from September 2014 to February 2015 at two IBD units in Spain. Treatment adherence was measured by the Morisky-Green scale. RESULTS: We included 203 patients (mean MSZ dose: 2.6 +/- 1.0 g/d; median of treatment: 19.5 months [IQR: 8-48]). Doses < 2 g/d were used in 15.3% of cases, 2-2.9 g/d doses in 35.0%, 3-3.9 doses in 29.5%, and >= 4 g/d doses in the remaining 20.2%. A single daily dose was preferred in 51.2% of cases, two doses in 33.0% and three doses in 15.8%. A different MSZ brand had been previously used in 36.6% of patients. In 134 cases (66%), the maintenance dose had been increased during a flare-up, and in 49 (36.6% of cases) this higher dose had been kept for maintenance (dose >= 4 g/d in 36 patients). During the MSZ therapy, 14 patients (6.9%) suffered mild side effects (21.4% altered liver function tests). Therapy adherence was good in 81.8% of cases. CONCLUSIONS: Half of our UC patients take high MSZ doses (>= 3 g/d) as maintenance therapy, with acceptable safety and good adherence. Half of all patients take a single daily dose, and one third needed a different commercial brand during therapy. Opting for a higher MSZ maintenance dose is a possible strategy for a satisfactory maintenance therapy. PMID- 28026202 TI - Abstracts from the August 2014 North American Society for Pediatric Exercise Medicine Conference Minneapolis, MN. PMID- 28026201 TI - The Learning Curve in Prostate MRI Interpretation: Self-Directed Learning Versus Continual Reader Feedback. AB - OBJECTIVE: The purpose of this study is to evaluate the roles of self-directed learning and continual feedback in the learning curve for tumor detection by novice readers of prostate MRI. MATERIALS AND METHODS: A total of 124 prostate MRI examinations classified as positive (n = 52; single Prostate Imaging Reporting and Data System [PI-RADS] category 3 or higher lesion showing Gleason score >= 7 tumor at MRI-targeted biopsy) or negative (n = 72; PI-RADS category 2 or lower and negative biopsy) for detectable tumor were included. These were divided into four equal-sized batches, each with matching numbers of positive and negative examinations. Six second-year radiology residents reviewed examinations to localize tumors. Three of the six readers received feedback after each examination showing the preceding case's solution. The learning curve, plotting accuracy over time, was assessed by the Akaike information criterion (AIC). Logistic regression and mixed-model ANOVA were performed. RESULTS: For readers with and without feedback, the learning curve exhibited an initial rapid improvement that slowed after 40 examinations (change in AIC > 0.2%). Accuracy improved from 58.1% (batch 1) to 71.0-75.3% (batches 2-4) without feedback and from 58.1% to 72.0-77.4% with feedback (p = 0.027-0.046), without a difference in the extent of improvement (p = 0.800). Specificity improved from 53.7% to 68.5 81.5% without feedback and from 55.6% to 74.1-81.5% with feedback (p = 0.006 0.010), without a difference in the extent of improvement (p = 0.891). Sensitivity improved from 59.0-61.5% (batches 1-2) to 71.8-76.9% (batches 3-4) with feedback (p = 0.052), though did not improve without feedback (p = 0.602). Sensitivity for transition zone tumors exhibited larger changes (p = 0.024) with feedback than without feedback. Sensitivity for peripheral zone tumors did not improve in either group (p > 0.3). Reader confidence increased only with feedback (p < 0.001). CONCLUSION: The learning curve in prostate tumor detection largely reflected self-directed learning. Continual feedback had a lesser effect. Clinical prostate MRI interpretation by novice radiologists warrants caution. PMID- 28026203 TI - Sexual dimorphism in bone-muscle relationship in young adults. AB - The purpose of this study was to analyse associations between lean soft tissue (LST), a surrogate of skeletal muscle mass and key fracture-related geometric characteristics of the proximal femur. Moreover, we examined the role that muscle played on the proximal femur geometry in response to physical activity (PA). Participants were 83 young adults. Leg LST (exposure) was assessed by dual energy X-ray absorptiometry (DXA). Proximal femur geometry was derived from a left hip DXA scan. Geometric variables (outcomes) included the femoral neck axis length (FNAL), the femoral neck width (FNW), the neck-shaft angle and FNW|FNAL (an index of robustness). PA was evaluated by accelerometry. Linear regression was used to analyse relationships. Additional exposure variables included body height and mass. In males, leg LST explained 17.4% of variation in FNAL (P < 0.001) and 15% in FNW (P = 0.015). In females, it explained 8.8% of the variance in FNAL (P = 0.020). Associations remained significant in males, but not in females, when vigorous PA was added to the models. These results suggest that public health approaches to promote PA may be particularly important in females since vigorous PA seems to convey advantages in femur geometry and consequently in bone strength. PMID- 28026206 TI - Inaccurate Citations in Biomedical Journalism: Effect on the Impact Factor of the American Journal of Roentgenology. AB - OBJECTIVE: The aim of this study is to investigate the frequency of incorrect citations and its effects on the impact factor of a specific biomedical journal: the American Journal of Roentgenology. MATERIALS AND METHODS: The Cited Reference Search function of Thomson Reuters' Web of Science database (formerly the Institute for Scientific Information's Web of Knowledge database) was used to identify erroneous citations. This was done by entering the journal name into the Cited Work field and entering "2011-2012" into the Cited Year(s) field. The errors in any part of the inaccurately cited references (e.g., author names, title, year, volume, issue, and page numbers) were recorded, and the types of errors (i.e., absent, deficient, or mistyped) were analyzed. Erroneous citations were corrected using the Suggest a Correction function of the Web of Science database. The effect of inaccurate citations on the impact factor of the AJR was calculated. RESULTS: Overall, 183 of 1055 citable articles published in 2011-2012 were inaccurately cited 423 times (mean [+/- SD], 2.31 +/- 4.67 times; range, 1 44 times). Of these 183 articles, 110 (60.1%) were web-only articles and 44 (24.0%) were print articles. The most commonly identified errors were page number errors (44.8%) and misspelling of an author's name (20.2%). Incorrect citations adversely affected the impact factor of the AJR by 0.065 in 2012 and by 0.123 in 2013. CONCLUSION: Inaccurate citations are not infrequent in biomedical journals, yet they can be detected and corrected using the Web of Science database. Although the accuracy of references is primarily the responsibility of authors, the journal editorial office should also define a periodic inaccurate citation check task and correct erroneous citations to reclaim unnecessarily lost credit. PMID- 28026205 TI - Preoperative Breast MRI: Surgeons' Patient Selection Patterns and Potential Bias in Outcomes Analyses. AB - OBJECTIVE: The purpose of this study is to determine which patient- and tumor related and clinical variables influence dedicated breast surgeons' and general surgeons' referrals for preoperative breast MRI for patients with newly diagnosed breast cancer. MATERIALS AND METHODS: Surgeons who perform breast surgery responded to a survey from June 16, 2014, through August 11, 2014. Participants self-identified as breast or general surgeons and provided professional practice details. They used Likert scores (range, 1-7 with increasing likelihood to order MRI) to weigh numerous patient- and tumor-related and clinical variables. Mean likelihood scores were calculated and compared using a linear mixed model. A p <= 0.05 was considered statistically significant. RESULTS: Two hundred eighty-nine surveys from 154 (53%) breast surgeons and 135 (47%) general surgeons showed an overall likelihood to refer for patients with a BRCA mutation (mean Likert score, 6.17), familial (mean Likert score, 5.33) or personal (mean Likert score, 5.10) breast cancer history, extremely dense breasts (mean Likert score, 5.30), age younger than 40 years (mean Likert score, 5.24), axillary nodal involvement (mean Likert score, 6.22), tumor that is mammographically occult (mean Likert score, 5.62) or fixed to the pectoralis (mean Likert score, 5.49), tumor that is a candidate for neoadjuvant treatment (mean Likert score, 5.38), multifocal or multicentric disease (mean Likert score, 5.22), invasive lobular carcinoma (mean Likert score, 5.20), T3 (mean Likert score, 4.48) or T2 (mean Likert score, 4.41) tumor, triple-negative breast cancer (mean Likert score, 4.66), a patient who is a candidate for mastectomy requesting breast conservation therapy (mean Likert score, 5.27), and radiologists' recommendations (mean Likert score, 5.19). Across all patient ages, breast surgeons referred more often than did general surgeons (mean Likert score, 4.32 vs 3.92; p = 0.03), especially for patients with BRCA mutation (mean Likert score, 6.39 vs 5.93; p = 0.01) and tumors smaller than 1 cm (mean Likert score, 3.84 vs 3.40; p = 0.002). Breast surgeons referred less often than did general surgeons for multifocal or multicentric disease (mean Likert score, 5.02 vs 5.44; p = 0.001). Breast surgeons and general surgeons similarly weighed other variables. CONCLUSION: Preoperative breast MRI referral trended with certain higher risk patient- and tumor-related and clinical variables and were nonuniform between the breast surgeons and general surgeon cohorts. Selection bias could affect outcomes analyses for preoperative breast MRI. PMID- 28026207 TI - Impact sports and bone fractures among adolescents. AB - The objective of the present study was to investigate the effects of different sports on stress fractures among adolescents during a 9-month follow-up period. The sample was composed of 184 adolescents divided into three groups (impact sports [n = 102]; swimming [n = 35]; non-sports [n = 47]). The occurrence of stress fracture was reported by participants and coaches. As potential confounders we considered age, sex, resistance training, body composition variables and age at peak of height velocity. There were 13 adolescents who reported fractures during the 9-month period. Bone mineral density values were higher in adolescents engaged in impact sports (P-value = 0.002). Independently of confounders, the risk of stress fracture was lower in adolescents engaged in impact sports than in non-active adolescents (hazard ratio [HR] = 0.23 [95% confidence interval (CI) = 0.05 to 0.98]), while swimming practice was not associated to lower risk of fracture (HR = 0.49 [95% CI = 0.09 to 2.55]). In conclusion, the findings from this study indicate the importance of sports participation among adolescents in the reduction of stress fracture risk, especially with impact sports. More importantly, these results could be relevant for recognising adolescents in danger of not reaching their potential for peak bone mass and later an increased risk of fractures. PMID- 28026208 TI - MRI of Small Hepatocellular Carcinoma: Typical Features Are Less Frequent Below a Size Cutoff of 1.5 cm. AB - OBJECTIVE: The purposes of this study were to analyze MRI features of small hepatocellular carcinomas (HCCs) on the basis of size and to evaluate the difference in frequency of typical radiologic hallmarks of HCC (arterial enhancement and washout) according to the tumor size. MATERIALS AND METHODS: Enrolled were 86 patients with 110 HCCs 3 cm or smaller who underwent surgical resection or transplantation. Two radiologists reviewed gadoxetic acid-enhanced MRI features for signal intensity of T2-weighted and T1-weighted imaging, diffusion restriction, presence of arterial enhancement, washout on portal and transitional phases, and signal intensity on the hepatobiliary phase. ROC curve analysis was performed to determine the optimal HCC cutoff size for radiologic hallmarks of HCC. Tumors were divided into two groups by cutoff size, and the frequencies of MRI features were assessed. RESULTS: On ROC analysis, the optimal cutoff for radiologic hallmarks of HCC was 1.5 cm in independent and consensus reviews by two radiologists. HCCs smaller than 1.5 cm showed typical finding of HCC less frequently than HCCs 1.5 cm or larger in diameter. In subgroup analyses, HCCs with diameters between 1 and 1.5 cm showed similar MRI findings to HCCs with diameters 1 cm or less but significantly different findings compared with HCCs with diameters from 1.5 to 2 cm and 2-3 cm. CONCLUSION: HCCs smaller than 1.5 cm in size less frequently showed MRI findings seen typically in larger HCCs. Therefore, small HCCs are harder to detect with certainty not only because of small size but also because of the lower frequency of typical MRI findings. PMID- 28026209 TI - Correlation of PET/CT and Image-Guided Biopsies of Pediatric Malignancies. AB - OBJECTIVE: The purpose of this study was to evaluate an early experience with correlation of PET/CT findings and image-guided biopsy results in pediatric patients. MATERIALS AND METHODS: In a single-center retrospective case series, the inclusion criterion was performance of image-guided biopsy within 6 weeks of PET/CT, either before or after the biopsy. RESULTS: Forty-five patients (23 boys, 22 girls; age range, 4-17 years; median, 10.5 years; weight range, 14.6-86.2 kg; median, 48 kg) underwent 47 PET/CT examinations and biopsies. Nineteen patients (20 biopsies) had known malignancy, and 26 patients had suspected malignancy. The results were malignant in 24 cases, benign in 16, and inadequate or normal in 7 cases. Thirty-nine of 47 PET/CT examinations had positive results, and eight had negative results. Final analysis of 37 of the 47 cases (confounders excluded) showed concordant results between biopsy and PET in 36 cases and discordant results in one case. CONCLUSION: PET/CT can be used for disease staging and follow-up. In the future PET/CT can play a valuable role in directing image guided biopsies of children. PMID- 28026210 TI - Interpretive Error in Radiology. AB - OBJECTIVE: Although imaging technology has advanced significantly since the work of Garland in 1949, interpretive error rates remain unchanged. In addition to patient harm, interpretive errors are a major cause of litigation and distress to radiologists. In this article, we discuss the mechanics involved in searching an image, categorize omission errors, and discuss factors influencing diagnostic accuracy. Potential individual- and system-based solutions to mitigate or eliminate errors are also discussed. CONCLUSION: Radiologists use visual detection, pattern recognition, memory, and cognitive reasoning to synthesize final interpretations of radiologic studies. This synthesis is performed in an environment in which there are numerous extrinsic distractors, increasing workloads and fatigue. Given the ultimately human task of perception, some degree of error is likely inevitable even with experienced observers. However, an understanding of the causes of interpretive errors can help in the development of tools to mitigate errors and improve patient safety. PMID- 28026211 TI - Abstracts from the September 2015 Pediatric Work Physiology Meeting. PMID- 28026402 TI - The Digest. PMID- 28026654 TI - L1CAM in the Early Enteric and Urogenital System. AB - L1 cell adhesion molecule (L1CAM) is a transmembrane molecule belonging to the L1 protein family. It has shown to be a key player in axonal guidance in the course of neuronal development. Furthermore, L1CAM is also crucial for the establishment of the enteric and urogenital organs and is aberrantly expressed in cancer originating in these organs. Carcinogenesis and embryogenesis follow a lot of similar molecular pathways, but unfortunately, comprehensive data on L1CAM expression and localization in human developing organs are lacking so far. In the present study we, therefore, examined the spatiotemporal distribution of L1CAM in the early human fetal period (weeks 8-12 of gestation) by means of immunohistochemistry and in situ hybridization (ISH). In the epithelia of the gastrointestinal organs, L1CAM localization cannot be observed in the examined stages most likely due to their advanced polarization and differentiation. Despite these results, our ISH data indicate weak L1CAM expression, but only in few epithelial cells. The genital tracts, however, are distinctly L1CAM positive throughout the entire fetal period. We, therefore, conclude that in embryogenesis L1CAM is crucial for further differentiation of epithelia. PMID- 28026694 TI - Strengthening systems and scholarship for global health - and public health. AB - No abstract available. PMID- 28026695 TI - Missing and murdered Indigenous women: Working with families to prepare for the National Inquiry. AB - No abstract available. PMID- 28026696 TI - Capacity building in human resources for health: The experience of the region of the Americas. AB - SETTING: Since the year 2003, most countries of the Region of the Americas have experienced sustained economic growth and inclusive development policies. In the health sector, achieving universal access became the overarching goal. However, the structural limitations of the health workforce represented a formidable obstacle to change. National Health Authorities were confronted with the challenge of developing critical capacities to redress entrenched inequalities in access to qualified health personnel. INTERVENTION: Under the auspices of the Pan American Health Organization, the Ministers of Health of the Region adopted, in September 2007, twenty regional goals for Human Resources for Health 2007-2015, aligned with the renewed strategy of Primary Health Care. Subsequently, a set of indicators and a methodology were developed to assess the goals and to monitor progress at the country level. OUTCOMES: Fifteen countries carried out a baseline assessment in 2009 or 2010 and conducted a second assessment in 2013. Although differences were noted across goals and between countries, the results suggested improvements in all twenty goals overall. The goals linked to the distribution of personnel, the management of migration, and the cooperation with education institutions appeared to be more resilient to change. IMPLICATIONS: The twenty Regional Goals for Human Resources for Health provided a common vision for action and a framework for cooperation within and among countries, and was a catalyst for change. Faced with evolving challenges, the countries should consider adopting a new shared agenda that builds on progress made and further supports intergovernmental policy alignment and capacity building in health workforce development, governance and management. PMID- 28026697 TI - Women health extension workers: Capacities, opportunities and challenges to use eHealth to strengthen equitable health systems in Southern Ethiopia. AB - OBJECTIVES: This study assesses the feasibility of female health extension workers (HEWs) using eHealth within their core duties, supporting both the design and capacity building for an eHealth system project focussed initially on tuberculosis, maternal child health, and gender equity. PARTICIPANTS: Health extension workers, Health Centre Heads, District Health Officers, Zonal Health Department and Regional Health Bureau representatives in Southern Ethiopia. SETTING: The study was undertaken in Southern Ethiopia with three districts in Sidama zone (population of 3.5 million) and one district in Gedeo zone (control zone with similar health service coverage and population density). METHODS: Mixed method baseline data collection was undertaken, using quantitative questionnaires (n = 57) and purposively sampled qualitative face-to-face semi-structured interviews (n = 10) and focus group discussions (n = 3). RESULTS: Themes were identified relating to HEW commitment and role, supervision, and performance management. The Health Management Information System (HMIS) was seen as important by all participants, but with challenges of information quality, accuracy, reliability and timeliness. Participants' perceptions varied by group regarding the purpose and benefits of HMIS as well as the potential of an eHealth system. Mobile phones were used regularly by all participants. CONCLUSION: eHealth technology presents a new opportunity for the Ethiopian health system to improve data quality and community health. Front-line female HEWs are a critical bridge between communities and health systems. Empowering HEWs, supporting them and responding to the challenges they face will be an important part of ensuring the sustainability and responsiveness of eHealth strategies. Findings have informed the subsequent eHealth technology design and implementation, capacity strengthening approach, supervision, and performance management approach. PMID- 28026698 TI - ? AB - Dans ce commentaire, nous proposons une conceptualisation des principes qui fondent la recherche sur les politiques et systemes de sante dans les pays a faible et moyen revenu, afin de favoriser l'ancrage des chercheurs dans ce champ. Ces principes sont la complementarite des angles d'analyse; l'interdisciplinarite; la transversalite des connaissances; et l'ancrage theorique et conceptuel. Ils sont illustres par l'analyse de deux reformes d'Afrique subsaharienne : les politiques de gratuite des soins et le financement base sur les resultats. La prise en compte de ces principes permet une comprehension plus large des enjeux des systemes de sante, et une reflexion plus fine sur chacun des angles d'analyse investigues. Ces exemples montrent l'interet d'opter pour une approche holistique et systemique des politiques et systemes de sante pour elargir une vision techniciste dominante, souvent centree sur leur performance et leur financement. PMID- 28026699 TI - An impact evaluation of Plan Indonesia's early childhood program. AB - OBJECTIVES: High-quality preschools are known to prepare children for success in primary school. Over half of Indonesia's children now pass through preschools whose quality and effectiveness are unknown. Our goal was to evaluate two government preschool models, namely kindergarten (TK) and the less formal health post (PAUD), with and without capacity-building efforts of a non-governmental organization (NGO-Plan), on children's language and math skills. METHODS: Thirteen TK and 17 PAUD Plan-supported and the same number of government supported preschools were randomly selected from East Nusa Tenggara, Indonesia. Five children from each (n = 292) and five who had graduated from each and were now in first grade (n = 241) were randomly selected and tested on language and math measures. The Plan-supported preschools were assessed for quality. Mothers reported on their family's socio-demographic situation and their child's preventive health practices, illnesses and diet over the previous two weeks. RESULTS: Analyses of covariance adjusting for clusters indicated that children attending Plan-supported preschools performed better overall, and especially those in TK preschools. Plan-supported TKs were observed to have higher quality than Plan-supported PAUDs. First graders who graduated from Plan-supported preschools, both TK and PAUD, achieved higher scores on language and math tests than government-supported graduates. Preventive health practices were better in the Plan group, though diet and height-for-age were poor overall. CONCLUSIONS: Upgrades to the government preschool program are needed to raise its quality and effectiveness, specifically by introducing a mix of instructional and indoor free choice play, resources and teacher training to support children's learning. PMID- 28026700 TI - How are Canadian universities training and supporting undergraduate medical, physiotherapy and occupational therapy students for global health experiences in international low-resource settings? AB - OBJECTIVES: Canadian medical (MD), physiotherapy (PT) and occupational therapy (OT) students increasingly show an interest in global health experiences (GHEs). As certain moral hazards can occur as a result of student GHEs, a growing consensus exists that universities must have an established selection process, in depth pre-departure training (PDT), adequate onsite supervision and formal debriefing for their students. This study aimed to identify current practices in Canadian MD, PT and OT programs and discuss areas for improvement by comparing them with recommendations found in the literature. METHODS: Canadian MD, PT and OT programs (n = 45) were invited to answer an online survey about their current practices for GHE support and training. The survey included 24 close-ended questions and 18 open-ended questions. Descriptive statistics and a thematic analysis were performed on the data and results were discussed in comparison with recommendations found in the literature. RESULTS: Twenty-three programs responded to the survey. Student selection processes varied across universities; examples included using academic performance, interviews and motivation letters. All but one MD program had mandatory PDT; content and teaching formats varied, as did training duration (2-38 hours). All but one MD program had onsite supervision; local clinicians were frequently involved. Debriefing, although not systematic, covered similar content; debriefing was variable in duration (1-8 hours). CONCLUSIONS: Many current practices are encouraging, but areas for improvement exist. Integrating global health content into the regular curriculum, with advanced study options for students participating in GHEs, could help universities standardize support and training. PMID- 28026701 TI - Building the capacity to solve complex health challenges in sub-Saharan Africa: CARTA's multidisciplinary PhD training. AB - OBJECTIVES: To develop a curriculum (Joint Advanced Seminars [JASs]) that produced PhD fellows who understood that health is an outcome of multiple determinants within complex environments and that approaches from a range of disciplines is required to address health and development within the Consortium for Advanced Research Training in Africa (CARTA). We sought to attract PhD fellows, supervisors and teaching faculty from a range of disciplines into the program. METHODS: Multidisciplinary teams developed the JAS curriculum. CARTA PhD fellowships were open to academics in consortium member institutions, irrespective of primary discipline, interested in doing a PhD in public and population health. Supervisors and JAS faculty were recruited from CARTA institutions. We use routine JAS evaluation data (closed and open-ended questions) collected from PhD fellows at every JAS, a survey of one CARTA cohort, and an external evaluation of CARTA to assess the impact of the JAS curriculum on learning. RESULTS: We describe our pedagogic approach, arguing its centrality to an appreciation of multiple disciplines, and illustrate how it promotes working in multidisciplinary ways. CARTA has attracted PhD fellows, supervisors and JAS teaching faculty from across a range of disciplines. Evaluations indicate PhD fellows have a greater appreciation of how disciplines other than their own are important to understanding health and its determinants and an appreciation and capacity to employ mixed methods research. CONCLUSIONS: In the short term, we have been effective in promoting an understanding of multidisciplinarity, resulting in fellows using methods from beyond their discipline of origin. This curriculum has international application. PMID- 28026702 TI - Operational readiness for conducting global health research abroad. AB - Research excellence is the goal of all researchers. Conducting quality research with the ultimate aim of improving health is a shared goal among researchers in the global health domain. The competencies required for conducting and producing quality research in global health go far beyond the academic or scientific spheres. They incorporate aspects of research partnership, which places humility, empathy, and mutual respect at its core. Conducting quality respectful global health research requires an appropriate balance of operational readiness (i.e., technical, physical, and mental readiness). This paper reports on the pertinence and potential shaping of conceptual work and exploratory research focusing on aspects of mental readiness. These aspects may be perceived to be significant enough to influence success and warrant further investigation in the context of conducting global health research abroad. PMID- 28026703 TI - Corporate sponsorship of global health research: Questions to promote critical thinking about potential funding relationships. AB - Funding options for global health research prominently include grants from corporations, as well as from foundations linked to specific corporations. While such funds can enable urgently-needed research and interventions, they can carry the risk of skewing health research priorities and exacerbating health inequities. With the objective of promoting critical reflection on potential corporate funding options for global health research, we propose a set of three questions developed through an open conference workshop and reflection on experiences of global health researchers and their institutions: 1) Does this funding allow me/us to retain control over research design, methodology and dissemination processes? 2) Does accessing this funding source involve altering my/our research agenda (i.e., what is the impact of this funding source on research priorities)? 3) What are the potential "unintended consequences" of accepting corporate funding, in terms of legitimizing corporations or models of development that are at the root of many global health problems? These questions outline an intentional and cautionary approach to decision-making when corporate funding for global health research is being considered by funding agencies, institutions, researchers and research stakeholders. PMID- 28026704 TI - Moving toward holistic wellness, empowerment and self-determination for Indigenous peoples in Canada: Can traditional Indigenous health care practices increase ownership over health and health care decisions? AB - OBJECTIVES: This study aimed to understand the role that traditional Indigenous health care practices can play in increasing individual-level self-determination over health care and improving health outcomes for urban Indigenous peoples in Canada. METHODS: This project took place in Vancouver, British Columbia and included the creation and delivery of holistic workshops to engage community members (n = 35) in learning about aspects of traditional health care practices. Short-term and intermediate outcomes were discussed through two gatherings involving focus groups and surveys. Data were transcribed, reviewed, thematically analyzed, and presented to the working group for validation. RESULTS: When participants compared their experiences with traditional health care to western health care, they described barriers to care that they had experienced in accessing medical doctors (e.g., racism, mistrust), as well as the benefits of traditional healing (e.g., based on relationships, holistic approach). All participants also noted that they had increased ownership over their choices around, and access to, health care, inclusive of both western and traditional options. They stressed that increased access to traditional health care is crucial within urban settings. CONCLUSIONS: Self-determination within Indigenous urban communities, and on a smaller scale, ownership for individuals, is a key determinant of health for Indigenous individuals and communities; this was made clear through the analysis of the research findings and is also supported within the literature. This research also demonstrates that access to traditional healing can enhance ownership for community members. These findings emphasize that there is a continued and growing need for support to aid urban Indigenous peoples in accessing traditional health care supports. PMID- 28026705 TI - A screening mechanism to recognize and support at-risk Aboriginal children. AB - OBJECTIVES: The Aboriginal Children's Health and Well-Being Measure(c) (ACHWM) was developed to assess health from the perspectives of Aboriginal children. The purpose of this paper is to document the screening process, embedded within the ACHWM, and assess its effectiveness. METHODS: The ACHWM was implemented in 2014/2015 with children 8 to 18 years of age living on the Wiikwemkoong Unceded Territory. Survey responses were screened to identify potential risk, using an automated algorithm run on computer tablets. Local mental health workers conducted brief mental health assessments to identify and support children at risk. Data were analyzed to estimate effectiveness of this screening process. RESULTS: A total of 293 children completed the ACHWM. The screening tool identified 35% with potential risk. Mental health workers confirmed 18% of all participants as being at-risk, and all were referred for support. The sensitivity of the tool was 75% while specificity was 79%. Improvements to the screening algorithm resulted in a specificity of 97% and negative predictive value of 95%, with no loss of sensitivity. CONCLUSION: Responsible population health surveys require a process to recognize and respond to answers indicative of health risks. This paper provides an example of a screening and triage process that enabled our survey team to screen responses in real time, respond to potential risk immediately, and connect participants to local support services. This process proved essential to conducting an ethical survey. The high specificity and negative predictive value make it an effective triage tool that is particularly valuable in Aboriginal communities and with higher-risk populations. PMID- 28026706 TI - Patterns and trends in long-term opioid use for non-cancer pain in British Columbia, 2005-2012. AB - OBJECTIVES: We aimed to calculate trends in incidence and prevalence rates of long-term opioid use for non-cancer pain, as well as to describe the characteristics of long-term opioid users and their patterns of opioid use. METHODS: We used population-based linked health care and socio-demographic administrative data for British Columbia (BC) between 2005 and 2012. We included individuals who had at least one episode of long-term opioid use during the study period and who were not cancer or palliative care patients. RESULTS: Long-term users comprised only 10% of all individuals prescribed opioids for non-cancer pain, but accounted for 64% of all opioid prescriptions and 87% of all morphine equivalents dispensed in BC during this period. While the incidence rate did not significantly change, the prevalence rate increased by 27% for men and 22% for women. In 2012, there were 3.80 (3.72-3.88) new long-term opioid users per 1,000 men and 4.42 (4.34-4.51) new users per 1,000 women. At the same time, there were 18.3 (95% CI 18.1-18.5) existing long-term users per 1,000 men and 21.7 users (95% CI 21.5-21.9) per 1,000 women. Overall, 2.4% of BC residents were long-term users of prescription opioids in 2012. Most long-term users had one continuous episode of use spanning multiple years. Almost two thirds took opioids every other day or more frequently. CONCLUSION: There is a growing population of long term opioid users for non-cancer pain in BC, with higher incidence and prevalence rates observed among women than among men. PMID- 28026707 TI - Determinants of vitamin D status in pregnant women and neonates. AB - OBJECTIVES: Evidence suggests a beneficial effect of vitamin D on perinatal health; however, low vitamin D status is prevalent in pregnant women and neonates. The objective was to determine factors that are associated with vitamin D status of mothers in early pregnancy and neonates. METHODS: The study comprised 1,635 pregnant women from Quebec City and Halifax, Canada, 2002-2010. Vitamin D status was based on the concentration of 25-hydroxy-vitamin D [25(OH)D] determined with a chemiluminescence immunoassay in maternal sera collected at a median of 15 weeks' gestation and in neonatal cord sera at delivery. A questionnaire with information on potential determinants was completed midpregnancy. RESULTS: A total of 44.8% of mothers and 24.4% of neonates had 25(OH)D concentrations <50 nmol/L. Adjusted mean (95% confidence interval) maternal 25(OH)D levels were higher in summer than in winter by 16.1 nmol/L (13.6 18.7), and in those in the highest versus the lowest category of education by 6.1 nmol/L (0.5-11.8), in BMI <25 kg/m2 versus BMI >=35 kg/m2 by 8.2 nmol/L (4.0 12.3), and in the highest versus the lowest physical activity category by up to 9.5 nmol/L (2.9-16.1). Determinants of neonatal 25(OH)D levels were similar but also included maternal age, dairy intake, supplement use and 25(OH)D level. CONCLUSION: This study suggests that vitamin D status of pregnant women and/or neonates might be improved through supplementation, adequate dairy intake, a move towards a healthy pre-pregnancy body weight, and participation in physical activity. Controlled studies are needed to determine the effectiveness of interventions aimed at these factors. PMID- 28026708 TI - Beverages and snacks available in vending machines from a subset of Ontario secondary schools: Do offerings align with provincial nutrition standards? AB - OBJECTIVES: As part of an evaluation of Ontario's School Food and Beverage Policy (P/PM 150) in a populous Ontario region, this research aimed to: 1) identify, describe and categorize beverages and snacks available for purchase in secondary school vending machines according to P/PM 150 standards; and 2) compare the number and percentage of beverages and snacks within P/PM 150 categories (Sell Most, Sell Less, Not Permitted) from Time I (2012/2013) to Time II (2014). METHODS: Representatives from consenting secondary schools assisted researchers in completing a Food Environmental Scan checklist in Times I and II. Sourced nutritional content information (calories, fats, sodium, sugars, ingredients and % daily values) was used to categorize products. The number and percentage of products in P/PM 150 categories were compared between Times by paired t-tests. RESULTS: Of 26 secondary schools participating in total, 19 participated in both Time periods and were included in the study. There were 75 beverages identified (59 Time I, 45 Time II), mostly water, juices and milk-based beverages; and 132 types of snacks (87 Time I, 103 Time II), mostly grain-based snacks, vegetable/fruit chips, and baked goods. A majority of schools offered one or more Not Permitted beverages (47% Time I, 58% Time II) or snacks (74% Time I, 53% Time II). Significantly more schools met P/PM 150 standards for snacks (p = 0.02) but not beverages in Time II. CONCLUSION: Full P/PM 150 compliance was achieved by few schools, indicating that schools, school boards, public health, and food services need to continue to collaborate to ensure nutrient-poor products are not sold to students in school settings. PMID- 28026709 TI - Misclassification errors from postal code-based geocoding to assign census geography in Nova Scotia, Canada. AB - OBJECTIVES: Postal codes are often the only available geographic identifiers in many sources of health data in Canada. In order to conduct geographic analyses, postal codes are routinely geocoded to census geography to link to ecological data. Despite common use of this method, the extent of geographic misclassification errors is poorly understood. We estimated misclassification errors in the geocoding of postal codes to assign census geography in Nova Scotia, Canada. METHODS: We examined differences between counts and match rates for postal-code geocoded and actual locations of buildings in Nova Scotia at two census administrative area levels: dissemination areas (DAs) and census subdivisions (CSDs). Actual locations were based on the data collected by the provincial government containing actual latitude/longitude of buildings. Variation in misclassification by rurality, using Statistics Canada's classification, was also assessed. RESULTS: Outside two urban areas (Halifax Metro and Sydney) which had <10% differences in counts, many DAs had >30% differences. Match rates showed similar patterns, with the vast majority of non urban DAs having <40% match rates. Even in major urban areas, 10% of DAs had large misclassification errors. Misclassification errors at the CSD level were still too great to estimate counts or rates without further area aggregation. CONCLUSION: Routine use of postal code geocoding should be replaced with geocoding of location information using additional identifiers such as civic addresses or latitude and longitude. If data holders did this in-house before providing data to researchers, the accuracy and capacity of geographic analysis would be enhanced while protecting confidentiality. PMID- 28026710 TI - Trends in unintentional injury mortality in Canadian children 1950-2009 and association with selected population-level interventions. AB - OBJECTIVES: To examine unintentional injury mortality rates in children (0-19 years) in Canada from 1950 to 2009 against national population-level injury prevention interventions. METHODS: Injury mortality rates were age and sex adjusted. Changes in trend and level of mortality rates were assessed at pre specified intervention periods using segmented linear regression analyses for interrupted time series. Maximum likelihood estimation was used with a second order autoregressive error process. RESULTS: From 1950 to 2009, the overall unintentional injury mortality rate decreased by 86%. Males had consistently higher mortality rates compared to females; however, the standardized rate ratio decreased from 2.37:1 in 1950 to 1.97:1 in 2009. Substantial declines in choking/suffocation deaths were noted in children less than 1 year of age, predominantly during the period 1970-1988 when the Hazardous Products Act and Crib Regulations were implemented. For burns, significant changes in slope were noted comparing 1972-1994 to pre-1971 (introduction of the Hazardous Products Act - Flammability Regulations), where the greatest decline was noted in children ages 1-4 years (Est. = -0.03, 95% CI = -0.02, -0.04). For 15-19 year olds, there was a 408% increase in motor vehicle collision-related mortality rates between 1950 and 1971; however a significant change in slope was noted during the period 1978-1985, compared to 1972-1977 (Est. = -0.10, 95% CI = -0.20, -0.007) across all age groups. CONCLUSION: While this study is not a cause and effect analysis, there is a strong association with implementation of safety campaigns and legislative changes related to child safety and a dramatic decline in childhood fatalities related to injury. PMID- 28026711 TI - Sedentary behaviours among adults across Canada. AB - OBJECTIVES: While cross-Canada variations in physical activity and weight status have been illustrated, less is known about sedentary behaviour (SB). The aim of this study was to describe various SBs and their correlates among Canadian adults. METHODS: Cross-sectional data from the 2011-2012 Canadian Community Health Survey included 92,918 respondents aged 20-75+ years, representative of >22 million Canadian adults. TV/video viewing, computer, video game playing and reading time were self-reported. Associations with socio-demographic, health and health behaviour variables were examined. RESULTS: About 31% of adults reported >2 hours/day TV viewing, while 47% of men and 41% of women reported >5 hours/week computer use, 24% of men and 12% of women reported >=1 hour/week video game playing, and 33% of men and 46% of women reported >5 hours/week reading; 28% of respondents reported >=5 hours/day total SB time. Age was the strongest correlate: adults 75+ had 5 and 6 times greater odds respectively of reporting >2 hours/day TV viewing and >5 hours/week reading, but far lesser odds of reporting high computer or video game time, compared to adults 20-24. Other variables associated with specific SBs included gender, marital status, education, occupation, income and immigrant status, as well as BMI, weight perceptions, smoking, diet and physical activity. CONCLUSION: Common sedentary behaviours were associated with numerous socio-demographic, health and health behaviour characteristics in a large representative sample of Canadians. These correlates differed according to the type of SB. Public health interventions targeting SB should be behavior-specific and tailored to the population segment of interest. PMID- 28026712 TI - Hunger and overweight in Canadian school-aged children: A propensity score matching analysis. AB - OBJECTIVE: The last decade saw a higher prevalence of overweight reported among food-insecure families in Canada, but no robust evidence exists on the covariate adjusted association in children. In this study, we examined the association between hunger and overweight in Canadian students, using a propensity score matching analysis to reduce confounding. METHODS: This research used data from the 2009/2010 Canadian Health Behaviour in School-aged Children study on a representative national sample of students in Grades 6 through 10. Students self reported their height and weight and how often they have gone to school or to bed hungry due to a lack of food at home. Multivariate logistic regression modeling was conducted on the total sample (N = 17,694) and on the sample matched on propensity scores (n = 7,788). RESULTS: The overall prevalence of overweight among students was 20.2% with a significant difference between students who reported hunger (24.0%; 95% CI: 22.1-26.0) and students who did not (19.0%; 95% CI: 17.9-20.2). Analysis on the matched sample revealed a significant association between hunger and overweight in children (adjusted odds ratio: 1.30; 95% CI: 1.12-1.50). CONCLUSIONS: A substantial number of Canadian students have reported being hungry because of a lack of food at home. These students are at increased risk of overweight, regardless of their social class. Child hunger and household food insecurity exist in Canada and constitute a call for policy action at a national level. PMID- 28026713 TI - A family-centered lifestyle intervention for obese six- to eight-year-old children: Results from a one-year randomized controlled trial conducted in Montreal, Canada. AB - OBJECTIVES: Childhood obesity interventions should be family-centered and focused on lifestyle behaviours that achieve sustainable reductions in adiposity. The primary objective of this randomized controlled trial was to test a family centered lifestyle intervention using Canada's Food and Physical Activity (PA) Guidelines to reduce body mass index-for-age z-scores (BAZ) in overweight and obese (OW/OB) children. METHODS: Children (n = 78; ages 6-8.5 years) were randomized to standard (StnTx) or modified (ModTx) interventions or control (Ctrl). Measurements at baseline and every three months for one year included: anthropometry, BAZ, waist circumference (WC), and dual-energy X-ray absorptiometry scans for percent body fat (%BF), fat mass (FM) and trunk fat mass. Fatty acids measured by gas chromatography were used to assess compliance to the milk and alternatives interventions during the first six months. Six intervention sessions were based on Canada's Food and PA Guidelines and individualized to meet the needs of the family. ModTx were advised to consume four milk and alternatives/day versus the recommended two (StnTx) and to preferentially engage in daily weight-bearing PA. Ctrl were provided the guidelines. RESULTS: Baseline anthropometry did not differ among groups. At 12 months (n = 73), all groups increased height (p < 0.001) and lean mass (p < 0.001). ModTx decreased BAZ (p < 0.001); %BF decreased in ModTx (p = 0.018), but not in StnTx (p = 0.997) or Ctrl (p = 0.998). FM, WC and trunk fat mass all significantly increased in Ctrl (p < 0.001). At baseline and three months, fatty acids did not differ among groups, however they did decrease in ModTx at six months [C14:0 (-0.07%, p = 0.053), C15:0 (-0.04%, p = 0.049), C17:0 (-0.09%, p = 0.036)]. CONCLUSION: Participating in a family centered-lifestyle intervention that focused on Canadian dietary and PA Guidelines and emphasized increasing milk and alternatives and weight-bearing PA had positive effects on reducing adiposity in OW/OB children. Guidelines are appropriate for the obese pediatric population but need to be individualized to meet the needs of the family. Additional studies are warranted to test the use of biochemical indices to assess compliance to milk and alternative intakes in OW/OB children participating in lifestyle interventions. PMID- 28026714 TI - Prevalence of non-food allergies among non-immigrants, long-time immigrants and recent immigrants in Canada. AB - OBJECTIVES: The prevalence of allergic conditions has been increasing worldwide, with the highest rates seen in Western countries like Canada. The development of allergies is known to be related to both genetic and environmental factors, but the causal pathways remain unclear. Studies on immigrants provide a unique opportunity to disentangle these two factors and provide a better understanding of the disease aetiology. The aim of this study was to investigate the relationship between immigration status and prevalence of non-food allergies in a population-based study of Canadians. METHODS: Data of 116,232 respondents from the Canadian Community Health Survey (Cycle 3.1, 2005) were used in a multivariable logistic regression to assess the association between immigration status (non-immigrant, long-time immigrant [>10 years] and recent immigrant [<=10 years]) and self-reported doctor-diagnosed non-food allergies, adjusting for potential confounders. RESULTS: The highest prevalence of non-food allergies was found among non-immigrants (29.6%), followed by long-time immigrants (23.9%) and then recent immigrants (14.3%). The odds of non-food allergies were reduced by 60% (OR = 0.40, 95% CI: 0.35, 0.45) among recent immigrants and 25% (OR = 0.75, 95% CI: 0.70, 0.80) among long-time immigrants, compared with non-immigrants, after adjusting for sex, age, socio-economic status and rurality. CONCLUSION: This study finds a distinctly lower prevalence of non-food allergies among immigrants compared with non-immigrants, with the difference diminishing with longer duration of residence in Canada. The findings highlight the potential of environmental determinants of allergy development that warrant further investigation, and demonstrate the need for multicultural strategies to manage the public health burden of allergic conditions. PMID- 28026715 TI - Correlates of clinical breast examination among lesbian, gay, bisexual, and queer women. AB - OBJECTIVES: Lesbian, gay, bisexual, and queer (LGBQ) women have increased risk of breast cancer yet lower use of early detection screening than heterosexual women. This lower use may be due in part to sexual stigma. The study purpose was to explore correlates of past two-year clinical breast examination (CBE) among LGBQ women to better understand screening disparities, particularly among gender non conforming LGBQ women. METHODS: A cross-sectional Internet-based survey was conducted with LGBQ women in 2011-2012. We conducted multivariate logistic regression to assess the associations between individual, social/structural and health care factors and past two-year CBE among LGBQ women (n = 414), including a subsample of gender non-conforming LGBQ women (n = 148). RESULTS: In multivariate analyses, significant correlates of past two-year CBE among the full sample included sexually transmitted infection knowledge (OR: 1.12, 95% CI: 1.05, 1.19), sexual risk practices (OR: 0.92, 95% CI: 0.87, 0.98), past two-year Papanicolaou test (OR: 8.36, 95% CI: 4.24, 16.45), having a regular source of health care (OR: 4.84, 95% CI: 2.60, 9.01), and health care provider knowing one's sexual orientation (OR: 3.60, 95% CI: 2.29, 5.81). Among gender non-conforming LGBQ women, perceived gender non-conformity stigma (OR: 0.85, 95% CI: 0.74, 0.99) and belief that one's health care provider is uncomfortable with one's sexual orientation (OR: 0.33, 95% CI: 0.11, 1.00) were also associated with lower screening. CONCLUSION: These findings enhance understanding of individual, social/structural, and health care factors correlated with CBE among LGBQ women. More research is needed to understand the complex interplay of these factors to inform multi-level interventions to address screening disparities for diverse LGBQ women. PMID- 28026717 TI - Outcomes of an investment in administrative data infrastructure: An example of capacity building at the Manitoba Centre for Health Policy. AB - Using the Manitoba Centre for Health Policy as an example, this commentary discusses how even small investments in population health data can create a multitude of research benefits. The authors highlight that through infrastructure development such as acquiring databases, facilitating access to data and developing data management practices, new, innovative research can be achieved at relatively low cost. PMID- 28026716 TI - An update to the recommended core content for sun safety messages for public education in Canada: A consensus report. AB - Reducing ultraviolet radiation exposure decreases the risk of skin cancer and eye damage. Between 1996 and 2006, Canadians increased their time in the sun without improving protection. National consensus on sun protection information for the public was last achieved in 1994. Public messages have since been modified inconsistently. The Ontario Sun Safety Working Group initiated a review of messages and engaged a scientific panel to draft message content. Working Group members then delivered a national consensus process, engaging a National Steering Committee, a health communications expert and representatives from 28 organizations through a workshop with pre- and post-workshop surveys. The result of the consensus process is the updated Recommended Core Content for Sun Safety Messages in Canada. Four groups of statements comprise the new content: Key Facts, Primary Recommended Protective Action Statements, Additional Recommended Protective Action Statements, and Tips for Implementing the Primary Protective Actions. Organizations are encouraged to adopt, at minimum, the Primary Recommended Protective Action Statements as the basis for public messaging. The recommended core content establishes a common understanding of what is needed for effective sun protection. The underlying expectation is that, as a key next step, content will be tailored for different subpopulations and health promotion campaigns. PMID- 28026718 TI - Health equity and the value of public health generalists: An interview with Connie Clement. AB - No abstract available. PMID- 28026719 TI - Politics, health systems and population health: An interview with David Levine. AB - No abstract available. PMID- 28026720 TI - Knowledge and practices of Village Health Team members in early detection and care for children with severe acute malnutrition at the community level: A case study in rural Uganda. PMID- 28026721 TI - Standard Approaches to the Acetabulum Part 2: Ilioinguinal Approach. AB - The ilioinguinal approach is one of the standard approaches in the treatment of displaced acetabular fractures used during the last decades (9). The meta analysis of Giannoudis et al. showed that 21.9% of acetabular fractures were historically treated using this approach (3). One of the disadvantages of this study was, that studies focussing especially on posterior wall stabilization and studies dealing with more complex fracture types treated by extended approaches were integrated. Thus, these fracture types were overrepresented. Re-analysis excluding these data lead to an increase of the rate of anterior approaches to 25.9%. More recent data (years 2005-2007) from the German multicenter study showed that presently in almost 45% of the cases the single ilioinguinal approach was used and only 38% of patients were stabilized via the KocherLangenbeck approach (11). Historically, the Smith-Peterson approach (15, 17) and the iliofemoral approach were used to treat acetabular fractures. In the 60ies, based on the work by Letournel and Judet, the ilioinguinal approach was developed for acetabular fracture fixation (9). It is an extrapelvic approach resulting in an indirect reconstruction concept of the acetabulum without direct visualization of the articular acetabulum. The ilioinguinal approach was the standard anterior approach during the last 30-40 years. An important advantage is the reduced soft tissue detachment of periarticular muscles with only a small risk of developing heterotopic bone formation. The aim of the second part of "Standard approaches to the acetabulum" is to report on the special topics indication, positioning, exposure, incision, dissection, the anatomical basis of osteosynthesis and present results using ilioinguinal approach. PMID- 28026722 TI - Non-Union in Upper Limb Fractures - Clinical Evaluation and Treatment Options. AB - Although non-unions in the upper limb are rare different treatment options of this challenging situation are still affected with up to 20% of failure rate due to current literature. Risk factors for delayed and non-union of fractures are mainly the size of the fracture gap and bone loss of open fractures or in primary surgery followed by other relevant internal and external factors. In the upper limb non-unions of long bones are described with up to 30% after operative intervention. Especially in the upper limb range of motion is limited in non union cases and disables adjacent joints like the shoulder, elbow and wrist hence reducing the total activity level of affected patients. Beside careful investigation of the causes leading to the non-union a comprehensive treatment plan should be defined to achieve successful results. Treatment can be non operative in several, selected cases, but in the majority of cases revision surgery is necessary to achieve osseous healing. Our own experience showed that non-union in the upper limb are rare and account for only 1.7% of all surgical managed upper limb fractures. Non-union of upper limb fractures occur most frequently in clavicle fractures followed by humeral fractures. Atrophic non union is the most frequent reason for osseous non-union (57%) and osseous healing after revision surgery in non-unions is completed after a mean of 6.45 months. This article will give a brief overview of the genesis, clinical evaluation, treatment options and recommendations in upper limb non-unions according to the current literature. Key words: fracture, upper-limb, non-union, osteosynthesis, cancellous bone-graft. PMID- 28026723 TI - Comminuted Fracture of Elbow - Ostheosynthesis vs. Total Joint Replacement. AB - Comminuted fractures of the elbow are very rare and in most cases very complex and the successful treatment can be a challenge for the treating surgeon. Due to the elbow joint's complex functional anatomy, the multi-fragmentary nature of many fractures and concomitant destabilizing associated injuries, comminuted fractures of the elbow still present a serious challenge for the orthopedic surgeon. Especially in more severe communicated injuries an osteosynthesis or endoprosthesis must be discussed with the patient. There is a lack of clear treatment recommendations based on solid evidence. An overview of the literature including a treatment algorithm to guide decision making for the distal humeral fracture in the adults is presented and own results are analyzed. Key words: comminuted fracture of elbow, total joint replacement of the elbow, elbow prosthesis, elbow arthroplasty, distal humeral fracture. PMID- 28026724 TI - [Gait Analysis in Patients with Hip Disorders]. AB - Recent studies have shown that the evaluation of both conservative and surgical therapy cannot do without gait analysis. Orthopaedic textbooks, with some exceptions, deal in great detail with a thorough clinical examination of the patient but gait assessment is mentioned only marginally. More attention is paid to gait analysis in rehabilitation medicine. Motion and gait analysis laboratories equipped with optoelectronic cameras and force platforms were first developed for cerebral palsy children. Recently, several studies have been published on the use of these methods in disorders of hip and knee joints or spine diseases. Key words: gait analysis, hip joint. PMID- 28026725 TI - [Operative Treatment for Saddle-Shaped Femoral Heads]. AB - PURPOSE OF THE STUDY A saddle-shaped deformity of the femoral head has a poor prognosis due to rapid development of secondary changes. A new method of treatment by intra-articular anteromedial wedge reduction osteotomy (AWRO) of the femoral head may preserve the hip for the future. This study was designed to ascertain that this invasive technique was safe and effective and to confirm our hypothesis that AWRO significantly improved functional and radiological parameters of the hip joint. MATERIAL AND METHODS Patients who underwent AWRO between 2010 and 2013 were enrolled in this study. The indication criteria for the procedure included Stulberg grade V hips on AP radiographs, hinged abduction with pain, limping and a limited range of movement. Values of the Stulberg grading, capital diaphyseal index, caput-collum-diaphyseal angle and Harris hip score were recorded before and after surgery and the results were statistically evaluated using the paired t-test. The AWRO procedure was performed from the anterolateral approach after subperiosteal protection of the vessels had been ensured. The central necrotic part of the femoral head was removed, and the medial segment was mobilised and fixed to the intact lateral segment. Either a hip spica cast or bed-rest for six weeks was indicated. Full weight bearing was allowed at 3 months after surgery. RESULTS Twelve patients with an average follow up of 55 months were evaluated. There were eight boys and four girls with an average age of 14 years at the time of surgery. The average Harris hip score improved from 54.52 before to 73.58 after surgery. The post-operative outcomes according to the Stulberg classification included one grade II hip, seven grade III hips, three grade IV hips and one grade V hip. The average capital-diaphyseal index dropped from 1.56 (1.19-1.92) to 1.28 (0.95-1.67) and the average caput collum-diaphyseal angle increased from 134 degrees (121-143) to 140 degrees (130 155) after surgery. Avascular necrosis developed in two patients. All the differences were statistically significant. DISCUSSION Reduction osteotomies of the femoral head reported in the literature differ from the AWRO procedure used in this study in both the approach and the performance. The results presented here are in agreement with those published in the relevant literature. They showed no significant deterioration in comparison with the outcomes of our short term study reported earlier. The outcome of treatment is related to the disease aetiology, functional parameters and previous procedures involving the hip joint. CONCLUSIONS AWRO is a salvage procedure that prolongs the longevity of joints in incongruent hips with very high morbidity. This procedure gave significantly better results in years after surgery, which confirmed our hypothesis. Level of evidence IV Key words: hinge abduction, Perthes disease, Stulberg, femoral head reduction osteotomy, avascular necrosis, arteria circumflexa femoris medialis. PMID- 28026726 TI - [Intra-Articular Application of Tranexamic Acid Significantly Reduces Blood Loss and Transfusion Requirement in Primary Total Knee Arthroplasty]. AB - PURPOSE OF THE STUDY The aim of this prospective study was to investigate the effect of topical application of tranexamic acid (TXA, Exacyl) on the amount of post-operative blood loss, and blood transfusion requirement in patients undergoing primary total knee arthroplasty (TKA). Attention was paid to early complications potentially associated with TXA administration, such as haematoma, wound exudate, or knee swelling. In addition, the economic benefit of TXA treatment was also taken into account. MATERIAL AND METHODS The study included 238 patients (85 men and 153 women) who underwent primary total knee arthroplasty (TKA) at our department between January 2013 and November 2015. A group of 119 patients (41 men and 78 women) received intraarticular TXA injections according to the treatment protocol (TXA group). A control group matched in basic characteristics to the TXA group also consisted of 119 patients. The average age in the TXA group was 69.8 years, and the most frequent indication for TKA surgery was primary knee osteoarthritis (81.5%). In each patient, post-operative volume of blood lost from drains and total blood loss including hidden blood loss were recorded, as well as post-operative haemoglobin and haematocrit levels. On discharge of each patient from hospital, the size and site of a haematoma; wound exudate, if present after post-operative day 4; joint swelling; range of motion and early revision surgery, if performed, were evaluated. Requirements of analgesic drugs after surgery were also recorded. RESULTS In the TXA group, blood losses from drains were significantly lower than in the control group (456.7 +/- 270.8 vs 640.5 +/-448.2; p = 0.004). The median value for blood losses from drains was lower by 22% and the average value for total blood loss, including hidden losses, was also lower than in the control group (762.4 +/- 345.2 ml vs 995.5 +/- 457.3 ml). The difference in the total amount of blood loss between the two groups was significant (p = 0.0001), including hidden blood loss (p = 0.030). The TXA patients had significantly fewer requirements for allogeneic blood transfusion (p < 0.0004), higher post-operative haemoglobin levels (p = 0.014), lower incidence of haematomas (p = 0.0003), and a significantly higher flexion degree on discharge from hospital (p < 0.0001). No higher volume of wound drainage was found (p = 1.000). Only one patient of the TXA group underwent revision surgery due to wound healing disturbance. The total costs of blood transfusion requirements were significantly lower in the TXA group than in the control group (p = 0.0004). DISCUSSION Topical administration allows the antifibrinolytic effect of TXA to act directly at a bleeding site. Its advantages involve easy application, maximum TXA concentration at the site of application, no danger associated with administration of a higher TXA dose and minimal TXA resorption into the circulation. On the other hand, there are no exact instructions for an effective and safe topical application of TXA and some authors are concerned that a coagulum arising after TXA application might affect soft tissue behaviour (healing, swelling, rehabilitation) or result in infection. CONCLUSIONS The study showed the efficacy and safety of topical TXA administration resulting in lower peri-operative bleeding, fewer blood transfusion requirements and higher haemoglobin levels after TKA. The patients treated with TXA had less knee swelling, lower incidence of haematomas and used fewer analgesic drugs in the early post-operative period. The economic benefit is also worth considering. In agreement with the recent literature, it is suggested to add topical TXA application to the recommended procedures for TKA surgery. Key words: tranexamic acid, Exacyl, topical application, intra-articular application, blood loss, hidden blood loss, total knee arthroplasty, complications. PMID- 28026727 TI - Radiological Changes after Interspinous Dynamic Stabilisation for Lateral Stenosis of Lumbar Spinal Canal: A Parallel Group Randomised Trial. AB - PURPOSE OF THE STUDY Interspinous dynamic stabilisation devices (IDSDs) are used for stabilisation and indirect decompression of the spinal motion segment in minimally invasive treatment of degenerative conditions of lumbar spine. Good methodological quality studies on biomechanical effects of IDSDs are lacking in scientific literature. The purpose of this study was to evaluate the biomechanical effect of dynamic IDSD implantation on a spinal motion segment. MATERIAL AND METHODS We conducted a parallel group randomised trial (RT) on twelve patients, comparing radiological stabilisation and indirect decompression outcome measures between groups of patients with an isolated degenerative condition of L4-L5 motion segment and unilateral L5 nerve root radiculopathy. One group of six patients was operated by decompression and dynamic IDSD implantation and the other group of six patients by decompression alone. The radiological assessment was performed 6 months postoperatively in all patients. RESULTS Dynamic IDSD implantation significantly decreased segmental intervertebral angle (IA) and significantly increased segmental foraminal height (FH) and foraminal width (FW). The implantation had no effect on segmental range of motion (ROM) and posterior disc height (PDH). CONCLUSIONS The studied dynamic IDSD improved radiological indirect decompression outcome measures while only partially improved radiological stabilisation outcome measures. Oxford Centre for Evidence Based Medicine 2011 Level 3: randomised trial with small effect size. Key words: lumbar spine, degenerative lateral stenosis, interspinous dynamic stabilisation, DIAM, randomised trial. PMID- 28026728 TI - [Influence of the Weather on the Incidence of Fractures in the Elderly]. AB - PURPOSE OF THE STUDY The incidence of geriatric fractures (proximal femur, distal radius, proximal humerus and thoracolumbar spine injuries) in the population increases with ageing. However, the role of weather conditions, such as icy and slippery winter, should not be overlooked. A deeper insight into this relationship may bring about a better understanding of the fracture aetiology and thus allow for improvement in the prevention of fractures in elderly people. MATERIAL AND METHODS This prospective study included 676 patients (469 women and 207 men) aged 65 and over. Relationships between the incidence of geriatric fractures in these patients and the season, weather phenomena (i.e., air temperature, atmospheric pressure, air humidity, wind speed, visibility, rain, snow, mist and storm) and global biometeorological data in the period from 1 January 2012 to 31 December 2013 were investigated. Patients with high velocity trauma or those with pathological fractures were excluded. Time (day/night), the place of injury (outdoor/indoor/home environment), comorbidities and chronicuse medication were also recorded. Weather forecast records with weather health loads (biotropic indices) were obtained from the commercial service Weather Underground and the Czech Hydrometeoro-logical Institute. The results were statistically analysed using the Statistika 12 programme. RESULTS The incidence of fractures was higher in winter months but there was no statistically significant correlation between the number of fractures and various weather characteristics (temperature, atmospheric pressure, air humidity, wind speed, visibility, rainfall, snow, mist or storm). On the other hand, a relationship between the incidence of geriatric fractures and the biometeorological data (biotropic index) for that day was significant (r = 0.65, p= 0.0401). The majority of fractures occurred during the daytime (83.7%) and in the indoor environment (83.1%); of the latter fractures, 85.2% were home injuries. The most frequent comorbidities included cardiovascular disease (36.2%), obesity (31.1%) and diabetes mellitus (25.4%). DISCUSSION Studies investigating seasonal patterns in relation to the incidence of geriatric fractures are contradictory. Sixteen previous studies have examined seasonal variations and the incidence of some types of geriatric fractures in different parts of the world. The majority of them have dealt with hip fractures, three with forearm injuries and one compared the incidence of hip, distal forearm, proximal humerus and ankle fractures in the four seasons of the year. Of 13 studies in geographic areas located north of 40 degrees latitude, eight showed no seasonal variation in the incidence of fractures, four recorded an increase in the number of fractures in winter and two showed an increased number of fractures in summer. Three of them also studied the effect of daily temperature. Only one study paid attention to biometeorological data and related the biotropic index to the number of injuries treated at the emergency department. Three studies showed that fractures occurred most frequently in the home environment and during the daytime. CONCLUSIONS This study did not prove any statistically significant relationship between the incidence of geriatric fractures and different weather phenomena. Nevertheless, it showed a higher incidence of fractures in winter, from December to February. Most fractures occurred in indoor environments and during the day. A high value of the biotropic index was significantly related to the incidence of geriatric fractures. The most frequent comorbidities included cardiovascular disease, obesity and diabetes mellitus. Key words: geriatric fracture, season, weather, biometeorological forecast. PMID- 28026729 TI - [Traumatic Thrombosis of the Renal Artery following Seat-Belt Injury]. AB - Renal artery thrombosis is a rare complication of blunt abdominal injury. It occurs most frequently in car accidents in which sudden deceleration results in multiple internal injuries. Renal artery occlusion occurs rarely as an isolated blunt trauma. This report presents a case of traumatic occlusion of the left renal artery with complete ischaemia of the left kidney in a haemodynamically stable girl who suffered multiple seat-belt injuries in a car crash. Ambiguous findings on a CT scan of the abdominal cavity indicated surgical inspection of the abdomen and, since the injury-to-surgery interval was short, an attempt at revascularisation of the left kidney was made. This was performed using laparotomy through a lateral left-side incision, as an uncommon approach to the injured organs. A seat-belt fracture of the L2/3 spine was stabilised at secondstage surgery. Key words: renal artery thrombosis, seat-belt fracture of the lumbar spine. PMID- 28026730 TI - [Symptomatic Intraosseous Ganglion of the Trapezium. Case Report and Literature Review]. AB - An intraosseous ganglion cyst has been reported in nearly all of the carpal bones; it is a rare cause of chronic wrist pain. The case presented here is a rare finding of symptomatic intraosseous ganglion of the trapezium bone. The relevant literature is reviewed. Key words: ganglion cyst, trapezium bone, wrist. PMID- 28026731 TI - Treatment of Tibial Non-Unions - State of the Art and Future Implications. AB - healing disturbances occur in 5-10% of the cases. The anatomical region of the lower limb predisposes the tibia for bone healing disturbances. Reports about the incidence of non-unions of the tibial shaft are inhomogeneous. Different treatment strategies have been published which depend on the type of non-union as well as the history of the patient. These range from conservative approaches to complex procedures including segmental resection and bone transport. This review aimed to summarize the state of the art treatment of tibial non-unions and report about recent basic research results that may improve bone healing. Key words: tibial non-unions, treatment strategies, bone healing. PMID- 28026732 TI - [Spontaneous Tendon Ruptures in the Rheumatoid Hand]. AB - A spontaneous tendon rupture is a direct consequence of rheumatoid inflammation and can appear without any noticeable impact, often during sleep. The patient then presents with inability to flex or extend metacarpophalageal or interphalangeal joints. Multiple ruptures resulting in impaired function of several fingers can also occur and markedly limit the hand's grip strength. A tear may arise from either mechanical injury to the tendon along its course over bone or connective tissues, or by biochemical action of lysosomal enzymes, released during the inflammation process, on the connective tissue of the tendon. Ischaemic damage to a part of the tendon due to constriction of vessels supplying the peritenonium is found in hypertrophic peri-tenosynovitis. Spontaneous ruptures can be prevented, in the first place, by early synovectomy and then by a number of prophylactic procedures on soft tissues and carpal bones, which can stop or at least slow down the development of severe axial deformities of the wrist and hand. Simple end-to-end suture of the stumps is usually not possible; tendon repair surgery using free grafts or, more often, intact tendon transfer is necessary. In the flexor part, transfer of the superficial flexor tendon to a stump of the deep flexor tendon is frequently performed; a free graft can also be used at a two-stage tendon reconstruction. The repair of flexor tendons is technically more demanding and the results are less satisfactory compared to repair surgery on the extensor tendon. Key words: rheumatoid arthritis, metacarpophalageal joint, interphalangeal joint, tendon rupture. PMID- 28026733 TI - Long-Term Function following Periprosthetic Fractures. AB - PURPOSE OF THE STUDY Clinical results of long-term follow-up after traumatic periprosthetic femur fractures and different therapies (ORIF vs. revision arthroplasty) MATERIAL AND METHODS The Visual Analog Scale (VAS), Harris-Hip Score (HHS), Oxford-Hip-Score (OHS), Oxford-Knee-Score (OKS), Knee-Society-Score (KSS), SF-36 Questionnaire and Funktionsfragebogen Hannover (FFH) were used to evaluate outcome and functionality. Radiological examinations were performed and the Vancouver (THA) and Lewis and Rorabeck (TKA) classifications used. RESULTS 70 patients suffered a periprosthetic hip fracture (29* revision prosthesis, 41x ORIF), 23 patients underwent an ORIF due to periprosthetic fracture of a TKA (total mean age 75.2 years). 47 patients (follow-up rate 51%) were examined 40 months after surgery (mean age 72 years) (THA: 16* revision, 23* ORIF, TKA: 8* ORIF). The VAS revealed significant less pain in the group that had undergone revision hip arthroplasty than in the ORIF group: 3.9+/-1 vs. 5.1+/-1.7 (p<0.05), respectively. 5/16 patients with revision arthroplasty had excellent or good results in the HSS compared to 3/23 patients after ORIF. The OHS yielded excellent or good results in 12/16 patients after revision arthroplasty vs. 10/23 after ORIF. The VAS after ORIF in patients who suffered periprosthetic knee fractures was 4.9+/-2.1. 3/8 patients achieved excellent or good results according to the OKS. CONCLUSION Every functional score (HSS, OHS, FFH, SF-36) of those patients who had undergone revision arthroplasty was slightly higher and their VAS significantly lower than the scores of the patients after ORIF. Key words: periprosthetic fractures, trauma, open reduction and internal fixation, revision arthroplasty. PMID- 28026734 TI - [Callus Distraction in the Treatment of Post-Traumatic Defects of the Femur and Tibia]. AB - PURPOSE OF THE STUDY Evaluation of the results in patients treated for post traumatic defects by the method of callus distraction of the femur and tibia using a monolateral external fixator. MATERIAL AND METHODS The group comprised 42 patients, 38 men and 4 woman, who underwent callus distraction using a monolateral external fixator in the Trauma Hospital Brno in the period from 2003 to 2010. The average age of the patients on the day gradual callus distraction was commenced was 32 (18-64) years. Post-traumatic bone defects were treated in 31 patients and deformities resulting from resection of post-traumatic infection loci in 11 patients. The tibia was involved in 34 and the femur in eight patients. The average follow-up in the out-patient department was 24.3 months (range, 7 to 118 months) after the fixator had been removed. The monolateral external fixator LRS Orthofix (Italy) was used in all patients. RESULTS The average length of defects treated by callus distraction was 5.5 cm (3-16 cm). The average interval between osteotomy and distraction commencement was 6.1 days (4-8 days). The average duration of distraction was 74 days (33-162 days); the average time of fixator application was 168 days (138-416 days). The average healing index was 42 days per cm of bone (26-88 days per cm). The treatment of soft tissue loss during callus distraction was necessary in six patients (14.3%). Of these, two (4.8%) had local fasciocutaneous flap skin coverage, and four (9.5%) free issue transfer. A total of 38 complications were treated, i.e., 0.9 complication per each callus distraction of the femur or tibia. Of them, pin tract infection was most frequent and was recorded in 21 patients (50%). It was usually managed by regimen arrangement and oral antibiotic therapy. The screw had to be removed due to septic loosening in five patients (11.9%). Breakage of a fixator pin occurred in three patients (7.1%). No fracture after fixator removal was recorded. Callus angulations were managed by correction of fixator during distraction in two patients (4,8%). In one patient (2.4%), premature healing of fibular osteotomy was treated by a new resection osteotomy. One patient (2.4%), following callus distraction, underwent Achilles tenotomy. The docking site after segmental bone transport did not heal in two patients (4.8%) who subsequently underwent revision surgery involving spongioplasty; bone union was achieved. Callus distraction in all patients was completed with the use of external fixators initially applied. All patients achieved full weight-bearing on the treated extremity. DISCUSSION In this study we evaluated the results of callus distraction carried out by means of a monolateral external fixator. This type of fixation seems very useful because the telescopic system allows for adjustment without necessity to change its assembly. Dynamic adjustment is important at the stage of callus maturation. A monolateral fixator is better tolerated by patients than is a circular fixator, though both systems give the same results. The process of callus distraction is associated with many different complications. Neither the height of femoral or tibial osteotomy, nor the method of its performance had any significant effect on callus formation. Spin-tract infection is the most common complication. Its frequency can be reduced by using 6-mm pins coated with hydroxyapatite. Delayed healing is rare in simple callus distraction but occurs in the cases of segmental bone transport or repeated osteotomy. CONCLUSIONS The method of callus distraction is effective in the management of large bone defects. The treatment procedure depends on the extent of bone loss, size and type of soft tissue damage and presence or absence of infection. We prefer the use of monolateral external fixators for their ability of form adjustment and of 6-mm pins coated with hydroxyapatite. Key words: callus distraction, post-traumatic bone defect, external fixator. PMID- 28026735 TI - [Quantitative Analysis of Power Doppler Images in Lateral Humeral Enthesopathy]. AB - PURPOSE OF THE STUDY The evaluation of efficiency of power Doppler sonography in the diagnosis of lateral humeral enthesopathy, role of correct assessment of Doppler sonographic images with the method of quantitative analysis, assessment of statistical differences between a group of patients with lateral humeral enthesopathy and a control group of healthy subjects and assessment of the diagnostic power of this test. In addition, consideration of the relevance of each area of the lateral compartment for assessment and diagnosis making in lateral humeral enthesopathy. MATERIAL AND METHODS A total of 41 subjects, aged 18 to 60 years, entered the study. Thirteen patients were diagnosed with lateral humeral enthesopathy on the basis of clinical tests and a positive reaction of the lateral humeral epicondylus to administration of local anaesthetic. The control group consisted of 28 subjects without clinical signs of lateral humeral enthesopathy and subjective complaints. Power Doppler activity was evaluated in the whole region studied and in sub-regions involving the enthesis of the common extensor tendon and the periosteum of the lateral epicondyle with the area distal to it. The evaluation was based on calculating the overall surface with power Doppler activity using the method of quantitative image analysis. Each patient was measured on three occasions and the median of values obtained was used in calculation. To assess the diagnostic power of this test, all values obtained from the whole power Doppler region measured were used. The optimal dividing criterion at which the method had a maximum of sensitivity and specificity was determined. RESULTS The most evident, statistically significant difference between the patient and the control group was recorded in the whole "Range of Interest" (ROI) region (p=1.34x10-6). A significant difference was also found in sub-regions corresponding chiefly to the tendon of the extensor carpi radialis brevis muscle and to the periosteum of the lateral epicondyle (p=0.0043). On the other hand, no significant difference was recorded in the sub-region of the proximal common extensor tendon (p=0.066). A Receiver Operating Characteristic (ROC) was performed to evaluate the sensitivity and specificity for a colour representation of each power Doppler image (a cut-off level). Calculation of the diagnostic power of the test gave a value of 0.915 (p=0.05) below the ROC curve. The optimal marginal value, at which both sensitivity and specificity were highest, was determined to be 455 pixels (sensitivity, 80.5%; specificity, 93.8%). DISCUSSION Power Doppler sonography has already been investigated in view of its potential for the diagnosis of lateral humeral enthesopathy. The results, however, have so far been assessed chiefly categorially, based on the examining physician's opinion. The problematic step in the whole procedure is the technique of power Doppler examination. It is necessary to maintain a constant setting and an examination technique eliminating artefacts. When these conditions are met, the method has both high sensitivity and specificity. In addition, because of being non-invasive, the method is convenient for routine use. CONCLUSIONS Power Doppler sonography is a method convenient to confirm or exclude the diagnosis of lateral humeral enthesopathy. Our results showed its statistical significance and diagnostic power (sensitivity and specificity). In the future, the quantitative image analysis could become a valuable adjunct method of evaluation not only for power Doppler images. Key words: Doppler sonography, quantitative image analysis, lateral humeral enthesopathy. PMID- 28026736 TI - [Peripheral Factures of the Talus. Mid-Term Results]. AB - PURPOSE OF THE STUDY Peripheral fractures of the talus (lateral talar process and posterior talar process) are rare injuries, easy to miss on examination due to their location and clinical manifestation. They account for 0.3% to 1.0% of all fractures of the talus. An incorrect or late treatment of talar process fractures can result in permanent pain, impingement syndrome, healing in malposition, pseudoarthrosis development and also, due to joint instability, in a potential development of severe subtalar arthritis. The aim of this retrospective study was to evaluate the results of surgical management of these fractures in our department. MATERIAL AND METHODS The study included 14 adult patients with fractures of the peripheral talar processes who met the criteria of the retrospective study and were treated in our department between 2008 and 2014. All patients underwent clinical examination with evaluation based on the AOFAS Ankle Hindfoot score, VAS score and radiographic evidence of arthritis. Follow-up ranged from 24 to 95 months. The average age of the patients at the time of surgery was 34 years (range, 21-59 years); there was one woman and 13 men. All underwent pre-operative CT scanning. The surgical procedure included open reduction and internal fixation (ORIF) which, in indicated cases, was preceded by partial or total removal of the processes. RESULTS Of the 14 patients, seven were treated for fractures of the lateral talar process (LTP group) and seven for the posterior talar process (PTP group). All fractures healed completely. The median AOFAS score was 87 (72-100) points in the LTP group, and 84 (58-100) points in the PTP group. Excellent and good results on the AOFAS Ankle-Hindfoot scale were achieved in 10 (72%), satisfactory in two (14%) and poor in two (14%) patients. Of the LTP group, six patients (86%) showed the VAS score <= 3, and one (14%) had the VAS score = 4. In the PTP group, the VAS score <= 3 was reported by three (43%) and values of up to 5 by four (57%) patients. Arthritis in the talocrural and subtalar joints was evaluated as zero or grade 1 in 11 (79%) of all patients; of these 11 patients only two (14%) had a VAS score higher than 3. Only one patient had marginal wound necrosis; no deep wound infection was recorded. DISCUSSION The majority of fractures in our group were due to falls from a height or traffic accidents, which is in accordance with the literature data. In about 70% of these injuries, more parts of the leg are affected and, therefore, a thorough medical inspection is necessary. These mechanisms of injury most frequently produce type II LTP fracture (Hawkins classification). Four patients with a LTP fracture, who had the process partially removed, achieved good results on the AOFAS scale and the VAS score less than or equal to 3. As also published in the literature, the removal of small fragments has no crucial effect on ankle stability. CONSLUSIONS An adequate surgical treatment of displaced peripheral fractures of the talar processes provides good functional outcomes. In fractures with associated leg injuries or high-energy traumata, the prognosis is poorer. Fractures of talar processes often show symptoms and signs similar to those of more serious forms of dislocation of the talus and therefore a careful assessment of standard X-ray images taken for a "swollen ankle" is necessary. If the findings are not clear, CT examination is indicated. Key words: fracture, talus, processus lateralis tali, processus posterior tali. PMID- 28026737 TI - [Bilateral Total Knee Arthroplasty. Short-Term Results]. AB - PURPOSE OF THE STUDY Evaluation of short-term functional results in patients undergoing one-stage surgery involving sequential bilateral total knee arthroplasty (TKA) and comparison with the results of patients after unilateral TKA. MATERIAL AND METHODS The group with bilateral TKA consisted of 171 patients with 342 total knee replacements treated between 2009 and 2013. The control group included 50 patients with 50 TKAs operated on in the years 2010 to 2012. The indications to bilateral knee replacement included bilateral gonarthrosis, grade III or more in patients who were in good health and had a stable knee joint with axis deviation up to 20 degrees. A cemented TKA was used and the posterior cruciate ligament was preserved. Assessment of functional results was based on the Womac score, Knee Society Score (KSS 1, 2) range of motion and presence of specific complications in both groups. The follow-up lasted three years. RESULTS The average results in the bilateral vs the control group were as follows: the Womac score, 39.4/42.2 pre-operatively, 87.2/71.0 at 3 years; KSS 1, 48.5 / 44.8 pre-operatively, 87.4 / 79.9 at 3 years; KSS 2, 44.1 / 50.6 pre-operatively, 86.1 / 72.8 at 3 years; motion-flexion, 105.2 degrees / 105.7 degrees preoperatively, 114.0 degrees / 100.2 degrees at 3 years. In the bilateral group, infection was recorded in one patient. DISCUSSION Bilateral total knee replacement is a controversial issue. A higher risk of non-specific complications has been reported. Functional outcomes are good. The key problem is to set the correct indication to this procedure after an individual assessment of the patient's general health condition and the state of his/her knee joints. CONCLUSIONS The patients undergoing bilateral TKA at one-stage surgery showed functional results comparable (range of motion was even better) with the results of the unilateral TKA group. The number of specific complications was low. Every patient should be carefully assessed. Key words: total knee arthroplasty, bilateral implantation, functional results. PMID- 28026738 TI - [Infectious Inflammation of Pubic Symphysis (Symphysitis Pubis Purulenta): Five Case Reports and Literature View]. AB - Purulent inflammation of the pubic symphysis is a rare condition involving the symphysis and parasymphyseal parts of the pubic bones. It is usually found in immuno-compromised patients and its most frequent cause is Staphylococcus aureus. Conservative treatment is based on long-term administration of antibiotics and has been efficient, as reported, in about 50% of the patients. The authors treated five patients with a late diagnosis of purulent infection of the pubic symphysis in whom the antibiotic therapy had to be completed by surgical intervention. Three patients undergoing surgery with removal of the infected necrotic tissue healed fast and well. One patient required repeated surgery because of recurrent purulency; eventually, the infection cleared up. One patient was treated only conservatively because she refused surgical treatment. Consequently, pubic diastasis developed and she suffered from persistent pelvic pain. One year after treatment her condition became complicated by pelvic fracture following a fall. The patient refused surgery again. However, the development of non-union and progression of complaints made her agree to a surgical treatment; fixation of the non-union had a satisfactory outcome. In the literature, infection in the symphysis region is referred to by several different names. One - in the authors' opinion incorrect use - is "arthritis" (septic arthritis of the pubic symphysis; pubic symphysis septic arthritis; infectious osteoarthritis of the pubis). Another term is "osteomyelitis" (acute pubic osteomyelitis; pubic osteomyelitis; osteomyelitis of the pubis; osteomyelitis pubis; osteomyelitis of the pubic symphysis; osteomyelitis of the symphysis pubis). None of the names shows clearly whether it is primary an infection of the symphysis or of the parasymphyseal bone. A combination of the term "osteitis" with "infectious" (infectious osteitis pubis) is an attempt to distinguish purulent symphysitis pubis from osteitis pubis. The authors completed both the Czech and English title of this paper with the Latin designation symphysis pubis purulenta. A possibility of using a new name, such as "pubosymphysitis", in analogy to "spondylodiscitis" can also be discussed. However, the use of simple terms "infection of symphysis" or "infection of pubic symphysis" seems to be most practicable. Based on the experience with the treatment of five patients with infection of the pubic symphysis, the authors suggest that the late phase with abscess formation or purulent discharge should be managed by surgery. This treatment has good clinical outcomes although it may be complicated by slow healing of soft tissues around the symphysis and instability of the anterior pelvic segment with its sequelae. Key words: infection of the symphysis, infection of the pubic symphysis, septic arthritis of the pubic symphysis, pubic osteomyelitis. PMID- 28026739 TI - [Avulsion of the Proximal Hamstring Insertion. Case Reports]. AB - Proximal hamstring avulsion is an uncommon muscle injury with a lack of consensus on indications and the timing and technique of surgery. Poor clinical symptoms and difficulties in the diagnostic process can lead to a false diagnosis. The authors present three cases of proximal hamstring avulsion, two complete and one partial ruptures of the biceps femoris muscle. MRI and ultrasound scans were used for optimal treatment alignment. Acute surgery reconstruction (< 4 weeks) was done in two patients. Re-attachment of the full thickness ruptures was performed to the original place and secured by suture anchors, the partial rupture was fixed by a simple suture. Two patients were free of any symptoms at 6 months after surgery, the last one had pain in the subgluteal area and a mild deficit in hamstring strength. Two interesting systematic reviews published on the treatment of proximal hamstring avulsion are discussed in the final part of the paper. Key words: hamstring, rupture, avulsion. PMID- 28026740 TI - Comparative Hemodynamic Effects of Contemporary Percutaneous Mechanical Circulatory Support Devices in a Porcine Model of Acute Myocardial Infarction. AB - OBJECTIVES: The aim of this study was to directly compare the hemodynamic effects of 2 contemporary percutaneous mechanical circulatory support devices in a porcine model of acute myocardial infarction. BACKGROUND: Percutaneous support devices offer the ability to unload the ischemic left ventricle, but the comparative hemodynamic effects of contemporary platforms are unclear. METHODS: Yorkshire swine (mean weight 76 +/- 2 kg; n = 7) were instrumented with a left ventricular (LV) pressure-volume (PV) catheter and subjected to a 2-h coronary occlusion. Hemodynamic parameters and PV-derived indexes of LV performance were assessed 30 min after reperfusion and during LV support with Impella CP (ICP) and TandemHeart devices (in randomized order) at comparable flow rates. RESULTS: Myocardial infarction produced a rightward shift of the PV loop and increased LV end-diastolic pressure (from 9 +/- 2 mm Hg to 15 +/- 2 mm Hg; p = 0.04). After reperfusion, both devices maintained aortic pressure, shifted the PV loop to the left, and decreased LV end-diastolic pressure (ICP vs. TandemHeart; 11 +/- 1 mm Hg vs. 7 +/- 4 mm Hg; p = 0.04). However, only TandemHeart elicited significant reductions in native LV stroke volume (from 75 +/- 7 ml to 39 +/- 7 ml; p < 0.01), dP/dtmax (from 988 +/- 77 mm Hg/s to 626 +/- 42 mm Hg/s; p < 0.01), stroke work (from 0.70 +/- 0.03 J to 0.26 +/- 0.05 J; p < 0.01), PV area (from 0.95 +/- 0.11 J to 0.47 +/- 0.10 J; p < 0.01), and pre-load-recruitable stroke work slope (from 41.7 +/- 2.8 J/ml to 30.6 +/- 3.9 J/ml; p = 0.05). CONCLUSIONS: At comparable device flow rates, TandemHeart decreased LV pre-load, native LV stroke volume, and myocardial contractility to a greater degree than ICP. Reductions in load-independent indexes of LV performance indicate favorable effects on myocardial oxygen balance and support further study of TandemHeart in clinical scenarios requiring mechanical support in the setting of acute myocardial ischemia. PMID- 28026741 TI - Comparing Hemodynamics of Contemporary Mechanical Circulatory Support: Moving From In Silico to In Vivo Results. PMID- 28026742 TI - Transcatheter Aortic Valve Replacement for the Treatment of Pure Native Aortic Valve Regurgitation: A Systematic Review. AB - OBJECTIVES: This study sought to summarize available evidence on transcatheter aortic valve replacement (TAVR) for the treatment of native pure aortic regurgitation (AR). BACKGROUND: Surgical aortic valve replacement (SAVR) is the gold standard for the treatment of AR. However, case series of high-risk patients undergoing TAVR for native pure AR were reported. METHODS: We systematically searched Medline, Embase, and Scopus for reports of at least 5 patients with native pure AR undergoing TAVR. Patients' and procedural characteristics were summarized. The primary outcome of interest was all-cause mortality. Pooled estimates were calculated using a random-effects meta-analysis. The study protocol was registered in PROSPERO (CRD42016038422). RESULTS: Thirteen reports including 237 patients were included in the analysis. Self-expandable prostheses were used in 79% of patients, whereas 21% of the patients were treated with a balloon-expandable valve. Device success ranged between 74% and 100%. Seventeen patients (7%) required the implantation of a second valve. Conversion to SAVR was reported in 6 (2.5%) cases. The rate of all-cause mortality at 30 days amounted to 7% (95% confidence interval [CI]: 3% to 13%; I2 = 37%). Cerebrovascular events were rare (0%, 95% CI: 0% to 1%; I2 = 0); major bleeding and vascular complications occurred in 2% (95% CI: 0% to 7%; I2 = 41%), and 3% (95% CI: 1% to 7%; I2 = 0%), respectively. Permanent pacemaker implantation was required in 11% of patients (95% CI: 5% to 19%; I2 = 50%). The rate of moderate or severe post procedural AR amounted to 9% (95% CI: 0% to 28%; I2 = 90%). CONCLUSIONS: Among selected patients with native pure AR deemed at high risk for SAVR, TAVR is technically feasible and associated with an acceptable risk of early mortality. PMID- 28026744 TI - Interface Prostheses With Classifier-Feedback-Based User Training. AB - It is evident that user training significantly affects performance of pattern recognition-based myoelectric prosthetic device control. Despite plausible classification accuracy on offline datasets, online accuracy usually suffers from the changes in physiological conditions and electrode displacement. The user ability in generating consistent electromyographic (EMG) patterns can be enhanced via proper user training strategies in order to improve online performance. This study proposes a clustering-feedback strategy that provides real-time feedback to users by means of a visualized online EMG signal input as well as the centroids of the training samples, whose dimensionality is reduced to minimal number by dimension reduction. Clustering feedback provides a criterion that guides users to adjust motion gestures and muscle contraction forces intentionally. The experiment results have demonstrated that hand motion recognition accuracy increases steadily along the progress of the clustering-feedback-based user training, while conventional classifier-feedback methods, i.e., label feedback, hardly achieve any improvement. The result concludes that the use of proper classifier feedback can accelerate the process of user training, and implies prosperous future for the amputees with limited or no experience in pattern recognition-based prosthetic device manipulation.It is evident that user training significantly affects performance of pattern-recognition-based myoelectric prosthetic device control. Despite plausible classification accuracy on offline datasets, online accuracy usually suffers from the changes in physiological conditions and electrode displacement. The user ability in generating consistent electromyographic (EMG) patterns can be enhanced via proper user training strategies in order to improve online performance. This study proposes a clustering-feedback strategy that provides real-time feedback to users by means of a visualized online EMG signal input as well as the centroids of the training samples, whose dimensionality is reduced to minimal number by dimension reduction. Clustering feedback provides a criterion that guides users to adjust motion gestures and muscle contraction forces intentionally. The experiment results have demonstrated that hand motion recognition accuracy increases steadily along the progress of the clustering-feedback-based user training, while conventional classifier-feedback methods, i.e., label feedback, hardly achieve any improvement. The result concludes that the use of proper classifier feedback can accelerate the process of user training, and implies prosperous future for the amputees with limited or no experience in pattern-recognition-based prosthetic device manipulation. PMID- 28026745 TI - Wearable Vector Electrical Bioimpedance System to Assess Knee Joint Health. AB - OBJECTIVE: We designed and validated a portable electrical bioimpedance (EBI) system to quantify knee joint health. METHODS: Five separate experiments were performed to demonstrate the: 1) ability of the EBI system to assess knee injury and recovery; 2) interday variability of knee EBI measurements; 3) sensitivity of the system to small changes in interstitial fluid volume; 4) reducing the error of EBI measurements using acceleration signals; and 5) use of the system with dry electrodes integrated to a wearable knee wrap. RESULTS: 1) The absolute difference in resistance ( R) and reactance (X) from the left to the right knee was able to distinguish injured and healthy knees (p < 0.05); the absolute difference in R decreased significantly (p < 0.05) in injured subjects following rehabilitation. 2) The average interday variability (standard deviation) of the absolute difference in knee R was 2.5 Omega and for X was 1.2 Omega. 3) Local heating/cooling resulted in a significant decrease/increase in knee R (p < 0.01). 4) The proposed subject position detection algorithm achieved 97.4% leave-one subject out cross-validated accuracy and 98.2% precision in detecting when the subject is in the correct position to take measurements. 5) Linear regression between the knee R and X measured using the wet electrodes and the designed wearable knee wrap were highly correlated ( R2 = 0.8 and 0.9, respectively). CONCLUSION: This study demonstrates the use of wearable EBI measurements in monitoring knee joint health. SIGNIFICANCE: The proposed wearable system has the potential for assessing knee joint health outside the clinic/lab and help guide rehabilitation. PMID- 28026746 TI - Robust Estimation of Sparse Narrowband Spectra from Neuronal Spiking Data. AB - OBJECTIVE: Characterizing the spectral properties of neuronal responses is an important problem in computational neuroscience, as it provides insight into the spectral organization of the underlying functional neural processes. Although spectral analysis techniques are widely used in the analysis of noninvasive neural recordings such as EEG, their application to spiking data is limited due to the binary and nonlinear nature of neuronal spiking. In this paper, we address the problem of estimating the power spectral density of the neural covariate driving the spiking statistics of a neuronal population from binary observations. METHODS: We consider a neuronal ensemble spiking according to Bernoulli statistics, for which the conditional intensity function is given by the logistic map of a harmonic second-order stationary process with sparse narrowband spectra. By employing sparsity-promoting priors, we compute the maximum a posteriori estimate of the power spectral density of the process from the binary spiking observations. Furthermore, we construct confidence intervals for these estimates by an efficient posterior sampling procedure. RESULTS: We provide simulation studies which reveal that our method outperforms the existing methods for extracting the frequency content of spiking data. Application of our method to clinically recorded spiking data from a patient under general anesthesia reveals a striking resemblance between our estimated power spectral density and that of the local field potential signal. This result corroborates existing findings regarding the salient role of the local field potential as a major neural covariate of rhythmic cortical spiking activity under anesthesia. CONCLUSION: Our technique allows us to analyze the harmonic structure of spiking activity in a robust fashion, independently of the local field potentials, and without any prior assumption of the spectral spread and content of the underlying neural processes. SIGNIFICANCE: Other than its usage in the spectral analysis of neuronal spiking data, our technique can be applied to a wide variety of binary data, such as heart beat data, in order to obtain a robust spectral representation. PMID- 28026747 TI - Joint Dictionary Learning-Based Non-Negative Matrix Factorization for Voice Conversion to Improve Speech Intelligibility After Oral Surgery. AB - Objective: This paper focuses on machine learning based voice conversion (VC) techniques for improving the speech intelligibility of surgical patients who have had parts of their articulators removed. Because of the removal of parts of the articulator, a patient's speech may be distorted and difficult to understand. To overcome this problem, VC methods can be applied to convert the distorted speech such that it is clear and more intelligible. To design an effective VC method, two key points must be considered: 1) the amount of training data may be limited (because speaking for a long time is usually difficult for postoperative patients); 2) rapid conversion is desirable (for better communication). Methods: We propose a novel joint dictionary learning based non-negative matrix factorization (JD-NMF) algorithm. Compared to conventional VC techniques, JD-NMF can perform VC efficiently and effectively with only a small amount of training data. Results: The experimental results demonstrate that the proposed JD-NMF method not only achieves notably higher short-time objective intelligibility (STOI) scores (a standardized objective intelligibility evaluation metric) than those obtained using the original unconverted speech but is also significantly more efficient and effective than a conventional exemplar-based NMF VC method. Conclusion: The proposed JD-NMF method may outperform the state-of-the-art exemplar-based NMF VC method in terms of STOI scores under the desired scenario. Significance: We confirmed the advantages of the proposed joint training criterion for the NMF-based VC. Moreover, we verified that the proposed JD-NMF can effectively improve the speech intelligibility scores of oral surgery patients.Objective: This paper focuses on machine learning based voice conversion (VC) techniques for improving the speech intelligibility of surgical patients who have had parts of their articulators removed. Because of the removal of parts of the articulator, a patient's speech may be distorted and difficult to understand. To overcome this problem, VC methods can be applied to convert the distorted speech such that it is clear and more intelligible. To design an effective VC method, two key points must be considered: 1) the amount of training data may be limited (because speaking for a long time is usually difficult for postoperative patients); 2) rapid conversion is desirable (for better communication). Methods: We propose a novel joint dictionary learning based non-negative matrix factorization (JD-NMF) algorithm. Compared to conventional VC techniques, JD-NMF can perform VC efficiently and effectively with only a small amount of training data. Results: The experimental results demonstrate that the proposed JD-NMF method not only achieves notably higher short-time objective intelligibility (STOI) scores (a standardized objective intelligibility evaluation metric) than those obtained using the original unconverted speech but is also significantly more efficient and effective than a conventional exemplar-based NMF VC method. Conclusion: The proposed JD-NMF method may outperform the state-of-the-art exemplar-based NMF VC method in terms of STOI scores under the desired scenario. Significance: We confirmed the advantages of the proposed joint training criterion for the NMF-based VC. Moreover, we verified that the proposed JD-NMF can effectively improve the speech intelligibility scores of oral surgery patients. PMID- 28026749 TI - Jointly Learning Heterogeneous Features for RGB-D Activity Recognition. AB - In this paper, we focus on heterogeneous features learning for RGB-D activity recognition. We find that features from different channels (RGB, depth) could share some similar hidden structures, and then propose a joint learning model to simultaneously explore the shared and feature-specific components as an instance of heterogeneous multi-task learning. The proposed model formed in a unified framework is capable of: 1) jointly mining a set of subspaces with the same dimensionality to exploit latent shared features across different feature channels, 2) meanwhile, quantifying the shared and feature-specific components of features in the subspaces, and 3) transferring feature-specific intermediate transforms (i-transforms) for learning fusion of heterogeneous features across datasets. To efficiently train the joint model, a three-step iterative optimization algorithm is proposed, followed by a simple inference model. Extensive experimental results on four activity datasets have demonstrated the efficacy of the proposed method. A new RGB-D activity dataset focusing on human object interaction is further contributed, which presents more challenges for RGB D activity benchmarking. PMID- 28026750 TI - Aligning Where to See and What to Tell: Image Captioning with Region-Based Attention and Scene-Specific Contexts. AB - Recent progress on automatic generation of image captions has shown that it is possible to describe the most salient information conveyed by images with accurate and meaningful sentences. In this paper, we propose an image captioning system that exploits the parallel structures between images and sentences. In our model, the process of generating the next word, given the previously generated ones, is aligned with the visual perception experience where the attention shifts among the visual regions-such transitions impose a thread of ordering in visual perception. This alignment characterizes the flow of latent meaning, which encodes what is semantically shared by both the visual scene and the text description. Our system also makes another novel modeling contribution by introducing scene-specific contexts that capture higher-level semantic information encoded in an image. The contexts adapt language models for word generation to specific scene types. We benchmark our system and contrast to published results on several popular datasets, using both automatic evaluation metrics and human evaluation. We show that either region-based attention or scene specific contexts improves systems without those components. Furthermore, combining these two modeling ingredients attains the state-of-the-art performance. PMID- 28026751 TI - Online Object Tracking, Learning and Parsing with And-Or Graphs. AB - This paper presents a method, called AOGTracker, for simultaneously tracking, learning and parsing (TLP) of unknown objects in video sequences with a hierarchical and compositional And-Or graph (AOG) representation. The TLP method is formulated in the Bayesian framework with a spatial and a temporal dynamic programming (DP) algorithms inferring object bounding boxes on-the-fly. During online learning, the AOG is discriminatively learned using latent SVM [1] to account for appearance (e.g., lighting and partial occlusion) and structural (e.g., different poses and viewpoints) variations of a tracked object, as well as distractors (e.g., similar objects) in background. Three key issues in online inference and learning are addressed: (i) maintaining purity of positive and negative examples collected online, (ii) controling model complexity in latent structure learning, and (iii) identifying critical moments to re-learn the structure of AOG based on its intrackability. The intrackability measures uncertainty of an AOG based on its score maps in a frame. In experiments, our AOGTracker is tested on two popular tracking benchmarks with the same parameter setting: the TB-100/50/CVPR2013 benchmarks , [3] , and the VOT benchmarks [4] VOT 2013, 2014, 2015 and TIR2015 (thermal imagery tracking). In the former, our AOGTracker outperforms state-of-the-art tracking algorithms including two trackers based on deep convolutional network [5] , [6] . In the latter, our AOGTracker outperforms all other trackers in VOT2013 and is comparable to the state-of-the-art methods in VOT2014, 2015 and TIR2015. PMID- 28026752 TI - Directional Enlacement Histograms for the Description of Complex Spatial Configurations between Objects. AB - The analysis of spatial relations between objects in digital images plays a crucial role in various application domains related to pattern recognition and computer vision. Classical models for the evaluation of such relations are usually sufficient for the handling of simple objects, but can lead to ambiguous results in more complex situations. In this article, we investigate the modeling of spatial configurations where the objects can be imbricated in each other. We formalize this notion with the term enlacement, from which we also derive the term interlacement, denoting a mutual enlacement of two objects. Our main contribution is the proposition of new relative position descriptors designed to capture the enlacement and interlacement between two-dimensional objects. These descriptors take the form of circular histograms allowing to characterize spatial configurations with directional granularity, and they highlight useful invariance properties for typical image understanding applications. We also show how these descriptors can be used to evaluate different complex spatial relations, such as the surrounding of objects. Experimental results obtained in the different application domains of medical imaging, document image analysis and remote sensing, confirm the genericity of this approach. PMID- 28026748 TI - In Situ Mechanical Characterization of Multilayer Soft Tissue Using Ultrasound Imaging. AB - In this paper, we report the development of a technique to characterize layer specific nonlinear material properties of soft tissue in situ with the potential for in vivo testing. A soft tissue elastography robotic arm system comprising of a robotically manipulated 30 MHz high-resolution ultrasound probe, a custom designed compression head, and load cells has been developed to perform compression ultrasound imaging on the target tissue and measure reaction forces. A multilayer finite element model is iteratively optimized to identify the material coefficients of each layer. Validation has been performed using tissue mimicking agar-based phantoms with a low relative error of ~7% for two-layer phantoms and ~10% error for three layer phantoms when compared to known ground truth values obtained using a commercial material testing system. The technique has then been used to successfully determine the in situ layer-specific mechanical properties of intact porcine stomach. The mean C10 and C20 for a second-order reduced polynomial material model were determined for the muscularis (6.41 +/- 0.60, 4.29 +/- 1.87 kPa), submucosal (5.21 +/- 0.57, 3.68 +/- 3.01 kPa), and mucosal layers (0.06 +/- 0.02, 0.09 +/- 0.24 kPa). Such a system can be utilized to perform in vivo mechanical characterization, which is left as future work. PMID- 28026753 TI - Weakly-Supervised Image Annotation and Segmentation with Objects and Attributes. AB - We propose to model complex visual scenes using a non-parametric Bayesian model learned from weakly labelled images abundant on media sharing sites such as Flickr. Given weak image-level annotations of objects and attributes without locations or associations between them, our model aims to learn the appearance of object and attribute classes as well as their association on each object instance. Once learned, given an image, our model can be deployed to tackle a number of vision problems in a joint and coherent manner, including recognising objects in the scene (automatic object annotation), describing objects using their attributes (attribute prediction and association), and localising and delineating the objects (object detection and semantic segmentation). This is achieved by developing a novel Weakly Supervised Markov Random Field Stacked Indian Buffet Process (WS-MRF-SIBP) that models objects and attributes as latent factors and explicitly captures their correlations within and across superpixels. Extensive experiments on benchmark datasets demonstrate that our weakly supervised model significantly outperforms weakly supervised alternatives and is often comparable with existing strongly supervised models on a variety of tasks including semantic segmentation, automatic image annotation and retrieval based on object-attribute associations. PMID- 28026754 TI - Automated Melanoma Recognition in Dermoscopy Images via Very Deep Residual Networks. AB - Automated melanoma recognition in dermoscopy images is a very challenging task due to the low contrast of skin lesions, the huge intraclass variation of melanomas, the high degree of visual similarity between melanoma and non-melanoma lesions, and the existence of many artifacts in the image. In order to meet these challenges, we propose a novel method for melanoma recognition by leveraging very deep convolutional neural networks (CNNs). Compared with existing methods employing either low-level hand-crafted features or CNNs with shallower architectures, our substantially deeper networks (more than 50 layers) can acquire richer and more discriminative features for more accurate recognition. To take full advantage of very deep networks, we propose a set of schemes to ensure effective training and learning under limited training data. First, we apply the residual learning to cope with the degradation and overfitting problems when a network goes deeper. This technique can ensure that our networks benefit from the performance gains achieved by increasing network depth. Then, we construct a fully convolutional residual network (FCRN) for accurate skin lesion segmentation, and further enhance its capability by incorporating a multi-scale contextual information integration scheme. Finally, we seamlessly integrate the proposed FCRN (for segmentation) and other very deep residual networks (for classification) to form a two-stage framework. This framework enables the classification network to extract more representative and specific features based on segmented results instead of the whole dermoscopy images, further alleviating the insufficiency of training data. The proposed framework is extensively evaluated on ISBI 2016 Skin Lesion Analysis Towards Melanoma Detection Challenge dataset. Experimental results demonstrate the significant performance gains of the proposed framework, ranking the first in classification and the second in segmentation among 25 teams and 28 teams, respectively. This study corroborates that very deep CNNs with effective training mechanisms can be employed to solve complicated medical image analysis tasks, even with limited training data. PMID- 28026755 TI - Passive Acoustic Mapping with the Angular Spectrum Method. AB - In the present proof of principle study, we evaluated the homogenous angular spectrum method for passive acoustic mapping (AS-PAM) of microbubble oscillations using simulated and experimental data. In the simulated data we assessed the ability of AS-PAM to form 3D maps of a single and multiple point sources. Then, in the two dimensional limit, we compared the 2D maps from AS-PAM with alternative frequency and time domain passive acoustic mapping (FD- and TD-PAM) approaches. Finally, we assessed the ability of AS-PAM to visualize microbubble activity in vivo with data obtained during 8 different experiments of FUS-induced blood-brain barrier disruption in 3 nonhuman primates, using a clinical MR-guided FUS system. Our in silico results demonstrate AS-PAM can be used to perform 3D passive acoustic mapping. 2D AS-PAM as compared to FD- PAM and TD-PAM is 10 and 200 times faster respectively and has similar sensitivity, resolution, and localization accuracy, even when the noise was 10-fold higher than the signal. In vivo, the AS-PAM reconstructions of emissions at frequency bands pertinent to the different types of microbubble oscillations were also found to be more sensitive than TD-PAM. AS-PAM of harmonic-only components predicted safe blood-brain barrier disruption, whereas AS-PAM of broadband emissions correctly identified MR evident tissue damage. The disparity (3.2 mm) in the location of the cavitation activity between the three methods was within their resolution limits. These data clearly demonstrate that AS-PAM is a sensitive and fast approach for PAM, thus providing a clinically relevant method to guide therapeutic ultrasound procedures. PMID- 28026756 TI - Longitudinal Analysis of Pre-Term Neonatal Cerebral Ventricles From 3D Ultrasound Images Using Spatial-Temporal Deformable Registration. AB - Preterm neonates with a very low birth weight of less than 1,500 grams are at increased risk for developing intraventricular hemorrhage (IVH), which is a major cause of brain injury in preterm neonates. Quantitative measurements of ventricular dilatation or shrinkage play an important role in monitoring patients and evaluating treatment options. 3D ultrasound (US) has been developed to monitor ventricle volume as a biomarker for ventricular changes. However, ventricle volume as a global indicator does not allow for precise analysis of local ventricular changes, which could be linked to specific neurological problems often seen in the patient population later in life. In this work, a 3D+t spatial-temporal deformable registration approachis proposed, which is applied to the analysis of the detailed local changes of preterm IVH neonatal ventricles from 3D US images. In particular, a novel sequential convex/dual optimization algorithm is introduced to extract the optimal 3D+t spatial-temporal deformable field, which simultaneously optimizes the sequence of 3D deformation fieldswhile enjoying both efficiencyand simplicity in numerics. The developed registration technique was evaluated by comparing two manually extracted ventricle surfaces from the baseline and the registered follow-up images using the metrics of Dice similarity coefficient (DSC), mean absolute surface distance (MAD), and maximum absolute surface distance (MAXD). The performed experiments using 14 patients with 5 time-point images per patient show that the proposed 3D+t registration approach accurately recovered the longitudinal deformation of ventricle surfaces from 3D US images. The proposed approach may be potentially used to analyse the change pattern of cerebral ventricles of IVH patients, their response to different treatment options, and to elucidate the deficiencies that a patient could have later in life. To the best of our knowledge, this paper reports the first study on the longitudinalanalysis of neonatal ventricular system from 3D US images. PMID- 28026758 TI - A Compressed Sensing Strategy for Synthetic Transmit Aperture Ultrasound Imaging. AB - A novel beamforming technique, named compressed sensing based synthetic transmit aperture (CS-STA) is proposed to speed up the acquisition of ultrasound imaging. This technique consists of three steps. First, the ultrasound transducer transmits randomly apodized plane waves for a number of times and receives the backscattered echoes. Second, the recorded backscattered echoes are used to recover the full channel dataset of synthetic transmit aperture (STA) with a compressed sensing (CS) reconstruction algorithm. Finally, an STA image is beamformed from the recovered full STA dataset. As CS allows recovering a signal from its few linear measurements with high probability, CS-STA is capable of recovering the STA image with fewer firings (i.e., higher frame rate) and retaining the high resolution of STA. In addition, the contrast of the STA image can be improved at the same time owing to the higher energy of plane wave firing in CS-STA. Simulations demonstrate that CS-STA is capable of recovering the STA channel dataset with a smaller number of firings. The performance of CS-STA is evaluated in phantom experiments through comparisons with STA, multi-element STA, conventional focused mode and coherent plane wave imaging. The results demonstrate that, implemented with the same frame rate, CS-STA achieves higher or comparable resolution and contrast. Moreover, comparisons are conducted on the biceps brachii muscle and thyroid of a human subject, and the results demonstrate the feasibility and competitiveness of CS-STA in the in vivo conditions. PMID- 28026757 TI - Use of Sub-Ensembles and Multi-Template Observers to Evaluate Detection Task Performance for Data That are Not Multivariate Normal. AB - The Hotelling Observer (HO) is widely used to evaluate image quality in medical imaging. However, applying it to data that are not multivariate-normally (MVN) distributed is not optimal. In this paper, we apply two multi-template linear observer strategies to handle such data. First, the entire data ensemble is divided into sub-ensembles that are exactly or approximately MVN and homoscedastic. Next, a different linear observer template is estimated for and applied to each sub-ensemble. The first multi-template strategy, adapted from previous work, applies the HO to each sub-ensemble, calculates the area under the receiver operating characteristics curve (AUC) for each sub-ensemble, and averages the AUCs from all the sub-ensembles. The second strategy applies the Linear Discriminant (LD) to estimate test statistics for each sub-ensemble and calculates a single global AUC using the pooled test statistics from all the sub ensembles. We show that this second strategy produces the maximum AUC when only shifting of the HO test statistics is allowed. We compared these strategies to the use of a single HO template for the entire data ensemble by applying them to the non-MVN data obtained from reconstructed images of a realistic simulated population of myocardial perfusion SPECT studies with the goal of optimizing the reconstruction parameters. Of the strategies investigated, the multi-template LD strategy yielded the highest AUC for any given set of reconstruction parameters. The optimal reconstruction parameters obtained by the two multi-template strategies were comparable and produced higher AUCs for each sub-ensemble than the single-template HO strategy. PMID- 28026759 TI - Partial Discreteness: A Novel Prior for Magnetic Resonance Image Reconstruction. AB - An important factor influencing the quality of magnetic resonance (MR) images is the reconstruction method that is employed, and specifically, the type of prior knowledge that is exploited during reconstruction. In this work, we introduce a new type of prior knowledge, partial discreteness (PD), where a small number of regions in the image are assumed to be homogeneous and can be well represented by a constant magnitude. In particular, we mathematically formalize the partial discreteness property based on a Gaussian Mixture Model (GMM) and derive a partial discreteness image representation that characterizes the salient features of partially discrete images: a constant intensity in homogeneous areas and texture in heterogeneous areas. The partial discreteness representation is then used to construct a novel prior dedicated to the reconstruction of partially discrete MR images. The strength of the proposed prior is demonstrated on various simulated and real k-space data-based experiments with partially discrete images. Results demonstrate that the PD algorithm performs competitively with state-of the-art reconstruction methods, being flexible and easy to implement. PMID- 28026761 TI - Detection of Stationary Foreground Objects Using Multiple Nonparametric Background-Foreground Models on a Finite State Machine. AB - There is a huge proliferation of surveillance systems that require strategies for detecting different kinds of stationary foreground objects (e.g., unattended packages or illegally parked vehicles). As these strategies must be able to detect foreground objects remaining static in crowd scenarios, regardless of how long they have not been moving, several algorithms for detecting different kinds of such foreground objects have been developed over the last decades. This paper presents an efficient and high-quality strategy to detect stationary foreground objects, which is able to detect not only completely static objects but also partially static ones. Three parallel nonparametric detectors with different absorption rates are used to detect currently moving foreground objects, short term stationary foreground objects, and long-term stationary foreground objects. The results of the detectors are fed into a novel finite state machine that classifies the pixels among background, moving foreground objects, stationary foreground objects, occluded stationary foreground objects, and uncovered background. Results show that the proposed detection strategy is not only able to achieve high quality in several challenging situations but it also improves upon previous strategies. PMID- 28026760 TI - Guidelines for Finite-Element Modeling of Acoustic Radiation Force-Induced Shear Wave Propagation in Tissue-Mimicking Media. AB - Ultrasound shear wave elastography is emerging as an important imaging modality for evaluating tissue material properties. In its practice, some systematic biases have been associated with ultrasound frequencies, focal depths and configuration, and transducer types (linear versus curvilinear), along with displacement estimation and shear wave speed estimation algorithms. Added to that, soft tissues are not purely elastic, so shear waves will travel at different speeds depending on their spectral content, which can be modulated by the acoustic radiation force (ARF) excitation focusing, duration, and the frequency-dependent stiffness of the tissue. To understand how these different acquisition and material property parameters may affect the measurements of shear wave velocity, the simulations of the propagation of shear waves generated by ARF excitations in viscoelastic media are a very important tool. This paper serves to provide an in-depth description of how these simulations are performed. The general scheme is broken into three components: 1) simulation of the 3-D ARF push beam; 2) applying that force distribution to a finite-element model; and 3) extraction of the motion data for post-processing. All three components will be described in detail and combined to create a simulation platform that is powerful for developing and testing algorithms for academic and industrial researchers involved in making quantitative shear-wave-based measurements of tissue material properties. PMID- 28026762 TI - Learning Multi-Instance Deep Discriminative Patterns for Image Classification. AB - Finding an effective and efficient representation is very important for image classification. The most common approach is to extract a set of local descriptors, and then aggregate them into a high-dimensional, more semantic feature vector, like unsupervised bag-of-features and weakly supervised part based models. The latter one is usually more discriminative than the former due to the use of information from image labels. In this paper, we propose a weakly supervised strategy that using multi-instance learning (MIL) to learn discriminative patterns for image representation. Specially, we extend traditional multi-instance methods to explicitly learn more than one patterns in positive class, and find the "most positive" instance for each pattern. Furthermore, as the positiveness of instance is treated as a continuous variable, we can use stochastic gradient decent to maximize the margin between different patterns meanwhile considering MIL constraints. To make the learned patterns more discriminative, local descriptors extracted by deep convolutional neural networks are chosen instead of hand-crafted descriptors. Some experimental results are reported on several widely used benchmarks (Action 40, Caltech 101, Scene 15, MIT indoor, SUN 397), showing that our method can achieve very remarkable performance. PMID- 28026763 TI - Reconstruction of Structurally-Incomplete Matrices With Reweighted Low-Rank and Sparsity Priors. AB - Most matrix reconstruction methods assume that missing entries randomly distribute in the incomplete matrix, and the low-rank prior or its variants are used to well pose the problem. However, in practical applications, missing entries are structurally rather than randomly distributed, and cannot be handled by the rank minimization prior individually. To remedy this, this paper introduces new matrix reconstruction models using double priors on the latent matrix, named Reweighted Low-rank and Sparsity Priors (ReLaSP). In the proposed ReLaSP models, the matrix is regularized by a low-rank prior to exploit the inter column and inter-row correlations, and its columns (rows) are regularized by a sparsity prior under a dictionary to exploit intra-column (-row) correlations. Both the low-rank and sparse priors are reweighted on the fly to promote low rankness and sparsity, respectively. Numerical algorithms to solve our ReLaSP models are derived via the alternating direction method under the augmented Lagrangian multiplier framework. Results on synthetic data, image restoration tasks, and seismic data interpolation show that the proposed ReLaSP models are quite effective in recovering matrices degraded by highly structural missing and various types of noise, complementing the classic matrix reconstruction models that handle random missing only. PMID- 28026764 TI - A New Intrinsic-Lighting Color Space for Daytime Outdoor Images. AB - Extracting or separating intrinsic information and illumination from natural images is crucial for better solving computer vision tasks. In this paper, we present a new illumination-based color space, the IL (intrinsic information and lighting level) space. Its first two channels represent 2D intrinsic information, and the third channel is for lighting levels. The IL color space has a one-to-one correspondence with the RGB color space. One valuable benefit of the IL color space is that illumination-related processing can be realized by directly operating on the lighting channel. As an example, based on the extracted lighting channel, we propose a new algorithm to estimate the intrinsic lighting level of an image such that the shadow-free color image and relighting series are obtained. In contrast to the existing color spaces for display or printing, the IL color space intuitively shows the information of reflectance and lighting levels for colors separately. PMID- 28026765 TI - A Maximum a Posteriori Estimation Framework for Robust High Dynamic Range Video Synthesis. AB - High dynamic range (HDR) image synthesis from multiple low dynamic range exposures continues to be actively researched. The extension to HDR video synthesis is a topic of significant current interest due to potential cost benefits. For HDR video, a stiff practical challenge presents itself in the form of accurate correspondence estimation of objects between video frames. In particular, loss of data resulting from poor exposures and varying intensity makes conventional optical flow methods highly inaccurate. We avoid exact correspondence estimation by proposing a statistical approach via maximum a posterior estimation, and under appropriate statistical assumptions and choice of priors and models, we reduce it to an optimization problem of solving for the foreground and background of the target frame. We obtain the background through rank minimization and estimate the foreground via a novel multiscale adaptive kernel regression technique, which implicitly captures local structure and temporal motion by solving an unconstrained optimization problem. Extensive experimental results on both real and synthetic data sets demonstrate that our algorithm is more capable of delivering high-quality HDR videos than current state-of-the-art methods, under both subjective and objective assessments. Furthermore, a thorough complexity analysis reveals that our algorithm achieves better complexity-performance tradeoff than conventional methods. PMID- 28026766 TI - Perceptual Depth Quality in Distorted Stereoscopic Images. AB - Subjective and objective measurement of the perceptual quality of depth information in symmetrically and asymmetrically distorted stereoscopic images is a fundamentally important issue in stereoscopic 3D imaging that has not been deeply investigated. Here, we first carry out a subjective test following the traditional absolute category rating protocol widely used in general image quality assessment research. We find this approach problematic, because monocular cues and the spatial quality of images have strong impact on the depth quality scores given by subjects, making it difficult to single out the actual contributions of stereoscopic cues in depth perception. To overcome this problem, we carry out a novel subjective study where depth effect is synthesized at different depth levels before various types and levels of symmetric and asymmetric distortions are applied. Instead of following the traditional approach, we ask subjects to identify and label depth polarizations, and a depth perception difficulty index (DPDI) is developed based on the percentage of correct and incorrect subject judgements. We find this approach highly effective at quantifying depth perception induced by stereo cues and observe a number of interesting effects regarding image content dependency, distortion-type dependence, and the impact of symmetric versus asymmetric distortions. Furthermore, we propose a novel computational model for DPDI prediction. Our results show that the proposed model, without explicitly identifying image distortion types, leads to highly promising DPDI prediction performance. We believe that these are useful steps toward building a comprehensive understanding on 3D quality-of-experience of stereoscopic images. PMID- 28026767 TI - Fast and Exact Newton and Bidirectional Fitting of Active Appearance Models. AB - Active appearance models (AAMs) are generative models of shape and appearance that have proven very attractive for their ability to handle wide changes in illumination, pose, and occlusion when trained in the wild, while not requiring large training data set like regression-based or deep learning methods. The problem of fitting an AAM is usually formulated as a non-linear least squares one and the main way of solving it is a standard Gauss-Newton algorithm. In this paper, we extend AAMs in two ways: we first extend the Gauss-Newton framework by formulating a bidirectional fitting method that deforms both the image and the template to fit a new instance. We then formulate a second order method by deriving an efficient Newton method for AAMs fitting. We derive both methods in a unified framework for two types of AAMs, holistic and part-based, and additionally show how to exploit the structure in the problem to derive fast yet exact solutions. We perform a thorough evaluation of all algorithms on three challenging and recently annotated in-the-wild data sets, and investigate fitting accuracy, convergence properties, and the influence of noise in the initialization. We compare our proposed methods to other algorithms and show that they yield state-of-the-art results, out-performing other methods while having superior convergence properties. PMID- 28026768 TI - Multiresolution Subdivision Snakes. AB - We present a new family of snakes that satisfy the property of multiresolution by exploiting subdivision schemes. We show in a generic way how to construct such snakes based on an admissible subdivision mask. We derive the necessary energy formulations and provide the formulas for their efficient computation. Depending on the choice of the mask, such models have the ability to reproduce trigonometric or polynomial curves. They can also be designed to be interpolating, a property that is useful in user-interactive applications. We provide explicit examples of subdivision snakes and illustrate their use for the segmentation of bioimages. We show that they are robust in the presence of noise and provide a multiresolution algorithm to enlarge their basin of attraction, which decreases their dependence on initialization compared to singleresolution snakes. We show the advantages of the proposed model in terms of computation and segmentation of structures with different sizes. PMID- 28026769 TI - Haze Removal Using the Difference- Structure-Preservation Prior. AB - Fog cover is generally present in outdoor scenes, which limits the potential for efficient information extraction from images. In this paper, the goal of the developed algorithm is to obtain an optimal transmission map as well as to remove hazes from a single input image. To solve the problem, we meticulously analyze the optical model and recast the initial transmission map under an additional boundary prior. For better preservation of the results, the difference-structure preservation dictionary could be learned, such that the local consistency features of the transmission map could be well preserved after coefficient shrinkage. Experimental results show that the method preserves the natural appearance of the image. PMID- 28026770 TI - Bayesian Contrast Measures and Clutter Distribution Determinants of Human Target Detection. AB - Human target detection is known to be dependent on a number of components: one, basic electro-optics including image contrast, the target size, pixel resolution, and contrast sensitivity; two, target shape, image type and features, types of clutter; and three, context and task requirements. Here, we consider a Bayesian approach to investigating how these components contribute to target detection. To this end, we develop and compare three different formulations for contrast: mean contrast, perceptual contrast, and a Bayesian-based histogram contrast statistic. Results on past detection data show how the latter contrast measure correlates well with human performance factoring out all other dimensions. As for clutter, our findings show that with large targets, there are effectively no clutter effects. Furthermore, clutter does not have a major effect on detection when it is not contiguous with the target even when it is smaller. However, except for large targets, when the target is contiguous with the clutter, detection clearly decreases as a function of the similarity of target and clutter features-creating type of "clutter camouflage". This Bayesian formulation uses priors based on the contrast histogram statistics derived from all the images, the image context, and implies that human observers have adapted their criteria to fit with the image set, context, and task. PMID- 28026771 TI - Prescribed Velocity Gradients for Highly Viscous SPH Fluids with Vorticity Diffusion. AB - Working with prescribed velocity gradients is a promising approach to efficiently and robustly simulate highly viscous SPH fluids. Such approaches allow to explicitly and independently process shear rate, spin, and expansion rate. This can be used to, e.g., avoid interferences between pressure and viscosity solvers. Another interesting aspect is the possibility to explicitly process the vorticity, e.g., to preserve the vorticity. In this context, this paper proposes a novel variant of the prescribed-gradient idea that handles vorticity in a physically motivated way. In contrast to a less appropriate vorticity preservation that has been used in a previous approach, vorticity is diffused. The paper illustrates the utility of the vorticity diffusion. Therefore, comparisons of the proposed vorticity diffusion with vorticity preservation and additionally with vorticity damping are presented. The paper further discusses the relation between prescribed velocity gradients and prescribed velocity Laplacians which improves the intuition behind the prescribed-gradient method for highly viscous SPH fluids. Finally, the paper discusses the relation of the proposed method to a physically correct implicit viscosity formulation. PMID- 28026772 TI - Real-Time 3D Eye Performance Reconstruction for RGBD Cameras. AB - This paper proposes a real-time method for 3D eye performance reconstruction using a single RGBD sensor. Combined with facial surface tracking, our method generates more pleasing facial performance with vivid eye motions. In our method, a novel scheme is proposed to estimate eyeball motions by minimizing the differences between a rendered eyeball and the recorded image. Our method considers and handles different appearances of human irises, lighting variations and highlights on images via the proposed eyeball model and the -based optimization. Robustness and real-time optimization are achieved through the novel 3D Taylor expansion-based linearization. Furthermore, we propose an online bidirectional regression method to handle occlusions and other tracking failures on either of the two eyes from the information of the opposite eye. Experiments demonstrate that our technique achieves robust and accurate eye performance reconstruction for different iris appearances, with various head/face/eye motions, and under different lighting conditions. PMID- 28026773 TI - Scalable Visualization of Time-varying Multi-parameter Distributions Using Spatially Organized Histograms. AB - Visualizing distributions from data samples as well as spatial and temporal trends of multiple variables is fundamental to analyzing the output of today's scientific simulations. However, traditional visualization techniques are often subject to a trade-off between visual clutter and loss of detail, especially in a large-scale setting. In this work, we extend the use of spatially organized histograms into a sophisticated visualization system that can more effectively study trends between multiple variables throughout a spatial domain. Furthermore, we exploit the use of isosurfaces to visualize time-varying trends found within histogram distributions. This technique is adapted into both an on-the-fly scheme as well as an in situ scheme to maintain real-time interactivity at a variety of data scales. PMID- 28026774 TI - JackIn Head: Immersive Visual Telepresence System with Omnidirectional Wearable Camera. AB - Sharing one's own immersive experience over the Internet is one of the ultimate goals of telepresence technology. In this paper, we present JackIn Head, a visual telepresence system featuring an omnidirectional wearable camera with image motion stabilization. Spherical omnidirectional video footage taken around the head of a local user is stabilized and then broadcast to others, allowing remote users to explore the immersive visual environment independently of the local user's head direction. We describe the system design of JackIn Head and report the evaluation results of real-time image stabilization and alleviation of cybersickness. Then, through an exploratory observation study, we investigate how individuals can remotely interact, communicate with, and assist each other with our system. We report our observation and analysis of inter-personal communication, demonstrating the effectiveness of our system in augmenting remote collaboration. PMID- 28026775 TI - Sounding Solid Combustibles: Non-Premixed Flame Sound Synthesis for Different Solid Combustibles. AB - With the rapidly growing VR industry, in recent years, more and more attention has been paid for fire sound synthesis. However, previous methods usually ignore the influences of the different solid combustibles, leading to unrealistic sounding results. This paper proposes SSC (sounding solid combustibles), which is a new recording-driven non-premixed flame sound synthesis framework accounting for different solid combustibles. SSC consists of three components: combustion noise, vortex noise and popping sounds. The popping sounds are the keys to distinguish the differences of solid combustibles. To improve the quality of fire sound, we extract the features of popping sounds from the real fire sound examples based on modified Empirical Mode Decomposition (EMD) method. Unlike previous methods, we take both direct combustion noise and vortex noise into account because the fire model is non-premixed flame. In our method, we also greatly resolve the synchronization problem during blending the three components of SSC. Due to the introduction of the popping sounds, it is easy to distinguish the fire sounds of different solid combustibles by our method, with great potential in practical applications such as games, VR system, etc. Various experiments and comparisons are presented to validate our method. PMID- 28026776 TI - Trending Paths: A New Semantic-Level Metric for Comparing Simulated and Real Crowd Data. AB - We propose a new semantic-level crowd evaluation metric in this paper. Crowd simulation has been an active and important area for several decades. However, only recently has there been an increased focus on evaluating the fidelity of the results with respect to real-world situations. The focus to date has been on analyzing the properties of low-level features such as pedestrian trajectories, or global features such as crowd densities. We propose the first approach based on finding semantic information represented by latent Path Patterns in both real and simulated data in order to analyze and compare them. Unsupervised clustering by non-parametric Bayesian inference is used to learn the patterns, which themselves provide a rich visualization of the crowd behavior. To this end, we present a new Stochastic Variational Dual Hierarchical Dirichlet Process ( SV DHDP) model. The fidelity of the patterns is computed with respect to a reference, thus allowing the outputs of different algorithms to be compared with each other and/or with real data accordingly. Detailed evaluations and comparisons with existing metrics show that our method is a good alternative for comparing crowd data at a different level and also works with more types of data, holds fewer assumptions and is more robust to noise. PMID- 28026777 TI - Local and Remote Cooperation With Virtual and Robotic Agents: A P300 BCI Study in Healthy and People Living With Spinal Cord Injury. AB - The development of technological applications that allow people to control and embody external devices within social interaction settings represents a major goal for current and future brain-computer interface (BCI) systems. Prior research has suggested that embodied systems may ameliorate BCI end-user's experience and accuracy in controlling external devices. Along these lines, we developed an immersive P300-based BCI application with a head-mounted display for virtual-local and robotic-remote social interactions and explored in a group of healthy participants the role of proprioceptive feedback in the control of a virtual surrogate (Study 1). Moreover, we compared the performance of a small group of people with spinal cord injury (SCI) to a control group of healthy subjects during virtual and robotic social interactions (Study 2), where both groups received a proprioceptive stimulation. Our attempt to combine immersive environments, BCI technologies and neuroscience of body ownership suggests that providing realistic multisensory feedback still represents a challenge. Results have shown that healthy and people living with SCI used the BCI within the immersive scenarios with good levels of performance (as indexed by task accuracy, optimizations calls and Information Transfer Rate) and perceived control of the surrogates. Proprioceptive feedback did not contribute to alter performance measures and body ownership sensations. Further studies are necessary to test whether sensorimotor experience represents an opportunity to improve the use of future embodied BCI applications. PMID- 28026778 TI - Proactive Selective Inhibition Targeted at the Neck Muscles: This Proximal Constraint Facilitates Learning and Regulates Global Control. AB - While individual muscle function is known, the sensory and motor value of muscles within the whole-body sensorimotor network is complicated. Specifically, the relationship between neck muscle action and distal muscle synergies is unknown. This work demonstrates a causal relationship between regulation of the neck muscles and global motor control. Studying violinists performing unskilled and skilled manual tasks, we provided ultrasound feedback of the neck muscles with instruction to minimize neck muscle change during task performance and observed the indirect effect on whole-body movement. Analysis of ultrasound, kinematic, electromyographic and electrodermal recordings showed that proactive inhibition targeted at neck muscles had an indirect global effect reducing the cost of movement, reducing complex involuntary, task-irrelevant movement patterns and improving balance. This effect was distinct from the effect of gaze alignment which increased physiological cost and reduced laboratory-referenced movement. Neck muscle inhibition imposes a proximal constraint on the global motor plan, forcing a change in highly automated sensorimotor control. The proximal location ensures global influence. The criterion, inhibition of unnecessary action, ensures reduced cost while facilitating task-relevant variation. This mechanism regulates global motor function and facilitates reinforcement learning to change engrained, maladapted sensorimotor control associated with chronic pain, injury and performance limitation. PMID- 28026779 TI - Combining Improved Gray-Level Co-Occurrence Matrix With High Density Grid for Myoelectric Control Robustness to Electrode Shift. AB - Pattern recognition-based myoelectric control is greatly influenced by electrode shift, which is inevitable during prosthesis donning and doffing. This study used gray-level co-occurrence matrix (GLCM) to represent the spatial distribution among high density (HD) electrodes and improved its calculation based on the using condition of myoelectric system, proposing a new feature, iGLCM, to improve the robustness of the system. The effects of its two parameters, quantization level and input data, were first evaluated and it was found that improved discrete Fourier transform (iDFT) performed better than the other three (time domain, autoregressive, root mean square) as the input data of iGLCM, and increasing quantization level did not significantly decrease the error rate of iGLCM when it was above 8. The performance of iGLCM with iDFT as input data and 8 as quantization level was subsequently compared with previous robust approaches (time domain autoregressive, variogram, common spatial pattern and optimal less channel configuration) and its input data, iDFT. It was showed that iGLCM achieved comparable classification accuracy without shift, and significantly decreased the sensitivity to electrode shift with 1 cm (p < 0.05). More importantly, it could reduce the perpendicular shift distance to half interelectrode distance with the electrodes worn as a band around the circumference of the forearm. Combined with the small interelectrode distance of HD electrodes, it provided a way to control the effect of perpendicular shifts fundamentally, which were the main source of performance degradation. Finally, the analysis of feature space revealed that the robustness was improved by discarding information sensitivity to shift and keeping as much as useful information. This study highlighted the importance of HD electrodes in robust myoelectric control, and the outcome would help the design of robust control system based on pattern recognition and promote its application in real-world condition. PMID- 28026780 TI - Hierarchically Micro- and Nanopatterned Topographical Cues for Modulation of Cellular Structure and Function. AB - Living cells receive biochemical and physical information from the surrounding microenvironment and respond to this information. Multiscale hierarchical substrates with micro- and nanogrooves have been shown to mimic the native extracellular matrix (ECM) better than conventional nanopatterned substrates; therefore, substrates with hierarchical topographical cues are considered suitable for investigating the role of physical factors in tissue functions. In this study, precisely controllable, multiscale hierarchical substrates that could mimic the micro- and nanotopography of complex ECMs were fabricated and used to culture various cell types, including fibroblasts, endothelial cells, osteoblasts, and human mesenchymal stem cells. These substrates had both microscale wrinkles and nanoscale patterns and enhanced the alignment and elongation of all the cells tested. In particular, the nanotopography on the microscale wrinkles promoted not only the adhesion, but also the functions of the cells. These findings suggest that the hierarchical multiscale substrates effectively regulated cellular structure and functions and that they can be used as a platform for tissue engineering and regenerative medicine. PMID- 28026781 TI - Exploring Consensus RNA Substructural Patterns Using Subgraph Mining. AB - Frequently recurring RNA structural motifs play important roles in RNA folding process and interaction with other molecules. Traditional index-based and shape based schemas are useful in modeling RNA secondary structures but ignore the structural discrepancy of individual RNA family member. Further, the in-depth analysis of underlying substructure pattern is insufficient due to varied and unnormalized substructure data. This prevents us from understanding RNAs functions and their inherent synergistic regulation networks. This article thus proposes a novel labeled graph-based algorithm RnaGraph to uncover frequently RNA substructure patterns. Attribute data and graph data are combined to characterize diverse substructures and their correlations, respectively. Further, a top-k graph pattern mining algorithm is developed to extract interesting substructure motifs by integrating frequency and similarity. The experimental results show that our methods assist in not only modelling complex RNA secondary structures but also identifying hidden but interesting RNA substructure patterns. PMID- 28026782 TI - A Hybrid CMOS-Memristor Neuromorphic Synapse. AB - Although data processing technology continues to advance at an astonishing rate, computers with brain-like processing capabilities still elude us. It is envisioned that such computers may be achieved by the fusion of neuroscience and nano-electronics to realize a brain-inspired platform. This paper proposes a high performance nano-scale Complementary Metal Oxide Semiconductor (CMOS)-memristive circuit, which mimics a number of essential learning properties of biological synapses. The proposed synaptic circuit that is composed of memristors and CMOS transistors, alters its memristance in response to timing differences among its pre- and post-synaptic action potentials, giving rise to a family of Spike Timing Dependent Plasticity (STDP). The presented design advances preceding memristive synapse designs with regards to the ability to replicate essential behaviours characterised in a number of electrophysiological experiments performed in the animal brain, which involve higher order spike interactions. Furthermore, the proposed hybrid device CMOS area is estimated as [Formula: see text] in a [Formula: see text] process-this represents a factor of ten reduction in area with respect to prior CMOS art. The new design is integrated with silicon neurons in a crossbar array structure amenable to large-scale neuromorphic architectures and may pave the way for future neuromorphic systems with spike timing-dependent learning features. These systems are emerging for deployment in various applications ranging from basic neuroscience research, to pattern recognition, to Brain-Machine-Interfaces. PMID- 28026783 TI - Tactile Perception and Friction-Induced Vibrations: Discrimination of Similarly Patterned Wood-Like Surfaces. AB - The tactile perception of a surface texture is mediated by factors such as material, topography, and vibrations induced by the sliding contact. In this paper, sensory characterizations are developed together with topographical and tribo-tactile characterizations to relate perceived features with objective measurements of tribological and dynamic signals. Two sets of surface samples are used in this study: the first set is made of a commercial floor covering tiles that aim at counter-typing natural wood flooring, with both a visual and a tactile texture mimicking wood. A second set is custom-made by replicating the first set using a plain purple polyurethane resin. The comparison between tribo tactile signals and sensory analysis allowed the identification of objective indices for textures with slight topographical differences. Even though the topography of the replicated samples is the same as their corresponding commercial products, the fact that the material is different, induces differences in the contact and vibrational parameters. This in turn modifies the discrimination performances during the sensory experiment. Tactile characteristics collected during sensory procedures are found to be in agreement with objective indices such as friction coefficients and induced vibrations. PMID- 28026784 TI - KiloHertz Bandwidth, Dual-Stage Haptic Device Lets You Touch Brownian Motion. AB - This paper describes a haptic interface that has a uniform response over the entire human tactile frequency range. Structural mechanics makes it very difficult to implement articulated mechanical systems that can transmit high frequency signals. Here, we separated the frequency range into two frequency bands. The lower band is within the first structural mode of the corresponding haptic device while the higher one can be transmitted accurately by a fast actuator operating from conservation of momentum, that is, without reaction forces to the ground. To couple the two systems, we adopted a channel separation approach akin to that employed in the design of acoustic reproduction systems. The two channels are recombined at the tip of the device to give a uniform frequency response from DC to one kHz. In terms of mechanical design, the high frequency transducer was embedded inside the tip of the main stage so that during operation, the human operator has only to interact with a single finger interface. In order to exemplify the type of application that would benefit from this kind of interface, we applied it to the haptic exploration with microscopic scales objects which are known to behave with very fast dynamics. The novel haptic interface was bilaterally coupled with a micromanipulation platform to demonstrate its capabilities. Operators could feel interaction forces arising from contact as well as those resulting from Brownian motion and could manoeuvre a micro bead in the absence of vision. PMID- 28026785 TI - Nonlinear Process Fault Diagnosis Based on Serial Principal Component Analysis. AB - Many industrial processes contain both linear and nonlinear parts, and kernel principal component analysis (KPCA), widely used in nonlinear process monitoring, may not offer the most effective means for dealing with these nonlinear processes. This paper proposes a new hybrid linear-nonlinear statistical modeling approach for nonlinear process monitoring by closely integrating linear principal component analysis (PCA) and nonlinear KPCA using a serial model structure, which we refer to as serial PCA (SPCA). Specifically, PCA is first applied to extract PCs as linear features, and to decompose the data into the PC subspace and residual subspace (RS). Then, KPCA is performed in the RS to extract the nonlinear PCs as nonlinear features. Two monitoring statistics are constructed for fault detection, based on both the linear and nonlinear features extracted by the proposed SPCA. To effectively perform fault identification after a fault is detected, an SPCA similarity factor method is built for fault recognition, which fuses both the linear and nonlinear features. Unlike PCA and KPCA, the proposed method takes into account both linear and nonlinear PCs simultaneously, and therefore, it can better exploit the underlying process's structure to enhance fault diagnosis performance. Two case studies involving a simulated nonlinear process and the benchmark Tennessee Eastman process demonstrate that the proposed SPCA approach is more effective than the existing state-of-the-art approach based on KPCA alone, in terms of nonlinear process fault detection and identification. PMID- 28026786 TI - A One-Layer Recurrent Neural Network for Constrained Complex-Variable Convex Optimization. AB - In this paper, based on calculus and penalty method, a one-layer recurrent neural network is proposed for solving constrained complex-variable convex optimization. It is proved that for any initial point from a given domain, the state of the proposed neural network reaches the feasible region in finite time and converges to an optimal solution of the constrained complex-variable convex optimization finally. In contrast to existing neural networks for complex-variable convex optimization, the proposed neural network has a lower model complexity and better convergence. Some numerical examples and application are presented to substantiate the effectiveness of the proposed neural network. PMID- 28026787 TI - Insights Into the Robustness of Minimum Error Entropy Estimation. AB - The minimum error entropy (MEE) is an important and highly effective optimization criterion in information theoretic learning (ITL). For regression problems, MEE aims at minimizing the entropy of the prediction error such that the estimated model preserves the information of the data generating system as much as possible. In many real world applications, the MEE estimator can outperform significantly the well-known minimum mean square error (MMSE) estimator and show strong robustness to noises especially when data are contaminated by non-Gaussian (multimodal, heavy tailed, discrete valued, and so on) noises. In this brief, we present some theoretical results on the robustness of MEE. For a one-parameter linear errors-in-variables (EIV) model and under some conditions, we derive a region that contains the MEE solution, which suggests that the MEE estimate can be very close to the true value of the unknown parameter even in presence of arbitrarily large outliers in both input and output variables. Theoretical prediction is verified by an illustrative example. PMID- 28026788 TI - Synchronization of General Chaotic Neural Networks With Nonuniform Sampling and Packet Missing: A Switched System Approach. AB - This paper is concerned with the exponential synchronization issue of general chaotic neural networks subject to nonuniform sampling and control packet missing in the frame of the zero-input strategy. Based on this strategy, we make use of the switched system model to describe the synchronization error system. First, when the missing of control packet does not occur, an exponential stability criterion with less conservatism is established for the resultant synchronization error systems via a superior time-dependent Lyapunov functional and the convex optimization approach. The characteristics induced by nonuniform sampling can be used to the full because of the structure and property of the constructed Lyapunov functional, that is not necessary to be positive definite except sampling times. Then, a criterion is obtained to guarantee that the general chaotic neural networks are synchronous exponentially when the missing of control packet occurs by means of the average dwell-time technique. An explicit expression of the sampled-data static output feedback controller is also gained. Finally, the effectiveness of the proposed new design methods is shown via two examples. PMID- 28026789 TI - A Deep Convolutional Coupling Network for Change Detection Based on Heterogeneous Optical and Radar Images. AB - We propose an unsupervised deep convolutional coupling network for change detection based on two heterogeneous images acquired by optical sensors and radars on different dates. Most existing change detection methods are based on homogeneous images. Due to the complementary properties of optical and radar sensors, there is an increasing interest in change detection based on heterogeneous images. The proposed network is symmetric with each side consisting of one convolutional layer and several coupling layers. The two input images connected with the two sides of the network, respectively, are transformed into a feature space where their feature representations become more consistent. In this feature space, the different map is calculated, which then leads to the ultimate detection map by applying a thresholding algorithm. The network parameters are learned by optimizing a coupling function. The learning process is unsupervised, which is different from most existing change detection methods based on heterogeneous images. Experimental results on both homogenous and heterogeneous images demonstrate the promising performance of the proposed network compared with several existing approaches. PMID- 28026790 TI - Stabilization of Neural-Network-Based Control Systems via Event-Triggered Control With Nonperiodic Sampled Data. AB - This paper focuses on a problem of event-triggered stabilization for a class of nonuniformly sampled neural-network-based control systems (NNBCSs). First, a new event-triggered data transmission mechanism is designed based on the nonperiodic sampled data. Different from the previous works, the proposed triggering scheme enables the NNBCSs design to enjoy the advantages of both nonuniform and event triggered sampling schemes. Second, under the nonperiodic event-triggered data transmission scheme, the nonperiodic sampled-data three-layer fully connected feedforward neural-network (TLFCFFNN)-based event-triggered controller is constructed, and the resulting closed-loop TLFCFFNN-based event-triggered control system is modeled as a state delay system based on time-delay system modeling approach. Then, the stability criteria for the closed-loop system is formulated using Lyapunov-Krasovskii functional approach. Third, the sufficient conditions for the codesign of the TLFCFFNN-based controller and triggering parameters are given in terms of solvability of matrix inequalities to guarantee the asymptotical stability of the closed-loop system and an upper bound on the given cost function while reducing the updates of the controller. Finally, three numerical examples are provided to illustrate the effectiveness and benefits of the proposed results. PMID- 28026791 TI - Intelligent Noninvasive Diagnosis of Aneuploidy: Raw Values and Highly Imbalanced Dataset. AB - The objective of this paper is to introduce a noninvasive diagnosis procedure for aneuploidy and to minimize the social and financial cost of prenatal diagnosis tests that are performed for fetal aneuploidies in an early stage of pregnancy. We propose a method by using artificial neural networks trained with data from singleton pregnancy cases, while undergoing first trimester screening. Three different datasets1 with a total of 122 362 euploid and 967 aneuploid cases were used in this study. The data for each case contained markers collected from the mother and the fetus. This study, unlike previous studies published by the authors for a similar problem differs in three basic principles: 1) the training of the artificial neural networks is done by using the markers' values in their raw form (unprocessed), 2) a balanced training dataset is created and used by selecting only a representative number of euploids for the training phase, and 3) emphasis is given to the financials and suggest hierarchy and necessity of the available tests. The proposed artificial neural networks models were optimized in the sense of reaching a minimum false positive rate and at the same time securing a 100% detection rate for Trisomy 21. These systems correctly identify other aneuploidies (Trisomies 13&18, Turner, and Triploid syndromes) at a detection rate greater than 80%. In conclusion, we demonstrate that artificial neural network systems can contribute in providing noninvasive, effective early screening for fetal aneuploidies with results that compare favorably to other existing methods. PMID- 28026792 TI - A Deep Learning Approach to on-Node Sensor Data Analytics for Mobile or Wearable Devices. AB - The increasing popularity of wearable devices in recent years means that a diverse range of physiological and functional data can now be captured continuously for applications in sports, wellbeing, and healthcare. This wealth of information requires efficient methods of classification and analysis where deep learning is a promising technique for large-scale data analytics. While deep learning has been successful in implementations that utilize high-performance computing platforms, its use on low-power wearable devices is limited by resource constraints. In this paper, we propose a deep learning methodology, which combines features learned from inertial sensor data together with complementary information from a set of shallow features to enable accurate and real-time activity classification. The design of this combined method aims to overcome some of the limitations present in a typical deep learning framework where on-node computation is required. To optimize the proposed method for real-time on-node computation, spectral domain preprocessing is used before the data are passed onto the deep learning framework. The classification accuracy of our proposed deep learning approach is evaluated against state-of-the-art methods using both laboratory and real world activity datasets. Our results show the validity of the approach on different human activity datasets, outperforming other methods, including the two methods used within our combined pipeline. We also demonstrate that the computation times for the proposed method are consistent with the constraints of real-time on-node processing on smartphones and a wearable sensor platform. PMID- 28026793 TI - Wireless sEMG-Based Body-Machine Interface for Assistive Technology Devices. AB - Assistive technology (AT) tools and appliances are being more and more widely used and developed worldwide to improve the autonomy of people living with disabilities and ease the interaction with their environment. This paper describes an intuitive and wireless surface electromyography (sEMG) based body machine interface for AT tools. Spinal cord injuries at C5-C8 levels affect patients' arms, forearms, hands, and fingers control. Thus, using classical AT control interfaces (keypads, joysticks, etc.) is often difficult or impossible. The proposed system reads the AT users' residual functional capacities through their sEMG activity, and converts them into appropriate commands using a threshold-based control algorithm. It has proven to be suitable as a control alternative for assistive devices and has been tested with the JACO arm, an articulated assistive device of which the vocation is to help people living with upper-body disabilities in their daily life activities. The wireless prototype, the architecture of which is based on a 3-channel sEMG measurement system and a 915-MHz wireless transceiver built around a low-power microcontroller, uses low cost off-the-shelf commercial components. The embedded controller is compared with JACO's regular joystick-based interface, using combinations of forearm, pectoral, masseter, and trapeze muscles. The measured index of performance values is 0.88, 0.51, and 0.41 bits/s, respectively, for correlation coefficients with the Fitt's model of 0.75, 0.85, and 0.67. These results demonstrate that the proposed controller offers an attractive alternative to conventional interfaces, such as joystick devices, for upper-body disabled people using ATs such as JACO. PMID- 28026794 TI - Classification of Exacerbation Frequency in the COPDGene Cohort Using Deep Learning with Deep Belief Networks. AB - This study aims to develop an automatic classifier based on deep learning for exacerbation frequency in patients with chronic obstructive pulmonary disease (COPD). A threelayer deep belief network (DBN) with two hidden layers and one visible layer was employed to develop classification models and the models' robustness to exacerbation was analyzed. Subjects from the COPDGene cohort were labeled with exacerbation frequency, defined as the number of exacerbation events per year. 10,300 subjects with 361 features each were included in the analysis. After feature selection and parameter optimization, the proposed classification method achieved an accuracy of 91.99%, using a 10-fold cross validation experiment. The analysis of DBN weights showed that there was a good visual spatial relationship between the underlying critical features of different layers. Our findings show that the most sensitive features obtained from the DBN weights are consistent with the consensus showed by clinical rules and standards for COPD diagnostics. We thus demonstrate that DBN is a competitive tool for exacerbation risk assessment for patients suffering from COPD. PMID- 28026795 TI - Transfer Boosting With Synthetic Instances for Class Imbalanced Object Recognition. AB - A challenging problem in object recognition is to train a robust classifier with small and imbalanced data set. In such cases, the learned classifier tends to overfit the training data and has low prediction accuracy on the minority class. In this paper, we address the problem of class imbalanced object recognition by combining synthetic minorities over-sampling technique (SMOTE) and instance-based transfer boosting to rebalance the skewed class distribution. We present ways of generating synthetic instances under the learning framework of transfer Adaboost. A novel weighted SMOTE technique (WSMOTE) is proposed to generate weighted synthetic instances with weighted source and target instances at each boosting round. Based on WSMOTE, we propose a novel class imbalanced transfer boosting algorithm called WSMOTE-TrAdaboost and experimentally demonstrate its effectiveness on four datasets (Office, Caltech256, SUN2012, and VOC2012) for object recognition application. Bag-of-words model with SURF features and histogram of oriented gradient features are separately used to represent an image. We experimentally demonstrated the effectiveness and robustness of our approaches by comparing it with several baseline algorithms in boosting family for class imbalanced learning. PMID- 28026796 TI - Data-Driven Adaptive Probabilistic Robust Optimization Using Information Granulation. AB - In this paper, we consider a generic class of adaptive optimization problems under uncertainty, and develop a data-driven paradigm of adaptive probabilistic robust optimization (APRO) in a robust and computationally tractable manner. The paradigm comprises two phases: 1) bilayer information granulation (IG), which involves the data-mining techniques and nested decomposition of convex sets that establish and restructure the knowledge from data and 2) robustization and optimization over the restructured knowledge by the IG, which forms the APRO model. The tradeoff between the solution optimality and the robustness of the resulting data-driven APRO model can be achieved by adjusting the number of clusters and the number of nested decomposition units of the IG process. We draw the connections of the APRO model with the stochastic programming and the regular robust optimization models, respectively, and show that the APRO model can be regarded as a generalized version of both models. We show that the APRO model can be transformed into the second-order conic programming which is computationally tractable and can be solved efficiently by the off-the-shelf solvers. Furthermore, the model can be extended by robustizing the probability parameters. Finally, an application on two-stage facility location planning is presented, and the computational results demonstrate the performance and the insights of using the data-driven APRO models. PMID- 28026797 TI - A Bi-Level Optimization Model for Grouping Constrained Storage Location Assignment Problems. AB - In this paper, a novel bi-level grouping optimization (BIGO) model is proposed for solving the storage location assignment problem with grouping constraint (SLAP-GC). A major challenge in this problem is the grouping constraint which restricts the number of groups each product can have and the locations of items in the same group. In SLAP-GC, the problem consists of two subproblems, one is how to group the items, and the other one is how to assign the groups to locations. It is an arduous task to solve the two subproblems simultaneously. To overcome this difficulty, we propose a BIGO. BIGO optimizes item grouping in the upper level, and uses the lower-level optimization to evaluate each item grouping. Sophisticated fitness evaluation and search operators are designed for both upper and lower level optimization so that the feasibility of solutions can be guaranteed, and the search can focus on promising areas in the search space. Based on the BIGO model, a multistart random search method and a tabu search algorithm are proposed. The experimental results on the real-world dataset validate the efficacy of the BIGO model and the advantage of the tabu search method over the random search method. PMID- 28026798 TI - Joint-Feature Guided Depth Map Super-Resolution With Face Priors. AB - In this paper, we present a novel method to super-resolve and recover the facial depth map nicely. The key idea is to exploit the exemplar-based method to obtain the reliable face priors from high-quality facial depth map to improve the depth image. Specifically, a new neighbor embedding (NE) framework is designed for face prior learning and depth map reconstruction. First, face components are decomposed to form specialized dictionaries and then reconstructed, respectively. Joint features, i.e., low-level depth, intensity cues and high-level position cues, are put forward for robust patch similarity measurement. The NE results are used to obtain the face priors of facial structures and smooth maps, which are then combined in an uniform optimization framework to recover high-quality facial depth maps. Finally, an edge enhancement process is implemented to estimate the final high resolution depth map. Experimental results demonstrate the superiority of our method compared to state-of-the-art depth map super-resolution techniques on both synthetic data and real-world data from Kinect. PMID- 28026799 TI - Background Extraction Using Random Walk Image Fusion. AB - It is important to extract a clear background for computer vision and augmented reality. Generally, background extraction assumes the existence of a clean background shot through the input sequence, but realistically, situations may violate this assumption such as highway traffic videos. Therefore, our probabilistic model-based method formulates fusion of candidate background patches of the input sequence as a random walk problem and seeks a globally optimal solution based on their temporal and spatial relationship. Furthermore, we also design two quality measures to consider spatial and temporal coherence and contrast distinctness among pixels as background selection basis. A static background should have high temporal coherence among frames, and thus, we improve our fusion precision with a temporal contrast filter and an optical-flow-based motionless patch extractor. Experiments demonstrate that our algorithm can successfully extract artifact-free background images with low computational cost while comparing to state-of-the-art algorithms. PMID- 28026800 TI - Predictive significance of smudge cell on routine blood smear in lymphocytosis. PMID- 28026801 TI - Evaluation of concordance between labelling and content of 52 hair dye products: overview of the market of oxidative hair dye. AB - Hair dyes contain strong allergens and are widely available. Correct labelling is a necessity in order to provide information about the contents. To compare the labelling and content of hair dyes. In total, 52 hair dyes, from 11 different countries, were bought over the counter. High-pressure liquid chromatography was used for the analysis of p-phenylenediamine (PPD), toluene-2,5-diamine (2,5-TDA), and three oxidation products of PPD. There was good agreement between labelling and content, although seven of the 52 products (13.5%) studied were incorrectly labelled. There were differences in the geographical use of PPD and 2,5-TDA; 2,5 TDA was more common in European products, while PPD was more common in products purchased outside Europe and was present in higher concentrations. All dyes purchased in Europe contained PPD and 2,5-TDA at levels within the limits defined by European legislation, however, levels were higher in some products purchased outside Europe. Only a small group of hair dyes sold in Europe were mislabelled. Further improvement in labelling, by providing the concentration of chemicals, may facilitate products to be purchased both locally and within the global market, when travelling or on the internet. PMID- 28026802 TI - Ethosuximide-induced lupus-scleroderma syndrome with disease-specific autoantibodies. PMID- 28026803 TI - [Furin as proprotein convertase and its role in normaland pathological biological processes]. AB - Furin belongs to serine intracellular Ca2+-dependent endopeptidases of the subtilisin family, also known as proprotein convertase (PC). Human furin is synthesized as zymogen with a molecular weight of 104 kDa, which is then activated by autocatalytic in two stages. This process can occur when zymogen migrates from the endoplasmic reticulum to the Golgi apparatus, where a large part of furin is accumulated. The molecular weigh t of the active furin is 98 kDa. Furin relates to enzymes with a narrow substrate specificity: it hydrolyzes peptide bonds at the site of paired basic amino acids and furin activity exhibits in a wide pH range 5-8. Its main biological function is activation of the functionally important protein precursors. It is accompanied by the launch of a cascade of reactions, which lead to appearance of biologically active molecules involved in realization of specific biological functions both in normal and in some patologicheskih processes. Furin substrates are biologically important proteins such as enzymes, hormones, growth factors and differentiation, receptors, adhesion proteins, proteins of blood plasma. Furin plays an important role in the development of processes such as proliferation, invasion, cell migration, survival, maintenance of homeostasis, embryogenesis, as well as the development of a number of pathologies, including cardiovascular, oncologic and neurodegenerative diseases. Furin and furin-like proprotein convertases participate as key factors in the realization of the regulatory functions of proteolytic enzymes, the value of which is currently being evaluated as most important in comparison with the degradative function of proteases. PMID- 28026804 TI - [Role of fibroblast growth factors in pancreatic cancer]. AB - Fibroblast growth factors belong to a family of growth factors that are involved in various processes in organism and have a wide range of biological functions. Specifically for pancreas, FGFs are important during both organogenesis and carcinogenesis. One of the main characteristic of pancreatic cancer, is it close interaction between cancer and stromal cells via different factors, including FGF. Pathological changes in FGF/FGFR signaling pathway is a complex process. The remodeling effects and stimulation of tumor growth are mostly depend not only on types of receptors, but also from their isoforms. FGF/FGFR signaling pathway is a perspective specific marker for cancer progression, and a potential drug target, which can be used for treatment of pancreatic cancer. PMID- 28026805 TI - [Conformational polymorphysm of G-rich fragments of DNA Alu-repeats. II. the putative role of G-quadruplex structures in genomic rearrangements]. AB - Three evolutionary conserved sites of Alu repeats (PQS2, PQS3 and PQS4) were shown to form stable inter- and intramolecular G-quadruplexes (GQs) in vitro. Structures and topologies of these GQs were elucidated using spectral methods. Self-association of G-rich Alu fragments was studied. Dimeric GQ formation from two distal identical or different putative quadruplex sites - (PQS2)2, (PQS3)2 or PQS2-PQS3 - within one lengthy DNA strand was demonstrated by a FRET-based method. Oligomer PQS4 (folded into a parallel intramolecular GQ) was shown to form stacks of quadruplexes that are stabilized by stacking interactions of external G-tetrads (this was confirmed by DOSY NMR, AFM microscopy and differential CD spectroscopy). Comparative analysis of the properties of various GQs allowed us to put forward a hypothesis of two general mechanisms of intermolecular GQ-dependant genomic rearrangements: 1) formation of a dimeric GQs; 2) association of pre-folded intramolecular parallel GQs from different strands into GQ-stacks. Thus, the observed co-localization of G-rich motifs of Alu elements with double-strand break hotspots and rearrangement hotspots may be accounted for by the specific secondary structure of these motifs. At the same time, this is likely primarily due to high abundance of such G-rich Alu fragments in the genome. PMID- 28026806 TI - [Determination of EGFR gene somatic mutations in tissues and plasma of patients with advanced non-small cell lung cancer]. AB - The presence of activating mutations in the EGFR gene influences cell proliferation, angiogenesis, and increases metastatic ability; it has a significant impact on the choice of medical therapy of non-small cell lung cancer (NSCLC). The use of targeted therapy with tyrosine kinase inhibitors requires performance of appropriate genetic tests. The aim of this study was to design a real-time PCR-based diagnostic kit for fast and cheap of EGFR mutations testing in paraffin blocks and plasma, and kit validation using samples from patients with NSCLC, and also comparative estimation of diagnostic features of real-time PCR with wild type blocking and digital PCR for mutation testing in blood plasma. The study included 156 patients with various types of adenocarcinoma differentiation. It was designed a simple and efficient real-time PCR-based method of detecting L858R activating mutation and del19 deletion in the EGFR gene for DNA isolated from paraffin blocks. Kit for EGFR mutations was validated using 411 samples of paraffin blocks. The proposed system showed high efficiency for DNA testing from paraffin blocks: a concordance with results of testing with therascreen(r) EGFR RGQ PCR Kit ("Qiagen", Germany) was 100%. It has been shown the possibility of using this test system for the detection of mutations in plasma. PMID- 28026807 TI - [Features of influence adenosine, AMP and hyperadrenalinemiya on the immune status, metabolic enzymes of purine nucleotides and the antioxidant defense system]. AB - Administration of a large dose of adrenaline (4 mg/kg 60 min before analysis) increased blood levels of total leukocytes, lymphocytes, decreased T-cell suppressors, leukocyte migration inhibition reaction (LMIR) and NBT test, but increased the level of conjugated dienes (CD). Administration of AMPand adenosine increased levels of total leukocytes, lymphocytes, T- lymphocytes, T-helpers, decreased the level of malondialdehyde (MDA), LMIR, and T-cell suppressors. Sympathetic hyperactivation induced by administration of a large dose of adrenaline (4 mg/kg 60 min before analysis) was accompanied by an increase in heart and liver activities of glutathione peroxidase (GPx), catalase, AMP deaminase (AMPD), and adenosine deaminase (AD). Administration of AMP or adenosine caused a decrease in activities of glutathione reductase (GR), GPx, catalase, a decrease in the MDA level and an increase in activities of AMPD and AD in the heart. In the liver AMP and adenosine also caused a decrease in activities of glutathione reductase (GR), GPx, a decrease in the MDA level and an increase in activities of AMPD and AD. The data obtained suggest that administration of adrenaline, AMP, and adenosine influences activity of enzymes involved in purine nucleotide metabolism. However, in contrast to adrenaline, administration of AMP or adenosine does not provoke stress reaction. PMID- 28026808 TI - [Standardization and regulation of the rate of the superoxide-generating adrenaline autoxidation reaction used for evaluation of pro/antioxidant properties of various materials]. AB - The superoxide-generating reaction of adrenaline autoxidation is widely used for determination of the activity of superoxide dismutase and pro/antioxidant properties of various materials. There are two variants of the spectrophotometric registration of the products of this reaction. The first is based on registration of adrenochrome, as adrenaline autooxidation product at 347 nm; the second employs nitro blue tetrazolium (NBT) and registration of diformazan, a product of NBT reduction at 560 nm. In the present work, recommendations for the standardization of the reaction rate in both variants have been proposed. The main approach consists in the use of the pharmaceutical form of 0.1% adrenaline hydrochloride solution. Although each of two adrenaline preparations available in the Russian market has some features in kinetic behavior of its autooxidation; they are applicable in the superoxide generating system based on adrenaline autooxidation. Performing measurements at 560 nm, the reaction rate can be regulated by lowering the concentration of added adrenaline, whereas during spectrophotometric registration at 347 nm, this cannot be done. These features of adrenaline autoxidation may be due to the fact that the intrinsic multistage process of the conversion of adrenaline to adrenochrome, which is recorded at 347 nm, is coupled with the transition of electrons from adrenaline and intermediate products of its oxidation to oxygen, carbon dioxide, and carbonate bicarbonate ions, which is detected in the presence of added NBT. PMID- 28026809 TI - [Trophic factors deprivation induces long-term protection of neurons against excitotoxic damage]. AB - One of the strategies to induce tolerance of neurons to toxic injury is preconditioning. Preconditioning is caused by a weak damage of cells, which become more resistant to subsequent, more severe damage. We found that preconditioning by deprivation of trophic factors, or deprivation of trophic factor and glucose effectively protects neurons against subsequent toxic effects of glutamate. Deprivation of trophic factors plays a decisive role in the development of resistance, regardless of whether it has been combined with glucose deprivation or not. Neuronal protection is achieved when the deprivation lasts from 30 min to two hours and is kept for a period of from one to five days. Preconditioning is accompanied neuronal secretion of cathepsin B occurs. We suggest that this phenomenon is associated with a more general process of exocytosis of lysosomes triggered by deprivation of trophic factors. PMID- 28026810 TI - [Development of blood-brain barrier under the modulation of HIF activity in astroglialand neuronal cells in vitro]. AB - Barriergenesis is the process of maturation of the primary vascular network of the brain responsible for the establishment of the blood-brain barrier. It represents a combination of factors that, on the one hand, contribute to the process of migration and tubulogenesis of endothelial cells (angiogenesis), on the other hand, contribute to the formation of new connections between endothelial cells and other elements of the neurovascular unit. Astrocytes play a key role in barriergenesis, however, mechanisms of their action are still poorly examined. We have studied the effects of HIF-1 modulators acting on the cells of non-endothelial origin (neurons and astrocytes) on the development of the blood brain barrier in vitro. Application of FM19G11 regulating expression of HIF-1 activity and GSI-1 suppressing gamma-secretase and/or proteasomal activity resulted in the elevated expression of thrombospondins and matrix metalloproteinases in the developing blood-brain barrier. However, it caused the opposite effect on VEGF expression thus promoting barrier maturation in vitro. PMID- 28026811 TI - [The role of heat shock proteins 27 and 70 in redox-dependent regulation of apoptosis in Jurkat tumor cells]. AB - Heat shock proteins Hsp) act as molecular chaperones, protecting enzymes and other proteins against reactive oxygen species. The objective of the study was to investigate the role of Hsp27 in maintaining the balance of the glutathione system and Hsp70 concentrations as well as in implementing Jurkat tumor cell apoptosis. Addition of the Hsp27 inhibitor KRIBB3 (5-(5-ethyl-2-hydroxy-4 methoxyphenyl)-4-(4-methoxyphenyl)-isoxazol) to Jurkat cells resulted in glutathione redox imbalance (increased GSSG and increased glutathione reductase activity), a decrease in Hsp70 concentrations, and also increased cell apoptosis as compared with to the intact cell culture. The proposed selective regulation of chaperone activity is a promising direction in regulating apoptosis at the cellular level. PMID- 28026812 TI - [The hepatic differentiation of adult and fetal liver stromal cells in vitro]. AB - The liver has a marked capacity for regeneration. In most cases the liver regeneration is determined by hepatocytes. The regenerative capacity of hepatocytes is significantly reduced in acute or chronic damage. In particular, repair mechanisms are not activated in patients with alcoholic cirrhosis. Organ transplantation or advanced methods of regenerative medicine can help such patients. The promising results were obtained in clinical trials involving patients with various forms of liver disease who received transplantation of autologous bone marrow stem cells. However, to improve the effectiveness of such treatment it is necessary to search for more optimal sources of progenitor cells, as well as to evaluate the possibility of using descendants of these cells differentiated in vitro. In this study we isolated stromal cells from the liver biopsies of three patients with alcoholic cirrhosis, conducted their morphological and phenotypic analysis, and evaluated the hepatic potential of these cells in vitro. The stromal cells isolated from fetal liver were used for comparison. The results of this can serve as a basis for the development of a new method for the treatment of end-stage liver disease. The stromal cells isolated from the liver biopsies for a long time proliferate in a culture and this which makes it possible to expand them to large amounts for subsequent differentiation into hepatocyte-like cells and autologous transplantation. PMID- 28026813 TI - [Mechanisms of perioperative corneal abrasions: alterations in tear film proteome]. AB - Perioperative corneal abrasion is an ophthalmic complication commonly found in patients underwent general anesthesia. In this study, correlations between development of corneal injury and proteomic changes in tear film during general anesthesia were examined using an animal (rabbit) model. Being started after 1-h anesthesia, the process of accumulation of pathological changes in the cornea unequivocally led clinically significant abrasions following 3-6 h of the narcosis. The corneal damage was associated with alterations in profiles of major proteins of the tear film. Analysis of the tear proteome pointed to depression of lachrymal glands function, and suggested serotransferrin, serum albumin and annexin A1 as potential tear markers of the complication. The tear film alterations included fast drop of total antioxidant activity and activity of superoxide dismutase, and decrease in interleukin-4 and increase in interleukin-6 content indicating development of oxidative and pro-inflammatory responses. These findings suggest antioxidant and anti-inflammatory therapy as prospective approach for prevention/treatment of perioperative corneal abrasions. The observed anesthesia-induced effects should be considered in any study of ocular surface diseases employing anesthetized animals. PMID- 28026814 TI - [Prediction of selective inhibition of neuraminidase from various influenza virus strains by potential inhibitors]. AB - A universal model of inhibition of neuraminidases from various influenza virus strains by a particular has been developed. It is based on known 3D data for neuraminidases from three influenza virus strains (A/Tokyo/3/67, A/tern/Australia/G70C/75, B/Lee/40) and modeling of 3D structure of neuraminidases from other strains (A/PR/8/34 e A/Aichi/2/68). Using docking and molecular dynamics, we have modeled 235 enzyme-ligand complexes for 89 compounds with known IC50 values. Selection of final variants among three results obtained for each enzyme-ligand pair and calculation of independent variables for generation of linear regression equations was performed using MM-PBSA/MM-GBSA. This resulted in the set of equations individual strains and the equations pooling all the data. Thus using this approach it is possible to predict inhibition for neuraminidase from each the considered strains by a particular inhibitor and to predict the range of its action on neuraminidases from various influenza virus strains. PMID- 28026815 TI - [Investigation of efficacy of phospholipovit for correction of the hepatic encephalopathy]. AB - This paper presents the results of clinical studies on the efficacy and safety of the drug Phospholipovit in different groups of patients, in particular with hepatic encephalopathy and with a high risk of its development (chronic alcohol intoxication). Efficacy of treatmernt was evaluated by the LNT test (link numbers test), and standard liver plasma markers (ALT, AST, GGT, AP). The LNT test in patients with encephalopathy showed better improvement after 5 days course of Phos-pholipovit than after standard therapy. In both clinical trials liver enzyme activities, assayed in pa-tients declined more rapidly in the group of patients treated with Phospholipovit, as compared in patients received standard therapy alone. The highest clinical effect of the drug on the liver function tests was observed at a daily dose of 6.4 g of phospholipids (infusional 2 times a day) for 5-10 days. At the end of treatment a two-fold decrease in the activity of AST was observed in patients receiv-ing Phospholipovit compared to the control. This results of clinical results can be regarded as a manifestation of the expressed membrane repairing action of essential phospholipids, reinforced by their introduction into the body in the form of nanoparticles. PMID- 28026817 TI - [A possibility to use the DNA-based probes as internal standards for Agilent Technologies microarray transcriptomic analysis]. AB - Accuracy of the microarray technology results is raised by using the multi-stage normalization of results. One of the principal requirements of such normalization is usage of internal standards. The routine Agilent microarray-based gene expression analysis protocol utilizes a Spike-In Kit during preparation of the samples representing a mixture of RNA fragments in different ratios. RNA probes which were synthesized in vitro conditions could be also used to establish how the magnitude of the fluorescent signal reflects the presence of RNA in the sample. A significant disadvantage of this type of standards is a difficulty of their production and the low RNA stability. In accordance with the Agilent protocol, the presence of the T7 promoter is necessary for the synthesis of labeled cRNA during sample preparation procedure. We hypothesized that we can successfully synthesize any RNA sequence having such type of promoter in its start position. Moreover, DNA sequence would serve as a matrix in this case. Using a set of different genes attached downstream of the T7-promoter in the plasmid DNA we have demonstrated in this study that such system can serve as a reliable template for the fluorescent labeled RNA sequence synthesis. In comparison with the routinely used internal RNA based controls, this template is stable, easy to manufacture and can be easily obtained in large quantities. PMID- 28026816 TI - [GSTP1, APC and RASSF1 gene methylation in prostate cancer samples: comparative analysis of MS-HRM method and Infinium HumanMethylation450 BeadChip beadchiparray diagnostic value]. AB - There is a clear need in molecular markers for prostate cancer (PC) risk stratification. Alteration of DNA methylation is one of processes that occur during DN progression. Methylation-sensitive PCR with high resolution melting curve analysis (MS-HRM) can be used for gene methylation analysis in routine laboratory practice. This method requires very small amounts of DNA for analysis. Numerous results have been accumulated on DNA methylation in PC samples analyzed by the Infinium HumanMethylation450 BeadChip (HM450). However, the consistency of MS-HRM results with chip hybridization results has not been examined yet. The aim of this study was to assess the consistency of results of GSTP1, APC and RASSF1 gene methylation analysis in DN biopsy samples obtained by MS-HRM and chip hybridization. The methylation levels of each gene determined by MS-HRM were statistically different in the group of PC tissue samples and the samples without signs of tumor growth. Chip hybridization data analysis confirmed the results obtained with the MS-HRM. Differences in methylation levels between tumor tissue and histologically intact tissue of each sample determined by MS-HRM and chip hybridization, were consistent with each other. Thus, we showed that the assessment of GSTP1, APC and RASSF1 gene methylation analysis using MS-HRM is suitable for the design of laboratory assays that will differentiate the PC tissue from the tissue without signs of tumor growth. PMID- 28026818 TI - [The effect of neuroprotector isatin on binding of some model proteins with beta amyloid peptide: a biosensor study]. AB - The amyloid-beta peptide 1-42 formed during proteolytic processing of the amyloid precursor protein (APP) plays a key role in the development or progression of Alzheimer's disease (AD) and other pathologies associated with formation of protein aggregates in the central nervous system. Recent proteomic profiling of mouse and rat brain preparations by means of beta-amyloid peptide immobilized on Affigel-10 revealed a large group of amyloid-binding proteins (n>80). Many (about 25%) of these proteins were previously identified as isatin-binding proteins. The aim of this study was to validate direct interaction between beta-amyloid peptide and highly purified intact and oxidized peroxiredoxin, M-type pyruvate kinase, alpha-enolase, and the effect of isatin on this interaction. The study performed using SPR-based Biacore 3000 and Biacore X100 biosensors has shown that all the proteins form molecular complexes with immobilized beta-amyloid peptide. The Kd values for these complexes varied from 8.36x10-8 M (peroxiredoxin) to 1.97x10-6 M (alpha-enolase). Oxidative modification of investigated proteins caused opposite effects on complexes of these peptides with beta-amyloid. The endogenous neuroprotector isatin increased dissociation of complexes formed by beta-amyloid peptide with both intact proteins (peroxiredoxin, glyceraldehyde-3-phosphate dehydrogenase) and/or oxidized proteins (peroxiredoxin, pyruvate kinase) used in this study. PMID- 28026819 TI - [Nitrobenzofuroxane derivatives as dual action hiv-1 inhibitors]. AB - Human immunodeficiency virus first type (HIV-1) is a main cause of one of the most dangerous diseases, AIDS. The search for new inhibitors of the virus still remains an urgent task. One approach to suppress the HIV infection is to use a double-acting inhibitors, i.e. inhibitors directed to two stages of the viral life cycle. The catalytic domain of HIV-1 integrase has a similar spatial organization with ribonuclease (RNase H) domain of HIV-1 reverse transcriptase, and approach aimed to create HIV-1 integrase and RNase H double-acting is very promising. In this work we synthesized a series of 6-nitrobenzofuroxane derivatives and studied their ability to inhibit two viral enzymes - integrase and RNase H HIV-1. PMID- 28026820 TI - Mechanisms of angiogenesis in neoplasia. AB - Mechanism of forming new capillary from basal vessels, named angiogenesis, exist under both physiological and pathological conditions. Initiation of this process requires imbalance between proangiogenic and antiangiogenic factors, which can occur for instance under hypoxic conditions. Angiogenesis is complex process which allow tumor cells to proliferate, thus providing tumor to increase its structure. This dependence is highly connected to enhanced migration of tumor cells through blood, which often ends up being an onset of metastasis. It has been proved that capillaries that form during tumor lifetime are different in case of morphology. However, it seems that antigens spread through these blood vessel are the same as antigens produced during physiological angiogenesis. In recent years angiogenesis has become one of the most important targets in therapies used in oncology. Antiangiogenic therapies have proven itself to be very spectacular and promising in treatment of renal and pancreatic cancers or multiple myeloma. Bewacizumab, Sunitinib, Cetuximab and Talidomid are examples of drugs used in such therapies. Tyrosine kinase inhibitors are group that represents most of the drugs of antiangiogenic properties. It is worth mentioning that during administration of such substances spectrum of side effects is observed. However, antiangiogenic therapy is one of the most promising targets in today's oncology. Therefore, it is highly explainable to continue further research in this area. PMID- 28026821 TI - The role of survivin in the diagnosis and therapy of gynaecological cancers. AB - Survivin is a member of the family of apoptosis inhibitors. It regulates several essential cellular processes, i.e. it inhibits apoptosis and promotes cell proliferation, DNA repair and autophagy. Survivin is responsible for development of the cell's resistance to chemotherapy and radiotherapy. Overexpression of survivin generally correlates with poor prognosis. Its presence has been detected in most types of human tumours. Currently much attention is paid to the possibilities of using this protein as a diagnostic marker of cancer or a prognostic factor. Survivin occurs selectively in cancer cells and is essential for their survival. These features make survivin a promising target for cancer therapy. There are some strategies for discovering survivin inhibitors. The most common strategies are antisense nucleotides, RNA interference and small molecule inhibitors of protein. Scientists are also working on using survivin to induce an immune response in cancer patients. This article discusses the potential role of survivin in the diagnosis of various types of cancer, as well as selected strategies for the inhibition of both gene expression and protein function. Detailed knowledge of the mechanisms of survivin action may therefore be crucial for effective antitumor therapy development. PMID- 28026822 TI - The matrix metalloproteinase in larynx cancer. AB - One of the most common carcinoma occurring in the head and neck is laryngeal cancer. Despite the rapid scientific advances in medicine the prognosis for patients with such type of disease is not satisfying. In the last few years matrix metalloproteinases - MMPs and their tissue inhibitors - TIMPs, mostly MMP 2 and MMP-9, arouses a great interest, especially in the process of carcinogenesis. It seems that their impact in the formation and development of laryngeal cancer is significant. MMPs a group of zinc- and calcium- dependent endopeptidases play crucial role extracellular matrix collagen degradation. That are enzymes, that degrade and the basement membrane by facilitating tumor growth, cell migration and tumor invasion. They are implicated in metastasis and angiogenesis potentiate within the tumor. Clear tendency was observed towards the higher MMPs and TIMPs expression in larynx cancer than in the stroma. Recent studies show correlations between increased MMP-2 gene expression in the tumor tissue and clinical status, histopathological grading and metastases occurrence. The similar MMP2 over expression dependence were found on tumor recurrence and survival. Many authors pointed out, significant higher MMP-2 expression as a potential marker of tumor invasiveness and worse prognosis in patients with larynx cancer. However, association of MMP 9 gene expression with laryngeal cancer clinicopathological features and survival of patients are ambiguous. Although, numerous researches show that this relationship does exists. Similar correlations could be found in TIMPs, but further studies are necessary because of small amount of literature. PMID- 28026823 TI - Anti-cytokine therapy for psoriasis - not only TNF-alpha blockers. Overview of reports on the effectiveness of therapy with IL-12/IL-23 and T and B lymphocyte inhibitors. AB - TNF-alpha inhibitors - infliximab, etanercept and adalimumab - can be used in the treatment of psoriasis vulgaris and psoriatic arthritis, along with other inhibitors of proinflammatory cytokines, such as interleukin-12 (IL-12) and IL 23. This paper presents the results of research on the use of biological drugs other than the tumor necrosis factor blockers (TNF-alpha), namely inhibitors of IL-12 and IL-23 (ustekinumab), T-cell inhibitors (alefacept and efalizumab), B cell inhibitors (rituximab), anti-IL-17 agents (secukinumab, ixekizumab, and brodalumab) and IL23p19 inhibitors (guselkumab and tildrakizumab). The paper presents an analysis of the mechanism of action, recommended doses and methods of therapy, taking into account the adverse events associated with the use of anti cytokine therapy. The use of biological drugs is discussed based on a review of the current literature. PMID- 28026824 TI - Nuclear matrix - structure, function and pathogenesis. AB - The nuclear matrix (NM), or nuclear skeleton, is the non-chromatin, ribonucleoproteinaceous framework that is resistant to high ionic strength buffers, nonionic detergents, and nucleolytic enzymes. The NM fulfills a structural role in eukaryotic cells and is responsible for maintaining the shape of the nucleus and the spatial organization of chromatin. Moreover, the NM participates in several cellular processes, such as DNA replication/repair, gene expression, RNA transport, cell signaling and differentiation, cell cycle regulation, apoptosis and carcinogenesis. Short nucleotide sequences called scaffold/matrix attachment regions (S/MAR) anchor the chromatin loops to the NM proteins (NMP). The NMP composition is dynamic and depends on the cell type and differentiation stage or metabolic activity. Alterations in the NMP composition affect anchoring of the S/MARs and thus alter gene expression. This review aims to systematize information about the skeletal structure of the nucleus, with particular emphasis on the organization of the NM and its role in selected cellular processes. We also discuss several diseases that are caused by aberrant NM structure or dysfunction of individual NM elements. PMID- 28026825 TI - Transformation of medicinal plants using Agrobacterium tumefaciens. AB - For many years attempts are made to develop efficient methods for transformation of medicinal plants via Agrobacterium tumefaciens. It is a soil bacteria which possess a natural ability to infect plants in places of injures which results in arise of cancerous growths (crown gall). This is possible thanks a transfer of fragment of Ti plasmid into plant cells and stable integration with a plant genome. Efficiency of medicinal plant transformation depends on many factors for example: Agrobacterium strain, methods and procedures of transformation as well as on plant species, type and age of the explants and regeneration conditions. The main goal of plant transformation is to increase the amount of naturally occurring bioactive compounds and the production of biopharmaceuticals. Genetic plant transformation via bacteria of the genus Agrobacterium is a complex process which requires detailed analysis of incorporated transgene expression and occurs only in the case when the plant cell acquires the ability to regenerate. In many cases, the regeneration efficiency observed in medicinal plants are inefficient after applied transformation procedures. To date there have been attempts of genetic transformation by using A. tumefaciens of medicinal plants belonging to the families: Apocynaceae, Araceae, Araliaceae, Asphodelaceae, Asteraceae, Begoniaceae, Crassulaceae, Fabaceae, Lamiaceae, Linaceae, Papaveraceae, Plantaginaceae, Scrophulariaceae and Solanaceae. PMID- 28026826 TI - Programmed cell death - strategy for maintenance cellular organisms homeostasis. AB - Programmed cell death (PCD) is a cellular suicide process, commonly found in organisms, that is important for elimination unnecessary and damaged cells during development and adaptation to abiotic and biotic environmental stresses. PCD is a complex and precise, genetically controlled cellular process, in opposite to non programmed death, necrosis, in which cells are "killed" by strong abiotic factors. This article shows: the occurrence of PCD during animals and plants ontogenesis, classification of cell death types in these organisms with description of autophagy, apoptosis and necrotic cell death and with discussion on plant cell death by apoptosis. The role of Bcl-2 protein and other proteins involved in the regulation of apoptosis induction and detection in the plant's (whose genomes do not encode these proteins) proteins of analogous function is also discussed. The paper also presents the effects of the expression of animals pro- and anti-apoptotic genes transformed into yeast and plants, and the use of transformed yeast as model to identify in cDNA libraries animal and plant genes involved in regulation of the induction and course of the PCD. PMID- 28026827 TI - Insulin resistance and chronic inflammation. AB - Insulin resistance is a condition of reduced biological response to insulin. Growing evidence indicates the role of the chronic low-grade inflammatory response in the pathogenesis of insulin resistance. Adipose tissue in obesity is characterized by increased lipolysis with the excessive release of free fatty acids, and is also a source of proinflammatory cytokines. Both these factors may inhibit insulin action. Proinflammatory cytokines exert their effect by stimulating major inflammatory NFkappaB and JNK pathways within the cells. Inflammatory processes in other insulin responsive tissues may also play a role in inducing insulin resistance. This paper is an overview of the chronic low grade inflammation in adipose tissue, skeletal muscle, liver and endothelial cells during the development of insulin resistance. PMID- 28026828 TI - Microevolution of BCG substrains. AB - Tuberculosis was, and still is, one of the main causes of morbidity and mortality in the world. Thus it still remains a public health priority. Nonetheless, without a newly developed vaccine, it is rather unlikely to be easily resolved. The only available vaccine against tuberculosis (BCG) has been used for nearly 100 years. Currently a variety of BCG substrains are used by many manufacturers in the world. All these substrains were obtained from a single parental strain of Mycobacterium bovis. Attempts to explain the complete mechanisms of attenuation, as well as tracing the microevolution resulting from the different distribution time and conditions of production of BCG vaccines in the different parts of the world, might explain the differences in the observed efficacy of vaccines produced with different substrains. The most important marker associated with attenuation of virulent M. bovis is the loss of the RD1 region observed in all BCG substrains. Among other attenuation markers, still not completely identified, accumulation of SNP mutations seems to be an important one. The different number of passages and culture conditions of the parental vaccine strain have led to there being about 50 different sister vaccine BCG substrains throughout the world. Among them, there are "early strains", distributed until 1927, and "later strains" with the RD2 deletion obtained during 1927-1961. It has also been found that 22 regions containing 52 genes were lost during the distribution of sister substrains during the period 1924-1966. Genetic differences due to selection pressure, revealing specific microevolutionary traits, may explain the variability in immunogenicity and residual virulence of each vaccine BCG substrain. PMID- 28026829 TI - Retinol-binding protein 4 (RBP4) as the causative factor and marker of vascular injury related to insulin resistance. AB - One of adipokines involved in the development of insulin resistance is retinol binding protein 4(RBP4). The physiological role of RBP4 is transport of retinol from the liver to peripheral tissues. One of the first events related to the excessive visceral fat accumulation is the development of inflammation followed by hormonal adipose tissue dysfunction, including excessive RBP4 production. Reduced density of the membrane-type glucose transporter 4 (GLUT4) is considered as a direct cause for the stimulation of RBP4 release to the circulation by adipocytes. Circulating RBP4 inhibits the signal pathways stimulated by insulin in skeletal muscle cells, resulting in the development of insulin resistance. Drugs stimulating receptor peroxisome proliferator-activated gamma (PPARgamma) - thiazolidinediones - inhibit the production of RBP4 by adipose tissue and increase the insulin sensitivity of the tissues. Increased secretion of RBP4 stimulates the expression of adhesion molecules in the endothelial cells, promoting development of atherosclerosis and arterial hypertension. Population studies demonstrated an association between serum RBP4 in the circulation, and the severity of atherosclerosis and risk of the cardiovascular events and type 2 diabetes. It also appears that the rbp4 gene functional polymorphisms may influence the risk of metabolic complications of obesity, including vascular injury. Therefore, the concentration of RBP4 in the circulation may be considered both as the causative factor and marker of chronic vascular injury. This article summarizes the current state of knowledge on the potential role of RBP4 in the pathogenesis of cardiovascular diseases, particularly related to insulin resistance. PMID- 28026830 TI - Cyclic guanosine monophosphate in the regulation of the cell function. AB - Intracellular concentration of cGMP depends on the activity of guanylate cyclase, responsible for its synthesis, on the activity of cyclic nucleotide degrading enzymes - phosphodiesterases (PDEs). There are two forms of guanylate cyclase: the membrane-bound cyclase and the soluble form. The physiological activators of the membrane guanylate cyclase are natriuretic peptides (NPs), and of the cytosolic guanylate cyclase - nitric oxide (NO) and carbon monoxide (CO). Intracellular cGMP signaling pathways arise from its direct effect on the activity of G protein kinases, phosphodiesterases and cyclic nucleotide dependent cation channels. It has been shown in recent years that cGMP can also affect other signal pathways in cell signaling activity involving Wnt proteins and sex hormones. The increased interest in the research on the role of cGMP, resulted also in the discovery of its role in the regulation of phototransduction in the eye, neurotransmission, calcium homeostasis, platelet aggregation, heartbeat, bone remodeling, lipid metabolism and the activity of the cation channels. Better understanding of the mechanisms of action of cGMP in the regulation of cell function can create new opportunities for the cGMP affecting drugs use in the pharmacotherapy. PMID- 28026831 TI - The role of YKL-40 in a cancerous process. AB - YKL-40 is a secretory protein secreted among others by tumor cells and tumor associated macrophages. Due to the structural homology this protein was classified to chitinases family CLP (chitinase - like protein) and to 18 of glycosyl hydrolase family, but it has no catalytic function. Elevated levels of YKL-40 in serum is observed in the inflammatory diseases of various aetiology and in cancers, such as breast, ovarian, colon or lung. The results of many studies suggest a significant relationship of YKL-40 with progression of cancer: incidence of metastases, shorter relapse-free survival and shorter overall survival. It is believed that YKL-40 may be a prognostic factor of cancer development and the patient's response to the applied therapy. Elevated levels of protein in serum of cancer patients may play a role in angiogenesis, proliferation and migration of tumor cells. Probably the mechanism of this phenomenon is the result of YKL-40 action by FAK and PI3K/AKT signaling pathways. Results obtained so far are largely based on an analysis of the YKL-40 level in the patients' serum and on the assessment of changes in the expression level of this protein in studies in vitro and in vivo. PMID- 28026832 TI - Significance of SYT8 For the Detection, Prediction, and Treatment of Peritoneal Metastasis From Gastric Cancer. AB - OBJECTIVE: To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). BACKGROUND: Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. METHODS: We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. RESULTS: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. CONCLUSIONS: SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC. PMID- 28026833 TI - Antiviral drugs for seasonal influenza 2016-2017. PMID- 28026834 TI - Another insulin glargine (Basaglar) for diabetes. PMID- 28026835 TI - Ustekinumab (Stelara) for Crohn's disease. PMID- 28026836 TI - Tenofovir alafenamide (Vemlidy) for hepatitis B. PMID- 28026837 TI - Trigeminal sensitivity in chronic rhinosinusitis: topographical differences and the effect of surgery. AB - INTRODUCTION: Little is known on endonasal trigeminal sensitivity in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of our study was to investigate changes in trigeminal sensitivity in patients with CRSwNP and the effect of functional endoscopic sinus surgery (FESS) on trigeminal perception. METHODS: A prospective study was performed to investigate the trigeminal sensitivity at three different locations within the nose (anterior septum, anterior lateral wall, middle turbinate) using electrical stimuli. Therefore 45 CRSwNP patients were compared to 30 healthy subjects. Further, the effect of FESS was investigated in 31 patients before and 3 months after surgery. RESULTS: CRSwNP patients had a significantly higher trigeminal threshold at all tested locations than healthy subjects. The lowest trigeminal detection threshold could be shown at the entrance of the nose in healthy subjects and in patients with CRSwNP. Three months after FESS a significant improvement of trigeminal detection threshold was observed at the anterior nasal septum. CONCLUSION: Protective function of the trigeminal system is preserved in CRSwNP patients. FESS seems to show beneficial effects on restoring sentinel function at the entrance of the nose. PMID- 28026838 TI - Predictors of unanticipated admission within 30 days of outpatient sinonasal surgery. AB - OBJECTIVES: To identify predictive factors of readmission after day-case rhinologic surgery. METHODS: A 2-year retrospective chart review of patients scheduled for ambulatory sinonasal surgery in a tertiary medical center was conducted. The operating room and the anesthetic files were screened to identify demographic data, types of procedure, comorbidities and post-operative complications. RESULTS: From January 2014 to January 2016, 924 outpatient sinonasal procedures were identified. The overall readmission rate within the 30 postoperative days was 5.1% (2.9% for overnight hospital stay, 2.2% for unplanned post procedure visit to the hospital via the emergency room, or directly to the surgical unit within 30 days of discharge). Age at least 50 years, surgical duration at least 80 min, endoscopic sinus surgery procedures and postoperative nasal packing were identified as negative predictive factors of readmission. CONCLUSION: Careful scheduling of those higher-risk patients undergoing sinonasal surgery and appropriate postoperative observation should be implemented to improve healthcare quality in an outpatient setting. PMID- 28026840 TI - ? PMID- 28026841 TI - ? PMID- 28026839 TI - [Acute splenic sequestration in children with sickle cell disease--an overview]. AB - Acute splenic sequestration in children with sickle cell disease - an overview Acute splenic sequestration (ASS) is a life-threatening complication of sickle cell disease (SCD). The condition is important to recognize due to the fact that it can occur with previously unknown disease. ASS is one of the most common causes of death in children with SCD and is the result of blood suddenly getting congested in the spleen, resulting in splenomegaly, acute anemia, and hypovolemic shock. Timely and appropriate treatment is essential in preventing death. Episodes of ASS before one year of age are associated with a higher risk of recurrence. There is no established effective treatment for recurrent ASS; however, there is evidence that all children with SCD should be treated with hydroxyurea. In Sweden, our recommendation is to evaluate the indications for splenectomy after the first episode of ASS. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, and all children with SCD should be evaluated with regard to the potential success of HSCT. This article presents an overview of the condition with Swedish recommendations. PMID- 28026842 TI - [The point of virtual care]. PMID- 28026843 TI - ? PMID- 28026844 TI - ? PMID- 28026845 TI - Double inferior vena cava with three shunts: a rare anomaly with important implications for surgeons. AB - Inferior vena cava (IVC) is the largest single vein that collects systemic venous blood from the lower part of the body except the gut and drains into the right atrium. Double IVC is a rare anomaly in humans and usually is discovered incidentally during the interventional radiological procedures or routine cadaveric dissection. Here we report a rare case of unusual observations in an adult female Thai cadaver with a duplicated left IVC with three short venous shunts and a variant pattern of the hemiazygos vein. Also included in this case was the presence of unilateral double renal vein on the right kidney. This type of anatomic variation of the great vein has never been reported before. A detailed description of these variations is useful and essential for the surgeons during approaching the retroperitoneal region. PMID- 28026846 TI - Vascular anatomy of the thenar eminence: its relevance to a pedicled or free thenar flap. AB - BACKGROUND: The aim of this study was to clarify the arterial supply of the skin covering the prominent part of the thenar eminence in order to describe the possibility and potential for harvesting a pedicled or a free flap from the thenar eminence. MATERIALS AND METHODS: The arteries were studied in 30 post mortem specimens of human hands; 3 previously perfused with 4% formaldehyde solution, and injected with black India ink, and 27 injected with methyl methacrylate and afterwards corroded in 40% potassium hydroxide solution. RESULTS: In all hands we found two little palmar arteries coming from the anatomical snuff-box portion of the radial artery. We labelled the first (proximal) branch as the middle thenar artery, because it supplies the middle third of the thenar eminence skin. Its diameter varied from 0.25 to 0.55 mm (mean 0.4 mm). The distal, more prominent branch of the radial artery, vascularised the lateral third of the thenar eminence skin, and was named the lateral thenar artery; its diameter ranged from 0.40 to 0.90 mm (mean 0.67 mm). The superficial palmar branch of the radial artery, always present, was classified as: hypoplastic, average or prominent, with a diameter ranging from 0.8 to 2.7 mm (mean 1.47 mm). CONCLUSIONS: Three individually developed branches of the radial artery supplied the skin of the thenar eminence. Cutaneous branches of these three arteries were interconnected via anastomotic vessels. PMID- 28026847 TI - The challenge of extra-intra craniometry: a computer-assisted three-dimensional approach on the equine skull. AB - BACKGROUND: The topographical correlations between certain extracranial and intracranial osseous points of interest (POIs), and their age-related changes, are indispensable to know for a diagnostical or surgical access to intracranial structures; however, they are difficult to assess with conventional devices. MATERIALS AND METHODS: In this pilot study, the 3-dimensional coordinates of extra-/intracranial POIs were determined, thus avoiding perspective distortions that used to be intrinsic problems in 2-dimensional morphometry. The data sets were then analysed by creating virtual triangles. The sizes, shapes, and positions of these triangles described the extent and the directions of the age related shifts of the POIs. A selection of extracranial and intracranial POIs were marked on half skulls of four warmblood horses in two age groups (young: 6 weeks, n = 2; old: 14 and 17 years, n = 2). The x-, y-, and z-coordinates of these POIs were determined with a measurement arm (FaroArm Fusion, FARO Europe(r)). Direct distances between the POIs as well as their indirect distances on the x-, y-, and z-axis, and angles were calculated. RESULTS: The analysed virtual triangles revealed that some parts of the skull grew in size, but did not change in shape/relative proportions (proportional type of growth, as displayed by POI A and POI B at the Arcus zygomaticus). The same POIs (A and B) remained in a very stable relationship to their closest intracranial POI at the Basis cranii on the longitudinal axis, however, shifted markedly in the dorso-lateral direction. In contrast, a disproportional growth of other parts of the cranium was, for example, related to POI C at the Crista nuchae, which shifted strongly in the caudal direction with age. A topographically stable reference point (so called anchor point) at the Basis cranii was difficult to determine. CONCLUSIONS: Two candidates (one at the Synchondrosis intersphenoidalis, another one at the Synchondrosis sphenooccipitalis) were relatively stable in their positions. However, the epicentre of (neuro-)cranial growth could only be pinpointed to an area between them. PMID- 28026848 TI - Three-dimensional computed tomography angiography of the pulmonary veins and their anatomical variations: involvement in video-assisted thoracoscopic surgery lobectomy for lung cancer. AB - BACKGROUND: Identification and section of pulmonary veins are an essential part of anatomical pulmonary resections. Intraoperative misunderstandings of pulmonary venous anatomy can lead to serious complications such as bleeding and delayed lung infarction or necrosis. We evaluated principally the rate of pulmonary veno us anatomical variations, and secondarily the reliability and clinical outcomes of a preoperative morphological analysis. MATERIALS AND METHODS: Between November 2012 and October 2013, we studied 100 consecutive patients with highly suspected or diagnosed stage I-II primitive lung cancer lesion. The surgical procedure initially retained was video-assisted thoracoscopic surgery (VATS) pulmonary resections and we studied preoperatively the proximal pulmonary venous anatomy using 64 channels multi- -detector computed tomography (CT)-scan angiography to describe the venous anatomical variations. RESULTS: There were 65 men and 35 women with a mean age of 63 years. A pulmonary venous anatomical variation was present in 36 (36%) patients, and right-sided anatomical variations were more frequent than on left-sided ones (25% vs. 11%). The most frequent variation encountered on the right side was the existence of three separate pulmonary veins (16%), and on the left side a single pulmonary vein (8%). Surgical conversion occurred in 21% and we didn't experience a pulmonary venous lesion (0%) or a post operative lung infarction (0%). CONCLUSIONS: We described pulmonary venous anatomical variations and their frequency. Anatomical variations exist and preoperative assessment of pulmo-nary venous anatomy using CT scan is a useful tool in VATS lobectomy to avoid unnecessary extension of pulmonary resections or iatrogenic complications in lung cancer surgery. PMID- 28026850 TI - Diastema size and type of upper lip midline frenulum attachment. AB - BACKGROUND: Diastema is a space between teeth. The most often is maxillary midline diastema between upper central incisors. One of the main causes of diastema is enlarged upper lip frenulum attachment. The aim of the study was to assess frenulum attachment in patients with diastema and investigate if type of upper lip frenulum attachment has an impact on the width of diastema. MATERIALS AND METHODS: Upper lip frenulum attachment was assessed clinically in two groups of adult patients: study group with diastema and control group without diastema. Moreover the width of diastema was measured on plaster models of dentition. The results were statistically analysed. RESULTS: In study material the most often was diastema in range more than 2 mm. There were statistically significant differences between study and control group in upper lip frenulum attachment (p < 0.05). Normal frenulum attachment (mucosal or gingival) was typical for group without diastema, but enlarged frenulum (papillary or papilla penetrating) was characteristic for diastema group. Type of frenulum had significant (p < 0.05) impact to the width of diastema. Small diastema (<= 2 mm) more often coexisted with normal frenulum. Oversized frenulum was observed in the big diastema (> 2 mm). CONCLUSIONS: Patients with diastema have more often oversized upper lip frenulum attachment then patients without diastema. The most often type of frenulum in patients with diastema is papillary and papilla penetrating type. Type of upper lip frenulum attachment has an impact to the size of diastema. PMID- 28026849 TI - Prevalence and distribution of the fabella: a radiographic study in Turkish subjects. AB - BACKGROUND: The purpose of this study is to examine the plain knee radiographs in Turkish subjects in order to determine the prevalence of the fabella and analyse the differences between age, gender, laterality and its symmetry pattern. MATERIALS AND METHODS: Bilateral antero-posterior and lateral knee radiographs of 500 patients (250 male and 250 female subjects, 1000 knee radiographs) were randomly selected from the clinical database and retrospectively evaluated. Data on patient age, gender, and knee laterality (right-left) were evaluated from hospital records. The differences between the sesamoid bones at a particular location and the side, sex and age groups were analysed. RESULTS: The overall prevalence of the fabella (unilateral or bilateral) was 22.8% (114 subjects). The fabella was present unilaterally in 38 (7.6%) subjects, while it was present bilaterally in 76 (15.2%) subjects. The prevalence of the fabella was similar between the body sides. The prevalence of the fabella was also similar between genders (unilateral or bilateral cases) and age groups. CONCLUSIONS: We examined the prevalence, symmetry pattern, age and gender differences in Turkish population. It is the first study performed on Turkish population with the largest sample in current literature. Prevalence of fabella is found to be 22.8% which is quite similar with other Caucasian ethnic populations. PMID- 28026851 TI - The Terminologia Anatomica matters: examples from didactic, scientific, and clinical practice. AB - The proper usage of the anatomical terminology is of paramount importance to all medical professionals. Although a multitude of studies have been devoted to issues associated with the use and application of the recent version of the anatomical terminology in both theoretical medicine and clinical practice, there are still many unresolved problems such as confusing terms, inconsistencies, and errors, including grammar and spelling mistakes. The aim of this article is to describe the current situation of the anatomical terminology and its usage in practice, as well as explain why it is so important to use precise, appropriate, and valid anatomical terms during the everyday communication among physicians from all medical branches. In this review, we discuss some confusing, obsolete, and erroneous terms that are still commonly used by many clinicians, and surgeons in particular, during the process of diagnosis and treatment. The use of these ambiguous, erroneous, and obsolete terms enhances the risk of miscommunication. We also provide some edifying examples from everyday clinical practice. PMID- 28026852 TI - Altered topography of systemic veins following lung tissue resection: the effect on de novo cardiac implantable electronic device implantation. AB - Venous anomalies discovered on cardiac implantable electronic device (CIED) implantation may hinder both the insertion of cardiac leads and the selection of their optimal intraventricular placement. Such venous anomalies may be a result of congenital vascular defects, e.g. anomalies of the foetal venous system, or be a consequence of earlier cardio- or thoracosurgical procedures. In the case of the latter, the extent of morphometric changes to mediastinal structures may depend on the extent of prior lung tissue resection. This paper presents 3 cases of CIED implantation procedures performed in patients with systemic veins topographically and morphometrically altered post lung surgery. PMID- 28026853 TI - LYVE1 and PROX1 in the reconstruction of hepatic sinusoids after partial hepatectomy in mice. AB - BACKGROUND: Revascularisation is crucial to liver regeneration after liver injury, but the process remains unclear. This study investigated changes in the levels and distribution of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) and prospero homeobox protein 1 (PROX1) in liver tissue sections after partial hepatectomy in mice. MATERIALS AND METHODS: Mice were subjected to partial hepatectomy. Control animals were sham-operated. From days 1 through 8, the remaining liver tissues were collected from 8 animals each day. Histology showed that after partial hepatectomy, the remaining liver tissue samples underwent initial degeneration and then hepatocyte proliferation and regeneration. Using immunohistochemical analysis, relative to the control a significantly higher number of vascular endothelial growth factor A (VEGFA) positive hepatocytes was observed on days 4 and 5 after partial hepatectomy. RESULTS: LYVE1 was mainly present in the liver sinusoidal endothelial cells and the number of LYVE1-positive cells gradually increased with time. PROX1 was detected in some of the hepatocytes, but liver sinusoidal endothelial cells, artery, and vein were negative for PROX1 staining in the early stage after liver injury. The presence of PROX1 could be observed in some central veins as well as liver sinusoidal endothelial cells. Seven days after partial hepatectomy, colocalisation of PROX1 and LYVE1 was observed in liver sinusoidal endothelial cells and veins. CONCLUSIONS: This study revealed the dynamic process of revascularisation and hepatic sinusoid reconstruction during liver regeneration in response to liver injury in mice. PROX1 and LYVE1 may participate in this process and serve as biomarkers for identification of newly formed liver sinusoidal endothelial cells. PMID- 28026854 TI - Investigations on renal vascularisation pathology in the Polish population. 1. Incidence of multiple kidney arteries. AB - BACKGROUND: The aim of the study was to determine the incidence of multiple kidney arteries in the Polish population. MATERIALS AND METHODS: The study group comprised 924 deceased patients aged between 1 month and 94 years (mean age: 63.4 +/- 22.4 years) who were subject to aortonephrography and sample preparation. The ratio of male to female patients was 479:445. RESULTS: Multiple kidney arteries were observed in 44.8% male and 31.5% female patients (p = 0.004). Considering male patients, right multiple kidney arteries were diagnosed in 24.4%, and left multiple kidney arteries in 31.3% of cases (p = 0.017). In female patients, right multiple kidney arteries were observed in 17.8% of cases, and left multiple kidney arteries in 19.6% of cases (p = 0.49). CONCLUSIONS: The incidence of multiple kidney arteries in the Polish population is a frequent phenomenon, and should be considered in case of urological surgery and kidney transplantation. PMID- 28026855 TI - Does hormonal therapy for fertility preservation affect the survival of young women with early-stage endometrial cancer? AB - BACKGROUND: The incidence of endometrial cancer among young women is increasing. Some patients with low-grade endometrial cancer receive hormone therapy (HT) before surgery to preserve fertility. It is unclear whether this adversely affects survival. METHODS: Patients with localized, low-grade endometrial cancer who were aged <45 years were selected from the Surveillance, Epidemiology, and End Results database between 1993 and 2012. Propensity score matching was used to select comparable groups receiving HT or primary surgery. Cancer-specific and overall survival were measured using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (95% CIs) were estimated using Cox models adjusted for age, period of diagnosis, marital status, race, tumor grade, morphology, and previous radiotherapy. RESULTS: A total of 6339 women were included in the current study cohort, 161 of whom initially received HT and 6178 of whom received primary surgery. After 15 years of follow-up, all-cause mortality did not differ between the groups (HT group: 14.1% [95% CI, 6.7%-28.4%] and propensity score-matched primary surgery group: 9.3% [95% CI, 4.1%-20.5%]). Cancer-specific mortality appeared higher in patients treated with HT compared with those treated with primary surgery (9.2% [95% CI, 3.4%-24.0%] vs 2.1% [95% CI, 1.5%-2.8%]). However, this difference was driven by 3 late deaths in the HT group. Sensitivity analyses using a broader definition of cancer-specific mortality provided no statistical evidence of a survival difference between the treatment groups. The hazard ratio for the overall risk of death was 1.45 (95% CI, 0.44-4.74). CONCLUSIONS: Based on this population-based cohort, young patients with low-grade endometrial cancer appear to have excellent survival, regardless of the primary therapy chosen (HT vs primary surgery). The current selection of patients for HT to preserve fertility, which is managed carefully by experienced clinicians, does not appear to significantly worsen clinical outcomes. Cancer 2017;123:1545-1554. (c) 2017 American Cancer Society. PMID- 28026856 TI - Gene tracing analysis reveals the contribution of neural crest-derived cells in pituitary development. AB - The anterior pituitary originates from the adenohypophyseal placode. Both the preplacode region and neural crest (NC) derive from subdivision of the neural border region, and further individualization of the placode domain is established by a reciprocal interaction between placodal precursors and NC cells (NCCs). It has long been known that NCCs are present in the adenohypophysis as interstitial cells. A recent report demonstrated that NCCs also contribute to the formation of pericytes in the developing pituitary. Here, we attempt to further clarify the role of NCCs in pituitary development using P0-Cre/EGFP reporter mice. Spatiotemporal analyses revealed that GFP-positive NCCs invaded the adenohypophysis in a stepwise manner. The first wave was detected on mouse embryonic day 9.5 (E9.5), when the pituitary primordium begins to be formed by adenohypophyseal placode cells; the second wave occurred on E14.5, when vasculogenesis proceeds from Atwell's recess. Finally, fate tracing of NCCs demonstrated that NC-derived cells in the adenohypophysis terminally differentiate into all hormone-producing cell lineages as well as pericytes. Our data suggest that NCCs contribute to pituitary organogenesis and vasculogenesis in conjunction with placode-derived pituitary stem/progenitor cells. PMID- 28026861 TI - Diagnosis and treatment of epidural metastases. AB - Epidural metastases occur in 5% to 10% of cancer patients and represent a neurological emergency. Patients most commonly present with an acute onset of motor weakness, and restoration of neurological function is critically dependent on prompt diagnosis and treatment. This review discusses the clinical, epidemiological, and radiological features associated with epidural metastases and resulting spinal cord compression. Moreover, current treatment paradigms are reviewed. The timely initiation of radiation as well as surgery in select cases is critical for preserving neurological function and achieving local tumor control and pain control. Future studies investigating surgical and radiation treatment for metastatic epidural cord compression are urgently needed. Cancer 2017;123:1106-1114. (c) 2016 American Cancer Society. PMID- 28026860 TI - Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study. AB - BACKGROUND: We recently reported that peroxisome proliferator-activated receptor gamma agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add-on therapy to imatinib would impact CML residual disease, as assessed by BCR-ABL1 transcript quantification. METHODS: CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR4.5 ) defined by BCR-ABL1/ABL1IS RNA levels <= 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR4.5 over 12 months. RESULTS: Twenty-four patients were included (age range, 24-79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR4.5 was 56% (95% confidence interval, 37%-76%) by 12 months, despite a wide range of therapy duration (1.9-15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients. CONCLUSION: Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009-011675-79). Cancer 2017;123:1791-1799. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 28026862 TI - Evaluation of the accuracy of common weight estimation formulae in a Zambian paediatric surgical population. AB - Limited resources and access to healthcare in sub-Saharan Africa are associated with high rates of malnourished children, although many countries globally are demonstrating increasing childhood obesity. This study evaluated how well current age- or height-based formulae estimate the weight of children undergoing surgery in Zambia. All children under 14 years of age presenting for elective surgery at the University Teaching Hospital, Lusaka, had both height and weight measured. Their actual weight was compared against estimated weight from various formulae. The Broselow tape outperformed all the age-based formulae, demonstrating the lowest median percentage error of -5.8%, with 46.0% of estimates falling within 10% of the actual measured weight (p < 0.001). Of the 1111 children who were eligible for World Health Organization growth standard appraisal, 88 (8%) met the weight criteria for severe acute malnutrition. Our results are consistent with other studies in finding that the Broselow tape is the best estimator of weight in a lower middle-income country, followed by the original Advanced Paediatric Life Support formula if the Broselow tape is unavailable. PMID- 28026863 TI - Early and late brain signatures of emotional prosody among individuals with high versus low power. AB - Using ERPs, we explored the relationship between social power and emotional prosody processing. In particular, we investigated differences at early and late processing stages between individuals primed with high or low power. Comparable to previously published findings from nonprimed participants, individuals primed with low power displayed differentially modulated P2 amplitudes in response to different emotional prosodies, whereas participants primed with high power failed to do so. Similarly, participants primed with low power showed differentially modulated amplitudes in response to different emotional prosodies at a later processing stage (late ERP component), whereas participants primed with high power did not. These ERP results suggest that high versus low power leads to emotional prosody processing differences at the early stage associated with emotional salience detection and at a later stage associated with more in-depth processing of emotional stimuli. PMID- 28026864 TI - Complications, hospital length of stay, and readmission after total laryngectomy. AB - BACKGROUND: The purpose of this study was to describe the 30-day incidence of complications after total laryngectomy (TL) in a high-volume institution and their impact on the hospital length of stay (LOS) and readmission rates. METHODS: A retrospective cohort study of all patients who underwent TL at The University of Texas MD Anderson Cancer Center from January 1, 2010 through June 30, 2013 was conducted. The patient demographics, treatment history, LOS, and 30-day post-TL complications and readmissions were extracted from the medical record. Univariate associations were analyzed, and stepwise backward selection methods were used to fit multivariate models. RESULTS: Two hundred forty-five patients were included. Complications occurred in 83 patients (33.9%) and included 3 deaths (1.2%). Wound complications occurred in 53 patients (21.6%), and 34 were pharyngocutaneous fistulas (PCFs; 13.9% overall). Thirty-four patients (13.9%) were readmitted within 30 days. A multivariate analysis revealed the following: wound complications were associated with former (odds ratio [OR], 5.1; P = .03) and current smokers (OR, 5.8; P = .02), PCFs were associated with prior wide-field radiation (OR, 3.1; P = .01) but not prior narrow-field (larynx-only) radiation (OR, 1.4; P = .61), LOS was associated with the type of flap (P = .002) and postoperative hematomas (P = .05), and readmissions were associated with preoperative hypoalbuminemia (P = .003) and postoperative wound complications (P < .001). CONCLUSIONS: Complications occurred in approximately one-third of TL patients and particularly in patients with poor wound-healing risk factors such as prior smoking and radiation. As expected, LOS was longer among reconstructed patients. Readmission was associated with hypoalbuminemia and postoperative wound complications. These data can inform quality improvement efforts and the counseling of high-risk patients undergoing TL. Cancer 2017;123:1760-1767. (c) 2016 American Cancer Society. PMID- 28026865 TI - Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer. AB - BACKGROUND: Skeletal-related events (SREs) are common complications of bone metastatic castration-resistant prostate cancer (mCRPC). To the authors' knowledge, there are limited data regarding which factors predict SREs. The authors identified risk factors for SREs in men with bone mCRPC using characteristics commonly available in the medical record. METHODS: Data from 454 patients with nonmetastatic CRPC were identified from 2 Veteran Affairs Medical Centers from 2000 through 2013. Among these men, 233 (51%) developed bone metastases during follow-up and represented the study cohort. First occurrence of an SRE was abstracted from the medical records. A stepwise multivariable Cox model was used to select the strongest predictors of time to SRE. RESULTS: The median age of the patients at the time of diagnosis of bone mCRPC was 75 years (interquartile range, 68-81 years), and there were 153 nonblack patients (66%). During follow-up (median, 7.8 months [interquartile range, 2.9-18.3 months]), 88 patients (38%) had an SRE. On univariable analysis, more recent year of metastasis (hazard ratio [HR], 0.91), prostate-specific antigen doubling time of >=9 months versus <9 months (HR, 0.50), and bone pain (HR, 3.34) were all found to be associated with SRE risk. On multivariable analysis, year of metastasis (HR, 0.93), biopsy Gleason score of 7 versus <=6 (HR, 1.74), radiotherapy as the primary localized treatment versus none (HR, 2.33), and bone pain (HR, 3.64) were associated with SRE risk. The area under the curve for a multivariable model based upon these risk factors was 0.744. CONCLUSIONS: The authors identified several significant predictors of SREs among men with mCRPC. In particular, men with bone pain are at high risk of an SRE. If confirmed, future trials should focus on prolonging life and reducing SRE risk in patients with mCRPC with bone pain. Cancer 2017;123:1528-1535. (c) 2017 American Cancer Society. PMID- 28026866 TI - Comment on 'Annotated checklist of the living sharks, batoids and chimaeras (Chondrichthyes) of the world, with a focus on biogeographical diversity by Weigmann (2016)'. PMID- 28026867 TI - Heart rate, health, and hurtful behavior. AB - Hostility is a risk factor for cardiovascular events. When challenged, individuals high on hostility exhibit a hyperreactive psychophysiological response to stressors, thereby increasing risk for developing cardiovascular disease. However, low resting heart rate (HR) is associated with physical aggression and hostility in children, adolescents, and adults. Based on a community sample of 296 men (mean age = 32.0), we (a) address whether aggression/hostility relates to physical health through relationships with cardiovascular levels at rest and in response to stressors, and (b) determine how relations between aggression and health are altered by including psychophysiological indices in statistical models. The Cook-Medley cynical/hostile attitudes and the Buss-Perry physical aggression and hostility measures assessed aggression. Health was assessed as systolic blood pressure (SBP), report of medical conditions, and a metabolic composite. Reactivity to stressors was assessed with HR, SBP, and diastolic blood pressure. Aggression was negatively related to both resting HR and reactivity. High resting HR and reactivity were, however, positively related to poor health. Thus, the relationship between aggression and HR and reactivity suppressed an overall relationship between high aggression/hostility and poor health. In the presence of covariates for socioeconomic status, race, health behaviors, and medications, the relationship between aggression and health was significantly strengthened when HR level and reactivity were included in models. In sum, at early midlife, low HR among aggressive and hostile individuals is related to less health risk. Aggression and hostility have a deleterious influence on health, but primarily among individuals with higher HR and possibly greater cardiovascular reactivity. PMID- 28026869 TI - The Relationship Between Perfectionism and Psychopathology: A Meta-Analysis. AB - OBJECTIVE: The clinical significance of 2 main dimensions of perfectionism (perfectionistic strivings and perfectionistic concerns) was examined via a meta analysis of studies investigating perfectionism in the psychopathology literature. METHOD: We investigated relationships between psychopathology outcomes (clinical diagnoses of depression, anxiety disorders, obsessive compulsive disorder, and eating disorders; symptoms of these disorders; and outcomes related to psychopathology, such as deliberate self-harm, suicidal ideation, and general distress) and each perfectionism dimension. The relationships were examined by evaluating (a) differences in the magnitude of association of the 2 perfectionism dimensions with psychopathology outcomes and (b) subscales of 2 common measures of perfectionism. RESULTS: A systematic literature search retrieved 284 relevant studies, resulting in 2,047 effect sizes that were analysed with meta-analysis and meta-regression while accounting for data dependencies. CONCLUSION: Findings support the notion of perfectionism as a transdiagnostic factor by demonstrating that both dimensions are associated with various forms of psychopathology. PMID- 28026868 TI - Degeneracy in the regulation of short-term plasticity and synaptic filtering by presynaptic mechanisms. AB - KEY POINTS: We develop a new biophysically rooted, physiologically constrained conductance-based synaptic model to mechanistically account for short-term facilitation and depression, respectively through residual calcium and transmitter depletion kinetics. We address the specific question of how presynaptic components (including voltage-gated ion channels, pumps, buffers and release-handling mechanisms) and interactions among them define synaptic filtering and short-term plasticity profiles. Employing global sensitivity analyses (GSAs), we show that near-identical synaptic filters and short-term plasticity profiles could emerge from disparate presynaptic parametric combinations with weak pairwise correlations. Using virtual knockout models, a technique to address the question of channel-specific contributions within the GSA framework, we unveil the differential and variable impact of each ion channel on synaptic physiology. Our conclusions strengthen the argument that parametric and interactional complexity in biological systems should not be viewed from the limited curse-of-dimensionality standpoint, but from the evolutionarily advantageous perspective of providing functional robustness through degeneracy. ABSTRACT: Information processing in neurons is known to emerge as a gestalt of pre- and post-synaptic filtering. However, the impact of presynaptic mechanisms on synaptic filters has not been quantitatively assessed. Here, we developed a biophysically rooted, conductance-based model synapse that was endowed with six different voltage-gated ion channels, calcium pumps, calcium buffer and neurotransmitter-replenishment mechanisms in the presynaptic terminal. We tuned our model to match the short-term plasticity profile and band-pass structure of Schaffer collateral synapses, and performed sensitivity analyses to demonstrate that presynaptic voltage-gated ion channels regulated synaptic filters through changes in excitability and associated calcium influx. These sensitivity analyses also revealed that calcium- and release-control mechanisms were effective regulators of synaptic filters, but accomplished this without changes in terminal excitability or calcium influx. Next, to perform global sensitivity analysis, we generated 7000 randomized models spanning 15 presynaptic parameters, and computed eight different physiological measurements in each of these models. We validated these models by applying experimentally obtained bounds on their measurements, and found 104 (~1.5%) models to match the validation criteria for all eight measurements. Analysing these valid models, we demonstrate that analogous synaptic filters emerge from disparate combinations of presynaptic parameters exhibiting weak pairwise correlations. Finally, using virtual knockout models, we establish the variable and differential impact of different presynaptic channels on synaptic filters, underlining the critical importance of interactions among different presynaptic components in defining synaptic physiology. Our results have significant implications for protein-localization strategies required for physiological robustness and for degeneracy in long-term synaptic plasticity profiles. PMID- 28026870 TI - Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma. AB - BACKGROUND: Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers. METHODS: In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel. RESULTS: In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B-Raf proto-oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF-mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD-L1 (56%) and PD-1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had KIT mutations, wild-type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A). CONCLUSIONS: The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333-1344. (c) 2016 American Cancer Society. PMID- 28026872 TI - Understanding Outcomes in a Randomized Controlled Trial of a Ward-based Intervention on Psychiatric Inpatient Wards: A Qualitative Analysis of Staff and Patient Experiences. AB - OBJECTIVE: Team formulation is advocated to improve quality of care in mental health care and evidence from a recent U.K.-based trial supports its use in inpatient settings. This study aimed to identify the effects of formulation on practice from the perspectives of staff and patient participating in the trial, including barriers and enhancers to implementing the intervention. METHOD: We carried out semistructured interviews with 57 staff and 20 patients. Data were analyzed using thematic analysis. RESULTS: Main outcomes were: improved staff understanding of patients, better team collaboration and increased staff awareness of their own feelings. Key contextual factors were as follows: overcoming both staff and patient anxiety, unwelcome expert versus collaborative stance, competing demands, and management support. CONCLUSION: Team formulation should be implemented to improve quality of care in inpatient settings and larger definitive trials should be carried out to assess the effect of this intervention on patient outcomes. PMID- 28026871 TI - Radiation therapy dose is associated with improved survival for unresected anaplastic thyroid carcinoma: Outcomes from the National Cancer Data Base. AB - BACKGROUND: The outcomes of patients with unresected anaplastic thyroid carcinoma (ATC) from the National Cancer Data Base (NCDB) were assessed, and potential correlations were explored between radiation therapy (RT) dose and overall survival (OS). METHODS: The study cohort was comprised of patients who underwent either no surgery or grossly incomplete resection. Correlates of OS were explored using univariate analysis and multivariable analysis (MVA). RESULTS: In total, 1288 patients were analyzed. The mean patient age was 70.2 years, 59.7% of patients were women, and 47.6% received neck RT. The median OS was 2.27 months, and 11% of patients remained alive at 1 year. A positive RT dose-survival correlation was observed for the entire study cohort, for those who received systemic therapy, and for those with stage IVA/IVB and IVC disease. On MVA, older age (hazard ratio [HR], 1.317; 95% confidence interval [CI], 1.137-1.526), >= 1 comorbidity (HR, 1.587; 95% CI, 1.379-1.827), distant metastasis (HR, 1.385; 95% CI, 1.216-1.578), receipt of systemic therapy (HR, 0.637; 95% CI, 0.547-0.742), and receipt of RT compared with no RT (<45 grays [Gy]:HR, 0.843; 95% CI, 0.718 0.988; 45-59.9 Gy: HR, 0.596; 95% CI, 0.479-0.743; 60-75 Gy: HR, 0.419; 95% CI, 0.339-0.517) correlated with OS. The RT dose-survival correlation for patients who received higher (60-75 Gy) versus lower (45-59.9 Gy) therapeutic doses was confirmed by propensity-score matching. CONCLUSIONS: Survival was poor in this cohort of patients with unresected ATC, and more effective therapies are needed. However, the association of RT dose with OS highlights the importance of identifying patients with unresected ATC who may still yet benefit from multimodal locoregional treatment that incorporates higher dose RT. Cancer 2017;123:1653-1661. (c) 2017 American Cancer Society. PMID- 28026873 TI - Reply to Borsa (2017): Comment on 'Annotated checklist of the living sharks, batoids and chimaeras (Chondrichthyes) of the world, with a focus on biogeographical diversity by Weigmann (2016)'. PMID- 28026874 TI - The influence of leaf size and shape on leaf thermal dynamics: does theory hold up under natural conditions? AB - Laboratory studies on artificial leaves suggest that leaf thermal dynamics are strongly influenced by the two-dimensional size and shape of leaves and associated boundary layer thickness. Hot environments are therefore said to favour selection for small, narrow or dissected leaves. Empirical evidence from real leaves under field conditions is scant and traditionally based on point measurements that do not capture spatial variation in heat load. We used thermal imagery under field conditions to measure the leaf thermal time constant (tau) in summer and the leaf-to-air temperature difference (?T) and temperature range across laminae (Trange ) during winter, autumn and summer for 68 Proteaceae species. We investigated the influence of leaf area and margin complexity relative to effective leaf width (we ), the latter being a more direct indicator of boundary layer thickness. Normalized difference of margin complexity had no or weak effects on thermal dynamics, but we strongly predicted tau and ?T, whereas leaf area influenced Trange . Unlike artificial leaves, however, spatial temperature distribution in large leaves appeared to be governed largely by structural variation. Therefore, we agree that small size, specifically we , has adaptive value in hot environments but not with the idea that thermal regulation is the primary evolutionary driver of leaf dissection. PMID- 28026875 TI - The evidence for and against different modes of tumour cell extravasation in the lung: diapedesis, capillary destruction, necroptosis, and endothelialization. AB - The development of lung metastasis is a significant negative prognostic factor for cancer patients. The extravasation phase of lung metastasis involves interactions of tumour cells with the pulmonary endothelium. These interactions may have broad biological and medical significance, with potential clinical implications ranging from the discovery of lung metastasis biomarkers to the identification of targets for intervention in preventing lung metastases. Because of the potential significance, the mechanisms of tumour cell extravasation require cautious, systematic studies. Here, we discuss the literature pertaining to the proposed mechanisms of extravasation and critically compare a recently proposed mechanism (tumour cell-induced endothelial necroptosis) with the already described extravasation mechanisms in the lung. We also provide novel data that may help to explain the underlying physiological basis for endothelialization as a mechanism of tumour cell extravasation in the lung. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28026876 TI - Variability of ICA decomposition may impact EEG signals when used to remove eyeblink artifacts. AB - Despite the growing use of independent component analysis (ICA) algorithms for isolating and removing eyeblink-related activity from EEG data, we have limited understanding of how variability associated with ICA uncertainty may be influencing the reconstructed EEG signal after removing the eyeblink artifact components. To characterize the magnitude of this ICA uncertainty and to understand the extent to which it may influence findings within ERP and EEG investigations, ICA decompositions of EEG data from 32 college-aged young adults were repeated 30 times for three popular ICA algorithms. Following each decomposition, eyeblink components were identified and removed. The remaining components were back-projected, and the resulting clean EEG data were further used to analyze ERPs. Findings revealed that ICA uncertainty results in variation in P3 amplitude as well as variation across all EEG sampling points, but differs across ICA algorithms as a function of the spatial location of the EEG channel. This investigation highlights the potential of ICA uncertainty to introduce additional sources of variance when the data are back-projected without artifact components. Careful selection of ICA algorithms and parameters can reduce the extent to which ICA uncertainty may introduce an additional source of variance within ERP/EEG studies. PMID- 28026877 TI - School-based education programmes for the prevention of unintentional injuries in children and young people. AB - BACKGROUND: Unintentional injuries are the leading cause of death in children aged four to 18 years and are a major cause of ill health. The school setting offers the opportunity to deliver preventive interventions to a large number of children and has been used to address a range of public health problems. However, the effectiveness of the school setting for the prevention of different injury mechanisms in school-aged children is not well understood. OBJECTIVES: To assess the effects of school-based educational programmes for the prevention of injuries in children and evaluate their impact on improving children's safety skills, behaviour and practices, and knowledge, and assess their cost-effectiveness. SEARCH METHODS: We ran the most recent searches up to 16 September 2016 for the following electronic databases: Cochrane Injuries Group Specialised Register; Cochrane Central Register of Controlled Trials; Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations; Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R); Embase and Embase Classic (Ovid); ISI Web of Science: Science Citation Index Expanded; ISI Web of Science Conference Proceedings Citation Index Science; ISI Web of Science: Social Sciences Citation Index; ISI Web of Science: Conference Proceedings Citation Index - Social Sciences & Humanities; and the 14 October 2016 for the following electronic databases: Health Economics Evaluations Database (HEED); Health Technology Assessment Database (HTA); CINAHL Plus (EBSCO); ZETOC; LILACS; PsycINFO; ERIC; Dissertation Abstracts Online; IBSS; BEI; ASSIA; CSA Sociological Abstracts; Injury Prevention Web; SafetyLit; EconLit (US); PAIS; UK Clinical Research Network Study Portfolio; Open Grey; Index to Theses in the UK and Ireland; Bibliomap and TRoPHI. SELECTION CRITERIA: We included randomised controlled trials (RCTs), non-randomised controlled trials (non-RCTs), and controlled before-and-after (CBA) studies that evaluated school based educational programmes aimed at preventing a range of injury mechanisms. The primary outcome was self-reported or medically attended unintentional (or unspecified intent) injuries and secondary outcomes were observed safety skills, observed behaviour, self-reported behaviour and safety practices, safety knowledge, and health economic outcomes. The control groups received no intervention, a delayed injury-prevention intervention or alternative school based curricular activities. We included studies that aimed interventions at primary or secondary prevention of injuries from more than one injury mechanism and were delivered, in part or in full, in schools catering for children aged four to 18 years. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors identified relevant trials from title and abstracts of studies identified in searches and two review authors extracted data from the included studies and assessed risk of bias. We grouped different types of interventions according to the outcome assessed and the injury mechanism targeted. Where data permitted, we performed random-effects meta analyses to provide a summary of results across studies. MAIN RESULTS: The review included 27 studies reported in 30 articles. The studies had 73,557 participants with 12 studies from the US; four from China; two from each of Australia, Canada, the Netherlands and the UK; and one from each of Israel, Greece and Brazil. Thirteen studies were RCTs, six were non-RCTs and eight were CBAs. Of the included studies, 18 provided some element of the intervention in children aged four to 11 years, 17 studies included children aged 11 to 14 years and nine studies included children aged 14 to 18 years.The overall quality of the results was poor, with the all studies assessed as being at high or unclear risks of bias across multiple domains, and varied interventions and data collection methods employed. Interventions comprised information-giving, peer education or were multi-component.Seven studies reported the primary outcome of injury occurrence and only three of these were similar enough to combine in a meta-analysis, with a pooled incidence rate ratio of 0.73 (95% confidence interval (CI) 0.49 to 1.08; 2073 children) and substantial statistical heterogeneity (I2 = 63%). However, this body of evidence was low certainty, due to concerns over this heterogeneity (inconsistency) and imprecision. This heterogeneity may be explained by the non RCT study design of one of the studies, as a sensitivity analysis with this study removed found stronger evidence of an effect and no heterogeneity (I2 = 0%).Two studies report an improvement in safety skills in the intervention group. Likewise, the four studies measuring observed safety behaviour reported an improvement in the intervention group relative to the control. Thirteen out of 19 studies describing self-reported behaviour and safety practices showed improvements, and of the 21 studies assessing changes in safety knowledge, 19 reported an improvement in at least one question domain in the intervention compared to the control group. However, we were unable to pool data for our secondary outcomes, so our conclusions were limited, as they were drawn from highly diverse single studies and the body of evidence was low (safety skills) or very low (behaviour, safety knowledge) certainty. Only one study reported intervention costs but did not undertake a full economic evaluation (very low certainty evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether school-based educational programmes can prevent unintentional injuries. More high-quality studies are needed to evaluate the impact of educational programmes on injury occurrence. There is some weak evidence that such programmes improve safety skills, behaviour/practices and knowledge, although the evidence was of low or very low quality certainty. We found insufficient economic studies to assess cost-effectiveness. PMID- 28026878 TI - Erratum. PMID- 28026879 TI - Corrective Experiences of Psychotherapists in Training. AB - Although the concept of corrective experiences (CEs) is usually linked to the process of change in psychotherapy patients, we investigated them in the professional development of therapists-in-training. Inasmuch as psychotherapy is a relational process, it is important to look closely at how therapists reach the position of a competent partner in corrective experiencing. In this study, we interviewed 10 therapists-in-training undergoing their own training therapy. Responses to these semistructured interviews were analyzed using a computer assisted grounded theory method. The 499 first-level categories were grouped into 5 main themes: therapist characteristics, therapist technical interventions, therapist relational interventions, relationship experience, and outcome experience. Two core categories representing corrective experiencing were (a) unexpected unconditional support from and trust in their own therapist and (b) unexpected confrontation and limitation with their therapist as well as awareness of self-other boundaries. Results are discussed in the broader context of the CE literature, relational theory, and relational practice. PMID- 28026880 TI - Prenatal Diagnosis of Congenital Epulis: Implications for Delivery. PMID- 28026881 TI - Intrinsic factors, adrenal gland morphology, and disease burden in captive cheetahs (Acinonyx jubatus) in South Africa. AB - Adrenal gland weight (AW) and corticomedullary ratio (ACMR) are used as indicators of stress in animals. Captive cheetahs (Acinonyx jubatus) have higher ACMRs than free-ranging ones and stress has been linked to gastritis, amyloidosis, glomerulosclerosis, and myocardial fibrosis. We reviewed age, sex, body weight (BW), kidney weight (KW), and left AW and ACMR with necropsy findings in 51 South African captive cheetahs. Eleven common histopathologic lesions were counted for each animal as measure of its disease burden. Adrenal corticomedullary hyperplasia was significantly correlated with left AW and ACMR. Males had significantly higher AWs than females; other parameters showed no difference between the sexes. Disease burden, gastritis, and myocardial fibrosis were moderately correlated with adrenal morphology supporting prior evidence that gastritis and myocardial fibrosis are linked to stress. Glomerulosclerosis was not correlated with adrenal morphology and neither kidney nor liver amyloidosis contributed significantly to variation in AW or ACMR on multivariate analyses. Interstitial nephritis showed much stronger correlations with kidney and liver amyloidosis than gastritis. All three adrenal parameters were correlated with age; age was the only significant variable affecting ACMR on the multivariate analyses; and disease burden as well as systemic amyloidosis and kidney disease (except for fibrosis) showed moderate correlations with age. Age may, therefore, be important in the pathogenesis of disease in captive cheetahs, particularly of amyloidosis and kidney disease. None of the intrinsic measurements or adrenal parameters were sufficiently closely linked to disease to be used as ante-mortem proxies for disease burden or specific diseases. Zoo Biol. 36:40-49, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026882 TI - Supplemental feeding of captive neonatal koalas (Phascolarctos cinereus). AB - Koalas (Phascolarctos cinereus) are cautious animals, making supplemental feeding of neonates challenging because of disturbances to the normal routine. However, supplemental feeding is beneficial in improving juvenile nutrition using less formula than required for hand-rearing, and allowing maternal bonding to continue through suckling. In this study, two neonatal koalas, delivered by the same mother in 2 years, exhibited insufficient growth post-emergence from the pouch; supplemental feeding was therefore initiated. The amount of formula fed was determined according to the product instructions, and offspring weight was monitored. Slower than normal growth was not initially noticed in the first offspring. This caused delayed commencement of supplemental feeding. An attempt was made to counteract this by providing more formula for a longer period; however, this meant No. 1 was unable to eat enough eucalyptus when weaning. Supplemental feeding was started earlier for the second offspring than for the first, and was terminated at weaning; this juvenile showed a healthy body weight increase. Furthermore, it was able to eat eucalyptus leaves at an earlier stage than No. 1. Although No. 1 showed delayed growth, both koalas matured and are still living. This study showed that supplemental feeding is useful for koalas, if the mother will accept human intervention. The key factors for successful supplemental feeding of koalas identified by comparing the two feeding systems observed in this study are that: (1) it should be initiated as soon as insufficient growth is identified; and (2) it should be terminated before weaning age. Zoo Biol. 36:62-65, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28026883 TI - What is your diagnosis? A mass on the right tarsus in a rabbit. PMID- 28026884 TI - Making a queen: an epigenetic analysis of the robustness of the honeybee (Apis mellifera) queen developmental pathway. AB - Specialized castes are considered a key reason for the evolutionary and ecological success of the social insect lifestyle. The most essential caste distinction is between the fertile queen and the sterile workers. Honeybee (Apis mellifera) workers and queens are not genetically distinct, rather these different phenotypes are the result of epigenetically regulated divergent developmental pathways. This is an important phenomenon in understanding the evolution of social insect societies. Here, we studied the genomic regulation of the worker and queen developmental pathways, and the robustness of the pathways by transplanting eggs or young larvae to queen cells. Queens could be successfully reared from worker larvae transplanted up to 3 days age, but queens reared from older worker larvae had decreased queen body size and weight compared with queens from transplanted eggs. Gene expression analysis showed that queens raised from worker larvae differed from queens raised from eggs in the expression of genes involved in the immune system, caste differentiation, body development and longevity. DNA methylation levels were also higher in 3-day-old queen larvae raised from worker larvae compared with that raised from transplanted eggs identifying a possible mechanism stabilizing the two developmental paths. We propose that environmental (nutrition and space) changes induced by the commercial rearing practice result in a suboptimal queen phenotype via epigenetic processes, which may potentially contribute to the evolution of queen-worker dimorphism. This also has potentially contributed to the global increase in honeybee colony failure rates. PMID- 28026885 TI - Alexithymia and Emotional Processing: A Mediation Model. AB - OBJECTIVE: Although alexithymia has been associated with difficulties in emotional regulation, both constructs are complex and this association remains unclear. This research attempts to study the relation between both constructs to identify better ways to guide clinical intervention. METHOD: Emotion awareness, differentiation, and regulation were tested as mediators of the associations between alexithymia and severity of symptoms. The model was tested in a clinical (121 participants) and a nonclinical sample (188 participants). RESULTS: Mediation effects were found in both samples with respect to different alexithymia factors, with the effects being higher in the clinical sample. CONCLUSION: Emotional awareness and emotional differentiation mediate the relationship between alexithymia and emotion regulation. The similarities between samples suggest that emotional processing may be better thought of as being on a continuum. Being aware of the differential effect each alexithymia factor has on emotional processing may be helpful to guide intervention. PMID- 28026886 TI - Haploidentical hematopoietic cell transplantation for disseminated Ewing sarcoma. AB - We describe the case of a 13-year-old girl with multifocal disseminated Ewing sarcoma family of tumor (ESFT) who received a 5/8 human leukocyte antigen-matched haploidentical hematopoietic cell transplantation to generate a graft-versus tumor effect. The patient had grade 2 acute graft-versus-host disease (GVHD) of the skin and chronic GVHD nausea and abdominal pain that required prednisolone for 17 months, but has been free from ESFT for 3 years 10 months after therapy. The present case suggests a beneficial effect of haploidentical hematopoietic cell transplantation in disseminated ESFT. PMID- 28026887 TI - Combined spinal-epidural anesthesia with hypobaric ropivacaine in sitting position significantly increases the incidence of hypotension in parturients undergoing cesarean section. AB - AIM: Maternal position during induction of combined spinal-epidural anesthesia (CSEA) may affect hemodynamics and block characteristics. This study aimed to assess whether the sitting position is more likely to induce hypotension and higher block level than the lateral position in CSEA with hypobaric ropivacaine. METHODS: Ninety American Society of Anesthesiologists physical status I and II parturients undergoing elective cesarean section were randomized into three groups: the sitting, left-lateral, and right-lateral position groups. The L3-4 interspace was selected as the puncture site, and subarachnoid injection of 2.5 mL 0.5% hypobaric ropivacaine was administered. After the epidural catheter was inserted and fixed, the patient's position was changed to the left-leaning supine position. The blood pressure was measured once every 1 min followed by once every 3 min after the delivery. The sensory block level was regularly measured. RESULTS: A total of 88 parturients were included in this study. The incidences of hypotension in the sitting, left-lateral, and right-lateral position groups were 72%, 38%, and 40%, respectively, P = 0.012. Incidence and total dose of the phenylephrine supplement in the sitting position group were significantly higher than in the other two groups. The sitting position group showed a significantly higher block level (T4 [T3, T4]) as compared to the left-lateral (T6 [T5, T6]) and right-lateral position groups (T6 [T4, T6]), P < 0.01. The Apgar scores of neonates at 1 min and 5 min, and the pH values of the umbilical arterial and venous blood were similar among the three groups. CONCLUSION: As compared to the lateral positions, CSEA with hypobaric ropivacaine in the sitting position is more likely to cause hypotension and excessively high block level. PMID- 28026888 TI - Measurement of Blood Flow in an Intracranial Artery Bypass From the Internal Maxillary Artery by Intraoperative Duplex Sonography. AB - This study explored the hemodynamic characteristics of a subcranial-intracranial bypass from the internal maxillary artery by measuring blood flow on intraoperative duplex sonography. The hemodynamic parameters of the internal maxillary artery (n = 20), radial artery (n = 20), internal maxillary artery middle cerebral artery bypass (n = 42), and internal maxillary artery-posterior cerebral artery bypass (n = 9) were measured by intraoperative duplex sonography. There was no significant difference in the internal diameters of the internal maxillary and radial arteries (mean +/- SD, 2.51 +/- 0.34 versus 2.56 +/- 0.22 mm; P = .648). The mean radial artery graft length for subcranial-intracranial bypasses was 88.5 +/- 12.78 mm (95% confidence interval [CI], 80.8-90.2 mm). Internal maxillary artery-middle cerebral artery bypasses required a shorter radial artery graft than internal maxillary artery-posterior cerebral artery bypasses (77.8 +/- 2.47 versus 104.8 +/- 4.77 mm; P = .001). The mean flow volumes were 85.3 +/- 18.5 mL/min (95% CI, 76.6-93.9 mL/min) for the internal maxillary artery, 72.6 +/- 26.4 mL/min (95% CI, 64.3-80.9 mL/min) for internal maxillary artery-middle cerebral artery bypasses, and 45.4 +/- 6.7 mL/min (95% CI, 40.7-50.0 mL/min) for internal maxillary artery-posterior cerebral artery bypasses. All grafts were opened after the success of the salvage procedures had been established, and the early patency rates (1 month after the operation) were 95% for internal maxillary artery-middle cerebral artery bypasses and 100% the internal maxillary artery-posterior cerebral artery bypasses. Measurement of blood flow by intraoperative sonography can be helpful in decision making and predicting graft patency and success after neurosurgical bypass procedures. PMID- 28026889 TI - Genomic data detect corresponding signatures of population size change on an ecological time scale in two salamander species. AB - Understanding the demography of species over recent history (e.g. <100 years) is critical in studies of ecology and evolution, but records of population history are rarely available. Surveying genetic variation is a potential alternative to census-based estimates of population size, and can yield insight into the demography of a population. However, to assess the performance of genetic methods, it is important to compare their estimates of population history to known demography. Here, we leveraged the exceptional resources from a wetland with 37 years of amphibian mark-recapture data to study the utility of genetically based demographic inference on salamander species with documented population declines (Ambystoma talpoideum) and expansions (A. opacum), patterns that have been shown to be correlated with changes in wetland hydroperiod. We generated ddRAD data from two temporally sampled populations of A. opacum (1993, 2013) and A. talpoideum (1984, 2011) and used coalescent-based demographic inference to compare alternate evolutionary models. For both species, demographic model inference supported population size changes that corroborated mark recapture data. Parameter estimation in A. talpoideum was robust to our variations in analytical approach, while estimates for A. opacum were highly inconsistent, tempering our confidence in detecting a demographic trend in this species. Overall, our robust results in A. talpoideum suggest that genome-based demographic inference has utility on an ecological scale, but researchers should also be cognizant that these methods may not work in all systems and evolutionary scenarios. Demographic inference may be an important tool for population monitoring and conservation management planning. PMID- 28026890 TI - Influence of the interval between antenatal corticosteroid therapy and delivery on respiratory distress syndrome. AB - AIM: In spite of the recommendation for rescue antenatal corticosteroids (ACS), the optimal time interval between primary and rescue courses has not been clearly demonstrated. The aim of this study was to determine the effects of the interval between a single ACS course and delivery on the incidence of respiratory distress syndrome (RDS). METHODS: In this retrospective study, we included singleton pregnant women who received a single course of ACS and delivered beyond 48 h after ACS administration between 24 and 33 weeks' gestation. The risk of RDS was compared between patients who delivered within seven days (Group I), 7-14 days (Group II) and beyond 14 days (Group III) after ACS administration. RESULTS: We included 83, 14 and 20 patients in Groups I, II and III, respectively. After adjusting for confounders, the ACS delivery interval was significantly associated with RDS in Group II (adjusted odds ratio 12.8, 95% confidence interval 1.31 164.7) and Group III (adjusted odds ratio 64.0, 95% confidence interval 1.32 5808.6). CONCLUSION: A longer ACS delivery interval is associated with a higher risk of RDS. Thus, the use of a rescue course could be expected to reduce the incidence of RDS in patients beyond seven days after ACS administration who remain at risk for preterm delivery within seven days, especially in cases of placenta previa and/or women bearing a male fetus. PMID- 28026891 TI - Fetus in Fetu in Lieu of a Sacrococcygeal Teratoma: A Case Illuminating the Utility of Serial Prenatal Sonographic Examinations in Diagnosis. PMID- 28026892 TI - Integration of a Low-Cost Introductory Ultrasound Curriculum Into Existing Procedural Skills Education for Preclinical Medical Students. AB - We evaluated integration of an introductory ultrasound curriculum into our existing mandatory procedural skills program for preclinical medical students. Phantoms consisting of olives, pimento olives, and grapes embedded in opaque gelatin were developed. Four classes encouraged progressive refinement of phantom scanning and object identification skills. Students improved their ability to identify hidden objects, although each object type achieved a statistically significant improvement in correct identification at different time points. The total phantom cost per student was $0.76. Our results suggest that short repeated experiences scanning simple, low-cost ultrasound phantoms confer basic ultrasound skills. PMID- 28026893 TI - Cryptic diversity in a fig wasp community-morphologically differentiated species are sympatric but cryptic species exhibit competitive exclusion. AB - A key debate in ecology centres on the relative importance of niche and neutral processes in determining patterns of community assembly with particular focus on whether ecologically similar species with similar functional traits are able to coexist. Meanwhile, molecular studies are increasingly revealing morphologically indistinguishable cryptic species with presumably similar ecological roles. Determining the geographic distribution of such cryptic species provides opportunities to contrast predictions of niche vs. neutral models. Discovery of sympatric cryptic species increases alpha diversity and supports neutral models, while documentation of allopatric/parapatric cryptic species increases beta diversity and supports niche models. We tested these predictions using morphological and molecular data, coupled with environmental niche modelling analyses, of a fig wasp community along its 2700-km latitudinal range. Molecular methods increased previous species diversity estimates from eight to eleven species, revealing morphologically cryptic species in each of the four wasp genera studied. Congeneric species pairs that were differentiated by a key morphological functional trait (ovipositor length) coexisted sympatrically over large areas. In contrast, morphologically similar species, with similar ovipositor lengths, typically showed parapatric ranges with very little overlap. Despite parapatric ranges, environmental niche models of cryptic congeneric pairs indicate large regions of potential sympatry, suggesting that competitive processes are important in determining the distributions of ecologically similar species. Niche processes appear to structure this insect community, and cryptic diversity may typically contribute mostly to beta rather than alpha diversity. PMID- 28026894 TI - By their own devices: invasive Argentine ants have shifted diet without clear aid from symbiotic microbes. AB - The functions and compositions of symbiotic bacterial communities often correlate with host ecology. Yet cause-effect relationships and the order of symbiont vs. host change remain unclear in the face of ancient symbioses and conserved host ecology. Several groups of ants exemplify this challenge, as their low-nitrogen diets and specialized symbioses appear conserved and ancient. To address whether nitrogen-provisioning symbionts might be important in the early stages of ant trophic shifts, we studied bacteria from the Argentine ant, Linepithema humile - an invasive species that has transitioned towards greater consumption of sugar rich, nitrogen-poor foods in parts of its introduced range. Bacteria were present at low densities in most L. humile workers, and among those yielding quality 16S rRNA amplicon sequencing data, we found just three symbionts to be common and dominant. Two, a Lactobacillus and an Acetobacteraceae species, were shared between native and introduced populations. The other, a Rickettsia, was found only in two introduced supercolonies. Across an eight-year period of trophic reduction in one introduced population, we found no change in symbionts, arguing against a relationship between natural dietary change and microbiome composition. Overall, our findings thus argue against major changes in symbiotic bacteria in association with the invasion and trophic shift of L. humile. In addition, genome content from close relatives of the identified symbionts suggests that just one can synthesize most essential amino acids; this bacterium was only modestly abundant in introduced populations, providing little support for a major role of nitrogen-provisioning symbioses in Argentine ant's dietary shift. PMID- 28026895 TI - Self-fertilization, long-distance flash invasion and biogeography shape the population structure of Pseudosuccinea columella at the worldwide scale. AB - Population genetic studies are efficient for inferring the invasion history based on a comparison of native and invasive populations, especially when conducted at species scale. An expected outcome in invasive populations is variability loss, and this is especially true in self-fertilizing species. We here focus on the self-fertilizing Pseudosuccinea columella, an invasive hermaphroditic freshwater snail that has greatly expanded its geographic distribution and that acts as intermediate host of Fasciola hepatica, the causative agent of human and veterinary fasciolosis. We evaluated the distribution of genetic diversity at the largest geographic scale analysed to date in this species by surveying 80 populations collected during 16 years from 14 countries, using eight nuclear microsatellites and two mitochondrial genes. As expected, populations from North America, the putative origin area, were strongly structured by selfing and history and harboured much more genetic variability than invasive populations. We found high selfing rates (when it was possible to infer it), none-to-low genetic variability and strong population structure in most invasive populations. Strikingly, we found a unique genotype/haplotype in populations from eight invaded regions sampled all over the world. Moreover, snail populations resistant to infection by the parasite are genetically distinct from susceptible populations. Our results are compatible with repeated introductions in South America and flash worldwide invasion by this unique genotype/haplotype. Our study illustrates the population genetic consequences of biological invasion in a highly selfing species at very large geographic scale. We discuss how such a large-scale flash invasion may affect the spread of fasciolosis. PMID- 28026896 TI - Genomics, transcriptomics and proteomics: enabling insights into social evolution and disease challenges for managed and wild bees. AB - Globally, there are over 20 000 bee species (Hymenoptera: Apoidea: Anthophila) with a host of biologically fascinating characteristics. Although they have long been studied as models for social evolution, recent challenges to bee health (mainly diseases and pesticides) have gathered the attention of both public and research communities. Genome sequences of twelve bee species are now complete or under progress, facilitating the application of additional 'omic technologies. Here, we review recent developments in honey bee and native bee research in the genomic era. We discuss the progress in genome sequencing and functional annotation, followed by the enabled comparative genomics, proteomics and transcriptomics applications regarding social evolution and health. Finally, we end with comments on future challenges in the postgenomic era. PMID- 28026897 TI - Pregnancy outcome of gestational diabetes mellitus using a structured model of care : WINGS project (WINGS-10). AB - AIM: To evaluate the impact of a structured model of care (MOC) prepared for resource-constrained settings, on the pregnancy outcomes of Asian Indian women with gestational diabetes mellitus (GDM). METHODS: Pregnant women were screened under the Women in India with GDM Strategy (WINGS) MOC for GDM using the International Association of Diabetes and Pregnancy Study Groups criteria. Women with GDM went through a structured MOC that included medical nutrition therapy (MNT), regular physical activity (PA); and insulin when indicated. Fasting blood glucose and post-prandial blood sugar were monitored every 2 weeks. The pregnancy outcomes of women with GDM who underwent the MOC were compared with those without GDM. RESULTS: Under the MOC, 212 women with GDM were followed through pregnancy, of whom 33 (15.6%) required insulin and 179 (84.4%) were managed with MNT and PA. The maternal and neonatal outcomes of women with GDM were similar to the non-GDM women: there were no significant differences in pregnancy complications such as cesarean section, macrosomia, pre-eclampsia, oligo/polyhydramnios, preterm delivery, neonatal death, fetal distress, hyperbilirubinemia and low birthweight. CONCLUSION: Implementation of a structured MOC for women with GDM helped achieve pregnancy outcomes similar to those without GDM. PMID- 28026898 TI - Factors associated with changes in exposure to anticholinergic and sedative medications in elderly hospitalized patients: multicentre longitudinal study. AB - BACKGROUND AND PURPOSE: Elderly patients exposed to drugs with anticholinergic or sedative properties may have an increased risk of adverse events. This study aimed to assess the relationship between patient characteristics and changes of exposure to anticholinergic and sedative medications during their hospital stay. METHODS: A multicentre longitudinal study was set up on hospitalized patients (aged >=65 years) using at least one drug at admission. The primary outcome was change of exposure to anticholinergic and sedative drugs between admission and discharge. Sociodemographic characteristics of the patients, comorbidities, life habits and information about the hospital stay (origin of admission, reasons for hospitalization) were collected. RESULTS: The study included 337 patients (mean age, 85.4 years) with an average hospital stay of 30.1 +/- 37.5 days. The drug burden index increased during the hospital stay among males (P = 0.03), patients for whom the reason for hospitalization was either a stroke (P = 0.001) or inability to stay in their own home (P = 0.001), and patients with diabetes mellitus (P = 0.009). In the adjusted model, drug burden index increased among patients hospitalized for stroke, inability to stay in their own home or post surgery, and for patients with diabetes mellitus or hypertension. CONCLUSIONS: The drug management of elderly patients during hospital stays may increase exposure to anticholinergic and sedative drugs. Although the anticholinergic and sedative properties may be in relation to the therapeutic purpose, they also represent an unexpected risk. Physicians and clinical pharmacists should consider performing optimization of the drug prescriptions for patients at risk. PMID- 28026899 TI - An anomalous abundance of megakaryocytes in thyroid fine needle aspirates: two immunocytochemically confirmed cases. PMID- 28026900 TI - Doppler Ultrasound in Liver Cirrhosis: Correlation of Hepatic Artery and Portal Vein Measurements With Model for End-Stage Liver Disease Score. AB - OBJECTIVES: To determine whether hepatic arterial and portal venous Doppler ultrasound measurements of the liver in cirrhotic patients correlate with patients' Model for End-Stage Liver Disease (MELD) scores, splenomegaly, or ascites. MATERIALS AND METHODS: Sonographic images and reports were reviewed of 264 patients with hepatic cirrhosis who underwent abdominal ultrasound with Doppler in this internal review board-approved retrospective study. MELD scores were recorded at the time of ultrasound. On gray-scale ultrasound, spleen length was measured and the presence of ascites was noted. Hepatic arterial velocity (HAv) with angle correction, hepatic arterial resistive index, and portal vein velocity with angle correction were measured on Doppler ultrasound. Correlation of hepatic arterial and portal venous Doppler values with MELD score, presence of splenomegaly, and presence of ascites was tested using linear or binary logistic regression analysis. Diagnostic performance of Doppler parameters for high-risk MELD was assessed. RESULTS: The HAv statistically significantly correlated with the MELD score (P = .0001), spleen size (P =.027), and presence of ascites (P =.0001), whereas the hepatic arterial resistive index and portal vein velocity did not correlate with these factors. For MELD scores greater than 19, an HAv greater than 120 cm/s showed accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 74, 42, 90, 67, and 76%, respectively. With an HAv greater than 160 cm/s, the odds ratio for MELD scores greater than 19 was 42.1. CONCLUSIONS: We found a statistically significant correlation with elevated HAv and increasing MELD scores, splenomegaly, and presence of ascites in patients with cirrhotic liver disease; this may be a useful imaging biomarker in the evaluation of patients with cirrhosis. PMID- 28026901 TI - The effect of exercise on body composition and bone mineral density in breast cancer survivors taking aromatase inhibitors. AB - OBJECTIVE: This study examined the effect of 12 months of aerobic and resistance exercise versus usual care on changes in body composition in postmenopausal breast cancer survivors taking aromatase inhibitors (AIs). METHODS: The Hormones and Physical Exercise study enrolled 121 breast cancer survivors and randomized them to either supervised twice-weekly resistance exercise training and 150 min/wk of aerobic exercise (N = 61) or a usual care (N = 60) group. Dual-energy X ray absorptiometry scans were conducted at baseline, 6 months, and 12 months to assess changes in body mass index, percent body fat, lean body mass, and bone mineral density. RESULTS: At 12 months, the exercise group relative to the usual care group had a significant increase in lean body mass (0.32 vs. -0.88 kg, P = 0.03), a decrease in percent body fat (-1.4% vs. 0.48%, P = 0.03), and a decrease in body mass index (-0.73 vs. 0.17 kg/m2 , P = 0.03). Change in bone mineral density was not significantly different between groups at 12 months (0.001 vs. 0.006 g/cm2 , P = 0.37). CONCLUSIONS: A combined resistance and aerobic exercise intervention improved body composition in breast cancer survivors taking AIs. Exercise interventions may help to mitigate the negative side effects of AIs and improve health outcomes in breast cancer survivors. PMID- 28026902 TI - Initial body fat gain is related to brain volume changes in adolescents: A repeated-measures voxel-based morphometry study. AB - OBJECTIVE: Individuals with obesity versus those within a healthy weight range show brain volume differences, but it is unclear whether these differences reflect initial vulnerability factors or are secondary to weight gain. METHODS: One hundred sixty-two adolescents (M age = 15.3 +/- 1.1; 81 females) with healthy weight were scanned at baseline. Sixty subjects (M baseline age: 15.2 +/- 1.1; M follow-up age: 17.7 +/- 1.2; 34 females) completed a second scan at 2- or 3-year follow-up. Voxel-based morphometry assessed global and regional gray matter (GM) and white matter (WM) volumes. Body fat percentage was assessed yearly over follow-up. RESULTS: Baseline global/regional GM/WM volume did not predict body fat gain over follow-up. Adolescents who gained body fat showed greater decreases in GM volume in the putamen compared with those who showed loss of body fat. Adolescents who gained body fat showed greater increases in WM volume in the anterior cingulate cortex compared with those who showed stability of or loss of body fat. CONCLUSIONS: Body fat gain versus stability and loss produce GM and WM volume changes, rather than baseline volumetric differences predicting body fat gain. PMID- 28026903 TI - Impaired adrenergic agonist-dependent beige adipocyte induction in aged mice. AB - OBJECTIVE: There are two types of thermogenic adipocytes expressing uncoupling protein (UCP)-1: the brown adipocyte activated by adrenergic stimulation and the beige adipocyte that appears within the white adipose tissue (WAT) in response to chronic adrenergic stimulation. This study examined age-related changes in responses of both types of adipocytes to adrenergic stimulation in mice. METHODS: Aged (age 20 months) and young (4 months) mice were injected daily with either saline or beta3-adrenergic receptor agonist CL316,243 (CL; 0.1 mg/kg, once a day) for 1 week. RESULTS: The body and WAT weight tended to be higher in aged mice. CL treatment increased UCP-1 protein amounts in both brown adipose tissue and inguinal WAT, suggesting activation of brown and beige adipocytes. However, induction of beige adipocytes was impaired in aged mice, whereas brown adipocyte activation was comparable to young mice. The number of platelet-derived growth factor receptor alpha-expressing progenitor cells, which were reported to differentiate into beige adipocytes, significantly decreased in inguinal WAT of aged mice compared with that of young mice. CONCLUSIONS: Inductive ability of beige adipocytes in WAT declines with aging in mice. It may be partly because of a decreased number of progenitor cells associated with aging. PMID- 28026904 TI - Weight loss and carotid intima-media thickness-a meta-analysis. AB - OBJECTIVE: Obesity is a risk factor for clinical cardiovascular disease, putatively via increased burden of atherosclerosis. It remains contentious as to whether weight loss in people with obesity is accompanied by a reduction in intima-media thickness, a noninvasive marker of subclinical atherosclerosis, consistent with a lowering of risk of cardiovascular events. METHODS: A systematic literature search was performed to identify all surgical and nonsurgical weight loss interventions that reported intima-media thickness. A meta-analysis was undertaken to obtain pooled estimates for change in intima media thickness. RESULTS: From the 3,197 articles screened, 9 studies were included in the meta-analysis, with a total of 393 participants who lost an average of 16 kg (95% CI 9.4-22.5) of body weight over an average follow-up of 20 months. The pooled mean change in carotid intima-media thickness was -0.03 mm (95% CI -0.05 to -0.01), which was similar between surgical and nonsurgical interventions. CONCLUSIONS: In people with obesity, weight loss was associated with a reduction in carotid intima-media thickness, consistent with a lowering in risk of cardiovascular events. PMID- 28026905 TI - Identification of Visceral Leishmaniasis-Susceptible Areas using Spatial Modelling in Southern Caucasus. AB - This study explores the application of spatial modelling techniques to generate susceptibility maps for a neglected zoonotic disease, visceral leishmaniasis (VL), in an endemic area in southern Caucasus that includes Iran, Armenia and Azerbaijan. The social and physical environment of southern Caucasus has been mainly characterized by the presence of several factors that are strongly associated with VL, which has caused a significant number of infections during the past decade. Three popular spatial modelling techniques, consisting of the weights of evidence, logistic regression and fuzzy logic methods, were evaluated and trained using a study area in north-western Iran where an inventory of highly infected areas and high-quality evidential factors was available. Model performance was assessed using the receiver-operating characteristic (ROC) approach. According to the results of these assessments, the fuzzy logic method with gamma = 0.5 was chosen for the prediction of VL incidence in southern Caucasus. The susceptibility map generated using the fuzzy logic method indicated that VL followed a spatial pattern at the conjunction of the three countries, which suggests that the prevalence of VL in southern Caucasus is socio ecologically dependent. PMID- 28026906 TI - Recurrence of Helicobacter pylori infection and the affecting factors: A follow up study. AB - OBJECTIVE: Recurrence of Helicobacter pylori (H. pylori) infection weakens the protective effect and long-term prognosis of eradication. With the widespread therapies, decreasing prevalence of H. pylori infection and improvement in living conditions, the recurrence of H. pylori infection may present with new features. We conducted this prospective, large-scale, multicenter follow-up study to determine the recurrence rate of H. pylori infection and its affecting factors. METHODS: A total of 827 patients receiving successful H. pylori eradication in our previous randomized controlled trial were enrolled. 13 C-urea breath test (UBT) was repeated one year after the eradication therapy to determine its recurrence. Moreover, a questionnaire survey was performed to explore the potential factors affecting the recurrence. RESULTS: A total of 743 patients completed 13 C-UBT (follow-up rate 89.8%), and the result was positive in 13 patients one year after eradication therapy, with an annual recurrence rate of 1.75% (95% confidence interval [CI] 0.81-2.69%). Six hundred and ninety-two patients (13 with recurrence and 679 without recurrence) returned their questionnaires, with a response rate of >80%. Multivariate analysis revealed that peptic ulcer (odds ratio [OR] 3.385, 95% CI 1.016-11.274), close contact with individuals having H. pylori infection (OR 4.231, 95% CI 1.201-14.911), and hospitalization (OR 9.302, 95% CI 2.441-35.440) were independent risk factors of H. pylori infection recurrence. CONCLUSIONS: The recurrence of H. pylori infection one year after eradication therapy is low in urban population of China. Peptic ulcer, contact history with individuals having H. pylori infection and hospitalization are risk factors. PMID- 28026907 TI - Campylobacter fetus Bacteremia in a Healthy Patient Returning from a Trip to the Ecuadorian Amazonia. AB - Campylobacter fetus is an opportunistic pathogen which causes bacteremia and other invasive infections in immunocompromised patients who have been exposed to livestock or ingested animal products (uncooked meat or unpasteurized milk). The present report describes a C. fetus infection in a healthy adult (immunocompetent) who returned from a visit to the Ecuadorian Amazonia and who did not report exposure to the typical sources of infection. PMID- 28026908 TI - An alternative approach to modelling HbA1c trajectories in patients with type 2 diabetes mellitus. AB - AIMS: Time-dependent HbA1c trajectories in health economic models of type 2 diabetes mellitus (T2DM) are typically informed by the UK Prospective Diabetes Study (UKPDS). However, this approach may not accurately predict HbA1c progression in patients who do not conform to the demographic profile of the original UKPDS cohort. This study aimed to develop an alternative mathematical model (MM) to simulate HbA1c progression in T2DM. MATERIALS AND METHODS: A systematic literature review identified studies, published between 2005 and 2015, that reported HbA1c in adult T2DM patients over a minimum duration of 18 months. Pooled data from eligible studies were used to develop an alternative MM equation for HbA1c progression, which was then contrasted with the UKPDS 68 progression equation in illustrative scenarios. RESULTS: A total of 68 studies were eligible for data extraction (mean follow-up time 4.1 years). HbA1c progression was highly heterogeneous across studies, varying with baseline HbA1c, treatment group and patient age. The MM equation was fitted with parameters for mean baseline HbA1c (8.3%), initial change in HbA1c (-0.62%) and upper quartile of maximum observed HbA1c (9.3%). Differences in HbA1c trajectories between the MM and UKPDS approaches altered the timing of therapy escalation in illustrative scenarios. CONCLUSIONS: The MM represents an alternative approach to simulate HbA1c trajectories in T2DM models, as UKPDS data may not adequately reflect the heterogeneity of HbA1c profiles observed in clinical studies. However, the choice of approach should ultimately be determined by the characteristics of individual patients under consideration and the clinical face validity of the modelled trajectories. PMID- 28026909 TI - Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. AB - BACKGROUND AND PURPOSE: Cancer patients with cryptogenic stroke often have high plasma D-dimer levels and lesions in multiple vascular regions. Hence, if patients with cryptogenic stroke display such characteristics, occult cancer could be predicted. This study aimed to investigate the clinical characteristics of cryptogenic stroke as the first manifestation of occult cancer and to determine whether plasma D-dimer levels and lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. METHODS: Between January 2006 and October 2015, data on 1225 patients with acute ischaemic stroke were extracted from the stroke database of Osaka University Hospital. Among them, 184 patients were classified as having cryptogenic stroke, and 120 patients without a diagnosis of cancer at stroke onset were identified. Clinical variables were analyzed between cryptogenic stroke patients with and without occult cancer. RESULTS: Among 120 cryptogenic stroke patients without a diagnosis of cancer, 12 patients had occult cancer. The body mass index, hemoglobin levels and albumin levels were lower; plasma D-dimer and high-sensitivity C-reactive protein levels were higher; and lesions in multiple vascular regions were more common in patients with than in those without occult cancer. Multiple logistic regression analysis revealed that plasma D-dimer levels (odds ratio, 3.48; 95% confidence interval, 1.68-8.33; P = 0.002) and lesions in multiple vascular regions (odds ratio, 7.40; 95% confidence interval, 1.70-39.45; P = 0.01) independently predicted occult cancer. CONCLUSIONS: High plasma D-dimer levels and lesions in multiple vascular regions can be used to predict occult cancer in patients with cryptogenic stroke. PMID- 28026910 TI - Participatory Policy Making by Dairy Producers to Reduce Anti-Microbial use on Farms. AB - Pressures for more responsible use of anti-microbial (AM) medicines in food animals are likely to increase from policymakers and the food industry, including retailers. To address this challenge, participatory approaches to welfare interventions and disease prevention may also be necessary alongside more conventional regulatory measures. This article describes the process of enabling groups of dairy producers to use a participatory policy making approach to develop an AM stewardship policy. The policy includes measures agreed to by all producers for more responsible use of AMs, whilst maintaining or improving dairy herd health and welfare. This process provided a unique opportunity for collaboration and dialogue between producers, veterinarians, industry and researchers. Its participatory nature encouraged comprehensive learning for all involved. This integration of science with producers' knowledge and experience led to credible and practical recommendations designed to deliver real and lasting change in AM use. The multidisciplinary nature of this research marks a significant contribution to embedding social science skills and approaches into the veterinary sphere. As an initial step in creating better understanding of how participatory approaches with farmers can be applied in a UK context and more widely, this work serves as a pilot for promoting more responsible use of veterinary medicines in other livestock species. PMID- 28026911 TI - Managing glycaemia in older people with type 2 diabetes: A retrospective, primary care-based cohort study, with economic assessment of patient outcomes. AB - AIMS: To describe the relative health and economic outcomes associated with different second-line therapeutic approaches to manage glycaemia in older type 2 diabetes patients requiring escalation from metformin monotherapy. MATERIALS AND METHODS: The Clinical Practice Research Datalink database was used to inform a retrospective observational cohort study of patients with type 2 diabetes treated with metformin monotherapy requiring escalation (addition or switch) to a second line oral regimen from January 1, 2008 to December 31, 2014. Primary outcomes included time to first event (any event, myocardial infarction [MI], stroke, or composite of MI/stroke [major adverse cardiovascular event; MACE]) and total event rate. The health economic consequences associated with the choice of second line treatment in older patients were assessed using the CORE Diabetes Model. RESULTS: A total of 10 484 patients were included; the majority escalated to second-line treatment with metformin + sulphonylurea (SU; 42%) or switched to SU monotherapy (28%). In multivariate adjusted analyses, total event rates for MACE with metformin + dipeptidyl peptidase-4 (DPP-4) inhibitor were significantly lower than with metformin + SU (0.61, 95% confidence interval [CI] 0.39-0.98), driven by a lower MI rate in the metformin + DPP-4 inhibitor group (0.52, 95% CI 0.27-0.99). Economic analyses estimated that metformin + DPP-4 inhibitor treatment was associated with the largest gain in health benefit, and cost effectiveness ratios were favourable (=5%, >=10%, and >=15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation. RESULTS: NB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea. CONCLUSIONS: Treatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB-facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated. PMID- 28026921 TI - N@a and N@d: Oligomer and Partner Specification by Asparagine in Coiled-Coil Interfaces. AB - The alpha-helical coiled coil is one of the best-studied protein-protein interaction motifs. As a result, sequence-to-structure relationships are available for the prediction of natural coiled-coil sequences and the de novo design of new ones. However, coiled coils adopt a wide range of oligomeric states and topologies, and our understanding of the specification of these and the discrimination between them remains incomplete. Gaps in our knowledge assume more importance as coiled coils are used increasingly to construct biomimetic systems of higher complexity; for this, coiled-coil components need to be robust, orthogonal, and transferable between contexts. Here, we explore how the polar side chain asparagine (Asn, N) is tolerated within otherwise hydrophobic helix helix interfaces of coiled coils. The long-held view is that Asn placed at certain sites of the coiled-coil sequence repeat selects one oligomer state over others, which is rationalized by the ability of the side chain to make hydrogen bonds, or interactions with chelated ions within the coiled-coil interior of the favored state. We test this with experiments on de novo peptide sequences traditionally considered as directing parallel dimers and trimers, and more widely through bioinformatics analysis of natural coiled-coil sequences and structures. We find that when located centrally, rather than near the termini of such coiled-coil sequences, Asn does exert the anticipated oligomer-specifying influence. However, outside of these bounds, Asn is observed less frequently in the natural sequences, and the synthetic peptides are hyperthermostable and lose oligomer-state specificity. These findings highlight that not all regions of coiled-coil repeat sequences are equivalent, and that care is needed when designing coiled-coil interfaces. PMID- 28026922 TI - Architectural Effects on Solution Self-Assembly of Poly(3-hexylthiophene)-Based Graft Copolymers. AB - While solution assembly of conjugated block copolymers has been widely used to produce long 1-D nanowires (NWs), it remains a great challenge to provide a higher level of control over structure and function of the NWs. Herein, for the first time, we report the solution assembly of graft copolymers containing a conjugated polymer backbone in a selective solvent and demonstrate that their self-assembly behaviors can be manipulated by the molecular structures of the graft copolymers. A series of poly(3-hexylthiophene)-graft-poly(2-vinylpyridine) (P3HT-g-P2VP) copolymers was designed with two different architectural parameters: grafting fraction (fg) and molecular weight of P2VP chains (Mn,P2VP) on the P3HT backbone. Interestingly, crystallization of the P3HT-g-P2VP copolymers was systematically modulated by changes in fg and Mn,P2VP, thus allowing for control of the growth kinetics and curvatures of solution-assembled NWs. When Mn,P2VP (4.4 to 15.1 kg/mol) or fg (2.8 to 9.2%) of the P3HT-g-P2VP polymers was increased, the crystallinity of the copolymers was reduced significantly. Steric hindrance from the grafted P2VP chains apparently modified the growth of NWs, leading to shorter NWs with a greater degree of curvature for graft copolymers with more hindrance. Therefore, we envision that such conjugated chain-based graft copolymers can be versatile building blocks for producing NWs with controlled length and shape, which can be important for tailoring the optical and electrical properties of NW-based devices. PMID- 28026923 TI - Inkjet Printing NiO-Based p-Type Dye-Sensitized Solar Cells. AB - Fabrication at low cost of transparent p-type semiconductors with suitable electronic properties is essential toward the scalability of many electronic devices, especially for photovoltaic and photocatalytic applications. In this context, the synthesis of mesoporous NiO films through inkjet printing of a sol gel ink was investigated for the first time. Nickel chloride and Pluronic F-127, used as nickel oxide precursor and pore-forming agent, respectively, were formulated in a water/ethanol mixture to prepare a jettable ink for Dimatix printer. Multilayer NiO films were formed, and different morphologies could be obtained by playing on the interlayer thermal treatment. At low temperature (30 degrees C), a porous nanoparticulate-nanofiber dual-pore structure was observed. On the other hand, with a high temperature treatment (450 degrees C), nanoparticulate denser films without any dual structure were obtained. The mechanism for NiO formation during the final sintering step, investigated by means of X-ray photolectron spectroscopy, shows that a Ni(OH)2 species is an intermediate between NiCl2 and NiO. The different morphologies and thicknesses of the NiO films were correlated to their performance in a p-DSSC configuration, using a new push-pull dye (so-called "RBG-174") and an iodine-based electrolyte. Moreover, the positive impact of a nanometric NiOx layer deposited by spin coating and introduced between FTO and the NiO mesoporous network is highlighted in the present work. The best results were obtained with NiOx/four layer-NiO mesoporous photocathodes of 860 nm, with a current density at the short circuit of 3.42 mA cm-2 (irradiance of 100 mW cm-2 spectroscopically distributed following AM 1.5). PMID- 28026924 TI - SiO2/TiO2 Nanocomposite Films on Polystyrene for Light-Induced Cell Detachment Application. AB - Light-induced cell detachment shows much potential in in vitro cell culture and calls for high-performance light-responsive films. In this study, a smooth and dense SiO2/TiO2 nanocomposite thin film with thickness of around 250 nm was first fabricated on H2O2 treated polystyrene (PS) substrate via a low-temperature sol gel method. It was observed that the film could well-adhere on the PS surface and the bonding strength became increasingly high with the increase of SiO2 content. The peeling strength and shear strength reached 3.05 and 30.02 MPa, respectively. It was observed the surface of the film could transform into superhydrophilic upon 20 min illumination of ultraviolet with a wavelength of 365 nm (UV365). In cell culture, cells, i.e., NIH3T3 and MC3T3-E1 cells, cultured on SiO2/TiO2 nanocomposite film were easily detached after 10 min of UV365 illumination; the detachment rates reached 90.8% and 88.6%, respectively. Correspondingly, continuous cell sheets with good viability were also easily obtained through the same way. The present work shows that SiO2/TiO2 nanocomposite thin film could be easily prepared on polymeric surface at low temperature. The corresponding film exhibits excellent biocompatibility, high bonding strength, and good light responses. It could be a good candidate for the surface of cell culture utensils with light-induced cell detachment property. PMID- 28026925 TI - Elevated Performance of Thin Film Nanocomposite Membranes Enabled by Modified Hydrophilic MOFs for Nanofiltration. AB - Metal-organic frameworks (MOFs) are studied for the design of advanced nanocomposite membranes, primarily due to their ultrahigh surface area, regular and highly tunable pore structures, and favorable polymer affinity. However, the development of engineered MOF-based membranes for water treatment lags behind. Here, thin-film nanocomposite (TFN) membranes containing poly(sodium 4 styrenesulfonate) (PSS) modified ZIF-8 (mZIF) in a polyamide (PA) layer were constructed via a facile interfacial polymerization (IP) method. The modified hydrophilic mZIF nanoparticles were evenly dispersed into an aqueous solution comprising piperazine (PIP) monomers, followed by polymerizing with trimesoyl chloride (TMC) to form a composite PA film. FT-IR spectroscopy and XPS analyses confirm the presence of mZIF nanoparticles on the top layer of the membranes. SEM and AFM images evince a retiform morphology of the TFN-mZIF membrane surface, which is intimately linked to the hydrophilicity and adsorption capacity of mZIF nanoparticles. Furthermore, the effect of different ZIF-8 loadings on the overall membrane performance was studied. Introducing the hydrophilizing mZIF nanoparticles not only furnishes the PA layer with a better surface hydrophilicity and more negative charge but also more than doubles the original water permeability, while maintaining a high retention of Na2SO4. The ultrahigh retentions of reactive dyes (e.g., reactive black 5 and reactive blue 2, >99.0%) for mZIF-functionalized PA membranes ensure their superior nanofiltration performance. This facile, cost-effective strategy will provide a useful guideline to integrate with other modified hydrophilic MOFs to design nanofiltration for water treatment. PMID- 28026926 TI - 3D Printing Biocompatible Polyurethane/Poly(lactic acid)/Graphene Oxide Nanocomposites: Anisotropic Properties. AB - Blending thermoplastic polyurethane (TPU) with poly(lactic acid) (PLA) is a proven method to achieve a much more mechanically robust material, whereas the addition of graphene oxide (GO) is increasingly applied in polymer nanocomposites to tailor further their properties. On the other hand, additive manufacturing has high flexibility of structure design which can significantly expand the application of materials in many fields. This study demonstrates the fused deposition modeling (FDM) 3D printing of TPU/PLA/GO nanocomposites and its potential application as biocompatible materials. Nanocomposites are prepared by solvent-based mixing process and extruded into filaments for FDM printing. The addition of GO largely enhanced the mechanical property and thermal stability of the nanocomposites. Interestingly, we found that the mechanical response is highly dependent on printing orientation. Furthermore, the 3D printed nanocomposites exhibit good biocompatibility with NIH3T3 cells, indicating promise as biomaterials scaffold for tissue engineering applications. PMID- 28026927 TI - PEGylated Polyaniline Nanofibers: Antifouling and Conducting Biomaterial for Electrochemical DNA Sensing. AB - Biofouling arising from nonspecific adsorption is a substantial outstanding challenge in diagnostics and disease monitoring, and antifouling sensing interfaces capable of reducing the nonspecific adsorption of proteins from biological complex samples are highly desirable. We present herein the preparation of novel composite nanofibers through the grafting of polyethylene glycol (PEG) polymer onto polyaniline (PANI) nanofibers and their application in the development of antifouling electrochemical biosensors. The PEGylated PANI (PANI/PEG) nanofibers possessed large surface area and remained conductive and at the same time demonstrated excellent antifouling performances in single protein solutions as well as complex human serum samples. Sensitive and low fouling electrochemical biosensors for the breast cancer susceptibility gene (BRCA1) can be easily fabricated through the attachment of DNA probes to the PANI/PEG nanofibers. The biosensor showed a very high sensitivity to target BRCA1 with a linear range from 0.01 pM to 1 nM and was also efficient enough to detect DNA mismatches with satisfactory selectivity. Moreover, the DNA biosensor based on the PEGylated PANI nanofibers supported the quantification of BRCA1 in complex human serum, indicating great potential of this novel biomaterial for application in biosensors and bioelectronics. PMID- 28026928 TI - Harnessing Photovoltage: Effects of Film Thickness, TiO2 Nanoparticle Size, MgO and Surface Capping with DSCs. AB - High photovoltage dye-sensitized solar cells (DSCs) offer an exceptional opportunity to power electrocatalysts for the production of hydrogen from water and the reduction of CO2 to usable fuels with a relatively cost-effective, low toxicity solar cell. Competitive recombination pathways such as electron transfer from TiO2 films to the redox shuttle or oxidized dye must be minimized to achieve the maximum possible photovoltage (Voc) from DSC devices. A high Voc of 882 mV was achieved with the iodide/triiodide redox shuttle and a ruthenium NCS-ligated dye, HD-2-mono, by utilizing a combined approach of (1) modulating the TiO2 surface area through film thickness and nanoparticle size selection, (2) addition of a MgO insulating layer, and (3) capping available TiO2 film surface sites post film sensitization with an F-SAM (fluorinated self-assembled monolayer) treatment. The exceptional Voc of 882 mV observed is the highest achieved for the popular NCS containing ruthenium sensitizers with >5% PCE and compares favorably to the 769 mV value observed under common device preparation conditions. PMID- 28026930 TI - Metal-Organic Framework-Derived NiSb Alloy Embedded in Carbon Hollow Spheres as Superior Lithium-Ion Battery Anodes. AB - The MOFs (metal-organic frameworks) have been extensively used for electrode materials due to their high surface area, permanent porosity, and hollow structure, but the role of antimony on the MOFs is unclear. In this work, we design the hollow spheres Ni-MOFs with SbCl3 to synthesize NiSb?CHSs (NiSb embedded carbon hollow spheres) via simple annealing and galvanic replacement reactions. The NiSb?CHSs inherited the advantages of Ni-MOFs with hollow structure, high surface area, and permanent porosity, and the NiSb nanoparticles are coated by the formed carbon particles which could effectively solve the problem of vigorous volume changes during the Li+ insertion/extraction process. The porous and network structure could well provide an extremely reduced pathway for fast Li+ diffusion and electron transport and provide extra free space for alleviating the structural strain. The NiSb?CHSs with these features were used as Li-ion batteries for the first time and exhibited excellent cycling performance, high specific capacity, and great rate capability. When coupled with a nanostructure LiMn2O4 cathode, the NiSb?CHSs//LiMn2O4 full cell also characterized a high voltage operation of ~3.5 V, high rate capability (210 mA h g-1 at a current density of 2000 mA g-1), and high Coulombic efficiency of approximate 99%, meeting the requirement for the increasing demand for improved energy devices. PMID- 28026929 TI - Near-Infrared Quantum Dot and 89Zr Dual-Labeled Nanoparticles for in Vivo Cerenkov Imaging. AB - Cerenkov luminescence (CL) is an emerging imaging modality that utilizes the light generated during the radioactive decay of many clinical used isotopes. Although it is increasingly used for background-free imaging and deep tissue photodynamic therapy, in vivo applications of CL suffer from limited tissue penetration. Here, we propose to use quantum dots (QDs) as spectral converters that can transfer the CL UV-blue emissions to near-infrared light that is less scattered or absorbed in vivo. Experiments on tissue phantoms showed enhanced penetration depth and increased transmitted intensity for CL in the presence of near-infrared (NIR) QDs. To realize this concept for in vivo imaging applications, we developed three types of NIR QDs and 89Zr dual-labeled nanoparticles based on lipid micelles, nanoemulsions, and polymeric nanoplatforms, which enable codelivery of the radionuclide and the QDs for maximized spectral conversion efficiency. We finally demonstrated the application of these self-illuminating nanoparticles for imaging of lymph nodes and tumors in a prostate cancer mouse model. PMID- 28026931 TI - Mechanochemistry at Solid Surfaces: Polymerization of Adsorbed Molecules by Mechanical Shear at Tribological Interfaces. AB - Polymerization of allyl alcohol adsorbed and sheared at a silicon oxide interface is studied using tribo-tests in vapor phase lubrication conditions and reactive molecular dynamics simulations. The load dependences of product formation obtained from experiments and simulations were consistent, indicating that the atomic-scale processes observable in the simulations were relevant to the experiments. Analysis of the experimental results in the context of mechanically assisted thermal reaction theory, combined with the atomistic details available from the simulations, suggested that the association reaction pathway of allyl alcohol molecules induced by mechanical shear is quite different from chemically induced polymerization reactions. Findings suggested that some degree of distortion of the molecule from its equilibrium state is necessary for mechanically induced chemical reactions to occur and such a distortion occurs during mechanical shear when molecules are covalently anchored to one of the sliding surfaces. PMID- 28026932 TI - Smart Fluorescent Nanoparticles in Water Showing Temperature-Dependent Ratiometric Fluorescence Color Change. AB - We synthesized two different amphiphilic small molecules 1 and 2 by attaching the same oligo(ethylene glycol) (OEG) unit to the same dicyanodistyrylbenzene (DCS) fluorophore but at different positions. These molecules self-assemble into nanoparticles in water and show lower critical solution temperature (LCST) at 26 and 58 degrees C, respectively. Upon heating, the transition of hydrophilic coils to hydrophobic globules of the OEG unit leads to the change in the stacking structure of the luminescent DCS cores. As a result, it shows significant ratiometric fluorescence color changes from excimeric yellow emission to monomer dominated green emission. Interestingly, the coassembly of 1 and 2 exhibits single transition temperature between the transition temperatures of the two components. Moreover, it is demonstrated that the transition temperature of the coassembly is delicately tuned over 26-58 degrees C by varying the molar mixing ratio of them. PMID- 28026933 TI - Thiazolidine-Masked alpha-Oxo Aldehyde Functionality for Peptide and Protein Modification. AB - alpha-Oxo aldehyde-based bioconjugation chemistry has been widely explored in peptide and protein modifications for various applications in biomedical research during the past decades. The generation of alpha-oxo aldehyde via sodium periodate oxidation is usually limited to the N-terminus of a target protein. Internal-site functionalization of proteins with the alpha-oxo aldehyde handle has not been achieved yet. Herein we report a novel method for site-specific peptide and protein modification using synthetically or genetically incorporated thiazolidine-protected alpha-oxo aldehyde. Efficient unmasking of the aldehyde was achieved by silver ion-mediated hydrolysis of thiazolidine under mild conditions for the first time. A model peptide and a recombinant protein were used to demonstrate the utility of this new method, which were site-specifically modified by oxime ligation with an oxyamine-functionalized peptide labeling reagent. Therefore, our current method has enriched the alpha-oxo aldehyde synthetic tool box in peptide and protein bioconjugation chemistry and holds great potential to be explored in novel applications in the future. PMID- 28026934 TI - Modifying Mechanical, Optical Properties and Thermal Processability of Iridescent Cellulose Nanocrystal Films Using Ionic Liquid. AB - Iridescent films formed from the self-assembly of cellulose nanocrystals (CNCs) are brittle and difficult to handle or integrate within an industrial process. Here we present a simple approach to prepare iridescent CNC films with tunable pliability and coloration through the addition of ionic liquids (ILs) of 1-allyl 3-methylimidazolium chloride (AmimCl) as plasticizers. By using the undried CNC film as a filter membrane and ILs solution as a leaching liquid, it was found that the filtration process made ILs uniformly interpenetrate into CNC film due to the strong ionic interaction between CNC and AmimCl. Unexpectedly, the filtration process also gave rise to partial desulfurization of CNC film, which is conducive to the improvement of thermal stability. Benefiting from the improved thermal stability and the dissolving capacity of AmimCl for cellulose at high temperature, the incorporated ILs enable the cholesteric CNC film to be further toughened via a hot-pressing treatment. This study demonstrates that ionic liquids have great potential to modify the mechanical, optical properties as well as the thermal stability of iridescent CNC films. PMID- 28026935 TI - Thermoresponsive Semi-IPN Hydrogel Microfibers from Continuous Fluidic Processing with High Elasticity and Fast Actuation. AB - Hydrogels with rapid and strong response to external stimuli and possessing high elasticity and strength have been considered as platform materials for numerous applications, e.g., in biomaterials engineering. Thermoresponsive hydrogels based on semi-interpenetrating polymer networks (semi-IPN) featuring N isopropylacrylamide with copolymers of poly(N-isopropylacrylamide-co-hydroxyethyl methacrylate) p(NIPAM-HEMA) chains are prepared and described. The copolymer was characterized by FTIR, NMR, and GPC. The semi-IPN structured hydrogel and its responsive properties were evaluated by dynamic mechanical measurements, SEM, DSC, equilibrium swelling ratio, and dynamic deswelling tests. The results illustrate that the semi-IPN structured hydrogels possess rapid response and high elasticity compared to conventional pNIPAM hydrogels. By using a microfluidic device with double coaxial laminar flow, we succeeded in fabricating temperature responsive ("smart") hydrogel microfibers with core-shell structures that exhibit typical diameters on the order of 100 MUm. The diameter of the fibers can be tuned by changing the flow conditions. Such hydrogel fibers can be used to fabricate "smart" devices, and the core layer can be potentially loaded with cargos to incorporate biological function in the constructs. The platforms obtained by this approach hold promise as artificial "muscles", and also "smart" hydrogel carriers providing a unique biophysical and bioactive environment for regenerative medicine and tissue engineering. PMID- 28026937 TI - A Lithium/Polysulfide Battery with Dual-Working Mode Enabled by Liquid Fuel and Acrylate-Based Gel Polymer Electrolyte. AB - The low density associated with low sulfur areal loading in the solid-state sulfur cathode of current Li-S batteries is an issue hindering the development of this type of battery. Polysulfide catholyte as a recyclable liquid fuel was proven to enhance both the energy density and power density of the battery. However, a critical barrier with this lithium (Li)/polysulfide battery is that the shuttle effect, which is the crossover of polysulfides and side deposition on the Li anode, becomes much more severe than that in conventional Li-S batteries with a solid-state sulfur cathode. In this work, we successfully applied an acrylate-based gel polymer electrolyte (GPE) to the Li/polysulfide system. The GPE layer can effectively block the detrimental diffusion of polysulfides and protect the Li metal from the side passivation reaction. Cathode-static batteries utilizing 2 M catholyte (areal sulfur loading of 6.4 mg cm-2) present superior cycling stability (727.4 mAh g-1 after 500 cycles at 0.2 C) and high rate capability (814 mAh g-1 at 2 C) and power density (~10 mW cm-2), which also possess replaceable and encapsulated merits for mobile devices. In the cathode flow mode, the Li/polysulfide system with catholyte supplied from an external tank demonstrates further improved power density (~69 mW cm-2) and stable cycling performance. This novel and simple Li/polysulfide system represents a significant advancement of high energy density sulfur-based batteries for future power sources. PMID- 28026936 TI - Safe-by-Design CuO Nanoparticles via Fe-Doping, Cu-O Bond Length Variation, and Biological Assessment in Cells and Zebrafish Embryos. AB - The safe implementation of nanotechnology requires nanomaterial hazard assessment in accordance with the material physicochemical properties that trigger the injury response at the nano/bio interface. Since CuO nanoparticles (NPs) are widely used industrially and their dissolution properties play a major role in hazard potential, we hypothesized that tighter bonding of Cu to Fe by particle doping could constitute a safer-by-design approach through decreased dissolution. Accordingly, we designed a combinatorial library in which CuO was doped with 1 10% Fe in a flame spray pyrolysis reactor. The morphology and structural properties were determined by XRD, BET, Raman spectroscopy, HRTEM, EFTEM, and EELS, which demonstrated a significant reduction in the apical Cu-O bond length while simultaneously increasing the planar bond length (Jahn-Teller distortion). Hazard screening was performed in tissue culture cell lines and zebrafish embryos to discern the change in the hazardous effects of doped vs nondoped particles. This demonstrated that with increased levels of doping there was a progressive decrease in cytotoxicity in BEAS-2B and THP-1 cells, as well as an incremental decrease in the rate of hatching interference in zebrafish embryos. The dissolution profiles were determined and the surface reactions taking place in Holtfreter's solution were validated using cyclic voltammetry measurements to demonstrate that the Cu+/Cu2+ and Fe2+/Fe3+ redox species play a major role in the dissolution process of pure and Fe-doped CuO. Altogether, a safe-by-design strategy was implemented for the toxic CuO particles via Fe doping and has been demonstrated for their safe use in the environment. PMID- 28026938 TI - Anomeric Selectivity and Product Profile of a Processive Cellulase. AB - Cellobiohydrolases (CBHs) make up an important group of enzymes for both natural carbon cycling and industrial deconstruction of lignocellulosic biomass. The consecutive hydrolysis of one cellulose strand relies on an intricate pattern of enzyme-substrate interactions in the long, tunnel-shaped binding site of the CBH. In this work, we have investigated the initial complexation mode with cellulose of the most thoroughly studied CBH, Cel7A from Hypocrea jecorina (HjCel7A). We found that HjCel7A predominantly produces glucose when it initiates a processive run on insoluble microcrystalline cellulose, confirming the validity of an even and odd product ratio as an estimate of processivity. Moreover, the glucose released from cellulose was predominantly alpha-glucose. A link between the initial binding mode of the enzyme and the reducing end configuration was investigated by inhibition studies with the two anomers of cellobiose. A clear preference for beta-cellobiose in product binding site +2 was observed for HjCel7A, but not the homologous endoglucanase, HjCe7B. Possible relationships between this anomeric preference in the product site and the prevalence of odd numbered initial-cut products are discussed, and a correlation between processivity and anomer selectivity is proposed. PMID- 28026939 TI - Correction to Simulating Protein Fold Switching by Replica Exchange with Tunneling. PMID- 28026941 TI - Cobalt-Catalyzed Carbozincation of Ynamides. AB - An original cobalt-catalyzed ynamide carbozincation leading mainly to diverse 3 aryl enamides with mild reaction conditions and good functional-group tolerance has been developed. This reaction displays an excellent regio- and total stereoselectivity and opens the way to appealing synthetic applications. Moreover, this approach allows the selective synthesis of biologically relevant 3,5-disubstituted oxazolone frameworks. PMID- 28026940 TI - Active Site Hydrophobicity and the Convergent Evolution of Paraoxonase Activity in Structurally Divergent Enzymes: The Case of Serum Paraoxonase 1. AB - Serum paraoxonase 1 (PON1) is a native lactonase capable of promiscuously hydrolyzing a broad range of substrates, including organophosphates, esters, and carbonates. Structurally, PON1 is a six-bladed beta-propeller with a flexible loop (residues 70-81) covering the active site. This loop contains a functionally critical Tyr at position 71. We have performed detailed experimental and computational analyses of the role of selected Y71 variants in the active site stability and catalytic activity in order to probe the role of Y71 in PON1's lactonase and organophosphatase activities. We demonstrate that the impact of Y71 substitutions on PON1's lactonase activity is minimal, whereas the kcat for the paraoxonase activity is negatively perturbed by up to 100-fold, suggesting greater mutational robustness of the native activity. Additionally, while these substitutions modulate PON1's active site shape, volume, and loop flexibility, their largest effect is in altering the solvent accessibility of the active site by expanding the active site volume, allowing additional water molecules to enter. This effect is markedly more pronounced in the organophosphatase activity than the lactonase activity. Finally, a detailed comparison of PON1 to other organophosphatases demonstrates that either a similar "gating loop" or a highly buried solvent-excluding active site is a common feature of these enzymes. We therefore posit that modulating the active site hydrophobicity is a key element in facilitating the evolution of organophosphatase activity. This provides a concrete feature that can be utilized in the rational design of next-generation organophosphate hydrolases that are capable of selecting a specific reaction from a pool of viable substrates. PMID- 28026942 TI - Electrostatic Interactions Govern "Odd/Even" Effects in Water-Induced Gemini Surfactant Self-Assembly. AB - Gemini surfactants comprise two single-tailed surfactants connected by a linker at or near the hydrophilic headgroup. They display a variety of water concentration-dependent lyotropic liquid crystal morphologies that are sensitive to surfactant molecular structure and the nature of the headgroups and counterions. Recently, an interesting dependence of the aqueous-phase behavior on the length of the linker has been discovered; odd-numbered linker length surfactants exhibit characteristically different phase diagrams than even numbered linker surfactants. In this work, we investigate this "odd/even effect" using computer simulations, focusing on experimentally studied gemini dicarboxylates with Na+ counterions, seven nonterminal carbon atoms in the tails, and either three, four, five, or six carbon atoms in the linker (denoted Na-73, Na-74, Na-75, and Na-76, respectively). We find that the relative electrostatic repulsion between headgroups in the different morphologies is correlated with the qualitative features of the experimental phase diagrams, predicting destabilization of hexagonal phases as the cylinders pack close together at low water content. Significant differences in the relative headgroup orientations of Na-74 and Na-76 compared to those of Na-73 and Na-75 surfactants lead to differences in linker-linker packing and long-range headgroup-headgroup electrostatic repulsion, which affects the delicate electrostatic balance between the hexagonal and gyroid phases. Much of the fundamental insight presented in this work is enabled by the ability to computationally construct and analyze metastable phases that are not observable in experiments. PMID- 28026943 TI - Reactive Uptake of Dimethylamine by Ammonium Sulfate and Ammonium Sulfate-Sucrose Mixed Particles. AB - Short-chain alkyl amines can undergo gas-to-particle partitioning via reactive uptake by ammonium salts, whose phases have been thought to largely influence the extent of amine uptake. Previous studies mainly focused on particles of single ammonium salt at either dry or wet conditions without any addition of organic compounds. Here we report the uptake of dimethylamine (DMA) by ammonium sulfate (AS) and AS-sucrose mixed particles at different relative humidities (RHs) using an electrodynamic balance coupled with in situ Raman spectroscopy. DMA is selected as a representative of short-chain alkyl amines, and sucrose is used as a surrogate of viscous and hydrophilic organics. Effective DMA uptake was observed for most cases, except for the water-limiting scenario at <5% RH and the formation of an ultraviscous sucrose coating at 10% RH and below. DMA uptake coefficients (gamma) were estimated using the particle mass measurements during DMA uptake. Addition of sucrose can increase gamma by absorbing water or inhibiting AS crystallization and decrease gamma by elevating the particle viscosity and forming a coating layer. DMA uptake can be facilitated for crystalline AS or retarded for aqueous AS with hydrophilic viscous organics (e.g., secondary organic material formed via the oxidation of biogenic volatile organic compounds) present in aerosol particles. PMID- 28026944 TI - MDANSE: An Interactive Analysis Environment for Molecular Dynamics Simulations. AB - The MDANSE software-Molecular Dynamics Analysis of Neutron Scattering Experiments is presented. It is an interactive application for postprocessing molecular dynamics (MD) simulations. Given the widespread use of MD simulations in material and biomolecular sciences to get a better insight for experimental techniques such as thermal neutron scattering (TNS), the development of MDANSE has focused on providing a user-friendly, interactive, graphical user interface for analyzing many trajectories in the same session and running several analyses simultaneously independently of the interface. This first version of MDANSE already proposes a broad range of analyses, and the application has been designed to facilitate the introduction of new analyses in the framework. All this makes MDANSE a valuable tool for extracting useful information from trajectories resulting from a wide range of MD codes. PMID- 28026945 TI - Reduction of Intersex in a Wild Fish Population in Response to Major Municipal Wastewater Treatment Plant Upgrades. AB - Intersex in fish downstream of municipal wastewater treatment plants (MWWTPs) is a global concern. Consistent high rates of intersex in male rainbow darter (Etheostoma caeruleum) have been reported for several years in the Grand River, in southern Ontario, Canada, in close proximity to two MWWTPs. The larger MWWTP (Kitchener) recently underwent upgrades that included the conversion from a carbonaceous activated sludge to nitrifying activated sludge treatment process. This created a unique opportunity to assess whether upgrades designed to improve effluent quality could also remediate the intersex previously observed in wild fish. Multiple years (2007-2012) of intersex data on male rainbow darter collected before the upgrades at sites associated with the MWWTP outfall were compared with intersex data collected in postupgrade years (2013-2015). These upgrades resulted in a reduction from 70 to 100% intersex incidence (preupgrade) to <10% in postupgrade years. Although the cause of intersex remains unknown, indicators of effluent quality including nutrients, pharmaceuticals, and estrogenicity improved in the effluent after the upgrades. This study demonstrated that investment in MWWTP upgrades improved effluent quality and was associated with an immediate change in biological responses in the receiving environment. This is an important finding considering the tremendous cost of wastewater infrastructure. PMID- 28026946 TI - Monascustin, an Unusual gamma-Lactam from Red Yeast Rice. AB - Monascustin (1), an unusual gamma-lactam, was isolated from an ethanol extract of the Monascus purpureus fermented rice. Its structure including the absolute configuration was determined by spectroscopic data analysis and confirmed by X ray crystallography. A plausible biosynthetic pathway is discussed on the basis of amino acid derivatization. Compound 1 showed inhibitory activity against histone deacetylase 1. PMID- 28026948 TI - One-Pot Synthesis of Rotationally Restricted, Conjugatable, BODIPY Derivatives from Phthalides. AB - O-Ethylation of phthalides with Meerwein's reagent followed by reaction of the ensuing salts with pyrrole, results in the formation of 5-alkoxy-5-phenyl dipyrromethane derivatives, which function as ready precursors of ortho substituted 8-aryl BODIPY derivatives by reaction with borontrifluoride etherate, an overall process that can be carried out in a one-pot operation. PMID- 28026947 TI - Biodegradable Kojic Acid-Based Polymers: Controlled Delivery of Bioactives for Melanogenesis Inhibition. AB - Kojic acid (KA) is a naturally occurring fungal metabolite that is utilized as a skin-lightener and antibrowning agent owing to its potent tyrosinase inhibition activity. While efficacious, KA's inclination to undergo pH-mediated, thermal-, and photodegradation reduces its efficacy, necessitating stabilizing vehicles. To minimize degradation, poly(carbonate-esters) and polyesters comprised of KA and natural diacids were prepared via solution polymerization methods. In vitro hydrolytic degradation analyses revealed KA release was drastically influenced by polymer backbone composition (e.g., poly(carbonate-ester) vs polyester), linker molecule (aliphatic vs heteroatom-containing), and release conditions (physiological vs skin). Tyrosinase inhibition assays demonstrated that aliphatic KA dienols, the major degradation product under skin conditions, were more potent then KA itself. All dienols were found to be less toxic than KA at all tested concentrations. Additionally, the most lipophilic dienols were statistically more effective than KA at inhibiting melanin biosynthesis in cells. These KA-based polymer systems deliver KA analogues with improved efficacy and cytocompatible profiles, making them ideal candidates for sustained topical treatments in both medical and personal care products. PMID- 28026949 TI - Atomic-Level Structure Characterization of Biomass Pre- and Post-Lignin Treatment by Dynamic Nuclear Polarization-Enhanced Solid-State NMR. AB - Lignocellulosic biomass is a promising sustainable feedstock for the production of biofuels, biomaterials, and biospecialty chemicals. However, efficient utilization of biomass has been limited by our poor understanding of its molecular structure. Here, we report a dynamic nuclear polarization (DNP) enhanced solid-state (SS)NMR study of the molecular structure of biomass, both pre- and postcatalytic treatment. This technique enables the measurement of 2D homonuclear 13C-13C correlation SSNMR spectra under natural abundance, yielding, for the first time, an atomic-level picture of the structure of raw and catalytically treated biomass samples. We foresee that further such experiments could be used to determine structure-function relationships and facilitate the development of more efficient, and chemically targeted, biomass-conversion technologies. PMID- 28026950 TI - LC- and GC-QTOF-MS as Complementary Tools for a Comprehensive Micropollutant Analysis in Aquatic Systems. AB - Efficient strategies are required to implement comprehensive suspect screening methods using high-resolution mass spectrometry within environmental monitoring campaigns. In this study, both liquid and gas chromatography time-of-flight mass spectrometry (LC-QTOF-MS and GC-QTOF-MS) were used to screen for >5000 target and suspect compounds in the Sacramento-San Joaquin River Delta in Northern California. LC-QTOF-MS data were acquired in All-Ions fragmentation mode in both positive and negative electrospray ionization (ESI). LC suspects were identified using two accurate mass LC-QTOF-MS/MS libraries containing pesticides, pharmaceuticals, and other environmental contaminants and a custom exact mass database with predicted transformation products (TPs). The additional fragment information from the All-Ions acquisition improved the confirmation of the compound identity, with a low false positive rate (9%). Overall, 25 targets, 73 suspects, and 5 TPs were detected. GC-QTOF-MS extracts were run in negative chemical ionization (NCI) for 21 targets (mainly pyrethroids) at sub-ng/L levels. For suspect screening, extracts were rerun in electron ionization (EI) mode with a retention time locked method using a GC-QTOF-MS pesticide library (containing exact mass fragments and retention times). Sixteen targets and 42 suspects were detected, of which 12 and 17, respectively, were not identified by LC-ESI-QTOF MS. The results highlight the importance of analyzing water samples using multiple separation techniques and in multiple ionization modes to obtain a comprehensive chemical contaminant profile. The investigated river delta experiences significant pesticide inputs, leading to environmentally critical concentrations during rain events. PMID- 28026951 TI - Polymer-Drug Nanoparticles Combine Doxorubicin Carrier and Heparin Bioactivity Functionalities for Primary and Metastatic Cancer Treatment. AB - Here, a biocompatible amphiphilic copolymer of low molecular weight heparin (LMWH) and doxorubicin (DOX) connected by an acid-sensitive hydrazone bond for enhanced tumor treatment efficacy and safety has been designed and tested. The conjugate combines DOX delivery with LMWH antimetastatic capabilities. After the nanoparticles reach the tumor site, the acidic tumor microenvironment triggers the breakage of the hydrazone bond releasing DOX from the nanoparticles, which results in an increase in the cellular uptake and enhanced in vivo antitumor efficacy. A 3.4-fold and 1.5-fold increase in tumor growth inhibition were observed compared to the saline-treated control group and free DOX treated group, respectively. The LMWH-based nanoparticles effectively inhibited interactions between tumor cells and platelets mediated by P-selectin reducing metastasis of cells in both in vitro and in vivo models. The improved safety and therapeutic effect of LMWW-DOX nanoparticles offers new potential for tumor therapy. PMID- 28026952 TI - Alkali Metal-Hydroxide-Catalyzed C(sp)-H Bond silylation. AB - Disclosed is a mild, scalable, and chemoselective catalytic cross-dehydrogenative C-H bond functionalization protocol for the construction of C(sp)-Si bonds in a single step. The scope of the alkyne and hydrosilane partners is substantial, providing an entry point into various organosilane building blocks and additionally enabling the discovery of a number of novel synthetic strategies. Remarkably, the optimal catalysts are NaOH and KOH. PMID- 28026954 TI - Kinetics and Mechanistic Investigations of Atmospheric Oxidation of HFO-1345fz by OH Radical: Insights from Theory. AB - HFO-1345fz (CF3CF2CH?CH2 or 3,3,4,4,4-pentafluoro-1-butene) belongs to a class of hydrofluoro-olefins and represents a new generation of potential foam expansion agents. Its atmospheric impact and environmental acceptability can be estimated from the studies of kinetics and mechanism of its oxidative degradation. The molecular insights accompanying the reaction pathways in terms of the characterization of intermediates or products and radiative properties should prove useful for large-scale industrial applications. Systematic mechanistic gas phase kinetics investigations on the reactivity of HFO-1345fz with the *OH facilitating a variety of degradation routes have been carried out employing the M06-2x-based density functional theory. Structure and energetics of different reaction pathways such as hydrogen abstraction, *OH addition, isomerization dissociation, or interaction with atmospheric O2 have been analyzed. The formation of gaseous products from the interaction of HFO-1345fz with *OH in the absence and presence of NOx atmospheric conditions has been reported. Calculated branching ratios have shown that the addition channel dominates such oxidative degradation, whereas the abstraction channel contributes negligibly to the global rate constant and addition of *OH to the terminal carbon is favored over the nonterminal one. The rate constants for all reaction channels were computed by conventional transition state theory (TST) and canonical variation transition state theory (CVT) including small curvature tunneling (SCT) over the temperature range of 200-1000 K at atmospheric pressure. The CVT calculated rate constant for the reaction at 298 K was shown to be 1.17 * 10-12 cm3 molecule-1 s-1, which compares well with the 1.24 * 10-12 cm3 molecule-1 s-1 as obtained from TST and is in excellent agreement with the experiments reported earlier. The atmospheric lifetime, radiative efficiency, and global warming potential (GWP) have also been obtained. PMID- 28026953 TI - Role of the Conserved Valine 236 in Access of Ligands to the Active Site of Thermus thermophilus ba3 Cytochrome Oxidase. AB - Knowledge of the role of conserved residues in the ligand channel of heme-copper oxidases is critical for understanding how the protein scaffold modulates the function of these enzymes. In this study, we investigated the role of the conserved valine 236 in the ligand channel of ba3 cytochrome c oxidase from Thermus thermophilus by mutating the residue to a more polar (V236T), smaller (V236A), or larger (V236I, V236N, V236L, V236M, and V236F) residue. The crystal structures of the mutants were determined, and the effects of the mutations on the rates of CO, O2, and NO binding were investigated. O2 reduction and NO binding were unaffected in V236T, while the oxidation of heme b during O-O bond cleavage was not detected in V236A. The V236A results are attributed to a decrease in the rate of electron transfer between heme b and heme a3 during O-O bond cleavage in V236A, followed by faster re-reduction of heme b by CuA. This interpretation is supported by classical molecular dynamics simulations of diffusion of O2 to the active site in V236A that indicated a larger distance between the two hemes compared to that in the wild type and increased contact of heme a3 with water and weakened interactions with residues R444 and R445. As the size of the mutant side chain increased and protruded more into the ligand cavity, the rates of ligand binding decreased correspondingly. These results demonstrate the importance of V236 in facilitating access of ligands to the active site in T. thermophilus ba3. PMID- 28026955 TI - Tunable Synthesis of Mesoporous Silica Particles with Unique Radially Oriented Pore Structures from Tetramethyl Orthosilicate via Oil-Water Emulsion Process. AB - Numerous studies of the synthesis of mesoporous silica (MPS) particles with tailored properties have been published. Among those studies, tetraethyl orthosilicate (TEOS) is commonly used as a silica source, but tetramethyl orthosilicate (TMOS) is rarely used because its reaction is fast and difficult to control. In this study, MPS particles were synthesized via one-step controlled polymerization of styrene and hydrolysis of TMOS, followed by the addition of hexadecyltrimethylammonium bromide (CTAB) and n-octane. The MPS particles obtained from TMOS generally have small inner pores, but the MPS particles obtained in this study had a unique radially oriented structure, a high surface area up to 800 m2 g-1, and large pores, of size 20 nm. The content of styrene in the emulsion system played a key role in increasing pore sizes of the MPS particles. A plausible mechanism for particle formation based on the phase behavior and type of the emulsion system is proposed. For further research, this material is expected to be useful for various applications, such as in drug delivery, filtration, and catalyst supports. PMID- 28026956 TI - Thermochemical Analysis of Molybdenum Thin Films on Porous Alumina. AB - Molybdenum (Mo) thin films (thickness <100 nm) were physically deposited by e beam evaporation on a porous alumina substrate and were analyzed for their stability and reactivity under various thermal and gas conditions. The Mo thin film composites were stable below 300 degrees C but had no reactivity toward gases. Mo thin films showed nitrogen incorporation on the surface as well as in the subsurface at 450 degrees C, as confirmed by X-ray photoelectron spectroscopy. The reactivity toward nitrogen was diminished in the presence of CO2, although no carbon species were detected either on the surface or in the subsurface. The Mo thin films have a very stable native oxide layer, which may further oxidize to higher oxidation states above 500 degrees C due to the reaction with the porous anodized alumina substrate. The oxidation of Mo thin films was accelerated in the presence of oxidizing gases. At 600 degrees C in N2, the Mo thin film on anodized alumina was completely oxidized and may also have been volatilized. The results imply that choosing thermally stable and inactive porous supports and operating in nonoxidizing conditions below 500 degrees C will likely maintain the stability of the Mo composite. This study provides key information about the chemical and structural stability of a Mo thin film on a porous substrate for future membrane applications and offers further insights into the integrity of thin-film composites when exposed to harsh conditions. PMID- 28026957 TI - Comparison of Avidin, Neutravidin, and Streptavidin as Nanocarriers for Efficient siRNA Delivery. AB - Protein-based drug delivery carrier has been one of the most employed modalities in biopharmaceuticals. In this study, we have compared avidin and its two analogues, neutravidin and streptavidin, as nanocarriers for the delivery of biotin-labeled siRNA with the help of biotinylated cholesterol (targeting ligand) and protamine (condensing agent). These proteins have similar binding affinity to biotin but substantial difference in their physical and chemical characteristics. Here, we have shown how these characteristics affect the size, cellular uptake, and activity of the avidin-based siRNA nanocomplex. In contrast to avidin and streptavidin nanocomplexes, neutravidin-based nanocomplex shows very low endosome entrapment and high cytoplasmic localization at extended times. High amount of the siRNA released in the cytoplasm by neutravidin-based nanocomplex at extended times (24 h) results in extensive and sustained PCBP2 gene silencing activity in HSC-T6 rat hepatic stellate cells. Neutravidin-based nanocomplex shows significantly low exocytosis in comparison to the streptavidin-based nanocomplex. Avidin-, neutravidin-, and streptavidin-based nanocomplexes are similar in size and had no significant cytotoxicity in transfected HSC-T6 cells or inflammatory cytokine induction in a whole blood assay. Compared to free siRNA, the neutravidin-based siRNA nanocomplex exhibits higher accumulation at 2 h in the liver of the rats with CCl4-induced liver fibrosis. Neutravidin has therefore been shown to be the most promising avidin analogue for the delivery of siRNA. PMID- 28026958 TI - Human alpha-Defensin 6 Self-Assembly Prevents Adhesion and Suppresses Virulence Traits of Candida albicans. AB - Human alpha-defensin 6 (HD6) is a host-defense peptide that contributes to intestinal innate immunity and mediates homeostasis at mucosal surfaces by forming noncovalent oligomers that capture bacteria and prevent bacterial invasion of the epithelium. This work illustrates a new role of HD6 in defending the host epithelium against pathogenic microorganisms. We report that HD6 blocks adhesion of Candida albicans to human intestinal epithelial cells and suppresses two C. albicans virulence traits, namely, invasion of human epithelial cells and biofilm formation. Moreover, a comparison of HD6 and a single-point variant F2A that does not form higher-order oligomers demonstrates that the self-assembly properties of HD6 are essential for functional activity against C. albicans. This opportunistic fungal pathogen, which resides in the intestine as a member of the gut microbiota in healthy individuals, can turn virulent and cause a variety of diseases ranging from superficial infections to life-threatening systemic infections. Our results indicate that HD6 may allow C. albicans to persist as a harmless commensal in the gastrointestinal tract. Moreover, HD6 and HD6-inspired molecules may provide a foundation for exploring new antimicrobial strategies that attenuate the virulence traits of C. albicans and other microbial pathogens. PMID- 28026959 TI - Phase Separation of Dirac Electrons in Topological Insulators at the Spatial Limit. AB - In this work we present unique signatures manifested by the local electronic properties of the topological surface state in Bi2Te3 nanostructures as the spatial limit is approached. We concentrate on the pure nanoscale limit (nanoplatelets) with spatial electronic resolution down to 1 nm. The highlights include strong dependencies on nanoplatelet size: (1) observation of a phase separation of Dirac electrons whose length scale decreases as the spatial limit is approached, and (2) the evolution from heavily n-type to lightly n-type surface doping as nanoplatelet thickness increases. Our results show a new approach to tune the Dirac point together with reduction of electronic disorder in topological insulator (TI) nanostructured systems. We expect our work will provide a new route for application of these nanostructured Dirac systems in electronic devices. PMID- 28026960 TI - Two-Dimensional Ultrathin MXene Ceramic Nanosheets for Photothermal Conversion. AB - Ceramic biomaterials have been investigated for several decades, but their potential biomedical applications in cancer therapy have been paid much less attentions, mainly due to their lack of related material functionality for combating the cancer. In this work, we report, for the first time, that MAX ceramic biomaterials exhibit the unique functionality for the photothermal ablation of cancer upon being exfoliated into ultrathin nanosheets within atomic thickness (MXene). As a paradigm, biocompatible Ti3C2 nanosheets (MXenes) were successfully synthesized based on a two-step exfoliation strategy of MAX phase Ti3AlC2 by the combined HF etching and TPAOH intercalation. Especially, the high photothermal-conversion efficiency and in vitro/in vivo photothermal ablation of tumor of Ti3C2 nanosheets (MXenes) were revealed and demonstrated, not only in the intravenous administration of soybean phospholipid modified Ti3C2 nanosheets but also in the localized intratumoral implantation of a phase-changeable PLGA/Ti3C2 organic-inorganic hybrid. This work promises the great potential of Ti3C2 nanosheets (MXenes) as a novel ceramic photothermal agent used for cancer therapy and may arouse much interest in exploring MXene-based ceramic biomaterials to benefit the biomedical applications. PMID- 28026961 TI - Interlayer Excitons and Band Alignment in MoS2/hBN/WSe2 van der Waals Heterostructures. AB - van der Waals heterostructures (vdWH) are ideal systems for exploring light matter interactions at the atomic scale. In particular, structures with a type-II band alignment can yield detailed insight into carrier-photon conversion processes, which are central to, for example, solar cells and light-emitting diodes. An important first step in describing such processes is to obtain the energies of the interlayer exciton states existing at the interface. Here we present a general first-principles method to compute the electronic quasi particle (QP) band structure and excitonic binding energies of incommensurate vdWHs. The method combines our quantum electrostatic heterostructure (QEH) model for obtaining the dielectric function with the many-body GW approximation and a generalized 2D Mott-Wannier exciton model. We calculate the level alignment together with intra- and interlayer exciton binding energies of bilayer MoS2/WSe2 with and without intercalated hBN layers, finding excellent agreement with experimental photoluminescence spectra. A comparison to density functional theory calculations demonstrates the crucial role of self-energy and electron-hole interaction effects. PMID- 28026962 TI - Ultrafast Three-Dimensional X-ray Imaging of Deformation Modes in ZnO Nanocrystals. AB - Imaging the dynamical response of materials following ultrafast excitation can reveal energy transduction mechanisms and their dissipation pathways, as well as material stability under conditions far from equilibrium. Such dynamical behavior is challenging to characterize, especially operando at nanoscopic spatiotemporal scales. In this letter, we use X-ray coherent diffractive imaging to show that ultrafast laser excitation of a ZnO nanocrystal induces a rich set of deformation dynamics including characteristic "hard" or inhomogeneous and "soft" or homogeneous modes at different time scales, corresponding respectively to the propagation of acoustic phonons and resonant oscillation of the crystal. By integrating the 3D nanocrystal structure obtained from the ultrafast X-ray measurements with a continuum thermo-electro-mechanical finite element model, we elucidate the deformation mechanisms following laser excitation, in particular, a torsional mode that generates a 50% greater electric potential gradient than that resulting from the flexural mode. Understanding of the time-dependence of these mechanisms on ultrafast scales has significant implications for development of new materials for nanoscale power generation. PMID- 28026963 TI - Tandem Addition/Cyclization for Access to Isoquinolines and Isoquinolones via Catalytic Carbopalladation of Nitriles. AB - The first example of the palladium-catalyzed sequential nucleophilic addition followed by an intramolecular cyclization of functionalized nitriles with arylboronic acids has been achieved, providing an efficient synthetic pathway to access structurally diverse isoquinolines and isoquinolones. This methodology has also been successfully applied to the total synthesis of the topoisomerase I inhibitor CWJ-a-5 (free base). PMID- 28026964 TI - New Class of 3D Topological Insulator in Double Perovskite. AB - We predict a new class of 3D topological insulators (TIs) in which the spin-orbit coupling (SOC) can more effectively generate band gap. Band gap of conventional TI is mainly limited by two factors, the strength of SOC and, from electronic structure perspective, the band gap when SOC is absent. While the former is an atomic property, the latter can be minimized in a generic rock-salt lattice model in which a stable crossing of bands at the Fermi level along with band character inversion occurs in the absence of SOC. Thus large-gap TIs or TIs composed of lighter elements can be expected. In fact, we find by performing first-principles calculations that the model applies to a class of double perovskites A2BiXO6 (A = Ca, Sr, Ba; X = Br, I) and the band gap is predicted up to 0.55 eV. Besides, surface Dirac cones are robust against the presence of dangling bond at boundary. PMID- 28026965 TI - Assessing the Efficacy of Poly(N-isopropylacrylamide) for Drug Delivery Applications Using Molecular Dynamics Simulations. AB - All-atom molecular dynamic simulations (AA-MD) are performed for aqueous solutions of hydrophobic drug molecules (phenytoin) with model polymer excipients, namely, (1) N-isopropylacrylamide, (pNIPAAm), (2) pNIPAAm-co acrylamide (Am), and (3) pNIPAAm-co-dimethylacrylamide (DMA). After validating the force field parameters using the well-known lower critical solution behavior of pNIPAAm, we simulate the polymer-drug complex in water and its behavior at temperatures below (295 K) and above the LCST (310 K). Using radial distribution functions, we find that there is an optimum comonomer molar fraction of around 20 30% DMA at which interaction with phenytoin drug molecules is strongest, consistent with recent experimental findings. The results provide evidence that molecular simulations are able to provide guidance in the optimization of novel polymer excipients for drug release. PMID- 28026966 TI - Facet-Selective Growth of Organic Heterostructured Architectures via Sequential Crystallization of Structurally Complementary pi-Conjugated Molecules. AB - In contrast to those for their polymeric counterparts, the controlled construction of organic heterostructured architectures derived from pi-conjugated organic molecules has been rare and remains a great challenge. Herein, we develop a simple single-step solution strategy for the realization of organic heterostructures comprising coronene and perylene. Under a sequential crystallization process, an efficient doping step for coronene and perylene domains enables their perfect lattice matching, which facilitates facet-selective epitaxial growth of perylene domains on both the tips and the side surfaces of the preformed seed microwires by manipulating the growth pathways of the two pairs of materials. The present synthetic route provides a promising platform to investigate the detailed formation mechanism of complex organic heterostructures with specific topological configurations, further directing the construction of more functional heterostructured materials. PMID- 28026967 TI - Identification of Molecular Targets for 4,5-Dichloro-2-n-octyl-4-isothiazolin-3 one (DCOIT) in Teleosts: New Insight into Mechanism of Toxicity. AB - Environmental pollutants are capable of concomitantly inducing diverse toxic effects. However, it is largely unknown which effects are directly induced and which effects are secondary, thus calling for definitive identification of the initiating molecular event for a pollutant to elucidate the mechanism of toxicity. In the present study, affinity pull-down assays were used to identify target proteins for 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT), a costal pollutant of emerging concern, in various tissues (e.g., brain, liver, plasma, and gonad) from marine medaka (Oryzias melastigma) and zebrafish (Danio rerio). Pull-down results showed that, in male and female brains from medaka and zebrafish, DCOIT had a consistently high affinity for G protein alpha subunits (Galpha), suggesting the targeted effects of DCOIT on signaling transduction from G protein-coupled receptors (GPCRs) and an extrapolatable mode of action in teleost brains. Validation using recombinant proteins and molecular docking analysis confirmed that binding of DCOIT to Galpha protein competitively inhibited its activation by substrate. Considering the involvement of GPCRs in the regulation of myriad biological processes, including the hypothalamus pituitary-gonadal-liver axis, binding of DCOIT to upstream Galpha proteins in the brain may provide a plausible explanation for the diversity of toxic effects resulting from DCOIT challenge, especially abnormal hormonal production through the mitogen-activated protein kinase pathway. A new mechanism of action based on GPCR signaling is thus hypothesized for endocrine disrupting chemicals and warrants further research to clearly elucidate the link between GPCR signaling and endocrine disruption. PMID- 28026968 TI - Scientific Evaluation and Review of Claims in Health Care (SEaRCH): A Streamlined, Systematic, Phased Approach for Determining "What Works" in Healthcare. AB - BACKGROUND: Answering the question of "what works" in healthcare can be complex and requires the careful design and sequential application of systematic methodologies. Over the last decade, the Samueli Institute has, along with multiple partners, developed a streamlined, systematic, phased approach to this process called the Scientific Evaluation and Review of Claims in Health Care (SEaRCHTM). The SEaRCH process provides an approach for rigorously, efficiently, and transparently making evidence-based decisions about healthcare claims in research and practice with minimal bias. METHODS: SEaRCH uses three methods combined in a coordinated fashion to help determine what works in healthcare. The first, the Claims Assessment Profile (CAP), seeks to clarify the healthcare claim and question, and its ability to be evaluated in the context of its delivery. The second method, the Rapid Evidence Assessment of the Literature (REAL(c)), is a streamlined, systematic review process conducted to determine the quantity, quality, and strength of evidence and risk/benefit for the treatment. The third method involves the structured use of expert panels (EPs). There are several types of EPs, depending on the purpose and need. Together, these three methods CAP, REAL, and EP-can be integrated into a strategic approach to help answer the question "what works in healthcare?" and what it means in a comprehensive way. DISCUSSION: SEaRCH is a systematic, rigorous approach for evaluating healthcare claims of therapies, practices, programs, or products in an efficient and stepwise fashion. It provides an iterative, protocol-driven process that is customized to the intervention, consumer, and context. Multiple communities, including those involved in health service and policy, can benefit from this organized framework, assuring that evidence-based principles determine which healthcare practices with the greatest promise are used for improving the public's health and wellness. PMID- 28026969 TI - The Influence of Social Circumstances on "Risky" Patterns of Alcohol Consumption Among Mothers With Preschool-Aged Children in England. AB - BACKGROUND: Social factors have been linked to patterns of alcohol use among women. However, conflicting evidence on the ways in which socio-economic circumstances are linked to women's alcohol use impedes our understanding. Interest in women's alcohol use has moved up the policy agenda. Nevertheless, existing research fails to attend to differences among groups of women according to their social circumstances, including whether or not they are mothers. OBJECTIVES: This study aims to enhance our understanding of "risky" patterns of alcohol use among mothers in the UK during very early motherhood. METHODS: Secondary analyses of 2000/1 data from the Millennium Cohort Study (MCS) was undertaken. Using a broad outcome measure of "risky" alcohol use, patterns of consumption among a sub-set of mothers recruited in England (n = 7048) were explored according to a number of social and domestic variables. Using logistic regression, mutually adjusted analyses that included adjustment for age were undertaken. Odds ratios were calculated for the likelihood of "risky" drinking according to mothers' social circumstances and level of disadvantage. RESULTS: "Risky" alcohol use was more likely with increased levels of disadvantage: disadvantaged childhood circumstances, lower levels of educational attainment, lower household income, younger age at first birth, lone parenthood. CONCLUSIONS: Social gradients were evident for "risky" alcohol use among mothers with 9-month old babies in England who took part in the MCS. These findings emphasize the importance of exploring patterns of alcohol use among sub-groups of the population that are currently under-represented in the research literature. PMID- 28026970 TI - Engineering 3D-Bioplotted scaffolds to induce aligned extracellular matrix deposition for musculoskeletal soft tissue replacement. AB - PURPOSE: Tissue engineering and regenerative medicine approaches have the potential to overcome the challenges associated with current treatment strategies for meniscus injuries. 3D-Bioplotted scaffolds are promising, but have not demonstrated the ability to guide the formation of aligned collagenous matrix in vivo, which is critical for generating functional meniscus tissue. In this study, we evaluate the ability of 3D-Bioplotted scaffold designs with varying interstrand spacing to induce the deposition of aligned matrix in vivo. MATERIALS AND METHODS: 3D-Bioplotted polycaprolactone scaffolds with 100, 200, or 400 MUm interstrand spacing were implanted subcutaneously in a rat model for 4, 8, or 12 weeks. Scaffolds were harvested, paraffin-embedded, sectioned, and stained to visualize cell nuclei and collagen. Quantitative image analysis was used to evaluate cell density, matrix fill, and collagen fiber alignment within the scaffolds. RESULTS: By 4 weeks, cells had infiltrated the innermost scaffold regions. Similarly, collagenous matrix filled interstrand regions nearly completely by 4 weeks. By 12 weeks, aligned collagen was present in all scaffolds. Generally, alignment along the scaffold strands increased over time for all three interstrand spacing groups. Distribution of collagen fiber alignment angles narrowed as interstrand spacing decreased. CONCLUSIONS: 3D Bioplotted scaffolds allow for complete cell infiltration and collagenous matrix production throughout the scaffold. The ability to use interstrand spacing as a means of controlling the formation of aligned collagen in vivo was demonstrated, which helps establish a design space for scaffold-based meniscus tissue engineering. PMID- 28026971 TI - Assessment of Corneal and Tear Film Parameters in Rheumatoid Arthritis Patients Using Anterior Segment Spectral Domain Optical Coherence Tomography. AB - PURPOSE: To study the corneal changes in rheumatoid arthritis (RA) patients in vivo, using spectral domain anterior segment optical coherence tomography (AS OCT). METHODS: A case-control study was done on 43 RA patients and 40 controls. The disease activity score (DAS28-ESR) was calculated and all participants had lower tear meniscus, corneal thickness, and epithelial thickness evaluation using AS-OCT. RESULTS: The lower tear meniscus height (LTMH) and the lower tear meniscus area (LTMA) were significantly lower in the RA patients than in controls (p < 0.001). RA patients also had a significantly thinner central corneal thickness (p = 0.02) and their epithelium was found to be thinner in the superotemporal peripheral sector. CONCLUSIONS: The LTMH and LTMA are significantly reduced in RA patients, despite the absence of clinical diagnosis of dry eye. RA patients have thinner corneal thickness and epithelial thickness than controls, which did not correlate with either disease duration or activity. PMID- 28026972 TI - Feasibility of Preoperative FDG PET/CT Total Hepatic Glycolysis in the Remnant Liver for the Prediction of Postoperative Liver Function. AB - OBJECTIVE: The objective of our study was to investigate the prognostic value of total glycolysis of the remnant liver, which reflects both metabolic and anatomic liver function, for predicting postoperative hepatic insufficiency. MATERIALS AND METHODS: Patients who underwent 18F-FDG PET/CT and abdominal CT within 1 month of major hepatectomy were retrospectively analyzed. Total liver volume, remnant liver volume, the ratio of the remnant hepatic volume to the preoperative hepatic volume (RFRHV), and mean standardized uptake value (SUVmean) were measured, and total glycolysis of the remnant liver was calculated. Clinical hepatic function reserve values, including the indocyanine green retention rate at 15 minutes, the model for end-stage liver disease (MELD) score, and aspartate aminotransferase to platelet ratio index (APRI), were calculated. Univariate and multivariate analyses were performed, and an optimal model for predicting hepatic insufficiency was developed. ROC curves were used to compare diagnostic performance. RESULTS: Of 149 patients, seven patients had hepatic insufficiency. The SUVmean showed the highest sensitivity (100%; specificity, 31.7%) for predicting hepatic insufficiency, and total glycolysis of the remnant liver showed the highest specificity (96.5%; sensitivity, 57.1%) for predicting hepatic insufficiency. On multivariate analysis, the odds ratio of APRI (> 5.4) and total glycolysis of the remnant liver (<= 625.6) was 46.3 and 82.9, respectively, for predicting hepatic insufficiency. On ROC curve analysis, a new model composed of APRI and total glycolysis of the remnant liver showed a higher area under the ROC curve (Az) value (Az = 0.899) than SUVmean (0.659), MELD score (0.618), APRI (0.693), RFRHV (0.797), and remnant liver volume (0.762). CONCLUSION: The total glycolysis of the remnant liver has moderate sensitivity and high specificity for predicting hepatic insufficiency. Combining the total glycolysis of the remnant liver and APRI yielded the best diagnostic performance for predicting hepatic insufficiency. PMID- 28026973 TI - VIDEO: Preoperative CT Angiography for Anterolateral Thigh Flap Reconstructions. AB - OBJECTIVE: This video article will review the relevant vascular anatomy of the anterolateral thigh flap, describe the CT angiography (CTA) image acquisition, and describe how to report the locations of the perforating arteries along with characteristics that may be important to the surgeon. CONCLUSION: Our method of performing and reporting CTA for patients scheduled to undergo anterolateral thigh flap reconstruction provides a reproducible method of identifying perforating vessels and communicating their location to surgeons. PMID- 28026974 TI - Anger, Smoking Behavior, and the Mediator Effects of Gender: An Investigation of Heavy and Moderate Smokers. AB - BACKGROUND: The existing literature suggests the presence of a possible relationship between high anger levels and smoking behavior; however, there are no available data highlighting possible differences between moderate and heavy smokers and the putative effect of gender on smoking behavior. OBJECTIVES: The aims of the current study were to assess the relationship among anger, depression, and anxiety and smoking patterns taking into account the possible mediator role of gender. METHODS: 150 smokers and 50 nonsmokers volunteers were recruited from the staff of the University of Messina, Italy. The final sample consisted of 90 smokers, divided in 50 heavy smokers (HS: more than 40 cigarettes per day), 40 moderate smokers (MS: 10-30 cigarettes per day), and 42 nonsmokers (NS). All subjects were assessed by State-Trait Anger Expression Inventory-2, Self-Rating Depression Scale, and Self-Rating Anxiety Scale. RESULTS: On anger, depression, and anxiety measures the HS group scored higher than MS and NS groups. HS showed higher than expected levels of trait-anger, a greater tendency to control anger reactions and to access to anger-management techniques. A moderate consumption of cigarettes (10-30 cigarettes per day) was not associated with negative emotions, as MS only showed higher than expected levels of state anger. Cigarettes consumption was related to gender-specific anger features. Conclusions/Importance: Our study highlighted the importance of anger in smoking behavior and its related gender differences. Recognizing the link among anger, gender differences and smoking behavior could improve the knowledge for future focused interventions on smoking cessation. PMID- 28026975 TI - The NOTCH1-autophagy interaction: Regulating self-eating for survival. AB - T-cell subsets in the mammalian immune system use varied mechanisms for survival, a demand imposed by the diverse and dynamic niches that they function in. In a recent study, we showed that survival of natural T-regulatory cells (Tregs) was determined by spatially regulated NOTCH1 activity signaling leading to the activation of macroautophagy/autophagy. While this interaction was revealed in experimental conditions of limited nutrient availability in vitro, the consequences of this interaction were confirmed in the context of immune physiology. Consistently, disrupting NOTCH signaling or the autophagy cascade was deleterious to Tregs. At the molecular level, ligand-activated NOTCH1, which is enriched outside the nucleus in Tregs, was detected in complexes that included specific molecular intermediates controlling the progression of autophagy. Mitochondria were a prominent cellular target, with organelle remodeling and function dependent on NOTCH1 signaling to autophagy. It is tempting to speculate that the link between autophagy and the developmental regulator NOTCH1 identified in this work may be conserved in other biological contexts. PMID- 28026976 TI - Spermidine boosts autophagy to protect from synapse aging. AB - All animals form memories to adapt their behavior in a context-dependent manner. With increasing age, however, forming new memories becomes less efficient. While synaptic plasticity promotes memory formation, the etiology of age-induced memory formation remained enigmatic. Previous work showed that simple feeding of polyamine spermidine protects from age-induced memory impairment in Drosophila. Most recent work now shows that spermidine operates directly at synapses, allowing for an autophagy-dependent homeostatic regulation of presynaptic specializations. How exactly autophagic regulations intersect with synaptic plasticity should be an interesting subject for future research. PMID- 28026979 TI - Estimating the Number of Heroin Users in Metropolitan France Using Treatment Centers Data: An Exploratory Analysis. AB - BACKGROUND: An updated prevalence estimate for heroin users in France is lacking. Accurate figures are needed to estimate the potential need for treatment. METHOD: This research relies on a capture-recapture framework and, for the first time, makes use of individual data collected by a standardized survey conducted within treatment centers. Taking the hierarchical structure of data collection into consideration, a multilevel Zelterman regression model was used, thus enabling estimates at national level. RESULTS: The number of heroin users was estimated to be 76,000, 95% CI = [68,000; 85,000] in 2009 (prevalence of 1.90/00 [1.7-2.1]), 101,000 in 2011, 95% CI = [66,000-137,000] (prevalence of 2.50/00 [1.6-3.4]), and 107,000 in 2013, 95% CI = [85,000-124,000] (prevalence of 2.60/00 [2.1-3.1]), with a 4:1 ratio of male:female. Less than one heroin users out of three was seen in treatment centers in 2013. CONCLUSIONS: The rise in the number of heroin users is related to an increasing availability of heroin, increasing use in more remote areas, and providers targeting new types of users. The figures, however, should be completed with alternative estimates and enhance the need for a perennial monitoring. PMID- 28026977 TI - Adverse Childhood Experiences Predict Alcohol Consumption Patterns Among Kenyan Mothers. AB - OBJECTIVE: We analyze whether adverse childhood experiences predict weekly alcohol consumption patterns of Kenyan mothers and their partners. METHOD: Randomly selected respondents (n = 1,976) were asked about adverse childhood experiences and alcohol consumption patterns for themselves and their partners. Fixed effect models were used to determine odds of reporting weekly alcohol consumption and the number of beverages typically consumed, controlling for wealth, age, education, and partner alcohol consumption. RESULTS: Cumulative adverse childhood experiences predicted higher odds of weekly alcohol consumption of the respondent and her partner. Childhood exposure to physical abuse, emotional neglect, and mental illness in the household significantly increased odds of weekly alcohol consumption by the respondent. More drinks consumed per typical session were higher among respondents with more cumulative adversities. Physical and emotional abuse significantly predicted number of drinks typically consumed by the respondent. CONCLUSIONS: To our knowledge, this is the first study to explore and find associations between adverse childhood experiences and alcohol consumption in Kenya. Consistent with high-income settings, exposure to childhood adversities predicted greater alcohol consumption among Kenyan women. PMID- 28026980 TI - Addiction-Related Stigma and Discrimination: A Qualitative Study in Treatment Centers in Mexico City. AB - : Social rejection of drug use is greater than that directed at other psychiatric conditions, like depression and anxiety, which may lead to social exclusion of substance users and prevent them from seeking and receiving treatment. OBJECTIVE: The objective of this study is to investigate the stigma and discrimination related to addiction in treatment centers in Mexico City. METHODS: Data are from a broad mixed methods study. The present study is a qualitative analysis of 35 in depth interviews of drug users, family members, and providers, using guidelines for the exploration of experiences of stigma and discrimination related to substance abuse. A thematic analysis was carried out using specialized software (Atlas.ti 6.2.23). RESULTS: The common practices of stigma and discrimination (e.g., judging, mockery, inappropriate comments, overprotection, and hostile looks), were identified in participant testimonies. The narratives provide evidence of varied conditions of social and gender inequality, as well as experience of violence and abuse, that refer to a structural context of discrimination surrounding addiction, and that constitute obstacles to treatment. CONCLUSIONS: The findings allow for a description of the stigmatization process surrounding addiction as a shared problem that requires the implementation of coordinated treatment strategies. They also suggest the need for more comprehensive policies of inclusion, based on human rights, which favor prevention and treatment. PMID- 28026981 TI - Challenges to Practicing HIV Sex-Risk Prevention Among People in Continuing Care for Cocaine Addiction. AB - BACKGROUND: Intimate partnerships are discouraged during early recovery, despite research that highlights their capacity to be resources for change. OBJECTIVE: This study seeks to provide descriptions of intimate partnerships and how such partnerships challenge and/or support minimizing HIV sex-risk among participants in continuing care for cocaine addiction in order to inform substance use programming. METHODS: Forty-two recorded continuing care counseling sessions of 33 people who discussed HIV sex-risk behavior were transcribed and analyzed using thematic analysis. This sample was derived from a larger randomized controlled trial that looked at the impact of a continuing care intervention for people with cocaine use problems. RESULTS: Although participants expressed the desire for a primary intimate partnership, casual intimate partnerships that often involved HIV sex-risk behavior were more prevalent. Challenges to having a primary intimate partner included the belief that intimate partnerships do not support recovery, difficulty in developing friendships with women among heterosexual men, and the ubiquity of drug use and sex work in home environments with limited economic opportunity. Despite these challenges, some participants reported having primary intimate partners that supported their recovery through open communication. CONCLUSION: Clinicians providing substance use interventions can consider encouraging components of intimate partnerships that support recovery. In addition, the strong environmental influence on individual HIV sex-risk behavior should be considered in delivering any substance use intervention. PMID- 28026982 TI - Reproducibility of Muscle Strength Testing for Children with Spina Bifida. AB - AIMS: Examine the inter-rater reliability of the Daniels and Worthingham (D&W) manual muscle test (MMT) protocol for children with spina bifida between experienced and novice physiotherapists. METHODS: Thirteen children with spina bifida (two males) aged 6 to 18 years were recruited from a spina bifida service in a state-wide tertiary children's hospital. Each child had the muscle strength of 19, and lower limb muscles were measured bilaterally by one experienced and one novice physiotherapist using the D&W MMT protocol. Examiner and limb order were counterbalanced. Standard training and recording sheets were used. Agreement between raters was examined with quadratic weighted kappa (kappaw2), percentage exact agreement (%EA), and the Bland-Altmann Limits of Agreement (LoA). Minimal detectable change (MDC) was calculated. RESULTS: Inter-rater agreement between the experienced and novice raters was excellent (kappaw2 = 0.95; 95% confidence interval: 0.94-0.96); %EA was good (72.3%); and clinically appropriate LoA levels were -1.30-1.40. The MDC was 1.11 points on a six-point MMT scale. CONCLUSIONS: The D&W MMT protocol, when used after standard training and with standard recording sheets, was reproducible for children with spina bifida, aged 6-18 years. PMID- 28026983 TI - Comprehensive Diagnostic Assessment of Health Status of Patients with Asthma or COPD: A Delphi Panel Study among Dutch Experts. AB - A comprehensive diagnostic assessment is needed to improve understanding of the health status of patients with chronic obstructive pulmonary disease (COPD) or asthma. Therefore, this study investigated which components and subsequent instruments should be part of a holistic assessment in secondary care. We also explored which data need to be exchanged for an adequate transfer of patients between primary and secondary care, and vice versa. A cross-sectional Web-based survey was conducted among Dutch healthcare professionals using a Delphi-like procedure; these included professionals working in primary or secondary care, medical advisors of health insurance companies and patients' representatives. The national guidelines were used as a starting point, resulting in a questionnaire addressing 55 components related to a comprehensive diagnostic assessment, covering the domains physiological impairments, symptoms, functional limitations and quality of life. Of the 151 experts and stakeholders invited, 92 (60.9%) completed the first round and 79 (52.3%) the second round; most respondents were pulmonologists. There was a high level of agreement between respondents from primary versus secondary care regarding which components should be measured during a comprehensive assessment of patients with asthma or COPD in secondary care and the instruments to measure these components. Regarding the exchange of information, upon referral, pulmonologists required little information from the general practitioners, whereas general practitioners required more extensive information after referral. An overview is provided of what should be part of a holistic assessment of health status in asthma and COPD. This information can be used as input for integrated care pathways. PMID- 28026984 TI - Examining Changes to Center of Pressure During the First Trials of Wii Gameplay. AB - OBJECTIVE: Use of the Nintendo WiiTM as a balance assessment and rehabilitation tool continues to grow. One advantage of the Wii is that games can serve as a virtual reality training tool; however, a disadvantage of the Wii is the human machine interface and the learning effect over multiple trials. The purpose of this study was to assess changes in postural control during Wii gameplay over a series of trials in novice players. MATERIALS AND METHODS: Thirty-one university athletes (aged 18-25 years) completed four trials of the Nintendo Wii FitTM soccer heading (SH) balance game. Center of pressure (COP) was calculated in the anterior-posterior (AP) and medial-lateral (ML) directions for each 70-second time trial at 1000 Hz. COP was assessed using six linear and two nonlinear measures. Repeated measures analysis of variances compared COP measures over the four trials. RESULTS: Significant differences in COP magnitude and velocity were found between trials 1 and 2 in the ML direction. No significant effects of trial were found in the AP direction. In contrast, a measure of the overall area of COP using an ellipse method revealed a significant reduction to COP area between trials 3 and 4. No significant differences between trials were observed in nonlinear measures. CONCLUSIONS: These results demonstrate how magnitude and velocity measures of COP control stabilize after the first trial of Wii SH game play in novice young adults. As Wii rehabilitation focuses on individuals with balance difficulties, an important consideration when using the game as an assessment tool is that more than four trials may be required to capture learning in these populations. In addition, contrasting results from ellipse measurement methods point to the use of multiple measures for robust description of COP behavior. This work provides understanding of normative postural control responses with further research in clinical populations needed. PMID- 28026986 TI - Xenophagy: A battlefield between host and microbe, and a possible avenue for cancer treatment. AB - In eukaryotes, xenophagy is defined as a type of selective macroautophagy/autophagy that is used for eliminating invading pathogens. In contrast to other types of selective autophagy, such as mitophagy, pexophagy and ribophagy, xenophagy is used by eukaryotes for targeting microbes-hence the prefix "xeno" meaning "other" or "foreign"-that have infected a host cell, leading to their lysosomal degradation. This unique characteristic links xenophagy to antibacterial and antiviral defenses, as well as the immune response. Furthermore, recent studies suggest a complicated role of xenophagy in cancer, through either suppressing tumorigenesis or promoting survival of established tumors. In this issue, Sui et al. summarize previous and current studies of xenophagy and consider them in the context of anticancer treatment. PMID- 28026985 TI - Getting Research on Games for Health Funded. PMID- 28026987 TI - The Relationship Between Perceived Hookup Attitudes and Negative Hookup Consequences: Do Perceived Attitudes of Close Friends Matter? AB - Research suggests that the perceived hookup attitudes of close referents are generally a poor predictor of hookup behavior and likely a poor direct predictor of negative hookup consequences. The current study aimed to examine three intervening variables as mediators of the relationship between the perceived hookup attitudes of college students' close friends and negative hookup consequences (e.g., regret, embarrassment). Self-report data were collected from 589 heavy-drinking college students from three midsized universities. The results indicated that students' own attitudes toward hooking up, motivation to hook up, and self-reported number of hookup partners significantly mediated the relationship between the perceived hookup attitudes of close friends and negative hookup consequences. The perceived hookup attitudes of close friends were positively associated with participants' attitudes toward hooking up. Participants' attitudes toward hooking up were positively associated with social sexual motivation to hook up. Elevated social-sexual motivation to hook up was positively associated with hooking up with multiple partners, with hooking up with multiple partners positively associated with negative hookup consequences. A better understanding of the predictors and mediators of negative hookup consequences has the potential to inform prevention and intervention efforts. PMID- 28026988 TI - Development of early numerical abilities of Spanish-speaking Mexican preschoolers: A new assessment tool. AB - This article presents a tool for assessing the early numerical abilities of Spanish-speaking Mexican preschoolers. The Numerical Abilities Test, from the Evaluacion Neuropsicologica Infantil-Preescolar (ENI-P), evaluates four core abilities of number development: magnitude comparison, counting, subitizing, and basic calculation. We evaluated 307 Spanish-speaking Mexican children aged 2 years 6 months to 4 years 11 months. Appropriate internal consistency and test retest reliability were demonstrated. We also investigated the effect of age, children's school attendance, maternal education, and sex on children's numerical scores. The results showed that the four subtests captured development across ages. Critically, maternal education had an impact on children's performance in three out of the four subtests, but there was no effect associated with children's school attendance or sex. These results suggest that the Numerical Abilities Test is a reliable instrument for Spanish-speaking preschoolers. We discuss the implications of our outcomes for numerical development. PMID- 28026989 TI - Should We Invest in Martian Brine Research to Reduce Mars Exploration Costs? PMID- 28026991 TI - Correction to: Hum Gene Ther 2016;27(10):749-757. PMID- 28026990 TI - A Possible Role for Stochastic Astrophysical Ionizing Radiation Events in the Systematic Disparity between Molecular and Fossil Dates. AB - Major discrepancies have been noted for some time between fossil ages and molecular divergence dates for a variety of taxa. Recently, systematic trends within avian clades have been uncovered. The trends show that the disparity is much larger for mitochondrial DNA than for nuclear DNA, also that it is larger for crown fossil dates than stem fossil dates. It has been argued that this pattern is largely inconsistent with incompleteness of the fossil record as the principal driver of the disparity. A case is presented that, given the expected mutations from a fluctuating background of astrophysical radiation from such sources as supernovae, the rate of molecular clocks is variable and should increase back to a few million years, before returning to the long-term average rate. This is a possible explanation for the disparity. One test of this hypothesis is to look for an acceleration of molecular clocks at 2 to 2.5 Ma due to one or more moderately nearby supernovae known to have happened at that time. Another is to look for reduced disparity in benthic organisms of the deep ocean. In addition, due to the importance of highly penetrating muon irradiation, the disparity should be magnified for megafauna. Key Words: Extreme events in Earth history-Molecular clock-Radiation physics-Evolution. Astrobiology 17, 87-90. PMID- 28026992 TI - Sesquiterpene Lactone Composition and Cellular Nrf2 Induction of Taraxacum officinale Leaves and Roots and Taraxinic Acid beta-d-Glucopyranosyl Ester. AB - Taraxacum officinale, the common dandelion, is a plant of the Asteraceae family, which is used as a food and medical herb. Various secondary plant metabolites such as sesquiterpene lactones, triterpenoids, flavonoids, phenolic acids, coumarins, and steroids have been described to be present in T. officinale. Dandelion may exhibit various health benefits, including antioxidant, anti inflammatory, and anticarcinogenic properties. We analyzed the leaves and roots of the common dandelion (T. officinale) using high-performance liquid chromatography/mass spectrometry to determine its sesquiterpene lactone composition. The main compound of the leaf extract taraxinic acid beta-d glucopyranosyl ester (1), a sesquiterpene lactone, was isolated and the structure elucidation was conducted by nuclear magnetic resonance spectrometry. The leaf extract and its main compound 1 activated the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in human hepatocytes more significantly than the root extract. Furthermore, the leaf extract induced the Nrf2 target gene heme oxygenase 1. Overall, present data suggest that compound 1 may be one of the active principles of T. officinale. PMID- 28026993 TI - Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity. AB - The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated beta-galactosidase (SA beta-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema. PMID- 28026995 TI - Scale-up production and characterization of anti-human cardiac troponin I monoclonal antibody in ascitic fluid of balb/c mice. AB - The Human Cardiac Troponin I (hcTnI) is a 210 amino acid protein, 23 kDa in molecular weight. This biomarker is commonly used to diagnose myocardial infarction, micro injury, and acute coronary syndrome (ACS) in patients referring to emergency departments. The American Heart Association (AHA) and European Society of Cardiology (ESC) proposed troponin I as the gold biomarker for early detection of heart attack, especially in myocardial infarction (MI). Therefore, developing monoclonal antibodies against this biomarker could help in for early detection of heart attack. Hybridoma technology is a well-known technique introduced to produce monoclonal antibodies in specialized cells. The aim of this study was to produce large scale of monoclonal antibody against human cardiac troponin I using Hybridoma technology in order to design a diagnostic kit. The monoclonal antibody was produced using conventional Hybridoma technology in ascitic fluid of mouse and characterized for its ability to detect Human Cardiac Troponin I in a rapid test system. The results indicate the successful detection of Troponin I using the obtained monoclonal antibody. According to the achieved results it seems that ascites production of monoclonal antibody is very versatile, inexpensive, and economically useful for monoclonal antibody production. PMID- 28026996 TI - On hybrid parallel-crossover designs for assessing drug interchangeability of biosimilar products. AB - In recent years, a specific hybrid parallel-crossover design that consists of two sequences of treatments, namely R-R-R-R and R-T-R-T, where T and R is a proposed biosimilar product and an innovative biological product, respectively, have been proposed and received much attention for assessing drug interchangeability between T and R, where R could be either a US-licensed product or an EU-reference product. In practice, there are three types of hybrid parallel-crossover designs that are commonly employed in assessing drug interchangeability of biosimilar products. These three types of parallel-crossover hybrid designs include (1) a parallel + 2 * 2 crossover design, (2) a parallel + 2 * 3 crossover design, and (3) a parallel + 2 * 4 crossover design. This article provides a comprehensive review of these study designs including a complete N-of-1 randomized trial design. A specific hybrid parallel-crossover design, that is, (RRRR, RTRT) for addressing drug interchangeability in terms of switching and the relative risk between with/without alternation is discussed. PMID- 28026997 TI - Multifaceted Roles of the Ras Guanine-Nucleotide Exchange Factor ChRgf in Development, Pathogenesis, and Stress Responses of Colletotrichum higginsianum. AB - The infection process of Colletotrichum higginsianum, which causes a disease of crucifers, involves several key steps: conidial germination, appressorial formation, appressorial penetration, and invasive growth in host tissues. In this study, the ChRgf gene encoding a Ras guanine-nucleotide exchange factor protein was identified by screening T-DNA insertion mutants generated from Agrobacterium tumefaciens-mediated transformation that were unable to cause disease on the host Arabidopsis thaliana. Targeted gene deletion of ChRgf resulted in a null mutant (DeltaChrgf-42) with defects in vegetative growth, hyphal morphology, and conidiation, and poor surface attachment and low germination on hydrophobic surfaces; however, there were no apparent differences in appressorial turgor pressure between the wild type and the mutant. The conidia of the mutant were unable to geminate on attached Arabidopsis leaves and did not cause any disease symptoms. Intracellular cyclic adenosine monophosphate levels in the DeltaChrgf mutant were lower than that of the wild type. Our results suggest that ChRgf is a key regulator in response to salt and osmotic stresses in C. higginsianum, and indicate that it is involved in fungal pathogenicity. This gene seems to act as an important modulator upstream of several distinct signaling pathways that are involved in regulating vegetative growth, conidiation, infection-related structure development, and stress responses of C. higginsianum. PMID- 28026998 TI - Can Oak Powdery Mildew Severity be Explained by Indirect Effects of Climate on the Composition of the Erysiphe Pathogenic Complex? AB - Coinfection by several pathogens is increasingly recognized as an important feature in the epidemiology and evolution of plant fungal pathogens. Oak mildew is induced by two closely related Erysiphe invasive species (Erysiphe alphitoides and E. quercicola) which differ in their mode of overwintering. We investigated how climate influences the co-occurrence of the two species in oak young stands and whether this is important for the disease epidemiology. We studied the frequency of flag-shoots (i.e., shoots developing from infected buds, usually associated with E. quercicola) in 95 oak regenerations over a 6-year period. Additionally, in 2012 and 2013, the oak mildew severity and the two Erysiphe spp. relative frequencies were determined in both spring and autumn in 51 regenerations and 43 1-year-old plantations of oaks. Both the frequency of flag shoots and the proportion of Erysiphe lesions with E. quercicola presence were related to climate. We showed that survival of E. quercicola was improved after mild winters, with increase of both the flag-shoot frequency and the proportion of Erysiphe lesions with E. quercicola presence in spring. However, disease severity was not related to any complementarity effect between the two Erysiphe spp. causing oak powdery mildew. By contrast, increased E. alphitoides prevalence in spring was associated with higher oak mildew severity in autumn. Our results point out the critical role of between-season transmission and primary inoculum to explain disease dynamics which could be significant in a climate-warming context. PMID- 28026999 TI - The Association of Sleep Duration and Morbid Obesity in a Working Population: The Baptist Health South Florida Employee Study. AB - BACKGROUND: The current study aimed to determine the relationship between self reported sleep duration and morbid obesity in an employee population. METHODS: Baptist Health South Florida conducts an annual Health Risk Assessment (HRA) for its employees. Data for this cross-sectional study was collected via this HRA in 2014, and included information on self-reported sleep duration, height and weight for body mass index (BMI), and other biometric measures. Average sleep duration was categorized as short sleep (<6 hr), optimal sleep (6-7.9 hr), and long sleep duration (>=8 hr), while obesity status was categorized as nonobese (BMI <30 kg/m2), obese (30-34.9 kg/m2), and morbid obese (>=35 kg/m2). RESULTS: A total of 9505 participants (mean age 42.8 +/- 12.1 years, 75% females, and 55% Hispanic) were included in this study. Prevalence of morbid obesity was about 24% among employees who were sleeping for less than 6 hr compared to 13% and 14% among those sleeping for 6-7.9 hours, and 8 or more hours respectively. In regression analyses, persons who slept less than 6 hr had almost twice the odds of morbid obesity compared to those who slept 6-7.9 hr (odds ratio = 1.8; 1.5-2.2). CONCLUSION: Our finding that short sleep duration (<6 hr) is significantly associated with a higher risk of morbid obesity should facilitate the development of workplace-based programs that focus on improving sleep among at-risk employees, especially those who work in shift duties to reduce the risk of morbid obesity and other comorbid conditions. Future studies are needed to further explore the relationship of sleep duration and morbid obesity in employee populations. PMID- 28027000 TI - Viroid quasispecies revealed by deep sequencing. AB - Viroids are non-coding single-stranded circular RNA molecules that replicate autonomously in infected host plants causing mild to lethal symptoms. Their genomes contain about 250-400 nucleotides, depending on viroid species. Members of the family Pospiviroidae, like the Potato spindle tuber viroid (PSTVd), replicate via an asymmetric rolling-circle mechanism using the host DNA-dependent RNA-Polymerase II in the nucleus, while members of Avsunviroidae are replicated in a symmetric rolling-circle mechanism probably by the nuclear-encoded polymerase in chloroplasts. Viroids induce the production of viroid-specific small RNAs (vsRNA) that can direct (post-)transcriptional gene silencing against host transcripts or genomic sequences. Here, we used deep-sequencing to analyze vsRNAs from plants infected with different PSTVd variants to elucidate the PSTVd quasipecies evolved during infection. We recovered several novel as well as previously known PSTVd variants that were obviously competent in replication and identified common strand-specific mutations. The calculated mean error rate per nucleotide position was less than [Formula: see text], quite comparable to the value of [Formula: see text] reported for a member of Avsunviroidae. The resulting error threshold allows the synthesis of longer-than-unit-length replication intermediates as required by the asymmetric rolling-circle mechanism of members of Pospiviroidae. PMID- 28027001 TI - A Case of Rectal Ureaplasma Infection and Implications for Testing in Young Men Who Have Sex with Men: The P18 Cohort Study. AB - Ureaplasma is a significant cause of nongonococcal urethritis. This is a case of rectal Ureaplasma found on culture in a young man who has sex with men not previously reported in the literature. Nucleic acid amplification tests are now standard of care for sexually transmitted infection testing, but they do not test for Ureaplasma and, therefore, may be missing important infections. Ureaplasma could have important implications in urethritis and rectal HIV transmission among men who have sex with men engaging in condomless anal intercourse. Further study of Ureaplasma's role as a rectal pathogen may be warranted. PMID- 28027002 TI - Mathematical modeling based on ordinary differential equations: A promising approach to vaccinology. AB - New contributions that aim to accelerate the development or to improve the efficacy and safety of vaccines arise from many different areas of research and technology. One of these areas is computational science, which traditionally participates in the initial steps, such as the pre-screening of active substances that have the potential to become a vaccine antigen. In this work, we present another promising way to use computational science in vaccinology: mathematical and computational models of important cell and protein dynamics of the immune system. A system of Ordinary Differential Equations represents different immune system populations, such as B cells and T cells, antigen presenting cells and antibodies. In this way, it is possible to simulate, in silico, the immune response to vaccines under development or under study. Distinct scenarios can be simulated by varying parameters of the mathematical model. As a proof of concept, we developed a model of the immune response to vaccination against the yellow fever. Our simulations have shown consistent results when compared with experimental data available in the literature. The model is generic enough to represent the action of other diseases or vaccines in the human immune system, such as dengue and Zika virus. PMID- 28027003 TI - LZAP is a novel Wip1 binding partner and positive regulator of its phosphatase activity in vitro. AB - The phosphatase Wip1 attenuates the DNA damage response (DDR) by removing phosphorylation marks from a number of DDR proteins (p53, MDM2, Chk1/2, p38). Wip1 also dephosphorylates and inactivates RelA. Notably, LZAP, a putative tumor suppressor, has been linked to dephosphorylation of several of these substrates, including RelA, p38, Chk1, and Chk2. LZAP has no known catalytic activity or functional motifs, suggesting that it exerts its effects through interaction with other proteins. Here we show that LZAP binds Wip1 and stimulates its phosphatase activity. LZAP had been previously shown to bind many Wip1 substrates (RelA, p38, Chk1/2), and our results show that LZAP also binds the previously identified Wip1 substrate, MDM2. This work identifies 2 novel Wip1 substrates, ERK1 and HuR, and demonstrates that HuR is a binding partner of LZAP. Pleasingly, LZAP potentiated Wip1 catalytic activity toward each substrate tested, regardless of whether full length substrates or phosphopeptides were utilized. Since this effect was observed on ERK1, which does not bind LZAP, as well as for each of 7 peptides tested, we hypothesize that LZAP binding to the substrate is not required for this effect and that LZAP directly binds Wip1 to augment its phosphatase activity. PMID- 28027004 TI - Has VZV epidemiology changed in Italy? Results of a seroprevalence study. AB - The aim of the study was to evaluate if and how varicella prevalence has changed in Italy. In particular a seroprevalence study was performed, comparing it to similar surveys conducted in pre-immunization era. During 2013-2014, sera obtained from blood samples taken for diagnostic purposes or routine investigations were collected in collaboration with at least one laboratory/center for each region, following the approval of the Ethics Committee. Data were stratified by sex and age. All samples were processed in a national reference laboratory by an immunoassay with high sensitivity and specificity. Statutory notifications, national hospital discharge database and mortality data related to VZV infection were analyzed as well. A total of 3707 sera were collected and tested. In the studied period both incidence and hospitalization rates decreased and about 5 deaths per year have been registered. The seroprevalence decreased in the first year of life in subjects passively protected by their mother, followed by an increase in the following age classes. The overall antibody prevalence was 84%. The comparison with surveys conducted with the same methodology in 1996-1997 and 2003-2004 showed significant differences in age groups 1-19 y. The study confirms that in Italy VZV infection typically occurs in children. The impact of varicella on Italian population is changing. The comparison between studies performed in different periods shows a significant increase of seropositivity in age class 1 - 4 years, expression of vaccine interventions already adopted in some regions. PMID- 28027005 TI - Serological survey of hepatitis B immunity in healthcare workers in Catalonia (Spain). AB - Healthcare workers (HCW) are exposed to preventable infectious diseases, notably hepatitis B (HB). The aim of this study was to determine the immunity of HCW against hepatitis B. We made a seroprevalence study using a self-administered survey and obtained blood samples. Antibodies against the HB surface antigen (anti-HBs) and against the HB core antigen (anti-HBc) were studied. The odds ratio (OR) and 95% confidence intervals (CI) were calculated. The adjusted OR were calculated using logistic regression. Of the 644 HCW who participated (29.7% physicians, 38.7% nurses, 13.4% other clinical workers and 18.3% non-clinical workers), 46.4% were primary care workers and 53.6% hospital workers. The overall prevalence of anti-HBs was 64.4%. HCW aged <25 y had a significantly higher prevalence (86.7%) than those aged 35-44 y (adjusted OR 3.40; 95% CI 1.06-10.90). The prevalence of anti-HBc was 4.1%, and increased with age. Significant differences were found for HCW aged >44 y with respect to those aged 25-34 y. 75.6% of HCW stated they were vaccinated, but only 39.3% had a vaccination card. In HCW who stated they were unvaccinated, 10.8% had a vaccinated serological pattern (anti-HBc-negative and anti-HBs -positive). Written, updated vaccination records are essential to reliably determine the vaccination status. PMID- 28027007 TI - Multiple roles of nitric oxide in root development and nitrogen uptake. AB - Nitric oxide (NO) is widely recognized for its role as a signaling molecule in regulating plant developmental processes. We summarize recent work on NO generation via nitrate reductase (NR) or/and NO synthase (NOS) pathway in response to nutrient fluctuation and its regulation of plant root growth and N metabolism. The promotion or inhibition of root development most likely depends on NO concentrations and/or experimental conditions. NO plays an important role in regulating plant NR activity at posttranslational level probably via a direct interaction mechanism, thus contributing largely to N assimilation. NO also regulates N distribution and uptake in many plant species. In rice cultivar, NR generated NO plays a pivotal role in improving N uptake capacity by increasing root growth and inorganic N uptake, representing a potential strategy for rice adaption to a fluctuating nitrate supply. PMID- 28027008 TI - Development of an immunoassay using an anti-wogonin glucuronide monoclonal antibody. AB - Wogonin 7-O-beta-D-glucuronide (Wgn) is a bioactive flavone present in the dried root of Scutellaria baicalensis Georgi. To generate a monoclonal antibody (MAb) against Wgn, BALB/c mice injected with Wgn-bovine serum albumin yielded splenocytes that we fused with SP2/0 myeloma cells using the polyethylene glycol method. We obtained a hybridoma designated 315A that produced a MAb reactive to Wgn. The anti-Wgn MAb 315A was applied to an indirect competitive enzyme-linked immunosorbent assay (icELISA) to quantify Wgn. Subsequent validation revealed that icELISA using the 315A anti-Wgn MAb is an accurate and reliable method for the quantification of Wgn in S. baicalensis. PMID- 28027009 TI - You Get What You Give: Understanding Reply Reciprocity and Social Capital in Online Health Support Forums. AB - Adopting a social network analysis approach, the present study examined social capital and network dynamics of online support seeking and support provision in a depression forum. We constructed a depression forum network by mapping out all of the users and the reply ties among them. The findings showed a consistently reciprocal pattern between users' replies sent to others and replies received from others. Forum users' bridging social capital was positively associated with the source diversity of their received replies and negatively associated with the average length of their received replies. Furthermore, forum users' bonding social capital was positively associated with the average length of their received replies and negatively associated with the source diversity of their received replies. PMID- 28027010 TI - Attending to Timely Contingencies: Promoting Physical Activity Uptake Among Adults with Serious Mental Illness with an Exercise-For-Mood vs. an Exercise-For Fitness Prescription. AB - Despite evidence for both physical and mental health benefits achieved through regular exercise, most Americans fail to meet minimum recommendations. Altering the behavioral contingency from a focus on long-term health benefits to immediate mood benefits represents a novel method for exercise promotion. The current study examined a single-session exercise-for-mood intervention against two time-matched comparison conditions in 152 patients with serious mental illness attending a partial hospital program, a population marked by significant health disparities. This intervention was compared to a standard exercise-for-fitness intervention and a time-matched no-exercise control. Among patients with high levels of exercise prior to the partial hospital program, the exercise-for-mood intervention yielded significant increases in exercise. Implications for exercise promotion interventions among psychiatrically ill patients are discussed. PMID- 28027011 TI - Smokeless tobacco use among United States Air Force trainees. AB - BACKGROUND: The prevalence of smokeless tobacco use in the United States Air Force (USAF) exceeds civilian use rates. The prevalence and correlates of smokeless tobacco use were assessed and evaluated in a sample of USAF trainees. METHODS: We conducted a cross-sectional survey of USAF technical training school personnel at Joint Base San Antonio-Lackland and Fort Sam Houston (N = 14,810). Survey completion rate was 78%. Logistic regression was used to analyze the associations between demographic variables, tobacco use, and social factors for both regular and infrequent smokeless tobacco (e.g., chewing tobacco, snuff) users. RESULTS: Overall, 16% of Airmen had ever used smokeless tobacco and 10% regularly used smokeless tobacco. In multivariate analyses, men had greater odds than women of regular smokeless tobacco use (adjusted odds ratio [OR] = 15.2; 95% confidence interval [CI]: 10.8-21.5) and infrequent smokeless tobacco use (adjusted OR = 4.2; 95% CI: 3.1-5.7). Smokeless tobacco use was associated with participation in high school sports (adjusted OR = 1.9; 95% CI: 1.6-2.3 for regular users; adjusted OR = 1.4; 95% CI: 1.1-1.7 for infrequent users), smoking cigarettes (adjusted OR = 4.3; 95% CI: 3.6-5.1 for regular users; adjusted OR = 4.0; 95% CI: 3.2-5.0 for infrequent users), or living with someone who used smokeless tobacco (adjusted OR = 2.2; 95% CI: 1.9-2.6 for regular users; adjusted OR = 1.4; 95% CI: 1.1-1.7 for infrequent users). Black or African Americans were less likely than whites to be regular (adjusted OR = 0.3; 95% CI: 0.1-0.4) or infrequent (adjusted OR = 0.3; 95% CI: 0.2-0.4) users of smokeless tobacco. CONCLUSIONS: Smokeless tobacco use among incoming Air Force recruits is common and negatively impacts the Air Force's goal to be tobacco-free. Understanding sociodemographic characteristics perpetuating smokeless tobacco use in the Air Force population can inform the development of health promotion interventions. PMID- 28027012 TI - Dynamic chromatin regulation at Notch target genes. AB - RBPJ is the central transcription factor that controls the Notch-dependent transcriptional response by coordinating repressing histone H3K27 deacetylation and activating histone H3K4 methylation. Here, we discuss the molecular mechanisms how RBPJ interacts with opposing NCoR/HDAC-corepressing or KMT2D/UTX coactivating complexes and how this is controlled by phosphorylation of chromatin modifiers. PMID- 28027014 TI - Exercise and executive functioning in older women. AB - Research suggests that exercise can slow the rate of decline in cognitive functioning in older adults. The effects of aerobic and resistance exercise on executive functioning was examined in 68 women over 50 years of age. Participants completed the Tower of London and Benton Controlled Oral Word Association tests. Findings indicated that individuals participating in both aerobic and resistance exercises performed significantly better than individuals not participating in exercise. Individuals who were participating in both aerobic and resistance exercises did not perform disproportionately better. Thus the form of exercise appears to be less important than engaging in some form of exercise. PMID- 28027013 TI - Overuse of Diagnostic Imaging for Work-Related Injuries. AB - Overuse of health care in the United States is a growing concern. This article addresses the use of diagnostic imaging for work-related injuries. Diagnostic imaging drives substantial cost for increases in workers' compensation. Despite guidelines published by the American College of Radiology and the American College of Occupational Medicine and the Official Disability Guidelines, practitioners are prematurely ordering imaging sooner than recommended. Workers are exposed to unnecessary radiation and are incurring increasing costs without evidence of better outcomes. Practitioners caring for workers and submitting workers' compensation claims should adhere to official guidelines, using their professional judgment to consider financial impact and health outcomes of diagnostic imaging including computed tomography, magnetic resonance imaging, nuclear medicine imaging, radiography, and ultrasound. PMID- 28027015 TI - Caring for Individuals with Chronic Illness and Minor Depression: Latino Perceptions of Caregiver Burden. AB - Informal caregiving can be fundamental to disease management. Yet, the psychosocial, physical, and financial burden experienced by caregivers can be significant. In the US, Latinos experience increasing rates of chronic conditions, the highest uninsured rates in the country, and a growing dependence on informal caregivers. This article explores the impact of caregiving on caregivers of individuals with comorbid chronic disease and depression. Findings highlight the impact of caregiving on financial insecurity, balancing competing demands, increased emotional distress, and community supports. Findings support the inclusion of caregivers in disease management programs to enhance psychosocial outcomes for both caregivers and their patients. PMID- 28027016 TI - Opioid overdose prevention training with naloxone, an adjunct to basic life support training for first-year medical students. AB - BACKGROUND: Opioid overdose deaths have reached epidemic proportions in the United States. This problem stems from both licit and illicit opioid use. Prescribing opioids, recognizing risky use, and initiating prevention, including opioid overdose prevention training (OOPT), are key roles physicians play. The American Heart Association (AHA) modified their basic life support (BLS) algorithms to consider naloxone in high-risk populations and when a pulse is appreciated; however, the AHA did not provide OOPT. The authors' intervention filled this training deficiency by teaching medical students opioid overdose resuscitation with a Train-the-Trainer model as part of mandatory BLS training. METHODS: The authors introduced OOPT, following a Train-the-Trainer model, into the required basic life support (BLS) training for first-year medical students at a single medical school in a large urban area. The authors administered pre- and post-evaluations to assess the effects of the training on opioid overdose knowledge, self-reported preparedness to respond to opioid overdoses, and attitudes towards patients with substance use disorders (SUDs). RESULTS: In the fall 2014, 120 first-year medical students received OOPT. Seventy-three students completed both pre- and posttraining evaluations. Improvements in knowledge about and preparedness to respond to opioid overdoses were statistically significant (P < .01) and large (Cohen's D = 2.70 and Cohen's D = 2.10, respectively). There was no statistically significant change in attitudes toward patients with SUDs. CONCLUSIONS: The authors demonstrated the effectiveness of OOPT as an adjunct to BLS in increasing knowledge about and preparedness to respond to opioid overdoses; improving attitudes toward patients with SUDs likely requires additional intervention. The authors will characterize knowledge and preparedness durability, program sustainability, and long-term changes in attitudes in future evaluations. These results support dissemination of OOPT as a part of BLS training for all medical students, and potentially all BLS providers. PMID- 28027018 TI - Resilience in low-income African American women living and aging with HIV. AB - Women are living with HIV into middle and older age and are likely to face multiple comorbidities and stressors as they age. This study focused on understanding how women who experience multiple forms of oppression and ongoing adversity are still able to adapt and stand strong. Using a theoretical framework of resilience and a feminist research ideology, interviews of eight middle-aged and older African American women living with HIV were analyzed. Despite experiences of HIV-related discrimination, trauma, and violence, these women demonstrated a remarkable ability to adapt and maintain support. Implications for research and practice are discussed. PMID- 28027017 TI - Shared decision making with frail older patients: Proposed teaching framework and practice recommendations. AB - This study has two aims: The first aim is to identify core competencies for shared decision making (SDM) with frail older persons, and the second is to determine key elements of a teaching framework, based on the authors' recently developed model for SDM with older patients who are frail. To this end the authors conducted a qualitative inquiry among health professionals (n = 53) and older patients who are frail (n = 16). Participants formulated core competencies and educational needs for SDM with older patients who are frail, which were further explored in the literature. This resulted in practice recommendations and a teaching framework with the following key elements: create a knowledge base for all health professionals, offer practical training, facilitate communication, identify discussion partners, engage patients, and collaborate. The authors' teaching framework for SDM with older patients who are frail may be useful for clinicians, educators, and researchers who aim to promote SDM with older patients who are frail. PMID- 28027019 TI - Screening and brief intervention in high schools: School nurses' practices and attitudes in Massachusetts. AB - BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT) is recommended as a strategy to prevent or reduce adolescent substance use. Offering SBIRT in schools may provide an opportunity to reach adolescents not accessing primary care. The objective is to assess school nurses' attitudes and practices regarding adolescent SBIRT. METHODS: The authors administered electronically and in person a questionnaire including 29 items on SBIRT attitudes and practices to school nurses registered for the Northeastern University's School Health Institute Summer Program in Massachusetts (N = 168). Survey questions were adapted from a questionnaire originally developed by the American Academy of Pediatrics. RESULTS: One hundred and forty-four nurses completed the survey for a response rate of 85.7%. More than three quarters of the respondents (77.0%) were in favor of universal alcohol screening in schools. None of the respondents reported screening their students on a regular basis. More than half (64.4%) of nurses reported screening students; however, they did so only when they suspected alcohol use. During these instances, only 17.9% used a validated screening tool and almost all (98.2%) used face-to-face clinical interviews. When addressing alcohol use by a student, the large majority of respondents reported including the following recommended clinical strategies: asking about problems related to alcohol use (56.3%), explaining the harms of alcohol use (70.1%), and advising abstinence (73.6%). On average, respondents spend 5 to 10 minutes discussing alcohol use with their students. CONCLUSION: Survey respondents were supportive of universal alcohol screening in school, although few were doing so at the time. When respondents identified students using alcohol, their interventions were closely aligned with clinical recommendations for brief intervention. Implementation of SBIRT that focuses on standardized, annual screening has the potential to deliver high-quality care in this setting. PMID- 28027020 TI - A Direct-Learning Approach to Acquiring a Bimanual Tapping Skill. AB - The theory of direct learning (D. M. Jacobs & C. F. Michaels, 2007 ) has proven useful in understanding improvement in perception and exploratory action. Here the authors assess its usefulness for understanding the learning of a motor skill, bimanual tapping at a difficult phase relation. Twenty participants attempted to learn to tap with 2 index fingers at 2 Hz with a phase lag of 90 degrees (i.e., with a right-right period of 500 ms and a right-left period of 125 ms). There were 30 trials, each with 50 tapping cycles. Computer-screen feedback informed of errors in both period and phase for each pair of taps. Participants differed dramatically in their success. Learning was assessed by identifying the succession of attractors capturing tapping over the experiment. A few participants' attractors migrated from antiphase to 90 degrees with an appropriate period; others became attracted to a fixed right-left interval, rather than phase, with or without attraction to period. Changes in attractor loci were explained with mixed success by direct learning, inviting elaboration of the theory. The transition to interval attractors was understood as a change in intention, and was remarkable for its indifference to typical bimanual interactions. PMID- 28027021 TI - Whole-Body Movements in Long-Term Weightlessness: Hierarchies of the Controlled Variables Are Gravity-Dependent. AB - Switching between contexts affects the mechanisms underlying motion planning, in particular it may entail reranking the variables to be controlled in defining the motor solutions. Three astronauts performed multiple sessions of whole-body pointing, in normogravity before launch, in prolonged weightlessness onboard the International Space Station, and after return. The effect of gravity context on kinematic and dynamic components was evaluated. Hand trajectory was gravity independent; center-of-mass excursion was highly variable within and between subjects. The body-environment effort exchange, expressed as inertial ankle momentum, was systematically lower in weightlessness than in normogravity. After return on Earth, the system underwent a rapid 1-week readaptation. The study indicates that minimizing the control effort is given greater weight when optimizing the motor plan in weightlessness compared to normogravity: the hierarchies of the controlled variables are gravity dependent. PMID- 28027022 TI - Social Work Research in Practice: Lessons Learned. AB - Using data and research to drive and evaluate clinical decision-making continues to slowly gain prominence across social work settings. This article shares insights and recommendations from a novice social work investigator to encourage other social workers to consider the value of researching while in practice. Practitioners new to research need encouragement and support. This article provides ideas for easing the first steps towards research to avoid potentially discouraging pitfalls. PMID- 28027023 TI - Interventions for healthy aging among mature Black lesbians: Recommendations gathered through community-based research. AB - Black lesbians have unique needs for gerontological services that reflect their experiences of intersectional oppression and resilience. Yet there is a major knowledge gap about interventions that promote healthy aging in this population, as voiced by Black lesbians themselves. To address this need, 100 Black lesbians, ranging in age from 41 to 91, participated in focus groups in Atlanta, Georgia, to discuss their experiences of aging, health needs, and recommendations for interventions. Through thematic analysis, we identified six themes related to suggested approaches for healthy aging interventions. We discuss implications of these findings for aging practice and future research. PMID- 28027024 TI - WHOP, a Genomic Region Associated With Woody Hosts in the Pseudomonas syringae Complex Contributes to the Virulence and Fitness of Pseudomonas savastanoi pv. savastanoi in Olive Plants. AB - Bacteria from the Pseudomonas syringae complex belonging to phylogroups 1 and 3 (PG1 and PG3, respectively) isolated from woody hosts share a genomic region herein referred to as WHOP (from woody host and Pseudomonas spp.), which is absent in strains infecting herbaceous organs. In this work, we show that this region is also encoded in P. syringae pv. actinidifoliorum (PG1) and six additional members of PG3, namely, Pseudomonas savastanoi pv. retacarpa, three P. syringae pathovars, Pseudomonas meliae, and Pseudomonas amygdali. Partial conservation of the WHOP occurs in only a few PG2 strains. In P. savastanoi pv. savastanoi NCPPB 3335, the WHOP region is organized into four operons and three independently transcribed genes. While the antABC and catBCA operons mediate the catabolism of anthranilate and catechol, respectively, the ipoABC operon confers oxygenase activity to aromatic compounds. The deletion of antABC, catBCA, or ipoABC in NCPPB 3335 caused reduced virulence in woody olive plants without affecting knot formation in nonwoody plants; catBCA, dhoAB, and PSA3335_3206 (encoding a putative aerotaxis receptor) were also required for the full fitness of this strain exclusively in woody olive plants. Overall, this study sheds light on the evolution and adaptation of bacteria from the P. syringae complex to woody hosts and highlights the enzymatic activities encoded within the WHOP region that are essential for this process. PMID- 28027025 TI - Fall Armyworm-Associated Gut Bacteria Modulate Plant Defense Responses. AB - Mechanical damage caused by insect feeding along with components present in insect saliva and oral secretions are known to induce jasmonic acid-mediated defense responses in plants. This study investigated the effects of bacteria from oral secretions of the fall armyworm Spodoptera frugiperda on herbivore-induced defenses in tomato and maize plants. Using culture-dependent methods, we identified seven different bacterial isolates belonging to the family Enterobacteriacea from the oral secretions of field-collected caterpillars. Two isolates, Pantoea ananatis and Enterobacteriaceae-1, downregulated the activity of the plant defensive proteins polyphenol oxidase and trypsin proteinase inhibitors (trypsin PI) but upregulated peroxidase (POX) activity in tomato. A Raoultella sp. and a Klebsiella sp. downregulated POX but upregulated trypsin PI in this plant species. Conversely, all of these bacterial isolates upregulated the expression of the herbivore-induced maize proteinase inhibitor (mpi) gene in maize. Plant treatment with P. ananatis and Enterobacteriaceae-1 enhanced caterpillar growth on tomato but diminished their growth on maize plants. Our results highlight the importance of herbivore-associated microbes and their ability to mediate insect plant interactions differently in host plants fed on by the same herbivore. PMID- 28027026 TI - Host Tissue Environment Directs Activities of an Epichloe Endophyte, While It Induces Systemic Hormone and Defense Responses in Its Native Perennial Ryegrass Host. AB - Increased resilience of pasture grasses mediated by fungal Epichloe endophytes is crucial to pastoral industries. The underlying mechanisms are only partially understood and likely involve very different activities of the endophyte in different plant tissues and responses of the plant to these. We analyzed the transcriptomes of Epichloe festucae and its host, Lolium perenne, in host tissues of different function and developmental stages. The endophyte contributed approximately 10* more to the transcriptomes than to the biomass of infected tissues. Proliferating mycelium in growing host tissues highly expressed genes involved in hyphal growth. Nonproliferating mycelium in mature plant tissues, transcriptionally equally active, highly expressed genes involved in synthesizing antiherbivore compounds. Transcripts from the latter accounted for 4% of fungal transcripts. Endophyte infection systemically but moderately increased transcription of L. perenne genes with roles in hormone biosynthesis and perception as well as stress and pathogen resistance while reducing expression of genes involved in photosynthesis. There was a good correlation between transcriptome-based observations and physiological observations. Our data indicate that the fitness-enhancing effects of the endophyte are based both on its biosynthetic activities, predominantly in mature host tissues, and also on systemic alteration of the host's hormonal responses and induction of stress response genes. [Formula: see text] Copyright (c) 2017 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license . PMID- 28027028 TI - A Novel Tool to Measure Extracellular Glutamate in the Zebrafish Nervous System In Vivo. AB - Glutamate is the major excitatory neurotransmitter in the brain. Its release and eventual recycling are key to rapid sustained neural activity. We have paired the gfap promoter region with the glutamate reporter molecule, iGluSnFR, to drive expression in glial cells throughout the nervous system. Tg(gfap:iGluSnFR) is expressed on the glial membrane of Muller glia cells in the retina, which rapidly respond to stimulation and the release of extracellular glutamate. As glial cells are associated with most, if not all, synapses, Tg(gfap:iGluSnFR) is a novel and exciting tool to measure neuronal activity and extracellular glutamate dynamics in many regions of the nervous system. PMID- 28027027 TI - Estimating State Transitions for Opioid Use Disorders. AB - AIM: The aim was to estimate transitions between periods in and out of treatment, incarceration, and legal supervision, for prescription opioid (PO) and heroin users. METHODS: We captured all individuals admitted for the first time for publicly funded treatment for opioid use disorder (OUD) in California (2006 to 2010) with linked mortality and criminal justice data. We used Cox proportional hazards and competing risks models to assess the effect of primary PO use (v. heroin) on the hazard of transitioning among 5 states: (1) opioid detoxification treatment; (2) opioid agonist treatment (OAT); (3) legal supervision (probation or parole); (4) incarceration (jail or prison); and (5) out-of-treatment. Transitions were conditional on survival, and death was modeled as an absorbing state. RESULTS: Both primary PO (n = 11,733) and heroin (n = 19,926) users spent most of their median 2.3 y of observation out of treatment. Primary PO users were significantly younger (median age 30 v. 34 y), and a higher percentage were female (43.1% v. 31.5%; P < 0.001), white (74.6% v. 63.1%; P < 0.001), and had completed high school (31.8% v. 18.9%; P < 0.001). When compared to primary heroin users, PO users had a higher hazard of transitioning from detoxification to OAT (Hazard Ratio (HR), 1.65; 95% CI, 1.54 to 1.77), and had a lower hazard of transitioning from out-of-treatment to either detoxification (0.75 [0.70, 0.81]) or OAT (0.90 [0.85, 0.96]). CONCLUSION: Our findings can be applied directly in state transition modeling to improve the validity of health economic evaluations. Although PO users tended to remain in treatment for longer durations than heroin users, they also tended to remain out of treatment for longer after transitioning to an out-of-treatment state. Despite the proven effectiveness of time-unlimited treatment, individuals with OUD spend most of their time out of treatment. PMID- 28027029 TI - Mechanisms of Chromosomal Diversification in Species of Rineloricaria (Actinopterygii: Siluriformes: Loricariidae). AB - Cytogenetic studies in fish of the Rineloricaria genus have already shown a high variation in diploid number (2n). Along with fusion/fission events for 2n alteration, inversions contribute to the diversification of chromosome formulae within this group. The present study assessed different populations/species of the Rineloricaria aiming to describe the karyotype organization of its members and understand the mechanisms that lead to the variation of chromosome numbers. Cytogenetic data showed distinct karyotype organization among Rineloricaria populations/species studied, ranging in diploid number from 46 to 64 chromosomes, syntopic species and two karyomorphs in Rineloricaria pentamaculata. Using ribosomal DNAs (rDNAs) and TTAGGGn probes by fluorescence in situ hybridization in species with low diploid numbers, we detected sites of 18S rDNA, 5S rDNA, and TTAGGGn in centromeric regions of metacentric chromosomes, which participated in chromosome rearrangements like centric fusions. In species with high 2n, centric fissions probably occurred in karyotypic diversification. In this study, we assessed the telomeric instability, chromosomal breaks, and rearrangements due to interstitial telomeric site vestiges detection, in addition to the probable role of rDNAs in chromosome fusions in karyotypic diversification of this group. PMID- 28027030 TI - AJOT Celebrates AOTA's Centennial. AB - Each issue of the 2017 volume of the American Journal of Occupational Therapy will feature a special Centennial Topics section containing two to four articles related to a specific theme. The goal is to acknowledge occupational therapy's history while focusing on the future of the profession. The Centennial Topics section is intended to help occupational therapy professionals in all aspects of the profession take stock of how far the profession has come and to spark interest in the many exciting paths for the future development of the field. PMID- 28027032 TI - The Bluebirds: World War I Soldiers' Experiences of Occupational Therapy. AB - OBJECTIVE: More is known about the experience of occupational therapists than the experience of patients during the profession's early years. We examined soldiers' experiences of occupational therapy in American Base Hospital 9 in France during World War I through analysis of a 53-line poem by Corporal Frank Wren contained in the unpublished memoir of occupational therapy reconstruction aide Lena Hitchcock. METHOD: Historical documentary research methods and thematic analysis were used to analyze the poem, the memoir, and the hospital's published history. RESULTS: The poem describes the activities engaged in during occupational therapy, equipment used, and the context of therapy. It articulates positive dimensions of the experience of engaging in activities, including emotional benefits, diversion, and orthopedic benefits. CONCLUSION: Previous historical research has identified core philosophical premises about the use of occupational therapy; in this article, the enactment of these principles is established through the analysis of a soldier's account of receiving occupational therapy. PMID- 28027031 TI - Occupational Therapy and Management of Multiple Chronic Conditions in the Context of Health Care Reform. AB - One in four individuals living in the United States has multiple chronic conditions (MCCs), and the already high prevalence of MCCs continues to grow. This population has high rates of health care utilization yet poor outcomes, leading to elevated concerns about fragmented, low-quality care provided within the current health care system. Several national initiatives endeavor to improve care for the population with MCCs, and occupational therapy is uniquely positioned to contribute to these efforts for more efficient, effective, client centered management of care. By integrating findings from the literature with current policy and practice, we aim to highlight the potential role for occupational therapy in managing MCCs within the evolving health care system. PMID- 28027033 TI - Willard and Spackman's Enduring Legacy for Future Occupational Therapy Pathways. AB - Helen Willard (1894-1980) and Clare Spackman (1909-1992) paved the way for modern and future occupational therapy. This article validates the need for historical research in occupational therapy and presents a historical study on how the personal and professional collaboration of Willard and Spackman influenced occupational therapy. Data were gathered from archival documents, private papers, and 10 oral histories with colleagues, students, family, and friends. We used text analysis with triangulation to develop themes to reconstruct a proximity of the historical story. Two major themes that describe Willard's and Spackman's influence on occupational therapy are (1) Enduring Legacies and (2) Sacred Solitude and Chosen Gatherings. Subthemes within Enduring Legacies include Guiding Practice, Leaders in Service, and Educational Leadership. These women strongly influenced practitioners worldwide while maintaining the sacredness of their private lives. Their example can serve as a model for current and future occupational therapy practitioners and leaders. PMID- 28027034 TI - A Century of Therapeutic Use of the Physical Environment. AB - In this article, we describe the use of the objects and spaces of the physical environment by occupational therapy practitioners in the United States over the profession's first 100 years. Using professional literature selected by decade from the years 1917 through 2016 to obtain data, we applied grounded theory methods to complete a detailed description. Team-based analysis over four coding schemes yielded a theoretical description of the profession's therapeutic use of the physical environment. Study findings included descriptions across occupational therapy's history of (1) treatment spaces, (2) the concepts of adapting and grading, and (3) a typology of constructive and nonconstructive applications of objects and activities by occupational therapy clients and practitioners. This extended historical perspective on trajectories of change in intervention space, the role of physical products in intervention, therapist repertoire, and the enduring role of adaptation suggests how the physical environment may be used in future practice. PMID- 28027035 TI - Justice and U.S. Occupational Therapy Practice: A Relationship 100 Years in the Making. AB - At 99 years old, occupational therapy is a global health care profession with a growing orientation toward justice. Because much of the occupational justice discourse has developed outside the United States, parallels between the profession's ethos and its current focus on justice must be examined more closely in this country. Although occupational therapy practitioners in the United States are better equipped than their predecessors with language and theories that explicitly emphasize justice, the potential for bringing that focus to bear depends on practitioners' willingness to think differently about their practices. We argue that a focus on justice can be naturally integrated with curriculum standards by emphasizing the link between cultural humility, client-centeredness, and embodied habits of "seeking out unknown others." Outside formal education, practitioners can be encouraged to think of justice as something that already intersects with practice, not something that practitioners must choose whether to take up. PMID- 28027036 TI - Fostering Full Implementation of Evidence-Based Practice. AB - Evidence-based practice (EBP) is a widely endorsed concept, but many occupational therapy practitioners would like to be more informed and supported in its full implementation. They need information on the evolving definitions and concepts of EBP, encouragement to develop and adopt EBP models that link to occupational therapy's professional values, and methods that translate evidence into answers for clinical questions. This column discusses these needs and makes recommendations to the American Occupational Therapy Association for addressing them. PMID- 28027037 TI - Current Evidence and Opportunities for Expanding the Role of Occupational Therapy for Adults With Musculoskeletal Conditions. AB - Musculoskeletal conditions are the second greatest cause of disability worldwide, and chronic musculoskeletal conditions affect nearly the same percentage of the general population as chronic circulatory and respiratory conditions combined. Moreover, people with musculoskeletal conditions experience a significant decline in independence with daily activities and occupational performance, key areas targeted by occupational therapy interventions. This special issue of the American Journal of Occupational Therapy provides comprehensive summaries of evidence for the care of common musculoskeletal conditions, highlights important implications that support evidence-informed practice, and proposes ways to advance the practice of occupational therapy to improve the lives of people with musculoskeletal conditions. PMID- 28027038 TI - Effectiveness of Occupational Therapy Interventions for Adults With Musculoskeletal Conditions of the Forearm, Wrist, and Hand: A Systematic Review. AB - Occupational therapy practitioners are key health care providers for people with musculoskeletal disorders of the distal upper extremity. It is imperative that practitioners understand the most effective and efficient means for remediating impairments and supporting clients in progressing to independence in purposeful occupations. This systematic review provides an update to a previous review by summarizing articles published between 2006 and July 2014 related to the focused question, What is the evidence for the effect of occupational therapy interventions on functional outcomes for adults with musculoskeletal disorders of the forearm, wrist, and hand? A total of 59 articles were reviewed. Evidence for interventions was synthesized by condition within bone, joint, and general hand disorders; peripheral nerve disorders; and tendon disorders. The strongest evidence supports postsurgical early active motion protocols and splinting for various conditions. Very few studies have examined occupation-based interventions. Implications for occupational therapy practice and research are provided. PMID- 28027039 TI - Effectiveness of Occupational Therapy Interventions for Musculoskeletal Shoulder Conditions: A Systematic Review. AB - People with musculoskeletal disorders of the shoulder commonly experience pain, decreased strength, and restricted range of motion (ROM) that limit participation in meaningful occupational activities. The purpose of this systematic review was to evaluate the current evidence for interventions within the occupational therapy scope of practice that address pain reduction and increase participation in functional activities. Seventy-six studies were reviewed for this study-67 of Level I evidence, 7 of Level II evidence, and 2 of Level III evidence. Strong evidence was found that ROM, strengthening exercises, and joint mobilizations can improve function and decrease pain. The evidence to support physical modalities is moderate to mixed, depending on the shoulder disorder. Occupational therapy practitioners can use this evidence to guide daily clinical decision making. PMID- 28027040 TI - Effectiveness of Occupational Therapy Interventions for Lower-Extremity Musculoskeletal Disorders: A Systematic Review. AB - Lower-extremity (LE) musculoskeletal disorders (MSDs) can have a major impact on the ability to carry out daily activities. The effectiveness of interventions must be examined to enable occupational therapy practitioners to deliver the most appropriate services. This systematic review examined the literature published between 1995 and July 2014 that investigated the effectiveness of occupational therapy interventions for LE MSDs. Forty-three articles met the criteria and were reviewed. Occupational therapy interventions varied on the basis of population subgroup: hip fracture, LE joint replacement, LE amputation or limb loss, and nonsurgical osteoarthritis and pain. The results indicate an overall strong role for occupational therapy in treating clients with LE MSDs. Activity pacing is an effective intervention for nonsurgical LE MSDs, and multidisciplinary rehabilitation is effective for LE joint replacement and amputation. Further research on specific occupational therapy interventions in this important area is needed. PMID- 28027041 TI - Effectiveness of Occupational Therapy Interventions for Adults With Fibromyalgia: A Systematic Review. AB - OBJECTIVE: This systematic review addresses the effectiveness of occupational therapy-related interventions for adults with fibromyalgia. METHOD: We examined the literature published between January 2000 and June 2014. A total of 322 abstracts from five databases were reviewed. Forty-two Level I studies met the inclusion criteria. Studies were evaluated primarily with regard to the following outcomes: daily activities, pain, depressive symptoms, fatigue, and sleep. RESULTS: Strong evidence was found for interventions categorized for this review as cognitive-behavioral interventions; relaxation and stress management; emotional disclosure; physical activity; and multidisciplinary interventions for improving daily living, pain, depressive symptoms, and fatigue. There was limited to no evidence for self-management, and few interventions resulted in better sleep. CONCLUSION: Although the evidence supports interventions within the scope of occupational therapy practice for people with fibromyalgia, few interventions were occupation based. PMID- 28027042 TI - Effectiveness of Occupational Therapy Interventions for Adults With Rheumatoid Arthritis: A Systematic Review. AB - OBJECTIVE: We reviewed the efficacy of occupational therapy-related interventions for adults with rheumatoid arthritis. METHOD: We examined 51 Level I studies (19 physical activity, 32 psychoeducational) published 2000-2014 and identified from five databases. Interventions that focused solely on the upper or lower extremities were not included. RESULTS: Findings related to key outcomes (activities of daily living, ability, pain, fatigue, depression, self-efficacy, disease symptoms) are presented. Strong evidence supports the use of aerobic exercise, resistive exercise, and aquatic therapy. Mixed to limited evidence supports dynamic exercise, Tai Chi, and yoga. Among the psychoeducation interventions, strong evidence supports the use of patient education, self management, cognitive-behavioral approaches, multidisciplinary approaches, and joint protection, and limited or mixed evidence supports the use of assistive technology and emotional disclosure. CONCLUSION: The evidence supports interventions within the scope of occupational therapy practice for rheumatoid arthritis, but few interventions were occupation based. PMID- 28027043 TI - Optimal Grasp Distance and Muscle Loads for People With Rheumatoid Arthritis Using Carpometacarpal and Metacarpophalangeal Immobilization Orthoses. AB - OBJECTIVES: The objectives of this study were to investigate whether people with rheumatoid arthritis (RA) require greater muscle loads to equal the grip strength of healthy adults and to find the optimal grip distance for people with RA using carpometacarpal and metacarpophalangeal immobilization orthoses as measured by electromyography of the forearm muscles. METHOD: A 2 * 2 (Group * Orthosis) experiment and a 2 * 3 (Orthosis * Grasp Distance) factorial were conducted. Grip strength and muscle load were measured. RESULTS: Grip strength was significantly lower, and muscle load was greater, in 18 participants with RA than in 18 healthy adults. No effect of orthosis use on grip strength and muscle load was found. Muscle load was lower for the 42.25-mm diameter dynamometer handle than for handles with larger diameters. CONCLUSION: People with RA require more muscle load than healthy adults to produce the same exertion, and 42.25 mm is recommended for people with RA as the optimal grasp distance. PMID- 28027044 TI - Evaluation of Hand Forces During a Joint-Protection Strategy for Women With Hand Osteoarthritis. AB - OBJECTIVE: We evaluated whether a joint-protection strategy changes the mechanics of opening a sealed jar. METHOD: Thirty-one adult women with hand osteoarthritis attempted to open a "sealed" jar instrument when using and not using nonskid material. Grip force, torque, success, and pain were recorded for each trial. RESULTS: Participants used less grip force when twisting with their left hand. The greatest torque and success, yet the least amount of grip force across time, and pain was noted when the left hand turned the lid, the jar was held vertically, the right hand supported the base, and nonskid material was used. CONCLUSION: Women with hand osteoarthritis should be educated to consider the hand they use and their approach when opening sealed jars. Use of nonskid material without additional reasoning may increase load on arthritic joints, pain, and dysfunction. Additional research on task kinematics and the kinetics of the stabilizing hand is needed. PMID- 28027045 TI - Role of Occupational Therapy in Preventing Work-Related Musculoskeletal Disorders With Recycling Workers: A Pilot Study. AB - Little is known about injury prevention in recycling workers; therefore, in this study, I aimed to identify physical and psychosocial risk factors for employees involved in single-stream recycling and to explore strategies for prevention and wellness. Fifteen participants who were either recycling workers or supervisors located throughout seven locations on an urban university campus participated. A mixed-methods research design was used to obtain data through a variety of standardized work environment and health questionnaires and semistructured interviews. Approximately 80% of participants expressed satisfaction with their jobs; 50% reported having a musculoskeletal injury; and 33% reported a lack of support from coworkers or supervisors, which created stress and anxiety. Additional risk factors included poor body mechanics, equipment issues, poor social interactions, and lack of supervisor knowledge for prevention. Occupational therapy practitioners are well situated to support preventive interventions that address the combined physical and psychosocial needs of recycling workers. PMID- 28027046 TI - Factors Associated With Success in an Occupational Rehabilitation Program for Work-Related Musculoskeletal Disorders. AB - Work-related musculoskeletal disorders are a significant burden; however, no consensus has been reached on how to maximize occupational rehabilitation programs for people with these disorders, and the impact of simulating work tasks as a mode of intervention has not been well examined. In this retrospective cohort study, the authors used logistic regression to identify client and program factors predicting success for 95 clients in a general occupational rehabilitation program and 71 clients in a comprehensive occupational rehabilitation program. The final predictive model for general rehabilitation included gender, number of sessions completed, and performance of work simulation activities. Maximum hours per session was the only significant predictor of success in the comprehensive rehabilitation program. This study identifies new factors associated with success in occupational rehabilitation, specifically highlighting the importance of intensity (i.e., session length and number of sessions) of therapy and occupation-based activities for this population. PMID- 28027047 TI - Predictors of Disability and Quality of Life With an Upper-Extremity Peripheral Nerve Disorder. AB - OBJECTIVE: We sought to understand the wide range of problems that patients with upper-extremity peripheral nerve disorders experience and to identify predictors of disability and quality of life (QOL). METHOD: Data from standardized assessments of disability and QOL, physical examination results, and intake surveys from 627 patients were analyzed using descriptive and inferential statistics. We compared results between groups and built multivariate models measuring disability, work disability, and physical and mental QOL. RESULTS: The sample demonstrated substantial disability and even greater work disability, which both closely correlated with poorer QOL. Work status was integral in predicting disability. Common predictors across models included problems with sleep and intimate relationships, deficits in work and household performance, and higher pain. CONCLUSION: To decrease disability and improve QOL, occupational therapy practitioners should help patients with upper-extremity peripheral nerve disorders identify strategies to maintain meaningful work and household roles, intimate relationships, and sleep, while continuing to address pain. PMID- 28027048 TI - Alignment of Outcome Instruments Used in Hand Therapy With the Occupational Therapy Practice Framework: Domain and Process and the International Classification of Functioning, Disability and Health: A Scoping Review. AB - OBJECTIVE: We sought to identify outcome instruments used in rehabilitation of the hand and upper extremity; to determine their alignment with the constructs of the International Classification of Functioning, Disability and Health (ICF) and the Occupational Therapy Practice Framework: Domain and Process; and to report gaps in the constructs measured by outcome instruments as a basis for future research. METHOD: We searched CINAHL, MEDLINE, OTseeker, and the Cochrane Central Register of Controlled Trials using scoping review methodology and evaluated outcome instruments for concordance with the ICF and the Framework. RESULTS: We identified 18 outcome instruments for analysis. The findings pertain to occupational therapists' focus on body functions, body structures, client factors, and activities of daily living; a gap in practice patterns in use of instruments; and overestimation of the degree to which instruments used are occupationally based. CONCLUSION: Occupational therapy practitioners should use outcome instruments that embody conceptual frameworks for classifying function and activity. PMID- 28027049 TI - Occupational Therapy Interventions for Adolescents With Autism Spectrum Disorder. AB - Evidence Connection articles provide a clinical application of systematic reviews developed in conjunction with the American Occupational Therapy Association's (AOTA's) Evidence-Based Practice Project. In this Evidence Connection article, we describe a case report of an adolescent with autism spectrum disorder. The occupational therapy assessment and treatment processes for school, home, community, and transition settings are described. Findings from the systematic reviews on this topic were published in the September/October 2015 issue of the American Journal of Occupational Therapy and in AOTA's Occupational Therapy Practice Guidelines for Individuals With Autism Spectrum Disorder. Each article in this series summarizes the evidence from the published reviews on a given topic and presents an application of the evidence to a related clinical case. Evidence Connection articles illustrate how the research evidence from the reviews can be used to inform and guide clinical decision making. PMID- 28027051 TI - Accounting for Local Dependence with the Rasch Model: The Paradox of Information Increase. AB - Test theories imply statistical, local independence. Where local independence is violated, models of modern test theory that account for it have been proposed. One violation of local independence occurs when the response to one item governs the response to a subsequent item. Expanding on a formulation of this kind of violation between two items in the dichotomous Rasch model, this paper derives three related implications. First, it formalises how the polytomous Rasch model for an item constituted by summing the scores of the dependent items absorbs the dependence in its threshold structure. Second, it shows that as a consequence the unit when the dependence is accounted for is not the same as if the items had no response dependence. Third, it explains the paradox, known, but not explained in the literature, that the greater the dependence of the constituent items the greater the apparent information in the constituted polytomous item when it should provide less information. PMID- 28027052 TI - Applying the Many-Facet Rasch Measurement Model to Explore Reviewer Ratings of Conference Proposals. AB - For academic conferences, when proposals are submit they are often judged using a rating scale on identified criterion by reviewers who have a shared interest and expertise in the area under consideration. Given the multiple and varied reviewers, an analysis of psychometric properties like rater severity and consistency are important. However, many of the problems that plague the conference proposal selection process are the same issues that plague survey research: rater bias/severity, misuse of rating scale, and the use of raw scores as measures. We propose the use of the many-facet Rasch measurement model (MFRM) to combat these shortcomings and improve the quality of the conference proposal selection process. A set of American Educational Research Association (AERA) Special Interest Group (SIG) proposals is used as an example. The results identify proposals that were accepted based on calculating the mean of summed raw scores, but when MFRM is applied to adjust for judge severity the rank order of the proposals is substantially altered. PMID- 28027053 TI - Sample Size and Probability Threshold Considerations with the Tailored Data Method. AB - This article discusses sample size and probability threshold considerations in the use of the tailored data method with the Rasch model. In the tailored data method, one performs an initial Rasch analysis and then reanalyzes data after setting item responses to missing that are below a chosen probability threshold. A simple analytical formula is provided that can be used to check whether or not the application of the tailored data method with a chosen probability threshold will create situations in which the number of remaining item responses for the Rasch calibration will or will not meet minimum sample size requirements. The formula is illustrated using a real data example from a medical imaging licensure exam with several different probability thresholds. It is shown that as the probability threshold was increased more item responses were set to missing and the parameter standard errors and item difficulty estimates also tended to increase. It is suggested that some consideration should be given to the chosen probability threshold and how this interacts with potential examinee sample sizes and the accuracy of parameter estimates when calibrating data with the tailored data method. PMID- 28027054 TI - Development of an Upper Extremity Function Measurement Model. AB - This study demonstrated the development of a measurement model for gross upper extremity function (GUE). The dependent variable was the Rasch calibration of the 27 ICF-GUE test items. The predictors were object weight, lifting distance from floor, carrying, and lifting. Multiple regression was used to investigate the contribution that each independent variable makes to the model with 203 outpatients. Object weight and lifting distance were the only statistically and clinically significant independent variables in the model, accounting for 83% of the variance (p < 0.01). The model indicates that, with each one pound increase in object weight, item challenge increases by 0.16 (p < 0.00) logits, and with each one inch increase in distance lifted from floor, item challenge increased by 0.02 logits (p < 0.02). The findings suggest that the majority of the variance of the measurement model for the ICF-GUE can be explained by object weight and distance lifted from the floor. PMID- 28027055 TI - Differential Item Functioning (DIF) and Subsequent Bias in Group Comparisons using a Composite Measurement Scale: A Simulation Study. AB - OBJECTIVE: To determine the conditions in which the estimation of a difference between groups for a construct evaluated using a composite measurement scale is biased if the presence of Differential Item Functioning (DIF) is not taken into account. METHODS: Datasets were generated using the Partial Credit Model to simulate 642 realistic scenarios. The effect of seven factors on the bias on the estimated difference between groups was evaluated using ANOVA: sample size, true difference between groups, number of items in the scale, proportion of items showing DIF, DIF-size for these items, position of these items location parameters along the latent trait, and uniform/non-uniform DIF. RESULTS: For uniform DIF, only the DIF-size and the proportion of items showing DIF (and their interaction term) had meaningful effects. The effect of non-uniform DIF was negligible. CONCLUSION: The measurement bias resulting from DIF was quantified in various realistic conditions of composite measurement scale use. PMID- 28027056 TI - The Self-assessment Practices of Hong Kong Secondary Students: Findings with a New Instrument. AB - Self-assessment is a core skill that enables students to engage in self-regulated learning. The purpose of this study was to examine the psychometric properties of a Self-assessment Practice Scale and to depict the characteristics of self assessment practices of Hong Kong secondary students using this newly developed instrument. A total of 6,125 students from 10 Hong Kong secondary schools completed the survey. Both Rasch and factor analyses revealed a two-dimension scale structure (i.e., Self-directed Feedback Seeking and Self-reflection). The two subscales demonstrated acceptable psychometric properties and suggestions for further improvement were proposed. The findings regarding self-assessment practices of secondary students indicated that, in general, students were quite used to engaging in self-reflection based on available feedback, but they were less disposed to taking the initiative to seek feedback on their own performance. Key demographic variables, e.g., gender and year level, played important roles in students' self-assessment practices. Girls had significantly higher self assessment measures on both scales than did boys. Junior students had higher measures on both scales than did their senior counterparts. Implications and directions for future research were discussed. PMID- 28027057 TI - The Measurement Properties of the Assessing Math Concepts' Assessments of Primary Students' Number Sense Skills. AB - The purpose of this study was to examine the measurement properties of the Assessing Math Concepts AMC Anywhere Hiding and Ten Frame Assessments, formative assessments of primary students' number sense skills. Each assessment has two parts, where Part 1 is intended to be foundational skills for part two. Part 1 includes manipulatives whereas Part 2 does not. Student data from 228 kindergarten through second grade teachers with a total of 3,666 students was analyzed using Rasch scaling. Data analyses indicated that when the two assessments were examined separately the intended order of item difficulty was clear. When the parts of both assessments were analyzed together, the items in Part 2 were not consistently more difficult that the items in Part 1. This suggests an alternative sequence of tasks in that students may progress from working with a specific number with manipulatives then without manipulatives rather than working with a variety of numbers with manipulatives before moving onto assessments without manipulatives. PMID- 28027058 TI - Rasch Analysis of the Malaysian Secondary School Student Leadership Inventory (M3SLI). AB - The importance of instilling leadership skills in students has always been a main subject of discussion in Malaysia. Malaysian Secondary School Students Leadership Inventory (M3SLI) is an instrument which has been piloted tested in year 2013. The main purpose of this study is to examine and optimize the functioning of the rating scale categories in M3SLI by investigating the rating scale category counts, average and expected rating scale category measures, and steps calibrations. In detail, the study was aimed to (1) identify whether the five point rating scale was functioning as intended and (2) review the effect of a rating scale category revision on the psychometric characteristics of M3SLI. The study was carried out on students aged between 13 to 18 years (2183 students) by stratified random sampling in 26 public schools in Sabah, Malaysia, with the results analysed using Winsteps. This study found that the rating scale of Personality and Values constructs needed to be modified while the scale for Leadership Skills was maintained. For future studies, other aspects of psychometric properties like differential item functioning (DIF) based on demographic variables such as gender, school locations and forms should be researched on prior to the use of the instrument. PMID- 28027059 TI - Avoiding complications in endoscopic skull base surgery. AB - PURPOSE OF REVIEW: Endoscopic skull base surgery has become an established approach for the removal of tumors and cerebrospinal fluid fistulae repair. Compared with external approaches, it provides better aesthetic results and quality of life postoperatively. However, as it becomes popular and expands its indications possible complications should be reassessed in terms of incidence and variability in order to confirm its efficacy and safety. This article reviews the recent literature describing the main categories of possible complications suggesting strategies to minimize their incidence. RECENT FINDINGS: Detailed preoperative planning based on imaging and histology can prevent major complications. Intraoperative use of image guidance and meticulous hemostasis provide the surgical field needed to avoid complications. Postoperative patient counseling, along with close and detailed nasal postoperative care are significant factors for an optimal outcome. SUMMARY: Monitoring of complications after endoscopic skull base surgery is necessary in order to standardize protocols of management and improve our surgical techniques. The presence of late onset complications underlines the need of a special focus in postoperative care and follow-up. PMID- 28027060 TI - Methodological Quality of Surgical Mortality Studies Using Large Hospital Databases: A Systematic Review. AB - OBJECTIVE: To review the methodology employed in surgical mortality studies to control for potential confounders. SUMMARY BACKGROUND DATA: Nationwide hospital data are increasingly used to investigate surgical outcomes. However, poor data granularity and coding inaccuracies may lead to flawed findings. METHODS: We conducted a systematic review in accordance with the PRISMA statement in 6 major journals (NEJM, Lancet, BMJ, JAMA, Medical Care, Annals of Surgery) using PubMed from its inception until December 31, 2014. Two reviewers independently reviewed citations. Using a predesigned data collection form, we extracted information about study aim and design, data source, selected population, outcome definition, patient and hospital adjustment, statistics, and sensitivity analyses. The methodological quality of studies was assessed based on 5 criteria and explored over time. RESULTS: Among 89 included studies from 1987 to 2014, 54 explored surgical mortality determinants, 13 compared surgical procedure effectiveness, 13 evaluated the impact of healthcare policy, and 9 described outcome trends for specific procedures. A total of 89% (n = 79) of studies did not describe population selection criteria at patient and hospital level, 64% (n = 57) did not consider secular trends, 52% (n = 46) neglected hospital clustering or characteristics, 21% (n = 19) did not perform sensitivity analyses, and 4% did not adjust outcomes for patient risk (n = 4). The percentage of studies satisfying at least 3 of these criteria increased significantly from 44% before 1999 to 52% between 2000 and 2009 and 78% after 2010 (P = 0.008). CONCLUSIONS: Although methodological quality of studies has improved over time, confounder control could be improved through better study design, homogeneous population selection, the consideration of hospital factors and secular trends influencing surgical mortality, and the systematic performance of sensitivity analyses. PMID- 28027061 TI - Zika virus congenital syndrome, the new Z in TORCHZ? Prospects for diagnosis prevention and treatment. PMID- 28027062 TI - Organ donation and imminent death: pro position. AB - PURPOSE OF REVIEW: Donation after cardiac death is associated with many problems including ischemic injury, high rates of delayed allograft function, prolonged time to asystole, and frequent organ discard. Imminent death donation (IDD) has been proposed as a separate category of organ donation: distinct from living donation and donation after cardiac death. RECENT FINDINGS: A protocol for IDD was developed at Rhode Island Hospital and published in the ethics literature. The United Network for Organ Sharing (UNOS) Ethics Committee reviewed the protocol and stated that IDD was ethically appropriate in some cases. A wider review by a working group within UNOS concluded similarly, but felt that a myriad of policy revisions would be required and were concerned about a possible negative impact on public trust in organ donation. Nonetheless, IDD and other nontraditional strategies continue to be proposed, implemented in other countries and discussed by patients and donor families. SUMMARY: This review, on the 'Pro' side of IDD, proposes that the medical community continue to work toward implementing IDD. Donor family's wishes are best met by organ donation, successful outcomes for the recipients, and a dignified death for their loved one. In some cases, IDD is the best strategy to meet these goals. PMID- 28027063 TI - Rubinstein-Taybi because of a novel EP300 mutation with novel clinical findings. PMID- 28027064 TI - Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome. AB - Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases. PMID- 28027065 TI - Joint Contractures Resulting From Prolonged Immobilization: Etiology, Prevention, and Management. AB - Patients who are immobilized for a prolonged period are at risk for developing joint contractures, which often affect functional outcomes. Nonsurgical interventions are useful for preventing joint contractures. However, once contractures develop, these interventions frequently fail to restore function over the long term. To increase the rehabilitation potential of an extremity with refractory function-limiting contractures, surgery is often required. PMID- 28027066 TI - Complementary Use of Effect Site-Target Controlled Infusion and SmartPilot View for Anesthetic Management in Semi-awake Craniotomy Near BIS 85. PMID- 28027067 TI - Mannitol Shower: The Artefactual Air Embolism! PMID- 28027068 TI - Is Propofol Safe in Patients With Phenylketonuria? PMID- 28027069 TI - 2016 Society for Neuroscience in Anesthesiology and Critical Care (SNACC) Annual Meeting Report. PMID- 28027070 TI - Innovations in Functional Neurosurgery and Anesthetic Implications. AB - Functional neurosurgery has undergone rapid growth over the last few years fueled by advances in imaging technology and novel treatment modalities. These advances have led to new surgical treatments using minimally invasive and precise techniques for conditions such as Parkinson's disease, essential tremor, epilepsy, and psychiatric disorders. Understanding the goals and technological issues of these procedures is imperative for the anesthesiologist to ensure safe management of patients presenting for functional neurosurgical procedures. In this review, we discuss the advances in neurosurgical techniques for deep brain stimulation, focused ultrasound and minimally invasive laser-based treatment of refractory epilepsy and provide a guideline for anesthesiologists caring for patients undergoing these procedures. PMID- 28027072 TI - Spectrum of Drug-induced Chronic Diarrhea. AB - The evaluation of a patient with chronic diarrhea can be quite frustrating, as it is expensive and involves multiple diagnostic studies. Moreover, identification of a drug as a cause of chronic diarrhea is a challenge in patients taking multiple medications. The disease may either be associated with intestinal mucosal changes, mimicking diseases such as celiac disease, or purely functional, with no histopathologic change. Drug-induced diarrhea may or may not be associated with malabsorption of nutrients, and a clinical improvement may occur within days of discontinuation of the drug, or may take longer when associated with mucosal injury. Diarrhea in diabetics, often attributed to poor management and lack of control, may be due to oral hypoglycaemic agents. Chemotherapy can result in diffuse or segmental colitis, whereas olmesartan and a few other medications infrequently induce a disease that mimics celiac disease, but is not associated with gluten intolerance. In short, increased awareness of a drug, as a cause for diarrhea and a clear understanding of the clinical manifestations will help clinicians to solve this challenging problem. This article aims to review drug-induced diarrhea to (a) understand known pathophysiological mechanisms; (b) assess the risk associated with frequently prescribed medications, and discuss the pathogenesis; and PMID- 28027071 TI - Covert Hepatic Encephalopathy: Can My Patient Drive? AB - Liver cirrhosis is a public health problem and hepatic encephalopathy is one of its main complications, which can be either overt meaning thereby evident and readily diagnosed, or covert/minimal (covert hepatic encephalopathy-CHE) needing psychometric testing for diagnosis. Patients with CHE hepatic encephalopathy have deficits in multiple domains including visuospatial assessment, attention, response inhibition, working memory, along with psychomotor speed to name a few areas. These patients have poor navigational skills, get fatigued easily, and demonstrate poor insight into their driving deficits. The combination of all these leads them to have poor driving skills leading to traffic violations and crashes as demonstrated not only on the simulation testing but also in real-life driving events. There are multiple psychometric tests for CHE testing but these are not easily available and there is no uniform consensus on the gold standard testing as of yet. It does not automatically connote that all patients who test positive on driving simulation testing are unfit to drive. The physicians are encouraged to take driving history from the patient and the caregivers on every encounter and focus their counseling efforts more on patients with recent history of traffic crashes, with abnormal simulation studies and history of alcohol cessation within last year. As physicians are not trained to determine fitness to drive, their approach toward CHE patients in regards to driving restrictions should be driven by ethical principles while as respecting the local laws. PMID- 28027073 TI - Value of the coronary artery disease consortium rule in patients with acute chest pain and negative troponins referred for exercise stress testing. AB - OBJECTIVE: To assess the value of the pretest probability (PTP) of coronary artery disease (CAD) for predicting stress testing results and coronary events in patients with acute chest pain and negative troponins. PATIENTS AND METHODS: A total of 3527 patients without a history of CAD referred to our chest pain unit with suspected acute coronary syndromes, nondiagnostic ECGs, and negative troponin levels underwent exercise stress testing. PTP was estimated with the CAD consortium prediction rule, and was categorized as low (<15%), low-intermediate (15-65%), intermediate-high (66-85%), and high (>85%). The endpoints were the presence of signs of inducible myocardial ischemia on stress testing and the occurrence of coronary events within 6 months. RESULTS: The probability of exercise-induced myocardial ischemia was 2.6, 12.6, 42.9, and 82.1% in patients with low, low-intermediate, intermediate-high, and high PTP, respectively (Ptrend<0.001). The cumulative rate of coronary events within 6 months was also significantly lower in patients with low PTP of CAD (0.8%) than in those with low intermediate (6.9%), intermediate-high (32.5%), or high PTP (66.7%) (Ptrend<0.001). Per 10% increment in PTP of CAD, the adjusted odds ratios for inducible myocardial ischemia and coronary events within 6 months were, respectively, 1.71 (95% confidence interval: 1.61-1.85) and 1.87 (95% confidence interval: 1.74-2.01). CONCLUSION: PTP was associated strongly with the likelihood of exercise-induced myocardial ischemia and coronary events in patients with suspected acute coronary syndromes and negative troponins. The yield of stress testing in the subset of patients with low PTP was very low. PMID- 28027074 TI - A randomized-controlled trial of a patient-centred intervention in high-risk discharged older patients. AB - BACKGROUND: The risk of early reattendance after discharge has been proposed as a performance indicator for emergency departments (EDs), but is not uniform in all patients. Those individuals at the highest risk of reattendance may benefit from an intense intervention to reduce this risk, and our objective was to test this hypothesis in a clinical trial. METHODS: A randomized-controlled trial was conducted in the EDs of two hospitals. Very high-risk adults aged 65 years and older, identified using a validated risk-prediction nomogram and being discharged from ED, were randomized to receive a postdischarge patient-centred intervention or standard care. The intervention focused on identifying and supporting patients to address risk factors for future hospital presentation. The primary outcome measure was any unplanned ED reattendance within 28 days. Secondary outcomes included 28-day and 1-year hospital usage, institutionalization and death. RESULTS: We enrolled 164 patients, 82 in each study arm. There was an 8% absolute (95% confidence interval: -7%-20%) and a 20% relative risk reduction for an intervention patient making an unplanned ED reattendance within 28 days. This difference was not statistically significant (P=0.26). CONCLUSION: This postdischarge intervention was associated with only small and nonsignificant reductions in ED reattendance. PMID- 28027075 TI - Single use and disposable flexible ureteroscopes. AB - PURPOSE OF REVIEW: Flexible ureteroscopy has been widely developed in the last decade been nowadays one of the first line treatment options for urolithiasis and conservative management for upper tract urothelial tumors. Even though some unfavorable features of the reusable flexible scopes can limit the surgical procedure such as their availability, lack of sterilization or costly repairs. Disposable scopes have been developed with the intention of improving such problems. RECENT FINDINGS: To our knowledge, seven devices have been developed. Of the scopes features, size, deflection, image quality and ergonomic handling have to be at least as good as reusable ones as they are expected to be noninferior. Three devices match all the features of reusable scopes, although only one has been properly studied. SUMMARY: Not all the available disposable devices have been properly studied or compared with standard scopes. Although some devices are promising more studies are needed to proof their benefits. PMID- 28027076 TI - Serious Gaming in Medical Education: A Proposed Structured Framework for Game Development. AB - STATEMENT: Serious games are increasingly being used for medical education. However, the design and development of serious games for the education of health professionals is highly variable, and very few articles report the development process used for game development. There are many established processes for software development that can improve and streamline development, and incorporating the best practices from educational pedagogy and software development may enhance teamwork and communication, decrease development costs, and improve the quality of serious games. In this article, we review and summarize the literature for serious game development for medical education, and combining the best practices, we propose a structured three-phase iterative development framework for serious game development. PMID- 28027077 TI - Rectal Carcinoma Model: A Novel Simulation in Pathology Training. AB - INTRODUCTION: Until now, the apprenticeship training model is used to train pathology residents. Pathology residents are trained using patient specimens that are received during the course of normal daily pathology service. However, this training method could result in inconsistency in knowledge and experience among trainees because of variation in specimens that are received for analysis. The use of simulated specimens in pathology residency training could help ensure that all pathology residents receive consistent knowledge and experience. The aim of this study was to develop prototype rectal carcinoma model to be used as a simulation tool and to evaluate its effectiveness in pathology training. METHODS: Five units of a prototype rectal carcinoma model were produced in latex rubber. The model was used as a simulation tool for training in 12 pathology residents and 7 pathologist assistants. Pretesting and posttesting of each participant was conducted by multiple choice question test. A questionnaire was also given to study participants to elicit their views regarding the fidelity of the model and the model's efficacy and usefulness relative to the gross examination technique. RESULTS: Among the 19 participants, the mean pretest score was 79.24% and the mean posttest score was 88.54% (P = 0.045). The fidelity of the model was rated as moderate to marked by all participants. Most participants (94.74%) rated the models efficacy and usefulness relative to the gross examination technique as being moderate to marked. DISCUSSIONS: The rectal carcinoma model introduced in this study was found to be an effective simulation tool for pathology training. The model had good fidelity on appearance and good efficacy as well as usefulness relative to the gross examination technique. PMID- 28027078 TI - Back to Basics. PMID- 28027079 TI - Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date. AB - Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities. PMID- 28027080 TI - Carcinoid-Like/Labyrinthine Pattern in Sebaceous Neoplasms Represents a Sebaceous Mantle Phenotype: Immunohistochemical Analysis of Aberrant Vimentin Expression and Cytokeratin 20-Positive Merkel Cell Distribution. AB - This study investigated the nature of carcinoid-like, labyrinthine, rippled, and conventional cell arrangements in sebaceous neoplasms, focusing on vimentin expression and Merkel cell distribution in sebaceous neoplasms relative to these findings in normal sebaceous units and other sebaceous conditions. Immunohistochemistry for vimentin and cytokeratin 20 (CK20) was evaluated in carcinoid-like (n = 2), labyrinthine (n = 4), rippled (n = 3), and conventional (n = 6) sebaceomas; sebaceous mantle hyperplasia (n = 1); steatocystomas (n = 5); fibrofolliculomas (n = 4); sebaceous mantleoma (n = 1); sebaceous gland hyperplasias (n = 4); sebaceous adenomas (n = 4); and sebaceous carcinomas (n = 4) as well as normal skin tissue. The sebaceous mantle and its hamartoma (fibrofolliculoma) showed weak positivity for vimentin in the basal layer of the epithelial component and contained a few CK20-positive Merkel cells within the epithelial component, whereas mature sebaceous lobules were negative for vimentin and did not contain any Merkel cells. All sebaceomas with carcinoid-like or labyrinthine pattern highly expressed vimentin. CK20-positive Merkel cells were distributed with varying numbers in carcinoid-like pattern (2/2) and labyrinthine pattern (3/4) sebaceomas, sebaceous mantle hyperplasia (1/1), steatocystomas (3/5), fibrofolliculomas (3/4), and sebaceous mantleoma (1/1). Vimentin expression and Merkel cell distribution were observed in normal sebaceous mantles and sebaceous mantle-associated lesions, which could be evidence of a sebaceous mantle nature in the limited setting of sebaceous lesions. Furthermore, carcinoid like/labyrinthine pattern sebaceomas also showed vimentin immunoreactivity and contained Merkel cells. Therefore, carcinoid-like/labyrinthine pattern of cell arrangement in sebaceous neoplasms may represent a morphological phenotype of sebaceous mantles. PMID- 28027084 TI - Caring for the Amish: What Every Anesthesiologist Should Know. AB - The Amish are a relatively isolated group with cultural and religious customs that differ significantly from the mainstream American population. Functioning as tight-knit communities with strong conservative Christian beliefs, the Amish maintain a culture based on intentional separateness from the outside world. Key aspects of Amish life include distinct clothing and behaviors, a unique language, an agrarian lifestyle, limited formal education, nonviolence/nonaggression, and a general lack of modern technology, as exemplified by the use of the traditional horse-and-buggy. The Amish have distinct health care practices, beliefs, and goals, and because of differing genetics and lifestyle, also have a distinct constellation of health and disease characteristics. This article reviews the core beliefs, community and lifestyle, health care beliefs and practices, and health characteristics of this unique and medically challenging population. Generalizable strategies for providing culturally competent care for any such ethnically, socially, or medically unique community are presented. PMID- 28027081 TI - Altered Expression of Toll-like Receptors in Human Oral Epithelium in Oral Lichenoid Reactions. AB - Oral lichenoid reactions (OLRs) are chronic inflammatory lesions induced by contact with allergens. Toll-like receptors (TLRs) are members of pattern recognition receptor superfamily. Once activated, TLRs induce production of cytokines and chemokines, thus leading to inflammatory reaction in host tissue. In the present study, we aimed to investigate the potential role of TLRs in the initiation and perpetuation of OLRs, in which TLRs induce innate immune responses mounted against allergens. TLRs, 1 through 10, were mapped in tissue samples obtained from healthy donors and OLR patients using real-time quantitative reverse transcription polymerase chain reaction, immunostaining, and image analyses. We found that the immunoreactivity for all TLRs was increased in OLRs, except for TLR5, which was noticeably reduced. Gene analysis revealed that TLR1, TLR2, TLR4, TLR7, TLR8, and TLR9 transcripts were upregulated in OLRs compared with controls. In contrast, expression of TLR3, TLR5, and TLR6 genes were negatively regulated in OLRs. TLR10 remained unchanged in both groups. In conclusion, TLRs expression is deranged in OLRs in which TLRs could be sensitized by allergens and haptens derived from dental restorations. TLR reactivity is further enhanced by recruitment of T lymphocytes forming a diffuse lymphocytic infiltrate and thus creating a proinflammatory loop cycle. These findings suggest that TLRs are involved in OLRs and pave the way for alternative cost-effective therapeutic intervention. PMID- 28027085 TI - Bispectral Index Can Reliably Detect Deep Sedation in Mechanically Ventilated Patients: A Prospective Multicenter Validation Study. AB - BACKGROUND: Excessively deep sedation is prevalent in mechanically ventilated patients and often considered suboptimal. We hypothesized that the bispectral index (BIS), a quantified electroencephalogram instrument, would accurately detect deep levels of sedation. METHODS: We prospectively enrolled 90 critically ill mechanically ventilated patients who were receiving sedation. The BIS was monitored for 24 hours and compared with the Richmond Agitation Sedation Scale (RASS) evaluated every 4 hours. Deep sedation was defined as a RASS of -3 to -5. Threshold values of baseline BIS (the lowest value before RASS assessment) and stimulated BIS (the highest value after standardized assessment) for detecting deep sedation were determined in a training set (45 patients, 262 RASS assessments). Diagnostic accuracy was then analyzed in a validation set (45 patients, 264 RASS assessments). RESULTS: Deep sedation was only prescribed in 6 (6.7%) patients, but 76 patients (84.4%) had at least 1 episode of deep sedation. Thresholds for detecting deep sedation of 50 for baseline and 80 for stimulated BIS were identified, with respective areas under the receiver-operating characteristic curve of 0.771 (95% confidence interval, 0.714-0.828) and 0.805 (0.752-0.857). The sensitivity and specificity of baseline BIS were 94.0% and 66.5% and of stimulated BIS were 91.0% and 66.5%. When baseline and stimulated BIS were combined, the sensitivity, specificity, and clinical utility index were 85.0% (76.1%-91.1%), 85.9% (79.5%-90.7%), and 66.9% (57.8%-76.0%), respectively. CONCLUSIONS: Combining baseline and stimulated BIS may help detect deep sedation in mechanically ventilated patients. PMID- 28027086 TI - An Ambulatory Surgery Perioperative Surgical Home in Kaiser Permanente Settings: Practice and Outcomes. AB - BACKGROUND: The aim of this study is to describe the design, implementation, and associated outcome changes of a Perioperative Surgical Home (PSH) for patients undergoing ambulatory laparoscopic cholecystectomy in a Kaiser Permanente practice model. METHODS: A multidisciplinary planning committee of 15 individuals developed and implemented a new PSH program. A total of 878 subjects were included in the preimplementation period (T-fast), and 1082 patients were included in the postimplementation period (PSH) based on the date of their surgery. The primary goal of this report was to assess the changes in patient outcomes associated with this new PSH implementation on variables such as total length of stay and unplanned hospital admission (UHA). RESULTS: Patients assigned to the PSH model had a significantly shorter mean length of stay compared with patients in the T-fast group (162 +/- 308 vs 369 +/- 790 minutes, P = .00005). UHA was significantly higher in the T-fast group as compared with the PSH group (8.5% [95% CI 6.6-10.4] vs 1.7% [0.9-2.5], P < .00005). There was no difference in the 7 days readmission rates between patients managed in the T-fast track and the PSH track (5.4% [3.8-7.0] vs 5.0% [3.6-6.3], P = .066). CONCLUSIONS: Introduction of the PSH into a Kaiser Permanente model of care was associated with a simultaneous decrease of length of stay and UHA for laparoscopic cholecystectomy patients. PMID- 28027087 TI - Standardized Care Versus Precision Medicine in the Perioperative Setting: Can Point-of-Care Testing Help Bridge the Gap? PMID- 28027088 TI - Feasibility of Automated Propofol Sedation for Transcatheter Aortic Valve Implantation: A Pilot Study. AB - BACKGROUND: Recently, several trials have shown that closed-loop sedation is feasible. No study has used automated sedation in extremely frail patients, such as those scheduled for transcatheter aortic valve implantation (TAVI). We developed and tested a novel automated sedation system for this kind of population and surgery. The system integrates a decision support system that detects respiratory and hemodynamic events via smart alarms, which provide pertinent/related clinical suggestions and treatment options. The main objective was the feasibility of closed-loop sedation, defined as successful automated sedation without manual override. Secondary qualitative observations were clinical and controller performance. METHODS: Twenty patients scheduled for elective TAVI were enrolled. Sedation was administered via a closed-loop delivery system designed for propofol. The clinical performance of sedation was the efficacy to maintain a bispectral index (BIS) of 65. To evaluate the sedation performance, BIS values were stratified into 4 categories: excellent, very good, good, and inadequate sedation control, defined as BIS values within 10%, ranging from 11% to 20%, ranging from 21% to 30%, or >30% from the target value, respectively. The controller performance was calculated using Varvel parameters. Critical respiratory and hemodynamic events were documented. The former was defined as peripheral oxygen saturation <92% and/or respiratory rate <8/min, whereas the latter was considered a mean arterial pressure <60 mm Hg and/or heart rate <40 bpm. RESULTS: Automated sedation was successful in 19 patients undergoing TAVI. One patient was excluded from the final analysis because of conversion to general anesthesia. The secondary observations revealed that the clinical performance allowed an excellent to good control during 69% (99% confidence interval, 53%-77%; interquartile range, 59%-79%) of the sedation time. Fifteen patients presented critical respiratory episodes, with a median of 3 events per hour of sedation. Six patients presented critical hemodynamic episodes, with a median of 2 events per hour of procedure. CONCLUSIONS: The automated closed-loop sedation system tested could be used successfully for patients scheduled for a TAVI procedure. The results showed a satisfactory clinical performance of sedation control. PMID- 28027089 TI - "Awake" or "Sedated": Safe Flexible Bronchoscopic Intubation of the Difficult Airway. PMID- 28027090 TI - Teaching the Diagnostic Process as a Model to Improve Medical Education. PMID- 28027091 TI - The Role for Virtual Patients in the Future of Medical Education. PMID- 28027092 TI - The Role for Virtual Patients in the Future of Medical Education. PMID- 28027093 TI - In Reply to Robison et al and White et al. PMID- 28027094 TI - The "Triple P": Adaptive Challenges in Medical Education and Practice. PMID- 28027095 TI - In Reply to Ventres and McAuliffe. PMID- 28027096 TI - Rural Postgraduate Medical Education: A Missed Opportunity? PMID- 28027097 TI - The Trainee Perspective: What Can Residency Programs Do to Promote Learner Well Being? PMID- 28027098 TI - Artist's Statement: Isolation. PMID- 28027099 TI - My First Patient: More Than Obstructive Jaundice. PMID- 28027101 TI - Chemotherapy. PMID- 28027100 TI - "I Kinda Like Just to Talk". PMID- 28027102 TI - Commentary on Chemotherapy. PMID- 28027103 TI - Neoadjuvant approach for nonsmall cell lung cancer: overview of the current issues. AB - PURPOSE OF REVIEW: Despite the large numbers of studies, role of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy is debated. This approach would increase resectability in locally advanced patients, and improve surgical outcome in resectable patients. Thus, an overview of recent literature is relevant to highlight the current issues. RECENT FINDINGS: Literature in the previous year mainly focused on overall treatment strategy, radiotherapy technique, role of radiological response and metabolic imaging, and biological agents in this setting. SUMMARY: Current data suggest that neoadjuvant chemotherapy is beneficial if compared with surgery alone or definitive chemoradiotherapy. Benefit of radiotherapy addition in this setting is not clear, especially in patients undergoing pneumonectomy. Hypofractionated regimens and dose escalation protocols should be considered for further investigation. Response evaluation with radiologic and metabolic assessment is prognostic for survival outcome; its usefulness as a selection tool for adaptive strategies has been investigated recently. More robust data on biological agents and immunological agents in this setting are needed; further investigation on predictive biomarker is suggested. PMID- 28027104 TI - Critical aspects to achieve a high-quality melanoma clinic. AB - PURPOSE OF REVIEW: With incidence of melanoma growing worldwide and new therapies prolonging the survival of patients with advanced disease, complex medical care is needed. RECENT FINDINGS: Best care of complicated melanoma cases is achieved in specialized referral centers. Aims to provide optimized melanoma therapy, best patient-reported treatment outcome, and successful clinical and translational research, necessitate a dedicated interdisciplinary team. SUMMARY: We report on critical aspects of the interaction between patients, medical care givers, clinical trial and biobanking teams, and emphasize the importance of interdisciplinary tumor boards. Specialized skin cancer nurses and local patient advocacy groups should be involved in patient care and could be the binding link between the patients and the treatment team. PMID- 28027105 TI - Concurrent driver mutations/rearrangements in non-small-cell lung cancer. AB - PURPOSE OF REVIEW: The concept of mutually exclusive oncogenic driver alterations has prevailed over the past decade, but recent reports have stressed the possible occurrence of dual-positive non-small-cell lung cancer (NSCLC) and even triple positive disease for these oncogenes. This entity presents novel prognostic and therapeutic challenges. The present review highlights the available data in an effort to clarify the clinical and pathological significance of coexisting mutations as well as the subsequent therapeutic consequences. RECENT FINDINGS: Patients with a known driver oncogene can be successfully treated with the appropriate tyrosine kinase inhibitor, which will provide them with significant responses and lesser toxicities compared with cytotoxic therapy. Unfortunately, most patients will eventually progress. Although some resistance mechanisms have been identified, others remain to be determined but the emergence of secondary oncogenes could be part of the answer. SUMMARY: Approximately 20-25% of NSCLC harbor treatable driver mutations/rearrangements; epidermal growth factor receptor mutation, anaplastic lymphoma kinase and ROS-1 gene rearrangements are the main alterations for which a Food and Drug Administration-approved tyrosine kinase inhibitor can be used.Because of recent technological advances, high sensitivity assays with a broad range of genomic targets have become more easily accessible in clinical practice, which has led to an increased detection of coexisting driver alterations in patients with advanced NSCLC. The prognostic/predictive and therapeutic implications of this novel entity are still unsettled for the time being. Randomized trials specifically designed to address this subset of patients will soon be necessary to help determine the optimal therapeutic agent to administer. PMID- 28027106 TI - Systemic treatment for thymic malignancies. AB - PURPOSE OF REVIEW: The management of thymic epithelial tumors is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered as part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. RECENT FINDINGS: More options have become available for advanced, refractory, and recurrent thymic epithelial tumors, which include cytotoxic agents such as carboplatin-paclitaxel, pemetrexed, and oral etoposide. Angiogenesis targeting is a standard in advanced lines of treatment, after results of a phase II trial with sunitinib were reported. Ongoing studies are assessing the opportunity of targeting the immune-response checkpoint programmed death-1/programmed death ligand-1, with preliminary promising results whereas safety, with a higher risk of auto-immunity, may represent a concern. SUMMARY: Overall, a dramatic improvement in our knowledge of the management of thymic tumors has occurred in the past few years, resulting in the development of databases, translational research programmes, and clinical trials. Although access to innovative strategies represents a major challenge, as the rarity of the tumor precludes specific approval of drugs to be obtained, patient-centered initiatives, such as the establishment of dedicated networks, are warranted. PMID- 28027107 TI - Meditation and Mindfulness. PMID- 28027108 TI - Some Reflections on Meditation and Mindfulness. PMID- 28027109 TI - The Relationship Between Early Haloperidol Response and Associated Extrapyramidal Side Effects. AB - BACKGROUND: Early response to antipsychotic medication within 2 weeks of initiating treatment can predict psychiatric outcomes. However, it is unclear whether early response is also predictive of extrapyramidal side effects (EPSs) associated with antipsychotic medications. METHODS: In this study, we investigated 136 consecutive antipsychotic-naive, first-episode psychosis patients naturalistically treated with haloperidol. Patients were assessed at baseline and weekly after treatment initiation using the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. Dystonia, parkinsonism, akathisia, and dyskinesia were also assessed weekly using standardized rating scales. Regression analyses were used to determine whether early response at week 2 of treatment predicted the incidence of EPS at any point during hospitalization. A secondary analysis was conducted to determine whether early response continued to predict EPS in patients who experienced no EPS within the first 2 weeks of treatment. RESULTS: The analyses demonstrated that greater Brief Psychiatric Rating Scale percent improvement at week 2 predicted a decreased risk of EPSs (P = 0.004), even in patients who did not show any EPSs within the first 2 weeks of treatment (P = 0.005). For specific EPS, early response predicted decreased incidences of parkinsonism (P = 0.028) and dyskinesia (P = 0.025), but not akathisia or dystonia. Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale improvement at week 2 did not predict EPSs. In addition, EPSs were not predicted by the maximum antipsychotic dose received during hospitalization. CONCLUSIONS: These results indicate that early antipsychotic response is valuable not only for predicting psychiatric outcomes, but also for predicting the risk of EPSs. PMID- 28027110 TI - Unaltered Dopamine Transporter Availability in Drug-Naive Patients With Schizophrenia After 6 Months of Antipsychotics Treatment: A Naturalistic Study. AB - BACKGROUND: Dopaminergic dysfunction, namely, dopamine transporter (DAT) availability variations in patients with drug-naive schizophrenia after long-term treatment, is still not well understood. The aims of the study were to explore (i) whether the DAT availability in patients with drug-naive schizophrenia differed after antipsychotic treatment and (ii) whether treatment with different generations of antipsychotics influenced the DAT availability after follow-up for 6 months. METHODS: Twenty-four first-episode, drug-naive patients with schizophrenia were divided into first- and second-generation antipsychotic groups naturalistically. After 6 months of follow-up, 7 patients who received first generation antipsychotic treatment and 17 patients who received second-generation antipsychotic treatment completed the study. The patients underwent premedication and 6-month follow-up measurements using single-photon emission computed tomography with technetium Tc 99m (Tc) TRODAT-1. Psychopathological evaluations and adverse effects were recorded using appropriate scales. RESULTS: Both of the treatment groups significantly improved according to Positive and Negative Symptoms Scale evaluation. However, no significant difference was noticed between the premedication and 6-month follow-up DAT scans. Nonsignificant differences existed even in the groups of different generations of antipsychotics. CONCLUSIONS: Improvements in psychotic symptoms in patients with schizophrenia may not be influenced by DAT availability, even under treatment with different antipsychotics for a sufficient treatment period. PMID- 28027111 TI - A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome. AB - BACKGROUND: Neuroleptic malignant syndrome requires prompt recognition for effective management, but there are no established diagnostic criteria. This is the first validation study of recently published international expert consensus (IEC) diagnostic criteria, which include priority points assigned on the basis of the importance of each criterion for making a diagnosis of neuroleptic malignant syndrome. METHODS: Data were extracted from 221 archived telephone contact reports of clinician-initiated calls to a national telephone consultation service from 1997 to 2009; each case was given a total priority point score on the basis of the IEC criteria. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) research criteria, in original form and modified to accept less than "severe" rigidity, served as the primary diagnostic reference standard. Consultants' diagnostic impressions were used as a secondary reference standard. Receiver operating characteristic curve analysis was used to optimize the priority point cutoff score with respect to the reference standards. RESULTS: Area under the receiver operating characteristic curve ranged from 0.715 (95% confidence interval, 0.645-0.785; P = 1.62 * 10) for consultant diagnoses to 0.857 (95% confidence interval, 0.808-0.907; P < 5 * 10) for modified DSM-IV-TR criteria. The latter was associated with 69.6% sensitivity and 90.7% specificity. CONCLUSIONS: Agreement was best between IEC criteria with a cutoff score of 74 and modified DSM-IV-TR criteria (sensitivity, 69.6%; specificity, 90.7%); this cutoff score demonstrated the highest agreement in all comparisons. Consultant diagnoses showed much better agreement with modified, compared with original, DSM-IV-TR criteria, suggesting that the DSM-IV-TR criterion of "severe" rigidity may be more restrictive than what most knowledgeable clinicians use in practice. PMID- 28027112 TI - Alcohol Triggers Reemergence of Ketamine-Like Experience in a Ketamine Ex-User. PMID- 28027113 TI - Methotrimeprazine-Associated Stevens-Johnson Syndrome in 2 Ashkenazi Jewish Patients. PMID- 28027114 TI - 5-HT1A C-1019G (rs6295) Predicts Aripiprazole Treatment Response Specifically for Cognitive and Depressive Symptoms in Schizophrenia. PMID- 28027115 TI - Memantine Plasma Concentrations Among Patients With Dementia. PMID- 28027116 TI - Association study of GRM7 polymorphisms with major depressive disorder in the Chinese Han population. PMID- 28027117 TI - Precision Medicine Starts With Preanalytics: Real-Time Assessment of Tissue Fixation Quality by Ultrasound Time-of-Flight Analysis. AB - Personalized medicine promises diagnosis and treatment of disease at the individual level and relies heavily on clinical specimen integrity and diagnostic assay quality. Preanalytics, the collection and handling steps of a clinical specimen before immunohistochemistry or other clinical assay, are critically important to enable the correct diagnosis of disease. However, the effects of preanalytics are often overlooked due to a lack of standardization and limited assessment tools to quantify their variation. Here, we report a novel real-time ultrasound time-of-flight instrument that is capable of monitoring and imaging the critical step in formalin fixation, diffusion of the fixative into tissue, which provides a quantifiable quality metric for tissue fixation in the clinical laboratory ensuring consistent downstream molecular assay results. We analyzed hundreds of tissue specimens from 34 distinct human tissue types and 12 clinically relevant diseased tissues for diffusion and fixation metrics. Our measurements can be converted into tissue diffusivity constants that correlate with the apparent diffusion constant calculated using magnetic resonance imaging (R=0.83), despite the differences in the approaches, indicating that our approach is biophysically plausible. Using data collected from time-of-flight analysis of many tissues, we have therefore developed a novel rapid fixation program that could ensure high-quality downstream assay results for a broad range of human tissue types. PMID- 28027118 TI - Gain of TP53 Mutation in Imatinib-treated SDH-Deficient Gastrointestinal Stromal Tumor and Clinical Utilization of Targeted Next-generation Sequencing Panel for Therapeutic Decision Support. AB - Patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) have few therapeutic options. Despite lack of KIT or platelet derived growth factor receptor A (PDGFRA) driver mutations, SDH-deficient GISTs display strong expression of KIT by immunohistochemistry and these patients are often treated with tyrosine kinase inhibitors, including imatinib as a first-line therapy. Using a targeted next-generation sequencing panel of mutation hotspots of 50-clinically relevant genes, we investigated (1) concurrence of somatic/actionable mutations and (2) tumor molecular evolution by comparing 2 resection specimens 1.5 years apart while the patient was on imatinib adjuvant therapy. We found the tumors did not harbor KIT, PDGFRA, or any other clinically actionable mutations. However, a TP53 mutation (c.422G>A; p.C141Y) was detected in the second recurrent lesion. This represents the first study to monitor the molecular evolution of a SDH-deficient GIST during adjuvant treatment. These findings emphasize the critical need for next-generation sequencing testing before initiating targeted therapy. PMID- 28027119 TI - Comparison of beta-Catenin and LEF1 Immunohistochemical Stains in Desmoid-type Fibromatosis and its Selected Mimickers, With Unexpected Finding of LEF1 Positivity in Scars. AB - beta-catenin immunohistochemical stain can be useful in the diagnosis of many tumors including desmoid-type fibromatosis (DTF). Lymphoid enhancer-factor 1 (LEF1), a recently emerged marker, is part of the Wnt pathway with beta-catenin but has not been studied in DTF. We performed LEF1 and beta-catenin immunohistochemistry in DTF (n=26), superficial fibromatosis (n=19), sclerosing mesenteritis (n=12), gastrointestinal stromal tumor (n=17), and cutaneous scar (n=14) using tissue microarray and whole sections. The staining intensity was scored as strong (visible at *2 objective, value of 3), moderate (visible at *4, value of 2), weak (visible at *10, value of 1), and negative (not visible at *10, value of 0). The percentage of positive nuclei was recorded in 10% increment. Histologic scores were generated by multiplying numerical value of intensity and percentage of positive nuclei. A score of at least 10 was defined as positive. Eighteen of the 25 DTF were positive for LEF1 while 12 of 25 were positive for beta-catenin (1 excluded due to loss of tissue). Gastrointestinal stromal tumor cases were negative for both markers. All superficial fibromatoses were negative except 2 cases with weak positivity for LEF1 but not beta-catenin. Only 2 case of sclerosing mesenteritis were weakly positive for LEF1 but negative for beta catenin. Ten of 14 scars were positive for LEF1 but only 1 of them was weakly positive for beta-catenin. In conclusion, this study demonstrated that LEF1 may be a useful marker in the differential diagnosis of DTF in certain contexts. However, caution should be exercised since LEF1 positivity can also be seen in scars. PMID- 28027120 TI - Cervical Cancer Screening of Adolescents Should Not Be Encouraged. AB - OBJECTIVE: The study aims to assess the frequency of cytological abnormalities in adolescents and young women, to establish the optimum age to start screening. METHODS: A retrospective study of cervical cytology results were obtained from the data center at the Santa Casa Hospital of Sao Paulo between January 2006 and December 2014, adopting the Bethesda nomenclature system. The cytology exams were divided into 3 groups: group 1-adolescents (10-19 years old); group 2-young women (20-24 years old); and group 3-adults, comprising the remaining cytology exams. The frequency of cytological abnormalities in the 3 groups was compared using version 3.4.3 of the Epi Info software program and the chi-square statistical test (p < .05). RESULTS: A total of 177,075 satisfactory cytology exams were included in the study. The cytological abnormalities detected in the adolescent group were predominantly low-grade lesions (97.4%); in the young women group, low grade lesions represented 89.12%, and in the adult group, 76.33%. A significantly greater proportion of high-grade lesions were noted in the adult group, accounting for approximately 24% of all abnormalities detected; in the young women group, it was approximately 11%, and in the adolescent group, it was 2.6%. CONCLUSIONS: The natural history of HPV infection shows it is transient in young women, with most cases regressing within 2 years of presentation. Our data confirm that screening of adolescents is not recommended because serious cytological abnormalities and cancer are rare in this group. PMID- 28027121 TI - Carcinogenesis of Vulvar Lesions: Morphology and Immunohistochemistry Evaluation. AB - OBJECTIVES: The aim of the study was to assess the 2 pathways of vulvar carcinogenesis and correlate immunohistochemical expression of p53 with histopathological findings. MATERIALS AND METHODS: This cross-sectional study included 76 cases. Patients were classified according to the 2004 International Society for the Study of Vulvovaginal Disease Terminology, followed by a review of clinical records and immunohistochemical staining for p53. RESULTS: Fifteen cases were in the human papillomavirus (HPV)-associated pathway (12 cases of usual vulvar intraepithelial neoplasia [VIN] and 3 of warty squamous cell carcinoma [SCC]), and 13 cases were in the HPV-independent pathway (5 cases of differentiated VIN and 8 of keratinizing SCC). Significant differences in p53 expression were observed between the 2 pathways of carcinogenesis: in the lesions related to the HPV-independent pathway, the percentage of p53-positive cells was greater (>25%, p < .001), and the staining pattern was basal (extending into the middle layer) in differentiated VIN and diffuse or infiltrative in warty SCC (p < 0.001). In the lesions HPV-associated pathway, p53 staining was less extensive (<=10% of cells, p < 0.001) and followed basal pattern in usual VIN, whereas warty SCCs were negative for p53 (p < 0.001). CONCLUSIONS: Unique patterns of histological appearance and p53 expression can separate vulvar lesions into 2 distinct pathways of carcinogenesis. We propose that p53 immunohistochemistry may be performed simultaneously with histopathological examination in all cases of VIN and vulvar SCC, because it would aid in definition of the pathway of carcinogenesis and thus enable better clinical follow-up of patients with these conditions. PMID- 28027122 TI - Genitogluteal Porokeratosis in a Well Woman. PMID- 28027124 TI - Letters. PMID- 28027123 TI - The Effects of High-Concentration Oxygen on Inflammatory Markers in Laparoscopic Cholecystectomy: A Randomized Controlled Trial. AB - BACKGROUND: This study assessed effect of administration of high-concentration supplemental perioperative oxygen on systemic inflammatory and immune response in patients undergoing elective laparoscopic cholecystectomy. MATERIALS AND METHODS: One hundred seventy-seven patients were assigned randomly to an oxygen/air mixture with a fraction of inspired oxygen (FiO2) of 30% (n=88) or 80% (n=89). White blood cells, peripheral lymphocytes subpopulation, human leukocyte antigen DR, neutrophil elastase, interleukin (IL)-1 and IL-6, and C-reactive protein were investigated. RESULTS: Significantly higher concentration of neutrophil elastase, IL-1, IL-6 and C-reactive protein was detected postoperatively in the 30% FiO2 group patients in comparison with the 80% FiO2 group (P<0.05). Statistically significant change in human leukocyte antigen-DR expression was recorded postoperatively at 24 hours, as a reduction of this antigen expressed on monocyte surface in patients from 30% FiO2 group. CONCLUSIONS: This study demonstrated that high-concentration (80%) supplemental perioperative oxygen can lead to a reduction in postoperative inflammatory response and avoid postoperative immunosuppression. PMID- 28027127 TI - The evolution of hope in patients with terminal illness. PMID- 28027129 TI - Cognitive stacking: Strategies for the busy RN. PMID- 28027128 TI - Mumps makes a comeback: What nurses need to know. PMID- 28027131 TI - Improving health literacy in patients with diabetes. PMID- 28027132 TI - The mystery of vulvodynia: Can it be solved? PMID- 28027133 TI - A sound intervention. PMID- 28027134 TI - Escape the vape: Health hazards of the latest nicotine craze. PMID- 28027135 TI - Caring for adolescents with familial dysautonomia. PMID- 28027136 TI - Preventing infections after renal transplant. PMID- 28027137 TI - Are "quiet-at-night" initiatives impacting staff alertness? PMID- 28027138 TI - Animal-assisted therapy for inpatient adults. PMID- 28027139 TI - Acute vaso-occlusive crisis in patients with sickle cell disease. PMID- 28027140 TI - Implantable loop recorders vs. Holter monitors. PMID- 28027141 TI - Online resources for stroke victims. PMID- 28027142 TI - Antiretroviral drugs. PMID- 28027144 TI - Orthopaedic Surgery in Dystonic Cerebral Palsy. AB - BACKGROUND: Outcomes after orthopaedic interventions in patients with dystonic cerebral palsy (DCP) are historically regarded as unpredictable. This study aims to evaluate the overall outcome of orthopaedic surgery in children with DCP. METHOD: Children with DCP who underwent lower limb orthopaedic surgery with a minimum follow-up of 12 months were included. Data collected included age at time of surgery, surgical procedures performed, Gross Motor Function Classification System (GMFCS) level, and Barry Albright Dystonia Scale (BADS) score. The cohort was divided into 2 groups. Group 1 (GMFCS levels I to III), mean age 12 years 7 months and group 2 (GMFCS levels IV to V), mean age 10 years 7 months. Group 1 had surgery aimed at deformity correction to improve gait and mobility, and group 2 for the management or prevention of hip displacement. Outcome measures analyzed were: the incidence of unpredictable results related to surgery and early recurrence of deformity in both groups. Functional mobility scale scores were evaluated for group 1 and hip migration percentage for group 2. Linear mixed models were used to take into account repeated measures over time and correlations between measurements from the same patient. RESULTS: Group 1 (n=18); had low BADS scores and were considered to have mild dystonia. Three children experienced unpredictable results, 2 had early recurrence of deformity, 3 had a decline, and 1 child improved in the functional mobility scale.Group 2 (n=19); had high BADS scores and were considered to have moderate to severe dystonia. Nine surgical events involved bony procedures and 15 were soft tissue surgery only. One surgical event lead to unpredictable results and 2 children had early recurrence of deformity. Postoperatively, a linear trend of increasing migration percentage [0.49% (95% confidence interval, 0.23-0.74; P=0.0002)] was seen up to 21 months. There was no significant change after 21 months [-0.08% (95% confidence interval, -0.24 to +0.041; P=0.18)]. CONCLUSIONS: This study suggests that unpredictable results and early recurrence of deformity following orthopaedic surgery in children with DCP are not as common as previously regarded. Furthermore, functional mobility and hip morphology can be improved. LEVEL OF EVIDENCE: Level IV-this is a case-series. PMID- 28027145 TI - Chance Fractures in the Pediatric Population are Often Misdiagnosed. AB - BACKGROUND: Flexion injuries of the spine range from mild compression fractures to severe flexion-distraction injuries, that is, Chance fractures. Chance fractures are often unstable and Arkader and colleagues demonstrated improved outcomes when Chance fractures are treated operatively compared with those managed nonoperatively. METHODS: A retrospective review was conducted of all patients treated over a 5-year period (2008 to 2013) for a flexion injury, either a Chance or a compression fracture, of the thoracolumbar spine at our tertiary pediatric level I trauma center. Patients were excluded if they had prior spine surgery or had a pathologic fracture. RESULTS: Of the 26 patients who met the inclusion criteria, 27% (7/26 patients) had a Chance fracture and 73% (19/26) had compression fracture(s). The mean age of the 7 patients with Chance fractures was 14.6 years (range, 13 to 16 y). In total, 71% (5/7) of the patients with Chance fractures were initially misdiagnosed: (3 as compression fractures, 1 as a burst fracture, 1 as muscular pain) and 80% (4/5) of these misdiagnoses were made by a neurosurgeon or orthopaedic surgeon. Average delay to correct diagnosis was 95 days (range, 2 to 311 d), with 57% (4/7) of the patients having >=1 month delay. These 4 patients with a Chance fracture and >=1 month delay in correct diagnosis presented to our clinic electively with chronic back pain. None of the patients with Chance fractures had a neurological injury. Six patients with posterior ligamentous disruption were treated with surgical instrumentation and fusion. All Chance fractures occurred between the levels of T12 and L3. CONCLUSIONS: The majority of pediatric Chance fractures in this series were initially misdiagnosed (71%; 5/7) or mistreated (14%; 1/7) by neurosurgeons or orthopaedic surgeons. Mean time to the correct diagnosis was 3 months for the Chance fractures in this series. LEVEL OF EVIDENCE: Level IV. PMID- 28027146 TI - Gradual Deformity Correction in Blount Disease. AB - BACKGROUND: Blount disease is a disorder of the posteromedial proximal tibial physis which causes a progressive varus, procurvatum, and internal rotation deformity of the tibia. Untreated, it can cause significant limb malalignment. The goal of this study is to evaluate the results of correction of Blount disease using types of external fixation. METHODS: We conducted a retrospective review of 41 patients (51 limbs) who underwent correction of Blount disease with an Ilizarov external fixator or a Taylor spatial frame (TSF) by a single surgeon. The medial proximal tibial angle (MPTA), mean axis deviation (MAD), posterior proximal tibial angle, and joint line congruence angle (JLCA) were measured on radiographs preoperatively, at frame removal and at final follow-up. RESULTS: The average age at treatment was 9.6 years old, with a mean follow-up time of 34 months. Mean preoperative MPTA, MAD, and JLCA were significantly improved at the time of frame removal as well as at final follow-up with no significant changes in correction between the time of frame removal and final follow-up. There was no difference in MPTA and MAD in patients treated with an Ilizarov frame versus a TSF. MPTA, MAD, and JLCA all significantly improved regardless of the underlying diagnosis (infantile vs. adolescent Blount disease) or history of prior surgical intervention. The most common complication was superficial pin-site infection. CONCLUSIONS: Both Iliazarov and TSF are viable treatment options for infantile and adolescent Blount disease, with the ability to significantly improve both the limb mechanical axis and the mechanical axis of the affected tibia. Correction can be attained regardless of whether patients have previously failed surgical intervention. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 28027147 TI - Breaking Bad News in the High-concern, Low Trust Setting: How to Get Your Story Heard. PMID- 28027148 TI - Welcome to the Fifty-Second Annual Meeting of the National Council on Radiation Protection and Measurements: Meeting the Needs of the Nation for Radiation Protection. PMID- 28027149 TI - Thirteenth Annual Warren K. Sinclair Keynote Address: Where Are the Radiation Professionals (WARP)? AB - In July 2013, the National Council on Radiation Protection and Measurements convened a workshop for representatives from government, professional organizations, academia, and the private sector to discuss a potential shortage of radiation protection professionals in the not-too-distant future. This shortage manifests itself in declining membership of professional societies, decreasing enrollment in university programs in the radiological sciences, and perhaps most importantly, the imminent retirement of the largest birth cohort in American history, the so-called "baby boomer" generation. Consensus emerged that shortages already are, or soon will be, felt in government agencies (including state radiation control programs); membership in professional societies is declining precipitously; and student enrollments and university support for radiological disciplines are decreasing with no reversals expected. The supply of medical physicists appears to be adequate at least in the near term, although a shortage of available slots in accredited clinical training programs looms large. In general, the private sector appears stable, due in part to retirees joining the consultant ranks. However, it is clear that a severe problem exists with the lack of an adequate surge capacity to respond to a large-scale reactor accident or radiological terrorism attack in the United States. The workshop produced a number of recommendations, including increased funding of both fellowships and research in the radiological sciences, as well as creation of internships, practicums, and post-doctoral positions. A federal joint program support office that would more efficiently manage the careers of radiological professionals in the civil service would enhance recruiting and development, and increase the flexibility of the various agencies to manage their staffing needs. PMID- 28027150 TI - Radiation Brain Drain? The Impact of Demographic Change on U.S. Radiation Protection. AB - The use of radiation has a substantial beneficial impact, particularly in the areas of medicine, energy production, basic science research, and industrial applications. Radiation protection knowledge and experience are required for acquiring and implementing scientific knowledge to protect workers, members of the public, and the environment from potential harmful effects of ionizing radiation while facilitating the beneficial use and development of radiation based technologies. However, demographic changes are negatively impacting U.S. radiation protection and response capabilities. The number of radiation professionals continues to decrease even as the demand for such professionals is growing. These concerns are most pronounced in the medical, energy, research, and security arenas. Though the United States has been the world leader in radiation protection and radiation sciences for many years, the country has no strategic plan to ensure the maintenance of expertise in radiobiology, radiation physics, and radiation protection. Solving this problem will require a significant increase in federal and state funding as well as formal partnerships and initiatives among academia, professional societies, government, and the private sector. PMID- 28027151 TI - Membership Trends in the Health Physics Society: How Did We Get Here and Where Are We Going? AB - The Health Physics Society (HPS), formed in 1956, is a scientific organization of professionals who specialize in radiation safety. Its mission is to support its members in the practice of their profession and to promote excellence in the science and practice of radiation safety. HPS has been a diverse body since its beginnings, encompassing professionals from different disciplines with an interest in radiation safety issues. At that time, health physics was just beginning to emerge as a distinct discipline, initially spurred by the development of the atomic bomb and amplified by the commercial use of nuclear power, and there was a need for a professional group to discuss issues and share ideas and experiences in the field. Over the following years, both the field of health physics and the ranks of the HPS membership experienced a steady increase in numbers and interest. HPS continued to grow in numbers and thrive through the mid-1990s but then began to retract. Concern regarding the "graying" of HPS was being discussed as far back as the late 1990s, yet despite efforts to broaden the base of membership through additional membership criteria, the numbers of Plenary (now referred to as Full) members have continued to shrink. The "graying" of HPS is real-although age demographic data are only available for about the past 15 y (and are provided voluntarily), the shift in age distribution over this timeframe is clear. A recent survey indicated that over 50% of HPS members are over 50 y of age, and over half of the respondents plan to retire within 10 y. As members age, they convert to Emeritus membership or drop their membership altogether, with some members unable to continue for financial or health-related reasons. There is now an age gap-members in their 30s and early 40s are missing from the mix. Potential causes for declining membership may include smaller enrollments in academic programs, reduced employment opportunities, and societal factors. There appears to be reduced employer support for participation in professional activities and travel to conferences. Societal factors include easy access to professional information through the internet, balancing of family commitments, other volunteer opportunities, and a general decline in joining professional groups. So, what is the fate of HPS? We are not alone-other professional groups are experiencing the same overall trends in membership to differing degrees. A number of initiatives have been launched or are being considered by HPS in an effort to offset this trend. PMID- 28027152 TI - The Medical Physics Workforce. AB - The medical physics workforce comprises approximately 24,000 workers worldwide and approximately 8,200 in the United States. The occupation is a recognized, established, and mature profession that is undergoing considerable growth and change, with many of these changes being driven by scientific, technical, and medical advances. Presently, the medical physics workforce is adequate to meet societal needs. However, data are emerging that suggest potential risks of shortages and other problems that could develop within a few years. Some of the governing factors are well established, such as the increasing number of incident cancers thereby increasing workload, while others, such as the future use of radiation treatments and changes in healthcare economic policies, are uncertain and make the future status of the workforce difficult to forecast beyond the next several years. This review examines some of the major factors that govern supply and demand for medical physicists, discusses published projections and their uncertainties, and presents other information that may help to inform short- and long-term planning of various aspects of the future workforce. It includes a description of the general characteristics of the workforce, including information on its size, educational attainment, certification, age distribution, etc. Because the supply of new workers is governed by educational and training pathways, graduate education, post-doctoral training, and residency training are reviewed, along with trends in state and federal support for research and education. Selected professional aspects of the field also are considered, including professional certification and compensation. We speculate on the future outlook of the workforce and provide recommendations regarding future actions pertaining to the future medical physics workforce. PMID- 28027153 TI - Changing Roles of State Health Physicists. AB - State radiation control programs are responsible for many aspects of radiation protection under their purview. These may include all aspects of radiation protection for sources of radiation not exclusively under federal control under an agreement with the U.S. Nuclear Regulatory Commission and the use of some sources of radiation not regulated by the federal government, such as radiation machines and naturally occurring radioactive material. The roles of state health physicists are ever-evolving, and the scope of their work is constantly expanding. This has come about most recently due to several factors, including additional federal requirements involving source security, emerging radiation machine technologies, expansion of emergency planning to include terrorist incidents, and more states with issues involving technologically enhanced naturally occurring radioactive material. These changes in the role of state health physicists and the new challenges are adding to the need for health physics resources and knowledge base. Several approaches are being used to address the training needs and technological and regulatory challenges, but these will continue to be needed to meet future workforce needs. PMID- 28027154 TI - NCRP 52nd Annual Meeting, Meeting the Needs of the Nation for Radiation Protection: How Did We Get Here? Session Q&A (Session Chairs Kathryn H. Pryor and Richard E. Toohey). PMID- 28027155 TI - Commercial Nuclear Power Industry: Assessing and Meeting the Radiation Protection Workforce Needs. AB - This paper will provide an overview of the process used by the commercial nuclear power industry in assessing the status of existing industry staffing and projecting future supply demand needs. The most recent Nuclear Energy Institute developed "Pipeline Survey Results" will be reviewed with specific emphasis on the radiation protection specialty. Both radiation protection technician and health physicist specialties will be discussed. The industry-initiated Nuclear Uniform Curriculum Program will be reviewed as an example of how the industry has addressed the need for developing additional resources. Furthermore, the reality of challenges encountered in maintaining the needed number of health physicists will also be discussed. PMID- 28027156 TI - Education vs. Training: Does it Matter? AB - The National Council on Radiation Protection and Measurements' (NCRP) "Where are the Radiation Professionals?" initiative brought renewed attention to the declining numbers of individuals in radiation protection fields. This paper is an expanded version of the oral presentation by the author at the 2016 NCRP Annual Meeting. Health physics (HP) as a discipline and vocation is at a critical juncture. Perhaps less well recognized is the extreme peril facing academic HP programs. Higher education today is vastly different from what it was even 20 y ago. Every academic program must now make a budget case to justify its existence. Consequently, HP programs, which are by anyone's measure minuscule, are in very real danger of closing. Given that the country will continue to need radiation protection expertise, we must take immediate steps to reinvigorate the profession and preserve academic programs. We simply cannot train or short-course our way out of this problem. Under routine conditions, individuals trained in basic HP can be expected to safely manage daily operations. But life is full of the unexpected. When the unexpected event involves radiation, we need someone well versed in radiological fundamentals to understand, assess and safely deal with the problem. A three-pronged approach to bolster academic programs was offered: (1) increase academic cooperation and provide an infusion of cash, (2) more formally recognize the discipline of HP and increase respect for its role in safety, and (3) regulate who can be designated as a health physicist while increasing retention of individuals within the discipline. PMID- 28027157 TI - Developing A Radiation Protection Hub. AB - The Where are the Radiation Professionals (WARP)? statement issued by the National Council on Radiation Protection and Measurements estimates that in 10 y, there will be a human capital crisis across the radiation safety community. The ability to respond to this shortage will be amplified by the fact that many radiation protection (health physics) academic programs will find it difficult to justify their continued existence since they are low-volume programs, both in terms of enrollment and research funding, compared to the research funding return and visibility of more highly subscribed and highly funded academic disciplines. In addition, across the national laboratory complex, radiation protection research groups have been disbanded or dramatically reduced in size. The loss of both of these national resources is being accelerated by low and uncertain government funding priorities. The most effective solution to this problem would be to form a consortium that would bring together the radiation protection research, academic, and training communities. The goal of such a consortium would be to engage in research, education, and training of the next generation of radiation protection professionals. Furthermore, the consortium could bring together the strengths of different universities, national laboratory programs, and other entities in a strategic manner to accomplish a multifaceted research, educational, and training agenda. This vision would forge a working and funded relationship between major research universities, national laboratories, 4-y degree institutions, technical colleges, and other partners. PMID- 28027158 TI - Meeting Regulatory Needs. AB - The world is experiencing change at an unprecedented pace, as reflected in social, cultural, economic, political, and technological advances around the globe. Regulatory agencies, like the U.S. Nuclear Regulatory Commission (NRC), must also transform in response to and in preparation for these changes. In 2014, the NRC staff commenced Project Aim 2020 to transform the agency by enhancing efficiency, agility, and responsiveness, while accomplishing NRC's safety and security mission. Following Commission review and approval in 2015, the NRC began implementing the approved strategies, including strategic workforce planning to provide confidence that NRC will have employees with the right skills and talents at the right time to accomplish the agency's mission. Based on the work conducted so far, ensuring an adequate pipeline of radiation protection professionals is a significant need that NRC shares with states and other government agencies, private industry, academia, as well as international counterparts. NRC is working to ensure that sufficient radiation protection professionals will be available to fulfill its safety and security mission and leverage the work of the National Council on Radiation Protection and Measurements, the Conference of Radiation Control Program Directors, the Health Physics Society, the Organization of Agreement States, the International Atomic Energy Agency, the Nuclear Energy Agency, and others. PMID- 28027159 TI - NCRP 52nd Annual Meeting, Meeting The Needs of the Nation for Radiation Protection: Where Do We Need To Be? Session Q&A (Session co-chairs Ralph L. Andersen and Robert C. Whitcomb, Jr.). PMID- 28027160 TI - Introduction of the 40th Lauriston S. Taylor Lecturer: John W. Poston, Sr. PMID- 28027161 TI - Fortieth Lauriston S. Taylor Lecture: Radiation Protection and Regulatory Science. AB - It took about 30 y after Wilhelm Konrad Roentgen's discovery of x rays and Henri Becquerel's discovery of natural radioactivity for scientists in the civilized world to formulate recommendations on exposure to ionizing radiation. We know of these efforts today because the organizations that resulted from the concerns raised in 1928 at the Second International Congress of Radiology still play a role in radiation protection. The organizations are known today as the International Commission on Radiological Protection and, in the United States, the National Council on Radiation Protection and Measurements (NCRP). Today, as we have many times in the past, we honor Dr. Lauriston Sale Taylor, the U.S. representative to the 1928 Congress, for his dedication and leadership in the early growth of NCRP. NCRP's mission is "to support radiation protection by providing independent scientific analysis, information, and recommendations that represent the consensus of leading scientists." The developments in science and technology, including radiation protection, are occurring so rapidly that NCRP is challenged to provide its advice and guidance at a faster pace than ever before. NCRP's role has also expanded as the Council considers newer uses and applications of ionizing radiation in research and medicine as well as the response to nuclear or radiological terrorism. In such a technical world, new areas have been established to deal with the nexus of science and regulation, especially in the United States. Lord Ernest Rutherford supposedly said, "That which is not measurable is not science. That which is not physics is stamp collecting." I wonder what he would say if he were alive today as now many embrace a new field called "regulatory science." This term was suggested by Professor Mitsuru Uchiyama in Japan in 1987 and was reviewed in literature published in English in 1996. Some have attributed a similar idea to Dr. Alvin Weinberg, for many years Director of the Oak Ridge National Laboratory. He actually introduced the term "trans-science," which he defined as the policy relevant fields for which scientists have no answers for many of the questions being asked. He was influenced by the heavy involvement of the Laboratory in developing methods to assess environmental impacts as mandated by the 1969 National Environmental Policy Act. Professor Uchiyama defined regulatory science as "the science of optimizing scientific and technological developments according to objectives geared toward human health." In essence, regulatory science is that science generated to answer political questions. This paper will introduce regulatory science and discuss the differences between what some call "academic science" and "regulatory science." In addition, a short discussion is included of how regulatory science has and will impact the practice of radiation protection and all areas involving the use of radiation and radioactivity. PMID- 28027162 TI - Critical Issues in Radiation Protection Knowledge Management for Preserving Radiation Protection Research and Development Capabilities. AB - As a hub of domestic radiation protection capabilities, Oak Ridge National Laboratory's Center for Radiation Protection Knowledge has a mandate to develop and actuate a formal knowledge management (KM) effort. This KM approach exceeds recruitment and training efforts but focuses on formalized strategies for knowledge transfer from outgoing subject matter experts in radiation protection to incoming generations. It is envisioned that such an effort will provide one avenue for preserving domestic capabilities to support stakeholder needs in the federal government and the nuclear industry while continuing to lead and innovate in research and development on a global scale. However, in the absence of broader coordination within the United States, preservation of radiation protection knowledge continues to be in jeopardy in the absence of a dedicated KM effort. PMID- 28027163 TI - The Business of Health Physics-Jobs In A Changing Market. AB - The health physics profession was born abruptly when once rare and precious radioactive materials became commonplace. The technological advancements that triggered an industrial complex and ended World War II demanded radiation safety on an unprecedented scale. Until then, protective measures against radiation were largely absent in laboratories. Over the subsequent decades, health physicists began protecting people and the environment in a wide range of settings including medical, research, and industrial. The use of radioactive materials and radiation generating devices is prevalent today. Radiation doses occur continuously including during airline flights, in our homes, during medical procedures, and in energy production. Radiation is integral to numerous applications including those in medicine, dentistry, manufacturing, construction, scientific research, nuclear electric power generation, and oil and gas exploration. Activities that were once groundbreaking have now become routine and scripted. At higher doses, health effects are understood and avoided. Instruments for the detection and measurement of radiation are at times smarter than their users. Ironically, the same health physics community that has been successful in demonstrating that exposures to radiation and to radioactive materials can be effectively managed is shrinking at an increasingly rapid rate. This paper highlights the creation of past and current jobs, predicts the future opportunities in the profession, and makes recommendations necessary to protect the disappearing specialties. PMID- 28027164 TI - Meeting the Needs for Radiation Protection: Diagnostic Imaging. AB - Radiation and potential risk during medical imaging is one of the foremost issues for the imaging community. Because of this, there are growing demands for accountability, including appropriate use of ionizing radiation in diagnostic and image-guided procedures. Factors contributing to this include increasing use of medical imaging; increased scrutiny (from awareness to alarm) by patients/caregivers and the public over radiation risk; and mounting calls for accountability from regulatory, accrediting, healthcare coverage (e.g., Centers for Medicare and Medicaid Services), and advisory agencies and organizations as well as industry (e.g., NEMA XR-29, Standard Attributes on CT Equipment Related to Dose Optimization and Management). Current challenges include debates over uncertainty with risks with low-level radiation; lack of fully developed and targeted products for diagnostic imaging and radiation dose monitoring; lack of resources for and clarity surrounding dose monitoring programs; inconsistencies across and between practices for design, implementation and audit of dose monitoring programs; lack of interdisciplinary programs for radiation protection of patients; potential shortages in personnel for these and other consensus efforts; and training concerns as well as inconsistencies for competencies throughout medical providers' careers for radiation protection of patients. Medical care providers are currently in a purgatory between quality- and value based imaging paradigms, a state that has yet to mature to reward this move to quality-based performance. There are also deficits in radiation expertise personnel in medicine. For example, health physics academic programs and graduates have recently declined, and medical physics residency openings are currently at a third of the number of graduates. However, leveraging solutions to the medical needs will require money and resources, beyond personnel alone. Energy and capital will need to be directed to:* innovative and cooperative cross disciplinary institutional/practice oversight of and guidance for the use of diagnostic imaging (e.g., radiology, surgical specialties, cardiologists, and intensivists);* initiatives providing practical benchmarks (e.g., dose index registries);* comprehensive (consisting of access, integrity, metrology, analytics, informatics) and effective and efficient dose monitoring programs;* collaboration with industry;* improved use of imaging, such as through decision support combined with evidence-based appropriateness for imaging use;* integration with e-health such as medical records;* education, including information extending beyond the medical imaging community that is relevant to patients, public, and providers and administration;* identification of opportunities for alignment with salient media and advocacy organizations to deliver balanced information regarding medical radiation and risk;* open lines of communication between medical radiation experts and appropriate bodies such as the U.S. Environmental Protection Agency, the U.S. Food and Drug Administration, and the Joint Commission to assure appropriate guidance on documents and actions originating from these organizations; and* increased grant funding to foster translational work that advances understanding of low-level radiation and biological effects. PMID- 28027165 TI - NCRP 52nd Annual Meeting, Meeting The Needs of The Nation for Radiation Protection: How Did We Get Here? Session Q&A (Session co-chairs Pamela J. Henderson and Chad A. Mitchell). PMID- 28027166 TI - NCRP Vision for the Future and Program Area Committee Activities. AB - The National Council on Radiation Protection and Measurements (NCRP) believes that the most critical need for the nation in radiation protection is to train, engage, and retain radiation professionals for the future. Not only is the pipeline shrinking, but for some areas there is no longer a pipe! When the call comes to respond, there may be no one to answer the phone! The NCRP "Where are the Radiation Professionals?" initiative, Council Committee (CC) 2, and this year's annual meeting are to focus our efforts to find solutions and not just reiterate the problems. Our next major initiative is CC 1, where the NCRP is making recommendations for the United States on all things dealing with radiation protection. Our last publication was NCRP Report No. 116, Limitation of Exposure to Ionizing Radiation, in 1993-time for an update. NCRP has seven active Program Area Committees on biology and epidemiology, operational concerns, emergency response and preparedness, medicine, environmental issues and waste management, dosimetry, and communications. A major scientific research initiative is the Million Person Study of Low Dose Radiation Health Effects. It includes workers from the Manhattan Project, nuclear weapons test participants (atomic veterans), industrial radiographers, and early medical workers such as radiologists and technologists. This research will answer the one major gap in radiation risk evaluation: what are the health effects when the exposure occurs gradually over time? Other cutting edge initiatives include a re-evaluation of science behind recommendations for lens of the eye dose limits, recommendations for emergency responders on dosimetry after a major radiological incident, guidance to the National Aeronautics and Space Administration with regard to possible central nervous system effects from galactic cosmic rays (the high energy, high mass particles bounding through space), re-evaluating the population exposure to medical radiation (NCRP Report No. 160, Ionizing Radiation Exposure of the Population of the United States, is over 10 y old, and computed tomography exams have increased substantially since then), and concerning whether the linear no-, threshold model is still the best available for purposes of radiation protection (not for risk assessment). We believe evaluation of heart disease and cerebral vascular disease following low-dose and dose-rate exposure is important for assessments of possible detriment from such exposures. We continue to seek the necessary resources to follow our quest to improve radiation protection for the public! PMID- 28027167 TI - Meeting the Needs of the Nation for Radiation Protection: Summary of the 52nd Annual Meeting of the National Council on Radiation Protection and Measurements. AB - The 52nd Annual Meeting of the National Council on Radiation Protection and Measurements (NCRP) was held in Bethesda, MD, 11-12 April 2016, on the topic of "Meeting National Needs for Radiation Protection." This meeting was an outgrowth of the NCRP initiative "Where are the Radiation Professionals?" (WARP), which addresses looming shortages in professional personnel trained in the radiological disciplines, including but not limited to health physics, radiological engineering, radiobiology, radiochemistry, radioecology, radiation emergency response; and the medical disciplines of diagnostic and interventional radiology, radiation oncology, nuclear medicine, and medical physics. A shortage of radiation professionals has been predicted for at least 20 y but now seems to be imminent. Obviously radiation professionals are needed for regulatory responsibilities at both state and federal levels, national defense, energy production, waste management, industrial applications, education, and medicine. Although the supply of radiation professionals in medicine appears to be adequate for the next decade or so, the use of radiation in medical diagnosis and therapy will continue to increase with the aging of the general population. PMID- 28027170 TI - Rare and Serious Complications of Sinusitis in Pediatric Patients: Epidural Abscess. AB - Intracranial abscess has serious mortality. Therefore, early diagnosis and treatment is important. Intracranial abscess is rarely seen as a complication of sinusitis. Specially in children it has been reported rarely. Fever and headache can indicate complications in children. PMID- 28027171 TI - Measurement of Distraction Force in Cleft Lip and Palate Patients During Le Fort I Maxillary Advancement With Rigid External Distraction. AB - OBJECTIVE: Maxillary distraction osteogenesis (DO) is a mainstream surgical technique for patients who have severe maxillary hypoplasia associated with craniofacial syndromes and cleft-related deformities. However, limited information about the biomechanical aspects of maxillary DO is available limiting broad utilization and improvements to the procedure. The objective of this study was to analyze force levels during the active distraction process and to investigate the relationship between distraction force and maxillary movement during Le Fort I maxillary DO using a rigid external distraction (RED) system. PATIENTS: Microtension gauges were integrated into the distraction wires on each side of the RED system. Six patients with cleft lip and palate aged 12.8 to 23.5 years underwent strain gauge measurements during maxillary advancement with DO using an RED system. Lateral cephalograms were taken to measure maxillary horizontal, vertical, and linear movements after DO. RESULTS: The average linear maxillary movement was 11.2 mm (range 8.5-15.9 mm). The applied forces ranged from 13.4 to 26.8 N. The distance of maxillary movement was proportional to the distraction force. CONCLUSIONS: The measurement of distraction forces during DO provides important information with which to establish appropriate protocols. Patients requiring more advancement may require more distraction force. However, other factors such as scarring, patient anatomy, surgical freedom of the osteotomized maxilla, and the like, may affect the required force during DO with the RED system. PMID- 28027172 TI - An Uncommon Occurrence of Three-Fourth Molars Concomitant to Hypodontia in a Nonsyndromic Patient. AB - Bilaterally mandibular and maxillary fourth molars, concomitant to hypodontia, are uncommon. These dental anomalies, called hypohyperdontia, are rare and etiology is not well defined. Several complications may occur as a consequence of supernumerary teeth, such as teeth impaction, resorption of adjacent teeth, and development of cysts and tumors. The authors present an uncommon occurrence of three-fourth molars concomitant to hypodontia and dentigerous cyst associated with impacted mandibular second and third molars in a nonsyndromic patient. The authors attempt to discuss the occurrence of bilaterally fourth molars and reinforce the importance of clinical approach, considering risks and benefits for the patient. PMID- 28027173 TI - The Shape of the Foramen Ovale: A Visualization Aid for Cannulation Procedures. AB - Several neurosurgical procedures, including rhizotomy for the management of trigeminal neuralgia, cannulate the foramen ovale (FO) to access intracranial structures. Cannulation procedures, including those utilizing neuronavigational technology, are occasionally complicated by anatomical variation of the FO, sometimes resulting in miscannulation and subsequent adverse events. The FO, while commonly thought of as oval-shaped, has also been described as "almond," "banana," "D shape," "pear," and "triangular." Because of the importance of the FO in neurosurgical procedures and the misunderstanding of FO shape, the aim of this study is to objectively describe the shape of the FO and its most likely shape variation. A total of 211 FO were evaluated by geometric morphometric analysis. A consensus shape is presented for the FO. No significant difference was found between the shapes of left- and right-sided FO. The most likely shape variation of the FO occurs as an inverse relationship between the anteromedial posterolateral and anterolateral-posteromedial aspects of the foramen. The capacity to visualize the average FO shape and understand the most likely shape variance, as illustrated by this report, will aid neurosurgeons in their approach to procedures requiring cannulation of the FO. PMID- 28027174 TI - Anatomy of the Platysma Muscle. AB - The aim of this paper was to review the anatomy the platysma systematically.The term "platysma AND anatomy" was used to search PubMed and Scopus, producing 394 and 214 papers, respectively. After excluding 95 duplicate titles, 513 abstracts and 98 full papers were reviewed. Among these 98 papers, 83 were excluded and 5 were added. Ultimately, 20 papers were analyzed.The most common aging-related change of the platysma was shortening (70.7%), followed by thinning (25.2%). The platysma most commonly originated from the upper portion of thorax anterior to clavicle (67.7%), followed by the subcutaneous tissue of the subclavicular and acromial regions (22.6%) and pectoralis (9.7%). The platysma ascended upward and medially (68.5%) or ascended from the clavicle to the face (31.5%). The platysma most commonly inserted on the cheek skin (57.5%), followed by the cutaneous muscles around the mouth (18.6%), the mandibulocutaneous ligament or zygoma (18.6%), and the parotid fascia or periosteum of the mandible (5.3%). The platysma was most commonly innervated by the cervical branch of the facial nerve (38.2%) or the cervical branch and mandibular branch of the facial nerve (60.5%), followed by the cervical plexus (0.6%), the cervical motor nucleus (0.6%), and the glossopharyngeal nerve (0.1%). The most common action of the platysma was drawing the lips inferiorly (83.3%) or posteriorly (12.9%). Four papers classified the platysma into subtypes; however, these classification strategies used arbitrary standards.Further studies will be necessary to establish the thickness of the platysma and to characterize age-related changes of the platysma. PMID- 28027175 TI - Surgical Management of Duplication of the Pituitary Gland-Plus Syndrome With Epignathus, Cleft Palate, Duplication of Mandible, and Lobulated Tongue. AB - A 1-day-old male infant was referred to our department for evaluation of multiple malformations in his oral cavity. He was diagnosed duplication of the pituitary gland-plus syndrome with epignathus, cleft palate, duplication of the mandible, and a lobulated tongue. A thumb-sized mass lesion was visible on the hard palate. The duplicated mandible and lower lip was fused at the midline. The alveolar ridge was protruding through a wide-cleft soft palate involving the uvula. Further examination showed a lobulated tongue, which was seen behind the duplicated part of the mandible. Five days after birth, tracheotomy and epignathus resection were performed. At 7 months of age, the excess tissue of the duplicated mandible was resected at the area of adhesion on the lingual side, and the duplicated tongue and lip were reconstructed. A palatoplasty was performed at 20 months of age. Thereafter, the patient's progress was uneventful, with no abnormality in swallowing. No recurrence of epignathus has been observed during 2 years of follow-up. PMID- 28027177 TI - The Visor Flap: A Novel Design for Scalp Wound Closure. AB - Full-thickness scalp defects pose a reconstructive problem in the setting of infection, radiation, and underlying calvarial defects. Current options include dermal matrices, skin grafts, and local fasciocutaneous flaps. Free tissue transfer is frequently required when scalp-based flaps fail or the wound is significantly large or complex. The authors present 7 patients of complex scalp defect reconstruction using the novel visor flap. The visor flap is a bipedicled advancement flap with a triangular posterior extension. The flap was designed to redistribute tension over a large surface area that prioritizes tension-free closure of the wound over a relatively small remote donor site. This method achieved complete primary healing of the recipient site in all patients. This flap design is a durable adjunct to minimize donor site morbidity and avoid microsurgical reconstruction of hostile scalp wounds. PMID- 28027178 TI - Influence of Two Types of Connections in Driver-Retention Screw Assembly. AB - Rehabilitation with implant-supported prostheses has reached high success rates. However, mechanical failures are still reported, mainly in retention screws of abutments in single implant-supported crowns; which is designed to be the weakest structure and the first component to fail under overloading. In this sense, the aim of this in vitro study was to evaluate the influence of different joint designs (square or hexagonal) on resistance to deformation of driver-retention screw assembly of 3 commercial brands (Neodent, Singular, and Sin). A total of 42 retention screws from 3 commercial brands were used. The samples were divided into 2 joint groups, square (SQU) and hexagonal (HEX), and separated by commercial brands. Several components (implants and abutments) with standard platform (4.1 mm in diameter) were used. The resistance to deformation of the driver-retention screw assembly was measured using an accurate digital torque wrench for all commercial brands (Neodent [NEO], Singular [SGL], and Sin [SIN]) and joint designs (square or hexagonal). It was found no statistically significant difference (P <0.05) among the brands evaluated. On the other hand, square screws showed higher resistance to torsion than hexagonal screws; regardless the commercial brand. PMID- 28027179 TI - Sliced Costochondral Chip Grafts in Posttraumatic Enophthalmos Correction. AB - BACKGROUND: Posttraumatic enophthalmos is a relatively common problem following orbitozygomatic fractures. However, inadequate long-term results are frequently observed due to the difficulty of performing intraoperative fine adjustments to soft-tissue volume and orbital size and gradual absorption of some grafted materials. Here, the authors describe an efficient method of enophthalmos correction using sliced costochondral bone and cartilage combination grafts. METHODS: From 2005 to 2011, the authors corrected enophthalmos in 12 patients using sliced costochondral grafts. The mean follow-up period was 13 months. For costochondral graft harvest, an approximately 5-cm skin incision was made directly above the seventh costal cartilage, the perichondrium was peeled back, and a small piece of rib bone and costal cartilage was harvested from the anterior part of the seventh rib bone and cartilage and cut into 2-mm-thick slices. A subciliary and/or transcaruncular incision was made in the affected side eyelid to expose the operating field, subperiosteal dissection was performed in the orbit and orbital floor. The cartilage chips were gradually grafted onto the dissected areas from the posterior orbit. RESULTS: Aesthetically satisfactory results were obtained in all patients. No complications in the donor area were observed. Furthermore, no patients experienced a recurrence or deterioration of diplopia over the follow-up period. One patient experienced temporary high intraocular pressure, which spontaneously resolved with medication and eye drops. CONCLUSION: The costochondral graft is adequate for the reconstruction of the fracture, easy to obtain, easily adaptable to the orbital walls, and has minimal morbidity at the donor site. PMID- 28027180 TI - Pediatric Sialadenosis Due to Valproic Acid. AB - Sialadenosis is a rare entity characterized by bilateral diffuse, painless swelling of the parotid glands. Its etiology is not clear; however, it may occur due to adverse effects of some drugs. To our knowledge, sialadenosis due to valproic acid has not been reported in the literature up to date in any child. In this article, the authors presented a child who developed sialadenosis due to valproic acid, and improved after stopping use of the drug. PMID- 28027181 TI - Treatment of the Crooked Nose: The Final Steps to Perfection. AB - Perfection is sometimes approached in treatment of the crooked nose today but not fully achieved due to the continued existence of flaws. While the traditional surgical algorithm envisages the use of 2 series of procedures to straighten the nasal bones and cartilaginous septum, the addition of a third appears very useful with a view to obtaining truly excellent results, above all in the case of marked deviation. The authors present their experience in the use of certain procedures designed to correct asymmetry of the upper lateral and lower lateral cartilages, as well as the soft covering tissues where necessary.A retrospective study was carried out on 105 patients treated for crooked nose over a 3-year period, 90% of the patients being due to trauma and the remaining 10% to congenital malformation. All the patients involved severe deviation of the nasal pyramid.The mean follow-up period was 18 months (range: 8-36 months). The use of these additional surgical procedures made it possible to obtain excellent final results in 83 (97.6%) patients with crooked nose of traumatic origin and in 17 (85%) patients with crooked nose due to congenital malformation. No major complication was registered, although 3 patients did present minor complications not connected with the nasal deviation.In conclusion, more modern approach to correction of the crooked nose should involve not only realignment of the osteocartilaginous axis but also treatment of the neighboring structures. PMID- 28027182 TI - Treatment Options for Exposed Calvarium Due to Trauma and Burns. AB - Wounds involving the calvarium secondary to trauma or burns are rare. However, they can present with challenging potential clinical sequelae. A wide variety of reconstructive options have evolved over the last century. Technical aspects have progressively improved as well over time. For proper surgical restoration of function and cosmesis reconstructive surgeons must have a detailed understanding of both the scalp and skull anatomy. Several factors such as etiology of the injury, including whether or not calvarial bone defects exists or simply soft tissue loss, as well as size, local tissue environment and patient comorbidities play major roles in appropriate choice for reconstruction. Currently, there is no single treatment option for scalp or calvarial reconstruction after trauma or burns. However, reconstructive alternatives are constantly emerging with promising results. PMID- 28027183 TI - Coincidence of Eagle Syndrome and Diffuse Idiopathic Skeletal Hyperostosis Presenting With Dysphagia as a Result of Compression of the Hypopharynx. AB - Coincidence of the Eagle syndrome and diffuse idiopathic skeletal hyperostosis can very rarely result with compression of the hypopharynx. The authors here described a very rare case of hypopharyngeal airway compression secondary to cervical osteophytes in a patient with coincidence of Eagle syndrome and diffuse idiopathic skeletal hyperostosis. Multidetector computed tomography accuracy showed compression to the hypopharyngeal air column by the Eagle syndrome and diffuse idiopathic skeletal hyperostosis. PMID- 28027184 TI - Piezosurgery an Asset in Treatment of Pierre Robin Sequence. AB - Pierre Robin sequence (formerly a syndrome) is named after the French stomatologist who, in 1923 and 1934, described the problems associated with micrognathia in newborn. It comprises mandibular micrognathia, U-shaped cleft palate, and glossoptosis. The typical symptoms are hypoxaemia, noisy breathing, snoring, stridor, cyanosis, bradycardia, feeding difficulties, and failure to thrive. Distraction osteogenesis has recently been considered as a surgical option for early intervention to lengthen the mandible and relieve respiratory problems. Piezosurgery offers a modality to make precise bone cuts preserving vital structures, minimizing the invasiveness of the surgical procedure, and offering bloodless field. We present case of 1-year-old male malnourished child with Pierre Robin sequence and tracheostomy in situ since day 11 of his birth. The staged treatment plan involving mandibular lengthening in which mandibular osteotomies were performed with the piezoelectric scalpel followed by decannulation of tracheostomy, which has been described in detail in this article. PMID- 28027186 TI - Horizontally Opposed V-Y Advancement Flaps for Surgical Reconstruction of Central Upper Lip Defects. PMID- 28027185 TI - Use of Virtual Surgical Planning for Simultaneous Maxillofacial Osteotomies and Custom Polyetheretherketone Implant in Secondary Orbito-Frontal Reconstruction: Importance of Restoring Orbital Volume. AB - Correction of orbito-frontal defects involves a multitude of surgical challenges, and requires careful and detailed planning. In the trauma setting, one must be prepared to deal with injuries to adjacent structures and be able to incorporate their repair into the surgical plan to maximize the functional and esthetic reconstruction for the benefit of the patient. Victims who have sustained trauma of the cranial complex in combination with mid-facial trauma, particularly involving the orbit, present a difficult scenario, especially when future ocular prosthetic rehabilitation is a concern. The authors present a patient of virtual surgical planning-guided planning of mid-facial osteotomies and custom implant creation for the secondary reconstruction of a patient who sustained extensive orbito-frontal trauma, requiring not only cranial vault recontouring, but also reconstruction of the mid-facial and orbital complex to accommodate an ocular prosthesis that would demonstrate proper anatomical relationships to maximize esthetics and function. PMID- 28027187 TI - Analysis of Morbidity, Readmission, and Reoperation After Craniosynostosis Repair in Children. AB - The impact of specific patient comorbidities on outcomes in craniosynostosis surgical repair is not well defined. The aim of this retrospective review was to evaluate the short-term 30-day reoperation rate, unplanned readmission rate, and overall morbidity of craniosynostosis surgical repair using the 2012 through 2014 American College of Surgeons National Surgical Quality Improvement Program Pediatrics (ACS NSQIP-Pediatric) database. Overall morbidity included pneumonia, wound occurrence, shock/sepsis, venous thromboembolism, cardiac complication, renal and urinary complications, or nerve injury. The authors identified patients undergoing craniosynostosis repair by CPT code resulting in 2,037 patients. A univariate and multivariate analysis was performed to identify risk factors for reoperation, readmission, and morbidity. The reoperation rate was 2.4%, the overall morbidity rate was 2.8%, and readmission rate was 3.4%.Regression analysis identified age, high American Society of Anesthesiologists (ASA) classification, and history of either neurologic or pulmonary disorders as associated with unplanned reoperations within 30 days. High ASA classification also demonstrated significant correlation with unplanned 30-day readmission, and a history of neurologic disorders was associated with overall morbidity. The most common reason for readmission was wound complications (n = 15) followed by respiratory complications (n = 7). Gender, gastrointestinal comorbidities, blood disorders, cardiac risk factors, and prior operation within 30 days did not show significant association with any outcome. Craniosynostosis surgical repair is safe and associated with low complication and readmission rates. Careful patient selection and preoperative optimization of these factors should be sought to reduce detrimental outcomes. PMID- 28027188 TI - Lower Eyelid Complications in Facial Fracture Surgery. AB - BACKGROUND: Facial fractures may lead to sequelae due to the trauma but also as a result of surgery. Complications to lower eyelid incisions include ectropion, scleral show, entropion, canthal malposition, and lid edema. The aim of this study was to compare the occurrence of such complications depending on whether a subciliary or transconjunctival incision was used for surgical access. METHODS: All consecutive patients surgically treated for a facial fracture between June 2005 and December 2012 with a lower eyelid incision and a minimal follow-up of 6 months were included in this retrospective study. Patients were grouped according to type of lower eyelid incision (transconjunctival vs subciliary). RESULTS: Out of 128 patients, 37 (29%) had a subciliary and 91 (71%) had a transconjunctival incision. In the subciliary incision group, 3 patients (8.1%) had ectropion and 4 patients (11%) had scleral show whereas 2 patients (2.2%) had ectropion, 4 patients (4.4%) had scleral show, and 2 patients (2.2%) displayed canthal malposition in the transconjunctival incision group. The differences between the groups were not statistically significant. No patient had an entropion. CONCLUSIONS: Subciliary incisions had a higher incidence of ectropion and scleral show compared with transconjunctival incisions. Transconjunctival incisions did show a low risk of canthal malposition needing surgical correction; however, the actual numbers were low. Based on this and earlier studies, the authors routinely perform transconjunctival incisions, without a lateral canthotomy if possible, for surgery of facial fractures. PMID- 28027189 TI - A New Method of Fixation With the Yang's Keyhole Plate System for the Treatment of Mandible Fractures. AB - PURPOSE: This study was designed to assess the clinical outcomes and surgical convenience of a newly designed Yang's Keyhole plate (YK plate) system for treatment of subcondyle and angle fractures of the mandible. To evaluate the system's clinical outcomes and surgical convenience, chart review and surgical simulation using a mandible replica model were performed. METHODS: The YK plate system, which is a slightly modified sliding plate, has 0.8-mm thick titanium and a widened hole in the anterior region to permit a screw head to be inserted. The clinical results and clinical convenience of the newly developed YK plate system and the existing 4-hole miniplate fixation technique were compared using a surgical simulation. Moreover, the clinical results of the patients who underwent mandibular surgery were compared during the follow-up examination periods (ie, weeks 1, 2, 4, 8, and 16). RESULTS: No critical complications in any of the 22 patients were reported during the 4-month follow-up period. The results of the assessment of clinical convenience using the surgical simulation showed that using the YK plate system was more convenient and saved time compared to using the 4-hole miniplate. CONCLUSION: The newly developed YK plate system can be applied to subcondyle and angle fractures of the mandible and can provide reliable and convenient application and use. PMID- 28027191 TI - Intentional Intra-arterial Injection of Heroin: A Case Report. AB - Intravenous injection of drugs is associated with a host of medical complications, notably soft-tissue infections. On the contrary, intra-arterial injections of drugs have also been reported, largely restricted to inadvertent injections. Here we describe a patient who engaged in repeated intra-arterial injections of heroin when she exhausted most of her venous access, and presented acutely with a radial artery occlusion requiring thrombolytic therapy. Clinicians should have a high index of suspicion for intra-arterial injection in injection drug users who present with limb pain, ischemia, and motor/sensory deficits. Given the reluctance patients may have in discussing their injection practices, clinicians should proactively discuss and counsel patients about safe injection practices and the dangers of intra-arterial injections. PMID- 28027190 TI - Purified Human Skeletal Muscle-Derived Stem Cells Enhance the Repair and Regeneration in the Damaged Urethra. AB - BACKGROUND: Postoperative damage of the urethral rhabdosphincter and nerve vascular networks is a major complication of radical prostatectomy and generally causes incontinence and/or erectile dysfunction. The human skeletal muscle derived stem cells, which have a synchronized reconstitution capacity of muscle nerve-blood vessel units, were applied to this damage. METHODS: Cells were enzymatically extracted from the human skeletal muscle, sorted using flow cytometry as CD34/45 (Sk-34) and CD29/34/45 (Sk-DN/29) fractions, and separately cultured/expanded in appropriate conditions within 2 weeks. Urethral damage was induced by manually removing one third of the wall of the muscle layer in nude rats. A mixture of expanded Sk-34 and Sk-DN/29 cells was applied on the damaged portion for the cell transplantation (CT) group. The same amount of media was used for the non-CT (NT) group. Urethral pressure profile was evaluated via electrical stimulation to assess functional recovery. Cell engraftments and differentiations were detected using immunohistochemistry and immunoelectron microscopy. Expression of angiogenic cytokines was also analyzed using reverse transcriptase-polymerase chain reaction and protein array. RESULTS: At 6 weeks after transplantation, the CT group showed a significantly higher functional recovery than the NT group (70.2% and 39.1%, respectively; P < 0.05). Histological analysis revealed that the transplanted human cells differentiated into skeletal muscle fibers, nerve-related Schwann cells, perineuriums, and vascular pericytes. Active paracrine angiogenic cytokines in the mixed cells were also detected with enhanced vascular formation in vivo. CONCLUSIONS: The transplantation of Sk-34 and Sk-DN/29 cells is potentially useful for the reconstitution of postoperative damage of the urethral rhabdosphincter and nerve vascular networks. PMID- 28027193 TI - Brain Injury Vision Symptom Survey (BIVSS) Questionnaire. AB - PURPOSE: Validation of the Brain Injury Vision Symptom Survey (BIVSS), a self administered survey for vision symptoms related to traumatic brain injury (TBI). METHODS: A 28-item vision symptom questionnaire was completed by 107 adult subjects (mean age 42.1, 16.2 SD, range 18-75) who self-reported as having sustained mild-to-moderate TBI and two groups of reference adult subjects (first year optometry students: mean age 23.2, 2.8 SD, range 20-39; and 71 third-year optometry students: mean age 26.0, 2.9 SD, range 22-42) without TBI. Both a Likert-style method of analysis with factor analysis and a Rasch analysis were used. Logistic regression was used to determine sensitivity and specificity. RESULTS: At least 27 of 28 questions were completed by 93.5% of TBI subjects, and all 28 items were completed by all of the 157 reference subjects. BIVSS sensitivity was 82.2% for correctly predicting TBI and 90.4% for correctly predicting the optometry students. Factor analysis identified eight latent variables; six factors were positive in their risk for TBI. Other than dry eye and double vision, the TBI patients were significantly more symptomatic than either cohort of optometry students by at least one standard deviation (p < 0.001). Twenty-five of 28 questions were within limits for creating a single dimension Rasch scale. CONCLUSIONS: Nearly all of the adult TBI subjects were able to self-complete the BIVSS, and there was significant mean score separation between TBI and non-TBI groups. The Rasch analysis revealed a single dimension associated with TBI. Using the Likert method with the BIVSS, it may be possible to identify different vision symptom profiles with TBI patients. The BIVSS seems to be a promising tool for better understanding the complex and diverse nature of vision symptoms that are associated with brain injury. PMID- 28027194 TI - Big Data Management in US Hospitals: Benefits and Barriers. AB - Big data has been considered as an effective tool for reducing health care costs by eliminating adverse events and reducing readmissions to hospitals. The purposes of this study were to examine the emergence of big data in the US health care industry, to evaluate a hospital's ability to effectively use complex information, and to predict the potential benefits that hospitals might realize if they are successful in using big data. The findings of the research suggest that there were a number of benefits expected by hospitals when using big data analytics, including cost savings and business intelligence. By using big data, many hospitals have recognized that there have been challenges, including lack of experience and cost of developing the analytics. Many hospitals will need to invest in the acquiring of adequate personnel with experience in big data analytics and data integration. The findings of this study suggest that the adoption, implementation, and utilization of big data technology will have a profound positive effect among health care providers. PMID- 28027195 TI - Hospital Chief Executive Officer Perspectives on Health Care Administration Academic Preparations. AB - A dynamic health care industry continues to call upon health care leaders to possess not one but multiple competencies. A post hoc review of 3 secondary data sets (previous parallel surveys administered in 2007, 2011, and 2015) was conducted to determine what preferred academic program of study (master of health administration, master of business administration, or a clinical degree preparation) may exist by current hospital executives and potential trending of executive degree preparations over time. In addition, any relationships among individual hospital administrator, individual personal characteristics, and their preferred degree preparations were also investigated at an exploratory level. Findings suggest and support the researchers' hypothesis that the preferred degree preference for a career in hospital administration (master of business administration, master of health administration, or clinical) is highly dependent on an individual executive's graduate degree earned. Many areas for future research are identified from this study that include additional survey analysis and future research questions related to initial findings. PMID- 28027196 TI - A Qualitative Study of Health Care Experiences Among International Students. AB - The purpose of this qualitative study was to explore the health care experiences of international students at a college in Indiana. The study answered the following research question: What are the lived experiences of international students while seeking health care? This research question was identified after a literature review, which showed a lack of research regarding international students' health care experiences. The data in this study were collected through in-depth interviews with 5 participants who resided at the college. After the interviews, the identification of themes and the analysis of results revealed the international students' lived experiences and perceptions of health care in the United States. PMID- 28027197 TI - The Effects of the Transforming Care at the Bedside Program on Perceived Team Effectiveness and Patient Outcomes. AB - The objective of the study was to document the impact of Transforming Care at the Bedside (TCAB) program on health care team's effectiveness, patient safety, and patient experience. A pretest and posttest (team effectiveness) and a time-series study design (patient experience and safety) were used. The intervention (the TCAB program) was implemented in 8 units in a multihospital academic health science center in Montreal, Quebec, Canada. The impact of TCAB interventions was measured using the Team Effectiveness (TCAB teams, n = 50), and Clostridium difficile-associated diarrhea and vancomycin-resistant Enterobacter rates (patient safety) and Hospital Consumer Assessment of Healthcare Providers and Systems (patient experience; n = 551 patients). The intervention was composed of 4 learning modules, each lasting 12 to 15 weeks of workshops held at the start of each module, combined with hands-on learning 1 day per week. Transforming Care at the Bedside teams also selected 1 key safety indicator to improve throughout the initiative. Pretest and posttest differences indicate improvement on the 5 team effectiveness subscales. Improvement in vancomycin-resistant Enterococcus rate was also detected. No significant improvement was detected for patient experience. These findings call to attention the need to support ongoing quality improvement competency development among frontline teams. PMID- 28027198 TI - A Topical Anesthetic and Lidocaine Mixture for Pain Relief During Keloid Treatment: A Double-Blind, Randomized Controlled Trial. AB - BACKGROUND: Keloids are abnormal overgrowth of collagen fibers, and the first line treatment includes intralesional injection of triamcinolone acetonide (TA), which is associated with pain. OBJECTIVE: To study the benefit of applying topical anesthetics or a 1:1 mixture of 1% lidocaine and TA at the TA injection site to alleviate pain during keloid treatment. METHODS AND MATERIALS: A double blind, randomized controlled trial was conducted. Four TA injection methods were tested: control, lidocaine, topical, and combined. A visual analog scale (VAS) was used to assess needle-stick and injection pain. Data on pain duration after injection were also collected. RESULTS: Forty patients were enrolled (mean age, 37.1 years). The VAS scores of needle-stick pain in the control, lidocaine, topical, and combined groups were 4.18 +/- 2.12, 3.82 +/- 2.48, 2.03 +/- 2.02, and 2.20 +/- 1.99, respectively. Pain statistically decreased in the topical and combined groups. Intralesional injection pain (VAS) scores in the control, lidocaine, topical, and combined groups were similar as follows: 4.97 +/- 2.50, 4.97 +/- 2.79, 4.10 +/- 2.80, and 4.43 +/- 2.68, respectively. CONCLUSION: Application of topical anesthetics significantly relieved needle-stick pain, especially at sternum and auricular keloids; administration of a lidocaine mixture did not alleviate pain during injection. PMID- 28027199 TI - The Combination of Resveratrol and High-Fluence Light Emitting Diode-Red Light Produces Synergistic Photobotanical Inhibition of Fibroblast Proliferation and Collagen Synthesis: A Novel Treatment for Skin Fibrosis. AB - BACKGROUND: Skin fibrosis is a debilitating condition that significantly impacts patient quality of life. Ultraviolet phototherapy is currently used to treat several diseases featuring skin fibrosis. High-fluence light-emitting diode generated red light (HF-LED-RL) does not cause DNA damage associated with skin cancer, and it is generally regarded as safe, portable, and cost-effective. Early clinical observations suggest that LED-generated light may possess antifibrotic effects, although these findings are largely unexplored. Previously published research demonstrated that HF-LED-RL decreases fibroblast proliferation and collagen in vitro. OBJECTIVE: The goal of this study was to compare the combination effects of HF-LED-RL alone with HF-LED-RL in combination with resveratrol. MATERIALS AND METHODS: It is hypothesized that resveratrol, an active ingredient in red wine, a potent antioxidant scavenger of reactive oxygen species, and an inhibitor of collagen production, may synergistically decrease fibroblast proliferation and collagen production when combined with HF-LED-RL. RESULTS: In this study, evidence is provided that resveratrol combined with HF LED-RL acts synergistically to decrease fibroblast proliferation and procollagen 1A1 production, and this represents a new potential therapeutic modality that is termed the "photobotanical" effect due to the combined light and botanical properties observed. CONCLUSION: The study, discovery, and use of photobotanical combinations may usher in new therapeutics or phototherapy adjuvants for the treatment of dermatologic diseases. PMID- 28027200 TI - Vascular Supply of the Auricle: Anatomical Study and Applications to External Ear Reconstruction. AB - BACKGROUND: Reliable reconstructive flaps require convenient vascular supply. Thus, precise description of the vascular patterns of external ear is not completely elucidated. OBJECTIVE: This anatomical study aims to provide comprehensive data of the arterial network of the auricular region, anastomosis, and patterns of arterial dependence regarding external ear subunits. MATERIALS AND METHODS: After dyed latex injections in the external carotid artery, eleven auricles have been carefully dissected to examine the vascular network of the auricular region. RESULTS: In all cases, the posterior auricular artery (PAA) supplied the cranial side of the auricle, as well as the concha on the lateral side through consistent perforating branches. The superficial temporal artery (STA) network supplied the upper third of the lateral aspect of the auricle. The authors' dissections showed a clear dominance of the PAA supply. However, the two arteries consistently developed anastomoses particularly in the cranial upper third of the auricle. CONCLUSION: Consistent branches and anastomoses between the PAA and the STA network provide reliable pedicles for auricular and facial reconstruction. PMID- 28027202 TI - Patient Satisfaction and Quality of Life Following Surgery for Hidradenitis Suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a progressive, recurrent inflammatory disorder. OBJECTIVE: To assess long-term satisfaction and postoperative perceptions among patients who underwent surgical management of HS. MATERIALS AND METHODS: A questionnaire was mailed to 499 HS surgical patients to assess surgical outcome, satisfaction, and quality of life. RESULTS: Of the 499 questionnaires mailed, 113 were returned (22.6% response rate) and 2 were excluded for redundancy. Of the 111 respondents, 65 (58.6%) were female, 91 (82.0%) had Hurley Stage III disease, 88 (79.3%) were treated with excision and 23 (20.7%) with unroofing, 45 (40.5%) had perianal or perineal disease, and 41 (36.9%) had axillary disease. Most patients were satisfied or very satisfied with their surgical results (84.7%; 94 of 111), were glad they underwent surgery (96.3%; 105 of 109), and would recommend surgery to a friend or relative (82.6%; 90 of 109). Most patients were satisfied or very satisfied with the appearance of their healed wound (62.4%; 68 of 109). Retrospective mean quality of life increased significantly from 5 preoperatively to 8.4 postoperatively (p < .001). CONCLUSION: Hidradenitis suppurativa surgical management was well regarded by patients and should be considered by future patients to limit the morbidity of HS. PMID- 28027203 TI - Developing standardised advanced training in neuroanaesthesia: Results of a Europe-wide survey. PMID- 28027201 TI - Incidence and Clinical Features of Rare Cutaneous Malignancies in Olmsted County, Minnesota, 2000 to 2010. AB - BACKGROUND: The incidence of rare cutaneous malignancies is unknown. Current estimates of rare cutaneous malignancy incidences are based on broad epidemiologic data or single institution experiences, not population-based data. OBJECTIVE: To determine the incidence of several rare nonmelanoma skin cancers. MATERIALS AND METHODS: The authors conducted a retrospective chart review of a population-based cohort between the years 2000 and 2010. Residents of Olmsted County, Minnesota, who were diagnosed with a biopsy-proven nonmelanoma skin cancer-excluding basal cell carcinoma and squamous cell carcinoma-were included in this study. The primary outcome was tumor incidence. Additionally, the authors extracted patient demographics, tumor characteristics, treatment modalities, and outcomes. RESULTS: The age-adjusted and sex-adjusted incidences per 100,000 persons of multiple rare cutaneous malignancies were: atypical fibroxanthoma (1.8), sebaceous carcinoma (0.8), dermatofibrosarcoma protuberans (0.4), microcystic adnexal carcinoma (0.7), eccrine carcinoma (0.4), eccrine porocarcinoma (0.2), and leiomyosarcoma (0.2). CONCLUSION: The authors report population-based incidences and clinical characteristics for these rare cutaneous malignancies. The immune status and smoking status of patients and the treatment and outcomes of these tumors are reported. Additional studies in a broader population are needed to further define the epidemiology and outcomes of these malignancies. PMID- 28027204 TI - Minimally invasive analgesia after cardiac surgery. PMID- 28027205 TI - Posterior wall puncture during ultrasound-guided arterial cannulation suggests inadequate operator skills. PMID- 28027206 TI - Reply to: posterior wall puncture during ultrasound-guided arterial cannulation suggests inadequate operator skills. PMID- 28027207 TI - Association of increased N terminal B-type natriuretic propeptide levels with short-term adverse outcomes after noncardiac surgery. PMID- 28027208 TI - Reply to: association of increased N terminal B-type natriuretic propeptide levels with short-term adverse outcomes after noncardiac surgery. PMID- 28027209 TI - Volume therapy in obstetrics. PMID- 28027210 TI - Reply to: volume therapy in obstetrics. PMID- 28027211 TI - The small details that influence postoperative pain. PMID- 28027212 TI - Reply to: the small details that influence postoperative pain. PMID- 28027213 TI - Bermuda triangle; heart failure, atrial fibrillation, and vitamin D deficiency. PMID- 28027214 TI - IBD-Like Features in Syndromic Diarrhea/Trichohepatoenteric Syndrome. AB - BACKGROUND: Very early onset inflammatory bowel disease (VEOIBD) (inflammatory bowel disease [IBD] before 6 years of age) may manifest as a monogenic disease affecting the gastrointestinal tract. Syndromic diarrhea/trichohepatoenteric syndrome (SD/THE), a rare disorder caused by alteration of a complex involved in RNA degradation, has been reported to present with some degree of colitis and in some cases an IBD-like presentation. METHODS: We reviewed clinical and biological data of 4 previously published cases and added detailed data of 2 new cases of SD/THE with an IBD-like presentation. RESULTS: All the 6 patients presented with typical intractable diarrhea and hair abnormalities. The colon was affected in all of the patients: 1 had ileitis, 2 had panenteritis, and 2 presented with perianal disease. Fecal calprotectin level and erythrosedimentation rate were elevated in 2 cases each. All the therapeutic classes of IBD treatment (mesalazine, steroids, immunomodulators, and biological therapy) were used in the 6 cases. In 2 patients, treatment had no effect. Three showed a partial effect, and 1 patient sustained only a transient effect. CONCLUSIONS: SD/THE can have a similar presentation as VEOIBD, often as pancolitis. IBD treatments appear to have little efficacy for SD/THE, suggesting a different pathogenesis for the IBD like features in SD/THE compared with classical IBD. PMID- 28027215 TI - Complementary Feeding: A Position Paper by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee on Nutrition. AB - : This position paper considers different aspects of complementary feeding (CF), focussing on healthy term infants in Europe. After reviewing current knowledge and practices, we have formulated these recommendations: Timing: Exclusive or full breast-feeding should be promoted for at least 4 months (17 weeks, beginning of the 5th month of life) and exclusive or predominant breast-feeding for approximately 6 months (26 weeks, beginning of the 7th month) is a desirable goal. Complementary foods (solids and liquids other than breast milk or infant formula) should not be introduced before 4 months but should not be delayed beyond 6 months. CONTENT: Infants should be offered foods with a variety of flavours and textures including bitter tasting green vegetables. Continued breast feeding is recommended alongside CF. Whole cows' milk should not be used as the main drink before 12 months of age. Allergenic foods may be introduced when CF is commenced any time after 4 months. Infants at high risk of peanut allergy (those with severe eczema, egg allergy, or both) should have peanut introduced between 4 and 11 months, following evaluation by an appropriately trained specialist. Gluten may be introduced between 4 and 12 months, but consumption of large quantities should be avoided during the first weeks after gluten introduction and later during infancy. All infants should receive iron-rich CF including meat products and/or iron-fortified foods. No sugar or salt should be added to CF and fruit juices or sugar-sweetened beverages should be avoided. Vegan diets should only be used under appropriate medical or dietetic supervision and parents should understand the serious consequences of failing to follow advice regarding supplementation of the diet. METHOD: Parents should be encouraged to respond to their infant's hunger and satiety queues and to avoid feeding to comfort or as a reward. PMID- 28027216 TI - Recycling Small Intestinal Contents From Proximal Ileostomy in Low-Birth-Weight Infants With Small Bowel Perforation. PMID- 28027217 TI - Enteral Iron Supplementation in Preterm Infants Has No Adverse Effect on Growth: Evidence From Randomized Trials. PMID- 28027218 TI - Discussion: Risk Factor Analysis for Capsular Contracture, Malposition, and Late Seroma in Subjects Receiving Natrelle 410 Form-Stable Silicone Breast Implants. PMID- 28027220 TI - Outcomes of Prosthetic Reconstruction of Irradiated and Nonirradiated Breasts with Fat Grafting. AB - BACKGROUND: Fat grafting may be beneficial in prosthetic reconstruction of irradiated tissues, but there is a paucity of data on the complication rates associated with this clinical scenario. METHODS: All consecutive patients who had undergone fat grafting and prosthetic reconstruction from 2010 to 2013 were enrolled. Variables obtained related to fat grafting and history of irradiation. Implant-related complications in relation to irradiation status were also noted. RESULTS: Eighty-five patients (age 49 +/- 10 years) underwent 117 fat grafting procedures. The mean follow-up was 2.6 +/- 0.7 years. Fat grafting was predominantly performed to correct soft-tissue deficiency [112 of 117 (95.7 percent)] or to alter skin after irradiation [five of 117 (4.3 percent)]. Thirty two procedures (27.4 percent) were associated with a complication, with the most common being palpable fat necrosis (23.1 percent). Volume of transferred fat averaged 151.2 +/- 76.6 ml per breast. Fat grafting complications did not depend on donor site, technique of fat processing, volume of transferred fat, number of procedures, or irradiation. Implant-related complications were observed after 26 of 117 overall procedures (22.2 percent). No association between implant-related complications and irradiation was observed (OR, 1.3; 95 percent CI, 0.4 to 4.1; p = 0.63). Overall complications following fat grafting in nonirradiated [37 of 82 (45.1 percent)] and irradiated [16 of 35 (45.7 percent)] breasts were not statistically different (OR, 1.02; 95 percent CI, 0.41 to 2.57; p = 0.96). CONCLUSION: Similar outcomes of irradiated and nonirradiated prosthetic breast reconstruction can be achieved with additional fat grafting. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027219 TI - Cancer Risk after Fat Transfer: A Multicenter Case-Cohort Study. AB - BACKGROUND: Fat transfer is an increasingly popular method for refining postmastectomy breast reconstructions. However, concern persists that fat transfer may promote disease recurrence. Adipocytes are derived from adipose derived stem cells and express adipocytokines that can facilitate active breast cancer cells in laboratory models. The authors sought to evaluate the association between fat transfer to the reconstructed breast and cancer recurrence in patients diagnosed with local or regional invasive breast cancers. METHODS: A multicenter, case-cohort study was performed. Eligible patients from four centers (Memorial Sloan Kettering, M. D. Anderson Cancer Center, Alvin J. Siteman Cancer Center, and the University of Chicago) were identified by each site's institutional tumor registry or cancer data warehouse. Eligibility criteria were as follows: mastectomy with immediate breast reconstruction between 2006 and 2011, age older than 21 years, female sex, and incident diagnosis of invasive ductal carcinoma (stage I, II, or III). Cases consisted of all recurrences during the study period, and controls consisted of a 30 percent random sample of the study population. Cox proportional hazards regression was used to evaluate for association between fat transfer and time to recurrence in bivariate and multivariate models. RESULTS: The time to disease recurrence unadjusted hazard ratio for fat transfer was 0.99 (95 percent CI, 0.56 to 1.7). After adjustment for age, body mass index, stage, HER2/Neu receptor status, and estrogen receptor status, the hazard ratio was 0.97 (95 percent CI, 0.54 to 1.8). CONCLUSION: In this population of breast cancer patients who had mastectomy with immediate reconstruction, fat transfer was not associated with a higher risk of cancer recurrence. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027221 TI - Late Surgical-Site Infection in Immediate Implant-Based Breast Reconstruction. AB - BACKGROUND: Surgical-site infection causes devastating reconstructive failure in implant-based breast reconstructions. Large national database studies offer insights into complication rates, but only capture outcomes within 30 days postoperatively. This study evaluates both early and late surgical-site infection in immediate implant-based reconstruction and identifies predictors. METHODS: As part of the Mastectomy Reconstruction Outcomes Consortium Study, 1662 implant based breast reconstructions in 1024 patients were evaluated for early versus late surgical-site infection. Early surgical-site infection was defined as infection occurring within 30 days postoperatively; late surgical-site infection was defined as infection occurring 31 days to 1 year postoperatively. Minor infection required oral antibiotics only, and major infection required hospitalization and/or surgical treatment. Direct-to-implant patients had 1-year follow-up, and tissue expander patients had 1-year post-exchange follow-up. RESULTS: Among 1491 tissue expander and 171 direct-to-implant reconstructions, overall surgical-site infection rate for tissue expander was 5.7 percent (85 of 1491) after first-stage, 2.5 percent (31 of 1266) after second-stage, and 9.9 percent (17 of 171) for direct-to-implant reconstruction. Over 47 to 71 percent of surgical-site infection complications were late surgical-site infection. Multivariate analysis identified radiotherapy and increasing body mass index as significant predictors of late surgical-site infection. No significant difference between the direct-to-implant and tissue expander groups in the occurrence of early, late, or overall surgical-site infection was found. CONCLUSIONS: The majority of surgical-site infection complications in immediate implant-based breast reconstructions occur more than 30 days after both first-stage and second stage procedures. Radiotherapy and obesity are significantly associated with late onset surgical-site infection. Current studies limited to early complications do not present a complete assessment of infection associated with implant-based breast reconstructions or their long-term clinical outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 28027222 TI - The Effect of Neoadjuvant Chemotherapy Compared to Adjuvant Chemotherapy in Healing after Nipple-Sparing Mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy is the latest advancement in the treatment of breast cancer. The authors aimed to investigate the effects of neoadjuvant and adjuvant chemotherapy in nipple-sparing mastectomy. METHODS: Patients undergoing nipple-sparing mastectomy from 2006 to June of 2015 were identified. Results were stratified by presence of neoadjuvant or adjuvant chemotherapy. RESULTS: A total of 840 nipple-sparing mastectomies were performed. Twenty-eight were in those who received neoadjuvant chemotherapy and 93 were in patients receiving adjuvant chemotherapy. Patients receiving both neoadjuvant and adjuvant chemotherapy were included in the neoadjuvant group. Nipple-sparing mastectomies that received neoadjuvant (with or without adjuvant) chemotherapy were compared to those in patients who received adjuvant chemotherapy. Those with neoadjuvant (with or without adjuvant) chemotherapy were more likely to have explantation (p = 0.0239) and complete nipple-areola complex necrosis (p = 0.0021). Those with neoadjuvant (with or without adjuvant) chemotherapy were more likely to have implant explantation (p = 0.0015) and complete nipple-areola complex necrosis (p = 0.0004) compared to those with no chemotherapy. Compared to nipple-sparing mastectomies in patients with no chemotherapy, those with adjuvant chemotherapy were more likely to have a hematoma (p = 0.0021). Those that received both neoadjuvant and adjuvant chemotherapy were more likely to have complete nipple areola complex necrosis compared with both the neoadjuvant chemotherapy-only and adjuvant chemotherapy-only groups (p < 0.0001). CONCLUSIONS: Nipple-sparing mastectomy is safe to perform in the setting of neoadjuvant and adjuvant chemotherapy. As a whole, neoadjuvant (with or without adjuvant) chemotherapy increases risk of complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027223 TI - Staged Suprapectoral Expander/Implant Reconstruction without Acellular Dermal Matrix following Nipple-Sparing Mastectomy. AB - BACKGROUND: Since the introduction of nipple-sparing mastectomy as an oncologically safe procedure for the treatment of breast cancer, reconstructive efforts for immediate staged expander/implant reconstruction have focused on submuscular implantation with or without acellular dermal matrix. Suprapectoral reconstruction without acellular dermal matrix has received little attention in the reconstructive literature of nipple-sparing mastectomy. METHODS: Between 2005 and 2015, 155 patients (250 breasts) underwent nipple-sparing mastectomy with prepectoral staged expander/implant reconstruction using thick mastectomy skin flaps without acellular dermal matrix. Patients with different breast sizes, including those patients with very large breasts who required a primary mastopexy, were considered candidates for the suprapectoral reconstruction. Tumor related data, comorbidities, and preoperative or postoperative radiation therapy were evaluated for correlation with the final outcome. RESULTS: Patients were followed up for an average of 55.5 months (range, 138.1 to 23.6 months). The tumor recurrence rate was 2.6 percent. Adverse outcomes such as capsular contracture, implant dystopia, and rippling were studied. Aesthetic outcome, based on a three-point evaluation scale, showed 53.6 percent of patients as having a very good result, 31.6 percent showing a good result, 9 percent showing a fair result, and 5.8 percent showing a poor result. CONCLUSIONS: The suprapectoral two-stage expander/implant reconstruction without acellular dermal matrix in nipple-sparing mastectomy has certain advantages with respect to breast shape, less morbidity related to expansion, ease of reconstruction, and cost effectiveness. These advantages have to be weighed against those of subpectoral reconstruction with acellular dermal matrix to determine the method of choice. CLINCAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027224 TI - Ultrasound-Guided Bilateral Thoracic Paravertebral Blocks as an Adjunct to General Anesthesia in Patients Undergoing Reduction Mammaplasty: A Historical Cohort Study. AB - BACKGROUND: This study investigates whether ultrasound-guided thoracic paravertebral blocks would improve postoperative analgesia in patients undergoing bilateral reduction mammaplasty. METHODS: After obtaining ethics committee approval, data of 70 patients who underwent bilateral reduction mammaplasty were reviewed. Sixty-four patients' data were evaluable; 30 were in the general anesthesia group and 34 were in the thoracic paravertebral block group. Data such as time to first pain, intraoperative fentanyl requirement, postoperative numeric rating scale scores, number of patients who required tramadol in the postoperative care unit, and rescue analgesic consumption through the first 2 postoperative days were analyzed. RESULTS: Time to first pain was 311 minutes (range, 0 to 1605 minutes) and 20 minutes (range, 0 to 120 minutes) in the thoracic paravertebral block and general anesthesia groups, respectively (p < 0.001). Fentanyl requirement was 52.94 +/- 11.94 ug and 115 +/- 29.79 ug in the thoracic paravertebral block and general anesthesia groups, respectively (p < 0.001). Numeric rating scale scores were lower in the thoracic paravertebral block group through the first 2 postoperative hours (p < 0.001), and only two of 34 patients required tramadol in the postoperative care unit (p < 0.001). On postoperative day 1, both metamizole sodium (p < 0.001) and paracetamol (p = 0.018), and on day 2, only metamizole sodium (p < 0.001) consumption was lower in the thoracic paravertebral block group. CONCLUSION: Adding ultrasound-guided thoracic paravertebral blocks to general anesthesia postponed time to first pain and reduced analgesic consumption in patients undergoing bilateral reduction mammaplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027225 TI - Discussion: Platysma Bands: Is a Change Needed in the Surgical Paradigm? PMID- 28027226 TI - Base Nasal Bone Resection versus Oblique Nasal Bone Resection: A Comparative Study of the Outcomes for the Deviated Nose. AB - BACKGROUND: The aim of this study was to compare the techniques used for resection of the long side of the base and the top of the bone based on the patient's perspective, surgeon's approach, aesthetic results, complications, and need for secondary surgery in patients with asymmetric nasal bones. This study also aimed to determine the perspective of another plastic surgeon who did not perform rhinoplasty in comparison with the perspective of the primary plastic surgeon. METHODS: One hundred sixty-six patients with nasal bone asymmetry between 2010 and 2015 were included in this study. Patients were divided into two groups: group 1, those treated with wedge resection of the bony nasal pyramid from the base of the nasal bone; and group 2, those treated with an oblique hump resection. Three different plastic surgeons and plastic surgery nurses who had no information regarding the randomization, patients, and primary plastic surgeon evaluated the surgical results. RESULTS: The mean secondary surgery rate was significantly greater in group 2 than in group 1. The mean satisfaction ratio was significantly decreased with different plastic surgeons than with the primary plastic surgeon. Base nasal bone resection was more successful than oblique hump resection in patients with greater than or equal to 0.5-cm nasal bone asymmetry. CONCLUSIONS: Surgeons who did not perform the rhinoplasties can evaluate the results differently from the primary surgeon. Performing base bone resection may reduce the secondary surgery rate in patients with greater than or equal to 0.5 cm nasal bone asymmetry. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 28027227 TI - Improving Results in Closed Nasal Reduction: A Protocol for Reducing Secondary Deformity. AB - BACKGROUND: Nasal fractures are the most common facial fracture. Improper reduction is a common occurrence, resulting in a residual deformity that requires secondary surgery. A treatment protocol for nasal fracture management is presented with the aim of reducing secondary deformities requiring corrective surgery. METHODS: After institutional review board approval, a retrospective review of all closed nasal reductions performed by a single surgeon between 2006 and 2015 was conducted. Patient age, sex, presence of secondary deformity, and need for a correctional operation were recorded. Clinical records were analyzed for evidence of postoperative deformity and need for subsequent manipulation or surgery. RESULTS: A total of 90 patients with nasal bone fractures who underwent closed nasal reduction were identified. The mean age of patients was 24.9 years. The male-to-female ratio was 2.2:1. Postoperative deformity was reported in 14 patients (15.6 percent). Four of the 90 patients (4.4 percent) were found to have avulsion of their upper lateral cartilage from the nasal bone. Nine of the 14 subjects (64.3 percent) presenting with secondary deformity were managed with external manipulation, avoiding a secondary operation. Five patients (5.5 percent) from the original cohort of 90 underwent revision surgery. CONCLUSIONS: By using the described protocol to treat nasal fractures, we have seen a low rate of postreduction deformity and a small percentage of need for secondary operation. The overall success rate of closed nasal reduction with postoperative manipulation (when necessary) was identified to be 94.5 percent. Using this protocol, surgeons may see a decrease in secondary deformities following closed nasal reduction procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027228 TI - Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. AB - BACKGROUND: The purpose of this study was to determine whether the aesthetic results of subpectoral augmentation mammaplasty using anatomically shaped versus round prostheses are differentiable. METHODS: Thirty observers (i.e., plastic surgeons and nurses) assessed preoperative and postoperative photographs (frontal and oblique views) of 30 patients who had undergone subpectoral augmentation mammaplasty with cohesive silicone gel implants, with an average implant volume of 295 cc (range, 220 to 340 cc). The observers classified each case as round or shaped on two different occasions with a 12-week time interval. A statistical concordance analysis was performed, calculating the overall concordance rate, the interobserver, the intraobserver, and the overall intraobserver kappa indexes, to evaluate the expert observers' capacity to differentiate the implant type. RESULTS: Among the total of 1800 observations (30 observers assessed 30 cases on two occasions), the overall concordance rate was 50.33 percent (95 percent CI, 47.99 to 52.67). The interobserver kappa value was 0.010 (95 percent CI, 0.0025 to 0.04). The overall intraobserver kappa value was 0.0602 (95 percent CI, 0.0025 to 0.123). The observers were unable to recognize the type of implant used, nor was interobserver concordance noted. An agreement was not reached before the different observers, nor was an intraobserver concordance seen between the first and second classifications of the same cases by each observer. CONCLUSION: The results obtained from subpectoral augmentation mammaplasty using anatomically shaped and round prostheses with a volume of 340 cc or less are indistinguishable, not justifying the systematic use of anatomically shaped implants in this patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027229 TI - Discussion: Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28027230 TI - Use of Poly-4-Hydroxybutyrate Mesh to Optimize Soft-Tissue Support in Mastopexy: A Single-Site Study. AB - BACKGROUND: The ptotic breast is surgically rejuvenated through a mastopexy procedure. Recurrent ptosis or other negative changes to the breast shape are not uncommon following mastopexy, as the tissue laxity and skin quality that contributed to ptosis are not surgically corrected. The purpose of this study was to assess the postsurgical changes in the breasts of patients who underwent a primary mastopexy procedure with soft-tissue reinforcement using a long-term poly 4-hydroxybutyrate resorbable scaffold (i.e., GalaFLEX). METHODS: From July of 2012 to January of 2014, 11 consecutive patients underwent a central mound mastopexy with soft-tissue reinforcement in the lower pole using a poly-4 hydroxybutyrate resorbable scaffold. Patients returned for postoperative follow up visits that included three-dimensional scans of their breasts at months 1, 3, 6, and 12. RESULTS: There were no major complications in the study. Changes in the breast shape defined by distances between predefined landmarks between months 1 and 12 ranged from 1.5 to 9.6 percent. Some postoperative breast settlement occurred between months 1 and 3. The mean change in the nipple-to-inframammary fold distance from months 1 to 12 was 8 mm. Lower pole stretch was 5 percent. CONCLUSIONS: Initial findings suggest that central mound mastopexy with soft tissue reinforcement in the lower pole performed on difficult larger breasts yields a relatively stable result for 1 year after surgery. There was no statistically significant change between months 3 and 12 from the sternal notch to lowest point on the breast as determined by established three-dimensional imaging techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027231 TI - The Lipo-Body Lift: A New Circumferential Body-Contouring Technique Useful after Bariatric Surgery. AB - BACKGROUND: After bariatric surgery, lifting of the lower body involves a contouring technique used to achieve optimal lower trunk reconstruction. The authors describe an innovative procedure applicable after massive weight loss: the lipo-body lift method. The authors describe their experience with this novel, safe procedure. METHODS: Twenty-five abdominal body-contouring reconstructions following massive weight loss were treated by means of circumferential lipo-body lift. The authors describe the indications for the procedure and their perioperative and postoperative management. RESULTS: The mean patient age was 39.4 years. The mean pre-body lift body mass index was 26.71 kg/m; the average weight loss before surgery was 56.6 kg, with a mean delta body mass index loss of 20.82 kg/m. The average hospital stay was 3.52 days and the drainage duration 3.56 days. No patient experienced any major complication (e.g., hematoma, thromboembolism, bleeding, skin necrosis, or a need for revision surgery to treat complications). Minor complications including wound dehiscence, wound infection, and fat necrosis were reported in 40 percent of patients. The occurrence of complications was associated with smoking status (p = 0.0280), the volume of liposuction (p = 0.0399), and the liposuction volume per unit of body mass index (p = 0.0071). CONCLUSIONS: The authors' novel technique is less invasive than the traditional lower body-lifting method, as shown by the absence of major complications, and allows excellent conservation of connective tissue and vessels; undermining is minimal. As obesity becomes a major problem worldwide, lifting procedures that are safe and effective are important components of reconstructive strategies and should be widely offered to patients who experience massive weight loss. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027232 TI - Anatomy of the Facial Danger Zones: Maximizing Safety during Soft-Tissue Filler Injections. AB - With limited downtime and immediate results, facial filler injections are becoming an ever more popular alternative to surgical rejuvenation of the face. The results, and the complications, can be impressive. To maximize safety during injections, the authors have outlined general injection principles followed by pertinent anatomy within six different facial danger zones. Bearing in mind the depth and the location of the vasculature within each zone, practitioners can tailor their injection techniques to prevent vessel injury and avoid cannulation. PMID- 28027233 TI - Microporous Polysaccharide Hemospheres Potentiate Ischemia-Induced Skin Flap Necrosis in a Murine Model. AB - BACKGROUND: Microporous polysaccharide hemospheres are an increasingly used adjunctive measure for obtaining operative field hemostasis. However, the impact of these agents on survival of vascularly challenged tissues is unknown. The aim of this study was to investigate the effect, if any, of microporous hemospheres on tissue survival in a murine model. METHODS: Eighteen Sprague-Dawley rats underwent creation of two flanking dorsal, modified McFarlane-style flaps using a length-to-width ratio of 4:1. Microporous polysaccharide hemospheres were applied to the underside of only one flap in each animal. In a subset of five rats, tissue malondialdehyde activity was measured at 24 hours. The remaining 13 animals were killed after 7 days, and the area of flap necrosis was measured photographically. Histopathologic analysis was also performed on the margins of the necrotic area. RESULTS: Size comparison showed a significantly larger area of necrosis in the microporous polysaccharide hemosphere-treated flaps relative to controls (1.69 +/- 1.21 cm versus 0.28 +/- 0.28 cm; p = 0.00135). Higher malondialdehyde levels were also found in the microporous polysaccharide hemosphere-treated flaps at 24 hours (0.462 +/- 0.098 versus 0.315 +/- 0.065; p = 0.047). The areas of skin necrosis were noted to be partial thickness on histologic examination. CONCLUSIONS: Microporous polysaccharide hemospheres are associated with an increased incidence of distal tip necrosis in dorsal rat skin flaps. Despite their efficacy in surgical hemostasis, their use should be judicious, especially with marginally perfused tissues such as mastectomy skin flaps. PMID- 28027234 TI - Selective Nerve Root Transection in the Rat Produces Permanent, Partial Nerve Injury Models with Variable Levels of Functional Deficit. AB - BACKGROUND: The goal of this study was to develop a partial, nonregenerative nerve injury model in a rat that results in permanently reduced motoneuron numbers and function. This model could serve as a platform for the study of therapeutics, such as a reverse end-to-side nerve transfer (i.e., supercharge). The authors hypothesized that transection of one or more of the L4 to L6 nerve roots supplying the sciatic nerve would cause a permanent reduction in muscle force. METHODS: Rats were randomized into five groups that underwent variations of nerve root transections or sham injury. The L4 to L6 nerve roots were selectively transected and capped to prevent regeneration. Tibial and common peroneal nerves were harvested for quantitative histology and retrograde-labeled to assess the number of motoneurons projecting axons. Muscle force and relative muscle mass were assessed as metrics of postinjury motor function. RESULTS: At 6 months, the number of motoneurons projecting axons and myelinated axon counts were reduced in both the tibial and common peroneal nerves after injury in all groups. Transecting both L4 and L5 or both L4 and L6 reduced motoneuron numbers sufficiently below sham numbers to reduce muscle force and mass in major muscles of the hindlimb innervated by both nerves. Transecting L4 reduced muscle force and mass in common peroneal-innervated muscles, whereas transecting L5 reduced muscle force and mass in tibial-innervated muscles. These findings were stable over time. CONCLUSION: Transection of nerve roots produces stable (time independent) partial nerve injury models with a selective decrease in motor function. PMID- 28027235 TI - Establishment of an Acquired Lymphedema Model in the Mouse Hindlimb: Technical Refinement and Molecular Characteristics. AB - BACKGROUND: The pathophysiology of secondary lymphedema remains poorly understood. This study aimed to establish a consistent mouse hindlimb lymphedema model for further investigation of the mechanism and treatment of lymphedema. METHODS: The authors developed a novel postsurgical lymphedema model in the mouse hindlimb by modifying previously described methods. Lymphedema in the hindlimb was created by removing both the inguinal and popliteal lymph nodes together with the surrounding fat pads, followed by silicone splint placement in the inguinal region. Using this modified mouse model, the authors analyzed lymphatic function, histologic changes, and the expression of lymphangiogenic factors including vascular endothelial growth factor C at various time points. RESULTS: The splinted lymphedema model showed a significant increase of edema formation in the hindlimb compared with the sham surgery control animals. Indocyanine green lymphography revealed lymphatic drainage impairment shown by dermal backflow and rerouting of lymph flow in the lymphedema model. Histopathologic and immunohistochemical examinations showed a significant increase of skin thickness and abnormally dilated lymphatics in the lymphedema model. The expression of lymphangiogenic factors in lymphedematous tissues of the splinted lymphedema model was significantly increased compared with controls, depending on the degree of lymphedema. CONCLUSIONS: This splinted lymphedema model closely simulates the volume response, histopathology, and lymphography characteristics of human acquired lymphedema. Given these similarities to human lymphedema, this refinement of a mouse hindlimb model of acquired lymphedema represents a promising platform for the study of lymphatic vascular insufficiency and for the evaluation of new therapeutic modalities. PMID- 28027236 TI - Complementary Effects of Negative-Pressure Wound Therapy and Pulsed Radiofrequency Energy on Cutaneous Wound Healing in Diabetic Mice. AB - BACKGROUND: Negative-pressure wound therapy and pulsed radiofrequency energy are two clinical modalities used to treat soft-tissue wounds. They are purported to affect healing differently. The aim of this experimental study was to contrast the two modalities at a mechanistic level and to investigate whether their combined therapy could achieve additive and complementary effects on wound healing. METHODS: Full-thickness dorsal cutaneous wounds of diabetic, db/db, mice were treated with either negative-pressure wound therapy, pulsed radiofrequency energy, or combined therapies. Macroscopic healing kinetics were examined. Epidermal regeneration (proliferation rate and length of reepithelialization) and neovascularization (blood vessel density) were investigated. Messenger RNA levels indicative of angiogenic (basic fibroblast growth factor), profibrotic (transforming growth factor-beta), epidermal proliferative (keratinocyte growth factor), and extracellular matrix remodeling (collagen 1) processes were measured in wound tissues. RESULTS: All three treatment groups displayed faster wound healing. The negative-pressure wound therapy/pulsed radiofrequency energy combined therapy led to significantly faster healing than either the negative pressure wound therapy or pulsed radiofrequency energy therapy alone. Epidermal regeneration and neovascularization were enhanced in all three groups. The two negative-pressure wound therapy groups (alone and combined with pulsed radiofrequency energy) demonstrated more significant increases in expression of all assayed growth factors than the pulsed radiofrequency energy group. Furthermore, the combined therapy exhibited a more profound elevation in collagen 1 expression than either of the two therapies alone. CONCLUSION: Combining the negative-pressure wound therapy and pulsed radiofrequency energy modalities can achieve additive benefits in cutaneous healing, and the two therapies can be easily used together to complement each other in clinical wound treatments. PMID- 28027237 TI - Experimental Rat Skin Flap Model That Distinguishes between Venous Congestion and Arterial Ischemia: The Reverse U-Shaped Bipedicled Superficial Inferior Epigastric Artery and Venous System Flap. AB - BACKGROUND: The commonly used flap models have drawbacks that limit their usefulness. In the random skin flap model, flap necrosis is caused by both arterial and venous insufficiency. In the axial skin flap model, flap viability is easily affected by the pedicle blood flow and can result in complete necrosis. This study aimed to establish a new rat skin flap model that has a consistent flap survival rate and in which venous congestion and arterial ischemia can be readily distinguished macroscopically. METHODS: Rats underwent reverse U-shaped bipedicled superficial epigastric artery flap elevation. The right superficial epigastric vessels formed the pedicle. In the control rats (n = 3), the left superficial epigastric vessels were left intact. In the ischemia group (n = 10), the left superficial epigastric artery was ligated. In the congestion group (n = 10), the left superficial epigastric vein was ligated. The flap was returned to the original site and sutured. The surrounding neovascularization was blocked by polyurethane film. Flap survival rates were evaluated on postoperative day 3. RESULTS: The flaps in the ischemia and congestion groups were noticeably pale and violet, respectively. Flap necrosis was noted in the contralateral distal zone only. It started on postoperative day 2 in the ischemia and congestion groups. The mean flap survival rates of the control, ischemia, and congestion groups were 100 percent, 61.8 percent (range, 56.9 to 67.1 percent), and 42.3 percent (35.7 to 48.7 percent), respectively (all p < 0.001). CONCLUSIONS: The flap facilitated discrimination of the effects of ischemia and congestion. This new rat skin flap model is simple and easy to construct, and has a consistent flap survival rate. PMID- 28027238 TI - Free Functioning Gracilis Muscle Transfer for Elbow Flexion Reconstruction after Traumatic Adult Brachial Pan-Plexus Injury: Where Is the Optimal Distal Tendon Attachment for Elbow Flexion? AB - BACKGROUND: Reconstruction after pan-plexus root avulsions often includes gracilis free functioning muscle transfer. For elbow flexion reconstruction, the free functioning muscle transfer distal tendon is inserted into the biceps tendon or more distally (i.e., flexor digitorum profundus/flexor pollicis longus tendons) for combined elbow and finger flexion; the theoretical drawback of the latter approach is weaker elbow flexion. The authors compared elbow flexion strength with a biceps tendon versus a flexor digitorum profundus/flexor pollicis longus tendon attachment to determine which insertion point resulted in better elbow flexion. METHODS: Thirty-nine patients underwent free functioning muscle transfer with either a biceps tendon or a distal attachment. Groups were compared on postoperative elbow flexion strength, preoperative and postoperative Disabilities of the Arm, Shoulder, and Hand questionnaire scores, range of motion, and other surgical and demographic characteristics. A biomechanical analysis simulating different tendon attachments determined which reconstruction resulted in optimal elbow flexion mechanics. RESULTS: Distal tendon attachment was associated with M3 or M4 elbow flexion and greater range of motion compared with the biceps tendon attachment (p < 0.05). There were no statistically significant improvements in Disabilities of the Arm, Shoulder, and Hand questionnaire scores. Biomechanical analysis demonstrated that all distal tendon attachments studied generated a 15 to 30 percent greater torque compared with the biceps tendon attachment; this was true for attachments either at the flexor digitorum profundus/flexor pollicis longus tendon, or directly at the radius at 10 cm or 15 cm from the elbow axis of rotation. CONCLUSIONS: The flexor digitorum profundus/flexor pollicis longus tendon attachment of the gracilis free functioning muscle transfer distal tendon was superior in achieving elbow flexion strength. Patients with only elbow flexion reconstruction may also benefit from a flexor digitorum profundus/flexor pollicis longus tendon attachment or from a more distal attachment to the radius. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027239 TI - Skoog Primary Periosteoplasty versus Secondary Alveolar Bone Grafting in Unilateral Cleft Lip and Alveolus: Long-Term Effects on Alveolar Bone Formation and Maxillary Growth. AB - BACKGROUND: Clefts involving the alveolus are treated using one of two strategies: primary periosteoplasty at the time of lip repair or secondary alveolar bone grafting at mixed dentition. Most teams favor secondary alveolar bone grafting because of its high success rate, and concerns have been raised that primary periosteoplasty may interfere with maxillary growth. However, primary periosteoplasty may obviate the need for future bone grafting and is still practiced in some centers. Few studies compare the long-term outcomes of these two strategies. METHODS: Fifty-seven consecutive patients born with unilateral cleft lip and alveolus were studied retrospectively. All patients underwent primary lip repair using Skoog's method; 28 patients underwent primary periosteoplasty at the time of lip repair and the remaining 29 underwent secondary alveolar bone grafting at mixed dentition. Occlusal radiographs obtained at ages 10 and 16 years were analyzed for alveolar bone height. Cephalometric analysis assessed growth at ages 5, 10, and 18 years. RESULTS: Seventeen of 28 patients treated using primary periosteoplasty required later secondary bone grafting, and the bone height at age 16 years was lower in the primary periosteoplasty group (p < 0.0001). There was a more pronounced decrease in maxillary protrusion from ages 5 to 10 years in the primary periosteoplasty group (p < 0.03). However, at age 18 there was no significant difference in maxillary growth between the two groups. CONCLUSION: Primary periosteoplasty did not seem to inhibit long-term maxillary growth but was ineffective as a method of reconstructing the alveolar cleft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027240 TI - Gastrostomy Placement Rates in Infants with Pierre Robin Sequence: A Comparison of Tongue-Lip Adhesion and Mandibular Distraction Osteogenesis. AB - BACKGROUND: This study was conducted to compare the gastrostomy rates in infants with Pierre Robin sequence treated with tongue-lip adhesion or mandibular distraction osteogenesis. METHODS: This was a retrospective study of symptomatic plastic and reconstructive surgery patients treated over an 8-year period. The primary predictor variable was surgical intervention (tongue-lip adhesion or distraction osteogenesis). Secondary predictor variables were categorized as demographic and clinical factors. The primary outcome was the need for gastrostomy tube placement. Secondary outcomes were complication rates, costs, and length of stay. RESULTS: Thirty-one tongue-lip adhesion and 30 distraction osteogenesis patients were included in the study. The groups were statistically comparable with regard to demographic and clinical factors (p > 0.18). Gastrostomy rates were higher in patients who underwent tongue-lip adhesion (48 percent) versus those who underwent distraction osteogenesis (16.7 percent; p = 0.008). In an adjusted model, subjects undergoing tongue-lip adhesion were more likely to require gastrostomy tube for nutritional support (OR, 6.5; 95 percent CI, 1.7 to 25.2; p = 0.007). There were two major complications in the tongue-lip adhesion group and none in the distraction osteogenesis group. There were three minor complications in the tongue-lip adhesion group and five in the distraction osteogenesis group. Total operating room costs were higher for distraction osteogenesis (p = 0.05), and total hospital costs and length of stay were higher for tongue-lip adhesion (p < 0.05). CONCLUSIONS: Among infants with symptomatic Pierre Robin sequence, treatment by distraction osteogenesis is associated with a lower risk for gastrostomy placement for nutritional support. Hospital costs are higher for tongue-lip adhesion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28027241 TI - Evaluation and Implementation of a High-Fidelity Cleft Palate Simulator. AB - BACKGROUND: Cleft palate repair is a challenging procedure to learn because of the delicate tissue handling required and the small confines of the infant oral cavity. As a result, cleft palate simulators have previously been described to augment cleft palate repair training. Although valuable, they lack the fidelity for this complex procedure. METHODS: A high-fidelity cleft palate simulator was evaluated by staff and fellows in pediatric plastic surgery who provided feedback on its realism, anatomical accuracy, and effectiveness as a training tool. The simulator was implemented within a training workshop following a didactic session on cleft palate repair and anatomy. A test was administered to each participant before and immediately after the workshop to assess knowledge transfer. Perceived confidence of performing a repair following the workshop was also assessed, as was the workshop's effectiveness. RESULTS: Overall, participants agreed that the simulator is anatomically accurate and realistic and strongly agreed that the simulator is a valuable training tool. The average test score increased from 25 percent before the workshop to 77.27 percent after the workshop. Overall, participants of the workshop felt more confident performing a repair and strongly agreed that the workshop was valuable and effective. CONCLUSIONS: A high-fidelity cleft palate simulator has been evaluated as realistic, anatomically accurate, and valuable as a training tool. The simulator was successfully integrated into a training workshop, which resulted in significant knowledge increase on anatomy and the procedure and perceived confidence and comfort in performing a cleft palate repair. PMID- 28027242 TI - Very Low Prevalence of Intracranial Hypertension in Trigonocephaly. AB - BACKGROUND: Trigonocephaly is caused by metopic suture synostosis. It is treated by fronto-orbital remodeling, not only to correct the deformity but also to prevent intracranial hypertension, the reported prevalence in trigonocephaly of which ranges from 0 to 33 percent. To support treatment analysis and the design of a treatment protocol for intracranial hypertension in these patients, the authors wished to more accurately quantify the prevalence of preoperative and postoperative intracranial hypertension in a large patient cohort. METHODS: The authors included all trigonocephaly patients born between 2001 and 2013 who had all been operated on at a single center. During follow-up, the presence of intracranial hypertension was evaluated by funduscopy, and occipitofrontal head circumference was measured. The occipitofrontal head circumference curve was analyzed and its relation to intracranial hypertension assessed. RESULTS: In total, 262 patients with trigonocephaly were included. Before surgery, 1.9 percent of them had intracranial hypertension; after surgery, 1.5 percent did (mean age at last follow-up, 4.9 years). Sixteen of 176 patients (9 percent) had occipitofrontal head circumference curve stagnation, which was significantly related to intracranial hypertension (p = 0.001, Fisher's exact test). CONCLUSIONS: Intracranial hypertension occurs only sporadically in patients with metopic suture synostosis. Occipitofrontal head circumference measurement should take a prominent place in the postoperative follow-up of metopic suture synostosis patients; stagnation of the occipitofrontal head circumference requires additional screening for intracranial hypertension. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027243 TI - Correction of Sagittal Craniosynostosis Using Distraction Osteogenesis Based on Strategic Categorization. AB - BACKGROUND: Distraction osteogenesis has been used to correct sagittal craniosynostosis in various ways. The purpose of this study was to introduce three distraction osteogenesis procedures by describing four objective measurements. METHODS: Fifty-four patients with sagittal synostosis were recruited and assigned to one of three therapeutic groups: group 1, anteroposterior compression with bitemporal expansion (n = 35); group 2, bitemporal expansion (n = 9); and group 3, anteroposterior expansion with bitemporal expansion (n = 10). Distraction procedures were performed while maintaining dural attachment. Four indices-namely cranial index, head circumference, intracranial volume, and neurodevelopmental index (using the Bayley Scales of Infant Development II), were analyzed. RESULTS: The preoperative cranial index of group 1 (68.51 +/- 4.73) differed significantly from those of groups 2 (76.75 +/- 2.4; p < 0.05) and 3 (86.8 +/- 3.99; p < 0.05). Postoperative cranial index in all groups converged to the mesocephalic cranial index. Preoperative intracranial volume determinations were within the normal range for the majority of participants in groups 1 and 2; however, most fell below -1 SD in group 3 [n = 8 (80 percent)]. Postoperatively, 90 percent of group 3 participants had intracranial volume values within the normal range. The preoperative mental and psychomotor developmental indices of group 3 were significantly lower than those in the other two groups. The postoperative analysis showed significant improvement in these indices in groups 1 and 3 or when all patients were analyzed. CONCLUSION: Symmetric sagittal synostosis can be effectively treated with distraction osteogenesis reformation guided by strategic categorization. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027244 TI - Definitive Management of Persistent Frontal Sinus Infections and Mucocele with a Vascularized Free Fibula Flap. AB - Chronic frontal sinus infections in the setting of previous trauma or tumor removal are challenging clinical scenarios. To remove and debride all chronically infected tissue, obliterate dead space, and provide a stable reconstructive yet aesthetic contour are critical tasks in managing these patients. The vascularized free fibula is an ideal flap for this situation; in this article, the authors detail their technique in a patient with chronic frontal sinus infections complicated by mucocele formation. PMID- 28027245 TI - Intranasal Pathology in the Migraine Surgery Population: Incidence, Patterns, and Predictors of Surgical Success. AB - BACKGROUND: The purpose of this study was to identify patterns of nasal pathology in patients with rhinogenic migraine headaches (site III). METHODS: A retrospective review was performed on patients with rhinogenic migraine headaches. Demographics, pre- and post-migraine surgery symptoms, and pathology seen on preoperative computed tomographic scans were reviewed. RESULTS: Twenty percent of 98 patients had preoperative sinus disease. The following abnormalities were seen on computed tomographic scan: septal deviation, 75 (77 percent); septal spur, 33 (34 percent); middle concha bullosa, 48 (49 percent); sinus pathology, 20 (20 percent); and intranasal contact points, 62 (62 percent). A higher incidence of clinical sinusitis (20 percent migraine versus 5 to 15 percent in the general population) was also seen. Septoplasty was performed in 89 percent of patients, and conservative turbinectomy was performed in 60 percent of patients. Patients who failed surgery (<50 percent reduction in migraine headache index) had a significantly higher incidence of contact points (80 percent versus 56 percent; p = 0.034) than successful migraine patients. The surgery success group also had a higher incidence of preoperative middle concha bullosa compared with the failure group (71 percent versus 48 percent; p = 0.035). CONCLUSIONS: This is the first cohort study to identify the incidence and pattern of nasal pathology in migraine III patients. It is likely that the failure to achieve more successful outcomes in this patient population was the consequence of conservative nasal management and residual contact points because of concern for the development of nasal dryness. More frequent middle turbinate surgery may result in better clinical outcomes in this group of patients. PMID- 28027246 TI - Discussion: Intranasal Pathology in the Migraine Surgery Population: Incidence, Patterns, and Predictors of Surgical Success. PMID- 28027248 TI - Quality of Life after Face Transplantation: Outcomes, Assessment Tools, and Future Directions. AB - BACKGROUND: Face transplantation has emerged as a clinical reality for the restoration of complex facial defects. Critical to the advancement of the burgeoning field of reconstructive transplantation is the quality of the methods used to measure and report the impact of face transplantation on quality of life. METHODS: A systematic search using PubMed and EMBASE was conducted for all studies matching the a priori inclusion criteria from 2005 through 2015. Bibliographies of included studies were also reviewed. Two authors (M.A.A and H.K) independently performed screening of titles. RESULTS: The authors identified 17 articles reporting on quality-of-life outcomes among 14 face transplant recipients. Combinations of objective and subjective measures were used to assess quality of life. Instruments used to assess quality of life after face transplantation included over 25 different instruments. Four centers, comprising eight patients, have reported using prospective, systematic data with validated instruments. Overall, there is reported improvement in quality of life after face transplantation. Heterogeneity and a paucity of data between articles preclude a quantitative analysis. CONCLUSIONS: Anecdotal and subjective reports of improvements in quality of life after face transplantation constitute the majority of reported outcomes in the English peer-reviewed literature. Improved efforts in methods and standardization of collection and reporting of quality-of life data after face transplantation are needed to better appreciate the impact of face transplantation on quality of life and justify lifelong immunosuppression and its attendant risks and morbidity. PMID- 28027247 TI - Optimizing Outcomes in Pharyngoesophageal Reconstruction and Neck Resurfacing: 10 Year Experience of 294 Cases. AB - BACKGROUND: Pharyngoesophageal reconstruction is a complex endeavor that poses many challenges. This 10-year series examines factors impacting the need for neck skin resurfacing and evaluates the impact of reconstructive modalities on outcomes. METHODS: A review identified 294 patients who underwent pharyngoesophageal reconstruction from 2002 to 2012. Patients were divided based on neck skin resurfacing requirements. Patients undergoing neck resurfacing were further subdivided into reconstructive technique, including a second skin paddle or muscle component from the same free flap pedicle, a local flap, or a second free flap. All groups were compared by comorbidities, complications, and functional outcomes. RESULTS: Of 294 patients, 179 (60.9 percent) required neck skin resurfacing. In the resurfaced group, there were 90 circumferential defects (50.3 percent) and 89 partial defects (49.7 percent). In the resurfaced group, 110 (61.4 percent) underwent reconstruction with a second skin paddle from the same free flap pedicle, 21 (11.7 percent) underwent reconstruction with a muscle component from the same pedicle, and 25 (13.9 percent) received a pectoralis major flap. There were five external paddle flap losses in the resurfaced group (2.8 percent) and no internal flap losses. Overall complications were similar among groups. The resurfaced group had a lower pharyngocutaneous fistula rate (4.5 percent) compared with the primary closure group (11.3 percent) (p = 0.026). Prior neck surgery and radiation therapy were strong predictors of neck skin resurfacing (p < 0.001). CONCLUSIONS: Neck resurfacing is often required in salvage pharyngoesophageal reconstruction. Providing additional vascularized tissue over the neoconduit is predictive of lower pharyngocutaneous fistula rates. An algorithmic approach to neck resurfacing is presented. PMID- 28027249 TI - Neurectomy for the Treatment of Chronic Postoperative Pain after Surgery of the Trunk. AB - BACKGROUND: Incidence of chronic postoperative neurogenic pain after open and laparoscopic trunk operations is reported between 1 and 20 percent, rendering a large population in the United States and worldwide. One possible treatment is selective surgical neurectomy. METHODS: All patients who underwent neurectomy for chronic trunk or groin postoperative neurogenic pain were identified. Based on individual history and examination, patients underwent neurectomies of the ilioinguinal, iliohypogastric, genitofemoral, lateral-femoral cutaneous, or intercostal nerves. Recorded preoperative pain levels (Likert score ranging from 0 to 10) were compared to postoperative pain levels and quality-of-life indices were assessed. RESULTS: Fifty-six patients (32 men and 24 women) were included. Mean age was 49 years. All patients underwent preoperative nerve blocks by either surgeon, radiologist, or referring physician, and had either complete or significant response defined as over 50 percent relief. Forty-five patients completed the survey. Median follow-up was 2.8 years (range, 1.0 to 5.7 years). Average pain level was 9.0 preoperatively and 3.5 postoperatively. Quality-of life impairment improved from 8.3 preoperatively to 3.5 postoperatively. A subset of patients (n = 12) had minimal improvement, reporting a decrease in pain from 8.5 to 7.2 and quality-of-life improvement from 8.5 to 7.1. CONCLUSIONS: Complete avoidance of nerve injury during all trunk and groin operations is likely unattainable. When chronic postoperative neurogenic pain develops, neurectomy can be an effective means of treatment, significantly improving pain and quality of life in most patients. Better insight is necessary into a patient subset responding to nerve blocks yet experiencing minimal postoperative improvement. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28027250 TI - Important Developments in Burn Care. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Explain the epidemiology of severe burn injury in the context of socioeconomic status, gender, age, and burn cause. 2. Describe challenges with burn depth evaluation and novel methods of adjunctive assessment. 3. Summarize the survival and functional outcomes of severe burn injury. 4. State strategies of fluid resuscitation, endpoints to guide fluid titration, and sequelae of overresuscitation. 5. Recognize preventative measures of sepsis. 6. Explain intraoperative strategies to improve patient outcomes, including hemostasis, restrictive transfusion, temperature regulation, skin substitutes, and Meek skin grafting. 7. Translate updates in the pathophysiology of hypertrophic scarring into novel methods of clinical management. 8. Discuss the potential role of free tissue transfer in primary and secondary burn reconstruction. SUMMARY: Management of burn-injured patients is a challenging and unique field for plastic surgeons. Significant advances over the past decade have occurred in resuscitation, burn wound management, sepsis, and reconstruction that have improved outcomes and quality of life after thermal injury. However, as patients with larger burns are resuscitated, an increased risk of nosocomial infections, sepsis, compartment syndromes, and venous thromboembolic phenomena have required adjustments in care to maintain quality of life after injury. This article outlines a number of recent developments in burn care that illustrate the evolution of the field to assist plastic surgeons involved in burn care. PMID- 28027251 TI - Evidence-Based Medicine: A Graded Approach to Lower Lid Blepharoplasty. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Define the anatomy of the lower eyelid tarsoligamentous framework and the related periorbital retaining ligaments, and cite their surgical relevance. 2. Perform a systematic functional and aesthetic evaluation of the lower eyelid focusing on the lid-cheek junction, and clinical tests that predict the need for lateral canthal tightening. 3. Enumerate the different approaches to lower eyelid rejuvenation and discuss their merits/limitations. 4. Describe surgical strategies to blend the lid-cheek junction and tighten the lateral canthal retinaculum. SUMMARY: Modern lower lid blepharoplasty requires a thorough understanding of periorbital anatomy, age-related changes of the lid-cheek junction, and the variables controlling lower lid tone and position. The surgical strategies are best used in a graded fashion. The patient with isolated lower lid bags may be treated by transconjunctival fat resection alone. Additional mild skin laxity can be improved with skin pinch or skin-only undermining. Skin resurfacing using chemical peeling or laser can further address fine lines. In these patients with an abnormality of the lid-cheek junction, release of the medial orbicularis oculi muscle and variable amounts of the orbicularis retaining ligament is essential. This is combined with orbital fat resection or repositioning through a transconjunctival or transcutaneous skin-muscle flap. The transcutaneous approach most often necessitates lateral canthal tightening to optimize lid margin control. Generally, the degree of laxity dictates whether a canthopexy or a canthoplasty is most appropriate. Lateral canthal procedures can be applied to patients displaying clinical signs predictive of lid malposition and to those presenting with varying degrees of established lid descent. PMID- 28027252 TI - Evidence-Based Medicine: Face Lift. AB - LEARNING OBJECTIVES: After studying this article, the participants should be able to: 1. Describe pertinent surgical anatomy relevant to safe and effective face lifting techniques. 2. Identify key aspects of facial aging. 3. Incorporate risk reduction strategies during preoperative assessment. 4. Tailor their approach to face lifting based on patient anatomy. 5. Identify and treat complications after face-lift surgery. 6. Incorporate use of valid patient outcomes assessment tools in their practice to facilitate standardized outcomes reporting in the face-lift literature. SUMMARY: Treating the aged face requires an understanding of bone and soft-tissue anatomy, including the analogous lamellar layers of the face and neck, and the techniques designed to restore youthful skin tone and facial contours. Although volume restoration with fillers is effective for restoring youthful facial contours, the power of face lifting is unmatched in its ability to rejuvenate a sagging facial shape. Standard face-lifting techniques are described, along with the authors' preferred approach, supplemented by video demonstration of the high-superficial musculoaponeurotic system technique. Complications, along with their prevention and treatment, are reviewed. Currently available comparative studies of face-lifting outcomes consider surgeon opinion and postoperative complications rates. A valid, standardized, patient-reported outcome tool, the FACE-Q, has been available since 2010, and should be a component of any comparative discussion of face-lifting techniques in the future. PMID- 28027253 TI - Evidence-Based Medicine: Evaluation and Treatment of Zygoma Fractures. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Diagnose zygomaticomaxillary complex fractures from physical examination and radiographic findings. 2. Plan the necessary surgical approaches for operative treatment of zygomaticomaxillary complex fractures depending on severity. 3. Understand the three-dimensional anatomy of the orbit and zygomaticomaxillary complex and the importance of the zygomaticosphenoid suture along the lateral orbital sidewall. 4. Be aware of pitfalls and associated fractures that can complicate anatomical reduction of zygomaticomaxillary complex fractures. SUMMARY: Fractures of the zygoma are some of the most commonly treated facial fractures, yet reconstruction of the three-dimensional structure of the zygomaticomaxillary complex can be challenging, and malunions are common. This article presents an evidence-based, systemic approach to the assessment and treatment of zygoma fractures from the simple to the complex. Anatomy, approaches, techniques, and pitfalls are described in an effort to improve the treatment of these common facial fractures. PMID- 28027254 TI - Evidence-Based Medicine: Cutaneous Facial Malignancies: Nonmelanoma Skin Cancer. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Identify clinical features of nonmelanoma skin cancer; 2. Distinguish low risk versus high-risk basal cell carcinoma and squamous cell carcinoma; 3. Define appropriate management based on current guidelines for various types of basal cell and squamous cell carcinoma. SUMMARY: Skin malignancies are the most prevalent cancers, and plastic surgeons are often the primary physicians engaged in diagnosis and management of these lesions. Proper management includes distinguishing between high-risk and low-risk lesions and determining treatment accordingly. The aim of this Continuing Medical Education article is to review the diagnosis and management of common and uncommon facial skin malignancies, including basal cell carcinoma, squamous cell carcinoma, actinic keratosis, keratoacanthoma, Merkel cell carcinoma, atypical fibroxanthoma, sebaceous carcinoma, and microcystic adnexal carcinoma. PMID- 28027255 TI - Evidence-Based Medicine: Cleft Palate. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the incidence of cleft palate and risk factors associated with development of an orofacial cleft. 2. Understand differences among several techniques to repair clefts of both the hard and soft palates. 3. Discuss risk factors for development of postoperative fistulas, velopharyngeal insufficiency, and facial growth problems. 4. Establish a treatment plan for individualized care of a cleft palate patient. SUMMARY: Orofacial clefts are the most common congenital malformations of the head and neck region, and approximately three quarters of these patients have some form of cleft palate deformity. Cleft palate repair is generally performed in children between 6 and 12 months of age. The goals of palate repair are to minimize the occurrence of fistulas, establish a normal velopharyngeal mechanism, and optimize facial growth. This Maintenance of Certification review discusses the incidence and epidemiology associated with cleft palate deformity and specifics associated with patient care, including analgesia, surgical repair techniques, and complications associated with repair of the cleft palate. PMID- 28027256 TI - Evidence-Based Medicine: Autologous Breast Reconstruction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Gain an understanding of the different methods of autologous reconstruction available. 2. Understand the timing of autologous breast reconstruction and the impact of adjuvant and neoadjuvant treatments. 3 Understand the factors necessary for a comprehensive patient assessment. 4. Gain knowledge of patient factors that will affect autologous reconstruction and potential contraindications. 5. Summarize the patient-reported and clinical outcomes of autologous breast reconstruction. SUMMARY: This article was prepared to accompany practice-based assessment with ongoing surgical education for the Maintenance of Certification for the American Board of Plastic Surgery. It is structured to outline the care of the patient with the postmastectomy breast deformity. PMID- 28027257 TI - Evidence-Based Medicine: Reduction Mammaplasty. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the multiple reduction mammaplasty techniques available for patients and describe the advantages and disadvantages associated with each. 2. Describe the indications for the treatment of macromastia in patients younger than 18 years. 3. Identify the preoperative indications for breast imaging before surgery. 4. Describe the benefits of breast infiltration with local anesthesia with epinephrine before surgery. 5. Understand the use of deep venous thrombosis prophylaxis in breast reduction surgery. 6. Describe when the use of drains is indicated after breast reduction surgery. SUMMARY: The goal of this Continuing Medical Education module is to summarize key evidence-based data available to plastic surgeons to improve their care of patients with breast hypertrophy. The authors' goal is to present the current controversies regarding their treatment and provide a discussion of the various options in their care. The article was prepared to accompany practice-based assessment with ongoing surgical education for the Maintenance of Certification Program of the American Board of Plastic Surgery. PMID- 28027258 TI - Evidence-Based Medicine: Options for Dupuytren's Contracture: Incise, Excise, and Dissolve. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand updates in the basic science, epidemiology, and treatment of Dupuytren's disease. 2. Understand treatment with needle aponeurotomy, collagenase, and fasciectomy. 3. Understand advanced needle techniques for Dupuytren's contracture. 4. Understand the safety and effectiveness of a new treatment, collagenase. SUMMARY: The literature on Dupuytren's disease encompasses many specialties. Its treatment is generally by perforating, excising, or dissolving the affected tissues. This article reviews the changing understanding of this disease and treatment options. PMID- 28027259 TI - Evidence-Based Medicine: Thumb Basal Joint Arthritis. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Assess the patient's history, clinical examination, and radiographic findings to diagnose and stage basilar joint arthritis. 2. Recall the cause and epidemiology of the condition. 3. Formulate a management plan including nonoperative management, and evaluate the candidacy for surgical treatment. 4. Understand the rationale for the various surgical options available (including rehabilitation), their potential complications, and the evidence related to outcomes. SUMMARY: This article has been prepared to accompany practice-based assessment with ongoing surgical education for the Maintenance of Certification for the American Board of Plastic Surgery. It is designed for clinicians to analyze and structure their care of a patient with arthritis of the trapeziometacarpal joint. PMID- 28027260 TI - Evidence-Based Medicine: Liposuction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Review the appropriate indications and techniques for suction-assisted lipectomy body contouring surgery. 2. Accurately calculate the patient limits of lidocaine for safe dosing during the tumescent infiltration phase of liposuction. 3. Determine preoperatively possible "red flags" or symptoms and signs in the patient history and physical examination that may indicate a heightened risk profile for a liposuction procedure. 4. Provide an introduction to adjunctive techniques to liposuction such as energy-assisted liposuction and to determine whether or not the reader may decide to add them to his or her practice. SUMMARY: With increased focus on one's aesthetic appearance, liposuction has become the most popular cosmetic procedure in the world since its introduction in the 1980s. As it has become more refined with experience, safety, patient selection, preoperative assessment, fluid management, proper technique, and overall care of the patient have been emphasized and improved. For the present article, a systematic review of the relevant literature regarding patient workup, tumescent fluid techniques, medication overview, and operative technique was conducted with a practical approach that the reader will possibly find clinically applicable. Recent trends regarding energy-assisted liposuction and body contouring local anesthesia use are addressed. Deep venous thromboembolism prophylaxis is mentioned, as are other common and less common possible complications. The article provides a literature-supported overview on liposuction techniques with an emphasis on preoperative assessment, medicines used, operative technique, and outcomes. PMID- 28027261 TI - Evidence-Based Medicine: The Evaluation and Treatment of Pressure Injuries. AB - LEARNING OBJECTIVE: After studying this article, the participant should be able to: 1. Discuss the approach to and rationale for pressure injury management, including specific techniques for prevention and preoperative evaluation. 2. Develop a management algorithm for these wounds that includes operative and nonoperative modalities. 3. Understand how to identify and manage the complications of surgical intervention for pressure injuries, including recurrence. SUMMARY: Pressure injuries are a common problem associated with great morbidity and cost, often presenting as complex challenges for plastic surgeons. Although the cause of these wounds is largely prolonged pressure, the true pathogenesis involves many other factors, including friction, shear, moisture, nutrition, and infection. This article outlines a systematic approach to evaluating and staging pressure injuries, and provides strategies for treatment and prevention. Critical to surgical intervention is thorough debridement, including any involved or causative bony tissues, and postoperative management to prevent wound dehiscence and recurrence. PMID- 28027262 TI - Evidence-Based Medicine: Management of Acute Lower Extremity Trauma. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Select and design flaps for the acutely injured lower limb based on wound location, size, and complexity. 2. Select and design tissue-specific flaps based on the functional demand of the zone of injury. 3. Understand the indications for using a flap with a skin component versus a muscle-only flap. 4. Understand the preoperative vascular assessment for lower extremity flap reconstruction. 5. Recognize and manage risk factors to decrease complications and improve flap survival. SUMMARY: The Maintenance of Certification series is designed to help the experienced surgeon structure the study of specific areas appropriate to his or her clinical practice. This article is designed to accompany practice-based evaluation of preoperative assessment, surgical treatment plan, and outcomes. In this format, he or she is invited to compare his or her methods with authoritative, information-based references. This information base is then used for self-assessment and benchmarking in Parts II and IV of the Maintenance of Certification process used by the American Board of Plastic Surgery. This article is not meant to be an exhaustive treatise on the subject, but rather designed to serve as a reference point for further in-depth study by review of the articles referenced. The goal of this article is to present evidence that may serve as practice-changing information. Furthermore, this article is designed with the recognition that participants may have different backgrounds, experience, expertise, and resources. The breadth of the topics discussed is designed to accommodate these differences. PMID- 28027263 TI - Pregnancy and the Plastic Surgery Resident. AB - BACKGROUND: Combining pregnancy with plastic surgery residency has historically been difficult. Two decades ago, 36 percent of plastic surgery program directors surveyed actively discouraged pregnancy among residents, and 33 percent of women plastic surgeons suffered from infertility. Most alarmingly, 26 percent of plastic surgery trainees had had an elective abortion during residency. With increasing numbers of women training in plastic surgery, this historical lack of support for pregnancy deserves further attention. METHODS: To explore the current accommodations made for the pregnant plastic surgery resident, an electronic survey was sent to 88 plastic surgery program directors in the United States. RESULTS: Fifty-four responded, for a response rate of 61.36 percent. On average, a director trained a total of 7.91 women among 17.28 residents trained over 8.19 years. Of the women residents, 1.43 were pregnant during a director's tenure, with 1.35 of those residents taking maternity leave. An average 1.75 male residents took paternity leave. Approximately one-third of programs had a formal maternity/paternity leave policy (36.54 percent) which, in most cases, was limited to defining allowed weeks of leave, time required to fulfill program requirements, and remuneration during leave. CONCLUSIONS: This survey of plastic surgery directors is a first step in defining the challenges training programs face in supporting the pregnant resident. Directors provided comments describing their challenges accommodating an absent resident in a small program and complying with the American Board of Plastic Surgery's required weeks of training per year. A discussion of these challenges is followed by suggested solutions. PMID- 28027264 TI - Discussion: Pregnancy and the Plastic Surgery Resident. PMID- 28027265 TI - The Importance of Patient Satisfaction: A Blessing, a Curse, or Simply Irrelevant? AB - New regulations require that physician performance must be evaluated and graded in both objective and subjective ways. This represents a novel factor in American health care delivery driven by the reality that the United States spends more than any other nation on health care yet still lags behind in key outcome measures. Patient satisfaction has been established as a core component of physician rankings and reimbursement. In fact, it already has acted as both a powerful motivator and stressor. Patient feedback has driven hospital administrators' agendas to improve facilities and provide relative luxuries to inpatients, and individual providers have been tempted to ignore sound medical judgment by relenting to patient requests to increase their satisfaction scores. Unfortunately, there is little high-level evidence to support that patient satisfaction will improve medical outcomes, and there are plenty of contradictory data in smaller studies. Part of the difficulty of these studies may lie in the diversity of patient expectations, which are dependent on the disease process and the inherently subjective and labile nature of people's responses. Reliable tools are needed that will take into account what constitutes a superior quality of patient care in a more systematic, meaningful, and validated way. PMID- 28027267 TI - Reply: Early versus Delayed Excision and Grafting of Full-Thickness Burns in a Porcine Model: A Randomized Study. PMID- 28027268 TI - Reply: Office-Based Postaxial Polydactyly Excision in Neonates, Infants, and Children. PMID- 28027269 TI - Reply: Which Factors Are Associated with Open Reduction of Adult Mandibular Condylar Injuries? PMID- 28027270 TI - A Novel Approach to Keloid Reconstruction with Bilaminar Dermal Substitute and Epidermal Skin Grafting. PMID- 28027271 TI - Reply: Correction of Pectus Excavatum by Custom-Made Silicone Implants: Contribution of Computer-Aided Design Reconstruction. A 20-Year Experience and 401 Cases. PMID- 28027272 TI - Reply: Applying to Integrated Plastic Surgery Residency Programs: Trends in the Past 5 Years of the Match. PMID- 28027273 TI - Oxygen Tension Beneath Scleral Lenses of Different Clearances. AB - PURPOSE: To evaluate the relative partial pressure in oxygen (pO2) at the corneal surface under Boston XO2 scleral lenses (SL) fitted with targeted clearances of 200 and 400 MUm (SL200 and SL400). METHODS: During this prospective study, the right eyes of eight normal subjects were fitted with SL200 and SL400. Clearance, validated after 5 minutes of wear with an optical coherence tomograph, was used with lens thicknesses to calculate transmissibility and estimate pO2. Corneal pO2s were measured with an oxygen electrode after 5 minutes of (1) corneal exposure to calibrating gases with various pO2 or of (2) SL wear. Decays in pO2 were modeled to an exponential. Linear regression between exponent k of these decays and calibrating gas pO2s allowed for the calculation of corneal pO2 under SL. Differences between pO2s beneath SL200 and SL400 were tested with a mixed ANOVA. RESULTS: The estimated transmissibility based on thicknesses and clearances (239.7 +/- 34.7; 434.5 +/- 33.2 MUm) predicted a corneal pO2 of 8.52 +/- 0.51 and 6.37 +/- 0.28% for SL200 and SL400. These values were close to measured pO2: 9.07 +/- 0.86 and 6.19 +/- 0.87% (mean +/- SEM) (P < .05) for SL200 and SL400, respectively. Both pO2 measurements fall short of the theoretical values needed to prevent hypoxia during lens wear (9.9% and above). CONCLUSIONS: As shown in vivo for the first time, an 18-mm scleral lens fitted with a 400-MUm clearance reduces the oxygen tension available to the cornea by 30% compared to a similar lens fitted with a 200-MUm clearance after 5 minutes of wear. PMID- 28027274 TI - Effect of Accommodation on Peripheral Eye Lengths of Emmetropes and Myopes. AB - PURPOSE: To investigate the effect of accommodation on central and peripheral axial lengths in young adult emmetropes and myopes. METHODS: On-axis and peripheral axial lengths were measured with the Haag-Streit Lenstar in 83 young adult participants for 0D and 6D accommodation demands. A Badal system was used to both correct refractive errors and induce accommodation. Participants were emmetropes (n = 29, mean spherical equivalent refraction +0.35 +/- 0.35D), low myopes (32, -1.38 +/- 0.73D), and higher myopes (22, -4.30 +/- 0.73D). Ages were similar for all groups (22 +/- 2 years). Pupils were dilated with 2.5% phenylephrine to allow a large field of measurement while maintaining active accommodation. Axial lengths were measured in 5 degrees steps to +/-30 degrees across the horizontal visual field. RESULTS: With accommodation, axial length increased for all refractive groups at all positions, but with lessening effect away from fixation. Axial length changes were greater for higher myopes than for emmetropes on-axis (higher myopes 41 +/- 14 MUm, emmetropes 30 +/- 12 MUm, P = .005), for higher myopes than for low myopes at 30 degrees nasal (P = .03), and for the higher myopes than for the other groups at 20 degrees nasal (P < .05). There were significant correlations between myopia and changes in axial length at all positions, with the highest correlation on-axis (R = 0.30, P < .001). CONCLUSIONS: During accommodation, eye length increased out to at least +/-30 degrees visual angle in young adult myopes and emmetropes. The increase was significantly greater for higher myopes than for the other groups at some positions. At all positions, there were significant correlations between myopia and accommodation-induced changes in axial length. PMID- 28027275 TI - Development of a Keratoconus-Specific Questionnaire Using Rasch Analysis. AB - PURPOSE: To develop and validate a keratoconus-specific quality of life (QoL) questionnaire: the Keratoconus Outcomes Research Questionnaire (KORQ). METHODS: The study was carried out in three phases. Phase I: content identifications: items were identified based on an extensive literature review, open-ended patient mail survey, and expert consultations. Each item was scored on a visual analog scale (VAS). Phase II: pilot testing using Rasch analysis. Phase III: testing psychometric properties of the final version of the KORQ. RESULTS: Phase I identified 44 items across 3 different content areas: activity limitation (26), symptoms (20), and convenience (8). The 44-item KORQ was self-administered to 158 people with keratoconus. The 44-item KORQ was multidimensional. Unidimensionality was restored by separating items across three content areas (subscales) as identified in phase I. The activity limitation and symptoms subscales demonstrated adequate measurement precision, but convenience (precision, 1.01) did not. Hence, the convenience subscale was discarded. Rasch analysis revealed that the VAS was disordered. The ordering of the VAS was restored by collapsing categories into 4. An iterative Rasch analysis guided item-removal resulted into a 29-item KORQ (18-item activity limitation and 11-item symptoms). The VAS was replaced by a discrete 4-option labeled categorical rating scale, and it was self administered by 169 people with keratoconus. Both the subscales demonstrated good psychometric properties. The KORQ scores strongly correlated with visual acuity and contrast sensitivity demonstrating its construct validity. CONCLUSIONS: The 29-item KORQ was a psychometrically robust and valid instrument to assess the impact of keratoconus on activity limitation and symptoms. PMID- 28027276 TI - Accommodation and Phoria in Children Wearing Multifocal Contact Lenses. AB - PURPOSE: To determine the effect of multifocal contact lenses on accommodation and phoria in children. METHODS: This was a prospective, non-dispensing, randomized, crossover, single-visit study. Myopic children with normal accommodation and binocularity and no history of myopia control treatment were enrolled and fitted with CooperVision Biofinity single vision (SV) and multifocal (MF, +2.50D center distance add) contact lenses. Accommodative responses (photorefraction) and phorias (modified Thorington) were measured at four distances (>3 m, 100 cm, 40 cm, 25 cm). Secondary measures included high- and low contrast logMAR acuity, accommodative amplitude, and facility. Differences between contact lens designs were analyzed using repeated measures regression and paired t-tests. RESULTS: A total of 16 subjects, aged 10 to 15 years, completed the study. There was a small decrease in high (SV: -0.08, MF: +0.01) and low illumination (SV: -0.03, MF: +0.08) (both P < .01) visual acuity, and contrast sensitivity (SV: 2.0, MF: 1.9 log units, P = .015) with multifocals. Subjects were more exophoric at 40 cm (SV: -0.41, MF: -2.06 Delta) and 25 cm (SV: -0.83, MF: -4.30 Delta) (both P < .01). With multifocals, subjects had decreased accommodative responses at distance (SV: -0.04; MF: -0.37D, P = .02), 100 cm (SV: +0.37; MF: -0.35D, P < .01), 40 cm (SV: +1.82; MF: +0.62D, P < .01), and 25 cm (SV: +3.38; MF: +1.75D, P < .01). There were no significant differences in accommodative amplitude (P = .66) or facility (P = .54). CONCLUSIONS: Children wearing multifocal contact lenses exhibited reduced accommodative responses and more exophoria at increasingly higher accommodative demands than with single vision contact lenses. This suggests that children may be relaxing their accommodation and using the positive addition or increased depth of focus from added spherical aberration of the multifocals. Further studies are needed to evaluate other lens designs, different amounts of positive addition and aberrations, and long-term adaptation to lenses. PMID- 28027278 TI - Group B Streptococcal Colonization Among Pregnant Women in Delhi, India. AB - BACKGROUND: Little is known regarding maternal group B streptococcal (GBS) colonization prevalence and capsular (CPS) serotype distribution among pregnant women in India. The objective of this prospective cohort study was to determine GBS recto-vaginal colonization prevalence in pregnant women at Dr. Ram Manohar Lohia Hospital in Delhi, India. METHODS: Literature review identified reports from India assessing GBS colonization prevalence in pregnant women. Rectal and vaginal swabs were inoculated into Strep B Carrot Broth (Hardy Diagnostics, Santa Maria, CA) and subcultured onto GBS Detect plates (Hardy Diagnostics, Santa Maria, CA). Isolates were serotyped using ImmuLex Strep-B latex kits (Statens Serum Institut, Copenhagen, Denmark). RESULTS: Thirteen studies were identified citing GBS colonization prevalence during pregnancy as 0.47%-16%. Among 300 pregnant women (mean age: 26.9 years; mean gestation: 34 weeks) enrolled (August 2015 to April 2016), GBS colonization prevalence was 15%. Fifteen percent of women had vaginal only, 29% had rectal only and 56% had both sites colonized. CPS types were Ia (13.3%), Ib (4.4%), II (20%), III (22.2%), V (20%) and VII (6.7%); 13.3% were nontypable. Fetal loss in a prior pregnancy at >=20-weeks gestation was more common in colonized than noncolonized women (15.6% vs. 3.5%; P = 0.004). Employing recent census data for the birth cohort and estimating that 1%-2% of neonates born to colonized women develop early-onset disease, at least 39,000 cases of early-onset disease may occur yearly in India. CONCLUSIONS: Using optimal methods, 15% of third trimester pregnant women in India are GBS colonized. A multivalent vaccine containing 6 CPS types (Ia, Ib, II, III, V and VII) would encompass ~87% of GBS carried by pregnant women in India. PMID- 28027279 TI - The Influence of the Route of Antibiotic Administration, Methicillin Susceptibility, Vancomycin Duration and Serum Trough Concentration on Outcomes of Pediatric Staphylococcus aureus Bacteremic Osteoarticular Infection. AB - BACKGROUND: Bacteremia is often one factor used in deciding the need for prolonged intravenous antimicrobial therapy in osteoarticular infections (OAIs). We examined treatment practices and outcomes of Staphylococcus aureus bacteremic osteoarticular infections (BOAIs) evaluated at Texas Children's Hospital. METHODS: Cases of acute hematogenous OAI in children with positive blood cultures for S. aureus at Texas Children's Hospital between 2011 and 2014 were reviewed. Orthopedic complications included chronic osteomyelitis, growth arrest, pathologic fracture, avascular necrosis and chronic dislocation. Acute kidney injury was defined as a doubling of the baseline creatinine. RESULTS: One hundred and ninety-two cases of S. aureus OAI were identified with 102 cases of BOAI included [35 methicillin-resistant S. aureus (MRSA)]. Twenty-five patients were discharged home on oral antibiotics. Patients discharged on oral antibiotics had a shorter duration of fever, had a more rapid decline in C-reactive protein and were less likely to have MRSA. The frequency of orthopedic complications did not increase in patients who received early transition to oral antibiotics. For patients with MRSA bacteremia, the rates of complications between those who received >=7 days versus <7 days of vancomycin did not differ. Vancomycin serum troughs >15 ug/mL were not associated with a decreased duration of fever, bacteremia or hospitalization, need for repeat operation or orthopedic complications but were associated with acute kidney injury. CONCLUSIONS: S. aureus BOAIs are associated with substantial morbidity. Early transition to oral therapy may be a safe option for select patients with S. aureus BOAI, including those due to MRSA. Prolonged courses of vancomycin and vancomycin troughs >15 MUg/mL were not associated with improved outcomes for MRSA OAI. PMID- 28027280 TI - Clinical and Virus Surveillance After the First Wheezing Episode: Special Reference to Rhinovirus A and C Species. AB - BACKGROUND: Susceptibility to rhinovirus (RV)-induced early wheezing episode has been recognized as an important risk factor for asthma, but the data on different RV species are limited. Our aim was to investigate the risk for recurrences in first-time wheezing children with special focus on RV species. METHODS: First time wheezing children (88 inpatients and 23 outpatients) were prospectively followed at 2-week, 2-month and 12-month time-points, and at first recurrence within 12 months. The respiratory virus etiology was analyzed using polymerase chain reaction. RV-positive samples were sequenced. The primary outcomes were time to a new physician-confirmed wheezing episode, time to a new RV-induced wheezing episode and time to the initiation of regular controller medication for asthma symptoms. RESULTS: The median age of the children was 12 months (standard deviation, 6.0), 67% were males and 23% were sensitized. RV dominated in symptomatic and asymptomatic infections. Different RV strains were observed in 97% (67/69) of consecutive samples during follow-up. First-time wheezing children with RV-C and RV-A had an increased risk for a new physician-confirmed wheezing episode and a new RV-associated wheezing episode than non-RV group (all P < 0.05). Also, the risk for the initiation of regular controller medication was increased in RV-A and RV-C groups when compared with non-RV group (both P < 0.05). CONCLUSIONS: RV causes reinfections with different strains in small children after the first wheezing episode. Both RV-A and RV-C affected children have an increased risk for recurrence, especially RV associated, and initiation of regular controller medication than those with other viruses. PMID- 28027282 TI - Role of Rifampin in Reducing Inflammation and Neuronal Damage in Childhood Bacterial Meningitis: A Pilot Randomized Controlled Trial. AB - BACKGROUND: Treatment of acute bacterial meningitis in children with bactericidal antibiotics causes cell wall lysis and a surge in inflammatory cascade, which in turn contributes to neuronal damage and morbidity. Pretreatment with a nonbacteriolytic antibiotic, such as rifampin, has been shown to attenuate the inflammatory response in experimental models of bacterial meningitis. In a pilot study, in children with bacterial meningitis, we have studied markers of inflammatory response and neuronal damage in 2 groups of children with bacterial meningitis; one group received rifampin pretreatment with ceftriaxone and the other group received ceftriaxone alone. PATIENTS AND METHODS: Forty children with bacterial meningitis, who were 3 months to 12 years of age, were randomly assigned to receive either a single dose rifampin (20 mg/kg) 30 minutes before ceftriaxone or ceftriaxone alone was given. The primary outcome variables were cerebrospinal fluid (CSF) concentrations of tumor necrosis factor alpha (TNFalpha), S100B and neuron-specific enolase on day 1 and day 5, and secondary outcome variables were the values of TNFalpha and interleukin 6 in serum on day 1 and day 5; hearing and neurologic sequelae at 3 months after recovery from the illness. RESULTS: Children in rifampin pretreatment group had significantly lower CSF TNFalpha concentrations [median (interquartile range [IQR]): 15.5 (7.2-22.0) vs. 53.0 (9.0-87.5) pg/mL, P = 0.019] and S100B [median (IQR): 145.0 (54.7-450.0) vs. 447.5 (221.0-804.6) pg/mL, P = 0.033] on day 1 and S100B [median (IQR): 109.7 (64.0-287.0) vs. 322 (106.7-578.0) pg/mL, P = 0.048] and neuron-specific enolase [median (IQR): 8.6 (5-14.75) vs. 18.2 (7.0-28.75) ng/mL, P = 0.035] on day 5 when compared with ceftriaxone alone group. The rifampin-treated group also had reduced morbidity and neurologic sequelae; however, these were not statistically significant. CONCLUSIONS: Pretreatment with single dose rifampin 30 minutes before ceftriaxone administration reduced the CSF concentrations of markers of inflammation and neuronal damage in children with bacterial meningitis. PMID- 28027283 TI - Divergent Memory B Cell Responses in a Mixed Infant Pneumococcal Conjugate Vaccine Schedule. AB - BACKGROUND: Vaccine-induced immunity against pneumococcal infection relies on the generation of high concentrations of antibody and B cell memory. Both the 10- and the 13-valent pneumococcal conjugate vaccines (PCV-10 and PCV-13) effectively reduce disease caused by vaccine serotypes. It is unknown whether the generation of B cell memory requires several doses of the same vaccine or whether different PCVs are interchangeable. METHODS: Children in the United Kingdom (n=178) who had previously received PCV-13 at 2 and 4 months were randomized 1:1 to receive a PCV 13 or PCV-10 booster at age 12 months. Peripheral blood memory B cells (BMEM) were quantified before and at 1 and 12 months after vaccination using a cultured enzyme-linked immunospot assay for pneumococcal serotypes 1, 3, 4, 9V, 14, 19A, and diphtheria and tetanus toxoid. Correlations between BMEM frequencies and simultaneously measured antibody (IgG and opsonophagocytic assay) was also assessed. RESULTS: A significant rise in postbooster BMEM frequency was seen for 5 out of 6 serotypes in the PCV-13 group and none in the PCV-10 group. In the PCV 13 group, there was a particularly large increase in serotype 3-specific BMEM associated with only a small increase in antibody. Postbooster BMEM responses correlated positively with antibody, but correlations between prebooster BMEM and subsequent BMEM and antibody responses were inconsistent. CONCLUSIONS: After priming with PCV-13 in early infancy, a booster dose of PCV-10 does not induce detectable peripheral blood BMEM responses but a PCV-13 booster does induce robust responses. Booster responses to PCVs may be dependent on homologous carrier protein priming. PMID- 28027284 TI - Antiretroviral Treatment Initiated in the First Month of Life. AB - BACKGROUND: Earlier diagnosis of HIV-infected infants facilitates earlier access to therapy and improved clinical outcomes. The aim of this study was to describe the management of infants who started antiretroviral therapy (ART) in the first month of life. METHODS: A retrospective review was performed on HIV-infected neonates who started ART within the first month of life between January 2013 and March 2015. RESULTS: A total of 997 neonates had 1 HIV polymerase chain reaction test. Of the 997 neonates, 26 (2.6%) tested positive for HIV and 22 initiated therapy in the first month of life. The median age of first HIV polymerase chain reaction test was 7 days. Neonates were started on ART within a median of 7 days of their first HIV test, which equated to a median age of 13.5 [interquartile range (IQR) 7-20] days of life. Median gestational age was 35 weeks (IQR 33-38 weeks), and birth weight was 2170 g (IQR 1773-2480). Nineteen (86.4%) had low birth weight (<2.5 kg) and 16 (72.7%) were premature. Median baseline HIV viral loads were log 4.444 copies/mL (IQR 3.457-5.125), median CD4 counts were 1338 (IQR 803-1928) and CD4% percentages were 36.1% (22.2-45.4). All children initiated zidovudine and lamivudine, 10 with lopinavir/ritonavir and 12 with nevirapine. All children in care are now receiving lopinavir/ritonavir. Of the 22 neonates initiated on treatment, 11 are in care (mean age, 2.1 years), and 2 of these infants had a viral load of <50 copies/ mL when last measured. CONCLUSIONS: Early ART initiation in neonates is feasible. Challenges include safe, palatable regimens and continued close follow-up of mothers and infants. PMID- 28027285 TI - Acute Rhinosinusitis in Immunosuppressed Children: Diagnostic and Therapeutic Management. AB - BACKGROUND: Immunosuppressive therapy places pediatric patients at risk of developing life-threatening sinonasal infections. Diagnosis and treatment are challenging owing to nonspecific signs and symptoms. The aim of this study was to present our department's experience with the surgical management of acute rhinosinusitis in immunosuppressed children. METHODS: The records of all children with a hematologic or oncologic disease who underwent endoscopic sinus surgery (ESS) for acute rhinosinusitis from January 2005 to May 2014 were reviewed. Data were retrospectively collected on demographics, clinical and imaging characteristics, microbiology, pathology, treatment and outcome. RESULTS: Thirty four-immunosuppressed children underwent ESS for acute rhinosinusitis. Most patients had a fungal infection. Nineteen patients died at the end of follow-up; 10 deaths were infection-related. Facial swelling was the only symptom that correlated with death of infection. Relapse of the underlying disease, bone marrow transplantation, and long duration of neutropenia correlated with infection-related mortality. Fungal infection, and specifically Aspergillus, correlated with death from infection. CONCLUSIONS: ESS is a safe and efficient procedure for diagnosing and treating immunosuppressed pediatric patients with acute rhinosinusitis. Early detection and aggressive medical and surgical treatment, with control of underlying risk factors, are crucial to improve outcome. PMID- 28027286 TI - Relationship of the Middle Ear Effusion Microbiome to Secretory Mucin Production in Pediatric Patients With Chronic Otitis Media. AB - BACKGROUND: Acute otitis media, an infection of the middle ear, can become chronic after multiple episodes. Microbial influence on chronic otitis media remains unclear. It has been reported that mucin glycoproteins are required for middle ear immune defense against pathogens. We aim to characterize the middle ear effusion (MEE) microbiome using high-throughput sequencing and assess potential associations in microbiome diversity with the presence of the secretory mucins MUC5B and MUC5AC. We hypothesize that MEEs containing MUC5B will exhibit a microbiome largely devoid of typical acute otitis media bacteria. METHODS: Fifty five MEEs from children undergoing myringotomy at Children's National Health System were recovered. Mucin was semiquantitatively determined through Western blot analysis. DNA was subjected to 16S rRNA amplicon sequencing using the Illumina MiSeq platform. Raw data were processed in mothur (SILVA reference database). Alpha- and beta-diversity metrics were determined. Abundance differences between sample groups were estimated. RESULTS: MUC5B was present in 94.5% and MUC5AC in 65.5% of MEEs. Sequencing revealed 39 genera with a relative abundance >=0.1%. Haemophilus (22.54%), Moraxella (11.11%) and Turicella (7.84%) were the most abundant. Turicella and Pseudomonas proportions were greater in patients older than 24 months of age. In patients with hearing loss, Haemophilus was more abundant, while Turicella and Actinobacteria were less abundant. Haemophilus was also more abundant in samples containing both secretory mucins. CONCLUSIONS: The microbiome of MEEs from children with chronic otitis media differs according to specific clinical features, such as mucin content, age and presence of hearing loss. These associations provide novel pathophysiologic insights across the spectrum of otitis media progression. PMID- 28027288 TI - Cost-effectiveness Comparison of Monovalent C Versus Quadrivalent ACWY Meningococcal Conjugate Vaccination in Canada. AB - BACKGROUND: In Quebec, 1 dose of monovalent C meningococcal conjugate vaccine (Men-C-Con) is offered at 12 months of age and a booster dose in grade 9 (14-15 years of age). In other Canadian provinces, a quadrivalent vaccine against serogroups ACWY (Men-4-Con) is increasingly used for adolescents. An economic analysis was performed to assess the value of a switch from Men-C-Con to Men-4 Con. METHODS: A compartmental static simulation model was developed to assess the burden of invasive meningococcal disease due to serogroups AWY (AWY-IMD) in a cohort of 100,000 persons with different vaccination programs. Univariate and multivariate sensitivity analyses were performed, including variation in vaccine price difference ($12; range: $0-$20), AWY-IMD rate (0.08/100,000 to 0.28/100,000 person-years), level of herd immunity generated by adolescent vaccination (from zero to disease elimination) and discounting rate (0%, 3% or 6%). RESULTS: In the low AWY-IMD rate base scenario, replacing Men-C-Con by Men-4-Con for adolescents would reduce disease burden by 16% (no herd effect) to 58% (moderate herd effect), with an incremental cost-effectiveness ratios between $445,000 per quality-adjusted life-year (QALY) and $167,000/QALY in a societal perspective. In the high AWY-IMD rate scenario, incremental cost-effectiveness ratio would be in the range of $97,000/QALY to $19,000/QALY. CONCLUSION: Based on the epidemiologic conditions in Quebec and in most other Canadian provinces, the benefits of Men-4 Con in reducing the burden of disease would be low for a high cost. The switch would, however, be more economically attractive with a much higher incidence rate (as in a few provinces) or with a reduced vaccine price in conditions assuming a moderate to high herd effect. PMID- 28027287 TI - Despite Access to Antiretrovirals for Prevention and Treatment, High Rates of Mortality Persist Among HIV-infected Infants and Young Children. AB - BACKGROUND: Outcomes of HIV-infected children before widespread use of antiretroviral therapy (ART) for treatment and prevention of mother-to-child transmission (PMTCT) have been well characterized but less is known about children who acquire HIV infection in the context of good ART access. METHODS: We enrolled newly diagnosed HIV-infected children <=24 months of age at 3 hospitals and 2 clinics in Johannesburg, South Africa. We report ART initiation and mortality rates during 6 months from enrollment and factors associated with mortality. RESULTS: Of 272 children enrolled, median age 6.1 months, 69.5% were diagnosed during hospitalization. By 6 months postenrollment, 53 (19.5%) died and 73 (26.8%) were lost-to-follow-up. Using Kaplan-Meier analysis, the probability of death by 6 months after enrollment was 23.5%. The median age of death was 9.1 months [95% confidence interval (CI): 8.6-12.0]. Overall, 226 (83%) children initiated ART which was associated with a 71% reduction in risk of death [hazard ratio (HR) = 0.29 (95% CI: 0.15-0.58)]. In multivariable analysis of infant factors, weight-for-age Z score < -2 standard deviation (SD) [HR = 2.43 (95% CI: 1.03-5.73)], CD4 <20% [HR = 3.29 (95% CI: 1.60-6.76)] and identification during hospitalization [HR = 2.89 (95% CI: 1.16-7.25)] were independently associated with mortality. In multivariable analysis of maternal factors, CD4 <=350/no maternal ART was associated with increased mortality risk [HR = 2.57 (95% CI: 1.19-5.59)] versus CD4 >350/no maternal ART; exposure to maternal/infant antiretrovirals for PMTCT was associated with reduced mortality risk [HR = 0.53 (95% CI: 0.28-0.99)] versus no PMTCT. CONCLUSIONS: ART initiation is highly protective against death in young children. However, despite improved access to ART, young children remain at risk for early death; innovative approaches to rapidly diagnose and initiate treatment as early in life as possible are needed. PMID- 28027289 TI - Paraoxonase-1 (PON1) rs662 Polymorphism and Its Association with Serum Lipid Levels and Longevity in the Bama Zhuang Population. AB - BACKGROUND The present study was performed to identify the association of PON1 rs662 polymorphism with serum lipid levels and human longevity in the Bama Zhuang population. MATERIAL AND METHODS PON1 genotypes were determined by Taqman SNP Genotyping Assays in 110 long-lived inhabitants (longevity group, aged 90-110 years), 110 healthy inhabitants in Bama County (control 1 group, aged 43-82 years) and 110 healthy inhabitants in Nandan County (control 2 group, aged 28-82 years) without family history of longevity. RESULTS BMI (body mass index) and TG (serum total triglyceride) level were lower in the longevity group than in the two control groups, while the contents of serum LDL-c (low-density lipoprotein cholesterol) and HDL-c (high-density lipoprotein cholesterol) and the levels of SBP (systolic blood pressure) and DBP (diastolic blood pressure) in the longevity group were higher than in the two control groups (p<0.01). Significant differences in the frequencies of three genotypes (GG, AG, and AA) were observed between the longevity group and control 2 group (chi2=15.190, p=0.001). The minor allele frequency (MAF) of rs662 was significantly higher in the longevity group than in the two control groups. The levels of HDL-c in the longevity group were different among the three genotypes (p<0.05). The levels of TG for GG and GG+AG genotypes were significantly different, while the levels of TC (total cholesterol) and HDL-c for AG and GG+AG genotypes were significantly different among the three groups (p<0.05). Serum lipid parameters were correlated with several environmental factors, including age, gender, DBP, SBP, and BMI. The association of PON1 rs662 polymorphism and serum lipid levels was different among the three groups. CONCLUSIONS PON1 polymorphism might be one of the genetic factors of longevity in the Bama Zhuang population. The PON1 rs662 SNP (single nucleotide polymorphism) was associated with serum HDL-c levels in the longevity group. PMID- 28027292 TI - Shedding Light on the Grey Zone of Speciation along a Continuum of Genomic Divergence. AB - Speciation results from the progressive accumulation of mutations that decrease the probability of mating between parental populations or reduce the fitness of hybrids-the so-called species barriers. The speciation genomic literature, however, is mainly a collection of case studies, each with its own approach and specificities, such that a global view of the gradual process of evolution from one to two species is currently lacking. Of primary importance is the prevalence of gene flow between diverging entities, which is central in most species concepts and has been widely discussed in recent years. Here, we explore the continuum of speciation thanks to a comparative analysis of genomic data from 61 pairs of populations/species of animals with variable levels of divergence. Gene flow between diverging gene pools is assessed under an approximate Bayesian computation (ABC) framework. We show that the intermediate "grey zone" of speciation, in which taxonomy is often controversial, spans from 0.5% to 2% of net synonymous divergence, irrespective of species life history traits or ecology. Thanks to appropriate modeling of among-locus variation in genetic drift and introgression rate, we clarify the status of the majority of ambiguous cases and uncover a number of cryptic species. Our analysis also reveals the high incidence in animals of semi-isolated species (when some but not all loci are affected by barriers to gene flow) and highlights the intrinsic difficulty, both statistical and conceptual, of delineating species in the grey zone of speciation. PMID- 28027290 TI - Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process. AB - In some recent studies, a view emerged that stochastic dynamics governing the switching of cells from one differentiation state to another could be characterized by a peak in gene expression variability at the point of fate commitment. We have tested this hypothesis at the single-cell level by analyzing primary chicken erythroid progenitors through their differentiation process and measuring the expression of selected genes at six sequential time-points after induction of differentiation. In contrast to population-based expression data, single-cell gene expression data revealed a high cell-to-cell variability, which was masked by averaging. We were able to show that the correlation network was a very dynamical entity and that a subgroup of genes tend to follow the predictions from the dynamical network biomarker (DNB) theory. In addition, we also identified a small group of functionally related genes encoding proteins involved in sterol synthesis that could act as the initial drivers of the differentiation. In order to assess quantitatively the cell-to-cell variability in gene expression and its evolution in time, we used Shannon entropy as a measure of the heterogeneity. Entropy values showed a significant increase in the first 8 h of the differentiation process, reaching a peak between 8 and 24 h, before decreasing to significantly lower values. Moreover, we observed that the previous point of maximum entropy precedes two paramount key points: an irreversible commitment to differentiation between 24 and 48 h followed by a significant increase in cell size variability at 48 h. In conclusion, when analyzed at the single cell level, the differentiation process looks very different from its classical population average view. New observables (like entropy) can be computed, the behavior of which is fully compatible with the idea that differentiation is not a "simple" program that all cells execute identically but results from the dynamical behavior of the underlying molecular network. PMID- 28027291 TI - Interaction of Prions Causes Heritable Traits in Saccharomyces cerevisiae. AB - The concept of "protein-based inheritance" defines prions as epigenetic determinants that cause several heritable traits in eukaryotic microorganisms, such as Saccharomyces cerevisiae and Podospora anserina. Previously, we discovered a non-chromosomal factor, [NSI+], which possesses the main features of yeast prions, including cytoplasmic infectivity, reversible curability, dominance, and non-Mendelian inheritance in meiosis. This factor causes omnipotent suppression of nonsense mutations in strains of S. cerevisiae bearing a deleted or modified Sup35 N-terminal domain. In this work, we identified protein determinants of [NSI+] using an original method of proteomic screening for prions. The suppression of nonsense mutations in [NSI+] strains is determined by the interaction between [SWI+] and [PIN+] prions. Using genetic and biochemical methods, we showed that [SWI+] is the key determinant of this nonsense suppression, whereas [PIN+] does not cause nonsense suppression by itself but strongly enhances the effect of [SWI+]. We demonstrated that interaction of [SWI+] and [PIN+] causes inactivation of SUP45 gene that leads to nonsense suppression. Our data show that prion interactions may cause heritable traits in Saccharomyces cerevisiae. PMID- 28027293 TI - The Effect of Gap Junctional Coupling on the Spatiotemporal Patterns of Ca2+ Signals and the Harmonization of Ca2+-Related Cellular Responses. AB - Calcium ions (Ca2+) are important mediators of a great variety of cellular activities e.g. in response to an agonist activation of a receptor. The magnitude of a cellular response is often encoded by frequency modulation of Ca2+ oscillations and correlated with the stimulation intensity. The stimulation intensity highly depends on the sensitivity of a cell to a certain agonist. In some cases, it is essential that neighboring cells produce a similar and synchronized response to an agonist despite their different sensitivity. In order to decipher the presumed function of Ca2+ waves spreading among connecting cells, a mathematical model was developed. This model allows to numerically modifying the connectivity probability between neighboring cells, the permeability of gap junctions and the individual sensitivity of cells to an agonist. Here, we show numerically that strong gap junctional coupling between neighbors ensures an equilibrated response to agonist stimulation via formation of Ca2+ phase waves, i.e. a less sensitive neighbor will produce the same or similar Ca2+ signal as its highly sensitive neighbor. The most sensitive cells within an ensemble are the wave initiator cells. The Ca2+ wave in the cytoplasm is driven by a sensitization wave front in the endoplasmic reticulum. The wave velocity is proportional to the cellular sensitivity and to the strength of the coupling. The waves can form different patterns including circular rings and spirals. The observed pattern depends on the strength of noise, gap junctional permeability and the connectivity probability between neighboring cells. Our simulations reveal that one highly sensitive region gradually takes the lead within the entire noisy system by generating directed circular phase waves originating from this region. PMID- 28027294 TI - The Hamiltonian Brain: Efficient Probabilistic Inference with Excitatory Inhibitory Neural Circuit Dynamics. AB - Probabilistic inference offers a principled framework for understanding both behaviour and cortical computation. However, two basic and ubiquitous properties of cortical responses seem difficult to reconcile with probabilistic inference: neural activity displays prominent oscillations in response to constant input, and large transient changes in response to stimulus onset. Indeed, cortical models of probabilistic inference have typically either concentrated on tuning curve or receptive field properties and remained agnostic as to the underlying circuit dynamics, or had simplistic dynamics that gave neither oscillations nor transients. Here we show that these dynamical behaviours may in fact be understood as hallmarks of the specific representation and algorithm that the cortex employs to perform probabilistic inference. We demonstrate that a particular family of probabilistic inference algorithms, Hamiltonian Monte Carlo (HMC), naturally maps onto the dynamics of excitatory-inhibitory neural networks. Specifically, we constructed a model of an excitatory-inhibitory circuit in primary visual cortex that performed HMC inference, and thus inherently gave rise to oscillations and transients. These oscillations were not mere epiphenomena but served an important functional role: speeding up inference by rapidly spanning a large volume of state space. Inference thus became an order of magnitude more efficient than in a non-oscillatory variant of the model. In addition, the network matched two specific properties of observed neural dynamics that would otherwise be difficult to account for using probabilistic inference. First, the frequency of oscillations as well as the magnitude of transients increased with the contrast of the image stimulus. Second, excitation and inhibition were balanced, and inhibition lagged excitation. These results suggest a new functional role for the separation of cortical populations into excitatory and inhibitory neurons, and for the neural oscillations that emerge in such excitatory-inhibitory networks: enhancing the efficiency of cortical computations. PMID- 28027295 TI - Blood-Based Analysis of Circulating Cell-Free DNA and Tumor Cells for Early Cancer Detection. AB - In a Perspective, Klaus Pantel discusses prospects for use of cell-free DNA and circulating tumor cells in cancer detection. PMID- 28027296 TI - Cancer Genomics: Large-Scale Projects Translate into Therapeutic Advances. AB - Elaine Mardis and Marc Ladanyi discuss how large-scale genomics has driven advances in cancer translational medicine, with a focus on publications in this month's Special Issue. PMID- 28027297 TI - Efficacy of the Rabbit Polyclonal Anti-leptospira Antibody against Homotype or Heterotype Leptospira Infection in Hamster. AB - Leptospirosis, caused by Leptospira, is one of the most important of neglected emerging zoonotic diseases that has important impacts on public health worldwide. Polyclonal antibody (pcAb) therapy is a potential method to process a series of pathogens for which there are limited determination of treatment, such as leptospirosis. First, we evaluated the efficacy of pcAb, derived from the sera of rabbits inoculated with Leptospira, against homotype (Leptospira interrogans serovar Lai) or heterotype (Leptospira interrogans serovar Autumnalis) Leptospira infection in a lethal hamster model. The pcAb treatment improved survival compared to the controls. The histopathology's of the infected kidney, liver and lung were also examined by hematoxylin and eosin staining. Using real-time quantitative PCR, we determined that most of the leptospires in the primary organs were almost completely removed by pcAb. In the second experiment, treatments, including antibiotic, pcAb, and combination, were started immediately after occurrence of the first serious sickness mouse in any group. No significant difference in survival rate between pcAb group and antibiotic group was found, but the combination therapy group significantly improved survival rate compared to the others (P<0.05). We conclude that the rabbit pcAb treatment may cure both the homotype and the heterotype lethal Leptospira infections in hamster, and combination therapy improved survival compared to antibiotic group in the late treatment of homotype leptospirosis. PMID- 28027298 TI - Inferential Structure Determination of Chromosomes from Single-Cell Hi-C Data. AB - Chromosome conformation capture (3C) techniques have revealed many fascinating insights into the spatial organization of genomes. 3C methods typically provide information about chromosomal contacts in a large population of cells, which makes it difficult to draw conclusions about the three-dimensional organization of genomes in individual cells. Recently it became possible to study single cells with Hi-C, a genome-wide 3C variant, demonstrating a high cell-to-cell variability of genome organization. In principle, restraint-based modeling should allow us to infer the 3D structure of chromosomes from single-cell contact data, but suffers from the sparsity and low resolution of chromosomal contacts. To address these challenges, we adapt the Bayesian Inferential Structure Determination (ISD) framework, originally developed for NMR structure determination of proteins, to infer statistical ensembles of chromosome structures from single-cell data. Using ISD, we are able to compute structural error bars and estimate model parameters, thereby eliminating potential bias imposed by ad hoc parameter choices. We apply and compare different models for representing the chromatin fiber and for incorporating singe-cell contact information. Finally, we extend our approach to the analysis of diploid chromosome data. PMID- 28027299 TI - Past and Ongoing Tsetse and Animal Trypanosomiasis Control Operations in Five African Countries: A Systematic Review. AB - BACKGROUND: Control operations targeting Animal African Trypanosomiasis and its primary vector, the tsetse, were covering approximately 128,000 km2 of Africa in 2001, which is a mere 1.3% of the tsetse infested area. Although extensive trypanosomiasis and tsetse (T&T) control operations have been running since the beginning of the 20th century, Animal African Trypanosomiasis is still a major constraint of livestock production in sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: We performed a systematic review of the existing literature describing T&T control programmes conducted in a selection of five African countries, namely Burkina Faso, Cameroon, Ethiopia, Uganda and Zambia, between 1980 and 2015. Sixty eight documents were eventually selected from those identified by the database search. This was supplemented with information gathered through semi-structured interviews conducted with twelve key informants recruited in the study countries and selected based on their experience and knowledge of T&T control. The combined information from these two sources was used to describe the inputs, processes and outcomes from 23 major T&T control programmes implemented in the study countries. Although there were some data gaps, involvement of the target communities and sustainability of the control activities were identified as the two main issues faced by these programmes. Further, there was a lack of evaluation of these control programmes, as well as a lack of a standardised methodology to conduct such evaluations. CONCLUSIONS/SIGNIFICANCE: Past experiences demonstrated that coordinated and sustained control activities require careful planning, and evidence of successes, failures and setbacks from past control programmes represent a mine of information. As there is a lack of evaluation of these programmes, these data have not been fully exploited for the design, analyses and justification of future control programmes. PMID- 28027300 TI - Gene Expression Differences in Prostate Cancers between Young and Old Men. AB - Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (<= 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort. Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence. Our results provide clues on the mechanisms of tumor development and point to potential biomarkers for early detection and treatment for prostate cancer in young men. PMID- 28027301 TI - Feedback, Mass Conservation and Reaction Kinetics Impact the Robustness of Cellular Oscillations. AB - Oscillations occur in a wide variety of cellular processes, for example in calcium and p53 signaling responses, in metabolic pathways or within gene regulatory networks, e.g. the circadian system. Since it is of central importance to understand the influence of perturbations on the dynamics of these systems a number of experimental and theoretical studies have examined their robustness. The period of circadian oscillations has been found to be very robust and to provide reliable timing. For intracellular calcium oscillations the period has been shown to be very sensitive and to allow for frequency-encoded signaling. We here apply a comprehensive computational approach to study the robustness of period and amplitude of oscillatory systems. We employ different prototype oscillator models and a large number of parameter sets obtained by random sampling. This framework is used to examine the effect of three design principles on the sensitivities towards perturbations of the kinetic parameters. We find that a prototype oscillator with negative feedback has lower period sensitivities than a prototype oscillator relying on positive feedback, but on average higher amplitude sensitivities. For both oscillator types, the use of Michaelis-Menten instead of mass action kinetics in all degradation and conversion reactions leads to an increase in period as well as amplitude sensitivities. We observe moderate changes in sensitivities if replacing mass conversion reactions by purely regulatory reactions. These insights are validated for a set of established models of various cellular rhythms. Overall, our work highlights the importance of reaction kinetics and feedback type for the variability of period and amplitude and therefore for the establishment of predictive models. PMID- 28027302 TI - Stereotypical Escape Behavior in Caenorhabditis elegans Allows Quantification of Effective Heat Stimulus Level. AB - A goal of many sensorimotor studies is to quantify the stimulus-behavioral response relation for specific organisms and specific sensory stimuli. This is especially important to do in the context of painful stimuli since most animals in these studies cannot easily communicate to us their perceived levels of such noxious stimuli. Thus progress on studies of nociception and pain-like responses in animal models depends crucially on our ability to quantitatively and objectively infer the sensed levels of these stimuli from animal behaviors. Here we develop a quantitative model to infer the perceived level of heat stimulus from the stereotyped escape response of individual nematodes Caenorhabditis elegans stimulated by an IR laser. The model provides a method for quantification of analgesic-like effects of chemical stimuli or genetic mutations in C. elegans. We test ibuprofen-treated worms and a TRPV (transient receptor potential) mutant, and we show that the perception of heat stimuli for the ibuprofen treated worms is lower than the wild-type. At the same time, our model shows that the mutant changes the worm's behavior beyond affecting the thermal sensory system. Finally, we determine the stimulus level that best distinguishes the analgesic-like effects and the minimum number of worms that allow for a statistically significant identification of these effects. PMID- 28027303 TI - Olfactory Sensory Neurons Control Dendritic Complexity of Mitral Cells via Notch Signaling. AB - Mitral cells (MCs) of the mammalian olfactory bulb have a single primary dendrite extending into a single glomerulus, where they receive odor information from olfactory sensory neurons (OSNs). Molecular mechanisms for controlling dendritic arbors of MCs, which dynamically change during development, are largely unknown. Here we found that MCs displayed more complex dendritic morphologies in mouse mutants of Maml1, a crucial gene in Notch signaling. Similar phenotypes were observed by conditionally misexpressing a dominant negative form of MAML1 (dnMAML1) in MCs after their migration. Conversely, conditional misexpression of a constitutively active form of Notch reduced their dendritic complexity. Furthermore, the intracellular domain of Notch1 (NICD1) was localized to nuclei of MCs. These findings suggest that Notch signaling at embryonic stages is involved in the dendritic complexity of MCs. After the embryonic misexpression of dnMAML1, many MCs aberrantly extended dendrites to more than one glomerulus at postnatal stages, suggesting that Notch signaling is essential for proper formation of olfactory circuits. Moreover, dendrites in cultured MCs were shortened by Jag1-expressing cells. Finally, blocking the activity of Notch ligands in OSNs led to an increase in dendritic complexity as well as a decrease in NICD1 signals in MCs. These results demonstrate that the dendritic complexity of MCs is controlled by their presynaptic partners, OSNs. PMID- 28027304 TI - Decoding Single Molecule Time Traces with Dynamic Disorder. AB - Single molecule time trajectories of biomolecules provide glimpses into complex folding landscapes that are difficult to visualize using conventional ensemble measurements. Recent experiments and theoretical analyses have highlighted dynamic disorder in certain classes of biomolecules, whose dynamic pattern of conformational transitions is affected by slower transition dynamics of internal state hidden in a low dimensional projection. A systematic means to analyze such data is, however, currently not well developed. Here we report a new algorithm Variational Bayes-double chain Markov model (VB-DCMM)-to analyze single molecule time trajectories that display dynamic disorder. The proposed analysis employing VB-DCMM allows us to detect the presence of dynamic disorder, if any, in each trajectory, identify the number of internal states, and estimate transition rates between the internal states as well as the rates of conformational transition within each internal state. Applying VB-DCMM algorithm to single molecule FRET data of H-DNA in 100 mM-Na+ solution, followed by data clustering, we show that at least 6 kinetic paths linking 4 distinct internal states are required to correctly interpret the duplex-triplex transitions of H-DNA. PMID- 28027305 TI - Evaluation of Polymerase Chain Reaction (PCR) with Slit Skin Smear Examination (SSS) to Confirm Clinical Diagnosis of Leprosy in Eastern Nepal. AB - BACKGROUND: Detection of Mycobacterium leprae in slit skin smear (SSS) is a gold standard technique for the leprosy diagnosis. Over recent years, molecular diagnosis by using PCR has been increasingly used as an alternative for its diagnosis due to its higher sensitivity. This study was carried out for comparative evaluation of PCR and SSS microscopy in a cohort of new leprosy cases diagnosed in B. P. Koirala Institute of health Sciences, Dharan, Nepal. METHODOLOGY/PRINCIPAL FINDINGS: In this prospective crossectional study, 50 new clinically diagnosed cases of leprosy were included. DNA was extracted from SSS and PCR was carried out to amplify 129 bp sequence of M. leprae repetitive element. Sensitivity of SSS and PCR was 18% and 72% respectively. Improvement of 54% case detection by PCR clearly showed its advantage over SSS. Furthermore, PCR could confirm the leprosy diagnosis in 66% of AFB negative cases indicating its superiority over SSS. In the paucibacillary (PB) patients, whose BI was zero; sensitivity of PCR was 44%, whereas it was 78% in the multibacillary patients. CONCLUSIONS/SIGNIFICANCE: Our study showed PCR to be more sensitive than SSS microscopy in diagnosing leprosy. Moreover, it explored the characteristic feature of PCR which detected higher level of early stage(PB) cases tested negative by SSS. Being an expensive technique, PCR may not be feasible in all the cases, however, it would be useful in diagnosis of early cases of leprosy as opposed to SSS. PMID- 28027306 TI - Collective Resistance in Microbial Communities by Intracellular Antibiotic Deactivation. AB - The structure and composition of bacterial communities can compromise antibiotic efficacy. For example, the secretion of beta-lactamase by individual bacteria provides passive resistance for all residents within a polymicrobial environment. Here, we uncover that collective resistance can also develop via intracellular antibiotic deactivation. Real-time luminescence measurements and single-cell analysis demonstrate that the opportunistic human pathogen Streptococcus pneumoniae grows in medium supplemented with chloramphenicol (Cm) when resistant bacteria expressing Cm acetyltransferase (CAT) are present. We show that CAT processes Cm intracellularly but not extracellularly. In a mouse pneumonia model, more susceptible pneumococci survive Cm treatment when coinfected with a CAT expressing strain. Mathematical modeling predicts that stable coexistence is only possible when antibiotic resistance comes at a fitness cost. Strikingly, CAT expressing pneumococci in mouse lungs were outcompeted by susceptible cells even during Cm treatment. Our results highlight the importance of the microbial context during infectious disease as a potential complicating factor to antibiotic therapy. PMID- 28027307 TI - Population Heterogeneity in the Epithelial to Mesenchymal Transition Is Controlled by NFAT and Phosphorylated Sp1. AB - Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble transforming growth factor beta (TGF-beta) family members, and restricted by vascular endothelial growth factor family members. While many downstream molecular regulators of EMT have been identified, these have been largely evaluated individually without considering potential crosstalk. In this study, we created an ensemble of dynamic mathematical models describing TGF-beta induced EMT to better understand the operational hierarchy of this complex molecular program. We used ordinary differential equations (ODEs) to describe the transcriptional and post-translational regulatory events driving EMT. Model parameters were estimated from multiple data sets using multiobjective optimization, in combination with cross-validation. TGF-beta exposure drove the model population toward a mesenchymal phenotype, while an epithelial phenotype was enhanced following vascular endothelial growth factor A (VEGF-A) exposure. Simulations predicted that the transcription factors phosphorylated SP1 and NFAT were master regulators promoting or inhibiting EMT, respectively. Surprisingly, simulations also predicted that a cellular population could exhibit phenotypic heterogeneity (characterized by a significant fraction of the population with both high epithelial and mesenchymal marker expression) if treated simultaneously with TGF-beta and VEGF-A. We tested this prediction experimentally in both MCF10A and DLD1 cells and found that upwards of 45% of the cellular population acquired this hybrid state in the presence of both TGF-beta and VEGF-A. We experimentally validated the predicted NFAT/Sp1 signaling axis for each phenotype response. Lastly, we found that cells in the hybrid state had significantly different functional behavior when compared to VEGF-A or TGF-beta treatment alone. Together, these results establish a predictive mechanistic model of EMT susceptibility, and potentially reveal a novel signaling axis which regulates carcinoma progression through an EMT versus tubulogenesis response. PMID- 28027308 TI - Cell Fate Decision as High-Dimensional Critical State Transition. AB - Cell fate choice and commitment of multipotent progenitor cells to a differentiated lineage requires broad changes of their gene expression profile. But how progenitor cells overcome the stability of their gene expression configuration (attractor) to exit the attractor in one direction remains elusive. Here we show that commitment of blood progenitor cells to the erythroid or myeloid lineage is preceded by the destabilization of their high-dimensional attractor state, such that differentiating cells undergo a critical state transition. Single-cell resolution analysis of gene expression in populations of differentiating cells affords a new quantitative index for predicting critical transitions in a high-dimensional state space based on decrease of correlation between cells and concomitant increase of correlation between genes as cells approach a tipping point. The detection of "rebellious cells" that enter the fate opposite to the one intended corroborates the model of preceding destabilization of a progenitor attractor. Thus, early warning signals associated with critical transitions can be detected in statistical ensembles of high-dimensional systems, offering a formal theory-based approach for analyzing single-cell molecular profiles that goes beyond current computational pattern recognition, does not require knowledge of specific pathways, and could be used to predict impending major shifts in development and disease. PMID- 28027309 TI - Novel Models of Visual Topographic Map Alignment in the Superior Colliculus. AB - The establishment of precise neuronal connectivity during development is critical for sensing the external environment and informing appropriate behavioral responses. In the visual system, many connections are organized topographically, which preserves the spatial order of the visual scene. The superior colliculus (SC) is a midbrain nucleus that integrates visual inputs from the retina and primary visual cortex (V1) to regulate goal-directed eye movements. In the SC, topographically organized inputs from the retina and V1 must be aligned to facilitate integration. Previously, we showed that retinal input instructs the alignment of V1 inputs in the SC in a manner dependent on spontaneous neuronal activity; however, the mechanism of activity-dependent instruction remains unclear. To begin to address this gap, we developed two novel computational models of visual map alignment in the SC that incorporate distinct activity dependent components. First, a Correlational Model assumes that V1 inputs achieve alignment with established retinal inputs through simple correlative firing mechanisms. A second Integrational Model assumes that V1 inputs contribute to the firing of SC neurons during alignment. Both models accurately replicate in vivo findings in wild type, transgenic and combination mutant mouse models, suggesting either activity-dependent mechanism is plausible. In silico experiments reveal distinct behaviors in response to weakening retinal drive, providing insight into the nature of the system governing map alignment depending on the activity dependent strategy utilized. Overall, we describe novel computational frameworks of visual map alignment that accurately model many aspects of the in vivo process and propose experiments to test them. PMID- 28027310 TI - m6A-Driver: Identifying Context-Specific mRNA m6A Methylation-Driven Gene Interaction Networks. AB - As the most prevalent mammalian mRNA epigenetic modification, N6-methyladenosine (m6A) has been shown to possess important post-transcriptional regulatory functions. However, the regulatory mechanisms and functional circuits of m6A are still largely elusive. To help unveil the regulatory circuitry mediated by mRNA m6A methylation, we develop here m6A-Driver, an algorithm for predicting m6A driven genes and associated networks, whose functional interactions are likely to be actively modulated by m6A methylation under a specific condition. Specifically, m6A-Driver integrates the PPI network and the predicted differential m6A methylation sites from methylated RNA immunoprecipitation sequencing (MeRIP-Seq) data using a Random Walk with Restart (RWR) algorithm and then builds a consensus m6A-driven network of m6A-driven genes. To evaluate the performance, we applied m6A-Driver to build the context-specific m6A-driven networks for 4 known m6A (de)methylases, i.e., FTO, METTL3, METTL14 and WTAP. Our results suggest that m6A-Driver can robustly and efficiently identify m6A-driven genes that are functionally more enriched and associated with higher degree of differential expression than differential m6A methylated genes. Pathway analysis of the constructed context-specific m6A-driven gene networks further revealed the regulatory circuitry underlying the dynamic interplays between the methyltransferases and demethylase at the epitranscriptomic layer of gene regulation. PMID- 28027311 TI - Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution. AB - Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies. PMID- 28027312 TI - The Subclonal Architecture of Metastatic Breast Cancer: Results from a Prospective Community-Based Rapid Autopsy Program "CASCADE". AB - BACKGROUND: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. However, evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. METHODS AND FINDINGS: Three patients with oestrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program (CASCADE). Cases represented a range of management problems in breast cancer, including late relapse after early stage disease, de novo metastatic disease, discordant disease response, and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism (SNP) arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing. Between cases, there were significant differences in mutational burden, driver mutations, mutational processes, and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross-seeding was found in each case, and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the role of mutational processes in subclonal evolution. Limitations of this study include the potential for bias introduced by joint analysis of formalin-fixed archival specimens with fresh specimens and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. CONCLUSIONS: This study highlights various mechanisms that shape the genome of metastatic breast cancer and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm. PMID- 28027313 TI - Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study. AB - BACKGROUND: Circulating tumor DNA (ctDNA) is an approved noninvasive biomarker to test for the presence of EGFR mutations at diagnosis or recurrence of lung cancer. However, studies evaluating ctDNA as a noninvasive "real-time" biomarker to provide prognostic and predictive information in treatment monitoring have given inconsistent results, mainly due to methodological differences. We have recently validated a next-generation sequencing (NGS) approach to detect ctDNA. Using this new approach, we evaluated the clinical usefulness of ctDNA monitoring in a prospective observational series of patients with non-small cell lung cancer (NSCLC). METHODS AND FINDINGS: We recruited 124 patients with newly diagnosed advanced NSCLC for ctDNA monitoring. The primary objective was to analyze the prognostic value of baseline ctDNA on overall survival. ctDNA was assessed by ultra-deep targeted NGS using our dedicated variant caller algorithm. Common mutations were validated by digital PCR. Out of the 109 patients with at least one follow-up marker mutation, plasma samples were contributive at baseline (n = 105), at first evaluation (n = 85), and at tumor progression (n = 66). We found that the presence of ctDNA at baseline was an independent marker of poor prognosis, with a median overall survival of 13.6 versus 21.5 mo (adjusted hazard ratio [HR] 1.82, 95% CI 1.01-3.55, p = 0.045) and a median progression-free survival of 4.9 versus 10.4 mo (adjusted HR 2.14, 95% CI 1.30-3.67, p = 0.002). It was also related to the presence of bone and liver metastasis. At first evaluation (E1) after treatment initiation, residual ctDNA was an early predictor of treatment benefit as judged by best radiological response and progression-free survival. Finally, negative ctDNA at E1 was associated with overall survival independently of Response Evaluation Criteria in Solid Tumors (RECIST) (HR 3.27, 95% CI 1.66-6.40, p < 0.001). Study population heterogeneity, over-representation of EGFR-mutated patients, and heterogeneous treatment types might limit the conclusions of this study, which require future validation in independent populations. CONCLUSIONS: In this study of patients with newly diagnosed NSCLC, we found that ctDNA detection using targeted NGS was associated with poor prognosis. The heterogeneity of lung cancer molecular alterations, particularly at time of progression, impairs the ability of individual gene testing to accurately detect ctDNA in unselected patients. Further investigations are needed to evaluate the clinical impact of earlier evaluation times at 1 or 2 wk. Supporting clinical decisions, such as early treatment switching based on ctDNA positivity at first evaluation, will require dedicated interventional studies. PMID- 28027314 TI - Streptococcal Immunity Is Constrained by Lack of Immunological Memory following a Single Episode of Pyoderma. AB - The immunobiology underlying the slow acquisition of skin immunity to group A streptococci (GAS), is not understood, but attributed to specific virulence factors impeding innate immunity and significant antigenic diversity of the type specific M-protein, hindering acquired immunity. We used a number of epidemiologically distinct GAS strains to model the development of acquired immunity. We show that infection leads to antibody responses to the serotype specific determinants on the M-protein and profound protective immunity; however, memory B cells do not develop and immunity is rapidly lost. Furthermore, antibodies do not develop to a conserved M-protein epitope that is able to induce immunity following vaccination. However, if re-infected with the same strain within three weeks, enduring immunity and memory B-cells (MBCs) to type-specific epitopes do develop. Such MBCs can adoptively transfer protection to naive recipients. Thus, highly protective M-protein-specific MBCs may never develop following a single episode of pyoderma, contributing to the slow acquisition of immunity and to streptococcal endemicity in at-risk populations. PMID- 28027316 TI - Correction: Influenza A Virus Assembly Intermediates Fuse in the Cytoplasm. AB - [This corrects the article DOI: 10.1371/journal.ppat.1003971.]. PMID- 28027315 TI - Non-human Primate Schlafen11 Inhibits Production of Both Host and Viral Proteins. AB - Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is species-specific in its activity against HIV 1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified. PMID- 28027317 TI - Infection with Schistosoma mansoni has an Effect on Quality of Life, but not on Physical Fitness in Schoolchildren in Mwanza Region, North-Western Tanzania: A Cross-Sectional Study. AB - BACKGROUND: Infection with Schistosoma mansoni negatively impact children's physical health and may influence their general well-being. The aim of this study was to investigate the effect of S. mansoni infections on a panel of morbidity indicators with emphasis on quality of life (PedsQL; measured in four different dimensions) and physical fitness (measured as VO2 max) among 572 schoolchildren aged 7-8 years. METHODOLOGY/PRINCIPAL FINDINGS: Prevalence of S. mansoni infections was 58.7%, with an arithmetic mean (95% CI) among positives of 207.3 (169.2-245.4) eggs per gram (epg). Most infections were light (56.5%), while 16.4% had heavy infections. Girls had significantly higher arithmetic mean intensities (95% CI) than boys (247.4 (189.2-305.6) vs. 153.2 (110.6-195.8); P = 0.004). A total of 30.1% were anaemic with no sex difference. Stunting and wasting was found in less than 10% of the population. There was no association between S. mansoni prevalence or intensities and the following parameters: anthropometry, anaemia, liver or spleen pathology in neither univariable nor multivariable linear regression analyses. However, in univariable analyses children with S. mansoni infection had a significantly lower score in emotional PedsQL (95% CI) than uninfected (77.3 (74.5-80.1) vs. 82.7 (79.9-85.5); P = 0.033) and infected children had a higher VO2 max (95% CI) compared to uninfected (51.4 (51.0-51.8) vs. 50.8 (50.3-51.3); P = 0.042). In multivariable linear regression analyses, age, S. mansoni infection, haemoglobin and VO2 max were significant predictors for emotional PedsQL while significant predictors for VO2 max were physical PedsQL, height, age and haemoglobin. S. mansoni infection was thus not retained in the multivariable regression analyses on VO2 max. CONCLUSIONS/SIGNIFICANCE: Of the measured morbidity parameters, S. mansoni infection had a significant effect on the emotional dimension of quality of life, but not on physical fitness. If PedsQL should be a useful tool to measure schistosome related morbidity, more in depth studies are needed in order to refine the tool so it focuses more on aspects of quality of life that may be affected by schistosome infections. PMID- 28027318 TI - Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments. AB - Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design. PMID- 28027319 TI - Scavenger Receptor C Mediates Phagocytosis of White Spot Syndrome Virus and Restricts Virus Proliferation in Shrimp. AB - Scavenger receptors are an important class of pattern recognition receptors that play several important roles in host defense against pathogens. The class C scavenger receptors (SRCs) have only been identified in a few invertebrates, and their role in the immune response against viruses is seldom studied. In this study, we firstly identified an SRC from kuruma shrimp, Marsupenaeus japonicus, designated MjSRC, which was significantly upregulated after white spot syndrome virus (WSSV) challenge at the mRNA and protein levels in hemocytes. The quantity of WSSV increased in shrimp after knockdown of MjSRC, compared with the controls. Furthermore, overexpression of MjSRC led to enhanced WSSV elimination via phagocytosis by hemocytes. Pull-down and co-immunoprecipitation assays demonstrated the interaction between MjSRC and the WSSV envelope protein. Electron microscopy observation indicated that the colloidal gold-labeled extracellular domain of MjSRC was located on the outer surface of WSSV. MjSRC formed a trimer and was internalized into the cytoplasm after WSSV challenge, and the internalization was strongly inhibited after knockdown of Mjbeta-arrestin2. Further studies found that Mjbeta-arrestin2 interacted with the intracellular domain of MjSRC and induced the internalization of WSSV in a clathrin-dependent manner. WSSV were co-localized with lysosomes in hemocytes and the WSSV quantity in shrimp increased after injection of lysosome inhibitor, chloroquine. Collectively, this study demonstrated that MjSRC recognized WSSV via its extracellular domain and invoked hemocyte phagocytosis to restrict WSSV systemic infection. This is the first study to report an SRC as a pattern recognition receptor promoting phagocytosis of a virus. PMID- 28027322 TI - Correction: ATX-2, The C. elegans Ortholog of Human Ataxin-2, Regulates Centrosome Size and Microtubule Dynamics. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006370.]. PMID- 28027320 TI - Genomic Analysis of Uterine Lavage Fluid Detects Early Endometrial Cancers and Reveals a Prevalent Landscape of Driver Mutations in Women without Histopathologic Evidence of Cancer: A Prospective Cross-Sectional Study. AB - BACKGROUND: Endometrial cancer is the most common gynecologic malignancy, and its incidence and associated mortality are increasing. Despite the immediate need to detect these cancers at an earlier stage, there is no effective screening methodology or protocol for endometrial cancer. The comprehensive, genomics-based analysis of endometrial cancer by The Cancer Genome Atlas (TCGA) revealed many of the molecular defects that define this cancer. Based on these cancer genome results, and in a prospective study, we hypothesized that the use of ultra-deep, targeted gene sequencing could detect somatic mutations in uterine lavage fluid obtained from women undergoing hysteroscopy as a means of molecular screening and diagnosis. METHODS AND FINDINGS: Uterine lavage and paired blood samples were collected and analyzed from 107 consecutive patients who were undergoing hysteroscopy and curettage for diagnostic evaluation from this single-institution study. The lavage fluid was separated into cellular and acellular fractions by centrifugation. Cellular and cell-free DNA (cfDNA) were isolated from each lavage. Two targeted next-generation sequencing (NGS) gene panels, one composed of 56 genes and the other of 12 genes, were used for ultra-deep sequencing. To rule out potential NGS-based errors, orthogonal mutation validation was performed using digital PCR and Sanger sequencing. Seven patients were diagnosed with endometrial cancer based on classic histopathologic analysis. Six of these patients had stage IA cancer, and one of these cancers was only detectable as a microscopic focus within a polyp. All seven patients were found to have significant cancer-associated gene mutations in both cell pellet and cfDNA fractions. In the four patients in whom adequate tumor sample was available, all tumor mutations above a specific allele fraction were present in the uterine lavage DNA samples. Mutations originally only detected in lavage fluid fractions were later confirmed to be present in tumor but at allele fractions significantly less than 1%. Of the remaining 95 patients diagnosed with benign or non-cancer pathology, 44 had no significant cancer mutations detected. Intriguingly, 51 patients without histopathologic evidence of cancer had relatively high allele fraction (1.0%-30.4%), cancer-associated mutations. Participants with detected driver and potential driver mutations were significantly older (mean age mutated = 57.96, 95% confidence interval [CI]: 3.30-infinity, mean age no mutations = 50.35; p-value = 0.002; Benjamini-Hochberg [BH] adjusted p-value = 0.015) and more likely to be post-menopausal (p-value = 0.004; BH-adjusted p-value = 0.015) than those without these mutations. No associations were detected between mutation status and race/ethnicity, body mass index, diabetes, parity, and smoking status. Long-term follow-up was not presently available in this prospective study for those women without histopathologic evidence of cancer. CONCLUSIONS: Using ultra-deep NGS, we identified somatic mutations in DNA extracted both from cell pellets and a never previously reported cfDNA fraction from the uterine lavage. Using our targeted sequencing approach, endometrial driver mutations were identified in all seven women who received a cancer diagnosis based on classic histopathology of tissue curettage obtained at the time of hysteroscopy. In addition, relatively high allele fraction driver mutations were identified in the lavage fluid of approximately half of the women without a cancer diagnosis. Increasing age and post-menopausal status were associated with the presence of these cancer-associated mutations, suggesting the prevalent existence of a premalignant landscape in women without clinical evidence of cancer. Given that a uterine lavage can be easily and quickly performed even outside of the operating room and in a physician's office-based setting, our findings suggest the future possibility of this approach for screening women for the earliest stages of endometrial cancer. However, our findings suggest that further insight into development of cancer or its interruption are needed before translation to the clinic. PMID- 28027321 TI - Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice. AB - Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome. PMID- 28027323 TI - A Multi-Host Agent-Based Model for a Zoonotic, Vector-Borne Disease. A Case Study on Trypanosomiasis in Eastern Province, Zambia. AB - BACKGROUND: This paper presents a new agent-based model (ABM) for investigating T. b. rhodesiense human African trypanosomiasis (rHAT) disease dynamics, produced to aid a greater understanding of disease transmission, and essential for development of appropriate mitigation strategies. METHODS: The ABM was developed to model rHAT incidence at a fine spatial scale along a 75 km transect in the Luangwa Valley, Zambia. The method offers a complementary approach to traditional compartmentalised modelling techniques, permitting incorporation of fine scale demographic data such as ethnicity, age and gender into the simulation. RESULTS: Through identification of possible spatial, demographic and behavioural characteristics which may have differing implications for rHAT risk in the region, the ABM produced output that could not be readily generated by other techniques. On average there were 1.99 (S.E. 0.245) human infections and 1.83 (S.E. 0.183) cattle infections per 6 month period. The model output identified that the approximate incidence rate (per 1000 person-years) was lower amongst cattle owning households (0.079, S.E. 0.017), than those without cattle (0.134, S.E. 0.017). Immigrant tribes (e.g. Bemba I.R. = 0.353, S.E.0.155) and school-age children (e.g. 5-10 year old I.R. = 0.239, S.E. 0.041) were the most at-risk for acquiring infection. These findings have the potential to aid the targeting of future mitigation strategies. CONCLUSION: ABMs provide an alternative way of thinking about HAT and NTDs more generally, offering a solution to the investigation of local-scale questions, and which generate results that can be easily disseminated to those affected. The ABM can be used as a tool for scenario testing at an appropriate spatial scale to allow the design of logistically feasible mitigation strategies suggested by model output. This is of particular importance where resources are limited and management strategies are often pushed to the local scale. PMID- 28027324 TI - Insecticide and Repellent Mixture Pour-On Protects Cattle against Animal Trypanosomosis. AB - BACKGROUND: African animal trypanosomosis (AAT), transmitted by tsetse flies and tick-borne diseases are the main constraints to livestock production in sub Saharan Africa. Vector control methods such as pour-on offer individual protection against ticks but not against tsetse so far, for which protection has always been communal, through a reduction of their density. The latter requires the treatment of a large part of the herd in a given landscape and is not instantaneous. METHODOLOGY/PRINCIPAL FINDINGS: Two prospective surveys were conducted to evaluate the efficacy and persistence of a pour-on formulation composed of cypermetrhin, chlorpyrifos, piperonyl butoxid and citronella (Vectoclor, CEVA Sante Animal). In experimental conditions, tsetse flies were exposed to treated and control cattle. Flies knockdown and engorgement rates were determined and the product persistence was assessed as the time for these parameters to drop below 50% (T50). T50 was 37 days (95%CI: [33-41] days) and 46 days (95%CI: [39-56] days) for the knockdown and engorgement rates respectively. In field conditions, two cattle herds were monitored following a case-control experimental design, in the Adamaoua region of Cameroon. One herd was treated once with Vectoclor pour-on (treated group) and the second used as a control group (not treated). Ticks infestation rate, trypanosomosis prevalence and packed cell volume were measured over the two months following treatment. The treatment was highly effective against ticks with a complete elimination three days after application in the treated group. Trypanosomosis prevalence was also significantly reduced during the study (by 4, P<0.001) and PCV of the treated group increased significantly in the same time (P<0.001), contrary to the control group. CONCLUSIONS/SIGNIFICANCE: The protection of this new pour-on against tsetse bites and trypanosomosis is demonstrated here for the first time. Moreover, this insecticide and repellent mixture offer a longer persistence of the efficacy against both tsetse and ticks than similar products currently on the market. It offers a great new opportunity for an integrated AAT control strategy including the treatment of residual cases with trypanocides. It might also allow controlling the spread of resistance against these trypanocides. PMID- 28027325 TI - Using a Novel Partitivirus in Pseudogymnoascus destructans to Understand the Epidemiology of White-Nose Syndrome. AB - White-nose syndrome is one of the most lethal wildlife diseases, killing over 5 million North American bats since it was first reported in 2006. The causal agent of the disease is a psychrophilic filamentous fungus, Pseudogymnoascus destructans. The fungus is widely distributed in North America and Europe and has recently been found in some parts of Asia, but interestingly, no mass mortality is observed in European or Asian bats. Here we report a novel double-stranded RNA virus found in North American isolates of the fungus and show that the virus can be used as a tool to study the epidemiology of White-nose syndrome. The virus, termed Pseudogymnoascus destructans partitivirus-pa, contains 2 genomic segments, dsRNA 1 and dsRNA 2 of 1.76 kbp and 1.59 kbp respectively, each possessing a single open reading frame, and forms isometric particles approximately 30 nm in diameter, characteristic of the genus Gammapartitivirus in the family Partitiviridae. Phylogenetic analysis revealed that the virus is closely related to Penicillium stoloniferum virus S. We were able to cure P. destructans of the virus by treating fungal cultures with polyethylene glycol. Examination of 62 isolates of P. destructans including 35 from United States, 10 from Canada and 17 from Europe showed virus infection only in North American isolates of the fungus. Bayesian phylogenetic analysis using nucleotide sequences of the viral coat protein geographically clustered North American isolates indicating fungal spread followed by local adaptation of P. destructans in different regions of the United States and Canada. This is the first demonstration that a mycovirus potentially can be used to study fungal disease epidemiology. PMID- 28027326 TI - Haemophilus ducreyi Cutaneous Ulcer Strains Diverged from Both Class I and Class II Genital Ulcer Strains: Implications for Epidemiological Studies. AB - BACKGROUND: Haemophilus ducreyi has emerged as a major cause of cutaneous ulcers (CU) in yaws-endemic regions of the tropics in the South Pacific, South East Asia and Africa. H. ducreyi was once thought only to cause the genital ulcer (GU) disease chancroid; GU strains belong to 2 distinct classes, class I and class II. Using whole-genome sequencing of 4 CU strains from Samoa, 1 from Vanuatu and 1 from Papua New Guinea, we showed that CU strains diverged from the class I strain 35000HP and that one CU strain expressed beta-lactamase. Recently, the Center for Disease Control and Prevention released the genomes of 11 additional CU strains from Vanuatu and Ghana; however, the evolutionary relationship of these CU strains to previously-characterized CU and GU strains is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We performed phylogenetic analysis of 17 CU and 10 GU strains. Class I and class II GU strains formed two distinct clades. The class I strains formed two subclades, one containing 35000HP and HD183 and the other containing the remainder of the class I strains. Twelve of the CU strains formed a subclone under the class I 35000HP subclade, while 2 CU strains formed a subclone under the other class I subclade. Unexpectedly, 3 of the CU strains formed a subclone under the class II clade. Phylogenetic analysis of dsrA-hgbA ncaA sequences yielded a tree similar to that of whole-genome phylogenetic tree. CONCLUSIONS/SIGNIFICANCE: CU strains diverged from multiple lineages within both class I and class II GU strains. Multilocus sequence typing of dsrA-hgbA-ncaA could be reliably used for epidemiological investigation of CU and GU strains. As class II strains grow relatively poorly and are relatively more susceptible to vancomycin than class I strains, these findings have implications for methods to recover CU strains. Comparison of contemporary CU and GU isolates would help clarify the relationship between these entities. PMID- 28027328 TI - Opicapone: A Novel Adjunct for an Old Standard. PMID- 28027329 TI - Marketing Claims for Infant Formula: The Need for Evidence. PMID- 28027327 TI - Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis. AB - BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2 mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival. CONCLUSIONS: This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations. PMID- 28027330 TI - Spending on Children's Health Care in the United States: Accomplishments and Challenges in Financing Health Services for Children. PMID- 28027331 TI - Is Serum Albumin Associated With Guillain-Barre Syndrome Outcomes? PMID- 28027332 TI - Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. AB - Importance: Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. Objective: To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. Design: This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014. Main Outcomes and Measures: The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time. Results: A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, 101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 [95% CI, 96.2 to -12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 [95% CI, -80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase. Conclusions and Relevance: Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated. Trial Registration: clinicaltrials.gov Identifier: NCT01227655. PMID- 28027333 TI - Personalized Prescription Feedback Using Routinely Collected Data to Reduce Antibiotic Use in Primary Care: A Randomized Clinical Trial. AB - Importance: Feedback interventions using routinely collected health data might reduce antibiotic use nationwide without requiring the substantial resources and structural efforts of other antibiotic stewardship programs. Objective: To determine if quarterly antibiotic prescription feedback over 2 years reduces antibiotic use when implemented in a complex health care system. Design, Setting, and Participants: Pragmatic randomized trial using routinely collected claims data on 2900 primary care physicians with the highest antibiotic prescription rates in Switzerland. Interventions: Physicians were randomized to quarterly updated personalized antibiotic prescription feedback over 2 years (n = 1450) or usual care (n = 1450). Feedback was provided both by mail and online from October 2013 to October 2015 and was supported by an initial 1-time provision of evidence based guidelines. Main Outcomes and Measures: The primary outcome was the prescribed defined daily doses (DDD) of any antibiotic to any patient per 100 consultations in the first year analyzed by intention-to-treat. We further analyzed prescriptions of specific antibiotics, age groups, and sex for the first and second year to investigate persistency of effects over time. Results: The 2900 physicians had 10 660 124 consultations over 2 years of follow-up, prescribed 1 175 780 packages of antibiotics with 10 290 182 DDD. Physicians receiving feedback prescribed the same amount of antibiotics to all patients in the first year (between-group difference, 0.81%; 95% CI, -2.56% to 4.30%; P = .64) and second year (between-group difference, -1.73%; 95% CI, -5.07% to 1.72%; P = .32) compared with the control group. Prescribing to children aged 6 to 18 years was -8.61% lower in the feedback than in the control group in the first year (95% CI, -14.87% to -1.90%; P = .01). This difference diminished in the second year (between-group difference, -4.10%; 95% CI, -10.78% to 3.07%; P = .25). Physicians receiving feedback prescribed fewer antibiotics to adults aged 19 to 65 years in the second year (between-group difference, -4.59%; 95% CI, 7.91% to -1.16%; P < .01). Prescribing to other patient groups or of specific antibiotic types was not significantly different between groups. Conclusions and Relevance: This nationwide antibiotic stewardship program with routine feedback on antibiotic prescribing was not associated with a change of antibiotic use. In older children, adolescents, and younger adults less antibiotics were prescribed, but not consistently over the entire intervention period. Trial Registration: clinicaltrials.gov Identifier: NCT01773824. PMID- 28027334 TI - Weight Gain and Obesity in Infants and Young Children Exposed to Prolonged Antibiotic Prophylaxis. AB - Importance: An association between antibiotic use and excessive weight gain or obesity in healthy infants and young children has been reported, but evidence is inconsistent and based on observational studies of growth in relation to incidental antibiotic exposures. Objective: To evaluate whether prolonged antibiotic exposure is associated with weight gain in children participating in a clinical trial of antibiotic prophylaxis to prevent recurrent urinary tract infection. Design, Setting, and Participants: Secondary analysis of data from the Randomized Intervention for Children With Vesicoureteral Reflux Study, a 2-year randomized clinical trial that enrolled participants from 2007 to 2011. All 607 children who were randomized to receive antibiotic (n = 302) or placebo (n = 305) were included. Children with urinary tract anomalies, premature birth, or major comorbidities were excluded from participation. Interventions: Trimethoprim sulfamethoxazole or placebo taken orally, once daily, for 2 years. Main Outcomes and Measures: Weight gain as measured by change in weight-for-age z score from baseline to the end-of-study visit at 24 months. Secondary outcomes included weight gain at 6, 12, and 18 months and the prevalence of overweight or obesity at 24 months. Results: Participants had a median age of 12 months (range, 2-71 months) and 558 of 607 (91.9%) were female. Anthropometric data were complete at the 24-month visit for 428 children (214 in the trimethoprim-sulfamethoxazole group and 214 in the placebo group). Weight gain in the trimethoprim sulfamethoxazole group and the placebo group was similar (mean [SD] change in weight-for-age z score: +0.14 [0.83] and +0.18 [0.85], respectively; difference, 0.04 [95% CI, -0.19 to 0.12]; P = .65). There was no significant difference in weight gain at 6, 12, or 18 months or in the prevalence of overweight or obesity at 24 months (24.8% vs 25.7%; P = .82). Subgroup analyses showed no significant interaction between weight gain effect and age, sex, history of breastfeeding, prior antibiotic use, adherence to study medication, or development of urinary tract infection during the study. Conclusions and Relevance: Based on a secondary analysis of data from a large clinical trial of trimethoprim-sulfamethoxazole prophylaxis, there was no evidence that prolonged exposure to this antibiotic has a concurrent effect on weight gain or the prevalence of overweight or obesity in healthy infants and young children. PMID- 28027335 TI - Has Marijuana Legalization Increased Marijuana Use Among US Youth? PMID- 28027336 TI - Understanding the Full Effect of the Changing Legal Status of Marijuana on Youth: Getting It Right. PMID- 28027337 TI - Association of Albumin Levels With Outcome in Intravenous Immunoglobulin-Treated Guillain-Barre Syndrome. AB - Importance: There is an urgent need for biomarkers to monitor treatment efficacy and anticipate outcome in patients with Guillain-Barre syndrome (GBS). Objective: To assess whether there is an association between serum albumin levels, a widely used and relatively easily measurable biomarker of health and inflammation, and the clinical course and outcome of GBS in patients treated with intravenous immunoglobulin (IVIG). Design, Setting, and Participants: We used serum samples derived from a cohort of patients with GBS admitted to hospitals across the Netherlands participating in national GBS studies from May 5, 1986, through August 2, 2000. Serum albumin was measured from January 13 to 20, 2011. Analysis was performed from February 25, 2013, to September 6, 2016. All patients fulfilled the criteria for GBS and had severe disease (defined as not being able to walk unaided >10 m). Patients misdiagnosed as having GBS were retrospectively excluded from the study. Serum samples were obtained before and after IVIG treatment at 4 standardized time points from 174 patients. Albumin levels were determined by routine diagnostic turbidimetry and related to demographics and clinical course during a follow-up of 6 months. Main Outcomes and Measures: Serum albumin concentration was determined before and after treatment with IVIG and related to clinical outcome: muscle weakness (measured by Medical Research Council sum score), respiratory failure (measured by requirement and duration of mechanical ventilation), and ability to walk (measured by GBS disability score). Results: Serum albumin levels were determined in 174 patients with GBS (mean [SD] age, 49.6 [20.1] years; 99 males [56.9%]). Before treatment, the median serum albumin level was 4.2 g/dL (interquartile range, 3.8-4.5 g/dL), with hypoalbuminemia (albumin, <3.5 g/dL) in 20 (12.8%) of 156 patients. Two weeks after commencing treatment with IVIG (2 g/kg), the median serum albumin level decreased to 3.7 g/dL (interquartile range, 3.2-4.1 g/dL) (P < .001), and the number with hypoalbuminemia increased to 60 (34.5%) of 174 (P < .001). Hypoalbuminemia was associated with an increased chance of respiratory failure before (16 [36.4%] of 44, P = .001) or after (29 [54.7%] of 53, P < .001) IVIG treatment, inability to walk unaided (21 [35.0%] of 60 vs 6 [5.3%] of 114, P < .001), and severe muscle weakness at 4 weeks (Medical Research Council sum score, 31.8 vs 52.9, P < .001) and 6 months (Medical Research Council sum score, 49.4 vs 58.4, P < .001). Conclusions and Relevance: Patients with GBS may develop hypoalbuminemia after treatment with IVIG, which is related to a more severe clinical course and a poorer outcome. Further studies are required to confirm that serum albumin can be used as a biomarker to monitor disease activity and treatment response to IVIG in patients with GBS. PMID- 28027338 TI - Effect of an Intensive Outpatient Program to Augment Primary Care for High-Need Veterans Affairs Patients: A Randomized Clinical Trial. AB - Importance: Many organizations are adopting intensive outpatient care programs for high-need patients, yet little is known about their effectiveness in integrated systems with established patient-centered medical homes. Objective: To evaluate how augmenting the Veterans Affairs (VA) medical home (Patient Aligned Care Teams [PACT]) with an Intensive Management program (ImPACT) influences high need patients' costs, health care utilization, and experience. Design, Setting, and Participants: Randomized clinical trial at a single VA facility. Among 583 eligible high-need outpatients whose health care costs or hospitalization risk were in the top 5% for the facility, 150 were randomly selected for ImPACT; the remaining 433 received standard PACT care. Interventions: The ImPACT multidisciplinary team addressed health care needs and quality of life through comprehensive patient assessments, intensive case management, care coordination, and social and recreational services. Main Outcomes and Measures: Primary difference-in-difference analyses examined changes in health care costs and acute and extended care utilization over a 16-month baseline and 17-month follow-up period. Secondary analyses estimated the intervention's effect on ImPACT participants (using randomization as an instrument) and for patients with key sociodemographic and clinical characteristics. ImPACT participants' satisfaction and activation levels were assessed using responses to quality improvement surveys administered at baseline and 6 months. Results: Of 140 patients assigned to ImPACT, 96 (69%) engaged in the program (mean [SD] age, 68.3 [14.2] years; 89 [93%] male; mean [SD] number of chronic conditions, 10 [4]; 62 [65%] had a mental health diagnosis; 21 [22%] had a history of homelessness). After accounting for program costs, adjusted person-level monthly health care expenditures decreased similarly for ImPACT and PACT patients (difference-in-difference [SE] -$101 [$623]), as did acute and extended care utilization rates. Among respondents to the ImPACT follow-up survey (n = 54 [56% response rate]), 52 (96%) reported that they would recommend the program to others, and pre-post analyses revealed modest increases in satisfaction with VA care (mean [SD] increased from 2.90 [0.72] to 3.16 [0.60]; P = .04) and communication (mean [SD] increased from 2.99 [0.74] to 3.18 [0.60]; P = .03). Conclusions and Relevance: Intensive outpatient care for high-need patients did not reduce acute care utilization or costs compared with standard VA care, although there were positive effects on experience among patients who participated. Implementing intensive outpatient care programs in integrated settings with well-established medical homes may not prevent hospitalizations or achieve substantial cost savings. Trial Registration: clinicaltrials.gov Identifier: NCT02932228. PMID- 28027339 TI - Sleep Loss in the Homeless-An Additional Factor of Precariousness: Survey in a Group of Homeless People. PMID- 28027340 TI - Transcatheter Aortic Valve Replacement in Younger Individuals. PMID- 28027341 TI - Antibiotics and Obesity-A Burgeoning or Thinning Argument? PMID- 28027342 TI - Trust but Verify (Ideally With a Randomized Clinical Trial). PMID- 28027343 TI - Recommendations for the Treatment of Patients With Parkinson Disease During Ramadan. AB - Importance: Every year, Ramadan fasting is practiced by many Muslim individuals. In cases of chronic disease, religious texts allow fasting to be broken. However, many believers still want to fast even at the risk of damaging their health. To our knowledge, there are no published recommendations on the medical management of Parkinson disease (PD) during Ramadan. Effective treatments exist in PD and usually require several daily drug intakes. Apart from worsening symptoms, interrupting PD treatment might lead to a severe withdrawal syndrome. Observations: Although no specific studies on this topic have led to formal recommendations, we suggest some options for adapting the treatment for patients who fast during Ramadan. The general principle is based on switching the patient's treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch. However, such an option is only feasible for patients who require a moderate amount of PD treatment and can tolerate dopamine agonist therapy. Conclusions and Relevance: Because many patients with PD require regular multiple daily administration of dopamine replacement medication, the management of Ramadan fasting is not easy. Switching the patient's treatment to an equivalent dosage of a dopamine agonist that can be administered once daily or by transdermal patch seems to be a reasonable option to consider for patients treated with a low-to-moderate amount of PD medication. PMID- 28027344 TI - Spending on Children's Personal Health Care in the United States, 1996-2013. AB - Importance: Health care spending on children in the United States continues to rise, yet little is known about how this spending varies by condition, age and sex group, and type of care, nor how these patterns have changed over time. Objective: To provide health care spending estimates for children and adolescents 19 years and younger in the United States from 1996 through 2013, disaggregated by condition, age and sex group, and type of care. Evidence Review: Health care spending estimates were extracted from the Institute for Health Metrics and Evaluation Disease Expenditure 2013 project database. This project, based on 183 sources of data and 2.9 billion patient records, disaggregated health care spending in the United States by condition, age and sex group, and type of care. Annual estimates were produced for each year from 1996 through 2013. Estimates were adjusted for the presence of comorbidities and are reported using inflation adjusted 2015 US dollars. Findings: From 1996 to 2013, health care spending on children increased from $149.6 (uncertainty interval [UI], 144.1-155.5) billion to $233.5 (UI, 226.9-239.8) billion. In 2013, the largest health condition leading to health care spending for children was well-newborn care in the inpatient setting. Attention-deficit/hyperactivity disorder and well-dental care (including dental check-ups and orthodontia) were the second and third largest conditions, respectively. Spending per child was greatest for infants younger than 1 year, at $11 741 (UI, 10 799-12 765) in 2013. Across time, health care spending per child increased from $1915 (UI, 1845-1991) in 1996 to $2777 (UI, 2698-2851) in 2013. The greatest areas of growth in spending in absolute terms were ambulatory care among all types of care and inpatient well-newborn care, attention-deficit/hyperactivity disorder, and asthma among all conditions. Conclusions and Relevance: These findings provide health policy makers and health care professionals with evidence to help guide future spending. Some conditions, such as attention-deficit/hyperactivity disorder and inpatient well-newborn care, had larger health care spending growth rates than other conditions. PMID- 28027345 TI - Association of State Recreational Marijuana Laws With Adolescent Marijuana Use. AB - Importance: Historical shifts are occurring in marijuana policy. The effect of legalizing marijuana for recreational use on rates of adolescent marijuana use is a topic of considerable debate. Objective: To examine the association between the legalization of recreational marijuana use in Washington and Colorado in 2012 and the subsequent perceived harmfulness and use of marijuana by adolescents. Design, Setting, and Participants: We used data of 253 902 students in eighth, 10th, and 12th grades from 2010 to 2015 from Monitoring the Future, a national, annual, cross-sectional survey of students in secondary schools in the contiguous United States. Difference-in-difference estimates compared changes in perceived harmfulness of marijuana use and in past-month marijuana use in Washington and Colorado prior to recreational marijuana legalization (2010-2012) with postlegalization (2013-2015) vs the contemporaneous trends in other states that did not legalize recreational marijuana use in this period. Main Outcomes and Measures: Perceived harmfulness of marijuana use (great or moderate risk to health from smoking marijuana occasionally) and marijuana use (past 30 days). Results: Of the 253 902 participants, 120 590 of 245 065(49.2%) were male, and the mean (SD) age was 15.6 (1.7) years. In Washington, perceived harmfulness declined 14.2% and 16.1% among eighth and 10th graders, respectively, while marijuana use increased 2.0% and 4.1% from 2010-2012 to 2013-2015. In contrast, among states that did not legalize recreational marijuana use, perceived harmfulness decreased by 4.9% and 7.2% among eighth and 10th graders, respectively, and marijuana use decreased by 1.3% and 0.9% over the same period. Difference-in-difference estimates comparing Washington vs states that did not legalize recreational drug use indicated that these differences were significant for perceived harmfulness (eighth graders: % [SD], -9.3 [3.5]; P = .01; 10th graders: % [SD], -9.0 [3.8]; P = .02) and marijuana use (eighth graders: % [SD], 5.0 [1.9]; P = .03; 10th graders: % [SD], 3.2 [1.5]; P = .007). No significant differences were found in perceived harmfulness or marijuana use among 12th graders in Washington or for any of the 3 grades in Colorado. Conclusions and Relevance: Among eighth and 10th graders in Washington, perceived harmfulness of marijuana use decreased and marijuana use increased following legalization of recreational marijuana use. In contrast, Colorado did not exhibit any differential change in perceived harmfulness or past-month adolescent marijuana use following legalization. A cautious interpretation of the findings suggests investment in evidence-based adolescent substance use prevention programs in any additional states that may legalize recreational marijuana use. PMID- 28027346 TI - Graphic Medicine: The Best of 2016. PMID- 28027347 TI - Incorrect data. PMID- 28027348 TI - How Can the United States Spend Its Health Care Dollars Better? PMID- 28027349 TI - Intra-articular Corticosteroids and Knee Osteoarthritis: Interpreting Different Meta-analyses. PMID- 28027350 TI - Randomized Clinical Trials to Evaluate Mental Health Interventions in Resource Poor Societies. PMID- 28027351 TI - Intra-articular Corticosteroids for Osteoarthritis of the Knee. AB - Clinical Question: Are intra-articular corticosteroids associated with improvement in pain and physical function compared with sham injection or no intervention in patients with knee osteoarthritis? Bottom Line: Intra-articular corticosteroids may be associated with moderate improvement in pain and a small improvement in physical function up to 6 weeks after injection. However, the quality of the evidence is low. PMID- 28027352 TI - New 5-Year Targets Announced for Health Care-Associated Infections. PMID- 28027353 TI - First Inactivated Zika Vaccine Trial. PMID- 28027354 TI - NIH Awards $150 Million for BRAIN Initiative Research in 2016. PMID- 28027356 TI - Improving Health Care for Homeless People. PMID- 28027357 TI - The Right and Wrong of Making Experiments on Human Beings. PMID- 28027358 TI - Association Between In-Hospital Critical Illness Events and Outcomes in Patients on the Same Ward. PMID- 28027359 TI - Prenatal Carrier Screening. PMID- 28027360 TI - Abdominal vs Minimally Invasive Hysterectomy. PMID- 28027361 TI - Prenatal Carrier Screening-Reply. PMID- 28027362 TI - Abdominal vs Minimally Invasive Hysterectomy-Reply. PMID- 28027364 TI - Still No Migraine Relief for Kids. PMID- 28027363 TI - Physicians Can Motivate Patients to Shed Pounds. PMID- 28027365 TI - Celecoxib Similar to 2 NSAIDs for Cardiovascular Safety. PMID- 28027366 TI - US Spending on Personal Health Care and Public Health, 1996-2013. AB - Importance: US health care spending has continued to increase, and now accounts for more than 17% of the US economy. Despite the size and growth of this spending, little is known about how spending on each condition varies by age and across time. Objective: To systematically and comprehensively estimate US spending on personal health care and public health, according to condition, age and sex group, and type of care. Design and Setting: Government budgets, insurance claims, facility surveys, household surveys, and official US records from 1996 through 2013 were collected and combined. In total, 183 sources of data were used to estimate spending for 155 conditions (including cancer, which was disaggregated into 29 conditions). For each record, spending was extracted, along with the age and sex of the patient, and the type of care. Spending was adjusted to reflect the health condition treated, rather than the primary diagnosis. Exposures: Encounter with US health care system. Main Outcomes and Measures: National spending estimates stratified by condition, age and sex group, and type of care. Results: From 1996 through 2013, $30.1 trillion of personal health care spending was disaggregated by 155 conditions, age and sex group, and type of care. Among these 155 conditions, diabetes had the highest health care spending in 2013, with an estimated $101.4 billion (uncertainty interval [UI], $96.7 billion-$106.5 billion) in spending, including 57.6% (UI, 53.8%-62.1%) spent on pharmaceuticals and 23.5% (UI, 21.7%-25.7%) spent on ambulatory care. Ischemic heart disease accounted for the second-highest amount of health care spending in 2013, with estimated spending of $88.1 billion (UI, $82.7 billion-$92.9 billion), and low back and neck pain accounted for the third-highest amount, with estimated health care spending of $87.6 billion (UI, $67.5 billion-$94.1 billion). The conditions with the highest spending levels varied by age, sex, type of care, and year. Personal health care spending increased for 143 of the 155 conditions from 1996 through 2013. Spending on low back and neck pain and on diabetes increased the most over the 18 years, by an estimated $57.2 billion (UI, $47.4 billion $64.4 billion) and $64.4 billion (UI, $57.8 billion-$70.7 billion), respectively. From 1996 through 2013, spending on emergency care and retail pharmaceuticals increased at the fastest rates (6.4% [UI, 6.4%-6.4%] and 5.6% [UI, 5.6%-5.6%] annual growth rate, respectively), which were higher than annual rates for spending on inpatient care (2.8% [UI, 2.8%-2.8%] and nursing facility care (2.5% [UI, 2.5%-2.5%]). Conclusions and Relevance: Modeled estimates of US spending on personal health care and public health showed substantial increases from 1996 through 2013; with spending on diabetes, ischemic heart disease, and low back and neck pain accounting for the highest amounts of spending by disease category. The rate of change in annual spending varied considerably among different conditions and types of care. This information may have implications for efforts to control US health care spending. PMID- 28027367 TI - Association Between Hospital Penalty Status Under the Hospital Readmission Reduction Program and Readmission Rates for Target and Nontarget Conditions. AB - Importance: Readmission rates declined after announcement of the Hospital Readmission Reduction Program (HRRP), which penalizes hospitals for excess readmissions for acute myocardial infarction (AMI), heart failure (HF), and pneumonia. Objective: To compare trends in readmission rates for target and nontarget conditions, stratified by hospital penalty status. Design, Setting, and Participants: Retrospective cohort study of Medicare fee-for-service beneficiaries older than 64 years discharged between January 1, 2008, and June 30, 2015, from 2214 penalty hospitals and 1283 nonpenalty hospitals. Difference interrupted time-series models were used to compare trends in readmission rates by condition and penalty status. Exposure: Hospital penalty status or target condition under the HRRP. Main Outcomes and Measures: Thirty-day risk adjusted, all-cause unplanned readmission rates for target and nontarget conditions. Results: The study included 48 137 102 hospitalizations of 20 351 161 Medicare beneficiaries. In January 2008, the mean readmission rates for AMI, HF, pneumonia, and nontarget conditions were 21.9%, 27.5%, 20.1%, and 18.4%, respectively, at hospitals later subject to financial penalties and 18.7%, 24.2%, 17.4%, and 15.7% at hospitals not subject to penalties. Between January 2008 and March 2010, prior to HRRP announcement, readmission rates were stable across hospitals (except AMI at nonpenalty hospitals). Following announcement of HRRP (March 2010), readmission rates for both target and nontarget conditions declined significantly faster for patients at hospitals later subject to financial penalties compared with those at nonpenalized hospitals (for AMI, additional decrease of -1.24 [95% CI, -1.84 to -0.65] percentage points per year relative to nonpenalty discharges; for HF, -1.25 [95% CI, -1.64 to -0.86]; for pneumonia, 1.37 [95% CI, -1.80 to -0.95]; and for nontarget conditions, -0.27 [95% CI, -0.38 to -0.17]; P < .001 for all). For penalty hospitals, readmission rates for target conditions declined significantly faster compared with nontarget conditions (for AMI, additional decline of -0.49 [95% CI, -0.81 to -0.16] percentage points per year relative to nontarget conditions [P = .004]; for HF, -0.90 [95% CI, -1.18 to -0.62; P < .001]; and for pneumonia, -0.57 [95% CI, -0.92 to -0.23; P < .001]). In contrast, among nonpenalty hospitals, readmissions for target conditions declined similarly or more slowly compared with nontarget conditions (for AMI, additional increase of 0.48 [95% CI, 0.01-0.95] percentage points per year [P = .05]; for HF, 0.08 [95% CI, -0.30 to 0.46; P = .67]; for pneumonia, 0.53 [95% CI, 0.13-0.93; P = .01]). After HRRP implementation in October 2012, the rate of change for readmission rates plateaued (P < .05 for all except pneumonia at nonpenalty hospitals), with the greatest relative change observed among hospitals subject to financial penalty. Conclusions and Relevance: Medicare fee-for-service patients at hospitals subject to penalties under the HRRP had greater reductions in readmission rates compared with those at nonpenalized hospitals. Changes were greater for target vs nontarget conditions for patients at the penalized hospitals but not at the other hospitals. PMID- 28027368 TI - Effect of a Primary Care-Based Psychological Intervention on Symptoms of Common Mental Disorders in Zimbabwe: A Randomized Clinical Trial. AB - Importance: Depression and anxiety are common mental disorders globally but are rarely recognized or treated in low-income settings. Task-shifting of mental health care to lay health workers (LHWs) might decrease the treatment gap. Objective: To evaluate the effectiveness of a culturally adapted psychological intervention for common mental disorders delivered by LHWs in primary care. Design, Setting, and Participants: Cluster randomized clinical trial with 6 months' follow-up conducted from September 1, 2014, to May 25, 2015, in Harare, Zimbabwe. Twenty-four clinics were randomized 1:1 to the intervention or enhanced usual care (control). Participants were clinic attenders 18 years or older who screened positive for common mental disorders on the locally validated Shona Symptom Questionnaire (SSQ-14). Interventions: The Friendship Bench intervention comprised 6 sessions of individual problem-solving therapy delivered by trained, supervised LHWs plus an optional 6-session peer support program. The control group received standard care plus information, education, and support on common mental disorders. Main Outcomes and Measures: Primary outcome was common mental disorder measured at 6 months as a continuous variable via the SSQ-14 score, with a range of 0 (best) to 14 and a cutpoint of 9. The secondary outcome was depression symptoms measured as a binary variable via the 9-item Patient Health Questionnaire, with a range of 0 (best) to 27 and a cutpoint of 11. Outcomes were analyzed by modified intention-to-treat. Results: Among 573 randomized patients (286 in the intervention group and 287 in the control group), 495 (86.4%) were women, median age was 33 years (interquartile range, 27-41 years), 238 (41.7%) were human immunodeficiency virus positive, and 521 (90.9%) completed follow-up at 6 months. Intervention group participants had fewer symptoms than control group participants on the SSQ-14 (3.81; 95% CI, 3.28 to 4.34 vs 8.90; 95% CI, 8.33 to 9.47; adjusted mean difference, -4.86; 95% CI, -5.63 to -4.10; P < .001; adjusted risk ratio [ARR], 0.21; 95% CI, 0.15 to 0.29; P < .001). Intervention group participants also had lower risk of symptoms of depression (13.7% vs 49.9%; ARR, 0.28; 95% CI, 0.22 to 0.34; P < .001). Conclusions and Relevance: Among individuals screening positive for common mental disorders in Zimbabwe, LHW administered, primary care-based problem-solving therapy with education and support compared with standard care plus education and support resulted in improved symptoms at 6 months. Scaled-up primary care integration of this intervention should be evaluated. Trial Registration: pactr.org Identifier: PACTR201410000876178. PMID- 28027369 TI - JAMA Patient Page: Epilepsy. PMID- 28027370 TI - Ensuring Staff Safety When Treating Potentially Violent Patients. PMID- 28027372 TI - A piece of my mind:Bearing the Silence of Tragedy. PMID- 28027373 TI - New-Onset Seizure in Adults and Adolescents: A Review. AB - Importance: Approximately 8% to 10% of the population will experience a seizure during their lifetime. Only about 2% to 3% of patients go on to develop epilepsy. Understanding the underlying etiology leading to an accurate diagnosis is necessary to ensure appropriate treatment and that patients with low risk for recurrence are not treated unnecessarily. Observations: Patients can present with new-onset seizure for a variety of reasons such as acute symptomatic seizures due to acute brain injury or metabolic derangements, or unprovoked seizures that are the initial manifestation of epilepsy. A patient history and physical examination may identify features more consistent with an epileptic event and laboratory studies and brain imaging can identify an acute insult contributing to the presentation. Patients diagnosed with first-time unprovoked seizure require electroencephalography and epilepsy protocol-specific magnetic resonance imaging of the brain, which includes thin-cut coronal slices to determine risk of recurrence and the need for long-term treatment. In patients who meet the criteria for diagnosis of epilepsy, a carefully selected antiepileptic medication with consideration of comorbidities, adverse effect profile, and type of epilepsy is essential along with appropriate counseling. Conclusions and Relevance: Approximately 3% of the population will develop epilepsy but 2 to 3 times as many patients will experience a single seizure or seizure-like event. A diagnosis of epilepsy has significant medical, social, and emotional consequences. A careful patient history and physical examination, electroencephalography, and brain imaging are necessary to separate patients with acute symptomatic seizures, single unprovoked seizures, and nonepileptic events from those with new-onset epilepsy. PMID- 28027374 TI - Notice of Retraction: Das RR, Singh M. Oral Zinc for the Common Cold. JAMA. 2014;311(14):1440-1441. PMID- 28027376 TI - Higher Mortality in Weekend Admissions to the Hospital: True, False, or Uncertain? PMID- 28027377 TI - Reducing Bias in Academic Search Committees. PMID- 28027378 TI - Negative Control Outcomes: A Tool to Detect Bias in Randomized Trials. PMID- 28027379 TI - As Teenage Pregnancies Decline, So Do Preterm Births. PMID- 28027380 TI - Inflammatory Bowel Disease Is More Common Than Earlier Studies Showed. PMID- 28027381 TI - Sleeping on the Street. PMID- 28027382 TI - Training eye movements for visual search in individuals with macular degeneration. AB - We report a method to train individuals with central field loss due to macular degeneration to improve the efficiency of visual search. Our method requires participants to make a same/different judgment on two simple silhouettes. One silhouette is presented in an area that falls within the binocular scotoma while they are fixating the center of the screen with their preferred retinal locus (PRL); the other silhouette is presented diametrically opposite within the intact visual field. Over the course of 480 trials (approximately 6 hr), we gradually reduced the amount of time that participants have to make a saccade and judge the similarity of stimuli. This requires that they direct their PRL first toward the stimulus that is initially hidden behind the scotoma. Results from nine participants show that all participants could complete the task faster with training without sacrificing accuracy on the same/different judgment task. Although a majority of participants were able to direct their PRL toward the initially hidden stimulus, the ability to do so varied between participants. Specifically, six of nine participants made faster saccades with training. A smaller set (four of nine) made accurate saccades inside or close to the target area and retained this strategy 2 to 3 months after training. Subjective reports suggest that training increased awareness of the scotoma location for some individuals. However, training did not transfer to a different visual search task. Nevertheless, our study suggests that increasing scotoma awareness and training participants to look toward their scotoma may help them acquire missing information. PMID- 28027383 TI - Priority Levels in Medical Intensive Care at an Academic Public Hospital. PMID- 28027384 TI - An Anatomical Study on the Safe Placement of Orthopedic Hardware for Syndesmosis Fixation. AB - Articular cartilage and bony contact at the distal tibiofibular cartilage contact zone (TFCCZ) is variable. The appropriate placement of syndesmotic hardware would benefit from a more accurate characterization of the proximal extent of the TFCCZ allowing surgeons to place hardware that simultaneously improves biomechanical stability and decreases the risk of iatrogenic cartilage damage. In addition, Ilizarov wire fixation through the distal fibula and tibia can pass through the syndesmosis recess. Anatomically defining the proximal extent of this recess can help decrease the risk of inadvertent capsular penetration. This study anatomically defines the TFCCZ and syndesmosis recess establishing a safe and biomechanically advantageous distance from the plafond for orthopedic fixation. This study measured the height of the TFCCZ and the syndesmotic recess in 3158 anatomical and cadaveric specimens. A TFCCZ was present in 59% of the Robert J. Terry Anatomical Collection specimens. Maximal height of the TFCCZ averaged 5.7+/ 1.7 mm (99% confidence interval [CI], 5.6-5.8 mm) for anatomical specimens and 5.6+/-1.6 mm (99% CI, 4.6-6.5 mm) for cadaveric dissections. The maximum TFCCZ height was 11.71 mm. Maximal height of the syndesmotic recess averaged 12.8+/-2.1 mm for anatomical specimens and 13.7+/-2.7 mm for cadaveric specimens. The "3 cm rule" appears to be appropriate for fine wire fixation accounting for capsular distension that can be associated with injuries but not applicable for syndesmotic fixation. There is a less than 0.1% chance of encountering the TFCCZ cartilage at 10.9 mm above the plafond and a less than 0.01% chance at 12 mm above the plafond. [Orthopedics. 2017; 40(2):e329-e333.]. PMID- 28027385 TI - A Novel Screening Technique for Ulnar-Sided Carpometacarpal Dislocations. AB - Diagnosing ulnar-sided carpometacarpal joint dislocation is difficult, and more than half of injuries are missed on initial examination. The authors hypothesized that measuring the angle between the capitate and the metacarpals (capitate metacarpal angle) on a plain radiograph would provide a simple, reliable tool to aid in the diagnosis of ulnar-sided carpometacarpal dislocation. This study retrospectively reviewed patients who underwent surgery for ulnar-sided carpometacarpal dislocation (study group). Two authors identified the contour of the capitate and the second, fourth, and fifth metacarpals on plain radiographs. The control group consisted of patients who had radiographs and no bony carpal or metacarpal pathology. Information on the contour of each bone was entered into MATLAB, version 8.5, software (MathWorks, Natick, Massachusetts), which calculated the 2-dimensional angles. A 3-dimensional model based on computed tomography scan data was used to obtain a "true lateral" image to account for variable rotation on plain radiographs. With the use of conventional lateral hand radiographs, the average capitate-metacarpal angle in the control group was 10 degrees compared with 19 degrees in the study group. Using a screening value of 15 degrees on plain radiographs, the sensitivity of the capitate-metacarpal angle was 0.85 and the specificity was 0.79. Both 2-dimensional and 3-dimensional measurements showed that the angle between the capitate and the lesser metacarpals is a reliable screening tool for carpometacarpal dislocation. During evaluation of patients with posttraumatic hand pain, an increased capitate metacarpal angle may indicate the need for advanced imaging studies to further evaluate the carpometacarpal joints. [Orthopedics. 2017; 40(2):e352-e356.]. PMID- 28027386 TI - Paresis of the Peroneal Nerve: A Rare But Severe Long-term Complication of Polyethylene Wear in Knee Arthroplasty. AB - One of the most important limiting factors in the long-term success of total knee arthroplasty is polyethylene wear. Particles of the polyethylene inserts have been shown to elicit a foreign body response, which produces bone resorption and osteolysis, ultimately leading to loosening and component failure. The authors report on a case of an elderly patient who underwent a total knee arthroplasty almost 2 decades ago. Clinical and radiological checkups of the knee had not been performed recently. He now presented with a painful and swollen knee, recurrent joint effusion and swelling of the lower leg, and paresis of the peroneal nerve. Radiological examination showed asymmetric wear of the polyethylene insert and pronounced periprosthetic osteolysis of the proximal tibia and the distal femur. Furthermore, a large ganglion on the anterolateral aspect of the lower leg, resulting in pressure on the peroneal nerve, was detected on ultrasound examination. Open excision of the ganglion was performed initially, followed by 1 stage revision knee arthroplasty using a modular system a few weeks later. This case shows a rare but severe long-term complication of total knee arthroplasty and highlights the importance of regular clinical and radiological checkups after total joint replacements, even for asymptomatic patients and especially in the long term (ie, beyond 10 years after implantation). The current case shows that wear of the polyethylene insert may also lead to ganglion formation that causes paresis of the peroneal nerve. [Orthopedics. 2017; 40(3):e538-e540.]. PMID- 28027387 TI - Impact of Smoking Cessation Counseling Prior to Total Joint Arthroplasty. AB - Perioperative smoking has been linked to surgical complications including poor wound healing, infection, myocardial infarction, prolonged length of stay, need for mechanical ventilation, and death. This study evaluated the effectiveness of preoperative counseling on smoking cessation for patients undergoing elective total joint arthroplasty. Thirty smokers with hip or knee osteoarthritis seeking hip or knee replacement surgery were enrolled prospectively. Interventions included counseling, referrals to smoking cessation programs including the California Smokers' Helpline and the Fontana Tobacco Treatment Program, nicotine replacement therapy (NRT), or instructing patients quit through the "cold turkey" method of abstinence. Patients were scheduled for surgery if they demonstrated abstinence from smoking, confirmed via expired carbon monoxide (CO) breath testing. Short- and long-term smoking cessation rates were evaluated. Thirty patients were enrolled; 21 patients (70%) passed the CO test, whereas 9 patients (30%) failed or did not follow up with a CO test. Thirteen of 21 patients (62%) quit using the "cold turkey" method, 5 of 21 patients (24%) quit using NRT, and 3 of 21 patients (14%) quit using outpatient treatment programs. Eighteen of 21 patients (86%) who quit smoking underwent surgery, and 14 patients had surgery within 6 months of smoking abstinence. Nine of the 14 patients (64%) remained smoke-free 6 months postoperatively confirmed through telephone questionnaire. These results suggest that elective surgery offers a strong incentive for patients to quit smoking, and surgeons can play a role offering a teachable moment and motivating this potentially life-altering behavioral change. [Orthopedics. 2017; 40(2):e323-e328.]. PMID- 28027388 TI - Spinal Anesthesia in Elderly Patients Undergoing Lumbar Spine Surgery. AB - Spinal anesthesia is increasingly viewed as a reasonable alternative to general anesthesia for lumbar spine surgery. However, the results of spinal anesthesia in elderly patients undergoing lumbar spine decompression and combined decompression and fusion procedures are limited in the literature. The aim of this study was to report a single institution's experience using spinal anesthesia in elderly patients undergoing lumbar spine surgery. A retrospective review was conducted using a prospectively collected database of consecutive lumbar spine surgeries performed under spinal anesthesia in patients 70 years or older at a single center between December 2013 and October 2015. A total of 56 patients were included in the study; 27 patients (48%) underwent lumbar decompression and 29 patients (52%) underwent combined decompression and fusion procedures. Mean operative time was 101 minutes (range, 30-210 minutes), and mean operative blood loss was 187 mL (range, 20-700 mL). Mean maximum inpatient postoperative visual analog scale score was 6.2 (range, 1-10). Nausea occurred in 21% (12 of 56) of the patients. Mean length of stay was 2.4 days (range, 1-6 days). No mortality, stroke, permanent loss of function, or pulmonary embolism occurred. None of the cases required conversion to general anesthesia. All of the patients were ambulatory on either the day of the surgery or the next morning. These results demonstrate that spinal anesthesia is a viable method of anesthesia for patients 70 years and older undergoing lumbar spine surgery. They also demonstrate the safety of this method for patients older than 84 years and for surgeries lasting up to 31/2 hours. [Orthopedics. 2017; 40(2):e317-e322.]. PMID- 28027389 TI - Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults. AB - BACKGROUND: Paracetamol, either alone or in combination with codeine or dihydrocodeine, is commonly used to treat chronic neuropathic pain. This review sought evidence for efficacy and harm from randomised double-blind studies. OBJECTIVES: To assess the analgesic efficacy and adverse events of paracetamol with or without codeine or dihydrocodeine for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to July 2016, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks' duration or longer, comparing paracetamol, alone or in combination with codeine or dihydrocodeine, with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE. MAIN RESULTS: No study satisfied the inclusion criteria. Effects of interventions were not assessed as there were no included studies. We have only very low quality evidence and have no reliable indication of the likely effect. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the suggestion that paracetamol alone, or in combination with codeine or dihydrocodeine, works in any neuropathic pain condition. PMID- 28027390 TI - FGF11 induced by hypoxia interacts with HIF-1alpha and enhances its stability. AB - Fibroblast growth factor 11 (FGF11) is an intracellular FGF. Although induction of FGF11 by hypoxia has been observed in several cell types, the molecular function of FGF11 is not clearly understood yet. Here, we investigated the role of FGF11 under hypoxia. We identified hypoxia-inducible factor-1alpha (HIF 1alpha) as an interacting protein of FGF11 using immunoprecipitation and mass spectrometry. FGF11 knockdown decreased HIF-1alpha protein, while FGF11 overexpression increased it, without affecting HIF-1alpha mRNA. Protein stability test and ubiquitination assay showed that FGF11 increased HIF-1alpha stability by acting upstream of proteasomal degradation. Altogether, these results suggest a cross-regulation between HIF-1alpha and FGF11, through which hypoxia-induced FGF11 reinforces hypoxia responses by enhancing the stability of HIF-1alpha. PMID- 28027391 TI - Regulation of BC200 RNA-mediated translation inhibition by hnRNP E1 and E2. AB - The long noncoding RNA BC200 (brain cytoplasmic RNA, 200 nucleotides) acts as a translational modulator of local protein synthesis at dendrites. BC200 RNA has been shown to inhibit translation in vitro, but it remains unknown how this translation inhibition might be controlled in a cell. Here, we performed yeast three-hybrid screening and identified hnRNP E1 and hnRNP E2 as BC200 RNA interacting proteins. We found that: these hnRNA proteins could restore BC200 RNA inhibited translation; BC200 RNA interacts with hnRNP E1 and E2 mainly through its unique 3' C-rich domain; and the RNA binding specificities and modes of the two proteins differed somewhat. Our results offer new insights into the regulation of BC200 RNA-mediated translation inhibition. PMID- 28027392 TI - High-density lipoprotein-like particle formation of Synuclein variants. AB - alpha-Synuclein (alpha-Syn) is an intrinsically disordered protein in solution whose fibrillar aggregates are the hallmark of Parkinson's disease (PD). Although the specific function of alpha-Syn is still unclear, its high structural plasticity is key for the interactions of alpha-Syn with biological membranes. Recently, it has been observed that alpha-Syn is able to form high-density lipoprotein-like (HDL-like) particles that are reminiscent of self-assembling phospholipid bilayer nanodiscs. Here, we extended our preparation method for the production of alpha-Syn lipoprotein particles to the beta- and gamma-Syn variants, and the PD-related familial alpha-Syn mutants. We show that all human Syns can form stable and homogeneous populations of HDL-like particles with distinct morphologies. Our results characterize the impact of the individual Syns on the formation capacity of these particles and indicate that Syn HDL-like particles are neither causing toxicity nor a toxicity-related loss of alpha-Syn in PD. PMID- 28027393 TI - The self-association of HMGB1 and its possible role in the binding to DNA and cell membrane receptors. AB - High mobility group box 1 (HMGB1), a chromatin protein, interacts with DNA and controls gene expression. However, when HMGB1 is released from apoptotic or damaged cells, it triggers proinflammatory reactions by interacting with various receptors, mainly receptor for advanced glycation end-products (RAGE) and toll like receptors (TLRs). The self-association of HMGB1 has been found to be crucial for its DNA-related biological functions. It is influenced by several factors, such as ionic strength, pH, specific divalent metal cations, redox environment and acetylation. This self-association may also play a role in the interaction with RAGE and TLRs and the concomitant inflammatory responses. Future studies should address the potential role of HMGB1 self-association on its interactions with DNA, RAGE and TLRs, as well as the influence of physicochemical factors in different cellular environments on these interactions. PMID- 28027395 TI - Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease? AB - Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-beta in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD. PMID- 28027394 TI - IRE1alpha nucleotide sequence cleavage specificity in the unfolded protein response. AB - Inositol-requiring enzyme 1 (IRE1) is a conserved sensor of the unfolded protein response that has protein kinase and endoribonuclease (RNase) enzymatic activities and thereby initiates HAC1/XBP1 splicing. Previous studies demonstrated that human IRE1alpha (hIRE1alpha) does not cleave Saccharomyces cerevisiae HAC1 mRNA. Using an in vitro cleavage assay, we show that adenine to cytosine nucleotide substitution at the +1 position in the 3' splice site of HAC1 RNA is required for specific cleavage by hIRE1alpha. A similar restricted nucleotide specificity in the RNA substrate was observed for XBP1 splicing in vivo. Together these findings underscore the essential role of cytosine nucleotide at +1 in the 3' splice site for determining cleavage specificity of hIRE1alpha. PMID- 28027396 TI - Edward R. Long. PMID- 28027397 TI - In vivo Confocal Raman Spectroscopic Analysis of the Effects of Infrared Radiation in the Human Skin Dermis. AB - Human skin is the outer covering of the body, and its composition changes with overexposure to environmental pollution and solar radiation. Infrared (IR) radiation is capable of penetrating more deeply into the skin producing free radicals causing irreversible damage. Confocal Raman spectroscopy was considered as a potential tool for the in vivo analysis of the different metabolic conditions with respect to different depths of the skin. In this regard, this work verifies the influence of infrared radiation on the skin dermis after having been exposed to 432 J cm-2 which corresponds to the dose received in a day in the summer time in a tropical region. This study was performed with 17 female volunteers who were divided into two groups. The marked skin area was exposed twice to IR radiation for a duration of 30 min each with an interval of 30 min. The spectral signatures were collected in the fingerprint region before (T0) and after 60 min (T60) of IR irradiation. The analysis shows that, on average, no significant variations occurred in group I and decreased collagen was observed in group II. However, when considering the effect seen in each individual, collagen degradation was detected in 60% of volunteers. PMID- 28027398 TI - Retracted: Physiologically based pharmacokinetic predictions of intestinal BCRP mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. AB - 'Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans' by Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon and Dong-Seok Yim The above article, published online on 06 February 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, K. Sandy Pang, and John Wiley & Sons, Ltd. The authors retracted the paper due to errors associated with use of log D vs. log P of telmisartan as inputs of the PBPK model. The authors concluded that there are too many changes in the article to be resolved by an Erratum, and had requested a retraction. Reference Bae, S. H., Park, W.-S., Han, S., Park, G., Lee, J., Hong, T., Jeon, S., and Yim, D.-S. (2016) Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharm. Drug Dispos., doi: 10.1002/bdd.2060. PMID- 28027399 TI - Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep. AB - Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA-12). On experimental days, rats received PPT microinjections and their sleep-wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA-12 dose-dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose-dependent suppression of PPT BDNF up-regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF-TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive. PMID- 28027400 TI - Elevated intracellular Na+ concentrations in developing spinal neurons. AB - Over 25 years ago it was first reported that intracellular chloride levels (Cl-in ) were higher in developing neurons than in maturity. This finding has had significant implications for understanding the excitability of developing networks and recognizing the underlying causes of hyperexcitability associated with disease and neural injury. While there is some evidence that intracellular sodium levels (Na+in ) change during the development of non-neural cells, it has largely been assumed that Na+in is the same in developing and mature neurons. Here, using the sodium indicator SBFI, we test this idea and find that Na+in is significantly higher in embryonic spinal motoneurons and interneurons than in maturity. We find that Na+in reaches ~ 60 mM in mid-embryonic development and is then reduced to ~ 30 mM in late embryonic development. By retrogradely labeling motoneurons with SBFI we can reliably follow Na+in levels in vitro for hours. Bursts of spiking activity, and blocking voltage-gated sodium channels did not influence observed motoneuron sodium levels. On the other hand, Na+in was reduced by blocking the Na+ -K+ -2Cl- cotransporter NKCC1, and was highly sensitive to changes in external Na+ and a blocker of the Na+ /K+ ATPase. Our findings suggest that the Na+ gradient is weaker in embryonic neuronal development and strengthens in maturity in a manner similar to that of Cl- . PMID- 28027401 TI - Breast milk polyunsaturated fatty acids: associations with adolescent allergic disease and lung function. AB - BACKGROUND: It has been hypothesized that n-3 PUFA in breast milk may assist immune and lung development. There are very limited data on possible long-term effects on allergic disease and lung function. The aim was to investigate associations of n-3 and n-6 PUFA levels in colostrum and breast milk with allergic disease and lung function at ages 12 and 18 years. METHODS: Polyunsaturated fatty acids were measured in 194 colostrum samples and in 118 three-month expressed breast milk samples from mothers of children enrolled in the Melbourne Atopy Cohort (MACS) Study, a high-risk birth cohort study. Associations with allergic diseases, skin prick tests and lung function assessed at 12 and 18 years were estimated using multivariable regression. RESULTS: Higher levels of n-3 but not n-6 PUFAs in colostrum were associated with a trend towards increased odds of allergic diseases, with strong associations observed for allergic rhinitis at 12 (OR = 5.69[95% CI: 1.83,17.60] per weight%) and 18 years (4.43[1.46,13.39]) and eczema at 18 years (9.89[1.44, 68.49]). Higher levels of colostrum n-3 PUFAs were associated with reduced sensitization (3.37[1.18, 9.6]), mean FEV1 (-166 ml [-332, -1]) and FEV1 /FVC ratio (-4.6%, [-8.1, -1.1]) at 12 years. CONCLUSION: Higher levels of colostrum n-3 PUFAs were associated with increased risks of allergic rhinitis and eczema up to 18 years, and sensitization and reduced lung function at 12 years. As residual confounding may have caused these associations, they should be replicated, but these results could indicate that strategies that increase maternal n-3 PUFA intake may not aid in allergic disease prevention. PMID- 28027402 TI - Shellfish allergens: tropomyosin and beyond. AB - IgE-mediated shellfish allergy constitutes an important cause of food-related adverse reactions. Shellfish are classified into mollusks and crustaceans, the latter belonging to the class of arthropoda. Among crustaceans, shrimps are the most predominant cause of allergic reactions and thus more extensively studied. Several major and minor allergens have been identified and cloned. Among them, invertebrate tropomyosin, arginine kinase, myosin light chain, sarcoplasmic calcium-binding protein, and hemocyanin are the most relevant. This review summarizes our current knowledge about these allergens. PMID- 28027403 TI - Accurate measurement of JHH in overlapped signals by a TOCSY-edited SERF Experiment. AB - Selective refocusing (GSERF or the recent PSYCHEDELIC) experiments were originally designed to determine all proton-proton coupling constants (JHH ) for a selected proton resonance. They work for isolated signals on which selective excitation can be successfully applied but, as it happens in other selective experiments, fail for overlapped signals. To circumvent this limitation, a doubly selective TOCSY-GSERF scheme is presented for the measurement of JHH in protons resonating in crowded regions. This new experiment takes advantage of the editing features of an initial TOCSY transfer to uncover hidden resonances that become accessible to perform the subsequent frequency-selective refocusing. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28027409 TI - Atopic dermatitis is associated with a fivefold increased risk of polysensitisation in children. AB - AIM: It has been hypothesised that in atopic dermatitis, the dysfunctional skin barrier facilitates the transcutaneous presentation of allergens to the immune system. This study examined whether atopic dermatitis increased the likelihood of polysensitisation, namely sensitisation to five or more allergens. METHODS: We examined the electronic hospital charts of 1743 children aged 0-17 years who had visited primary or secondary care physicians with allergic symptoms, whose blood was examined for the presence of specific immunoglobulin E (IgE) to the 10 most common inhaled and food allergens and whose files contained documentation of the presence of atopic dermatitis and other skin disorders. Sensitisation was defined as a specific IgE level of >=0.35 kU/L. RESULTS: Polysensitisation was more common in children with atopic dermatitis (268/1197, 22.4%) than those without (30/546, 5.5%, p < 0.001). This remained significant after adjustment for gender and age in a multiple logistic regression model (odds ratio: 5.63, 95% confidence interval 3.77-8.40). Other skin disorders did not show an increased risk of polysensitisation (5/97, 5.2%). CONCLUSION: Polysensitisation was considerably more common in children with atopic dermatitis than those without. This supports the hypothesis that sensitisation occurs through a defective skin barrier and appears to be specific for atopic dermatitis. PMID- 28027410 TI - Diagnosing gestational diabetes mellitus in the Danish National Birth Cohort. AB - INTRODUCTION: The Danish National Birth Cohort (DNBC) contains comprehensive information on diet, lifestyle, constitutional and other major characteristics of women during pregnancy. It provides a unique source for studies on health consequences of gestational diabetes mellitus. Our aim was to identify and validate the gestational diabetes mellitus cases in the cohort. MATERIAL AND METHODS: We extracted clinical information from hospital records for 1609 pregnancies included in the Danish National Birth Cohort with a diagnosis of diabetes during or before pregnancy registered in the Danish National Patient Register and/or from a Danish National Birth Cohort interview during pregnancy. We further validated the diagnosis of gestational diabetes mellitus in 2126 randomly selected pregnancies from the entire Danish National Birth Cohort. From the individual hospital records, an expert panel evaluated gestational diabetes mellitus status based on results from oral glucose tolerance tests, fasting blood glucose and Hb1c values, as well as diagnoses made by local obstetricians. RESULTS: The audit categorized 783 pregnancies as gestational diabetes mellitus, corresponding to 0.89% of the 87 792 pregnancies for which a pregnancy interview for self-reported diabetes in pregnancy was available. From the randomly selected group the combined information from register and interviews could correctly identify 96% (95% CI 80-99.9%) of all cases in the entire Danish National Birth Cohort population. Positive predictive value, however, was only 59% (56-61%). CONCLUSIONS: The combined use of data from register and interview provided a high sensitivity for gestational diabetes mellitus diagnosis. The low positive predictive value, however, suggests that systematic validation by hospital record review is essential not to underestimate the health consequences of gestational diabetes mellitus in future studies. PMID- 28027411 TI - DNA Repair by the Radical SAM Enzyme Spore Photoproduct Lyase: From Biochemistry to Structural Investigations. AB - Radical S-adenosyl-L-methionine (SAM) enzymes have emerged as one of the last superfamilies of enzymes discovered to date. Arguably, it is the most versatile group of enzymes involved in at least 85 biochemical transformations. One of the founding members of this enzyme superfamily is the spore photoproduct (SP) lyase, a DNA repair enzyme catalyzing the direct reversal repair of a unique DNA lesion, the so-called spore photoproduct, back into two thymidine residues. Discovered more than 20 years ago in the bacterium Bacillus subtilis, SP lyase has been shown to be widespread in the endospore-forming Firmicutes from the Bacilli and Clostridia classes and to use radical-based chemistry to perform C-C bond breakage, a chemically challenging reaction. This review describes how the work on SP lyase has illuminated a unique strategy for DNA repair and provided major advances in our understanding of the emerging radical SAM superfamily of enzymes, from a biochemical and structural perspective. PMID- 28027412 TI - Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between alpha-tocopherol and ezetimibe. AB - Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that alpha-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of alpha-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of alpha-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. alpha-Tocopherol (10 mg/kg) and ezetimibe (0.1 mg/kg) were administered to rats, and the plasma concentration profiles of alpha-tocopherol and tissue concentrations were investigated. The plasma concentration of alpha-tocopherol was decreased by the combination use of ezetimibe in the case of concurrent single administration. On the other hand, inhibition of the absorption of alpha tocopherol was prevented by an administration interval of 4 h. In a group of rats administered for 2 months with a 4 h interval, not only the plasma concentration but also the liver concentration was increased compared with those in a group with concurrent combination intake of alpha-tocopherol and ezetimibe. The absorption of alpha-tocopherol was inhibited by ezetimibe. The inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h, although ezetimibe is a medicine of enterohepatic circulation. Attention should be paid to the use of ezetimibe and components of NPC1L1 substrates such as alpha tocopherol. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28027413 TI - Omega 3: a novel treatment agent in oral submucous fibrosis: a pilot study. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a chronic debilitating disease and a premalignant condition of the oral cavity. It is well known for its impervious nature to medical therapy. Omega-3 polyunsaturated fatty acids have been reported to have anti-inflammatory properties. However, its role in OSF is still not known. This preliminary study assessed the efficacy of systemic omega 3 in this disease. METHODS: A randomized single-blinded controlled trial was designed, and a total of 10 clinically confirmed adult patients with OSF were included in the study. Group A was given biweekly intralesional injections of dexamethasone 1.5 ml and hyaluronidase 1500 IU mixed with lignocaine for 6 weeks and a placebo for 3 months. Group B was also given similar intralesional injections but with 1 gm of omega 3 three times daily continuously for 3 months. Patients were followed every month for 3 months and then after 6 months. RESULTS: Significant improvement was noted among all clinical parameters (interincisal distance, tongue protrusion, cheek flexibility, and visual analogue scale) in both the groups. Intergroup comparison showed significant reduction in burning sensation in group B; that is, P value was 0.005, while improvement in rest of the three clinical features was not statistically significant. CONCLUSION: Omega 3 can be used as an adjunctive treatment option in patients with OSF to reduce subjective symptoms. More studies should be conducted with a larger sample size to study the effect of omega 3 in patients with OSF. PMID- 28027414 TI - Roles of p62 in BDNF-dependent autophagy suppression and neuroprotection against mitochondrial dysfunction in rat cortical neurons. AB - Previously, we have reported that pre-conditioning of primary rat cortical neurons with brain-derived neurotrophic factor (BDNF) may exert neuroprotective effects against 3-nitropropionic acid (3-NP), a mitochondrial complex II inhibitor. However, the underlying mechanisms, especially potential involvements of autophagy, remain elusive. In this work, we tested the hypothesis that BDNF may suppress 3-NP-induced autophagy to exert its neuroprotective effects by inducing the expression of p62/sequestosome-1 in primary cortical neurons. We found that 3-NP increased total level of microtubule-associated protein 1A/1B light chain (LC)-3 as well as the LC3-II/LC3-I ratio, an index of autophagy, in primary cortical neurons. BDNF decreased LC3-II/LC3-I ratio and time-dependently induced expression of p62. Knockdown of p62 by siRNA restored LC3-II/LC3-I ratio and increased total LC3 levels associated with BDNF exposure; p62 knockdown also abolished BDNF-dependent neuroprotection against 3-NP. Upstream of p62, we found that BDNF triggered phosphorylation of mammalian target of rapamycin (mTOR) and its downstream mediator p70S6K; importantly, the mTOR inhibitor rapamycin reduced both BDNF-dependent p62 induction as well as 3-NP resistance. BDNF is known to induce c-Jun in cortical neurons. We found that c-Jun knockdown in part attenuated BDNF-mediated p62 induction, whereas p62 knockdown had no significant effects on c-Jun expression. In addition to suppressing p62 induction, rapamycin also partially suppressed BDNF-induced c-Jun expression, but c-Jun knockdown failed to affect mTOR activation. Together, our results suggested that BDNF inhibits 3-NP-induced autophagy via, at least in part, mTOR/c-Jun-dependent induction of p62 expression, together contributing to neuroprotection against mitochondrial inhibition. PMID- 28027416 TI - Correction. PMID- 28027415 TI - Is rectal indomethacin ineffective in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis in the general population? PMID- 28027417 TI - Correction. PMID- 28027419 TI - A retrospective cohort study of the influence of lifestyle factors on the survival of patients undergoing surgery for colorectal cancer. AB - AIM: Several modifiable and nonmodifiable health-related behaviours are associated with the incidence of colorectal cancer (CRC), but there is little research on their association with survival. This work aimed to investigate possible relationships between modifiable behavioural factors and outcomes on a study cohort of CRC patients undergoing potentially curative surgery. METHOD: A retrospective cohort study was carried out of patients diagnosed with nonmetastatic CRC residing in the NHS Greater Glasgow and Clyde area, UK and undergoing elective curative surgery (January 2011 to December 2012). Data were obtained from the Scottish Cancer Registry, National Scottish Death Records. Preoperative assessment of smoking, alcohol consumption, nurse-measured body mass index (BMI) and exercise levels were recorded, and patients were followed until death or censorship. Survival analysis was carried out and proportional hazards assumptions were assessed graphically using plots and were then formally tested using the PHTEST procedure in stata. RESULT: Of the initial 527 patients, 181 (34%) satisfied the inclusion criteria. The total duration of follow-up was 480 person-years. At the preoperative assessment, 75% of patients were overweight or obese, 10.6% were current smokers, 13.1% recorded excess alcohol consumption and 8.5% had physical difficulty climbing stairs. Age, BMI, histopathological stage and physical capacity all independently affected survival (P < 0.05). Overweight patients [hazard ratio (HR) 2.81] and those who had difficulty climbing stairs (HR 3.31) had a significantly poorer survival. CONCLUSION: This study found evidence that preoperative exercise capacity and BMI are important independent prognostic factors of survival in patients undergoing curative surgery for CRC. PMID- 28027421 TI - Endoscopic retrieval of an entrapped nasopancreatic drainage tube. PMID- 28027420 TI - Sex differences in leucocyte telomere length in a free-living mammal. AB - Mounting evidence suggests that average telomere length reflects previous stress and predicts subsequent survival across vertebrate species. In humans, leucocyte telomere length (LTL) is consistently shorter during adulthood in males than in females, although the causes of this sex difference and its generality to other mammals remain unknown. Here, we measured LTL in a cross-sectional sample of free living Soay sheep and found shorter telomeres in males than in females in later adulthood (>3 years of age), but not in early life. This observation was not related to sex differences in growth or parasite burden, but we did find evidence for reduced LTL associated with increased horn growth in early life in males. Variation in LTL was independent of variation in the proportions of different leucocyte cell types, which are known to differ in telomere length. Our results provide the first evidence of sex differences in LTL from a wild mammal, but longitudinal studies are now required to determine whether telomere attrition rates or selective disappearance are responsible for these observed differences. PMID- 28027422 TI - Care-related predictors for negative intrusive thoughts after prostate cancer diagnosis-data from the prospective LAPPRO trial. AB - OBJECTIVE: Negative intrusive thoughts about one's prostate cancer have been associated with depressive mood and impaired quality of life among prostate cancer patients. However, little is known about possible predictors for negative intrusive thoughts among this group. We aimed to identify health- and care related predictors for such thoughts among a population of men newly diagnosed with prostate cancer and undergoing radical prostatectomy. METHODS: In the LAPPRO trial, 3154 men (80%) answered study-specific questionnaires at admission and 3 months after surgery. Questions concerned socio-demographics, health, uncertainty, preparedness for symptoms, and the outcome-negative intrusive thoughts. Associations between variables were analyzed by log-binominal and multivariable approach. RESULTS: The strongest predictor of negative intrusive thoughts at admission to surgery was uncertainty of cure, followed by binge drinking, poor physical health, antidepressant medication, not being prepared for urinary symptoms, age under 55, and physical pain. Reporting it not probable to obtain urinary symptoms after surgery lowered the odds. Negative intrusive thoughts before surgery were the strongest predictor for such thoughts 3 months later followed by uncertainty of cure, physical pain, younger age, living alone, and poor self-reported physical health. CONCLUSIONS: Our findings showed an association of preoperative uncertainty of cure as well as low preparedness for well-known surgery-induced symptoms with higher occurrence of negative intrusive thoughts about prostate cancer. Future studies should examine if interventions designed to have healthcare professionals inform patients about their upcoming prostatectomy reduce patients' negative intrusive thoughts and thereby, improve their psychological well-being. PMID- 28027423 TI - Global analysis reveals that cryptic diversity is linked with habitat but not mode of life. AB - The ubiquity of genetically distinct, cryptic species is limiting any attempt to estimate local or global biodiversity as well as impeding efforts to conserve species or control pests and diseases. Environmental factors or biological traits promoting rapid diversification into morphologically similar species remain unclear. Here, using a meta-analysis of 1230 studies using DNA sequences to search for cryptic diversity in metazoan taxa, we test two hypotheses regarding the frequency of cryptic taxa based on mode of life and habitat. First, after correcting for study effort and accounting for higher taxonomic affinities and biogeographical region of origins, our results do not support the hypothesis that cryptic taxa are more frequent among parasitic than free-living taxa. Second, in contrast, the results support the hypothesis that cryptic taxa are more common in certain habitats than others: for a given study effort, more cryptic taxa are found in freshwater than in terrestrial or marine taxa. These findings suggest that the greater heterogeneity and fragmentation of freshwater habitats may promote higher rates of genetic differentiation among its inhabitants, a general pattern with serious implications for freshwater conservation biology. PMID- 28027425 TI - Indel-seq: a fast-forward genetics approach for identification of trait associated putative candidate genomic regions and its application in pigeonpea (Cajanus cajan). AB - Identification of candidate genomic regions associated with target traits using conventional mapping methods is challenging and time-consuming. In recent years, a number of single nucleotide polymorphism (SNP)-based mapping approaches have been developed and used for identification of candidate/putative genomic regions. However, in the majority of these studies, insertion-deletion (Indel) were largely ignored. For efficient use of Indels in mapping target traits, we propose Indel-seq approach, which is a combination of whole-genome resequencing (WGRS) and bulked segregant analysis (BSA) and relies on the Indel frequencies in extreme bulks. Deployment of Indel-seq approach for identification of candidate genomic regions associated with fusarium wilt (FW) and sterility mosaic disease (SMD) resistance in pigeonpea has identified 16 Indels affecting 26 putative candidate genes. Of these 26 affected putative candidate genes, 24 genes showed effect in the upstream/downstream of the genic region and two genes showed effect in the genes. Validation of these 16 candidate Indels in other FW- and SMD resistant and FW- and SMD-susceptible genotypes revealed a significant association of five Indels (three for FW and two for SMD resistance). Comparative analysis of Indel-seq with other genetic mapping approaches highlighted the importance of the approach in identification of significant genomic regions associated with target traits. Therefore, the Indel-seq approach can be used for quick and precise identification of candidate genomic regions for any target traits in any crop species. PMID- 28027424 TI - HCV reinfection incidence among individuals treated for recent infection. AB - One challenge to HCV elimination through therapeutic intervention is reinfection. The aim of this analysis was to calculate the incidence of HCV reinfection among both HIV-positive and HIV-negative individuals treated for recent HCV infection (estimated infection duration <18 months). Individuals with recent HCV infection who achieved an end-of-treatment response in four open-label studies between 2004 and 2015 in Australia and New Zealand were assessed for HCV reinfection, confirmed by sequencing of the Core-E2 and/or NS5B regions. Reinfection incidence was calculated using person-time of observation. Exact Poisson regression analysis was used to assess factors associated with HCV reinfection. The cohort at risk for reinfection (n=120; 83% male; median age 36 years) was composed of HIV-positive men-who-have-sex-with-men (53%) and people who inject drugs (current 49%, ever 69%). Total follow-up time at risk was 135 person-years (median 1.08 years, range 0.17, 2.53). Ten cases of HCV reinfection were identified, for an incidence of 7.4 per 100 py (95% CI 4.0, 13.8). Reinfection incidence was significantly higher among participants who reported injection drug use at end of or post-treatment, irrespective of HIV status (15.5 per 100 py, 95% CI 7.8, 31.1). In adjusted analysis, factors associated with reinfection were older age (aIRR 5.3, 95% CI 1.15, 51.5, P=.042) and injection drug use at end of or post treatment (aIRR 7.9, 95% CI 1.6, 77.2, P=.008). High reinfection incidence following treatment for recent HCV infection in individuals with ongoing risk behaviour emphasizes the need for post-treatment surveillance, harm reduction strategies and education in at-risk populations. PMID- 28027426 TI - Microwave-assisted extraction versus Soxhlet extraction to determine triterpene acids in olive skins. AB - Microwave-assisted extraction is compared with a more classical technique, Soxhlet extraction, to determine the content of triterpene acids in olive skins. The samples used in their original unmilled state and milled were extracted with ethyl acetate or methanol as solvents. The optimized operating conditions (e.g., amount and type of solvent, and time and temperature of extractions) to attain the better extraction yields have been established. For the identification and quantitation of the target compounds, an ultra high performance liquid chromatography with tandem mass spectrometry method was employed. The best results were achieved using the microwave-assisted extraction technique, which was much faster than the Soxhlet extraction method, and showed higher efficiency in the extraction of the triterpenic acids (oleanolic and maslinic). PMID- 28027427 TI - The adiposity of children is associated with their lifestyle behaviours: a cluster analysis of school-aged children from 12 nations. AB - BACKGROUND: The relationship between children's adiposity and lifestyle behaviour patterns is an area of growing interest. OBJECTIVES: The objectives of this study are to identify clusters of children based on lifestyle behaviours and compare children's adiposity among clusters. METHODS: Cross-sectional data from the International Study of Childhood Obesity, Lifestyle and the Environment were used. PARTICIPANTS: the participants were children (9-11 years) from 12 nations (n = 5710). MEASURES: 24-h accelerometry and self-reported diet and screen time were clustering input variables. Objectively measured adiposity indicators were waist-to-height ratio, percent body fat and body mass index z-scores. ANALYSIS: sex-stratified analyses were performed on the global sample and repeated on a site-wise basis. Cluster analysis (using isometric log ratios for compositional data) was used to identify common lifestyle behaviour patterns. Site representation and adiposity were compared across clusters using linear models. RESULTS: Four clusters emerged: (1) Junk Food Screenies, (2) Actives, (3) Sitters and (4) All-Rounders. Countries were represented differently among clusters. Chinese children were over-represented in Sitters and Colombian children in Actives. Adiposity varied across clusters, being highest in Sitters and lowest in Actives. CONCLUSIONS: Children from different sites clustered into groups of similar lifestyle behaviours. Cluster membership was linked with differing adiposity. Findings support the implementation of activity interventions in all countries, targeting both physical activity and sedentary time. PMID- 28027428 TI - Pinecone of Pinus koraiensis Inducing Apoptosis in Human Lung Cancer Cells by Activating Caspase-3 and its Chemical Constituents. AB - Pinecones from Pinus koraiensisSiebold & Zucc. (Pinaceae), which have historically been treated as an undesired waste by-product in the processing of seeds, have recently been shown to contain ingredients with potent biological activities, such as polyphenols exhibiting antitumor activity. With this study, we seek to broaden our understanding of antitumor compounds contained in these pinecones beyond just polyphenols. We found that the water extract of P. koraiensis pinecones exhibits significant cytotoxic activity, with IC50 values ranging from 0.62 to 1.73 mg/ml in four human lung cancer cell lines, A549, H1264, H1299, and Calu-6, irrespective of their p53 status. We also demonstrate that pinecone water extract induces apoptosis associated with caspase-3 activation in the same cancer cell lines. Chemical investigation of the pinecone water extract revealed eight main components (1 - 8), and their structures were identified as dehydroabietic acid (1), 15-hydroxy-7-oxodehydroabietic acid (2), 7beta,15-dihydroxydehydroabietic acid (3), beta-d-glucopyranosyl labda-8(17,13) diene-(15,16)-lactone-19-oate (4), 7alpha,15-dihydroxydehydroabietic acid (5), (+)-(1S,2S,4R)-limonene-1,2-diol (6), sobrerol (7), and 4-hydroxybenzoic acid (8). These findings suggest a novel biological application of P. koraiensis pinecones in combatting human lung cancer, and further identify the major compounds that could contribute to this anticancer activity. PMID- 28027429 TI - Intrahepatic angiopoietin-2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems. AB - BACKGROUND & AIMS: Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied. METHODS: Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined. RESULTS: Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV. CONCLUSIONS: Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool. PMID- 28027430 TI - Pharmacological Properties of Melanin and its Function in Health. AB - The biological pigment melanin is present in most of the biological systems. It manifests a host of biological and pharmacological properties. Its role as a molecule with special properties and functions affecting general health, including photoprotective and immunological action, are well recognized. Its antioxidant, anti-inflammatory, immunomodulatory, radioprotective, hepatic, gastrointestinal and hypoglycaemic benefits have only recently been recognized and studied. It is also associated with certain disorders of the nervous system. In this MiniReview, we consider the steadily increasing literature on the bioavailability and functional activity of melanin. Published literature shows that melanin may play a number of possible pharmacological effects such as protective, stimulatory, diagnostic and curative roles in human health. In this MiniReview, possible health roles and pharmacological effects are considered. PMID- 28027431 TI - From classical mutagenesis to nuclease-based breeding - directing natural DNA repair for a natural end-product. AB - Production of mutants of crop plants by the use of chemical or physical genotoxins has a long tradition. These factors induce the natural DNA repair machinery to repair damage in an error-prone way. In the case of radiation, multiple double-strand breaks (DSBs) are induced randomly in the genome, leading in very rare cases to a desirable phenotype. In recent years the use of synthetic, site-directed nucleases (SDNs) - also referred to as sequence-specific nucleases - like the CRISPR/Cas system has enabled scientists to use exactly the same naturally occurring DNA repair mechanisms for the controlled induction of genomic changes at pre-defined sites in plant genomes. As these changes are not necessarily associated with the permanent integration of foreign DNA, the obtained organisms per se cannot be regarded as genetically modified as there is no way to distinguish them from natural variants. This applies to changes induced by DSBs as well as single-strand breaks, and involves repair by non-homologous end-joining and homologous recombination. The recent development of SDN-based 'DNA-free' approaches makes mutagenesis strategies in classical breeding indistinguishable from SDN-derived targeted genome modifications, even in regard to current regulatory rules. With the advent of new SDN technologies, much faster and more precise genome editing becomes available at reasonable cost, and potentially without requiring time-consuming deregulation of newly created phenotypes. This review will focus on classical mutagenesis breeding and the application of newly developed SDNs in order to emphasize similarities in the context of the regulatory situation for genetically modified crop plants. PMID- 28027432 TI - An allelic series at pax7a is associated with colour polymorphism diversity in Lake Malawi cichlid fish. AB - Despite long-standing interest in the evolution and maintenance of discrete phenotypic polymorphisms, the molecular genetic basis of such polymorphism in the wild is largely unknown. Female sex-associated blotched colour polymorphisms found in cichlids of Lake Malawi, East Africa, represent a highly successful polymorphic phenotype, found and maintained in four genera across the geographic expanse of the lake. Previously, we identified an association with an allelic variant of the paired-box transcription factor gene pax7a and blotched colour morphs in Lake Malawi cichlid fishes. Although a diverse range of blotched phenotypes are present in Lake Malawi cichlid species, they all appeared to result from an allele of pax7a that produces increased levels of transcript. Here, we examine the developmental and genetic basis of variation among blotched morphs. First, we confirm that pax7a-associated blotch morphs result primarily from modulation of melanophore development and survival. From laboratory crosses and natural population studies, we identify at least three alleles of pax7a associated with discrete subtypes of blotched morphs, in addition to the ancestral pax7a allele. Genotypes at pax7a support initial evolution of a novel pax7a allele to produce the blotched class of morphs, followed by subsequent evolution of that pax7a blotched allele to produce additional alleles associated with discrete colour morphs. Variant alleles of pax7a produce different levels of pax7a transcript, correlating with pigmentation phenotype at the cellular level. This naturally selected allelic series should serve as a case study for understanding the molecular genetic control of pax7a expression and the evolution of sex-associated alleles. PMID- 28027433 TI - Nutritional status of children with Wilms' tumour on admission to a South African hospital and its influence on outcome. AB - BACKGROUND: In developing countries up to 77% of children with cancer have been shown to be malnourished on admission. High rates of malnutrition occur due to factors such as poverty and advanced disease. Weight can be an inaccurate parameter for nutritional assessment of children with solid tumours as it is influenced by tumour mass. This study aimed to assess the prevalence of malnutrition amongst children with Wilms tumour (WT), the level of nutritional support received on admission and the influence of nutritional status on outcome. METHODS: Seventy-six children diagnosed with WT and admitted to Inkosi Albert Luthuli Central Hospital between 2004 and 2012 were studied prospectively. Nutritional assessment was conducted using weight, height, mid-upper arm circumference (MUAC) and triceps skinfold thickness (TSFT) prior to initiating treatment. Outcome was determined 2 years after admission. Time until commencement of nutritional resuscitation and nature, thereof, were recorded. RESULTS: Stunting and wasting was evident in 12% and 15% of patients, respectively. The prevalence of malnutrition was 66% when MUAC, TSFT and albumin were used. Malnutrition was not a predictor of poor outcome and did not predict advanced disease. The majority of patients (84%) received nutritional resuscitation within 2 weeks of admission. CONCLUSIONS: When classifying nutritional status in children with WT, the utilisation of weight and height in isolation can lead to an underestimation of the prevalence of malnutrition. Nutritional assessment of children with WT should also include MUAC and TSFT. Early aggressive nutritional resuscitation is recommended. PMID- 28027434 TI - Ultralow 1/f Noise in a Heterostructure of Superconducting Epitaxial Cobalt Disilicide Thin Film on Silicon. AB - High-precision resistance noise measurements indicate that the epitaxial CoSi2/Si heterostructures at 150 and 2 K (slightly above its superconducting transition temperature Tc of 1.54 K) exhibit an unusually low 1/f noise level in the frequency range of 0.008-0.2 Hz. This corresponds to an upper limit of Hooge constant gamma <= 3 * 10-6, about 100 times lower than that of single-crystalline aluminum films on SiO2 capped Si substrates. Supported by high-resolution cross sectional transmission electron microscopy studies, our analysis reveals that the 1/f noise is dominated by excess interfacial Si atoms and their dimer reconstruction induced fluctuators. Unbonded orbitals (i.e., dangling bonds) on excess Si atoms are intrinsically rare at the epitaxial CoSi2/Si(100) interface, giving limited trapping-detrapping centers for localized charges. With its excellent normal-state properties, CoSi2 has been used in silicon-based integrated circuits for decades. The intrinsically low noise properties discovered in this work could be utilized for developing quiet qubits and scalable superconducting circuits for future quantum computing. PMID- 28027435 TI - Planar Diamond-Based Multiarrays to Monitor Neurotransmitter Release and Action Potential Firing: New Perspectives in Cellular Neuroscience. AB - High biocompatibility, outstanding electrochemical responsiveness, inertness, and transparency make diamond-based multiarrays (DBMs) first-rate biosensors for in vitro detection of electrochemical and electrical signals from excitable cells together, with potential for in vivo applications as neural interfaces and prostheses. Here, we will review the electrochemical and physical properties of various DBMs and how these devices have been employed for recording released neurotransmitter molecules and all-or-none action potentials from living cells. Specifically, we will overview how DBMs can resolve localized exocytotic events from subcellular compartments using high-density microelectrode arrays (MEAs), or monitoring oxidizable neurotransmitter release from populations of cells in culture and tissue slices using low-density MEAs. Interfacing DBMs with excitable cells is currently leading to the promising opportunity of recording electrical signals as well as creating neuronal interfaces through the same device. Given the recent increasingly growing development of newly available DBMs of various geometries to monitor electrical activity and neurotransmitter release in a variety of excitable and neuronal tissues, the discussion will be limited to planar DBMs. PMID- 28027436 TI - Tunable Pseudocapacitance in 3D TiO2-delta Nanomembranes Enabling Superior Lithium Storage Performance. AB - Nanostructured TiO2 of different polymorphs, mostly prepared by hydro/solvothermal methods, have been extensively studied for more than a decade as anode materials in lithium ion batteries. Enormous efforts have been devoted to improving the electrical conductivity and lithium ion diffusivity in chemically synthesized TiO2 nanostructures. In this work we demonstrate that 3D Ti3+-self-doped TiO2 (TiO2-delta) nanomembranes, which are prepared by physical vapor deposition combined with strain-released rolled-up technology, have a great potential to address several of the long-standing challenges associated with TiO2 anodes. The intrinsic electrical conductivity of the TiO2 layer can be significantly improved by the in situ generated Ti3+, and the amorphous, thin TiO2 nanomembrane provides a shortened Li+ diffusion pathway. The fabricated material shows a favorable electrochemical reaction mechanism for lithium storage. Further, post-treatments are employed to adjust the Ti3+ concentration and crystallinity degree in TiO2 nanomembranes, providing an opportunity to investigate the important influences of Ti3+ self-doping and amorphous structures on the electrochemical processes. With these experiments, the pseudocapacitance contributions in TiO2 nanomembranes with different crystallinity degree are quantified and verified by an in-depth kinetics analysis. Additionally, an ultrathin metallic Ti layer can be included, which further improves the lithium storage properties of the TiO2, giving rise to the state-of-the-art capacity (200 mAh g-1 at 1 C), excellent rate capability (up to 50 C), and ultralong lifetime (for 5000 cycles at 10 C, with an extraordinary retention of 100%) of TiO2 anodes. PMID- 28027437 TI - Covalent Functionalization by Cycloaddition Reactions of Pristine Defect-Free Graphene. AB - Based on a low-temperature scanning tunneling microscopy study, we present a direct visualization of a cycloaddition reaction performed for some specific fluorinated maleimide molecules deposited on graphene. Up to now, it was widely admitted that such a cycloaddition reaction can not happen without pre-existing defects. However, our study shows that the cycloaddition reaction can be carried out on a defect-free basal graphene plane at room temperature. In the course of covalently grafting the molecules to graphene, the sp2 conjugation of carbon atoms was broken, and local sp3 bonds were created. The grafted molecules perturbed the graphene lattice, generating a standing-wave pattern with an anisotropy which was attributed to a (1,2) cycloaddition, as revealed by T-matrix approximation calculations. DFT calculations showed that while both (1,4) and (1,2) cycloadditions were possible on free-standing graphene, only the (1,2) cycloaddition could be obtained for graphene on SiC(0001). Globally averaging spectroscopic techniques, XPS and ARPES, were used to determine the modification in the elemental composition of the samples induced by the reaction, indicating an opening of an electronic gap in graphene. PMID- 28027438 TI - Omnidirectional Self-Assembly of Transparent Superoleophobic Nanotextures. AB - Engineering surface textures that are highly transparent and repel water, oil, and other low surface energy fluids can transform our interaction with wet environments. Despite extensive progress, current top-down methods are based on directional line-of-sight fabrication mechanisms that are limited by scale and cannot be applied to highly uneven, curved, and enclosed surfaces, while bottom up techniques often suffer from poor optical transparency. Here, we present an approach that enables the rapid, omnidirectional synthesis of flexible and up to 99.97% transparent superhydrophobic and -oleophobic textures on many variable surface types. These features are obtained by the spontaneous formation of a multi re-entrant morphology during the controlled self-assembly of nanoparticle aerosols. We also develop a mathematical model to explain and control the self assembly dynamics, providing important insights for the rational engineering of functional materials. We envision that our findings represent a significant advance in imparting superoleophobicity and superamphiphobicity to a so-far inapplicable family of materials and geometries for multifunctional applications. PMID- 28027440 TI - Shape-Controlled TiO2 Nanocrystals for Na-Ion Battery Electrodes: The Role of Different Exposed Crystal Facets on the Electrochemical Properties. AB - Rechargeable sodium-ion batteries are becoming a viable alternative to lithium based technology in energy storage strategies, due to the wide abundance of sodium raw material. In the past decade, this has generated a boom of research interest in such systems. Notwithstanding the large number of research papers concerning sodium-ion battery electrodes, the development of a low-cost, well performing anode material remains the largest obstacle to overcome. Although the well-known anatase, one of the allotropic forms of natural TiO2, was recently proposed for such applications, the material generally suffers from reduced cyclability and limited power, due to kinetic drawbacks and to its poor charge transport properties. A systematic approach in the morphological tuning of the anatase nanocrystals is needed, to optimize its structural features toward the electrochemical properties and to promote the material interaction with the conductive network and the electrolyte. Aiming to face with these issues, we were able to obtain a fine tuning of the nanoparticle morphology and to expose the most favorable nanocrystal facets to the electrolyte and to the conductive wrapping agent (graphene), thus overcoming the intrinsic limits of anatase transport properties. The result is a TiO2-based composite electrode able to deliver an outstandingly stability over cycles (150 mA h g-1 for more than 600 cycles in the 1.5-0.1 V potential range) never achieved with such a low content of carbonaceous substrate (5%). Moreover, it has been demonstrated for the first time than these outstanding performances are not simply related to the overall surface area of the different morphologies but have to be directly related to the peculiar surface characteristics of the crystals. PMID- 28027439 TI - Carbamate Insecticides Target Human Melatonin Receptors. AB - Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7 benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT1 and MT2 melatonin receptors in silico. Carbaryl and carbofuran then were tested for competition with 2-[125I]-iodomelatonin (300 pM) binding to hMT1 or hMT2 receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[125I]-iodomelatonin binding to the hMT2 compared to the hMT1 melatonin receptor (33 and 35-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 MUM), which decouples the G protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[125I]-iodomelatonin binding for the hMT1 melatonin receptor was not affected but significantly decreased for the hMT2 melatonin receptor compatible with receptor antagonist/inverse agonist and agonist efficacy, respectively. Altogether, our data points to a potentially new mechanism through which carbamate insecticides carbaryl and carbofuran could impact human health by altering the homeostatic balance of key regulatory processes by directly binding to melatonin receptors. PMID- 28027441 TI - Design of Amorphous Manganese Oxide@Multiwalled Carbon Nanotube Fiber for Robust Solid-State Supercapacitor. AB - Solid-state fiber-based supercapacitors have been considered promising energy storage devices for wearable electronics due to their lightweight and amenability to be woven into textiles. Efforts have been made to fabricate a high performance fiber electrode by depositing pseudocapacitive materials on the outer surface of carbonaceous fiber, for example, crystalline manganese oxide/multiwalled carbon nanotubes (MnO2/MWCNTs). However, a key challenge remaining is to achieve high specific capacitance and energy density without compromising the high rate capability and cycling stability. In addition, amorphous MnO2 is actually preferred due to its disordered structure and has been proven to exhibit superior electrochemical performance over the crystalline one. Herein, by incorporating amorphous MnO2 onto a well-aligned MWCNT sheet followed by twisting, we design an amorphous MnO2@MWCNT fiber, in which amorphous MnO2 nanoparticles are distributed in MWCNT fiber uniformly. The proposed structure gives the amorphous MnO2@MWCNT fiber good mechanical reliability, high electrical conductivity, and fast ion diffusion. Solid-state supercapacitor based on amorphous MnO2@MWCNT fibers exhibits improved energy density, superior rate capability, exceptional cycling stability, and excellent flexibility. This study provides a strategy to design a high performance fiber electrode with microstructure control for wearable energy storage devices. PMID- 28027442 TI - Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy. AB - Photodynamic therapy (PDT), a noninvasive cancer therapeutic method triggered by light, would lead to severe tumor hypoxia after treatment. Utilizing a hypoxia activated prodrug, AQ4N, which only shows toxicity to cancer cells under hypoxic environment, herein, a multipurpose liposome is prepared by encapsulating hydrophilic AQ4N and hydrophobic hexadecylamine conjugated chlorin e6 (hCe6), a photosensitizer, into its aqueous cavity and hydrophobic bilayer, respectively. After chelating a 64Cu isotope with Ce6, the obtained AQ4N-64Cu-hCe6-liposome is demonstrated to be an effective imaging probe for in vivo positron emission tomography, which together with in vivo fluorescence and photoacoustic imaging uncovers efficient passive homing of those liposomes after intravenous injection. After being irradiated with the 660 nm light-emitting diode light, the tumor bearing mice with injection of AQ4N-hCe6-liposome show severe tumor hypoxia, which in turn would trigger activation of AQ4N, and finally contributes to remarkably improved cancer treatment outcomes via sequential PDT and hypoxia activated chemotherapy. This work highlights a liposome-based theranostic nanomedicine that could utilize tumor hypoxia, a side effect of PDT, to trigger chemotherapy, resulting in greatly improved efficacy compared to conventional cancer PDT. PMID- 28027443 TI - Molybdenum Carbide-Derived Chlorine-Doped Ordered Mesoporous Carbon with Few Layered Graphene Walls for Energy Storage Applications. AB - In this work, we propose a one-step process to realize the in situ evolution of molybdenum carbide (Mo2C) nanoflakes into ordered mesoporous carbon with few layered graphene walls (OMG) by chloridization and self-organization, and simultaneously the Cl-doping of OMG (OMG-Cl) by modulating chloridization and annealing processes is fulfilled. Benefiting from the improvement of electroconductivity induced by Cl-doping, together with large specific surface area (1882 cm2 g-1) and homogeneous pore structures, as anode of lithium ion batteries, OMG-Cl shows remarkable charge capacity of 1305 mA h g-1 at current rate of 50 mA g-1 and fast charge-discharge rate within dozens of seconds (a charge time of 46 s), as well as retains a charge capacity of 733 mA h g-1 at a current rate of 0.5 mA g-1 after 100 cycles. Furthermore, as a promising electrode material for supercapacitors, OMG-Cl holds the specific capacitances of 250 F g-1 in 1 M H2SO4 solution and 220 F g-1 at a current density of 0.5 A g-1 in 6 M KOH solution, which are ~40% and 20% higher than those of undoped OMG electrode, respectively. The high capacitive performance of OMG-Cl material can be due to the additional fast Faradaic reactions induced from Cl-doping species. PMID- 28027444 TI - Knowledge, Representations, Attitudes, and Behaviors of Women Faced With Taking Medications While Breastfeeding. AB - BACKGROUND: Breastfeeding is a major public health issue in terms of its benefits to both mothers and infants. Despite recommendations, breastfeeding initiation and duration are low in many industrialized countries. Although human milk is viewed as the most appropriate food for infants, when it is perceived as contaminated, doubts about its quality can lead to negative behaviors concerning breastfeeding. This is especially true when mothers are taking medication. Research aim: The aim of this review is to evaluate the data in the literature on the knowledge, representations, attitudes, and behaviors of women with regard to taking medication while breastfeeding. These elements should aid our understanding of how the mothers' behaviors are constructed in this situation. METHODS: The authors conducted a scoping review to map and analyze the available data from literature sources regarding breastfeeding mothers' knowledge, representations, attitudes, and behaviors about medicines. A staged approach to the scoping review was used. RESULTS: Eighteen studies met the selection criteria. They described safety behaviors like noninitiation, duration reduction, breastfeeding cessation, and refusal to take medication in order to breastfeed. Most showed a conflict between taking medication and breastfeeding. Because the knowledge, representations, and attitudes behind such behaviors have received very little study, it is difficult to explain how these behaviors are constructed. CONCLUSION: The results of this review confirm the need for a qualitative study to explore the knowledge, representations, and attitudes of breastfeeding women faced with taking medications, so that we can understand their connection with observed behaviors and take appropriate educational action. PMID- 28027445 TI - Efficacy of an Osteopathic Treatment Coupled With Lactation Consultations for Infants' Biomechanical Sucking Difficulties. AB - BACKGROUND: Despite well-known recommendations from national and international bodies including the World Health Organization, few mothers achieve the goal of breastfeeding exclusively for 6 months. Half of mothers stop breastfeeding due to biomechanical issues in the first month, despite increasing support from lactation consultants. Osteopaths worldwide work with these babies, but there is little empirical evidence for this type of treatment. Research aim: This study aimed to determine the efficacy of an osteopathic treatment coupled with usual lactation consultations on infants' ability to latch. Secondary objectives included assessment of nipple pain and mothers' perceptions of the effect of treatment. METHODS: We conducted a single blind, randomized controlled trial at a mother-to-mother support group between January and December 2015. Data were collected at four different times over a 10-day period (T0-T10) from 97 mother infant dyads using the LATCH assessment tool, a visual analog scale (VAS) to document mothers' nipple pain, and a de novo questionnaire for breastfeeding management and potential treatment side effects. RESULTS: There were consistent statistical and clinical differences in the mean LATCH scores between the treatment and the control groups ( p < .001). However, no significant differences in the VAS scores were reported over time ( p = .713). Mothers reported no serious or unexpected side effects during the follow-up period. CONCLUSION: This study is one of the first to bring together lactation consultants and osteopaths to address infants with biomechanical sucking difficulties. Findings support the hypothesis that the addition of osteopathy to regular lactation consultations is beneficial and safe. PMID- 28027446 TI - Current Trends in Multidrug Optimization: An Alley of Future Successful Treatment of Complex Disorders. AB - The identification of effective and long-lasting cancer therapies still remains elusive, partially due to patient and tumor heterogeneity, acquired drug resistance, and single-drug dose-limiting toxicities. The use of drug combinations may help to overcome some limitations of current cancer therapies by challenging the robustness and redundancy of biological processes. However, effective drug combination optimization requires the careful consideration of numerous parameters. The complexity of this optimization problem is clearly nontrivial and likely requires the assistance of advanced heuristic optimization techniques. In the current review, we discuss the application of optimization techniques for the identification of optimal drug combinations. More specifically, we focus on the application of phenotype-based screening approaches in the field of cancer therapy. These methods are divided into three categories: (1) modeling methods, (2) model-free approaches based on biological search algorithms, and (3) merged approaches, particularly phenotypically driven network biology methods and computation network models relying on phenotypic data. In addition to a brief description of each approach, we include a critical discussion of the advantages and disadvantages of each method, with a strong focus on the limitations and considerations needed to successfully apply such methods in biological research. PMID- 28027447 TI - Dynamic Compound-Dependent Acoustic Transfer to Investigate Inhibitor Reversibility. AB - Automated mechanism of action studies are introducing the need for tailored compound delivery, which can be challenging for standard compound management procedures. Jump dilution assays investigating inhibitor reversibility require compound delivery at specific volumes to assay specific concentrations of 10 * IC50 for each inhibitor. Creating custom-made source plates with unique compound concentrations to dispense a uniform single volume can be prohibitively slow. A broadly applicable tool that enables on-the fly dispensing of variable amounts of stock concentrations was developed using the Acoustic Transfer System (ATS). The Dynamic Transfer Modification Program (DTMP) is an integrated LabVIEW program used to automate customized volume transfers from each well based on compound identity within a given source plate. A jump dilution investigating the time dependent inhibition of the enzyme dipeptidyl peptidase-4 (DPP4) with multiple inhibitors is described here to demonstrate the delivery of specific volumes of various compounds in a high-throughput manner. The ability to automate this process allows for the characterization of inhibitor reversibility earlier in the drug discovery process, resulting in better informed lead candidate selection. PMID- 28027448 TI - Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery. AB - Huntington's disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine [polyQ]) in the huntingtin ( HTT) gene, which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability, and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients, and induced pluripotent stem cells from patients. A transgenic nonhuman primate model of HD (HD monkey) shows neuropathological, behavioral, and molecular changes similar to an HD patient. In addition, neural progenitor cells (NPCs) derived from HD monkeys can be maintained in culture and differentiated to neural cells with distinct HD cellular phenotypes including the formation of mHTT aggregates, intranuclear inclusions, and increased susceptibility to oxidative stress. Here, we evaluated the potential application of HD monkey NPCs and neural cells as an in vitro model for HD drug discovery research. PMID- 28027449 TI - Novel Chemical Scaffolds for Inhibition of Rifamycin-Resistant RNA Polymerase Discovered from High-Throughput Screening. AB - Rifampin has been a cornerstone of tuberculosis (TB) treatment since its introduction. The rise of multidrug-resistant and extensively drug-resistant TB makes the development of novel therapeutics effective against these strains an urgent need. Site-specific mutations in the target enzyme of rifampin, RNA polymerase (RNAP) comprises the majority (~97%) of rifamycin-resistant (RifR) strains of Mycobacterium tuberculosis (MTB). To identify novel inhibitors of bacterial RNAP, an in vitro plasmid-based transcription assay that uses malachite green (MG) to detect transcribed RNA containing MG aptamers was developed. This assay was optimized in a 384-well plate format and used to screen 150,000 compounds against an Escherichia coli homolog of the most clinically relevant RifR RNAP (betaS531L) containing a mutation (beta'V408G) that compensates for the fitness defect of this RifR mutant. Following confirmation and concentration response studies, 10 compounds were identified with similar in vitro inhibition values across a panel of wild-type and RifR E. coli and MTB RNAPs. Four compounds identified from the screen are active against MTB in culture at concentrations below 200 uM. Initial follow-up has resulted in the elimination of one scaffold due to potential pan-assay interference. PMID- 28027450 TI - Enabling 1536-Well High-Throughput Cell-Based Screening through the Application of Novel Centrifugal Plate Washing. AB - Cell-based assays have long been important within hit discovery paradigms; however, improving the disease relevance of the assay system can positively affect the translation of small-molecule drug discovery, especially if adopted in the initial hit identification assay. Consequently, there is an increasing need for disease-relevant assay systems capable of running at large scale, including the use of induced pluripotent stem cells and donor-derived primary cells. Major hurdles to adopting these assays for high-throughput screening are the cost, availability of cells, and complex protocols. Miniaturization of such assays to 1536-well format is an approach that can reduce costs and increase throughput. Adaptation of these complex cell assays to 1536-well format brings major challenges in liquid handling for high-content assays requiring washing steps and coating of plates. In addition, problematic edge effects and reduced assay quality are frequently encountered. In this study, we describe the novel application of a centrifugal plate washer to facilitate miniaturization of a range of 1536-well cell assays and techniques to reduce edge effects, all of which improved throughput and data quality. Cell assays currently limited in throughput because of cost and complex protocols may be enabled by the techniques presented in this study. PMID- 28027451 TI - The Use of Platelet-Rich and Platelet-Poor Plasma to Enhance Differentiation of Skeletal Myoblasts: Implications for the Use of Autologous Blood Products for Muscle Regeneration. AB - BACKGROUND: Platelet-rich plasma (PRP) has been used to augment tissue repair and regeneration after musculoskeletal injury. However, there is increasing clinical evidence that PRP does not show a consistent clinical effect. Purpose/Hypothesis: This study aimed to compare the effects of the following non-neutrophil containing (leukocyte-poor) plasma fractions on human skeletal muscle myoblast (HSMM) differentiation: (1) PRP, (2) modified PRP (Mod-PRP), in which transforming growth factor beta1 (TGF-beta1) and myostatin (MSTN) were depleted, and (3) platelet-poor plasma (PPP). The hypothesis was that leukocyte-poor PRP would lead to myoblast proliferation (not differentiation), whereas certain modifications of PRP preparations would increase myoblast differentiation, which is necessary for skeletal muscle regeneration. STUDY DESIGN: Controlled laboratory study. METHODS: Blood from 7 human donors was individually processed to simultaneously create leukocyte-poor fractions: PRP, Mod-PRP, PPP, and secondarily spun PRP and Mod-PRP (PRPss and Mod-PRPss, respectively). Mod-PRP was produced by removing TGF-beta1 and MSTN from PRP using antibodies attached to sterile beads, while a second-stage centrifugal spin of PRP was performed to remove platelets. The biologics were individually added to cell culture groups. Analysis for induction into myoblast differentiation pathways included Western blot analysis, reverse-transcription polymerase chain reaction, and immunohistochemistry, as well as confocal microscopy to assess polynucleated myotubule formation. RESULTS: HSMMs cultured with PRP showed an increase in proliferation but no evidence of differentiation. Western blot analysis confirmed that MSTN and TGF-beta1 could be decreased in Mod-PRP using antibody-coated beads, but this modification mildly improved myoblast differentiation. However, cell culture with PPP, PRPss, and Mod-PRPss led to a decreased proliferation rate but a significant induction of myoblast differentiation verified by increased multinucleated myotubule formation and myosin heavy chain expression (mean 8-fold change in mRNA level; P < .05), which was comparable with 2% horse serum, the positive control. CONCLUSION: PPP and leukocyte-poor PRP preparations subjected to a second spin to remove the platelets led to induction of myoblast cells into the muscle differentiation pathway, whereas unmodified leukocyte-poor PRP led to myoblast proliferation. CLINICAL RELEVANCE: These results indicate that traditionally formulated PRP may not be appropriate to induce muscle regeneration. Laboratory evidence suggests that PPP or non-neutrophil-containing PRPss, subjected to an additional spin to remove platelets, should be used to stimulate myoblast differentiation, which is necessary for skeletal muscle regeneration. Clinical studies will be required to confirm the effect of these biologics on muscle regeneration. PMID- 28027452 TI - All-Inside, All-Epiphyseal Anterior Cruciate Ligament Reconstruction in Skeletally Immature Athletes: Return to Sport, Incidence of Second Surgery, and 2 Year Clinical Outcomes. AB - BACKGROUND: Anterior cruciate ligament (ACL) injuries in skeletally immature athletes are increasing. PURPOSE: To evaluate the 2-year clinical outcomes of all inside, all-epiphyseal ACL reconstruction in skeletally immature athletes with 3 to 6 years of remaining growth, with a focus on return to sport and the incidence of second surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-three skeletally immature athletes were prospectively evaluated after all epiphyseal ACL reconstruction utilizing a hamstring autograft. The athletes' age, sex, sport, mechanism of injury, radiographs, and magnetic resonance imaging (MRI) findings were noted. The evaluation included a physical examination, KT 1000 arthrometer measurements, isokinetic testing, and validated outcome scores. Standing radiographs and spoiled gradient recalled echo MRI scans were obtained at 6, 12, and 24 months postoperatively. A quality of movement assessment and return-to-sport performance analysis were also performed. RESULTS: Of the 23 athletes, 6 were female (mean age, 11.3 years), and 17 were male (mean age, 12.6 years). At a minimum follow-up of 2 years (range, 24-45 months), the mean International Knee Documentation Committee score was 94.6 +/- 4.9, the mean Lysholm score was 97.9 +/- 4.0, the mean Marx activity rating scale score was 13.4 +/- 3.6, and the mean Hospital for Special Surgery Pediatric Functional Activity Brief Scale score was 23.9 +/- 7.0. Lachman and pivot-shift test results were negative in all patients. The mean side-to-side difference on the KT-1000 arthrometer was 0.9 +/- 0.5 mm and less tight on the operated side. No significant growth disturbances were noted; however, 6 athletes had a leg-length discrepancy of more than 5 mm (range, 6-18 mm). Two patients had overgrowth in the femur of more than 15 mm (16 mm and 18 mm). Two athletes (8.7%) required second surgery. The mean time to return to unrestricted activity was 13.5 months (range, 8-22 months). CONCLUSION: The all-inside, all-epiphyseal ACL reconstruction technique using a hamstring autograft demonstrates excellent subjective and objective clinical outcomes in skeletally immature athletes without physeal arrest. PMID- 28027453 TI - Pethidine efficacy in achieving the ultrasound-guided oblique subcostal transversus abdominis plane block in laparoscopic cholecystectomy: A prospective study. AB - Pethidine is a synthetic opioid with local anesthetic properties. Our goal was to evaluate the analgesic efficacy of pethidine for achieving the ultrasound-guided oblique subcostal transversus abdominis plane (OSTAP) block in laparoscopic cholecystectomy. This prospective, double-blind study included 79 patients of physical status I and II according to American Society of Anesthesiologists, scheduled for elective laparoscopic cholecystectomy. The patients were randomly allocated into three groups, depending on the drug used to achieve preoperative bilateral OSTAP block: 1) OSTAP-Placebo (treated with normal saline); 2) OSTAP Bupivacaine (treated with 0.25% bupivacaine); and 3) OSTAP-Pethidine (treated with 1% pethidine). The efficacy of pethidine in achieving the OSTAP block was analyzed using visual analog scale (VAS), intraoperative opioid dose, opioid consumption in post anesthesia care unit, and opioid consumption in the first 24 postoperative hours. The pain scores assessed by VAS at 0, 2, 4, 6, 12, and 24 hours were significantly lower in OSTAP-Pethidine than in OSTAP-Placebo group (p < 0.001). The mean intraoperative opioid consumption was significantly lower in OSTAP-Pethidine compared to OSTAP-Placebo group (150 versus 400 mg, p < 0.001), as well as the mean opioid consumption in the first 24 hours (20.4 versus 78 mg, p < 0.001). Comparing VAS assessment between OSTAP-Bupivacaine and OSTAP Pethidine groups, statistically significant differences were observed only for the immediate postoperative pain assessment (0 hours), where lower values were observed in OSTAP-Pethidine group (p = 0.004). There were no statistically significant differences in the incidence of postoperative nausea and vomiting (p = 0.131) between the groups. The use of 1% pethidine can be an alternative to 0.25% bupivacaine in achieving OSTAP block for laparoscopic cholecystectomy. PMID- 28027454 TI - Apocrine carcinoma of the breast: A brief update on the molecular features and targetable biomarkers. AB - Apocrine carcinoma of the breast is a rare, primary breast cancer characterized by the apocrine morphology, estrogen receptor-negative and androgen receptor positive profile with a frequent overexpression of Her-2/neu protein (~30%). Apart from the Her-2/neu target, advanced and/or metastatic apocrine carcinomas have limited treatment options. In this review, we briefly describe and discuss the molecular features and new theranostic biomarkers for this rare mammary malignancy. The importance of comprehensive profiling is highlighted due to synergistic and potentially antagonistic molecular events in the individual patients. PMID- 28027455 TI - Analysis of pulmonary surfactant by Fourier transform infrared spectroscopy after exposure to sevoflurane and isoflurane. AB - Pulmonary surfactant, consisting primarily of phospholipids and four surfactant specific proteins, is among the first structures that is exposed to inhalation anesthetics. Consequently, changes of pulmonary surfactant due to this exposure could cause respiratory complications after long anesthetic procedures. Fourier transform infrared (FTIR) spectroscopy was used to explore the effects of two inhalation anesthetics, sevoflurane and isoflurane, on a commercially available pulmonary surfactant. The research was primarily focused on the effect of anesthetics on the lipid component of the surfactant. Four different concentrations of anesthetics were added, and the doses were higher from the low clinical doses typically used. Recorded spectra were analyzed using principal component analysis, and the Student's t-test was performed to confirm the results. The exposure to both anesthetics induced similar changes, consistent with the increase of the anesthetic concentration. The most pronounced effect was on the hydrophilic head group of phospholipids, which is in agreement with the disruption of the hydrogen bond, caused by the anesthetics. A change in the band intensities of CH2 stretching vibrations, indicative of a disordering effect of anesthetics on the hydrophobic tails of phospholipids, was also observed. Changes induced by isoflurane appear to be more pronounced than those induced by sevoflurane. Furthermore, our results suggest that FTIR spectroscopy is a promising tool in studying anesthetic effects on pulmonary surfactant. PMID- 28027457 TI - Emergency Department Management Of Priapism. AB - Priapism is a genitourinary emergency that demands a thorough, time-sensitive evaluation. There are 3 types of priapism: ischemic, nonischemic, and recurrent ischemic priapism; ischemic priapism accounts for 95% of cases. Ischemic priapism must be treated within 4 to 6 hours to minimize morbidity, including impotence. The diagnosis of ischemic priapism relies heavily on the history and physical examination and may be facilitated by penile blood gas analysis and penile ultrasound. This issue reviews current evidence regarding emergency department treatment of ischemic priapism using a stepwise approach that begins with aspiration of cavernosal blood, cold saline irrigation, and penile injection with sympathomimetic agents. Evidence-based management and appropriate urologic follow up of nonischemic and recurrent ischemic priapism maximizes patient outcomes and resource utilization. PMID- 28027456 TI - Immunohistochemical localization of ionotropic glutamate receptors in the rat red nucleus. AB - In this study, we aimed to determine the presence as well as the diverse distribution of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor subunits in the rat red nucleus. Using adult Sprague-Dawley rats as the experimental animals, immunohistochemistry was performed on 30 um thick coronal brain sections with antibodies against alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (GluA1-4), kainate (GluK1, GluK2/3, and GluK5), and NMDA (GluN1 and GluN2A) receptor subunits. The results showed that all ionotropic glutamate receptor subunits are expressed in the red nucleus. Specific staining was localized in the neuron bodies and processes. However, the pattern of immunoreactivity and the number of labeled neurons changed depending on the type of ionotropic glutamate receptor subunits and the localization of neurons in the red nucleus. The neurons localized in the magnocellular part of the red nucleus were particularly immunopositive for GluA2, GluA4, GluK2/3, GluK5, GluN1, and GluN2A receptor proteins. In the parvocellular part of the red nucleus, ionotropic glutamate receptor subunit immunoreactivity of variable intensity (lightly to moderately stained) was detected in the neurons. These results suggest that red nucleus neurons in rat heterogeneously express ionotropic glutamate receptor subunits to form functional receptor channels. In addition, the likelihood of the coexpression of different subunits in the same subgroup of neurons suggests the formation of receptor channels with diverse structure by way of different subunit combination, and the possibility of various neuronal functions through these channels in the red nucleus. PMID- 28027458 TI - Altered Level Of Consciousness: Evidence-Based Management In The Emergency Department. AB - A child who presents to the emergency department with an altered level of consciousness can be clinically unstable and can pose a great diagnostic challenge. The emergency clinician must quickly develop a wide differential of possible etiologies in order to administer potentially life-saving medications or interventions. The history, physical examination, and appropriate diagnostic tests can aid greatly in rapidly narrowing the differential diagnosis. Once initial stabilization, workup, and first-line interventions are completed, most patients who present with unresolved or unidentified altered level of consciousness should be admitted for further evaluation and close monitoring. This issue provides a review of the etiologies of altered level of consciousness as well as guidance for the management and disposition of patients with this condition. PMID- 28027459 TI - Dignity and autonomy in the care for patients with dementia: Differences among formal caretakers of varied cultural backgrounds and their meaning. AB - BACKGROUND: A key message in the World Health Organization report on dementia (2012) emphasizes this disease as a top priority in public health and the need to improve professional attitudes to patients with dementia, while acknowledging that the workforce in dementia care is becoming increasingly diverse culturally. AIMS: To trace whether there are substantial gaps between formal caretakers from different cultural groups (Israeli born Jews [Sabras], Israeli Arabs [Arabs] and migrants from Russia [Russians]) regarding their stances on the human dignity and autonomy of patients with dementia, as well as understand the meaning of these gaps. DESIGN & METHOD: quantitative analysis utilizing questionnaires that were filled-out by approximately 200 caretakers from the different cultural groups, working in a nursing home or a hospital. RESULTS: In nursing homes, substantial differences were found in the attitudes to human dignity and autonomy of patients with dementia between Russian and Arab as well as Sabra caretakers. In the hospital, there was no influence for the ethno-culture variable on dignity or autonomy. CONCLUSION: Contrary to past research, in nursing homes, significant differences were found between certain ethno-cultural groups (Arabs and Russians) regarding their stance towards the dignity of patients with dementia. Arab caretakers hold a conception of dignity and autonomy that resonates strongly with person-centered care and outweighs institutional settings as well as may be related to the fostering of virtues. PMID- 28027460 TI - SM-RuleMiner: Spider monkey based rule miner using novel fitness function for diabetes classification. AB - Diabetes is a major health challenge around the world. Existing rule-based classification systems have been widely used for diabetes diagnosis, even though they must overcome the challenge of producing a comprehensive optimal ruleset while balancing accuracy, sensitivity and specificity values. To resolve this drawback, in this paper, a Spider Monkey Optimization-based rule miner (SM RuleMiner) has been proposed for diabetes classification. A novel fitness function has also been incorporated into SM-RuleMiner to generate a comprehensive optimal ruleset while balancing accuracy, sensitivity and specificity. The proposed rule-miner is compared against three rule-based algorithms, namely ID3, C4.5 and CART, along with several meta-heuristic-based rule mining algorithms, on the Pima Indians Diabetes dataset using 10-fold cross validation. It has been observed that the proposed rule miner outperforms several well-known algorithms in terms of average classification accuracy and average sensitivity. Moreover, the proposed rule miner outperformed the other algorithms in terms of mean rule length and mean ruleset size. PMID- 28027461 TI - Tomographic image reconstruction via estimation of sparse unidirectional gradients. AB - Since computed tomography (CT) was developed over 35 years ago, new mathematical ideas and computational algorithms have been continuingly elaborated to improve the quality of reconstructed images. In recent years, a considerable effort can be noticed to apply the sparse solution of underdetermined system theory to the reconstruction of CT images from undersampled data. Its significance stems from the possibility of obtaining good quality CT images from low dose projections. Among diverse approaches, total variation (TV) minimizing 2D gradients of an image, seems to be the most popular method. In this paper, a new method for CT image reconstruction via sparse gradients estimation (SGE), is proposed. It consists in estimating 1D gradients specified in four directions using the iterative reweighting algorithm. To investigate its properties and to compare it with TV and other related methods, numerical simulations were performed according to the Monte Carlo scheme, using the Shepp-Logan and more realistic brain phantoms scanned at 9-60 directions in the range from 0 to 179 degrees , with measurement data disturbed by additive Gaussians noise characterized by the relative level of 0.1%, 0.2%, 0.5%, 1%, 2% and 5%. The accuracy of image reconstruction was assessed in terms of the relative root-mean-square (RMS) error. The results show that the proposed SGE algorithm has returned more accurate images than TV for the cases fulfilling the sparsity conditions. Particularly, it preserves sharp edges of regions representing different tissues or organs and yields images of much better quality reconstructed from a small number of projections disturbed by relatively low measurement noise. PMID- 28027462 TI - The influence of asymmetric force requirements on a multi-frequency bimanual coordination task. AB - An experiment was designed to determine the impact of the force requirements on the production of bimanual 1:2 coordination patterns requiring the same (symmetric) or different (asymmetric) forces when Lissajous displays and goal templates are provided. The Lissajous displays have been shown to minimize the influence of attentional and perceptual constraints allowing constraints related to neural crosstalk to be more clearly observed. Participants (N=20) were randomly assigned to a force condition in which the left or right limb was required to produce more force than the contralateral limb. In each condition participants were required to rhythmically coordinate the pattern of isometric forces in a 1:2 coordination pattern. Participant performed 13 practice trials and 1 test trial per force level. The results indicated that participants were able to effectively coordinate the 1:2 multi-frequency goal patterns under both symmetric and asymmetric force requirements. However, consistent distortions in the force and force velocity time series were observed for one limb that appeared to be associated with the production of force in the contralateral limb. Distortions in the force produced by the left limb occurred regardless of the force requirements of the task (symmetric, asymmetric) or whether the left or right limb had to produce more force than the contralateral limb. However, distinct distortions in the right limb occurred only when the left limb was required to produce 5 times more force than the right limb. These results are consistent with the notion that neural crosstalk can influence both limbs, but may manifest differently for each limb depending on the force requirements of the task. PMID- 28027463 TI - Quantifying knee mechanics during balance training exercises. AB - Patellofemoral pain (PFP) is common among runners and those recovering from anterior cruciate ligament reconstruction. Training programs designed to prevent or treat injuries often include balance training, although balance interventions have been reported to coincide with more knee injuries. Knowledge of the effect of balance exercises on knee mechanics may be useful when designing training programs. High knee abduction moment has been implicated in the development of PFP, and imbalance between vastus lateralis (VL) and vastus medialis oblique (VMO) may contribute to patellofemoral stress. The purpose was to quantify knee abduction moment and vasti muscle activity during balance exercises. Muscle activity of VMO and VL, three-dimensional lower-extremity kinematics, and ground reaction forces of healthy recreational athletes (12M, 13F) were recorded during five exercises. Peak knee abduction moment, ratio of VMO:VL activity, and delay in onset of VMO relative to VL were quantified for each exercise. The influence of sex and exercise on each variable was determined using a mixed-model ANOVA. All analyses indicated a significant main effect of exercise, p<0.05. Follow-up comparisons showed low peak knee abduction moment and high VMO:VL ratio for the task with anterior-posterior motion. Delay of VMO relative to VL was similar among balance board tasks. PMID- 28027464 TI - Risk factors for child maltreatment in an Australian population-based birth cohort. AB - Child maltreatment and other adverse childhood experiences adversely influence population health and socioeconomic outcomes. Knowledge of the risk factors for child maltreatment can be used to identify children at risk and may represent opportunities for prevention. We examined a range of possible child, parent and family risk factors for child maltreatment in a prospective 27-year population based birth cohort of 2443 Australians. Physical abuse, sexual abuse, emotional abuse, neglect and witnessing of domestic violence were recorded retrospectively in early adulthood. Potential risk factors were collected prospectively during childhood or reported retrospectively. Associations were estimated using bivariate and multivariate logistic regressions and combined into cumulative risk scores. Higher levels of economic disadvantage, poor parental mental health and substance use, and social instability were strongly associated with increased risk of child maltreatment. Indicators of child health displayed mixed associations and infant temperament was uncorrelated to maltreatment. Some differences were observed across types of maltreatment but risk profiles were generally similar. In multivariate analyses, nine independent risk factors were identified, including some that are potentially modifiable: economic disadvantage and parental substance use problems. Risk of maltreatment increased exponentially with the number of risk factors experienced, with prevalence of maltreatment in the highest risk groups exceeding 80%. A cumulative risk score based on the independent risk factors allowed identification of individuals at very high risk of maltreatment, while a score that incorporated all significant risk and protective factors provided better identification of low-risk individuals. PMID- 28027465 TI - Nitrogen-doped carbon spheres: A new high-energy-density and long-life pseudo capacitive electrode material for electrochemical flow capacitor. AB - One of the most challenging issues in developing electrochemical flow capacitor (EFC) technology is the design and synthesis of active electrode materials with high energy density and long cycle life. However, in practical cases, the energy density and cycle ability obtained currently cannot meet the practical need. In this work, we propose a new active material, nitrogen-doped carbon spheres (NCSs), as flowable electrodes for EFC application. The NCSs were prepared via one-pot hydrothermal synthesis in the presence of resorcinol/formaldehyde as carbon precursors and melamine as nitrogen precursor, followed by carbonization in nitrogen flow at various temperatures. The results of EFC experiments demonstrate that NCSs obtained at 800 degrees C exhibit a high energy density of 13.5Whkg-1 and an excellent cycle ability, indicating the superiority of NCSs for EFC application. PMID- 28027466 TI - Dynamics of aggregate size and shape properties under sequenced flocculation in a turbulent Taylor-Couette reactor. AB - This paper concerns experimental investigation of the sequenced flocculation of latex particles in a Taylor-Couette reactor. The aim of this work was to investigate the evolution of both the size and the shape of aggregates under sequenced hydrodynamics. A number of studies have focused on the evolution of the aggregate size or size distribution during steps of growth-breakage-regrowth, but aggregates generally experience steps of breakage-regrowth on repeated occasions in real operating conditions (passages near the impeller or during the transfer processes, for example). The experiments conducted in this work consisted thus of an alternation of six steps with alternately low and high shear rates under turbulent conditions. The particle size distributions were monitored throughout the sequencing, and the circularity and convexity (shape parameters) distributions were measured, enabling a more precise description of the entire floc population, rather than a fractal dimension. While the aggregate size distribution was clearly controlled by hydrodynamics, the shape distributions continuously evolved during the sequencing. The main new finding of our work notes the independence between the aggregate shape and hydrodynamics. Indeed, after multiples steps of breakage-regrowth, regardless of the aggregate size distribution and hydrodynamics, the aggregate shape seemed to reach a unique steady-state morphological distribution. PMID- 28027467 TI - Influence of hydrophobicity distribution of particle mixtures on emulsion stabilization. AB - Whilst emulsions stabilized by uniform particles are well established, the emulsification behavior of heterogeneous mixtures of particles with varying hydrophobicity is rarely examined. Consequently, the influence of the distribution of particle hydrophobicity on oil-water emulsion stabilization is poorly understood. In the present work, the wettability of the bitumen froth fine solids from Alberta oil sands was studied by film flotation and toluene-water emulsification tests, before and after a hydrothermal treatment at 300-420 degrees C. This approach provided a series of populations of particles with different distributions of hydrophobicity. The initial fine particles in the bitumen froth had a critical surface tension ranging from 26 to 56mN/m, with a mean value of 39mN/m. Hydrothermal treatment at 300-420 degrees C progressively shifted the hydrophobicity distribution of the fine particles, resulting in a lower mean critical surface tension and a narrower critical surface tension range. The emulsifying capacity of the fine particle mixtures, as indicated by the volume of the produced toluene-water emulsions, was unrelated to the mean critical surface tension. Instead, emulsification depended on the proportion of a specific sub-fraction of particles with a critical surface tension of 27-30mN/m. This sub-fraction of particles, with intermediate hydrophobicity, dominated the emulsification behavior of the particle mixtures. PMID- 28027468 TI - A strategy to achieve efficient dual-mode luminescence in lanthanide-based magnetic hybrid nanostructure and its demonstration for the detection of latent fingerprints. AB - We have synthesized a novel inorganic-organic hybrid nanostructure (IOHN) composed of fluoride nanophosphor (NaGd0.78Er0.02Yb0.2F4) and beta-diketones complex (Eu(DBM)3Phen). The Le Bail fitting of X-ray diffraction data suggests that the nanophoshor crystallizes in a hexagonal structure (P63/m space group). The TEM studies reveal that the nanophosphor and the IOHN both have average particle size of 6-8nm. The Eu(DBM)3Phen and NaGd0.78Er0.02Yb0.2F4 show characteristic down-shifting (DS) and up-conversion (UC) emission, under UV and NIR excitation, respectively. The IOHN comprises an excellent dual-mode optical features (DS and UC) of both the phases. Energy transfer from Er3+ (doped in inorganic phase) to Eu3+ (coordinated in organic phase) clearly demonstrates for a viable coupling between both the phases. IOHN material was found to be unique for the visualization of latent fingermarks. Because of ultrafine particle size the surface to volume ratio is relatively higher which improves the attachment of particles with the fingermarks. On the other hand, the strong paramagnetic property helps to remove excess material with magnetic wand easily. These properties provide an opportunity to probe even very weak fingermarks. Notwithstanding this, the dual-mode emission is useful for the visualization of latent fingermarks on multi-color surfaces as well. PMID- 28027469 TI - Biopolymer-induced morphology control of brushite for enhanced defluorination of drinking water. AB - Due to the relatively lower potential health risks as well as the good affinity for fluoride anion, calcium-based minerals have been widely carried out for the adsorption of fluoride. The improvement of adsorption capacity can be accomplished by regulation of particle size, shape and structure. Thus, here we report the controllable synthesis of petal-like nanosheets of brushite by using chitosan as a regulator. The addition of chitosan polymer in calcium precursor not only could serve ideal nucleation sites but also could play a vital role in confining the calcium phosphate aggregates and thus controlling the size of the brushite flakes. When the concentration of chitosan was 0.01wt%, the as synthesized brushite showed nanosheet-structured with the dimensions ranged from 100 to 200nm and displayed outstanding fluoride adsorption capacity of 231.5mg/g according to the fitted Langmuir model, which was comparatively higher than that of the previously reported calcium-based adsorbents. Moreover, the pH change and common co-existing anions in solution almost presented less negative effect on the F- adsorption onto petal-like brushite nanosheets. We hope that these petal like nanosheets based on green nanotechnology can help to achieve the intention of safe drinking water. PMID- 28027470 TI - Performance of a novel atrazine-induced cerebellar toxicity in quail (Coturnix C. coturnix): Activating PXR/CAR pathway responses and disrupting cytochrome P450 homeostasis. AB - Atrazine is well known to be a biologically hazardous substance with toxic effects, but atrazine-induced neurotoxicity remains unclear. The aim of this study was to investigate the mechanisms of atrazine-induced cerebellar toxicity. To determine atrazine-exerted potential neurotoxicity, quails were treated with 50, 250 and 500 mg/kg atrazine by gavage administration for 45 days. Notably, the changes of cytochrome P450 enzyme system (CYP450s) were observed in atrazine exposed quails. The contents of cytochrome P450 (CYP450) and Cytochrome b5 (Cyt b5) and the activities of NADPH-cytochrome c reductase (NCR), aminopyrin N demethylase (APND) and aniline-4-hydeoxylase (AH) were increased and erythromycin N-demethylase (ERND) was decreased in quail cerebellum. Nuclear xenobiotic receptors (NXRs) and the transcriptions of NXRs-related target molecules were influenced in cerebellum. Atrazine disrupted the CYP450s balance in quail cerebellum. These results suggested that atrazine-induced cerebellar toxicity in birds was associated with activating PXR/CAR pathway responses and disrupting cytochrome P450 homeostasis. This study provided novel evidences that atrazine exposure induced cerebellar toxicity. PMID- 28027471 TI - Oxidative and cellular metabolic stress of Oreochromis mossambicus as biomarkers indicators of trace element contaminants. AB - Antioxidative status, cellular metabolic stress and neurotransmitter enzyme assay as a pollution biomarker in Oreochromis mossambicus collected from Bhima river were investigated. O. mossambicus was collected from 18 different sites of Bhima river, which differ in their extent and type of contamination load. The antioxidative status were determined such as catalase (CAT), superoxide dismutase (SOD) and glutathione-s-transferase (GST) in the liver, gill, brain, gonad and kidney. All the studied parameters indicated potent signals for contamination of the aquatic water body. The antioxidative status was substantially high (p < 0.01) in the fish collected from Bhima river. The cellular stress enzymes such as lactate dehdrogenase (LDH), and malate dehydrogenase (MDH) in liver, gill, brain, gonad and muscle were remarkably (p < 0.01) elevated in O. mossambicus collected from Bhima river. The brain acetylcholine esterase (AChE) was noticeably inhibited (p < 0.01) whereas lipid peroxide (LPO) elevated in fish collected from a few sites. We also used morphological study as biomarkers indicators such as condition factor (CF), hepatosomatic index (HSI), gonadosomatic index (GSI). The results of condition factor and gonadosomatic index are significantly (p < 0.01) poor and hepatosomatic index was significantly (p < 0.01) elevated in O. mossambicus. The finding of the present investigation provides a rational application of oxidative stress, cellular stress, neurotransmitter, lipid peroxide and some morphological parameters to be used as biomarkers for biomonitoring the contamination of trace elements in polluted aquatic environment. PMID- 28027472 TI - Assessment of major and trace element bioavailability in vineyard soil applying different single extraction procedures and pseudo-total digestion. AB - A different single extraction procedures (CH3COOH, Na2EDTA, CaCl2, NH4NO3, deionized water), and pseudo-total digestion (aqua regia) were applied to determine major (Al, Fe, K, Mn, Na, P, S, and Si) and trace (Cd, Co, Cr, Cu, Mo, Ni, Pb, V, and Zn) element bioavailability in a topsoil from the experimental vineyard ("Radmilovac", Belgrade, Serbia). For the first time, the extraction with deionized water during 16 h was tested as an alternative method for isolating bioavailable major and trace elements from the soil. Concentrations of the elements were determined by inductively coupled plasma - optical emission spectroscopy (ICP-OES). The extraction of Cu and S from the soil by deionized water during 16 h extracting, NH4NO3, and CaCl2 indicated that these elements could originate from the anthropogenic sources, such as fungicide. In addition according to the soil - plant experiment, performed as a preliminary experiment for future studies in vineyards, deionized water was recommended for isolation of bioavailable elements from grape seed and grape pulp; CH3COOH, Na2EDTA, CaCl2 and NH4NO3 for grape skin, while for assessment of leaf bioavailable elements from soil fraction, aqua regia was recommended. In addition, identification of similarities between the plant parts and the plant species were performed. Applying environmental risk assessment formulas, the most polluted vineyard parcel in the vineyard region "Radmilovac" was determined. The leaves of some grapevine species showed the high ability for accumulation some of the potentially toxic trace elements from the soil. PMID- 28027473 TI - Pyrosequencing reveals microbial community dynamics in integrated simultaneous desulfurization and denitrification process at different influent nitrate concentrations. AB - Integrated simultaneous desulfurization and denitrification (ISDD) process has proven to be feasible for the coremoval of sulfate, nitrate, and chemical oxygen demand (COD). In this study, we aimed to reveal the microbial community dynamics in the ISDD process with different influent nitrate (NO3-) concentrations. For all tested scenarios, full denitrification was accomplished while sulfate removal efficiency decreased along with increased influent NO3- concentrations. The proportion of S0 to influent SO42- maintained a low level (5.6-17.0%) regardless of the increased influent NO3- concentrations. Microbial community analysis results showed that higher influent NO3- concentrations affected the microbial community structure greatly. Phyla Proteobacteria, Spirochaetae, Firmicutes, Synergistetes, and Chloroflexi dominated in all the community compositions, of which Proteobacteria exhibited a clear difference among eight microbial samples. Members of delta-Proteobacteria, with 16S rRNA gene sequences related to Desulfobulbus, were clearly decreased at influent NO3- = 3000 and 3500 mg/L, suggesting an inhibitory effect of NO3- on sulfate reduction. In contrast, as influent NO3- concentration increased, microbial community was notably enriched in gamma-Proteobacteria and epsilon-Proteobacteria, which revealed the enrichment of 16S rRNA gene sequences related to Pseudomonas (gamma-Proteobacteria), and Arcobacteria and Sulfurospirillum (epsilon-Proteobacteria). PMID- 28027474 TI - Solubilization of Pb-bearing apatite Pb5(PO4)3Cl by bacteria isolated from polluted environment. AB - The main purpose of this study was to test if microorganisms isolated from heavily polluted environments can enhance dissolution of Pb-apatite (pyromorphite) resulting in remobilization of lead. Three bacterial strains belonging to the genus Pseudomonas isolated from underground mines in SW Poland were used in batch experiments of pyromorphite solubilization carried out in phosphate reach and phosphate poor media. Bacteria growth and evolution of Pb and phosphate concentrations as well as pH were determined. Additionally the concentration of bacterial siderophores in leaching solution was assayed. All bacterial strains were able to grow in both media in the presence of pyromorphite. The number of bacterial cells was from one to two orders of magnitude higher in the phosphate rich media. In the phosphate poor media the only source of P was the dissolving lead apatite. Bacteria enhanced the solubility of pyromorphite resulting in elevated Pb concentrations, up to 853 MUg L-1 in phosphate-rich medium and 6112 MUg L-1 in phosphate-poor medium, compared to less than 100 MUg L-1 in an abiotic control sample. Production of siderophores was characteristic for each culture and was much lower (10-1000 fold) in the phosphate-poor medium. This study demonstrates for the first time that indigenous bacteria can directly and indirectly promote the mobilization of lead from pyromorphite. This phenomenon should be considered in long term risk assessment of Pb contaminated soils after reclamation processes because bacteria can play a significant role in the efficiency of clean-up efforts and overall geochemical cycling of Pb. PMID- 28027475 TI - The robustness of single-point Tenax extractions of pyrethroids: Effects of the Tenax to organic carbon mass ratio on exposure estimates. AB - Use of Tenax extractable concentrations to estimate biological exposure to hydrophobic organic contaminants is well documented, yet method variation exists between studies, specifically in the ratio of Tenax mass to organic carbon mass in the sediment (Tenax:OC ratio) being extracted. The effects of this variation on exposure estimates are not well understood. As Tenax is theoretically in direct competition with organic carbon for freely dissolved chemical in sediment interstitial water, varying the Tenax:OC ratio could impact single-point Tenax extraction (SPTE) exposure estimates. Therefore, the effects of varying Tenax:OC ratios on SPTE pyrethroid concentrations from field-contaminated and laboratory spiked sediments were compared to bioaccumulation by Lumbriculus variegatus. The Tenax:OC ratio had minimal effect on SPTE pyrethroid concentrations. The SPTE pyrethroid concentrations obtained using the highest and lowest Tenax:OC ratios ranged from 0.85- to 3.91-fold different, which is unlikely to contribute substantial error to bioaccessibility estimates. Comparisons to Tenax exposure endpoints from previous research reveal the variation in these endpoints is likely due to toxicokinetic and toxicodynamic differences; processes common to exposure estimates provided by any chemical extraction technique. As the pyrethroid concentrations in the experimental sediments caused toxicity to L. variegatus, thus affecting bioaccumulation, the SPTE concentrations overestimated bioaccumulation. However, SPTE concentrations strongly correlated with growth inhibition regardless of the Tenax:OC ratio, providing accurate estimates of the correct exposure endpoint. Tenax masses of 0.500-0.800 g should provide sufficient Tenax to achieve Tenax:OC ratios of at least 5:1, which will provide accurate exposure estimates while retaining the ease of conducting SPTEs. PMID- 28027476 TI - Are silver nanoparticles always toxic in the presence of environmental anions? AB - Increasing amounts of silver nanoparticles (AgNPs) are expected to enter the ecosystems where their toxicity in the environment is proposed. In this study, we exploited the effect of environmental anions on AgNP toxicity. AgNP were mixed with various environmental anions, and then exposed to Escherichia coli to determine the effect on bacteria growth inhibition. The results demonstrated that AgNP are not always toxic in the presence of sulfide, but can stimulate microbial growth at certain concentrations. Environmental chloride and phosphate anions cannot induce the stimulation because of their weak capacity to control the release of Ag+ from AgNP. Ag+ that released from AgNP is proven to be responsible for AgNP toxicity. Moreover, we found that AgNP toxicity is dependent on sulfuration rate. At the same sulfuration rate, AgNP shows an identical pattern of toxicity. This study indicates that only sulfide of the tested environmental anions can induce AgNP stimulation to microbial growth in a sulfuration rate dependent pattern and the toxicity originate from Ag+ that released from AgNP. PMID- 28027477 TI - Aerobic biodegradation of amphoteric amine-oxide-based surfactants: Effect of molecular structure, initial surfactant concentration and pH. AB - The present study was designed to provide information regarding the effect of the molecular structure of amphoteric amine-oxide-based surfactants and the initial surfactant concentration on their ultimate biodegradation. Moreover, given this parameter's pH-dependence, the effect of pH was also investigated. Three amine oxide-based surfactants with structural differences in their hydrophobic alkyl chain were tested: Lauramine oxide (AO-R12), Myristamine oxide (AO-R14) and Cocamidopropylamine oxide (AO-Cocoamido). We studied the ultimate biodegradation using the Modified OECD Screening Test at initial surfactant concentrations ranged from 5 to 75 mg L-1 and at pH levels from 5 to 7.4. The results demonstrate that at pH 7.4, amine-oxide-based surfactants are readily biodegradable. In this study, we concluded that omega-oxidation can be assumed to be the main biodegradation pathway of amine-oxides and that differences in the biodegradability between them can be explained by the presence of an amide group in the alkyl chain of AO-Cocoamido; the CN fission of the amide group slows down their mineralization process. In addition, the increase in the concentration of the surfactant from 5 to 75 mg L-1 resulted in an increase in the final biodegradation of AO-R12 and AO-R14. However, in the case of AO-Cocoamido, a clear relationship between the concentration and biodegradation cannot be stated. Conversely, the biodegradability of AO-R12 and AO-R14 was considerably lower in an acid condition than at a pH of 7.4, whereas AO-Cocoamido reached similar percentages in acid conditions and at a neutral pH. However, microorganisms required more time to acclimate. PMID- 28027478 TI - A conserved region in the Closterovirus 1a polyprotein drives extensive remodeling of endoplasmic reticulum membranes and induces motile globules in Nicotiana benthamiana cells. AB - In infected plant cells, closterovirus replicative polyproteins 1a and 1ab drive membrane remodeling and formation of multivesicular replication platforms. Polyprotein 1a contains a variable Central Region (CR) between the methyltransferase and helicase domains. In a previous study, we have found that transient expression of the Beet yellows virus CR-2 segment (aa 1305-1494) in Nicotiana benthamiana induces the formation of ~1um mobile globules originating from the ER membranes. In the present study, sequence analysis has shown that a part of the CR named the "Zemlya region" (overlapping the CR-2), is conserved in all members of the Closterovirus genus and contains a predicted amphipathic helix (aa 1368-1385). By deletion analysis, the CR-2 region responsible for the induction of 1-MUm globules has been mapped to aa 1368-1432. We suggest that the conserved membrane-modifying region of the BYV 1a may be involved in the biogenesis of closterovirus replication platforms. PMID- 28027480 TI - Neck lymph node metastases from unknown primary. AB - Metastatic cervical carcinoma from unknown primary is a metastatic disease in the lymph nodes of the neck without any evidence of a primary tumour after appropriate investigation. The condition is rare and definite evidence is lacking for both diagnosis and treatment. In this review of the literature, we tried to draw some clinical indications based on the few available studies. We ultimately came to the following conclusions: (1) a thorough and accurate diagnostic work-up should be systematically offered. It includes accurate inspection with fibroscopy, CT or MRI, fine needle aspiration, panendoscopy and positron emission tomography, (2) Patients with low-volume neck disease, N1 and N2a stage and without extracapsular extension on histopathological examination should receive single modality treatment. Radiotherapy and surgery may be similarly effective but, if possible, surgery (excisional biopsy, neck dissection and tonsillectomy) should be favoured because it consents a more precise staging, (3) patients with more advanced conditions require combined treatment in the form of either resection followed by adjuvant radiation (+/-chemotherapy) or primary chemoradiation (+/-post-therapy neck dissection). PMID- 28027479 TI - Characterization of founder viruses in very early SIV rectal transmission. AB - : A better understanding of HIV-1 transmission is critical for developing preventative strategies. To that end, we analyzed 524 full-length env sequences of SIVmac251 at 6 and 10 days post intrarectal infection of rhesus macaques. There was no tissue compartmentalization of founder viruses across plasma, rectal and distal lymphatic tissues for most animals; however one animal has evidence of virus tissue compartmentalization. Despite identical viral inoculums, founder viruses were animal-specific, primarily derived from rare variants in the inoculum, and have a founder virus signature that can distinguish dominant founder variants from minor founder or untransmitted variants in the inoculum. Importantly, the sequences of post-transmission defective viruses were phylogenetically associated with competent viral variants in the inoculum and were mainly converted from competent viral variants by frameshift rather than APOBEC mediated mutations, suggesting the converting the transmitted viruses into defective viruses through frameshift mutation is an important component of rectal transmission bottleneck. SIGNIFICANCE: Anorectal receptive intercourse is a common route of HIV-1 transmission and a better understanding of the transmission mechanisms is critical for developing HIV-1 preventative strategies. Here, we report that there is no tissue compartmentalization of founder viruses during very early rectal transmission of SIV in the majority of rhesus macaques and founder viruses are preferentially derived from rare variant in the inoculum. We also found that founder viruses are animal-specific despite identical viral inoculums. After viruses cross the mucosal barriers, the host further reduces viral diversity by converting some of the transmitted functional viruses into defective viruses through frameshift rather than APOBEC derived mutations. To our knowledge, this is the first study of founder viruses at multiple tissue sites during very early rectal transmission. PMID- 28027481 TI - Toward improved mechanical, tribological, corrosion and in-vitro bioactivity properties of mixed oxide nanotubes on Ti-6Al-7Nb implant using multi-objective PSO. AB - Recently, the robust optimization and prediction models have been highly noticed in district of surface engineering and coating techniques to obtain the highest possible output values through least trial and error experiments. Besides, due to necessity of finding the optimum value of dependent variables, the multi objective metaheuristic models have been proposed to optimize various processes. Herein, oriented mixed oxide nanotubular arrays were grown on Ti-6Al-7Nb (Ti67) implant using physical vapor deposition magnetron sputtering (PVDMS) designed by Taguchi and following electrochemical anodization. The obtained adhesion strength and hardness of Ti67/Nb were modeled by particle swarm optimization (PSO) to predict the outputs performance. According to developed models, multi-objective PSO (MOPSO) run aimed at finding PVDMS inputs to maximize current outputs simultaneously. The provided sputtering parameters were applied as validation experiment and resulted in higher adhesion strength and hardness of interfaced layer with Ti67. The as-deposited Nb layer before and after optimization were anodized in fluoride-base electrolyte for 300min. To crystallize the coatings, the anodically grown mixed oxide TiO2-Nb2O5-Al2O3 nanotubes were annealed at 440 degrees C for 30min. From the FESEM observations, the optimized adhesive Nb interlayer led to further homogeneity of mixed nanotube arrays. As a result of this surface modification, the anodized sample after annealing showed the highest mechanical, tribological, corrosion resistant and in-vitro bioactivity properties, where a thick bone-like apatite layer was formed on the mixed oxide nanotubes surface within 10 days immersion in simulated body fluid (SBF) after applied MOPSO. The novel results of this study can be effective in optimizing a variety of the surface properties of the nanostructured implants. PMID- 28027482 TI - Developing national best practice recommendations for harm reduction programmes: Lessons learned from a community-based project. AB - Through promotion of consistent, evidence-based policy and practice, best practice recommendations can improve service delivery. Nationally relevant best practice recommendations, including guidance for programmes that provide service to people who use drugs, are often created and disseminated by government departments or other national organisations. However, funding priorities do not always align with stakeholder- and community-identified needs for such recommendations, particularly in the case of harm reduction. We achieved success in developing and widely disseminating best practice documents for Canadian harm reduction programmes by bringing together a multi-stakeholder, cross-regional team of people with relevant and diverse experience and expertise. In this commentary, we summarise key elements of our experience to contribute to the literature more detailed and transparent dialogue about team processes that hold much promise for developing best practice resources. We describe our project's community-based principles and process of working together (e.g., regularly scheduled teleconferences to overcome geographic distance and facilitate engagement), and integrate post-project insights shared by our team members. Although we missed some opportunities for power-sharing with our community partners, overall team members expressed that the project offered them valuable opportunities to learn from each other. We aim to provide practical considerations for researchers, other stakeholders, and community members who are planning or already engaged in a process of developing best practice recommendations for programmes and interventions that address drug use. PMID- 28027483 TI - Experiences of peer-trainers in a take-home naloxone program: Results from a qualitative study. AB - BACKGROUND: Take-home naloxone programs (THN) are harm reduction programs with the aim of reducing the number of deaths caused by opioid overdoses. A THN program in Montreal called the PROFAN project was implemented with the goal of reducing overdoses through the use of peer-trainers. Peer-trainers are people who are currently or have previously used drugs, who are trained in overdose prevention and are then responsible for delivering a training session to other individuals who use drugs. While studies on other peer-led programs have shown that peer-helpers gain numerous benefits from their role, little attention has been devoted to understanding this role in the context of overdose prevention. Additionally, to our knowledge, this is the first time that the impacts of the peer-trainer role are being studied and documented for a scientific journal. METHODS: This research represents a qualitative study using individual interviews with the six peer-trainers of the Montreal program to explore the benefits and challenges encountered in their role. RESULTS: Interview results suggest that there are psychological benefits received through the peer-trainer role, such as empowerment and recovery. As well, there are a number of challenges associated with their role and suggestions to improve the program. CONCLUSION: Knowledge about the impacts of the peer-trainer role will contribute to the development of THN programs. Additionally, the findings may also serve to demonstrate that THN programs are capable of not only reducing the number of deaths by opioid overdose, but that these programs may also have wider effects on a psychological level. PMID- 28027485 TI - Does habituation really happen? Investigation of psycho-biological responses to body exposure in bulimia nervosa. AB - BACKGROUND: Body exposure is a common and effective treatment for body image disturbance in bulimia nervosa (BN). However, little is known about treatment mechanisms. Based on models of emotional processing and neurovisceral integration, we expected to observe a) initial activation and b) habituation of cognitive-affective and autonomic responding within one and between two standardized body exposure sessions. METHODS: A group of 13 women with BN and 13 healthy controls (HC) were repeatedly exposed to their bodies. Prior to and after treatment with three individualized mirror exposure sessions participants received a session of standardized exposure to videographic recordings of their body. Subjective ratings of body-related emotions and thoughts were assessed repeatedly throughout the standardized exposure sessions and autonomic responses were recorded continuously. RESULTS: Subjective and sympathetic responses were activated initially in both groups. Cognitive-affective responses habituated within the standardized sessions in both groups, whereas between the standardized sessions habituation was only found in women with BN. Increasing sympathetic responses were found within the sessions in both groups. CONCLUSIONS: The results support cognitive-affective habituation during body exposure in BN and to a lesser extent in HC. Autonomic responses however did not show a corresponding pattern and did not distinguish between groups. Implications for body exposure research and practice are discussed. PMID- 28027484 TI - Alcohol use screening and intervention by American primary care providers. AB - BACKGROUND: Regular/chronic drinking, defined by five or more drinks in one sitting on each of five or more occasions in the past 30 days, is a significant problem contributing to negative health outcomes, morbidity, and mortality. Regular/chronic and heavy episodic drinking largely goes undetected by primary care providers due to a lack of screening and intervention. The present study explores the extent to which healthcare practitioners screen for alcohol use, provide interventions, and refer to treatment across different types of drinkers. METHODS: A retrospective analysis of the 2014 National Survey on Drug Use and Health was analysed in 2016. Respondents who visited primary care settings were asked if healthcare providers queried them about their drinking, amount they drank, frequency of drinking, and if they received interventions. Simple tests among proportions and logistic regression were used to analyse these data. RESULTS: Healthcare professionals asked 76.5% of patients if they drank alcohol at all in the past year, and only 11.8% were asked if they had a drinking problem. The chance of being asked increased for heavy episodic and regular/chronic drinkers (F[1.97, 98.38]=44.81, p<0.001). Healthcare providers infrequently suggested cutting down on drinking (5.5% overall), but the chance of receiving a suggestion increased across heavy episodic and regular/chronic drinkers (F[1.92,96.02]=196.22, p<0.001). Information about alcohol treatment referral was rarely given (7.3% of regular/chronic drinkers). Moreover, minority, older, male, and uninsured patients were queried about alcohol use less often. CONCLUSION: Healthcare practitioners in primary care are screening for alcohol use at moderate rates, yet follow-up questions, brief advice, and treatment referrals are inconsistently targeted. There is a need for consistent screening of all patients and systematic follow-up protocols in primary care delivery. PMID- 28027486 TI - Differential expression of the nucleolar protein fibrillarin during mammalian spermatogenesis and its probable association with chromatoid body components. AB - Chromatoid body (CB) is a cytoplasmic structure of male germ cells that has been indicated as having a role in the RNA and protein storage for the final differentiation of spermatozoa. Recent studies have indicated that some of these macromolecular complex components have nucleolar origin. The aims of the present study were to monitor the expression of fibrillarin nucleolar protein in mammalian seminiferous tubules at different stages of the spermatogenic cycle; to check fibrillarin distribution during the CB assembly; and also its interaction with two well-known CB markers (MIWI and HSP70). Seminiferous tubules were isolated by transilluminating microscope from testis of adult mice. Fibrillarin expression and also co-localization between fibrillarin and MIWI/HSP70 were performed by Western blot (WB) and by immunofluorescence (IF), respectively. Total proteins from testis of adult mice were also used to perform co immunoprecipitation (Co-IP) experiments. Our results demonstrated higher fibrillarin expression in seminiferous tubules in stages IV-VI, and a close localization of fibrillarin with MIWI (a protein that plays a role in RNA metabolism in the CB), as well as with HSP70 (a protein that plays a role in the proteasome folding in the CB). We also performed Co-IP between fibrillarin/MIWI and between fibrillarin/HSP70 in order to determine whether MIWI or HSP70 interacts with this nucleolar protein. We found MIWI in the Co-IP precipitate, but not HSP70. In conclusion, our results show that fibrillarin may participate in the physiological activities performed by the CB by interacting with CB components that play a role in RNA metabolism. PMID- 28027487 TI - Functional selectivity and dualsteric/bitopic GPCR targeting. AB - Functional selectivity provides a new avenue to selectively engage particular pathways of the pleiotropic signaling repertoire of a G protein-coupled receptor. First examples for signaling biased compounds at the angiotensin II receptor and the MU opioid receptor have progressed to clinical trials and are promising in regard to selective activation of signaling pathways that can be linked to beneficial clinical outcomes. Dualsteric/bitopic hybrid compounds which consist of at least two pharmacophores combined in one single ligand are more recent examples for functionally selective ligands. Their binding topography makes them ideally suited to disrupt receptor flexibility and rationally induce signaling bias. Therefore, the dualsteric/bitopic design principle is most promising to facilitate generation of structurally diverse biased agonists at G protein coupled receptors. PMID- 28027488 TI - Assessment of lead-time bias in estimates of relative survival for breast cancer. AB - Relative survival ratios (RSRs) can be useful for evaluating the impact of changes in cancer care on the prognosis of cancer patients or for comparing the prognosis for different subgroups of patients, but their use is problematic for cancer sites where screening has been introduced due to the potential of lead time bias. Lead-time is survival time that is added to a patient's survival time because of an earlier diagnosis irrespective of a possibly postponed time of death. In the presence of screening it is difficult to disentangle how much of an observed improvement in survival is real and how much is due to lead-time bias. Even so, RSRs are often presented for breast cancer, a site where screening has led to early diagnosis, with the assumption that the lead-time bias is small. We describe a simulation-based framework for studying the lead-time bias due to mammography screening on RSRs of breast cancer based on a natural history model developed in a Swedish setting. We have performed simulations, using this framework, under different assumptions for screening sensitivity and breast cancer survival with the aim of estimating the lead-time bias. Screening every second year among ages 40-75 was introduced assuming that screening had no effect on survival, except for lead-time bias. Relative survival was estimated both with and without screening to enable quantification of the lead-time bias. Scenarios with low, moderate and high breast cancer survival, and low, moderate and high screening sensitivity were simulated, and the lead-time bias assessed in all scenarios. PMID- 28027489 TI - Multispecies reactive transport modelling of electrokinetic remediation of harbour sediments. AB - We implemented a numerical model to simulate transport of multiple species and geochemical reactions occurring during electrokinetic remediation of metal contaminated porous media. The main phenomena described by the model were: (1) species transport by diffusion, electromigration and electroosmosis, (2) pH dependent buffering of H+, (3) adsorption of metals onto particle surfaces, (4) aqueous speciation, (5) formation and dissolution of solid precipitates. The model was applied to simulate the electrokinetic extraction of heavy metals (Pb, Zn and Ni) from marine harbour sediments, characterized by a heterogeneous solid matrix, high buffering capacity and aged pollution. A good agreement was found between simulations of pH, electroosmotic flow and experimental results. The predicted residual metal concentrations in the sediment were also close to experimental profiles for all of the investigated metals. Some removal overestimation was observed in the regions close to the anode, possibly due to the significant metal content bound to residual fraction. PMID- 28027490 TI - Magnesium alloys and graphite wastes encapsulated in cementitious materials: Reduction of galvanic corrosion using alkali hydroxide activated blast furnace slag. AB - Magnesium alloys and graphite from spent nuclear fuel have been stored together in La Hague plant. The packaging of these wastes is under consideration. These wastes could be mixed in a grout composed of industrially available cement (Portland, calcium aluminate...). Within the alkaline pore solution of these matrixes, magnesium alloys are imperfectly protected by a layer of Brucite resulting in a slow corrosion releasing hydrogen. As the production of this gas must be considered for the storage safety, and the quality of wasteform, it is important to select a cement matrix capable of lowering the corrosion kinetics. Many types of calcium based cements have been tested and most of them have caused strong hydrogen production when magnesium alloys and graphite are conditioned together because of galvanic corrosion. Exceptions are binders based on alkali hydroxide activated ground granulated blast furnace slag (BFS) which are presented in this article. PMID- 28027491 TI - Comparative and competitive adsorption of Pb(II) and Cu(II) using tetraethylenepentamine modified chitosan/CoFe2O4 particles. AB - In this paper, tetraethylenepentamine (TEPA) modified chitosan/CoFe2O4 particles were prepared for comparative and competitive adsorption of Cu(II) and Pb(II) in single and bi-component aqueous solutions. The characteristics results of SEM, FTIR and XRD indicated that the adsorbent was successfully fabricated. The magnetic property results manifested that the particles with saturation magnetization value of 63.83emug-1 would have a fast magnetic response. The effects of experimental parameters including contact time, pH value, initial metal ions concentration and coexisting ions on single and bi-component adsorption were investigated. The results revealed that the adsorption kinetic was followed pseudo-second-order kinetic model, indicating that chemical adsorption was the rate-limiting step. Sorption isotherms were also determined in single and bi-component solutions with different mass ratio of Cu(II) to Pb(II) (Cu(II)/Pb(II)) and fitted using Langmuir and Freundlich isotherm models. A better fit for Cu(II) and Pb(II) adsorption were obtained with Langmuir model, with a maximum sorption capacity of 168.067 and 228.311mgg-1 for Cu(II) and Pb(II) in single component solution, 139.860 and 160.256mgg-1 in bi-component solution (Cu(II)/Pb(II)=1:1), respectively. The present results suggest that TEPA modified chitosan/CoFe2O4 particles are feasible and satisfactory adsorbent for efficient removal of Cu(II) and Pb(II) ions. PMID- 28027492 TI - Design of antibacterial biointerfaces by surface modification of poly (epsilon caprolactone) with fusion protein containing hydrophobin and PA-1. AB - Class IIa bacteriocin pediocin PA-1 has broad-spectrum activity and is a well characterized candidate food biopreservative. Here, a simple approach is designed to extend the application of pediocin PA-1 in improving the antibacterial activity of electrospun poly(caprolactone) (PCL) grafts through combining PA-1 with HGFI, which is a self-assembled protein with characteristics allowing the modulation of surface properties of other materials originated from Grifola frondosa. Saccharomyces cerevisiae was used as the host for expression of fusion protein PA-1-linker-HGFI (pH) and his-tag purification was used to purify recombinant protein pH. An antibacterial activity assay showed the fusion protein pH retained the biological property of native PA-1. Water contact angle, X-ray photoelectron spectroscopy, immunofluorescence assay and atomic force microscopy indicated the surface properties of HGFI were greatly preserved by the fusion protein pH. Finally, antibacterial activity of pH-modified PCL substrate measurements implied the fusion protein significantly improved the bacterial resistance of the PCL film through dressing the PCL fibers with the recombinant pH protein. This work presents a new perspective on the application of hydrophobin and pediocin PA-1 in antibacterial medical devices. PMID- 28027493 TI - Hydrophilic modification of intraocular lens via surface initiated reversible addition-fragmentation chain transfer polymerization for reduced posterior capsular opacification. AB - Phacoemulsification followed with intraocular lens (IOL) implantation is the most effective clinical surgeries in treating cataracts. However, posterior capsular opacification (PCO), a common complication of this surgery, may cause vision decrease after surgery. PCO is mainly caused by the adhesion, proliferation and trans-differentiation of the residual lens epithelial cells (LEC) after surgery. Surface modification of IOL to reduce the LEC adhesion is of great importance in PCO prevention. Herein, surface initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization was utilized to modify the IOL materials for generating a comb-like polyethylene glycol (PEG) brush coating on the surface. The ATR-FTIR, XPS, and contact angle characterizations indicate the successful immobilization of the RAFT agent, as well as the subsequent SI-RAFT polymerization of PEG macromonomer. More interestingly, the PEG brush coating shows excellent hydrophilicity on the surface. The in vitro LEC culture and bacteria adhesion results show that the hydrophilic modification can effectively reduce the bio-adhesion. The in vivo implantation results show that the PEG brush modified IOL presents good biocompatibility, and significantly decreases the posterior capsular hyperplasia. These results demonstrate that the surface modification of IOL with excellent hydrophilic brush via SI-RAFT may provide a good alternative for IOL anti-PCO modification. PMID- 28027494 TI - Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex. AB - Dorsolateral prefrontal cortex mediates high-order cognitive functions that are impaired early in the aging process in monkeys and humans. Here, we report pronounced changes in mitochondrial morphology in dendrites of dorsolateral prefrontal cortex neurons from aged rhesus macaques. Electron microscopy paired with 3D reconstruction from serial sections revealed an age-related increase in mitochondria with thin segments that intermingled with enlarged ones, the 'mitochondria-on-a-string' phenotype, similar to those recently reported in patients with Alzheimer's disease. The thin mitochondrial segments were associated with endoplasmic reticulum cisterns, and the mitochondrial proteins Fis1 and Drp1, all of which initiate mitochondrial fission. These data suggest that the 'mitochondria-on-a-string' phenotype may reflect malfunction in mitochondrial dynamics, whereby fission is initiated, but the process is incomplete due to malfunction of subsequent step(s). Thus, aged rhesus monkeys may be particularly helpful in exploring the age-related changes that render higher cortical circuits so vulnerable to degeneration. PMID- 28027495 TI - Update of Ireland's national average indoor radon concentration - Application of a new survey protocol. AB - In 2002, a National Radon Survey (NRS) in Ireland established that the geographically weighted national average indoor radon concentration was 89 Bq m 3. Since then a number of developments have taken place which are likely to have impacted on the national average radon level. Key among these was the introduction of amending Building Regulations in 1998 requiring radon preventive measures in new buildings in High Radon Areas (HRAs). In 2014, the Irish Government adopted the National Radon Control Strategy (NRCS) for Ireland. A knowledge gap identified in the NRCS was to update the national average for Ireland given the developments since 2002. The updated national average would also be used as a baseline metric to assess the effectiveness of the NRCS over time. A new national survey protocol was required that would measure radon in a sample of homes representative of radon risk and geographical location. The design of the survey protocol took into account that it is not feasible to repeat the 11,319 measurements carried out for the 2002 NRS due to time and resource constraints. However, the existence of that comprehensive survey allowed for a new protocol to be developed, involving measurements carried out in unbiased randomly selected volunteer homes. This paper sets out the development and application of that survey protocol. The results of the 2015 survey showed that the current national average indoor radon concentration for homes in Ireland is 77 Bq m-3, a decrease from the 89 Bq m-3 reported in the 2002 NRS. Analysis of the results by build date demonstrate that the introduction of the amending Building Regulations in 1998 have led to a reduction in the average indoor radon level in Ireland. PMID- 28027497 TI - Association between anxiety and metabolic syndrome: A systematic review and meta analysis of epidemiological studies. AB - OBJECTIVE: Epidemiological studies have repeatedly investigated the association between anxiety and metabolic syndrome (MetS). However, the results have been inconsistent. We performed a meta-analysis of observational studies to summarize the evidence regarding the relation of anxiety and MetS risk. METHODS: We performed a systematic literature search of all studies published in PubMed and EMBASE from its inception to June 2016. Cross-sectional and cohort studies that reported an association between the two conditions in adults were included. Data on prevalence, incidence, unadjusted or adjusted odds ratio (OR), and 95% CI were extracted or provided independently by the authors. Random effects model was used to report the pooled OR. The I2 statistic was used to assess heterogeneity. Egger's test and Begger's test were used to evaluate the publication bias. RESULTS: The search yielded 18 cross-sectional studies and two cohort studies. The pooled finding from cross-sectional studies showed that anxiety had a significant positive association with MetS (OR 1.07, 95% CI 1.01-1.12), with moderate heterogeneity (I2=45.7%, P=0.018). Findings from two cohort studies indicated that the association between anxiety and MetS was insignificant. CONCLUSION: Our results suggest that there is an association between anxiety and MetS. In individuals with MetS anxiety should be detected and managed. Further prospective studies are needed to explore the bidirectional association between anxiety and MetS. PMID- 28027496 TI - Allostatic load and reduced cortical thickness in schizophrenia. AB - Structural imaging studies have consistently found reduced gray matter thickness of the cerebral cortex in schizophrenia, a finding that is evident in first episode psychosis and may be progressive in some cases. Although genetic predisposition and medication effects may contribute to cortical thinning, we hypothesize that the cumulative effects of stress may represent an environmental factor impacting brain morphology in schizophrenia. We examined the relationship between allostatic load, an index of peripheral biomarkers representing the cumulative effects of stress, and cortical thickness. Allostatic load was calculated for 44 patients with schizophrenia spectrum disorders (SSD) and 33 normal controls (NC) based on 13 cardiovascular, neuroendocrine, immune, and metabolic measurements. Controlling for age, SSD had significantly elevated allostatic load as compared with NC (p=0.008). Controlling for age, whole brain average cortical thickness was lower in SSD patients compared to NC (p=0.008). However, once allostatic load was accounted for, the group difference in cortical thickness became marginal (p=0.058). Exploratory analyses on subcomponents of allostatic load suggested that elevated immune marker C-reactive protein, stress hormones, and cardiovascular indices within allostatic load were more strongly associated with reduced cortical thickness in SSD. In NC, only the association between immune marker C-reactive protein and cortical thickness was replicated. These results support the hypothesis that allostatic load may account for some of the gray matter deficits observed in schizophrenia. Among the allostatic indices, the inflammatory mechanism appears particularly relevant to cortical thickness in both schizophrenia patients and normal controls. PMID- 28027498 TI - Comparison of cellular responses to Xanthomonas perforans infection between resistant and susceptible tomato accessions. AB - Bacterial spot of tomato (Solanum lycopersicum L.) caused by several Xanthomonas species is one of the most destructive diseases. Genes regulating the hypersensitive resistance and field resistance to X. perforans race T3 have been intensively investigated over the last decade. However, a comparative analysis of cellular responses to the pathogen in susceptible and resistant hosts has not been completed, which prevents the detailed understanding of the interactions between the pathogen and tomato plants. In this study, the characteristics of lesions, stomata, and pathogen colonization in hypersensitive response (HR) PI 128216, field-resistant PI 114490, and susceptible OH 88119 tomato plants after inoculation with green fluorescent protein-labeled X. perforans race T3 bacteria were investigated. Significant differences in developmental processes and the micromorphology of spot lesions among three tomato lines were observed. Our results suggested that the faster lesion development in OH 88119 plants compared with that of the other two lines was associated with a greater increase in the stomatal apertures over a longer period following bacterial inoculation. The depth of bacterial colonization and pathogen density inside infected leaves in OH 88119 were also significantly different from that of resistant tomato plants. Determination of the ultrastructural responses to X. perforans among three tomato lines revealed that cell wall defense response was the main difference between resistant and susceptible tomato lines. These results may provide fundamental information for understanding the cellular and molecular mechanisms regulating tomato responses to X. perforans race T3. PMID- 28027499 TI - Imbalance between the anti- and pro-inflammatory milieu in blood leukocytes of autistic children. AB - Accumulating evidence suggests an association between immune dysfunction and autism disorders in a significant subset of children. In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA 4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children. In the current study, we investigated the expression of IL 21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin. In our study, cells from children with AU had increased IL 21 and IL-22 and decreased CTLA-4 expression on CD4+ T cells as compared with cells from the TD control. Similarly, AU cells showed decreased IL-27 production by CD14+ cells compared to that of TD control cells. These results were confirmed by real-time PCR and western blot analyses. Our study shows dysregulation of the immune balance in cells from autistic children as depicted by enhanced pro inflammatory cytokines, 'IL-21/IL-22' and decreased anti-inflammatory molecules, 'IL-27/CTLA-4'. Thus, further study of this immune imbalance in autistic children is warranted in order to facilitate development of biomarkers and therapeutics. PMID- 28027500 TI - Local measure of the electromagnetic field in magnetic resonance coils: How do simulations help to disentangle the contributions of the electric and magnetic fields? AB - The development of probes for Nuclear Magnetic Resonance (NMR) spectroscopy of metabolites, biomolecules or materials requires the accurate determination of the radio-frequency (RF) magnetic field strength, B1, at the position of the sample since this RF-field strength is related to the signal sensitivity and the excitation bandwidth. The Ball Shift (BS) technique is a commonly employed test bench method to measure the B1 value. Nevertheless, the influence of the RF electric field, E1, on BS is often overlooked. Herein, we derive, from Maxwell equations, an analytical expression of the BS, which shows the contribution of both the electric and magnetic energies to the BS value. This equation shows that the BS allows quantifying the B1 field strength only in regions where the electric energy is small with respect to the magnetic one. The numerical simulations of electromagnetic (EM) field and energy prove that this condition is fulfilled at 100.5MHz inside the electrically balanced coil of a double-resonance 1H/X 4mm Magic Angle Spinning (MAS) probe since for that circuit, the center of the coil is an antinode for the B1 standing wave and a node for the E1 one. We also show that the simulated BS values agree well with the experimental ones. Conversely, NMR experiments show that the contribution of the electric energy to BS becomes significant when the X channel of this probe is connected to a frequency splitter. In that case, the use of BS method to estimate the B1 value is compromised. PMID- 28027501 TI - Disruption of homeobox containing gene, hbx9 results in the deregulation of prestalk cell patterning in Dictyostelium discoideum. AB - We have earlier classified the homeobox containing genes from Dictyostelium discoideum and identified 5 genes belonging to the TALE class. Here, we have characterized hbx9, a member of TALE class. In situ hybridization results show it to be preferentially expressed in the prestalkA (pstA) cells but not in the prestalkO (pstO) cells. Disruption of the hbx9 gene in Ax2 cells delay initiation of development and also slows cell proliferation. There was decreased cadA expression during the development of hbx9- cells, which results in inappropriate cell contacts, altered cell motility and patterning properties. ecmA and ecmB were mis-expressed in the pstO and pstA regions resulting in an effectively smaller pstO region. Surprisingly, the total ecmAO expression in pstAO cells was comparable to the wild type, suggesting that in hbx9- cells, ecmA was expressed in the pstO region. In hbx9-, proportioning and patterning was altered in favour of pstA cell-type. Moreover, precocious expression of ecmB and pspA was also observed in the vegetative cells. Expression profiling of components of cAMP signalling suggest that Hbx9 controls cell proportioning of prestalk cells by modulating cAMP signalling during growth-to-development transition. PMID- 28027502 TI - Bioactive polysaccharide-based pH-sensitive polymers for cytoplasmic delivery of antigen and activation of antigen-specific immunity. AB - For establishment of cancer immunotherapy, antigen carriers are needed which have functions not only to deliver antigen into cytosol of dendritic cells (DCs), which induces antigen-specific cellular immune responses, but also to activate DCs. We previously reported cytoplasmic delivery of antigen using liposomes modified with pH-sensitive polymers such as carboxylated poly(glycidol)s or dextran. Modification using these polymers provides stable liposomes with pH sensitive fusogenic/membrane-disruptive ability. For this study, bioactive polysaccharide-based pH-sensitive polymers were constructed to achieve not only cytoplasmic delivery of antigen but also activation of DCs. Curdlan and mannan were used as bioactive polysaccharides because they are known to activate DCs via their respective interactions with Dectin-1 and Dectin-2. Carboxylated curdlan and mannan promoted Th1 cytokine production from DCs, indicating the activation of DCs by these polysaccharide derivatives. These polymer-modified liposomes released their contents at weakly acidic pH and delivered model antigenic proteins into cytosol of DCs. Subcutaneous administration of curdlan derivative modified or mannan derivative-modified liposomes induced strong antigen-specific immune responses and stronger antitumor effects than those of liposomes modified with dextran derivative. Therefore, bioactive polysaccharide-modified liposomes that achieve both cytoplasmic delivery of antigen and activation of DCs are promising for cancer immunotherapy. PMID- 28027503 TI - A single fluorescent probe enables clearly discriminating and simultaneously imaging liquid-ordered and liquid-disordered microdomains in plasma membrane of living cells. AB - Liquid-ordered (Lo) and liquid-disordered (Ld) microdomains in plasma membrane play different yet essential roles in various bioactivities. However, discrimination of the two microdomains in living cells is difficult, due to the similarity in their constituents and structures. Up to now, polarity sensitive probes are the only tool for imaging the two microdomains, but their small difference between emission spectra in the two microdomains (less than 50 nm) limited their application in living cells. In this work, we first presented an aggregation/monomer type of fluorescent probe (2,7-9E-BHVC12) with much larger separation in emission wavelength (up to 100 nm), for dual-color visualizing the two membrane microdomains in living cells. The probe can form red-emissive aggregates and yellow-emissive monomers when induced by Lo and Ld microdomains, respectively, and thus enables clear visualization of the two membrane microdomains in living cells with dual colors, and thus high-fidelity images of substructures of plasma membrane have been obtained. According to the images of three kinds of normal cells and three kinds of cancer cells stained with 2,7-9E BHVC12, significant difference in plasma membrane microstructure of cancer cells was found. In terms of 2,7-9E-BHVC12, normal cells were mainly consisted of either Lo or Ld microdomains all over their membranes, while cancer cells all clearly display coexistence of Lo and Ld membrane microdomains. Therefore, 2,7-9E BHVC12 can serve as a powerful tool for studies of membrane microdomains, and the different results of normal and cancer cells would also deepen our understanding in cancer science. PMID- 28027504 TI - A key esterase required for the mineralization of quizalofop-p-ethyl by a natural consortium of Rhodococcus sp. JT-3 and Brevundimonas sp. JT-9. AB - A natural consortium, named L1, of Rhodococcus sp. JT-3 and Brevundimonas sp. JT 9 was obtained from quizalofop-p-ethyl (QE) polluted soil. The consortium was able to use QE as a sole carbon source for growth and degraded 100mgL-1 of QE in 60h. Strain JT-3 initiated the catabolism of QE to quizalofop acid (QA), which was used by strain JT-9 as carbon source for growth and to simultaneously feed strain JT-3. A novel esterase EstS-JT, which was responsible for the transformation of QE to QA and essential for the mineralization of QE by the consortium, was cloned from strain JT-3. EstS-JT showed low amino acid identity to other reported esterases from esterase family VIII and represents a new member of this family. The deduced amino acid sequence contained the esterase family VIII conserved motifs S-X-X-K, YSV and WAG. The purified recombinant EstS-JT displayed maximal esterase activity at 35 degrees C and pH 7.5. An inhibitor assay, site-directed mutagenesis and 3D modeling analysis revealed that S64, K67 and Y175 were essential for catalysis and probably comprised the catalytic center of EstS-JT. Additionally, EstS-JT had broad substrate specificity and was capable of hydrolyzing p-nitrophenyl esters (C2-C8) and various AOPP herbicides. PMID- 28027505 TI - Impairment of dynamic thiol-disulphide homeostasis in patients with idiopathic Parkinson's disease and its relationship with clinical stage of disease. AB - OBJECTIVE: The aim of this study was to investigate dynamic thiol-disulphide homeostasis in patients with idiopathic Parkinson's disease and to determine its relationship with the clinical stage as assessed by the modified Hoehn and Yahr scale. DESIGN AND METHODS: Fifty-two patients with Parkinson's disease (PD), diagnosed according to the United Kingdom Brain Bank Criteria for idiopathic PD, and 41 healthy individuals were included in the study. Clinical staging of patients was performed according to the Hoehn and Yahr scale. Peripheral blood samples were taken from all participants, and their native thiol and total thiol concentrations were measured using the newly developed automated method. In addition, their amount of disulphide bonds, disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios were calculated. RESULTS: Considering the data obtained from Parkinson's patients and the control group, both native thiol (-SH) and total thiol (-SH+-S-S) levels were found significantly lower in patients with Parkinson's disease. A negative and statistically significant relationship was found between both disease duration and disease stage and native thiol (-SH), total thiol (-SH+-S-S) levels and -SH/( SH+-S-S-) ratio. A positive and statistically significant relationship was found between both disease duration and stage and -S-S-/-SH and -S-S-/(-SH+-S-S-) ratios. CONCLUSION: In patients with Parkinson's disease, dynamic thiol disulphide homeostasis is disrupted, according to disease stage and duration. This balance, easily measured by using the newly developed automated method, can be used in monitoring disease progression. To our knowledge, our study will be the first report in the literature. PMID- 28027506 TI - Posterior short-segment fixation in thoracolumbar unstable burst fractures - Transpedicular grafting or six-screw construct? AB - OBJECTIVES: Early implant failure and donor-site complication remain a concern in patients with thoracolumbar burst fracture underwent one-above and-below short segment posterior pedicle screw fixation with fusion. Our aim was to evaluate the results of short-segment pedicle instrumentation enforced by two augmenting screws or injectable artificial bone cement in the fractured vertebra, and compare the differences between these two PATIENTS AND METHODS: We conducted a retrospective clinical and radiographic study. Twenty-seven patients were treated with a six-screw construct (group 1), and twenty-nine patients underwenta four screw construct and fractured vertebra augmentation by injectable calcium sulfate/phosphate cement (group 2). Posterior or posterolateral fusions were not performed in both groups. The severity of the fractured vertebra was evaluated by the load-sharing classification (LSC). Local kyphosis and anterior body height of the fractured vertebra were measured and were follow-up at least 2 years. Any implant failure or loss of correction >10 degrees degrees at the final was defined as failure of surgery. Patients' clinical results were assessed by the Denis scale. RESULTS: Blood loss and operation time were less in group 1 (126.2+/ 9.7 vs. 267.6+/-126.1ml, p<0.001 and 141.2+/-48.7 vs. 189.8+/-16.4min, p<0.001). Immediately after surgery, group 2 had a better local kyphosis angle (3.7+/-5.3 vs.6.0+/-4.1 degrees , p=0.047) and acquired more anterior body height (94.9%+/ 7.6% vs. 84.9%+/-10.0%, p<0.001). Both groups had similar clinical results (pain score: 1.5+/-0.8vs. 1.4+/-0.6, p=0.706; work score: 1.7+/-0.9 vs. 1.6+/-1.0, p=0.854). Group 1 had 3 cases of surgery failure; group 2 had 8 cases of implant failure (p=0.121). The average LSC score of these 11 patients with surgical failure was 7.2. CONCLUSION: Thesix-screw construct had the advantage of shorter operating time, less blood loss, and lower failure rate. For those patients with anLSC score ?7, posterior short-segment instrumentation should be used cautiously. PMID- 28027507 TI - Randomized controlled antiepileptic drug trials miss almost all patients with ongoing seizures. AB - In spite of the marketing of numerous new antiepileptic drugs (AEDs), their real life effectiveness has often been disappointing. We therefore retrospectively investigated how many adult patients with drug-resistant epilepsy would have been potential candidates for the last five phase II and III trials that have been performed at our center. Out of a group of 216 consecutively collected patients, only 18 (8.3%) would have been acceptable for recruitment. Treatment with enzyme inducing AEDs or concomitant medications (47.2%), too few seizures during a baseline period (41.7%), and EEGs showing a pattern not consistent with a diagnosis of focal epilepsy (e.g. generalized spike-wave) (31.5%) were the leading exclusion criteria. If only one criterion prevented recruitment, too few seizures during the baseline period and treatment with enzyme-inducing medications were the most frequent limitations for potential recruitment. Due to the limiting inclusion and exclusion factors of clinical AED trials, only a small fraction of patients with drug-resistant epilepsy is suitable. When new AEDs have passed such trials and are introduced, we have no information about the potential efficacy and tolerability in >90% of our patients with AED-resistant epilepsies. This may be one reason for the disappointing efficacy of many new AEDs after launch. PMID- 28027508 TI - Quizalofop-P-ethyl exposure increases estrogen axis activity in male and slightly decreases estrogen axis activity in female zebrafish (Danio rerio). AB - The herbicide Quizalofop-P-ethyl (QpE) exerts toxic effects in fish, but limited information is currently available on its effects on the endocrine system. In the current study, adult zebrafish (Danio rerio) were exposed to different concentrations (0, 2, 20, 200MUg/L) of QpE for 30days. In males, QpE exposure significantly increased plasma estradiol (E2) and vitellogenin (VTG) levels, concomitant with up-regulation of hepatic esr1 and vtg gene expression. In females, plasma sex hormone levels and VTG concentrations were not altered significantly, but an increased expression of hepatic esr1 in addition to decreased expression of hepatic vtg, esr2a and esr2b was observed. Marked histological lesions were also observed in the gonads of both males and females. Moreover, QpE exposure significantly increased transcriptional profiles of some genes in the HPG axis and liver in males, while the majority of these genes were down-regulated in females. Docking studies showed QpE forming stable interactions with the ligand-binding domain (LBD) of zebrafish ESR1 and ESR2a, suggesting QpE may bind to estrogen receptors (ESRs). This study for the first time reveals QpE as an endocrine-disrupting chemical (EDC) disrupting the zebrafish endocrine system in a sex-specific manner, whereby it increases estrogen axis activity in males and slightly decreases estrogen axis activity in females, which may be accounted for by QpE regulating steroidogenesis and/or activating ESR(s). PMID- 28027509 TI - CHARMM force field parameters for 2'-hydroxybiphenyl-2-sulfinate, 2 hydroxybiphenyl, and related analogs. AB - 2'-Hydroxybiphenyl-2-sulfinate (HBPS) desulfinase (DszB) catalyzes the cleavage of the carbon-sulfur bond from HBPS in the final step of microbial 4S pathway desulfurization reactions. DszB is notable for its substrate specificity and exhibits product inhibition, both of which hinder the overall 4S pathway turnover rate. To understand the molecular-level contributions to substrate and inhibitor binding to DszB, we plan to perform molecular dynamic simulations bound to an array of naphthenic molecules and biphenyl analogues of HBPS. However, many of the small molecules we are interested in are not included in standard force field packages, and thus, we must first produce accurate molecular mechanics force fields. Here, we develop and validate CHARMM-compatible force field parameters for the HBPS substrate, the 2-hydroxybiphenyl product, and potential inhibitors including: 2,2'-biphenol, 2-biphenyl carboxylic acid, 1,8-naphthosultam, and 1,8 naphthosultone. The selected molecules represent biphenyl compounds having both a single and double functional group and the planar naphthenic molecule class, all likely present in the oil-rich environment surrounding DszB-producing microorganisms. The Force Field Toolkit (ffTK) in VMD was used to optimize charge, bond distance, angle, and dihedral parameters. Optimized geometries were determined from quantum mechanical calculations. Molecular simulations of the molecules in explicit and implicit water solutions were conducted to assess the abilities of optimized parameters to recapitulate optimized geometries. Calculated infrared (IR) spectra were obtained and compared with experimental IR spectra for validation of the optimized MM parameters. PMID- 28027510 TI - Sense of agency in continuous action: Assistance-induced performance improvement is self-attributed even with knowledge of assistance. AB - In a task involving continuous action to achieve a goal, the sense of agency increases with an improvement in task performance that is induced by unnoticed computer assistance. This study investigated how explicit instruction about the existence of computer assistance affects the increase of sense of agency that accompanies performance improvement. Participants performed a continuous action task in which they controlled the direction of motion of a dot to a goal by pressing keys. When instructions indicated the absence of assistance, the sense of agency increased with performance improvement induced by computer assistance, replicating previous findings. Interestingly, this increase of sense of agency was also observed even when instructions indicated the presence of assistance. These results suggest that even when a plausible cause of performance improvement other than one's own action exists, the improvement can be misattributed to one's own control of action, resulting in an increased sense of agency. PMID- 28027511 TI - Manic espisode, confusional syndrome and reversible splenial lesion after abrupt withdrawal of oxcarbazepine. AB - BACKGROUND: Anticonvulsants are considered a second line option for bipolar disorder, it is known that the abrupt withdrawal is rarely related with demyelinated lesions of the splenium of the corpus callosum. Oxcarbazepine is used in bipolar disorder although it is not stated in the data sheet. CLINICAL CASE: We presented a case of a 50 years old woman with bipolar disorder who is treated with lithium and oxcarbazepine, she presented a manic episode and a confusional syndrome after she stopped taking the medication. The magnetic resonance showed a restricted diffusion area at the splenium of the corpus callosum and bifrontal hygromas that disappear two weeks later. CONCLUSIONS: The results of this study suggest that for a patient presenting with a mild encephalopathy and reversible splenial lesion, one should consider whether it is related to withdrawal of oxcarbazepine. PMID- 28027512 TI - Shaping plant development through the SnRK1-TOR metabolic regulators. AB - SnRK1 (Snf1-related protein kinase 1) and TOR (target of rapamycin) are evolutionarily conserved protein kinases that lie at the heart of energy sensing, playing central and antagonistic roles in the regulation of metabolism and gene expression. Increasing evidence links these metabolic regulators to numerous aspects of plant development, from germination to flowering and senescence. This prompts the hypothesis that SnRK1 and TOR modify developmental programs according to the metabolic status to adjust plant growth to a specific environment. The aim of this review is to provide support to this hypothesis and to incentivize further studies on this topic by summarizing the work that establishes a genetic connection between SnRK1-TOR and plant development. PMID- 28027513 TI - Major infections, secondary cancers and autoimmune diseases occur in different clinical subsets of chronic lymphocytic leukaemia patients. AB - BACKGROUND: Major infections (MIs), secondary cancers (SCs) and autoimmune diseases (ADs) are the most common and relevant complications in patients with chronic lymphocytic leukaemia. METHODS: We performed a single-centre retrospective study to investigate the prevalence of the above quoted complications, the association with most important prognostic markers and their impact on survival (n = 795). RESULTS: Almost one out of three patients experienced at least one complication and only 0.9% of the cohort developed all three complications. One hundred and twenty (20%) subjects developed SC, 98 MI (12%) and 80 AD (10%); these complications seem to occur in a mutually exclusive manner. By Kaplan-Meier analysis we estimated that after 20 years from the diagnosis SC, MI and AD occurred in 48%, 42% and 29% of patients, respectively. Furthermore, we showed that some clinical and biological markers are skewed among patients with different complications and that subjects with MI and SC had a worse prognosis than those with AD and all other patients (p < 0.0001). CONCLUSIONS: This study reveals the existence of different clinical subsets of chronic lymphocytic leukaemia patients characterised by an increased and different risk for developing specifically MI, SC and AD. PMID- 28027514 TI - EGFR-independent Elk1/CIP2A signalling mediates apoptotic effect of an erlotinib derivative TD52 in triple-negative breast cancer cells. AB - OBJECTIVES: Cancerous inhibitor of protein phosphatase 2A (CIP2A) has emerged as a therapeutic determinant mediating the anti-cancer effects of several new agents. We investigated the efficacy and mechanism of TD52, an erlotinib derivative with minimal p-EGFR inhibition but significant CIP2A downregulation, in triple-negative breast cancer (TNBC) cells. METHODS: TNBC lines were used for in vitro studies. Cell apoptosis was examined by flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western blot. In vivo efficacy of TD52 was tested in xenograft nude mice. RESULTS: We explored the CIP2A mRNA expression in a publically available database and found that higher levels of CIP2A mRNA is associated with worse recurrence-free survival in patients with TNBC. TD52-enhanced apoptosis accompanied with CIP2A downregulation and CIP2A overexpression protected cells from TD52-mediated apoptosis. The activity of protein phosphatase 2A (PP2A) was also increased in TD52-treated cells. TD52-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, TD52 indirectly downregulated CIP2A transcription via disturbing the binding of Elk1 to the CIP2A promoter. Importantly, TD52 showed anti-tumour activity in mice bearing TNBC xenograft tumours and downregulated CIP2A and p-Akt in these xenografted tumours. Interestingly, higher Elk1 mRNA expression was also associated with worse recurrence-free survival in TNBC patients by Kaplan-Meier survival analysis. CONCLUSION: Our findings indicated that EGFR-independent pharmacological modulation on Elk1/CIP2A signalling mediates the apoptotic effect of TD52 in TNBC cells, suggesting the potential therapeutic strategy. PMID- 28027515 TI - Organ or sphincter preservation for rectal cancer. The role of contact X-ray brachytherapy in a monocentric series of 112 patients. AB - BACKGROUND: Contact X-ray brachytherapy (CXB) has been used at Centre Antoine Lacassagne since 2002 to increase the chance of conservative treatment (organ or sphincter preservation) in rectal cancer. A consecutive series of 112 patients (pts) is reported. METHODS: Three protocols were used in selected rectal adenocarcinomas. Group 1: T1 N0 treated with local excision (LE) followed by adjuvant CXB. Group 2: T2 or 'early' T3 N0 treated with CXB combined with chemoradiotherapy (CRT) followed by surveillance or LE. Group 3: distal 'locally advanced' T3 N0-2 treated with CXB and CRT before total proctectomy. RESULTS: Group 1: 27 pt (pTis: 3; pT1: 21; pT2: 3). After LE with CXB alone (20 pt) or CXB + CRT (7 pt) one local recurrence occurred. Organ preservation was achieved in 26 pt (96%). Group 2: 45 pt (T1: 2; T2: 23; T3: 20) treated with CXB alone (4 pt) or CXB + CRT or external beam radiotherapy (EBRT) (41 pt). A clinical complete response (cCR) was observed in 43/45 (96%) and 3 pt developed a local recurrence (11% at 5 years). The specific survival was 76% at 5 years and the rate of organ preservation was 89% (40/45 pt) with good bowel function in 36 pt. Group 3: 40 pt, anterior resection (with sphincter preservation) was possible in 35 pt (86%) with a 3-year local recurrence of 6%. CONCLUSION: CXB usually combined as a boost with CRT or EBRT may safely increase the chance of a conservative treatment (organ or sphincter preservation) for selected rectal cancers. PMID- 28027516 TI - Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients. AB - BACKGROUND: Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. PATIENTS AND METHODS: This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin) and 3-month PSA response. RESULTS: From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50-78]). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4-15.6) versus 8.0 ng/mL (CI 95% 5.8-11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01-1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31 0.99], 12.2 [CI 95% 9.2-19.5] versus 7.4 [CI 95% 5.5-14.7] months otherwise, P = 0.044). CONCLUSIONS: We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients. PMID- 28027517 TI - 18F-FDG PET/CT surveillance for the detection of recurrence in patients with head and neck cancer. AB - BACKGROUND: Posttreatment detection of recurrence may lead to salvage treatment and prognostic prediction in patients with head and neck squamous cell carcinoma (HNSCC). We evaluated the diagnostic and prognostic values of 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) after definitive treatment of HNSCC. METHODS: This prospective study included 278 consecutive patients who underwent curative surgery (n = 143, 51.4%) or definitive radiotherapy/chemoradiotherapy (n = 135, 48.6%) for previously untreated HNSCC. The patients were regularly followed up and evaluated by 18F-FDG PET/CT, head and neck CT/magnetic resonance imaging (MRI), and chest CT at regular intervals after treatment. The imaging interpretations were compared with the histological results for recurrence. Receiver operating characteristics curves analysis, McNemar's test and logistic regression using generalised estimating equations were used to compare the diagnostic accuracy of 18F-FDG PET/CT and standard imaging of CT/MRI or chest CT, and a Cox proportional hazards model was used to assess the prognostic value of PET/CT. RESULTS: During a median follow-up of 44 months (range, 24-62 months), 73 patients (26.3%) had recurrence or persistent diseases. The area under curves for 18F-FDG PET/CT and CT/MRI were 0.975 (0.964-0.992) and 0.789 (0.713-0.874), respectively (P < 0.001). 18F-FDG PET/CT detected 65 of 66 recurrences (98.5%) not suggested by physical examination and endoscopy. Positive findings on 18F-FDG PET/CT scans were independent predictors of poorer cancer-specific and overall survival outcomes (P < 0.01). CONCLUSIONS: Posttreatment 18F-FDG PET/CT surveillance helps to properly detect recurrence and to predict the survival following treatment of HNSCC. PMID- 28027518 TI - Impact of industry collaboration on randomised controlled trials in oncology. AB - BACKGROUND: Industry funders can simply provide money or collaborate in trial design, analysis or reporting of clinical trials. Our aim was to assess the impact of industry collaboration on trial methodology and results of randomised controlled trials (RCT). METHODS: We searched PubMed for oncology RCTs published May 2013 to December 2015 in peer-reviewed journals with impact factor > 5 requiring reporting of funder role. Two authors extracted methodologic (primary end-point; blinding of the patient, clinician and outcomes assessor; and analysis) and outcome data. We used descriptive statistics and two-sided Fisher exact tests to compare characteristics of trials with collaboration, with industry funding only, and without industry funding. RESULTS: We included 224 trials. Compared to those without industry funding, trials with collaboration used more placebo control (RR 3.59, 95% CI [1.88-6.83], p < 0001), intention-to treat analysis (RR 1.32, 95% CI [1.04-1.67], p = 02), and blinding of patients (RR 3.05, 95% CI [1.71-5.44], p < 0001), clinicians (RR 3.36, 95% CI [1.83-6.16], p<=.001) and outcomes assessors (RR 3.03, 95% CI [1.57-5.83], p = 0002). They did not differ in use of overall survival as a primary end-point (RR 1.27 95% CI [0.72-2.24]) and were similarly likely to report positive results (RR 1.11 95% CI [0.85-1.46], p = 0.45). Studies with funding only did not differ from those without funding. CONCLUSIONS: Oncology RCTs with industry collaboration were more likely to use some high-quality methods than those without industry funding, with similar rates of positive results. Our findings suggest that collaboration is not associated with trial outcomes and that mandatory disclosure of funder roles may mitigate bias. PMID- 28027519 TI - Estimation of net survival for cancer patients: Relative survival setting more robust to some assumption violations than cause-specific setting, a sensitivity analysis on empirical data. AB - Net survival is the survival that would be observed if the only possible underlying cause of death was the disease under study. It can be estimated with either cause-specific or relative survival data settings, if the informative censoring is properly considered. However, net survival estimators are prone to specific biases related to the data setting itself. We examined which data setting was the most robust against violation of key assumptions (erroneous cause of death and inappropriate life tables). We identified 4285 women in the Geneva Cancer Registry, diagnosed with breast, colorectal, lung cancer and melanoma between 1981 and 1991 and estimated net survival up to 20 years using cause specific and relative survival settings. We used weights to tackle informative censoring in both settings and performed sensitivity analyses to evaluate the impact of misclassification of cause of death in the cause-specific setting or of using inappropriate life tables on net survival estimates in the relative survival setting. For all the four cancers, net survival was highest when using the cause-specific setting and the absolute difference between the two estimators increased with time since diagnosis. The sensitivity analysis showed that (i) the use of different life tables did not compromise net survival estimation in the relative survival setting, whereas (ii) a small level of misclassification for the cause of death led to a large change in the net survival estimate in the cause-specific setting. The relative survival setting was more robust to the above assumptions violations and is therefore recommended for estimation of net survival. PMID- 28027520 TI - Lymph node yield after rectal resection in patients treated with neoadjuvant radiation for rectal cancer: A systematic review and meta-analysis. AB - BACKGROUND: The lymph node status represents a major prognostic factor in colorectal cancer. However, it was demonstrated that neoadjuvant chemoradiotherapy (CRT) decreases the numbers of lymph nodes in the specimen. Several studies describe less than 12 lymph nodes in the resected specimen of rectal cancer patients after neoadjuvant radiation. This meta-analysis quantifies the influence of neoadjuvant CRT or radiotherapy (RT) only on the lymph node yield in rectal cancer patients. METHODS: We performed a systematic review and searched PubMed, EMBASE and the Cochrane Library without any language restriction from 1st of January 1980 until 31st March 2015. Two reviewers examined all publications independently and extracted the relevant data if the study assessed lymph node counts or positive lymph node yields of patients who received neoadjuvant treatment compared with patients who did not receive neoadjuvant treatment. Meta-analyses were conducted to quantify the mean difference in lymph node yield. RESULTS: A total of 34 articles (including 37 datasets) were included in the meta-analyses. Neoadjuvant CRT resulted in a mean reduction of 3.9 lymph nodes (95% confidence interval [CI] 3.7-4.1) and an average reduction in harvested positive lymph nodes of 0.7 (95% CI 0.2-1.2) compared with patients who received no neoadjuvant therapy. Individuals who received neoadjuvant RT had, in average, 2.1 lymph node less (95% CI 1.7-2.5) resected compared with their counterparts who received no neoadjuvant treatment. CONCLUSIONS: Neoadjuvant CRT or RT only in rectal cancer patients leads to a decrease in lymph node harvest of approximately four and two lymph nodes, respectively. We therefore stress the importance of intensifying all efforts from involved subspecialities (i.e. surgeons and pathologists) to reach the benchmark harvest of 12 resected lymph nodes according to current guidelines. PMID- 28027521 TI - Correlation between severe infection and breast cancer metastases in the EORTC 10994/BIG 1-00 trial: Investigating innate immunity as a tumour suppressor in breast cancer. AB - BACKGROUND: Breast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti tumour immune response. We investigated whether 'severe infection' can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones. METHODS: Clinical data of the European Organisation for Research and Treatment of Cancer 10994/BIG 1-00 phase III trial which randomised 1856 patients treated with NACT between 2001 and 2006, were used. Severe infection was febrile neutropenia or any other grade III-IV infective adverse event during NACT. The IRF7 signature was calculated from gene expression data available for 160 patients on a pre-NACT biopsy. Cox models for distant relapse-free interval (DRFI) investigated the effect of the severe infection and IRF7. Fine and Gray models studied the occurrence of bone metastases as first distant relapse. RESULTS: Median follow-up was 4.8 years. No association between severe infection and DFRI was observed in the entire population (n = 1615 eligible patients) hazard ratio [(HR] = 0.99, 90% CI, confidence interval [CI] = 0.81-1.20). For IRF7 (N = 160), a trend towards an association with DRFI was observed (HR = 0.89 for a 50 unit increase, 90% CI = 0.78-1.02, p = 0.081). Higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: (HR = 0.76 for a 50 unit increase, 95% CI, 0.62-0.94, p = 0.012). CONCLUSIONS: In this study it was shown that severe infection during NACT was not associated with decreased DRFI while high expression of the IRF7 gene signature was significantly associated with reduced bone relapse. This result may be useful for future adjuvant bisphosphonate/denosumab use. PMID- 28027522 TI - Preparation of ionic liquid-mediated imprinted monolith for selective capture and purification of corilagin. AB - A method for solid-phase extraction (SPE) of corilagin from natural plant extracts based on molecularly imprinted polymers (MIPs) was developed. For the preparation of corilagin-MIP monoliths, 4-vinylpyridine was used as functional monomer, and ethylene glycol dimethacrylate was used as cross-linking monomer, using a mixture of 1-butyl-3-methylimidazoliumtetrafluoroborate (ionic liquid) N,N-dimethylformamide-dimethyl sulfoxide as a porogen. A morphological characteristic of the corilagin imprinted monolith was further studied by scanning electron microscopy and nitrogen sorption method. The greatest imprinting factor of COR was up to 9. The MIPs were used as solid-phase extraction (SPE) sorbents for purification of COR and the mean recoveries of corilagin was 78.0% with COR purity of 98.0% from the crude extract of phyllanthus urinaria L. The resulting COR-imprinted polymer also displayed the good performance of fragment imprinting polymer for gallic acid with the mean recoveries of 94.0% and purity of 99.7%. PMID- 28027523 TI - Preparation, characterization and in vivo evaluation of a formulation of dantrolene sodium with hydroxypropyl-beta-cyclodextrin. AB - Dantrolene sodium (Da) is an effective skeletal muscle relaxant. However, its pharmacological effects are severely limited owing to its poor solubility and low oral bioavailability. In order to solve these problems, an inclusion complex using hydroxypropyl-beta-cyclodextrin (HP-beta-CD) to improve the oral bioavailability of Da was prepared successfully by freeze-drying. The prepared complex was characterized by Powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR) and evaluated by a dissolution test and a pharmacokinetic study. The results of PXRD and FTIR proved the formation of a complex between Da and HP-beta-CD. The dissolution rate of Da was markedly improved from inclusion complex with more than 90% being released within 5min. The in vivo pharmacokinetics of Da and dantrolene sodium-hydroxypropyl-beta cyclodextrin (Da-HP-beta-CD) inclusion complex were investigated in rats using a UPLC/MS/MS method. The Cmax and AUC0-t of the Da-HP-beta-CD inclusion complex were 5- and 3-fold higher than that of the Da. These results suggested that the Da-HP-beta-CD inclusion complex markedly improved the dissolution rate and bioavailability of Da. PMID- 28027524 TI - Challenges with secondary use of multi-source water-quality data in the United States. AB - Combining water-quality data from multiple sources can help counterbalance diminishing resources for stream monitoring in the United States and lead to important regional and national insights that would not otherwise be possible. Individual monitoring organizations understand their own data very well, but issues can arise when their data are combined with data from other organizations that have used different methods for reporting the same common metadata elements. Such use of multi-source data is termed "secondary use"-the use of data beyond the original intent determined by the organization that collected the data. In this study, we surveyed more than 25 million nutrient records collected by 488 organizations in the United States since 1899 to identify major inconsistencies in metadata elements that limit the secondary use of multi-source data. Nearly 14.5 million of these records had missing or ambiguous information for one or more key metadata elements, including (in decreasing order of records affected) sample fraction, chemical form, parameter name, units of measurement, precise numerical value, and remark codes. As a result, metadata harmonization to make secondary use of these multi-source data will be time consuming, expensive, and inexact. Different data users may make different assumptions about the same ambiguous data, potentially resulting in different conclusions about important environmental issues. The value of these ambiguous data is estimated at $US12 billion, a substantial collective investment by water-resource organizations in the United States. By comparison, the value of unambiguous data is estimated at $US8.2 billion. The ambiguous data could be preserved for uses beyond the original intent by developing and implementing standardized metadata practices for future and legacy water-quality data throughout the United States. PMID- 28027525 TI - An integrated AMBBR and IFAS-SBR process for municipal wastewater treatment towards enhanced energy recovery, reduced energy consumption and sludge production. AB - The conventional activated sludge (CAS) process has been widely employed for wastewater treatment for more than one hundred years. Recently, more and more concerns have been raised on the CAS process due to its high energy consumption and production of huge amount of waste activated sludge, which are inevitably linked to the issue of environmental sustainability and global climate change. Facing to such emerging and challenging situation, this study reported a novel A B process in which an anaerobic moving bed biofilm reactor (AMBBR) served a lead A-stage for COD capture towards biogas production and an integrated fixed-biofilm and activated sludge sequencing batch reactor (IFAS-SBR) was employed as B-stage for biological nitrogen removal. Results showed that about 85% of wastewater COD was removed in the steady-state AMBBR with a total energy production rate of 0.28 kWh/m3 wastewater treated, while 85% of N-removal was achieved when the stable nitrite shunt was established in the IFAS-SBR. Moreover, 90% of dissolved methane in the AMBBR effluent could be removed by the proposed flash chamber at the lower energy demand of 0.12 kWh/m3 which could be offset by the potential energy harvested from produced methane. Compared to the CAS process, the production of waste sludge was reduced by about 75% in the proposed A-B process due to the efficient COD capture at the A-stage, leading to significant energy savings from aeration for COD oxidation and post-treatment of waste sludge at the B-stage. Consequently, this study offers in-depth insights into A-B process which should be considered as an ideal candidate for achieving the energy-neutral or even energy positive operation of a municipal wastewater treatment. Given the complex situation in A-B process, future study is needed to look into the system optimization towards the operational synergy between A- and B-stage in terms of energy recovery and nitrogen removal. PMID- 28027526 TI - Probing the intracellular organic matters released from the photocatalytic inactivation of bacteria using fractionation procedure and excitation-emission matrix fluorescence. AB - Photocatalysis provides a "green" and effective strategy for water disinfection. During the photocatalytic disinfection process, intracellular organic matter (IOM) from bacterial cells may be released into the bulk solution. In this study, the role of released IOM in the photocatalytic bacterial inactivation was investigated by fractionation procedure and fluorescence excitation-emission matrix (EEM) combined with parallel factor analysis (PARAFAC) approaches. The normal bacterial cells treated by TiO2-UVA in the presence and absence with fractionated IOM results implied that the released IOM would be either absorbed on the surface of the photocatalysts or reacted by the photo-generated reactive species, and thereby affecting the kinetics of photocatalytic bacterial inactivation. Fluorescence EEM-PARAFAC results showed that two components (C1 and C3) associated with tryptophan- and tyrosine-like proteins were released. While another two components (C2 and C4) were the oxidation products, and their intensities were found to negatively correlate with those of C1 and C3, respectively. Microtox(r) test results indicated that toxicity occurred during the photocatalytic bacterial inactivation process. The toxicity was found to decrease after the bacteria were completely inactivated, and completely removed if provided a sufficient reaction time. Of particular interest is that a significant high linear correlation was observed between the toxicity and the maximum fluorescence intensity of C4. The results and information obtained in this study will be important for further developing photocatalysis in water/wastewater disinfection. PMID- 28027527 TI - Predicting the impact of feed spacer modification on biofouling by hydraulic characterization and biofouling studies in membrane fouling simulators. AB - Feed spacers are an essential part of spiral-wound reverse osmosis (RO) and nanofiltration (NF) membrane modules. Geometric modification of feed spacers is a potential option to reduce the impact of biofouling on the performance of membrane systems. The objective of this study was to evaluate the biofouling potential of two commercially available reference feed spacers and four modified feed spacers. The spacers were compared on hydraulic characterization and in biofouling studies with membrane fouling simulators (MFSs). The virgin feed spacer was characterized hydraulically by their resistance, measured in terms of feed channel pressure drop, performed by operating MFSs at varying feed water flow rates. Short-term (9 days) biofouling studies were carried out with nutrient dosage to the MFS feed water to accelerate the biofouling rate. Long-term (96 days) biofouling studies were done without nutrient dosage to the MFS feed water. Feed channel pressure drop was monitored and accumulation of active biomass was quantified by adenosine tri phosphate (ATP) determination. The six feed spacers were ranked on pressure drop (hydraulic characterization) and on biofouling impact (biofouling studies). Significantly different trends in hydraulic resistance and biofouling impact for the six feed spacers were observed. The same ranking for biofouling impact on the feed spacers was found for the (i) short term biofouling study with nutrient dosage and the (ii) long-term biofouling study without nutrient dosage. The ranking for hydraulic resistance for six virgin feed spacers differed significantly from the ranking of the biofouling impact, indicating that hydraulic resistance of clean feed spacers does not predict the hydraulic resistance of biofouled feed spacers. Better geometric design of feed spacers can be a suitable approach to minimize impact of biofouling in spiral wound membrane systems. PMID- 28027528 TI - Obstacles to engaging in young driver licensing: Perspectives of parents. AB - INTRODUCTION: Young novice drivers remain at greater risk of injury and death despite a wealth of interventions including graduated driver licensing (GDL) programs. The key to implementing safer practices inherent in GDL appears to lie with optimising the role of parents. This qualitative research explored the parent's perspectives of obstacles to engaging in the driver licensing process within a GDL program. Parents also shared advice on what they found helpful, and where relevant, recommended changes in the process to enable safer practices for young drivers. METHOD: Twenty-three parents (aged 35-60 years, M=49.52, SD=8.01, 11 males) participated in semi-structured interviews regarding licensing experiences with their young driver children. The young drivers included learner (n=11), provisional (restricted/intermediate) (n=9) and open (unrestricted/full) licence drivers (n=3), ranging from 16 to 24 years (M=18.04, SD=2.21, 13 males). FINDINGS AND CONCLUSIONS: Content analysis revealed that most obstacles were encountered at the learner licensing phase, with the parent-reported difficult temperament of the learner driver the most prominent. Unsurprisingly, advice to other parents to be patient and remain calm featured heavily during the same phase. Anxiety from not having control of the vehicle was another obstacle at the learner phase, translating to anxieties for child safety in the early stages of provisional driving. Recommendations for the current GDL included more rigorous road rule testing, with general support for the program, professional driver training at learner and provisional stages facilitated parental engagement through the licensing phases. PRACTICAL APPLICATIONS: The findings overwhelmingly suggest a need for parents to be educated regarding their importance in, and of, the driver licensing process, and the efficacy of their instruction, content and practices. PMID- 28027529 TI - Automatic classification of gait in children with early-onset ataxia or developmental coordination disorder and controls using inertial sensors. AB - Early-Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) are two conditions that affect coordination in children. Phenotypic identification of impaired coordination plays an important role in their diagnosis. Gait is one of the tests included in rating scales that can be used to assess motor coordination. A practical problem is that the resemblance between EOA and DCD symptoms can hamper their diagnosis. In this study we employed inertial sensors and a supervised classifier to obtain an automatic classification of the condition of participants. Data from shank and waist mounted inertial measurement units were used to extract features during gait in children diagnosed with EOA or DCD and age-matched controls. We defined a set of features from the recorded signals and we obtained the optimal features for classification using a backward sequential approach. We correctly classified 80.0%, 85.7%, and 70.0% of the control, DCD and EOA children, respectively. Overall, the automatic classifier correctly classified 78.4% of the participants, which is slightly better than the phenotypic assessment of gait by two pediatric neurologists (73.0%). These results demonstrate that automatic classification employing signals from inertial sensors obtained during gait maybe used as a support tool in the differential diagnosis of EOA and DCD. Furthermore, future extension of the classifier's test domains may help to further improve the diagnostic accuracy of pediatric coordination impairment. In this sense, this study may provide a first step towards incorporating a clinically objective and viable biomarker for identification of EOA and DCD. PMID- 28027530 TI - Sagittal spinopelvic alignment predicts hip function after total hip arthroplasty. AB - The aim of this study was to investigate the association between preoperative sagittal spinopelvic alignment and postoperative clinical outcomes after total hip arthroplasty (THA). This retrospective study included 92 patients with hip osteoarthritis who underwent primary THA between May 2013 and October 2015. Patients' characteristics, radiographic sagittal spinopelvic parameters and modified Harris Hip Scores, including function scores (gait scores and functional activities scores), were investigated. Multivariate linear regression analysis was performed to determine the associations between each preoperative sagittal spinopelvic parameter and postoperative hip function The preoperative sagittal spinopelvic parameters that were associated with postoperative gait scores were sagittal vertical axis (adjusted beta-coefficient=-0.28, P=0.02), lumbar lordosis angle (adjusted beta-coefficient=0.29, P=0.0089), pelvic tilt (adjusted beta coefficient=-0.25, P=0.045), sacral slope (adjusted beta-coefficient=0.27, P=0.017) and pelvic incidence minus lumbar lordosis angle (adjusted beta coefficient=-0.31, P=0.01). The preoperative sagittal spinopelvic parameters that were related to the postoperative functional activities scores were sagittal vertical axis (adjusted beta-coefficient=-0.38, P=0.0051) and pelvic incidence minus lumbar lordosis angle (adjusted beta-coefficient=-0.39, P=0.0033). Patients with preoperative imbalanced sagittal alignment such as larger sagittal vertical axis, larger pelvic incidence minus lumbar lordosis and retroversion of pelvis had poorer clinical outcomes than others after THA. While, those preoperative imbalanced patients with anteversion of pelvis may have a compensatory ability which could correct the abnormal sagittal alignment after THA. Preoperative sagittal spinopelvic alignment affected postoperative clinical outcomes after THA. PMID- 28027531 TI - Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors. AB - A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC50 values lower than 10 nM. Subsequently, the most potent 10 analogues were tested for their cytotoxic activities against two multiple myeloma (MM) cell lines RPMI-8226 and MM-1S. Based on these experiments, selected derivatives were further evaluated for their ex vivo and in vivo blood cell proteasome inhibitory activities. The most potential compound 35 (proteasome inhibition IC50: 1.2 +/- 0.1 nM) with potent anti-proliferation (IC50: RPMI-8226 8.4 +/- 0.8 nM; MM-1S: 6.3 +/- 0.8 nM), ex vivo and in vivo activities also had a prolonged half life in plasma, which demonstrated that the enzymatic stabilities of this series of compounds have been improved by constructing a six-membered ring into the peptide skeleton. All the experiments confirmed the correctness of design concept, which made this series of compounds potential leads for exploring new anti-MM drugs. PMID- 28027532 TI - Discovery of novel polycyclic spiro-fused carbocyclicoxindole-based anticancer agents. AB - A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 10l, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC50 values of less than 30 MUM. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, CT26, and HCT116 cells. Further studies illustrated that compound 10i arrested cell cycle in G1 phase and induced apoptosis of HCT116 cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 10i could bind well to the p53 binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions. PMID- 28027533 TI - Quercetin ameliorates oxidative stress, inflammation and apoptosis in the heart of streptozotocin-nicotinamide-induced adult male diabetic rats. AB - INTRODUCTION: Quercetin is known to possess beneficial effects in ameliorating diabetic complications, however the mechanisms underlying cardioprotective effect of this compound in diabetes is not fully revealed. In this study, quercetin effect on oxidative stress, inflammation and apoptosis in the heart in diabetes were investigated. Normal and streptozotocin-nicotinamide induced adult male diabetic rats received quercetin (10, 25 and 50mg/kg/bw) orally for 28days were anesthetized and hemodynamic parameters i.e. systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured. Blood was collected for analyses of fasting glucose (FBG), insulin and cardiac injury marker levels (troponin-C, CK-MB and LDH). Following sacrificed, heart was harvested and histopathological changes were observed. Heart was subjected for analyses of oxidative stress marker i.e. lipid peroxidation and activity and expression levels of anti-oxidative enzymes i.e. SOD, CAT and GPx. Levels of inflammation in the heart were determined by measuring nuclear factor (p65-NF kappaB), tumor necrosis factor (TNF-alpha), interleukins (IL)-1beta and IL-6 levels by using enzyme-linked immunoassay (ELISA). Distribution and expression levels of TNF-alpha and Ikk-beta (inflammatory markers), caspase-3, caspase-9, Blc-2 and Bax (apoptosis markers) in the heart were identified by immunohistochemistry and Western blotting respectively. RESULTS: Administration of quercetin to diabetic rats caused significant decrease in FBG and cardiac injury marker levels with increased in insulin levels. In diabetic rat heart, lesser histopathological changes were observed with oxidative stress, inflammation and apoptosis levels markedly decreased. CONCLUSIONS: Quercetin could potentially be used to ameliorate myocardial damage due to oxidative stress, inflammation and apoptosis in diabetes. PMID- 28027534 TI - Asymptomatic hyperuricemia is a strong risk factor for resistant hypertension in elderly subjects from general population. AB - OBJECTIVE: In clinical practice, patient characteristics predicting resistant hypertension (RH) include higher blood pressure levels, left ventricular hypertrophy, older age, obesity, chronic kidney disease and diabetes. On the contrary little is known about the role of serum uric acid (SUA) as a risk factor for RH in subjects from general population. MATERIAL AND METHODS: 580 elderly subjects aged >=65 years were enrolled in the Risk Of Vascular complications Impact of Genetics in Old people (ROVIGO) study. RH was defined as the failure to maintain blood pressure values below 140mmHg (systolic) and 90mmHg (diastolic) despite therapeutic interventions that include appropriate lifestyle measures plus adherence to treatment with full doses of at least three antihypertensive drugs, including a diuretic. RH was confirmed using 24-h ambulatory blood pressure measurement. Hyperuricemic was defined as the subjects having SUA >=6.8mg/dl or taking uricosuric drugs. Gender-specific odds ratio (OR) for RH was calculated by logistic regression analysis. RESULTS: The prevalence of RH was 5.7% in the cohort and was higher in women (8.3%) than in men (3.0%, p<0.05). Independent of chronic kidney disease (OR 3.89, 95% confidence interval 1.49 10.1), hyperuricemia predicted resistant hypertension in women (odds ratio 3.11, 95% confidence intervals 1.06-9.1, p=0.03) but not in men. CONCLUSIONS: In elderly women from the general population, an SUA value of >=6.8mg/dl triples the risk of RH. SUA assessment should be recommended to better define the pattern of risk associated with RH. PMID- 28027535 TI - Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer. AB - This work aimed to develop hyaluronic acid (HA) decorated pluronic 85 (P85) coated solid lipid nanoparticles (SLN) loaded with paclitaxel (HA-PTX-P85-SLN) and to evaluate its potential to overcome drug resistance and to increase antitumor efficacy in mice bearing cervical and breast tumor. P85-Distearoyl Phosphoethanolamine (DSPE) was synthesized from P85 and DSPE by coupling in the presence of 1,10-carbonyldiimidazole (CDI) as a catalyst. The SLN were prepared by the hot homogenization technique and electrostatic interaction. PTX-loaded SLN was characterized for mean diameter, zeta potential, morphology, entrapment efficiency (EE), drug loading capacity (LC) and in vitro drug release. In vivo animal evaluation containing antitumor effect, pharmacokinetics and biodistribution were conducted in mice bearing cervical and breast tumor. The HA PTX-P85-SLN showed a mean diameter of 160.3nm, negative zeta potential (-31.6mV), EE of 88.2%, and LC of 4.9%. PTX from HA-PTX-P85-SLN exhibited greater sustained drug release profiles compared free PTX. Pharmacokinetics results indicated that HA-PTX-P85-SLN exhibited a 5.5-fold increase in AUC in comparison to free PTX. Biodistribution results revealed that HA-PTX-P85-SLN exhibited higher tumor drug concentration compared with free PTX. PMID- 28027536 TI - Effects of a standardized extract of Rheum turkestanicum Janischew root on diabetic changes in the kidney, liver and heart of streptozotocin-induced diabetic rats. AB - Numerus studies highlighted benefits of natural flavonoids in the management of diabetes. The present study was aimed to investigate the effects of a high flavonoids containing extract of Rheum turkestanicum on diabetic changes in different tissues. Male Wistar rats were divided into normal and streptozotocin induced diabetic groups received saline or hydroalcoholic extract of R. turkestanicum root (100, 200 and 300mg/kg) through orogastric gavage for 4 weeks. Serum glucose, HbA1c, lipids, creatinine, uric acid, liver enzymes (alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase), and cardiac enzymes (lactate dehydrogenase and creatine phosphokinase) in diabetic control group were significantly higher compared to normal control group (p<0.001). The extract significantly reduced these factors, increased body weight, and improved both glucosurea and proteinuria. Lipid peroxidation was high in the liver of diabetic rats compared to normal rats (p<0.001) and reverted toward control values by R. turkestanicum. Also, the extract significantly protected the liver, kidney, and heart of diabetic rats against histopathological changes. In conclusion, R. turkestanicum inhibited the development of nephropathy, liver injury, and myocardial damage in diabetes by lowering the serum levels of glucose and lipids, and by inhibiting oxidative stress mediated lipid peroxidation. PMID- 28027537 TI - Low density lipoprotein peptide conjugated submicron emulsions for combating prostate cancer. AB - Submicron emulsions (SEs) is an advanced formulation that possesses good biocompatibility, high loading of hydrophobic drugs, and good stability through autoclave sterilization. To enhance tumor targeting and tumor cell uptake, SEs could be modified with positive charge and targeting moieties. In the present study, three formulations were prepared: Docetaxel-loaded SEs (DocSEs), cationic DocSEs (DocCSEs), and low density lipoprotein receptor (LDLR) targeted peptide RLT (CEKLKEAFRLTRKRGLKLA) modified DocCSEs (RLT-DocCSEs). The optimized RLT DocCSEs showed a particle size 182.2+/-10nm, a zeta potential 39.62+/-2.41mV, and a loading efficiency of Docetaxel (Doc) 98%. RLT-DocCSEs demonstrated sustained release in 96h and was stable for two months at 4 degrees C. Compared to DocSEs and DocCSEs, RLT-DocCSEs caused significantly more PC-3 cell inhibition and cell apoptosis. RLT-DocCSEs also showed more cellular uptake and slower cellular elimination than that of DocSEs and DocCSEs. The present study indicated RLT DocCSEs could be a potential formulation for injection of anti-cancer therapeutics with increased tumor targeting and anti-tumor efficacy. PMID- 28027538 TI - The arguments for and against cannabinoids application in glaucomatous retinopathy. AB - Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature. In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed. PMID- 28027539 TI - Construction and comparison of different nanocarriers for co-delivery of cisplatin and curcumin: A synergistic combination nanotherapy for cervical cancer. AB - PURPOSE: Co-delivery of two or more drugs into the same cancer cells or tissues in the same nanocarriers provides a new paradigm in cancer treatment. In this study, two kinds of nanocarriers: lipid-polymer hybrid nanoparticles (LPNs) and polymeric nanoparticles (PNPs) were constructed and compared for co-delivery of cisplatin (DDP) and curcumin (CUR). METHODS: DDP and CUR loaded LPNs (D/C/LPNs) and PNPs (D/C/PNPs) were prepared. Two kinds of nanocarriers were characterized in terms of particle size, zeta potential, drug encapsulation efficiency (EE), and drug release. Their in vitro cytotoxicity and in vivo anti-tumor efficacy was studied on human cervix adenocarcinoma cell line (HeLa cells) and mice bearing cervical cancer model. RESULTS: Compared with D/C/PNPs, D/C/LPNs showed significantly higher cytotoxicity in vitro. D/C/LPNs also displayed the best antitumor activity than other formulations tested in vivo. CONCLUSIONS: The results demonstrated that LPNs could improve the anticancer efficacy of drugs to higher levels than PNPs and free drugs, thus could serve as an effective drug system for targeted and synergistic co-delivery nanomedicine for cervical cancer chemotherapy. PMID- 28027540 TI - State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" - research activities and scientific advance in 2015. AB - Research activities and scientific advance achieved in 2014 at the State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" (NRCRM) concerning medical problems of the Chornobyl disaster, radiation medicine, radiobiology, radiation hygiene and epidemiology in collaboration with the WHO network of medical preparedness and assistance in radiation accidents are outlined in the annual report.The report presents the results of fundamental and applied research works of the study of radiation effects and health effects of the Chornobyl accident; fulfillment of tasks of "State social program for improving safety, occupational health and working environment in 2014-2018 years".The report also shows the results of scientific organizational and health care work, staff training.The NRCRM Annual Report was approved at the Scientific Council meeting of NAMS on March 17, 2016. PMID- 28027541 TI - Initial healthcare to pediatric population under the radiation events. AB - The objective of this paper is to analyze the data from scientific literature and available recommendations for health professionals on healthcare providing to pediatric population in the events associated with risk of radiation exposure. Over the past sixty years there were several large scale radiological events with a large number of chil dren affected, namely the atomic bombing of Hiroshima and Nagasaki, accident at the Chornobyl nuclear power plant, contact to 137Cs radiation source unutilized at the hospital shutdown in Brazil etc. Further research has crys tallized injuries and health disorders in the survived children in all cases being much more significant vs. other pop ulations. Analysis of circumstances and features of a number of emergency situations or incidents in the nuclear industry for several decades has shown a high probability of radioactive materials release into the environment. The danger of terrorism with the use of ionizing radiation sources resulting in a considered inevitable hazard to the chil dren is estimated as serious in recent years and deserves an especial mention here. PMID- 28027542 TI - Influence radio and chemotherapy cancer patients to development of male infertility (literature review). AB - The questions that reflect the pathogenesis of disorders under the influence of radiation and chemotherapy on spermatogenesis considered dose effects resulting from the course of treatment, a group of drugs used for chemotherapy protection principles reflected spermatogenesis in cancer patients and methods of recovery. Actuality further research. PMID- 28027543 TI - Ionizing radiation: brain effects and related neuropsychiatric manifestations. AB - Recently, an increasing interest has been directed towards the investigation of brain effects of ionizing radiation (IR), as it is now evident that, depending on the doses, the damages character and severity, as well as clinical man ifestations are different. They are generally considered to be the result of a blending of atherosclerotic, cardiovas cular, cerebrovascular and neurodegenerative processes. Further, an ongoing debate has been opened on the pos sible brain abnormalities following medical radiation from X ray in interventional radiology and nuclear medicine procedures that would involve both patients and medical workers. The aim of the present paper is to summarize literature data on brain effects of IR exposure, with a special focus on those gathered by some of the authors after the Chornobyl nuclear plant disaster, and how they can be related to the pathophysiology of different neuropsy chiatric disorders. PMID- 28027544 TI - Sanitary protective zones of NPPS, radiation and hygienic requirements for. AB - The article analyzes the requirements of legislative and regulatory documents of Ukraine regarding purposes of san itary protective zones of nuclear power plants (NPP), radiation and hygienic principles for substantiation of their sizes. Problems of application of requirements to establish the sizes of sanitary protective zones of NPPs arising from their "emergency" purposes are discussed. The proposals for changes in legislative and regulatory documents of Ukraine are given. Their implementation will not only solve the problem of zoning around NPPs and other radia tion and nuclear facilities, but also to harmonize the legislation of Ukraine with the regulatory requirements of the European Union. PMID- 28027545 TI - Social and psychological state of the Chornobyl clean up workers. Risk factors for negative changes. AB - : It is generally recognized that the Chornobyl nuclear accident caused strong psychosocial stress affecting the entire population of Ukraine, primarily people involved in recovery operations. But what are the reasons? What is the struc ture of stressors? What are their social, medical and biological consequences, what are strategy and preventive meas ures? Issues that require special research and development. OBJECTIVE: To study social and psychological state of the Chornobyl cleanup workers 1986-1987, and to determine regularities of changes and dangerous risk factors. MATERIALS AND METHODS: On the basis of Polyclinic of Radiation Registry, NRCRM, we conducted sample epidemiolog ical study of social and psychological state of the Chornobyl clean up workers 1986-1987. We used method of inter viewing based on "questionnaire", specially developed for this purpose. The study was conducted in October 2013 - May 2015. The sample numbered 235 males aged 18-50 at the time of the accident. Their average age was (31.3 +/- 5.3) years at the time of the accident and (58.9 +/- 5.3) at the time of survey. RESULTS: The results revealed that the Chornobyl nuclear accident and its consequences caused strong social and psychological stress among clean up workers 1986-1987. We have identified a set of factors closely related to the Chornobyl accident, they have caused a sustainable development of mental syndrome - "Anxiety about their own health and the health of family members, especially children". The other set of stressors which are not closely relat ed to the Chornobyl accident but are the result of the social and economic, social and political situation in the coun try. However the former was found to be the cause of such a psychological state as "dissatisfaction with the com pleteness and quality of life". CONCLUSIONS: Social and psychological state of the Chornobyl clean up workers 1986-1987 is estimated as "poor" and it integrally can be characterized as a state of chronic psychosocial stress. Mental syndrome "Anxiety about per sonal health and the health of family members" and psychological syndrome "Dissatisfaction with living condi tions" are main consequences of this state. We identified the main stressors closely related to the consequences of the Chornobyl accident as well as those that are not related to the accident but affect profoundly the level of men tal, social and physical well being. Results of the research are of great importance in organization and provision of social, medical and antiradiation protection of population under emergency situations involving radiation exposure. Key words: Chornobyl accident, clean up workers, social and psychological state, risk factors. PMID- 28027546 TI - Experimental reconstruction of historical WBC measuring procedure in 1986. AB - OBJECTIVE: Examination and experimental reconstruction of the historical WBC measuring procedure in 1986 and estimation of the minimum detectable activity (MDA) of those measurements. MATERIALS AND METHODS: The SRP 68 01 gamma spectrometer with attached scintillation detector based on a NaI(Tl) O 30 x 25 mm2 crystal and NC 482 VM one channel spectrometer (Bicron Co.) with attached scintillation detector based on a NaI(Tl) O 52 x 52 mm2 crystal were used for the study. Protective chamber of the expert type whole body counter (WBC) and homogenous human body dummy phantoms filled with dry radioactive material were applied. Results of measurements on the WBC "Screener 3M" were retrieved from the Radiation Registry of the NRCRM. Dosimetry and mathematical methods were applied too. RESULTS AND CONCLUSIONS: The WBC measurement procedure was reconstructed using the examples tested in 1986 to assay the level of incorporated radioactive cesium in population of contaminated territories. MDA under the WBC measurements in 1986 was found being from 1.3 kBq per human body using the NC 482 VM one channel spectrom eter with attached scintillation detector based on a NaI(Tl) O 52 x 52 mm2 crystal up to 7.4 kBq per human body using the SRP 68 01 gamma radiometer radiometer with attached scintillation detector based on a NaI(Tl) O 30 x 25 mm2 crystal in adults under the 60 seconds measurement time. The respective values for adolescents and chil dren were within 0.8-5.6 kBq per body and 0.5-3.8 kBq per body. PMID- 28027547 TI - Structural characteristics of children and adolescents at the time of the Chornobyl nuclear power plant accident residing in the most intensively contaminated territories of Ukraine. AB - OBJECTIVE: Appraisal of trends in structure of characteristics in population of radiologically contaminated territo ries (RCT) born in 1968-1986 (children and adolescents at the time of the ChNPP accident).Study Object. Persons born since 1968 till 1986 i.e. children and adolescents at the time of the ChNPP accident, who lived on the most intensively contaminated territories of Ukraine (Ivankiv and Poliske regions of Kyiv oblast and Narodichi and Ovruch regions of Zhytomyr oblast) within 1986-2011. MATERIALS AND METHODS: The State Service of Statistics of Ukraine was a principal information base of the study. Specifically the statistical report forms R 11 "Distribution of residential population by gender and age in yearly intervals at a turn of the year" and A 1 "General totals of natural population development" were retrieved. Survey was conducted for the period of 1986-2012. Mathematical, statistical, demographic and software technological methods were applied. RESULTS AND CONCLUSIONS: Summarization of statistical data on population size, both with its gender and age pat terns in the most intensively contaminated territories of Ukraine, namely in Ivankiv and Poliske regions of Kyiv oblast and Narodichi and Ovruch regions of Zhytomyr oblast resulted in conclusion of 27,200 people living there who were born in 1968 1986. They are a critical group of the ChNPP accident survivors. At the beginning of 1987 the male generations of the same age were present in more even manner (4.53-5.82 %%) vs. females (3.04 6.02 %%). No significant change both in gender and year of birth was found in 2012 vs. 1987. Change in gender proportion in surveyed population within 1986 2011 requires some more precise evaluation. PMID- 28027548 TI - Genoprotective properties of astaxanthin revealed by ionizing radiation exposure in vitro on human peripheral blood lymphocytes. AB - OBJECTIVE: to identify possible radioprotective properties of astaxanthin by means of cytogenetic criteria. METHODS: Cultivation of peripheral blood lymphocytes from five apparently healthy volunteers; treatment of lym phocytes' cultures by astaxanthin in final concentrations 20 MUg/ml in Go phase of mitotic cycle, prior to ? irradia tion in vitro in a dose 1 Gy; cytogenetic analysis the uniformly stained slides of metaphase chromosomes. The elec trophoresis of individual cells (Comet assay); visualization of results under fluorescent microscope; accounting the number of nucleoid the fourth grade that correspond to apoptosis of the cells. RESULTS: Established that astaxanthin in final concentration 20.0 MUg/ml exposed to the culture of human peripher al blood lymphocytes in the early G0 phase of mitotic cycle leads to significant reduction of cytogenetic effects induced by gamma irradiation in vitro in dose 1.0 Gy (from 26.05 +/- 1.81 to 9.08 +/- 0.78 per 100 cells, respectively) and to significant increase the frequency of apoptotic cells at the 48 hour of cultivation (from (3.78 +/- 0.24) to (8.26 +/- 0.91) %, respectively). CONCLUSIONS: The results obtained show the ability of astaxanthin to considerable weakening of radioinduced muta genic effect in human peripheral blood lymphocytes, which testify its powerful radioprotective potential. PMID- 28027549 TI - Damage of chromosoms under irradiation of human blood lymphocytes and development of bystander effect. AB - OBJECTIVE: the research the distribution of radiation induced damages among chromosomes and their bands in irra diated in vitro human blood lymphocytes and in unirradiated bystander cells.Material and methods of research: cultivation of human peripheral blood lymphocytes by semi micromethod D.A. Hungerford, modeling of radiation induced bystander effect in mixed cultures consisting of irradiated in vitro and non irradiated blood lymphocytes from persons of different gender, GTG staining of metaphase chromosomes and their cytogenetic analysis. RESULTS: Break points in chromosomes under the formation of aberrations were identified in exposed in vitro human peripheral blood lymphocytes in doses 0.25 Gy (95 breaks in 1248 cells) and 1.0 Gy (227 breaks in 726 cells) and in non irradiated bystander cells under their joint cultivation with irradiated in vitro human lymphocytes (51 breaks in 1137 cells at irradiation of adjacent populations of lymphocytes in dose 0.25 Gy and 75 breaks in 1321 cells at irradiation of adjacent population of lymphocytes in a dose 1.0 Gy). The distribution of injuries among the chromo somes and their bands was investigated. CONCLUSIONS: in radiation exposed in vitro human peripheral blood lymphocytes as well as in bystander cells the fre quency of damaged bands and number of breaks which localized in them exceeded the control value (p < 0.01). As under direct radiation exposure, as under formation of breaks due to induction of bystander effect, chromosomes were damaged according to their relative length. Location of bands with increasing number of breaks coincided with the "hot spots" of chromosome damage following irradiation and fragile sites. More sensitive to damage were G negative euchromatin chromosome bands, in which were localized 82 88 % breaks. Damageability of telomeric regions in the irradiated cells had no significant difference from the control, while in bystander cells was lower than control value (p < 0.05). PMID- 28027550 TI - Modification of radiation induced chromosome damage in Allium test by sodium humate. AB - OBJECTIVE: Cytogenetic analysis of the effects of sodium humate in induced gamma irradiation mutagenesis in Allium test. MATERIALS AND METHODS: Analysis of the root meristem cells of Allium cepa L. seeds carried by ana telophase. Inves tigated the effect of sodium humate (100 mg/l) on cytogenetic effects gamma irradiation (137Cs) at doses of 5, 10 and 20 Gy. RESULTS: Antimutagenic effect of sodium humate was revealed, what allows to consider it as potential therapeutic modifier of radiation damage. Antimutagenic effect of sodium humate increased with increasing irradiation dose. Spotted differential activity of the drug with respect to various types of aberrations are most effectively reducing the frequency of radiation markers mutagenesis - chromosomal aberrations manifested in lower efficiency of long term survivors against potential changes of chromosomes compared with short lived. CONCLUSIONS: Revealed different mechanisms for implementing antimutagenic properties of sodium humate in con dition of gamma irradiation induced mutagenesis in Allium test. PMID- 28027551 TI - The risk of macular degeneration development in persons antenatally irradiated as a result of Chornobyl NPP accident. AB - OBJECTIVE: Assess the risk of macular degeneration development in persons exposed in utero as a result of Chornobyl NPP accident. MATERIALS AND METHODS: The object of the study was the state of the macular area of the retina of 84 individuals exposed in utero as a result of the Chornobyl disaster. They were surveyed at the age of 14-30. The results of stan dardized ophthalmic examinations conducted between 2000 and 2016 were used. The control group consisted of 165 persons who have not undergone prenatal exposure and were examined at the same age as the core group. All patients were examined according to the formalized ophthalmic protocol procedure, examination included ophthal moscopy and fundus camera photography (VISUCAM lite Digital Camera, Zeiss). Statistical analysis of the survey results was carried out using the free trial version of "Open Epi 2.2.1" software package. RESULTS: It is shown that the prevalence of macular degeneration of the retina at the age of 14-30 for persons exposed in utero was 95.23 +/- 32.03 in 1000 and compared with control age (17.86 +/- 10.31 in 1000) was significant ly higher (chi2 = 7.827, p = 0.0026). CONCLUSIONS: In the under 30 age group of the antenatally exposed there already appear macular degenerations whose clinical picture resembles age related macular degeneration. It is proved that the prevalence of macular degeneration was significantly higher in the group of antenatally exposed as compared with non irradiated control at the same age. PMID- 28027552 TI - State of erythroid, granulocyte and platelet branches of hematopoiesis on stages of chemotherapy in children with acute lymphoblastic leukemia, who were exposed to ionizing radiation after the Chornobyl NPP accident. AB - OBJECTIVE: Evaluation of proliferation and differentiation processes of progenitor cells in bone marrow by the com position of elements of erythroid, granulocyte and platelet branches of hematopoiesis on the treatment stages in children with acute lymphoblastic leukemia (ALL), who were exposed to radiation from the Chornobyl NPP accident. MATERIALS AND METHODS: The 46 children with ALL were studied, who lived in Kyiv, Zhytomyr and Chernihiv regions. Studies were conducted before the start of chemotherapy (ChT), on the 33 day of ChT (phase I), and after the com pletion of ChT (phase II). Exposure doses of patients, hemogram and myelogram parameters both with indices of mat uration of progenitor cells were evaluated. Signs of dysplasia of hematopoietic branch elements were revewed. RESULTS: The 46 patients were studied. They have had the B ALL, namely pro B ALL (n=5), "common type" (n=36), pre B ALL (n=3), and T ALL in 2 other cases. In a debut of ALL the bone marrow was represented by lymphoblasts. Along with ChT conduction the bone marrow hematopoiesis recovered by such types, as erythroid, granulocyte, gran ulocyte whith monocytes, and uniform, when the cells number of all branches was within a normal quantity. At the phase II of ChT the number of patients with hematopoiesis recovery by erythroid type decreased and number of chil dren with activation of granulocyte branch of hematopoiesis increased. In children with pro B ALL the number of erythroid elements was higher than normative at both ChT phases. A direct correlation was established between the number of myelokaryocytes (Mkc) and megakaryocytes (Mgkc) in both phase I and phase II of treatment (Rs = +0.72; Rs = +0.56, respectively). There was no correlation between the radiation dose in patients (3.73 +/- 0.12 mSv) and studied parameters. CONCLUSIONS: Types of bone marrow recovery were established in ALL patients after the ChT indicating to the differ ent kinetic pathways of hematopoietic progenitor cells. Evaluation of reasons of prevalence of some hematopoietic branches will allow to reveal their role in leukemogenesis and to correct the treatment programs. PMID- 28027553 TI - Effect of radiation and non radiation environmental factors on children hematopoietic system. AB - OBJECTIVE: Identification of impact of radiation and non radiation environmental factors on development of hematopoi etic abnormalities in children and justification of criteria for the increased risk groups of hematologic diseases. MATERIALS AND METHODS: The results of clinical and hematological survey of 1465 children living in Kyiv, Zhytomyr and Chernihiv regions for the period from 2008 to 2014 were presented. There were 777 children with anemia, 466 with changes in hemogram, 191 with acute leukemia. The irradiation doses, correlation of integrated pollution degree of territories with hematopoietic parameters and course hematologic diseases were estimated. Metal con tent in hair, nails, and blood was determined in 121 children. RESULTS: We have found the most common cause of anemia in children and peculiarities of acute leukemia depend ing on the area integrated contamination. Number of children living in contaminated areas with pro B ALL and T ALL having an initial leukocytosis and unfavorable course of the disease was higher compared to the number of patients from moderately polluted regions (r = 0.47). There is a direct correlation between percentage of children with monocytosis and degree of territory contamination: the 20.2 % of such children lived in the intensively polluted areas and 10,3 % in moderately contaminated ones (p < 0.05). Content of Pb, Cu, Cr, Mn, Zn in biological tissues did not exceed the permissible MAC. Level of Zn in all children was at the lower normal threshold. Individual levels of metals in hair, nails and blood did not depend on gender of patients and their radiation doses. Criteria of increased risk of hematologic diseases in children living in ecologically unfavorable regions were grounded. CONCLUSIONS: Radiation and non radiation environmental factors influencing the development of changes in hematopoiesis and characteristics of the blood system diseases in children play a role in leukeima development processes. These findings are the basis for a further research in the field of radiobiology and ecology. PMID- 28027554 TI - Features of coronary heart disease development in emergency workers of the Chornobyl accident depending on the action of radiation and non radiation risk factors and genotypes of single nucleotide polymorphism rs966221 of phosphodiesterase 4D gene. AB - OBJECTIVE: This study devoted to specific features of coronary heart disease (CHD) development in emergency work ers (EW) of the accident at the Chernobyl nuclear power plant (ChNPP) based on analysis the interaction between radiation and non radiation risk factors and single nucleotide polymorphism (SNP) rs966221 of phosphodiesterase (PDE) 4D gene. METHODS: It was examined 397 men with CHD, including 274 EW of 1986-1987 and 123 non irradiated persons (con trol group) who were 66+/-10 and 69+/-11 years old relatively. The program studies included clinical examination, elec trocardiography (ECG), ECG daily monitoring, ECG stress testing, echo doppler cardiography, analysis of serum lipid spectrum, polymerase chain reaction with restriction of reaction products, retrospective analysis of case histories. Diagnosis of CHD or its approval was carried out in accordance with the standards of diagnosis, accepted in Ukraine. All EW before their taking part in cleaning ChNPP territory did not suffered from CHD. RESULTS: According to the analysis of contingency tables, carriers of the TT genotype of rs966221 increased the risk of myocardial infarction (MI) in 2.538 times compared with carriers of genotypes CC and CT. The use of Kaplan Meier method showed that a half of EW with the TT genotype developed MI before 64 years old, while with the other geno types up to 78.7 years old. In the control group statistically significant increase of cumulative proportion of patients with MI, carriers of the TT genotype, began from 60 years old. Compared to the non irradiated patients EW fell ill with CHD on 9.4 years earlier. Using proportional hazards analysis (Cox regression), it was found that EW had 3.9 times higher risk of CHD than in non irradiated individuals. Smoking and overweight brought three times less but significant risk - 1.37 and 1.33 respectively. The TT genotype unlike genotypes CC and CT gene PDE4D increased risk of MI in 1.757 times more both in EW and control group. CONCLUSIONS: The risk of CHD development was determined by radiation factor, such as the involvement in the emer gency works of the accident consequences, as well as non radiation factors, namely smoking and overweight. Only one factor, the TT genotype of rs966221 PDE4D gene, determined the risk of MI occurrence in EW and non irradiated controls. In the post emergency period, CHD developed 6 years earlier in EW with the TT genotype than in patients with genotypes CC and CT. PMID- 28027555 TI - Vestibular and acustic dysfunctions in clean up workers of Chornobyl accident (30 years of follow up). AB - OBJECTIVE: The objective of the work was to study the clinical and electrophysiological disorders in vestibular and acustic dysfunctions in clean up workers of Chornobyl accident depending on the dose and duration of action of ion izing radiation, the peculiarities of determined effects for 30 years after the accident. MATERIALS AND METHODS: The standard clinical and electrophysiological examinations of vestibular and acoustic ana lyzers functions were conducted in 7812 males' clean up workers including 325 persons selected for prolonged stud ies in 1986 2015. The mathematical methods of analysis were carried out using the software package SYSTAT, EPICURE and EGRET. RESULTS: Vestibular dysfunction and acoustic dysfunction according the central type of progressive development of inhibitory processes in the brain stem, subcortical and cortical structures of vestibular and acoustic analyzers were determined. The dependence of changes in these structures on the dose and duration of ionizing radiation effect was defined. The regularities of determined radiation effects in correlation with the formation of organic cerebrovascu lar pathology in the clean up workers in remote post accident years that are consistent with neurophysiological, MRI and other examinations confirmed with correlation analysis were established. CONCLUSIONS: It was registered that the vestibular and acoustic dysfunctions in the clean up workers were manifest ed by the clinical and electrophysiological changes at the level of central structures in the studied analyzers, which indicate the parallelism of common mechanism of determined radiation effects already at a dose of 0.20 Gy, and also their dose dependency in dynamics of 30 post accidental years. It was established that vestibular dysfunction in the clean up workers is clinically early manifested, and the electroacoustic and electrophysiological changes in a case of normal hearing are evidence of preclinical inhibitory processes in the brain stem, subcortical and cortical structures of acoustic analyzer in the early post accident years. The features of the clinical course of vestibular and acoustic dysfunctions in long term monitoring of short term effects of ionizing radiation in high doses in the group of the clean up workers who have acute radiation sickness, and the manifestation of change is greater and accelerated in time under long term IR effect, than the relatively short term ones in similar small doses in distant years. Significant increase of hearing disorders by type of presbyacuzis precox in the respective age categories, which is one of the symptoms of their premature their aging was studied in clean up workers. PMID- 28027556 TI - Overexpression of TP53, TP53I3 and BIRC5, alterations of gene regulation of apoptosis and aging of human immune cells in a remote period after radiation exposure. AB - OBJECTIVE: To identify a contributive role of changes in gene regulation of apoptosis and telomere length at tran scriptional and translational levels to the formation of radiation induced effects in immune system. PATIENTS AND METHODS: Study groups included 310 Chornobyl (Chornobyl) cleanup workers (dose of external expo sure (360.82 +/- 32.3) mSv; age 58.9 +/- 0.6 (M +/- SD) years) and control (n = 77; age (52.9 +/- 0.64) (M +/- SD) years). Expression of CD95, phosphatidylserine receptors, bcl2 and p53 proteins was studied by flow cytometry; the relative expression (RQ) of BAX, BIRC5, FASLG, MADD, MAPK14, TP53, TP53I3, TERT, TERF1, TERF2 genes was performed using 7900 HT Fast RT PCR System and TagMan technology. Relative telomere length (RTL) was quantified by flow FISH assay. RESULTS: Dose dependent deregulation of apoptosis was shown at transcriptional level (TP53, TP53 I3, BAX, BIRC5, FASL genes) and translational level (bcl 2 and p53 proteins) with blocking entry to apoptosis, dose dependent activation of anti apoptotic proteins and TP53 mediated expression of genes inhibitors of apoptosis. After exposure below 100 mSv a decrease in TERT gene RQ was associated with shortened telomeres, after exposure to doses over 500 mSv the TERT RQ and RTL increase were associated with imbalance in TERF1 and TERF2 genes expression. CONCLUSION: Our study demonstrates a presence of subsequent changes in gene expression, regulatory proteins pres entation, telomere length and distribution of cells by the stages of apoptosis in a late period after radiation expo sure from low dose range to doses over 500 mSv. Results of the study contribute to the basic concepts on the late biological effects in immune system. PMID- 28027557 TI - Pathological personality development after the Chornobyl disaster and the anti terrorist operation. AB - : Objective of the study was to determine pathological changes of the personality of the clean up workers (liquida tors) of the Chornobyl accident and the participants in the anti terrorist operation (ATO) in Eastern Ukraine and radiation threat perception assessment.Design, object and methods. The cross sectional and retrospective assessments of the clean up workers of the Chornobyl accident (n = 185), evacuees from the Chornobyl Exclusion Zone (n = 112) from the randomized sample of individuals who are registered in the Clinical and epidemiological registry (CER) of the State Institution "National Research Center for Radiation Medicine of National Academy of Medical Sciences of Ukraine" [NRCRM] and partici pants of the ATO in Eastern Ukraine (n = 62) who underwent treatment and rehabilitation in the Department of Radiation Psychoneurology of the NRCRM Clinic have been done. The neuropsychiatric clinical and psychometric methods as General Health Questionnaire, GHQ 28; Eysenck Personality Inventory, EPI; method of personality diag nostic by H. Schmischek - K. Leongard, and modified social psychological questionnaire (Joint Study Project 1993) - "dangers questionnaire" were used. RESULTS: Extraversion, hyperthymia and demonstrativity in the clean up workers of the Chornobyl accident and evac uees decreased, while emotiveness, pedantry, anxiety, cyclothymia, excitability and dysthymia increased. Extraversion and hyperthymia decreased in the ATO participants while jams, pedantry, cyclothymia, excitability and dysthymia increased. According to the social psychological assessment ("dangers questionnaire") there were found that at present the "national conflict" factor takes among the clean up workers the 22th rank place, evacuees - the 18th, while the participants ATO - the 11th, however the risk perception of disease associated with the presence in the environment of radioactive substances in the ATO participants takes the 6th place, the liquidators - the 8th, the evac uees - the 7th. Hypertrophic radiation threat perception in the clean up workers and evacuees correlates with increasing concern about the nuclear industry (p < 0.001); the degree of psychological stress related to the Chornobyl disaster (p < 0.001); the degree of psychological stress of evacuation (p < 0.01); with concern of radia tion impact on health (p < 0.001); negative social and economic changes due to the Chornobyl disaster (p < 0.001). The ATO combatants do not trust to the competence of those responsible for the events in Eastern Ukraine (46.3 %), while quite strongly concerned about the future (48.8 %) and hostile attitude to themselves (25.0 %). CONCLUSIONS: There are signs of personality exacerbation/maladjustment and personality accentuation increasing in all studied groups. In ATO combatants the pathological personality development of frustration is forming, that social stress, post traumatic stress and psychosomatic disorders integrates. Hypertrophic radiation risk perception is inherent in all groups surveyed. PMID- 28027558 TI - Cognitive evoked potentials P300 after radiation exposure. AB - OBJECTIVE: The study was aimed at evaluating features of brain information processes and cognitive functioning in the remote period after irradiation due to the Chornobyl accident by using cognitive evoked potentials P300. MATERIALS AND METHODS: The study included 128 people, 112 male Chornobyl clean up workers in 1986-1987 with the records of radiation doses available in Clinical and Epidemiological Registry (CER) of State Institution "National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine" (NRCRM) (study group) and 16 unexposed persons due to the Chornobyl disaster (control group). At the time of the survey the average age of clean up workers (M +/- SD) was (57.3 +/- 5.9) years, range 44-65 years, and of unex posed persons was (57.3 +/- 6.5) years, range 44-65 years. Radiation doses were within the range 0.0002-1.23 Gy, with the arithmetic mean dose (M +/- SD) of (0.2 +/- 0.2) Gy and the geometric mean dose of 0.1 Gy. RESULTS: The radiocerebral effect in the projection of the left posterior superior temporal gyrus (Wernicke's area) proportionally to the radiation dose with the possible threshold of 0.05 Gy of total irradiation was revealed, with increasing radiation dose cognitive component P300 amplitude reduces and its latency period (LP) increases, espe cially at doses > 0.3-0.5 Gy. At doses > 0.5 Gy the functional relationship with the radiation dose for LP P300 increase in the projection of Wernicke's area (r = 0.9; p = 0.027) has been found. CONCLUSIONS: The neurophysiological features detected are fully consistent with hypotheses both on radiosensitiv ity of human central nervous system and accelerated aging of the brain under the influence of small doses of ioniz ing radiation, and have questioned the feasibility of long term manned space flights (including Mars) until the development of adequate radiation hygiene standardization for space crews and invention of means for radiation protection of space flights. Further dynamic clinical and neurophysiological monitoring of individuals exposed to ionizing radiation is necessary. To identify the neurophysiological biological markers of ionizing radiation further international researches with adequate dosimetry support are needed. PMID- 28027559 TI - The contribution of hereditary thrombophilia to increasing the frequency of thrombosis in patients with Ph negative myeloproliferative neoplasms, including the victims from the Chornobyl accident. AB - OBJECTIVE: The definition of a contribution of the carriage of the G1691A allele of thecoagulation factor V gene and the G20210A allele of the coagulation factor II gene in the development of thrombosis in Ph negative myeloprolifer ative neoplasms (MPN) patients, who were irradiated in the dose range 0,001 0,99 Gy and who were not. MATERIALS AND METHODS: The clinical and molecular genetic characteristics of patients with radiation associated and spontaneous polycythemia vera (PV), essential trombotsytemiya (ET) and primary myelofibrosis (PMF) were ana lyzed. The group of radiation associated PV, ET and PMF represented by 35, 10 and 22 patients respectively, and the cohort of spontaneous PV, ET and PMF - 149, 111 and 78 patients respectively. RESULTS AND CONCLUSIONS: The carriage of any of the two molecular genetic markers of hereditary thrombophilia at spontaneous PMF increases the frequency (3 of 6 vs 8 of 72; p = 0.033) and risk (RR = 6.09; 95 % CI = 1.40-26.43) of thrombosis. The presence of the G1691A allele of the proaccelerin gene in patients with PMF, who were not exposed to ionizing radiation, causes increase the likelihood of venous thrombosis at 10.14 times (95 % CI = 1.67-61.33). At spontaneous and radiation associated Ph negative MPN (in individuals exposed to doses in the range 0,001 0,99 Gy), the higher rate of the occurrence of venous, arterial and any thrombosis was observed in carriers of the G1691A allele the coagulation factor V gene, than in those, whose have the wild type allele. In particular, the G1691A allele of the proaccelerin gene carriers, that are belonged to the group of patients with radiation associated PV, have at 33.33 person years bigger rate of any thrombosis (95 % CI = 0.22-100.00, p = 0.048) and venous vascular events (95 % CI = 12.50-50.00; p = 0.003).In PMF patients with a radiation anamnesis were found the difference (20.00 person years; 95 % CI = 1.51-50.00, p = 0.035) between the ratio of any thrombosis and arterial vascular events, which was calculated for the G1691A allele of the proaccelerin gene and for those, who have the wild type allele. The carriers of the G20210A nucleotide variant of the coagulation factor II gene with spontaneous ET and PMF, compared with patients with the wild type allele, have a higher rate of venous thrombosis per 100 patient years. PMID- 28027560 TI - Structural and functional state of heart left ventricle depending on polymorphism rs966221 phosphodiesterase 4D gene in emergency workers of the Chornobyl NPP suffering from coronary heart disease. AB - OBJECTIVE: This study consisted in examination the features of structural and functional state of the cardiovascular system in emergency workers (EW) of the Chernobyl nuclear power plant (ChNPP) who suffered from coronary heart disease (CHD) and having different genotypes due to polymorphism rs966221 phosphodiesterase 4D (PDE4D) gene. MATERIALS AND METHODS: The study involved 121 EW and 63 non irradiated patients with CHD. Standardized survey included echo doppler cardiography (EchoCG) that was done by Diagnostic Ultrasound System DS N3 (Mindray). Polymorphism rs966221 PDE4D determined by polymerase chain reaction followed by restriction reaction products. RESULTS: The distribution of genotypes PDE4D in EW was as follows: CC - 42, CT - 49 and TT - 30 patients. In the con trol group, carriers of the same genotypes were 27, 21 and 15 persons respectively. All echocardiographic parame ters in EW workers and non irradiated patients did not differ significantly. Amongst TT genotype carriers of both groups the proportion of patients with increased myocardial mass index was the highest (82.9%) compared to CC genotype (78.4%) and CT (71.4%). The concentric type of left ventricular (LV) hypertrophy was found in 54.9% of patients with CC genotype, in 51.8% with CT genotype and 45.7% with TT genotype, while the eccentric type in 23.5, 21.4 and 37.1% respectively. The relative number of people with high LV end diastolic volume (EDV) normalized by body surface area (BSA) was 27.5% in CC genotype carriers, 26.8% in CT genotype and 40% in TT genotype carriers (p > 0.05). The increase of BSA indexed LV end systolic volume (ESV) was found in 27.5, 30.4 and 28.6%, and the ejection fraction in 15.7, 23.2 and 22.9% respectively. The largest number of CHD patients with inadequate dias tolic function was in carriers of TT genotype (75%) compared with the data in CC (66.7%) and CT genotypes (42.9%) carriers. CONCLUSIONS: In patients with the same genotype, both EW and non irradiated persons there were virtually no dif ferences in indicators of the structural and functional status of LV. The analysis of changes of LV structure the fol lowing feature was revealed: eccentric type of LV hypertrophy was more common for patients with TT genotype, but concentric type for CC genotype carriers. In one third of patients with CC and CT genotypes and in 40% of TT geno type carriers it was observed LV systolic function disorders. Diastolic dysfunction manifested as often in patients with TT genotype compared with CC and CT genotypes carriers. PMID- 28027561 TI - Correction of endothelial dysfunction in children residents of radioactively contaminated areas by nitric oxide donator. AB - OBJECTIVE: to determine the effectiveness of NO L arginine donator for correcting endothelial dysfunction in chil dren residents of radioactively contaminated areas. MATERIALS AND METHODS: A group of children residents of radioactively contaminated areas with the presence of clinical and paraclinical signs of endothelial dysfunction was selected to assess the effectiveness of correcting endothelial dysfunction by NO L arginine donator according to selective screening. Biochemical parameters for the content of stable NO metabolites, serum L arginine; instrumental parameters of endothelium dependent vascular reaction on occlusion test, the ventilation capacity of the lungs were determined. A course of NO BetarhinT dona tor, which active substance is L arginine, was received by examined children. RESULTS AND CONCLUSIONS: A group of children residents of radioactively contaminated areas with the presence of clinical and paraclinical signs of endothelial dysfunction was selected according to selective screening. The pro nounced positive therapeutic effect, good tolerability, absence of side effects were observed in children with endothelial dysfunction, who were received a course of NO L arginine donator. It has been established that L argi nine use contributed to increasing the content of serum arginine, nitrite, nitrate, and amounts of NO metabolites in children with endothelial dysfunction. Bronchospasm elimination was noted after L arginine use in the significant part of examined patients. An increase in the diameter of the brachial artery and its space in the test with post occlusion reactive hyperemia after the use of L arginine course was revealed by an evaluation of indicators for endothelium dependent vasodilatation of the large vessels using ultrasound method visualizing the brachial artery lumen. This indicates an increase in endothelial vasomotor capacity. PMID- 28027563 TI - Erratum. PMID- 28027562 TI - Microcirculation violations of the conjunctiva in clean up workers of the Chornobyl NPP accident. AB - OBJECTIVE: Explore hemomicrocirculation changes after radiation exposure depending of irradiation dose in dynam ics. MATERIALS AND METHODS: The research conducted on 470 clean up workers of the Chornobyl NPP accident. After 10-15 years after radiation exposure examined 450 Chornobyl clean up workers in age of 28 to 65 years. The con trol group consisted of 110 industrial workers who had not a contact of IR. In 22 years after radiation exposure sep arately examined 20 randomly selected Chornobyl clean up workers accident. The microcirculation state examine by the vessels biomicroscopy of the bulbar conjunctiva. The statistical analysis of the results of the study included the determination of the t coefficient (Student's), correlation coefficient and its error. RESULTS: The research of the state of microcirculation in the conjunctiva revealed the presence of significant irreg ularities in exposure persons in the period of 10 15 years after radiation exposure. The dependence educed of the degree and frequency of pathology of the microvessels of dose accumulation. In 22 years after radiation exposure hemomicrocirculation violations remained widespread, a large proportion was vascular and perivascular changes. Established that the dose dependences for changes of the microcirculation in the remote period in participants work at Chornobyl in 1986 save. CONCLUSIONS: It is shown that the appearance of the significant violations of microcirculation state in the conjunc tiva observed in exposed persons in the period from 10 to 15 years after radiation exposure. In 22 years after radi ation exposure dose dependence hemomicrocirculation violations remained widespread, and clinical features are preserved. PMID- 28027564 TI - Introducing Joan W. Miller, the 2015 Recipient of the Weisenfeld Award. PMID- 28027565 TI - Beyond VEGF-The Weisenfeld Lecture. AB - Purpose: To review advances made in the treatment of age-related macular degeneration (AMD) and share perspectives on the future of AMD treatment. Methods: Review of published clinical and experimental studies. Results: Inhibitors of vascular endothelial growth factor (VEGF) truly revolutionized the treatment of AMD. However, available results from longer-term studies suggest that a degenerative process is unveiled, and continues to occur, even when neovascularization is controlled. Furthermore, anti-VEGF therapy may play a role in the development of atrophic changes. We have proposed using neuroprotection to prevent atrophy, and multiple models of retinal degeneration have shown that it is necessary to block both apoptotic and necrotic cell death pathways. Despite the success of anti-VEGF therapy and the promise of neuroprotection, neither addresses the underlying cause of AMD. It has been postulated that in early AMD, the retention and abnormal accumulation of lipids in Bruch's membrane and below the retinal pigmented epithelium (RPE) lead to drusen. Thus, it is conceivable to target the retained lipoproteins and seek to remove them. In a case study and pilot multicenter clinical trial, we observed significant regression of drusen and an improvement in visual acuity in patients taking high-dose statin therapy. These results, though preliminary, warrant further investigation. Conclusion: Future treatment of AMD should be based on biology, which will require continued elucidation of the pathogenic mechanisms of AMD development. Neuroprotection represents a potential therapeutic approach, and other promising targets include immune pathways (e.g., inflammation, complement, and inflammasomes) and lipid/lipoprotein accumulation. Finally, due to the heterogeneity of AMD, future progress in therapy will benefit from improved phenotyping and classification. PMID- 28027566 TI - Tarlov Cyst Is Correlated with a Short Broad Terminal of the Thecal Sac. AB - Background In clinical practice, we noted that the end section of the thecal sac is apparently different in patients with Tarlov cyst compared with that of the normal population. We conducted this clinical study based on magnetic resonance imaging (MRI). Methods Our study included 30 patients with Tarlov cyst and 30 healthy volunteers as the control. The L4, L5 cross-section areas, the L4, L5 anteroposterior diameters, and the terminal length of the thecal sac were measured from the lumbosacral spine MRI. Results The L4, L5 cross-section areas and the L4, L5 anteroposterior diameters are larger for the Tarlov cyst patients than the controls, but the terminal length of the thecal sac is shorter. Conclusion The Tarlov cyst is correlated with a short broad end of the thecal sac. Possibly, this anatomical variant is a causative factor of Tarlov cyst. PMID- 28027567 TI - Elastographic Evaluation of Indeterminate Breast Masses on Ultrasound. AB - Objective To evaluate the diagnostic accuracy of elastography for breast cancer identification in patients with indeterminate lesions on ultrasound. Methods This prospective, descriptive study included patients with indeterminate breast lesions in the ultrasound and with indication for percutaneous or surgical biopsy. The elastography was evaluated by qualitative analysis and by two methods for the semi quantitative analysis. Results We evaluated 125 female patients with 159 lesions, with a mean age of 47 years, and a range of 20-85 years. Ultrasound has shown to be a method with good sensitivity (98.1%), but with a lower specificity (40.6%). On the elastography qualitative analysis, the specificity and accuracy were of 80.2% and 81.8% respectively. The mean size of the lesions showed no difference in classification by elastography. For the semiquantitative elastography, the mean values of the malignant lesions were statistically higher when compared with the subcutaneous tissue or the adjacent fibroglandular tissue. The analysis of the receiver operating characteristic (ROC) curves for these two semiquantitative methods showed that both are considered satisfactory, with an area under the curve above 0.75 and statistical significance (p < 0.0001). The best results were obtained when using the findings of combined conventional ultrasound and qualitative elastography, with 100% sensitivity and 63.2% specificity. Conclusions Elastography can be a useful complementary method, increasing the specificity and diagnostic accuracy of conventional ultrasound for the diagnosis of breast cancer in patients with indeterminate breast lesions. PMID- 28027568 TI - Perineal Massage Improves the Dyspareunia Caused by Tenderness of the Pelvic Floor Muscles. AB - Aim To evaluate the long-term effectiveness of perineal Thiele massage in the treatment of women with dyspareunia caused by tenderness of the pelvic floor muscles. Methods A total of 18 women with diagnoses of dyspareunia caused by tenderness of the pelvic floor muscles were included in the study. The women were divided in two groups: the dyspareunia (D) group - 8 women with dyspareunia caused by tenderness of the pelvic floor muscles; and the chronic pelvic pain group (CPP) group - 10 women with dyspareunia caused by tenderness of the pelvic floor muscles associated with CPP. Each patient filled out the Visual Analogue Scale (VAS), the McGill Pain Index, the Female Sexual Function Index (FSFI) and the Hospital Anxiety and Depression Scale (HADS). After an evaluation, the women underwent transvaginal massage using the Thiele technique over a period of 5 minutes, once a week for 4 weeks. Results All women had significant improvements in their dyspareunia according the VAS and the McGill Pain Index (p < 0,001), but the HADS scores did not show significant differences. Regarding sexual function, the D group showed improvements on all aspects of sexual function, while the CPP group showed differences only in the pain domain. Conclusion Thiele massage is effective in the treatment of dyspareunia caused by tenderness of the pelvic floor muscles with a long-term pain relief. PMID- 28027569 TI - Treatment of Super-Refractory Status Epilepticus in FIRES. PMID- 28027570 TI - Aldehyde dehydrogenase-2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice. AB - : Potential biomarkers that can be used to determine prognosis and perform targeted therapies are urgently needed to treat patients with hepatocellular carcinoma (HCC). To meet this need, we performed a screen to identify functional genes associated with hepatocellular carcinogenesis and its progression at the transcriptome and proteome levels. We identified aldehyde dedydrogenase-2 (ALDH2) as a gene of interest for further study. ALDH2 levels were significantly lower at the mRNA and protein level in tumor tissues than in normal tissues, and they were even lower in tissues that exhibited increased migratory capacity. A study of clinical associations showed that ALDH2 is correlated with survival and multiple migration-associated clinicopathological traits, including the presence of metastasis and portal vein tumor thrombus. The result of overexpressing or knocking down ALDH2 showed that this gene inhibited migration and invasion both in vivo and in vitro. We also found that ALDH2 altered the redox status of cells by regulating acetaldehyde levels and that it further activated the AMP-activated protein kinase (AMPK) signaling pathway. CONCLUSION: Decreased levels of ALDH2 may indicate a poor prognosis in HCC patients, while forcing the expression of ALDH2 in HCC cells inhibited their aggressive behavior in vitro and in mice largely by modulating the activity of the ALDH2-acetaldehyde-redox-AMPK axis. Therefore, identifying ALDH2 expression levels in HCC might be a useful strategy for classifying HCC patients and for developing potential therapeutic strategies that specifically target metastatic HCC. (Hepatology 2017;65:1628-1644). PMID- 28027571 TI - Bottom-up and trait-mediated effects of resource quality on amphibian parasitism. AB - Leaf litter subsidies are important resources for aquatic consumers like tadpoles and snails, causing bottom-up effects on wetland ecosystems. Recent studies have shown that variation in litter nutritional quality can be as important as litter quantity in driving these bottom-up effects. Resource subsidies likely also have indirect and trait-mediated effects on predation and parasitism, but these potential effects remain largely unexplored. We generated predictions for differential effects of litter nutrition and secondary polyphenolic compounds on tadpole (Lithobates sylvatica) exposure and susceptibility to Ribeiroia ondatrae, based on ecological stoichiometry and community-ecology theory. We predicted direct and indirect effects on key traits of the tadpole host (rates of growth, development and survival), the trematode parasite (production of the cercaria infective stages) and the parasite's snail intermediate host (growth and reproduction). To test these predictions, we conducted a large-scale mesocosm experiment using a natural gradient in the concentrations of nutrients (nitrogen) and toxic secondary compounds (polyphenolics) of nine leaf litter species. To differentiate between effects on exposure vs. susceptibility to infection, we included multiple infection experiments including one with constant per capita exposure. We found that increased litter nitrogen increased tadpole survival, and also increased cercaria production by the snail intermediate hosts, causing opposing effects on tadpole per capita exposure to trematode infection. Increased litter polyphenolics slowed tadpole development, leading to increased infection by increasing both their susceptibility to infection and the length of time they were exposed to parasites. Based on these results, recent shifts in forest composition towards more nitrogen-poor litter species should decrease trematode infection in tadpoles via density- and trait-mediated effects on the snail intermediate hosts. However, these shifts also involve increased abundance of litter species with high polyphenolic levels, which should increase trematode infection via trait-mediated effects on tadpoles. Future studies will be needed to determine the relative strength of these opposing effects in natural wetland communities. [Correction added after online publication on 5 January 2017: wording changed to 'which should increase trematode infection via trait-mediated effects on tadpoles'.]. PMID- 28027572 TI - Free radical scavenging properties of mannitol and its role as a constituent of hyaluronic acid fillers: a literature review. AB - Mannitol has both hydrating and antioxidant properties that make it an ideal excipient for use with hyaluronic acid (HA) fillers. This review examines the role of reactive oxygen species in the ageing process and their effects on both endogenous HA and HA products developed for aesthetic use. Evidence is presented to show that the free radical scavenging properties of mannitol provide it with a two-fold mechanism of action when combined with HA fillers: reducing the inflammation and swelling associated with the injection procedure itself, and preventing the degradation of the injected HA by free radicals. Mannitol also has a long- and well-established safety profile in both the food and pharmaceutical industry. Having established the rationale for using mannitol in combination with an HA filler, the products using this strategy are then reviewed. The addition of mannitol to HA fillers is a viable and safe option for improving both short- and long-term HA aesthetic effects. PMID- 28027573 TI - Defects in myosin VB are associated with a spectrum of previously undiagnosed low gamma-glutamyltransferase cholestasis. AB - : Hereditary cholestasis in childhood and infancy with normal serum gamma glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low-GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow-up. Liver biopsy specimens revealed giant-cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP-deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated cholestasis patients (11 of 38 vs. 0 of 13). CONCLUSION: MYO5B deficiency may underlie 20% of previously undiagnosed low-GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655-1669). PMID- 28027574 TI - New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment. AB - : Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate, which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir-based therapy for 78 weeks. Progressive, indeterminate, and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. CONCLUSION: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017;65:1438 1450). PMID- 28027575 TI - Dual role of the bile acid receptor Takeda G-protein-coupled receptor 5 for hepatic lipid metabolism in feast and famine. PMID- 28027577 TI - A practical approach to nutritional screening and assessment in cirrhosis. AB - Malnutrition is one of the most common complications of cirrhosis, associated with an increased risk of morbidity and mortality. As a potentially modifiable condition, it is of particular importance to identify malnourished patients so that nutritional therapy can be instituted. Nutrition screening and assessment are infrequently performed in patients with cirrhosis. The reasons for this are multifactorial, including the absence of a validated "rapid" screening tool, multiple definitions of what constitutes malnutrition, and challenges with interpreting body composition and laboratory results in the setting of volume overload and liver dysfunction. This article summarizes the clinically relevant evidence and presents key issues, tools, and clinical options that are applicable to patients with cirrhosis. The definition, etiology, and clinically relevant outcomes associated with malnutrition are reviewed. Rapid nutritional screening is differentiated from more detailed nutritional assessment. Nutritional assessment in special populations, including women and the obese, and the role of inflammation are discussed. Multicenter studies using a common nutritional screening/assessment strategy are the next steps to fast-track adoption and implementation of nutrition-related evaluations into routine clinical practice. (Hepatology 2017;65:1044-1057). PMID- 28027576 TI - Human macrophage ferroportin biology and the basis for the ferroportin disease. AB - : Ferroportin (FPN1) is the sole iron exporter in mammals, but its cell-specific function and regulation are still elusive. This study examined FPN1 expression in human macrophages, the cells that are primarily responsible on a daily basis for plasma iron turnover and are central in the pathogenesis of ferroportin disease (FD), the disease attributed to lack-of-function FPN1 mutations. We characterized FPN1 protein expression and traffic by confocal microscopy, western blotting, gel filtration, and immunoprecipitation studies in macrophages from control blood donors (donor) and patients with either FPN1 p.A77D, p.G80S, and p.Val162del lack of-function or p.A69T gain-of-function mutations. We found that in normal macrophages, FPN1 cycles in the early endocytic compartment does not multimerize and is promptly degraded by hepcidin (Hepc), its physiological inhibitor, within 3-6 hours. In FD macrophages, endogenous FPN1 showed a similar localization, except for greater accumulation in lysosomes. However, in contrast with previous studies using overexpressed mutant protein in cell lines, FPN1 could still reach the cell surface and be normally internalized and degraded upon exposure to Hepc. However, when FD macrophages were exposed to large amounts of heme iron, in contrast to donor and p.A69T macrophages, FPN1 could no longer reach the cell surface, leading to intracellular iron retention. CONCLUSION: FPN1 cycles as a monomer within the endocytic/plasma membrane compartment and responds to its physiological inhibitor, Hepc, in both control and FD cells. However, in FD, FPN1 fails to reach the cell surface when cells undergo high iron turnover. Our findings provide a basis for the FD characterized by a preserved iron transfer in the enterocytes (i.e., cells with low iron turnover) and iron retention in cells exposed to high iron flux, such as liver and spleen macrophages. (Hepatology 2017;65:1512-1525). PMID- 28027578 TI - Long noncoding RNA HULC modulates the phosphorylation of YB-1 through serving as a scaffold of extracellular signal-regulated kinase and YB-1 to enhance hepatocarcinogenesis. AB - : Dysregulated expression of long noncoding RNAs has been reported in many types of cancers, indicating that it may play a critical role in tumorigenesis. The long noncoding RNA highly up-regulated in liver cancer (HULC) was first characterized in hepatocellular carcinoma. However, the detailed mechanisms of HULC remain unclear. Here, we demonstrate a novel mechanism by which long noncoding RNA plays oncogenic roles through modulating the phosphorylation status of its interaction protein. First, we validated the markedly increased expression levels of HULC in hepatocellular carcinoma tissues compared to their adjacent noncancerous tissues. Furthermore, up-regulation of HULC was correlated with grading and overall survival. Meanwhile, HULC could promote cell proliferation, migration, and invasion in vitro and inhibit cisplatin-induced apoptosis. Moreover, we show that HULC specifically binds to Y-box binding protein 1 (YB-1) protein both in vitro and in vivo. YB-1 is a major component of translationally inactive messenger ribonucleoprotein particles which keeps mRNA in a silent state. Our study further demonstrated that HULC could promote the phosphorylation of YB-1 protein, which leads to the release of YB-1 from its bound mRNA. As a consequence, translation of silenced oncogenic mRNAs would be activated, including cyclin D1, cyclin E1, and matrix metalloproteinase 3. In addition, we found that HULC promotes the phosphorylation of YB-1 protein mainly through extracellular signal-regulated kinase. CONCLUSION: We demonstrate that HULC promotes the phosphorylation of YB-1 through the extracellular signal-regulated kinase pathway, in turn regulates the interaction of YB-1 with certain oncogenic mRNAs, and consequently accelerates the translation of these mRNAs in the process of tumorigenesis. (Hepatology 2017;65:1612-1627). PMID- 28027579 TI - Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection. AB - : Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus-infected patients who are treatment-naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real world experience. Using data from real-world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut fur Interdisziplinare Medizin), Burman's Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta-analysis of six additional real-world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow-up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment-eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta analysis of six additional real-world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98-1.00). CONCLUSION: An 8-week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094 1103). PMID- 28027580 TI - Effects of predation and nutrient enrichment on the success and microbiome of a foundational coral. AB - By inflicting damage to prey tissues, consumer species may increase stress in prey hosts and reduce overall fitness (i.e., primary effects, such as growth or reproduction) or cause secondary effects by affecting prey interactions with other species such as microbes. However, little is known about how abiotic conditions affect the outcomes of these biotic interactions. In coral reef communities, both nutrient enrichment and predation have been linked to reduced fitness and disease facilitation in corals, yet no study to date has tested their combined effects on corals or their associated microbial communities (i.e., microbiomes). Here, we assess the effects of grazing by a prevalent coral predator (the short coral snail, Coralliophila abbreviata) and nutrient enrichment on staghorn coral, Acropora cervicornis, and its microbiomes using a factorial experiment and high-throughput DNA sequencing. We found that predation, but not nutrients, significantly reduced coral growth and increased mortality, tissue loss, and turf algae colonization. Partial predation and nutrient enrichment both independently altered coral microbiomes such that one bacterial genus came to dominate the microbial community. Nutrient-enriched corals were associated with significant increases in Rickettsia-like organisms, which are currently one of several microbial groups being investigated as a disease agent in this coral species. However, we found no effects of nutrient enrichment on coral health, disease, or their predators. This research suggests that in the several months following coral transplantation (i.e., restoration) or disturbance (i.e., recovery), Caribbean acroporid corals appear to be highly susceptible to negative effects caused by predators, but not or not yet susceptible to nutrient enrichment despite changes to their microbial communities. PMID- 28027581 TI - Reply. PMID- 28027582 TI - Fecal microbiota transplantation induces hepatitis B virus e-antigen (HBeAg) clearance in patients with positive HBeAg after long-term antiviral therapy. PMID- 28027583 TI - Genetic variation in resistance to leaf fungus indirectly affects spider density. AB - Many host-plants exhibit genetic variation in resistance to pathogens; however, little is known about the extent to which genetic variation in pathogen resistance influences other members of the host-plant community, especially arthropods at higher trophic levels. We addressed this knowledge gap by using a common garden experiment to examine whether genotypes of Populus trichocarpa varied in resistance to a leaf-blistering pathogen, Taphrina sp., and in the density of web-building spiders, the dominant group of predatory arthropods. In addition, we examined whether variation in spider density was explained by variation in the density and size of leaf blisters caused by Taphrina. We found that P. trichocarpa genotypes exhibited strong differences in their resistance to Taphrina and that P. trichocarpa genotypes that were more susceptible to Taphrina supported more web-building spiders, the dominant group of predatory arthropods. We suspect that this result is caused by blisters increasing the availability of suitable habitat for predators, and not due to variation in herbivores because including herbivore density as a covariate did not affect our models. Our study highlights a novel pathway by which genetic variation in pathogen resistance may affect higher trophic levels in arthropod communities. PMID- 28027584 TI - Interleukin 6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis. AB - : Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For patients with liver cancer, surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long-term survival of these patients. We have shown that partial hepatectomy in multidrug resistance 2 knockout (Mdr2-/- ) mice, a model of chronic inflammation-associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the postsurgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2-/ mice by perioperative pharmacological inhibition of interleukin-6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following partial hepatectomy without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2-/- mice contain hepatocytes with a notable persistent DNA damage response (gammaH2AX, 53BP1) due to chronic inflammation. We show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei, a marker of genomic instability, which is suppressed by IL6 blockade. CONCLUSION: Our findings indicate that genomic instability derived during the IL6-mediated liver regenerative response within a milieu of chronic inflammation links partial hepatectomy to accelerated hepatocarcinogenesis; this suggests a new therapeutic approach through the usage of an anti-IL6 treatment to extend the tumor-free survival of patients undergoing surgical resection. (Hepatology 2017;65:1600 1611). PMID- 28027585 TI - Rho-kinase inhibition is beneficial in fibrosis. PMID- 28027586 TI - Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. AB - : Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin-sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose-limiting side effects thought to be due to activation of the peroxisome proliferator-activated receptor gamma. We sought to determine whether a next-generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator-activated receptor gamma (MSDC-0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated through an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC-0602. We found that MSDC-0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans-fatty acids, fructose, and cholesterol. Moreover, mice with liver-specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC-0602 directly reduced hepatic stellate cell activation in vitro, and MSDC-0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. CONCLUSION: Collectively, these data demonstrate the effectiveness of MSDC-0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. (Hepatology 2017;65:1543-1556). PMID- 28027588 TI - Integrating multiple data sources in species distribution modeling: a framework for data fusion. AB - The last decade has seen a dramatic increase in the use of species distribution models (SDMs) to characterize patterns of species' occurrence and abundance. Efforts to parameterize SDMs often create a tension between the quality and quantity of data available to fit models. Estimation methods that integrate both standardized and non-standardized data types offer a potential solution to the tradeoff between data quality and quantity. Recently several authors have developed approaches for jointly modeling two sources of data (one of high quality and one of lesser quality). We extend their work by allowing for explicit spatial autocorrelation in occurrence and detection error using a Multivariate Conditional Autoregressive (MVCAR) model and develop three models that share information in a less direct manner resulting in more robust performance when the auxiliary data is of lesser quality. We describe these three new approaches ("Shared," "Correlation," "Covariates") for combining data sources and show their use in a case study of the Brown-headed Nuthatch in the Southeastern U.S. and through simulations. All three of the approaches which used the second data source improved out-of-sample predictions relative to a single data source ("Single"). When information in the second data source is of high quality, the Shared model performs the best, but the Correlation and Covariates model also perform well. When the information quality in the second data source is of lesser quality, the Correlation and Covariates model performed better suggesting they are robust alternatives when little is known about auxiliary data collected opportunistically or through citizen scientists. Methods that allow for both data types to be used will maximize the useful information available for estimating species distributions. PMID- 28027587 TI - Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. AB - : To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis-1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low gamma-glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder-to-colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 +/- 4.0 vs. 2.9 +/- 4.1 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 +/- 465 vs. 457 +/- 319 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 +/- 70 vs. 260 +/- 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. CONCLUSION: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645 1654). PMID- 28027590 TI - Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study. AB - : Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) has not been prospectively studied. HBsAg-negative, anti-HBc-positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (>=10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg-negative, anti-HBc positive, of whom 62 were recruited and monitored for a median of 48 (4-104) weeks. The 2-year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8-100) weeks. Multivariate analysis showed that age >=50 years (P = 0.004, hazard ratio = 8.2) and chronic graft-versus-host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft-versus-host disease, compared with the remaining patient cohort, had a significantly lower 2 year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis. CONCLUSION: HBsAg-negative, anti-HBc-positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age >=50 years and chronic graft-versus-host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017;65:1451-1461). PMID- 28027591 TI - TM6SF2 rs58542926 impacts lipid processing in liver and small intestine. AB - : The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high-fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. CONCLUSIONS: These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride-rich lipoproteins. (Hepatology 2017;65:1526-1542). PMID- 28027592 TI - Outcomes of liver retransplantation in patients with primary sclerosing cholangitis. AB - Liver retransplantation in patients with primary sclerosing cholangitis (PSC) has not been well studied. The aims of this study were to characterize patients with PSC listed for and undergoing retransplantation and to describe the outcomes in these patients. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was used to identify all primary liver transplantations and subsequent relistings and first retransplantations in adults with PSC between 1987 and 2015. A total of 5080 adults underwent primary transplantation for PSC during this period, and of the 1803 who experienced graft failure (GF), 762 were relisted, and 636 underwent retransplantation. Younger patients and patients with GF due to vascular thrombosis or biliary complications were more likely to be relisted, whereas those with Medicaid insurance or GF due to infection were less likely. Both 5-year graft and patient survival after retransplantation were inferior to primary transplantation (P < 0.001). Five-year survival after retransplantation for disease recurrence (REC), however, was similar to primary transplantation (graft survival, P = 0.45; patient survival, P = 0.09) and superior to other indications for retransplantation (graft and patient survival, P < 0.001). On multivariate analysis, mechanical ventilation, creatinine, bilirubin, albumin, advanced donor age, and a living donor were associated with poorer outcomes after retransplantation. In conclusion, although survival after liver retransplantation in patients with PSC was overall inferior to primary transplantation, outcomes after retransplantation for PSC REC were similar to primary transplantation at 5 years. Retransplantation may therefore represent a treatment option with the potential for excellent outcomes in patients with REC of PSC in the appropriate clinical circumstances. Liver Transplantation 23 769-780 2017 AASLD. PMID- 28027593 TI - Behavior of sheep fed babassu cake (Orbygnia speciosa) as a substitution for elephant grass silage. AB - This study aimed to evaluate the behavior of sheep fed babassu cake as a substitution for elephant grass silage. The experiment was conducted at the Federal Rural University of Amazonia (Universidade Federal Rural da Amazonia - UFRA), Brazil, using 45 sheep housed in individual stalls, with unlimited access to feed and distributed in a completely randomized design with five treatments (0, 12.5, 25, 37.5 and 50% inclusion of babassu cake) and nine replications. All of the treatments contained a roughage-to-concentrate ratio of 40:60. No differences were observed in the time spent feeding (P > 0.05), regardless of the source of roughage used. However, there was a reduction in the time spent in rumination (P < 0.05) and an increase in time spent idling (P < 0.05) when babassu cake was included in the diet. Although there was a reduction in the time spent chewing the ruminal bolus (P < 0.05), the total daily chewing time was the same for all animals (P > 0.05). However, the sheep fed babassu cake showed higher feeding and rumination efficiency (P < 0.05). Therefore, the substitution of elephant grass silage with babassu cake can be performed at up to 50% without compromising the total time spent eating and chewing, which allows increased feeding and rumination efficiency. PMID- 28027594 TI - Neuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome. AB - BACKGROUND: Abnormal abdominal pain perception is the most bothersome and difficult to treat symptom of functional gastrointestinal disorders (FGIDs). Visceral pain stimuli are perceived and transmitted by afferent neurons residing in the dorsal root ganglia that have sensory nerve endings in the gut wall and mesentery. Accumulating evidence indicates that peripheral activation and sensitization of these sensory nerve endings by bioactive mediators released by activated immune cells, in particular mast cells, can lead to aberrant neuroimmune interactions and the development and maintenance of visceral hypersensitivity. Besides direct neuronal activation, low concentrations of proteases, histamine, and serotonin can chronically sensitize nociceptors, such as TRP channels, leading to persistent aberrant pain perception. PURPOSE: This review discusses the potential mechanisms underlying aberrant neuroimmune interactions in peripheral sensitization of sensory nerves. A better understanding of the cells, mediators, and molecular mechanisms triggering persistent aberrant neuroimmune interactions brings new insights into their contribution to the physiology and pathophysiology of visceral pain perception and provides novel opportunities for more efficient therapeutic treatments for these disorders. PMID- 28027595 TI - Inhibition of the sterol regulatory element-binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice. AB - : Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element-binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78 kDa cell-surface glycoprotein or SREBP cleavage-activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine-induced HCC progression by down regulating tumor-promoting cytokines, including interleukin (IL)-6, tumor necrosis factor alpha, and IL-1beta. CONCLUSION: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936-1947). PMID- 28027598 TI - Registered reports at the European Journal of Neuroscience: consolidating and extending peer-reviewed study pre-registration. PMID- 28027596 TI - Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium. AB - Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach. PMID- 28027599 TI - Longterm prognosis of combined hepatocellular carcinoma-cholangiocarcinoma following liver transplantation and resection. AB - Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CC) is a rare disease. We investigated the clinicopathological features of cHCC-CC and compared the longterm outcomes following liver transplantation (LT) and hepatic resection (HR). We identified 32 LT patients with cHCC-CC through an institutional database search. The HR control group (n = 100) was selected through propensity score matching. The incidence of cHCC-CC among all adult LT patients was 1.0%. Mean patient age was 53.4 +/- 6.7 years, and 26 patients were male. Thirty patients had hepatitis B virus infection. All patients of cHCC-CC were diagnosed incidentally in the explanted livers. Mean tumor diameter was 2.5 +/- 1.3 cm, and 28 patients had single tumors. Tumor stage was stage I in 23 and II in 9. Concurrent hepatocellular carcinoma (HCC) was detected in 12 patients with stage I in 5 and II in 7. Mean tumor diameter was 1.9 +/- 1.2 cm, and 5 had single tumors. Tumor recurrence and survival rates were 15.6% and 84.4% at 1 year and 32.2% and 65.8% at 5 years, respectively. Patients with very early stage cHCC-CC (1 or 2 tumors <= 2.0 cm) showed 13.3% tumor recurrence and 93.3% patient survival rates at 5 years, which were significantly improved than those with advanced tumors (P = 0.002). Tumor recurrence and survival rates did not differ significantly between the LT and HR control groups (P = 0.22 and P = 0.91, respectively); however, postrecurrence patient survival did (P = 0.016). In conclusion, cHCC-CC is rarely diagnosed following LT, and one-third of such patients have concurrent HCC. The longterm posttransplant prognosis was similar following LT and HR. Very early cHCC-CC resulted in favorable posttransplant prognosis, thus this selection condition can be prudently considered for LT indication. Liver Transplantation 23 330-341 2017 AASLD. PMID- 28027600 TI - Comparison of longterm outcomes and quality of life in recipients of donation after cardiac death liver grafts with a propensity-matched cohort. AB - The use of liver grafts from donation after cardiac death (DCD) has been limited due to the increased rate of graft failure, mostly related to ischemic cholangiopathy (IC). It is our hypothesis that longterm outcomes and quality of life (QOL) similar to patients undergoing liver transplantation (LT) with donation after brain death (DBD) can be achieved. Clinical outcomes of all patients undergoing DCD LT (n = 300) between 1998 and 2015 were compared with a propensity score-matched cohort of patients undergoing DBD LT (n = 300). Patients were contacted for a follow-up questionnaire and short-form (SF)-12 QOL Survey administration. Median follow-up was >5 years. Graft survival at 1-, 3-, and 5 years was 83.8%, 75.5%, and 70.1% in the DCD LT group and 88.4%, 80.3%, and 73.9% in the DBD LT group (P = 0.27). Patient survival at 1-, 3-, and 5-years was 92.3%, 86.1%, and 80.3% in the DCD LT group and 92.3%, 85.1%, and 79.5% in the DBD LT group (P = 0.81). IC developed in 11.7% and 2% of patients in the DCD LT group and DBD LT group, respectively (P < 0.001). DCD LT recipients who developed IC had inferior graft survival compared with both the DCD non-IC group (P < 0.001) and the DBD LT group (P < 0.001); no difference in graft survival was observed between the DCD non-IC group and the DBD LT group (P = 0.50). Physical and Mental Composite Scores on the SF-12 QOL questionnaire were similar between the DCD LT and DBD LT groups (44.0 versus 45.4; P = 0.34 and 51.9 versus 52.2; P = 0.83), respectively. Similar longterm survival and QOL scores can be achieved between DCD LT and DBD LT. Prevention of IC in DCD LT yields excellent graft and patient survival with virtually no difference compared with DBD LT. Liver Transplantation 23 342-351 2017 AASLD. PMID- 28027601 TI - Hysteresis in myo-inositol utilization by Salmonella Typhimurium. AB - Growth of Salmonella enterica serovar Typhimurium strain 14028 with myo-inositol (MI) as the sole carbon and energy source is characterized by a bistable phenotype that manifests in a growth phenotype with an extraordinarily long and length-variable lag phase. However, in the presence of hydrogen carbonate, in the absence of IolR that represses the MI degradation pathway, or if cells are already adapted to minimal medium (MM) with MI, the lag phase is drastically shortened, and the bistable phenotype is abolished. We hypothesized that memory development or hysteresis is a further characteristic of MI degradation by S. Typhimurium; therefore, we investigated the transition from a short to a long lag phase in more detail. Growth experiments demonstrated that memory on the population level is successively lost within approximately 8 hr after cells, which had been adapted to MI utilization, were transferred to lysogeny broth (LB) medium. Flow cytometry (FC) analysis using a chromosomal fusion to PiolE , a promoter controlling the expression of the enzymatic genes iolE and iolG involved in MI degradation, indicated a gradual reversion within a few hours from a population in the "ON" status with respect to iolE transcription to one that is mainly in the "OFF" status. Growth and FC experiments revealed that IolR does not affect hysteresis. PMID- 28027602 TI - Is size the only determinant of delayed abdominal closure in pediatric liver transplant? AB - The aim was to determine the factors associated with the use of delayed abdominal closure in pediatric liver transplantation (LT) and whether this affected outcome. From a prospectively maintained database, transplants performed in children (<=18 years) were identified (October 2010 to March 2015). Primary abdominal closure was defined as mass closure performed at time of transplant. Delayed abdominal closure was defined as mass closure not initially performed at the same time as transplant; 230 children underwent LT. Of these, 176 (76.5%) had primary closure. Age was similar between the primary and delayed groups (5.0 +/- 4.9 versus 3.9 +/- 5.0 years; P = 0.13). There was no difference in the graft-to recipient weight ratio (GRWR) in the primary and delayed groups (3.4 +/- 2.8 versus 4.1 +/- 2.1; P = 0.12). Children with acute liver failure (ALF) were more likely to experience delayed closure then those with chronic liver disease (CLD; P < 0.001). GRWR was similar between the ALF and CLD (3.4 +/- 2.4 versus 3.6 +/- 2.7; P = 0.68). Primary closure children had a shorter hospital stay (P < 0.001), spent fewer days in pediatric intensive care unit (PICU; P = 0.001), and required a shorter duration of ventilation (P < 0.001). Vascular complications (arterial and venous) were similar (primary 8.2% versus delayed 5.6%; P = 0.52). Graft (P = 0.42) and child survival (P = 0.65) in the primary and delayed groups were similar. Considering timing of mass closure after transplant, patients in the early delayed closure group (<6 weeks) were found to experience a shorter time of ventilation (P = 0.03) and in PICU (P = 0.003). In conclusion, ALF was the main determinant of delayed abdominal closure rather than GRWR. The optimal time for delayed closure is within 6 weeks. The use of delayed abdominal closure does not adversely affect graft/child survival. Liver Transplantation 23 352-360 2017 AASLD. PMID- 28027603 TI - Survival implications of opioid use before and after liver transplantation. AB - Implications of prescription opioid use for outcomes after liver transplantation (LT) have not been described. We integrated national transplant registry data with records from a large pharmaceutical claims clearinghouse (2008-2014; n = 29,673). Opioid fills on the waiting list were normalized to morphine equivalents (MEs), and exposure was categorized as follows: > 0-2 ME/day (level 1), > 2-10 ME/day (level 2), > 10-70 ME/day (level 3), and >70 ME/day (level 4). Associations (adjusted hazard ratio [aHR], 95% LCL aHR 95% UCL ) of pretransplant ME level with patient and graft survival over 5 years after transplant were quantified by multivariate Cox regression including adjustment for recipient, donor, and transplant factors, as well as propensity adjustment for opioid use. Overall, 9.3% of recipients filled opioids on the waiting list. Compared with no use, level 3 (aHR 1.06 1.281.55 ) and 4 (aHR 1.16 1.521.98 ) opioid use during listing were associated with increased mortality over 5 years after transplant. These associations were driven by risk after the first transplant anniversary, such that mortality >1-5 years increased in a graded manner with higher use on the waiting list (level 2, aHR, 1.00 1.271.62 ; level 3, aHR, 1.08 1.381.77 ; level 4, aHR, 1.49 2.012.72 ). Similar patterns occurred for graft failure. Of recipients with the highest level of opioids on the waiting list, 65% had level 3 or 4 use in the first year after transplant, including 55% with use at these levels from day 90-365 after transplant. Opioid use in the first year after transplant also bore graded associations with subsequent death and graft loss >1 5 years after transplant. Opioid use history may be relevant in assessing and providing care to LT candidates. Liver Transplantation 23 305-314 2017 AASLD. PMID- 28027605 TI - Species Specificity of Aldehyde and Fatty Acid Profiles of Four Family Group Representatives within the Insect Infraorder Pentatomomorpha (Hemiptera: Heteroptera). AB - Reactive alpha,beta-unsaturated aldehydes, including 4-oxoalk-2-enals, are known to be present in volatile secretions of numerous heteropteran insect species. Because the aldehydes are likely to originate from metabolism of fatty acids (FAs), the present study aimed to examine and compare the aldehyde and FA profiles of four model heteropteran species. The model species consisted of adult family group representatives within the infraorder Pentatomomorpha (Hemiptera: Heteroptera): seed bug (Lygaeus equestris (Lygaeoidea)), dock leaf bug (Coreus marginatus (Coreoidea)), red firebug (Pyrrhocoris apterus (Pyrrhocoroidea)), and European stink bug (Graphosoma lineatum (Pentatomoidea)). Solid-phase microextraction combined with two-dimensional gas-chromatography/time-of-flight mass spectrometry was used to establish the profiles of volatile secretions in stressed living insects. The FA profiles of acylglyceride and phospholipid fractions deposited in fat body and/or hemolymph were obtained by liquid chromatography/mass spectrometry and gas chromatography with flame ionization detection techniques. Our results based on multivariate statistical analyses of the data imply that volatile secretion blends as well as fat body and/or hemolymph lipid profiles are species specific but the differences in volatile blends between different species do not mirror the changes in corresponding fat body and/or hemolymph lipid profiles of stressed and non-stressed individuals. PMID- 28027606 TI - ERRATUM. PMID- 28027607 TI - Third- or Fourth-Degree Intrapartum Anal Sphincter Tears Are Associated With Levator Ani Avulsion in Primiparas. AB - OBJECTIVES: We evaluated primiparous women with clinically diagnosed third- and fourth-degree and anal sphincter tears, to evaluate the rate of levator ani muscle injury compared to primiparous women without sphincter tears. METHODS: Primiparous women delivering in our maternity ward with intrapartum diagnoses of third- or fourth-degree anal sphincter tears, repaired by the overlapping technique, were recruited to undergo 3-dimensional transperineal sonography of the pelvic floor anatomy, including the anterior and posterior compartments. Primiparas with uncomplicated vaginal deliveries were recruited as a comparison group. Patient files were examined, and maternal backgrounds and delivery and neonatal details were extracted for all patients. RESULTS: Ninety-four women with tears were recruited to the study group, and 464 women with normal vaginal deliveries constituted the comparison group. The groups differed significantly in the rates of levator ani defects: 38 of 94 women (40.4%) in the study group versus 75 of 464 (16.2%) in the comparison group (P < .001; odds ratio, 3.53; 95% confidence interval, 2.18-5.7). Neonatal head circumference differed significantly between the study and comparison groups: (mean +/- SD, 34.5 +/- 1.3 cm in the study group versus 33.9 +/- 1.3 cm in the comparison group; P= .005), as did birth weight (3322 +/- 430 g in the study group versus 3169 +/- 458 g in the comparison group; P = .007). The groups did not differ in maternal age, gestational age at delivery, length of second stage of labor, and rates of epidural anesthesia, episiotomy, and vacuum extraction. CONCLUSIONS: Third- and fourth-degree intrapartum sphincter tears are associated with levator ani avulsion. Knowledge of complex pelvic floor damage may allow for prompt referral to secondary preventive measures for pelvic floor disorders. PMID- 28027608 TI - Portable A-Mode Ultrasound for Body Composition Assessment in Adolescents. AB - OBJECTIVES: Ultrasound (US) imaging is a low-cost, highly feasible alternative method for monitoring the nutritional status of a population; however, only a few studies have tested the body composition agreement between US and reference standard methods, especially in adolescents. The purposes of this study were to assess the agreement of portable US with a reference standard method, dual-energy x-ray absorptiometry (DXA), for body fat percentage (BF%) in adolescents and to verify whether the use of a new mathematical model, based on the anatomic thickness obtained by US, is capable of improving BF% prediction. METHODS: This research was a descriptive study. Measures of total body mass, BF% on DXA, and BF% on US were collected from 105 adolescents. RESULTS: The participants included 71 male adolescents (median age +/- interquartile range, 14.0 +/- 2.0 years) and 34 female adolescents (13.0 +/- 2.3 years). Ultrasound yielded significantly lower BF% values than DXA for male (mean +/- SD, US, 9.6% +/- 6.6%; DXA, 20.0% +/ 7.2%; R= 0.848; P< .05) and female (US, 22.5% +/- 5.7%; DXA, 30.3% +/- 4.9%; R = 0.495; P < .05) participants. In addition, Bland-Altman analysis showed low concordance. When a multivariate regression was tested, the results improved for both sexes (US, 20.3% +/- 4.6%; R= 0.848; P= .503) and female participants (US, 29.0% +/- 5.7%; R = 0.712; P = .993) with a standard estimate of error of 1.57%. CONCLUSIONS: This study has shown that US applied in a specific regression for BF% prediction in adolescents has a strong correlation with DXA as well as concordance with Bland-Altman analysis. PMID- 28027609 TI - Prediction of High-grade Vesicoureteral Reflux in Children Younger Than 2 Years Using Renal Sonography: A Preliminary Study. AB - OBJECTIVES: To investigate the predictive value of renal sonography for vesicoureteral reflux (VUR) and the efficacy of renal sonography, technetium Tc 99m-labeled dimercaptosuccinic acid (DMSA) scanning, and a combination of the two for VUR screening in children younger than 2 years with a first episode of febrile urinary tract infection. METHODS: Thirty-eight patients younger than 2 years with a first febrile urinary tract infection were included in our study, which was conducted from April through October 2014. Each kidney was considered a separate renal unit. A retrospective review of clinical information and images (renal sonography, DMSA scanning, and voiding cystourethrography) was performed. RESULTS: Of the 14 renal units (18.4%) with VUR, 4 (28.5%) had high-grade VUR. Among single findings, dilatation of the renal collecting system, wall thickening of the renal collecting system, and DMSA scans significantly predicted VUR (P= .038, .027, and .01, respectively). Dilatation was the most common single finding (46 of 76 renal units). The sensitivity values for dilatation, wall thickening, and DMSA scans were 85.7%, 64.2%, and 50.0%, and the negative predictive values were 93.3%, 89.7%, and 87.9%. CONCLUSIONS: The negative predictive values indicate that normal renal sonographic and DMSA findings can predict the absence of high-grade VUR. We propose that renal sonographic findings of wall thickening as well as dilatation of the renal collecting system should be considered predictive of high-grade VUR. PMID- 28027610 TI - Effects of Low-Intensity Pulsed Ultrasound on Implant Osseointegration in Ovariectomized Rats. AB - OBJECTIVES: To investigate the effect of low-intensity pulsed ultrasound (US) on peri-implant bone healing and osseointegration under osteoporotic conditions. METHODS: Seventy-two 12-week-old female Sprague Dawley rats received bilateral ovariectomies. Twelve weeks later, titanium implants were bilaterally placed in the proximal tibial metaphysis. The right tibia was exposed to low-intensity pulsed US (40 mW/cm2 , spatial and temporal average) for 20 min/d starting the 2nd day after implantation, and the left tibia served as a control without stimulation. The rats were randomly assigned to 6 groups of 12 each according to the US duration (group 1: weeks 0-2, 280 minutes; group 2: weeks 0-4, 560 minutes; group 3: weeks 0-6, 840 minutes; group 4: weeks 0-8, 1120 minutes; group 5: weeks 0-10, 1400 minutes; group 6: weeks 0-12, 1680 minutes). At the end of the 2nd, 4th, 6th, 8th, 10th, and 12th weeks, the rats were euthanized, and bilateral tibias were harvested. Peri-implant bone volume and bone-implant contact were assessed by micro-computed tomography; the implant-bone interface was assessed histologically; and implant fixation strength was determined by a removal torque test. RESULTS: Low-intensity pulsed US increased bone-implant contact at the 4th, 6th, 8th, 10th, and 12th weeks (P = .019, .017, <.001, <.001, and <.001, respectively) and peri-implant bone volume at all times (P = <.001, .002, .012, .007, .005, and .010). Removal torque on the US side was improved at the 6th, 8th, 10th, and 12th weeks (P= .012, <.001, .006, and .009). Ultrasound evoked a favorable bone response in the histologic study. CONCLUSIONS: Low intensity pulsed US might enhance new bone formation, especially at an early stage, and improve osseointegration in osteoporotic bone as an auxiliary method. However, further studies are needed to elucidate the mechanisms underlying its action. PMID- 28027611 TI - Ultrasound-Guided Fasciotomy for Anterior Chronic Exertional Compartment Syndrome of the Leg. AB - Chronic exertional compartment syndrome is characterized by exertional pain and elevated intracompartmental pressures affecting the leg in physically active young people. In patients who have failed conservative measures, fasciotomy is the treatment of choice. This study presents a new method for performing fasciotomy using high-resolution ultrasound (US) guidance and reports on the clinical outcomes in a group of these patients. Over a 3-year period, 7 consecutive patients with a total of 9 involved legs presented clinically with anterior compartment chronic exertional compartment syndrome, which was confirmed by intracompartmental pressure measurements before and after exercise. After a US examination, fasciotomy under US guidance was performed. Preoperative and postoperative pain and activity levels were assessed as well as number of days needed to "return to play." All patients had a decrease in pain, and all except 1 returned to presymptomatic exercise levels with a median return to play of 35 days. PMID- 28027612 TI - Nonobliteration of the Processus Vaginalis: Sonography of Related Abnormalities in Children. AB - The objective of this pictorial essay is to systematically classify processus vaginalis-related disorders in the light of embryology and present illustrative sonograms with corresponding diagrams. Failure of the processus vaginalis to obliterate during gestation results in a wide spectrum of anomalies, including communicating and noncommunicating hydroceles and inguinal and inguinoscrotal hernias, along with other related disorders of the genital system. There are varying classifications in the literature regarding the aforementioned entities. Proper and timely diagnosis of these entities is essential, given the differences in treatment. Although physical examination can narrow the differential diagnosis, sonography plays an essential role in establishing the diagnosis. PMID- 28027613 TI - Reply. PMID- 28027614 TI - Decision modeling in donation after circulatory death liver transplantation. AB - Donation after circulatory death (DCD) liver allografts are increasingly used for transplantation. However, the posttransplantation clinical and quality of life outcomes of DCD recipients are traditionally considered to be inferior compared with donation after brain death (DBD) allograft recipients. Decision making for such marginal organs can be difficult. This study investigated the optimal decision to accept or decline a DCD liver allograft for a patient based on their current health. A Markov decision process model was constructed to predict the 5 year clinical course of patients on the liver transplant waiting list. Clinical outcomes were determined from the UK transplant registry or appropriate literature. Quality-adjusted life years (QALYs) were determined using the condition-specific short form of liver disease quality of life (SF-LDQoL) questionnaire. There were 293/374 (78.3%) eligible patients who completed the SF LDQoL questionnaire. A total of 73 respondents (24.9%) were before transplant and 220 were after transplant (DBD recipient, 56.3%; DCD recipient, 8.5%; ischemic cholangiopathy patient, 2.4%; retransplant recipient, 7.9%). Predictive modeling indicated that QALYs gained at 5 years were significantly higher in DCD recipients (3.77; 95% confidence interval [CI], 3.44-4.10) compared with those who remained on the waiting list for a DBD transplant with Model for End-Stage Liver Disease (MELD) scores of 15-20 (3.36; 95% CI, 3.28-3.43), or >20 (3.07; 95% CI, 3.00-3.14). There was no significant advantage for individuals with MELD scores <15 (3.55; 95% CI, 3.47-3.63). In conclusion, this model predicts that patients on the UK liver transplant waiting list with MELD scores >15 should receive an offered DCD allograft based on the QALYs gained at 5 years. This analysis only accounts for donor-recipient risk pairings seen in current practice. The optimal decision for patients with MELD scores <15 remains unclear. However, a survival benefit was observed when a DCD organ was accepted. Liver Transplantation 23 594-603 2017 AASLD. PMID- 28027615 TI - Living donor liver transplantation using an extended right lateral sector graft. PMID- 28027617 TI - ERRATUM. PMID- 28027616 TI - Living donor liver transplantation using a right anterior section of the liver. PMID- 28027620 TI - ERRATUM. PMID- 28027618 TI - Differential Accumulation of Volatile Organic Compounds by Leaves and Roots of Two Guianese Philodendron Species, P. fragrantissimum Kunth and P. melinonii Brongn. AB - Leaf and root essential oils of two closely related but ecologically distant Philodendron species were extracted in natural conditions in French Guiana and analysed by GC/MS to i) describe the blends of volatile organic compounds (VOCs) produced by those species and ii) analyse species and environment-based variations in extracts composition. A total of 135 VOCs were detected with a majority of aliphatic sesquiterpenes. P. fragrantissimum produced mainly beta bisabolene (on average 29.12% of the extract) as well as alpha- and beta-selinene (14.52% and 17.50%, respectively) while in P. melinonii, four aliphatic sesquiterpenes could alternatively be the main component: (E)-beta-farnesene (up to 91.42% of the extract), germacrene-D (73.74%), beta-caryophyllene (51.63%) and trans-alpha-bergamotene (41.26%). A significant effect of species and organs on extracts composition was observed while the environment (sun exposure) only affected the relative proportions of monoterpenes and sesquiterpenes in roots of P. melinonii. These results are discussed in the light of the potential role of leaf and root terpenes in Philodendron species. PMID- 28027621 TI - Scorecard and insights from approaches to liver allocation around the world. PMID- 28027622 TI - Erratum. PMID- 28027623 TI - Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection. AB - Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2 specific CARs were engineered: one comprising a CD28-CD3zeta signaling domain (CAR) and one lacking an intracellular signaling domain (DeltaCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or DeltaCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and DeltaCAR Tregs preferentially transmigrated across HLA-A2 expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation. PMID- 28027624 TI - Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments. PMID- 28027626 TI - Developments in clinical food and nutrition science in Indonesia. AB - Indonesia, as a major population in the Asia Pacific region, threatened with food and health insecurity through climate change and rapid economic development, faces the challenge to build capacity among its science-based food and health professionals and institutions. The nutrition research agenda is now being more actively set within the region, rather than by external imposition. A series of papers emanating from a new generation of public health and clinical nutrition scientists is reported in this issue of APJCN. It draws attention to the importance of food patterns and background culture as contributors to the failure of the nutrient rather than a food, food system and socio-ecological approach to solve the region's intransigent nutritionally-related health problems. New understandings of human eco-social biology are providing opportunities to accelerate the resolution of these problems. The challenge is to transform the food-health construct from one which is not sufficiently concerned about the precarious state of ecologically dysfunctional health and its nutrient market drivers to one which strives for more sustainable and affordable solutions. The present reports address a range of options to these ends. PMID- 28027627 TI - Association of vitamin D deficiency with cardiovascular disease risk in children: implications for the Asia Pacific Region. AB - BACKGROUND AND OBJECTIVES: Vitamin D deficiency significantly affects cardiovascular disease risk. Cardiovascular disease is epidemic in nature. Because the prevalence of cardiovascular disease has been increasing in children, it has been changing from an adulthood disease to a childhood disease. Therefore, formulating an effective prevention strategy against cardiovascular disease development in children is crucial. METHODS AND STUDY DESIGN: From PubMed, we identified and reviewed studies evaluating the association of vitamin D deficiency with cardiovascular disease risk in children. RESULTS: The mechanism through which vitamin D protects against cardiovascular disease has yet to be fully elucidated. Vitamin D deficiency may be associated with various risk factors for cardiovascular disease that are already manifested in childhood, including obesity, hypertension, dyslipidaemia, insulin resistance, and metabolic syndrome. Vitamin D deficiency has been associated with cardiovascular disease because it promotes vascular stiffness and calcification, leading to atherosclerosis. However, studies investigating the effectiveness of vitamin D in preventing cardiovascular disease risk by using an ideal study design are scant. CONCLUSIONS: Vitamin D deficiency in children may increase cardiovascular disease risk, which tends to manifest in childhood. Because data on the association of vitamin D deficiency with cardiovascular disease risk among children are limited and inconclusive, additional studies are required to investigate this association in children in general and in a setting with naturally abundant sun exposure. PMID- 28027625 TI - Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial. AB - In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus. PMID- 28027628 TI - Development and evaluation of a semiquantitative food frequency questionnaire for estimating omega-3 and omega-6 fatty acid intakes in Indonesian children. AB - BACKGROUND AND OBJECTIVE: A balance ratio of dietary omega-3 (n-3) and omega-6 (n 6) fatty acids reduces childhood obesity. However, few studies have focused on validation of semiquantitative food frequency questionnaire (SFFQ) for determining the n-3 and n-6 intakes in children. Therefore, a valid SFFQ for assessing n-3 and n-6 intakes among Indonesian children is required. METHODS AND STUDY DESIGN: A cross-sectional study was conducted by selecting 89 healthy children through multistage random sampling. Dietary intakes were assessed using the SFFQ and a 3-day non-consecutive 24-h recall. Randomly selected children (n=35) were assessed for plasma phospholipid fatty acid (PFA). In total, 78 food items in the SFFQ, as in the Thai, Vietnamese, and American food composition databases, were validated using dietary recall and PFA. The SFFQ was readministered after 4 weeks to assess its reproducibility. The validity and reproducibility of the SFFQ were determined by Bland-Altman analysis. RESULTS: Favourable agreement was found between the SFFQ and recall for docosahexanoic acid, eicosapentanoic acid, docosapentanoic acid, and arachidonic acid, but not for total n-3, n-6, alpha-linolenic acid, or linoleic acid. Significant correlations were found between the SFFQ estimations and plasma n-6 and LA (r=0.40, p=0.025; and r=0.42, p=0.018, respectively). A 95% limit of Bland-Altman agreement was observed between the first and repeat SFFQ for all fatty acids. CONCLUSION: The proposed SFFQ is sufficiently valid and reliable for assessment of essential fatty acids intakes in Indonesian children. PMID- 28027629 TI - Limitations in vitamin A supplementation to optimise serum retinol in preschool children from two central Java districts. AB - BACKGROUND AND OBJECTIVES: Vitamin A deficiency is particularly common among children younger than 5 years. In 2011, a study conducted in West Java revealed that the prevalence of vitamin A deficiency in children aged 6-11 months, 12-23 months, and 24-59 months was 18.2%, 15.2%, and 9.9%, respectively. The present study analysed the differences in vitamin A intake and serum retinol in all the preschool children from Grobogan and Kudus, Central Java. METHODS AND STUDY DESIGN: The baseline data of vitamin A efficacy were analysed. A total of 143 children aged 1-3 years participants (n=71 from Kudus and n=71 from Grobogan) were recruited and we used independent t-tests to analyse the data. RESULTS: Among the study population, 50.7% and 48.6% were boys and 49.3% and 51.4% were girls from Kudus and Grobogan, respectively. The average intake of energy, carbohydrates, protein, fat, and vitamin A was 698+/-440 (Kcal), 89+/-60 (g), 25.9+/-18.5 (g), 26.1+/-18.5 (g), and 435.3+/-554.0 (MUg) in Kudus and 868+/-493 (Kcal), 109+/-67 (g), 30.9+/-20.1 (g), 35.1+/-23.1 (g), and 538.1+/-622.9 (MUg) in Grobogan, respectively. The average serum retinol in Kudus and Grobogan were 26.7+/-6.4 (MUg/dL) and 29.6+/-5.9 (MUg/dL), respectively. Significant differences in energy and fat intake (p<0.05) were also observed between the Kudus and Grobogan districts; however, no differences in protein, carbohydrates, and vitamin A intake (p>=0.05) were noted. A significant difference in serum retinol was observed between these two districts (p<0.05). CONCLUSIONS: An increase in vitamin A intake through various foods should improve the serum retinol in preschool children. PMID- 28027630 TI - Complementary food supplementation with a small-quantity of lipid-based nutrient supplements prevents stunting in 6-12-month-old infants in rural West Madura Island, Indonesia. AB - BACKGROUND AND OBJECTIVES: Stunting during childhood is a common public health problem in Indonesia. Complementary food supplementation with a small quantity of lipid-based nutrient supplements (SQ-LNSs) can promote growth and prevent undernutrition. This study investigated the effects of the daily provision of SQ LNSs and biscuits on linear growth and reduction in the incidence of stunting among infants in rural Indonesia. METHODS AND STUDY DESIGN: A 6-month, non randomised, controlled trial was conducted on 168 infants who received 20 g of SQ LNSs, 3 pieces of biscuits, or no intervention. The outcome was length gain and incidence of stunting (length-age-z score (LAZ) <-2SD) during a 6-month follow up. RESULTS: After the 6-month intervention, the adjusted length gain and change in the LAZ (8.57 cm and -0.09 z-score unit, respectively) were higher in the SQLNS group than in the control (7.15 cm and -0.87 z-score unit, respectively) and biscuit groups (7.79 cm and -0.46 z-score unit, respectively; p<0.01). The rate of length gain was significantly higher in the SQ-LNS group (1.43 cm/month; 95% CI: 1.12-1.26) than in the biscuit (1.29 cm/month, 95% CI: 1.23-1.36) and control groups (1.19 cm/month, 95% CI: 1.12-1.26; p<0.01). At the end study, the incidence of stunting in SQ-LNS group was lower (1.8%) than in the biscuit group (8.5%) and control group (14.6%). In the SQ-LNS group, the relative risk (RR) of stunting was 0.35 and in the biscuit group (0.94). CONCLUSIONS: SQ-LNSs improved linear growth and reducing the incidence of stunting over 6-months intervention. PMID- 28027631 TI - Factors affecting breastfeeding intention and its continuation among urban mothers in West Jakarta: a follow-up qualitative study using critical point contact for breastfeeding. AB - BACKGROUND AND OBJECTIVES: Although breastfeeding is recommended by WHO, the breastfeeding rate in Indonesia remains low, because many women fail to maintain their breastfeeding intention during the breastfeeding period. The decision whether to breastfeed or not, like any other nutritional behaviour, may develop over a lifetime and is rooted in many aspects of life; however, many factors may affect a mother's decision about whether to stop or continue breastfeeding during the breastfeeding period. A critical time point of contact for breastfeeding is a time point when the mother experiences difficulties and encounters influences that may affect breastfeeding continuation. METHODS AND STUDY DESIGN: A qualitative approach was used to investigate the factors affecting breastfeeding intention and continuation. A follow-up approach was used to assess actual experiences and problems at each time point of contact. The interviewees in this study were pregnant women who lived and worked in West Jakarta and were in at least Week 36 of their pregnancy. The key interviewees for triangulation were 2 grandmothers and 2 healthcare providers. RESULTS AND CONCLUSIONS: Knowledge, beliefs, and support were the factors affecting the women's intentions. Perceived obstacles; common beliefs; stigmas regarding breastfeeding; and support and influences from husbands, mothers, family members, and relatives were the factors influencing breastfeeding continuation within the first month postpartum. PMID- 28027632 TI - Timely initiation of breastfeeding is associated with the practice of exclusive breastfeeding in Indonesia. AB - BACKGROUND AND OBJECTIVES: Exclusive breastfeeding has been proven to be essential for optimal health, and for reducing infections and mortality in children. However, exclusive breastfeeding coverage both in Indonesia and in globalremains low. This study evaluated the relationship between the timely initiation of breastfeeding and the practice of exclusive breastfeeding in Indonesia. METHODS AND STUDY DESIGN: This cross-sectional study used Riskesdas 2013 data. Participants were 7,667 mothers whose children were aged 6-23 months in Indonesia, and were selected based on the completeness of the variables. The data were analysed using descriptive statistics, chisquare tests, and a multiple logistic regression that considered the sampling weight. STATA 13.0 was used for the analyses, and the significance level was set at p<0.05. RESULTS: Timely initiation of breastfeeding within 1 hour of parturition (OR=3.66, 95% CI: 2.14 3.64), timely initiation of breastfeeding at or after 1 hour following parturition (OR=2.79, 95% CI: 3.00-4.46), and neonatal illness (OR=0.69, 95% CI: 0.53-0.91) were significantly associated with an exclusive breastfeeding history among children aged 6-23 months. Other factors, such as the mother's age, mother's educational level, child's birth weight, household economic status, and residential area were not associated with an exclusive breastfeeding history. CONCLUSION: Timely initiation of breastfeeding and the prevention of neonatal illness should be the main interventions to improve exclusive breastfeeding coverage in Indonesia. PMID- 28027633 TI - Pancreatic exocrine insufficiency in malnourished children and those with persistent diarrhoeae. AB - BACKGROUND AND OBJECTIVES: Persistent diarrhoea, a serious health problem, is closely related to malnutrition. Children with severe malnutrition have a 9-fold risk of death, and children with severe stunting have a 4-fold risk of death. Prolonged mucosal injury from diarrhoea causes reduced secretin and cholecystokinin secretion, which decreases stimulation to the pancreas, and is indicated by faecal elastase-1 levels. This further aggravates persistent diarrhoea and malnutrition because of the low levels of digestive enzyme production. This study evaluated the exocrine function of the pancreas in children with persistent diarrhoea and malnutrition. METHODS AND STUDY DESIGN: This study used a cross-sectional design to compare exocrine pancreatic function among children with persistent diarrhoea, children with malnutrition, and apparently healthy children as reference Children aged 6-60 months were selected from the inpatient and outpatient units of various general hospitals in Jakarta. Faecal elastase- 1 levels were used to determine exocrine pancreatic function. RESULTS: The median values of faecal elastase- 1 in children with persistent diarrhoea, children with malnutrition, and reference children were 743 (1-1503) mcg/g, 861 (17-2909) mcg/g, and 1210 (26-3000) mcg/g, respectively. A significant difference was observed in the faecal elastase-1 levels between reference children and those with persistent diarrhoea (p<0.001). However, no differences in the faecal elastase-1 levels were noted between malnourished and reference children (p>0.05). Children with both persistent diarrhoea and malnutrition showed mean FE-1 392.3+/-206.9 and median 419 (125- 593). CONCLUSIONS: Exocrine pancreatic insufficiency is found in children with persistent diarrhoea. Children with combined persistent diarrhoea and malnutrition have the lowest FE-1, to which persistent diarrhea has the most significant contribution. PMID- 28027634 TI - Dietary optimisation with omega-3 and omega-6 fatty acids for 12-23-month-old overweight and obese children in urban Jakarta. AB - BACKGROUND AND OBJECTIVES: Diets with a specific omega-6/omega-3 fatty acid ratio have been reported to have favourable effects in controlling obesity in adults. However, development a local-based diet by considering the ratio of these fatty acids for improving the nutritional status of overweight and obese children is lacking. Therefore, using linear programming, we developed an affordable optimised diet focusing on the ratio of omega- 6/omega-3 fatty acid intake for obese children aged 12-23 months. METHODS AND STUDY DESIGN: A crosssectional study was conducted in two subdistricts of East Jakarta involving 42 normal weight and 29 overweight and obese children, grouped on the basis of their body mass index for-age Z scores and selected through multistage random sampling. A 24 h recall was performed for 3-nonconsecutive days to assess the children's dietary intake levels and food patterns. We conducted group and structured interviews as well as market surveys to identify food availability, accessibility and affordability. RESULTS: Three types of affordable optimised 7-day diet meal plans were developed on the basis of breastfeeding status. The optimised diet plan fulfilled energy and macronutrient intake requirements within the acceptable macronutrient distribution range. The omega-6/omega-3 fatty acid ratio in the children was between 4 and 10. Moreover, the micronutrient intake level was within the range of the recommended daily allowance or estimated average recommendation and tolerable upper intake level. CONCLUSIONS: The optimisation model used in this study provides a mathematical solution for economical diet meal plans that approximate the nutrient requirements for overweight and obese children. PMID- 28027635 TI - Placental weight ratio affects placental mRNA expression of insulin-like growth factor-I and long isoform of the leptin receptor in Plasmodium falciparuminfected pregnant women. AB - BACKGROUND AND OBJECTIVES: Plasmodium falciparum infection during pregnancy is characterised by placental inefficiency caused by infected erythrocyte sequestration. Reduced placental efficiency leads to placental intrauterine adaptation for sustaining fetal growth, which is reflected by changes in the expression of placental genes involved in intrauterine growth regulation. Therefore, we aimed to determine whether the placental weight ratio, an indicator of placental efficiency, affects the placental expression of the components of the insulin-like growth factor axis and leptin signalling pathway in P. falciparum-infected pregnant women. METHODS AND STUDY DESIGN: A malaria case-only analysis of 50 P. falciparum-infected pregnant women in Timika, Papua, Indonesia, was conducted. The placental mRNA expression of insulin-like growth factor-I, insulin-like growth factor binding protein-1, leptin, and the long and short isoforms of the leptin receptor was measured through quantitative realtime PCR. RESULTS: The placental weight ratio exerted a positive effect on the placental mRNA expression of insulin- like growth factor-I (coefficient=6.10, p=0.002) and the long isoform of the leptin receptor (coefficient= 4.73, p=0.015) in malaria infected pregnant women without fever or chill symptoms. CONCLUSION: Our results indicate that placental adaptive responses caused by adverse intrauterine conditions in P. falciparuminfected pregnant women vary depending on the presence or absence of fever and chill symptoms. PMID- 28027636 TI - A social cognitive theory-based programme for eating patterns and sedentary activity among overweight adolescents in Makassar, South Sulawesi : a cluster randomised controlled trial. AB - BACKGROUND AND OBJECTIVES: Social cognitive theory provides the opportunity for program development to enhance healthy personal behvioural characteristics. We devised study to employ social cognitive theory to reduce snacking habits and sedentary activity among overweight adolescents . METHODS AND STUDY DESIGN: Eight junior high schools in Makassar city were randomly assigned as intervention and control schools. A total of 238 overweight students aged 11-15 years (BMI z-score >=1 SD, according to a 2007 report from the WHO) were recruited. Adolescents from the intervention schools attended 12 weekly 75-min nutrition education group sessions, which focused on behavioural modification assisted by trained facilitators; furthermore, their parents received weekly nutrition education leaflets. Adolescents from the control schools, but not their parents, received leaflets on evidenced-based nutrition information. The BMI z-scores, waist circumference, snacking habits, sedentary activity, and the adolescents' self efficacy data were assessed prior to and after 3 months of intervention. The outcomes were analysed on an intent-to-treat basis. RESULTS: Compared with the control group, the intervention group showed a higher reduction in BMI z-scores ( 0.08; p<0.05) and waist circumference (-1.5; p<0.05) at 3 months. Significant between-group differences were also observed for decreased snacking habits, but not for sedentary activity. Additionally, the programme improved self-efficacy for reducing these behaviours. Mean compliance and satisfaction with the programme were 95% and 92%, respectively. CONCLUSIONS: These high reduction rates suggest that the programme is promising and may address the problem of overweightness in adolescents. Additional studies are required to develop the programme in community settings. PMID- 28027637 TI - Sexual dimorphism in interleukin 17A and adipocytokines and their association with insulin resistance among obese adolescents in Yogyakarta, Indonesia. AB - BACKGROUND AND OBJECTIVES: Pro-inflammatory cytokines interleukin 17A (IL-17), leptin, and adiponectin have been associated with obesity and insulin resistance. Moreover, differences in sex and ethnicity as well as plasma concentration of adipocytokines and cytokines have been associated with the risk of insulin resistance. This study was conducted to elucidate whether sex differences exist in the risk of insulin resistance in Indonesian adolescents and to determine how plasma leptin, adiponectin, and IL-17 predict insulin resistance. METHODS AND STUDY DESIGN: The study participants were 69 obese-overweight boys, 53 obese overweight girls, 59 non-obese boys, and 50 non-obese girls aged 15-18 years. Insulin resistance was determined using the homeostatic model assessment of insulin resistance index. Plasma IL-17, leptin, and adiponectin were measured using ELISA. Data were analysed using one-way ANOVA and linear regression analysis. Odd ratios [ORs; 95% confidence intervals (CIs)] were analysed to estimate the risk of insulin resistance; the significance level was set at 95%. RESULT: The OR (95% CI) for insulin resistance was higher in obese-overweight boys than in obese-overweight girls. The plasma IL-17 was higher in boys, whereas plasma adiponectin and leptin were significantly higher in girls. In all participants, obesity status and plasma leptin were the most efficient predictors of insulin resistance, whereas the IL-17 could not significantly predict insulin resistance. CONCLUSION: Sexual dimorphism exists in IL17 as well as leptin and adiponectin in adolescents. Plasma IL-17 cannot be used to predict insulin resistance in adolescents of both sex. PMID- 28027638 TI - Effects of Bifidobacterium animalis lactis HN019 (DR10TM), inulin, and micronutrient fortified milk on faecal DR10TM, immune markers, and maternal micronutrients among Indonesian pregnant women. AB - BACKGROUND AND OBJECTIVES: Maternal nutrition affects fetal growth and development. This study evaluates the effects of milk powder fortified with micronutrients, docosahexaenoic acid (DHA), a prebiotic, and probiotic Bifidobacterium animalis subsp. lactis HN019 DR10TM on the micronutrient status, as well as the presence of faecal probiotic and immune markers in pregnant women. METHODS AND STUDY DESIGN: This randomised, double- blind, placebo-controlled trial was conducted at Budi Kemuliaan and Cipto Mangunkusumo Hospital in Jakarta from 2013 to 2014. A total of 104 participants were randomly allocated to receive either completely enriched milk powder (intervention group) or iron- and vitamin folic-acid-enriched milk powder (control group). Data were collected using standardised measures and were statistically analysed using the independent t or Mann-Whitney test. RESULTS: At the baseline, the micronutrient status of the participants was acceptable, except for 25-OH-vitamin D, in both the intervention and control groups. Vitamin B-1, zinc, total free fatty acid, linoleic acid, arachidonic acid, and DHA were significantly higher in the intervention group in the second trimester (p=0.014, 0.028, 0.023, 0.014, 0.001, and 0.032, respectively). Interleukin-6 and tumor necrosis factor-alpha levels did not significantly vary during pregnancy. B. animalis subsp. lactis DR10TM was present in the faeces of the intervention group but not the control group (61.1% vs 0%). CONCLUSION: Milk fortified with a prebiotic, probiotic, DHA and micronutrients increases the faecal concentration of the organism used for fortification in Indonesian pregnant women. This may represent an improvement in intra-partum maternal gut health. PMID- 28027639 TI - Helical Self-Assembly-Induced Singlet-Triplet Emissive Switching in a Mechanically Sensitive System. AB - In nanoscience, chirality has shown a significant ability to tune materials' electronic properties, whereas imposing macrochirality into the regulation of singlet-triplet features of organic optoelectronics remains a challenging research topic. Since the tuning for singlet and triplet excited-state properties in a single pi-functional molecule connects to its multicolor luminescent application and potential improvement of internal quantum efficiency, we here report that supramolecular chirality can be employed to toggle the singlet and triplet emissions in a well-designed asterisk-shaped molecule. Employing a hexathiobenzene-based single luminophore as a prototype and functionalizing it with chiral alpha-lipoiate side groups, we find that helical nanoarchitectures can accordingly form in mixed DMF/H2O solution. On this basis, switching between fluorescence and phosphorescence of the material can be realized upon helical self-assembly and dissociation. Such a behavior can be attributed to a helical conformation-dependent manipulation of the intersystem crossing. Furthermore, reversible mechanoluminescence of the corresponding solid sample was also observed to rely on an analogous molecular self-assembly alternation. These results can probably provide new visions for the development of next-generation supramolecular chiral functional materials. PMID- 28027640 TI - Hydrogels for Therapeutic Delivery: Current Developments and Future Directions. AB - Hydrogels are attractive materials for the controlled release of therapeutics because of their capacity to embed biologically active agents in their water swollen network. Recent advances in organic and polymer chemistry, bioengineering and nanotechnology have resulted in several new developments in the field of hydrogels for therapeutic delivery. In this Perspective, we present our view on the state-of-the-art in the field, thereby focusing on a number of exciting topics, including bioorthogonal cross-linking methods, multicomponent hydrogels, stimuli-responsive hydrogels, nanogels, and the release of therapeutics from 3D printed hydrogels. We also describe the challenges that should be overcome to facilitate translation from academia to the clinic and last, we share our ideas about the future of this rapidly evolving area of research. PMID- 28027641 TI - Dietary Wolfberry Extract Modifies Oxidative Stress by Controlling the Expression of Inflammatory mRNAs in Overweight and Hypercholesterolemic Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - In the present study, we evaluated the antioxidative and anti-inflammatory effects of an aqueous extract of wolfberry fruit (WBE) in mild hypercholesterolemic and overweight subjects. This study was a double-blind randomized trial of two parallel groups of free-living subjects (n = 53). The participants consumed the contents of an 80 mL pouch containing 13.5 g WBE or placebo after one meal per day over an 8-week period. Following 8 weeks of WBE supplementation, we observed a slight but significant decrease in erythrocyte superoxide dismutase activity and an increase in catalase activity. Furthermore, to assess endogenous DNA damage in lymphocytes, the alkaline comet assay was performed, showing that the percentage of DNA in the tail was significantly decreased by 8-week WBE intake. Additionally, the proportion of significantly deregulated mRNAs related to oxidative or inflammatory stress was considerably higher in the WBE intake group. The present data indicate that WBE intake has antioxidative and anti-inflammatory effects in overweight and hypercholesterolemic subjects by modulating mRNA expression. PMID- 28027642 TI - Direct Blow-Spinning of Nanofibers on a Window Screen for Highly Efficient PM2.5 Removal. AB - Particulate matter (PM) pollution has caused many serious public health issues. Whereas indoor air protection usually relies on expensive and energy-consuming filtering devices, direct PM filtration by window screens has attracted increasing attention. Recently, electrospun polymer nanofiber networks have been developed as transparent filters for highly efficient PM2.5 removal; however, it remains challenging to uniformly coat the nanofibers on window screens on a large scale and with low cost. Here, we report a blow-spinning technique that is fast, efficient, and free of high voltages for the large-scale direct coating of nanofibers onto window screens for indoor PM pollution protection. We have achieved a transparent air filter of 80% optical transparency with >99% standard removal efficiency level for PM2.5. A test on a real window (1 m * 2 m) in Beijing has proven that the nanofiber transparent air filter acquires excellent PM2.5 removal efficiency of 90.6% over 12 h under extremely hazy air conditions (PM2.5 mass concentration > 708 MUg/m3). Moreover, we show that the nanofibers can be readily coated on the window screen for pollution protection and can be easily removed by wiping the screen after hazardous days. PMID- 28027643 TI - Switching Apoptosis to Ferroptosis: Metal-Organic Network for High-Efficiency Anticancer Therapy. AB - Discovering advanced materials for regulating cell death is of great importance in the development of anticancer therapy. Herein, by harnessing the recently discovered oxidative stress regulation ability of p53 and the Fenton reaction inducing capability of metal-organic network (MON), MON encapsulated with p53 plasmid (MON-p53) was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. After confirming the detailed mechanism of MON-p53 in evoking ferroptosis, we further discovered that MON-p53 mediated a "bystander effect" to further sensitize cancer cells toward the MON-p53 induced ferroptosis. A 75-day anticancer experiment indicated that MON-p53 treatment not only suppressed the tumor growth but also prolonged the life-span of tumor bearing mice. Owing to its ability to promote intracellular oxidative stress, MON p53 decreased the blood metastasis, lung metastasis, and liver metastasis. As a consequence, discovering methods to induce cell ferroptosis would provide a new insight in designing anticancer materials. PMID- 28027644 TI - Label-free Imaging of Neurotransmitter Acetylcholine at Neuromuscular Junctions with Stimulated Raman Scattering. AB - Acetylcholine is an important neurotransmitter that relays neural excitation from lower motor neurons to muscles. It also plays significant roles in the central nervous system by modulating neurotransmission. However, there is a lack of tools to directly measure the quantity and distribution of acetylcholine at the subcellular level. In this Communication, we demonstrate for the first time that label-free imaging of acetylcholine is achieved with frequency-modulated spectral focusing stimulated Raman scattering (FMSF-SRS) microscopy: a technical improvement over traditional SRS microscopy that effectively removes imaging backgrounds. Moreover, we directly quantified the local concentration of acetylcholine at the neuromuscular junction of frog cutaneous pectoris muscle. PMID- 28027645 TI - Biocarriers Improve Bioaugmentation Efficiency of a Rapid Sand Filter for the Treatment of 2,6-Dichlorobenzamide-Contaminated Drinking Water. AB - Aminobacter sp. MSH1 immobilized in an alginate matrix in porous stones was tested in a pilot system as an alternative inoculation strategy to the use of free suspended cells for biological removal of micropollutant concentrations of 2,6-dichlorobenzamide (BAM) in drinking water treatment plants (DWTPs). BAM removal rates and MSH1 cell numbers were recorded during operation and assessed with specific BAM degradation rates obtained in lab conditions using either freshly grown cells or starved cells to explain reactor performance. Both reactors inoculated with either suspended or immobilized cells showed immediate BAM removal under the threshold of 0.1 MUg/L, but the duration of sufficient BAM removal was 2-fold (44 days) longer for immobilized cells. The longer sufficient BAM removal in case of immobilized cells compared to suspended cells was mainly explained by a lower initial loss of MSH1 cells at operational start due to volume replacement and shear. Overall loss of activity in the reactors though was due to starvation, and final removal rates did not differ between reactors inoculated with immobilized and suspended cells. Management of assimilable organic carbon, in addition to cell immobilization, appears crucial for guaranteeing long-term BAM degradation activity of MSH1 in DWTP units. PMID- 28027646 TI - Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control. AB - Carcinoma-associated fibroblasts (CAFs) are found in many types of cancer and play an important role in tumor growth and metastasis. Fibroblast-activation protein (FAP), which is overexpressed on the surface of CAFs, has been proposed as a universal tumor targeting antigen. However, recent studies show that FAP is also expressed on multipotent bone marrow stem cells. A systematic anti-FAP therapy may lead to severe side effects and even death. Hence, there is an urgent need of a therapy that can selectively kill CAFs without causing systemic toxicity. Herein we report a nanoparticle-based photoimmunotherapy (nano-PIT) approach that addresses the need. Specifically, we exploit ferritin, a compact nanoparticle protein cage, as a photosensitizer carrier, and we conjugate to the surface of ferritin a FAP-specific single chain variable fragment (scFv). With photoirradiation, the enabled nano-PIT efficiently eliminates CAFs in tumors but causes little damage to healthy tissues due to the localized nature of the treatment. Interestingly, while not directly killing cancer cells, the nano-PIT caused efficient tumor suppression in tumor-bearing immunocompetent mice. Further investigations found that the nano-PIT led to suppressed C-X-C motif chemokine ligand 12 (CXCL12) secretion and extracellular matrix (ECM) deposition, both of which are regulated by CAFs in untreated tumors and mediate T cell exclusion that prevents physical contact between T cells and cancer cells. By selective killing of CAFs, the nano-PIT reversed the effect, leading to significantly enhanced T cell infiltration, followed by efficient tumor suppression. Our study suggests a new and safe CAF-targeted therapy and a novel strategy to modulate tumor microenvironment (TME) for enhanced immunity against cancer. PMID- 28027647 TI - Plasmonic Solar Cells: From Rational Design to Mechanism Overview. AB - Plasmonic effects have been proposed as a solution to overcome the limited light absorption in thin-film photovoltaic devices, and various types of plasmonic solar cells have been developed. This review provides a comprehensive overview of the state-of-the-art progress on the design and fabrication of plasmonic solar cells and their enhancement mechanism. The working principle is first addressed in terms of the combined effects of plasmon decay, scattering, near-field enhancement, and plasmonic energy transfer, including direct hot electron transfer and resonant energy transfer. Then, we summarize recent developments for various types of plasmonic solar cells based on silicon, dye-sensitized, organic photovoltaic, and other types of solar cells, including quantum dot and perovskite variants. We also address several issues regarding the limitations of plasmonic nanostructures, including their electrical, chemical, and physical stability, charge recombination, narrowband absorption, and high cost. Next, we propose a few potentially useful approaches that can improve the performance of plasmonic cells, such as the inclusion of graphene plasmonics, plasmon upconversion coupling, and coupling between fluorescence resonance energy transfer and plasmon resonance energy transfer. This review is concluded with remarks on future prospects for plasmonic solar cell use. PMID- 28027650 TI - Fabrication of CuFe2O4/alpha-Fe2O3 Composite Thin Films on FTO Coated Glass and 3 D Nanospike Structures for Efficient Photoelectrochemical Water Splitting. AB - Recently, photoelectrochemical conversion (PEC) of water into fuel is attracting great attention of researchers due to its outstanding benefits. Herein, a systematic study on PEC of water using CuFe2O4/ alpha-Fe2O3 composite thin films is presented. CuFe2O4/ alpha-Fe2O3 composite thin films were deposited on two different substrates; (1) planner FTO glass and (2) 3-dimensional nanospike (NSP). The films on both substrates were characterized and tested as anode material for photoelectrochemical water splitting reaction. During PEC studies, it was observed that the ratio between two components of composite is crucial and highest PEC activity results were achieved by 1:1 component ratio (CF-1) of CuFe2O4 and alpha-Fe2O3. The CF-1 ratio sample deposited on planar FTO substrate provided a photocurrent density of 1.22 mA/cm2 at 1.23 VRHE which is 1.9 times higher than bare alpha-Fe2O3 sample. A significant PEC activity outperformance was observed when CF-1 ratio composite thin films were deposited on 3D NSP. The highest photocurrent density of 2.26 mA/cm2 at 1.23 VRHE was achieved for 3D NSP sample which is around 3.6 times higher than photocurrent density generated by alpha-Fe2O3 thin film only. The higher photocurrent densities of 3D nanostructured devices compared to planar one are attributed to the enhanced light trapping and increased surface area for photoelectrochemical water oxidation on the surface. The difference between valence and conduction bands of CuFe2O4 and alpha-Fe2O3 allows better separation of photogenerated electrons and holes at the CuFe2O4/ alpha-Fe2O3 interface which makes it more active for photoelectrochemical water splitting. PMID- 28027651 TI - The Senior Companion Program Plus: A culturally tailored psychoeducational training program (innovative practice). AB - A purposive sample of African American Senior Companions ( N = 23) participated in a 5-day, 20-hour psychoeducational training designed to address the unique cultural needs of African American dementia caregivers. Previous studies have not utilized lay caregiver volunteers such as Senior Companions in dementia research in the United States. Pre- and post-tests were administered to determine whether African American Senior Companions increased their knowledge of Alzheimer's disease after participating in the Senior Companion Program Plus. Results from both the quantitative and qualitative data suggest that participants improved their understanding of Alzheimer's disease. Findings from the Senior Companion Program Plus pilot warrant further study for its potential as cost effective, culturally tailored training for Senior Companions who serve persons with dementia and their family caregivers. PMID- 28027648 TI - Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products. AB - Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review will chronicle the successful efforts of synthetic chemists in the construction of these biologically active molecules. Key carbon-carbon bond forming reactions will be highlighted, as well as the methods used to install the numerous stereocenters present in this class of compounds. PMID- 28027652 TI - Melatonin Ameliorates Busulfan-Induced Spermatogonial Stem Cell Oxidative Apoptosis in Mouse Testes. AB - AIMS: Many men endure immunosuppressive or anticancer treatments that contain alkylating agents before the age of sexual maturity, especially the increasing number of preadolescent males who undergo busulfan treatment for myeloablative conditioning before hematopoietic stem cell transplantation. Before sperm production, there are no sperm available for cryopreservation. Thus, it is necessary to identify a solution to ameliorate the busulfan-induced damage of spermatogonial stem cells (SSCs). RESULTS: In this study, we demonstrated that melatonin relieved the previously described SSC loss and apoptosis in mouse testes. Melatonin increased the expression of manganese superoxide dismutase (MnSOD), which regulated the production of busulfan-induced reactive oxygen species (ROS). Moreover, melatonin promoted sirtuin type 1 (SIRT1) expression. SIRT1 participated in the deacetylation of p53, which promotes p53 ubiquitin degradation. Decreased concentrations of deacetylated p53 resulted in spermatogonial cell resistance to apoptosis. Acute T cell leukemia cell assay demonstrated that melatonin does not affect busulfan-induced cancer cell apoptosis and ROS. INNOVATION: The current evidence suggests that melatonin may alleviate the side effects of alkylating drugs, such as busulfan. CONCLUSION: Melatonin promoted MnSOD and SIRT1 expression, which successfully ameliorated busulfan-induced SSC apoptosis caused by high concentrations of ROS and p53. Antioxid. Redox Signal. 28, 385-400. PMID- 28027653 TI - Biomechanical Comparison of Anterolateral Procedures Combined With Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Anterolateral soft tissue structures of the knee have a role in controlling anterolateral rotational laxity, and they may be damaged at the time of anterior cruciate ligament (ACL) ruptures. PURPOSE: To compare the kinematic effects of anterolateral operative procedures in combination with intra-articular ACL reconstruction for combined ACL plus anterolateral-injured knees. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve cadaveric knees were tested in a 6 degrees of freedom rig using an optical tracking system to record the kinematics through 0 degrees to 90 degrees of knee flexion with no load, anterior drawer, internal rotation, and combined loading. Testing was first performed in ACL-intact, ACL-deficient, and combined ACL plus anterolateral injured (distal deep insertions of the iliotibial band and the anterolateral ligament [ALL] and capsule cut) states. Thereafter, ACL reconstruction was performed alone and in combination with the following: modified MacIntosh tenodesis, modified Lemaire tenodesis passed both superficial and deep to the lateral collateral ligament, and ALL reconstruction. Anterolateral grafts were fixed at 30 degrees of knee flexion with both 20 and 40 N of tension. Statistical analysis used repeated-measures analyses of variance and paired t tests with Bonferroni adjustments. RESULTS: ACL reconstruction alone failed to restore native knee kinematics in combined ACL plus anterolateral-injured knees ( P < .05 for all). All combined reconstructions with 20 N of tension, except for ALL reconstruction ( P = .002-.01), restored anterior translation. With 40 N of tension, the superficial Lemaire and MacIntosh procedures overconstrained the anterior laxity in deep flexion. Only the deep Lemaire and MacIntosh procedures with 20 N of tension-restored rotational kinematics to the intact state ( P > .05 for all), while the ALL underconstrained and the superficial Lemaire overconstrained internal rotation. The same procedures with 40 N of tension led to similar findings. CONCLUSION: In a combined ACL plus anterolateral-injured knee, ACL reconstruction alone failed to restore intact knee kinematics. The addition of either the deep Lemaire or MacIntosh tenodesis tensioned with 20 N, however, restored native knee kinematics. CLINICAL RELEVANCE: The current study indicates that unaddressed anterolateral injuries, in the presence of an ACL deficiency, result in abnormal knee kinematics that is not restored if only treated with intra-articular ACL reconstruction. Both the modified MacIntosh and modified deep Lemaire tenodeses (with 20 N of tension) restored native knee kinematics at time zero. PMID- 28027654 TI - Self-Resemblance and Social Rejection. AB - Humans perceive and treat self-resembling others in ways that suggest that self resemblance is a cue of kinship. However, we know little about how individuals respond to treatment by self-resembling others. Here we approach this problem by connecting facial self-resemblance to social rejection. Given that individuals should expect to cooperate with kin, we hypothesized that (1) social inclusion by perceived kin should elicit lesser feelings of rejection and (2) social exclusion by perceived kin should elicit greater feelings of rejection relative to inclusion or exclusion, respectively, by nonkin. To test these hypotheses, we recruited 90 participants to play two games of Cyberball, a virtual ball-tossing game, with separate pairs of ostensible partners. In one game, the ostensible partners were programed to fully include the participants in group play and, in the other game, they were programed to exclude the participants after a few rounds; the order of inclusion and exclusion was counterbalanced across participants. Partner faces were digitally manipulated to be either self- or nonself-resembling, and these conditions were also counterbalanced. Rejection feelings differed significantly as a function of self-resemblance between the inclusion and exclusion conditions, but only for participants who experienced inclusion first. Moreover, for these individuals, inclusion by self-resembling partners led to significantly lesser feelings of rejection than did inclusion by nonself-resembling partners. To explain this effect, we explore potential mechanisms of kin recognition and social rejection. Although nuanced, our results suggest that perceptions of kinship can moderate psychological responses to the actions of others. PMID- 28027655 TI - Removal of Hardware After Syndesmotic Screw Fixation: A Systematic Literature Review. AB - BACKGROUND: While trans-syndesmotic fixation with metal screws is considered the gold standard in treating syndesmotic injuries, controversy exists regarding the need and timing of postoperative screw removal. Formal recommendations have not been well established in the literature and clinical practice is highly variable in this regard. The purpose of this systematic review is to critically examine the most recent literature regarding syndesmotic screw removal in order to provide surgeons an evidence-based approach to management of these injuries. METHODS: The Cochrane Library and PubMed Medline databases were explored using search terms for syndesmosis and screw removal between October 1, 2010 and June 1, 2016. RESULTS: A total of 9 studies (1 randomized controlled trial and 8 retrospective cohort studies) were found that described the outcomes of either retained or removed syndesmotic screws. Overall, there was no difference in functional, clinical or radiographic outcomes in patients who had their syndesmotic screw removed. There was a higher likelihood of recurrent syndesmotic diastasis when screws were removed between 6 and 8 weeks. There was a higher rate of postoperative infections when syndesmotic screws were removed without administering preoperative antibiotics. CONCLUSION: Removal of syndesmotic screws is advisable mainly in cases of patient complaints related to the other implanted perimalleolar hardware or malreduction of the syndesmosis after at least 8 weeks postoperatively. Broken or loose screws should not be removed routinely unless causing symptoms. Antibiotic prophylaxis is recommended on removal. Radiographs should be routinely obtained immediately prior to removal and formal discussions should be had with patients prior to surgery to discuss management options if a broken screw is unexpectedly encountered intraoperatively. Radiographs and/or computed tomography imaging should be obtained after syndesmotic screw removal when indicated for known syndesmotic malreduction. LEVELS OF EVIDENCE: Level IV: Systematic review. PMID- 28027656 TI - Sexual identity and behavior in an online sample of Indian men who have sex with men. AB - Indian men who have sex with men are disproportionately impacted by HIV. While prevention efforts to date have focused on men who visit drop-in centers or physical cruising sites, little is known about men who are meeting sexual partners on virtual platforms. This paper explores issues related to sexual identity and sexual behaviors in an online sample of men who identified as gay (n = 279) or bisexual (n = 123). There were significant differences in outedness between the two groups, with 48% of bisexually identified men reporting that they were out to "no one" and 82% stating that they present themselves as heterosexual to family and friends. Corresponding rates for gay-identified men were 15% and 41%, respectively (both p < .001). Twenty-nine percent of bisexually identified men reported being married, compared to only 3% of the gay-identified men (p < .001). Bisexually identified men were also more likely to report having exclusively insertive anal sex (49% vs 30% p < .001), while gay-identified men were more likely to report exclusively receptive anal sex (41% vs 13% p < .0001). Rates of unprotected anal sex (UAS) in the two groups were similar; however, married men were significantly more likely to report unprotected vaginal sex (76% vs 35%, p < .012). Positive attitudes toward UAS and lower self-efficacy were associated with sexual risk in both groups; however, substance use was associated with sexual risk only among bisexually identified men. These findings show that a large proportion of Indian bisexually identified men lead closeted lives, especially in their interactions with friends and family, with the vast majority presenting as heterosexual. The lower condom use with wives may be due to societal pressures to have children. The results suggest that bisexually identified men may benefit from targeted programs and non-directive, non judgmental individual or couples counseling which emphasizes condom use with both male and female partners. PMID- 28027657 TI - The Therapeutic Effect of Intra-articular Normal Saline Injections for Knee Osteoarthritis: A Meta-analysis of Evidence Level 1 Studies. AB - BACKGROUND: Intra-articular normal saline (IA-NS) injections have been utilized as a placebo in a number of randomized controlled trials pertaining to the management of knee osteoarthritis (OA); however, it is believed that these "placebo" injections may have a therapeutic effect that has not been quantified in the literature. PURPOSE: To (1) quantify the effect of IA-NS injections on patient-reported outcomes (PROs) and (2) compare postinjection PROs to established minimal clinically important difference (MCID) criteria to demonstrate a potential therapeutic effect. STUDY DESIGN: Meta-analysis. METHODS: A review was conducted to identify all randomized, placebo-controlled trials on injection therapy for knee OA between 2006 and 2016. Patient demographics and PROs before the injection and at 3 and 6 months after the injection were collected for patients in the IA-NS injection group in each study. A random effects model was used to compare preinjection scores and scores at each postinjection time point in a pairwise fashion. RESULTS: In total, there were 14 placebo cohorts in 13 studies that were analyzed after meeting inclusion criteria for this meta-analysis. This included 1076 patients (Kellgren-Lawrence grade 1 4), with a weighted mean age of 62.53 years and mean body mass index of 28.67 kg/m2. There was only sufficient information to perform analyses of visual analog scale (VAS) pain and Western Ontario and McMaster Universities Arthritis Index (WOMAC) total scores. At 3 months after the IA-NS placebo injection, there was a significant improvement in VAS pain scores (mean difference [MD], 12.10 [95% CI, 3.27 to 20.93]; P = .007), whereas improvement in the WOMAC total scores approached but did not reach statistical significance (MD, 19.75 [95% CI, -0.50 to 40.09]; P = .06). At 6 months, both VAS pain scores (MD, 16.62 [95% CI, 12.13 21.10]; P < .00001) and WOMAC total scores (MD, 11.34 [95% CI, 7.03-15.65]; P < .00001) were significantly improved in comparison to preinjection values. Furthermore, improvements in both the VAS pain and WOMAC total scores at 6 months were clinically significant (MCID, 1.37 and 9, respectively). CONCLUSION: The administration of an IA-NS placebo injection yields a statistically and clinically meaningful improvement in PROs up to 6 months after the injection in patients with knee OA. This observation supports the notion that the so-called placebo effect for IA-NS injections achieves a clinically meaningful response in patients with OA when provided during comparison studies to an active treatment group (ie, hyaluronic acid). PMID- 28027658 TI - Is Incisura Fibularis a Reliable Landmark for Assessing Syndesmotic Stability? A Systematic Review of Morphometric Studies. AB - : Incisura fibularis (IF) is an important landmark in assessing syndesmotic stability radiologically postinjury. The purpose of this review was to explore the anatomy and morphometrics of this widely used anatomical landmark and to further the understanding of the same. A systematic review was conducted online using PubMed and Google Scholar, per PRISMA guidelines. Predefined eligibility criteria were applied, and the data thus compiled were analyzed. Wide variability in morphometrics and, thus, anatomy of IF were observed in the present review, which was influenced by gender. There was no side-to-side variability seen in this study. The study stresses the need to consider the anatomical and gender based variability while assessing syndesmotic stability and further supports the recommendation of side-to-side comparison. LEVELS OF EVIDENCE: Anatomical, Level V. PMID- 28027659 TI - Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism in 400 Patients With Active Cancer: A Single-Center Experience. AB - PURPOSE: To study the safety and efficacy of rivaroxaban-a direct oral anticoagulant-use in patients with active cancer and venous thromboembolism (VTE). PATIENTS AND METHODS: Retrospective cohort study of 400 patients with active cancer and associated VTE, defined as deep venous thrombosis and/or pulmonary embolism. This single-center study was carried out from January 2012 to June 2015. The aim of this study was to determine the efficacy and safety, using the incidence of recurrent symptomatic VTE and major bleeding, respectively, throughout the treatment with rivaroxaban. RESULTS: Of the 400 patients enrolled, 223 (55.8%) were female. A total of 362 (90.5%) patients had solid tumors and 244 (61%) had metastatic disease. A total of 302 (75.5%) received initial parenteral therapy with enoxaparin (median: 3, mean: 5.6, standard deviation [SD]: 6.4 days) followed by rivaroxaban. Ninety-eight patients (24.5%) were treated with on label rivaroxaban treatment. Recurrence rates were 3.25% with major bleeding occurring in 5.5% during the anticoagulant therapy (median: 118, mean: 163.9, SD: 159.9 days). CONCLUSION: Rivaroxaban can be an attractive alternative for the treatment of cancer-associated thrombosis. PMID- 28027660 TI - Cross-Sectional Study to Assess the Functional Outcome of Neglected Bimalleolar Fracture. AB - INTRODUCTION: Ankle fracture is the most common intra-articular fracture of a weight-bearing joint and accounts for 9% of all fractures. Ankle fractures are classified into 3 subgroups: unimalleolar, bimalleolar, and trimalleolar fractures. Accurate reduction and stable internal fixation is necessary in bimalleolar fractures; otherwise, it may lead to posttraumatic painful restriction of movements or osteoarthritis. The purpose of this study is to assess the functional outcome and results of treatment of neglected bimalleolar fracture. MATERIALS AND METHODS: Seventeen neglected bimalleolar fracture patients were treated with open reduction and internal fixation. Patients were followed-up at 1, 2, and 5 years and functional ability was assessed by using the modified Weber Rating Scale. RESULTS: The mean age of patients was 41.4 +/- 13.28 years. After 2 year of surgery, 13 out of 17 patients showed excellent results and 4 patients had fair results. CONCLUSION: Good to excellent functional results were observed after long-term follow-up in neglected bimalleolar fracture treated with open reduction and internal fixation, and we advise surgical intervention in all such patients. LEVELS OF EVIDENCE: Therapeutic, Level III: Retrospective Cohort study. PMID- 28027661 TI - Economic evaluation of HIV testing for men who have sex with men in community based organizations - results from six European cities. AB - The non-decreasing incidence of HIV among men who have sex with men (MSM) has motivated the emergence of Community Based Voluntary Counselling and Testing (CBVCT) services specifically addressed to MSM. The CBVCT services are characterized by facilitated access and linkage to care, a staff largely constituted by voluntary peers, and private not-for-profit structures outside the formal health system institutions. Encouraging results have been measured about their effectiveness, but these favourable results may have been obtained at high costs, questioning the opportunity to expand the experience. We performed an economic evaluation of HIV testing for MSM at CBVCT services, and compared them across six European cities. We collected retrospective data for six CBVCT services from six cities (Copenhagen, Paris, Lyon, Athens, Lisbon, and Ljubljana), for the year 2014, on the number of HIV tests and HIV reactive tests, and on all expenditures to perform the testing activities. The total costs of CBVCTs varied from 54,390? per year (Ljubljana) to 245,803? per year (Athens). The cost per HIV test varied from to 41? (Athens) to 113? (Ljubljana). The cost per HIV reactive test varied from 1966? (Athens) to 9065? (Ljubljana). Our results show that the benefits of CBVCT services are obtained at an acceptable cost, in comparison with the literature (values, mostly from the USA, range from 1600$ to 16,985$ per HIV reactive test in clinical and non-clinical settings). This result was transversal to several European cities, highlighting that there is a common CBVCT model, the cost of which is comparable regardless of the epidemiological context and prices. The CBVCT services represent an effective and "worth it" experience, to be continued and expanded in future public health strategies towards HIV. PMID- 28027663 TI - HIV risk inside U.S. prisons: a systematic review of risk reduction interventions conducted in U.S. prisons. AB - HIV prevalence in correctional populations is approximately five times that of the general adult population. This systematic review examines the broad question of HIV prevention and interventions to reduce inmate HIV-related risk behaviors in U.S. federal and state prisons. We conducted a systematic review of multiple databases and Google Scholar to identify behavioral, biomedical, social, and policy studies related to HIV among U.S. prison populations from 1980-2014. Studies were excluded if they did not focus on HIV, prison inmates, if they were conducted outside of the U.S., if they involved juvenile offenders, or if they included post-release outcomes. Twenty-seven articles met the study criteria. Evidence suggests that research related to the HIV care continuum, risk behaviors, gender, prevention (e.g., peer education), and policy are key topics to enhance HIV prevention interventions in the criminal justice system. This review provides a prison-specific overview of HIV in U.S. correctional populations and highlight effective interventions, including inmate peer education. There is an urgent need to continue to implement HIV prevention interventions across all prisons and improve the quality of life among those at heightened risk of HIV infection. PMID- 28027664 TI - Barriers and facilitators to HIV and sexually transmitted infections testing for gay, bisexual, and other transgender men who have sex with men. AB - Transgender men who have sex with men (trans MSM) may be at elevated risk for HIV and other sexually transmitted infections (STI), and therefore require access to HIV and STI testing services. However, trans people often face stigma, discrimination, and gaps in provider competence when attempting to access health care and may therefore postpone, avoid, or be refused care. In this context, quantitative data have indicated low access to, and uptake of, HIV testing among trans MSM. The present manuscript aimed to identify trans MSM's perspectives on barriers and facilitators to HIV and STI testing. As part of a community-based research project investigating HIV risk and resilience among trans MSM, 40 trans MSM aged 18 and above and living in Ontario, Canada participated in one-on-one qualitative interviews in 2013. Participants described a number of barriers to HIV and other STI testing. These included both trans-specific and general difficulties in accessing sexual health services, lack of trans health knowledge among testing providers, limited clinical capacity to meet STI testing needs, and a perceived gap between trans-inclusive policies and their implementation in practice. Two major facilitators were identified: access to trusted and flexible testing providers, and integration of testing with ongoing monitoring for hormone therapy. Based on these findings, we provide recommendations for enhancing access to HIV and STI testing for this key population. PMID- 28027665 TI - Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers. AB - We explored the duration of immune responses and the effect of a late third HIV modified vaccinia virus Ankara (MVA) boost in HIV-DNA primed and HIV-MVA boosted Tanzanian volunteers. Twenty volunteers who had previously received three HIV-DNA and two HIV-MVA immunizations were given a third HIV-MVA immunization 3 years after the second HIV-MVA boost. At the time of the third HIV-MVA, 90% of the vaccinees had antibodies to HIV-1 subtype C gp140 (median titer 200) and 85% to subtype B gp160 (median titer 100). The majority of vaccinees had detectable antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, 70% against CRF01_AE virus-infected cells (median titer 239) and 84% against CRF01_AE gp120 coated cells (median titer 499). A high proportion (74%) of vaccinees had IFN gamma ELISpot responses, 63% to Gag and 42% to Env, 3 years after the second HIV MVA boost. After the third HIV-MVA, there was an increase in Env-binding antibodies and ADCC-mediating antibodies relative to the response seen at the time of the third HIV-MVA vaccination, p < .0001 and p < .05, respectively. The frequency of IFN-gamma ELISpot responses increased to 95% against Gag or Env and 90% to both Gag and Env, p = .064 and p = .002, respectively. In conclusion, the HIV-DNA prime/HIV-MVA boost regimen elicited potent antibody and cellular immune responses with remarkable durability, and a third HIV-MVA immunization significantly boosted both antibody and cellular immune responses relative to the levels detected at the time of the third HIV-MVA, but not to higher levels than after the second HIV-MVA. PMID- 28027666 TI - Distress Tolerance Treatment for Weight Concern in Smoking Cessation Among Women: The WE QUIT Pilot Study. AB - Fear of gaining weight after quitting cigarette smoking is a major barrier to smoking cessation among women. Distress tolerance, which refers to one's ability and willingness to tolerate physical and emotional discomfort, predicts successful behavior change. Novel interventions rooted in Acceptance and Commitment Therapy (ACT) have emerged that aim to increase distress tolerance and engagement in values-oriented behavior. In this study, we developed a 9-week, group-based distress tolerance intervention for weight concern in smoking cessation among women (DT-W). Using an iterative process, we piloted DT-W with two small groups ( n = 4 and n = 7) of female weight-concerned smokers. Results indicated that we successfully established the feasibility and acceptability of DT-W, which was well-attended and well-received. Biochemically verified 7-day point-prevalence abstinence rates at post-intervention, 1, 3, and 6 months were 64%, 36%, 27%, and 27%, respectively. We are now evaluating DT-W in a randomized controlled trial. PMID- 28027662 TI - Redox Control of Skeletal Muscle Regeneration. AB - Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 27, 276-310. PMID- 28027667 TI - Do Structural Changes of the Foot Influence Plantar Pressure Patterns During Various Stages of Pregnancy and Postpartum? AB - BACKGROUND: The foot of a pregnant woman undergoes morphological changes with the advancement of pregnancy. It is important to understand the structural changes of the foot during pregnancy and postpartum because any such change may alter the plantar pressure pattern and the entire foot biomechanics. METHOD: Primigravidae with a gestational age of 12 weeks or less, aged between 18 and 35 years were included in the study. They were prospectively studied across 5 time periods during pregnancy and postpartum. The measures recorded were length, width, navicular height, truncated foot length and normalized navicular height, truncated ratio of the foot, and the static plantar pressure pattern. Repeated measures ANOVA was done to analyze the changes across various time periods. RESULTS: All the foot parameters, except foot length and truncated foot length, showed significant differences across various time periods of pregnancy and postpartum (P < .001). It was found that the static plantar pressures also varied significantly (P <= .001).The maximum pressure was recorded at the hindfoot of the dominant leg. CONCLUSION: The feet of pregnant women tend to get pronated as pregnancy advances but do not reach baseline values even at 6 weeks postpartum. Pregnant women tend to bear more weight on the dominant foot with an increased static hindfoot pressure as pregnancy progresses. LEVELS OF EVIDENCE: Prognostic study, Level I: Prospective. PMID- 28027669 TI - The vertebroplacental ratio as an alternative to the cerebroplacental ratio in the evaluation of the fetus at the end of pregnancy. AB - OBJECTIVE: Low cerebroplacental ratio (CPR) near term has emerged as a marker of fetal adverse outcome. The aim of this study was to evaluate the predictive accuracy of an alternative ratio using the vertebral artery (VA) (vertebroplacental ratio or VPR) for acid-base status at birth. METHODS: This was a prospective cohort study of 1470 pregnancies undergoing an ultrasound assessment of the umbilical artery, middle cerebral artery and VA Doppler beyond 34 weeks' gestation within 14 days of delivery. The CPR multiples of the median (MoM) and VPR MoM were calculated to adjust for gestational age. The relationship between the fetal Dopplers and the umbilical cord pH (arterial and venous) was evaluated statistically, and depicted graphically using three-dimensional (3D) trend surfaces, 2D contour graphs and ROC curves. RESULTS: All the studied parameters were poorly associated with neonatal acid-base status, although this association was slightly better for venous pH. The importance of BW centile was smaller than that of CPR and VPR MoM, however, both hemodynamic parameters were similarly associated with neonatal pH. CONCLUSIONS: Concerning fetal surveillance near term, the importance of cerebroplacental hemodynamics surpasses that of BW. Furthermore, in the evaluation of fetal wellbeing VPR behaves as a valid alternative to CPR. PMID- 28027668 TI - Social determinants of health and retention in HIV care in a clinical cohort in Ontario, Canada. AB - : Continuous HIV care supports antiretroviral therapy initiation and adherence, and prolongs survival. We investigated the association of social determinants of health (SDH) and subsequent retention in HIV care in a clinical cohort in Ontario, Canada. The Ontario HIV Treatment Network Cohort Study is a multi-site cohort of patients at 10 HIV clinics. Data were collected from medical charts, interviews, and via record linkage with the provincial public health laboratory for viral load tests. For participants interviewed in 2009, we used three category multinomial logistic regression to identify predictors of retention in 2010-2012, defined as (1) continuous care (>=2 viral loads >=90 days in all years; reference category); (2) discontinuous care (only 1 viral load/year in >=1 year); and (3) a gap in care (>=1 year in 2010-2012 with no viral load). In total, 1838 participants were included. In 2010-2012, 71.7% had continuous care, 20.9% had discontinuous care, and 7.5% had a gap in care. Discontinuous care in 2009 was predictive (p < .0001) of future retention. SDH associated with discontinuous care were Indigenous ethnicity, being born in Canada, being employed, reporting hazardous drinking, and non-injection drug use. Being a heterosexual male was associated with having a gap in care, and being single and younger were associated with discontinuous care and a gap in care. Various SDH were associated with retention. Care discontinuity was highly predictive of future gaps. Targeted strategic interventions that better engage those at risk of suboptimal retention merit exploration. ABBREVIATIONS: AOR: adjusted odds ratio; ART: antiretroviral therapy; AUDIT: Alcohol Use Disorders Identification Test; CES-D: Center for Epidemiologic Studies Depression Scale; CIs: confidence intervals; HIV: human immunodeficiency virus; IQR: interquartile range; MSM: men who have sex with men; NA-ACCORD: North American AIDS Cohort Collaboration on Research and Design; OCS: Ontario HIV Treatment Network Cohort Study; OHTN: Ontario HIV Treatment Network; OR: odds ratio; PHOL: Public Health Ontario Laboratories; REB: Research Ethics Board; SDH: social determinants of health; US: United States. PMID- 28027670 TI - Knowledge and Perception of Consumption of Iodized Salt Among Food Handlers in Southern Ethiopia. AB - BACKGROUND: Iodine deficiency is the world's single most important cause of preventable mental retardation. In Ethiopia, the knowledge and perception of food handlers toward the iodized salt consumption (ISC) was very low. OBJECTIVE: To assess knowledge and perception of food handlers toward consumption of iodized salt in Wolaita Sodo town and Sodo Zuria woreda, 2014. METHODS: The community based cross-sectional study design was done from May 10 to May 30, 2014 in Sodo town and Sodo Zuria woreda (district), Wolaita zone, southern Ethiopia. Systematic sampling techniques were used to identify study participants. Data entered into the software Epi Info version 3.5.3 and analyzed using the software SPSS version 16. To assess an association, odds ratio was used at 95% confidence interval, whereas confounding was controlled by employing multivariate logistic regression. RESULTS: Lower knowledge and perception on iodine deficiency was observed. About 239 (44.7%) of the respondents had good knowledge and 228 (42.6%) had positive attitude toward consumption of iodized salt. Most (346, 64.7%) of the participants had heard about goiter, whereas only 170 (31.8%) of them associated it with iodine deficiency. About 46.4% of respondents heard about iodized salt. Respondents' age, education, family income, place of residence, and occupation had significant association with good knowledge and positive attitude toward consumption of iodized salt. CONCLUSION: The study revealed the existence of knowledge and perception gap in iodine deficiency disorder and ISC. Household income, education of respondents, and place of residence were determinant factors for poor knowledge and perception of iodized salt. Therefore, efforts to scale-up the knowledge and perception toward ISC should focus on households with low income, educational level, and rural residence. PMID- 28027671 TI - Nutrition Status of Primary School Students in Two Rural Regions of Guinea Bissau. AB - BACKGROUND: The nutrition status of primary schoolchildren in Africa has received relatively little attention in comparison to that of younger children. We surveyed primary school students in Guinea-Bissau, a nation that is among the poorest in the world. OBJECTIVE: Anthropometry and prevalence of anemia and vitamin A deficiency were assessed in schoolchildren participating in International Partnership for Human Development's school feeding program in 2 regions of Guinea-Bissau. METHODS: A cross-sectional survey of 32 schools in the regions of Cacheu and Oio was conducted in November 2011. Variables included age, gender, weight, height, hemoglobin, and retinol-binding protein concentrations. Z scores for height for age (HAZ), body mass index for age (BAZ), and weight for age were calculated using World Health Organization reference data. RESULTS: Anthropometric assessment of 4784 students revealed stunting (HAZ < -2) in 15.5%, thinness (BAZ < -2) in 13.2%, and anemia in 42.0%. Stunting, thinness, and anemia were significantly more common in males, in students from Oio, and in older students. Vitamin A deficiency, detected in 21.5% of the population, was the only assessment that did not demonstrate significant differences between genders or regions. About 61.1% of all children had 1 or more indicators of undernutrition. CONCLUSION: There are substantial rates of stunting, thinness, underweight, anemia, and vitamin A deficiency in primary schoolchildren in Guinea-Bissau, even among those participating in a school lunch program and particularly among males and older students. The results suggest the need for evaluating feeding programs and other methods to improve nutrition status in primary school students, especially in older students. PMID- 28027672 TI - Relationship between first trimester aneuploidy screening test serum analytes and placenta accreta. AB - OBJECTIVE: The aim of this study is to determine whether there is a relationship between first trimester serum pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (fbetahCG) MoM values and placenta accreta in women who had placenta previa. STUDY DESIGN: A total of 88 patients with placenta previa who had first trimester aneuploidy screening test results were enrolled in the study. Nineteen of these patients were also diagnosed with placenta accreta. As probable markers of excessive placental invasion, serum PAPP A and fbetahCG MoM values were compared in two groups with and without placenta accreta. RESULTS: Patients with placenta accreta had higher statistically significant serum PAPP-A (1.20 versus 0.865, respectively, p = 0.045) and fbetahCG MoM (1.42 versus 0.93, respectively, p = 0.042) values than patients without accreta. CONCLUSIONS: Higher first trimester serum PAPP-A and fbetahCG MoM values seem to be associated with placenta accreta in women with placenta previa. Further studies are needed to use these promising additional tools for early detection of placenta accreta. PMID- 28027673 TI - Noninvasive assessment of altered activity following restraint in mice using an automated physiological monitoring system. AB - In the laboratory setting, typical endocrine and targeted behavioral tests are limited in their ability to provide a direct assessment of stress in animals housed in undisturbed conditions. We hypothesized that an automated phenotyping system would allow the detection of subtle stress-related behavioral changes well beyond the time-frames examined using conventional methods. In this study, we have utilized the TSE PhenoMaster system to continuously record basal behaviors and physiological parameters including activity, body weight, food intake and oxygen consumption in undisturbed and stressed C57Bl/6J male mice (n = 12/group), with a pharmacological intervention using the conventional anxiolytic, diazepam (5 mg kg-1 i.p.; n = 8/group). We observed significant 20-30% reductions in locomotor activity in the dark phase, with subtle reductions in light phase activity for up to 96 h following a single 2 h episode of restraint stress. A single administration of diazepam reduced plasma corticosterone concentrations by 30-35% during stress exposure when compared to mice treated with vehicle. This treatment did not result in significantly different locomotor activity compared to vehicle within the first 48 h following restraint stress. However, diazepam treatment facilitated restoration of locomotor activity at 72 and 96 h after restraint stress exposure in comparison to vehicle-treated mice. Hence, the use of an automated phenotyping system allows a real time assessment of basal behaviors and empirical metabolism following exposure to restraint stress and demonstrates major and subtle changes in activity persist for several days after stress exposure. PMID- 28027674 TI - Ethical decision-making regarding infant viability: A discussion. AB - BACKGROUND:: There are no universally agreed rules of healthcare ethics. Ethical decisions and standards tend to be linked to professional codes of practice when dealing with complex issues. OBJECTIVES:: This paper aims to explore the ethical complexities on who should decide to give infants born on the borderline of viability lifesaving treatment, parents or the healthcare professionals. METHOD:: The paper is a discussion using the principles of ethics, professional codes of practice from the UK, Nursing Midwifery Council and UK legal case law and statute. Healthcare professionals' experiences that influence parental decision are also considered. FINDINGS & DISCUSSION:: There are considerable barriers to an effective discussion taking place in an environment where clinical decisions have to be made quickly once the baby is born. This is compounded by the need and respect for parental autonomy and the difficulties they face when making a best interest's decision knowing that this could cause more harm than good for their infant child and balancing any decision they make with quality of life. CONCLUSION:: On deciding whether to give lifesaving treatment born at the borderline of viability, it should be a joint decision between the parents and the neonatal team. PMID- 28027675 TI - Nurses' moral experiences of assisted death. AB - BACKGROUND: Legislative changes are resulting in assisted death as an option for people at the end of life. Although nurses' experiences and perspectives are underrepresented within broader ethical discourses about assisted death, there is a small but significant body of literature examining nurses' experiences of caring for people who request this option. AIM: To synthesize what has been learned about nurses' experiences of caring for patients who request assisted death and to highlight what is morally at stake for nurses who undertake this type of care. DESIGN: Qualitative meta-synthesis. METHODS: Six databases were searched: CINAHL, Medline, EMBASE, Joanna Briggs Institute, PsycINFO, and Web of Science. The search was completed on 22 October 2014 and updated in February 2016. Of 879 articles identified from the database searches, 16 articles were deemed relevant based on inclusion criteria. Following quality appraisal, 14 studies were retained for analysis and synthesis. RESULTS: The moral experience of the nurse is (1) defined by a profound sense of responsibility, (2) shaped by contextual forces that nurses navigate in everyday end-of-life care practice, and (3) sustained by intra-team moral and emotional support. DISCUSSION: The findings of this synthesis support the view that nurses are moral agents who are deeply invested in the moral integrity of end-of-life care involving assisted death. The findings further demonstrate that to fully appreciate the ethics of assisted death from a nursing standpoint, it is necessary to understand the broader constraints on nurses' moral agency that operate in everyday end-of-life care. Ethical considerations: Research ethics board approval was not required for this synthesis of previously published literature. CONCLUSION: In order to understand how to enact ethical practice in the area of assisted death, the moral experiences of nurses should be investigated and foregrounded. PMID- 28027676 TI - Computer-based self-help therapy: A qualitative analysis of attrition. AB - The impact of computer-based cognitive-behavioral self-help therapy programs is limited by high attrition. This study explored reactions to computer-based cognitive-behavioral self-help therapy use among individuals not completing a full treatment course. Individuals receiving outpatient substance use disorder treatment at a Veterans Health Administration clinic who enrolled in a study implementing a computer-based cognitive-behavioral self-help therapy for insomnia, but subsequently dropped out prior to completion, were interviewed. Reactions to use and reasons for attrition were explored through thematic analysis of interviews. Among barriers to use, themes of competing demands, personal attributes, the computer-based format of computer-based cognitive behavioral self-help therapies, and negative experiences with the specific program used were identified. Among facilitators of use, themes of personal support, the computer-based cognitive-behavioral self-help therapy format, and personal attributes were identified. Recommendations for future implementation efforts to include additional person-to-person contact during computer-based cognitive-behavioral self-help therapy participation were made. These themes may be employed to develop strategies for computer-based cognitive-behavioral self help therapy implementation in order to maximize program engagement and completion. PMID- 28027677 TI - Do prerecorded lecture VODcasts affect lecture attendance of first-yearpre clinical Graduate Entry to Medicine students? AB - BACKGROUND: There is increasing concern amongst educators that the provision of recorded lectures may reduce student attendance of live lectures. We therefore sought to determine if the provision of prerecorded lecture video podcasts (VODcasts) to first-year Graduate Entry to Medicine (GEM) students, affected attendance at 21 Physiology lectures within three separate pre-clinical modules. METHODS: Data on lecture attendance, utilization of VODcasts, and whether VODcasts should replace live lectures were drawn from three surveys conducted in academic years 2014-2015 and 2015-2016 on all first-year GEM students in two first-year pre-clinical modules where prerecorded Physiology VODcasts were available for viewing or downloading prior to scheduled live lectures. RESULTS: A total of 191/214 (89%) students responded to the three surveys, with 84.3% of students attending all 21 lectures in the study. Only 4% of students missed more than one lecture in each of the three lecture series, with 79% indicating that VODcasts should not replace lectures. CONCLUSION: Therefore, we conclude that the attendance of pre-clinical GEM students at live lectures is not significantly impacted upon by the provision of lecture VODcasts, with most students viewing them as useful revision tools rather than as a replacement for live lectures. PMID- 28027678 TI - Participatory design methods in telemedicine research. AB - Healthcare systems require a paradigm shift in the way healthcare services are delivered to counteract demographic changes in patient populations, expanding technological developments and the increasing complexity of healthcare. Participatory design (PD) is a methodology that promotes the participation of users in the design process of potential telehealth applications. A PD project can be divided into four phases including: the identification and analysis of participant needs; the generation of ideas and development of prototypes; testing and further development of prototypes; and evaluation. PD is an iterative process where each phase is planned by reflecting on the results from the previous phase with respect to the participants' contribution. Key activities of a PD project include: fieldwork; literature reviewing; and development and testing. All activities must be applied with a participatory mindset that will ensure genuine participation throughout the project. Challenges associated with the use of PD include: the time required to properly engage with participants; language and culture barriers amongst participants; the selection of participants to ensure good representation of the user group; and empowerment. PD is an important process, which is complemented by other evaluation strategies that assess organisational requirements, clinical safety, and clinical and cost effectiveness. PD is a methodology which encourages genuine involvement, where participants have an opportunity to identify practical problems and to design and test technology. The process engages participants in storytelling, future planning and design. PD is a multifaceted assessment tool that helps explore more accurately clinical requirements and patient perspectives in telehealth. PMID- 28027679 TI - The comparison of telerehabilitation and face-to-face rehabilitation after total knee arthroplasty: A systematic review and meta-analysis. AB - Introduction The objective of this study was to assess the efficacy of telerehabilitation for patients after total knee arthroplasty (TKA) compared with face-to-face rehabilitation. Methods Medline, SCOPUS, Google Scholar, EMBASE, Springer, Science Direct, and Cochrane databases were searched electronically. Relevant journals and references of studies included were hand-searched for randomized controlled trials (RCTs) regarding the efficacy of telerehabilitation on functional recovery in patients after TKA. Two reviewers independently performed data extraction and quality assessment. Data were analysed using RevMan 5.3 software and Stata 12.0 software. Results Four RCTs involving 442 patients were included in the meta-analysis. Overall, compared with face-to-face rehabilitation, telerehabilitation could achieve comparable pain relief (mean difference = 0.52; 95% confidence interval (CI) = -0.20 to 1.24; p = 0.16) and better Western Ontario and McMaster Universities Osteoarthritis Index improvement (mean difference = 1.13; 95% CI = 0.23 to 2.02; p = 0.014). In addition, telerehabilitation treatment resulted in a significantly higher extension range ( p < 0.00001) and quadriceps strength ( p = 0.0002) than face-to-face rehabilitation. Discussion Telerehabilitation should be recommended for patients after TKA because of its comparable pain control and better improvement of functional recovery as compared to face-to-face rehabilitation. PMID- 28027680 TI - Comparative effectiveness of interferons in relapsing-remitting multiple sclerosis: a meta-analysis of real-world studies. AB - BACKGROUND: Differences between interferons have been evaluated for over 20 years. While randomized controlled trial (RCT) data is mainly used for assessments and strong data for causal inferences, it does not necessarily reflect everyday practice. Real-world data may provide additional information. PURPOSE: To assess the results, quality, and representativeness of observational studies directly comparing interferons (IFNs) in RRMS. METHODS: Medline and Embase were searched for observational studies comparing IFN-beta-1a 30 mcg IM (Avonex 1 ), IFN-beta-1a 44 mcg SC (Rebif 2 ) and/or IFN-beta-1b 250 mcg SC (Betaseron 3 ). Outcomes included annualized relapse rate (ARR), proportions relapse free, confirmed progression free, treatment persistence, and neutralizing antibodies rates (NABs) measured up to 5 years of treatment. Data was combined using random effects meta-analyses. Categorical values were analyzed using chi squared and Mann-Whitney tests. RESULTS: Thirty-six studies examining 32,026 patients (72.5% females, age = 39.2 +/- 3.7 years, disease duration = 5.6 +/- 2.0 years) were identified. Thirty-three studies investigated IFN-beta-1a IM (N = 11,925), 30 IFN-beta-1a SC (N = 10,684) and 34 IFN-beta-1b SC (N = 9417). Baseline ARRs were similar (1.37 +/- 0.35, 1.51 +/- 0.27 and 1.55 +/- 0.23, respectively; P = .101) as were EDSS scores (2.24 +/- 0.39, 2.33 +/- 0.30, 2.55 +/- 0.38; P = .070) and >75% were naive to IFNs. On treatment, ARRs were comparable (IFN-beta-1a IM 0.52 +/- 0.27, IFN-beta-1a SC 0.51 +/- 0.24, IFN-beta 1b SC 0.55 +/- 0.23; P = .595). Proportions of relapse-free patients were similar between drugs (P > .05 for all data points), except that IFN-beta-1a SC was superior to IFN-beta-1b SC in years 3-5 (all P <= .001). After 1 year, EDSS scores were comparable; after 2 years, IFN-beta-1a IM and IFN-beta-1a SC incurred less disease progression than IFN-beta-1b SC (P < .02). Confirmed progression free rates and persistence were similar over 5 years. Fewer patients developed NABs with IFN-beta-1a IM (4.7 +/- 1.5%) versus IFN-beta-1a SC (21.4 +/- 2.8%) (P < 0.001) or IFN-beta-1b SC (32.2% +/- 3.3%) (P < .001). CONCLUSIONS: In this comprehensive meta-analysis of real-world studies in RRMS, IFN-beta-1a IM, IFN beta-1a SC and IFN-beta-1b SC had similar clinical profiles. When selecting an IFN, practitioners should consider observational data in their decision making process. PMID- 28027681 TI - Foetal electrocardiograph (ST-analyser or STAN) for intrapartum foetal heart rate monitoring: a friend or a foe? AB - Cardiotocograph (CTG) is associated with a high false positive rate of up to 60% which may increase the risk of unnecessary intrapartum interventions (emergency caesarean sections or operative vaginal deliveries) without any significant benefits. A recent study on variation of caesarean section rates in England has concluded that there was a very wide variation even in the adjusted rates of caesarean section from 14.9% to 32.1%. Cochrane Systematic Reviews have concluded that the use of FBS does not reduce caesarean section rate or any pre-specified neonatal outcomes. Fetal ECG (ST-Analyser or STAN) has been used in the clinical practice for more than 20 years. Although, initial randomised controlled trials (RCTs) showed great promise regarding the role of STAN in reducing operative delivery rates (instrumental vaginal births and emergency caesarean sections) and neonatal metabolic acidosis, subsequent studies have questioned the role of STAN in clinical practice. A recent meta-analysis which included six randomised controlled trials (a total of 26,446 women) has concluded that there was a 36% reduction in the rate of neonatal metabolic acidosis. Practising clinicians currently face a dilemma as to whether STAN has a place in contemporary obstetric practice or whether it?s use should be discouraged and discontinued. PMID- 28027682 TI - The effect of Achillea millefolium and Hypericum perforatum ointments on episiotomy wound healing in primiparous women. AB - BACKGROUND: The purpose of this study was to assess the efficacy of Achillea millefolium and Hypericum perforatum ointments on episiotomy wound healing in primiparous women. MATERIALS AND METHODS: This is a double-blind clinical trial study performed on 140 primiparous women. They were randomly divided into four groups, each group containing 35 women: 2control groups including nonintervention and placebo ointment; and 2 case groups including Hypericum perforatum ointment and Achillea millefolium ointment. Healing process was assessed by five specifications: redness, ecchymosis, edema, discharge and wound dehiscence on 7th, 10th, and 14th days after delivery; pain level was assessed by means of visual analog scale. RESULTS: There was significant difference between groups in perineal pain level at 7th, 10th and 14th days postpartum, redness and edema at 7th and 10th days postpartum and ecchymosis at 7th day postpartum; the pain level, redness, edema and ecchymosis in groups who consume Hypericum perforatum and Achillea millefolium ointments were less than the control groups (p < 0.05). But, discharge and dehiscence incidence showed no significant difference between groups (p > 0.05). CONCLUSIONS: Achillea millefolium and Hypericum perforatum ointments reduce perineal pain level, redness, edema and ecchymosis of episiotomy wound, so it seems that consuming them was useful for episiotomy treatment. PMID- 28027683 TI - Adjustment modes in the trajectory of progressive multiple sclerosis: a qualitative study and conceptual model. AB - OBJECTIVE: We examined cognitive and behavioural challenges and adaptations for people with progressive multiple sclerosis (MS) and developed a preliminary conceptual model of changes in adjustment over time. DESIGN: Using theoretical sampling, 34 semi-structured interviews were conducted with people with MS. Participants were between 41 and 77 years of age. Thirteen were diagnosed with primary progressive MS and 21 with secondary progressive MS. Data were analysed using a grounded theory approach. RESULTS: Participants described initially bracketing the illness off and carrying on their usual activities but this became problematic as the condition progressed and they employed different adjustment modes to cope with increased disabilities. Some scaled back their activities to live a more comfortable life, others identified new activities or adapted old ones, whereas at times, people disengaged from the adjustment process altogether and resigned to their condition. Relationships with partners, emotional reactions, environment and perception of the environment influenced adjustment, while people were often flexible and shifted among modes. CONCLUSIONS: Adjusting to a progressive condition is a fluid process. Future interventions can be tailored to address modifiable factors at different stages of the condition and may involve addressing emotional reactions concealing/revealing the condition and perceptions of the environment. PMID- 28027684 TI - Associations between circadian and stress response cortisol in children. AB - Hypothalamic-pituitary-adrenal (HPA) axis functioning is characterized by the baseline production of cortisol following a circadian rhythm, as well as by the superimposed production of cortisol in response to a stressor. However, it is relatively unknown whether the basal cortisol circadian rhythm is associated with the cortisol stress response in children. Since alterations in cortisol stress responses have been associated with mental and physical health, this study investigated whether the cortisol circadian rhythm is associated with cortisol stress responses in 6-year-old children. To this end, 149 normally developing children (Mage = 6.09 years; 70 girls) participated in an innovative social evaluative stress test that effectively provoked increases in cortisol. To determine the cortisol stress response, six cortisol saliva samples were collected and two cortisol stress response indices were calculated: total stress cortisol and cortisol stress reactivity. To determine children's cortisol circadian rhythm eight cortisol circadian samples were collected during two days. Total diurnal cortisol and diurnal cortisol decline scores were calculated as indices of the cortisol circadian rhythm. Hierarchical regression analyses indicated that higher total diurnal cortisol as well as a smaller diurnal cortisol decline, were both uniquely associated with higher total stress cortisol. No associations were found between the cortisol circadian rhythm indices and cortisol stress reactivity. Possible explanations for the patterns found are links with children's self-regulatory capacities and parenting quality. PMID- 28027685 TI - Effect of Etomidate on Pneumonia Development in Critically Ill, Nontrauma Patients. AB - PURPOSE: To determine whether etomidate use before intubation increased development of hospital-acquired pneumonia (HAP) in critically ill, nontrauma patients. MATERIALS AND METHODS: A single-center, retrospective, cohort study of critically ill, nontrauma patients admitted to the medical intensive care unit (ICU) from 2012 to 2015 and intubated with or without etomidate was conducted. Demographics, comorbidities, primary diagnosis, critical illness scores, concomitant medications, and outcomes were obtained from medical records. Student t, chi-square, and Fisher exact tests were performed as appropriate. Relevant characteristics were modeled using logistic regression techniques to determine whether any predicted HAP independently. RESULTS: Of the 174 patients, 94 (54%) received etomidate and 80 (46%) did not. There was no difference in HAP between etomidate and no etomidate groups (13.8% vs 23.7%, P = .092). Duration of mechanical ventilation (4.4 vs 4.6 days, P = .845), ICU length of stay (7.4 vs 6.9 days, P = .547), ICU mortality (14.9% vs 12.5%, P = .648), and hospital mortality (17% vs 16.2%, P = .892) were similar between the groups. For each 1 day increase in mechanical ventilation duration, the likelihood of HAP development increased by 21%. Patients who received etomidate but no neuromuscular-blocking drug were 80% less likely to develop HAP than those who did not receive etomidate or a neuromuscular-blocking drug (odds ratio: 0.202, 95% confidence interval: 0.045-0.908). CONCLUSION: Etomidate use was not associated with a difference in HAP development in critically ill, nontrauma patients. PMID- 28027686 TI - The effect of uterine leiomyoma on the risk of malpresentation and cesarean: a meta-analysis. AB - BACKGROUND: some epidemiological studies have found that uterine leiomyoma can increase the risk of cesarean and malpresentation at term. To date, the meta analysis has not been conducted for assessing the relationship between uterine leiomyoma and cesarean/malpresentation. This meta-analysis was conducted to estimate the association between uterine leiomyoma and the risk of cesarean/malpresentation. METHODS: A literature search was conducted out in major databases PubMed, Web of Science, and Scopus up to September 2016. The heterogeneity across studies was conducted by Q-test and I2 statistic. The publication bias was assessed by Begg's and Egger's tests. The results were shown using odds ratio (OR) estimate with 95% confidence intervals (CI) conducting a random-effect model. RESULTS: The literature search included 1244 articles until September 2016 with 232,177 participants. Based on OR estimates obtained from case-control and cohort studies, there was significant association between uterine leiomyoma and cesarean (2.60; 95% CI: 2.02, 3.18) and between leiomyoma and malpresentation at term (2.65; 95% CI: 1.60, 3.70). CONCLUSIONS: We showed based on reports in observational studies that uterine leiomyoma increased the risk of cesarean and malpresentation at term. PMID- 28027687 TI - ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival. AB - BACKGROUND: ASXL1 gene mutations include nonsense, missense, and frameshift mutations. Although their clinical significance is still debated, they may play an important role in the pathogenesis of several hematologic malignancies. METHODS: Herein, we offer a comprehensive review on ASXL1 mutations, and link them with survival and clinical outcomes in patients with various myeloid neoplasms. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2016. FINDINGS: In acute myeloid leukemia (AML), ASXL1 mutations tend to correlate with older age and male gender, and affect predominantly patients with secondary AML. De novo AML patients with ASXL1 mutations had significantly lower complete remission rates after standard high-dose chemotherapy and shorter survival. In chronic myelomonocytic leukemia and low- or intermediate-risk myelodysplastic syndromes, frameshift and nonsense mutations correlated with shorter survival and a higher risk of leukemic transformation. Overall survival was also shorter in primary myelofibrosis in the presence of ASXL1 mutations. CONCLUSIONS: Further research on the role of ASXL1 mutations and therapeutic implications in neoplastic myeloid disorders is stringently needed. Given the relatively high prevalence of ASXL1 mutations, larger studies involving patients affected by these mutations will be feasible in the near future. PMID- 28027689 TI - Entrustable professional activities (EPAs) for teachers in medical education: Has the time come? AB - On a daily basis, patients put their trust in the healthcare system for safe and high-quality healthcare. However, what evidence do we have as an educational community that our supervising faculty members are competent to fulfill this responsibility? Few, if any, requirements exist for faculty members to have continuous professional development in the field of medical education. Many faculty "love to teach", however, this love of teaching does not make them competent to teach or assess the competence of trainees whom they supervise. Faculty members who have a significant role as a teacher in the clinical setting should be assessed with regards to their baseline competence in applicable teaching EPAs. When competence is reached, an entrustment decision can be made. Once proficient or expert, a statement of awarded responsibility (STAR) may be granted. The time has come to reach beyond the "standards" of the old adage "see one, do one, teach one" in medical education. In this personal view, the authors outline an argument for and list the potential benefits for teachers, learners, and patients when we assess clinical teachers using EPAs within a competency based medical education framework. PMID- 28027688 TI - Silibinin sensitizes chemo-resistant breast cancer cells to chemotherapy. AB - CONTEXT: Multiple drug resistance is the major obstacle to conventional chemotherapy. Silibinin, a nontoxic naturally occurring compound, has anticancer activity and can increase the cytotoxic effects of chemotherapy in various cancer models. OBJECTIVE: To evaluate the effects of silibinin on enhancing the sensitivity of chemo-resistant human breast cell lines to doxorubicin (DOX) and paclitaxel (PAC). MATERIALS AND METHODS: The cells were treated with silibinin (at 50 to 600 MUM concentrations) and/or chemo drugs for 24 and 48 h, then cell viability and changes in oncogenic proteins were determined by MTT assay and Western blotting/RT-PCR, respectively. Flow cytometry was used to study apoptosis in the cells receiving different treatments. The antitumorigenic effects of silibinin (at 200 to 400 MUM concentration) were evaluated by mammosphere assay. RESULTS: Silibinin exerted significant growth inhibitory effects with IC50 ranging from 200 to 570 MUM in different cell lines. Treatment of DOX-resistant MDA-MB-435 cells with silibinin at 200 MUM reduced DOX IC50 from 71 to 10 MUg/mL and significantly suppressed the key oncogenic pathways including STAT3, AKT, and ERK in these cells. Interestingly treatment of DOX-resistant MDA-MB-435 cells with silibinin at 400 MUM concentration for 48 h induced a 50% decrease in the numbers of colonies as compared with DMSO-treated cells. Treatment of PAC resistant MCF-7 cells with silibinin at 400 MUM concentration generated synergistic effects when it was used in combination with PAC at 250 nM concentration (CI = 0.81). CONCLUSION: Silibinin sensitizes chemo-resistant cells to chemotherapeutic agents and can be useful in treating breast cancers. PMID- 28027691 TI - Effect of various diets on biomarkers of the metabolic syndrome. AB - The impact of the normal whole diet in different countries and of special types of diet on the biomarkers of the metabolic syndrome (MetS) is reviewed. Diet type, specification, risk of MetS and studied biomarkers, as far as could be traced, are included. Critical points in published studies are mentioned. Description of the traditional dietary patterns for the various countries is not always well-defined and numbers of persons in the studied population are sometimes quite limited, which hamper drawing definite conclusions. Since a Nordic diet, a dietary approach to stop hypertension (DASH), and especially a Mediterranean diet are quite promising, due to its health claims, the food pattern is studied more in detail and a large spectrum of vegetarian diets are included as well. Most of the time lipid profile and high sensitive C-reactive protein (hsCRP) are the studied biomarkers in response to diet intake. PMID- 28027690 TI - Limitation of therapeutic effort experienced by intensive care nurses. AB - BACKGROUND:: Nurses who practice limitation of therapeutic effort become fully involved in emotionally charged situations, which can affect them significantly on an emotional and professional level. OBJECTIVES:: To describe the experience of intensive care nurses practicing limitation of therapeutic effort. METHOD:: A qualitative, phenomenological study was performed within the intensive care units of the Madrid Hospitals Health Service. Purposeful and snowball sampling methods were used, and data collection methods included semi-structured and unstructured interviews, researcher field notes, and participants' personal letters. The Giorgi proposal for data analysis was used on the data. ETHICAL CONSIDERATIONS:: This study was approved by the Ethical Research Committee of the relevant hospital and by the Ethics Committee of the Rey Juan Carlos University and was guided by the ethical principles of voluntary enrollment, anonymity, privacy, and confidentiality. RESULTS:: In total, 22 nurses participated and 3 themes were identified regarding the nurses' experiences when faced with limitation of therapeutic effort: (a) experiencing relief, (b) accepting the medical decision, and (c) implementing limitation of therapeutic effort. CONCLUSION:: Nurses felt that, although they were burdened with the responsibility of implementing limitation of therapeutic effort, they were being left out of the final decision making process regarding the same. PMID- 28027692 TI - Comparison of 3D-Printed Poly-E-Caprolactone Scaffolds Functionalized with Tricalcium Phosphate, Hydroxyapatite, Bio-Oss, or Decellularized Bone Matrix. AB - Three-dimensional (3D)-printing facilitates rapid, custom manufacturing of bone scaffolds with a wide range of material choices. Recent studies have demonstrated the potential for 3D-printing bioactive (i.e., osteo-inductive) scaffolds for use in bone regeneration applications. In this study, we 3D-printed porous poly-E caprolactone (PCL) scaffolds using a fused deposition modeling (FDM) process and functionalized them with mineral additives that have been widely used commercially and clinically: tricalcium phosphate (TCP), hydroxyapatite (HA), Bio Oss (BO), or decellularized bone matrix (DCB). We assessed the "print quality" of the composite scaffolds and found that the print quality of PCL-TCP, PCL-BO, and PCL-DCB measured ~0.7 and was statistically lower than PCL and PCL-HA scaffolds (~0.8). We found that the incorporation of mineral particles did not significantly decrease the compressive modulus of the graft, which was on the order of 260 MPa for solid blocks and ranged from 32 to 83 MPa for porous scaffolds. Raman spectroscopy revealed the surfaces of the scaffolds maintained the chemical profile of their dopants following the printing process. We evaluated the osteo-inductive properties of each scaffold composite by culturing adipose-derived stromal/stem cells in vitro and assessing their differentiation into osteoblasts. The calcium content (normalized to DNA) increased significantly in PCL-TCP (p < 0.05), PCL-BO (p < 0.001), and PCL-DCB (p < 0.0001) groups relative to PCL only. The calcium content also increased in PCL-HA but was not statistically significant (p > 0.05). Collagen 1 expression was 10-fold greater than PCL in PCL-BO and PCL-DCB (p < 0.05) and osteocalcin expression was 10-fold greater in PCL-BO and PCL-DCB (p < 0.05) as measured by quantitative-real time polymerase chain reaction. This study suggests that PCL-BO and PCL-DCB hybrid material may be advantageous for bone healing applications over PCL-HA or PCL-TCP blends. PMID- 28027693 TI - Patupilone-loaded poly(L-glutamic acid)-graft-methoxy-poly(ethylene glycol) micelle for oncotherapy. AB - Patupilone, an original natural anti-cancer agent, also known as epothilone B or Epo906, has shown promise for the treatment of a variety of cancers, however, the systematic side effects of patupilone significantly impaired its clinical translation. Herein, patupilone-loaded PLG-g-mPEG micelles were prepared. Patupilone was grafted to a poly(L-glutamic acid)-graft-methoxy-poly(ethylene glycol) (PLG-g-mPEG) by Steglich esterification reaction to give PLG-g mPEG/Epo906 that could self-assemble to form patupilone-loaded micelles (Epo906 M). The Epo906-M was able to inhibit the proliferation of A549, MCF-7 cancer cells and BEAs-2B cells in vitro. For in vivo treatment of orthotopic xenograft tumor models (MCF-7), the Epo906-M exhibited higher tumor inhibition efficiency with lower side effects as compared with free Epo906. Seventeen percent of the body weight loss appeared in the group treated with free Epo906 of 0.25 mg kg-1, while the group treated with Epo906-M of 10 mg kg-1 showed less than ten percent of body weight loss and displayed stronger tumor inhibiting effect. Therefore, the polypeptide-patupilone conjugate has improved potential for oncotherapy. PMID- 28027694 TI - Awareness and Perception of Strabismus Among the Youths and Women of Child Bearing Age in a Local Government in South Western Nigeria: A Qualitative Study. AB - Purpose To determine the awareness and perception of strabismus among the youths and women of child-bearing age in Ikenne Local Government Area (LGA) of Ogun State, South Western Nigeria. Methodology Fifteen focus group discussions (FGDs) were carried out in the LGA on the perceptions and attitudes of people to strabismus. Their responses were tape-recorded and later transcribed. A thematic phenomenological approach was used for the analysis. Result A total of 139 people participated in the FGDs, with a male:female ratio of 1:~4. Although there was a fairly high level of awareness of strabismus in the populace, their knowledge and perception of the disease were poor. Attitudes toward the disease were based on unfounded fears and misconceptions of the disease. Conclusions We conclude that the perception and acceptance of people with strabismus by the people of Ikenne LGA was based on their poor knowledge of the disease. This in turn interfered with the uptake of health-care services for the condition. PMID- 28027695 TI - Inhibitory Mechanism of the Outer Membrane Growth of Chronic Subdural Hematomas. AB - We previously demonstrated that the inflammatory cytokine interleukin-6 (IL-6) activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway in fibroblasts within the outer membranes of chronic subdural hematomas (CSDHs), and the activation of this pathway may induce CSDH outer membrane growth. The inhibitory system for this signal transduction pathway is unknown. CSDH fluids were obtained from 10 patients during trepanation surgery as the case group, and cerebrospinal fluid (CSF) samples were obtained from seven patients suffering from subarachnoid hemorrhage (SAH) on Day 1 as the control group. The concentrations of IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 (sgp130) in CSDH fluid and CSF were measured using enzyme immunoassay kits. The co-localization of IL-6 and sgp130 in CSDH fluid was examined by immunoprecipitation. The expression levels of STAT3, JAK2, suppressor of cytokine signaling 3 (SOCS3), and protein inhibitor of activated Stat3 (PIAS3) in the outer membranes of CSDHs were examined by immunostaining. Soluble IL-6R and sgp130 concentrations in CSDH fluid were significantly higher than those in CSF after SAH. Sgp130 and IL-6 were co-immunoprecipitated from CSDH fluid. Immunostaining revealed STAT3, JAK2, SOCS3, and PIAS3 expression in fibroblasts located in the outer membranes of CSDHs. Soluble gp130 binds to IL-6/sIL-6R and acts as an antagonist of the JAK/STAT signaling pathway. SOCS3 also binds to JAK and inhibits its signaling pathway. In addition, PIAS3 regulates STAT3 activation. These factors might down-regulate the IL-6/JAK/STAT signaling pathway in fibroblasts within CSDH outer membranes. Therefore, these molecules may be novel therapeutic targets for the inhibition of CSDH growth. PMID- 28027697 TI - Ergonomics at 60: mature, thriving and still leading the way. PMID- 28027696 TI - A Dose-Volume Response Model for Brain Metastases Treated With Frameless Single Fraction Robotic Radiosurgery: Seeking to Better Predict Response to Treatment. AB - : Purpose/Objective(s): To establish a dose-volume response relationship for brain metastases treated with single-fraction robotic stereotactic radiosurgery and identify predictors of local control. MATERIALS/METHODS: We reviewed a prospective institutional database of all patients treated for intact brain metastases with stereotactic radiosurgery alone using the CyberKnife robotic radiosurgery system from 2012 to 2015. Tumor response was determined based on Response Evaluation Criteria In Solid Tumors version 1.1. Survival was estimated using the Kaplan-Meier method. Logistic regression modeling was used to identify predictors of outcome and establish a dose-volume response relationship. Receiver operating characteristic curves were constructed to evaluate the predictive capability of the relationship. RESULTS: There were 357 metastases evaluated in 111 patients with a median diameter of 8.14 mm (2.00-40.77 mm). At 6 and 12 months, local control was 86.9% and 82.2%, respectively. For lesions of similar volumes, higher maximum dose, mean dose, and minimum dose (all P values <.05) predicted for better local control. Tumor volume and diameter were strongly correlated, and a dose-volume response relationship was constructed using mean dose per lesion diameter (Gy/mm) that was predictive of local control (odds ratio: 1.34, 95% confidence interval: 1.06-1.70). Area under the receiver operating characteristic curve for local control and mean dose by volume was 0.6199 with a threshold of 2.05 Gy/mm (local failure 7.6% above and 17.3% below 2.05 Gy/mm). CONCLUSION: A dose-volume response relationship exists for brain metastases treated with robotic stereotactic radiosurgery. Mean dose per volume is strongly predictive of local control and can be potentially useful during stereotactic radiosurgery plan evaluation while respecting previously established dose constraints. PMID- 28027698 TI - Hypertension and functional capacities in community-dwelling older women: a cross sectional study. AB - PURPOSE: The present study aimed to investigate the association between hypertension and physical/functional capacities in community-dwelling older females. MATERIALS AND METHODS: Older female volunteers were dichotomized in two groups: hypertensive (n = 134) and normotensive (n = 244). Volunteers had their medical records reviewed and underwent evaluations of anthropometric data (weight, height and body mass index) and of physical and functional capacities. RESULTS: The results showed that hypertensive older females presented higher values for age, weight, body mass index, and resting diastolic blood pressure than normotensive older females. Normotensive older females showed a higher performance in the one-leg stand test and six-minute walk test compared with hypertensive older females. Age, body mass index, maximal walking speed, performance in the Time Up and Go and six-minute walk test, and diagnosis of diabetes mellitus type II were factors associated with hypertension using the chi square test. However, the multivariate regression analysis indicated that performance in the six-minute walk test was the only factor associated with hypertension. CONCLUSIONS: The patients with higher scores in the six-minute walk test, which is associated with aerobic capacity, show less odds to have clinical diagnosis of hypertension. However, hypertension was not associated with poor physical and functional capacity. PMID- 28027699 TI - Two new compounds from Atractylodes macrocephala with neuroprotective activity. AB - In the present study, two new compounds, together with six known compounds, were isolated from rhizome of Atractylodes macrocephala Koidz by a series of silica gel, ODS column chromatography, and preparative HPLC. Their structures were characterized as atractylenolide II (1), atractylenolide I (2), biepiasterolid (3), isoatractylenolide I (4), atractylenolide III (5), 3beta-acetoxyl atractylenolide I (6), (4E,6E,12E)-tetradeca-4,6,12-triene-8,10-diyne-13,14-triol (7), (3S,4E,6E,12E)-1-acetoxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol (8) on the basis of 1D, 2D NMR, and circular dichroism analyses. Among them, compounds 6 and 8 were novel compounds. In addition, their neuroprotective activity against MPP+-induced SH-SY5Y cells was evaluated by MTT colorimetry. The results showed that all these compounds have definite protective effect on MPP+-induced SH-SY5Y cells. PMID- 28027700 TI - Management of persistent occiput posterior position: a substantial role of instrumental rotation in the setting of failed manual rotation. AB - INTRODUCTION: To compare the maternal and neonatal outcomes associated with Instrumental Rotation (IR) to operative vaginal delivery in occiput posterior (OP) position with Thierry's spatulas (TS), in the setting of failed manual rotation (MR). STUDY DESIGN: We led a prospective observational cohort study in a tertiary referral hospital in Toulouse, France. All women presenting in labor with persistent OP position at full cervical dilatation and who delivered vaginally after failed MR and with IR or OP assisted delivery were included from January 2014 to December 2015. The main outcomes measured were maternal morbidity parameters including episiotomy rate, incidence and severity of perineal lacerations, perineal hematomas and postpartum hemorrhage. Severe perineal tears corresponded to third and fourth degree lacerations. Fetal morbidity outcomes comprised neonatal Apgar scores, acidemia, fetal injuries, birth trauma and neonatal intensive care unit admissions. RESULTS: Among 9762 women, 910 (9.3%) presented with persistent OP position at full cervical dilatation and 222 deliveries were enrolled. Of 111 attempted IR, 97 were successful (87.4%). The incidence of anal sphincter injuries was significantly reduced after IR attempt (1.8% vs. 12.6%; p < 0.002). Both groups were similar regarding most fetal outcomes and no birth trauma occurred in our study population. In a multivariable logistic regression analysis, OP operative delivery was a significant risk factor of severe perineal lacerations (OR = 9.5; 95% CI: 2.05-44.05). CONCLUSION: Our results support the use of IR in order to reduce perineal morbidity associated with OP assisted delivery, in the setting of a failed manual rotation. PMID- 28027701 TI - An introductory word from the editor. PMID- 28027702 TI - Making a global sensation: Vanilla flavor, synthetic chemistry, and the meanings of purity. AB - How did vanilla, once a rare luxury, become a global sensation? Rather than taking the vanilla flavor of vanilla beans as a pre-existing natural fact, this essay argues that the sensory experience that came to be recognized as vanilla was a hybrid artifact produced by an expanding global trade in a diverse set of pleasurable substances, including cured beans from artificially pollinated vanilla orchids, synthetic vanillin, sugar, and a far-flung miscellany of other botanical and chemical materials. Global trade and large-scale production resulted not in the production of a homogenous, stable commodity, but in a range of local vanillas, heterogeneous mixtures with a range of qualities and virtues. As local commercial and regulatory interests competed to define the origins, and thus the market value, of authentic vanilla flavor, scientific experts were called upon to adjudicate these rival claims. In the United States, these debates played out in the context of the 1906 Pure Food and Drug Act, where efforts to define and chemically enforce a 'standard' vanilla extract, in contradistinction from adulterated, 'imitation' extracts, clashed with the interests of makers and users of both synthetic and 'genuine' vanilla flavorings. As regulatory chemists grappled with the growing variety of vanillas, they were required to determine the appropriate chemical components of genuine vanilla, and consequently to delimit the subjective sensory effects proper to the flavor. Nonetheless, the materials, experiences, and meanings popularly associated with vanilla flavor continued to exceed the limits prescribed by officials. PMID- 28027703 TI - "The greatest victory which the chemist has won in the fight (...) against Nature": Nitrogenous fertilizers in Great Britain and the British Empire, 1910s 1950s. AB - This paper analyses the rise of synthetic nitrogen in Great Britain and its empire, from the First World War to the aftermath of the Second World War. Rather than focus solely on technological innovations and consumption statistics, it seeks to explain how nitrogen was a central element in the expansion of a form of agricultural governance, which needed simplified, stable, and seemingly universal input/output formulae. In the first half of the twentieth century, nitrogen was thus gradually constructed as a global indicator of development, as it was particularly adapted to scientific and political regimes increasingly relying upon abstraction and quantification. Yet, the history of nitrogenous fertilizers in the interwar years also shows that this cannot be reduced to a simple story of triumphant modernity, as their development and globalization was imperfect, unstable, accompanied by resistance and the resilience or emergence of other models. Rather than assuming an all-powerful "state" project, the paper thus seeks to recover the multiplicity of actors, and attempts to account for the rise of nitrogenous fertilizers; not just as the progressive application of a technological breakthrough, but as a difficult process embedded in technological, financial, and military constraints, corporate strategies, political imperatives, and the changing institutional framework of agricultural research. PMID- 28027704 TI - Local impacts, global sources: The governance of boundary-crossing chemicals. AB - Over the last half century, a multijurisdictional, multiscale system of governance has emerged to address concerns associated with toxic chemicals that have the capacity to bioaccumulate in organisms and biomagnify in food chains, leading to fish consumption advisories. Components of this system of governance include international conventions (such as the Stockholm Convention on Persistent Organic Pollutants and the Minamata Convention on Mercury), laws enacted by nation states and their subjurisdictions, and efforts to adaptively manage regional ecosystems (such as the U.S.-Canadian Great Lakes). Given that many of these compounds - including mercury, industrial chemicals such as polychlorinated biphenyls, and pesticides such as toxaphene - circulate throughout the globe through cycles of deposition and reemission, regional efforts to eliminate the need for fish consumption advisories cannot be successful without efforts to reduce emissions everywhere in the world. This paper argues that the scientific community, by monitoring the concentrations of these compounds in the atmosphere and by modeling their fate and transport, play an important role in connecting the various jurisdictional scales of governance. In addition, the monitoring networks that this community of scientists has established can be visualized as a technology of governance essential in an era in which societies have the capacity to produce and release such chemicals on an industrial scale. PMID- 28027705 TI - Parachemistries: Colonial chemopolitics in a zone of contest. AB - The globalization of modern chemistry through European colonialism resulted, by the end of the nineteenth century, in the emergence of a number of parachemical knowledges. Parachemistries were bodies of non-European knowledge which came to be related to modern chemistry within particular historical milieux. Their relationship with modern chemistry was not necessarily epistemic and structural, but historical and performative. Actual historically located intellectuals posited their relationship. Such relationships were not merely abstract intellectual exercises; at a time when the practical uses of modern chemistry in statecraft were growing, the existence of these rival, competing parachemical knowledges challenged modern chemistry's regulatory deployments. Colonial locations emerged then not as mere 'contact zones', but as 'zones of conflict' where colonial chemopolitics was interrupted by the continued legitimacy and practice of parachemistries such as rasayana, kimiya, and neidan. PMID- 28027706 TI - From bauxite to cooking pots: Aluminum, chemistry, and West African artisanal production. AB - The history of aluminum's transformation from a precious to a commonplace metal over the course of the late nineteenth and twentieth centuries has frequently been told as a narrative about intrepid western chemists, whose discoveries made it possible for industrialized manufacturers to make the metal global. This paper questions both the singularity of that discovery and the inevitability of aluminum's global dominance as a 'modern' material of manufacture. It does so by considering the history of aluminum in West Africa and the ways in which artisans in that region domesticated the substance to an artisanal mode of production and developed quotidian chemical knowledge of it in the process. Considering aluminum from the perspective of West Africa suggests that aluminum may not have been discovered once, but many times, and that everyday material engagements can inspire forms of chemical knowhow that operate well beyond the bounds of the laboratory and industrial manufacturing plant. PMID- 28027707 TI - Exploring global history through the lens of history of Chemistry: Materials, identities and governance. AB - As global history continues to take shape as an important field of research, its interactive relationships with the history of science, technology, and medicine are recognized and being investigated as significant areas of concern. Strangely, despite the fact that it is key to understanding so many of the subjects that are central to global history and would itself benefit from a broader geographical perspective, the history of chemistry has largely been left out of this process - particularly for the modern historical period. This article argues for the value of integrating the history of chemistry with global history, not only for understanding the past, but also for thinking about our shared present and future. Toward this end, it (1) explores the various ways in which 'chemistry' has and can be defined, with special attention to discussions of 'indigenous knowledge systems'; (2) examines the benefits of organizing historical inquiry around the evolving sociomaterial identities of substances; (3) considers ways in which the concepts of 'chemical governance' and 'chemical expertise' can be expanded to match the complexities of global history, especially in relation to environmental issues, climate change, and pollution; and (4) seeks to sketch the various geographies entailed in bringing the history of chemistry together with global histories. PMID- 28027708 TI - Re-emergence of an orphan therapeutic target for the treatment of resistant prostate cancer - a thorough conformational and binding analysis for ROR-gamma protein. AB - Recent studies have linked a deadly form of prostate cancer known as metastatic castration-resistant prostate cancer to retinoic acid-related orphan-receptor gamma (ROR-gamma). Most of these studies continued to place ROR-gamma as orphan because of unidentifiable inhibitor. Recently identified inhibitors of ROR-gamma and their therapeutic potential were evaluated, among which inhibitor XY018 was the potent. However, molecular understanding of the conformational features of XY018-ROR-gamma complex is still elusive. Herein, molecular dynamics simulations were conducted on HC9-ROR-gamma and XY018-ROR-gamma complexes to understand their conformational features at molecular level and the influence of XY018 binding on the dynamics of ROR-gamma with the aid of post-dynamic analytical tools. These include; principal component analysis, radius of gyration, binding free energy calculation (MM/GBSA), per-residue fluctuation and hydrogen bond occupancy. Findings from this study revealed that (1) hydrophobic packing contributes significantly to binding free energy, (2) Ile136 and Leu60 exhibited high hydrogen-bond occupancy in XY018-ROR-gamma and HC9-ROR-gamma, respectively, (3) XY018-ROR-gamma displayed a relatively high loop region residue fluctuation compared to HC9-ROR-gamma, (4) electrostatic interactions are a potential binding force in XY018-ROR-gamma complex compared to HC9-ROR-gamma, (5) XY018-ROR-gamma assumes a rigid conformation which is highlighted by a decrease in residual fluctuation, (6) XY018 could potentially induce pseudoporphyria, nephritis and interstitial nephritis but potentially safe in renal failure. This study could serve as a base line for the design of new potential ROR-gamma inhibitors. PMID- 28027709 TI - Conditioned Medium from Periodontal Ligament Stem Cells Enhances Periodontal Regeneration. AB - Periodontal disease is one of the most common infectious diseases in adults and is characterized by the destruction of tooth-supporting tissues. Mesenchymal stem cells (MSCs) comprise the mesoderm-originating stem cell population, which has been studied and used for cell therapy. However, because of the lower rate of cell survival after MSC transplantation in various disease models, paracrine functions of MSCs have been receiving increased attention as a regenerative mechanism. The aim of this study was to investigate the regenerative potential of transplanted conditioned medium (CM) obtained from cultured periodontal ligament stem cells (PDLSCs), the adult stem cell population in tooth-supporting tissues, using a rat periodontal defect model. Cell-free CM was collected from PDLSCs and fibroblasts, using ultrafiltration and transplanted into surgically created periodontal defects. Protein content of CM was examined by antibody arrays. Formation of new periodontal tissues was analyzed using microcomputed tomography and histological sections. PDLSC-CM transplantation enhanced periodontal tissue regeneration in a concentration-dependent manner, whereas fibroblast-CM did not show any regenerative function. Proteomic analysis revealed that extracellular matrix proteins, enzymes, angiogenic factors, growth factors and cytokines were contained in PDLSC-CM. Furthermore, PDLSC-CM transplantation resulted in the decreased mRNA level of tumor necrosis factor-alpha (TNF-alpha) in healing periodontal tissues. In addition, we found that PDLSC-CM suppressed the mRNA level of TNF-alpha in the monocyte/macrophage cell line, RAW cells, stimulated with IFN-gamma. Our findings suggested that PDLSC-CM enhanced periodontal regeneration by suppressing the inflammatory response through TNF-alpha production, and transplantation of PDLSC-CM could be a novel approach for periodontal regenerative therapy. PMID- 28027710 TI - Prison Experience and Reoffending: Exploring the Relationship Between Prison Terms, Institutional Treatment, Infractions, and Recidivism for Sex Offenders. AB - Given that sex offenders have been found to serve longer prison terms compared with other types of violent criminals, it has been suggested that the influence of imprisonment may impact subsequent reoffending. However, institutional factors are often overlooked in risk assessment studies and very few risk assessment instruments include institutional items within their models. The current study explores prison experience explanations for recidivism among convicted sex offenders and indicates that, with respect to time served, both institutional treatment and institutional infractions demonstrate a significant impact. Findings indicate that misconduct in custody was positively associated with revocation and sexual recidivism. Moreover, longer periods of incarceration significantly increase postrelease reoffending for high-risk sex offenders. Policy implications are made regarding further modifications to risk assessment instruments that will take into account institutional risk factors. PMID- 28027711 TI - Molecular modeling and statistical analysis in the design of derivatives of human dipeptidyl peptidase IV. AB - Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4 dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies. PMID- 28027712 TI - qSOFA should replace SIRS as the screening tool for sepsis. PMID- 28027713 TI - Parenting and adolescents' psychological adjustment: Longitudinal moderation by adolescents' genetic sensitivity. AB - We examined whether adolescents' genetic sensitivity, measured by a polygenic index score, moderated the longitudinal associations between parenting and adolescents' psychological adjustment. The sample included 323 mothers, fathers, and adolescents (177 female, 146 male; Time 1 [T1] average age = 12.61 years, SD = 0.54 years; Time 2 [T2] average age = 13.59 years, SD = 0.59 years). Parents' warmth and hostility were rated by trained, independent observers using videotapes of family discussions. Adolescents reported their symptoms of anxiety, depressed mood, and hostility at T1 and T2. The results from autoregressive linear regression models showed that adolescents' genetic sensitivity moderated associations between observations of both mothers' and fathers' T1 parenting and adolescents' T2 composite maladjustment, depression, anxiety, and hostility. Compared to adolescents with low genetic sensitivity, adolescents with high genetic sensitivity had worse adjustment outcomes when parenting was low on warmth and high on hostility. When parenting was characterized by high warmth and low hostility, adolescents with high genetic sensitivity had better adjustment outcomes than their counterparts with low genetic sensitivity. The results support the differential susceptibility model and highlight the complex ways that genes and environment interact to influence development. PMID- 28027714 TI - Impact of national policies on the microbial aetiology of surgical site infections in acute NHS hospitals in England: analysis of trends between 2000 and 2013 using multi-centre prospective cohort data. AB - Our study aimed to evaluate changes in the epidemiology of pathogens causing surgical site infections (SSIs) in England between 2000 and 2013 in the context of intensified national interventions to reduce healthcare-associated infections introduced since 2006. National prospective surveillance data on target surgical procedures were used for this study. Data on causative organism were available for 72% of inpatient-detected SSIs meeting the standard case definitions for superficial, deep and organ-space infections (9767/13 531) which were analysed for trends. A multivariable logistic linear mixed model with hospital random effects was fitted to evaluate trends by pathogen. Staphylococcus aureus was the predominant cause of SSI between 2000 (41%) and 2009 (24%), decreasing from 2006 onwards reaching 16% in 2013. Data for 2005-2013 showed that the odds of SSI caused by S. aureus decreased significantly by 14% per year [adjusted odds ratio (aOR) 0.86, 95% confidence interval (CI) 0.83-0.89] driven by significant decreases in methicillin-resistant S. aureus (MRSA) (aOR 0.71, 95% CI 0.68-0.75). However a small significant increase in methicillin-sensitive S. aureus was identified (aOR 1.06, 95% CI 1.02-1.10). Enterobacteriaceae were stable during 2000-2007 (12% of cases overall), increasing from 2008 (18%) onwards, being present in 25% of cases in 2013; the model supported these increasing trends during 2007-2013 (aOR 1.12, 95% CI 1.07-1.18). The decreasing trends in S. aureus SSIs from 2006 and the increases in Enterobacteriaceae SSIs from 2008 may be related to intensified national efforts targeted at reducing MRSA bacteraemia combined with changes in antibiotic use aimed at controlling C. difficile infections. PMID- 28027715 TI - Enlarged vestibular aqueducts and other inner-ear abnormalities in patients with Down syndrome. AB - BACKGROUND: Histopathological anomalies of inner-ear structures in individuals with Down syndrome have been well documented; however, few studies have examined the radiological features. METHODS: A retrospective study was conducted of temporal bone computed tomography images in 38 individuals (75 ears) with Down syndrome to evaluate the prevalence of inner-ear abnormalities and assess vestibular aqueduct widths. RESULTS: Inner-ear anomalies were identified in 20 of the 38 individuals (52.6 per cent). Seven of the 75 temporal bones (9.3 per cent) were found to have higher than previously reported. A dilated internal auditory canal and vestibule were more common among the present study group, while prior studies have demonstrated internal auditory canal stenosis and decreased vestibule size. CONCLUSION: Down syndrome patients exhibit a high prevalence of dysplastic inner-ear features that confer substantial risk of sensorineural hearing loss. Computed tomography is a useful screening aid to detect inner-ear abnormalities, particularly enlarged vestibular aqueducts, which cause preventable sensorineural hearing loss in this population. PMID- 28027716 TI - Pathogen and Procedure Trends Among Surgical-Site Infections at a Children's Hospital: A 20-Year Experience. PMID- 28027717 TI - Efficiency of slaughterhouse surveillance for the detection of bovine tuberculosis in cattle in Northern Ireland. AB - Post-mortem examination continues to play an important surveillance role in the bovine tuberculosis (bTB) eradication programme in Northern Ireland. It is estimated that 18-28% of new bTB herd breakdowns are disclosed by the detection of bTB lesions in animals routinely slaughtered. The purpose of this study was to compare the performance of different slaughterhouses in Northern Ireland in detecting bTB-lesioned animals at routine slaughter (LRS) and to apply the findings to maximize the sensitivity of bTB slaughterhouse surveillance. Univariate statistical analysis on cattle slaughtered in Northern Ireland during 2011-2013 revealed that the risk of LRS disclosure varied between slaughterhouses, ranging from 0.08% to 0.54%. Furthermore, the risk of confirmation of these LRS as bTB varied between slaughterhouses, ranging from 57.9% to 72.4%. Logistic regression modelling of selected risk factors found that the risk of LRS disclosure increased with age, and was higher in purchased animals, during winter months, in animals coming from high bTB incidence areas and in animals slaughtered from herds with a bTB restriction in the last 2-3 years. Adjusting for these selected factors, the risk of LRS disclosure and bTB confirmation changed very little from the univariable analysis, suggesting that differences in disclosure risks between slaughterhouses were likely to be due to factors related to the slaughterhouses, rather than to the risk status of the animals presented. Examination of procedures within these slaughterhouses is recommended to identify ways that could increase the sensitivity of their bTB surveillance. PMID- 28027718 TI - Prevalence of overweight, obesity, underweight and normal weight in French youth from 2009 to 2013. AB - OBJECTIVE: To determine the prevalence of underweight, overweight and obesity in French youth from 2009 to 2013 and to determine if there are differences in weight categories according to socio-economic status. DESIGN: Cross-sectional study performed in different regions of France. Physical measures included weight, height and BMI. Underweight, overweight and obesity were defined according to age- and sex-specific BMI cut-off points from the International Obesity Task Force. SETTING: France. SUBJECTS: Children and adolescents (n 9670; 4836 boys, 4834 girls) from the French national BOUGE Program between 2009 and 2013. RESULTS: The prevalence of obesity was higher in boys than girls (P0.05) and remained unchanged in boys (7.1-7.3 %) between 2009 and 2013. Overweight and obesity were higher in low socio-economic families (P<0.0001). CONCLUSIONS: Findings suggest that the prevalence of overweight was stable although high in French children and adolescents, while the prevalence of obesity increased significantly. Changes in underweight, although not significant, were high in girls and merit further attention. Improving public health interventions, especially in high-risk low socio-economic populations, may help to modify the behaviour that contributes to underweight, overweight and obesity in young boys and girls. PMID- 28027719 TI - Childhood body mass index at 5.5 years mediates the effect of prenatal maternal stress on daughters' age at menarche: Project Ice Storm. AB - Early pubertal timing is known to put women at greater risk for adverse physiological and psychological health outcomes. Of the factors that influence girls' pubertal timing, stress experienced during childhood has been found to advance age at menarche (AAM). However, it is not known if stress experienced by mothers during or in the months before conception can be similarly associated with earlier pubertal timing. Prenatal maternal stress (PNMS) is associated with metabolic changes, such as increased childhood adiposity and risk of obesity, that have been associated with earlier menarchal age. Using a prospective longitudinal design, the present study tested whether PNMS induced by a natural disaster is either directly associated with earlier AAM, or whether there is an indirect association mediated through increased girls' body mass index (BMI) during childhood. A total of 31 girls, whose mothers were exposed to the Quebec's January 1998 ice storm during pregnancy were followed from 6 months to 15.5 years of age. Mother's stress was measured within 6 months of the storm. BMI was measured at 5.5 years, and AAM was assessed through teen's self-report at 13.5 and 15.5 years of age. Results revealed that greater BMI at 5.5 years mediated the effect of PNMS on decreasing AAM [B=-0.059, 95% confidence intervals (-0.18, 0.0035)]. The present study is the first to demonstrate that maternal experience of stressful conditions during pregnancy reduces AAM in the offspring through its effects on childhood BMI. Future research should consider the impact of AAM on other measures of reproductive ability. PMID- 28027720 TI - Distribution of Central Line-Associated Bloodstream Infections Determined From Washington State's Annual Reporting Validation Program, 2009-2013. AB - Healthcare-associated infection reporting validation is essential because this information is increasingly used in public healthcare quality assurances and care reimbursement. Washington State's validation of central line-associated bloodstream infection reporting applies credible quality sciences methods to ensure that hospital reporting accuracy is maintained. This paper details findings and costs from our experience. Infect Control Hosp Epidemiol 2017;38:489 492. PMID- 28027721 TI - A deterministic evaluation of heat stress mitigation and feed cost under climate change within the smallholder dairy sector. AB - In the global South, dairying is often promoted as a means of poverty alleviation. Yet, under conditions of climate warming, little is known regarding the ability of small-scale dairy producers to maintain production and/or the robustness of possible adaptation options in meeting the challenges presented, particularly heat stress. The authors created a simple, deterministic model to explore the influence of breed and heat stress relief options on smallholder dairy farmers in Odisha, India. Breeds included indigenous Indian (non-descript), low-grade Jersey crossbreed and high-grade Jersey crossbreed. Relief strategies included providing shade, fanning and bathing. The impact of predicted critical global climate parameters, a 2 degrees C and 4 degrees C temperature rise were explored. A feed price scenario was modelled to illustrate the importance of feed in impact estimation. Feed costs were increased by 10% to 30%. Across the simulations, high-grade Jersey crossbreeds maintained higher milk yields, despite being the most sensitive to the negative effects of temperature. Low-capital relief strategies were the most effective at reducing heat stress impacts on household income. However, as feed costs increased the lower-grade Jersey crossbreed became the most profitable breed. The high-grade Jersey crossbreed was only marginally (4.64%) more profitable than the indigenous breed. The results demonstrate the importance of understanding the factors and practical trade-offs that underpin adaptation. The model also highlights the need for hot-climate dairying projects and programmes to consider animal genetic resources alongside environmentally sustainable adaptation measures for greatest poverty impact. PMID- 28027722 TI - Celastrol suppresses expression of adhesion molecules and chemokines by inhibiting JNK-STAT1/NF-kappaB activation in poly(I:C)-stimulated astrocytes. AB - In the central nervous system, viral infection can induce inflammation by up regulating pro-inflammatory mediators that contribute to enhanced infiltration of immune cells into the central nervous areas. Celastrol is known to exert various regulatory functions, including anti-microbial activities. In this study, we investigated the regulatory effects and the mechanisms of action of celastrol against astrocytes activated with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic dsRNA, as a model of pro-inflammatory mediated responses. Celastrol significantly inhibited poly(I:C)-induced expression of adhesion molecules, such as ICAM-1/VCAM-1, and chemokines, such as CCL2, CXCL8, and CXCL10, in CRT-MG human astroglioma cells. In addition, celastrol significantly suppressed poly(I:C)-induced activation of JNK MAPK and STAT1 signaling pathways. Furthermore, celastrol significantly suppressed poly(I:C)-induced activation of the NF-kappaB signaling pathway. These results suggest that celastrol may exert its regulatory activity by inhibiting poly(I:C)-induced expression of pro inflammatory mediators by suppressing activation of JNK MAPK-STAT1/NF-kappaB in astrocytes. [BMB Reports 2017; 50(1): 25-30]. PMID- 28027723 TI - Selective packing for uncontrollable traumatic thoracic wall bleeding preserving cardiopulmonary function. AB - BACKGROUND: Uncontrollable chest wall bleeding secondary to thoracic trauma has been a challenging problem faced by surgeons. Thoracic packing has been described as a good alternative although most thoracic surgeons avoid it because of the potential deleterious effects on cardiopulmonary function. METHODS: We describe a selective gauze packing technique of the thoracic wall preserving cardiopulmonary function in 3 patients with uncontrollable bleeding, where gauze packs were placed on bleeding areas holding them in a "sandwich-like" arrangement between the skin and the pleura and tightly fixed with coated wire stitches using internal and external-thoracic Ventrofil(r) devices. RESULTS: Successful hemostasis and cardio-respiratory stability were achieved in all cases after selective packing. X-ray showed acceptable lung expansion and no heart compression. CONCLUSIONS: This selective packing technique is simple, feasible and highly effective in managing uncontrollable post-traumatic or even post operative chest wall hemorrhages when the life of patients is in danger. PMID- 28027724 TI - In Heart Failure, Where You Have Been May Be More Important Than Where You Are: A Role for Patient-Reported Outcomes. AB - Current advanced care for patients with heart failure requires unique resources available only at a few large institutions. As a result, end-stage heart failure patients are often referred for care by teams who lack the insight of their regular primary cardiologist into their unique disease trajectory. This situation may result in clinical missteps. By tapping into a patient's familiarity with their own trajectory through the use of patient-reported outcome metrics however, it is possible that this problem may be easily addressed. PMID- 28027726 TI - Neurocognitive mechanisms modulating attention bias in anxiety: Current perspectives. PMID- 28027725 TI - Effect of Chronic Kidney Disease on Mortality in Patients Who Underwent Lower Extremity Peripheral Vascular Intervention. AB - It is known that chronic kidney disease (CKD) is associated with increased postoperative morbidity and mortality in patients with peripheral artery disease who underwent lower extremity surgical revascularization; however, outcomes after peripheral vascular intervention (PVI) are less well established. This study sought to determine the impact of CKD on adverse outcomes in patients with peripheral artery disease who underwent PVI. Using data from the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we identified a cohort of 755 patients who underwent lower extremity PVI from June 2005 to August 2010 at 33 sites. The outcomes of interest were mortality, progression to dialysis, myocardial infarction, limb amputation, and stroke. Kaplan-Meier survival analysis and Cox proportional hazard frailty models assessed the association between CKD and adverse outcomes. Of the patients who underwent lower extremity PVI, 201 patients (27%) had CKD. The presence of CKD was associated with decreased survival (5-year survival probability of CKD compared with non CKD: 49.9% [41.6% to 59.9%] vs 80.1% [76.2% to 84.1]), which persisted after risk adjustment (HR 1.57; 95% confidence interval 1.13 to 2.19). In addition, there was a significant association between CKD and progression to dialysis (HR 6.62; 95% confidence interval 2.25 to 19.43). In contrast, there was no association between CKD and re-hospitalization for myocardial infarction, limb amputation, or stroke. In conclusion, CKD is present in 1 of 4 patients who underwent PVI and is associated with increased risk of mortality and progression to dialysis. PMID- 28027727 TI - New investigators in glycoscience. PMID- 28027728 TI - Billion dollar baby. PMID- 28027729 TI - Stems Cells in Psychiatric Disease: Physiology, Pathophysiology & Treatment. PMID- 28027730 TI - Vancomycin Paste Does Not Reduce the Incidence of Deep Sternal Wound Infection After Cardiac Operations. AB - BACKGROUND: Deep sternal wound infection (DSWI) is a devastating complication that increases morbidity and death in cardiac surgical patients. Vancomycin is often administered intravenously for antibiotic prophylaxis in cardiac operations. Many cardiac surgeons also apply vancomycin paste topically to the sternal edges. We examined the effect of vancomycin paste on the incidence of DSWI in patients undergoing elective cardiac operations. METHODS: We retrospectively reviewed the medical records of all patients from 2003 to 2015 who underwent coronary artery bypass grafting, valve, or combined coronary artery bypass grafting and valve operations at a single institution. We derived The Society for Thoracic Surgeons (STS) DSWI risk index for each patient and systematically reviewed operative, pharmacy, microbiology, and discharge records to document DSWI in these patients. Multivariate analyses were used to identify predictors of DSWI in this cohort and to quantify the effect of vancomycin paste. RESULTS: Of the 14,492 patients whose records we examined, DSWI developed in 136 patients, resulting in an overall incidence of 0.9%. After multivariate analysis, body mass index, New York Heart Association Functional Classification, and the STS DSWI risk index remained statistically significant and associated with DSWI. Although the incidence of DSWI decreased over time, the use of vancomycin paste was not associated with a reduced incidence of DSWI. CONCLUSIONS: There was a marked decrease in the incidence of DSWI during the study period, concurrent with institutional implementation of revised STS antibiotic dosing guidelines in 2007 and other strategies. However, the application of vancomycin paste to the sternal edges of patients undergoing cardiac operations was not associated with a reduced risk of DSWI. PMID- 28027731 TI - Pathologic Findings and Long-Term Results After Surgical Treatment for Pulmonary Sarcomatoid Tumors: A Multicenter Analysis. AB - BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a very rare subtype of non small cell lung cancer (NSCLC). The aim of this study was to clarify the pathologic characteristics and long-term survival after surgical treatment in patients with PSC. METHODS: From January 2003 to December 2013, we retrospectively reviewed the clinical findings, surgical notes, and pathologic and follow-up data from 148 consecutive patients who underwent curative resection for PSC in 5 institutions. The Kaplan-Meier method, log-rank test, and Cox regression analysis were used. RESULTS: Mean age and male to female ratio were 66.6 +/- 9.9 years and 120:28, respectively. Surgical resection (pneumonectomy in 8 patients, bilobectomy in 132 patients, and sublobar resection in 8 patients) was complete in 142 cases (96%). At pathologic evaluation, 36 patients (24%) had stage I, 69 patients (47%) had stage II, 33 patients (22%) had stage III, and 10 patients (7%) had stage IV disease. A "biphasic tumor" (PSC with an NSCLC component) was observed in 77 patients (52%). We detected a high rate of vascular emboli in the surgical specimens (overall, 68%; 57% in pathologic stage I tumors), whereas lymphatic emboli were found in 30% of cases (5% of pathologic stage I tumors). Overall median and 5-year long-term survival (LTS) was 19 months and 12.6% (LTS, 16.3% in pathologic stage I), respectively. Distant recurrences frequently occurred after surgical treatment (81%), even in pathologic stage I tumors that underwent R0 resection (62%). Multivariable survival analysis identified R+ resection (hazard ratio [HR],12.3; 95% confidence interval [CI], 3.67-41.28; p < 0.0001), advanced pathologic stage (HR, 5.75; 95% CI, 2.55-12.98; p < 0.0001), and the presence of vascular emboli (HR, 1.67; 95% CI, 1.05-2.67; p = 0.0327) as independent negative prognostic factors. CONCLUSIONS: PSCs have very aggressive behavior and high metastatic potential even in early stages. R+ resection, pathologic TNM status, and the presence of vascular emboli are independent prognostic factors. PMID- 28027732 TI - Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in the Nodal Staging of Stereotactic Ablative Body Radiotherapy Patients. AB - BACKGROUND: Patients with non-small cell lung cancer (NSCLC) being evaluated for stereotactic ablative body radiotherapy (SABR) are typically staged noninvasively with positron emission tomography/computed tomography (PET/CT). Incorporating endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) into the staging workup of these patients has not been evaluated. Our primary objective was to compare the performance of PET/CT with EBUS-TBNA for intrathoracic nodal assessment among SABR-eligible patients. METHODS: This was a retrospective study consisting of two parts. First, we assessed the concordance for nodal metastasis of PET/CT and EBUS-TBNA. Second, we evaluated clinical outcomes among patients who underwent SABR with and without a prior EBUS-TBNA. RESULTS: We identified 246 eligible patients. Compared with PET/CT, EBUS-TBNA led to a stage shift in 48 of 246 patients (19%). Of 174 N0 patients by PET/CT, 6 (3.4%) had nodal metastasis on EBUS-TBNA. Among 72 clinical N1 patients, 36 (50%) were downstaged to N0 after EBUS-TBNA, therefore becoming eligible for SABR. Concordance between PET/CT and EBUS-TBNA for nodal metastasis was 83% (kappa = 0.53). Clinical outcomes of patients who underwent SABR with or without a prior EBUS-TBNA did not differ significantly. CONCLUSIONS: Concordance of PET/CT and EBUS-TBNA for nodal disease was only moderate. Incorporating EBUS-TBNA into the staging workup was beneficial in identifying occult nodal metastasis that would otherwise be left untreated with SABR and in expanding the pool of potentially SABR-eligible patients. PMID- 28027733 TI - Restricted Albumin Utilization Is Safe and Cost Effective in a Cardiac Surgery Intensive Care Unit. AB - BACKGROUND: Volume expansion is often necessary after cardiac surgery, and albumin is often administered. Albumin's high cost motivated an attempt to reduce its utilization. This study analyzes the impact limiting albumin infusion in a cardiac surgery intensive care unit. METHODS: This retrospective study analyzed albumin use between April 2014 and April 2015 in patients admitted to a cardiac surgery intensive care unit. During the first 9 months, there were no restrictions. In January 2015, institutional guidelines limited albumin use to patients requiring more than 3 L crystalloid in the early postoperative period, hypoalbuminemic patients, and to patients considered fluid overloaded. Albumin utilization was obtained from pharmacy records and compared with outcome quality metrics. RESULTS: In all, 1,401 patients were admitted over 13 months. Albumin use, mortality, ventilator days, patients receiving transfusions, and length of stay were compared for 961 patients before and 440 patients after guidelines were initiated. After restrictive guidelines were instituted, albumin utilization was reduced from a mean of 280 monthly doses to a mean of 101 monthly doses (p < 0.001). There was also a trend toward reduced ventilator days. Mortality, length of stay, and transfusion requirements demonstrated no significant change. Based on an average wholesale price and an average monthly reduction of 180 albumin doses, the cardiac surgery intensive care unit demonstrated more than $45,000 of wholesale savings per month after restrictions were implemented. CONCLUSIONS: Albumin restriction in the cardiac surgery intensive care unit was feasible and safe. Significant reductions in utilization and cost with no changes in morbidity or mortality were demonstrated. These findings may provide a strategy for reducing cost while maintaining quality of care. PMID- 28027734 TI - Prevalence and characteristics of intravertebral enhancement on contrast-enhanced CT scans in cancer patients. AB - STUDY DESIGN: This was a single center, retrospective observational study. OBJECTIVE: to investigate-in a cancer population-the prevalence and hallmarks of intravertebral enhancement (IVE) detected on contrast-enhanced CT. SUMMARY OF BACKGROUND DATA: Intravertebral enhancements secondary to iodinated contrast stagnation have been described. Cancer patients have an increased risk of perivertebral venous thrombosis or stenosis secondary to several risk factors (cancer or drug induced hypercoagulability, deterioration of venous flow linked to catheter insertion, prolonged immobilization). In case of a high density lesion identified on CT, the diagnostic choice between metastasis and contrast media within bone marrow vessels may be an issue, especially as oncologic follow up CT scans are usually performed with contrast medium injection. METHODS: 2572 contrast-enhanced body CT scans performed in cancer patients over 3 months in the medical imaging department of a university hospital were retrospectively reviewed. IVE was sought when paravertebral venous collateral circulation was detected and bone metastasis ruled out and classified as linear or nodular. Their locations within vertebra, their relation to the injection side and the predominant collateral venous network side were evaluated. RESULTS: Sixty-seven (2.8%) patients had a collateral paravertebral venous system and among them 21 had IVE (37%). There were 208 IVE locations involving 75 vertebrae. 199 IVE were linear-shaped (95.7%) and 9 nodular-shaped (4.3%). 80.8% were located between C6 and T4. 88.9% were localized in the vertebral body. 73.1% were located medially or ipsilateral to the injection side. CONCLUSION: Intravertebral enhancement is found in 37% of the patients with paraspinal collateral venous circulation when a CT scan is performed for cancer. The ipsilateral or medial position of the IVE relative to the injection side and the side of the dominant perivertebral venous system, and the possibility of connecting the IVE to a paravertebral vein may be in favor of vascular opacification. PMID- 28027735 TI - Comparison of T2* relaxation times of articular cartilage of the knee in elite professional football players and age-and BMI-matched amateur athletes. AB - OBJECTIVE: Recent investigation has underlined the potential of quantitative MR imaging to be used as a complementary tool for the diagnosis of cartilage degeneration at an early state. The presented study analyses T2* relaxation times of articular cartilage of the knee in professional athletes and compares the results to age- and BMI (Body Mass Index)-matched healthy amateur athletes. MATERIALS AND METHODS: 22 professional football players and 22 age- and BMI matched individuals were underwent knee Magnetic Resonance Imaging (MRI) at 3T including qualitative and quantitative analysis. Qualitative analysis included e.g. meniscal tears, joint effusion and bone edema. For quantitative analysis T2* (22 ET: 4.6-53.6ms) measurements in 3D data acquisition were performed. Deep and superficial layers of 22 predefined cartilage segments were analysed. All data sets were postprocessed using a dedicated software tool. Statistical analysis included Student t-test, confidence intervals and a random effects model. RESULTS: In both groups, T2* relaxation times were significantly higher in the superficial compared to the deep layers (p<0.001). Professional athletes had significantly higher relaxation times in eight superficial and three deep cartilage layers in the predefined cartilage segments (p<0.05). Highly significant differences were found in the weight-bearing segments of the lateral superficial femoral condyle (p<0.001). CONCLUSION: Elevated T2* values in cartilage layers of professional football players compared to amateur athletes were noted. The effects seem to predominate in superficial cartilage layers. PMID- 28027736 TI - Proton-density fat fraction measurement: A viable quantitative biomarker for differentiating adrenal adenomas from nonadenomas. AB - PURPOSE: This study aims to compare the accuracy of proton-density fat fraction (PDFF) measurements with chemical shift magnetic resonance imaging (CSI) for quantifying the fat content of adrenal nodules and for differentiating adenomas from nonadenomas. MATERIALS AND METHODS: Oil-saline phantom measurements was performed to compare the correlation between PDFF and CSI in detecting and quantifying fat content. 43 consecutive patients who had known adrenal nodules were imaged on a 3.0-T MR scanner. PDFF was measured, and the signal intensity (SI) index (SII), SI adrenal-to-liver ratio (ALR) and SI adrenal-to-spleen ratio (ASR) of the adrenal nodules were calculated. RESULTS: In the phantom study, PDFF ranged from 12.6% to 99.1% and the SII was between 0.72 and 1.23. There was good correlation between these two methods (R square=0.972, p<0.0001). The PDFF of adrenal adenoma was significantly increased compared with that of nonadenoma (p<0.001). PDFF was an effective tool for distinguishing adenoma from nonadenoma, with an area under the curve (AUC) of 0.98. In comparing SII, ALR and ASR the AUC was 0.94, 0.95 and 0.93, respectively. No significant difference was noted between these two methods (p>0.05). CONCLUSION: PDFF measurements provide an accurate estimation of fat content in discriminating adenomas from nonadenomas compared with CSI, avoiding complicated data calculations and offering a simpler technique using 3T. PMID- 28027737 TI - Diffusion MRI for rectal cancer staging: ADC measurements before and after ultrasonographic gel lumen distension. AB - OBJECTIVES: To compare Apparent Diffusion Coefficient (ADC) measurements in rectal neoplastic lesions before and after lumen distension obtained with sonography transmission gel. METHODS: From January 2014 to July 2016, 25 patients (average age 63.7, range 41-85, 18 males) were studied for pre-treatment rectal cancer staging using a 1.5T MRI. Diffusion MRI was obtained using echo-planar imaging with b=800 value; all patients were studied acquiring diffusion sequences with and without rectal lumen distension obtained using sonography transmission gel. In both diffusion sequences, two blinded readers calculated border ADC values and small ADC values, drawing regions of interest respectively along tumour borders and far from tumour borders. Mean ADC values among readers - for each type of ADC measurement - were compared using Wilcoxon matched pairs signed rank test. Correlation was assessed using Pearson analysis. RESULTS: Border ADC mean value for diffusion MR sequences without endorectal contrast was 1.122mm2/sec, with 95% Confidence Interval (CI)=1.02-1.22; using gel lumen distension, higher border ADC mean value of 1.269mm2/s (95% CI=1.16-1.38) was obtained. Wilcoxon matched pairs signed rank test revealed statistical difference (p<0.01); a strong Pearson correlation was reported, with r value of 0.69. Small ADC mean value was 1.038mm2/s (95% CI=0.91-1.16) for diffusion sequences acquired without endorectal distension and 1.127mm2/s (95% CI=0.98-1.27) for diffusion sequences obtained after endorectal gel lumen distension. Wilcoxon analysis did not show statistical difference (p=0.13). A very strong positive correlation was observed, with r value of 0.81. CONCLUSIONS: ADC measurements are slightly higher using endorectal sonographic transmission gel; ROI should be traced far from tumour borders, to minimize gel filled-pixel along the interface between lumen and lesion. Further studies are needed to investigate better reliability of ADC in rectal cancer MRI using sonographic gel intraluminal distension. PMID- 28027738 TI - Prostate cancer diagnosis: Efficacy of a simple electromagnetic MRI-TRUS fusion method to target biopsies. AB - OBJECTIVE: To assess that transrectal ultrasound guidance (TRUS) targeted biopsies (TB) aimed with an easy to use electronic real-time fusion registration device have a higher rate of prostate cancer (PC) detection than standard biopsies (SB). MATERIAL AND METHODS: This prospective study included 130 patients referred for TRUS biopsies after suspicious MRI. They underwent 16-core SB and 2 to 3 cores in each MRI suspicious area, using a fusion software. We noted SB and TB positivity for PC and Gleason score (GS). We used the McNemar test to compare SB and TB, with a statistical significance p<0.05. RESULTS: Among 130 patients, 68.5% had PC. Additional time due to the fusion registration was 3.3 min. One hundred fifteen patients (88.4%) had pathological findings on the histological analysis (prostate cancer n=89, others n=26). TB diagnosed PC in 75 patients with negative SB. Positivity rate for PC was significantly higher for TB than SB (p=0.03). Among highly suspicious MRI lesions, detection rate of histological abnormalities using SB and TB was 96% with 79.7% of PC. Most PC that TB diagnosed alone were clinically significant (86.3%). CONCLUSION: TRUS biopsies performed with a simple MRI and US electronic fusion is an unrestrainedly method to increase PC diagnosis. PMID- 28027739 TI - Intracranial arterial wall enhancement using gadolinium-enhanced 3D black-blood T1-weighted imaging. AB - PURPOSE: We investigated the enhancement of the intracranial arterial walls with gadolinium-enhanced, black-blood three-dimensional T1-weighted imaging (Gd-3DBB) by using an improved motion-sensitized driven-equilibrium (iMSDE)-prepared volumetric isotropic turbo spin-echo acquisition (VISTA). METHODS: A total of 115 patients underwent FLAIR, 3D-TOF-MRA and Gd-3DBB with a 1.5-T scanner. The degree and distribution of the arterial wall enhancement on Gd-3DBB was assessed. The association of the degree of wall enhancement with brain infarction/ischemic lesions on FLAIR, luminal changes on 3D-TOF-MRA, and cardiovascular risk factors (CVRFs) was investigated by univariate and multiple logistic regression analyses. RESULTS: Strong enhancement of the arterial walls was observed in 77 vertebral arteries (33.5%), 4 basilar arteries (3.5%), 31 supraclinoid internal carotid arteries (ICAs) (13.5%) and 8 middle cerebral arteries (3.5%). In addition, 221 intrapetrous ICAs (96.1%) showed strong enhancement. After adjusting for confounding factors, multivariate analyses showed that the patient age was independently associated with the strong wall enhancement of the arteries for both the posterior (OR, 1.088; 95% CI, 1.034-1.146) and the anterior circulation (OR, 1.098, 95% CI 1.029-1.172). In addition, the presence of the supratentorial brain infarctions was independently associated with the strong wall enhancement in the anterior circulation excluding the intrapetrous ICAs (OR, 4.097; 95% CI, 1.483-11.319). CONCLUSIONS: Although the arterial wall enhancement on the Gd-3DBB probably reflects normal aging, the enhancement in the anterior circulation might be related to brain infarctions. On the other hand, the intrapetrous ICA enhancement is considered a nonspecific finding and should not be mistaken for arterial pathologies such as atherosclerosis or arteritis. PMID- 28027740 TI - Awareness of radiation protection and dose levels of imaging procedures among medical students, radiography students, and radiology residents at an academic hospital: Results of a comprehensive survey. AB - PURPOSE: To evaluate the awareness of radiation protection issues and the knowledge of dose levels of imaging procedures among medical students, radiology residents, and radiography students at an academic hospital. MATERIAL AND METHODS: A total of 159 young doctors and students (including 60 radiology residents, 56 medical students, and 43 radiography students) were issued a questionnaire consisting of 16 multiple choice questions divided into three separated sections (i.e., demographic data, awareness about radiation protection issues, and knowledge about radiation dose levels of common radiological examinations). RESULTS: Medical students claimed to have at least a good knowledge of radiation protection issues more frequently than radiology residents and radiography students (94.4% vs 55% and 35.7%, respectively; P<0.05), with no cases of perceived excellent knowledge among radiography students. However, the actual knowledge of essential radiation protection topics such as regulations, patient and tissue susceptibility to radiation damage, professional radiation risk and dose optimisation, as well as of radiation doses delivered by common radiological procedures was significantly worse among medical students than radiology residents and radiography students (P<0.05). Those latter significantly outperformed radiology residents as to knowledge of radiation protection issues (P<0.01). Overall, less than 50% of survey respondents correctly answered all questions of the survey. CONCLUSIONS: Radiology residents, radiography students and medical students have a limited awareness about radiation protection, with a specific gap of knowledge concerning real radiation doses of daily radiological examinations. Both undergraduate and postgraduate teaching needs to be effectively implemented with radiation safety courses. PMID- 28027741 TI - Transarterial embolization (TAE) as add-on to percutaneous radiofrequency ablation (RFA) for the treatment of renal tumors: Review of the literature, overview of state-of-the-art embolization materials and further perspective of advanced image-guided tumor ablation. AB - Percutaneous radiofrequency ablation (RFA) for the treatment of stage I renal cell carcinoma has recently gained significant attention as the now available long-term and controlled data demonstrate that RFA can result in disease-free and cancer-specific survival comparable with partial and/or radical nephrectomy. In the non-controlled single center trials, however, the rates of treatment failure vary. Operator experience and ablation technique may explain some of the different outcomes. In the controlled trials, a major limitation is the lack of adequate randomization. In case reports, original series and overview articles, transarterial embolization (TAE) before percutaneous RFA was promising to increase tumor control and to reduce complications. The purpose of this study was to systematically review the literature on TAE as add-on to percutaneous RFA for renal tumors. Specific data regarding technique, tumor and patient characteristics as well as technical, clinical and oncologic outcomes have been analyzed. Additionally, an overview of state-of-the-art embolization materials and the radiological perspective of advanced image-guided tumor ablation (TA) will be discussed. In conclusion, TAE as add-on to percutaneous RFA is feasible and very effective and safe for the treatment of T1a tumors in difficult locations and T1b tumors. Advanced radiological techniques and technologies such as microwave ablation, innovative embolization materials and software-based solutions are now available, or will be available in the near future, to reduce the limitations of bland RFA. Clinical implementation is extremely important for performing image-guided TA as a highly standardized effective procedure even in the most challenging cases of localized renal tumors. PMID- 28027742 TI - Prognostic value of CT-derived left atrial and left ventricular measures in patients with acute chest pain. AB - PURPOSE: To determine which left atrial (LA) and left ventricular (LV) parameters are associated with future major adverse cardiac event (MACE) and whether these measurements have independent prognostic value beyond risk factors and computed tomography (CT)-derived coronary artery disease measures. MATERIALS AND METHODS: This retrospective analysis was performed under an IRB waiver and in HIPAA compliance. Subjects underwent coronary CT angiography (CCTA) using a dual-source CT system for acute chest pain evaluation. LV mass, LV ejection fraction (EF), LV end-systolic volume (ESV) and LV end-diastolic volume (EDV), LA ESV and LA diameter, septal wall thickness and cardiac chamber diameters were measured. MACE was defined as cardiac death, non-fatal myocardial infarction, unstable angina, or late revascularization. The association between cardiac CT measures and the occurrence of MACE was quantified using Cox proportional hazard analysis. RESULTS: 225 subjects (age, 56.2+/-11.2; 140 males) were analyzed, of whom 42 (18.7%) experienced a MACE during a median follow-up of 13 months. LA diameter (HR:1.07, 95%CI:1.01-1.13permm) and LV mass (HR:1.05, 95%CI:1.00-1.10perg) remained significant prognostic factor of MACE after controlling for Framingham risk score. LA diameter and LV mass were also found to have prognostic value independent of each other. The other morphologic and functional cardiac measures were no significant prognostic factors for MACE. CONCLUSION: CT-derived LA diameter and LV mass are associated with future MACE in patients undergoing evaluation for chest pain, and portend independent prognostic value beyond traditional risk factors, coronary calcium score, and obstructive coronary artery disease. PMID- 28027743 TI - IgG4-related cardiovascular disease. The emerging role of cardiovascular imaging. AB - Immunoglobulin 4-related disease (IgG4-related disease) is a systemic inflammatory disease that presents with increases of serum IgG4. It may affect various systems, including the cardiovascular (CV) system. Assessment of serum IgG4 levels and involved organ biopsy are necessary for diagnosis. IgG4-related disease is characterized by fibrosclerosis, lymphocytic infiltration and presence of IgG4-positive plasma cells. The disease usually responds to treatment with corticosteroids and/or immunosuppressive medication. CV involvement may manifest as cardiac pseudotumors, inflammatory periaortitis, coronary arteritis and/or pericarditis. IgG4-related cardiovascular disorders can severely affect patient prognosis. Various imaging techniques, including echocardiography, Computed Tomography (CT), 18FDG-PET, Cardiovascular Magnetic Resonance (CMR) and cardiac catheterisation, have been successfully used for early disease detection and follow-up. Echocardiography and vascular ultrasound are the most commonly used non-invasive, non-radiating imaging techniques for the evaluation of IgG4-related CV disease. Periaortitis/periarteritis can be also assessed by CT, showing a soft tissue thickening around arteries. Coronary artery aneurysms can be easily diagnosed by coronary CT. In case of active periarterial or coronary artery inflammation, 18FDG-PET will show FDG uptake at the area of the lesion. CMR, due to its capability to perform function and tissue characterisation, can offer an integrated imaging of aorta, coronary arteries and the heart, assessment of disease acuity, extent of fibrosis and guide further treatment. However, multimodality imaging may be necessary for assessment of disease activity and fibrosis extent in those cases with multifocal CV involvement. PMID- 28027744 TI - Prognostic value of pretreatment volume-based quantitative 18F-FDG PET/CT parameters in patients with malignant pleural mesothelioma. AB - PURPOSE: To investigate the relationships between pretreatment volume-based quantitative 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) parameters and overall survival (OS) in patients with malignant pleural mesothelioma (MPM). MATERIALS AND METHODS: We retrospectively reviewed data from 201 MPM patients, of whom 38 underwent surgical resection, and calculated the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), including primary tumors and nodal or distant metastatic lesions, on pretreatment 18F-FDG PET/CT. Relationships between clinicopathological factors (age, sex, performance status, European Organization for Research and Treatment of Cancer [EORTC] score, histological subtype, TNM stage, and treatment strategy), volume-based quantitative PET/CT parameters, and OS were evaluated using a Cox proportional hazards model and log-rank test. RESULTS: The median follow-up was 15 months (range, 1-96 months; median, 17 months). In a univariate analysis of all patients, older age (p<0.05), high EORTC score (p<0.001), non-epithelioid histological subtype (p<0.001), high T stage (p<0.001), positive N/M status (p<0.05, p<0.001), advanced TNM stage (p<0.001), non-surgical treatment (p<0.001), and high SUVmax (p<0.001), MTV (p<0.001), or TLG (p<0.001) were associated with significantly shorter OS. A multivariate analysis confirmed non-epithelioid subtype (hazard ratio [HR]: 1.69, 95% confidence interval [CI]: 1.14-2.48; p<0.05), non-surgical treatment (HR: 0.58, 95% CI: 0.34-0.95; p<0.05), and high TLG (HR: 1.97, 95% CI: 1.14-3.44; p<0.05) as independent negative predictors. CONCLUSIONS: Pretreatment volume-based quantitative 18F-FDG PET/CT parameters, especially TLG, could serve as potential surrogate markers for MPM prognosis. PMID- 28027745 TI - Contrast monitoring techniques in CT pulmonary angiography: An important and underappreciated contributor to breast dose. AB - OBJECTIVE: The aims of our study were to evaluate the contribution of contrast monitoring techniques to breast dose in pregnant and non-pregnant women, and to investigate the effect of a reduced peak kilovoltage (kV) monitoring scan protocol on breast dose and Computed Tomography Pulmonary Angiography (CTPA) diagnostic quality. MATERIALS AND METHODS: Single center retrospective study of 221 female patients undergoing a reduced kV 80kV contrast-monitoring CTPA protocol compared to 281 patients using the conventional 120kV contrast monitoring protocol (Siemens Somatom Definition AS+). 99 pregnant patients analyzed separately. ImPACT dosimetry software was used to calculate dose. Group subsets were evaluated to assess CTPA diagnostic quality. RESULTS: The contrast monitoring component of a CTPA study constituted 27% of the overall breast dose when using a standard 120kV protocol compared to only 7% of the overall breast dose in the 80kV study group. The dose to the breast from the contrast-monitoring component alone was reduced by 79% in the non-pregnant patients (0.36mGy+/-0.37 versus 1.7mGy+/-1.02; p<0.001), and by 88% in the pregnant population (0.25mGy+/ 0.67 versus 2.24mGy+/-1.61; p<0.001). There was no statistical difference in CTPA diagnostic quality or timing. CONCLUSION: Despite a short scan length and relatively small DLP, contrast-monitoring techniques (test-bolus or bolus tracked) set at 120kV can account for 27% of the overall breast dose accrued from a CTPA study. By decreasing the kilovoltage of the contrast-monitoring component, a significant reduction in breast dose for pregnant and non-pregnant female patients can be achieved without affecting CTPA quality or timing. PMID- 28027747 TI - Imaging findings of Kaposiform Hemangioendothelioma in children. AB - PURPOSE: Kaposiform hemangioendothelioma (KHE) is a rare, aggressive vascular tumor that typically occurs during infancy or early childhood. Though several case reports have discussed the imaging findings of KHE, larger comprehensive studies are lacking. The purpose of this study was to evaluate the imaging findings of KHE in children. MATERIALS AND METHODS: A total of twelve cases of pathologically proven KHE were collected by searching our institution's pathology database for children diagnosed between January 2004 and April 2016 (6 male, 6 female; median age: 3 months; age range 7days - 18 years). CT (n=7) and MRI (n=9) findings were retrospectively evaluated. The location, morphology, enhancement, and growth pattern were analyzed. RESULTS: KHEs involved various locations: superficial or deep soft tissue of the extremities (n=4); abdomen (n=3; 2 cases, pancreas; 1 case, small bowel), neck and mediastinum (n=1); chest wall, diaphragm, and pericardium (n=1); abdominal wall (n=1); and head (IAC, CP angle) (n=2). Eight of 10 cases (80%) with CT/MR findings were locally invasive and involved two or more adjacent organs. Three cases presented as well-defined solid masses, and seven were associated with infiltrative lesions of the surrounding areas with (n=4) or without definite solid regions (n=3). In nine patients with MRI, all KHEs were heterogeneous and hyperintense to muscles on T2-weighted images (T2WI), while four KHEs consisted of some regions that were nearly isointense to muscle. Eight of the 10 cases with imaging exhibited heterogeneous intense enhancement, while only one demonstrated mild enhancement. Signal voids (n=2), engorged vessels (n=1), calcification (n=3), hemorrhage (n=1), or bone changes (n=4) were infrequently observed. Four patients (33%) had Kasabach Merritt phenomenon, and recurrence was observed in two cases. CONCLUSION: KHEs occurred in various locations, affected mostly infants, and generally exhibited intense heterogeneous enhancement. In more than half of the included cases, KHEs were highly infiltrative and locally invasive with ill-defined margins. Awareness of these features should prompt radiologists to include KHE in the differential diagnosis for pediatric masses. PMID- 28027746 TI - Image quality of ct angiography using model-based iterative reconstruction in infants with congenital heart disease: Comparison with filtered back projection and hybrid iterative reconstruction. AB - PURPOSE: To compare the image quality, rate of coronary artery visualization and diagnostic accuracy of 256-slice multi-detector computed tomography angiography (CTA) with prospective electrocardiographic (ECG) triggering at a tube voltage of 80kVp between 3 reconstruction algorithms (filtered back projection (FBP), hybrid iterative reconstruction (iDose4) and iterative model reconstruction (IMR)) in infants with congenital heart disease (CHD). METHODS: Fifty-one infants with CHD who underwent cardiac CTA in our institution between December 2014 and March 2015 were included. The effective radiation doses were calculated. Imaging data were reconstructed using the FBP, iDose4 and IMR algorithms. Parameters of objective image quality (noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR)); subjective image quality (overall image quality, image noise and margin sharpness); coronary artery visibility; and diagnostic accuracy for the three algorithms were measured and compared. RESULTS: The mean effective radiation dose was 0.61+/-0.32 mSv. Compared to FBP and iDose4, IMR yielded significantly lower noise (P<0.01), higher SNR and CNR values (P<0.01), and a greater subjective image quality score (P<0.01). The total number of coronary segments visualized was significantly higher for both iDose4 and IMR than for FBP (P=0.002 and P=0.025, respectively), but there was no significant difference in this parameter between iDose4 and IMR (P=0.397). There was no significant difference in the diagnostic accuracy between the FBP, iDose4 and IMR algorithms (chi2=0.343, P=0.842). CONCLUSIONS: For infants with CHD undergoing cardiac CTA, the IMR reconstruction algorithm provided significantly increased objective and subjective image quality compared with the FBP and iDose4 algorithms. However, IMR did not improve the diagnostic accuracy or coronary artery visualization compared with iDose4. PMID- 28027748 TI - Intra-individual comparison of CAIPIRINHA VIBE technique with conventional VIBE sequences in contrast-enhanced MRI of focal liver lesions. AB - PURPOSE: To evaluate the impact of controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) volume interpolated breath-hold examination (VIBE) magnetic resonance imaging (MRI) technique on image quality, reader confidence, and inter-observer agreement for the assessment of focal liver lesions in comparison with the standard VIBE approach. MATERIAL AND METHODS: In this IRB-approved intra-individual comparison study, abdominal arterial and portal-venous contrast-enhanced MRI studies were retrospectively analyzed in 38 patients with malignant liver lesions. Each patient underwent both CAIPIRINHA and conventional VIBE 3T MRI within 3 months, showing stable disease. Images were evaluated using 5-point rating scales by two blinded radiologists with more than 20 and 5 years of experience in MRI, respectively. Readers scored dignity of liver lesions and assessed which liver segments were affected by malignancy (ranging from 1=definitely benign/not affected to 5=definitely malignant/affected by malignancy). Readers also rated overall image quality, sharpness of intrahepatic veins, and diagnostic confidence (ranging from 1=poor to 5=excellent). RESULTS: Reviewers achieved a higher inter-observer reliability using CAIPIRINHA when they reported which liver segments were affected by malignancy compared to traditional VIBE series (kappa=0.62 and 0.54, respectively, p<0.05). Similarly, CAIPIRINHA showed a slightly higher inter-rater agreement for the dignity of focal liver lesions versus the standard VIBE images (kappa=0.50 and 0.49, respectively, p<0.05). CAIPIRINHA series also scored higher in comparison to standard VIBE sequences (mean scores: image quality, 4.2 and 3.5; sharpness of intrahepatic vessels, 3.8 and 3.2, respectively, p<0.05) for both reviewers and allowed for higher subjective diagnostic confidence (ratings, 3.8 and 3.2, respectively, p<0.05). CONCLUSION: Compared to the standard VIBE approach, CAIPIRINHA VIBE technique provides improved image quality and sharpness of intrahepatic veins, as well as higher diagnostic confidence. Additionally, this technique allows for higher inter-observer agreement when reporting focal liver lesions for both dignity and allocation. PMID- 28027749 TI - Pancreatic cancer in patients with chronic calcifying pancreatitis: Computed tomography findings - a retrospective analysis of 48 patients. AB - OBJECTIVE: Chronic calcifying pancreatitis (CCP) is a risk factor for pancreatic cancer (PC). Symptoms of PC are non-specific in patients with CCP, and diagnostic imaging can be difficult. Some studies have shown that diagnosis may take several months, leading to delays in treatment (Lin et al., 2015; Lennon et al., 2014) [2,3]. The aim of this study was to describe the radiological signs of PC in patients with CCP. METHODS: This retrospective, single-center study was conducted between January 2004 and December 2014. Patients with CCP who were being monitored for PC were included. Each patient diagnosed with PC was matched with two CCP controls who did not develop PC. RESULTS: We studied 48 patients with CCP (30 men (62%) and 18 women (38%), mean age 69.4 years). Sixteen patients (with 18 tumor sites) who developed PC (1.52%) were compared with 32 controls who did not develop PC. A hypodense mass was observed in all of the patients with PC, predominantly in the pancreatic head (61.2%). No such masses were observed in the controls (p<0.001). The average mass size was 36.3mm, and the masses were observed to push aside the calcifications in all patients (p<0.001). Calcifications were very abundant (>10) in 33.3% of the patients with PC and in 71.9% of the controls (p=0.0076). The main pancreatic duct (MPD) was dilated in all of the patients with PC (average diameter 8.6mm; homogeneous in 83.3%) and in only 46.9% of the controls (average 7.4mm; homogeneous in 37.5%) (p>0.05). Dilation of the intrahepatic bile ducts and common bile duct was observed in 15 (94.4%) of the patients with PC and in none of the controls (p<0.0001). The average alcohol consumption was 1g/day (0-5g/day) in the PC group and 4.6g/day (0 20g/day) in the control group. In addition, the average smoking history was 14.25 pack-years (0-40 PY) in the PC group and 27.70 PY (0-60 PY) in the control group. CONCLUSION: The presence of a pancreatic mass in a patient with CCP is suggestive of malignancy, especially when few pancreatic calcifications are observed (that are pushed aside by the tumor) and when the tumor causes dilation of the common bile duct and main pancreatic duct. PMID- 28027750 TI - Multi-parametric quantification of tricuspid regurgitation using cardiovascular magnetic resonance: A comparison to echocardiography. AB - BACKGROUND: Velocity-encoding is used to quantify tricuspid regurgitation (TR) by cardiovascular magnetic resonance (CMR), but requires additional dedicated imaging. We hypothesized that size and signal intensity (SI) of the cross sectional TR jet area in the right atrium in short-axis steady-state free precession images could be used to assess TR severity. METHODS: We studied 61 patients with TR, who underwent CMR and echocardiography within 24h. TR severity was determined by vena contracta: severe (N=20), moderate or mild (N=41). CMR TR jet area and normalized SI were measured in the plane and frame that depicted maximum area. ROC analysis was performed in 21/61 patients to determine diagnostic accuracy of differentiating degrees of TR. Optimal cutoffs were independently tested in the remaining 40 patients. RESULTS: Measurable regions of signal loss depicting TR jets were noted in 51/61 patients, while 9/10 remaining patients had mild TR by echocardiography. With increasing TR severity, jet area significantly increased (15+/-14 to 38+/-20mm2), while normalized SI decreased (57+/-27 to 23+/-11). ROC analysis showed high AUC values in the derivation group and good accuracy in the test group. CONCLUSION: TR can be quantified from short axis CMR images in agreement with echocardiography, while circumventing additional image acquisition. PMID- 28027751 TI - A matrix of morphology and distribution of calcifications in the breast: Analysis of 849 vacuum-assisted biopsies. AB - OBJECTIVE: The purpose of this retrospective analysis was to evaluate the likelihood of malignancy in prospectively categorized BI-RADS 4 and BI-RADS 5 calcifications. MATERIAL AND METHODS: This analysis included 849 women who underwent vacuum biopsy for BI-RADS 4 (with the subgroups 4A, 4B and 4C) or BI RADS 5 calcifications between February 2007 and May 2015. Calcifications were classified according to the morphology and distribution descriptors of the BI RADS lexicon (BI-RADS 4th edition lexicon). A standardized scheme (matrix) was used to combine the characteristics of the grouped calcifications with the BI RADS assessment category. RESULTS: Overall, 275/849 (32%) lesions were found to be malignant. 285/327/208/29 calcified lesions were prospectively classified as BI-RADS 4A/4B/4C/5 indicating a risk for malignancy of 16%/27%/55%/90%, respectively. The morphology descriptors predicted the risk for malignancy as follows: typically benign (n=55): 2%; indeterminate (n=676): 27%; typically malignant (n=118): 80%. The distribution descriptors correlated with a malignant histology as follows: diffuse (n=0); round or oval (n=261): 22%; regional (n=398): 33%; segmental (n=106): 42%; linear or branching (n=85): 55%. There was a significant difference between the descriptor categories (p<0.0001). CONCLUSION: A standard scheme combining the morphology and distribution characteristics proved to be a helpful tool in diagnosis of calcifications, bridging the gap between description and classification of these lesions. PMID- 28027752 TI - Optimal timing of image acquisition for arterial first pass CT myocardial perfusion imaging. AB - PURPOSE: To determine the optimal timing of arterial first pass computed tomography (CT) myocardial perfusion imaging (CTMPI) based on dynamic CTMPI acquisitions. METHODS AND MATERIALS: Twenty-five patients (59+/-8.4years, 14 male)underwent adenosine-stress dynamic CTMPI on second-generation dual-source CT in shuttle mode (30s at 100kV and 300mAs). Stress perfusion magnetic resonance imaging (MRI) was used as reference standard for differentiation of non-ischemic and ischemic segments. The left ventricle (LV) wall was manually segmented according to the AHA 16-segment model. Hounsfield units (HU) in myocardial segments and ascending (AA) and descending aorta (AD) were monitored over time. Time difference between peak AA and peak AD and peak myocardial enhancement was calculated, as well as the, time delay from fixed HU thresholds of 150 and 250 HU in the AA and AD to a minimal difference of 15 HU between normal and ischemic segments. Furthermore, the duration of the 15 HU difference between ischemic and non-ischemic segments was calculated. RESULTS: Myocardial ischemia was observed by MRI in 10 patients (56.3+/-9.0years; 8 male). The delay between the maximum HU in the AA and AD and maximal HU in the non-ischemic segments was 2.8s [2.2-4.3] and 0.0s [0.0-2.8], respectively. Differentiation between ischemic and non ischemic myocardial segments in CT was best during a time window of 8.6+/-3.8s. Time delays for AA triggering were 4.5s [2.2-5.6] and 2.2s [0-2.8] for the 150 HU and 250 HU thresholds, respectively. While for AD triggering, time delays were 2.4s [0.0-4.8] and 0.0s [-2.2-2.6] for the 150 HU and 250 HU thresholds, respectively. CONCLUSION: In CTMPI, the differentiation between normal and ischemic myocardium is best accomplished during a time interval of 8.6+/-3.8s. This time window can be utilized by a test bolus or bolus tracking in the AA or AD using the time delays identified here. PMID- 28027753 TI - Liver failure after hepatectomy: A risk assessment using the pre-hepatectomy shear wave elastography technique. AB - OBJECTIVE: To determine the efficacy of liver stiffness (LS) measurements utilizing the Shear Wave Elastography (SWE) technique for predicting post hepatectomy liver failure (PHLF) among patients with hepatocellular carcinoma (HCC). METHODS: Data from eighty consecutive patients who were undergoing hepatectomy for HCC were prospectively identified and evaluated with preoperative SWE. The SWE was measured with advanced ultrasound equipment (Philips EPIQ7; Philips Healthcare, Seattle, WA, USA). PHLF classification was defined according to the International Study Group of Liver Surgery Recommendations (ISGLS). RESULTS: SWE was successfully performed in 77 patients. According to the ISGLS criteria, PHLF occurred in 35.1% of patients (27 patients), including 2/25 patients with Grade A/B, respectively. Elevated SWE values (P=0.002) and histological cirrhosis (P=0.003) were independent predictors of PHLF according to the multivariate analysis. Patients with SWE values higher than or equal to 6.9kPa were identified at higher risk of PHLF (area under the curve: 0.843, sensitivity: 77.8% and specificity: 78.0%). Postoperative dynamic course of the median the Model For End-stage Liver Disease (MELD) score showed irregular changes among patients with an SWE >6.9kPa. Patients with an SWE <6.9kPa, postoperative dynamic course of the median MELD score gradually decreased. CONCLUSION: LS measured with SWE is a valid and reliable method for the prediction of PHLF grade A/B among patients with HCC. SWE could become a routine examination for the preoperative evaluation of PHLF. PMID- 28027754 TI - Correlation between intravoxel incoherent motion MR parameters and MR nodular grade of parotid glands in patients with Sjogren's syndrome: A pilot study. AB - PURPOSE: To explore the correlation between intravoxel incoherent motion (IVIM) magnetic resonance (MR) parameters and MR nodular grade of parotid glands in patients with Sjogren's syndrome (SS). MATERIALS AND METHODS: A total of 31 consecutive patients with SS and 28 gender- and age-matched healthy volunteers underwent bilateral parotid 3.0T MR examination including the IVIM sequence (9 b values, 0-800s/mm2). The apparent diffusion coefficient (ADC), diffusion coefficient D, pseudo-diffusion coefficient D*, and perfusion fraction f of bilateral parotid glands were obtained, and the nodular grade of each parotid gland was evaluated according to the MR morphological appearance. RESULTS: Sixty two parotid glands in 31 patients with SS consisted of 32, 14, 8, and 8 parotid glands at MR nodular grades 0, 1, 2, and 3, respectively. In parotid glands of grade 0, 1, 2, 3 and healthy volunteers, the ADC values were (1.13+/-0.25, 1.11+/ 0.17, 1.05+/-0.24, 0.89+/-0.04 and 1.00+/-0.21)*10-3mm2/s, D values were (0.92+/ 0.13, 0.90+/-0.19, 0.90+/-0.03, 0.67+/-0.03, 0.81+/-0.03)*10-3mm2/s, f values were 0.20+/-0.04, 0.18+/-0.02, 0.15+/-0.01, 0.11+/-0.01, 0.15+/-0.06, and D*values were (53.89+/-28.26, 41.78+/-16.35, 51.24+/-18.69, 31.83+/-18.03, 36.83+/-16.14)*10-3mm2/s respectively. The ADC, D, f, and D* values of parotid glands in patients with SS at grade 0 were significantly higher than those in healthy volunteers (all P<0.05). Significant differences were observed in the D and f values of parotid glands in patients with SS among different grades (P=0.003,<0.001, respectively). The IVIM parameters (D, f) of parotid glands at early (grades 0-1) and advanced (grades 2-3) stages in patients with SS were significantly higher and lower, respectively, than those in healthy volunteers (all P<0.05). The D and f values inversely correlated with MR nodular grades significantly (r=- 0.297, P=0.019; r=- 0.653, P<0.001, respectively) CONCLUSION: The parotid glands with different MR nodular grades in patients with SS showed different IVIM parameters, reflecting different pathophysiological characteristics of parotid glands at different stages. PMID- 28027755 TI - A preliminary study of shear wave elastography for the evaluation of unilateral palpable undescended testes. AB - OBJECTIVES: We sought to compare unilateral palpable undescended testes and contralateral descended testes using shear wave elastography (SWE) to show potential quantitative differences in elasticity patterns, which might reflect the histologic features. METHODS: Approval for this prospective study was obtained from the local ethics committee. A total of 29 patients (mean age, 7.52 years; range, 1-18 years) with unilateral palpable undescended testes and contralateral descended testes were examined by greyscale ultrasonography and SWE between February 2015 and April 2016. The volume and the elasticity of each testicle were the main factors evaluated. RESULTS: There was no difference between undescended testes and contralateral descended testes in terms of volume. However, a significant difference was evident in SWE-derived quantitative data. CONCLUSIONS: SWE seems to be a useful sonographic technique to predict histologic features of the undescended testicle, which might replace testicular biopsy in modern management of the undescended testis. PMID- 28027756 TI - T1 relaxation time constants, influence of oxygen, and the oxygen transfer function of the human lung at 1.5T-A meta-analysis. AB - PURPOSE: To pool and summarize published data from magnetic resonance longitudinal relaxation measurements of the human lung at 1.5T to provide a reliable basis of T1 relaxation time constants of healthy lung tissue both under respiration of room air and of pure oxygen. In particular, the oxygen-induced shortening of T1 was evaluated. MATERIALS AND METHODS: The PubMed database was comprehensively searched up to June 2016 for original publications in English containing quantitative T1 data (at least mean values and standard deviations) of the lung parenchyma of healthy subjects (minimum subject number: 3) at 1.5T. From all included publications, T1 values of the lung of healthy subjects were extracted (inhaling room air and, if available, inhaling pure oxygen). Weighted mean values and standard deviations of all extracted data and the oxygen transfer function (OTF) were calculated. RESULTS: 22 publications were included with a total number of 188 examined healthy subjects. 103 of these subjects (from 13 studies) were examined while breathing pure oxygen and room air; 85 subjects were examined only under room-air conditions. The weighted mean value (weighted sample standard deviation) of the room-air T1 values over all 22 studies was 1196ms (152ms). Based on studies with room-air and oxygen results, the mean T1 value at room-air conditions was 1172ms (161ms); breathing pure oxygen, the mean T1 value was reduced to 1054ms (138 ms). This corresponds to a mean T1 reduction by 118ms (35ms) or 10.0 % (2.3 %) and to a mean OTF value of 1.22 (0.32)*10-3s-1/(%O2). CONCLUSION: This meta-analysis with data from 188 subjects indicates that the average T1 relaxation time constant of healthy lung tissue at 1.5T is distributed around 1200ms with a standard deviation of about 150 ms; breathing pure oxygen reduces this value significantly by 10 % to about 1050 ms. PMID- 28027757 TI - Free-breathing dynamic liver examination using a radial 3D T1-weighted gradient echo sequence with moderate undersampling for patients with limited breath holding capacity. AB - PURPOSE: To compare free-breathing radial VIBE with moderate undersampling (us radial-VIBE) with a standard breathhold T1-weighted volumetric interpolated sequence (3D GRE VIBE) in patients unable to suspend respiration during dynamic liver examination. MATERIAL AND METHODS: 23 consecutive patients underwent dynamic liver MR examination using the free-breathing us-radial-VIBE sequence as part of their oncologic follow-up. All patients were eligible for the free breathing protocol due to severe respiratory artifacts at the planning or precontrast sequences. The us-radial-VIBE acquisitions were compared to the patients last staging liver MRI including a standard breathhold 3D GRE VIBE. For an objective image evaluation, signal intensity (SI), image noise (IN), signal-to noise ratio (SNR) and contrast-enhancement ratio (CER) were compared. Representative image quality parameters, including typical artifacts were independently, retrospectively and blindly scored by four readers. RESULTS: Us radial-VIBE had significant lower SNR (p<0.0001) and higher IN (p<0.0001), whereas SI did not differ (p=0.62). Temporal resolution assessed with CER in the arterial phase showed higher values for us-radial-VIBE (p=0.028). Subjective image quality parameters received generally slightly higher scores for 3D GRE VIBE. In a smaller subgroup comprising patients with severe respiratory artifacts also at reference breathhold 3D GRE VIBE examination, us-radial-VIBE showed significantly higher image quality scores. Furthermore, there were generally more severe respiratory artifacts in 3D GRE VIBE, whereas streaking was characteristic in almost all us-radial-VIBE acquisitions but did not affect diagnostic validity. CONCLUSION: Free-breathing dynamic liver imaging using us-radial-VIBE delivers accurate temporal resolution, low motion artifact susceptibility and good image quality and represents a promising alternative in patients unable to suspend respiration. PMID- 28027758 TI - Role of pharmacokinetic parameters derived with high temporal resolution DCE MRI using simultaneous PET/MRI system in breast cancer: A feasibility study. AB - PURPOSE: To evaluate the reliability of pharmacokinetic parameters like Ktrans, Kep and ve derived through DCE MRI breast protocol using 3T Simultaneous PET/MRI (3Tesla Positron Emission Tomography/Magnetic Resonance Imaging) system in distinguishing benign and malignant lesions. MATERIALS AND METHODS: High temporal resolution DCE (Dynamic Contrast Enhancement) MRI performed as routine breast MRI for diagnosis or as a part of PET/MRI for cancer staging using a 3T simultaneous PET/MRI system in 98 women having 109 breast lesions were analyzed for calculation of pharmacokinetic parameters (Ktrans, ve, and Kep) at 60s time point using an in-house developed computation scheme. RESULTS: Receiver operating characteristic (ROC) curve analysis revealed a cut off value for Ktrans, Kep, ve as 0.50, 2.59, 0.15 respectively which reliably distinguished benign and malignant breast lesions. Data analysis revealed an overall accuracy of 94.50%, 79.82% and 87.16% for Ktrans, Kep, ve respectively. Introduction of native T1 normalization with an externally placed phantom showed a higher accuracy (94.50%) than without native T1 normalization (93.50%) with an increase in specificity of 87% vs 84%. CONCLUSION: Overall the results indicate that reliable measurement of pharmacokinetic parameters with reduced acquisition time is feasible in a 3TMRI embedded PET/MRI system with reasonable accuracy and application may be extended to exploit the potential of simultaneous PET/MRI in further work on breast cancer. PMID- 28027759 TI - Imaging features of automated breast volume scanner: Correlation with molecular subtypes of breast cancer. AB - OBJECTIVES: To investigate the correlation between the imaging features obtained by an automated breast volume scanner (ABVS) and molecular subtypes of breast cancer. METHODS: We examined 303 malignant breast tumours by ABVS for specific imaging features and by immunohistochemical analysis to determine the molecular subtype. ABVS imaging features, including retraction phenomenon, shape, margins, echogenicity, post-acoustic features, echogenic halo, and calcifications were analysed by univariate and multivariate logistic regression analyses to determine the significant predictive factors of the molecular subtypes. RESULTS: By univariate logistic regression analysis, the predictive factors of the Luminal-A subtype (n=128) were retraction phenomenon (odds ratio [OR]=10.188), post acoustic shadowing (OR=5.112), and echogenic halo (OR=3.263, P<0.001). The predictive factors of the Human-epidermal-growth-factor-receptor-2-amplified subtype (n=39) were calcifications (OR=6.210), absence of retraction phenomenon (OR=4.375), non-mass lesions (OR=4.286, P<0.001), absence of echogenic halo (OR=3.851, P=0.035), and post-acoustic enhancement (OR=3.641, P=0.008). The predictors for the Triple-Negative subtype (n=47) were absence of retraction phenomenon (OR=5.884), post-acoustic enhancement (OR=5.255, P<0.001), absence of echogenic halo (OR=4.138, P=0.002), and absence of calcifications (OR=3.363, P=0.001). Predictors for the Luminal-B subtype (n=89) had a relatively lower association (OR<=2.328). By multivariate logistic regression analysis, retraction phenomenon was the strongest independent predictor for the Luminal-A subtype (OR=9.063, P<0.001) when present and for the Triple-Negative subtype (OR=4.875, P<0.001) when absent. CONCLUSIONS: ABVS imaging features, especially retraction phenomenon, have a strong correlation with the molecular subtypes, expanding the scope of ultrasound in identifying breast cancer subtypes with confidence. PMID- 28027760 TI - CT angiography for planning transcatheter aortic valve replacement using automated tube voltage selection: Image quality and radiation exposure. AB - PURPOSE: To assess image quality and accuracy of CT angiography (CTA) for transcatheter aortic valve replacement (TAVR) planning performed with 3rd generation dual-source CT (DSCT). MATERIAL AND METHODS: We evaluated 125 patients who underwent TAVR-planning CTA on 3rd generation DSCT. A two-part protocol was performed including retrospectively ECG-gated coronary CTA (CCTA) and prospectively ECG-triggered aortoiliac CTA using 60mL of contrast medium. Automated tube voltage selection and advanced iterative reconstruction were applied. Effective dose (ED), signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were calculated. Five-point scales were used for subjective image quality analysis. In patients who underwent TAVR, sizing parameters were obtained. RESULTS: Image quality was rated good to excellent in 97.6% of CCTA and 100% of aortoiliac CTAs. CTA studies at >100kV showed decreased objective image quality compared to 70-100kV (SNR, all p<=0.0459; CNR, all p<=0.0462). Mean ED increased continuously from 70 to >100kV (CCTA: 4.5+/-1.7mSv-13.6+/-2.9mSv, all p<=0.0233; aortoiliac CTA: 2.4+/-0.9mSv-6.8+/-2.7mSv, all p<=0.0414). In 39 patients TAVR was performed and annulus diameter was within the recommended range in all patients. No severe cardiac or vascular complications were noted. CONCLUSION: 3rd generation DSCT provides diagnostic image quality in TAVR-planning CTA and facilitates reliable assessment of TAVR device and delivery option while reducing radiation dose. PMID- 28027761 TI - Radiation dose reduction during transjugular intrahepatic portosystemic shunt implantation using a new imaging technology. AB - OBJECTIVE: To compare patient radiation dose in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) implantation before and after an imaging processing technology upgrade. METHODS: In our retrospective single-center-study, cumulative air kerma (AK), cumulative dose area product (DAP), total fluoroscopy time and contrast agent were collected from an age- and BMI-matched collective of 108 patients undergoing TIPS implantation. 54 procedures were performed before and 54 after the technology upgrade. Mean values were calculated and compared using two-tailed t-tests. Two blinded, independent readers assessed DSA image quality using a four-rank likert scale and the Wilcoxcon test. RESULTS: The new technology demonstrated a significant reduction of 57% of mean DAP (402.8 vs. 173.3Gycm2, p<0.001) and a significant reduction of 58% of mean AK (1.7 vs. 0.7Gy, p<0.001) compared to the precursor technology. Time of fluoroscopy (26.4 vs. 27.8min, p=0.45) and amount of contrast agent (109.4 vs. 114.9ml, p=0.62) did not differ significantly between the two groups. The DSA image quality of the new technology was not inferior (2.66 vs. 2.77, p=0.56). CONCLUSIONS: In our study the new imaging technology halved radiation dose in patients undergoing TIPS maintaining sufficient image quality without a significant increase in radiation time or contrast consumption. PMID- 28027762 TI - Pressure-standardised mammography does not affect visibility, contrast and sharpness of stable lesions. AB - INTRODUCTION: A recent technological development allows pressure-standardised mammography by personalizing the compression force to the breast size and firmness. The technique has been shown to reduce pain and compression variability between consecutive exams, but also results in a slightly thicker compressed breast during exposure. This raises the question whether visibility, contrast and sharpness of lesions are affected? METHODS: Four experienced radiologists compared 188 stable lesions and structures including (clusters of) calcifications, (oil) cysts and lymph nodes that were visible in mammograms obtained in 2009 with a pain-tolerance limited 18 daN target force compression protocol, and in 2014/2015 obtained with a 10kPa (75mmHg) pressure-standardised compression protocol. Observers were blinded for all DICOM metadata and rated which of the randomly ordered, side by side presented images had better lesion visibility, contrast and sharpness, or whether they saw no difference. They also indicated which overall image they preferred, if any, and whether the non preferred image was still adequate. Statistical non-inferiority is concluded when the lower limit of the 95% confidence interval of the 4-rater averaged 'new protocol better' proportions exceed the non-inferiority limit of 0.463. RESULTS: In 2014/2015, the compressions were significantly milder, with on average 17% (mediolateral oblique) to 29% (craniocaudal) lower forces. Breasts remained on average 2.4% (1.4mm) thicker. Dose was significantly lower (6.5%), which is explained by glandular atrophy. The 95% confidence interval lower limits are 0.479 for visibility, 0.473 for contrast, 0.488 for sharpness and 0.486 for preference, all exceeding the non-inferiority limit. Of the 60 non-preferred mammograms, multiple observers found only five to be inadequate: 4 obtained with the force protocol and 1 with the pressure protocol. CONCLUSION: Pain-reduced mammography with 10kPa pressure-standardised compression has non-inferior visibility, contrast and sharpness for stable lesions compared to pain-tolerance limited 18daN target force compression. PMID- 28027763 TI - Increased interreader agreement in diagnosis of hepatocellular carcinoma using an adapted LI-RADS algorithm. AB - PURPOSE: To evaluate a simplified Liver Imaging Reporting and Data System (LI RADS) algorithm to improve interreader agreement while maintaining diagnostic performance for HCC. MATERIALS AND METHODS: MRI scans of 84 cirrhotic patients with 104 distinct liver observations were retrospectively selected to equivocally match each of the LI-RADS grades (LR1-5) using histopathology and imaging follow up as standard of reference. Four independent radiologists categorized all observations as benign (LR1-2) or potentially malignant (LR3-5) and determined LI RADS based imaging features including observation size, arterial phase hyperenhancement, washout, capsule appearance and threshold growth for LR3-5 observations and timed their readouts. LR3-5 observations were categorized according to the LI-RADS v2014 algorithm and according to a modified LI-RADS (mLI RADS) version. Diagnostic performance and Interreader agreement were determined for LI-RADS and mLI-RADS using receiver operating characteristics (ROC) and Fleiss' and Cohen's Kappa analysis respectively. RESULTS: ROC analysis revealed equal diagnostic performance for LI-RADS and mLI-RADS (area under the ROC curve=0.91). Interreader agreement was higher using mLI-RADS as compared to current LI-RADS showing an improved overall (kappa=0.53+/-0.04 vs. 0.45+/-0.04), and pair-wise agreement between most readers (kappa range 0.44-0.62 vs. 0.35 0.60) at a reduced median evaluation time (51 vs. 62s per observation, p<0.0001). CONCLUSION: Focusing on observation size and washout criteria using a modified, stepwise LI-RADS decision tree for LR3-5 observations results in higher interobserver reliability and faster categorization while maintaining diagnostic accuracy. PMID- 28027764 TI - Xenon-enhanced CT using subtraction CT: Basic and preliminary clinical studies for comparison of its efficacy with that of dual-energy CT and ventilation SPECT/CT to assess regional ventilation and pulmonary functional loss in smokers. AB - PURPOSE: To prospectively and directly compare the capability for assessments of regional ventilation and pulmonary functional loss in smokers of xenon ventilation CT obtained with the dual-energy CT (DE-CT) and subtraction CT (Sub CT) MATERIALS AND METHODS: Twenty-three consecutive smokers (15 men and 8 women, mean age: 69.7+/-8.7years) underwent prospective unenhanced and xenon-enhanced CTs, the latter by Sub-CT and DE-CT methods, ventilation SPECT and pulmonary function tests. Sub-CT was generated from unenhanced and xenon-enhanced CT, and all co-registered SPECT/CT data were produced from SPECT and unenhanced CT data. For each method, regional ventilation was assessed by using a 11-point scoring system on a per-lobe basis. To determine the functional lung volume by each method, it was also calculated for individual sublets with a previously reported method. To determine inter-observer agreement for each method, ventilation defect assessment was evaluated by using the chi2 test with weighted kappa statistics. For evaluation of the efficacy of each method for pulmonary functional loss assessment, functional lung volume was correlated with%FEV1. RESULTS: Each inter observer agreement was rated as substantial (Sub-CT: kappa=0.69, p<0.0001; DE-CT: kappa=0.64, p<0.0001; SPECT/CT: kappa=0.64, p<0.0001). Functional lung volume for each method showed significant to good correlation with%FEV1 (Sub-CT: r=0.72, p=0.0001; DE-CT: r=0.74, p<0.0001; SPECT/CT: r=0.66, p=0.0006). CONCLUSION: Xenon enhanced CT obtained by Sub-CT can be considered at least as efficacious as that obtained by DE-CT and SPECT/CT for assessment of ventilation abnormality and pulmonary functional loss in smokers. PMID- 28027765 TI - Selective visualization of pelvic splanchnic nerve and pelvic plexus using readout-segmented echo-planar diffusion-weighted magnetic resonance neurography: A preliminary study in healthy male volunteers. AB - PURPOSE: To evaluate the potential of readout-segmented echo-planar diffusion weighted magnetic resonance neurography (RS-EPI DW-MRN) for the selective visualization of pelvic splanchnic nerve and pelvic plexus in healthy male volunteers. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. RS-EPI DW-MRN images were acquired from thirteen healthy male volunteers aged 25-48 years between September 2013 and December 2013. For RS-EPI DW-MRN, the following parameters were used: spatial resolution, 1.1*1.1*2.5mm; b-value, 250s/mm2; number of readout-segments, seven; and acquisition time, 7min 45s. For qualitative assessment, two abdominal radiologists independently evaluated the visibility of the pelvic splanchnic nerves and pelvic plexuses bilaterally in each subject on oblique coronal thin slab 10-mm-thick maximum intensity projection images and scored it with a 4-point grading scale (excellent, good, fair, poor). Both readers scored twice at 6-month intervals. Inter-observer and intra-observer variability were evaluated using Cohen's quadratically weighted kappa statistics. Image artifact level was scored on a 4-point grading scale by other two abdominal radiologists in order to evaluate the correlation between the nerve visibility and the severity of imaging artifacts using the Spearman's correlation coefficient. RESULTS: Qualitative grading showed the following success rate (number of nerves qualitatively scored as excellent or good divided by total number of nerves): reader 1 (first set), 73% (19/26); reader 2 (first set), 77% (20/26); reader 1 (second set), 81% (21/26); and reader 2 (second set), 77% (20/26). Inter-observer agreement between readers 1 and 2 was excellent: kappa=0.947 (first set) and 0.845 (second set). Intra-observer agreement was also excellent: kappa=0.810 (reader 1) and 0.946 (reader 2). The visibility of pelvic splanchnic nerve and pelvic plexus showed a moderate correlation with the image artifact level (rho=0.54, p=0.004). CONCLUSION: This study demonstrated that RS-EPI DW-MRN is a promising approach for selectively visualizing the pelvic splanchnic nerve and pelvic plexus. PMID- 28027766 TI - Radiological assessment of the breast following enhancement with Macrolane: Managing the challenges. AB - Macrolane VRF(r), a biodegradable, stabilized hyaluronic acid gel, was used for breast enhancement 2008-2012. Similar to permanent implants, the presence of Macrolane gel may interfere with interpretation of mammography. This short communication aims to provide a guide to the appearance of Macrolane on radiology examination (including mammography, ultrasound and magnetic resonance imaging) and aid selection of the most appropriate imaging modality to facilitate breast examination in women who have undergone Macrolane breast enhancement. PMID- 28027767 TI - T1 mapping cardiovascular magnetic resonance imaging to detect myocarditis-Impact of slice orientation on the diagnostic performance. AB - BACKGROUND: T1 mapping is a promising diagnostic tool to improve the diagnostic accuracy of cardiovascular magnetic resonance (CMR) in patients with suspected myocarditis. However, there are currently no data on the potential influence of slice orientation on the diagnostic performance of CMR. Thus, we compared the diagnostic performance of global myocardial T1 and extracellular volume (ECV) values to differentiate patients with myocarditis from healthy individuals between different slice orientations. METHODS: This study included 48 patients with clinically defined myocarditis and 13 healthy controls who underwent CMR at 1.5T. A modified Look-Locker inversion-recovery (MOLLI) sequence was used for T1 mapping before and 15min after administration of 0.075mmol/kg Gadolinium-BOPTA. T1 mapping was performed on three short and on three long axes slices, respectively. Native T1, post-contrast T1 and extracellular volume (ECV) -BOPTA maps were calculated using a dedicated plug-in written for the OsiriX software and compared between the mean value of three short-axes slices (3SAX), the central short-axis (1SAX), the mean value of three long-axes slices (3LAX), the four-chamber view (4CH), the three-chamber view (3CH) and the two-chamber view (2CH). RESULTS: There were significantly lower native T1 values on 3LAX (1081ms (1037-1131ms)) compared to 3SAX (1107ms (1069-1143ms), p=0.0022) in patients with myocarditis, but not in controls (1026ms (1009-1059ms) vs. 1039ms (1023-1055ms), p=0.2719). The areas under the curve (AUC) to discriminate between myocarditis and healthy controls by native myocardial T1 were 0.85 (p<0.0001) on 3SAX, 0.85 (p<0.0001) on 1SAX, 0.76 (p=0.0002) on 3LAX, 0.70 (p=0.0075) on 4CH, 0.72 (p=0.0020) on 3CH and 0.75 (p=0.0003) on 2CH. The AUCs for ECV-BOPTA were 0.83 (p<0.0001) on 3 SAX, 0.82 (p<0.0001) on 1SAX, 0.77 (p=0.0005) on 3LAX, 0.71 (p=0.0079) on 4CH, 0.69 (p=0.0371) on 3CH and 0.75 (p=0.0006) on 2CH. CONCLUSION: Native T1 and ECV-BOPTA on short axes slices provide a better diagnostic performance in myocarditis than long axes slices since long axes slices seem to underestimate native myocardial T1 in myocarditis. T1 mapping in suspected myocarditis can be restricted to a single mid-ventricular short-axis slice without a significant loss in diagnostic performance. PMID- 28027768 TI - The evolution of radiation dose over time: Measurement of a patient cohort undergoing whole-body examinations on three computer tomography generations. AB - OBJECTIVES: To evaluate and compare the radiation dose and image quality of whole body-CT (WBCT) performed on the 3rd-generation dual-source-CT (DSCT) with 2nd generation DSCT and 64-slices-Single-Source-CT (SSCT) in a large patient cohort. MATERIAL AND METHODS: Using a monitoring and tracking software 1451, 747 and 1861 patients scanned with a one-spiral-thorax-abdomen-pelvis-CT-examination on a 3rd , 2nd-generation DSCT and SSCT, respectively, were extracted from the PACS server. For the intra-individual analysis, 203 patients on the 3rd-generation DSCT were identified. Out of those 203 patients, 155 had the same examination on the 2nd-generation DSCT, 91 patients had the same examination on the SSCT and 43 patients had an examination on all three CT-generations. Automatic tube current modulation was active on all three CT-generations, whereas automatic tube voltage selection was only available on both DSCT-generations. Dose was recorded by the size-specific-dose-estimate-method (SSDE); signal-to-noise-ratio (SNR) and contrast-to-noise-ratio (CNR) were calculated placing a ROI on the ascending aorta/liver and the subcutaneous adipose tissue at comparable level. Image quality of axillary and mediastinal lymph nodes and adrenal glands was assessed by two experienced radiologists. RESULTS: Subjective image quality was excellent throughout all three CT-generations (p=0.38-0.98). Quantitative image quality in both DSCT generations was superior to SSCT (p<0.001). SNR and CNR in the liver parenchyma were superior in the 3rd-generation DSCT compared to the 2nd generation DSCT (p<0.001), whereas there was no difference in the aorta. In the inter-individual analysis, CTDIvol was lower by 26.9% and 44.3% in the 3rd generation DSCT, when compared to the 2nd-generation DSCT and SSCT, respectively; SSDE was lower by 31.5% and 51% in the 3rd-generation DSCT, when compared to the 2nd-generation DSCT and SSCT, respectively. In the intra-individual comparison CTDIVol in the 3rd-generation DSCT was lower by 33% and 45%, when compared to the 2nd-gneration DSCT and the SSCT, respectively. Consequently, SSDE in the 3rd generation DSCT was lower by 29% and by 43% when compared to the 2nd-generation DSCT and SSCT, respectively. CONCLUSION: State-of-the-art CT-equipment substantially reduce radiation dose without affecting image quality. PMID- 28027769 TI - Brain metabolite alterations in Eisenmenger syndrome: Evaluation with MR proton spectroscopy. AB - OBJECTIVE: Eisenmenger syndrome (ES) is a life-threatening disease characterized by pulmonary hypertension and cyanosis in patients with congenital heart diseases. The aim of this study was to determine the brain metabolite changes in Eisenmenger syndrome compared with a control group using MR proton spectroscopy. METHODS AND MATERIALS: The study included 10 children (3 male, 7 female) with congenital heart diseases and a diagnosis of Eisenmenger syndrome. The control group consisted of 10 healthy volunteer children. All were examined with a 1.5T MRI scanner and single voxel spectroscopy was performed to obtain spectra from three different regions; left frontal subcortical white matter, left lentiform nucleus and left thalamus. Peak integral values obtained from the spectra were used as quantitative data. RESULTS: The ages of the children with ES were between 5 and 16 years, and between 5 and 15 years in the control group. Periventricular white matter hyperintensities were observed in 3 patients. On MR spectroscopy study, significantly lower levels of Choline metabolite (Cho) were detected in the frontal subcortical region and thalamus regions of the patients compared with the control group. There was no statistically significant difference between the levels of other metabolites (NAA, Cr, mI and Glx). In the lentiform nucleus, although the average value of Cho in ES patients was lower than that of the control group, it was not statistically significant. CONCLUSION: Cho metabolite was determined to have an important role in brain metabolism in Eisenmenger syndrome patients. Oral Cho treatment may help to extend survival. PMID- 28027770 TI - Contrast enhanced renal MR angiography at 7 Tesla: How much gadolinium do we need? AB - OBJECTIVES: To investigate whether a dose reduction of Gadobutrol for renal magnetic resonance angiography (MRA) at 7 Tesla (T) is feasible while preserving diagnostic image quality. METHODS: Ten healthy volunteers were enrolled for a renal MRA on a 7T scanner. Fast low angle shot (FLASH) MRA data sets were obtained utilizing three different doses of Gadobutrol (0.1, 0.05 and 0.025mmol/kg body weight [BW]). Contrast ratios (CR) were measured in the aorta as well as in the intra- and extraparenchymal arteries compared to the psoas muscle. Qualitative analysis regarding the delineation of vessel structures was performed using a four-point-scale. RESULTS: All doses of Gadobutrol allowed for a good delineation of the aorta and renal arteries. For the extra- and intraparenchymal segmental arteries higher values were observed for full and half dose in comparison to quarter dose. No significant difference was observed for full and half dose. A lower CR was observed for quarter compared to half dose (p<0.05) for the renal arteries. CONCLUSIONS: While best results were observed for half and full dose, a dose reduction to 0.025mmol/kg BW is justifiable, maintaining a diagnostic image quality. This may be of high interest considering patients with renal impairment. PMID- 28027771 TI - Dynamic contrast-enhanced perfusion area-detector CT assessed with various mathematical models: Its capability for therapeutic outcome prediction for non small cell lung cancer patients with chemoradiotherapy as compared with that of FDG-PET/CT. AB - PURPOSE: To directly compare the capability of dynamic first-pass contrast enhanced (CE-) perfusion area-detector CT (ADCT) and PET/CT for early prediction of treatment response, disease progression and overall survival of non-small cell carcinoma (NSCLC) patients treated with chemoradiotherapy. MATERIALS AND METHODS: Fifty-three consecutive Stage IIIB NSCLC patients who had undergone PET/CT, dynamic first-pass CE-perfusion ADCT, chemoradiotherapy, and follow-up examination were enrolled in this study. They were divided into two groups: 1) complete or partial response (CR+PR) and 2) stable or progressive disease (SD+PD). Pulmonary arterial and systemic arterial perfusions and total perfusion were assessed at targeted lesions with the dual-input maximum slope method, permeability surface and distribution volume with the Patlak plot method, tumor perfusion with the single-input maximum slope method, and SUVmax, and results were averaged to determine final values for each patient. Next, step-wise regression analysis was used to determine which indices were the most useful for predicting therapeutic effect. Finally, overall survival of responders and non responders assessed by using the indices that had a significant effect on prediction of therapeutic outcome was statistically compared. RESULTS: The step wise regression test showed that therapeutic effect (r2=0.63, p=0.01) was significantly affected by the following three factors in order of magnitude of impact: systemic arterial perfusion, total perfusion, and SUVmax. Mean overall survival showed a significant difference for total perfusion (p=0.003) and systemic arterial perfusion (p=0.04). CONCLUSION: Dynamic first-pass CE-perfusion ADCT as well as PET/CT are useful for treatment response prediction in NSCLC patients treated with chemoradiotherapy. PMID- 28027772 TI - Metabolic response assessment with 18F-FDG-PET/CT is superior to modified RECIST for the evaluation of response to platinum-based doublet chemotherapy in malignant pleural mesothelioma. AB - PURPOSE: Efficient monitoring of tumor responsiveness to chemotherapy is essential to mitigate high mortality risks and cytotoxic effects of chemotherapeutics. However, there is no consensus on the most suitable diagnostic technique/parameters for assessing response to chemotherapy in malignant pleural mesothelioma (MPM). We compared the tumor responsiveness of MPM patients as assessed using modified RECIST (mRECIST) criteria and integrated 18F-FDG-PET/CT. METHODS: Histologically confirmed MPM patients (N=82) who were treated with three cycles of cisplatin and pemetrexed, or carboplatin and pemetrexed, were included. mRECIST and integrated 18F-FDG-PET/CT were used to evaluate MPM tumor response to chemotherapy. Metabolic non-responders were defined as those with a 25% or greater increase in SUVmax compared with the previous value. Time to progression (TTP) and overall survival (OS) were compared between metabolic-responders and non-responders. RESULTS: After three cycles of chemotherapy, 62(75.6%) of the patients were classified as having SD, 15 (18%) with partial remission (PR), and 5 (6%) with progressive disease (PD), based on mRECIST criteria. The cumulative median OS was 728.0days (95% confidence interval [CI]: 545.9-910.1) and cumulative median TTP was 365.0days (95% CI: 296.9-433.1). For the 82 patients, the disease control rate was 93.9%, whereas the metabolic response rate was only 71.9% (p<0.001). All PD and PR patients were found to be metabolic responders on 18F-FDG-PET/CT; however, among the 62mRECIST SD patients, 18 (29%) were classified as metabolic non-responders. The median TTP for metabolic responders was 13.7 months, while it was 10.0 months for non-responders(p<0.001). Metabolic responders had a trend toward longer OS, although the difference did not reach statistical significance (metabolic responders:33.9 months; non-responders: 21.6 months; p>0.05). CONCLUSION: Several mRECIST-confirmed SD MPM patients may be classified as metabolic non-responders on18F-FDGPET/CT. Metabolic response is significantly correlated with the median TTP, suggesting it should be included in the evaluation of the response to chemotherapy in MPM patients classified as mRECIST SD, to identify non-responders. PMID- 28027773 TI - Ex vivo characterization of pathologic fluids with quantitative phase-contrast computed tomography. AB - PURPOSE: X-ray phase-contrast imaging (PCI) provides additional information beyond absorption characteristics by detecting the phase shift of the X-ray beam passing through material. The grating-based system works with standard polychromatic X-ray sources, promising a possible clinical implementation. PCI has been shown to provide additional information in soft-tissue samples. The aim of this study was to determine if ex vivo quantitative phase-contrast computed tomography (PCCT) may differentiate between pathologic fluid collections. MATERIALS AND METHODS: PCCT was performed with the grating interferometry method. A protein serial dilution, human blood samples and 17 clinical samples of pathologic fluid retentions were imaged and correlated with clinical chemistry measurements. Conventional and phase-contrast tomography images were reconstructed. Phase-contrast Hounsfield Units (HUp) were used for quantitative analysis analogously to conventional HU. The imaging was analyzed using overall means, ROI values as well as whole-volume-histograms and vertical gradients. Contrast to noise ratios were calculated between different probes and between imaging methods. RESULTS: HUp showed a very good linear correlation with protein concentration in vitro. In clinical samples, HUp correlated rather well with cell count and triglyceride content. PCI was better than absorption imaging at differentiating protein concentrations in the protein samples as well as at differentiating blood plasma from cellular components. PCI also allowed for differentiation of watery samples (such as lymphoceles) from pus. CONCLUSION: Phase-contrast computed tomography is a promising tool for the differentiation of pathologic fluids that appear homogenous with conventional attenuation imaging. PMID- 28027774 TI - Corrigendum to "Effect of guava leaves on growth and the non-specific immune response of Penaeus monodon" [Fish Shellfish Immunol 40 (2014) 190-196]. PMID- 28027775 TI - Triterpene derivatives from Euphorbia enhance resistance against Verticillium wilt of tomato. AB - Oxidation of alpha-euphorbol and 31-norlanostenol, two triterpenic compounds isolated from the latex of Euphorbia resinifera and Euphorbia officinarum respectively, yielded four products named 3beta-tosyloxy-4alpha,14alpha-dimethyl 5alpha-cholesta-7,9-diene; 4alpha,14alpha-dimethyl-5alpha-cholesta-7,9-dien-3beta ol; 24-methylen-elemo-lanosta-8,24-dien-3-one and elemo-lanost-8-en-3,11,24 trione. They were evaluated for protection of tomato plants against Verticillium dahliae in a greenhouse. The four semisynthesized products were phytotoxic at higher concentrations as they completely inhibited tomato germination at 100 and 500 MUg/ml. However at lower concentrations (10 and 50 MUg/ml) germination and root length were not affected. Disease resistance against Verticillium wilt was assessed in tomato plants derived from seeds that germinated in the presence of 10 and 50 MUg/ml of the four products. All of them were able to reduce significantly disease severity, with 10 MUg/ml being more effective than 50 MUg/ml. Reduction of leaf alteration index and of stunting index ranged from 52 to 68% and from 43 to 67%, respectively, while vessel discoloration was reduced by at least 95%. The compounds were also able to elicit H2O2 accumulation before and after fungal inoculation and to significantly enhance peroxidase and polyphenol oxidase activities. These results suggest that the hemisynthetized triterpenes can be used as elicitors of disease resistance. PMID- 28027776 TI - VegeSafe: A community science program measuring soil-metal contamination, evaluating risk and providing advice for safe gardening. AB - The extent of metal contamination in Sydney residential garden soils was evaluated using data collected during a three-year Macquarie University community science program called VegeSafe. Despite knowledge of industrial and urban contamination amongst scientists, the general public remains under-informed about the potential risks of exposure from legacy contaminants in their home garden environment. The community was offered free soil metal screening, allowing access to soil samples for research purposes. Participants followed specific soil sampling instructions and posted samples to the University for analysis with a field portable X-ray Fluorescence (pXRF) spectrometer. Over the three-year study period, >5200 soil samples, primarily from vegetable gardens, were collected from >1200 Australian homes. As anticipated, the primary soil metal of concern was lead; mean concentrations were 413 mg/kg (front yard), 707 mg/kg (drip line), 226 mg/kg (back yard) and 301 mg/kg (vegetable garden). The Australian soil lead guideline of 300 mg/kg for residential gardens was exceeded at 40% of Sydney homes, while concentrations >1000 mg/kg were identified at 15% of homes. The incidence of highest soil lead contamination was greatest in the inner city area with concentrations declining towards background values of 20-30 mg/kg at 30-40 km distance from the city. Community engagement with VegeSafe participants has resulted in useful outcomes: dissemination of knowledge related to contamination legacies and health risks; owners building raised beds containing uncontaminated soil and in numerous cases, owners replacing all of their contaminated soil. PMID- 28027777 TI - Analysis of contrast time-enhancement curves to optimise CT pulmonary angiography. AB - AIM: To assess enhancement profiles of the pulmonary artery (PA) and determine optimal scan timing in PA computed tomography (CT) angiography. MATERIALS AND METHODS: One hundred consecutive patients referred for contrast-enhanced chest CT were prospectively studied. Fifteen low-radiation monitoring images were acquired at 2-second intervals, 5 seconds after the start of an injection of 370 mg iodine/I contrast medium for 1 ml/kg of body weight injected over 20 seconds. Contrast time-enhancement data were measured over the PA. The time and magnitude of peak as well as times to five different enhancement thresholds (50, 100, 150, 200, 250 HU) were calculated. A set of candidate fixed and circulation-adjusted scan delays were analysed and compared in terms of the quality of contrast enhancement over the 4-second diagnostic scan duration. RESULTS: The mean degree of peak PA enhancements was 431.4+/-65.2HU (range, 263.8-575.3HU). The mean time to peak enhancement was 22.4+/-3.1 seconds (range, 11-27 seconds). From potential fixed delays ranging 11-27 seconds, 19 seconds showed the highest enhancement quality. For the circulation-adjusted delays, the combination of 150 HU bolus track threshold with diagnostic delay of 10 seconds had the highest enhancement quality. CONCLUSION: Peak enhancement of PA occurred, on average, right after completion of contrast injection for 20 seconds. The fixed scan delay of 19 seconds or circulation-adjusted delay with the bolus-threshold of 150 HU and diagnostic delay of 10 seconds appear optimal. PMID- 28027778 TI - Imaging and reporting considerations for suspected physical abuse (non-accidental injury) in infants and young children. Part 2: axial skeleton and differential diagnoses. AB - Recognising the skeletal manifestations of inflicted injury (II) in infants and young children is of crucial importance. There are specific fracture patterns which are highly suspicious of II in addition to common differential diagnoses with which radiologists should be familiar. Our objective is to provide a non exhaustive review of the important factors relevant to the imaging and reporting of II as a platform for further learning. Part 2 encompasses fracture patterns of the axial skeleton and important differential diagnoses. PMID- 28027779 TI - Association of MRI-classified subventricular regions with survival outcomes in patients with anaplastic glioma. AB - AIM: To investigate the prognostic role of subventricular zone (SVZ) involvement in anaplastic glioma. MATERIALS AND METHODS: The magnetic resonance imaging and clinical data of 160 patients with histopathologically confirmed anaplastic glioma treated at Beijing Tiantan hospital were retrospectively reviewed. The relationship between survival and the region of the SVZ involved was determined via univariate and multivariate analysis. RESULTS: In the univariate analysis, SVZ involvement significantly correlated with progression-free survival (p=0.021) and overall survival (p<0.001). Multivariate analysis showed that SVZ involvement was an independent prognostic factor for unfavourable survival (p=0.016 for overall survival), as was the involvement of the occipital horn of the SVZ (p<0.001 for progression-free survival, and p=0.016 for overall survival). CONCLUSION: The current study shows that SVZ involvement is a valid prognostic indicator in anaplastic glioma. It is associated with worse prognosis in patients with anaplastic gliomas, particularly those with tumours invading the occipital horn of the SVZ. PMID- 28027780 TI - Star excursion balance test for assessment of dynamic instability of the ankle in patients after harvest of a fibular free flap: a two-centre study. AB - We aimed to show that the star excursion balance test can identify instability in the ankle of patients who have had harvest of a fibular free flap. We compared the reach distance of the operated leg against that of the non-operated leg in 26 patients who had had harvest of the flap over a period of three years from August 2009 at two different centres. The goal of the test is to reach as far as possible with one leg in eight directions while balancing on the other. We also assessed the overall function of the operated leg using the Foot and Ankle Disability Index (FADI) and the American Orthopaedic Foot and Ankle Score (AOFAS). The star excursion balance test is simple and cheap, and is quick and easy to do in the outpatient department. PMID- 28027781 TI - Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy. AB - Radiation-induced fibrosis in the head and neck is a well-established pathophysiological process after radiotherapy. Recently pentoxifylline and tocopherol have been proposed as treatments to combat the late complications of radiation-induced fibrosis and a way of dealing with osteoradionecrosis. They both have a long history in the management of radiation-induced fibrosis at other anatomical sites. In this paper we review their use in sites other than the head and neck to illustrate the potential benefit that they offer to our patients. PMID- 28027782 TI - The effects of nitrogen pollutants on the isotopic signal (delta15N) of Ulva lactuca: Microcosm experiments. AB - Effects of two chemical forms of Nitrogen (NH4+ and NO3-) on delta15N in Ulva lactuca were analysed separately and in mixture at two concentrations. We assessed whether the delta15N values of U. lactuca discriminate between Nitrogen from synthetic fertilisers (inorganic) and from fresh cow manure (organic), and the isotopic ability of the macroalga to reflect Nitrogen concentrations. Isotopic signature and N content of the macroalga reflected different nitrogenous sources and their concentrations after 48h. The inorganic Nitrogen source (NH4NO3) altered the isotopic values of the macroalgae more than Nitrogen from fresh cow manure (NO3-). delta15N values observed in the mixed solution did not differ from those displayed in NH4NO3 treatment alone. We conclude that stable isotope analysis of U. lactuca collected in an unpolluted site and experimentally submerged in sites suspected of being affected by disturbance is a useful tool for rapid monitoring of anthropogenic discharges of Nitrogen pollutants. PMID- 28027783 TI - Has the Surviving Sepsis Campaign been successful in Spain? PMID- 28027784 TI - Analysis of three cases of diffuse alveolar hemorrhage: False-negative results in pulmonary ultrasound. PMID- 28027785 TI - Sinusal reversion of supraventricular tachyarrhythmias after propofol administration. A case series. PMID- 28027786 TI - Acute kidney injury secondary to diarrhea caused by "sprue-like" enteropathy associated with olmesartan. PMID- 28027787 TI - High-sensitivity cardiac troponin in the emergency department: The perfect storm? PMID- 28027788 TI - Non-alcoholic fatty liver disease and subclinical atherosclerosis: A comparison of metabolically- versus genetically-driven excess fat hepatic storage. AB - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is frequently associated with atherosclerosis. However, it is unclear whether this association is related to excess fat liver storage per se or to metabolic abnormalities that typically accompany NAFLD. To investigate this, we compared individuals with hepatic steatosis driven by metabolic disturbances to those with hepatic steatosis associated with the rs738409 GG genotype in the patatin-like phospholipase domain-containing 3 gene (PNPLA3). METHODS: Carotid intima-media thickness (CIMT), as a surrogate marker of subclinical atherosclerosis, was measured in 83 blood donors with the mutant GG genotype (group G), 100 patients with features of metabolic syndrome (MetS) but the wildtype CC genotype (group M), and 74 blood donors with the wildtype CC genotype (controls). Fatty liver was evaluated by ultrasonography and hepatic fat fraction (HFF) was measured using magnetic resonance (MRS/MRI) in 157 subjects. RESULTS: Compared with group G and controls, group M subjects were older and had increased adiposity indices, dyslipidemia, insulin resistance and elevated transaminase levels (all p < 0.05). They also had a more fatty liver on both ultrasonography and MRS/MRI. After adjustment for confounders (including severity of hepatic steatosis), the median CIMT in group M (0.84 [0.70-0.95] mm) was significantly greater than that in group G (0.66 [0.55-0.74] mm; p < 0.001), which was similar to that in controls (0.70 [0.64-0.81] mm). Results were similar in the subgroup evaluated using MRS/MRI. CONCLUSIONS: Excess liver fat accumulation appeared to increase the burden of subclinical atherosclerosis only when it is associated with metabolic abnormalities. PMID- 28027789 TI - Management and cost of surgical site infection in patients undergoing surgery for spinal metastasis. AB - BACKGROUND: Surgical site infection (SSI) is a serious potential complication of spinal surgery. SSI may impact significantly on inpatient hospitalization and the costs associated with extra care. AIM: To investigate the management of patients experiencing SSI following surgery for spinal metastatic tumours, and to estimate the costs associated with SSI in this context. METHODS: Patients experiencing SSI following spinal tumour surgery at a large spinal surgery centre between January 2009 and December 2012 were identified. Existing case notes were reviewed and patient and procedural data, details of the infection, and treatment interventions were recorded. A bottom-up approach to calculating costs associated with infection was used for patients experiencing SSI and compared with a quasi random sample of similar patients without SSI. FINDINGS: The mean cost of treating patients with SSI was significantly greater than costs associated with those without SSI (P=0.019). Mean cost of inpatient hospital stay was 60% higher in patients with SSI compared to those without SSI (P=0.004). Inpatient hospital stay alone accounted for 59% of total costs. Return to theatre was the second most costly intervention overall, accounting for 38% of costs, and was the most expensive single intervention involved in the treatment of SSI. CONCLUSION: SSI significantly increases healthcare costs for patients undergoing surgery for spinal metastasis, with prolonged inpatient hospitalization and return to theatre for wound management being major contributors. The actual total cost to society derived from SSI in this patient group is likely to be far beyond just the direct costs to healthcare providers. PMID- 28027790 TI - The impact of red blood cell storage duration on tissue oxygenation in cardiac surgery. AB - OBJECTIVE: Although storage alters red blood cells, several recent, randomized trials found no differences in clinical outcomes between patients transfused with red blood cells stored for shorter versus longer periods of time. The objective of this study was to see whether storage impairs the in vivo ability of erythrocytes to traverse the microcirculation and deliver oxygen at the tissue level. METHODS: A subset of subjects from a clinical trial of cardiac surgery patients randomized to receive transfusions of red blood cells stored <=10 days or >=21 days were assessed for thenar eminence and cerebral tissue hemoglobin oxygen saturation (StO2) via the use of near-infrared spectroscopy and sublingual microvascular blood flow via side-stream darkfield videomicroscopy. RESULTS: Among 55 subjects, there was little change in the primary endpoint (thenar eminence StO2 from before to after transfusion of one unit) and the change was similar in the 2 groups: +1.7% (95% confidence interval, -0.3, 3.8) for shorter storage and +0.8% (95% confidence interval, -1.1, 2.9) for longer-storage; P = .61). Similarly, no significant differences were observed for cerebral StO2 or sublingual microvascular blood flow. These parameters also were not different from preoperatively to 1 day postoperatively, reflecting the absence of a cumulative effect of all red blood cell units transfused during this period. CONCLUSIONS: There were no differences in thenar eminence or cerebral StO2, or sublingual microcirculatory blood flow, in cardiac surgery patients transfused with red blood cells stored <=10 days or >=21 days. These results are consistent with the clinical outcomes in the parent study, which also did not differ, indicating that storage may not impair oxygen delivery by red blood cells in this setting. PMID- 28027791 TI - Characterizing saccular aortic arch aneurysms from the geometry-flow dynamics relationship. AB - OBJECTIVE: Low wall shear stress (WSS) has been reported to be associated with accelerated atherosclerosis, aneurysm growth, or rupture. We evaluated the geometry of aortic arch aneurysms and their relationship with WSS by using the 4 dimensional flow magnetic resonance imaging to better characterize the saccular aneurysms. METHODS: We analyzed the geometry in 100 patients using multiplanar reconstruction of computed tomography. We evaluated WSS and vortex flow using 4 dimensional flow magnetic resonance imaging in 16 of them, which were compared with 8 age-matched control subjects and eight healthy young volunteers. RESULTS: Eighty-two patients had a saccular aneurysm, and 18 had a fusiform aneurysm. External diameter/aneurysm length ratio and sac depth/neck width ratio of the fusiform aneurysms were constant at 0.76 +/- 0.18 and 0.23 +/- 0.09, whereas those of saccular aneurysms, especially those involving the outer curvature, were higher and more variable. Vortex flow was always present in the aneurysms, resulting in low WSS. When the sac depth/neck width ratio was less than 0.8, peak WSS correlated inversely with luminal diameter even in the saccular aneurysms. When this ratio exceeded 0.8, which was the case only with the saccular aneurysms, such correlation no longer existed and WSS was invariably low. CONCLUSIONS: Fusiform aneurysms elongate as they dilate, and WSS is lower as the diameter is larger. Saccular aneurysms dilate without proportionate elongation, and they, especially those occupying the inner curvature, have higher and variable sac depth/neck width ratio. When this ratio exceeds 0.8, WSS is low regardless of diameter, which may explain their malignant clinical behavior. PMID- 28027792 TI - [Clinical practice guidelines: Irritable bowel syndrome with constipation and functional constipation in adults: Concept, diagnosis, and healthcare continuity. (Part 1 of 2)]. AB - In this Clinical practice guide, an analysis is made of the diagnosis and treatment of adult patients with constipation and abdominal discomfort, under the spectrum of irritable bowel syndrome and functional constipation. These have an important personal, health and social impact, affecting the quality of life of these patients. In irritable bowel syndrome with a predominance of constipation, this is the predominant change in bowel movements, with recurrent abdominal pain, bloating and frequent abdominal distension. Constipation is characterised by infrequent or difficulty in bowel movements, associated with excessive straining during bowel movement or sensation of incomplete evacuation. There is often no underling cause, with an intestinal functional disorder being considered. They have many clinical and pathophysiological similarities, with a similar response of the constipation to common drugs. The fundamental difference is the presence or absence of pain, but not in a way evaluable way; "all or nothing". The severity depends on the intensity of bowel symptoms and other factors, a combination of gastrointestinal and extra-intestinal symptoms, level of involvement, forms of perception, and behaviour. The Rome criteria diagnose functional bowel disorders. This guide is adapted to the Rome criteria IV (May 2016) and in this first part an analysis is made of the alarm criteria, diagnostic tests, and the criteria for referral between Primary Care and Digestive Disease specialists. In the second part, a review will be made of the therapeutic alternatives available (exercise, diet, drug therapies, neurostimulation of sacral roots, or surgery), making practical recommendations for each one of them. PMID- 28027793 TI - Growth of the maxillary sinus in children and adolescents: A longitudinal study. AB - Maxillary sinus volumetric and surface area data and growth models from longitudinal samples of children and adolescents are presented. Cone-beam radiographic CT scans from two small retrospective longitudinal samples, one from the Baylor College of Dentistry, Dallas, TX (N=17, 12 females, 5 males, 10.9-17.4 years) and one from a group private orthodontic practice in Nevada (N=15, 9 females, 6 males, 6.4-13.4 years) were used to collect maxillary sinus volumes and surface areas from each individual imaged at two times separated by variable intervals. Volume and surface area values were collected in Analyze(r) (Mayo Clinic) and growth models were produced in MLwiN(r), a multi-level modeling program. There is a large degree of inter-individual variation. Surface area and surface-area-to-volume ratio (SA:V) changes are particularly variable. Growth models suggest linear growth in both volume and surface area, without growth spurts. PMID- 28027794 TI - Intraperitoneal Vancomycin Plus Either Oral Moxifloxacin or Intraperitoneal Ceftazidime for the Treatment of Peritoneal Dialysis-Related Peritonitis: A Randomized Controlled Pilot Study. AB - BACKGROUND: Intraperitoneal administration of antibiotics is recommended as a first treatment for managing peritoneal dialysis (PD)-related peritonitis. However, the efficacy of oral administration of quinolones has not been well studied. STUDY DESIGN: Randomized controlled pilot study. SETTING & PARTICIPANTS: 80 eligible patients with PD-related peritonitis from Peking University First Hospital (40 in each arm). INTERVENTION: Intraperitoneal vancomycin, 1g, every 5 days plus oral moxifloxacin, 400mg, every day (treatment group) versus intraperitoneal vancomycin, 1g, every 5 days plus intraperitoneal ceftazidime, 1g, every day (control group). OUTCOMES: The primary end point was complete resolution of peritonitis, and secondary end points were primary or secondary treatment failure. MEASUREMENTS: PD effluent white blood cell count. RESULTS: Baseline demographic and clinical characteristics of the 2 groups were comparable. There were 24 and 22 Gram-positive organisms, 6 and 7 Gram-negative organisms, 9 and 10 culture-negative samples, and 1 and 1 fungal sample in the treatment and control groups, respectively. Complete resolution of peritonitis was achieved in 78% and 80% of cases in the treatment and control groups, respectively (OR, 0.86; 95% CI, 0.30-2.52; P=0.8). There were 3 and 1 cases of relapse in the treatment and control groups, respectively. Primary and secondary treatment failure rates were not significantly different (33% vs 20% and 10% vs 13%, respectively). In each group, there was 1 peritonitis-related death and 6 transfers to hemodialysis therapy. During the 3-month follow-up period, 7 and 3 successive episodes of peritonitis occurred in the treatment and control groups, respectively. Only 2 adverse drug reactions (mild nausea and mild rash, respectively) were observed in the 2 groups. LIMITATIONS: Sample size was relatively small and the eligibility ratio was low. Also, the number of peritonitis episodes was low, limiting the power to detect a difference between groups. CONCLUSIONS: This pilot study suggests that intraperitoneal vancomycin with oral moxifloxacin is a safe, well-tolerated, practical, and effective first line treatment for PD-related peritonitis. Larger adequately powered clinical trials are warranted. PMID- 28027795 TI - Performance of the CKD-EPI Equation to Estimate GFR in a Longitudinal Study of Autosomal Dominant Polycystic Kidney Disease. PMID- 28027796 TI - Associations of serum fibroblast growth factor 23 levels with obesity and visceral fat accumulation. AB - BACKGROUND & AIMS: Recent findings raise the possibility that fibroblast growth factor (FGF) 23 may be related with fat contents and distribution. The present study aimed to elucidate the associations of serum FGF23 levels with the fat contents and distribution. METHODS: A total of 1599 normoglycemic individuals with preserved kidney function were enrolled. Serum levels of intact FGF23 were detected using a sandwich enzyme-linked immunosorbent assay. Overweight/obesity was defined by a body mass index of >=25.0 kg/m2. Visceral fat area (VFA) was assessed by magnetic resonance imaging, and abdominal obesity was defined as VFA >=80 cm2. RESULTS: Among the study population of 597 men, 411 premenopausal women, and 591 postmenopausal women, serum FGF23 levels were significantly increased in participants with overweight/obesity and abdominal obesity, respectively (both P < 0.001). Each one-unit increase in VFA was associated with a 0.028-pg/mL increase in serum FGF23 levels in men (P = 0.001) and a 0.051-pg/mL increase in serum FGF23 levels in postmenopausal women (P < 0.001). Whether in the presence of overweight/obesity or not, the presence of abdominal obesity was independently associated with the increase in serum FGF23 levels in men and postmenopausal women (all P < 0.05). CONCLUSIONS: Serum FGF23 levels are elevated in obese individuals, especially those with abdominal obesity. The independent associations between the presence of abdominal obesity and the increase in serum FGF23 levels in specific groups suggest that serum FGF23 levels may indicate the risk of metabolic and cardiovascular disease in men and postmenopausal women. PMID- 28027797 TI - Corrigendum to "ESPEN guidelines on chronic intestinal failure in adults" [Clin Nutr 35 (2) (2016) 247-307]. PMID- 28027798 TI - Improved deep two-photon calcium imaging in vivo. AB - Two-photon laser scanning calcium imaging has emerged as a useful method for the exploration of neural function and structure at the cellular and subcellular level in vivo. The applications range from imaging of subcellular compartments such as dendrites, spines and axonal boutons up to the functional analysis of large neuronal or glial populations. However, the depth penetration is often limited to a few hundred micrometers, corresponding, for example, to the upper cortical layers of the mouse brain. Light scattering and aberrations originating from refractive index inhomogeneties of the tissue are the reasons for these limitations. The depth penetration of two-photon imaging can be enhanced through various approaches, such as the implementation of adaptive optics, the use of three-photon excitation and/or labeling cells with red-shifted genetically encoded fluorescent sensors. However, most of the approaches used so far require the implementation of new instrumentation and/or time consuming staining protocols. Here we present a simple approach that can be readily implemented in combination with standard two-photon microscopes. The method involves an optimized protocol for depth-restricted labeling with the red-shifted fluorescent calcium indicator Cal-590 and benefits from the use of ultra-short laser pulses. The approach allows in vivo functional imaging of neuronal populations with single cell resolution in all six layers of the mouse cortex. We demonstrate that stable recordings in deep cortical layers are not restricted to anesthetized animals but are well feasible in awake, behaving mice. We anticipate that the improved depth penetration will be beneficial for two-photon functional imaging in larger species, such as non-human primates. PMID- 28027799 TI - Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry. AB - Store-operated Ca2+ entry (SOCE) is a conserved mechanism of Ca2+ influx that regulates Ca2+ signaling in many cell types. SOCE is activated by depletion of endoplasmic reticulum (ER) Ca2+ stores in response to physiological agonist stimulation. After it was first postulated by J.W. Putney Jr. in 1986, SOCE has been described in a large number of non-excitable cell types including secretory cells of different exocrine glands. Here we discuss the mechanisms by which SOCE controls salt and fluid secretion in exocrine glands, with a special focus on eccrine sweat glands. In sweat glands, SOCE plays an important, non-redundant role in regulating the function of Ca2+-activated Cl- channels (CaCC), Cl- secretion and sweat production. In the absence of key regulators of SOCE such as the CRAC channel pore subunit ORAI1 and its activator STIM1, the Ca2+-activated chloride channel TMEM16A is inactive and fails to secrete Cl-, resulting in anhidrosis in mice and human patients. PMID- 28027800 TI - Prenatal airborne polycyclic aromatic hydrocarbon exposure, LINE1 methylation and child development in a Chinese cohort. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAH) are carcinogenic, neurotoxic environmental pollutants generated during incomplete combustion of fossil fuel and other organic material. PAH exposure has been associated with adverse fetal development and epigenetic alterations in cord blood. Several molecular epidemiology studies have established PAH-DNA adducts as biomarkers of PAH exposure. OBJECTIVES: We investigated the relationship between LINE1 DNA methylation and PAH-DNA adduct levels in cord blood, and with neurodevelopmental outcomes. METHODS: In Tongliang County, China, the current study enrolled two population-based cohorts of nonsmoking pregnant women before (2002) and after (2005) the closure of a local coal-fired power plant in May 2004. We analyzed cord blood samples collected from mothers in the two cohorts (n=110 from 2002 cohort and n=107 from 2005 cohort) for PAH-DNA adducts and genomic LINE1 DNA methylation. Neurodevelopmental data on children were collected using the Gesell Developmental Scales (GDS) at age 2 and using the Wechsler Intelligence Scale for Children (WISC) at age 5. RESULTS: A significant inverse relationship was observed between PAH-DNA adducts and LINE1 DNA methylation (beta=-0.010, p<0.038). A significant, positive association between LINE1 methylation and scores on WISC full scale and verbal (beta=85.31, p<0.005; beta=94.36, p<0.003) but not on the GDS. Mediation analysis did not find LINE1 to be a direct mediator between PAH-DNA adducts and IQ score. CONCLUSION: LINE1 methylation in cord blood DNA was a positive predictor of IQ at age 5 and was decreased at higher levels of prenatal PAH exposure measured by PAH-DNA adducts in cord blood. However, the adverse effects of prenatal exposure to PAH on IQ scores did not appear to be directly mediated by altered LINE1 methylation. PMID- 28027801 TI - Long term flow change threatens invertebrate diversity in temporary streams: Evidence from an island. AB - Here we provide the first evidence of long term reductions in flow in temporary streams on the Mediterranean island of Mallorca and use a simple metric of the degree of water permanence (the number of days with water) to highlight the implications of flow change for aquatic invertebrate diversity. Analysis of a 33year data set for 13 streams on the island yielded evidence of consistent downward trends in water permanence, particularly in spring and summer. Data from 27 relatively undisturbed mountain streams indicate that the diversity of benthic invertebrates in temporary streams across the island is directly related to water permanence. Streams with lower values of water permanence support few species overall and have less abundant invertebrate assemblages; the abundance and species richness of sensitive mayfly, stonefly and caddisfly taxonomic groups is also reduced in streams with lower water permanence. Although developed using spatial data, these flow-invertebrate relationships suggest that future reductions in water permanence may lead to reduced diversity. We argue that the 'number of days with water' is a simple but ecologically-relevant metric of water permanence that can be used effectively to monitor change in threatened temporary streams worldwide. PMID- 28027802 TI - Assessing pesticide wet deposition risk within a small agricultural watershed in the Southeastern Coastal Plain (USA). AB - Pesticide volatilization and deposition with precipitation is widely documented and has been connected to adverse ecological impact. Here we describe a 3-yr study of current use and legacy pesticides in event-based rain samples within a 123-ha agricultural watershed. Crops in farm fields were documented quarterly with data used to estimate target compound use. The median number of pesticide detections in samples was 6. The fungicide, chlorothalonil which was used most intensively was detected in nearly all samples. It had the highest mean and peak concentrations with total deposition ~0.1% of the estimated amount applied. The insecticide endosulfan also had relatively high use with behavior mirroring chlorothalonil. There was strong seasonal variation in concentration and depositional dynamics with the highest values measured during growing seasons. Similar behavior was observed with other compounds detected in rain samples with a general decrease in deposition and mean concentrations as use decreased. Comparison of measured concentrations to values associated with toxic impact on aquatic organisms indicated that chlorothalonil, endosulfan, chlorpyrifos, malathion and atrazine may contribute to adverse impact. The number of samples exceeding risk endpoints ranged from 1 to 77%. The highest value was for endosulfan; however its on-going phase-out is expected to reduce risks. Another finding was that the wet deposition of the herbicide, metolachlor exceeded measured runoff rates in the watershed by 5-fold. The study has demonstrated that localized pesticide wet deposition may present ecological risks and that volatilization and wet deposition is an important pesticide transport pathway at the local scale. Findings point to the need to include wet deposition in assessments of pesticide ecological risk and environmental fate. PMID- 28027804 TI - William B. Robertson - the pioneer of the placental bed. AB - A fortuitous collaboration between British and Belgian researchers more than 50 years ago led to discovery that major obstetrical disorders, such as preeclampsia and fetal growth restriction, originate from vascular lesions in placental bed, i.e. the myometrial portion of the uterine spiral arteries. William B Robertson, a gregarious pioneering vascular pathologist, played a key role in this seminal discovery that continues to shape obstetrical research to date. PMID- 28027803 TI - Rules of Engagement: The Type VI Secretion System in Vibrio cholerae. AB - Microbial species often exist in complex communities where they must avoid predation and compete for favorable niches. The type VI secretion system (T6SS) is a contact-dependent bacterial weapon that allows for direct killing of competitors through the translocation of proteinaceous toxins. Vibrio cholerae is a Gram-negative pathogen that can use its T6SS during antagonistic interactions with neighboring prokaryotic and eukaryotic competitors. The T6SS not only promotes V. cholerae's survival during its aquatic and host life cycles, but also influences its evolution by facilitating horizontal gene transfer. This review details the recent insights regarding the structure and function of the T6SS as well as the diverse signals and regulatory pathways that control its activation in V. cholerae. PMID- 28027805 TI - Variations in outcomes of hemodialysis vascular access by race/ethnicity in the elderly. AB - OBJECTIVE: Prevalence of end-stage renal disease, modality of treatment, and type of hemodialysis vascular access used varies widely by race/ethnicity in the United States, but outcomes of hemodialysis vascular access by race/ethnicity are poorly described. The objective of this study is to evaluate variations in outcomes of hemodialysis vascular access in the elderly by race/ethnicity. METHODS: Medicare outpatient, inpatient, and carrier files were queried from 2006 to 2011 for beneficiaries that were age >=66 years and dialysis-dependent at time of index fistula/graft creation, qualified for Medicare by age only, and were continuously enrolled in Medicare 12 months before and after index fistula/graft creation. Primary outcome measures were early vascular access failure and 12 month failure-free survival, specifically, the variation in the difference between fistula and graft in non-White vs White race/ethnicity groups. RESULTS: Fistulas comprised a smaller proportion of index procedures performed in Blacks (65.9%; P < .001) and Asians (71.4%; P < .001), compared with Whites (78.0%) with no difference in Hispanics (78.7%; P = .59). Incidence of early failure after graft vs fistula was Whites, 34.9% vs 43.5% (P < .001), Blacks, 32.9% vs 49.1% (P < .001), Asians, 30.8% vs 40.5% (P = .014), and Hispanics 35.2% vs 43.2% (P = .005). The difference in early failure after fistula vs graft in Blacks was significantly larger than the difference in Whites (P < .001). The 12-month failure-free survival after index graft vs fistula was Whites 41.9% vs 38.9% (P = .008), Blacks 48.5% vs 37.3% (P < .001), Asians 51.6% vs 45.2% (P = .98), and Hispanics 51.9% vs 42.2% (P < .001). The difference in 12-month failure-free survival after graft vs fistula in Blacks and in Hispanics was larger than the difference in Whites (P < .001 and P = .02, respectively). CONCLUSIONS: Outcomes of fistulas vs grafts in the elderly vary significantly by race/ethnicity. The decreased risk of early failure after graft vs fistula creation is larger in Blacks compared with Whites. The higher failure-free survival at 12 months after graft vs fistula creation is larger in Blacks compared with Whites and trends toward being larger in Hispanics compared with Whites. PMID- 28027806 TI - [Actinomycotic brain abscess in immunocompetent patient]. AB - BACKGROUND: The actinomyces is germ commonly found in the normal flora of the oral cavity and gastro-intestinal and uro-genital tracts. Involvement in other locations is a very uncommon event. OBJECTIVES: To describe a patient with an actinomicotyc brain abscess CLINICAL CASE: We report the case of a patient who suffered a seizure and decreased level of consciousness. Imaging tests revealed the presence of lesions both in the lung and in the brain. An urgent craniotomy was performed and the diagnosis of actinomicotyc abscess was obtained. CONCLUSION: We describe the differential characteristics of this type of infection, discussing the diagnostic process and management in detail. PMID- 28027807 TI - [Thoracoscopic lobectomy for the treatment of tracheal bronchus. A pediatric case report]. AB - BACKGROUND: Tracheal bronchus is considered a rare, congenital anomaly, which implies the abnormal origin of a bronchus. When related to repetitive infections the bronchus must be resected, usually via an open procedure. OBJECTIVE: The aim of this paper is to present the case of a patient with tracheal bronchus of the upper right lobe who presented with repetitive pneumonias. Additionally, this text intends to expose the methodology for its diagnosis and surgical resolution through a thoracoscopic lobectomy. CLINICAL CASE: One year old female patient who presented with the disorder at two months of age. The patient presented with constant coughing and persistent fever alongside repetitive pneumonias in the upper right lobe. In order to discard the possibility of gastroesophageal reflux, a bronchoscopy and a panendoscopy of the digestive tube were conducted. The aforesaid procedure demonstrated the existence of a tracheal bronchus located in the right lobe, with functional bronchial segmentation. With these findings and due to the presence of repetitive infections, an apical right lobectomy was performed through a thoracoscopy, with favourable results. CONCLUSIONS: Tracheal bronchus is a rare anomaly that on many occasions is asymptomatic; nonetheless, when related to repetitive infections, a lobectomy must be carried out to avoid further pulmonary damage. This can be done through a thoracoscopy, as was the case with our patient. When treating these patients, it is worth considering they tend to have a different anatomy and to consider the ease at which they can sustain severe inflammation due to repetitive infections. PMID- 28027808 TI - [Splenic rupture secondary to abscess: Rare cause of pneumoperitoneum. Case report]. AB - BACKGROUND: Splenic abscesses are rare entities; reports are commonly described in immunocompromised patients (72%) as: hematologic diseases, diabetes, endocarditis, acquired immunodeficiency syndrome, transplant patients and subjects who had abdominal trauma or splenic infarction. The main and most serious complication is the abscess rupture into the peritoneal cavity or adjacent organs (stomach or colon), which determines hemodynamic instability or septic state. CLINICAL CASE: Fifty-year-old man, who was admitted at Emergency Room due eight days' progressive, oppressive, and current pain; intensity 4/10, irradiated at hemi-back, which was higher intensity during the standing and decreased at supine position. It was accompanied by nausea and vomiting in two occasions. LABORATORY RESULTS: Hemoglobin 15.1g/dl, hematocrit 45.2%, platelets 176*103, 23.1*103 leukocytosis, neutrophils 92%. Simple abdominal radiographic studies revealed in 'ground glass' and radiopaque imagines. CONCLUSIONS: At presence of free air inside the abdominal cavity, is usually to think of a complicated diverticular disease, intestinal perforation or perforated peptic ulcer. The actual medical literature described very few cases of splenic abscess with pneumoperitoneum as cardinal manifestation. In our case, the splenic abscess was detected during exploratory laparotomy and only in retrospective the imaging studies were interpreted. PMID- 28027809 TI - [Laparoscopic anterior pelvic exenteration in a patient with locally advanced melanoma]. AB - BACKGROUND: Pelvic exenteration is one of the most mutilating surgical procedures with high post-operative morbidity. The laparoscopic technique aims to reduce perioperative complications and reduce post-surgical recovery. OBJECTIVE: We present the first case of laparoscopic anterior exenteration for locally advanced melanoma, held at the National Cancer Institute and published in Mexico. CASE REPORT: Patient 60 years of age diagnosed with invasive vulvar melanoma with bladder extension upon whom laparoscopic anterior pelvic exenteration with external urinary reconstruction was performed. Time in surgery was 505minutes and estimated blood loss was 400ml. No complications occurred during or immediately after surgery. The final histopathological study reported: nodular lesion that completely replaces the clitoris and spreads to the left labia majora, measures 3*2.5*2cm and is located relative to the free margins with perineural invasion intraepithelial spread in space and urethra and bladder trigone. CONCLUSIONS: The laparoscopic anterior pelvic exenteration is a safe alternative in well-selected patients, with acceptable time in surgery, surgical complications and recovery time. PMID- 28027810 TI - First-in-human safety and immunogenicity investigations of three adjuvanted reduced dose inactivated poliovirus vaccines (IPV-Al SSI) compared to full dose IPV Vaccine SSI when given as a booster vaccination to adolescents with a history of IPV vaccination at 3, 5, 12months and 5years of age. AB - BACKGROUND: There is a demand of affordable IPV in the World. Statens Serum Institut (SSI) has developed three reduced dose IPV formulations adsorbed to aluminium hydroxide; 1/3 IPV-Al, 1/5 IPV-Al and 1/10 IPV-Al SSI, and now report the results of the first investigations in humans. METHODS: 240 Danish adolescents, aged 10-15years, and childhood vaccinated with IPV were booster vaccinated with 1/3 IPV-Al, 1/5 IPV-Al, 1/10 IPV-Al or IPV Vaccine SSI. The booster effects (GMTRs) of the three IPV-Al SSI were compared to IPV Vaccine SSI, and evaluated for non-inferiority. IMMUNOGENICITY RESULTS: The pre-vaccination GMTs were similar across the groups; 926 (type 1), 969 (type 2) and 846 (type 3) in the total trial population. The GMTRs by poliovirus type and IPV formulation were: Type 1: 17.0 (1/3 IPV-Al), 13.0 (1/5 IPV-Al), 7.1 (1/10 IPV-Al) and 42.2 (IPV Vaccine SSI). Type 2: 12.5 (1/3 IPV-Al), 13.1 (1/5 IPV-Al), 7.6 (1/10 IPV Al) and 47.8 (IPV Vaccine SSI). Type 3: 14.5 (1/3 IPV-Al), 16.2 (1/5 IPV-Al), 8.9 (1/10 IPV-Al) and 62.4 (IPV Vaccine SSI) Thus, the three IPV-Al formulations were highly immunogenic, but inferior to IPV Vaccine SSI, in this booster vaccination trial. SAFETY RESULTS: No SAE and no AE of severe intensity occurred. 59.2% of the subjects reported at least one AE. Injection site pain was the most frequent AE in all groups; from 24.6% to 43.3%. Injection site redness and swelling frequencies were<5% in most and<10% in all groups. The most frequent systemic AEs were fatigue (from 8.2% to 15.0%) and headache (from 15.0% to 28.3%). Most AEs were of mild intensity. In conclusion, the three IPV-Al SSI were safe in adolescents and the booster effects were satisfactory. ClinicalTrials.gov registration number: NCT02280447. PMID- 28027811 TI - Letter to Prof Yong-Sheng Wang. PMID- 28027812 TI - New psychoactive substances (NPS) on cryptomarket fora: An exploratory study of characteristics of forum activity between NPS buyers and vendors. AB - BACKGROUND: The continual diversification of new psychoactive substances (NPS) circumventing legislation creates a public health and law enforcement challenge, and one particularly challenged by availability on Hidden Web cryptomarkets. METHODS: This is the first study of its kind which aimed to explore and characterise cryptomarket forum members' views and perspectives on NPS vendors and products within the context of Hidden Web community dynamics. An internal site search was conducted on two cryptomarkets popular with NPS vendors and hosting fora; Alphabay and Valhalla, using the search terms of 40 popular NPS in the seven categories of stimulant/cathinone; GABA activating; hallucinogen, dissociative, cannabinoid, opioid and other/unspecified/uncategorised NPS. 852 identified threads relating to the discussion of these NPS were generated. Following exclusion of duplicates, 138 threads remained. The Empirical Phenomenological Psychological method of data analysis was applied. Four themes and 32 categories emerged. RESULTS: 120 vendors selling NPS were visible on Alphabay, and 21 on Valhalla. Themes were 'NPS Cryptomarkets and Crypto-community interest in NPS'; 'Motives for NPS use'; 'Indigenous Crypto Community Harm Reduction'; and 'Cryptomarket Characteristics underpinning NPS trafficking', with two higher levels of abstraction centring on 'NPS vendor reputation' and 'NPS transactioning for personal use'. NPS cryptomarket characteristics centred on generation of trust, honesty and excellent service. Users appeared well informed, with harm reduction and vendor information exchange central to NPS market dynamics. GABA activating substances appeared most popular in terms of buyer interest on cryptomarkets. Interest in sourcing 'old favorite' stimulant and dissociative NPS was evident, alongside the sequential and concurrent poly use of NPS, and use of NPS with illicit drugs such as MDMA. CONCLUSION: Continued monitoring of new trends in NPS within Surface Web and cryptomarkets are warranted. A particular focus on the rising market in prescribed benzodiazepine and Z-hypnotic drugs should be included. PMID- 28027813 TI - Environmental and economic evaluation of pre-disaster plans for disaster waste management: Case study of Minami-Ise, Japan. AB - Although it is important that disaster waste be demolished and removed as soon as possible after a natural disaster, it is also important that its treatment is environmentally friendly and economic. Local municipalities do not conduct environmental and economic feasibility studies of pre-disaster waste management; nevertheless, pre-disaster waste management is extremely important to promote treatment of waste after natural disasters. One of the reasons that they cannot conduct such evaluations is that the methods and inventory data required for the environmental and economic evaluation does not exist. In this study, we created the inventory data needed for evaluation and constructed evaluation methods using life cycle assessment (LCA) and life cycle cost (LCC) methodologies for future natural disasters. We selected the Japanese town of Minami-Ise for the related case study. Firstly, we estimated that the potential disaster waste generation derived from dwellings would be approximately 554,000t. Based on this result, the land area required for all the temporary storage sites for storing the disaster waste was approximately 55ha. Although the public domain and private land area in this case study is sufficient, several sites would be necessary to transport waste to other sites with enough space because local space is scarce. Next, we created inventory data of each process such as waste transportation, operation of the temporary storage sites, and waste treatment. We evaluated the environmental burden and cost for scenarios in which the disaster waste derived from specified kinds of home appliances (refrigerators, washing machines, air-conditioners and TV sets) was transported, stored and recycled. In the scenario, CO2, SOx, NOX and PM emissions and total cost were 142t, 7kg, 257kg, 38kg and 1772 thousand USD, respectively. We also focused on SOx emission as a regional pollution source because transportation and operation of the temporary storage sites generates air pollution. If the treatment of all waste were finished in 3years, the environmental standard would be satisfied by setting work duration to 4.8h/d. PMID- 28027814 TI - Outcome of Total Hip and Total Knee Revision Arthroplasty With Minor Infection Criteria: A Retrospective Matched-Pair Analysis. AB - BACKGROUND: Although diagnostic modalities for the detection of periprosthetic joint infection have improved, some infectious revision cases may still be diagnosed as aseptic complications. We raised the question whether patients with positive Musculoskeletal Infection Society minor infection criteria differ in their outcome parameters (revision-free survival, revision rate) when compared to patients with "true" aseptic complications. Additionally, we asked whether the indication for revision surgery (eg, loosening) might have an influence on possible outcome discrepancies. METHODS: A retrospective matched-pair analysis was performed with 98 patients who had undergone revision surgery after total joint arthroplasty. Forty-nine patients showed less than 3 positive minor criteria (PMC), whereas 49 patients without any PMC were compared regarding re revision rate and revision-free survival. Reasons for revisions were categorized according to loosening, liner wear, implant failure, and soft-tissue complication. RESULTS: In the group of patients with PMC, 30.6% (n = 15) had to undergo re-revision compared to 6.12% (n = 3) in the true aseptic complication control group. The long-term implant survival in the PMC group was 69.4% (95% confidence interval [CI], 47-69 months) and in the aseptic control group was 93.9% (95% CI, 82-94 months; P = .001). In patients with PMC and loosening of the implant, the long-term survival was 55.2% (95% CI survival time, 28.9-53.2 months) whereas in patients without PMC and loosening, the overall survival was 96.2% (95% CI survival time, 83.5-96 months; P = .001). CONCLUSION: Our findings suggest that in the presence of prosthetic loosening, even a single positive minor criterion may have a negative impact on the outcome after total hip arthroplasty and total knee arthroplasty revision surgeries. PMID- 28027815 TI - Long telomere length predicts poor clinical outcome in esophageal cancer patients. AB - BACKGROUND: Abnormal telomere length is widely reported in various human cancers, and it is considered to be an important hallmark of cancer. However, there is remarkably little consensus on the value of telomere length in the prognostic evaluation of esophageal cancers. Here, we attempted to determine the association of variable telomere length with clinical outcome of esophageal cancer patients. MATERIALS AND METHODS: Using real-time quantitative PCR, we examined relative telomere lengths (RTL) in a cohort of esophageal cancer and normal esophageal tissues, and statistically investigated the association between RTL and clinical outcomes of esophageal cancer patients. RESULTS: The majority of esophageal cancers in this study had longer RTLs as compared to adjacent non-tumor tissues. Enhanced tumor RTL was associated with smoking habit, poor differentiation, advanced tumor stage, lymph node metastasis and cancer related death. In particular, a close relationship between longer RTL and poor survival was fully demonstrated by using cox regression and Kaplan-Maier survival curves. CONCLUSIONS: We found frequent telomere elongation in esophageal cancer tissues, and demonstrated longer RTL may be an independent poor prognostic factor for esophageal cancer patients. PMID- 28027816 TI - Pancreatic anastomosis after pancreatoduodenectomy: A position statement by the International Study Group of Pancreatic Surgery (ISGPS). AB - BACKGROUND: Clinically relevant postoperative pancreatic fistula (grades B and C of the ISGPS definition) remains the most troublesome complication after pancreatoduodenectomy. The approach to management of the pancreatic remnant via some form of pancreatico-enteric anastomosis determines the incidence and severity of clinically relevant postoperative pancreatic fistula. Despite numerous trials comparing diverse pancreatico-enteric anastomosis techniques and other adjunctive strategies (pancreatic duct stenting, somatostatin analogues, etc), currently, there is no clear consensus regarding the ideal method of pancreatico-enteric anastomosis. METHODS: An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the best contemporary literature concerning pancreatico-enteric anastomosis and worked to develop a position statement on pancreatic anastomosis after pancreatoduodenectomy. RESULTS: There is inherent risk assumed by creating a pancreatico-enteric anastomosis based on factors related to the gland (eg, parenchymal texture, disease pathology). None of the technical variations of pancreaticojejunal or pancreaticogastric anastomosis, such as duct-mucosa, invagination method, and binding technique, have been found to be consistently superior to another. Randomized trials and meta-analyses comparing pancreaticogastrostomy versus pancreaticojejunostomy yield conflicting results and are inherently prone to bias due to marked heterogeneity in the studies. The benefit of stenting the pancreatico-enteric anastomosis to decrease clinically relevant postoperative pancreatic fistula is not supported by high-level evidence. While controversial, somatostatin analogues appear to decrease perioperative complications but not mortality, although consistent data across the more than 20 studies addressing this topic are lacking. The Fistula Risk Score is useful for predicting postoperative pancreatic fistula as well as for comparing outcomes of pancreatico-enteric anastomosis across studies. CONCLUSION: Currently, no specific technique can eliminate development of clinically relevant postoperative pancreatic fistula. While consistent practice of any standardized technique may decrease the rate of clinically relevant postoperative pancreatic fistula, experienced surgeons can have lower postoperative pancreatic fistula rates performing a variety of techniques depending on the clinical situation. There is no clear evidence on the benefit of internal or external stenting after pancreatico-enteric anastomosis. The use of somatostatin analogues may be important in decreasing morbidity after pancreatoduodenectomy, but it remains controversial. Future studies should focus on novel approaches to decrease the rate of clinically relevant postoperative pancreatic fistula with appropriate risk adjustment. PMID- 28027817 TI - Management of endoscopic retrograde cholangiopancreatography-related perforations: Experience of a tertiary center. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography-induced perforation (EP) is a rare but severe complication. We describe the risk factors, management, and outcome of ERCP-induced perforations in a tertiary center. METHODS: This is a case-control study. All EP cases between March 2004 and February 2015 were compared to a control group without perforation. Data on patients, procedures, presentation, perforation type, radiologic findings, management, and outcome were assessed. RESULTS: Of 6,934 endoscopic retrograde cholangiopancreatographies, 37 patients (0.53%) had EP. Independent risk factors included failure of cannulation, a procedure described as "difficult," performing a precut and resection of a periampullary adenoma. Perforation was diagnosed during the procedure in 7 patients (19%). Median interval for diagnosis was 11 hours (range: 0-201 hours), with 84% diagnosed within 30 hours. The periampullary region was the most common EP site (51%). Twenty-nine patients (78%) were managed conservatively and 8 (22%) were operated. Three patients failed conservative management and required delayed operation. Failure of conservative management had a detrimental effect on morbidity and duration of stay. All patients who required operative intervention had perforation of either the duodenal free wall or the periampullary region. CONCLUSION: Clear risk factors can be used to raise suspicion of EP. Early diagnosis and management are critical for better outcome. This is especially important when operative intervention is indicated. Nonetheless, the majority of patients may be managed conservatively. PMID- 28027818 TI - Laparoscopic colectomy for cancer: Improved compliance with guidelines for chemotherapy and survival. AB - BACKGROUND: Laparoscopic surgery for colon cancer has been demonstrated in clinical trials to have short-term benefits when compared to the open surgical approach. Guidelines of the National Comprehensive Cancer Network recommend that patients with stage III or high-risk stage II colon cancer undergo adjuvant chemotherapy. We hypothesized that laparoscopic colectomy is associated with increased compliance to recommendations for chemotherapy, a lesser time to start of chemotherapy, and increased overall survival. METHODS: The National Cancer Data Base was queried to identify patients with stage III or high-risk stage II colon cancer (T4, positive margins, <12 lymph nodes, or high tumor grade) diagnosed 2010-2012. Patients were divided into laparoscopic colectomy and open colectomy groups. Intent-to-treat analysis was used with converted cases included in the laparoscopic colectomy group. Rates of receiving adjuvant chemotherapy, time from diagnosis and date of operation to start of chemotherapy, and overall survival were compared. RESULTS: A total of 48,257 patients were included for analysis; 18,801 patients underwent laparoscopic colectomy and 29,456 underwent open colectomy. Laparoscopic colectomy patients received adjuvant chemotherapy at a somewhat greater rate than open colectomy (66.2% vs 59.4%, P < .01). Among patients who received chemotherapy, mean time to start of chemotherapy after definitive resection was somewhat less for laparoscopic colectomy than open colectomy (48.7 vs 52.7 days, P < .01). Two-year overall survival was greater for laparoscopic colectomy than open colectomy (81.9% vs 73.2%, P < .01). CONCLUSION: Compared to open colectomy, laparoscopic colectomy is associated with somewhat greater rates of compliance with guidelines for adjuvant chemotherapy for stage III and high-risk stage II colon cancer, as well as a slightly lesser time to start of chemotherapy and improved overall survival. PMID- 28027819 TI - Mortality and readmission of outcomes after discharge from the surgical intensive care unit to long-term, acute-care hospitals. AB - BACKGROUND: Patients with prolonged hospitalizations in the surgical intensive care unit often have ongoing medical needs that require further care at long term, acute-care hospitals upon discharge. Setting expectations for patients and families after protracted operative intensive care unit hospitalization is challenging, and there are limited data to guide these conversations. The purpose of this study was to determine patient survival and readmission rates after discharge from the surgical intensive care unit directly to a long-term, acute care hospital. METHODS: All patients who were admitted to the surgical intensive care unit at an academic, tertiary care medical center from 2009-2014 and discharged directly to long-term, acute-care hospitals were retrospectively reviewed. Patients represented all surgical subspecialties excluding cardiac and vascular surgery patients. Primary outcomes included 30-day readmission, and 1- and 3-year mortality rates following discharge. RESULTS: In total, 296 patients were discharged directly from the surgical intensive care unit to a long-term, acute-care hospital during the study period. There were 190 men (64%) and mean age was 61 +/- 16 years. Mean duration of stay in the surgical intensive care unit was 27 +/- 17 days. The most frequent complication was prolonged mechanical ventilation (277, 94%) followed by pneumonia (139, 47%), sepsis (78, 26%), and acute renal failure (32, 11%); 93% of patients required tracheostomy and enteral feeding access prior to discharge, and 19 patients (6%) were newly dependent on hemodialysis. The readmission rate was 20%. There were 86 deaths within 1 year from discharge (29%) with an overall 3-year mortality of 32%. In a multiple logistic regression analysis, a history of end-stage renal disease had a greater odds of readmission (odds ratio 6.07, P = .028). Patients with history of cancer had greater odds of 1- and 3-year mortality (odds ratio = 2.99, P = .028 and odds ratio 2.56, P = .053, respectively), and patients with a neurologic diagnosis had greater odds of 3-year mortality (odds ratio 4.69, P = .031). Readmission significantly increased the odds of 1- and 3-year mortality (odds ratio 3.12, P = .020 and odds ratio 2.90, P = .027, respectively). Patients who had both private insurance and Medicare had greater odds of 1- and 3-year mortality (odds ratio 10.39, P = .005 and odds ratio 10.65, P = .004, respectively). CONCLUSION: Patients who are discharged to long-term, acute-care hospitals have prolonged hospitalizations with high complication rates. These patients have high readmission and 1-year mortality rates. Patients and families should be counseled regarding these outcomes related to post-intensive care unit recovery after discharge to a long-term, acute-care hospital to allow for realistic expectations of survival after prolonged intensive care unit hospitalization. PMID- 28027820 TI - Dramatic outcome of a "friendly fire". PMID- 28027821 TI - Entrococcus faecalis Elimination in Root Canals Using Silver Nanoparticles, Photodynamic Therapy, Diode Laser, or Laser-activated Nanoparticles: An In Vitro Study. AB - INTRODUCTION: The aim of this study was to compare the efficacy of silver nanoparticles (AgNPs), an 810-nm diode laser (DL), conventional photodynamic therapy (PDT) with the use of indocyanine green (ICG) photosensitizer, and modified PDT with the use of AgNPs for the disinfection of root canals inoculated with Enterococcus faecalis. METHODS: The root canals of 65 extracted human single rooted teeth were prepared, and E. faecalis was incubated in the root canals for 4 weeks. The teeth were then randomly divided into the following 4 experimental groups: the DL group: 810-nm DL irradiation (1 W, 4 times for 10 seconds), the AN group: 5 minutes of irrigation with 5 mL AgNPs (100 ppm), the ICG/DL group: conventional PDT with ICG (1 mg/mL)/810-nm DL (200 mW, 30 seconds), and the AN/ICG/DL group: modified PDT with AgNPs/ICG/810-nm DL (200 mW, 30 seconds). There was also a control group, which consisted of 5 minutes of irrigation with 5 mL 2.5% sodium hypochlorite (n = 9). Samples were obtained from dentin chips before and after the interventions. A reduction in colony count was assessed by counting the colony-forming units. RESULTS: Significant reductions were noted in E. faecalis colony counts in all groups (P < .05). The greatest reduction in colony count (99.12%) was noted in the AN/ICG/DL group (AgNPs/ICG/810-nm diode laser); however, the differences in this respect between the AN/ICG/DL group and the DL (97.41%), AN (94.42%), and control groups (94.61%) were not significant (P > .05). CONCLUSIONS: PDT with ICG, an 810-nm diode laser, and AgNPs has the potential to be used as an adjunct for disinfection of the root canal system. PMID- 28027822 TI - Semaphorin 4D Enhances Angiogenic Potential and Suppresses Osteo-/Odontogenic Differentiation of Human Dental Pulp Stem Cells. AB - INTRODUCTION: To investigate the roles of semaphorin 4D (Sema4D)/plexin-B1 signaling on the angiogenic potential and osteo-/odontogenic differentiation of human dental pulp stem cells (DPSCs) and to uncover the corresponding molecular mechanisms. METHODS: DPSCs were treated with Sema4D (10 MUg/mL) for different time durations. Osteo-/odontogenic differentiation was assessed by quantifying alkaline phosphatase activity, mineralized nodule formation, and osteo /odontogenic gene (ALP, Col1A1, BSP, RUNX2, and DSPP) and protein (Col1A1 and DSPP) expression. Involvement of the Sema4D/plexin-B1 signaling pathway was analyzed by Western blot analysis. Additionally, angiogenic gene and protein expression was assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. In vitro endothelial tube formation assay on Matrigel (BD Biosciences, San Jose, CA) was performed to evaluate the angiogenic inductive potential of the Sema4D-treated DPSCs conditioned medium. Results were analyzed using 1-way analysis of variance and the Student t test. RESULTS: Sema4D significantly inhibited ALP activity and mineralized nodule formation of DPSCs. Furthermore, Sema4D-treated DPSCs displayed marked down-regulation in the expression of osteo-/odontogenic genes (ALP, Col1A1, BSP, RUNX2, and DSPP) as well as proteins (Col1A1 and DSPP). Elevated levels of plexin-B1 and downstream RhoA protein expression together with phosphorylated plexin-B1 confirmed the involvement of Sema4D/plexin-B1 signaling. Protein expression of ErbB2 was up regulated, and Met was slightly down-regulated. Furthermore, Sema4D-treated DPSCs exhibited enhanced expression of vascular endothelial growth factor at both the messenger RNA and protein level. Accordingly, the conditioned medium of Sema4D treated DPSCs promoted the formation of vessel-like structures as shown by the Matrigel assay. CONCLUSIONS: Sema4D markedly enhances the angiogenic potential but suppresses osteo-/odontogenic differentiation of DPSCs. Sema4D/plexin-B signaling was activated via the RhoA-mediated pathway. PMID- 28027823 TI - As Low Dose as Sufficient Quality: Optimization of Cone-beam Computed Tomographic Scanning Protocol for Tooth Autotransplantation Planning and Follow-up in Children. AB - INTRODUCTION: Tooth autotransplantation (TAT) offers a viable biological approach to tooth replacement in children. To enhance the outcome predictability of the TAT procedure, a cone-beam computed tomographic (CBCT)-based surgical planning and transfer technique has been developed. The aim of this study was to optimize the CBCT scanning protocol to achieve a dose as low as possible and to maintain sufficient image quality. METHODS: A sectional head phantom (SK150; The Phantom Laboratory, Salem, NY) was scanned using 18 exposure protocols in 3 different CBCT machines: 3D Accuitomo 170 (Morita, Kyoto, Japan), ProMax 3D MAX (Planmeca, Helsinki, Finland), and NewTom VGI EVO (QR Verona, Verona, Italy). The effective dose (ED) was calculated using Monte Carlo simulation and pediatric voxel phantoms (5- and 8-year-old males and a 12-year-old female). Image quality was assessed by comparing segmented teeth volumes, evaluation of the visibility of the lamina dura, and morphologic surface analysis of 3-dimensional models. A general linear mixed model was fit to combine image quality parameters and radiation effective dose for each protocol in order to rank and compare the protocols examined in the study. RESULTS: The ED for the preoperative scan can be reduced to the range of 74.6-157.9 MUSv, with ProMax with ultra-low-dose high definition reconstruction (Planmeca) 100 * 90 scoring the highest. The ED for the postoperative scan can be reduced to the range of 24.2-41.5 MUSv with ProMax with ultra-low-dose normal-dose reconstruction 50 * 55 and NewTom 50 * 50 with the standard mode scoring the highest. CONCLUSIONS: A considerable reduction in the pediatric ED can be achieved while maintaining sufficient image quality for tooth autotransplantation planning and follow-up using the dose optimization protocols. PMID- 28027824 TI - Protective effect of chamomile (Matricaria recutita L.) decoction extract against alcohol-induced injury in rat gastric mucosa. AB - BACKGROUND: Matricaria recutita L. (Asteraceae), German chamomile, has been widely used in the traditional Tunisian medicine because of having the powerful health benefits. the current study was conducted to determine the protective effect of chamomile (Matricaria recutita L.) decoction extract (CDE) in ethanol induced ulcer and oxidative stress on gastric mucosa in rat. METHODS: Adult male wistar rats were used and divided into seven groups: Control, EtOH, EtOH+various doses of CDE (25, 50 and 100mg/kg, b.w.), EtOH+famotidine (FAM) and EtOH+ascorbic acid (AA). Gastric ulceration was induced by EtOH (4g/kg, b.w. p.o.). RESULTS: Firsly, we found that acute alcohol administration leads to mark macroscopic and histologic changes in gastric mucosa. EtOH also induced lipoperoxidation (486.99%), thiol (-SH) groups decrease (40.98%) as well as antioxidant enzyme activity depletion such as superoxide dismutase (SOD) (49.05%), catalase (CAT) (46.80%) and glutathione peroxidase (GPx) (38.20%). Our results also demonstrated that alcohol intoxication increased tissue and plasmatic hydrogen peroxide, calcium and free iron levels. More importantly, CDE reversed all macroscopic, histologic and biochemical changes induced by EtOH administration. CONCLUSION: A potential gastropreotective effect of CDE against EtOH-induced ulcer and oxidative stress might be partially to its antioxidant properties as well as to various gastric mucosal defense mechanisms, including protection of gastric sulfhydryls and its opposite effect on some intracellular mediators such as free iron, hydrogen peroxide and calcium. PMID- 28027825 TI - Inflammatory bowel disease among patients with psoriasis treated with ixekizumab: A presentation of adjudicated data from an integrated database of 7 randomized controlled and uncontrolled trials. AB - BACKGROUND: Inflammatory bowel disease (IBD) occurs more frequently in patients with psoriasis. The 2 diseases have significant genetic overlap, but the pathogenesis underlying their co-occurrence is unknown. OBJECTIVE: We sought to report adjudicated IBD cases (Crohn's disease [CD] and ulcerative colitis [UC]) in patients exposed to ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A. METHODS: Adverse events (AEs) integrated from 7 randomized controlled and uncontrolled trials were analyzed for the controlled induction period, controlled maintenance period, and all ixekizumab treated patients. Suspected IBD cases were reviewed by blinded external experts using internationally recognized criteria (Registre Epidemiologique des Maladies de l'Appareil Digestif registry). RESULTS: In all, 4209 patients (6480 patient exposure years) were exposed to ixekizumab. Suspected CD (N = 12) or UC (N = 17) AEs were reported; 19 were adjudicated as definite/probable IBD (CD, N = 7, incidence rate = 1.1/1000 patient-exposure years; UC, N = 12, incidence rate = 1.9/1000 patient-exposure years). Among these, 3 occurred during induction (CD, N = 1; UC, N = 2) and 7 during maintenance (CD, N = 4; UC, N = 3). Twelve of 16 patients with reported IBD history have not had an IBD treatment-emergent AE/serious AE to date. LIMITATIONS: Clinical review (adjudication) was not prespecified. AE data collected post-hoc may have been limited by length of time from occurrence. CONCLUSION: From an integrated database of 7 ixekizumab psoriasis trials, CD and UC cases were uncommon (<1%). PMID- 28027826 TI - Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. AB - BACKGROUND: Hand, foot, and mouth disease is a contagious viral infection usually affecting children. A resurgence of cases in adults, mainly caused by coxsackievirus A6 and with an atypical and more severe presentation, has taken place. OBJECTIVE: The goal was to examine the clinical, histologic, and immunohistochemical features of this disease in adults. METHODS: This is a retrospective study on documented cases of adult hand, foot, and mouth disease from France's Dermatology Department of Strasbourg University Hospital and Bel Air Hospital in Thionville. RESULTS: Six patients with severe and atypical presentation were included, 4 caused by coxsackievirus A6. The histologic features were: spongiosis, neutrophilic exocytosis, massive keratinocyte necrosis, shadow cells in the upper epidermis, vacuolization of basal cells, necrotic cells in follicles and sweat glands, dense superficial dermal infiltrate of CD3+ lymphocytes, and strong granulysin expression. LIMITATIONS: This is a retrospective case series. CONCLUSION: In adult patients presenting with atypical hand, foot, and mouth disease caused by coxsackievirus A6, biopsy specimens show distinctive changes in the epidermis but also in adnexal structures. The inflammatory infiltrate is made of T cells with a cytotoxic profile, with numerous granulysin-positive cells, as observed in severe drug-induced eruption with necrosis of keratinocytes. PMID- 28027827 TI - Recurrence of moderately dysplastic nevi with positive histologic margins. AB - BACKGROUND: The Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group recently published a consensus statement that incompletely excised moderately dysplastic nevi (MDN) without clinical residual pigmentation can be observed and not re-excised. However, data regarding recurrence of MDN with positive histologic margins are quite scant. OBJECTIVE: We sought to extend the reported findings with a study to determine the recurrence rate of MDN with positive histologic margins. METHODS: We performed a retrospective study on MDN with positive histologic margins that were not re-excised and for which at least 1 year of clinical follow-up was available. RESULTS: We found a total of 147 such nevi from January 1, 2007, to December 31, 2013. Six MDN (5 compound and 1 junctional) or 4% recurred with an average recurrence time of 1.7 years. All of these MDN were evaluated by shave biopsies. LIMITATIONS: Subjectivity in grading of atypia is a limitation of this study. CONCLUSION: These data from a large study focusing exclusively on recurrence of MDN with positive histologic margins support the conclusion of the Pigmented Lesion Subcommittee that incompletely excised MDN do not require re-excision. PMID- 28027828 TI - Prognosis and adjacent segment disease after lumbar spinal fusion surgery for destructive spondyloarthropathy in long-term hemodialysis patients. AB - BACKGROUND: Lumbar destructive spondyloarthropathy (DSA) is a serious complication in long-term hemodialysis patients. There have not been many reports regarding the surgical management for lumbar DSA. In addition, the adjacent segment pathology after lumbar fusion surgery for DSA is unclear. The objective of this study was to assess the clinical outcome and occurrence of adjacent segmental disease (ASD) after lumbar instrumented fusion surgery for DSA in long term hemodialysis patients. MATERIALS AND METHODS: A consecutive series of 36 long-term hemodialysis patients who underwent lumbar instrumented fusion surgery for DSA were included in this study. The mean age at surgery was 65 years. The mean follow-up period was 4 years. Symptomatic ASD was defined as symptomatic spinal stenosis or back pain with radiographic ASD. The Japanese Orthopedic Association score (JOA score), recovery rate (Hirabayashi method), complications, and reoperation were reviewed. RESULTS: The mean JOA score significantly increased from 13.5 before surgery to 21.3 at the final follow-up. The mean recovery rate was 51.4%. Six of the 36 patients died within 1 year after index surgery. One patient died due to perioperative complication. Symptomatic ASD occurred in 43% (13 of 30) of the cases. Of these 13 cases, 5 had adjacent segment disc degeneration and 8 had adjacent segment spinal stenosis. Three cases (10%) required reoperation due to proximal ASD. Multi-level fusion surgery increased the risk of ASD compared with single-level fusion surgery (59% vs. 23%). The recovery rate was significantly lower in the ASD group than the non-ASD group (38% vs. 61%). DISCUSSION: This study demonstrated that symptomatic ASD occurred in 43% of patients after surgery for lumbar DSA. A high mortality rate and complication rate were observed in long-term hemodialysis patients. Therefore, care should be taken for preoperative planning for surgical management of DSA. PMID- 28027829 TI - Complications of total hip arthroplasty following solid organ transplantation. AB - PURPOSE: Solid organ transplants (SOT) continue to increase with recipients living longer than ever before. The lifelong immunosuppression in these patients also may place them at increased risk for postoperative complications. The efficacy of total hip arthroplasty (THA) in this patient population is undisputed but previous studies investigating the complication profiles in these patients often are underpowered to identify rare complications as well as make comparisons between individual organs. The purpose of this study was to use a large database to compare complications of a combined SOT cohort as well as each individual organ to a control population. METHODS: A search of the entire Medicare database from 2005 to 2011 was performed using International Classification of Disease version 9 (ICD-9) codes to identify patients who underwent THA after one or more solid organ transplants. A large cohort of patients served as a control with minimum 2-year follow-up. Post-operative complications at 30-day, 90-day, and overall time points were investigated. RESULTS: Transplant patients carry more medical comorbidities and are prone to increased medical complications, dislocations (OR 1.45, p < 0.001), need for irrigation and debridement (OR 1.90, p < 0.001), and periprosthetic infection (OR 1.69, p < 0.001) compared to patients without SOT. Total hip arthroplasty after renal transplantation has the worst complication profile of the individual organs whereas lung and pancreas transplants were no different than control with regard to overall surgical complications. CONCLUSIONS: The complications of THA after SOT vary by individual organ and these results may aid in patient selection and perioperative patient counseling. PMID- 28027831 TI - A new method for scar tissue assessment: Modified POSAS observer scale. PMID- 28027830 TI - Erratum to "Systematic versus on-demand early palliative care: A randomised clinical trial assessing quality of care and treatment aggressiveness near the end of life" [Eur J Cancer 69 (2016) 110-118]. PMID- 28027832 TI - Analysis of the factors affecting outcome after combat-related cranial defect reconstruction. AB - INTRODUCTION: Reports on the outcomes of cranioplasty after combat-related injuries are relatively rare in the current literature. We present our results on the reconstruction of cranial defects resulting from injuries sustained in combat, comparing outcomes using autologous (iliac bone) grafts or (acrylate) allografts, and analysis of other factors that may influence the final outcome. MATERIAL AND METHODS: The study comprised 207 patients with cranial defects resulting from combat-related injuries, repaired with autografts or allografts. The final outcome was defined at least 5 years postoperatively on the basis of cosmetic restoration and the existence of complications as successful (acceptable cosmetic restoration + absence of complications) or unsuccessful (poor cosmetic restoration or acceptable cosmetic restoration + complications). RESULTS: Successful outcomes were achieved in 83.6% of patients; there was no operative mortality. There were 25 instances of complications: postoperative infection (n = 15, allograft (7/53), autograft (8/154)), autograft resorption (n = 8), and in two cases, graft luxation. Poor cosmetic restoration was noted in 9 (4.3%) patients who had received an autograft. CONCLUSIONS: Thin and poorly vascularized skin, a surface area of the defect larger than 88 cm2, previous local infection and communication with paranasal cavities significantly influenced outcomes after combat-related cranioplasty, the final three being independent predictors of an unsuccessful outcome. PMID- 28027833 TI - Usefulness of a healthcare database for epidemiological research in atrial fibrillation. AB - BACKGROUND: Big data are gaining attention as a valuable resource for providing insights into a range of issues and questions in healthcare. We evaluated the capacity of a Japanese healthcare database to conduct epidemiological research in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: We examined data collected between April 2008 and September 2013 in a Japanese healthcare database. Prior to the risk factor analysis, we validated the criteria for defining the occurrence of a stroke, systemic embolic event (SEE), and intracranial bleeding event during the study period. The validity was considered appropriate based on the resulting high positive predictive values. The data of 18,998 NVAF patients demonstrated that the incidence rates of stroke, SEE, and any bleeding events were 2.2, 0.08, and 2.4 per 100 patient-years, respectively. In patients who had not been treated with an anticoagulant, incidence of stroke significantly increased in higher CHADS2 or CHA2DS2-VASc score, 1.7 and 1.5 fold by 1 point increase, respectively. The use of a proton pump inhibitor (PPI) was also identified as an independent risk factor for stroke. In patients who had been treated with an anticoagulant, the independent risk factors for any bleeding events were hypertension, renal dysfunction, hepatic failure, medical history of stroke, older age (>=65 years), use of nonsteroidal anti-inflammatory drug, and PPIs. CONCLUSION: The data obtained in this study were comparable with results obtained in prospective cohort studies conducted in Japan. PMID- 28027834 TI - Second-order quadrupolar line shapes under molecular dynamics: An additional transition in the extremely fast regime. AB - NMR spectroscopy is a powerful tool for probing molecular dynamics. For the classic case of two-site exchange, NMR spectra go through the transition from exchange broadening through coalescence and then motional narrowing as the exchange rate increases passing through the difference between the resonance frequencies of the two sites. For central-transition spectra of half-integer quadrupolar nuclei in solids, line shape change due to molecular dynamics occurs in two stages. The first stage occurs when the exchange rate is comparable to the second-order quadrupolar interaction. The second spectral transition comes at a faster exchange rate which approaches the Larmor frequency and generally reduces the isotropic quadrupolar shift. Such a two-stage transition phenomenon is unique to half-integer quadrupolar nuclei. A quantum mechanical formalism in full Liouville space is presented to explain the physical origin of the two-stage phenomenon and for use in spectral simulations. Variable-temperature 17O NMR of solid NaNO3 in which the NO3- ion undergoes 3-fold jumps confirms the two-stage transition process. The spectra of NaNO3 acquired in the temperature range of 173 413K agree well with simulations using the quantum mechanical formalism. The rate constants for the 3-fold NO3- ion jumps span eight orders of magnitude (102-1010s 1) covering both transitions of the dynamic 17O line shape. PMID- 28027835 TI - Toward nitrogen-14 nuclear quadrupole resonance imaging by nutation experiments performed with a radio-frequency field gradient. AB - Until now, NQR imaging has been considered mainly in the case of Chlorine-35. This is a spin 3/2 resonating at relatively high frequency (around 30MHz) thus affording a favorable sensitivity. Conversely, Nitrogen-14 (spin 1) NQR is much less sensitive because its resonances frequencies are below 6MHz. In contrast to already existing methodologies for object localization by 14N NQR, we present here a new, more straightforward, approach and the principles of space dependent 14N Quadrupole Resonance are laid down. The method is based on nutation curves obtained with an inhomogeneous radio-frequency field produced by a dedicated transmit-receive coil. The gradient created that way does not need to be uniform although more accurate results would be obtained with a uniform gradient. Nutation curves have been simulated by a specially designed algorithm which takes into account the 14N Quadrupole Resonance particularities including the so-called powder average. Preliminary experiments were carried out with the highest resonance frequency (4.64MHz) of sodium nitrite (NaNO2). A cylindrical sample of powder sodium nitrite containing a spacer was used. Simulations of the corresponding nutation curves not only demonstrate the existence of this spacer but, in addition, provide its position and its thickness. This clearly ascertains the feasibility of 14N Quadrupole Resonance imaging. PMID- 28027836 TI - Frit inlet field-flow fractionation techniques for the characterization of polyion complex self-assemblies. AB - Polymer self-assemblies joining oppositely charged chains, known as polyion complexes (PICs), have been formed using poly(ethyleneoxide - b - acrylic acid)/poly(l-lysine), poly(ethyleneoxide-b-acrylic acid)/dendrigraft poly(l lysine) and poly[(3-acrylamidopropyl) trimethylammonium chloride - b - N - isopropyl acrylamide]/poly(acrylic acid). The self-assemblies have been first characterized in batch by Dynamic Light Scattering. In a second step, their analysis by Flow Field-Flow Fractionation techniques (FlFFF) was examined. They were shown to be very sensitive to shearing, especially during the focus step of the fractionation, and this led to an incompatibility with asymmetrical FlFFF. On the other hand, Frit Inlet FlFFF proved to be very efficient to observe them, either in its symmetrical (FI-FlFFF) or asymmetrical version (FI-AsFlFFF). Conditions of elution were found to optimize the sample recovery in pure water. Spherical self-assemblies were detected, with a size range between 70-400nm depending on the polymers. Compared to batch DLS, FI-AsFlFFF clearly showed the presence of several populations in some cases. The influence of salt on poly(ethyleneoxide-b-acrylic acid) (PEO-PAA) 6000-3000/dendrigraft poly(l-lysine) (DGL 3) was also assessed in parallel in batch DLS and FI-AsFlFFF. Batch DLS revealed a first process of swelling of the self-assembly for low concentrations up to 0.8M followed by the dissociation. FI-AsFlFFF furthermore indicated a possible ejection of DGL3 from the PIC assembly for concentrations as low as 0.2M, which could not be observed in batch DLS. PMID- 28027837 TI - Rapid determination of six carcinogenic primary aromatic amines in mainstream cigarette smoke by two-dimensional online solid phase extraction combined with liquid chromatography tandem mass spectrometry. AB - A fully automated, rapid, and reliable method for simultaneous determination of six carcinogenic primary aromatic amines (AAs), including o-toluidine (o-TOL), 2, 6-dimethylaniline (2, 6-DMA), o-anisidine (o-ASD), 1-naphthylamine (1-ANP), 2 naphthylamine (2-ANP), and 4-aminobiphenyl (4-ABP), in mainstream cigarette smoke was established. The proposed method was based on two-dimensional online solid phase extraction combined with liquid chromatography tandem mass spectrometry (SPE/LC-MS/MS). The particulate phase of the mainstream cigarette smoke was collected on a Cambridge filter pad and pretreated via ultrasonic extraction with 2% formic acid (FA), while the gas phase was trapped by 2% FA without pretreatment for determination. The two-dimensional online SPE comprised of two cartridges with different absorption characteristics was applied for sample pretreatment. Analysis was performed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) under multiple reaction monitoring mode. Each sample required about 0.5h for solid phase extraction and analysis. The limit of detections (LODs) for six AAs ranged from 0.04 to 0.58ng/cig and recoveries were within 84.5%-122.9%. The relative standard deviations of intra- and inter-day tests for 3R4F reference cigarette were less than 6% and 7%, respectively, while no more than 7% and 8% separately for a type of Virginia cigarette. The proposed method enabled minimum sample pretreatment, full automation, and high throughput with high selectivity, sensitivity, and accuracy. As a part of the validation procedure, fifteen brands of cigarettes were tested by the designed method. PMID- 28027838 TI - Extraction, isolation, and aromatase inhibitory evaluation of low-polar ginsenosides from Panax ginseng leaves. AB - A hyphenated accelerated solvent extraction (ASE) technique was elaborately coupled with centrifugal partition chromatography (CPC), ultra-high-performance liquid chromatography (UHPLC), and photo-diode array detector (PDA). This approach was applied to obtain low-polar ginsenoside fractions from the leaves of Panax ginseng. The CPC fractions were isolated and analyzed using the hyphenated technique, and followed by testing and evaluation of their aromatase inhibitory effects. Subsequently, the aromatase inhibition rates of the compositions in the CPC fractions were calculated using a multivariable linear regression model. A biphasic ethyl acetate/n-butanol/ethanol/water solvent system with respective volume ratios of 10:2:2:8 was used for the ASE and CPC separation of 200g of leaves of P. ginseng raw material. The (lower) aqueous phase of the abovementioned solvent system was used as the extraction solvent. The ginsenosides were subjected to ASE, and the extraction solution was pumped into the sample loop and then directly into the CPC column. The CPC fractions were collected and monitored by an online UHPLC/PDA system at 5-min intervals. The aromatase inhibitory activities of CPC fractions were analyzed by a fluorescence method, with mathematical calculations indicating that the inhibition rates of ginsenosides Rk1, Rg5, Rs5, 20R-Rg3, and Rs4 exceeded 50.00%; indicating that the aforementioned chemical compounds have potential for further development. The results were validated by comparison with authentic standards, indicating that the method used in this research was accurate and advantageous for matrix analysis. PMID- 28027839 TI - Countercurrent chromatography separation of saponins by skeleton type from Ampelozizyphus amazonicus for off-line ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry analysis and characterisation. AB - Ampelozizyphus amazonicus Ducke (Rhamnaceae), a medicinal plant used to prevent malaria, is a climbing shrub, native to the Amazonian region, with jujubogenin glycoside saponins as main compounds. The crude extract of this plant is too complex for any kind of structural identification, and HPLC separation was not sufficient to resolve this issue. Therefore, the aim of this work was to obtain saponin enriched fractions from the bark ethanol extract by countercurrent chromatography (CCC) for further isolation and identification/characterisation of the major saponins by HPLC and MS. The butanol extract was fractionated by CCC with hexane - ethyl acetate - butanol - ethanol - water (1:6:1:1:6; v/v) solvent system yielding 4 group fractions. The collected fractions were analysed by UHPLC HRMS (ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry) and MSn. Group 1 presented mainly oleane type saponins, and group 3 showed mainly jujubogenin glycosides, keto-dammarane type triterpene saponins and saponins with C31 skeleton. Thus, CCC separated saponins from the butanol-rich extract by skeleton type. A further purification of group 3 by CCC (ethyl acetate - ethanol - water (1:0.2:1; v/v)) and HPLC-RI was performed in order to obtain these unusual aglycones in pure form. PMID- 28027840 TI - Defining epidemics in computer simulation models: How do definitions influence conclusions? AB - Computer models have proven to be useful tools in studying epidemic disease in human populations. Such models are being used by a broader base of researchers, and it has become more important to ensure that descriptions of model construction and data analyses are clear and communicate important features of model structure. Papers describing computer models of infectious disease often lack a clear description of how the data are aggregated and whether or not non epidemic runs are excluded from analyses. Given that there is no concrete quantitative definition of what constitutes an epidemic within the public health literature, each modeler must decide on a strategy for identifying epidemics during simulation runs. Here, an SEIR model was used to test the effects of how varying the cutoff for considering a run an epidemic changes potential interpretations of simulation outcomes. Varying the cutoff from 0% to 15% of the model population ever infected with the illness generated significant differences in numbers of dead and timing variables. These results are important for those who use models to form public health policy, in which questions of timing or implementation of interventions might be answered using findings from computer simulation models. PMID- 28027842 TI - Editorial to the special issue on perspectives on human probabilistic inference and the 'Bayesian brain'. PMID- 28027841 TI - Kawasaki Disease With Coronary Artery Aneurysms: Psychosocial Impact on Parents and Children. AB - INTRODUCTION: For those living with Kawasaki disease and coronary artery aneurysms, little is known about the psychosocial burden faced by parents and their children. METHODS: Exploratory, descriptive, mixed-methods design examining survey and interview data about health-related uncertainty, intrusiveness, and self-efficacy. RESULTS: Parents' uncertainty was associated with missed diagnosis, higher income, and maternal education. Higher uncertainty scores among children were associated with absence of chest pain and lower number of echocardiograms. High intrusiveness scores among parents were associated with previous cardiac catheterization, use of anticoagulants, lower parent education and income, and missed diagnosis. High intrusiveness scores among children were associated with high paternal education. Children's total self-efficacy scores increased with chest pain and larger aneurysm size. Qualitative analysis showed two central themes: Psychosocial Struggle and Cautious Optimism. DISCUSSION: Negative illness impact is associated with a more intense medical experience and psychosocial limitations. Timely assessment and support are warranted to meet parents' and children's needs. PMID- 28027843 TI - Phaeoacremonium Tenosynovitis of the Wrist. AB - A 79-year-old man presented with a painless, soft, subcutaneous mass lesion of the right volar wrist that had been slowly growing for 3 years. A cloudy, yellow serous effusion was aspirated from the punctured mass, from which Phaeoacremonium spp., an extremely rare cause of tenosynovitis, was isolated in culture. Total synovectomy was performed without the use of antifungal agents. No recurrence or complications occurred as of 6 months after surgery. Fungal infection is rare but should be considered in the differentiation of chronic tenosynovitis. PMID- 28027844 TI - Effect of Hospital Volume on Success of Thumb Replantation. AB - PURPOSE: Hospital volume-outcome association has been examined for many high-risk surgical procedures. Little is known about this association for thumb replantation, a complex but essential surgical procedure to restore hand function. We aimed to determine patient and hospital characteristics that are associated with increased probability of replanted thumb survival and to examine volume-outcome association among hospitals that performed thumb replantation. METHODS: We used data from 2008 to 2012 from the National Trauma Data Bank. Our sample included 773 patients who underwent thumb replantation procedures in 1 of 180 hospitals during the study period. We used patient-level logistic models to examine the association between a hospital's annual thumb replantation volume and the probability of survival for the replanted thumb. RESULTS: Patients with drug/alcohol abuse record, and higher numbers of comorbid conditions had lower odds of replant success. Treatment in teaching hospitals and hospitals with a higher volume of thumb replantation increased the odds of replant survival. The risk-adjusted replantation success rate in high-volume hospitals was 12% higher than in low-volume hospitals. CONCLUSIONS: Regionalization of digit replantation procedures to high-volume centers can achieve the highest rate of successful revascularization. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic/Decision Analysis II. PMID- 28027845 TI - Differences in the Treatment of Distal Radius Fractures by Hand Fellowship Trained Surgeons: A Study of ABOS Candidate Data. AB - PURPOSE: The management of distal radius fractures differs based on the nature of the fracture and the experience of the surgeon. We hypothesized that patients requiring surgical intervention would undergo different procedures when in the care of a surgeon with subspecialty training in hand surgery as compared with surgeons with no subspecialty training in hand surgery. METHODS: We queried the ABOS database for case log information submitted for part II of the ABOS examination. Queries for all codes involved with distal radius fracture management were combined with associated codes for the management of median nerve neuropathy, triangular fibrocartilage complex tears, ulnar shaft, and styloid fractures. Hand fellowship trained orthopedic surgeons were compared with those completing other fellowships and non-fellowship trained orthopedic surgeons during their board collection period. RESULTS: During the study period, 2,317 orthopedic surgeons reported treatment of 15,433 distal radius fractures. Of these surgeons, 411 had hand fellowship training. On a per surgeon basis, fellowship trained hand surgeons operatively treated more multifragment intra articular distal radius fractures than their non-hand fellowship trained counterparts (5.3 vs 1.2). Additional procedures associated with the management of distal radius fractures were also associated with the fellowship training of the treating surgeon. CONCLUSIONS: Among orthopedic surgeons taking part II of the ABOS certifying examination, differences exist in the type, management, and reporting of distal radius fractures among surgeons with different areas of fellowship training. CLINICAL RELEVANCE: This study describes the association of hand surgery fellowship training on the choice of intervention for distal radius fractures and associated conditions. PMID- 28027846 TI - Pediatric Scaphoid Proximal Pole Nonunion With Avascular Necrosis. AB - A 13-year-old, right hand-dominant, otherwise healthy boy presented with left wrist pain 19 months after a nonmotorized scooter injury. Radiographs and magnetic resonance imaging at presentation demonstrated proximal pole scaphoid nonunion with avascular necrosis of the proximal fragment. Operative and nonsurgical treatment options were discussed and the family elected for an attempt at nonsurgical management. The patient was placed in a short-arm thumb spica cast, with a window for a bone stimulator, for 14 weeks. At the conclusion of the treatment, the pain had resolved and x-ray and computed tomography scan demonstrated bony union. The authors recommend considering an initial trial of nonsurgical management for treatment of all pediatric scaphoid nonunions. PMID- 28027847 TI - Improvement influenza HA2 DNA vaccine cellular and humoral immune responses with Mx bio adjuvant. AB - Immunization with DNA vaccines as a novel alternative to conventional vaccination strategy requires adjuvant for improving vaccine efficacy. The conserved immunogenic HA2 subunit, which harbors neutralizing epitopes is a promising vaccine candidate against influenza viruses. In this study, for the first time we explore the idea of using host interferon inducible Mx protein to increase the immunogenicity of HA2 H9N2 influenza DNA vaccine. The potency and safety of the Mx adjuvanted-HA2 vaccine was evaluated in BALB/c mice by different prime-boost strategies. To assess the effect of the vaccination on the virus clearance rate, mice were challenged with homologous influenza virus. Administration of the adjuvanted vaccine and boosting with the same regimen could effectively enhance both humoral and cellular immune responses in treated mice. These data demonstrated that Mx as host defense peptide can be potentiated for improving influenza vaccine efficacy. PMID- 28027848 TI - Preface: Issue 39. PMID- 28027849 TI - Chemotherapy for epithelial ovarian, fallopian tube and primary peritoneal cancer. AB - Chemotherapy plays a key role in the management of women with epithelial ovarian, fallopian tube and primary peritoneal cancer (EOC). Platinum- and taxane-based regimens are the standard of care for adjuvant treatment in early-stage EOC and first-line therapy for advanced stage disease. Efforts to define the optimal scheduling, timing and route of administration are ongoing. The majority of women with EOC will develop recurrent disease, and treatment options for these women are depend on the time that has elapsed from first-line therapy. Platinum-based doublet chemotherapy is preferred for women with platinum-sensitive recurrent cancer. In platinum-resistant relapsed EOC, options are much more limited, and careful consideration of symptoms, performance status, anticipated toxicity and quality of life is essential when recommending chemotherapy for these women. PMID- 28027850 TI - Nine-year Experience: Prophylactic Cranial Irradiation in Extensive Disease Small cell Lung Cancer. AB - BACKGROUND: In 2007, the European Organization for Research and Treatment of Cancer (EORTC) study (ClinicalTrials.gov identifier, NCT00016211) demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) for extensive disease (ED) small-cell lung cancer (SCLC). Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo magnetic resonance imaging (MRI) of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain MRI findings. MATERIALS AND METHODS: We examined the medical records of 136 patients with ED SCLC who had initially responded to chemotherapy and undergone PCI from 2007 to 2015. The outcomes, radiation toxicity, neurologic progression-free survival, and OS after PCI were analyzed. Survival and correlations were calculated using log rank and univariate Cox proportional hazard ratio analyses. RESULTS: The median OS and the median neurologic progression-free survival after PCI was 12 and 19 months, respectively. No significant survival difference was seen for patients who had undergone MRI before PCI compared with patients who had undergone contrast-enhanced computed tomography (P = .20). Univariate analysis for OS did not show a statistically significant effect for known cofactors. CONCLUSION: In the present cohort, PCI was associated with improved survival compared with the PCI arm of the EORTC trial, with a nearly doubled median OS period. Also, the median OS was prolonged by 2 months compared with the irradiation arm of the Japanese trial. PMID- 28027851 TI - Spatial learning deficits in Parkinson's disease with and without mild cognitive impairment. AB - BACKGROUND: Several MRI studies have demonstrated hippocampal atrophy in Parkinson's disease (PD), a structure considered a key element in spatial learning. Despite this, no study has been undertaken to investigate spatial navigation in PD using a virtual version of the Morris water maze, which is the gold standard for testing hippocampal function in rodents. METHODS: We studied 17 cognitively unimpaired PD patients, 12 PD patients with mild cognitive impairment (MCI) and 15 controls in a virtual water maze procedure. RESULTS: Measured by the main outcome parameters latency to locate the target and heading error (average difference between direction of movement toward anticipated target and real direction toward the target), controls performed significantly better on the virtual water maze task than cognitively unimpaired PD patients or PD patients with MCI, while there was no significant difference between latter two groups. CONCLUSIONS: The virtual water maze test differentiates PD patients from controls, but does not distinguish between cognitively normal and cognitively impaired PD patients, indicating a possible dopamine dependent component in spatial learning. Spatial performance deficits might thus constitute very early signs of dopamine depletion independent of the presence of MCI in Parkinson's disease. PMID- 28027853 TI - A haemovigilance team provides both significant financial and quality benefits in a University Hospital. AB - BACKGROUND: Haemovigilance is the process of surveillance of blood transfusion procedures including unexpected hazards and reactions during the transfusion pathway in both donors and recipients. The haemovigilance team aims to increase blood transfusion safety and to decrease both morbidity and mortality in donors and recipients. The team collects data about transfusion reactions and incidents, instructs the involved health workers and assures the tracing of blood components. The haemovigilance team at the University Hospitals Leuven has played a pioneering role in the development of haemovigilance in Belgium Although the literature about safety and quality improvements by haemovigilance systems is abundant, there are no published data available measuring their financial impact in a hospital. Therefore, we studied the costs and returns of the haemovigilance team at the University Hospitals Leuven. MATERIAL AND METHODS: This study has a descriptive explorative design. Research of the current costs and returns of the haemovigilance team were based upon data from the Medical Administration of the hospital. Data were analyzed descriptively. RESULTS: The haemovigilance team of the University Hospitals Leuven is financially viable: the direct costs are covered by the annual financial support of the National Public Health Service. The indirect returns come from two important tasks of the haemovigilance team itself: correction of the electronic registration of administered blood component and improvement of the return of conform preserved blood components to the blood bank. DISCUSSION: Besides safety and quality improvement, which are obviously their main goals, the haemovigilance team also implies a financial benefit for the hospital. PMID- 28027855 TI - Neuromodulation for chronic pain and double incontinence in children. PMID- 28027854 TI - Exome sequencing in children of women with skewed X-inactivation identifies atypical cases and complex phenotypes. AB - BACKGROUND: More than 100 X-linked intellectual disability (X-LID) genes have been identified to be involved in 10-15% of intellectual disability (ID). METHOD: To identify novel possible candidates, we selected 18 families with a male proband affected by isolated or syndromic ID. Pedigree and/or clinical presentation suggested an X-LID disorder. After exclusion of known genetic diseases, we identified seven cases whose mother showed a skewed X-inactivation (>80%) that underwent whole exome sequencing (WES, 50X average depth). RESULTS: WES allowed to solve the genetic basis in four cases, two of which (Coffin-Lowry syndrome, RPS6K3 gene; ATRX syndrome, ATRX gene) had been missed by previous clinical/genetics tests. One further ATRX case showed a complex phenotype including pontocerebellar atrophy (PCA), possibly associated to an unidentified PCA gene mutation. In a case with suspected Lujan-Fryns syndrome, a c.649C>T (p.Pro217Ser) MECP2 missense change was identified, likely explaining the neurological impairment, but not the marfanoid features, which were possibly associated to the p.Thr1020Ala variant in fibrillin 1. Finally, a c.707T>G variant (p.Phe236Cys) in the DMD gene was identified in a patient retrospectively recognized to be affected by Becker muscular dystrophy (BMD, OMIM 300376). CONCLUSION: Overall, our data show that WES may give hints to solve complex ID phenotypes with a likely X-linked transmission, and that a significant proportion of these orphan conditions might result from concomitant mutations affecting different clinically associated genes. PMID- 28027852 TI - Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice. AB - Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intraperitoneal (i.p.) injection of 1.8 g/kg ethanol or saline, and subsets of both groups were exposed to acute restraint stress for 15 min or controls. Gene expression in the hippocampus was examined using microarray analysis. Genes that were significantly (p < 0.05, q < 0.1) differentially expressed were further evaluated. Bioinformatic analyses were predominantly performed using tools available at GeneNetwork.org, and included gene ontology, presence of cis regulation or polymorphisms, phenotype correlations, and principal component analyses. Comparisons of differential gene expression between groups showed little overlap. Gene Ontology demonstrated distinct biological processes in each group with the combined exposure (RSE) being unique from either the ethanol (NOE) or stress (RSS) group, suggesting that the interaction between these variables is mediated through diverse molecular pathways. This supports the hypothesis that exposure to stress alters ethanol-induced gene expression changes and that exposure to alcohol alters stress-induced gene expression changes. Behavior was profiled in all groups following treatment, and many of the differentially expressed genes are correlated with behavioral variation within experimental groups. Interestingly, in each group several genes were correlated with the same phenotype, suggesting that these genes are the potential origins of significant genetic networks. The distinct sets of differentially expressed genes within each group provide the basis for identifying molecular networks that may aid in understanding the complex interactions between stress and ethanol, and potentially provide relevant therapeutic targets. Using Ptp4a1, a candidate gene underlying the quantitative trait locus for several of these phenotypes, and network analyses, we show that a large group of differentially expressed genes in the NOE group are highly interrelated, some of which have previously been linked to alcohol addiction or alcohol-related phenotypes. PMID- 28027856 TI - The Culture of Hospitality. PMID- 28027857 TI - Structured Reporting: A Tool to Improve Reimbursement. PMID- 28027858 TI - Culture and Diet Among Chinese American Children Aged 9-13 Years: A Qualitative Study. AB - OBJECTIVE: To examine Chinese American children's behaviors, food preferences, and cultural influences on their diet. DESIGN: Qualitative individual interviews using constructs from the proposed model of dietary acculturation. SETTING: Community centers and Chinese schools in Houston, TX. PARTICIPANTS: Twenty-five Chinese American children aged 9-13 years. PHENOMENON OF INTEREST: Diet, favorite restaurants, and parents' cooking and grocery shopping habits. ANALYSIS: Content analysis and thematic data analysis to identify code categories and themes. Coders also identified patterns based on demographic and acculturation factors. RESULTS: Overall, participants described their diets and associated behaviors as Asian and non-Asian. Key themes included preference for Asian and non-Asian foods; consumption of non-Asian foods for breakfast and lunch, but Asian foods for dinner; infrequent dining at restaurants; grocery shopping at Asian and non Asian stores; and familial influences on diet. Acculturated children and children of higher socioeconomic status appeared to prefer and consume a more Westernized/non-Asian diet. CONCLUSIONS AND IMPLICATIONS: Results illustrate that Chinese American children in this study practiced both Asian and non-Asian dietary behaviors. Findings corroborated existing acculturation research with parents and caregivers; supported constructs in the model of dietary acculturation; and provide guidance for research and programs related to dietary behaviors, determinants, and culture among this population. PMID- 28027859 TI - Response to commentary by Goedele M.A. Beckers. PMID- 28027860 TI - From nocturnal frontal lobe epilepsy to Sleep-Related Hypermotor Epilepsy: A 35 year diagnostic challenge. AB - Nocturnal frontal lobe epilepsy (NFLE) is a focal epilepsy with seizures arising mainly during sleep and characterized by complex, often bizarre, motor behavior or sustained dystonic posturing. First described in 1981, it was initially considered a motor disorder of sleep and was named nocturnal paroxysmal dystonia (NPD). The unusual seizure semiology, onset during sleep, and often uninformative scalp EEG and brain MRI make it difficult to distinguish NPD attacks from other non-epileptic nocturnal paroxysmal events, namely parasomnias. The long-debated epileptic origin of the condition was finally demonstrated in 1990 and the term NFLE introduced. Even though many aspects of parasomnias and NFLE have been clarified in the last two decades, the differential diagnosis remains a challenge for clinicians. To address controversial issues and define the diagnostic criteria for NFLE, a Consensus Conference was held in Bologna, Italy in 2014. Major points of agreement emerged on: (i) the relationship of the seizures with sleep and not with the circadian pattern of seizure occurrence; (ii) the possible extrafrontal origin of hypermotor seizures, without substantial differences in seizure semiology. In the wake of the Consensus, the syndrome was renamed Sleep Related Hypermotor Epilepsy (SHE). PMID- 28027861 TI - Situational communication self-confidence among community pharmacists: A descriptive analysis. PMID- 28027862 TI - Predictors of cognitive decline in people with cancer undergoing chemotherapy. AB - PURPOSE: The purpose of this study was to investigate the impact of demographic factors, disease/treatment-related factors, and psychological factors on cognitive function. METHOD: A cross-sectional study was conducted. Participants were recruited from the oncology inpatient units of two hospitals. A convenience sample of 175 patients with cancer who underwent chemotherapy were recruited. The Everyday Cognition Scale (ECog), the Korean version of the Mini Mental State Examination (K-MMSE), Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale, Hospital Anxiety and Depression Scale (HADS), and a questionnaire to collect information about demographic, disease, and treatment information were completed. RESULTS: More participants showed a mild decline in cognitive function and self-reported cognitive decline (39.4%) than had objectively confirmed decline (20%). Notably, 53.7-62.9% of the participants showed memory loss and a decline in divided attention. Demographic factors (age, sex), disease/treatment related factors (chemotherapy cycles, fatigue), and psychological factors (depression) were predictors of cognitive decline in 49.6% of participants. CONCLUSIONS: Old age and cumulative chemotherapy cycles were the main influential factors for objectively confirmed cognitive decline, and fatigue was the most common predictor of self-reported cognitive decline. Depression was one of the predictors of perceived cognitive decline, but it was not significant for objectively measured cognitive function. Thus, treatment-related factors such as fatigue had a greater impact on cognitive decline than psychological factors. PMID- 28027863 TI - An exploration of the transformational potential of supportive mentorship relationships within midwifery education and practice. PMID- 28027864 TI - Characterization of prompt gamma-ray emission with respect to the Bragg peak for proton beam range verification: A Monte Carlo study. AB - In this paper we report a Geant4 simulation study to investigate the characteristic prompt gamma (PG) emission in a water phantom for real-time monitoring of the Bragg peak (BP) during proton beam irradiation. The PG production, emission spatial correlation with the BP, and position preference for detection with respect to the BP have been quantified in different PG energy windows as a function of proton pencil-beam energy from 100 to 200MeV. The PG response to small BP shifts was evaluated using a 2cm-thick slab with different human body materials embedded in a water phantom. Our results show that the prominent characteristic PG emissions of 4.44, 5.21 and 6.13MeV exhibit distinctive correlation with the dose deposition curve. The accuracy in BP position identification using these characteristic PG rays is highly consistent as the beam energy increases from 100 to 200MeV. There exists a position preference for PG detection with respect to the BP position, which has a strong dependence on the proton beam energy and PG energies. It was also observed that a submillimeter shift of the BP position can be realized by using PG signals. These results indicate that the characteristic PG signal is sensitive and reliable for BP tracking. Although the maximization of the PG measurement associated with the BP is difficult, it can be optimized with energy and detection position preferences. PMID- 28027865 TI - Overcoming the Law of the Hidden in Cyberinfrastructures. AB - Cyberinfrastructure projects (CIPs) are complex, integrated systems that require interaction and organization amongst user, developer, hardware, technical infrastructure, and funding resources. Nevertheless, CIP usability, functionality, and growth do not scale with the sum of these resources. Instead, growth and efficient usage of CIPs require access to 'hidden' resources. These include technical resources within CIPs as well as social and functional interactions among stakeholders. We identify approaches to overcome resource limitations following the conceptual basis of Liebig's Law of the Minimum. In so doing, we recommend practical steps towards efficient and scaleable resource use, taking the iPlant/CyVerse CIP as an example. PMID- 28027866 TI - Analysis of Lipoprotein Subfractions in 920 Patients With and Without Type 2 Diabetes. AB - BACKGROUND: It has been demonstrated that diabetic dyslipidaemia is the chief bridge between diabetes and incremental risk of cardiovascular disease in patients with diabetes. However, the characteristics of lipoprotein subfractions distribution in patients with type 2 diabetes (T2D) have not been fully investigated. The aim of present study was to evaluate the distributions of lipoprotein subfractions in T2D patients. METHODS: A total of 920 patients, who have not received lipid-lowering drug treatment previously, were consecutively enrolled in this study. Based on the evidence of diabetes, patients were divided into T2D group (n=204) and non-T2D group (n=716). Both low- and high-density lipoprotein cholesterol (LDL- and HDL-C) subfractions were analysed using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated in patients with and without T2D. RESULTS: Compared with non-T2D individuals, the T2D group manifested significantly lower large HDL-C concentration/HDL subfraction percentage, smaller mean LDL particle size but higher small HDL-C and LDL-C concentrations as well as small HDL and LDL subfraction percentages. Moreover, the data indicated that the small HDL-C/ LDL-C concentrations, the small and large HDL subfraction percentages along with the mean LDL particle size were independently related to the existence of T2D (95% CI=1.009-1.067, p=0.009; 95% CI=0.938-0.983, p=0.001; 95% CI=1.023-1.135, p=0.005; 95% CI= 1.005-1.048, p=0.014; 95% CI=0.940-0.999, p=0.040; respectively) assessed by logistic regression analysis. CONCLUSIONS: The present study indicated that the changes of lipid profile in patients with T2D are characterised by abnormal distributions of lipoprotein subfractions apart from clinically atherogenic dyslipidaemia. PMID- 28027867 TI - A Prospective Study of Total Glans Resurfacing for Localized Penile Cancer to Maximize Oncologic and Functional Outcomes in a Tertiary Referral Network. AB - PURPOSE: Penile cancer is a rare malignancy worldwide, representing only 1% of all cancers affecting men. There are little data outlining the comparative effectiveness of penile preservation techniques and to our knowledge no guidelines regarding their use currently exist. Outcomes data reporting is nonstandardized and followup is not measured consistently. The aim of this study was to analyze the outcomes of total glans resurfacing in terms of oncologic control, form and function in localized penile cancer. MATERIALS AND METHODS: From 2013 to 2015, 19 prospectively enrolled patients underwent total glans resurfacing. Demographics, cosmesis, patient satisfaction and disease recurrence were assessed at followup to quantify oncologic and functional outcomes. At 3 months of followup patients completed the IIEF (International Index of Erectile Function) questionnaire detailing erectile and sexual function, and general satisfaction using a visual analog scale. All statistical analysis was performed with Prism(r) 6. RESULTS: No perioperative complications were experienced. Of the patients 94.7% had complete graft take with a median cosmesis score of 5 of 5 on the visual analog scale. There was 1 local and no regional nodal recurrence at a mean followup of 23 months. One-year progression-free and overall survival rates were 100% and the 1-year recurrence-free survival rate was 95%. Of the patients 81% reported an improved sex life postoperatively. CONCLUSIONS: Total glans resurfacing is a viable and acceptable option for glans preservation in patients with localized penile cancer. It demonstrates acceptable functional and oncologic outcomes. We believe that total glans resurfacing should be considered in all cases of localized penile cancer. PMID- 28027868 TI - Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. AB - PURPOSE: We systematically review the benefits and harms of intravesical therapies for nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Systematic literature searches were performed of Ovid MEDLINE (January 1990 through February 2016), the Cochrane databases and reference lists. Randomized and quasi-randomized trials of intravesical bacillus Calmette-Guerin, mitomycin C, gemcitabine, thiotepa, valrubicin, doxorubicin, epirubicin and interferon vs transurethral bladder tumor resection alone, and head-to-head trials of intravesical therapies were selected. Data were pooled using a random effects model. RESULTS: Overall 39 trials evaluated adjuvant intravesical therapy vs transurethral bladder tumor resection alone. Bacillus Calmette-Guerin was associated with a decreased risk of bladder cancer recurrence (3 trials, RR 0.56, 95% CI 0.43-0.71) and progression (4 trials, RR 0.39, 95% CI 0.24-0.64) (strength of evidence low). Mitomycin C, doxorubicin, epirubicin and thiotepa were also associated with a decreased risk of recurrence, with no difference in risk of progression (strength of evidence low). There were 55 trials that compared one intravesical therapy agent against another. There were no differences between bacillus Calmette-Guerin vs mitomycin C in recurrence risk (RR 0.95, 95% CI 0.81 1.11), but bacillus Calmette-Guerin was associated with a decreased risk of recurrence in the subgroup of trials of maintenance regimens (RR 0.79, 95% CI 0.71-0.87, strength of evidence low). Bacillus Calmette-Guerin was associated with a lower recurrence risk vs doxorubicin, epirubicin, interferon alpha-2a, bacillus Calmette-Guerin plus interferon alpha-2b, and thiotepa (strength of evidence low to moderate). Bacillus Calmette-Guerin was associated with higher rates of local and systemic adverse events than other intravesical agents (strength of evidence low). Head-to-head trials showed no clear differences between standard and lower doses of bacillus Calmette-Guerin in recurrence, progression or mortality risk (strength of evidence low). Limited evidence suggested that bacillus Calmette-Guerin maintenance regimens are associated with reduced recurrence risk vs no further intravesical therapy in responders to induction therapy (strength of evidence low). CONCLUSIONS: For nonmuscle invasive bladder cancer several intravesical therapies are associated with a decreased risk of recurrence vs transurethral bladder tumor resection alone. Bacillus Calmette-Guerin is the only agent associated with a decreased progression risk vs transurethral bladder tumor resection alone, but may be associated with a higher risk of adverse events than other intravesical therapies, indicating trade-offs between potential benefits and harms. PMID- 28027869 TI - New furoxan derivatives for the treatment of ocular hypertension. AB - A small series of water-soluble NO-donor furoxans bearing a basic center at the 4 position, having a wide lipophilic-hydrophilic balance range, and endowed with different NO-release capacities, were synthesized and characterized. Selected members were studied for their IOP-lowering activity in the transient ocular hypertensive rabbit model at 1% dose. The most effective IOP-lowering products were compounds 3 and 7, whose activity 60min after administration was similar to that of Timolol. Notably, 7 was characterized by a long-lasting action. The IOP lowering activity in this series of products appeared to be modulated by the lipophilic-hydrophilic balance rather than by the NO-donor capacity. PMID- 28027870 TI - Novel triclabendazole prodrug: A highly water soluble alternative for the treatment of fasciolosis. AB - In this work we present the synthesis, aqueous solubility and stability, hydrolysis by alkaline phosphatase, and in vivo fasciolicidal activity in sheep of a highly water soluble phosphate salt prodrug of triclabendazole (MFR-5). The aqueous solubility of MFR-5 at pH 7 was 88,000-fold that of triclabendazole. MFR 5 showed excellent aqueous stability (>95% after 26h) at pH 7, making it ideal for developing pharmaceutical compositions in the form of solutions that can easily be hydrolyzed by the enzyme alkaline phosphatase (t=13.6s) to liberate the precursor compound. An aqueous solution of MFR-5 administered intramuscularly to sheep at concentrations of 4, 6 and 8mg/kg presented a fasciolicidal efficiency of 96.5%, 98.4% and 99.2%, respectively. In the in vivo experiments, MFR-5 reduced 100% the excretion of eggs in all of the above concentrations. PMID- 28027871 TI - New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7 chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives. AB - In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4 yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5-14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC50 values (0.14-1.26MUM) lower than the standard drug metronidazole (IC50 1.80MUM). All nine compounds exhibited antimalarial activity (IC50 range: 1.42-19.62MUM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC50 range: 14.67-81.24MUM) than quinine (IC50: 275.6+/-16.46MUM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae. PMID- 28027873 TI - The IJP-JPS workshop for young prosthodontic educators. PMID- 28027872 TI - The effect of platelet-rich plasma on Achilles tendon healing in a rabbit model. AB - OBJECTIVE: The aim of the present study was to evaluate the effects of PRP on Achilles tendon healing in rabbits during the inflammatory, proliferative, and remodeling phases by histological examination and quantitative assessments. METHODS: Fifty mature male Japanese albino rabbits with severed Achilles tendons were divided into two equal groups and treated with platelet-rich plasma (PRP) or left untreated. Tendon tissue was harvested at 1, 2, 3, 4, and 6 weeks after treatment, and sections were stained with hematoxylin-eosin and monoclonal antibodies against CD31 and type I collagen. RESULTS: Collagen fibers proliferated more densely early after severance, and subsequent remodeling of the collagen fibers and approximation of normal tendinous tissue occurred earlier in the PRP group than in the control group. The fibroblast number was significantly higher in the PRP group than in the control group at 1 and 2 weeks. Similarly, the area ratio of CD31-positive cells was significantly higher in the PRP group than in the control group at 1 and 2 weeks. Positive staining for type I collagen was more intense in the PRP group than in the control group after 3 weeks, indicating tendon maturation. CONCLUSION: Administration of PRP shortened the inflammatory phase and promoted tendon healing during the proliferative phase. PMID- 28027874 TI - Deep brain stimulation of the anterior nucleus of the thalamus reverses the gene expression of cytokines and their receptors as well as neuronal degeneration in epileptic rats. AB - BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) is effective in seizure control. However, the mechanisms remain unclear. METHODS: Sixty-four rats were randomly assigned to the control group, the kainic acid (KA) group, the sham-DBS group and the DBS group. Video-electroencephalogram (EEG) was used to monitor seizures. Quantitative real time PCR (qPCR) was applied for detecting interleukin-1 beta (IL-1beta), IL-1 receptor (IL-1R), IL-6, IL-6 receptor (IL-6R), gp130, tumor necrosis factor-alpha (TNF-alpha), TNF-receptor 1 (TNF-R1) and TNF-receptor 2 (TNF-R2) expression 12h after the establishment of an epileptic model. The neuronal structural degeneration in the hippocampus was evaluated with transmission electron microscopy (TEM) at this same time point. RESULTS: The seizure frequency was 48.6% lower in the DBS group compared with the sham-DBS group (P<0.01). The expression of IL-1beta, IL-1R, IL-6, IL-6R, gp130, TNF-alpha and TNF-R1 was elevated in both the KA and the sham group compared with the control group (all Ps<0.01). Additionally, ANT-DBS was able to reverse this gene expression pattern in the DBS group compared with the sham-DBS group (all Ps<0.01). There was no significant difference in TNF-R2 expression among the four groups. The neuronal structural degeneration in the KA group and the sham-DBS group was more severe than that in the control group (injury scores, all Ps<0.01). ANT-DBS was also capable of relieving the degeneration compared with the sham-DBS group (injury score, P<0.01). CONCLUSIONS: This study demonstrated that ANT-DBS can reduce seizure frequency in the early stage in epileptic rats as well as relieve the pro-inflammatory state and neuronal injury, which may be one of the most effective mechanisms of ANT-DBS against epileptogenesis. PMID- 28027875 TI - Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model. AB - Inherited mitochondrial complex 1 deficiency causes Leber's hereditary Optic Neuropathy (LHON) and retinal ganglion cell (RGC) degeneration, and optic neuropathies are common in many inherited mitochondrial diseases. How mitochondrial defects pathomechanistically trigger optic neuropathy remains unclear. We observe that complex 1-deficient Ndufs4-/- mice present with acute vision loss around p30, and this vision loss is coincident with an 'inflammatory wave'. In order to understand what causes the inflammatory wave we explored retinal pathology that occurs from p20-p30. The results indicated that in the period p20-p30 in Ndufs4-/- retinas, there is: significant reduction in bipolar cells, RGC dendritic atrophy, reduced PSD95, increased oxidative stress as manifested by increased 4HNE, HO1 and Cuzn-SOD, increased mitochondrial biogenesis and increased apoptosis. These precede the major induction of 'inflammatory wave' at p30 shown previously, but occur earlier than frank RGC loss at p42. In general, complex 1 deficiency in retina triggers oxidative stress and mitochondrial respiratory dysfunction that causes death of the most sensitive cells, including bipolar cells and their synaptic contacts and amacrine cells in the early period, 20-24days. The early death of these cells is the likely precursor to the sharp rise in inflammatory molecules that occurs at day 30 and coincides with vision loss, and greatly precedes the death of RGCs that occurs at p42. These data suggest that metabolic antioxidant support of the most sensitive cells in the retina, or anti-inflammatory suppression of the consequences of their death, are both rational strategies for mitochondrial blinding disease. PMID- 28027876 TI - ERCC2/XPD Lys751Gln alter DNA repair efficiency of platinum-induced DNA damage through P53 pathway. AB - Platinum-based treatment causes Pt-DNA adducts which lead to cell death. The platinum-induced DNA damage is recognized and repaired by the nucleotide excision repair (NER) system of which ERCC2/XPD is a critical enzyme. Single nucleotide polymorphisms in ERCC2/XPD have been found to be associated with platinum resistance. The aim of the present study was to investigate whether ERCC2/XPD Lys751Gln (rs13181) polymorphism is causally related to DNA repair capacity of platinum-induced DNA damage. First, cDNA clones expressing different genotypes of the polymorphism was transfected to an ERCC2/XPD defective CHO cell line (UV5). Second, all cells were treated with cisplatin. Cellular survival rate were investigated by MTT growth inhibition assay, DNA damage levels were investigated by comet assay and RAD51 staining. The distribution of cell cycle and the change of apoptosis rates were detected by a flow cytometric method (FCM). Finally, P53mRNA and phospho-P53 protein levels were further investigated in order to explore a possible explanation. As expected, there was a significantly increased in viability of UV5ERCC2 (AA) as compared to UV5ERCC2 (CC) after cisplatin treatment. The DNA damage level of UV5ERCC2 (AA) was significant decreased compared to UV5ERCC2 (CC) at 24 h of treatment. Mutation of ERCC2rs13181 AA to CC causes a prolonged S phase in cell cycle. UV5ERCC2 (AA) alleviated the apoptosis compared to UV5ERCC2 (CC), meanwhile P53mRNA levels in UVERCC2 (AA) was also lower when compared UV5ERCC2 (CC). It co-incides with a prolonged high expression of phospho-P53, which is relevant for cell cycle regulation, apoptosis, and the DNA damage response (DDR). We concluded that ERCC2/XPD rs13181 polymorphism is possibly related to the DNA repair capacity of platinum-induced DNA damage. This functional study provides some clues to clarify the relationship between cisplatin resistance and ERCC2/XPDrs13181 polymorphism. PMID- 28027877 TI - Hydrogen sulfide may attenuate methylmercury-induced neurotoxicity via mitochondrial preservation. AB - Hydrogen sulfide (H2S) is a protective molecule and a novel gaseous mediator. Here we explored whether H2S donor (NaHS) could attenuate methylmercury (MeHg) induced neurotoxicity in rats. The adult rats were randomly divided into four groups, i.e., control, NaHS, MeHg, and NaHS + MeHg groups. Rats of the NaHS + MeHg group were intraperitoneally (i.p) injected with 5.6 mg/kg/d of NaHS together with 5 MUg/kg/d of MeHg. Rats of the MeHg group and NaHS group were injected with 5 MUg/kg/d of MeHg and 5.6 mg/kg/d of NaHS, respectively. All treatments were continued for 20 d, and the cerebral cortex of the rats was evaluated. The results showed that NaHS significantly reduced MeHg-induced oxidative stress, as indicated by reduced lipid peroxide content, and increased glutathione levels and glutathione peroxidase and thioredoxin reductase activities. NaHS attenuated MeHg-induced mitochondrial damage, as indicated by increased mitochondrial activity, reduced mitochondrial swelling, and the release of cytochrome C and apoptosis-inducing factors. NaHS also decreased the number of apoptotic cells compared to that observed in MeHg only-treated rats, as indicated in a TUNEL assay. Finally, NaHS increased DNA and RNA content, and the activities of acetylcholinesterase and Na+/K+-ATPase. These indices were all lower in the MeHg group than in the control group, and NaHS alone did not observably influence any of these indices compared to the control. Our results demonstrate that H2S may protect against MeHg-induced neurotoxicity, and the mechanisms appear to involve the inhibition of oxidative stress and the protection of mitochondria. PMID- 28027878 TI - Modeling the light-induced electric potential difference DeltaPsi across the thylakoid membrane based on the transition state rate theory. AB - In photosynthesis, electron transport-coupled proton movement initiates the formation of the light-induced electric potential difference, DeltaPsi, across the thylakoid membrane (TM). Ions are transported across the TM to counterbalance the charge of protons accumulated in the lumen. The objective of this work is to construct range of mathematical models for simulation of DeltaPsi, using the transition state rate theory (TSRT) for description of movement of ions through the channels. The TSRT considers either single-ion (TSRT-SI) or multi-ion occupancy (TSRT-MI) in the channels. Movement of ions through the channel pore is described by means of energy barriers and binding sites; ions move in and out of vacant sites with rate constants that depend on the barrier heights and well depths, as well as on the interionic repulsion in TSRT-MI model. Three energy motifs are used to describe the TSRT-SI model: two-barrier one-site (2B1S), three barrier two-site (3B2S), and four-barrier three-site (4B3S). The 3B2S energy motif is used for the TSRT-MI model. The accumulation of cations due to the TM surface negative fixed charges is also taken into account. A model employing the electro-diffusion theory instead of the TSRT is constructed for comparison. The dual wavelength transmittance signal (DeltaA515-560nm) measuring the electrochromic shift (ECS) provides a proxy for experimental light-induced DeltaPsi. The simulated DeltaPsi traces qualitatively agree with the measured ECS traces. The models can simulate different channel conducting regimes and assess their impact on DeltaPsi. The ionic flux coupling in the TSRT-MI model suggests that an increase in the internal or external K+ concentration may block the outward or the inward Mg2+ current, respectively. PMID- 28027879 TI - A novel mode of operation of SLC22A11: Membrane insertion of estrone sulfate versus translocation of uric acid and glutamate. AB - Estrone sulfate alias estrone-3-sulfate (E3S) is considerably larger and much more hydrophobic than typical substrates of SLC22 transporters. It is puzzling that many otherwise unrelated transporters have been reported to transport E3S. Here we scrutinized the mechanism of transport of E3S by SLC22A11 (alias OAT4), by direct comparison with uric acid (UA), an important physiological substrate. Heterologous expression of SLC22A11 in human 293 cells gave rise to a huge unidirectional efflux of glutamate (Glu) and aspartate, as determined by LC MS/MS. The uptake of E3S was 20-fold faster than the uptake of UA. Yet, the outward transport of Glu was inhibited by extracellular E3S, but not by UA. The release of E3S after preloading was trans-stimulated by extracellular dehydroepiandrosterone sulfate (DHEAS), but neither by UA nor 6 carboxyfluorescein (6CF). The equilibrium accumulation of E3S was enhanced 3-fold by replacement of chloride with gluconate, but the opposite effect was observed for UA. These results establish that SLC22A11 provides entirely different transport mechanisms for E3S and UA. Therefore, E3S must not be used as a substitute for UA to assay the function of SLC22A11. In equilibrium accumulation experiments, the transporter-mediated uptake was a linear function of the concentration of UA and 6CF. By contrast, in the same concentration range the graph for E3S was hyperbolic. This suggests that SLC22A11 inserts E3S into a small volume with limited capacity, the plasma membrane. Our data support the notion that the reverse process, extraction from the membrane, is also catalyzed by the carrier. PMID- 28027880 TI - 1,4-Anhydro-4-seleno-d-talitol (SeTal) protects endothelial function in the mouse aorta by scavenging superoxide radicals under conditions of acute oxidative stress. AB - Hyperglycaemia increases the generation of reactive oxidants in blood vessels and is a major cause of endothelial dysfunction. A water-soluble selenium-containing sugar (1,4-Anhydro-4-seleno-d-talitol, SeTal) has potent antioxidant activity in vitro and is a promising treatment to accelerate wound healing in diabetic mice. One possible mechanism of SeTal action is a direct effect on blood vessels. Therefore, we tested the hypothesis that SeTal prevents endothelial dysfunction by scavenging reactive oxidants in isolated mouse aorta under conditions of acute oxidative stress induced by hyperglycaemia. Aortae were isolated from C57BL/6 male mice and mounted on a wire-myograph to assess vascular function. In the presence of a superoxide radical generator, pyrogallol, 300MUM and 1mM of SeTal effectively prevented endothelial dysfunction compared to other selenium containing compounds. In a second set of ex vivo experiments, mouse aortae were incubated for three days with either normal or high glucose, and co-incubated with SeTal at 37 degrees C in 5% CO2. High glucose significantly reduced the sensitivity to the endothelium-dependent agonist, acetylcholine (ACh), increased superoxide production and decreased basal nitric oxide (NO) availability. SeTal (1mM) co-treatment prevented high glucose-induced endothelial dysfunction and oxidative stress in the mouse aorta. The presence of a cyclooxygenase inhibitor, indomethacin significantly improved the sensitivity to ACh in high glucose treated aortae, but had no effect in SeTal-treated aortae. Our data show that SeTal has potent antioxidant activity in isolated mouse aortae and prevents high glucose-induced endothelial dysfunction by decreasing superoxide levels, increasing basal NO availability and normalising the contribution of vasoconstrictor prostanoids. PMID- 28027881 TI - Perceived control moderates the relationship between social capital and binge drinking: longitudinal findings from the Montreal Neighborhood Networks and Health Aging (MoNNET-HA) panel. AB - BACKGROUND: Cross-sectional research suggests social capital has negative consequences for problem drinking behaviors. Previous studies have suggested psychosocial resources, including perceived control, may buffer this association. Little research has examined whether such relationships persist longitudinally. METHODS: Random effects models examined between-person relationships among problem drinking, social capital, and perceived control, and whether perceived control moderated the relationship between social capital and drinking. Fixed effects models assessed whether social capital and perceived control were related to changes in problem drinking. RESULTS: Greater network capital and generalized trust predicted higher odds of binge drinking (RR = 1.08; 95% CI = 1.03-1.12 and RR = 1.23; 95% CI = 1.03-1.48, respectively). Perceived control moderated the positive association of network capital with binge drinking (RR = 0.91; 95% CI = 0.87-0.96). CONCLUSIONS: The present findings support previous notions about the complex role of social capital on health, and offer new insights on the role of perceived control on problem drinking. PMID- 28027882 TI - Acute mercury vapor poisoning in a 3-month-old infant: A case report. AB - BACKGROUND: We investigated the clinical characteristics of a 3-month-old infant with acute mercury vapor poisoning. Clinical symptoms of acute mercury poisoning in infants include acute onset, rapid progression, severe illness with respiratory symptoms that may result in pneumothoraces and aspiration pneumonias. CASE PRESENTATION: A 3-month-old girl presented with pneumothoraces and respiratory failure to the hospital. Two days before hospitalization, the girl had stayed in a room containing mercury vapor for several hours. She was hospitalized for acute mercury poisoning. We used sodium dimercaptosulphonate (DMPS) for treatment. CONCLUSION: Pulmonary disease was mainly induced by the inhalation of mercury vapor. The disease was characterized by acute respiratory distress, pneumothorax and acute chemical pneumonitis. It responded to chelation therapy with the agent DMPS. PMID- 28027883 TI - Role of the H-bond between L53 and T56 for Aquaporin-4 epitope in Neuromyelitis Optica. AB - Aquaporin-4 (AQP4) is the CNS water channel organized into well-ordered protein aggregates called Orthogonal Arrays of Particles (OAPs). Neuromyelitis Optica (NMO) is an autoimmune disease caused by anti-OAP autoantibodies (AQP4-IgG). Molecular Dynamics (MD) simulations have identified an H-bond between L53 and T56 as the key for AQP4 epitope and therefore of potential interest for drug design in NMO field. In the present study, we have experimentally tested this MD prediction using the classic mutagenesis approach. We substituted T56 with V56 and tested this mutant for AQP4 aggregates and AQP4-IgG binding. gSTED super resolution microscopy showed that the mutation does not affect AQP4 aggregate dimension; immunofluorescence and cytofluorimetric analysis demonstrated its unaltered AQP4-IgG binding, therefore invalidating the MD-prediction. We later investigated whether AQP4, expressed in Sf9 insect and HEK-293F cells, is able to correctly aggregate before and after the purification steps usually applied to obtain AQP4 crystal. The results demonstrated that AQP4-IgG recognizes AQP4 expressed in Sf9 and HEK-293F cells by immunofluorescence even though BN-PAGE analysis showed that AQP4 forms smaller aggregates when expressed in insect cells compared to mammalian cell lines. Notably, after AQP4 purification, from both insect and HEK-293F cells, no aggregates are detectable by BN-PAGE and AQP4-IgG binding is impaired in sandwich ELISA assays. All together these results indicate that 1) the MD prediction under analysis is not supported by experimental data and 2) the procedure to obtain AQP4 crystals might affect its native architecture and, as a consequence, MD simulations. In conclusion, given the complex nature of the AQP4 epitope, MD might not be the suitable for molecular medicine advances in NMO. PMID- 28027884 TI - Health of US parents with and without disabilities. AB - BACKGROUND: The health of parents with disabilities is not well understood. Existing research has used small, non-representative samples. The lack of research using national representative data has hindered advocacy and policy making efforts. OBJECTIVE: In the present study, we used nationally representative data to examine the prevalence rates of chronic physical health conditions among parents with disabilities and compared them to parents without disabilities. METHODS: We analyzed pooled and linked data from the 2007-2011 Medical Expenditure Panel Survey and the corresponding National Health Interview Survey. We conducted logistic regression analyses to examine age-adjusted health differences of US parents with and without disabilities, controlling for covariates. Outcome measures included obesity, arthritis, asthma, cancer, heart disease, diabetes, emphysema, high cholesterol, hypertension, and stroke. RESULTS: After controlling for all model covariates and adjusting for age, parents with disabilities had significantly higher odds (aOR ranging from 1.69 to 4.82) of having each of the chronic conditions (P < 0.001). Parents with disabilities also have significant higher odds of having 2 conditions (aOR = 1.63), 3 conditions (aOR = 2.44), and 4 or more conditions (aOR = 5.56). CONCLUSIONS: Parents with disabilities have significantly poorer health than parents without disabilities. PMID- 28027885 TI - Structural differences in mixing behavior informing the role of asymptomatic infection and testing symptom heritability. AB - Most infectious disease data is obtained from disease surveillance which is based on observations of symptomatic cases only. However, many infectious diseases are transmitted before the onset of symptoms or without developing symptoms at all throughout the entire disease course, referred to as asymptomatic transmission. Fraser and colleagues [1] showed that this type of transmission plays a key role in assessing the feasibility of intervention measures in controlling an epidemic outbreak. To account for asymptomatic transmission in epidemic models, methods often rely on assumptions that cannot be verified given the data at hand. The present study aims at assessing the contribution of social contact data from asymptomatic and symptomatic individuals in quantifying the contribution of (a)symptomatic infections. We use a mathematical model based on ordinary differential equations (ODE) and a likelihood-based approach followed by Markov Chain Monte Carlo (MCMC) to estimate the model parameters and their uncertainty. Incidence data on influenza-like illness in the initial phase of the 2009 A/H1N1pdm epidemic is used to illustrate that it is possible to estimate either the proportion of asymptomatic infections or the relative infectiousness of symptomatic versus asymptomatic infectives. Further, we introduce a model in which the chance of developing symptoms depends on the disease state of the person that transmitted the infection. In conclusion, incorporating social contact data from both asymptomatic and symptomatic individuals allows inferring on parameters associated with asymptomatic infection based on disease data from symptomatic cases only. PMID- 28027886 TI - A novel window entry/exit trap for the study of endophilic behavior of mosquitoes. AB - To overcome the limitations of currently used window entry/exit traps, we developed an efficient new glue net entry/exit trap (GNT) that is economical, easily transported and assembled, and can be utilized for a variety of studies which aim to investigate the dynamics of mosquito movements between indoor and outdoor habitats. Cage experiments were conducted to determine what percentage of mosquitoes trying to pass through the netting are actually being caught. The GNT caught 97% of female and 98% of male Anopheles gambiae s.s., as well as 97.5% of female and 98% of male Culex pipiens attempting to cross into a bait chamber adjoining the release cage. During a six day field study, the bedroom windows of 12 homes in Mali were fitted with entry/exit GNTs. Traps without glue were fitted over the inside and outside bedroom windows of an additional 12 homes as a control. A total of 446 An. gambiae s.l. were caught attempting to exit dwellings while 773 An. gambiae s.l. were caught attempting to enter. The number of males and females attempting to exit dwellings were roughly similar (215 and 231 respectively) while there was a slight difference in the number of males and females trying to enter (382 and 430 respectively). Pyrethrum spray catches (PSC's) conducted inside the dwellings on the last day of the experiment yielded only six females and a single male. PMID- 28027887 TI - Adsorptive anodic stripping differential pulse voltammetric determination of CellCept at Fe3O4 nanoparticles decorated multi-walled carbon nanotubes modified glassy carbon electrode. AB - A simple and sensitive method based on adsorptive anodic stripping differential pulse voltammetry (AASDPV) for the determination of cellcept, using a magnetic Fe3O4 nanoparticles and functionalized (carboxylated) multi-walled carbon nanotubes modified glassy carbon electrode (f-MWCNs/Fe3O4/GCE) was developed. In phosphate buffer solution (pH = 5), the voltammogram of cellcept exhibited tow anodic peaks and the well-defined peak at about 0.611 V vs SCE was used for its monitoring. The modified electrode was characterized by different methods such as electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM) and cyclic voltammetry (CV). The experimental parameters, such as pH, deposition potential and time, as well as scan rate were optimized. Under the optimized conditions, Ip (MUA) was proportional to the cellcept concentration in the range of 0.05-200 MUM (R2 = 0.9989) with a detection limit of 9.0 nM and limit of quantification of 30.2 nM. The recovery was >98%. The practical analytical utilities of the modified electrode were demonstrated by the determination of cellcept in human urine and blood serum samples. Modified electrode showed an adequate sensitivity and stability for evaluated samples. PMID- 28027888 TI - Comparison between dried blood spot and plasma sampling for therapeutic drug monitoring of antiepileptic drugs in children with epilepsy: A step towards home sampling. AB - OBJECTIVES: To investigate if dried blood spots could be used for therapeutic drug monitoring of the antiepileptic drugs, carbamazepine, lamotrigine and valproic acid in children with epilepsy. METHODS: Fingerprick blood samples from 46 children at a neuropediatric outpatient clinic was collected on filterpaper at the same time as capillary plasma sampling. A validated dried blood spot liquid chromatography tandem mass spectrometry method for carbamazepine, lamotrigine and valproic acid was compared with the routine plasma laboratory methods. Method agreement was evaluated and plasma concentrations were estimated by different conversion approaches. RESULTS: Strong correlation was shown between dried blood spot and plasma concentrations for all three drugs, with R2 values>0.89. Regression analysis showed a proportional bias with 35% lower dried blood spot concentrations for valproic acid (n=33) and concentrations were 18% higher for carbamazepine (n=17). A ratio approach was used to make a conversion from dried blood spots to estimated plasma for these two drugs. Dried blood spot concentrations were directly comparable with plasma for lamotrigine (n=20). CONCLUSIONS: This study supports that dried blood spot concentrations can be used as an alternative to plasma in a children population for three commonly used antiepileptic drugs with the possibility to expand by adding other antiepileptic drugs. Clinical decisions can be made based on converted (carbamazepine, valproic acid) or unconverted (lamotrigine) dried blood spot concentrations. Dried blood spot sampling, in the future taken at home, will simplify an effective therapeutic drug monitoring for this group of patients who often have concomitant disorders and also reduce costs for society. PMID- 28027889 TI - Extensibility and Distensibility of the Thoracic Aorta in Patients with Aneurysm. AB - OBJECTIVES: Reference values of aortic deformation during the cardiac cycle can be valuable for the pre-operative planning of thoracic endovascular aortic repair (TEVAR) and for facilitating computational fluid dynamics. This study aimed to quantify normal aortic extensibility (longitudinal extension) and distensibility (radial expansion), as well as pulsatile strain, in a group of 10 (>60 years) individuals with abdominal or thoracic aortic aneurysms. METHODS: ECG gated CT images of the thoracic aorta were reconstructed into virtual 3D models of aortic geometry. The centre lumen line length of the thoracic aorta and three longitudinal segments, and the aortic diameter and luminal areas of four radial intersections were extracted with a dedicated software script to calculate extensibility, longitudinal strain, distensibility, and circumferential area strain. RESULTS: Mean extensibility and longitudinal strain of the entire thoracic aorta were 3.5 [1.3-6.8] * 10-3 N-1, and 2.7 [1.0-4.5]%, respectively. Extensibility and longitudinal strain were most pronounced in the ascending aorta (20.6 [5.7-36.2] * 10-3 N-1 and 15.9 [6.6-31.9]%) and smallest in the descending aorta (4.4 [1.6-12.3] * 10-3 N-1 and 2.2 [0.7-4.7]%). Mean distensibility and circumferential area strain were most pronounced at the sinotubular junction (1.7 [0.5-2.9] * 10-3 mmHg-1 and 11.3 [3.3-18.5]%, respectively). Distensibility varied between 0.9 [0.3-2.5] * 10-3 mmHg-1 and 1.2 [0.3-3.3] * 10-3 mmHg-1 at the intersections in the aortic arch and descending aorta. CONCLUSIONS: Pulsatile deformations in both longitudinal and circumferential directions are considerable throughout the thoracic aorta. These findings may have implications for pre operative TEVAR planning and highlight the need for devices that can mimic the significant aortic longitudinal and circumferential strains. PMID- 28027890 TI - Iliac Seal Zone Dynamics and Clinical Consequences After Endovascular Aneurysm Repair. AB - OBJECTIVE: To evaluate the dynamics of the iliac attachment zone after EVAR, and the association with clinical events. METHODS: A tertiary institution's prospective EVAR database was searched to identify common iliac arteries at risk. Internally validated measurements were made, using centre lumen line reconstructions. Iliac dilatation and endograft limb retraction were the main endpoints. Associations between dilatation, retraction, oversizing, and distal seal length were investigated. Association with clinical events (sealing or occlusion) was also explored. RESULTS: Of 452 primary EVAR patients treated from 2004 to 2012, 341 were included (mean age 72 years, 12% female, 597 common iliac arteries). Median follow-up was 4.7 years. At 30 days, the mean iliac diameter increased from 14 mm to 15 mm (p < .001). Over follow-up, it increased to 18 mm (p < .001). Iliac dilatation >=20% occurred in 295 cases (49.4%) and exceeded the implanted endograft diameter in 170 (28.7%). Limb retraction >=5 mm was identified in 54 patients (9.1%) and was associated with iliac seal complications (p < 0.001). Iliac endograft extension diameter >=24 mm (OR 3.3, 95% CI 1.7-6.4) and iliac artery dilatation beyond the endograft (OR 2.1, 95% CI 1.2-3.8) were independent risk factors. Overall, there were 34 (5.7%) iliac seal complications. Retraction of the iliac endograft (OR 1.17 per mm, 95% CI 1.10-1.24) and baseline AAA diameter (1.04 per mm, 95% CI 1.01-1.07) were independent risk factors for seal related complications. Greater initial post-operative iliac seal length was protective (OR 0.94 per mm, 95% CI 0.90-0.97). CONCLUSIONS: Iliac dilatation and endograft retraction are common findings during follow-up, potentially leading to adverse clinical events. Optimisation of the iliac seal zone providing a long distal seal length and added attention to patients with large aneurysms or receiving >=24 mm diameter iliac extensions are recommended. Also, long-term surveillance including CTA is advised to reveal and correct loss of seal at the iliac attachments before adverse clinical events occur. PMID- 28027891 TI - Ruptured Abdominal Aortic Aneurysm Post-EVAS: Nellix Explantation. PMID- 28027892 TI - Venous Arterialisation for Salvage of Critically Ischaemic Limbs: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Critical limb ischaemia (CLI) is the end stage of peripheral artery disease (PAD) and is associated with high amputation and mortality rates and poor quality of life. For CLI patients with no revascularisation options, venous arterialisation could be a last resort for limb salvage. OBJECTIVE: To review the literature on the clinical effectiveness of venous arterialisation for lower limb salvage in CLI patients with no revascularisation options. METHOD: Different databases were searched for papers published between January 1966 and January 2016. The criteria for eligible articles were studies describing outcomes of venous arterialisation, published in English, human studies, and with the full text available. Additionally, studies were excluded if they did not report limb salvage, wound healing or amputation as outcome measures. The primary outcome measure was post-operative limb salvage at 12 months. Secondary outcome measures were 30 day or in-hospital mortality, survival, patency, technical success, and wound healing. RESULTS: Fifteen articles met the inclusion criteria. The included studies described 768 patients. According to the MINORS score, methodological quality was moderate to poor. The estimated pooled limb salvage rate at one year was 75% (0.75, 95% CI 0.70-0.81). Thirty day or in-hospital mortality was reported in 12 studies and ranged from 0 to 10%. Overall survival was reported in 10 studies and ranged from 54% to 100% with a mean follow-up ranging from 5 to 60 months. Six studies reported on patency of the venous arterialisations performed, with a range of 59-71% at 12 months. CONCLUSION: In this systematic review on venous arterialisation in patients with non-reconstructable critical limb ischaemia, the pooled proportion of limb salvage at 12 months was 75%. Venous arterialisation could be a valuable treatment option in patients facing amputation of the affected limb; however, the current evidence is of low quality. PMID- 28027893 TI - Correction of Recessive Dystrophic Epidermolysis Bullosa by Transposon-Mediated Integration of COL7A1 in Transplantable Patient-Derived Primary Keratinocytes. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is caused by defects in type VII collagen (C7), a protein encoded by the COL7A1 gene and essential for anchoring fibril formation at the dermal-epidermal junction. Gene therapy of RDEB is based on transplantation of autologous epidermal grafts generated from gene corrected keratinocytes sustaining C7 deposition at the dermal-epidermal junction. Transfer of the COL7A1 gene is complicated by its very large size and repetitive sequence. This article reports a gene delivery approach based on the Sleeping beauty transposon, which allows integration of a full-length COL7A1 cDNA and secretion of C7 at physiological levels in RDEB keratinocytes without rearrangements or detrimental effects on their clonogenic potential. Skin equivalents derived from gene-corrected RDEB keratinocytes were tested in a validated preclinical model of xenotransplantation on immunodeficient mice, where they showed normal deposition of C7 at the dermal-epidermal junction and restoration of skin adhesion properties. These results indicate the feasibility and efficacy of a transposon-based gene therapy approach to RDEB. PMID- 28027894 TI - Improving Survival of Patients With Hodgkin Lymphoma Over 4 Decades: Experience of the British National Lymphoma Investigation (BNLI) With 6834 Patients. AB - BACKGROUND: The management of Hodgkin lymphoma (HL) has changed markedly over the last 50 years. This is due to the expanding understanding about the biology of the disease, the development of increasingly efficacious multimodal treatment, and the recognition of how to reduce late effects. The British National Lymphoma Investigation (BNLI) was formed in the 1970s to coordinate UK research in the diagnosis and treatment of lymphoma. We describe the improvement in trial patient survival over 4 decades. PATIENTS AND METHODS: This analysis is of data on 6834 patients with a de novo diagnosis of HL registered onto studies with BNLI oversight from January 1, 1970, to December 31, 2009. Patients were subdivided in 4 groups according to their decade of registration; 1970s, 1980s, 1990s, and 2000s. Because of the lengthy data collection period, there is a difference in duration of follow-up between decade groups, with median follow-up in the 1970s group of 28.2 years, 18.0 years in the 1980s group, 9.4 years in the 1990s group, and 5.4 years in the 2000s group. Comparison between data in all 4 groups is not possible beyond 13.4 years (maximum duration of follow-up in the 2000s group), and so a cutoff has been applied at 14 years. Data on overall survival, cause of death, primary treatment modality, and incidence of secondary malignancy were collected. RESULTS: Clear and statistically significant improvements in survival curves between the decades were present, with 10-year overall survival increasing from 62.4% in the 1970s to 89.6% in the 2000s. There was a suggestion that second malignancy and cardiac-related deaths have been reducing over time, but longer follow-up is needed for the later decades to confirm this trend. CONCLUSION: Results support existing registry data demonstrating that survival for HL has improved over the 4 decades analyzed. This data set is robust and validated, and it adds valuable understanding to the reasons behind the survival curves, which are a balance between efficacious therapies and decreased death related to cardiac conditions and second malignancies. PMID- 28027895 TI - Low Level of Blood CD4+ T Cells Is an Independent Predictor of Inferior Progression-free Survival in Diffuse Large B-cell Lymphoma. AB - BACKGROUND: Tumor-infiltrating immune cells influence diffuse large B-cell lymphoma (DLBCL) outcomes. Relatively little, however, is known about the significance of peripheral blood immune cell numbers on DLBCL behavior. PATIENTS AND METHODS: In the present study, 43 patients with newly diagnosed DLBCL had pretreatment multiparameter peripheral blood flow cytometry performed to assess the immune cell numbers. These cell numbers were correlated with the outcomes of progression-free survival (PFS) and overall survival. RESULTS: After follow-up period of 0.8 to 152 months (median, 73), 25 patients (56%) were still alive. As continuous variables on univariate analysis, the predictors of PFS were patient age and absolute CD4 cell count (ACD4C), with the International Prognostic Index (IPI) marginally significant. Age was also a significant predictor of overall survival, and the IPI and ACD4C were marginally significant (P = .08). The 17 patients with a greater ACD4C (>= 450/mm3) had better 5-year PFS than the 26 with a low ACD4C (88% vs. 50%; P = .02). Multivariable analysis, including age as a continuous variable, IPI group, and ACD4C of 450/mm3 showed that age and ACD4C were significant for PFS (P = .01 and P = .02, respectively). CONCLUSION: Our data, although from a small series, suggest that the blood ACD4C might be a predictor of PFS for patients with DLBCL, independent of age and the IPI. PMID- 28027896 TI - International consensus for the treatment of autoimmune pancreatitis. AB - BACKGROUND AND AIMS: The International Consensus Diagnostic Criteria (ICDC) for AIP has proposed two distinctive type of AIP, type 1 and type 2, and enabled us first to differentiate two types of AIP each other. By initial steroid treatment for induction of remission, remission can be successfully induced in almost all subjects with type 1 and type 2 AIP. As relapse rate in type 1 AIP is significantly higher than in type 2 AIP, there has been ongoing debate on how to treat effectively relapse of type 1 AIP. METHODS: By a modified Delphi approach, a panel of international experts has proposed an international consensus on the treatment of AIP after intense discussion and deliberation during an international consensus symposium of the International Association of Pancreatology (IAP) 2016. RESULTS: Individual statements for nine clinical questions with recommendation levels and the therapeutic strategy have been proposed. CONCLUSION: The recommendations are based on the available evidence, and eastern and western experts' opinions to find standard treatment of AIP worldwide. These recommendations can be tailored according to the local expertise and context in the management of individual patients. PMID- 28027897 TI - Relevance of dihydropyrimidine-dehydrogenase and thymidylate-synthase in patients with pancreatic neuroendocrine neoplasms treated with 5-FU-based chemotherapy. AB - BACKGROUND: Chemotherapy with 5-FU and Streptozotocin (STZ) is recommended as first-line treatment in patients with metastatic pancreatic neuroendocrine neoplasms (PNEN). However, data about biomarkers involved in the 5-FU metabolism to predict response are still limited. OBJECTIVES: Evaluation of clinicopathological features and potential predictive and prognostic markers of patients with PNEN treated with 5-FU based regimens. PATIENTS AND METHODS: We retrospectively analyzed 41 patients with PNEN who were treated at the University Hospital Marburg between 2000 and 2013. Dihydropyrimidine-Dehydrogenase (DPD) and Thymidylate-Synthase (TS) expression was correlated with treatment response in 19 patients who had available tumour tissue and response data. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan Meier and Cox regression methods, respectively. RESULTS: The median PFS in patients receiving 5-FU/STZ was 17 months with a median OS of 50 months. Objective response rate (ORR) and disease control rate (DCR) were 32% and 73%, respectively. Biochemical response (p = 0.005) and high DPD expression (p = 0.018) were predictive markers of response to 5-FU-based chemotherapy. Univariate analysis identified Ki-67 > 10%, no biochemical response, positive 5-HIAA levels and TS deficiency as independent risk factors for shorter PFS. Moreover, performance status (PS) >=1 was an independent risk factors for impaired OS. CONCLUSIONS: DPD expression and biochemical response represent promising predictive biomarkers for response to 5-FU based chemotherapy. Moreover, Ki-67, PS and TS are independent prognostic markers of OS and PFS in patients with PNEN. PMID- 28027898 TI - Lower plasma levels of glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PP) in patients with ductal adenocarcinoma of the pancreas and their relation to the presence of impaired glucoregulation and weight loss. AB - BACKGROUND: The changes in gastrointestinal hormones associated with pancreatic ductal adenocarcinoma (PDAC) in patients with impaired glucoregulation have yet to be evaluated. The aim of this study was to determine plasma concentrations of selected gastrointestinal hormones in PDAC patients with and without diabetes and to compare them with levels found in Type 2 diabetic patients without cancer. METHODS: In this study we examined plasma concentrations of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), and cytokines leptin and adiponectin in 94 patients with histologically confirmed PDAC. Thirty-nine patients with Type 2 diabetes without PDAC and 29 healthy individuals with no evidence of acute or chronic diseases were examined as controls. RESULTS: Significantly lower plasma concentrations of GIP were found in PDAC patients with new-onset diabetes/prediabetes (n = 76), or in those with normal glucose regulation (n = 18), compared to patients with Type 2 diabetes without PDAC and controls (15.5 (3.7-64.5) or 6.5 (1.7-24.5) vs. 39.8 (15.1-104.7) and 28.8 (7.4 112.2) ng/L, p < 0.001); the same relationship was observed for PP (38.9 (10.2 147.9) or 28.1 (7.9-100.0) vs 89.1 (38.0-208.9) and 75.8 (30.1-190.6) ng/L, p < 0.01), respectively. The lowest levels of GIP and PP concentrations were found in PDAC patients with new-onset diabetes/prediabetes and weight loss > 2 kg (p < 0.001). CONCLUSIONS: We conclude that GIP and PP plasma concentrations are lower in pancreatic cancer irrespective of the degree of glucose intolerance as compared to Type 2 diabetic patients and healthy controls. In new onset diabetes especially if associated with weight loss, these changes may represent a new clue for the diagnosis of PDAC. PMID- 28027899 TI - Impairment of the visuo-spatial sketch pad by left prefrontal transcranial direct current stimulation. PMID- 28027900 TI - Amorphous aggregate adducts of linker histone H1 turn highly immunologic in the cancers of oesophagus, stomach, gall bladder and ovary. AB - Hyperglycaemic influence on carcinogenesis and tumour progression is emerging as a link between diabetes and cancer. This work establishes the disturbed structural integrity of nucleosomal linker histone H1 by methyglyoxal (MG) and then correlates the role of modified H1 in the auto-immunopathogenesis of multiple cancers. MG modification caused a loss of free epsilon-amino groups in H1 and raised its beta-sheet structural component with a consequence of non amyloid aggregation. It changed the folding-unfolding denaturation pattern of H1 and attached itself to the lysine residues of the protein eventually making up Nepsilon-(carboxyethyl) lysine. The structural variations act as extra antigenic determinants on H1 that yield aggressive antibody response, when immunised in rabbits. The ELISA tests proved the immunoglobulin response very specific and gel based studies established the preferential binding of antibodies generated against MG-H1 with the modified protein. Cross reaction analysis inferred the multiple specific natures of immunoglobulins with binding tendencies against different inhibitors. The immunoglobulin content in blood sera derived from human subjects with tumours of oesophagus, stomach, gall bladder and ovary confirmed the antibody presence against MG-H1 and competitive ELISA showed their high specificity. This may suggest a link between nucleosomal linker H1, hyperglycaemia, glycoxidation and cancer. PMID- 28027901 TI - Fungicide Bac8c triggers attenuation of mitochondrial homeostasis and caspase dependent apoptotic death. AB - Bac8c (RIWVIWRR-NH2), an 8-mer peptide modified from amino acids 4-11 of Bac2a, shows broad-spectrum activity against pathogenic bacteria and yeast, and it has been the focus of attention owing to its low cost of synthesis. Although Bac8c is effective against Candida albicans, its mode of action needs to be investigated further. Bac8c causes yeast cell death in a dose-dependent manner by eliciting the production of reactive oxygen species, thereby attenuating the antioxidant defense system. It is also involved in Ca2+ signaling, and produces apoptotic features, such as phosphatidylserine externalization and DNA fragmentation. Bac8c induces cell death by oxidative stress-dependent apoptotic death via disruption of mitochondrial homeostasis and metacaspase activation. This suggests that the concentration of Bac8c is important for the induction of apoptotic death, which is not necessarily accompanied by cell cycle arrest in C. albicans. PMID- 28027902 TI - In silico prediction of the mutagenicity of nitroaromatic compounds using a novel two-QSAR approach. AB - Certain drugs are nitroaromatic compounds, which are potentially toxic. As such, it is of practical importance to assess and predict their mutagenic potency in the process of drug discovery. A classical quantitative structure-activity relationship (QSAR) model was developed using the linear partial least square (PLS) scheme to understand the underline mutagenic mechanism and a non-classical QSAR model was derived using the machine learning-based hierarchical support vector regression (HSVR) to predict the mutagenicity of nitroaromatic compounds based on a series of mutagenicity data (TA98-S9). It was observed that HSVR performed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical validations. A mock test designated to mimic real challenges also confirmed the better performance of HSVR. Furthermore, HSVR exhibited superiority in predictivity, generalization capabilities, consistent performance, and robustness when compared with various published predictive models. PLS, conversely, revealed some mechanistically interpretable relationships between descriptors and mutagenicity. Thus, this two-QSAR approach using the predictive HSVR and interpretable PLS models in a synergistic fashion can be adopted to facilitate drug discovery and development by designing safer drug candidates with nitroaromatic moiety. PMID- 28027903 TI - Seasonal changes and sexual dimorphism in gene expression of StAR protein, steroidogenic enzymes and sex hormone receptors in the frog brain. AB - The brain of amphibians contains all the key enzymes of steroidogenesis and has a high steroidogenic activity. In seasonally-breeding amphibian species brain steroid levels fluctuate synchronously with the reproductive cycle. Here we report a study of gene expression of StAR protein, key steroidogenic enzymes and sex hormone receptors in the telencephalon (T) and diencephalon-mesencephalon (D M) of male and female reproductive and post-reproductive Pelophylax esculentus, a seasonally breeding anuran amphibian. Significant differences in gene expression were observed between (a) the reproductive and post-reproductive phase, (b) the two brain regions and (c) male and female frogs. During the reproductive phase, star gene expression increased in the male (both T and D-M) but not in the female brain. Seasonal fluctuations in expression levels of hsd3b1, hsd17b1, srd5a1 and cyp19a1 genes for neurosteroidogenic enzymes occurred in D-M region of both sexes, with the higher levels in reproductive period. Moreover, the D-M region generally showed higher levels of gene expression than the T region in both sexes. Gene expression was higher in females than males for most genes, suggesting higher neurosteroid production in female brain. Seasonal and sex linked changes were also observed in gene expression for androgen (ar) and estrogen (esr1, esr2) receptors, with the males showing the highest ar levels in reproductive phase and the highest esr1 and esr2 levels in post-reproductive phase; in contrast, females showed the maximum expression for all three genes in reproductive phase. The results are the first evidence for seasonal changes and sexual dimorphism of gene expression of the neurosteroidogenic pathway in amphibians. PMID- 28027905 TI - Notochord isolation using laser capture microdissection. AB - BACKGROUND: Chordoma are malignant tumors of the axial skeleton, which arise from remnants of the notochord. The Notochord (chorda dorsalis) is an essential embryonic structure involved in the development of the nervous system and axial skeleton. Therefore, the notochord seems to be the most biologically relevant control tissue to study chordoma in molecular biology research. Nevertheless, up to now mainly different tissues but not the notochord have been used as control for chordoma, due to difficulty of isolating notochordal tissue. Here, we describe a fast and precise method of isolating notochordal cells. METHODS: Examination of human fetuses, with a gestation of 9, 11 and 13 weeks, using (immuno)histochemical methods was performed. To isolate pure notochord cells for further molecular biology investigation five flash frozen fetuses between 9 and 10 weeks of gestation were dissected by microtome slicing. Thereafter pure notochord cells for further molecular biology investigation where harvested by using laser capture microdissection (LCM). RNA was extracted from these samples and used in quantitative PCR. RESULTS: This study illustrates notochord of embryonic spines in three different stages of gestation (9-11-13 weeks). Immunohistochemical staining with brachyury showed strong staining of the notochord, but also weak staining of the intervertebral disc and vertebral body. LCM of notochord slices and subsequent total RNA extraction resulted in a good yield of total RNA. qPCR analysis of two housekeeping genes confirmed the quality of the RNA. CONCLUSION: LCM is a fast and precise method to isolate notochord and the quality and yield RNA extracted from this tissue is sufficient for qPCR analysis. Therefore early embryo notochord isolated by LCM is suggested to be the gold standard for future research in chordoma development, classification and diagnosis. PMID- 28027904 TI - Esculentoside A suppresses lipopolysaccharide-induced pro-inflammatory molecule production partially by casein kinase 2. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Esculentoside A (EsA) is a saponin isolated from the root of Phytolacca esculenta, an herb which has long been used in Traditional Chinese Medicine for various inflammatory diseases. EsA has been reported to have potent anti-inflammatory properties both in vitro and in vivo. AIM OF THE STUDY: The present study focused on the molecular mechanism of EsA for its anti inflammatory effects in RAW264.7 cells stimulated with lipopolysaccharide (LPS). METHODS AND RESULTS: Enzyme Linked Immunosorbent Assay (ELISA) showed EsA dose dependently inhibited the production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and nitric oxide in RAW264.7 cells. Real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay further confirmed the suppression of LPS-induced TNF-alpha, IL-6 and iNOS gene expression by EsA on a transcriptional level. Moreover, EsA treatment markedly suppressed LPS stimulated IkappaB phosphorylation and degradation as well as LPS-stimulated luciferase reporter construct driven by kappaB response elements in RAW264.7 cells. In addition, EsA significantly reduced LPS-induced stimulation of p38 and JNK, but not ERK1/2, phosphorylation. Furthermore, we used a computational method called "reverse docking" to search the possible binding proteins of EsA from the potential drug target database (PDTD), and focused on CK2 as the primary binding protein of EsA. Afterward, we further tested EsA directly interacts with recombinant CK2 using SPR assay. In CK2 kinase activity assay, EsA inhibited recombinant CK2 holoenzyme activity obviously in a dose-dependent manner. In addition, TBB (4, 5, 6, 7-tetrabromo-2-benzotriazole, a pharmacological inhibitor of CK2) blocked IL-6 release in a dose-dependent manner, whereas co-treatment of cells with EsA and TBB did not have an additive effect. CONCLUSIONS: Taken together, these results indicate that EsA blocks the LPS-induced pro-inflammatory molecules expression, at least in part, by impediment of LPS-triggered activation of NF-kappaB and p38/JNK MAPK pathways in macrophages. Furthermore, we discovered for the first time EsA as a ligand for CK2, which was involved in the inhibition of EsA to the expression of inflammatory cytokines. These findings extended our understanding on the cellular and molecular mechanisms responsible for the anti inflammatory activity of EsA. PMID- 28027906 TI - Assessment of Smith Algorithms for the Diagnosis of Acute Myocardial Infarction in the Presence of Left Bundle Branch Block. AB - INTRODUCTION AND OBJECTIVES: Recently, a new electrocardiography algorithm has shown promising results for the the diagnosis of acute myocardial infarction in the presence of left bundle branch block (LBBB). We aimed to assess these new electrocardiography rules in a cohort of patients referred for primary percutaneous coronary intervention (pPCI). METHODS: Retrospective observational cohort study that included all patients with suspected myocardial infarction and LBBB on the presenting electrocardiogram, referred for pPCI to 4 tertiary hospitals in Barcelona, Spain. RESULTS: A total of 145 patients were included. Fifty four (37%) had an ST-segment elevation myocardial infarction (STEMI) equivalent. Among patients with STEMI, 25 (46%) presented in Killip class III or IV, and in-hospital mortality was 15%. Smith I and II rules performed better than Sgarbossa algorithms and showed good specificity (90% and 97%, respectively) but their sensitivity was 67% and 54%, respectively. In a strategy guided by Smith I or Smith II rules, 18 (33%) or 25 (46%) patients with STEMI would have not received a pPCI, respectively. Moreover, the severity and prognosis of STEMI patients was similar regardless of the positivity of Smith rules. Cardiac biomarkers were positive in 54% of non-STEMI patients, limiting their usefulness for initial diagnostic screening. CONCLUSIONS: Diagnosis of STEMI in the presence of LBBB remains a challenge. Smith rules can be useful but are limited by suboptimal sensitivity. The search for new electrocardiography algorithms should be encouraged to avoid unnecessary aggressive treatments in the majority of patients, while providing timely reperfusion to a high-risk subgroup of patients. PMID- 28027907 TI - Effect of Ramadan fasting on fatigue, mood, sleepiness, and health-related quality of life of healthy young men in summer time in Germany: A prospective controlled study. AB - Muslims around the world fast during the lunar month of Ramadan. The month consists of 29 or 30 days, which vary in length depending on geographic location and the time of year. During this month, Muslims abstain from food, drink, smoking, and sex from dawn until sunset. In 2015, Ramadan fell during the summer. As a result, Muslims in Germany fasted 19 h a day. Previous research has shown associations between fasting and mood enhancement. This study aimed to determine the effect of fasting on young, healthy males who fasted in Germany during Ramadan 2015. In particular, this study examined the impact of fasting on mood, fatigue, and health-related Quality of Life (QoL). This study had 2 groups: fasting group (FG; n = 25), and non-fasting group (NFG; n = 25). In FG, participants were assessed at four different points: one week before Ramadan (T1), mid Ramadan (T2), the last days of Ramadan (T3), and one week after Ramadan (T4). In NFG, participants were assessed only at T1 and T3. The results revealed that there were no significant differences between the participants in the FG and the NFG at T1 or T3 for any of the outcomes. However, participants in the FG demonstrated significant improvement from T2 to T4 in fatigue (visual analogue scale p < 0.01; fatigue severity scale:p < 0.01), mood (Beck's Depression Index II; ANOVA; p < 0.05), and sleepiness during day time (Epworth Sleepiness Scale: ANOVA; p < 0.01). Participants in the FG also experienced significant loss of body weight (ANOVA; p < 0.001), body mass index (ANOVA; p < 0.001), skeletal muscle mass (ANOVA; p < 0.01) and fat free mass (ANOVA; p < 0.01). Findings demonstrate that Ramadan fasting did not significantly influence mood, fatigue and QoL, when compared to NFG. Even, it gives benefit to fasting group with regard to these parameters. PMID- 28027909 TI - How Do We Keep Information 'Online'? AB - New magnetoencephalography (MEG) results indicate that a putative marker of conscious processes - namely, the global broadcasting of information across large scale cortical networks - can also operate during the maintenance of non conscious input. I discuss the implications for the theoretical linkage between conscious awareness and working memory functions. PMID- 28027908 TI - Quantification of intervertebral displacement with a novel MRI-based modeling technique: Assessing measurement bias and reliability with a porcine spine model. AB - The purpose of this study was to develop a novel magnetic resonance imaging (MRI) based modeling technique for measuring intervertebral displacements. Here, we present the measurement bias and reliability of the developmental work using a porcine spine model. Porcine lumbar vertebral segments were fitted in a custom built apparatus placed within an externally calibrated imaging volume of an open MRI scanner. The apparatus allowed movement of the vertebrae through pre-assigned magnitudes of sagittal and coronal translation and rotation. The induced displacements were imaged with static (T1) and fast dynamic (2D HYCE S) pulse sequences. These images were imported into animation software, in which these images formed a background 'scene'. Three-dimensional models of vertebrae were created using static axial scans from the specimen and then transferred into the animation environment. In the animation environment, the user manually moved the models (rotoscoping) to perform model-to-'scene' matching to fit the models to their image silhouettes and assigned anatomical joint axes to the motion segments. The animation protocol quantified the experimental translation and rotation displacements between the vertebral models. Accuracy of the technique was calculated as 'bias' using a linear mixed effects model, average percentage error and root mean square errors. Between-session reliability was examined by computing intra-class correlation coefficients (ICC) and the coefficient of variations (CV). For translation trials, a constant bias (beta0) of 0.35 (+/ 0.11) mm was detected for the 2D HYCE S sequence (p=0.01). The model did not demonstrate significant additional bias with each mm increase in experimental translation (beta1Displacement=0.01mm; p=0.69). Using the T1 sequence for the same assessments did not significantly change the bias (p>0.05). ICC values for the T1 and 2D HYCE S pulse sequences were 0.98 and 0.97, respectively. For rotation trials, a constant bias (beta0) of 0.62 (+/-0.12) degrees was detected for the 2D HYCE S sequence (p<0.01). The model also demonstrated an additional bias (beta1Displacement) of 0.05 degrees with each degree increase in the experimental rotation (p<0.01). Using T1 sequence for the same assessments did not significantly change the bias (p>0.05). ICC values for the T1 and 2D HYCE S pulse sequences were recorded 0.97 and 0.91, respectively. This novel quasi static approach to quantifying intervertebral relationship demonstrates a reasonable degree of accuracy and reliability using the model-to-image matching technique with both static and dynamic sequences in a porcine model. Future work is required to explore multi-planar assessment of real-time spine motion and to examine the reliability of our approach in humans. PMID- 28027910 TI - Pharmacological chaperone approaches for rescuing GPCR mutants: Current state, challenges, and screening strategies. AB - A substantial number of G-protein coupled receptors (GPCRs) genetic disorders are due to mutations that cause misfolding or dysfunction of the receptor product. Pharmacological chaperoning approaches can rescue such mutant receptors by stabilizing protein conformations that behave similar to the wild type protein. For example, this can be achieved by improving folding efficiency and/or interaction with chaperone proteins. Although efficacy of pharmacological chaperones has been demonstrated in vitro for a variety of GPCRs, translation to clinical use has been limited. In this paper we discuss the history of pharmacological chaperones of GPCR's and other membrane proteins, the challenges in translation to the clinic, and the use of different assays for pharmacological chaperone discovery. PMID- 28027911 TI - Effects of Vitamin D3 on asymmetric- and symmetric dimethylarginine in arterial hypertension. AB - BACKGROUND AND AIMS: Accumulating evidence has proposed a correlation between vitamin D (25(OH)D) insufficiency and cardiovascular (CV) disease. Vitamin D associated effects on endothelial function have been suggested to be a possible culprit. The present study investigated the association of vitamin D3 treatment on markers of endothelial dysfunction in patients with arterial hypertension. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a double-blind, placebo-controlled, single-centre study conducted at the Medical University of Graz, Austria. A total of 200 study participants with arterial hypertension and 25(OH)D levels below 30ng/mL were enrolled. The study participants were randomized to receive 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for a duration of eight weeks. The present study uses an analysis of covariance (ANCOVA) to investigate the effect of vitamin D3 treatment on symmetric (SDMA) and asymmetric dimethylarginine (ADMA). A total of 187 participants (mean [SD] age 60.0 [11.3] years; 47% women; 25(OH)D 21.2 [5.6]ng/mL; mean systolic blood pressure of 131.4 [8.9] mmHg on a median of 2 antihypertensive drugs) completed the trial. Mean treatment effect was -0.004 (95%CI [-0.03 to 0.04]; P=0.819) on ADMA and 0.001 (95%CI [-0.05 to 0.05]; P=0.850) on SDMA. In the subgroup analysis patients with a 25(OH)D concentration <20ng/mL had a significant increase in their log l-arginine/ADMA ratio (mean treatment effect 18.4 95%CI [1.84-34.9]MUmol/L/MUmol/L; P=0.030). ClinicalTrials.gov Identifier: NCT02136771 EudraCT number: 2009-018125-70 CONCLUSIONS: Vitamin D3 supplementation in hypertensive patients with low 25 hydroxyvitamin D has no significant effect on ADMA and SDMA. PMID- 28027912 TI - Integrative genomic approaches to dissect clinically-significant relationships between the VDR cistrome and gene expression in primary colon cancer. AB - Recently, we undertook a pan-cancer analyses of the nuclear hormone receptor (NR) superfamily in The Cancer Genome Atlas (TCGA), and revealed that the vitamin D receptor (NR1I1/VDR) was commonly and significantly down-regulated specifically in colon adenocarcinoma cohort (COAD). To examine the consequence of down regulated VDR expression we re-analyzed VDR chromatin immunoprecipitation sequencing (ChIP-Seq) data from LS180 colon cancer cells (GSE31939). This analysis identified 1809 loci that displayed significant (p.adj<0.01) differential binding of the VDR in response 1,25(OH)2D3 treatment; 947 peaks annotated to 672 genes. We examined expression patterns in the COAD cohort of 286 tumors compared to 41 normal samples and revealed that VDR bound genes were significantly positively correlated to VDR expression compared to the background transcriptome, suggesting direct regulation by VDR. Gene set enrichment analyses revealed significant enrichment for genes known to be regulated by a number of other transcription factors including SMADs and JUN. Filtering VDR associated genes for those that were commonly and significantly altered in COAD revealed a cohort of 27 differentially expressed genes. The expression patterns of these genes clustered tumors and significantly associated with disease free survival. For instance, males with low expression of Lectin, Galactoside Binding Soluble 4 (LGALS4, encodes the colon tumor suppressor, Galactin 4) had significantly shorted disease free survival. These analyses suggest that reduced expression of VDR in colon cancer (but neither loss nor mutation) changes the actions of the VDR by both dampening the expression of tumor suppressors (e.g. LGALS4) whilst either stabilizing or not down-regulating expression of oncogenes (e.g. Carbonic Anhydrase 9 (CA9)). These integrative genomic approaches are relatively generic and applicable to the study of any transcription factor. PMID- 28027913 TI - Vitamin D and cardiovascular diseases: Causality. AB - Vitamin D regulates blood pressure, cardiac functions, and endothelial and smooth muscle cell functions, thus, playing an important role in cardiovascular health. Observational studies report associations between vitamin D deficiency with hypertension and cardiovascular-related deaths. Peer-reviewed papers were examined in several research databases as per the guidelines of the Preferred Reporting Items for Systematic Reviews, using key words that address the relationship between vitamin D and cardiovascular disease. Correlations and interpretations were made considering the risks-benefits, broader evidence, and implications. This review analyzed current knowledge regarding the effects of vitamin D on the cardiovascular system. 1,25(OH)2D and related epigenetic modifications subdue cellular inflammation, improve overall endothelial functions, reduce age-related systolic hypertension and vascular rigidity, and attenuate the actions of the renin-angiotensin-aldosterone system. Most observational and ecological studies support 25(OH)vitamin D having protective effects on the cardiovascular system. However, the association of vitamin D deficiency with cardiovascular diseases is based primarily on observational and ecological studies and thus, is a matter of controversy. Adequately powered, randomized controlled clinical trial data are not available to confirm these associations. Thus, to test the hypothesis that correction of vitamin D deficiency protects the cardiovascular system, well-designed, statistically powered, longer-term clinical trials are needed in persons with vitamin D deficiency. Nevertheless, the available data support that adequate vitamin D supplementation and/or sensible sunlight exposure to achieve optimal vitamin D status are important in the prevention of cardiovascular disease and other chronic diseases. PMID- 28027915 TI - Developmental vitamin D deficiency and autism: Putative pathogenic mechanisms. AB - Autism is a neurodevelopmental disease that presents in early life. Despite a considerable amount of studies, the neurobiological mechanisms underlying autism remain obscure. Both genetic and environmental factors are involved in the development of autism. Vitamin D deficiency is emerging as a consistently reported risk factor in children. One reason for the prominence now being given to this risk factor is that it would appear to interact with several other epidemiological risk factors for autism. Vitamin D is an active neurosteroid and plays crucial neuroprotective roles in the developing brain. It has important roles in cell proliferation and differentiation, immunomodulation, regulation of neurotransmission and steroidogenesis. Animal studies have suggested that transient prenatal vitamin D deficiency is associated with altered brain development. Here we review the potential neurobiological mechanisms linking prenatal vitamin D deficiency and autism and also discuss what future research targets must now be addressed. PMID- 28027914 TI - Vitamin D and intestinal calcium transport after bariatric surgery. AB - Bariatric surgery is a highly effective treatment for obesity, but it may have detrimental effects on the skeleton. Skeletal effects are multifactorial but mediated in part by nutrient malabsorption. While there is increasing interest in non-nutritional mechanisms such as changes in fat-derived and gut-derived hormones, nutritional factors are modifiable and thus represent potential opportunities to prevent and treat skeletal complications. This review begins with a discussion of normal intestinal calcium transport, including recent advances in our understanding of its regulation by vitamin D, and areas of continued uncertainty. Human and animal studies of vitamin D and intestinal calcium transport after bariatric surgery are then summarized. In humans, even with optimized 25-hydroxyvitamin D levels and recommended calcium intake, fractional calcium absorption decreased dramatically after Roux-en-Y gastric bypass (RYGB). In rats, intestinal calcium absorption was lower after RYGB than after sham surgery, despite elevated 1,25-dihyroxyvitamin D levels and intestinal gene expression evidence of vitamin D responsiveness. Such studies have the potential to shed new light on the physiology of vitamin D and intestinal calcium transport. Moreover, understanding the effects of bariatric surgery on these processes may improve the clinical care of bariatric surgery patients. PMID- 28027916 TI - Vitamin D in Saudi Arabia: Prevalence,distribution and disease associations. AB - More than 33 years have passed since the first paper highlighting vitamin D deficiency as a public health concern in Saudi Arabia was published in 1983. Despite "early" detection,it wasn't until the year 2010 where the interest in vitamin D research grew exponentially worldwide and was finally visible in Saudi clinical and academic areas. Since then,many landmark studies have been generated with regards to the physiologic functions of vitamin D,both skeletal and extra skeletal. This review is limited to the prevalence,distribution A systematic review on the prevalence studies done in KSA from 2011 to 2016 was done and revealed that the prevalence of vitamin D deficiency (<50nmol/l) in Saudi Arabia among different populations (adults,children and adolescents,newborns and pregnant/lactating women) is 81.0% (Confidence Interval 95% 68.0-90.0),in line with most neighboring Gulf countries. Vitamin D deficiency in KSA has been mostly associated with bone and insulin-resistant diseases but limited data are available to prove causality. In conclusion,there is a need to develop local consensus guidelines that will identify candidates for screening,monitoring and treating those who are at most risk for vitamin D deficiency complications. PMID- 28027917 TI - Profile of anti-herpetic action of ASP2151 (amenamevir) as a helicase-primase inhibitor. AB - The antiherpetic drugs acyclovir (ACV, valaciclovir) and penciclovir (famciclovir) are phosphorylated by viral thymidine kinase and terminate DNA synthesis. ASP2151 (amenamevir) and foscavir (PFA) directly inhibit viral helicase-primase and DNA polymerase, respectively, and inhibit replication of herpes simplex virus (HSV) and varicella-zoster virus. ACV, ASP2151, and PFA all inhibit HSV with a different mechanism of action and as a consequence, the kinetics of viral DNA accumulation and progeny virus production differ. This study focused on how viral DNA synthesis and its related events in the replication cycle would influence anti-HSV action of ACV, ASP2151, and PFA. ASP2151 suppressed HSV replication more efficiently than ACV at 10 * 50% effective concentration of plaque formation (EC50), when treatments were started 0-24 h after infection. ASP2151 and PFA were more potent than ACV in suppressing viral DNA synthesis and infectious virus production when they were added up to 3 h following infection. The virus replicated in the presence of ACV was compared for the ratios of HSV DNA copy number to infectivity with that without ACV and infectivity of ACV-treated virus was less efficient than that without ACV treatment. The EC50 of infected cells in the time course after infection was preserved in PFA, limited in ASP2151, and much increased for ACV, indicating that viral DNA synthesis had little effect on antiviral action of PFA and ASP2151 but reduced the susceptibility of ACV. ASP2151 showed a preferable profile as an anti herpetic agent with a better pharmacokinetic profile than ACV. PMID- 28027918 TI - Building parity between brand and generic peptide products: Regulatory and scientific considerations for quality of synthetic peptides. AB - Peptides are a fast growing segment in the pharmaceutical industry. Consequently, the industry and regulatory agencies are increasing their focus on the regulatory path and quality considerations for peptide development and manufacturing. Although most peptides are synthetic, manufactured by solid phase synthesis, nevertheless they are complex molecules with challenging quality and regulatory aspects. This paper provides a structured overview of relevant quality issues for chemically synthesized peptides used as active pharmaceutical ingredients (API) in drug products. It addresses the unique characteristics of peptides pertaining to structural and physicochemical characterization, manufacturing and in process controls, impurities and aggregates arising from manufacturing and storage, along with their potential impact on safety (including immunogenicity) and efficacy of the peptide drug products. PMID- 28027919 TI - Physicochemical characterisation and investigation of the bonding mechanisms of API-titanate nanotube composites as new drug carrier systems. AB - Titanate nanotube (TNT) has recently been explored as a new carrier material for active pharmaceutical ingredients (API). The aim of the present work was to reveal the physicochemical properties of API-TNT composites, focusing on the interactions between the TNTs and the incorporated APIs. Drugs belonging to different Biopharmaceutical Classification System (BCS) classes were loaded into TNTs: diltiazem hydrochloride (BCS I.), diclofenac sodium (BCS II.), atenolol (BCS III.) and hydrochlorothiazide (BCS IV.). Experimental results demonstrated that it is feasible for spiral cross-sectioned titanate nanotubes to carry drugs and maintain their bioactivity. The structural properties of the composites were characterized by a range of analytical techniques, including FT-IR, DSC, TG-MS, etc. The interactions between APIs and TNTs were identified as electrostatic attractions, mainly dominated by hydrogen bonds. Based on the results, it can be stated that the strength of the association depends on the hydrogen donor strength of the API. The drug release of incorporated APIs was evaluated from compressed tablets and compared to that of pure APIs. Differences noticed in the dissolution profiles due to incorporation showed a correlation with the strength of interactions between the APIs and the TNTs observed in the above analytical studies. PMID- 28027920 TI - Examining the short term effects of emotion under an Adaptation Level Theory model of tinnitus perception. AB - OBJECTIVES: Existing evidence suggests a strong relationship between tinnitus and emotion. The objective of this study was to examine the effects of short-term emotional changes along valence and arousal dimensions on tinnitus outcomes. Emotional stimuli were presented in two different modalities: auditory and visual. The authors hypothesized that (1) negative valence (unpleasant) stimuli and/or high arousal stimuli will lead to greater tinnitus loudness and annoyance than positive valence and/or low arousal stimuli, and (2) auditory emotional stimuli, which are in the same modality as the tinnitus, will exhibit a greater effect on tinnitus outcome measures than visual stimuli. STUDY DESIGN: Auditory and visual emotive stimuli were administered to 22 participants (12 females and 10 males) with chronic tinnitus, recruited via email invitations send out to the University of Auckland Tinnitus Research Volunteer Database. Emotional stimuli used were taken from the International Affective Digital Sounds- Version 2 (IADS 2) and the International Affective Picture System (IAPS) (Bradley and Lang, 2007a, 2007b). The Emotion Regulation Questionnaire (Gross and John, 2003) was administered alongside subjective ratings of tinnitus loudness and annoyance, and psychoacoustic sensation level matches to external sounds. RESULTS: Males had significantly different emotional regulation scores than females. Negative valence emotional auditory stimuli led to higher tinnitus loudness ratings in males and females and higher annoyance ratings in males only; loudness matches of tinnitus remained unchanged. The visual stimuli did not have an effect on tinnitus ratings. The results are discussed relative to the Adaptation Level Theory Model of Tinnitus. CONCLUSIONS: The results indicate that the negative valence dimension of emotion is associated with increased tinnitus magnitude judgements and gender effects may also be present, but only when the emotional stimulus is in the auditory modality. Sounds with emotional associations may be used for sound therapy for tinnitus relief; it is of interest to determine whether the emotional component of sound treatments can play a role in reversing the negative responses discussed in this paper. PMID- 28027921 TI - T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort. AB - BACKGROUND: Psoriasis is known to be associated with an up-regulation of T-helper (Th)-1 & Th-17 cytokines and a relative down-regulation of Th-2 and T-regulatory (T-reg) cytokines. Certain allelic variants of these cytokine genes may alter Th1/Th17 and Th2/T-reg balance and may be associated with the risk of psoriasis. Hence we aimed to determine the association of IL-4 (rs2243250), IL-10 (rs1800871 and rs1800896) and FOXP3 (rs3761548) gene polymorphisms with risk of psoriasis in South Indian Tamils. METHODS: A total of 360 cases of psoriasis and 360 healthy controls were recruited. The polymorphism in IL-4 (rs2243250) & IL-10 (rs1800871) were typed by ARMS-PCR and IL-10 (rs1800896) & FOXP3 (rs3761548) were typed by TaqMan 5'allele discrimination assay. RESULTS: We observed that IL-4 (rs2243250) had a reduced risk of psoriasis, while the IL-10 (rs1800871) conferred an increased susceptibility to psoriasis, as compared with controls. However, IL-10 (rs1800896) and FOXP3 (rs3761548) gene polymorphisms were not associated with psoriasis risk. The plasma IL-4 levels was not different between the cases and controls, however the heterozygous CT genotype demonstrated significant high IL-4 levels. Plasma IL-10 levels were significantly increased in cases compared to controls, however none of the genotypes were associated with the plasma IL-10 levels. CONCLUSION: Our results suggest that IL-4 (rs2243250) polymorphism is protective against psoriasis, while IL-10 (rs1800871) polymorphism confers increased risk of psoriasis in South Indian Tamils. Detection of these genetic variants as predictive risk factors may lead to the selection of patient-tailored therapy to maximize the effectiveness of therapy. PMID- 28027922 TI - The protective effect of resveratrol in the transmission of neuropathic pain mediated by the P2X7 receptor in the dorsal root ganglia. AB - The P2X7 receptor mediates afferent nerve activation and is related to chronic neuropathic pain. Resveratrol (RES) has also been reported to exhibit anti inflammatory effects. In this study, we investigated the neuroprotective effect of RES on the transmission of neuropathic pain mediated by the P2X7 receptor. The P2X7 mRNA and protein expression levels in L4-L5 dorsal root ganglia (DRG)s of the chronic constriction injury (CCI) group were significantly higher than those observed in the Ctrl + NS, Sham + RES and Sham groups. RES increased the threshold of thermal and mechanical hypersensitivity in rats with chronic neuropathic pain. The P2X7 mRNA and protein expression levels in the CCI + RES group were decreased compared with those in the CCI group. Our results showed that RES inhibited the upregulated co-expression of P2X7 and glial fibrillary acidic protein (GFAP, a marker of satellite glial cells) in satellite glial cells of DRG in the CCI group. The results demonstrated that the expression of GFAP was increased in the CCI group and that RES inhibited the upregulated expression of GFAP in the rats in the CCI group. In addition, the phosphorylation levels of p38 and extracellular regulated protein kinases (ERK)1/2 in the CCI group were markedly higher than those observed in the Ctrl + NS, Sham + RES and Sham groups, whereas the phosphorylation levels of p38 and ERK1/2 in CCI + RES group were markedly lower than those observed in the CCI group. RES inhibited BzATP activated currents in DRG non-neurons in the CCI rats. Our data provide evidence that RES may suppress the transmission of neuropathic pain mediated by the P2X7 receptor in the satellite glial cells of dorsal root ganglia. PMID- 28027923 TI - Specific uptake mechanisms of well-tolerated thermoresponsive polyglycerol-based nanogels in antigen-presenting cells of the skin. AB - Engineered nanogels are of high value for a targeted and controlled transport of compounds due to the ability to change their chemical properties by external stimuli. As it has been indicated that nanogels possess a high ability to penetrate the stratum corneum, it cannot be excluded that nanogels interact with dermal dendritic cells, especially in diseased skin. In this study the potential crosstalk of the thermoresponsive nanogels (tNGs) with the dendritic cells of the skin was investigated with the aim to determine the immunotoxicological properties of the nanogels. The investigated tNGs were made of dendritic polyglycerol (dPG) and poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME co-EGE)), as polymer conferring thermoresponsive properties. Although the tNGs were taken up, they displayed neither cytotoxic and genotoxic effects nor any induction of reactive oxygen species in the tested cells. Interestingly, specific uptake mechanisms of the tNGs by the dendritic cells were depending on the nanogels cloud point temperature (Tcp), which determines the phase transition of the nanoparticle. The study points to caveolae-mediated endocytosis as being the major tNGs uptake mechanism at 37 degrees C, which is above the Tcp of the tNGs. Remarkably, an additional uptake mechanism, beside caveolae-mediated endocytosis, was observed at 29 degrees C, which is the Tcp of the tNGs. At this temperature, which is characterized by two different states of the tNGs, macropinocytosis was involved as well. In summary, our study highlights the impact of thermoresponsivity on the cellular uptake mechanisms which has to be taken into account if the tNGs are used as a drug delivery system. PMID- 28027924 TI - Pleiotropic effects of oxidized phospholipids. AB - Oxidized phospholipids (OxPLs) are increasingly recognized to play a role in a variety of normal and pathological states. OxPLs were implicated in regulation of inflammation, thrombosis, angiogenesis, endothelial barrier function, immune tolerance and other important processes. Rapidly accumulating evidence suggests that OxPLs are biomarkers of atherosclerosis and other pathologies. In addition, successful application of experimental drugs based on structural scaffold of OxPLs in animal models of inflammation was recently reported. This review briefly summarizes current knowledge on generation, methods of quantification and biological activities of OxPLs. Furthermore, receptor and cellular mechanisms of these effects are discussed. The goal of the review is to give a broad overview of this class of lipid mediators inducing pleiotropic biological effects. PMID- 28027925 TI - Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome. AB - Mounting evidence shows that the gut microbiota, an important player within the gut-brain communication axis, can affect metabolism, inflammation, brain function and behavior. Interestingly, gut microbiota composition is known to be altered in patients with metabolic syndrome (MetS), who also often display neuropsychiatric symptoms. The use of prebiotics, which beneficially alters the microbiota, may therefore be a promising way to potentially improve physical and mental health in MetS patients. This hypothesis was tested in a mouse model of MetS, namely the obese and type-2 diabetic db/db mice, which display emotional and cognitive alterations associated with changes in gut microbiota composition and hippocampal inflammation compared to their lean db/+ littermates. We assessed the impact of chronic administration (8weeks) of prebiotics (oligofructose) on both metabolic (body weight, food intake, glucose homeostasis) and behavioral (increased anxiety like behavior and impaired spatial memory) alterations characterizing db/db mice, as well as related neurobiological correlates, with particular attention to neuroinflammatory processes. Prebiotic administration improved excessive food intake and glycemic dysregulations (glucose tolerance and insulin resistance) in db/db mice. This was accompanied by an increase of plasma anti-inflammatory cytokine IL-10 levels and hypothalamic mRNA expression of the anorexigenic cytokine IL-1beta, whereas unbalanced mRNA expression of hypothalamic orexigenic (NPY) and anorexigenic (CART, POMC) peptides was unchanged. We also detected signs of improved blood-brain-barrier integrity in the hypothalamus of oligofructose-treated db/db mice (normalized expression of tight junction proteins ZO-1 and occludin). On the contrary, prebiotic administration did not improve behavioral alterations and associated reduction of hippocampal neurogenesis displayed by db/db mice, despite normalization of increased hippocampal IL-6 mRNA expression. Of note, we found a relationship between the effect of treatment on dentate gyrus neurons and spatial memory. These findings may prove valuable for introducing novel approaches to treat some of the comorbidities associated with MetS. PMID- 28027926 TI - Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer's disease mouse model. AB - Exposure to stress during the sensitive period of early-life increases the risk to develop cognitive impairments and psychopathology later in life. In addition, early-life stress (ES) exposure, next to genetic causes, has been proposed to modulate the development and progression of Alzheimer's disease (AD), however evidence for this hypothesis is currently lacking. We here tested whether ES modulates progression of AD-related neuropathology and assessed the possible contribution of neuroinflammatory factors in this. We subjected wild-type (WT) and transgenic APP/PS1 mice, as a model for amyloid neuropathology, to chronic ES from postnatal day (P)2 to P9. We next studied how ES exposure affected; 1) amyloid beta (Abeta) pathology at an early (4month old) and at a more advanced pathological (10month old) stage, 2) neuroinflammatory mediators immediately after ES exposure as well as in adult WT mice, and 3) the neuroinflammatory response in relation to Abeta neuropathology. ES exposure resulted in a reduction of cell-associated amyloid in 4month old APP/PS1 mice, but in an exacerbation of Abeta plaque load at 10months of age, demonstrating that ES affects Abeta load in the hippocampus in an age-dependent manner. Interestingly, ES modulated various neuroinflammatory mediators in the hippocampus of WT mice as well as in response to Abeta neuropathology. In WT mice, immediately following ES exposure (P9), Iba1 immunopositive microglia exhibited reduced complexity and hippocampal interleukin (IL)-1beta expression was increased. In contrast, microglial Iba1 and CD68 were increased and hippocampal IL-6 expression was decreased at 4months, while these changes resolved by 10months of age. Finally, Abeta neuropathology triggered a neuroinflammatory response in APP/PS1 mice that was altered after ES exposure. APP/PS1 mice exhibited increased CD68 expression at 4months, which was further enhanced by ES, whereas the microglial response to Abeta neuropathology, as measured by Iba1 and CD11b, was less prominent after ES at 10months of age. Finally, the hippocampus appears to be more vulnerable for these ES-induced effects, since ES did not affect Abeta neuropathology and neuroinflammation in the entorhinal cortex of adult ES exposed mice. Overall, our results demonstrate that ES exposure has both immediate and lasting effects on the neuroinflammatory response. In the context of AD, such alterations in neuroinflammation might contribute to aggravated neuropathology in ES exposed mice, hence altering disease progression. This indicates that, at least in a genetic context, ES could aggravate AD pathology. PMID- 28027927 TI - Prenatal stress affects placental cytokines and neurotrophins, commensal microbes, and anxiety-like behavior in adult female offspring. AB - Recent studies demonstrate that exposure to stress changes the composition of the intestinal microbiota, which is associated with development of stress-induced changes to social behavior, anxiety, and depression. Stress during pregnancy has also been related to the emergence of these disorders; whether commensal microbes are part of a maternal intrauterine environment during prenatal stress is not known. Here, we demonstrate that microbiome changes are manifested in the mother, and also found in female offspring in adulthood, with a correlation between stressed mothers and female offspring. Alterations in the microbiome have been shown to alter immune responses, thus we examined cytokines in utero. IL-1beta was increased in placenta and fetal brain from offspring exposed to the prenatal stressor. Because IL-1beta has been shown to prevent induction of brain derived neurotrophic factor (BDNF), we examined BDNF and found a reduction in female placenta and adult amygdala, suggesting in utero impact on neurodevelopment extending into adulthood. Furthermore, gastrointestinal microbial communities were different in adult females born from stressed vs. non-stressed pregnancies. Adult female offspring also demonstrated increased anxiety-like behavior and alterations in cognition, suggesting a critical window where stress is able to influence the microbiome and the intrauterine environment in a deleterious manner with lasting behavioral consequences. The microbiome may be a key link between the intrauterine environment and adult behavioral changes. PMID- 28027928 TI - Dengue virus non-structural Protein-1 expression and associated risk factors among febrile Patients attending University of Abuja Teaching Hospital, Nigeria. AB - BACKGROUND: Dengue is a mosquito-borne and neglected tropical viral disease that has been reported to be hyper-endemic in Nigeria. However, this is the first dengue study in Abuja. OBJECTIVE: This hospital-based cross-sectional study investigated the prevalence of Dengue virus (DENV) non-structural protein-1 (NS1) antigenaemia, anti-Dengue virus IgG and their associated risk factors among febrile patients attending the University of Abuja Teaching Hospital (UATH), Nigeria. MATERIALS AND METHODS: From May to August 2016, blood samples were individually collected from 171 consented participants. These samples were analyzed using DENV NS1 and anti-DENV IgG Enzyme Linked Immunosorbent Assay (ELISA) kits. Well-structured questionnaires was used to collect sociodemographic variables of participants. RESULTS: Out of the 171 participants, the prevalence of Dengue virus NS1 antigenaemia and IgG seropositivity were 8.8% and 43.3%, respectively. Three (1.8%) of the patients were NS1 (+) IgG (-), 12 (7.0%) had NS1 (+) IgG (+), 62 (36.3%) were NS1 (-) IgG (+), while 97 (56.7%) of the remaining patients were NS1 (-) IgG (-). There was statistical association between DENV NS1 antigenaemia with age of patients (p=0.034), residence in proximity to waste dumpsites (p<0.0001) but not with occupation of patients (p=0.166), use of indoor insecticide sprays (p=0.4910) and presence of household artificial water containers (p=0.3650). There was statistical association between the prevalence of anti-Dengue virus IgG with occupation (p=0.0034) and education level of patients (p<0.001). However, there was no statistical association between the prevalence of anti-Dengue virus IgG with gender (p=0.4060) and residential area of patients (p=0.3896). CONCLUSION: Findings from this study revealed that DENV infection is one of the etiological agents of acute febrile illnesses in Abuja. It's recommended that Dengue testing be considered during differential diagnosis of febrile patients. PMID- 28027929 TI - Nrf2 exerts cell-autonomous antifibrotic effects: compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative. AB - The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) governs antioxidant, innate immune and cytoprotective responses and its deregulation is prominent in chronic inflammatory conditions. To examine the hypothesis that Nrf2 might be implicated in systemic sclerosis (SSc), we investigated its expression, activity, and mechanism of action in SSc patient samples and mouse models of fibrosis and evaluated the effects of a novel pharmacologic Nrf2 agonist. We found that both expression and activity of Nrf2 were significantly reduced in SSc patient skin biopsies and showed negative correlation with inflammatory gene expression. In skin fibroblasts, Nrf2 mitigated fibrotic responses by blocking canonical transforming growth factor beta (TGF-beta)-Smad signaling, whereas silencing Nrf2 resulted in constitutively elevated collagen synthesis, spontaneous myofibroblast differentiation, and enhanced TGF-beta responses. Bleomycin treatment of Nrf2-null mice resulted in exaggerated fibrosis. In wild-type mice, treatment with a novel pharmacologic Nrf2 agonist 2-trifluoromethyl-2'-methoxychalcone prevented dermal fibrosis induced by TGF-beta. These findings are the first to identify Nrf2 as a cell intrinsic antifibrotic factor with key roles in maintaining extracellular matrix homeostasis and a pathogenic role in SSc. Pharmacologic reactivation of Nrf2, therefore, represents a novel therapeutic strategy toward effective treatment of fibrosis in SSc. PMID- 28027930 TI - Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation. AB - Tocilizumab (TCZ) is an effective treatment for rheumatoid arthritis (RA). However, the changes that occurred after TCZ therapy on endothelial dysfunction, monocyte activity, NETosis, and oxidative stress, the principal effectors of atherosclerosis and cardiovascular disease, have not been analyzed yet. A total of 20 RA patients received 162 mg per week subcutaneous TCZ for 6 months. Endothelial function was measured through postocclusive hyperemia using Laser Doppler. Oxidative stress markers in monocytes and neutrophils were analyzed by flow cytometry. NETosis was measured through SYTOX staining of DNA fibers and the expression of myeloperoxidase and neutrophil elastase. Percentage of low-density granulocytes was analyzed through flow cytometry. Gene expression and phosphorylation of intracellular pathways was analyzed in monocytes. TCZ improved endothelial function and decreased oxidative stress in RA leukocytes. Percentage of low-density granulocytes and NETosis generation were reduced. The proinflammatory and prothrombotic status of RA monocytes was also reversed through a modulation of specific intracellular pathways. All these results were recapitulated after in vitro treatment with TCZ of monocytes and neutrophils purified from RA patients and cocultured with endothelial cells. TCZ might reduce the proatherothrombotic profile in RA patients through the restoration of the endothelial function, oxidative stress reduction, inhibition of monocytes' prothrombotic and inflammatory profile, and abridged NETosis generation. PMID- 28027931 TI - Copper chaperone Atox1 plays role in breast cancer cell migration. AB - Copper (Cu) is an essential transition metal ion required as cofactor in many key enzymes. After cell uptake of Cu, the metal is transported by the cytoplasmic Cu chaperone Atox1 to P1B-type ATPases in the Golgi network for incorporation into Cu-dependent enzymes in the secretory path. Cu is vital for many steps of cancer progression and Atox1 was recently suggested to have additional functionality as a nuclear transcription factor. We here investigated the expression level, cellular localization and role in cell migration of Atox1 in an aggressive breast cancer cell line upon combining immunostaining, microscopy and a wound healing assay. We made the unexpected discovery that Atox1 accumulates at lamellipodia borders of migrating cancer cells and Atox1 silencing resulted in migration defects as evidenced from reduced wound closure. Therefore, we have discovered an unknown role of the Cu chaperone Atox1 in breast cancer cell migration. PMID- 28027932 TI - RanBPM inhibits BLT2-mediated IL-8 production and invasiveness in aggressive breast cancer cells. AB - RanBPM is a scaffolding protein that regulates several cellular processes by interacting with various proteins. Previously, we reported that RanBPM acts as a negative regulator of BLT2, a low-affinity leukotriene B4 receptor; thus, it interferes with BLT2-mediated cell motility. In the present study, we observed that the expression levels of RanBPM were markedly reduced in the highly aggressive MDA-MB-435 and MDA-MB-231 human breast cancer cell lines compared with those in non-invasive MCF-7 cells. Additionally, we found that the restoration of RanBPM levels suppressed the invasiveness of these aggressive breast cancer cells in a manner dependent on BLT2 activation. In contrast, the knockdown of endogenous RanBPM by shRNA strongly promoted invasiveness in non-invasive MCF-7 cells. We also observed that RanBPM suppressed the invasiveness of aggressive breast cancer cells by inhibiting BLT2-mediated reactive oxygen species (ROS) generation and IL-8 production. Taken together, our results suggest that RanBPM acts as a negative regulator of BLT2, thus attenuating the invasiveness of aggressive breast cancer cells. PMID- 28027933 TI - Structural and functional analysis of BF2549, a PadR-like transcription factor from Bacteroides fragilis. AB - A phenolic acid decarboxylase (padC) regulator, PadR and its homologs proteins belong to the PadR family. Despite the growing numbers of the PadR family members and their various roles in bacteria, such as detoxifications, drug transports and circadian rhythms, biochemical and biophysical studies of the PadR family are very limited. Thus, a ligand-induced regulatory mechanism of the PadR family transcription factors remains to be elucidated. Here, we report a crystal structure of a Bacteroides fragilis PadR-like protein, BF2549 and revealed its interaction with putative operator DNA and ligand molecules. Comparative structural and primary sequence analyses provide a PadR-specific motif that is conserved in the PadR family but deviated from the MarR family. Furthermore, putative ligand binding sites are observed in the BF2549 structure. Finally, a homology-based structure model of BF2549 and 29-mer dsDNA propose regulatory mechanisms of the PadR family in transcriptional derepression. PMID- 28027934 TI - Histone modifications in FASN modulated by sterol regulatory element-binding protein 1c and carbohydrate responsive-element binding protein under insulin stimulation are related to NAFLD. AB - Non-alcoholic fatty liver disease (NAFLD) and its causal factors of hepatic insulin resistance (IR) and type 2 diabetes are rapidly growing worldwide. Developing new therapeutic methods for these conditions requires a comprehensive understanding between hepatic lipid metabolism and IR. Sterol regulatory element binding transcription factor 1c (SREBP-1c) and carbohydrate responsive-element binding protein (ChREBP) are the major regulators of fatty acid synthase (FASN), a key enzyme of de novo fatty acid synthesis. They are induced by insulin, which directly binds to the sterol regulatory elements (SRE) or carbohydrate-responsive elements (ChORE) of the FASN promoter to induce its expression. The insulin pathway involved in NAFLD has well studied, but the role of histone modification in NAFLD is just beginning to be investigated, and there is minimal data regarding its involvement. In the current study, we investigated histone modifications in FASN under insulin stimulation. H3K4 hypertrimethylation and H3, H4 hyperacetylation in the FASN promoter was found in HepG2 cells and primary hepatocytes following insulin stimulation. We also found that insulin treatment induced the transcription factor SREBP-1c, ChREBP and could accelerate FASN expression by enhancing SREBP-1c, SRE, and ChREBP ChORE binding and inducing H3, H4 hyperacetylation at SRE, ChORE, or transcription start site (TSS) regions of the FASN promoter in hepatocellular carcinoma cell line (HepG2) and primary hepatocytes. Finally, histone acetylation could influence FASN expression by impairing SREBP-1c SRE and ChREBP ChORE binding. PMID- 28027935 TI - Cross-sectional associations of objectively measured physical activity with brain derived neurotrophic factor in adolescents. AB - OBJECTIVE: The purpose of this study was to examine the associations between objectively measured physical activity and serum brain-derived neurotrophic factor (BDNF) in adolescents. METHODS: Cross-sectional analyses were performed using data from 415 adolescents who participated in the 2015 follow-up of the Childhood Health Activity and Motor Performance School Study Denmark (the CHAMPS study DK). Physical activity was objectively measured by accelerometry monitors. Serum BDNF levels were analyzed using the Enzyme-linked immunosorbent assay (ELISA). Anthropometrics and pubertal status were measured using standardized procedures. RESULTS: With adjustment for age, pubertal status and body mass index, mean physical activity (counts per minute) was negatively associated with serum BDNF in boys (P=0.013). Similarly, moderate-to-vigorous physical activity (MVPA) was negatively associated with serum BDNF in boys (P=0.035). In girls, mean physical activity and MVPA were not associated with serum BDNF. Without adjustment for wear time, sedentary time was not associated with serum BDNF in either sex. CONCLUSION: These findings indicate that higher physical activity is associated with lower serum BDNF in boys, but not in girls. PMID- 28027936 TI - Sensorimotor gating in healthy adults tested over a 15 year period. AB - BACKGROUND: Prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to study normal and pathological brain function. From 2001 to 2016, we screened healthy subjects (HS) to establish their suitability for tests of drug effects on PPI. Because of the size and systematic characterization of this sample across variables of relevance to PPI, we now report these screening results. METHODS: Acoustic startle and PPI were assessed in HS to identify those eligible for studies of drug effects on PPI from 2001 to 2016, yielding 457 "eligible" subjects. RESULTS: Data confirmed the consistency of PPI across this 15-year period, and supported the role of several variables previously reported to moderate either startle or PPI. CONCLUSIONS: Startle and PPI are robust physiological measures that are predictably moderated by specific physiological variables in healthy adults. As such, these measures serve as robust markers of neurobiological processes in healthy and patient populations. PMID- 28027938 TI - Superimposed pressure oscillations: An alternative to treat airway hyperresponsiveness in an acute sensitized airways mouse model. AB - The main driving mechanism during an asthma attack is the hyper-constrictions of airway smooth muscle (ASM), which reduces the airway lumen and makes normal breathing difficult. In spite of some noticeable side effects, bronchodilator drugs such as salbutamol are used to alleviate these symptoms by inducing temporary relaxation of the contracted ASM. In vitro studies have shown that mechanical oscillation can induce relaxation in isolated contracted ASM obtained from healthy subjects but not from asthmatics. To date, little is known about in vivo ASM behaviours, in particular in asthmatic subjects. This in vivo study aims at determining the effect of various superimposed pressure oscillation (SIPO) patterns (different to those occurring during normal breathing) on sensitized airways during an ACh challenge (mimicking an asthmatic attack) and comparing it with the effect of a widely studied broncho-relaxant drug, Isoproterenol (ISO). The study shows that superimposed pressure oscillation in the range of 5-15Hz induces approximately 50% relaxation on pre-constricted sensitized airways in vivo; however, this behaviour was not observed at 20Hz. Our finding suggests that mechanical oscillation, particularly SIPO, may act as a bronchodilator and achieve ASM relaxation. PMID- 28027937 TI - Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate. AB - OBJECTIVES: In patients with systemic sclerosis (SSc), fingertip digital ulcers (DUs) are believed to be ischaemic, and extensor surface DUs a result of mechanical factors/microtrauma. Our aim was to assess blood flow response to topical glyceryl trinitrate (GTN) compared to placebo in SSc DUs, looking for differences in pathophysiology between fingertip and extensor lesions. METHOD: This was a double-blind, randomised, crossover, placebo-controlled study. Sixteen (6 fingertip, 10 extensor) DUs were each studied twice (one day apart): once with GTN and once with placebo ointment. Perfusion at the DU centre ('DUCore') and periphery ('DUPeriphery'), as measured by laser Doppler imaging was performed before and immediately after ointment application, then every 10min, up to 90min post-application. We calculated the area under the response curve (AUC) and the ratio of peak perfusion to baseline, then compared these between GTN and placebo. RESULTS: Perfusion was lower in the DUCore compared to the DUPeriphery (ratio of 0.52). The microvessels of the DUCore were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. The AUC and peak/baseline perfusion difference in means (ratio, 95% confidence interval) between GTN and placebo at the DUCore were 1.2 (1.0-1.6) and 1.2 (1.0-1.5) respectively, and at the DUPeriphery were 1.1 (0.8-1.6) and 1.0 (0.9-1.2) respectively. CONCLUSION: DUs (both fingertip and extensor) were responsive to topical GTN, with an increase in perfusion to the ischaemic DU centre. If both fingertip and extensor DUs have a (potentially reversible) ischaemic aetiology, this has important treatment implications. PMID- 28027939 TI - Multiple major histocompatibility complex class I genes in Asian anurans: Ontogeny and phylogeny. AB - Amphibians, as the first terrestrial vertebrates, offer a window into early major histocompatibility complex (MHC) evolution. We characterized the MHC class I of two Korean amphibians, the Asiatic toad (Bufo gargarizans) and the Japanese tree frog (Hyla japonica). We found at least four transcribed MHC class I (MHC I) loci, the highest number confirmed in any anuran to date. Furthermore, we identified MHC I transcripts in terrestrial adults, and possibly in aquatic larvae, of both species. We conducted a phylogenetic analysis based on MHC I sequence data and found that B. gargarizans and H. japonica cluster together in the superfamily Nobleobatrachia. We further identified three supertypes shared by the two species. Our results reveal substantial variation in the number of MHC I loci in anurans and suggest that certain supertypes have particular physiochemical properties that may confer pathogen resistance. PMID- 28027940 TI - Cholesterol in situ forming gel loaded with doxycycline hyclate for intra periodontal pocket delivery. AB - Cholesterol has been widely used in drug delivery systems including implant. Doxycycline hyclate (DH)-loaded cholesterol in situ forming gels using N-methyl pyrrolidone as a solvent were prepared and investigated for their properties including viscosity, rheology, syringeability, gel formation, drug release, degradation and antimicrobial activities. The burst drug release of a DH-loaded in situ forming gel using cholesterol as the gelling agent was minimized when the amount of benzyl benzoate was increased. The viscosity of the system was increased as the amount of benzyl benzoate was increased with Newtonian flow. The systems were easy to inject into the target site because of their minimal force of syringeability. They could transform from solution into matrix-like structures, but formulations with higher concentrations of benzyl benzoate took a longer time. However, the degradability was decreased when the amount of benzyl benzoate was increased. These systems inhibited P. gingivalis, S. mutans and S. aureus effectively. DH-loaded cholesterol in situ forming gel system comprising 10% benzyl benzoate was the most suitable owing to its sustainable release manner for 10days and therefore was the proper formulation for periodontitis treatment. PMID- 28027941 TI - Analysis of pharmaceutical adulterants in plant food supplements by UHPLC-MS/MS. AB - A method based on the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction and ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was successfully developed and validated for the analysis of 26 pharmaceutical compounds belonging to different therapeutic classes (anorexics, stimulants, anxiolytics, antidepressants and laxatives), which are all prone to be illegally added into weight-loss plant food supplements (PFS) for their pharmacological activity. Internal standard calibration with six isotopically labelled compounds rendered good linearity in the range of 5 to 1000MUg/l, depending on the compound, and good sensitivity with limits of quantification in the range of 0.02-9.80MUg/l. Recoveries were assessed for all the 16 samples analysed and were found between 70% and 120% for over 90% of the analytes. The average recovery value was 90.8%, for the different studied matrices (liquids, liquid ampoules, tablets and capsules), with RSD values lower than 10% for all forms. The changes introduced to the QuEChERS procedure maintained the good performance characteristics of the extraction method while preserving the chromatographic system for the introduction of unwanted matrix compounds. Synephrine was the only compound detected and quantified in one sample, but at a very low concentration (768MUg/l) and its presence may be due to the plant extracts used in the formulation, as synephrine is known to be a natural constituent of Citrus aurantium amara. Despite none of the 16 evaluated samples were found to be adulterated by the illegal addition of the drugs included in this work, the developed methodology can be very useful for monitoring the adulteration of weight-loss PFS. PMID- 28027942 TI - Achyrocline satureioides essential oil-loaded in nanocapsules reduces cytotoxic damage in liver of rats infected by Trypanosoma evansi. AB - The aim of this study was to evaluate whether the treatment with Achyrocline satureioides essential oil-loaded in nanocapsules (AS-NC) is able to protect the hepatic tissue against cytotoxic damage caused by Trypanosoma evansi. Thus, the rats were divided into four groups (n = 6 per group): uninfected/saline, uninfected/AS-NC, infected/saline, and infected/AS-NC. At day 4 post-infection (PI), the animals were euthanized and liver and sera samples were collected to perform the hepatic cell viability assay, and to determine seric levels of reactive oxygen species (ROS) and nitric oxide metabolites (NOx). Cell viability decreased (p < 0.05) in the infected/saline group compared to uninfected/saline group, while the treatment with AS-NC avoided this alteration in infected rats. Seric ROS and NOx levels increased (p < 0.05) in the infected/saline group compared to uninfected/saline group, while the treatment with AS-NC avoided this effect on ROS levels of infected rats. In summary, the treatment with AS-NC was able to protect the liver tissue against the cytotoxic effect caused by the parasite by avoiding exacerbated production of ROS. PMID- 28027943 TI - Fowl typhoid in laying hens cause hepatic oxidative stress. AB - The aim of this study was to analyses nitric oxide, antioxidant status, and oxidative profile in the liver of laying hens naturally infected by Salmonella enterica subsp enterica serovar Gallinarum (S. Gallinarum). The nitrite/nitrate (NOx), reactive oxygen species (ROS), thiobarbituric acid-reactive substances (TBARS), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities were measured in liver samples, as well the biomarkers of hepatic function (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), total protein and albumin levels measured in serum. NOx levels and CAT activity were reduced in hepatic tissue of infected hens. On the other hand, TBARS and ROS levels, GR, GPx and GST activities were higher in infected animals. On biomarkers of tissue damage, ALT, AST, GGT and total protein levels were higher in serum of infected hens, and showed decreased albumin levels. In summary, ROS and TBARS production lead to damage on the membrane lipids that alter activities of antioxidant enzymes CAT, GR, GPx and GSH, an adaptive response against S. Gallinarum infection, contributing to the pathophysiology and clinical signs of the disease. PMID- 28027944 TI - Antibiofilm efficacy of green synthesized graphene oxide-silver nanocomposite using Lagerstroemia speciosa floral extract: A comparative study on inhibition of gram-positive and gram-negative biofilms. AB - Biofilm architecture provides bacteria with enhanced antibiotic resistance, thus raising the need to search for alternative therapies that can inhibit the bacterial colonization. In the present study, we synthesized graphene oxide silver nanocomposite (GO-Ag) by non-toxic and eco-friendly route using a floral extract of Legistromia speciosa (L.) Pers. The gas chromatography-mass spectrometry (GC-MS) analysis of plant extract revealed the presence of compounds which can simultaneously act as reducing and capping agents. The sub-inhibitory concentrations of synthesized GO-Ag reduced the biofilm formation in both gram negative (E. cloacae) and gram-positive (S. mutans) bacterial models. Growth curve assay, membrane integrity assay, scanning electron microscopy (SEM) and confocal scanning laser microscopy (CSLM) revealed different mechanisms of biofilm inhibition in E. cloacae and S. mutans. Moreover, quantitative RT-PCR (qRT-PCR) results suggested GO-Ag is acting on S. mutans biofilm formation cascade. Biofilm inhibitory concentrations GO-Ag were also found to be non-toxic against HEK-293 (human embryonic kidney cell line). The whole study highlights the therapeutic potential of GO-Ag to restrain the onset of biofilm formation in bacteria. PMID- 28027945 TI - Next-Generation Assessment of Human Epidermal Growth Factor Receptor 2 (ERBB2) Amplification Status: Clinical Validation in the Context of a Hybrid Capture Based, Comprehensive Solid Tumor Genomic Profiling Assay. AB - Establishing ERBB2 [human epidermal growth factor receptor 2 (HER2)] amplification status in breast and gastric carcinomas is essential to treatment selection. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) constitute the current standard for assessment. With further advancements in genomic medicine, new clinically relevant biomarkers are rapidly emerging and options for targeted therapy are increasing in patients with advanced disease, driving the need for comprehensive molecular profiling. Next-generation sequencing (NGS) is an attractive approach for up-front comprehensive assessment, including ERBB2 status, but the concordance with traditional methods of HER2 assessment is not well established. The Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, a hybrid capture-based NGS assay interrogating the coding regions of 410 cancer-related genes, was performed on manually macrodissected unstained sections from formalin fixed, paraffin-embedded breast (n = 213) and gastroesophageal (n = 39) tumors submitted for clinical mutation profiling. ERBB2 status was assessed using a custom bioinformatics pipeline, and NGS results were compared to IHC and FISH. NGS ERBB2 amplification calls had an overall concordance of 98.4% (248/252) with the combined IHC/FISH results in this validation set. Discrepancies occurred in the context of low tumor content and HER2 heterogeneity. ERBB2 amplification status can be reliably determined by hybridization capture-based NGS methods, allowing efficient concurrent testing for other potentially actionable genomic alterations, particularly in limited material. PMID- 28027946 TI - How serpins transport hormones and regulate their release. AB - The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S-S bridge, in the hypertensive complication of pregnancy, pre eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure. PMID- 28027947 TI - Hyaluronic acid coated PLGA nanoparticulate docetaxel effectively targets and suppresses orthotopic human lung cancer. AB - PLGA nanotherapeutics though representing a most promising platform for targeted cancer therapy are confronted with low stability and insufficient tumor cell uptake. Here, we report that hyaluronic acid (HA) coated PLGA nanoparticulate docetaxel (DTX-HPLGA) is particularly robust and can effectively target and suppress orthotopic human lung cancer. DTX-HPLGA was easily prepared with a small size of 154nm and negative surface charge of -22.7mV by nanoprecipitation and covalent coating with HA. DTX-HPLGA displayed a low IC50 of 0.91MUg/mL in CD44+ A549 cells and a prolonged elimination half-life of 4.13h in nude mice. Interestingly, DTX-HPLGA demonstrated 4.4-fold higher accumulation in the cancerous lung than free DTX, reaching a remarkable level of 13.7%ID/g at 8h post injection, in orthotopic human A549 lung cancer-bearing mice. Accordingly, DTX HPLGA exhibited significantly better inhibition of tumor growth than free DTX, leading to healthy mice growth and markedly improved survival time. DTX-HPLGA with easy fabrication, excellent stability and tumor accumulation, effective tumor suppression, and low side effects is of particular interest for targeted chemotherapy of lung cancers. PMID- 28027948 TI - Safe approaches for camptothecin delivery: Structural analogues and nanomedicines. AB - Twenty-(S)-camptothecin is a strongly cytotoxic molecule with excellent antitumor activity over a wide spectrum of human cancers. However, the direct formulation is limited by its poor water solubility, low plasmatic stability and severe toxicity, which currently limits its clinical use. As a consequence, two strategies have been developed in order to achieve safe and efficient delivery of camptothecin to target cells: structural analogues and nanomedicines. In this review, we summarize recent advances in the design, synthesis and development of camptothecin molecular derivatives and supramolecular vehicles, following a systematic classification according to structure-activity relationships (structural analogues) or chemical nature (nanomedicines). A series of organic, inorganic and hybrid materials are presented as nanoplatforms to overcome camptothecin restrictions in administration, biodistribution, pharmacokinetics and toxicity. Nanocarriers which respond to a variety of stimuli endogenously (e.g., pH, redox potential, enzyme activity) or exogenously (e.g., magnetic field, light, temperature, ultrasound) seem the best positioned therapeutic materials for optimal spatial and temporal control over drug release. The main goal of this review is to be used as a source of relevant literature for others interested in the field of camptothecin-based therapeutics. To this end, final remarks on the most important formulations currently under clinical trial are provided. PMID- 28027949 TI - Toileting behaviours and lower urinary tract symptoms among female nurses: A cross-sectional questionnaire survey. AB - BACKGROUND: Unhealthy toileting behaviours exist among women, and lower urinary tract symptoms have a high prevalence and significant effects on quality of life. However, the relationship between toileting behaviours and lower urinary tract symptoms is unclear. OBJECTIVES: This study aimed to investigate the prevalence of lower urinary tract symptoms among female nurses, and the association between toileting behaviours and lower urinary tract symptoms. DESIGN: A cross-sectional stratified cluster sampling study. PARTICIPANTS: A total of 636 female clinical nurses from tertiary hospitals in Jinan (the capital city of Shandong Province, China). METHODS: The Toileting Behaviour-Women's Elimination Behaviours and the International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms scales were used to assess the participants' toileting behaviours and lower urinary tract symptoms, respectively. Multiple linear regression analysis was used to evaluate the association between toileting behaviours and lower urinary tract symptoms. RESULTS: Unhealthy toileting behaviours were common among the female nurses, with delayed voiding being the unhealthiest toileting behaviour, which was followed by place and position preference for voiding. Nearly 68% of the female nurses had at least one lower urinary tract symptom, nearly 50% had incontinence symptoms, 40% had filling symptoms, and 18% had voiding symptoms. Unhealthy toileting behaviours (premature voiding, delayed voiding, and straining to void) were positively associated with lower urinary tract symptoms. However, lower urinary tract symptoms were not significantly associated with voiding place or position preference. Among the control variables, being married or having a history of a urinary tract infection was associated with lower urinary tract symptoms. Having a higher income and regular menstrual period were negatively associated with lower urinary tract symptoms. Compared with vaginal delivery, caesarean delivery had a protective association with lower urinary tract symptoms. CONCLUSION: Lower urinary tract symptoms among female nurses should not be overlooked, because their prevalence among female clinical nurses exceeded that among the general population of women. These findings highlight the importance of avoiding unhealthy toileting behaviours (especially premature voiding, delayed voiding, and straining to void), as these unhealthy toileting behaviours were significantly associated with susceptibility to lower urinary tract symptoms. PMID- 28027951 TI - Mutation of AREA affects growth, sporulation, nitrogen regulation, and pathogenicity in Colletotrichum gloeosporioides. AB - The GATA transcription factor AreA is a global nitrogen regulator that restricts the utilization of complex and poor nitrogen sources in the presence of good nitrogen sources in microorganisms. In this study, we report the biological function of an AreA homolog (the CgareA gene) in the fruit postharvest pathogen Colletotrichum gloeosporioides. Targeted gene deletion mutants of areA exhibited significant reductions in vegetative growth, increases in conidia production, and slight decreases in conidial germination rates. Quantitative RT-PCR (qRT-PCR) analysis revealed that the expression of AreA was highly induced under nitrogen limiting conditions. Moreover, compared to wild-type and complemented strains, nitrogen metabolism-related genes were misregulated in DeltaareA mutant strains. Pathogenicity assays indicated that the virulence of DeltaareA mutant strains were affected by the nitrogen content, but not the carbon content, of fruit hosts. Taken together, our results indicate that CgareA plays a critical role in fungal development, conidia production, regulation of nitrogen metabolism and virulence in Colletotrichum gloeosporioides. PMID- 28027952 TI - Internet Addiction in adolescence: Neurobiological, psychosocial and clinical issues. AB - Despite it has not been formally included in DSM-5 as a disorder, 'Internet addiction (IA)' has become a worldwide issue. It can be broadly defined as a non chemical, behavioral addiction, which involves human-machine interaction. We pinpoint it as an "instrumental" form of social interaction (i.e. mediated by machines), a notion that appears useful for the sake of possible preclinical modeling. The features of Internet use reveals as addictive when this comes at the expense of genuine real-life sociability, with an overlap towards the hikikomori phenomenon (i.e., extreme retreat to one's own room). Due to the specific neuro-developmental plasticity in adolescence, IA poses risks to youths' mental health, and may likely produce negative consequences in everyday life. The thwarted development of adolescents' identity, self-image and adaptive social relationships is discussed: the IA adolescents often suffer loss of control, feelings of anger, symptoms of distress, social withdrawal, and familial conflicts. Further, more severe clinical conditions are also associated to IA, such as dysthymic, bipolar, affective, social-anxiety disorders, as well as major depression. This paper overviews the literature on IA, from neuro-biological, psycho-social and clinical standpoints, taking into account recent debates on diagnostic criteria, nosographic label and assessment tools. Neuroimaging data and neurochemical regulations are illustrated with links to pathogenetic hypotheses, which are amenable to validation through innovative preclinical modeling. PMID- 28027950 TI - DIETFITS study (diet intervention examining the factors interacting with treatment success) - Study design and methods. AB - Numerous studies have attempted to identify successful dietary strategies for weight loss, and many have focused on Low-Fat vs. Low-Carbohydrate comparisons. Despite relatively small between-group differences in weight loss found in most previous studies, researchers have consistently observed relatively large between subject differences in weight loss within any given diet group (e.g., ~25kg weight loss to ~5kg weight gain). The primary objective of this study was to identify predisposing individual factors at baseline that help explain differential weight loss achieved by individuals assigned to the same diet, particularly a pre-determined multi-locus genotype pattern and insulin resistance status. Secondary objectives included discovery strategies for further identifying potential genetic risk scores. Exploratory objectives included investigation of an extensive set of physiological, psychosocial, dietary, and behavioral variables as moderating and/or mediating variables and/or secondary outcomes. The target population was generally healthy, free-living adults with BMI 28-40kg/m2 (n=600). The intervention consisted of a 12-month protocol of 22 one-hour evening instructional sessions led by registered dietitians, with ~15-20 participants/class. Key objectives of dietary instruction included focusing on maximizing the dietary quality of both Low-Fat and Low-Carbohydrate diets (i.e., Healthy Low-Fat vs. Healthy Low-Carbohydrate), and maximally differentiating the two diets from one another. Rather than seeking to determine if one dietary approach was better than the other for the general population, this study sought to examine whether greater overall weight loss success could be achieved by matching different people to different diets. Here we present the design and methods of the study. PMID- 28027953 TI - Neurophysiological assessment of neural network plasticity and connectivity: Progress towards early functional biomarkers for disease interception therapies in Alzheimer's disease. AB - Despite a great deal of research into Alzheimer's disease (AD) over the last 20 years, an effective treatment to halt or slow its progression has yet to be developed. With many aspects of the disease progression still to be elucidated, focus has shifted from reducing levels of amyloid beta (Abeta) in the brains of AD patients towards tau, another pathology, which initiates much earlier in deeper brainstem networks and is thought to propagate via cell-to-cell processes prior to the onset of amyloid pathology and cognitive impairments. In-vitro, ex vivo molecular biology/biochemistry read-outs, and various transgenic animal models have been developed, yet clinical failures have highlighted a clear disconnect and inadequate use of such animal models in translational research across species. AD pathology is now estimated to begin at least 10-20 years before clinical symptoms, and imaging and cerebrospinal fluid biomarkers are leading the way in assessing the disease progression at a stage where neuronal damage has already occurred. Here, we emphasize the relevance of assessing early disruptions in network connectivity and plasticity that occur before neuropathological damage and progressive memory dysfunction, which can have high translational value for discovery of pre-symptomatic AD biomarkers and early mechanism-based disease interception therapeutics. PMID- 28027954 TI - Simulating social interactions for the experimental investigation of joint attention. AB - Social interactions are, by their nature, dynamic and reciprocal - your behaviour affects my behaviour, which affects your behaviour in return. However, until recently, the field of social cognitive neuroscience has been dominated by paradigms in which participants passively observe social stimuli from a detached "third person" perspective. Here we consider the unique conceptual and methodological challenges involved in adopting a "second person" approach whereby social cognitive mechanisms and their neural correlates are investigated within social interactions (Schilbach et al., 2013). The key question for researchers is how to distil a complex, intentional interaction between two individuals into a tightly controlled and replicable experimental paradigm. We explore these issues within the context of recent investigations of joint attention - the ability to coordinate a common focus of attention with another person. We review pioneering neurophysiology and eye-tracking studies that have begun to address these issues; offer recommendations for the optimal design and implementation of interactive tasks, and discuss the broader implications of interactive approaches for social cognitive neuroscience. PMID- 28027956 TI - Neuropsychological changes in melancholic and atypical depression: A systematic review. AB - There is not a consensus as to whether neuropsychological profiling can distinguish depressive subtypes. We aimed to systematically review and critically analyse the literature on cognitive function in patients with melancholic and atypical depression. We searched in databases PubMed, SCOPUS, Web of Knowledge and PsycInfo for papers comparing the neuropsychological performance of melancholic patients (MEL) to non-melancholic depressive patients (NMEL), including atypical depressives, and healthy controls (HC). All studies were scrutinised to determine the main methodological characteristics and particularly possible sources of bias influencing the results reported, using the STROBE statement checklist. We also provide effect size of the results reported for contrasts between MEL; patients and NMEL patients. Seventeen studies were included; most of them demonstrated higher neuropsychological impairments of MEL patients compared to both NMEL patients and HC on tasks requiring memory, executive function, attention and reaction time. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the participants' sociodemographic characteristics, clinical characteristics of patients and differences in neuropsychological assessment. These findings suggest that MEL may have a distinct and impaired cognitive performance compared to NMEL depressive patients on tasks involving verbal and visual memory, executive function, sustained attention and span, as well as psychomotor speed, this last especially when cognitive load is increased. Additional studies with adequate control of potentially confounding variables will help to clarify further differences in the neuropsychological functioning of depressive subtypes. PMID- 28027957 TI - Site-Directed Chemical Probing to map transient RNA/protein interactions. AB - RNA-protein interactions are at the bases of many biological processes, forming either tight and stable functional ribonucleoprotein (RNP) complexes (i.e. the ribosome) or transitory ones, such as the complexes involving RNA chaperone proteins. To localize the sites where a protein interacts on an RNA molecule, a common simple and inexpensive biochemical method is the footprinting technique. The protein leaves its footprint on the RNA acting as a shield to protect the regions of interaction from chemical modification or cleavages obtained with chemical or enzymatic nucleases. This method has proven its efficiency to study in vitro the organization of stable RNA-protein complexes. Nevertheless, when the protein binds the RNA very dynamically, with high off-rates, protections are very often difficult to observe. For the analysis of these transient complexes, we describe an alternative strategy adapted from the Site Directed Chemical Probing (SDCP) approach and we compare it with classical footprinting. SDCP relies on the modification of the RNA binding protein to tether an RNA probe (usually Fe-EDTA) to specific protein positions. Local cleavages on the regions of interaction can be used to localize the protein and position its domains on the RNA molecule. This method has been used in the past to monitor stable complexes; we provide here a detailed protocol and a practical example of its application to the study of Escherichia coli RNA chaperone protein S1 and its transitory complexes with mRNAs. PMID- 28027958 TI - Chasing the tail: The emergence of autocatalytic networks. AB - A ubiquitous feature of all living systems is their ability to sustain a biochemistry in which all reactions are coordinated by catalysts, and all reactants (along with the catalysts) are either produced by the system itself or are available from the environment. This led to the hypothesis that 'autocatalytic networks' play a key role in both the origin and the organization of life, which was first proposed in the early 1970s, and has been enriched in recent years by a combination of experimental studies and the application of mathematical and computational techniques. The latter have allowed a formalization and detailed analysis of such networks, by means of RAF theory. In this review, we describe the development of these ideas, from pioneering early work of Stuart Kauffman through to more recent theoretical and experimental studies. We conclude with some suggestions for future work. PMID- 28027959 TI - Polysarcosine brush stabilized gold nanorods for in vivo near-infrared photothermal tumor therapy. AB - : Gold nanorods (AuNRs) are suitable candidates for photothermal therapy in vivo, because of their excellent ability to transfer near-infrared (NIR) light into heat. However, appropriate surface should be generated on AuNRs before their in vivo application because of the low colloidal stability in complicate biological environment and relatively strong toxicity compared to their pristine stabilizer cetyltrimethylammonium bromide. In the current study, polysarcosine (PS), a non ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural alpha-amino acid, was used to stabilize AuNRs due to its excellent hydrophilicity and biocompatibility. Polysarcosine with optimized molecular weight was synthesized and used to modify AuNRs by traditional ligand exchange. The grafting of PS on AuNRs was evidenced by fourier transform infrared (FTIR) spectroscopy and the alternation of surface zeta potential. The polysarcosine coated AuNRs (Au@PS) showed good stabilities in wide pH range and simulated physiological buffer with the ligand competition of dithiothreitol (DTT). The Au@PS NRs had neglectable cytotoxicity and showed efficient ablation of tumor cells in vitro. Moreover, Au@PS NRs had a longer circulation time in body that resulted in a higher accumulation in solid tumors after intravenous injection, compared to AuNRs capped with polyethylene glycol (PEG). Photothermal therapy in vivo demonstrated that the tumors were completely destroyed by single time irradiation of NIR laser after one-time injection of the polysarcosine capped AuNRs. The Au@PS NRs did not cause obvious toxicity in vivo, suggesting promising potential in cancer therapy. STATEMENT OF SIGNIFICANCE: In current study, polysarcosine (PS), a non-ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural alpha-amino acid, was used to stabilize AuNRs due to its excellent hydrophilicity and biocompatibility. The polysarcosine coated AuNRs (Au@PS) showed good stabilities in wide pH range and simulated physiological buffer. The Au@PS NRs had very low cytotoxicity and showed high efficacy for the ablation of cancer cells in vitro. Moreover, Au@PS NRs had a longer circulation time in blood that led to a higher accumulation in tumors after intravenous injection, compared to AuNRs capped with polyethylene glycol (PEG). In vivo photothermal therapy showed that tumors were completely cured without reoccurrence by one-time irradiation of NIR laser after a single injection of the polysarcosine modified AuNRs. PMID- 28027955 TI - Oxytocin pathways in the intergenerational transmission of maternal early life stress. AB - Severe stress in early life, such as childhood abuse and neglect, constitutes a major risk factor in the etiology of psychiatric disorders and somatic diseases. Importantly, these long-term effects may impact the next generation. The intergenerational transmission of maternal early life stress (ELS) may occur via pre-and postnatal pathways, such as alterations in maternal-fetal-placental stress physiology, maternal depression during pregnancy and postpartum, as well as impaired mother-offspring interactions. The neuropeptide oxytocin (OT) has gained considerable attention for its role in modulating all of these assumed transmission pathways. Moreover, central and peripheral OT signaling pathways are highly sensitive to environmental exposures and may be compromised by ELS with implications for these putative transmission mechanisms. Together, these data suggest that OT pathways play an important role in the intergenerational transmission of maternal ELS in humans. By integrating recent studies on gene environment interactions and epigenetic modifications in OT pathway genes, the present review aims to develop a conceptual framework of intergenerational transmission of maternal ELS that emphasizes the role of OT. PMID- 28027960 TI - Investigating resting-state functional connectivity in the cervical spinal cord at 3T. AB - The study of spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord. Two ultra high field functional magnetic resonance imaging (fMRI) studies in humans have provided evidence for reproducible resting-state connectivity between the dorsal horns as well as between the ventral horns, and a study in non-human primates has shown that these resting-state signals are impacted by spinal cord injury. As these studies were carried out at ultra-high field strengths using region-of interest (ROI) based analyses, we investigated whether such resting-state signals could also be observed at the clinically more prevalent field strength of 3T. In a reanalysis of a sample of 20 healthy human participants who underwent a resting state fMRI acquisition of the cervical spinal cord, we were able to observe significant dorsal horn connectivity as well as ventral horn connectivity, but no consistent effects for connectivity between dorsal and ventral horns, thus replicating the human 7T results. These effects were not only observable when averaging along the acquired length of the spinal cord, but also when we examined each of the acquired spinal segments separately, which showed similar patterns of connectivity. Finally, we investigated the robustness of these resting-state signals against variations in the analysis pipeline by varying the type of ROI creation, temporal filtering, nuisance regression and connectivity metric. We observed that - apart from the effects of band-pass filtering - ventral horn connectivity showed excellent robustness, whereas dorsal horn connectivity showed moderate robustness. Together, our results provide evidence that spinal cord resting-state connectivity is a robust and spatially consistent phenomenon that could be a valuable tool for investigating the effects of pathology, disease progression, and treatment response in neurological conditions with a spinal component, such as spinal cord injury. PMID- 28027962 TI - Multilocus and multiregional phylogeny reconstruction of the genus Sarcophaga (Diptera, Sarcophagidae). AB - The flesh-fly genus Sarcophaga is extremely diverse and contains ca. 30% of the species in the family Sarcophagidae (~3000 species). The phylogenetic position of the genus-group taxa Helicobia, Lipoptilocnema, and Peckia remains uncertain with respect to the hyperdiverse Sarcophaga, due to conflicting phylogenetic trees and insufficient sampling in recent studies. We present maximum-likelihood and Bayesian phylogenetic analyses of 145 species of 48 subgenera of the genus Sarcophaga from all biogeographic regions based on the molecular markers COI, 28 D1-D3 expansion regions, EF1alpha, and white. Our analyses find (Lipoptilocnema+Peckia) as the sister group of the monophyletic Sarcophaga. The genus Helicobia is placed outside Sarcophaga. Our hypotheses suggest that the ancestor shared by Sarcophaga and its sister clade originated in the Neotropical region, and the subsequent range expansion might be related to the formation of the Isthmus of Panama. This study supports the monophyly of most of the subgenera of Sarcophaga included here, and it shows the evolution of this genus to be a rapid radiation occurring in the Nearctic region with a subsequent dispersal into the Old World. The subgeneric clusters within Sarcophaga are in agreement with the current classification, with only Mauritiella, Rosellea, Helicophagella, Liosarcophaga, and Sarcorohdendorfia being non-monophyletic. We also validate the monotypic condition of 10 subgenera. PMID- 28027961 TI - The clinical relevance of distortion correction in presurgical fMRI at 7T. AB - Presurgical planning with fMRI benefits from increased reliability and the possibility to reduce measurement time introduced by using ultra-high field. Echo planar imaging suffers, however, from geometric distortions which scale with field strength and potentially give rise to clinically significant displacement of functional activation. We evaluate the effectiveness of a dynamic distortion correction (DDC) method based on unmodified single-echo EPI in the context of simulated presurgical planning fMRI at 7T and compare it with static distortion correction (SDC). The extent of distortion in EPI and activation shifts are investigated in a group of eleven patients with a range of neuropathologies who performed a motor task. The consequences of neglecting to correct images for susceptibility-induced distortions are assessed in a clinical context. It was possible to generate time series of EPI-based field maps which were free of artifacts in the eloquent brain areas relevant to presurgical fMRI, despite the presence of signal dropouts caused by pathologies and post-operative sites. Distortions of up to 5.1mm were observed in the primary motor cortex in raw EPI. These were accurately corrected with DDC and slightly less accurately with SDC. The dynamic nature of distortions in UHF clinical fMRI was demonstrated via investigation of temporal variation in voxel shift maps, confirming the potential inadequacy of SDC based on a single reference field map, particularly in the vicinity of pathologies or in the presence of motion. In two patients, the distortion correction was potentially clinically significant in that it might have affected the localization or interpretation of activation and could thereby have influenced the treatment plan. Distortion correction is shown to be effective and clinically relevant in presurgical planning at 7T. PMID- 28027963 TI - Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effect. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) represents the only curative therapy for many haematological malignancies. Its curative potential is mostly attributed to the graft-versus-leukemia effect (GvL), which is mainly driven by donor T-cells. Donor lymphocyte infusions (DLI), likewise a second allo HCT, have become a standard approach to treat AML and MDS relapses post allo-HCT. Although DLI have been used in this setting for decades, its effectivity and toxicity are still unpredictable in many patients. Over these recent years, new DLI strategies and therapies have been developed for AML and MDS. In this review, we will overview the recent use of DLI for AML and MDS, with up to date information from novel studies and research lines. PMID- 28027964 TI - Characterization of Bombyx mori mitochondrial transcription factor A, a conserved regulator of mitochondrial DNA. AB - In the present study, we initially cloned and characterized a mitochondrial transcription factor A (Tfam) homologue in the silkworm, Bombyx mori. Bombyx mori TFAM (BmTFAM) localized to mitochondria in cultured silkworm and human cells, and co-localized with mtDNA nucleoids in human HeLa cells. In an immunoprecipitation analysis, BmTFAM was found to associate with human mtDNA in mitochondria, indicating its feature as a non-specific DNA-binding protein. In spite of the low identity between BmTFAM and human TFAM (26.5%), the expression of BmTFAM rescued mtDNA copy number reductions and enlarged mtDNA nucleoids in HeLa cells, which were induced by human Tfam knockdown. Thus, BmTFAM compensates for the function of human TFAM in HeLa cells, demonstrating that the mitochondrial function of TFAM is highly conserved between silkworms and humans. BmTfam mRNA was strongly expressed in early embryos. Through double-stranded RNA (dsRNA)-based RNA interference (RNAi) in silkworm embryos, we found that the knockdown of BmTFAM reduced the amount of mtDNA and induced growth retardation at the larval stage. Collectively, these results demonstrate that BmTFAM is a highly conserved mtDNA regulator and may be a good candidate for investigating and modulating mtDNA metabolism in this model organism. PMID- 28027965 TI - The serine/threonine phosphatase DhSIT4 modulates cell cycle, salt tolerance and cell wall integrity in halo tolerant yeast Debaryomyces hansenii. AB - The highly conserved family of Phosphoprotein phosphatases (PPP) regulates several major physiological processes in yeast. However, very little is known about the PPP orthologs from the yeast species inhabiting extreme environmental niches. In the present study we have identified DhSIT4, a member of PPP6 class of serine threonine phosphatases from the halotolerant yeast Debaryomyces hansenii. Deletion of DhSIT4 in D. hansenii was not lethal but the mutant exhibited reduced growth due to its effect on the cell cycle. The knock out mutant Dhsit4Delta showed sensitivity towards Li+, Na+ and cell wall damaging agents. The expression of DhSit4p rescued salt, caffeine and calcofluor white sensitivity of Dhmpk1Delta strain and thereby indicating a genetic interaction of this phosphatase with the cell wall integrity pathway in this species. Our study also demonstrated the antagonistic roles of DhSit4p and DhPpz1p in maintaining the cell cycle and ion homeostasis in D. hansenii. PMID- 28027966 TI - Sequence motifs associated with paternal transmission of mitochondrial DNA in the horse mussel, Modiolus modiolus (Bivalvia: Mytilidae). AB - In the majority of metazoans paternal mitochondria represent evolutionary dead ends. In many bivalves, however, this paradigm does not hold true; both maternal and paternal mitochondria are inherited. Herein, we characterize maternal and paternal mitochondrial control regions of the horse mussel, Modiolus modiolus (Bivalvia: Mytilidae). The maternal control region is 808bp long, while the paternal control region is longer at 2.3kb. We hypothesize that the size difference is due to a combination of repeated duplications within the control region of the paternal mtDNA genome, as well as an evolutionarily ancient recombination event between two sex-associated mtDNA genomes that led to the insertion of a second control region sequence in the genome that is now transmitted via males. In a comparison to other mytilid male control regions, we identified two evolutionarily Conserved Motifs, CMA and CMB, associated with paternal transmission of mitochondrial DNA. CMA is characterized by a conserved purine/pyrimidine pattern, while CMB exhibits a specific 13bp nucleotide string within a stem and loop structure. The identification of motifs CMA and CMB in M. modiolus extends our understanding of Sperm Transmission Elements (STEs) that have recently been identified as being associated with the paternal transmission of mitochondria in marine bivalves. PMID- 28027967 TI - Co-phylogeographic study of the flatworm Gyrodactylus gondae and its goby host Pomatoschistus minutus. AB - We performed a comparative phylogeographic study on the monogenean flatworm Gyrodactylus gondae Huyse, Malmberg & Volckaert 2005 (Gyrodactylidae) and its sand goby host Pomatoschistus minutus (Pallas, 1770) (Gobiidae). G. gondae is a host-specific parasite with a direct life cycle and a very short generation time. These properties are expected to increase the chance to track the genealogical history of the host with genetic data of the parasite ('magnifying glass principle'). To investigate this hypothesis we screened nine sand goby populations (n=326) along the Atlantic coasts of Europe for Gyrodactylus specimens. Low parasite prevalence resulted in partially overlapping host and parasite datasets. Ninety-two G. gondae collected on five sand goby populations were subsequently sequenced for a 460bp cytochrome c oxidase subunit II (coxII) fragment, which, in combination with previously published haplotype data for the hosts, allowed for partially overlapping host and parasite datasets. Haplotype diversity was lowest in the Irish Sea while nucleotide diversity was highest in the Southern North Sea. The host population also showed the lowest diversity in the Irish Sea but the highest nucleotide diversity, based on cytochrome b sequences of 850bp, was found in Skagerrak. Phylogeographic networks suggest postglacial expansion in both the host and the parasite. Pair-wise population differentiation was however not consistently higher in the parasite than in the host, rejecting the magnifying glass hypothesis for this host-parasite system. The parasite network offered limited resolution and was characterized by many extinctions and/or missing haplotypes, which could be attributed to 1) sampling bias, 2) size fluctuations in the parasite populations resulting in frequent extinctions and genetic drift and 3) the relatively young age of the host parasite association. A more exhaustive study including a broader geographical and genomic coverage is needed to discriminate among these competing hypotheses. PMID- 28027968 TI - Establishment of the complete life cycle of Spirometra (Cestoda: Diphyllobothriidae) in the laboratory using a newly isolated triploid clone. AB - Methods to maintain the life cycle of pathogenic organisms become powerful tools for studying molecular and cellular bases of infectious diseases. Spirometra erinaceieuropaei is a parasitic tapeworm that causes sparganosis in humans. Because S. erinaceieuropaei has a complex life cycle with different stages and host species requirements, there have been no reports to establish the complete life cycle in the laboratory. In this study, using Cyclops as the first intermediate host, mouse as the experimental second intermediate host, and dog as the final host, we succeeded in maintaining S. erinaceieuropaei in the laboratory. By repeating the established life cycle five times, we obtained a clonal population of S. erinaceieuropaei from a single adult worm. A karyotype study showed that the chromosome of this clone is triploid (3n=27), indicating that a genetically uniform strain is established by apomictic reproduction. The strain was named Kawasaki triploid (Kt). A partial sequence of mitochondrial cytochrome c oxidase subunit 1 gene of the strain Kt showed more than 98% similarity with those of S. erinaceieuropaei isolates from Australia, China, and South Korea, and the resultant phylogeny indicated that the strain Kt is a member of a distinctive clade from East Asia and Oceania. Our system will be particularly useful for studies of S. erinaceieuropaei infection and human sparganosis. PMID- 28027969 TI - Morphological and molecular characterization of the metacercaria of Paragonimus caliensis, as a separate species from P. mexicanus in Costa Rica. AB - The trematode Paragonimus mexicanus is the etiological agent of paragonimiasis, a food-borne zoonotic disease in Latin America. This species, as well as Paragonimus caliensis, have been reported from Costa Rica, but it is not known if the two are synonymous. Two types of Paragonimus metacercariae from freshwater pseudothelphusid crabs from several localities in Costa Rica were recognized by light microscopy. Morphologically, these corresponded to descriptions of P. mexicanus and P. caliensis. Metacercariae of the former species lacked a membrane or cyst and their bodies were yellow in color. Those of P. caliensis were contained in a transparent thin cyst and were pink in color. Morphotypes of metacercariae were determined using scanning electron microscopy (SEM). Based on the number and distribution of papillae in the ventral sucker, three morphotypes were found for P. mexicanus and two for P. caliensis. Analysis of DNA sequences (nuclear ribosomal 28S and ITS2 genes, and partial mitochondrial cox1 gene) confirmed the presence of P. mexicanus and provided the first molecular data for P. caliensis. The two species are phylogenetically distinct from each other and distant from the Asian species. The confirmation of P. caliensis as a separate species from P. mexicanus raises several questions about the ecology, biological diversity, and epidemiology of the genus Paragonimus in Costa Rica. PMID- 28027970 TI - HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1beta production via suppressing the NF-kappaB pathway and ROS production. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) has developed strategies to evade immune responses. However, the mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1beta has been shown to inhibit HBV infection in vivo. This study aims to assess whether HBV can affect the NLRP3 inflammasome signaling pathways and shed light on the underlying mechanisms HBV utilizes to evade host innate immune responses. METHODS: HBV inhibition of the lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation was evaluated by Western blot, quantitative RT-PCR, flow cytometry and immunofluorescence. RESULTS: Kupffer cells expressed significantly more NLRP3 and IL-1beta after LPS stimulation; whereas, chronic HBV infection suppressed LPS-induced NLRP3 and pro-IL-1beta expression as well as IL-1beta maturation. This inhibitory activity is mediated by HBeAg, and is involved in the inhibition of NF-kappaB signal pathway and reactive oxygen species (ROS) production. The inhibitory effect of HBeAg was confirmed in patients with chronic hepatitis B (CHB) and hepatocellular carcinoma by comparing the levels of IL 1beta and NLRP3-related proteins in para-carcinoma tissues from HBeAg-positive or negative patients. Moreover, chronic HBV infection increases the susceptibility of mice to S. typhimurium infection, possibly via inhibiting the NLRP3 inflammasome activation and IL-1beta production. CONCLUSIONS: HBeAg inhibits LPS induced NLRP3 inflammasome activation and IL-1beta production via suppressing NF kappaB pathway and ROS production. This finding provides a novel mechanism for HBV-mediated suppression of innate immune responses, and identifies new therapeutic targets for chronic HBV infection and related diseases. LAY SUMMARY: HBeAg suppresses LPS-induced NLRP3 inflammasome activation and IL-1beta production in two ways, one is to repress NLRP3 and pro-IL-1beta expression via inhibiting NF-kappaB phosphorylation, and the other is to repress caspase-1 activation and IL-1beta maturation via inhibiting ROS production. This effect contributes to the HBV persistence and immune tolerance. PMID- 28027972 TI - Pelvic Symptoms, Body Image, and Regret after LeFort Colpocleisis: A Long-Term Follow-Up. AB - STUDY OBJECTIVE: To evaluate the impact of LeFort colpocleisis on body image, regret, and pelvic floor symptoms long-term after surgery. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Tertiary university affiliated hospital. PATIENTS: Between April 2011 and April 2015, 334 patients underwent LeFort colpocleisis. INTERVENTION: LeFort colpocleisis. MEASUREMENT AND MAIN RESULTS: Patient characteristics (e.g., age, body mass index, parity, blood loss, and length of operation), comorbidities, and complications were obtained from medical records. The Chinese version of the Pelvic Floor Distress Inventory Questionnaire (PFDI-20) was used to evaluate self-perceived quality of life. A modified body image scale was used to assess self-image. Regret was assessed by the following question: "Do you regret choosing to undergo colpocleisis for pelvic organ prolapse (yes or no)?" In total, 278 women responded and were considered for statistical evaluation. Of these women, 234 (84%) had at least 1 comorbid condition. After a median 3-year follow-up (range, 1.5-4.5), only 1 woman had experienced recurrent prolapse and required a second surgery. The mean and total body image scores improved significantly from preoperation (p < .001). Approximately 97% of the patients were satisfied with their decision to undergo surgery, and none of the patients regretted their decision. Pelvic symptoms improved significantly from baseline (i.e., preoperation) to follow-up according to the following measures: PFDI-20, 67.5 +/- 23.1 versus 23.8 +/- 15.0 (p < .001); Pelvic Organ Prolapse Distress Inventory-6, 33.2 +/- 19.6 versus 11.4 +/- 10.6 (p < .001); Colorectal-Anal Distress Inventory-8, 10.8 +/- 10.3 versus 3.6 +/- 5.3 (p < .001); and Urinary Distress Inventory-6, 23.5 +/- 18.5 versus 8.8 +/ 9.7 (p < .001). CONCLUSIONS: LeFort colpocleisis is a highly effective surgical treatment option for pelvic organ prolapse that improves both pelvic floor symptoms and body image. The high satisfaction and low regret in the long term after surgery indicate that LeFort colpocleisis is an excellent option for appropriate patients. PMID- 28027971 TI - Host conditioning and rejection monitoring in hepatocyte transplantation in humans. AB - BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre transplant levels of 1343+/-48MUM (normal 30-119MUM) to 854+/-25MUM (treatment goal <=360MUM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900MUM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients. PMID- 28027973 TI - Role of Imaging Tools for the Diagnosis of Borderline Ovarian Tumors: A Systematic Review and Meta-Analysis. AB - Borderline ovarian tumors (BOTs) have a low malignant potential and occur most often in young women. Its preoperative diagnosis can improve surgical strategy and reproductive approach. This study systematically reviews the literature for the accuracy of transvaginal ultrasound (TVUS), magnetic resonance (MRI), and computed tomography (CT) in the diagnostic of BOTs. We conducted a search in PubMed/Medline of articles in English from the last 5 years and included 14 studies for systematic review, 9 of them in the meta-analysis. The pooled sensibility and specificity was respectively 77.0% and 83.0% for TVUS (5 studies) and 85% and 74% for MRI (4 studies) in differentiating benign from malignant BOTs. CT and positron emission tomography (PET)-CT techniques were heterogeneous between studies, so a meta-analysis was not performed for the 4 studies on CT and PET-CT. However, these 4 studies have also shown a high accuracy in differentiating BOTs from malignant ovarian cancers. PMID- 28027974 TI - Fallopian Tubes Take Center Stage with the Ovary. PMID- 28027975 TI - Transferability of Virtual Reality, Simulation-Based, Robotic Suturing Skills to a Live Porcine Model in Novice Surgeons: A Single-Blind Randomized Controlled Trial. AB - STUDY OBJECTIVE: To assess whether a robotic simulation curriculum for novice surgeons can improve performance of a suturing task in a live porcine model. DESIGN: Randomized controlled trial (Canadian Task Force classification I). SETTING: Academic medical center. PATIENTS: Thirty-five medical students without robotic surgical experience. INTERVENTIONS: Participants were enrolled in an online session of training modules followed by an in-person orientation. Baseline performance testing on the Mimic Technologies da Vinci Surgical Simulator (dVSS) was also performed. Participants were then randomly assigned to the completion of 4 dVSS training tasks (camera clutching 1, suture sponge 1 and 2, and tubes) versus no further training. The intervention group performed each dVSS task until proficiency or up to 10 times. A final suturing task was performed on a live porcine model, which was video recorded and blindly assessed by experienced surgeons. The primary outcomes were Global Evaluative Assessment of Robotic Skills (GEARS) scores and task time. The study had 90% power to detect a mean difference of 3 points on the GEARS scale, assuming a standard deviation (SD) of 2.65, and 80% power to detect a mean difference of 3 minutes, assuming an SD of 3 minutes. MEASUREMENTS AND MAIN RESULTS: There were no differences in demographics and baseline skills between the 2 groups. No significant differences in task time in minutes or GEARS scores were seen for the final suturing task between the intervention and control groups, respectively (9.2 [2.65] vs 9.9 [2.07] minutes, p = .406; and 15.37 [2.51] vs 15.25 [3.38], p = .603). The 95% confidence interval for the difference in mean task times was -2.36 to .96 minutes and for mean GEARS scores -1.91 to 2.15 points. CONCLUSIONS: Live suturing task performance was not improved with a proficiency-based virtual reality simulation suturing curriculum compared with standard orientation to the da Vinci robotic console in a group of novice surgeons. PMID- 28027976 TI - A Review of Laparoscopic Salpingo-Oophorectomy: Technique and Perioperative Considerations. AB - Hysterectomy is the most frequently performed major gynecologic surgery in women in the United States. This procedure is often accompanied by unilateral or bilateral removal of the fallopian tubes and ovaries. Although the overall incidence of bilateral salpingo-oophorectomy has been shown to be in a decreasing trend in recent years, it is possibly 1 of the most common scenarios that the gynecologic surgeon will encounter. As the field of minimally invasive surgery continues to expand, it is expected that most of these surgeries will be performed using a laparoscopic approach. In fact, data support that adnexal surgery is more likely to take place during a laparoscopic hysterectomy when compared with abdominal or vaginal routes. This article reviews the basic surgical principles and relevant anatomic relations that every pelvic surgeon should know and aims to serve as a guide for effectively and proficiently performing a salpingo-oophorectomy at the time of hysterectomy. PMID- 28027977 TI - Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families. AB - Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271_1272ins20) and one other being predicted benign in frame gross deletion (c.241_258del). PMID- 28027978 TI - In silico analysis for predicting pathogenicity of five unclassified mitochondrial DNA mutations associated with mitochondrial cytopathies' phenotypes. AB - Mitochondrial DNA (mtDNA) mutations have been assigned as a major cause of genetic disease. When a novel sequence variation is found, it is necessary to evaluate its functional impact, usually requiring functional molecular studies. Given the fact that this approach is difficult to put in practice in a routine basis, it is possible to take advantage of the in silico tools available and predict protein/RNA structure changes and therefore pathogenicity. Here, we describe the characterization of five undescribed mtDNA variants, upon detection of 23 unclassified alterations at Laboratory of Biochemical Genetics, from 2004 to 2014. Those five sequence variations are located in protein-coding genes, in five patients with a diverse range of mitochondrial respiratory chain disease phenotypes including encephalopathy, optic neuropathy, developmental delay, deafness and epilepsy. According to the prediction established by in silico analysis using tools to predict structure and function changes (ClustalW2(r), PolyPhen-2(r), SIFT(r), MutationAssessor(r), PredictProtein(r), Provean(r), I TASSER(r), Haplogrep(r)), from the 23 variants analyzed, the five described are potentially pathogenic. This approach is inexpensive and compatible with a rapid first line response to clinical demanding, contributing to a more rationale genetic diagnosis concerning novel mutations and to clarify the mtDNA involvement in these pathologies. PMID- 28027979 TI - The impairment of glucose-stimulated insulin secretion in pancreatic beta-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response. AB - Type 2 diabetes (T2D) is a progressive disease characterized by sustained hyperglycemia and is frequently accompanied by hyperlipidemia. Deterioration of beta-cell function in T2D patients may be caused, in part, by long-term exposure to high concentrations of glucose and/or lipids. We developed systems to study how chronic glucotoxicity and lipotoxicity might be linked to the impairment of glucose-stimulated insulin secretion (GSIS) machinery in pancreatic beta-cells. INS-1 (832/13) were exposed to glucose and/or palmitate for up to 10 weeks. Chronic high glucose and/or palmitate exposure resulted in impaired GSIS accompanied by a dramatic increase in oxidative stress, as determined by basal intracellular peroxide levels. In addition, the GSIS-associated reactive oxygen species (ROS) signals, assessed as glucose-stimulated peroxide accumulation positively correlated with GSIS in glucose- and/or palmitate-exposed cells, as well as glucose-stimulated reductions in GSH/GSSG ratios. Furthermore, the impairment of GSIS caused by chronic high glucose and/or palmitate exposures were attributed to the induction of adaptive antioxidant response and mitochondrial uncoupling, which negatively regulates glucose-derived ROS generation. Taken together, persistent glucotoxicity- and/or lipotoxicity-mediated oxidative stress and subsequent adaptive antioxidant response impair glucose-derived ROS signaling and GSIS in pancreatic beta-cells. PMID- 28027980 TI - Assessment of the carcinogenic potential of high intense-sweeteners through the test for detection of epithelial tumor clones (warts) in Drosophila melanogaster. AB - High intensity-sweeteners (HIS) are natural or synthetic substances, sweeter than sugar, providing sweetness without calories. Sweeteners are mainly used as an aid in losing weight, preventing obesity and controlling blood sugar levels for diabetics. The objective of this study was to evaluate the carcinogenic potential of the sweeteners aspartame, sucralose, sodium saccharin and steviol glycoside, using the test for detection of epithelial tumor clones in Drosophila melanogaster. Larvae of 72 +/- 4h, obtained from wts/TM3 female mated with mwh/mwh males, were treated for approximately 48h with different concentrations of aspartame (0.85, 1.7, 3.4, 6.8 or 13.6 mM ); sucralose (0.5, 1.25, 2.5, 5.0 or 10 mM); sodium saccharin (25; 50; 100; 200 or 400 mM) and steviol glycoside (2.5; 5.0; 10; 20 or 40 mM). Water (Reverse Osmosis) and doxorubicin (DXR 0.4 mM) were used as negative and positive controls, respectively. No statistically significant differences were observed (p > 0.05) in tumor frequencies in individuals treated with all concentrations of these sweeteners when compared to negative control. It was therefore concluded that, in these experimental conditions, aspartame, sucralose, sodium saccharin and steviol glycoside have no carcinogenic effect in D. melanogaster. PMID- 28027981 TI - Occurrence of halogenated flame retardants in commercial seafood species available in European markets. AB - PBDEs (congeners 28, 47, 99, 100, 153, 154, 183, 209), HBCD (alpha, beta, gamma), emerging brominated flame retardants (PBEB, HBB and DBDPE), dechloranes (Dec 602, 603, 604, syn- and anti-DP), TBBPA, 2,4,6-TBP and MeO-PBDEs (8 congeners) were analysed in commercial seafood samples from European countries. Levels were similar to literature and above the environmental quality standards (EQS) limit of the Directive 2013/39/EU for PBDEs. Contaminants were found in 90.5% of the seafood samples at n. d.-356 ng/g lw (n. d.-41.1 ng/g ww). DBDPE was not detected and 2,4,6-TBP was detected only in mussels, but at levels comparable to those of PBDEs. Mussel and seabream were the most contaminated species and the Mediterranean Sea (FAO Fishing Area 37) was the most contaminated location. The risk assessment revealed that there was no health risk related to the exposure to brominated flame retardants via seafood consumption. However, a refined risk assessment for BDE-99 is of interest in the future. Moreover, the cooking process concentrated PBDEs and HBB. PMID- 28027982 TI - Development of a clinical path for the emergency care of hand bite injuries without signs of infection. AB - HYPOTHESIS: The care of bite injuries has not currently reached a consensus, including in our department. The goal of this study was to evaluate our current care of bite injuries by an assessment of professional practices (APP), then formulate and validate a flowchart to standardize our practices. MATERIAL AND METHODS: During a first round of file reviewing, 30 files were randomly selected and then evaluated using a 15 item auditing form (group 1). A flowchart was then designed to standardize the care of hand bite injuries and released in our department. Six months later, 30 new files were randomly selected and evaluated using the same auditing form (group 2). RESULTS: When comparing the results of the 15 items before and after the release of the flowchart, 7 items reached 100% in group 2. The wounds were described more precisely, signs of severity were systematically researched and the antibiotic treatment was standardized. Two items decreased but did not reach 0%: systematic prescription of bacteriologic swabs and X-rays. Using these results the flowchart was improved. DISCUSSION AND CONCLUSION: Our results showed an improvement of the care of hand bites for 11 items, including 5 that were statistically significant. This flowchart enabled to standardize our practices and could be used in other emergency departments. PMID- 28027983 TI - Effect of ammonia-N and pathogen challenge on complement component 8alpha and 8beta expression in the darkbarbel catfish Pelteobagrus vachellii. AB - The complement components C8alpha and C8beta mediate the formation of the membrane attack complex (MAC) to resist pathogenic bacteria and play important roles in innate immunity. Full-length complement C8alpha (Pv-C8alpha) and C8beta (Pv-C8beta) cDNA were identified in the darkbarbel catfish Pelteobagrus vachellii, and their mRNA expression levels were analyzed after ammonia-N and pathogen treatment. The Pv-C8alpha gene contained 1983 bp, including a 1794-bp open reading frame (ORF) encoding 598 amino acids. The Pv-C8beta gene contained 1952 bp, including a 1761-bp ORF encoding 587 amino acids. Pv-C8alpha and Pv C8beta had the highest amino acid identity with rainbow trout Oncorhynchus mykiss C8alpha (62%) and Japanese flounder Paralichthys olivaceus C8beta (83%), respectively. Sequence analysis indicated that both Pv-C8alpha and Pv-C8beta contained a thrombospondin type-1 (TSP1) domain, a low-density lipoprotein receptor class A (LDLR-A) domain, a membrane attack complex/perforin (MACPF) domain and an epidermal growth factor-like (EGF-like) domain. In addition, Pv C8alpha and Pv-C8beta were mainly distributed in the liver, head kidney, spleen, and eggs. Under ammonia-N stress, the Pv-C8alpha and Pv-C8beta mRNA levels significantly decreased (P < 0.05), with minimum levels, respectively, attained at 24 and 48 h in the liver, 48 and 24 h in the head kidney, and 24 and 24 h in the spleen. After Aeromonas hydrophila challenge, the Pv-C8alpha and Pv-C8beta mRNA levels significantly increased (P < 0.05), with maximum levels, respectively, attained at 48 and 24 h in the liver, 24 and 48 h in the head kidney, and 48 and 48 h in the spleen. The present study indicated that Pv C8alpha and Pv-C8beta exhibited important immune responses to infection and that ammonia-N in water decreased the immune responses of Pv-C8alpha and Pv-C8beta. PMID- 28027984 TI - High carotenoids content can enhance resistance of selected Pinctada fucata families to high temperature stress. AB - Carotenoids are a class of natural antioxidants widely found in aquatic, and they have significant effects on the growth, survival, and immunity of these organisms. To investigate the mechanisms of carotenoids in high temperature resistance, we observed the immune response of selected pearl oyster Pinctada fucata (Akoya pearl oyster) families with different carotenoids contents to high temperature stress. The results indicated that the survival rate (SR) of P. fucata decreased significantly with increase in temperature from 26 degrees C to 34 degrees C and with the decrease of total carotenoids content (TCC); when the TCC was higher, the SR tended to be higher. TCC and total antioxidant capacity (TAC) decreased significantly at 30 degrees C with increasing stress time. Correlation analysis indicated that TAC was positively and linearly correlated with TCC, and SR was S-type correlated with TCC and TAC. Immune analysis indicated that levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) in selected families (with higher TCC) under temperature stress (at 30 degrees C) were generally significantly lower than in the control group (with lowest TCC) and from 0 to 96 h, the levels of each of these substances varied significantly. Levels of SOD, CAT, and MDA within each family first rose from 0 to 3 h, then decreased to their lowest point after 24 h, and then rose again to their highest levels at 96 h. When TCC was higher, the levels of SOD, CAT, and MDA tended to be lower. These findings indicated that carotenoids play an important role in improving survival rates of P. fucata under high temperature stress by enhancing animals' antioxidant system, and could serve as an index for breeding stress-resistant lines in selective breeding practices. PMID- 28027985 TI - Characterization of basic immune function parameters in the fathead minnow (Pimephales promelas), a common model in environmental toxicity testing. AB - The fathead minnow (Pimephales promelas) is an environmental sentinel species, commonly used in toxicity testing. However, there is a lack of data regarding basic immune function in this species. To improve the usefulness of the fathead minnow as a model for basic immune function and immunotoxicity, this study sought to 1) compare the differential expression of immune function genes in naive fathead minnows and 2) determine the effects of pathogen exposure on immune gene expression and spleen index. To accomplish this, kidney, spleen and liver tissue were collected three days post injection (dpi) from adult male fathead minnows from each of the following groups: 1) uninjected control 2) sham-injected (Hank's balanced salt solution) and 3) pathogen-injected (Yersinia ruckeri). Spleen tissue was also collected at seven and 14 dpi. Differential tissue expression of immune function genes was evaluated in naive minnows and expression patterns were similar to those found in other fish species, with liver tissue generally having the highest amount of expression. Following pathogen injection, the expression of complement component 3 (c3) (4.4-fold, kidney; 2.5-fold, liver), interleukin 11 (il11) (4.8-fold, kidney; 15.2-fold, liver) and interleukin 1beta (il1beta) (8.2 fold, kidney; 17.2-fold, spleen; 2.6-fold, liver) were significantly upregulated. Elastase 2 (elas2) was significantly downregulated (5.8-fold) in liver tissue. A significant increase in spleen index at seven dpi was also observed in pathogen injected minnows. This study has identified endpoints that are part of the normal response to pathogen in fathead minnows, an essential step toward the development of the fathead minnow as a model for immunotoxicity evaluations. PMID- 28027986 TI - Alpha-2-macroglobulin is a modulator of prophenoloxidase system in pacific white shrimp Litopenaeus vannamai. AB - The shrimp multifunctional protein alpha-2-macroglobulin (A2M) is abundantly expressed in plasma, highly up-regulated upon microbial infection and involved in several immune pathways such as blood clotting system, phagocytosis and melanization. Herein, the function of LvA2M from Litopenaeus vannamei on the prophenoloxidase (proPO) system is reported. The recombinant (r)LvA2M produced strongly and specifically inhibited trypsin and the PO activity in shrimp plasma in a dose-dependent manner. Silencing of LvA2M led to an increase in the PO activity in shrimp plasma although the expression of proPO-associated genes, proPO-activating enzyme (PPAE) and prophenoloxidase (proPO) but not the proPO activating factor (PPAF) was down-regulated. In Vibrio parahaemolyticus AHPND infected shrimp, the LvA2M activity was suppressed in an early phase of infection while the PO activity was increased. Thus, the proPO-activating system was regulated by the LvA2M. PMID- 28027987 TI - Leucine-rich repeats containing protein functions in the antibacterial immune reaction in stomach of kuruma shrimp Marsupenaeus japonicus. AB - Leucine rich repeat (LRR) motif exists in many immune receptors of animals and plants. Most LRR containing (LRRC) proteins are involved in protein-ligand and protein-protein interaction, but the exact functions of most LRRC proteins were not well-studied. In this study, an LRRC protein was identified from kuruma shrimp Marsupenaeus japonicus, and named as MjLRRC1. MjLRRC1 was consistently expressed in different tissues of normal shrimp with higher expression in gills and stomach. At the transcriptional level, there were no significant changes of MjLRRC1 after injection of Vibrio anguillarum or Staphylococcus aureus in gills and hepatopancreas. While in V. anguillarum oral infection, MjLRRC1 was upregulated in stomach but not in intestine. The recombinant MjLRRC1 protein could bind to Gram-positive and Gram-negative bacteria, bacterial cell wall components including peptidoglycan, lipoteichoic acid, and lipopolysaccharide. MjLRRC1 regulated the expression of some antimicrobial peptide (AMP) genes and participated in bacteria clearance of stomach. All these results suggested that MjLRRC1 might play important roles in antibacterial immune response of kuruma shrimp. PMID- 28027988 TI - The immune response of the C-Jun in the black tiger shrimp (Penaeus monodon) after bacterial infection. AB - The transcription factor C-Jun widely exists in vertebrates and invertebrates and plays an important role in various kinds of stimulus response. In this study, PmC jun gene was first cloned from Penaeus monodon. The full-length cDNA of PmC-jun was 1857 bp in length and included an 879 bp open reading frame (ORF), which encoded 293 amino acids. qRT-PCR analysis results showed that PmC-jun mRNAs were ubiquitously expressed in all the examined tissues. The highest expression level was observed in gill, followed by hepatopancreas. The expression patterns of PmC jun after Vibrio harveyi and Streptococcus agalactiae injections were studied by qRT-PCR experiment. PmC-jun increased obviously in the gill and hepatopancreas. The expression pattern of PmC-jun in the hepatopancreas was further studied using in situ hybridization (ISH) method. The mRNA expression level of PmC-jun significantly increased in the hepatopancreas after bacterial infection. The expression sites of PmC-jun were almost unchanged. PmC-jun played a regulatory role in pathogen invasion. PMID- 28027989 TI - Effects of compensating the temperature coefficient of frequency with the acoustic reflector layers on the overall performance of solidly mounted resonators. AB - Thin film acoustic wave resonator based devices require compensation of temperature coefficient of frequency (TCF) in many applications. This work presents the design and fabrication of temperature compensated solidly mounted resonators (SMRs). The characteristics of each material of the layered structure have an effect on the device TCF but depending on the relative position with respect to the piezoelectric material in the stack. The influence of material properties of the different layers composing the device on the TCF is discussed in detail. TCF behavior simulation is done with Mason's model and, to take into account the deterioration of overall performance due to the finite lateral size and shape of the resonator, we have used 2D and 3D finite element modelling of the resonators. The overall behavior of the device for external loads is predicted. SMRs are designed according to simulations and fabricated with different configurations to obtain TCF as near to zero as possible with an optimized response. Resonators are made by depositing Mo/AlN/Mo piezoelectric stacks on acoustic reflectors. As reflector materials, conductive W and insulating WOx films have been used as high acoustic impedance materials. SiO2 films are used as low acoustic impedance material. PMID- 28027990 TI - Dual sexual and drug-related predictors of hepatitis C incidence among sex workers in a Canadian setting: gaps and opportunities for scale-up of hepatitis C virus prevention, treatment, and care. AB - BACKGROUND: Hepatitis C virus (HCV) represents a significant cause of morbidity and mortality globally. While sex workers may face elevated HCV risks through both drug and sexual pathways, incidence data among sex workers are severely lacking. HCV incidence and predictors of HCV seroconversion among women sex workers in Vancouver, BC were characterized in this study. METHODS: Questionnaire and serological data were drawn from a community-based cohort of women sex workers (2010-2014). Kaplan-Meier methods and Cox regression were used to model HCV incidence and predictors of time to HCV seroconversion. RESULTS: Among 759 sex workers, HCV prevalence was 42.7%. Among 292 baseline-seronegative sex workers, HCV incidence density was 3.84/100 person-years (PY), with higher rates among women using injection drugs (23.30/100 PY) and non-injection crack (6.27/100 PY), and those living with HIV (13.27/100 PY) or acute sexually transmitted infections (STIs) (5.10/100 PY). In Cox analyses adjusted for injection drug use, age (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86-1.01), acute STI (HR 2.49, 95% CI 1.02-6.06), and non-injection crack use (HR 2.71, 95% CI 1.18-6.25) predicted time to HCV seroconversion. DISCUSSION: While HCV incidence was highest among women who inject drugs, STIs and the use of non-injection stimulants appear to be pathways to HCV infection, suggesting potential dual sexual/drug transmission. Integrated HCV services within sexual health and HIV/STI programs are recommended. PMID- 28027991 TI - Successful treatment of severe Clostridium difficile infection by administration of crushed fidaxomicin via a nasogastric tube in a critically ill patient. AB - OBJECTIVE: To report the successful use of crushed fidaxomicin via a nasogastric tube for treatment of a severe Clostridium difficile infection in a critically ill patient. DATA SOURCES: Clinical observation of a patient, images of abdominal computed tomography, antimicrobial therapy and course of infection parameters. DATA EXTRACTION: Relevant information contained in the medical observation of the patient and selection of image and laboratory parameters performed in the patient. DATA SYNTHESIS: We report a case of a 79-year old patient who developed septic shock with an increasing need for norepinephrine and acute renal failure due to a severe Clostridium difficile infection. Antimicrobial therapy with vancomycin via a nasogastric tube and metronidazole i.v. did not lead to improvement, infection parameters further increased, and the clinical condition became increasingly impaired. After 10 days, antimicrobial therapy was changed to fidaxomicin, crushed and administered via nasogastric tube. Within 24hours, infection parameters decreased. Further diarrhoea ceased and stool samples were negative for Clostridium difficile antigen. CONCLUSIONS: Our case confirms that administration of fidaxomicin via a nasogastric tube was safe and effective in this patient. Further studies are needed to evaluate the efficacy of this strategy in critically ill patients systematically. PMID- 28027992 TI - Short-course antimicrobial treatment for acute cholangitis with Gram-negative bacillary bacteremia. AB - OBJECTIVES: The optimal antimicrobial treatment duration for patients with acute cholangitis with bacteremia remains unknown. The updated Tokyo Guidelines 2013 recommend a minimum duration of 2 weeks only when bacteremia with Gram-positive cocci is present. Since May 2013, a shorter antimicrobial treatment duration of under 2 weeks has been implemented at the authors' institution for acute cholangitis with Gram-negative bacillary bacteremia. The aim of the present study was to validate this modified practice. METHODS: A single-center retrospective cohort study was conducted. The antimicrobial treatment duration, 30-day mortality rate, and recurrence rate within 3 months were compared between patients treated before May 2013 and after May 2013. RESULTS: Ninety-one patients with cholangitis with bacteremia were analyzed. The median antimicrobial treatment duration was 14.5days in patients treated before May 2013 and 10.0days after May 2013 (p <0.001). While the 30-day mortality rate did not differ significantly, the recurrence rate was higher in those treated before May 2013 (5.7% vs. 0.0%, p=0.17 and 13.3% vs. 0.0%, p=0.03, respectively). The median treatment duration after May 2013 was 8days for grade I patients, 10days for grade II patients, and 11.5days for grade III patients. CONCLUSIONS: The results of this study suggest that acute cholangitis with Gram-negative bacillary bacteremia can be treated safely with a shorter antimicrobial treatment duration of <14 days. PMID- 28027993 TI - Tuberculosis and hypertension-a systematic review of the literature. AB - BACKGROUND: Tuberculosis (TB) remains a major health problem in low- and middle income countries, and in many of these countries, the burden of non-communicable diseases such as hypertension is rising. Knowledge about how these diseases influence each other is limited. METHODS: A systematic review of the literature was performed to evaluate the evidence for an association between hypertension and TB. RESULTS: Three retrospective cohort studies, three case-control studies, eight cross-sectional studies, 12 case series, and 20 case reports exploring the association between hypertension and TB were included in the review. One cohort study found a significantly higher prevalence of hypertension among TB patients compared to controls. Cross-sectional studies reported a prevalence of hypertension in TB patients ranging from 0.7% to 38.3%. No studies were designed to assess whether hypertension is a risk factor for developing active TB. CONCLUSIONS: Overall, no evidence was found to support an association between TB and hypertension; however, the results of this review must be interpreted with caution due to the lack of properly designed studies. PMID- 28027994 TI - Variations in IL-1R1 Gene Influence Risk for Hepatitis B Virus Infection of Children in a Han Chinese population. AB - BACKGROUND/AIMS: Host genetic factors play an important role in the pathogenesis of hepatitis B virus (HBV) infection. However, the role of Interleukin1Receptor, Type I (IL-1R1) gene in HBV infection and breakthrough infection in children remains unclear. The aim of this study was to investigate the association between SNPs in IL-1 family and HBV infection and breakthrough infection in children. PATIENTS AND METHODS: A total of 627 Chinese children (274 HBV infected children and 353 controls) ages 6 months to 12 years were recruited from October 2013 to May 2015.Six SNPs were genotyped in IL-1R1, Interleukin-1beta (IL-1B) and Interleukin-18 (IL-18) genes. RESULTS: A statistically significant association was found between genotype AA in rs3917267 (IL-1R1) and HBV infection in children (OR, 1.740; 95%CI, 1.091-2.774; p=0.020), which was also found at allele A (OR, 1.316;95%CI, 1.050-1.648; p=0.017). Furthermore, rs3917267 was also significantly associated with breakthrough infection of HBV in children born of hepatitis B surface antigen (HBsAg) positive mothers (OR,3.675; 95%CI, 1.160-11.646; P=0.027). CONCLUSION: Our study confirmed that genetic variant in IL 1R1(rs3917267) has significant association with HBV infection and HBV breakthrough infection in children, which provides new clues for the study of pathogenesis of chronic HBV infection in children. PMID- 28027995 TI - A systematic review and network meta-analysis of neoadjuvant therapy combined with surgery for patients with resectable esophageal squamous cell carcinoma. AB - BACKGROUND: The role of neoadjuvant therapy combined with surgery for treating esophageal squamous cell carcinoma (ESCC) remains controversial. We performed a network meta-analysis to synthesize direct and indirect evidence to identify the optimal therapeutic method for ESCC. METHODS: We identified 15 randomized controlled trials that compared any of the following 4 therapeutic measures: surgery alone (S), preoperative chemotherapy followed by surgery (CTS), preoperative radiotherapy followed by surgery (RTS), and preoperative chemoradiotherapy followed by surgery (CRTS). The main outcomes were 5-year survival, rate of radical resection, operative mortality and postoperative complications. RESULTS: Network meta-analysis showed that CRTS was associated with improved survival as compared with S (OR = 1.50 [95% CI 1.21 to 1.97]) and decreased occurrence of complications as compared with RTS (OR = 0.50 [95% CI 0.22 to 0.99]). Direct evidence revealed CRTS associated with improved survival (OR = 1.61 [95% CI 1.01 to 2.57]) and radical resection (OR = 4.01 [95% CI 1.66 to 9.69]) as compared with S. In terms of radical resection, CTS was more effective than S (OR = 1.73 [95% CI 1.09 to 2.76]). Findings for CTS and RTS did not differ for 5-year survival, operative mortality and postoperative complications. CONCLUSIONS: Overall, CRTS might be the best choice for resectable ESCC because it could increase the radical resection rate and lower the occurrence of complications, thereby prolonging survival time. PMID- 28027996 TI - 3D white light interferometry assessment of robotic laser scalpel assisted surgery to minimise scar tissue formation. PMID- 28027997 TI - Impact on the upper airway space of different types of orthognathic surgery for the correction of skeletal class III malocclusion: A systematic review and meta analysis. AB - OBJECTIVE: This study is aimed at assembling, through a systematic review and meta-analysis, scientific evidence related to the effects of mandibular setback (MdS) surgery and bimaxillary surgery for the correction of Class III malocclusion on the cross-sectional area (CSA) and volume of the upper airway as assessed using CT. METHODS: An electronic search was conducted on Cochrane Library, EMBASE, PubMed, Scopus and Web of Science up to June 20, 2016. The inclusion criteria were prospective or retrospective studies, with the aim of comparing the impact on the upper airway space of orthognathic surgery for the treatment of the skeletal class III malocclusion. The methodological index for non-randomized studies (MINORS) was chosen as the evaluation instrument and Revman5.3 was used for the meta-analysis. RESULTS: A total of 1213 studies were retrieved, of which only 18 met the eligibility criteria. The results of meta analysis showed that the mean decrease in the upper airway volume after MdS surgery was 3.24 cm3 [95%CI (-5.25,-1.23), p = 0.85]; the mean decrease in minimum CSA after a combined surgery of maxillary advancement with mandibular setback (MdS + MxA) was 27.66 mm2 [95%CI (-52.81,-2.51), p = 0.51], but there was no significant decrease in upper airway volume (mean 0.86 cm3); comparison between MdS + MxA and isolated MdS showed significant differences in the CSA of the posterior nasal spine plane (PNS) and epiglottis plane (EP); statistically significant differences in nasopharynx volume (P < 0.0001) and upper airway total volume (P = 0.002) were observed, but no statistically meaningful variations existed in oropharynx volume (P = 0.08) and hypopharynx volume (P = 0.64). CONCLUSION: The results of this study suggest that bimaxillary surgery promotes less decrease on the upper airway than mandibular setback surgery alone for the correction of the skeletal class III malocclusion. PMID- 28027998 TI - An optimized abnormal muscle response recording method for intraoperative monitoring of hemifacial spasm and its long-term prognostic value. AB - BACKGROUND: Intraoperative electrophysiological monitoring is used to determine whether decompression is sufficient during microvascular decompression (MVD) for hemifacial spasm (HFS). However, the real offending vessel is sometimes neglected by the neurosurgeons. Here, we reported our experience in using optimized abnormal muscle response (AMR) monitoring and continuous intraoperative monitoring for MVD. METHODS: This study included 2161 HFS patients who underwent MVD using traditional (1023 patients) and optimized (1138 patients) methods. Modified AMR monitoring was adopted in our study, with the zygomatic branch of the facial nerve stimulated and the temporal branch, buccal branch, marginal mandibular branch and cervical branch of the facial nerve detected for AMR. These cases were analyzed retrospectively with emphasis on the postoperative outcomes and intraoperative findings. The therapeutic effect was evaluated at day 1, month 3 and year 1 after operation. RESULTS: The relief rate at day 1, month 3 and year 1 after operation for patients who employed optimized AMR recording method was 95.1%, 97.4% and 99.3%, comparing with 92.2%, 95.0% and 97.8% in traditional method. There was significant difference in achieved immediate remission and recovery rate during 12-month follow-up between the two groups (P < 0.05). The modified intraoperative monitoring showed the sensitivity of AMR disappearance to judge the relief at day 1, month 3 and year 1 after HFS operation was 95.7%, 96.3% and 97.3%, respectively; the specificity was 44.6%, 43.3% and 50.0%, respectively; the accuracy was 93.1%, 94.9% and 97.4%, respectively. CONCLUSIONS: Our findings demonstrated that the optimized method could improve the positive detection rate of AMR and accuracy of decompression effect prediction. The evaluation for the decompression effect by optimized intraoperative monitoring can increase the immediate remission rate and reduce the delayed recovery rate. PMID- 28027999 TI - Secondary cytoreductive surgery in recurrent epithelial ovarian cancer: A prognostic analysis with 103 cases. AB - BACKGROUND: Due to satisfactory cytoreductive surgery combined with platinum based chemotherapy in epithelial ovarian cancer has improved greatly, however, the relapse rate also high. In current study, we analyzed prognostic factors related to secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer. METHODS: Clinical and follow-up data from 103 patients with recurrent epithelial ovarian cancer who received secondary cytoreductive surgery and were admitted to our hospital between January 2000 and December 2008 were analyzed. RESULTS: Median survival after recurrence (RS) after the first relapse for the 103 patients was 36 months, and median overall survival (OS) was 60 months. Patients without visible residual tumors after secondary cytoreductive surgery had longer RS and OS compared to those with residual tumors >=1 cm. The RS and OS of patients without visible residual tumors after secondary cytoreductive surgery were not significantly different compared to those with residual tumors between 0.1 and 1 cm. Patients with disease free interval (DFI) >= 12 months at secondary cytoreductive surgery had longer RS and OS compared to those with DFI < 12 months. Patients with one recurrent lesion had longer RS and OS compared to those with more than one lesion. CONCLUSIONS: Residual tumor at secondary cytoreductive surgery, DFI and number of lesions were independent prognostic factors for secondary cytoreductive surgery in patients with epithelial ovarian cancer. Patients with DFI >=12 months and a single lesion had better prognosis for achieving satisfactory cytoreduction, especially the absence of visible residual tumors. PMID- 28028000 TI - Phylogeography of Toxoplasma gondii points to a South American origin. AB - Toxoplasma gondii, a protozoan found ubiquitously in mammals and birds, is the etiologic agent of toxoplasmosis, a disease causing substantial public health burden worldwide, including about 200,000 new cases of congenital toxoplasmosis each year. Clinical severity has been shown to vary across geographical regions, with South America exhibiting the highest burden. Unfortunately, the drivers of these heterogeneities are still poorly understood, and the geographical origin and historical spread of the pathogen worldwide are currently uncertain. A worldwide sample of 168 T. gondii isolates gathered in 13 populations was sequenced for five fragments of genes (140 single nucleotide polymorphisms from 3153bp per isolate). Phylogeny based on Maximum likelihood methods with estimation of the time to the most recent common ancestor (TMRCA) and geostatistical analyses were performed for inferring the putative origin of T. gondii. We show that extant strains of the pathogen likely evolved from a South American ancestor, around 1.5 million years ago, and reconstruct the subsequent spread of the pathogen worldwide. This emergence is much more recent than the appearance of ancestral T. gondii, believed to have taken place about 11 My ago, and follows the arrival of felids in this part of the world. We posit that an ancestral lineage of T. gondii likely arrived in South America with felids and that the evolution of oral infectivity through carnivorism and the radiation of felids in this region enabled a new strain to outcompete the ancestral lineage and undergo a pandemic radiation. PMID- 28028001 TI - Pharmacokinetic aspects of retinal drug delivery. AB - Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory. PMID- 28028003 TI - Reply: "Auer Rod-Like Inclusions in Reactive Plasma Cells in a Case of Acute Myeloid Leukemia". PMID- 28028004 TI - Auer Rods Are Not Seen in Non-Neoplastic Cells. PMID- 28028006 TI - Identification and analysis of the human sex-biased genes. AB - Tremendous differences between human sexes are universally observed. Therefore, identifying and analyzing the sex-biased genes are becoming basically important for uncovering the mystery of sex differences and personalized medicine. Here, we presented a computational method to identify sex-biased genes from public gene expression databases. We obtained 1407 female-biased genes (FGs) and 1096 male biased genes (MGs) across 14 different tissues. Bioinformatics analysis revealed that compared with MGs, FGs have higher evolutionary rate, higher single nucleotide polymorphism density, less homologous gene numbers and smaller phyletic age. FGs have lower expression level, higher tissue specificity and later expressed stage in body development. Moreover, FGs are highly involved in immune-related functions, whereas MGs are more enriched in metabolic process. In addition, cellular network analysis revealed that MGs have higher degree, more cellular activating signaling and tend to be located in cellular inner space, whereas FGs have lower degree, more cellular repressing signaling and tend to be located in cellular outer space. Finally, the identified sex-biased genes and the discovered biological insights together can be a valuable resource helpful for investigating sex-biased physiology and medicine, for example sex-biased disease diagnosis and therapy, which represents one important aspect of personalized and precision medicine. PMID- 28028005 TI - Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli: Unique Effects of Plasminogen Activation and alpha2-Antiplasmin Inactivation. AB - BACKGROUND: In patients with hemodynamically significant pulmonary embolism, physiological fibrinolysis fails to dissolve thrombi acutely and r-tPA (recombinant tissue-type plasminogen activator) therapy may be required, despite its bleeding risk. To examine potential mechanisms, we analyzed the expression of key fibrinolytic molecules in experimental pulmonary emboli, assessed the contribution of alpha2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and alpha2-antiplasmin inactivation on experimental thrombus dissolution and bleeding. METHODS: Pulmonary embolism was induced by jugular vein infusion of 125I-fibrin or fluorescein isothiocyanate fibrin labeled emboli in anesthetized mice. Thrombus site expression of key fibrinolytic molecules was determined by immunofluorescence staining. The effects of r-tPA and alpha2-antiplasmin inactivation on fibrinolysis and bleeding were examined in a humanized model of pulmonary embolism. RESULTS: The plasminogen activation and plasmin inhibition system assembled at the site of acute pulmonary emboli in vivo. Thrombus dissolution was markedly accelerated in mice with normal alpha2-antiplasmin levels treated with an alpha2-antiplasmin-inactivating antibody (P<0.0001). Dissolution of pulmonary emboli by alpha2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with alpha2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone (P<0.001) or alpha2-antiplasmin inactivation alone (P<0.001). Despite greater thrombus dissolution, alpha2-antiplasmin inactivation alone, or in combination with low dose r-tPA, did not lead to fibrinogen degradation, did not cause bleeding (versus controls), and caused less bleeding than clinical-dose r-tPA (P<0.001). CONCLUSIONS: Although the fibrinolytic system assembles at the site of pulmonary emboli, thrombus dissolution is halted by alpha2-antiplasmin. Inactivation of alpha2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, alpha2-antiplasmin inactivation showed a unique pattern of thrombus specificity, because unlike r-tPA, it did not degrade fibrinogen or enhance experimental bleeding. This suggests that modifying the activity of a key regulator of the fibrinolytic system, like alpha2-antiplasmin, may have unique therapeutic value in pulmonary embolism. PMID- 28028007 TI - Ectopic left ventricular apical diverticulum. PMID- 28028002 TI - Aqueous outflow - A continuum from trabecular meshwork to episcleral veins. AB - In glaucoma, lowered intraocular pressure (IOP) confers neuroprotection. Elevated IOP characterizes glaucoma and arises from impaired aqueous humor (AH) outflow. Increased resistance in the trabecular meshwork (TM), a filter-like structure essential to regulate AH outflow, may result in the impaired outflow. Flow through the 360 degrees circumference of TM structures may be non-uniform, divided into high and low flow regions, termed as segmental. After flowing through the TM, AH enters Schlemm's canal (SC), which expresses both blood and lymphatic markers; AH then passes into collector channel entrances (CCE) along the SC external well. From the CCE, AH enters a deep scleral plexus (DSP) of vessels that typically run parallel to SC. From the DSP, intrascleral collector vessels run radially to the scleral surface to connect with AH containing vessels called aqueous veins to discharge AH to blood-containing episcleral veins. However, the molecular mechanisms that maintain homeostatic properties of endothelial cells along the pathways are not well understood. How these molecular events change during aging and in glaucoma pathology remain unresolved. In this review, we propose mechanistic possibilities to explain the continuum of AH outflow control, which originates at the TM and extends through collector channels to the episcleral veins. PMID- 28028008 TI - Congenital 'bifid' left ventricular apex masquerading as pseudo-aneurysm following acute myocardial infarction. PMID- 28028009 TI - Do we need another heart failure biomarker: focus on soluble suppression of tumorigenicity 2 (sST2). PMID- 28028010 TI - Haemophilus influenzae Serotype f Epiglottitis: A Case Report and Review. PMID- 28028011 TI - A research and evaluation capacity building model in Western Australia. AB - Evaluation of public health programs, services and policies is increasingly required to demonstrate effectiveness. Funding constraints necessitate that existing programs, services and policies be evaluated and their findings disseminated. Evidence-informed practice and policy is also desirable to maximise investments in public health. Partnerships between public health researchers, service providers and policymakers can help address evaluation knowledge and skills gaps. The Western Australian Sexual Health and Blood-borne Virus Applied Research and Evaluation Network (SiREN) aims to build research and evaluation capacity in the sexual health and blood-borne virus sector in Western Australia (WA). Partners' perspectives of the SiREN model after 2 years were explored. Qualitative written responses from service providers, policymakers and researchers about the SiREN model were analysed thematically. Service providers reported that participation in SiREN prompted them to consider evaluation earlier in the planning process and increased their appreciation of the value of evaluation. Policymakers noted benefits of the model in generating local evidence and highlighting local issues of importance for consideration at a national level. Researchers identified challenges communicating the services available through SiREN and the time investment needed to develop effective collaborative partnerships. Stronger engagement between public health researchers, service providers and policymakers through collaborative partnerships has the potential to improve evidence generation and evidence translation. These outcomes require long-term funding and commitment from all partners to develop and maintain partnerships. Ongoing monitoring and evaluation can ensure the partnership remains responsive to the needs of key stakeholders. The findings are applicable to many sectors. PMID- 28028013 TI - How to tackle antimalarial resistance? PMID- 28028012 TI - Genetically engineered mouse models in oncology research and cancer medicine. AB - Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start. Given that GEMMs capture both tumor cell-intrinsic and cell-extrinsic factors that drive de novo tumor initiation and progression toward metastatic disease, these models are indispensable for preclinical research. GEMMs have successfully been used to validate candidate cancer genes and drug targets, assess therapy efficacy, dissect the impact of the tumor microenvironment, and evaluate mechanisms of drug resistance. In vivo validation of candidate cancer genes and therapeutic targets is further accelerated by recent advances in genetic engineering that enable fast track generation and fine-tuning of GEMMs to more closely resemble human patients. In addition, aligning preclinical tumor intervention studies in advanced GEMMs with clinical studies in patients is expected to accelerate the development of novel therapeutic strategies and their translation into the clinic. PMID- 28028014 TI - Cardiovascular Magnetic Resonance-Guided Electrophysiological Interventions: Radiofrequency Ablation of Typical Atrial Flutter. PMID- 28028015 TI - Pollen-mediated gene flow and fine-scale spatial genetic structure in Olea europaea subsp. europaea var. sylvestris. AB - Background and Aims: Wild olive ( Olea europaea subsp. europaea var. sylvestris ) is important from an economic and ecological point of view. The effects of anthropogenic activities may lead to the genetic erosion of its genetic patrimony, which has high value for breeding programmes. In particular, the consequences of the introgression from cultivated stands are strongly dependent on the extent of gene flow and therefore this work aims at quantitatively describing contemporary gene flow patterns in wild olive natural populations. Methods: The studied wild population is located in an undisturbed forest, in southern Spain, considered one of the few extant hotspots of true oleaster diversity. A total of 225 potential father trees and seeds issued from five mother trees were genotyped by eight microsatellite markers. Levels of contemporary pollen flow, in terms of both pollen immigration rates and within population dynamics, were measured through paternity analyses. Moreover, the extent of fine-scale spatial genetic structure (SGS) was studied to assess the relative importance of seed and pollen dispersal in shaping the spatial distribution of genetic variation. Key Results: The results showed that the population under study is characterized by a high genetic diversity, a relatively high pollen immigration rate (0.57), an average within-population pollen dispersal of about 107 m and weak but significant SGS up to 40 m. The population is a mosaic of several intermingled genetic clusters that is likely to be generated by spatially restricted seed dispersal. Moreover, wild oleasters were found to be self-incompatible and preferential mating between some genotypes was revealed. Conclusions: Knowledge of the within-population genetic structure and gene flow dynamics will lead to identifying possible strategies aimed at limiting the effect of anthropogenic activities and improving breeding programmes for the conservation of olive tree forest genetic resources. PMID- 28028016 TI - Multiple and asymmetrical origin of polyploid dog rose hybrids (Rosa L. sect. Caninae (DC.) Ser.) involving unreduced gametes. AB - Background and Aims: Polyploidy and hybridization are important factors for generating diversity in plants. The species-rich dog roses ( Rosa sect. Caninae ) originated by allopolyploidy and are characterized by unbalanced meiosis producing polyploid egg cells (usually 4 x ) and haploid sperm cells (1 x ). In extant natural stands species hybridize spontaneously, but the extent of natural hybridization is unknown. The aim of the study was to document the frequency of reciprocal hybridization between the subsections Rubigineae and Caninae with special reference to the contribution of unreduced egg cells (5 x ) producing 6 x offspring after fertilization with reduced (1 x ) sperm cells. We tested whether hybrids arose by independent multiple events or via a single or few incidences followed by a subsequent spread of hybrids. Methods: Population genetics of 45 mixed stands of dog roses across central and south-eastern Europe were analysed using microsatellite markers and flow cytometry. Hybrids were recognized by the presence of diagnostic alleles and multivariate statistics were used to display the relationships between parental species and hybrids. Key Results: Among plants classified to subsect. Rubigineae , 32 % hybridogenic individuals were detected but only 8 % hybrids were found in plants assigned to subsect. Caninae . This bias between reciprocal crossings was accompanied by a higher ploidy level in Rubigineae hybrids, which originated more frequently by unreduced egg cells. Genetic patterns of hybrids were strongly geographically structured, supporting their independent origin. Conclusions: The biased crossing barriers between subsections are explained by the facilitated production of unreduced gametes in subsect. Rubigineae . Unreduced egg cells probably provide the highly homologous chromosome sets required for correct chromosome pairing in hybrids. Furthermore, the higher frequency of Rubigineae hybrids is probably influenced by abundance effects because the plants of subsect. Caninae are much more abundant and thus provide large quantities of pollen. Hybrids are formed spontaneously, leading to highly diverse mixed stands, which are insufficiently characterized by the actual taxonomy. PMID- 28028017 TI - Genetic variation in the invasive weed Mikania micrantha (Asteraceae) suggests highways as corridors for its dispersal in southern China. AB - BACKGROUND AND AIMS: Roads as corridors of seed or fruit spatial dispersal have major impacts on the establishment and spread of invasive species, but their precise role in population genetic variation remains poorly understood. The South American weed Mikania micrantha has spread rapidly across southern China since its introduction to the Shenzhen area in 1984. This study investigated how its genetic diversity is distributed along highways, and whether highways have acted as corridors for the rapid expansion of M. micrantha METHODS: Twenty-seven roadside populations were sampled along four highways in southern China, and 787 samples were examined using 12 microsatellite markers. Variation in genetic diversity among populations was quantified and patterns of genetic differentiation were analysed. KEY RESULTS: A high level of genetic diversity was found at both the species and the population levels in this self-incompatible plant (expected heterozygosity = 0.497 and 0.477, respectively; allelic richness = 2.580 and 2.521, respectively). The Wright F-statistic value among populations (0.044, P < 0.01) and the analysis of molecular variance (91 % of genetic variation residing within populations, 9 % among populations within highways and 0 % among the four highways) showed a relatively low level of genetic differentiation among populations, while the principal coordinate and cluster analyses also indicated a lack of clear geographical genetic structure among populations. The calculated Nm value of 5.5 signifies strong gene flow. CONCLUSIONS: The pattern of genetic variation is consistent with facilitated dispersal along highways. The genetic admixtures among the roadside populations imply the occurrence of multiple population introductions during colonization. The long-distance dispersal of seeds associated with vehicular transportation on highways may have played important roles in shaping the genetic variation. This finding highlights the importance of highways as corridors for the spread of M. micrantha in southern China. PMID- 28028018 TI - Ontogenesis and functions of saxophone stem in Acrocomia aculeata (Arecaceae). AB - BACKGROUND AND AIMS: The underground saxophone stem systems produced by seedlings of certain palm species show peculiar growth patterns and distinctive morphologies, although little information is available concerning their development and function. We studied the ontogenesis of the saxophone stem in Acrocomia aculeata, an important neotropical oleaginous palm, and sought to experimentally define its function. METHODS: Morpho-anatomical evaluations were performed during 240 d on seedlings using traditional methodologies. The tuberous region of the structure was submitted to histochemical tests and evaluated by transmission electron microscopy. The aerial portions of 130 1- to 3-year-old greenhouse plants were removed and their continuous growth capacity was evaluated after 30 d. Severed saxophone stems were also stored at room temperature (average 25 degrees C) for up to 90 d and then cultured for 60 d to evaluate root and shoot emission. KEY RESULTS: The development of the saxophone stem is distinct from other underground systems previously described, and involves three processes: growth and curvature of the cotyledonary petiole, expansion and curvature of the hypocotyl, and expansion of the plumule internodes. The tuberous region stores water and starch, as well as lesser amounts of mucilage and oil. Growth of the aerial portion occurred in 84 % of the separated saxophone stems and in 53 % of the stems held in storage. CONCLUSIONS: The saxophone stem represents an important adaptation of A. aculeata to anthropogenically impacted and/or dry environments by promoting the burial of both the shoot meristem and storage reserves, which allows the continuous growth of aerial organs. PMID- 28028019 TI - Convergence in leaf size versus twig leaf area scaling: do plants optimize leaf area partitioning? AB - BACKGROUND AND AIMS: Corner's rule states that thicker twigs bear larger leaves. The exact nature of this relationship and why it should occur has been the subject of numerous studies. It is obvious that thicker twigs should support greater total leaf area ([Formula: see text]) for hydraulical and mechanical reasons. But it is not obvious why mean leaf size ([Formula: see text]) should scale positively with [Formula: see text] We asked what this scaling relationship is within species and how variable it is across species. We then developed a model to explain why these relationships exist. METHODS: To minimize potential sources of variability, we compared twig properties from six co-occurring and functionally similar species: Acer grandidentatum, Amelanchier alnifolia, Betula occidentalis, Cornus sericea, Populus fremontii and Symphoricarpos oreophilus We modelled the economics of leaf display, weighing the benefit from light absorption against the cost of leaf tissue, to predict the optimal [Formula: see text] combinations under different canopy openings. KEY RESULTS: We observed a common [Formula: see text] by [Formula: see text] exponent of 0.6, meaning that [Formula: see text]and leaf number on twigs increased in a specific coordination. Common scaling exponents were not supported for relationships between any other measured twig properties. The model consistently predicted positive [Formula: see text] by [Formula: see text] scaling when twigs optimally filled canopy openings. The observed 0.6 exponent was predicted when self-shading decreased with larger canopy opening. CONCLUSIONS: Our results suggest Corner's rule may be better understood when recast as positive [Formula: see text] by [Formula: see text] scaling. Our model provides a tentative explanation of observed [Formula: see text] by [Formula: see text] scaling and suggests different scaling may exist in different environments. PMID- 28028020 TI - Museomics resolve the systematics of an endangered grass lineage endemic to north western Madagascar. AB - BACKGROUND AND AIMS: Recent developments in DNA sequencing, so-called next generation sequencing (NGS) methods, can help the study of rare lineages that are known from museum specimens. Here, the taxonomy and evolution of the Malagasy grass lineage Chasechloa was investigated with the aid of NGS. METHODS: Full chloroplast genome data and some nuclear sequences were produced by NGS from old herbarium specimens, while some selected markers were generated from recently collected Malagasy grasses. In addition, a scanning electron microscopy analysis of the upper floret and cross-sections of the rachilla appendages followed by staining with Sudan IV were performed on Chasechloa to examine the morphology of the upper floret and the presence of oils in the appendages. KEY RESULTS: Chasechloa was recovered within tribe Paniceae, sub-tribe Boivinellinae, contrary to its previous placement as a member of the New World genus Echinolaena (tribe Paspaleae). Chasechloa originated in Madagascar between the Upper Miocene and the Pliocene. It comprises two species, one of them collected only once in 1851. The genus is restricted to north-western seasonally dry deciduous forests. The appendages at the base of the upper floret of Chasechloa have been confirmed as elaiosomes, an evolutionary adaptation for myrmecochory. CONCLUSIONS: Chasechloa is reinstated at the generic level and a taxonomic treatment is presented, including conservation assessments of its species. Our study also highlights the power of NGS technology to analyse relictual or probably extinct groups. PMID- 28028021 TI - Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation. AB - Mitogen-activated protein kinases (MAPKs) are expressed in platelets and are activated downstream of physiological agonists. Pharmacological and genetic evidence indicate that MAPKs play a significant role in hemostasis and thrombosis, but it is not well understood how MAPKs are activated upon platelet stimulation. Here, we show that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, is expressed in both human and murine platelets. ASK1 is rapidly and robustly activated upon platelet stimulation by physiological agonists. Disruption of Ask1 (Ask1-/- ) resulted in a marked functional defect in platelets. Ask1-/- platelets showed an impaired agonist-induced integrin alphaIIbbeta3 activation and platelet aggregation. Although there was no difference in Ca2+ rise, platelet granule secretion and thromboxane A2 (TxA2) generation were significantly attenuated in Ask1-/- platelets. The defective granule secretion observed in Ask1-/- platelets was a consequence of impaired TxA2 generation. Biochemical studies showed that platelet agonists failed to activate p38 MAPK in Ask1-/- platelets. On the contrary, activation of c-Jun N terminal kinases and extracellular signal-regulated kinase 1/2 MAPKs was augmented in Ask1-/- platelets. The defect in p38 MAPK results in failed phosphorylation of cPLA2 in Ask1-/- platelets and impaired platelet aggregate formation under flow. The absence of Ask1 renders mice defective in hemostasis as assessed by prolonged tail-bleeding times. Deletion of Ask1 also reduces thrombosis as assessed by delayed vessel occlusion of carotid artery after FeCl3 induced injury and protects against collagen/epinephrine-induced pulmonary thromboembolism. These results suggest that the platelet Ask1 plays an important role in regulation of hemostasis and thrombosis. PMID- 28028022 TI - Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity. AB - Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon (CRBN) is an essential requirement for IMiD action, the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated sensitivity or resistance remain unknown. Here, we report that IMiDs work primarily via inhibition of peroxidase-mediated intracellular H2O2 decomposition in MM cells. MM cells with lower H2O2-decomposition capacity were more vulnerable to lenalidomide-induced H2O2 accumulation and associated cytotoxicity. CRBN dependent degradation of IKZF1 and IKZF3 was a consequence of H2O2-mediated oxidative stress. Lenalidomide increased intracellular H2O2 levels by inhibiting thioredoxin reductase (TrxR) in cells expressing CRBN, causing accumulation of immunoglobulin light-chain dimers, significantly increasing endoplasmic reticulum stress and inducing cytotoxicity by activation of BH3-only protein Bim in MM. Other direct inhibitors of TrxR and thioredoxin (Trx) caused similar cytotoxicity, but in a CRBN-independent fashion. Our findings could help identify patients most likely to benefit from IMiDs and suggest direct TrxR or Trx inhibitors for MM therapy. PMID- 28028024 TI - ACE inhibitors and cytoreductive therapy in polycythemia vera. PMID- 28028023 TI - Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. AB - Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general. PMID- 28028025 TI - Genomics of chronic neutrophilic leukemia. AB - Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population. PMID- 28028027 TI - Emerging treatments for classical myeloproliferative neoplasms. AB - There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients' major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders. PMID- 28028026 TI - Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. AB - Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone. PMID- 28028028 TI - Introduction to a review series on myeloproliferative neoplasms. PMID- 28028029 TI - Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. AB - The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN. PMID- 28028030 TI - Myeloid neoplasms with eosinophilia. AB - Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, "Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2" In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed-phenotype leukemias or lymphomas. Eosinophilia is a common, but not invariable, feature of these diseases. The natural history of PDGFRA- and PDGFRB-rearranged neoplasms has been dramatically altered by imatinib. In contrast, patients with FGFR1 and JAK2 fusion TK genes exhibit a more aggressive course and variable sensitivity to current TK inhibitors, and in most cases, long-term disease-free survival may only be achievable with allogeneic hematopoietic stem cell transplantation. Similar poor prognosis outcomes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ETV6), and further investigation is needed to validate their inclusion in the current WHO-defined group of eosinophilia-associated TK fusion-driven neoplasms. The diagnosis chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is assigned to patients with MPN with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance, reclassifying some of these cases as eosinophilia associated neoplasms. Looking forward, one of the many challenges will be how to use the results of molecular profiling to guide prognosis and selection of actionable therapeutic targets. PMID- 28028031 TI - HDAC2 promotes loss of primary cilia in pancreatic ductal adenocarcinoma. AB - Loss of primary cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose primary cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores primary cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of primary cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of primary cilium formation in PDAC cells. PMID- 28028032 TI - PRC1-labeled microtubule bundles and kinetochore pairs show one-to-one association in metaphase. AB - In the mitotic spindle, kinetochore microtubules form k-fibers, whereas overlap or interpolar microtubules form antiparallel arrays containing the cross-linker protein regulator of cytokinesis 1 (PRC1). We have recently shown that an overlap bundle, termed bridging fiber, links outermost sister k-fibers. However, the relationship between overlap bundles and k-fibers throughout the spindle remained unknown. Here, we show that in a metaphase spindle more than 90% of overlap bundles act as a bridge between sister k-fibers. We found that the number of PRC1 GFP-labeled bundles per spindle is nearly the same as the number of kinetochore pairs. Live-cell imaging revealed that kinetochore movement in the equatorial plane of the spindle is highly correlated with the movement of the coupled PRC1 GFP-labeled fiber, whereas the correlation with other fibers decreases with increasing distance. Analysis of endogenous PRC1 localization confirmed the results obtained with PRC1-GFP PRC1 knockdown reduced the bridging fiber thickness and interkinetochore distance throughout the spindle, suggesting a function of PRC1 in bridging microtubule organization and force balance in the metaphase spindle. PMID- 28028033 TI - Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian network meta-analysis. AB - Background: The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. Methods: We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects. Results: A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11-0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01- 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06-0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05-0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death. Conclusion: Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention. PMID- 28028034 TI - Rapamycin-insensitive companion of mTOR (RICTOR) amplification defines a subset of advanced gastric cancer and is sensitive to AZD2014-mediated mTORC1/2 inhibition. AB - Background: Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed. Patients and methods: Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition. Results: NGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control >2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line. Conclusions: RICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling. PMID- 28028035 TI - Cardiometabolic risk improvement in response to a 3-yr lifestyle modification program in men: contribution of improved cardiorespiratory fitness vs. weight loss. AB - Our objective was to examine the respective contributions of changes in visceral adiposity, subcutaneous adiposity, liver fat, and cardiorespiratory fitness (CRF) to the improvements in cardiometabolic risk markers in response to a 3-yr healthy eating/physical activity lifestyle intervention. Ninety-four out of 144 viscerally obese healthy men completed a 3-yr lifestyle intervention. Body weight, body composition, and fat distribution were assessed by anthropometry and DEXA/computed tomography. CRF, adipokines, lipoprotein/lipid profile, and 75 g of oral glucose tolerance were assessed. CRF and visceral and subcutaneous adiposity significantly improved over the 3-yr intervention, with a nadir in year 1 and a partial regain in year 3 Liver fat (estimated by insulin hepatic extraction) stabilized from year 1 to year 3, whereas HOMA-IR, ISI-Matsuda index, and adiponectin continued to improve. Multivariate analysis revealed that both visceral adiposity and estimated liver fat reductions contributed to the improved ISI-Matsuda index observed over 3 yr (r2 = 0.28, P < 0.001). Three-year changes in fat mass and CRF were independently associated with changes in visceral fat (adjusted r2 = 0.40, P < 0.001), whereas only changes in CRF were associated with changes in estimated liver fat (adjusted r2 = 0.18, P < 0.001). A long-term (3 yr) healthy eating/physical activity intervention in men improves several cardiometabolic risk markers over the long term (3 yr) despite a partial body weight regain observed between year 1 and year 3 The improvement in CRF contributes to visceral and estimated liver fat losses over the long term, which in turn explain the benefits of the lifestyle intervention on cardiometabolic risk profile. PMID- 28028037 TI - Muscle interleukin-6 and fasting-induced PDH regulation in mouse skeletal muscle. AB - Fasting prompts a metabolic shift in substrate utilization from carbohydrate to predominant fat oxidation in skeletal muscle, and pyruvate dehydrogenase (PDH) is seen as a controlling link between the competitive oxidation of carbohydrate and fat during metabolic challenges like fasting. Interleukin (IL)-6 has been proposed to be released from muscle with concomitant effects on both glucose and fat utilization. The aim was to test the hypothesis that muscle IL-6 has a regulatory impact on fasting-induced suppression of skeletal muscle PDH. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) were either fed or fasted for 6 or 18 h. Lack of muscle IL-6 elevated the respiratory exchange ratio in the fed and early fasting state, but not with prolonged fasting. Activity of PDH in the active form (PDHa) was higher in fed and fasted IL-6 MKO than in control mice at 18 h, but not at 6 h, whereas lack of muscle IL-6 did not prevent downregulation of PDHa activity in skeletal muscle or changes in plasma and muscle substrate levels in response to 18 h of fasting. Phosphorylation of three of four sites on PDH-E1alpha increased with 18 h of fasting, but was lower in IL-6 MKO mice than in control. In addition, both PDK4 mRNA and protein increased with 6 and 18 h of fasting in both genotypes, but PDK4 protein was lower in IL-6 MKO than in control. In conclusion, skeletal muscle IL 6 seems to regulate whole body substrate utilization in the fed, but not fasted, state and influence skeletal muscle PDHa activity in a circadian manner. However, skeletal muscle IL-6 is not required for maintaining metabolic flexibility in response to fasting. PMID- 28028036 TI - Reduced islet function contributes to impaired glucose homeostasis in fructose fed mice. AB - Increased sugar consumption, particularly fructose, in the form of sweetened beverages and sweeteners in our diet adversely affects metabolic health. Because these effects are associated with features of the metabolic syndrome in humans, the direct effect of fructose on pancreatic islet function is unknown. Therefore, we examined the islet phenotype of mice fed excess fructose. Fructose-fed mice exhibited fasting hyperglycemia and glucose intolerance but not hyperinsulinemia, dyslipidemia, or hyperuricemia. Islet function was impaired, with decreased glucose-stimulated insulin secretion and increased glucagon secretion and high fructose consumption leading to alpha-cell proliferation and upregulation of the fructose transporter GLUT5, which was localized only in alpha-cells. Our studies demonstrate that excess fructose consumption contributes to hyperglycemia by affecting both beta- and alpha-cells of islets in mice. PMID- 28028038 TI - Function and evolution of a Lotus japonicus AP2/ERF family transcription factor that is required for development of infection threads. AB - Legume-rhizobium symbiosis is achieved by two major events evolutionarily acquired: root hair infection and organogenesis. Infection thread (IT) development is a distinct element for rhizobial infection. Through ITs, rhizobia are efficiently transported from infection foci on root hairs to dividing meristematic cortical cells. To unveil this process, we performed genetic screening using Lotus japonicus MG-20 and isolated symbiotic mutant lines affecting nodulation, root hair morphology, and IT development. Map-based cloning identified an AP2/ERF transcription factor gene orthologous to Medicago truncatula ERN1. LjERN1 was activated in response to rhizobial infection and depended on CYCLOPS and NSP2. Legumes conserve an ERN1 homolog, ERN2, that functions redundantly with ERN1 in M. truncatula. Phylogenetic analysis showed that the lineages of ERN1 and ERN2 genes originated from a gene duplication event in the common ancestor of legume plants. However, genomic analysis suggested the lack of ERN2 gene in the L. japonicus genome, consistent with Ljern1 mutants exhibited a root hair phenotype that is observed in ern1/ern2 double mutants in M. truncatula. Molecular evolutionary analysis suggested that the nonsynonymous/synonymous rate ratios of legume ERN1 genes was almost identical to that of non-legume plants, whereas the ERN2 genes experienced a relaxed selective constraint. PMID- 28028039 TI - Draft genome sequence of bitter gourd (Momordica charantia), a vegetable and medicinal plant in tropical and subtropical regions. AB - Bitter gourd (Momordica charantia) is an important vegetable and medicinal plant in tropical and subtropical regions globally. In this study, the draft genome sequence of a monoecious bitter gourd inbred line, OHB3-1, was analyzed. Through Illumina sequencing and de novo assembly, scaffolds of 285.5 Mb in length were generated, corresponding to ~84% of the estimated genome size of bitter gourd (339 Mb). In this draft genome sequence, 45,859 protein-coding gene loci were identified, and transposable elements accounted for 15.3% of the whole genome. According to synteny mapping and phylogenetic analysis of conserved genes, bitter gourd was more related to watermelon (Citrullus lanatus) than to cucumber (Cucumis sativus) or melon (C. melo). Using RAD-seq analysis, 1507 marker loci were genotyped in an F2 progeny of two bitter gourd lines, resulting in an improved linkage map, comprising 11 linkage groups. By anchoring RAD tag markers, 255 scaffolds were assigned to the linkage map. Comparative analysis of genome sequences and predicted genes determined that putative trypsin-inhibitor and ribosome-inactivating genes were distinctive in the bitter gourd genome. These genes could characterize the bitter gourd as a medicinal plant. PMID- 28028040 TI - Whole-genome expression analysis of mammalian-wide interspersed repeat elements in human cell lines. AB - With more than 500,000 copies, mammalian-wide interspersed repeats (MIRs), a sub group of SINEs, represent ~2.5% of the human genome and one of the most numerous family of potential targets for the RNA polymerase (Pol) III transcription machinery. Since MIR elements ceased to amplify ~130 myr ago, previous studies primarily focused on their genomic impact, while the issue of their expression has not been extensively addressed. We applied a dedicated bioinformatic pipeline to ENCODE RNA-Seq datasets of seven human cell lines and, for the first time, we were able to define the Pol III-driven MIR transcriptome at single-locus resolution. While the majority of Pol III-transcribed MIR elements are cell specific, we discovered a small set of ubiquitously transcribed MIRs mapping within Pol II-transcribed genes in antisense orientation that could influence the expression of the overlapping gene. We also identified novel Pol III-transcribed ncRNAs, deriving from transcription of annotated MIR fragments flanked by unique MIR-unrelated sequences, and confirmed the role of Pol III-specific internal promoter elements in MIR transcription. Besides demonstrating widespread transcription at these retrotranspositionally inactive elements in human cells, the ability to profile MIR expression at single-locus resolution will facilitate their study in different cell types and states including pathological alterations. PMID- 28028042 TI - Mental Disorders in Deaf and Hard of Hearing Adult Outpatients: A Comparison of Linguistic Subgroups. AB - Deaf and hard of hearing (DHH) individuals who use signed language and those who use spoken language face different challenges and stressors. Accordingly, the profile of their mental problems may also differ. However, studies of mental disorders in this population have seldom differentiated between linguistic groups. Our study compares demographics, mental disorders, and levels of distress and functioning in 40 patients using Norwegian Sign Language (NSL) and 36 patients using spoken language. Assessment instruments were translated into NSL. More signers were deaf than hard of hearing, did not share a common language with their childhood caregivers, and had attended schools for DHH children. More Norwegian-speaking than signing patients reported medical comorbidity, whereas the distribution of mental disorders, symptoms of anxiety and depression, and daily functioning did not differ significantly. Somatic complaints and greater perceived social isolation indicate higher stress levels in DHH patients using spoken language than in those using sign language. Therefore, preventive interventions are necessary, as well as larger epidemiological and clinical studies concerning the mental health of all language groups within the DHH population. PMID- 28028047 TI - Content analysis of UK newspaper and online news representations of women's and men's 'binge' drinking: a challenge for communicating evidence-based messages about single-episodic drinking? AB - OBJECTIVES: In the UK, men's alcohol-related morbidity and mortality still greatly exceeds women's, despite an increase in women's alcohol consumption in recent decades. New UK alcohol guidelines introduce gender-neutral low-risk alcohol consumption guidance. This study explores how UK newspaper and online news represent women's and men's 'binge' drinking to identify opportunities to better align reporting of harmful drinking with evidence. DESIGN: Quantitative and qualitative content analysis of 308 articles published in 7 UK national newspapers and the BBC News website between 1 January 2012 and 31 December 2013. RESULTS: Articles associated women with 'binge' drinking more frequently than men, and presented women's drinking as more problematic. Men were more frequently characterised as violent or disorderly, while women were characterised as out of control, putting themselves in danger, harming their physical appearance and burdening men. Descriptions of female 'binge' drinkers' clothing and appearance were typically moralistic. CONCLUSIONS: The UK news media's disproportionate focus on women's 'binge' drinking is at odds with epidemiological evidence, may reproduce harmful gender stereotypes and may obstruct public understandings of the gender-neutral weekly consumption limits in newly proposed alcohol guidelines. In order to better align reporting of harmful drinking with current evidence, public health advocates may engage with the media with a view to shifting media framing of 'binge' drinking away from specific groups (young people; women) and contexts (public drinking) and towards the health risks of specific drinking behaviours, which affect all groups regardless of context. PMID- 28028048 TI - Erratum. George A. Bray, MD: Progress in Obesity-Multidisciplinary Research, Multidimensional Man. Diabetes Care 2016;39:1481-1485. PMID- 28028049 TI - Predicting Risk of RRT in Patients with CKD. PMID- 28028050 TI - New Organ Allocation System for Combined Liver-Kidney Transplants and the Availability of Kidneys for Transplant to Patients with Stage 4-5 CKD. AB - A new proposal has been created for establishing medical criteria for organ allocation in recipients receiving simultaneous liver-kidney transplants. In this article, we describe the new policy, elaborate on the points of greatest controversy, and offer a perspective on the policy going forward. Although we applaud the fact that simultaneous liver-kidney transplant activity will now be monitored and appreciate the creation of medical criteria for allocation in simultaneous liver-kidney transplants, we argue that some of the criteria proposed, especially those for allocating a kidney to a liver recipient with AKI, are too liberal. We call on the nephrology community to follow the consequences of this new policy and push for a re-examination of the longstanding policy of allocating kidneys to multiorgan transplant recipients before all other candidates. The charge to protect our system of equitable organ allocation is very challenging, but it is a challenge that we must embrace. PMID- 28028051 TI - Predicting 5-Year Risk of RRT in Stage 3 or 4 CKD: Development and External Validation. AB - BACKGROUND AND OBJECTIVES: Only a minority of patients with CKD progress to renal failure. Despite the potential benefits of risk stratification in the CKD population, risk prediction models are not routinely used. Our objective was to develop and externally validate a clinically useful and pragmatic prediction model for the 5-year risk of progression to RRT in stage 3 or 4 CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used a retrospective cohort design. The development cohort consisted of 22,460 Kaiser Permanente Northwest members with stage 3 or 4 CKD (baseline 2002-2008). The validation cohort consisted of 16,553 Kaiser Permanente Colorado members with stage 3-4 CKD (baseline 2006-2008). The final model included eight predictors: age, sex, eGFR, hemoglobin, proteinuria/albuminuria, systolic BP, antihypertensive medication use, and diabetes and its complications. RESULTS: In the Northwest and Colorado cohorts, there were 737 and 360 events, and observed 5-year Kaplan-Meier risks of 4.72% (95% confidence interval [95% CI], 4.38 to 5.06) and 2.57% (95% CI, 2.30 to 2.83), respectively. Our prediction model performed extremely well in the development cohort, with a c-statistic of 0.96, an R2 of 79.7%, and good calibration. We had similarly good performance in the external validation cohort, with a c-statistic of 0.95, R2 of 81.2%, and good calibration. In the external validation cohort, the observed risk was slightly lower than the predicted risk in the highest-risk quintile. Using the top quintile of predicted risk as a cutpoint gave a sensitivity of 92.2%. CONCLUSIONS: We developed a pragmatic prediction model and risk score for predicting the 5-year RRT risk in stage 3 and 4 CKD. This model uses variables that are typically available in routine primary care settings, and can be used to help guide important decisions such as timing of referral to nephrology and fistula placement. PMID- 28028052 TI - An RNA-binding atypical tropomyosin recruits kinesin-1 dynamically to oskar mRNPs. AB - Localization and local translation of oskar mRNA at the posterior pole of the Drosophila oocyte directs abdominal patterning and germline formation in the embryo. The process requires recruitment and precise regulation of motor proteins to form transport-competent mRNPs. We show that the posterior-targeting kinesin-1 is loaded upon nuclear export of oskar mRNPs, prior to their dynein-dependent transport from the nurse cells into the oocyte. We demonstrate that kinesin-1 recruitment requires the DmTropomyosin1-I/C isoform, an atypical RNA-binding tropomyosin that binds directly to dimerizing oskar 3'UTRs. Finally, we show that a small but dynamically changing subset of oskar mRNPs gets loaded with inactive kinesin-1 and that the motor is activated during mid-oogenesis by the functionalized spliced oskar RNA localization element. This inefficient, dynamic recruitment of Khc decoupled from cargo-dependent motor activation constitutes an optimized, coordinated mechanism of mRNP transport, by minimizing interference with other cargo-transport processes and between the cargo-associated dynein and kinesin-1. PMID- 28028053 TI - MRTF potentiates TEAD-YAP transcriptional activity causing metastasis. AB - Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical extracellular cues. The mechanism underlying this crosstalk, however, remains unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD-YAP transcriptional complex and potentiate its transcriptional activity. We show this interaction of MRTF and YAP is critical for LPA-induced cancer cell invasion in vitro and breast cancer metastasis to the lung in vivo We also demonstrate the significance of MRTF-YAP binding in regulation of YAP activity upon acute actin cytoskeletal damage. Acute actin disruption induces nucleo-cytoplasmic shuttling of MRTF, and this process underlies the LATS-independent regulation of YAP activity. Our results provide clear evidence of crosstalk between MRTF and YAP independent of the LATS kinases that normally act upstream of YAP signaling. Our results also suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP. PMID- 28028055 TI - The role of hybridization in facilitating tree invasion. AB - Hybridization events can generate additional genetic diversity upon which natural selection can act and at times enhance invasiveness of the species. Invasive tree species are a growing ecological concern worldwide, and some of these invasions involve hybridization events pre- or post-introduction. There are 20 hybrid invasive tree taxa in 15 genera (11 plant families) discussed here. When reported, abundance of hybrids comprised 10-100% of an invasion, the remainder being parental taxa. In seven hybrid taxa researchers identified phenotypes that may make hybrids better invaders. Twelve hybrid tree taxa involved introgression and more hybrids involved all non-native taxa than native x non-native taxa. Three hybrid tree taxa were the result of intentional crosses and all hybrid taxa involved intentional introduction of either one or more parental taxon or the hybrid itself. The knowledge gaps present in some hybrid tree taxa can weaken our effectiveness in predicting and controlling invasions, as hybrids can add a level of complexity to an invasion by being morphologically cryptic, causing genetic pollution of a native parental taxon, presenting novel genotypes for which there may not be coevolved biological control agents, or evolving adaptive traits through increased genetic variation. PMID- 28028054 TI - Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins. AB - Autophagy is a cellular surveillance pathway that balances metabolic and energy resources and transports specific cargos, including damaged mitochondria, other broken organelles, or pathogens for degradation to the lysosome. Central components of autophagosomal biogenesis are six members of the LC3 and GABARAP family of ubiquitin-like proteins (mATG8s). We used phage display to isolate peptides that possess bona fide LIR (LC3-interacting region) properties and are selective for individual mATG8 isoforms. Sensitivity of the developed sensors was optimized by multiplication, charge distribution, and fusion with a membrane recruitment (FYVE) or an oligomerization (PB1) domain. We demonstrate the use of the engineered peptides as intracellular sensors that recognize specifically GABARAP, GABL1, GABL2, and LC3C, as well as a bispecific sensor for LC3A and LC3B. By using an LC3C-specific sensor, we were able to monitor recruitment of endogenous LC3C to Salmonella during xenophagy, as well as to mitochondria during mitophagy. The sensors are general tools to monitor the fate of mATG8s and will be valuable in decoding the biological functions of the individual LC3/GABARAPs. PMID- 28028056 TI - Regucalcin plays a role in the cytoskeleton regulation of HepG2 cells. PMID- 28028058 TI - Beyond the Headlines: Insights on Potassium Supplementation for the Treatment of Hypertension From the Canadian Hypertension Education Program Guidelines (CHEP). PMID- 28028059 TI - Putting the Acute Coronary Syndrome in Context After 80 Years of Age. PMID- 28028060 TI - Smoking: A Dual Pathogen for Arterial and Venous Thrombosis. PMID- 28028061 TI - Clinical Impact of Pharmacogenomics of Clopidogrel in Stroke. PMID- 28028062 TI - Cardiovascular Effects of Performance-Enhancing Drugs. AB - Exercise and competitive sports should be associated with a wide range of health benefits with the potential to inspire a positive community health legacy. However, the reputation of sports is being threatened by an ever-expanding armamentarium of agents with real or perceived benefits in performance enhancement. In addition to the injustice of unfair advantage for dishonest athletes, significant potential health risks are associated with performance enhancing drugs. Performance-enhancing drugs may have an effect on the cardiovascular system by means of directly altering the myocardium, vasculature, and metabolism. However, less frequently considered is the potential for indirect effects caused through enabling athletes to push beyond normal physiological limits with the potential consequence of exercise-induced arrhythmias. This review will summarize the known health effects of PEDs but will also focus on the potentially greater health threat posed by the covert search for performance enhancing agents that have yet to be recognized by the World Anti-Doping Agency. History has taught us that athletes are subjected to unmonitored trials with experimental drugs that have little or no established efficacy or safety data. One approach to decrease drug abuse in sports would be to accept that there is a delay from when athletes start experimenting with novel agents to the time when authorities become aware of these drugs. This provides a window of opportunity for athletes to exploit with relative immunity. It could be argued that all off label use of any agent should be deemed illegal. PMID- 28028064 TI - Highlights From the Circulation Family of Journals. PMID- 28028063 TI - Highlights of the American Heart Association Scientific Sessions 2016. PMID- 28028065 TI - Handheld Technologies May Lead to Better Detection of Atrial Fibrillation. PMID- 28028066 TI - Head-to-Head Comparison of the AliveCor Heart Monitor and Microlife WatchBP Office AFIB for Atrial Fibrillation Screening in a Primary Care Setting. PMID- 28028067 TI - Letter by Maesen et al Regarding Article, "Ablation of Atrial Fibrillation: Patient Selection, Periprocedural Anticoagulation, Techniques, and Preventive Measures After Ablation". PMID- 28028068 TI - Response by Link et al to Letter Regarding Article, "Ablation of Atrial Fibrillation: Patient Selection, Periprocedural Anticoagulation, Techniques, and Preventive Measures After Ablation". PMID- 28028069 TI - Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis. AB - Aims: The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results: Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8-26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1-25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions: RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans. PMID- 28028070 TI - Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression. AB - AIMS: The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with focus on arterial thrombosis and its key trigger tissue factor have not been previously investigated. METHODS AND RESULTS: Human aortic endothelial cells were treated with ticagrelor or clopidogrel active metabolite (CAM) and stimulated with tumour necrosis factor-alpha (TNF-alpha); effects on procoagulant tissue factor (TF) expression and activity, its counter-player TF pathway inhibitor (TFPI) and the underlying mechanisms were determined. Further, arterial thrombosis by photochemical injury of the common carotid artery, and TF expression in the murine endothelium were examined in C57BL/6 mice treated with ticagrelor or clopidogrel. Ticagrelor, but not CAM, reduced TNF-alpha-induced TF expression via proteasomal degradation and TF activity, independently of the P2Y12 receptor and the equilibrative nucleoside transporter 1 (ENT1), an additional target of ticagrelor. In C57BL/6 mice, ticagrelor prolonged time to arterial occlusion, compared with clopidogrel, despite comparable antiplatelet effects. In line with our in vitro results, ticagrelor, but not clopidogrel, reduced TF expression in the endothelium of murine arteries. CONCLUSION: Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor. PMID- 28028071 TI - Erratum for Siccardi et al., Validation of Computational Approaches for Antiretroviral Dose Optimization. PMID- 28028072 TI - Model-based analysis of DNA replication profiles: predicting replication fork velocity and initiation rate by profiling free-cycling cells. AB - Eukaryotic cells initiate DNA synthesis by sequential firing of hundreds of origins. This ordered replication is described by replication profiles, which measure the DNA content within a cell population. Here, we show that replication dynamics can be deduced from replication profiles of free-cycling cells. While such profiles lack explicit temporal information, they are sensitive to fork velocity and initiation capacity through the passive replication pattern, namely the replication of origins by forks emanating elsewhere. We apply our model-based approach to a compendium of profiles that include most viable budding yeast mutants implicated in replication. Predicted changes in fork velocity or initiation capacity are verified by profiling synchronously replicating cells. Notably, most mutants implicated in late (or early) origin effects are explained by global modulation of fork velocity or initiation capacity. Our approach provides a rigorous framework for analyzing DNA replication profiles of free cycling cells. PMID- 28028073 TI - Thiazolidinediones are associated with a decreased risk of atrial fibrillation compared with other antidiabetic treatment: a nationwide cohort study. AB - Aim: The aim of this study was to investigate the association between thiazolidinediones (TZDs) vs. other antidiabetic drugs and risk of atrial fibrillation (AF) in diabetic patients. Method and results: Diabetes mellitus (diabetes) increases the risk of AF by approximately 34%. TZD is an insulin sensitizer that also has anti-inflammatory effects, which might decrease the risk of AF compared with other antidiabetic drugs. We used data from the Danish nationwide registries to study 108 624 patients with diabetes and without prior AF who were treated with metformin or sulfonylurea as first-line drugs. The incidence of AF was significantly lower with TZD as the second-line antidiabetic treatment compared with other second-line antidiabetic drugs (P < 0.001). The 10 year cumulative incidence [95% confidence interval (95% CI)] of AF was 6.2% (3.1 9.3%) with TZD vs. 10.2% (9.8-10.6%) with other antidiabetic drugs. The decreased risk of AF remained significant after adjusting for age, sex, and comorbidities with a hazard ratio (95% CI) of 0.76 (0.57-1.00), P = 0.047 associated with TZD treatment compared with other antidiabetic drugs. Conclusion: Use of a TZD to treat diabetes was associated with reduced risk of developing AF compared with other antidiabetic drugs as second-line treatment. PMID- 28028074 TI - Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion. AB - In heterozygous patients with a diabetic syndrome called mutant INS gene-induced diabetes of youth (MIDY), there is decreased insulin secretion when mutant proinsulin expression prevents wild-type (WT) proinsulin from exiting the endoplasmic reticulum (ER), which is essential for insulin production. Our previous results revealed that mutant Akita proinsulin is triaged by ER associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shifting Akita proinsulin from high molecular weight (MW) complexes toward smaller oligomeric species that are competent to undergo ERAD. Strikingly, overexpressing Grp170 also liberates WT proinsulin, which is no longer trapped in these high-MW complexes, enhancing ERAD of Akita proinsulin and restoring WT insulin secretion. Our data reveal that Grp170 participates in preparing mutant proinsulin for degradation while enabling WT proinsulin escape from the ER. In principle, selective destruction of mutant proinsulin offers a rational approach to rectify the insulin secretion problem in MIDY. PMID- 28028075 TI - An Increased Diagnostic Sensitivity of Truncated GAD65 Autoantibodies in Type 1 Diabetes May Be Related to HLA-DQ8. AB - N-terminally truncated (96-585) GAD65 (tGAD65) autoantibodies may better delineate type 1 diabetes than full-length GAD65 (fGAD65) autoantibodies. We aimed to compare the diagnostic sensitivity and specificity between fGAD65 and tGAD65 autoantibodies for type 1 diabetes in relation to HLA-DQ. Sera from children and adolescents with newly diagnosed type 1 diabetes (n = 654) and healthy control subjects (n = 605) were analyzed in radiobinding assays for fGAD65 (fGADA), tGAD65 (tGADA), and commercial 125I-GAD65 (RSRGADA) autoantibodies. The diagnostic sensitivity and specificity in the receiver operating characteristic curve did not differ between fGADA and tGADA. At the optimal cutoff, the diagnostic sensitivity for fGADA was lower than tGADA at similar diagnostic specificities. In 619 patients, 64% were positive for RSRGADA compared with 68% for fGADA and 74% for tGADA. Using non-DQ2/non-DQ8 patients as reference, the risk of being diagnosed with fGADA and tGADA was increased in patients with DQ2/2 and DQ2/8. Notably, logistic regression analysis suggested that DQ8/8 patients had an increased risk to be diagnosed with tGADA (P = 0.003) compared with fGADA (P = 0.09). tGADA had a higher diagnostic sensitivity for type 1 diabetes than both fGADA and RSRGADA. As DQ8/8 patients represent 10-11% of patients with newly diagnosed type 1 diabetes <18 years of age, tGADA analysis should prove useful for disease classification. PMID- 28028076 TI - Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and gamma-Aminobutyric Acid Release. AB - Exercise is an effective intervention for the prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals that contribute to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance, and performance. The transcriptional regulator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type IIb) to oxidative slow-twitch (type I) and intermediate (type IIa) fibers, an effect reversed in insulin resistance and diabetes. We found that nitrate induces PGC1alpha expression and a switch toward type I and IIa fibers in rat muscle and myotubes in vitro. Nitrate induces the release of exercise/PGC1alpha-dependent myokine FNDC5/irisin and beta aminoisobutyric acid from myotubes and muscle in rats and humans. Both exercise and nitrate stimulated PGC1alpha-mediated gamma-aminobutyric acid (GABA) secretion from muscle. Circulating GABA concentrations were increased in exercising mice and nitrate-treated rats and humans; thus, GABA may function as an exercise/PGC1alpha-mediated myokine-like small molecule. Moreover, nitrate increased circulating growth hormone levels in humans and rodents. Nitrate induces physiological responses that mimic exercise training and may underlie the beneficial effects of this metabolite on exercise and cardiometabolic health. PMID- 28028077 TI - Endogenous alpha2A-Adrenoceptor-Operated Sympathoadrenergic Tones Attenuate Insulin Secretion via cAMP/TRPM2 Signaling. AB - In pancreatic beta-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in beta-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K+ channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in beta-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the alpha2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an alpha2 adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of alpha2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes. PMID- 28028079 TI - Paradigms in Eastern Spruce Budworm (Lepidoptera: Tortricidae) Population Ecology: A Century of Debate. AB - Three main hypotheses have been postulated over the past century to explain the outbreaking population dynamics of eastern spruce budworm, Choristoneura fumiferana (Clemens). The Silviculture Hypothesis first arose in the 1920s, with the idea that outbreaks were driven by forestry practices favoring susceptible softwood species. In the 1960s, it was proposed that populations were governed by Multiple Equilibria, with warm weather conditions releasing low-density populations from the regulatory control of natural enemies. Dispersal from outbreak foci, or "epicenters," was seen as causing widespread outbreaks that eventually collapsed following resource depletion. However, in the 1980s, following the re-analysis of data from the 1940s outbreak in New Brunswick, this interpretation was challenged. The alternative Oscillatory Hypothesis proposed that budworm population dynamics were governed by a second-order density dependent process, with oscillations being driven by natural enemy-victim interactions. Under this hypothesis, weather and resource availability contribute to secondary fluctuations around the main oscillation, and weather and moth dispersal serve to synchronize population cycles regionally. Intensive, independent population studies during the peak and declining phases of the 1980s outbreak supported the principal tenet of the Oscillatory Hypothesis, but concluded that host plant quality played a more important role than this hypothesis proposed. More recent research on the early phase of spruce budworm cycles suggests that mate-finding and natural-enemy-driven Allee effects in low density populations might be overcome by immigration of moths, which can facilitate the onset of outbreaks. Even more recent research has supported components of all three hypotheses attempting to explain spruce budworm dynamics. In the midst of a new rising outbreak (2006-present), we discuss the evolution of debates surrounding these hypotheses from a historic perspective, examine gaps in current knowledge, and suggest avenues for future research (e.g., intensive studies on low-density populations) to better understand and manage spruce budworm populations. PMID- 28028080 TI - MODIS Imagery Improves Pest Risk Assessment: A Case Study of Wheat Stem Sawfly (Cephus cinctus, Hymenoptera: Cephidae) in Colorado, USA. AB - Wheat stem sawfly (Cephus cinctus Norton, Hymenoptera: Cephidae) has long been a significant insect pest of spring, and more recently, winter wheat in the northern Great Plains. Wheat stem sawfly was first observed infesting winter wheat in Colorado in 2010 and, subsequently, has spread rapidly throughout wheat production regions of the state. Here, we used maximum entropy modeling (MaxEnt) to generate habitat suitability maps in order to predict the risk of crop damage as this species spreads throughout the winter wheat-growing regions of Colorado. We identified environmental variables that influence the current distribution of wheat stem sawfly in the state and evaluated whether remotely sensed variables improved model performance. We used presence localities of C. cinctus and climatic, topographic, soils, and normalized difference vegetation index and enhanced vegetation index data derived from Moderate Resolution Imaging Spectroradiometer (MODIS) imagery as environmental variables. All models had high performance in that they were successful in predicting suitable habitat for C. cinctus in its current distribution in eastern Colorado. The enhanced vegetation index for the month of April improved model performance and was identified as a top contributor to MaxEnt model. Soil clay percent at 0-5 cm, temperature seasonality, and precipitation seasonality were also associated with C. cinctus distribution in Colorado. The improved model performance resulting from integrating vegetation indices in our study demonstrates the ability of remote sensing technologies to enhance species distribution modeling. These risk maps generated can assist managers in planning control measures for current infestations and assess the future risk of C. cinctus establishment in currently uninfested regions. PMID- 28028078 TI - Ire1alpha in Pomc Neurons Is Required for Thermogenesis and Glycemia. AB - Whether neuronal inositol-requiring enzyme 1 (Ire1) is required for the proper regulation of energy balance and glucose homeostasis is unclear. We found that pro-opiomelanocortin (Pomc)-specific deficiency of Ire1alpha accelerated diet induced obesity concomitant with a decrease in energy expenditure. This hypometabolic phenotype included deficits in thermogenic responses to diet and cold exposure as well as "beiging" of white adipose tissue. We also demonstrate that loss of Ire1alpha in Pomc neurons impaired whole-body glucose and insulin tolerance as well as hepatic insulin sensitivity. At the cellular level, deletion of Ire1alpha in Pomc neurons elevated hypothalamic endoplasmic reticulum (ER) stress and predisposed Pomc neurons to leptin and insulin resistance. Together, the current studies extend and confirm conclusions that Ire1alpha-Xbp1s and associated molecular targets link ER stress in arcuate Pomc neurons to aspects of normal energy and glucose homeostasis. PMID- 28028081 TI - Density-Dependent Recruitment and Diapause in the Spring-Feeding Generation of Hemlock Woolly Adelgid (Hemiptera: Adelgidae) in Western North America. AB - Insect populations are affected by density-dependent and density-independent factors, and knowing how these factors affect long-term population growth is critical to pest management. In this study, we experimentally manipulated densities of the hemlock woolly adelgid on eastern and western hemlock trees in the western USA to evaluate the effects of density and host species on hemlock woolly adelgid crawler colonization. We then followed development of hemlock woolly adelgid on each hemlock species. Settlement of crawlers was strongly density-dependent and consistent between host species. In addition, a period of hot days that coincided with the settlement of hemlock woolly adelgid crawlers put our experimental and naturally occurring populations into diapause during April. Diapause resulted in one generation that yr in our experimental population. Analyses of long-term air temperature records indicated that diapause inducing temperatures in April similar to those observed in our experiment have occurred rarely since 1909 and the frequency of these events has not changed over time. Prior work suggests that hemlock woolly adelgid completes two generations per yr in the western USA with a diapause occurring in the summer. This typical life history reflects the long-term influence of regional average seasonal temperature patterns on development and the timing of diapause-inducing temperatures. However, the timing of unseasonal weather, such as the hot days observed in our experiment, occasionally changes life history trajectories from this normal pattern. Our results show that density-dependent and density independent factors have strong effects on generational mortality and life history of hemlock woolly adelgid that are important to its population dynamics and management. PMID- 28028082 TI - A Variable-Instar Climate-Driven Individual Beetle-Based Phenology Model for the Invasive Asian Longhorned Beetle (Coleoptera: Cerambycidae). AB - Efforts to manage and eradicate invasive species can benefit from an improved understanding of the physiology, biology, and behavior of the target species, and ongoing efforts to eradicate the Asian longhorned beetle (Anoplophora glabripennis Motschulsky) highlight the roles this information may play. Here, we present a climate-driven phenology model for A. glabripennis that provides simulated life-tables for populations of individual beetles under variable climatic conditions that takes into account the variable number of instars beetles may undergo as larvae. Phenology parameters in the model are based on a synthesis of published data and studies of A. glabripennis, and the model output was evaluated using a laboratory-reared population maintained under varying temperatures mimicking those typical of Central Park in New York City. The model was stable under variations in population size, simulation length, and the Julian dates used to initiate individual beetles within the population. Comparison of model results with previously published field-based phenology studies in native and invasive populations indicates both this new phenology model, and the previously published heating-degree-day model show good agreement in the prediction of the beginning of the flight season for adults. However, the phenology model described here avoids underpredicting the cumulative emergence of adults through the season, in addition to providing tables of life stages and estimations of voltinism for local populations. This information can play a key role in evaluating risk by predicting the potential for population growth, and may facilitate the optimization of management and eradication efforts. PMID- 28028083 TI - Emergence, Seasonality, and Hybridization of Laricobius nigrinus (Coleoptera: Derodontidae), an Introduced Predator of Hemlock Woolly Adelgid (Hemiptera: Adelgidae), in the Tennessee Appalachians. AB - From 2010 through 2013, adult emergence and seasonality of Laricobius nigrinus Fender, an introduced predatory species native to western North America, as well as hybridization with the native species Laricobius rubidus (LeConte), were evaluated using emergence traps and beat-sheet sampling in areas of previous release against hemlock woolly adelgid, Adelges tsugae Annand. The shortest emergence period of adult L. nigrinus was 7 wk beginning 22 October 2010, and the longest emergence was 15 wk beginning 17 October 2012. Native L. rubidus also were collected from emergence traps placed on the ground surface and beat-sheet samples all 3 yr, with emergence of L. rubidus initiating later than L. nigrinus each season. Seasonality of both Laricobius species was similar across a 44-mo study period. Adult L. nigrinus were present from October through April, and larvae of Laricobius spp. were collected from February to May. The average number of L. nigrinus from emergence traps was significantly greater than the average number of beetles collected from beat-sheet samples in 2010, while the converse was observed during 2012. Hybridization between L. nigrinus and L. rubidus was documented from 10.75% of specimens collected during 2010 and 2011, indicating periodic interbreeding between the introduced and native species. These findings suggest emergence trapping may be a useful method to assess establishment, population densities, and seasonality of Laricobius species in areas of release to enhance their use in management of A. tsuage. PMID- 28028084 TI - Using Global and Regional Species Distribution Models (SDM) to Infer the Invasive Stage of Latrodectus geometricus (Araneae: Theridiidae) in the Americas. AB - The brown widow spider, Latrodectus geometricus C. L. Koch, 1841, is a large spider of the family Theridiidae that belongs to a genus of medical interest owing to its potent neurotoxic venom, which causes severe pain in humans. In America, this alien spider has been found in virtually all countries in the region, mainly associated with human dwellings, but also in agricultural sectors. However, the invasive process and potential distribution of this invasive species across the American continent are completely unknown. In this context, using a combination of both global and regional niche models, it is possible to hypothesize the invasive phase of the species as well as the geographic space where these different phases occur. By comparing the global and regional niches of L. geometricus, we examined its invasive process and potential distribution across the American continent. This work is an innovative approach to understanding the invasion of the brown widow spider in this area and the ecological processes that underlie this invasion. In this context, the global and regional niche comparison constitutes an appropriate tool to account for the complexities of the invasive process, generating different hypotheses amenable to being tested in future studies. PMID- 28028085 TI - Diversity and Resource Use Patterns of Anthophile Insects in Cuatro Cienegas, Coahuila, Mexico. AB - Bees and flies are the main pollinators responsible for the maintenance of plant diversity and crop production. Studies of pollinator communities have focused on bees; however, community structures may vary among groups of pollinators. We describe and compare the diversity and resource use patterns of six Apoidea and two Diptera anthophile families in Cuatro Cienegas in the northeast of Mexico. We sampled insects in two distinct geographic units (valley and mountains) and two seasons (rainy and dry). Spatial and temporal patterns in species composition and abundance of these families were identified and the diversity in each family compared. The spatial and temporal patterns in species composition, diversity, and resource use were different for each family. Overall, diversity was higher during the rainy season. Only fly families and the Andrenidae presented season specific differences in species composition, in contrast with the other Apoidea. Two bee families visited more plant species per insect species during the rainy season, whereas flies visited the same number of plant species in both seasons. Apidae, Megachilidae, and Bombyliidae visited more plant species in the mountains, while the other families exhibited no differences between the mountains and the valley. The variation in the community structures of each group may reflect distinct life histories, resources needs during larval stages, and foraging behaviors. These differences are relevant in management and conservation programs that could benefit one group of pollinators while harming others with different characteristics. The traits of some families indicate their potential value as pollinators. PMID- 28028086 TI - Extending the "Ecology of Fear" Beyond Prey: Reciprocal Nonconsumptive Effects Among Competing Aphid Predators. AB - Nonconsumptive effects of predators on prey are well known, but similar effects among competing predators are not. Aphidophagous insect larvae are notorious for cannibalism and intraguild predation, as they compete for aggregated but ephemeral prey. We tested for indirect effects of competitors on the development of Coleomegilla maculata DeGeer and Hippodamia convergens Guerin-Meneville (Coleoptera: Coccinellidae), and a green lacewing, Chrysoperla carnea Stephens (Neuroptera: Chrysopidae), with all larvae reared on eggs of Ephestia kuehniella Zeller (Lepidoptera: Pyralidae). Control larvae were reared singly, while treatment larvae were reared pairwise, with either a conspecific or heterospecific, in partitioned Petri dishes that allowed the passage of chemical cues. Larvae of C. maculata, a dietary generalist, appeared stressed by the presence of competing larvae, whether con- or heterospecific, and suffered fitness costs (longer pupation times, lower male adult mass). In contrast, H. convergens and C. carnea, both aphid specialists, responded to competing larvae with accelerated development, and without any apparent costs in terms of adult size or reproductive performance. Adult C. carnea in some treatments were heavier than solitary controls, suggesting a higher consumption rate by the induced phenotype, and those exposed to H. convergens began oviposition earlier. Thus, the phenotypes induced in the specialized aphid predators were adaptive for development in aphid colonies, whereas that induced in the generalist was not. These results indicate that nonconsumptive effects are not simply a vertical force acting on prey, but can also impact conspecific and heterospecific competitors on the same trophic level. PMID- 28028087 TI - Floral Visitors of Three Asteraceae Species in a Xeric Environment in Central Mexico. AB - We describe the spatial variation in the structure and composition of the communities of insects visiting the inflorescences of Flaveria ramosissima Klatt, Florestina pedata (Cav.) Cass., and Parthenium bipinnatifidum (Ort.) Rollins (Asteraceae) in a xeric environment in Central Mexico. Inflorescences of the three Asteraceae were visited by a total of 96 species of Hymenoptera, Diptera, Lepidoptera, Coleoptera, and Hemiptera. Total species richness of floral visitors to the three Asteraceae and total abundance of insects of Fl. pedata and P. bipinnatifidum did not differ between low and high vegetation cover sites. Total abundance of insects visiting the inflorescences of F. ramosissima and abundance of Hymenoptera in all three Asteraceae were higher at the low vegetation coverage (LVC) site than at the high vegetation coverage (HVC) one. Diversity of insects of Fl. pedata and P. bipinnatifidum was higher at the HVC site. However, in F. ramosissima diversity was higher at the LVC site. The communities of insects of each Asteraceae were dissimilar between sites. These differences can be attributed to variation in the abundance of Lepidophora (Diptera: Bombyliidae), Miridae (Hemiptera), Melyridae (Coleoptera), Tiphiidae (Hymenoptera), Myrmecocystus mexicanus Wesmael, and Dorymyrmex grandulus (Forel) (Hymenoptera: Formicidae). The first three insect groups were sensitive to LVC, high temperature, and low humidity, whereas the last three tolerated those same environmental conditions. Changes in temperature, humidity, and resources associated with vegetation coverage seem to differentially affect each species of floral visitors of the three Asteraceae species studied. PMID- 28028088 TI - Antimicrobial Activity of Actinobacteria Isolated From the Guts of Subterranean Termites. AB - Subterranean termites need to minimize potentially pathogenic and competitive fungi in their environment in order to maintain colony health. We examined the ability of Actinobacteria isolated from termite guts in suppressing microorganisms commonly encountered in a subterranean environment. Guts from two subterranean termite species, Reticulitermes flavipes (Kollar) and Reticulitermes tibialis Banks, were extracted and plated on selective chitin media. A total of 38 Actinobacteria isolates were selected for in vitro growth inhibition assays. Target microbes included three strains of Serratia marcescens Bizio, two mold fungi (Trichoderma sp. and Metarhizium sp.), a yeast fungus (Candida albicans (C.P. Robin) Berkhout), and four basidiomycete fungi (Gloeophyllum trabeum (Persoon) Murrill, Tyromyces palustris (Berkeley & M.A. Curtis) Murrill, Irpex lacteus (Fries) Fries, and Trametes versicolor (L.) Lloyd). Results showed both broad and narrow ranges of antimicrobial activity against the mold fungi, yeast fungus, and S. marcescens isolates by the Actinobacteria selected. This suggests that termite gut-associated Actinobacteria produce secondary antimicrobial compounds that may be important for pathogen inhibition in termites. Basidiomycete fungi were strongly inhibited by the selected Actinobacteria isolates, with G. trabeum and T. versicolor being most inhibited, followed by I. lacteus and T. palustris The degree of inhibition was correlated with shifts in pH caused by the Actinobacteria. Nearly all Actinobacteria isolates raised pH of the growth medium to basic levels (i.e. pH ~8.0-9.5). We summarize antimicrobial activity of these termite gut-associated Actinobacteria and examine the implications of these pH shifts. PMID- 28028089 TI - Wolbachia in Parasitoids Attacking Native European and Introduced Eastern Cherry Fruit Flies in Europe. AB - The eastern cherry fruit fly, Rhagoletis cingulata Loew (Diptera: Tephritidae), is an economically important pest of cherries in North America. In 1983 it was first reported in Europe where it shares its ecological niche with the native European cherry fruit fly, Rhagoletis cerasi L. (Diptera: Tephritidae). Their coexistence in Europe led to the recent horizontal transmission of the Wolbachia strain wCer1 from R. cerasi to R. cingulata Horizontal Wolbachia transmission is mediated by either sharing of ecological niches or by interacting species such as parasitoids. Here we describe for the first time that two braconid wasps, Psyttalia rhagoleticola Sachtleben (Hymenoptera: Braconidae) and Utetes magnus Fischer (Hymenoptera: Braconidae), naturally parasitizing R. cerasi, use the invasive R. cingulata in Europe as a new host. In contrast, no parasitoids that parasitize R. cingulata in its native American range were detected in the introduced European range. Diagnostic Wolbachia PCR screening and sequence analyses demonstrated that all P. rhagoleticola individuals were infected with the newly described Wolbachia strain wRha while all U. magnus individuals were uninfected. wRha is different from wCer1 but had an Wolbachia surface protein (wsp) gene sequence that was identical to wCer2 of R. cerasi and wCin2 of R. cingulata. However, multi locus sequence typing revealed differences in all loci between wRha and the tephritid's strains. The horizontal transmission of wCer1 between the two tephritid species did not result in fixed heritable infections in the parasitoids. However, the parasitoids may have acted as a transient wCer1 vector. PMID- 28028090 TI - Native Bee Diversity and Pollen Foraging Specificity in Cultivated Highbush Blueberry (Ericaceae: Vaccinium corymbosum) in Rhode Island. AB - We identified 41 species of native bees from a total of 1,083 specimens collected at cultivated highbush blueberry plantings throughout Rhode Island in 2014 and 2015. Andrena spp., Bombus spp., and Xylocopa virginica (L.) were collected most often. Bombus griseocollis (DeGeer), B. impatiens Cresson, B. bimaculatus Cresson, B. perplexus Cresson, and Andrena vicina Smith collected the largest mean numbers of blueberry pollen tetrads. The largest mean percent blueberry pollen loads were carried by the miner bees Andrena bradleyi Viereck (91%), A. carolina Viereck (90%), and Colletes validus Cresson (87%). The largest mean total pollen grain loads were carried by B. griseocollis (549,844), B. impatiens (389,558), X. virginica (233,500), and B. bimaculatus (193,132). Xylocopa virginica was the fourth and fifth most commonly collected bee species in 2014 and 2015, respectively. They exhibit nectar robbing and females carried relatively low blueberry pollen loads (mean 33%). Overall, we found 10 species of bees to be the primary pollinators of blueberries in Rhode Island. PMID- 28028091 TI - Evaluation of Host-Plant Resistance of Selected Rice Genotypes to the Rice Water Weevil (Coleoptera: Curculionidae). AB - The rice water weevil, Lissorhoptrus oryzophilus Kuschel, is the most important insect pest of rice in the United States. Management of L. oryzophilus mainly depends upon the use of insecticides due to the lack of effective alternative management tactics. A 3-yr field study was conducted to determine if difference exists among rice genotypes and cultivars of inbred tropical japonica subspecies commercially grown in the southern United States [Cocodrie (PI 606331), CL171, and CL151 (PI 654463)] and the germplasm lines of indica subspecies adapted to tropical climates of Asia [WC 4644 (PI 312777), TNI (PI 495830), Rondo (PI 615022), 4612 (PI 615039), TeQing (PI 536047), and 4593 (PI 615031)] for resistance to L. oryzophilus Experiments were established as a split-plot design with cultivars as main plots and insecticide treatment as subplots. No significant differences were observed in number of L. oryzophilus larvae recovered across cultivars and genotypes, indicating no significant variation in their preference to L. oryzophilus oviposition. Insecticide treatment had a significant impact on L. oryzophilus larval density. However, grain yield did not vary significantly between treated and untreated plots for any of the cultivars and genotypes. The amount of yield loss in response to L. oryzophilus infestation did not vary significantly across genotypes and cultivars, indicating no variation among these genotypes for resistance to L. oryzophilus. PMID- 28028092 TI - Contribution of Noncolonizing Aphids to Potato Virus Y Prevalence in Potato in Idaho. AB - Potato virus Y (PVY) is a major concern for potato production in the United States given its impact on both crop quality and yield. Although green peach aphid, Myzus persicae (Sulzer), is the most efficient PVY vector, it may be less abundant in potato-growing areas of Idaho relative to non-potato-colonizing aphid vectors of PVY that may disperse from nearby cereal fields and other crops. A field study was conducted during 2012-2013 to examine if noncolonizing aphids disperse to nearby potato fields as cereal crops dry down before harvest. The aphid fauna was sampled weekly in four different potato fields in south-central and southeastern Idaho using yellow sticky traps and yellow pan traps. Potato fields were chosen with an adjacent cereal field such that the prevailing westerly wind would facilitate aphid dispersal from cereal fields to potato. Non potato-colonizing aphids sampled included 10 cereal aphid species, the most abundant of which were Rhopalosiphum padi L. and Metopolophium dirhodum (Walker). More than 35 species from noncereal hosts also were found. Overall, green peach aphid abundance was relatively low, ranging from 0.5-2.5% of the total aphid capture between years and among fields. In both years and all locations, cereal aphid abundance peaked in mid- to late July (cereal ripening stage) and decreased thereafter as cereal crops dried. PVY prevalence in the potato fields increased following these increases in aphid abundance. This study suggests that cereal aphids and other noncolonizing aphids are important contributors to PVY prevalence in potato in southern Idaho. PMID- 28028093 TI - Sapwood Stored Resources Decline in Whitebark and Lodgepole Pines Attacked by Mountain Pine Beetles (Coleoptera: Curculionidae). AB - Recent outbreaks of forest insects have been directly linked to climate change induced warming and drought, but effects of tree stored resources on insects have received less attention. We asked whether tree stored resources changed following mountain pine beetle (Dendroctonus ponderosae Hopkins) attack and whether they affected beetle development. We compared initial concentrations of stored resources in the sapwood of whitebark pine (Pinus albicaulis Engelmann) and lodgepole pine (Pinus contorta Douglas ex. Louden) with resource concentrations one year later, in trees that were naturally attacked by beetles and trees that remained unattacked. Beetles did not select host trees based on sapwood resources there were no consistent a priori differences between attacked versus unattacked trees-but concentrations of nonstructural carbohydrate (NSC), lipids, and phosphorus declined in attacked trees, relative to initial concentrations and unattacked trees. Whitebark pine experienced greater resource declines than lodgepole pine; however, sapwood resources were not correlated with beetle success in either species. Experimental manipulation confirmed that the negative effect of beetles on sapwood and phloem NSC was not due to girdling. Instead, changes in sapwood resources were related to the percentage of sapwood with fungal blue-stain. Overall, mountain pine beetle attack affected sapwood resources, but sapwood resources did not contribute directly to beetle success; instead, sapwood resources may support colonization by beetle-vectored fungi that potentially accelerate tree mortality. Closer attention to stored resource dynamics will improve our understanding of the interaction between mountain pine beetles, fungi, and host trees, an issue that is relevant to our understanding of insect range expansion under climate change. PMID- 28028094 TI - Aggregation of Thaumatomyia glabra (Diptera: Chloropidae) Males on Iris spp. Flowers Releasing Methyl Anthranilate. AB - Aggregations of Thaumatomyia glabra (Diptera: Chloropidae) were observed on flowers of Iris pallida Lamarck (Asparagales: Iridaceae), whereas no T. glabra (Meigen) were observed on nearby Iris germanica L. flowers. Sampling of T. glabra on I. pallida flowers revealed the presence of males only. In a previous study, T. glabra males were attracted to methyl anthranilate. We found methyl anthranilate in extracts of I. pallida flowers on which T. glabra aggregated, but not in extracts of I. germanica flowers. Applying methyl anthranilate to I. germanica flowers elicited attraction of T. glabra to the flowers. This study suggests that I. pallida flowers may attract T. glabra males to aggregate because they release the known attractant, methyl anthranilate, whereas I. germanica flowers may not be attractive because they do not release methyl anthranilate. PMID- 28028095 TI - Behavioral Responses of Drosophila suzukii (Diptera: Drosophilidae) to Visual Stimuli Under Laboratory, Semifield, and Field Conditions. AB - Drosophila suzukii Matsumura (Diptera: Drosophilidae) is an invasive pest in North America and Europe that attacks soft-skinned ripening fruit such as raspberries, blackberries, and blueberries. Little is known regarding the specific cues D. suzukii utilizes to locate and select host fruit, and inconsistencies in trap performance indicate the need for the development of improved monitoring and management techniques for this insect. Our studies focused on identifying attractive visual cues for adult D. suzukii and incorporating these cues into a potential attract-and-kill tactic for D. suzukii management. We evaluated D. suzukii response to color, shape, and size-specific stimuli. For color, we evaluated 10.2-cm-diameter spheres painted black, red, purple, orange, green, yellow, blue, or white. Shape stimuli (254 cm3 surface area) included sphere, cube, pyramid, inverted pyramid, vertical or horizontal cylinder and were painted red. Size stimuli included red 2.5-, 10.2-, 15.2-, and 25.4-cm-diameter spheres. Trials were conducted under laboratory, semifield, and field conditions. For color, adults preferred black and red spheres to all other colors evaluated. Among shapes, there was no significant preference. For size, larger spheres captured significantly more D. suzukii compared with a small 2.5 cm-diameter sphere. Determining D. suzukii visual preference will aid in trapping and behaviorally based management programs. PMID- 28028096 TI - Finding Prospective Mates by the Parasitoid Wasp Urolepis rufipes (Hymenoptera: Pteromalidae). AB - Cues from emergence sites may be predictive of mating opportunities if potential mates are slow to disperse after emergence, and particularly if emergence sites are clumped, as in the solitary parasitoid wasp Urolepis rufipes Ashmead. Males emerge before females, and the present study suggests that males may use emergence sites of conspecific males to locate mates. In choice experiments, virgin males spent more time on a male-emerged host (a host from which a male had recently emerged) than on a female-emerged host. Relative to when no host was present, virgin males also marked more in the presence of a male-emerged host, but did not mark more in the presence of a female-emerged host. Females, but not other males, are known to be attracted to male marks. Unlike for males, there was no evidence that females distinguished between male-emerged and female-emerged hosts. Virgin females preferred areas where multiple males had marked over areas where a single male had marked. Such areas had more total marks, yet marks per male did not differ between aggregated and solitary males. Thus, through his own attraction to male-emerged hosts and by marking near other males a male may find and attract females, and with no apparent increase in the cost of attraction. PMID- 28028097 TI - Behavior and Survival of the Filth Fly Parasitoids Spalangia endius and Urolepis rufipes (Hymenoptera: Pteromalidae) in Response to Three Granular House Fly Baits and Components. AB - Behaviors and mortality of two filth fly parasitoid wasps, Spalangia endius Walker and Urolepis rufipes Ashmead, were tested in response to granular fly baits containing one of the three active ingredients (AI): Golden Malrin (methomyl), QuickBayt (imidacloprid), or Quikstrike (dinotefuran). Behavioral responses to each of the two components of the baits, the AIs and the fly attractant pheromone (Z)-9-tricosene, were also examined independently. Spalangia endius avoided contact with bait granules, regardless of bait type. However, when S. endius contacted bait residue, the imidacloprid bait appeared to be the least harmful of the baits for S. endius, at least in the short term. Spalangia endius was attracted to imidacloprid by itself. However, S. endius avoided (Z)-9 tricosene. In contrast to S. endius' attraction to imidacloprid, S. endius neither avoided nor was attracted to methomyl or dinotefuran. For U. rufipes, the methomyl bait appeared to be especially harmful. Urolepis rufipes avoided bait granules with imidacloprid or dinotefuran but not with methomyl, died quickly in the presence of methomyl bait residue, and had a methomyl LC50 that was lower than that for S. endius The avoidance by U. rufipes of granules with imidacloprid or dinotefuran appears to be related to components other than the AIs or the (Z) 9-tricosene because U. rufipes did not avoid either individually. The behavioral avoidance of the parasitoids in the present study occurred despite no exposure recently, if ever, to these pesticides. PMID- 28028098 TI - Spatial Distribution and Coexisting Patterns of Adults and Nymphs of Tibraca limbativentris (Hemiptera: Pentatomidae) in Paddy Rice Fields. AB - The rice stem stink bug, Tibraca limbativentris Stal (Hemiptera: Pentatomidae), is a primary insect pest of paddy rice in South America. Knowledge of its spatial distribution can support sampling plans needed for timely decisions about pest control. This study aimed to investigate the spatial distribution of adults and nymphs of T. limbativentris and determine the spatial coexistence of these stages of development. Fifteen paddy rice fields were scouted once each season to estimate insect densities. Scouting was performed on regular grids with sampling points separated by ~50 m. Moran's I and semivariograms were used to determine spatial distribution patterns. Spatial coexistence of nymphs and adults was explored via spatial point process. Here, adults and nymphs had typically contrasting spatial distribution patterns within the same field; however, the frequency of aggregation was not different between these developmental stages. Adults and nymphs were aggregated in seven fields and randomly distributed in the other eight fields. Uniform distribution of adults or nymphs was not observed. The study-wide semivariogram ranges were ~40 m for adults and ~55 m for nymphs. Nymphs and adults spatially coexisted on 67% of the fields. Coexisting patterns were classified using one of the following processes: stage-independent, bidirectional attractive, unidirectional attractive, bidirectional inhibiting, or unidirectional inhibiting. The information presented herein can be important for developing sampling plans for decision-making, implementing tactics for site specific management, and monitoring areas free of T. limbativentris. PMID- 28028099 TI - Interactions Among Latitude, Nematode Parasitization, and Female Sirex nigricornis (Hymenoptera: Siricidae) Fitness. AB - Sirex nigricornis F. (Hymenoptera: Siricidae) is an innocuous pine-inhabiting woodwasp native to eastern North America, utilizing dead or dying pine trees as hosts. Although S. nigricornis F. does not cause economic damage, a closely related species, Sirex noctilio, was discovered in New York in 2004 and has continually spread throughout the northeastern United States and southern Canada, threatening the multi-billion-dollar pine timber industry of the southeastern United States and raising interest about potential interactions with native woodwasps and associated mortality agents. A non-sterilizing strain of the biological control agent, Deladenus siricidicola Bedding (Tylenchida: Neotylenchidae), was introduced along with S. noctilio but is not inhibiting the spread or establishment of S. noctilio A North American congener, Deladenus proximus Bedding, has been recently isolated from S. noctilio and shows promise as a biological control agent. To better understand the potential of D. proximus as a control agent for S. noctilio, we measured and dissected nearly 1,200 S. nigricornis females from Arkansas and Mississippi and evaluated differences among collection location with regard to nematode virulence, woodwasp body size, and egg load. Body size and egg load were related to collection location, and nematode infestation resulted in significantly smaller females who produced significantly fewer eggs. Female woodwasps, especially those collected in Arkansas, were often fully sterilized by nematodes, and a higher percent sterilization was inversely related to body size and fewer eggs. We propose field studies to test the nematode's ability to sterilize S. noctilio in the northeastern United States. PMID- 28028100 TI - Impact of Regionally Distinct Agroecosystem Communities on the Potential for Autonomous Control of the Coffee Leaf Rust. AB - Recent theoretical work suggests that two ineffective control agents can provide effective biological control when coupled together. We explore the implications of this work with the system of coffee leaf rust (CLR), caused by the fungal agent Hemileiae vastatrix, and two of its natural enemies, a fungal pathogen (Lecanicillium lecanii) and a spore predator (Mycodiplosis hemileiae). Here we report on comparative surveys of the CLR and its two natural enemies in Mexico, where the CLR has been at epidemic status since 2012, and Puerto Rico, where the CLR is present but has not reached epidemic densities. We found that the densities of the two control agents per CLR lesion is higher in Puerto Rico than in Mexico, and we hypothesize that their joint presence at higher densities is contributing to the suppression of the CLR in Puerto Rico but not in Mexico. Furthermore, we found that the presence of Azteca sericeasur, a keystone ant species that occurs in Mexico but not Puerto Rico, significantly reduces the prevalence of M. hemileiae on coffee plants. Our work provides data that allows us to hypothesize that the joint presence of these two control agents may potentially provide control of the CLR and also highlights the importance of regionally specific communities within agroecosystems, and how variation in community composition may lead to varying outcomes for biological control. Additionally, this is the first report of the presence of a potentially important biological control agent, M. hemileiae, in Latin America and the Caribbean. PMID- 28028101 TI - Field-Cage Evaluation of Survival, Reproduction, and Feeding Behavior of Adult Scymnus coniferarum (Coleoptera: Coccinellidae), a Predator of Adelges tsugae (Hemiptera: Adelgidae). AB - The hemlock woolly adelgid, Adelges tsugae Annand, is an invasive pest of eastern (Tsuga canadensis (L.) Carriere) and Carolina hemlock (Tsuga caroliniana Engelmann) forests in the eastern United States. Scymnus (Pullus) coniferarum Crotch (Coleoptera: Coccinellidae) is a lady beetle that preys on A. tsugae in the western United States, where A. tsugae infestations on western hemlocks are not lethal. It is thought that S. coniferarum could be an important predator that helps keep A. tsugae populations from reaching damaging levels in this region. This study assesses the potential of this predator as a biological control agent for A. tsugae in the eastern United States. S. coniferarum predation, reproductive potential, and survival were evaluated in field-cages on adelgid infested T. canadensis at two sites in southwestern Virginia. Sampling was conducted between December 2012 and June 2014 to evaluate the impact of S. coniferarum on both generations of A. tsuage (sistens and progrediens). Adult S. coniferarum fed on both generations and all life stages of A. tsugae during both field trials at rates comparable to other adelgid-specific predators. Evidence of S. coniferarum oviposition was minimal, and may be attributed to low temperatures and prey availability. S. coniferarum mortality was greatest when exposed to winter temperatures at the higher elevation site in 2013, and least throughout the 2014 spring sample period. S. coniferarum demonstrated a high predation rate on A. tsugae and survived for extended periods of time at sites in southwest Virginia, indicating that this species could be an effective predator of hemlock woolly adelgid in similar climates. PMID- 28028102 TI - Parasitism and Predation on Sentinel Egg Masses of the Brown Marmorated Stink Bug (Hemiptera: Pentatomidae) in Three Vegetable Crops: Importance of Dissections for Evaluating the Impact of Native Parasitoids on an Exotic Pest. AB - We conducted a survey to examine parasitism, predation, and the species composition of native parasitoids attacking sentinel egg masses of the invasive pest, the brown marmorated stink bug, Halyomorpha halys (Stal), in bell pepper, squash, and tomato. A 2-yr survey was conducted for each crop. The species composition of parasitoids was determined for parasitoids that successfully emerged from eggs, parasitoids that were identified from dissections, and parasitoids that were found attending egg masses at the time of collection. The overall rate of brown marmorated stink bug nymphal emergence was 82.7% from laboratory-reared control egg masses compared with only 23.4% from sentinel egg masses due to a combination of predation, parasitism, and unknown mortality causes. Overall, 12.4% of sentinel eggs were parasitized. Parasitoids emerged successfully from only 2.3% of eggs, but they were dissected from an additional 10.1% of eggs. Telenomus podisi Ashmead was the predominant species identified from emerged parasitoids (57.4%), dissected parasitoids (90.2%), and parasitoids attending egg masses (77%). This study provides further evidence that the impact of native parasitoids on brown marmorated stink bug egg mortality may be greatly underestimated based solely on parasitoid emergence rates alone. PMID- 28028103 TI - The Effect of Conservation Tillage and Cover Crop Residue on Beneficial Arthropods and Weed Seed Predation in Acorn Squash. AB - Conservation tillage combined with cover crops or mulching may enhance natural enemy activity in agroecosystems by reducing soil disturbance and increasing habitat structural complexity. In particular, weed seed predation can increase with vegetation cover and reduced tillage, indicating that mulches may improve the quality of the habitat for weed seed foraging. The purpose of this study was to quantify the effects of tillage and mulching for conservation biological control in cucurbit fields. The effects of mulch and reduced tillage on arthropods and rates of weed seed loss from arenas were examined in field trials on sandy soils in 2014 and 2015. Experimental factors included tillage and cover crop, each with two levels: strip-tillage or full-tillage, and cover crop mulch (rye residue) or no cover crop mulch (unmulched). Arthropod abundance on the crop foliage was not affected by tillage or cover crops. Contrary to expectations, epigeal natural enemies of insects and rates of weed seed removal either did not respond to treatments or were greater in full-tilled plots and plots without mulch. Our study demonstrates the potential importance of weed seed predators in reducing weed seedbanks in vegetable agroecosystems, and suggests that early season tillage may not be detrimental to epigeal predator assemblages. PMID- 28028104 TI - Comparison of Leg Regeneration Potency Between Holometabolous Helicoverpa armigera (Lepidoptera: Noctuidae) and Hemimetabolous Locusta migratoria manilensis (Orthoptera: Acrididae). AB - After injury many insects could regenerate lost limb. In this study, Helicoverpa armigera Hubner and Locusta migratoria manilensis (Meyen, 1835) were chosen to compare the regeneration potency of holometabolous and hemimetabolous insects. We employed the classical approach of surgical excision to verify the regeneration ability and to investigate the factors that affect the extent of regeneration. The results found that H. armigera could regenerate intact legs when the larval legs were excised at the first and second instar and that legs of adult H. armigera had a close relationship with their larval counterparts. However, the adult legs became malformed or disappeared when excised at other older instars. For the L. migratoria, we found the legs have weak partial regeneration ability when amputation was conducted at the joint of two segments. The regeneration potency might be stronger the more proximal the operation. Regeneration process had a negative impact on the larval development. This is the first report of complete leg regeneration capacity having a strong correlation with the instar but not with the position where amputation occurred for H. armigera, while for the L. migratoria, partial regenerative ability had a close relationship with the position where amputation occurred but not with instars. PMID- 28028105 TI - Flight Period of Mountain Pine Beetle (Coleoptera: Curculionidae) in its Recently Expanded Range. AB - The ability to predict key phenological events, such as the timing of flight periods, is useful for the monitoring and management of insect pests. We used empirical data to describe the flight period of mountain pine beetle, Dendroctonus ponderosae Hopkins, in its recently expanded range east of the Rocky Mountains in Canada and developed a degree-day model based on the number of trapped beetles. Data were collected over four degrees of latitude and six years. The main flight period, when the middle 70% of the total number of beetles were caught, started during the second or third week of July, lasted 26 d, and peaked within 2 wk of starting. The best model accounted for 89% of the variation in the data. Mountain pine beetle's flight tended to start later and be more contracted at higher latitudes. The synchrony of mountain pine beetle's flight period in the expanded range appears to be comparable to the limited reports from the historic range, although it may start earlier. This suggests that conditions in the new range are suitable for a coordinated dispersal flight, which is critical for the beetle's strategy of overwhelming tree defenses by attacking en masse. Forest managers can use the model to support operational decisions, e.g., when to impose hauling restrictions to reduce the risk of spread through the transport of infested material, or the time frame for control programs. Understanding the flight period may also improve our ability to assess the response of mountain pine beetle to novel and changing climates in the future. PMID- 28028106 TI - Imaginal Feeding for Progression of Diapause Phenotype in the Two-Spotted Spider Mite (Acari: Tetranychidae). AB - Adult females of the two-spotted spider mite (Tetranychus urticae Koch) enter diapause under conditions of short-day length and low temperature. A conspicuous body color change, from greenish yellow to bright orange, accompanies diapause induction. This pigmentation is attributed to accumulation of keto-carotenoids produced internally from beta-carotene, which is a precursor of vitamin A essential for inducing diapause. The quantity of beta-carotene transferred from females to eggs has been considered sufficient to induce diapause. Moreover, carotenoid biosynthesis genes were recently found in this mite. Therefore, imaginal feeding is not likely to be necessary to progress to diapause. In contrast, diapause-induced adult females have been known to feed between the last molt and the time of body color changes. Consequently, the function of imaginal feeding in diapause-induced females was largely unknown. We aimed to clarify whether imaginal feeding was essential to enter diapause. First, we verified that body color change occurred in connection with the feeding behavior, and also verified the change in the composition of carotenoids in diapausing females. Subsequently, we tested the effects of restraints on feeding after molting on carotenoid composition and diapausing rates. Body color change required imaginal feeding. Fed, but not unfed, females accumulated astaxanthin. Moreover, starvation reduced diapausing rates. We concluded that imaginal feeding between the last molt and the time of body color change was necessary to progress to the diapausing phenotype and that starvation at the adult stage reduced the percentage of adults entering reproductive diapause. PMID- 28028107 TI - Body Size in Males of the Ant Lasius niger (Hymenoptera: Formicidae) Along a Metal Pollution Gradient. AB - Environmental stress can lead to a decrease in the body size of insects. As social insects, ants have a complex caste system; each caste has its own morphological traits and functions in the colony, hence the effects of stress may manifest differentially among different ant castes. Here we investigated the body size of males of the common garden ant, Lasius niger L., 1758, living in a postmining area polluted mainly by Zn, Cd, and Pb. We examined if individual body size decreases with the pollution gradient. The ants were sampled from 39 wild colonies originating from 17 sites located along the metal pollution gradient; head width was used as the estimator of body size. We failed to show a significant correlation between pollution and male body size, indicating no direct effect of pollution on the body size of males of the investigated ant. However, we found a significant dependence with the colony of origin, which is in line with a previous study performed on this species in unpolluted sites. These results further strengthen a general conclusion that morphological traits in ants, such as body size or fluctuating asymmetry, are relatively invariable and stable across gradients of metal pollution. PMID- 28028108 TI - Erratum. PMID- 28028114 TI - Distinct GATA1 Point Mutations in Monozygotic Twins With Down Syndrome and Transient Abnormal Myelopoiesis From a Triplet Pregnancy: A Case Report and Review of Literature. AB - OBJECTIVES: Down syndrome (DS)-associated transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL) in monozygotic twins is exceedingly rare and has not been well characterized. METHODS: We describe a unique case of monozygotic twins with simultaneous TAM from a triplet pregnancy at 34 weeks' gestation. Previously reported cases of TAM and DS-AMKL in monozygotic twins have been reviewed to compare with our cases. The current concept of a sequential multistep process in leukemogenesis and disease evolution of TAM into DS-AMKL through the collaboration among trisomy 21, GATA1, and other gene mutations is also reviewed. RESULTS: Distinct GATA1 mutations are identified in our neonate twins with TAM from a triplet pregnancy, whereas precisely identical GATA1 mutations have been detected in all three monozygotic DS twins reported in the literature. CONCLUSIONS: Identical GATA1 mutations in cases of monozygotic twins are likely derived from twin-twin transmission. Distinct GATA1 mutations identified in our neonate twins with TAM provide unequivocal evidence of independent intra-utero GATA1 mutations, a completely different mechanism of development of TAM in monozygotic twins from previously reported cases. Interaction of trisomy 21 and GATA1 mutation produces TAM, but additional gene mutations are required for TAM to transform into DS-AMKL. PMID- 28028115 TI - Epidemiologic Analysis of Respiratory Viral Infections Mainly in Hospitalized Children and Adults in a Midwest University Medical Center After the Implementation of a 14-Virus Multiplex Nucleic Acid Amplification Test. AB - Objectives: To investigate the etiology of viral respiratory tract infections mainly in hospitalized children and adults over a 12-month consecutive period after implementation of a 14-virus multiplex nucleic acid amplification test. Methods: From January 2014 to January 2015, a total of 2,237 respiratory samples were analyzed with the US Food and Drug Administration-cleared eSensor Respiratory Viral Panel (GenMark Diagnostics, Carlsbad, CA). Results: Of the 2,237 specimens tested, 788 specimens were positive for at least one virus, giving a positivity rate of 35.2%, and because of viral codetection, a total of 862 viral targets were identified. The age groups with the highest positivity rates were the 0- to 1-year (73.5%) and 2- to 6-year (78.4%) age groups. The overall viral codetection rate was 9.1%. Human rhinovirus (HRV) was the most prevalent respiratory virus found in children and adults. The peak of HRV seen in September 2014 represented a combination of HRV and enterovirus D68, 2014 epidemic respiratory infections. Conclusion: The ability to detect a wider range of respiratory viruses gave us a better understanding of the etiology of respiratory infections in our population, particularly for HRV and enhanced our ability to detect viral coinfection. PMID- 28028116 TI - Measures of Completeness and Accuracy of Clinical Information in Skin Biopsy Requisition Forms: An Analysis of 249 Cases. AB - OBJECTIVES: To define indices of completeness and accuracy of clinical information in the skin biopsy requisition form (RF) and correlate them with health care delivery outcomes and pathology service utilization. METHODS: RFs in our pathology information system were reviewed and assessed for the presence of 10 clinical elements considered critical for dermatopathologic diagnosis. Accuracy was determined by reviewing corresponding clinical notes. RESULTS: In total, 249 RFs were reviewed. In inflammatory dermatoses, provision of a clinical impression, provision of more than two elements, and achieving more than 75% accuracy were associated with improved outcomes and decreased utilization. For all nonlymphoproliferative cases, higher quality clinical information was associated with decreased turnaround time (P < .001). More clinical information was associated with increased utilization and turnaround time (P = .0235) for lymphoproliferative cases and higher resampling rates for melanocytic lesions (P = .0066). CONCLUSIONS: In inflammatory dermatoses, providing high-quality clinical information on the RF promotes optimal histopathologic diagnostic performance and appropriate pathology service utilization. PMID- 28028117 TI - Standard Operating Procedure Utilization for Tuberculosis Microscopy in Mekelle City, North Ethiopia. AB - Objectives: The aim of this study was to assess the utilization of standard operating procedures for acid-fast bacilli (AFB) smear microscopy. Methods: A facility-based cross-sectional study was conducted in select health institutions in Mekelle City, Ethiopia, from July 1, 2015, through August 30, 2015. Using a simple random sampling technique, 18 health facilities were included in the study. Data were collected using a standard checklist and entered into Epi Info version 3.5.4 (Centers for Disease Control and Prevention, Atlanta, GA) for editing. Analysis was done using SPSS version 20 (SPSS, Chicago, IL). Results: Of the 18 laboratory facilities, only seven (38.9%) had a legible AFB registration book. In three (16.7%) of the laboratories, heat fixation was not applied before adding primary staining reagent. In 12 (66.7%), the staining reagents had precipitates. Two laboratories had microscopes with mechanical stages that could not move freely on both axes. Seven (38.9%) of the laboratories reported samples to be negative before examining all required fields. Most laboratories, 16 (88.9%) and 17 (94.4%), respectively, did not run positive and negative controls after new batch reagent preparation. Conclusions: Tuberculosis microscopy was found to be substandard with clear gaps in documentation, sample collection, and processing. PMID- 28028118 TI - Rapid Evaluation of Platelet Function With T2 Magnetic Resonance. AB - OBJECTIVES: The clinical diagnosis of qualitative platelet disorders (QPDs) based on light transmission aggregometry (LTA) requires significant blood volume, time, and expertise, all of which can be barriers to utilization in some populations and settings. Our objective was to develop a more rapid assay of platelet function by measuring platelet-mediated clot contraction in small volumes (35 uL) of whole blood using T2 magnetic resonance (T2MR). METHODS: We established normal ranges for platelet-mediated clot contraction using T2MR, used these ranges to study patients with known platelet dysfunction, and then evaluated agreement between T2MR and LTA with arachidonic acid, adenosine diphosphate, epinephrine, and thrombin receptor activator peptide. RESULTS: Blood from 21 healthy donors was studied. T2MR showed 100% agreement with LTA with each of the four agonists and their cognate inhibitors tested. T2MR successfully detected abnormalities in each of seven patients with known QPDs, with the exception of one patient with a novel mutation leading to Hermansky-Pudlak syndrome. T2MR appeared to detect platelet function at similar or lower platelet counts than LTA. CONCLUSIONS: T2MR may provide a clinically useful approach to diagnose QPDs using small volumes of whole blood, while also providing new insight into platelet biology not evident using plasma-based platelet aggregation tests. PMID- 28028119 TI - Inactivating Mutations of RB1 and TP53 Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors. AB - OBJECTIVES: Loss-of-function mutations in TP53 and CDKN2A have been found at varying frequencies in gastrointestinal stromal tumors (GISTs), while no mutations of RB1 have been reported to date. The aim of the current study was to determine the mutation frequency of TP53, RB1, and CDKN2A in GISTs. METHODS: A cohort of 83 primary untreated GISTs was analyzed for mutations in TP53, RB1, and CDKN2A by massive parallel sequencing. Tumors with mutations in TP53 and RB1 were analyzed by fluorescence in situ hybridization for the corresponding gene loci. RESULTS: Two GISTs harbored inactivating mutations in RB1, and two other GISTs displayed inactivating mutations in TP53 All four tumors were KIT mutant high risk tumors with highly cellular sarcomatous histomorphology and variable combinations of plump spindle cells to epithelioid highly atypical cells and high mitotic activity. Three of these patients developed recurrent or metastatic disease, while the fourth patient showed tumor rupture intraoperatively. The combined overall frequency of TP53 and RB1 mutations was 13% considering high risk or malignant GISTs. CONCLUSIONS: TP53 and RB1 mutations seem to be restricted to high-risk/malignant GISTs and occur at an equal although relatively low frequency. PMID- 28028120 TI - CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma. AB - OBJECTIVES: Mantle cell lymphoma (MCL) may present de novo or undergo progression to a clinically aggressive variant, known as a blastoid or pleomorphic variant. We report an unusual case of classic MCL in a 78-year-old man with a typical immunophenotype, including CD5 positivity, who subsequently relapsed with CD5 negative pleomorphic variant MCL. METHODS: Biopsy specimens were evaluated using Wright-Giemsa-stained or H&E-stained sections, flow cytometry, immunohistochemistry, conventional cytogenetic, next-generation sequencing, and fluorescence in situ hybridization. RESULTS: The patient continued to be refractory to intensive chemotherapy and radiation therapy. Initial conventional cytogenetic analysis showed a complex karyotype with amplification of the CCND1 IGH fusion gene on the der(14): 44, Y, t(X;2)(p22.3;q21), del(2)(p21), del(6)(p23), add(7)(p22),-9, del(9)(p22), add(11)(q13),-13, add(14)(p11.2), der(14)t(11;14)(q13;q32)hsr(14)(q32), add(18)(q23), add(21)(p11.1),-22,+mar[12]. A repeat biopsy revealed MCL, pleomorphic variant, with loss of CD5 expression and extra copies of the MYC CONCLUSIONS: CCND1-IGH fusion-amplification with MYC copy number gain is extremely rare and may play a role in disease progression in a subset of MCL cases. PMID- 28028122 TI - Evolution of Chemosensory Gene Families in Arthropods: Insight from the First Inclusive Comparative Transcriptome Analysis across Spider Appendages. AB - Unlike hexapods and vertebrates, in chelicerates, knowledge of the specific molecules involved in chemoreception comes exclusively from the comparative analysis of genome sequences. Indeed, the genomes of mites, ticks and spiders contain several genes encoding homologs of some insect membrane receptors and small soluble chemosensory proteins. Here, we conducted for the first time a comprehensive comparative RNA-Seq analysis across different body structures of a chelicerate: the nocturnal wandering hunter spider Dysdera silvatica Schmidt 1981. Specifically, we obtained the complete transcriptome of this species as well as the specific expression profile in the first pair of legs and the palps, which are thought to be the specific olfactory appendages in spiders, and in the remaining legs, which also have hairs that have been morphologically identified as chemosensory. We identified several ionotropic (Ir) and gustatory (Gr) receptor family members exclusively or differentially expressed across transcriptomes, some exhibiting a distinctive pattern in the putative olfactory appendages. Furthermore, these IRs were the only known olfactory receptors identified in such structures. These results, integrated with an extensive phylogenetic analysis across arthropods, uncover a specialization of the chemosensory gene repertoire across the body of D. silvatica and suggest that some IRs likely mediate olfactory signaling in chelicerates. Noticeably, we detected the expression of a gene family distantly related to insect odorant binding proteins (OBPs), suggesting that this gene family is more ancient than previously believed, as well as the expression of an uncharacterized gene family encoding small globular secreted proteins, which appears to be a good chemosensory gene family candidate. PMID- 28028125 TI - CALCULATION OF FLUENCE-TO-EFFECTIVE DOSE CONVERSION COEFFICIENTS FOR THE OPERATIONAL QUANTITY PROPOSED BY ICRU RC26. AB - Fluence-to-effective dose conversion coefficients have been calculated for photons, neutrons, electrons, positrons, protons, muons, pions and helium ions for various incident angles of radiations. The aim of this calculation is to provide a set of conversion coefficients to the Report Committee 26 (RC26) of the International Commission on Radiation Units and Measurements (ICRU) for use in defining personal dose equivalent for individual monitoring. The data sets comprise effective dose conversion coefficients for incident angles of radiations from 0 degrees to +/-90 degrees in steps of 15 degrees and at +/-180 degrees . Conversion coefficients for rotational, isotropic, superior hemisphere semi isotropic and inferior hemisphere semi-isotropic irradiations are also included. Numerical data of the conversion coefficients are presented as supplementary data. The conversion coefficients are used to define the personal dose equivalent, which is being considered by the ICRU RC26, as the operational quantity for individual monitoring. PMID- 28028124 TI - Characterizing Gemcitabine Effects Administered as Single Agent or Combined with Carboplatin in Mice Pancreatic and Ovarian Cancer Xenografts: A Semimechanistic Pharmacokinetic/Pharmacodynamics Tumor Growth-Response Model. AB - In this work, a semimechanistic tumor growth-response model for gemcitabine in pancreatic (administered as single agent) and ovarian (given as single agent and in combination with carboplatin) cancer in mice was developed. Tumor profiles were obtained from nude mice, previously inoculated with KP4, ASPC1, MIA PACA2, PANC1 (pancreas), A2780, or SKOV3*luc (ovarian) cell lines, and then treated with different dosing schedules of gemcitabine and/or carboplatin. Data were fitted using the population approach with Nonlinear Mixed Effect Models 7.2. In addition to cell proliferation, the tumor progression model for both types of cancer incorporates a carrying capacity representing metabolite pool for DNA synthesis required to tumor growth. Analysis of data from the treated groups revealed that gemcitabine exerted its tumor effects by promoting apoptosis as well as decreasing the carrying capacity compartment. Pharmacodynamic parameters were cell-specific and overall had similar range values between cancer types. In pancreas, a linear model was used to describe both gemcitabine effects with parameter values between 3.26 * 10-2 and 4.2 * 10-1 L/(mg * d). In ovarian cancer, the apoptotic effect was driven by an EMAX model with an efficacy/potency ratio of 5.25-8.65 L/(mg * d). The contribution of carboplatin to tumor effects was lower than the response exerted by gemcitabine and was incorporated in the model as an inhibition of the carrying capacity. The model developed was consistent in its structure across different tumor cell lines and two tumor types where gemcitabine is approved. Simulation-based evaluation diagnostics showed that the model performed well in all experimental design scenarios, including dose, schedule, and tumor type. PMID- 28028126 TI - Susan Lindquist: Visionary scientist and peerless mentor. AB - The science universe is dimmer after one of our brightest stars, Susan Lee Lindquist, was taken by cancer on October 27, 2016. Sue was an innovative, creative, out-of-the-box scientific thinker. She had unique biological intuition an instinct for both the way things worked and the right questions to ask to uncover new research insights. Her wide-ranging career began with the study of protein folding and molecular chaperones, and she went on to show that protein folding can have profound and unexpected biological effects on such diverse processes as cancer, evolution, and neurodegenerative disease. As Sue's laboratory manager, I would like to offer a ground-floor perspective on what made her an exceptional scientist, mentor, and leader. She created a harmonious, collegial environment where collaborative synergy fueled meaningful progress that will impact science for decades to come. PMID- 28028128 TI - Association Between School-Level Prevalence of Electronic Cigarette Use and Student-Level Use Behaviors, Pre-Use Intentions, and Risk Perceptions: Evidence From the 2014 US National Youth Tobacco Survey. AB - Background: Adolescent electronic cigarette ("e-cigarette") use tripled in recent years, yet little is known about the school-level correlates of teenage e cigarette use, harm and risk perceptions, or pre-use intentions to use. Methods: Multilevel regression and 2014 National Youth Tobacco Survey data were used to assess school-level e-cigarette prevalence and person-level e-cigarette use as well as age at initiation and frequency of use (among initiates), expectations for future use (among abstainers), and perceived e-cigarette addictivity and harm. Results: Lifetime use was higher among students in medium- (odds ratio [OR] = 2.30, 95% confidence interval [CI] = 1.82, 2.89) and high- (OR = 4.66, 95% CI = 3.67, 5.90) versus low-use schools. Past 30-day use followed a similar pattern. Multilevel ordinal logistic models revealed that initiates from high-use schools reported more days of use in the past month (OR = 2.25, 95% CI = 1.52, 3.33) and higher age-at-first-use (OR = 1.45, 95% CI = 1.08, 2.00) than students at low-use schools. Expectations for future use were higher among abstainers from medium- and high- versus low-use schools, and among all students, perceived addictivity and harm caused by e-cigarettes were lower in medium- and high- versus low-use schools. Conclusion: School context is associated with multiple dimensions of e cigarette use, pre-use intentions, and perceptions of e-cigarette health risks. Implications: The current study demonstrates a link between school prevalence of e-cigarette use and student-level use, as well as perceived risks of e-cigarette use, age of initiation and frequency of use among users, and intentions to use among abstainers. Health communication and prevention initiatives should target school social environments to promote nicotine abstinence and a culture of health. PMID- 28028123 TI - Exploring cells with targeted biosensors. AB - Cellular signaling networks are composed of multiple pathways, often interconnected, that form complex networks with great potential for cross-talk. Signal decoding depends on the nature of the message as well as its amplitude, temporal pattern, and spatial distribution. In addition, the existence of membrane-bound organelles, which are both targets and generators of messages, add further complexity to the system. The availability of sensors that can localize to specific compartments in live cells and monitor their targets with high spatial and temporal resolution is thus crucial for a better understanding of cell pathophysiology. For this reason, over the last four decades, a variety of strategies have been developed, not only to generate novel and more sensitive probes for ions, metabolites, and enzymatic activity, but also to selectively deliver these sensors to specific intracellular compartments. In this review, we summarize the principles that have been used to target organic or protein sensors to different cellular compartments and their application to cellular signaling. PMID- 28028127 TI - Myofibrillar Z-discs Are a Protein Phosphorylation Hot Spot with Protein Kinase C (PKCalpha) Modulating Protein Dynamics. AB - The Z-disc is a protein-rich structure critically important for the development and integrity of myofibrils, which are the contractile organelles of cross striated muscle cells. We here used mouse C2C12 myoblast, which were differentiated into myotubes, followed by electrical pulse stimulation (EPS) to generate contracting myotubes comprising mature Z-discs. Using a quantitative proteomics approach, we found significant changes in the relative abundance of 387 proteins in myoblasts versus differentiated myotubes, reflecting the drastic phenotypic conversion of these cells during myogenesis. Interestingly, EPS of differentiated myotubes to induce Z-disc assembly and maturation resulted in increased levels of proteins involved in ATP synthesis, presumably to fulfill the higher energy demand of contracting myotubes. Because an important role of the Z disc for signal integration and transduction was recently suggested, its precise phosphorylation landscape further warranted in-depth analysis. We therefore established, by global phosphoproteomics of EPS-treated contracting myotubes, a comprehensive site-resolved protein phosphorylation map of the Z-disc and found that it is a phosphorylation hotspot in skeletal myocytes, underscoring its functions in signaling and disease-related processes. In an illustrative fashion, we analyzed the actin-binding multiadaptor protein filamin C (FLNc), which is essential for Z-disc assembly and maintenance, and found that PKCalpha phosphorylation at distinct serine residues in its hinge 2 region prevents its cleavage at an adjacent tyrosine residue by calpain 1. Fluorescence recovery after photobleaching experiments indicated that this phosphorylation modulates FLNc dynamics. Moreover, FLNc lacking the cleaved Ig-like domain 24 exhibited remarkably fast kinetics and exceedingly high mobility. Our data set provides research community resource for further identification of kinase-mediated changes in myofibrillar protein interactions, kinetics, and mobility that will greatly advance our understanding of Z-disc dynamics and signaling. PMID- 28028129 TI - Long-term outcomes after carbon-ion radiotherapy for oral mucosal malignant melanoma. AB - Oral mucosal malignant melanoma (OMM) is extremely rare and has a poor prognosis. Owing to its rarity, it has not yet been possible to establish an optimal treatment modality. The objective of this study was to evaluate the long-term efficacy of carbon-ion radiotherapy (C-ion RT) for OMM. Between 1997 and 2013, 19 patients with OMM were treated with C-ion RT alone. Patient ages ranged from 44 to 84 years (median, 69 years). Nine men and 10 women were included. OMMs were restaged in accordance with the seventh edition of the tumour/node/metastasis (TNM) Staging System of the International Union Against Cancer. Before treatment, 14 patients had T3 disease and 5 had T4a disease. Three patients were classified as having N1 disease. All patients were classified as having M0. The hard palate was the most frequently involved oral subsite. All patients were treated with 57.6 Gy (relative biological effectiveness) in 16 fractions. The median follow-up period was 61 months (range, 8-190 months). The 5-year local control, overall survival and progression-free survival rates were 89.5%, 57.4% and 51.6%, respectively. For local control and overall survival, T classification was found to be a significant prognostic factor. Grade 2 and 3 osteoradionecrosis was observed in three and four patients, respectively. The presence of teeth within the planning target volume was a significant risk factor for developing osteoradionecrosis. C-ion RT was an effective treatment option with acceptable toxicity for OMM. PMID- 28028130 TI - Does tax-based health financing offer protection from financial catastrophe? Findings from a household economic impact survey of ischaemic heart disease in Malaysia. AB - BACKGROUND: Malaysia is an upper-middle income country with a tax-based health financing system. Health care is relatively affordable, and safety nets are provided for the needy. The objectives of this study were to determine the out-of pocket health spending, proportion of catastrophic health spending (out-of-pocket spending >40% of non-food expenditure), economic hardship and financial coping strategies among patients with ischaemic heart disease (IHD) in Malaysia under the present health financing system. METHODS: A cross-sectional study was conducted at the National Heart Institute of Malaysia involving 503 patients who were hospitalized during the year prior to the survey. RESULTS: The mean annual out-of-pocket health spending for IHD was MYR3045 (at the time US$761). Almost 16% (79/503) suffered from catastrophic health spending (out-of-pocket health spending >=40% of household non-food expenditures), 29.2% (147/503) were unable to pay for medical bills, 25.0% (126/503) withdrew savings to help meet living expenses, 16.5% (83/503) reduced their monthly food consumption, 12.5% (63/503) were unable to pay utility bills and 9.0% (45/503) borrowed money to help meet living expenses. CONCLUSIONS: Overall, the economic impact of IHD on patients in Malaysia was considerable and the prospect of economic hardship likely to persist over the years due to the long-standing nature of IHD. The findings highlight the need to evaluate the present health financing system in Malaysia and to expand its safety net coverage for vulnerable patients. PMID- 28028131 TI - Treasurer's Report for Financial Year (FY) 2015: Prepared by Juliette de Meaux, SMBE Treasurer. PMID- 28028133 TI - Retraction. PMID- 28028132 TI - Novel Candidate Genes Underlying Extreme Trophic Specialization in Caribbean Pupfishes. AB - The genetic changes responsible for evolutionary transitions from generalist to specialist phenotypes are poorly understood. Here we examine the genetic basis of craniofacial traits enabling novel trophic specialization in a sympatric radiation of Cyprinodon pupfishes endemic to San Salvador Island, Bahamas. This recent radiation consists of a generalist species and two novel specialists: a small-jawed "snail-eater" and a large-jawed "scale-eater." We genotyped 12 million single nucleotide polymorphisms (SNPs) by whole-genome resequencing of 37 individuals of all three species from nine populations and integrated genome-wide divergence scans with association mapping to identify divergent regions containing putatively causal SNPs affecting jaw size-the most rapidly diversifying trait in this radiation. A mere 22 fixed variants accompanied extreme ecological divergence between generalist and scale-eater species. We identified 31 regions (20 kb) containing variants fixed between specialists that were significantly associated with variation in jaw size which contained 11 genes annotated for skeletal system effects and 18 novel candidate genes never previously associated with craniofacial phenotypes. Six of these 31 regions showed robust signs of hard selective sweeps after accounting for demographic history. Our data are consistent with predictions based on quantitative genetic models of adaptation, suggesting that the effect sizes of regions influencing jaw phenotypes are positively correlated with distance between fitness peaks on a complex adaptive landscape. PMID- 28028134 TI - Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness. AB - Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort (n=131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients. PMID- 28028136 TI - HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy. AB - Idiopathic membranous nephropathy (MN) is associated with HLA; however, the HLA allele involved remains unknown. To identify the HLA risk alleles associated with phospholipase A2 receptor (PLA2R)-related MN in the Chinese population, we sequenced the entire MHC region in DNA samples from 99 patients with PLA2R related MN, 50 patients with PLA2R-unrelated MN, and 100 healthy subjects. Two HLA risk alleles, HLA-DRB1*15:01 and HLA-DRB3*02:02, independently and strongly associated with an increased risk of PLA2R-related MN. After adjusting for HLA DRB1*15:01 and HLA-DRB3*02:02, no other alleles showed significant association with PLA2R-related MN. A replication study in an independent cohort of 293 participants with PLA2R-related MN and 285 healthy controls validated these findings. In a joint analysis, a multivariate logistic regression model confirmed that HLA-DRB1*15:01 (odds ratio [OR], 24.9; 95% confidence interval [95% CI], 15.3 to 42.6; P=2.3*10-35) and HLA-DRB3*02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P=8.0*10-29) independently and strongly associated with PLA2R-related MN. As many as 98.7% of patients with PLA2R-related MN, compared with 43.9% of control subjects, carried at least one HLA risk allele. Subjects with either risk allele had higher odds of developing PLA2R-related MN than those without a risk allele (OR, 98.9; 95% CI, 44.4 to 281.7; P=2.5*10-23). These HLA risk alleles also associated with the age at disease onset in patients with PLA2R-related MN. In conclusion, our findings provide clear evidence that the HLA-DRB1*15:01 and HLA DRB3*02:02 alleles independently and strongly associate with PLA2R-related MN in the Chinese population. PMID- 28028135 TI - Unique Transcriptional Programs Identify Subtypes of AKI. AB - Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function. PMID- 28028137 TI - Diversification of Cell Lineages in Ureter Development. AB - The mammalian ureter consists of a mesenchymal wall composed of smooth muscle cells and surrounding fibrocytes of the tunica adventitia and the lamina propria and an inner epithelial lining composed of layers of basal, intermediate, and superficial cells. How these cell types arise from multipotent progenitors is poorly understood. Here, we performed marker analysis, cell proliferation assays, and genetic lineage tracing to define the lineage relations and restrictions of the mesenchymal and epithelial cell types in the developing and mature mouse ureter. At embryonic day (E) 12.5, the mesenchymal precursor pool began to subdivide into an inner and outer compartment that began to express markers of smooth muscle precursors and adventitial fibrocytes, respectively, by E13.5. Smooth muscle precursors further diversified into lamina propria cells directly adjacent to the ureteric epithelium and differentiated smooth muscle cells from E16.5 onwards. Uncommitted epithelial progenitors of the ureter differentiated into intermediate cells at E14.5. After stratification into two layers at E15.5 and three cell layers at E18.5, intermediate cells differentiated into basal cells and superficial cells. In homeostasis, proliferation of all epithelial and mesenchymal cell types remained low but intermediate cells still gave rise to basal cells, whereas basal cells divided only into basal cells. These studies provide a framework to further determine the molecular mechanisms of cell differentiation in the tissues of the developing ureter. PMID- 28028138 TI - Prevalence and Diversity of Tick-Borne Pathogens in Nymphal Ixodes scapularis (Acari: Ixodidae) in Eastern National Parks. AB - Tick-borne pathogens transmitted by Ixodes scapularis Say (Acari: Ixodidae), also known as the deer tick or blacklegged tick, are increasing in incidence and geographic distribution in the United States. We examined the risk of tick-borne disease exposure in 9 national parks across six Northeastern and Mid-Atlantic States and the District of Columbia in 2014 and 2015. To assess the recreational risk to park visitors, we sampled for ticks along frequently used trails and calculated the density of I. scapularis nymphs (DON) and the density of infected nymphs (DIN). We determined the nymphal infection prevalence of I. scapularis with a suite of tick-borne pathogens including Borrelia burgdorferi, Borrelia miyamotoi, Anaplasma phagocytophilum, and Babesia microti. Ixodes scapularis nymphs were found in all national park units; DON ranged from 0.40 to 13.73 nymphs per 100 m2. Borrelia burgdorferi, the causative agent of Lyme disease, was found at all sites where I. scapularis was documented; DIN with B. burgdorferi ranged from 0.06 to 5.71 nymphs per 100 m2. Borrelia miyamotoi and A. phagocytophilum were documented at 60% and 70% of the parks, respectively, while Ba. microti occurred at just 20% of the parks. Ixodes scapularis is well established across much of the Northeastern and Mid-Atlantic States, and our results are generally consistent with previous studies conducted near the areas we sampled. Newly established I. scapularis populations were documented in two locations: Washington, D.C. (Rock Creek Park) and Greene County, Virginia (Shenandoah National Park). This research demonstrates the potential risk of tick borne pathogen exposure in national parks and can be used to educate park visitors about the importance of preventative actions to minimize tick exposure. PMID- 28028139 TI - Relationships Between Maternal Engorgement Weight and the Number, Size, and Fat Content of Larval Ixodes scapularis (Acari: Ixodidae). AB - The relationship between engorgement weight of female Ixodes scapularis Say and characteristics of offspring was studied using field-collected females fed on rabbits in the laboratory. The number of eggs laid was positively related to maternal engorgement weight in one trial, and larval size (estimated by scutal area) was positively related to maternal engorgement weight in the other. These results suggest a trade-off in number of eggs produced versus average size of offspring, possibly determined during late engorgement. The adults for the two trials were collected from different sites in southern Rhode Island and in different seasons (the fall adults were newly emerged, while the spring adults had presumably lived through the winter), so it is not clear whether these results reflect genetic differences or subtle environmental differences between trials. Percent egg hatch and average fat content of larvae were not related to female engorgement weight. We present a modified method to measure lipid content of pooled larval ticks. PMID- 28028140 TI - Comparative Evaluation of a Silicone Membrane as an Alternative to Skin for Testing Mosquito Repellents. AB - Repellents prevent mosquito bites and help reduce mosquito-borne disease, a global public health issue. Laboratory-based repellent bioassays predict the ability of compounds to deter mosquito feeding, but the variety of repellent bioassays and statistical analysis methods makes it difficult to compare results across methodologies. The most realistic data are collected when repellents are applied on the skin; however, this method exposes volunteers to chemicals and mosquito bites. Silicone membranes were investigated as an alternative to human skin in assays of repellent efficacy. Results from module system bioassays conducted in vitro with a silicone membrane were compared with in vivo bioassays conducted with N,N-diethyl-3-methylbenzamide (referred to as DEET), 1 piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester (referred to as Picaridin), ethyl 3-[acetyl(butyl)amino]propanoate (referred to as IR3535), and para-menthane-3,8-diol (referred to as PMD) applied directly on the skin of the leg. No significant difference in mosquito feeding was found when comparing skin and volunteer-worn membrane controls using blood; however, feeding was significantly lower in unworn membrane controls using either 10% sucrose or blood, indicating that worn membranes are a possible surrogate for untreated human skin. Pooled data from six volunteers were used to generate dose-response curves of blood-feeding activity. Results from skin-applied repellents were modeled to determine if membranes could provide a predictive correlate for skin. Goodness-of-fit comparisons indicated that the nonlinear dose-response curves for the skin and membrane differed significantly for DEET and Picaridin, but did not differ significantly for IR3535 and PMD. With knowledge of the dose-response relationships and further modifications to this system, the membrane-based tests could be used for standardized repellent testing with infected vectors. PMID- 28028141 TI - First Records of Culicoides sonorensis (Diptera: Ceratopogonidae), a Known Vector of Bluetongue Virus, in Southern Ontario. AB - Ceratopogonidae (Diptera) were collected on sheep farms in southern Ontario to establish whether Culicoides spp. pose a threat to the livestock industry. Specimens were collected in modified CO2-baited Centers for Disease Control and Prevention light traps, returned to the laboratory, freeze-killed, and identified to species under a microscope. In addition to Culicoides variipennis (Coquillet), we found that Culicoides sonorensis Wirth & Jones occurred on a number of farms over a 2-yr period. These records represent a significant departure from C. sonorensis' previously known geographical distribution. We present spatial and temporal distribution data for both species, with an emphasis on C. sonorensis. DNA sequence information is presented so that researchers lacking the necessary taxonomic skills can determine whether C. sonorensis is present in their collections. To differentiate C. sonorensis from C. variipennis, taxonomically reliable and informative traits were found in EF1alpha and, to a lesser extent, in ITS1, whereas the universal barcode region of cytochrome oxidase subunit 1 (CO1) was unsuitable. PMID- 28028142 TI - Identification of Disease-Transmitting Mosquitoes: Development of Species Specific Probes for DNA Chip Assay Using Mitochondrial COI and ND2 Genes and Ribosomal Internal Transcribed Spacer 2. AB - Mosquitoes, which transmit infectious diseases, such as malaria and dengue fever, are harmful to human health. Thus, accurate and rapid identification of vectors is a critical step for the control of mosquito-borne diseases. However, phenotypic variations in adults, lack of recognizable features of the immature, and fragility of mosquitoes make identification difficult. Molecular approaches have been widely applied to identify mosquitoes, yet these methods have been focused only on the identification of a few species. This study used sequences of two mitochondrial genes, COI and ND2, and a ribosomal gene, ITS2, to design species-specific probes. Biochips thus developed were able to provide simultaneous identification of nine important medical and veterinary species, including the immature, from genera of Aedes, Anopheles, Armigeres, and Culex. This chip was also applied to samples collected from the field. Despite its inability to resolve the close affinity species of Culex quinquefasciatus and Culex pipiens molestus, pertinent biochips are expected to be applied to a mass screening method. PMID- 28028144 TI - Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction. METHODS: Rats were randomized in a 2*2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post SAH, brain tissue damage was measured with T2-weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test. RESULTS: In the groups with KCl application, lesion growth between days 1 and 3 was 57+/-73 mm3 in the valproate-treated versus 237+/-232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproate- and vehicle-treated groups was 8+/-20 mm3 versus 27+/-52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (P=0.04). Number and duration of SDs, mortality, and neurological function were not statistically significantly different between groups. Lesion growth on magnetic resonance imaging correlated to histological infarct volume (Spearman's rho =0.83; P=0.0004), with areas of lesion growth exhibiting reduced neuronal death compared with primary lesions. CONCLUSIONS: In our rat SAH model, valproate treatment significantly reduced brain lesion growth after KCl application. Future studies are needed to confirm that this protective effect is based on SD inhibition. PMID- 28028143 TI - ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke. AB - BACKGROUND AND PURPOSE: ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke. METHODS: Middle-aged male specific brain ABCA1-deficient (ABCA1-B/-B) and floxed-control (ABCA1fl/fl) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1-B/-B stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo. RESULTS: No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1fl/fl ischemic mice, ABCA1 B/-B ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1-B/-B ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-B/-B-induced deficits. In vitro, GW3965 treatment (5 MUM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. HDL treatment (80 MUg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1-B/-B embryos. CONCLUSIONS: ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke. PMID- 28028146 TI - Sex Is Not a Risk Factor in Outcome When a Stroke Unit Treats the Patient. PMID- 28028147 TI - Cannabis, Tobacco, Alcohol Use, and the Risk of Early Stroke: A Population-Based Cohort Study of 45 000 Swedish Men. AB - BACKGROUND AND PURPOSE: Current knowledge on cannabis use in relation to stroke is based almost exclusively on clinical reports. By using a population-based cohort, we aimed to find out whether there was an association between cannabis use and early-onset stroke, when accounting for the use of tobacco and alcohol. METHODS: The cohort comprises 49 321 Swedish men, born between 1949 and 1951, who were conscripted into compulsory military service between the ages of 18 and 20. All men answered 2 detailed questionnaires at conscription and were subject to examinations of physical aptitude, psychological functioning, and medical status. Information on stroke events up to ~60 years of age was obtained from national databases; this includes strokes experienced before 45 years of age. RESULTS: No associations between cannabis use in young adulthood and strokes experienced <=45 years of age or beyond were found in multivariable models: cannabis use >50 times, hazard ratios=0.93 (95% confidence interval [CI], 0.34-2.57) and 0.95 (95% CI, 0.59-1.53). Although an almost doubled risk of ischemic stroke was observed in those with cannabis use >50 times, this risk was attenuated when adjusted for tobacco usage: hazards ratio=1.47 (95% CI, 0.83-2.56). Smoking >=20 cigarettes per day was clearly associated both with strokes before 45 years of age, hazards ratio=5.04 (95% CI, 2.80-9.06), and with strokes throughout the follow-up, hazards ratio=2.15 (95% CI, 1.61-2.88). CONCLUSIONS: We found no evident association between cannabis use in young adulthood and stroke, including strokes before 45 years of age. Tobacco smoking, however, showed a clear, dose-response shaped association with stroke. PMID- 28028148 TI - Strokes Associated With Pregnancy and Puerperium: A Nationwide Study by the Japan Stroke Society. AB - BACKGROUND AND PURPOSE: The incidence and cause of strokes associated with pregnancy and the puerperium are still not fully understood. The aim of this study was to characterize pregnancy-related strokes in Japan using a large-scale survey with current imaging techniques. METHODS: A retrospective analysis was conducted based on clinical chart reviews in 736 stroke teaching hospitals certified by the Japan Stroke Society between 2012 and 2013, using a web-based questionnaire requesting the detailed clinical course without any personally identifying information. The collection rate of this questionnaire was 70.5%, with 151 pregnancy-associated strokes extracted. RESULTS: Hemorrhagic strokes were observed in 111 cases (73.5%), ischemic strokes in 37 (24.5%), and mixed type in 3 cases (2.0%). The estimated incidence of pregnancy-associated stroke was 10.2 per 100 000 deliveries. Major causes of hemorrhage were aneurysm (19.8%), arteriovenous malformation (17.1%), pregnancy-induced hypertension (11.7%), and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) (8.1%). Preexisting cerebrovascular diseases responsible for hemorrhage were detected in 59 cases (53.1%). Among the ischemic strokes, 28 (75.7%) were arterial and 9 (24.3%) were venous infarctions. The most frequent cause of arterial infarctions was reversible cerebral vasoconstriction syndrome. Hemorrhagic stroke showed much poorer prognosis than ischemic stroke. CONCLUSIONS: The incidence of pregnancy-associated stroke in Japan did not seem higher than that in other Asian and Western countries. The proportion of hemorrhagic stroke among Japanese women was much higher than that in white women. Preexisting cerebrovascular diseases and reversible cerebral vasoconstriction syndrome play a key role in hemorrhagic and ischemic stroke, respectively. PMID- 28028149 TI - Sex and Stroke in Thrombolyzed Patients and Controls. AB - BACKGROUND AND PURPOSE: We hypothesized that any sex-related difference in outcome poststroke is explained by other prognostic factors and that the response to intravenous recombinant tissue-type plasminogen activator (r-tPA) is equal in males and females after adjustment for such factors. METHODS: We accessed an independent collection of randomized clinical trials-the VISTA (Virtual International Stroke Trials Archive). Data were preprocessed by selecting complete cases (n=8028) and matching females to males (coarsened exact matching, n=4575, 24.3% r-tPA). Outcome was assessed by the 7-point modified Rankin Scale (mRS) measured at 90 days after ischemic stroke. Relationship among variables was estimated by adjusted regression analysis. RESULTS: In nonthrombolyzed patients, ordinal analysis of mRS adjusting for stroke- and sex-related prognostic factors suggested comparable outcomes for females and males (odds ratio, 0.96; 95% confidence interval, 0.85-1.06). Females responded comparably to r-tPA as did males, irrespective of the outcome definition of mRS (ordinal: PInteraction=0.46, relative excess risk because of interaction=0). The number needed to treat was 6.8 and 11.2 for 1 female to achieve mRS score of 0 to 2 and 0 to 1, which was highly congruent with males. Analysis for a nonlinear variation of age-by-sex revealed a good outcome for females <45 years with significant disadvantage thereafter (mRS score of 0-2: PInteraction=0.004). No relationship between sex, r tPA, and bleeding complications was evident. CONCLUSIONS: Functional outcome (mRS) without r-tPA was overall similar between the sexes, as was the response to r-tPA. Nonlinear sex-by-age interaction improved estimates of functional independence; this should be considered in sex-related studies in stroke. PMID- 28028150 TI - Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke: Results From the SWIFT-PRIME Trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke). AB - BACKGROUND AND PURPOSE: Clinical trials have demonstrated improved 90-day outcomes for patients with acute ischemic stroke treated with stent retriever thrombectomy plus tissue-type plasminogen activator (SST+tPA) compared with tPA. Previous studies suggested that this strategy may be cost-effective, but models were derived from pooled data and older assumptions. METHODS: In this prospective economic substudy conducted alongside the SWIFT-PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), in-trial costs were measured for patients using detailed medical resource utilization and hospital billing data. Utility weights were assessed at 30 and 90 days using the EuroQol-5 dimension questionnaire. Post-trial costs and life-expectancy were estimated for each surviving patient using a model based on trial data and inputs derived from a contemporary cohort of ischemic stroke survivors. RESULTS: Index hospitalization costs were $17 183 per patient higher for SST+tPA than for tPA ($45 761 versus $28 578; P<0.001), driven by initial procedure costs. Between discharge and 90 days, costs were $4904 per patient lower for SST+tPA than for tPA ($11 270 versus $16 174; P=0.014); total 90-day costs remained higher with SST+tPA ($57 031 versus $44 752; P<0.001). Higher utility values for SST+tPA led to higher in-trial quality-adjusted life years (0.131 versus 0.105; P=0.005). In lifetime projections, SST+tPA was associated with substantial gains in quality-adjusted life years (6.79 versus 5.05), cost savings of $23 203 per patient and was economically dominant when compared with tPA in 90% of bootstrap replicates. CONCLUSIONS: Among patients with acute ischemic stroke enrolled in the SWIFT-PRIME trial, SST increased initial treatment costs, but was projected to improve quality-adjusted life-expectancy and reduce healthcare costs over a lifetime horizon compared with tPA. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657461. PMID- 28028151 TI - LRCH1 interferes with DOCK8-Cdc42-induced T cell migration and ameliorates experimental autoimmune encephalomyelitis. AB - Directional autoreactive CD4+ T cell migration into the central nervous system plays a critical role in multiple sclerosis. Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. Little is known about whether DOCK8 is related to multiple sclerosis (MS) and how to restrict its GEF activity. Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration. In response to chemokine stimulation, PKCalpha phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration. Point mutations at the DOCK8 serine sites block chemokine- and PKCalpha-induced T cell migration. Importantly, Dock8 mutant mice or Lrch1 transgenic mice were protected from MOG (35-55) peptide-induced experimental autoimmune encephalomyelitis (EAE), whereas Lrch1-deficient mice displayed a more severe phenotype. Notably, DOCK8 expression was markedly increased in PBMCs from the acute phase of MS patients. Together, our study demonstrates LRCH1 as a novel effector to restrain PKCalpha-DOCK8-Cdc42 module-induced T cell migration and ameliorate EAE. PMID- 28028153 TI - Rheumatology post-Brexit. PMID- 28028152 TI - Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy. AB - The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90beta is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy. Inhibition of Hsp90, but not Hsp70, increased GLT-1 levels. Mechanistically, Hsp90beta recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90beta and GLT-1. Using a model of TLE, we demonstrated that long-term systemic administration of 17AAG dramatically suppressed spontaneous recurrent seizures and ameliorated astrogliosis. Overall, these results suggest that up-regulation of GLT-1 by inhibiting Hsp90beta in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity. PMID- 28028154 TI - Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. AB - OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The aim of this analysis was to characterize changes in haematological parameters following tofacitinib treatment, and to compare changes in haemoglobin with markers of disease activity, fatigue and vitality. METHODS: Changes in neutrophil counts, lymphocyte counts and haemoglobin levels were analysed in patients with RA from six phase 3 randomized controlled trials (n = 4271) of tofacitinib 5 or 10 mg bd, placebo or active comparators of up to 24 months' duration, and two long-term extension (LTE) studies (n = 4858) of tofacitinib of up to 84 months' duration. Disease activity markers included CRP and ESR. Fatigue and vitality were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Short Form Health Survey-36 vitality domain scores. RESULTS: In phase 3 studies, mean neutrophil and lymphocyte counts decreased and mean haemoglobin levels increased in all tofacitinib treatment groups. Haemoglobin levels and neutrophil counts stabilized in the LTE studies, while lymphocyte count decreases stabilized at approximately month 48. Increased haemoglobin was associated with decreased ESR and CRP levels. Clinically meaningful reductions in haemoglobin levels (?3 g/dl from baseline or haemoglobin ?7 g/dl) occurred in <1.0% of patients in all treatment groups. FACIT-F and Short Form Health Survey-36 vitality scores were weakly correlated with haemoglobin levels. CONCLUSION: Small changes in haematological parameters were seen with tofacitinib treatment, which stabilized over time in the LTE studies. Changes in haemoglobin levels, although associated with changes in ESR and CRP, were not associated with fatigue or vitality. PMID- 28028155 TI - Abatacept reduces disease activity and ultrasound power Doppler in ACPA-negative undifferentiated arthritis: a proof-of-concept clinical and imaging study. AB - OBJECTIVES: No proven treatment exists for ACPA-negative undifferentiated arthritis (UA). The aim of this study was to evaluate whether abatacept is effective in treating poor prognosis, ACPA-negative UA, including its effect on power Doppler on US (PDUS). METHODS: A proof-of-concept, open-label, prospective study of 20 patients with DMARD-naive, ACPA-negative UA (?2 joint synovitis) and PDUS ? 1 with clinical and 20-joint US (grey scale/PDUS) assessments at baseline, 6, 12, 18 and 24 months. All patients received 12 months of abatacept (monotherapy for minimum first 6 months). The primary end point was a composite of the proportion of patients that at 6 months achieved DAS44 remission, a maximum of one swollen joint for at least 3 consecutive months and no radiographic progression (over 0-12 months). RESULTS: Twenty of the 23 patients screened were enrolled [14 female; mean (sd) age 53.4 (11.2) years, symptom duration 7.5 (0.9) months]. Two (10%) achieved the composite primary end point. A reduction in the mean (sd) DAS44 was observed from a baseline value of 2.66 (0.77) to 2.01 (0.81) at 6 months and to 1.78 (0.95) at 12 months. The DAS44 remission rates were 6/20 (30%; 95% CI: 15, 51%) at 6 months and 8/20 (40%; 95% CI: 22, 62%) at 12 months. A striking decrease in the median (interquartile range; IQR) total PDUS score was noted from 10 (4-23) at baseline to 3 (2-12) and 3 (0-5) at 6 and 12 months, respectively. CONCLUSION: This report is a first in potentially identifying an effective therapy, abatacept monotherapy, for poor prognosis, ACPA-negative UA, supported by a clear reduction in PDUS. These data justify evaluation in a controlled study. PMID- 28028156 TI - Patients' preferences and economic considerations play an important role in treatment decisions: a discrete choice experiment among rheumatologists. AB - OBJECTIVE: To evaluate to what extent rheumatologists consider economic aspects and patients' preferences when choosing drug treatments in patients with active RA. METHODS: In a discrete choice experiment, rheumatologists were asked to choose between two unlabelled drug treatment options for a hypothetical RA patient with moderate disease activity who failed two synthetic DMARDs. Attributes and levels of drug treatments were selected based on existing literature, rheumatologists' opinion and expert consensus. This resulted in five attributes each described by three levels: efficacy (level of improvement and achieved state on DAS28), safety (probability of a serious adverse event), patients' preference (level of agreement), annual medication costs and cost effectiveness (incremental cost-effectiveness ratio). An efficient experimental design generated 14 treatment choices and a random parameter logit model estimated the relative importance of attributes. RESULTS: Sixty-three rheumatologists from the Netherlands contributed to the analysis; 44% were female and mean (sd) age was 49 (8) years. Drug efficacy had the strongest relative contribution to the drug choice (44%) followed by medication costs (24%), patients' preference (17%) and cost-effectiveness (14%). Patients' preferences were most relevant when patients disliked a proposed treatment. The risk of serious but uncommon or rare side effects only played a minor role in the treatment choice (1%). CONCLUSION: In addition to drug efficacy, rheumatologists account for economic aspects and for patients' preferences when deciding on drugs. Decisions are more influenced by absolute costs than relative cost effectiveness and by patients' disliking as opposed to favouring the treatment. PMID- 28028157 TI - Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. AB - OBJECTIVES: Neuropsychiatric (NP) involvement is a poorly understood manifestation of SLE. We studied post-mortem histopathology in relation to clinical NPSLE syndromes and complement deposition in brains of NPSLE and SLE patients and controls. Furthermore, we investigated the correlation between cerebral post-mortem histopathology and ex vivo 7 T MRI findings in SLE and NPSLE. METHODS: A nationwide search for autopsy material yielded brain tissue from 16 NPSLE and 18 SLE patients. Brains obtained from 24 patients who died of acute cardiac events served as controls. Apart from a histopathological evaluation, paraffin-embedded cortical tissue was stained for components of the classical, lectin and terminal complement pathways. RESULTS: Diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE than SLE patients and were absent in controls. Focal vasculopathy was found in both SLE patients and controls. Complement deposition was strongly associated with both SLE and NPSLE, but not with controls (P < 0.001). Microthrombi were found uniquely in NPSLE and were associated with C4d and C5b-9 deposits (P < 0.05). A 7 T MRI was unable to detect most small vessel injury that was visible histopathologically. CONCLUSION: Our study demonstrates that histopathological lesions in NPSLE represent a continuum, ranging from non-specific lesions such as focal vasculopathy, to more specific lesions including C4d- and C5b-9-associated microthrombi and diffuse vasculopathy related to clinical syndromes defining NPSLE. Complement deposition may be a key factor in the interaction between circulating autoantibodies and thromboischaemic lesions observed in NPSLE. Therefore, complement inhibition may have novel therapeutic potential in NPSLE. PMID- 28028158 TI - Comparison of change in end tidal carbon dioxide after three minutes of step exercise between systemic sclerosis patients with and without pulmonary hypertension. AB - OBJECTIVES: Pulmonary hypertension (PH) is an important cause of morbidity and mortality in patients with SSc. The submaximal heart and pulmonary evaluation (step test) is a non-invasive, submaximal stress test that could be used to identify SSc patients with PH. Our aims were to determine whether change in end tidal carbon dioxide ([Formula: see text]) from rest to end-exercise, and the minute ventilation to carbon dioxide production ratio ([Formula: see text]), both as measured by the step test, differ between SSc patients with and without PH. We also examined differences in validated self-report questionnaires and potential PH biomarkers between SSc patients with and without PH. METHODS: We performed a cross-sectional study of 27 patients with limited or dcSSc who underwent a right heart catheterization within 24 months prior to study entry. The study visit consisted of questionnaire completion; history; physical examination; step test performance; and phlebotomy. [Formula: see text], [Formula: see text], self report data and biomarkers were compared between patients with and without PH. RESULTS: SSc patients with PH had a statistically significantly lower median (interquartile range) [Formula: see text] than SSc patients without PH [-2.1 ( 5.1 to 0.7) vs 1.2 (-0.7 to 5.4) mmHg, P = 0.035], and a statistically significantly higher median (interquartile range) [Formula: see text] [53.4 (39 64.1) vs 36.4 (31.9-41.1), P = 0.035]. There were no statistically significant differences in self-report data or biomarkers between groups. CONCLUSION: [Formula: see text] and [Formula: see text] as measured by the step test are statistically significantly different between SSc patients with and without PH. [Formula: see text] and [Formula: see text] may be useful screening tools for PH in the SSc population. PMID- 28028159 TI - Racial differences in health-related quality of life and functional ability in patients with gout. AB - OBJECTIVE: To compare the health-related quality of life (HRQOL) and the functional ability by race in patients with gout. METHODS: In a 9-month prospective cohort multicentre study, patients with gout self-reported race, dichotomized as Caucasian or African American (others excluded). We calculated HRQOL/function scores adjusted for age, study site and college education for Short Form-36 (SF-36; generic HRQOL), Gout Impact Scale (GIS; disease-specific HRQOL) and HAQ-disability index (HAQ-DI; functional ability). Longitudinally adjusted scores were computed using multivariable mixed-effect regression models with a random patient effect and fixed sequential visit effect (3-monthly visits). RESULTS: Compared with Caucasians (n = 107), African Americans (n = 60) with gout were younger (61.1 vs 67.3 years) and had higher median baseline serum urate (9.0 vs 7.9 mg/dl) (P < 0.01). African Americans with gout had worse HRQOL scores on three SF-36 domains, the mental component summary (MCS) and two of the five GIS scales than Caucasians [mean (se); P ? 0.02 for all]: SF-36 mental health, 39.7 (1.1) vs 45.2 (0.9); SF-36 role emotional, 42.1 (4.2) vs 51.4 (4.2); SF-36 social functioning, 36.0 (1.1) vs 40.0 (0.9) (P = 0.04); SF-36 MCS, 43.2 (3.1) vs 50.0 (3.2); GIS unmet treatment need, 37.6 (1.6) vs 31.5 (1.4); and GIS concern during attacks, 53.3 (3.7) vs 47.4 (3.7). Differences between the respective HAQ-DI total scores were not statistically significant; 0.98 (0.1) vs 0.80 (1.0) (P = 0.11). Racial differences in SF-36 mental health, role emotional and MCS scales exceeded, and for HAQ-DI approached, the minimal clinically important difference thresholds. CONCLUSIONS: African Americans with gout have significantly worse HRQOL compared with Caucasians. Further research is necessary in the form of studies targeted at African Americans on how best to improve these outcomes. PMID- 28028160 TI - Predictive value of MRI features for development of radiographic osteoarthritis in a cohort of participants with pre-radiographic knee osteoarthritis-the CHECK study. AB - OBJECTIVE: To determine whether MRI features are associated with development of radiographic knee OA and can be used as a predictive tool in early knee OA. METHODS: In 148 participants of the Cohort Hip and Cohort Knee study (mean age 56 years, 78% women), with a Kellgren Lawrence (KL) score ?1, we obtained semi quantitatively scored knee MRI scans and radiographs at baseline. After 5 years, we determined the development of radiographic knee OA (KL ?2). We calculated odds ratios (ORs), with 95% CIs adjusted for age, sex and BMI, to identify MRI features associated with OA development. With these MRI features, we constructed an internally validated prediction model, for which we measured the area under the receiver operating characteristics curve, sensitivity and specificity. RESULTS: Radiographic OA developed in 28% of the participants after 5 years. Statistically significant associations were: cartilage defects OR = 1.7 (95% CI: 1.1, 2.6), osteophytes OR = 3.1 (1.7, 5.7), bone marrow lesions OR = 2.0 (1.2, 3.4), effusion OR = 2.1 (1.2, 3.5) and meniscal pathology OR = 2.8 (1.3, 6.3). With the combined MRI features in a prediction model, the sensitivity was 66%, the specificity 67% and the optimism-corrected area under the receiver operating characteristics curve 0.685. CONCLUSION: In early knee OA, MRI depicts significantly associated pathology in cartilage, bone and menisci, whereas the radiograph fails to detect these changes. Although MRI has potential for identifying patients at risk for developing radiographic knee OA, it cannot be used as an absolute diagnostic tool in early knee OA due to its low discriminative ability. PMID- 28028162 TI - Should baseline-dependent cut-offs really be used to define disease improvement in juvenile idiopathic arthritis? And few other considerations. PMID- 28028163 TI - Peroneal neuropathy in giant cell arteritis. PMID- 28028161 TI - Cartilage biomarkers in the osteoarthropathy of alkaptonuria reveal low turnover and accelerated ageing. AB - OBJECTIVE: Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis. Typically, this occurs in joint cartilages, leading to an early onset, rapidly progressing osteoarthropathy. The aim of this study was to examine tissue turnover in cartilage affected by ochronosis and its role in disease initiation and progression. METHODS: With informed patient consent, hip and knee cartilages were obtained at surgery for arthropathy due to AKU (n = 6; 2 knees/4 hips) and OA (n = 12; 5 knees/7 hips); healthy non-arthritic (non-OA n = 6; 1 knee/5 hips) cartilages were obtained as waste from trauma surgery. We measured cartilage concentrations (normalized to dry weight) of racemized aspartate, GAG, COMP and deamidated COMP (D-COMP). Unpaired AKU, OA and non-OA samples were compared by non-parametric Mann-Whitney U test. RESULTS: Despite more extractable total protein being obtained from AKU cartilage than from OA or non-OA cartilage, there was significantly less extractable GAG, COMP and D-COMP in AKU samples compared with OA and non-OA comparators. Racemized Asx (aspartate and asparagine) was significantly enriched in AKU cartilage compared with in OA cartilage. CONCLUSIONS: These novel data represent the first examination of cartilage matrix components in a sample of patients with AKU, representing almost 10% of the known UK alkaptonuric population. Compared with OA and non-OA, AKU cartilage demonstrates a very low turnover state and has low levels of extractable matrix proteins. PMID- 28028164 TI - Thermoperiodic Control of Floral Induction Involves Modulation of the Diurnal FLOWERING LOCUS T Expression Pattern. AB - Thermoperiodism is defined as the ability to discriminate between day temperature (DT) and night temperature (NT). Our aim was to shed light on the mechanistic basis of thermoperiodic floral induction with acceleration under lower DT than NT compared with other DT-NT combinations at the same average daily temperature (ADT), a response exploited in temperate area greenhouses. Arabidopsis thaliana floral pathway mutants and a lhy circadian clock mutant as well as the expression of floral integrators and LHY (LATE ELONGATED HYPOCOTYL) were studied under different DT-NT combinations, all at the same ADT. We show that acceleration of floral induction under lower DT than NT is linked to increased FT expression early during the day and generally increased LFY expression preceding visible flower buds, compared with higher DT than NT or equal DT and NT. Consistent with FLOWERING LOCUS T (FT) action through LEAFY (LFY), time to floral transition in ft-1 and lfy-1 was similar under all treatments, in contrast to the situation for soc1-1, which behaved like the wild type (WT). The lhy-21 mutants did not discriminate between opposite DT-NT combinations, whereas LHY expression in the WT differed in these temperature regimes. This might suggest that LHY plays a role in thermoperiodic control of floral induction. We conclude that thermoperiodic control of floral transition is associated with modulation of the diurnal expression patterns of FT, with timing of temperature alteration being important rather than ADT. PMID- 28028165 TI - Genetics of the Blue Light-Dependent Signal Cascade That Controls Phototaxis in the Cyanobacterium Synechocystis sp. PCC6803. AB - The Synechocystis sp. PCC6803 can move on a solid surface in response to light, a phenomenon called phototaxis. Although many of the photoreceptors involved in phototaxis have been identified, the mechanisms that regulate directional motility of Synechocystis are not well understood. Previous studies showed that a mutant lacking the blue light-using flavin (BLUF) photoreceptor PixD exhibits negative phototaxis under conditions where the wild type responds positively. PixD interacts with the pseudo-response regulator-like protein PixE in a light dependent manner, suggesting that this intermolecular interaction is important for phototaxis regulation, although genetic evidence has been lacking. To gain further insight into phototaxis regulation by PixD-PixE signaling, we constructed the deletion mutants DeltaPixE and DeltaPixD-DeltaPixE, and characterized their phenotypes, which matched those of the wild type (positive phototaxis). Because DeltaPixD exhibited negative phototaxis, PixE must function downstream of PixD. Under intense blue light (>100 MUmol m-2 s-1; 470 nm) the wild type exhibited negative phototaxis, but DeltaPixD-PixE exhibited positive phototaxis toward low intensity blue light (~0.8 MUmol m-2 s-1; 470 nm). These results suggest that an unknown light-sensing system(s), that is necessary for directional cell movement, can be activated by low-intensity blue light; on the other hand, PixD needs high intensity blue light to be activated. We also isolated spontaneous mutants that compensated for the pixE deletion. Genome-wide sequencing of the mutants revealed that the uncharacterized gene sll2003 regulates positive and negative phototaxis in response to light intensity. PMID- 28028166 TI - Potato Tuber Induction is Regulated by Interactions Between Components of a Tuberigen Complex. AB - Photoperiod-regulated flowering and potato tuber formation involve leaf-produced mobile signals, florigen and tuberigen, respectively. The major protein component of florigen has been identified as the FLOWERING LOCUS T (FT) protein. In rice, an FT-like protein, Heading date 3a (Hd3a), induces flowering by making the florigen activation complex (FAC) through interactions with 14-3-3 and OsFD1, a rice FD-like protein. In potato, StSP6A, an FT-like protein, was identified as a major component of tuberigen. However, the molecular mechanism of how StSP6A triggers tuber formation remains elusive. Here we analyzed the significance of the formation of a complex including StSP6A, 14-3-3 and FD-like proteins in tuberization. Yeast two-hybrid, bimolecular fluorescence complementation and in vitro pull-down assays showed that StSP6A and StFDL1, a potato FD-like protein, interact with St14-3-3s. StSP6A overexpression induced early tuberization in a 14 3-3-dependent manner, and suppression of StFDL1 delayed tuberization. These results strongly suggest that an FAC-like complex, the tuberigen activation complex (TAC), comprised of StSP6A, St14-3-3s and StFDL1, regulates potato tuber formation. PMID- 28028167 TI - Potato Psyllid (Hemiptera: Triozidae) Response to Insecticides Under Controlled Greenhouse Conditions. AB - Bactericera cockerelli (Sulc) is a common pest of solanaceous crops largely known for vectoring "psyllid yellows" in potatoes. In recent years, however, this pest has attracted considerable attention for vectoring Zebra Chip, a devastating bacterial disease that was first reported in the United States in 2004 and has spread across the southern and northwestern states, causing significant economic losses to potato growers and the industry. Management of the disease is mainly achieved by reducing the psyllid population using insecticides, including pyrethroids and neonicotinoids; however, new insecticides with different modes of action are needed to avoid the acquisition of resistance. In the current study, the immediate and residual effects of conventional and new materials were tested under greenhouse conditions against adults and nymphs. Cyantraniliprole at a high rate and spinetoram showed the highest immediate and residual activity against adults, whereas cyantraniliprole and oxamyl (low and high rates) were effective against nymphs, with no differences between rates. Soil applications of cyantraniliprole, oxamyl, and imidacloprid were still toxic to adults and nymphs 7 and 14 d after treatment. Also, cyantraniliprole and tolfenpyrad were detrimental to psyllid reproduction. The incorporation of new chemistry in rotation programs may provide a useful management tool against this pest. PMID- 28028168 TI - Acute Exposure to Worst-Case Concentrations of Amitraz Does Not Affect Honey Bee Learning, Short-Term Memory, or Hemolymph Octopamine Levels. AB - Amitraz, an acaricide used to treat Varroa destructor Anderson & Trueman, is one of the most commonly detected pesticides in honey bee (Apis mellifera L.) hives. Acaricides sometimes negatively impact honey bee cognition, but potential effects of amitraz on honey bee learning have been rarely studied. We topically exposed foragers to 95th percentile field-relevant levels of amitraz and, 24 h later, tested the ability of bees to associate a sucrose reward with a conditioned odor (learning response) using the proboscis extension response (PER). We then tested the ability of the bees to retain this memory 1 h and 2 h post-conditioning. Because amitraz is thought to affect octopamine metabolism in honey bees, and because octopamine is directly related to honey bee learning and memory, we also examined effects of exposure to amitraz on octopamine levels in honey bee hemolymph. We found that acute exposure to 95th percentile doses of amitraz had no impact on honey bee learning or short-term memory as measured by PER. Concentrations of octopamine in hemolymph from our low amitraz treatment were 1.4 fold higher than control levels, but other treatments had no effect. Our results from worst-case acute exposure experiments with worker bees in the laboratory suggest that typical field-relevant (within hive) exposures to amitraz probably have little effect on honey bee learning and memory. PMID- 28028169 TI - Phytosanitary Treatments Against Bactrocera dorsalis (Diptera: Tephritidae): Current Situation and Future Prospects. AB - Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) is arguably the most important tephritid attacking fruits after Ceratitis capitata (Wiedemann) (Diptera: Tephritidae). In 2003 it was found in Africa and quickly spread to most of the sub-Saharan part of the continent, destroying fruits and creating regulatory barriers to their export. The insect is causing new nutritional and economic losses across Africa, as well as the losses it has caused for decades in infested areas of Asia, New Guinea, and Hawaii. This new panorama represents a challenge for fruit exportation from Africa. Phytosanitary treatments are required to export quarantined commodities out of infested areas to areas where the pest does not exist and could become established. This paper describes current phytosanitary treatments against B. dorsalis and their use throughout the world, the development of new treatments based on existing research, and recommendations for further research to provide phytosanitary solutions to the problem. PMID- 28028170 TI - Influences of Temperature and Ootheca Age on the Life History of the Cockroach Ootheca Parasitoid Aprostocetus hagenowii (Hymenoptera: Eulophidae). AB - The influences of ootheca age and temperature on the life history of Aprostocetus hagenowii (Ratzeburg) (Hymenoptera: Eulophidae), a gregarious ootheca parasitoid of the American cockroach Periplaneta americana (L.) (Dictyoptera: Blattidae), were evaluated. Oothecae were incubated at 20, 25, and 30 degrees C to produce oothecae aged 1-60, 1-40, and 1-30 d old, respectively. Fitness traits (development time, percentage emergence, number of progeny, percentage female progeny, and female body size) of A. hagenowii developing in these different-aged oothecae were determined. For oothecae incubated at 20, 25, and 30 degrees C, parasitoids successfully developed in oothecae aged up to 50, 30, and 20 d old, which represent 72.9%, 65.9%, and 61.9% of the total embryonic development time of P. americana, respectively, without any changes in their fitness traits. When A. hagenowii from oothecae kept at constant temperatures (20, 25, 30, 32, and 35 degrees C) were compared, the immature development time (71.0-34.0 d) and adult life span decreased with increasing temperature. No parasitoid emerged at 35 degrees C. The lower, upper, and optimal temperature-dependent developmental thresholds were 9.5, 34.2, and 31.1 degrees C, respectively. Thermal constant for total immature development was 666.7 degree-days. Temperature did not affect lifetime realized fecundity and number of oothecae parasitized by females but did influence parasitism activities over time. Sugar-fed females sustained longer periods of high parasitism rates (>=70%) at 20-30 degrees C (15-30 d) than at 32 35 degrees C (1-5 d). These results are useful for determining the ootheca age and temperature range optimal for parasitoid rearing and for estimating the effectiveness of biological control by the wasps. PMID- 28028171 TI - Single-stranded DNA Binding by the Helix-Hairpin-Helix Domain of XPF Protein Contributes to the Substrate Specificity of the ERCC1-XPF Protein Complex. AB - The nucleotide excision repair protein complex ERCC1-XPF is required for incision of DNA upstream of DNA damage. Functional studies have provided insights into the binding of ERCC1-XPF to various DNA substrates. However, because no structure for the ERCC1-XPF-DNA complex has been determined, the mechanism of substrate recognition remains elusive. Here we biochemically characterize the substrate preferences of the helix-hairpin-helix (HhH) domains of XPF and ERCC-XPF and show that the binding to single-stranded DNA (ssDNA)/dsDNA junctions is dependent on joint binding to the DNA binding domain of ERCC1 and XPF. We reveal that the homodimeric XPF is able to bind various ssDNA sequences but with a clear preference for guanine-containing substrates. NMR titration experiments and in vitro DNA binding assays also show that, within the heterodimeric ERCC1-XPF complex, XPF specifically recognizes ssDNA. On the other hand, the HhH domain of ERCC1 preferentially binds dsDNA through the hairpin region. The two separate non overlapping DNA binding domains in the ERCC1-XPF heterodimer jointly bind to an ssDNA/dsDNA substrate and, thereby, at least partially dictate the incision position during damage removal. Based on structural models, NMR titrations, DNA binding studies, site-directed mutagenesis, charge distribution, and sequence conservation, we propose that the HhH domain of ERCC1 binds to dsDNA upstream of the damage, and XPF binds to the non-damaged strand within a repair bubble. PMID- 28028173 TI - Human Mitochondrial Transcription Factor B2 Is Required for Promoter Melting during Initiation of Transcription. AB - The mitochondrial transcription initiation machinery in humans consists of three proteins: the RNA polymerase (POLRMT) and two accessory factors, transcription factors A and B2 (TFAM and TFB2M, respectively). This machinery is required for the expression of mitochondrial DNA and the biogenesis of the oxidative phosphorylation system. Previous experiments suggested that TFB2M is required for promoter melting, but conclusive experimental proof for this effect has not been presented. Moreover, the role of TFB2M in promoter unwinding has not been discriminated from that of TFAM. Here we used potassium permanganate footprinting, DNase I footprinting, and in vitro transcription from the mitochondrial light-strand promoter to study the role of TFB2M in transcription initiation. We demonstrate that a complex composed of TFAM and POLRMT was readily formed at the promoter but alone was insufficient for promoter melting, which only occurred when TFB2M joined the complex. We also show that mismatch bubble templates could circumvent the requirement of TFB2M, but TFAM was still required for efficient initiation. Our findings support a model in which TFAM first recruits POLRMT to the promoter, followed by TFB2M binding and induction of promoter melting. PMID- 28028172 TI - Histone Deacetylase 1 Is Essential for Rod Photoreceptor Differentiation by Regulating Acetylation at Histone H3 Lysine 9 and Histone H4 Lysine 12 in the Mouse Retina. AB - Histone acetylation has a regulatory role in gene expression and is necessary for proper tissue development. To investigate the specific roles of histone deacetylases (HDACs) in rod differentiation in neonatal mouse retinas, we used a pharmacological approach that showed that inhibition of class I but not class IIa HDACs caused the same phenotypic changes seen with broad spectrum HDAC inhibitors, most notably a block in the differentiation of rod photoreceptors. Inhibition of HDAC1 resulted in increase of acetylation of lysine 9 of histone 3 (H3K9) and lysine 12 of histone 4 (H4K12) but not lysine 27 of histone 3 (H3K27) and led to maintained expression of progenitor-specific genes such as Vsx2 and Hes1 with concomitant block of expression of rod-specific genes. ChiP experiments confirmed these changes in the promoters of a group of progenitor genes. Based on our results, we suggest that HDAC1-specific inhibition prevents progenitor cells of the retina from exiting the cell cycle and differentiating. HDAC1 may be an essential epigenetic regulator of the transition from progenitor cells to terminally differentiated photoreceptors. PMID- 28028174 TI - DOCK8 Protein Regulates Macrophage Migration through Cdc42 Protein Activation and LRAP35a Protein Interaction. AB - DOCK8 is an atypical guanine nucleotide exchange factor for Cdc42, and its mutations cause combined immunodeficiency in humans. Accumulating evidence indicates that DOCK8 regulates the migration and activation of various subsets of leukocytes, but its regulatory mechanism is poorly understood. We here report that DOCK8-deficient macrophages exhibit a migration defect in a 2D setting. Although DOCK8 deficiency in macrophages did not affect the global Cdc42 activation induced by chemokine stimulation, rescue experiments revealed that the guanine nucleotide exchange factor activity of DOCK8 was required for macrophage migration. We found that DOCK8 associated with LRAP35a, an adaptor molecule that binds to the Cdc42 effector myotonic dystrophy kinase-related Cdc42-binding kinase, and facilitated its activity to phosphorylate myosin II regulatory light chain. When this interaction was disrupted in WT macrophages, they showed a migration defect, as seen in DOCK8-deficient macrophages. These results suggest that, during macrophage migration, DOCK8 links Cdc42 activation to actomyosin dynamics through the association with LRAP35a. PMID- 28028175 TI - The Transcriptional Corepressor SIN3 Directly Regulates Genes Involved in Methionine Catabolism and Affects Histone Methylation, Linking Epigenetics and Metabolism. AB - Chromatin modification and cellular metabolism are tightly connected. Chromatin modifiers regulate the expression of genes involved in metabolism and, in turn, the levels of metabolites. The generated metabolites are utilized by chromatin modifiers to affect epigenetic modification. The mechanism for this cross-talk, however, remains incompletely understood. The corepressor SIN3 controls histone acetylation through association with the histone deacetylase RPD3. The SIN3 complex is known to regulate genes involved in a number of metabolic processes. Here, we find that Drosophila SIN3 binds to the promoter region of genes involved in methionine catabolism and that this binding affects histone modification, which in turn influences gene expression. Specifically, we observe that reduced expression of SIN3 leads to an increase in S-adenosylmethionine (SAM), which is the major cellular donor of methyl groups for protein modification. Additionally, Sin3A knockdown results in an increase in global histone H3K4me3 levels. Furthermore, decreased H3K4me3 caused by knockdown of either SAM synthetase (Sam S) or the histone methyltransferase Set1 is restored to near normal levels when SIN3 is also reduced. Taken together, these results indicate that knockdown of Sin3A directly alters the expression of methionine metabolic genes to increase SAM, which in turn leads to an increase in global H3K4me3. Our study reveals that SIN3 is an important epigenetic regulator directly connecting methionine metabolism and histone modification. PMID- 28028176 TI - A Two-component NADPH Oxidase (NOX)-like System in Bacteria Is Involved in the Electron Transfer Chain to the Methionine Sulfoxide Reductase MsrP. AB - MsrPQ is a newly identified methionine sulfoxide reductase system found in bacteria, which appears to be specifically involved in the repair of periplasmic proteins oxidized by hypochlorous acid. It involves two proteins: a periplasmic one, MsrP, previously named YedY, carrying out the Msr activity, and MsrQ, an integral b-type heme membrane-spanning protein, which acts as the specific electron donor to MsrP. MsrQ, previously named YedZ, was mainly characterized by bioinformatics as a member of the FRD superfamily of heme-containing membrane proteins, which include the NADPH oxidase proteins (NOX/DUOX). Here we report a detailed biochemical characterization of the MsrQ protein from Escherichia coli We optimized conditions for the overexpression and membrane solubilization of an MsrQ-GFP fusion and set up a purification scheme allowing the production of pure MsrQ. Combining UV-visible spectroscopy, heme quantification, and site-directed mutagenesis of histidine residues, we demonstrated that MsrQ is able to bind two b-type hemes through the histidine residues conserved between the MsrQ and NOX protein families. In addition, we identify the E. coli flavin reductase Fre, which is related to the dehydrogenase domain of eukaryotic NOX enzymes, as an efficient cytosolic electron donor to the MsrQ heme moieties. Cross-linking experiments as well as surface Plasmon resonance showed that Fre interacts with MsrQ to form a specific complex. Taken together, these data support the identification of the first prokaryotic two-component protein system related to the eukaryotic NOX family and involved in the reduction of periplasmic oxidized proteins. PMID- 28028177 TI - Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation. AB - beta-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal beta-secretase for amyloid-beta generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation. Here, we report that induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition. A significant portion of BACE1 is recruited to the autophagy pathway and co-migrates robustly with autophagic vacuoles along axons. Moreover, we reveal that autophagic vacuole associated BACE1 is accumulated in the distal axon of Alzheimer's disease-related mutant human APP transgenic neurons and mouse brains. Inducing autophagy in mutant human APP neurons augments autophagic retention of BACE1 in distal axons, leading to enhanced beta-cleavage of APP. This phenotype can be reversed by Snapin-enhanced retrograde transport, which facilitates BACE1 trafficking to lysosomes for degradation. Therefore, our study provides new insights into autophagy-mediated regulation of BACE1 turnover and APP processing, thus building a foundation for future development of potential Alzheimer's disease therapeutic strategies. PMID- 28028178 TI - C-FLIPL Modulated Wnt/beta-Catenin Activation via Association with TIP49 Protein. AB - Cellular FLICE-like inhibitory protein (c-FLIPL) is a key inhibitory protein in the extrinsic apoptotic pathway. Recent studies showed that c-FLIPL could translocate into the nucleus and might be involved in the Wnt signaling pathway. The nuclear function of c-FLIPL was still unclear. Here we found a novel c-FLIPL associated protein TIP49, which is a nuclear protein identified as a cofactor in the transcriptional regulation of beta-catenin. They had co-localization in the nucleus and the DED domain of c-FLIPL was required for the association with TIP49. By performing ChIP experiments, C-FLIPL was detected in the ITF-2 locus and facilitated TIP49 accumulation in the formation of complexes at the T-cell specific transcription factor site of human ITF-2 promoter. When TIP49 knockdown, c-FLIPL-driven Wnt activation, and cell proliferation were inhibited, suggesting that a role of nuclear c-FLIPL involved in modulation of the Wnt pathway was in a TIP49-dependent manner. Elevated expression of c-FLIPL and TIP49 that coincided in human lung cancers were analyzed in silico using the Oncomine database. Their high expressions were reconfirmed in six lung cancer cell lines and correlated with cell growth. The association of c-FLIPL and TIP49 provided an additional mechanism involved in c-FLIPL-mediated functions, including Wnt activation. PMID- 28028179 TI - Functional Effects of AKT3 on Aurora Kinase Inhibitor-induced Aneuploidy. AB - The suppression of mitotic Aurora kinases (AURKs) by AURK inhibitors frequently causes cytokinetic failure, leading to polyploidy or aneuploidy, indicating the critical role of AURK-mediated phosphorylation during cytokinesis. We demonstrate the deregulated expression of AKT3 in Aurora kinase inhibitor (AURKi)-resistant cells, which we established from human colorectal cancer HCT 116 cells. The AKT family, which includes AKT1, -2, and -3, plays multiple roles in antiapoptotic functions and drug resistance and is involved in cell growth and survival pathways. We found that an AKT inhibitor, AZD5363, showed synergistic effect with an AURKi, VX-680, on two AKT3-expressing AURKi-resistant cell lines, and AKT3 knockdown sensitized cells to VX-680. Consistent with these activities, AKT3 expression suppressed AURKi-induced apoptosis and conferred resistance to AURKi. Thus, AKT3 expression affects cell sensitivity to AURKi. Moreover, we found that AKT3 expression suppressed AURKi-induced aneuploidy, and inversely AKT3 knockdown enhanced it. In addition, partial co-localization of AKT3 with AURKB was observed during anaphase. Overall, this study suggests that AKT3 could repress the antiproliferative effects of AURKi, with a novel activity particularly suppressing the aneuploidy induction. PMID- 28028180 TI - Dissecting the Process of Activation of Cancer-promoting Zinc-requiring Ectoenzymes by Zinc Metalation Mediated by ZNT Transporters. AB - Zinc-requiring ectoenzymes, including both secreted and membrane-bound enzymes, are considered to capture zinc in their active site for their activation in the early secretory pathway. This idea has been confirmed by our studies conducted using tissue-nonspecific alkaline phosphatase (TNAP), which is elaborately activated by means of a two-step mechanism by zinc transporter 5 (ZNT5)-ZNT6 heterodimers and ZNT7 homodimers, through protein stabilization followed by enzyme activation with zinc in the early secretory pathway. However, the molecular basis of the activation process in other zinc-requiring ectoenzymes remains largely unknown. In this study, we investigated this activation process by using three cancer-promoting zinc-requiring ectoenzymes, autotaxin (ATX), matrix metalloproteinase 9 (MMP9), and carbonic anhydrase IX (CAIX), and the chicken DT40 cell mutants that we generated; we specifically focused on clarifying whether the same or a similar activation mechanism operates in these ectoenzymes. ATX activation required ZNT5-ZNT6 heterodimers and ZNT7 homodimers in a manner similar to TNAP activation, although the protein stability of ATX was differently regulated from that of TNAP. MMP9 required ZNT5-ZNT6 heterodimers and ZNT7 homodimers for its activation as well as secretion; MMP9 was not secreted into the spent medium unless both zinc-transport complexes were present. Finally, CAIX activation by zinc was mediated not only by ZNT5-ZNT6 heterodimers and ZNT7 homodimers but also by ZNT4 homodimers; thus, these three zinc-transport complexes redundantly contribute to CAIX activation. Our results provide pivotal insights into the activation processes of zinc-requiring ectoenzymes, and furthermore, they offer novel insights for potential cancer therapy applications given the cancer-promoting potencies of ATX, MMP9, and CAIX. PMID- 28028181 TI - RYBP Expression Is Regulated by KLF4 and Sp1 and Is Related to Hepatocellular Carcinoma Prognosis. AB - The expression of Ring1- and YY1-binding protein (RYBP) is reduced in several human cancers, but the molecular mechanism(s) have remained elusive. In this study, we used human hepatocellular carcinoma (HCC) cell lines and tissue specimens to study the mechanism and herein report several new findings. First, we cloned and characterized the basal promoter region of the human RYBP gene. We found that the decreased RYBP expression in HCC tissues was not due to promoter sequence variation/polymorphisms or CpG dinucleotide methylation. We identified two transcription factors, KLF4 and Sp1, which directly bind the promoter region of RYBP to induce and suppress RYBP transcription, respectively. We mapped the binding sites of KLF4 and Sp1 on the RYBP promoter. Studies in vitro showed that KLF4 suppresses whereas Sp1 promotes HCC cell growth through modulating RYBP expression. Deregulated KLF4 and Sp1 contributed to decreased expression of RYBP in HCC tumor tissues. Our studies of human HCC tissues indicated that a diminished RYBP level in the tumor (in association with altered KLF4 and Sp1 expression) was statistically associated with a larger tumor size, poorer differentiation, and an increased susceptibility to distant metastasis. These findings help to clarify why RYBP is decreased in HCC and indicate that deregulated KLF4, Sp1, and RYBP may lead to a poorer prognosis. Our findings support the idea that RYBP may represent a target for cancer therapy and suggest that it may be useful as a prognostic biomarker for HCC, either alone or in combination with KLF4 and Sp1. PMID- 28028184 TI - Science and Culture: Solving a math problem to create art. PMID- 28028186 TI - Acknowledgment of Reviewers, 2016. PMID- 28028182 TI - Domain Mapping of Heat Shock Protein 70 Reveals That Glutamic Acid 446 and Arginine 447 Are Critical for Regulating Superoxide Dismutase 2 Function. AB - Stress-inducible heat shock protein 70 (hsp70) interacts with superoxide dismutase 2 (SOD2) in the cytosol after synthesis to transfer the enzyme to the mitochondria for subsequent activation. However, the structural basis for this interaction remains to be defined. To map the SOD2-binding site in hsp70, mutants of hsp70 were made and tested for their ability to bind SOD2. These studies showed that SOD2 binds in the amino acid 393-537 region of the chaperone. To map the hsp70-binding site in SOD2, we used a series of pulldown assays and showed that hsp70 binds to the amino-terminal domain of SOD2. To better define the binding site, we used a series of decoy peptides derived from the primary amino acid sequence in the SOD2-binding site in hsp70. This study shows that SOD2 specifically binds to hsp70 at 445GERAMT450 Small peptides containing GERAMT inhibited the transfer of SOD2 to the mitochondria and decreased SOD2 activity in vitro and in vivo To determine the amino acid residues in hsp70 that are critical for SOD2 interactions, we substituted each amino acid residue for alanine or more conservative residues, glutamine or asparagine, in the GERAMT-binding site. Substitutions of E446A/Q and R447A/Q inhibited the ability of the GERAMT peptide to bind SOD2 and preserved SOD2 function more than other substitutions. Together, these findings indicate that the GERAMT sequence is critical for hsp70-mediated regulation of SOD2 and that Glu446 and Arg447 cooperate with other amino acid residues in the GERAMT-binding site for proper chaperone-dependent regulation of SOD2 antioxidant function. PMID- 28028187 TI - Evaluating the Effectiveness of Written Dry Powder Inhaler Instructions and Health Literacy in Subjects Diagnosed With COPD. AB - BACKGROUND: Improper inhaler use results in decreased drug deposition in the lungs. The impact of health literacy and poor vision on the patient's ability to learn inhaler technique by reading instructions has not been confirmed. This study evaluated the effectiveness of learning inhaler technique from written instructions and the impact of health literacy for patients diagnosed with COPD who used a dry powder inhaler (DPI). METHODS: This pilot study recruited subjects diagnosed with COPD. A trained assessor scored subjects' inhaler technique before and after reading the appropriate American College of Chest Physicians handouts. Peak inspiratory flows (PIFs) were measured using an InCheck Dial. Health literacy was measured by the S-TOFHLA (Short Test of Functional Health Literacy in Adults), and visual acuity was measured by a Snellen chart. Associations between health literacy and visual acuity and changes in subjects' inhaler technique scores were assessed by Spearman's rho. Inhaler technique change scores were assessed by the Wilcoxon signed-rank test at P = .05. RESULTS: Of the 24 participants enrolled, 63% were female, mean age was 65.6 y, and 83% were Global Initiative for Chronic Obstructive Lung Disease air-flow limitation 2 or 3. Wilcoxon scores were significant for improved total scores for both the Diskus and HandiHaler, with medians improving from 6.5 to 7.0 (interquartile range 6.0 7.8) (P = .047) and from 6.0 to 7.5 (interquartile range 7.0-9.0) (P = .002), respectively. The minimum required PIF was achieved by 93.8% of the Diskus and 94.4% of the HandiHaler groups. There were no associations detected between the handout intervention (Diskus and HandiHaler) and health literacy level and vision. CONCLUSIONS: The educational handouts for DPIs helped participants already using a DPI to improve their inhaler technique. Stable participants diagnosed with COPD are able to generate appropriate PIFs to properly use DPIs. Neither vision nor health literacy was associated with the inability to learn inhaler technique from patient education inhaler device handouts. PMID- 28028188 TI - Feasibility of a Respiratory Movement Evaluation Tool to Quantify Thoracoabdominal Movement for Neuromuscular Diseases. AB - BACKGROUND: An objective method to evaluate thoracoabdominal movement is needed in daily clinical practice to detect patients at risk of hypoventilation and to allow for timely interventions in neuromuscular diseases. The clinical feasibility, reliability, and validity of a newly developed method for quantifying respiratory movement using fiber grating sensors, called the Respiratory Movement Evaluation Tool (RMET), was evaluated. METHODS: The time needed to measure respiratory movement and the usability of the measurement were determined by 5 clinicians using the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST) 2.0 questionnaire. Thoracoabdominal movement was measured using RMET 3 times in 10 healthy subjects to evaluate intraclass correlation coefficients (ICC). The subjects were encouraged to breathe 10 times while voluntarily changing the amount of air during ventilation simultaneously with the RMET and a spirometer, and their correlations were evaluated to test validity using Pearson's product-moment correlation coefficients. The same measurements were also performed in 10 subjects with Duchenne muscular dystrophy. RESULTS: Real-time recordings of thoracoabdominal movements were obtained over a mean time of 374 +/- 23.9 s. With QUEST 2.0, the median score of each item exceeded 3 (more or less satisfied). In healthy subjects, ICC(1,1) ranged from 0.82 to 0.99, and ICC(2,1) ranged from 0.83 to 0.97. Significant correlations were observed between the respiratory amplitudes measured with RMET, and the amount of air during ventilation was measured with a spirometer (r = 0.995, P < .001). In subjects with Duchenne muscular dystrophy, ICC(1,1) ranged from 0.87 to 0.97, and ICC(2,1) ranged from 0.84 to 0.99. The respiratory amplitudes measured with RMET correlated significantly with the amount of air during ventilation with a spirometer (r = 0.957, P < .001). CONCLUSIONS: We developed a novel method of quantifying respiratory movement called RMET that was feasible to use in daily clinical practice. PMID- 28028189 TI - Implementation of a beta-Agonist/Airway Clearance Protocol in a Pediatric ICU. AB - BACKGROUND: Respiratory therapist (RT)-driven protocols have been in use for over 30 years. Protocols have been reported to decrease unnecessary or harmful therapy, health-care costs, and hospital stay. This study represents the evaluation of an original respiratory care protocol in the pediatric ICU at Arkansas Children's Hospital for beta-agonist and airway clearance interventions where one did not exist. METHODS: This project was composed of 2 parts: a survey administered to RTs and licensed independent practitioners and a retrospective review of outcome data comparing a therapist-driven beta-agonist/airway clearance protocol with physician-directed respiratory care ordering in a patient population admitted for acute respiratory failure. RESULTS: Acceptance of the protocol was evident in the survey responses because overall perceptions surrounding the implementation of the beta-agonist/airway clearance protocol were positive, and responders perceived that the protocol implementation elevated the status and increased the value of respiratory therapists. For the comparison of physician-directed orders with therapist-driven protocols, there were no significant differences between pre- and post-intervention groups for mean age, sex, mean daily acuity, or mean weighted daily acuity (P = .33, .19, >.99, and .79, respectively). There were also no differences in pediatric index of mortality 2, pediatric index of mortality 2 rate of mortality, pediatric risk of mortality 3 probability of death, and pediatric risk of mortality 3 scores (P = .63, .56, .19, and .44, respectively) between the 2 groups. When comparing physician-directed orders to therapist-driven protocols, all outcome measures (length of stay, beta-agonist therapies, airway clearance therapies, and ventilator days) showed statistically and clinically important reductions, adjusting for subject characteristics (P < .001) for the therapist-driven protocol group. CONCLUSIONS: In this institution, implementation of a beta agonist/airway clearance protocol resulted in significant reductions of subject interventions and improved outcomes by decreasing length of stay and ventilator days as well as contributing information where clinical evidence is scant, specifically the pediatric ICU. PMID- 28028190 TI - Beliefs and Attitudes Associated With Hookah Smoking Among a United States College Population. AB - BACKGROUND: This study explores the differences among smokers of waterpipe tobacco in a college population to better inform campaigns to curb waterpipe use. METHODS: Participants included undergraduate and graduate students attending a liberal arts university in Florida. E-mail-based, cross-sectional surveys were collected in 2 sequential years. RESULTS: The majority of respondents (64%) reported having ever smoked a hookah, even if just 1-2 puffs. Of those who had ever smoked a hookah, 34% reported smoking a hookah within the previous 30 d. Constructs from the theory of reasoned action were all correlated with smoking behavior. The range of beliefs endorsed by smokers were more strongly associated with hookah-related attitudes compared with subjective norms. Concerns about health were stronger among never-smokers. CONCLUSIONS: Young adult college students continue to engage in waterpipe tobacco smoking at high rates. Campaigns need to focus on subsets of smokers and nonsmokers, independently. PMID- 28028191 TI - Clinic Versus Daytime Ambulatory Blood Pressure Difference in Hypertensive Patients: The Impact of Age and Clinic Blood Pressure. AB - Clinic blood pressure (BP) is usually higher than daytime ambulatory BP in hypertensive patients, but some recent studies have challenged this view, suggesting that this relationship is strongly influenced by age. We used the Spanish ambulatory BP monitoring cohort to examine differences between clinic and daytime BP by age among 104 639 adult hypertensive patients (office systolic/diastolic BP >=140/90 mm Hg or treated) in usual primary-care practice, across the wide age spectrum. To assess the impact of age, cardiovascular variables, and clinic BP on the clinic-daytime BP differences, we built multivariable regression models of the average BP differences, white-coat hypertension (high clinic BP and normal daytime BP), and masked hypertension (normal clinic BP and high daytime BP). In most patients, mean clinic BP values were higher than daytime BP at all ages. Some 36.7% of patients had white-coat hypertension (amounting to 50% at clinic systolic BP of 140-159 mm Hg) and 3.9% had masked hypertension (amounting to 18% at clinic systolic BP of 130-139 mm Hg). Age explained 0.1% to 1.7% of the variance of quantitative or categorical BP differences (P<0.001). Cardiovascular variables explained an additional 1.6% to 3.4% of the variance (P<0.001). Finally, clinic BP generally explained >=20% more of the variance (P<0.01). In this large study in usual clinical practice, clinic BP misclassified hypertension status in >40% of patients. This misclassification was not importantly influenced by age but was more evident in patients with borderline/grade 1 hypertension. These findings reinforce the importance of ambulatory BP monitoring for defining BP status in routine clinical practice. PMID- 28028192 TI - Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease. AB - : Among those with moderate-to-advanced chronic kidney disease, the relationship between blood pressure (BP) and cardiovascular disease seems U shaped but is loglinear in apparently healthy adults. The SHARP (Study of Heart and Renal Protection) randomized 9270 patients with chronic kidney disease to ezetimibe/simvastatin versus matching placebo and measured BP at each follow-up visit. Cox regression was used to assess the association between BP and risk of cardiovascular disease among (1) those with a self-reported history of cardiovascular disease and (2) those with no such history and, based on plasma troponin-I concentration, a low probability of subclinical cardiac disease. A total of 8666 participants had a valid baseline BP and troponin-I measurement, and 2188 had at least 1 cardiovascular event during follow-up. After adjustment for relevant confounders, the association between systolic BP and cardiovascular events was U shaped, but among participants without evidence of previous cardiovascular disease, there was a positive loglinear association throughout the range of values studied. Among those with the lowest probability of subclinical cardiac disease, each 10 mm Hg higher systolic BP corresponded to a 27% increased risk of cardiovascular disease (hazard ratio, 1.27; 95% confidence interval, 1.11 1.44). In contrast, the relationship between diastolic BP and cardiovascular risk remained U shaped irrespective of cardiovascular disease history or risk of subclinical disease. In conclusion, the lack of a clear association between systolic BP and cardiovascular risk in this population seems attributable to confounding, suggesting that more intensive systolic BP reduction may be beneficial in such patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00125593. PMID- 28028193 TI - Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling. AB - The role of smooth muscle endothelinB (ETB) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ETB receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ETB receptors were selectively deleted from smooth muscle by crossing floxed ETB mice with those expressing cre recombinase controlled by the transgelin promoter. Functional consequences of ETB deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ETB was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ETB-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ETB-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ETB knockout compared with controls (+4.2+/-0.2 mm Hg; P<0.0001), but salt-induced and ETB blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ETB-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ETB knockout mice. In the absence of other pathology, ETB receptors in vascular smooth muscle make a small but significant contribution to ETB-dependent regulation of BP. These ETB receptors have no effect on vascular contraction or neointimal remodeling. PMID- 28028195 TI - How Registries Can Guide Our Future? PMID- 28028194 TI - Effect of Uric Acid-Lowering Agents on Endothelial Function: A Randomized, Double Blind, Placebo-Controlled Trial. AB - Higher levels of serum uric acid are independently associated with endothelial dysfunction, a mechanism for incident hypertension. Overweight/obese individuals are more prone to endothelial dysfunction than their lean counterparts. However, the effect of lowering serum uric acid on endothelial dysfunction in these individuals has not been examined thoroughly. In this randomized, double-blind, placebo-controlled trial of nonhypertensive, overweight, or obese individuals with higher serum uric acid (body mass index >=25 kg/m2 and serum uric acid >=5.0 mg/dL), we assigned subjects to probenecid (500-1000 mg/d), allopurinol (300-600 mg/d), or matching placebo. The primary outcome was endothelium-dependent vasodilation measured by brachial artery ultrasound at baseline and 8 weeks. By the end of the trial, 47, 49, and 53 participants had been allocated to receive probenecid, allopurinol, and placebo, respectively. Mean serum uric acid levels significantly decreased in the probenecid (from 6.1 to 3.5 mg/dL) and allopurinol groups (from 6.1 to 2.9 mg/dL) but not in the placebo group (6.1 to 5.6 mg/dL). None of the interventions produced any significant change in endothelium dependent vasodilation (probenecid, 7.4+/-5.1% at baseline and 8.3+/-5.1% at 8 weeks; allopurinol, 7.6+/-6.0% at baseline and 6.2+/-4.8% at 8 weeks; and placebo, 6.5+/-3.8% at baseline and 7.1+/-4.9% at 8 weeks). In this randomized, double-blind, placebo-controlled trial, uric acid lowering did not affect endothelial function in overweight or obese nonhypertensive individuals. These data do not support the hypothesis that uric acid is causally related to endothelial dysfunction, a potential mechanism for development of hypertension. PMID- 28028196 TI - Adenosine Shifts Plasticity Regimes between Associative and Homeostatic by Modulating Heterosynaptic Changes. AB - Endogenous extracellular adenosine level fluctuates in an activity-dependent manner and with sleep-wake cycle, modulating synaptic transmission and short-term plasticity. Hebbian-type long-term plasticity introduces intrinsic positive feedback on synaptic weight changes, making them prone to runaway dynamics. We previously demonstrated that co-occurring, weight-dependent heterosynaptic plasticity can robustly prevent runaway dynamics. Here we show that at neocortical synapses in slices from rat visual cortex, adenosine modulates the weight dependence of heterosynaptic plasticity: blockade of adenosine A1 receptors abolished weight dependence, while increased adenosine level strengthened it. Using model simulations, we found that the strength of weight dependence determines the ability of heterosynaptic plasticity to prevent runaway dynamics of synaptic weights imposed by Hebbian-type learning. Changing the weight dependence of heterosynaptic plasticity within an experimentally observed range gradually shifted the operating point of neurons between an unbalancing regime dominated by associative plasticity and a homeostatic regime of tightly constrained synaptic changes. Because adenosine tone is a natural correlate of activity level (activity increases adenosine tone) and brain state (elevated adenosine tone increases sleep pressure), modulation of heterosynaptic plasticity by adenosine represents an endogenous mechanism that translates changes of the brain state into a shift of the regime of synaptic plasticity and learning. We speculate that adenosine modulation may provide a mechanism for fine-tuning of plasticity and learning according to brain state and activity.SIGNIFICANCE STATEMENT Associative learning depends on brain state and is impaired when the subject is sleepy or tired. However, the link between changes of brain state and modulation of synaptic plasticity and learning remains elusive. Here we show that adenosine regulates weight dependence of heterosynaptic plasticity: adenosine strengthened weight dependence of heterosynaptic plasticity; blockade of adenosine A1 receptors abolished it. In model neurons, such changes of the weight dependence of heterosynaptic plasticity shifted their operating point between regimes dominated by associative plasticity or by synaptic homeostasis. Because adenosine tone is a natural correlate of activity level and brain state, modulation of plasticity by adenosine represents an endogenous mechanism for translation of brain state changes into a shift of the regime of synaptic plasticity and learning. PMID- 28028197 TI - Limited Cognitive Resources Explain a Trade-Off between Perceptual and Metacognitive Vigilance. AB - : Why do experimenters give subjects short breaks in long behavioral experiments? Whereas previous studies suggest it is difficult to maintain attention and vigilance over long periods of time, it is unclear precisely what mechanisms benefit from rest after short experimental blocks. Here, we evaluate decline in both perceptual performance and metacognitive sensitivity (i.e., how well confidence ratings track perceptual decision accuracy) over time and investigate whether characteristics of prefrontal cortical areas correlate with these measures. Whereas a single-process signal detection model predicts that these two forms of fatigue should be strongly positively correlated, a dual-process model predicts that rates of decline may dissociate. Here, we show that these measures consistently exhibited negative or near-zero correlations, as if engaged in a trade-off relationship, suggesting that different mechanisms contribute to perceptual and metacognitive decisions. Despite this dissociation, the two mechanisms likely depend on common resources, which could explain their trade-off relationship. Based on structural MRI brain images of individual human subjects, we assessed gray matter volume in the frontal polar area, a region that has been linked to visual metacognition. Variability of frontal polar volume correlated with individual differences in behavior, indicating the region may play a role in supplying common resources for both perceptual and metacognitive vigilance. Additional experiments revealed that reduced metacognitive demand led to superior perceptual vigilance, providing further support for this hypothesis. Overall, results indicate that during breaks between short blocks, it is the higher-level perceptual decision mechanisms, rather than lower-level sensory machinery, that benefit most from rest. SIGNIFICANCE STATEMENT: Perceptual task performance declines over time (the so-called vigilance decrement), but the relationship between vigilance in perception and metacognition has not yet been explored in depth. Here, we show that patterns in perceptual and metacognitive vigilance do not follow the pattern predicted by a previously suggested single-process model of perceptual and metacognitive decision making. We account for these findings by showing that regions of anterior prefrontal cortex (aPFC) previously associated with visual metacognition are also associated with perceptual vigilance. We also show that relieving metacognitive task demand improves perceptual vigilance, suggesting that aPFC may house a limited cognitive resource that contributes to both metacognition and perceptual vigilance. These findings advance our understanding of the mechanisms and dynamics of perceptual metacognition. PMID- 28028198 TI - Sex-Dependent Regulation of Aromatase-Mediated Synaptic Plasticity in the Basolateral Amygdala. AB - The basolateral amygdala (BLA) integrates sensory input from cortical and subcortical regions, a function that requires marked synaptic plasticity. Here we provide evidence that cytochrome P450 aromatase (AROM), the enzyme converting testosterone to 17beta-estradiol (E2), contributes to the regulation of this plasticity in a sex-specific manner. We show that AROM is expressed in the BLA, particularly in the basolateral nucleus (BL), in male and female rodents. Systemic administration of the AROM inhibitor letrozole reduced spine synapse density in the BL of adult female mice but not in the BL of male mice. Similarly, in organotypic corticoamygdalar slice cultures from immature rats, treatment with letrozole significantly reduced spine synapses in the BL only in cultures derived from females. In addition, letrozole sex-specifically altered synaptic properties in the BL: in acute slices from juvenile (prepubertal) female rats, wash-in of letrozole virtually abolished long-term potentiation (LTP), whereas it did not prevent the generation of LTP in the slices from males. Together, these data indicate that neuron-derived E2 modulates synaptic plasticity in rodent BLA sex dependently. As protein expression levels of AROM, estrogen and androgen receptors did not differ between males and females and were not sex-specifically altered by letrozole, the findings suggest sex-specific mechanisms of E2 signaling.SIGNIFICANCE STATEMENT The basolateral amygdala (BLA) is a key structure of the fear circuit. This research reveals a sexually dimorphic regulation of synaptic plasticity in the BLA involving neuronal aromatase, which produces the neurosteroid 17beta-estradiol (E2). As male and female neurons in rodent BLA responded differently to aromatase inhibition both in vivo and in vitro, our findings suggest that E2 signaling in BLA neurons is regulated sex dependently, presumably via mechanisms that have been established during sexual determination. These findings could be relevant for the understanding of sex differences in mood disorders and of the side effects of cytochrome P450 aromatase inhibitors, which are frequently used for breast cancer therapy. PMID- 28028199 TI - Idiosyncratic Patterns of Representational Similarity in Prefrontal Cortex Predict Attentional Performance. AB - : The efficiency of finding an object in a crowded environment depends largely on the similarity of nontargets to the search target. Models of attention theorize that the similarity is determined by representations stored within an "attentional template" held in working memory. However, the degree to which the contents of the attentional template are individually unique and where those idiosyncratic representations are encoded in the brain are unknown. We investigated this problem using representational similarity analysis of human fMRI data to measure the common and idiosyncratic representations of famous face morphs during an identity categorization task; data from the categorization task were then used to predict performance on a separate identity search task. We hypothesized that the idiosyncratic categorical representations of the continuous face morphs would predict their distractability when searching for each target identity. The results identified that patterns of activation in the lateral prefrontal cortex (LPFC) as well as in face-selective areas in the ventral temporal cortex were highly correlated with the patterns of behavioral categorization of face morphs and search performance that were common across subjects. However, the individually unique components of the categorization behavior were reliably decoded only in right LPFC. Moreover, the neural pattern in right LPFC successfully predicted idiosyncratic variability in search performance, such that reaction times were longer when distractors had a higher probability of being categorized as the target identity. These results suggest that the prefrontal cortex encodes individually unique components of categorical representations that are also present in attentional templates for target search. SIGNIFICANCE STATEMENT: Everyone's perception of the world is uniquely shaped by personal experiences and preferences. Using functional MRI, we show that individual differences in the categorization of face morphs between two identities could be decoded from the prefrontal cortex and the ventral temporal cortex. Moreover, the individually unique representations in prefrontal cortex predicted idiosyncratic variability in attentional performance when looking for each identity in the "crowd" of another morphed face in a separate search task. Our results reveal that the representation of task-related information in prefrontal cortex is individually unique and preserved across categorization and search performance. This demonstrates the possibility of predicting individual behaviors across tasks with patterns of brain activity. PMID- 28028200 TI - Differences in Glomerular-Layer-Mediated Feedforward Inhibition onto Mitral and Tufted Cells Lead to Distinct Modes of Intensity Coding. AB - Understanding how each of the many interneuron subtypes affects brain network activity is critical. In the mouse olfactory system, mitral cells (MCs) and tufted cells (TCs) comprise parallel pathways of olfactory bulb output that are thought to play distinct functional roles in odor coding. Here, in acute mouse olfactory bulb slices, we test how the two major classes of olfactory bulb interneurons differentially contribute to differences in MC versus TC response properties. We show that, whereas TCs respond to olfactory sensory neuron (OSN) stimulation with short latencies regardless of stimulation intensity, MC latencies correlate negatively with stimulation intensity. These differences between MCs and TCs are caused in part by weaker excitatory and stronger inhibitory currents onto MCs than onto TCs. These differences in inhibition between MCs and TCs are most pronounced during the first 150 ms after stimulation and are mediated by glomerular layer circuits. Therefore, blocking inhibition originating in the glomerular layer, but not granule-cell-mediated inhibition, reduces MC spike latency at weak stimulation intensities and distinct temporal patterns of odor-evoked responses in MCs and TCs emerge in part due to differences in glomerular-layer-mediated inhibition.SIGNIFICANCE STATEMENT Olfactory bulb mitral and tufted cells display different odor-evoked responses and are thought to form parallel channels of olfactory bulb output. Therefore, determining the circuit-level causes that drive these differences is vital. Here, we find that longer-latency responses in mitral cells, compared with tufted cells, are due to weaker excitation and stronger glomerular-layer-mediated inhibition. PMID- 28028201 TI - Decoding the Cortical Dynamics of Sound-Meaning Mapping. AB - : Comprehending speech involves the rapid and optimally efficient mapping from sound to meaning. Influential cognitive models of spoken word recognition (Marslen-Wilson and Welsh, 1978) propose that the onset of a spoken word initiates a continuous process of activation of the lexical and semantic properties of the word candidates matching the speech input and competition between them, which continues until the point at which the word is differentiated from all other cohort candidates (the uniqueness point, UP). At this point, the word is recognized uniquely and only the target word's semantics are active. Although it is well established that spoken word recognition engages the superior (Rauschecker and Scott, 2009), middle, and inferior (Hickok and Poeppel, 2007) temporal cortices, little is known about the real-time brain activity that underpins the computations and representations that evolve over time during the transformation from speech to meaning. Here, we test for the first time the spatiotemporal dynamics of these processes by collecting MEG data while human participants listened to spoken words. By constructing quantitative models of competition and access to meaning in combination with spatiotemporal searchlight representational similarity analysis (Kriegeskorte et al., 2006) in source space, we were able to test where and when these models produced significant effects. We found early transient effects ~400 ms before the UP of lexical competition in left supramarginal gyrus, left superior temporal gyrus, left middle temporal gyrus (MTG), and left inferior frontal gyrus (IFG) and of semantic competition in MTG, left angular gyrus, and IFG. After the UP, there were no competitive effects, only target-specific semantic effects in angular gyrus and MTG. SIGNIFICANCE STATEMENT: Understanding spoken words involves complex processes that transform the auditory input into a meaningful interpretation. This effortless transition occurs on millisecond timescales, with remarkable speed and accuracy and without any awareness of the complex computations involved. Here, we reveal the real-time neural dynamics of these processes by collecting data about listeners' brain activity as they hear spoken words. Using novel statistical models of different aspects of the recognition process, we can locate directly which parts of the brain are accessing the stored form and meaning of words and how the competition between different word candidates is resolved neurally in real time. This gives us a uniquely differentiated picture of the neural substrate for the first 500 ms of word recognition. PMID- 28028202 TI - Family-Provided Health Care for Children With Special Health Care Needs. AB - BACKGROUND AND OBJECTIVES: Many children with special health care needs (CSHCN) receive health care at home from family members, but the extent of this care is poorly quantified. This study's goals were to create a profile of CSHCN who receive family-provided health care and to quantify the extent of such care. METHODS: We analyzed data from the 2009-2010 National Survey of Children with Special Health Care Needs, a nationally representative sample of 40 242 parents/guardians of CSHCN. Outcomes included sociodemographic characteristics of CSHCN and their households, time spent by family members providing health care at home to CSHCN, and the total economic cost of such care. Caregiving hours were assessed at (1) the cost of hiring an alternative caregiver (the "replacement cost" approach), and (2) caregiver wages (the "foregone earnings" approach). RESULTS: Approximately 5.6 million US CSHCN received 1.5 billion hours annually of family-provided health care. Replacement with a home health aide would have cost an estimated $35.7 billion or $6400 per child per year in 2015 dollars ($11.6 billion or $2100 per child per year at minimum wage). The associated foregone earnings were $17.6 billion or $3200 per child per year. CSHCN most likely to receive the greatest amount of family-provided health care at home were ages 0 to 5 years, were Hispanic, lived below the federal poverty level, had no parents/guardians who had finished high school, had both public and private insurance, and had severe conditions/problems. CONCLUSIONS: US families provide a significant quantity of health care at home to CSHCN, representing a substantial economic cost. PMID- 28028203 TI - Development of a Pediatric Adverse Events Terminology. AB - In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute's Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well- and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute's Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization. PMID- 28028204 TI - The importance of urban gardens in supporting children's biophilia. AB - Exposure to and connection with nature is increasingly recognized as providing significant well-being benefits for adults and children. Increasing numbers of children growing up in urban areas need access to nature to experience these benefits and develop a nature connection. Under the biophilia hypothesis, children should innately affiliate to nature. We investigated children's independent selection of spaces in their neighborhoods in relation to the biodiversity values of those spaces, in three New Zealand cities, using resource selection analysis. Children did not preferentially use the more biodiverse areas in their neighborhoods. Private gardens and yards were the most preferred space, with the quality of these spaces the most important factor defining children's exposure to nature. Children's reliance on gardens and yards for nature experiences raises concerns for their development of a nature connection, given disparities in biodiversity values of private gardens in relation to socioeconomic status, and the decline in sizes of private gardens in newer urban developments. PMID- 28028205 TI - QnAs with Gregg Semenza. PMID- 28028207 TI - Holocene carbonate record of Lake Kivu reflects the history of hydrothermal activity. AB - The sediment record of Lake Kivu reveals a complex volcanogenic and climatic Holocene history. Investigation of the inorganic carbonate record dates the onset of carbonate deposition in the mid-Holocene in Kivu's deep northern and eastern basins and identifies conditions enabling deposition. The magnitude and timing of carbonate-rich sedimentation is not so much controlled by climate but, instead, linked strongly to hydrothermal activity in the basin. Sublacustrine springs supply the vast majority of the calcium and carbonate ions required for supersaturation with respect to aragonite. This major hydrothermal activity that permanently stratifies Lake Kivu today was initiated ~3,100 y before present (3.1 ka), when carbonate-rich sediments first appeared in the Holocene record. Aragonite is the dominant CaCO3 mineral present in the lake deposits. Both delta13C and delta18O of the aragonite are enriched above the expected kinetic fractionation of meteoric waters, suggesting a volcanogenic influence on the formation waters. Repeated major fluctuations in the carbonate record after 3.1 ka therefore most likely reflect the historical variation in hydrothermal inputs. PMID- 28028206 TI - Two distinct pools of B12 analogs reveal community interdependencies in the ocean. AB - Organisms within all domains of life require the cofactor cobalamin (vitamin B12), which is produced only by a subset of bacteria and archaea. On the basis of genomic analyses, cobalamin biosynthesis in marine systems has been inferred in three main groups: select heterotrophic Proteobacteria, chemoautotrophic Thaumarchaeota, and photoautotrophic Cyanobacteria. Culture work demonstrates that many Cyanobacteria do not synthesize cobalamin but rather produce pseudocobalamin, challenging the connection between the occurrence of cobalamin biosynthesis genes and production of the compound in marine ecosystems. Here we show that cobalamin and pseudocobalamin coexist in the surface ocean, have distinct microbial sources, and support different enzymatic demands. Even in the presence of cobalamin, Cyanobacteria synthesize pseudocobalamin-likely reflecting their retention of an oxygen-independent pathway to produce pseudocobalamin, which is used as a cofactor in their specialized methionine synthase (MetH). This contrasts a model diatom, Thalassiosira pseudonana, which transported pseudocobalamin into the cell but was unable to use pseudocobalamin in its homolog of MetH. Our genomic and culture analyses showed that marine Thaumarchaeota and select heterotrophic bacteria produce cobalamin. This indicates that cobalamin in the surface ocean is a result of de novo synthesis by heterotrophic bacteria or via modification of closely related compounds like cyanobacterially produced pseudocobalamin. Deeper in the water column, our study implicates Thaumarchaeota as major producers of cobalamin based on genomic potential, cobalamin cell quotas, and abundance. Together, these findings establish the distinctive roles played by abundant prokaryotes in cobalamin-based microbial interdependencies that sustain community structure and function in the ocean. PMID- 28028208 TI - Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics. AB - The renewed effort to eliminate malaria and permanently remove its tremendous burden highlights questions of what combination of tools would be sufficient in various settings and what new tools need to be developed. Gene drive mosquitoes constitute a promising set of tools, with multiple different possible approaches including population replacement with introduced genes limiting malaria transmission, driving-Y chromosomes to collapse a mosquito population, and gene drive disrupting a fertility gene and thereby achieving population suppression or collapse. Each of these approaches has had recent success and advances under laboratory conditions, raising the urgency for understanding how each could be deployed in the real world and the potential impacts of each. New analyses are needed as existing models of gene drive primarily focus on nonseasonal or nonspatial dynamics. We use a mechanistic, spatially explicit, stochastic, individual-based mathematical model to simulate each gene drive approach in a variety of sub-Saharan African settings. Each approach exhibits a broad region of gene construct parameter space with successful elimination of malaria transmission due to the targeted vector species. The introduction of realistic seasonality in vector population dynamics facilitates gene drive success compared with nonseasonal analyses. Spatial simulations illustrate constraints on release timing, frequency, and spatial density in the most challenging settings for construct success. Within its parameter space for success, each gene drive approach provides a tool for malaria elimination unlike anything presently available. Provided potential barriers to success are surmounted, each achieves high efficacy at reducing transmission potential and lower delivery requirements in logistically challenged settings. PMID- 28028210 TI - Correction for Debono Spiteri et al., Regional asynchronicity in dairy production and processing in early farming communities of the northern Mediterranean. PMID- 28028209 TI - Tracking solvents in the skin through atomically resolved measurements of molecular mobility in intact stratum corneum. AB - Solvents are commonly used in pharmaceutical and cosmetic formulations and sanitary products and cleansers. The uptake of solvent into the skin may change the molecular organization of skin lipids and proteins, which may in turn alter the protective skin barrier function. We herein examine the molecular effects of 10 different solvents on the outermost layer of skin, the stratum corneum (SC), using polarization transfer solid-state NMR on natural abundance 13C in intact SC. With this approach it is possible to characterize the molecular dynamics of solvent molecules when present inside intact SC and to simultaneously monitor the effects caused by the added solvent on SC lipids and protein components. All solvents investigated cause an increased fluidity of SC lipids, with the most prominent effects shown for the apolar hydrocarbon solvents and 2-propanol. However, no solvent other than water shows the ability to fluidize amino acids in the keratin filaments. The solvent molecules themselves show reduced molecular mobility when incorporated in the SC matrix. Changes in the molecular properties of the SC, and in particular alternation in the balance between solid and fluid SC components, may have significant influences on the macroscopic SC barrier properties as well as mechanical properties of the skin. Deepened understanding of molecular effects of foreign compounds in SC fluidity can therefore have strong impact on the development of skin products in pharmaceutical, cosmetic, and sanitary applications. PMID- 28028211 TI - Wireless physical layer security. AB - Security in wireless networks has traditionally been considered to be an issue to be addressed separately from the physical radio transmission aspects of wireless systems. However, with the emergence of new networking architectures that are not amenable to traditional methods of secure communication such as data encryption, there has been an increase in interest in the potential of the physical properties of the radio channel itself to provide communications security. Information theory provides a natural framework for the study of this issue, and there has been considerable recent research devoted to using this framework to develop a greater understanding of the fundamental ability of the so-called physical layer to provide security in wireless networks. Moreover, this approach is also suggestive in many cases of coding techniques that can approach fundamental limits in practice and of techniques for other security tasks such as authentication. This paper provides an overview of these developments. PMID- 28028212 TI - Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice. AB - The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration. PMID- 28028213 TI - Programming function into mechanical forms by directed assembly of silk bulk materials. AB - We report simple, water-based fabrication methods based on protein self-assembly to generate 3D silk fibroin bulk materials that can be easily hybridized with water-soluble molecules to obtain multiple solid formats with predesigned functions. Controlling self-assembly leads to robust, machinable formats that exhibit thermoplastic behavior consenting material reshaping at the nanoscale, microscale, and macroscale. We illustrate the versatility of the approach by realizing demonstrator devices where large silk monoliths can be generated, polished, and reshaped into functional mechanical components that can be nanopatterned, embed optical function, heated on demand in response to infrared light, or can visualize mechanical failure through colorimetric chemistries embedded in the assembled (bulk) protein matrix. Finally, we show an enzyme loaded solid mechanical part, illustrating the ability to incorporate biological function within the bulk material with possible utility for sustained release in robust, programmably shapeable mechanical formats. PMID- 28028214 TI - Arginine substitution of a cysteine in transmembrane helix M8 converts Na+,K+ ATPase to an electroneutral pump similar to H+,K+-ATPase. AB - Na+,K+-ATPase and H+,K+-ATPase are electrogenic and nonelectrogenic ion pumps, respectively. The underlying structural basis for this difference has not been established, and it has not been revealed how the H+,K+-ATPase avoids binding of Na+ at the site corresponding to the Na+-specific site of the Na+,K+-ATPase (site III). In this study, we addressed these questions by using site-directed mutagenesis in combination with enzymatic, transport, and electrophysiological functional measurements. Replacement of the cysteine C932 in transmembrane helix M8 of Na+,K+-ATPase with arginine, present in the H+,K+-ATPase at the corresponding position, converted the normal 3Na+:2K+:1ATP stoichiometry of the Na+,K+-ATPase to electroneutral 2Na+:2K+:1ATP stoichiometry similar to the electroneutral transport mode of the H+,K+-ATPase. The electroneutral C932R mutant of the Na+,K+-ATPase retained a wild-type-like enzyme turnover rate for ATP hydrolysis and rate of cellular K+ uptake. Only a relatively minor reduction of apparent Na+ affinity for activation of phosphorylation from ATP was observed for C932R, whereas replacement of C932 with leucine or phenylalanine, the latter of a size comparable to arginine, led to spectacular reductions of apparent Na+ affinity without changing the electrogenicity. From these results, in combination with structural considerations, it appears that the guanidine+ group of the M8 arginine replaces Na+ at the third site, thus preventing Na+ binding there, although allowing Na+ to bind at the two other sites and become transported. Hence, in the H+,K+-ATPase, the ability of the M8 arginine to donate an internal cation binding at the third site is decisive for the electroneutral transport mode of this pump. PMID- 28028215 TI - Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes. AB - The Bcl-2 (B-cell lymphoma 2) protein Bax (Bcl-2 associated X, apoptosis regulator) can commit cells to apoptosis via outer mitochondrial membrane permeabilization. Bax activity is controlled in healthy cells by prosurvival Bcl 2 proteins. C-terminal Bax transmembrane domain interactions were implicated recently in Bax pore formation. Here, we show that the isolated transmembrane domains of Bax, Bcl-xL (B-cell lymphoma-extra large), and Bcl-2 can mediate interactions between Bax and prosurvival proteins inside the membrane in the absence of apoptotic stimuli. Bcl-2 protein transmembrane domains specifically homooligomerize and heterooligomerize in bacterial and mitochondrial membranes. Their interactions participate in the regulation of Bcl-2 proteins, thus modulating apoptotic activity. Our results suggest that interactions between the transmembrane domains of Bax and antiapoptotic Bcl-2 proteins represent a previously unappreciated level of apoptosis regulation. PMID- 28028216 TI - Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport. AB - The thick ascending limb (TAL) of Henle's loop drives paracellular Na+, Ca2+, and Mg2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins that consist of four transmembrane segments, two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to a severe disturbance of renal ion homeostasis. We combined electrophysiological measurements on microperfused mouse TAL segments with subsequent analysis of claudin expression by immunostaining and confocal microscopy. Claudin interaction properties were examined using heterologous expression in the TJ-free cell line HEK 293, live cell imaging, and Forster/FRET. To reveal determinants of interaction properties, a set of TAL claudin protein chimeras was created and analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na+ over Mg2+, whereas TJs dominated by cldn16 favor Mg2+ over Na+; (iii) cldn10b does not interact with other TAL claudins, whereas cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. We suggest the existence of at least two spatially distinct types of paracellular channels in TAL: a cldn10b-based channel for monovalent cations such as Na+ and a spatially distinct site for reabsorption of divalent cations such as Ca2+ and Mg2. PMID- 28028217 TI - Relationship between local structure and relaxation in out-of-equilibrium glassy systems. AB - The dynamical glass transition is typically taken to be the temperature at which a glassy liquid is no longer able to equilibrate on experimental timescales. Consequently, the physical properties of these systems just above or below the dynamical glass transition, such as viscosity, can change by many orders of magnitude over long periods of time following external perturbation. During this progress toward equilibrium, glassy systems exhibit a history dependence that has complicated their study. In previous work, we bridged the gap between structure and dynamics in glassy liquids above their dynamical glass transition temperatures by introducing a scalar field called "softness," a quantity obtained using machine-learning methods. Softness is designed to capture the hidden patterns in relative particle positions that correlate strongly with dynamical rearrangements of particle positions. Here we show that the out-of-equilibrium behavior of a model glass-forming system can be understood in terms of softness. To do this we first demonstrate that the evolution of behavior following a temperature quench is a primarily structural phenomenon: The structure changes considerably, but the relationship between structure and dynamics remains invariant. We then show that the relaxation time can be robustly computed from structure as quantified by softness, with the same relation holding both in equilibrium and as the system ages. Together, these results show that the history dependence of the relaxation time in glasses requires knowledge only of the softness in addition to the usual state variables. PMID- 28028218 TI - High fishery catches through trophic cascades in China. AB - Indiscriminate and intense fishing has occurred in many marine ecosystems around the world. Although this practice may have negative effects on biodiversity and populations of individual species, it may also increase total fishery productivity by removing predatory fish. We examine the potential for this phenomenon to explain the high reported wild catches in the East China Sea-one of the most productive ecosystems in the world that has also had its catch reporting accuracy and fishery management questioned. We show that reported catches can be approximated using an ecosystem model that allows for trophic cascades (i.e., the depletion of predators and consequent increases in production of their prey). This would be the world's largest known example of marine ecosystem "engineering" and suggests that trade-offs between conservation and food production exist. We project that fishing practices could be modified to increase total catches, revenue, and biomass in the East China Sea, but single-species management would decrease both catches and revenue by reversing the trophic cascades. Our results suggest that implementing single-species management in currently lightly managed and highly exploited multispecies fisheries (which account for a large fraction of global fish catch) may result in decreases in global catch. Efforts to reform management in these fisheries will need to consider system wide impacts of changes in management, rather than focusing only on individual species. PMID- 28028219 TI - Future urban land expansion and implications for global croplands. AB - Urban expansion often occurs on croplands. However, there is little scientific understanding of how global patterns of future urban expansion will affect the world's cultivated areas. Here, we combine spatially explicit projections of urban expansion with datasets on global croplands and crop yields. Our results show that urban expansion will result in a 1.8-2.4% loss of global croplands by 2030, with substantial regional disparities. About 80% of global cropland loss from urban expansion will take place in Asia and Africa. In both Asia and Africa, much of the cropland that will be lost is more than twice as productive as national averages. Asia will experience the highest absolute loss in cropland, whereas African countries will experience the highest percentage loss of cropland. Globally, the croplands that are likely to be lost were responsible for 3-4% of worldwide crop production in 2000. Urban expansion is expected to take place on cropland that is 1.77 times more productive than the global average. The loss of cropland is likely to be accompanied by other sustainability risks and threatens livelihoods, with diverging characteristics for different megaurban regions. Governance of urban area expansion thus emerges as a key area for securing livelihoods in the agrarian economies of the Global South. PMID- 28028220 TI - Spatiotemporal dynamics of similarity-based neural representations of facial identity. AB - Humans' remarkable ability to quickly and accurately discriminate among thousands of highly similar complex objects demands rapid and precise neural computations. To elucidate the process by which this is achieved, we used magnetoencephalography to measure spatiotemporal patterns of neural activity with high temporal resolution during visual discrimination among a large and carefully controlled set of faces. We also compared these neural data to lower level "image based" and higher level "identity-based" model-based representations of our stimuli and to behavioral similarity judgments of our stimuli. Between ~50 and 400 ms after stimulus onset, face-selective sources in right lateral occipital cortex and right fusiform gyrus and sources in a control region (left V1) yielded successful classification of facial identity. In all regions, early responses were more similar to the image-based representation than to the identity-based representation. In the face-selective regions only, responses were more similar to the identity-based representation at several time points after 200 ms. Behavioral responses were more similar to the identity-based representation than to the image-based representation, and their structure was predicted by responses in the face-selective regions. These results provide a temporally precise description of the transformation from low- to high-level representations of facial identity in human face-selective cortex and demonstrate that face selective cortical regions represent multiple distinct types of information about face identity at different times over the first 500 ms after stimulus onset. These results have important implications for understanding the rapid emergence of fine-grained, high-level representations of object identity, a computation essential to human visual expertise. PMID- 28028221 TI - Stable population coding for working memory coexists with heterogeneous neural dynamics in prefrontal cortex. AB - Working memory (WM) is a cognitive function for temporary maintenance and manipulation of information, which requires conversion of stimulus-driven signals into internal representations that are maintained across seconds-long mnemonic delays. Within primate prefrontal cortex (PFC), a critical node of the brain's WM network, neurons show stimulus-selective persistent activity during WM, but many of them exhibit strong temporal dynamics and heterogeneity, raising the questions of whether, and how, neuronal populations in PFC maintain stable mnemonic representations of stimuli during WM. Here we show that despite complex and heterogeneous temporal dynamics in single-neuron activity, PFC activity is endowed with a population-level coding of the mnemonic stimulus that is stable and robust throughout WM maintenance. We applied population-level analyses to hundreds of recorded single neurons from lateral PFC of monkeys performing two seminal tasks that demand parametric WM: oculomotor delayed response and vibrotactile delayed discrimination. We found that the high-dimensional state space of PFC population activity contains a low-dimensional subspace in which stimulus representations are stable across time during the cue and delay epochs, enabling robust and generalizable decoding compared with time-optimized subspaces. To explore potential mechanisms, we applied these same population level analyses to theoretical neural circuit models of WM activity. Three previously proposed models failed to capture the key population-level features observed empirically. We propose network connectivity properties, implemented in a linear network model, which can underlie these features. This work uncovers stable population-level WM representations in PFC, despite strong temporal neural dynamics, thereby providing insights into neural circuit mechanisms supporting WM. PMID- 28028222 TI - Influenza A surface glycosylation and vaccine design. AB - We have shown that glycosylation of influenza A virus (IAV) hemagglutinin (HA), especially at position N-27, is crucial for HA folding and virus survival. However, it is not known whether the glycosylation of HA and the other two major IAV surface glycoproteins, neuraminidase (NA) and M2 ion channel, is essential for the replication of IAV. Here, we show that glycosylation of HA at N-142 modulates virus infectivity and host immune response. Glycosylation of NA in the stalk region affects its structure, activity, and specificity, thereby modulating virus release and virulence, and glycosylation at the catalytic domain affects its thermostability; however, glycosylation of M2 had no effect on its function. In addition, using IAV without the stalk and catalytic domains of NA as a live attenuated vaccine was shown to confer a strong IAV-specific CD8+ T-cell response and a strong cross-strain as well as cross-subtype protection against various virus strains. PMID- 28028223 TI - Climate change damages to Alaska public infrastructure and the economics of proactive adaptation. AB - Climate change in the circumpolar region is causing dramatic environmental change that is increasing the vulnerability of infrastructure. We quantified the economic impacts of climate change on Alaska public infrastructure under relatively high and low climate forcing scenarios [representative concentration pathway 8.5 (RCP8.5) and RCP4.5] using an infrastructure model modified to account for unique climate impacts at northern latitudes, including near-surface permafrost thaw. Additionally, we evaluated how proactive adaptation influenced economic impacts on select infrastructure types and developed first-order estimates of potential land losses associated with coastal erosion and lengthening of the coastal ice-free season for 12 communities. Cumulative estimated expenses from climate-related damage to infrastructure without adaptation measures (hereafter damages) from 2015 to 2099 totaled $5.5 billion (2015 dollars, 3% discount) for RCP8.5 and $4.2 billion for RCP4.5, suggesting that reducing greenhouse gas emissions could lessen damages by $1.3 billion this century. The distribution of damages varied across the state, with the largest damages projected for the interior and southcentral Alaska. The largest source of damages was road flooding caused by increased precipitation followed by damages to buildings associated with near-surface permafrost thaw. Smaller damages were observed for airports, railroads, and pipelines. Proactive adaptation reduced total projected cumulative expenditures to $2.9 billion for RCP8.5 and $2.3 billion for RCP4.5. For road flooding, adaptation provided an annual savings of 80-100% across four study eras. For nearly all infrastructure types and time periods evaluated, damages and adaptation costs were larger for RCP8.5 than RCP4.5. Estimated coastal erosion losses were also larger for RCP8.5. PMID- 28028224 TI - APE2 Zf-GRF facilitates 3'-5' resection of DNA damage following oxidative stress. AB - The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3'-5' nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3alpha (TOP3alpha) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure guided Zf-GRF mutations impact APE2 DNA binding and 3'-5' exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9. PMID- 28028226 TI - Single-pixel interior filling function approach for detecting and correcting errors in particle tracking. AB - We present a general method for detecting and correcting biases in the outputs of particle-tracking experiments. Our approach is based on the histogram of estimated positions within pixels, which we term the single-pixel interior filling function (SPIFF). We use the deviation of the SPIFF from a uniform distribution to test the veracity of tracking analyses from different algorithms. Unbiased SPIFFs correspond to uniform pixel filling, whereas biased ones exhibit pixel locking, in which the estimated particle positions concentrate toward the centers of pixels. Although pixel locking is a well-known phenomenon, we go beyond existing methods to show how the SPIFF can be used to correct errors. The key is that the SPIFF aggregates statistical information from many single particle images and localizations that are gathered over time or across an ensemble, and this information augments the single-particle data. We explicitly consider two cases that give rise to significant errors in estimated particle locations: undersampling the point spread function due to small emitter size and intensity overlap of proximal objects. In these situations, we show how errors in positions can be corrected essentially completely with little added computational cost. Additional situations and applications to experimental data are explored in SI Appendix In the presence of experimental-like shot noise, the precision of the SPIFF-based correction achieves (and can even exceed) the unbiased Cramer-Rao lower bound. We expect the SPIFF approach to be useful in a wide range of localization applications, including single-molecule imaging and particle tracking, in fields ranging from biology to materials science to astronomy. PMID- 28028225 TI - The global decline of cheetah Acinonyx jubatus and what it means for conservation. AB - Establishing and maintaining protected areas (PAs) are key tools for biodiversity conservation. However, this approach is insufficient for many species, particularly those that are wide-ranging and sparse. The cheetah Acinonyx jubatus exemplifies such a species and faces extreme challenges to its survival. Here, we show that the global population is estimated at ~7,100 individuals and confined to 9% of its historical distributional range. However, the majority of current range (77%) occurs outside of PAs, where the species faces multiple threats. Scenario modeling shows that, where growth rates are suppressed outside PAs, extinction rates increase rapidly as the proportion of population protected declines. Sensitivity analysis shows that growth rates within PAs have to be high if they are to compensate for declines outside. Susceptibility of cheetah to rapid decline is evidenced by recent rapid contraction in range, supporting an uplisting of the International Union for the Conservation of Nature (IUCN) Red List threat assessment to endangered. Our results are applicable to other protection-reliant species, which may be subject to systematic underestimation of threat when there is insufficient information outside PAs. Ultimately, conserving many of these species necessitates a paradigm shift in conservation toward a holistic approach that incentivizes protection and promotes sustainable human wildlife coexistence across large multiple-use landscapes. PMID- 28028227 TI - Oxytocin reactivity during intergroup conflict in wild chimpanzees. AB - Intergroup conflict is evident throughout the history of our species, ubiquitous across human societies, and considered crucial for the evolution of humans' large scale cooperative nature. Like humans, chimpanzee societies exhibit intragroup coordination and coalitionary support during violent intergroup conflicts. In both species, cooperation among group members is essential for individuals to gain access to benefits from engaging in intergroup conflict. Studies suggest that a contributive mechanism regulating in-group cooperation during intergroup conflicts in humans involves the neuropeptide hormone oxytocin, known to influence trust, coordination, and social cognition, although evidence from natural settings is lacking. Here, applying a noninvasive method, we investigate oxytocinergic system involvement during natural intergroup conflicts in wild chimpanzees. We found that chimpanzees of both sexes had significantly higher urinary oxytocin levels immediately before and during intergroup conflict compared with controls. Also, elevated hormone levels were linked with greater cohesion during intergroup conflicts, rather than with the level of potential threat posed by rival groups, intragroup affiliative social interactions, or coordinated behavior alone. Thus, the oxytocinergic system, potentially engendering cohesion and cooperation when facing an out-group threat, may not be uniquely human but rather a mechanism with evolutionary roots shared by our last common ancestor with chimpanzees, likely expediting fitness gains during intergroup conflict. PMID- 28028228 TI - Large-scale heterochromatin remodeling linked to overreplication-associated DNA damage. AB - Previously, we have shown that loss of the histone 3 lysine 27 (H3K27) monomethyltransferases ARABIDOPSIS TRITHORAX-RELATED 5 (ATXR5) and ATXR6 (ATXR6) results in the overreplication of heterochromatin. Here we show that the overreplication results in DNA damage and extensive chromocenter remodeling into unique structures we have named "overreplication-associated centers" (RACs). RACs have a highly ordered structure with an outer layer of condensed heterochromatin, an inner layer enriched in the histone variant H2AX, and a low-density core containing foci of phosphorylated H2AX (a marker of double-strand breaks) and the DNA-repair enzyme RAD51. atxr5,6 mutants are strongly affected by mutations in DNA repair, such as ATM and ATR. Because of its dense packaging and repetitive DNA sequence, heterochromatin is a challenging environment in which to repair DNA damage. Previous work in animals has shown that heterochromatic breaks are translocated out of the heterochromatic domain for repair. Our results show that atxr5,6 mutants use a variation on this strategy for repairing heterochromatic DNA damage. Rather than being moved to adjacent euchromatic regions, as in animals, heterochromatin undergoes large-scale remodeling to create a compartment with low chromatin density. PMID- 28028229 TI - Achromatopsia mutations target sequential steps of ATF6 activation. AB - Achromatopsia is an autosomal recessive disorder characterized by cone photoreceptor dysfunction. We recently identified activating transcription factor 6 (ATF6) as a genetic cause of achromatopsia. ATF6 is a key regulator of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, ATF6 migrates from the ER to Golgi to undergo regulated intramembrane proteolysis to release a cytosolic domain containing a basic leucine zipper (bZIP) transcriptional activator. The cleaved ATF6 fragment migrates to the nucleus to transcriptionally up-regulate protein-folding enzymes and chaperones. ATF6 mutations in patients with achromatopsia include missense, nonsense, splice site, and single-nucleotide deletion or duplication changes found across the entire gene. Here, we comprehensively tested the function of achromatopsia-associated ATF6 mutations and found that they group into three distinct molecular pathomechanisms: class 1 ATF6 mutants show impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; class 2 ATF6 mutants bear the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress; and class 3 ATF6 mutants have complete loss of transcriptional activity because of absent or defective bZIP domains. Primary fibroblasts from patients with class 1 or class 3 ATF6 mutations show increased cell death in response to ER stress. Our findings reveal that human ATF6 mutations interrupt distinct sequential steps of the ATF6 activation mechanism. We suggest that increased susceptibility to ER stress-induced damage during retinal development underlies the pathology of achromatopsia in patients with ATF6 mutations. PMID- 28028231 TI - Correction for Bonardi et al., Expanded functions for a family of plant intracellular immune receptors beyond specific recognition of pathogen effectors. PMID- 28028230 TI - Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite. AB - Organic hydroperoxide resistance (Ohr) enzymes are unique Cys-based, lipoyl dependent peroxidases. Here, we investigated the involvement of Ohr in bacterial responses toward distinct hydroperoxides. In silico results indicated that fatty acid (but not cholesterol) hydroperoxides docked well into the active site of Ohr from Xylella fastidiosa and were efficiently reduced by the recombinant enzyme as assessed by a lipoamide-lipoamide dehydrogenase-coupled assay. Indeed, the rate constants between Ohr and several fatty acid hydroperoxides were in the 107-108 M 1?s-1 range as determined by a competition assay developed here. Reduction of peroxynitrite by Ohr was also determined to be in the order of 107 M-1?s-1 at pH 7.4 through two independent competition assays. A similar trend was observed when studying the sensitivities of a ?ohr mutant of Pseudomonas aeruginosa toward different hydroperoxides. Fatty acid hydroperoxides, which are readily solubilized by bacterial surfactants, killed the ?ohr strain most efficiently. In contrast, both wild-type and mutant strains deficient for peroxiredoxins and glutathione peroxidases were equally sensitive to fatty acid hydroperoxides. Ohr also appeared to play a central role in the peroxynitrite response, because the ?ohr mutant was more sensitive than wild type to 3-morpholinosydnonimine hydrochloride (SIN-1 , a peroxynitrite generator). In the case of H2O2 insult, cells treated with 3-amino-1,2,4-triazole (a catalase inhibitor) were the most sensitive. Furthermore, fatty acid hydroperoxide and SIN-1 both induced Ohr expression in the wild-type strain. In conclusion, Ohr plays a central role in modulating the levels of fatty acid hydroperoxides and peroxynitrite, both of which are involved in host-pathogen interactions. PMID- 28028232 TI - Two independent S-phase checkpoints regulate appressorium-mediated plant infection by the rice blast fungus Magnaporthe oryzae. AB - To cause rice blast disease, the fungal pathogen Magnaporthe oryzae develops a specialized infection structure called an appressorium. This dome-shaped, melanin pigmented cell generates enormous turgor and applies physical force to rupture the rice leaf cuticle using a rigid penetration peg. Appressorium-mediated infection requires septin-dependent reorientation of the F-actin cytoskeleton at the base of the infection cell, which organizes polarity determinants necessary for plant cell invasion. Here, we show that plant infection by M. oryzae requires two independent S-phase cell-cycle checkpoints. Initial formation of appressoria on the rice leaf surface requires an S-phase checkpoint that acts through the DNA damage response (DDR) pathway, involving the Cds1 kinase. By contrast, appressorium repolarization involves a novel, DDR-independent S-phase checkpoint, triggered by appressorium turgor generation and melanization. This second checkpoint specifically regulates septin-dependent, NADPH oxidase-regulated F actin dynamics to organize the appressorium pore and facilitate entry of the fungus into host tissue. PMID- 28028235 TI - Correction for Chang et al., Construction of a male sterility system for hybrid rice breeding and seed production using a nuclear male sterility gene. PMID- 28028234 TI - Reversal of a cyanobacterial bloom in response to early warnings. AB - Directional change in environmental drivers sometimes triggers regime shifts in ecosystems. Theory and experiments suggest that regime shifts can be detected in advance, and perhaps averted, by monitoring resilience indicators such as variance and autocorrelation of key ecosystem variables. However, it is uncertain whether management action prompted by a change in resilience indicators can prevent an impending regime shift. We caused a cyanobacterial bloom by gradually enriching an experimental lake while monitoring an unenriched reference lake and a continuously enriched reference lake. When resilience indicators exceeded preset boundaries, nutrient enrichment was stopped in the experimental lake. Concentrations of algal pigments, dissolved oxygen saturation, and pH rapidly declined following cessation of nutrient enrichment and became similar to the unenriched lake, whereas a large bloom occurred in the continuously enriched lake. This outcome suggests that resilience indicators may be useful in management to prevent unwanted regime shifts, at least in some situations. Nonetheless, a safer approach to ecosystem management would build and maintain the resilience of desirable ecosystem conditions, for example, by preventing excessive nutrient input to lakes and reservoirs. PMID- 28028233 TI - Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins. AB - The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/beta catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/beta-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM. PMID- 28028236 TI - In operando evidence of deoxygenation in ionic liquid gating of YBa2Cu3O7-X. AB - Field-effect experiments on cuprates using ionic liquids have enabled the exploration of their rich phase diagrams [Leng X, et al. (2011) Phys Rev Lett 107(2):027001]. Conventional understanding of the electrostatic doping is in terms of modifications of the charge density to screen the electric field generated at the double layer. However, it has been recently reported that the suppression of the metal to insulator transition induced in VO2 by ionic liquid gating is due to oxygen vacancy formation rather than to electrostatic doping [Jeong J, et al. (2013) Science 339(6126):1402-1405]. These results underscore the debate on the true nature, electrostatic vs. electrochemical, of the doping of cuprates with ionic liquids. Here, we address the doping mechanism of the high temperature superconductor YBa2Cu3O7-X (YBCO) by simultaneous ionic liquid gating and X-ray absorption experiments. Pronounced spectral changes are observed at the Cu K-edge concomitant with the superconductor-to-insulator transition, evidencing modification of the Cu coordination resulting from the deoxygenation of the CuO chains, as confirmed by first-principles density functional theory (DFT) simulations. Beyond providing evidence of the importance of chemical doping in electric double-layer (EDL) gating experiments with superconducting cuprates, our work shows that interfacing correlated oxides with ionic liquids enables a delicate control of oxygen content, paving the way to novel electrochemical concepts in future oxide electronics. PMID- 28028237 TI - Nrf2 mitigates LRRK2- and alpha-synuclein-induced neurodegeneration by modulating proteostasis. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) and alpha-synuclein lead to Parkinson's disease (PD). Disruption of protein homeostasis is an emerging theme in PD pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. We determined if activating nuclear factor erythroid 2-related factor (Nrf2), a potential therapeutic target for neurodegeneration, could reduce PD-associated neuron toxicity by modulating the protein homeostasis network. Using a longitudinal imaging platform, we visualized the metabolism and location of mutant LRRK2 and alpha-synuclein in living neurons at the single-cell level. Nrf2 reduced PD-associated protein toxicity by a cell autonomous mechanism that was time-dependent. Furthermore, Nrf2 activated distinct mechanisms to handle different misfolded proteins. Nrf2 decreased steady state levels of alpha-synuclein in part by increasing alpha-synuclein degradation. In contrast, Nrf2 sequestered misfolded diffuse LRRK2 into more insoluble and homogeneous inclusion bodies. By identifying the stress response strategies activated by Nrf2, we also highlight endogenous coping responses that might be therapeutically bolstered to treat PD. PMID- 28028238 TI - Major transitions in dinoflagellate evolution unveiled by phylotranscriptomics. AB - Dinoflagellates are key species in marine environments, but they remain poorly understood in part because of their large, complex genomes, unique molecular biology, and unresolved in-group relationships. We created a taxonomically representative dataset of dinoflagellate transcriptomes and used this to infer a strongly supported phylogeny to map major morphological and molecular transitions in dinoflagellate evolution. Our results show an early-branching position of Noctiluca, monophyly of thecate (plate-bearing) dinoflagellates, and paraphyly of athecate ones. This represents unambiguous phylogenetic evidence for a single origin of the group's cellulosic theca, which we show coincided with a radiation of cellulases implicated in cell division. By integrating dinoflagellate molecular, fossil, and biogeochemical evidence, we propose a revised model for the evolution of thecal tabulations and suggest that the late acquisition of dinosterol in the group is inconsistent with dinoflagellates being the source of this biomarker in pre-Mesozoic strata. Three distantly related, fundamentally nonphotosynthetic dinoflagellates, Noctiluca, Oxyrrhis, and Dinophysis, contain cryptic plastidial metabolisms and lack alternative cytosolic pathways, suggesting that all free-living dinoflagellates are metabolically dependent on plastids. This finding led us to propose general mechanisms of dependency on plastid organelles in eukaryotes that have lost photosynthesis; it also suggests that the evolutionary origin of bioluminescence in nonphotosynthetic dinoflagellates may be linked to plastidic tetrapyrrole biosynthesis. Finally, we use our phylogenetic framework to show that dinoflagellate nuclei have recruited DNA-binding proteins in three distinct evolutionary waves, which included two independent acquisitions of bacterial histone-like proteins. PMID- 28028239 TI - Asymmetric unwrapping of nucleosomal DNA propagates asymmetric opening and dissociation of the histone core. AB - The nucleosome core particle (NCP) is the basic structural unit for genome packaging in eukaryotic cells and consists of DNA wound around a core of eight histone proteins. DNA access is modulated through dynamic processes of NCP disassembly. Partly disassembled structures, such as the hexasome (containing six histones) and the tetrasome (four histones), are important for transcription regulation in vivo. However, the pathways for their formation have been difficult to characterize. We combine time-resolved (TR) small-angle X-ray scattering and TR-FRET to correlate changes in the DNA conformations with composition of the histone core during salt-induced disassembly of canonical NCPs. We find that H2A H2B histone dimers are released sequentially, with the first dimer being released after the DNA has formed an asymmetrically unwrapped, teardrop-shape DNA structure. This finding suggests that the octasome-to-hexasome transition is guided by the asymmetric unwrapping of the DNA. The link between DNA structure and histone composition suggests a potential mechanism for the action of proteins that alter nucleosome configurations such as histone chaperones and chromatin remodeling complexes. PMID- 28028240 TI - Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers. AB - The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers. PMID- 28028241 TI - Abscisic acid signaling is controlled by a BRANCHED1/HD-ZIP I cascade in Arabidopsis axillary buds. AB - Shoot-branching patterns determine key aspects of plant life and are important targets for crop breeding. However, we are still largely ignorant of the genetic networks controlling locally the most important decision during branch development: whether the axillary bud, or branch primordium, grows out to give a lateral shoot or remains dormant. Here we show that, inside the buds, the TEOSINTE BRANCHED1, CYCLOIDEA, PCF (TCP) transcription factor BRANCHED1 (BRC1) binds to and positively regulates the transcription of three related Homeodomain leucine zipper protein (HD-ZIP)-encoding genes: HOMEOBOX PROTEIN 21 (HB21), HOMEOBOX PROTEIN 40 (HB40), and HOMEOBOX PROTEIN 53 (HB53). These three genes, together with BRC1, enhance 9-CIS-EPOXICAROTENOID DIOXIGENASE 3 (NCED3) expression, lead to abscisic acid accumulation, and trigger hormone response, thus causing suppression of bud development. This TCP/HD-ZIP genetic module seems to be conserved in dicot and monocotyledonous species to prevent branching under light-limiting conditions. PMID- 28028243 TI - Transparent amorphous oxide semiconductors for organic electronics: Application to inverted OLEDs. AB - Efficient electron transfer between a cathode and an active organic layer is one key to realizing high-performance organic devices, which require electron injection/transport materials with very low work functions. We developed two wide bandgap amorphous (a-) oxide semiconductors, a-calcium aluminate electride (a C12A7:e) and a-zinc silicate (a-ZSO). A-ZSO exhibits a low work function of 3.5 eV and high electron mobility of 1 cm2/(V . s); furthermore, it also forms an ohmic contact with not only conventional cathode materials but also anode materials. A-C12A7:e has an exceptionally low work function of 3.0 eV and is used to enhance the electron injection property from a-ZSO to an emission layer. The inverted electron-only and organic light-emitting diode (OLED) devices fabricated with these two materials exhibit excellent performance compared with the normal type with LiF/Al. This approach provides a solution to the problem of fabricating oxide thin-film transistor-driven OLEDs with both large size and high stability. PMID- 28028242 TI - Lanthanide-dependent cross-feeding of methane-derived carbon is linked by microbial community interactions. AB - The utilization of methane, a potent greenhouse gas, is an important component of local and global carbon cycles that is characterized by tight linkages between methane-utilizing (methanotrophic) and nonmethanotrophic bacteria. It has been suggested that the methanotroph sustains these nonmethanotrophs by cross-feeding, because subsequent products of the methane oxidation pathway, such as methanol, represent alternative carbon sources. We established cocultures in a microcosm model system to determine the mechanism and substrate that underlay the observed cross-feeding in the environment. Lanthanum, a rare earth element, was applied because of its increasing importance in methylotrophy. We used co-occurring strains isolated from Lake Washington sediment that are involved in methane utilization: a methanotroph and two nonmethanotrophic methylotrophs. Gene expression profiles and mutant analyses suggest that methanol is the dominant carbon and energy source the methanotroph provides to support growth of the nonmethanotrophs. However, in the presence of the nonmethanotroph, gene expression of the dominant methanol dehydrogenase (MDH) shifts from the lanthanide-dependent MDH (XoxF)-type, to the calcium-dependent MDH (MxaF)-type. Correspondingly, methanol is released into the medium only when the methanotroph expresses the MxaF-type MDH. These results suggest a cross-feeding mechanism in which the nonmethanotrophic partner induces a change in expression of methanotroph MDHs, resulting in release of methanol for its growth. This partner induced change in gene expression that benefits the partner is a paradigm for microbial interactions that cannot be observed in studies of pure cultures, underscoring the importance of synthetic microbial community approaches to understand environmental microbiomes. PMID- 28028244 TI - Origin of hydrophobicity and enhanced water hydrogen bond strength near purely hydrophobic solutes. AB - Hydrophobicity plays an important role in numerous physicochemical processes from the process of dissolution in water to protein folding, but its origin at the fundamental level is still unclear. The classical view of hydrophobic hydration is that, in the presence of a hydrophobic solute, water forms transient microscopic "icebergs" arising from strengthened water hydrogen bonding, but there is no experimental evidence for enhanced hydrogen bonding and/or icebergs in such solutions. Here, we have used the redshifts and line shapes of the isotopically decoupled IR oxygen-deuterium (O-D) stretching mode of HDO water near small purely hydrophobic solutes (methane, ethane, krypton, and xenon) to study hydrophobicity at the most fundamental level. We present unequivocal and model-free experimental proof for the presence of strengthened water hydrogen bonds near four hydrophobic solutes, matching those in ice and clathrates. The water molecules involved in the enhanced hydrogen bonds display extensive structural ordering resembling that in clathrates. The number of ice-like hydrogen bonds is 10-15 per methane molecule. Ab initio molecular dynamics simulations have confirmed that water molecules in the vicinity of methane form stronger, more numerous, and more tetrahedrally oriented hydrogen bonds than those in bulk water and that their mobility is restricted. We show the absence of intercalating water molecules that cause the electrostatic screening (shielding) of hydrogen bonds in bulk water as the critical element for the enhanced hydrogen bonding around a hydrophobic solute. Our results confirm the classical view of hydrophobic hydration. PMID- 28028246 TI - Efficient small molecular organic light emitting diode with graphene cathode covered by a Sm layer with nano-hollows and n-doped by Bphen:Cs2CO3 in the hollows. AB - Graphene is a favorable candidate for electrodes of organic light emitting diodes (OLEDs). Graphene has quite a high work function of ~4.5 eV, and has been extensively studied when used as anodes of OLEDs. In order to use graphene as a cathode, the electron injection barrier between the graphene cathode and the electron transport layer has to be low enough. Using 4,7-diphenyl-1,10 phenanthroline (Bphen):Cs2CO3 to n-dope graphene is a very good method, but the electron injection barrier between the n-doped graphene and Bphen:Cs2CO3 is still too high to be ~1.0 eV. In this work, in order to further reduce the electron injection barrier, a novel method is suggested. On the graphene cathode, a Sm layer with a lot of nano-hollows, and subsequently a layer of Bphen:Cs2CO3, are deposited. The Bphen:Cs2CO3 can n-dope graphene in the nano-hollows, and the Fermi level of the graphene rises. The nano Sm layer is very easily oxidized. Oxygen adsorbed on the surface of graphene may react with Sm to form an O--Sm+ dipole layer. On the areas of the Sm oxide dipole layer without nano-hollows, the electron injection barrier can be further lowered by the dipole layer. Electrons tend to mainly inject through the lower electron barrier where the dipole layer exists. Based on this idea, an effective inverted small molecular OLED with the structure of graphene/1 nm Sm layer with a lot of nano hollows/Bphen:Cs2CO3/Alq3:C545T/NPB/MoO3/Al is presented. The maximum current efficiency and maximum power efficiency of the OLED with a 1 nm Sm layer are about two and three times of those of the reference OLED without any Sm layer, respectively. PMID- 28028245 TI - Synthesis of arborane triterpenols by a bacterial oxidosqualene cyclase. AB - Cyclic triterpenoids are a broad class of polycyclic lipids produced by bacteria and eukaryotes. They are biologically relevant for their roles in cellular physiology, including membrane structure and function, and biochemically relevant for their exquisite enzymatic cyclization mechanism. Cyclic triterpenoids are also geobiologically significant as they are readily preserved in sediments and are used as biomarkers for ancient life throughout Earth's history. Isoarborinol is one such triterpenoid whose only known biological sources are certain angiosperms and whose diagenetic derivatives (arboranes) are often used as indicators of terrestrial input into aquatic environments. However, the occurrence of arborane biomarkers in Permian and Triassic sediments, which predates the accepted origin of angiosperms, suggests that microbial sources of these lipids may also exist. In this study, we identify two isoarborinol-like lipids, eudoraenol and adriaticol, produced by the aerobic marine heterotrophic bacterium Eudoraea adriatica Phylogenetic analysis demonstrates that the E. adriatica eudoraenol synthase is an oxidosqualene cyclase homologous to bacterial lanosterol synthases and distinct from plant triterpenoid synthases. Using an Escherichia coli heterologous sterol expression system, we demonstrate that substitution of four amino acid residues in a bacterial lanosterol synthase enabled synthesis of pentacyclic arborinols in addition to tetracyclic sterols. This variant provides valuable mechanistic insight into triterpenoid synthesis and reveals diagnostic amino acid residues to differentiate between sterol and arborinol synthases in genomic and metagenomic datasets. Our data suggest that there may be additional bacterial arborinol producers in marine and freshwater environments that could expand our understanding of these geologically informative lipids. PMID- 28028247 TI - Air-stable few-layer black phosphorus phototransistor for near-infrared detection. AB - We have demonstrated a few-layer black phosphorus (BP) phototransistor of stable operation in ambient air environment and at near-infrared light (lambda = 1550 nm). The air-stable electronic and optoelectronic properties of the few-layer BP phototransistor have been achieved by a proper Al2O3 passivation. The optical identification method and qualitative and quantitative electrical characterizations of the few-layer BP phototransistor in dark state confirmed that the device performance was robust in ambient air, to further chemical treatments, and storage of more than six months. In addition, the low-frequency noise characterizations had revealed that the noise spectral density related to the sensitivity of phototransistor was reduced. Owing to the suppression of interaction between few-layer BP and adsorbates arising from the Al2O3 passivation, a fast rise time of the few-layer BP phototransistor, less than 100 MUs, had been observed, demonstrating the intrinsic photoresponse properties of few-layer BP. The low dark current of ~4 nA at the operation bias and the reasonable responsivity of ~6 mA W-1 were obtained under the condition lacking adsorbates interactions. Internally, the dark current and responsivity level was tunable by changing the operation bias. Our results are close to the intrinsic properties of the few-layer BP phototransistor, implying that it can be a building block of functioned few-layer BP photodetectors. PMID- 28028249 TI - Thermal conductivity of single-layer WSe2 by a Stillinger-Weber potential. AB - In this study, we present the parameters of the Stillinger-Weber (SW) potential for single-layer WSe2 and calculate its in-plane thermal conductivity using a reverse non-equilibrium molecular dynamics simulation. The parameters are fitted to the phonon dispersion curves from literature density functional perturbation theory and experimental structural properties. The set reproduces the phonon dispersion well. The in-plane thermal conductivity of single-layer WSe2 and its dependency on sample length and temperature are calculated and the results are in good agreement with experimental values. Our developed SW-type potential facilitates further investigations on thermal, mechanical and other properties of WSe2. PMID- 28028248 TI - Facile fabrication of tissue-engineered constructs using nanopatterned cell sheets and magnetic levitation. AB - We report a simple and versatile method for in vitro fabrication of scaffold-free tissue-engineered constructs with predetermined cellular alignment, by combining magnetic cell levitation with thermoresponsive nanofabricated substratum (TNFS) based cell sheet engineering technique. The TNFS based nanotopography provides contact guidance cues for regulation of cellular alignment and enables cell sheet transfer, while magnetic nanoparticles facilitate the magnetic levitation of the cell sheet. The temperature-mediated change in surface wettability of the thermoresponsive poly(N-isopropylacrylamide), substratum enables the spontaneous detachment of cell monolayers, which can then be easily manipulated through use of a ring or disk shaped magnet. Our developed platform could be readily applicable to production of tissue-engineered constructs containing complex physiological structures for the study of tissue structure-function relationships, drug screening, and regenerative medicine. PMID- 28028250 TI - Fabrication of Bi2Te3-x Se x nanowires with tunable chemical compositions and enhanced thermoelectric properties. AB - Uniform Bi2Te3-x Se x nanowires (NWs) with tunable components are synthesized by a modified solution method free of any template, and inter-diffusion mechanism is proposed for the growth and transformation of ternary nanowires. Spark plasma sintering is adopted to fabricate the pellets of Bi2Te3-x Se x NWs and thermoelectric transport properties are measured. As compared to Bi2Te3 pellets, Se doping results in lowered electrical conductivity because of the reduced carrier concentration, both the Seebeck coefficient and the power factor are enhanced substantially. The Bi2Te2.7Se0.3 pellet exhibits the highest power factor at room temperature as a result of optimized carrier concentration (4.37 * 1019 cm-3) and mobility (60.22 cm2 V-1 s-1). As compared to Bi2Te3, the thermal conductivity of Bi2Te3-x Se x is lowered owing to the enhanced phonon scattering by dopants and grain boundaries. As a result, the ZT value at 300 K is substantially improved from 0.045 of Bi2Te3 to 0.42 of Bi2Te2.7Se0.3. It is suggested that Se doping is an effective way to enhance the thermoelectric performance of Bi2Te3 based materials. PMID- 28028251 TI - [Employment Support for Cancer Patients]. AB - In Japan, the number of people who suffer with cancer once in their lives has increased since 1985, and the 5-year relative survival rate for cancer patients continues to improve. As a result, there have been reports on the difficulties faced by working age patients because they attempt to simultaneously undergo cancer treatment and work. In June 2012, the Ministry of Health, Labour and Welfare published the Basic Plan to Promote Cancer Control Programs with improved cancer countermeasures for working people and children to manage problems related to the employment of cancer patients, and it has been subsequently promoting these initiatives. A report on the needs and problems faced by medical facilities regarding the employment of cancer patients, survivors, and their family members was presented at an investigative commission in August 2014 that assessed ways to support the employment of cancer patients and survivors. In February 2016, the Ministry of Health, Labour and Welfare released its guidelines on providing workplace support to people attempting to simultaneously undergo treatment and continue working. The authors conducted an interview survey of clinical nurses who provided employment and life support to cancer patients. In this study, we present examples of employment support practices provided to cancer patients by clinical nurses that we hope will be helpful to medical facilities providing such support. PMID- 28028252 TI - [Chemotherapeutic Strategies for Peritoneal Dissemination of Gastric Cancer]. AB - The prognosis of unresectable or metastatic gastric cancer is poor. One of the reasons for this is peritoneal dissemination, which is often observed in gastric cancer. Here, we discuss some new therapeutic strategies, especially chemotherapeutic strategies, for peritoneal dissemination of gastric cancer. Occasionally, in cases of peritoneal dissemination, patients have severe ascites or bowel obstruction. For those who have such complications, treatment via chemotherapy including S-1, capecitabine, or cisplatin is inappropriate. Therefore, methotrexate plus 5-fluorouracil(5-FU), 5-FU continuous infusion, 5- FU plus l-levofolinate, or paclitaxel are generally administered to such patients. To improve the efficacy of chemotherapy for such patients, an ongoing clinical trial(JCOG1108)is comparing triplet chemotherapy(FLTAX)including 5-FU plus l-levofolinate plus paclitaxel with chemotherapy including 5-FU plus l levofolinate. For gastric cancer with positive lavage cytology, S-1 monotherapy or S-1 plus cisplatin therapy are often used. However, till date there has been no prospective clinical trial that has evaluated the efficacy of these therapies in gastric cancer with peritoneal dissemination. Therefore, further clinical trials are warranted to evaluate which chemotherapy is more suitable for patients with gastric cancer with peritoneal dissemination. Moreover, the use of conventional combination chemotherapy and intraperitoneal(IP)chemotherapy for patients with gastric cancer with peritoneal dissemination is now under evaluation. At the latest ASCOmeeting, the results of the "PHOENIX-GC trial" were reported. In this trial, patients receiving IP paclitaxel, intravenous(IV)paclitaxel, and S-1(experimental arm)and those receiving S-1 plus cisplatin(control arm)were compared. Longer survival was observed in the IP paclitaxel group compared with the other groups; however, this difference did not reach statistical significance. We hope that the evaluation of data from clinical trials would result in the identification of the optimal treatment strategy for patients with gastric cancer with peritoneal dissemination. PMID- 28028253 TI - [Intraperitoneal Chemotherapy for Peritoneal Metastasis of Gastric Cancer]. AB - Peritoneal metastasis of gastric cancer remains a refractory disease, and the standard treatment strategy is still unclear. Intraperitoneally administered paclitaxel(PTX)remains in the intraperitoneal(IP)cavity for a long time and directly infiltrates peritoneal metastatic nodules, thereby producing antitumor effects. We designed an IP chemotherapy regimen of S-1 combined with weekly intravenous(IV)and IP PTXadministration. In our phase I study, the recommended dose of IP PTXwas determined to be 20mg/m2. In our phase II study for patients with P1(macroscopic peritoneal metastasis-positive)or CY1 (cytology positive)gastric cancer, the 1-year overall survival(OS)rate was 78%and the median survival time(MST)was 23.6 months. In another phase II study of patients with P1 gastric cancer, the 1-year OS rate was 77%and the MST was 17.1 months. A phase III PHOENIX-GC trial comparing IP chemotherapy to S-1 plus cisplatin has recently been completed. Phase II studies of the IP administration of docetaxel have also shown favorable results. Recently, the results of several clinical studies investigating the effects of S-1 combined with weekly IV and IP PTXadministration for peritoneal metastasis of pancreatic cancer have been published. PMID- 28028254 TI - [Palliative Surgery for Peritoneal Metastasis of Gastric Cancer]. AB - Different surgical interventions can be applied for the treatment of peritoneal metastasis of gastric cancer according to the extent of metastasis. Gastrectomy is a consensus-based standard treatment for gastric cancer with minimal peritoneal metastasis, although there is a lack of established evidence. Conversely, gastrectomy for an intermediate to high extent of peritoneal metastasis is not considered a suitable treatment based on the results of the JCOG0705 study. Colostomy or bypass surgery is often performed for intestinal stenosis due to peritoneal metastasis to palliate symptoms and allow the introduction of chemotherapy. PMID- 28028255 TI - [A New Treatment Strategy-Novel Cell-Free and Concentrated Ascites Reinfusion System(KM-CART)for Massive Malignant Ascites]. AB - Massive ascites associated with cancerous peritonitis can result in severe respiratory discomfort and abdominal fullness. Additionally, it can significantly impair the activities of daily living of a patient, and relaxation is difficult to achieve, even with opioids. Frequent ascites drainage can cause rapid worsening of the patient's general condition, and a large amount of ascites can lead to discontinuation of anti-cancer treatment. Cell-free and concentrated ascites reinfusion therapy(CART)for refractory ascites was first covered by the insurance system in 1981. However, cancerous ascites includes many cellular components as well as mucus, and purification was a difficult process. Therefore, since the 1990s, CART disappeared from the field of cancer treatment. I have devised a Keisuke Matsusaki(KM)-CART system that has the ability to clean the filtration membrane. This system enables purification of massive cancerous ascites that may exceed 20 L. The general condition of the patients and their symptoms improve after use of KM-CART, making it possible to initiate or resume anti-cancer therapy. KM-CART helps remove unwanted components, such as cancer cells, cytokines, and vascular endothelial growth factors from the abdominal cavity through filtration of drained ascites. Therefore, the peritoneal environment can be improved, leading to enhancement of the efficacy of intraperitoneal chemotherapy. In addition, a large number of cancer cells and lymphocytes can be obtained with KM-CART, and it is possible to use these cells for customized cancer treatments, such as dendritic cell vaccine therapy, and to perform anti-cancer agent susceptibility testing. I believe that KM-CART is a good treatment approach for massive ascites associated with cancerous peritonitis. PMID- 28028256 TI - [Treatment Continuation and Safety of Eribulin for the Treatment of Metastatic Breast Cancer]. AB - The purpose of treatment for patients with metastatic breast cancer is to maintain the patient's quality of life(QOL)with continued treatment for as long as possible.Eribulin was approved in April 2011 for the treatment of metastatic breast cancer, further increasing the selection of therapies available for the management of this disease.The current study presents a retrospective review of 31 patients who received eribulin in our hospital, and analyzes the factors related to the continuation and safety of its use.The median treatment continuation was 114 days(range, 8-281 days), and the treatment involved an average of 5 courses(range, 1-13 courses).There were no significant differences in the continuation of eribulin with regard to the number of previous chemotherapy regimens and modifications undergone by the patients.Neutropenia accounted for 80.6% of adverse eventsBGrade 3; however, the recovery was rapid.The rates of peripheral neuropathy and liver function failures were 12.9% and 6.5%, respectively. These results suggest that eribulin can be continued to be administered with the aim of maintaining QOL, and the therapy can be adjusted according to the patient's situation and the occurrence of adverse events by reducing the dose and treatment delays. PMID- 28028257 TI - [Effectiveness of Dexrazoxane for Extravasation of Anthracycline Antitumor Antibiotics - Reporting Measures Developed against Extravasation in the Hospital]. AB - Dexrazoxane(DXZ)is a drug used for treating extravasation(EV)of anthracycline antitumor antibiotics based on 2 of its mechanisms of action through Topo II. In Japan, it has been used in approximately 150 patients as of January 2016, but there is no detailed report. Three DXZ treatments were carried out for 2 cases in our facilities. One case involved a patient's right forearm while 2 cases occurred involved the left and right forearms of each of the patients, and both were Grade 2(CTCAE v4.0). The EV healed in all cases, and surgical procedures were not needed. Moreover, chemotherapy was performed without extending the treatment period. One year 8 months after administration there was no recurrence in both cases, and skin disorders did not develop. In our hospital, DXZ is managed based on the regimen as well as the anticancer agents, and administration within 6 hours from extravasation was made possible by the cooperation of pharmaceutical wholesalers. Nurses and pharmacists who engage in chemotherapy are encouraged to participate in the study sessions of the hospital, it has been the effort to learn the day-to-day knowledge and technology. DXZ is effective in treating the EV of anthracycline antitumor antibiotics and may be well tolerated. To properly use DXZ by integrating these cases, it is necessary to verify its effectiveness and safety. PMID- 28028258 TI - [Exploration of the Factors Influencing Multi-Drug Cancer Chemotherapy in the Elderly - A Retrospective Study]. AB - Multi-drug administration is problematic in elderly patients, and the situation is further complicated in those with cancer, owing to a high possibility of side effects and augmentation due to interactions between concomitant or previous drugs the patients are receiving and the anti-cancer drugs administered. Analysis of the factors that influence the likelihood of cancer chemotherapy multi-drug administration in the elderly showed that age alone was a fundamental risk factor for multi-drug administration, comorbidities, and drug interactions. In addition, the risks of drug interaction with chemotherapy were approximately 5.8 fold for drugs administered to treat hypertension, and approximately 10.3 fold for cardiovascular agents. Because of increased cancer morbidity, it is important to reduce the risks associated with the treatment. PMID- 28028259 TI - [An Autopsy Case of Pulmonary Tumor Thrombotic Microangiopathy That Progressed Slowly during Chemotherapy for Advanced Gastric Cancer]. AB - A man in his 50s presented to our hospital for anemia and was diagnosed with advanced gastric cancer with para-aortic lymph node metastases. He underwent gastrojejunostomy and received postoperative chemotherapy. Despite stable disease with chemotherapy, he complained of cough and respiratory discomfort and was subsequently admitted with progressive respiratory distress. Pulmonary hypertension and right-sided heart failure developed, and he died of sudden cardiopulmonary arrest 9 days after admission. An autopsy revealed widespread tumor metastasis, and he was diagnosed with pulmonary tumor thrombotic microangiopathy(PTTM)associated with gastric cancer. Although PTTM is a rare clinicopathological entity that causes severe pulmonary hypertension, it should be considered in the differential diagnosis of acute dyspnea in patients with carcinoma, regardless of clinical improvement. PMID- 28028260 TI - [A Case of Poorly Differentiated Adenocarcinoma of the Colon with Rapid Postoperative Progression Suggestive of Peritoneal Dissemination]. AB - A 62-year-old man was admitted to our hospital because of pain in the right lower abdomen and was diagnosed with cecal cancer and an associated abscess. The patient subsequently underwent right hemicolectomy. Histopathological examination was positive for por1, se, bd3, ly3, v0, PM0, and DM0. He was discharged from the hospital 21 days postoperatively. He was hospitalized with bloating of the right lower abdomen and inflammation 31 days postoperatively. He was later diagnosed with recurrence of the initial abscess, but his symptoms did not improve, and he was considered to have peritoneal dissemination. His general condition deteriorated rapidly, and he died approximately 1.5 months postoperatively. Histopathological and anatomical examination later confirmed multiple organ failure with peritoneal dissemination. It is reported that prognosis of poorly differentiated adenocarcinoma is worse than that for well- or moderately differentiated adenocarcinoma. Poorly differentiated adenocarcinoma may recur immediately after curative surgery. PMID- 28028261 TI - [Two Cases of ER-Positive Postmenopausal Breast Cancer That Increased in Size during Neoadjuvant Hormone Therapy]. AB - The first patient was a 62-year-old woman who was referred to our hospital with the complaint of a left breast tumor. She was diagnosed with invasive ductal carcinoma(T1N0M0, stage I). The tumor was ER-positive, PgR-negative, and HER2- negative. She was treated with toremifene, letrozole, and anastrozole as neoadjuvant hormone therapy for 4 months, but the tumor increased in size. The clinical response was judged as progressive disease, and a left partial mastectomy and axillary lymph node dissection were performed. Chemotherapy and radiotherapy were performed after surgery. The second patient was a 68-year-old woman who was referred to our hospital with the complaint of a right breast tumor. She was diagnosed as invasive ductal carcinoma(T1N0M0, stage I). The tumor was ER-positive, PgR-negative, and HER2-negative. She was treated with letrozole as neoadjuvant hormone therapy for 4 months, but the tumor increased in size. The clinical response was judged as progressive disease, and a right partial mastectomy and axillary lymph node dissection were performed. Chemotherapy and radiotherapy were performed after surgery. Although the evidence is still insufficient, with neoadjuvant hormone therapy for hormone-sensitive breast cancer, improved tumor shrinkage and breast conservation have been reported. We experienced two cases in which the tumor increased in size during neoadjuvant hormone therapy; however, even though these cases showed no apparent effect, chemotherapy may be effective in future cases. PMID- 28028262 TI - [Maintenance of Long-Term Stable Disease(SD)in Metastatic Breast Cancer with Eribulin - A Case Report of Long-Term SD in Japan]. AB - This case report discusses a 48-year-old woman with metastatic breast cancer: T4c(10.5 cm)N2bM1,(OSS, LYM), stage IV, estrogen receptor(ER)(+), progesterone receptor(PgR)(+), human epidermal growth factor receptor-2(HER2) (-), and Ki-67 17.2%. Administration of eribulin was initiated after treatment with anthracycline and taxane. Thereafter, 28 courses of eribulin maintained a SD state for over a year and improved the quality of life(QOL). Eribulin is effective for both prolonging life and improving QOL, which are the main goals in the treatment of metastatic or recurrent cancer. Therefore, this evidence suggests that eribulin can be effective in various clinical situations. PMID- 28028263 TI - [Residual Disease Status after Primary Cytoreductive Surgery in Patients with Advanced Ovarian, Fallopian Tube, or Peritoneal Carcinoma and Long-Term Progression-Free Survival]. AB - OBJECTIVE: To investigate residual disease status after primary cytoreductive surgery(PCS)in patients with advanced ovarian, Fallopian tube, or peritoneal carcinoma and long-term progression-free survival(PFS). METHODS: The study included patients with stage III C/IVepithelial ovarian, fallopian tube, or peritoneal carcinoma who had undergone surgery and carbo- platin/taxane chemotherapy, and had a PFSduration of >=48 months. RESULTS: The study group consisted of 11 patients with stage III C disease, which accounted for 23%(8/35)of stage III C patients aged <=59 years and 11%(3/27)of stage III C patients aged >=60 years. No stage IV patients had a long-term PFS(0/11). Of 8 patients aged <=59 years, 2 had residual disease of 0.1-1 cm(optimal debulking), 5 had residual disease of >1 cm after PCS, and 1 who had received neoadjuvant chemotherapy(NAC)had optimal debulking during interval cytoreductive surgery. Of 3 patients aged >=60 years, 2 had no macroscopic residual disease, and 1 had residual disease of >1 cm after PCS. CONCLUSION: In patients with stage III C ovarian, fallopian tube, or peritoneal carcinoma, a subgroup of those aged <=59 years had long-term PFSdespite suboptimal PCS. In this age group, carboplatin/taxane chemotherapy may improve the prognosis, irrespective of residual disease status after PCS. In contrast, complete cytoreduction during PCSappears to be necessary in patients aged >=60 years who achieve long-term PFS. PMID- 28028264 TI - [Case of Central Venous Catheter Laceration of the Pectoralis Minor Muscle]. AB - A 50's underwent gastrectomy for gastric cancer 4 years before. He had received chemotherapy for para-aortic lymph node metastases. A central venous catheter with a subcutaneous port was implanted via the right subclavian vein, under ultrasonographic guidance, 1 year 3 months earlier. The patient complained of swelling in his right chest during intravenous injection of ramucirumab and paclitaxel via the port. A chest radiograph revealed that a catheter fracture. A CT scan showed that the fractured catheter had lacerated the pectoralis minor muscle and the tip was in the right inferior pulmonary artery. The catheter fragment was removed using a pigtail catheter and a snare catheter via a percutaneous transfemoral approach, without any complication. The catheter was cut at 15.5 cm from the tip. This fracture was thought to be caused by a kink in the pectoralis muscle. PMID- 28028265 TI - [Current State of Medical Support by Nurses to Guide Cancer Patients to at Home Death]. AB - The aim of this study is to clarify the palliative care support in home-based settings for patients with end-stage cancer. Fifty patients who died at home were analyzed. MSC nurses listened to the patients and informal caregivers for their preferences for place of death. Home death was selected by 30%of participants prior to the environment adjustment support and by 68% after. The period leading up to home care that started with the adjustment assistance by MSC was 5 days(median). Nurse support by the MSC is intended to promote decision making regarding the place of end-of-life care. The dialogue between the hospital and local medical institutions is accelerating the period until the start of home care. PMID- 28028266 TI - [Case Study - A Successful Cooperation of Clinic Pharmacist and Pharmacies in Home Palliative Care with PCA Pump]. AB - To make a good end at home and provide good palliative care for patients with cancer are urgent issues in Setagaya ward, as shown by certain statistics. Medical opioids are greatly needed for palliative care; as patient controlled analgesia(PCA) develops, it can lead to decisions by patients and their families to receive end-of-life care at home because the patient can choose to receive the same advanced palliative care received at the hospital. With in-home palliative care, given the rapid change in the medical condition of the patient and the sentiment of the family, the role of pharmacists is to quickly and reliably supply the pharmaceuticals and medical equipment that doctors need. The following are important in order to enable this; 1 ) a pharmacy stocked with medicalopioids in accordance with needs, 2 ) a pharmacy with a system that can provide support quickly, 3 ) the presence of people who understand the area of resources, and 4 ) a constant face-to-face relationship. The "Sakura-HOPPS(Sakurashinmachi Homecare Pharmacists PartnershipS)"is a group intended to provide exchange and cooperation of pharmacists beyond the framework of organizationalaffil iation, and authors hope to encourage the participation of increasingly more pharmacists to develop a close-cooperation system of acute care hospitals and community medical/home care. PMID- 28028267 TI - [Strengthening Cooperation between Medical and Nursing Care(Part 2) - A Collaborative Meeting of Home Care Doctors, Dentists, and Care Managers in Shinjuku City]. AB - In order to strengthen the cooperation between medical and nursing care, Shinjuku Ward held a collaborative meeting for home care doctors and care managers in 2014. Because cooperation with the dentist was also necessary in elderly care from the viewpoint of eating deglutition and oral health care, Shinjuku Ward held a collaborative meeting for home care doctors, dentists, and care managers in 2015. A questionnaire was given to the participants, and almost all respondents answered "Helpful"when asked if the meeting was useful. Besides, all respondents answered that their"understanding of each other's areas and perspectives has deepened."Therefore, this collaborative meeting was suggested to promote cooperation and mutual understanding among doctors, dentists, and care managers. PMID- 28028268 TI - [Consideration of the Work Content of the Clinic Pharmacist and Its Usefulness]. AB - "Medical teams"have been promoted in the home care setting. For the pharmacist, it is possible to maintain the safety and improve the quality of medical care by working with a multidisciplinary team. The arrangement of the pharmacist with the clinic is specified in Article 18 of the Medical Care Law, but there is no medical treatment fee for the clinic pharmacist. We examined the work content and usefulness of the clinic pharmacist. The work content was to participate in visiting consultation, introduce pharmacotherapy management based on the clinic pharmacist's working protocol, propose prescriptions, provide drug information service, and cooperate with insurance pharmacy pharmacists. Because the pharmacist was working in the clinic, he or she was able to actively intervene in drug treatment. Intervention in medication requires organizing and gathering information, which is difficult in the position of the insurance pharmacy pharmacist. The fact that the clinic pharmacist assumes this role and works with insurance pharmacy pharmacists makes it possible to maintain the safety and improve the quality of medical care. PMID- 28028269 TI - [Promoting Appropriate Pharmacotherapy for Home Care Patients: Coordination between Regional Comprehensive Support Centers and Pharmacies]. AB - Japan is rapidly developing into an aged society, and its construction of a regional comprehensive care system is urgently needed for the baby boomer generation, who will reach 75 years of age in 2025. As part of providing medical care and longterm caregiving in a regional comprehensive care system, ordinary citizens will be supported in their local neighborhoods by multidisciplinary care, team medicine, and information sharing. However, pharmacists visit only once or twice per month; therefore, it can be difficult for them to grasp the overall status of patients' lifestyles. For pharmacies to support ordinary citizens, information on local residents must be shared, and coordination with regional comprehensive support centers is essential. This paper discusses a case where a pharmacy was able to promote appropriate pharmacotherapy through coordination with a regional comprehensive support center. PMID- 28028270 TI - [Empathy to be Shown by Pharmacists toward Home Patients - Initiatives Undertaken by Pharmacists to Promote the Proper Use of Pharmaceutical Products]. AB - Separation of medical and dispensary services has taken root in Japan as a healthcare system;8 00 million prescriptions have been issued, and 70% of medical institutions now participate in this practice. Additionally, discussions are ongoing regarding patient-oriented family pharmacies from a"back-to basics"perspective of the separation drug dispensing from medical practice. Through a series of such discussions, the Ministry of Health, Labour and Welfare published a paper entitled"Vision for Pharmacies Working for Patients"with a focus on 3 functions to be implemented by family pharmacists and pharmacies. In home healthcare, there have been cases so far, as shown in the Vision paper, of suggestions from and initiatives taken by pharmacists that have helped improve patient home care services. This paper explores home care-related initiatives undertaken by our pharmacy, including 2 cases in which our pharmacists intervened to prevent duplicate prescriptions and promoted adherence to a medication regimen, having noticed a change in a patient's physical abilities caused by the presence of drug residues. Our pharmacists will inform other relevant professionals about this issue. The study discusses our experience, which may help provide insight on the ideal roles of pharmacists in this time of partnerships among professionals. PMID- 28028271 TI - [Differential Diagnosis of Interstitial Pneumonia by Home Ultrasound Examination]. AB - BACKGROUND: Patients receiving home care present clinically diverse forms of chronic respiratory failure, for which it is difficult to establish a definite diagnosis. CT diagnosis requires the patient to be transported, and obtaining the blood test results for the serum maker KL-6 requires a few days. Nevertheless, with the widespread use of portable ultrasound devices, we can now make an immediate ultrasound diagnosis of the lung in the home care setting. In our experience, most patients with deteriorated interstitialpneumonia show characteristic large disseminated B-lines or pleural effusion. This makes it possible to differentiate it from pneumonia, pulmonary emphysema, or cardiac insufficiency, which have similar clinical findings. PURPOSE: To consider the possibility of using ultrasonography for the differential diagnosis of interstitial pneumonia. SUBJECTS: Eighteen patients with chronic respiratory failure receiving home care underwent ultrasonography and blood test(serum KL-6). METHODS: We examined the presence or absence of pleural effusion and B-line in patients who underwent lung echocardiogram examination and had a serum KL-6 level greater or less than 500 U/mL. RESULTS: All 8 patients with KL-6 levels greater than 500 U/mL showed B-lines or pleural effusion. However, only 2 of the 10 patients with KL-6 levels less than 500 U/mL showed B-lines. CONCLUSION: Ultrasonography of patients with interstitial pneumonia, which is a cause of chronic respiratory failure, revealed a characteristic large and disseminated hyperechoic area. Although the number of patients was limited, we may consider ultrasonography effective for the diagnosis of interstitial pneumonia in the home care setting. PMID- 28028272 TI - [Collaboration of Hospitals and Home Care Providers - Lessons to be Learned from an Actual Case to Enable Patients to Keep Living at Home by Their Own Values]. AB - The aging society has arrived, and home care options are being promoted. To date, because of an increase in the number of patients with higher disability levels in greater need of medical help and senior people living alone or in senior-person households, more patients are in need of discharge support. Many medical institutions cannot consider the option of staying at home and receiving home care services for such patients, and such patients often give up on going home. In the case of service recipients suffering from incurable diseases or disabilities and undergoing age-related changes, it is necessary that they decide on their own"where and how they want to live."For their decision to be respected, a key is collaboration with those who support patient discharge from the hospital and those who support patient home care. This paper explores a patient appropriate for level-3 care with brain hemorrhage and paralysis of the left half of the body. This patient required supportive and adaptive devices, a cane for walking, and constant observation. In consideration of the wishes of the patient and his family, he was allowed to go home. PMID- 28028273 TI - [Continuation Participation Factor to Interchange Activity Such as the Golden Age Club of the Elderly Man]. AB - The present study examined exchange activities, such as the elderly club(hereinafter referred to as"exchange activities"). In older men who continued their participation, we clarified the factors that enabled them to continue participation and provided opportunity to have participated in the"exchange activities."Data were collected from semi-structured interviews and analyzed. As a result, older men after retirement were found to have no connection with the local community, and they joined local"exchange activities"out of a desire for interaction with other locals. In addition, expectations and evaluation of the achievement and the area of self-realization have been suggested as factors that allow continued participation in "exchange activities". PMID- 28028274 TI - [Integrated Community Care from the Perspective of Patients Receiving End-of-Life Treatment]. AB - I studied patients who had received end-of-life care at our clinic and investigated integrated community care based on these experiences. Atotal of 543 patients received end-of-life care at our clinic from October of 2007 to December of 2012. The number of those who received such care at home showed a growing trend while the number of patients receiving such care at hospitals tended to decrease. This was believed to be the effect of the aging population rate continuing to increase each year in Akita City. Understanding of home healthcare is still insufficient not only among patients' families but even among healthcare professionals as well. However, now that extensive home care collaboration networks have been formed, provision of end-of-life care at hospitals may be showing a declining trend. The first report by the Headquarters for the Promotion of Social Security System Reform, dated June 15, 2015, which was compiled by cabinet members, estimated the number of beds considered appropriate as of 2025. According to the report, there were over 150,000 excess beds throughout Japan with Akita Prefecture having approximately 3,500 extra beds. Collaboration between hospitals and home-based healthcare becomes important for many reasons, one of which is to make effective use of the limited number of beds. Therefore, there is a need to further improve and strengthen the integrated community care system. PMID- 28028275 TI - [Methods of Training for Pharmacists Involved in Home Care - Cultivation of a Medical Professional Mindset of Not Selecting the Patient, Time, or Place]. AB - Home visits by pharmacists for home care patients initiated when dispensing the"home care patient drug management guidance fee(550 points)"were established in Japan in 1994. At that time, the home-visit activities of pharmacists for home care patients were not generally recognized by patients, medical doctors, or nurses. With the subsequent introduction of long-term care insurance in 2000, pharmacists became more actively involved in home visits for home care patients. However, with the increasing number of patients with dementia and in the acute stage of diseases requiring home care, an evaluation of pharmacist qualifications and skills, pharmacy functions, and the dispensing fee system now requires consideration. In particular, providing opportunities for multidisciplinary lifelong learning is essential to ensure the qualifications and skills of pharmacists involved in home care. This study explores the methods of training for pharmacists involved in home care. PMID- 28028276 TI - [Measures to Raise Awareness on Home Care Medicine for Staff at an Acute Medical Care Facility - Multi-Professional Collaboration on the Strengths Dissemination Project]. AB - Kohka Public Hospital(KPH)focuses primarily on the treatment of acute diseases. However, as the only general hospital in the medical district and established under the National Health Insurance, KPH has a mandate in comprehensive medical care. With the aim of becoming a hospital that can cope with the anticipated super-aging society, a meeting was started to raise staff awareness of home care medicine. Senior managers were placed in each team along with staff with no involvement on the issue. Initially, a SWOT analysis was conducted to understand the current status. Views raised in the meetings will be summarized, and consequent measures will be announced both internally and externally as part of the Strengths Dissemination Project. Interest in home care medicine at acute medical care hospitals is undeniably low, but the reality is that many do not know how to get involved due to the lack of exposure. It is unquestionable that the need for home care medicine and regional cooperation will rise in our nation. We must direct the attention of health care providers there and start discussions. PMID- 28028277 TI - [Significance of Allowing Pharmacy Students to Attend Visits to Home Care Patients]. AB - In 2006, with the admission of a new batch of students, pharmaceutical education became a 6-year course. This was a result of the urgent need to train a new generation of pharmacists to respond to increasingly advanced and intricate medical care as well as the specific need to coordinate with multiple occupational categories. Meanwhile, with Japan becoming an aged society, medical care has undergone functional differentiation, and home care is now being promoted. As part of an 11- week practical course for 5th-year practical training, students attended visits to home care patients from an early stage, making it possible for them to be present at multiple visits. This was highly significant because it allowed students to experience various disease states of different patients and increase their practical knowledge of pharmaceuticals. This study explores the case example of proposals made by pharmacy students for improving medication-related problems in home care patients during 5th-year practical training. PMID- 28028278 TI - [Feasibility Study of a One-Day Educational Program to Train Advance Care Planning Facilitators(ACPFs)in Regional Areas]. AB - Promoting advance care planning in regional areas is important. Education For Implementing End-of-Life Discussion(EFIELD) is a two-day educational program for Advance Care Planning Facilitators(ACPFs)developed by the National Center for Geriatrics and Gerontology. Unfortunately, some trainers experience difficulties implementing the content of the program, and some trainees feel the program is too long for implementation in many regional areas. The purpose of the research is to clarify the feasibility of ACPFs education using a one-day program in regional areas. The methods involved documenting the process of a one-day program from implementation to evaluation from May of 2015 to March of 2016 and then evaluating the effectiveness of the program 3 months after the implementation using meeting minutes from 7 local hospitals. The results indicated a need for 5 steps from program implementation to evaluation as well as 5 categories for final evaluation. The most important finding is that E-FIELD challenged trainers to shorten and simplify their expressions in order to teach the content more efficiently. The second finding is that Group for Promoting Advance Care Planning & End Of Life Discussion in Chita(GACPEL) activities encouraged ACPimplementation within each hospital. The limitations of this research are related to small regional areas. In conclusion, a one-day regional ACPFs educational program is feasible. PMID- 28028279 TI - [Study of Appropriate Risk Management for People Receiving Care at Home - Actions of the High-Risk People Receiving Care at Home in Times of Disasters]. AB - Although preparation for frequently occurring disasters is required in the context of preparing a home care environment wherein people reside and receive care, existing preparations cannot be described as sufficient. Therefore, effective preparation has become a research focus. This study aimed to identify the risks faced by people receiving home care in disaster situations and to clarify the risk-related actions taken by various stakeholders in order to study appropriate risk management for people receiving care. We interviewed 8 individuals, including people receiving care and their family members, who were victims in the large-scale disasters associated with the Great Hanshin-Awaji Earthquake(1995)or later, conducted the factorsearch qualitative analysis, and mapped the actions taken by stakeholders. As a result, identified risks were classified into 5 categories and 13 subcategories. Risk actions taken by professionals and others could be elucidated from the stakeholder map. Our findings indicate the necessity of establishing risk management protocols for people receiving home care and preparing in ordinary times. PMID- 28028280 TI - [Supporting Patients with Disease Living at Home]. AB - In daily life, many are not familiar with progressive intractable disease. It is often the case that the patient's family confronts a rare progressive disease only once a diagnosis is made. In recent years, the internet has made it possible for families to learn about diseases in detail, and they can more or less predict the likely course of nursing care required by the patient in the days to come. Yet families often lack understanding of terms related to a disease and how to respond to disease progression. It is desirable that, when a patient confronts a disease and home health care is going to be provided, a care provider be able to show empathy for the patient and the family and build a trust relationship with them. Under the theme of"living at home with disease,"this study examines the case of a patient who copes with the diagnosis of a specified disease and who remains at home. This paper highlights the importance of ongoing collaboration between community medicine and home health care service. PMID- 28028281 TI - [Sequential Post-Operative Nutrition Care at Home for Patients Receiving Surgical Treatment for Esophageal Cancer]. AB - OBJECTIVE AND METHODS: We evaluated the outcomes of sequential nutrition care provided at home to patients who had undergone surgery for esophageal cancer. For 44 such patients, we investigated caloric intake(kcal), percentage of preoperative body weight(%), and requests and complains related to home nutrition care every 3 months for 1 year after surgery. RESULTS: Duringthe observation period, the mean postoperative caloric intake decreased to a minimum level at 1 month, but nearly recovered to the baseline at 12 months. The percentage of preoperative body weight decreased postoperatively, and this decrease was maintained. The average weight percentage reached 87%at 6 months after surgery, and recovered to only 89% at 12 months. Regarding requests and complaints, many reports of digestive symptoms related to gastrointestinal surgery were reported up to 3 months postoperatively. Additionally, the large number of requests for cancellation of enteral support indicates the difficulty in managing home enteral nutrition. On the other hand, guidance about dietary quality with oral intake enhancement increased at 6 months postoperatively. CONCLUSION: The aims of postoperative nutrition care should change over time with the patient's postoperative progress. In the early stage, weight loss management is important. In addition to dietary guidance with regard to digestive reconstruction, nutrition support with acceptable enteral nutrition is recommended. Guidance regarding problems with dietary behavior is needed for every patient when the digestive adaptation has advanced. PMID- 28028282 TI - [Intervention for COPD Exacerbation - How To Prevent and Treat COPD Exacerbation ?] AB - COPD exacerbation is associated with a high mortality rate and severe decrease in the QOL.Most medical expenses associated with COPD involve treatment costs related to exacerbation.However, the identification of pre-exacerbation changes in respiratory conditions from self controlled range, risk assessment, and multidisciplinary integrated respiratory care intervention could truly stabilize the condition of a patient with COPD and thus decrease the frequency of exacerbation.Such a decrease would be expected to lead to a high QOL, better COPD survival rate, and medical economic benefits.In addition, a reduced frequency of exacerbation would increase the stability of a patient's condition, allowing the continuation of effective pulmonary rehabilitation and maintenance of beneficial physical activity. PMID- 28028283 TI - [A Case of HPN, In Which QOL Improvement Was Achieved by Combining Continuous Infusion with Once-Weekly Intermittent Infusion - Contribution of Pharmacists to Health Promotion among Home Patients Receiving Infusion Therapy]. AB - Patients receiving parenteral nutrition at home have the following two options: 24-h continuous or intermittent infusion. To date, for patients with impaired glucose tolerance and/or other metabolic disorders or for those with decreased cardiac/ pulmonary/renal function, it is desirable to opt for continuous infusion to minimize the variance in the body's metabolic rate as much as possible. Furthermore, it should be noted that continuous infusion evokes a stronger feeling among patients of being constrained because it restricts their everyday activities. This case witnesses collaborations among the patient's doctor, dispensary's pharmacy, and patient's family. Because ofthe use ofintermittent infusion more or less once per week in addition to continuous infusion, significant improvement in quality of life was achieved, and the patient was able to enjoy taking a short trip. To assist a home patient receiving infusion therapy, it is essential that the pharmacist be equipped with skills to manage risks associated with infusion therapy and have knowledge about insurance to cover incidents concerning infusion fluids or medical materials. It will certainly depend on the degree ofindependence ofpatients and the level ofcare their families can provide; however, should we manage to use a similar medical procedure in at least a few cases in the future, we may be able to contribute to "joie de vivre" in home patients receiving infusion therapy. PMID- 28028284 TI - [Revision of Medical Fee System for Treatment at Nursing Homes - The Influential Consideration of the Introduction of One-Patient-Per-Visit Method on the Welfare of Elderly Patients at Nursing Homes]. AB - The 2014 revision of the medical fee system includes the introduction of a one patient-per-visit method at nursing homes, which should be followed to avoid a drastic reduction in medical fees. We followed the new method, resulting in much more frequent visits to nursing homes(For example, we visit a facilitythree times per week instead of the previous two times per month). Frequent visits to multiple facilities are time- and effort-consuming on our side as a clinic, but, on the other hand, patients have more opportunities to see a doctor when theyare sick even if theyare not scheduled to do so. In this study, we examined how the new method affects the welfare of elderlypatients at nursing homes. PMID- 28028285 TI - [A Study of Job Retention among Nurses Engaged in Home-Visit Bathing Services]. AB - It is necessary to include a nurse as staff in"Home Visit Bathing Long-Term Care"because nurses provide medical care such as vital sign measurement. However, the shortage of nurses is serious. A questionnaire survey was administered to nurses of E company, and findings showed that more than 50% of nurses felt physical fatigue. Correlation analysis showed that there was a significant correlation between"the intentions to continue working"and"good relationship between nurses and staff" (r=0.398, p<0.001), and there was a negative correlation with"low payment"(r=-0.232, p<0.01)and"physical fatigue" (r=-0.272, p<0.01). Although physical fatigue and low payment are factors that inhibit the intentions to continue working, the most important factor is human relationships. It was suggested that maintaining good human relationships enhances the intentions of nurses to continue working. PMID- 28028286 TI - [Inter-Occupational Cooperation Levels in a Day Care Service and Its Subjects - From the Viewpoint of Multiple Occupations]. AB - We clarified the role of cooperation of nursing personnel who work in day care services, to precede our examination of inter-occupational cooperation. The study results revealed that there were four cooperation levels. Subjects for the cooperation included:"difficulty in sharing information,""difficulty in understanding the whole picture,""difficulty in finding directions, "and"difficulty in dealing with emergency cases."The purpose of this study was to clarify the inter-occupational cooperation levels in a day care service and its subjects. We also conducted semi-structured interviews with 13 persons of differing occupations(other than nurses), and who worked in day-care services in A prefecture. As a result, it was revealed that there were three inter occupational cooperation levels and its subjects included:"difficulty in sharing information" (which was answered the same as the nurses),"difficulty in sharing goals"(which were different among individual occupations), "lack of consistency in care,""necessity of learning because of insufficient knowledge,"and"hesitation to notify." PMID- 28028287 TI - [Nursing Problems and Challenges in a Nursing Care Facility]. AB - The purpose of this study was to elucidate nursing problems and challenges in a nursing care facility. The study sample comprised 365 days special instructions written by nurses and care workers. The results show that a change in the state concerning fever, pressure ulcers, falls, aspiration scored significantly high. Nurses and care workers must consider in detail the extent of the problems and take steps to improve them. PMID- 28028288 TI - A cost-effectiveness analysis of self-debriefing versus instructor debriefing for simulated crises in perioperative medicine in Canada. AB - PURPOSE: High-fidelity simulation training is effective for learning crisis resource management (CRM) skills, but cost is a major barrier to implementing high-fidelity simulation training into the curriculum. The aim of this study was to examine the cost-effectiveness of self-debriefing and traditional instructor debriefing in CRM training programs and to calculate the minimum willingness-to pay (WTP) value when one debriefing type becomes more cost-effective than the other. METHODS: This study used previous data from a randomized controlled trial involving 50 anesthesiology residents in Canada. Each participant managed a pretest crisis scenario. Participants who were randomized to self-debrief used the video of their pretest scenario with no instructor present during their debriefing. Participants from the control group were debriefed by a trained instructor using the video of their pretest scenario. Participants individually managed a post-test simulated crisis scenario. We compared the cost and effectiveness of self-debriefing versus instructor debriefing using net benefit regression. The cost-effectiveness estimate was reported as the incremental net benefit and the uncertainty was presented using a cost-effectiveness acceptability curve. RESULTS: Self-debriefing costs less than instructor debriefing. As the WTP increased, the probability that self-debriefing would be cost-effective decreased. With a WTP <=Can$200, the self-debriefing program was cost-effective. However, when effectiveness was priced higher than cost-savings and with a WTP >Can$300, instructor debriefing was the preferred alternative. CONCLUSION: With a lower WTP (<=Can$200), self-debriefing was cost-effective in CRM simulation training when compared to instructor debriefing. This study provides evidence regarding cost-effectiveness that will inform decision-makers and clinical educators in their decision-making process, and may help to optimize resource allocation in education. PMID- 28028289 TI - An eventful year for the Journal of Educational Evaluation for Health Professions. PMID- 28028290 TI - What is interesting in the issue 2016 of Journal of Educational Evaluation for Health Professions? PMID- 28028291 TI - Contaminated milk is a common cause of necrotising enterocolitis: A hypothesis. AB - Necrotising enterocolitis (NEC) is the most commonly acquired gastrointestinal disease of neonates, particularly the very preterm (gestation <32 weeks) and/or very low birth weight (<1500g). It is associated with high morbidity and mortality. Despite improvement in neonatal care and increased use of expressed breast milk (EBM), the incidence remains high in many neonatal intensive care units (NICU), and even shows increasing trend in some countries. Numerous studies have pointed to the infective nature of NEC. Some investigators have reported an increase in the incidence of NEC in their NICU when the percentage of infants with pathogens isolated from their gut increased, and decreased when gut colonisation rate was low. Both bacteria and viruses have been reported to be associated with outbreaks of NEC. The majority (>90%) of the NEC cases occurred in neonates on enteral feeding. Studies have shown that milk (whether EBM or formula) fed to neonates was not sterile and were further contaminated during collection, transport, storage and/or feeding. Other investigators have reported a reduction in the incidence of NEC when they improved infection control measures and hygienic procedures in handling milk. It is, therefore, hypothesised that the most common cause of NEC is due to the feeding of neonates, particularly the vulnerable very preterm small neonates, with milk heavily contaminated during collection at source, transport, storage and/or feeding. Because of the immaturity of the immune system of the neonates, excessive inflammatory response to the pathogen load in the gut leads to the pathogenesis of NEC. PMID- 28028292 TI - Glypican-3 is useful but not superior to Hep Par 1 in differentiating hepatocellular carcinoma from other liver tumours. AB - To assess the diagnostic utility of glypican-3 (GPC-3) in comparison to Hep Par 1 in the diagnosis of liver tumours, a cross-sectional study involving 66 resected liver tumours were tested for the protein expression of these markers by immunohistochemistry using monoclonal antibodies. Of the 66 cases, 26 (39.4%) were hepatocellular carcinoma (HCC), 4 (6.1%) were intrahepatic cholangiocarcinoma and 36 (54.5%) were metastatic tumours. Hep Par 1 and GPC-3 expressions in HCC were 24/26 (92.3%) and 19/26 (73.1%) respectively. In contrast, of non-HCC cases, only 2/40 cases (5.0%) expressed Hep Par 1, including a metastatic colorectal adenocarcinoma and a metastatic gastric adenocarcinoma. GPC-3 was expressed in 3/40 cases (7.5%), i.e. a metastatic adenocarcinoma of unknown origin, a metastatic gastric adenocarcinoma and an intrahepatic cholangiocarcinoma. The sensitivity and specificity for Hep Par 1 were 92.3% and 95% respectively while that of GPC-3 was 73.1% and 92.5% respectively. GPC-3 is a useful marker in the diagnosis of HCC. However it is not superior to Hep Par 1 in its sensitivity and specificity. We recommend that it is utilized together with Hep Par 1 as a panel in the diagnosis of HCC. PMID- 28028293 TI - Potential use of cord blood for Hb E hemoglobinopathy screening programme using capillary electrophoresis. AB - BACKGROUND: Thalassemia and hemoglobinopathies are inherited red blood cell disorders found worldwide. Hemoglobin (Hb) E disorder is one of the hemoglobinopathies known to have the high prevalence in South East Asia. Most of transfusion-dependent thalassemias were genotypically compound heterozygous Hb E/ beta-thalassemia. In Malaysia, the national screening program for thalassemia was implemented for early pregnancy or secondary school girls; however many participants do not turn-up and missed the screening test. Screening for thalassemia using samples from cord blood is an alternative choice as it is a readily available source of blood and hence early detection of the disease. The purpose of this study was to determine the potential use of cord blood for the screening of HbE hemoglobinopathy by using capillary electrophoresis (CE). METHODS: Cord blood samples were collected from 300 newborns of healthy mothers. Hematological parameters were determined and hemoglobin quantitation for all cord blood samples were performed using capillary electrophoresis system (CES) and high performance liquid chromatography (HPLC). RESULTS: Majority of cord blood samples (63%) revealed Hb AF followed by Hb AFA2 (20%). Hb AFE was detected in 10.7% with the mean value of Hb E ranging from 2.3%-11.1%. CONCLUSION: Hemoglobin E was detected in cord blood using capillary electrophoresis system. It can be recommended in areas where Hb E/beta is prevalent. Implementation of a screening strategy using CE on cord blood sampling will identify the disease early. With regular follow-up on these patients, the status of their disease can be determined earlier and appropriate management implemented. PMID- 28028294 TI - Emergence of CTX-M-15 producing E. coli O25b-ST131 clone in a tertiary care hospital of Bangladesh. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL) producing uropathogens has become prevalent worldwide. E. coli O25b-ST131 clone, associated with blaCTX-M 15, has been reported from many parts of the world and is frequently associated with multidrug resistance. Thus far, there are no reports about this clone in Bangladesh. The objective of this study was to investigate ESBL producing uropathogens and to survey the prevalence of E. coli O25b-ST131 clone among ESBL positive E. coli isolates. METHODS: From symptomatic urinary tract infection cases, a total of 800 urine samples were collected. Bacterial identification and antimicrobial susceptibility testing was performed using established methods. Screening of ESBL producers was done using the disk diffusion method. Screening positive isolates were phenotypically confirmed by double disk synergy (DDS) test. Genes encoding ESBLs (blaCTX-M-15, blaOXA-1) were identified both by PCR and DNA sequencing. Phenotypic positive ESBL producers were also studied by PCR for existence of class 1 integron. Subsequently, O25b-ST131 clone was identified by allele specific PCR. RESULTS: Of 138 gram-negative uropathogens, 45 (32.6%) were positive for ESBLs. ESBL producers showed high frequency of antimicrobial resistance except imipenem. Among 45 ESBL producers, 36 (80%) produced blaCTX-M 15, 18 (40%) produced blaOXA-1. Fifteen (33.3%) strains simultaneously produced both blaOXA-1 and blaCTX-M-15. Class 1 integron was present in 30 (66.7%) isolates. Of the 31 blaCTX-M-15 positive E. coli, 22 (71%) were positive for E. coli O25b-ST131 clone and all (100%) belonged to B2 phylogenetic group. CONCLUSION: Rising antimicrobial resistance among uropathogens, and especially the emergence of blaCTX-M-15 positive E. coli O25b-ST131 clone in Bangladesh has provided urgency to the development of novel preventive and therapeutic strategies. PMID- 28028295 TI - Current trends of seroprevalence of transfusion transmitted infections in Pakistani beta-thalassaemic patients. AB - BACKGROUND: Though regular blood transfusion improves the survival, it carries the unavoidable risk of transfusion transmitted infections (TTI) in beta thalassaemic patients. Owing to the lack of uniformity in blood screening practices in Pakistan, TTI is still a major challenge. OBJECTIVES: To study the current trends of TTI in regularly transfused beta-thalassaemics and their correlation with age, number of transfusions, hematological and biochemical markers. METHODS: We carried out a prospective case-control study. 100 beta thalassemic patients and 200 healthy donors were recruited from June 2011 to June 2014. HCV antibodies, Hepatitis B surface antigen and human immunodeficiency virus antibodies (I & II) were evaluated. Complete blood counts, LFTs and serum ferritin were tested on all patients. RESULTS: Mean age of patients and controls was 11.18+/-5.07 and 20.5+/-1.87 years respectively. In patients, 54% and 46% were males and females respectively. Anti-HCV antibody and HbsAg were positive in 27% versus 3% and 3% versus 2% in patients and controls respectively. None of the patients and controls was HIV reactive. Seropositivity of Anti-HCV was significantly higher in patients than that of controls (P<0.001). Anti-HCV positively correlated with age above 10 years, numbers of transfusions (>=150 units), high serum ferritin, elevated ALT and alkaline phosphatase (P<0.001). CONCLUSIONS: Over the decade, TTI magnitude has significantly reduced, but hepatitis C is still a main hazard. Further preventive measures including nucleic acid testing, voluntary donation and stringent donor selection will be required for reducing TTI in beta-thalassaemics. PMID- 28028296 TI - Human papillomavirus (HPV) in Egyptian females: study by cytology, histopathology, colposcopy and molecular diagnosis of high risk types. AB - OBJECTIVES: In Northern Africa, the region Egypt belongs to, about 10.7% of women are estimated to harbour cervical human papillomavirus (HPV) infection and 78.4% of invasive cancers are attributed to HPVs 16 or 18. We aimed at comparing HPV detection by ISH-PCR tissue with other conventional available cheaper techniques, finding which of them can be relied upon in a developing country like Egypt for HPV detection. METHODS: Sixty patients were included. For them colposcopy, PAP smear, histopathology and detection of HPV using ISH PCR tissue and PCR swab were achieved. RESULTS: PCR-ISH tissue was positive in 53.33%, 46.6% were negative. Pap smear was negative in 26 cases (43.33%) and 43 cases (56.67%) were positive. LSIL with perinuclear halo represented nearly half of the positive cases (16/34; 47.05%), 10 cases were diagnosed as HSIL, 4 cases as ASCUS and 4 as AGC. Histopathology was negative in 12 (20%) cases and 48 (80%) cases were positive. CIN I and CIN I+ koliocytosis represented half of the cases (30/60) and more than half of positive cases (30/48; 62.5%). Comparing the results of pap smear, histopathology, colposcopy and PCR swab with ISH PCR tissue, highly significant results were seen with sensitivity of 87.5%, 100%, 62.5% and 56.2% respectively but the specificity were 78.6%, 42.9%, 28.6% and 100% respectively. CONCLUSION: Conventional cytology and histopathology were sensitive tests for detection of HPV. This may help for early detection of cancer cervix in a developing country like Egypt. PCR swab showed the highest specificity and the lowest sensitivity. PMID- 28028297 TI - Histopathological features of coeliac disease in a sample of Sudanese patients. AB - INTRODUCTION: Coeliac disease can occur at any age but is more common in children. Its diagnosis requires correlation between clinical presentations, serological results, endoscopic findings and histopathological classification using the modified Marsh grading system. This study of coeliac disease with biopsies received in the department of histopathology at Soba University Hospital, and Fedail Hospital aimed to gain insight into the demographic profile, clinical presentations and histopathological classification of patients with coeliac disease. METHODS: This was a descriptive study carried out at Soba University Hospital and Fedail Hospital during the period from January 2010 December 2013. Haematoxylin & Eosin and CD3-stained slides of small intestinal biopsies of coeliac disease patients were reviewed for various histological features (1) intraepithelial lymphocytes (IEL) count per 100 enterocytes, (2) crypt hyperplasia and (3) degree of villous atrophy. Based on the histopathological findings, the cases were categorized according to the modified Marsh classification. Demographic and clinical data were obtained from the patient request forms. The data were analyzed using Statistical Package for Social Sciences Software (SPSS). RESULTS: The study included 60 patients. Their age ranged from 2 to 70 years with a mean of 19.5 years (+/-15.7 SD). The most common age group was below 10 years old (41.6%). Male and female are equally affected. The most common clinical presentation was chronic diarrhoea (55.0%), followed by iron deficiency anemia (41.7%). The degree of villous atrophy ranged from complete atrophy (45.0%), marked atrophy (38.3%) to mild atrophy (16.6%). Marsh grade IIIC was the most common grade. The younger age-groups had a higher prevalence of iron deficiency anaemia and higher Marsh grade. PMID- 28028299 TI - Gene expression in obstetric antiphospholipid syndrome: a systematic review. AB - BACKGROUND: Antiphospholipid syndrome (APS) is a multisystem disease that may present as venous or arterial thrombosis and/or pregnancy complications with the presence of antiphospholipid antibodies. Until today, heterogeneity of pathogenic mechanism fits well with various clinical manifestations. Moreover, previous studies have indicated that genes are differentially expressed between normal and in the disease state. Hence, this study systematically searched the literature on human gene expression that was differentially expressed in Obstetric APS. METHODOLOGY: Electronic search was performed until 31st March 2015 through PubMed and Embase databases; where the following Medical Subject Heading (MeSH) terms were used and they had been specified as the primary focus of the articles; gene, antiphospholipid, obstetric, and pregnancy in the title or abstract. From 502 studies retrieved from the search, only original publications that had performed gene expression analyses of human placental tissue that reported on differentially expressed gene in pregnancies with Obstetric APS were included. Two reviewers independently scrutinized the titles and the abstracts before examining the eligibility of studies that met the inclusion criteria. For each study; diagnostic criteria for APS, method for analysis, and the gene signature were extracted independently by two reviewers. The genes listed were further analysed with the DAVID and the KEGG pathways. RESULTS: Three eligible gene expression studies involving obstetric APS, comprising the datasets on gene expression, were identified. All three studies showed a reduction in transcript expression on PRL, STAT5, TF, DAF, ABCA1, and HBEGF in Obstetric APS. The high enrichment score for functionality in DAVID had been positive regulation of cell proliferation. Meanwhile, pertaining to the KEGG pathway, two pathways were associated with some of the listed genes, which were ErBb signalling pathway and JAK-STAT signalling pathway. CONCLUSION: Ultimately, studies on a genetic level have the potential to provide new insights into the regulation and to widen the basis for identification of changes in the mechanism of Obstetric APS. PMID- 28028298 TI - MicroRNA expression in antiphospholipid syndrome: a systematic review and microRNA target genes analysis. AB - INTRODUCTION: Antiphospholipid antibodies (aPL) are autoantibodies that attack phospholipid through anti-beta 2-glycoprotein 1. The actions of aPL are associated with events leading to thrombosis and morbidity in pregnancy. Antiphospholipid syndrome (APS) is diagnosed when a patient is persistently positive for aPL and also has recognised clinical manifestations such as recurrent pregnancy losses, arterial or venous thrombosis and in a catastrophic case, can result in death. Unfortunately, the pathogenesis of APS is still not well established. Recently, microRNA expressed in many types of diseased tissues were claimed to be involved in the pathological progression of diseases and has become a useful biomarker to indicate diseases, including APS. OBJECTIVE: This systematic review aims to search for research papers that are focussing on microRNA expression profiles in APS. METHOD: Three search engines (Ebcohost, ProQuest and Ovid) were used to identify papers related to expression of specific microRNA in antiphospholipid syndrome. RESULTS AND DISCUSSION: A total of 357 papers were found and screened, out of which only one study fulfilled the requirement. In this particular study blood samples from APS patients were tested. The microRNAs found to be related to APS were miR-19b and miR-20a. No data was found on specific microRNA being expressed in obstetric antiphospholipid syndrome. Analysis on the microRNA target genes revealed that most genes targeted by miR-19b and miR-20a involve in TGF-Beta Signalling and VEGF, hypoxia and angiogenesis pathways. CONCLUSION: In view of the limited data on the expressions of microRNA in APS we recommend further research into this field. Characterization of microRNA profile in blood as well as in placenta tissue of patients with APS could be useful in identifying microRNAs involved in obstetric APS. PMID- 28028300 TI - High-quality cell block preparation from scraping of conventional cytology slide: a technical report on a modified cytoscrape cell block technique. AB - BACKGROUND: Immunocytochemistry (ICC) on formalin-fixed paraffin embedded cell blocks is an ancillary tool commonly recruited for differential diagnoses of fine needle aspiration cytology (FNAC) samples. However, the quality of conventional cell blocks in terms of adequate cellularity and evenness of distribution of cytologic material is not always satisfactory for ICC. We introduce a modified agarose-based cytoscrape cell block (CCB) technique that can be effectively used for the preparation of cell blocks from scrapings of conventional FNAC slides. METHODS: A decoverslipped FNAC slide was mounted with a small amount of water. The cytological material was scraped off the slide into a tissue mold by scraping with a cell scraper. The cytoscrape material was pelleted by centrifugation and pre-embedded in ultra-low gelling temperature agarose and then re-embedded in conventional agarose. The final agarose gel disk was processed and embedded in paraffin. RESULTS: The quality of the ICC on the CCB sections was identical to that of the immunohistochemical stains on histological sections. By scrapping and harvesting the entirety of the cytological material off the cytology slide into a compact agarose cell button, we could avoid the risk of losing diagnostic material during the CCB preparation. CONCLUSION: This modified CCB technique enables concentration and focusing of minute material while maintaining the entire amount of the cytoscrape material on the viewing spot of the CCB sections. We believe this technique can be effectively used to improve the level of confidence in diagnosis of FNAC especially when the FNAC slides are the only sample available. PMID- 28028302 TI - Acute promyelocytic leukaemia with a novel translocation t(16;17)(q12;p13): a case report. AB - Acute promyelocytic leukaemia (APML) is characterised by the t(15;17)(q22;q21), that results in the fusion of the promyelocytic leukaemia (PML) gene at 15q22 with the retinoic acid alpha-receptor (RARA) gene at 17q21. The current case report describes a 13-year-old male with APML, who was negative for PML/RARA fusion signal but reported to have an atypical translocation t(16;17). To the best of our knowledge this is the first case report of APML responsive to ATRA with such a translocation. PMID- 28028301 TI - Biochemical and molecular characteristics of Malaysian patients with lysinuric protein intolerance. AB - Lysinuric protein intolerance (LPI) is an inborn error of dibasic amino acid transport due to a defect in the dibasic amino acid transporter in the renal and intestine and has a heterogenous presentation. Three Malaysian patients with LPI were studied and their biochemical and molecular findings compared. There were differences and similarities in the biochemical and molecular findings. Molecular analysis of SLC7A7 gene revealed a novel mutation c.235G>A; p.(Gly79Arg) in exon three in Patient 1 and a mutation c.1417C>T; p.(Arg473*) in exon 10 in patient 2 and 3. The degree of concentration of dibasic amino acids may determine the type of disease of the cell membrane transport, however, a positive molecular confirmation will secure the diagnosis. PMID- 28028303 TI - Dismal outcome of therapy-related myeloid neoplasm associated with complex aberrant karyotypes and monosomal karyotype: a case report. AB - INTRODUCTION: Individuals who are exposed to cytotoxic agents are at risk of developing therapyrelated myeloid neoplasms (t-MN). Cytogenetic findings of a neoplasm play an important role in stratifying patients into different risk groups and thus predict the response to treatment and overall survival. CASE REPORT: A 59-year-old man was diagnosed with acute promyelocytic leukaemia. Following this, he underwent all-trans retinoic acid (ATRA) based chemotherapy and achieved remission. Four years later, the disease relapsed and he was given idarubicin, mitoxantrone and ATRA followed by maintenance chemotherapy (ATRA, mercaptopurine and methotrexate). He achieved a second remission for the next 11 years. During a follow-up later, his full blood picture showed leucocytosis, anaemia and leucoerythroblastic picture. Bone marrow examination showed hypercellular marrow with trilineage dysplasia, 3% blasts but no abnormal promyelocyte. Fluorescence in-situ hybridisation (FISH) study of the PML/RARA gene was negative. Karyotyping result revealed complex abnormalities and monosomal karyotype (MK). A diagnosis of therapy-related myelodysplastic syndrome/myeloproliferative neoplasm with unfavourable karyotypes and MK was made. The disease progressed rapidly and transformed into therapy-related acute myeloid leukaemia in less than four months, complicated with severe pneumonia. Despite aggressive treatment with antibiotics and chemotherapy, the patient succumbed to the illness two weeks after the diagnosis. DISCUSSION AND CONCLUSION: Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents. Karyotyping analysis is crucial for risk stratification as MK in addition to complex aberrant karyotypes predicts unfavourable outcome. Further studies are required to address the optimal management for patients with t-MN. PMID- 28028304 TI - Zollinger-Ellison syndrome: an unusual case of chronic diarrhoea in a child. AB - Most cases of Zollinger-Ellison syndrome (ZES) are described in adults. It is a rare disorder in childhood. Most cases present with abdominal pain due to peptic ulceration and chronic diarrhoea not responding to general measures. The symptom complex is initially confused with other more common diseases, which lead to a delay in diagnosis. We present a rare case of a-12-year boy who initially presented with abdominal pain, diarrhoea, vomiting and progressive weight loss for over a two-year period before he was finally diagnosed as a case of ZES with the primary tumour in the pancreatic head and with multiple metastasis in both the liver and lymph nodes. PMID- 28028306 TI - Abstracts of the 2016 3rd Annual Scientific Meeting of Malaysian Division of the International Academy of Pathology. PMID- 28028305 TI - Rare post-operative complications in a previously undiagnosed Congenital Factor X deficiency patient. AB - Factor X (FX) deficiency is a rare autosomal recessive congenital bleeding disorder. The clinical presentation is among the most severe among the rare coagulation defects. Thus, majority of diagnosed patients will receive factor replacement therapy before surgical manipulation. However, the diagnosis of FX deficiency may be overlooked because it is a rare entity. This is a case report of a 15-year-old male patient who was diagnosed with FX deficiency after developing post-operative complications. With regular fresh frozen plasma infusion given, the patient responded well and recovered. However, had he been diagnosed earlier pre-operatively, the post-operative complication could have been prevented. Therefore, pre-operative coagulation screening should be performed in patients with significant bleeding history in both emergency and elective situations to prevent surgical morbidity related to post-operative bleeding. PMID- 28028307 TI - Identification of a RNA-Seq Based 8-Long Non-Coding RNA Signature Predicting Survival in Esophageal Cancer. AB - BACKGROUND Accumulating evidence suggests the involvement of long non-coding RNAs (lncRNAs) as oncogenic or tumor suppressive regulators in the development of various cancers. In the present study, we aimed to identify a lncRNA signature based on RNA sequencing (RNA-seq) data to predict survival in esophageal cancer. MATERIAL AND METHODS The RNA-seq lncRNA expression data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed lncRNAs were screened out between esophageal cancer and normal tissues. Univariate and multivariate Cox regression analysis were performed to establish a lncRNA-related prognostic model. Receiver operating characteristic (ROC) analysis was conducted to test the sensitivity and specificity of the model. GO (gene ontology) functional and KEGG pathway enrichment analyses were performed for mRNAs co-expressed with the lncRNAs to explore the potential functions of the prognostic lncRNAs. RESULTS A total of 265 differentially expressed lncRNAs were identified between esophageal cancer and normal tissues. After univariate and multivariate Cox regression analysis, eight lncRNAs (GS1-600G8.5, LINC00365, CTD 2357A8.3, RP11-705O24.1, LINC01554, RP1-90J4.1, RP11-327J17.1, and LINC00176) were finally screened out to establish a predictive model by which patients could be classified into high-risk and low-risk groups with significantly different overall survival. Further analysis indicated independent prognostic capability of the 8-lncRNA signature from other clinicopathological factors. ROC curve analysis demonstrated good performance of the 8-lncRNA signature. Functional enrichment analysis showed that the prognostic lncRNAs were mainly associated with esophageal cancer related biological processes such as regulation of glucose metabolic process and amino acid and lipids metabolism. CONCLUSIONS Our study developed a novel candidate model providing additional and more powerful prognostic information beyond conventional clinicopathological factors for survival prediction of esophageal cancer patients. Moreover, it also brings us new insights into the molecular mechanisms underlying esophageal cancer. PMID- 28028308 TI - Metastatic Squamous Cell Carcinoma of the Pleura: A Rare Complication of Hidradenitis Suppurativa. AB - BACKGROUND Squamous cell carcinoma (SCC), also known as Marjolin ulcer, is a rare complication of hidradenitis suppurativa (HS). Metastatic SCC from HS typically involves the axial skeleton or abdominopelvic viscera. Metastatic disease to the lungs is a rare phenomenon with only three reported cases of lung parenchyma. We present a biopsy proven case of metastatic SCC to the pleura from gluteal HS. CASE REPORT A 46-year-old male with a history of recently diagnosed Marjolin ulcer secondary to gluteal HS was transferred to our intensive care unit for acute hypoxemic respiratory failure secondary to recurrent pleural effusion. On examination, patient was febrile (38.3 degrees C), normotensive (blood pressure 98/65 mm Hg), tachycardic (116 beats/minute) and tachypneic (40 breaths/minute) with oxygen saturation of 93% on room air. He was in moderate distress requiring endotracheal intubation and mechanical ventilation. Chest examination revealed decreased breath sounds bilaterally and skin examination was significant for 18 cm wide sacral lesion. CT thorax showed bilateral pleural effusions, pleural thickening, and scattered nodular densities within both lungs concerning for metastatic disease. Thoracentesis showed lymphocyte predominant exudate with negative cytology for malignant cells. A video-assisted thoracoscopic surgery (VATS) illustrated thickened pleural rind with histopathology and positive p40 stain consistent with invasive well-to-moderately differentiated keratinizing SCC. CONCLUSIONS SCC arising from HS is rare and metastatic disease to the pleura has not been reported previously. Strong clinical suspicion for malignancy is warranted in patients with advanced HS and evolving pulmonary symptoms despite negative cytology. PMID- 28028309 TI - Symbiosis: New horizons for Wolbachia. PMID- 28028311 TI - The complement system is also important in immunogenic cell death. PMID- 28028312 TI - Reply: The complement system is also important in immunogenic cell death. PMID- 28028310 TI - Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. AB - Immune responses are regulated by effector cytokines and chemokines that signal through cell surface receptors. Mammalian decoy receptors - which are typically soluble or inactive versions of cell surface receptors or soluble protein modules termed binding proteins - modulate and antagonize signalling by canonical effector-receptor complexes. Viruses have developed a diverse array of molecular decoys to evade host immune responses; these include viral homologues of host cytokines, chemokines and chemokine receptors; variants of host receptors with new functions; and novel decoy receptors that do not have host counterparts. Over the past decade, the number of known mammalian and viral decoy receptors has increased considerably, yet a comprehensive curation of the corresponding structure-mechanism relationships has not been carried out. In this Review, we provide a comprehensive resource on this topic with a view to better understanding the roles and evolutionary relationships of mammalian and viral decoy receptors, and the opportunities for leveraging their therapeutic potential. PMID- 28028313 TI - Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T cell acute lymphoblastic leukemia. AB - The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1 regulated super-enhancer controlling the GIMAP locus, which resides within an insulated chromosomal locus in T-ALL cells. The GIMAP genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The GIMAP enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukemogenesis. PMID- 28028316 TI - Multiple sclerosis: Is there a safe time to discontinue therapy in MS? PMID- 28028314 TI - Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors. AB - Recent advances in antibody technology to harness T cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), have led to innovative methods for directing cytotoxic T cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T cells and cancer cells. Another approach infuses ex vivo-engineered T cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR). Both bispecific antibodies and CARs circumvent natural target cell recognition by creating a physical connection between cytotoxic T cells and target cancer cells to activate a cytolysis signaling pathway; this connection allows essentially all cytotoxic T cells in a patient to be engaged because typical tumor cell resistance mechanisms (such as T-cell receptor specificity, antigen processing and presentation, and major histocompatibility complex context) are bypassed. Both the bispecific T-cell engager (BiTE) antibody construct blinatumomab and CD19-CARs are immunotherapies that have yielded encouraging remission rates in CD19-positive r/r ALL, suggesting that they might serve as definitive treatments or bridging therapies to allogeneic hematopoietic cell transplantation. With the introduction of these immunotherapies, new challenges arise related to unique toxicities and distinctive pathways of resistance. An increasing body of knowledge is being accumulated on how to predict, prevent, and manage such toxicities, which will help to better stratify patient risk and tailor treatments to minimize severe adverse events. A deeper understanding of the precise mechanisms of action and immune resistance, interaction with other novel agents in potential combinations, and optimization in the manufacturing process will help to advance immunotherapy outcomes in the r/r ALL setting. PMID- 28028317 TI - Oral leptin supplementation throughout lactation in rats prevents later metabolic alterations caused by gestational calorie restriction. AB - OBJECTIVES: Calorie-restriction during gestation in rats has been seen to produce lasting detrimental effects in the offspring, affecting energy balance control and other related metabolic functions. Our aim was to assess whether leptin supplementation throughout lactation may prevent the dysmetabolic phenotype in adulthood associated with gestational calorie restriction. METHODS: Three groups of male Wistar rats were followed: the offspring of ad libitum fed dams (controls); the offspring of 20% calorie-restricted dams during gestation (CR); and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Pups were weaned with a standard diet (SD) until 4 months of age, and then half of the animals of each group were moved to a Western diet (WD) until 6 months of age. Body weight and food intake were recorded. Energy expenditure, locomotive activity, blood parameters, liver triglycerides (TG), and gene expression and specific proteins in liver and white adipose tissue (WAT) were measured in adulthood. RESULTS: Adult CR rats, but not CR-Leptin rats, displayed greater adiposity index and feed efficiency (both under SD) than controls, along with lower locomotive activity and energy expenditure, higher HOMA-IR index and greater circulating TG and leptin levels. CR animals also exhibited increased values of the respiratory exchange ratio and more severe signs of hepatic steatosis under WD than CR-Leptin animals. Gene expression analysis revealed that CR, but not CR-Leptin, animals displayed indicators of lower capacity for WAT expansion, along with decreased lipogenesis and lipolytic capacity under SD, and impaired lipogenic response of the liver to WD feeding, in accordance with diminished insulin sensitivity and WAT leptin signaling. CONCLUSIONS: Oral leptin supplementation in physiological doses throughout lactation in rats prevents most of the detrimental effects on energy homeostasis and metabolic alterations in adulthood caused by inadequate fetal nutrition. PMID- 28028318 TI - Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Obese men commonly have reductions in circulating testosterone and report symptoms consistent with androgen deficiency. We hypothesized that testosterone treatment improves constitutional and sexual symptoms over and above the effects of weight loss alone. METHODS: We conducted a pre-specified analysis of a randomized double-blind, placebo-controlled trial at a tertiary referral center. About 100 obese men (body mass index (BMI)?30 kg m-2) with a repeated total testosterone level ?12 nmol l-1 and a median age of 53 years (interquartile range 47-60) receiving 10 weeks of a very-low-energy diet (VLED) followed by 46 weeks of weight maintenance were randomly assigned at baseline to 56 weeks of intramuscular testosterone undecanoate (n=49, cases) or matching placebo (n=51, controls). Pre-specified outcomes were the between-group differences in Aging Male Symptoms scale (AMS) and international index of erectile function (IIEF-5) questionnaires. RESULTS: Eighty-two men completed the study. At study end, cases showed significant symptomatic improvement in AMS score, compared with controls, and improvement was more marked in men with more severe baseline symptoms (mean adjusted difference (MAD) per unit of change in AMS score -0.34 (95% confidence interval (CI) -0.65, -0.02), P=0.04). This corresponds to improvements of 11% and 20% from baseline scores of 40 and 60, respectively, with higher scores denoting more severe symptoms. Men with erectile dysfunction (IIEF-5?20) had improved erectile function with testosterone treatment. Cases and controls lost the same weight after VLED (testosterone -12.0 kg; placebo -13.5 kg, P=0.40) and maintained this at study end (testosterone -11.4 kg; placebo -10.9 kg, P=0.80). The improvement in AMS following VLED was not different between the groups (-0.05 (95% CI -0.28, 0.17), P=0.65). CONCLUSIONS: In otherwise healthy obese men with mild to moderate symptoms and modest reductions in testosterone levels, testosterone treatment improved androgen deficiency symptoms over and above the improvement associated with weight loss alone, and more severely symptomatic men achieved a greater benefit. PMID- 28028319 TI - An educational intervention to promote healthy lifestyles in preschool children: a cluster-RCT. AB - OBJECTIVE: Promoting four healthy behaviours among preschool children:?4 servings of fruit and vegetables/day, ?2 h/day of active play, ?1 h per day of TV-watching and 0 sugar sweetened beverages/day. METHODS: We conducted a c-RCT on 425 3-year old children at 16 childcare centres based in Cesena, Italy. We randomly allocated eight childcare centres (199 children) to the intervention group and eight childcare centres (226 children) to the control group. All the randomized childcare centres completed our study protocol. Parents recorded their children's target behaviours at home over 3 Saturdays, at baseline and at follow-up. Then trained nurses measured children's weight and height. We conducted a 6-month-long intervention trial in local health care centres where nurses and primary care pediatricians, respectively, conducted two subsequent motivational interviews with parents to encourage children's healthy behaviours at home. At the same time, teachers involved children in learning experiences about healthy behaviours. Our primary outcome is a children's combined health behaviour score (CHBS) at home. Our secondary outcomes measure the BMI z-score and the percentage of children that show a BMI trajectory crossing upward. After collecting the CHBS and BMI data at baseline as well as at 1- and 2-year follow-ups, we performed an Intent-to-Treat (ITT) analysis. RESULTS: After 2 years from baseline, 48.4% of intervention group children showed a low-risk CHBS in comparison with 28.0% of control group children. A multilevel analysis showed that they were by far more likely to achieve low-risk scores (adjusted OR: 3.41; 95% CI: 1.48-7.88; P=0.004). Our BMI outcomes showed no significant difference between groups. CONCLUSIONS: A multidimensional educational intervention, which consists of motivational interviews with parents and teacher-led learning experiences for children, improved preschool children's CHBS in the long term without influencing the outcomes of BMI z-score and BMI increase. PMID- 28028321 TI - Is It Time to Panic? PMID- 28028320 TI - Protein intake and dietary glycemic load of 4-year-olds and association with adiposity and serum insulin at 7 years of age: sex-nutrient and nutrient-nutrient interactions. AB - BACKGROUND/OBJECTIVES: The role of Protein Intake (PI) at preschool age on later adiposity is understudied, and prospective studies also examining Dietary Glycemic Load (GL) are lacking. The current study evaluated the association of PI and GL at 4 years with adiposity and Fasting Serum Insulin (FSI) 3 years later, and examined the possible interaction between PI and GL on these associations, by sex. DESIGN: This prospective study included 1999 singleton children enrolled in the population-based birth cohort, Generation XXI (Porto, Portugal, 2005-2006). Diet at 4 years was assessed by 3-days food diaries. Energy-adjusted PI and GL (g per day) were converted into sex-specific tertiles (T). At 7 years, Body Mass Index (BMI) z-scores were defined according to the World Health Organization. Sample's sex-specific z-scores were computed for Fat Mass Index (FMI), Waist-to Height ratio (W/Ht) and FSI. Associations were estimated by linear regression coefficients (beta) and 95% confidence intervals (95% CI). RESULTS: After adjustment for confounders, PI was positively associated with BMI in girls (T2 vs T1: beta=0.187; 95% CI: 0.015, 0.359) and boys (T3 vs T1: beta=0.205; 95% CI: 0.003, 0.406), being associated with FSI only in boys (T3 vs T1: beta=0.207; 95% CI: 0.011, 0.404; P-interaction=0.026). Also, GL was associated with BMI only in boys (T3 vs T1: beta=0.362; 95% CI: 0.031, 0.693; P-interaction=0.006), in whom significant interactions between PI and GL were found on the association with FMI (P=0.019) and W/Ht (P=0.039). Boys within the third T of both PI and GL at 4 years had higher FMI (beta=0.505; 95% CI: 0.085, 0.925) and W/Ht (beta=0.428; 95% CI: 0.022, 0.834) at 7 years. CONCLUSIONS: In both girls and boys, PI at preschool age is positively associated with later BMI, being positively associated with FSI only in boys. Dietary GL is associated with adiposity only in boys, in whom it seems to interact with PI enhancing increased adiposity. PMID- 28028322 TI - Surviving and Thriving Your First Year in Private Practice. AB - Taking the leap toward a career as a private practice owner is daunting. When in the initial stages of starting a private practice, I searched for current advice from an audiologist who had recently confronted the same challenges I was about to face. Because of the limited information available, I documented my process in hopes of providing an overview of my startup experience to help others. Included is a timeline of startup tasks and a sample budget to use as a reference. In this chapter, I share my experiences, both the positives and the negatives, and tips with the goal of helping you survive and thrive in your first year in private practice. PMID- 28028323 TI - Using Key Performance Indicators to Do More with Less in Your Practice. AB - Key performance indicators (KPIs) are important to managing any sustainable business. This tutorial provides audiologists, especially those with little formal business education, with a working definition of KPIs. A major theme of this article is that a relatively small group of about a dozen KPIs are an essential part of managing a successful audiology practice. The most useful KPIs for managing retail-oriented and medically oriented practices will be provided. Best practice benchmarks and how to use them to hire, coach, and train your staff also is covered. PMID- 28028324 TI - Patient Satisfaction by Design. AB - The concept of the patient experience as it relates to patient satisfaction is a complex dynamic. It is a dynamic that is becoming increasingly more important as patients are faced with multiple choices for their hearing and balance care. As reimbursement and performance policies have become more normative within health care, patient satisfaction has become a metric to measure quality. Patient satisfaction is no longer contained to just the interaction with the audiologist. It extends to the entire experience-the staff, the service, the product, and other factors. Many practices fail to capitalize on one of the primary components of the patient experience-office design. This article discusses the role of evidence-based design in facility planning as it relates to patient satisfaction. It will illustrate how design principles and ideal attributes may be used to send conscious and subconscious cues that will motivate staff, facilitate patient centered care, and ultimately increase patient satisfaction. PMID- 28028325 TI - Can You Hear Me Now? Marketing Essentials for Audiologists in a Noisy Health Care World. AB - Audiologists, even those with a strong acumen for business, are not traditionally taught the basics of creating a robust practice identity and dynamic marketing plan. This activity will teach learners how to create a distinct brand that separates them from others in a competitive and distracted marketplace. Additionally, learners will gain an understanding for how to blend traditional marketing tools with more modern online options and social media. Upon completion, learners will be familiar with the skills necessary to actively create, implement, and track the effectiveness of their marketing strategy using proven methodologies. PMID- 28028326 TI - Practice Management: The Game Changer. AB - The reimbursement landscape is undergoing significant changes. Practice management, which encompasses reimbursement, is becoming increasingly more important in securing business success. Each practitioner within a facility is responsible for fortifying the practice through thoughtful business protocols. Knowing legislation that impacts health care along with understanding the foundational components of reimbursement is key for keeping a practice financially healthy. Change is good, but making the changes is what counts! Legislation such as the Medicare Access and Chip Reauthorization Act defines the new payment models. Correcting current business practices might seem difficult on the surface, but implementing change is rewarding and an obligation of the practitioners within a facility to their patients. Financial stability for a practice occurs when sound business practices are routine. Today's audiologist must not only be proficient at performing his or her scope of practice, but must also accept that performing best business practices is part of the job. In the end, the patients seeking the services of the audiologist benefit most when a practice has the financial stability to be best in its class. PMID- 28028327 TI - Audiology Assistants in Private Practice. AB - Using audiology assistants allows a practice to meet the expected increase in patient demand in a cost-effective manner, without compromise to quality of patient care. Assistants are particularly valuable in private practice settings that have an emphasis in amplification, as many of the tasks involved do not require the unique skills of the doctor of audiology. Regulatory considerations, methods of training, and scope of practice of the assistant are discussed. PMID- 28028328 TI - Tools for Success in Private Practice. AB - When it comes to business, there is no one thing that ensures success. However, focusing on helping as many patients as possible and tracking those results, creating a program to gather referrals from your own patients, setting a goal each month, and having a key employee to guide operations at the front desk to ensure that every patient is treated well and has an awesome experience at your office will go a long way to steering a practice to success. PMID- 28028329 TI - The Future of Private Practice in Audiology. AB - Although private practice in audiology has evolved during the past 40 years, hearing aids have remained as a central component to success. This article will discuss present and future trends for the next 40 years, including parallels to other professions and the need to innovate beyond technology. PMID- 28028330 TI - Utility of manual liquid-based cytology and conventional smears in the evaluation of various fine-needle aspiration samples. AB - BACKGROUND: Liquid-based cytology (LBC) preparation is a way to improve and refine the fine-needle aspiration (FNA) samples. There are a few studies comparing LBC with conventional smear (CS). AIM: The present study was undertaken to evaluate the utility of manual LBC (MLBC) and CS preparations in various FNA samples. MATERIALS AND METHODS: In this cross-sectional study, a total of 100 FNA samples from various anatomical sites were evaluated using MLBC and CS preparations. Cellularity, blood, informative background, monolayers, cell architecture, cytoplasmic, and nuclear preservation were compared with MLBC and CS preparations by Wilcoxon signed rank test. P < 0.05 is considered statistically significant. RESULTS: MLBC preparations were superior to CS preparations in view of absence of blood and debris (P = 0.001), presence of monolayers (P < 0.001), and preservation of cytoplasmic (P = 0.001) and nuclear details (P = 0.001). However, no statistically significant differences were found between MLBC and CS preparations with regard to cellularity (P = 0.157), informative background (P = 0.083), and architecture (P = 0.739). CONCLUSION: MLBC preparations in FNAC are a safe, easy, and less time-consuming procedure, and it may have promising diagnostic value in the evaluation of FNA samples from various anatomical sites. However, the use of both MLBC and CS preparations is recommended to achieve optimal diagnostic yield. PMID- 28028331 TI - Correlation between cytological and histological grading of breast cancer and its role in prognosis. AB - CONTEXT: Assigning grade to breast cancer on FNAC provides prognostic information and guides optimal therapy. AIMS: The present study was undertaken to grade breast carcinoma on cytology by Robinson's grading system and correlate it with Elstons modified Bloom Richardson histological grading system. SETTINGS AND DESIGN: It is a prospective study done on fifty cases of breast cancer reported on cytology. MATERIALS AND METHODS: Fifty patients who underwent FNAC and mastectomy for breast carcinoma were cytologically and histologically graded. Correlation between cytological and histological grading system was determined. Sensitivity and specificity of Robinson's cytological grading system was calculated in each grade. All cases evaluated for presence of metastasis to axillary lymph nodes. STATISTICAL ANALYSIS USED: Correlation between cytological and histological grading was established using the non parametric Spearmana?TM s correlation coefficient. RESULTS: Concordance rate between cytological and histological grade was 78%. The coefficient of correlation between cytological grade and histological grade was 0.804 and P value was <0.001 which indicated a strong correlation and significant association between the cytological and histological grade. Sensitivity was maximum in cytological grade I tumors (100%) and least in cytological grade III tumors (45.45%). Specificity was maximum in cytological grade III tumors (94.87%) and least in cytological grade II tumors (72.72%). The incidence of axillary lymph node metastasis was maximum in cytological grade III tumors and grade I tumors. CONCLUSIONS: Cytological grade strongly predicts histological grade and is useful in selecting neoadjuvant chemotherapy. PMID- 28028332 TI - Comparison of liquid-based preparation and conventional smear of fine-needle aspiration cytology of lymph node. AB - BACKGROUND: In this paper, we have compared the cytomorphologic characteristics of liquid-based preparation (LBP) [SurePath (SP)] cytology and conventional smear (CP) preparations on fine-needle aspiration (FNAC) material by a semi quantitative scoring system for cases of lymphadenopathy. MATERIALS AND METHODS: In this prospective study, a total of 52 consecutive cases of FNAC of lymphadenopathy were included. The first pass was used for CP followed by LBP with the help of SP technique. The smears were independently compared and assessed by two observers (PS and PD). RESULTS: The semiquantitative grading was compared in two groups by Wilcoxon signed-rank test. The background information, cell architecture, pleomorphism, nuclear and cytoplasmic details, and three dimensional structures were significantly different in LBP and CP smears. CONCLUSIONS: Liquid-based cytology (LBC) is a relatively simple technique, which exhibits good nuclear and cytoplasmic details with the absence of obscuring background material. Even the number of slides and area per slide to be screened were less than the conventional preparation but caution must be applied to interpret the slides and secure a diagnosis, especially if LBC is the first and only method applied for diagnosis. PMID- 28028333 TI - An analysis of trends of incidence and cytohistological correlation of papillary carcinoma of the thyroid gland with evaluation of discordant cases. AB - BACKGROUND: The role of fine-needle aspiration cytology (FNAC) in thyroid nodules has been well-studied but there is a paucity of studies solely involving papillary thyroid carcinoma (PTC). The diagnostic criteria for PTC are established but still there is a worrisome possibility of false positive and false-negative results, which can have a serious impact on patient care. This article correlates the cytological and histological diagnosis of PTC with an eventual aim of analyzing the cause of false positive and false negative results in order to prevent misdiagnosis. An increase in the incidence of PTC in the younger population has been noted. AIMS: To analyze the epidemiological trends and cytohistological correlation of PTC and evaluate the discordant cases and pitfalls of FNAC. MATERIALS AND METHODS: Seventy-two cases who had undergone both FNAC and histopathological examination (HPE) of the thyroid gland were selected. Age and sex distribution as well as cytohistological correlation were done for all the cases. RESULTS: Cytohistological correlation was 81.94%. False positives were 5.56% and the false negative rate was 13.2%. Sensitivity was 86.7% and the positive predictive value was 93.6%. The peak age was 31-40 years among females and 41-60 years among males. Seven of our patients were <20 years of age (10%). CONCLUSION: FNAC is an indispensible tool for the early diagnosis of PTC. However, certain conditions of the thyroid gland can cause diagnostic dilemma. Awareness of pathologists regarding these pitfalls can prevent misdiagnosis and provide better patient care. Increasing the incidence of PTC with a more striking increase in the younger population makes early diagnosis all the more important owing to better prognosis in this age group. PMID- 28028334 TI - Liquid-based versus conventional cytology in solid pediatric neoplasm: Comparison of their diagnostic and morphological spectra. AB - BACKGROUND: Conventional cytology (CC) is a well-established and effective methodology for the evaluation of pediatric tumors. Liquid-based cytology (LBC) is a better technique of smear preparation and is at present the standard protocol in cervical cytology samples. AIMS: In the present study, we analyzed both smear preparatory techniques in fine-needle aspiration (FNA) samples from solid pediatric neoplasms in terms of adequacy and efficacy with objectives to study the changes in background and morphology of tumor cells in LBC smears. MATERIALS AND METHODS: This was a prospective observational study conducted in a tertiary care teaching hospital, which included 52 pediatric patients with clinical diagnosis of malignancy and an assessable lump. Both conventional aspiration cytology and LBC smears were prepared as per standard protocols (SurePath BDTM) from FNA samples of cases and examined. RESULTS AND CONCLUSION: On comparing the diagnostic efficacy of cytology smears prepared by both techniques, LBC alone was diagnostic in 80.8% of the cases and conventional smear (CS) alone was diagnostic in 71.2% of the cases (agreement was 83.7%, P = 0.3). Cellular morphology was better preserved in LBC and interpretation was easier. There was a lower inadequacy rate in LBC and none of the samples was inadequate due to poor morphology in LBC smears (P = 0.0003). LBC showed an overall 40% improvement in inadequate cases by CS. LBC has been recommended as a complement to CC in nongynecological samples. Improved morphology and lower inadequacy rate make LBC a finer technique compared to CS in pediatric tumors as well. PMID- 28028335 TI - Utility of squash smear cytology in intraoperative diagnosis of central nervous system tumors. AB - BACKGROUND: Central nervous system (CNS) squash cytology (CSC) has established itself as a technically simple, rapid, inexpensive, fairly accurate, and dependable intraoperative diagnostic tool. It helps neurosurgeons immensely when management is dependent on it. AIMS: This study aimed at finding out the utility of CSC as an intraoperative diagnostic tool from a neurosurgeon's perspective. MATERIALS AND METHODS: Fifty prospectively registered patients with clinical diagnosis of CNS tumors were enrolled in the study. All the patients were subjected to magnetic resonance imaging (MRI). Intraoperative CSC was performed and smears were stained with Leishman and rapid Hematoxylin and Eosin (H and E) stain. The diagnosis of CSC was compared with MRI diagnosis and histopathological diagnosis. The CNS tumors were categorized based on clinical and therapeutic implications. Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive value of MRI and CSC were calculated by using appropriate formulae. RESULTS AND CONCLUSIONS: The age range of the CNS tumors included in the study was 2 to 68 years. There was a slight female preponderance. Sensitivity, specificity, positive predictive value, and negative predictive value of preoperative MRI were 90.47%, 82.76%, 79.17%, and 92.31% respectively. These values of utility parameters for CSC were 100% for each of the clinical and therapeutic implications. It helped neurosurgeons in optimizing surgical procedure in 12 cases of meningioma. It influenced surgical management in 1 case of infratentorial pilocytic astrocytoma, and helped in the diagnosis and management of 9 unexpected tumors missed on MRI. PMID- 28028336 TI - Comparative study of bronchoalveolar lavage, bronchial brushing, and FNAC in diagnosing malignant neoplasms of lungs. AB - BACKGROUND: Lung cancer is the leading cause of death in developed countries and is increasing at alarming rates in developing countries. Cytological techniques such as bronchoalveolar lavage (BAL), bronchial brushing (BB), and fine needle aspiration cytology (FNAC) can aid in the early diagnosis of lung malignancies. MATERIALS AND METHODS: A total of 67 cases, suspected of lung cancer between January 2010 and December 2012, were selected where samples of BAL, BB, FNAC, as well as biopsy were obtained and processed according to the standard procedures of cytology and histology. The aim of this study was to compare the diagnostic efficacy of the three modalities, i.e., BAL, BB, and FNAC in diagnosing malignant neoplasms of the lung. Biopsy was considered to be the gold standard diagnostic test. RESULTS: Sensitivity of BAL, BB, and FNAC was found to be 47.61, 65.07, and 88.88%, respectively, whereas specificity of BAL, BB, and FNAC was 75, 75, and 100%, respectively. CONCLUSIONS: FNAC is the best technique among the three for the diagnosis of lung cancers. PMID- 28028337 TI - Thyroid FNAC containing hurthle cells and hurthle-like cells: A study of 128 cases. AB - AIM: It is a diagnostic challenge to differentiate benign and malignant cytology in the presence of Hurthle cells. In our previous study, it was determined that in fine needle aspirations (FNA), the malignancy outcome of the Hurthle cells containing group tend to be papillary thyroid carcinoma (PTC) in a higher percentage. The most common misinterpretation is caused by PTC cells with large cytoplasm-like Hurthle cells. The aim of this study is to predict histologic outcome of the nodules, which have Hurthle cells in FNA according to cytological, clinical features, and BRAFV600E mutation status. MATERIALS AND METHODS: Detailed cytological features of 128 cases were compared with histopathological diagnosis. The analysis of BRAFV600E mutation of the PTC cases were performed by real-time polymerase chain reaction. RESULTS: The neoplastic outcome was increased statistically significantly with younger age (P = 0.020), increase in cellular dyshesion (P = 0.016), presence of nuclear budding (P = 0.046), and granular chromatin (P = 0.003). Nuclear budding (P = 0.014), granular chromatin (P = 0.012), and hypoechoic nodules in ultrasonography (P = 0.011) were significant independent factors for the increase in the malignancy risk. Increased lymphocytes (P= 0.015) and colloid were related to non-neoplastic outcome. According to the surgical outcome, more than half of the malign cases were PTC (74%). BRAFV600E mutation was detected in 27.8% of the PTC cases. CONCLUSION: PTC cases containing Hurthle cell-like cells may lead to diagnostic errors. Nuclear budding and granular chromatin of Hurthle cells are significant, remarkable findings to predict the outcome of neoplasm and malignancy. PMID- 28028338 TI - Cytological diagnosis of pediatric thyroid nodule in perspective of the Bethesda System for Reporting Thyroid Cytopathology. AB - BACKGROUND: Thyroid nodule is one of the most common endocrinopathies occurring children and adolescents. Though thyroid nodule is rare in the pediatric age group, the rate of malignancy is much higher in this age group compared to adult population. AIM: The objective is to study the application of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) in pediatric patients and compare the findings with histology. MATERIALS AND METHODS: A total of 218 cases younger than 18 years were studied in a 4-year period from August 2010 to July 2014. The smears were categorized according to TBSRTC into six categories - Nondiagnostic, benign, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), suspicious for follicular neoplasm (SFN), suspicious for malignancy (SM), and malignancy. RESULTS: Out of 218 cases, 33 were males and 185 were females. Histological follow-up was available in 44 cases. The diagnosis according to TBSRTC included 12 (5.5%) nondiagnostic, 151 (69.26%) benign, 23 (10.5%) AUS/FLUS, 18 (8.2%) SFN, 5 (2.3%) SM, and 9 (4.1%) malignancy cases. On histological follow-up, the rate of malignancy in each category was 0%, 0%, 8.3%, 10% 100%, and 100%, respectively. CONCLUSION: The study demonstrates that TBSRTC in pediatric thyroid nodule is as sensitive and specific as in adults, especially with 100% accuracy in the diagnosis of benign and malignant categories. PMID- 28028339 TI - Benign phyllodes tumor with tubular adenoma-like epithelial component in FNAC: A diagnostic pitfall. AB - Benign phyllodes tumor (BPT) is a biphasic neoplasm composed of bland stromal and epithelial elements. Cytologic diagnostic criteria of BPT, though documented in the literature, diagnostic pitfalls in fine-needle aspiration cytology (FNAC) may occur due to sampling error, high cellularity, ductal hyperplasia, paucity of stromal component, and occasional dissociation of epithelial cells. Here, we describe a case of BPT diagnosed by histology in a 19-year-old female, where FNAC features were inconclusive due to paucity of stromal component, predominance of tubular adenoma-like epithelial component, and due to the presence of other overlapping features with fibroadenoma. PMID- 28028340 TI - Diffuse large B-cell lymphoma of the parotid gland: Cytological, histopathological, and immunohistochemical features: A rare case report. AB - Primary malignant lymphomas of the salivary glands are rare, accounting for 2-5% of salivary gland tumors and 5% of extranodal lymphomas, frequently seen in the parotid gland. There are single case reports mentioned in the literature. Clinical presentation is not characteristic and the disease is often overlooked with delay in diagnosis and treatment. We are reporting a case of bilateral parotid gland lymphoma in a 55-year-old male, presented with bilateral enlarged parotids. Magnetic resonance imaging (MRI) showed bilateral enlarged parotid glands with multiple well-defined intraparotid lesions. Fine Needle Aspiration Cytology (FNAC) of both showed mixed population of lymphoid cells with large monocytoid cells with scant cytoplasm, anisonucleosis with prominent nucleoli, and numerous mitoses suggestive of non-Hodgkin's lymphoma (NHL). Histopathology showed sheets of large lymphoma cells destructing the salivary acini and infiltrating the periparotid fat. Immunohistochemistry (IHC) showed diffuse CD20 positivity, B-cell lymphoma 6 protein (Bcl-6) was focally positive and negative for cluster of differentiation (CD) 3, CD5, CD10, and Multiple myeloma oncogene-1 (MUM1) which led to the diagnosis of NHL-Diffuse large B cell type. PMID- 28028341 TI - Solid pseudopapillary tumor of pancreas: A lesser known entity-diagnosis and pitfalls: A case report. AB - Solid pseudopapillary tumor (SPT) is a rare pancreatic neoplasm with a reported incidence of 0.1% to 2.7% of all pancreatic tumors. Because radiological presentation of pancreatic tumors is quite overlapping, distinctive features in fine needle aspiration cytology (FNAC) helps in its diagnosis preoperatively. Being a low-grade malignancy presenting predominantly in young females, correct preoperative diagnosis minimizes the need of extensive surgery. SPT carries good prognosis without any adjuvant chemotherapy/radiotherapy in most cases, even in the presence of metastatic disease. On the other hand, aggressive surgical resection is required for ductal adenocarcinoma which is more common pancreatic tumor (90%). We report here a case of a 49-year-old female diagnosed as SPT. The importance of the need for the radiologist, pathologist, and surgeon to be familiar with SPT is highlighted so that it is more often diagnosed as there are significant therapeutic and prognostic implications. PMID- 28028342 TI - Kimura's disease: A diagnostic challenge experienced with cytology of postauricular swelling with histopathological relevance. AB - Kimura's disease is a rare, chronic inflammatory disorder of unknown cause. It is endemic in Asia, affecting more number of males than females, with a ratio of 3:1. The typical clinical manifestations include a triad of painless unilateral cervical lymphadenopathy or subcutaneous masses predominantly in the head and neck region, blood and tissue eosinophilia, and an elevated serum immunoglobulin E (IgE) levels. Variable conditions both benign and malignant may mimic Kimura's disease both clinically and on fine needle aspirates. The confirmatory diagnosis is established only by histopathological examination. We report a case of Kimura's disease in a patient who underwent multiple investigations in view of her past history and family history of pulmonary Koch's. Fine needle aspiration cytology (FNAC) was performed thrice with consistently similar result of reactive lymphadenitis with numerous histiocytes and eosinophilia. The final diagnosis of Kimura's disease could finally be established only on histopathological examination. PMID- 28028343 TI - Cribriform morular variant of papillary thyroid carcinoma: Cytomorphology, differential diagnosis and diagnostic implications in patients with adenomatous polyposis coli. AB - Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC), which has a better prognosis, is seen mostly in the setting of familial adenomatous polyposis (FAP). The cytomorphology of CMV-PTC is diverse; hence, it could be mistaken for other thyroid neoplasms with bad prognostic outcome. This case is of a 24-year old female diagnosed with polyposis coli found to have thyroid nodules at screening ultrasonography. Aspirated thyroid smears were hypercellular with epithelial cells arranged in monolayer sheets, papillae with discohesion, and spindling of cells at the edges, cribriform clusters, and cell morules. Individual cell morphology ranged from polygonal, tall columnar to spindle cells. Nuclei were round-to-oval with coarse chromatin, indistinct nucleoli, and mitotic figures. Nuclear inclusions and grooves were rare and colloid was sparse. Cytomorphology was suspicious, however, was not classical of CMV-PTC documented so far. Subsequent histology confirmed a CMV-PTC. PMID- 28028344 TI - Colloid goiter in ectopic thyroid tissue presenting as submandibular swelling with a coexisting functional orthotopic thyroid gland in a pregnant female. PMID- 28028345 TI - Subcutaneous Pheohyphomycois-A Rare Mycotic Infection from a North Himalayan State of India Diagnosed on Cytopathology. PMID- 28028346 TI - The Anti-VEGF Epidemic: What are the Implications for Glaucoma Services? AB - : The early reports on intraocular bevacizumab injections talked about a transient predictable probably volume-related rise in intraocular pressure (IOP). As the usage of the drug increased across the globe, sustained IOP elevation was noted. This article provides an insightly into the causes of IOP spikes and its impact on glaucoma practice. HOW TO CITE THIS ARTICLE: Skalicky SE, I Clement C. The Anti-VEGF Epidemic: What are the Implications for Glaucoma Services? J Current Glau Prac 2012;6(2):55-57. PMID- 28028347 TI - Experts Opinion. AB - In this editions' 'Experts Opinion', the management of hy-potony and choroidal effusion following glaucoma filtration surgery is discussed. We are delighted to welcome Clinical Associate Professor Ivan Goldberg and Professor Franz Grehn and Paul Chew to the panel to provide opinion on this very challenging clinical situation. PMID- 28028348 TI - Assessment of Structural Glaucoma Progression. AB - PURPOSE: To provide an update on the role of optic nerve head and peripapillary retinal nerve fiber layer imaging in monitoring glaucoma progression. METHODS: Review of literature. RESULTS: Imaging technologies, such as optical coherence tomography, scanning laser polarimetry, and confocal scanning laser ophthalmoscopy, objectively and quantitatively measure the structural change associated with glaucoma. Rates of retinal nerve fiber layer (RNFL) and rim area loss are significantly faster in progressing compared with nonprogressing subjects. A number of strategies to detect progression have been proposed. The precision of these methods is generally high. However, there is no agreement as to which instrument or parameter is most appropriate for the evaluation of structural progression associated with glaucoma at this moment. The agreement between structural and functional glaucoma progression is generally poor regardless of the strategies used. Structural progression analyses appear to complement visual field progression analyses, detecting a different subset of progressing subjects. SUMMARY: Imaging devices are promising tools for monitoring patients with glaucoma. Combining structural and functional analyses is useful for accurate monitoring of glaucoma progression. HOW TO CITE THIS ARTICLE: Miki A. Assessment of Structural Glaucoma Progression. J Current Glau Prac 2012;6(2):62-67. PMID- 28028349 TI - Anterior Segment Optical Coherence Tomography and its Clinical Applications in Glaucoma. AB - : Anterior segment optical coherence tomography (ASOCT) is an imaging modality that provides both quantitative and qualitative information on the cornea, anterior chamber angle, iris and crystalline lens. ASOCT shows excellent repeatability and reproducibility for the measurement of corneal thickness, anterior chamber angle and anterior chamber depth. With realtime video recording, ASOCT can also effectively capture the dynamic changes of the iris and lens in response to light and eye accommodation. With this additional information, physiological and pathological changes of the anterior segment structures are now better understood. This article aims to provide an overview of the current applications of ASOCT in glaucoma. HOW TO CITE THIS ARTICLE: Li H, Jhanji V, Dorairaj S, Liu A, Lam DSC, Leung CK. Anterior Segment Optical Coherence Tomography and its Clinical Applications in Glaucoma. J Current Glau Prac 2012;6(2):68-74. PMID- 28028350 TI - Bevacizumab in Glaucoma: Where do We Stand? AB - : The use of antivascular endothelial growth factors such as bevacizumab and ranibizumab has brought about a revolution in management protocols of various ophthalmic disorders. A lot has been written about these agents, still lacunae exist in our understanding due to paucity of randomized control trials with large number of patients. This brief review attempts to throw light on the clinical applications of these molecules for glaucoma. HOW TO CITE THIS ARTICLE: Khanna A. Bevacizumab in Glaucoma: Where do We Stand? J Current Glau Prac 2012;6(2):75-78. PMID- 28028351 TI - Selective Laser Trabeculoplasty: An Overview. AB - : Given the obvious quality of life concerns with medical and surgical lowering of intraocular pressure (IOP), lasers have received considerable attention as a therapeutic modality for glaucoma. Selective laser trabeculoplasty (SLT) is increasingly being used in clinical practice as both the primary procedure and as an adjunct to medical and surgical therapy. Preliminary published evidence suggests that SLT is an effective, compliance-free, repeatable and safe therapeutic modality having only minor, transient, self-limiting or easily controlled side effects with no sequelae. This review attempts a broad overview of the current knowledge of its mechanism, efficacy, indications and limitations, point out the knowledge lacunae that still exist with respect to this highly promising technology which has captured the attention of glaucoma surgeons all over the world. HOW TO CITE THIS ARTICLE: Jha B, Bhartiya S, Sharma R, Arora T, Dada T. Selective Laser Trabeculoplasty: An Overview. J Current Glau Prac 2012;6(2):79-90. PMID- 28028352 TI - The Blitz Anesthesia Technique in Non-English Speaking Patients Undergoing Glaucoma Surgery. AB - AIM: To describe a less invasive method of providing anesthesia in non-English speaking patients undergoing glaucoma surgery. SETTINGS AND DESIGN: Prospective observational study conducted in a tertiary Care Eye Institute, Wills Eye Institute, Philadelphia, PA, USA. MATERIALS AND METHODS: The blitz anesthesia technique was applied to 15 non-English speaking patients (Vietnamese, Mandarin, Russian and Korean) during glaucoma surgery. With input from family members, a diagram was created for each patient. The diagram consisted of a translation and phonetic guide to pronunciation of common words or phrases in the patient's native language that might be used by the surgical team during the operation. RESULTS: The blitz anesthesia technique worked well to provide patient comfort during the procedures. All patients reported adequate pain control and described their experience as comfortable. Additionally, patients reported feeling reassured that they were able to understand basic information from the surgical team during their case. This technique decreased patient anxiety prior to and during the surgical procedure. CONCLUSION: Blitz anesthesia provided adequate pain control with no complications. KEY MESSAGE: Blitz anesthesia with a phonetic language diagram, a less invasive technique of providing anesthesia in non English speaking patients undergoing glaucoma surgery. HOW TO CITE THIS ARTICLE: Almodin J, Ichhpujani P, Prasad A, Fudemberg SJ, Moster MR. The Blitz Anesthesia Technique in Non-English Speaking Patients Undergoing Glaucoma Surgery. J Current Glau Prac 2012;6(2):91-93. PMID- 28028354 TI - Editorial. PMID- 28028353 TI - Bleb Revision using Reversed Scleral Flap and Pedical Conjunctival Graft. AB - : Bleb revision for hypotony maculopathy following trabeculectomy is an effective technique for raising intraocular pressure and limiting visual loss. The presence for scleral fistula causing over-filtration obviates the need for reinforcing materials, such as donor sclera or pericardium to cover the defect. However, if the surrounding scleral tissue is healthy, a partial thickness scleral flap can be upturned and sutured over the fistula. Moreover, a vascularized pedical conjunctival graft can also be used in cases where there is a large conjunctival defect. HOW TO CITE THIS ARTICLE: Sharma S, Patel D, Sharma R, Dada T. Bleb Revision using Reversed Scleral Flap and Pedical Conjunctival graft. J Current Glau Prac 2012;6(2):94-97. PMID- 28028355 TI - From blood to breath: New horizons for esophageal cancer biomarkers. AB - Esophageal cancer is a lethal cancer encompassing adenocarcinoma and squamous cell carcinoma sub-types. The global incidence of esophageal cancer is increasing world-wide, associated with the increased prevalence of associated risk factors. The asymptomatic nature of disease often leads to late diagnosis and five-year survival rates of less than 15%. Current diagnostic tools are restricted to invasive and costly endoscopy and biopsy for histopathology. Minimally and non invasive biomarkers of esophageal cancer are needed to facilitate earlier detection and better clinical management of patients. This paper summarises recent insights into the development and clinical validation of esophageal cancer biomarkers, focussing on circulating markers in the blood, and the emerging area of breath and odorant biomarkers. PMID- 28028356 TI - Sirtuins and nonalcoholic fatty liver disease. AB - Mammalian sirtuins are seven members belonging to the silent information regulator 2 family, a group of Class III histone/protein deacetylases. Sirtuins (SIRT 1-7) have different subcellular localization and function and they regulate cellular protein function through various posttranslational modifications. SIRT1 and 3, the most studied sirtuins, use the product of cellular metabolism nicotinamide adenine dinucleotide as a cofactor to post-translationally deacetylate cellular proteins and consequently link the metabolic status of the cell to protein function. Sirtuins have been shown to play a key role in the development and rescue of various metabolic diseases including non-alcoholic fatty liver disease (NAFLD). NAFLD is currently the most chronic liver disease due mainly to high-calorie consumption and lower physical activity. No pharmacological approach is available to treat NAFLD, the current recommended treatment are lifestyle modification such as weight loss through calorie restriction and exercise. Recent studies have shown downregulation of sirtuins in human as well as animal models of NAFLD indicating an important role of sirtuins in the dynamic pathophysiology of NAFLD. In this review, we highlight the recent knowledge on sirtuins, their role in NAFLD and their unique potential role as novel therapeutic target for NAFLD treatment. PMID- 28028357 TI - Can probiotics benefit children with autism spectrum disorders? AB - Children with autism are commonly affected by gastrointestinal problems such as abdominal pain, constipation and diarrhea. In recent years, there has been a growing interest in the use of probiotics in this population, as it hypothetically may help to improve bowel habits and the behavioral and social functioning of these individuals. The gut microbiome plays an important role in the pathophysiology of organic as well as functional gastrointestinal disorders. Microbial modification with the use of antibiotics, probiotics, and fecal transplantation have been effective in the treatment of conditions such as recurrent Clostridium difficile infection, pouchitis, and irritable bowel syndrome. The present review presents a number of reported clinical, immunological and microbiome-related changes seen in children with autism compared to normally developed children. It also discusses gut inflammation, permeability concerns, and absorption abnormalities that may contribute to these problems. Most importantly, it discusses evidence, from human and animal studies, of a potential role of probiotics in the treatment of gastrointestinal symptoms in children with autism. PMID- 28028359 TI - Role of dupA in virulence of Helicobacter pylori. AB - Helicobacter pylori (H. pylori) is a gastric human pathogen associated with acute and chronic gastritis, 70% of all gastric ulcers, 85% of all duodenal ulcers, and both forms of stomach cancer, mucosal-associated lymphoid tissue (MALT) lymphoma and adenocarcinoma. Recently, attention has focused on possible relationship between presence of certain virulence factor and H. pylori-associated diseases. Some contradictory data between this bacterium and related disorders has been observed since not all the colonized individuals develop to severe disease. The reported diseases plausibility related to H. pylori specific virulence factors became an interesting story about this organism. Although a number of putative virulence factors have been identified including cytotoxin-associated gene a (cagA) and vacA, there are conflicting data about their actual participation as specific risk factor for H. pylori-related diseases. Duodenal ulcer promoting gene a (dupA) is a virulence factor of H. pylori that is highly associated with duodenal ulcer development and reduced risk of gastric cancer. The prevalence of dupA in H. pylori strains isolated from western countries is relatively higher than in H. pylori strains from Asian countries. Current confusing epidemiological reports will continue unless future sophisticated and molecular studies provide data on functional and complete dupA cluster in H. pylori infected individuals. This paper elucidates available knowledge concerning role of dupA in virulence of H. pylori after a decade of its discovery. PMID- 28028358 TI - Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective. AB - The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications. PMID- 28028360 TI - Dilemma of first line regimens in metastatic pancreatic adenocarcinoma. AB - Pancreatic cancer is one of the deadliest cancers, ranking fourth among cancer related deaths. Despite all the major molecular advances and treatment breakthroughs, mainly targeted therapies, the cornerstone treatment of metastatic pancreatic cancer (mPC) remains cytotoxic chemotherapy. In 2016, more than 40 years after the introduction of gemcitabine in the management of mPC, the best choice for first-line treatment has not yet been fully elucidated. Two main strategies have been adopted to enhance treatment efficacy. The first strategy is based on combining non-cross resistant drugs, while the second option includes the development of newer generations of chemotherapy. More recently, two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel (GNP), have both been shown to improve overall survival in comparison with gemcitabine alone, at the cost of increased toxicity. Therefore, the best choice for first line therapy is a matter of debate. For some authors, FOLFIRINOX should be the first choice in patients with an Eastern Cooperative Oncology Group score (0-1) given its lower hazard ratio. However, others do not share this opinion. In this paper, we review the main comparison points between FOLFIRINOX and GNP. We analyze the two pivotal trials to determine the similarities and differences in study design. In addition, we compare the toxicity profile of the two regimens as well as the impact on quality of life. Finally, we present studies revealing real life experiences and review the advantages and disadvantages of possible second-line therapies including their cost effectiveness. PMID- 28028361 TI - Characterization of smooth muscle, enteric nerve, interstitial cells of Cajal, and fibroblast-like cells in the gastric musculature of patients with diabetes mellitus. AB - AIM: To investigate histologic abnormalities in the gastric smooth muscle of patients with diabetes mellitus (DM). METHODS: Full-thickness gastric specimens were obtained from patients undergoing surgery for gastric cancer. H&E stain and Masson's Trichrome stain were performed to assess the degree of fibrosis. Immunohistochemical staining using various antibodies was also performed [antibodies against protein gene product 9.5 (PGP9.5), neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP), neurokinin-1 (NK1) receptor, c-Kit, and platelet-derived growth factor receptor-alpha, (PDGFRalpha)]. Immunofluorescent staining and evaluation with confocal microscopy were also conducted. RESULTS: Twenty-six controls and 35 diabetic patients (21 short-duration patients and 14 long-duration patients) were included. There were no significant differences in basic demographics between the two groups except in mean body mass index (BMI) (higher in the DM group). Proportions of moderate-to severe intercellular fibrosis in the muscle layer were significantly higher in the DM group than in the control group (P < 0.01). On immunohistochemical staining, c-Kit- and PDGFRalpha-positive immunoreactivity were significantly decreased in the DM group compared with the control group (P < 0.05). There were no statistically significant differences in PGP9.5, nNOS, VIP, and neurokinin 1 expression. On immunofluorescent staining, cellularity of interstitial cells of Cajal (ICC) was observed to decrease with increasing duration of DM. CONCLUSION: Our study suggests that increased intercellular fibrosis, loss of ICC, and loss of fibroblast-like cells are found in the smooth muscle of DM patients. These abnormalities may contribute to changes in gastric motor activity in patients with DM. PMID- 28028362 TI - Correlation between colonic secretion and colonic motility in rats: Role of ghrelin. AB - AIM: To explore the relationship between colonic secretory function and colonic motility. METHODS: Using a rat model chronically implanted with intracerebroventricular (ICV) and cecal catheters, we validated the correlation between colonic secretion and colonic motor functions, as well as the role of ICV injection volume. RESULTS: Compared to saline controls (5 MUL/rat), ICV acyl ghrelin at 1 nmol/5 MUL enhanced the total fecal weight, accelerated the colonic transit time, and increased the fecal pellet output during the first hour post injection, while ICV des-acyl ghrelin at 1 nmol/5 MUL only accelerated the colonic transit time. These stimulatory effects on colonic motility and/or secretion from acyl ghrelin and des-acyl ghrelin disappeared when the ICV injection volume increased to 10 MUL compared with saline controls (10 MUL/rat). Additionally, the ICV injection of 10 MUL of saline significantly shortened the colonic transit time compared with the ICV injection of 5 MUL of saline. The total fecal weight during the first hour post-injection correlated with the colonic transit time and fecal pellet output after the ICV injection of acyl ghrelin (1 nmol/5 MUL), whereas the total fecal weight during the first hour post injection correlated with the fecal pellet output but not the colonic transit time after the ICV injection of des-acyl ghrelin (1 nmol/5 MUL). CONCLUSION: Colonic secretion does not always correlate with colonic motility in response to different colonic stimulations. Acyl ghrelin stimulates colonic secretion. PMID- 28028363 TI - C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38-MAPK activation in acute liver failure. AB - AIM: To investigate the role of the complement 5a (C5a)/C5a receptor (C5aR) pathway in the pathogenesis of acute liver failure (ALF) in a mouse model. METHODS: BALB/c mice were randomly assigned to different groups, and intraperitoneal injections of lipopolysaccharide (LPS)/D-galactosamine (D-GalN) (600 mg/kg and 10 MUg/kg) were used to induce ALF. The Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase (ALT) levels, at different time points within a 1-wk period, were detected with a biochemistry analyzer. Pathological examination of liver tissue was performed 36 h after ALF induction. Serum complement 5 (C5), C5a, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, high-mobility group protein B1 (HMGB1) and sphingosine-1-phosphate levels were detected by enzyme-linked immunosorbant assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of C5aR, sphingosine kinase 1 (SphK1), p38-MAPK and p-p38-MAPK in liver tissue, peripheral blood mononuclear cells (PBMCs) and peritoneal exudative macrophages (PEMs) of mice or RAW 264.7 cells was analyzed by western blotting. C5aR mRNA levels were detected by quantitative real-time PCR. RESULTS: Activation of C5 and up-regulation of C5aR were observed in liver tissue and PBMCs of mice with ALF. Blockade of C5aR with a C5aR antagonist (C5aRa C5aRa) significantly reduced the levels of serum ALT, inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and HMGB1, as well as the liver tissue damage, but increased the survival rates (P < 0.01 for all). Blockade of C5aR decreased SphK1 expression in both liver tissue and PBMCs significantly at 0.5 h after ALF induction. C5aRa pretreatment significantly down regulated the phosphorylation of p38-MAPK in liver tissues of ALF mice and C5a stimulated PEMs or RAW 264.7 cells. Moreover, inhibition of p38-MAPK activity with SB203580 reduced SphK1 protein production significantly in PEMs after C5a stimulation. CONCLUSION: The C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38 MAPK activation in ALF in mice, which provides a potential immunotherapeutic strategy for ALF in patients. PMID- 28028364 TI - NADPH oxidase-1 deficiency offers little protection in Salmonella typhimurium induced typhlitis in mice. AB - AIM: To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium (S. Tm) in a mouse model. METHODS: Eight-week-old male wild-type (WT) and Nox1 knockout (KO) C57BL6/J (B6) mice were administered metronidazole water for 4 d to make them susceptible to S. Tm infection by the oral route. The mice were given plain water and administered with 4 different doses of S. Tm by oral gavage. The mice were followed for another 4 d. From the time of the metronidazole application, the mice were observed twice daily and weighed daily. The ileum, cecum and colon were removed for sampling at the fourth day post-inoculation. Portions of all three tissues were fixed for histology and placed in RNAlater for mRNA/cDNA preparation and quantitative real-time PCR. The contents of the cecum were recovered for estimation of S. Tm CFU. RESULTS: We found Nox1-knockout (Nox1-KO) mice were not more sensitive to S. Tm colonization and infection than WT B6 mice. This conclusion is based on the following observations: (1) S. Tm-infection induced similar weight loss in Nox1-KO mice compared to WT mice; (2) the same S. Tm CFU was recovered from the cecal content of Nox1-KO and WT mice regardless of the inoculation dose, except the lowest inoculation dose (2 * 106 CFU) for which the Nox1-KO had one-log lower CFU than WT mice; (3) there is no difference in cecal pathology between WT and Nox1-KO groups; and (4) there are no S. Tm infection-induced changes in gene expression levels (IL-1b, TNF-alpha, and Duox2) between WT and Nox1-KO groups. The Alpi gene expression was more suppressed by S. Tm treatment in WT than the Nox1-KO cecum. CONCLUSION: Nox1 does not protect mice from S. Tm colonization. Nox1-KO provides a very minor protective effect against S. Tm infection. Using NOX1-specific inhibitors for colitis therapy should not increase risks in bacterial infection. PMID- 28028365 TI - Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4 induced liver fibrosis. AB - AIM: To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS: Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. RESULTS: LSM by ElastPQ was significantly correlated with histologic fibrosis stage (r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. CONCLUSION: ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl4-induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy. PMID- 28028366 TI - Hepatoprotective and antioxidant effects of lycopene on non-alcoholic fatty liver disease in rat. AB - AIM: To evaluate the hepatoprotective effect of lycopene (Ly) on non-alcoholic fatty liver disease (NAFLD) in rat. METHODS: A rat model of NAFLD was first established by feeding a high-fat diet for 14 wk. Sixty-five rats were randomly divided into normal group, model group and Ly treatment groups. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), total cholesterol (TC) in serum and low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), free fatty acid (FFA), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) in liver tissue were evaluated, respectively. While the hepatoprotective effect was also confirmed by histopathological analysis, the expression levels of TNF-alpha and cytochrome P450 (CYP) 2E1 in rat liver were determined by immunohistochemistry analysis. RESULTS: A significant decrease was observed in the levels of serum AST (2.07-fold), ALT (2.95-fold), and the blood lipid TG (2.34-fold) and TC (1.66 fold) in the dose of 20 mg/kg Ly-treated rats (P < 0.01), compared to the model group. Pretreatment with 5, 10 and 20 mg/kg of Ly significantly raised the levels of antioxidant enzyme SOD in a dose-dependent manner, to 90.95 +/- 9.56, 109.52 +/- 11.34 and 121.25 +/- 10.68 (P < 0.05, P < 0.01), as compared with the model group. Similarly, the levels of GSH were significantly increased (P < 0.05, P < 0.01) after the Ly treatment. Meanwhile, pretreatment with 5, 10 and 20 mg/kg of Ly significantly reduced MDA amount by 30.87, 45.51 and 54.49% in the liver homogenates, respectively (P < 0.01). The Ly treatment group showed significantly decreased levels of lipid products LDL-C (P < 0.05, P < 0.01), improved HDL-C level and significantly decreased content of FFA, compared to the model group (P < 0.05, P < 0.01). Furthermore, the Ly-treated group also exhibited a down regulated TNF-alpha and CYP2E1 expression, decreased infiltration of liver fats and reversed histopathological changes, all in a dose-dependent manner (P < 0.05, P < 0.01). CONCLUSION: This study suggests that Ly has a protective effect on NAFLD, down-regulates expression of TNF-alpha, and that CYP2E1 may be one of the action mechanisms for Ly. PMID- 28028367 TI - Use of a saline-coupled bipolar sealer open liver resection for hepatic malignancy: Medical resource use and costs. AB - AIM: To evaluate outcomes associated with use of a saline coupled bipolar sealer during open partial liver resection. METHODS: This retrospective analysis utilized the United States PremierTM insurance claims database (2010-2014). Patients were selected with codes for liver malignancy and partial hepatectomy or lobectomy. Cases were defined by use the saline-coupled bipolar sealer; controls had no use. A Propensity Score algorithm was used to match one case to five controls. A deviation-based cost modeling (DBCM) approach provided an estimate of cost-effectiveness. RESULTS: One hundred and forty-four cases and 720 controls were available for analysis. Patients in the case cohort received fewer transfusions vs controls (18.1% vs 29.4%, P = 0.007). In DBCM, more patients in the case cohort experienced "on-course" hospitalizations (53.5% vs 41.9%, P = 0.009). The cost calculation showed an average savings in total hospitalization costs of $1027 for cases vs controls. In multivariate analysis, cases had lower odds of receiving a transfusion (OR = 0.44, 95%CI: 0.27-0.71, P = 0.0008). CONCLUSION: Use of a saline-coupled bipolar sealer was associated with a greater proportion of patients with an "on course" hospitalization. PMID- 28028368 TI - Nodular lymphoid hyperplasia: A marker of low-grade inflammation in irritable bowel syndrome? AB - AIM: To evaluate the prevalence of nodular lymphoid hyperplasia (NLH) in adult patients undergoing colonoscopy and its association with known diseases. METHODS: We selected all cases showing NLH at colonoscopy in a three-year timeframe, and stratified them into symptomatic patients with irritable bowel syndrome (IBS) type symptoms or suspected inflammatory bowel disease (IBD), and asymptomatic individuals undergoing endoscopy for colorectal cancer screening. Data collection included medical history and final diagnosis. As controls, we considered all colonoscopies performed for the aforementioned indications during the same period. RESULTS: One thousand and one hundred fifty colonoscopies were selected. NLH was rare in asymptomatic individuals (only 3%), while it was significantly more prevalent in symptomatic cases (32%). Among organic conditions associated with NLH, the most frequent was IBD, followed by infections and diverticular disease. Interestingly, 31% of IBS patients presented diffuse colonic NLH. NLH cases shared some distinctive clinical features among IBS patients: they were younger, more often female, and had a higher frequency of abdominal pain, bloating, diarrhoea, unspecific inflammation, self-reported lactose intolerance and metal contact dermatitis. CONCLUSION: About 1/3 of patients with IBS-type symptoms or suspected IBD presented diffuse colonic NLH, which could be a marker of low-grade inflammation in a conspicuous subset of IBS patients. PMID- 28028369 TI - Effect of switching from treatment with nucleos(t)ide analogs to pegylated interferon alpha-2a on virological and serological responses in chronic hepatitis B patients. AB - AIM: To investigate the efficacy of switching to pegylated interferon-alpha-2a (PegIFNalpha-2a) treatment in nucleos(t)ide analog (NA)-treated chronic hepatitis B (CHB) responder patients. METHODS: A 48-wk prospective and retrospective treatment trial of NA-treated CHB patients who had received entecavir (ETV) for at least 48 wk and had serum hepatitis B virus (HBV)-DNA < 500 IU/mL, serum hepatitis B envelope antigen (HBeAg) < 100 S/CO, serum alanine aminotransferase, and aspartate aminotransferase levels < 2 * the upper limit of normal of 40 IU/L was performed. The effects on virological and serological responses and adverse reactions to 0.5 mg daily ETV for 48 wk vs switching to PegIFNalpha-2a were compared. Forty-four patients were randomized to be switched from NA treatment to the PegIFNalpha-2a group, and 44 patients were simultaneously randomized to the ETV group. RESULTS: After 48 wk of therapy, the decrease in hepatitis B surface antigen (HBsAg) levels was greater in the PegIFNalpha-2a group than in the ETV group (3.1340 log10 IU/mL vs 3.6950 log10 IU/mL, P = 0.00). Seven patients who were anti-HBs-positive at baseline achieved HBsAg loss when switched to PegIFNalpha-2a (15.91% vs 0%, P = 0.018). The HBeAg serological conversion rate was higher in the PegIFNalpha-2a group than in the ETV group; however, the difference was not significant because of the small sample sizes (34.38% vs 21.88%, P = 0.232). In the PegIFNalpha-2a group, patients with HBsAg levels < 1500 IU/mL at baseline had higher HBeAg seroconversion and HBsAg loss rates at week 48 than those with HBsAg levels >= 1500 IU/mL (HBeAg seroconversion: 17.86% vs 62.5%, P = 0.007; HBsAg loss: 41.67% vs 6.25%, P = 0.016). Moreover, patients with HBsAg levels < 1500 IU/mL at week 24 had higher HBsAg loss rates after therapy than those with HBsAg levels >= 1500 IU/mL (36.84% vs 0%, P = 0.004). However, there were no statistically significant differences in HBeAg seroconversion rates (47.06% vs 25.93%, P = 0.266). CONCLUSION: NA-treated CHB patients switched to sequential PegIFNalpha-2a achieved highly potent treatment termination safely. PMID- 28028371 TI - Genotype specific peripheral lipid profile changes with hepatitis C therapy. AB - AIM: To evaluate magnitude/direction of changes in peripheral lipid profiles in patients undergoing direct acting therapy for hepatitis C by genotype. METHODS: Mono-infected patients with hepatitis C were treated with guideline-based DAAs at a university-based liver clinic. Patient characteristics and laboratory values were collected before and after the treatment period. Baseline demographics included age, ethnicity, hypertension, diabetes, hyperlipidemia, treatment regimen, and fibrosis stage. Total cholesterol (TCHOL), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), and liver function tests were measured prior to treatment and ETR. Changes in lipid and liver function were evaluated by subgroups with respect to genotype. Mean differences were calculated for each lipid profile and liver function component (direction/magnitude). The mean differences in lipid profiles were then compared between genotypes for differences in direction/magnitude. Lipid profile and liver function changes were evaluated with Levene's test and student's t test. Mean differences in lipid profiles were compared between genotypes using ANOVA, post hoc analysis via the Bonferroni correction or Dunnett T3. RESULTS: Three hundred and seventy five patients enrolled with 321 (85.6%) achieving sustained-viral response at 12 wk. 72.3% were genotype 1 (GT1), 18.1% genotype 2 (GT2), 9.7% genotype 3 (GT3). Baseline demographics were similar. Significant change in lipid profiles were seen with GT1 and GT3 (DeltaGT1, p and DeltaGT3, p), with TCHOL increasing (+5.3, P = 0.005 and +16.1, P < 0.001), HDL increasing (+12.5, P < 0.001 and +7.9, P = 0.038), LDL increasing (+7.4, P = 0.058 and +12.5, P < 0.001), and TG decreasing (-5.9, P = 0.044 and -9.80 P = 0.067). Among genotypes (DeltaGT1 v. DeltaGT2 v. DeltaGT3, ANOVA), significant mean differences were seen with TCHOL (+5.3 v. +0.1 v. +16.1, P = 0.017) and HDL (+12.3 v. +2 v. +7.9, P = 0.040). Post-hoc, GT3 was associated with a greater increase in TCHOL than GT1 and GT2 (P = 0.028 and P = 0.019). CONCLUSION: Successful DAA therapy results in increases in TCHOL, LDL, and HDL and decrease in TG, particularly in GT1/GT3. Changes are most pronounced in GT3. PMID- 28028370 TI - Incidence of hepatocellular carcinoma in outpatients with cirrhosis in Brazil: A 10-year retrospective cohort study. AB - AIM: To determine the incidence of hepatocellular carcinoma (HCC) and the impact of HCC surveillance on early diagnosis and survival of cirrhotic outpatients. METHODS: In this retrospective cohort study, cirrhotic outpatients undergoing HCC surveillance between March 2005 and March 2014 were analyzed. Exclusion criteria were HIV coinfection; previous organ transplantation; diagnosis of HCC at first consultation; missing data in the medical chart; and less than 1 year of follow up. Surveillance was carried out every six months using ultrasound and serum alpha-fetoprotein determination. Ten-year cumulative incidence and survival were estimated through Kaplan-Meier analysis. RESULTS: Four hundred and fifty-three patients were enrolled, of which 57.6% were male. Mean age was 55 years. Hepatitis C virus and heavy use of alcohol were the main etiologic agents of cirrhosis. HCC was diagnosed in 75 patients (16.6%), with an estimated cumulative incidence of 2.6% in the 1st year, 15.4% in the 5th year, and 28.8% in the 10th year. Median survival was estimated at 17.6 mo in HCC patients compared to 234 mo in non-HCC patients (P < 0.001). Early-stage HCC was more often detected in patients who underwent surveillance every 6 mo or less (P = 0.05). However, survival was not different between patients with early stage vs non-early stage tumors [HR = 0.54 (0.15-1.89), P = 0.33]. CONCLUSION: HCC is a frequent complication in patients with cirrhosis and adherence to surveillance programs favors early diagnosis. PMID- 28028372 TI - Long-term prognostic impact of circulating tumour cells in gastric cancer patients. AB - AIM: To analyse the long-term prognostic impact of circulating tumour cells (CTCs) in gastric cancer patients who underwent surgery. METHODS: A 7.5-mL peripheral vein blood sample was obtained from each patient with treatment negative gastric adenocarcinoma before surgery. OBP-401, a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein gene, was used to label CTCs. Correlations between the number of CTCs and clinical end points were evaluated. RESULTS: The median follow-up period of the surviving patients with gastric cancer was 60 mo. The CTC number tended to increase concomitantly with disease progression. The overall survival of patients with more than five CTCs in 7.5-mL of peripheral blood was lower than that of patients with five or less CTCs, although the difference was not significant (P = 0.183). A significant difference in relapse-free survival was found between patients with more than five and those with five or less CTCs (P = 0.034). CONCLUSION: A lower number of CTCs was correlated with higher relapse-free survival rates in patients. Detection of CTCs using OBP-401 may be useful for predicting prognosis in gastric cancer. PMID- 28028373 TI - Randomized controlled study of the safety and efficacy of nitrous oxide-sedated endoscopic ultrasound-guided fine needle aspiration for digestive tract diseases. AB - AIM: To evaluate the efficacy and safety of nitrous oxide-sedated endoscopic ultrasound-guided fine needle aspiration. METHODS: Enrolled patients were divided randomly into an experimental group (inhalation of nitrous oxide) and a control group (inhalation of pure oxygen) and heart rate, blood oxygen saturation, blood pressure, electrocardiogram (ECG) changes, and the occurrence of complications were monitored and recorded. All patients and physicians completed satisfaction questionnaires about the examination and scored the process using a visual analog scale. RESULTS: There was no significant difference in heart rate, blood oxygen saturation, blood pressure, ECG changes, or complication rate between the two groups of patients (P > 0.05). However, patient and physician satisfaction were both significantly higher in the nitrous oxide compared with the control group (P < 0.05). CONCLUSION: Nitrous oxide-sedation is a safe and effective option for patients undergoing endoscopic ultrasound-guided fine needle aspiration. PMID- 28028374 TI - "En bloc" caudate lobe and inferior vena cava resection following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal and liver metastasis of colorectal cancer. AB - There are diverse protocols to manage patients with recurrent disease after primary cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. We describe a case of metachronous liver metastasis after CRS and HIPEC for colorectal cancer, successfully treated with a selective metastectomy and partial graft of the inferior vena cava. A 35-year-old female presented with a large tumour in the cecum and consequent colonic stenosis. After an emergency right colectomy, the patient received adjuvant chemotherapy. One year later she was diagnosed with peritoneal carcinomatosis, and it was decided to carry out a CRS/HIPEC. After 2 years of total remission, an isolated metachronous liver metastasis was detected by magnetic resonance imaging surveillance. The patient underwent a third procedure including a caudate lobe and partial inferior vena cava resection with a prosthetic graft interposition, achieving an R0 situation. The postoperative course was uneventful and the patient was discharged on postoperative day 17 after the liver resection. At 18-mo follow-up after the liver resection the patient remained free of recurrence. In selected patients, the option of re operation due to recurrent disease should be discussed. Even liver resection of a metachronous metastasis and an extended vascular resection are acceptable after CRS/HIPEC and can be considered as a potential treatment option to remove all macroscopic lesions. PMID- 28028375 TI - Response of BRCA1-mutated gallbladder cancer to olaparib: A case report. AB - Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European Commission for the treatment of ovarian cancer with any BRCA1/2 mutations. The first case of a BRCA1-mutated GBC patient who responded to olaparib treatment is reported here. PMID- 28028376 TI - Schwannoma in the hepatoduodenal ligament: A case report and literature review. AB - Schwannomas are mesenchymal neoplasms with low malignant potential that arise from Schwann cells. They can occur almost anywhere, although the most common locations are the head, neck and extremities. Primary benign schwannoma of the hepatoduodenal ligament is rare. To date, only three cases have been reported in the English literature. In the present study, we report a case of hepatoduodenal ligament schwannoma in a 43-year-old male, who was admitted to our hospital because of a abdominal mass found by physical examination. It was hard to determine the definitive location and diagnosis of the mass using ultrasound, computed tomography and magnetic resonance cholangiopancreatography. During laparotomy, the mass was found in the hepatoduodenal ligament and close to the cholecystic duct, so we resected the gallbladder and cholecystic duct along with the mass. The gross specimen revealed an 8.5 cm * 5.5 cm * 3.0 cm localized tumor. Microscopic examination showed that the tumor was mainly composed of spindle-shaped cells. Immunohistochemical staining showed a strong positive S-100 protein reaction. Finally, the lesion was diagnosed as a benign schwannoma in the hepatoduodenal ligament. However, one month later, the patient was readmitted to our hospital because of skin and sclera jaundice caused by common bile duct stenosis without common bile duct stone or tumor. The patient recovered well after implantation of a common bile duct stent under endoscopic retrograde cholangiopancreatography. He was followed up for a period of 17 mo, during which he was well with no complications. PMID- 28028377 TI - Adult helpers increase the recruitment of closely related offspring in the cooperatively breeding rifleman. AB - Indirect fitness benefits gained through kin-selected helping are widely invoked to explain the evolution of cooperative breeding behavior in birds. However, the impact of helpers on productivity of helped broods can be difficult to determine if the effects are confounded by territory quality or if the benefit of helpers is apparent only in the long term. In riflemen Acanthisitta chloris, helping and group membership are effectively decoupled as adult helpers are individuals that have dispersed from their natal territory and live independently from breeders in "kin neighborhoods." Nevertheless, helpers direct their care toward close relatives, suggesting that helping provides indirect fitness benefits. The aim of this study was to examine the benefits of helpers to recipient offspring in the rifleman, investigating both short- and long-term effects. The total amount of food delivered to nestlings in helped broods was greater than that received by broods without helpers. This did not result in any short-term increase in nestling mass or nestling body condition nor was there any reduction in length of the nestling period at helped nests. However, helpers were associated with a significant increase in juvenile recruitment, with twice the proportion of fledglings surviving to the next breeding season from helped broods relative to unhelped broods. Thus, helpers gain indirect fitness by improving the survival of kin, and in contrast to a previous study of riflemen, we conclude that kin selection has played a key role in the evolution of cooperative breeding in this species. PMID- 28028378 TI - The benefits of being toxic to deter predators depends on prey body size. AB - Many prey have evolved toxins as a defense against predation. Those species that advertise their toxicity to would-be predators with conspicuous warning signals are known as "aposematic." Investment in toxicity by aposematically signaling prey is thought to underpin how aversive prey are to predators; increasing toxicity means that predators learn to avoid prey faster and attack them at lower rates. However, predators' foraging decisions on aposematic prey are determined not only by their toxicity, but also by their nutrient content: predators can trade-off the costs of ingesting toxin with the benefits of acquiring nutrients. Prey body size is a cue that positively correlates with nutrient content, and that varies within and between aposematic species. We predicted that a dose of quinine (known to be toxic to birds) would be a more effective deterrent to avian predators when prey were small compared with when they were large, and that the benefits of possessing toxin would be greater for small-bodied prey. Using an established laboratory protocol of European starlings (Sturnus vulgaris) foraging on mealworms (Tenebrio molitor), we found evidence for increased protection from a dose of quinine for small-bodied compared with large-bodied prey. This shows that larger prey need more toxin to attain the same level of defense as smaller prey, which has implications for the evolution of aposematism and mimicry. PMID- 28028379 TI - Exploration is dependent on reproductive state, not social state, in a cooperatively breeding bird. AB - Personality is an intriguing phenomenon in populations because it constrains behavioral flexibility. One theory suggests that personality could be generated and maintained if dependent on asset protection. It is predicted that trade-offs with fitness expectations and survival probability encourage consistent behavioral differences among individuals (personality). Although not mutually exclusive, the social niche specialization hypothesis suggests that a group of individuals that repeatedly interact will develop personality to avoid costly social conflict. The point at which behavioral consistency originates in the social niche hypothesis is still unclear, with predictions for development after a change in social status. In the facultative cooperatively breeding Seychelles warbler (Acrocephalus sechellensis), residing on Cousin Island, breeding vacancies are limited and this forces individuals into different social roles. We used this system to test whether reproductive and social state predicted among individual differences in exploration. We had 2 predictions. First, that an individual's start in life can predict personality, whereby young individuals with a good start to life (associated with early age reproduction and earlier onset survival senescence) are fast explorers, suggesting reproductive state dependence. Second, that an individual's social status can predict personality, whereby dominant individuals will be fast explorers, suggesting that the behavior is social state-dependent. Neither of the behaviors was associated with social state and social state did not affect behavioral consistency. However, novel object exploration was associated with a proxy of reproductive state. Our results provide further support for state being a mechanism for generating individual differences in behavior. PMID- 28028380 TI - Small-Bowel Obstruction Secondary to Adhesions After Open or Laparoscopic Colorectal Surgery. AB - BACKGROUND AND OBJECTIVES: Small-bowel obstruction (SBO) is a common surgical emergency that occurs in 9% of patients after abdominal surgery. Up to 73% are caused by peritoneal adhesions. The primary purpose of this study was to compare the rate of SBOs between patients who underwent laparoscopic (LPS) and those who had open (OPS) colorectal surgery. The secondary reasons were to evaluate the rate of adhesive SBO in a cohort of patients who underwent a range of colorectal resections and to assess risk factors for the development of SBO. METHOD: This was a retrospective observational cohort study. Data were analyzed from a prospectively collected database and cross checked with operating theater records and hospital patient management systems. RESULTS: During the study period, 707 patients underwent colorectal resection, 350 of whom (49.5%) were male. Median follow-up was 48.3 months. Of the patients included, 178 (25.2%) underwent LPS, whereas 529 (74.8%) had OPS. SBO occurred in 72 patients (10.2%): 20 (11.2%) in the LPS group and 52 (9.8%) in the OPS group [P = .16; hazards ratio (HR) 1.4 95% CI 0.82-2.48] within the study period. Conversion to an open procedure was associated with increased risk of SBO (P = .039; HR 2.82; 95% CI 0.78-8.51). Stoma formation was an independent risk factor for development of SBO (P = .049; HR, 0.63; 95% CI 0.39-1.03). The presence of an incisional hernia in the OPS group was associated with SBO (P = .0003; HR, 2.85; 95% CI 1.44-5.283). There was no difference in SBO between different types of procedures: right colon, left colon, and rectal surgery. Patients who developed early small-bowel obstruction (ESBO) were more often treated surgically compared to late SBO (P = .0001). CONCLUSION: The use of laparoscopy does not influence the rate of SBO, but conversion from laparoscopic to open surgery is associated with an increased risk of SBO. Stoma formation is associated with a 2-fold increase in SBO. Development of ESBO is highly associated with a need for further surgical intervention. PMID- 28028381 TI - Intraocular Pressure Changes With Positioning During Laparoscopy. AB - BACKGROUND AND OBJECTIVES: Pneumoperitoneum during laparoscopy can produce changes in intraocular pressure (IOP) that may be influenced by several factors. In this study, we investigated changes in IOP during laparoscopy with different positioning. METHODS: We recruited adult patients without eye disease scheduled to undergo laparoscopic operation requiring a reverse Trendelenburg tilt (rTr; group A; n = 20) or Trendelenburg tilt (Tr; Group B; n = 20). IOP was measured at 7 time points (T1-T7). All procedures were performed with standardized anaesthetic protocol. Mean arterial pressure (MAP), heart rate (HR), peak and plateau airway pressure, and end-tidal carbon dioxide (ETCO2) measurements were taken at each time point. RESULTS: Both groups were similar in age, sex, mean body mass index (BMI), duration of surgery, and preoperative IOP. A decrease in IOP was observed in both groups after induction of anaesthesia (T2), whereas induction of pneumoperitoneum produced a mild increase in IOP (T3) in both groups. The Trendelenburg tilt produced IOP elevations in 80% of patients compared to 45% after the reverse Trendelenburg tilt (P = .012). A significant IOP increase of 5 mm Hg or more was recorded in 3 (15%) patients in the Trendelenburg tilt group and in none in the reverse Trendelenburg group. At T7, IOP had returned to preoperative levels in all but 3 (15%) in the Trendelenburg and 1 (5%) in the reverse Trendelenburg group. Reversible changes were observed in the MAP, HR, ETCO2, and airway pressures in both groups. CONCLUSIONS: IOP changes induced by laparoscopy are realigned after evacuation of pneumoperitoneum. A Trendelenburg tilt however produced significant changes that may require careful patient monitoring during laparoscopic procedures. PMID- 28028382 TI - FICE vs Narrow Band Imaging for In Vivo Histologic Diagnosis of Polyps. AB - BACKGROUND AND OBJECTIVES: Gastrointestinal cancers are the most frequently occurring cancers worldwide. Diagnosis and removal of polyps during screening endoscopy decreases the prevalence of colon cancer and cancer-related mortality, and it is considered to be the gold standard in gastrointestinal system cancer prevention. Technological innovations in endoscopy have led to revolutionary developments in many areas. Flexible spectral imaging color enhancement (FICE) and narrow-band imaging (NBI) are forms of digital chromoendoscopy and enhance the endoscopic images without the need for a dye. This study seeks to evaluate the efficacy of FICE and NBI on polyp screening and real-time histologic diagnosis with endoscopy and to compare them. METHODS: A total of 134 patients (male/female = 72/62) and 161 polyps were evaluated with FICE or NBI, and real time histologic diagnosis predictions were classified as neoplastic or nonneoplastic, according to Kudo's pit pattern classification. Pathological results and real-time endoscopic diagnoses were statistically interpreted for both FICE and NBI. Positive predictive value, negative predictive value, sensitivity, specificity, and accuracy rates were calculated and compared for both modalities. RESULTS: When both systems were compared, the negative predictive value of NBI was found to be higher than that of FICE statistically (P < .001). Specificity and positive predictive value in the FICE group were higher than in the NBI group, but the difference was not statistically significant (P = .082 and P = .153, respectively). CONCLUSIONS: Aside from being safe in polyp detection, digital chromoendoscopy also helps the endoscopist in selecting the type of simultaneous intervention (eg, polypectomy, endomucosal resection, or submucosal dissection) by enabling endoscopic histologic diagnosis. PMID- 28028384 TI - Retraction: Mitigation of NaCl Stress by Arbuscular Mycorrhizal Fungi through the Modulation of Osmolytes, Antioxidants and Secondary Metabolites in Mustard (Brassica juncea L.) Plants. AB - [This retracts the article on p. 869 in vol. 7, PMID: 27458462.]. PMID- 28028383 TI - Vitamin D and adolescent health. AB - Vitamin D is a hormone sequentially produced at different body sites, and which plays a significant role in human health, particularly bone health. However, other roles are emerging. When the serum concentration of vitamin D is very low, the risk of rickets, osteomalacia and osteoporosis is increased. In children and adolescents there is a high prevalence of low vitamin D status, especially in females and during the winter-the prevalence being lower than during the summer. Although there is no unanimous agreement over the minimum values necessary for good health, serum 25-hydroxyvitamin D [25(OH)D] levels below 20 ng/mL may be regarded as a vitamin D-deficient condition, and levels between 20-30 ng/mL may be the range of vitamin D insufficiency. Mild low levels have been associated with bone mass accrual alterations in children and adolescents, diminished muscle strength, negative cardiovascular outcomes, insulin resistance and obesity, and neurological disorders. Effective preventive strategies are needed to guarantee adequate vitamin D levels throughout childhood and adolescence, taking into account the geographical setting, season of the year, the level of environmental pollution, skin characteristics, eating habits and body weight, with a view to securing optimum health during these phases, and the prevention of complications in adulthood. There needs to be a renewed appreciation of the beneficial effect of moderate sunlight for providing all humans with the vitamin D needed for ensuring good health. Prolonged sun exposure is not advised, however, due to the risk of skin cancer. In addition, a balanced diet is indicated, since vitamin D rich foods are better assimilated than supplements. When such conditions cannot be met, then the supplementation of 400 IU/day of vitamin D is advised in children and adolescents-though correcting vitamin D insufficiency or deficiency may require 1000 IU/day or more. High-dose calcifediol depots are an alternative for guaranteeing treatment adherence and in patients with liver disease. PMID- 28028385 TI - HPLC estimation of iothalamate to measure glomerular filtration rate in humans. AB - Glomerular filtration rate (GFR) is usually determined by estimation of iothalamate (IOT) clearance. We have developed and validated an accurate and robust method for the analysis of IOT in human plasma and urine. The mobile phase consisted of methanol and 50 mM sodium phosphate (10:90; v/v). Flow rate was 1.2 mL/min on a C18 reverse phase column, Synergi-hydro (250 * 4.6 mm) 4 um 80 A, with an ultraviolet detector set to 254 nm. Acetonitrile was used for the deproteination and extraction of IOT from human plasma and urine. Precision and accuracy were within 15% for IOT in both plasma and urine. The recoveries of IOT in urine and plasma ranged between 93.14% and 114.74 and 96.04-118.38%, respectively. The linear range for urine and plasma assays were 25-1500 and 1-150 ug/mL respectively. The lower limits of detection were 0.5 ug/mL for both urine and plasma, with no interference from plasma and urine matices. This method has been fully validated according to FDA guidelines and the new HPLC assay has been applied to a new formulation of IOT (ConrayTM 43), to calculate GFR in healthy volunteers. The new method is simple, less expensive and it would be instrumental in future clinical and pharmacokinetic studies of iothalamate in kidney patients. PMID- 28028386 TI - In vitro drug release characteristic and cytotoxic activity of silibinin-loaded single walled carbon nanotubes functionalized with biocompatible polymers. AB - In this paper, we demonstrate the preparation of silibinin-loaded carbon nanotubes (SWSB) with surface coating agents via non-covalent approach as an effective drug delivery system. The resulting surface-coated SWSB nanocomposites are extensively characterized by Fourier transform infrared (FTIR) and Raman spectroscopies, ultraviolet-visible (UV-Vis) spectrometry and field emission scanning electron microscopy (FESEM). The FTIR and Raman studies show that an additional layer is formed by these coating agents in the prepared nanocomposites during the coating treatment and these results are confirmed by FESEM. Drug loading and release profiles of the coated SWSB nanocomposites in phosphate buffered saline solution at pH 7.4 is evaluated by UV-Vis spectrometry. The in vitro results indicate that the surface-modified nanocomposites, with SB loading of 45 wt%, altered the initial burst and thus, resulted in a more prolonged and sustained release of SB. In addition, these nanocomposites exhibit a pseudo second-order release kinetic which was driven by the ion exchange between the ionized SWSB and the anions in the release medium. The cytotoxicity effect of the resulting nanocomposites on normal mouse fibroblast cells is evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. It is observed that the surfactant and polymer coating improved the biocompatibility of the SWSB nanocomposites significantly, which deem further exploitation for their application as potential anticancer drug delivery system. PMID- 28028388 TI - Detection of Cancer Stem Cells in Colorectal Cancer: Histopathological and Immunohistochemical Study. AB - BACKGROUND: Growing evidence supports the notion that the onset of tumorigenesis could occur through cancer stem cells (CSCs). These tumour cells show low proliferative rates, high self-renewal capacity, propensity to differentiate into active proliferating tumour cells & resistance to chemoradiotherapy thus, possibly causing local recurrences & metastasis formation. CD44 has been used as a marker to isolate CSCs from colorectal carcinoma (CRC). AIM: To investigate the immunohistochemical expression of cancer stem cells marker (CD44) in CRC and correlate its expression with the clinicopathological aspects, TNM staging and modified Dukes' classification. MATERIALS AND METHODS: Tumour biopsies from colectomy specimens of 60 patients with CRC were stained with hematoxylin-eosin for histological evaluation then immunostained with monoclonal antibodies against CD44 which was detected in term of negative or positive expression. RESULTS: CD44 was demonstrated in 58.3% (35/60) of cases and showed statistically significant correlation with tumour site and histological type (p-value < 0.05). However, CD44 showed statistically insignificant inverse correlation with tumour invasiveness (T), lymph node status (N), grade, TNM stage grouping and modified Dukes' classification, while it was directly correlated with distant metastasis (M) (p-value > 0.05). Chi-square /Fisher exact test proportion independence and the p-value are set significant at 0.05 level. CONCLUSION: the CD44 rate of expression is higher in the colon than rectum and in adenocarcinoma than mucinous and undifferentiated carcinoma. CD44 showed statistically insignificant relation with T, N, M, grade, TNM stage grouping and modified Dukes' classification. PMID- 28028387 TI - Her2/neu Protein Expression and Oncogene Amplification in Gastric Carcinoma with Clinico-Pathological Correlation in Egyptian Patients. AB - AIM: Amplification of the Her2/neu gene and overexpression of the Her2/neu protein in gastric carcinoma (GC) is a golden criterion for target therapy with trastuzumab (Herceptin). We aim to evaluate the immunohistochemical protein expression and amplification of the oncogene Her2/neu by FISH technique in the epithelial gastric carcinoma and to compare their association with different clinicopathologic parameters aiming at identifying positive cases that may benefit from targeted therapy. MATERIALS AND METHODS: This study was done on eighty-five tumour tissue samples from patients with GC as well as thirty non malignant lesions (Gastritis, intestinal metaplasia, adenoma with low-grade dysplasia, adenoma with high-grade dysplasia). All were immunohistochemically stained with Her2/neu antibody. RESULTS: All equivocal and some selected GC cases were submitted for FISH technique to detect Her2/neu gene amplification. By immunohistochemistry twenty-three cases (27%) were defined as positive for Her2/neu gene amplification and/or protein overexpression. The levels of Her2/neu positive (3+), Her2/neu equivocal (2+) and Her2/neu negative (1+/0) were measurable in 14.2%, 32.9% and 52.9% of the samples, respectively. FISH showed that Her2/neu gene was amplified in 22 cases, 10 Her2/neu positive (3+), 11 (39.3%) Her2/neu equivocal (2+) and 1 Her2/neu negative (1+) cases with IHC staining those who can benefit from anti Her2/neu target therapy. Her2/neu was overexpressed positivity (3+) more in intestinal type and mixed carcinoma, and moderately differentiated tumours. None of gastritis, intestinal metaplasia or adenoma with low-grade dysplasia cases showed positivity for Her2/neu (3+). The Her2/neu positivity (3+) was associated with both adenocarcinoma cases and high grade dysplasia (P = 0.002). CONCLUSIONS: The results highlight the necessity of FISH test for further categorization when gastric cancer cases are equivocal (2+) by IHC to determine eligibility for the targeted therapy. Stepwise increase in the expression of Her2/neu was seen in low-grade dysplasia, high-grade dysplasia and carcinoma cases implying its role in cancer evolution. Overexpression of Her 2/neu in GC patients can be promising in selecting those who can get benefit from anti-Her2/neu target therapy. PMID- 28028389 TI - Short-term Exposure to 50-Hz Electromagnetic Field and Alterations in NQO1 and NQO2 Expression in MCF-7 Cells. AB - AIM: Extremely low-frequency electromagnetic fields (ELF-EMFs) have some genotoxic effects and it may alter the mRNA levels of antioxidant genes. The NAD(P)H: quinone oxidoreductase-1 (NQO1) and NQO2 are ubiquitously expressed. Considering that there is no published data on the effect(s) of ELF-EMF (50-Hz) exposure and expression levels of NQO1 and NQO2 in the human MCF-7 cells, the present study was carried out. METHODS: The ELF-EMF (0.25 and 0.50 mT) exposure patterns were: 5 min field-on/5 min filed-off, 15 min field-on/15 min field-off, and 30 min field-on continuously. In all exposure conditions, total exposure time were 30 minutes. The RNA extraction was done at two times; immediately post exposure and two hours post exposure. The effect of ELF-EMF on gene expression was assessed by real-time PCR. RESULTS: The NQO1 mRNA level (at 0h) decreased in the cells exposed to 5 min field-on/5 min filed-off condition at 0.25 mT EMF when compared with the unexposed cells. The NQO2 mRNA level (at 0h and 2h) increased in the cells exposed to 5 min field-on/5 min filed-off condition at 0.50 mT EMF when compared with the unexposed cells. CONCLUSIONS: Alterations in the NQO1 and NQO2 mRNA levels seem at the "5 min field-on/5 min field-off" condition. PMID- 28028390 TI - Spectrum of Childhood and Adolescent Ovarian Tumors in India: 25 Years Experience at a Single Institution. AB - BACKGROUND: Ovarian tumour in children and adolescent girls form an uncommon but important part of gynaecological malignancies. They account for 1% of all the childhood malignancies and 8% of all abdominal tumours in children. Since the ovarian cysts are thought to arise from mature follicles, these tumours were considered to be infrequent in the paediatric population. AIM: The rarity of this condition prompted us to conduct this study and share our experience on the incidence and clinicopathological features of different ovarian tumours in girls up to 20 years of age observed in last 25 years at a single tertiary care hospital. MATERIAL AND METHODS: This was a retrospective study conducted in the Department of Pathology at a tertiary hospital, Delhi. All ovarian tumours up to the age of 20 years in the past 25 years (1990-2014) were included for the purpose of studying the clinicopathological aspects of ovarian tumours in this age group. Descriptive statistics for prevalence and age-wise prevalence was done. Chi-square test, to find an association between the age, laterality and size with malignancy was performed. RESULTS: We received a total of 1102 cases of ovarian tumours over the period of 25 years (1990 to 2014), of which 112 (10%) cases were seen in girls up to 20 years of age. The mean age of the patients was 15.3 +/- 4 years. The most common presenting complaint was pain abdomen (46.4 %) There was a statistically significant correlation found between size and malignancy status of tumours in our study (p = 0.00). Of 112 cases of ovarian tumours, 39/112 (34.8%) were malignant and 73/112 (65.2%) were benign. Mature cystic teratoma (27.6%) was the most common type of benign tumour in this age group and immature teratomas were the most common type of malignant ovarian neoplasms. CONCLUSION: Premenarchal girls with ovarian masses may have varied presentations. Abdominal pain is the most common presenting complaint of young adolescent girls with adnexal masses. So the index of suspicion should be kept high and prompt investigations like ultrasound must be performed early to rule out such adnexal masses. Immature Teratoma was the most common malignant and mature cystic teratoma was the most common benign tumour in our study. PMID- 28028391 TI - Vascular Genetic Variants and Ischemic Stroke Susceptibility in Albanians from the Republic of Macedonia. AB - BACKGROUND: Acute first-ever ischemic stroke (FIS) is a heterogeneous, polygenic disorder. The contribution of vascular genetic variants as inherited causes of ischemic stroke has remained controversial. AIM: To examine the association of genetic variants in vascular factors with the occurrence of FIS. MATERIAL AND METHODS: The current research was performed in a group of 39 patients with FIS (study group) and 102 healthy volunteers (control group). We analyzed the prevalence of vascular genetic variants in following genes: factor V, prothrombin, methylenetetrahydrofolate reductase (MTHFR), factor XIII, plasminogen activator 1, endothelial protein C receptor (EPCR), apolipoprotein B, apolipoprotein E, beta-fibrinogen, human platelet antigen 1, angiotensin converting enzyme (ACE), endothelial nitric oxide synthase (eNOS) and lymphotoxin alpha. RESULTS: It was found that heterozygous LTA 804C>A and FXIII V34L Leu/Leu were significantly more frequent in patients with FIS than in control group (p = 0.036 and p = 0.017, respectively). The frequency of FXIII V34L Val/Val was significantly lower in patients with FIS than in control group (p = 0.020). Other frequencies of vascular gene variants in patients with FIS and in control group were not significantly different. CONCLUSIONS: This is the first comprehensive study to present data indicating that polymorphism of vascular genes in the prevalence of acute FIS exists in the Albanian population from the Republic of Macedonia. Variations in these genes have been detected in patients with acute FIS, suggesting that their combination might act in a susceptible or protective manner in this Albanian population. PMID- 28028392 TI - Effect of Pseudocereal-Based Breakfast Meals on the First and Second Meal Glucose Tolerance in Healthy and Diabetic Subjects. AB - BACKGROUND: Many studies have indicated that the incidence of serious diabetic complications may be reduced through strict glycemic control. A low glycemic index diet is one tool to improve insulin resistance and improve glycemic control in type 2 diabetes mellitus (T2DM). AIM: The objective was to study the effect of pseudocereals-based breakfasts (quinoa and buckwheat) on glucose variations at first meal (breakfast) and second meal (standardised lunch) in healthy and diabetic subjects. SUBJECTS AND METHODS: Twelve healthy subjects and 12 patients with Type 2 DM (not- insulin dependent) were recruited in the study. Subjects were provided with quinoa and buckwheat breakfast meals. A standardised lunch was provided 4 h after breakfast. Postprandial blood glucose response after breakfast and the second meal effect was measured in healthy and diabetic subjects. Incremental area under the curve (IAUC) values for glucose was measured in response to the breakfast and lunch. The glycemic index of the 2 pseudocereals based test breakfasts was determined. A white wheat bread (WWB) was served as a reference breakfast meal. RESULTS: In post-breakfast analyses, healthy subjects showed that buckwheat meal had significantly lower IAUC values for blood glucose compared to WWB reference meal (P < 0.001) while quinoa meal showed no significance. In diabetic subjects, buckwheat and quinoa meals had significantly lower IAUC values for blood glucose compared to WWB reference meal (P < 0.001 and P < 0.05 respectively). Blood glucose concentrations started to decline gradually for the quinoa and buckwheat but not for WWB in all healthy and diabetic subjects and returned to near-fasting baseline levels by 210 min. Post-lunch analyses indicated higher IAUC for the two breakfast types in healthy and diabetic subjects. In addition, the quinoa and buckwheat breakfast meals were followed by a significantly flatter blood glucose response to the second meal for the period between 270 and 330 min. At the end of the second meal period, values were below or near-fasting baseline levels in the breakfast period. The blood glucose concentration after consuming quinoa meal showed a high peak at 30 min similar to that of WWB reference meal. This peak resulted in a high glycemic index (GI) for quinoa (89.4). The GI of buckwheat recorded a low value (26.8). CONCLUSION: The two studied pseudocereals; quinoa and buckwheat have high potential to improve glucose tolerance at the first and second meal (lunch) and are recommended to be introduced in our daily diet for healthy and diabetic subjects. PMID- 28028393 TI - Assessment of the -174G/C (rs1800795) and -572G/C (rs1800796) Interleukin 6 Gene Polymorphisms in Egyptian Patients with Rheumatoid Arthritis. AB - AIM: This study aimed to investigate genotype and allele frequencies of -174 (rs1800795) and -572 (rs1800796) IL-6 promoter gene polymorphisms in Egyptian patients with rheumatoid arthritis (RA) in comparison to control group. METHODS: The study was conducted on 198 Egyptian subjects (99 RA patients and 99 healthy control). The promoter region of the IL-6 gene was amplified by PCR using DNAs from patients and the controls, and their PCR products were digested by suitable enzymes. RESULTS: No statistical differences were found in -572G/C genotype (P = 0.177) or allele (P = 0.147) frequencies between RA patients and controls. Significant differences were observed in -174G/C genotype (P < 0.001) and allele (P < 0.001) frequencies between RA patients and controls. CONCLUSION: A significant association of IL-6 -174G/C gene polymorphism and RA in Egyptian population was found with significantly higher frequencies of GC and CC genotypes and C allele in RA patients compared to controls. No association was found between IL-6 -572G/C gene polymorphism and RA. PMID- 28028394 TI - Fibrosis in Chronic Hepatitis C: Correlation between Immunohistochemically Assessed Virus Load with Steatosis and Cellular Iron Content. AB - AIM: We aimed study impact of hepatocytic viral load, steatosis, and iron load on fibrosis in chronic hepatitis C and role of VEGF and VEGFR overexpression in cirrhotic cases in evolving HCC. MATERIAL AND METHODS: Total of 120 cases were included from TBRI and Beaujon Hospital as chronic hepatitis C (CHC), post hepatitis C cirrhosis, and HCC. Cases of CHC were stained for Sirius red, Prussian blue and immunohistochemically (IHC) for HCV-NS3/NS4. HCC were stained IHC for VEGF and by FISH. RESULTS: Stage of fibrosis was significantly correlated with inflammation in CHC (P < 0.01). Noticed iron load did not correlate with fibrosis. Steatosis was associated with higher inflammation and fibrosis. The cellular viral load did not correlate with inflammation, steatosis or fibrosis. VEGF by IHC was significantly higher in cases of HCC when compared to cirrhotic group (P < 0.001). Amplification of VEGFR2 was confirmed in 40% of cases of HCC. Scoring of VEGF by IHC was the good indicator of VEGFR2 amplification by FISH (P < 0.005). CONCLUSION: Grade of inflammation is the factor affecting fibrosis in CHC. The degree of liver damage is not related to cellular viral load or iron load. Steatosis is associated with higher inflammation and fibrosis. VEGF by IHC is correlated with overexpression of VEGFR2 by FISH. PMID- 28028395 TI - Microbiological Assessment of Moringa Oleifera Extracts and Its Incorporation in Novel Dental Remedies against Some Oral Pathogens. AB - AIM: To assess the antibacterial and antifungal potentials of different parts of Moringa oleifera plant using different extraction methods in attempts to formulate natural dental remedies from this plant. MATERIAL AND METHODS: Three solvents extracts (Ethanol, acetone, and ethyl acetate) of different parts of Egyptian Moringa tree were prepared and tested against oral pathogens: Staphylococcus aureus, Streptococcus mutans, and Candida albicans using disc diffusion method; As well as to incorporate the plant extract to formulate experimental toothpaste and mouthwash. The two dental remedies were assessed against the same microbial strains. Statistical analysis was performed using One Way ANOVA test to compare the inhibition zone diameter and t-test. RESULTS: Ethanol extracts as well as leaves extracts demonstrated the highest significant mean inhibition zone values (P <= 0.05) against Staphylococcus aureus and Streptococcus mutans growth. However, all extracts revealed no inhibition zone against Candida albicans. For dental remedies, experimental toothpaste exhibited higher mean inhibition than the mouthwash against Staphylococcus aureus, Streptococcus mutans and only the toothpaste revealed antifungal effect against Candida albicans. CONCLUSION: The different extracts of different parts of Moringa showed an antibacterial effect against Staphylococcus aureus and Streptococcus mutans growth. The novel toothpaste of ethanolic leaves extract has antimicrobial and antifungal potential effects all selected strains. PMID- 28028396 TI - The Hidden Function of Vitamin D. AB - AIM: There are no reports regarding the influence of vitamin D on thymosin beta4 and the cluster of differentiation CD4 levels which are important for maintaining a healthy immune system. Consequently, we aimed to explore this relationship through a study. MATERIAL AND METHODS: The study was carried out on 35 subjects, screened for 25-hydroxy vitamin D[25 (OH) D] using ELISA method and they were divided into two groups: Group 1 consists of 10 healthy subjects with sufficient vit. D level > 24.8 ng/ml. Group 2 consists of 25 subjects suffering, severely, from vitamin D deficiency at level < 11.325 ng/ml. Also, Thymosin beta4, CD4 and zinc levels were performed. RESULTS: There were significant differences between the two groups in the concentration levels of thymosin beta4, as the group 1 has shown higher levels (P = 0.005). Whereas, CD4 and zinc levels didn't show any significant difference between the two groups. At the same time, a significant positive correlation has been observed between vitamin D, thymosin beta4, and CD4 at (r = 0.719; P = 0.001), and (r = 0.559, P = 0.001) respectively. CONCLUSION: We concluded that vitamin D may be an essential factor that influence or determine the level of thymosin beta4. This study is the first that focused on demonstrating that sufficient level of vitamin D may have the ability to influence the thymic hormone thymosin beta4 levels. Further studies on large scale of subjects are needed to explore the positive correlation we had found between vitamin D and thymosin beta4 and CD4. PMID- 28028397 TI - Vitamin D Status, Insulin Resistance, Leptin-To-Adiponectin Ratio in Adolescents: Results of a 1-Year Lifestyle Intervention. AB - AIM: We aimed to study the relationships between circulating 25-hydroxyvitamin D [25(OH)D], insulin resistance and leptin-to-adiponectin (L/A) ratio in Guadeloupean children and adolescents and to analyse the changes in 25(OH)D levels after a 1-year lifestyle intervention program. METHODS: 25(OH)D concentrations were measured via a chemiluminescence assay. Cardiometabolic risk factors, homoeostasis model assessment of insulin resistance (HOMA-IR), and adipokines were measured. The lifestyle intervention included dietary counselling, regular physical activity. RESULTS: Among 117 girls and boys (11-15 years old, 31.6% obese), 40% had vitamin D deficiency (25(OH)D levels < 20 ng/mL). With linear regression models where 25(OH)D and HOMA-IR acted as independent variables and age, sex, BMI, L/A ratio as covariates, 25(OH)D was significantly associated with HOMA-IR alone (P = 0.036). HOMA-IR was also associated with BMI z-score >= 2, L/A ratio and an interaction term BMI z-score >= 2*L/A ratio (P < 0.001 for all). After one year, in 78 children/adolescent, mean serum 25(OH)D increased significantly from 21.4 +/- 4.9 ng/mL at baseline to 23.2 +/- 6.0 after 1 year; P = 0.003 whereas BMI z-score, HOMA-IR and L/A ratio decreased significantly (P = 0.003, P < 0.001 and P = 0.012; respectively). CONCLUSION: The association between 25(OH)D and HOMA-IR, independently of obesity and the high prevalence of vitamin D deficiency should be considered in order to prevent the later incidence of T2DM. A healthy lifestyle including non-sedentary and outdoor activities could be a way for improving vitamin D status. PMID- 28028398 TI - O Blood Group as Risk Factor for Preeclampsia among Sudanese Women. AB - AIM: To investigate blood groups and the other possible risk factors for preeclampsia among Sudanese women. MATERIAL AND METHODS: A case - control study was conducted at Saad Abualila Hospital, Khartoum, Sudan during the period of July 2013 through December 2014. The cases were women with preeclampsia and healthy pregnant women were the controls. RESULTS: Two hundred eighty pregnant women were enrolled (140 in each arm of the study). Around one-quarter of all women (280) were primiparae (74.0, 26.4%), the majority were housewives (201, 71.7%). Seventy-nine (28.2%) were illiterate or had no informal education. Around half of the women (130, 46.4%) had O blood group. Binary logistic regression showed association between preeclampsia and lack of antenatal care (OR = 2.75, 95% CI = 1.172-6.494, P = 0.020) as well as O blood group (OR = 1.78, 95% CI = 1.088-2.934, P=0.022). CONCLUSION: The current study showed that women with blood group O were at higher risk of preeclampsia. PMID- 28028399 TI - Indexes of Insulin Resistance in Hyperinsulinemic Polycystic Ovary Syndrome in a Macedonian Cohort of Women of Reproductive Age: A Cross-Sectional Study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is complex hormonal, metabolic and reproductive disorder and is a leading cause of female infertility. Hyperinsulinemia secondary to insulin resistance plays important role in the pathogenesis of PCOS. AIM: To assess the sensitivity of different indices of insulin resistance and their relevance in a clinical setting. MATERIAL AND METHODS: A cross-sectional study of 43 patients with PCOS and 29 noromo ovulatory women as a control group was conducted. Standard clinical, anthropometrical and hormonal testing for hyperandrogenism was conducted, as well as oral glucose tolerance test with determination of basal and stimulated glucose and insulin values. RESULTS: The dynamic I/G index showed the highest sensitivity and specificity, but the static indexes HOMA-IR and QUICKI, although based on only basal glycemic and insulinemic values, showed good sensitivity, 90.38% and 94.01% respectively. HOMA-IR showed significant positive correlation with the stimulated insulin values. CONCLUSIONS: Our results support the use of static indexes in the evaluation of insulin resistance in women with PCOS in a clinical setting, offering a simple assessment of insulin resistance in PCOS, which holds great prognostic and treatment implications. PMID- 28028400 TI - Transcatheter Closure of Patent Foramen Ovale: A Single Center Experience. AB - BACKGROUND: Percutaneous transcatheter closure (PTC) of patent foramen ovale (PFO) is implicated in cryptogenic stroke, transitional ischemic attack (TIA) and treatment of a migraine. AIM: Our goal was to present our experience in the interventional treatment of PFO, as well as to evaluate the short and mid-term results in patients with closed PFO. MATERIAL AND METHODS: Transcatheter closure of PFO was performed in 52 patients (67.3% women, mean age 40.7 +/- 11.7 years). Patients were interviewed for subjective grading of the intensity of headaches before and after the PFO closure. RESULTS: During 2 years of follow-up, there was no incidence of new stroke, TIA and/or syncope. Follow-up TCD performed in 35 patients showed complete PFO closure in 20 patients (57.1%). Out of 35 patients, 22 (62.9%) reported having a migraine before the procedure with an intensity of headaches at 8.1 +/- 1.9 on a scale from 1 to 10. During 2 years of follow-up, symptoms of a migraine disappeared in 4 (18.2%) and the remaining 18 patients reported the significant decrease in intensity 4.8 +/- 2.04 (p = 0.0001). In addition, following PFO closure the incidence of the headaches decreased significantly (p = 0.0001). CONCLUSIONS: Percutaneous transcatheter closure of PFO is a safe and effective procedure showing mid-term relief of neurological symptoms in patients as well as significant reduction of migraine symptoms. PMID- 28028401 TI - The Prevalence of Allergic Rhinitis, Eczema and Asthma in Students of Guidance Schools in Mazandaran Province, Iran. AB - BACKGROUND: Eczema, allergic rhinitis and asthma are common chronic allergic disorders in childhood. AIM: The aim of this study was to determine the prevalence of common allergic disorders among Iranian guidance schools students in Mazandaran Province, northern Iran. METHODS: This analytical cross-sectional study was performed on 3000 children aged 11-14 years old during 2012-13 according to ISAAC study. Of 3000 recruited children 1576 (52.54%) were female and 1424 (47.46%) were male. Data gathered by ISAAC first phase questionnaire analysed by SPSS software 20. RESULTS: The prevalence of wheezing, allergic rhinitis symptoms (sneezing and pruritus) and atopic dermatitis symptoms (pruritus skin lesion) were 30.5%, 30% and 15% respectively. History of pets contact and smoking was positive 6.6% and 36 % respectively. About 52% was born with caesarian section. There was wheezing in 32.5% during sport. The diagnosis of asthma, allergic rhinitis and eczema were 12.2%, 28.5% and 15% respectively. Eczema, asthma and allergic rhinitis were significantly more common in boys students (p < 0.05). CONCLUSIONS: The results of this study showed that asthma, allergic rhinitis and eczema have a high prevalence and they are more common in boys. PMID- 28028402 TI - Academic Achievement and Psychosocial Profile of Egyptian Primary School Children in South Sinai. AB - BACKGROUND: Population of South Sinai has suffered from negligence for many years. Solving educational problems of this population is the main concern nowadays. AIM: To assess academic achievement in primary school children in South Sinai in relation to intelligence and psychosocial profile. SUBJECTS AND METHODS: A descriptive cross-sectional survey was conducted on 407 Bedouin and urban students randomly selected from twelve public primary schools in six cities in South Sinai. Intelligence was assessed using Goodenough-Harris test. The midyear Arabic language and Arithmetic scores were used to assess academic achievement. The teachers completed a Pediatric-Symptom Checklist for evaluation of children behaviour. RESULTS: A statistically significant difference in academic achievement (P < 0.001), total psychosocial scores, (P < 0.05), and externalization (P < 0.05) was found between urban and Bedouin students with significant gender differences (P < 0.05). Highly significant positive correlations were observed between IQ percentile and mid-year Arabic language scores and Arithmetic scores (P < 0.001), and significant negative correlations with the total score of PSCL and its subscale scores (externalising, inattention, and internalising behaviour) (P < 0.001) among the students. CONCLUSION: Comorbid academic and psychosocial dysfunction in primary school children were observed in South Sinai. A national strategy to minimise the educational gap between Bedouin and urban areas should be implemented. PMID- 28028403 TI - Assessment of Increase in Aortic and Carotid Intimal Medial Thickness in Type 1 Diabetic Patients. AB - AIM: To assess aortic and carotid intima-media thickness (aIMT and cIMT) in diabetic patients. PATIENTS AND METHODS: The study included 75 type 1 diabetic patients and 30 age and sex matched healthy volunteer. A blood sample was taken for analysis of HbA1 and lipid profile and the urine sample was taken for analysis of albumin/creatinine ratio. aIMT and cIMT via ultrasound were also done. RESULTS: cIMT & aIMT were significantly higher in diabetics. aIMT was found to be significantly higher than cIMT in diabetic patients (0.72 +/- 0.11 vs. 0.52 +/- 0.06, P = 0.0001). Ten of our patients (14%) with normal cIMT revealed significantly increased aIMT. aIMT had a significant positive correlation with age of patients, waist/hip ratio & cIMT. CONCLUSION: Diabetic patients had increased aIMT and cIMT with a relatively greater increase in the aIMT than in the cIMT. Because atherosclerosis begins first in the intima of the aorta, these data suggest that the aIMT might provide the best currently available noninvasive marker of preclinical atherosclerosis in children. We recommend frequent follow up of diabetic patients for early detection of diabetic complication. PMID- 28028404 TI - Cigarette Smoking and Oxidative Stress in Patients with Coronary Artery Disease. AB - AIM: To determine whether cigarette smoking, as a risk factor for CAD, affects (anti)oxidant status. MATERIAL AND METHODS: The study included patients with CAD, divided according to their smoking status and the number of cigarettes smoked during a day. Biological markers of oxidative stress (concentration of oxidants and activity of antioxidant enzymes) were measured in all subjects. RESULTS: The study included 300 patients with CAD, (average age of 63 +/- 11 years), predominantly males. Of the total, 34.0% were active smokers, 23.0% were former smokers, and 43.0% were non-smokers. Most of the active smokers smoked 1-20 cigarettes/day. In terms of concentration of oxidants (MDA and HP) there was not a significant difference between smokers versus non-smokers. As for the activity of antioxidant enzymes (SOD, CAT and GPX), a statistically significant difference was found in the activity of GPX among the active smokers with CAD and the non smokers with CAD (p = 0.039). CONCLUSION: Smoking as a risk factor for CAD is closely associated with increased oxidative stress, and the number of cigarettes smoked plays an important role in increasing the level of oxidative damage and reducing antioxidant defence. PMID- 28028405 TI - Complications of Laparoscopic Cholecystectomy: Our Experience from a Retrospective Analysis. AB - AIM: The aim of this study was to evaluate the intraoperative and postoperative complications of laparoscopic cholecystectomy, as well as the frequency of conversions. MATERIAL AND METHODS: Medical records of 740 patients who had laparoscopic cholecystectomy were analysed retrospectively. We evaluated patients for the presence of potential risk factors that could predict the development of complications such as age, gender, body mass index, white blood cell count and C reactive protein (CRP), gallbladder ultrasonographic findings, and pathohistological analysis of removed gallbladders. The correlation between these risk factors was also analysed. RESULTS: There were 97 (13.1%) intraoperative complications (IOC). Iatrogenic perforations of a gallbladder were the most common complication - 39 patients (5.27%). Among the postoperative complications (POC), the most common ones were bleeding from abdominal cavity 27 (3.64%), biliary duct leaks 14 (1.89%), and infection of the surgical wound 7 patients (0.94%). There were 29 conversions (3.91%). The presence of more than one complication was more common in males (OR = 2.95, CI 95%, 1.42-4.23, p < 0.001). An especially high incidence of complications was noted in patients with elevated white blood cell count (OR = 3.98, CI 95% 1.68-16.92, p < 0.01), and CRP (OR = 2.42, CI 95% 1.23-12.54, p < 0.01). The increased incidence of complications was noted in patients with ultrasonographic finding of gallbladder empyema and increased thickness of the gallbladder wall > 3 mm (OR = 4.63, CI 95% 1.56-17.33, p < 0.001), as well as in patients with acute cholecystitis that was confirmed by pathohistological analysis (OR = 1.75, CI 95% 2.39-16.46, p < 0.001). CONCLUSION: Adopting laparoscopic cholecystectomy as a new technique for treatment of cholelithiasis, introduced a new spectrum of complications. Major biliary and vascular complications are life threatening, while minor complications cause patient discomfort and prolongation of the hospital stay. It is important recognising IOC complications during the surgery so they are taken care of in a timely manner during the surgical intervention. Conversion should not be considered a complication. PMID- 28028406 TI - Midshaft Clavicular Fractures - Osteosynthesis with Minimally Invasive Technique. AB - BACKGROUND: Fractures of the clavicle are one of the most common fractures in modern orthopaedics and traumatology practice. Knowing the mechanism of trauma, and it's pathophysiological elements, it's clear distinction and it's individual features are essential to the development of more new and effective methods for their treatment, and the minimising of postoperative complications. AIM: The aim of this paper was to present the results of our patients treated with minimally invasive plate osteosynthesis (MIPO). MATERIAL AND METHODS: Between January 2011 and March 2013, 12 patients were treated with MIPO technique. The mean age was 47.5 years (range, 16-79 years). Outcomes and complications of clinical treatment were reviewed. RESULTS: All fractures healed within a mean period of 4.9 months (range, 2-10 months). Regarding complications, there was no occurrence of implant failure or deep infection. There were no nonunions, but one 79-year-old man had a delayed union. Almost of all the cases didn't need bending of the plate. Seven plates were removed by their hopes. And there weren't any cases that required new incisions. CONCLUSIONS: A pre-contoured plate anatomically configured to fit the clavicle was easier to apply. MIPO technique for midshaft clavicle fractures may be a good option. PMID- 28028407 TI - Endoscopic Anatomy and Features of Anterior Cervical Foraminotomy by Destandau Technique. AB - BACKGROUND: Minimally invasive spine surgery limits surgical trauma and avoids traditional open surgery so in the majority of cases, recovery is much quicker and patients have less pain after surgery. AIM: The authors describe an endoscopic approach to anterior cervical foraminotomy (ACF) by Destandau's method. MATERIAL AND METHODS: Anterior cervical foraminotomy by Destandau's method is carried out under general anaesthesia. A 3 cm transverse skin incision is used just slightly past the anterior border of the sternocleidomastoid's muscle laterally. After exposing and dissecting superficial cervical fascia, platysma muscle, and deep cervical fascia, Endospine material designed by Destandau will be inserted. As from this moment, the procedure will continue using endoscopy. RESULTS: the Endoscopic approach to anterior cervical foraminotomy by Destandau's method offers a convenient access to the cervical foraminal stenosis with fewer complications and negligible morbidity and gives maximum exposure to discal space with the goal of minimising cutaneous incision. CONCLUSION: Contrary to the other minimally invasive approaches, the visual field in foraminotomy by Destandau technique is broad and depending on the workability of Endospine an adequate access to cervical disc is possible. PMID- 28028408 TI - Treatment of the Aged Patients at a Large Cardiac Rehabilitation Center in the Southern Brazil and Some Aspects of Their Dropout from the Therapeutic Programs. AB - AIM: This paper aims to assess the dropout rate in different age groups through the example of the large cardiac rehabilitation centre affiliated with the Institute of Sports Medicine, University of Caxias do Sul. MATERIAL AND METHODS: A historic cohort study comprising the following groups: Non-Old < 65 (n = 141); Young-Old 65-74 (n = 128); and Middle-Old 75-84 years old (n = 57). The exercise program lasted 48 sessions and dropout was defined as attendance of 50% of sessions or less. Logistic binominal regression was performed to assess the risk of dropout. For all analyses, a two-tailed P value of < 0.05 was used. RESULTS: The total dropout rate was 38.6%. The Young-Old and Middle-Old groups showed lower dropouts compared to Non-Old patients (p = 0.01). Young-Old has 96% less risk for dropout compared to Non-Old group (adjusted odds ratios = 1.96 [1.16 3.29]). Furthermore, patients underwent the Coronary Artery Bypass Graft showed a lower rate of dropout (p = 0.001). The absence of CABG involved three times more risk of dropout (p = 0.001). CONCLUSION: The Non-Old and the Middle-Old patients showed higher dropout rates compared to Young-Old. To ensure the best possible rehabilitation and to improve patients' participation in CR, these programs should be adjusted to the needs of patients in terms of their age. PMID- 28028409 TI - Influence of Early Intensive Rehabilitation on Functional Mobility after Low Back Surgery. AB - AIM: The research aims to determine the influence of early goal-oriented physical therapy program in combination with educational booklet and standard physical therapy without written instructions on functional mobility outcomes in patients after low back surgery. MATERIAL AND METHODS: Thirty patients with similar functional impairments were randomly divided into two groups, a control group (CG n = 10) and an experimental group (EG n = 20). The outcome measures include time to move from lying to sitting position, the TUG test and the 6-meter walk test. Rehabilitation program includes daily physical therapy with mild to moderate intensity, achieving sitting position and education sessions how to perform activities of daily living (ADL) from the first day after surgery. RESULTS: There was a significant improvement from baseline in two groups for all performed tests (p < 0.001). Statistical significant differences between two groups for transfers in bed on discharge (p < 0.05), in one month (p < 0.01) and for TUG in one month (p < 0.05) were found. CONCLUSION: The study revealed that early rehabilitation program consists of therapeutic exercises and written educational booklet after low back surgery improves transfer abilities and basic activities in one month. PMID- 28028410 TI - The Association between Urinary Incontinence and Low Back Pain and Radiculopathy in Women. AB - AIM: Urinary incontinence (UI) is a common dysfunction, affecting especially women of all ages. The terminology of low back pain (LBP) and radiculopathy (RP) may be misused interchangeably with each other. There are many reports of the association with LBP and incontinence but those involving compression of nerve root(as RP), has not been distinguished from isolated low back pain. This study was structured to analyse the association of UI, LBP and RP. METHODS: One hundred twenty patients were included in the study. Patients with spinal or urinary infection, tumour (spinal or others), cauda equine, pelvic operation, spinal trauma, spinal surgery, urogenital pathology were not accepted for this study. Age and weight of all patients were determined. Oswestry Disability Index (ODI) was utilised for assessment of loss of function and SEAPI incontinence index was used for urinary incontinence. All patients were examined for neurological pathology to differentiate between the LBP and RP by department of neurosurgery. Student t-test and Mann-Whitney-U tests were used for statistical significance. RESULTS: There was no statistical significance between low back pain with overall urinary incontinence (p = 0.131), urge (p = 0.103) or stress incontinence (p = 0.68), respectively. However; The statistical aspects were identified relationship between overall (p = 0.026) and urge (p = 0.001) urinary incontinence with radiculopathy. The association of urge incontinence and radiculopathy seems to show a more significant relationship. Yet there was no correlation between radiculopathy and stress incontinence (P = 0.062). CONCLUSION: Low back pain should not be regarded as a predisposing factor for urinary incontinence; however, radiculopathy has a statistically positive correlation between overall incontinence and urge incontinence. PMID- 28028411 TI - Diaphyseal Fractures of the Forearm in Adults, Plating Or Intramedullary Nailing Is a Better Option for the Treatment? AB - BACKGROUND: Fractures of the radius and ulna occupy a large field of the modern traumatology. Therefore, these fractures are a major subject in modern orthopaedics and traumatology. The study of the mechanisms of the trauma, and the pathophysiological changes that occur are of great importance for the development of ever more efficient and varied ways of the treatment and prophylactics of this type of fracture. AIM: The aim of this paper was to study the pattern of the diaphyseal fractures of the forearm in adults, to decide the modalities of surgical management, to observe the period of fracture healing clinically and radiologically, as well to study the rehabilitation of the patients. MATERIAL AND METHODS: The present study included 45 cases of diaphyseal fractures of both bones forearm in adults presenting to the orthopaedic outpatient department. For all the patients a detailed history was taken. A thorough clinical examination was carried out, required X-rays were taken, and initial treatment was given and admitted as in all patients. After careful pre-operative planning and evaluation for anaesthetic fitness, patients were operated for the fractures of both bone forearms. Twenty-three cases with 46 fractures were treated by open reduction and rigid fixation with DCP & Semi-tubular plates and 22 cases with 44 fractures were treated by closed reduction and fixation with "Talwarkar" intramedullary square nails. RESULTS: United results were found in 100% of plating group vs. 86% in the nailing group. Delayed and non-union results were found in 9% of the nailing group only. Average time to union in weeks was 9.4 weeks in the plating group vs. 10.2 weeks in the nailing group. CONCLUSION: Open reduction and internal fixation with compression plates with strict adherence to surgical technique is the gold standard method of treatment in both bones forearm fractures with excellent results than closed reduction, internal fixation with "Talwarkar" square nails which is also again a simple method with better results than conservative methods. PMID- 28028412 TI - The Role of the Velopharyngeal Sphincter in the Speech of Patients with Cleft Palate or Cleft Lip and Palate Using Perceptual Methods. AB - BACKGROUND: The velopharyngeal sphincter (VPS) plays the main role in speech formation. The cleft palate, due to the damage of the soft palate, leads to dysfunction of the velopharyngeal sphincter thus causing speech disorder. AIM: To establish a link between the nasal air escape and the perceptual symptoms in the speech of patients with cleft palate or cleft lip and palate using auditory visual perceptual procedures for determining the influence the velopharyngeal dysfunction has on speech. MATERIAL AND METHODS: Twenty patients with speech disorders, out of which 10 have cleft palate or cleft lip and palate (experimental group), participated in the perceptual assessment by means of Czermak mirror fogging test for assessing the nasal air escape and Pittsburgh Weighted Speech Scale (PWSS) for assessing the probable nature of the velopharyngeal sphincter. RESULTS: The respondents with a considerable nasal air escape have a higher velopharyngeal inability, that is, probably incompetent nature of the velopharyngeal sphincter. There is a strong correlation between the nasal air escape and the probable nature of the velopharyngeal sphincter (the coefficient of linear correlation r = 0.9756). The calculated p-value is p = 0.000002. CONCLUSION: The perceptual speech symptoms and the nasal air escape provide unique insight into the state and role the velopharyngeal sphincter has in speech. PMID- 28028413 TI - Treatment of Pediatric Open Supracondylar Humerus Fractures: Case Report. AB - BACKGROUND: Open supracondylar fractures of the humerus are rare in children, and the treatment strategy for these fractures is yet to be standardised. AIM: We present the case of a 7-year-old boy with open supracondylar humerus fracture that was managed with an external wrist fixator. CASE PRESENTATION: A 7-year-boy was brought to our department with pain in the right arm after a fall from a height about 3 hours before admission. On examination, the elbow was found to be markedly swollen with restriction of movement of the right arm. A 4-cm-wide wound was also observed on the flexural aspect of the elbow, indicating severe contamination of the fractured site. Neurological examination revealed restriction of hand movement and decreased sensations, which suggested the possibility of nerve injuries. CONCLUSION: A good clinical outcome was achieved in this case, without the development of any complications over a 6-month follow up period. PMID- 28028414 TI - Goodpasture Syndrome Diagnosed One Year And A Half after the Appearance of the First Symptoms (Case Report). AB - BACKGROUND: Goodpasture syndrome was originally described as an association of alveolar haemorrhage and glomerulonephritis. It occurs when the immune system attacks and destroys healthy body tissue. AIM: We are presenting a patient with a clinical picture of pulmonary haemorrhage and glomerulonephritis, which is diagnosed by renal biopsy. CASE PRESENTATION: His illness began a year and a half before being diagnosed. In that period he had occasional exacerbations. He was received at our Clinic in extremely serious condition, and after stabilisation of his medical condition, there was made a biopsy of the kidney. The p-ANCA was 8.93 U/ml (neg < 3, poz > 5 U/ml). Histopathological diagnosis of biopsy of the kidney was: Glomerulonephritis extra capillaries focalis, segmentalis et globalis. Based on this he was diagnosed with Goodpasture syndrome. He received corticosteroid therapy and cyclophosphamide, with good response to treatment, and he is currently in a stable condition, receiving only corticosteroid therapy. CONCLUSION: Goodpasture syndrome is a severe illness caused by the formation of antibodies to the glomerular basement membrane and alveolus with consequential damage to renal and pulmonary function. With current therapy, long-term survival is more than 50%. PMID- 28028415 TI - Scapular Fractures in Blunt Chest Trauma - Self-Experience Study. AB - AIM: The aim of this retrospective study was to report the scapular fractures in patients with blunt chest trauma and to present the type and the frequency of associated thoracic injuries. MATERIAL AND METHODS: Nine patients with fractures of the scapula were included in the study. The mechanisms of the injury, the type of scapular fractures and associated thoracic injuries were analysed. RESULTS: Scapular fractures were caused by high-energy blunt chest trauma. The body of the scapula was fractured in all scapular fractures. In all cases, scapular fractures were associated with other thoracic injuries (average 3.25/per case). Rib fractures were present in eight patients, fractured clavicula - in four cases, the affection of pleural cavity - in eight of the patients and pulmonary contusion in all nine cases. Eight patients were discharged from the hospital up to the 15th day. One patient had died on the 3rd day because of postconcussional lung oedema. CONCLUSIONS: The study confirms the role of scapular fractures as a marker for the severity of the chest trauma (based on the number of associated thoracic injuries), but doesn't present scapular fractures as an indicator for high mortality in blunt chest trauma patients. PMID- 28028416 TI - Right Hemispheric Leukoencephalopathy as an Incidental Finding Following a Lightning Strike. AB - BACKGROUND: Lightning injuries may produce a variety of medical conditions, and specific neurological complications have been identified, with the character of immediate aftershock effects or even long-term consequences. AIM: The authors describe the incidental finding following a routine unenhanced brain MRI performed to a young female patient, suffering from a headache. CASE REPORT: Diffuse white matter changes with the character of a leukoencephalopathy were seen, which strictly interested only the right cerebral hemisphere. The parents referred that she suffered from an indoor lightning strike at age of seven months, although she survived with almost no external burns or signs, and recovered uneventfully at that time. A discussion over the effects of electrocution and lightning strike on the human body in general, and over the nervous system, is made. Particular attention must be shown when making the differential diagnosis of leukoencephalopathies with a strictly one-hemisphere extension since several other conditions might resemble each other under the radiological aspect, here including brain viral infections, genetic disorders, and so on. CONCLUSION: The particularity of the long-term aftershock effects of the lightning strike on the central nervous system raise again the necessity of collecting data and duly reporting every electrical accident, lightning events included. PMID- 28028417 TI - A Twofold Comparison between Dual Cure Resin Modified Cement and Glass Ionomer Cement for Orthodontic Band Cementation. AB - AIM: To test the solubility of dual cure resin modified resin cement in a food simulating solution and the shear bond strength compared to conventional Glass ionomer cement. MATERIALS AND METHOD: The materials tested were self-adhesive dual cure resin modified cement and Glass Ionomer (GIC). Twenty Teflon moulds were divided into two groups of tens. The first group was injected and packed with the modified resin cement, the second group was packed with GIC. To test the solubility, each mould was weighed before and after being placed in an analytical reagent for 30 days. The solubility was measured as the difference between the initial and final drying mass. To measure the Shear bond strength, 20 freshly extracted wisdom teeth were equally divided into two groups and embedded in self cure acrylic resin. Four mm sections of stainless steel bands were cemented to the exposed buccal surfaces of teeth under a constant load of 500 g. Shear bond strength was measured using a computer controlled materials testing machine and the load required to deband the samples was recorded in Newtons. RESULTS: GIC showed significantly higher mean weight loss and an insignificant lower Shear bond strength, compared to dual cure resin Cement. CONCLUSION: It was found that dual cure resin modified cement was less soluble than glass ionomer cement and of comparable bond strength rendering it more useful clinically for orthodontic band cementation. PMID- 28028418 TI - Buccal Corridors: A Fact or a Myth in the Eyes of Laymen? AB - AIM: This study aimed to investigate laymen knowledge of the existence of the buccal corridor and whether it was an important factor for them in judging smile attractiveness and the effect of introducing the knowledge to them on their further judgment. MATERIALS AND METHODS: Nine subjects were randomly selected with variable buccal corridor percentages. They were coached to smile in a posed fashion and full face smile photographs were taken from a standardised distance. The photographs were randomly arranged in a power point presentation and displayed to a panel of thirty-nine randomly selected laymen judges. The judges made their beauty judgment on a visual analogue scale (VAS) and filled a questionnaire. After their education about the buccal corridor, they were asked to make a second judgment on a second sheet with VAS and with a different random sequence of the photographs. RESULTS: Intra-class correlation agreement for all the judges between the first and second scores was 0.713. The Spearman's rho Correlation coefficient indicated a positive correlation for all the photos. For the male judges, the agreement between the ratings was 0.839, and the correlation was positive for all the photos. For the female judges, the agreement between the ratings was 0.510, and the correlation was positive for all the photographs. Hundred percent of the judges were not familiar with the buccal corridor. Eighty percent of the female judges and 44.4% of the male judges mentioned that it would affect their further judgment. CONCLUSION: Laymen build their esthetic judgments on what we teach them, and modifying treatment plans to include corrections of buccal corridors for esthetic reasons only is a myth. PMID- 28028419 TI - The Effect of Orthognathic Surgery on Osteoprotegerin as Immunological Caliper of Bone Healing. AB - BACKGROUND: Osteoprotegerin (OPG) is considered to be the cytokine that plays an important role in the healing process. OPG regulates bone cell biology, osteoblast-osteoclast, bone-immune cross-talk and maintenance of bone mass. It plays an important role in the development, induction, and repair of bone. Orthognathic surgery as multiples segmental osteotomies has been taken as a model surgery to assess the changes in osteoprotegerin levels in the post-operative bone healing period. AIM: The aim of the study was to evaluate OPG as immunological caliper of bone healing. MATERIAL AND METHODS: OPG was evaluated in nine patients seeking orthognathic surgery. Patients were examined and checked to be medically and immunologically free prior to surgery. Blood samples were collected immediate pre-operative as control group and for six weeks post operative as study group. RESULTS: Data were collected from nine consecutive patients. The results showed higher levels of OPG. it showed significant increase in the immediate post-operative value (p = 0.001) which started to increase gradually during the six weeks (p < 0.001). CONCLUSIONS: Significant higher levels of OPG during the healing period of orthognathic surgery suggest the its use as immunological caliper of bone healing. PMID- 28028420 TI - Dental Implantation of Atrophic Jaws Reconstructed with Iliac Bone Graft Crest - Outcome of Seven Cases. AB - BACKGROUND: Iliac bone grafts are used to augment alveolar ridges followed by subsequent dental implants in completely edentulous patients. In Albania the information about these issues is scarce. AIM: To describe the procedure of iliac bone grafts augmentation of alveolar ridges and evaluate the survival rate of dental implants in completely edentulous patients in Albania. SUBJECTS AND METHODS: Seven totally edentulous patients (three males, average age 45.9 years) presenting at Durres Regional Hospital during 2008-2015 and seeking a solution to their problem through implantation procedures were included in the study. Patients were thoroughly examined, evaluated and the best augmentation procedure, using iliac crest bone grafts, and dental implantation technique was chosen. The number of dental implants placed was recorded and their survival rate was calculated. RESULTS: The most common intervention site was maxillae (in 71.4% of cases). Dental implants were installed six months after augmentation, all fixed on the very stable augmented alveolar ridge. On average between 20%-30% of bone grafts, volume was resorbed. Of 37 implants settled, 36 of them or 97.3% survived. CONCLUSION: Iliac bone grafts are a suitable augmentation source of bone in a patient suffering from complete edentulism in Albania. The survival rate of dental implants is very satisfactory. PMID- 28028421 TI - The Use of Different Irrigation Techniques to Decrease Bacterial Loads in Healthy and Diabetic Patients with Asymptomatic Apical Periodontitis. AB - BACKGROUND: Diabetes mellitus is a multisystem disease which weakens the human's immunity. Subsequently, it worsens the sequelae of apical periodontitis by raising a fierce bacterial trait due to the impaired host response. AIM: This study aimed to estimate bacterial reduction after using different irrigation techniques in systemically healthy and diabetic patients with asymptomatic apical periodontitis. MATERIAL AND METHODS: Enterococcus faecalis, Peptostreptococcus micros, and Fusobacterium necleatum bacteria were chosen, as they are the most common and prevailing strains found in periodontitis. Bacterial samples were retrieved from necrotic root canals of systemically healthy and diabetic patients, before and after endodontic cleaning and shaping by using two different irrigation techniques; the conventional one and the EndoVac system. Quantitive polymerase chain reaction (qPCR) was utilised to detect the reduction in the bacterial count. RESULTS: The EndoVac irrigation system was effective in reducing bacteria, especially Peptostreptococcus micros in the diabetic group when compared to conventional irrigation technique with a statistically significant difference. CONCLUSION: The EndoVac can be considered as a promising tool in combination with irrigant solution to defeat the bacterial colonies living in the root canal system. Additional studies ought to be done to improve the means of bacterial clearance mainly in immune-compromised individuals. PMID- 28028422 TI - Can Low Level Laser Therapy Benefit Bone Regeneration in Localized Maxillary Cystic Defects? - A Prospective Randomized Control Trial. AB - AIM: The aim of the study was to evaluate the effect of Low-Level Laser Therapy (LLLT) on bone formation in cystic defects following cyst enucleation. PATIENTS AND METHODS: The sample was composed of sixteen patients with enucleated maxillary bony cystic lesions. With an age range from 20 - 44 grouped as eight Laser and eight Control patients. Laser group was subjected to low intensity diode laser immediately after surgery and then for three times per week for two weeks using a therapeutic laser irradiation. Group B (control group): patients were not subjected laser therapy. RESULTS: The predictor variable was exposure of bone defect to LLLT or none. The outcome variable was bone density changes measured by digital radiographs at day 1 and days 90 postoperatively. Descriptive and bivariate statistics were computed. There were no statistically significant differences between the 2 groups for the bone density at day 1. There was a statistically significant difference in bone density changes in each group at day 90: Significant at P <= 0.05. After adjusting for differences in day 1 for bone density, the estimated mean change in bone density changes at day 90 was significantly larger for Laser compared with control. CONCLUSION: The results of this study suggested that LLLT can enhance bone healing in maxillary cystic defects. This can serve as an adjunct method in preventing possible delayed healing and pathological fractures This also will be helpful for more researchers in early loading in case of dental implants to accelerate osseointegration. PMID- 28028423 TI - Implant Supported Fixed Restorations versus Implant Supported Removable Overdentures: A Systematic Review. AB - AIM: The aim of this study is to systematically evaluate and compare implant retained fixed restoration versus implant retained over denture. MATERIAL AND METHODS: Search was made in 2 databases including PubMed and PubMed Central. Title and abstract were screened to select studies comparing implant retained fixed restorations versus implant retained removable overdentures. Articles which did not follow the inclusion criteria were excluded. Included papers were then read carefully for a second stage filter, this was followed by manual searching of bibliography of selected articles. RESULTS: The search resulted in 5 included papers. One study evaluated the masticatory function, while the other 4 evaluated the patient satisfaction. Two of them used Visual Analogue Scale (VAS) as a measurement tool, while the other two used VAS and Categorical Scales (CAT). Stability, ability to chew, ability to clean, ability to speak and esthetics were the main outcomes of the 4 included papers. CONCLUSION: Conflicting results was observed between the fixed and removable restorations. PMID- 28028424 TI - Aortic Root Enlargement or Sutureless Valve Implantation? AB - Aortic valve replacement (AVR) in patients with a small aortic annulus is a challenging issue. The importance of prosthesis-patient mismatch (PPM) post aortic valve replacement (AVR) is controversial but has to be avoided. Many studies support the fact that PPM has a negative impact on short and long term survival. In order to avoid PPM, aortic root enlargement may be performed. Alternatively and keeping in mind that often some comorbidities are present in old patients with small aortic root, the Perceval S suturelles valve implantation could be a perfect solution. The Perceval sutureless bioprosthesis provides reasonable hemodynamic performance avoiding the PPM and providing the maximum of aortic orifice area. We would like to see in the near future the role of the aortic root enlargement techniques in the era of surgical implantation of the sutureless valve (SAVR) and the transcatheter valve implantation (TAVI). PMID- 28028425 TI - Should surgeons control fluoroscopy during urology procedures? AB - INTRODUCTION: Our study explored the impact of switching from surgeon- to radiation technologist (RT)-controlled fluoroscopy on fluoroscopy and operative times. We also identified factors impacting fluoroscopy and operative times for ureteroscopy (URS) with laser lithotripsy. METHODS: Patients undergoing urological procedures requiring fluoroscopy six months before and after the change from surgeon- to RT-controlled fluoroscopy were identified. Median fluoroscopy and operative times were compared between cohorts. Subgroup analyses were performed based on procedure performed. A multivariate analysis identified factors associated with increased fluoroscopy and operative times for URS with laser lithotripsy. RESULTS: Overall, no difference was found between surgeon and RT cohorts for fluoroscopy (58.0 vs. 56.7 seconds; p=0.34) or operative times (39 vs. 36 minutes; p=0.14). For URS with laser lithotripsy, fluoroscopy and operative times were longer in the surgeon-controlled cohort (76.0 vs. 54.0 seconds; p<0.01 and 48 vs. 40 minutes; p<0.01, respectively). For URS only, fluoroscopy time was decreased in the surgeon-controlled cohort (47.0 vs. 73.0 seconds; p=0.01). For URS with laser lithotripsy, factors independently associated with increased fluoroscopy time were male sex, flexible URS, glidewire use, and difficult ureteric stent insertion (p<0.05). Flexible ureteroscopy, glidewire use, previous ureteric stent placement, and difficult ureteric stent insertion were independently associated with increased operative time (p<0.05). CONCLUSIONS: Fluoroscopy and operative times are not significantly influenced by who controls fluoroscopy during urologic procedures. Patients undergoing URS with laser lithotripsy have decreased fluoroscopy and operative times with RT controlled fluoroscopy. Patients undergoing URS only have decreased fluoroscopy times with surgeon-controlled fluoroscopy. PMID- 28028426 TI - Nonprofessional Care in Chronic Critically Ill Patient: A Qualitative Study. AB - BACKGROUND: Decision-making about patients with critical condition transfer from Intensive Care Unit to the general wards be delegated to their families. The aim of the study was explaining the experiences of family caregiver's about care of chronic critically ill patient. METHODS: This study was conducted with a qualitative content analysis using unstructured interview. Participants were selected purposively from May 2014 to May 2015 and data collection continued until data saturation. Analysis was based on conventional content analysis. RESULTS: Participants' experiences classified into three main categories as following: nonprofessional care, enhancing factors of care, and inhibiting factors of care. CONCLUSIONS: Finding of the current study showed different aspects of care. Care of chronic critically ill patients is a long-term process that affected by different factors. It seems that the exploration of caregivers needs and planning supportive interventions based on their needs improve the quality of care. PMID- 28028427 TI - Effects of Iron on Vitamin D Metabolism: A Systematic Review. AB - Vitamin D is a prohormone nutrient, which is involved in skeletal and extra skeletal functions. Iron is another essential nutrient that is necessary for the production of red blood cells and oxygen transport. This element plays important roles in enzymatic systems including those required for Vitamin D activation. To the best of our knowledge, there is no exclusive review on the relationship between iron deficiency anemia (IDA), as the most prevalent type of anemia, and Vitamin D deficiency and the effect of recovery from iron deficiency on Vitamin D status. The aim of this study was to conduct a systematic search of observational and clinical trials in this field. The databases of PubMed, ProQuest, Cochrane Library, ISI Web of Knowledge, and SCOPUS were searched comprehensively. English language human studies conducted on iron deficient patients or interventions on the effect of iron therapy on Vitamin D were extracted (n = 10). Our initial search yielded 938 articles. A total of 23 papers met the inclusion criteria. Thirteen studies were excluded because they were not relevant or not defining anemia types. The final analysis was performed on ten articles (3 cross-sectional and 7 interventional studies). Observational data indicated a positive relationship between iron status and Vitamin D, while trials did not support the effectiveness of iron supplementation on improving Vitamin D status. The mechanism underlying this association may involve the reduction of the activation of hydroxylases that yield calcitriol. Future randomized controlled trials with large sample sizes and proper designs are needed to highlight underlying mechanisms. PMID- 28028428 TI - Item Response Theory Applied to Factors Affecting the Patient Journey Towards Hearing Rehabilitation. AB - To develop a tool for use in hearing screening and to evaluate the patient journey towards hearing rehabilitation, responses to the hearing aid rehabilitation questionnaire scales aid stigma, pressure, and aid unwanted addressing respectively hearing aid stigma, experienced pressure from others; perceived hearing aid benefit were evaluated with item response theory. The sample was comprised of 212 persons aged 55 years or more; 63 were hearing aid users, 64 with and 85 persons without hearing impairment according to guidelines for hearing aid reimbursement in the Netherlands. Bias was investigated relative to hearing aid use and hearing impairment within the differential test functioning framework. Items compromising model fit or demonstrating differential item functioning were dropped. The aid stigma scale was reduced from 6 to 4, the pressure scale from 7 to 4, and the aid unwanted scale from 5 to 4 items. This procedure resulted in bias-free scales ready for screening purposes and application to further understand the help-seeking process of the hearing impaired. PMID- 28028429 TI - Gastric Schwannoma: A Case Report. AB - Schwannomas are generally benign, slow growing tumors. They are rarely observed in the gastrointestinal tract with the most common site being the stomach. These tumors are usually asymptomatic. The preoperative diagnosis via endoscopy is a challenging issue due to the difficulty of differentiation from other submucosal tumors. A 54-year-old woman presented with epigastric pain persisting for the last 10 months. Upper endoscopy revealed an elevated submucosal mass of the gastric antrum. The overlying mucosa was normal. Biopsy specimens yielded only unspecific signs of mild inactive chronic inflammation. Endoscopic ultrasound examination noted a hypoechoic homogeneous mass lesion located in the gastric antrum. The mass appeared to arise from the muscularis propria, and there was no perigastric lymphadenopathy. A contrast-enhanced computed tomography scan identified a homogeneous round mass and arising from the antrum of the stomach. Submucosal tumor was suspected and surgical intervention was recommended. The patient underwent an elective laparoscopic partial gastrectomy. The histopathologic features and immunohistochemical-staining pattern were consistent with a benign gastric schwannoma. Our patient shows no recurrence with a follow up of one year. The definitive diagnosis of gastric schwannomas requires immunohistochemical studies. Complete margin negative surgical resection, as in this case, is the curative treatment of choice. The clinical course is generally benign. PMID- 28028430 TI - A Child with Debilitating Pruritus. AB - We describe a case of two-year-old boy presenting with debilitating pruritus, patchy alopecia and jaundice since the age of 6 months. On evaluation he had intrahepatic cholestasis with persistently raised serum alkaline phosphatase, normal Gamma glutamyl transferase and raised serum bile acid levels. His liver biopsy showed bland cholestasis and electron microscopy showed granular bile suggestive of progressive familial intrahepatic cholestasis type I. Medical therapy with ursodeoxycholic acid, cholestyramine, rifampicin with nutritional modification was successful in alleviating the symptoms and correcting the nutritional status. To our knowledge this is only the sixth case of progressive familial intrahepatic cholestasis type I reported from India. Herein we discuss the diagnostic and therapeutic hurdles that one encounters in managing progressive familial intrahepatic cholestasis and also review the literature regarding this rare disorder. PMID- 28028431 TI - Oncocytic Pleomorphic Adenoma of Palatal Salivary Gland with Macrophages and Giant Cells Associated with Cholesterol Crystals. AB - Pleomorphic adenoma (PA) is the most common salivary gland tumor characterized by histo-morphological diversity in the form of myxoid, hyalinized, chondroid, osseous, and squamous areas. In this paper, we report a rare case of predominantly oncocytic variant of PA in a 45-year-old male patient on the posterior palatal region. Microscopic examination showed homogenous eosinophilic cellular mass composed of epithelial components arranged in the form of tubular and solid patterns. The polygonal and oval cells showed abundant dark eosinophilic granular cytoplasm. The cell borders were distinct with a central nucleus showing prominent nucleoli. Interestingly at few places, cholesterol clefts were seen surrounded by macrophages and giant cells. The tumor was surgically excised with no evidence of recurrence after 2 years. PMID- 28028432 TI - Rhabdomyolysis and Autoimmune Variant Stiff-Person Syndrome. AB - Stiff-person syndrome (SPS) is a rare neurologic disorder characterized by waxing and waning muscular rigidity, stiffness and spasms. Three subtypes have been described: paraneoplastic, autoimmune and idiopathic. Rhabdomyolysis has been described in the paraneoplastic variant, but to our knowledge no case has been reported involving the autoimmune variant. We report a case report of a 50-year old man with history of SPS who presented with recurrent episodes of severe limb and back spasms. He was hospitalized on two separate occasions for uncontrollable spasms associated with renal failure and creatinine phosphokinase elevations of 55,000 and 22,000 U/L respectively. Laboratory tests were otherwise unremarkable. The acute renal failure resolved during both admissions with supportive management. Rhabdomyolysis has the potential to be fatal and early diagnosis is essential. It should be considered in patients who have SPS and are experiencing an exacerbation of their neurologic condition. PMID- 28028433 TI - Universal coverage and economic burden from epidemiological changes of diabetes in Latin America. PMID- 28028434 TI - Infection prevention and control of Clostridium difficile: a global review of guidelines, strategies, and recommendations. AB - BACKGROUND: Clostridium difficile is the leading cause of health care-associated infections. Given the high incidence of C. difficile infection (CDI) and the lack of primary prevention through immunization, health care professionals should be aware of the most current guidance, as well as strengths and limitations of the evidence base underpinning this guidance. METHODS: We identified publicly available national or organizational guidelines related to CDI infection and prevention control (IPC) published between 2000 and 2015 and for any health care setting through an internet search using the Google search engine. We reviewed CDI-targeted IPC recommendations and describe the assessment of evidence in available guidelines. RESULTS: We identified documents from 28 countries/territories, mainly from acute care hospitals in North America, the Western Pacific, and Europe (18 countries). We identified only a few specific recommendations for long-term care facilities (LTCFs) and from countries in South America (Uruguay and Chile), South East Asia (Thailand), and none for Africa or Eastern Mediterranean. Of 10 IPC areas, antimicrobial stewardship was universally recognized as essential and supported by high quality evidence. Five other widely reported "strong" recommendations were: effective environment cleaning (including medical equipment), case isolation, use of personal protective equipment, surveillance, and education. Several unresolved and emerging issues were documented and currently available evidence was classified mainly as of mixed quality. CONCLUSION: Our review underlines the need for targeted CDI IPC guidelines in several countries and for LTCFs. International harmonisation on the assessment of the evidence for best practices is needed as well as more robust evidence to support targeted recommendations. PMID- 28028435 TI - Age or health status: which influences medical insurance enrollment greater? AB - BACKGROUND: The New Cooperative Medical Scheme (NCMS) for peasantries implemented in 2003 and the Urban Resident Basic Medical Insurance (URBMI) for the urban unemployed implemented in 2007 have many similarities. They both apply the financing mode of individual premiums plus government's subsidies, and the voluntary enrollment. The Chinese government plans to integrate these two systems and build a unified basic medical insurance system for the unemployed in order to achieve the medical equity and increase the general health level. Thus, to analyze the main influencing factors of the enrollment of the urban unemployed and rural residents is very important for improving the system and securing the stability of the system during the transition. METHODS: The study uses data from the China Health and Nutrition Survey (CHNS) and adopts logistic regression models to test which factors influence the enrollment of the URBMI and the NCMS under the background of rather high enrollment rate of Chinese basic medical insurances and strong fiscal support of the Chinese government, especially whether health status or age influences enrollment of these two insurances greater. RESULTS: There is indeed some adverse selection in the URBMI and the NCMS. Whether the individual has chronic diseases have significant influence on enrollments of both the urban unemployed and rural residents, while whether the individual got ill in last four weeks just influences enrollments of the urban unemployed. Age influences enrollment greater than health status. The older the insured are, the larger the enrollment rates are. CONCLUSION: Because of the active support for basic medical insurances of the Chinese government, the enrollment performance of the urban unemployed and rural residents has already changed. When implementing the new policy, the government should pay attention to the willingness to enroll in and the change of enrollment performance of the insured. Therefore, under the policy of voluntary enrollment, every coordinated province and city should enlarge the proportion of young people to insuring group, optimizing the age structure, and the financing proportion of governments and individuals should be measured properly. With the increasing of governments' subsidies, the proportion of individual's premiums should also be increased. PMID- 28028436 TI - Causes of death in children younger than five years in China in 2015: an updated analysis. AB - BACKGROUND: Substantial progress in reducing the child mortality rate has been made globally in the last two decades. However, for China, the number of children dying from preventable diseases is still very large. It is important to have regularly updated information on the distribution of causes of death (COD) in children to inform policy and research. In this study, we aim to estimate the COD spectrum in children younger than five years old from 2009 to 2015 with a focus on the year 2015 and to provide an updated COD prediction model for China. METHODS: Updated data of under-five mortality rates (U5MRs) and the number of live births at national and provincial levels were obtained from United Nation's Inter-agency Group for Child Mortality Estimation (UN IGME), Institute for Health Metrics and Evaluation (IHME), and United Nations Population Division (UNPD). Then, we conducted a systematic review across four Chinese and English bibliographic databases and identified high-quality community-based longitudinal studies of COD in children younger than five years in China. We developed a number of single-cause models to predict the number of child death for main COD in different age groups at both national and provincial levels. The jackknife procedure was applied to construct the 95% Uncertainty Ranges (URs). RESULTS: From 2009 to 2015, the under-five mortality rates have declined by 37.1%. The leading causes of death in 2015 were preterm birth complications (17.4%), birth asphyxia (15.2%), congenital abnormalities (14.1%), accidents (13.5%) and pneumonia (12.4%) for children under five years old. The COD spectrum varied substantially across Chinese provinces with different development levels. The leading cause in children under five years in the wealthier provinces (with lower U5MRs) was congenital abnormalities (up to 18.9%), while in the poorer provinces (with higher U5MRs), pneumonia was the dominant COD (up to 23.4%). CONCLUSIONS: This study updates and validates the accuracy of the findings of our previous COD study and proposes a new modelling method to predict proportions for the most common causes of child death in China. These updated COD estimates suggest that current strategies to reduce child mortality should prioritise action on neonatal deaths and target interventions against the top COD according to the local COD spectrum. Special attention should also be given to reducing differences between Chinese provinces and regions with differing development levels. PMID- 28028437 TI - Preventing delayed diagnosis of cancer: clinicians' views on main problems and solutions. AB - BACKGROUND: Delayed diagnosis is a major contributing factor to the UK's lower cancer survival compared to many European countries. In the UK, there is a significant national variation in early cancer diagnosis. Healthcare providers can offer an insight into local priorities for timely cancer diagnosis. In this study, we aimed to identify the main problems and solutions relating to delay cancer diagnosis according to cancer care clinicians. METHODS: We developed and implemented a new priority-setting approach called PRIORITIZE and invited North West London cancer care clinicians to identify and prioritize main causes for and solutions to delayed diagnosis of cancer care. RESULTS: Clinicians identified a number of concrete problems and solutions relating to delayed diagnosis of cancer. Raising public awareness, patient education as well as better access to specialist care and diagnostic testing were seen as the highest priorities. The identified suggestions focused mostly on the delays during referrals from primary to secondary care. CONCLUSIONS: Many identified priorities were feasible, affordable and converged around common themes such as public awareness, care continuity and length of consultation. As a timely, proactive and scalable priority-setting approach, PRIORITZE could be implemented as a routine preventative system for determining patient safety issues by frontline staff. PMID- 28028438 TI - hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma. AB - In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients. PMID- 28028439 TI - N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics. AB - N-Myc is a global transcription factor that regulates the expression of genes involved in a number of essential cellular processes including: ribosome biogenesis, cell cycle and apoptosis. Upon deregulation, N-Myc can drive pathologic expression of many of these genes, which ultimately defines its oncogenic potential. Overexpression of N-Myc has been demonstrated to contribute to tumorigenesis, most notably for the pediatric tumor, neuroblastoma. Herein, we provide evidence that deregulated N-Myc alters the expression of proteins involved in mitochondrial dynamics. We found that N-Myc overexpression leads to increased fusion of the mitochondrial reticulum secondary to changes in protein expression due to aberrant transcriptional and post-translational regulation. We believe the structural changes in the mitochondrial network in response to N-Myc amplification in neuroblastoma contributes to two important aspects of tumor development and maintenance-bioenergetic alterations and apoptotic resistance. Specifically, we found that N-Myc overexpressing cells are resistant to programmed cell death in response to exposure to low doses of cisplatin, and demonstrated that this was dependent on increased mitochondrial fusion. We speculate that these changes in mitochondrial structure and function may contribute significantly to the aggressive clinical ph9enotype of N-Myc amplified neuroblastoma. PMID- 28028440 TI - Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation or beta-amyloid. AB - Neuron death during development and in Alzheimer's disease (AD) is associated with aberrant regulation/induction of cell cycle proteins. However, the proximal events in this process are unknown. Cell cycle initiation requires dephosphorylation of cyclin-dependent kinases by cell division cycle 25A (Cdc25A). Here, we show that Cdc25A is essential for neuronal death in response to NGF deprivation or beta-amyloid (Abeta) treatment and describe the mechanisms by which it is regulated in these paradigms. Cdc25A mRNA, protein and Cdc25A phosphatase activity were induced by NGF deprivation and Abeta treatment. Enhanced Cdc25A expression was also observed in rat brains infused with Abeta and in Abeta-overexpressing AbetaPPswe-PS1dE9 mice. In cultured neurons Cdc25A inhibition by chemical inhibitors or shRNA prevented cell death and neurite degeneration caused by NGF deprivation or Abeta. Additionally, Cdc25A inhibition diminished distal signaling events including Cdk-dependent elevation of phospho pRb and subsequent caspase-3 activation. Mechanism studies revealed that Cdc25A induction by NGF deprivation and Abeta is mediated by activation of Forkhead transcription factors that in turn suppress miR-21, a negative regulator of Cdc25A. Our studies thus identify Cdc25A as a required upstream element of the apoptotic cell cycle pathway that is required for neuron death in response to trophic factor deprivation and to Abeta exposure and therefore as a potential target to suppress pathologic neuron death. PMID- 28028441 TI - Granzymes A and K differentially potentiate LPS-induced cytokine response. AB - Granzymes are serine proteases that, upon release from cytotoxic cells, induce apoptosis in tumor cells and virally infected cells. In addition, a role of granzymes in inflammation is emerging. Recently, we have demonstrated that extracellular granzyme K (GrK) potentiates lipopolysaccharide (LPS)-induced cytokine response from monocytes. GrK interacts with LPS, disaggregates LPS micelles, and stimulates LPS-CD14 binding and Toll-like receptor signaling. Here we show that human GrA also potentiates cytokine responses in human monocytes initiated by LPS or Gram-negative bacteria. Similar to GrK, this effect is independent of GrA catalytic activity. Unlike GrK, however, GrA does not bind to LPS, has little influence on LPS micelle disaggregation, and does not augment LPS CD14 complex formation. We conclude that GrA and GrK differentially modulate LPS Toll-like receptor signaling in monocytes, suggesting functional redundancy among cytotoxic lymphocyte proteases in the anti-bacterial innate immune response. PMID- 28028442 TI - Regulation of VDAC trafficking modulates cell death. AB - The voltage-dependent anion channel (VDAC) and mitochondria-associated hexokinase (HxK) have crucial roles in both cell survival and death. Both the individual abundances and their ratio seem to influence the balance of survival and death and are thus critical in scenarios, such as neurodegeneration and cancer. Elevated levels of both VDAC and HxK have been reported in cancerous cells. Physical interaction is surmised and specific residues or regions involved have been identified, but details of the interaction and the mechanism by which it modulates survival are yet to be elucidated. We and others have shown that heterologous expression of VDAC can induce cell death, which can be mitigated by concomitant overexpression of HxK. We have also observed that upon overexpression, fluorescently tagged VDAC is distributed between the cytosol and mitochondria. In this study, we show that cell death ensues only when the protein, which is synthesized on cytoplasmic ribosomes, migrates to the mitochondrion. Further, coexpression of rat HxK II (rHxKII) can delay the translocation of human VDAC1 (hVDAC1) protein to mitochondria and thereby inhibit VDAC-induced cell death. Variation in the level of HxK protein as seen endogenously in different cell lines, or as experimentally manipulated by silencing and overexpression, can lead to differential VDAC translocation kinetics and related cell death. The N-terminal region of HxK and the Glu73 residue of hVDAC1, which have previously been implicated in a physical interaction, are required for cytosolic retention of VDAC. Finally, we show that, in otherwise unperturbed cells in culture, there is a small but significant amount of soluble VDAC in the cytosol present in a complex with HxK. This complex could well determine how a cell is poised with respect to incoming thanatopic signals, thereby tilting the survival/death balance in pharmacologically interesting situations, such as neurodegeneration and cancer. PMID- 28028443 TI - Commentary on: Can the anxiety domain of EQ-5D and mental health items from SF-36 help predict outcomes after surgery for lumbar degenerative disorders? By Carreon et al. PMID- 28028444 TI - Commentary on the management of type II odontoid process fractures in octogenarians: Article by Graffeo et al. and Editorial by Falavigna (J Neurosurgery Spine August 19, 2016). AB - BACKGROUND: Establishing a clear treatment paradigm for octogenarians with type II odontoid fractures in hampered by a literature replete with level III articles. METHODS: In the study by Graffeo et al., the authors evaluated 111 patients over the age of 79 (average age: 87) with type II odontoid fractures undergoing nonoperative (94 patients) vs. operative intervention (17 total; 15 posterior and 2 anterior). They studied multiple variables and utilized several scales [abbreviated injury scale (AIS), injury severity score (ISS), and the Glasgow coma scale (GCS)] to determine the outcomes of nonoperative vs. operative management. RESULTS: Graffeo et al. concluded that there were no significant differences between nonoperative and operative management for type II odontoid fractures in octogenarians. They found similar frequencies of additional cervical fractures, mechanisms of injury, GCS of 8 or under, AIS/ISS scores, and disposition to "nonhome" facilities. Furthermore, both appeared to have increased mortality rates at 1-year post injury; 13% during hospitalization, 26% within the first post-injury month, and 41% at 1 year. CONCLUSIONS: In the editorial by Falavigna, his major criticism of Graffeo's article was the marked disparity in the number of patients in the operative (17 patients) vs. the nonoperative group (94 patients), making it difficult to accept any conclusions as "significant". He further noted that few prior studies provided level I evidence, and that most, like this one, were level III analyses that did not "significantly" advance our knowledge as to whether to treat octogenarians with type II odontoid fractures operatively vs. nonoperatively. PMID- 28028445 TI - Long standing lumbosacral dermoid tumor and intracranial fat droplet dissemination: A case report. AB - BACKGROUND: Dermoid tumors are slow growing, benign CNS lesions. CASE DESCRIPTION: This case study concerns a 29-year-old female with a 6-year history of lower extremity paresthesias attributed to magnetic resonance (MR)/computed tomography (CT) documented intradural dermoid tumor that extended from L1 to S1. On MR, it was hypointense on T1, hyperintense on T2, and did not enhance with gadolinium. CT showed hyperdensity at the L1-L2 levels. The craniocervical MR imaging showed small hyperintense foci in the cisternal space favoring "fat dissemination." L1-S2 laminectomy revealed an intradural lesion characterized by "a solid and firm component compatible with fat tissue adherent to the conus medullaris and a solid-soft component within the cauda equina;" there were also "multiple fragments of white-creamy soft tissue with hair." Following tumor resection, the brain CT scan demonstrated fat dissemination within the intraventricular and cisternal space. Histopathologic examination confirmed the diagnosis of a dermoid tumor. CONCLUSION: Dermoid tumors should be considered among the differential diagnosis of intradural lesions in young patients even without any other congenital abnormality. PMID- 28028446 TI - A purely extradural lumbar nerve root cavernoma mimicking acute myeloid leukemia recurrence: Case report and literature review. AB - BACKGROUND: Myeloid sarcoma (MS) is a malignant tumor that usually occurs concomitantly with or following acute myeloid leukemia (AML). Cavernomas are benign congenital malformations that are unusual in the spine and exceedingly rare in pure extradural locations. CASE DESCRIPTION: We report a 73-year-old female with a previous medical history of AML in remission for 3 years who presented with symptoms of low back pain and right lower extremity radiculopathy. A magnetic resonance scan showed an extradural, foraminal lesion centered at the L2 level involving the right L2 nerve root. In view of the history of AML, this lesion was potentially considered MS, a form of AML relapse. Surgery consisting of a right L1 and L2 hemilaminectomy facilitated gross total resection of the purely extradural lesion the proved histologically to be a cavernoma. CONCLUSION: In patients with a history of leukemia, MS must be considered in the differential diagnosis for any epidural or nerve root lesion that appears following treatment. Although rare, cavernomas must be considered among the differential diagnoses for epidural nerve root lesions in the setting of AML. PMID- 28028447 TI - Spinal epidural abscess in a patient with piriformis pyomyositis. AB - BACKGROUND: Spinal epidural abscess resulting from piriformis pyomyositis is extremely rare. Such condition can result in serious morbidity and mortality if not addressed in a timely manner. CASE DESCRIPTION: The authors describe the case of a 19-year-old male presenting with a 2-week history of fever, low back pain, and nuchal rigidity. When found to have radiographic evidence of a right piriformis pyomyositis, he was transferred to our institution for further evaluation. Because he demonstrated rapid deterioration, cervical, thoracic, and lumbar magnetic resonance imaging scans were emergently performed. They revealed an extensive posterior spinal epidural abscess causing symptomatic spinal cord compression extending from C2 to the sacrum. He underwent emergent decompression and abscess evacuation through a dorsal midline approach. Postoperatively, he markedly improved. Upon discharge, the patient regained 5/5 strength in both upper and lower extremities. Cultures from the epidural abscess grew methicillin sensitive Staphylococcus aureus warranting a 6-week course of intravenous nafcillin. CONCLUSION: A 19-year-old male presented with a holospinal epidural abscess (C2 to sacrum) originating from piriformis pyomyositis. The multilevel cord abscess was emergently decompressed, leading to a marked restoration of neurological function. PMID- 28028448 TI - A novel technique to repair a transverse sacral fracture in a previously fused lumbosacral spondylolisthesis. AB - BACKGROUND: Transverse fractures of the sacrum are rare, and surgical treatment for these fractures ranges from conservative to challenging. Transverse stress fractures of the sacrum after placement of lumbar-to-sacral instrumentation have been previously described. We report a new technique to repair a transverse Type 2 Roy-Camille fracture with spondylolisthesis of S1 over S2 in a previously fused instrumented high-grade L4-L5, L5-S1 spondylolisthesis. CASE DESCRIPTION: A 64 year-old female who previously had an L4-L5, L5-S1 fusion for spondylolisthesis presented with excruciating lower back pain and radiculopathy for over 6 months. She was found to have an S1-S2 transverse fracture caused by previous implantation of pedicle screws. She underwent repositioning of several failed right lumbar and sacral screws and then had bilateral S1-S2 screws placed directly across the fracture line. The patient had an unremarkable postoperative course. She discontinued most of her pain medications within 6 weeks postoperatively. In the months following surgery, she reported only minimal lower back pain and no radiculopathy with the last appointment 5 years postoperatively. CONCLUSIONS: We describe a novel technique to reduce an iatrogenic transverse type-2 Roy-Camille fracture at S1-S2 in a previously instrumented high-grade L4 L5, L5-S1 spondylolisthesis. The patient's fracture achieved adequate reduction and fusion with symptomatic relief. PMID- 28028449 TI - Intradural-extramedullary isolated compressive sarcoid lesion. AB - BACKGROUND: Sarcoid involvement of the central nervous system is a rare occurrence, with involvement in approximately 5-10% of all cases. Isolated spinal involvement is an even rarer encounter, only 0.3-1% of all cases. These lesions can form compressive nodules leading to myelopathy. In the presented case of cervical sarcoid, the patient required a decompressive procedure to address cord compression. CASE DESCRIPTION: This is the case of a 39-year-old male presenting with cervical myelopathy caused by a compressive sarcoid nodule who underwent a successful posterior decompressive procedure. The pathology demonstrated a non caseating granuloma, consistent with sarcoid. Postoperatively, the patient's myelopathic symptoms improved. CONCLUSIONS: Sarcoid is rarely associated with an isolated compressive cervical lesion. Although sarcoid management typically involves immune suppression, in cases of active cord compression surgical intervention is warranted. PMID- 28028450 TI - SYNTAX Score in Patients with High Computed Tomography Coronary Calcium Score. AB - OBJECTIVES: To study the conventional coronary angiogram ( CA) findings in patients with high coronary calcium on multidetector computed tomogram. MATERIALS AND METHODS: Fifty patients with coronary calcium high enough in its extent and location to interfere with the interpretation of a contrast-filled coronary artery for a significant lesion were studied with conventional CA. Framingham risk score (FRS), computed tomography (CT) coronary calcium score (CCS), and SYNTAX score (SS) from the CA were calculated by separate investigators who were blinded to other scores. Effectively, 250 coronary arteries (left main, left anterior descending, left circumflex, and right coronary artery and posterior descending artery in each subject) with calcium scores were studied for lesions on CA. RESULTS: Thirty-five subjects had high FRS, 10 had intermediate FRS, and 5 had low FRS. Eight subjects of 25 (32%) with CCS between 350 and 1000 had no significant coronary artery disease (CAD). Overall, the CCS and the SS had a strong agreement with each other (r = 0.68, P < 0.01) that persisted in those with very high scores >1000 (r = 0.55, P < 0.01, n = 30), but only a nonsignificant weak correlation with scores between 350 and 1000 (r = 0.1, P = 0.62, n = 20). Individual vessel calcium scores correlated strongly for the presence of any lesion (r = 0.52, P < 0.01) in the same artery but only weakly for a significant lesion (r = 0.29, P = 0.05). CONCLUSION: High CT CCS in this cohort of intermediate to high (Framingham score) risk patients correlated strongly with the subject's global burden of the CAD as derived by the SS, more so for subjects with very high scores. Similarly, CCS correlated strongly with the presence of any lesion but only weakly for a significant stenosis; also, about one-third of patients with CCS between 350 and 1000 may not have significant disease on conventional CA. PMID- 28028451 TI - Diagnostic and Clinical Management of Skull Fractures in Children. AB - OBJECTIVE: The indications of routine skull X-rays after mild head trauma are still in discussion, and the clinical management of a child with a skull fracture remains controversial. The aim of our retrospective study was to evaluate our diagnostic and clinical management of children with skull fractures following minor head trauma. METHODS: We worked up the medical history of all consecutive patients with a skull fracture treated in our hospital from January 2009 to October 2014 and investigated all skull X-rays in our hospital during this period. RESULTS: In 5217 skull radiographies, 66 skull fractures (1.3%) were detected. The mean age of all our patients was 5.9 years (median age: 4.0 years); the mean age of patients with a diagnosed skull fracture was 2.3 years (median age: 0.8 years). A total of 1658 children (32%) were <2 years old. A typical boggy swelling was present in 61% of all skull fractures. The majority of injuries were caused by falls (77%). Nine patients (14%) required a computed tomography (CT) scan during their hospital stay due to neurological symptoms, and four patients had a brain magnetic resonance imaging. Nine patients (14%) showed an intracranial hemorrhage (ICH; mean age: 7.3 years); one patient had a neurosurgery because of a depressed skull fracture. Nine patients (14%) were observed at our pediatric intensive care unit for a mean time of 2.9 days. The mean hospital stay was 4.2 days. CONCLUSIONS: Our findings support previous evidence against the routine use of skull X-rays for evaluation of children with minor head injury. The rate of diagnosed skull fractures in radiographs following minor head trauma is low, and additional CT scans are not indicated in asymptomatic patient with a linear skull fracture. All detected ICHs could be treated conservatively. Children under the age of 2 years have the highest risk of skull fractures after minor head trauma, but do not have a higher incidence of intracranial bleeding. Neuroobservation without initial CT scans is safe in infants and children following minor head trauma and CT scans should be reserved for patients with neurological symptoms. PMID- 28028452 TI - Burkholderia pseudomallei type III secreted protein BipC: role in actin modulation and translocation activities required for the bacterial intracellular lifecycle. AB - Melioidosis, an infection caused by the facultative intracellular pathogen Burkholderia pseudomallei, has been classified as an emerging disease with the number of patients steadily increasing at an alarming rate. B. pseudomalleipossess various virulence determinants that allow them to invade the host and evade the host immune response, such as the type III secretion systems (TTSS). The products of this specialized secretion system are particularly important for the B. pseudomallei infection. Lacking in one or more components of the TTSS demonstrated different degrees of defects in the intracellular lifecycle of B. pseudomallei. Further understanding the functional roles of proteins involved in B. pseudomallei TTSS will enable us to dissect the enigma of B. pseudomallei-host cell interaction. In this study, BipC (a translocator), which was previously reported to be involved in the pathogenesis of B. pseudomallei, was further characterized using the bioinformatics and molecular approaches. The bipCgene, coding for a putative invasive protein, was first PCR amplified from B. pseudomallei K96243 genomic DNA and cloned into an expression vector for overexpression in Escherichia coli. The soluble protein was subsequently purified and assayed for actin polymerization and depolymerization. BipC was verified to subvert the host actin dynamics as demonstrated by the capability to polymerize actin in vitro. Homology modeling was also attempted to predict the structure of BipC. Overall, our findings identified that the protein encoded by the bipC gene plays a role as an effector involved in the actin binding activity to facilitate internalization of B. pseudomalleiinto the host cells. PMID- 28028453 TI - Identification and characterization of Daldinia eschscholtzii isolated from skin scrapings, nails, and blood. AB - BACKGROUND: Daldinia eschscholtzii is a filamentous wood-inhabiting endophyte commonly found in woody plants. Here, we report the identification and characterization of nine D. eschscholtzii isolates from skin scrapings, nail clippings, and blood. METHODS: The nine isolates were identified based on colony morphology, light microscopy, and internal transcribed spacer (ITS)-based phylogeny. In vitro antifungal susceptibility of the fungal isolates was evaluated by the Etest to determine the minimum inhibitory concentration (MIC). RESULTS: The nine isolates examined were confirmed as D. eschscholtzii. They exhibited typical features of Daldinia sp. on Sabouraud Dextrose Agar, with white felty colonies and black-gray coloration on the reverse side. Septate hyphae, branching conidiophore with conidiogenous cells budding from its terminus, and nodulisporium-like conidiophores were observed under the microscope. Phylogenetic analysis revealed that the nine isolates were clustered within the D. eschscholtzii species complex. All the isolates exhibited low MICs against azole agents (voriconazole, posaconazole, itraconazole, and ketoconazole), as well as amphotericin B, with MIC of less than 1 ug/ml. DISCUSSION: Early and definitive identification of D. eschscholtzii is vital to reducing misuse of antimicrobial agents. Detailed morphological and molecular characterization as well as antifungal profiling of D. eschscholtzii provide the basis for future studies on its biology, pathogenicity, and medicinal potential. PMID- 28028454 TI - Simplified large African carnivore density estimators from track indices. AB - BACKGROUND: The range, population size and trend of large carnivores are important parameters to assess their status globally and to plan conservation strategies. One can use linear models to assess population size and trends of large carnivores from track-based surveys on suitable substrates. The conventional approach of a linear model with intercept may not intercept at zero, but may fit the data better than linear model through the origin. We assess whether a linear regression through the origin is more appropriate than a linear regression with intercept to model large African carnivore densities and track indices. METHODS: We did simple linear regression with intercept analysis and simple linear regression through the origin and used the confidence interval for beta in the linear model y = alphax + beta, Standard Error of Estimate, Mean Squares Residual and Akaike Information Criteria to evaluate the models. RESULTS: The Lion on Clay and Low Density on Sand models with intercept were not significant (P > 0.05). The other four models with intercept and the six models thorough origin were all significant (P < 0.05). The models using linear regression with intercept all included zero in the confidence interval for beta and the null hypothesis that beta = 0 could not be rejected. All models showed that the linear model through the origin provided a better fit than the linear model with intercept, as indicated by the Standard Error of Estimate and Mean Square Residuals. Akaike Information Criteria showed that linear models through the origin were better and that none of the linear models with intercept had substantial support. DISCUSSION: Our results showed that linear regression through the origin is justified over the more typical linear regression with intercept for all models we tested. A general model can be used to estimate large carnivore densities from track densities across species and study areas. The formula observed track density = 3.26 * carnivore density can be used to estimate densities of large African carnivores using track counts on sandy substrates in areas where carnivore densities are 0.27 carnivores/100 km2 or higher. To improve the current models, we need independent data to validate the models and data to test for non-linear relationship between track indices and true density at low densities. PMID- 28028455 TI - Whole-genome single-nucleotide polymorphism (SNP) marker discovery and association analysis with the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content in Larimichthys crocea. AB - Whole-genome single-nucleotide polymorphism (SNP) markers are valuable genetic resources for the association and conservation studies. Genome-wide SNP development in many teleost species are still challenging because of the genome complexity and the cost of re-sequencing. Genotyping-By-Sequencing (GBS) provided an efficient reduced representative method to squeeze cost for SNP detection; however, most of recent GBS applications were reported on plant organisms. In this work, we used an EcoRI-NlaIII based GBS protocol to teleost large yellow croaker, an important commercial fish in China and East-Asia, and reported the first whole-genome SNP development for the species. 69,845 high quality SNP markers that evenly distributed along genome were detected in at least 80% of 500 individuals. Nearly 95% randomly selected genotypes were successfully validated by Sequenom MassARRAY assay. The association studies with the muscle eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content discovered 39 significant SNP markers, contributing as high up to ~63% genetic variance that explained by all markers. Functional genes that involved in fat digestion and absorption pathway were identified, such as APOB, CRAT and OSBPL10. Notably, PPT2 Gene, previously identified in the association study of the plasma n-3 and n-6 polyunsaturated fatty acid level in human, was re-discovered in large yellow croaker. Our study verified that EcoRI-NlaIII based GBS could produce quality SNP markers in a cost-efficient manner in teleost genome. The developed SNP markers and the EPA and DHA associated SNP loci provided invaluable resources for the population structure, conservation genetics and genomic selection of large yellow croaker and other fish organisms. PMID- 28028457 TI - Metal to phosphorus stoichiometries for freshwater phytoplankton in three remote lakes. AB - Simultaneous measurements of changes in phytoplankton biomass and the metal and phosphorus (P) content of cells have been captured to attest to metal to P stoichiometries for freshwater phytoplankton. Three Scottish lakes that had received high, medium or low metal contamination from the atmosphere were selected for study. Phytoplankton cells were collected and Inductively Coupled Plasma-Mass Spectrometry was used to measure their lead (Pb), cadmium (Cd), mercury (Hg), copper (Cu), zinc (Zn), nickel (Ni), chromium (Cr), manganese (Mn), cobalt (Co) and P content. Increased phytoplankton growth in the lakes resulted in significant algae growth dilution of the mass-specific Pb, Cd, Hg, Cu, Ni and Cr in the phytoplankton. Changes in the phytoplankton cell count and their Hg, Pb, Cd, Cu, Mn, Co, Ni and Cr concentrations showed the process of algae bloom dilution to be subject to exponential decay, which accelerated in the order of Mn < Cu < Ni < Pb and Cd < Cr and Hg < Co. This indicated a metabolic and detoxification mechanism was involved in the active selection of metals. For the first time simultaneous measurements of metals and P stoichiometry in freshwater phytoplankton are reported. The mean metal to P stoichiometry generated was (C106P1N16)1000Pb0.019Hg0.00004Cu0.013Cd0.005Cr0.2Co0.0008Mn0.2Ni0.012 based on field measurements and the Redfield average C, N and P stoichiometry of (CH2O)106(NH3)16H3PO4. PMID- 28028456 TI - Seqenv: linking sequences to environments through text mining. AB - Understanding the distribution of taxa and associated traits across different environments is one of the central questions in microbial ecology. High throughput sequencing (HTS) studies are presently generating huge volumes of data to address this biogeographical topic. However, these studies are often focused on specific environment types or processes leading to the production of individual, unconnected datasets. The large amounts of legacy sequence data with associated metadata that exist can be harnessed to better place the genetic information found in these surveys into a wider environmental context. Here we introduce a software program, seqenv, to carry out precisely such a task. It automatically performs similarity searches of short sequences against the "nt" nucleotide database provided by NCBI and, out of every hit, extracts-if it is available-the textual metadata field. After collecting all the isolation sources from all the search results, we run a text mining algorithm to identify and parse words that are associated with the Environmental Ontology (EnvO) controlled vocabulary. This, in turn, enables us to determine both in which environments individual sequences or taxa have previously been observed and, by weighted summation of those results, to summarize complete samples. We present two demonstrative applications of seqenv to a survey of ammonia oxidizing archaea as well as to a plankton paleome dataset from the Black Sea. These demonstrate the ability of the tool to reveal novel patterns in HTS and its utility in the fields of environmental source tracking, paleontology, and studies of microbial biogeography. To install seqenv, go to: https://github.com/xapple/seqenv. PMID- 28028458 TI - Risk of lung cancer in patients with gastro-esophageal reflux disease: a population-based cohort study. AB - This large-scale, controlled cohort study estimated the risks of lung cancer in patients with gastro-esophageal reflux disease (GERD) in Taiwan. We conducted this population-based study using data from the National Health Insurance Research Database of Taiwan during the period from 1997 to 2010. Patients with GERD were diagnosed using endoscopy, and controls were matched to patients with GERD at a ratio of 1:4. We identified 15,412 patients with GERD and 60,957 controls. Compared with the controls, the patients with GERD had higher rates of osteoporosis, diabetes mellitus, asthma, chronic obstructive pulmonary disease, pneumonia, bronchiectasis, depression, anxiety, hypertension, dyslipidemia, chronic liver disease, congestive heart failure, atrial fibrillation, stroke, chronic kidney disease, and coronary artery disease (all P < .05). A total of 85 patients had lung cancer among patients with GERD during the follow-up of 42,555 person-years, and the rate of lung cancer was 0.0020 per person-year. By contrast, 232 patients had lung cancer among patients without GERD during the follow-up of 175,319 person-years, and the rate of lung cancer was 0.0013 per person-year. By using stepwise Cox regression model, the overall incidence of lung cancer remained significantly higher in the patients with GERD than in the controls (hazard ratio, 1.53; 95% CI [1.19-1.98]). The cumulative incidence of lung cancer was higher in the patients with GERD than in the controls (P = .0012). In conclusion, our large population-based cohort study provides evidence that GERD may increase the risk of lung cancer in Asians. PMID- 28028459 TI - Deciphering the preservation of fossil insects: a case study from the Crato Member, Early Cretaceous of Brazil. AB - Exceptionally well-preserved three-dimensional insects with fine details and even labile tissues are ubiquitous in the Crato Member Konservat Lagerstatte (northeastern Brazil). Here we investigate the preservational pathways which yielded such specimens. We employed high resolution techniques (EDXRF, SR-SXS, SEM, EDS, micro Raman, and PIXE) to understand their fossilisation on mineralogical and geochemical grounds. Pseudomorphs of framboidal pyrite, the dominant fossil microfabric, display size variation when comparing cuticle with inner areas or soft tissues, which we interpret as the result of the balance between ion diffusion rates and nucleation rates of pyrite through the originally decaying carcasses. Furthermore, the mineral fabrics are associated with structures that can be the remains of extracellular polymeric substances (EPS). Geochemical data also point to a concentration of Fe, Zn, and Cu in the fossils in comparison to the embedding rock. Therefore, we consider that biofilms of sulphate reducing bacteria (SRB) had a central role in insect decay and mineralisation. Therefore, we shed light on exceptional preservation of fossils by pyritisation in a Cretaceous limestone lacustrine palaeoenvironment. PMID- 28028460 TI - Life history and past demography maintain genetic structure, outcrossing rate, contemporary pollen gene flow of an understory herb in a highly fragmented rainforest. AB - INTRODUCTION: Theory predicts that habitat fragmentation, by reducing population size and increasing isolation among remnant populations, can alter their genetic diversity and structure. A cascade of effects is expected: genetic drift and inbreeding after a population bottleneck, changes in biotic interactions that may affect, as in the case of plants, pollen dynamics, mating system, reproductive success. The detection of the effects of contemporary habitat fragmentation on the genetic structure of populations are conditioned by the magnitude of change, given the few number of generations since the onset of fragmentation, especially for long-lived organisms. However, the present-day genetic structure of populations may bear the signature of past demography events. Here, we examine the effects of rainforest fragmentation on the genetic diversity, population structure, mating system (outcrossing rate), indirect gene flow and contemporary pollen dynamics in the understory herb Aphelandra aurantiaca. Also, we assessed its present-day genetic structure under different past demographic scenarios. METHODS: Twelve populations of A. aurantiaca were sampled in large (4), medium (3), and small (5) forest fragments in the lowland tropical rainforest at Los Tuxtlas region. Variation at 11 microsatellite loci was assessed in 28-30 reproductive plants per population. In two medium- and two large-size fragments we estimated the density of reproductive plants, and the mating system by analyzing the progeny of different mother plants per population. RESULTS: Despite prevailing habitat fragmentation, populations of A. aurantiaca possess high genetic variation (He = 0.61), weak genetic structure (Rst = 0.037), and slight inbreeding in small fragments. Effective population sizes (Ne ) were large, but slightly lower in small fragments. Migrants derive mostly from large and medium size fragments. Gene dispersal is highly restricted but long distance gene dispersal events were detected. Aphelandra aurantiaca shows a mixed mating system (tm = 0.81) and the outcrossing rate have not been affected by habitat fragmentation. A strong pollen pool structure was detected due to few effective pollen donors (Nep ) and low distance pollen movement, pointing that most plants received pollen from close neighbors. Past demographic fluctuations may have affected the present population genetic structure as Bayesian coalescent analysis revealed the signature of past population expansion, possibly during warmer conditions after the last glacial maximum. DISCUSSION: Habitat fragmentation has not increased genetic differentiation or reduced genetic diversity of A. aurantiaca despite dozens of generations since the onset of fragmentation in the region of Los Tuxtlas. Instead, past population expansion is compatible with the lack of observed genetic structure. The predicted negative effects of rainforest fragmentation on genetic diversity and population structure of A. aurantiaca seem to have been buffered owing to its large effective populations and long-distance dispersal events. In particular, its mixed-mating system, mostly of outcrossing, suggests high efficiency of pollinators promoting connectivity and reducing inbreeding. However, some results point that the effects of fragmentation are underway, as two small fragments showed higher membership probabilities to their population of origin, suggesting genetic isolation. Our findings underscore the importance of fragment size to maintain genetic connectivity across the landscape. PMID- 28028461 TI - An integrative systematic revision and biogeography of Rhynchocalamus snakes (Reptilia, Colubridae) with a description of a new species from Israel. AB - BACKGROUND: The colubrid snakes of the genus Rhynchocalamus are seldom studied and knowledge of their ecology and life history is scarce. Three species of Rhynchocalamus are currently recognized, R. satunini (from Turkey eastwards to Iran), R. arabicus (Yemen and Oman), and R. melanocephalus (from the Sinai Peninsula northwards to Turkey). All are slender, secretive, mainly nocturnal and rare fossorial snakes. This comprehensive study is the first to sample all known Rhynchocalamus species in order to review the intra-generic phylogenetic relationships and historical biogeography of the genus. METHODS: We revised the systematics of Rhynchocalamus using an integrative approach and evaluated its phylogeography. The phylogenetic position within the Colubridae and the phylogenetic relationships within the genus were inferred using 29 individuals belonging to the three known species, with additional sampling of two other closely-related genera, Muhtarophis and Lytorhynchus. We analysed three mitochondrial (12S, 16S, cytb) and one nuclear (c-mos) gene fragments. Phylogenetic trees were reconstructed using maximum likelihood and Bayesian inference methods; the latter method also used to provide the first time calibrated molecular phylogeny of the genus. We generated a nuclear network and carried out a topology test and species delimitation analysis. Morphological comparisons were used to differentiate among species and to describe a new species from Israel. The studied material was comprised of 108 alcohol-preserved specimens, 15 photographs, and data from the literature for the examination of 17 mensural, 14 meristic, and two categorical characters. RESULTS: The molecular results support Rhynchocalamus as monophyletic, and as having split from its sister genus Lytorhynchus during the Late Oligocene. The three recognized species of Rhynchocalamus comprise four independently evolving groups. The molecular results reveal that the genus began to diverge during the Middle Miocene. We revealed that the best-studied species, R. melanocephalus, is paraphyletic. A population, formally ascribed to this species, from the Negev Mountain area in southern Israel is phylogenetically closer to R. arabicus from Oman than to the northern populations of the species from Israel, Syria and Turkey. Herein we describe this population as a new species: Rhynchocalamus dayanaesp. nov. DISCUSSION: We identify four species within Rhynchocalamus: R. satunini, R. arabicus, R. melanocephalus, and R. dayanaesp. nov., the latter, to the best of our knowledge, is endemic to southern Israel. The onset of Rhynchocalamus diversification is very old and estimated to have occurred during the Middle Miocene, possibly originating in the Levant region. Radiation probably resulted from vicariance and dispersal events caused by continuous geological instability, sea-level fluctuations and climatic changes within the Levant region. PMID- 28028463 TI - A review and meta-analysis of the enemy release hypothesis in plant-herbivorous insect systems. AB - A suggested mechanism for the success of introduced non-native species is the enemy release hypothesis (ERH). Many studies have tested the predictions of the ERH using the community approach (native and non-native species studied in the same habitat) or the biogeographical approach (species studied in their native and non-native range), but results are highly variable, possibly due to large variety of study systems incorporated. We therefore focused on one specific system: plants and their herbivorous insects. We performed a systematic review and compiled a large number (68) of datasets from studies comparing herbivorous insects on native and non-native plants using the community or biogeographical approach. We performed a meta-analysis to test the predictions from the ERH for insect diversity (number of species), insect load (number of individuals) and level of herbivory for both the community and biogeographical approach. For both the community and biogeographical approach insect diversity was significantly higher on native than on non-native plants. Insect load tended to be higher on native than non-native plants at the community approach only. Herbivory was not different between native and non-native plants at the community approach, while there was too little data available for testing the biogeographical approach. Our meta-analysis generally supports the predictions from the ERH for both the community and biogeographical approach, but also shows that the outcome is importantly determined by the response measured and approach applied. So far, very few studies apply both approaches simultaneously in a reciprocal manner while this is arguably the best way for testing the ERH. PMID- 28028462 TI - Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF) and blood reveals new candidate genes for multiple sclerosis. AB - BACKGROUND: The involvement of multiple genes and missing heritability, which are dominant in complex diseases such as multiple sclerosis (MS), entail using network biology to better elucidate their molecular basis and genetic factors. We therefore aimed to integrate interactome (protein-protein interaction (PPI)) and transcriptomes data to construct and analyze PPI networks for MS disease. METHODS: Gene expression profiles in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) samples from MS patients, sampled in relapse or remission and controls, were analyzed. Differentially expressed genes which determined only in CSF (MS vs. control) and PBMCs (relapse vs. remission) separately integrated with PPI data to construct the Query-Query PPI (QQPPI) networks. The networks were further analyzed to investigate more central genes, functional modules and complexes involved in MS progression. RESULTS: The networks were analyzed and high centrality genes were identified. Exploration of functional modules and complexes showed that the majority of high centrality genes incorporated in biological pathways driving MS pathogenesis. Proteasome and spliceosome were also noticeable in enriched pathways in PBMCs (relapse vs. remission) which were identified by both modularity and clique analyses. Finally, STK4, RB1, CDKN1A, CDK1, RAC1, EZH2, SDCBP genes in CSF (MS vs. control) and CDC37, MAP3K3, MYC genes in PBMCs (relapse vs. remission) were identified as potential candidate genes for MS, which were the more central genes involved in biological pathways. DISCUSSION: This study showed that network-based analysis could explicate the complex interplay between biological processes underlying MS. Furthermore, an experimental validation of candidate genes can lead to identification of potential therapeutic targets. PMID- 28028464 TI - Hairiness: the missing link between pollinators and pollination. AB - BACKGROUND: Functional traits are the primary biotic component driving organism influence on ecosystem functions; in consequence, traits are widely used in ecological research. However, most animal trait-based studies use easy-to-measure characteristics of species that are at best only weakly associated with functions. Animal-mediated pollination is a key ecosystem function and is likely to be influenced by pollinator traits, but to date no one has identified functional traits that are simple to measure and have good predictive power. METHODS: Here, we show that a simple, easy to measure trait (hairiness) can predict pollinator effectiveness with high accuracy. We used a novel image analysis method to calculate entropy values for insect body surfaces as a measure of hairiness. We evaluated the power of our method for predicting pollinator effectiveness by regressing pollinator hairiness (entropy) against single visit pollen deposition (SVD) and pollen loads on insects. We used linear models and AICC model selection to determine which body regions were the best predictors of SVD and pollen load. RESULTS: We found that hairiness can be used as a robust proxy of SVD. The best models for predicting SVD for the flower species Brassica rapa and Actinidia deliciosa were hairiness on the face and thorax as predictors (R2 = 0.98 and 0.91 respectively). The best model for predicting pollen load for B. rapa was hairiness on the face (R2 = 0.81). DISCUSSION: We suggest that the match between pollinator body region hairiness and plant reproductive structure morphology is a powerful predictor of pollinator effectiveness. We show that pollinator hairiness is strongly linked to pollination-an important ecosystem function, and provide a rigorous and time-efficient method for measuring hairiness. Identifying and accurately measuring key traits that drive ecosystem processes is critical as global change increasingly alters ecological communities, and subsequently, ecosystem functions worldwide. PMID- 28028465 TI - The effect of cognitive training on the subjective perception of well-being in older adults. AB - BACKGROUND: There is a growing number of studies indicating the major consequences of the subjective perception of well-being on mental health and healthcare use. However, most of the cognitive training research focuses more on the preservation of cognitive function than on the implications of the state of well-being. This secondary analysis of data from a randomised controlled trial investigated the effects of individualised television-based cognitive training on self-rated well-being using the WHO-5 index while considering gender and education as influencing factors. The effects of cognitive training were compared with leisure activities that the elderly could be engaged in to pass time. METHODS: Cognitively healthy participants aged 60 years or above screened using the Mini-Mental State Examination (MMSE) and Major Depression Inventory (MDI) were randomly allocated to a cognitive training group or to an active control group in a single-blind controlled two-group design and underwent 24 training sessions. Data acquired from the WHO-5 questionnaire administered before and after intervention were statistically analysed using a mixed design model for repeated measures. The effect of individualised cognitive training was compared with leisure activities while the impact of gender and education was explored using estimated marginal means. RESULTS: A total of 81 participants aged 67.9 +/- 5.59 [60-84] without cognitive impairments and absent of depression symptoms underwent the study. Participants with leisure time activities declared significantly higher scores compared to participants with cognitive training M = 73.48 +/- 2.88, 95% CI [67.74-79.22] vs M = 64.13 +/- 3.034, 95% CI [58.09-70.17] WHO-5 score. Gender and education were found to moderate the effect of cognitive training on well-being when compared to leisure activities. Females engaged in leisure activities in the control group reported higher by M = 9.77 +/- 5.4, 95% CI [-0.99-20.54] WHO-5 scores than females with the cognitive training regimen. Participants with high school education declared leisure activities to increase WHO-5 scores by M = 14.59 +/- 5.39, 95% CI [3.85-25.34] compared to individualised cognitive training. DISCUSSION: The findings revealed that individualised cognitive training was not directly associated with improvements in well-being. Changes in the control group indicated that involvement in leisure time activities, in which participants were partly free to choose from, represented more favourable stimulation to a self-perceived sense of well-being than individualised cognitive training. Results also supported the fact that gender and education moderated the effect of cognitive training on well-being. Females and participants with high school education were found to be negatively impacted in well-being when performance connected with cognitive training was expected. PMID- 28028466 TI - Consumption of antimicrobial manuka honey does not significantly perturb the microbiota in the hind gut of mice. AB - The aim of this study was to test the hypothesis that consuming manuka honey, which contains antimicrobial methylglyoxal, may affect the gut microbiota. We undertook a mouse feeding study to investigate whether dietary manuka honey supplementation altered microbial numbers and their production of organic acid products from carbohydrate fermentation, which are markers of gut microbiota function. The caecum of C57BL/6 mice fed a diet supplemented with antimicrobial UMF(r) 20+ manuka honey at 2.2 g/kg animal did not show any significantly changed concentrations of microbial short chain fatty acids as measured by gas chromatography, except for increased formate and lowered succinate organic acid concentrations, compared to mice fed a control diet. There was no change in succinate-producing Bacteroidetes numbers, or honey-utilising Bifidobacteria, nor any other microbes measured by real time quantitative PCR. These results suggest that, despite the antimicrobial activity of the original honey, consumption of manuka honey only mildly affects substrate metabolism by the gut microbiota. PMID- 28028467 TI - Identifying stably expressed genes from multiple RNA-Seq data sets. AB - We examined RNA-Seq data on 211 biological samples from 24 different Arabidopsis experiments carried out by different labs. We grouped the samples according to tissue types, and in each of the groups, we identified genes that are stably expressed across biological samples, treatment conditions, and experiments. We fit a Poisson log-linear mixed-effect model to the read counts for each gene and decomposed the total variance into between-sample, between-treatment and between experiment variance components. Identifying stably expressed genes is useful for count normalization and differential expression analysis. The variance component analysis that we explore here is a first step towards understanding the sources and nature of the RNA-Seq count variation. When using a numerical measure to identify stably expressed genes, the outcome depends on multiple factors: the background sample set and the reference gene set used for count normalization, the technology used for measuring gene expression, and the specific numerical stability measure used. Since differential expression (DE) is measured by relative frequencies, we argue that DE is a relative concept. We advocate using an explicit reference gene set for count normalization to improve interpretability of DE results, and recommend using a common reference gene set when analyzing multiple RNA-Seq experiments to avoid potential inconsistent conclusions. PMID- 28028468 TI - The tuberculocidal activity of polyaniline and functionalised polyanilines. AB - Tuberculosis is considered a leading cause of death worldwide. More than 95% of cases and deaths occur in low- and middle-income countries. In resource-limited countries, hospitals often lack adequate facilities to manage and isolate patients with infectious tuberculosis (TB), relying instead on personal protective equipment, such as facemasks, to reduce nosocomial transmission of the disease. Facemasks impregnated with an antimicrobial agent may be a cost effective way of adding an extra level of protection against the spread of TB by reducing the risk of disease transmission. Conducting polymers, such as polyaniline (PANI), and their functionalised derivatives are a novel class of antimicrobial agents with potential as non-leaching additives to provide contamination resistant surfaces. We have investigated the antimicrobial action of PANI and a functionalised derivative, poly-3-aminobenzoic acid (P3ABA), against mycobacteria and have determined the optimal treatment time and concentration to achieve significant knockdown of Mycobacterium smegmatis and Mycobacterium tuberculosis on an agar surface. Results indicated that P3ABA is a potential candidate for use as an anti-tuberculoid agent in facemasks to reduce TB transmission. PMID- 28028469 TI - Comparison between Mother, ActiGraph wGT3X-BT, and a hand tally for measuring steps at various walking speeds under controlled conditions. AB - INTRODUCTION: Walking is endorsed as health enhancing and is the most common type of physical activity among older adults. Accelerometers are superior to self reports when measuring steps, however, if they are to be used by clinicians the validity is of great importance. The aim of this study was to investigate the criterion validity of Mother and ActiGraph wGT3X-BT in measuring steps by comparing the devices to a hand tally under controlled conditions in healthy participants. METHODS: Thirty healthy participants were fitted with a belt containing the sensor of Mother (Motion Cookie) and ActiGraph. Participants walked on a treadmill for two minutes at each of the following speeds; 3.2, 4.8, and 6.4 km/h. The treadmill walking was video recorded and actual steps were subsequently determined by using a hand tally. Wilcoxon's signed ranks test was used to determine whether Mother and ActiGraph measured an identical number of steps compared to the hand tally. Intraclass correlation coefficients were calculated to determine the relationship and Root Mean Square error was calculated to investigate the average error between the devices and the hand tally. Percent differences (PD) were calculated for between-instrument agreement (Mother vs. the hand tally and ActiGraph vs. the hand tally) and PDs below 3% were interpreted as acceptable and clinically irrelevant. RESULTS: Mother and ActiGraph under-counted steps significantly compared to the hand tally at all walking speeds (p < 0.001). Mother had a median of total differences of 9.5 steps (IQR = 10) and ActiGraph 59 steps (IQR = 77). Mother had smaller PDs at all speeds especially at 3.2 km/h (2.5% compared to 26.7%). Mother showed excellent ICC values >=0.88 (0.51-0.96) at all speeds whilst ActiGraph had poor and fair to good ICC values ranging from 0.03 (-0.09-0.21) at a speed of 3.2 km/h to 0.64 (0.16-0.84) at a speed of 6.4 km/h. CONCLUSION: Mother provides valid measures of steps at walking speeds of 3.2, 4.8, and 6.4 km/h with clinically irrelevant deviations compared to a hand tally while ActiGraph only provides valid measurements at 6.4 km/h based on the 3% criterion. These results have significant potential for valid objective measurements of low walking speeds. However, further research should investigate the validity of Mother in patients at even slower walking speeds and in free-living conditions. PMID- 28028470 TI - Molecular phylogenetics, seed morphometrics, chromosome number evolution and systematics of European Elatine L. (Elatinaceae) species. AB - The genus Elatine contains ca 25 species, all of which are small, herbaceous annuals distributed in ephemeral waters on both hemispheres. However, due to a high degree of morphological variability (as a consequence of their amphibious life-style), the taxonomy of this genus remains controversial. Thus, to fill this gap in knowledge, we present a detailed molecular phylogenetic study of this genus based on nuclear (rITS) and plastid (accD-psaI, psbJ-petA, ycf6-psbM-trnD) sequences using 27 samples from 13 species. On the basis of this phylogenetic analysis, we provide a solid phylogenetic background for the modern taxonomy of the European members of the genus. Traditionally accepted sections of this tree (i.e., Crypta and Elatinella) were found to be monophyletic; only E. borchoni found to be a basal member of the genus-has to be excluded from the latter lineage to achieve monophyly. A number of taxonomic conclusions can also be drawn: E. hexandra, a high-ploid species, is most likely a stabilised hybrid between the main sections; E. campylosperma merits full species status based on both molecular and morphological evidence; E. gussonei is a more widespread and genetically diverse species with two main lineages; and the presence of the Asian E. ambigua in the European flora is questionable. The main lineages recovered in this analysis are also supported by a number of synapomorphic morphological characters as well as uniform chromosome counts. Based on all the evidence presented here, two new subsections within Elatinella are described: subsection Hydropipera consisting of the temperate species of the section, and subsection Macropodae including the Mediterranean species of the section. PMID- 28028471 TI - Refining the reaction mechanism of O2 towards its co-substrate in cofactor-free dioxygenases. AB - Cofactor-less oxygenases perform challenging catalytic reactions between singlet co-substrates and triplet oxygen, in spite of apparently violating the spin conservation rule. In 1-H-3-hydroxy-4-oxoquinaldine-2,4-dioxygenase, the active site has been suggested by quantum chemical computations to fine tune triplet oxygen reactivity, allowing it to interact rapidly with its singlet substrate without the need for spin inversion, and in urate oxidase the reaction is thought to proceed through electron transfer from the deprotonated substrate to an aminoacid sidechain, which then feeds the electron to the oxygen molecule. In this work, we perform additional quantum chemical computations on these two systems to elucidate several intriguing features unaddressed by previous workers. These computations establish that in both enzymes the reaction proceeds through direct electron transfer from co-substrate to O2 followed by radical recombination, instead of minimum-energy crossing points between singlet and triplet potential energy surfaces without formal electron transfer. The active site does not affect the reactivity of oxygen directly but is crucial for the generation of the deprotonated form of the co-substrates, which have redox potentials far below those of their protonated forms and therefore may transfer electrons to oxygen without sizeable thermodynamic barriers. This mechanism seems to be shared by most cofactor-less oxidases studied so far. PMID- 28028472 TI - Candidate pathogenicity islands in the genome of 'Candidatus Rickettsiella isopodorum', an intracellular bacterium infecting terrestrial isopod crustaceans. AB - The bacterial genus Rickettsiellabelongs to the order Legionellales in the Gammaproteobacteria, and consists of several described species and pathotypes, most of which are considered to be intracellular pathogens infecting arthropods. Two members of this genus, R. grylliand R. isopodorum, are known to infect terrestrial isopod crustaceans. In this study, we assembled a draft genomic sequence for R. isopodorum, and performed a comparative genomic analysis with R. grylli. We found evidence for several candidate genomic island regions in R. isopodorum, none of which appear in the previously available R. grylli genome sequence.Furthermore, one of these genomic island candidates in R. isopodorum contained a gene that encodes a cytotoxin partially homologous to those found in Photorhabdus luminescensand Xenorhabdus nematophilus (Enterobacteriaceae), suggesting that horizontal gene transfer may have played a role in the evolution of pathogenicity in Rickettsiella. These results lay the groundwork for future studies on the mechanisms underlying pathogenesis in R. isopodorum, and this system may provide a good model for studying the evolution of host-microbe interactions in nature. PMID- 28028473 TI - Spatio-temporal monitoring of deep-sea communities using metabarcoding of sediment DNA and RNA. AB - We assessed spatio-temporal patterns of diversity in deep-sea sediment communities using metabarcoding. We chose a recently developed eukaryotic marker based on the v7 region of the 18S rRNA gene. Our study was performed in a submarine canyon and its adjacent slope in the Northwestern Mediterranean Sea, sampled along a depth gradient at two different seasons. We found a total of 5,569 molecular operational taxonomic units (MOTUs), dominated by Metazoa, Alveolata and Rhizaria. Among metazoans, Nematoda, Arthropoda and Annelida were the most diverse. We found a marked heterogeneity at all scales, with important differences between layers of sediment and significant changes in community composition with zone (canyon vs slope), depth, and season. We compared the information obtained from metabarcoding DNA and RNA and found more total MOTUs and more MOTUs per sample with DNA (ca. 20% and 40% increase, respectively). Both datasets showed overall similar spatial trends, but most groups had higher MOTU richness with the DNA template, while others, such as nematodes, were more diverse in the RNA dataset. We provide metabarcoding protocols and guidelines for biomonitoring of these key communities in order to generate information applicable to management efforts. PMID- 28028474 TI - Cretaceous origin of dogwoods: an anatomically preserved Cornus (Cornaceae) fruit from the Campanian of Vancouver Island. AB - BACKGROUND: Cornaceae consists of 58 species, all within the genus Cornus. The Cenozoic record of Cornus is extensive and well documented. Molecular divergence time studies suggest that crown-group Cornus may have originated by the Late Cretaceous. However, there has been no formal report of Cornus from Cretaceous deposits. Here, we characterize a permineralized fossil fruit assignable to Cornus subg. Cornus from the Upper Cretaceous (Campanian) Shelter Point locality of Vancouver Island, British Columbia, Canada. METHODS: Serial sections of the specimen were made using the cellulose acetate peel technique. Peels were mounted onto microscope slides and studied by light microscopy. RESULTS: The fossil fruit consists of a tri-locular woody endocarp with dorsal germination valves. The locules are sub-triangular to ellipsoidal in transverse section and are separated by thin septa. Endocarp tissue consists of elongated and isodiametric sclereids and secretory cavities. Internal vascular tissue was not observed, but is interpreted to have been located along the outer periphery of the septa for some length, common in many cornalean taxa. There is one seed in each locule, one of which was found to have endosperm and a dicotyledonous embryo. DISCUSSION: Woody endocarps with germination valves, without central vascular bundles, and with one seed per locule are characteristic of several families within the order Cornales. The interpreted vascular pattern and presence of secretory cavities indicates that the fossil fruit is assignable to Cornus subg. Cornus. Comparative analysis suggests that the fossil is most similar to Cornus piggae, a species described from the Paleocene of North Dakota. This fossil is the first evidence of crown group Cornaceae from the Cretaceous and sheds light on both the plesiomorphic fruit characters and the timing of the initial diversification of the family and basal asterid lineage, Cornales. PMID- 28028475 TI - Trends in mortality rates of cutaneous melanoma in East Asian populations. AB - The incidence of cutaneous melanoma (CM) has rapidly increased over the past four decades. CM is often overlooked in East Asian populations due to its low incidence, despite East Asia making up 22% of the world's population. Since the 1990s, Caucasian populations have seen a plateau in CM mortality rates; however, there is little data investigating the mortality rates of CM in East Asian populations. In this study, the World Health Organization Mortality Database with the joinpoint regression method, and a generalized additive model were used to investigate trends in age standardized mortality rates (ASMRs) of CM in four East Asia regions (Japan, Republic of Korea (Korea), China: Hong Kong (Hong Kong), and Singapore) over the past six decades. In addition, mortality rate ratios by different variables (i.e., sex, age group, and region) were analyzed. Our results showed ASMRs of CM in East Asia significantly increased non-linearly over the past six decades. The joinpoint regression method indicated women had greater annual percentage changes than men in Japan, Korea, and Hong Kong. Men had significantly greater mortality rate ratio (1.51, 95% CI [1.48-1.54]) than women. Mortality rate ratios in 30-59 and 60+ years were significant greater than in the 0-29 years. Compared to Hong Kong, mortality rate ratio was 0.72 (95% CI [0.70 0.74]) times, 0.73 (95% CI [0.70-0.75]) times, and 1.02 (95% CI [1.00-1.05]) times greater in Japan, Korea, and Singapore, respectively. Although there is limited research investigating CM mortality rates in East Asia, results from the present study indicate that there is a significant growth in the ASMRs of CM in East Asian populations, highlighting a need to raise awareness of CM in the general population. PMID- 28028476 TI - Floral development and vascularization help to explain merism evolution in Paepalanthus (Eriocaulaceae, Poales). AB - BACKGROUND: Flowers in Eriocaulaceae, a monocot family that is highly diversified in Brazil, are generally trimerous, but dimerous flowers occur in Paepalanthus and a few other genera. The floral merism in an evolutionary context, however, is unclear. Paepalanthus encompasses significant morphological variation leading to a still unresolved infrageneric classification. Ontogenetic comparative studies of infrageneric groups in Paepalanthus and in Eriocaulaceae are lacking, albeit necessary to establish evolution of characters such as floral merism and their role as putative synapomorphies. METHODS: We studied the floral development and vascularization of eight species of Paepalanthus that belong to distinct clades in which dimery occurs, using light and scanning electron microscopies. RESULTS: Floral ontogeny in dimerous Paepalanthus shows lateral sepals emerging simultaneously and late-developing petals. The outer whorl of stamens is absent in all flowers examined here. The inner whorl of stamens becomes functional in staminate flowers and is reduced to staminodes in the pistillate ones. In pistillate flowers, vascular bundles reach the staminodes. Ovary vascularization shows ventral bundles in a commissural position reaching the synascidiate portion of the carpels. Three gynoecial patterns are described for the studied species: (1) gynoecium with a short style, two nectariferous branches and two long stigmatic branches, in most species; (2) gynoecium with a long style, two nectariferous branches and two short stigmatic branches, in P. echinoides; and (3) gynoecium with long style, absent nectariferous branches and two short stigmatic branches, in P. scleranthus. DISCUSSION: Floral development of the studied species corroborates the hypothesis that the sepals of dimerous flowers of Paepalanthus correspond to the lateral sepals of trimerous flowers. The position and vascularization of floral parts also show that, during dimery evolution in Paepalanthus, a flower sector comprising the adaxial median sepal, a lateral petal, a lateral stamen and the adaxial median carpel was lost. In the staminate flower, the outer whorl of staminodes, previously reported by different authors, is correctly described as the apical portion of the petals and the pistillodes are reinterpreted as carpellodes. The occurrence of fused stigmatic branches and protected nectariferous carpellodes substantiates a close relationship between P. sect. Conodiscus and P. subg. Thelxinoe. Free stigmatic branches and exposed carpellodes substantiate a close relationship between P. sect. Diphyomene, P. sect. Eriocaulopsis and P. ser. Dimeri. Furthermore, the loss of nectariferous branches may have occurred later than the fusion of stigmatic branches in the clade that groups P. subg. Thelxinoe and P. sect. Conodiscus. PMID- 28028477 TI - Emergent adaptive behaviour of GRN-controlled simulated robots in a changing environment. AB - We developed a bio-inspired robot controller combining an artificial genome with an agent-based control system. The genome encodes a gene regulatory network (GRN) that is switched on by environmental cues and, following the rules of transcriptional regulation, provides output signals to actuators. Whereas the genome represents the full encoding of the transcriptional network, the agent based system mimics the active regulatory network and signal transduction system also present in naturally occurring biological systems. Using such a design that separates the static from the conditionally active part of the gene regulatory network contributes to a better general adaptive behaviour. Here, we have explored the potential of our platform with respect to the evolution of adaptive behaviour, such as preying when food becomes scarce, in a complex and changing environment and show through simulations of swarm robots in an A-life environment that evolution of collective behaviour likely can be attributed to bio-inspired evolutionary processes acting at different levels, from the gene and the genome to the individual robot and robot population. PMID- 28028478 TI - Reappraisal of Europe's most complete Early Cretaceous plesiosaurian: Brancasaurus brancai Wegner, 1914 from the "Wealden facies" of Germany. AB - The holotype of Brancasaurus brancai is one of the most historically famous and anatomically complete Early Cretaceous plesiosaurian fossils. It derived from the Gerdemann & Co. brickworks clay pit near Gronau (Westfalen) in North Rhine Westphalia, northwestern Germany. Stratigraphically this locality formed part of the classic European "Wealden facies," but is now more formally attributed to the upper-most strata of the Buckeberg Group (upper Berriasian). Since its initial description in 1914, the type skeleton of B. brancai has suffered damage both during, and after WWII. Sadly, these mishaps have resulted in the loss of substantial information, in particular many structures of the cranium and limb girdles, which are today only evidenced from published text and/or illustrations. This non-confirmable data has, however, proven crucial for determining the relationships of B. brancai within Plesiosauria: either as an early long-necked elasmosaurid, or a member of the controversial Early Cretaceous leptocleidid radiation. To evaluate these competing hypotheses and compile an updated osteological compendium, we undertook a comprehensive examination of the holotype as it is now preserved, and also assessed other Buckeberg Group plesiosaurian fossils to establish a morphological hypodigm. Phylogenetic simulations using the most species-rich datasets of Early Cretaceous plesiosaurians incorporating revised scores for B. brancai, together with a second recently named Buckeberg Group plesiosaurian Gronausaurus wegneri (Hampe, 2013), demonstrated that referral of these taxa to Leptocleididae was not unanimous, and that the topological stability of this clade is tenuous. In addition, the trait combinations manifested by B. brancai and G. wegneri were virtually identical. We therefore conclude that these monotypic individuals are ontogenetic morphs and G. wegneri is a junior synonym of B. brancai. Finally, anomalies detected in the diagnostic features for other "Wealden" plesiosaurians have prompted reconsiderations of interspecies homology versus intraspecific variability. We therefore propose that the still unresolved taxonomy of B. brancai should emphasize only those character states evident in the examinable fossil material, and specifically accommodate for growth-related modifications delimited via osteologically mature referred specimens. PMID- 28028479 TI - Impacts of land-use management on ecosystem services and biodiversity: an agent based modelling approach. AB - The science of ecosystem service (ES) mapping has become increasingly sophisticated over the past 20 years, and examples of successfully integrating ES into management decisions at national and sub-national scales have begun to emerge. However, increasing model sophistication and accuracy-and therefore complexity-may trade-off with ease of use and applicability to real-world decision-making contexts, so it is vital to incorporate the lessons learned from implementation efforts into new model development. Using successful implementation efforts for guidance, we developed an integrated ES modelling system to quantify several ecosystem services: forest timber production and carbon storage, water purification, pollination, and biodiversity. The system is designed to facilitate uptake of ES information into land-use decisions through three principal considerations: (1) using relatively straightforward models that can be readily deployed and interpreted without specialized expertise; (2) using an agent-based modelling framework to enable the incorporation of human decision making directly within the model; and (3) integration among all ES models to simultaneously demonstrate the effects of a single land-use decision on multiple ES. We present an implementation of the model for a major watershed in Alberta, Canada, and highlight the system's capabilities to assess a suite of ES under future management decisions, including forestry activities under two alternative timber harvest strategies, and through a scenario modelling analysis exploring different intensities of hypothetical agricultural expansion. By using a modular approach, the modelling system can be readily expanded to evaluate additional ecosystem services or management questions of interest in order to guide land-use decisions to achieve socioeconomic and environmental objectives. PMID- 28028480 TI - Changes in understory species occurrence of a secondary broadleaved forest after mass mortality of oak trees under deer foraging pressure. AB - The epidemic of mass mortality of oak trees by Japanese oak wilt has affected secondary deciduous broadleaved forests that have been used as coppices in Japan. The dieback of oak trees formed gaps in the crown that would be expected to enhance the regeneration of shade-intolerant pioneer species. However, foraging by sika deer Cervus nippon has also affected forest vegetation, and the compound effects of both on forest regeneration should be considered when they simultaneously occur. A field study was conducted in Kyoto City, Japan to investigate how these compound effects affected the vegetation of the understory layer of these forests. The presence/absence of seedlings and saplings was observed for 200 quadrats sized 5 m *5 m for each species in 1992, before the mass mortality and deer encroachment, and in 2014 after these effects. A hierarchical Bayesian model was constructed to explain the occurrence, survival, and colonization of each species with their responses to the gaps that were created, expanded, or affected by the mass mortality of Quercus serrata trees. The species that occurred most frequently in 1992, Eurya japonica, Quercus glauca, and Cleyera japonica, also had the highest survival probabilities. Deer unpalatable species such as Symplocos prunifolia and Triadica sebifera had higher colonization rates in the gaps, while the deer-palatable species Aucuba japonica had the smallest survival probability. The gaps thus promoted the colonization of deer-unpalatable plant species such as Symplocos prunifolia and Triadica sebifera. In the future, such deer-unpalatable species may dominate gaps that were created, expanded, or affected by the mass mortality of oak trees. PMID- 28028481 TI - Brain transcriptomes of harbor seals demonstrate gene expression patterns of animals undergoing a metabolic disease and a viral infection. AB - Diseases of marine mammals can be difficult to diagnose because of their life history and protected status. Stranded marine mammals have been a particularly useful resource to discover and comprehend the diseases that plague these top predators. Additionally, advancements in high-throughput sequencing (HTS) has contributed to the discovery of novel pathogens in marine mammals. In this study, we use a combination of HTS and stranded harbor seals (Phoca vitulina) to better understand a known and unknown brain disease. To do this, we used transcriptomics to evaluate brain tissues from seven neonatal harbor seals that expired from an unknown cause of death (UCD) and compared them to four neonatal harbor seals that had confirmed phocine herpesvirus (PhV-1) infections in the brain. Comparing the two disease states we found that UCD animals showed a significant abundance of fatty acid metabolic transcripts in their brain tissue, thus we speculate that a fatty acid metabolic dysregulation contributed to the death of these animals. Furthermore, we were able to describe the response of four young harbor seals with PhV-1 infections in the brain. PhV-1 infected animals showed a significant ability to mount an innate and adaptive immune response, especially to combat viral infections. Our data also suggests that PhV-1 can hijack host pathways for DNA packaging and exocytosis. This is the first study to use transcriptomics in marine mammals to understand host and viral interactions and assess the death of stranded marine mammals with an unknown disease. Furthermore, we show the value of applying transcriptomics on stranded marine mammals for disease characterization. PMID- 28028482 TI - Three new species of Bertolonia (Melastomataceae) from Espirito Santo, Brazil. AB - We describe and illustrate three new species of Bertolonia, all endemic to the state of Espirito Santo, Brazil. Bertolonia duasbocaensis and B. macrocalyx occur close to each other, in the municipalities of Cariacica and Viana. Bertolonia ruschiana has a wider distribution, occurring in the municipalities of Santa Leopoldina, Santa Maria de Jetiba and Santa Teresa. The first two species are classified as critically endangered (CR), and the latter as endangered (EN). We also present an identification key for the species of Bertolonia that occur in Espirito Santo. PMID- 28028483 TI - An extensive comparison of species-abundance distribution models. AB - A number of different models have been proposed as descriptions of the species abundance distribution (SAD). Most evaluations of these models use only one or two models, focus on only a single ecosystem or taxonomic group, or fail to use appropriate statistical methods. We use likelihood and AIC to compare the fit of four of the most widely used models to data on over 16,000 communities from a diverse array of taxonomic groups and ecosystems. Across all datasets combined the log-series, Poisson lognormal, and negative binomial all yield similar overall fits to the data. Therefore, when correcting for differences in the number of parameters the log-series generally provides the best fit to data. Within individual datasets some other distributions performed nearly as well as the log-series even after correcting for the number of parameters. The Zipf distribution is generally a poor characterization of the SAD. PMID- 28028484 TI - Personality, mental health and demographic correlates of hoarding behaviours in a midlife sample. AB - We describe the Temperament and Character Inventory personality traits, demographic features, physical and mental health variables associated with hoarding behaviour in a random community sample of midlife participants in New Zealand. A sample of 404 midlife participants was recruited to a study of ageing. To assess hoarding behaviours participants completed the Savings Inventory Revised (SI-R), personality was assessed by the Temperament and Character Inventory and self-reported health was measured by the Short Form-36v2 (SF-36v2). Other measures were used to assess socio-demographic variables and current mental disorders. Participants were split into four groups by SI-R total score (scores: 0-4, 5-30, 31-41 and >41). Those who scored >41 on the SI-R were classified as having pathological hoarding. Trend tests were calculated across the four hoarding groups for socio-demographic, personality, mental and physical health variables. SI-R scores ranged from 0 to 58. The prevalence of pathological hoarding was 2.5% and a further 4% reported sub-clinical symptoms of hoarding. Higher hoarding behaviour scores were related to higher Temperament and Character Inventory scores for Harm Avoidance and lower scores for Self-directedness. Persistence and Cooperativeness scores were lower too but to a lesser extent. Trend analysis revealed that those with higher hoarding behaviour scores were more likely to be single, female, unemployed, receive income support, have a lower socio-economic status, lower household income and have poorer self-reported mental health scores. Current depression rates were considerably higher in the pathological hoarding group. Increasing SI-R hoarding behaviour scores were associated with higher scores of negative affect (Harm Avoidance) and lower scores of autonomy (Self-directedness). Those with pathological hoarding or sub clinical symptoms of hoarding also reported widespread mental and socio-economic problems. In this study it is clear to see the physical, mental and socio economic problems experienced by those achieving the highest hoarding scores. The prevalence of pathological hoarding was 2.5%, similar to the prevalence reported by other studies. The personality traits associated with hoarding behaviours are discussed. PMID- 28028485 TI - Culturable bioaerosols along an urban waterfront are primarily associated with coarse particles. AB - The source, characteristics and transport of viable microbial aerosols in urban centers are topics of significant environmental and public health concern. Recent studies have identified adjacent waterways, and especially polluted waterways, as an important source of microbial aerosols to urban air. The size of these aerosols influences how far they travel, their resistance to environmental stress, and their inhalation potential. In this study, we utilize a cascade impactor and aerosol particle monitor to characterize the size distribution of particles and culturable bacterial and fungal aerosols along the waterfront of a New York City embayment. We seek to address the potential contribution of bacterial aerosols from local sources and to determine how their number, size distribution, and taxonomic identity are affected by wind speed and wind direction (onshore vs. offshore). Total culturable microbial counts were higher under offshore winds (average of 778 CFU/m3 +/- 67), with bacteria comprising the majority of colonies (58.5%), as compared to onshore winds (580 CFU/m3 +/- 110) where fungi were dominant (87.7%). The majority of cultured bacteria and fungi sampled during both offshore winds (88%) and onshore winds (72%) were associated with coarse aerosols (>2.1 um), indicative of production from local sources. There was a significant correlation (p < 0.05) of wind speed with both total and coarse culturable microbial aerosol concentrations. Taxonomic analysis, based on DNA sequencing, showed that Actinobacteria was the dominant phylum among aerosol isolates. In particular, Streptomyces and Bacillus, both spore forming genera that are often soil-associated, were abundant under both offshore and onshore wind conditions. Comparisons of bacterial communities present in the bioaerosol sequence libraries revealed that particle size played an important role in microbial aerosol taxonomy. Onshore and offshore coarse libraries were found to be most similar. This study demonstrates that the majority of culturable bacterial aerosols along a New York City waterfront were associated with coarse aerosol particles, highlighting the importance of local sources, and that the taxonomy of culturable aerosol bacteria differed by size fraction and wind direction. PMID- 28028486 TI - Effects of wind energy generation and white-nose syndrome on the viability of the Indiana bat. AB - Wind energy generation holds the potential to adversely affect wildlife populations. Species-wide effects are difficult to study and few, if any, studies examine effects of wind energy generation on any species across its entire range. One species that may be affected by wind energy generation is the endangered Indiana bat (Myotis sodalis), which is found in the eastern and midwestern United States. In addition to mortality from wind energy generation, the species also faces range-wide threats from the emerging infectious fungal disease, white-nose syndrome (WNS). White-nose syndrome, caused by Pseudogymnoascus destructans, disturbs hibernating bats leading to high levels of mortality. We used a spatially explicit full-annual-cycle model to investigate how wind turbine mortality and WNS may singly and then together affect population dynamics of this species. In the simulation, wind turbine mortality impacted the metapopulation dynamics of the species by causing extirpation of some of the smaller winter colonies. In general, effects of wind turbines were localized and focused on specific spatial subpopulations. Conversely, WNS had a depressive effect on the species across its range. Wind turbine mortality interacted with WNS and together these stressors had a larger impact than would be expected from either alone, principally because these stressors together act to reduce species abundance across the spectrum of population sizes. Our findings illustrate the importance of not only prioritizing the protection of large winter colonies as is currently done, but also of protecting metapopulation dynamics and migratory connectivity. PMID- 28028487 TI - Exploring the cockatiel (Nymphicus hollandicus) fecal microbiome, bacterial inhabitants of a worldwide pet. AB - BACKGROUND: Cockatiels (Nymphicus hollandicus) were originally endemic to Australia; now they are popular pets with a global distribution. It is now possible to conduct detailed molecular studies on cultivable and uncultivable bacteria that are part of the intestinal microbiome of healthy animals. These studies show that bacteria are an essential part of the metabolic capacity of animals. There are few studies on bird microbiomes and, to the best of our knowledge, this is the first report on the cockatiel microbiome. METHODS: In this paper, we analyzed the gut microbiome from fecal samples of three healthy adult cockatiels by massive sequencing of the 16S rRNA gene. Additionally, we compared the cockatiel fecal microbiomes with those of other bird species, including poultry and wild birds. RESULTS: The vast majority of the bacteria found in cockatiels were Firmicutes, while Proteobacteria and Bacteroidetes were poorly represented. A total of 19,280 different OTUs were detected, of which 8,072 belonged to the Erysipelotrichaceae family. DISCUSSION: It is relevant to study cockatiel the microbiomes of cockatiels owing to their wide geographic distribution and close human contact. This study serves as a reference for cockatiel bacterial diversity. Despite the large OTU numbers, the diversity is not even and is dominated by Firmicutes of the Erysipelotrichaceae family. Cockatiels and other wild birds are almost depleted of Bacteroidetes, which happen to be abundant in poultry-related birds, and this is probably associated with the intensive human manipulation of poultry bird diets. Some probable pathogenic bacteria, such as Clostridium and Serratia, appeared to be frequent inhabitants of the fecal microbiome of cockatiels, whereas other potential pathogens were not detected. PMID- 28028488 TI - Bilateral ectopia lentis with isolated lens coloboma in Marfan syndrome. AB - A rare case of bilateral ectopia lentis with isolated lens coloboma in Marfan syndrome is reported. A 21-year-old female presented with decreased vision in both eyes. Her unaided visual acuity was 20/200 and 20/400 in the right and left eye, respectively, improving to 20/40 with -4.5 DS/-3.0 DC x 10 degrees correction in the right eye and 20/80 with -10.0 DS/-6.5 Dc x10 degrees correction in the left eye. On slit lamp examination under mydriasis, both eyes revealed ectopia lentis with lens coloboma and stretched zonules. Fundus examination revealed pigmentary changes at the fovea. On systemic evaluation, she was diagnosed with Marfan syndrome. She was prescribed a refractive correction in form of a contact lens and kept under observation. PMID- 28028490 TI - Discussion on software aging management of nuclear power plant safety digital control system. AB - Managing the aging of digital control systems ensures that nuclear power plant systems are in adequate safety margins during their life cycles. Software is a core component in the execution of control logic and differs between digital and analog control systems. The hardware aging management for the digital control system is similar to that for the analog system, which has matured over decades of study. However, software aging management is still in the exploratory stage. Software aging evaluation is critical given the higher reliability and safety requirements of nuclear power plants. To ensure effective inputs for reliability assessment, this paper provides the required software aging information during the life cycle. Moreover, the software aging management scheme for safety digital control system is proposed on the basis of collected aging information. PMID- 28028491 TI - Cryptococcal meningitis associated with increased adenosine deaminase in the cerebrospinal fluid. AB - INTRODUCTION: Clinically, increased cerebrospinal fluid (CSF) adenosine deaminase (ADA) level is an important diagnostic clue of tuberculous meningitis. However, increased CSF ADA level can be caused by other neurological diseases. CASE DESCRIPTION: We report a case of a 67-year-old woman with cryptococcal meningitis presented with increased ADA level of the CSF. In parallel with her recovery, the ADA level of CSF decreased steadily. This is the first case described the chronological change in CSF ADA level of the patient with cryptococcal meningitis in detail. DISCUSSION AND EVALUATION: Clinically, increased CSF ADA level is an important diagnostic clue of tuberculous meningitis. However, previously, it was reported that increased CSF ADA level can be caused by other neurological diseases. In this case, the patient was diagnosed with cryptococcal meningitis, and the possibility of coinfection with tuberculous meningitis has been discarded by the negative PCR, negative cultures and the clinical course. In addition, the chronological change in CSF ADA level was useful for follow-up assessment. CONCLUSIONS: Cryptococcal meningitis should be considered for the differential diagnosis for diseases presented increased CSF ADA. PMID- 28028489 TI - Biomarkers for diagnosis of sepsis in patients with systemic inflammatory response syndrome: a systematic review and meta-analysis. AB - BACKGROUND: Sepsis is one of the most common diseases that seriously threaten human health. Although a large number of markers related to sepsis have been reported in the last two decades, the diagnostic accuracy of these biomarkers remains unclear due to the lack of similar baselines among studies. Therefore, we conducted a large systematic review and meta-analysis to evaluate the diagnostic value of biomarkers from studies that included non-infectious systemic inflammatory response syndrome patients as a control group. METHODS: We searched Medline, Embase and the reference lists of identified studies beginning in April 2014. The last retrieval was updated in September 2016. RESULTS: Ultimately, 86 articles fulfilled the inclusion criteria. Sixty biomarkers and 10,438 subjects entered the final analysis. The areas under the receiver operating characteristic curves for the 7 most common biomarkers, including procalcitonin, C-reactive protein, interleukin 6, soluble triggering receptor expressed on myeloid cells-1, presepsin, lipopolysaccharide binding protein and CD64, were 0.85, 0.77, 0.79, 0.85, 0.88, 0.71 and 0.96, respectively. The remaining 53 biomarkers exhibited obvious variances in diagnostic value and methodological quality. CONCLUSIONS: Although some biomarkers displayed moderate or above moderate diagnostic value for sepsis, the limitations of the methodological quality and sample size may weaken these findings. Currently, we still lack an ideal biomarker to aid in the diagnosis of sepsis. In the future, biomarkers with better diagnostic value as well as a combined diagnosis using multiple biomarkers are expected to solve the challenge of the diagnosis of sepsis. PMID- 28028492 TI - Traveling wave solutions of the time-delayed generalized Burgers-type equations. AB - BACKGROUND: Recently, nonlinear time-delayed evolution equations have received considerable interest due to their numerous applications in the areas of physics, biology, chemistry and so on. METHODS: In this paper, we obtain traveling wave solutions by using the extended [Formula: see text]-expansion method. RESULTS: Based on the method, we get many solutions of the time-delayed generalized Burgers-type equations. CONCLUSIONS: The results reveal that the extended [Formula: see text]-expansion method is direct, effective and can be used for many other nonlinear time-delayed evolution equations. PMID- 28028493 TI - Mutation detection in Chinese patients with familial hypercholesterolemia. AB - BACKGROUND: Familial hypercholesterolemia (FH) is the first molecularly and clinically characterized genetic disease of lipid metabolism. It is an autosomal dominant disorder with significantly elevated levels of total cholesterol and low density of lipoprotein cholesterol in serum, which would lead to extensive xanthomas and premature coronary heart disease. Mutations in low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 and Apo lipoprotein B-100 (APOB) have been identified to be the underlying cause of this disease. METHODS: Genetic testing and reports of the mutations in the Chinese population are still limited. In this study, 11 unrelated Chinese FH families were enrolled to detect the candidate gene variants by DNA direct sequencing. RESULTS AND CONCLUSION: We identified 12 mutations (11 in LDLR and one in APOB) in ten FH families. Three novel LDLR mutations (c.516C>A/p.D172E, c.1720C>A/p.R574S and c.760C>T/p.Q254X) were identified and co-segregated with the affected individuals in the families. Our discoveries not only further supports the significant role of LDLR in FH, but also expands the spectrum of LDLR mutations. These new insights will contribute to the genetic diagnosis and counseling of FH patients. PMID- 28028494 TI - Interdisciplinary Researches in Iran VI: Student Clubs. PMID- 28028495 TI - Evaluation of a Low-cost and Low-noise Active Dry Electrode for Long-term Biopotential Recording. AB - Wet Ag/AgCl electrodes, although very popular in clinical diagnosis, are not appropriate for expanding applications of wearable biopotential recording systems which are used repetitively and for a long time. Here, the development of a low cost and low-noise active dry electrode is presented. The performance of the new electrodes was assessed for recording electrocardiogram (ECG) and electroencephalogram (EEG) in comparison with that of typical gel-based electrodes in a series of long-term recording experiments. The ECG signal recorded by these electrodes was well comparable with usual Ag/AgCl electrodes with a correlation up to 99.5% and mean power line noise below 6.0 MUVRMS. The active electrodes were also used to measure alpha wave and steady state visual evoked potential by recording EEG. The recorded signals were comparable in quality with signals recorded by standard gel electrodes, suggesting that the designed electrodes can be employed in EEG-based rehabilitation systems and brain computer interface applications. The mean power line noise in EEG signals recorded by the active electrodes (1.3 MUVRMS) was statistically lower than when conventional gold cup electrodes were used (2.0 MUVRMS) with a significant level of 0.05, and the new electrodes appeared to be more resistant to the electromagnetic interferences. These results suggest that the developed low-cost electrodes can be used to develop wearable monitoring systems for long-term biopotential recording. PMID- 28028496 TI - Cepstral Analysis of EEG During Visual Perception and Mental Imagery Reveals the Influence of Artistic Expertise. AB - In this article, multichannel electroencephalogram (EEG) signals of artists and nonartists were analyzed during the performances of visual perception and mental imagery of paintings using cepstrum coefficients. Each of the calculated cepstrum coefficients and their parameters such as energy, average, standard deviation and entropy were separately used for distinguishing the two groups. It was found that a distinguishing coefficient might exist among the cepstrum coefficients, which could separate the two groups despite electrode placement. It was also observed that the two groups were distinguishable during the three states using the cepstrum coefficient parameters. However, separating the two groups was dependent on channel selection in this regard. The cepstrum coefficient parameters were found significantly lower for artists as compared to nonartists during the visual perception and the mental imagery, indicating a decreased average energy of EEG for artists. In addition, a similar significant decreasing trend in the cepstrum coefficient parameters was observed from occipital to frontal brain regions during the performances of the two cognitive tasks for the two groups, suggesting that visual perception and its mental imagery overlap in neuronal resources. The two groups were also classified using a neural gas classifier and a support vector machine classifier. The obtained average classification accuracies during the visual perception, the mental imagery, and at rest in the case of using the best selected distinguishable cepstrum coefficients were 76.87%, 77.5%, and 97.5%, respectively; however, a decrease in average recognition accuracy was found for classifying the two groups using the cepstrum coefficient parameters. PMID- 28028497 TI - Providing an Efficient Algorithm for Finding R Peaks in ECG Signals and Detecting Ventricular Abnormalities With Morphological Features. AB - Ventricular arrhythmias are one of the most important causes of annual deaths in the world, which may lead to sudden cardiac deaths. Accurate and early diagnosis of ventricular arrhythmias in heart diseases is essential for preventing mortality in cardiac patients. Ventricular activity on the electrocardiogram (ECG) signal is in the interval from the beginning of QRS complex to T wave end. Variations in the ECG signal and its features may indicate heart condition of patients. The first step to extract features of ECG in time domain is finding R peaks. In this paper, a combination of two algorithms of Pan-Tompkins and state logic machine has been used to find R peaks in heart signals for normal sinus signals and ventricular abnormalities. Then, a healthy or sick beat may be realized by comparing the difference between R peaks obtained from two algorithms in each beat. The morphological features of the ECG signal in the range of QRS complex are evaluated. Ventricular tachycardia (VT), ventricular flutter (VFL), ventricular fibrillation (VFI), ventricular escape beat (VEB), and premature ventricular contractions (PVCs) are abnormalities studied in this paper. In the classification step, the support vector machine (SVM) classifier with Gaussian kernel (one in front of everyone) is used. Accuracy percentages of ventricular abnormalities mentioned above and normal sinus rhythm are respectively obtained as 95.8%, 92.8%, 94.5, 98.9%, 91.5%, and 100%. The database of this paper has been taken from normal sinus rhythm and MIT-SCD banks available on Physionet.org. PMID- 28028498 TI - Human Verification Using a Combination of Static and Dynamic Characteristics in Foot Pressure Images. AB - Since gait is the mixture of many complex movements, each individual can define with a unique foot pressure image that can be used as a reliable biometric scale for human verification. Foot pressure color images of Center for Biometrics and Security Research (CBSR) dataset from 45 men and 5 women were used in this study. Owing to the properties of this dataset, an index of foot pressure in addition to external feature and contourlet coefficient of images was extracted. A multilayer perceptron (MLP) was utilized for verification of subjects (it is a common practice to explain more about the training and test dataset). To validate the algorithm performance, results were obtained using a 5-fold cross validation approach. The results indicated accuracy of 99.14+/-0.65 and equal error rate (EER) of 0.02. These results demonstrated the reliability of proposed neural network in human verification application. Hence, it can be utilized in other verification systems. PMID- 28028500 TI - Effects of Nano-biphasic Calcium Phosphate Composite on Bioactivity and Osteoblast Cell Behavior in Tissue Engineering Applications. AB - In this paper, preparation, bioactivity, and osteoblast cell behavior of cortical bone derived nano-biphasic calcium phosphate (nano-BCP) are presented. The calcined bovine bone samples with the addition of di-ammonium hydrogen phosphate were heated at 700 degrees C for 100 min, and thus nano-BCP with the composition of 63/37 hydroxyapatite (HA)/beta-tricalcium phosphate (beta-TCP) was produced. Scanning electron microscopy (SEM) images, energy dispersive X-ray spectroscopy (EDS), and X-ray diffraction (XRD) analysis of immersed samples in simulated body fluid (SBF) solution showed that a uniform layer was formed on the surface after 7 days with the chemical composition of HA. The results indicated that the nano BCP sample developed excellent bioactivity after 28 days. The nano-BCP samples showed better cell proliferation compared to pure HA samples. After 7 days in cell culture, the prepared nano-BCP (HA/beta-TCP) exhibited the maximum proliferation of the MG-63 osteoblast cells. PMID- 28028499 TI - Barrett's Mucosa Segmentation in Endoscopic Images Using a Hybrid Method: Spatial Fuzzy c-mean and Level Set. AB - Barrett's mucosa is one of the most important diseases in upper gastrointestinal system that caused by gastro-esophagus reflux. If left untreated, the disease will cause distal esophagus and gastric cardia adenocarcinoma. The malignancy risk is very high in short segment Barrett's mucosa. Therefore, lesion area segmentation can improve specialist decision for treatment. In this paper, we proposed a combined fuzzy method with active models for Barrett's mucosa segmentation. In this study, we applied three methods for special area segmentation and determination. For whole disease area segmentation, we applied the hybrid fuzzy based level set method (LSM). Morphological algorithms were used for gastroesophageal junction determination, and we discriminated Barrett's mucosa from break by applying Chan-Vase method. Fuzzy c-mean and LSMs fail to segment this type of medical image due to weak boundaries. In contrast, the full automatic hybrid method with correlation approach that has used in this paper segmented the metaplasia area in the endoscopy image with desirable accuracy. The presented approach omits the manually desired cluster selection step that needed the operator manipulation. Obtained results convinced us that this approach is suitable for esophagus metaplasia segmentation. PMID- 28028501 TI - Aptamer-conjugated Magnetic Nanoparticles as Targeted Magnetic Resonance Imaging Contrast Agent for Breast Cancer. AB - Early detection of breast cancer is the most effective way to improve the survival rate in women. Magnetic resonance imaging (MRI) offers high spatial resolution and good anatomic details, and its lower sensitivity can be improved by using targeted molecular imaging. In this study, AS1411 aptamer was conjugated to Fe3O4@Au nanoparticles for specific targeting of mouse mammary carcinoma (4T1) cells that overexpress nucleolin. In vitro cytotoxicity of aptamer-conjugated nanoparticles was assessed on 4T1 and HFFF-PI6 (control) cells. The ability of the synthesized nanoprobe to target specifically the nucleolin overexpressed cells was assessed with the MRI technique. Results show that the synthesized nanoprobe produced strongly darkened T2-weighted magnetic resonance (MR) images with 4T1 cells, whereas the MR images of HFFF-PI6 cells incubated with the nanoprobe are brighter, showing small changes compared to water. The results demonstrate that in a Fe concentration of 45 MUg/mL, the nanoprobe reduced by 90% MR image intensity in 4T1 cells compared with the 27% reduction in HFFF-PI6 cells. Analysis of MR signal intensity showed statistically significant signal intensity difference between 4T1 and HFFF-PI6 cells treated with the nanoprobe. MRI experiments demonstrate the high potential of the synthesized nanoprobe as a specific MRI contrast agent for detection of nucleolin-expressing breast cancer cells. PMID- 28028502 TI - Sustainable Health Development Becoming Agenda for Public Health Academia. AB - BACKGROUND: Sustainable Development Goals (SDGs) aim to transform our world, and each goal has specific targets to be achieved by 2030. For the goals to be achieved, everyone needs to do their part: governments, academia, the private sector and all people. This paper summarizes the main evidence-based recommendations made by excellent academics and scholars who discussed their experiences and views during the conference to respond to the challenges of sustainable health development. METHODS: To contribute to exploring to the academia's role in reaching SDGs, the 1st International Conference on Sustainable Health Development was held at Tehran University of Medical Sciences, on 24-25 April 2016, in Tehran, Iran. RESULTS: In line with Goal 3 of SDGs: "ensure healthy lives and promote well-being for all at all ages", the conference discussed various aspects of Universal Health Coverage (UHC), as well as Global Action Plans for prevention and control of Non-Communicable Diseases (NCDs), and explained the special role of academic public health institutes in education, research and service provision in the two above-mentioned areas. CONCLUSION: To fulfill the requirements of SDGs, modern approaches to funding, education, teaching, research priority setting and advocacy, which in turn need novel strategies in collaboration and constructive partnerships among academic public health institutes from low, middle and high-income countries, are essential. PMID- 28028503 TI - Cardiac Hydatid Cyst: A Case Report. AB - Hydatid disease commonly involves liver but in rare cases, it can involve cardiac structures. A 75-yr-old farmer from Parsabad-Moghan, northwestern Iran was presented to the Emergency Room of Tehran Imam Khomeini Hospital, Tehran, Iran with dyspnea and without chest pain in 2014. A lesion compatible with hydatid cyst was found in echocardiography and confirmed by serology and MRI. Surgical treatment was done but the patient was died in recovery room because of cardiac arrhythmia. In endemic areas, hydatid cyst should be considered in differential diagnosis of heterogeneous echogenic lesions even if the serologic tests are negative. Physician can use cardiac MRI to earn valuable information about the lesion and its relation to other structures. However, with all of these assessments, surgical removal of cardiac cysts may have some complications. PMID- 28028504 TI - Modeling Occurrence of Dengue Cases in Malaysia. PMID- 28028505 TI - The Effects of Social Medical Insurance Participation on Migrant Workers in China: Estimation Based on the Propensity Score Matching Approach. PMID- 28028506 TI - Helplessness of Doctors and Nurses in China. PMID- 28028507 TI - Electronic Smoke. PMID- 28028508 TI - Effects of Aspirin as an Anti-inflammatory Drug on Azole-resistant Candida glabrata In Vitro. PMID- 28028509 TI - Pertussis Incidence by Time, Province and Age Group in Iran, 2006-2011. PMID- 28028510 TI - Some Facts on Problematic Internet Use and Sleep Disturbance among Adolescents. PMID- 28028511 TI - Assessment of a 2D electronic portal imaging devices-based dosimetry algorithm for pretreatment and in-vivo midplane dose verification. AB - BACKGROUND: The use of electronic portal imaging devices (EPIDs) is a method for the dosimetric verification of radiotherapy plans, both pretreatment and in vivo. The aim of this study is to test a 2D EPID-based dosimetry algorithm for dose verification of some plans inside a homogenous and anthropomorphic phantom and in vivo as well. MATERIALS AND METHODS: Dose distributions were reconstructed from EPID images using a 2D EPID dosimetry algorithm inside a homogenous slab phantom for a simple 10 * 10 cm2 box technique, 3D conformal (prostate, head-and-neck, and lung), and intensity-modulated radiation therapy (IMRT) prostate plans inside an anthropomorphic (Alderson) phantom and in the patients (one fraction in vivo) for 3D conformal plans (prostate, head-and-neck and lung). RESULTS: The planned and EPID dose difference at the isocenter, on an average, was 1.7% for pretreatment verification and less than 3% for all in vivo plans, except for head and-neck, which was 3.6%. The mean gamma values for a seven-field prostate IMRT plan delivered to the Alderson phantom varied from 0.28 to 0.65. For 3D conformal plans applied for the Alderson phantom, all gamma1% values were within the tolerance level for all plans and in both anteroposterior and posteroanterior (AP PA) beams. CONCLUSION: The 2D EPID-based dosimetry algorithm provides an accurate method to verify the dose of a simple 10 * 10 cm2 field, in two dimensions, inside a homogenous slab phantom and an IMRT prostate plan, as well as in 3D conformal plans (prostate, head-and-neck, and lung plans) applied using an anthropomorphic phantom and in vivo. However, further investigation to improve the 2D EPID dosimetry algorithm for a head-and-neck case, is necessary. PMID- 28028512 TI - Effect of teicoplanin on the expression of c-myc and c-fos proto-oncogenes in MCF 7 breast cancer cell line. AB - BACKGROUND: Teicoplanin is a member of vancomycin-ristocetin family of glycopeptide antibiotics. It mediated wound healing by increasing neovascularization possibly through activation of MAP kinase signaling pathway. The aim of this study is an evaluation of c-myc and c-fos genes expression after treatment of cells by teicoplanin and determines whether this glycopeptide antibiotic exerts its proliferation effects by influencing the expression of these genes. Hence, this study was designed to elucidate one possible mechanism underlying teicoplanin effects on cell proliferation using 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. MATERIALS AND METHODS: Breast cancer cell line, MCF-7, was cultured, and three different concentrations of teicoplanin were added to the plates. We measured the cell proliferation rate by MTT assay. After cell harvesting, total RNA was extracted to synthesize single stranded cDNA. Real-time polymerase chain reaction was performed, and the data were analyzed. RESULTS: It was observed that the level of c-fos and c-myc genes' expressions was decreased at all three different concentrations of teicoplanin. CONCLUSION: it could be concluded that although teicoplanin is considered as an enhancing cell growth and proliferation, but probably its effect is not through MAP kinase signaling pathway or perhaps even has inhibitory effect on the expression of some genes such as c-myc and c-fos in this pathway. Hence, the mechanism of action of teicoplanin for increasing cell propagation, through cell signaling pathways or chromosomal abnormalities, remains unclear, and further studies should be conducted. PMID- 28028513 TI - Evaluation of endothelial function in exogenous subclinical hyperthyroidism and the effect of treatment. AB - BACKGROUND: Subclinical hyperthyroidism (SHy) is a widespread condition in which cardiovascular manifestations are frequently occur, but there is still a debate about the vascular responsiveness in it. Measuring flow-mediated dilation (FMD) and intimae-media thickness (IMT) are used to evaluate endothelial function in these patients. MATERIALS AND METHODS: Twenty-five patients with a diagnosis of exogenous SHy and 25 full matched healthy subjects were enrolled. At first FMD of brachial artery and IMT of common carotid artery were obtained from all the participants. In the second phase, in the second phase of study, the dosage of levothyroxine was reduced at least 25% of prior dosage, and this was continued until thyroid stimulating hormone became normal range. Measuring FMD and IMT was repeated after this intervention in the case group. RESULTS: The mean age of case and control groups were 38.48 +/- 12.05 and 36.72 +/- 11.15 years, respectively. The mean of FMD in healthy people was dramatically higher than the subclinical hyperthyroid patients (P < 0.001) but no statistically significant difference was found for IMT (P = 0.459). After intervention in the case group, FMD was meaningfully increased (P < 0.001) but IMT of common carotid artery was not considerably changed (P = 0.491). CONCLUSIONS: This study demonstrated that FMD decreased in exogenous subclinical hyperthyroid patients which could be partially restored by treatment. These findings suggest that treatment of subclinical hyperthyroid state could improve endothelial dysfunction and at the end decreased the cardiovascular complications. PMID- 28028514 TI - The effect of melatonin on endothelial dysfunction in patient undergoing coronary artery bypass grafting surgery. AB - BACKGROUND: In this study, we investigated the effect of melatonin administration on four markers of endothelial cell function including intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), C-reactive protein (CRP), and nitric oxide (NO) on patients with three vessels coronary disease. MATERIALS AND METHODS: This double-blind, randomized, controlled trial study was conducted on 39 patients (32 men and 7 women) with three vessels coronary disease. The case group included 20 patients who received 10 mg oral melatonin 1 h before sleeping for 1 month. The control group included 19 patients who received placebo 1 h before sleeping for 1 month. The serum levels of CRP, ICAM, VCAM, and NO were compared after 1 month treatment. RESULTS: After 1 month of melatonin treatment, the mean level of ICAM, VCAM, and CRP showed a statistically significant decrease in the case group. On the other hand, the mean level of VCAM increased significantly in the control group. The mean levels of CRP and ICAM were also increased in the control group, but the difference did not reach the significant threshold. With respect to NO, there was a statistically significant increase in the case group, while there was a statistically significant decrease in serum NO in the control group. CONCLUSIONS: The results of this study suggested that melatonin may have beneficial effects on endothelial oxidative stress even in patient with severe and advanced atherosclerosis. PMID- 28028515 TI - Comparison of respiratory and hemodynamic stability in patients with traumatic brain injury ventilated by two ventilator modes: Pressure regulated volume control versus synchronized intermittent mechanical ventilation. AB - BACKGROUND: This study aimed to compare pressure regulated volume control (PRVC) and synchronized intermittent mechanical ventilation (SIMV) modes of ventilation according to respiratory and hemodynamic stability in patients with traumatic brain injury (TBI) admitted to Intensive Care Unit (ICU). MATERIALS AND METHODS: In a randomized, single-blinded, clinical trial study, 100 patients who hospitalized in ICU due to TBI were selected and randomly divided into two groups. The first and second groups were ventilated by PRVC and SIMV modes, respectively. During mechanical ventilation, arterial blood gas and respiratory and hemodynamic parameters were also recorded and compared between the two groups. RESULTS: According to the t-test, the mean rapid shallow breathing index (RSBI) after the first 8 h of mechanical ventilation was significantly higher in SIMV group compared with PRVC group (107.6 +/- 2.75 vs. 102.2 +/- 5.2, respectively, P < 0.0001). Further, according to ANOVA with repeated measures, the trend of RSBI changes had a significant difference between the two groups (P < 0.001). The trend of ratio of partial pressure arterial oxygen and fraction of inspired oxygen was different between the two groups according to Mann-Whitney Wilcoxon test (P < 0.001). CONCLUSIONS: Using PRVC mode might be more desirable than using SIMV mode in patients with TBI due to better stability of ventilation and oxygenating. To ensure for more advantages of PRVC mode, further studies with longer follow-up and more detailed measurements are recommended. PMID- 28028516 TI - The effect of head covering in prevention of phototherapy-induced hypocalcemia in icterus newborns with gestational age less than 35 weeks. AB - BACKGROUND: Hypocalcemia is one of the complications of phototherapy resulted from influence of phototherapy in melatonin secretion reducing corticosterone and ultimately increasing bone uptake. In this study, effect of head covering in prevention of this common and serious complication is studied. MATERIALS AND METHODS: This prospective, randomized clinical trial study conducted on premature infants with gestational age <35 weeks with jaundice. Infants were divided into two groups (n = 43). The first group (intervention group) and the second group (control group) while on the cut, underwent phototherapy using four blue fluorescent lamps in distance of 35 cm. Eyes and genitalia were protected using appropriate clothing. In the first group, head was covered using cloth helmet with a suitable size. For both groups, serum calcium was measured before and 36 h after starting phototherapy. RESULTS: Mean serum calcium before phototherapy in both intervention and control groups was 8.72 +/- 1.12 and 8.79 +/- 0.87 mg/dL, respectively, and the difference between groups was not significant (P = 0.76). After treatment, calcium level in both intervention and control groups was 8.9 +/ 0.82 and 8.43 +/- 0.91, respectively, and the difference between the two groups was significant (P = 0.015). Mean serum calcium levels after phototherapy in the intervention group was -0.17 +/- 1.46 (increase) and it was 0.35 +/- 0.71 (decrease) in the control group. According to t-test, the difference between the two groups was significant (P = 0.036). CONCLUSION: Head covering during phototherapy probably prevents from hypocalcemia. PMID- 28028517 TI - Preparation and characterization of poly (hydroxy butyrate)/chitosan blend scaffolds for tissue engineering applications. AB - BACKGROUND: Poly (hydroxy butyrate) (PHB) is a biodegradable and biocompatible polymer with good mechanical properties. This polymer could be a promising material for scaffolds if some features improve. MATERIALS AND METHODS: In the present work, new PHB/chitosan blend scaffolds were prepared as a three dimensional substrate in cartilage tissue engineering. Chitosan in different weight percent was added to PHB and solved in trifluoroacetic acid. Statistical Taguchi method was employed in the design of experiments. RESULTS: The Fourier transform infrared spectroscopy test revealed that the crystallization of PHB in these blends is suppressed with increasing the amount of chitosan. Scanning electron microscopy images showed a thin and rough top layer with a nodular structure, supported with a porous sub-layer in the surface of the scaffolds. In vitro degradation rate of the scaffolds was higher than pure PHB scaffolds. Maximum degradation rate has been seen for the scaffold with 90% wt. NaCl and 40% wt. chitosan. CONCLUSIONS: The obtained results suggest that these newly developed PHB/chitosan blend scaffolds may serve as a three-dimensional substrate in cartilage tissue engineering. PMID- 28028518 TI - Study of the effects of controlled morphine administration for treatment of anxiety, depression and cognition impairment in morphine-addicted rats. AB - BACKGROUND: Morphine dependency usually results in undesired outcomes such as anxiety, depression, and cognitive alterations. In this study, morphine was used to manage morphine dependence-induced anxiety, depression, and learning and memory disturbances. MATERIALS AND METHODS: Forty rats were divided equally into five groups. Group 1 received saline for 21 days. Groups 2-5 were dependent by increasing administration of morphine (15-45 mg/kg) for 7 days. For the next 14 days, morphine was administered as the following regimen: Group 2: once daily; 45 mg/kg (positive controls), Group 3: the same dose with an increasing interval (6 h longer than the previous intervals each time), Group 4: the same dose with an irregular intervals (12, 24, 36 h intervals interchangeably), and Group 5: decreasing doses once daily (every time 2.5 mg/kg less than the former dosage). On days 22-26, elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were performed to investigate anxiety level and depression in animals. Between 17th and 21st days, Morris water maze (MWM) was used to evaluate the spatial learning and memory. RESULTS: Chronic morphine administration caused depression and anxiety as observed by FST, EPM, and TST and decreased motor activity in OFT and caused impairment in learning and memory performance in MWM. Treatment with our protocol as increasing interval, irregular interval, and decreasing dosage of morphine caused marked reduction in depression, anxiety, and improved cognition performance compared with positive control group; and attenuated motor deficits in morphine-dependent rats, remarkably. CONCLUSIONS: Change in dosage regimens of morphine can reduce morphine-induced anxiety, depression, and cognitive impairments. PMID- 28028519 TI - Beneficial effects of platelet-rich plasma on improvement of pain severity and physical disability in patients with plantar fasciitis: A randomized trial. AB - BACKGROUND: The present study aimed to clinically examine the effects of platelet rich plasma (PRP) on improvement of plantar fasciitis and its related manifestations. PATIENTS AND METHODS: This single-blind randomized controlled trial was performed on 32 consecutive patients with the final diagnosis of plantar fasciitis that were randomly assigned to the case group (that received PRP, n = 16) and the control group (that received corticosteroid as methylprednisolone 1 ml plus lidocaine 1 ml, n = 16). The endpoints in the present study were changes in the visual analog scale score and the modified Roles and Maudsley score (RMS) from baseline, 1-month, 3 months, and 6 months follow-up. Plantar fascia was also assessed by B-mode sonography before and also 3 months after primary assessment. RESULTS: Regarding the pain severity, the PRP group had significantly higher mean pain score at 3 time points of before injection, as well as 1 and 3 months after PRP use when compared to the corticosteroid group (P < 0.05); however, the control group experienced significantly higher pain severity than the PRP group at 6 months after interventions. Also, RMS was lower in PRP group than in corticosteroid group at baseline as well as at 1 and 3 months after injections (P < 0.05). In sonography assessment, no difference was revealed. CONCLUSION: Administration of PRP leads to significant improvement in pain severity and physical limitation in patients with plantar fasciitis. This healing effect may be begun at least 3 months after injection. PMID- 28028520 TI - Evaluation of structural and mechanical properties of electrospun nano-micro hybrid of poly hydroxybutyrate-chitosan/silk scaffold for cartilage tissue engineering. AB - BACKGROUND: One of the new methods of scaffold fabrication is a nano-micro hybrid structure in which the properties of the scaffold are improved by introducing nanometer and micrometer structures. This method could be suitable for scaffold designing if some features improve. MATERIALS AND METHODS: In this study, electrospun nanofibers of 9% weight solution of poly (3-hydroxybutyrate) (P3HB) and a 15% weight of chitosan by trifluoroacetic acid were coated on both the surface of a silk knitted substrate in the optimum condition to improve the mechanical properties of scaffolds for cartilage tissue engineering application. These hybrid nano-micro fibrous scaffolds were characterized by structural and mechanical evaluation methods. RESULTS: Scanning electron microscopy values and porosity analysis showed that average diameter of nanofibers was 584.94 nm in electrospinning part and general porosity was more than 80%. Fourier transform infrared spectroscopy results indicated the presence of all elements without pollution. The tensile test also stated that by electrospinning, as well as adding chitosan, both maximum strength and maximum elongation increased to 187 N and 10 mm. It means that the microfibrous part of scaffold could affect mechanical properties of nano part of the hybrid scaffold, significantly. CONCLUSIONS: It could be concluded that P3HB-chitosan/silk hybrid scaffolds can be a good candidate for cartilage tissue engineering. PMID- 28028521 TI - Beijing strains of Mycobacterium tuberculosis in smear-positive tuberculosis patients in North-West and West of Iran. AB - BACKGROUND: Tuberculosis (TB) is the leading cause of morbidity and mortality among chronic infectious diseases. The goal of this cross-sectional study (2012 2014) was to examine the prevalence of Mycobacterium TB (MTB) Beijing strains in regions near the Iranian border and to identify any epidemiological links. MATERIALS AND METHODS: To this end, MTB isolates were harvested, from 64 HIV negative, pulmonary smear-positive TB patients from the Iranian border provinces of East Azerbaijan (North-West), Kurdistan (West), and Kermanshah (West) (2012 2014). Isolates were subjected to restriction fragment length polymorphism (RFLP) analysis, using the insertion sequence IS6110 as a probe (IS6110 RFLP), and drug susceptibility testing by the proportion method. We gathered demographic and clinical data using a questionnaire and reviewing patient records. Results were analyzed with Gel Compare II 6.6 and SPSS-18. RESULTS: The mean age of the patients was 54.4 years and 46.9% were male. The prevalence of Beijing strains among the isolates was 9.4% (17.6% in the Western provinces and 0% in East Azerbaijan). There was a statistically significant relationship between the Beijing strains and drug resistance and also between these strains, and the recurrence of TB in patients that had previously received treatment (P = 0.02 and P = 0.04, respectively). CONCLUSIONS: Finally, the prevalence of Beijing strains in Western Iran was greater than expected. Our results therefore indicate that regional and cross-border tracing may be necessary to control spread of this organism. PMID- 28028522 TI - Preparation and evaluation of a hair wax containing propolis and Eruca sativa seed oil for hair growth. AB - BACKGROUND: Hair growth as a key consumer objective has important role in the hair care products researches. This study was aimed to investigate the effect of a hair wax containing propolis, a resinous mixture produced by honeybees in Eruca sativa seed oil base on hair growth. MATERIALS AND METHODS: The hair wax was designed and formulated compared with marketed brand hair wax and evaluated for pharmaceutical parameters including pH, homogeneity, consistency, spread ability, in vitro drug release, and stability. After selection of the best formulation containing 10% ethanolic extract of propolis and 10% E. sativa seed oil, the hair growth potential was evaluated by application of 1 g hair wax daily on 4 cm2 area of dorsal side of Wistar rats and compared with controls and standard medication (1 ml of 2% minoxidil). After 30 days treatment, the length and weight of hairs and percentage of hair follicles in different phases of growth in skin biopsies were assessed. RESULTS: The selected hair wax formulation was stable and easy to wash. The formulation significantly increased hair length on 10th, 20th, and 30th day compared control group (5.8 +/- 0.3 vs. 2.6 +/- 0.4, 11.4 +/- 0.6 vs. 5.8 +/- 0.4, and 17.5 +/- 0.5 vs. 12.7 +/- 0.4 mm, respectively) and also the weight of newly grown hairs on 30th day (0.056 +/- 0.006 vs. 0.043 +/- 0.005). It improved hair follicles percentages in anagen phase without any sensitivity reaction. CONCLUSIONS: The results of this study suggest that the formulated hair wax containing of propolis and E. sativa seed oil could have significant effect on promoting hair growth. PMID- 28028523 TI - Anxiety, depression and distress among irritable bowel syndrome and their subtypes: An epidemiological population based study. AB - BACKGROUND: Psychiatric disorders are common in irritable bowel syndrome (IBS). We conducted this study to investigate the relationship of IBS and their subtypes with some of psychological factors. MATERIALS AND METHODS: A cross-sectional study was performed among 4763 staff of Isfahan University of Medical Sciences in 2011. Modified ROME III questionnaire and Talley Bowel Disease Questionnaire were used to evaluate IBS symptoms. Hospital Anxiety and Depression Scale and 12-item General Health Questionnaire were utilized to assess anxiety, depression and psychological distress. Logistic regression analysis was used to determine the association of psychological states and IBS in the total subject and both genders. RESULTS: About, 4763 participants with mean age 36/58 +/- 8/09 were included the 2106 males and 2657 females. Three thousand and seven hundred and seventy-six (81.2%) and 2650 (57.2%) participants were married and graduated respectively. Subtype analysis of IBS and its relationship with anxiety, depression and distress comparing the two genders can be observed that: IBS and clinically-significant IBS have higher anxiety, depression symptoms, and distress than the subject without IBS (P < 0.001). Women with IBS, have higher scores than men (P < 0.001). Compared to other subtypes, mixed IBS subtype has a higher anxiety, depression, and distress score. CONCLUSION: A high prevalence of anxiety, depression symptoms and distress in our subjects emphasize the importance of the psychological evaluation of the patients with IBS, in order to better management of the patients and may also help to reduce the burden of health care costs. PMID- 28028524 TI - Effect of phone call versus face-to-face follow-up on recurrent suicide attempts prevention in individuals with a history of multiple suicide attempts. AB - BACKGROUND: To evaluate the efficacy of different ways of communications on prevention of suicidal reattempt, we compared the efficacy of phone call versus face-to-face follow-up in patients with previous attempt. MATERIALS AND METHODS: In a randomized controlled clinical trial, 55 suicide reattempters who were admitted to the poisoning emergency were divided into phone call (29 patients) and face-to-face (26 patients) groups randomly. They were followed at 8 occasions: 2nd and 4th weeks, and the 2nd, 3rd, 4th, 5th, 6th, and 8th months. The suicidal reattempt, suicidal thought, hope, and interest of the patients were assessed on each occasion, and the patients were guided to visit by a therapist, if needed. The findings were analyzed by Mann-Whitney, Chi-square, Cochran, Friedman, and independent t-tests using SPSS 20. RESULTS: The status of "hope" and "interest" improved in both groups, but it showed more significant difference in the face-to-face group. Suicidal thoughts in both groups decreased over time, and this was more significant in the face-to-face group. However, we did not found any significant difference in the frequency of the suicidal reattempts between two groups. CONCLUSION: Face-to-face versus phone call follow-up of suicide attempters can significantly alleviate suicidal thoughts and improve hopes and interests. PMID- 28028525 TI - Is there any relationship between different phenotypes of metabolic syndrome and cardiovascular mortality rate? AB - BACKGROUND: This study aimed to focus on different phenotypes of metabolic syndrome (MetS) and their impact on the cardiovascular disease (CVD) events among a sample of the Iranian population. MATERIALS AND METHODS: The Isfahan cohort study is a population-based, on-going longitudinal study of adults aged 35 years old or more, living in urban and rural areas of three counties in central Iran namely Isfahan, Najafabad and Arak. Participants were selected by multistage random sampling and were recruited to reflect the age, sex and urban/rural distribution of the community. The sample was restricted to subjects with MetS based on the National Cholesterol Education Program Adult Treatment Panel III criteria and no history of coronary heart disease, stroke, or cancer at the time of the baseline clinical examination. RESULTS: Among different phenotypes of MetS components, clustering of high triglycerides (TGs), low high-density lipoprotein (HDL) and abdominal obesity (ABO) was the most related to the all-cause mortality among women and followed in order by high TGs, hypertension (HTN) and ABO. In men, the highest rate of all-cause mortality was related to high TGs, low HDL, and HTN. Clustering of four components (high TGs, low HDL and HTN and obesity) is the most related to all-cause mortality in the both sexes (12.1% in men, and 21.5% in women). CONCLUSION: This study showed different phenotypes of MetS related with all-cause mortality rate and existing HTN in the phenotype of MetS increased the incidence of CVD mortality. PMID- 28028526 TI - Investigation of the relationship between idiopathic microscopic hematuria (in the first and second trimesters) and major adverse outcomes of pregnancy. AB - BACKGROUND: The aim of this study was to investigate the relationship between idiopathic microscopic hematuria (in the first and second trimesters) and major adverse outcomes of pregnancy. MATERIALS AND METHODS: Urinalysis was done for 700 pregnant women before 24 weeks of pregnancy. Those who had 3-5 red blood cells per milliliter in urinalysis were considered positive urinalysis. Then, all individuals were examined for blood pressure and other alarm signs of pregnancy complications in each visit. All mothers were followed for the incidence of preeclampsia, preterm delivery, and pregnancy outcome until the end of pregnancy. RESULTS: The results of this study showed that no significant difference in terms of incident of pregnancy complications between the pregnant women with and without hematuria and the only abortions and neonatal deaths differed between the two groups. CONCLUSION: These results suggest that further studies are needed to determine whether idiopathic microscopic hematuria can be a predictive value for pregnancy complications or not. PMID- 28028527 TI - From conventional therapy toward microRNA-based therapy in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a hematopoietic malignancy that is known with its special cytogenetic feature. Several studies have surveyed expression signature of microRNAs (miRNAs) in APL patients, especially patients who are treated with conventional therapy of this disease. Using miRNAs as diagnostic or prognostic biomarkers in various cancers has been widely studied. Currently, most studies are focusing on exploiting miRNAs as therapeutic tools, and promising progress has been achieved in this field. Recently, studies in the field of miRNA based therapy in APL have been started. PMID- 28028528 TI - The comparison of treatments with and without azithromycin in irritable bowel syndrome with diarrhea-predominant in gastrointestinal Clinic of Al-Zahra Hospital, Isfahan, Iran. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Recent studies suggest the importance of gut flora in the pathophysiology of it. Therefore, antibiotics have demonstrated a substantial benefit to reduce gut flora. Having few side effects, and applying one-dose per day, we studied the effect of azithromycin to treat IBS. MATERIALS AND METHODS: One hundred and twenty-six patients enrolled a randomized, double-blind, placebo-controlled study. The treatment group received azithromycin in addition to common treatment. Patients were followed for 12 weeks. Patients completed daily diaries documenting their symptoms. RESULTS: One hundred and thirteen patients completed the study. The onset of relief occurred significantly sooner, and duration of relief was significantly longer in azithromycin group. Movement, abdominal pain, bloating, and gas were significantly better in azithromycin group. Monthly results showed superior relief in bloating, gas, overall symptom, and overall bloating during 3 months. Significantly more patients in azithromycin group felt relief in bloating and gas and had greater consistency relief in almost all weeks. CONCLUSION: In our study, azithromycin significantly relieved most symptoms, such as abdominal pain, bloating, and gas. Overall symptom and overall bloating were relieved significantly in more patients in the intervention group in all weeks. PMID- 28028529 TI - Purification of lactoperoxidase from bovine whey and investigation of kinetic parameters. AB - BACKGROUND: Lactoperoxidase (LPO) is related to mammalian peroxidase family which contains a wide spectrum of biological activities. Despite the wide studies on the LPO, there is little study has been performed to simplify and shorten the procedure of enzyme purification. The aim of this project was to purify the enzyme through a simple method, and investigating enzyme kinetic parameters. MATERIALS AND METHODS: LPO was purified from bovine whey through modified method of Yoshida (1990) using two steps of ammonium sulfate precipitation and ion exchange chromatography. The purity of isolated enzyme was monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: The enzyme was purified 59.13-fold with a recovery of 10.26 having a specific activity of 5.78 U/mg protein and an Rz value of 0.8. The enzyme activity was measured using guaiacol as a chromogenic substrate in phosphate buffer pH 6. SDS PAGE showed a single bond with molecular weight of 78 kDa. The purified enzyme displayed optimum activity at pH 6 in 30 mM phosphate buffer and at a temperature of 50 degrees C, with a Km value of 178 mM and Vmax 0.63 U/ml.min for guaiacol. CONCLUSION: Using only one step ion-exchange chromatography, LPO was isolated from bovine whey in high purity. PMID- 28028530 TI - Acid-base and hemodynamic status of patients with intraoperative hemorrhage using two solution types: Crystalloid Ringer lactate and 1.3% sodium bicarbonate in half-normal saline solution. AB - BACKGROUND: Intraoperative hemorrhage is one of the problems during surgery and, if it happens in a high volume without an immediate action to control, it can be fatal. Nowadays, various injectable solutions are used. The aim of this study was to compare the acid-base and hemodynamic status of the patient using two solutions, Ringer lactate and 1.3% sodium bicarbonate, in half saline solution. MATERIALS AND METHODS: This clinical trial was performed at the Al-Zahra Hospital in 2013 on 66 patients who were randomly selected and put in two studied groups at the onset of hemorrhage. For the first group, crystalloid Ringer lactate solution and for the second group, 1.3% sodium bicarbonate in half-normal saline solution was used. Electrocardiogram, heart rate, O2 saturation non-invasive blood pressure and end-tidal CO2 were monitored. The arterial blood gas, blood electrolytes, glucose and blood urea nitrogen were measured before serum and blood injection. After the infusion of solutions and before blood transfusions, another sample was sent for measurement of blood parameters. Data were analyzed using SPSS software. RESULTS: The mean arterial pressure was significantly higher in the second group than in the first group at some times after the infusion of solutions. pHh levels, base excess, bicarbonate, sodium, strong ion differences and osmolarity were significantly greater and potassium and chloride were significantly lower in the second group than in the first group after the infusion of solutions. CONCLUSION: 1.3% sodium bicarbonate in half-normal saline solution can lead to a proper correction of hemodynamic instability. By maintaining hemodynamic status, osmolarity and electrolytes as well as better balance of acid-base, 1.3% sodium bicarbonate solution in half-normal saline solution can be more effective than Ringer lactate solution during intraoperative bleeding. PMID- 28028531 TI - Prophylactic steroid administration for strictures after endoscopic resection of large superficial esophageal squamous cell carcinoma. AB - Background and study aims: One of the major complications after endoscopic resection (ER) for large superficial esophageal squamous cell carcinoma (ESCC) is benign esophageal stricture, which can reduce quality of life even if ESCC achieves a cure without organ resection. Recently, steroid administration has been reported as a prophylactic treatment to prevent esophageal strictures. This retrospective study evaluated the stricture rate according to the different width of mucosal defects due to ER and compared it to that seen with prophylactic steroid administration. Patients and methods: Between June 2007 and December 2013, we enrolled patients with ESCC who had 3/4 or larger circumferential mucosal defects due to ER. In December 2009, steroid injections (triamcinolone acetonide 50 mg) into the ulcer bed due to ER were introduced. Beginning in November 2012, we commenced oral steroid administration (prednisolone 30 mg/day, tapered gradually for 8 weeks) in addition to steroid injection. Patients were classified into 3 groups according to the width of mucosal defect after ER (Group A, >= 3/4 and < 7/8; Group B, >= 7/8 and less than the entire circumference; and Group C, the entire circumference). We retrospectively evaluated the stricture rate by comparing no treatment, steroid injection, or steroid injection followed by oral steroid according to the width of mucosal defect. Results: A total of 115 patients met the selection criteria. In Group B, no treatment had a significantly higher stricture rate (100 %, vs. steroid injection: 56 % P = 0.015; vs steroid injection followed by oral steroid: 20 % P < 0.001). Conversely, in Group C, the stricture rate was high, regardless of treatment (no treatment: 100 %; steroid injection: 100 %; steroid injection followed by oral steroid: 71 %). Conclusions: Although prophylactic steroid administration is effective to prevent strictures for 7/8 circumference or larger mucosal defects, it is ineffective for whole circumference defects. Further investigation is required. PMID- 28028532 TI - Near-infrared-to-visible highly selective thermal emitters based on an intrinsic semiconductor. AB - Control of the thermal emission spectra of emitters will result in improved energy utilization efficiency in a broad range of fields, including lighting, energy harvesting, and sensing. In particular, it is challenging to realize a highly selective thermal emitter in the near-infrared-to-visible range, in which unwanted thermal emission spectral components at longer wavelengths are significantly suppressed, whereas strong emission in the near-infrared-to-visible range is retained. To achieve this, we propose an emitter based on interband transitions in a nanostructured intrinsic semiconductor. The electron thermal fluctuations are first limited to the higher-frequency side of the spectrum, above the semiconductor bandgap, and are then enhanced by the photonic resonance of the structure. Theoretical calculations indicate that optimized intrinsic Si rod-array emitters with a rod radius of 105 nm can convert 59% of the input power into emission of wavelengths shorter than 1100 nm at 1400 K. It is also theoretically indicated that emitters with a rod radius of 190 nm can convert 84% of the input power into emission of <1800-nm wavelength at 1400 K. Experimentally, we fabricated a Si rod-array emitter that exhibited a high peak emissivity of 0.77 at a wavelength of 790 nm and a very low background emissivity of <0.02 to 0.05 at 1100 to 7000 nm, under operation at 1273 K. Use of a nanostructured intrinsic semiconductor that can withstand high temperatures is promising for the development of highly efficient thermal emitters operating in the near-infrared-to-visible range. PMID- 28028533 TI - Extracellular electrical recording of pH-triggered bursts in C6 glioma cell populations. AB - Glioma patients often suffer from epileptic seizures because of the tumor's impact on the brain physiology. Using the rat glioma cell line C6 as a model system, we performed long-term live recordings of the electrical activity of glioma populations in an ultrasensitive detection method. The transducer exploits large-area electrodes that maximize double-layer capacitance, thus increasing the sensitivity. This strategy allowed us to record glioma electrical activity. We show that although glioma cells are nonelectrogenic, they display a remarkable electrical burst activity in time. The low-frequency current noise after cell adhesion is dominated by the flow of Na+ ions through voltage-gated ion channels. However, after an incubation period of many hours, the current noise markedly increased. This electric bursting phenomenon was not associated with apoptosis because the cells were viable and proliferative during the period of increased electric activity. We detected a rapid cell culture medium acidification accompanying this event. By using specific inhibitors, we showed that the electrical bursting activity was prompted by extracellular pH changes, which enhanced Na+ ion flux through the psalmotoxin 1-sensitive acid-sensing ion channels. Our model of pH-triggered bursting was unambiguously supported by deliberate, external acidification of the cell culture medium. This unexpected, acidosis-driven electrical activity is likely to directly perturb, in vivo, the functionality of the healthy neuronal network in the vicinity of the tumor bulk and may contribute to seizures in glioma patients. PMID- 28028535 TI - Kinematics and dynamics of the East Pacific Rise linked to a stable, deep-mantle upwelling. AB - Earth's tectonic plates are generally considered to be driven largely by negative buoyancy associated with subduction of oceanic lithosphere. In this context, mid ocean ridges (MORs) are passive plate boundaries whose divergence accommodates flow driven by subduction of oceanic slabs at trenches. We show that over the past 80 million years (My), the East Pacific Rise (EPR), Earth's dominant MOR, has been characterized by limited ridge-perpendicular migration and persistent, asymmetric ridge accretion that are anomalous relative to other MORs. We reconstruct the subduction-related buoyancy fluxes of plates on either side of the EPR. The general expectation is that greater slab pull should correlate with faster plate motion and faster spreading at the EPR. Moreover, asymmetry in slab pull on either side of the EPR should correlate with either ridge migration or enhanced plate velocity in the direction of greater slab pull. Based on our analysis, none of the expected correlations are evident. This implies that other forces significantly contribute to EPR behavior. We explain these observations using mantle flow calculations based on globally integrated buoyancy distributions that require core-mantle boundary heat flux of up to 20 TW. The time-dependent mantle flow predictions yield a long-lived deep-seated upwelling that has its highest radial velocity under the EPR and is inferred to control its observed kinematics. The mantle-wide upwelling beneath the EPR drives horizontal components of asthenospheric flows beneath the plates that are similarly asymmetric but faster than the overlying surface plates, thereby contributing to plate motions through viscous tractions in the Pacific region. PMID- 28028534 TI - Cellular uptake and dynamics of unlabeled freestanding silicon nanowires. AB - The ability to seamlessly merge electronic devices with biological systems at the cellular length scale is an exciting prospect for exploring new fundamental cell biology and in designing next-generation therapeutic devices. Semiconductor nanowires are well suited for achieving this goal because of their intrinsic size and wide range of possible configurations. However, current studies have focused primarily on delivering substrate-bound nanowire devices through mechanical abrasion or electroporation, with these bulkier substrates negating many of the inherent benefits of using nanoscale materials. To improve on this, an important next step is learning how to distribute these devices in a drug-like fashion, where cells can naturally uptake and incorporate these electronic components, allowing for truly noninvasive device integration. We show that silicon nanowires (SiNWs) can potentially be used as such a system, demonstrating that label-free SiNWs can be internalized in multiple cell lines (96% uptake rate), undergoing an active "burst-like" transport process. Our results show that, rather than through exogenous manipulation, SiNWs are internalized primarily through an endogenous phagocytosis pathway, allowing cellular integration of these materials. To study this behavior, we have developed a robust set of methodologies for quantitatively examining high-aspect ratio nanowire-cell interactions in a time-dependent manner on both single-cell and ensemble levels. This approach represents one of the first dynamic studies of semiconductor nanowire internalization and offers valuable insight into designing devices for biomolecule delivery, intracellular sensing, and photoresponsive therapies. PMID- 28028536 TI - Engineered feature used to enhance gardening at a 3800-year-old site on the Pacific Northwest Coast. AB - Humans use a variety of deliberate means to modify biologically rich environs in pursuit of resource stability and predictability. Empirical evidence suggests that ancient hunter-gatherer populations engineered ecological niches to enhance the productivity and availability of economically significant resources. An archaeological excavation of a 3800-year-old wetland garden in British Columbia, Canada, provides the first direct evidence of an engineered feature designed to facilitate wild plant food production among mid-to-late Holocene era complex fisher-hunter-gatherers of the Northwest Coast. This finding provides an example of environmental, economic, and sociopolitical coevolutionary relationships that are triggered when humans manipulate niche environs. PMID- 28028537 TI - A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets. AB - The autophagic digestion of lipid droplets (LDs) through lipophagy is an essential process by which most cells catabolize lipids as an energy source. However, the cellular machinery used for the envelopment of LDs during autophagy is poorly understood. We report a novel function for a small Rab guanosine triphosphatase (GTPase) in the recruitment of adaptors required for the engulfment of LDs by the growing autophagosome. In hepatocytes stimulated to undergo autophagy, Rab10 activity is amplified significantly, concomitant with its increased recruitment to nascent autophagic membranes at the LD surface. Disruption of Rab10 function by small interfering RNA knockdown or expression of a GTPase-defective variant leads to LD accumulation. Finally, Rab10 activation during autophagy is essential for LC3 recruitment to the autophagosome and stimulates its increased association with the adaptor protein EHBP1 (EH domain binding protein 1) and the membrane-deforming adenosine triphosphatase EHD2 (EH domain containing 2) that, together, are essential in driving the activated "engulfment" of LDs during lipophagy in hepatocytes. PMID- 28028538 TI - Polymer ligand-induced autonomous sorting and reversible phase separation in binary particle blends. AB - The tethering of ligands to nanoparticles has emerged as an important strategy to control interactions and organization in particle assembly structures. We demonstrate that ligand interactions in mixtures of polymer-tethered nanoparticles (which are modified with distinct types of polymer chains) can impart upper or lower critical solution temperature (UCST/LCST)-type phase behavior on binary particle mixtures in analogy to the phase behavior of the corresponding linear polymer blends. Therefore, cooling (or heating) of polymer tethered particle blends with appropriate architecture to temperatures below (or above) the UCST (or LCST) results in the organization of the individual particle constituents into monotype microdomain structures. The shape (bicontinuous or island-type) and lengthscale of particle microdomains can be tuned by variation of the composition and thermal process conditions. Thermal cycling of LCST particle brush blends through the critical temperature enables the reversible growth and dissolution of monoparticle domain structures. The ability to autonomously and reversibly organize multicomponent particle mixtures into monotype microdomain structures could enable transformative advances in the high throughput fabrication of solid films with tailored and mutable structures and properties that play an important role in a range of nanoparticle-based material technologies. PMID- 28028539 TI - Reactive nitrogen chemistry in aerosol water as a source of sulfate during haze events in China. AB - Fine-particle pollution associated with winter haze threatens the health of more than 400 million people in the North China Plain. Sulfate is a major component of fine haze particles. Record sulfate concentrations of up to ~300 MUg m-3 were observed during the January 2013 winter haze event in Beijing. State-of-the-art air quality models that rely on sulfate production mechanisms requiring photochemical oxidants cannot predict these high levels because of the weak photochemistry activity during haze events. We find that the missing source of sulfate and particulate matter can be explained by reactive nitrogen chemistry in aerosol water. The aerosol water serves as a reactor, where the alkaline aerosol components trap SO2, which is oxidized by NO2 to form sulfate, whereby high reaction rates are sustained by the high neutralizing capacity of the atmosphere in northern China. This mechanism is self-amplifying because higher aerosol mass concentration corresponds to higher aerosol water content, leading to faster sulfate production and more severe haze pollution. PMID- 28028540 TI - Ocean heat drives rapid basal melt of the Totten Ice Shelf. AB - Mass loss from the West Antarctic ice shelves and glaciers has been linked to basal melt by ocean heat flux. The Totten Ice Shelf in East Antarctica, which buttresses a marine-based ice sheet with a volume equivalent to at least 3.5 m of global sea-level rise, also experiences rapid basal melt, but the role of ocean forcing was not known because of a lack of observations near the ice shelf. Observations from the Totten calving front confirm that (0.22 +/- 0.07) * 106 m3 s-1 of warm water enters the cavity through a newly discovered deep channel. The ocean heat transport into the cavity is sufficient to support the large basal melt rates inferred from glaciological observations. Change in ocean heat flux is a plausible physical mechanism to explain past and projected changes in this sector of the East Antarctic Ice Sheet and its contribution to sea level. PMID- 28028541 TI - Butterfly magnetoresistance, quasi-2D Dirac Fermi surface and topological phase transition in ZrSiS. AB - Magnetoresistance (MR), the change of a material's electrical resistance in response to an applied magnetic field, is a technologically important property that has been the topic of intense study for more than a quarter century. We report the observation of an unusual "butterfly"-shaped titanic angular magnetoresistance (AMR) in the nonmagnetic Dirac material, ZrSiS, which we find to be the most conducting sulfide known, with a 2-K resistivity as low as 48(4) nOmega?cm. The MR in ZrSiS is large and positive, reaching nearly 1.8 * 105 percent at 9 T and 2 K at a 45 degrees angle between the applied current (I || a) and the applied field (90 degrees is H || c). Approaching 90 degrees , a "dip" is seen in the AMR, which, by analyzing Shubnikov de Haas oscillations at different angles, we find to coincide with a very sharp topological phase transition unlike any seen in other known Dirac/Weyl materials. We find that ZrSiS has a combination of two-dimensional (2D) and 3D Dirac pockets comprising its Fermi surface and that the combination of high-mobility carriers and multiple pockets in ZrSiS allows for large property changes to occur as a function of angle between applied fields. This makes it a promising platform to study the physics stemming from the coexistence of 2D and 3D Dirac electrons as well as opens the door to creating devices focused on switching between different parts of the Fermi surface and different topological states. PMID- 28028542 TI - Syrosingopine sensitizes cancer cells to killing by metformin. AB - We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine's known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme alpha-enolase in vitro, and the expression of the gamma-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer. PMID- 28028543 TI - Solute segregation and deviation from bulk thermodynamics at nanoscale crystalline defects. AB - It has long been known that solute segregation at crystalline defects can have profound effects on material properties. Nevertheless, quantifying the extent of solute segregation at nanoscale defects has proven challenging due to experimental limitations. A combined experimental and first-principles approach has been used to study solute segregation at extended intermetallic phases ranging from 4 to 35 atomic layers in thickness. Chemical mapping by both atom probe tomography and high-resolution scanning transmission electron microscopy demonstrates a markedly different composition for the 4-atomic-layer-thick phase, where segregation has occurred, compared to the approximately 35-atomic-layer thick bulk phase of the same crystal structure. First-principles predictions of bulk free energies in conjunction with direct atomistic simulations of the intermetallic structure and chemistry demonstrate the breakdown of bulk thermodynamics at nanometer dimensions and highlight the importance of symmetry breaking due to the proximity of interfaces in determining equilibrium properties. PMID- 28028544 TI - General and programmable synthesis of hybrid liposome/metal nanoparticles. AB - Hybrid liposome/metal nanoparticles are promising candidate materials for biomedical applications. However, the poor selectivity and low yield of the desired hybrid during synthesis pose a challenge. We designed a programmable liposome by selective encoding of a reducing agent, which allows self crystallization of metal nanoparticles within the liposome to produce stable liposome/metal nanoparticles alone. We synthesized seven types of liposome/monometallic and more complex liposome/bimetallic hybrids. The resulting nanoparticles are tunable in size and metal composition, and their surface plasmon resonance bands are controllable in visible and near infrared. Owing to outer lipid bilayer, our liposome/Au nanoparticle shows better colloidal stability in biologically relevant solutions as well as higher endocytosis efficiency than gold nanoparticles without the liposome. We used this hybrid in intracellular imaging of living cells via surface-enhanced Raman spectroscopy, taking advantage of its improved physicochemical properties. We believe that our method greatly increases the utility of metal nanoparticles in in vivo applications. PMID- 28028545 TI - Characterization of the Candida albicans Amino Acid Permease Family: Gap2 Is the Only General Amino Acid Permease and Gap4 Is an S-Adenosylmethionine (SAM) Transporter Required for SAM-Induced Morphogenesis. AB - Amino acids are key sources of nitrogen for growth of Candida albicans. In order to detect and take up these amino acids from a broad range of different and changing nitrogen sources inside the host, this fungus must be able to adapt via its expression of genes for amino acid uptake and further metabolism. We analyzed six C. albicans putative general amino acid permeases based on their homology to the Saccharomyces cerevisiae Gap1 general amino acid permease. We generated single- and multiple-deletion strains and found that, based on growth assays and transcriptional or posttranscriptional regulation, Gap2 is the functional orthologue to ScGap1, with broad substrate specificity. Expression analysis showed that expression of all GAP genes is under control of the Csy1 amino acid sensor, which is different from the situation in S. cerevisiae, where the expression of ScGAP1 is not regulated by Ssy1. We show that Gap4 is the functional orthologue of ScSam3, the only S-adenosylmethionine (SAM) transporter in S. cerevisiae, and we report that Gap4 is required for SAM-induced morphogenesis. IMPORTANCECandida albicans is a commensal organism that can thrive in many niches in its human host. The environmental conditions at these different niches differ quite a bit, and this fungus must be able to sense these changes and adapt its metabolism to them. Apart from glucose and other sugars, the uptake of amino acids is very important. This is underscored by the fact that the C. albicans genome encodes 6 orthologues of the Saccharomyces. cerevisiae general amino acid permease Gap1 and many other amino acid transporters. In this work, we characterize these six permeases and we show that C. albicans Gap2 is the functional orthologue of ScGap1 and that C. albicans Gap4 is an orthologue of ScSam3, an S-adenosylmethionine (SAM) transporter. Furthermore, we show that Gap4 is required for SAM-induced morphogenesis, an important virulence factor of C. albicans. PMID- 28028546 TI - Identification and Characterization of Novel Rat Polyomavirus 2 in a Colony of X SCID Rats by P-PIT assay. AB - Polyomaviruses (PyVs) are known to infect a wide range of vertebrates and invertebrates and are associated with a broad spectrum of diseases, including cancers, particularly in immune-suppressed hosts. A novel polyomavirus, designated rat polyomavirus 2 (RatPyV2), was identified from a breeding colony of rats having X-linked severe combined immunodeficiency. Using a human panpolyomavirus immunohistochemistry test (P-PIT), RatPyV2 was initially detected in the parotid salivary gland of a colony member. Rolling circle amplification using DNA from harderian and parotid glands identified a novel 5.1-kb polyomavirus genome closely related to human Washington University (WU) and Karolinska Institute (KI) and vole polyomaviruses but notably divergent from Rattus norvegicus PyV1 (RnorPyV1; also designated RatPyV1). Further screening showed RatPyV2 inclusion body infection in the lung epithelium and variably in other respiratory, reproductive, and glandular tissues of 12/12 (100%) rats. IMPORTANCE Although P-PIT was developed to detect diseases associated with known human polyomaviruses, the identification of a new polyomavirus in rats suggests that it may have utility as a broad-based screen for new, as well as known polyomaviruses. Our findings suggest that RatPyV2 may be a commensal infection of laboratory rats that can lead to disseminated disease in T cell immune-deficient rats. Infection of the X-SCID rats with RatPyV2 and Pneumocystis carinii is a potential model for coinfection pathogenesis and treatment options during transplant preclinical studies. PMID- 28028547 TI - Recent Outbreaks of Shigellosis in California Caused by Two Distinct Populations of Shigella sonnei with either Increased Virulence or Fluoroquinolone Resistance. AB - Shigella sonnei has caused unusually large outbreaks of shigellosis in California in 2014 and 2015. Preliminary data indicated the involvement of two distinct bacterial populations, one from San Diego and San Joaquin (SDi/SJo) and one from the San Francisco (SFr) Bay area. Whole-genome analysis and antibiotic susceptibility testing of 68 outbreak and archival isolates of S. sonnei were performed to investigate the microbiological factors related to these outbreaks. Both SDi/SJo and SFr populations, as well as almost all of the archival S. sonnei isolates belonged to sequence type 152 (ST152). Genome-wide single nucleotide polymorphism (SNP) analysis clustered the majority of California (CA) isolates to an earlier described lineage III. Isolates in the SDi/SJo population had a novel lambdoid bacteriophage carrying genes encoding Shiga toxin (STX) that were most closely related to that found in Escherichia coli O104:H4. However, the STX genes (stx1A and stx1B) from this novel phage had sequences most similar to the phages from Shigella flexneri and S. dysenteriae. The isolates in the SFr population were resistant to ciprofloxacin due to point mutations in gyrA and parC genes and were related to the fluoroquinolone-resistant S. sonnei clade within lineage III that originated in South Asia. The emergence of a highly virulent S. sonnei strain and introduction of a fluoroquinolone-resistant strain reflect the changing traits of this pathogen in California. An enhanced monitoring is advocated for early detection of future outbreaks caused by such strains. IMPORTANCE Shigellosis is an acute diarrheal disease causing nearly half a million infections, 6,000 hospitalizations, and 70 deaths annually in the United States. S. sonnei caused two unusually large outbreaks in 2014 and 2015 in California. We used whole-genome sequencing to understand the pathogenic potential of bacteria involved in these outbreaks. Our results suggest the persistence of a local S. sonnei SDi/SJo clone in California since at least 2008. Recently, a derivative of the original clone acquired the ability to produce Shiga toxin (STX) via exchanges of bacteriophages with other bacteria. STX production is connected with more severe disease, including bloody diarrhea. A second population of S. sonnei that caused an outbreak in the San Francisco area was resistant to fluoroquinolones and showed evidence of connection to a fluoroquinolone-resistant lineage from South Asia. These emerging trends in S. sonnei populations in California must be monitored for future risks of the spread of increasingly virulent and resistant clones. PMID- 28028549 TI - SSUnique: Detecting Sequence Novelty in Microbiome Surveys. AB - High-throughput sequencing of small-subunit (SSU) rRNA genes has revolutionized understanding of microbial communities and facilitated investigations into ecological dynamics at unprecedented scales. Such extensive SSU rRNA gene sequence libraries, constructed from DNA extracts of environmental or host associated samples, often contain a substantial proportion of unclassified sequences, many representing organisms with novel taxonomy (taxonomic "blind spots") and potentially unique ecology. Indeed, these novel taxonomic lineages are associated with so-called microbial "dark matter," which is the genomic potential of these lineages. Unfortunately, characterization beyond "unclassified" is challenging due to relatively short read lengths and large data set sizes. Here we demonstrate how mining of phylogenetically novel sequences from microbial ecosystems can be automated using SSUnique, a software pipeline that filters unclassified and/or rare operational taxonomic units (OTUs) from 16S rRNA gene sequence libraries by screening against consensus structural models for SSU rRNA. Phylogenetic position is inferred against a reference data set, and additional characterization of novel clades is also included, such as targeted probe/primer design and mining of assembled metagenomes for genomic context. We show how SSUnique reproduced a previous analysis of phylogenetic novelty from an Arctic tundra soil and demonstrate the recovery of highly novel clades from data sets associated with both the Earth Microbiome Project (EMP) and Human Microbiome Project (HMP). We anticipate that SSUnique will add to the expanding computational toolbox supporting high-throughput sequencing approaches for the study of microbial ecology and phylogeny. IMPORTANCE Extensive SSU rRNA gene sequence libraries, constructed from DNA extracts of environmental or host associated samples, often contain many unclassified sequences, many representing organisms with novel taxonomy (taxonomic "blind spots") and potentially unique ecology. This novelty is poorly explored in standard workflows, which narrows the breadth and discovery potential of such studies. Here we present the SSUnique analysis pipeline, which will promote the exploration of unclassified diversity in microbiome research and, importantly, enable the discovery of substantial novel taxonomic lineages through the analysis of a large variety of existing data sets. PMID- 28028548 TI - Spatial Molecular Architecture of the Microbial Community of a Peltigera Lichen. AB - Microbes are commonly studied as individual species, but they exist as mixed assemblages in nature. At present, we know very little about the spatial organization of the molecules, including natural products that are produced within these microbial networks. Lichens represent a particularly specialized type of symbiotic microbial assemblage in which the component microorganisms exist together. These composite microbial assemblages are typically comprised of several types of microorganisms representing phylogenetically diverse life forms, including fungi, photosymbionts, bacteria, and other microbes. Here, we employed matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry to characterize the distributions of small molecules within a Peltigera lichen. In order to probe how small molecules are organized and localized within the microbial consortium, analytes were annotated and assigned to their respective producer microorganisms using mass spectrometry-based molecular networking and metagenome sequencing. The spatial analysis of the molecules not only reveals an ordered layering of molecules within the lichen but also supports the compartmentalization of unique functions attributed to various layers. These functions include chemical defense (e.g., antibiotics), light harvesting functions associated with the cyanobacterial outer layer (e.g., chlorophyll), energy transfer (e.g., sugars) surrounding the sun-exposed cyanobacterial layer, and carbohydrates that may serve a structural or storage function and are observed with higher intensities in the non-sun-exposed areas (e.g., complex carbohydrates). IMPORTANCE Microbial communities have evolved over centuries to live symbiotically. The direct visualization of such communities at the chemical and functional level presents a challenge. Overcoming this challenge may allow one to visualize the spatial distributions of specific molecules involved in symbiosis and to define their functional roles in shaping the community structure. In this study, we examined the diversity of microbial genes and taxa and the presence of biosynthetic gene clusters by metagenomic sequencing and the compartmentalization of organic chemical components within a lichen using mass spectrometry. This approach allowed the identification of chemically distinct sections within this composite organism. Using our multipronged approach, various fungal natural products, not previously reported from lichens, were identified and two different fungal layers were visualized at the chemical level. PMID- 28028550 TI - Development of a Facile and High-Throughput Bioluminescence Assay Using Vibrio fischeri to Determine the Chronic Toxicity of Contaminated Samples. AB - Chronic toxicity testing using the luminescent bacterium, Vibrio fischeri, has recently been demonstrated to be a suitable bioassay for water quality monitoring. The toxicity evaluation is typically based on determining the EC50 at specific time points which may lead to overlooking the dynamic nature of luminescence response and limits information regarding the possible mechanisms of action of target compounds. This study investigated various approaches (standard, integral, and luminescence rate inhibition) to evaluate the chronic toxicity of three target compounds (atrazine, trimethoprim, and acetamiprid) using a 96-well plate based method. The chronic toxicity assay and the methods used for EC50 calculation provided in this work resulted in a high-throughput method of chronic toxicity testing and indicated lower EC50 than the values provided by the standard short term methods, indicating higher toxicity. This study emphasizes the need for additional chronic toxicity testing to further evaluate the toxicity of compounds or unknown samples. PMID- 28028551 TI - Structure-based engineering of a pectate lyase with improved specific activity for ramie degumming. AB - Biotechnological applications of microbial pectate lyases (Pels) in plant fiber processing are promising, eco-friendly substitutes for conventional chemical degumming processes. However, to potentiate the enzymes' use for industrial applications, resolving the molecular structure to elucidate catalytic mechanisms becomes necessary. In this manuscript, we report the high resolution (1.45 A) crystal structure of pectate lyase (pelN) from Paenibacillus sp. 0602 in apo form. Through sequence alignment and structural superposition with other members of the polysaccharide lyase (PL) family 1 (PL1), we determined that pelN shares the characteristic right-handed beta-helix and is structurally similar to other members of the PL1 family, while exhibiting key differences in terms of catalytic and substrate binding residues. Then, based on information from structure alignments with other PLs, we engineered a novel pelN. Our rational design yielded a pelN mutant with a temperature for enzymatic activity optimally shifted from 67.5 to 60 degrees C. Most importantly, this pelN mutant displayed both higher specific activity and ramie fiber degumming ability when compared with the wild-type enzyme. Altogether, our rational design method shows great potential for industrial applications. Moreover, we expect the reported high-resolution crystal structure to provide a solid foundation for future rational, structure based engineering of genetically enhanced pelNs. PMID- 28028552 TI - Venous thromboembolic events in critically ill traumatic brain injury patients. AB - PURPOSE: To estimate the prevalence, risk factors, prophylactic treatment and impact on mortality for venous thromboembolism (VTE) in patients with moderate to severe traumatic brain injury (TBI) treated in the intensive care unit. METHODS: A post hoc analysis of the erythropoietin in traumatic brain injury (EPO-TBI) trial that included twice-weekly lower limb ultrasound screening. Venous thrombotic events were defined as ultrasound-proven proximal deep venous thrombosis (DVT) or clinically detected pulmonary embolism (PE). Results are reported as events, percentages or medians and interquartile range (IQR). Cox regression analysis was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to VTE and death. RESULTS: Of 603 patients, 119 (19.7%) developed VTE, mostly comprising DVT (102 patients, 16.9%) with a smaller number of PE events (24 patients, 4.0%). Median time to DVT diagnosis was 6 days (IQR 2-11) and to PE diagnosis 6.5 days (IQR 2-16.5). Mechanical prophylaxis (MP) was used in 91% of patients on day 1, 97% of patients on day 3 and 98% of patients on day 7. Pharmacological prophylaxis was given in 5% of patients on day 1, 30% of patients on day 3 and 57% of patients on day 7. Factors associated with time to VTE were age (HR per year 1.02, 95% CI 1.01-1.03), patient weight (HR per kg 1.01, 95% CI 1-1.02) and TBI severity according to the International Mission for Prognosis and Analysis of Clinical Trials risk of poor outcome (HR per 10% increase 1.12, 95% CI 1.01-1.25). The development of VTE was not associated with mortality (HR 0.92, 95% CI 0.51-1.65). CONCLUSIONS: Despite mechanical and pharmacological prophylaxis, VTE occurs in one out of every five patients with TBI treated in the ICU. Higher age, greater weight and greater severity of TBI increase the risk. The development of VTE was not associated with excess mortality. PMID- 28028553 TI - Family care, visiting policies, ICU performance, and efficiency in resource use: insights from the ORCHESTRA study. PMID- 28028554 TI - Imminent risk of fracture after fracture. AB - : The risk of major osteoporotic fracture (MOF) after a first MOF is increased over the whole duration of follow-up, but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner. INTRODUCTION: A history of fracture is a strong risk factor for future fractures. The aim of the present study was to determine whether the predictive value of a past MOF for future MOF changed with time. METHODS: The study was based on a population-based cohort of 18,872 men and women born between 1907 and 1935. Fractures were documented over 510,265 person-years. An extension of Poisson regression was used to investigate the relationship between the first MOF and the second. All associations were adjusted for age and time since baseline. RESULTS: Five thousand thirty-nine individuals sustained one or more MOFs, of whom 1919 experienced a second MOF. The risk of a second MOF after a first increased by 4% for each year of age (95% CI 1.02-1.06) and was 41% higher for women than men (95% CI 1.25-1.59). The risk of a second MOF was highest immediately after the first fracture and thereafter decreased with time though remained higher than the population risk throughout follow-up. For example, 1 year after the first MOF, the risk of a second fracture was 2.7 (2.4-3.0) fold higher than the population risk. After 10 years, this risk ratio was 1.4 (1.2-1.6). The effect was more marked with increasing age. CONCLUSIONS: The risk of MOF after a first MOF is increased over the whole follow-up, but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner, particularly in the elderly. PMID- 28028555 TI - Hip and other fragility fracture incidence in real-world teriparatide-treated patients in the United States. AB - : This study demonstrates real-world effectiveness of teriparatide in reducing the risk of hip and other fragility fractures. Fracture incidence significantly decreased as adherence and persistence increased for any clinical, vertebral, nonvertebral, and hip fractures among patients who were observed for 2 years after teriparatide initiation. INTRODUCTION: Examine the relationship of treatment adherence and persistence to teriparatide with hip and other fractures. METHODS: Truven MarketScan Research Databases, 2004 through 2014, provided teriparatide users >=18 years old with continuous coverage 12 months pre- and 24 months post-teriparatide prescription. Adherence (medication possession ratio, MPR) groups were defined as high (>=0.80), medium (0.50 <= MPR < 0.80), and low (<0.50). Persistence, allowing for <=90-day gaps between prescriptions, was defined as 1-6, 7-12, 13-18, and 19-24 months. Fracture incidence was summarized and compared by using ANOVA and logistic regression models; the effects of adherence were examined with Cox proportional hazard models with time-dependent covariates for teriparatide exposure. RESULTS: Among 14,284 teriparatide subjects, mean age was 68.4 years, 89.8% were female, and 29.6% had a fracture in the previous year; these characteristics were similar across MPR and persistence groups. The effects of adherence and persistence to teriparatide were statistically significant (P < .001) for all fracture types except wrist (P >= .125). By logistic regression, high vs low adherence was associated with reduced risk for any (OR = 0.67; P < .001); vertebral (OR = 0.64; P < .001); nonvertebral (OR = 0.71; P < .001); and hip fractures (OR = 0.52; P < .001) and longer (19-24 months) vs shorter persistence (1-6 months) was associated with reduced risk for any (OR = 0.63, P < .001); vertebral (OR = 0.56, P < .001); nonvertebral (OR = 0.69, P < .001); and hip fractures (OR = 0.48, P < .001). Cox models revealed a significantly reduced risk between high and low adherence for any (OR = 0.69, P < .001); vertebral (OR = 0.60, P < .001); nonvertebral (OR = 0.77, P < .001); and hip fractures (OR = 0.55, P < .001). CONCLUSION: Fracture incidence significantly decreased as persistence and adherence to teriparatide increased. PMID- 28028556 TI - Effect of intravenous gadoxetate disodium and flip angle on hepatic proton density fat fraction estimation with six-echo, gradient-recalled-echo, magnitude based MR imaging at 3T. AB - PURPOSE: The aim of the study was to determine in patients undergoing gadoxetate disodium (Gx)-enhanced MR exams whether proton density fat fraction (PDFF) estimation accuracy of magnitude-based multi-gradient-echo MRI (MRI-M) could be improved by using high flip angle (FA) on post-contrast images. MATERIALS AND METHODS: Thirty-one adults with known or suspected hepatic steatosis undergoing 3T clinical Gx-enhanced liver MRI were enrolled prospectively. MR spectroscopy (MRS), the reference standard, was performed before Gx to measure MRS-PDFF. Low (10 degrees )- and high (50 degrees )-flip angle (FA) MRI-M sequences were acquired before and during the hepatobiliary phase after Gx administration; MRI PDFF was estimated in the MRS-PDFF voxel location. Linear regression parameters (slope, intercept, average bias, R 2) were calculated for MRS-PDFF as a function of MRI-PDFF for each MRI-M sequence (pre-Gx low-FA, pre-Gx high-FA, post-Gx low FA, post-Gx high-FA) for all patients and for patients with MRS-PDFF <10%. Regression parameters were compared (Bonferroni-adjusted bootstrap-based tests). RESULTS: Three of the four MRI-M sequences (pre-Gx low-FA, post-Gx low-FA, post Gx high-FA) provided relatively unbiased PDFF estimates overall and in the low PDFF range, with regression slopes close to 1 and intercepts and biases close to zero. Pre-Gx high-FA MRI overestimated PDFF in proportion to MRS-PDFF, with slopes of 0.72 (overall) and 0.63 (low-PDFF range). Based on regression bias closest to 0, the post-Gx high-FA sequence was the most accurate overall and in the low-PDFF range. This sequence provided statistically significant improvements in at least two regression parameters compared to every other sequence. CONCLUSION: In patients undergoing Gx-enhanced MR exams, PDFF estimation accuracy of MRI-M can be improved by using high-FA on post-contrast images. PMID- 28028557 TI - 18F-FDG PET/CT delayed images with forced diuresis for revaluating abdominopelvic malignancies. AB - PURPOSE: The aim of this retrospective study was to evaluate the role of delayed images after forced diuresis coupled with oral hydration in abdominopelvic 18F FDG PET/CT. MATERIALS AND METHODS: Forty-six patients consisting of 17 urological diseases, 9 gynecological tumors, 18 colorectal malignancies, and 2 cancers of unknown primary site were retrospectively analyzed. All patients who presented with indeterminate or equivocal abdominopelvic foci on standard 18F-FDG PET/CT underwent a delayed abdominopelvic imaging after administration of 20 mg furosemide intravenously and extra water intake of 500 mL. PET/CT images before and after furosemide were compared with each other and their findings correlated with pathology or clinical follow-up (>6 months). RESULTS: On initial PET/CT, the glucose metabolism characters of lesions were disguised by radioactive urine, or some undetermined 18F-FDG accumulating foci near the urinary tract appeared. While postdiuretic PET/CT demonstrated an excellent urinary tracer washout, and hypermetabolic lesions could be clearly detected and precisely localized in all cases. On the other hand, the suspected active foci caused by potential stagnation of excreted 18F-FDG in urinary tract were eliminated. The sensitivity, specificity, and accuracy were 94.4% (34/36), 8/10, 91.3% (42/46), respectively. Furthermore, the additional lesions with surrounding invasion or locoregional metastasis were discovered in 8 of 46 (17.4%) patients only by the delayed images, including 2 gynecological and 6 rectal malignancies. CONCLUSION: Detection of abdominopelvic malignancies can be improved using delayed 18F-FDG PET/CT images after a diuretic and oral hydration. PMID- 28028558 TI - mRNA length-sensing in eukaryotic translation: reconsidering the "closed loop" and its implications for translational control. AB - Most eukaryotic mRNAs are recruited to the ribosome by recognition of a 5' m7GpppN cap. 30 years of genetic and biochemical evidence point to a role for interaction between the 5' cap-interacting factors and the 3' poly(A)-binding protein in bringing the ends of the mRNA into close proximity and promoting both translation and stability of the mRNA, in a form known as the "closed loop". However, the results of recent RNA-protein interaction studies suggest that not all mRNAs have equal access to the closed loop factors. Furthermore, association with closed loop factors appears to be highly biased towards mRNAs with short open reading frames, echoing the trend for higher translation of short mRNAs that has been observed in many eukaryotes. We recently reported that the ribosomal signaling scaffold protein RACK1 promotes the efficient translation of short mRNAs that strongly associate with the closed loop factors. Here, we discuss the implications of these observations with respect to translational control and suggest avenues through which the universality of the closed loop in eukaryotic translation could be revisited. PMID- 28028559 TI - Real world epidemiology of myeloproliferative neoplasms: a population based study in Korea 2004-2013. AB - Myeloproliferative neoplasms (MPNs), with an expected increment in number, impose substantial economic and social burdens. To this end, we conducted a nationwide population-based descriptive epidemiology study. We also investigated medical cost associated with MPNs. Prevalence was the highest for essential thrombocythemia (ET) (range 4.1-9.0 per 100,000), followed by polycythemia vera (PV) (range 2.8-5.4 per 100,000) and primary myelofibrosis (PMF) (range 0.5-0.9 per 100,000). ET incurred the highest cumulative total cost at US$35 million and the most frequent hospital visits, while PMF incurred the highest average cost per person at US$5000. The mean hemoglobin level was 16.9 +/- 2.2 g/dL for PV males and 15.5 +/- 2.7 g/dL for PV females. Further analyses on hemoglobin levels showed the true positive rate of PV from the significantly elevated hemoglobin group (defined as >18.5 g/dL for men and >16.5 g/dL for women) was 3.01% and that of MPNs was 3.1%. Here, we provide the biggest population-based report on MPN epidemiology that can readily be used as a representative Asian data. PMID- 28028560 TI - Pathophysiology, prevention, treatment, and outcomes of intestinal failure associated liver disease. AB - BACKGROUND: Intestinal failure-associated liver disease (IFALD) remains a serious problem in the treatment of infants with nutritional problems and short bowel syndrome. METHODS: A review of the recent literature from 2010 to 2016, concentrating on articles related to the pathophysiology of IFALD and to outcomes of novel nutritional and pharmacological therapies for neonatal cholestasis in the post-surgical neonate. RESULTS: The pathophysiology of IFALD relates to an increase sensitivity of the neonatal liver to cholestasis in the non-fed state; prolonged cholestasis almost inevitably results in liver damage which will progress from fibrosis to cirrhosis. Clinically discerned risk factors include premature birth, inflammation, sepsis, disruption of the enterohepatic circulation by creation of a proximal stoma, and the duration and type of parenteral nutritional support. Within the hepatocyte, the regulatory enzyme farsanoid receptor X (FXR) appears to play a pivotal role in the development of cholestasis. Recent studies have shown that its activity is suppressed by sepsis, and by plant phytosterols found in soy-based lipid preparations. This paradigm is reflected in the emerging consensus for the care of post-surgical neonates, which is based around a multi-disciplinary team approach. Using an algorithm-driven approach, an appropriate balance between caloric support and prevention of IFALD can be achieved. CONCLUSIONS: Further prospective studies are required to further refine the optimal sequence of use of these therapies and the long-term effects on neurological development and hepatic function. However, with optimal care, the number of IF patients progressing to end-stage liver disease because of IFALD should be very low. PMID- 28028561 TI - Management of paediatric liver trauma. AB - Of all the intra-abdominal solid organs, the liver is the most vulnerable to blunt abdominal trauma. The majority of liver ruptures present in combination with other abdominal or extra-abdominal injuries. Over the last three decades, the management of blunt liver trauma has evolved from obligatory operative to non operative management in over 90% of cases. Penetrating liver injuries more often require operative intervention and are managed according to adult protocols. The greatest clinical challenge remains the timely identification of the severely damaged liver with immediate and aggressive resuscitation and expedition to laparotomy. The operative management can be taxing and should ideally be performed in a dedicated paediatric surgical centre with experience in dealing with such trauma. Complications can occur early or late and include haemobilia, intrahepatic duct rupture with persistent biliary fistula, bilaemia, intrahepatic haematoma, post-traumatic cysts, vascular outflow obstruction, and gallstones. The prognosis is generally excellent. PMID- 28028562 TI - Characterization of MHC class IA in the endangered southern corroboree frog. AB - Southern corroboree frogs (Pseudophryne corroboree) have declined to near extinction in the wild after the emergence of the amphibian chytrid fungus Batrachochytrium dendrobatidis in southeastern Australia in the 1980s. A major captive breeding and reintroduction program is underway to preserve this iconic species, but improving resistance to B. dendrobatidis would help the wild population to be self-sustaining. Using 3' and 5' rapid amplification of complementary DNA ends (RACE), we characterized the major histocompatibility complex (MHC) class IA locus in this species. We then used sequences generated from RACE to design primers to amplify the peptide-binding region (PBR) of this functional genetic marker. Finally, we analysed the diversity, phylogeny, and selection patterns of PBR sequences from four P. corroboree populations and compared this with other amphibian species. We found moderately high MHC class IA genetic diversity in this species and evidence of strong positive and purifying selection at sites that are associated with putative PBR pockets in other species, indicating that this gene region may be under selection for resistance to Bd. Future studies should focus on identifying alleles associated with Bd resistance in P. corroboree by performing a Bd laboratory challenge study to confirm the functional importance of our genetic findings and explore their use in artificial selection or genetic engineering to increase resistance to chytridiomycosis. PMID- 28028563 TI - Whole genome sequencing reveals a 7 base-pair deletion in DMD exon 42 in a dog with muscular dystrophy. AB - Dystrophin is a key cytoskeletal protein coded by the Duchenne muscular dystrophy (DMD) gene located on the X-chromosome. Truncating mutations in the DMD gene cause loss of dystrophin and the classical DMD clinical syndrome. Spontaneous DMD gene mutations and associated phenotypes occur in several other species. The mdx mouse model and the golden retriever muscular dystrophy (GRMD) canine model have been used extensively to study DMD disease pathogenesis and show efficacy and side effects of putative treatments. Certain DMD gene mutations in high-risk, the so-called hot spot areas can be particularly helpful in modeling molecular therapies. Identification of specific mutations has been greatly enhanced by new genomic methods. Whole genome, next generation sequencing (WGS) has been recently used to define DMD patient mutations, but has not been used in dystrophic dogs. A dystrophin-deficient Cavalier King Charles Spaniel (CKCS) dog was evaluated at the functional, histopathological, biochemical, and molecular level. The affected dog's phenotype was compared to the previously reported canine dystrophinopathies. WGS was then used to detect a 7 base pair deletion in DMD exon 42 (c.6051-6057delTCTCAAT mRNA), predicting a frameshift in gene transcription and truncation of dystrophin protein translation. The deletion was confirmed with conventional PCR and Sanger sequencing. This mutation is in a secondary DMD gene hotspot area distinct from the one identified earlier at the 5' donor splice site of intron 50 in the CKCS breed. PMID- 28028564 TI - Evolution of diffusion tensor imaging parameters after acute subarachnoid haemorrhage: a prospective cohort study. AB - INTRODUCTION: Few studies assessed diffusion tensor imaging (DTI) changes in the acute phase of subarachnoid haemorrhage (SAH). We prospectively evaluated DTI parameters in the acute phase of SAH and 8-10 days after and analysed whether changes could be related to SAH severity or to the development of delayed cerebral ischemia (DCI). METHODS: Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) changes over time were assessed in a prospective cohort of patients with acute SAH. Two MRI studies were performed at <72 h (MRI 1) and 8-10 days (MRI-2). DTI parameters were recorded in 15 ROIs. Linear mixed regression models were used. RESULTS: Forty-two patients were included. Subtle changes in DTI parameters were found between MRI-1 and MRI-2. At the posterior limb of internal capsule (PLIC), a weak evidence of a 0.02 mean increase in FA (p = 0.064) and a 17.55 * 10-6 mm2/s decrease in ADC (p = 0.052) were found in MRI 2. Both FA and ADC changed over time at the cerebellum (increase of 0.03; p = 0.017; decrease of 34.73 * 10-6 mm2/s; p = 0.002, respectively). Patients with DCI had lower FA values on MRI-1 and lower ADC on MRI-2, although not reaching statistical significance, compared to non-DCI patients. DTI parameters on MRI-1 were not correlated to clinical admission scales. CONCLUSION: ADC and FA values show subtle changes over time in acute SAH at the PLIC and cerebellum although not statistically associated with the severity of SAH or the occurrence of DCI. However, DTI changes occurred mainly in DCI patients, suggesting a possible role of DTI as a marker of DCI. PMID- 28028565 TI - Severe cerebral hypovolemia on perfusion CT and lower body weight are associated with parenchymal haemorrhage after thrombolysis. AB - INTRODUCTION: Haemorrhagic transformation of acute ischemic stroke (AIS) and particularly parenchymal haemorrhage (PH) remains a feared complication of intravenous thrombolysis (IVT). We aimed to identify clinical and perfusion CT (PCT) variables which are independently associated with PHs. METHODS: In this observational cohort study, based on the Acute Stroke Registry Analysis of Lausanne (ASTRAL) from 2003 to December 2013, we selected patients with AIS involving the middle cerebral artery (MCA) territory who were thrombolysed within 4.5 h of symptoms' onset and who had a good quality baseline PCT at the beginning of IVT. In addition to demographic, clinical, laboratory and non-contrast CT data, volumes of salvageable tissue and ischemic core on PCT, as well as absolute CBF and CBV values within the ischemic regions were compared in patients with and without PH in multivariate analysis. RESULTS: Of the 190 included patients, 24 (12.6%) presented a PH (11 had PH1 and 13 had PH2). In multivariate analysis of the clinical and radiological variables, the lowest CBV in the core and lower body weight was both significantly associated with PH (p = 0.009 and p = 0.024, respectively). CONCLUSION: In thrombolysed MCA strokes, maximal hypoperfusion severity depicted by lowest CBV values in the core region and lower body weight are independently correlated with PH. This information, if confirmed in other case series, may add to the stratification of revascularisation decisions in patients with a perceived high PH risk. PMID- 28028566 TI - Lacinutrix chionocetis sp. nov., isolated from gut of a red snow crab. AB - A Gram-negative, aerobic, non-motile, rod-shaped bacterial strain, designated MAB 07T, was isolated from the gut of a red snow crab. The novel strain grew optimally at 20 degrees C, pH 7.0-8.0, and in the presence of 3% (w/v) NaCl. A phylogenetic analysis based on the 16S rRNA gene sequence indicated that the strain MAB-07T belongs to the type strains of species of the genus Lacinutrix. Strain MAB-07T exhibited 16S rRNA gene sequence similarity values of 95.5-97.8% with the type strains of species of the genus Lacinutrix. The predominant cellular fatty acids of strain MAB-07T were iso-C15:1 G (27.5%) and iso-C15:0 (21.7%). The major respiratory quinine was identified as MK-6. The polar lipids consisted of phosphatidylethanolamine, four unidentified aminolipids, and two unidentified lipids. The genomic DNA G + C content was determined to be 33.3%, and its DNA-DNA relatedness values with the type strains of L. venerupis, L. mariniflava, L. jangbogonensis, L. algicola, and Olleya aquimaris were 28-32%. Based on the data from this polyphasic taxonomic study, strain MAB-07T is considered to represent a novel species of the genus Lacinutrix, for which the name L. chionocetis sp. nov. is proposed. The type strain is MAB-07T (=KCTC 42767T = JCM 30988T). PMID- 28028567 TI - The use of Achilles tendon allograft for latissimus dorsi tendon reconstruction: a minimally invasive technique. AB - Treatment of subacute, retracted latissimus dorsi and teres major tendon ruptures in young overhead athletes is challenging. This case report describes management of a subacute retracted latissimus dorsi and teres major rupture with Achilles tendon allograft reconstruction using a two-incision minimally invasive technique. Level of evidence V. PMID- 28028568 TI - Arthroscopic all-inside ramp lesion repair using the posterolateral transseptal portal view. AB - PURPOSE: The purpose of this study was to evaluate and describe the clinical results and outcomes of a novel method for all-inside suture repair of medial meniscus ramp lesions through posteromedial and posterolateral transseptal portals during anterior cruciate ligament (ACL) reconstruction. Further, this investigation compared the posterolateral view to the notch view for diagnosis and repair. METHODS: Between 2011 and 2014, 166 patients had ramp lesions concomitantly with ACL injury; 128 patients (107 men and 21 women) were enrolled in the study after qualification. All patients underwent repair of the posterior horn ramp lesion of the medial meniscus, using a suture hook device with PDS No. 1 through a posteromedial portal while viewing from the posterolateral transseptal portal during ACL reconstruction, with a minimum of a 2-year follow up. RESULTS: Patients were followed up for a minimum of 2 years (range 24-47 months). Their average Lysholm score increased from 61.7 +/- 3.2 preoperatively to 87.8 +/- 3.9 at last follow-up (p < 0.001). Moreover, their average IKDC scores also improved from 53.6 +/- 2.1 (pre-op) to 82.1 +/- 3.5 (at last follow up) (p < 0.001). The peroneal nerve and the popliteal neurovascular bundle were not damaged in any of the patients. CONCLUSION: This study provides evidence that the posterolateral transseptal technique protects neurovascular structures. This technique may be used safely and easily for repair of the posterior horn ramp lesion of the medial meniscus during ACL reconstruction. LEVEL OF EVIDENCE: IV. PMID- 28028569 TI - Functional testing and return to sport following stabilization surgery for recurrent lateral patellar instability in competitive athletes. AB - PURPOSE: Medial patellofemoral ligament (MPFL) reconstruction and tibial tubercle osteotomy are commonly used to treat recurrent lateral patellar instability, yet there are limited available data on return to sport (RTS) following these procedures. The purpose of this study is to evaluate patient factors associated with excellent functional outcomes, including successful RTS, following surgical stabilization including MPFL reconstruction in competitive athletes with recurrent lateral patellar instability. METHODS: Athletes undergoing primary MPFL reconstruction for recurrent lateral instability from 2005 to 2013 were identified at a single institution. Concomitant procedures, such as tibial tubercle osteotomy (TTO), were included. Patient demographic information, including BMI, gender, age, and pre-injury Tegner score, was recorded. In addition, radiographs were reviewed for pre-operative patellar height (Caton Deschamps index) and trochlear dysplasia (Dejour classification). All patients underwent a standardized rehabilitation/post-operative protocol, with isokinetic strength and functional testing being performed at 6 months post-operatively. Final Tegner scores, RTS status, subjective instability ratings, and Kujala scores were collected at a minimum of 2 years. Chi-squared analysis for categorical variables and Wilcoxon rank-sum analysis for continuous variables were used to determine the relationship between the previously mentioned patient and knee characteristics with isokinetic data, RTS status, or Kujala scores. RESULTS: Thirty-nine athletes (23 male, 16 female) at a mean age of 17.5 +/- 2.9 years (range, 13-26) underwent primary MPFL reconstruction (32 autografts, seven allografts) for recurrent patellar instability with a mean follow-up of 47.0 +/- 16.4 months. Sixteen patients (41%) underwent concomitant tibial tubercle osteotomies. Isokinetic data collected at 6 months post-operatively demonstrated mean knee flexion and extension strength deficits of 15.8 +/- 10.1% and 21.4 +/- 14.3%, respectively, compared to the contralateral leg (p < 0.001 for both). Patients who underwent concomitant tibial tubercle osteotomy (p = 0.04), males (p = 0.01) and those with patella alta (p = 0.04) had weaker 6-month isokinetic testing. Thirty-three of the thirty-nine (85%) athletes were able to RTS at a mean of 8.1 +/- 3.9 months. Patients undergoing MPFL with concomitant TTO (p = 0.02) returned to sport at a slower rate. One patient (3%) reported an episode of recurrent dislocation requiring revision surgery. Kujala and Tegner scores at final follow-up were 91.1 +/- 6.3 and 6 (range, 4-9), respectively. CONCLUSION: Surgical stabilization including MFPL reconstruction for recurrent lateral patellar instability is an effective procedure for returning athletes to competitive sports. However, strength deficits persist at 6 months after surgery, especially in those undergoing concomitant TTO, which may delay return to sport. Physicians can use these results to counsel patients that return to competitive sports is safe with good clinical outcomes and low rate of recurrence at 4-year follow-up; however, predisposing factors, like a lateralized tibial tubercle, should be addressed if necessary, but athletes should be counselled that a slower recovery and longer return to sport time may be expected. LEVEL OF EVIDENCE: IV. PMID- 28028570 TI - Comparable outcomes after total knee arthroplasty in patients under 55 years than in older patients: a matched prospective study with minimum follow-up of 10 years. AB - PURPOSE: To compare outcomes after TKA for osteoarthritis between patients younger than 55 years and older patients. METHODS: A cohort of 61 patients aged 55 years or younger was prospectively matched for gender, body mass index and knee function with patients with median age of 66 (range 60-70) years. Clinical evaluation was performed by the Knee Society scores (KSS), reduced Western Ontario and McMasters Universities (WOMAC) and Short-Form 12 (SF12) questionnaires. Radiological evaluation was also performed. RESULTS: The median follow-up was 12 (range 10-14) years. Survival at 14 years was 96.7% (95% CI 92 100%) in the younger group and 98.2% (95% CI 95-100%) in the older group (n.s.). There was no deep infection or loosening of femoral or patellar component in either group. In the younger group, 2 patients required revision (aseptic tibial loosening at 8 years, and polyethylene wear at 10 years). In the older group, there was 1 revision (aseptic tibial loosening). Revision rate was not significantly different (n.s.). Multivariate analysis showed no significant relationship between revision and age, gender or BMI. At 5-year follow-up, there were no significant differences between groups in KSS knee or function, WOMAC pain or function, or SF12 physical or mental, but in the last evaluation there were better results in younger patients for KSS-function (p = 0.018), WOMAC function (p = 0.028), SF12-physical (p = 0.001) and SF12-mental (p = 0.035), although these differences were not clinically relevant. A significant decline was noted for KSS-function in either group from 5-year to at last follow-up. CONCLUSIONS: The TKA survival in younger patients was comparable to older active patients, without increased complications or revisions at a minimum follow-up of 10 years. Primary hybrid TKA can provide successful pain relief, function and quality of life in younger patients than 55 years with osteoarthritis. TKA is a suitable option for these young patients with appropriate surgical indications. LEVEL OF EVIDENCE: II. PMID- 28028572 TI - Romanian medicine, European medicine. AB - The aim of the present paper is to present the message transmitted by the Presidential Lecture given during the first congress of arthroscopy organised in Romania, in March 2016, by the Romanian Society of Arthroscopy and Sports Trauma (SRATS). The goal was to present the evolution of medical care in Romania over the years, with the remarkable progress made in the first half of the twentieth century and the current status of arthroscopic surgery as seen from the point of view of medical professionals, as well as from a governmental point of view. PMID- 28028571 TI - Correlation analysis between injury patterns of medial patellofemoral ligament and vastus medialis obliquus after acute first-time lateral patellar dislocation. AB - PURPOSE: To evaluate the correlation between injury patterns of the medial patellofemoral ligament (MPFL) and vastus medialis obliquus (VMO) after acute first-time lateral patellar dislocation (LPD) in adults. METHODS: Magnetic resonance imaging (MRI) was prospectively performed in 132 consecutive adults with acute first-time LPD. Images were acquired and evaluated using standardized protocols. Injury patterns of MPFL were grouped by location and severity for analysis of the prevalence of VMO injury. RESULTS: MRI demonstrated VMO injury in 63 (47.7%) patients. Twenty (38.5%) and 43 cases (56.6%) were present in partial and complete MPFL tear subgroups, respectively. Compared with partial MPFL tears, complete tears showed a higher prevalence of VMO injury (P = 0.044). The mean coronal (28.5 mm) and mean sagittal VMO elevations (20.7 mm) were higher in the complete MPFL tear subgroup than in the partial tear subgroup (19.8 mm, P = 0.005; 11.9 mm, P < 0.001). No correlations were identified between the prevalence of VMO injury and location subgroups of MPFL injury (n.s.). Mean VMO elevations were higher in isolated femoral-side (FEM) and combined MPFL tear (COM) subgroups (mean coronal VMO elevation of 29 mm and mean sagittal VMO elevation of 20.8 mm in the FEM subgroup; mean coronal VMO elevation of 29.6 mm and mean sagittal VMO elevation of 23.1 mm in the COM subgroup) than in the isolated patellar-side MPFL tear (PAT) subgroup (P = 0.022, P < 0.001) (mean coronal VMO elevation of 20.7 mm and mean sagittal VMO elevation of 10.6 mm). CONCLUSIONS: Complete MPFL tear predisposes to VMO injury and has a higher elevation of torn VMO after acute first-time LPD in adults. Isolated femoral-side and combined MPFL tears predispose to higher elevation of torn VMO. LEVEL OF EVIDENCE: IV. PMID- 28028573 TI - Diffusion tensor imaging and tractography of the sciatic nerve: assessment of fractional anisotropy and apparent diffusion coefficient values relative to the piriformis muscle, a preliminary study. AB - OBJECTIVE: Piriformis muscle syndrome (PMS) is underdiagnosed. To evaluate the potential of diffusion tensor imaging and diffusion tensor tractography as innovative tools for the diagnosis of PMS by functional assessment of the sciatic nerve, the aims of this study are to assess the reproducibility and to evaluate the changes in the parameters at levels proximal and distal to the piriformis. MATERIALS AND METHODS: Fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) of the sciatic nerve at three levels were quantified twice each by two examiners using the fiber-tracking method. In the first part of the study, laterality and reproducibility were evaluated using intraclass correlation coefficients (ICC) in ten healthy volunteers. In the second part of the study, the healthy side and symptomatic side were assessed in ten consecutive patients with sciatica. There were three patients with no findings on lumbar magnetic resonance imaging (MRI). RESULTS: There was no laterality in either FA or ADC values in asymptomatic patients at any level. The mean intra-rater ICC was 0.90 and the mean inter-rater ICC was 0.87. FA was significantly lower and ADC significantly higher on the symptomatic side at each level in patients with sciatica. In the three sciatica patients with no findings on lumbar MRI, FA was significantly lower and ADC was significantly higher only at levels distal to the piriformis. These patients experienced full pain relief after ultrasound-guided injection of local anesthesia. CONCLUSIONS: Diffusion tensor imaging and diffusion tensor tractography might be innovative tools for the diagnosis of PMS. PMID- 28028574 TI - Prospective pilot study of CT-guided microwave ablation in the treatment of osteoid osteomas. AB - PURPOSE: The aims of this work were to assess the feasibility and efficacy of CT guided microwave ablation (MWA) in the treatment of osteoid osteomas (OOs). MATERIALS AND METHODS: Thirteen consecutive patients (range 11-31 years old) presenting with OO were prospectively included and treated by CT-guided MWA. Power and duration of MWA were both recorded. The patient's pain was assessed using a numeric pain rating scale (NRS), and side effects were recorded during procedures, after 1 day, 7 days and 1 month. The nidus vascularization and the volume of necrosis induced by MWA were assessed using contrast-enhanced MRI. Success was defined as the complete relief of the patient's pain 1 month after the first procedure, associated with necrosis of the nidus on follow-up MRI. RESULTS: The success rate was up to 92.3% (12/13). At 1 day, 7 days and 1 month, the median NRSs were respectively 5 [interquartile range (IQR) 2-5], 0 (IQR 0-1) and 0 (IQR 0-0). Side effects observed were one partial and self-resolving lesion of a sensory branch of the radial nerve and two skin burns. The median power of the MWA used was 60 W (IQR 50-60) with a 1.5-min duration (IQR 1-2), leading to MWA-induced necrosis measuring on average 23 * 15 * 16 mm. CONCLUSION: CT-guided MWA of OO has a success rate that appears to be almost similar to that of laser or radiofrequency ablation, but care must be taken to prevent nerve or skin lesions. PMID- 28028575 TI - 3D-MR vs. 3D-CT of the shoulder in patients with glenohumeral instability. AB - OBJECTIVE: To determine whether 3D-MR osseous reformats of the shoulder are equivalent to 3D-CT osseous reformats in patients with glenohumeral instability. MATERIALS AND METHODS: Patients with glenohumeral instability, who were to be imaged with both CT and MRI, were prospectively selected. CT and MR were performed within 24 h of one another on 12 shoulders. Each MR study included an axial 3D isotropic VIBE sequence. The image data from the isotropic VIBE sequence were post-processed using subtraction and 3D software. CT data were post processed using 3D software. The following measurements were obtained for both 3D CT and 3D-MR post-processed images: height and width of the humeral head and glenoid, Hill-Sachs size and percent humeral head loss (if present), size of glenoid bone loss and percent glenoid bone loss (if present). Paired t-tests and two one-sided tests for equivalence were used to assess the differences between imaging modalities and equivalence. RESULTS: The measurement differences from the 3D-CT and 3D-MR post-processed images were not statistically significant. The measurement differences for humeral height, glenoid height and glenoid width were borderline statistically significant; however, using any adjustment for multiple comparisons, this failed to be significant. Using an equivalence margin of 1 mm for measurements and 1.5% for percent bone loss, the 3D-MR and 3D-CT post processed images were equivalent. CONCLUSION: Three-dimensional-MR osseous models of the shoulder using a 3D isotropic VIBE sequence were equivalent to 3D-CT osseous models, and the differences between modalities were not statistically significant. PMID- 28028576 TI - Protective Capnothorax During Transthoracic Needle Biopsy. AB - PURPOSE: Transthoracic needle biopsy (TTNB) is an established procedure in the management of pulmonary nodules. The most common complications are directly related to crossing the lung or visceral pleura during the biopsy. In this study, we describe the use of carbon dioxide instead of room air to create a protective "capnothorax" during TTNB. MATERIALS AND METHODS: Five patients underwent creation of a capnothorax during TTNB. Parameters recorded were location and size of target, distance from pleura, length of procedure, volume of carbon dioxide, periprocedural complications and biopsy result. RESULTS: Induction of capnothorax was successful in all cases. In two patients, a continuous infusion of carbon dioxide was required to maintain an adequate volume of intrapleural gas. In two patients, the carbon dioxide resolved spontaneously and in the remaining patients it was aspirated at the end of the procedure. All biopsies were diagnostic with no periprocedural or postprocedural complications. CONCLUSION: This study suggests that protective iatrogenic capnothorax is a safe and effective technique during TTNB. The intrinsic properties and availability of carbon dioxide make it an attractive alternative to room air. PMID- 28028577 TI - Percutaneous Ultrasound-Guided Carpal Tunnel Release: Study Upon Clinical Efficacy and Safety. AB - OBJECTIVES: To evaluate the feasibility and 6 months clinical result of sectioning of the transverse carpal ligament (TCL) and median nerve decompression after ultra-minimally invasive, ultrasound-guided percutaneous carpal tunnel release (PCTR) surgery. METHODS: Consecutive patients with carpal tunnel syndrome were enrolled in this descriptive, open-label study. The procedure was performed in the interventional radiology room. Magnetic resonance imaging was performed at baseline and 1 month. The Boston Carpal Tunnel Questionnaire was administered at baseline, 1, and 6 months. RESULTS: 129 patients were enrolled. Significant decreases in mean symptom severity scores (3.3 +/- 0.7 at baseline, 1.7 +/- 0.4 at Month 1, 1.3 +/- 0.3 at Month 6) and mean functional status scores (2.6 +/- 1.1 at baseline, 1.6 +/- 0.4 at Month 1, 1.3 +/- 0.5 at Month 6) were noted. Magnetic resonance imaging showed a complete section of all TCL and nerve decompression in 100% of patients. No complications were identified. CONCLUSIONS: Ultrasound-guided PCTR was used successfully to section the TCL, decompress the median nerve, and reduce self-reported symptoms. PMID- 28028578 TI - Combination of Surgical Drainage and Renal Artery Embolization: An Alternative Treatment for Xanthogranulomatous Pyelonephritis. AB - Conventionally, xanthogranulomatous pyelonephritis is treated with antibiotics and drainage of abscess followed by nephrectomy for definitive treatment. Surgical excision of the affected kidney carries risk of significant complications. An alternative treatment modality is described in the form of embolization of the renal artery to devascularise the renal parenchyma and ablate the renal tissue, thus avoiding a major surgical procedure and the significant risks involved. PMID- 28028579 TI - Prophylactic Uterine Artery Embolization in Mid-trimester Pregnancy Termination for Placenta Previa: Required for All Patients? PMID- 28028580 TI - Arthropods associated with fungal galls: do large galls support more abundant and diverse inhabitants? AB - Fungus-induced galls can attract spore-feeding arthropods as well as gall-feeding ones, resulting in diverse communities. Do large fungal galls support more abundant and diverse arthropod communities than small fungal galls? To address this question, we investigated the structure of the arthropod community associated with bud galls induced by the fungus Melanopsichium onumae on the tree species Cinnamomum yabunikkei (Lauraceae) in central Japan. Thirteen species of arthropods were associated with M. onumae galls. Dominant arthropod species were represented by the larvae of a salpingid beetle (a spore feeder), a nitidulid beetle (a spore feeder), a cosmopterigid moth (a spore feeder), an unidentified moth (a gall tissue feeder), and a drosophilid species (a gall tissue feeder). Arthropod abundance and species richness were positively correlated with gall diameter. The majority of the most abundant species were more frequently found in large galls than in small ones, indicating that large fungal galls, which have more food and/or space for arthropods, could support a more abundant and diverse arthropod community. PMID- 28028583 TI - Syncopation affects free body-movement in musical groove. AB - One of the most immediate and overt ways in which people respond to music is by moving their bodies to the beat. However, the extent to which the rhythmic complexity of groove-specifically its syncopation-contributes to how people spontaneously move to music is largely unexplored. Here, we measured free movements in hand and torso while participants listened to drum-breaks with various degrees of syncopation. We found that drum-breaks with medium degrees of syncopation were associated with the same amount of acceleration and synchronisation as low degrees of syncopation. Participants who enjoyed dancing made more complex movements than those who did not enjoy dancing. While for all participants hand movements accelerated more and were more complex, torso movements were more synchronised to the beat. Overall, movements were mostly synchronised to the main beat and half-beat level, depending on the body-part. We demonstrate that while people do not move or synchronise much to rhythms with high syncopation when dancing spontaneously to music, the relationship between rhythmic complexity and synchronisation is less linear than in simple finger tapping studies. PMID- 28028581 TI - Time trends in first admission rates for schizophrenia and other psychotic disorders in Taiwan, 1998-2007: a 10-year population-based cohort study. AB - PURPOSE: To examine the trend in annual first admission rates for psychotic disorders as a whole as well as individual psychotic disorders in Taiwan from 1998 to 2007, and influences of age, sex, and geographic region on the trend. METHOD: Using the inpatient claims records in the National Health Insurance Research Database, we estimated the yearly first admission rates for schizophrenia and other psychotic disorders, including voluntary (1998-2007) and involuntary (2004-2007) admissions. Both narrow and broad definitions of psychotic disorders were examined. RESULTS: While involuntary first admission rates were stable, a crescendo-decrescendo change in voluntary first admission rates for psychotic disorders was observed, peaking in 2001. The increase from 1998 to 2001 was closely associated with health insurance expansion. Before 2001, the voluntary first admission rates in males aged 15-24 were underestimated as military personnel records were not included in the database. From 2001 to 2007, voluntary first admissions for psychotic disorders decreased 38%; the decrease could not be accounted for by the mild diagnostic shifts away from schizophrenia to affective psychosis or substance-induced psychosis. During the entire observation period, first admission rates for schizophrenia decreased 48%, while affective psychosis increased 84%. Gender disparities in the first admission rates gradually diminished, but geographic disparities persisted. CONCLUSIONS: First admission rates for psychosis significantly reduced in Taiwan between 1998 and 2007, mainly driven by the reduced hospitalization risk for schizophrenia. Special attention should be paid to the increased hospitalization for other types of psychotic disorders (especially affective psychosis) and the unresolved geographic disparities. PMID- 28028582 TI - Genetic dissection of sorghum grain quality traits using diverse and segregating populations. AB - KEY MESSAGE: Coordinated association and linkage mapping identified 25 grain quality QTLs in multiple environments, and fine mapping of the Wx locus supports the use of high-density genetic markers in linkage mapping. There is a wide range of end-use products made from cereal grains, and these products often demand different grain characteristics. Fortunately, cereal crop species including sorghum [Sorghum bicolor (L.) Moench] contain high phenotypic variation for traits influencing grain quality. Identifying genetic variants underlying this phenotypic variation allows plant breeders to develop genotypes with grain attributes optimized for their intended usage. Multiple sorghum mapping populations were rigorously phenotyped across two environments (SC Coastal Plain and Central TX) in 2 years for five major grain quality traits: amylose, starch, crude protein, crude fat, and gross energy. Coordinated association and linkage mapping revealed several robust QTLs that make prime targets to improve grain quality for food, feed, and fuel products. Although the amylose QTL interval spanned many megabases, the marker with greatest significance was located just 12 kb from waxy (Wx), the primary gene regulating amylose production in cereal grains. This suggests higher resolution mapping in recombinant inbred line (RIL) populations can be obtained when genotyped at a high marker density. The major QTL for crude fat content, identified in both a RIL population and grain sorghum diversity panel, encompassed the DGAT1 locus, a critical gene involved in maize lipid biosynthesis. Another QTL on chromosome 1 was consistently mapped in both RIL populations for multiple grain quality traits including starch, crude protein, and gross energy. Collectively, these genetic regions offer excellent opportunities to manipulate grain composition and set up future studies for gene validation. PMID- 28028584 TI - The prognostic significance of atrial fibrillation in heart failure with preserved ejection function: insights from KaRen, a prospective and multicenter study. AB - The prognostic value of atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFPEF) remains controversial. We sought to study the prognostic value of AF in a prospective cohort and to characterize the HFPEF patients with AF. KaRen was a prospective, multicenter, international, observational study intended to characterize HFPEF; 538 patients presenting with an acute decompensated cardiac failure and a left ventricular EF > 45% were included. EKG and echocardiogram performed 4-8 week following the index hospitalization were analyzed in core centers. Clinical and echocardiographic characteristics of patients in sinus rhythm vs. with documented AF at enrolment (decompensated HF), upon their 4-8-week visit (in presumed stable clinical condition) and according to patients' cardiac history, were compared. The primary study endpoint was death from any cause or first hospitalization for decompensated heart failure (HF). A total of 413 patients (32% in AF) were analyzed, with a mean follow-up period of 28 months. The patients were primarily elderly individuals (mean age: 76.2 years), with a slight female predominance and a high prevalence of non-cardiovascular comorbidities. The baseline echocardiographic characteristics and the natriuretic peptide levels were indicative of a more severe heart condition among the patients with AF. However, the patients with AF exhibited a similar survival-free interval compared with the patients in sinus rhythm. In this elderly HFPEF population with a high prevalence of non-cardiovascular comorbidities, the presence of AF was not associated with a worse prognosis despite impaired clinical and echocardiographic features.ClinicalTrials.gov: NCT00774709. PMID- 28028585 TI - Effects of a primary care intervention to improve the quality of zolpidem prescriptions in elderly patients. AB - PURPOSE: The objective of this study was to measure the impact of an intervention on the prescription habits of general practitioners (GPs) in order to improve the quality of zolpidem prescriptions in patients aged 75 or older. METHODS: A prospective multicentric non-randomized trial was performed in the Metropolitan Granada Primary Healthcare Area (Andalusian Public Healthcare Service, Spain), which serves a total population of approximately 675,000 inhabitants. All health centers volunteering to participate in the trial were included. The intervention consisted of training sessions, individualized feedback, clinical information, and financial incentives. A daily dose over 5 mg was considered non-safe. Reduction in non-safe prescriptions of zolpidem in the elderly population became a quality prescribing indicator in a pay-for-performance scheme. RESULTS: Statistically significant differences versus baseline were found between the intervention and control groups in mean zolpidem prescription prevalence (28.5 vs. 37.50/00, respectively; p = 0.008) and mean non-safe zolpidem prescription prevalence (16.5 vs. 34.20/00, respectively; p < 0.001). At the end of the study period, the total number of non-safe prescriptions was 1309, 35% lower versus baseline, with a significant difference of p < 0.001; the number in the intervention (510 vs. 1118; p < 0.001) and control (799 vs. 893; p = 0.0064) groups was also significantly lower, with a significantly greater percentage reduction in the intervention group (54.4 vs. 10.5%, p < 0.001). CONCLUSION: The quality prescribing indicator in our area was improved by the intervention developed. Further studies that include an intervention group of GPs who receive no financial incentive are required to evaluate the relative importance of an economic reward in achieving this improvement. PMID- 28028586 TI - Role of miRNA and its potential as a novel diagnostic biomarker in drug-induced liver injury. AB - PURPOSE: MicroRNAs (miRNA or miR) are the most abundant and stable class of small RNA. Unlike the typical RNA molecules present in the cell, they do not encode proteins but can control translation. and Hhence, they are found to play a major role in the regulation of cellular processes. miRNAs have been shown to differentially regulate various genes, and the expression levels of some miRNAs changes several fold in liver and serum, during drug- induced toxicity. This review summarises some of the latest findings about the biological functions of miRNA and its potential use as diagnostic biomarkers in drug- induced liver injury. METHODS: The information presented in this article is taken from published literature, both original work and reviews on mechanisms of drug- induced liver injury, miRNA in liver pathophysiology, and studies exploring the use of miRNA as biomarker in drug- induced liver injury. Literature search was done using search engines:- PUBMED, Google scholar, and relevant journal sites. RESULTS AND CONCLUSIONS: Recent research provides insight into the ability of miRNA to regulate various pathways in diseased and nondiseased states of liver. They also lay a foundation for development of diagnostic tests utilizing the potential of miRNAs that can not only be used for early detection of DILI but also to differentiate between different types of DILI. More studies on biological functions of miRNA and standardisation of protocol between research laboratories can lead to further advancement in this field. Considering the therapeutic and diagnostic potential of miRNA, the major challenge would be to integrate these findings to clinical settings where it can be used for the treatment of cases with DILI. PMID- 28028587 TI - Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand. AB - BACKGROUND: Zidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network. METHODS: Fourteen cohorts provided data on patients <18 years of age taking ZDV/3TC scored tablets between 2008 and 2012. Rates of Division of AIDS (DAIDS) grade >=3 laboratory adverse events (AEs) for hepatobiliary and haematological disorders were estimated by duration on drug (<12, 12-24, >24 months). Clinical adverse events and reasons for tablet discontinuation were described. RESULTS: Of 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed >=14 kg and were eligible for tablet use; 161 (41%) were aged <10 years on an approved dose, 189 (49%) aged >=10 years on an approved dose, and 30 (8%) were on an unapproved dose. Median age at ZDV/3TC start was 10 years, and 79% had taken ART previously (60% had prior exposure to ZDV/3TC). Overall rates of grade >=3 AEs for absolute neutrophil counts, bilirubin, haemoglobin, platelet counts, white blood cell counts (WBC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were <=2/100 person years (PY) for patients taking approved doses. Two hundred thirty-three (43%) patients were not on ZDV/3TC tablets at most recent follow-up; a small number (17 (7%)) discontinued due to AEs (17 (7%)), and the most common reason for discontinuation was treatment simplification (73 (31%)). CONCLUSIONS: Scored ZDV/3TC tablets, both approved and taken off-label, appear to be well tolerated with few side effects. Few patients discontinued treatment due to toxicity. As ZDV/3TC tablets are taken with other antiretrovirals, it is difficult to infer association between toxicities and specific agents, highlighting the importance of widening long-term pharmacovigilance to a broader spectrum of drug combinations. PMID- 28028588 TI - Microscope-assisted UV-initiated preparation of well-defined porous polymer monolithic plugs in glass microchips for peptide preconcentration. AB - Herein, highly defined monolithic beds were prepared in glass microchips by photopolymerization of ethylene glycol methacrylate phosphate (EGMP), acrylamide, and N,N'-methylenebisacrylamide (BAA) using an epifluorescence microscope as UV irradiation source. Such a fast and easy method allowed precise control of (i) the edge shape, (ii) the location along the microchannel, and (iii) the length of the monolithic plugs within glass microchips. The addition of hydroquinone, a polymerization inhibitor, to the prepolymerization mixture was beneficial for achieving local and robust incorporation of monoliths with sharp edges within microchannels. The monolith length was easily tuned from 160 to 400 MUm through simple change in the magnification of the objective and was found to be repeatable (relative standard deviation <7.5%). Further application for on-chip monolith-assisted solid - phase extraction is demonstrated for fluorescently labeled peptide. Both binding and subsequent elution behaviors were found to fully agree with a cation-exchange mechanism in concordance with the presence of phosphate groups at the monolith surface. Graphical abstract In-chip microscope UV-synthesis of monolithic plugs with sharp edges. PMID- 28028589 TI - Ultrasound-air-assisted demulsified liquid-liquid microextraction by solidification of a floating organic droplet for determination of three antifungal drugs in water and biological samples. AB - A novel ultrasound-air-assisted demulsified liquid-liquid microextraction by solidification of a floating organic droplet (UAAD-LLM-SFO) followed by HPLC-UV detection was developed for the analysis of three antifungal drugs in water and biological samples. In this method, 1-dodecanol was used as the extraction solvent. The emulsion was rapidly formed by pulling in and pushing out the mixture of sample solution and extraction solvent for 5 times repeatedly using a 10-mL glass syringe while sonication was performed. Therefore, an organic dispersive solvent required in common microextraction methods was not used in the proposed method. After dispersing, an aliquot of acetonitrile was introduced as a demulsifier solvent into the sample solution to separate two phases. Therefore, some additional steps, such as the centrifugation, ultrasonication, or agitation of the sample solution, are not needed. Parameters influencing the extraction recovery were investigated. The proposed method showed a good linearity for the three antifungal drugs studied with the correlation coefficients (R 2 > 0.9995). The limits of detection (LODs) and the limits of the quantification (LOQs) were between 0.01-0.03 MUg L-1 and 0.03-0.08 MUg L-1, respectively. The preconcentration factors (PFs) were in the range of 107-116, respectively. The precisions, as the relative standard deviations (RSDs) (n = 5), for inter-day and intra-day analysis were in the range of 2.1-4.5% and 6.5-8.5%, respectively. This method was successfully applied to determine the three antifungal drugs in tap water and biological samples. The recoveries of antifungal drugs in these samples were 92.4-98.5%. Graphical abstract Ultrasound-air-assisted demulsified liquid liquid microextraction by solidification of a floating organic droplet for the analysis of three antifungal drugs prior HPLC-UV. PMID- 28028590 TI - A turn-on fluorescence probe for the selective and sensitive detection of fluoride ions. AB - The sensitive and selective determination of fluoride ions is particularly significant in environmental protection, food safety, and health care products. In this work, a highly selective turn-on fluorescent probe for fluoride ions has been synthesized by simply functionalizing fluorescent isophthalaldehyde with silicone-oxygen bonding. The selectivity of the probe is based on the specific reactivity of the silyl group toward fluoride ions in aqueous solution. The nucleophilic substitution reaction of fluoride ions triggers the cleavage of the Si-O bond to release a strongly fluorescent product, which can be used for the determination of fluoride ions by fluorescence intensity enhancement. The probe molecules are specifically responsive and highly selective for the fluoride anion over other relevant anions and cations. This fluorescent probe also shows high photostability and exhibits good sensitivity for fluoride ions, and the limit of detection is as low as 67 ppb. We have demonstrated its application for on-site sensitive determination of fluoride ions for environmental monitoring and protection. PMID- 28028591 TI - Determination of diuron, terbuthylazine, and terbutryn in wastewater and soil by micellar liquid chromatography. AB - An analytical method for the quantification of the herbicides and algaecides diuron, terbuthylazine, and terbutryn in wastewater and soil by micellar liquid chromatography was developed. The sample preparation was expedited to reduce the number of intermediate steps and the use of chemicals. The analytes in soils were recovered by ultrasonication in the mobile phase. The obtained supernatant and the water samples were directly injected, thus avoiding intermediate steps. The chromatographic behavior of the analytes, depending on the surfactant and alcohol was studied, in order to optimize the chromatographic run, by a chemometrical approach. The herbicides were resolved in <16 min using a C18 column and a mobile phase of 0.07 M sodium dodecyl sulfate/6% 1-pentanol phosphate buffered at pH 3, running under isocratic mode at 1 mL/min. The detection absorbance wavelength was set to 240 nm. The method was successfully validated in terms of selectivity, detection limit (0.06 mg/L in water and 0.3 mg/kg in soil), quantitation range (0.2-2 mg/L in water and 1-10 mg/kg in soil), trueness (-6.1 to +5.0%), precision (<9.4%), and ruggedness (<8.3%). The procedure was reliable, practical, easy-to handle, available, short-time and ecofriendly and useful for routine analysis. Its applicability to real samples was evaluated by analyzing several wastewater, decorative reservoir, and soil samples from agricultural and urban sources. PMID- 28028592 TI - The quantification of short-chain chlorinated paraffins in sediment samples using comprehensive two-dimensional gas chromatography with MUECD detection. AB - The analysis of persistent organic pollutants in environmental samples is a challenge due to the very large number of compounds with varying chemical and physical properties. Chlorinated paraffins (CPs) are complex mixtures of chlorinated n-alkanes with varying chain lengths (C10 to C30) and degree of chlorination (30 to 70% by weight). Their physical-chemical properties make these compounds persistent in the environment and able to bioaccumulate in living organisms. Comprehensive two-dimensional gas chromatography (GC * GC) coupled with micro-electron capture detection (MUECD) was used to separate and quantify short-chain chlorinated paraffins (SCCP) in sediment samples. Distinct ordered bands were observed in the GC * GC chromatograms pointing to group separation. Using the Classification function of the ChromaTOF software, summary tables were generated to determine total area counts to set up multilevel-calibration curves for different technical mixes. Fortified sediment samples were analyzed by GC * GC-MUECD with minimal extraction and cleanup. Recoveries ranged from 120 to 130%. To further validate the proposed method for the analysis of SCCPs, the laboratory participated in interlaboratory studies for the analysis of standards and sediment samples. The results showed recoveries between 75 and 95% and z-score values <2, demonstrating that the method is suitable for the analysis of SCCPs in soil/sediment samples. Graphical abstract Quantification of SCCPs by 2D-GC-MUECD. PMID- 28028593 TI - Quantification of dimethylsulfoniopropionate (DMSP) in Acropora spp. of reef building coral using mass spectrometry with deuterated internal standard. AB - Dimethylsulfoniopropionate (DMSP) in scleractinian coral is usually analysed indirectly as dimethylsulfide (DMS) using gas chromatography (GC) with a sulfur specific detector. We developed a headspace GC method for mass spectral analysis of DMSP in branching coral where hexa-deuterated DMSP (d 6 -DMSP) was added to samples and standards to optimise the analytical precision and quantitative accuracy. Using this indirect HS-GC-MS method, we show that common coral sample handling techniques did not alter DMSP concentrations in Acropora aspera and that endogenous DMS was insignificant compared to the store of DMSP in A. aspera. Field application of the indirect HS-GC-MS method in all seasons over a 5-year period at Heron Island in the southern Great Barrier Reef indicated that healthy colonies of A. aspera ordinarily seasonally conserve their branch tip store of DMSP; however, this store increased to a higher concentration under extended thermal stress conditions driven by a strong El Nino Southern Oscillation event. A liquid chromatography mass spectral method (LC-MS) was subsequently developed for direct analysis of DMSP in branching coral, also utilising the d 6 -DMSP internal standard. The quantitative comparison of DMSP in four species of Acropora coral by indirect HS-GC-MS and direct LC-MS analyses gave equivalent concentrations in A. aspera only; in the other three species, HS-GC-MS gave consistently higher concentrations, indicating that indirect analysis of DMSP may lead to artificially high values for some coral species. Graphical Abstract Dimethylsulfoniopropionate (DMSP) was quantified in Acropora spp. of branching coral using deuterated stable isotope dilution mass spectrometry. PMID- 28028594 TI - Major phytopathogens and strains from cocoa (Theobroma cacao L.) are differentiated by MALDI-MS lipid and/or peptide/protein profiles. AB - Phytopathogens are the main disease agents that promote attack of cocoa plantations in all tropical countries. The similarity of the symptoms caused by different phytopathogens makes the reliable identification of the diverse species a challenge. Correct identification is important in the monitoring and management of these pests. Here we show that matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) in combination with multivariate data analysis is able to rapidly and reliably differentiate cocoa phytopathogens, namely Moniliophthora perniciosa, Phytophthora palmivora, P. capsici, P. citrophthora, P. heveae, Ceratocystis cacaofunesta, C. paradoxa, and C. fimbriata. MALDI-MS reveals unique peptide/protein and lipid profiles which differentiate these phytopathogens at the level of genus, species, and single strain coming from different hosts or cocoa tissues collected in several plantations/places. This fast methodology based on molecular biomarkers is also shown to be sufficiently reproducible and selective and therefore seems to offer a suitable tool to guide the correct application of sanitary defense approaches for infected cocoa plantations. International trading of cocoa plants and products could also be efficiently monitored by MALDI-MS. It could, for instance, prevent the entry of new phytopathogens into a country, e.g., as in the case of Moniliophthora roreri fungus that is present in all cocoa plantations of countries bordering Brazil, but that has not yet attacked Brazilian plantations. Graphical Abstract Secure identification of phytopathogens attacking cocoa plantations has been demonstrated via typical chemical profiles provided by mass spectrometric screening. PMID- 28028595 TI - Comprehensive two-dimensional gas chromatographic profiling and chemometric interpretation of the volatile profiles of sweat in knit fabrics. AB - Human axillary sweat is a poorly explored biofluid within the context of metabolomics when compared to other fluids such as blood and urine. In this paper, we explore the volatile organic compounds emitted from two different types of fabric samples (cotton and polyester) which had been worn repeatedly during exercise by participants. Headspace solid-phase microextraction (SPME) and comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOFMS) were employed to profile the (semi)volatile compounds on the fabric. Principal component analysis models were applied to the data to aid in visualizing differences between types of fabrics, wash treatment, and the gender of the subject who had worn the fabric. Statistical tools included with commercial chromatography software (ChromaTOF) and a simple Fisher ratio threshold-based feature selection for model optimization are compared with a custom-written algorithm that uses cluster resolution as an objective function to maximize in a hybrid backward-elimination forward-selection approach for optimizing the chemometric models in an effort to identify some compounds that correlate to differences between fabric types. The custom algorithm is shown to generate better models than the simple Fisher ratio approach. Graphical Abstract A route from samples and questions to data and then answers. PMID- 28028596 TI - Erratum to: "Inherently chiral" thiophene-based electrodes at work: a screening of enantioselection ability toward a series of pharmaceutically relevant phenolic or catecholic amino acids, amino esters, and amine. PMID- 28028597 TI - Intra and inter-observer reliability of determining degree of pelvic obliquity in neuromuscular scoliosis using the EOS-CHAIR(r) protocol. AB - PURPOSE: Scoliosis with pelvic obliquity (PO) could be investigated with the EOS CHAIR protocol as the most common deformity especially in patients with trunk hypotonia and quadriplegia. However, the intra-observer and inter-observer reliability of various angles assessing PO was not investigated with this new imaging protocol. METHODS: A retrospective cohort of 36 EOS frontal full-spine acquisitions made in sitting position was used. The sacroiliac pelvic obliquity angle, iliac crest pelvic obliquity angle, and ischiatic pelvic obliquity angle were assessed in an intra-observer and inter-observer study. RESULTS: The use of the EOS-CHAIR protocol was implemented satisfactory with a high acceptance rate by all caregivers and patients and their families. Intra-observer and inter observer reliability was excellent for the three tested angular measurements. DISCUSSION: As for idiopathic scoliosis, we postulate the EOS system as being superior to standard radiographs to assess 3D spinal deformities in neuromuscular conditions. The EOS-CHAIR protocol improves preoperative comprehension of the lumbosacral junction anatomy in patients with poor standing or sitting postures. Our results show a very high reliability of three different angular measurements of the frontal pelvic obliquity in sitting position. Then it is possible to use one of these three angles as well as the others to assess frontal pelvic obliquity in neuromuscular patients. This frontal pelvic obliquity protocol in sitting position with the EOS-CHAIR is a validated measurement technique that needs to be used now to measure PO as a critical parameter of the global trunk balance in neuromuscular patients. PMID- 28028598 TI - A comparison of the MOMS trial results to a contemporaneous, single-institution, postnatal closure cohort. AB - PURPOSE: We evaluate a single-institution cohort of mothers contemporaneous with the Management of Myelomeningocele Study (MOMS) trial to determine the generalizability of MOMS results and compare shunt rates. METHODS: A retrospective chart review identified patients with myelomeningocele born between 2003 and 2009. We applied MOMS eligibility criteria and compared sociodemographic variables between patients at our institution who would have been eligible or ineligible and MOMS participants. Finally, we applied the original MOMS primary outcome and the revised primary outcome to our cohort. RESULTS: Of the 78 patients, 55 (70.5%) were eligible for the MOMS trial. Mean maternal age, race, and marital status were different from both MOMS groups. Comparing our series to MOMS postnatal shows fewer female infants (44.9 vs. 63.8%, p = 0.017) and more thoracic lesions (12.8 vs. 3.8%, p = 0.038). Shunt rates in our cohort (84.6%) were higher than MOMS prenatal and similar to MOMS postnatal (44.0 and 83.7%, respectively). Fewer children met the original primary outcome than the postnatal group (84.6 vs. 97.8%, p = 0.002). There was no significant difference between our cohort and the prenatal group (84.6 vs. 72.5%, p = 0.058). When applying the revised criteria, we find the opposite: a significant difference between local and MOMS prenatal (84.6 vs. 49.5%, p < 0.001) but no difference between the local group and MOMS postnatal (84.6 vs. 87.0%, p = 0.662). CONCLUSIONS: Mothers in our cohort differ from mothers enrolled in MOMS via several sociodemographic factors. Baseline fetal characteristics show a significantly higher functional lesion level in between our cohort and MOMS. Treatment of hydrocephalus in our series tracks almost identically with original MOMS shunt criteria. Revision of the criteria led to greater concordance between meeting criteria and receiving a shunt in MOMS patients, but changes the results in our series. PMID- 28028599 TI - Circadian behavior of adult mice exposed to stress and fluoxetine during development. AB - INTRODUCTION: Women of child-bearing age are the population at greatest risk for depression. The stress experienced during pregnancy and the associated antidepressant treatments can both affect fetal development. Fluoxetine (FLX) is among the most common antidepressants used by pregnant women. We have previously demonstrated that perinatal exposure to FLX can alter expression of circadian rhythms in adulthood. Here, we examine the combined effects of maternal stress during pregnancy and perinatal exposure to the antidepressant FLX on the circadian behavior of mice as adults. METHODS: Mouse dams were exposed to chronic unpredictable stress (embryonic (E) day 7 to E18), FLX (E15 to postnatal day 12), a combination of both stress and FLX, or were left untreated. At 2 months of age, male offspring were placed in recording chambers and circadian organization of wheel running rhythms and phase shifts to photic and non-photic stimuli were assessed. RESULTS: Mice exposed to prenatal stress (PS) had smaller light-induced phase delays. Mice exposed to perinatal FLX required more days to re-entrainment to an 8-h phase advance of their light-dark cycle. Mice subjected to either perinatal FLX or to PS had larger light-induced phase advances and smaller phase advances to 8-OH-DPAT. FLX treatment partially reversed the effect of PS on phase shifts to late-night light exposure and to 8-OH-DPAT. CONCLUSIONS: Our results suggest that, in mice, perinatal exposure to either FLX, or PS, or their combination, leads to discernible, persistent changes in their circadian systems as adults. PMID- 28028600 TI - The contribution of alpha4beta2 and non-alpha4beta2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice. AB - RATIONALE: The extent to which non-alpha4beta2 versus alpha4beta2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear. OBJECTIVES: The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-alpha4beta2 nAChR mechanisms. METHODS: Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2 mg/kg) or nicotine (1 mg/kg). Test drugs included mecamylamine; the nAChR agonists epibatidine, nicotine, cytisine, varenicline, and RTI-102; the beta2-containing nAChR antagonist dihydro-beta-erythroidine (DHbetaE); the alpha7 nAChR agonist PNU-282987; the alpha7 antagonist methyllycaconitine (MLA); the alpha3beta4 antagonist 18-methoxycoronaridine (18-MC); and the non-nAChR drugs midazolam and cocaine. RESULTS: In nicotine-trained mice, maximum nicotine appropriate responding was 95% nicotine, 94% epibatidine, 63% varenicline, 58% cytisine, and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was 90% varenicline, 86% epibatidine, 74% cytisine, 80% RTI-102, 50% cocaine, and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHbetaE antagonized the discriminative stimulus and rate-decreasing effects of nicotine but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not the rate-decreasing, effects of epibatidine were antagonized by DHbetaE regardless of the training drug. CONCLUSIONS: These results suggest that alpha4beta2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-alpha4beta2 nAChR activity. PMID- 28028601 TI - Voluntary inhalation of methamphetamine: a novel strategy for studying intake non invasively. AB - RATIONALE: The abuse of the psychostimulant methamphetamine (MA) is associated with substantial costs and limited treatment options. To understand the mechanisms that lead to abuse, animal models of voluntary drug intake are crucial. OBJECTIVES: We aimed to develop a protocol to study long-term non invasive voluntary intake of MA in mice. METHODS: Mice were maintained in their home cages and allowed daily 1 h access to an attached tunnel leading to a test chamber in which nebulized MA was available. Restated, if they went to the nebulizing chamber, they self-administered MA by inhalation. This protocol was compared to injected and to imposed exposure to nebulized MA, in a series of seven experiments. RESULTS: We established a concentration of nebulized MA at which motor activity increases following voluntary intake resembled that following MA injection and imposed inhalation. We found that mice regulated their exposure to MA, self-administering for shorter durations when concentrations of nebulized MA were increased. Mice acquire the available MA by repeatedly running in and out of the nebulizing chamber for brief bouts of intake. Such exposure to nebulized MA elevated plasma MA levels. There was limited evidence of sensitization of locomotor activity. Finally, blocking access to the wheel did not affect time spent in the nebulizing chamber. CONCLUSIONS: We conclude that administration of MA by nebulization is an effective route of self administration, and our new protocol represents a promising tool for examining the transitions from first intake to long-term use and its behavioral and neural consequences in a non-invasive protocol. PMID- 28028602 TI - Negative affect subtypes and craving differentially predict long-term cessation success among smokers achieving initial abstinence. AB - OBJECTIVE: This study aimed to examine the associations of individual trajectories of three types of negative affect (NA: anxiety, depression, and anger) and craving during a 44-day period of incentivized smoking abstinence period with cessation outcome at 3 months and at 1 year. METHODS: Adult smokers (N = 140) completed questionnaire assessments of NA and craving during pre-quit baseline sessions and 15 postquit sessions over the 45 days of biochemically verified abstinence while on nicotine or placebo patch treatment. Growth curve and logistic regression analyses were used to examine the associations of trajectory parameters of the individual NA states and craving with the abstinence outcomes at 3 months and 1 year postquit. RESULTS: Greater declines in anxiety, depression, and anger symptoms over the first 44 days of smoking cessation were predictive of higher odds of abstinence at both 3 months and 1 year. Moreover, the greater declines in anxiety and anger remained as significant predictors of abstinence at both time points, independent of the predictive ability of the trajectory profiles of craving. CONCLUSIONS: The findings suggest that slower dissipation of NA, especially anxiety and anger, represents a greater risk for relapse to smoking beyond that predicted by craving during early abstinence. Thus, temporal profiles of the affective symptoms convey unique motivational significance in relapse. Reduction in NA during early abstinence may be a valid target for interventions to increase long-term cessation success rates particularly among individuals with refractory affective symptoms. PMID- 28028603 TI - Guanfacine alters the effect of stress and smoking on heart rate variability in regular daily smokers. AB - BACKGROUND: We had previously demonstrated that guanfacine, an alpha2a-adrenergic agonist, attenuated the effect of stress on smoking-lapse behavior in regular daily smokers. Heart rate variability (HRV), a measure of vagal activity, may be a potential mechanism underlying the relationship between stress, smoking, and relapse. METHODS: We examined whether guanfacine (0 mg/day vs. 3 mg/day; n = 26) altered changes in high-frequency heart rate variability (HF-HRV) following stress and ad-lib smoking using a validated laboratory analogue of smoking-lapse behavior. All participants completed a parent study evaluating the effects of guanfacine on stress-precipitated smoking. Each subject completed two laboratory sessions assessing the effects of guanfacine on HF-HRV following stress imagery (vs. neutral imagery; order counterbalanced) and smoking. RESULTS: Results demonstrated that guanfacine did not increase tonic levels of HF-HRV relative to placebo. Following the stress versus neutral imagery manipulation (prior to ad lib smoking), there were no significant changes in HF-HRV in the placebo group. In contrast, guanfacine increased phasic HF-HRV following stress imagery and decreased HF-HRV following neutral imagery. Ad libitum smoking following both the stress and neutral conditions decreased HF-HRV in the placebo group across both imagery conditions. In contrast, guanfacine attenuated stress- and smoking related decreases in phasic HF-HRV relative to the neutral imagery condition. CONCLUSIONS: This is the first demonstration that a noradrenergic target altered dynamic changes in HF-HRV in response to stress and smoking, suggesting that guanfacine alters HF-HRV response to stress. Findings support current theories which suggest that phasic changes in HRV are an important marker of the stress response. PMID- 28028604 TI - Molecular mechanisms of group I metabotropic glutamate receptor mediated LTP and LTD in basolateral amygdala in vitro. AB - The roles of group I metabotropic glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) and mGluR5, in regulating synaptic plasticity and metaplasticity in the basolateral amygdala (BLA) remain unclear. The present study examined mGluR1- and mGluR5-mediated synaptic plasticity in the BLA and their respective signaling mechanisms. Bath application of the group I mGluR agonist, 3,5-dihydroxyphenylglycine (DHPG) (20 MUM), directly suppressed basal fEPSPs (84.5 +/- 6.3% of the baseline). The suppressive effect persisted for at least 30 min after washout; it was abolished by the mGluR1 antagonist 7 (hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) but was unaffected by the mGluR5 antagonist 2-methyl-6- (phenylethynyl)-pyridine (MPEP). Interestingly, application of DHPG (at both 2 and 20 MUM), regardless of the presence of CPCCOEt, could transform single theta burst stimulation (TBS)-induced short-term synaptic potentiation into a long-term potentiation (LTP). Such a facilitating effect could be blocked by the mGluR5 antagonist MPEP. Blockade of phospholipase C (PLC), the downstream enzyme of group I mGluR, with U73122, prevented both mGluR1- and mGluR5-mediated effects on synaptic plasticity. Nevertheless, blockade of protein kinase C (PKC), the downstream enzyme of PLC, with chelerythrine (5 MUM) only prevented the transforming effect of DHPG on TBS induced LTP and did not affect DHPG-induced long-term depression (LTD). These results suggest that mGluR1 activation induced LTD via a PLC-dependent and PKC independent mechanism, while the priming action of mGluR5 receptor on the BLA LTP is both PLC and PKC dependent. The BLA metaplasticity mediated by mGluR1 and mGluR5 may provide signal switching mechanisms mediating learning and memory with emotional significance. PMID- 28028606 TI - Novelty seeking mediates the effect of DRD3 variation on onset age of amphetamine dependence in Han Chinese population. AB - The dopamine receptor D3 (DRD3) gene, one of the candidate genes for amphetamine dependence (AD), is involved in the mesolimbic dopaminergic system, implicated as the underlying mechanism of addiction. Our case-control study aimed to investigate whether the DRD3 gene is associated with the susceptibility to AD and specific personality traits in AD patients. A total of 1060 unrelated Han Chinese subjects (559 AD patients and 501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. All patients met the DSM-IV-TR criteria for AD, and personality traits of 539 were assessed using a Tridimensional Personality Questionnaire. Furthermore, AD individuals were divided into four clinical subgroups based on gender and psychosis status, to reduce the clinical heterogeneity. We found that the ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total AD patients (p = 0.0003 after 10,000 permutations). Similar results were observed in the both male and non-psychosis subgroup but not in other subgroups. In addition, DRD3 rs9825563 may influence onset age of drug use, partially mediated by novelty seeking in the non-psychosis AD group. In conclusion, DRD3 is a potential genetic factor in the susceptibility to AD and is associated with onset age of drug use through interaction with novelty seeking in a specific patient group in the Han Chinese population. PMID- 28028607 TI - Transoral laser microsurgery for T1b glottic cancer: review of 51 cases. AB - For the treatment of T1b glottic carcinoma, different treatment options, such as transoral laser microsurgery, open surgical techniques, and primary radiotherapy, are under discussion. In this context, the aim of the present study was to describe oncologic results and complication rates of transoral laser microsurgery in treatment of T1b glottic carcinoma. This is a retrospective unicenter chart review of patients treated at an academic tertiary referral center between 1986 and 2006. Fifty-one previously untreated T1b cases were exclusively treated by transoral laser microsurgery and included into this study, 47 were male, and 4 were female. The main outcome measures included local control rate and complications, overall, disease specific, and recurrence-free survival. The median follow-up period was 98 months. The 5-year local control rate was 90.2%; larynx preservation rate was 92.2%. No intra- or postoperative complications, such as wound infections, postoperative bleeding, hematoma, edema, and fistula development, were observed. A single patient required revision surgery due to synechia. Five-year survival rates were: overall 84.7%, disease specific 97.7%, and recurrence free 72.4%. Our data support the conclusion that transoral laser microsurgery is a considerable treatment option in T1b glottic carcinoma. The oncologic outcome was at least comparable to other treatment options, while the perioperative morbidity and complication rate were lower. PMID- 28028605 TI - Neuropeptide systems and new treatments for nicotine addiction. AB - RATIONALE: The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. OBJECTIVES: The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking. RESULTS: The reviewed studies indicate that several drugs that target neuropeptide systems diminish the rewarding effects of nicotine by preventing the activation of dopaminergic systems. Other peptide-based drugs diminish the hyperactivity of brain stress systems and diminish withdrawal-associated symptom severity. Blockade of hypocretin-1 and nociceptin receptors and stimulation of galanin and neurotensin receptors diminishes the rewarding effects of nicotine. Both corticotropin releasing factor type 1 and kappa-opioid receptor antagonists diminish dysphoria and anxiety-like behavior associated with nicotine withdrawal and inhibit stress induced reinstatement of nicotine seeking. Furthermore, blockade of vasopressin 1b receptors diminishes dysphoria during nicotine withdrawal, and melanocortin 4 receptor blockade prevents stress-induced reinstatement of nicotine seeking. The role of neuropeptide systems in nicotine-primed and cue-induced reinstatement is largely unexplored, but there is evidence for a role of hypocretin-1 receptors in cue-induced reinstatement of nicotine seeking. CONCLUSION: Drugs that target neuropeptide systems might decrease the euphoric effects of smoking and improve relapse rates by diminishing withdrawal symptoms and improving stress resilience. PMID- 28028608 TI - Accumulation of foreign polypeptides to rice seed protein body type I using prolamin portion sequences. AB - KEY MESSAGE: Rice prolamins are accumulated in endoplasmic reticulum (ER)-derived proteins bodies, although conserved sequences retained in ER are not confirmed. We investigated portion sequences of prolamins that must accumulate in PB-Is. Rice seed prolamins are accumulated in endoplasmic reticulum (ER)-derived protein body type I (PB-I), but ER retention sequences in rice prolamin polypeptides have not been confirmed. Here we investigated the lengths of the prolamin portion sequences required for accumulation in PB-Is. Of the rice prolamins, we compared 13a and 13b prolamins because the amino acid sequences of these prolamins are quite similar except for the presence or absence of Cys-residues. We also generated and analyzed transgenic rice expressing several prolamin portion sequence-GFP fusion proteins. We observed that in 13a prolamin, when the portion sequences were extended more than the 68th amino acid residue from the initiating methionine, the prolamin portion sequence-GFP fusion proteins were accumulated in PB-Is. In 13b prolamin, when the portion sequences were extended by more than the 82nd amino acid residue from the initiating methionine, the prolamin portion sequence-GFP fusion proteins were accumulated in PB-Is. When those fusion proteins were extracted under non-reduced or reduced conditions, the 13a prolamin portion sequence-GFP fusion proteins in PB-Is were soluble under only the reduced condition. In contrast, 13b prolamin portion sequence-GFP fusion proteins were soluble under both non-reduced and reduced conditions. These results suggest that the accumulation of 13a prolamin in PB-Is is associated with the formation of disulfide bonds and/or hydrophobicity in 13a prolamin polypeptide, whereas the accumulation of 13b prolamin in PB-Is was less involved in the formation of disulfide bonds. PMID- 28028609 TI - Modelling the Release, Transport and Fate of Engineered Nanoparticles in the Aquatic Environment - A Review. AB - Engineered nanoparticles, that is, particles of up to 100 nm in at least one dimension, are used in many consumer products. Their release into the environment as a consequence of their production and use has raised concern about the possible consequences. While they are made of ordinary substances, their size gives them properties that are not manifest in larger particles. It is precisely these properties that make them useful. For instance titanium dioxide nanoparticles are used in transparent sunscreens, because they are large enough to scatter ultraviolet light but too small to scatter visible light.To investigate the occurrence of nanoparticles in the environment we require practical methods to detect their presence and to measure the concentrations as well as adequate modelling techniques. Modelling provides both a complement to the available detection and measurement methods and the means to understand and predict the release, transport and fate of nanoparticles. Many different modelling approaches have been developed, but it is not always clear for what questions regarding nanoparticles in the environment these approaches can be applied. No modelling technique can be used for every possible aspect of the release of nanoparticles into the environment. Hence it is important to understand which technique to apply in what situation. This article provides an overview of the techniques involved with their strengths and weaknesses. Two points need to be stressed here: the modelling of processes like dissolution and the surface activity of nanoparticles, possibly under influence of ultraviolet light, or chemical transformation has so far received relatively little attention. But also the uncertainties surrounding nanoparticles in general-the amount of nanoparticles used in consumer products, what constitutes the appropriate measure of concentration (mass or numbers) and what processes are relevant-should be explicitly considered as part of the modelling. PMID- 28028610 TI - Incidence and clinical outcomes of intestinal Behcet's disease in Korea, 2011 2014: a nationwide population-based study. AB - BACKGROUND: Intestinal Behcet's disease (BD) is very rare, and epidemiologic data regarding BD are scarce. Moreover, there have been no population-based studies focusing on intestinal BD. We conducted a nationwide population-based study to examine the incidence and clinical course of Korean patients with intestinal BD. METHODS: We collected data on 365 patients diagnosed with intestinal BD from 2011 to 2014 using the Health Insurance Review and Assessment Services claims database. We analyzed the incidence and clinical outcomes, including cumulative rates of bowel resection, hospitalization, and medication use. RESULTS: During the study period, the average annual incidence for intestinal BD was 0.18 per 105 population, and the proportion of cases with intestinal involvement was 3.9%. At 1 and 4 years after diagnosis, the cumulative rates of surgery were 5.0 and 10.9%, respectively, whereas those of hospitalization were 27.8 and 32.4%, respectively. The 1- and 4-year cumulative rates of requirements for medications were 39.8 and 49.1% for moderate- to high-dose corticosteroids, 33.6 and 42.1% for immunomodulators, and 3.5 and 6.8% for biologics, respectively. The cumulative probability of corticosteroid and immunomodulator use was higher in male than in female patients and in younger (<40 years) than in older (>=40 years) patients. However, there were no significant differences in the cumulative probabilities of surgery, hospitalization, and biologics use according to sex and age group. CONCLUSIONS: The incidence of intestinal BD in Korea is quite low and has been stable in recent years. PMID- 28028611 TI - Comparative analysis of the gut microbiota of black bears in China using high throughput sequencing. AB - The Asiatic black bear (Ursus thibetanus) is a protected species from eastern Asia. In China, the Asiatic black bear occurs in 17 provinces from northeast to southwest regions. To date, information on microbial diversity in the gut of the Asiatic black bears from different populations remains limited. To determine the species composition and community structure of the gut microbiota in the Asiatic black bear, we characterized 36 fecal samples from Sichuan, Yunnan, and Heilongjiang provinces, China, by pyrosequencing the 16S V3-V4 hypervariable regions using the Illumina Miseq platform. Results showed that Firmicutes and Proteobacteria were the predominant phyla in the samples, which were largely comprised Escherichia-Shigella, Peptostreptococcaceae_incertae_sedis, Turicibacter, Streptococcus, and Clostridium. By analyzing the community structure from these 36 samples, we found that there were significant differences in the species diversity and richness between Sichuan, Yunnan, and Heilongjiang populations. In conclusion, our results reveal the species composition and structure of the gut microbiota in captive black bears in China, and suggest that biogeography could affect the black bear' gut microbiota. PMID- 28028612 TI - QTLs for cell wall-bound phenolics in relation to the photosynthetic apparatus activity and leaf water status under drought stress at different growth stages of triticale. AB - The present study aimed at identifying the regions of triticale genome responsible for cell wall saturation with phenolic compounds under drought stress during vegetative and generative growth. Moreover, the loci determining the activity of the photosynthetic apparatus, leaf water content (LWC) and osmotic potential (Psi o) were identified, as leaf hydration and functioning of the photosynthetic apparatus under drought are associated with the content of cell wall-bound phenolics (CWPh). Compared with LWC and Psi o, CWPh fluctuations were more strongly associated with changes in chlorophyll fluorescence. At the vegetative stage, CWPh fluctuations were due to the activity of three loci, of which only QCWPh.4B was also related to changes in F v/F m and ABS/CSm. In the other QTLs (QCWPh.6R.2 and QCWPh.6R.3), the genes of these loci determined also the changes in majority of chlorophyll fluorescence parameters. At the generative stage, the changes in CWPh in loci QCWPh.4B, QCWPh.3R and QCWPh.6R.1 corresponded to those in DIo/CSm. The locus QCWPh.6R.3, active at V stage, controlled majority of chlorophyll fluorescence parameters. This is the first study on mapping quantitative traits in triticale plants exposed to drought at different stages of development, and the first to present the loci for cell wall-bound phenolics. PMID- 28028613 TI - Microbial diversity and autotrophic activity in Kamchatka hot springs. AB - Microbial communities of Kamchatka Peninsula terrestrial hot springs were studied using molecular, radioisotopic and cultural approaches. Analysis of 16S rRNA gene fragments performed by means of high-throughput sequencing revealed that aerobic autotrophic sulfur-oxidizing bacteria of the genus Sulfurihydrogenibium (phylum Aquificae) dominated in a majority of streamers. Another widely distributed and abundant group was that of anaerobic bacteria of the genus Caldimicrobium (phylum Thermodesulfobacteria). Archaea of the genus Vulcanisaeta were abundant in a high temperature, slightly acidic hot spring, where they were accompanied by numerous Nanoarchaeota, while the domination of uncultured Thermoplasmataceae A10 was characteristic for moderately thermophilic acidic habitats. The highest rates of inorganic carbon assimilation determined by the in situ incubation of samples in the presence of 14C-labeled bicarbonate were found in oxygen-dependent streamers; in two sediment samples taken from the hottest springs this process, though much weaker, was found to be not dependent on oxygen. The isolation of anaerobic lithoautotrophic prokaryotes from Kamchatka hot springs revealed a wide distribution of the ability for sulfur disproportionation, a new lithoautotrophic process capable to fuel autonomous anaerobic ecosystems. PMID- 28028614 TI - The outcomes and risk factors of early reoperation after initial intestinal resective surgery in patients with intestinal Behcet's disease. AB - PURPOSE: Patients with intestinal Behcet's disease who underwent intestinal resective surgery often require reoperation. However, there have been no studies on the risk factors and outcomes of early reoperation in these patients. METHODS: We retrospectively evaluated 41 patients with intestinal Behcet's disease who received repeated intestinal resective surgeries between 2006 and 2016. We analyzed two different patient groups-those who required early reoperation within 6 months and those who underwent reoperation >6 months after the initial surgery and determined the risk factors for early reoperation. RESULTS: Eleven patients (26.8%) underwent reoperation within 6 months and 30 patients (73.2%) after 6 months. Emergency surgery at the initial operation and higher initial perioperative erythrocyte sedimentation rate and C-reactive protein levels were significantly associated with early reoperation in the univariate analysis. After the multivariate analysis, initial emergency operation (P = 0.020; hazard ratio [HR], 42.625; 95% confidence interval [CI], 1.817-1000.088) and high erythrocyte sedimentation rate (P = 0.039; HR, 1.049; 95% CI, 1.002-1.097) were determined to be the independent factors for early reoperation. CONCLUSIONS: Emergency surgery and high perioperative erythrocyte sedimentation rate levels were the prognostic factors for early reoperation (within 6 months) in patients with intestinal Behcet's disease after initial bowel resective surgery. PMID- 28028615 TI - Podocyte number and density changes during early human life. AB - BACKGROUND: Podocyte depletion, which drives progressive glomerulosclerosis in glomerular diseases, is caused by a reduction in podocyte number, size or function in the context of increasing glomerular volume. METHODS: Kidneys obtained at autopsy from premature and mature infants who died in the first year of life (n = 24) were used to measure podometric parameters for comparison with previously reported data from older kidneys. RESULTS: Glomerular volume increased 4.6-fold from 0.13 +/- 0.07 MUm3 x106 in the pre-capillary loop stage, through 0.35 MUm3 x106 at the capillary loop, to 0.60 MUm3 x106 at the mature glomerular stage. Podocyte number per glomerulus increased from 326 +/- 154 per glomerulus at the pre-capillary loop stage to 584 +/- 131 per glomerulus at the capillary loop stage of glomerular development to reach a value of 589 +/- 166 per glomerulus in mature glomeruli. Thus, the major podocyte number increase occurs in the early stages of glomerular development, in contradistinction to glomerular volume increase, which continues after birth in association with body growth. CONCLUSIONS: As glomeruli continue to enlarge, podocyte density (number per volume) rapidly decreases, requiring a parallel rapid increase in podocyte size that allows podocyte foot processes to maintain complete coverage of the filtration surface area. Hypertrophic stresses on the glomerulus and podocyte during development and early rapid growth periods of life are therefore likely to play significant roles in determining how and when defects in podocyte structure and function due to genetic variants become clinically manifest. Therapeutic strategies aimed at minimizing mismatch between these factors may prove clinically useful. PMID- 28028616 TI - Impact of flexion versus extension of knee position on outcomes after total knee arthroplasty: a meta-analysis. AB - INTRODUCTION: Controversy still exists regarding positioning of the knee in flexion or in extension after total knee arthroplasty (TKA) impacts treatment outcomes. In this meta-analysis, we evaluated if a postoperative knee position regime could positively affect the rehabilitation. METHODS: A comprehensive search for randomized controlled trials (RCTs) assessing the effect of knee positioning after TKA was conducted. The outcomes of interest were blood loss and range of motion (ROM); total calculated blood loss (CBL), drainage volume, hidden blood loss (HBL), decline of hemoglobin level and requirement for blood transfusion. RESULTS: Ten RCTs involving 962 knees were eligible for meta analysis. Positioning the knee in flexion after TKA was significantly associated with lesser CBL (P < 0.00001), less HBL (P < 0.00001) and decreased requirement for blood transfusion (P = 0.06). On subgroup analyses, the flexion group was found to have significantly less decrease in hemoglobin level 48 h to 6 days after surgery (P = 0.003), while no significant difference was noted at 24 h after surgery (P = 0.29). Further,a superior ROM was observed in flexion group (5 7 days after surgery) (P = 0.002), while there was no significant difference at 6 weeks. No significant inter-group difference in wound drainage was observed at 24 h after surgery. CONCLUSION: Positioning the knee in flexion in the early postoperative stage was associated with significantly lesser CBL, lesser HBL, decreased requirement for blood transfusion and better ROM at least in the early postoperative period, which may contribute to early rehabilitation. However, no significant difference was found in ROM at 6 weeks. PMID- 28028618 TI - Characterization and genome analysis of novel bacteriophages infecting the opportunistic human pathogens Klebsiella oxytoca and K. pneumoniae. AB - Klebsiella is a genus of well-known opportunistic human pathogens that are associated with diabetes mellitus and chronic pulmonary obstruction; however, this pathogen is often resistant to multiple drugs. To control this pathogen, two Klebsiella-infecting phages, K. oxytoca phage PKO111 and K. pneumoniae phage PKP126, were isolated from a sewage sample. Analysis of their host range revealed that they infect K. pneumoniae and K. oxytoca, suggesting host specificity for members of the genus Klebsiella. Stability tests confirmed that the phages are stable under various temperature (4 to 60 degrees C) and pH (3 to 11) conditions. A challenge assay showed that PKO111 and PKP126 inhibit growth of their host strains by 2 log and 4 log, respectively. Complete genome sequencing of the phages revealed that their genome sizes are quite different (168,758 bp for PKO111 and 50,934 bp for PKP126). Their genome annotation results showed that they have no human virulence-related genes, an important safety consideration. In addition, no lysogen-formation gene cluster was detected in either phage genome, suggesting that they are both virulent phages in their bacterial hosts. Based on these results, PKO111 and PKP126 may be good candidates for development of biocontrol agents against members of the genus Klebsiella for therapeutic purposes. A comparative analysis of tail-associated gene clusters of PKO111 and PKP126 revealed relatively low homology, suggesting that they might differ in the way they recognize and infect their specific hosts. PMID- 28028617 TI - Calcium-gated K+ channels of the KCa1.1- and KCa3.1-type couple intracellular Ca2+ signals to membrane hyperpolarization in mesenchymal stromal cells from the human adipose tissue. AB - Electrogenesis in mesenchymal stromal cells (MSCs) remains poorly understood. Little is known about ion channels active in resting MSCs and activated upon MSC stimulation, particularly, by agonists mobilizing Ca2+ in the MSC cytoplasm. A variety of Ca2+-gated ion channels may couple Ca2+ signals to polarization of the plasma membrane. Here, we studied MSCs from the human adipose tissue and found that in cells responsive to ATP and adenosine with Ca2+ transients or exhibiting spontaneous Ca2+ oscillations, Ca2+ bursts were associated with hyperpolarization mediated by Ca2+-gated K+ channels. The expression analysis revealed transcripts for KCNMA1 and KCNN4 genes encoding for Ca2+-activated K+ channels of large (KCa1.1) and intermediate (KCa3.1) conductance, respectively. Moreover, transcripts for the Ca2+-gated cation channel TRPM4 and anion channels Ano1, Ano2, and bestrophin-1, bestrophin-3, and bestrophin-4 were revealed. In all assayed MSCs, a rise in cytosolic Ca2+ stimulated K+ currents that were inhibited with iberiotoxin. This suggested that KCa1.1 channels are invariably expressed in MSCs. In ATP- and adenosine-responsive cells, iberiotoxin and TRAM-34 diminished electrical responses, implicating both KCa1.1 and KCa3.1 channels in coupling agonist-dependent Ca2+ signals to membrane voltage. Functional tests pointed at the existence of two separate MSC subpopulations exhibiting Ca2+-gated anion currents that were mediated by Ano2-like and bestrophin-like anion channels, respectively. Evidence for detectable activity of Ano1 and TRPM4 was not obtained. Thus, KCa1.1 channels are likely to represent the dominant type of Ca2+ activated K+ channels in MSCs, which can serve in concert with KCa3.1 channels as effectors downstream of G-protein-coupled receptor (GPCR)-mediated Ca2+ signaling. PMID- 28028619 TI - Effects of protein-carbohydrate supplementation on immunity and resistance training outcomes: a double-blind, randomized, controlled clinical trial. AB - PURPOSE: To examine the impact of ingesting hydrolyzed beef protein, whey protein, and carbohydrate on resistance training outcomes, body composition, muscle thickness, blood indices of health and salivary human neutrophil peptides (HNP1-3), as reference of humoral immunity followed an 8-week resistance training program in college athletes. METHODS: Twenty-seven recreationally physically active males and females (n = 9 per treatment) were randomly assigned to one of the three groups: hydrolyzed beef protein, whey protein, or non-protein isoenergetic carbohydrate. Treatment consisted of ingesting 20 g of supplement, mixed with orange juice, once a day immediately post-workout or before breakfast on non-training days. Measurements were performed pre- and post-intervention on total load (kg) lifted at the first and last workout, body composition (via plethysmography) vastus medialis thickness (mm) (via ultrasonography), and blood indices of health. Salivary HNP1-3 were determined before and after performing the first and last workout. RESULTS: Salivary concentration and secretion rates of the HNP1-3 decreased in the beef condition only from pre-first-workout (1.90 +/- 0.83 MUg/mL; 2.95 +/- 2.83 MUg/min, respectively) to pre-last-workout (0.92 +/- 0.63 MUg/mL, p = 0.025, d = 1.03; 0.76 +/- 0.74 MUg/min, p = 0.049, d = 0.95), and post-last-workout (0.95 +/- 0.60 MUg/mL, p = 0.032, d = 1.00; 0.59 +/- 0.52 MUg/min, p = 0.027, d = 1.02). No other significant differences between groups were observed. CONCLUSIONS: Supplementation with a carbohydrate-protein beverage may support resistance training outcomes in a comparable way as the ingestion of only carbohydrate. Furthermore, the ingestion of 20 g of hydrolyzed beef protein resulted in a decreased level and secretion rates of the HNP1-3 from baseline with no negative effect on blood indices of health. PMID- 28028620 TI - Prospective evaluation of abnormal glucose metabolism and insulin resistance in patients with atypical endometrial hyperplasia and endometrial cancer. AB - PURPOSE: Obesity and diabetes (DM) are known to increase the risk of endometrial cancer (EC). However, little is known about the prevalence of abnormal glucose metabolism and insulin resistance (IR) in EC patients. We aimed to evaluate the prevalence of abnormal glucose metabolism and IR in EC patients. METHODS: We prospectively enrolled atypical endometrial hyperplasia (AEH) and EC patients who had received planned treatment at Chiba University Hospital, Japan. All patients, except those with a confirmed diagnosis of DM, underwent the 75-g oral glucose tolerance test (OGTT) before treatment. We evaluated the prevalence of obesity, defined as body mass index (BMI) >=25, IR, abnormal glucose metabolism, and the associations between these three factors and the clinical characteristics of AEH and EC patients. RESULTS: We enrolled 279 patients from April 2009 to March 2015. Of these, 56 had a confirmed diagnosis of DM. Abnormal OGTT results, including impaired fasting glucose (n = 7), impaired glucose tolerance (n = 69), and newly identified DM (n = 33), were noted in 109 patients. Obesity, IR, and abnormal glucose metabolism were observed in 49.8, 51.6, and 59.1% of patients, respectively. Abnormal glucose metabolism was significantly associated with age (P < 0.001), body mass index (P = 0.004), and IR status (P < 0.001) in multivariate analysis. CONCLUSION: Abnormal glucose metabolism, IR, and obesity were highly prevalent in patients with AEH and EC. These results indicate that physicians should consider a patient's metabolic status in the postoperative management of AEH and EC patients. PMID- 28028621 TI - Expression of Bruton's tyrosine kinase in B-cell neoplasms evaluated by flow cytometry. AB - Bruton's tyrosine kinase (BTK) is a cytoplasmatic protein that is part of the B cell antigen receptor signaling pathway. Our aim was to evaluate the expression of BTK in B-cell neoplasms and compare it to normal B-cell lymphocytes. After surface staining with CD19 and CD45, flow cytometry staining for intracellular BTK was performed in leukemic or mature B-cells from bone marrow or peripheral blood samples. No differences in BTK expression were identified between groups, or in comparison to control samples, there was no association between BTK expression and the clinical variables evaluated. BTK expression in B-cell neoplasms was similar to that of normal B-cell lymphocytes. PMID- 28028622 TI - Market approval for drugs in the EU: time to change direction? PMID- 28028624 TI - Intravenous thrombolysis of stroke in early pregnancy: a case report and review of the literature. PMID- 28028625 TI - An unsuspected cause of hypnic-like headache. PMID- 28028623 TI - Cognitive impairment and structural brain changes in patients with clinically isolated syndrome at high risk for multiple sclerosis. AB - Patients with clinically isolated syndrome (CIS), unlike those with multiple sclerosis (MS), have a selective cognitive impairment which is not consistently related to structural brain changes. Our objective was to characterize a profile of cognitive impairment and its association with structural brain changes in patients with CIS who are at high risk of developing MS. Patients with CIS at high risk for MS on interferon-beta (n = 51) and age-, gender-, and education matched controls (n = 44) underwent comprehensive neuropsychological testing and MRI brain scan with voxel-based morphometry. The CIS group had lower cognitive performance in verbal and nonverbal memory, information processing speed/attention/working memory, and executive and visuo-spatial functions compared to controls (p <= 0.040). Lower cognitive performance was present in 18 37 and 14-26% of patients with CIS at high risk for MS depending on the criteria used. Brain volume was reduced predominantly in fronto-temporal regions and the thalamus in the CIS group (p <= 0.019). Cognitive performance was not associated with structural brain changes except for the association between worse visuo spatial performance and lower white matter volume in the CIS group (beta = 0.29; p = 0.042). Our results indicated that patients with CIS at high risk for MS may have a pattern of lower cognitive performance and regional brain atrophy similar to that found in patients with MS. Lower cognitive performance may be present in up to one-third of patients with CIS at high risk for MS, but, unlike patients with MS, variability in their cognitive performance may lead to a lack of consistent associations with structural brain changes. PMID- 28028626 TI - Migraine causes retinal and choroidal structural changes: evaluation with ocular coherence tomography. AB - Few studies have evaluated whether the retina is involved in migraine through the evaluation of retinal nerve fiber layer (RNFL) examined with ocular coherence tomography (OCT) with conflicting results. Aim of this case-control study is to evaluate the retina and the choroid in migraine. Patients having migraine with aura (MwA) or without aura (MoA) and chronic migraine (CM) were evaluated. Age- and sex-matched normal subjects were selected as healthy controls (HC). Patients and HC were examined with OCT. RNFL, ganglion cell layer (GCL), foveal thickness (FT), choroidal thickness (CT) and total macular volume (TMV) were calculated for right eyes (RE) and left eyes (LE). Seventy-seven patients (62 women; 80.5%), 21 MoA, 12 MwA, 44 CM and 42 HC were enrolled in the study. Patients compared to HC had a significant reduction of RNFL (RE: 91.2 +/- 9.2 vs 99.3 +/- 7.5 MUm; p < 0.001. LE: 93.3 +/- 8.7 vs 100.2 +/- 6.5 MUm; p < 0.001). GCL (RE: 80.6 +/- 6.4 vs 86.9 +/- 2.1 MUm; p < 0.0001. LE: 81.5 +/- 5.7 vs 87.1 +/- 2.6 MUm; p < 0.0001) and CT (RE: 286.4 +/- 31.4 vs 333.2 +/- 3.1 MUm; p < 0.0001. LE: 287.2 +/ 31.6 vs 334.5 +/- 4.1 MUm; p < 0.0001) were thinner in patients compared to HC. Moreover, CM showed reduction of RNFL and of GCL compared to the other migraineurs. Finally, we found a significant inverse correlation between RNFL thickness and total number of headache attacks per months. Our data suggest the involvement of retina and choroid in migraineurs, especially in the CM group. Although migraine is an episodic and recurrent disease, its chronic nature might cause permanent structural abnormalities involving not only the brain, but also the retina. PMID- 28028627 TI - Effect of electroacupuncture on the cervicospinal P2X7 receptor/fractalkine/CX3CR1 signaling pathway in a rat neck-incision pain model. AB - Increasing evidence supports that acupuncture intervention is an effective approach for intraoperative and postoperative pain. Neuron-microglia crosstalk, mediated by the purinergic P2X7 receptor (R)/fractalkine/CX3CR1 cascade in the spinal cord dorsal horn, plays a pivotal role in pain processing. However, its involvement in the analgesic effect of electroacupuncture (EA) remains unclear. In this study, a rat neck-incision pain model was established by making a longitudinal incision along the midline of the neck and subsequent repeated mechanical stimulation. EA stimulation was applied to bilateral LI18, LI4-PC6, or ST36-GB34. The thermal pain threshold, cervicospinal ATP concentration, expression levels of purinergic P2XR and P2YR subunits mRNAs, and fractalkine, CX3CR1 and p38 MAPK proteins, were detected separately. The neck incision induced strong thermal hyperalgesia and upregulation of spinal ATP within 48 h. No significant change was found in thermal hyperalgesia after a single session of EA intervention. However, a single session of EA dramatically enhanced the neck incision-induced upregulation of ATP and upregulated the expression of P2X7R, which was reversed by two sessions of EA. Two sessions of EA at bilateral LI18 or LI4-PC6 attenuated hyperalgesia significantly, accompanied with downregulation of P2X7R/fractalkine/ CX3CR1 signaling after three sessions of EA. EA stimulation of LI18 or LI4-PC6 alleviates thermal hyperalgesia in neck-incision pain rats, which may be associated with its effects in regulating the neck incision-induced increase of ATP and P2X7R and subsequently suppressing fractalkine/CX3CR1 signaling in the cervical spinal cord. PMID- 28028628 TI - Risk of drug resistance in Plasmodium falciparum malaria therapy-a systematic review and meta-analysis. AB - Plasmodium falciparum is responsible for the vast majority of the morbidity and mortality associated with malaria infection globally. Although a number of studies have reported the emergence of drug resistance in different therapies for P. falciparum infection, the degree of the drug resistance in different antimalarials is still unclear. This research investigated the risk of drug resistance in the therapies with different medications based on meta-analyses. Relevant original randomized control trials (RCTs) were searched in all available electronic databases. Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were used to evaluate the risk of drug resistance resulting from different treatments. Seventy-eight studies were included in the meta-analysis to compare drug resistance in the treatment of P. falciparum infections and yielded the following results: chloroquine (CQ) > sulfadoxine-pyrimethamine (SP) (RR = 3.67, p < 0.001 ), mefloquine (MQ) < SP (RR = 0.26, p < 0.001), artesunate + sulfadoxine-pyrimethamine (AS + SP) > artemether + lumefantrine (AL) (RR = 2.94, p < 0.001), dihydroartemisinin + piperaquine (DHA + PQ) < AL (RR = 0.7, p < 0.05), and non-artemisinin-based combination therapies (NACTs) > artemisinin based combination therapies (ACTs) (RR = 1.93, p < 0.001); no significant difference was found in amodiaquine (AQ) vs. SP, AS + AQ vs. AS + SP, AS + AQ vs. AL, or AS + MQ vs. AL. These results presented a global view for the current status of antimalarial drug resistance and provided a guidance for choice of antimalarials for efficient treatment and prolonging the life span of the current effective antimalarial drugs. PMID- 28028630 TI - Characterizations and bioactivities of abendazole sulfoxide-loaded thermo sensitive hydrogel. AB - Albendazole (ABZ), a widely used anthelmintic, attributes its primary metabolite albendazole sulfoxide (ABZSO)-as an effective agent against helminthes. For a purpose of long-lasting releasing ABZSO in a special lesion, the present study successfully manufactured ABZSO-loaded thermo-sensitive hydrogel, which was proved by FTIR and 1H NMR, in the interim; in vitro and in vivo behaviors of the thermo-sensitive hydrogel containing ABZSO were studied too. The in vivo pharmacokinetics parameters indicated ABZSO-loaded hydrogel as a better choice for sustained release compared with simple ABZSO. Additionally, the effect of the prepared hydrogels against helminth was investigated by the lethality of Caenorhabditis elegans, the results indicated that the lethality of ABZSO-loaded hydrogel (1, 2, and 4 mg/ml, respectively) on C. elegans was higher than that of PLGA-PEG-PLGA group (P < 0.05). It suggested that the hydrogels loaded with albendazole sulfoxide could be considered highly effective against the nematode C. elegans. PMID- 28028631 TI - Molecular detection and genetic diversity of bovine Babesia spp., Theileria orientalis, and Anaplasma marginale in beef cattle in Thailand. AB - Babesia spp., Theileria orientalis, and Anaplasma marginale are significant tick borne pathogens that affect the health and productivity of cattle in tropical and subtropical areas. In this study, we used PCR to detect the presence of Babesia bovis, Babesia bigemina, and T. orientalis in 279 beef cattle from Western Thailand and A. marginale in 608 beef cattle from the north, northeastern, and western regions. The PCRs were performed using species-specific primers based on the B. bovis spherical body protein 2 (BboSBP2), B. bigemina rhoptry-associated protein 1a (BbiRAP-1a), T. orientalis major piroplasm surface protein (ToMPSP), and A. marginale major surface protein 4 (AmMSP4) genes. To determine the genetic diversity of the above parasites, amplicons of B. bovis and B. bigemina ITS1-5.8s rRNA gene-ITS2 regions (B. bovis ITS, B. bigemina ITS), ToMPSP, and AmMSP4 genes were sequenced for phylogenetic analysis. PCR results revealed that the prevalence of B. bovis, B. bigemina, T. orientalis, and A. marginale in the Western region was 11.1, 12.5, 7.8, and 39.1 %, respectively. Coinfections of two or three parasites were observed in 17.9 % of the animals sampled. The study revealed that the prevalence of A. marginale in the western region was higher than in the north and northeastern regions (7 %). Sequence analysis showed the BboSBP2 gene to be more conserved than B. bovis ITS in the different isolates and, similarly, the BbiRAP-1a was more conserved than B. bigemina ITS. In the phylogenetic analysis, T. orientalis MPSP sequences were classified into types 3, 5, and 7 as previously reported. A. marginale MSP4 gene sequences shared high identity and similarity with each other and clustered with isolates from other countries. This study provides information on the prevalence and genetic diversity of tick-borne pathogens in beef cattle and highlights the need for effective strategies to control these pathogens in Thailand. PMID- 28028632 TI - The rs3736228 polymorphism in the LRP5 gene is associated with calcaneal ultrasound parameter but not with body composition in a cohort of young Caucasian adults. AB - The aim of the present study was to investigate the possible influence of low density lipoprotein receptor-related protein 5 (LRP5) and sclerostin (SOST) genes as genetic factors contributing to calcaneal quantitative ultrasound (QUS) and body composition variables in a population of young Caucasian adults. The study population comprised a total of 575 individuals (mean age 20.41years; SD 2.36) whose bone mass was assessed through QUS to determine broadband ultrasound attenuation (BUA, dB/MHz). Body composition measurements were performed using a body composition analyser. Seven single-nucleotide polymorphisms (SNPs) of LRP5 (rs2306862, rs599083, rs556442 and rs3736228) and SOST (rs4792909, rs851054 and rs2023794) were selected as genetic markers and genotyped using TaqMan OpenArray(r) technology. Linear regression analysis was used to test the possible association of the tested SNPs with QUS and body composition parameters. Linear regression analysis revealed that the rs3736228 SNP of LPR5 was significantly associated with BUA after adjustment for age, sex, weight, height, physical activity and calcium intake (P = 0.028, beta (95% CI) = 0.089 (0.099-1.691). For the remaining SNPs, no significant association with the QUS measurement was observed. Regarding body composition, no significant association was found between LRP5 and SOST polymorphisms and body mass index, total fat mass and total lean mass after adjustment for age and sex as covariates. We concluded that the rs3736228 LRP5 genetic polymorphism influences calcaneal QUS parameter in a population of young Caucasian adults. This finding suggests that LRP5 might be an important genetic marker contributing to bone mass accrual early in life. PMID- 28028633 TI - Real-world evidence of raloxifene versus alendronate in preventing non-vertebral fractures in Japanese women with osteoporosis: retrospective analysis of a hospital claims database. AB - We conducted a retrospective cohort study using a de-identified hospital administrative claims database to assess the risk of non-vertebral fracture in Japanese women with osteoporosis treated with raloxifene compared with alendronate. The study included Japanese women >=50 years of age with newly initiated alendronate or raloxifene treatment between July 2008 and March 2013 (index date was defined as the day of first prescription for alendronate or raloxifene), and had any claim with an osteoporosis definition during the study period. A total of 37,056 patients in the database initiated treatment, and there were 4802 and 1250 patients included in the alendronate and raloxifene analysis groups, respectively. The mean observation period in the alendronate group (529.2 days) was significantly longer than that for the raloxifene group (473.5 days, P < 0.001). Non-vertebral fractures accumulated linearly, at a similar rate, for both study drugs: incidence at 1 year was 2.83 and 2.64% for the alendronate and raloxifene groups, respectively. For the relative risk of non-vertebral fracture within 1 year, the adjusted hazard ratio was 0.933 for raloxifene versus alendronate, indicating that the relative risk of non-vertebral fracture was similar for the two drugs. The effectiveness of raloxifene in preventing non vertebral fractures in Japanese women with osteoporosis was similar to that of alendronate. Therefore, raloxifene may be worthy of consideration as an alternative treatment. PMID- 28028634 TI - Evaluation of body weight and visual scores for genetic improvement of Nelore cattle. AB - The aims of our study were to estimate genetic parameters for body weight and visual scores and to evaluate their inclusion as selection criteria in the Nelore breeding program in Brazil. The traits studied were the body weight adjusted to 210 (W210) and to 450 (W450) days of age and visual scores for body structure, finishing precocity, and muscling evaluated at weaning (BSW, FPW, and MSW) and yearling (BSY, FPY, and MSY) ages. A total of 33,242, 26,259, 23,075, and 26,057 observations were considered to analyze W210, W450, and visual scores at weaning and yearling. The significant (P < 0.05) fixed effects for all traits were farm, birth season, birth year, sex, and management group. Single-trait analyses were performed to define the most fitting model to our data using the average information restricted maximum likelihood algorithm, for weaning traits. Subsequently, these models were used in single- and two-trait analyses considering the Bayesian inference algorithm. Two-trait Bayesian analyses resulted in average direct heritability estimates for BSW, FPW, MSW, W210, BSY, FPY, MSY, and W450 of 0.28, 0.30, 0.27, 0.28, 0.40, 0.44, 0.39, and 0.50, respectively. Genetic correlations varied from 0.40 to 0.96. Benefits to animal performance can best be achieved by considering body structure, finishing precocity, and muscling as selection criteria in the Nelore breeding programs. The decision to use visual scores measured at weaning should be considered in order to decrease generation interval and assist pre-selecting individuals, expecting carcass improvements in the future progeny. PMID- 28028635 TI - In vitro control of parasitic nematodes of small ruminants using some plant species containing flavonoids. AB - This study determined in vitro anthelmintic efficacy of three plant species: Trema orientalis, Urtica dioica and Zanthozylum capense on nematode larvae of small ruminants. Dried leaf samples (40 g) were extracted in 70% ethanol, in portions of 10 g and concentrated to 100 ml. Half and one quarter of the original crude extract were both made to 100 ml. Rectal faecal material from 10 Merino sheep and 25 Nguni goats was pooled within species and thoroughly hand-mixed. Dung samples, each of 5 g were cultured for 12 days at 27 degrees C. On day 13, 4 plates were watered and 4 others treated with ethanol to correct for solvent effect on mortality. The design was 2 (animal species) * 3 (plant species) * 3 (extract concentrations). In each of three runs, three plates were treated with each crude extract in three incremental concentrations. Surviving L3 larvae were isolated, counted and mortalities became indices of anthelmintic efficacy. Data from nematode larval mortality were analysed to determine the effect of animal species, plant species, concentration and their interactions. Efficacy was affected by concentration (P = 0.0001), animal species (P = 0.0046), plant species (P = 0.0572), the interactions of animal species and concentration (P = 0.0010), plant species and concentration (P = 0.0123) and concentration * animal * plant species (P = 0.0435). PMID- 28028636 TI - Utilization of a sero-muscular patch for safe wound closure after free jejunum transfer for a skin-esophageal fistula. AB - This paper introduces our original technique of free jejunum transfer, in which a sero-muscular patch is used to cover the jejunum. Our results demonstrate its effectiveness for touch-up surgery after esophageal leakage. PMID- 28028637 TI - Phase I clinical trial of olprinone in liver surgery. AB - PURPOSE: Post-hepatectomy liver failure is one of the most serious complications liver surgeons must overcome. We previously examined olprinone, a selective phosphodiesterase III inhibitor, and demonstrated its hepatoprotective effects in rats and pigs. We herein report the results of a phase I clinical trial of olprinone in liver surgery (UMIN000004975). METHODS: Twenty-three patients who underwent hepatectomy between 2011 and 2015 were prospectively registered. In the first 6 cases, olprinone (0.1 MUg/kg/min) was administered for 24 h from the start of surgery. In the remaining 17 cases, olprinone (0.05 MUg/kg/min) was administered from the start of surgery until just before the transection of the liver parenchyma. The primary endpoint was safety, and the secondary endpoint was efficacy. For the evaluation of efficacy, the incidence of post-hepatectomy liver failure in 20 hepatocellular carcinoma patients was externally compared with 20 propensity score-matched patients. RESULTS: No intraoperative side effects were observed, and the morbidity rates in the analyzed cohorts were acceptable. The rate of post-hepatectomy liver failure frequency tended to be lower in the olprinone group. CONCLUSIONS: The safety of olprinone in liver surgery was confirmed. The efficacy of olprinone will be re-evaluated in clinical trials. PMID- 28028638 TI - Long-term morbidity in adolescents and young adults with surgically treated esophageal atresia. AB - PURPOSE: To investigate the long-term morbidity of surgically treated esophageal atresia (EA) in adolescents and young adults and establish whether these long term morbidities are affected by the type of EA. PATIENTS AND METHODS: We reviewed the medical records, including backgrounds and associated conditions, of 69 long-term survivors of EA, aged >15 years. The long-term morbidities included neurodevelopmental abnormality, nutritional impairment (short height <-2SD, low BMI <18.5), subjective symptoms, and musculoskeletal deformities. Comparisons of the results were made between Gross A-type EA (n = 6) and Gross C-type EA (n = 63). RESULTS: All patients underwent esophageal anastomosis without esophageal replacement. Cardiac anomalies and long gap were present in 26 and 18%, respectively. Esophageal dilatation, fundoplication, and aortopexy were performed in 40, 34, and 18%, respectively. The incidence of long gap and esophageal stenosis was higher in Gross A-type EA than in Gross C-type EA. The long-term morbidities included neurodevelopmental abnormality (13%), nutritional impairment (62%: as short height in 34% and as low BMI in 46%), subjective symptoms (14%), and musculoskeletal deformities (59%). There were no differences in the long-term morbidities between Gross A and Gross C. CONCLUSIONS: The incidence of the long term morbidities is high in adolescents and young adults, regardless of the type of EA. Early detection of morbidity is important to improve the long-term outcomes of EA. PMID- 28028639 TI - Relationship between ABO blood group and clinicopathological factors and their effect on the survival of Japanese patients with esophageal squamous cell carcinoma. AB - PURPOSE: Several studies have evaluated the association between ABO blood group and the prognosis of various types of cancer; however, little is known about the relationship between ABO blood group and esophageal squamous cell carcinoma (SCC). We investigated how ABO blood group and clinicopathological characteristics are related to the survival of Japanese patients with esophageal SCC. METHODS: We reviewed the medical records of 181 patients who underwent surgery for esophageal SCC between June, 2004 and December, 2015 and analyzed the association between ABO blood group and clinicopathological factors. Clinicopathological factors were also evaluated by univariate and multivariate analyses for possible association with survival. RESULTS: The prevalence of each blood group was as follows: A, 35.5%; B, 22.4%; O, 32.8%; and AB, 8.2%. The 5 year overall survival of all patients was 37.1%. Patients with non-type B blood had significantly worse 5-year overall survival than those with type B blood (30.2 vs. 58.8%, P < 0.05). CONCLUSIONS: ABO blood groups were associated with the survival of Japanese patients with esophageal SCC. Patients with non-B blood groups had significantly worse overall survival than those with the B blood group. PMID- 28028640 TI - Effect of dietary probiotic supplementation on intestinal microbiota and physiological conditions of Nile tilapia (Oreochromis niloticus) under waterborne cadmium exposure. AB - The heavy metal cadmium (Cd) is a hazardous pollutant that exerts various toxic effects on aquatic animals. The biomagnifying effects of this non-essential element in the food chain also pose threats to human health. In this study, the protective effect of a dietary probiotic supplementation, Lactobacillus plantarum CCFM8610, on the intestinal microbiota and physiological conditions of Nile tilapia (Oreochromis niloticus) exposed to waterborne Cd was evaluated. Two hundred fish were divided into four groups, i.e., control, probiotic-only, Cd only and Cd-plus-probiotic. The fish were exposed to waterborne Cd at a level of 1 mg L-1 for 4 weeks and the probiotic was administered twice daily at 108 CFU g 1 in the fish diet. Waterborne Cd exposure caused a profound decline in the gut microbial diversity and marked alterations in the composition of the microbiota. Dietary supplementation with L. plantarum CCFM8610 reversed the changes in the intestinal microbiota composition in the Cd-exposed fish and reduced the abundance of Flavobacterium and Pseudomonas. Compared with the Cd-only group, the probiotic treatment significantly promoted growth performance and prevented the death of the Cd-exposed fish. L. plantarum CCFM8610 supplementation also decreased Cd accumulation and alleviated oxidative stress in the tissues, and reversed the alterations in hemato-biochemical parameters in the blood of fish. The results suggest that L. plantarum CCFM8610 can be considered a safe dietary supplement for the prevention of Cd-exposure-induced problems in aquaculture and food safety. PMID- 28028642 TI - Nanomedicine in brain repair: Alzheimer's, Parkinson's and the proteome. PMID- 28028641 TI - The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and nicotine dependence in schizophrenia patients. AB - We investigated the relationship between the functional insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk of nicotine dependence in Croatian schizophrenia patients. We also tested whether interactions between ACE-I/D polymorphism and smoking status affected the clinical psychopathology findings in patients as measured using Positive and Negative Symptom Scale (PANSS) scores. Polymerase chain reaction analysis was used to genotype 267 chronically ill schizophrenia patients (140 males/127 females). There were no significant differences in the distribution of ACE genotypes and alleles in male or female schizophrenia patients who were stratified based on their smoking status. However, there was a trend toward a difference in the ACE genotype distribution in female smokers vs. nonsmokers (chi 2 = 5.13, p = 0.077) that was due mainly to the significant overrepresentation of ACE-ID heterozygous genotypes in female smokers compared to nonsmokers (62.3 vs. 42.0%, p = 0.025). ACE-ID heterozygous females had about a twofold higher smoking risk than ACE-II and ACE-DD homozygous carriers (OR = 2.29, 95% CI 1.1-4.7, p = 0.026). We observed no contribution of the ACE genotype-smoking interaction to PANSS psychopathology. This is the first study to investigate the possible association between ACE-I/D polymorphism and nicotine dependence in schizophrenia. Our results suggest that the ACE-I/D polymorphism may be relevant in determining the risk of nicotine dependence in female patients with schizophrenia while the ACE genotype-smoking interaction does not contribute to the clinical expression of schizophrenia. PMID- 28028643 TI - Parkinson's: a syndrome rather than a disease? AB - Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder. The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease. PMID- 28028644 TI - Preliminary application of a multi-level 3D printing drill guide template for pedicle screw placement in severe and rigid scoliosis. AB - PURPOSE: Accurate implantation of pedicle screw in spinal deformity correction surgeries is always challenging. We have developed a method of pedicle screw placement in severe and rigid scoliosis with a multi-level 3D printing drill guide template. METHODS: From November 2011 to March 2015, ten patients (4 males and 6 females) with severe and rigid scoliosis (Cobb angle >70 degrees and flexibility <30%)were included. Multi-level template was designed and manufactured according to the part (two or three levels) of the most severe deformity. The drill template was then placed on the corresponding vertebral surface. Then, pedicle screws were carefully inserted along the trajectories. The other screws were placed in free hand. After surgery, the positions of the pedicle screws were evaluated by CT scan and graded for validation. RESULTS: 48 screws were implanted using templates, other 104 screws in free hand, and the accuracies were 93.8 and 78.8%, respectively, with significant difference. The deformity correction ratio was 67.1 and 41.2% in coronal and sagittal plane post operatively, respectively. The average operation time was 234.0 +/- 34.1 min, and average blood loss was 557 +/- 67.4 ml. CONCLUSIONS: With the application of multi-level template, the incidence of cortex perforation in severe and rigid scoliosis decreased and this technology is, therefore, potentially applicable in clinical practice. PMID- 28028645 TI - Comparison of a calcium phosphate bone substitute with recombinant human bone morphogenetic protein-2: a prospective study of fusion rates, clinical outcomes and complications with 24-month follow-up. AB - PURPOSE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) generally provides high rates of clinical improvement and fusion. However, rhBMP-2 has been associated with adverse effects. Recently, a beta tricalcium phosphate (beta-TCP) bone substitute has been developed. The aim of this study was to determine the fusion rates and clinical outcomes of patients treated with beta-TCP compared to rhBMP-2. METHODS: One hundred and thirty-five consecutive patients who underwent lateral lumbar interbody fusion with beta-TCP (n = 25) or rhBMP-2 (n = 110) in the interbody cage were included in the study. The 25 beta-TCP patients were a group of consecutive patients from numbers 46 to 70. Clinical outcomes included back and leg pain, Oswestry Disability Index (ODI), and SF-36 physical and mental component scores (PCS and MCS). CT scans were performed at 6, 12, 18, and 24 months until confirmation of solid interbody fusion, with no further scans performed once fusion was achieved. Targeted CT at the operative level(s) was performed to reduce radiation exposure. RESULTS: At 24 months there was no significant difference between clinical outcomes of the beta-TCP or rhBMP-2 patients, with improvements in back pain (46% and 49%; P = 0.98), leg pain (31 and 52%; P = 0.14), ODI (38 and 41%; P = 0.81), SF-36 PCS (37 and 38%; P = 0.87), and SF-36 MCS (8 and 8%; P = 0.93). The fusion rate was significantly higher for rhBMP-2 with 96% compared to 80% for beta-TCP (P = 0.01). Separating patients into those with a standalone cage and those with supplemental posterior instrumentation, there was no significant difference between instrumented fusion rates of the beta-TCP and rhBMP-2 patients at 6 (P = 0.44), 12 (P = 0.49), 18 (P = 0.31) or 24 (P = 0.14) months. For standalone patients there was a significant difference at 6 (P = 0.01), 12 (P = 0.008) and 18 months (P = 0.004) with higher fusion rates in the rhBMP-2 group; however, by 24 months this was not significant (P = 0.18). CONCLUSIONS: Comparable clinical outcomes and complication rates suggest that beta-TCP is a viable alternative to rhBMP-2. The difference in fusion rates for the standalone patients suggests that beta-TCP may require supplemental posterior instrumentation to enhance fusion. PMID- 28028646 TI - First clinical results of minimally invasive vector lumbar interbody fusion (MIS VLIF) in spondylodiscitis and concomitant osteoporosis: a technical note. AB - PURPOSE: First description of MIS-VLIF, a minimally invasive lumbar stabilization, to evaluate its safety and feasibility in patients suffering from weak bony conditions (lumbar spondylodiscitis and/or osteoporosis). METHODS: After informed consent, 12 patients suffering from lumbar spondylodiscitis underwent single level MIS-VLIF. Eight of them had a manifest osteoporosis, either. Pre- and postoperative clinical status was documented using numeric rating scale (NRS) for leg and back pain. In all cases, the optimal height for the cage was preoperatively determined using software-based range of motion and sagittal balance analysis. CT scans were obtained to evaluate correct placement of the construct and to verify fusion after 6 months. RESULTS: Since 2013, 12 patients with lumbar pyogenic spondylodiscitis underwent MIS-VLIF. Mean surgery time was 169 +/- 28 min and average blood loss was less than 400 ml. Postoperative CT scans showed correct placement of the implants. Eleven patients showed considerable postoperative improvement in clinical scores. In one patient, we observed screw loosening. After documented bony fusion in the CT scan, the fixation system was removed in two cases to achieve lower material load. CONCLUSIONS: The load-bearing trajectories (vectors) of MIS-VLIF are different from those of conventional coaxial pedicle screw implantation. The dorsally converging construct combines the heads of the dorsoventral pedicle screws with laminar pedicle screws following cortical bone structures within a small approach. In case of lumbar spondylodiscitis and/or osteoporosis, MIS-VLIF relies on cortical bony structures for all screw vectors and the construct does not depend on conventional coaxial pedicle screws in the presence of inflamed, weak, cancellous or osteoporotic bone. MIS-VLIF allows full 360 degrees lumbar fusion including cage implantation via a small, unilateral dorsal midline approach. PMID- 28028647 TI - Accuracy of pedicle screw insertion in posterior scoliosis surgery: a comparison between intraoperative navigation and preoperative navigation techniques. AB - PURPOSE: This study was conducted to compare the efficacy and accuracy of intraoperative navigation (O-arm or Arcadis navigation) and preoperative CT-based navigation in adolescent idiopathic scoliosis (AIS) surgery. METHODS: Sixty-seven patients with scoliosis were grouped according to the method of navigation used in their fixation surgeries. A total of 492 pedicle screws were implanted in 27 patients using intraoperative navigation, and 626 screws were implanted in 40 patients using preoperative navigation. We analyzed the postoperative CT images for pedicle violations using the Gertzbein classification. RESULTS: There was no statistical difference in the accuracy of pedicle screw placement between two groups. However, in the apical region (the apex +/- 2 vertebrae), the accuracy of safe pedicle screw placement (grades 0, 1) was significantly higher in the intraoperative navigation group than in the preoperative navigation group (94.8 vs 89.2%, respectively; P = 0.035). Intraoperative navigation significantly diminished medial perforation compared to preoperative navigation (P = 0.027), and the number of screws per vertebra that could be placed in the apical region was significantly higher in intraoperative navigation group (P < 0.001). In addition, the time required for the registration procedure and insertion of one pedicle screw was 11.3 +/- 2.1 min in the preoperative group, but significantly decreased to 5.1 +/- 1.1 min in the intraoperative group (P < 0.001). CONCLUSIONS: Both preoperative CT-based and intraoperative navigation systems provide sufficient accuracy and safety in pedicle screw insertion for AIS surgery. Intraoperative navigation systems facilitate pedicle screw insertion in the apical region and reduce registration time during AIS surgery which improves the efficacy and accuracy of pedicle screw insertion. PMID- 28028648 TI - Expansive open-door laminoplasty versus laminectomy and instrumented fusion for cases with cervical ossification of the posterior longitudinal ligament and straight lordosis. AB - PURPOSE: To identify whether expansive open-door laminoplasty (Lam) is more appropriate than laminectomy and instrumented fusion (LIF) for cases with ossification of the posterior longitudinal ligament (OPLL) and straight cervical lordosis. METHODS: A total of 67 cases were included and divided into Group Lam (n = 32) and Group LIF (n = 35), and the mean follow-up periods were 38 and 42 months, respectively. The cervical lordosis was elevated by C2-7 Cobb angle and cervical sagittal balance by C2-C7 sagittal vertical axis (SVA). Japanese Orthopedic Association (JOA), neurological recovery rate (RR) being calculated by the JOA, visual analog scale (VAS) and neck disability index (NDI) were used to assess clinical outcomes. RESULTS: Differences in general data between two groups were not significant. Total blood loss and operation duration in Group Lam were both significantly less than that in the Group LIF. By the final follow-up, the cervical lordosis significantly decreased in Group Lam and increased in Group LIF, the SVA significantly increased in Group Lam and kept unchanged in Group LIF, and the JOA, VAS, NDI significantly improved in both groups. Although there was no significant difference in RR between the two groups, cases in Group Lam had significantly larger incidence of postoperative kyphosis and kyphotic change rate, and less VAS, NDI and incidence of axial pain than cases in Group LIF. CONCLUSIONS: When compared with the LIF, the Lam is recommended for cases with OPLL and straight cervical lordosis when taking comparable neurological recovery, less axial pain and better neck function improvement into consideration. PMID- 28028649 TI - Application of a modified thoracoabdominal approach that avoids cutting open the costal portion of diaphragm during anterior thoracolumbar spine surgery. AB - PURPOSE: In the present prospective randomized controlled study, we compared the feasibility and effectiveness of our modified thoracoabdominal approach to anterior thoracolumbar spine surgery without cutting open the costal portion of diaphragm (extradiaphragmatic approach) with the traditional transdiaphragmatic thoracoabdominal approach. The traditional combined thoracoabdominal approach in anterior thoracolumbar surgery for spine tuberculosis is effective but seriously damages the diaphragm and causes various lung complications. We used an extradiaphragmatic approach for complete anterior debridement, bone grafting, and nerve decompression and compared its efficacy and complications with those of the traditional transdiaphragmatic thoracolumbar approach. METHODS: The study included 106 patients with spinal tuberculosis. After a standard preoperative chemotherapy regimen, all patients underwent posterior deformity correction and internal fixation, anterior debridement, decompression, and bone grafting. Patients were divided into the modified extradiaphragmatic thoracolumbar approach group (the modified group) and the traditional transdiaphragmatic thoracolumbar approach group (the traditional group). During the treatment, we strictly followed the standard chemotherapy regimen. RESULTS: The mean follow-up duration was 36.2 months (range 25-38 months). There were significant differences between the two groups in intraoperative blood loss, length of incision, recovery time, and postoperative complications but no significant differences in preoperative and postoperative erythrocyte sedimentation rates and C-reactive protein values, kyphosis, and neurologic function, recovery of ability to live and work, and postoperative healing of bone grafts. CONCLUSION: The modified extradiaphragmatic thoracolumbar approach for anterior thoracolumbar spine surgery is as effective as the traditional approach. However, associated surgical trauma is minimal, and the incidence of pulmonary complications is low. PMID- 28028651 TI - Erratum to: Posterior implant removal in patients with thoracolumbar spine fractures: long-term results. PMID- 28028650 TI - Occult subaxial cervical disco-ligamentous injuries in computer tomography negative trauma patients. AB - PURPOSE: Due to lack of cervical clearance consensus in literature and the devastating consequences of missed cervical injuries, Magnetic resonance imaging (MRI) of the neurologically intact symptomatic patient with negative CT scan is frequently done to rule out disco-ligamentous injuries. This study retrospectively evaluates occult disco-ligamentous injuries detected by MRI in patients with no abnormalities detected by modern multi-detector CT scanning and postulates a new theory of ligamentous stability of cervical spine. METHODS: Cervical spine injury patients treated at a spinal trauma referral centre from 2010 to 2013 were retrospectively identified. Available clinical records and radiographic imaging were reviewed to find neurologically intact symptomatic patients with no identifiable acute cervical spine injury on CT scan but MRI evidence of isolated subaxial disco-ligamentous injuries. Patient demographics, injury profile, and treatment details were extracted. Subaxial Cervical Spine Injury Classification (SLIC) and Denis three-column spinal stability theory were adopted to assess stability of injuries. RESULT: 316/566 cervical spinal admissions had CT and MRI scans. 11 (3.5%) CT negative patients were found to have occult discoligamentous injuries on MRI. The average age (51.1 years) was not significantly different to all cervical trauma admissions (p = 0.09). Eight had flexion type and three had extension type injuries. The most common mechanisms were sports and fall on flat surface. The average SLIC score was 3.1. Four patients were classified as having unstable or potentially unstable injuries (two patients each) and three of these patients were surgically managed. Subtle CT changes to indicate discoligamentous injury could be retrospectively identified in all four of these patients. CONCLUSION: CT scans alone may be inadequate for clearing occult disco-ligamentous injuries of the subaxial cervical spine in trauma. Denis three-column stability theory may be beneficial in determining stability and guiding treatment along with the SLIC system for occult discoligamentous injuries of the subaxial cervical spine. PMID- 28028652 TI - Factors Associated with Geophagy and Knowledge About Its Harmful Effects Among Native Sub-Saharan African, Caribbean and French Guiana HIV Patients Living in Northern France. AB - Geophagy, or the ingestion of earth or clay, is widespread among women of Sub Saharan African, Caribbean or French Guiana origin. Little is known about this practice among HIV patients native of these countries and who are followed-up in France. The aims of this study were to determine (i) the prevalence and factors associated with geophagy among HIV patients native of these countries, (ii) patients' knowledge about the harmful effects of geophagy, and (iii) the association of geophagy with iron deficiency, or a history of anemia or constipation. Among the 119 included patients, current geophagy and previous geophagy were present in 11/119 (9%) and 47/119 (40%) patients, respectively. Female gender was the only factor associated with consumption (OR 5.37; 95% CI 2.07-15.92 p = 0.001). Awareness about the risk of iron-deficient anemia was low (24%). Preventive education should be integrated into the care of HIV adults from countries in which geophagy is a culture and widely accepted practice. PMID- 28028653 TI - Quantification of radial arterial pulse characteristics change during exercise and recovery. AB - It is physiologically important to understand the arterial pulse waveform characteristics change during exercise and recovery. However, there is a lack of a comprehensive investigation. This study aimed to provide scientific evidence on the arterial pulse characteristics change during exercise and recovery. Sixty five healthy subjects were studied. The exercise loads were gradually increased from 0 to 125 W for female subjects and to 150 W for male subjects. Radial pulses were digitally recorded during exercise and 4-min recovery. Four parameters were extracted from the raw arterial pulse waveform, including the pulse amplitude, width, pulse peak and dicrotic notch time. Five parameters were extracted from the normalized radial pulse waveform, including the pulse peak and dicrotic notch position, pulse Area, Area1 and Area2 separated by notch point. With increasing loads during exercise, the raw pulse amplitude increased significantly with decreased pulse period, reduced peak and notch time. From the normalized pulses, the pulse Area, pulse Area1 and Area2 decreased, respectively, from 38 +/- 4, 61 +/- 5 and 23 +/- 5 at rest to 34 +/- 4, 52 +/- 6 and 13 +/- 5 at 150-W exercise load. During recovery, an opposite trend was observed. This study quantitatively demonstrated significant changes of radial pulse characteristics during different exercise loads and recovery phases. PMID- 28028654 TI - Potential Mediators in Parenting and Family Intervention: Quality of Mediation Analyses. AB - Parenting and family interventions have repeatedly shown effectiveness in preventing and treating a range of youth outcomes. Accordingly, investigators in this area have conducted a number of studies using statistical mediation to examine some of the potential mechanisms of action by which these interventions work. This review examined from a methodological perspective in what ways and how well the family-based intervention studies tested statistical mediation. A systematic search identified 73 published outcome studies that tested mediation for family-based interventions across a wide range of child and adolescent outcomes (i.e., externalizing, internalizing, and substance-abuse problems; high risk sexual activity; and academic achievement), for putative mediators pertaining to positive and negative parenting, family functioning, youth beliefs and coping skills, and peer relationships. Taken as a whole, the studies used designs that adequately addressed temporal precedence. The majority of studies used the product of coefficients approach to mediation, which is preferred, and less limiting than the causal steps approach. Statistical significance testing did not always make use of the most recently developed approaches, which would better accommodate small sample sizes and more complex functions. Specific recommendations are offered for future mediation studies in this area with respect to full longitudinal design, mediation approach, significance testing method, documentation and reporting of statistics, testing of multiple mediators, and control for Type I error. PMID- 28028655 TI - Computer-aided volumetric assessment of malignant pleural mesothelioma on CT using a random walk-based method. AB - OBJECTIVE: The aim of this study is to assess the performance of a computer-aided semi-automated algorithm we have adapted for the purpose of segmenting malignant pleural mesothelioma (MPM) on CT. METHODS: Forty-five CT scans were collected from 15 patients (M:F [Formula: see text] 10:5, mean age 62.8 years) in a multi centre clinical drug trial. A computer-aided random walk-based algorithm was applied to segment the tumour; the results were then compared to radiologist drawn contours and correlated with measurements made using the MPM-adapted Response Evaluation Criteria in Solid Tumour (modified RECIST). RESULTS: A mean accuracy (Sorensen-Dice index) of 0.825 (95% CI [0.758, 0.892]) was achieved. Compared to a median measurement time of 68.1 min (range [40.2, 102.4]) for manual delineation, the median running time of our algorithm was 23.1 min (range [10.9, 37.0]). A linear correlation (Pearson's correlation coefficient: 0.6392, [Formula: see text]) was established between the changes in modified RECIST and computed tumour volume. CONCLUSION: Volumetric tumour segmentation offers a potential solution to the challenges in quantifying MPM. Computer-assisted methods such as the one presented in this study facilitate this in an accurate and time-efficient manner and provide additional morphological information about the tumour's evolution over time. PMID- 28028656 TI - Motivating future directions of behavioral medicine. PMID- 28028657 TI - PML-RARA mutations confer varying arsenic trioxide resistance. PMID- 28028658 TI - Chronic Abdominal Pain and Symptoms 5 Years After Gastric Bypass for Morbid Obesity. AB - INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is widely performed as treatment of morbid obesity. Long-term weight loss, effects on co-morbidities, and quality of life after RYGB have been well addressed. Other long-term outcomes are less elucidated. The aim of this study was to evaluate the prevalence, symptom characteristics, and possible predictors of chronic abdominal pain and gastrointestinal symptoms during consultations 5 years after RYGB. METHODS: A 5 year follow-up study of patients operated with RYGB 2008-2009 was performed. The patients completed questionnaires regarding chronic abdominal pain, the Gastrointestinal Symptom Rating Scale (GSRS), the ROME III questionnaire, the Hospital Anxiety and Depression Scale, Pain Catastrophing Scale (PCS), the Brief Pain Inventory, and SF-36. Uni- and multivariable logistic regression analyses of characteristics associated with chronic abdominal pain were performed. RESULTS: A total of 165/234 (71%) patients met to the follow-up, 160 of these accepted study inclusion. The mean follow-up was 64 (SD 4.2) months. The mean age was 42.5 (SD 8.7) years and 59% were females. The mean total weight loss was 23.9% (SD 11.2). Chronic abdominal pain was reported by 33.8%. Female gender, average strength of bodily pain, and the PCS sum score were associated with chronic abdominal pain. Symptoms of indigestion and irritable bowel syndrome were reported by 48.8% and 29.1%, respectively. Chronic abdominal pain was associated with reduced health related quality of life. CONCLUSION: A substantial proportion of patients experienced chronic abdominal pain and symptoms 5 years after RYGB. Abdominal pain should be addressed at follow-up consultations after RYGB. PMID- 28028659 TI - Role of Religiosity in Psychological Well-Being Among Medical and Non-medical Students. AB - Religion has been generally considered as a protective factor for the psychological health of the people. As many studies have publicized a high prevalence of psychological morbidities among the medical students during their academic stages of medical schools, it is significant to investigate whether religiosity functions as a protective factor, to explore religiosity as a predictor of psychological well-being in a sample of medical students, and to compare the results of medical students as well as non-medical students with respect to religiosity and psychological well-being. The study is carried out in Federal Medical and Dental College and International Islamic University, Islamabad. The present study examined a sample of 120 medical students from Federal Medical and Dental College and 120 non-medical students from International Islamic University, Islamabad. Purposive sampling was used. The respondents completed religious orientation scale and scale of psychological well being scale along with a demographic data sheet. In order to measure the study variables, linear regression and t test were used. The findings revealed that religiosity is a strong predictor of psychological well-being. Extrinsic and intrinsic religiosity predicts psychological well-being among the students. The results indicated a significant difference in psychological well-being between medical and non-medical students. No significant difference was found in religiosity of medical and non-medical students. The gender differences in religiosity and psychological well-being were found to be insignificant. The results emphasize that psychological well-being is prophesied by religiosity. The present research suggests further investigations and also endows with trends for psychological evaluation, development of religious beliefs, and interventions for augmenting psychological well-being among the medical students. PMID- 28028660 TI - Sex-Specific Impact of Spiritual Beliefs and Sleep Quality on Degree of Psychological Distress. AB - The purpose of this study was to test a set of hypotheses suggesting sleep quality and spiritual beliefs differed according to degree of psychological distress and biological sex. The Pittsburgh Sleep Quality Index measured sleep quality, the Beliefs and Values Scale measured spiritual beliefs, and the Kessler 6 Psychological Distress Scale measured distress. A factorial MANOVA tested the model. Higher sleep quality and greater spiritual beliefs were associated with lower levels of distress. Women exhibited lower sleep quality than men, whereas spiritual beliefs were equivalent between sexes. To decrease psychological distress, interventions should improve sleep quality and increase spiritual engagement. PMID- 28028661 TI - Volunteer Work, Religious Commitment, and Resting Pulse Rates. AB - Research indicates that greater involvement in volunteer activities is associated with better health. We aim to contribute to this literature in two ways. First, rather than rely on self-reports of health, measured resting pulse rates serve as the dependent variable. Second, an effort is made to see if religious commitment moderates the relationship between volunteering and resting pulse rates. Data that come from a recent nationwide survey (N = 2265) suggest that volunteer work is associated with lower resting pulse rates. The results also reveal that the relationship between engaging in volunteer work and resting pulse rates improves among study participants who are more deeply committed to religion. PMID- 28028662 TI - Self Addressed Questions and Filled Pauses: A Cross-linguistic Investigation. AB - There is an ongoing debate whether phenomena of disfluency (such as filled pauses) are produced communicatively. Clark and Fox Tree (Cognition 84(1):73-111, 2002) propose that filled pauses are words, and that different forms signal different lengths of delay. This paper evaluates this Filler-As-Words hypothesis by analyzing the distribution of self-addressed-questions or SAQs (such as "what's the word") in relation to filled pauses. We found that SAQs address different problems in different languages (most frequently about memory-retrieval in English and Chinese, and about appropriateness in Japanese). In relation to filled pauses, British but not American English uses "um" to signal a more severe problem than "uh". Chinese uses different filled pauses to signal the syntactic category of the problem constituent. Japanese uses different filled pauses to signal levels of interaction with the interlocuter. Overall, our data supports the Filler-As-Words hypothesis that filled pauses are used communicatively. However, the dimensions of its meanings vary across languages and dialects. PMID- 28028663 TI - Family Social Support Modifies the Relationships Between Childhood Maltreatment Severity, Economic Adversity and Postpartum Depressive Symptoms. AB - OBJECTIVES: This study examines the main and moderating effects of childhood abuse or neglect severity, income, and family social support on the presence of postpartum depressive symptoms (PDS). METHODS: Participants included 183 postpartum mothers who endorsed a history of childhood maltreatment (CM) and enrolled in a longitudinal study of mother and child outcomes. Participants completed questionnaires to assess CM severity, associated societal and maternal characteristics, and depressive symptom severity. RESULTS: The results confirm previously identified links between CM severity and PDS. Further, hierarchical linear regression analyses indicate the interaction of household income and interpersonal support from the family attenuates the relationship between CM severity and PDS. The final model accounted for 29% of the variance of PDS scores, a large effect size. CONCLUSIONS: This study is the first to demonstrate interrelationships between income and social support on resilience to postpartum psychopathology in childhood trauma-surviving women. Social support appeared to protect against PDS for all mothers in this study while income only conferred a protective effect when accompanied by family support. For clinicians, this implies the need to focus on improving family and other relationships, especially for at-risk mothers. PMID- 28028664 TI - Prognostic factors in 868 advanced gastric cancer patients treated with second line chemotherapy in the real world. AB - BACKGROUND: Although second-line therapy is often considered for advanced gastric cancer patients, the optimal candidates are not well defined. METHODS: We retrospectively collected baseline parameters, tumour features, and treatment data for 868 advanced gastric cancer patients exposed to multiple treatment lines at 19 Italian centres. Cross-tables and chi-square tests were used to describe categorical features. To predict the impact of clinical variables on progression free survival and overall survival, Kaplan-Meier and Cox regression analyses were performed. RESULTS: At the start of second-line therapy, median age was 64.8 years (25th-75th percentiles: 55.2-71.9 years). Overall, 43% of patients received single-agent chemotherapy, 47.4% a doublet, and 7.3% a triplet. Median second line progression-free survival was 2.8 months (25th-75th percentiles: 1.8-5.2 months) and median second-line overall survival was 5.6 months (25th-75th percentiles: 2.9-10.0 months). Multivariate analysis showed that performance status, LDH level, neutrophils/lymphocytes ratio, and progression-free survival in the first-line therapy all impacted on prognosis. Based on these four prognostic factors, a prognostic index was constructed that divided patients into good, intermediate, and poor risk groups; median second-line overall survival for each group was 7.7, 4.5, and 2.0 months, respectively (log-rank p < 0.0001). CONCLUSIONS: Advanced gastric cancer patients with a favourable ECOG performance status, lower LDH levels, and a lower neutrophils/lymphocytes ratio at the start of second-line therapy seem to have better outcomes, regardless of age and intensity of treatment. A longer progression-free survival in the first-line therapy also had positive prognostic value. Our real-life study might help clinicians to identify the patients who may benefit most from a second-line therapy. PMID- 28028665 TI - Surgery after intraperitoneal and systemic chemotherapy for gastric cancer with peritoneal metastasis or positive peritoneal cytology findings. AB - BACKGROUND: Despite recent progress in systemic chemotherapy, the prognosis of gastric cancer patients with peritoneal metastasis (P1) or positive peritoneal cytology findings (CY1) is still poor. We developed a regimen combining intraperitoneal (IP) paclitaxel (PTX) with S-1 and PTX, which can produce notable efficacy with regard to peritoneal lesions. Surgery after response to combination chemotherapy is a promising option for P1 or CY1 gastric cancer. A retrospective study was performed to evaluate the safety and efficacy. METHODS: This study enrolled 100 primary P1 or CY1 gastric cancer patients treated with IP PTX plus S 1 and PTX at the University of Tokyo Hospital between 2005 and 2011. Radical gastrectomy was performed when peritoneal cytology findings became negative, and the disappearance or obvious shrinkage of peritoneal metastasis was confirmed by laparoscopy. The same chemotherapy regimen was restarted after surgery and repeated with appropriate dose reduction. RESULTS: Gastrectomy was performed in 64 (P1 56, P0CY1 8) of 100 (P1 90, P0CY1 10) patients. R0 resection was achieved in 44 patients (69%). The median survival time was 30.5 months [95% confidence interval (CI) 23.6-37.7 months] from the initiation of intraperitoneal chemotherapy and 34.6 months (95% CI 26.8-39.4 months) from the diagnosis of gastric cancer. Postoperative complications included anastomotic leakage and pancreatic fistula, each in two patients, which were cured conservatively. There were no treatment-related deaths. The median survival time of the 36 patients who did not undergo surgery was 14.3 months (95% CI 10.0-17.8 months). CONCLUSIONS: Surgery after response to intraperitoneal and systemic chemotherapy is safe and may prolong the survival of P1 and CY1 gastric cancer patients. PMID- 28028666 TI - Is Male Androphilia a Context-Dependent Cross-Cultural Universal? AB - The cross-cultural ethnographic literature has traditionally used the label male "homosexuality" to describe sexual relationships between biological males without considering whether or not the concept encompasses primary sexual attraction to adult males. Although male androphilia seems to be found in all national populations, its universal existence in tribal populations has been questioned. Our goal is to review previous cross-cultural classifications and surveys of male same sex behavior to present a system that does justice to its varied expressions, especially as it is informed by contemporary sexuality research. Previous comparative research does not effectively distinguish male same sex behavior from male androphilia. Using the standard cross-cultural sample (SCCS) as a sampling frame and the ethnographic sources in the human relations area files and elsewhere, we present distributional data on various forms of male same sex behavior. The SCCS is useful because it is designed to be representative of all historically known social formations and the sample is designed to reduce similarities as a consequence of common descent or historical origin as well as reduce the probability of diffusion of sociocultural practices from one culture to another. Our results show that male same sex behavior as well as male androphilia is much more common than previously estimated in the SCCS. With our findings, we make an argument that male androphilia is a context-dependent cross cultural universal. PMID- 28028667 TI - Interpersonal Goals and Well-Being in Couples Coping with Genito-Pelvic Pain. AB - In the context of genito-pelvic pain, consideration of interpersonal goals is particularly relevant given that couples' distress is often predicated upon the relational setting. However, relationship goals have not been examined in this population. We investigated (1) the associations between relationship goals and women's pain during intercourse as well as the sexual, relational, and psychological well-being of women with provoked vestibulodynia (PVD) and their partners and (2) the moderating role of sexual goals in these associations. Women with PVD (N = 134) and their partners completed measures of relationship goals, sexual goals, sexual satisfaction, relationship satisfaction, and depressive symptoms. Women also reported on their average pain intensity during intercourse. Women with stronger relationship approach goals reported more sexual satisfaction. When the partner pursued more relationship approach goals, both women and partners reported more sexual and relationship satisfaction and partners reported less depression. Stronger relationship avoidance goals in the partner were associated with less sexual satisfaction in women. Several significant interactions showed that the combination of relationship and sexual approach goals was associated with greater relationship and sexual satisfaction, and fewer depressive symptoms, whereas the combination of relationship and sexual avoidance goals was related to lower relationship satisfaction as well as to greater pain during intercourse for women. Targeting relationship approach and avoidance goals as well as those goals specific to sexual activity may improve the quality and efficacy of couples-based psychological interventions for PVD. PMID- 28028668 TI - Suicidal Ideation, Resilience, and Healthcare Implications for Newly Diagnosed HIV-Positive Men Who Have Sex with Men in China: A Qualitative Study. AB - Globally, suicidal ideation and behavior have been widely reported among people living with human immunodeficiency virus (HIV). Knowledge gaps exist regarding the longer life and resilience-related experiences of people living with HIV (PLWH). Specifically, there is a dearth of data about the interaction of perceived risk and resilient factors resulting in a wide spectrum of intentional suicidal ideation outcomes in a Chinese cultural context. This qualitative research drew from a larger ethnographic study of newly diagnosed HIV-positive men who have sex with men (MSM) in Mainland China. Interviews were conducted with 31 MSM within 6 months of diagnosis of HIV infection. Initial suicidal ideation was commonly reported with participants subsequently feeling more resilient to these thoughts through gaining a greater understanding of their prognosis and treatment. Post-HIV diagnosis, some participants reported forming new relationships and receiving increased support from their partners, friends, peers, families, and community-based organizations. At follow-up, these participants generally reported suicidal ideation had declined. However, participants who continued to express suicidal ideation perceived extended pressure from their families' expectations for them to engage in heterosexual marriages and parenthood. Furthermore, these men reported ongoing hardships in their daily life, unemployment, lack of social support, and isolation. Among this Mainland Chinese cohort of HIV-positive MSM, suicidal ideation may be a transient phenomenon experienced initially following HIV diagnosis that resolves with increased and specific familial, social, and service-based support. It is crucial to identify the causes of stress and social suffering associated with HIV diagnosis in order to reduce suicidal ideation. In China, action is needed to develop routine mental health screening and to increase services that support PLWH. Important services mechanism to accomplish this are promoting resilience through intentional activities as well as continued public health campaigns to reduce stigma toward HIV-positive MSM. PMID- 28028669 TI - Transforaminal migration of an epidural catheter. PMID- 28028670 TI - Preventing intravenous bag contamination. PMID- 28028671 TI - Anesthesia considerations for patients with an implanted deep brain stimulator undergoing surgery: a review and update. AB - PURPOSE: Deep brain stimulation (DBS) can be an effective treatment option for patients with essential tremor and Parkinson's disease. This review provides an overview on the functioning of neurostimulators and recent advances in this technology and presents an updated guide on the anesthetic management of patients with an implanted neurostimulator undergoing surgery or medical intervention. SOURCE: A search was conducted on MEDLINE(r), EMBASETM, and Cochrane Database of Systematic Reviews databases to identify studies published in English from 1974 to December 2015. Our search also included relevant and available incident reports from the manufacturers, Health Canada, the United States Food and Drug Administration, and the European Medicines Agency. Thirty of 232 articles identified were found to be relevant to this review. PRINCIPAL FINDINGS: Deep brain stimulation systems now offer a range of options, including pulse generators with dual-channel capabilities, rechargeable batteries, and current control modes. Preoperatively, the anesthesiologist should ascertain the indications for DBS therapy, identify the type of device implanted, and consult a DBS specialist for specific precautions and device management. The major perioperative concern is the potential for interactions with the medical device resulting in patient morbidity. Neurostimulators should be turned off intraoperatively to minimize electromagnetic interference, and precautions should be taken when using electrosurgical equipment. Following surgery, the device should be turned on and checked by a DBS specialist. CONCLUSION: The anesthesiologist plays an important role to ensure a safe operating environment for patients with an implanted DBS device. Pertinent issues include identifying the type of device, involving a DBS-trained physician, turning off the device intraoperatively, implementing precautions when using electrosurgical equipment, and checking the device postoperatively. PMID- 28028672 TI - Con: Pure service delivery is no longer needed in global surgical missions. PMID- 28028673 TI - Outcomes of elderly critically ill medical and surgical patients: a multicentre cohort study. AB - PURPOSE: Very elderly (over 80 yr of age) critically ill patients admitted to medical-surgical intensive care units (ICUs) have a high incidence of mortality, prolonged hospital length of stay, and dependent living conditions should they survive. The primary purpose of this study is to describe the outcomes and differences in outcomes between very elderly medical patients and their surgical counterparts admitted to Canadian ICUs, thereby informing decision-making for clinicians and substitute decision-makers. METHODS: This was a prospective multicentre cohort study of very elderly medical and surgical patients admitted to 22 Canadian academic and non-academic ICUs. Outcome measures included ICU length of stay and mortality, hospital length of stay and mortality, and disposition following hospital discharge. RESULTS: There were 1,671 patients evaluated in this study. Patient demographics included a mean age of 84.5 yr, baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score of 22.4, baseline Sequential Organ Failure Assessment (SOFA) score of 5.3, overall ICU mortality of 21.8%, and overall hospital mortality of 35.0%. Medical patient median ICU length of stay was 4.1 days, hospital length of stay was 16.2 days, ICU mortality was 26.5%, and hospital mortality was 41.5%. Surgical patient median ICU length of stay was 3.8 days, hospital length of stay was 20.1 days, ICU mortality was 18.7%, and hospital mortality was 31.6%. Only 45.0% of medical patients and 41.6% of surgical emergency patients were able to return home to live. CONCLUSIONS: In this large sample of critically ill medical and surgical patients, the admission SOFA score and hospital lengths of stay were not different between the two groups, but medical patients had longer ICU lengths of stay and higher ICU and hospital mortality than surgical patients. PMID- 28028674 TI - The effect of verbal and video feedback on learning direct laryngoscopy among novice laryngoscopists: a randomized pilot study. AB - PURPOSE: Skill acquisition in direct laryngoscopy (DL) and tracheal intubation is complex. This pilot study aims to assess feasibility and determine sample size for a subsequent trial comparing DL instruction using a Macintosh-style video laryngoscope (MacVL), with and without video recordings, with conventional DL instruction. METHODS: Medical students with no prior laryngoscopy experience were recruited during their two-week anesthesia rotation. During the first (TRAINING) week, students were randomized into three groups: Control (Macintosh direct laryngoscope), VL-1 (MacVL with real-time feedback), and VL-2 (MacVL with real time feedback plus video recordings of laryngoscopies). During the second (TESTING) week, all students were tested using a Macintosh direct laryngoscope. Feasibility objectives were recruitment and attrition rates, ability to time and video record intubations, and the availability of a MacVL. The primary clinical outcome during the TESTING week was total time to intubate, and secondary outcomes included intubation success rate, intubating opportunities, complications, and confidence scores. RESULTS: Sixty-eight of 87 (78%) consecutive medical students approached to participate in the study were recruited over 18 months. Eight (12%) students withdrew from the study, and data are available on the remaining 60 participants. The times to intubate were recorded for 92% of the TESTING intubations, but only 71% of the TRAINING intubations in the VL-2 group were video recorded. The MacVLs were available in 100% of cases. We estimate that 190 participants would be required for a study restricted to a comparison of DL vs video laryngoscopy with real-time feedback. CONCLUSION: This pilot study establishes feasibility and provides a sample size estimate for a future RCT. Required modifications to the study protocol include wider hospital involvement and consideration regarding standardization of airway education, teaching, feedback, and patient characteristics. PMID- 28028675 TI - Glottic impersonation. PMID- 28028676 TI - Impact of autonomic dysfunctions on the quality of life in Parkinson's disease patients. AB - Autonomic dysfunctions are part of a spectrum of non-motor symptoms in Parkinson's disease (PD) patients. The aim of the study was to assess the prevalence of autonomic dysfunctions and their influence on the quality of life (QoL) in PD patients, adjusted for age, sex, disease duration and motor symptoms. Patients were evaluated for motor function (Unified Parkinson's Disease Rating Scale, UPDRS part III), disease stage (Hoehn and Yahr scale, H&Y scale), autonomic dysfunction (Scales for Outcomes in Parkinson's disease, Autonomic, SCOPA-AUT) and QoL (Parkinson's Disease Questionnaire-39, PDQ-39). Urinary, gastrointestinal and sexual autonomic dysfunctions were most frequently reported, while the most severe symptoms were reported for sexual and urinary systems. Age and motor symptoms did not correlate with autonomic dysfunction, while disease duration correlated with cardiovascular dysfunction. There were sex differences on the thermoregulation subscale. All types of autonomic dysfunction influenced QoL, mostly gastrointestinal and thermoregulatory dysfunctions, except for sexual one. Many aspects of QoL (activity of daily living, emotion, cognitive functions, communication and social support) except for stigma and mobility were affected by autonomic dysfunctions. Age, disease duration, sex and motor symptoms were not found to affect global QoL scores, but had detrimental effects on different PDQ 39 dimensions. Autonomic dysfunctions influence QoL in more aspects than motor symptoms, age, disease duration and sex. Patients tend to be more stigmatized with motor than non-motor symptoms. PMID- 28028677 TI - Psychosocial Influences on Disaster Preparedness in San Francisco Recipients of Home Care. AB - Disasters disproportionately impact certain segments of the population, including children, pregnant women, people living with disabilities and chronic conditions and those who are underserved and under-resourced. One of the most vulnerable groups includes the community-dwelling elderly. Post-disaster analyses indicate that these individuals have higher risk of disaster-related morbidity and mortality. They also have suboptimal levels of disaster preparedness in terms of their ability to shelter-in-place or evacuate to a shelter. The reasons for this have not been well characterized, although impaired health, financial limitations, and social isolation are believed to act as barriers to preparedness as well as to adaptability to changes in the environment both during and in the immediate aftermath of disasters. In order to identify strategies that address barriers to preparedness, we recently conducted a qualitative study of 50 elderly home care recipients living in San Francisco. Data were collected during in-home, in-person interviews using a semi-structured interview guide that included psychosocial constructs based on the social cognitive preparedness model and a new 13-item preparedness checklist. The mean preparedness score was 4.74 (max 13, range 1-11, SD. 2.11). Over 60 % of the participants reported that they had not made back-up plans for caregiver assistance during times of crisis, 74 % had not made plans for transportation to a shelter, 56 % lacked a back-up plan for electrical equipment in case of power outages, and 44 % had not prepared an emergency contacts list-the most basic element of preparedness. Impairments, disabilities, and resource limitations served as barriers to preparedness. Cognitive processes that underlie motivation and intentions for preparedness behaviors were lacking. There were limitations with respect to critical awareness of hazards (saliency), self-efficacy, outcome expectancy, and perceived responsibility. There was also a lack of trust in response agencies and authorities and a limited sense of community. Participants wanted to be prepared and welcomed training, but physical limitations kept many of them home bound. Training of home care aides, the provision of needed resources, and improved community outreach may be helpful in improving disaster outcomes in this vulnerable segment of the population. PMID- 28028678 TI - The Effect of Advance Directive Completion on Hospital Care Among Chronically Homeless Persons: a Prospective Cohort Study. AB - Advance care planning is relevant for homeless individuals because they experience high rates of morbidity and mortality. The impact of advance directive interventions on hospital care of homeless individuals has not been studied. The objective of this study was to determine if homeless individuals who complete an advance directive through a shelter-based intervention are more likely to have information from their advance directive documented and used during subsequent hospitalizations. The advance directive included preferences for life-sustaining treatments, resuscitation, and substitute decision maker(s). A total of 205 homeless men from a homeless shelter for men in Toronto, Canada, were enrolled in the study and offered an opportunity to complete an advance directive with the guidance of a trained counselor from April to June 2013. One hundred and three participants chose to complete an advance directive, and 102 participants chose to not complete an advance directive. Participants were provided copies of their advance directives. In addition, advance directives were electronically stored, and hospitals within a 1.0-mile radius of the shelter were provided access to the database. A prospective cohort study was performed using chart reviews to ascertain the documentation, availability, and use of advance directives, end-of life care preferences, and medical treatments during hospitalizations over a 1 year follow-up period (April 2013 to June 2014) after the shelter-based advance directive intervention. Chart reviewers were blinded as to whether participants had completed an advance directive. The primary outcome was documentation or use of an advance directive during any hospitalization. The secondary outcome was documentation of end-of-life care preferences, without reference to an advance directive, during any hospitalization. After unblinding, charts were studied to determine whether advance directives were available, hospital care was consistent with patient preferences as documented in advance directives, and hospital resource utilization during admission. During the 1-year follow-up period, 38 participants who completed an advance directive and 37 participants who did not complete an advance directive had at least one hospitalization (36.9 vs. 36.2 %, p = 0.93). Participants who completed an advance directive were significantly more likely to have documentation or use of an advance directive in hospital, compared to participants who did not complete an advance directive (9.7 vs. 2.9 %, p = 0.047). Without reference to an advance directive, documentation of end-of life care preferences occurred in 30.1 vs. 30.4 % of participants, respectively (p = 0.96), most often due to documentation of code status. There were no significant differences in resource utilization between admitted patients who completed and did not complete an advance directive. In conclusion, homeless men who complete an advance directive through a shelter-based intervention are more likely to have their detailed care preferences documented or used during subsequent hospitalizations. PMID- 28028680 TI - Establishment of mouse leukemia cell lines expressing human CD4/CCR5 using lentiviral vectors. AB - A low-cost rodent model of HIV infection and which presents high application value is an effective tool to investigate HIV infection and pathogenesis. However, development of such a small animal model has been hampered by the unsuitability of rodent cells for HIV-1 replication given that the retrovirus HIV 1 has high selectivity to its host cell. Our study used the mouse leukemia cell lines L615 and L1210 that were induced by murine leukemia virus and transfected with hCD4/CCR5 loaded-lentiviral vector. Lentiviral vectors containing the genes hCD4/CCR5 under the transcriptional control of cytomegalovirus promoter were designed. Transfection efficiencies of human CD4 and CCR5 in L615 and L1210 cells were analyzed by quantitative real-time polymerase chain reaction (RT-PCR) and Western blot assay. Results showed that hCD4 and CCR5 proteins were expressed on the cell surface, demonstrating that the L615 and L1210 cells were humanized and that they possess the characteristics necessary for HIV infection of human host cells. Moreover, the sensitivity of human CD4/CCR5 transgenic mouse cells to HIV infection was confirmed by RT-PCR and ELISA. Mouse leukemia cell lines that could express hCD4 and CCR5 were thus established to facilitate normal entry of HIV-1 so that a human CD4/CCR5 transgenic mice cell model can be used to investigate the transmission and pathogenesis of HIV/AIDS and potential antiviral drugs against this disease. PMID- 28028679 TI - HFE Variants and the Expression of Iron-Related Proteins in Breast Cancer Associated Lymphocytes and Macrophages. AB - The association of HFE (High Iron FE) major variants with breast cancer risk and behavior has been a matter of discussion for a long time. However, their impact on the expression of iron-related proteins in the breast cancer tissue has never been addressed. In the present study, hepcidin, ferroportin 1, transferrin receptor 1 (TfR1), and ferritin expressions, as well as tissue iron deposition were evaluated in a collection of samples from breast cancers patients and analyzed according to the patients' HFE genotype. Within the group of patients with invasive carcinoma, those carrying the p.Cys282Tyr variant in heterozygosity presented a higher expression of hepcidin in lymphocytes and macrophages than wild-type or p.His63Asp carriers. An increased expression of TfR1 was also observed in all the cell types analyzed but only in p.Cys282Tyr/p.His63Asp compound heterozygous patients. A differential impact of the two HFE variants was further noticed with the observation of a significantly higher percentage of p.Cys282Tyr heterozygous patients presenting tissue iron deposition in comparison to p.His63Asp heterozygous. In the present cohort, no significant associations were found between HFE variants and classical clinicopathological markers of breast cancer behavior and prognosis. Although limited by a low sampling size, our results provide a new possible explanation for the previously reported impact of HFE major variants on breast cancer progression, i.e., not by influencing systemic iron homeostasis but rather by differentially modulating the local cellular expression of iron-related proteins and tissue iron deposition. PMID- 28028681 TI - Culture, PCR, DNA sequencing, and second harmonic generation (SHG) visualization of Bartonella henselae from a surgically excised human femoral head. PMID- 28028682 TI - Interstitial lung disease increases mortality in systemic sclerosis patients with pulmonary arterial hypertension without affecting hemodynamics and exercise capacity. AB - Published data suggest that coexisting interstitial lung disease (ILD) has an impact on mortality in patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), but there is scarce knowledge if this is reflected by hemodynamics, exercise capacity, autoantibody profile, or pulmonary function. In this partially retrospective study, 27 SSc-PAH patients were compared to 24 SSc-PAH patients with coexisting ILD respecting to survival, pulmonary function, hemodynamics, exercise capacity, and laboratory parameters. Survival was significantly worse in SSc-PAH-ILD patients than in SSc patients with isolated PAH (1, 5, and 10-year survival rates 86, 54, and 54% versus 96, 92, and 82%, p = 0.013). Compared to isolated SSc-PAH patients, patients with SSc-PAH-ILD revealed lower forced expiratory volume after 1 s (FEV1) values at the time of PAH diagnosis as well as 1 and 2 years later (p = 0.002) without significant decrease in the PAH course in both groups. At PAH diagnosis, diffusion capacity for carbon monoxide (DLCO) values were lower in the ILD-PAH group. Coexisting ILD was not associated with lower exercise capacity, different FEV1/forced vital capacity (FVC) ratio, higher WHO functional class, or reduced hemodynamics. Higher levels of antibodies against angiotensin and endothelin receptors predict mortality in all SSc-PAH patients but could not differentiate between PAH patients with and without ILD. Our study confirmed an impact of ILD on mortality in SSc-PAH patients. Pulmonary function parameters can be used to distinguish PAH from PAH ILD. The higher mortality rate cannot be explained by differences in hemodynamics, exercise capacity, or autoantibody levels. Mechanisms of mortality remain to be studied. PMID- 28028683 TI - Muckle-Wells syndrome in Chinese patients: a single center case series. AB - Muckle-Wells syndrome (MWS) is a rare autoinflammatory disease. This study aimed to report the clinical features and gene variations of the first case series of MWS patients in Chinese population. Four Han Chinese patients were diagnosed with MWS and followed up at our adult clinic for autoinflammatory diseases. All relevant phenotypes and genotypes were collected. All patients were adult male. The median age of disease onset was 4.5 years, and one patient had adult-onset disease. No positive family history was observed. All patients had a remittent disease course. The duration of fever attacks ranged from 0.5 to 7 days. Skin rashes were present in all patients. The other manifestations included polyarthralgia/arthritis (n = 3), oral ulcers (n = 2), conjunctivitis (n = 2), myalgia (n = 2), headache (n = 2), pharyngitis (n = 1), abdominal pain (n = 1), severe sensorineural hearing loss (n = 1), and chronic meningitis with communicating hydrocephalus (n = 1). None of the patients showed evidence of renal amyloidosis. Each patient carried a heterozygous mutation in an NLRP3 gene, including D29V, V70M, T348M, and Q703K, respectively. D29V and V70M variants were novel mutations in exon 1 of NLRP3. All patients had good response to corticosteroids. Our study suggests that MWS could be identified in Chinese population. Our finding of novel mutations in NLRP3 may expand the diversity of MWS. PMID- 28028685 TI - RAPID3 scores and hand outcome measurements in RA patients: a preliminary study. AB - The Routine Assessment of Patient Index Data 3 (RAPID3) is a patient-reported disease activity measure used to assess physical function, pain, and global health in patients with rheumatoid arthritis (RA) without formal joint counts. Since hand involvement and its decreased function are hallmarks of RA, the aim of our study was to investigate the performance of RAPID3 scores with regard to hand function and to confirm previous findings that the RAPID3 score as a disease activity measure is strongly correlated with the DAS28 score. Sixty-eight consecutive patients with RA (85% female), aged 18-75 years, were included in the study and were recruited during their outpatient visit. Apart from demographic and clinical data, the obtained parameters of interest included RAPID3 scores and assessments of the function of the hand, namely, the signal of functional impairment (SOFI)-hand, grip strength, and pulp-to-palm distance, as well the Health Assessment Questionnaire- Disability Index (HAQ-DI) and DAS28 scores. Pearson's correlation coefficient, Student's t test and linear regression were used in the statistical analysis of the results. The significance was set to p < 0.05. A positive correlation was found between RAPID3 scores and HAQ-DI scores, SOFI-hand scores, and pulp-to-palm distance, and negative correlation was observed between RAPID3 scores and grip strength. The order regarding the strength of correlations between RAPID3 scores and other variables (from the strongest to the weakest) was as follows: HAQ-DI, grip strength, SOFI-hand and pulp-to-palm distance. The hand assessment variables had stronger correlations with RAPID3 scores than with DAS28 scores. Our preliminary study showed that RAPID3 scores were strongly correlated with measurements of the functional ability of the hand, demonstrating that RAPID3 can be used as a measure of disease activity in clinical practice and to characterize hand function. Further studies are needed to confirm this result. PMID- 28028686 TI - Biomarkers of chondriome topology and function: implications for the extension of healthy aging. AB - Multiple theories of aging (e.g., free radical, error catastrophe, mitochondrial) are complementary but fail to provide adequate models that comprehensively predict lifelong aging processes and that are valid across species. Hayflick (PLoS Genet 3(12):2351-2354, 2007) described six universal characteristics of aging that focus upon post-reproductive molecular entropy. Here we present a thermodynamic potential model of aging in which the energetic and topological properties of the mitochondrion drive functional and structural stabilities within living systems. Using multivariate regressions of physiological assessments from the National Health and Nutrition Examination Survey, VO2 max consistently declined with age regardless of gender or race, although it had a significantly greater decline for African American females. Percent fat (negative), hematocrit (negative), and urine creatinine (negative) were strongly and significantly associated with VO2 max and male aging, although cholesterol (positive) was an additional factor for African American males. Bioenergetic measures such as VO2 max can be useful for physical assessments to promote healthy aging. PMID- 28028684 TI - Are obesity, ACPAs and periodontitis conditions that influence the risk of developing rheumatoid arthritis in first-degree relatives? AB - The aim of this study was to investigate the body mass index (BMI), anti citrullinated protein antibodies (ACPAs) status and the presence of periodontitis and IgG-1/IgG-2 antibodies against Porphyromonas gingivalis (Pg) in the first degree relatives (FDRs) of rheumatoid arthritis (RA) patients and compare these variables with a control group of healthy individuals from the general population. In total, 100 FDR individuals and 200 healthy controls matched by age and gender were included. Rheumatologic and periodontal assessment was performed, and the presence of ACPAs and anti-P. gingivalis antibodies was evaluated. Groupwise comparisons were analysed using the McNemar and Wilcoxon tests. A conditional logistic regression analysis was performed to establish the associations between BMI, ACPAs and periodontitis in both groups. In the FDR group, 70% of the subjects were female, with a mean age of 37.3 +/- 13 years. Obesity was observed in 17 and 7% of the FDRs and controls, respectively. ACPAs were found in 7% of the FDRs vs. 2.5% of the controls. Periodontitis was diagnosed in 79 and 56% of the FDRs and controls, respectively. Among the FDRs, 15% had severe periodontitis. There were associations in the FDR group related to the presence of obesity (OR 2.93, 95% CI 1.03-8.28), ACPAs (OR 2.45, 95% CI 0.7 8.32) and periodontitis (OR 3.70 95% CI 1.89-7.29). Regarding anti-P. gingivalis antibodies and smoking history, no differences were found between the groups. Obesity, ACPAs and periodontitis (diagnosis and severity) can be considered as relevant conditions associated with the development of RA in FDRs. PMID- 28028687 TI - Internet Gamblers Differ on Social Variables: A Latent Class Analysis. AB - Online gambling has gained popularity in the last decade, leading to an important shift in how consumers engage in gambling and in the factors related to problem gambling and prevention. Indebtedness and loneliness have previously been associated with problem gambling. The current study aimed to characterize online gamblers in relation to indebtedness, loneliness, and several in-game social behaviors. The data set was obtained from 584 Internet gamblers recruited online through gambling websites and forums. Of these gamblers, 372 participants completed all study assessments and were included in the analyses. Questionnaires included those on sociodemographics and social variables (indebtedness, loneliness, in-game social behaviors), as well as the Gambling Motives Questionnaire, Gambling Related Cognitions Scale, Internet Addiction Test, Problem Gambling Severity Index, Short Depression-Happiness Scale, and UPPS-P Impulsive Behavior Scale. Social variables were explored with a latent class model. The clusters obtained were compared for psychological measures and three clusters were found: lonely indebted gamblers (cluster 1: 6.5%), not lonely not indebted gamblers (cluster 2: 75.4%), and not lonely indebted gamblers (cluster 3: 18%). Participants in clusters 1 and 3 (particularly in cluster 1) were at higher risk of problem gambling than were those in cluster 2. The three groups differed on most assessed variables, including the Problem Gambling Severity Index, the Short Depression-Happiness Scale, and the UPPS-P subscales (except the sensation seeking subscore). Results highlight significant between-group differences, suggesting that Internet gamblers are not a homogeneous group. Specific intervention strategies could be implemented for groups at risk. PMID- 28028688 TI - Reliability, Construct and Predictive Validity of the Hong Kong Chinese Orebro Musculoskeletal Pain Screening Questionnaire. AB - Purpose The aim of this study was to evaluate the reliability, construct validity and predictive validity of the Hong Kong Chinese version of the Orebro Musculoskeletal Pain Screening Questionnaire (COMPSQ-HK). Methods The COMPSQ-HK was developed using the forward-backward translation. Internal consistency was assessed using Cronbach's alpha and test-retest reliability was examined using intraclass correlation coefficient with one-way random-effects model (ICC1,1), minimum detectable change (MDC) and 95% limits of agreement (LoA). Construct validity was evaluated by correlating the COMPSQ-HK with the Numeric Pain Rating Scale, Roland-Morris Disability Questionnaire, Northwick Park Neck Pain Questionnaire, Tampa Scale for Kinesiophobia, and Medical Outcomes Study Short Form 12. The predictive validity was investigated using receiver operating characteristics (ROC) curve analyses with sick leave >60 days and return-to-work for >=4 consecutive weeks as outcomes at 1 year follow-up. The areas under the curve (AUC) were calculated. Results The COMPSQ-HK was administered to 305 patients with acute/subacute low back pain and 160 patients with acute/subacute neck pain. The Cronbach's alphas and ICC1,1 ranged from 0.83 to 0.84 and 0.81 to 0.92 respectively. The MDC were 32.1 and 21.1. The 95% LoA were -32.4 to 31.8 and -15.4 to 26.7. The Pearson r ranged from 0.333 to 0.697 in absolute value. The AUC for the ROC curve analyses ranged from 0.59 to 0.71. Conclusions The COMPSQ HK has good internal consistency, moderate test-retest reliability, satisfactory construct validity and predictive validity as a screening tool for patients with back and neck pain at risk of chronic disability. PMID- 28028689 TI - The Quality of Care for Gastroesophageal Reflux Disease. AB - Improving the quality of healthcare delivery is a cornerstone of modern medical care shared between all stakeholders. However, effectively improving quality requires both an understanding of the tenets of healthcare quality and how they relate to an individual disease process. This is especially important for common diseases, such as gastroesophageal reflux disease (GERD), where wide variations in practice exist. The high prevalence of GERD coupled with wide variation in clinical approach results in significant economic burden and poor quality of care. Thus, GERD serves as a useful framework to highlight the opportunities and current challenges of delivering high-quality care. In this article, we identify quality metrics in GERD and the areas in need of research to improve the quality of the management of GERD. Additionally, we suggest strategies for improvement as it relates to the proper diagnostic testing utilization and the decision-making process. PMID- 28028690 TI - Effect of Lactobacillus reuteri on Cell Viability and PGE2 Production in Human Gingival Fibroblasts. AB - Emerging evidence suggests that probiotic therapy can play a role in the prevention and management of oral inflammatory diseases through immunomodulation and down-regulation of the inflammatory cascade. The aim of this in vitro study was to investigate the viability of human gingival fibroblasts (HGF) and its production of prostaglandin E2 (PGE2), when exposed to supernatants of two mixed Lactobacillus reuteri strains (ATCC PTA 5289 and DSM 17938). The experiments were conducted in the presence and absence of the pro-inflammatory cytokine IL-1beta. L. reuteri strains were grown and the bacterial supernatant was collected. The cell-free supernatant was diluted to concentrations equivalent to the ones produced by 0.5 to 5.0 * 107 CFU/mL bacteria. Cell viability was assessed with the MTT colorimetric assay and the amount of PGE2 in the cell culture medium was determined using the monoclonal enzyme immune assay kits. Our findings showed that none of the L. reuteri supernatants were cytotoxic or affected the viability of HGF. The most concentrated bacterial supernatant stimulated the production of PGE2 by the gingival cells in a significant way in the presence of IL-1beta (p < 0.05), suggesting that bacterial products secreted from L. reuteri might play a role in the resolution of inflammation in HGF. Thus, our findings justify further investigations on the influence of probiotic bacteria on gingival inflammatory reactions. PMID- 28028691 TI - Sirolimus Therapy Is Associated with Elevation in Circulating PCSK9 Levels in Cardiac Transplant Patients. AB - Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 +/- 105 ng/mL to 343 +/- 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2-3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia. PMID- 28028692 TI - In Vitro Hydrodynamic Assessment of a New Transcatheter Heart Valve Concept (the TRISKELE). AB - This study presents the in vitro hydrodynamic assessment of the TRISKELE, a new system suitable for transcatheter aortic valve implantation (TAVI), aiming to mitigate the procedural challenges experienced with current technologies. The TRISKELE valve comprises three polymeric leaflet and an adaptive sealing cuff, supported by a novel fully retrievable self-expanding nitinol wire frame. Valve prototypes were manufactured in three sizes of 23, 26, and 29 mm by automated dip coating of a biostable polymer, and tested in a hydrodynamic bench setup in mock aortic roots of 21, 23, 25, and 27 mm annulus, and compared to two reference valves suitable for equivalent implantation ranges: Edwards SAPIEN XT and Medtronic CoreValve. The TRISKELE valves demonstrated a global hydrodynamic performance comparable or superior to the controls with significant reduction in paravalvular leakage. The TRISKELE valve exhibits enhanced anchoring and improved sealing. The valve is currently under preclinical investigation. PMID- 28028694 TI - A new model of flavonoids affinity towards P-glycoprotein: genetic algorithm support vector machine with features selected by a modified particle swarm optimization algorithm. AB - Flavonoids exhibit a high affinity for the purified cytosolic NBD (C-terminal nucleotide-binding domain) of P-glycoprotein (P-gp). To explore the affinity of flavonoids for P-gp, quantitative structure-activity relationship (QSAR) models were developed using support vector machines (SVMs). A novel method coupling a modified particle swarm optimization algorithm with random mutation strategy and a genetic algorithm coupled with SVM was proposed to simultaneously optimize the kernel parameters of SVM and determine the subset of optimized features for the first time. Using DRAGON descriptors to represent compounds for QSAR, three subsets (training, prediction and external validation set) derived from the dataset were employed to investigate QSAR. With excluding of the outlier, the correlation coefficient (R2) of the whole training set (training and prediction) was 0.924, and the R2 of the external validation set was 0.941. The root-mean square error (RMSE) of the whole training set was 0.0588; the RMSE of the cross validation of the external validation set was 0.0443. The mean Q2 value of leave many-out cross-validation was 0.824. With more informations from results of randomization analysis and applicability domain, the proposed model is of good predictive ability, stability. PMID- 28028693 TI - A Study of Coronary Bifurcation Shape in a Normal Population. AB - During percutaneous coronary intervention, stents are placed in narrowings of the arteries to restore normal blood flow. Despite improvements in stent design, deployment techniques and drug-eluting coatings, restenosis and stent thrombosis remain a significant problem. Population stent design based on statistical shape analysis may improve clinical outcomes. Computed tomographic (CT) coronary angiography scans from 211 patients with a zero calcium score, no stenoses and no intermediate artery, were used to create statistical shape models of 446 major coronary artery bifurcations (left main, first diagonal and obtuse marginal and right coronary crux). Coherent point drift was used for registration. Principal component analysis shape scores were tested against clinical risk factors, quantifying the importance of recognised shape features in intervention including size, angles and curvature. Significant differences were found in (1) vessel size and bifurcation angle between the left main and other bifurcations; (2) inlet and curvature angle between the right coronary crux and other bifurcations; and (3) size and bifurcation angle by sex. Hypertension, smoking history and diabetes did not appear to have an association with shape. Physiological diameter laws were compared, with the Huo-Kassab model having the best fit. Bifurcation coronary anatomy can be partitioned into clinically meaningful modes of variation showing significant shape differences. A computational atlas of normal coronary bifurcation shape, where disease is common, may aid in the design of new stents and deployment techniques, by providing data for bench-top testing and computational modelling of blood flow and vessel wall mechanics. PMID- 28028695 TI - 5-Fluorouracil inhibits cell migration by induction of Sestrin2 in colon cancer cells. AB - 5-Fluorouracil (5-FU) is a chemotherapeutic agent used in the treatment of colorectal cancer. In this study, we investigated whether 5-FU induces Sestrin2 (SESN2), an antioxidant enzyme, and the role of SESN2 in 5-FU action in colon cancer cells. We found that 5-FU upregulated SESN2 protein expression in both HCT116 and HT29 cells. It also increased transcripts of SESN1 and SESN2, but not of SESN3. Furthermore, we investigated whether production of reactive oxygen species (ROS) was involved in 5-FU-induced SESN2 expression. 5-FU did not increase ROS production nor affect Nrf2 phosphorylation and expression levels. Moreover, SESN2 upregulation by 5-FU was not prevented by pretreatment with antioxidants. Next, we investigated p53 levels after 5-FU treatment to elucidate the regulation of SESN2 by 5-FU. An increase in p53 levels was detected following 5-FU treatment; pifithrin-alpha, an inhibitor of p53 activation, reversed 5-FU induced SESN2 expression. 5-FU prevented serum-induced in vitro cell migration, but knockdown of SESN2 or treatment with pifithrin-alpha reversed a 5-FU-mediated decrease in cell migration. Taken together, our results suggest that 5-FU increases SESN2 levels via a p53-dependent pathway, which contributes to inhibition of cancer cell migration in vitro. PMID- 28028696 TI - Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1 yl)salicylhydrazones: revitalizing an old drug. AB - The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39-1.5 MUg/mL) compared to the marketed drugs isoniazid, rifampicin and ethambutol. Moreover, the most active analogue N-(1-(4-chlorobenzyl)-2 oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potent than PAS and equipotent to rifampicin (MIC 0.39 ug/mL), while exhibiting low cytotoxicity with a selectivity index of >128. In addition, this compound was shown to be active against persistent forms of mycobacteria comparable to standard drugs in nutrient starvation model. Accordingly, we introduce compound 20 as a valuable lead for further development. A 3D-QSAR study was also conducted to help in explaining the observed activity and to serve as a tool for further development. PMID- 28028697 TI - Quality of life in adults with asthma treated in allergy and pneumology subspecialties: relationship with sociodemographic, clinical and psychological variables. AB - PURPOSE: Prior studies suggest that specialist care associates with improved health-related quality of life (HRQL) in asthmatic patients. However, there are limited studies focused on differences in HRQL among subspecialties. The aim of this study was to assess the differences in HRQL between adult asthmatic patients treated in pneumology or allergy practices, and to estimate to what extent the differences in HRQL can be explained by sociodemographic, clinical or psychological characteristics of patients from each specialty. METHODS: We recruited adult asthmatic outpatients from allergy and pneumology practices. Information on sociodemographic, clinical and psychological characteristics was collected, and HRQL was assessed with generic and disease-specific questionnaires. HRQL was compared between groups adjusting for sociodemographic, clinical and psychological characteristics. RESULTS: A total of 287 asthmatic patients participated in the study (105 from pneumology and 182 from allergy). Patients treated by pneumologists reported significantly poorer HRQL in physical dimensions of generic questionnaire and all dimensions of disease-specific questionnaire. Pneumology patients were older (p < .001) and had a lower education level (p < .001); a higher number of patients were in a non-active employment situation (p = .003) and had worse pulmonary function (p < .001), longer duration of disease (p = .020), higher prevalence of obesity (p < .001) and uncontrolled asthma (p < .001), and a higher rate of previous absenteeism (p = .001). Depression and the use of cognitive avoidance coping were also higher among pneumology patients (p = .050 and p = .022, respectively). There were not significant differences in HRQL between pneumology and allergy patients after adjustment for these sociodemographic, clinical and psychological characteristics. CONCLUSIONS: Asthmatic patients treated by pneumologists reported poorer HRQL than patients treated by allergists, but this outcome is attributed to differences in several sociodemographic, clinical and psychological characteristics between the two groups of patients. PMID- 28028698 TI - A dose-response relationship for marketable yield reduction of two lettuce (Lactuca sativa L.) cultivars exposed to tropospheric ozone in Southern Europe. AB - The present study investigated the response to ozone (O3) of two cultivars (cv.'Romana' and cv. 'Canasta') of irrigated lettuce grown in an open-top chamber (OTC) experiment in Mediterranean conditions. Two different levels of O3 were applied, ambient O3 in non-filtered OTCs (NF-OTCs) and -40% of ambient O3 in charcoal-filtered OTCs (CF-OTCs), during four consecutive growing cycles. At the end of each growing cycle, the marketable yield (fresh biomass) was assessed while during the growing periods, measurements of the stomatal conductance at leaf level were performed and used to define a stomatal conductance model for calculation of the phytotoxic ozone dose (POD) absorbed by the plants.Results showed that O3 caused statistically significant yield reductions in the first and in the last growing cycle. In general, the marketable yield of the NF-OTC plants was always lower than the CF-OTC plants for both cultivars, with mean reductions of -18.5 and -14.5% for 'Romana' and 'Canasta', respectively. On the contrary, there was no statistically significant difference in marketable yield due to the cultivar factor or to the interaction between O3 and cultivar in any of the growing cycle performed.Dose-response relationships for the marketable relative yield based on the POD values were calculated according to different flux threshold values (Y). The best regression fit was obtained using an instantaneous flux threshold of 6 nmol O3 m-2 s-1 (POD6); the same value was obtained also for other crops. According to the generic lettuce dose-response relationship, an O3 critical level of 1 mmol O3 m-2 of POD6 for a 15% of marketable yield loss was found. PMID- 28028699 TI - Evaluation of cotton burdock (Arctium tomentosum Mill.) responses to multi-metal exposure. AB - Plants have immense potential for their use in the minimization of emerging environmental pollution issues. Under simulated laboratory conditions, this work investigated the growth and biochemical responses of 14-day-old cotton burdock (Arctium tomentosum Mill.) seedlings to the body burdens of multi-metals including Pb, Cu, Ni, and Zn (1.0 MUM-10 mM). Biochemical traits (superoxide generation, lipid peroxidation, content of total peroxides), growth traits (axial organs growth, dry weight accumulation, leaf area), and also metal body burdens varied with types and concentrations of metals. Results indicated a significant tolerance of A. tomentosum to multi-metals that can be implicated for its potential role in the metal phytoremediation programs. PMID- 28028700 TI - Changes in growth rate and macroelement and trace element accumulation in Hydrocharis morsus-ranae L. during the growing season in relation to environmental contamination. AB - The temporal variations in plant chemistry connected with its life cycle may affect the cycling of elements in an ecosystem as well as determine the usefulness of the species in phytoremediation and bioindication. In this context, there is a gap in knowledge on the role of floating plants for elements cycling in aquatic reservoirs. The aim of the study was to determine if there are variations in Hydrocharis morsus-ranae (European frog-bit) bioaccumulation capacity and the growth rate of its population during the growing season and to test the impact of environmental pollution on these features. The content of macroelements (Ca, K, Mg, N, Na, P, S) and trace metals (Cd, Co, Cu, Cr, Hg, Fe, Mn, Ni, Pb, Zn) was determined in H. morsus-ranae collected monthly from June to October from habitats differing in environmental contamination. The results showed that the highest content of most trace metals (Co, Cr, Cu, Hg, Mn, Ni, Zn) and some nutrients (N, P) in plants as well as the greatest bioaccumulation efficiency occurred simultaneously in the beginning of the growing season. In the following months, a dilution effect (manifested by a decrease in content) related to the rapid growth was observed. Co, Mn, and Ni content in plant tissues reflected the level of environmental contamination throughout the growing season which makes H. morsus-ranae a potential biomonitor of pollution for these metals. Considering the great bioaccumulation ability, high sensitivity to contamination, and low biomass of European frog-bit in polluted systems, further investigation is required to assess the real phytoremediation capability of the species. PMID- 28028701 TI - Catchment land use-dependent effects of barrage fishponds on the functioning of headwater streams. AB - Extensive fish production systems in continental areas are often created by damming headwater streams. However, these lentic systems favour autochthonous organic matter production. As headwater stream functioning is essentially based on allochthonous organic matter (OM) supply, the presence of barrage fishponds on headwater streams might change the main food source for benthic communities. The goal of this study was thus to identify the effects of barrage fishponds on the functioning of headwater streams. To this end, we compared leaf litter breakdown (a key ecosystem function in headwater streams), their associated invertebrate communities and fungal biomass at sites upstream and downstream of five barrage fishponds in two dominant land use systems (three in forested catchments and two in agricultural catchments). We observed significant structural and functional differences between headwater stream ecosystems in agricultural catchments and those in forested catchments. Leaf litter decay was more rapid in forest streams, with a moderate, but not significant, increase in breakdown rate downstream from the barrage fishponds. In agricultural catchments, the trend was opposite with a 2-fold lower leaf litter breakdown rate at downstream sites compared to upstream sites. Breakdown rates observed at all sites were closely correlated with fungal biomass and shredder biomass. No effect of barrage fishponds were observed in this study concerning invertebrate community structure or functional feeding groups especially in agricultural landscapes. In forest streams, we observed a decrease in organic pollution (OP)-intolerant taxa at downstream sites that was correlated with an increase in OP-tolerant taxa. These results highlighted that the influence of barrage fishponds on headwater stream functioning is complex and land use dependent. It is therefore necessary to clearly understand the various mechanisms (competition for food resources, complementarities between autochthonous and allochthonous OM) that control ecosystem functioning in different contexts in order to optimize barrage fishpond management. PMID- 28028702 TI - Field evidence of bird poisonings by imidacloprid-treated seeds: a review of incidents reported by the French SAGIR network from 1995 to 2014. AB - The large-scale use of neonicotinoid insecticides has raised growing concerns about their potential adverse effects on farmland birds, and more generally on biodiversity. Imidacloprid, the first neonicotinoid commercialized, has been identified as posing a risk for seed-eating birds when it is used as seed treatment of some crops since the consumption of a few dressed seeds could cause mortality. But evidence of direct effects in the field is lacking. Here, we reviewed the 103 wildlife mortality incidents reported by the French SAGIR Network from 1995 to 2014, for which toxicological analyses detected imidacloprid residues. One hundred and one incidents totalling at least 734 dead animals were consistent with an agricultural use as seed treatment. Grey partridges (Perdix perdix) and "pigeons" (Columba palumbus, Columba livia and Columba oenas) were the main species found. More than 70% of incidents occurred during autumn cereal sowings. Furthermore, since there is no biomarker for diagnosing neonicotinoid poisonings, we developed a diagnostic approach to estimate the degree of certainty that these mortalities were due to imidacloprid poisoning. By this way, the probability that mortality was due to poisoning by imidacloprid-treated seeds was ranked as at least "likely" in 70% of incidents. As a result, this work provides clear evidence to risk managers that lethal effects due to the consumption by birds of imidacloprid-treated seeds regularly occur in the field. This in turn raises the question of the effectiveness of the two main factors (seed burying and imidacloprid-treated seeds avoidance) that are supposed to make the risk to birds negligible. Risk factors and the relevance of mitigation measures are discussed. PMID- 28028703 TI - Removal of organic matter, nitrogen and faecal indicators from diluted anaerobically digested slurry using tidal flow constructed wetlands. AB - The rapid implementation of anaerobic digestion for renewable energy production has resulted in increased generation of anaerobically digested slurry, which contains a variety of pollutants and therefore has the potential to cause serious environmental problems. Tidal flow constructed wetlands, which could generate beneficial oxygen conditions, were investigated for their success in removing nitrogen, organic matter and pathogens in anaerobically digested slurry. The results indicated that tidal operation had a positive effect on promoting NH4+-N and organic matter (chemical oxygen demand (COD)) removal. With an average influent NH4+-N concentration of 288 mg/L and COD concentration of 839 mg/L, the average removal efficiency reached up to 93% (325 g/m2 day) for NH4+-N and 53% (603 g/m2 day) for COD, with total inorganic nitrogen (TIN) removal efficiency of 51% (226 g/m2 day). The nitrogen removal in the tidal-operated CWs is highly dependent on the flooded and drained (F/D) time ratio. Changing flooded time from 3 to 5 h enhanced denitrification (nitrite reductase-K (nirK) abundance) and further resulted in improved TIN removal efficiency of 62% (237 g/m2 day). The removal of faecal indicators was also examined, with reduction rate of approximately 0.9 log10 CFU/100 mL for both Escherichia coli and total coliforms, which was independent of the influent loadings and differing flooded/drained time ratio. Tidal flow CWs were demonstrated to have the high potential to treat diluted anaerobically digested slurry. PMID- 28028704 TI - Assessment of mercury exposure and maternal-foetal transfer in Miniopterus schreibersii (Chiroptera: Miniopteridae) from southeastern Iberian Peninsula. AB - Mercury (Hg) is a highly toxic and widely distributed metal that is bioaccumulated in insectivorous mammals and may cause adverse effects on the reproductive system. Bats are considered excellent Hg bioindicators due to their wide distribution, life span, trophic position, metabolic rate and food intake. However, few studies have analysed Hg residues in bats, and to the best of our knowledge, no studies have been made in the Iberian Peninsula. The main aim of this study was to undertake the first ever assessment of Hg exposure in Schreiber's bent-winged bats inhabiting a natural cave in the southeast of Spain. The findings suggest that Schreiber's bent-winged bats in the sampling area are chronically exposed to low levels of Hg. The Hg concentrations found in different tissues (fur, kidney, liver, muscle and brain) were below the threshold levels associated with toxic effects in mammals. Non-gestating females showed Hg concentrations in the brain and muscle that doubled those found in gestating females. This could be due to Hg mobilization from the mother to the foetus in gestating females, although other factors could contribute to explain this result such as variations in hunting areas and the insect-prey consumed and/or different energetic needs and average food consumption during the breeding season. Hg levels were 1.7 times higher, although not significant, in foetus' brains than in the maternal brains, and Hg concentration in foetus' brain was significantly correlated with levels in the corresponding mothers' kidney. These results suggest that there could be an active mother-to-foetus transfer of Hg in bats, which would be of special relevance in a scenario of higher Hg exposure than that found in this study. However, further research is needed to support this view due to the limited number of samples analysed. Given the scarce ecotoxicological data available for bats and their protected status, we encourage further opportunistic studies using carcasses found in the field, the validation of non-destructive samples such as fur and guano for Hg monitoring, and new modelling approaches that will increase the data needed for proper ecological risk assessment in bat populations. PMID- 28028705 TI - Effects of rapid temperature rising on nitrogen removal and microbial community variation of anoxic/aerobic process for ABS resin wastewater treatment. AB - ABS resin wastewater is a high-temperature nitrogenous organic wastewater. It can be successfully treated with anoxic/aerobic (A/O) process. In this study, the effect of temperature on nitrogen removal and microbial community after quick temperature rise (QTR) was investigated. It was indicated that QTR from 25 to 30 degrees C facilitated the microbial growth and achieved a similar effluent quality as that at 25 degrees C. QTR from 25 to 35 degrees C or 40 degrees C resulted in higher effluent concentration of chemical oxygen demand (COD), biochemical oxygen demand (BOD5), total nitrogen (TN), and total phosphorus (TP). Illumina MiSeq pyrosequencing analysis illustrated that the richness and diversity of the bacterial community was decreased as the temperature was increased. The percentage of many functional groups was changed significantly. QTR from 25 to 40 degrees C also resulted in the inhibition of ammonia oxidation rate and high concentration of free ammonia, which then inhibited the growth of NOB (Nitrospira), and thus resulted in nitrite accumulation. The high temperature above 35 degrees C promoted the growth of a denitrifying bacterial genus, Denitratisoma, which might increase N2O production during the denitrification process. PMID- 28028706 TI - Photosynthesis and growth response of maize (Zea mays L.) hybrids exposed to cadmium stress. AB - Cadmium (Cd) is a biologically non-essential heavy metal while the cultivation of Cd-tolerant varieties/hybrids (V) seems the most promising strategy for remediation of Cd-contaminated soils. For this, 24-day-old seedlings of seven maize hybrids, DKC 65-25, DKC 61-25, DKC 919, 23-T-16, 32-B-33, 31-P-41, and Syn hybrid, were grown in hydroponic conditions for 21 additional days in various Cd concentrations (0, 5, 10, and 15 MUM). Effects of variety, Cd, and their interaction were highly significant (p <= 0.05) for studied plant agronomic and physiological traits except the V * Cd interaction for leaf chlorophyll content, root-shoot length, and root dry weight. The Cd accumulation in root and shoot increased gradually with increasing Cd treatments while copper (Cu), zinc (Zn), and manganese (Mn) uptake was decreased in all hybrids. The reduction in root and shoot biomass and Cd uptake was lower in 32-B-33 and 23-T-16 compared to other hybrids. The highest accumulation of Cu, Zn, and Mn was observed in 32-B-33, DK C65-25, and 31-P-41, respectively. The differential uptake and accumulation of Cd by maize hybrids may be useful in selection and breeding for Cd-tolerant genotypes. PMID- 28028707 TI - Synergistic use of an oil drift model and remote sensing observations for oil spill monitoring. AB - In case of oil spills due to disasters, one of the environmental concerns is the oil trajectories and spatial distribution. To meet these new challenges, spill response plans need to be upgraded. An important component of such a plan would be models able to simulate the behaviour of oil in terms of trajectories and spatial distribution, if accidentally released, in deep water. All these models need to be calibrated with independent observations. The aim of the present paper is to demonstrate that significant support to oil slick monitoring can be obtained by the synergistic use of oil drift models and remote sensing observations. Based on transport properties and weathering processes, oil drift models can indeed predict the fate of spilled oil under the action of water current velocity and wind in terms of oil position, concentration and thickness distribution. The oil spill event that occurred on 31 May 2003 in the Baltic Sea offshore the Swedish and Danish coasts is considered a case study with the aim of producing three-dimensional models of sea circulation and oil contaminant transport. The High-Resolution Limited Area Model (HIRLAM) is used for atmospheric forcing. The results of the numerical modelling of current speed and water surface elevation data are validated by measurements carried out in Kalmarsund, Simrishamn and Kungsholmsfort stations over a period of 18 days and 17 h. The oil spill model uses the current field obtained from a circulation model. Near-infrared (NIR) satellite images were compared with numerical simulations. The simulation was able to predict both the oil spill trajectories of the observed slick and thickness distribution. Therefore, this work shows how oil drift modelling and remotely sensed data can provide the right synergy to reproduce the timing and transport of the oil and to get reliable estimates of thicknesses of spilled oil to prepare an emergency plan and to assess the magnitude of risk involved in case of oil spills due to disaster. PMID- 28028708 TI - Aquatic photolysis of beta2-agonist salbutamol: kinetics and mechanism studies. AB - Salbutamol (SAL) has been widely used as medicine both in treating asthma and in animal primary production; an increasing number of reports have detected SAL in natural waters. The photolysis kinetic and pathway of SAL in aquatic system were studied, as well as the effect of several natural water constituents, such as nitrate, dissolved oxygen (DO) and ferric ions. According to our research, the direct photolysis of SAL followed pseudo-first-order reaction kinetics. Alkaline condition could promote the degradation of SAL; the increase of solution pH would simultaneously increase the fraction of the deprotonated forms of SAL (including the deprotonated and zwitterionic species), which were easier to be excited, and result in the bathochromic shift of the UV-Vis spectrum and, finally, accelerate the degradation rate of SAL. The presence of nitrate could enhance the removal rate of SAL via generation hydroxyl radical (.OH) under irradiation. In addition, the absence of oxygen in the reaction solution could decrease the photolysis. Moreover, Fe(III) was able to chelate with SAL to form an octahedral complex, which was photochemically reactive. The octahedral complex could generate .OH to oxidize SAL itself in turn. The pathways of SAL photolysis were also investigated by means of the solid phase extraction (SPE)-LC-MS method. The major pathways of SAL photodegradation included oxidation and side-chain cleavage. PMID- 28028709 TI - Morphological studies on adult mosquitoes (Diptera: Culicidae) and first report of the potential Zika virus vector Aedes (Stegomyia) unilineatus (Theobald, 1906) in Iran. AB - Beside numerous extensive studies on Anophelinae mosquitoes of Iran, little is known on Aedes species in the country and existing reports are dispersed. The objective of this study was to identify adults of Culicinae species occurring in the Sistan and Baluchestan Province, southeast of Iran, during 2012-2014. Mosquito collections were carried out three times (May-June, September, October November) in four counties by Centers for Diseases Control (CDC) light traps and human landing catches outdoors and under bed nets baited with carbon dioxide. These trapping were carried out two consecutive nights during the field studies. Several mosquito collections were also conducted with aspirator and pyrethrum spray space catches during the day. A total of 1885 mosquitoes were collected, belonging to 10 species of genus Culex including Cx. pipiens Complex, Cx. laticinctus, Cx. sinaiticus, and Cx. tritaeniorhynchus, one species of the genus Culiseta, Cs. longiareolata, and five species of the genus Aedes, Ae. caspius, Ae. vexans, Ae. detritus, Ae. albopictus, and Ae. unilineatus. Ae. vexans was the dominant species in the area (77.7%). During the study, seven Ae. unilineatus were collected in two villages near the city of Chabahar located in a coastal area; this is the first record for Iran and identification was confirmed by Cytochrome oxidase (COI) sequences analysis. Confirmation of the presence of Ae. unilineatus in the country raises the number of species of the genus Aedes to 12. The detection of this species reveals its probable establishment in the southeast of the country, which has implications for public health such as dengue and Zika infections and requires active entomological surveillance and implementation of adapted vector control measures in the area. PMID- 28028711 TI - Bioengineering the Uterus: An Overview of Recent Advances and Future Perspectives in Reproductive Medicine. AB - Since the initial in vitro attempts to more complex models, research on uterine regeneration is moving towards the creation of a functional bioengineered uterus with possible clinical applications. We describe here the most relevant advances in bioengineering of the uterus published in the last decades considering the use of stem cells and biomaterials as well as future developing techniques in Regenerative Medicine. PMID- 28028710 TI - Restoring Ovarian Endocrine Function with Encapsulated Ovarian Allograft in Immune Competent Mice. AB - Premature ovarian insufficiency (POI) is a major complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. In pediatric cancer patients modern therapy has improved the long-term survival to over 80% in the United States. However, these cancer survivors face long-term health problems related to treatment toxicity. In female cancer survivors POI leads to sterility, along with the consequences of estrogen deficiency such as premature osteopenia, muscle wasting, accelerated cardiovascular diseases and a vast array of other health and developmental problems. These long-lasting effects are particularly significant for young girls reaching puberty. As such, restoring ovarian endocrine function is paramount in this population. In the present study, we evaluated the feasibility of restoring ovarian endocrine function in ovariectomized mice by transplanting syngeneic and allogeneic ovarian tissue encapsulated in alginate capsules or TheraCyte(r). Histological analysis of the implants retrieved after 7 and 30 days' post implantation showed follicular development up to the secondary and antral stages in both syngeneic and allogeneic implants. Implantation of syngeneic and allogeneic ovarian grafts encapsulated in TheraCyte devices restored ovarian endocrine function, which was confirmed by decreased serum FSH levels from 60 to 70 ng/mL in ovariectomized mice to 30-40 ng/mL 30 days after implantation. Absence of allo-MHC-specific IgG and IgM antibodies in the sera of implanted mice with allogeneic ovarian tissue encapsulated in TheraCyte indicate that the implants did not evoke an allo-immune response, while the allogeneic controls were rejected 21 days after implantation. Our results show that TheraCyte effectively isolates the graft from immune recognition but also supports follicular growth. PMID- 28028712 TI - Numerical Study of Blood Clots Influence on the Flow Pattern and Platelet Activation on a Stented Bifurcation Model. AB - Stent implantation is a common procedure followed in arteries affected by atherosclerosis. This procedure can lead to other stenting-related problems. One of these is the deposition and accumulation of blood clots over stent struts. This process can have further consequences, in so far as it can introduce modifications to the flow pattern. This problem is especially critical in stented bifurcations, where resulting stent geometry is more complex. In this regard, a numerical study is presented of the effect on the flow pattern and platelet activation of blood clot depositions on the stent struts of a stented coronary bifurcation. The numerical model is first validated with experimental measurements performed for this purpose. Experiments considered a flow with suspended artificial thrombi, which naturally deposited on stent struts. The location and shape observed were used to create numerical thrombi. Following this, numerical simulations were performed to analyze the influence of the presence of thrombi depositions on parameters such as Time Averaged Wall Shear Stress, Oscillatory Shear Index or Relative Residence Time. Finally, a study was also carried out of the effect of different geometrical configurations, from a straight tube to a stented bifurcation model with thrombus depositions, on platelet activation. PMID- 28028713 TI - Magnetically Controlled Endourethral Artificial Urinary Sphincter. AB - Urinary incontinence is a largely spread disfunction that affects more than 300 million people worldwide. At present, no technological solutions are able to restore continence in a minimally invasive and effective way. In this article the authors report the design, fabrication, and testing of a novel artificial endourethral urinary sphincter able to fully restore continence. The device can be inserted/retracted in a minimally invasive fashion without hospital admission, does not alter the body scheme and can be applied to both women and men. The device core is a unidirectional polymeric valve and a magnetically activated system able to modulate its opening pressure. Bench tests and ex vivo tests on a human cadaver demonstrated that the device is able to fully restore continence and to allow urination when desired. Overall, the proposed system shows a high potential as a technological solution able to restore a normal daily life in patients affected by urinary incontinence. PMID- 28028714 TI - Study on Force Mechanism for Therapeutic Effect of Pushing Manipulation with One Finger Meditation Base on Similarity Analysis of Force and Waveform. AB - OBJECTIVE: To reveal the force mechanism for therapeutic effect of pushing manipulation with one-finger meditation. METHODS: A total of 15 participants were recruited in this study and assigned to an expert group, a skilled group and a novice group, with 5 participants in each group. Mechanical signals were collected from a biomechanical testing platform, and these data were further observed via similarity analysis and cluster analysis. RESULTS: Comparing the force waveforms of manipulation revealed that the manipulation forces were similar between the expert group and the skilled group (P>0.05). The mean value of vertical force was 9.8 N, and 95% CI rang from 6.37 to 14.70 N, but there were significant differences compared with the novice group (P<0.05). The result of overall similarity coefficient cluster analysis showed that two kinds of manipulation forces curves were existed between the expert group and the skilled group. CONCLUSION: Pushing manipulation with one-finger meditation is a kind of light stimulation manipulation on the acupoint, and force characteristics of double waveforms continuously alternated during manual operation. PMID- 28028715 TI - Study on the intervention effects of Pinggan Prescription () on spontaneously hypertensive rats based on metabonomic combined with pharmacodynamic methods. AB - OBJECTIVE: To investigate the effects of Pinggan Prescription (, PGP) on hypertension by the associated methods of metabonomic and pharmacodynamic. METHODS: A total of 32 male spontaneously hypertensive rats (SHRs) were randomly divided into two groups by using the random number table method: a treatment group (n=18) and a model group (n=14). The Wistar rats (n=14) were used as the normal group. Different prescription were used to intervene three groups: the treatment group in which PGP extract was administered orally at a dose of 18.336 g/kg (PGP/body weight), and the model group in which physiological saline was administered at the equivalent dose. The same treatment was applied to the normal group as the model group. The blood pressure was measured by tail-cuff method, and pharmacodynamic indexes including cyclic adenosine monophosphate (cAMP) and angiotensinII (Ang II) were tested by enzyme-linked immunosorbent assay. The plasma samples from three groups were detected by gas chromatography-mass spectrometry (GC-MS). RESULTS: Compared with the model group, blood pressure of treatment group was obviously reduced after continuous curing with PGP (P<0.01). The pharmacodynamic results illustrated that the content of Ang II increased with the raised blood pressure and the cAMP expressed the converse trend. After curing with PGP, the content of Ang II decreased, the difference between model group and treatment group was significant (P<0.01), and the cAMP expressed the converse trend. Five potential biomarkers were identified, including arachidonic acid, hexadecanoic acid, elaidic acid, octadecanedioic acid and 9,12-octadecadienoic acid. These metabolites had shown significantly change as followed: arachidonic acid, hexadecanoic acid and elaidic acid were significantly higher in the model group than those in the normal group, but lower levels of octadecanedioic acid and 9,12-octadecadienoic acid. After the treatment of PGP, the metabolites above all had the trends of returning to normal combined with the reduced blood pressure. CONCLUSIONS: PGP intervention in hypertension played a major role in the metabolism of arachidonic acid and linoleic acid. Metabonomic combined with pharmacodynamic methods could be potentially powerful tools to investigate the mechanism of Chinese medicine. PMID- 28028716 TI - Evaluation of the health status of six volunteers from the Mars 500 project using pulse analysis. AB - OBJECTIVE: To comprehensively evaluate the health status of 6 volunteers from the Mars 500 Project through analyzing their pulse graphs and determining the changes in cardiovascular function, degree of fatigue and autonomic nervous function. METHODS: Six volunteers were recruited; all were male aged 26-38 years (average 31.83+/-4.96 years). Characteristic parameters reflflecting the status of cardiovascular functions were extracted, which included left ventricular contraction, vascular elasticity and peripheral resistance. The degree of fatigue was determined depending on the difference between the calendar age and biological age, which was calculated through the analysis of blood pressure value and characteristic parameters. Based on the values of pulse height variation and pulse time variation on a 30-s pulse graph, autonomic nervous function was evaluated. All parameters examined were marked on an equilateral polygon to form an irregular polygon of the actual fifigure, then health status was evaluated based on the coverage area of the actual fifigure. RESULTS: The results demonstrated: (1) volunteers developed weakened pulse power, increased vascular tension and peripheral resistance, and slight decreased ventricular systolic function; (2) the degree of fatigue was basically mild or moderate; and (3) autonomic nervous function was excited but generally balanced. CONCLUSIONS: These volunteers were in the state of sub-health. According to Chinese medicine theories, such symptoms are mainly caused by the weakening of healthy qi, Gan (Liver) failing in free coursing, and disharmony between Gan and Wei (Stomach), which manifests as a weak and string-like pulse. PMID- 28028717 TI - Multi-drug resistant uropathogenic Escherichia coli and its treatment by Chinese medicine. AB - OBJECTIVES: To investigate the resistance and virulence profiles of uropathogenic Escherichia coli (UPEC) and its treatment by Chinese medicine (CM) Fuzheng Qingre Lishi Formula (, FQLF). METHODS: UPEC strains were isolated from recurrent urinary tract infections (UTIs) patients. Patient sensitivities to 17 antibiotics were tested by the disk diffusion method. Virulence genes were screened by plolymerase chain reaction. A mouse model was constructed using a multi-drug resistant and virulent UPEC strain and treated with FQLF or the antibiotic imipenem. The treatment efficacy was evaluated by bacterial clearance from urine and the urinary organs. RESULTS: A total of 90 UPEC strains were collected, and 94.4% of the isolates were resistant to at least 1 antibiotic. Approximately 66.7% of the UPEC strains were multi-drug resistant. More than one virulence gene was found in 85.6% of the isolates. The extended-spectrum beta-lactamases (ESBL) positive strains were more resistant than the negative ones. The virulence gene number was positively correlated with the resistance number (P<0.05). A mouse model was successfully constructed using UPEC10. Treatment with either FQLF or antibiotics significantly cleared bacteria from the mouse urine after 14 days. In the untreated control, the bacteria lasted for 28 days. FQLF treatment of the UTI mouse model greatly reduced the bacterial number in the kidney and bladder, but could not completely clear the bacteria. CONCLUSIONS: Multi-drug resistance is common among UPEC isolates, and the resistance is positively related with virulence. FQLF could treat UPEC UTIs, but could not completely clear the bacteria from the host. PMID- 28028718 TI - Recent highlights of Chinese medicine for advanced lung cancer. AB - Owing to its unique superiority in improving quality of life and prolonging survival time among advanced lung cancer patients, Chinese medicine (CM) has, in recent years, received increased attentions worldwide. We utilized a bibliometric statistical method based on MEDLINE/GoPubMed to conduct a comprehensive analysis of the current application status of CM in lung cancer, by including annual and accumulated publications, origin distribution of countries and journals, and keywords with a higher frequency score. Then the relevant clinical trials and mechanistic studies were systematically summarized within the field according to research types. We have raised potential problems and provided potentially useful reference information that could guide similar studies in the future. The basic experimental results are highly consistent with clinical trials, leading us to conclude that CM can offer better overall therapeutic benefits when used in combination with routine Western medicine for patients with advanced lung cancer. PMID- 28028719 TI - Identification of Chinese medicine constitution in public health services. AB - Public health is the science and art of preventing disease, prolonging life and prompting physical and mental health through evaluation, policy development and sanitary measures. The development of public health has become an important part of health care reform in China, and it requires the participation of Chinese medicine (CM) in the practice of public health. This study analyzed the problems of CM services in public health, suggested that the identification of CM constitution could propose an application paradigm of CM services in public health, and described from aspects of theory, technology and application. The identification of CM constitution gained national approval and support of government and industry. With the application and popularization of this technology, it will promote the establishment of characteristic CM preventive care system and the development of public health. PMID- 28028720 TI - Liuwei Dihuang Pill () Treats Postmenopausal Osteoporosis with Shen (Kidney) Yin Deficiency via Janus Kinase/Signal Transducer and Activator of Transcription Signal Pathway by Up-regulating Cardiotrophin-Like Cytokine Factor 1 Expression. AB - OBJECTIVES: To investigate the mechanism of Liuwei Dihuang Pill (, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency. METHODS: In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group (Group A), PMOP Shen-yang deficiency group (Group B), PMOP without Shen deficiency group (Group C), and control group (Group N). Real-time polymerase chain reaction (RT-PCR) and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 (CLCF1), ankyrin repeat and SOCS box containing 1 (ASB1), and prokineticin 2 (PROK2) genes and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. RESULTS: The mRNA (P<0.05) and protein (P<0.01) expression levels of the CLCF1 gene in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gene were obviously up regulated (P<0.01). After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated (both P<0.01), and the average bone density of the top femur had significantly increased (P<0.05). In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3. CONCLUSIONS: The CLCF1 gene is an important gene associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gene expression and activation of the JAK/STAT signaling pathway. PMID- 28028721 TI - Prevalence and Determinants of Traditional, Complementary and Alternative Medicine Provider Use among Adults from 32 Countries. AB - OBJECTIVE: To estimate recent prevalence data (2011-2013) on traditional, complementary and alternative medicine (TCAM) provider use and sociodemographic and health related correlates in nationally representative population samples from 32 countries from all world regions. METHODS: This secondary analysis was based on the International Social Survey Program (ISSP), 2011-2013, Health and Health Care Module. In a cross-sectional population-based survey (N=52,801), simple or multi-stage stratified random sampling was used, resulting in representative samples of the adult population of respective countries. RESULTS: Overall, the 12-month TCAM provider use prevalence was 26.4%, ranging from under 10% in Bulgaria, Poland and Slovenia to over 50% in China mainland, the Philippines and Republic of Korea. Over 80% TCAM treatment satisfaction was found in Europe in Denmark, Slovenia, Spain and Switzerland, in Asia in Taiwan (China) and USA. Multivariate logistic regression found sociodemographic variables (middle age, female sex, lower educational status, not having a religious affiliation, and lower economic indicators) and health variables (perceived poor or fair health status, being unhappy and depressed, having a chronic condition or disability, and having positive attitudes towards TCAM) were associated with TCAM provider use. CONCLUSIONS: A high prevalence TCAM provider use was found in all world regions and several sociodemographic and health related factors of its use were identified. PMID- 28028722 TI - Relationship between two blood stasis syndromes and inflammatory factors in patients with acute coronary syndrome. AB - OBJECTIVE: To investigate the relationship between inflammatory factors and two Chinese medicine (CM) syndrome types of qi stagnation and blood stasis (QSBS) and qi deficiency and blood stasis (QDBS) in patients with acute coronary syndrome (ACS). METHODS: Sixty subjects with ACS, whose pathogenesis changes belongs to qi disturbance blood stasis syndrome, were divided into 2 groups: 30 in the QSBS group and 30 in the QDBS group. The comparative analysis on them was carried out through comparing general information, coronary angiography and inflammatory factors including intracellular adhesion molecule-1 (ICAM-1), chitinase-3-like protein 1 (YKL-40) and lipoprotein-associated phospholipase A2 (Lp-PLA2). RESULTS: Compared with the QSBS group, Lp-PLA2 and YKL-40 levels in the QDBS group showed no-significant difference (P>0.05); ICAM-1 was significantly higher in the QDBS group than in the QSBS group in the pathological processes of qi disturbance and blood stasis syndrome of ACS (P<0.05). CONCLUSIONS: Inflammatory factor ICAM-1 may be an objective basis for syndrome typing of QSBS and QDBS, which provides a research direction for standardization research of CM syndrome types. PMID- 28028724 TI - Correlation study of basic Chinese medicine syndromes and neurotransmitter levels in patients with primary insomnia. AB - OBJECTIVE: To investigate the correlation between basic Chinese medicine (CM) syndromes (deficiency and excess syndromes) and intracranial neurotransmitter levels in primary insomnia (PI), to provide objective indicators and syndrome based medical evidence for the differentiation of PI. METHODS: A total of 158 patients with PI were recruited for CM syndrome differentiation. Another 30 healthy people without sleep disorders were selected as control group. An encephalofluctuograph analyzer was used to test the levels of intracranial neurotransmitters, including gamma- aminobutyric acid (GABA), glutamate (Glu), 5 hydroxytryptamine (5-HT), dopamine (DA), etc., and their relevance were analyzed. RESULTS: The neurotransmitter levels in the basic-deficiency group were lower than those in the healthy-control group, while the basic-excess group had higher levels than the healthy-control and basic-deficiency groups. Among the neurotransmitters, the 5-HT level was higher in the basic-excess group than in the basic-deficiency group (24.20+/-4.07 vs. 21.13+/-3.23; P<0.05); for the intermingled deficiency-excess group, the level of GABA was higher than that in the basic-deficiency group (9.48+/-3.07 vs. 7.23+/-3.67; P<0.05), Glu level was higher than that in the healthy-control group (7.53+/-4.10 vs. 5.83+/-0.99, P<0.05), and 5-HT and DA levels were lower than those in the healthy-control group (19.80+/-5.68 vs. 22.63+/-3.31, 5.27+/-3.79 vs. 6.83+/-1.58, respectively; P<0.05). CONCLUSIONS: There was a correlation between the basic syndromes and intracranial neurotransmitter levels in patients with PI, which could objectively reflect the CM differentiation in PI. This information could be important for improving CM diagnosis and treatment in PI. PMID- 28028723 TI - Shenfu Injection () inhibits inflammation in patients with acute myocardial infarction complicated by cardiac shock. AB - OBJECTIVES: To investigate the effect of Shenfu Injection (, SFI) on inflammatory factors in patients with acute myocardial infarction complicated by cardiogenic shock (CS) treated with and intra-aortic balloon pump (IABP). METHODS: This study enrolled 60 patients with ST-segment elevation myocardial infarction (STEMI) complicated by CS. Patients underwent IABP and emergency percutaneous coronary intervention (PCI) were randomly divided into two groups by random number table with 30 cases in each group, one given Sfitreatment (100 mL/24 h), one not. The two groups were then compared in a clinical setting for left ventricular function, biochemical indicators and Inflammatory factors, including C-reactive proteins (CRP), interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). Major adverse cardiac and cerebrovascular events (MACCE) events were compared between patients of the two groups both in-hospital and in follow-ups. RESULTS: The IABP support treatment times of patients in the IABP+Sfigroup were signifificantly shorter than the IABP group (52.87+/-28.84 vs. 87.45+/-87.31, P=0.047). In the patients of the IABP+Sfigroup, the CRP peak appeared in 24 h after PCI operation. The CRP peak in the patients of the IABP+Sfigroup was signifificantly lower than that in the IABP group (31.27+/-3.93 vs. 34.62+/-3.47, P=0.001). The increases in range of TNF-alpha in the patients of the IABP+Sfigroup were signifificantly lower than those of the IABP group (182.29+/ 22.79 vs. 195.54+/-12.02, P=0.007). The increases in range of IL-1 in the patients of the IABP+Sfigroup were signifificantly lower than those of the IABP group (214.98+/-29.22 vs. 228.60+/-7.03, P=0.019). The amplitude elevated TNF alpha 72 h after admission was an independent risk factor of in-hospital MACCE events (OR 0.973, 95% CI 0.890-0.987, P=0.014) in patients with STEMI and CS. CONCLUSION: Patients with STEMI complicated by CS treated by IABP and Sfihad a reduced inflammatory reaction, a reduced dependence of CS on IABP and shortened the course of disease. PMID- 28028725 TI - Substituted tetrazoles as multipurpose screening compounds. AB - Tetrazoles are small functional heterocycles that are suited to serve simultaneously as aromatic platform for diversity and as functional interaction motif. Furthermore, the tetrazole ring and its deprotonated tetrazolate counterpart are metal ion complexing ligands that possess a rich variety of binding and bridging modes. We recently demonstrated that fragments containing the tetrazole moiety and a metal chelating hydrazide group are well suited to discover selective screening hits with high ligand efficiency for a given protein target. Here, we report the synthesis and characterization of new polydentate tetrazole-containing screening compounds and their synthetic precursors as well as their deposition in a multipurpose screening library in the frame of the EU OPENSCREEN network. The pure and well-characterized screening compounds could be useful to aid drug discovery programs for multiple or hitherto undruggable targets by enclosure of under-represented tetrazole derivatives. PMID- 28028726 TI - Predictors of in-hospital mortality and dependence at discharge in patients with MCA stroke with intravenous thrombolysis. AB - Early risk stratification of mortality and dependence is important for guiding medical decision-making in stroke care. The study aim is to evaluate whether there are any differences between risk factors for in-hospital mortality and dependence at discharge in patients with first-episode ischemic stroke in the middle cerebral artery (MCA) receiving intravenous thrombolysis (IVT) treatment. The study comprised a single-center cohort of patients admitted consecutively for first-episode MCA ischemic stroke. A logistic regression analysis was performed to determine the variables associated with in-hospital mortality and dependence at discharge. We included 169 patients (50.9% women) with a mean age of 64.1 +/- 12.9 years and a median National Institute of Health Stroke Scale (NIHSS) score of 13 (range 3-26) at admission. Nineteen patients (11.2%) died as inpatients [the main cause of death was found to be infection (47.4%)]. The independent predictors for in-hospital mortality were: age (OR 1.09, 95% CI 1.03-1.15, p = 0.004) and NIHSS score (>17) at admission (OR 1.17, 95% CI 1.05-1.30, p = 0.004). Two other crude models used to analyze in-hospital mortality (age and symptoms-to needle time, and age and symptomatic intracerebral hemorrhage) were significant. NIHSS score (>11) at admission (OR 1.29, 95% CI 1.17-1.42, p < 0.001) and large artery atherosclerosis stroke (OR 3.10, 95% CI 1.10-8.76, p = 0.031) were independently associated with dependence at discharge. Overall, the predictors for mortality and dependence in patients with first-episode MCA ischemic stroke treated with IVT were different. This knowledge might help to improve the management of this devastating disease. PMID- 28028727 TI - Vitamin D deficiency in older adults and its associated factors: a cross sectional analysis of the Mexican Health and Aging Study. AB - : Vitamin D deficiency was common in older adults from a country with adequate sun exposure. The variables associated with this deficiency provide insight into the next steps needed to characterize older adults with this deficiency and to treat it accordingly. PURPOSE: The aim of this study was to describe the prevalence of and factors associated with vitamin D deficiency among Mexican older adults. METHODS: This was a secondary analysis of the last wave of the Mexican Health and Aging Study. Vitamin D levels along with other biomarkers were obtained from a sub-sample of Mexican adults older than 60 years. Prevalence was described by sex and age group, and a multivariate analysis was performed to test the factors associated with this condition. RESULTS: Data from 1088 adults over the age of 60 years were analyzed. The mean serum vitamin D level was 23.1 +/- 8.1 ng/mL and was significantly higher among men than women (25.6 +/- 0.6 and 22.8 +/- 0.5 ng/mL, respectively; p < 0.001). In total, 37.3% (n = 406) presented with vitamin D deficiency, 65% of whom were women. Low 25-(OH)-vitamin D levels were associated with female sex (OR 1.74, 95% CI 1.59-2.42), current smoking (OR 2.21, 95% CI 1.47-3.39), education (OR 1.1, 95% CI 1.06-1.13), physical activity (OR 1.74, 95% CI 1.31-2.23), and high levels of glycated hemoglobin (OR 1.16, 95% CI 1.07-1.25). CONCLUSIONS: Vitamin D deficiency was highly prevalent in Mexican older adults and was associated with a number of factors, indicating the multifactorial causality of this deficiency. PMID- 28028728 TI - Tissue Concentration of Dodecafluoropentane (DDFP) Following Repeated IV Administration in the New Zealand White Rabbit. AB - IV injection of dodecafluoropentane emulsion (DDFPe) increases oxygen transportation and reduces brain infarct volume in a rabbit stroke model. Tissue distribution of the parent perfluorocarbon dodecafluoropentane (DDFP) is unknown but is critical to understanding the mechanism by which DDFPe is effective in treating ischemia and for determining safe dosing. Previous studies showed a DDFP blood half-life of <2 min yet therapeutic effects lasted >90 min after injection. We describe DDFP distribution in brain, kidney, liver, spleen, and lung following nine dosing regimens in New Zealand White (NZW) rabbits. Single and multi-dose schedules were administered to NZW rabbits (n = 27). A single DDFPe dose (0.6 ml/kg) group was sacrificed 2 min after dosing and eight multi-dose groups (4 doses of 0.3 or 0.6 ml/kg and 15 doses of 0.1, 0.3, or 0.6) were sacrificed 90 min after final injections. Tissues were flash frozen and analyzed with headspace sampling/GC-MS. DDFP brain concentration increased with increasing dose in the 15 dose groups (4.70, 8.34, and 14.3 MUg/g) and indicative of linear pharmacokinetics within this dose range. The DDFP lung concentration was not reflective of increasing dose or dose frequency. The total clearance of DDFP was consistent with previous reports showing 98% of DDFP is cleared within 2 h of administration. PMID- 28028729 TI - Cardiovascular Ion Channel Inhibitor Drug-Drug Interactions with P-glycoprotein. AB - P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that plays a major role in cardiovascular drug disposition by effluxing a chemically and structurally diverse range of cardiovascular therapeutics. Unfortunately, drug drug interactions (DDIs) with the transporter have become a major roadblock to effective cardiovascular drug administration because they can cause adverse drug reactions (ADRs) or reduce the efficacy of drugs. Cardiovascular ion channel inhibitors are particularly susceptible to DDIs and ADRs with Pgp because they often have low therapeutic indexes and are commonly coadministered with other drugs that are also Pgp substrates. DDIs from cardiovascular ion channel inhibitors with the transporter occur because of inhibition or induction of the transporter and the transporter's tissue and cellular localization. Inhibiting Pgp can increase absorption and reduce excretion of drugs, leading to elevated drug plasma concentrations and drug toxicity. In contrast, inducing Pgp can have the opposite effect by reducing the drug plasma concentration and its efficacy. A number of in vitro and in vivo studies have already demonstrated DDIs from several cardiovascular ion channel inhibitors with human Pgp and its animal analogs, including verapamil, digoxin, and amiodarone. In this review, Pgp mediated DDIs and their effects on pharmacokinetics for different categories of cardiovascular ion channel inhibitors are discussed. This information is essential for improving pharmacokinetic predictions of cardiovascular therapeutics, for safer cardiovascular drug administration and for mitigating ADRs emanating from Pgp. PMID- 28028730 TI - Exposure-Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer. AB - The phase III trial comparing onartuzumab + erlotinib vs. erlotinib in the second and third-line non-small cell lung cancer (NSCLC) did not meet its primary endpoint of overall survival (OS). The objective was to assess whether doses higher than the phase III dose (15 mg/kg) might yield better efficacy without compromising the safety profile. Data were from 636 patients from the phase II and III NSCLC studies. Tumor growth inhibition (TGI) models were fit to longitudinal tumor size data to estimate individual TGI metrics including time to tumor re-growth (TTG). Cox regression models were developed for time-to-event endpoints (progression-free survival (PFS), OS, and TTG) to investigate relationships with baseline prognostic factors and onartuzumab exposure. Incidence of adverse events was modeled by logistic regression. In the final models, higher onartuzumab exposure was associated with longer PFS, but not with longer OS. Longer OS was associated with higher baseline albumin, longer TTG, smaller number of metastatic sites, female gender, lower ECOG score, and younger age. TTG was the only TGI metric retained in the final OS model. Onartuzumab exposure was not significantly associated with TTG after adjusting for prognostic factors. Higher Cmin was associated with increased incidence of infusion reactions and peripheral edema. Higher onartuzumab exposure was not significantly associated with improved OS after adjusting for prognostic factors and TTG, and there was a trend of unknown clinical significance toward increased incidence of infusion reactions and peripheral edema. These results did not support testing higher onartuzumab doses. PMID- 28028731 TI - Frameshift Mutation of FXR1 Encoding a RNA-Binding Protein in Gastric and Colorectal Cancers with Microsatellite Instability. PMID- 28028732 TI - Interactive Voice Response with Feedback Intervention in Outpatient Treatment of Substance Use Problems in Adolescents and Young Adults: A Randomized Controlled Trial. AB - PURPOSE: Substance use disorders and problematic substance use are common problems in adolescence and young adulthood. Brief personalized feedback has been suggested for treatment of alcohol and drug problems and poor mental health. This repeated measurement randomized controlled trial examines the effect of an interactive voice response (IVR) system for assessing stress, depression, anxiety and substance use. METHODS: The IVR system was used twice weekly over 3 months after treatment initiation, with or without addition of a personalized feedback intervention on stress and mental health symptoms. Both IVR assessment only (control group) and IVR assessment including feedback (intervention group) were provided as an add-on to treatment-as-usual procedures (TAU) in outpatient treatment of substance use problems in adolescents and young adults (N = 73). RESULTS: By using a mixed models approach, differences in change scores were analyzed over the three-month assessment period. Compared to the control group, the intervention group demonstrated significantly greater improvement in the Arnetz and Hasson stress score (AHSS, p = 0.019), the total Symptoms Checklist 8 score (SCL-8D, p = 0.037), the SCL-8D anxiety sub-score (p = 0.017), and on a summarized feedback score (p = 0.026), but not on the depression subscale. There were no differences in global substance use scores between the intervention group (feedback on mental health symptoms) and the control group. CONCLUSION: In conclusion, IVR may be useful for follow-up and repeated interventions as an add on to regular treatment, and personalized feedback could potentially improve mental health in adolescents and young adults with problematic substance use. PMID- 28028733 TI - Re-entrant cholesteric phase in DNA liquid-crystalline dispersion particles. AB - In this research, we observe and rationalize theoretically the transition from hexagonal to cholesteric packing of double-stranded (ds) DNA in dispersion particles. The samples were obtained by phase exclusion of linear ds DNA molecules from water-salt solutions of poly(ethylene glycol)-PEG-with concentrations ranging from 120 mg ml-1 to 300 mg ml-1. In the range of PEG concentrations from 120 mg ml-1 to 220 mg ml-1 at room temperature, we find ds DNA molecule packing, typical of classical cholesterics. The corresponding parameters for dispersion particles obtained at concentrations greater than 220 mg ml-1 indicate hexagonal packing of the ds DNA molecules. However, slightly counter-intuitively, the cholesteric-like packing reappears upon the heating of dispersions with hexagonal packing of ds DNA molecules. This transition occurs when the PEG concentration is larger than 220 mg ml-1. The obtained new cholesteric structure differs from the classical cholesterics observed in the PEG concentration range 120-220 mg ml-1 (hence, the term 're-entrant'). Our conclusions are based on the measurements of circular dichroism spectra, X-ray scattering curves and textures of liquid-crystalline phases. We propose a qualitative (similar to the Lindemann criterion for melting of conventional crystals) explanation of this phenomenon in terms of partial melting of so-called quasinematic layers formed by the DNA molecules. The quasinematic layers change their spatial orientation as a result of the competition between the osmotic pressure of the solvent (favoring dense, unidirectional alignment of ds DNA molecules) and twist Frank orientation energy of adjacent layers (favoring cholesteric-like molecular packing). PMID- 28028734 TI - Galectin-1 Reduces Neuroinflammation via Modulation of Nitric Oxide-Arginase Signaling in HIV-1 Transfected Microglia: a Gold Nanoparticle-Galectin-1 "Nanoplex" a Possible Neurotherapeutic? AB - Galectins are a family of beta-galactoside-binding lectins that are important modulators of homeostasis in the central nervous system (CNS). Galectin-1 is a pivotal regulator of microglia activation that alters the immune balance from neurodegeneration to neuroprotection and could have therapeutic relevance in HIV associated neurocognitive disorders (HAND). We have previously shown that galectin-1 treatment decreased oxidative stress in microglia and hypothesize that the mechanism underlying this phenomenon is the cross regulatory interactions between Nitric oxide (NO) and Arginase I activity in microglia. We induced microglial activation and examined the effect of galectin-1 on the expression of various M1/M2 microglial phenotypic markers. Since, TNF-alpha is associated with activation of microglial cells involved in pathogenesis of neurodegenerative diseases, we treated HIV transfected human microglial cell cultures (CHME-5/HIV) with TNF-alpha followed by treatment with galectin-1, to examine the galectin-1 mediated neuro-modulatory response. Our results show that treatment of CHME-5/HIV microglia with galectin-1 reduced TNF-alpha induced oxidative stress by ~40%, and also significantly reduced iNOS gene expression and NO production while correspondingly increasing arginase-1, cationic amino acid transporter (CAT-1) gene expression and arginase activity. Galectin-1 treatment results in shifting microglia polarization from M1 toward the beneficial M2 phenotype which may prevent neurodegeneration and promote neuroprotection. Thus, our data suggests that galectin-1 treatment reduces neuroinflammation in the CNS microenvironment via the modulation of the NO-arginase network in microglia and thus could play a neuroprotective role in HAND. Further, the therapeutic potential of galectin-1 could be enhanced by conjugation of galectin-1 onto gold nanoparticles (Au-NP), resulting in a nanogold-galectin-1 (Au-Gal-1) multivalent complex that will have more clinical translational efficacy than free galectin-1 by virtue of increasing the payload influx. PMID- 28028735 TI - Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein. AB - Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson's disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1-10) and all C-terminal epitopes (90-140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha synuclein. In a phospholipid ELISA, the N-terminus and mid-region of alpha synuclein (i.e., 1-90) were associated with phosphatidylserine and thus occluded from antibody binding. The antibodies that reacted most strongly with epitopes in the in vitro aggregates (i.e., 1-10 and epitopes between positions 90-140) also labeled alpha-synuclein inclusions in brains from transgenic (Thy-1)-h[A30P] alpha-synuclein mice and Lewy bodies and Lewy neurites in brains of patients with alpha-synucleinopathies. However, differences in reactivity were observed with the C-terminal antibodies when brain tissue from human and transgenic mice was compared. Taken together, the study shows that although similar epitopes are exposed in both in vitro and in vivo formed alpha-synuclein inclusions, structural heterogeneity can be observed between different molecular species. PMID- 28028736 TI - Fast H-DROP: A thirty times accelerated version of H-DROP for interactive SVM based prediction of helical domain linkers. AB - Efficient and rapid prediction of domain regions from amino acid sequence information alone is often required for swift structural and functional characterization of large multi-domain proteins. Here we introduce Fast H-DROP, a thirty times accelerated version of our previously reported H-DROP (Helical Domain linker pRediction using OPtimal features), which is unique in specifically predicting helical domain linkers (boundaries). Fast H-DROP, analogously to H DROP, uses optimum features selected from a set of 3000 ones by combining a random forest and a stepwise feature selection protocol. We reduced the computational time from 8.5 min per sequence in H-DROP to 14 s per sequence in Fast H-DROP on an 8 Xeon processor Linux server by using SWISS-PROT instead of Genbank non-redundant (nr) database for generating the PSSMs. The sensitivity and precision of Fast H-DROP assessed by cross-validation were 33.7 and 36.2%, which were merely ~2% lower than that of H-DROP. The reduced computational time of Fast H-DROP, without affecting prediction performances, makes it more interactive and user-friendly. Fast H-DROP and H-DROP are freely available from http://domserv.lab.tuat.ac.jp/ . PMID- 28028737 TI - Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer. AB - INTRODUCTION: Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards. METHODS: Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42-96 years had to be eligible for ADT and to be either naive to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2-12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl. RESULTS: After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80-92%, from 83-93%, and from 65-97% with median (interquartile range) serum testosterone values of 2.9 (2.9-6.5), 5.0 (2.9 8.7), and 8.7 (5.8-14.1) ng/dl at study end, respectively. CONCLUSION: In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted. PMID- 28028738 TI - Risk and Resilience Factors Associated with Resident Burnout. AB - OBJECTIVE: We investigated hypothesized risk and resilience factors and their association with burnout in first year medicine and psychiatry residents at an urban teaching hospital in order to help guide the development of interventions targeted at reducing burnout. METHODS: We administered the Maslach Burnout Inventory (MBI), Perceived Stress Scale-10, Functional Assessment of Chronic Illness Therapy-Fatigue Scale, Penn State Worry Questionnaire, Patient Health Questionnaire-9 (depression symptoms), Revised Life Orientation Test (optimism), Self-Efficacy Questionnaire, Cognitive and Affective Mindfulness Scale, Interpersonal Reactivity Index Perspective-Taking Scale (empathy), and Measure of Current Status-Part A to first year medicine and psychiatry residents prior to initiation of clinical rotations in June. RESULTS: The response rate was 91 % (68 of 75 residents). Nineteen respondents (28 %) met criteria for burnout as measured by the MBI. Residents with burnout scored higher on self-report measures assessing perceived stress (Cohen's d = 0.97; p = 0.004), fatigue (d = 0.79; p = 0.018), worry (d = 0.88; p = 0.0009), and depression symptoms (d = 0.84; p = 0.035) and scored lower on questionnaires assessing mindfulness (d = -0.63; p = 0.029) and coping ability (d = -0.79; p = 0.003). CONCLUSIONS: In a cross sectional assessment using self-report measures, we found that nearly a third of first year residents prior to starting their internships experience burnout. They exhibit lower levels of mindfulness and coping skills and higher levels of depression symptoms, fatigue, worry, and stress. These preliminary findings should encourage programs to initiate and study curricula that combine mindfulness and self-awareness coping strategies to enhance or protect against burnout as well as cognitive behavioral coaching strategies to offset symptoms of burnout when present. PMID- 28028739 TI - Multimodal imaging in a case of bilateral outer retinitis associated with mumps infection. AB - PURPOSE: To report the results of multimodal imaging of acute outer retinitis associated to mumps infection. METHODS: A patient with mumps-associated outer retinitis evaluated by color fundus photography, spectral domain optical coherence tomography (SD-OCT), optical coherence tomography angiography, fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICGA). RESULTS: We report a case of a 12-year-old boy who developed bilateral outer retinitis related to mumps. Ophthalmoscopy showed confluent areas of outer retinitis involving the posterior pole and the periphery with a centrifugal gyrate pattern. SD-OCT revealed a marked disorganization of the outer retinal layers with multiple highly reflective spicules. FA shows diffuse late hyperfluorescence with optic disk staining. ICGA shows macular and peripheral hyperfluorescent lesions with a geographical pattern in the late phases. The patient was treated with acyclovir and oral prednisone. Four weeks after presentation visual acuity remained unchanged, and retinal changes seen at the acute phase had resolved leading to extensive retinal atrophy and optic disk pallor. SD-OCT showed atrophy of the retinal pigment epithelial and outer retinal layers. FAF revealed scattered hyperautofluorescent lesions. Electrophysiology showed generalized retinal dysfunction. CONCLUSIONS: Mumps infection should be considered in the differential diagnosis of bilateral necrotizing outer retinitis in children and young adults. A multimodal imaging approach may help distinguish mumps-associated retinitis from other causes of viral retinitis and facilitate appropriate management. PMID- 28028740 TI - Impact of Ethnic Composition on Mechanisms of Change in School-Based Substance Use Intervention Groups. AB - Delivering alcohol use intervention services in the school setting represents a key approach to engaging youth of all backgrounds, particularly underserved populations, in such programming. Relative progress has been made toward implementing culturally responsive services for youth; however, little is known about the role of ethnic composition on group processes purported to underlie mechanisms of change. We examined associations between ethnic group composition and therapeutic processes within a voluntary, school-based alcohol use intervention at seven schools across three cities (N groups = 353). Ethnic composition was characterized as: group ethnic diversity on a continuum, group ethnic homogeneity (i.e., where at least 66% of participants shared the same ethnicity), and comparing groups where one of the three largest ethnicities in the sample reached the majority (i.e., African-American vs. Hispanic vs. non Hispanic white). Ratings on group processes were obtained from participants (satisfaction; belonging), facilitators (empathy; rapport), and coders (engagement; responsiveness). Mixed-effects models revealed that students in groups with African-American and Hispanic majorities reported a higher sense of satisfaction compared to groups with non-Hispanic white majorities. Facilitators endorsed expressing empathy more frequently with majority African-American and Hispanic groups than with non-Hispanic white groups. Study findings highlight the importance of considering different dimensions of ethnic composition when examining mechanisms of change in group intervention research. PMID- 28028741 TI - Can Universal SEL Programs Benefit Universally? Effects of the Positive Action Program on Multiple Trajectories of Social-Emotional and Misconduct Behaviors. AB - Behavioral trajectories during middle childhood are predictive of consequential outcomes later in life (e.g., substance abuse, violence). Social and emotional learning (SEL) programs are designed to promote trajectories that reflect both growth in positive behaviors and inhibited development of negative behaviors. The current study used growth mixture models to examine effects of the Positive Action (PA) program on behavioral trajectories of social-emotional and character development (SECD) and misconduct using data from a cluster-randomized trial that involved 14 schools and a sample of predominately low-income, urban youth followed from 3rd through 8th grade. For SECD, findings indicated that PA was similarly effective at improving trajectories within latent classes characterized as "high/declining" and "low/stable". Favorable program effects were likewise evident to a comparable degree for misconduct across observed latent classes that reflected "low/rising" and "high/rising" trajectories. These findings suggest that PA and perhaps other school-based universal SEL programs have the potential to yield comparable benefits across subgroups of youth with differing trajectories of positive and negative behaviors, making them promising strategies for achieving the intended goal of school-wide improvements in student outcomes. PMID- 28028742 TI - Growth, enzymatic glutathione peroxidase activity and biochemical status of juvenile barramundi (Lates calcarifer) fed dietary fermented soybean meal and organic selenium. AB - Solvent-extracted soybean meal (SBM) was fermented using baker's yeast Saccharomyces cerevisae at 30 degrees C for 5 days. Four isonitrogenous and isocaloric diets containing 75% SBM protein, either fermented or non-fermented (SBM and FSBM), and supplemented or not with organic Se (OS) (SBMOS and FSBMOS), were fed to triplicate groups of juvenile barramundi (Lates calcarifer) (initial weight of 5 g) for 75 days. A fishmeal (FM)-based diet formulated for juvenile barramundi was used as a reference diet. The growth of fish was significantly affected by either the interaction of SBM type or by the OS level. In fish fed diets supplemented with OS (SBMOS and FSBMOS), final weight (FW), specific growth rate (SGR) and weight gain (WG) were higher in fish fed the fermented SBM (FSBMOS) than in those fed the non-fermented SBM (SBMOS). The apparent digestibility coefficient (ADC) of protein was higher in the fish fed the fermented SBM, either supplemented or unsupplemented with OS. However, there were no significant differences in the ADC of dry matter (DM) and lipids among the tested diets and in comparison to the reference diet. The haematocrit and leucocrit of fish fed the FSBMOS diet were lower than those of fish fed the FM diet. Furthermore, glutathione peroxidase (GPx) activity was significantly influenced by OS supplementation in the experimental diets; GPx activity was greater in the fish fed diets supplemented with OS. Creatinine kinase (CK) of all groups of fish was higher than the CK of those fed the reference diet. These results suggest that with a proper nutritional level, OS supplementation may act as an important factor in enzymatic GPx activity and in the haematology and blood biochemistry status of juvenile barramundi fed fermented SBM-based diets, encouraging improvement of the overall growth performance. PMID- 28028743 TI - Changes in Home and Health over Nine Years among very Old People in Latvia - Results from the ENABLE-AGE Project. AB - To meet the needs of an increasing, heterogeneous, ageing population it is imperative to understand links between home and health. In Latvia, only limited research targeting the health and home situation of very old people is available. Consequently, the aim of this study was to describe how the home environment and aspects of health have changed over nine years between 2002 and 2011 for very old people in Latvia, living in their home environment. This study is based on the Latvian part of the cross-national European ENABLE-AGE Project comprising data on objective, as well as perceived, aspects of home and health. Longitudinal data from those involved on both data collection occasions (N = 59) was used. At the nine-year follow-up, participants were between 86 and 90 years of age, still living in their own homes. The results show that not only health aspects varied along the ageing process, objective and perceived aspects of home also changed. The physical as well as the cognitive and emotional bonding to the home significantly increased i.e. aspects of meaning such as familiarity and feeling safe in your home, privacy and independence became more important for the very old participants over time. Life satisfaction increased over the years even though objective health factors decreased. Since aspects of home as well as health can be assumed to impact on the outcome of ageing, the situation for this age group in Latvia must be further studied in order to develop suitable and appropriate social and health services, policies and living conditions. PMID- 28028744 TI - Bacterial production of site specific 13C labeled phenylalanine and methodology for high level incorporation into bacterially expressed recombinant proteins. AB - Nuclear magnetic resonance spectroscopy studies of ever larger systems have benefited from many different forms of isotope labeling, in particular, site specific isotopic labeling. Site specific 13C labeling of methyl groups has become an established means of probing systems not amenable to traditional methodology. However useful, methyl reporter sites can be limited in number and/or location. Therefore, new complementary site specific isotope labeling strategies are valuable. Aromatic amino acids make excellent probes since they are often found at important interaction interfaces and play significant structural roles. Aromatic side chains have many of the same advantages as methyl containing amino acids including distinct 13C chemical shifts and multiple magnetically equivalent 1H positions. Herein we report economical bacterial production and one-step purification of phenylalanine with 13C incorporation at the Calpha, Cgamma and Cepsilon positions, resulting in two isolated 1H-13C spin systems. We also present methodology to maximize incorporation of phenylalanine into recombinantly overexpressed proteins in bacteria and demonstrate compatibility with ILV-methyl labeling. Inexpensive, site specific isotope labeled phenylalanine adds another dimension to biomolecular NMR, opening new avenues of study. PMID- 28028745 TI - Hexagonal ice in pure water and biological NMR samples. AB - Ice, in addition to "liquid" water and protein, is an important component of protein samples for NMR spectroscopy at subfreezing temperatures but it has rarely been observed spectroscopically in this context. We characterize its spectroscopic behavior in the temperature range from 100 to 273 K, and find that it behaves like pure water ice. The interference of magic-angle spinning (MAS) as well as rf multiple-pulse sequences with Bjerrum-defect motion greatly influences the ice spectra. PMID- 28028746 TI - Beyond Cuticular Hydrocarbons: Chemically Mediated Mate Recognition in the Subsocial Burying Beetle Nicrophorus vespilloides. AB - Burying beetles have fascinated scientists for centuries due to their elaborate form of biparental care that includes the burial and defense of a vertebrate carcass, as well as the subsequent feeding of the larvae. However, besides extensive research on burying beetles, one fundamental question has yet to be answered: what cues do males use to discriminate between the sexes? Here, we show in the burying beetle Nicrophorus vespilloides that cuticular lipids trigger male mating behavior. Previous chemical analyses have revealed sex differences in cuticular hydrocarbon (CHC) composition; however, in the current study, fractionated-guided bioassay showed that cuticular lipids, other than CHCs, elicit copulation. Chemical analyses of the behaviorally active fraction revealed 17 compounds, mainly aldehydes and fatty acid esters, with small quantitative but no qualitative differences between the sexes. Supplementation of males with hexadecanal, the compound contributing most to the statistical separation of the chemical profiles of males and females, did not trigger copulation attempts by males. Therefore, a possible explanation is that the whole profile of polar lipids mediates sex recognition in N. vespilloides. PMID- 28028747 TI - Non-occlusive mesenteric ischemia accompanied by aortic regurgitation after transcatheter aortic valve implantation. AB - An 81-year-old male with severe symptomatic aortic stenosis with ventricular tachycardia was referred for treatment. Balloon aortic valvuloplasty was performed under cardiopulmonary resuscitation. Though transcatheter aortic valve implantation (TAVI) was considered high risk for annulus rupture and aortic regurgitation due to annular calcification, TAVI was performed because of extremely high surgical risk. Moderate-to-severe aortic regurgitation (AR) remained and progression of acidosis could not be managed with continuous hemodiafiltration. His autopsy revealed the development of non-occlusive mesenteric ischemia (NOMI) as the cause of progressive acidosis. AR and hemodynamic instability might contribute to the development and progression of NOMI after TAVI. PMID- 28028748 TI - Mouse immune thrombocytopenia is associated with Th1 bias and expression of activating Fcgamma receptors. AB - Immune thrombocytopenia (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. We recently established a mouse ITP model exhibiting regulatory T cell (Treg) deficiency, although only one-third of the Treg-deficient mice developed ITP. To clarify mechanisms involved in the emergence of platelet specific autoimmunity in this model, we examined the T helper (Th)-cell balance and macrophage Fcgamma receptor (FcgammaR) expression profiles in Treg-deficient mice with and without ITP. Splenocytes from both populations of Treg-deficient mice and control BALB/c mice were subjected to flow cytometry-based analyses to evaluate Th cell subset proportions and the expression of activating and inhibitory FcgammaRs on macrophages. In addition, IgG subclass distribution of anti-platelet autoantibodies in splenocyte culture supernatants was determined by flow cytometry using IgG subclass-specific antibodies. Treg-deficient ITP mice exhibited a significantly higher proportion of Th1 cells than either Treg deficient non-ITP or control mice. The predominant anti-platelet autoantibody subclasses in the ITP mice were Th1-associated IgG2a and IgG2b. Furthermore, the FcgammaRI/FcgammaRIIB expression ratio in splenic macrophages was higher in the Treg-deficient ITP than in the Treg-deficient non-ITP and control mice. In summary, Th1 polarization and macrophages' activating FcgammaR expression profile are associated with the development of ITP in Treg-deficient mice. PMID- 28028749 TI - Oral cyclophosphamide was effective for Coombs-negative autoimmune hemolytic anemia in CD16+CD56- chronic lymphoproliferative disorder of NK-cells. AB - An 84-year-old woman was referred to our hospital presenting anemia. Her hemoglobin level was 5.8 g/dL, and white blood cell count was 9400/MUL, consisting of 82% lymphocytes. Given the lymphocyte phenotype (CD2+, CD3-, CD16+, and CD56-) and negative whole blood EBV viral load, we made a diagnosis of chronic lymphoproliferative disorder of NK cells (CLPD-NK). We suspected hemolytic anemia because of the high levels of reticulocytes in the peripheral blood and the low haptoglobin value. Although the direct Coombs test was negative and there was no cold agglutination, we examined her red-blood-cell-bound IgG (RBC-IgG), which was elevated. She was diagnosed as having as Coombs-negative autoimmune hemolytic anemia (AIHA). We report the effectiveness of oral cyclophosphamide for Coombs-negative autoimmune hemolytic anemia in CLPD-NK. PMID- 28028750 TI - Early clinical experience with the da Vinci Xi Surgical System in general surgery. AB - The da Vinci Xi Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA) has been released in 2014 to facilitate minimally invasive surgery. Novel features are targeted towards facilitating complex multi-quadrant procedures, but data is scarce so far. Perioperative data of patients who underwent robotic general surgery with the da Vinci Xi system within the first 6 month after installation were collected and analyzed. The gastric bypass procedures performed with the da Vinci Xi Surgical System were compared to an equal amount of the last procedures with the da Vinci Si Surgical System. Thirty-one foregut (28 Roux-en-Y gastric bypasses), 6 colorectal procedures and 1 revisional biliary procedure were performed. The mean operating room (OR) time was 221.8 (+/-69.0) minutes for gastric bypasses and 306.5 (+/-48.8) for colorectal procedures with mean docking time of 9.4 (+/-3.8) minutes. The gastric bypass procedure was transitioned from a hybrid to a fully robotic approach. In comparison to the last 28 gastric bypass procedures performed with the da Vinci Si Surgical System, the OR time was comparable (226.9 versus 230.6 min, p = 0.8094), but the docking time significantly longer with the da Vinci Xi Surgical System (8.5 versus 6.1 min, p = 0.0415). All colorectal procedures were performed with a single robotic docking. No intraoperative and two postoperative complications occurred. The da Vinci Xi might facilitate single-setups of totally robotic gastric bypass and colorectal surgeries. However, further comparable research is needed to clearly determine the significance of this latest version of the da Vinci Surgical System. PMID- 28028751 TI - Epigenetic Modification Mediates the Increase of LAG-3+ T Cells in Chronic Osteomyelitis. AB - Immune suppression plays critical roles in the development of chronic osteomyelitis, and the mechanisms underlying the development of immune suppression in chronic osteomyelitis have attracted much attention. LAG-3 is an important suppressor of T cell activation, but the role of LAG-3 in the immune regulation of chronic osteomyelitis is currently unknown. We sought to demonstrate if LAG-3 plays crucial roles in chronic osteomyelitis progression and has effects on immune suppression and exhausting of T cells, and what is the mechanism underlying LAG-3 deregulation in chronic osteomyelitis. We examined the expression of LAG-3 in the T cells of peripheral blood of 50 healthy controls and 50 patients with chronic osteomyelitis by flow cytometry. Clinical data were analyzed to determine the correlation between inflammation index and LAG-3 expression. Moreover, we isolated the CD4+ T cells from healthy controls and chronic osteomyelitis patients to compare cell proliferation and IFN-gamma production. Chromatin immunoprecipitation assays were utilized to analyze the epigenetic modification on LAG-3 expression in T cells. We found that LAG-3 was significantly increased in the T cells of peripheral blood from chronic osteomyelitis patients. Subsequently, clinical data analysis suggested that the higher expression of LAG-3 was associated with severer inflammation situation. Consistently, LAG-3+CD4+ T cells exhibited impaired cell proliferation and IFN gamma secretion. Deregulation of histone methylation mediated the increase of LAG 3+ T cells during chronic osteomyelitis. Taken together, our study demonstrates the increase of LAG-3+ T cells and its immune regulatory roles in chronic osteomyelitis progression, suggesting new mechanisms and potential therapeutic targets for chronic osteomyelitis. PMID- 28028752 TI - Cigarette Smoke-Induced Pulmonary Inflammation and Autophagy Are Attenuated in Ephx2-Deficient Mice. AB - Cigarette smoke (CS) increases the risk of chronic obstructive pulmonary disease (COPD) by causing inflammation, emphysema, and reduced lung function. Additionally, CS can induce autophagy which contributes to COPD. Arachidonic acid derived epoxyeicosatrienoic acids (EETs) have promising anti-inflammatory properties that may protect the heart and liver by regulating autophagy. For this reason, the effect of decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on inflammation, emphysema, lung function, and autophagy was here studied in CS-induced COPD in vivo. Adult male wild-type (WT) C57BL/6J and Ephx2 /- mice were exposed to air or CS for 12 weeks, and lung inflammatory responses, air space enlargement (emphysema), lung function, and autophagy were assessed. Lungs of Ephx2-/- mice had a less pronounced inflammatory response and less autophagy with mild distal airspace enlargement accompanied by restored lung function and steady weight gain. These findings support the idea that Ephx2 may hold promise as a therapeutic target for COPD induced by CS, and it may be protective property by inhibiting autophagy. PMID- 28028753 TI - Chlorogenic Acid Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting TLR4/NF-kappaB Signal Pathway. AB - Chlorogenic acid (CGA), a polyphenolic compound, exists widely in medicinal herbs, which has been shown a strong antioxidant and anti-inflammatory effect. This study investigated the protective effects and mechanism of CGA on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Treatment of CGA successfully ameliorates LPS-induced renal function and pathological damage. Moreover, CGA dose-dependently suppressed LPS-induced blood urea nitrogen (BUN), creatinine levels, and inflammatory cytokines TNF-alpha, IL-6, and IL-1beta in serum and tissue. The relative proteins' expression of TLR4/NF-kappaB signal pathway was assessed by western blot analysis. Our results showed that CGA dose dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. CGA also suppressed LPS-induced TNF-alpha, IL-6, and IL-1beta production both in serum and kidney tissues. Furthermore, our results showed that CGA significantly inhibited the LPS-induced expression of phosphorylated NF kappaB p65 and IkappaB as well as the expression of TLR4 signal. In conclusion, our results provide a mechanistic explanation for the anti-inflammatory effects of CGA in LPS-induced AKI mice through inhibiting TLR4/NF-kappaB signaling pathway. PMID- 28028754 TI - Alteration of Lysophosphatidylcholine-Related Metabolic Parameters in the Plasma of Mice with Experimental Sepsis. AB - Plasma concentration of lysophosphatidylcholine (LPC) was reported to decrease in patients with sepsis. However, the mechanisms of sepsis-induced decrease in plasma LPC levels are not currently well known. In mice subjected to cecal ligation and puncture (CLP), a model of polymicrobial peritoneal sepsis, we examined alterations in LPC-related metabolic parameters in plasma, i.e., the plasma concentration of LPC-related substances (i.e., phosphatidylcholine (PC) and lysophosphatidic acid (LPA)), and activities or levels in the plasma of some enzymes that can be involved in the regulation of plasma LPC concentration (i.e., secretory phospholipase A2 (sPLA2), lecithin:cholesterol acyltransferase (LCAT), acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT), and autotaxin (ATX)), as well as plasma albumin concentration. We found that levels of LPC and albumin and enzyme activities of LCAT, ATX, and sPLA2 were decreased, whereas levels of PC, LPA, and LPCAT1-3 were increased in the plasma of mice subjected to CLP. Bacterial peritonitis led to alterations in all the measured LPC-related metabolic parameters in the plasma, which could potentially contribute to sepsis induced decrease in plasma LPC levels. These findings could lead to the novel biomarkers of sepsis. PMID- 28028755 TI - Effects of Ezetimibe, Simvastatin, and their Combination on Inflammatory Parameters in a Rat Model of Adjuvant-Induced Arthritis. AB - Statins are hypocholesterolemic drugs that are prescribed for patients with an increased risk of cardiovascular and cerebrovascular complications. Ezetimibe has an atheroprotective activity through inhibition of the expression of vascular adhesion molecule-I and vascular CD14, a marker of the infiltration of mononuclear leukocytes. Ezetimibe reduces the amount of chemoattractant protein-1 that is available for monocytes and macrophages and alters the activity of nuclear factor kappaB in leukocytes. The mechanisms of action of statins complement those of ezetimibe. Previous studies have demonstrated that the combination of statins and ezetimibe has beneficial effects, including antiinflammatory activity. The present study evaluated the effects of monotherapy with ezetimibe and simvastatin compared with ezetimibe + simvastatin combined on the evolution of the inflammatory response in a rat model of Complete Freund's Adjuvant-induced arthritis. The animals were treated with 10 mg/kg ezetimibe, 40 mg/kg simvastatin, or 10 mg/kg ezetimibe + 40 mg/kg simvastatin for 1, 7, 14, or 28 days. We analyzed leukocyte rolling behavior, leukocyte adhesion to the endothelium, the number of leukocytes that were recruited to the knee joint cavity, and the concentration of cytokines that are involved in the inflammatory response. The data were analyzed using paired t tests or analysis of variance followed by Bonferroni post hoc test. The treatments reduced leukocyte rolling behavior and leukocyte adhesion. The monotherapies did not change the number of leukocytes that were recruited to the knee joint cavity, whereas the ezetimibe + simvastatin combination significantly reduced this parameter. The treatments reduced the levels of proinflammatory cytokines and increased the levels of the antiinflammatory cytokine IL-10, indicating antiinflammatory properties of these drugs in this experimental model of inflammation. PMID- 28028756 TI - Expression of miRNA-155, miRNA-223, miRNA-31, miRNA-21, miRNA-125b, and miRNA 146a in the Inflammatory Pathway of Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) has been associated with marked inflammatory perturbation. The mechanisms regulating the inflammatory network remain elusive. microRNAs (miRNAs) have been described as gene regulators of inflammation. We evaluated the messenger RNA (mRNA) expression levels of six selected inflammation related miRNAs in lesional and perilesional skin samples of HS patients and in healthy controls. Samples of 15 HS patients and 10 healthy controls were included in this prospective study. Expression levels of the miRNAs miRNA-155-5p, miRNA 223-5p, miRNA-31-5p, miRNA-21-5p, miRNA-125b-5p, and miRNA-146a-5p were studied by quantitative real-time reverse transcription polymerase chain reaction. We observed a significant overexpression of miRNA-155-5p, miRNA-223-5p, miRNA-31-5p, miRNA-21-5p, and miRNA-146a-5p in lesional HS skin compared to healthy controls. Expression of these miRNAs was also significantly increased in lesional HS skin when compared to perilesional skin. Only miRNA-155-5p showed an increased expression in perilesional skin compared to healthy controls. In contrast, miRNA 125b-5p had a significantly lower expression in lesional HS skin compared to perilesional skin. We found that the studied inflammation-related miRNAs were significantly dysregulated in lesional HS skin and may have regulatory roles in the inflammatory process of HS. Given their predicted targets and functions, our findings point to these miRNAs as potential disease biomarkers, and manipulation might be used therapeutically to target the inflammatory pathway in HS. PMID- 28028757 TI - Dimethyl Sulfoxide Attenuates Acute Lung Injury Induced by Hemorrhagic Shock/Resuscitation in Rats. AB - Inflammation following hemorrhagic shock/resuscitation (HS/RES) induces acute lung injury (ALI). Dimethyl sulfoxide (DMSO) possesses anti-inflammatory and antioxidative capacities. We sought to clarify whether DMSO could attenuate ALI induced by HS/RES. Male Sprague-Dawley rats were allocated to receive either a sham operation, sham plus DMSO, HS/RES, or HS/RES plus DMSO, and these were denoted as the Sham, Sham + DMSO, HS/RES, or HS/RES + DMSO group, respectively (n = 12 in each group). HS/RES was achieved by drawing blood to lower mean arterial pressure (40-45 mmHg for 60 min) followed by reinfusion with shed blood/saline mixtures. All rats received an intravenous injection of normal saline or DMSO immediately before resuscitation or at matching points relative to the sham groups. Arterial blood gas and histological assays (including histopathology, neutrophil infiltration, and lung water content) confirmed that HS/RES induced ALI. Significant increases in pulmonary expression of tumor necrosis factor-alpha (TNF-alpha), malondialdehyde, nuclear factor-kappa B (NF-kappaB), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) confirmed that HS/RES induced pulmonary inflammation and oxidative stress. DMSO significantly attenuated the pulmonary inflammation and ALI induced by HS/RES. The mechanisms for this may involve reducing inflammation and oxidative stress through inhibition of pulmonary NF-kappaB, TNF-alpha, iNOS, and COX-2 expression. PMID- 28028758 TI - Photodynamic Inactivation of E. coli PTCC 1276 Using Light Emitting Diodes: Application of Rose Bengal and Methylene Blue as Two Simple Models. AB - The lack of a comparative study about potential of high-power light emitting diodes (LEDs) for photodynamic inactivation (PDI) of pathogenic microorganisms has remained as a challenging issue for researchers. Therefore, the aim of this study is to fill this gap through introduction of an efficient model for in vitro PDI in an aqueous medium. For this purpose, two individual 30 mW/cm2 irradiation systems were designed using suitable sets of green and red LEDs. At another work, Methylene blue (MB) and Rose bengal (RB) as two simple models in the range of 5 150 MUM were used in order to compare PDI of E. coli PTCC 1276 using red and green LED systems. Our results showed that a first-order mathematical model has the strength to describe the temporal variation of survival curves. Based on our results, when concentration of photosensitizer increased, the rate of inactivation for RB increased while MB depicted a maximum rate value at 25 MUM. In a comparative study, optimum inactivation of E. coli PTCC 1276 obtained during 2- and 10-min irradiation of the LED systems using RB and MB at 150 and 25 MUM, respectively. With regard to lower value of inactivation time and higher rate of inactivation for RB, use of simultaneous green high-power LEDs and RB is proposed as an efficient approach for PDI of pathogenic bacteria in future industrial applications. PMID- 28028760 TI - Nuclear cardiology in the literature: A selection of recent, original research papers. PMID- 28028759 TI - The expression of DAMP proteins HSP70 and cancer-testis antigen SPAG9 in peripheral blood of patients with HCC and lung cancer. AB - There are different views of how the immune system participates in the reaction to cancer. Here, we evaluated expression of DAMP proteins HSP70 and cancer-testis antigen SPAG9 in patients with hepatocellular carcinoma (HCC) and lung cancer to explore tumor immunity. Our analysis showed that levels of HSP70 and SPAG9 antibody were significantly higher in the serum of lung cancer and HCC patients than in the serum of healthy subjects (P < 0.001), but there were no differences in levels of HSP70 antibody in patients and controls. Levels of serum SPAG9 antibody in newly diagnosed lung cancer patients were significantly higher than in treated lung cancer patients (P < 0.05), but there were no differences in levels of HSP70 or HSP70 antibody. Levels of serum HSP70 and SPAG9 antibody, but not HSP70 antibody, were also higher in hepatitis/cirrhosis patients than in healthy subjects (P = 0.005, P < 0.001). Levels of serum SPAG9 antibody were significantly higher in HCC patients than in hepatitis/cirrhosis patients, but there were no differences in HSP70 or HSP70 antibody levels. Finally, levels of serum HSP70 and SPAG9 antibody were significantly higher in HCC patients than in lung cancer patients (P < 0.05, P < 0.001). These results indicate that cancer testis antigen SPAG9 induces a strong humoral immune response in cancer patients but HSP70 does not. These results show that SPAG9 has potential as a tumor specific biomarker. PMID- 28028761 TI - Relationships between left ventricular sympathetic innervation and diastolic dysfunction: the role of myocardial innervation/perfusion mismatch. AB - BACKGROUND: A possible relationship between cardiac sympathetic denervation and left ventricular (LV) diastolic dysfunction has been suggested. However, an evaluation of the interactions between myocardial adrenergic tone and LV perfusion and diastolic function is lacking. METHODS AND RESULTS: Seventy-two patients underwent 99mTc-tetrofosmin/123I-metaiodobenzylguanidine (123I-MIBG) cardiac Cadmium-Zinc-Telluride (CZT) imaging. The summed rest score (SRS) and summed 123I-MIBG score (SS-MIBG) were computed as measures of regional perfusion and innervation heterogeneities. LV segments showing an impaired innervation, despite a relatively preserved perfusion (99mTc-tetrofosmin-123I-MIBG tracers' uptake >=25%), were individuated (innervation/perfusion mismatch). The peak filling rate (PFR) was computed as a measure of LV diastolic function. Nineteen of the 72 (26%) patients presented a normal LV diastolic function, while 29 (40%) and 24 (34%) had a mild and overt diastolic dysfunction. Subjects with diastolic dysfunction showed more abnormal SRS and SS-MIBG values (P < 0.001). In the global population, 502/1224 (41%) LV segments showed an innervation/perfusion mismatch. A modest correlation between the extent of cardiac innervation/perfusion mismatch and PFR values was evident (R = -0.27, P = 0.029). On multivariate analysis, the extent of regional innervation/perfusion mismatch remained an independent predictor of overt LV diastolic abnormalities (P = 0.017). CONCLUSIONS: The burden of LV regions showing an innervation/perfusion mismatch associates with the occurrence of overt diastolic dysfunction. PMID- 28028762 TI - Screening for thyroid cancer in survivors of childhood and young adult cancer treated with neck radiation. AB - BACKGROUND: The optimal method of screening for thyroid cancer in survivors of childhood and young adult cancer exposed to neck radiation remains controversial. Outcome data for a physical exam-based screening approach are lacking. METHODS: We conducted a retrospective review of adult survivors of childhood and young adult cancer with a history of neck radiation followed in the Adult Long-Term Follow-Up Clinic at Memorial Sloan Kettering between November 2005 and August 2014. Eligible patients underwent a physical exam of the thyroid and were followed for at least 1 year afterwards. Ineligible patients were those with prior diagnosis of benign or malignant thyroid nodules. RESULTS: During a median follow-up of 3.1 years (range 0-9.4 years), 106 ultrasounds and 2277 physical exams were performed among 585 patients. Forty survivors had an abnormal thyroid physical exam median of 21 years from radiotherapy; 50% of those with an abnormal exam were survivors of Hodgkin lymphoma, 60% had radiation at ages 10-19, and 53% were female. Ultimately, 24 underwent fine needle aspiration (FNA). Surgery revealed papillary carcinoma in seven survivors; six are currently free of disease and one with active disease is undergoing watchful waiting. Among those with one or more annual visits, representing 1732 person-years of follow-up, no cases of thyroid cancer were diagnosed within a year of normal physical exam. CONCLUSIONS: These findings support the application of annual physical exam without routine ultrasound for thyroid cancer screening among survivors with a history of neck radiation. IMPLICATIONS FOR CANCER SURVIVORS: Survivors with a history of neck radiation may not require routine thyroid ultrasound for thyroid cancer screening. Among adult survivors of childhood and young adult cancer with a history of radiation therapy to the neck, annual physical exam is an acceptable thyroid cancer screening strategy. PMID- 28028763 TI - Building a Personalized Cancer Treatment System. AB - This paper reports the process by which a personalized cancer treatment system was built, following a user-centered approach. We give some background on personalized cancer treatment, the particular tumor chemosensitivity assay supported by the system, as well as some quality and legal issues related to such health systems. We describe how Contextual Design was applied when building the system. Contextual design is a user-centered design technique involving seven steps. We also provide some details about the system implementation. Finally, we explain how the Think-Aloud protocol and Heuristic Evaluation methods were used to evaluate the system and report its results. A qualitative assessment from the users perspective is also provided. Results from the heuristic evaluation indicate that only one of ten heuristics was missing from the system, while five were partially covered and four were fully covered. PMID- 28028764 TI - Literature Review of Patient Record Structures from the Physician's Perspective. AB - The Finnish Patient Data Repository is a nationwide electronic health record (EHR) system collecting patient data from all healthcare providers. The usefulness of the large amount of data stored in the system depends on the underlying data structures, and thus a solid understanding of these structures is in focus in further development of the data repository. This study seeks to improve that understanding by a systematic literature review. The review takes the physician's perspective to the use and usefulness of the data structures. The articles included in this review study data structures intended to be used in the actual care process. Secondary use and nursing aspects have been covered in separate reviews. After applying the predefined inclusion and exclusion criteria only 40 articles were included in the review. The research on widespread systems in everyday use was especially scarce, most studies concentrated on narrow fields. Majority of these studies were primarily developed for specialist use in secondary care units. Most structures or applications studied were at an early stage of development. In many applications the use of structured data was found to improve the completeness of the documented data and facilitate its automated use. However, there seem to be some applications where narrative text cannot be easily replaced by structured data. Usability results regarding structured representation were conflicting. The scattered nature and paucity of research hinders the generalizability of the findings, and from the system design or implementation point of view the practical value of the scientific literature reviewed is limited. PMID- 28028765 TI - An Alternative Method for Screening Gastric Cancer Based on Serum Levels of CEA, CA19-9, and CA72-4. AB - PURPOSE: The goal of this study was to create a novel method for screening gastric cancer (GC) based on serum levels of carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4) tumor markers. METHODS: Retrospectively, the predictive value for GC was calculated using a logistic analysis on serum levels of CEA, CA19-9, and CA72-4 from 216 GC and 49 benign patients. The predictive value was used to make a recommendation system on whether further GC screening was necessary. Prospectively, 80 GC and 33 benign patients were used to assess the value of this method. RESULTS: The recommendation system to determine whether additional GC screening was necessary consisted of three grades: grade I, no proposals; grade II, proposals; grade III, strong proposals. Additional screening was suggested when the predictive value was <=0.700 (grade I), 0.700-0.850 (grade II), and >0.850 (grade III). Of the total 216 GC patients, 20.4, 27.8, and 51.9% were classified as grades I, II, and III, respectively. Of the 49 benign cases, 57.1, 32.7, and 10.2% were classified as grades I, II, and III, respectively. Of the 80 prospective GC patients, 17.3, 28.4, and 54.3% were classified as grades I, II, and III, respectively. Of the 33 prospective benign cases, 54.6, 33.3, and 12.1% were classified as grades I, II, and III, respectively. CONCLUSION: The new screening recommendation system based on serum levels of CEA, CA19-9, and CA72-4 is an effective approach for detecting GC. PMID- 28028766 TI - Health-Related Quality of Life in Patients with Metastatic Pancreatic Cancer. AB - PURPOSE: Due to its clinical course and often-late detection, many patients with metastatic pancreatic cancer (mPC) experience poor quality of life (QoL). This pilot project assessed real-world QoL in patients with mPC at different stages of treatment. METHODS: A cross-sectional survey was conducted in the following groups of patients with mPC: before initiation of first-line (1L) chemotherapy (no treatment); with partial response (PR) or stable disease (SD) upon receipt of >=3 cycles of 1L nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine PR or SD); and with disease progression during >=1L chemotherapy and not currently receiving nab-paclitaxel (>=1L PD). Eligible participants completed three QoL instruments, EORTC QLQ-C30, the pancreatic cancer module of EORTC QLQ PAN26, and the EQ-5D, during their clinical visits at 14 clinics across the USA. RESULTS: Demographic characteristics were similar among groups (no treatment, n = 29; nab-paclitaxel plus gemcitabine PR or SD, n = 26; >=1L PD, n = 17). Patients in the nab-paclitaxel plus gemcitabine PR or SD group had lower mean pain scores by EORTC-QLQ-C30 (27.6 vs 47.1; P = 0.02) and lower mean pancreatic pain scores by EORTC-QLQ-PAN26 (27.9 vs 45.4; P = 0.02) compared with the no treatment group. The groups did not differ significantly in QoL as measured by the EQ-5D. CONCLUSIONS: Patients who experienced PR or SD with 1L nab-paclitaxel plus gemcitabine had improved general and pancreatic pain scores and no clinically meaningful deterioration in QoL compared with patients who had not yet initiated chemotherapy. PMID- 28028767 TI - Authors' Reply to Kamel et al.: "Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study". PMID- 28028768 TI - Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption. AB - PURPOSE: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically induced hypochlorhydria. METHODS: In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions. PMID- 28028769 TI - Are Polymorphisms in Genes Relevant to Drug Disposition Predictors of Susceptibility to Drug-Induced Liver Injury? AB - Despite considerable progress in identifying specific HLA alleles as genetic risk factors for some forms of drug-induced liver injury, progress in understanding whether genetic polymorphisms relevant to drug disposition also contribute to risk for developing this serious toxicity has been more limited. Evidence from both candidate-gene case control studies and genome-wide association studies is now discussed. In the case of genes relevant to drug metabolism, polymorphisms in cytochromes P450, UDP-glucuronosyltransferases, N-acetyltransferases and glutathione S-transferases as risk factors for DILI are assessed. The relevance of ABC transporters to drug-induced liver injury is also considered, together with data showing associations of particular ABCB11, ABCB1 and ABCC2 polymorphisms with some forms of drug-induced liver injury. Very few of the associations with genes relevant to drug disposition that have been reported have been well replicated. Even apparently well-studied associations such as that between isoniazid liver injury and N-acetyltransferase 2 slow acetylators remain problematic, though it seems likely that polymorphisms in drug metabolism genes do contribute to risk for some specific drugs. A better understanding of genetic risk factors for drug-induced liver injury will require further genome-wide association studies with larger numbers of cases, especially for forms of drug induced liver injury where HLA genotype does not appear to be a risk factor. PMID- 28028770 TI - On the Nature of Physiologically-Based Pharmacokinetic Models -A Priori or A Posteriori? Mechanistic or Empirical? AB - Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be "bottom up" as opposed to "top down". Modeling approaches can be characterized as either a posteriori (observational) or a priori (based solely on theory). Furthermore, approaches can be mechanistic (structure and components based on mechanisms) or empirical (based on observations alone). Both "bottom up" and "top down" approaches can incorporate either empirical or mechanistic components. In this perspective, we discuss some of the methods and assumptions of current PBPK modeling approaches. Specifically, we discuss drug partitioning into phospholipids and neutral lipids, use of blood-plasma ratios to estimate basic drug tissue partitioning, and clearance of neutral and acidic drugs. Based on these discussions, we believe that current PBPK models are mechanistic but a posteriori and semi-empirical. PMID- 28028771 TI - Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes. AB - PURPOSE: This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects. METHODS: Three phase 1 clinical studies in healthy human subjects were pooled. Non-linear mixed effects modeling techniques were used to study the effect of ponesimod on lymphocyte subsets such as B cells, T helper cells, T cytotoxic cells, and natural killer cells in a qualitative and quantitative manner. RESULTS: Indirect response Imax models including circadian variation best described the effect of ponesimod on lymphocyte subsets. B cells and T helper cells were shown to be more affected compared to T cytotoxic cells with respect to the maximum possible reduction (100% for B and T helper cells, 95% for T cytotoxic cells) and the concentration required to reach half the maximum effect. Inter-individual variability was found to be larger for T cytotoxic compared to T helper, and B cells. CONCLUSION: These first models for ponesimod on the level of lymphocyte subsets offer a valuable tool for the analysis and interpretation of results from ponesimod trials in autoimmune diseases. PMID- 28028772 TI - Hydroxypropyl cellulose supplementation in vitrification solutions: a prospective study with donor oocytes. AB - PURPOSE: Hydroxypropyl cellulose (HPC), a polysaccharide that forms a viscous gel under low temperatures, is a promising substitute of the blood-derived macromolecules traditionally used in cryopreservation solutions. The performance of a protein-free, fully synthetic set of vitrification and warming solutions was assessed in a matched pair analysis with donor oocytes. METHODS: A prospective study including 219 donor MII oocytes was carried out, comparing the laboratory outcomes of oocytes vitrified with HPC-based solutions and their fresh counterparts. The primary performance endpoint was the fertilization rate. Secondary parameters assessed were embryo quality on days 2 and 3. RESULTS: 70/73 (95.9%) vitrified MII oocytes exhibited morphologic survival 2 h post-warming, with 49 (70.0%) presented normal fertilization, compared to 105 of 146 (71.9%) MII fresh oocytes. Similar embryo quality was observed in both groups. A total of 18 embryos implanted, out of 38 embryos transferred (47.3%), resulting in 13 newborns. PMID- 28028773 TI - 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children. AB - PURPOSE: This study aims to make an account of the children born following transplantation of frozen-thawed ovarian tissue worldwide with specific focus on the perinatal outcome of the children. Furthermore, perinatal outcome of seven deliveries (nine children) from Denmark is reported. METHODS: PubMed was searched for papers of deliveries resulting from ovarian tissue cryopreservation (OTC). Seven women underwent OTC prior to chemotherapy. Four of these women still had low ovarian function and had tried to conceive. They therefore had tissue autotransplanted to augment their fertility. The other three women had developed premature ovarian insufficiency (POI) after the end of treatment. RESULTS: Worldwide, approximately 95 children have been born or will be born in the near future from OTC, including these 9 new children. Information on the perinatal outcome was found on 40 children. The mean gestational age was 39 weeks and the mean birth weight was 3168 g of the singleton pregnancies, which is within internationally recognized normal standards. Furthermore, half the singletons resulted from natural conception and all twins resulted from in vitro fertilization treatment. All seven Danish women became pregnant within 1-3 years after transplantation. They gave birth to nine healthy children. CONCLUSION: The data is reassuring and further suggests that cryopreservation of ovarian tissue is becoming an established fertility preservation method. The seven Danish women reported in this study were all in their early thirties when OTC was performed. Most other reported cases were in the women's twenties. This suggests that the follicular pool in the thirties is large enough and sufficient to sustain fertility. PMID- 28028775 TI - Effects of a no-go Task 2 on Task 1 performance in dual - tasking: From benefits to costs. AB - When two tasks are combined in a dual-task experiment, characteristics of Task 2 can influence Task 1 performance, a phenomenon termed the backward crosstalk effect (BCE). Besides instances depending on the (spatial) compatibility of both responses, a particularly interesting example was introduced by Miller (2006): If Task 2 was a no-go task (i.e., one not requiring any action at all), responses were slowed in Task 1. Subsequent work, however, also reported the opposite result-that is, faster Task 1 responses in cases of no-go Task 2 trials. We report three experiments aiming to more precisely identify the conditions under which a no-go Task 2 facilitates or impedes Task 1 performance. The results suggest that an adverse no-go BCE is only observed when the Task 2 response(s) are sufficiently prepared in advance, yielding strong inhibitory control demands for Task 2 that eventually hamper Task 1 processing as well (i.e., inhibitory costs). If this is not the case, encountering a no-go Task 2 trial facilitates Task 1 performance, suggesting that the underlying task representation is reduced to a single - task. These results are discussed in the context of other recent work on BCEs and of recently suggested accounts of the no-go BCE. PMID- 28028774 TI - Embryo wastage rates remain high in assisted reproductive technology (ART): a look at the trends from 2004-2013 in the USA. AB - This work examined the trend in "embryo wastage" rates after ART in USA and its relationship to the number of embryos transferred, live born infants delivered across patient age, and the yearly percentage of embryos wasted. The data were obtained from the US-clinics SART databank for the years 2004-2013. A total of 1,808,082 non-donor embryos were transferred in 748,394 fresh cycles resulting in 358,214 liveborn. During the years of analysis, the mean number of embryos transferred has progressively decreased leading to an overall significant decrease in Embryo Wastage rates (83.2 to 76.5%, p < 0.001) while the percentage of transfers leading to a live born increased (24.8 to 27.8%, p = 0.002). Embryo Wastage negatively correlated with percentage of transfers resulting in live birth (p = 0.001), and the average number of embryos transferred positively correlated with the percentage of embryos wasted (p < 0.001). The overwhelming majority of embryos transferred still do not result into a live birth confirming that only few embryos per ART cycle are competent. The overall "Embryo Wastage" rates have consistently decreased from a high of 90% in 1995 to a rate of 76.5% in 2013. Transferring fewer embryos particularly at the blastocyst-stage and improved methods of embryo selection may further decrease "Embryo Wastage" rates. PMID- 28028776 TI - Motion direction discrimination training reduces perceived motion repulsion. AB - Participants often exaggerate the perceived angular separation between two simultaneously presented motion stimuli, which is referred to as motion repulsion. The overestimation helps participants differentiate between the two superimposed motion directions, yet it causes the impairment of direction perception. Since direction perception can be refined through perceptual training, we here attempted to investigate whether the training of a direction discrimination task changes the amount of motion repulsion. Our results showed a direction-specific learning effect, which was accompanied by a reduced amount of motion repulsion both for the trained and the untrained directions. The reduction of the motion repulsion disappeared when the participants were trained on a luminance discrimination task (control experiment 1) or a speed discrimination task (control experiment 2), ruling out any possible interpretation in terms of adaptation or training-induced attentional bias. Furthermore, training with a direction discrimination task along a direction 150 degrees away from both directions in the transparent stimulus (control experiment 3) also had little effect on the amount of motion repulsion, ruling out the contribution of task learning. The changed motion repulsion observed in the main experiment was consistent with the prediction of the recurrent model of perceptual learning. Therefore, our findings demonstrate that training in direction discrimination can benefit the precise direction perception of the transparent stimulus and provide new evidence for the recurrent model of perceptual learning. PMID- 28028777 TI - Spatial attention is necessary for object-based attention: Evidence from temporal order judgments. AB - Attentional selection is a dynamic process that relies on multiple types of representations. That object representations contribute to attentional selection has been known for decades; however, most evidence for this contribution has been gleaned from studies that have relied on various forms of spatial cueing (some endogenous and some exogenous). It has thus remained unclear whether object-based attentional selection is a direct result of spatial cuing, or whether it still emerges without any spatial marker. Here we used a novel method-the temporal order judgment (TOJ)-to examine whether object-based guidance emerges in the absence of spatial cuing. Participants were presented with two rectangles oriented either horizontally or vertically. Following a 150-ms preview time, two target stimuli were presented on the same or on different objects, and participants were asked to report which of the two stimuli had appeared first. The targets consisted of stimuli that formed a percept of a "hole" or a "hill." First, we demonstrated that the "hill" target was indeed processed faster, as evidenced by a positive perceived simultaneity (PSS) measure. We then demonstrated that if two targets appeared with equal probabilities on the same and on different objects, the PSS values, although positive, were not modulated by the objects. In a subsequent set of experiments, we showed that objects can modulate attentional allocation-however, only when they are biased by a spatial (endogenous) cue. In other words, in the absence of a spatial cue or bias, object representations do not guide attentional selection. In addition to providing new constraints for theories of object-based attentional guidance, these experiments introduce a novel paradigm for measuring object-based attentional effects. PMID- 28028778 TI - Ethics and the UN Sustainable Development Goals: The Case for Comprehensive Engineering : Commentary on "Using Student Engagement to Relocate Ethics to the Core of the Engineering Curriculum". AB - In the twenty-first century, the urgent problems the world is facing (the UN Sustainable Development Goals) are increasingly related to vast and intricate 'systems of systems', which comprise both socio-technical and eco-systems. In order for engineers to adequately and responsibly respond to these problems, they cannot focus on only one technical or any other aspect in isolation, but must adopt a wider and multidisciplinary perspective of these systems, including an ethical and social perspective. Engineering curricula should therefore focus on what we call 'comprehensive engineering'. Comprehensive engineering implies ethical coherence, consilience of scientific disciplines, and cooperation between parties. PMID- 28028779 TI - When fast logic meets slow belief: Evidence for a parallel-processing model of belief bias. AB - Two experiments pitted the default-interventionist account of belief bias against a parallel-processing model. According to the former, belief bias occurs because a fast, belief-based evaluation of the conclusion pre-empts a working-memory demanding logical analysis. In contrast, according to the latter both belief based and logic-based responding occur in parallel. Participants were given deductive reasoning problems of variable complexity and instructed to decide whether the conclusion was valid on half the trials or to decide whether the conclusion was believable on the other half. When belief and logic conflict, the default-interventionist view predicts that it should take less time to respond on the basis of belief than logic, and that the believability of a conclusion should interfere with judgments of validity, but not the reverse. The parallel processing view predicts that beliefs should interfere with logic judgments only if the processing required to evaluate the logical structure exceeds that required to evaluate the knowledge necessary to make a belief-based judgment, and vice versa otherwise. Consistent with this latter view, for the simplest reasoning problems (modus ponens), judgments of belief resulted in lower accuracy than judgments of validity, and believability interfered more with judgments of validity than the converse. For problems of moderate complexity (modus tollens and single-model syllogisms), the interference was symmetrical, in that validity interfered with belief judgments to the same degree that believability interfered with validity judgments. For the most complex (three-term multiple-model syllogisms), conclusion believability interfered more with judgments of validity than vice versa, in spite of the significant interference from conclusion validity on judgments of belief. PMID- 28028780 TI - Task difficulty moderates the revelation effect. AB - Tasks that precede a recognition probe induce a more liberal response criterion than do probes without tasks-the "revelation effect." For example, participants are more likely to claim that a stimulus is familiar directly after solving an anagram, relative to a condition without an anagram. Revelation effect hypotheses disagree whether hard preceding tasks should produce a larger revelation effect than easy preceding tasks. Although some studies have shown that hard tasks increase the revelation effect as compared to easy tasks, these studies suffered from a confound of task difficulty and task presence. Conversely, other studies have shown that the revelation effect is independent of task difficulty. In the present study, we used new task difficulty manipulations to test whether hard tasks produce larger revelation effects than easy tasks. Participants (N = 464) completed hard or easy preceding tasks, including anagrams (Exps. 1 and 2) and the typing of specific arrow key sequences (Exps. 3-6). With sample sizes typical of revelation effect experiments, the effect sizes of task difficulty on the revelation effect varied considerably across experiments. Despite this variability, a consistent data pattern emerged: Hard tasks produced larger revelation effects than easy tasks. Although the present study falsifies certain revelation effect hypotheses, the general vagueness of revelation effect hypotheses remains. PMID- 28028781 TI - A meta-analysis of response-time tests of the sequential two-systems model of moral judgment. AB - The (generalized) sequential two-system ("default interventionist") model of utilitarian moral judgment predicts that utilitarian responses often arise from a system-two correction of system-one deontological intuitions. Response-time (RT) results that seem to support this model are usually explained by the fact that low-probability responses have longer RTs. Following earlier results, we predicted response probability from each subject's tendency to make utilitarian responses (A, "Ability") and each dilemma's tendency to elicit deontological responses (D, "Difficulty"), estimated from a Rasch model. At the point where A = D, the two responses are equally likely, so probability effects cannot account for any RT differences between them. The sequential two-system model still predicts that many of the utilitarian responses made at this point will result from system-two corrections of system-one intuitions, hence should take longer. However, when A = D, RT for the two responses was the same, contradicting the sequential model. Here we report a meta-analysis of 26 data sets, which replicated the earlier results of no RT difference overall at the point where A = D. The data sets used three different kinds of moral judgment items, and the RT equality at the point where A = D held for all three. In addition, we found that RT increased with A-D. This result holds for subjects (characterized by Ability) but not for items (characterized by Difficulty). We explain the main features of this unanticipated effect, and of the main results, with a drift-diffusion model. PMID- 28028782 TI - Interrupted: The roles of distributed effort and incubation in preventing fixation and generating problem solutions. AB - Fixation on inappropriate concepts is a key barrier to problem solving. Previous research has shown that continuous work is likely to cause repeated retrieval of those concepts, resulting in increased fixation. Accordingly, distributing effort across problems through multiple, brief, and interlaced sessions (distributed effort) should prevent such fixation and in turn enhance problem solving. This study examined whether distributed effort can provide an advantage for problem solving, particularly for problems that can induce fixation (Experiment 1), and whether and how incubation can be combined with distributed effort to further enhance performance (Experiment 2). Remote Associates Test (RAT) problems were used as the problem-solving tasks. Half of them (i.e., misleading RAT) were more likely to mislead individuals to fixate on incorrect associates than the other half. Experiments revealed a superiority of distributed over massed effort on misleading RAT performance and a differing time course of incubation for the massed and distributed groups. We conclude that distributed effort facilitates problem solving, most likely via overcoming fixation. Cognitive mechanisms other than the commonly posited forgetting of inappropriate ideas may occur during incubation to facilitate problem solving. The experiments in this article offer support for the occurrence of spreading activation during incubation. PMID- 28028783 TI - Primary mesenteric neuroendocrine tumor that changed its internal composition from cystic to solid: a case report. AB - Mesenteric neuroendocrine tumors are usually metastases originating from the small intestine; however, primary mesenteric cases are rare. We present an interesting case of a mesenteric neuroendocrine tumor that changed its internal composition from cystic to solid. A 72-year-old male visited our hospital because of epigastralgia 4 years earlier. A 25-mm tumor was recognized around the terminal duodenum on computed tomography and magnetic resonance imaging, and was diagnosed as a cystic lesion. Over the following 2 years, the tumor grew to 40 mm and its internal composition changed from cystic to solid. The lesion showed positive findings on fluorodeoxyglucose positron emission tomography. Upon laparotomy, a solid tumor was detected in the mesentery of the jejunum near the ligament of Treitz. The tumor was extracted without intestinal resection and was diagnosed as a low-grade neuroendocrine tumor after histopathological and immunohistochemical examination. One year has passed since the operation, and there has been no recurrence. PMID- 28028784 TI - Is cardiorespiratory fitness impaired in PCOS women? A review of the literature. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder, affecting 8-12% of reproductive-aged women. Insulin resistance and body fat excess are common features in these subjects. Increased physical activity and diet modifications are the first recommended approach in the management of these women, at least in overweight/obese subjects. Evaluation of cardiorespiratory fitness (CRF) is important in assessing exercise performance and in monitoring the effects of physical exercise interventions. Several studies have shown that CRF may be impaired in metabolic and endocrine disorders. However, there are little data on this issue in PCOS women. The aim of this narrative review is to critically evaluate whether aerobic capacity is altered in PCOS women, focusing on maximal oxygen uptake. METHODS: An updated search of the literature was performed, identifying papers with maximal oxygen consumption measurements in women with PCOS compared to healthy controls. RESULTS: We have identified six studies on this specific topic: four of them showed an alteration of maximal oxygen consumption in PCOS women, whereas two did not. However, taken together these studies suggest that CRF may be strikingly impaired in both normal-weight and overweight/obese subjects with this condition. CONCLUSIONS: Women with PCOS appear to be characterized by a reduced cardiopulmonary fitness. However, further research on this topic is needed. This information may hopefully help clinicians and exercise specialist in planning individualized exercise programs aimed at improving the metabolic and endocrine outcomes in these women. PMID- 28028785 TI - Disturbed nitric oxide and homocysteine production are involved in the increased risk of cardiovascular diseases in the F1 offspring of maternal obesity and malnutrition. AB - PURPOSE: The present study aimed to evaluate the changes in levels of different independent risk factors for vascular diseases in the rat offspring of maternal obesity and malnutrition as maternal health disturbances are thought to have direct consequences on the offspring health. The effect of postnatal diet on the offspring was also assessed. METHODS: Three groups of female Wistar rats were used (control, obese and malnourished). After the pregnancy and delivery, the offspring were weaned to control diet or high-caloric (HCD) diet and followed up for 30 weeks. Every 5 weeks postnatal, 20 pups (10 males and 10 females) of each subgroup were sacrificed after overnight fasting, the blood sample was obtained, and the rats were dissected out to obtain heart muscle. The following parameters were assessed; lipid profile, NEFA, homocysteine (Hcy), nitric oxide end product (NOx) and myocardial triglyceride content. RESULTS: Maternal obesity and malnutrition caused significant elevation in the body weight, triglycerides, NEFA, Hcy and NOx in the F1 offspring especially those maintained under HCD. Also, the male offspring showed more prominent changes than female offspring. CONCLUSIONS: Maternal malnutrition and obesity may increase the risk of the development of cardiovascular diseases in the offspring, especially the male ones. PMID- 28028786 TI - Determination of Fluoride in Organic and Non-organic Wines. AB - Fluorine is an element of great importance to human health, as it is considered to be an essential element. However, both a deficiency and an excess, it can cause various problems. It is for this reason that values have been established regarding the recommended daily intake (RDI) and acceptable daily intake (ADI). The largest source of incorporation of fluoride is water, but it can be found in other foods and beverages, such as vegetables, tea, and wine. The aim of the study was to establish the fluoride concentration in organic and non-organic wines from different appellations of origin of the Canary Islands and mainland Spain, in order to assess the contribution of fluoride and toxic risk. A total of 53 samples of red, white, and rose wines, both organic and non-organic, from different appellations of origin were analyzed. They were analyzed by potentiometric determination with ion-selective electrode for fluoride using the method of standard addition. The wines analyzed are within the recommended limits set by the International Organisation of Vine and Wine. RDI is not exceeded for adults, taking into account the data provided by the Spanish Agency for Consumer Affairs, Food Safety and Nutrition on the average consumption of "table wines" in Spain. Fluoride intake from wine poses no risk to the health of adults. The fluoride concentration of organic and non-organic wines is within the range of 0.03 to 0.70 mg/L. PMID- 28028787 TI - A Study on the Anticarcinogenic Effects of Calcium Fructoborate. AB - Evidences about the preventive and therapeutic effects of boron compounds on cancer have been increasing in the last years. Although calcium fructoborate (CaFB) is used as a nutritional supplement, data about its preventive and therapeutic effects on neoplastic transformations are limited. In the present study, the various concentrations of CaFB were applied to the MDA-MB-231 metastatic breast cancer cell line. First, we examined the cytotoxic effect and IC50 value of CaFB by MTT assay. For the evaluation of the DNA damage, apoptosis and metastatic potential, expression levels of ATM, pATM, PARP, p53, p-p53, caspase-3, caspase-9, and VEGF were investigated by using immunoblotting and immunohistochemical methods. Cell viability was significantly reduced at 50 MUM CaFB treatment. pATM, p-p53, and caspase-9 levels increased significantly in all groups; furthermore, there was approximately 12.5-, 2.4-, and 10.7-fold increase, respectively, for 100 MUM CaFB treatment. ATM and p53 levels did not change with CaFB treatment, but PARP levels significantly 2.5-fold decreased. While VEGF immunoreactivity decreased in all groups, significant increase in caspase-3 immunoreactivity was observed only in the group treated with 50 MUM CaFB (p < 0,001). Our results imply that CaFB may have therapeutic potential as well as preventive benefits in cancer. PMID- 28028788 TI - Factors Associated with the Need for Intensive Care Unit Admission Following Supratentorial Intracerebral Hemorrhage: The Triage ICH Model. AB - BACKGROUND: Providing the correct level of care for patients with intracerebral hemorrhage (ICH) is crucial, but the level of care needed at initial presentation may not be clear. This study evaluated factors associated with admission to intensive care unit (ICU) level of care. METHODS: This is an observational study of all adult patients admitted to our institution with non-traumatic supratentorial ICH presenting within 72 h of symptom onset between 2009-2012 (derivation cohort) and 2005-2008 (validation cohort). Factors associated with neuroscience ICU admission were identified via logistic regression analysis, from which a triage model was derived, refined, and retrospectively validated. RESULTS: For the derivation cohort, 229 patients were included, of whom 70 patients (31 %) required ICU care. Predictors of neuroscience ICU admission were: younger age [odds ratio (OR) 0.94, 95 % CI 0.91-0.97; p = 0.0004], lower Full Outline of UnResponsiveness (FOUR) score (0.39, 0.28-0.54; p < 0.0001) or Glasgow Coma Scale (GCS) score (0.55, 0.45-0.67; p < 0.0001), and larger ICH volume (1.04, 1.03-1.06; p < 0.0001). The model was further refined with clinician input and the addition of intraventricular hemorrhage (IVH). GCS was chosen for the model rather than the FOUR score as it is more widely used. The proposed triage ICH model utilizes three variables: ICH volume >=30 cc, GCS score <13, and IVH. The triage ICH model predicted the need for ICU admission with a sensitivity of 94.3 % in the derivation cohort [area under the curve (AUC) = 0.88; p < 0.001] and 97.8 % (AUC = 0.88) in the validation cohort. CONCLUSIONS: Presented are the derivation, refinement, and validation of the triage ICH model. This model requires prospective validation, but may be a useful tool to aid clinicians in determining the appropriate level of care at the time of initial presentation for a patient with a supratentorial ICH. PMID- 28028789 TI - Isoflurane Use in the Treatment of Super-Refractory Status Epilepticus is Associated with Hippocampal Changes on MRI. AB - BACKGROUND: Refractory status epilepticus (RSE) is associated with high morbidity and mortality. Experts recommend aggressive management with continuous intravenous infusions or inhaled anesthetics such as isoflurane. However, there is concern that MRI changes in RSE reflect isoflurane neurotoxicity. We performed a case-control study to determine whether isoflurane is neurotoxic, based on MRI signal changes. METHODS: We performed a retrospective case-control study of the incidence of MRI changes in RSE treated with and without isoflurane. Charts were reviewed for demographic and treatment information. T1, T2, and FLAIR sequences of MRIs were reviewed independently by two neuroradiologists blinded to treatment group for presence or absence of signal change or atrophy in the meninges, cortex, white matter, basal ganglia, thalamus, hippocampus, brainstem, and cerebellum. RESULTS: Eight cases of RSE receiving treatment with isoflurane were identified and double-matched with 15 controls who received only intravenous anesthetics. Baseline characteristics were similar. Hippocampal signal change was observed more frequently in cases receiving isoflurane (p = 0.026). CONCLUSIONS: Hippocampal signal changes were associated with isoflurane use in patients with RSE. They were also associated with number of seizure days prior to MRI and the use of multiple anesthetic agents. Similar changes have been seen as a result of RSE itself, and one cannot rule out the possibility these changes represent seizure-related effects. If isoflurane-related, these hippocampal signal changes may be the result of a direct neurotoxic effect of prolonged isoflurane use or failure of isoflurane to protect the hippocampus from seizure-induced injury despite achieving electrographic burst-suppression. PMID- 28028790 TI - Autoimmune Encephalitis at the Neurological Intensive Care Unit: Etiologies, Reasons for Admission and Survival. AB - BACKGROUND: Early recognition and treatment of autoimmune encephalitis (AE) has become an essential issue in clinical practice. However, little is known about patients with deteriorating conditions and the need for intensive care treatment. Here, we aimed to characterize underlying aetiologies, clinical symptoms, reasons for intensive care admission, and mortality of critically ill patients with AE. METHODS: We conducted a retrospective chart review of all patients with "definite" or "probable" diagnoses of AE treated at our neurological intensive care unit between 2002 and 2015. We collected and analyzed clinical, paraclinical, laboratory findings and assessed the mortality at last follow-up based on patient records. RESULTS: Twenty-seven patients [median age 55 years (range 25-87), male = 16] were included. Thirteen (48%) had "definite" AE. The most common reasons for admission were status epilepticus (7/27, 26%) and delirium (4/27, 15%). One-year survival was 82%, all five deceased were male, and 3 (60%) of them had "probable" disease. The non-survivors (median follow-up 1 year) were more likely to have underlying cancer and higher need for respiratory support compared to the survivors (p < 0.041, and p = 0.004, respectively). CONCLUSIONS: Clinical presentations and outcomes in critically ill patients with AE are diverse, and the most common leading cause for intensive care unit admission was status epilepticus. The association of comorbid malignancy and the need for mechanical ventilation with mortality deserves further attention. PMID- 28028791 TI - Clinical Value of Neutrophil to Lymphocyte and Platelet to Lymphocyte Ratio After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Inflammation and thrombosis are associated with the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) and neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are emerging as novel inflammatory markers in stroke. We aimed to identify the association of NLR and PLR with delayed cerebral ischemia (DCI) and 3-month outcome after aSAH. METHODS: Two hundred and forty-seven patients diagnosed with aSAH within 24 h of symptoms onset were enrolled. Clinical, neuroradiological, laboratory, and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Admission NLR, PLR, and combined NLR-PLR associated with outcomes were evaluated by logistic regression analysis, and we used receiver operating characteristic curves to detect the overall predictive accuracy of these markers. RESULTS: Fifty-five (22.3 %) patients had unfavorable outcome and 47 (19 %) developed DCI. Both NLR and PLR were correlated with WFNS grade (rho = 0.35[p < 0.001], rho = 0.28[p < 0.001]) and modified Fisher grade (rho = 0.25[p = 0.001], rho = 0.28[p = 0.003]) and independently related to DCI (OR 2.18, 95 %CI 1.51-3.15, p = 0.016; OR 2.21, 95 %CI 1.61-3.32, p = 0.008) and functional outcome (OR 1.89, 95 %CI 1.52-3.17, p = 0.015; OR 1.77, 95 %CI 1.48-3.21, p = 0.018) at 3 months after aneurysm repair. They had comparable predictive ability in DCI occurrence (area under the curve [AUC] 0.65, 95 %CI 0.55-0.74, p = 0.002; AUC 0.68, 95 %CI 0.60-0.76, p < 0.001) and poor outcome (AUC 0.70, 95 %CI 0.63 0.77, p < 0.001; AUC 0.65, 95 %CI 0.58-0.72, p = 0.001). However, combination of the two indexes showed a better predictive value than each alone (AUC 0.73, 95 %CI 0.66-0.81, p < 0.001 for DCI; AUC 0.76, 95 %CI 0.70-0.83, p < 0.001 for poor outcome). CONCLUSIONS: NLR and PLR as novel inflammatory biomarkers are independent predictors of DCI development and functional outcome after acute aSAH. When combined together, they may help to identify high-risk patients more powerfully. PMID- 28028792 TI - In Vitro and Ex Vivo Evaluation of Novel Curcumin-Loaded Excipient for Buccal Delivery. AB - This study aimed to develop a mucoadhesive polymeric excipient comprising curcumin for buccal delivery. Curcumin encompasses broad range of benefits such as antioxidant, anti-inflammatory, and chemotherapeutic activity. Hyaluronic acid (HA) as polymeric excipient was modified by immobilization of thiol bearing ligands. L-Cysteine (SH) ethyl ester was covalently attached via amide bond formation between cysteine and the carboxylic moiety of hyaluronic acid. Succeeded synthesis was proved by H-NMR and IR spectra. The obtained thiolated polymer hyaluronic acid ethyl ester (HA-SH) was evaluated in terms of stability, safety, mucoadhesiveness, drug release, and permeation-enhancing properties. HA SH showed 2.75-fold higher swelling capacity over time in comparison to unmodified polymer. Furthermore, mucoadhesion increased 3.4-fold in case of HA-SH and drug release was increased 1.6-fold versus HA control, respectively. Curcumin loaded HA-SH exhibits a 4.4-fold higher permeation compared with respective HA. Taking these outcomes in consideration, novel curcumin-loaded excipient, namely thiolated hyaluronic acid ethyl ester appears as promising tool for pharyngeal diseases. PMID- 28028793 TI - In Vitro Drug Transfer Due to Drug Retention in Human Epidermis Pretreated with Application of Marketed Estradiol Transdermal Systems. AB - Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P < 0.001) higher than that with product-C, product-A, gel, and spray. However, products-A and C, gel, and spray showed almost the same (P > 0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P < 0.001) higher than those with products-A and B, gel, and spray. The in vitro study results indicate a high potential of skin-to-skin drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined. PMID- 28028794 TI - Effect of Liquid Crystalline Systems Containing Antimicrobial Compounds on Infectious Skin Bacteria. AB - This study aimed (i) to prepare liquid crystalline systems (LCS) of glyceryl monooleate (GMO) and water containing antibacterial compounds and (ii) to evaluate their potential as drug delivery systems for topical treatment of bacterial infections. Therefore, LCS containing CPC (cetylpyridinium chloride) (LCS/CPC) and PHMB (poly(hexamethylene biguanide) hydrochloride) (LCS/PHMB) were prepared and the liquid crystalline phases were identified by polarizing light microscopy 24 h and 7 days after preparation. The in vitro drug release profile and in vitro antibacterial activity of the systems were assessed using the double layer agar diffusion method against Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, Escherichia coli, and Enterococcus faecalis. The interaction between GMO and the drugs was evaluated by a drug absorption study. Stable liquid crystalline systems containing CPC and PHMB were obtained. LCS/PHMB decreased the PHMB release rate and exerted strong antibacterial activity against all the investigated bacteria. In contrast, CPC interacted with GMO so strongly that it became attached to the system; the amount released was not sufficient to exert antibacterial activity. Therefore, the studied liquid crystalline systems were suitable to deliver PHMB, but not CPC. Accordingly, it was demonstrated that GMO interacts with each drug differently, which may interfere in the final efficiency of GMO/water LCS. PMID- 28028795 TI - Membrane-Loaded Doxorubicin Liposomes Based on Ion-Pairing Technology with High Drug Loading and pH-Responsive Property. AB - In order to achieve high drug loading and high entrapment efficiency, a doxorubicin-cholesteryl hemisuccinate ion-pair complex (DCHIP) was formed, and the ion-pair complex liposomes (DCHIP-Lip) were prepared based on conventional thin-film dispersion method. Firstly, DCHIP was fabricated and confirmed with FTIR, 1H-NMR, DSC, and XRD techniques. Afterwards, DCHIP-Lip were prepared and evaluated in terms of particle size, zeta potential, entrapment efficiency, and drug loading content. Finally, the in vitro and in vivo behavior of liposomes was further investigated. The DCHIP-Lip had a nanoscale particle size of about 120 nm with a negative zeta potential of about -22 mV. In addition, the entrapment efficiency and drug loading content of DOX reached 6.4 +/- 0.05 and 99.29 +/- 0.3%, respectively. Importantly, the release of DCHIP-Lip was pH sensitive and increased cell toxicity against MCF-7 cells was achieved. Upon dilution, the liposomes were fairly stable under physiological conditions. The in vivo pharmacokinetic study indicated that the AUC of DOX in DCHIP-Lip was 11.48-fold higher than that of DOX-HCl solution and the in vivo antitumor activity of DCHIP Lip showed less body weight loss and a significant prohibition effect of tumor growth. Based on these findings, it can be seen that the ion-pairing technology combined with conventional liposome drug loading method could be used to achieve high drug loading and it could be valuable for the study of liposomal delivery system. PMID- 28028796 TI - Erratum to: Efficient RNA Interference of Primary Leukemic Cells for Loss-of Function Studies in Xenograft Mouse Models. PMID- 28028797 TI - GLUT1, MCT1/4 and CD147 overexpression supports the metabolic reprogramming in papillary renal cell carcinoma. AB - Papillary Renal Cell carcinoma (pRCC) is the second most common type of RCC, accounting for about 15% of all RCCs. Surgical excision is the main treatment option. Still, 10 - 15 % of clinically localized tumours will recur and/or develop metastasis early after surgery, and no reliable prognostic biomarkers are available to identify them. It is known that pRCC cells rely on high rates of aerobic glycolysis, characterized by the up-regulation of many proteins and enzymes related with the glycolytic pathway. However, a metabolic signature enabling the identification of advanced pRCC tumours remains to be discovered. The aim of this study was to characterize the metabolic phenotype of pRCCs (subtypes 1-pRCC1 and 2-pRCC2) by evaluating the expression pattern of the glucose transporters (GLUTs) 1 and 4 and the monocarboxylate transporters (MCTs) 1 and 4, as well as their chaperon CD147. We analysed the clinico-pathological data and the protein and mRNA expression of GLUT1, GLUT4 and MCT1, MCT4 and CD147 in tumours from Porto and TCGA series (http://cancergenome.nih.gov/), respectively. With the exception of GLUT4, plasma membrane expression of all proteins was frequently observed in pRCCs. GLUT1 and MCT1 membrane overexpression was significantly higher in pRCC2 and significantly associated with higher pN stage and higher Fuhrman grade. Overexpression of GLUT1, MCT1/4 and CD147, supports the metabolic reprograming in pRCCs. MCT1 expression was associated with pRCC aggressiveness, regardless of the tumour histotype. PMID- 28028798 TI - A biomechanical view on stinger diversity in scorpions. AB - Scorpions have elongated metasomas that bear a telson, which is used as a stinger for venom injection. There is a remarkable diversity in the use of the stinger among scorpions, comprising defensive behavior, prey subjugation and mating. This diversity could be reflected by the shape of the telson, as different stinging behaviors will result in very different functional demands. Here we explored the diversity of telson shapes in scorpions by providing morphological measurements, such as curvature and tip angle, as well as by testing stingers under load using finite element analysis (FEA). FEA models were loaded with forces scaled to the surface area of the models, to allow comparison of the relative strain energy based on shape alone. Load force angle was rotated to identify the optimal stinging angle based on the lowest strain energy. Aculeus length and mean aculeus height correlated with minimal strain energy. Optimal stinging angle correlated with tip angle, and differed from the tip angle by about 28.4 +/- 6.22 degrees . We found that species that are more venomous have long aculei (stinger barbs) with a larger radius of curvature. FEA models of these longer aculei showed basal stress concentrations, indicating a potential greater risk of basal breakage due to shape alone. Telsons with shorter and thicker aculeus shapes showed stress concentrations at the tip only. Despite these marked differences in shape, we found no difference in the scaled strain energy between groups of species that are more venomous and less venomous groups of species. These results show that scorpion stingers may be biomechanically optimized, and this may indicate different usage of the stinger in different species. PMID- 28028800 TI - Sex- and Size-Related Patterns of Carrion Visitation in Necrodes littoralis (Coleoptera: Silphidae) and Creophilus maxillosus (Coleoptera: Staphylinidae). AB - The estimation of postmortem interval (PMI) based on successional patterns of adult insects is largely limited, due to the lack of potential PMI markers. Sex and size of adult insects could be easily used for such estimation. In this study, sex- and size-related patterns of carrion attendance by adult insects were analyzed in Necrodes littoralis (Coleoptera: Silphidae) and Creophilus maxillosus (Coleoptera: Staphylinidae). For both species, abundance of males and females changed similarly during decomposition. A slightly female-biased sex ratio was recorded in N. littoralis. Females of N. littoralis started visiting carcasses, on average, one day earlier than males. There was a rise in size of males of N. littoralis at the end of decomposition, whereas for females of both species and males of C. maxillosus, no size-related patterns of carrion visitation were found. Current results demonstrate that size and sex of adult carrion beetles are poor indicators of PMI. PMID- 28028799 TI - Residual force enhancement is regulated by titin in skeletal and cardiac myofibrils. AB - KEY POINTS: When a skeletal muscle is stretched while it contracts, the muscle produces a relatively higher force than the force from an isometric contraction at the same length: a phenomenon referred to as residual force enhancement. Residual force enhancement is puzzling because it cannot be directly explained by the classical force-length relationship and the sliding filament theory of contraction, the main paradigms in the muscle field. We used custom-built instruments to measure residual force enhancement in skeletal myofibrils, and, for the first time, in cardiac myofibrils. Our data report that residual force enhancement is present in skeletal muscles, but not cardiac muscles, and is regulated by the different isoforms of the titin protein filaments. ABSTRACT: When a skeletal muscle contracts isometrically, the muscle produces a force that is relative to the final isometric sarcomere length (SL). However, when the same final SL is reached by stretching the muscle while it contracts, the muscle produces a relatively higher force: a phenomenon commonly referred to as residual force enhancement. In this study, we investigated residual force enhancement in rabbit skeletal psoas myofibrils and, for the first time, cardiac papillary myofibrils. A custom-built atomic force microscope was used in experiments that stretched myofibrils before and after inhibiting myosin and actin interactions to determine whether the different cardiac and skeletal titin isoforms regulate residual force enhancement. At SLs ranging from 2.24 to 3.13 MUm, the skeletal myofibrils enhanced the force by an average of 9.0%, and by 29.5% after hindering myosin and actin interactions. At SLs ranging from 1.80 to 2.29 MUm, the cardiac myofibrils did not enhance the force before or after hindering myosin and actin interactions. We conclude that residual force enhancement is present only in skeletal muscles and is dependent on the titin isoforms. PMID- 28028801 TI - Transcranial Magnetic Stimulation: Basic Principles and Clinical Applications in Migraine. AB - PURPOSE: Transcranial magnetic stimulation (TMS) is a neurophysiological technique with a long established pedigree of safety, tolerability, and efficacy. Initially TMS was used to study the function of the cerebral cortex, but it has now become a treatment for migraine, one of the most common and debilitating neurological conditions. In this review we discuss the scientific background and development of the technique. We explore its application for the treatment of migraine and ponder the possible mechanisms of action in this most common neurological condition. OVERVIEW: The generation of brief magnetic pulses by a suitable coil can induce electrical fields in the body. When applied to the cerebral cortex, currents are painlessly induced in cortical neurons. These currents can lead to neuronal depolarization and may influence cortical excitability by means that are as yet not fully understood. This ability to modulate cortical excitability has been exploited as a treatment for migraine with aura. Aura is implicated in the pathophysiology of migraine. Experimental studies have shown that transcranial magnetic pulses can block waves of cortical spreading depression - the experimental equivalent of migrainous aura. DISCUSSION: Migraine is a debilitating condition characterized by headache, nausea, and sensory hypersensitivity. It may affect up to 15% of the population, yet current drug treatments are often poorly tolerated. Clinical studies have shown that TMS is an effective treatment for migraine. In addition, it has the added advantages of being safe and well tolerated by patients. PMID- 28028802 TI - Fatal Intoxication with alpha-PVP, a Synthetic Cathinone Derivative. AB - This study presents the fatal case of a young man who was admitted to the ICAU due to sudden cardiac arrest. An interview revealed that the patient had taken some unspecified crystals. From the moment of admission, his condition deteriorated dramatically as a result of increasing circulatory insufficiency. After a few hours, sudden cardiac arrest occurred again and the patient was pronounced dead. In the course of a medicolegal autopsy, samples of biological material were preserved for toxicology tests and histopathological examination. The analysis of samples using the LC-MS/MS technique revealed the presence of alpha-PVP in the following concentrations: blood-174 ng/mL, urine-401 ng/mL, brain-292 ng/g, liver-190 ng/g, kidney-122 ng/g, gastric contents-606 ng/g. The study also presents findings from the parallel histopathological examination. Based on these findings, cardiac arrest secondary to intoxication with alpha-PVP was determined as the direct cause of the patient's death. PMID- 28028803 TI - Cortical Alterations in Medication-Overuse Headache. AB - OBJECTIVE: Using surface-based morphometry we aimed to provide a detailed examination of cortical alterations in medication-overuse headache (MOH), by disentangling between altered cortical thickness and gyrification (folding). BACKGROUND: In MOH, pain modulation is probably dysfunctional at the cortical and subcortical level, resulting in a disequilibrium between pain inhibition and facilitation. Both increased and decreased cortical volumes have been reported in individuals with MOH. There is however no detailed examination to date that distinguishes between altered cortical thickness and gyrification. Such distinction would help to identify the nature and timing of neurodevelopmental mechanisms at play in affected individuals. METHODS: We investigated cortical thickness and gyrification in 29 patients with MOH according to International Headache Society criteria and 29 age- and gender-matched controls, using high resolution structural MRIs of the brain analyzed with FreeSurfer. This is a secondary analysis of data from a previously published voxel-based morphometry study. RESULTS: In patients with MOH compared to controls, reduced cortical thickness was observed in the left prefrontal cortex. We also observed higher local gyrification in one cluster extending from the fusiform cortex to adjacent medial temporal regions, and in another cluster in the right occipital pole. Higher gyrification in the right occipital pole predicted poor response after detoxification. CONCLUSIONS: Corroborating previous volumetric results, our study adds information on the putative neurobiological mechanisms involved in MOH, suggesting neurodevelopmental changes in MOH. PMID- 28028804 TI - Differential toxic effects of Ulva lactuca (Chlorophyta) on the herbivorous gastropods, Littorina littorea and L. obtusata (Mollusca). AB - Members of the genus Ulva are widespread and abundant in intertidal and shallow subtidal areas but there are conflicting data regarding susceptibility to herbivory. While some studies have documented that Ulva spp. were favored by a diversity of marine herbivores, other work has revealed herbivore deterrence. We investigated grazing and growth rates of the littorinid species, Littorina littorea and L. obtusata, when offered Fucus vesiculosus, Ascophyllum nodosum, Ulva lactuca, and Chondrus crispus, highlighting distinctive vulnerabilities to toxic effects of U. lactuca. Ulva lactuca was the preferred food of L. littorea, while L. obtusata showed no grazing on this ephemeral algal species. In contrast, F. vesiculosus was highly preferred by L. obtusata. Although L. littorea demonstrated a grazing preference for U. lactuca, growth rate of this gastropod species was nearly 3* greater when fed F. vesiculosus, suggesting a non-lethal, negative effect of U. lactuca on L. littorea with long-term exposure. Mortality of L. obtusata ranged from 0% to 100% when held in the presence of various Ulva densities for 1 week, and Ulva exudate depressed herbivory of this gastropod. We conclude that the water-soluble, toxic exudate produced by U. lactuca in response to herbivory had allelochemical properties, and may contain a cleavage product (acrylic acid) of dimethylsulfoniopropionate or reactive oxygen species (i.e., H2 O2 ). Observed differences in susceptibility to Ulva toxicity by the littorinid species may be related to generalist versus specialist feeding and habitat strategies. PMID- 28028806 TI - From channels to systems: Ca2+ -sensitive K+ currents, alternans and cardiac arrhythmia. PMID- 28028805 TI - Sexual Dysfunction in Women With Migraine and Overweight/Obesity: Relative Frequency and Association With Migraine Severity. AB - BACKGROUND/OBJECTIVE: Previous studies suggest that migraine might be associated with female sexual dysfunction (FSD), although this association may be complicated by overweight/obesity. To disentangle relationships of migraine and obesity with FSD, we examined: (1) FSD rates in women who had migraine and obesity with a matched sample of women with obesity who were free of migraine and (2) associations between indices of migraine severity and FSD in a larger sample of participants with migraine and overweight/obesity, controlling for important confounders. METHODS: Women with migraine and obesity seeking behavioral weight loss treatment to decrease headaches (n = 37) and nonmigraine controls (n = 37) with obesity seeking weight loss via bariatric surgery were matched on age (+/-5 years), body mass index (BMI; +/-3 kg/m2 ), and reported sexual activity during the past month. Both groups completed the Female Sexual Function Index (FSFI), with a validated FSFI-total cutoff score used to define FSD. In participants with migraine and overweight/obesity (n = 105), separate logistic regression models evaluated associations of migraine attack frequency, intensity, and duration with odds of having FSD, controlling for age, BMI, depression, and anxiety. RESULTS: On average, participants and matched controls had severe obesity (BMI = 42.4 +/- 3.8 kg/m2 ; range = 35-49.9) and were 37.3 +/- 7.2 years of age (range = 22-50). FSD rate did not differ between migraine participants and controls (56.8% vs. 54.1%, P = .82). In the larger sample of participants with migraine and overweight/obesity (38.2 +/- 7.8 years of age; BMI = 34.8 +/- 6.4 [range = 25-50 kg/m2 ]; 8.0 +/- 4.3 migraine days/month, maximum pain intensity = 5.9 +/- 1.4 on 0-10 scale; average attack duration = 18.3 +/- 9.7 hours), FSD was not associated with attack frequency (P = .31), pain intensity (P = .92), or attack duration (P = .35) but was associated with more severe anxiety symptoms (Ps < .017). CONCLUSIONS: Rates of sexual dysfunction did not differ in severely obese women with and without migraine. Moreover, indices of migraine severity were not associated with increased risk of FSD in women with overweight/obesity. Replication of present findings in wider populations of women with migraine and of both normal-weight and overweight/obese status are warranted. PMID- 28028807 TI - Topical photodynamic therapy for primary Bowen disease and basal cell carcinoma: optimizing patient selection. PMID- 28028808 TI - Structural Gray Matter Alterations in Chronic Migraine: Implications for a Progressive Disease? AB - OBJECTIVE: To identify possible gray matter alterations in patients with chronic migraine using voxel-based morphometry (VBM). BACKGROUND: VBM studies demonstrate structural alterations of gray matter (GM) in episodic migraine (EM) patients. Some of these alterations correlate with disease duration and headache frequency. We assessed GM alterations in chronic migraine (CM) and EM to evaluate the concept of migraine as a progressive disorder of the brain. METHODS: Individually age and sex-matched subjects with CM or EM (both without aura) and healthy controls (n = 21 per group) underwent magnetic resonance imaging-based VBM. RESULTS: We found an increase of GM volume (GMV) in amygdala and putamen, in CM compared to controls. GMV of EM compared to controls did not differ statistically significantly. Headache frequency in all migraineurs (EM and CM) correlated positively with GMV in putamen, frontal and temporal gyrus and negatively in left cuneus. CONCLUSION: CM is associated with structural changes in brain regions involved in pain processing but also in affective and cognitive aspects of pain. Some GM alterations are correlated with headache frequency assessed in EM and CM. The findings support the assumption that chronic pain alters brain plasticity. GMV increase may reflect a remodeling of the central nervous system due to repetitive headache attacks leading to chronic sensitization and a continuous ictal-like state of the brain in chronic migraineurs. PMID- 28028809 TI - Geridonin, a novel derivative of oridonin, inhibits proliferation of MGC 803 cells both in vitro and in vivo through elevating the intracellular ROS. AB - OBJECTIVES: To study the antitumour activity of a novel derivative of oridonin named geridonin in vitro and in vivo. METHODS: MTT and colony formation assay were used to test the cytotoxicity of geridonin; apoptosis, cell cycle arrest and the levels of reactive oxygen species were measured by flow cytometry; JC-1 staining assay was used to examine the mitochondrial membrane potential; the MGC 803 xenograft model was established to evaluate the antitumour effect of geridonin in vivo; H&E staining was performed for the histological analysis. KEY FINDINGS: In vitro, geridonin remarkably inhibited proliferation of gastrointestinal cancer cells including oesophageal, gastric, liver and colon cancers. On oesophageal, gastric cancer cells, geridonin displayed strong cytotoxicity than that of oridonin. In gastric cancer MGC 803 cells, geridonin triggered apoptosis through the mitochondrial pathway depending on caspase. In addition, geridonin sharply reduced the formation of cell colony, increased the intracellular levels of ROS and induced cell cycle arrest at G2/M phase. In vivo, geridonin delayed the growth of MGC 803 xenograft in athymic mice without obvious loss of bodyweight. CONCLUSIONS: The novel derivative of oridonin, geridonin, inhibited the growth of human gastric cancer cells MGC 803 both in vitro and in vivo mainly via triggering apoptosis depending on elevating intracellular level of ROS. PMID- 28028810 TI - Three-dimensional evaluation of subclinical extension of extramammary Paget disease: visualization of the histological border and its comparison to the clinical border. AB - BACKGROUND: In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown. OBJECTIVES: To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension. METHODS: Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries; biopsy samples were then taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anticytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border. RESULTS: In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. However, two samples exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema. CONCLUSIONS: In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema. PMID- 28028811 TI - Rapid frequency-dependent changes in free mitochondrial calcium concentration in rat cardiac myocytes. AB - KEY POINTS: Calcium ions regulate mitochondrial ATP production and contractile activity and thus play a pivotal role in matching energy supply and demand in cardiac muscle. The magnitude and kinetics of the changes in free mitochondrial calcium concentration in cardiac myocytes are largely unknown. Rapid stimulation frequency-dependent increases but relatively slow decreases in free mitochondrial calcium concentration were observed in rat cardiac myocytes. This asymmetry caused a rise in the mitochondrial calcium concentration with stimulation frequency. These results provide insight into the mechanisms of mitochondrial calcium uptake and release that are important in healthy and diseased myocardium. ABSTRACT: Calcium ions regulate mitochondrial ATP production and contractile activity and thus play a pivotal role in matching energy supply and demand in cardiac muscle. Little is known about the magnitude and kinetics of the changes in free mitochondrial calcium concentration in cardiomyocytes. Using adenoviral infection, a ratiometric mitochondrially targeted Forster resonance energy transfer (FRET)-based calcium indicator (4mtD3cpv, MitoCam) was expressed in cultured adult rat cardiomyocytes and the free mitochondrial calcium concentration ([Ca2+ ]m ) was measured at different stimulation frequencies (0.1 4 Hz) and external calcium concentrations (1.8-3.6 mm) at 37 degrees C. Cytosolic calcium concentrations were assessed under the same experimental conditions in separate experiments using Fura-4AM. The increases in [Ca2+ ]m during electrical stimulation at 0.1 Hz were rapid (rise time = 49 +/- 2 ms), while the decreases in [Ca2+ ]m occurred more slowly (decay half time = 1.17 +/- 0.07 s). Model calculations confirmed that this asymmetry caused the rise in [Ca2+ ]m during diastole observed at elevated stimulation frequencies. Inhibition of the mitochondrial sodium-calcium exchanger (mNCE) resulted in a rise in [Ca2+ ]m at baseline and, paradoxically, in an acceleration of Ca2+ release. IN CONCLUSION: rapid increases in [Ca2+ ]m allow for fast adjustment of mitochondrial ATP production to increases in myocardial demand on a beat-to-beat basis and mitochondrial calcium release depends on mNCE activity and mitochondrial calcium buffering. PMID- 28028812 TI - A Systematic Review and Meta-Analysis of the Efficacy of Cognitive Behavioral Therapy for the Management of Pediatric Migraine. AB - INTRODUCTION: Migraine headaches are common in children and adolescents. Current pharmacologic treatment options are limited despite the prevalence and debilitating effects of pediatric migraine. Cognitive behavioral therapy (CBT) is an evidence-based practice that focuses on the development of coping strategies and cognitive restructuring to alter the pain experience. Till date, no meta analysis has been done to examine the use of CBT in pediatric migraine. METHODS: Using the keywords (cognitive behavioral therapy OR cognitive behavior therapy OR cognitive behavioral therapy OR cognitive behavior therapy OR CBT) AND (headache OR migraine), a preliminary search on the PubMed and Ovid database yielded 3841 articles published in English between 1 Jan 1980 and 1 May 2016. Full articles were also reviewed for references of interest. After data extraction, 14 studies were included in the meta-analysis. RESULTS: The results of the meta-analysis well-support the clinical role of CBT in the management of pediatric migraine. The pooled odds ratios of clinically significant improvement, that is, 50% or greater headache activity reduction post-treatment and at follow-up (3 months or later) were OR 9.11 (95% CI: 5.01 to 16.58, P < .001) and OR 9.18 (95% CI: 5.69 to 14.81, P < .001) respectively, demonstrating significant clinical improvement with CBT as compared with wait-list control, placebo, or standard medication. Furthermore, the clinical improvement was stable, even at a 1-year follow-up as evident in some of the studies. CONCLUSION: There is good evidence that CBT is beneficial to children suffering from migraine, and may also augment the efficacy of standard medications such as amitriptyline. PMID- 28028813 TI - Accuracy of tablet splitting and liquid measurements: an examination of who, what and how. AB - OBJECTIVE: To examine factors that might affect the ability of patients to accurately halve tablets or measure a 5-ml liquid dose. METHODS: Eighty-eight participants split four different placebo tablets by hand and using a tablet splitter, while 85 participants measured 5 ml of water, 0.5% methylcellulose (MC) and 1% MC using a syringe and dosing cup. Accuracy of manipulation was determined by mass measurements. KEY FINDINGS: The general population was less able than pharmacy students to break tablets into equal parts, although age, gender and prior experience were insignificant factors. Greater accuracy of tablet halving was observed with tablet splitter, with scored tablets split more equally than unscored tablets. Tablet size did not affect the accuracy of splitting. However, >25% of small scored tablets failed to be split by hand, and 41% of large unscored tablets were split into >2 portions in the tablet splitter. In liquid measurement, the syringe provided more accurate volume measurements than the dosing cup, with higher accuracy observed for the more viscous MC solutions than water. CONCLUSION: Formulation characteristics and manipulation technique have greater influences on the accuracy of medication modification and should be considered in off-label drug use in vulnerable populations. PMID- 28028814 TI - Choline and acetylcholine: what a difference an acetate makes! PMID- 28028815 TI - Metabolic systems biology: a brief primer. AB - In the early to mid-20th century, reductionism as a concept in biology was challenged by key thinkers, including Ludwig von Bertalanffy. He proposed that living organisms were specific examples of complex systems and, as such, they should display characteristics including hierarchical organisation and emergent behaviour. Yet the true study of complete biological systems (for example, metabolism) was not possible until technological advances that occurred 60 years later. Technology now exists that permits the measurement of complete levels of the biological hierarchy, for example the genome and transcriptome. The complexity and scale of these data require computational models for their interpretation. The combination of these - systems thinking, high-dimensional data and computation - defines systems biology, typically accompanied by some notion of iterative model refinement. Only sequencing-based technologies, however, offer full coverage. Other 'omics' platforms trade coverage for sensitivity, although the densely connected nature of biological networks suggests that full coverage may not be necessary. Systems biology models are often characterised as either 'bottom-up' (mechanistic) or 'top-down' (statistical). This distinction can mislead, as all models rely on data and all are, to some degree, 'middle-out'. Systems biology has matured as a discipline, and its methods are commonplace in many laboratories. However, many challenges remain, especially those related to large-scale data integration. PMID- 28028816 TI - Physiological limits to endurance exercise performance: influence of sex. AB - This brief review summarizes factors associated with elite endurance performance, trends in distance running training, and participation by men and more recently women. It is framed in the context of key ideas about the physiological determinants of endurance performance but also touches on some historical and sociological factors relevant to the overall topic. Historical trends that served to increase women's participation in elite endurance events are also discussed as is the role of increased volume and intensity of training. The rapid improvement in women's world record marathon times in the 1970s and 80s are emblematic of these trends and represent a combination of increased training volume and intensity and more competitive opportunities. This occurred as bans on participation by women in endurance events were lifted. For men these same trends evolved over a much longer time frame. The main physiological factor responsible for 10-12% slower times in women compared to men at the elite level are also considered and probably centre aroundVO2 max . PMID- 28028817 TI - Ictal Epileptic Headache in Occipital Symptomatic Epilepsy: Not Only a Matter of Cortex. PMID- 28028818 TI - A mechanism for sickness sleep: lessons from invertebrates. AB - During health, animal sleep is regulated by an internal clock and by the duration of prior wakefulness. During sickness, sleep is regulated by cytokines released from either peripheral cells or from cells within the nervous system. These cytokines regulate central nervous system neurons to induce sleep. Recent research in the invertebrates Caenorhabditis elegans and Drosophila melanogaster has led to new insights into the mechanism of sleep during sickness. Sickness is triggered by exposure to environments such as infection, heat, or ultraviolet light irradiation, all of which cause cellular stress. Epidermal growth factor is released from stressed cells and signals to activate central neuroendocrine cell(s). These neuron(s) release neuropeptides including those containing an amidated arginine(R)-phenylalanine(F) motif at their C-termini (RFamide peptides). Importantly, mechanisms regulating sickness sleep are partially distinct from those regulating healthy sleep. We will here review key findings that have elucidated the central neuroendocrine mechanism of sleep during sickness. Adaptive mechanisms employed in the control of sickness sleep may play a role in correcting cellular homeostasis after various insults. We speculate that these mechanisms may play a maladaptive role in human pathological conditions such as in the fatigue and anorexia associated with autoimmune diseases, with major depression, and with unexplained chronic fatigue. PMID- 28028819 TI - A pilot randomized controlled trial comparing effectiveness of prism glasses, visual search training and standard care in hemianopia. AB - OBJECTIVE: Pilot trial to compare prism therapy and visual search training, for homonymous hemianopia, to standard care (information only). METHODS: Prospective, multicentre, parallel, single-blind, three-arm RCT across fifteen UK acute stroke units. PARTICIPANTS: Stroke survivors with homonymous hemianopia. INTERVENTIONS: Arm a (Fresnel prisms) for minimum 2 hours, 5 days per week over 6 weeks. Arm b (visual search training) for minimum 30 minutes, 5 days per week over 6 weeks. Arm c (standard care-information only). INCLUSION CRITERIA: Adult stroke survivors (>18 years), stable hemianopia, visual acuity better than 0.5 logMAR, refractive error within +/-5 dioptres, ability to read/understand English and provide consent. OUTCOMES: Primary outcomes were change in visual field area from baseline to 26 weeks and calculation of sample size for a definitive trial. Secondary measures included Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual, Short Form-12 questionnaires and Radner reading ability. Measures were post randomization at baseline and 6, 12 and 26 weeks. RANDOMIZATION: Randomization block lists stratified by site and partial/complete hemianopia. BLINDING: Allocations disclosed to patients. Primary outcome assessor blind to treatment allocation. RESULTS: Eighty-seven patients were recruited: 27-Fresnel prisms, 30 visual search training and 30-standard care; 69% male; mean age 69 years (SD 12). At 26 weeks, full results for 24, 24 and 22 patients, respectively, were compared to baseline. Sample size calculation for a definitive trial determined as 269 participants per arm for a 200 degree2 visual field area change at 90% power. Non significant relative change in area of visual field was 5%, 8% and 3.5%, respectively, for the three groups. Visual Function Questionnaire responses improved significantly from baseline to 26 weeks with visual search training (60 [SD 19] to 68.4 [SD 20]) compared to Fresnel prisms (68.5 [SD 16.4] to 68.2 [18.4]: 7% difference) and standard care (63.7 [SD 19.4] to 59.8 [SD 22.7]: 10% difference), P=.05. Related adverse events were common with Fresnel prisms (69.2%; typically headaches). CONCLUSIONS: No significant change occurred for area of visual field area across arms over follow-up. Visual search training had significant improvement in vision-related quality of life. Prism therapy produced adverse events in 69%. Visual search training results warrant further investigation. PMID- 28028820 TI - Risk factors for mortality in patients with anti-NMDA receptor encephalitis. AB - OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder with a mortality of 5%-7%, but few studies have focused on the predictors of death in this disease. In this study, we aim to investigate predictors and causes of death in patients with anti-NMDAR encephalitis. METHODS: In this cohort study, patients with anti-NMDAR encephalitis were enrolled at the West China Hospital of Sichuan University between June 2011 and October 2015. The outcomes of patients were evaluated by long-term follow-up. Cox regression analysis was used to assess the association between potential predictors and death. RESULTS: Altogether 96 patients were included in this study, and 11 died after median 24.5 (7-57) months of follow-up. The mortality of anti-NMDAR encephalitis was 11.46%. Multivariate analysis results showed that Glasgow Coma Scale (GCS) score <=8 at admission (HR=15.917, 95% CI=1.729-146.562; P=.015), the number of complications (HR=7.772, 95% CI=1.944-31.072; P=.004), and admission to an intensive care unit (HR=70.158, 95% CI=2.395-2055.459; P=.014) were significantly associated with increased risk of mortality. Twelve patients received second-line immunotherapy, and the cohort was relatively under-treated compared with other studies. The main causes of death were severe pneumonia, multiple organ dysfunction syndrome, and refractory status epilepticus. CONCLUSION: GCS score <=8 at admission, number of complications, and admission to an intensive care unit are predictors of death. Management of complications may improve the prognosis of anti-NMDAR encephalitis. PMID- 28028821 TI - Sarcopenia is associated with severe liver fibrosis in patients with non alcoholic fatty liver disease. AB - BACKGROUND: Sarcopenia recognises insulin resistance and obesity as risk factors, and is frequently associated with cardiometabolic disorders, including non alcoholic fatty liver disease (NAFLD). AIM: To test the prevalence of sarcopenia and its relation with the severity of fibrosis (main outcome) and the entire spectrum of liver histology in patients with NAFLD. METHODS: We considered 225 consecutive patients with histological diagnosis of NAFLD (Kleiner score). The skeletal muscle index (%) (total appendicular skeletal muscle mass (kg)/weight (kg) * 100), a validated measure of sarcopenia, was assessed by bioelectrical impedance analysis. Sarcopenia was defined as a skeletal muscle mass index <=37 in males and <=28 in females. RESULTS: The prevalence of sarcopenia showed a linear increase with the severity of fibrosis, and severe fibrosis (F3-F4) was more than doubled in sarcopenia (48.3% vs. 20.4% in fibrosis <=F2, P < 0.001). After adjusting for confounders, the association of sarcopenia with severe fibrosis was maintained (OR 2.36, CI 1.16-4.77, P = 0.01), together with age > 50 (OR 6.53, CI 2.95-14.4, P < 0.001), IFG/Diabetes (OR 2.14, CI 1.05-4.35, P = 0.03) and NASH (OR 13.3, CI 1.64-108.1, P = 0.01). Similarly, a significant association was found between sarcopenia and NASH (P = 0.01), steatosis severity (P = 0.006), and ballooning (P = 0.01), but only the association with severe steatosis was maintained (OR 2.02, CI 1.06-3.83, P = 0.03) after adjusting for confounders. CONCLUSIONS: In Western patients with NAFLD, with high prevalence of metabolic disorders and advanced liver disease, sarcopenia was associated with the severity of fibrosis and steatosis, independently of hepatic and metabolic risk factors. Studies are needed to assess the impact of interventions to reduce sarcopenia on NAFLD progression. PMID- 28028822 TI - Long-term outcomes for transobturator tension-free vaginal tapes in women with urodynamic mixed urinary incontinence. AB - AIMS: To assess the long-term patient reported outcomes following transobturator tension-free vaginal tapes (TO-TVT) in women with urodynamic mixed urinary incontinence (MUI). METHODS: A secondary analysis of the 9-year follow-up of the E-TOT study: 341 women with predominant stress urinary incontinence symptoms were randomized to undergo either inside-out or outside-in TO-TVT between April 2005 and April 2007. Forty-eight women had preoperative urodynamic MUI and were available for 9-year follow-up. Primary outcome was the patient-reported success rate defined as very/much improved on Patient's Global Impression of Improvement PGI-I. Secondary outcomes included impact on women's quality of life, sexual function, overactive bladder symptoms,and late adverse events. Statistical analysis was performed using SPSS v.23. RESULTS: Forty-eight women completed the 9-year follow-up, with adjusted response rate of 63%. The success based on the PGI-I was 64.6% (n = 31), with a further 14.6% (n = 7) who reported "improved." There was no significant difference between groups (OR 1.11; 95%CI 0.33, 3.70; P > 0.999). Clinically significant improvement in quality of life was found in 85.3%. Cure of urgency and UUI was reported by 35% and 41%, whereas worsening was reported in 6.5% and 2.3%, respectively. One patient reported chronic groin/leg pain. The small sample size and the sizeable loss to follow-up are limitations in this study. CONCLUSIONS: This is the first study to report the long-term outcomes of TO-TVT in women with urodynamic MUI; TO-TVT is associated with a good and sustained patient-reported success rate in women with MUI up to 9-years follow up. PMID- 28028823 TI - Point estimation and p-values in phase II adaptive two-stage designs with a binary endpoint. AB - Clinical trials in phase II of drug development are frequently conducted as single-arm two-stage studies with a binary endpoint. Recently, adaptive designs have been proposed for this setting that enable a midcourse modification of the sample size. While these designs are elaborated with respect to hypothesis testing by assuring control of the type I error rate, the topic of point estimation has up to now not been addressed. For adaptive designs with a prespecified sample size recalculation rule, we propose a new point estimator that both assures compatibility of estimation and test decision and minimizes average mean squared error. This estimator can be interpreted as a constrained posterior mean estimate based on the non-informative Jeffreys prior. A comparative investigation of the operating characteristics demonstrates the favorable properties of the proposed approach. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28028824 TI - Should we be offering fertility preservation by surgical sperm retrieval to men with Klinefelter syndrome? AB - Advances in surgical sperm retrieval have greatly increased the chances of men with Klinefelter syndrome achieving biological paternity. Despite this, the vast majority of attempts to achieve fertility by using extracted gametes to fertilize eggs in vitro do not result in viable pregnancies. A powerful obstacle to success lies with the natural history of seminiferous tubule and germ cell function in Klinefelter syndrome, which typically peak (and thereafter steeply decline) up to a decade before most individuals would be contemplating paternity. Herein we discuss, in relation to a real clinical case, both the exciting technical advances surgical sperm retrieval and the logistic and ethical factors that, in practice, may act to limit their successful application. PMID- 28028825 TI - Imbalance properties of centre-stratified permuted-block and complete randomisation for several treatments in a clinical trial. AB - Randomisation schemes are rules that assign patients to treatments in a clinical trial. Many of these schemes have the common aim of maintaining balance in the numbers of patients across treatment groups. The properties of imbalance that have been investigated in the literature are based on two treatment groups. In this paper, their properties for K > 2 treatments are studied for two randomisation schemes: centre-stratified permuted-block and complete randomisation. For both randomisation schemes, analytical approaches are investigated assuming that the patient recruitment process follows a Poisson gamma model. When the number of centres involved in a trial is large, the imbalance for both schemes is approximated by a multivariate normal distribution. The accuracy of the approximations is assessed by simulation. A test for treatment differences is also considered for normal responses, and numerical values for its power are presented for centre-stratified permuted-block randomisation. To speed up the calculations, a combined analytical/approximate approach is used. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28028826 TI - Identification of the potential biomarkers for the metastasis of rectal adenocarcinoma. AB - Rectal cancer is a common malignant tumor of the digestive tract, with a high incidence and high mortality. This study aimed to identify the potential biomarkers and therapeutic targets for rectal adenocarcinoma (RAC) metastasis. The expression profiling of RAC patients with metastasis and RAC patients without metastasis was downloaded from The Cancer Genome Atlas (TCGA) database. The datasets were used to identify the genes associated with RAC metastasis. Fifty up regulated genes and seventeen down-regulated genes were identified in the primary tumor loci of RAC metastasis compared with non-metastasis. Sixty-seven dysregulated gens were conducted to construct the protein-protein network, and CCND3 was the hub protein. The dysregulated genes were significantly enriched in pancreatic secretion, cell adhesion molecules pathways, response to vitamin D of biological process, and retinoid binding of molecular function. Quantitative real time polymerase chain reaction results demonstrated that CCND3, AQP3, PEG10, and RAB27B had the up-regulated tendency in RAC metastasis; ADCY1 had the down regulated tendency in RAC metastasis. CCND3, AQP3, PEG10, RAB27B, and ADCY1 might play essential roles in the metastasis process of RAC through pancreatic secretion and cell adhesion molecules pathways. The five genes could be potential diagnosis biomarkers or therapeutic targets for RAC metastasis. PMID- 28028827 TI - Novel application for electrochemotherapy: Immersion of nasal cavity in dog. AB - Electrochemotherapy is a new modality of local cancer treatment that increases the delivery of chemotherapy drugs into tumor cells by applying intense electric fields. This novel electrochemotherapy application was applied as an adjuvant to surgery and eliminated intranasal tumors in dog. The treatment challenges are the surgery limitations due to anatomy and residual tumor in the bone cavity. Most of the tumoral mass on nasal cavity was surgically removed. The internal nasal cavity was immersed in liquid and bleomycin before applying electric field. The solution was necessary to increase the superficial contact between plate electrodes and residual tumor. The numerical study demonstrated electrochemotherapy efficiency in different clinical situations. The proximity between electrodes and bone (<3 mm) and bone irregularities affect the electric field distribution on tumoral tissue. The tumoral tissue around bone protuberances tends to be eliminated. Electrochemotherapy with plate electrodes inside the cavity might not be effective. Different values of electric conductivity solution were studied; the ideal value was 0.5 S/m. The numerical and experimental results confirm the successful application of electrochemotherapy on dog nasal cavity. PMID- 28028828 TI - Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. AB - CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. OBJECTIVE: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. RESULTS: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1 (PD 1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1 inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%. PMID- 28028829 TI - Localization of nucleic acid-sensing toll-like receptors in human and mouse pancreas. AB - Nucleic acid-sensing toll-like receptors (TLRs) (3, 7, 8, 9) have a role both in antiviral innate immunity and in autoimmune disorders. We assessed the expression of TLR3, 7, 8 and 9 in human and mouse pancreas focusing on the subpopulations of cells in the Langerhans islets. We studied eight human samples with normal pancreatic islets and two samples from patients with type 1 diabetes. Additionally, 10 CD-1 mouse pancreases were analysed. Immunohistochemical double stainings for the TLRs and insulin, glucagon or somatostatin, respectively, were performed along with appropriate controls. In human pancreas, strong immunoreaction of TLR7 and TLR8 was observed in the insulin-positive beta cells, whereas glucagon- or somatostatin-expressing cells of the islets were weakly stained or negative. In type 1 diabetes, the expression in islets was weak or lost (TLR7: p = 0.014, TLR8: p = 0.053), correlating with loss of beta cells. TLR3 and 9 were expressed only weakly with no correlation with specific cell types. In mouse pancreas, only TLR9 was detected. Intra-pancreatic nerve ganglia strongly expressed TLR7. The strong expression of TLR7 and TLR8 in the beta cells of normal human islets could be an important piece in the puzzle of type 1 diabetes pathogenesis, and be linked with destruction of this particular subpopulation of the islet cells. In normal mice, only TLR9 can be constantly detected in the islets, highlighting differences between the species. PMID- 28028830 TI - Retrospective Evaluation of Postoperative Adverse Drug Events in Patients Receiving Rivaroxaban After Major Orthopedic Surgery Compared with Standard Therapy in a Community Hospital. AB - STUDY OBJECTIVES: To evaluate the occurrence of bleeding and venous thromboembolic (VTE) events in patients receiving rivaroxaban, warfarin, or warfarin with the addition of enoxaparin during the immediate postoperative period following major orthopedic surgery. METHODS: Patients older than 18 years who received at least one dose of rivaroxaban the morning following surgery, adjusted dose warfarin, or adjusted dose warfarin with the addition of enoxaparin for VTE prophylaxis after major orthopedic surgery between October 1, 2011, and February 28, 2015, were included. Data collected from the electronic health record included patient demographics, renal function, inpatient aspirin, P2Y12 inhibitor and/or nonsteroidal antiinflammatory drug (NSAID) use, type of surgery, postoperative analgesia, and presence of VTE risk factors. Adjusted incidence rate ratio for bleeding or VTE events was estimated using modified Poisson regression with robust standard errors. Covariates included in a multivariable model were age, sex, aspirin use, P2Y12 inhibitor use, NSAID use, obesity, VTE risk factors, and creatinine clearance. RESULTS: There were 3246 patients who met study inclusion criteria. Overall, incidences of bleeding and VTE events were rare. Bleeding event incidence ranged from 0.4% in the warfarin and warfarin with the addition of enoxaparin groups to 1.2% in the rivaroxaban group (p=0.088). There were two major bleeding events and 18 minor bleeding events (including hemorrhagic wound complications). VTE event incidence ranged from 0.2% in the warfarin with the addition of enoxaparin group to 0.6% in the rivaroxaban group (p=0.230). Two deep vein thromboses and 10 pulmonary emboli occurred. With use of the multivariable model, the warfarin and warfarin with the addition of enoxaparin groups had significantly lower incidence rates of bleeding compared with rivaroxaban (incidence rate ratio [IRR] = 0.218, p=0.0120, and IRR = 0.242, p=0.021, respectively). PRINCIPAL CONCLUSIONS: We observed a small, yet significant, increase in rivaroxaban-related bleeding in the immediate postoperative period relative to warfarin or warfarin with the addition of enoxaparin for the prevention of VTE after major orthopedic surgery. PMID- 28028831 TI - Diagnostic concordance of breast pathologists: lessons from the National Health Service Breast Screening Programme Pathology External Quality Assurance Scheme. AB - AIMS: Previous concordance studies examining accuracy of breast diagnosis by pathologists, typically targeting difficult, histologically challenging breast lesions using artificial and restrictive environments, have reported aberrantly high levels of diagnostic discordance. The results of these studies may be misinterpreted by non-pathologists and raise concerns relating to routine practice. This study aims to assess the diagnostic agreement among UK breast pathologists. METHODS: Two hundred and forty consecutive breast lesions, submitted by participants from their routine practice, included in the UK National Health Service Breast Screening Programme (NHSBSP) breast pathology EQA scheme during the last 10 years were reviewed. An average of approximately 600 participants viewed each case. Data on diagnostic categories (benign, atypical, in-situ malignant and invasive malignant) were collected. In this study, benign and atypical diagnoses were grouped together. RESULTS: The overall diagnostic agreement level was in the almost perfect range. Thirty-five cases (14.6%) showed diagnostic concordance of <=95%. Reasons for discordance included one or more of: (1) scheme methodology limitations such as: (i) miscoding of certain lesions (e.g. phyllodes tumours and lobular neoplasia) (n = 7) and (ii) variable representation of the index lesion on glass slides (n = 18); and (2) diagnostically challenging cases that may be interpreted more easily using immunohistochemistry (n = 28). These latter included benign and malignant papillary lesions (n = 12), complex sclerosing lesions (n = 7), intraductal epithelial proliferative lesions (n = 6) and an unusual special tumour type (n = 1). Further review identified pathologists' misinterpretation in 13 cases (5.4%), with an average discordance rate of only 4.2%. CONCLUSIONS: The performance of breast pathologists is high. Exclusion of the effect of the scheme methodology limitations highlights further the high performance rate and identifies true diagnostically challenging entities. These difficult cases may benefit from additional diagnostic work-up and second opinions. PMID- 28028832 TI - Design of experiment assisted concurrent enantioseparation of bupropion and hydroxybupropion by high-performance thin-layer chromatography. AB - A simple and efficient high-performance thin-layer chromatographic method was developed for chiral separation of rac-bupropion (BUP) and its active metabolite rac-hydroxybupropion (HBUP). Design of experiment (DoE)-based optimization was adopted instead of a conventional trial-and-error approach. The Box-Behnken design surface response model was used and the operating variables were optimized based on 17 trials design. The optimized method involved impregnation of chiral reagent, L(+)-tartaric acid, in the stationary phase with simultaneous addition in the mobile phase, which consisted of acetonitrile : methanol : dichloromethane : 0.50% L-tartaric acid (6.75:1.0:1.0:0.25, v/v/v/v). Under the optimized conditions, the resolution factor between the enantiomers of BUP and HBUP was 6.30 and 9.26, respectively. The limit of detection and limit of quantitation for (R)-BUP, (S)-BUP, (R,R)-HBUP, and (S,S)-HBUP were 9.23 and 30.78 ng spot-1 , 10.32 and 34.40 ng spot-1 , 12.19 and 40.65 ng spot-1 , and 14.26 and 47.53 ng spot-1 , respectively. The interaction of L-tartaric acid with analytes and their retention behavior was thermodynamically investigated using van't Hoff's plots. The developed method was validated as per the International Conference on Harmonization guidelines. Finally, the method was successfully applied to resolve and quantify the enantiomeric content from marketed tablets as well as spiked plasma samples. PMID- 28028833 TI - Incidence and predictors of edentulism among south Brazilian older adults. AB - OBJECTIVE: To identify socioeconomic, demographic, behavioural and clinical predictors of the 8-year incidence of edentulism in south Brazilian older adults. METHODS: Cohort of a representative sample of older persons in Carlos Barbosa, a south Brazil city. A cohort study was conducted using a simple random sample of 392 older people evaluated in 2004, with follow-ups in 2008 and 2012, when 199 participants were evaluated. Interviews and oral examinations were conducted. The baseline assessment was carried out in 2004, with follow-ups in 2008 and 2012. To evaluate the predictors of edentulism, Poisson regression models with robust variance were carried out. The outcome was modelled through the use of a hierarchical approach based on the conceptual framework proposed by Andersen and Davidson. RESULTS: Some 11.5% of the participants had become edentulous after 8 years. Higher income, use of partial removable dentures and low salivary flow were associated with the incidence of edentulism. CONCLUSIONS: Maintaining a good salivary function may be essential for the prevention of the incidence of edentulism in this age group. Furthermore, our findings suggest that rehabilitations with partial removable dentures may be detrimental to long-term oral health. PMID- 28028834 TI - The association between undiagnosed glycaemic abnormalities and cardiometabolic risk factors with periodontitis: results from 2007-2009 Canadian Health Measures Survey. AB - AIM: The aim was to investigate the association between undiagnosed glycaemic abnormalities and cardiometabolic risk factors with periodontitis. METHODS: Using Cycle 1 (2007-2009) of Canadian Health Measures Survey, survey-sampling weights were applied to a restricted sample of fasting, non-pregnant adults between 19 and 79 years of age without diagnosed or treated type 2 diabetes. We estimated the prevalence of periodontitis and various cardiometabolic risk factors according to the clinical diagnostic definition for metabolic syndrome (MetS), recognized by the American Heart Association and National Heart, Lung, and Blood Institute. Adjusted logistic regression models were used to estimate prevalence odds ratios (PORs) examining the association between cardiometabolic risk factors and periodontitis among dentate adults with available attachment loss measures. RESULTS: The prevalence of combined moderate-to-severe periodontitis was 17.93% (95% CI 15.85, 20.02). Hyperglycaemia (fasting plasma glucose (FPG) >= 5.6 mmol/l) was significantly associated with periodontitis, POR = 1.60 (95% (CI) 1.04, 2.45), but was no longer significant after controlling for socioeconomic status variables. Central adiposity, dyslipidaemia and hypertension were not associated with periodontitis. CONCLUSION: Glucose disruption measured by FPG was associated with periodontitis; however, no association was observed with other cardiometabolic risk factors or MetS in a cross-sectional, nationally representative sample of Canadian adults. PMID- 28028835 TI - TIMP4 expression is regulated by miR-200b-3p in prostate cancer cells. AB - In prostate cancer TIMP4 expression level fluctuates with tumor progression. The mechanism and factors influencing its expression remain unclear. The aim of the study was to test the hypothesis on regulation of TIMP4 by microRNA-200b-3p. The levels of TIMP4 and miR-200b-3p expression were determined by real time PCR in 27 prostate carcinomas and eight benign prostatic hyperplasia samples. We found that miR-200b-3p positively correlated with TIMP4 expression in cancer samples (r = 0.46; p < 0.02). Moreover, mean miR-200b-3p level and TIMP4 expression were both higher in cancer tissues compared to benign prostatic hyperplasia samples (p > 0.05). Next, to test probable mechanisms of the regulation androgen-sensitive human prostate adenocarcinoma cells (LNCaP) were transfected with synthetic-miR 200b-3p or its synthetic antagonist. Modulation of miR-200b-3p in LNCaP cells had an impact on TIMP4 expression confirming the observation made in analyzed clinical samples. Two targets of miR-200b-3p: ZEB1 and ETS1 were investigated subsequently as potential regulators of TIMP4, however, no effect of their modulation on TIMP4 expression in LNCaP cells was found. Concluding, miR-200b-3p mediates regulation of TIMP4 expression in prostate cancer but exact mechanism needs to be investigated. PMID- 28028836 TI - Does physical education influence eye-hand coordination? The Lifestyles of our Kids intervention study. AB - In Australian government-funded primary schools, the responsibility for physical education (PE) falls mainly on general classroom teachers, many of whom possess limited PE training. This study sought to examine the impact of specialist-taught PE on eye-hand coordination (EHC) development. In this 4-year cluster-randomized intervention, participants were 187 boys and 172 girls initially in grade 2 in 29 primary schools, where no school employed university-trained specialist PE teachers. In 13 (intervention) schools, specialist PE teachers conducted 268 PE classes (two 45-minute sessions/wk) from grade 2 to grade 6. The intervention was based on traditional PE educational objectives, including fundamental motor skills, but did not specifically focus on EHC. The remaining 16 (control) schools continued with common-practice PE taught by general classroom teachers (30-60 min/wk). EHC was measured by a ball throw and wall-rebound catch test and recorded at ages 8, 10, and 12 (SD 0.3) at ends of grades 2, 4, and 6, respectively. There was steady yearly improvement of EHC in both groups, but no evidence of any intervention effect in boys (P=.88) or girls (P=.20). The introduction of specialist-taught PE during 4 years of primary school did not influence EHC development. Considering evidence that classroom teachers make little contribution to PE in this jurisdiction, together with the steady progression of EHC over the 4 years, other influences such as organized sport, after-school activities, natural development, and parental instruction are conceivably more influential factors in EHC development during primary school years. PMID- 28028837 TI - A novel mechanism of tandem activation of ryanodine receptors by cytosolic and SR luminal Ca2+ during excitation-contraction coupling in atrial myocytes. AB - KEY POINTS: In atrial myocytes excitation-contraction coupling is strikingly different from ventricle because atrial myocytes lack a transverse tubule membrane system: Ca2+ release starts in the cell periphery and propagates towards the cell centre by Ca2+ -induced Ca2+ release from the sarcoplasmic reticulum (SR) Ca2+ store. The cytosolic Ca2+ sensitivity of the ryanodine receptor (RyRs) Ca2+ release channel is low and it is unclear how Ca2+ release can be activated in the interior of atrial cells. Simultaneous confocal imaging of cytosolic and intra-SR calcium revealed a transient elevation of store Ca2+ that we termed 'Ca2+ sensitization signal'. We propose a novel paradigm of atrial ECC that is based on tandem activation of the RyRs by cytosolic and luminal Ca2+ through a 'fire-diffuse-uptake-fire' (or FDUF) mechanism: Ca2+ uptake by SR Ca2+ pumps at the propagation front elevates Ca2+ inside the SR locally, leading to luminal RyR sensitization and lowering of the cytosolic Ca2+ activation threshold. ABSTRACT: In atrial myocytes Ca2+ release during excitation-contraction coupling (ECC) is strikingly different from ventricular myocytes. In many species atrial myocytes lack a transverse tubule system, dividing the sarcoplasmic reticulum (SR) Ca2+ store into the peripheral subsarcolemmnal junctional (j-SR) and the much more abundant central non-junctional (nj-SR) SR. Action potential (AP)-induced Ca2+ entry activates Ca2+ -induced Ca2+ release (CICR) from j-SR ryanodine receptor (RyR) Ca2+ release channels. Peripheral elevation of [Ca2+ ]i initiates CICR from nj-SR and sustains propagation of CICR to the cell centre. Simultaneous confocal measurements of cytosolic ([Ca2+ ]i ; with the fluorescent Ca2+ indicator rhod-2) and intra-SR ([Ca2+ ]SR ; fluo-5N) Ca2+ in rabbit atrial myocytes revealed that Ca2+ release from j-SR resulted in a cytosolic Ca2+ transient of higher amplitude compared to release from nj-SR; however, the degree of depletion of j-SR [Ca2+ ]SR was smaller than nj-SR [Ca2+ ]SR . Similarly, Ca2+ signals from individual release sites of the j-SR showed a larger cytosolic amplitude (Ca2+ sparks) but smaller depletion (Ca2+ blinks) than release from nj-SR. During AP-induced Ca2+ release the rise of [Ca2+ ]i detected at individual release sites of the nj-SR preceded the depletion of [Ca2+ ]SR , and during this latency period a transient elevation of [Ca2+ ]SR occurred. We propose that Ca2+ release from nj-SR is activated by cytosolic and luminal Ca2+ (tandem RyR activation) via a novel 'fire diffuse-uptake-fire' (FDUF) mechanism. This novel paradigm of atrial ECC predicts that Ca2+ uptake by sarco-endoplasmic reticulum Ca2+ -ATPase (SERCA) at the propagation front elevates local [Ca2+ ]SR , leading to luminal RyR sensitization and lowering of the activation threshold for cytosolic CICR. PMID- 28028838 TI - Long-term tooth retention in chronic periodontitis - results after 18 years of a conservative periodontal treatment regimen in a university setting. AB - AIM: The longitudinal study assessed the risk of tooth loss under a non regenerative treatment regimen and aimed to identify prognostic factors for tooth loss. METHODS: Three hundred and fifteen patients (8009 teeth) were examined before (T0) and after active periodontal therapy (APT, T1) as well as after (mean +/- SD) 18 +/- 6 years of supportive periodontal therapy (SPT, T2). Descriptive statistics and a Cox proportional hazards shared-frailty model were applied. RESULTS: Overall, 351 and 816 teeth were lost during APT and SPT, respectively, with 0.15 +/- 0.17 teeth being lost per patient and year. Seventy-two percentage patients lost 0-3, 24% 4-9 and 4% >=10 teeth. The proportion of teeth with probing-pocket depths (PPD) >6 mm was 17.2% (T0), 1.6% (T1) and remained stable at 1.7% up to T2. Tooth loss during SPT was significantly increased in older patients [HR (95% CI): 1.04 (1.01-1.07) per year] and smokers [2.62 (1.34-5.14)], with each mm of PPD [1.35 (1.17-1.56)], in multirooted compared with single rooted teeth [1.86 (1.36-2.56)] and teeth with bone loss [BL; HR up to 23.6 (12.1 45.6) for BL > 70%]. CONCLUSION: The risk of tooth loss was generally low under the provided non-regenerative treatment regimen; a minority of patients were responsible for the majority of teeth lost during SPT. PMID- 28028839 TI - Streptococcus pneumoniae IgA1 protease: A metalloprotease that can catalyze in a split manner in vitro. AB - IgA1 proteases (IgA1P) from diverse pathogenic bacteria specifically cleave human immunoglobulin A1 (IgA1) at the hinge region, thereby thwarting protective host immune responses. Streptococcus pneumoniae (S. pneumoniae) IgA1P shares no sequence conservation with serine or cysteine types of IgA1Ps or other known proteins, other than a conserved HExxH Zn-binding motif (1604-1608) found in metalloproteases. We have developed a novel expression system to produce the mature S. pneumoniae IgA1P and we have discovered that this form is both attached to the bacterial cell surface and released in its full form. Our data demonstrate that the S. pneumoniae IgA1P comprises two distinct regions that associate to form an active metalloprotease, the first such example of a metalloprotease that can be split in vitro and recombined to form an active enzyme. By capitalizing on this novel domain architecture, we show that the N-terminal region of S. pneumoniae IgA1P comprises the primary binding region for IgA1, although the C terminal region of S. pneumoniae IgA1P is necessary for cleavage of IgA1. Our findings lend insight into the protein domain architecture of the S. pneumoniae IgA1P and function of this important virulence factor for S. pneumoniae infection. PMID- 28028840 TI - Pain duration is associated with increased muscle sympathetic nerve activity in patients with Achilles tendinopathy. AB - Tendinopathy is a common condition, which has been linked to surrogate measures of sympathetic nervous system (SNS) activity and insulin resistance. This study aimed to compare in vivo measures of the SNS and insulin resistance between individuals with and without Achilles tendinopathy. This case-control study compared Achilles tendinopathy sufferers to healthy controls. SNS activity was quantified using muscle sympathetic nerve activity (MSNA), while metabolic status was assessed via a modified glucose tolerance test and fasting lipid panel. Ultrasound tissue characterization assessed tendon structure. Resting MSNA did not differ between the 15 cases and 20 controls. Tendon pain duration in tendinopathy patients was correlated with burst frequency (R2 =.32, P=.02) and burst incidence (R2 =.41, P=.01) of MSNA. After adjusting for multiple comparisons, there was a trend suggesting fasting glucose was greater in cases (median 4.80, IQR .70 in cases vs 4.51, .38 in controls) and correlated with pain severity (R2 =.14, P=.03), but no other metabolic measures were associated with tendon pain/structure. This study indicates that SNS activity is associated with tendon pain duration, building on previous data indicating the SNS is involved in recalcitrant tendinopathy. Metabolic parameters had little relationship with Achilles tendinopathy in this metabolically homogenous sample. Prospective studies are required to uncover the precise relationship between SNS activity, insulin resistance, and tendinopathy. PMID- 28028841 TI - Functional similarities between the dictyostelium protein AprA and the human protein dipeptidyl-peptidase IV. AB - Autocrine proliferation repressor protein A (AprA) is a protein secreted by Dictyostelium discoideum cells. Although there is very little sequence similarity between AprA and any human protein, AprA has a predicted structural similarity to the human protein dipeptidyl peptidase IV (DPPIV). AprA is a chemorepellent for Dictyostelium cells, and DPPIV is a chemorepellent for neutrophils. This led us to investigate if AprA and DPPIV have additional functional similarities. We find that like AprA, DPPIV is a chemorepellent for, and inhibits the proliferation of, D. discoideum cells, and that AprA binds some DPPIV binding partners such as fibronectin. Conversely, rAprA has DPPIV-like protease activity. These results indicate a functional similarity between two eukaryotic chemorepellent proteins with very little sequence similarity, and emphasize the usefulness of using a predicted protein structure to search a protein structure database, in addition to searching for proteins with similar sequences. PMID- 28028842 TI - First approach in the implementation of the nucleic acid amplification test in a resource-limited blood bank in Mexico. PMID- 28028843 TI - Epitaxial Growth and Air-Stability of Monolayer Antimonene on PdTe2. AB - Monolayer antimonene is fabricated on PdTe2 by an epitaxial method. Monolayer antimonene is theoretically predicted to have a large bandgap for nanoelectronic devices. Air-exposure experiments indicate amazing chemical stability, which is great for device fabrication. A method to fabricate high-quality monolayer antimonene with several great properties for novel electronic and optoelectronic applications is provided. PMID- 28028844 TI - Improved TLC Bioautographic Assay for Qualitative and Quantitative Estimation of Tyrosinase Inhibitors in Natural Products. AB - INTRODUCTION: TLC bioautography for tyrosinase inhibitors has made recent progress; however, an assay with a relative low consumption of enzyme and quantitative capability would greatly advance the efficacy of related TLC bioautographic assays. OBJECTIVE: An improved TLC bioautographic assay for detecting tyrosinase inhibitors was developed and validated in this study. METHODS: L-DOPA (better water-solubility than L-tyrosine) was used as the substrate instead of reported L-tyrosine. The effects of enzyme and substrate concentrations, reaction temperatures and times, and pH values of the reaction system as well as different plate types on the TLC bioautographic assay were optimised. The quantitative analysis was conducted by densitometric scanning of spot areas, and expressed as the relative tyrosinase inhibitory capacity (RTIC) using a positive control (kojic acid) equivalent. RESULTS: The limit of detection (LOD) of this assay was 1.0 ng for kojic acid. This assay has acceptable accuracy (101.73-102.90%), intra- and inter-day, and intra- and inter-plate precisions [relative standard deviation (RSD), less than 7.0%], and ruggedness (RSD, less than 3.5%). The consumption of enzyme (75 U/mL) is relatively low. Two tyrosinase inhibitory compounds including naringenin and 1-O-beta-D-glucopyranosyl-4 allylbenzene have been isolated from Rhodiola sacra guided by this TLC bioautographic assay. CONCLUSION: Our improved assay is a relatively low-cost, sensitive, and quantitative method compared to the reported TLC bioautographic assays. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28028845 TI - Genomewide SNP data reveal cryptic phylogeographic structure and microallopatric divergence in a rapids-adapted clade of cichlids from the Congo River. AB - The lower Congo River is a freshwater biodiversity hot spot in Africa characterized by some of the world's largest rapids. However, little is known about the evolutionary forces shaping this diversity, which include numerous endemic fishes. We investigated phylogeographic relationships in Teleogramma, a small clade of rheophilic cichlids, in the context of regional geography and hydrology. Previous studies have been unable to resolve phylogenetic relationships within Teleogramma due to lack of variation in nuclear genes and discrete morphological characters among putative species. To sample more broadly across the genome, we analysed double-digest restriction-associated sequencing (ddRAD) data from 53 individuals across all described species in the genus. We also assessed body shape and mitochondrial variation within and between taxa. Phylogenetic analyses reveal previously unrecognized lineages and instances of microallopatric divergence across as little as ~1.5 km. Species ranges appear to correspond to geographic regions broadly separated by major hydrological and topographic barriers, indicating these features are likely important drivers of diversification. Mitonuclear discordance indicates one or more introgressive hybridization events, but no clear evidence of admixture is present in nuclear genomes, suggesting these events were likely ancient. A survey of female fin patterns hints that previously undetected lineage-specific patterning may be acting to reinforce species cohesion. These analyses highlight the importance of hydrological complexity in generating diversity in certain freshwater systems, as well as the utility of ddRAD-Seq data in understanding diversification processes operating both below and above the species level. PMID- 28028846 TI - Ternary NiCo2 Px Nanowires as pH-Universal Electrocatalysts for Highly Efficient Hydrogen Evolution Reaction. AB - A bimetallic-structured ternary phosphide (NiCo2 Px ) as a novel pH-universal electrocatalyst for hydrogen evolution reaction is presented. It exhibits both high activity and long-term stability in all the tested alkaline, neutral, and acidic media. The excellent catalytic performance endows it with a bright future in the large-scale electrochemical water splitting industry. PMID- 28028847 TI - Muscle excitability during sustained maximal voluntary contractions by a separate analysis of the M-wave phases. AB - This study was designed to examine separately the changes in the first and second phases of the muscle compound action potential (M-wave) during and after a sustained 3-minutes maximal voluntary contraction (MVC). M-waves were evoked by supramaximal single shocks to the femoral nerve given at 10-seconds intervals throughout a sustained isometric 3-minutes MVC and also during six brief MVCs performed throughout a 30-minutes recovery period. The amplitude, duration, and area of the M-wave first and second phases, together with muscle conduction velocity and force, were measured. During the 3-minutes MVC, the amplitude of the first phase increased progressively for the first minute (33%-43%, P<.01) and remained stable thereafter, whereas the second phase initially increased for 25 35 seconds (30%-50%, P<.01), but subsequently decreased significantly before stabilizing. During the recovery period, the amplitude of the M-wave first phase showed a decreasing trend, returning to pre-fatigue values (P>.01) within 5-10 minutes, while the second phase increased progressively and remained higher than control (7%-20%, P<.01) after the 30-minutes recovery time. Maximal cross correlations between the time course of the first phase amplitude and those of conduction velocity and force (0.9-0.93) occurred for a lag of 0 seconds, whereas maximal cross-correlations corresponding to the second-phase amplitude (0.6-0.7) occurred for a 50-seconds time lag. The present findings indicate that the potentiation of the first phase results from impaired muscle membrane excitability. The peak-to-peak amplitude and second-phase amplitude are not valid indicators of muscle excitability as they might be critically affected by muscle architectural features. PMID- 28028848 TI - Functional Pyrimidine-Based Thermally Activated Delay Fluorescence Emitters: Photophysics, Mechanochromism, and Fabrication of Organic Light-Emitting Diodes. AB - A new series of molecules, T1-T4, possessing thermally activated delayed fluorescence (TADF) have been strategically designed and synthesized. Molecules T1-T4 contain the dimethyl acridine as the electron donor, which is linked to either symmetrical or unsymmetrical diphenyl pyrimidine as an acceptor. In comparison to the ubiquitous triazine acceptor, the selection of pyrimidine as an acceptor has advantages of facile functionalization and less stabilized unoccupied pi orbitals, so that the energy gap toward the blue region can be accessed. Together with acridine donors, the resulting donor-acceptor functional materials reveal remarkable TADF properties. In the solid state, molecules T1-T4 all exhibit intriguing mechanochromism. The crystal structures, together with spectroscopy and dynamics acquired upon application of stressing, lead us to propose two types of structural arrangement that give distinct emission properties, one with and the other without TADF. Upon fabricating organic light emitting diodes, the T1-T4 films prepared from sublimation all exhibit dominant TADF behavior; this accounts for their high performance: an electroluminescent emission at lambda=490 nm, with an external quantum efficiency of 14.2 %, can be attained when T2 is used as an emitter. PMID- 28028849 TI - Butyrate stimulates adipose lipolysis and mitochondrial oxidative phosphorylation through histone hyperacetylation-associated beta3 -adrenergic receptor activation in high-fat diet-induced obese mice. AB - NEW FINDINGS: What is the central question of this study? Butyrate can prevent diet-induced obesity through increasing energy expenditure. However, it is unclear whether beta3 -adrenergic receptors (ARbeta3) mediate butyrate-induced adipose lipolysis. What is the main finding and its importance? Short-term oral administration of sodium butyrate is effective in alleviating diet-induced obesity through activation of ARbeta3-mediated lipolysis in white adipose tissue. Butyrate can prevent diet-induced obesity through increasing energy expenditure. However, it is unclear whether ARbeta3 mediates butyrate-induced adipose lipolysis. In this study, weaned mice were were fed control (Con) or high-fat (HF) diet for 8 weeks to establish obesity. High-fat diet-induced obese mice maintained on the HF diet were divided into two subgroups; the HFB group was gavaged with 80 mg sodium butyrate (SB) per mouse every other day for 10 days, whereas the HF group received vehicle. Chromatin immunoprecipitation assay was performed to determine the status of histone H3 lysine 9 acetylation (H3K9Ac) on the promoter of the beta3 -adrenergic receptor (ARbeta3) gene in epididymal white adipose tissue. It was shown that five gavage doses of SB significantly alleviated HF diet-induced obesity and restored plasma leptin concentration to the control level. Protein contents of ARbeta3 and PKA, as well as ATGL and p-HSL (Ser563), were significantly upregulated in the HFB group compared with the HF group. Mitochondrial oxidative phosphorylation was enhanced by SB treatment. Sodium butyrate significantly increased the expression of four out of 13 mitochondrial DNA-encoded genes and significantly upregulated the protein contents of peroxisome proliferator-activated receptor-gamma coactivator 1alpha and COX4. Moreover, SB administration enhanced the expression of ARbeta3 and its downstream signalling. The G protein-coupled receptor 43 and p-CREB (Ser133) were significantly stimulated by SB. In addition, an active transcription marker, H3K9Ac, was significantly enriched on the promoter of the ARbeta3 gene. Our results indicate that short-term oral administration of SB is effective in alleviating diet-induced obesity through activation of the ARbeta3-mediated lipolysis in the epididymal white adipose tissue. PMID- 28028850 TI - History, geography and host use shape genomewide patterns of genetic variation in the redheaded pine sawfly (Neodiprion lecontei). AB - Divergent host use has long been suspected to drive population differentiation and speciation in plant-feeding insects. Evaluating the contribution of divergent host use to genetic differentiation can be difficult, however, as dispersal limitation and population structure may also influence patterns of genetic variation. In this study, we use double-digest restriction-associated DNA (ddRAD) sequencing to test the hypothesis that divergent host use contributes to genetic differentiation among populations of the redheaded pine sawfly (Neodiprion lecontei), a widespread pest that uses multiple Pinus hosts throughout its range in eastern North America. Because this species has a broad range and specializes on host plants known to have migrated extensively during the Pleistocene, we first assess overall genetic structure using model-based and model-free clustering methods and identify three geographically distinct genetic clusters. Next, using a composite-likelihood approach based on the site frequency spectrum and a novel strategy for maximizing the utility of linked RAD markers, we infer the population topology and date divergence to the Pleistocene. Based on existing knowledge of Pinus refugia, estimated demographic parameters and patterns of diversity among sawfly populations, we propose a Pleistocene divergence scenario for N. lecontei. Finally, using Mantel and partial Mantel tests, we identify a significant relationship between genetic distance and geography in all clusters, and between genetic distance and host use in two of three clusters. Overall, our results indicate that Pleistocene isolation, dispersal limitation and ecological divergence all contribute to genomewide differentiation in this species and support the hypothesis that host use is a common driver of population divergence in host-specialized insects. PMID- 28028851 TI - Review on the effects of potential prebiotics on controlling intestinal enteropathogens Salmonella and Escherichia coli in pig production. AB - Salmonella enterica serotypes (Salmonella sp.) are the second cause of bacterial foodborne zoonoses in humans after campylobacteriosis. Pork is the third most important cause for outbreak-associated salmonellosis, and colibacillosis is the most important disease in piglets and swine. Attachment to host cells, translocation of effector proteins into host cells, invasion and replication in tissues are the vital virulence steps of these pathogens that help them to thrive in the intestinal environment and invade tissues. Feed contamination is an important source for Salmonella infection in pig production. Many on-farm feeding strategies intervene to avoid the introduction of pathogens onto the farm by contaminated feeds or to reduce infection pressure when pathogens are present. Among the latter, prebiotics could be effective at protecting against these enteric bacterial pathogens. Nowadays, a wide range of molecules can potentially serve as prebiotics. Here, we summarize the prevalence of Salmonella sp. and Escherichia coli in pigs, understanding of the mechanisms by which pathogens can cause disease, the feed related to pathogen contamination in pigs and detail the mechanisms on which prebiotics are likely to act in order to fulfil their protective action against these pathogens in pig production. Many different mechanisms involve the inhibition of Salmonella and E. coli by prebiotics such as coating the host surface, modulation of intestinal ecology, downregulating the expression of adhesin factors or virulence genes, reinforcing the host immune system. PMID- 28028852 TI - Structural investigation on WlaRG from Campylobacter jejuni: A sugar aminotransferase. AB - Campylobacter jejuni is a Gram-negative bacterium that represents a leading cause of human gastroenteritis worldwide. Of particular concern is the link between C. jejuni infections and the subsequent development of Guillain-Barre syndrome, an acquired autoimmune disorder leading to paralysis. All Gram-negative bacteria contain complex glycoconjugates anchored to their outer membranes, but in most strains of C. jejuni, this lipoglycan lacks the O-antigen repeating units. Recent mass spectrometry analyses indicate that the C. jejuni 81116 (Penner serotype HS:6) lipoglycan contains two dideoxyhexosamine residues, and enzymological assay data show that this bacterial strain can synthesize both dTDP-3-acetamido-3,6 dideoxy-d-glucose and dTDP-3-acetamido-3,6-dideoxy-d-galactose. The focus of this investigation is on WlaRG from C. jejuni, which plays a key role in the production of these unusual sugars by functioning as a pyridoxal 5'-phosphate dependent aminotransferase. Here, we describe the first three-dimensional structures of the enzyme in various complexes determined to resolutions of 1.7 A or higher. Of particular significance are the external aldimine structures of WlaRG solved in the presence of either dTDP-3-amino-3,6-dideoxy-d-galactose or dTDP-3-amino-3,6-dideoxy-d-glucose. These models highlight the manner in which WlaRG can accommodate sugars with differing stereochemistries about their C-4' carbon positions. In addition, we present a corrected structure of WbpE, a related sugar aminotransferase from Pseudomonas aeruginosa, solved to 1.3 A resolution. PMID- 28028853 TI - In vitro labeling strategies for in cellulo fluorescence microscopy of single ribonucleoprotein machines. AB - RNA plays a fundamental, ubiquitous role as either substrate or functional component of many large cellular complexes-"molecular machines"-used to maintain and control the readout of genetic information, a functional landscape that we are only beginning to understand. The cellular mechanisms for the spatiotemporal organization of the plethora of RNAs involved in gene expression are particularly poorly understood. Intracellular single-molecule fluorescence microscopy provides a powerful emerging tool for probing the pertinent mechanistic parameters that govern cellular RNA functions, including those of protein coding messenger RNAs (mRNAs). Progress has been hampered, however, by the scarcity of efficient high yield methods to fluorescently label RNA molecules without the need to drastically increase their molecular weight through artificial appendages that may result in altered behavior. Herein, we employ T7 RNA polymerase to body label an RNA with a cyanine dye, as well as yeast poly(A) polymerase to strategically place multiple 2'-azido-modifications for subsequent fluorophore labeling either between the body and tail or randomly throughout the tail. Using a combination of biochemical and single-molecule fluorescence microscopy approaches, we demonstrate that both yeast poly(A) polymerase labeling strategies result in fully functional mRNA, whereas protein coding is severely diminished in the case of body labeling. PMID- 28028854 TI - HPLC-ELSD Quantification and Centrifugal Partition Chromatography Isolation of 8 O-Acetylharpagide from Oxera coronata (Lamiaceae). AB - INTRODUCTION: Iridoid glycosides possess highly functionalised monoterpenoid aglycon with several contiguous stereocentres. For the most common, they are often present in quantities reaching several percentage of the fresh plant weight, and thus they may be regarded as starting material for the synthesis of a number of new chiral and bioactive molecules. OBJECTIVE: To quantify and to isolate 8-O-acetylharpagide (AH) from several extracts of Oxera coronata R.P.J. de Kok, a Lamiaceae species endemic to New Caledonia, using HPLC-ELSD (evaporative light scattering detector) and centrifugal partition chromatography (CPC). METHODOLOGY: Oxera coronata produces high amounts of AH in leaves, twigs and fruits. Water and methanol extracts of these plant parts were prepared. The content of AH in each extract was quantified by HPLC-ELSD, using acetonitrile water (+0.1% formic acid) gradient elution. The HPLC method was validated for precision, linearity, limit of detection (LOD), limit of quantification (LOQ) and accuracy. A ternary solvent system ethyl acetate/n-propanol/water (3:2:5, v/v/v) was selected and applied to recover the target compound using Spot CPC from the leaves aqueous extract. RESULTS: HPLC-ELSD analysis followed by CPC purification led to the efficient isolation of AH from O. coronata leaves aqueous extract. CONCLUSION: HPLC-ELSD has proven to be a well-adapted detection and quantification method for iridoid glycosides, while CPC confirmed to be an efficient technique for the isolation of polar compounds. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28028855 TI - Odds of Viral Suppression by Single-Tablet Regimens, Multiple-Tablet Regimens, and Adherence Level in HIV/AIDS Patients Receiving Antiretroviral Therapy. AB - STUDY OBJECTIVE: To evaluate the odds of achieving viral suppression in human immunodeficiency virus (HIV) patients using antiretroviral therapy as a single tablet regimen (STR) or multiple-tablet regimen (MTR). DESIGN: Retrospective cohort study. DATA SOURCES: South Carolina Medicaid medical and pharmacy paid claims data were obtained from the South Carolina Revenue and Fiscal Affairs Office; laboratory data were obtained from the South Carolina Department of Health and Environmental Control. PATIENTS: A total of 1536 patients who were dispensed a complete STR (477 patients) or MTR (1059 patients) regimen lasting at least 60 days between January 1, 2006, and December 31, 2013. MEASUREMENTS AND MAIN RESULTS: The analysis examined adherence levels and regimen type on odds of viral load suppression. Regimen adherence levels (90-94%, 85-89%, 80-84%, and less than 80%) were compared with the gold standard adherence for HIV of 95% or greater. Patients were followed from index date until the earliest date of regimen discontinuation, treatment switch, end of study period, last date of eligibility, or death. Differences in outcomes were evaluated by chi2 , Wilcoxon rank sum statistical tests, and multivariate regression models controlling for covariates. For STR regimens we find that, when compared with 95% or greater adherence, there is no statistical difference in the odds of viral suppression with adherence levels greater than or equal to 80%. However, adherence levels greater than or equal to 95% were associated with a greater odds of viral suppression when compared with less than 80% STR adherence (odds ratio [OR] 2.57, Dunnett 95% confidence interval [CI] 1.04-6.32). For MTR regimens, there was no statistical difference in the odds of viral suppression for the adherence level 90-94% compared with the 95% or greater adherence (OR 3.59, Dunnett 95% CI 0.805 16.043). However, the 95% or greater adherence has greater odds of viral suppression compared with all other MTR adherence levels. In addition, no difference was found in the odds of viral suppression between STR and MTR for all adherence levels. CONCLUSIONS: Compared with 95% or greater adherence, STR regimens achieve viral suppression with adherence levels of 80% or greater, whereas MTR regimens require adherence levels of 90% or greater to achieve viral suppression in South Carolina Medicaid patients with HIV/AIDS. PMID- 28028856 TI - British Association of Dermatologists' national audit on nonmelanoma skin cancer excision, 2014. AB - BACKGROUND: Diagnosis and management of nonmelanoma skin cancer (NMSC) represents a large part of the dermatology workload, and complete excision is a required surgical standard for treatment. AIM: To conduct an audit of the surgical practice for the treatment of NMSC by dermatologists in the UK. METHODS: Data on 10 consecutive nonmicrographic excisions of nonmelanoma skin cancer by UK dermatologists. Data collected included site, preoperative diagnosis, histological diagnosis, proximity to previous scars, and histological deep and peripheral margins. RESULTS: A total of 227 responses from 135 centres reported 2739 excisions. Excisions on the head and neck accounted for 58.3% of cases. Tumour diameter (mean +/- SD) was 10.61 +/- 6.9 mm (maximum 130 mm), and 96.7% of cases were primary excisions, with 3.3% being re-excisions. Basal cell carcinomas (BCCs) accounted for 79.1% (n = 2167) of the total cases and squamous cell carcinomas (SCCs) for 17.9% n = 491). Of the suspected BCCs and SCCS, 94.4% (n = 2045) and 66.8% (328), respectively, were confirmed histologically to be the respective carcinomas. Similar proportions of BCC and SCC cases were within 10 mm of a previous excision. Lateral and deep margins were clear in 98.3% and 99.2% of BCC cases, respectively, and in 98.4% and 97.1% of SCC cases, respectively. Reported surgical complication rate in the audit was 3.4%. CONCLUSIONS: The majority of excisions for NMSC are for BCC and SCC. Our figures for diagnostic accuracy are at the upper range of previously published figures. Most patients were not followed up in secondary care, hence complication rates may be under reported. PMID- 28028857 TI - Cutaneous protothecosis on the bilateral wrists of a food handler. AB - Cutaneous protothecosis is caused by the achlorophyllic algae Prototheca, typically presenting as a localized plaque in immunocompetent individuals. We report a patient with bilateral erythematous plaques and pustules on her forearms, which had initially been treated with steroids for presumed eczema. Histology showed spherical spore-like bodies with internal morula-like septation, which were positive for periodic-acid-Schiff (PAS) staining, consistent with cutaneous protothecosis. Definitive treatment with oral itraconazole resulted in resolution of the lesions. PMID- 28028858 TI - Mid-face toddler excoriation syndrome (MiTES): a new paediatric diagnosis. AB - Chronic ulcerating lesions on the face are rarely seen in toddlers. Blistering disease, vasculitis, infections and self-mutilation due to neurometabolic disease can usually be excluded on clinical and histological grounds. In the absence of identifiable disease, such lesions are sometimes attributed to child abuse or fabricated illness. We describe three toddlers with chronic mid-face erosions, two from India and one from the UK. One had moderate developmental delay and one had had seizures. The lesions appeared to be self-inflicted, no underlying disease was identified and there was no suspicion of child abuse. Recognition of the same disease pattern in different continents implies a distinct pathological entity. The pattern closely resembles that seen in some patients with mutations in the pain-insensitivity genes PRDM12 and SCN11A. We suggest the term 'mid-face toddler excoriation syndrome' (MiTES) to acknowledge the existence of this condition, encourage further reports and help clarify the pathogenesis. PMID- 28028859 TI - Follicular pemphigus: an observation in patients treated with steroids. PMID- 28028860 TI - Possible association between germline methylenetetrahydrofolate reductase gene polymorphisms and psoriasis risk in a Turkish population. AB - BACKGROUND: Psoriasis is a common chronic inflammatory skin disease caused by genetic and epigenetic factors. There are conflicting results in the literature about the association between psoriasis and the methylenetetrahydrofolate reductase gene (MTHFR), ranging from strong linkage to no association. AIM: To investigate the association between the germline MTHFR polymorphisms C677T and A1298C with psoriasis risk in a Turkish population. METHODS: The study enrolled 84 patients with psoriasis and 212 healthy controls (HCs) without any history of psoriasis. DNA was extracted from peripheral blood samples of patients and HCs, and real-time PCR was used for genotyping. Results were compared by Pearson chi2 test and multiple logistic regression models. RESULTS: The frequency of both the MTHFR 677TT and A1298C (homozygous) genotypes was statistically significantly different from HCs. Point mutations were detected in all patients with early onset psoriasis (before the age of 20 years). The T allele of MTHFR 677 and the C allele of MTHFR 1298 increased psoriasis risk by 12.4- and 17.0-fold, respectively, in patients compared with HCs. CONCLUSION: A possible association was detected betweengermline MTHFR 677 C>T and 1298 A>C genotypes and psoriasis risk in a Turkish population. These results need to be confirmed in further studies with larger sample sizes. PMID- 28028861 TI - Creutzfeldt-Jakob disease. AB - This review will explore the clinical and pathological findings of the various forms of Creutzfeldt-Jakob disease (CJD). Clinical findings of CJD are characterized by rapidly progressive cognitive dysfunction, diffusion-weighted magnetic resonance imaging (DWI) hyperintensity, myoclonus, periodic sharp-wave complexes on electroencephalogram and akinetic mutism state. Neuropathologic findings of CJD are characterized by spongiform changes in gray matter, gliosis particularly hypertrophic astrocytosis-neuropil rarefaction, neuron loss and prion protein (PrP) deposition. The earliest pathological symptom observed by HE staining in the cerebral cortex is spongiform change. This spongiform change begins several months before clinical onset, and is followed by gliosis. Subsequently, neuropil rarefaction appears, followed by neuron loss. Regions showing fine vacuole-type spongiform change reflect synaptic-type PrP deposition and type 1 PrPSc deposition, whereas regions showing large confluent vacuole-type spongiform changes reflect perivacuolar-type PrP deposition and type 2 PrPSc deposition. Hyperintensities of the cerebral gray matter observed in DWI indicate the pathology of the spongiform change in CJD. The cerebral cortical lesions with large confluent vacuoles and type 2 PrPSc show higher brightness and more continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrPSc . CJD cases showing diffuse myelin pallor of cerebral white matter have been described as panencephalopathic-type, and this white matter pathology is mainly due to secondary degeneration caused by cerebral cortical involvement, particularly in regard to neuron loss. In conclusion, clinical and neuroimaging findings and neuropathologic observations are well matched in both typical and atypical cases in CJD. The clinical diagnosis of CJD is relatively easy for typical CJD cases such as the MM1-type. However, even in atypical cases it seems that clinical findings can be used for an accurate diagnosis. PMID- 28028862 TI - Evaluation of transmit efficiency and SAR for a tight fit transceiver human head phased array at 9.4 T. AB - Ultra-high field (UHF, >=7 T) tight fit transceiver phased arrays improve transmit (Tx) efficiency (B1+ /?P) in comparison with Tx-only arrays, which are usually larger to fit receive (Rx)-only arrays inside. One of the major problems limiting applications of tight fit arrays at UHFs is the anticipated increase of local tissue heating, which is commonly evaluated by the local specific absorption rate (SAR). To investigate the tradeoff between Tx efficiency and SAR when a tight fit UHF human head transceiver phased array is used instead of a Tx only/Rx-only RF system, a single-row eight-element prototype of a 400 MHz transceiver head phased array was constructed. The Tx efficiency and SAR of the array were evaluated and compared with that of a larger Tx-only array, which could also be used in combination with an 18-channel Rx-only array. Data were acquired on the Siemens Magnetom whole body 9.4 T human MRI system. Depending on the head size, positioning and the RF shim strategy, the smaller array provides from 11 to 23% higher Tx efficiency. In general, the Tx performance, evaluated as B1+ /?SAR, i.e. the safety excitation efficiency (SEE), is also not compromised. The two arrays provide very similar SEEs evaluated over 1000 random RF shim sets. We demonstrated that, in general, the tight fit transceiver array improves Tx performance without compromising SEE. However, in specific cases, the SEE value may vary, favoring one of the arrays, and therefore must be carefully evaluated. PMID- 28028864 TI - Genetic structure in the European endemic seabird, Phalacrocorax aristotelis, shaped by a complex interaction of historical and contemporary, physical and nonphysical drivers. AB - Geographically separated populations tend to be less connected by gene flow, as a result of physical or nonphysical barriers preventing dispersal, and this can lead to genetic structure. In this context, highly mobile organisms such as seabirds are interesting because the small effect of physical barriers means nonphysical ones may be relatively more important. Here, we use microsatellite and mitochondrial data to explore the genetic structure and phylogeography of Atlantic and Mediterranean populations of a European endemic seabird, the European shag, Phalacrocorax aristotelis, and identify the primary drivers of their diversification. Analyses of mitochondrial markers revealed three phylogenetic lineages grouping the North Atlantic, Spanish/Corsican and eastern Mediterranean populations, apparently arising from fragmentation during the Pleistocene followed by range expansion. These traces of historical fragmentation were also evident in the genetic structure estimated by microsatellite markers, despite significant contemporary gene flow among adjacent populations. Stronger genetic structure, probably promoted by landscape, philopatry and local adaptation, was found among distant populations and those separated by physical and ecological barriers. This study highlights the enduring effect of Pleistocene climatic changes on shag populations, especially within the Mediterranean Basin, and suggests a role for cryptic northern refugia, as well as known southern refugia, on the genetic structure of European seabirds. Finally, it outlines how contemporary ecological barriers and behavioural traits may maintain population divergence, despite long-distance dispersal triggered by extreme environmental conditions (e.g. population crashes). PMID- 28028863 TI - Stress and gender effects on prefrontal cortex oxygenation levels assessed during single and dual-task walking conditions. AB - The ability to walk is critical for functional independence and wellbeing. The pre-frontal cortex (PFC) plays a key role in cognitive control of locomotion, notably under attention-demanding conditions. Factors that influence brain responses to cognitive demands of locomotion, however, are poorly understood. Herein, we evaluated the individual and combined effects of gender and perceived stress on stride velocity and PFC Oxygenated Hemoglobin (HbO2 ) assessed during single and dual-task walking conditions. The experimental paradigm included Normal Walk (NW); Cognitive Interference (Alpha); and Walk-While-Talk (WWT) tasks. An instrumented walkway was used to assess stride velocity in NW and WWT conditions. Functional Near-Infrared-Spectroscopy (fNIRS) was used to quantify PFC HbO2 levels during NW, Alpha and WWT. Perceived task-related stress was evaluated with a single 11-point scale item. Participants were community residing older adults (age = 76.8 +/- 6.7 years; %female = 56). Results revealed that higher perceived stress was associated with greater decline in stride velocity from single to dual-task conditions among men. Three-way interactions revealed that gender moderated the effect of perceived stress on changes in HbO2 levels comparing WWT to NW and Alpha. Attenuation in the increase in HbO2 levels, in high compared to low perceived stress levels, from the two single task conditions to WWT was observed only in men. Thus, older men may be more vulnerable to the effect of perceived stress on the change in PFC oxygenation levels across walking conditions that vary in terms of cognitive demands. These findings confer important implications for assessment and treatment of individuals at risk of mobility impairments. PMID- 28028865 TI - Endemic species may have complex histories: within-refugium phylogeography of an endangered Iberian vole. AB - Glacial refugia protected and promoted biodiversity during the Pleistocene, not only at a broader scale, but also for many endemics that contracted and expanded their ranges within refugial areas. Understanding the evolutionary history of refugial endemics is especially important in the case of endangered species to recognize the origins of their genetic structure and thus produce better informed conservation practices. The Iberian Peninsula is an important European glacial refugium, rich in endemics of conservation concern, including small mammals, such as the Cabrera vole (Microtus cabrerae). This near-threatened rodent is characterized by an unusual suite of genetic, life history and ecological traits, being restricted to isolated geographic nuclei in fast-disappearing Mediterranean subhumid herbaceous habitats. To reconstruct the evolutionary history of the Cabrera vole, we studied sequence variation at mitochondrial, autosomal and sex linked loci, using invasive and noninvasive samples. Despite low overall mitochondrial and nuclear nucleotide diversities, we observed two main well supported mitochondrial lineages, west and east. Phylogeographic modelling in the context of the Cabrera vole's detailed fossil record supports a demographic scenario of isolation of two populations during the Last Glacial Maximum from a single focus in the southern part of the Iberian Peninsula. In addition, our data suggest subsequent divergence within the east, and secondary contact and introgression of the expanding western population, during the late Holocene. This work emphasizes that refugial endemics may have a phylogeographic history as rich as that of more widespread species, and conservation of such endemics includes the preservation of that genetic legacy. PMID- 28028866 TI - Factors affecting pain relief in response to physical exercise interventions among healthcare workers. AB - The aim of this study is to identify factors associated with musculo-skeletal pain reduction during workplace-based or home-based physical exercise interventions among healthcare workers. Two hundred female healthcare workers (age: 42.0, BMI: 24.1, average pain intensity: 3.1 on a scale of 0-10) from three hospitals participated. Participants were randomly allocated at the cluster level (18 departments) to 10 weeks of (i) workplace physical exercise (WORK) performed in groups during working hours for 5 * 10 minutes per week and up to five group based coaching sessions on motivation for regular physical exercise, or (ii) home based physical exercise (HOME) performed alone during leisure-time for 5 * 10 minutes per week. Linear mixed models accounting for cluster identified factors affecting pain reduction. On average 2.2 (SD: 1.1) and 1.0 (SD: 1.2) training sessions were performed per week in WORK and HOME, respectively. The multi adjusted analysis showed a significant effect on pain reduction of both training adherence (P=.04) and intervention group (P=.04) with participants in WORK experiencing greater reductions compared with HOME. Obesity at baseline was associated with better outcome. Leisure-time exercise, daily patient transfer, age, and chronic pain did not affect the changes in pain. In conclusion, even when adjusted for training adherence, performing physical exercise at the workplace is more effective than home-based exercise in reducing musculo-skeletal pain in healthcare workers. Noteworthy, obese individuals may especially benefit from physical exercise interventions targeting musculo-skeletal pain. PMID- 28028867 TI - The clinical status and economic savings associated with remission among patients with rheumatoid arthritis: leveraging linked registry and claims data for synergistic insights. AB - INTRODUCTION: Treat to target guidelines recommend achieving remission or low disease activity in rheumatoid arthritis (RA). However, the reduction in adverse events and costs associated with lower disease activity is unclear. METHODS: We used Corrona linked to Medicare data to identify RA patients. Time varying disease activity was measured using Clinical Disease Activity Index (CDAI); outcomes included all-cause hospitalization, a composite of hospitalization or emergency department (ED) visits, mortality, and medical costs. Outcome-specific Cox proportional models evaluated the adjusted hazard ratios between disease activity and outcomes, controlling for potential confounders including comorbidities grouped into four patient phenotypes. Costs were analyzed with mixed models using a Gaussian distribution with log transformation. RESULTS: Depending on outcome, 4593 RA patients contributed up to 12 001 person years. Median age was 71 years, 75% women. At baseline, approximately 50-60% of patients were in remission or low disease activity. There was a dose-response relationship between RA disease activity (remission, low, moderate, and high) and the incidence of hospitalizations (13.1, 17.8, 21.2, 27.5 per 100 py, respectively); all adjusted hazard ratios were significant: 0.68 (remission), 0.87 (low), and 1.24 (high) compared with moderate disease activity. Similar trends were observed for ED visits and mortality. The crude difference in annual medical costs between remission ($11 145) and moderate disease activity ($17 646) was $-6 500; the adjusted difference (95%CI) was $-3133 (-4737.72, -1528.43). CONCLUSION: Leveraging the benefits of linking registry and administrative data together, lower disease activity in RA was associated with incrementally reduced risks of all-cause hospitalization, ED visits, mortality, and medical costs in a dose dependent fashion. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28028868 TI - Neurometabolic profiles of the substantia nigra and striatum of MPTP-intoxicated common marmosets: An in vivo proton MRS study at 9.4 T. AB - Given the strong coupling between the substantia nigra (SN) and striatum (STR) in the early stage of Parkinson's disease (PD), yet only a few studies reported to date that have simultaneously investigated the neurochemistry of these two brain regions in vivo, we performed longitudinal metabolic profiling in the SN and STR of 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated common marmoset monkey models of PD (n = 10) by using proton MRS (1 H-MRS) at 9.4 T. T2 relaxometry was also performed in the SN by using MRI. Data were classified into control, MPTP_2weeks, and MPTP_6-10 weeks groups according to the treatment duration. In the SN, T2 of the MPTP_6-10 weeks group was lower than that of the control group (44.33 +/- 1.75 versus 47.21 +/- 2.47 ms, p < 0.05). The N-acetylaspartate to total creatine ratio (NAA/tCr) and gamma-aminobutyric acid to tCr ratio (GABA/tCr) of the MPTP_6-10 weeks group were lower than those of the control group (0.41 +/- 0.04 versus 0.54 +/- 0.08 (p < 0.01) and 0.19 +/- 0.03 versus 0.30 +/- 0.09 (p < 0.05), respectively). The glutathione to tCr ratio (GSH/tCr) was correlated with T2 for the MPTP_6-10 weeks group (r = 0.83, p = 0.04). In the STR, however, GABA/tCr of the MPTP_6-10 weeks group was higher than that of the control group (0.25 +/- 0.10 versus 0.16 +/- 0.05, p < 0.05). These findings may be an in vivo depiction of the altered basal ganglion circuit in PD brain resulting from the degeneration of nigral dopaminergic neurons and disruption of nigrostriatal dopaminergic projections. Given the important role of non-human primates in translational studies, our findings provide better understanding of the complicated evolution of PD. PMID- 28028869 TI - Leucocyte protein Trojan, a possible regulator of apoptosis. AB - Trojan is a leucocyte-specific protein, cloned from chicken embryonic thymocyte cDNA library. The molecule is a type I transmembrane protein with an extracellular CCP domain, followed by two FN3 domains. Its cytoplasmic tail is predicted to possess a MAPK docking and a PKA phosphorylation sites. Trojan has been proposed to have an anti-apoptotic role based on its differential expression on developing thymocyte subpopulations. Using a chicken cell line, our in vitro studies showed that upon apoptosis induction, Trojan expression rises dramatically on the surface of surviving cells and gradually decreases towards its normal levels as cells recover. When sorted based on their expression levels of Trojan, cells with high expression appeared less susceptible to apoptotic induction than those bearing no or low levels of Trojan on their surface. The mechanism by which the molecule exerts its function is yet to be discovered. We found that cells overexpressing Trojan from a cDNA plasmid show elevated steady state levels of intracellular calcium, suggesting the molecule is able to transmit cytoplasmic signals. The mechanistic nature of Trojan-induced signalling is a target of future investigation. In this article, we conducted a series of experiments that suggest Trojan as an anti-apoptotic regulator. PMID- 28028870 TI - Neuromuscular performance of maximal voluntary explosive concentric contractions is influenced by angular acceleration. AB - Torque production during maximal voluntary explosive contractions is considered to be a functionally more relevant neuromuscular measure than steady-state torque, but little is known about accelerated concentric contractions. This study investigated torque, muscle activity, and fascicle behavior during isometric and fast concentric contractions of quadriceps femoris. Ten participants performed maximal voluntary explosive isometric, isovelocity, and additional concentric knee extensions at angular accelerations ranging from 700 to 4000 degrees s-2 that resulted in an angular velocity of 300 degrees s-1 at 40 degrees knee flexion. Concentric torque at 40 degrees knee flexion was corrected for inertia, and the corresponding isometric torque was matched to the time when the target knee angle of 40 degrees was reached during concentric contractions. Electromyography of quadriceps femoris and hamstrings and ultrasound of vastus lateralis were measured to determine muscle activity, fascicle length, and fascicle velocity (FV). The faster the acceleration, the more torque was produced during concentric contractions at 40 degrees knee flexion, which was accompanied by a reduction in FV. In comparison with isometric conditions, concentric quadriceps muscle activity was increased and torque during accelerations >=3000 degrees s-2 equaled the time-matched isometric torque. Our results provide novel evidence that acceleration influences torque production during maximal voluntary explosive concentric contractions. This is suggested to be due to series elasticity and reduced force depression. PMID- 28028871 TI - From Composition to Cure: A Systems Engineering Approach to Anticancer Drug Carriers. AB - The molecular complexity and heterogeneity of cancer has led to a persistent, and as yet unsolved, challenge to develop cures for this disease. The pharmaceutical industry focuses the bulk of its efforts on the development of new drugs, but an alternative approach is to improve the delivery of existing drugs with drug carriers that can manipulate when, where, and how a drug exerts its therapeutic effect. For the treatment of solid tumors, systemically delivered drug carriers face significant challenges that are imposed by the pathophysiological barriers that lie between their site of administration and their site of therapeutic action in the tumor. Furthermore, drug carriers face additional challenges in their translation from preclinical validation to clinical approval and adoption. Addressing this diverse network of challenges requires a systems engineering approach for the rational design of optimized carriers that have a realistic prospect for translation from the laboratory to the patient. PMID- 28028872 TI - Photoinduced Charge Separation Catalyzed by Manganese Oxides onto a Y-Shaped Branching Acceptor Efficiently Preventing Charge Recombination. AB - A full-dimensional nonadiabatic electron wavepacket study is performed on Mn oxide catalytic charge separation to be created on an accepting molecular system, which is of Y-shaped structure and has a track-branching function for protons and electrons. This branching is necessary in cases in which the transferred electrons and protons are to be eventually carried to mutually different destinations without quick annihilation of the created pair (charge separation). However, as a result of the larger size of such a branched acceptor, the distance between the Mn oxide and the acceptor is so great that it is far from obvious whether an electron is successfully delivered through conical intersections. It is shown here that this can actually occur. PMID- 28028874 TI - Second trimester weight gain > 7 kg increases the risk of gestational diabetes after normal first trimester screening. AB - AIMS: The objective of this study was to determine the relationship between second trimester weight gain and the risk of gestational diabetes (GDM) after normal first trimester screening. METHODS: A total of 195 women at risk for GDM who had normal first trimester screening results were enrolled. The study group consisted of 65 women who had second trimester weight gain > 7 kg, while another 130 women with weight gain <= 7 kg served as the comparison group, matched 1:2 by pre-pregnancy body mass index. GDM screening was repeated during 24-28 weeks of gestation and the incidence of GDM was compared between the groups. Other possible associated factors were evaluated. RESULTS: Mean age, pre-pregnancy body mass index, parity, GDM risks, first trimester weight gain, timing of GDM screening and initial test results were comparable between the groups. The incidence of GDM was significantly higher in the study than in the comparison group (24.6% vs 10.8%, P = 0.012). Logistic regression analysis showed that second trimester weight gain >7 kg and an abnormal 1 oral glucose tolerance test value on first trimester screening independently increased the risk of GDM (adjusted odds ratio 2.6, 95% confidence interval 1.13-6.0, P = 0.025 and 8.36, 95% confidence interval 2.62-26.66, P < 0.001, respectively). CONCLUSION: Second trimester weight gain > 7 kg and an abnormal 1 oral glucose tolerance test value at first screening increased the risk of GDM in at-risk women. PMID- 28028873 TI - Development of a qualitative real-time PCR for microbiological quality control testing in mammalian cell culture production. AB - AIMS: The aim of this study was to develop and evaluate a real-time PCR technology for microbiological control methods to examine individualized cell therapeutics, an emerging class of pharmaceutical formulations. METHODS AND RESULTS: Oligonucleotide primers and hybridization probe for bacterial detection targeting the 16SrRNA gene were adapted based on Nadkarni et al. [Microbiology148 (2002) 257]. For detection of yeast and moulds, primers and probe were designed from conserved sequences of the 18SrRNA gene in this study. The real-time PCR assays were tested on genomic DNA of Escherichia coli and Candida albicans to assess efficiency and linear dynamic range. After successful establishment of robust real-time PCRs, applicability of the assays was evaluated by extracting microbial target DNA from cell-based preparations. Different commercial DNA extraction methods were compared identifying the MagNA Pure DNA Isolation Kit III as the method of choice. Sensitivity was examined for different strains and a detection limit of 102 -103 CFU per ml in a sample containing ~106 mammalian cells per ml was achieved. CONCLUSIONS: This study reports the successful establishment of two qualitative real-time PCR assays, enabling in general the broad-range detection of microbial contaminants in a cell-based sample matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: Individualized cell therapeutics tend to have a short shelf life. Due to lengthy incubation periods, compendial testing according to current pharmacopoeial guidelines may not be applicable. We report a suitable alternative method upon which future microbiological quality control methods for such products could be based on. However, to implement valid rapid microbiological testing methods using real-time PCR technology, further challenges need to be addressed. PMID- 28028876 TI - Welcome to Clinical and Experimental Allergy in 2017. PMID- 28028877 TI - Indole-associated predator-prey interactions between the nematode Caenorhabditis elegans and bacteria. AB - Indole is an intercellular and interkingdom signalling molecule found in diverse ecological niches. Caenorhabditis elegans is a bacterivorous nematode that lives in soil and compost environments and a useful model host for studies of host microbe interactions. Although various bacteria and some plants produce large quantities of extracellular indole, little is known about the effects of indole, its derivatives, or of indole-producing bacteria on the behaviours of C. elegans or other animals. Here, they show that C. elegans senses and moves toward indole and several indole-producing bacteria, but avoids non-indole producing pathogenic bacteria. Furthermore, it was found indole-producing and non-indole-producing bacteria exert divergent effects on the egg-laying behaviour of C. elegans, and that various indole derivatives also modulate chemotaxis, egg-laying behaviour and the survival of C. elegans. In contrast, indole at high concentration can kill C. elegans, which in turn, has the ability to detoxify indole by oxidation and glucosylation. Transcriptional analysis showed indole markedly up-regulated the gene expressions of cytochrome P450s, UDP-glucuronosyltransferases and glutathione S-transferase, which well explained the modification of indole by C. elegans while indole down-regulated the expressions of collagen and F-box genes. Their findings suggest that indole and its derivatives are important signalling molecules during bacteria-nematode interactions. PMID- 28028879 TI - Zika virus, coinfections and placenta. PMID- 28028880 TI - Metapopulation theory identifies biogeographical patterns among core and satellite marine bacteria scaling from tens to thousands of kilometers. AB - Metapopulation theory developed in terrestrial ecology provides applicable frameworks for interpreting the role of local and regional processes in shaping species distribution patterns. Yet, empirical testing of metapopulation models on microbial communities is essentially lacking. We determined regional bacterioplankton dynamics from monthly transect sampling in the Baltic Sea Proper using 16S rRNA gene sequencing. A strong positive trend was found between local relative abundance and occupancy of populations. Notably, the occupancy-frequency distributions were significantly bimodal with a satellite mode of rare endemic populations and a core mode of abundant cosmopolitan populations (e.g. Synechococcus, SAR11 and SAR86 clade members). Temporal changes in population distributions supported several theoretical frameworks. Still, bimodality was found among bacterioplankton communities across the entire Baltic Sea, and was also frequent in globally distributed datasets. Datasets spanning waters with widely different physicochemical characteristics or environmental gradients typically lacked significant bimodal patterns. When such datasets were divided into subsets with coherent environmental conditions, bimodal patterns emerged, highlighting the importance of positive feedbacks between local abundance and occupancy within specific biomes. Thus, metapopulation theory applied to microbial biogeography can provide novel insights into the mechanisms governing shifts in biodiversity resulting from natural or anthropogenically induced changes in the environment. PMID- 28028881 TI - The microtubule end-binding protein FgEB1 regulates polar growth and fungicide sensitivity via different interactors in Fusarium graminearum. AB - In yeasts, the end-binding protein 1 (EB1) homologs regulate microtubule dynamics, cell polarization, and chromosome stability. However, functions of EB1 orthologs in plant pathogenic fungi have not been characterized yet. Here, we observed that the FgEB1 deletion mutant (DeltaFgEB1) of Fusarium graminearum exhibits twisted hyphae, increased hyphal branching and curved conidia, indicating that FgEB1 is involved in the regulation of cellular polarity. Microscopic examination further showed that the microtubules of DeltaFgEB1 exhibited less organized in comparison with those of the wild type. In addition, the lack of FgEB1 also altered the distribution of polarity-related class I myosin via the interaction with the actin. On the other hand, we identified four core septins as FgEB1-interacting proteins, and found that FgEB1 and septins regulated conidial polar growth in the opposite orientation. Interestingly, FgEB1 and FgKar9 constituted another complex that modulated the response to carbendazim, a microtubule-damaging agent specifically. In addition, the deletion of FgEB1 led to dramatically decreased deoxynivalenol (DON) biosynthesis. Taken together, results of this study indicate that FgEB1 regulates cellular polarity, fungicide sensitivity and DON biosynthesis via different interactors in F. graminarum, which provides a novel insight into understanding of the biological functions of EB1 in filamentous fungi. PMID- 28028882 TI - Simultaneous lactic acidification and coagulation by using recombinant Lactococcus lactis strain. AB - AIMS: This study was an attempt to create a novel milk clotting procedure using a recombinant bacterium capable of milk coagulation. METHODS AND RESULTS: The Rhizomucor pusillus proteinase (RPP) gene was sub-cloned into a pALF expression vector. The recombinant pALF-RPP vector was then electro-transferred into Lactococcus lactis. Finally, the milk coagulation ability of recombinant L. lactis carrying a RPP gene was evaluated. Nucleotide sequencing of DNA insertion from the clone revealed that the RPP activity corresponded to an open reading frame consisting of 1218 bp coding for a 43.45 kDa RPP protein. The RPP protein assay results indicated that the highest RPP enzyme expression with 870 Soxhlet units (SU) per ml and 7914 SU/OD were obtained for cultures which were incubated at pH 5.5 and 30 degrees C. Interestingly, milk coagulation was observed after 205 min of inoculating milk with recombinant L. lactis carrying the RPP gene. CONCLUSION: The recombinant L. lactis carrying RPP gene has the ability to function as a starter culture for acidifying and subsequently coagulating milk by producing RPP as a milk coagulant agent. SIGNIFICANCE AND IMPACT OF THE STUDY: Creating a recombinant starter culture bacterium that is able to coagulate milk. It is significant because the recombinant L. lactis has the ability to work as a starter culture and milk coagulation agent. PMID- 28028883 TI - Plant community, geographic distance and abiotic factors play different roles in predicting AMF biogeography at the regional scale in northern China. AB - Arbuscular mycorrhizal fungi (AMF) are ubiquitous mutualists of terrestrial plants and play key roles in regulating various ecosystem processes, but little is known about AMF biogeography at regional scale. This study aims at exploring the key predictors of AMF communities across a 5000-km transect in northern China. We determined the soil AMF species richness and community composition at 47 sites representative of four vegetation types (meadow steppe, typical steppe, desert steppe and desert) and related them to plant community characteristics, abiotic factors and geographic distance. The results showed that soil pH was the strongest predictor of AMF richness and phylogenetic diversity. However, abiotic factors only have a low predictive effect on AMF community composition or phylogenetic patterns. By contrast, we found a significant relationship between community composition of AMF and plants, which was a surprising result given the extent of heterogeneity in the plant community across this transect. Moreover, the geographic distance predominantly explained the AMF phylogenetic structure, implying that history evolutionary may play a role in shaping AMF biogeographic patterns. This study highlighted the different roles of main factors in predicting AMF biogeography, and bridge landscape-scale studies to more recent global-scale efforts. This article is protected by copyright. All rights reserved. PMID- 28028884 TI - Pulmonary actinomycosis: a rare case diagnosed on bronchoalveolar lavage cytology. PMID- 28028885 TI - Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using "Click" Chemistry. AB - In a new, versatile approach to fun-ction-alizing recombinant spider silk, L azidohomoalanine is introduced residue-specifically in the minispidroin protein 4RepCT through expression in an E. coli methionine auxotroph. Both fluorophores and the antibiotic levofloxacin are attached to this bio-orthogonal amino acid using copper-catalyzed click chemistry, either before or after the silk fibers are self-assembled. PMID- 28028886 TI - Contribution of Interpersonal Problems to Eating Disorder Psychopathology via Negative Affect in Treatment-seeking Men and Women: Testing the Validity of the Interpersonal Model in an Understudied Population. AB - : Research on the psychosocial correlates and theoretical frameworks of men presenting with eating disorders (ED) psychopathology is limited. This study compared treatment-seeking men and women in terms of their levels of interpersonal functioning (affiliation and dominance), regulation of negative emotions (negative affect and instability) and ED psychopathology. The study also investigated the validity of the interpersonal model of ED in men. Results from the cross-sectional data of 388 participants (137 men and 251 women) demonstrated that the structural models fit and that paths were invariant across men and women. There were significant indirect effects of interpersonal functioning on ED psychopathology, mediated through negative affect and instability, for both men and women. Negative affect and instability partially explain the relationship between interpersonal problems and ED psychopathology in treatment-seeking men and women. Current findings highlight the need to evaluate the validity of the model using longitudinal designs to test whether men and women are likely to benefit equally from interpersonal therapies for ED. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Negative affect and instability mediated the relationship between interpersonal problems and eating disorder psychopathology for treatment-seeking men and women. There were no gender differences between levels of negative affect, emotional instability and interpersonal dysfunction, but women reported slightly higher eating concerns than men. Interpersonal model is a framework that is applicable to understanding and potentially treating men with eating disorders. PMID- 28028887 TI - Phytochemical Analysis of a Cytotoxic Fraction of Quassia silvestris using LC-HR ESI-MSn. AB - INTRODUCTION: The genus Quassia is a promising source of secondary metabolites with biological potential including antimalarial and cytotoxic activities. Limited data are available on the phytochemistry and pharmacology of Quassia silvestris Cheek & Jongkind, a Cameroonian medicinal plant used to treat various ailments. OBJECTIVES: To carry out the bioassay-guided fractionation and LC-HR ESI-MS analyses of the leaves extract from Q. silvestris; to purify the active fractions and isolate the major compounds using different chromatographic and spectroscopic methods. The obtained compounds will be evaluated for their biological activity. MATERIAL AND METHODS: Following the cytotoxic screening and LC-HR-ESI-MS profiling of fractions obtained from partition of the methanolic extract of Q. silvestris leaves, the CH2 Cl2 -soluble fraction which exhibited the highest cytotoxicity was retained for further investigations. RESULTS: Sixteen squalene-derived metabolites were identified with oxasqualenoid derivatives being the most predominant. Among the isolates, structure elucidation of two new oxasqualenoids quassiols E (1) and F (2), were achieved by NMR (one dimensional (1D) and two-dimensional (2D)) and MS methods. The newly characterised compounds 1 and 2, together with the known tetraol (3) and 3-oxo oleanoic acid (16) displayed moderate cytotoxicity. CONCLUSION: The identification and structural characterisation of highly oxidised squalene derived metabolites from this plant may provide important insight data for further pharmacological investigations. The LC-HR-ESI-MSn method reported here could be developed as a rapid and efficient tool for the analyses of structurally related compounds in the genera Quassia, Simarouba, and Eurycoma of the subfamily Simarouboideae. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28028888 TI - Laribacter hongkongensis anaerobic adaptation mediated by arginine metabolism is controlled by the cooperation of FNR and ArgR. AB - Laribacter hongkongensis is a fish-borne pathogen associated with invasive infections and gastroenteritis. Its adaptive mechanisms to oxygen-limiting conditions in various environmental niches remain unclear. In this study, we compared the transcriptional profiles of L. hongkongensis under aerobic and anaerobic conditions using RNA-sequencing. Expression of genes involved in arginine metabolism significantly increased under anoxic conditions. Arginine was exploited as the sole energy source in L. hongkongensis for anaerobic respiration via the arginine catabolism pathway: specifically via the arginine deiminase (ADI) pathway. A transcriptional regulator FNR was identified to coordinate anaerobic metabolism by tightly regulating the expression of arginine metabolism genes. FNR executed its regulatory function by binding to FNR boxes in arc operons promoters. Survival of isogenic fnr mutant in macrophages decreased significantly when compared with wild-type; and expression level of fnr increased 8 h post-infection. Remarkably, FNR directly interacted with ArgR, another regulator that influences the biological fitness and intracellular survival of L. hongkongensis by regulating arginine metabolism genes. Our results demonstrated that FNR and ArgR work in coordination to respond to oxygen changes in both extracellular and intracellular environments, by finely regulating the ADI pathway and arginine anabolism pathways, thereby optimizing bacterial fitness in various environmental niches. PMID- 28028890 TI - Evolution and significance of the triple risk model in sudden infant death syndrome. AB - Sudden infant death syndrome (SIDS) is a leading cause of death in infants, although the mechanisms leading to death remain unclear. Multiple theories have emerged over time, with one of the most influential hypotheses being the triple risk model. This model, first devised in 1972 and later revised in 1994 by Filiano and Kinney, is still widely used in assisting with conceptualising and understanding sudden death in infancy. This model has evolved over time, with each version stressing that SIDS is likely to occur when certain risk factors coincide, suggesting that the lethal mechanisms in SIDS are likely to be multifactorial. All versions of the triple risk model from 1972 to the present have emphasised the complexity of SIDS and serve as useful guides for current and future research into the enigma of sudden and unexpected death in infancy. PMID- 28028889 TI - The molecular response of the white-rot fungus Dichomitus squalens to wood and non-woody biomass as examined by transcriptome and exoproteome analyses. AB - The ability to obtain carbon and energy is a major requirement to exist in any environment. For several ascomycete fungi, (post-)genomic analyses have shown that species that occupy a large variety of habitats possess a diverse enzymatic machinery, while species with a specific habitat have a more focused enzyme repertoire that is well-adapted to the prevailing substrate. White-rot basidiomycete fungi also live in a specific habitat, as they are found exclusively in wood. In this study, we evaluated how well the enzymatic machinery of the white-rot fungus Dichomitus squalens is tailored to degrade its natural wood substrate. The transcriptome and exoproteome of D. squalens were analyzed after cultivation on two natural substrates, aspen and spruce wood, and two non woody substrates, wheat bran and cotton seed hulls. D. squalens produced ligninolytic enzymes mainly at the early time point of the wood cultures, indicating the need to degrade lignin to get access to wood polysaccharides. Surprisingly, the response of the fungus to the non-woody polysaccharides was nearly as good a match to the substrate composition as observed for the wood polysaccharides. This indicates that D. squalens has preserved its ability to efficiently degrade plant biomass types not present in its natural habitat. PMID- 28028891 TI - A decade of irrigation transforms the soil microbiome of a semi-arid pine forest. AB - The impact of climate change on the soil microbiome potentially alters the biogeochemical cycle of terrestrial ecosystems. In semi-arid environments, water availability is a major constraint on biogeochemical cycles due to the combination of high summer temperatures and low rainfall. Here, we explored how 10 years of irrigation of a water-limited pine forest in the central European Alps altered the soil microbiome and associated ecosystem functioning. A decade of irrigation stimulated tree growth, resulting in higher crown cover, larger yearly increments of tree biomass, increased litter fall and greater root biomass. Greater amounts of plant-derived inputs associated with increased primary production in the irrigated forest stands stimulated soil microbial activity coupled with pronounced shifts in the microbiome from largely oligotrophic to more copiotrophic lifestyles. Microbial groups benefitting from increased resource availabilities (litter, rhizodeposits) thrived under irrigation, leading to enhanced soil organic matter mineralization and carbon respired from irrigated soils. This unique long-term study provides new insights into the impact of precipitation changes on the soil microbiome and associated ecosystem functioning in a water-limited pine forest ecosystem and improves our understanding of the persistency of long-term soil carbon stocks in a changing climate. PMID- 28028892 TI - QTL-seq approach identified genomic regions and diagnostic markers for rust and late leaf spot resistance in groundnut (Arachis hypogaea L.). AB - Rust and late leaf spot (LLS) are the two major foliar fungal diseases in groundnut, and their co-occurrence leads to significant yield loss in addition to the deterioration of fodder quality. To identify candidate genomic regions controlling resistance to rust and LLS, whole-genome resequencing (WGRS)-based approach referred as 'QTL-seq' was deployed. A total of 231.67 Gb raw and 192.10 Gb of clean sequence data were generated through WGRS of resistant parent and the resistant and susceptible bulks for rust and LLS. Sequence analysis of bulks for rust and LLS with reference-guided resistant parent assembly identified 3136 single-nucleotide polymorphisms (SNPs) for rust and 66 SNPs for LLS with the read depth of >=7 in the identified genomic region on pseudomolecule A03. Detailed analysis identified 30 nonsynonymous SNPs affecting 25 candidate genes for rust resistance, while 14 intronic and three synonymous SNPs affecting nine candidate genes for LLS resistance. Subsequently, allele-specific diagnostic markers were identified for three SNPs for rust resistance and one SNP for LLS resistance. Genotyping of one RIL population (TAG 24 * GPBD 4) with these four diagnostic markers revealed higher phenotypic variation for these two diseases. These results suggest usefulness of QTL-seq approach in precise and rapid identification of candidate genomic regions and development of diagnostic markers for breeding applications. PMID- 28028893 TI - Little effect of climate change on body size of herbivorous beetles. AB - Ongoing climate change affects various aspects of an animal's life, with important effects on distribution range and phenology. The relationship between global warming and body size changes in mammals and birds has been widely studied, with most findings indicating a decline in body size over time. Nevertheless, little data exist on similar size change patterns of invertebrates in general and insects in particular, and it is unclear whether insects should decrease in size or not with climate warming. We measured over 4000 beetle specimens, belonging to 29 beetle species in 8 families, collected in Israel during the last 100 years. The sampled species are all herbivorous. We examined whether beetle body size had changed over the years, while also investigating the relationships between body size and annual temperature, precipitation, net primary productivity (NPP) at the collection site and collection month. None of the environmental variables, including the collection year, was correlated with the size of most of the studied beetle species, while there were strong interactions of all variables with species. Our results, though mostly negative, suggest that the effect of climate change on insect body size is species-specific and by no means a general macro-ecological rule. They also suggest that the intrapopulation variance in body size of insects collected as adults in the field is large enough to conceal intersite environmental effects on body size, such as the effect of temperature and NPP. PMID- 28028894 TI - Attacking 22 entries in rugby union: running demands and differences between successful and unsuccessful entries. AB - Global Positioning System (GPS) technology is commonly utilized in team sports, including rugby union. It has been used to describe the average running demands of rugby union. This has afforded an enhanced understanding of the physical fitness requirements for players. However, research in team sports has suggested that training players relative to average demands may underprepare them for certain scenarios within the game. To date, no research has investigated the running demands of attacking 22 entries in rugby union. Additionally, no research has been undertaken to determine whether differences exist in the running intensity of successful and unsuccessful attacking 22 entries in rugby union. The first aim of this study was to describe the running intensity of attacking 22 entries. The second aim of this study was to investigate whether differences exist in the running intensity of successful and unsuccessful attacking 22 entries. Running intensity was measured using meters per minute (m min-1 ) for (a) total distance, (b) running distance, (c) high-speed running distance, and (d) very high-speed running distance. This study provides normative data for the running intensity of attacking 22 entries in rugby union. Forwards achieved greater high-speed running intensity in successful (3.6 m min-1 ) compared to unsuccessful (1.8 m min-1 ) attacking 22 entries. Forwards should try and achieve greater high-speed running intensity in attacking 22 entries to increase the likelihood of successful outcomes during this period of gameplay. PMID- 28028895 TI - Characterization of Sox9-overexpressing human umbilical cord blood-derived mesenchymal stem cells-based engineered cartilage both in vitro and in vivo. AB - The source of seed cells is a critical factor for tissue engineering. The goal of this study was to evaluate the chondrogenesis of Sox9-overexpressing human umbilical cord mesenchymal stem cells (hUCMSCs) seeded onto bone matrix gelatin (BMG)/fibrin hybrid scaffolds both in vitro and in vivo. hUCMSCs were stably transfected with Sox9-expressing plasmid and grown on the three-dimensional BMG/fibrin hybrid scaffold for 8 weeks. Scanning electron microscopy and histochemistry were performed. The hUCMSC-loaded scaffolds were implanted into the subcutaneous layer of immunocompetent rats and chondrogenesis and host immune responses were monitored for 8 weeks. We found that hUCMSCs spread well and proliferated from 2 weeks after culturing. They produced abundant glycosaminoglycans and collagen II. At 8 weeks after implanting into rats, the hUCMSCs on the scaffolds formed cartilage-like tissue and displayed positive staining for toluidine blue, safranin O, Masson's trichrome, and collagen II. No significant changes in serum levels of lgG, lgA, lgM, C3, and C4 were observed after implantation of the hUCMSC-loaded scaffolds. Xenogeneic implantation of Sox9-overexpressing hUCMSCs embedded in the BMG/fibrin scaffolds promotes the formation of cartilage-like tissue without inducing evident host immune response. Therefore, Sox9-overexpressing hUCMSCs represent a promising cell candidate for cartilage tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1150-1155, 2017. PMID- 28028896 TI - Design of Bioinorganic Materials at the Interface of Coordination and Biosupramolecular Chemistry. AB - Protein assemblies have recently become known as potential molecular scaffolds for applications in materials science and bio-nanotechnology. Efforts to design protein assemblies for construction of protein-based hybrid materials with metal ions, metal complexes, nanomaterials and proteins now represent a growing field with a common aim of providing novel functions and mimicking natural functions. However, the important roles of protein assemblies in coordination and biosupramolecular chemistry have not been systematically investigated and characterized. In this personal account, we focus on our recent progress in rational design of protein assemblies using bioinorganic chemistry for (1) exploration of unnatural reactions, (2) construction of functional protein architectures, and (3) in vivo applications. PMID- 28028897 TI - Gastric peroral endoscopic pyloromyotomy as a salvage therapy for refractory gastroparesis: a case series of different subtypes. PMID- 28028898 TI - Recent advances in regenerative medicine to treat enteric neuropathies: use of human cells. AB - As current options for treating most enteric neuropathies are either non effective or associated with significant ongoing problems, cell therapy is a potential attractive possibility to treat congenital and acquired neuropathies. Studies using animal models have shown that following transplantation of enteric neural progenitors into the bowel of recipients, the transplanted cells migrate, proliferate, and generate neurons that are electrically active and receive synaptic inputs. Recent studies have transplanted human enteric neural progenitors into the mouse colon and shown engraftment. In this article, we summarize the significance of these recent advances and discuss priorities for future research that might lead to the use of regenerative medicine to treat enteric neuropathies in the clinic. PMID- 28028899 TI - Competency based medical education in gastrointestinal motility-the UK perspective. PMID- 28028900 TI - The role of pyloric manometry in gastric per-oral endoscopic pyloromyotomy (G POEM): response to Jacques et al. PMID- 28028902 TI - Glycemic Targets for Elderly Patients with Diabetes. PMID- 28028903 TI - 18 F-deoxyglucose positron emission tomography computed tomography as a useful diagnostic tool in an elderly patient with suspected but atypical polymyalgia rheumatica: A case report. PMID- 28028904 TI - Imatinib-sensitive myeloid neoplasm with low allele burden of FIP1L1-PDGFRA fusion gene in an elderly patient. PMID- 28028905 TI - Depression in older adults: Do close family members recognize it? PMID- 28028906 TI - "Glycemic Targets for Elderly Patients with Diabetes" of JDS/JGS joint committee: Similarity to, and Difference from, other guidelines. PMID- 28028907 TI - C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice. AB - : Essentials The role of C-type lectin-like receptor-2 (CLEC-2) in cancer progression is unclear. CLEC-2-depleted mouse model is generated by using a rat anti-mouse CLEC-2 monoclonal antibody. CLEC-2 depletion inhibits hematogenous tumor metastasis of podoplanin-expressing B16F10 cells. CLEC-2 depletion prolongs cancer survival by suppressing thrombosis and inflammation. SUMMARY: Background C type lectin-like receptor 2 (CLEC-2) is a platelet activation receptor of sialoglycoprotein podoplanin, which is expressed on the surface of certain types of tumor cells. CLEC-2-podoplanin interactions facilitate hematogenous tumor metastasis. However, direct evidence of the role of CLEC-2 in hematogenous metastasis and cancer progression is lacking. Objective and methods We generated immunological CLEC-2-depleted mice by using anti-mouse CLEC-2 monoclonal antibody 2A2B10 and investigated whether CLEC-2 promoted hematogenous tumor metastasis and tumor growth and exacerbated the prognosis of mice bearing podoplanin-expressing B16F10 melanoma cells. Results Our results showed that hematogenous metastasis was significantly inhibited in CLEC-2-depleted mice. B16F10 cells co-cultured with wild-type platelets, but not with CLEC-2-deficient platelets, showed increased proliferation. However, B16F10 cell proliferation was not inhibited in CLEC-2-depleted mice. Histological analysis showed that thrombus formation in tumor vessels was significantly inhibited and functional vessel density was significantly increased in CLEC-2-depleted mice. These data suggest that CLEC-2 deficiency may inhibit thrombus formation in tumor vessels and increase the density of functional vessels, thus improving oxygen and nutrient supply to tumors, indirectly promoting tumor proliferation. Furthermore, the overall survival of CLEC-2-depleted mice was significantly prolonged, which may be due to the suppression of thrombus formation in the lungs and subsequent inhibition of systemic inflammation and cachexia. Conclusions These data provide a rationale for the targeted inhibition of CLEC-2 as a new strategy for preventing hematogenous tumor metastasis and for inhibiting cancer-related thromboembolism. PMID- 28028908 TI - Allelic loss in amalgam-associated oral lichenoid lesions compared to oral lichen planus and mucosa. AB - BACKGROUND: The amalgam-associated oral lichenoid lesion (AAOLL) shows clinical and histopathological features similar to oral lichen planus (OLP). Molecular researches to improve knowledge of pathogenesis and clinical behavior of AAOLL are still scarce. OBJECTIVE: We investigated for the first time the use of loss of heterozygosity (LOH) as a molecular approach for genetic characterization of AAOLL in comparison with OLP and evaluated the cell proliferation index. MATERIALS AND METHODS: The sample comprised nine AAOLLs, 10 OLPs, and eight NOMs matched by patients' gender and age. LOH was assessed using polymorphic microsatellite markers at chromosomes 9p (D9S157, D9S162, D9S171), 11q (D11S1369), and 17p (TP53, AFM238WF2). Cell proliferation was assessed by immunohistochemical expression of Ki-67 (MIB-1). The association between LOH and Ki-67 was investigated. RESULTS: Loss of heterozygosity occurred in 5/9 AAOLLs and in 2/10 OLPs in at least one marker each, while NOM showed no LOH. Cell proliferation index in AAOLL ranged from 2 to 23%. There was no association between cell proliferation and LOH, independent of the marker. CONCLUSION: Our study shows that the profile of molecular changes in AAOLL and OLP, evaluated by LOH and Ki-67 expression, is similar. Additional studies including larger samples should be performed to confirm or to refute our findings. PMID- 28028910 TI - New Members of the Editorial Board and International Advisory Board. PMID- 28028909 TI - Regulation of Injury-Induced Ovarian Regeneration by Activation of Oogonial Stem Cells. AB - Some animals have the ability to generate large numbers of oocytes throughout life. This raises the question whether persistent adult germline stem cell populations drive continuous oogenesis and whether they are capable of mounting a regenerative response after injury. Here we demonstrate the presence of adult oogonial stem cells (OSCs) in the adult axolotl salamander ovary and show that ovarian injury induces OSC activation and functional regeneration of the ovaries to reproductive capability. Cells that have morphological similarities to germ cells were identified in the developing and adult ovaries via histological analysis. Genes involved in germ cell maintenance including Vasa, Oct4, Sox2, Nanog, Bmp15, Piwil1, Piwil2, Dazl, and Lhx8 were expressed in the presumptive OSCs. Colocalization of Vasa protein with H3 mitotic marker showed that both oogonial and spermatogonial adult stem cells were mitotically active. Providing evidence of stemness and viability of adult OSCs, enhanced green fluorescent protein (EGFP) adult OSCs grafted into white juvenile host gonads gave rise to EGFP OSCs, and oocytes. Last, the axolotl ovaries completely regenerated after partial ovariectomy injury. During regeneration, OSC activation resulted in rapid differentiation into new oocytes, which was demonstrated by Vasa+ /BrdU+ coexpression. Furthermore, follicle cell proliferation promoted follicle maturation during ovarian regeneration. Overall, these results show that adult oogenesis occurs via proliferation of endogenous OSCs in a tetrapod and mediates ovarian regeneration. This study lays the foundations to elucidate mechanisms of ovarian regeneration that will assist regenerative medicine in treating premature ovarian failure and reduced fertility. Stem Cells 2017;35:236-247. PMID- 28028911 TI - Editorial Board and International Advisory Board: Angew. Chem. Int. Ed. 1/2017. PMID- 28028912 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 1/2017. PMID- 28028913 TI - Iodine status and associations with feeding practices and psychomotor milestone development in six-month-old South African infants. AB - Iodine is important for normal growth and psychomotor development. While infants below 6 months of age receive iodine from breast milk or fortified infant formula, the introduction of complementary foods poses a serious risk for deteriorating iodine status. This cross-sectional analysis assessed the iodine status of six-month-old South African infants and explored its associations with feeding practices and psychomotor milestone development. Iodine concentrations were measured in infant (n = 386) and maternal (n = 371) urine (urinary iodine concentration [UIC]), and in breast milk (n = 257 [breast milk iodine concentrations]). Feeding practices and psychomotor milestone development were assessed in all infants. The median (25th-75th percentile) UIC in infants was 345 (213-596) MUg/L and was significantly lower in stunted (302 [195-504] MUg/L) than non-stunted (366 [225-641] MUg/L) infants. Only 6.7% of infants were deficient. Maternal UIC (128 [81-216] MUg/L; rs = 0.218, p < 0.001) and breast milk iodine concentrations (170 [110-270] MUg/kg; rs = 0.447, p < 0.0001) were associated with infant UIC. Most infants (72%) were breastfed and tended to have higher UIC than non-breastfed infants (p = 0.074). Almost all infants (95%) consumed semi solid or solid foods, with commercial infant cereals (60%) and jarred infant foods (20%) being the most common solid foods first introduced. Infants who reported to consume commercial infant cereals >=4 days weekly had significantly higher UIC (372 [225-637] MUg/L) than those reported to consume commercial infant cereals seldom or never (308 [200-517] MUg/L; p = 0.023). No associations between infant UIC and psychomotor developmental scores were observed. Our results suggest that iodine intake in the studied six-month-old infants was adequate. Iodine in breast milk and commercial infant cereals potentially contributed to this adequate intake. PMID- 28028914 TI - A systematic review of pregnancy exposure registries: examination of protocol specified pregnancy outcomes, target sample size, and comparator selection. AB - PURPOSE: Our study sought to systematically evaluate protocol-specified study methodology in prospective pregnancy exposure registries including pre-specified pregnancy outcomes, power calculations for sample size, and comparator group selection. METHODS: U.S. pregnancy exposure registries designed to evaluate safety of drugs or biologics were identified from www.clinicaltrials.gov, the FDA's Office of Women's Health website, and the FDA's list of postmarketing studies. Protocols or similar documentation were obtained. RESULTS: We identified 35 U.S. registries for drugs or biologic use during pregnancy. All registries assessed risk for overall major congenital malformations. Pre-specified target enrollment was stated for 18 (51%) registries, and ranged from 150 to 500 exposed pregnancies (median 300). Thirty-two (91%) registries identified at least one comparison group, but only nine (26%) planned to use an internal comparator. The most common external comparator group (n = 24, 69%) was the Metropolitan Atlanta Congenital Defects Program (MACDP). CONCLUSIONS: No registries were designed to have sufficient power to assess specific malformations, despite the plausibility that most teratogens cause specific defects. Only half of the registries included a power analysis. Despite their common use, external comparators, including MACDP, have important limitations. In the absence of randomized controlled trial data in pregnant women, pregnancy registries remain an important tool as part of a comprehensive pregnancy surveillance program; however, pregnancy registries alone may not be sufficient to obtain adequate data regarding risks of specific malformations. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 28028915 TI - Apatinib in gastric carcinoma: A case report of partial response for first-line treatment in advanced disease. AB - Gastric cancer (GC) is the most common gastrointestinal malignant tumor, with a gradual increasing incidence throughout the world. Mostly GC is diagnosed in its late stage. To date, there is no usable standardized treatment regimen for patients with advanced GC. Apatinib mesylate, small-molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor (TKI), has been approved as third-line treatment for patients with advanced gastric adenocarcinoma in China, October, 2014. Till now, there is no case report about apatinib as first-line treatment for patients with advanced GC in literature. We present an 83-year-old Chinese man with advanced gastric adenocarcinoma, who received apatinib as first-line option and obtained clinical benefit within 2 weeks. The lung metastases disappeared completely and the liver metastases shrank significantly. The patient's progression-free survival was 163 days and overall survival was 201 days. This paper reviews and discusses apatinib as a new targeted drug for patients with advanced GC by comparison with other effective molecular-targeted therapy. PMID- 28028916 TI - Enhancing the luminescence of Eu3+ /Eu2+ ion-doped hydroxyapatite by fluoridation and thermal annealing. AB - This paper reports a novel way for the synthesis of a europium (Eu)-doped fluor hydroxyapatite (FHA) nanostructure to control the luminescence of hydroxyapatite nanophosphor, particularly, by applying optimum fluorine concentrations, annealed temperatures and pH value. The Eu-doped FHA was made using the co-precipitation method followed by thermal annealing in air and reducing in a H2 atmosphere to control the visible light emission center of the nanophosphors. The intensities of the OH- group decreased with the increasing fluorine concentrations. For the specimens annealed in air, the light emission center of the nanophosphor was 615 nm, which was emission from the Eu3+ ion. However, when they were annealed in reduced gas (Ar + 5% H2 ), a 448 nm light emission center from the Eu2+ ion of FHA was observed. The presence of fluorine in Eu-doped FHA resulted in a significant enhancement of nanophosphor luminescence, which has potential application in light emission and nanomedicine. PMID- 28028917 TI - Preparation of a calcium carbonate-based bone substitute with cinnamaldehyde crosslinking agent with potential anti-inflammatory properties. AB - Calcium sulfate (CS), also known as POP (Plaster of Paris) is a self-setting, biocompatible, and osteoconductive biomaterial with a long history for the treatment of skeletal defects. However, CS cements show a too fast resorption rate and are unable to provide a long-term 3D framework during the osteogenesis process. In our previous studies, it was found that the incorporation of CaCO3 and CaCO3 hydrogel provided enhanced mechanical and degradation properties of POP composites. Furthermore, it was also found that the use of cinnamaldehyde to crosslink CaCO3 hydrogel may have some advantages, for example to crosslink the hydrogel and to act as anti-inflammatory control agent. The objective of the current study was to evaluate the effect of adding cinnamaldehyde crosslinked CaCO3 hydrogel into POP on the diametral tensile strength, weight loss, age swelling, degradation, cinnamaldehyde release, and porosity. The following composites were prepared: POP/HCin-025 (25% addition of hydrogel microsphere) and POP/HCin-050 (50% addition of hydrogel microsphere). The composites were assessed on their diametral tensile strength, weight loss of the POP composite, age swelling, degradation of the hydrogel CaCO3 , cinnamaldehyde release, and porosity, as well as XRD-patterns and FT-IR spectra. It was confirmed from the study that incorporation of cinnamaldehyde into CaCO3 hydrogel system significantly increased the mechanical strength of the POP composite. Weight loss, swelling ratio in both acid to neutral pH, and biodegradability of the POP composites were controllable by the addition of cinnamaldehyde-CaCO3 hydrogel. Moreover, the cinnamaldehyde incorporated into the hydrogel was proven to be released in a controlled manner. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1055-1062, 2017. PMID- 28028919 TI - Acetylation dictates the morphology of nanophase biosilica precipitated by a 14 amino acid leucine-lysine peptide. AB - N-terminal acetylation is a commonly used modification technique for synthetic peptides, mostly applied for reasons of enhanced stability, and in many cases regarded as inconsequential. In engineered biosilification - the controlled deposition of silica for nanotechnology applications by designed peptides - charged groups often play a deciding role. Here we report that changing the charge by acetylation of a 14-amino acid leucine-lysine (LK) peptide dramatically changes the morphology of precipitated biosilica; acetylated LK peptides produce nano-spheres, whereas nano-wires are precipitated by the same peptide in a non acetylated form. By using interface-specific vibrational spectroscopy and coarse grained molecular simulations, we show that this change in morphology is not the result of modified peptide-silica interactions, but rather caused by the stabilization of the hydrophobic core of peptide aggregates created by the removal of a peptide charge upon acetylation. These results should raise awareness of the potential impact of N-terminal modifications in peptide applications. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28028918 TI - Mailed outreach and facilitated test ordering to promote cholesterol screening in community health centers: A randomized trial. AB - RATIONALE, AIMS, AND OBJECTIVES: Lipid screening is central to cardiovascular risk assessment. We sought to determine whether a simple mailed outreach message and facilitated test ordering increase cholesterol screening among federally qualified community health center patients with no recent cholesterol screening test performed. METHODS: Using a patient-randomized controlled trial, we examined the effects of delivering a simple mailed outreach intervention promoting cholesterol testing and facilitated test ordering (without requiring an office visit). Participants were adult patients 50 to 75 years old, with no diagnosed cardiovascular disease or diabetes, and no cholesterol test within 5 years who had received care from community health centers in Illinois and Arizona. The intervention took place in 2014 and was powered to detect a 10% increase in screening due to the intervention. RESULTS: Participants' (n = 480) mean age was 57.5 years, 51.0% were male, and 43.8% were smokers. There was no significant difference between groups in the primary study outcome-completion of total cholesterol and high-density lipoprotein cholesterol tests or complete lipid panel within 3 months; 32 participants (13.3%) in intervention group versus 26 (10.8%) in control group met the primary outcome, with absolute difference of 2.5 percentage points (95% confidence interval -6.6 to 11.6). CONCLUSIONS: This outreach intervention promoting cholesterol screening was ineffective. Interventions that attempt to minimize barriers to cholesterol screening on multiple fronts and that are more compelling to patients are needed. PMID- 28028920 TI - The influence of substrate modulus on retinal pigment epithelial cells. AB - Although transplantation of retinal pigment epithelial (RPE) cells has shown promise for the treatment of retinal degenerative diseases, this therapeutic approach is not without challenges. Two major challenges are RPE cell dedifferentiation and inflammatory response following transplantation. The aim of this work is to understand how the rigidity of a scaffold, a relatively unexplored design aspect in retinal tissue engineering, affects RPE cells, particularly the pathways associated with the aforementioned challenges. Poly(ethylene glycol) diacrylate (PEGDA) of varying molecular weights from 3.4 to 20 kDa were photopolymerized to fabricate scaffolds. The Young's modulus of the scaffolds varied from 60 to 1200 kPa. A cell study was then conducted to test the effects of scaffold rigidity on RPE cells. A cell adhesion peptide motif of arginine-glycine-aspartic acid-serine (RGDS) was conjugated to 60 and 1200 kPa scaffolds and ARPE-19 cells, a human RPE cell line, were seeded onto these hydrogels. Cells grown on scaffolds demonstrated qualitatively different adhesion properties, metabolic activity, and gene expression at an mRNA level. IL-6 and MCP-1, two inflammation markers known to recruit microglial into the retina, had the same expression pattern with cells having the highest expression on the high modulus scaffold and lowest expression on the control substrate. This study demonstrates that scaffold rigidity, an important design parameter in other areas of tissue engineering, affects cell adhesion, activity, and expression of RPE cells. Though more exploration is needed, this begins to lay a foundation for optimizing scaffold rigidity to promote long-term success of RPE scaffolds. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1260-1266, 2017. PMID- 28028921 TI - Oscillospira and related bacteria - From metagenomic species to metabolic features. AB - Oscillospira is an under-studied anaerobic bacterial genus from Clostridial cluster IV that has resisted cultivation for over a century since the first time it was observed. In recent years its 16S rRNA gene was identified in several human gut microbiota studies where it was often associated with interesting traits, especially leanness. However, very little is known about its metabolism or physiology. Here we used nearly complete genomes derived from shot-gun metagenomic data from the human gut to analyze Oscillospira and related bacteria. We used sequence similarity, gene neighbourhood information and manual metabolic pathway curation to decipher key metabolic features of this intriguing bacterial genus. We infer that Oscillospira species are butyrate producers, and at least some of them have the ability to utilize glucuronate, a common animal-derived sugar that is both produced by the human host and consumed by that host in diets rich in animal products. These findings could help explain diet-related inter individual variation in faecal Oscillospira levels as well as the observation that the presence of this genus is reduced in diseases that involve inflammation. PMID- 28028922 TI - N-dihydrogalactochitosan as a potent immune activator for dendritic cells. AB - Immunotherapy has become one of the fastest growing areas of cancer research. A promising in situ autologous cancer vaccine (inCVAX) uses a novel immune activator, N-dihydrogalactochitosan (GC), that possesses the ability to stimulate dendritic cells (DC). inCVAX is a combination treatment procedure involving treatment of the tumor with a thermal near-infrared laser to liberate whole cell tumor antigens, followed by injection of GC (a glucosamine polymer with galactose attached to the amino groups) into the treated tumor thereby inducing a systemic antitumor immune response. Regression of both the treated tumor and distant untreated metastases has been observed in both nonclinical and clinical settings following inCVAX. We studied the stimulatory action of GC on relatively immature DCs (DC2.4 cell line) in vitro. GC at 1 mg/mL was a potent stimulator for DC with limited toxicity, giving increased expression of major histocompatibility complex class 2, CD80, and CD11c. Confocal imaging also revealed qualitatively increased uptake of antigen (Texas red-labeled ovalbumin) by DCs after the introduction of GC. To visualize cellular uptake, GC was conjugated with FITC-fluorophore revealing its cellular internalization after 8 hours. In some cases GC was more effective than the toxic TLR4 agonist, lipopolysaccharide. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 963-972, 2017. PMID- 28028923 TI - Exploration of cultivable fungal communities in deep coal-bearing sediments from ~1.3 to 2.5 km below the ocean floor. AB - Although subseafloor sediments are known to harbour a vast number of microbial cells, the distribution, diversity, and origins of fungal populations remain largely unexplored. In this study, we cultivated fungi from 34 of 47 deep coal associated sediment samples collected at depths ranging from 1289 to 2457 m below the seafloor (mbsf) off the Shimokita Peninsula, Japan (1118 m water depth). We obtained a total of 69 fungal isolates under strict contamination controls, representing 61 Ascomycota (14 genera, 23 species) and 8 Basidiomycota (4 genera, 4 species). Penicillium and Aspergillus relatives were the most dominant genera within the Ascomycetes, followed by the members of genera Cladosporium, Hamigera, Chaetomium, Eutypella, Acremonium, Aureobasidium, Candida, Eurotium, Exophiala, Nigrospora, Bionectria and Pseudocercosporella. Four Basidiomycota species were identified as genera Schizophyllum, Irpex, Bjerkandera and Termitomyces. Among these isolates, Cladosporium sphaerospermum and Aspergillus sydowii relatives were isolated from a thin lignite coal-sandstone formation at 2457 mbsf. Our results indicate that these cultivable fungal populations are indigenous, originating from past terrigenous environments, which have persisted, possibly as spores, through ~20 million years of depositional history. PMID- 28028925 TI - A case of advanced infantile myofibromatosis harboring a novel MYH10-RET fusion. PMID- 28028924 TI - Impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies. AB - The impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic-guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression-free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety-eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration-guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic-guided therapy. Genomic-guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling-guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies. PMID- 28028926 TI - How do groups of red imported fire ants (Hymenoptera: Formicidae) feed on a droplet of sugar water? AB - Many previous studies have focused on the foraging behaviors and strategies of the red imported fire ants, Solenopsis invicta Buren on solid food or granular bait; little attention has been paid to how liquid sugar is fed upon. In the present study, behavioral responses of S. invicta to 25% sucrose water droplets were observed. Five foraging patterns were identified in S. invicta colonies under laboratory conditions: (i) no feeding, no sucrose water feeding was observed; (ii) surround feeding, ants surrounded and fed along the edge of the sucrose droplet; (iii) stacked feeding, ants stacked and fed along the edge of the sucrose droplet; (iv) droplet-break feeding, ants broke the liquid droplet and sucked sucrose water that spread on surface of the substance or soil particles previously transported by ants; and (v) cover feeding, whole surface of the sucrose droplet was covered by layers of feeding ants. This is the first time cover feeding in S. invicta has been reported, which obviously requires more ants compared to the other patterns. In addition, individual ants were tracked in videos under laboratory conditions, and behavioral repertoires that led to stacking, covering and droplet-breaking were identified and described. The field investigation showed that surround feeding was most frequently performed by S. invicta foragers; however, cover feeding was not observed under field conditions during this study. Both laboratory and field studies showed colony-level variations in sugar-water feeding. PMID- 28028928 TI - New phthalimide-appended Schiff bases: Studies of DNA binding, molecular docking and antioxidant activities. AB - Herein, we investigated new phthalimide-based Schiff base molecules as promising DNA-binding and free radical scavenging agents. Physicochemical properties of these molecules were demonstrated on the basis of elemental analysis, ultraviolet visible (UV-Vis), infra-red (IR), 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy. All spectral data are agreed well with the proposed Schiff base framework. The DNA-binding potential of synthesized compounds were investigated by means of UV-visible, fluorescence, iodide quenching, circular dichroism, viscosity and thermal denaturation studies. The intrinsic binding constants (Kb ) were calculated from absorption studies were found to be 1.1 * 104 and 1.0 * 104 M-1 for compounds 2a and 2b suggesting that compound 2a binding abilities with DNA were stronger than the compound 2b. Our studies showed that the presented compounds interact with DNA through groove binding. Molecular docking studies were carried out to predict the binding between Ct-DNA and test compounds. Interestingly, in silico predictions were corroborated with in vitro DNA-binding conclusions. Furthermore, the title compounds displayed remarkable antioxidant activity compared with reference standard. PMID- 28028927 TI - FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer. AB - FOXC1 is a member of Forkhead box transcription factors that participates in embryonic development and tumorigenesis. Our previous study demonstrated that FOXC1 was highly expressed in triple-negative breast cancer. However, it remains unclear what is the relation between FOXC1 and ERalpha and if FOXC1 regulates expression of ERalpha. To explore relation between FOXC1 and ERalpha and discover regulation of ERalpha expression by FOXC1 in breast cancer, we analyzed data assembled in the Oncomine and TCGA, and found that there was significantly higher FOXC1 expression in estrogen receptor-negative breast cancer than that in estrogen receptor-positive breast cancer. Overexpression of FOXC1 reduced expression of ERalpha and cellular responses to estradiol (E2) and tamoxifen in the MCF-7 FOXC1 and T47D FOXC1 cells, while knockdown of FOXC1 induced expression of ERalpha and improved responses to estradiol (E2) and tamoxifen in BT549 FOXC1 shRNA and HCC1806 FOXC1 shRNA cells. In addition, overexpression of FOXC1 reduced expression of progesterone receptor (PR), Insulin receptor substrate 1 (IRS1), and XBP1 (X-Box Binding Protein 1) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay. These results suggested that FOXC1 regulated expression of ERalpha and affected sensitivity of tamoxifen treatment in breast cancer, and that FOXC1 may be used as a potential therapeutic target in ERalpha-negative breast cancer. PMID- 28028929 TI - Molecular genetic and biochemical responses in human airway epithelial cell cultures exposed to titanium nanoparticles in vitro. AB - Titanium nanoparticles (NPs) have very wide application areas such as paint, cosmetics, pharmaceuticals, and biomedical applications. And, to translate these nanomaterials to the clinic and industrial domains, their safety needs to be verified, particularly in terms of genotoxicity and cytotoxicity. Therefore, in this study, we aimed to investigate of cytotoxicity and changes in gene expression profiles influenced by commonly titanium (as titanium carbide, titanium carbo-nitride, titanium (II) oxide, titanium (III) oxide, titanium (IV) oxide, titanium nitride, titanium silicon oxide) NPs in human alveolar epithelial (HPAEpiC) and pharynx (HPPC) cell lines in vitro since inhalation is an important pathway for exposure to these NPs. HPAEpiC and HPPC cells were treated with titanium (0-100 ug/mL), NPs for 24 and 48 h, and then cytotoxicity was detected by, [3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide] (MTT), uptake of neutral red (NR) and lactate dehydrogenase (LDH) release assays, while genotoxicity was also analyzed by cDNA array - RT-PCR assay. According to the results of MTT, NR and LDH assays, all tested NPs induced cytotoxicity on both HPAEpiC and HPPC cells in a time- and dose-dependent manner. Determining and analyzing the gene expression profiles of HPAEpiC and HPPC cells, titanium NPs showed more changes in genes related to DNA damage or repair, oxidative stress, and apoptosis. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2056-2064, 2017. PMID- 28028930 TI - An update on cancer risk and surveillance in primary sclerosing cholangitis. AB - Malignancy represents substantial morbidity and mortality in patients with primary sclerosing cholangitis (PSC). This subset of patients has been proven to be at increased risk for developing cholangiocarcinoma, gallbladder carcinoma and colorectal cancer in those with overlapping inflammatory bowel disease. Herein, we review the prevalence of these malignancies and recommend screening tools and current knowledge to reduce the disease burden in this population. Cholangiocarcinoma is the most dominant malignancy affecting PSC patients, with a lifetime risk ranging from 5% to 20%. We advocate for serial US or MRI/MRCP and CA 19-9 to screen for cholangiocarcinoma. Gallbladder cancer has a lifetime risk around 2% in this population and we agree with annual imaging for lesions as recommended by national guidelines. Patients with PSC and concomitant IBD are at increased risk of colorectal carcinoma from time of diagnosis and therefore should likely undergo annual surveillance. The low rates of hepatocellular cancer and pancreatic cancer indicate surveillance for these malignancies is less advantageous. PMID- 28028931 TI - Clinical measures of obesity and cumulative cardiometabolic risk in adolescents. AB - Obesity tracks from childhood to adulthood most strongly of all cardiometabolic risk factors. To determine relationship of body mass index (BMI) and waist circumference (WC) with cardiometabolic risk (dyslipidemia, hyperglycemia and elevated blood pressure) in a large U.S. population ages 12-19 and demographic subgroups. Pooled 1999-2014 National Health and Nutrition Examination Survey data were analyzed (N = 23 438). In addition to standard cutoffs of BMI and WC, risk levels were identified for each laboratory variable: HDL-cholesterol, LDL cholesterol, triglycerides, total cholesterol (category = lipids); fasting glucose, glycated haemoglobin (category = glucose); systolic/diastolic pressures (category =blood pressure). Within each category, being high-risk on any of the variables was high-risk; being borderline-risk on any, without being high-risk on any, was borderline-risk. Obesity severity was strongly associated with increased cardiometabolic risk, with prevalence of borderline-risk greater than high-risk. Anthropometric indicators in males and Hispanics, versus females and Whites/Blacks, respectively, had stronger associations with cardiometabolic risks. BMI and WC performed well for identifying adolescents with at least one borderline-risk or high-risk level measure for lipids, glucose and blood pressure; relationship strength varying by gender and race/ethnicity. Thus, to prevent or better manage clinical diseases of adolescents with elevated BMI and/or WC, all recommended laboratory tests are warranted. PMID- 28028932 TI - Carbonyl-Grafted g-C3 N4 Porous Nanosheets for Efficient Photocatalytic Hydrogen Evolution. AB - Carbonyl-grafted g-C3 N4 porous nanosheets (COCNPNS) were fabricated by means of a two-step thermal process using melamine and oxalic acid as starting reagents. The combination of melamine with oxalic acid to form a melamine-oxalic acid supramolecule as a precursor is key to synthesizing carbonyl-grafted g-C3 N4 . The bulk carbonyl-grafted g-C3 N4 (COCN) was further thermally etched onto porous nanosheets by O2 under air. In such a process, the carbonyl groups were partly removed and the obtained sample showed remarkably enhanced visible-light harvesting and promoted the separation and transfer of photogenerated electrons and holes. With its unique porous structure and enhanced light-harvesting capability, under visible-light illumination (lambda>420 nm) the prepared COCNPNS exhibited a superior photocatalytic hydrogen evolution rate of 83.6 MUmol h-1 , which is 26 times that of the p-CN obtained directly from thermal polycondensation of melamine. PMID- 28028933 TI - Yield, Composition and Antioxidant Capacity of the Essential Oil of Sweet Basil and Holy Basil as Influenced by Distillation Methods. AB - The profile and bioactivity of essential oil (EO) depends on genetic, environmental, and other factors. We hypothesized that the basil EO may be influenced by the distillation methods. Hence, a study was conducted to evaluate the effect of steam distillation (SD) and hydrodistillation (HD) extraction method on the yield, composition, and bioactivity of EO of sweet basil (Ocimum basilicum) and holy basil (Ocimum tenuiflorum). In both basil species, the EO yield (content) was significantly higher from SD than from HD. There were significant differences in the compounds' concentrations of EO obtained from SD and HD as well, however, the same compounds were identified in the EO from HD and SD. In the EO of O. basilicum, the concentration of 74% of the identified compounds were higher in SD than HD, whereas in the EO of O. tenuiflorum, the concentration of 84% of identified compounds were higher in SD than in HD. However, the concentrations of two of the major compounds of O. basilicum EO (estragole and methyl cinnamate) and a major compound of O. tenuiflorum EO (methyl eugenol) were significantly higher in HD than in SD. The type of distillation did not affect the antioxidant capacity of basil EO within the species. This study demonstrated that the type of distillation may significantly affect oil yield and composition but not the antioxidant capacity of the EO from sweet and holy basil. PMID- 28028934 TI - RADseq provides unprecedented insights into molecular ecology and evolutionary genetics: comment on Breaking RAD by Lowry et al. (2016). AB - In their recently corrected manuscript, "Breaking RAD: An evaluation of the utility of restriction site associated DNA sequencing for genome scans of adaptation", Lowry et al. argue that genome scans using RADseq will miss many loci under selection due to a combination of sparse marker density and low levels of linkage disequilibrium in most species. We agree that marker density and levels of LD are important considerations when designing a RADseq study; however, we dispute that RAD-based genome scans are as prone to failure as Lowry et al. suggest. Their arguments ignore the flexible nature of RADseq; the availability of different restriction enzymes and capacity for combining restriction enzymes ensures that a well-designed study should be able to generate enough markers for efficient genome coverage. We further believe that simplifying assumptions about linkage disequilibrium in their simulations are invalid in many species. Finally, it is important to note that the alternative methods proposed by Lowry et al. have limitations equal to or greater than RADseq. The wealth of studies with positive impactful findings that have used RAD genome scans instead supports the argument that properly conducted RAD genome scans are an effective method for gaining insight into ecology and evolution, particularly for non-model organisms and those with large or complex genomes. PMID- 28028935 TI - Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2. AB - Members of the transient receptor potential (TRP) cation channel receptor family have unique sites of regulatory function in the kidney which enables them to promote regional vasodilatation and controlled Ca2+ influx into podocytes and tubular cells. Activated TRP vanilloid 1 receptor channels (TRPV1) have been found to elicit renoprotection in rodent models of acute kidney injury following ischaemia/reperfusion. Transient receptor potential cation channel, subfamily C, member 6 (TRPC6) in podocytes is involved in chronic proteinuric kidney disease, particularly in focal segmental glomerulosclerosis (FSGS). TRP vanilloid 4 receptor channels (TRPV4) are highly expressed in the kidney, where they induce Ca2+ influx into endothelial and tubular cells. TRP melastatin (TRPM2) non selective cation channels are expressed in the cytoplasm and intracellular organelles, where their inhibition ameliorates ischaemic renal pathology. Although some of their basic properties have been recently identified, the renovascular role of TRPV1, TRPV4, TRPC6 and TRPM2 channels in disease states such as obesity, hypertension and diabetes is largely unknown. In this review, we discuss recent evidence for TRPV1, TRPV4, TRPC6 and TRPM2 serving as potential targets for acute and chronic renoprotection in chronic vascular and metabolic disease. PMID- 28028937 TI - Stable Non-fused [22]Pentaphyrins and A Fused [24]Pentaphyrin Displaying Crystal Polymorphism between Huckel and Mobius Structures. AB - Partially beta-substituted and meso-tetrakis(pentafluorophenyl)-substituted [22]pentaphyrins 11 and 12 were synthesized by acid-catalyzed condensation of a meso-C6 F5 -substituted tripyrrane dicarbinol with beta-alkylated dipyrromethanes. These [22]pentaphyrins are stable, allowing their characterization by NMR and UV/Vis spectroscopies, and X-ray crystallography, and display strong aromaticity due to 22pi-electronic circuits. In methanol, beta,beta-diethoxycarbonylated pentaphyrin 12 underwent an N-fusion reaction to give N-fused pentaphyrin 13, which exhibits crystal polymorphism between Huckel and Mobius structures, depending upon the recrystallization solvent. PMID- 28028936 TI - Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression. AB - Lung cancer treatment is difficult owing to chemoresistance. Hypoxia-inducible factor 1 (HIF-1) and HIF-1-induced glycolysis are correlated with chemoresistance; however, this is not evident in lung cancer. We investigated the effect of HIF-1alpha and carbonic anhydrase IX (CAIX), a transmembrane protein neutralizing intracellular acidosis, on chemoresistance and prognosis of lung cancer patients after induction chemoradiotherapy. Associations of HIF-1alpha, glucose transporter 1 (GLUT1), and CAIX with chemoresistance of lung cancer were investigated using A549 lung cancer cells under normoxia or hypoxia in vitro. HIF 1alpha-induced reprogramming of glucose metabolic pathway in A549 cells and the effects of HIF-1 and CAIX on the cytotoxicity of vinorelbine were investigated. Immunohistochemical analyses were performed to determine HIF-1alpha, GLUT1, and CAIX expression levels in cancer specimens from lung cancer patients after induction chemoradiotherapy. Hypoxia induced HIF-1alpha expression in A549 cells. Moreover, hypoxia induced GLUT1 and CAIX expression in A549 cells in a HIF-1 dependent manner. Glucose metabolic pathway was shifted from oxidative phosphorylation to glycolysis by inducing HIF-1alpha in A549 cells. HIF-1 and CAIX induced chemoresistance under hypoxia, and their inhibition restored the chemosensitivity of A549 cells. The expression levels of HIF-1alpha, GLUT1, and CAIX were associated with poor overall survival of lung cancer patients after induction chemoradiotherapy. HIF-1 and CAIX affected the chemosensitivity of A549 cells and prognosis of lung cancer patients. Therefore, inhibition of HIF-1 and CAIX might improve prognosis of lung cancer patients after induction chemoradiotherapy. Further analysis might be helpful in developing therapies for lung cancer. PMID- 28028938 TI - Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure-Activity Relationship and Application as Orally Available Prodrugs. AB - Platinum(IV) bis-carboxylates are highly versatile prodrug scaffolds with different axial ligands that can be functionalized while keeping the platinum(II) pharmacophore intact. Using a sequential acylation strategy, we developed a class of PtIV prodrugs of cisplatin with contrasting lipophilic and hydrophilic ligands. We investigated their stability, reduction rates, lipophilicity, aqueous solubility, and antiproliferative efficacies, and assessed for correlations among the parameters that could be useful in drug design. We showed that compounds with high lipophilicity result in better antiproliferative effects in vitro and in vivo, with one of the three compounds tested showing better efficacy than satraplatin against an animal model of colorectal cancer, owing to its higher solubility and lower reduction rates. Our asymmetric PtIV prodrugs may pave the way for a highly predictable, fine-tuned class of orally available PtIV prodrugs for the treatment of colorectal cancer. PMID- 28028939 TI - Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake. AB - Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption. PMID- 28028940 TI - Capripox outbreak in a mixed flock of sheep and goats in India. AB - Generally, capripoxvirus infections are host specific in nature and occasionally infect more than one species. In this study, an investigation was carried out from an outbreak of capripox in a mixed flock of sheep and goats which occurred in 2013 in the State of Jammu & Kashmir. The genetic analysis of P32, RPO30 and GPCR genes revealed that both goats and sheep were infected with goatpox virus. PMID- 28028941 TI - The computer program structure for assigning individuals to populations: easy to use but easier to misuse. AB - The computer program Structure implements a Bayesian method, based on a population genetics model, to assign individuals to their source populations using genetic marker data. It is widely applied in the fields of ecology, evolutionary biology, human genetics and conservation biology for detecting hidden genetic structures, inferring the most likely number of populations (K), assigning individuals to source populations and estimating admixture and migration rates. Recently, several simulation studies repeatedly concluded that the program yields erroneous inferences when samples from different populations are highly unbalanced in size. Analysing both simulated and empirical data sets, this study confirms that Structure indeed yields poor individual assignments to source populations and gives frequently incorrect estimates of K when sampling is unbalanced. However, this poor performance is mainly caused by the adoption of the default ancestry prior, which assumes all source populations contribute equally to the pooled sample of individuals. When the alternative ancestry prior, which allows for unequal representations of the source populations by the sample, is adopted, accurate individual assignments could be obtained even if sampling is highly unbalanced. The alternative prior also improves the inference of K by two estimators, albeit the improvement is not as much as that in individual assignments to populations. For the difficult case of many populations and unbalanced sampling, a rarely used parameter combination of the alternative ancestry prior, an initial ALPHA value much smaller than the default and the uncorrelated allele frequency model is required for Structure to yield accurate inferences. I conclude that Structure is easy to use but is easier to misuse because of its complicated genetic model and many parameter (prior) options which may not be obvious to choose, and suggest using multiple plausible models (parameters) and K estimators in conducting comparative and exploratory Structure analysis. PMID- 28028942 TI - Effects of Propofol on the Liver Oxidative-Antioxidant Balance in a Rat Model of Parkinson's Disease. AB - BACKGROUND: Parkinson's disease is caused by the destruction of dopaminergic neurons in the substantia nigra of the midbrain. One of the possible factors involved in the pathogenesis of Parkinson's disease is impaired oxidativeantioxidative balance. OBJECTIVES: The present study aimed to evaluate selected parameters of the liver oxidative-antioxidative system in a Wistar rat model with Parkinson's disease treated with propofol. MATERIAL AND METHODS: Experiments were performed on 32 rats divided into 4 groups: 1 - control, 2 - Parkinson's disease, 3 - control with propofol, 4 - Parkinson's disease with propofol. The rats were decapitated at 8 weeks of age and their livers were collected. In the liver, the activities of catalase (CAT), glutathione peroxidase (GPx), glutathione transferase (GST), glutathione reductase (GR) and the concentrations of: Malondialdehyde (MDA), total antioxidant capacity (TAC), total oxidant status (TOS) were assessed. RESULTS: The study demonstrated a decrease in CAT activity and an increase in MDA, TOS concentrations in group 2 compared to that of group 1. Administration of propofol in rats of group 4 caused an increase in CAT activity and a decrease in MDA concentration compared to that of group 2 and an increase in TAC, CAT, GR levels, decrease in MDA levels compared to that of group 1. There was also an increase in GR and TAC in group 3 compared to that of group 1. CONCLUSIONS: Propofol in Parkinson's disease stimulates the production of antioxidant enzymes in the liver, simultaneously decreasing oxidative stress, which has a beneficial effect on the oxidative-antioxidative balance. PMID- 28028943 TI - The Effects of Anti-CD3/CD28 Coated Beads and IL-2 on Expanded T Cell for Immunotherapy. AB - BACKGROUND: The activation of peripheral blood mononucleated cells (PBMCs) with anti-CD3/CD28-coated magnetic beads promotes intrinsic resistance to HIV as well as cell expansion. OBJECTIVES: The aim of this study was to define an optimal cell isolation protocol for the expansion of PBMCs using anti-CD3/CD28-coated bead stimulation, with the ultimate goal of using these cells for adoptive therapy. MATERIAL AND METHODS: PBMCs were isolated from healthy donor blood samples. To determine the effect of varying the bead-to-cell ratios on the expansion rate and phenotypic characterization of the expanded cells, one million PBMCs were stimulated by anti-CD3/CD28-coated beads at bead-to-cell ratios of 0.1 : 1, 0.5 : 1 and 1.0 : 1 in the presence of 100 U/mL exogenous IL-2; also, one million PBMCs were stimulated by anti-CD3/CD28-coated beads at a bead-to-cell ratio of 0.5 : 1 in the presence of varying concentrations of IL-2 (20, 100 and 1000 U/mL). Cell expansion was carried out for three weeks. The cell numbers, cell viability and phenotypic characterization were determined by trypan blue exclusion and flow cytometry. RESULTS: The initial experiments showed no difference in the expansion rate from cells grown with the three different bead to-cell ratios. PBMCs can be expanded up to 1000-fold at a 0.5 : 1 bead-to-cell ratio after three weeks of cell expansion with a high viability (90%). Furthermore, in the presence of 100 U/mL IL-2, the percentages of CD3-CD16+CD56+ cells showed marked increases. CONCLUSIONS: The results demonstrate that PBMCs were stimulated with anti-CD3/CD28-coated beads. This method may provide an alternative for driving T cell expansion, which may be very useful in adoptive immunotherapy. PMID- 28028944 TI - A Comparison of Two Approaches to Laparoscopic Adrenalectomy: Lateral Transperitoneal Versus Posterior Retroperitoneal Approach. AB - BACKGROUND: Laparoscopic adrenalectomy is the gold standard for the surgical treatment of benign adrenal masses. It is most commonly performed using the lateral transperitoneal approach (LTA) and the posterior retroperitoneal approach (PRA). The choice of the method depends on contraindications for a particular approach in an individual case and surgical experience. The objective of the article is to compare two approaches, LTA and PRA, in view of our own experience and literature review. OBJECTIVES: The objective of the article is to compare two approaches, LTA and PRA, in view of our own experience and literature. MATERIAL AND METHODS: The assessment involved morphological characteristics of tumors, indications for PRA and LTA, operative time, perioperative blood loss and postoperative complications. RESULTS: Seventy-seven of the examined 104 laparoscopic adrenalectomies were performed retroperitoneally; 27 - transperitoneally. The mean size of tumors in PRA was 4.6 cm and in LTA 6.2 cm. The mean total operative time was 91.8 min in the case of PRA and 153.1 min in LTA. No differences in the amount of blood loss between the two approaches were recorded. The average hospitalization post PRA lasted 2.03 days and post LTA 2.67 days. CONCLUSIONS: Laparoscopic adrenalectomy proves to be an effective and safe surgical technique both in the case of LTA and PRA. The technique to be used should be suited to surgical team's experience, patient's general condition and tumor size and location. In our experience, the most advantageous approach in the case of tumors of less than 7 cm is PRA. PMID- 28028945 TI - The Correlation Between Non-Hodgkin Lymphoma and Expression Levels of B-Cell Activating Factor and Its Receptors. AB - BACKGROUND: Lymphoma is a malignant tumor of the immune system originating from lymph nodes and extralymphatic tissues. Its occurrence is believed to be associated with various immune cells due to the proliferation and differentiation of lymphocytes during the immune response. It has been found in many studies that B-cell activating factor (BAFF), as a member of the tumor necrosis factor (TNF) superfamily, could specifically activate B lymphocytes and promote their proliferation. OBJECTIVES: To explore correlations between non-Hodgkin lymphoma (NHL) and the expression of BAFF and its receptors in NHL patients. MATERIAL AND METHODS: The protein expression of BAFF and its receptors in serum and BAFF mRNA expression in peripheral blood mononuclear cells (PBMCs) of 47 NHL patients and 20 healthy subjects were detected by ELISA and RFQ-PCR and compared with LDH and beta2M levels. RESULTS: BAFF mRNA expression in the PBMCs of NHL patients was significantly higher than in healthy controls. The expression levels of serum BAFF and the three receptors (TACI, BCMA and BAFF-R) in NHL patients were significantly higher than in healthy controls, and were not significantly correlated with beta2M and LDH levels. CONCLUSIONS: The serum protein concentration of BAFF and the expression level of BAFF mRNA in PBMCs of NHL patients underwent abnormal changes, indicating that BAFF and its receptors may play some role in the pathogenesis of NHL. PMID- 28028946 TI - Bachmann's Bundle Pacing not Only Improves Interatrial Conduction but Also Reduces the Need for Ventricular Pacing. AB - BACKGROUND: Patients treated for sick sinus syndrome may have interatrial conduction disorder leading to atrial fibrillation. OBJECTIVES: This study was aimed to assess the influence of the atrial pacing site on interatrial and atrioventricular conduction as well as the percentage of ventricular pacing in patients with sick sinus syndrome implanted with atrioventricular pacemaker. MATERIAL AND METHODS: The study population: 96 patients (58 females, 38 males) aged 74.1 +/- 11.8 years were divided in two groups: Group 1 (n = 44) with right atrial appendage pacing and group 2 (n = 52) with Bachmann's area pacing. We assessed the differences in atrioventricular conduction in sinus rhythm and atrial 60 and 90 bpm pacing, P-wave duration and percentage of ventricular pacing. RESULTS: No differences in baseline P-wave duration in sinus rhythm between the groups (102.4 +/- 17 ms vs. 104.1 +/- 26 ms, p = ns.) were noted. Atrial pacing 60 bpm resulted in longer P-wave in group 1 vs. group 2 (138.3 +/- 21 vs. 106.1 +/- 15 ms, p < 0.01). The differences between atrioventricular conduction time during sinus rhythm and atrial pacing at 60 and 90 bpm were significantly longer in patients with right atrial appendage vs. Bachmann's pacing (44.1 +/- 17 vs. 9.2 +/- 7 ms p < 0.01 and 69.2 +/- 31 vs. 21.4 +/- 12 ms p < 0.05, respectively). The percentage of ventricular pacing was higher in group 1 (21 vs. 4%, p < 0.01). CONCLUSIONS: Bachmann's bundle pacing decreases interatrial and atrioventricular conduction delay. Moreover, the frequency dependent atrioventricular conduction lengthening is much less pronounced during Bachmann's bundle pacing. Right atrial appendage pacing in sick sinus syndrome patients promotes a higher percentage of ventricular pacing. PMID- 28028947 TI - The Effects of Controlled Physical Training on Peripheral Circulation Following Interventional Treatment of Coronary Artery Disease. AB - BACKGROUND: Controlled physical training induces specific changes in the peripheral circulatory system and can lead to positive changes in the vascular perfusion of the lower extremities. OBJECTIVES: The aim of the study was to evaluate changes in peripheral circulation in the calf in patients with acute coronary disease (ACD) undergoing controlled physical training. Impedance plethysmography was used to monitor peripheral circulation during the training. MATERIAL AND METHODS: A total of 90 patients were divided into three study groups. Group 1 (n = 30) participated in a two-week cardiac rehabilitation program consisting of interval training on a cycle ergometer and exercise to improve the participants' general physical condition. Group 2 (n = 30) went through the same cardiac rehabilitation program for four weeks. The control group (n = 30) was assigned breathing exercises, active free exercises of the peripheral joints and different muscle groups, and relaxation exercises. All the patients underwent impedance plethysmography tests before and after the training sessions. RESULTS: In Group 1, the systolic slope (PSlope) increased by 2%, pulse wave amplitude (PAmpl) increased by 4.2%, crest time (CT) increased by 1.5% and propagation time (PT) decreased by 1.2% (p > 0.05). In Group 2, the PSlope and PAmpl increased by 19% and 17% respectively, while the CT and PT decreased by 8% and 6.5% respectively (p < 0.05). In the control group, only the CT decreased, by 5% (p < 0.05). CONCLUSIONS: The study confirmed that cardiac rehabilitation improves blood flow in lower limb vessels in patients with ACD. The results depend on the duration and the type of physical training. Impedance plethysmography allows for precise and repeatable monitoring of local blood flow. PMID- 28028948 TI - The Association Between Dental Status and Risk of Acute Myocardial Infarction Among Poles: Case-control Study. AB - BACKGROUND: Results of scientific research on the effects of periodontitis on the incidence of myocardial infarction (MI) are ambiguous. OBJECTIVES: The aim of this study was to investigate the association of the severity and extent of periodontitis with acute MI in Poles. MATERIAL AND METHODS: This case-control study included 134 cases hospitalized with acute MI under the age of 70 years and 155 controls drawn from the general population with no MI history. Sociodemographic, cardiologic and periodontal variables were assessed. Three periodontal indicators were evaluated: (1) the severity of periodontitis classified in accordance with Page and Eke definition, (2) the extent of periodontitis determined on the basis of the percentage of sites with CAL >= 3 mm (Arbes Index) and (3) tooth loss (> 10 teeth). In a logistic regression model, the association of periodontal parameters with MI occurrence was evaluated after adjusting for well-known cardiovascular risk factors. RESULTS: The extent of periodontitis was significantly associated with the risk of acute MI even after adjusting for age, sex, tobacco smoking, hypertension, diabetes, BMI, education and income (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.1 to 5.2; p = 0.0203). However, the severity of periodontitis was associated with MI after adjusting for age and sex (OR = 2.0; 95% CI = 1.2-3.5; p = 0.0109), but not after adjusting for the other above-mentioned risk factors. The association between the number of lost teeth and acute MI was significant after adjusting for age, sex, tobacco smoking, arterial hypertension and diabetes mellitus (OR = 2.1; 95% CI = 1.2-5.9; p = 0.0151). CONCLUSIONS: This study proves the positive association between periodontitis and acute MI in Poles. This association seems to be stronger with regard to the extent rather than to the severity of periodontitis. PMID- 28028949 TI - Clarithromycin Decreases IL-6 Concentration in Serum and BAL Fluid in Patients with Cryptogenic Organizing Pneumonia. AB - BACKGROUND: Inflammatory cytokines are involved in the development of cryptogenic organizing pneumonia (COP). It has been shown that macrolides inhibit cytokine production in the alveolar macrophages of COP patients. OBJECTIVES: The aim of the study was to assess the concentrations of interleukin 1beta (IL-1beta), IL-6, IL-8 and transforming growth factor beta (TGF-beta) in serum and in bronchoalveolar lavage fluid (BAL-f) in COP patients treated with clarithromycin (CAM). MATERIAL AND METHODS: The study involved 26 patients (18 women and 8 men, mean age 56.46 +/- 8.83 years) with biopsy-proven COP. After being treated with CAM, a complete recovery was achieved in 22 patients, while four patients did not respond to the treatment. The ELISA method was used to measure the serum and BAL f concentrations of IL-1beta, IL-6, IL-8 and TGF-beta. RESULTS: Before treatment, the serum IL-1beta1, IL-6, IL-8 and TGF-beta1 concentrations were similar in responders and non-responders. Significant decreases in serum concentrations of IL-6 (8.98 +/- 13.26 pg/mL vs. 3.1 +/- 6.95 pg/mL; p = 0.005), IL-8 (20.14 +/- 25.72 pg/mL vs. 10.14 +/- 6.8 pg/mL; p = 0.007) and TGF-beta1 (37.89 +/- 12.49 ng/mL vs. 26.49 +/- 12.45 ng/mL; p = 0.001) were found after treatment, as well as a significant decrease in the BAL-f concentration of IL-6 (30.56 +/- 56.78 pg/mL vs. 4.53 +/- 5.84 pg/mL; p = 0.036). Clarithromycin treatment resulted in a significantly lower mean value of serum IL-6 responders than non-responders. CONCLUSIONS: In COP patients, response to clarithromycin treatment was associated with decreases in serum concentrations of IL-6, IL-8 and TGF-beta, and of rations, and of the BAL-f concentration of IL-6. PMID- 28028950 TI - Prospective Analysis of the Relationship Between the State of Periodontal Tissues and Changes in Selected Cardiovascular Parameters in Patients with Type 2 Diabetes. AB - BACKGROUND: Periodontitis is considered a risk factor in many systemic diseases, including cardiovascular pathologies and diabetes. Diabetes can also exacerbate early vascular changes, mainly due to the synthesis of advanced glycosylation end products and oxidative stress. It has not yet been fully explained whether the additional presence of periodontal disease can affect the course of atherosclerosis and left ventricle hypertrophy in diabetic patients. OBJECTIVES: The aim of the study was to assess the relationship between periodontal and cardiovascular diseases and their progression in patients with type 2 diabetes. MATERIAL AND METHODS: The study included 119 patients diagnosed with type 2 diabetes. Periodontal pocket depth (PD), clinical attachment loss (CAL), plaque index (PI) and bleeding index (BOP) were determined. Basic laboratory tests were performed. The intima-media thickness (IMT) and the left ventricular mass index (LVMI) were determined by means of ultrasonography. After one year the examinations were repeated. The statistical analysis included the 84 patients who took part in both the first and second examinations. RESULTS: A positive correlation between the number of deep and active periodontal pockets and LVMI value was observed in men. The IMT value correlated with the mean CAL, PI and BOP, while a negative correlation was found between the IMT and the number of deep pockets, as well as between the IMT and the number of retained teeth. A multivariate analysis demonstrated a significant correlation between CAL and both IMT and LVMI change after one year. CONCLUSIONS: A relationship between periodontitis and cardiovascular diseases has been confirmed in diabetic patients. The most significant periodontal parameter in relation to the progression of atherosclerosis and left ventricle hypertrophy was shown to be clinical attachment loss - a measure of the history of periodontal disease during the patient's lifetime. PMID- 28028951 TI - Increased Expression of TLR4 and TLR7 but Not Prolactin mRNA by Peripheral Blood Monocytes in Active Celiac Disease. AB - BACKGROUND: Celiac disease (CD) is an organ-specific autoimmune disease, and both adaptive and innate immunity are involved in its development. OBJECTIVES: The aim of the study was to determine whether the markers of intestinal mucosal inflammation in CD can be detected in peripheral blood monocytes (PBMs), and whether the immune properties of PBMs change as the clinical signs and symptoms of CD improve after the introduction of a gluten-free diet (GFD). The focus was on changes in mRNA expression of selected toll-like receptors (TLR2, TLR4, TLR7), stress cytokine prolactin (PRL), and proand anti-inflammatory cytokines (TNF alpha, IL-6, IL-12, IL-10) in PBMs. MATERIAL AND METHODS: The study involved 20 CD patients diagnosed according to the European Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria and Marsh criteria: 10 recently-diagnosed cases (rCD) and 10 on a GFD for a minimum of one year. The control group comprised 10 ageand sex-matched healthy volunteers. PBMs from peripheral blood specimens were separated using immunomagnetic CD14+ beads. Total RNA was isolated using a standard commercial kit. Cytokine and TLR mRNA levels were quantified by relative qPCR with PGK1 as a reference gene. RESULTS: Significantly higher expression of TLR4 and TLR7 mRNA was observed in PBMs from rCD patients compared to the healthy controls (1.63 times higher; p < 0.05). TLR7 mRNA levels in rCDs were also significantly elevated in comparison to the CD-GFD patients (2.11 times higher; p < 0.01). TNF-alpha mRNA expression tended to be higher in both groups of patients; by contrast, in IL-6 mRNA, a trend to a fourfold decrease was detected in PBMs from the CD-GFD subjects. IL-10, IL-12 and PRL levels did not differ among the groups. CONCLUSIONS: The data suggest that the inflammatory process in rCD intestinal mucosa and submucosa reflecting enterocyte damage can be detected in PBMs in peripheral blood. Further, the cytokine and TLR expression profile in PBMs alters after one year of GFD treatment. PMID- 28028952 TI - Mastalgia Due to Degenerative Changes of the Spine. AB - BACKGROUND: Mastalgia is a common and enigmatic condition; the cause and optimal treatment are still inadequately defined. Cervical radiculopathy, which is the result of cervical nerve root pathology often caused by spaceoccupying lesions such as cervical disc herniation, spondylosis, or osteophytosis, is frequently encountered in physical therapy. OBJECTIVES: The aim of the study was to evaluate the incidence of vertebral pathologies in patients with non-cyclic mastalgia and the efficacy of conservative treatment of these pathologies on relieving breast pain. MATERIAL AND METHODS: One hundred patients were included in the study, all with breast pain continuing throughout the day and lasting at least three months. Breast and axillary physical examinations, mammographic and/or ultrasonographic evaluations were normal in all the patients. The patients' pain levels were scored using a visual analog scale (VAS). Cervical and thoracic spine magnetic resonance imaging (MRI) was performed on all the participants. RESULTS: Among 96 patients that had pathological findings on magnetic resonance imaging (96%), 49 women had diffuse annular bulging of the cervical spine, and 47 had cervical disc protrusion. Additionally, 12 patients had thoracic disc protrusion. At the end of the three-month period, the patients who were given only conservative treatment returned for follow-up evaluations. According to the VAS scores, five patients had mild to moderate improvement, 55 showed significant improvement, and 29 achieved complete remission. CONCLUSIONS: The authors concluded that if none of the known causes of breast pain are found in a patient, the patient should be evaluated for vertebral pathologies. PMID- 28028953 TI - Opinions of Old Age According to Residents of Polish Public Nursing Homes and Members of the Universities of the Third Age. AB - BACKGROUND: Statistical data from the turn of the 21st century shows a significant increase in the average human life span and, what follows, an extension of old age. OBJECTIVES: The aim of this study was to become familiar with the opinions submitted by respondents regarding aging and old age, health problems connected with aging and preferred health behaviors. MATERIAL AND METHODS: The research was conducted between January 3rd 2013 and February 15th 2014 on a group of 200 residents of public nursing homes and 200 members of the University of the Third Age using a questionnaire created by the authors. RESULTS: Forty-two point five per cent of the residents of PNHs and 58.0% of the members of UTAs were of the opinion that old age can be a successful period of life. Sixty-one percent of all participants stated that the elderly are needed in society. According to respondents, the factor which was most important in delaying aging was an active lifestyle (80.0% of residents of PNH vs. 90.0% of UTA members). CONCLUSIONS: Perceptions of elderly people by the seniors are different, complex and multidimensional. The perception of elderly people to society can variously affect (positively or negatively) quality of life in this age group. The results of the study showed small differences between the residents of public nursing homes and students of Universities of the Third Age in the perception of old age. There is a need to integrate seniors with younger generations in order to eliminate the stereotypes prevailing in society about older people. PMID- 28028954 TI - The Role of Heavy Metal Salts in Pathological Biomineralization of Breast Cancer Tissue. AB - BACKGROUND: The process of pathological biomineralization plays an important part in the morphogenesis of tumors. The role of heavy metal salts in the pathological mineralization of breast cancer tissue should not be ruled out, considering their ability to enter into covalent bonds with calcium salt molecules. OBJECTIVES: The aim of the study was to investigate the microelement composition of breast cancer calcifications and the participation of heavy metals in their formation process. MATERIAL AND METHODS: The material for the study consisted of 20 specimens of breast cancer tissue in which calcifications had been found in histological tests (hematoxylin-eozin and alizarin red S staining). The chemical composition of the calcifications was studied using a scanning electron microscope with an energy dispersive spectrometer. RESULTS: Alizarin red S staining detected the presence of concrements in tumor tissue and rings of calcification around these deposits. Examining the biomineralization with energy dispersive spectrometry showed that along with calcium and phosphorus, it contained microelements such as iron, zinc, copper, chromium and nickel, which can replace calcium ions in the exterior part of hydroxyapatite molecules. This causes the hydroxyapatite molecule's molar mass to increase and its solubility to decrease; its chances of being deposited in tumor tissue also increase. This implies that an increased intake of heavy metal salts in organisms can lead to pathological mineralization of breast cancer tissue. CONCLUSIONS: Excessive intake of heavy metal salts into the body leads to their involvement in the pathological mineralization of breast cancer tissue. This happens due to these salts bonding to hydroxyapatite molecules, direct sedimentation of proteins and increasing degenerative-necrotic changes in breast cancer tissue as the mineralization process progresses. PMID- 28028955 TI - Unruptured Intracranial Aneurysms: Surgery Still Safe as a Treatment Option. AB - BACKGROUND: Despite a number of studies on the treatment of unruptured intracranial aneurysms (UIA), the optimal method still remains unclear. OBJECTIVES: The aim of the study was to demonstrate that UIA clipping is a safe procedure and can be a good alternative for patients not qualified for endovascular procedures and who have refused conservative management. MATERIAL AND METHODS: Results were gathered from a sample of 104 patients with UIA treated in our facility over a 9-year period starting January 2005. The data from a medical database was collected, followed by a long-term assessment of the functional outcomes using the modified Rankin Scale (mRS) and of quality of life (QoL) using a SF-36 questionnaire and comparing it to a Polish population reference. RESULTS: Overall postoperative morbidity was 5.7% and the mortality rate was 0%. The mean follow-up period was 6.5 years. A favorable outcome (mRS 0 2) was achieved in all the patients. Ninety-eight patients achieved an mRS score of 0, 2 patients an mRS score of 1, and 4 patients an mRS score of 2. All patients lived at home. Sixty-nine point two percent were fully employed, 27.0% were retired because of age, and only 3.8% relied on government help due to postoperative disability. The QoL index was similar to that of the standard Polish population. CONCLUSIONS: In unruptured cerebral aneurysms, clipping is a safe procedure that provides good outcomes and an unaffected quality of life. It remains a good option especially for patients with MCA aneurysms that are not appropriate for endovascular management. PMID- 28028956 TI - Assessment of Clinical Symptoms and Multichannel Intraluminal Impedance and pH Monitoring in Children After Thoracoscopic Repair of Esophageal Atresia and Distal Tracheoesophageal Fistula. AB - BACKGROUND: Motility disturbances of the esophagus and gastroesophageal reflux disease (GERD) are observed frequently in children after repair of congenital esophageal atresia with distal tracheoesophageal fistula (EA/TEF). Recently, in many pediatric surgical centers, thoracoscopic repair was introduced, which theoretically would change the postoperative course. OBJECTIVES: The goal of the study was to assess physical development, disease symptoms, and GERD symptom frequency in children who underwent thoracoscopic surgery of congenital EA/TEF. MATERIAL AND METHODS: The study comprised 22 children (14 boys and 8 girls), aged 16 to 79 months (average age 47.3 months) after surgery of EA/TEF. Clinical symptoms and physical development were analyzed. In 19 children, multichannel intraluminal esophageal impedance connected with pH-metry (MII/pH) was performed. In 11 patients, esophagogastroduodenoscopy with a histological study of mucosa samples was done. RESULTS: The most frequent symptoms were dysphagia, belching, cough and recurrent bronchitis. In 31.5% of the children, body mass deficiency was observed and in 28.6%, low body mass and short stature. Prematurity was present in half of the patients. Depending on the result of the MII/pH study, the children were divided into two groups: 10 children with GERD and 9 children without diagnosis of gastroesophageal reflux. In the 10 with GERD, acid reflux was diagnosed in 9 and non-acid reflux was diagnosed in one. MII/pH demonstrated statistically significant differences in the number of reflux episodes, reflux index, bolus exposure index, mean time of esophageal exposure and acid exposure and mean acid clearance time in children with GERD in comparison to children without this disease. In 36.4% of children who underwent endoscopy, esophagitis was diagnosed, esophageal stricture in 18% and gastric metaplasia in 9.1%. CONCLUSIONS: In children who underwent corrective thoracoscopic surgery of EA/TEF, GERD caused by motility disorders of the esophagus was frequently observed. These children require constant monitoring and early treatment of the complication. PMID- 28028957 TI - Allogeneic vs. Autologous Skin Grafts in the Therapy of Patients with Burn Injuries: A Restrospective, Open-label Clinical Study with Pair Matching. AB - BACKGROUND: Early application of autologous skin may lead to the loss of split thickness skin graft due to unclarified wound bed. Allogeneic skin grafts are performed on patients with extensive burn injuries after escharotomy, tangential excisions and deep debridement for the purpose of stabilizing the general condition and reducing the scope of local complications. OBJECTIVES: The aim of this paper is to determine how the use of allografts improves the conditions for the intake of autografts in burns treatment, and how it accelerates wound healing in comparison to the autografts-only option. MATERIAL AND METHODS: In 2012-2013, allogeneic skin was grafted on 46 patients, and in 8 cases grafting was repeated several times. An autologous split-thickness skin graft was applied to 32 patients. The analysis included the relationship between the duration of hospitalization and the number of skin transplantations, the relationship between the time of admission to debridement of the necrotic tissues and the total duration of hospitalization. Statistical analysis encompassed also pain assessment. RESULTS: The results suggest that multiple applications of autografts not only do not lead to quicker recovery, but even lengthen the hospitalization time. The dependency is visible also in the patients who underwent the skin grafting procedure in allogeneic and autologous systems twice or more. There was a statistical significant difference between the duration of hospitalization in groups of patients who underwent STSG preceded by allogeneic skin graft transplantation when compared to the group of patients who underwent allogeneic skin application (p < 0.05) and the group of patients who were grafted with autologous skin (p < 0.05). CONCLUSIONS: Allogeneic skin grafts are a perfect dressing when wound vascularization is insufficient to take free split-thickness skin graft. In patients with comparable burn surface areas, multiple applications of free autologous split-thickness skin grafts (STSG) extend the hospitalization time in comparison to application of allogeneic skin dressing as the first-line therapy. PMID- 28028958 TI - The Effectiveness of Exergames in Patients with Ankylosing Spondylitis: A Randomized Controlled Trial. AB - BACKGROUND: Exergames are a well-known type of game based on a virtual avatar's body movements. This hightech approach promotes an active lifestyle. OBJECTIVES: The aim of this randomized controlled trial was to evaluate the effects of exergames on pain, disease activity, functional capacity and quality of life in patients with ankylosing spondylitis (AS). MATERIAL AND METHODS: The study involved 60 patients, who were randomized into either the exergame group (EG) or the control group (CG). The EG patients engaged in exergaming, and CG patients did not engage in any exercises. The exergaming sessions were performed five times a week for eight weeks (40 sessions in total). The patients were assessed before and after the eight-week program on a visual analog scale (VAS), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire. RESULTS: A statistically significant improvement was observed in VAS, BASFI, BASDAI and ASQoL scores in the EG group after completion of the exercise program (p < 0.05). CONCLUSIONS: This study is a first step in investigating the possibilities of using an exergame platform to help patients with spondyloarthropathies to adopt a more physically active lifestyle. The results of this study suggest that exergames increase physical activity and decrease the pain scores in AS patients and also could, therefore, be feasible and safe. PMID- 28028959 TI - Comparison of Visual Field Measurement with Heidelberg Edge Perimeter and Humphrey Visual Field Analyzer in Patients with Ocular Hypertension. AB - BACKGROUND: Glaucoma is a group of eye diseases which result in damage to the optic nerve and vision loss. The most important examination in glaucoma patients is visual field assessment. One of the newer perimeters is Heidelberg Edge Perimeter (HEP). OBJECTIVES: The aim of the study was to compare visual field measurements made with Humphrey II 740 Visual Field (Carl Zeiss Meditec) and Heidelberg Edge Perimeter (HEP) (Heidelberg Engineering). FDF stimulus (flicker defined form) in HEP stimulates magnocellular retinal cells, which are the first to be damaged in the early stage of glaucoma. Even a small loss of magnocellular cells may influence HEP visual field. MATERIAL AND METHODS: The observed group consisted of 45 patients (82 eyes), age 60 +/- 9.8 years, glaucoma suspects, not treated pharmacologically or surgically before, with intraocular pressure >= 22 mm Hg. Visual field values were measured with two different devices: Humphrey II 740 Visual Field (Carl Zeiss Meditec, Jena, Germany) and Heidelberg Edge Perimeter (Heidelberg Engineering, Heidelberg, Germany). The patients were divided into two groups: Group 1 - tested with SITA Standard program on Humphrey perimeter and ASTA Standard HEP, and Group 2 - tested with SITA Fast program on Humphrey perimeter and ASTA Standard on HEP. RESULTS: Few positive DeltaMD results (DeltaMD = MD HEP - MD HUM) were obtained in Groups 1 and 2, which means that the deviation value on the HEP perimeter was only slightly higher than the mean deviation value on Humphrey. Therefore, one can conclude that HEP perimeter may detect visual field defects with greater precision. The visual field measurements between ASTA Standard on HEP and SITA Standard on Humphrey as well as ASTA Standard on HEP and SITA Fast on Humphrey are not equal: MD values on HEP perimeter are lower than MD on Humphrey, which can mean that HEP perimeter provides more precise results and shows even early visual field lesions. CONCLUSIONS: HEP perimeter measures visual field defects with greater precision so it should be taken into consideration for earlier glaucoma detection in routine ophthalmological diagnosis. PMID- 28028960 TI - Detection of Salmonella in Foods Using a Reference PN-ISO Method and an Alternative Method Based on Loop-mediated Isothermal Amplification Coupled with Bioluminescence. AB - BACKGROUND: Salmonella, one of the primary indicators of food safety, is a common cause of food poisoning of an epidemic nature around the world. These microorganisms can colonize the gastrointestinal tract of both people and animals, and next contaminate not only eggs, milk, meat and dairy products, but also vegetables, fruit, grains and even spices. OBJECTIVES: The aim of this study was to analyze the frequency of detection of Salmonella spp. in food samples using a reference PN-ISO method and an alternative method based on loop-mediated isothermal amplification (LAMP) coupled with bioluminescence. MATERIAL AND METHODS: Food samples were obtained in cooperation with the State Sanitary Epidemiological Station in Wroclaw. Dairy products, meat, fish, pastry and confectionery, vegetables, herbs and spices were analyzed. The food samples were examined using a standard culturing method according to PN-ISO 6579:2003 for Salmonella spp. and an alternative method based on the isothermal amplification and bioluminescence phenomenon using the 3M MDS device. RESULTS: In 399 tested food samples in 8 materials, using both the reference and the alternative LAMP based method, the presence of salmonella was confirmed. The results obtained show the 100% sensitivity, specificity and accuracy of the presented alternative, LAMP based technique compared to the reference PN-ISO method. CONCLUSIONS: The alternative method using isothermal amplification and bioluminescence makes it possible to detect Salmonella in foods in a much shorter time than the referential culturing method. PMID- 28028961 TI - Oral Health and Quality of Life in Old Age: A Cross-Sectional Pilot Project in Germany and Poland. AB - BACKGROUND: The process of ageing influences all dimensions of social life and personal well-being, but the influence of health on different dimensions of quality of life (QoL) among the elderly is rarely examined. OBJECTIVES: The aim of the pilot study is to test the feasibility of a comprehensive study design to evaluate general and dental health as well as QoL in a bi-national sample. In addition, this pilot study should allow for the exploration of potential interactions between QoL, socioeconomic, health and oral health variables. MATERIAL AND METHODS: Individuals aged 64 years and older (n = 100) from university dental clinics of the Wroclaw Medical University, Poland (n = 50) and of the University Hospital in Dresden, Germany (n = 50) were examined. The oral health status of participants was assessed by clinical examination. Socio demographic, environmental and general health status were evaluated during the medical interview. General quality of life (GQoL) was assessed by an overall question with a visual analogue scale (VAS) from -5 (worst) to +5 (best). Health related quality of life (HRQoL) and oral health-related quality of life (OHRQoL) were measured with the EQ-5D and OHIP-14 questionnaires. Statistical analyses comprised Pearson's c2 test, Wilcoxon test, linear regression model for statistical analysis and different multivariate linear regression analyses. RESULTS: For the GQoL-VAS-Score the results for QoL measurements were 1.22 +/- 2.62 (x+/- SD), for EQ-5D-Score 7.45 +/- 2.25 (x+/- SD), and for OHIP-14-ADD Score 11.04 +/- 13.56 (x+/- SD). Differences between Polish and German populations were observed. CONCLUSIONS: The study design proved to be feasible for a senior population. The overall GQoL question, EQ-5D and OHIP-14 were regarded as appropriate instruments. Subjective and objective (oral) health measures showed differences between Germany and Poland. For methodological reasons, these differences are not generalizable, but of value for study hypotheses in larger samples. PMID- 28028962 TI - Assessing the Penetrating Abilities of Experimental Preparation with Dental Infiltrant Features Using Optical Microscope: Preliminary Study. AB - BACKGROUND: The aim of the infiltration technique is to penetrate demineralized enamel with a low viscosity resin. Icon(r) (DMG) is the first ever and so far the only dental infiltrant. Bacteriostaticity is one of the properties that should be inherent in dental infiltrants, but Icon lacks this feature. OBJECTIVES: The aim of the preliminary study was to properly choose a dye which would allow us to assess the penetrating abilities of our own, experimental preparation with features of a dental infiltrant with bacteriostatic properties and to compare using an optical microscope the depth of infiltration of the designed experimental preparation with the infiltrant available on the market. MATERIAL AND METHODS: The preparation is supposed to infiltrate decalcified human enamel and be assessed with an optical microscope. Eosin, neutral fuchsine and methylene blue were added to experimental preparation with dental infiltrant features and to Icon(r) (DMG) in order to assess the depth of penetration of the experimental solution into the decalcified layers of enamel. RESULTS: The experimental solution mixes well with eosin, neutral fuchsine, and methylene blue. CONCLUSIONS: During the preliminary study, the authors concluded that the experimental solution mixes well with methylene blue, neutral fuchsine, and eosin. An addition of eosin to a preparation which infiltrates inner, demineralized enamel layers, facilitates the assessment of such a preparation with an optical microscope. A designed experimental solution with the main ingredients, i.e., 2-hydroxyethyl methacrylate (HEMA) and tetraethylene glycol dimethacrylate (TEGDMA) with a ratio of 75% to 25% penetrates the demineralized (decalcified) inner parts of the enamel and polymerizes when exposed to light. In order to assess the infiltration of the experimental solution into the demineralized enamel layers, it is required to improve the measurement techniques that utilize optical microscopy. PMID- 28028963 TI - MicroRNAs in the Occurrence and Development of Primary Hepatocellular Carcinoma. AB - Hepatocellular carcinoma is one of the deadliest types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor and there is an urgent need for development of targeted therapies. MicroRNAs represent a class of small RNAs, frequently deregulated in human malignancies. We are reviewing the role of microRNA in the development of primary hepatocellular carcinoma and its use as a biomarker for early diagnosis and clinical treatment. First, we describe the current incidence and possible causes of the incidence of hepatocellular carcinoma, followed by the introduction of microRNA synthesis, maturation and function, and finally we explain the role of microRNA in the development of hepatocellular carcinoma and its clinical value as a biological marker in the diagnosis and treatment of liver cancer. A comprehensive analysis of cellular microRNA is a benefit for early diagnosis of hepatocellular carcinoma and early clinical intervention, and microRNA is considered by some to be a key target of gene therapy to control the occurrence and development of hepatocellular carcinoma.. PMID- 28028964 TI - Genetic Factors in Selected Complex Congenital Malformations with Cleft Defect. AB - Cleft lips, alveolar ridges and palates are among the most common birth defects. There are over 500 different complex genetic disorders that include cleft defects. The most common related defects include abnormalities of the skeleton, skull, cardiovascular and nervous system. The occurrence of a cleft results from the interplay of multiple genes and environmental factors. Several thousand different mutations responsible for these syndromes have been discovered, whereas there are still numerous phenotypic cases of unknown genetic origin. The aim of this study was to present various clinical aspects and the latest discoveries with regard to genetic research in complex malformations, such as Van der Woude syndrome, popliteal pterygium syndrome, EEC syndrome, Pierre Robin sequence, various forms of Stickler syndrome, and Treacher Collins syndrome. These complex syndromes have different incidences, and most of them also have allelic variants with characteristic severities that differ even among close relatives. Easier access to genetic counseling and the lower cost of DNA testing in recent years can lead to new findings on the causes of such syndromes. PMID- 28028965 TI - Influence of Essential Oils on Infectious Agents. AB - Essential oils are substances of plant origin used to produce cosmetics, to preserve and aromatize food. Recently, they have become more popular among scientists and doctors due to their germicidal, antifungal, antiviral and anti parasitic properties. As a consequence, essential oils are regarded as the source of new therapeutic substances. Numerous publications have been written regarding their effect on microorganisms in vitro. There have also been reports regarding their use in therapy as an additive to the traditional medical treatment. Essential oils may have other properties with positive effect on health because they may have an influence on the central nervous system and human mental state. It should be, however, kept in mind that compounds of essential oils might also have side effects and lead, like antibiotics, to the selection of resistant pathogens. It is necessary to develop quality standards of obtaining and using these plant preparations, so that they may provide safe and effective assistance in the fight against human pathogens. PMID- 28028966 TI - Glycogen Synthase Kinase-3beta (GSK-3beta) and Nuclear Factor Kappa-B (NFKB) in Childhood Acute Lymphoblastic Leukemia. AB - BACKGROUND: Acute lymphocytic leukemia (ALL) is the most common hematologic malignancy in early childhood. In children with acute lymphoblastic leukemia (ALL), the activity of glycogen synthase kinase (GSK-3beta) has been associated with changes in the transcriptional activity and expression of nuclear factor kappa beta (NFKB) in the mononuclear cells of bone marrow. OBJECTIVES: The aim of the study was to determine the possible role of glycogen synthase kinase 3beta (GSK-3beta) and nuclear factor kappa beta (NFKB) as prognostic variables in pediatric patients with ALL. MATERIAL AND METHODS: This was a descriptive, transversal, and observational study. Bone marrow and blood samples were obtained from 30 children with newly-diagnosed ALL, who were seen at the Hematology Oncology Service, Hospital para el Nino (HPN), Toluca, Mexico, from 2014-2015. Anthropometric variables, clinical lab results, immunophenotype and cytogenetic abnormalities were registered. GSK-3beta was evaluated through immunohistochemistry, and NFKB messenger RNA (mRNA) with real-time polymerase chain reaction (qPCR). The cases of ALL were classified into two groups of risk: high and habitual. RESULTS: Thirty patients were included in this study, with a mean age of 7.1 years (range 2-13 years). Twenty-one were male and 9 female. Employing the morphological classification, 26 patients had type L1 ALL and the remaining 4 patients had type L2 ALL. Abnormal genes were found in 7 (23.33%) patients, ETV-RUNX1 in 3, followed by TCF3-PBX1 (two), STL1-TAL1 (one), and BCR ABL1 (one). NFKB relative expression levels, in comparison to the GSK-3beta immunohistochemistry results of the bone marrow samples, showed significant differences between positive and negative cases (p = 0.001) and between weak positive and negative cases (p = 0.002). CONCLUSIONS: These results suggest that GSK-3beta may be a prognostic biomarker in childhood ALL. PMID- 28028967 TI - Angiogenesis in CD5-positive Diffuse Large B Cell Lymphoma: A Morphometric Analysis. AB - BACKGROUND: CD5-positive diffuse large B cell lymphoma (DLBCL) is the least frequent immunohistochemical subgroup of DLBCL. The relatively little available data suggests a worse outcome in this population, resulting from a resistance to chemotherapy. OBJECTIVES: The aim was the comparative assessment of angiogenesis in both CD5-positive and CD5-negative DLBCL, as well as in lymphatic tissues without lymphoproliferative diseases. MATERIAL AND METHODS: The analysis included 36 cases of CD5-positive DLBCL (19 females and 17 males) aged 29-87 years (mean age 69), diagnosed and treated in the Maria Sklodowska-Curie Institute and Oncology Center and Medical University of Warsaw in 2002-2013. The control group comprised 28 cases of CD5-negative DLBCL (14 females and 14 males) aged 24-82 years (mean age 58.5). The secondary control group (13 cases) consisted of normal lymphatic tissue obtained from patients without lymphoproliferative diseases. The level of angiogenesis was assessed on the basis of immunohistochemical CD34, vWF and HIF1alpha expression measured using morphometric methods. RESULTS: CD5 positive DLBCL, in comparison to CD5-negative DLBCL, was characterized by: (1) higher mean of total blood vessel area, (2) higher mean total ratio of blood vessel area and staining intensity, (3) higher mean of total blood vessel area in regions defined as hot spots, (4) higher mean of total ratio of blood vessel area and staining intensity in hot spots. The measurements in lymph nodes without lymphoproliferative diseases lay between the values obtained in both DLBCL subgroups. CONCLUSIONS: We observed a significant exacerbation of angiogenesis in CD5-positive DLBCL in comparison to the CD5-negative subgroup, possibly explaining its more aggressive clinical course. Our data does not substantiate the hypothesis that angiogenesis is more pronounced in frequent CD5-negative DLBCL subgroup in comparison to benign lymphatic tissue. PMID- 28028968 TI - The Use of 3D Printing Technology in the Ilizarov Method Treatment: Pilot Study. AB - BACKGROUND: Significant developments in additive manufacturing technology have occurred in recent years. 3D printing techniques can also be helpful in the Ilizarov method treatment. OBJECTIVES: The aim of this study was to evaluate the usefulness of 3D printing technology in the Ilizarov method treatment. MATERIAL AND METHODS: Physical models of bones used to plan the spatial design of Ilizarov external fixator were manufactured by FDM (Fused Deposition Modeling) spatial printing technology. Bone models were made of poly(L-lactide) (PLA). RESULTS: Printed 3D models of both lower leg bones allow doctors to prepare in advance for the Ilizarov method treatment: detailed consideration of the spatial configuration of the external fixation, experimental assembly of the Ilizarov external fixator onto the physical models of bones prior to surgery, planning individual osteotomy level and Kirschner wires introduction sites. CONCLUSIONS: Printed 3D bone models allow for accurate preparation of the Ilizarov apparatus spatially matched to the size of the bones and prospective bone distortion. Employment of the printed 3D models of bone will enable a more precise design of the apparatus, which is especially useful in multiplanar distortion and in the treatment of axis distortion and limb length discrepancy in young children. In the course of planning the use of physical models manufactured with additive technology, attention should be paid to certain technical aspects of model printing that have an impact on the accuracy of mapping of the geometry and physical properties of the model. 3D printing technique is very useful in 3D planning of the Ilizarov method treatment. PMID- 28028969 TI - Polymorphisms of TGFbeta1T+869C and C-509T with Lung Cancer Risk: A Meta analysis. AB - BACKGROUND: Lung cancer is the most common malignancy worldwide. A better understanding of the mechanisms may contribute to early diagnosis and establishment of new therapeutic targets. OBJECTIVES: A meta-analysis was performed to investigate the association of transforming growth factor-beta 1 (TGFbeta1) T+869C and C-509T polymorphisms with lung cancer susceptibility. MATERIAL AND METHODS: Relevant studies were identified through PubMed, Medline, Embase and CNKI databases. The pooled odds ratios (ORs) with its 95% confidence intervals (CIs) were employed to assess these associations in a fixedor random effects model. RESULTS: For the TGFbeta1 T+869C polymorphism, 5 published case control studies with 1167 cases and 1365 controls were included. Overall, no significant association was found between the TGFbeta1 T+869C polymorphism and lung cancer susceptibility under any genetic models in the total population (p > 0.05). A subgroup analysis by ethnicity showed no significant association among the Asian population as well, while a significant association was observed in Caucasian descendants. For the TGFbeta1 C-509T polymorphism, 4 studies were considered, including 1029 cases and 1133 controls. However, this polymorphism also did not increase the risk of lung cancer in all genetic comparison models. CONCLUSIONS: This meta-analysis suggests that TGFbeta1 T+869C and C-509T polymorphisms may not contribute to lung cancer risk in the total population, while the T+869C polymorphism may increase the risk of lung cancer in the Caucasian population. However, many studies are still required to evaluate these associations in large populations. PMID- 28028970 TI - Diagnostic and Therapeutic Difficulties in Carotid Body Paragangliomas, Based on Clinical Experience and a Review of the Literature. AB - BACKGROUND: Paragangliomas are rare neuroendocrine tumors, representing 0.03% of all tumors. Half of them develop in the head and neck, and among these 50% are sporadic cervical tumors. OBJECTIVES: The aim of the study was to carry out an epidemiological and clinical analysis of paraganglioma patients diagnosed and treated at the authors' clinics between 1985 and 2014. MATERIAL AND METHODS: The medical data of 47 patients were analyzed. All the patients were qualified for surgery. In 43 cases (88%), simple resection of the tumor was performed, including 11 cases (22%) that additionally required vascular suturing, and 5 (10%) that required reconstruction of the internal carotid artery. Carotid vessel repair was performed by shortening the internal carotid artery in 3 cases (6%), using a saphenous vein graft in 2 cases (4%), and by creating an anastomosis between the external carotid artery and the distal portion of the internal carotid artery in one case (2%). RESULTS: In 40 cases (82%), the course of treatment was uneventful. Three patients (6%) were reoperated because of symptoms of cerebral stroke. Palsy of the hypoglossal nerve occurred in 3 cases (6%), and facial nerve palsy in 2 patients (4%). Six patients (12%) developed postoperative hematomas in the wound. In all the cases, histopathological examinations confirmed carotid paraganglioma. CONCLUSIONS: Cooperation with an otolaryngologist and vascular surgeon during surgery is recommended due to frequent damage to carotid vessels by carotid paragangliomas. Detection of the tumor in the early stages improves surgical treatment outcomes and reduces the number of complications. Regular postoperative check-ups are necessary due to possible occurrences of multiple tumors. PMID- 28028971 TI - Assessment of Pain When Uncovering Implants with Er:YAG Laser or Scalpel for Second Stage Surgery. AB - BACKGROUND: Different methods aimed at decreasing pain during some soft tissue procedures in dentistry are still under research. Modern devices as lasers could be a method to reduce the pain and duration of second stage implant surgery. OBJECTIVES: To assess the pain and the impression quality when uncovering implants with a laser and with a scalpel. MATERIAL AND METHODS: The analysis included 60 implants (Dentium SuperLine, Suwon, Korea) in 30 patients (23 women and 7 men) aged 25-69. In the experimental group, 30 implants were uncovered by means of an Er:YAG laser (LiteTouch(r), Syneron Dental, Yokneam, Israel) with the following fixed operation parameters: 300 mJ, 18 Hz, water cooling at 40%, energy density per pulse: 38.21 J/cm2, tip size: 1.0 * 17 mm, distance: 2 mm, tip angle set at 70 degrees , no anesthesia. As a control, 30 implants were uncovered using a scalpel and topical application of 20% benzocaine. An 11-point numeric pain rating scale (NRS-11) was used to evaluate the pain level. A 3-point prosthetic impression scale (PIS) designed by the authors was used to assess the quality of the impression of the implant emergence profile. RESULTS: The mean value of pain assessed on the NRS-11 for the Er:YAG laser and scalpel were 2.6 and 6, respectively. The mean value of pain for the laser and scalpel at a supracrestal height of periimplant soft tissue (SHPST) <= 3 mm were 1.8 and 4.7 respectively, and for SHPST > 3 mm the values were 3.3 and 7.4, respectively. The implant emergence profile impression showed satisfactory or ideal quality in 26 cases. CONCLUSIONS: The use of Er:YAG laser reduces pain and allows minor surgical procedures to be carried out without anesthesia. The impression quality is satisfactory for the preparation of prosthetic reconstructions. PMID- 28028972 TI - Positron Emission Tomography Scanning in the Management of Hodgkin Lymphoma Patients: A Single-Institution Experience. AB - BACKGROUND: Positron emission tomography (PET-CT) has become a valuable implement in the management of Hodgkin lymphoma (HL). However, since PET-CT is a relatively new imaging method, its capabilities have not been fully explored. OBJECTIVES: The aim of the study was to evaluate the role of PET-CT at different points in HL management. MATERIAL AND METHODS: The medical documentation of 47 HL patients treated at the Comprehensive Cancer Center in Bialystok, Poland, was analyzed retrospectively. The study group consisted of 15 men and 32 women, aged 18-59 years, in HL clinical stages II-IV, treated either with chemotherapy or sequential chemoradiotherapy. RESULTS: In 65.2% of the patients who underwent post-chemotherapy PET-CT scanning before their qualification for adjuvant radiotherapy (RT), PET-CT was decisive in qualifying them for RT, by establishing whether or not metabolic partial remission (PR) had occurred. With regard to the achievement of partial or complete response (CR), computed tomography (CT) and PET-CT results correlated in 45.5% of the patients after the completion of chemotherapy, and in 18.7% after the completion of the entire treatment (chemotherapy or chemoradiotherapy). Among the patients from the advanced-stage group (stages III/IV stage and/or bulky HL), morphological PR in CT scans after two to three courses of chemotherapy was more often associated with a lack of metabolic CR in posttreatment PET-CT scanning (p = 0.022) than in other patients. Post-treatment PET-CT scanning was shown to be highly prognostic of a relapse free follow-up (p < 0.0001) and superior to post-treatment CT imaging in relapse prediction (p < 0.0001). CONCLUSIONS: Compared to CT, PET-CT was more accurate in residual masses assessment. Notable ability of PET-CT in relapse-free follow-up prediction encourages to more common use of PET-CT in clinical practice. Further clinical research on the need for RT in patients with PR in CT parallel to CR in PET-CT is required. PMID- 28028973 TI - The Impact of 0.9% NaCl on Mesothelial Cells After Intraperitoneal Lavage During Surgical Procedures. AB - BACKGROUND: Normal saline gained wide popularity in abdominal surgery as a basic compound used in intraoperative drainage of the peritoneal cavity. However, recent studies have revealed that saline solution is not quite biocompatible with the intraperitoneal enviroment and may promote peritoneal adhesions. OBJECTIVES: The aim of the study was to evaluate the function and viability of human mesothelial cells cultured in vitro in 0.9% NaCl solution from intraperitoneal lavage carried out during laparoscopic cholecytectomies. MATERIAL AND METHODS: The study included 40 consecutive patients suffering from gallstones who underwent laparoscopic cholecystectomy. Fluid was collected after intraperitoneal lavage during the surgical procedures. The samples obtained were used as a medium for in vitro incubation of primary human mesothelial cells. After 24 h the synthesis of interleukin 6 (IL-6), plasminogen activator inhibitor (PAI) and tissue plasminogen activator (tPA), as well as the index of cell proliferation were assessed in all the experimental groups. RESULTS: All the mesothelium cell cultures treated with fluid samples obtained ex vivo were characterized by elevated levels of IL-6. The highest concentrations of PAI-1 were found in groups of cells exposed to fluid with bile; similarly, tPA synthesis was extremely elevated in groups treaded with fluid containing bile and small amounts of hemolyzed blood. In contrast, cell proliferation was exceedingly high in 2 groups of cells placed in a standard culture medium and in 0.9% NaCl solution. CONCLUSIONS: Normal saline introduced into the abdominal cavity modifies the biological and physicochemical conditions of the intraperitoneal environment. The impact of 0.9% NaCl on mesothelial cells is manifested in destabilized tissue regeneration, which supposedly initiates adhesion formation. PMID- 28028974 TI - Myocardial Ischaemia, Coronary Atherosclerosis and Pulmonary Pressure Elevation in Antiphospholipid Syndrome Patients. AB - BACKGROUND: Thrombotic events in antiphospholipid syndrome (APS) involve venous and arterial circulation with the possible involvement of coronary or pulmonary microcirculation. OBJECTIVES: To evaluate the influence of antiphospholipid antibodies (aPL) and on myocardial ischaemia assessed by single-photon emission computerized tomography (SPECT), coronary atherosclerosis assessed by multidetector computerized tomography (MDCT) and pulmonary pressure assessed by transthoracic echocardiography (TTE) in patients with primary antiphospholipid syndrome (PAPS). MATERIAL AND METHODS: TTE, SPECT (Tc 99m sestamibi) and MDCT based coronary calcium scoring were performed in 26 consecutive PAPS patients (20 females, 6 males, aged 20-61, mean 39.7) without any signs of other autoimmunological disease and without clinical symptoms of heart disease. RESULTS: Out of 26 patients, TEE showed normal left and right ventricle function in 25 (96.2%) and elevated (>= 30 mm Hg) right ventricle systolic pressure in 7 (26.9%) patients. SPECT revealed myocardial perfusion defects in 15 (57.7%) patients: exercise-induced in 6 (23.1%) and persistent in 11 (42.3%). MDCT revealed coronary calcifications in 4 (15.4%) patients. The number of plaques ranged from 1 to 11 (median 2), volume 3-201.7 mm3 (median 7), calcium scores 1.3 202.6 (median 5.7). In the group with perfusion defects or coronary calcifications (n = 15), all the patients showed elevated aCL IgG. CONCLUSIONS: In most of the relatively young APS patients, without any symptoms of ischemic heart disease, SPECT showed myocardial perfusion defects, and coronary calcifications in 1/6 of them. Right ventricle systolic pressure was elevated in 1/4 of APS patients. These pathologies, well known as cardiovascular risk markers, were associated with elevated levels of the IgG class of both anti cardiolipin and antiB2 GPI antibodies. Thus, in a high percentage of APS patients, clinically silent myocardial ischaemia, pulmonary pressure elevation and coronary atherosclerosis are present and related to the presence of antiphospholipid antibodies. PMID- 28028975 TI - Impact of Birth Weight and Smoking on Lung Function in Patients with Asthma, COPD, and Healthy Volunteers. AB - BACKGROUND: Birth weight (BW) is an important factor for determining the development of the respiratory system. The majority of research analyzed the impact of BW on lung function in youth. BW influence and smoking on lung function in adults with asthma and COPD is an interesting issue. OBJECTIVES: The aim of the study was to investigate relationships between BW, smoking, and lung function in adult healthy individuals and diagnosed with asthma or COPD. MATERIAL AND METHODS: Four hundred seventy-nine subjects were divided into 5 groups: 123 healthy non-smokers, 180 healthy smokers, 72 non-smoking asthmatics, 57 smoking asthmatics, and 47 COPD patients. Relationships between 4 BW quartiles and lung function was analyzed with respect to smoking. RESULTS: Impact analyzes of BW, smoking, and asthma on FVC% revealed that asthma is the only significant differentiating factor in this spirometric parameter (p < 0.01). FEV1% was significantly influenced by asthma and BW, and FEV1/ FVC% was exclusively influenced by asthma. Spirometric parameters increased proportionally to particular BW quartiles in healthy non-smokers group; however optimal BW quartile predicting increase of parameters was 2751-3250 g. In asthma, BW quartile predicting the increase of spirometric parameters was 3251-3750 g, but BW quartile predicting decrease of FEV1/FVC% was 2751-3250 g. The comparison of results between COPD group and results from other 4 groups showed that values of all parameters in patients with COPD did not change proportionally to all quartiles of BW. In terms of FEV1/FVC%, the proportional increase of parameter in BW quartile 2751-3250 g was observed. CONCLUSIONS: BW, as independent factor influences on spirometric parameters of healthy individuals, patients with asthma, COPD in a differentiated manner depending on quartile of BW rather than on simple linear increase of BW, regardless of smoking. PMID- 28028976 TI - Evaluating the Hearing of Patients with Pseudoexfoliation Syndrome. AB - BACKGROUND: It is estimated that pseudoexfoliation syndrome (PEX) occurs in 10 20% of the general population over 60 years of age, and its morbidity increases with age. Some research indicates that PEX may be a systemic disease. Some experts state that it can also lead to ear dysfunction. OBJECTIVES: The aim of the study was to evaluate the incidence and type of hearing disorders in patients with PEX. MATERIAL AND METHODS: The study included 51 patients (102 eyes) hospitalized in Wroclaw Medical University Hospital's Department of Ophthalmology and scheduled for cataract surgery in 2012-2014. Among these patients (whose age ranged from 55 to 92), 28 had PEX and 23 served as a control group. Both groups underwent ophtalmic examinations as well as ENT inspection and audiological tests (tonal audiometry, impedance audiometry, distortion product otoacoustic emission tests [DPOAE] and auditory brainstem response tests [ABR]). RESULTS: A statistically significant increase in the threshold of hearing in pure-tone audiometry was observed in PEX group for 2 kHz. In impedance audiometry tests, the stapedius reflex was identified in a greater proportion of patients in the PEX group than in the control group in all frequency ranges. There was no difference between the PEX groups and the control group in the results of the DPOAE and ABR tests. CONCLUSIONS: PEX can be a systemic disease that affects the functioning of the inner ear causing sensorineural hearing impairment. The increased hearing threshold in pure-tone audiometry of the patients with PEX affects the speech range (mainly the frequency of 2 kHz). Impedance audiometry and pure-tone audiometry appeared useful in audiological diagnostics of patients with PEX. PMID- 28028977 TI - The Effectiveness of Corticosteroid Usage in Complex Therapy for Severe Sepsis and Acute Respiratory Distress Syndrome in Cases of Severe Traumatic Brain Injury. AB - BACKGROUND: Severe traumatic brain injury (STBI) is an important issue in contemporary medicine and treatment strategies are still in need of improvement. The most dangerous complications of STBI are multiple organ failure and severe sepsis. As many as 80% of STBI patients with multiple organ failure have acute respiratory distress syndrome (ARDS). The need for better treatment strategies for STBI has led to investigations of the positive therapeutic effects of corticosteroids (CS). About 10 to 15 years ago research showed the inexpediency of CS in STBI therapy, but there were also contradictory findings showing their effectiveness. STBI is frequently followed by severe sepsis, which is not usually treated with CS. No scientific papers investigated the usage or non-usage of CS in patients with STBI followed by severe sepsis and ARDS. OBJECTIVES: The aim of the study was to investigate the influence of CS usage on treatment results in patients with STBI followed by severe sepsis and ARDS. MATERIAL AND METHODS: The study involved an analysis of the treatment results in 267 patients with STBI followed by severe sepsis and ARDS, who were treated with and without CS. RESULTS: The study showed that patients' mortality decreased 1.24 times with CS use (500 mg/day of Solu-Medrol(r) for three days, followed by dose reduction by one-half every 3 days). Patients who took CS survived longer than patients without this treatment. The duration mechanical ventilation was shorter in patients who were treated with CS compared to the other group. CONCLUSIONS: Further research into CS use is needed to improve treatment strategies for STBI followed by severe sepsis and ARDS. PMID- 28028978 TI - Determination of Selected Amino Acids in Serum of Patients with Liver Disease. AB - BACKGROUND: The determination of amino acids can be a reliable approach for extended diagnosis of liver diseases. This is because liver disease can be a cause of impaired amino acid metabolism. Therefore, a method for the determination of serum amino acids, applicable for clinical purposes, is necessary. OBJECTIVES: The aim of this study was to find differences in the levels of selected amino acids between patients with liver disease and a control group. MATERIAL AND METHODS: Samples of peripheral venous blood were obtained from a group of patients with liver disease (n = 131, 59 women at an average age of 60 years and 72 men at an average age of 52 years) and a control group (n = 105, 47 women at an average age of 62 years and 58 men at an average age of 58 years). Before the separation, the amino acids were derivatized with naphthalene 2,3-dicarboxaldehyde. For the separation, reverse phase column was used. The effluent was monitored with a fluorescence detector. RESULTS: There were significant differences in the concentrations of some amino acids between the patients and the control group, but also between women and men. Correlations between some amino acids and markers of liver blood tests and lipid metabolism were observed. CONCLUSIONS: A simple, relatively rapid and selective HPLC method with fluorescence detection for the determination of selected amino acids in serum has been developed. PMID- 28028979 TI - A Controlled Trial of the Efficacy of a Training Walking Program in Patients Recovering from Abdominal Aortic Aneurysm Surgery. AB - BACKGROUND: Major surgical procedures as well as general anesthesia contribute to muscle weakness and posture instability and may result in increased postoperative complications and functional disorders resulting from an elective operation. OBJECTIVES: We aim to state the significance of backward walking as a form of interval march training with patients after abdominal aortic aneurysm surgery. MATERIAL AND METHODS: Sixty-five patients were randomly divided into three subgroups and three various models of physiotherapy were applied. The participants were males, aged 65-75 years, with stable cardiologic status, absence of neurological disorders, and non-symptomatic aneurysm - non-ruptured, no pain complaints and no motor system impairments. The control group had only routine physiotherapy, since therapeutic groups I and II also had walking exercises, forward in group II and backward in group I. Both experimental groups were applied interval training. The patient data analyzed was as follows: hospitalization period-days; 6-min walking test-distance (m), training heart rate (1/min), mean speed (km/h), MET; spirometry test-FVC(L), FEV1(L), FEV1/FVC and PEF(L/s). RESULTS: The hospital stay period in all groups did not vary significantly. Statistical analysis showed that patients with backward walking had a statistically significantly lower reduction of walking distance in the corridor test when compared to the control group (p < 0.05). After the operation, a significant reduction of mean speed in the control group was noted in comparison with both the forward and backward walking groups (p < 0.05). No significant differences were noted between the experimental groups in average walking speed as well as in heart rate in all observed groups. CONCLUSIONS: Physical training applied to patients after major abdominal aortic aneurysm surgery influences sustaining the level of exercise tolerance to a small extent. Both backward and forward walking seem to be alternative methods when compared to classic post-surgery physiotherapy. PMID- 28028980 TI - Normal Values for Heart Electrophysiology Parameters of Healthy Swine Determined on Electrophysiology Study. AB - BACKGROUND: Swine are a well-recognized animal model for human cardiovascular diseases. Despite the widespread use of porcine model in experimental electrophysiology, still no reference values for intracardiac electrical activity and conduction parameters determined during an invasive electrophysiology study (EPS) have been developed in this species thus far. OBJECTIVES: The aim of the study was to develop a set of normal values for intracardiac electrical activity and conduction parameters determined during an invasive EPS of swine. MATERIAL AND METHODS: The study included 36 healthy domestic swine (24-40 kg body weight). EPS was performed under a general anesthesia with midazolam, propofol and isoflurane. The reference values for intracardiac electrical activity and conduction parameters were calculated as arithmetic means +/- 2 standard deviations. RESULTS: The reference values were determined for AH, HV and PA intervals, interatrial conduction time at its own and imposed rhythm, sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), anterograde and retrograde Wenckebach points, atrial, atrioventricular node and ventricular refractory periods. No significant correlations were found between body weight and heart rate of the examined pigs and their electrophysiological parameters. CONCLUSIONS: The hereby presented reference values can be helpful in comparing the results of various studies, as well as in more accurately estimating the values of electrophysiological parameters that can be expected in a given experiment. PMID- 28028981 TI - Assessment of Selected ROTEM Parameters, Kinetics of Fibrinogen Polymerization and Plasmin Amidolytic Activity in Patients with Congenital Fibrinogen Defects. AB - BACKGROUND: Congenital fibrinogen disorders (CFD) are rare fibrinogen deficiencies which may be quantitative or functional. The clinical course of hypofibrinogenemia (hypoFI) or dysfibrinogenemia (dysFI) is unpredictable and cannot be determined by the application of standard hemostasis tests. OBJECTIVES: The main aim of this study was to assess ROTEM parameters in CFD patients. MATERIAL AND METHODS: Nine patients with CFD were studied. The fibrinogen concentration was measured functionally and antigenically. EXTEM, INTEM, FIBTEM and APTEM tests were used to measure selected ROTEM parameters, including maximum clot firmness (MCF). Fibrin plasma polymerization, clot lysis and plasmin amidolytic activity were determined by spectrophotometric methods. RESULTS: Incorporating the antigenic, ELISA method, to the diagnostic workup allowed the initial diagnosis to be switched from hypoFI to dysFI in 3/7 patients. MCF readings (the most important parameter describing fibrin polymerization capacity) were significantly lower in patients than in controls according to all ROTEM tests. Cases with hypoFI demonstrated markedly lower readings of MCF according to all ROTEM tests than cases with dysFI. All patients demonstrated disturbances of fibrin polymerization process assessed by turbidimetry. In contrast, no marked differences were identified between studied groups in reference to plasmin amidolytic activity. CONCLUSIONS: Our data suggests that ROTEM and fibrin plasma polymerization according to the turbidimetric method have a high sensitivity towards detection of different CFD. Although ROTEM MCF assessment may help discriminate patients with hypoor dysfibrinogenemia, this finding has to be confirmed on larger groups of patients. PMID- 28028982 TI - Secondary Aortoenteric Fistula After Abdominal Aortic Graft Implementation in Our Own Material. AB - BACKGROUND: Secondary aortoenteric fistula is a rare but severe complication occurring after abdominal aortic graft implementation. OBJECTIVES: The aim of our study was to review the clinical presentation, diagnosis and postoperative course of patients with aortoenteric fistulas following vascular operations on the abdominal aorta in the years 2000-2014. MATERIAL AND METHODS: Among all the patients treated in our center, during a 10-year period, aortoenteric fistulas were observed in 24 cases. The first symptoms occurred between 4 weeks and 8 years after the procedure (3.4 years on average). The most common clinical presentation was gastrointestinal bleeding in 16 cases (66.7%). All patients underwent surgical repair of an aortoenteric fistula, with graft removal and replacement in situ using silver impregnated prosthesis. RESULTS: The 30-day mortality rate after surgical treatment of SAEF was 37.5% (9 patients). Causes of death included: hemorrhagic shock, multi-organ failure and myocardial infarction. The early complications after the surgical repair of an aortoenteric fistula occurred in 19 (79.2%) patients. Mortality during the one-year follow-up period was 38.5% (5 patients) and the one-year complication rate was 69.2%. CONCLUSIONS: Each patient with a history of abdominal aortic graft implementation and presenting symptoms of gastrointestinal bleeding requires careful diagnosing for aortoenteric fistula. New methods of surgical treatment offering lower mortality should be developed. PMID- 28028983 TI - Monitoring of Circulating Tumor Cells by a Combination of Immunomagnetic Enrichment and RT-PCR in Colorectal Cancer Patients Undergoing Surgery. AB - BACKGROUND: The presence of circulating tumor cells (CTC) has been reported in patients with advanced colorectal cancer. Monitoring CTC (also known as a liquid biopsy) has recently become the center of interest for low-invasive monitoring of cancer progression and predictive biomarkers testing. Along with high-cost technology and a complex methodology, a straightforward method based on magnetic beads enrichment followed by RT-PCR is set to allow for routine CTC analysis in colorectal cancer patients. OBJECTIVES: The main purpose of this study was to evaluate the possibility of CTC detection in routine monitoring of patients starting before and continuing after surgery. MATERIAL AND METHODS: The investigated group consisted of 30 patients mainly in advanced stages of colorectal cancer. In all patients, CTC detection was performed prior to surgery, in a subset of 14 patients additional sampling was done during and after surgery. In all cases, peripheral blood was processed using AdnaTest ColonCancer kit, which relies on enriching CTCs using EpCAM-functionalized magnetic beads and subsequently identifying tumorspecific CEA, EGFR and GA733-2 mRNA transcripts. RESULTS: Out of all the tested samples, CTC were found in one patient suffering from advanced disease with lung and liver metastases. There, however, the positive finding was confirmed in 3 consecutive samples acquired before, during and shortly after palliative R2 resection. CONCLUSIONS: The presence of CTC may be used to observe post-operative disease development. Due to the overall low CTC detection, further technology development may be necessary before its universal applicability to manage colorectal cancer patients. PMID- 28028984 TI - Whole-Body Cryostimulation as an Effective Method of Reducing Oxidative Stress in Healthy Men. AB - BACKGROUND: Whole-body cryostimulation (WBC) is the therapeutic exposure of the total human body (without underwear) to a very low temperature (below -100 degrees C) for 120-180 s. Currently, WBC is used more frequently not only in the treatment of patients suffering from various diseases, but also by healthy people as a wellness method. OBJECTIVES: The aim of this research is to evaluate the impact of WBC procedures on oxidative stress parameters in healthy men. MATERIAL AND METHODS: The study involved 32 healthy male subjects who were randomly divided into 2 groups: 16 men exposed to WBC procedures with subsequent kinesiotherapy (WBC group) and 16 men exposed only to kinesiotherapy procedures (KT group). Depending on the group, the subjects were exposed to 10 daily WBC procedures lasting 3 min, with a subsequent 60-min of kinesiotherapy, or exclusively to kinesiotherapy. In subjects from both groups, a day before the beginning of a cycle of treatment and a day after its completion, the level of selected indicators of oxidative stress and non-enzymatic antioxidants, as well as the activity of antioxidant enzymes in serum, plasma and erythrocyte lysates were determined. RESULTS: In the WBC group subjects, we recorded a statistically significant decrease in the concentrations of most of the parameters of oxidative stress with an accompanying increase in plasma concentrations of non-enzymatic antioxidants (total antioxidant status and uric acid). We recorded no significant changes in the activities of antioxidant enzymes (plasma total superoxide dismutase (SOD) and its isoenzymes SOD-Mn and SOD-ZnCu, erythrocyte catalase, glutathione peroxidase and glutathione reductase). CONCLUSIONS: The results we obtained confirmed that WBC decreases oxidative stress in healthy men. PMID- 28028985 TI - Using an Electron Scanning Microscope to Assess the Penetrating Abilities of an Experimental Preparation with Features of a Dental Infiltrant: Preliminary Study. AB - BACKGROUND: The resin infiltration technique is one of the micro-invasive methods whose aim is the penetration of demineralized enamel with a low viscosity resin. This technique allows the dentist to avoid the application of mechanical means of treatment. OBJECTIVES: The objective of this preliminary study was to attempt to determine the possibilities of using an electron microscope to assess the penetrating abilities of an experimental preparation with features of a dental infiltrant and to compare the depth of infiltration of the designed experimental preparation with an infiltrant available on the market. MATERIAL AND METHODS: A bioactive methacrylate monomer based on PMMAn with built-in metronidazole was synthesized. The commercially available Icon solution (with contrast agent YbF3) and the experimental solution were applied to the relevant parts of teeth. The dissected sections along the long tooth axis and polished surfaces were then examined with use of an electron scanning microscope. RESULTS: The backscattered electron technique gives much better results than the secondary electron method as it makes it possible to localize even very small YbF3 particles. CONCLUSIONS: The authors concluded that the backscattered electron technique gives much better results than the secondary electron method as it makes it possible to localize even very small particles of the contrast agent. In order to prevent blockage of decalcified enamel tissue by ytterbium trifluoride (YbF3) grains, a nanoparticle form of that compound should be used (that is, particles with sizes in the range of 10-9 m). PMID- 28028986 TI - Objectification of Orthodontic Treatment Needs: Does the Classification of Malocclusions or a History of Orthodontic Treatment Matter? AB - BACKGROUND: Orthodontic classifications make it possible to give an accurate diagnosis but do not indicate an objective orthodontic treatment need. In order to evaluate the need for treatment, it is necessary to use such indicators as the IOTN. OBJECTIVES: The aim of the study was to find (i) relationships between individual diagnosis and objective recommendations for treatment and (ii) an answer to the question whether and which occlusal anomalies play an important role in the objectification of treatment needs. MATERIAL AND METHODS: Two hundred three 18-year-old adolescents (104 girls, 99 boys) were examined. In order to recognize occlusal anomalies, the classifications proposed by Orlik-Grzybowska and Ackerman-Proffit were used. The occlusal anomalies were divided into three categories: belonging to both classifications, typical of OrlikGrzybowska classification and typical of Ackerman-Proffit classification. In order to determine the objective need for orthodontic treatment, the Dental Health Component (DHC) of the IOTN was used. RESULTS: The occurrence of the following malocclusions covered by both classifications, namely abnormal overjet, crossbite and Angle's class, had a statistically significant (p < 0.05) impact on an increase of treatment needs in the subjects (DHC > 3). As for the classification by Orlik-Grzybowska, dental malpositions and canine class significantly affected the need for orthodontic treatment, while in the case of the Ackerman-Proffit scheme, it was asymmetry and crowding. There was no statistically significant correlation between past orthodontic treatment and current orthodontic treatment need. CONCLUSIONS: IOTN may be affected by a greater number of occlusal anomalies than it was assumed. Orthodontic treatment received in the past slightly reduces the need for treatment in 18-year-olds. PMID- 28028987 TI - Evaluation of the Erosive Potential of Selected Isotonic Drinks: In Vitro Studies. AB - BACKGROUND: Isotonic drinks are an important component of the diet of athletes. Sports drinks cause the body to maintain proper hydration and supplement minerals which are lost in sweat during excessive exercising. Aside from the benefits of isotonic drinks, it is important to be aware of the harmful effects of citric acid within the products, which could cause enamel erosion. OBJECTIVES: The aim of the study was to evaluate the erosive potential of sports drinks using confocal scanning laser microscopy (CLSM). MATERIAL AND METHODS: The studies measured the change of surface roughness of the dental enamel after etching using Isostar, Powerade and Gatorade drinks, and Fortuna orange juice. Measurements were repeated after 1, 2 and 3 h of exposure to the selected liquid. The evaluation of calcium compound contents was carried out using the complexonometric method. RESULTS: The surface roughness measurements of dental enamel showed that the lowest values of the parameters Ra and Rz were obtained for Isostar and orange juice. The research of the calcium content in the selected beverages showed the highest value in Isostar (320.0 mg/L) and the lowest in Powerade (40.0 mg/L) and Gatorade (21.0 mg/L). CONCLUSIONS: Our study confirms that Isostar is the safest sports drink, among the analyzed beverages, for athletes, because it causes the least erosive changes in dental enamel. It is recommended to supplement beverages to reduce their potential for erosion using calcium compounds. PMID- 28028988 TI - Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment. AB - Direct oral anticoagulants (DOACs) or non-vitamin K oral anticoagulants (NOACs) are increasingly used in the prevention of recurrent venous thromboembolism (VTE), including that associated with thrombophilia. The efficacy of DOACs in thrombophilic patients, especially those with severe trombophilia or triple positive antiphospholipid syndrome (APS) with arterial thromboembolic events, remains controversial. Most case reports and case series indicate that DOACs are an attractive therapeutic option in the vast majority of these patients at high risk of recurrent VTE with more concerns raised in high-risk APS patients and these deficient in protein S (PS). Adherence to DOACs is of paramount importance in these patients. In this review we presented available data on the management of patients with thrombophilia using rivaroxaban, dabigatran or apixaban at standard doses. Moreover, we also demonstrated the overall effects of DOACs on coagulation tests, particularly those determined during thrombophilia screening such as lupus anticoagulant, antithrombin, protein C, PS, activated protein C ratio. Despite the paucity of data from randomized studies, the current evidence supports the use of DOACs in thrombophilia, especially those who prefer such treatment or have unstable anticoagulation with vitamin K antagonists or unacceptable adverse events while using these drugs. PMID- 28028989 TI - Thymosin beta as an Actin-binding Protein with a Variety of Functions. AB - According to current data, the thymosin beta family is composed of 20 short (40 44 amino acid) peptides, but in a healthy human body only 2 are expressed - thymosin beta4 and beta10. Their most characteristic feature is the ability to form a complex with monomeric actin, thereby preventing polymerization into a filamentous form, hence the name Actin-Binding Protein (ABP). These peptides play numerous different functions. Among others, they affect the processes of carcinogenesis, differentiation and angiogenesis, influence metalloproteinase activity and accelerate wound healing. Moreover, significant biological activity has also been displayed by Tbeta4 derived peptides: Ac-SDKP, the N-terminal fragment which is involved, inter alia, in stimulating angiogenesis and the inhibition of stem cell proliferation and Tbeta4 sulfoxide, an oxidation product of one of the peptide methionine by hydrogen peroxide, which inhibit the development of inflammation. The properties of these peptides have potential applications in cardiovascular medicine, dermatology, ophthalmology and other medical areas. PMID- 28028990 TI - Acquired von Willebrand Syndrome. AB - Acquired von Willebrand syndrome is a rare hemorrhagic diathesis, with clinical symptoms similar to those associated with the inherited form von Willebrand disease. This syndrome is characterized by a lack of previous bleeding symptoms, negative familial history, and occurrence in a relatively older age. Most commonly, acquired von Willebrand syndrome develops in the course of other conditions, such as lymphoproliferative, myeloproliferative, cardiovascular and autoimmune disorders; additionally, it can be associated with some non hematological malignancies and use of certain prescription drugs. Pathogenesis of von Willebrand syndrome is complex and not fully understood. Deficiency or impaired activity of von Willebrand factor can result from the presence of specific antibodies against this factor, its adsorption onto the surfaces of neoplastic cells, mechanic injury or proteolysis. Diagnosis is based on the measurements of plasma concentration and the activity of von Willebrand factor and multimer analysis. Management of acquired von Willebrand syndrome includes the therapy of the underlying disease and the control or prevention of bleeding. Hemostatic drugs that are most commonly prescribed in this syndrome include desmopressin, von Willebrand factor concentrates, recombinant activated factor VII, intravenous immunoglobulin and adjunctive antifibrinolytic therapy. Additionally, plasmapheresis is required in some cases. PMID- 28028991 TI - Computed tomography-based quantitative assessment of lower extremity lymphedema following treatment for gynecologic cancer. AB - OBJECTIVE: To develop an algorithmic quantitative skin and subcutaneous tissue volume measurement protocol for lower extremity lymphedema (LEL) patients using computed tomography (CT), to verify the usefulness of the measurement techniques in LEL patients, and to observe the structural characteristics of subcutaneous tissue according to the progression of LEL in gynecologic cancer. METHODS: A program for algorithmic quantitative analysis of lower extremity CT scans has been developed to measure the skin and subcutaneous volume, muscle compartment volume, and the extent of the peculiar trabecular area with a honeycombed pattern. The CT venographies of 50 lower extremities from 25 subjects were reviewed in two groups (acute and chronic lymphedema). RESULTS: A significant increase in the total volume, subcutaneous volume, and extent of peculiar trabecular area with a honeycombed pattern except quantitative muscle volume was identified in the more-affected limb. The correlation of CT-based total volume and subcutaneous volume measurements with volumetry measurement was strong (correlation coefficient: 0.747 and 0.749, respectively). The larger extent of peculiar trabecular area with a honeycombed pattern in the subcutaneous tissue was identified in the more-affected limb of chronic lymphedema group. CONCLUSION: CT-based quantitative assessments could provide objective volume measurements and information about the structural characteristics of subcutaneous tissue in women with LEL following treatment for gynecologic cancer. PMID- 28028992 TI - Impact of histological subtype on survival in patients with locally advanced cervical cancer that were treated with definitive radiotherapy: adenocarcinoma/adenosquamous carcinoma versus squamous cell carcinoma. AB - OBJECTIVE: To compare the survival outcomes of patients with cervical squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) among patients with locally advanced cervical cancer that were treated with definitive radiotherapy. METHODS: The baseline characteristics and outcome data of patients with locally advanced cervical cancer who were treated with definitive radiotherapy between November 1993 and February 2014 were collected and retrospectively reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of AC/ASC histology. RESULTS: The patients with AC/ASC of the cervix exhibited significantly shorter overall survival (OS) (p=0.004) and progression-free survival (PFS) (p=0.002) than the patients with SCC of the cervix. Multivariate analysis showed that AC/ASC histology was an independent negative prognostic factor for PFS. Among the patients who displayed AC/ASC histology, larger tumor size, older age, and incomplete response to radiotherapy were found to be independent prognostic factors. PFS was inversely associated with the number of poor prognostic factors the patients exhibited (the estimated 1-year PFS rates; 100.0%, 77.8%, 42.8%, 0.0% for 0, 1, 2, 3 factors, respectively). CONCLUSION: Locally advanced cervical cancer patients with AC/ASC histology experience significantly worse survival outcomes than those with SCC. Further clinical studies are warranted to develop a concurrent chemoradiotherapy (CCRT) protocol that is specifically tailored to locally advanced cervical AC/ASC. PMID- 28028993 TI - Update on immune checkpoint inhibitors in gynecological cancers. AB - In recent years, progress in our understanding of immune-modulatory signaling pathways in immune cells and the tumor microenvironment (TME) has led to rejuvenated interest in cancer immunotherapy. In particular, immunotherapy targeting the immune checkpoint receptors such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), programmed cell-death 1 (PD-1), and programmed cell-death ligand 1 (PD-L1) have demonstrated clinical activity in a wide variety of tumors, including gynecological cancers. This review will focus on the emerging clinical data on the therapeutic role of immune checkpoint inhibitors, and potential strategies to enhance the efficacy of this class of compounds, in the context of gynecological cancers. It is anticipated that future biomarker directed clinical trials will provide further insights into the mechanisms underlying response and resistance to immunotherapy, and help guide our approach to designing therapeutic combinations that have the potential to enhance the benefit of immunotherapy in patients with gynecologic cancers. PMID- 28028994 TI - An open-label, multicenter, phase I trial of a cremophor-free, polymeric micelle formulation of paclitaxel combined with carboplatin as a first-line treatment for advanced ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG-3016). AB - OBJECTIVE: This phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer. METHODS: This open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40-75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m2, once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group. RESULTS: In this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m2 or 260 mg/m2, but at 300 mg/m2, 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m2 or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%. CONCLUSION: Genexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m2 or less for a phase II study. PMID- 28028995 TI - Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations. AB - Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response. PMID- 28028996 TI - Genetic Profiles of Korean Patients With Glucose-6-Phosphate Dehydrogenase Deficiency. AB - BACKGROUND: We describe the genetic profiles of Korean patients with glucose-6 phosphate dehydrogenase (G6PD) deficiencies and the effects of G6PD mutations on protein stability and enzyme activity on the basis of in silico analysis. METHODS: In parallel with a genetic analysis, the pathogenicity of G6PD mutations detected in Korean patients was predicted in silico. The simulated effects of G6PD mutations were compared to the WHO classes based on G6PD enzyme activity. Four previously reported mutations and three newly diagnosed patients with missense mutations were estimated. RESULTS: One novel mutation (p.Cys385Gly, labeled G6PD Kangnam) and two known mutations [p.Ile220Met (G6PD Sao Paulo) and p.Glu416Lys (G6PD Tokyo)] were identified in this study. G6PD mutations identified in Koreans were also found in Brazil (G6PD Sao Paulo), Poland (G6PD Seoul), United States of America (G6PD Riley), Mexico (G6PD Guadalajara), and Japan (G6PD Tokyo). Several mutations occurred at the same nucleotide, but resulted in different amino acid residue changes in different ethnic populations (p.Ile380 variant, G6PD Calvo Mackenna; p.Cys385 variants, Tomah, Madrid, Lynwood; p.Arg387 variant, Beverly Hills; p.Pro396 variant, Bari; and p.Pro396Ala in India). On the basis of the in silico analysis, Class I or II mutations were predicted to be highly deleterious, and the effects of one Class IV mutation were equivocal. CONCLUSIONS: The genetic profiles of Korean individuals with G6PD mutations indicated that the same mutations may have arisen by independent mutational events, and were not derived from shared ancestral mutations. The in silico analysis provided insight into the role of G6PD mutations in enzyme function and stability. PMID- 28028997 TI - Comparative Analysis of Clinical Samples Showing Weak Serum Reaction on AutoVue System Causing ABO Blood Typing Discrepancies. AB - BACKGROUND: ABO blood typing in pre-transfusion testing is a major component of the high workload in blood banks that therefore requires automation. We often experienced discrepant results from an automated system, especially weak serum reactions. We evaluated the discrepant results by the reference manual method to confirm ABO blood typing. METHODS: In total, 13,113 blood samples were tested with the AutoVue system; all samples were run in parallel with the reference manual method according to the laboratory protocol. RESULTS: The AutoVue system confirmed ABO blood typing of 12,816 samples (97.7%), and these results were concordant with those of the manual method. The remaining 297 samples (2.3%) showed discrepant results in the AutoVue system and were confirmed by the manual method. The discrepant results involved weak serum reactions (<2+ reaction grade), extra serum reactions, samples from patients who had received stem cell transplants, ABO subgroups, and specific system error messages. Among the 98 samples showing <=1+ reaction grade in the AutoVue system, 70 samples (71.4%) showed a normal serum reaction (>=2+ reaction grade) with the manual method, and 28 samples (28.6%) showed weak serum reaction in both methods. CONCLUSIONS: ABO blood tying of 97.7% samples could be confirmed by the AutoVue system and a small proportion (2.3%) needed to be re-evaluated by the manual method. Samples with a 2+ reaction grade in serum typing do not need to be evaluated manually, while those with <=1+ reaction grade do. PMID- 28028998 TI - Long-Term Quality Control Program Plan for Cord Blood Banks in Korea: A Pilot Study for Cryopreservation Stability. AB - BACKGROUND: Maintaining the quality of cryopreserved cord blood is crucial. In this pilot study, we describe the results of the internal quality control program for a cord blood bank thus far. METHODS: Donated cord blood units unsuitable for transplantation were selected for internal quality control once a month. One unit of cord blood, aliquoted into 21 capillaries, was cryopreserved and thawed annually to analyze the total nucleated cell count, CD34+ cell count, cell viability test, and colony-forming units assay. RESULTS: No significant differences in the variables (total nucleated cell count, cell viability, CD34+ cell count) were observed between samples cryopreserved for one and two years. Upon comparing the variables before cryopreservation and post thawing with the capillaries of one year of storage, cell viability and CD34+ cell counts decreased significantly. The use of cord blood samples in capillaries, which can be easily stored for a long period, was similar to the methods used for testing segments attached to the cord blood unit. CONCLUSIONS: The results of this study may be useful for determining the period during which the quality of cryopreserved cord blood units used for transplantation is maintained. PMID- 28028999 TI - Automated Nucleic Acid Extraction Systems for Detecting Cytomegalovirus and Epstein-Barr Virus Using Real-Time PCR: A Comparison Study Between the QIAsymphony RGQ and QIAcube Systems. AB - BACKGROUND: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are increasingly important in immunocompromised patients. Nucleic acid extraction methods could affect the results of viral nucleic acid amplification tests. We compared two automated nucleic acid extraction systems for detecting CMV and EBV using real time PCR assays. METHODS: One hundred and fifty-three whole blood (WB) samples were tested for CMV detection, and 117 WB samples were tested for EBV detection. Viral nucleic acid was extracted in parallel by using QIAsymphony RGQ and QIAcube (Qiagen GmbH, Germany), and real-time PCR assays for CMV and EBV were performed with a Rotor-Gene Q real-time PCR cycler (Qiagen). Detection rates for CMV and EBV were compared, and agreements between the two systems were analyzed. RESULTS: The detection rate of CMV and EBV differed significantly between the QIAsymphony RGQ and QIAcube systems (CMV, 59.5% [91/153] vs 43.8% [67/153], P=0.0005; EBV, 59.0% [69/117] vs 42.7% [50/117], P=0.0008). The two systems showed moderate agreement for CMV and EBV detection (kappa=0.43 and 0.52, respectively). QIAsymphony RGQ showed a negligible correlation with QIAcube for quantitative EBV detection. QIAcube exhibited EBV PCR inhibition in 23.9% (28/117) of samples. CONCLUSIONS: Automated nucleic acid extraction systems have different performances and significantly affect the detection of viral pathogens. The QIAsymphony RGQ system appears to be superior to the QIAcube system for detecting CMV and EBV. A suitable sample preparation system should be considered for optimized nucleic acid amplification in clinical laboratories. PMID- 28029000 TI - Comparison Between Soluble ST2 and High-Sensitivity Troponin I in Predicting Short-Term Mortality for Patients Presenting to the Emergency Department With Chest Pain. AB - BACKGROUND: High-sensitivity cardiac troponin I (hs-cTnI) and the soluble isoform of suppression of tumorigenicity 2 (sST2) are useful prognostic biomarkers in acute coronary syndrome (ACS). The aim of this study was to test the short term prognostic value of sST2 compared with hs-cTnI in patients with chest pain. METHODS: Assays for hs-cTnI and sST2 were performed in 157 patients admitted to the Emergency Department (ED) for chest pain at arrival. In-hospital and 30-day follow-up mortalities were assessed. RESULTS: The incidence of ACS was 37%; 33 patients were diagnosed with ST elevation myocardial infarction (STEMI), and 25 were diagnosed with non-ST elevation myocardial infarction (NSTEMI). Compared with the no acute coronary syndrome (NO ACS) group, the median level of hs-cTnI was higher in ACS patients: 7.22 (5.24-14) pg/mL vs 68 (15.33-163.50) pg/mL (P<0.0001). In all patients, the sST2 level at arrival showed higher independent predictive power than hs-cTnI (odds ratio [OR] 20.13, P<0.0001 and OR 2.61, P<0.0008, respectively). sST2 at ED arrival showed a greater prognostic value for cardiovascular events in STEMI (area under the curve [AUC] 0.80, P<0.001) than NSTEMI patients (AUC 0.72, P<0.05). Overall, 51% of the STEMI patients with an sST2 value>35 ng/mL at ED arrival died during the 30-day follow-up. CONCLUSIONS: sST2 has a greater prognostic value for 30-day cardiac mortality after discharge in patients presenting to the ED for chest pain compared with hs-cTnI. In STEMI patients, an sST2 value >35 ng/mL at ED arrival showed the highest predictive power for short-term mortality. PMID- 28029001 TI - Performance of the Real-Q EBV Quantification Kit for Epstein-Barr Virus DNA Quantification in Whole Blood. AB - There has been increasing interest in standardized and quantitative Epstein-Barr virus (EBV) DNA testing for the management of EBV disease. We evaluated the performance of the Real-Q EBV Quantification Kit (BioSewoom, Korea) in whole blood (WB). Nucleic acid extraction and real-time PCR were performed by using the MagNA Pure 96 (Roche Diagnostics, Germany) and 7500 Fast real-time PCR system (Applied Biosystems, USA), respectively. Assay sensitivity, linearity, and conversion factor were determined by using the World Health Organization international standard diluted in EBV-negative WB. We used 81 WB clinical specimens to compare performance of the Real-Q EBV Quantification Kit and artus EBV RG PCR Kit (Qiagen, Germany). The limit of detection (LOD) and limit of quantification (LOQ) for the Real-Q kit were 453 and 750 IU/mL, respectively. The conversion factor from EBV genomic copies to IU was 0.62. The linear range of the assay was from 750 to 106 IU/mL. Viral load values measured with the Real-Q assay were on average 0.54 log10 copies/mL higher than those measured with the artus assay. The Real-Q assay offered good analytical performance for EBV DNA quantification in WB. PMID- 28029002 TI - Dengue Virus Serotypes Circulating in Khyber Pakhtunkhwa Province, Pakistan, 2013 2015. AB - From 2013 to 2015, the National Institute of Health, Pakistan, received 1,270 blood samples of suspected dengue cases reported from inpatient and outpatient departments of various hospitals in Khyber Pakhtunkhwa (KPK) province. In this study, we determined the circulating dengue virus (DENV) serotypes using real time reverse transcriptase (RT)-PCR to understand the serotype-based epidemiology of DENV. All four serotypes (DENV-1 [6%], DENV-2 [33%], DENV-3 [47%], and DENV-4 [0.1%]) were found circulating during the study period. Our findings suggest the need for an active surveillance system coupled with the laboratory diagnosis, especially in the chronic endemic areas of the country. Public awareness programs are needed for effective control and prevention of outbreaks in the future. PMID- 28029003 TI - Effect of Vitamin D Status on Von Willebrand Factor and ADAMTS13 in Diabetic Patients on Chronic Hemodialysis. AB - Von Willebrand factor (vWF) is a glycoprotein with a crucial role in the formation of platelet thrombi, and ADAMTS13 is the main enzyme responsible for vWF cleavage. Both are important in the relationship between diabetic nephropathy, hypercoagulability, and cardiovascular disease. This study evaluated a potential relationship between vitamin D (vitD) levels, vWF, ADAMTS13 activity, and inflammation in diabetic patients on chronic hemodialysis (HD). Blood samples from 52 diabetic patients on chronic HD were obtained to determine vitD levels, vWF, and ADAMTS13 activity, and inflammatory markers. HD patients were grouped according to 25-hydroxyvitamin D [25(OH) VitD]<25 nmol/L (n=16) or >25 nmol/L (n=36). vWF antigen and vWF activity were elevated in both groups, with an average of 214.3+/-82.6% and 175.8+/-72.6%, respectively. Average ADAMTS13 activity was within the normal range in both groups. Blood samples from the vitD <25 nmol/L group showed a positive correlation between c-reactive protein (CRP) and vWF levels (P=0.023; r=0.564; 95% confidence interval=0.095-0.828), with a negative correlation between HbA1c and 25(OH) VitD (P=0.015; r=-0.337; 95% confidence interval=-0.337-0.19). Diabetic patients on chronic HD had elevated vWF levels and activity with no significant change in ADAMTS13 activity. The correlation between CRP and vWF levels in the 25(OH) VitD<25 nmol/L group suggests inflammatory-related endothelial dysfunction in these patients. PMID- 28029004 TI - Differences in Hematological and Clinical Features Between Essential Thrombocythemia Cases With JAK2- or CALR-Mutations. PMID- 28029005 TI - Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous PRF1 Defects Involving a PRF1 Mutation, c.1091T>G. PMID- 28029006 TI - A Case of Therapy-Related Acute Leukemia With Mixed Phenotype With BCR-ABL1 After Treatment of Diffuse Large B-Cell Lymphoma. PMID- 28029007 TI - Thyroxine (T4) Autoantibody Interference of Free T4 Concentration Measurement in a Patient With Hashimoto's Thyroiditis. PMID- 28029008 TI - Colistin Resistance in Escherichia coli Isolates From Patients With Bloodstream Infection in Korea. PMID- 28029009 TI - Susceptibility of Ceftolozane-Tazobactam and Ceftazidime-Avibactam Against a Collection of beta-Lactam-Resistant Gram-Negative Bacteria. PMID- 28029010 TI - Concomitant AID Expression and BCL7A Loss Associates With Accelerated Phase Progression and Imatinib Resistance in Chronic Myeloid Leukemia. PMID- 28029012 TI - Efficacy of Moderate Intensity Statins in the Treatment of Dyslipidemia in Korean Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: There has been evidences of ethnic differences in the low density lipoprotein cholesterol (LDL-C) lowering effect of statin. We aimed to evaluate the efficacy of moderate-intensity statins in the treatment of dyslipidemia among Korean patients with type 2 diabetes mellitus (T2DM). METHODS: We analyzed a retrospective cohort that consisted of Korean patients with T2DM aged 40 to 75 years who had been prescribed any of the moderate-intensity statins (atorvastatin 10 or 20 mg, rosuvastatin 5 or 10 mg, pitavastatin 2 mg, or pravastatin 40 mg). Among them, only patients with baseline lipid profiles before starting statin treatment were selected, and changes in their lipid profiles before and 6 months after statin therapy were analyzed. RESULTS: Following the first 6 months of therapy, the overall LDL-C reduction was -47.4% (interquartile range, -56.6% to 34.1%). In total, 92.1% of the participants achieved an LDL-C level of <100 mg/dL, 38.3% had a 30% to 50% reduction in their LDL-C levels, and 42.3% had a reduction in their LDL-C levels greater than 50%. The response rates of each drug for achieving a LDL-C level <100 mg/dL were 81.7%, 93.1%, 95.0%, 95.0%, 96.5%, and 91.7% for treatment with atorvastatin doses of 10 or 20 mg, rosuvastatin 5 or 10 mg, pitavastatin 2 mg, and pravastatin 40 mg, respectively. CONCLUSION: In conclusion, the use of moderate-intensity statins reduced LDL-C levels less than 100 mg/dL in most of the Korean patients studied with T2DM. The efficacies of those statins were higher than expected in about 42% of Korean patients with T2DM. PMID- 28029011 TI - Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines. AB - Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings. PMID- 28029013 TI - Application of the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline to the Korean National Health and Nutrition Examination Surveys from 1998 to 2012. AB - BACKGROUND: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the treatment of blood cholesterol recommends statin therapy for individuals at high risk of atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to investigate serial trends in the percentages of Korean adults considered eligible for statin therapy according to the new ACC/AHA cholesterol guideline. METHODS: Data from the Korean National Health and Nutrition Examination Survey (KNHANES) I (1998, n=7,698), II (2001, n=5,654), III (2005, n=5,269), IV (2007 to 2009, n=15,727), and V (2010 to 2012, n=16,304), which used a stratified, multistage, probability sampling design, were used as representative of the entire Korean population. RESULTS: The percentage of adults eligible for statin therapy according to the ACC/AHA cholesterol guideline increased with time: 17.0%, 19.0%, 20.8%, 20.2%, and 22.0% in KNHANES I, II, III, IV, and V, respectively (P=0.022). The prevalence of ASCVD was 1.4% in KNHANES I and increased to 3.3% in KNHANES V. The percentage of diabetic patients aged 40 to 75 years with a low density lipoprotein cholesterol levels of 70 to 189 mg/dL increased from 4.8% in KNHANES I to 6.1% in KNHANES V. People with an estimated 10-year ASCVD risk >=7.5% and aged 40 to 75 years accounted for the largest percentage among the four statin benefit groups: 9.1% in KNHANES I and 11.0% in KNHANES V. CONCLUSION: Application of the 2013 ACC/AHA guideline has found that the percentage of Korean adults in the statin benefit groups has increased over the past 15 years. PMID- 28029014 TI - Regulating Hypothalamus Gene Expression in Food Intake: Dietary Composition or Calorie Density? AB - BACKGROUND: The proportion of saturated fatty acids/unsaturated fatty acids in the diet seems to act as a physiological regulation on obesity, cardiovascular diseases, and diabetes. Differently composed fatty acid diets may induce satiety of the hypothalamus in different ways. However, the direct effect of the different fatty acid diets on satiety in the hypothalamus is not clear. METHODS: Three experiments in mice were conducted to determine whether: different compositions of fatty acids affects gene mRNA expression of the hypothalamus over time; different types of fatty acids administered into the stomach directly affect gene mRNA expression of the hypothalamus; and fat composition changes in the diet affects gene mRNA expression of the hypothalamus. RESULTS: The type of fat in cases of purified fatty acid administration directly into the stomach may cause changes of gene expressions in the hypothalamus. Gene expression by dietary fat may be regulated by calorie amount ingested rather than weight amount or type of fat. CONCLUSION: Therefore, the calorie density factor of the diet in regulating hypothalamic gene in food intake may be detrimental, although the possibility of type of fat cannot be ruled out. PMID- 28029015 TI - Association between Blood Mercury Level and Visceral Adiposity in Adults. AB - BACKGROUND: Few studies have examined the association between mercury exposure and obesity. The aim of this study is to investigate the association between blood mercury concentrations and indices of obesity in adults. METHODS: A total of 200 healthy subjects, aged 30 to 64 years, who had no history of cardiovascular or malignant disease, were examined. Anthropometric and various biochemical profiles were measured. Visceral adipose tissue (VAT) was measured using dual-energy X-ray absorptiometry (DXA). RESULTS: All subjects were divided into three groups according to blood mercury concentrations. Compared with the subjects in the lowest tertile of mercury, those in the highest tertile were more likely to be male; were current alcohol drinkers and smokers; had a higher body mass index (BMI), waist circumference (WC), and VAT; had higher levels of blood pressure, fasting glucose, and insulin resistance; and consumed more fish. The blood mercury concentration was significantly associated with anthropometric parameters, showing relationships with BMI, WC, and VAT. After adjusting for multiple risk factors, the odds ratios (ORs) for high mercury concentration was significantly higher in the highest VAT tertile than in the lowest VAT tertile (OR, 2.66; 95% confidence interval, 1.05 to 6.62; P<0.05). CONCLUSION: The blood mercury concentration was significantly associated with VAT in healthy adults. Further studies are warranted to confirm our findings. PMID- 28029016 TI - Relationship between Regional Body Fat Distribution and Diabetes Mellitus: 2008 to 2010 Korean National Health and Nutrition Examination Surveys. AB - BACKGROUND: The aim of this study was to investigate the association between regional body fat distribution, especially leg fat mass, and the prevalence of diabetes mellitus (DM) in adult populations. METHODS: A total of 3,181 men and 3,827 postmenopausal women aged 50 years or older were analyzed based on Korea National Health and Nutrition Examination Surveys (2008 to 2010). Body compositions including muscle mass and regional fat mass were measured using dual energy X-ray absorptiometry. RESULTS: The odds ratios (ORs) for DM was higher with increasing truncal fat mass and arm fat mass, while it was lower with increasing leg fat mass. In a partial correlation analysis adjusted for age, leg fat mass was negatively associated with glycosylated hemoglobin in both sexes and fasting glucose in women. Leg fat mass was positively correlated with appendicular skeletal muscle mass and homeostasis model assessment of beta cell. In addition, after adjusting for confounding factors, the OR for DM decreased gradually with increasing leg fat mass quartiles in both genders. When we subdivided the participants into four groups based on the median values of leg fat mass and leg muscle mass, higher leg fat mass significantly lowered the risk of DM even though they have smaller leg muscle mass in both genders (P<0.001). CONCLUSION: The relationship between fat mass and the prevalence of DM is different according to regional body fat distribution. Higher leg fat mass was associated with a lower risk of DM in Korean populations. Maintaining leg fat mass may be important in preventing impaired glucose tolerance. PMID- 28029018 TI - Exenatide versus Insulin Lispro Added to Basal Insulin in a Subgroup of Korean Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) and obesity is increasing in Korea. Clinical studies in patients with T2DM have shown that combining the glucagon-like peptide-1 receptor agonist exenatide twice daily with basal insulin is an effective glucose-lowering strategy. However, these studies were predominantly conducted in non-Asian populations. METHODS: We conducted a subgroup analysis of data from a multinational, 30-week, randomized, open-label trial to compare the effects of exenatide twice daily (n=10) or three times daily mealtime insulin lispro (n=13) among Korean patients with T2DM inadequately controlled (glycosylated hemoglobin [HbA1c] >7.0%) on metformin plus optimized insulin glargine. RESULTS: Exenatide twice daily and insulin lispro both reduced HbA1c (mean -1.5% and -1.0%, respectively; P<0.01 vs. baseline). Fasting glucose and weight numerically decreased with exenatide twice daily (-0.7 mmol/L and -0.7 kg, respectively) and numerically increased with insulin lispro (0.9 mmol/L and 1.0 kg, respectively). Minor hypoglycemia occurred in four patients receiving exenatide twice daily and three patients receiving insulin lispro. Gastrointestinal adverse events were the most common with exenatide twice daily treatment. CONCLUSION: This analysis found treatment with exenatide twice daily improved glycemic control without weight gain in Korean patients with T2DM unable to achieve glycemic control on metformin plus basal insulin. PMID- 28029017 TI - Serum Calcium and the Risk of Incident Metabolic Syndrome: A 4.3-Year Retrospective Longitudinal Study. AB - BACKGROUND: An association between serum calcium level and risk of metabolic syndrome (MetS) has been suggested in cross-sectional studies. This study aimed to evaluate the association between baseline serum calcium level and risk of incident MetS in a longitudinal study. METHODS: We conducted a retrospective longitudinal study of 12,706 participants without MetS who participated in a health screening program, had normal range serum calcium level at baseline (mean age, 51 years), and were followed up for 4.3 years (18,925 person-years). The risk of developing MetS was analyzed according to the baseline serum calcium levels. RESULTS: A total of 3,448 incident cases (27.1%) of MetS developed during the follow-up period. The hazard ratio (HR) for incident MetS did not increase with increasing tertile of serum calcium level in an age- and sex-matched model (P for trend=0.915). The HRs (95% confidence interval [CI]) for incident MetS comparing the second and the third tertiles to the first tertile of baseline serum calcium level were 0.91 (95% CI, 0.84 to 0.99) and 0.85 (95% CI, 0.78 to 0.92) in a fully adjusted model, respectively (P for trend=0.001). A decreased risk of incident MetS in higher tertiles of serum calcium level was observed in subjects with central obesity and/or a metabolically unhealthy state at baseline. CONCLUSION: There was no positive correlation between baseline serum calcium levels and incident risk of MetS in this longitudinal study. There was an association between higher serum calcium levels and decreased incident MetS in individuals with central obesity or two components of MetS at baseline. PMID- 28029019 TI - Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment. AB - The tumor microenvironment is comprised of diverse stromal cell populations in addition to tumor cells. Increasing evidence now clearly supports the role of microenvironment stromal cells in tumor progression and metastasis, yet the regulatory mechanisms and interactions among tumor and stromal cells remain to be elucidated. Bone metastasis is the major problem in many types of human malignancies including prostate, breast and lung cancers, and the biological basis of bone metastasis let alone curative approaches are largely undetermined. Among the many types of stromal cells in bone, osteoblasts are shown to be an important player. In this regard, osteoblasts are a key target cell type in the development of bone metastasis, but there are currently no drugs or therapeutic approaches are available that specifically target osteoblasts. This review paper summarizes the current knowledge on osteoblasts in the metastatic tumor microenvironment, aiming to provide clues and directions for future research endeavor. PMID- 28029020 TI - Clinical Update in Aspects of the Management of Autoimmune Thyroid Diseases. AB - Aspects of autoimmune thyroid disease updated in this review include: immunoglobulin G4 (IgG4)-related thyroid disease (Riedel's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, IgG4-related Hashimoto's thyroiditis, and Graves' disease with elevated IgG4 levels); recent epidemiological studies from China and Denmark indicating that excess iodine increases the incidence of Hashimoto's thyroiditis and hypothyroidism; immunomodulatory agents (ipilimumab, pembrolizumab, nivolumab) activate immune response by inhibiting T-cell surface receptors which down-regulate immune response, i.e., cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 pathways; alemtuzumab is a humanised monoclonal antibody to CD52 which causes immune depletion and thyroid autoimmune disease especially Graves' hyperthyroidism; small molecule ligand (SML) agonists which activate receptors, SML neutral antagonists, which inhibit receptor activation by agonists, and SML inverse agonists which inhibit receptor activation by agonists and inhibit constitutive agonist independent signaling have been identified. SML antagonism of thyroid-stimulating hormone-receptor stimulatory antibody could treat Graves' hyperthyroidism and Graves' ophthalmopathy; and thyroxine treatment of subclinical hypothyroidism can produce iatrogenic subclinical hyperthyroidism with the risk of atrial fibrillation and osteoporosis. The increased risk of harm from subclinical hyperthyroidism may be stronger than the potential benefit from treatment of subclinical hypothyroidism. PMID- 28029021 TI - Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, occurring when fat is accumulated in the liver without alcohol consumption. NAFLD is the most common liver disorder in advanced countries. NAFLD is a spectrum of pathology involving hepatic steatosis with/without inflammation and nonalcoholic steatohepatitis with accumulation of hepatocyte damage and hepatic fibrosis. Recent studies have revealed that NAFLD results in the progression of cryptogenic cirrhosis that leads to hepatocarcinoma and cardiovascular diseases such as heart failure. The main causes of NAFLD have not been revealed yet, metabolic syndromes including obesity and insulin resistance are widely accepted for the critical risk factors for the pathogenesis of NAFLD. Nuclear receptors (NRs) are transcriptional factors that sense environmental or hormonal signals and regulate expression of genes, involved in cellular growth, development, and metabolism. Several NRs have been reported to regulate genes involved in energy and xenobiotic metabolism and inflammation. Among various NRs, farnesoid X receptor (FXR) is abundantly expressed in the liver and a key regulator to control various metabolic processes in the liver. Recent studies have shown that NAFLD is associated with inappropriate function of FXR. The impact of FXR transcriptional activity in NAFLD is likely to be potential therapeutic strategy, but still requires to elucidate underlying potent therapeutic mechanisms of FXR for the treatment of NAFLD. This article will focus the physiological roles of FXR and establish the correlation between FXR transcriptional activity and the pathogenesis of NAFLD. PMID- 28029022 TI - How to Begin Molecular Research of Metabolic Diseases. AB - Advancing higher education is an important goal within the scientific and medical communities. The Korean Endocrine Society has worked with medical researchers who hope to conduct molecular research in addition to their clinical education. Based on concepts developed at a 2016 educational workshop, this article summarizes the requirement for a strong foundation in the performance of molecular research. Specifically, recent articles in metabolic research are highlighted to provide examples of commonly used techniques in this field of study. PMID- 28029023 TI - Brain Regulation of Energy Metabolism. AB - In healthy individuals, energy intake is in balance with energy expenditure, which helps to maintain a normal body weight. The brain's inability to control energy homeostasis underlies the pathology of hyperphagia and obesity. The brain detects body energy excess and deficit by sensing the levels of circulating metabolic hormones and nutrients and by receiving metabolic information from the periphery via the autonomic nervous system. A specialized neuronal network coordinates energy intake behavior and the metabolic processes affecting energy expenditure. Here, we briefly review neuronal mechanisms by which our body maintains energy balance. PMID- 28029024 TI - Nonalbuminuric Renal Insufficiency: Can It Be a Novel Category of Diabetic Nephropathy? PMID- 28029025 TI - Klinefelter Syndrome and Metabolic Disorder. PMID- 28029026 TI - Waist Circumference as a Marker of Obesity Is More Predictive of Coronary Artery Calcification than Body Mass Index in Apparently Healthy Korean Adults: The Kangbuk Samsung Health Study. AB - BACKGROUND: We aimed to assess the risk for coronary artery calcification (CAC) according to groups subdivided by body mass index (BMI) and waist circumference (WC) in apparently healthy Korean adults. METHODS: Thirty-three thousand four hundred and thirty-two participants (mean age, 42 years) in a health screening program were divided into three groups according to BMI: <23 kg/m2 (normal), 23 to 25 kg/m2 (overweight), and >25 kg/m2 (obese). In addition, the participants were divided into two groups according to WC. Coronary artery calcium score (CACS) was measured with multi-detector computed tomography in all participants. Presence of CAC was defined as CACS >0. RESULTS: When logistic regression analysis was performed with the presence of CAC as the dependent variable, the risk for CAC increased as BMI increased after adjusting for confounding variables (1.102 [95% confidence interval (CI), 1.000 to 1.216]; 1.284 [95% CI, 1.169 to 1.410]; in the overweight and obese groups vs. the normal weight group). When the participants were divided into six groups according to BMI and WC, the subjects with BMI and WC in the obese range showed the highest risk for CAC (1.321 [95% CI, 1.194 to 1.461]) and those with BMI in the overweight range and WC in the obese range showed the second highest risk for CAC (1.235 [95% CI, 1.194 to 1.461]). CONCLUSION: Participants with obesity defined by both BMI and WC showed the highest risk for CAC. Those with BMIs in the overweight range but with WC in the obese range showed the second highest risk for CAC, suggesting that WC as a marker of obesity is more predictive of CAC than BMI. PMID- 28029027 TI - Prevalent Rate of Nonalbuminuric Renal Insufficiency and Its Association with Cardiovascular Disease Event in Korean Type 2 Diabetes. AB - BACKGROUND: Nonalbuminuric renal insufficiency is a unique category of diabetic kidney diseases. The objectives of the study were to evaluate prevalent rate of nonalbuminuric renal insufficiency and to investigate its relationship with previous cardiovascular disease (CVD) event in Korean patients with type 2 diabetes mellitus (T2DM). METHODS: Laboratory and clinical data of 1,067 subjects with T2DM were obtained and reviewed. Study subjects were allocated into four subgroups according to the CKD classification. Major CVD events were included with coronary, cerebrovascular, and peripheral vascular events. RESULTS: Nonalbuminuric stage >=3 CKD group, when compared with albuminuric stage >=3 CKD group, had shorter diabetic duration, lower concentrations of glycated hemoglobin, high density lipoprotein cholesterol, and high-sensitivity C-reactive protein, lower prevalent rates of retinopathy and previous CVD, and higher rate of treatment with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. Nonalbuminuric stage >=3 CKD group showed a greater association with prior CVD events than no CKD group; however, albuminuric stage >=3 CKD group made addition to increase prevalence of prior CVD events significantly when CKD categories were applied as covariates. Association of prior CVD events, when compared with normal estimated glomerular filtration rate (eGFR) and nonalbuminuria categories, became significant for declined eGFR, which was higher for eGFR of <30 mL/min/1.73 m2, and albuminuria. CONCLUSION: The results show that subjects with nonalbuminuric stage >=3 CKD is significantly interrelated with occurrence of prior CVD events than those with normal eGFR with or without albuminuria. Comparing with normal eGFR and nonalbuminuria categories, the combination of increased degree of albuminuria and declined eGFR is becoming significant for the association of prior CVD events. PMID- 28029028 TI - The Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome. AB - BACKGROUND: In subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown. METHODS: Thirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test. RESULTS: Levels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001). CONCLUSION: The HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients. PMID- 28029029 TI - Obesity and Hyperglycemia in Korean Men with Klinefelter Syndrome: The Korean Endocrine Society Registry. AB - BACKGROUND: The aim of this study was to investigate the prevalence of obesity in Korean men with Klinefelter syndrome (KS) and the associated risk factors for obesity and hyperglycemia. METHODS: Data were collected retrospectively from medical records from 11 university hospitals in Korea between 1994 and 2014. Subjects aged >=18 years with newly diagnosed KS were enrolled. The following parameters were recorded at baseline before treatment: chief complaint, height, weight, fasting glucose level, lipid panel, blood pressure, testosterone, luteinizing hormone, follicle-stimulating hormone, karyotyping patterns, and history of hypertension, diabetes, and dyslipidemia. RESULTS: Data were analyzed from 376 of 544 initially enrolled patients. The rate of the 47 XXY chromosomal pattern was 94.1%. The prevalence of obesity (body mass index >=25 kg/m2) in Korean men with KS was 42.6%. The testosterone level was an independent risk factor for obesity and hyperglycemia. CONCLUSION: Obesity is common in Korean men with KS. Hypogonadism in patients with KS was associated with obesity and hyperglycemia. PMID- 28029030 TI - Low-Temperature Solution-Processed Thiophene-Sulfur-Doped Planar ZnO Nanorods as Electron-Transporting Layers for Enhanced Performance of Organic Solar Cells. AB - 1-D ZnO represents a fascinating class of nanostructures that are significant to optoelectronics. In this work, we investigated the use of an eco-friendly, metal free in situ doping through a pure thiophene-sulfur (S) on low temperature processed (<95 degrees C) and annealed (<170 degrees C), planar 1-D ZnO nanorods (ZnRs) spin-coated as a hole-blocking and electron transporting layer (ETL) for inverted organic solar cells (iOSCs). The TEM, HRTEM, XPS, FT-IR, EDS and Raman studies clearly reveal that the thiophene-S (Thi-S) atom is incorporated on planar ZnRs. The investigations in electrical properties suggest the enhancement in conductivity after Thi-S doping on 1-D ZnRs. The iOSCs of poly(3-hexylthiophene-2,5-diyl) and phenyl-C61-butyric acid methyl ester (P3HT: PC60BM) photoactive layer containing thiophene-S doped planar ZnRs (Thi-S-PZnRs) as ETL exhibits power conversion efficiency (PCE) of 3.68% under simulated AM 1.5 G, 100 mW cm-2 illumination. The ~47% enhancement in PCE compared with pristine planar ZnRs (PCE = 2.38%) ETL is attributed to a combination of desirable energy level alignment, morphological modification, increased conductivity and doping effect. The universality of Thi-S-PZnRs ETL is demonstrated by the highest PCE of 8.15% in contrast to 6.50% exhibited by the iOSCs of ZnRs ETL for the photoactive layer comprising of poly[4,8-bis(5-(2-ethylhexyl)thiophene-2-yl)benzo[1,2-b;4,5 b]dithiophene-2,6-diyl-alt-(4-(2-ethylhexyl)-3-fluorothieno[3,4-b]thiophene-)-2 carboxylate-2-6-diyl)]: phenyl-C71-butyric acid methyl ester (PTB7-Th: PCB71M). This enhancement in PCE is observed to be driven mainly through improved photovoltaic parameters like fill factor (ff) as well as photocurrent density (Jsc), which are assigned to increased conductivity, exciton dissociation, and effective charge extraction, while; better ohmic contact, reduced charge recombination, and low leakage current density resulted in increased Voc. PMID- 28029031 TI - Inkjet-Printing Enzyme Inhibitory Assay Based on Determination of Ejection Volume. AB - An accurate, rapid, and cost-effective methodology for enzyme inhibitor assays is highly needed for large-scale screening to evaluate the efficacy of drugs at the molecular level. For the first time, we have developed an inkjet printing-based enzyme inhibition assay for the assessment of drug activity using a conventional inkjet printer composed of four cartridges. The methodology is based on the determination of the number of moles of the drug on the printed surface. The number of moles was quantified through the volume of substance ejected onto the printed surface. The volume ejected on the reaction spot was determined from the density of reagent ink solution and its weight loss after printing. A xanthine oxidase (XOD) inhibition assay was executed to quantitatively evaluate antioxidant activities of the drug based on the determination of the number of moles of the drug ejected by inkjet printing. The assay components of xanthine, nitro blue tetrazolium (NBT), superoxide dismutase (SOD)/drug, and XOD were printed systematically on A4 paper. A gradient range of the number of moles of SOD/drug printed on A4 paper could be successfully obtained. Because of the effect of enzyme activity inhibition, incrementally reduced NBT formazan colors appeared on the paper in a number-of-moles-dependent manner. The observed inhibitory mole (IM50) values of tested compounds exhibited a similar tendency in their activity order, compared to the IC50 values observed through absorption assay in well plates. Inkjet printing-based IM50 assessment consumed a significantly smaller reaction volume (by 2-3 orders of magnitude) and more rapid reaction time, compared to the well-plate-based absorption assay. PMID- 28029032 TI - Effective Thermo-Capillary Mixing in Droplet Microfluidics Integrated with a Microwave Heater. AB - In this study, we present a microwave-based microfluidic mixer that allows rapid mixing within individual droplets efficiently. The designed microwave mixer is a coplanar design with a small footprint, which is fabricated on a glass substrate and integrated with a microfluidic chip. The mixer works essentially as a resonator that accumulates an intensive electromagnetic field into a spiral capacitive gap (around 200 MUm), which provides sufficient energy to heat-up droplets that pass through the capacitive gap. This microwave actuation induces nonuniform Marangoni stresses on the interface, which results in three dimensional motion inside the droplet and thus fast mixing. In order to evaluate the performance of the microwave mixer, droplets with highly viscous fluid, 75% (w/w) glycerol solution, were generated, half of which were seeded with fluorescent dye for imaging purposes. The relative importance of different driving forces for mixing was evaluated qualitatively using magnitude analysis, and the effect of the applied power on mixing performance was also investigated. Mixing efficiency was quantified using the mixing index, which shows as high as 97% mixing efficiency was achieved within the range of milliseconds. This work demonstrates a very unique approach of utilizing microwave technology to facilitate mixing in droplet microfluidics systems, which can potentially open up areas for biochemical synthesis applications. PMID- 28029034 TI - Conductive Polymer-Coated Carbon Nanotubes To Construct Stretchable and Transparent Electrochemical Sensors. AB - Carbon nanotube (CNT)-based flexible sensors have been intensively developed for physical sensing. However, great challenges remain in fabricating stretchable CNT films with high electrochemical performance for real-time chemical sensing, due to large sheet resistance of CNT film and further resistance increase caused by separation between each CNT during stretching. Herein, we develop a facile and versatile strategy to construct single-walled carbon nanotubes (SWNTs)-based stretchable and transparent electrochemical sensors, by coating and binding each SWNT with conductive polymer. As a polymer with high conductivity, good electrochemical activity, and biocompatibility, poly(3,4-ethylenedioxythiophene) (PEDOT) acting as a superior conductive coating and binder reduces contact resistance and greatly improves the electrochemical performance of SWNTs film. Furthermore, PEDOT protects the SWNTs junctions from separation during stretching, which endows the sensor with highly mechanical compliance and excellent electrochemical performance during big deformation. These unique features allow real-time monitoring of biochemical signals from mechanically stretched cells. This work represents an important step toward construction of a high performance CNTs-based stretchable electrochemical sensor, therefore broadening the way for stretchable sensors in a diversity of biomedical applications. PMID- 28029033 TI - PB@Au Core-Satellite Multifunctional Nanotheranostics for Magnetic Resonance and Computed Tomography Imaging in Vivo and Synergetic Photothermal and Radiosensitive Therapy. AB - To integrate multiple diagnostic and therapeutic strategies on a single particle through simple and effective methods is still challenging for nanotheranostics. Herein, we develop multifunctional nanotheranostic PB@Au core-satellite nanoparticles (CSNPs) based on Prussian blue nanoparticles (PBNPs) and gold nanoparticles (AuNPs), which are two kinds of intrinsic theranostic nanomaterials, for magnetic resonance (MR)-computed tomography (CT) imaging and synergistic photothermal and radiosensitive therapy (PTT-RT). PBNPs as cores enable T1- and T2-weighted MR contrast and strong photothermal effect, while AuNPs as satellites offer CT enhancement and radiosensitization. As revealed by both MR and CT imaging, CSNPs realized efficient tumor localization by passively targeted accumulation after intravenous injection. In vivo studies showed that CSNPs resulted in synergistic PTT-RT action to achieve almost entirely suppression of tumor growth without observable recurrence. Moreover, no obvious systemic toxicity of mice confirmed good biocompatibility of CSNPs. These results raise new possibilities for clinical nanotheranostics with multimodal diagnostic and therapeutic coalescent design. PMID- 28029035 TI - Dual-Functional Carbon Dots Pattern on Paper Chips for Fe3+ and Ferritin Analysis in Whole Blood. AB - Though microfluidic paper analytical devices (MUPADs) have attracted paramounting attentions in recent years as promising devices for low cost point-of-care tests, their real applications for blood analysis are still challenged by integrating sample preparation with different detection modes on a same MUPAD. Herein, we developed a novel MUPAD, which well coupled automatic serum extraction with reliable dual mode iron health tests: fluorescent analysis for Fe3+ and colorimetric ELISA for ferritin. All these functions are made available by in situ carbon dots (CDs) and AuNPs sequential patterning techniques. For CDs immobilization, hydrothermal reaction was taken on paper, to which a patterned through-hole polydimethylsiloxane (PDMS) mask was applied. None fluorescence CDs (nF-CDs) were generated on exposed regions, while the fluorescent CDs (F-CDs) were generated simultaneously on covered regions. Sensitive serum iron quantification was realized on the F-CDs modified regions, where Fe3+ ion can selectively quench the fluorescence of F-CDs. For AuNPs immobilization, electroless plating was taken on nF-CDs modified regions. The resulting AuNPs on nF-CDs layer on one hand triggered the coagulation of blood cells and thus led to the longest ever wicking distance for serum separation, on the other hand facilitated colorimetric enzyme linked immunosorbent assay (ELISA) for detection of serum ferritin. Combining the two readings, the MUPAD can provide reliable measurement for serum iron and serum ferritin in whole blood. Furthermore, as CDs and AuNPs modified MUPAD has the features of easy handling, low-cost, lightweight, and disposability, it is accounting for a promising prototype for whole blood point-of-care analysis. PMID- 28029036 TI - Scout-MRM: Multiplexed Targeted Mass Spectrometry-Based Assay without Retention Time Scheduling Exemplified by Dickeya dadantii Proteomic Analysis during Plant Infection. AB - Targeted mass spectrometry of a surrogate peptide panel is a powerful method to study the dynamics of protein networks, but chromatographic time scheduling remains a major limitation for dissemination and implementation of robust and large multiplexed assays. We unveil a Multiple Reaction Monitoring method (Scout MRM) where the use of spiked scout peptides triggers complex transition lists, regardless of the retention time of targeted surrogate peptides. The interest of Scout-MRM method regarding the retention time independency, multiplexing capability, reproducibility, and putative interest in facilitating method transfer was illustrated by a 782-peptide-plex relative assay targeting 445 proteins of the phytopathogen Dickeya dadantii during plant infection. PMID- 28029038 TI - Dual Electrochemiluminescence Signal System for In Situ and Simultaneous Evaluation of Multiple Cell-Surface Receptors. AB - A mutiplex cytosensor based on a dual electrochemiluminescence (ECL) signal system was fabricated for in situ and simultaneous detection of the expression levels of multiple cell-surface receptors, mannose and epidermal growth factor receptor (EGFR), using luminol-capped gold nanoparticles (Au@luminol) and CdS quantum dots (CdS QDs) as potential-resolved ECL nanoprobes. Two spatially resolved areas on indium tin oxide (ITO) electrodes were modified with polyaniline (PANI) by electropolymerization, on which gold nanoparticles (AuNPs) were attached to strengthen conductivity and stability of the sensing interface. Human mucin1 protein (MUC1) aptamer was immobilized onto AuNPs for capturing MUC1 positive MCF-7 cells. Au@luminol and CdS QDs as ECL nanoprobes were covalently linked with concanavalin A (ConA) and epidermal growth factor (EGF) to label MCF 7 cells on the two areas of the cytosensor separately. Compared to conventional multiplex biosensor, we demonstrated a novel analysis platform for the simultaneous detection of multiple cell-surface receptors; it could provide two sensitive and potential-resolved ECL signals during one potential scanning and avoid cross-reactivity between the two nanoprobes. The quantification of MCF-7 cells on the two spatially resolved areas could be achieved over the linear range from 102 to 1.0 * 106 cells mL-1 with a detection limit of 20 cells mL-1. This multiplex cytosensor was further applied for simultaneous quantitative evaluation of the expression levels of mannose and EGFR on MCF-7 cells, revealed that the average numbers of mannose and EGFR per captured MCF-7 cell were 1.2 * 106 and 0.86 * 105 with the relative standard deviation of 5.3% and 4.2%, respectively. The multiplex cytosensor was capable of evaluating multiple cell-surface receptors, which would be beneficial to developing a better diagnostic tool for diseases. PMID- 28029037 TI - Investigation of the Complete Suite of the Leucine and Isoleucine Isomers: Toward Prediction of Ion Mobility Separation Capabilities. AB - In this study we investigated 11 isomers with the molecular formula C6H13NO2 (m/z 131) to ascertain the potential of utilizing drift tube ion mobility mass spectrometry to aid in the separation of isomeric mixtures. This study of small molecules provides a detailed examination of the application of uniform field ion mobility for a narrow scope of isomers with variations in both bond coordination and stereochemistry. For small molecules, it was observed that in general constitutional isomers are more readily separated by uniform field mobility in comparison to stereoisomers such as enantiomers or diastereomers. Diastereomers exhibited differences in their collision cross section (CCS), but were unresolvable in a mixture, whereas the enantiomers studied did not exhibit statistically different CCS values. A mathematical relationship relating the CCS to resolving power was developed in order to predict the required ion mobility resolving power needed to separate the various isomer classes. For the majority of isomers evaluated in this study, a uniform field-based resolving power of 100 was predicted to be sufficient to resolve over half (~60%) of all hypothetical isomer pairs, including leucine and isoleucine, whereas their stereoisomers (d- and l-forms) are predicted to be significantly more challenging, if not impossible, to separate by conventional drift tube techniques. PMID- 28029039 TI - Stimuli-Sensitive Biodegradable and Amphiphilic Block Copolymer-Gemcitabine Conjugates Self-Assemble into a Nanoscale Vehicle for Cancer Therapy. AB - The availability and the stability of current anticancer agents, particularly water-insoluble drugs, are still far from satisfactory. A widely used anticancer drug, gemcitabine (GEM), is so poorly stable in circulation that some polymeric drug-delivery systems have been under development for some time to improve its therapeutic index. Herein, we designed, prepared, and characterized a biodegradable amphiphilic block N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-GEM conjugate-based nanoscale and stimuli-sensitive drug-delivery vehicle. An enzyme-sensitive oligopeptide sequence glycylphenylalanylleucylglycine (GFLG) was introduced to the main chain with hydrophilic and hydrophobic blocks via the reversible addition-fragmentation chain transfer (RAFT) polymerization. Likewise, GEM was conjugated to the copolymer via the enzyme-sensitive peptide GFLG, producing a high molecular weight (MW) product (90 kDa) that can be degraded into smaller MW segments (<50 kDa), and ensuring potential rapid site-specific release and stability in vivo. The amphiphilic copolymer-GEM conjugate can self-assemble into compact nanoparticles. NIR fluorescent images demonstrated that the conjugate-based nanoparticles could accumulate and be retained within tumors, resulting in significant increased antitumor efficacy compared to free GEM. The conjugate was not toxic to organs of the mice as measured by body weight reductions and histological analysis. In summary, this biodegradable amphiphilic block HPMA copolymer-gemcitabine conjugate has the potential to be a stimuli-sensitive and nanoscale drug-delivery vehicle. PMID- 28029040 TI - Harvesting Triplet Excitons with Exciplex Thermally Activated Delayed Fluorescence Emitters toward High Performance Heterostructured Organic Light Emitting Field Effect Transistors. AB - The utilization of triplet excitons plays a key role in obtaining high emission efficiency for organic electroluminescent devices. However, to date, only phosphorescent materials have been implemented to harvest the triplet excitons in the organic light-emitting field effect transistors (OLEFETs). In this work, we report the first incorporation of exciplex thermally activated delayed fluorescence (TADF) emitters in heterostructured OLEFETs to harvest the triplet excitons. By developing a new kind of exciplex TADF emitter constituted by m MTDATA (4,4',4"-tris(N-3-methylphenyl-N-phenylamino)triphenylamine) as the donor and OXD-7 (1,3-bis[2-(4-tert-butylphenyl)-1,3,4-oxadiazo-5-yl]benzene) as the acceptor, an exciton utilization efficiency of 74.3% for the devices was achieved. It is found that the injection barrier between hole transport layer and emission layer as well as the ratio between donor and acceptor would influence the external quantum efficiency (EQE) significantly. Devices with a maximum EQE of 3.76% which is far exceeding the reported results for devices with conventional fluorescent emitters were successfully demonstrated. Moreover, the EQE at high brightness even outperformed the result for organic light-emitting diode based on the same emitter. Our results demonstrate that the exciplex TADF emitters can be promising candidates to develop OLEFETs with high performance. PMID- 28029041 TI - Analysis of HypD Disulfide Redox Chemistry via Optimization of Fourier Transformed ac Voltammetric Data. AB - Rapid disulfide bond formation and cleavage is an essential mechanism of life. Using large amplitude Fourier transformed alternating current voltammetry (FTacV) we have measured previously uncharacterized disulfide bond redox chemistry in Escherichia coli HypD. This protein is representative of a class of assembly proteins that play an essential role in the biosynthesis of the active site of [NiFe]-hydrogenases, a family of H2-activating enzymes. Compared to conventional electrochemical methods, the advantages of the FTacV technique are the high resolution of the faradaic signal in the higher order harmonics and the fact that a single electrochemical experiment contains all the data needed to estimate the (very fast) electron transfer rates (both rate constants >= 4000 s-1) and quantify the energetics of the cysteine disulfide redox-reaction (reversible potentials for both processes approximately -0.21 +/- 0.01 V vs SHE at pH 6). Previously, deriving such data depended on an inefficient manual trial-and-error approach to simulation. As a highly advantageous alternative, we describe herein an automated multiparameter data optimization analysis strategy where the simulated and experimental faradaic current data are compared for both the real and imaginary components in each of the 4th to 12th harmonics after quantifying the charging current data using the time-domain response. PMID- 28029042 TI - Carbon Isotopomer Analysis with Non-Unifom Sampling HSQC NMR for Cell Extract and Live Cell Metabolomics Studies. AB - Isotopomer analysis using either 13C NMR or LC/GC-MS has been an invaluable tool for studying metabolic activities in a variety of systems. Traditional challenges are, however, that 13C-detected NMR is insensitive despite its high resolution, and that MS-based techniques cannot easily differentiate positional isotopomers. In addition, current 13C NMR or LC/GC-MS has limitations in detecting metabolites in living cells. Here, we describe a non-uniform sampling-based 2D heteronuclear single quantum coherence (NUS HSQC) approach to measure metabolic isotopomers in both cell lysates and living cells. The method provides a high resolution that can resolve multiplet structures in the 13C dimension while retaining the sensitivity of the 1H-indirect detection. The approach was tested in L1210 mouse leukemia cells labeled with 13C acetate by measuring NUS HSQC with 25% sampling density. The results gave a variety of metabolic information such as (1) higher usage of acetate in acetylation pathway than aspartate synthesis, (2) TCA cycle efficiency changes upon the inhibition of mitochondrial oxidative phosphorylation by pharmacological agents, and (3) position-dependent isotopomer patterns in fatty acids in living cells. In addition, we were able to detect fatty acids along with other hydrophilic molecules in one sample of live cells without extraction. Overall, the high sensitivity and resolution along with the application to live cells should make the NUS HSQC approach attractive in studying carbon flux information in metabolic studies. PMID- 28029043 TI - Critical Conditions for Liquid Chromatography of Statistical Copolymers: Functionality Type and Composition Distribution Characterization by UP-LCCC/ESI MS. AB - Statistical ethylene oxide (EO) and propylene oxide (PO) copolymers of different monomer compositions and different average molar masses additionally containing two kinds of end groups (FTD) were investigated by ultra high pressure liquid chromatography under critical conditions (UP-LCCC) combined with electrospray ionization time-of flight mass spectrometry (ESI-TOF-MS). Theoretical predictions of the existence of a critical adsorption point (CPA) for statistical copolymers with a given chemical and sequence distribution1 could be studied and confirmed. A fundamentally new approach to determine these critical conditions in a copolymer, alongside the inevitable chemical composition distribution (CCD), with mass spectrometric detection, is described. The shift of the critical eluent composition with the monomer composition of the polymers was determined. Due to the broad molar mass distribution (MMD) and the presumed existence of different end group functionalities as well as monomer sequence distribution (MSD), gradient separation only by CCD was not possible. Therefore, isocratic separation conditions at the CPA of definite CCD fractions were developed. Although the various present distributions partly superimposed the separation process, the goal of separation by end group functionality was still achieved on the basis of the additional dimension of ESI-TOF-MS. The existence of HO-H besides the desired allylO-H end group functionalities was confirmed and their amount estimated. Furthermore, indications for a MSD were found by UPLC/MS/MS measurements. This approach offers for the first time the possibility to obtain a fingerprint of a broad distributed statistical copolymer including MMD, FTD, CCD, and MSD. PMID- 28029044 TI - Oxidative Aza-Annulation of Enynyl Azides to 2-Keto/Formyl-1H-pyrroles. AB - A method for the construction of pyrroles bearing a 2-keto or formyl group through the intramolecular oxidative aza-annulation of enynyl azides is reported for the first time. It involves a sequential carbon-nitrogen/carbon-oxygen bond formations, and the combination of AuCl3 with AgSbF6 was identified as a suitable reagent system to promote the present reaction. The required enynyl azides are readily prepared from Morita-Baylis-Hillman (MBH) acetates of acetylenic aldehydes. PMID- 28029045 TI - Asymmetric Total Syntheses of (-)-Hedycoropyrans A and B. AB - The first and asymmetric total synthesis of (-)-hedycoropyrans A (1) was accomplished in 18 steps with 5.4% overall yield. The key features of our strategy include (1) construction of the unusual trans-2-aryl-6-alkyl tetrahydropyran core via Achmatowicz rearrangement, Zn-mediated reductive deoxygenation, and Heck-Matsuda coupling reaction, and (2) installation of 3,4 anti-dihydroxy from the corresponding 3,4-syn-dihydroxy THP through chemo- and regioselective IBX oxidation and Evans-Saksena reduction. In addition, C2 epimerization of (-)-hedycoropyan A (1) under the acidic condition furnished (-) hedycoropyan B (2) with 71% yield. This finding might suggest the biogenetic origin of hedycoropyran B. PMID- 28029046 TI - Diverse Pathways in Catalytic Reactions of Propargyl Aryldiazoacetates: Selectivity between Three Reaction Sites. AB - Three catalyst-dependent divergent reaction pathways for reactions of propargyl aryldiazoacetates are disclosed. Transition metal catalysts including those of rhodium(II), palladium(0 and II), silver(I), mercury(II), copper(I and II), platinum(II), and cationic gold(I) are effective for reactions that proceed through dinitrogen extrusion, carbene/alkyne metathesis, and aromatic substitution to form fused indeno-furanones, and use of tetrakis(acetonitrile)copper(I) provides indeno-furanones in the highest product yields. A Lewis acid catalyzed pathway that forms furan-2-ones is uncovered with FeCl3, ZnBr2, and BF3.Et2O as catalysts that proceed through activation of the aryldiazoacetate ester for arylpropargyl cation dissociation followed by recombination through cation addition to the diazo carbon. Neutral gold catalysts selectively activate the triple bond of propargyl aryldiazoacetates, resulting in the formation of allenic aryldiazoesters that further undergo uncatalyzed rearrangement. PMID- 28029047 TI - Comparative Aroma Extract Dilution Analysis (cAEDA) of Fat from Tainted Boars, Castrated Male Pigs, and Female Pigs. AB - The aroma profile of porcine fat from tainted boars, female pigs, and castrated male pigs was investigated by application of comparative aroma extract dilution analysis (cAEDA) on a SAFE distillate of volatiles prepared from porcine back fat samples. The AEDA resulted in a total of 16 aroma active compounds for boar fat with flavor dilution (FD) factors ranging from 2 to 2048, whereas 12 aroma active compounds were found in fat of female pigs and 14 in fat of castrated male pigs, both with FD factors ranging from 2 to 32. Odor activity values (OAVs) of key components for each fat were identified: In boar fat androstenone, skatole, indole, and 2-aminoacetophenone showed highest OAVs, whereas 2,5 dimethylpyrazine, 2,4-decadienal, and delta-decalactone showed highest OAVs in fat of female pigs. Fat of castrated male pigs showed highest OAVs for skatole, indole, 1-octen-3-ol and methional. Finally, the off-flavor attributes of boar fat were successfully simulated by a recombinant of all odorants at their natural concentration level in deodorized sunflower oil. PMID- 28029048 TI - Correction to Rice Koji Extract Enhances Lipid Metabolism through Peroxisome Proliferator-Activated Receptor Alpha (PPARalpha) Activation in Mouse Liver. PMID- 28029049 TI - An N-Heterocyclic Carbene-Nickel Half-Sandwich Complex as a Precatalyst for Suzuki-Miyaura Coupling of Aryl/Heteroaryl Halides with Aryl/Heteroarylboronic Acids. AB - A nickel half-sandwich complex supported by our original NHC ligand was developed as a robust precatalyst for Suzuki-Miyaura cross-coupling. The addition of PPh3 was a crucial element in the suppression of side reactions and in accelerating the cross-coupling reaction. By employing the optimal conditions, aryl-aryl, heteroaryl-aryl, and heteroaryl-heteroaryl couplings were achieved. PMID- 28029050 TI - Palladium-Catalyzed, ortho-Selective C-H Halogenation of Benzyl Nitriles, Aryl Weinreb Amides, and Anilides. AB - A palladium-catalyzed, ortho-selective C-H halogenation methodology is reported herein. The highlight of the work is the highly selective C(sp2)-H functionalization of benzyl nitriles in the presence of activated C(sp3)-H bond, which results in good yields of the halogenated products with excellent regioselectivity. Along with benzyl nitriles, aryl Weinreb amides and anilides have been evaluated for the transformation using aprotic conditions. Mechanistic studies yield interesting aspects with respect to the pathway of the reaction and the directing group abilities. PMID- 28029051 TI - Adherence to a Mediterranean Diet Influences the Fecal Metabolic Profile of Microbial-Derived Phenolics in a Spanish Cohort of Middle-Age and Older People. AB - Despite the evidence regarding the influence of certain polyphenol food sources on the metabolic profile in feces, the association between the different phenolics provided by the diet and the fecal phenolic profile has not been elucidated. In this study, the composition of phenolic metabolites in fecal solutions was analyzed by UPLC-ESI-MS/MS in 74 volunteers. This fecal phenolic profile showed a high interindividual variation of the different compounds analyzed, phenylacetic and phenylpropionic acids being the major classes of phenolic metabolites excreted in feces. Subjects with higher adherence to a Mediterranean dietary pattern presented greater fecal concentrations of benzoic and 3-hydroxyphenylacetic acids, positively correlated with the intake of the principal classes and subclasses of polyphenols and fibers, and higher levels of Clostridium cluster XVIa and Faecalibacterium prausnitzii. These results provide a link among the Mediterranean dietary pattern, the bioactive compounds of the diet, and the fecal metabolic phenolic profile. PMID- 28029052 TI - Diagnosis, management and mortality in acute aortic syndrome: results of the Spanish Registry of Acute Aortic Syndrome (RESA-II). AB - BACKGROUND: Recent advances in the diagnosis and treatment of acute aortic syndrome should improve the outcome of this disease. The Spanish Registry of Acute Aortic Syndrome aimed to assess current results in acute aortic syndrome management in a wide cohort of hospitals in the same geographical area. METHODS: From January 2012 to January 2014, 26 tertiary hospitals included 629 consecutive patients with acute aortic syndrome: 73% men, mean age 64.7+/-14 years (range 22 92), 443 type A (70.4%) and 186 type B (29.6%). RESULTS: Time elapsed between symptom onset and diagnosis was <12 hours in 70.7% of cases and <24 hours in 84.0% (median 5 hours; 25th-75th percentiles, 2.7-15.5 hours). Computed tomography was the first diagnostic technique in 78% of patients and transthoracic echocardiography in 15%. Surgical treatment was indicated in 78.3% of type A acute aortic syndrome. The interval between diagnosis and surgery was 4.8 hours (quartile 1-3, 2.5-11.4 hours). Among the patients with type B acute aortic syndrome, treatment was medical in 116 cases (62.4%), endovascular in 61 (32.8%) and surgical in nine (4.8%). Type A mortality during hospitalisation was 25.1% in patients treated surgically and 68% in those treated medically. Mortality in type B was 13.8% in those with medical treatment, 18.0% with endovascular therapy and 33.0% with surgical treatment. CONCLUSION: Improvements in the diagnosis and treatment of acute aortic syndrome have not resulted in a significant reduction in hospital mortality. The results of this study reflect more overall and less selected information on acute aortic syndrome management and the need for sustained advances in the therapeutic strategy of acute aortic syndrome. PMID- 28029053 TI - Three-dimensional computed tomography as a novel method for the diagnosis and management of obstructed hemivagina and ipsilateral renal anomaly syndrome: A case report. PMID- 28029054 TI - Comprehensive clinical sitting balance measures for individuals following stroke: a systematic review on the methodological quality. AB - PURPOSE: The aim of this systematic review was to examine the psychometric properties of published clinical sitting measurement scales containing dynamic tasks in individuals following stroke. METHOD: Databases, including Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, EMBASE, Cochrane, PubMed and Allied and Complementary Medicine Database (AMED) were searched from inception to December 2015. The search strategy included terms relating to sitting, balance and postural control. Two reviewers independently selected and extracted data from the identified articles and assessed the methodological quality of the papers using the COnsensus-based Standards for selection of health status Measurement INstruments (COSMIN) checklist. RESULTS: Fourteen clinical sitting measurement scales (39 papers) containing dynamic tasks met the inclusion criteria and various measurement properties were evaluated. The methodological quality of the majority of the included studies was rated as poor to fair using the COSMIN checklist, with common limitations including small sample size and inappropriate use of statistical methods. CONCLUSIONS: This review was unable to identify measures with sufficient psychometric properties to enable recommendation as preferred tools. However, measures were identified that warrant further specific psychometric investigations to fulfil requirements for a high quality measure. Implications for Rehabilitation Fourteen clinical sitting balance scales containing dynamic tasks are available to measure sitting balance with individuals following stroke. No single scale has sufficient psychometric properties to enable recommendation as a preferred tool for measuring sitting balance with stroke survivors. Use of a balance scale or dedicated sitting balance measure containing static and dynamic sitting items should be utilised to monitor progress for individuals following stroke with more severe deficits. PMID- 28029055 TI - Improved risk stratification of patients with acute coronary syndromes using a combination of hsTnT, NT-proBNP and hsCRP with the GRACE score. AB - BACKGROUND: Clinical scores and biomarkers improve risk stratification of patients with acute coronary syndromes. However, little is known about their value in patients referred for coronary angiography. METHODS: Consecutive patients admitted at four Swiss university hospitals with a diagnosis of acute coronary syndrome were enrolled into the SPUM-ACS Biomarker Cohort between 2009 and 2012. Patients were followed at 30 days and 1 year with assessment of adjudicated events including all-cause mortality and the composite of all-cause mortality or non-fatal recurrent myocardial infarction. RESULTS: Events and biomarkers were analysed in 1892 patients (52.4% with ST-segment elevation myocardial infarction, 43.3% with non-ST-segment elevation myocardial infarction and 4.3% with unstable angina). Death at 30 days occurred in 35 patients (1.9%) and at 1 year in 80 patients (4.3%). The choice of troponin assay (conventional versus high sensitivity) to calculate the Global Registry of Acute Coronary Events (GRACE) score did not affect risk prediction. The prognostic accuracy of the GRACE score was improved when combined with three individual biomarkers including high sensitivity troponin T (hsTnT), N-terminal-pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) to yield a 9% increment (C-statistic 0.73->0.82) for the discrimination of short-term risk for all-cause mortality. In contrast, the novel biomarkers placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and the ratio sFlt-1/PlGF did not improve risk stratification. CONCLUSIONS: In patients with acute coronary syndrome referred for coronary angiography, combinations of biomarkers including hsTnT, NT-proBNP and hsCRP with the GRACE score enhanced risk discrimination. CLINICAL TRIALS REGISTRATION: NCT01000701. PMID- 28029056 TI - Ultrasound in dysphagia rehabilitation: a novel approach following partial glossectomy. AB - PURPOSE: While the presence of dysphagia following partial glossectomy has been widely reported, there is insufficient quality evidence to guide clinical decision making about the treatment of this disorder. This study investigated a novel dysphagia rehabilitation approach using ultrasound tongue imaging for patient training. METHOD: Initially, a pilot study was conducted to investigate the feasibility of ultrasound visual feedback during swallow tasks. The protocol was then replicated using a single-case experimental designed study to investigate therapeutic effect. Swallow, speech, and oromotor functions were measured across multiple baselines using an A-B-A intervention study design. RESULTS: During intervention, both participants were able to interpret ultrasound tongue images during swallow tasks. Following intervention, positive therapeutic effect was achieved with reduced frequency of aspiration and self-initiated swallow strategies. Generalization of intervention was evidenced by reduced bolus transit duration on videofluoroscopy and improved functional oral intake scores. Speech and oromotor functions remained stable throughout the study demonstrating experimental control. CONCLUSIONS: This study establishes that ultrasound visual feedback is feasible in dysphagia rehabilitation following partial glossectomy. In addition, the predicted therapeutic effect specifically to swallow but not speech or oromotor functions were demonstrated. Implications for Rehabilitation Partial glossectomy results in altered tongue shape, movement, and function which negatively impact on speech and swallowing There is limited research evidence to support previously used speech pathology interventions (in particular, tongue range of movement exercises) to rehabilitate dysphagia following tongue cancer surgery The tongue, and hence oral phase of swallowing, can be viewed by placing an ultrasound probe under the chin Ultrasound scanning of the tongue is not invasive, can be repeated without dosage side effect. It's also comfortable for the patient and if a portable probe and monitor are used, can be performed within a variety of clinical settings for assessment or therapy This study shows specific therapeutic benefit following ultrasound visual feedback along with a motor learning approach to rehabilitate swallow function following partial glossectomy Visual and verbal feedback that focus specifically on the motor movements undergoing adaptation (e.g., tongue wave movement, tongue elevation, bolus clearance) following partial glossectomy are recommended Patients who are able to see the ultrasound monitor, hear the feedback given, are cognitively able to self-evaluate tongue movement, and remember intervention goals will most benefit from ultrasound tongue visual feedback in therapy Clinicians also benefit from visualizing the tongue with ultrasound during assessment and therapy as a direct view reduces the subjectivity of rating task performance. PMID- 28029057 TI - Robust memory of where from way back when: evidence from behaviour and visual attention. AB - Retention of events typically exhibits a sharp initial decrease followed by levelling off of forgetting. In an apparent exception to this general rule, college students have robust memory for their own locations in obscured versions of photographs of their entering classes taken during orientation-related activities, whether tested 2 months or 42 months after the event. Experiment 1 of the present research was a test for conceptual replication of this finding in photographs depicting more than twice the number of students (and thus potential distracters). There was no difference in memory accuracy for personal spatial location across retention intervals of 6-30 months. Experiment 2 featured 40-h and 2-month retention intervals, thereby providing a more fine-grained test of the forgetting function. The findings replicated Experiment 1. In Experiment 3, eye-tracking measures of visual attention revealed that participants rapidly fixated their own spatial locations within the photographs, even in the absence of explicit awareness. In all three experiments, memory for temporal features of the orientation activities (e.g., day and time the photograph was taken) followed the typical forgetting function. The findings suggest differential preservation of episodic memory for where relative to other aspects of events and experiences, such as when. PMID- 28029058 TI - Prenatal central nervous system anomaly with skeletal dysplasia associated with a de novo interstitial tandem triplication of chromosome 14. PMID- 28029059 TI - Primary peritoneal carcinosarcoma. PMID- 28029060 TI - A new androstanoid metabolite from a soil fungus Curvularia borreriae strain HS FG-237. AB - A new androstanoid metabolite, 4alpha-methyl-9alpha-methoxyandrosta-8,15-diene 3,17-dione (1), was isolated from a soil fungus Curvularia borreriae (Pleosporaceae) strain HS-FG-237. Its structure was determined by extensive spectroscopic and X-ray diffraction analyses. Compound 1 exhibited poor cytotoxicity toward HCT-116 cells by CCK-8 assay and weak anti-inflammatory activity in an ANA-1 murine macrophages model. PMID- 28029061 TI - Constituents of Ramalina capitata (Ach.) Nyl. extracts. AB - The aim of this work was to determine the chemical composition of the ether, ethyl acetate and dichloromethane extracts of Ramalina capitata by GC-FID and GC MS for the first time. The main identified components in the ether, ethyl acetate and dichloromethane extracts were everninic acid (24.7, 33.7 and 22.2%), orcinol (25.8, 16.7 and 11.9%), orcinol monomethyl ether (11.6, 7.6 and 4.8%), 3 methylorsellinic acid (10.2, 7.1 and 9.0%) and usnic acid (4.4, 8.2 and 25.8%), respectively. Considerable amount (10.4%) of 2-hydroxy-4-methoxy-3,5,6 trimethylbenzoic acid was detected in ethyl acetate extract. Additionally, palmitic acid, linoleic acid, oleic acid and stearic acid and their esters were observed in the dichloromethane and ethyl acetate extracts in the range of 4.1 0.1%, while their amount was below 0.05% in the ether extract. According to the results reported here R. capitata predominantly biosynthesises derivatives of orcinol and, in much lesser extent, derivatives of beta-orcinol. PMID- 28029062 TI - The main constituents of Tulipa systola Stapf. roots and flowers; their antioxidant activities. AB - People living on the mountains of the Kurdistan Region, Iraq make a large use of herbs in the local traditional medicine. Among them, Tulipa systola, which grows under and between rocks, is very popular as an anti-inflammatory remedy and pain relief. The phytochemical study of an ethanolic extract obtained from flowers and roots of Tulip (T systola Stapf.) afforded three compounds, identified as (+)-1-O E-feruloyl-3-O-E-p-coumaroylglycerol (1), (+)-6-tuliposide A (2), and (-) kaempferol-3-O-rutinoside (3). The significant radical scavenging and antioxidant activity of the isolated compounds were evaluated on three tests, by determining the DPPH free radical scavenging activity, the total antioxidant activity and the hydrogen peroxide scavenging activity. Tuliposide A shows potent allergenic activity. PMID- 28029063 TI - Computerized physical activity training for persons with severe mental illness - experiences from a communal supported housing project. AB - PURPOSE: To study the effectiveness of Exergames in communal psychiatry for persons with severe mental illness, a randomized cluster study was performed. The hypothesis was to increase physical activity habits to improve somatic health. To identify factors promoting or impeding the use of the Exergames. METHODS: Assessments of BMI, blood pressure, physical fitness, SF36, GAF and social interactions were studied at baseline and 10 months. An integrated methods design using content analysis of focus group interviews was integrated with a statistical analysis. Forty-three persons were randomized to the intervention and 30 to the control group. The qualitative interviews included 18 users, 11 staffs and one technical assistant. RESULTS: There were no significant between-group changes in physical activity behaviours or somatic health parameters after 10 months. Only 5% of the intervention group made systematic use of the intervention. Technological difficulties and staff attitudes were found to be barriers. The Exergames were perceived as technically complicated. The staff did not see playing TV games as important and negative attitudes were found. CONCLUSIONS: Exergames was not a successful intervention to increase physical activity behaviours in persons with severe mental illness in the community. Exergames and motivation for physical activity in this group is problematic. Implications for rehabilitation There are difficulties to change passive physical activity habits for persons with severe mental illness, living in sheltered housing conditions in the community due to negative symptoms with depression, low motivation and bad self -confidence. An exergame intervention was not successful in this group of persons. No somatic health benefits were found. Simple physical activities and offering different choices meeting different user needs should be offered. Ensuring user and staff engagement, good technical knowledge and good monitoring is a need for a successful intervention, if Exergames are offered as an alternative physical activity. PMID- 28029064 TI - Civic Engagement of Older Adults in Mainland China. AB - Due to great challenges resulting from China's rapid population aging, Chinese elders are mobilized to address problems caused by this demographic trend through civic engagement. Based on an integrative review of policy, research, and practice, this article reveals that today's Chinese elders have a higher level and wider scope of civic engagement than previous cohorts. A set of factors contributing to such improvement are further identified, including the reform of the national economy, transformation of governmental functions, and the use of effective strategies applied to concrete programs. However, several constraints limiting Chinese elders' equal, active engagement in civic life remain, including the social stratification of older adults, preferential selection of participants due to the nation's socioeconomic development strategy, and family care work competing with other types of civic activities. Finally, future directions for policy, research, and practice are proposed in order to increase Chinese elders' civic engagement. PMID- 28029065 TI - Exploring the consequences of nonbelieved memories in the DRM paradigm. AB - In the current experiments, we attempted to elicit nonbelieved memories (NBMs) using the Deese/Roediger-McDermott (DRM) false memory paradigm. Furthermore, by using this approach, we explored the consequences of nonbelieved true and false memories. In Experiments 1 and 2, participants received several DRM wordlists and were presented with a recognition task. After the recognition task, participants' statements were contradicted by giving them feedback about true and false items. In this way, we succeeded in eliciting nonbelieved true and false memories. In Experiment 2, participants were also involved in a modified perceptual closure task after receiving belief-relevant feedback. In this task, participants received degraded visual representations of words (e.g., false and true) that became clearer over time. Participants had to identify them as fast as possible. We also measured dissociation, compliance, and social desirability. We found that undermining belief had contrasting consequences for true and false memories. That is, nonbelieved true memories were identified more slowly whereas nonbelieved false memories were identified more quickly. We did not find any relation between our individual differences measures and the formation of NBMs. PMID- 28029066 TI - Cardiac autonomic and haemodynamic recovery after a single session of aerobic exercise with and without blood flow restriction in older adults. AB - This study investigated the autonomic and haemodynamic responses to different aerobic exercise loads, with and without blood flow restriction (BFR). In a crossover study, 21 older adults (8 males and 13 females) completed different aerobic exercise sessions: low load without BFR (LL) (40% VO2max), low load with BFR (LL-BFR) (40% VO2max + 50% BFR) and high load without BFR (HL) (70% VO2max). Heart rate variability and haemodynamic responses were recorded during rest and throughout 30 min of recovery. HL reduced R-R interval, the root mean square of successive difference of R-R intervals and high frequency during 30 min of recovery at a greater magnitude compared with LL and LL-BFR. Sympathetic-vagal balance increased the values for HL during 30 min of recovery at a greater magnitude when compared with LL and LL-BFR. Post-exercise haemodynamic showed reduced values of double product at 30 min of recovery compared to rest in LL BFR, while HL showed higher values compared to rest, LL-BFR and LL. Reduced systolic blood pressure was observed for LL-BFR (30 min) compared to rest. Autonomic and haemodynamic responses indicate lower cardiovascular stress after LL-BFR compared to HL, being this method, besides the functional adaptations, a potential choice to attenuate the cardiovascular stress after exercise in older adults. PMID- 28029067 TI - The relationship between the implementation and effectiveness of a nationwide physical activity telephone counseling service for adults with spinal cord injury. AB - PURPOSE: Get in Motion (GIM) is an evidence-based telephone counseling service that promotes leisure-time physical activity (LTPA) among Canadian adults with spinal cord injury (SCI). The first phase of GIM sustained intentions for, and increased participation in, LTPA; however, it is unclear how GIM led to these outcomes. The purpose of this study was to explore the implementation correlates of change in LTPA intentions and behavior in the second phase of GIM. METHODS: The frequency, duration, and content of counseling sessions were tailored to meet clients' (N = 46; 50.0% male; 50.0% paraplegia; 51.46 (SD 12.36) years old) needs and preferences. Intervention dose and content were monitored using Counseling Session Checklists. Clients self-reported their intentions for and actual aerobic and strength-training LTPA participation at baseline, 2-, 4-, and 6-months, and their perceptions of service quality at 6-months. RESULTS: The second phase of GIM effectively sustained LTPA intentions and increased time spent on moderate-to vigorous strength-training and total LTPA. Increases in clients' moderate-to vigorous aerobic LTPA were significantly positively related to intervention dose, intervention content (both informational and behavioral strategies), and clients' perceptions of service credibility. CONCLUSIONS: This study identified intervention dose and content as key implementation variables for an LTPA telephone counseling service for adults with SCI. Implications for Rehabilitation An evidence- and theory-based telephone counseling service can effectively sustain LTPA intentions and increase LTPA behavior among adults with SCI. The first two months of the service are a critical period for enhancing LTPA participation and for minimizing dropouts. The provision of both informational and behavioral strategies is important for increasing aerobic LTPA levels among adults with SCI. PMID- 28029068 TI - Healthy-eating attitudes and the incidence of cardiovascular disease: the SUN cohort. AB - There is an emerging use of brief dietary questionnaires to investigate diet health relation. We prospectively assess the association between eating attitudes (yes/no) and incident cardiovascular disease (CVD) in 19,138 participants of the Seguimiento Universidad de Navarra (SUN) Cohort. We calculated a baseline healthy eating attitudes score (in quartiles), positively weighting answers on more fruit, vegetables, fish and fiber and less meat, sweets and pastries, fat, butter, fatty meats and added sugar in drinks. We observed 139 incident cases of CVD. A higher score was associated with a lower risk of CVD [3-5 points Hazard Ratio (HR): 0.38 (95% confidence interval: 0.18-0.81); 6-8 points: 0.57 (0.29 1.12); 9-10 points: 0.31 (0.15-0.67), compared to 0-2 points]. Key contributors were the attitude to increase fruit [HR: 0.59 (0.40-0.87)], vegetables [HR: 0.57 (0.29-1.12)] and fiber intake [HR: 0.69 (0.48-0.98)]. Brief questionnaire on attitudes towards healthy-eating may be a useful tool for the primary prevention of CVD. PMID- 28029069 TI - Effectiveness of osteopathic manipulative treatment versus osteopathy in the cranial field in temporomandibular disorders - a pilot study. AB - PURPOSE: Temporomandibular disorders are a common musculoskeletal condition causing severe pain, physical and psychological disability. The effect and evidence of osteopathic manipulative treatment and osteopathy in the cranial field is scarce and their use are controversial. The purpose of this pilot study was to evaluate the effectiveness of osteopathic manipulative treatment and osteopathy in the cranial field in temporomandibular disorders. METHODS: A randomized clinical trial in patients with temporomandibular disorders was performed. Forty female subjects with long-term temporomandibular disorders (>3 months) were included. At enrollment, subjects were randomly assigned into two groups: (1) osteopathic manipulative treatment group (20 female patients) and (2) osteopathy in the cranial field group (20 female patients). Examination was performed at baseline (E0) and at the end of the last treatment (E1), consisting of subjective pain intensity with the Visual Analog Scale, Helkimo Index and SF 36 Health Survey. Subjects had five treatments, once a week. 36 subjects completed the study (33.7 +/- 10.3 y). RESULTS: Patients in both groups showed significant reduction in Visual Analog Scale score (osteopathic manipulative treatment group: p = 0.001; osteopathy in the cranial field group: p< 0.001), Helkimo Index (osteopathic manipulative treatment group: p = 0.02; osteopathy in the cranial field group: p = 0.003) and a significant improvement in the SF-36 Health Survey - subscale "Bodily Pain" (osteopathic manipulative treatment group: p = 0.04; osteopathy in the cranial field group: p = 0.007) after five treatments (E1). All subjects (n = 36) also showed significant improvements in the above named parameters after five treatments (E1): Visual Analog Scale score (p< 0.001), Helkimo Index (p< 0.001), SF-36 Health Survey - subscale "Bodily Pain" (p = 0.001). The differences between the two groups were not statistically significant for any of the three target parameters. CONCLUSION: Both therapeutic modalities had similar clinical results. The findings of this pilot trial support the use of osteopathic manipulative treatment and osteopathy in the cranial field as an effective treatment modality in patients with temporomandibular disorders. The positive results in both treatment groups should encourage further research on osteopathic manipulative treatment and osteopathy in the cranial field and support the importance of an interdisciplinary collaboration in patients with temporomandibular disorders. Implications for rehabilitation Temporomandibular disorders are the second most prevalent musculoskeletal condition with a negative impact on physical and psychological factors. There are a variety of options to treat temporomandibular disorders. This pilot study demonstrates the reduction of pain, the improvement of temporomandibular joint dysfunction and the positive impact on quality of life after osteopathic manipulative treatment and osteopathy in the cranial field. Our findings support the use of osteopathic manipulative treatment and osteopathy in the cranial field and should encourage further research on osteopathic manipulative treatment and osteopathy in the cranial field in patients with temporomandibular disorders. Rehabilitation experts should consider osteopathic manipulative treatment and osteopathy in the cranial field as a beneficial treatment option for temporomandibular disorders. PMID- 28029070 TI - An exploration of factors influencing physical activity levels amongst a cohort of people living in the community after stroke in the south of England. AB - PURPOSE: To explore factors influencing physical activity (PA) reported by people living in rural/semi-rural communities in the south of England post-stroke, and to understand relationships between personal, interpersonal and environmental barriers and self-reported levels of PA. METHOD: A survey was mailed to patients of NHS Trusts who were identified as potential participants. Self-reported PA levels, type, and frequency of reported barriers were tabulated. Spearman's rank correlation coefficient was used to explore associations between self-reported PA level and: age, gender, level of physical function, fear of falling, beliefs regarding PA, available supports, and socioeconomic status. RESULTS: Seventy-six of 322 questionnaires distributed were returned (24%). Only 55.2% of respondents reported undertaking PA of sufficient intensity to meet current guidelines. Personal barriers included fear of falling, stroke-related disability, pain, and fatigue. Interpersonal and environmental barriers included lack of social support, transport, and inclement weather. Significant relationships existed between self-reported PA and fear of falling, functional mobility, and beliefs relating to PA. CONCLUSIONS: Almost half of the survey cohort reported PA levels insufficient to meet current guidelines. Similar to barriers reported in previous studies in USA and other parts of the UK, numerous interlinking and overlapping personal, interpersonal, and environmental barriers to undertaking PA were identified. Implications for Rehabilitation This study found that although more than 60% of the survey population were able to ambulate >200 m, only 55.2% reported undertaking sufficient PA to meet current guidelines, putting them at increased risk of further stroke and other co-morbidities. Participants reported a number of interlinking and overlapping personal, interpersonal, and environmental barriers to undertaking PA, which may explain this discrepancy between mobility status and self reported activity levels. Rehabilitation professionals and primary care providers are well positioned to address the barriers identified in this survey, such as providing interventions to reduce fear of falling, pain, and fatigue, providing support and education about safely increasing physical activity and addressing unhelpful beliefs about PA. Behaviour change strategies, such as increasing self-efficacy, and partnering with the person with stroke to problem solve strategies to address the barriers identified by this, and related research, are likely to be more successful in increasing PA than providing information alone. PMID- 28029071 TI - Predicting Citrullination Sites in Protein Sequences Using mRMR Method and Random Forest Algorithm. AB - BACKGROUND: As one of essential post-translational modifications (PTMs), the citrullination or deimination on an arginine residue would change the molecular weight and electrostatic charge of its side-chain. And it has been found that the citrullination in protein sequences was catalyzed by a type of Ca2+-dependent enzyme family called peptidylarginine deiminase (PAD), which include five isotypes: PAD1, 2, 3, 4/5, and 6. Citrullinated proteins participate in many biological processes, e.g. the citrullination of myelin basic protein (MBP) assists the early development of central nervous system. However, abnormal modifications on citrullinated proteins would also lead to some severe human diseases including multiple sclerosis and rheumatoid arthritis. OBJECTIVE: Therefore, it is necessary and important to identify the citrullination sites in protein sequences. The information about the location of citrulliantion sites in protein sequences will be useful to investigate the molecular functions and disease mechanisms related to citrullinated proteins. MATERIALS AND METHODS: In this study, we investigated the peptide segments that contain the citrullination sites in the centers, which were encoded into numeric digits from four aspects. Thus, we yielded a training set with 116 positive samples and 232 negative samples. Then, a reliable feature selection technique, called maximum-relevance minimum-redundancy (mRMR), was applied to analyze these features, and four algorithms, including random forest (RF), Dagging, nearest neighbor algorithm (NNA), and support vector machine (SVM), together with the incremental feature selection (IFS) method were adopted to extract important features. RESULTS: Finally an optimal classifier derived from RF algorithm was constructed to predict citrullination sites. 44 most prominent features were comprehensively analyzed and their biological characteristics in citrullination catalysis were also revealed. CONCLUSION: We believed that the biological features obtained in this pioneering work would provide some useful insights into the formation and function of citrullination and the optimal classifier could be a useful tool to identify citrullination sites in protein sequences. PMID- 28029072 TI - Secondary Metabolites from Cissampelos, A Possible Source for New Leads with Anti Inflammatory Activity. AB - The genus Cissampelos comprises of 21 species which have a wide global distribution and various pharmacological activities such as analgesic and antipyretic, antiinflammatory, anti-allergic, bronchodilation, and immunomodulation among others. Several compounds, mainly alkaloids with differing biological activities have been isolated from this genus. We will highlight antipyretic activities, anti-inflammatory, antiallergic, bronchodilatory, and immunomodulatory activities. In addition, we applied ligand-based-virtual screening associated with structure-based-virtual screening of a small dataset of 63 secondary metabolites from the Cissampelos genus of an in-house data bank, in order to select compounds with potential anti-inflammatory activity. Affinities were observed for hayatine (26), isochondrondendrine (30), pelosine (52), sepeerine (59), and warifteine (63) to the inhibiting enzymes MAPK p38 alpha, PKC beta, PKC theta and PKC zeta. The cissampeloflavone compound (8) alone showed no potential inhibitory activity for PKC zeta, or affinity for the PKC alpha. The compounds can be used as starting points for further studies on structures with potential anti-inflammatory activity. PMID- 28029074 TI - A Rational Approach to Target the Epidermal Growth Factor Receptor in Glioblastoma. AB - Glioblastoma (GBM) is a deadly brain cancer, and all attempts to control it have failed so far. However, the future looks bright, as we now know the molecular landscape of GBM through the work of The Cancer Genome Atlas (TCGA) program. GBMs exhibit significant inter- and intratumoral heterogeneity, and to control this type of tumor, a personalized approach is required. One target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But all attempts to target it have been unsuccessful. We attribute the reason for this failure to the molecular heterogeneity of EGFR in GBM, as well as to the poor brain penetration of previously tested EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs). In this review, we discuss the molecular heterogeneity of EGFR and provide rational preclinical and clinical guidelines for testing AZD9291, a third generation, irreversible EGFR-TKI with both a high affinity for EGFRvIII and excellent brain penetration. PMID- 28029075 TI - Connexin43 and Myocardial Ischemia-Reperfusion Injury. AB - BACKGROUND: Recently, the treatment and prevention of ischemic cardiomyopathy is one of the emerging research topics in the cardiovascular field. Gap junction is the basic structure of cardiac electrophysiology. Connexin is the basic unit of gap junctions. Connexin43(CX43) is the most abundant member of Cx family in the heart, the normal expression of Cx43 is important for heart development, electrically coupled cardiomyocytes activities and coordination of myocardial function. The connection between Cx43 and myocardial ischemia/reperfusion or reperfusion injury has become the focus of current research. METHODS: We undertook a structured search of bibliographic database for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyze the interventions and findings of included studies using a conceptual framework. RESULTS: Twenty-one papers were included in the review, eight papers outlined the relationship of Cx43 and reperfusion arrhythmias. Eight papers pointed out the effect on the infarct size of Cx43. CONCLUSION: The findings of this review confirm that Cx43 is the most abundant member of Cx family in the heart and is vital for myocardial protection during ischemia/reperfusion process and for ischemia/reperfusion injury. Many of its mechanism are still not very clear and require future research in the future. PMID- 28029073 TI - Exploring Optic Nerve Axon Regeneration. AB - BACKGROUND: Traumatic optic nerve injury is a leading cause of irreversible blindness across the world and causes progressive visual impairment attributed to the dysfunction and death of retinal ganglion cells (RGCs). To date, neither pharmacological nor surgical interventions are sufficient to halt or reverse the progress of visual loss. Axon regeneration is critical for functional recovery of vision following optic nerve injury. After optic nerve injury, RGC axons usually fail to regrow and die, leading to the death of the RGCs and subsequently inducing the functional loss of vision. However, the detailed molecular mechanisms underlying axon regeneration after optic nerve injury remain poorly understood. METHODS: Research content related to the detailed molecular mechanisms underlying axon regeneration after optic nerve injury have been reviewed. RESULTS: The present review provides an overview of regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways involved in intrinsic growth program and the inhibitory environment together with axon guidance cues for correct axon guidance. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which contributes to develop improved treatments for optic nerve regeneration. These findings are encouraging and open the possibility that clinically meaningful regeneration may become achievable in the future. CONCLUSION: Combination of treatments towards overcoming growth-inhibitory molecules and enhancing intrinsic growth capacity combined with correct guidance using axon guidance cues is crucial for developing promising therapies to promote axon regeneration and functional recovery after ON injury. PMID- 28029076 TI - EDITORIAL (Thematic Issue: Retinal Neurodegeneration in the Course of Diabetes: Neuroprotection as a Potential Treatment Target). PMID- 28029077 TI - EDITORIAL (Thematic Issue: Brain Gut Axis-New View). PMID- 28029078 TI - Nutrition and Exercise in Sarcopenia. AB - Sarcopenia is a debilitating condition that involves loss of muscle mass and function, which affects virtually everyone as they age, and can lead to frailty and ultimately disability. In growing recognition of the importance of both muscle strength and muscle mass relative to body size in contributing to functional decline, recent definitions have now incorporated grip strength and a correction for body mass as part of the key criteria that define sarcopenia. With this new definition, a much larger population of older adults are now at risk of sarcopenia. In the present article, we reviewed the literature for studies which tested the effects of diet or exercise interventions on changes in lean mass and/or functional outcomes in individuals with either sarcopenia and/or frailty and identified 19 clinical trials. There were a few key findings. First, dietary interventions involving protein supplementation improved functional and/or strength outcomes in a few trials; however, other dietary approaches were less effective. Exercise interventions and combined diet and exercise interventions produced consistent improvements in lower body muscle strength but had less consistent effects on walking speed and grip strength. Lifestyle interventions not involving calorie restriction generally did not induce significant changes in body composition. There were a limited number of trials in which participants with sarcopenia were specifically targeted, and thus there is an important need for more research to determine the appropriate types of intervention approaches for the high risk population of sarcopenic older adults. PMID- 28029079 TI - Facile and Solvent-free Domino Synthesis of New Quinolidinyl-2,4- thiazolidinones: Antifungal Activity and Molecular Docking. AB - OBJECTIVE: We have synthesized new quinolidinyl-thiazolidinones via Knoevenagel condensation- alkylation reaction, catalyzed by [Et3NH][HSO4]. The present approach offers several advantages such as higher yields, eco-friendly reaction condition and economic availability of the catalyst. METHOD: The newly synthesized compounds were evaluated for their in vitro antifungal activity against six fungal strains. Some of the synthesized conjugates displayed good to moderate antifungal activity. CONCLUSION: Again, the molecular docking study performed against the fungal sterol 14alpha-demethylase (CYP51) showed an excellent binding affinity towards the enzyme which could rationalize the promising antifungal activity portrayed by these derivatives and provides a platform for structure based drug design. PMID- 28029080 TI - Synthesis and Study of Analgesic and Anti-inflammatory Activities of Amide Derivatives of Ibuprofen. AB - : Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide and represent a mainstay in the therapy of acute and chronic pain and inflammation. The traditional NSAIDs like ibuprofen (I) contain free carboxylic acid group which can produce gastrointestinal (GI) damage for long term use. OBJECTIVE: In order to obtain the novel NSAIDs with less side effects; carboxylic acid moiety has been modified into various amide groups which is the most active area of research in this family. METHOD: In this research, synthesis of various pharmacological heterocyclic amides of ibuprofen is described. All the new compounds were tested for their analgesic and anti-inflammatory activities in mice and compared with standard (Ibuprofen) and control (saline) groups. RESULTS & CONCLUSION: The results revealed that all the synthesized compounds (III-VI) exhibited more analgesic and anti-inflammatory activities in tail immersion (as a model of acute thermal pain), formalin (as a model of acute chemical and chronic pain) and paw edema (as a model of acute inflammation) tests when compared with standard and control animals. These pharmacological activities were significant for VI compared to other new compounds (III-V) which may be concern to more effective role of morpholin for the reduction of pain and inflammation compared to other used heterocyclic amines. PMID- 28029082 TI - Probiotics in Curing Allergic and Inflammatory Conditions - Research Progress and Futuristic Vision. AB - BACKGROUND: Probiotics constitute the viable and beneficial microbes, which offer a dietary means to sustain the balance of gastro-intestinal (GI) microflora. Owing to their multiple health benefits, these have recently gained wide attention among researchers for exploring their potential in safeguarding the health of humans and animals. Probiotics could also modulate host-immune responses, thereby help in counteracting the immunological dysfunctions. Probiotics can inhibit the systemic invasion of pathogens entering through the GI mucosa/ oral cavity and have been found to possess effective prophylactic and therapeutic utilities against various infectious pathogens as well as non infectious diseases and disorders. OBJECTIVE: The present review expedites the role of probiotics in curing the ailments related to allergic and inflammatory disease conditions. METHOD: A thorough reviewing of the literature and patents available on probiotics and their role in countering inflammation and allergy was conducted using authentic published resources available on Medline, PubMed, PubMed Central, Science Direct and other scientific databases. The information retrieved has been compiled and analysed pertaining to the theme of the study. RESULTS: Various micro-organisms have been evaluated for their probiotic efficacy, among these, the lactic acid bacteria viz. Lactobacillus sp. and Bifidobacterium sp. have extensively been studied and widely exploited. In the current post-globalized era of self and complementary medicines, the concept of probiotics and their therapeutic as well as prophylactic usage is gaining wide acceptance. As more and more bacterial strains are being proven for their pronounced influence on down regulation of immune regulation, atopic, inflammatory conditions, the use of probiotics is getting increased especially in the developed countries where such indications are high in prevalence. Apart from usage in immune related disorders, probiotics have been found to be effective in treating pouchitis, infantile diarrhoea due to infections, bacterial vaginosis, urinary tract infections, dental carries, diabetes, cancers as well augmenting the gut mucosal tolerance to various antibiotics and lactose intolerance. CONCLUSION: The resent review gives an insight towards potent utility of this branch of beneficial microbial therapy in allergy and inflammations, which is still in the emerging phase and more scientific evidences need to be explored regarding exploration of the mechanisms of action, further experimental trials and validation of controlled clinical studies in humans along with designing novel strategies for monitoring the possible microbial changes in their composition and metabolism associated with their interaction upon host immune system. PMID- 28029083 TI - Psychopathological Behaviour and Cognition in Morbid Obesity. AB - BACKGROUND: Obesity is a chronic condition with high prevalence and multifaceted aetiology, accompanied by an increased risk of morbidity and mortality. Obesity has several negative effects on the psychological status, and the severity of psychological disorders correlates with the degree of obesity. OBJECTIVE: Aim of this review is to provide an overview of the literature concerning the psychological distress associated with severe obesity, which contributes to deterioration of the quality of life of affected patients. METHODS: Dysfunctional eating behaviours and eating disorders, psychiatric comorbidity, cognition and quality of life will be discussed together with the most common drugs that can be employed to treat the various disorders in this peculiar clinical setting. The effects of bariatric surgery will be also reviewed. RESULTS: Obesity is often the result of pathological behaviours implemented in an eating disorder. Inconsistent results have been reported with regard to the effect of severe obesity on cognition, which recognize a multifaceted aetiology. Serotonergic agents play an important role in the management of patients with obesity and binge episodes, fluoxetine being currently a drug approved for this disorder. The efficacy of lorcaserin, a combination of bupropion and naltrexone, or antiepileptic medications (topiramate and zonisamide) has also been proposed. A neuroprotective role of leptin and oestrogen has been hypothesized. Bariatric surgery is a helpful treatment of morbid obese patients, with long-term favourable results on the psychopathological profile. CONCLUSION: Psychological, psychoeducational and psychopharmacological treatment can facilitate weight loss in morbid obese subjects with psychopathological comorbidities. A precise definition of the mechanisms affecting appetite, satiety and energy balance is expected to foster the development of new effective antiobesity drugs. PMID- 28029085 TI - Preface. PMID- 28029086 TI - Editorial (Thematic Issue: New Targets for Structure-Based Drug Discovery). PMID- 28029084 TI - Variability of Zaleplon 5-Oxidase Activity in Mice and Humans, and Inhibition by Raloxifene. AB - BACKGROUND: Zaleplon (ZAL) is a sedative-hypnotic agent, which is mainly metabolized to inactive 5-oxidized zaleplon (5-oxo-ZAL) and N-des-ethylated ZAL (des-ethyl-ZAL) in mice and humans. The former reaction is considered to be catalyzed by aldehyde oxidase present in liver cytosol. METHODS: Here, we examined sex and strain differences of ZAL metabolism to 5-oxo-ZAL among four strains of mice, as well as the inter-individual variation in humans, in order to evaluate the variability of 5-oxo-ZAL-forming activity and its relationship with aldehyde oxidase activity. In mice, the activity in C57BL/6J strain was the highest, followed by C3H/He and BALB/c. The activity in DBA/2J was the lowest, being 2.3-fold lower than that of C57BL/6J mice. The activity of male mice was higher than that of female mice. Large inter-individual variations were observed among humans, with a range of 10- fold. Raloxifene, an inhibitor of aldehyde oxidase, markedly decreased the formation of 5-oxo-ZAL by liver cytosol of mice and humans. Further, the plasma level of 5-oxo-ZAL in mice was decreased when raloxifene was co-administered with ZAL. RESULTS: Our results indicate that the formation of 5-oxo-ZAL from ZAL is mainly catalyzed by aldehyde oxidase in mice and humans, and the variability of 5-oxo-ZAL formation is due primarily to differences of aldehyde oxidase activity. CONCLUSION: High inter-individual variability of ZAL 5-oxidase activity and potential for interaction of ZAL with other medicines that are inhibitors of aldehyde oxidase should be taken into consideration in clinical usage of ZAL. PMID- 28029088 TI - Two levels of specialization in bacteraemic Escherichia coli strains revealed by their comparison with commensal strains. AB - Bacteraemia caused by Escherichia coli are particularly frequent and severe, contrasting with the commensal character of the strains found in the digestive tract. A better understanding of the relationships between strains of both origins is needed to unravel the pathogenesis of this disease. Two hundred and forty-three commensal strains were compared to 243 bacteraemic strains isolated from adult hosts matched in terms of gender and age, and from similar location and epoch. Phylogenetic grouping, O-type determination, virulence factor content and antibiotic resistance were compared. Compared to commensal strains, the bacteraemic strains were characterized by a higher proportion of B2, C and D phylogroups, and a lower proportion of A, E and F phylogroups. They also had a lower proportion of the B2 subgroup IV (STc141), a higher proportion of virulence factors, and a higher frequency of antibiotic resistance. These differences were more marked for the bacteraemic strains of urinary tract origin with the presence of specific clones, whereas the bacteraemic strains of digestive origin remained non-significantly different from the commensal strains, except for their antibiotic resistance. Thus, two levels of specialization from commensal strains were demonstrated in the bacteraemic strains: resistance to antibiotics in all cases, and virulence for those of urinary tract origin. PMID- 28029089 TI - Perception of measures for dealing with Ebola disease in primary care. AB - BACKGROUND: An epidemic of Ebola virus disease (EVD) occurred in West Africa in 2014. In Catalonia, primary care is the first level of healthcare so it has a key role in the detection and initial management of possible cases of EVD and in identifying contacts. AIM: This study aimed to find out how the staff of primary care centers perceived the measures for dealing with EVD. METHOD: An online questionnaire was distributed to all primary care workers in Catalonia during the period February-March 2015. FINDINGS: The estimated response rate was 10.1%. They reported having received training/information, that a specific circuit had been organized and that the necessary equipment was available. They considered it unlikely that a patient with suspected EVD would present at the center and were aware of the action to take but were worried about this possibility. Rigorous scientific training in international health is essential to take on new global health challenges. PMID- 28029090 TI - Video evidence that parenting methods predict which infants develop long night time sleep periods by three months of age. AB - : Aim To examine two hypotheses about the longitudinal relationship between night time parenting behaviours in the first few postnatal weeks and infant night-time sleep-waking at five weeks, three months and six months of age in normal London home environments. BACKGROUND: Most western infants develop long night-time sleep periods by four months of age. However, around 20-30% of infants in many countries continue to sleep for short periods and cry out on waking in the night: the most common type of infant sleep behaviour problem. Preventive interventions may help families and improve services. There is evidence that 'limit-setting' parenting, which is common in western cultures, supports the development of settled infant night-time behaviour. However, this evidence has been challenged. The present study measures three components of limit-setting parenting (response delay, feeding interval, settling method), examines their stability, and assesses the predictive relationship between each of them and infant sleep-waking behaviours. METHODS: Longitudinal observations comparing a General-Community (n=101) group and subgroups with a Bed-Sharing (n=19) group on infra-red video, diary and questionnaire measures of parenting behaviours and infant feeding and sleep-waking at night. Findings Bed-Sharing parenting was highly infant-cued and stable. General-Community parenting involved more limit-setting, but was less stable, than Bed-Sharing parenting. One element of General-Community parenting - consistently introducing a short interval before feeding - was associated with the development of longer infant night-time feed intervals and longer day-time feeds at five weeks, compared with other General-Community and Bed-Sharing infants. Twice as many General-Community infants whose parents introduced these short intervals before feeding in the early weeks slept for long night-time periods at three months of age on both video and parent-report measures, compared with other General-Community and Bed-Sharing infants. The findings' implications for our understanding of infant sleep-waking development, parenting programmes, and for practice and research, are discussed. PMID- 28029092 TI - Clinical risk factors, bacterial aetiology, and outcome of urinary tract infection in children hospitalized with diarrhoea in Bangladesh. AB - Urinary tract infection (UTI) is common in children aged <5 years with diarrhoea, but little is known about risk factors, aetiology and outcome of such children. We aimed to evaluate these knowledge gaps of UTI in children aged <5 years with diarrhoea. We enrolled all children aged <5 years with diarrhoea admitted to Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, between May 2011 and April 2013, who had history of fever (?38 degrees C) and obtained a urine sample for culture. Diarrhoea with UTI (confirmed by culture) constituted cases (n = 26) and those without UTI constituted controls (n = 78). Threefold controls were randomly selected. The case-fatality rate was comparable in cases and controls (4% vs. 1%, P = 0.439). Escherichia coli (69%) and Klebsiella (15%) were the most commonly isolated pathogens. Persistent diarrhoea, pneumonia and prior antibiotics use were identified as risk factors for UTI in logistic regression analysis (P < 0.05 for all). Thus, children with diarrhoea presenting with persistent diarrhoea, pneumonia, and prior antibiotic use should be investigated for UTI for their prompt management that may reduce morbidity. PMID- 28029091 TI - Serological and genomic evidence of Rift Valley fever virus during inter-epidemic periods in Mauritania. AB - Rift Valley fever virus (RVFV) is an emerging pathogen of major concern throughout Africa and the Arabian Peninsula, affecting both livestock and humans. In the past recurrent epidemics were reported in Mauritania and studies focused on the analysis of samples from affected populations during acute outbreaks. To verify characteristics and presence of RVFV during non-epidemic periods we implemented a multi-stage serological and molecular analysis. Serum samples of small ruminants, cattle and camels were obtained from Mauritania during an inter epidemic period in 2012-2013. This paper presents a comparative analysis of potential variations and shifts of antibody presence and the capability of inter epidemic infections in Mauritanian livestock. We observed distinct serological differences between tested species (seroprevalence: small ruminants 3.8%, cattle 15.4%, camels 32.0%). In one single bovine from Nouakchott, a recent RVF infection could be identified by the simultaneous detection of IgM antibodies and viral RNA. This study indicates the occurrence of a low-level enzootic RVFV circulation in livestock in Mauritania. Moreover, results indicate that small ruminants can preferably act as sentinels for RVF surveillance. PMID- 28029093 TI - Why do Emergency Medical Services (EMS) Professionals Leave EMS? AB - OBJECTIVE: The objective was to determine why Emergency Medical Technician (EMT) Basics and Paramedics leave the Emergency Medical Services (EMS) workforce. METHODS: Data were collected through annual surveys of nationally registered EMT Basics and Paramedics from 1999 to 2008. Survey items dealing with satisfaction with the EMS profession, likelihood of leaving the profession, and likelihood of leaving their EMS job were assessed for both EMT-Basics and Paramedics, along with reasons for leaving the profession. Individuals whose responses indicated that they were not working in EMS were mailed a special exit survey to determine the reasons for leaving EMS. RESULTS: The likelihood of leaving the profession in the next year was low for both EMT-Basics and Paramedics. Although overall satisfaction levels with the profession were high, EMT-Basics were significantly more satisfied than Paramedics. The most important reasons for leaving the profession were choosing to pursue further education and moving to a new location. A desire for better pay and benefits was a significantly more important reason for EMT-Paramedics' exit decisions than for EMT-Basics. CONCLUSIONS: Given the anticipated increased demand for EMS professionals in the next decade, continued study of issues associated with retention is strongly recommended. Some specific recommendations and suggestions for promoting retention are provided. Blau G , Chapman SA . Why do Emergency Medical Services (EMS) professionals leave EMS? Prehosp Disaster Med. 2016;31(Suppl. 1):s105-s111. PMID- 28029094 TI - Visual projection neurons in the Drosophila lobula link feature detection to distinct behavioral programs. AB - Visual projection neurons (VPNs) provide an anatomical connection between early visual processing and higher brain regions. Here we characterize lobula columnar (LC) cells, a class of Drosophila VPNs that project to distinct central brain structures called optic glomeruli. We anatomically describe 22 different LC types and show that, for several types, optogenetic activation in freely moving flies evokes specific behaviors. The activation phenotypes of two LC types closely resemble natural avoidance behaviors triggered by a visual loom. In vivo two photon calcium imaging reveals that these LC types respond to looming stimuli, while another type does not, but instead responds to the motion of a small object. Activation of LC neurons on only one side of the brain can result in attractive or aversive turning behaviors depending on the cell type. Our results indicate that LC neurons convey information on the presence and location of visual features relevant for specific behaviors. PMID- 28029096 TI - Reconstruction of TiO2/MnO2-C nanotube/nanoflake core/shell arrays as high performance supercapacitor electrodes. AB - Construction of electrodes with fast reaction kinetics is of great importance for achieving advanced supercapacitors. Herein we report a facile combined synthetic strategy with atomic layer deposition (ALD) and electrodeposition to rationally fabricate nanotube/nanoflake core/shell arrays. ALD-TiO2 nanotubes are used as the skeleton core for assembly of electrodeposited MnO2-C nanoflake shells forming a core/shell structure. Highly porous architecture and good electrical conductivity are combined in this unique core/shell structure, resulting in fast ion/electron transfer. In tests of electrochemical performance, the TiO2/MnO2-C core/shell arrays are characterized as cathode for asymmetric supecapacitors and exhibit high specific capacitance (880 F g-1 at 2.5 A g-1), excellent rate properties (735 F g-1 at 30 A g-1) and good long-term cycling stability (94.3% capacitance retention after 20 000 cycles). The proposed electrode construction strategy is favorable for fabrication of other advanced supercapacitor electrodes. PMID- 28029095 TI - SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons. AB - The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (INa)-has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia induced linkage of SUMO1 to the channels is complete, shifting the voltage dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions. PMID- 28029097 TI - Influence of silver content on rifampicin adsorptivity for magnetite/Ag/rifampicin nanoparticles. AB - Magnetite nanoparticles (NPs) decorated with silver (magnetite/Ag) are intensively investigated due to their application in the biomedical field. We demonstrate that the increase of silver content on the surface of nanoparticles improves the adsorptivity of antibiotic rifampicin as well as antibacterial properties. The use of ginger extract allowed to improve the silver nucleation on the magnetite surface that resulted in an increase of silver content. Physicochemical and functional characterization of magnetite/Ag NPs was performed. Our results show that 5%-10% of silver content in magnetite/Ag NPs is already sufficient for antimicrobial properties against Streptococcus salivarius and Staphylococcus aureus. The rifampicin molecules on the magnetite/Ag NPs surface made the spectrum of antimicrobial activity wider. Cytotoxicity evaluation of the magnetite/Ag/rifampicin NPs showed no harmful action towards normal human fibroblasts, whereas the effect on human embryonic kidney cell viability was time and dose dependent. PMID- 28029098 TI - Mesenchymal stem cells cultured on magnetic nanowire substrates. AB - Stem cells have been shown to respond to extracellular mechanical stimuli by regulating their fate through the activation of specific signaling pathways. In this work, an array of iron nanowires (NWs) aligned perpendicularly to the surface was fabricated by pulsed electrodepositon in porous alumina templates followed by a partial removal of the alumina to reveal 2-3 MUm of the NWs. This resulted in alumina substrates with densely arranged NWs of 33 nm in diameter separated by 100 nm. The substrates were characterized by scanning electron microscopy (SEM) energy dispersive x-ray analysis and vibrating sample magnetometer. The NW array was then used as a platform for the culture of human mesenchymal stem cells (hMSCs). The cells were stained for the cell nucleus and actin filaments, as well as immuno-stained for the focal adhesion protein vinculin, and then observed by fluorescence microscopy in order to characterize their spreading behavior. Calcein AM/ethidium homodimer-1 staining allowed the determination of cell viability. The interface between the cells and the NWs was studied using SEM. Results showed that hMSCs underwent a re-organization of actin filaments that translated into a change from an elongated to a spherical cell shape. Actin filaments and vinculin accumulated in bundles, suggesting the attachment and formation of focal adhesion points of the cells on the NWs. Though the overall number of cells attached on the NWs was lower compared to the control, the attached cells maintained a high viability (>90%) for up to 6 d. Analysis of the interface between the NWs and the cells confirmed the re organization of F-actin and revealed the adhesion points of the cells on the NWs. Additionally, a net of filopodia surrounded each cell, suggesting the probing of the array to find additional adhesion points. The cells maintained their round shape for up to 6 d of culture. Overall, the NW array is a promising nanostructured platform for studying and influencing hMSCs differentiation. PMID- 28029099 TI - Highly methanol-tolerant platinum electrocatalyst derived from poly(vinylpoyrrolidone) coating. AB - The design and fabrication of a methanol-tolerant electrocatalyst is still one of the most important issues in direct methanol fuel cells (DMFCs). Here, we focus on the design of a cathodic electrocatalyst in DMFCs and describe a new methanol tolerant electrocatalyst fabricated from poly(vinylpyrrolidone) (PVP) coating on platinum nanoparticles assisted by hydrogen bonding between PVP and polybenzimidazole (PBI). The PVP layer has a negligible effect on the oxygen reduction reaction (ORR) activity, while the methanol oxidation reaction is retarded by the PVP layer. The PVP-coated electrocatalyst shows higher ORR activity under various methanol concentrations in the electrolyte, suggesting that the PVP-coated electrocatalyst has a higher methanol tolerance. Also, the PVP-coated electrocatalyst loses only 14% of the electrochemical surface area after 5000 potential cycles from 0.6-1.0 V versus the reversible hydrogen electrode, indicating better Pt stability than non-coated (27%) and commercial (38%) electrocatalysts due to the unique sandwich structure formed by the PVP and PBI. The power density of the PVP-coated electrocatalyst is four to five times higher compared to non-coated and commercial electrocatalysts with 12 M methanol feeding to the anode side, respectively. PVP coating is important for the enhancement of Pt stability and methanol tolerance. This study offers a new method for preparing a low-cost and high-methanol-tolerant Pt electrocatalyst, and useful information for real DMFC application to eliminate the methanol crossover problem in the cathode side. PMID- 28029100 TI - A novel fabrication methodology for sulfur-doped ZnO nanorods as an active photoanode for improved water oxidation in visible-light regime. AB - Incorporation of foreign moiety in the lattice of semiconductors significantly alters their optoelectronic behavior and opens a plethora of new applications. In this paper, we report the synthesis of sulfur-doped zinc oxide (S-doped ZnO) nanorods by reacting ZnO nanorods with diammonium sulfide in vapor phase. Microscopic investigation revealed that the morphological features, such as, the length (2-4 MUm) and width (100-250 nm) of the original hexagonal ZnO nanorods remained intact post-sulfidation. X-ray photoelectron spectroscopy analysis of the sulfide sample confirmed the incorporation of sulfur into ZnO lattice. The optical measurements suggested the extension of absorption threshold into visible region upon sulfidation. Photoelectrochemical (PEC) activities of pure and S doped ZnO nanorods were compared for water oxidation in visible light (lambda > 420 nm), which showed several-fold increment in the performance of S-doped ZnO sample; the observed amelioration in the PEC activity was rationalized in terms of preferred visible light absorption and low resistance of sulfide sample, as evidenced by optical and electrochemical impedance spectroscopy. PMID- 28029101 TI - Quantitative stability analyses of multiwall carbon nanotube nanofluids following water/ice phase change cycling. AB - Multiwall carbon nanotube nanofluids are regularly investigated for phase change enhancement between liquid and solid states owing to their improved heat transfer properties. The potential applications are numerous, the most notable being latent heat thermal energy storage, but the success of all nanofluid-assisted technologies hinges greatly on the ability of nanoparticles to remain stably dispersed after repeated phase change cycles. In this report, the stability of aqueous nanofluids made from oxygen-functionalized multiwall carbon nanotubes (f MWCNTs) was profiled over the course of 20 freeze/thaw cycles. Sonication was used after each cycle to re-disperse clusters formed from the crystallization process. This study offers a quantitative evaluation of f-MWCNT-nanofluid stability as a result of phase change through optical characterization of concentration and particle size. It also provides insight into the integrity of the surface functionalities through zeta potential and XPS analyses. Concentration and particle size measurements showed moderate and consistent recoverability of f-MWCNT dispersion following ultrasonication. XPS measurements of solid-state MWCNTs exposed to freeze/thaw cycling in water, and zeta potential analyses of the nanofluids indicate that the surface oxygen content is preserved throughout phase change and over repeated cycles. These results suggest a resilience of oxygen-functionalized MWCNTs to the freezing and thawing of water, which is ideal for their utilization as phase change enhancers. PMID- 28029102 TI - Determination of the S-ZnO structural interaction in thiol-capped ZnO nanoparticles: a sulfur K-edge XAS study. AB - ZnO nanoparticles capped with thiol molecules display room temperature ferromagnetism which has been associated with the structural details of the interface formed between the organic molecule and the ZnO core. Although the local order around sulfur atoms at the ZnS/ZnO interface has been related to the occurrence of the ferromagnetic like behavior, no direct structural determination has been obtained yet. We report here a detailed x-ray absorption spectroscopy study performed at the sulfur K-edge to determine the local structure around the sulfur atoms in these systems and how it is modified by varying the length of the organic molecule. PMID- 28029104 TI - Mesostructured perovskite solar cells based on highly ordered TiO2 network scaffold via anodization of Ti thin film. AB - An anodized TiO2 interconnected network was fabricated and utilized as a mesoporous scaffold and electron transporter in perovskite solar cells. By modifying the synthesis parameters, the morphological features of the interconnected TiO2 nanostructures can be widely tuned and precisely controlled. The functional properties of the anodized TiO2 network are found to be severely influenced by morphology as well as the extent of oxidation. The device with the optimized TiO2 network exhibits superior electron extraction and transferability, resulting in conspicuous enhancement of the photocurrent and power conversion efficiency (PCE). This work proposes a promising and facile method for improving the performance of perovskite solar cells. PMID- 28029103 TI - Core-shell PbS/Sn:In2O3 and branched PbIn2S4/Sn:In2O3 nanowires in quantum dot sensitized solar cells. AB - Core-shell PbS/Sn:In2O3 and branched PbIn2S4/Sn:In2O3 nanowires have been obtained via the deposition of Pb over Sn:In2O3 nanowires and post growth processing under H2S between 100 degrees C-200 degrees C and 300 degrees C-500 degrees C respectively. The PbS/Sn:In2O3 nanowires have diameters of 50-250 nm and consist of cubic PbS and In2O3 while the PbIn2S4/Sn:In2O3 nanowires consist of PbIn2S4 branches with diameters of 10-30 nm and an orthorhombic crystal structure. We discuss the growth mechanisms and also show that the density of electrons in the n-type Sn:In2O3 core is strongly dependent on the thickness of the p-type PbS shell, which must be smaller than 30 nm to prevent core depletion, via the self-consistent solution of the Poisson-Schrodinger equations in the effective mass approximation. The PbS/Sn:In2O3 and PbIn2S4/Sn:In2O3 nanowire networks had resistances of 100-200 Omega due to the large carrier densities and exhibited defect related photoluminescence at 2.2 eV and 1.5 eV respectively. We show that PbS in contact with polysulfide electrolyte has ohmic like behavior but the PbS/Sn:In2O3 nanowires gave, rectifying current voltage characteristics as a counter electrode in a quantum dot sensitized solar cell using a conventional ITO/TiO2/CdS/CdSe photo anode, an open circuit voltage of ~0.5 V, and short circuit current density of ~1 mA cm-2. In contrast the branched PbIn2S4/Sn:In2O3 nanowires exhibited a higher current carrying capability of ~7 mA cm-2 and higher power conversion efficiency of ~2%. PMID- 28029105 TI - Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target specific cancer therapy. AB - Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake. Incorporation of ICG in PGA nanoparticles provided the NIR-absorbing agent with time-dependent altered optical properties in the presence of cathepsin B. Having minimal dark toxicity, the formulation exhibited significant cytotoxicity upon NIR exposure. Combined use of the formulation with saporin, a ribosome inactivating protein, resulted in synergistically enhanced cytotoxicity attributed to the photo-induced release of saporin from endo/lysosomes. The results suggest that this therapeutic approach can offer significant therapeutic benefit in the treatment of superficial malignancies, such as head and neck tumours. PMID- 28029106 TI - Differences between graphene and graphene oxide in gelatin based systems for transient biodegradable energy storage applications. AB - A comparison between graphene flakes and graphene oxide as filler in gelatin based systems for low-cost transient biodegradable energy storage applications has been carried out. The two bio-composites have been prepared and characterized by rheological measurements, cyclic voltammetry measurements, chronopotentiometry measurements and impedance spectroscopy. Differences in dielectric and mechanical properties have been correlated to the different structural organizations determinate by the hydrophobic/hydrophilic character of the used filler. In particular, the addition of the graphene oxide to the gelatin causes an increase in the elastic modulus with a parallel increase in the mechanical stability with time as compared to the composites obtained by adding graphene. Conversely, the surface capacitance is slightly increased by the graphene oxide addition compared to the pure gelatin sample. On the other hand, the introduction of the graphene flakes into the gelatin leads to a marked increase of the dielectric properties of the resulting bio-composite. PMID- 28029107 TI - Modulation of nonlinear resistive switching behavior of a TaOx-based resistive device through interface engineering. AB - A resistive switching device with inherent nonlinear characteristics through a delicately engineered interfacial layer is an ideal component to be integrated into passive crossbar arrays for the suppression of sneaking current, especially in ultra-dense 3D integration. In this paper, we demonstrated a TaOx-based bipolar resistive switching device with a nearly symmetrical bi-directional nonlinear feature through interface engineering. This was accomplished by introducing an ultra-thin interfacial layer (SiO2-x) with unique features, including a large band gap and a certain level of negative heat of oxide formation between the top electrode (TiN) and resistive layer (TaOx). The devices exhibit excellent nonlinear property under both positive and negative bias. Modulation of the inherent nonlinearity as well as the resistive switching mechanism are comprehensively studied by scrutinizing the results of the experimental control groups and the extensive characterizations including detailed compositional analysis, which suggests that the underlying mechanism of the nonlinear behavior is associatively governed by the serially connected metallic conductive filament and Flower-Nordheim tunneling barrier formed by the SiO2-x interface layer. The proposed device in this work has great potential to be implemented in future massive storage memory applications of high-density selector-free crossbar structure. PMID- 28029108 TI - A ZnO nanowire bio-hybrid solar cell. AB - Harvesting solar energy as a carbon free source can be a promising solution to the energy crisis and environmental pollution. Biophotovoltaics seek to mimic photosynthesis to harvest solar energy and to take advantage of the low material costs, negative carbon footprint, and material abundance. In the current study, we report on a combination of zinc oxide (ZnO) nanowires with monolayers of photosynthetic reaction centers which are self-assembled, via a cytochrome c linker, as photoactive electrode. In a three-probe biophotovoltaics cell, a photocurrent density of 5.5 MUA cm-2 and photovoltage of 36 mV was achieved, using methyl viologen as a redox mediator in the electrolyte. Using ferrocene as a redox mediator a transient photocurrent density of 8.0 MUA cm-2 was obtained, which stabilized at 6.4 MUA cm-2 after 20 s. In-depth electronic structure characterization using photoemission spectroscopy in conjunction with electrochemical analysis suggests that the fabricated photoactive electrode can provide a proper electronic path for electron transport all the way from the conduction band of the ZnO nanowires, through the protein linker to the RC, and ultimately via redox mediator to the counter electrode. PMID- 28029109 TI - Highly stable 2D material (2DM) field-effect transistors (FETs) with wafer-scale multidyad encapsulation. AB - Field-effect transistors (FETs) composed of 2D materials (2DMs) such as transition-metal dichalcogenide (TMD) materials show unstable electrical characteristics in ambient air due to the high sensitivity of 2DMs to water adsorbates. In this work, in order to demonstrate the long-term retention of electrical characteristics of a TMD FET, a multidyad encapsulation method was applied to a MoS2 FET and thereby its durability was warranted for one month. It was well known that the multidyad encapsulation method was effective to mitigate high sensitivity to ambient air in light-emitting diodes (LEDs) composed of organic materials. However, there was no attempt to check the feasibility of such a multidyad encapsulation method for 2DM FETs. It is timely to investigate the water vapor transmission ratio (WVTR) required for long-term stability of 2DM FETs. The 2DM FETs were fabricated with MoS2 flakes by both an exfoliation method, that is desirable to attain high quality film, and a chemical vapor deposition (CVD) method, that is applicable to fabrication for a large-sized substrate. In order to eliminate other unwanted variables, the MoS2 FETs composed of exfoliated flakes were primarily investigated to assure the effectiveness of the encapsulation method. The encapsulation method uses multiple dyads comprised of a polymer layer by spin coating and an Al2O3 layer deposited by atomic layer deposition (ALD). The proposed method shows wafer-scale uniformity, high transparency, and protective barrier properties against adsorbates (WVTR of 8 * 10-6 g m-2 day-1) over one month. PMID- 28029110 TI - Synthesis and interface characterization of CNTs on graphene. AB - Carbon nanotubes (CNTs) and graphene are potential candidates for future interconnect materials. CNTs are promising on-chip via interconnect materials due to their readily formed vertical structures, their current-carrying capacity, which is much larger than existing on-chip interconnect materials such as copper and tungsten, and their demonstrated ability to grow in patterned vias with sub 50 nm widths; meanwhile, graphene is suitable for horizontal interconnects. However, they both present the challenge of having high-resistance contacts with other conductors. An all-carbon structure is proposed in this paper, which can be formed using the same chemical vapor deposition method for both CNTs and graphene. Vertically aligned CNTs are grown directly on graphene with an Fe or Ni catalyst. The structural characteristics of the graphene and the grown CNTs are analyzed using Raman spectroscopy and electron microscopy techniques. The CNT graphene interface is studied in detail using transmission electron microscopic analysis of the CNT-graphene heterostructure, which suggests C-C bonding between the two materials. Electrical measurement results confirm the existence of both a lateral conduction path within graphene and a vertical conduction path in the CNT graphene heterostructure, giving further support to the C-C bonding at the CNT graphene interface and resulting in potential applications for all-carbon interconnects. PMID- 28029112 TI - Loading of halloysite nanotubes with BSA, alpha-Lac and beta-Lg: a Fourier transform infrared spectroscopic and thermogravimetric study. AB - Halloysite nanotubes (HNTs) are considered as ideal materials for biotechnological and medical applications. An important feature of halloysite is that it has a different surface chemistry on the inner and outer sides of the tubes. This property means that negatively-charged molecules can be selectively loaded inside the halloysite nanoscale its lumen. Loaded HNTs can be used for the controlled or sustained release of proteins, drugs, bioactive molecules and other agents. We studied the interaction between HNTs and bovine serum albumin, alpha lactalbumin and beta -lactoglobulin loaded into HTNs using Fourier transform infrared spectroscopy and thermogravimetry. These techniques enabled us to study the protein conformation and thermal stability, respectively, and to estimate the amount of protein loaded into the HNTs. TEM images confirmed the loading of proteins into HTNs. PMID- 28029111 TI - Characterization of Gd loaded chitosan-TPP nanohydrogels by a multi-technique approach combining dynamic light scattering (DLS), asymetrical flow-field-flow fractionation (AF4) and atomic force microscopy (AFM) and design of positive contrast agents for molecular resonance imaging (MRI). AB - Chitosan CS-tripolyphosphate TPP/hyaluronic acid HA nanohydrogels loaded with gadolinium chelates (GdDOTA ? CS-TPP/HA NGs) synthesized by ionic gelation were designed for lymph node (LN) MRI. In order to be efficiently drained to LNs, nanogels (NGs) needed to exhibit a diameter phi < 100 nm. For that, formulation parameters were tuned, using (i) CS of two different molecular weights (51 and 37 kDa) and (ii) variable CS/TPP ratio (2 < CS/TPP < 8). Characterization of NG size distribution by dynamic light scattering (DLS) and asymetrical flow-field-flow fractionation (AF4) showed discrepancies since DLS diameters were consistently above 200 nm while AF4 showed individual nano-objects with phi < 100 nm. Such a difference could be correlated to the presence of aggregates inherent to ionic gelation. This point was clarified by atomic force microscopy (AFM) in liquid mode which highlighted the main presence of individual nano-objects in nanosuspensions. Thus, combination of DLS, AF4 and AFM provided a more precise characterization of GdDOTA ? CS-TPP/HA nanohydrogels which, in turn, allowed to select formulations leading to NGs of suitable mean sizes showing good MRI efficiency and negligible toxicity. PMID- 28029113 TI - A structural insight into mechanical strength of graphene-like carbon and carbon nitride networks. AB - Graphene, one of the strongest materials ever discovered, triggered the exploration of many 2D materials in the last decade. However, the successful synthesis of a stable nanomaterial requires a rudimentary understanding of the relationship between its structure and strength. In the present study, we investigate the mechanical properties of eight different carbon-based 2D nanomaterials by performing extensive density functional theory calculations. The considered structures were just recently either experimentally synthesized or theoretically predicted. The corresponding stress-strain curves and elastic moduli are reported. They can be useful in training force field parameters for large scale simulations. A comparative analysis of these results revealed a direct relationship between atomic density per area and elastic modulus. Furthermore, for the networks that have an armchair and a zigzag orientation, we observed that they were more stretchable in the zigzag direction than the armchair direction. A critical analysis of the angular distributions and radial distribution functions suggested that it could be due to the higher ability of the networks to suppress the elongations of the bonds in the zigzag direction by deforming the bond angles. The structural interpretations provided in this work not only improve the general understanding of a 2D material's strength but also enables us to rationally design them for higher qualities. PMID- 28029115 TI - Development of Orally Administered gamma-Tocotrienol (GT3) Nanoemulsion for Radioprotection. AB - The purpose of this study was two-fold: (1) to formulate gamma-tocotrienol (GT3) in a nanoemulsion formulation as a prophylactic orally administered radioprotective agent; and (2) to optimize the storage conditions to preserve the structural integrity of both the formulation and the compound. gamma-tocotrienol was incorporated into a nanoemulsion and lyophilized with lactose. Ultra performance liquid chromatography-mass spectroscopy (UPLC-MS) was used to monitor the chemical stability of GT3 over time, the particle size and zeta potential, and scanning electron microscopy (SEM) were used to study the physical stability of the nanoemulsion. Radioprotective and toxicity studies were performed in mice. The liquid formulation exhibited GT3 degradation at all storage temperatures. Lyophilization, in the presence of lactose, significantly reduced GT3 degradation. Both the liquid and lyophilized nanoemulsions had stable particle size and zeta potential when stored at 4 degrees C. Toxicity studies of the nanoemulsion resulted in no observable toxicity in mice at an oral dose of 600 mg/kg GT3. The nano-formulated GT3 (300 mg/kg) demonstrated enhanced survival efficacy compared to GT3 alone (200 and 400 mg/kg) in CD2F1 mice exposed to total body gamma radiation. The optimal long-term storage of formulated GT3 is as a powder at -20 degrees C to preserve drug and formulation integrity. Formulation of GT3 as a nanoemulsion for oral delivery as a prophylactic radioprotectant shows promise and warrants further investigation. PMID- 28029114 TI - Folate and Vitamin B12-Related Biomarkers in Relation to Brain Volumes. AB - AIM: We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B12 status and brain volumes. We furthermore compared brain volumes of participants who received daily folic acid and vitamin B12 supplementation with participants who did not. METHODS: Participants of the B-PROOF study (n = 2919) were assigned to 400 ug folic acid and 500 ug vitamin B12, or a placebo. After two years of intervention, T1 weighted magnetic resonance imaging (MRI) scans were made in a random subsample (n = 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B12, holotranscobalamin, and methylmalonic acid concentrations were measured. RESULTS: Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (beta = -0.91, 95% CI -1.85-0.03; p = 0.06) and between serum folate and TBV (beta = -0.20, 95% CI -0.38, -0.02; p = 0.03). No significant associations were observed for serum vitamin B12 and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058-1069 mL) than the non-supplemented group (1072, 95% CI 1067-1078 mL, p = 0.03). CONCLUSIONS: Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B12 supplementation will be beneficial above and beyond normal dietary intake for brain health. PMID- 28029117 TI - A Visual Analytics Approach for Station-Based Air Quality Data. AB - With the deployment of multi-modality and large-scale sensor networks for monitoring air quality, we are now able to collect large and multi-dimensional spatio-temporal datasets. For these sensed data, we present a comprehensive visual analysis approach for air quality analysis. This approach integrates several visual methods, such as map-based views, calendar views, and trends views, to assist the analysis. Among those visual methods, map-based visual methods are used to display the locations of interest, and the calendar and the trends views are used to discover the linear and periodical patterns. The system also provides various interaction tools to combine the map-based visualization, trends view, calendar view and multi-dimensional view. In addition, we propose a self-adaptive calendar-based controller that can flexibly adapt the changes of data size and granularity in trends view. Such a visual analytics system would facilitate big-data analysis in real applications, especially for decision making support. PMID- 28029116 TI - Metal-Free Carbon-Based Materials: Promising Electrocatalysts for Oxygen Reduction Reaction in Microbial Fuel Cells. AB - Microbial fuel cells (MFCs) are a promising green approach for wastewater treatment with the simultaneous advantage of energy production. Among the various limiting factors, the cathodic limitation, with respect to performance and cost, is one of the main obstacles to the practical applications of MFCs. Despite the high performance of platinum and other metal-based cathodes, their practical use is limited by their high cost, low stability, and environmental toxicity. Oxygen is the most favorable electron acceptor in the case of MFCs, which reduces to water through a complicated oxygen reduction reaction (ORR). Carbon-based ORR catalysts possessing high surface area and good electrical conductivity improve the ORR kinetics by lowering the cathodic overpotential. Recently, a range of carbon-based materials have attracted attention for their exceptional ORR catalytic activity and high stability. Doping the carbon texture with a heteroatom improved their ORR activity remarkably through the favorable adsorption of oxygen and weaker molecular bonding. This review provides better insight into ORR catalysis for MFCs and the properties, performance, and applicability of various metal-free carbon-based electrocatalysts in MFCs to find the most appropriate cathodic catalyst for the practical applications. The approaches for improvement, key challenges, and future opportunities in this field are also explored. PMID- 28029118 TI - Compound Event Barrier Coverage in Wireless Sensor Networks under Multi Constraint Conditions. AB - It is important to monitor compound event by barrier coverage issues in wireless sensor networks (WSNs). Compound event barrier coverage (CEBC) is a novel coverage problem. Unlike traditional ones, the data of compound event barrier coverage comes from different types of sensors. It will be subject to multiple constraints under complex conditions in real-world applications. The main objective of this paper is to design an efficient algorithm for complex conditions that can combine the compound event confidence. Moreover, a multiplier method based on an active-set strategy (ASMP) is proposed to optimize the multiple constraints in compound event barrier coverage. The algorithm can calculate the coverage ratio efficiently and allocate the sensor resources reasonably in compound event barrier coverage. The proposed algorithm can simplify complex problems to reduce the computational load of the network and improve the network efficiency. The simulation results demonstrate that the proposed algorithm is more effective and efficient than existing methods, especially in the allocation of sensor resources. PMID- 28029119 TI - Reverse Engineering and Security Evaluation of Commercial Tags for RFID-Based IoT Applications. AB - The Internet of Things (IoT) is a distributed system of physical objects that requires the seamless integration of hardware (e.g., sensors, actuators, electronics) and network communications in order to collect and exchange data. IoT smart objects need to be somehow identified to determine the origin of the data and to automatically detect the elements around us. One of the best positioned technologies to perform identification is RFID (Radio Frequency Identification), which in the last years has gained a lot of popularity in applications like access control, payment cards or logistics. Despite its popularity, RFID security has not been properly handled in numerous applications. To foster security in such applications, this article includes three main contributions. First, in order to establish the basics, a detailed review of the most common flaws found in RFID-based IoT systems is provided, including the latest attacks described in the literature. Second, a novel methodology that eases the detection and mitigation of such flaws is presented. Third, the latest RFID security tools are analyzed and the methodology proposed is applied through one of them (Proxmark 3) to validate it. Thus, the methodology is tested in different scenarios where tags are commonly used for identification. In such systems it was possible to clone transponders, extract information, and even emulate both tags and readers. Therefore, it is shown that the methodology proposed is useful for auditing security and reverse engineering RFID communications in IoT applications. It must be noted that, although this paper is aimed at fostering RFID communications security in IoT applications, the methodology can be applied to any RFID communications protocol. PMID- 28029120 TI - Experimental Investigations of a Precision Sensor for an Automatic Weapons Stabilizer System. AB - This paper presents the results of experimental investigations of a precision sensor for an automatic weapons stabilizer system. It also describes the experimental equipment used and the structure of the developed sensor. A weapons stabilizer is designed for automatic guidance of an armament unit in the horizontal and vertical planes when firing at ground and air targets that are quickly maneuvering, and at lower speeds when firing anti-tank missiles, as well as the bypass of construction elements by the armament unit, and the automatic tracking of moving targets when interacting with a fire control system. The results of experimental investigations have shown that the error of the precision sensor developed on the basis of a piezoelectric element is 6 * 10-10 m/s2 under quasi-static conditions, and ~10-5 m/s2 for mobile use. This paper defines metrological and calibration properties of the developed sensor. PMID- 28029121 TI - Change Analysis in Structural Laser Scanning Point Clouds: The Baseline Method. AB - A method is introduced for detecting changes from point clouds that avoids registration. For many applications, changes are detected between two scans of the same scene obtained at different times. Traditionally, these scans are aligned to a common coordinate system having the disadvantage that this registration step introduces additional errors. In addition, registration requires stable targets or features. To avoid these issues, we propose a change detection method based on so-called baselines. Baselines connect feature points within one scan. To analyze changes, baselines connecting corresponding points in two scans are compared. As feature points either targets or virtual points corresponding to some reconstructable feature in the scene are used. The new method is implemented on two scans sampling a masonry laboratory building before and after seismic testing, that resulted in damages in the order of several centimeters. The centres of the bricks of the laboratory building are automatically extracted to serve as virtual points. Baselines connecting virtual points and/or target points are extracted and compared with respect to a suitable structural coordinate system. Changes detected from the baseline analysis are compared to a traditional cloud to cloud change analysis demonstrating the potential of the new method for structural analysis. PMID- 28029122 TI - Network Allocation Vector (NAV) Optimization for Underwater Handshaking-Based Protocols. AB - In this paper, we obtained the optimized network allocation vector (NAV) for underwater handshaking-based protocols, as inefficient determination of the NAV leads to unnecessarily long silent periods. We propose a scheme which determines the NAV by taking into account all possible propagation delays: propagation delay between a source and a destination; propagation delay between a source and the neighbors; and propagation delay between a destination and the neighbors. Such an approach effectively allows the NAV to be determined precisely equal to duration of a busy channel, and the silent period can be set commensurate to that duration. This allows for improvements in the performance of handshaking-based protocols, such as the carrier sense multiple access/collision avoidance (CSMA/CA) protocol, in terms of throughput and fairness. To evaluate the performance of the proposed scheme, performance comparisons were carried out through simulations with prior NAV setting methods. The simulation results show that the proposed scheme outperforms the other schemes in terms of throughput and fairness. PMID- 28029123 TI - Parameters for Successful Parental RNAi as An Insect Pest Management Tool in Western Corn Rootworm, Diabrotica virgifera virgifera. AB - Parental RNAi (pRNAi) is an RNA interference response where the gene knockdown phenotype is observed in the progeny of the treated organism. pRNAi has been demonstrated in female western corn rootworms (WCR) via diet applications and has been described as a potential approach for rootworm pest management. However, it is not clear if plant-expressed pRNAi can provide effective control of next generation WCR larvae in the field. In this study, we evaluated parameters required to generate a successful pRNAi response in WCR for the genes brahma and hunchback. The parameters tested included a concentration response, duration of the dsRNA exposure, timing of the dsRNA exposure with respect to the mating status in WCR females, and the effects of pRNAi on males. Results indicate that all of the above parameters affect the strength of pRNAi phenotype in females. Results are interpreted in terms of how this technology will perform in the field and the potential role for pRNAi in pest and resistance management strategies. More broadly, the described approaches enable examination of the dynamics of RNAi response in insects beyond pRNAi and crop pests. PMID- 28029124 TI - Node Redeployment Algorithm Based on Stratified Connected Tree for Underwater Sensor Networks. AB - During the underwater sensor networks (UWSNs) operation, node drift with water environment causes network topology changes. Periodic node location examination and adjustment are needed to maintain good network monitoring quality as long as possible. In this paper, a node redeployment algorithm based on stratified connected tree for UWSNs is proposed. At every network adjustment moment, self examination and adjustment on node locations are performed firstly. If a node is outside the monitored space, it returns to the last location recorded in its memory along straight line. Later, the network topology is stratified into a connected tree that takes the sink node as the root node by broadcasting ready information level by level, which can improve the network connectivity rate. Finally, with synthetically considering network coverage and connectivity rates, and node movement distance, the sink node performs centralized optimization on locations of leaf nodes in the stratified connected tree. Simulation results show that the proposed redeployment algorithm can not only keep the number of nodes in the monitored space as much as possible and maintain good network coverage and connectivity rates during network operation, but also reduce node movement distance during node redeployment and prolong the network lifetime. PMID- 28029125 TI - Ameliorative Effect of Curcumin-Encapsulated Hyaluronic Acid-PLA Nanoparticles on Thioacetamide-Induced Murine Hepatic Fibrosis. AB - In this study, we developed curcumin-encapsulated hyaluronic acid-polylactide nanoparticles (CEHPNPs) to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA) receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs) rather than normal cells. CEHPNPs could bind to CD44 and be internalized effectively through endocytosis to release curcumin, a poor water-soluble liver protective agent. Thus, CEHPNPs were potentially not only improving drug efficiency, but also targeting aHSCs. HA and polylactide (PLA) were crosslinked by adipic acid dihydrazide (ADH). The synthesis of HA-PLA was monitored by Fourier-transform infrared (FTIR) and Nuclear Magnetic Resonance (NMR). The average particle size was approximately 60 70 nm as determined by dynamic light scattering (DLS) and scanning electron microscope (SEM). Zeta potential was around -30 mV, which suggested a good stability of the particles. This drug delivery system induced significant aHSC cell death without affecting quiescent HSCs, hepatic epithelial, and parenchymal cells. This system reduced drug dosage without sacrificing therapeutic efficacy. The cytotoxicity IC50 (inhibitory concentration at 50%) value of CEHPNPs was approximately 1/30 to that of the free drug treated group in vitro. Additionally, the therapeutic effects of CEHPNPs were as effective as the group treated with the same curcumin dose intensity in vivo. CEHPNPs significantly reduced serum aspartate transaminase/alanine transaminase (ALT/AST) significantly, and attenuated tissue collagen production and cell proliferation as revealed by liver biopsy. Conclusively, the advantages of superior biosafety and satisfactory therapeutic effect mean that CEHPNPs hold great potential for treating hepatic fibrosis. PMID- 28029126 TI - Legionella Risk Management and Control in Potable Water Systems: Argument for the Abolishment of Routine Testing. AB - Legionella is an opportunistic pathogen of public health significance. One of the main sources of Legionella is potable water systems. As a consequence of aging populations there is an increasing demographic considered at high risk for Legionellosis and, as such, a review of the guidelines is required. Worldwide, Legionella has been detected from many potable water sources, suggesting it is ubiquitous in this environment. Previous studies have identified the limitations of the current standard method for Legionella detection and the high possibility of it returning both false negative and false positive results. There is also huge variability in Legionella test results for the same water sample when conducted at different laboratories. However, many guidelines still recommend the testing of water systems. This commentary argues for the removal of routine Legionella monitoring from all water distribution guidelines. This procedure is financially consuming and false negatives may result in managers being over confident with a system or a control mechanism. Instead, the presence of the pathogen should be assumed and focus spent on managing appropriate control measures and protecting high-risk population groups. PMID- 28029127 TI - Organophosphorous Pesticide Detection in Olive Oil by Using a Miniaturized, Easy to-Use, and Cost-Effective Biosensor Combined with QuEChERS for Sample Clean-Up. AB - Herein, we report a portable electrochemical biosensor based on butyrylcholinesterase (BChE) immobilized on carbon black (CB)-modified screen printed electrodes (SPEs) for the detection of organophosphorous pesticides in olive oil. The BChE/CB-SPE biosensor was developed to detect paraoxon in standard solutions as well as in olive oil samples previously treated with the QuEChERS method to extract pesticides from the whole fatty matrix. The biosensor shows a linear concentration range of between 20 and 100 ppb for paraoxon both in standard solutions (phosphate buffer 0.05 M) and in olive oil extracts, with a detection limit of 6 ppb in olive oil extract, corresponding to 10% of inhibition. The accuracy of this biosensor in olive oil samples was assessed with olive oil spiked with paraoxon, obtaining satisfactory recovery values. PMID- 28029128 TI - Changing Diet Quality in China during 2004-2011. AB - Currently, under- and over-nutrition problems co-exist in China. However, systematic studies on the diet quality of Chinese residents have been scant. This study described the trend in diet quality of Chinese residents over a recent eight-year period and investigated the relevant influential factors. The data of Chinese adults aged 20-59 years was extracted from 2004, 2006, 2009, and 2011 China Health and Nutrition Survey. The China diet quality index (DQI) was employed to assess the diet quality of Chinese adults. The dietary consumption data of each individual was collected using a 24-h dietary recall and weighed food records implemented for three consecutive days. A mixed ordinary least squares regression model was applied to analyze the factors influencing the DQI scores of Chinese residents. Results showed that the diet quality of Chinese residents increased from 2004 to 2006, followed by a decrease in 2009 and 2011. The income, urbanicity index, and southern dummy were positively associated with DQI scores, whereas the size of household and labor intensity were negative predictors of DQI scores. The DQI scores also varied over BMI values. With an increase of the average income level in the future, the diet quality of Chinese residents is estimated to further improve. Moreover, urbanization could also contribute to reaching a more balanced diet. PMID- 28029130 TI - A Cu2+-Selective Probe Based on Phenanthro-Imidazole Derivative. AB - A novel fluorescent Probe 1, based on phenanthro-imidazole has been developed as an efficient chemosensor for the trace detection of copper ions (Cu2+). Probe 1 demonstrated sensitive fluorescence quenching upon binding with Cu2+ through 1:1 stoichiometric chelation. The detection limit for Cu2+ ions was projected through linear quenching fitting to be as low as 2.77 * 10-8 M (or 1.77 ppb). The sensing response was highly selective towards Cu2+ with minimal influence from other common metal ions, facilitating the practical application of Probe 1 in trace detection. PMID- 28029129 TI - Modeling Growth and Toxin Production of Toxigenic Fungi Signaled in Cheese under Different Temperature and Water Activity Regimes. AB - The aim of this study was to investigate in vitro and model the effect of temperature (T) and water activity (aw) conditions on growth and toxin production by some toxigenic fungi signaled in cheese. Aspergillus versicolor, Penicillium camemberti, P. citrinum, P. crustosum, P. nalgiovense, P. nordicum, P. roqueforti, P. verrucosum were considered they were grown under different T (0-40 degrees C) and aw (0.78-0.99) regimes. The highest relative growth occurred around 25 degrees C; all the fungi were very susceptible to aw and 0.99 was optimal for almost all species (except for A. versicolor, awopt = 0.96). The highest toxin production occurred between 15 and 25 degrees C and 0.96-0.99 aw. Therefore, during grana cheese ripening, managed between 15 and 22 degrees C, ochratoxin A (OTA), penitrem A (PA), roquefortine-C (ROQ-C) and mycophenolic acid (MPA) are apparently at the highest production risk. Bete and logistic function described fungal growth under different T and aw regimes well, respectively. Bete function described also STC, PA, ROQ-C and OTA production as well as function of T. These models would be very useful as starting point to develop a mechanistic model to predict fungal growth and toxin production during cheese ripening and to help advising the most proper setting of environmental factors to minimize the contamination risk. PMID- 28029131 TI - Assessment of a Culturally-Tailored Sexual Health Education Program for African American Youth. AB - African American youth are affected disproportionately by sexually transmitted infections (STIs), human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), and teenage pregnancy when compared to other racial groups. This paper evaluates the effectiveness of the To Help Young People Establish (2 HYPE) Abstinence Club, a behavioral intervention designed to promote delayed sexual activity among African American youth ages 12-18 in Atlanta, Georgia. The intervention included 20 h of curriculum and creative arts instruction. Pre- and post-intervention survey data collected from 2008-2010 were analyzed to determine the effectiveness of the intervention. Intervention (n = 651) and comparison (n = 112) groups were compared through analysis of variance and multivariate logistic regression models. There was a statistically significant increase in intervention youth who were thinking about being abstinent (p = 0.0005). Those who had not been engaged in sexual activity were two times more likely to plan abstinence compared to participants that had been previously sexually active previously (odds ratio 2.41; 95% confidence interval 1.62, 3.60). Significant results hold implications for subsequent community-based participatory research and practice that broadens the understanding of the relevance of marriage, as just one among other life success milestones that may hold more importance to African American youth in positioning the value of delayed and responsible sexual activity towards effective STIs, HIV/AIDS, and teen pregnancy risk reduction interventions. PMID- 28029132 TI - A Canopy Density Model for Planar Orchard Target Detection Based on Ultrasonic Sensors. AB - Orchard target-oriented variable rate spraying is an effective method to reduce pesticide drift and excessive residues. To accomplish this task, the orchard targets' characteristic information is needed to control liquid flow rate and airflow rate. One of the most important characteristics is the canopy density. In order to establish the canopy density model for a planar orchard target which is indispensable for canopy density calculation, a target density detection testing system was developed based on an ultrasonic sensor. A time-domain energy analysis method was employed to analyze the ultrasonic signal. Orthogonal regression central composite experiments were designed and conducted using man-made canopies of known density with three or four layers of leaves. Two model equations were obtained, of which the model for the canopies with four layers was found to be the most reliable. A verification test was conducted with different layers at the same density values and detecting distances. The test results showed that the relative errors of model density values and actual values of five, four, three and two layers of leaves were acceptable, while the maximum relative errors were 17.68%, 25.64%, 21.33% and 29.92%, respectively. It also suggested the model equation with four layers had a good applicability with different layers which increased with adjacent layers. PMID- 28029133 TI - Cinnamaldehyde Ameliorates Cadmium-Inhibited Root Elongation in Tobacco Seedlings via Decreasing Endogenous Hydrogen Sulfide Production. AB - Cinnamaldehyde (CA) is natural plant-derived compound that has been highly appreciated for its medicinal properties. However, little information is known about the regulation of plant intrinsic physiology by CA. To address these gaps, physiological, histochemical, and biochemical approaches were applied to investigate CA-facilitated cadmium (Cd) tolerance in the roots of tobacco (Nicotiana tabacum) seedlings. Treatment with CdCl2 at 20 MUM for 72 h resulted in the significant decrease in root elongation by 40.39% as compared to control. CA alleviated Cd-inhibited root elongation in dose- and time-dependent manners. The addition of CA at 20 MUM induced significant increase in root elongation by 42.58% as compared to Cd treatment alone. CA abolished Cd-induced ROS (reactive oxygen species) accumulation, lipid peroxidation, loss of membrane integrity, cell death, and free Cd2+ accumulation in roots. CA blocked the Cd-induced increase in the endogenous H2S level through the down-regulation of d-cysteine desulfhydrase (DCD) expression. H2S scavenger hypotaurine (HT) or potent H2S biosynthetic inhibitor dl-propargylglicine (PAG) were able mimic the action of CA on the blockade of Cd-induced H2S accumulation, cell death, and growth inhibition. Enhancement of the endogenous H2S level with NaHS (H2S donor) abrogated all the beneficial capabilities of CA, HT, and PAG. Collectively, these results suggest that CA has great potential to confer plant tolerance against Cd stress, which is closely associated with its capability to inhibit Cd-induced H2S production. This study not only provides evidences for the regulation of plant physiology by CA but also sheds new light on the cross-talk between CA and H2S in physiological modulations. PMID- 28029135 TI - Time-Resolved Fluorescence Spectroscopy and Fluorescence Lifetime Imaging Microscopy for Characterization of Dendritic Polymer Nanoparticles and Applications in Nanomedicine. AB - The emerging field of nanomedicine provides new approaches for the diagnosis and treatment of diseases, for symptom relief and for monitoring of disease progression. One route of realizing this approach is through carefully constructed nanoparticles. Due to the small size inherent to the nanoparticles a proper characterization is not trivial. This review highlights the application of time-resolved fluorescence spectroscopy and fluorescence lifetime imaging microscopy (FLIM) for the analysis of nanoparticles, covering aspects ranging from molecular properties to particle detection in tissue samples. The latter technique is particularly important as FLIM allows for distinguishing of target molecules from the autofluorescent background and, due to the environmental sensitivity of the fluorescence lifetime, also offers insights into the local environment of the nanoparticle or its interactions with other biomolecules. Thus, these techniques offer highly suitable tools in the fields of particle development, such as organic chemistry, and in the fields of particle application, such as in experimental dermatology or pharmaceutical research. PMID- 28029136 TI - Application of Lectin Array Technology for Biobetter Characterization: Its Correlation with FcgammaRIII Binding and ADCC. AB - Lectin microarray technology was applied to compare the glycosylation pattern of the monoclonal antibody MB311 expressed in SP2.0 cells to an antibody-dependent cellular cytotoxic effector function (ADCC)-optimized variant (MB314). MB314 was generated by a plant expression system that uses genetically modified moss protoplasts (Physcomitrella patens) to generate a de-fucosylated version of MB311. In contrast to MB311, no or very low interactions of MB314 with lectins Aspergillus oryzae l-fucose (AOL), Pisum sativum agglutinin (PSA), Lens culinaris agglutinin (LCA), and Aleuria aurantia lectin (AAL) were observed. These lectins are specific for mono-/biantennary N-glycans containing a core fucose residue. Importantly, this fucose indicative lectin-binding pattern correlated with increased MB314 binding to CD16 (FcgammaRIII; receptor for the constant region of an antibody)-whose affinity is mediated through core fucosylation-and stronger ADCC. In summary, these results demonstrate that lectin microarrays are useful orthogonal methods during antibody development and for characterization. PMID- 28029134 TI - Activity of Zearalenone in the Porcine Intestinal Tract. AB - This study demonstrates that low doses (somewhat above the No Observed Adverse Effect Level, NOAEL) of the mycoestrogen zearalenone (ZEN) and its metabolites display multispecificity towards various biological targets in gilts. The observed responses in gilts were surprising. The presence of ZEN and zearalenols (ZELs) did not evoke a response in the porcine gastrointestinal tract, which was attributed to dietary tolerance. Lymphocyte proliferation was intensified in jejunal mesenteric lymph nodes, and lymphocyte counts increased in the jejunal epithelium with time of exposure. In the distal digestive tract, fecal bacterial counts decreased, the activity of fecal bacterial enzymes and lactic acid bacteria increased, and cecal water was characterized by higher genotoxicity. The accompanying hyperestrogenism led to changes in mRNA activity of selected enzymes (cytochrome P450, hydroxysteroid dehydrogenases, nitric oxide synthases) and receptors (estrogen and progesterone receptors), and it stimulated post translational modifications which play an important role in non-genomic mechanisms of signal transmission. Hyperestrogenism influences the regulation of the host's steroid hormones (estron, estradiol and progesteron), it affects the virulence of bacterial genes encoding bacterial hydroxysteroid dehydrogenases (HSDs), and it participates in detoxification processes by slowing down intestinal activity, provoking energy deficits and promoting antiporter activity at the level of enterocytes. In most cases, hyperestrogenism fulfils all of the above roles. The results of this study indicate that low doses of ZEN alleviate inflammatory processes in the digestive system, in particular in the proximal and distal intestinal tract, and increase body weight gains in gilts. PMID- 28029137 TI - Adequacy Assessment of a Universal Salt Iodization Program Two Decades after Its Implementation: A National Cross-Sectional Study of Iodine Status among School Age Children in Tunisia. AB - In the framework of a worldwide policy to eliminate iodine deficiency (ID) disorders, universal salt iodization was adopted in Tunisia two decades ago. The present study aims to evaluate this strategy, using both performance and impact indicators. A total of 1560 children, aged 6-12 years, were randomly sampled using a national, two-stage, stratified, cross-sectional cluster survey in 2012. Urinary iodine concentration (UIC) of the subjects, and household salt iodine content, were analyzed. The national median UIC was 220 ug/L (95% confidence interval (CI): 199-241), indicating an acceptable iodine status at the population level. Only 11.4% (95% CI: 8.6-14.9) of the children had UIC <100 ug/L, but with large regional disparities (4.3% to 25.5%, p < 0.01); however, more than a quarter of the subjects were at risk of adverse health consequences due to iodine excess. Children from households of low socio-economic levels were more prone to inadequate UIC. The national median iodine concentration of household salt was 22 mg/kg (95% CI: 21-23). Only half of the households used adequately iodized salt (15-25 ppm), with large regional disparities. National ID rates are now well below the target criteria of WHO (World Health Organization) certification (<20% of children with UIC <50 ug/L and <50% with UIC <100 ug/L). The coverage of adequately iodized salt fell short in meeting the goals of USI (Universal Salt Iodization), i.e., >90% of households. Regular monitoring of iodized salt production lines must be strengthened with involvement by producers. PMID- 28029138 TI - The Potential of Cyclodextrins as Novel Active Pharmaceutical Ingredients: A Short Overview. AB - Cyclodextrins (CDs) are cyclic oligosaccharides of natural origin that were discovered more than 100 years ago. The peculiar cone-like conformation of the sugar ring, expressing a lipophilic cavity and a hydrophilic external surface, allows these substances to spontaneously complex poorly soluble compounds in an aqueous environment. For more than 50 years, these substances have found applicability in the pharmaceutical and food industries as solubilizing agents for poorly soluble chemical entities. Nowadays, several research groups all over the world are investigating their potential as active pharmaceutical ingredients (APIs) for the treatment of several illnesses (e.g., hypercholesterolemia, cancer, Niemann-Pick Type C disease). The aim of this review is to briefly retrace cyclodextrins' legacy as complexing agents and describe the current and future prospects of this class of chemical entities in pharmaceutics as new APIs. PMID- 28029139 TI - Modeling of the Bioactivation of an Organic Nitrate by a Thiol to Form a Thionitrate Intermediate. AB - Thionitrates (R-SNO2) have been proposed as key intermediates in the biotransformation of organic nitrates that have been used for the clinical treatment of angina pectoris for over 100 years. It has been proposed and widely accepted that a thiol would react with an organic nitrate to afford a thionitrate intermediate. However, there has been no example of an experimental demonstration of this elementary chemical process in organic systems. Herein, we report that aryl- and primary-alkyl-substituted thionitrates were successfully synthesized by the reaction of the corresponding lithium thiolates with organic nitrates by taking advantage of cavity-shaped substituents. The structure of a primary-alkyl substituted thionitrate was unambiguously established by X-ray crystallographic analysis. PMID- 28029140 TI - Prevention of Community-Acquired Pneumonia with Available Pneumococcal Vaccines. AB - Community-acquired pneumonia (CAP) places a considerable burden on society. A substantial number of pediatric and adult CAP cases are due to Streptococcus pneumoniae, but fortunately there are effective vaccines available that have a significant impact on CAP-related medical, social, and economic problems. The main aim of this paper is to evaluate the published evidence concerning the impact of pneumococcal vaccines on the prevention of CAP in children and adults. Available data indicate that pneumococcal conjugate vaccines (PCVs) are effective in children, reducing all-cause CAP cases and bacteremic and nonbacteremic CAP cases. Moreover, at least for PCV7 and PCV13, vaccination of children is effective in reducing the incidence of CAP among adults. Recently use of PCV13 in adults alone or in combination with the pneumococcal polysaccharide vaccine has been suggested and further studies can better define its effectiveness in this group of subjects. The only relevant problem for PCV13 is the risk of a second replacement phenomenon, which might significantly reduce its real efficacy in clinical practice. Protein-based pneumococcal vaccines might be a possible solution to this problem. PMID- 28029141 TI - Glycosaminoglycans and Their Mimetics. AB - n/a. PMID- 28029142 TI - An Indoor Positioning System Based on Wearables for Ambient-Assisted Living. AB - The urban population is growing at such a rate that by 2050 it is estimated that 84% of the world's population will live in cities, with flats being the most common living place. Moreover, WiFi technology is present in most developed country urban areas, with a quick growth in developing countries. New Ambient Assisted Living applications will be developed in the near future having user positioning as ground technology: elderly tele-care, energy consumption, security and the like are strongly based on indoor positioning information. We present an Indoor Positioning System for wearable devices based on WiFi fingerprinting. Smart-watch wearable devices are used to acquire the WiFi strength signals of the surrounding Wireless Access Points used to build an ensemble of Machine Learning classification algorithms. Once built, the ensemble algorithm is used to locate a user based on the WiFi strength signals provided by the wearable device. Experimental results for five different urban flats are reported, showing that the system is robust and reliable enough for locating a user at room level into his/her home. Another interesting characteristic of the presented system is that it does not require deployment of any infrastructure, and it is unobtrusive, the only device required for it to work is a smart-watch. PMID- 28029143 TI - Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice. AB - Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-kappaB (NF-kappaB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect. PMID- 28029144 TI - Enhancement of Fluorescence-Based Sandwich Immunoassay Using Multilayered Microplates Modified with Plasma-Polymerized Films. AB - A functional modification of the surface of a 96-well microplate coupled with a thin layer deposition technique is demonstrated for enhanced fluorescence-based sandwich immunoassays. The plasma polymerization technique enabling the deposition of organic thin films was employed for the modification of the well surface of a microplate. A silver layer and a plasma-polymerized film were consecutively deposited on the microplate as a metal mirror and the optical interference layer, respectively. When Cy3-labeled antibody was applied to the wells of the resulting multilayered microplate without any immobilization step, greatly enhanced fluorescence was observed compared with that obtained with the unmodified one. The same effect could be also exhibited for an immunoassay targeting antigen directly adsorbed on the multilayered microplate. Furthermore, a sandwich immunoassay for the detection of interleukin 2 (IL-2) was performed with the multilayered microplates, resulting in specific and 88-fold-enhanced fluorescence detection. PMID- 28029145 TI - Real-Time Multi-Target Localization from Unmanned Aerial Vehicles. AB - In order to improve the reconnaissance efficiency of unmanned aerial vehicle (UAV) electro-optical stabilized imaging systems, a real-time multi-target localization scheme based on an UAV electro-optical stabilized imaging system is proposed. First, a target location model is studied. Then, the geodetic coordinates of multi-targets are calculated using the homogeneous coordinate transformation. On the basis of this, two methods which can improve the accuracy of the multi-target localization are proposed: (1) the real-time zoom lens distortion correction method; (2) a recursive least squares (RLS) filtering method based on UAV dead reckoning. The multi-target localization error model is established using Monte Carlo theory. In an actual flight, the UAV flight altitude is 1140 m. The multi-target localization results are within the range of allowable error. After we use a lens distortion correction method in a single image, the circular error probability (CEP) of the multi-target localization is reduced by 7%, and 50 targets can be located at the same time. The RLS algorithm can adaptively estimate the location data based on multiple images. Compared with multi-target localization based on a single image, CEP of the multi-target localization using RLS is reduced by 25%. The proposed method can be implemented on a small circuit board to operate in real time. This research is expected to significantly benefit small UAVs which need multi-target geo-location functions. PMID- 28029146 TI - Protective Effects of Luteolin on Lipopolysaccharide-Induced Acute Renal Injury in Mice. AB - BACKGROUND Sepsis can cause serious acute kidney injury in bacterium-infected patients, especially in intensive care patients. Luteolin, a bioactive flavonoid, has renal protection and anti-inflammatory effects. This study aimed to investigate the effect and underlying mechanism of luteolin in attenuating lipopolysaccharide (LPS)-induced renal injury. MATERIAL AND METHODS ICR mice were treated with LPS (25 mg/kg) with or without luteolin pre-treatment (40 mg/kg for three days). The renal function, histological changes, degree of oxidative stress, and tubular apoptosis in these mice were examined. The effects of luteolin on LPS-induced expression of renal tumor necrosis factor-alpha (TNF alpha), NF-kappaB, MCP-1, ICAM-1, and cleaved caspase-3 were evaluated. RESULTS LPS resulted in rapid renal damage of mice, increased level of blood urea nitrogen (BUN), and serum creatinine (Scr), tubular necrosis, and increased oxidative stress, whereas luteolin pre-treatment could attenuate this renal damage and improve the renal functions significantly. Treatment with LPS increased TNF-alpha, NF-kappaB, IL-1beta, cleaved caspase-3, MCP-1, and ICAM-1 expression, while these disturbed expressions were reversed by luteolin pre treatment. CONCLUSIONS These results indicate that luteolin ameliorates LPS mediated nephrotoxicity via improving renal oxidant status, decreasing NF-kappaB activation and inflammatory and apoptosis factors, and then disturbing the expression of apoptosis-related proteins. PMID- 28029147 TI - SNP variants at the MAP3K1/SETD9 locus 5q11.2 associate with somatic PIK3CA variants in breast cancers. AB - Genome-wide association studies have revealed many breast cancer (BC) risk associated genetic variants that might functionally interact with other molecular determinants of BC. We analysed the association of 21 known risk-associated single-nucleotide variants (SNVs) with recurrent somatic variants in two cohorts of 77 and 754 oestrogen receptor alpha-positive BCs. Four SNVs located at 5q11.2 were found to be associated with the somatic PIK3CA variant status in the pilot cohort of 77 cases with odds ratio (OR) up to 6.5 indicating strong effects, and were selected for the validation phase. Two of these SNVs, rs252913 and rs331499, located in the MAP3K1/SETD9 gene boundary, were confirmed to be associated with somatic PIK3CA variants in the large cohort with OR 2.97 (1.17-7.75) and 1.76 (1.11-2.77), respectively, notably higher than their BC risk-associated values, both around 1.1. In the presence of the SNV or of somatic PIK3CA variants, cancers express significantly elevated levels of MAP3K1 and SETD9, with synergy of SNV and PIK3CA variants in MAP3K1 gene overexpression, consistent with a preferential PIK3CA-dependent regulation of the variant alleles. PMID- 28029148 TI - Investigating mitochondrial DNA relationships in Neolithic Western Europe through serial coalescent simulations. AB - Recent ancient DNA studies on European Neolithic human populations have provided persuasive evidence of a major migration of farmers originating from the Aegean, accompanied by sporadic hunter-gatherer admixture into early Neolithic populations, but increasing toward the Late Neolithic. In this context, ancient mitochondrial DNA data collected from the Neolithic necropolis of Gurgy (Paris Basin, France), the largest mitochondrial DNA sample obtained from a single archeological site for the Early/Middle Neolithic period, indicate little differentiation from farmers associated to both the Danubian and Mediterranean Neolithic migration routes, as well as from Western European hunter-gatherers. To test whether this pattern of differentiation could arise in a single unstructured population by genetic drift alone, we used serial coalescent simulations. We explore female effective population size parameter combinations at the time of the colonization of Europe 45000 years ago and the most recent of the Neolithic samples analyzed in this study 5900 years ago, and identify conditions under which population panmixia between hunter-gatherers/Early-Middle Neolithic farmers and Gurgy cannot be rejected. In relation to other studies on the current debate of the origins of Europeans, these results suggest increasing hunter-gatherer admixture into farmers' group migrating farther west in Europe. PMID- 28029149 TI - Clinical utility gene card for: Sitosterolaemia. PMID- 28029150 TI - Incorporating the single-step strategy into a random regression model to enhance genomic prediction of longitudinal traits. AB - In prediction of genomic values, the single-step method has been demonstrated to outperform multi-step methods. In statistical analyses of longitudinal traits, the random regression test-day model (RR-TDM) has clear advantages over other models. Our goal in this study was to evaluate the performance of a model that integrates both single-step and RR-TDM prediction methods, called the single-step random regression test-day model (SS RR-TDM), in comparison with the pedigree based RR-TDM and genomic best linear unbiased prediction (GBLUP) model. We performed extensive simulations to exploit the potential advantages of SS RR-TDM over the other two models under various scenarios with different levels of heritability, number of quantitative trait loci, as well as selection scheme. SS RR-TDM was found to achieve the highest accuracy and unbiasedness under all scenarios, exhibiting robust prediction ability in longitudinal trait analyses. Moreover, SS RR-TDM showed better persistency of accuracy over generations than the GBLUP model. In addition, we also found that the SS RR-TDM had advantages over RR-TDM and GBLUP in terms of its being a real data set of humans contributed by the Genetic Analysis Workshop 18. The findings of our study demonstrated the feasibility and advantages of SS RR-TDM, thus enhancing the strategies for genomic prediction of longitudinal traits in the future. PMID- 28029151 TI - Temporal stability in patterns of genetic diversity and structure of a marine foundation species (Zostera marina). AB - Genetic diversity and population structure reflect complex interactions among a diverse set of processes that may vary temporally, limiting their potential to predict ecological and evolutionary outcomes. Yet, the stability of these patterns is rarely tested. We resampled eelgrass (Zostera marina) meadows from published studies to determine variability in genetic diversity and structure within and between meadows over 5-12 years. The meadows sampled (San Francisco, Tomales and Bodega Bays in California and the Virginia coastal bays) represent a range of life histories (annual vs perennial), age (well-established vs restored) and environments (rural vs urbanized). In all of these systems, neither diversity nor differentiation (FST) changed over time. Differences among tidal heights within Bodega Bay were also remarkably consistent, with the high intertidal being more diverse than the subtidal, and tidal height differentiation being modest but significant at both time points. Historical studies used only a few microsatellite loci; therefore, our temporal comparisons were based on 4-5 loci. However, analysis of the current data using a set of 12 loci show that 4-5 loci are sufficient to describe diversity and differentiation patterns in this system. This temporal consistency was not because of the resampling of large clones, underscoring the feasibility and relevance of understanding drivers of the differences. Because seagrasses are declining at rapid rates, restoration and conservation are increasingly a coastal management priority. Our results argue that surveys of eelgrass genetic structure and diversity at decadal scales can provide accurate depictions of populations, increasing the utility of published genetic data for restoration and designing networks of reserves. PMID- 28029152 TI - Hypertension in 2016: Blood pressure goals, variability and SGLT2 blockade in CKD. PMID- 28029155 TI - Glomerular disease: Rituximab therapy for IgA nephropathy. PMID- 28029153 TI - Cellular senescence in renal ageing and disease. AB - The senescence programme is implicated in diverse biological processes, including embryogenesis, tissue regeneration and repair, tumorigenesis, and ageing. Although in vivo studies of senescence are in their infancy, evidence suggesting that senescent cells are a heterogeneous cell type is accumulating: senescence can be induced by different stressors, and senescent cells have varying degrees of genomic and epigenomic instability and different cell origins, contributing to their diversity. Two main classes of senescent cells have been identified: acute and chronic senescent cells. Acute senescent cells are generated during coordinated, beneficial biological processes characterized by a defined senescence trigger, transient senescent-cell signalling functions, and eventual senescent-cell clearance. In contrast, chronic senescent cells arise more slowly from cumulative, diverse stresses and are inefficiently eliminated, leading to their accumulation and deleterious effects through a secretory phenotype. Senescent cells have been identified in many tissues and organs, including the kidney. Here, we discuss the emerging roles of senescent cells in renal development, homeostasis, and pathology. We also address how senotherapy, or targeting of senescent cells, might be used to improve renal function with normal ageing, disease, or therapy-induced damage. PMID- 28029154 TI - Changes in the worldwide epidemiology of peritoneal dialysis. AB - As the global burden of chronic kidney disease continues to increase, so does the need for a cost-effective renal replacement therapy. In many countries, patient outcomes with peritoneal dialysis are comparable to or better than those with haemodialysis, and peritoneal dialysis is also more cost-effective. These benefits have not, however, always led to increased utilization of peritoneal dialysis. Use of this therapy is increasing in some countries, including China, the USA and Thailand, but has proportionally decreased in parts of Europe and in Japan. The variable trends in peritoneal dialysis use reflect the multiple challenges in prescribing this therapy to patients. Key strategies for facilitating peritoneal dialysis utilization include implementation of policies and incentives that favour this modality, enabling the appropriate production and supply of peritoneal dialysis fluid at a low cost, and appropriate training for nephrologists to enable increased utilization of the therapy and to ensure that rates of technique failure continue to decline. Further growth in peritoneal dialysis use is required to enable this modality to become an integral part of renal replacement therapy programmes worldwide. PMID- 28029156 TI - Copy number alterations unmasked as enhancer hijackers. AB - Our understanding of how DNA copy number changes contribute to disease, including cancer, has to a large degree been focused on the changes in gene dosage that they generate and has neglected the effects of the DNA rearrangements that lead to their formation. A new study reports an innovative analytical framework for copy number alterations that are oncogenic primarily owing to the genomic rearrangements that underlie them. PMID- 28029157 TI - How hormones regulate floral architecture in barley. AB - A defining characteristic of grasses, including major cereal crops, is the way in which flowers are arranged on an inflorescence. A new study finds that regulation of hormone levels during development is crucial for determining the arrangement of flowers on a barley inflorescence, opening new doors for increasing grain yield. PMID- 28029158 TI - Finally accepting plant domestication. PMID- 28029159 TI - Is a super-enhancer greater than the sum of its parts? PMID- 28029160 TI - A multitrait GWAS sheds light on insulin resistance. AB - A genome-wide study of fasting insulin, HDL cholesterol and triglycerides, designed to depict insulin resistance, identified 53 independent loci associated with a limited capacity to store fat in a healthy way. The increased power of this multitrait approach provides insights into an otherwise difficult-to-grasp phenotype. PMID- 28029162 TI - Genetic engineering: A genome-editing off switch. PMID- 28029163 TI - RNA: The code in the cap. PMID- 28029164 TI - Development: Modifying sex in flies. PMID- 28029161 TI - Down syndrome and the complexity of genome dosage imbalance. AB - Down syndrome (also known as trisomy 21) is the model human phenotype for all genomic gain dosage imbalances, including microduplications. The functional genomic exploration of the post-sequencing years of chromosome 21, and the generation of numerous cellular and mouse models, have provided an unprecedented opportunity to decipher the molecular consequences of genome dosage imbalance. Studies of Down syndrome could provide knowledge far beyond the well-known characteristics of intellectual disability and dysmorphic features, as several other important features, including congenital heart defects, early ageing, Alzheimer disease and childhood leukaemia, are also part of the Down syndrome phenotypic spectrum. The elucidation of the molecular mechanisms that cause or modify the risk for different Down syndrome phenotypes could lead to the introduction of previously unimaginable therapeutic options. PMID- 28029165 TI - Efficiency of endothelial dysfunctioncorrection in children residents of radioactively contaminated areas using the method of intermittent normobaric hypoxi therapy. AB - : Objective is to evaluate the effectiveness of intermittent normobaric hypoxi therapy as the means that can posi tively influence on the different links in the pathogenesis of endothelial dysfunction in children residents of radioactively contaminated areas. MATERIALS AND METHODS: Disorders of personal and emotional sphere, symptoms of asthenic vegetative and neurot ic character, the signs of the cardiovascular and respiratory systems, abdominal and dyspeptic syndromes are attrib uted to the clinical signs of endothelial dysfunction. There were determined the biochemical parameters of the con tent of stable metabolites of NO, L arginine, lipid peroxidation, antioxidant enzymes in the blood serum; the indices of cellular and humoral immunity; the instrumental indices of vascular endothelium dependent reaction to occlu sion test, ventilating ability of the lungs, the bioelectric activity of the myocardium. Intermittent normobaric hypoxi therapy (INHT) was performed using the individual device of mountain air of the "Borei" type produced by State Research Medical Engineering Center "NORT" NAS of Ukraine (Kyiv). RESULTS AND CONCLUSIONS: The clinical examination showed that the administration of additional intermittent nor mobaric hypoxi therapy to the basic treatment of 44 children with endothelial dysfunction who live in the radioac tively contaminated areas, promoted to reduce the frequency of complaints and intensity of clinical manifestations in the mentioned symptom complex. An increase of serum L arginine in the absence of significant changes in the content of NO stable metabolites was revealed in the most examined children residents of radioactively contami nated areas by studying NO system after using the course of intermittent normobaric hypoxi therapy. Positive changes in vascular endothelium dependent reaction to occlusion test, indicating the reduction length of the recovery period for thermographic circulation index after occlusive test, were determined. The decrease in the inten sity of lipid peroxidation processes - a reduction of serum LPO end products content that react with thiobarbituric acid - was observed. The bronchospasm elimination was revealed in a large number of children with the study of the lung ventilation capacity. There were trends to reduce the imbalance of different chain of the heart rhythm man agement. The immunomodulatory effect was detected as: the increase in the functional activity of neutrophils, the normalization of humoral immunity link indices. Intermittent normobaric hypoxi therapy is an effective tool that can positively affect the condition of nitric oxide system and endothelium dependent functions of the organs and systems in children residents of radioactively contaminated areas. PMID- 28029166 TI - Influence of cooling face masks on nasal air conditioning and nasal geometry. AB - INTRODUCTION: Nasal geometries and temperature of the nasal mucosa are the primary factors affecting nasal air conditioning. Data on intranasal air conditioning after provoking the trigeminal nerve with a cold stimulus simulating the effects of an arctic condition is still missing. The objective was to investigate the influence of skin cooling face masks on nasal air conditioning, mucosal temperature and nasal geometry. METHODS: Standardized in vivo measurements of intranasal air temperature, humidity and mucosal temperature were performed in 55 healthy subjects at defined detection sites before and after wearing a cooling face mask. Measurements of skin temperature, rhinomanometry and acoustic rhinometry were accomplished. RESULTS: After wearing the face mask the facial skin temperature was significantly reduced. Intranasal air temperature did not change. Absolute humidity and mucosal temperature increased significantly. The acoustic rhinometric results showed a significant increase of the volumes and the cross-sectional areas. There was no change in nasal airflow. CONCLUSIONS: Nasal mucosal temperature, humidity of inhaled air, and volume of the anterior nose increased after application of a cold face mask. The response is mediated by the trigeminal nerve. Increased mucosal temperatures as well as changes in nasal geometries seem to guarantee sufficient steady intranasal nasal air conditioning. PMID- 28029167 TI - Drug-Mediated Regulation of Glycosaminoglycan Biosynthesis. AB - Glycosaminoglycans (GAGs) are a heterogeneous family of unbranched polysaccharides that exist in either a free state or attached to proteins and are found on the cell surface as well as in the extracellular matrix. GAGs play essential roles in cellular and tissue homeostasis, and their metabolism is altered in response to several pathological conditions. Despite strong experimental evidence supporting the function of GAGs in various diseases, little is known about the regulation of GAG biosynthesis via pharmacological intervention. In recent studies, the effects of several experimental drugs on GAG biosynthesis in animal models of disease were examined and key enzymes involved in GAG biosynthesis were found to be druggable. In addition to experimental small molecule drugs that alter GAG biosynthesis, a number of clinically approved drugs modulate GAG metabolism, contributing to the therapeutic benefits associated with the use of these drugs. In this review article, we propose a classification scheme for drugs affecting GAG biosynthesis. Our goal is to present a rational approach to investigate the pharmacological regulation of these important biological molecules. PMID- 28029169 TI - The Past Is Present: Representations of Parents, Friends, and Romantic Partners Predict Subsequent Romantic Representations. AB - This study examined how representations of parent-child relationships, friendships, and past romantic relationships are related to subsequent romantic representations. Two-hundred 10th graders (100 female; Mage = 15.87 years) from diverse neighborhoods in a Western U.S. city were administered questionnaires and were interviewed to assess avoidant and anxious representations of their relationships with parents, friends, and romantic partners. Participants then completed similar questionnaires and interviews about their romantic representations six more times over the next 7.5 years. Growth curve analyses revealed that representations of relationships with parents, friends, and romantic partners each uniquely predicted subsequent romantic representations across development. Consistent with attachment and behavioral systems theory, representations of romantic relationships are revised by representations and experiences in other relationships. PMID- 28029170 TI - Alcohol Relapse and Change Needs a Broader View than Counting Drinks. PMID- 28029168 TI - Trends in Regenerative Medicine: Repigmentation in Vitiligo Through Melanocyte Stem Cell Mobilization. AB - Vitiligo is the most frequent human pigmentary disorder, characterized by progressive autoimmune destruction of mature epidermal melanocytes. Of the current treatments offering partial and temporary relief, ultraviolet (UV) light is the most effective, coordinating an intricate network of keratinocyte and melanocyte factors that control numerous cellular and molecular signaling pathways. This UV-activated process is a classic example of regenerative medicine, inducing functional melanocyte stem cell populations in the hair follicle to divide, migrate, and differentiate into mature melanocytes that regenerate the epidermis through a complex process involving melanocytes and other cell lineages in the skin. Using an in-depth correlative analysis of multiple experimental and clinical data sets, we generated a modern molecular research platform that can be used as a working model for further research of vitiligo repigmentation. Our analysis emphasizes the active participation of defined molecular pathways that regulate the balance between stemness and differentiation states of melanocytes and keratinocytes: p53 and its downstream effectors controlling melanogenesis; Wnt/beta-catenin with proliferative, migratory, and differentiation roles in different pigmentation systems; integrins, cadherins, tetraspanins, and metalloproteinases, with promigratory effects on melanocytes; TGF-beta and its effector PAX3, which control differentiation. Our long-term goal is to design pharmacological compounds that can specifically activate melanocyte precursors in the hair follicle in order to obtain faster, better, and durable repigmentation. PMID- 28029171 TI - Cardiac Orienting Response as an Early Indicator of Impairment in Fetal Alcohol Spectrum Disorders. PMID- 28029172 TI - Diagnosing eosinophilic asthma using a multivariate prediction model based on blood granulocyte responsiveness. AB - BACKGROUND: The identification of inflammatory asthma phenotypes, using sputum analysis, has proven its value in diagnosis and disease monitoring. However due to technical limitations of sputum analysis, there is a strong need for fast and noninvasive diagnostics. This study included the activation state of eosinophils and neutrophils in peripheral blood to phenotype and monitor asthma. OBJECTIVES: To (i) construct a multivariable model using the activation state of blood granulocytes, (ii) compare its diagnostic value with sputum eosinophilia as gold standard and (iii) validate the model in an independent patient cohort. METHODS: Clinical parameters, activation of blood granulocytes and sputum characteristics were assessed in 115 adult patients with asthma (training cohort/Utrecht) and 34 patients (validation cohort/Oxford). RESULTS: The combination of blood eosinophil count, fractional exhaled nitric oxide, Asthma Control Questionnaire, medication use, nasal polyposis, aspirin sensitivity and neutrophil/eosinophil responsiveness upon stimulation with formyl-methionyl-leucyl phenylalanine was found to identify sputum eosinophilia with 90.5% sensitivity and 91.5% specificity in the training cohort and with 77% sensitivity and 71% specificity in the validation cohort (relatively high percentage on oral corticosteroids [OCS]). CONCLUSIONS: The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS. PMID- 28029174 TI - Linking vitamin D, the microbiome and allergy. PMID- 28029173 TI - A Randomized Trial Evaluating Whether Topiramate Aids Smoking Cessation and Prevents Alcohol Relapse in Recovering Alcohol-Dependent Men. AB - BACKGROUND: Alcohol and nicotine dependence frequently co-occur, and quitting smoking might enhance long-term alcohol abstinence. Topiramate appears to help non-alcohol-dependent individuals quit smoking, and our pilot work suggested efficacy only in men. It also prevents relapse to alcohol in recently detoxified alcoholics. We evaluated topiramate in abstinent alcohol-dependent men to assess whether this medication (i) promotes smoking cessation and (ii) prevents alcohol and other drug relapse in the context of smoking cessation treatment. METHODS: One hundred and twenty-nine alcohol-abstinent (mean ~6 months) alcohol-dependent male smokers (80% with other substance use disorders) participated in this 12 week randomized, double blind, parallel group comparison of topiramate (up to 200 mg/d) and placebo with a 24-week nontreatment follow-up period. The study was carried out sequentially at 2 academic centers in the Midwest and Southern California between March 23, 2009 and November 20, 2014. All participants received manual-guided smoking cessation counseling combined with medication focused compliance enhancement therapy. Randomization was block designed by the research pharmacist in a 1:1 ratio. Participants, investigators, and research personnel were masked to treatment assignment. The primary smoking end point was biochemically confirmed 4-week continuous abstinence from smoking during weeks 9 to 12, while the secondary end point was relapse to any drinking or drug use during the entire 36-week evaluation period. Logistic regression was used to determine the effects of topiramate on quitting smoking and alcohol relapse, controlling for relevant covariates. The trial is registered at ClinicalTrials.gov (number NCT00802412) and is now closed. RESULTS: Only a small proportion (7.9%) of topiramate-treated participants were able to quit smoking, and this cessation rate was similar to placebo (10.6%; odds ratio = 1.60; 95% confidence interval 0.4, 6.5; p = 0.51). Roughly 30% of the sample had a documented relapse to drinking or drug use during the study, and these rates were similar in the topiramate (20/63; 31.8%) and placebo groups (18/66; 27.3%; p = 0.58). Results of a longitudinal logistic regression model examining time to any alcohol relapse revealed no medication effect. CONCLUSIONS: Topiramate at a daily dosage of up to 200 mg per day, combined with smoking cessation and medication adherence counseling, had no effects on smoking cessation or the prevention of alcohol or drug relapse in male smokers who were in early or sustained full remission from alcohol and motivated to make a quit attempt. Alternative approaches for treating this high-risk, dually dependent population are needed. PMID- 28029175 TI - Contraceptive non-use and emergency contraceptive use at first sexual intercourse among nearly 12 000 Scandinavian women. AB - INTRODUCTION: The aim of this study was to describe recent patterns of contraceptive use at first sexual intercourse and to examine whether selected factors are associated with non-use and emergency contraceptive pill use at first sexual intercourse, among 18- to 26-year-old women from Denmark, Norway and Sweden. MATERIAL AND METHODS: This was a population-based, questionnaire study of randomly chosen 18- to 26-year-old Scandinavian women. The prevalence of contraception methods used at first sexual intercourse was calculated. Factors associated with contraceptive non-use and emergency contraceptive pill use at first sexual intercourse were determined using log binomial models. RESULTS: The prevalence of contraceptive non-use and emergency contraceptive pill use was lowest in Denmark (9.6 and 2.1%, respectively) compared with Norway (14.1 and 4.4%) and Sweden (16.6 and 4.5%). The risk of contraceptive non-use increased in women who had first sexual intercourse at or before 14 years of age (13-14 years: prevalence ratio 1.40; 95% confidence interval 1.24-1.58). The risk of both non use and emergency contraceptive pill use increased when the partner at first sexual intercourse was 20 years or older, and with increasing age difference between the partner and the woman at her first sexual intercourse. Smoking initiation prior to first sexual intercourse increased risk of contraceptive non use (prevalence ratio 1.70; 95% confidence interval 1.50-1.92), and alcohol initiation prior to first sexual intercourse increased risk of emergency contraceptive pill use at first sexual intercourse (prevalence ratio 1.95; 95% confidence interval 1.49-2.54). CONCLUSIONS: Contraceptive non-use at first sexual intercourse was strongly associated with early age at first sexual intercourse. Emergency contraceptive pill and contraceptive non-use at first sexual intercourse were both strongly associated with increasing partner age and an increasing difference in age between the woman and her partner. Hence, young women should be educated to negotiate contraceptive use with their partners. PMID- 28029176 TI - Robot-assisted surgery in gynecological oncology: current status and controversies on patient benefits, cost and surgeon conditions - a systematic review. AB - INTRODUCTION: Robot-assisted surgery has become more widespread in gynecological oncology. The purpose of this systematic review is to present current knowledge on robot-assisted surgery, and to clarify and discuss controversies that have arisen alongside the development and deployment. MATERIAL AND METHODS: A database search in PubMed and EMBASE was performed up until 4 March 2016. The search strategy was developed in collaboration with an information specialist, and by application of the PRISMA guidelines. Human participants and English language were the only restrictive filters applied. Selection was performed by screening of titles and abstracts, and by full text scrutiny. From 2001 to 2016, a total of 76 references were included. RESULTS: Robot-assisted surgery in gynecological oncology has increased, and current knowledge supports that the oncological safety is similar, compared with previous surgical methods. Controversies arise because current knowledge does not clearly document the benefit of robot-assisted surgery, on perioperative outcome compared with the increased costs of the acquisition and application. CONCLUSIONS: The rapid development in robot-assisted surgery calls for long-term detailed prospective cohorts or randomized controlled trials. The costs associated with acquisition, application, and maintenance have an unfavorable impact on cost-benefit evaluations, especially when compared with laparoscopy. Future developments in robot-assisted surgery will hopefully lead to competition in the market, which will decrease costs. PMID- 28029177 TI - Discovery of Bisindole as a Novel Scaffold for Protein Tyrosine Phosphatase 1B Inhibitors. AB - Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3' bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity. The best active compound 9f inhibited PTP1B activity with an IC50 of 2.79 uM. Meanwhile, it had low cytotoxicity and enhanced glucose uptake in vitro. Further studies demonstrated that some of these active compounds had a specific selectivity over other PTPs. Computational analysis further showed the binding mode of compound 9f with the active pocket of PTP1B. Our studies provide a novel scaffold for further development of more promising PTP1B inhibitors and potential drugs for type II diabetes and obesity. PMID- 28029178 TI - Exercise during pregnancy and risk of preterm birth in overweight and obese women: a systematic review and meta-analysis of randomized controlled trials. AB - INTRODUCTION: The incidence of overweight and obesity in pregnancy has risen significantly in the last decades. Overweight and obesity have been shown to increase the risk for some adverse obstetric outcomes. Lifestyle interventions, such as diet, physical activity and behavior changes, may reduce these risks by promoting weight loss and/or preventing excessive weight gain. The possible impact of exercise on the risk of preterm birth (PTB) in overweight or obese women is controversial. Therefore, the aim of our study was to evaluate the effect of exercise on the risk of PTB in overweight or obese pregnant women. MATERIAL AND METHODS: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library were searched from their inception to November 2016. This meta-analysis included only randomized controlled trials (RCTs) of pregnant women assigned or not assigned before 25 weeks to an aerobic exercise regimen. Types of participants included overweight or obese (mean body mass index >=25 kg/m2 ) women with singleton pregnancies without any contraindication to physical activity. The summary measures were reported as relative risk (RR) or as mean difference (MD) with 95% confidence intervals (CI). The primary outcome was the incidence of PTB <37 weeks. RESULTS: Nine trials including 1502 overweight or obese singleton gestations were analyzed. Overweight and obese women who were randomized in early pregnancy to aerobic exercise for about 30-60 min three to seven times per week had a lower percentage of PTB <37 weeks (RR 0.62, 95% CI 0.41-0.95) compared with controls. The incidence of gestational age at delivery (MD 0.09 week, 95% CI -0.18 to 0.24) and cesarean delivery (RR 0.93, 95% CI 0.77-1.10) were similar in both groups. Women in the exercise group had a lower incidence of gestational diabetes mellitus (RR 0.61, 95% CI 0.41-0.90) compared with controls. No differences in birthweight (MD 16.91 g, 95% CI -89.33 to 123.19), low birthweight (RR 0.58, 95% CI 0.25-1.34), macrosomia (RR 0.92, 95% CI 0.72-1.18) and stillbirth (RR 2.13, 95% CI 0.22-20.4) between the exercise group and controls were found. CONCLUSIONS: Overweight and obese women with singleton pregnancy can be counseled that, compared with being more sedentary, aerobic exercise for about 30-60 min three to seven times per week during pregnancy is associated with a reduction in the incidence of PTB. Aerobic exercise in overweight and obese pregnant women is also associated with a significant prevention of gestational diabetes mellitus, and should therefore be encouraged. PMID- 28029179 TI - Prenatal diagnosis of congenital heart diseases by fetal echocardiography in second trimester: a Chinese multicenter study. AB - INTRODUCTION: The objective of our study was to evaluate the performance of detailed fetal echocardiography by skilled obstetric physician sonologists in the diagnosis of congenital heart disease (CHD) in a Chinese population. MATERIAL AND METHODS: This investigation included a multicenter prospective cohort of 10 259 pregnant women attending 10 regional tertiary hospitals in China. The inclusion criteria were singleton pregnancy and gestational age from 18 to <=28 weeks. Women with multiple pregnancies were excluded. A detailed fetal echocardiography was performed by trained physicians with at least 3 years of experience. The primary outcome measures included sensitivity, specificity, and positive and negative likelihood ratios of detailed fetal echocardiography in prenatal detection of CHD. RESULTS: The sensitivity and specificity of fetal echocardiography in detecting any CHD were 33.9 and 99.8%, respectively, in the low-risk population, and 68.8 and 99.4%, respectively, in the high-risk population. For detecting major CHDs, fetal echocardiography had a high sensitivity and specificity, and satisfactory positive and negative likelihood ratios in both the low-risk population (88.2, 100%, 6947.7, and 0.118, respectively) and high-risk population (100, 99.9%, 833.3, and <0.0001, respectively). The sensitivity and likelihood ratios were substantially lower for detecting minor CHDs in both populations. CONCLUSIONS: Detailed fetal echocardiography performed by skilled physicians had high detection rate for major CHD in both low-risk and high-risk populations. However, its value for detecting minor CHD was limited. The incorporation of fetal echocardiography with multiple cardiac views into routine ultrasound screening may improve the detection rate of fetal major CHD and facilitate appropriate parental counseling. PMID- 28029180 TI - Long-term childhood outcomes of breech presentation by intended mode of delivery: a population record linkage study. AB - INTRODUCTION: There is a lack of information on long-term outcomes by mode of delivery for term breech presentation. We aimed to compare childhood mortality, cerebral palsy, hospitalizations, developmental, and educational outcomes associated with intended vaginal breech birth (VBB) with planned cesarean section. MATERIAL AND METHODS: Population birth and hospital records from New South Wales, Australia, were used to identify women with non-anomalous pregnancies eligible for VBB during 2001-2012. Intended mode of delivery was inferred from labor onset and management. Death, hospital, and education records were used for follow up until 2014. Cox proportional hazards regression and modified Poisson regression were used for analysis. RESULTS: Of 15 281 women considered eligible for VBB, 7.7% intended VBB, 74.2% planned cesarean section, and intention was uncertain for 18.1%. Intended VBB did not differ from planned cesarean section on infant mortality (Fisher's exact p = 0.55), childhood mortality (Fisher's exact p = 0.50), cerebral palsy (Fisher's exact p = 1.00), hospitalization in the first year of life [adjusted hazard ratio (HR) 1.04; 95% CI 0.90-1.20], hospitalization between the first and sixth birthdays (HR 0.92; 95% CI 0.82-1.04), being developmentally vulnerable [adjusted relative risk (RR) 1.22; 95% CI 0.48-1.69] or having special needs status (RR 0.95; 95% CI 0.48 1.88) when aged 4-6, or scoring more than 1 standard deviation below the mean on tests of reading (RR 1.10; 95% CI 0.87-1.40) and numeracy (RR 1.04; 95% CI 0.81 1.34) when aged 7-9. CONCLUSIONS: Planned VBB confers no additional risks for child health, development or educational achievement compared with planned cesarean section. PMID- 28029181 TI - New horizons in the understanding of the causes and management of diabetic foot disease: report from the 2017 Diabetes UK Annual Professional Conference Symposium. AB - Diabetes-related foot disease remains a common problem. For wounds, classic teaching recommends the treatment of any infection, offloading the wound and ensuring a good blood supply, as well as ensuring that the other modifiable risk factors are addressed and optimized. There remain, however, several questions about these and other aspects of the care of diabetes-related foot disease. Some of these questions are addressed in the present report; in particular, the impact of newer technologies in the identification of any organisms present in a wound, as well as the use of novel approaches to treat infections. The use of new remote sensing technology to identify people at risk of developing foot ulceration is also considered, in an attempt to allow early intervention and prevention of foot ulcers. The psychological impact of foot disease is often overlooked, but with an increasing number of publications on the subject, the cause-and-effect role that psychology plays in foot disease, such as ulcers and Charcot neuroarthropathy, is considered. Finally, because of heterogeneity in diabetic foot studies, comparing results is difficult. A recently published document focusing on ensuring a standardized way of reporting foot disease trials is discussed. PMID- 28029182 TI - Nedd4 Deficiency in Vascular Smooth Muscle Promotes Vascular Calcification by Stabilizing pSmad1. AB - The nonosseous calcification process such as atherosclerosis is one of the major complications in several types of metabolic diseases. In a previous study, we uncovered that aberrant activity of transforming growth factor beta (TGF-beta) signaling pathway could contribute to the vascular smooth muscle cells' (VSMCs) calcification process. Also, we identified NEDD4 E3 ligase as a key suppressor of bone morphogenetic protein (BMP)/Smad pathway via a polyubiquitination-dependent selective degradation of C-terminal phosphorylated Smad1 (pSmad1) activated by TGF-beta. Here, we further validated and confirmed the role of Nedd4 in in vivo vascular calcification progression. First, Nedd4 deletion in SM22alpha-positive mouse tissues (Nedd4fl/fl ;SM22alpha-Cre) showed deformed aortic structures with disarranged elastin fibers at 24 weeks after birth. Second, vitamin D-induced aorta vascular calcification rate in Nedd4fl/fl ;SM22alpha-Cre mice was significantly higher than their wild-type littermates. Nedd4fl/fl ;SM22alpha-Cre mice showed a development of vascular calcification even at very low-level injection of vitamin D, but this was not exhibited in wild-type littermates. Third, we confirmed that TGF-beta1-induced pSmad1 levels were elevated in Nedd4 deficient primary VSMCs isolated from Nedd4fl/fl ;SM22alpha-Cre mice. Fourth, we further found that Nedd4fl/fl ;SM22alpha-Cre mVSMCs gained mesenchymal cell properties toward osteoblast-like differentiation by a stable isotope labeling in cell culture (SILAC)-based proteomics analysis. Finally, epigenetic analysis revealed that methylation levels of human NEDD4 gene promoter were significantly increased in atherosclerosis patients. Collectively, abnormal expression or dysfunction of Nedd4 E3 ligase could be involved in vascular calcification of VSMCs by activating bone-forming signals during atherosclerosis progression. (c) 2016 American Society for Bone and Mineral Research. PMID- 28029183 TI - Temporal monitoring of perfluorooctane sulfonate accumulation in aquatic biota downstream of historical aqueous film forming foam use areas. AB - Perfluoroalkyl substances (PFAS) have recently received increased research attention, particularly concerning aquatic organisms and in regions of exposure to aqueous film forming foams (AFFFs). Air Force bases historically applied AFFFs in the interest of fire training exercises and have since expressed concern for PFAS contamination in biota from water bodies surrounding former fire training areas. Six PFAS were monitored, including perfluorooctane sulfonate (PFOS), in aquatic species from 8 bayou locations at Barksdale Air Force Base in Bossier City, Louisiana (USA) over the course of 1 yr. The focus was to evaluate temporal and spatial variability in PFAS concentrations from historic use of AFFF. The PFOS concentrations in fish peaked in early summer, and also increased significantly downstream of former fire training areas. Benthic organisms had lower PFOS concentrations than pelagic species, contrary to previous literature observations. Bioconcentration factors varied with time but were reduced compared with previously reported literature values. The highest concentration of PFOS in whole fish was 9349 ng/g dry weight, with 15% of samples exceeding what is believed to be the maximum whole fish concentration reported to date of 1500 ng/g wet weight. Further studies are ongoing, to measure PFAS in larger fish and tissue-specific partitioning data to compare with the current whole fish values. The high concentrations presently observed could have effects on higher trophic level organisms in this system or pose a potential risk to humans consuming contaminated fish. Environ Toxicol Chem 2017;36:2022-2029. (c) 2016 SETAC. PMID- 28029185 TI - Case-control study demonstrates that surfactant without intubation delayed mechanical ventilation in preterm infants. AB - AIM: This Norwegian study explored whether administering surfactant without intubation (SWI) delayed the need for early mechanical ventilation and reduced respiratory and nonrespiratory complications in infants born before 32 weeks of gestational age. METHODS: We compared 262 infants admitted to a level-three neonatal intensive care unit: 134 born before the introduction of SWI on 1 December 2011 were in the control group and 128 infants born after this date were in the study group. RESULTS: The proportion of infants treated with surfactant did not differ between the groups, but mechanical ventilation before 72 hours of life was lower in the study group than the control group, with an odds ratio (OR) of 0.58 and a 95% confidence interval (CI) of 0.35-0.96. Fewer study group infants needed supplemental oxygen at 28 days of life. One study infant and nine control infants had intraventricular haemorrhage grades 3-4 and, or, cystic periventricular leukomalacia (OR 0.10, 95% CI 0.01-0.83). These results were strengthened in analyses restricted to surfactant-treated infants and the proportion needing supplemental oxygen at 36 weeks was reduced. CONCLUSION: Surfactant without intubation reduced the need for early mechanical ventilation and major brain injuries in infants born at <32 weeks of gestation. PMID- 28029184 TI - Effects of stressful life events on cerebral white matter hyperintensity progression. AB - OBJECTIVE: Exposure to stressful events is associated with both occurrence of depression and also vascular disease. The objective of this study was to determine whether higher levels of stress exposure was related to measures of pathological brain aging, specifically white matter hyperintensity volumes, in older adults with and without depression. METHODS: The sample included 130 depressed and 110 never-depressed older adults aged 60 years or older enrolled in a longitudinal study at an academic medical center. Participants completed clinical assessments, assessment of stressful event exposure and perceived stress, and magnetic resonance imaging at baseline and after 2 years. Analyses examined both cross-sectional and longitudinal relationships between stress measures and white matter hyperintensity volumes. RESULTS: There were no statistically significant relationships observed between cross-sectional baseline stress measures and either baseline hyperintensity volume or 2-year change in hyperintensity volume. However, after controlling for demographic variables and baseline measures, change in stressor exposure was associated with change in hyperintensity volumes. In this analysis, increased stressor exposure was associated with greater increases in white matter hyperintensity volume, while reductions in stressor exposure were associated with less increase in hyperintensity volume. This relationship did not significantly differ based on the presence of either depression or medical comorbidities. CONCLUSIONS: This work adds to a growing literature associating exposure to stressful events in later life with more rapid pathological brain aging. Work is needed to understand the physiological mechanisms by which stress exposure has this effect and examine whether stress reduction techniques may modify these observed outcomes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28029186 TI - Adipokine Chemerin Bridges Metabolic Dyslipidemia and Alveolar Bone Loss in Mice. AB - Chemerin is an adipokine that regulates adipogenesis and metabolic functions of mature adipocytes mainly through the activation of chemokine-like receptor 1 (CMKLR1). Elevated levels of chemerin have been found in individuals with obesity, type 2 diabetes, and osteoporosis. This adipokine was identified as an inflammatory and metabolic syndrome marker. Considering that the association between metabolic syndrome and bone health remains unclear, the present study aimed to clarify the role of chemerin in the pathophysiology of bone loss induced by dyslipidemia, particularly modulating osteoclastogenesis. In vitro analyses showed a downregulation of CMKLR1 at the early stage of differentiation and a gradual increase at late stages. Strikingly, chemerin did not modify osteoclast differentiation markers or osteoclast formation; however, it increased the actin ring formation and bone resorption activity in mature osteoclasts. The increased bone resorption activity induced by chemerin was effectively inhibited by CMKLR1 antagonist (CCX832). Chemerin boosting mature osteoclast activity involves ERK5 phosphorylation. Moreover, two models of dyslipidemia (high-fat diet [HFD] treated C57/BL6 and db/db mice) exhibited significantly increased level of chemerin in the serum and gingival tissue. Morphometric analysis showed that HFD treated and db/db mice exhibited increased alveolar bone loss compared to respective control mice, which was associated with an up-regulation of chemerin, CMKLR1 and cathepsin K mRNA expression in the gingival tissue. The treatment of db/db mice with CCX832 effectively inhibited bone loss. Antagonism of chemerin receptor also inhibited the expression of cathepsin K in the gingival tissue. Our results show that chemerin not only increases osteoclasts activity in vitro, but also that increased level of chemerin in dyslipidemic mice plays a critical role in bone homeostasis. (c) 2016 American Society for Bone and Mineral Research. PMID- 28029187 TI - Off-Label Uses for Flow Diversion in Intracranial Aneurysm Management. AB - Treatment of complex aneurysms using microsurgical and other conventional neuroendovascular techniques remains challenging. As a result, stent- and balloon assisted coiling are instead performed to treat morphologically complex aneurysms, which include giant, wide-necked, and fusiform aneurysms. While these techniques have had success in treating these complex aneurysms, recanalization rates associated with these techniques are still problematic. In the constant effort to improve the outcome of complex aneurysm treatment, flow-diverting stents (FDSs) have emerged in recent years as the preferred treatment. Instead of directly obstructing the flow of blood into the aneurysmal sac, as is the case for stent- and balloon-assisted coiling, FDSs are placed in the parent blood vessel to divert blood flow away from the aneurysm itself. Subsequent to the diverting away of blood from the aneurysm, a thrombotic cascade ensues that ultimately results in the closure of the aneurysm while the parent vessel's perforators are preserved. Current known risks for this procedure include vessel rupture or perforation, in-stent thrombosis, perforator occlusion, procedural or delayed hemorrhages, and perianeurysmal edema. In this review, we will evaluate the mechanisms of actions, clinical applications, complications, and ongoing studies for FDSs. PMID- 28029188 TI - A novel isolation protocol and probe-based RT-PCR for diagnosis of gastric infections with the zoonotic pathogen Helicobacter suis. AB - BACKGROUND: Helicobacter suis is a very fastidious microorganism associated with gastritis, gastric ulcers, and mucosa-associated lymphoid tissue lymphoma in humans. In vitro isolation of this agent from human patients has so far been unsuccessful. MATERIALS AND METHODS: A probe-based real-time PCR (RT-PCR) for the rapid detection of H. suis in gastric biopsies was developed. Secondly, a mouse passage-based protocol was optimized for isolation of low numbers of viable H. suis bacteria. Mice were inoculated with different numbers of viable H. suis (102 -108 ) and kept for 4 weeks to allow multiplication of this pathogen. RESULTS: The probe-based real-time PCR (RT-PCR) exhibited a high degree of diagnostic specificity and analytical sensitivity, high linear correlations (r2 between 0.995 and 0.999), and high amplification efficiencies (>90%) for H. suis. No cross-reactivity was detected with human, porcine, non-human primate, and murine DNA nor with DNA from other bacteria including Helicobacter spp. and Campylobacter spp. H. suis was successfully re-isolated from the stomach of mice inoculated with at least 104 viable H. suis, using a biphasic medium (pH 5), consisting of Brucella agar with Brucella broth on top, both supplemented with vitox supplement, Campylobacter-selective supplement, amphotericin (5 MUg/mL), HCl (0.05%), fetal bovine serum (20%), and linezolid (5 MUg/mL). Linezolid was necessary to inhibit proliferation of contaminants, including lactobacilli. CONCLUSION: The methods described above can be implemented for detection or isolation of H. suis from human gastric biopsies. PMID- 28029189 TI - Morphological and immunohistochemical analysis of the biocompatibility of resin modified cements. AB - The aim of this double-blind randomized study was to evaluate the biocompatibility of resin-modified glass ionomer cements (RMGIC) by means of morphological and immunohistochemical analyses. RMGICs were selected and divided into four groups: Group CK (Crosslink Orthodontic Band Cement); Group RS (Resilience Light Cure Band Cement) Group RMO (RMO Band Cement), Group TP (Transbond Plus Light Cure Band), and Group C (Control-polyethylene). The materials were implanted in rat subcutaneous tissues, randomly selected for this study. After time intervals of 7, 15, and 30 days the tissues were submitted to morphological analysis. In immunohistochemical analysis, the immuno-marking of antibody CD68 was evaluated. The results obtained were statistically analyzed by the Kruskal-Wallis and Dunn tests (p < .05). In the morphological analysis after 7 days, Groups RS, RMO and TP showed more intense inflammatory infiltrate (p = .004) and only Group RMO presented greater intensity of multinucleated giant cells (p = .027). In the immunohistochemical analysis, Groups RMO and RS were observed to present a larger quantity of CD68+ (p = .004) in the time interval of 7 days and only Group RMO presented statistically significant difference for this parameter after 15 days (p = .026). In the time interval of 30 days, Group RMO presented the largest quantity of multinucleated giant cells (p < .004). The RMGICS Crosslink and Transbond Plus provided significantly better tissue biocompatibility than the Resilience and RMO Cements. PMID- 28029190 TI - Scanning probe microscopy in soft matter and life sciences. PMID- 28029192 TI - Factors related to inter-observer reproducibility of conventional Pap smear cytology: a multilevel analysis of smear and laboratory characteristics. AB - OBJECTIVE: To identify factors that influence the inter-observer reproducibility of the routine, conventional Pap smear cytology (Pap smear test) in a network of certificated laboratories in a middle-income Latin American country. METHODS: Twenty-six laboratories provided each an average of 26 negative for malignancy (NILM) and high-grade squamous intraepithelial lesion (HSIL) Pap smears. An external panel reviewed the slides. The kappa index and multilevel logistic regression were used to estimate the reproducibility and odds ratios (OR) of a false result with 95% confidence intervals (95% CI), respectively. Results are presented for laboratories that collect (collector laboratories) and do not collect (non-collector laboratories) samples. RESULTS: The agreements ranged widely (median kappa 0.51, range 0.16-0.70). The overall false-positive (FP) and false-negative (FN) rates were 31% (95% CI 27-35) and 11% (95% CI 7-17). Among collector laboratories (N = 14), a bigger sample collection volume decreased the probability of a FP (OR-adjusted 0.05, 95% CI 0.02-0.1) whereas the number of quality defects (OR-adjusted 1.67, 95% CI 1.25-2.24), high workload (OR-adjusted 5.52, 95% CI 3.85-7.92) and collection by cytotechnologists (OR-adjusted 1.28, 95% CI 1.15-1.42) or health professionals (OR-adjusted 2.26, 95% CI 2.04-2.49) instead of nursing assistants increased it. Among non-collector laboratories (N = 9), the FP rate increased with the number of quality defects (OR-adjusted 1.86, 95% CI 1.06-3.26) but decreased if the samples were collected by health professionals instead of nursing assistants (OR-adjusted 0.37, 95%CI 0.17-0.80). No significant associations were observed for FN. CONCLUSIONS: Staff in charge of cervical sampling significantly determined the reproducibility of the Pap smear test, but this depended on whether the laboratory collects samples or read samples collected elsewhere. PMID- 28029193 TI - Disturbance and productivity interactions mediate stability of forest composition and structure. AB - Fire is returning to many conifer-dominated forests where species composition and structure have been altered by fire exclusion. Ecological effects of these fires are influenced strongly by the degree of forest change during the fire-free period. Response of fire-adapted species assemblages to extended fire-free intervals is highly variable, even in communities with similar historical fire regimes. This variability in plant community response to fire exclusion is not well understood; however, ecological mechanisms such as individual species' adaptations to disturbance or competition and underlying site characteristics that facilitate or impede establishment and growth have been proposed as potential drivers of assemblage response. We used spatially explicit dendrochronological reconstruction of tree population dynamics and fire regimes to examine the influence of historical disturbance frequency (a proxy for adaptation to disturbance or competition), and potential site productivity (a proxy for underlying site characteristics) on the stability of forest composition and structure along a continuous ecological gradient of pine, dry mixed-conifer, mesic mixed-conifer, and spruce-fir forests following fire exclusion. While average structural density increased in all forests, species composition was relatively stable in the lowest productivity pine-dominated and highest productivity spruce-fir-dominated sites immediately following fire exclusion and for the next 100 years, suggesting site productivity as a primary control on species composition and structure in forests with very different historical fire regimes. Species composition was least stable on intermediate productivity sites dominated by mixed-conifer forests, shifting from primarily fire-adapted species to competition-adapted, fire-sensitive species within 20 years of fire exclusion. Rapid changes to species composition and stand densities have been interpreted by some as evidence of high-severity fire. We demonstrate that the very different ecological process of fire exclusion can produce similar changes by shifting selective pressures from disturbance-mediated to productivity-mediated controls. Restoring disturbance-adapted species composition and structure to intermediate productivity forests may help to buffer them against projected increasing temperatures, lengthening fire seasons, and more frequent and prolonged moisture stress. Fewer management options are available to promote adaptation in forest assemblages historically constrained by underlying site productivity. PMID- 28029194 TI - Reverse Iontophoretic Extraction of Metabolites from Living Plants and their Identification by Ion-chromatography Coupled to High Resolution Mass Spectrometry. AB - INTRODUCTION: The identification and characterisation of cellular metabolites has now become an important strategy to obtain insight into functional plant biology. However, the extraction of metabolites for identification and analysis is challenging and, at the present time, usually requires destruction of the plant. OBJECTIVE: To detect different plant metabolites in living plants with no pre treatment using the combination of iontophoresis and ion-chromatography with mass spectrometry detection. METHODOLOGY: In this work, the simple and non-destructive method of reverse iontophoresis has been used to extract in situ multiple plant metabolites from intact Ocimum basilicum leaves. Subsequently, the analysis of these metabolites has been performed with ion chromatography coupled directly to high resolution mass spectrometric detection (IC-MS). RESULTS: The application of reverse iontophoresis to living plant samples has avoided the need for complex pre-treatments. With this approach, no less than 24 compounds, including organic acids and sugars as well as adenosine triphosphate (ATP) were successfully detected. CONCLUSION: The research demonstrates that it is feasible to monitor, therefore, a number of important plant metabolites using a simple, relatively fast and non-destructive approach. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 28029195 TI - Expression of tamoxifen-inducible CRE recombinase in Lcn5-CreERT2 transgenic mouse caput epididymis. AB - The epididymis, which connects the testis to vas deferens, plays a crucial role regulating sperm maturation and fertilization. Here, a tamoxifen-inducible CreERT2 recombinase transgenic mouse was generated to study the function of genes in the caput epididymis using the Cre/LoxP system, which is driven by the 1.8-kb Lcn5 promoter (Lcn5-CreERT2 ). Both CRE recombinase and ERT2 mRNA were specifically expressed in the caput epididymis, beginning at postnatal Day 30 and increasing thereafter. Crossing these Lcn5-CreERT2 transgenic mice with Rosa26; mT/mG reporter mice, which express membrane-bound GFP (mGFP) only after CRE is active at its genetic locus, resulted in the presence of GFP only in the middle/distal caput epididymis after tamoxifen induction. Efficiency of the CRE recombinase production in the caput epididymis was dose- and time-dependent. These tamoxifen-inducible caput epididymis-specific CRE recombinase transgenic mice thus provides a simple approach to modulate epididymal principal cells in vivo, allowing for the genetic investigation of caput epididymis-specific gene functions during sperm maturation. 84: 257-264, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28029196 TI - The emergence of performance trade-offs during local adaptation: insights from experimental evolution. AB - Environmental heterogeneity is considered a general explanation for phenotypic diversification, particularly when heterogeneity causes populations to diverge via local adaptation. Performance trade-offs, such as those stemming from antagonistic pleiotropy, are thought to contribute to the maintenance of diversity in this scenario. Specifically, alleles that promote adaptation in one environment are expected to promote maladaptation in alternative environments. Contrary to this expectation, however, alleles that underlie locally adaptive traits often fail to exhibit fitness costs in alternative environments. Here, we attempt to explain this paradox by reviewing the results of experimental evolution studies, including a new one of our own, that examined the evolution of trade-offs during adaptation to homogeneous versus heterogeneous environments. We propose that when pleiotropic effects vary, whether or not trade-offs emerge among diverging populations will depend critically on ecology. For example, adaptation to a locally homogeneous environment is more likely to occur by alleles that are antagonistically pleiotropic than adaptation to a locally heterogeneous environment, simply because selection is blind to costs associated with environments that are not experienced locally. Our literature review confirmed the resulting prediction that performance trade-offs were more likely to evolve during selection in homogeneous than heterogeneous environments. The nature of the environmental heterogeneity (spatial versus temporal) and the length of the experiment also contributed in predictable ways to the likelihood that performance trade-offs evolved. PMID- 28029197 TI - Application of peripherally inserted central catheter in acute myeloid leukaemia patients undergoing induction chemotherapy. AB - Increasingly, peripherally inserted central catheters (PICC) are applied in patients with haematological malignancies. The feasibility and safety of PICC for induction chemotherapy in acute myeloid leukaemia (AML) remain unclear. Medical records of 89 newly diagnosed adult de novo AML patients, who achieved complete remission, were retrospectively reviewed (PICC group, n = 43; intravenous [IV] line group, n = 46). Patients' clinical characteristics and the number of blind punctures for blood sampling were compared between these two groups, and risk factors associated with bacteraemia were identified by univariate analysis. Patients in the PICC group experienced significantly fewer blind punctures than those in the IV line group (3.3 +/- 3.6 vs. 14.4 +/- 6.0; p = .000); 20.9% of PICC patients had bacteraemia, compared with 23.9% in the IV line group (p = .803). Most patients (76.7%) removed their PICC because treatment was completed. PICC increased the quality of life in AML patients undergoing chemotherapy induction by reducing the number of blind blood punctures required. Bacteraemia in PICC patients was comparable to that in IV line patients. PICC is, therefore, a feasible and safe central venous device for use in AML patients. PMID- 28029199 TI - Mannose-Functionalized Hyperbranched Polyglycerol Loaded with Zinc Porphyrin: Investigation of the Multivalency Effect in Antibacterial Photodynamic Therapy. AB - The antibacterial photodynamic activity of hyperbranched polyglycerol (hPG) loaded with zinc porphyrin photosensitizers and mannose units was investigated. hPG, with a MW of 19.5 kDa, was functionalized with about 15 molecules of the photosensitizer {5,10,15-tris(3-hydroxyphenyl)-20-[4-(prop-2-yn-1 ylamino)tetrafluorophenyl]porphyrinato}-zinc(II) by using copper(I)-catalyzed 1,3 dipolar cycloaddition (CuAAC). These nanoparticle conjugates were functionalized systematically with increasing loadings of mannose in the range of approximately 20 to 110 groups. With higher mannose loadings (ca. 58-110 groups) the water insoluble zinc porphyrin photosensitizer could thus be transferred into a water soluble form. Targeting of the conjugates was proven in binding studies to the mannose-specific lectin concanavalin A (Con A) by using surface plasmon resonance (SPR). The antibacterial phototoxicity of the conjugates on Staphylococcus aureus (as a typical Gram-positive germ) was investigated in phosphate-buffered saline (PBS). It was shown that conjugates with approximately 70-110 mannose units exhibit significant antibacterial activity, whereas conjugates with approximately 20-60 units did not induce bacterial killing at all. These results give an insight into the multivalency effect in combination with photodynamic therapy (PDT). On addition of serum to the bacterial cultures, a quenching of this antibacterial phototoxicity was observed. In fluorescence studies with the conjugates in the presence of increasing bovine serum albumin (BSA) concentrations, protein-conjugate associations could be identified as a plausible cause for this quenching. PMID- 28029200 TI - The influence of Helicobacter pylori on the ethnic distribution of esophageal eosinophilia. AB - BACKGROUND: Environmental factors associated with ethnicity may contribute to the occurrence of eosinophilic esophagitis. Our study aimed to investigate the influence of Helicobacter pylori on the ethnic variation of esophageal eosinophilia in a large national sample of patients undergoing esophago-gastro duodenoscopy. METHODS: The Miraca Life Sciences Database is an electronic repository of histopathologic patient records. A case-control study evaluated the influence of ethnicity on the occurrence of esophageal eosinophilia and how age, gender, and histologic diagnosis of H. pylori modify this relationship. RESULTS: The total study population comprised 596 479 subjects, of whom 25 969 harbored a diagnosis of esophageal eosinophilia. Young age, male sex, and H. pylori infection in declining order exerted the strongest influence on the occurrence of esophageal eosinophilia. In comparison with the population comprising of Caucasians and African-Americans, esophageal eosinophilia was less common among patients of African (OR=0.10, 95% CI=0.01-0.46), Middle Eastern (0.22, 0.15 0.31), East Asian (0.32, 0.26-0.38), Indian (0.28, 0.21-0.37), Hispanic (0.40, 0.37-0.43), or Jewish descent (0.58, 0.51-0.66), but more common among patients of Northern European descent (1.25, 1.07-1.45). With the exception of Northern Europeans, all ethnic subgroups were characterized by a higher prevalence of H. pylori than the comparison group. A low prevalence of H. pylori was significantly associated with a high prevalence of esophageal eosinophilia (R2 =0.90, P<.001). CONCLUSION: Esophageal eosinophilia prevalence markedly varies by patient ethnicity. As there is a strong inverse correlation between H. pylori and esophageal eosinophilia, H. pylori infection may be in part responsible for the observed ethnic distribution of esophageal eosinophilia. PMID- 28029198 TI - Neural responses to negative outcomes predict success in community-based substance use treatment. AB - BACKGROUND AND AIMS: Patterns of brain activation have demonstrated promise as prognostic indicators in substance dependent individuals (SDIs) but have not yet been explored in SDIs typical of community-based treatment settings. DESIGN: Prospective clinical outcome design, evaluating baseline functional magnetic resonance imaging data from the Balloon Analogue Risk Task (BART) as a predictor of 3-month substance use treatment outcomes. SETTING: Community-based substance use programs in Bloomington, Indiana, USA. PARTICIPANTS: Twenty-three SDIs (17 male, aged 18-43 years) in an intensive outpatient or residential treatment program; abstinent 1-4 weeks at baseline. MEASUREMENTS: Event-related brain response, BART performance and self-report scores at treatment onset, substance use outcome measure (based on days of use). FINDINGS: Using voxel-level predictive modeling and leave-one-out cross-validation, an elevated response to unexpected negative feedback in bilateral amygdala and anterior hippocampus (Amyg/aHipp) at baseline successfully predicted greater substance use during the 3-month study interval (P <= 0.006, cluster-corrected). This effect was robust to inclusion of significant non-brain-based covariates. A larger response to negative feedback in bilateral Amyg/aHipp was also associated with faster reward seeking responses after negative feedback (r(23) = -0.544, P = 0.007; r(23) = 0.588, P = 0.003). A model including Amyg/aHipp activation, faster reward-seeking after negative feedback and significant self-report scores accounted for 45% of the variance in substance use outcomes in our sample. CONCLUSIONS: An elevated response to unexpected negative feedback in bilateral amygdala and anterior hippocampus (Amyg/aHipp) appears to predict relapse to substance use in people attending community-based treatment. PMID- 28029201 TI - Water Dynamics from THz Spectroscopy Reveal the Locus of a Liquid-Liquid Binodal Limit in Aqueous CaCO3 Solutions. AB - Many phenomena depend on CaCO3 nucleation where the role of water remains enigmatic. Changes in THz absorption during the early stages of CaCO3 nucleation evidence altered coupled motions of hydrated calcium and carbonate ions. The direct link between these changes and the continuous development of the ion activity product reveals the locus of a liquid-liquid binodal limit. The data strongly suggest that proto-structured amorphous CaCO3 forms through solidification of initially liquid precursors. Furthermore, polycarboxylates, which stabilize liquid precursors of CaCO3 , significantly enhance the kinetic stability of the metastable liquid-liquid state, but they do not affect the locus of the binodal limit. The importance of water network dynamics in phase separation mechanisms can be understood based on the notions of the pre nucleation cluster pathway, and is likely to be more general for aqueous systems. PMID- 28029202 TI - Three-Dimensional Ordered Antibody Arrays Through Self-Assembly of Antibody Polymer Conjugates. AB - Three-dimensional (3D) ordered arrays of human immunoglobulin G (IgG) were fabricated using well-defined full-length antibody-polymer conjugates (APCs). The conjugates were prepared through a two-step sequential click approach with a combination of oxime ligation and strain promoted alkyne-azide cycloaddition. They were able to self-assemble into lamellar nanostructures with alternating IgG and poly(N-isopropylacrylamide) (PNIPAM) nanodomains. As a proof-of-concept, these materials were fabricated into thin films and their specific binding ability was tested. The nanostructure not only improves the packing density and the proper orientation of the IgG, but also provides nanochannels to facilitate substrate transport. PMID- 28029203 TI - Not Only Columns: High Hole Mobility in a Discotic Nematic Mesophase Formed by Metal-Containing Porphyrin-Core Dendrimers. AB - We report a new family of multifunctional liquid-crystalline porphyrin-core dendrimers that have coumarin functional groups around the porphyrin core. Porphyrin metalation strongly affects the photophysical properties, and therefore ZnII and CuII derivatives have also been prepared. All the synthesized dendrimers form a nematic discotic mesophase. Their high tendency for homeotropic alignment makes these dendrimers excellent candidates for device applications, owing to their easy processability, spontaneous alignment between electrodes, and self healing of defects because of their dynamic nature. The charge mobility values of these materials are the highest ever reported for a nematic discotic phase. Moreover, these values are similar to the highest values reported for ordered columnar mesophases, and this shows that a supramolecular organization in columns is not necessary to achieve high charge mobility. PMID- 28029204 TI - Translating Thermal Response of Triblock Copolymer Assemblies in Dilute Solution to Macroscopic Gelation and Phase Separation. AB - The thermal response of semi-dilute solutions (5 w/w%) of two amphiphilic thermoresponsive poly(ethylene oxide)-b-poly(N,N-diethylacrylamide)-b-poly(N,N dibutylacrylamide) (PEO45 -PDEAmx -PDBAm12 ) triblock copolymers, which differ only in the size of the central responsive block, in water was examined. Aqueous PEO45 -PDEAm41 -PDBAm12 solutions, which undergo a thermally induced sphere-to worm transition in dilute solution, were found to reversibly form soft (G'~10 Pa) free-standing physical gels after 10 min at 55 degrees C. PEO45 -PDEAm89 PDBAm12 copolymer solutions, which undergo a thermally induced transition from spheres to large compound micelles (LCM) in dilute solution, underwent phase separation after heating at 55 degrees C for 10 min owing to sedimentation of LCMs. The reversibility of LCM formation was investigated as a non-specific method for removal of a water-soluble dye from aqueous solution. The composition and size of the central responsive block in these polymers dictate the microscopic and macroscopic response of the polymer solutions as well as the rates of transition between assemblies. PMID- 28029205 TI - Regioselective One-Pot Synthesis of Triptycenes via Triple-Cycloadditions of Arynes to Ynolates. AB - We developed the novel one-pot synthetic method of substituted triptycenes by the reaction of ynolates and arynes. This four-step process involves three cycloadditions and electrocyclic ring opening of the strained Dewar anthracene. Each of the three related but structurally distinct classes of nucleophiles (ynolate, enolate, and anthracenolate) reacts with o-benzyne in the same predictable manner controlled by chelation and negative hyperconjugation. The resulting functionalized C3 -symmetrical triptycenes hold promise in the design of functional materials. PMID- 28029206 TI - Investigating the Interaction of Water Vapour with Aminopropyl Groups on the Surface of Mesoporous Silica Nanoparticles. AB - The interaction of water molecules with the surface of hybrid silica-based mesoporous materials is studied by 29 Si, 1 H and 13 C solid-state NMR and IR spectroscopy, with the support of ab initio calculations. The surface of aminopropyl-grafted mesoporous silica nanoparticles is studied in the dehydrated state and upon interaction with controlled doses of water vapour. Former investigations described the interactions between aminopropyl and residual SiOH groups; the present study shows the presence of hydrogen-bonded species (SiOH to NH2 ) and weakly interacting "free" aminopropyl chains with restricted mobility, together with a small amount of protonated NH3+ groups. The concentration of the last-named species increased upon interaction with water, and this indicates reversible and fast proton exchange from water molecules to a fraction of the amino groups. Herein, this is discussed and explained for the first time, by a combination of experimental and theoretical approaches. PMID- 28029208 TI - Pulmonary and tricuspid valvuloplasty in carcinoid heart disease. AB - A 26-year-old female with carcinoid heart disease consisting of severe pulmonary and tricuspid valve stenosis was admitted with line associated sepsis. She recovered from sepsis with antibiotics and aggressive fluid resuscitation but became grossly volume overloaded with evidence of tense ascites and lower extremity edema. She developed worsening renal and hepatic function due to congestive nephropathy and hepatopathy, which did not respond to intravenous diuretics, and she was deemed too sick for surgical pulmonary and tricuspid valve replacement. Pulmonary and tricuspid valvuloplasty was performed as a rescue measure to alleviate her congestive symptoms and improve her candidacy for valve replacement. (c) 2016 Wiley Periodicals, Inc. PMID- 28029207 TI - Prospective comparison between three TAVR devices: ACURATE neo vs. CoreValve vs. SAPIEN XT. A single heart team experience in patients with severe aortic stenosis. AB - OBJECTIVE: We sought to compare the new transcatheter aortic valve replacement (TAVR) device ACURATE neo (ACT) with the already established CoreValve (MCV) and SAPIEN XT (SXT) for the treatment of severe aortic stenosis (AS). BACKGROUND: Very few data on TAVR devices are available beyond MCV and SAPIEN and there is no previous study comparing ACT with MCV and SXT. METHODS: We prospectively evaluated consecutive patients who underwent transfemoral TAVR for the treatment of severe AS. Clinical outcomes were reported following Valve Academic Research Consortium 2 (VARC-2) criteria. RESULTS: A total of 162 patients (ACT n = 49, MCV n = 56, SXT n = 57), were included. MCV group had higher valve embolization/migration rates (ACT none; MCV 9%; SXT 2%; P = 0.034) causing lower device success rates (ACT 98%; MCV 86%; SXT 95%; P = 0.043). At 30 days, there was no significant difference in all-cause mortality (P = 0.22), cardiovascular mortality (P = 0.20), periprocedural myocardial infarction (P = 0.40), stroke (P = 0.64), major vascular complications (P = 0.48), life-threatening bleeding (P = 0.29), acute kidney injury stage 2/3 (P = 0.69), or VARC-2 composite early safety endpoints (P = 0.21). MCV group had higher rates of new permanent pacemaker implantation (ACT 6%; MCV 25%; SXT 11%; P = 0.013). Follow-up echocardiography showed no significant difference in aortic valve mean pressure gradient (P = 0.73) or moderate/severe aortic regurgitation (P = 0.19) between groups. CONCLUSIONS: In a "real world" registry, ACT compared favorably against the well studied SXT and MCV devices in both safety and efficacy. MCV implantation was associated with lower device success rates and higher rates of new permanent pacemaker implantation. (c) 2016 Wiley Periodicals, Inc. PMID- 28029209 TI - Mortality after percutaneous coronary revascularization: Prior cardiovascular risk factor control and improved outcomes in patients with diabetes mellitus. AB - OBJECTIVES: To assess the mortality in patients with diabetes mellitus (DM) following percutaneous coronary intervention (PCI) according to their insulin requirement and PCI setting (elective, urgent, and emergency). BACKGROUND: DM is a major risk factor to develop coronary artery disease (CAD). It is unclear if meticulous glycemic control and aggressive risk factor management in patients with DM has improved outcomes following PCI. METHODS: Retrospective analysis of prospectively collected data on 9,224 patients treated with PCI at a regional tertiary center between 2008 and 2011. RESULTS: About 7,652 patients were nondiabetics (non-DM), 1,116 had non-insulin treated diabetes mellitus (NITDM) and 456 had ITDM. Multi-vessel coronary artery disease, renal impairment and non coronary vascular disease were more prevalent in DM patients. Overall 30-day mortality rate was 2.4%. In a logistic regression model, the adjusted odds ratios (95% confidence intervals [CI]) for 30-day mortality were 1.28 (0.81-2.03, P = 0.34) in NITDM and 2.82 (1.61-4.94, P < 0.001) in ITDM compared with non-DM. During a median follow-up period of 641 days, longer-term post-30 day mortality rate was 5.3%. In the Cox's proportional hazard model, the hazard ratios (95% CI) for longer-term mortality were 1.15 (0.88-1.49, P = 0.31) in NITDM and 1.88 (1.38 2.55, P < 0.001) in ITDM compared with non-DM group. Similar result was observed in all three different PCI settings. CONCLUSION: In the modern era of aggressive cardiovascular risk factor control in diabetes, this study reveals higher mortality only in insulin-treated diabetic patients following PCI for stable coronary artery disease and acute coronary syndrome. Importantly, diabetic patients with good risk factor control and managed on diet or oral hypoglycemics have similar outcomes to the non-diabetic population. (c) 2016 The Authors Catheterization and Cardiovascular Interventions Published by Wiley Periodicals, Inc. PMID- 28029210 TI - Impact of an optical coherence tomography guided approach in acute coronary syndromes: A propensity matched analysis from the international FORMIDABLE CARDIOGROUP IV and USZ registry. AB - AIM: To determine the potential clinical impact of OCT (Optical Coherence Tomography) during primary percutaneous coronary intervention in patients presenting with ACS (Acute Coronary Syndrome). METHODS AND RESULTS: FORMIDABLE is a multicentre retrospective registry enrolling all patients presenting with ACS and treated with an OCT-guided approach, while the USZ registry enrolled patients treated with a standard angiography guided approach. Multivariate adjustment was performed via a propensity score matching. The number stents useds was the primary outcome, while the incidence of MACE (a composite of death, myocardial infarction, target vessel revascularization, and stent thrombosis) was the secondary endpoint. A total of 285 patients OCT-guided and 1,547 angiography guided patients were enrolled, resulting in 270 for each cohort after propensity score with matching. Two stents were used in 12% versus 34%; 3 stents in 8% versus 38% of the patients (P < 0.001). After a follow up of 700 days (450-890), there was no difference in myocardial infarction (6% vs. 6%, P = 0.86), while MACE (11% vs. 16%, P = 0.06), target vessel revascularization (2% vs. 4%, P = 0.15) and stent thrombosis rates (0% vs. 2.7%, P = 0.26) were numerically lower for the OCT-guided cohort but none of these endpoints did reach statistical significance. CONCLUSIONS: An OCT-guided approach reduced the number of stents used, number of patients treated with more than one stent, while there was no statistically significant difference in clinical endpoints while most of them were numerically lower, including stent thrombosis rates. (c) 2016 Wiley Periodicals, Inc. PMID- 28029211 TI - Cardiovascular risk factors and incident albuminuria in screen-detected type 2 diabetes. AB - BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria 5 years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management. METHODS: In 1826 participants with newly diagnosed, screen-detected diabetes without albuminuria, we explored associations between risk of new albuminuria (>=2.5 mg mmol-1 for males and >=3.5 mg mmol-1 for females) and (1) baseline cardio-metabolic risk factors and (2) changes from baseline to 1 year in systolic blood pressure (DeltaSBP) and glycated haemoglobin (DeltaHbA1c ) using logistic regression. RESULTS: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in 5 years after detection of diabetes. In a model adjusted for age, gender, baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5 mm Hg decrease in SBP during the first year were independently associated with lower risks of albuminuria (odds ratio), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively. Further adjustment did not materially change these estimates. There was no interaction between DeltaSBP and DeltaHbA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease. CONCLUSIONS: Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria 4 years later. Established multifactorial treatment for diabetes applies to cases identified through screening. PMID- 28029212 TI - A new model to estimate insulin resistance via clinical parameters in adults with type 1 diabetes. AB - AIMS/HYPOTHESIS: Insulin resistance (IR) is a risk factor to assess the development of micro- and macro-vascular complications in type 1 diabetes (T1D). However, diabetes management in adults with T1D is limited by the difficulty of lacking simple and reliable methods to estimate insulin resistance. The aim of this study was to develop a new model to estimate IR via clinical parameters in adults with T1D. METHODS: A total of 36 adults with adulthood onset T1D (n = 20) or childhood onset T1D (n = 16) were recruited by quota sampling. After an overnight insulin infusion to stabilize the blood glucose at 5.6 to 7.8 mmol/L, they underwent a 180-minute euglycemic-hyperinsulinemic clamp. Glucose disposal rate (GDR, mg kg-1 min-1 ) was calculated by data collected from the last 30 minutes during the test. Demographic factors (age, sex, and diabetes duration) and metabolic parameters (blood pressure, glycated hemoglobin A1c [HbA1c ], waist to hip ratio [WHR], and lipids) were collected to evaluate insulin resistance. Then, age at diabetes onset and clinical parameters were used to develop a model to estimate lnGDR by stepwise linear regression. RESULTS: From the stepwise process, a best model to estimate insulin resistance was generated, including HbA1c , diastolic blood pressure, and WHR. Age at diabetes onset did not enter any of the models. We proposed the following new model to estimate IR as in GDR for adults with T1D: lnGDR = 4.964 - 0.121 * HbA1c (%) - 0.012 * diastolic blood pressure (mmHg) - 1.409 * WHR, (adjusted R2 = 0.616, P < .01). CONCLUSIONS/INTERPRETATION: Insulin resistance in adults living with T1D can be estimated using routinely collected clinical parameters. This simple model provides a potential tool for estimating IR in large-scale epidemiological studies of adults with T1D regardless of age at onset. PMID- 28029213 TI - On odds, age, and preterm birth. PMID- 28029214 TI - Long-term outcomes of rotational atherectomy for the percutaneous treatment of chronic total occlusions. AB - OBJECTIVES: To study the long-term outcomes of rotational atherectomy (RA) for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: There is little evidence on the incidence, procedural results and long-term outcomes of RA for CTO PCI. METHODS: This registry included data from consecutive patients undergoing CTO PCI at four specialized centers. Major adverse cardiac events (MACE: cardiac death, target-vessel myocardial infarction and ischemia-driven target-vessel revascularization) on follow-up were the primary endpoint. RESULTS: A total of 1003 patients were included. Of these, 35 (3.5%) required RA. As compared with Conventional PCI, RA patients were older (68.9 +/- 9.5 vs. 64.6 +/- 10.7 years, P = 0.02), had higher prevalence of diabetes (58% vs. 37%, P = 0.01) and of a J-CTO score >=2 (80% vs. 58%, P = 0.009), driven by severe calcification. Antegrade wire escalation was used more frequently in RA (74% vs. 53%, P = 0.08). RA was performed for balloon failure-to cross in 51% and failure-to-expand in 49%. One burr was utilized in 86%. The 1.25 mm burr was the largest burr used in 43%. Slow flow/no-reflow was observed in 17%. No other serious RA-related complications were observed. Procedural success was 77% vs. 89% (P = 0.04) in RA vs. Conventional PCI. After a mean follow-up of 658 +/- 412 days, MACE rates were similar between groups (15% vs. 13%, P = 0.70). CONCLUSIONS: The use of RA in CTO PCI was safe, despite a worse patient risk profile and higher procedural complexity, as compared with conventional techniques. Although procedural success was lower in the RA group, there were no differences in long-term clinical outcomes between groups. (c) 2016 Wiley Periodicals, Inc. PMID- 28029215 TI - Improving neonatal survival. PMID- 28029216 TI - Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study-level meta analysis of phase III randomized trials. AB - In patients with atrial fibrillation (AF), the safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin according to diabetes mellitus (DM) status are not completely characterized. We performed a meta analysis to clarify whether in these patients the strategy of oral anticoagulation should be tailored to diabetes status. In this study-level meta analysis, we included 4 randomized phase III trials comparing NOACs and warfarin in patients with nonvalvular AF; a total of 18 134 patients with DM and 40 454 without DM were overall considered. Incidence of the following outcome measures was evaluated during the follow-up: stroke or systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and vascular death. Use of NOACs compared with warfarin reduced stroke/systemic embolism in diabetic (Risk Ratios [RR] 0.80, 95% CI 0.68-0.93; P = .004) and nondiabetic patients (RR 0.83, 0.73-0.93; P = .001) (P for interaction .72). No interaction between diabetes status and benefits of NOACs was found for the occurrence of ischemic stroke, major bleeding, or intracranial bleeding (P for interaction >.05 for each comparison). Reduction of vascular death rates with NOACs was significant in diabetic patients (4.97% vs 5.99% with warfarin; RR 0.83, 0.72-0.96; P = .01), in whom absolute the reduction of this outcome measure was higher than in nondiabetics (1.02% vs 0.27%), although no interaction was present (P = .23). Results of this meta analysis support the safety and efficacy of NOACs compared with warfarin in diabetic patients with nonvalvular AF. PMID- 28029217 TI - Gestational diabetes alters the fetal heart rate variability during an oral glucose tolerance test: a fetal magnetocardiography study. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) potentially harms the child before birth. We previously found GDM to be associated with developmental changes in the central nervous system. We now hypothesise that GDM may also impact on the fetal autonomic nervous system under metabolic stress like an oral glucose tolerance test (OGTT). DESIGN: We measured heart rate variability (HRV) of mothers and fetuses during a three-point OGTT using fetal magnetocardiography (fMCG). SETTING: Measurements were performed in the fMEG Centre in Tubingen. POPULATION: After exclusion of 23 participants, 13 pregnant women with GDM and 36 pregnant women with normal glucose tolerance were examined. METHODS: All women underwent the same examination setting with OGTT during which fMCG was recorded three times. MAIN OUTCOME MEASURE(S): Parameters of heart rate variability were measured. RESULTS: Compared with mothers with normal glucose regulation, mothers with GDM showed increased heart rate but no significant differences of maternal HRV. In contrast, HRV in fetuses of mothers with GDM differed from those in the metabolically healthy group regarding standard deviation normal to normal beat (SDNN) (P = 0.012), low-frequency band (P = 0.008) and high-frequency band (P = 0.031). These HRV parameters exhibit a decrease only in GDM fetuses during the second hour of the OGTT. CONCLUSIONS: These results show an altered response of the fetal autonomic nervous system to metabolic stress in GDM-complicated pregnancies. Hence, disturbances in maternal glucose metabolism might not only impact on the central nervous system of the fetus but may also affect the fetal autonomic nervous system. TWEETABLE ABSTRACT: Metabolic stress reveals a different response of fetal autonomic nervous system in GDM-complicated pregnancies. PMID- 28029218 TI - Decreasing mortality during pregnancy and for a year after while mortality after termination of pregnancy remains high: a population-based register study of pregnancy-associated deaths in Finland 2001-2012. AB - OBJECTIVE: To investigate mortality in the non-pregnant fertile female population, and mortality during pregnancy and up to 1 year after the end of pregnancy, in Finland from 2001 to 2012 and compare the results with those of 1987-2000. DESIGN: Retrospective cohort study. SETTING: Finland. POPULATION: 10 427 deceased women of reproductive age (15-49). METHODS: Pregnancy outcomes were categorised into: ongoing pregnancy or birth, miscarriage or ectopic pregnancy and termination of pregnancy. Mortality was calculated per 100 000 pregnancies. The mortality rate of the non-pregnant female population of fertile age was calculated per 100 000 person-years, and the results were compared with those of 1987-2000. MAIN OUTCOME MEASURES: Pregnancy-associated mortality during pregnancy and up to 1 year after the end of pregnancy. Mortality of non-pregnant, fertile age, female population. RESULTS: The age-adjusted mortality rate during pregnancy and within 1 year after the end of pregnancy was 28.4/100 000 pregnancies, and it had significantly decreased compared with the period 1987-2000 [risk ratio (RR) 0.75 (95% CI, 0.65-0.88)]. Mortality in non-pregnant fertile-age females was 48.1/100 000 person-years. Mortality for diseases and medical conditions during and after pregnancy decreased by 26% [RR 0.74 (95% CI, 0.59-0.92)] and for external causes by 23% [RR 0.77 (95% CI, 0.62-0.95)]. The mortality rate for suicides was 3.3/100 000 in ongoing pregnancies and pregnancies ending in birth while it was 21.8/100 000 after termination of pregnancy and 10.2/100 000 among non-pregnant women. CONCLUSIONS: In comparison with earlier decades, pregnancy associated mortality has decreased in Finland. TWEETABLE ABSTRACT: Mortality decreases among pregnant women and within 1 year after pregnancy in Finland. PMID- 28029219 TI - Defining the Tipping Point in Surgical Performance for Laparoscopic Donor Nephrectomy Among Transplant Surgery Fellows: A Risk-Adjusted Cumulative Summation Learning Curve Analysis. AB - The United Network for Organ Sharing recommends that fellowship-trained surgeons participate in 15 laparoscopic donor nephrectomy (LDN) procedures to be considered proficient. The American Society of Transplant Surgeons (ASTS) mandates 12 LDNs during an abdominal transplant surgery fellowship. We performed a retrospective intraoperative case analysis to create a risk-adjusted cumulative summation (RACUSUM) model to assess the learning curve of novice transplant surgery fellows (TSFs). Between January 2000 and December 2014, 30 novice TSFs participated in the organ procurement rotation of our ASTS-approved abdominal transplant surgery fellowship. Measures of surgical performance included intraoperative time, estimated blood loss, and incidence of intraoperative complications. The performance of senior TSFs was used to benchmark novice TSF performance. Scores were tabulated in a learning curve model, adjusting for case complexity and prior TSF case volume. Rates of adverse surgical events were significantly higher for novice TSFs than for senior TSFs. In univariable analysis, multiple renal arteries, high BMI, prior abdominal surgery, male donor, and nephrolithiasis were correlated with higher incidence of adverse surgical events. Based on the RACUSUM model, high intraoperative time is mitigated after 28 procedures, incidence of intraoperative complications tends to diminish after 24 procedures, and improvement in estimated blood loss did not remain consistent. TSFs exhibit a tipping point in LDN performance by 24-28 cases and proficiency by 35-38 cases. PMID- 28029220 TI - Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate. AB - BACKGROUND: Recent advances in genomics methodologies, in particular the availability of next-generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only. METHODS: The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions. Filtering methods were applied to identify variants that are clinically relevant and present in affected individuals at minor allele frequencies (<=1%) in the 1000 Genomes Project single nucleotide polymorphism database, Exome Aggregation Consortium, and Exome Variant Server databases. The bioinformatics tool Systems Tool for Craniofacial Expression-Based Gene Discovery was used to prioritize cleft candidates in our list of variants, and Sanger sequencing was used to validate the presence of identified variants in affected and unaffected relatives. RESULTS: Our analyses approach narrowed the candidates down to the novel missense variant in ARHGAP29 (GenBank: NM_004815.3, NP_004806.3;c.1654T>C [p.Ser552Pro]. A functional assay in zebrafish embryos showed that the encoded protein lacks the activity possessed by its wild-type counterpart, and migration assays revealed that keratinocytes transfected with wild-type ARHGAP29 migrated faster than counterparts transfected with the p.Ser552Pro ARHGAP29 variant or empty vector (control). CONCLUSION: These findings reveal ARHGAP29 to be a regulatory protein essential for proper development of the face, identifies an amino acid that is key for this, and provides a potential new diagnostic tool.Birth Defects Research 109:27-37, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 28029221 TI - The antepartum stillbirth syndrome: risk factors and pregnancy conditions identified from the INTERGROWTH-21st Project. AB - OBJECTIVES: To identify risk factors for antepartum stillbirth, including fetal growth restriction, among women with well-dated pregnancies and access to antenatal care. DESIGN: Population-based, prospective, observational study. SETTING: Eight international urban populations. POPULATION: Pregnant women and their babies enrolled in the Newborn Cross-Sectional Study of the INTERGROWTH 21st Project. METHODS: Cox proportional hazard models were used to compare risks among antepartum stillborn and liveborn babies. MAIN OUTCOME MEASURES: Antepartum stillbirth was defined as any fetal death after 16 weeks' gestation before the onset of labour. RESULTS: Of 60 121 babies, 553 were stillborn (9.2 per 1000 births), of which 445 were antepartum deaths (7.4 per 1000 births). After adjustment for site, risk factors were low socio-economic status, hazard ratio (HR): 1.6 (95% CI, 1.2-2.1); single marital status, HR 2.0 (95% CI, 1.4-2.8); age >=40 years, HR 2.2 (95% CI, 1.4-3.7); essential hypertension, HR 4.0 (95% CI, 2.7 5.9); HIV/AIDS, HR 4.3 (95% CI, 2.0-9.1); pre-eclampsia, HR 1.6 (95% CI, 1.1 3.8); multiple pregnancy, HR 3.3 (95% CI, 2.0-5.6); and antepartum haemorrhage, HR 3.3 (95% CI, 2.5-4.5). Birth weight <3rd centile was associated with antepartum stillbirth [HR, 4.6 (95% CI, 3.4-6.2)]. The greatest risk was seen in babies not suspected to have been growth restricted antenatally, with an HR of 5.0 (95% CI, 3.6-7.0). The population-attributable risk of antepartum death associated with small-for-gestational-age neonates diagnosed at birth was 11%. CONCLUSIONS: Antepartum stillbirth is a complex syndrome associated with several risk factors. Although small babies are at higher risk, current growth restriction detection strategies only modestly reduced the rate of stillbirth. TWEETABLE ABSTRACT: International stillbirth study finds individual risks poor predictors of death but combinations promising. PMID- 28029222 TI - Role of adjuvant chemotherapy in T2N0M0 periampullary cancers. AB - AIMS: Surgery is the only modality that offers cure for periampullary adenocarcinoma. However, surgery alone results in failure in 60% of patients. Studies have shown some benefits of chemotherapy in node positive and higher tumor stage patients. We sought to determine the role of adjuvant chemotherapy in early tumors with uninvolved nodes. METHODS: A retrospective analysis of a prospectively maintained database of patients resected of periampullary tumors from 2007 to 2014 was performed. Patients were studied for adverse risk factors, adjuvant therapy received and the survival. RESULTS: Of 105 patients, 14 patients received adjuvant chemotherapy and 85 were observed. After a median follow-up of over 36 months, the overall 3-year survival was 94.2% in the observed group and 100% in the group that received chemotherapy (P = 0.33), with the 3-year disease free survival being 81.9% and 90.9%, respectively, (P = 0.477). Serum CA 19-9 levels above 100 U/mL were a poor prognostic factor. CONCLUSION: This study did not find a benefit with the use of adjuvant chemotherapy, but chemotherapy might improve survival. The benefit for adjuvant chemotherapy needs further confirmation in prospective trials. PMID- 28029223 TI - High Power Efficiency Blue-to-Green Organic Light-Emitting Diodes Using Isonicotinonitrile-Based Fluorescent Emitters. AB - Herein, 9,10-dihydro-9,9-dimethylacridine (Ac) or phenoxazine (PXZ)-substituted isonicotinonitrile (INN) derivatives, denoted as 2AcINN, 26AcINN, and 26PXZINN, were developed as a series of thermally activated delayed fluorescence (TADF) emitters. These emitters showed reasonably high photoluminescence quantum yields of 71-79 % in the host films and high power efficiency organic light-emitting diodes (OLEDs). Sky-blue emitter 26AcINN exhibited a low turn-on voltage of 2.9 V, a high external quantum efficiency (etaext ) of 22 %, and a high power efficiency (etap ) of 66 lm W-1 with Commission Internationale de l'Eclairage (CIE) chromaticity coordinates of (0.22, 0.45), whereas green emitter 26PXZINN exhibited a low turn-on voltage of 2.2 V, a high etaext of 22 %, and a high etap of 99 lm W-1 with CIE chromaticity coordinates of (0.37, 0.58). These performances are among the best for TADF OLEDs to date. PMID- 28029224 TI - Preterm prelabour rupture of membranes: a retrospective cohort study of association with adverse outcome in subsequent pregnancy. AB - OBJECTIVE: To assess the association of first pregnancy preterm prelabour rupture of membranes (PPROM) with adverse maternal and perinatal outcomes in the next pregnancy. DESIGN: Retrospective cohort study. SETTING: Grampian, Scotland, UK. POPULATION: Women with first deliveries recorded in the Aberdeen Maternity Neonatal Databank, 1986-2005. METHODS: Women identified from the AMND database (n = 37 776) were classified into exposed (PPROM in first pregnancy; n = 1979) and unexposed (no PPROM in first pregnancy; n = 35 797) cohorts. Each cohort (exposed n = 1174; unexposed n = 20 860) was followed up until December 2012 for next singleton pregnancy. MAIN OUTCOME MEASURES: Second pregnancy, miscarriage, pregnancy-induced hypertension (PIH), pre-eclampsia (PE), antepartum haemorrhage (APH) and postpartum haemorrhage, repeat PPROM, type of labour, mode of delivery, preterm delivery, low birth weight (LBW), admission to neonatal unit, neonatal infections and death. RESULTS: PPROM in the first singleton pregnancy was associated with an equal likelihood of second pregnancy but with a significantly increased risk of adverse outcomes in the next singleton pregnancy: PPROM [odds ratio (OR) (95% confidence interval (CI)): 6.6 (5.4-7.9)], PE [2.4 (1.7-3.5)], instrumental [2.2 (1.7-2.8)] and caesarean delivery [1.8 (1.5-2.3)], PIH [1.5 (1.2-1.9)] and APH [1.3 (1.1-1.6)] in the mother, and neonatal infection [5.4 (1.4-20.3)], death [2.6 (1.0-6.7)], admission to neonatal unit [2.4 (2.0-2.9)], preterm delivery [2.3 (1.8-2.9)] and LBW [1.44 (1.1-1.9)]. Even in women without a recurrent PPROM, there was still a significant increase in PIH [1.4 (1.1-1.8)], PE [2.3 (1.6-3.5)], instrumental [2.2 (1.7-2.9)] and caesarean delivery [1.9 (1.5 2.4)], and neonatal unit admission [1.6 (1.3-2.0)]. CONCLUSIONS: PPROM in the first pregnancy is associated with significant adverse maternal and perinatal outcomes in the next pregnancy, but not reduced likelihood of second pregnancy. TWEETABLE ABSTRACT: PPROM in the first singleton pregnancy increases risk of adverse maternal and perinatal outcomes in the next singleton pregnancy. PMID- 28029225 TI - What is the influence of preeclampsia on vertical transmission of HIV? PMID- 28029226 TI - Meeting the challenge of DNA barcoding Neotropical amphibians: polymerase chain reaction optimization and new COI primers. AB - Amphibians are one of the most threatened vertebrate classes, yet at the same time new species are being described every year, demonstrating that the number of existing species is grossly underestimated. In groups such as amphibians, with high extinction rates and poorly known species boundaries, DNA barcoding is a tool that can rapidly assess genetic diversity and estimate species richness for prioritizing conservation decisions. However, reliable recovery of the 5' region of the cytochrome c oxidase subunit 1 (COI) gene is critical for the ongoing effort to gather DNA barcodes for all amphibian species. Here, we provide new PCR conditions and tested new primers that increase the efficiency of barcode recovery in amphibians. We found that a low extension temperature for PCR cycles significantly improves the efficiency of amplification for all combinations of primers. Combining low PCR extension temperature and primers AnF1 + AnR1, we were able to recover COI sequences for 100% of the species analysed (N = 161), encompassing ~15% of the species known from Brazil (representing 77 genera and 23 families), which is an important improvement over previous studies. The preliminary assessment of species diversity suggested that number of species might be underestimated by about 25%. We conclude that DNA barcoding is an efficient, simple, and standardized protocol for identifying cryptic diversity in amphibians and advocate for its use in biodiversity inventories and across widespread populations within known species. PMID- 28029227 TI - Physicochemical, Antioxidant, and Cytotoxic Properties of Xao Tam Phan (Paramignya trimera) Root Extract and Its Fractions. AB - Xao tam phan (Paramignya trimera (Oliv.) Guillaum) has been used as a medicinal plant for cancer prevention and treatment in recent years. The objective of this study was to determine the physicochemical, antioxidant, and cytotoxic properties of crude P. trimera root (PTR) extract and its fractions using MeOH as a solvent and microwave-assisted extraction as an advanced technique for preparation of the PTR extract. The results showed that the PTR extract had high contents of saponins, phenolics, flavonoids, and proanthocyanidins (7731.05 mg escin equiv. (EE), 238.13 mg gallic acid equiv. (GAE), 81.49 mg rutin equiv., and 58.08 mg catechin equiv. (CE)/g dried extract, resp.). Antioxidant activity of PTR extract was significantly higher (P < 0.05) than those of four its fractions and ostruthin, a key bioactive compound in the P. trimera, while potent cytotoxic capacity of PTR extract on various cancer cell lines in terms of MiaPaCa-2 (pancreas), HT29 (colon), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), MCF-7 (breast), MCF-10A (normal breast), and U87, SJ-G2, SMA (glioblastoma) was observed with GI50 values ranging from 15 to 32 MUg/ml. Cytotoxic potential on pancreatic cancer cells of PTR extract (100 - 200 MUg/ml) was significantly higher (P < 0.05) than those of its four fractions (50 MUg/ml), ostruthin (20 MUg/ml) and gemcitabine (50 nm), and being comparable to a saponin-enriched extract from quillajia bark, a commercial product. Based on the results achieved, we can conclude that the PTR extract is a potential source for application of in the nutraceutical, medical, and pharmaceutical industries. PMID- 28029228 TI - Managing glaucoma drainage device tube leak with cyanoacrylate. PMID- 28029229 TI - On-site test to detect syphilis in pregnancy: a systematic review of test accuracy studies. AB - BACKGROUND: Syphilis in pregnancy can lead to fetal and neonatal death or congenital anomalies. Accurate on-site tests are an essential part of effective prevention of mother-to-child transmission of the disease. OBJECTIVE: This systematic review assessed the accuracy of on-site tests to detect infection with Treponema pallidum in pregnant women. SEARCH STRATEGY: Major databases were searched from inception to January 2016 using terms: 'pregnancy', 'antenatal', 'syphilis', 'Treponema pallidum' with their variations, and the search limit for the relevant study design. SELECTION CRITERIA: We included studies that used dual reference standard (non-treponemal and treponemal tests) to detected syphilis in pregnancy. DATA COLLECTION AND ANALYSIS: Extracted accuracy data were tabulated and pooled using hierarchical, bivariate random effects model. MAIN RESULTS: Seven studies (combined sample 17 546) reporting the accuracy of four on-site tests met the eligibility criteria. On average, DetermineTM and SD BioLine Syphilis 3.0 had the highest sensitivity of all the evaluated tests: 0.83 (95% CI 0.58, 0.98) and 0.86 (95% CI 0.82, 0.89), respectively, with a high specificity 0.96 (95% CI 0.89, 1.00) and 0.99 (95% CI 0.94, 1.00), respectively. The Qualitative Rapid Plasma Reagin card commonly used in clinical practice had a pooled sensitivity of 0.70 (95% CI 0.54, 0.88) and specificity of 0.97 (95% CI 0.96, 0.99). CONCLUSION: Immunochromatographic tests such as DetermineTM and SD BioLine Syphilis 3.0 seem to be acceptable options in antenatal testing for syphilis, especially in resource-limited settings. Future research should seek more evidence to strengthen this claim. TWEETABLE ABSTRACT: On-site test to detect syphilis-options during antenatal care. PMID- 28029230 TI - Water-Processable, Air-Stable Organic Nanoparticle-Carbon Nanotube Nanocomposites Exhibiting n-Type Thermoelectric Properties. AB - Water-dispersed organic base nanoparticles are utilized for the highly stable n type doping of single-walled carbon nanotubes in aqueous dispersion. Long-term stability is often a critical challenge in the application of n-type organic conductors. The present n-type organic materials exhibit almost no degradation in the thermoelectric properties over months, in air. PMID- 28029231 TI - Measurement of lacrimal punctum using spectralis domain anterior optical coherence tomography. AB - PURPOSE: Anterior segment optical coherence tomography (AS-OCT) was used to image the lacrimal punctum and establish normal punctal parameters including the tear volume inside the punctum. METHODS: This study included totally 67 eyes from 38 normal subjects. Punctal parameters and tear meniscus height (TMH) were measured using spectralis OCT anterior-segment scans. Outer punctal diameter (OPD), punctal depth, tear well diameter (TWD), tear well depth, punctal reserve (PR) and lower eyelid TMH were assessed. Authors defined a 'tear well' as a pool of standing tears in the punctum. Punctal reserve was defined as the difference between punctal depth and tear well depth. RESULTS: Outer punctal diameter was 614.6 +/- 195.6 MUm, the punctal depth was 545.8 +/- 270.1 MUm, TWD was 229.9 +/- 133.8 MUm, the tear well depth was 434.9 +/- 247.8 MUm, the PR was 110.9 +/- 72.9 MUm, the PR ratio was 0.20 +/- 0.17, and the TMH was 222.9 +/- 88.8 MUm. The punctal depth decreased significantly according to the patient's age (correlation coefficient = -0.352, respectively). CONCLUSION: AS-OCT is useful for improving anatomical understanding of the lacrimal punctal structure. Quantitative punctum and tear well measurements were correlated with TMH. PMID- 28029232 TI - Severe maternal morbidity requires regionalistion of obstetric critical care. PMID- 28029233 TI - A Review of Water-Resistant Hemicellulose-Based Materials: Processing and Applications. AB - Hemicelluloses, due to their hydrophilic nature, may tend to be overlooked as a component in water-resistant product applications. However, their domains of use can be greatly expanded by chemical derivatization. Research in which hydrophobic derivatives of hemicelluloses or combinations of hemicelluloses with hydrophobic materials are used with to prepare films and composites is considered herein. Isolation methods that have been used to separate hemicellulose from biomass are also reviewed. Finally, the most useful pathways to change the hydrophilic character of hemicelluloses to hydrophobic are reviewed. In this way, the water resistance can be increased and applications of targeted water-resistant hemicellulose developed. Several applications of these materials are discussed. PMID- 28029234 TI - Temporal Trends of Venous Thromboembolism Risk Before and After Diagnosis of Giant Cell Arteritis. AB - OBJECTIVE: Giant cell arteritis (GCA) and the use of glucocorticoids have both been associated with increased risk of venous thromboembolism (VTE). However, the possibility of confounding by indication has not been investigated. We undertook this study to examine the temporal risk of VTE in GCA patients before and after GCA diagnosis, accounting for confounders including glucocorticoid treatment. METHODS: We conducted a matched cohort study using an electronic medical record database representative of the UK population (1990-2013). We calculated age-, sex , and entry time-matched and multivariate relative risks (RRs) of VTE, comparing 6,441 patients with new-onset GCA (defined by corresponding diagnosis codes and prescribed glucocorticoid treatment) to 63,985 controls before and after GCA diagnosis. Analysis before GCA diagnosis was stratified by oral glucocorticoid use to account for confounding. RESULTS: There were 27 incident VTE events during the 12 months preceding GCA diagnosis and 195 afterward. Compared to controls, during the 12, 9, 6, and 3 months preceding GCA diagnosis, the age-, sex-, and entry time-matched RRs for VTE among patients with imminent GCA not treated with glucocorticoids were 1.8, 2.2, 2.4, and 3.6, respectively. In the first 3, 6, 12, 24, 48, and 96 months after GCA diagnosis, the corresponding RRs were 9.9, 7.7, 5.9, 4.4, 3.3, and 2.4. Multivariate analyses including several common VTE risk factors showed similar trends. CONCLUSION: The risk of VTE increases shortly before GCA diagnosis, peaks at the time of diagnosis, and then progressively declines thereafter. This risk is apparent in patients with imminent GCA unexposed to oral glucocorticoids, suggesting a role for inflammation-associated thrombosis that is independent of glucocorticoid use. PMID- 28029235 TI - Editorial: Defining and Refining the Risk of Venous Thromboembolism in Giant Cell Arteritis. PMID- 28029236 TI - Ethylene Detection Based on Organic Field-Effect Transistors With Porogen and Palladium Particle Receptor Enhancements. AB - Ethylene sensing is a highly challenging problem for the horticulture industry because of the limited physiochemical reactivity of ethylene. Ethylene plays a very important role in the fruit life cycle and has a significant role in determining the shelf life of fruits. Limited ethylene monitoring capability results in huge losses to the horticulture industry as fruits may spoil before they reach the consumer, or they may not ripen properly. Herein we present a poly(3-hexylthiophene-2,5-diyl) (P3HT)-based organic field effect transistor as a sensing platform for ethylene with sensitivity of 25 ppm V/V. To achieve this response, we used N-(tert-Butoxy-carbonyloxy)-phthalimide and palladium particles as additives to the P3HT film. N-(tert-Butoxy-carbonyloxy)-phthalimide is used to increase the porosity of the P3HT, thereby increasing the overall sensor surface area, whereas the palladium (<1 MUm diameter) particles are used as receptors for ethylene molecules in order to further enhance the sensitivity of the sensor platform. Both modifications give statistically significant sensitivity increases over pure P3HT. The sensor response is reversible and is also highly selective for ethylene compared to common solvent vapors. PMID- 28029237 TI - High Rate and Stable Li-Ion Insertion in Oxygen-Deficient LiV3O8 Nanosheets as a Cathode Material for Lithium-Ion Battery. AB - Low performance of cathode materials has become one of the major obstacles to the application of lithium-ion battery (LIB) in advanced portable electronic devices, hybrid electric vehicles, and electric vehicles. The present work reports a versatile oxygen-deficient LiV3O8 (D-LVO) nanosheet that was synthesized successfully via a facile oxygen-deficient hydrothermal reaction followed by thermal annealing in Ar. When used as a cathode material for LIB, the prepared D LVO nanosheets display remarkable capacity properties at various current densities (a capacity of 335, 317, 278, 246, 209, 167, and 133 mA h g-1 at 50, 100, 200, 500, 1000, 2000, and 4000 mA g-1, respectively) and excellent lithium ion storage stability, maintaining more than 88% of the initial reversible capacity after 200 cycles at 1000 mA g-1. The outstanding electrochemical properties are believed to arise largely from the introduction of tetravalent V (~15% V4+) and the attendant oxygen vacancies into LiV3O8 nanosheets, leading to intrinsic electrical conductivity more than 1 order of magnitude higher and lithium-ion diffusion coefficient nearly 2 orders of magnitude higher than those of LiV3O8 without detectable V4+ (N-LVO) and thus contributing to the easy lithium-ion diffusion, rapid phase transition, and the excellent electrochemical reversibility. Furthermore, the more uniform nanostructure, as well as the larger specific surface area of D-LVO than N-LVO nanosheets may also improve the electrolyte penetration and provide more reaction sites for fast lithium-ion diffusion during the discharge/charge processes. PMID- 28029238 TI - Construction of Tough, in Situ Forming Double-Network Hydrogels with Good Biocompatibility. AB - Hydrogels are required to have high mechanical properties, biocompatibility, and an easy fabrication process for biomedical applications. Double-network hydrogels, although strong, are limited because of the complicated preparation steps and toxic materials involved. In this study, we report a simple method to prepare tough, in situ forming polyethylene glycol (PEG)-agarose double-network (PEG-agarose DN) hydrogels with good biocompatibility. The hydrogels display excellent mechanical strength. Because of the easily in situ forming method, the resulting hydrogels can be molded into any form as needed. In vitro and in vivo experiments illustrate that the hydrogels exhibit satisfactory biocompatibility, and cells can attach and spread on the hydrogels. Furthermore, the residual amino groups in the network can also be functionalized for various biomedical applications in tissue engineering and cell research. PMID- 28029239 TI - Solid-State Nuclear Magnetic Resonance Analysis Reveals a Possible Calcium Binding Site of Pradimicin A. AB - Pradimicin A (PRM-A) is a unique natural product that recognizes d mannopyranoside (Man) in the presence of Ca2+ ion. Although the Man binding geometry of PRM-A is largely understood, the molecular basis of Man recognition has yet to be established because of the lack of information regarding Ca2+ binding geometry. In this work, to examine the Ca2+ binding site of PRM-A, we performed a solid-state nuclear magnetic resonance experiment using 111Cd2+ as a surrogate probe for Ca2+. Evaluation of 13C-111Cd distances in the [PRM A/111Cd2+] complexes by rotational-echo double resonance (REDOR) and 111Cd frequency selective REDOR (FSR) revealed that PRM-A binds 111Cd2+ at the anthraquinone moiety, which contradicts the previous hypothesis of the alanine moiety being the Ca2+ and Cd2+ binding sites of PRM-A. The distances between Cd2+ and the carbon atoms at the binding site of PRM-A were found to be 3.5 +/- 0.2 A. Importantly, Man binding was shown not to alter the distances, indicating that [PRM-A/Ca2+] and [PRM-A/Ca2+/Man] complexes have similar Ca2+ binding geometries. This study provides an important clue to understanding the molecular basis of Man recognition of PRM-A. PMID- 28029240 TI - beta-Lactone Synthetase Found in the Olefin Biosynthesis Pathway. AB - The first beta-lactone synthetase enzyme is reported, creating an unexpected link between the biosynthesis of olefinic hydrocarbons and highly functionalized natural products. The enzyme OleC, involved in the microbial biosynthesis of long chain olefinic hydrocarbons, reacts with syn- and anti-beta-hydroxy acid substrates to yield cis- and trans-beta-lactones, respectively. Protein sequence comparisons reveal that enzymes homologous to OleC are encoded in natural product gene clusters that generate beta-lactone rings, suggesting a common mechanism of biosynthesis. PMID- 28029242 TI - Correction to Understanding the Mechanism of Polymerization of epsilon Caprolactone Catalyzed by Aluminum Salen Complexes. PMID- 28029241 TI - Structure-Guided Reprogramming of a Hydroxylase To Halogenate Its Small Molecule Substrate. AB - Enzymatic installation of chlorine/bromine into unactivated carbon centers provides a versatile, selective, and environmentally friendly alternative to chemical halogenation. Iron(II) and 2-(oxo)-glutarate (FeII/2OG)-dependent halogenases are powerful biocatalysts that are capable of cleaving aliphatic C-H bonds to introduce useful functional groups, including halogens. Using the structure of the Fe/2OG halogenase, WelO5, in complex with its small molecule substrate, we identified a similar N-acyl amino acid hydroxylase, SadA, and reprogrammed it to halogenate its substrate, thereby generating a new chiral haloalkyl center. The work highlights the potential of FeII/2OG enzymes as platforms for development of novel stereospecific catalysts for late-stage C-H functionalization. PMID- 28029243 TI - Free Energy-Based Coarse-Grained Force Field for Binary Mixtures of Hydrocarbons, Nitrogen, Oxygen, and Carbon Dioxide. AB - The free energy based Lennard-Jones 12-6 (FE-12-6) coarse-grained (CG) force field developed for alkanes1 has been extended to model small molecules of light hydrocarbons (methane, ethane, propane, butane, and isobutane), nitrogen, oxygen, and carbon dioxide. The adjustable parameters of the FE-12-6 potential are determined by fitting against experimental vapor-liquid equilibrium (VLE) curves and heat of vaporization (HOV) data for pure substance liquids. Simulations using the optimized FE-12-6 parameters correctly reproduced experimental measures of the VLE, HOV, density, vapor pressure, compressibility, critical point, and surface tension for pure substances over a wide range of thermodynamic states. The force field parameters optimized for pure substances were tested on methane/butane, nitrogen/decane, and carbon dioxide/decane binary mixtures to predict their vapor-liquid equilibrium phase diagrams. It is found that for nonpolar molecules represented by different sized beads, a common scaling factor (0.08) that reduces the strength of the interaction potential between unlike beads, generated using Lorentz-Berthelot (LB) combination rules, is required to predict vapor-liquid phase equilibria accurately. PMID- 28029244 TI - Stationary Conditions of the Electron Density Along the Reaction Path: Connection with Conceptual DFT and Information Theory. AB - The Kohn-Sham density functional theory (DFT) formalism has been used to investigate the influence of the stationary behavior of the electron density (rho(r?;s)) along a minimum energy path on the corresponding stationary conditions observed in the total potential energy of the reactive system, information theory measures (Shannon information entropy and Onicescu information energy), and chemical reactivity indexes (the chemical hardness). The theoretical treatment presented in this work, combined with DFT calculations on 3 different test reactions: H' + H2, H' + CH4 and H- + CH4, suggest that for any reactive system, properties that can be cast as a functional of the electron density, must exhibit stationary points along the IRC path modulated by the corresponding stationary behavior of the electron density. PMID- 28029245 TI - Selective Binding of Genomic Escherichia coli DNA with ZnO Leads to White Light Emission: A New Aspect of Nano-Bio Interaction and Interface. AB - Here, we report for the first time, a novel and intriguing application of deoxyribonucleic acid (DNA) in the area of optics by demonstrating white light emission by tuning the emission of a nanomaterial, ZnO rods, exhibiting surface defects, in the presence of genomic Escherichia coli DNA with a comparatively high quantum efficiency. In order to understand the DNA specificity, we have also studied the interaction of ZnO with CT, and ML DNA, ss EC DNA, synthetic polynucleotides and different mononucleosides and bases. Further, in order to understand the effect of particle shape and defects present in ZnO, we have also extended our study with ZnO rods prepared at higher temperature exhibiting red emission and ZnO particles exhibiting yellow emission. Interestingly, none of the above studies resulted in white light emission from ZnO-DNA complex. Our studies unequivocally confirmed that the concentration and the nature of DNA and ZnO together plays a crucial role in obtaining CIE coordinates (0.33, 0.33) close to white light. The much enhanced melting temperature (Tm) of EC DNA and the energetics factors confirm enhanced hydrogen bonding of ZnO with EC DNA leading to a new emission band. Our experimental observations not only confirm the selective binding of ZnO to EC DNA but also open a new perspective for developing energy saving light emitting materials through nano-bio interactions. PMID- 28029246 TI - Synergetic Cues of Bioactive Nanoparticles and Nanofibrous Structure in Bone Scaffolds to Stimulate Osteogenesis and Angiogenesis. AB - Providing a nanotopological physical cue in concert with a bioactive chemical signal within 3D scaffolds, while it being considered a promising approach for bone regeneration, has yet to be explored. Here, we develop 3D porous scaffolds that are networked to be a nanofibrous structure and incorporated with bioactive glass nanoparticles (BGn) to tackle this issue. The presence of BGn and nanofibrous structure (BGn + nanofibrous) substantially increased the surface area, hydro-affinity and protein loading capacity of scaffolds. In particular, the BGn released Si and Ca ions to the levels known to be biologically effective, offering the bone scaffold an ability to deliver therapeutic ions. The mesenchymal stem cells (MSCs) from rats exhibited significantly accelerated adhesion events including cell anchorage, cytoskeletal extensions, and the expression of adhesion signaling molecules on the BGn/nanofibrous scaffolds. The cells gained a more rapid proliferation and migration (penetration) ability over 2 weeks within the BGn + nanofibrous scaffolds than within either nanofibrous or BGn scaffolds. The osteogenesis of MSCs, as confirmed by the expressions of bone associated genes and proteins, as well as the cellular mineralization was significantly stimulated by the BGn and nanofibrous topology in a synergistic manner. The behaviors of endothelial cells (HUVECs) including cell migration and tubule networking were also enhanced when influenced by the BGn and nanofibrous scaffolds (but more by BGn than by nanofiber). A subcutaneous tissue implantation of the scaffolds further evidenced the in vivo stimulation of neo-blood vessel formation by the BGn + nanofibrous cues, suggesting the possible promising role in bone regeneration. Taken together, the therapeutic ions and nanofibrous topology implemented within 3D scaffolds are considered to play synergistic actions in osteogenesis and angiogenesis, implying the potential usefulness of the BGn + nanofibrous scaffolds for bone tissue engineering. PMID- 28029247 TI - Enhancing the Catalytic Activity of Zn-Containing Magnetic Oxides in a Methanol Synthesis: Identifying the Key Factors. AB - A new family of Ni-, Co-, and Cr-doped Zn-containing magnetic oxide nanoparticles (NPs) stabilized by polyphenylquinoxaline (PPQ) and hyperbranched pyridylphenylene polymer (PPP) has been developed. These NPs have been synthesized by thermal decomposition of Zn and doping metal acetylacetonates in the reaction solution of preformed magnetite NPs, resulting in single-crystal NPs with spinel structure. For the PPQ-capped NPs, it was demonstrated that all three types of metal species (Fe, Zn, and a doping metal) reside within the same NPs, the surface of which is enriched with Zn and a doping metal, while the deeper layers are enriched with Fe. The Cr-doped NPs at the high Cr loading are an exception due to favored deposition of Cr on magnetite located in the NP depth. The PPP-capped NPs exhibit similar morphology and crystallinity; however, the detailed study of the NP composition was barred due to the high PPP amount retained on the NP surface. The catalyst testing in syngas conversion to methanol demonstrated outstanding catalytic properties of doped Zn-containing magnetic oxides, whose activities are dependent on the doping metal content and on the stabilizing polymer. The PPP stabilization allows for better access to the catalytic species due to the open and rigid polymer architecture and most likely optimized distribution of doping species. Repeat experiments carried out after magnetic separation of catalysts from the reaction mixture showed excellent catalyst stability even after five consecutive catalytic runs. PMID- 28029248 TI - Monoolein Cubic Phase Gels and Cubosomes Doped with Magnetic Nanoparticles-Hybrid Materials for Controlled Drug Release. AB - Hybrid materials consisting of a monoolein lipidic cubic phase (LCP) incorporating two types of magnetic nanoparticles (NP) were designed as addressable drug delivery systems. The materials, prepared in the form of a gel, were subsequently used as a macroscopic layer modifying an electrode and, after dispersion to nanoscale, as magnetocubosomes. These two LCPs were characterized by small-angle X-ray scattering (SAXS), cross-polarized microscopy, magnetic measurements, and phase diagrams. The magnetic dopants were hydrophobic NPoleic and hydrophilic NPcitric, characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and their influence on the properties of the cubic phases was investigated. The removal of the anticancer drug, Doxorubicin (Dox) from the hybrid cubic phase gels was studied by electrochemical methods. The advantages of incorporating magnetic nanoparticles into the self assembled lipid liquid crystalline phases include the ability to address the cubic phase nanoparticle containing large amounts of drug and to control the kinetics of the drug release. PMID- 28029249 TI - Structure and Function of AApeptides. AB - The intrinsic drawbacks encountered in bioactive peptides in chemical biology and biomedical sciences have diverted research efforts to the development of sequence specific peptidomimetics that are capable of mimicking the structure and function of peptides and proteins. Modifications in the backbone and/or the side chain of peptides have been explored to develop biomimetic molecular probes or drug leads for biologically important targets. To expand the family of oligomeric peptidomimetics to facilitate their further application, we recently developed a new class of peptidomimetics, AApeptides based on a chiral peptide nucleic acid backbone. AApeptides are resistant to proteolytic degradation and amenable to enormous chemical diversification. Moreover, they could mimic the primary structure of peptides and also fold into discrete secondary structure such as helices and turn-like structures. Furthermore, they have started to show promise in applications in material and biomedical sciences. Herein, we highlight the structural design and some function of AApeptides and present our perspective on their future development. PMID- 28029250 TI - Frutescone A-G, Tasmanone-Based Meroterpenoids from the aerial parts of Baeckea frutescens. AB - Frutescone A-G [(1-6), (+)-7, (-)-7], a new group of naturally occurring tasmanone-based meroterpenoids, were isolated from the aerial parts of Baeckea frutescens L. Compounds 1 and 4 featured a rare carbon skeleton with an unprecedented oxa-spiro[5.8] tetradecadiene ring system, existing as two favored equilibrating conformers in CDCl3 solution, identified by variable-temperature NMR. The regioselective syntheses of 4-7 were achieved in a concise manner by a biomimetically inspired key hetero-Diels-Alder reaction "on water". Compounds 1, 4, and 5 exhibited moderate cytotoxicities in vitro. PMID- 28029252 TI - Synthesis of Sulfonylated Lactones via Ag-Catalyzed Cascade Sulfonylation/Cyclization of 1,6-Enynes with Sodium Sulfinates. AB - A novel strategy for the synthesis of sulfonylated lactones via Ag-catalyzed radical addition/cyclization reaction of 1,6-enynes and sodium sulfinates has been developed. The reaction presents high stereoselectivity under mild conditions with C4 prochiral center construction in one step. The ESR experiments and relevant mechanistic studies indicated that a radical pathway should be involved in this transformation. PMID- 28029253 TI - Hydrogen Uptake by an Inclined Polycatenated Dynamic Metal-Organic Framework Based Material. AB - A 2D + 2D -> 3D inclined polycatenated dynamic metal-organic framework of {[Cu(4 bpe)(2-ntp)(H2O)2].2H2O}n [1, where 2-ntp2- = 2-nitroterephthalate and 4-bpe = 1,2-bis-(4-pyridyl)ethane] has been synthesized and characterized. The variable temperature powder X-ray diffraction study indicates the dynamic nature of the inclined polycatenated framework, and the dehydrated framework with exposed metal centers exhibits excellent type I H2 adsorption of 1.94 wt % at 77 K and 1 bar of pressure. PMID- 28029251 TI - Diversity of Secondary Structure in Catalytic Peptides with beta-Turn-Biased Sequences. AB - X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical beta-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H-1H-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions. PMID- 28029254 TI - PEGylated and Functionalized Aliphatic Polycarbonate Polyplex Nanoparticles for Intravenous Administration of HDAC5 siRNA in Cancer Therapy. AB - Guanidine and morpholine functionalized aliphatic polycarbonate polymers are able to deliver efficiently histone deacetylase 5 (HDAC5) siRNA into the cytoplasm of cancer cells in vitro leading to a decrease of cell proliferation were previously developed. To allow these biodegradable and biocompatible polyplex nanoparticles to overcome the extracellular barriers and be effective in vivo after an intravenous injection, polyethylene glycol chains (PEG750 or PEG2000) were grafted on the polymer structure. These nanoparticles showed an average size of about 150 nm and a slightly positive zeta-potential with complete siRNA complexation. Behavior of PEGylated and non-PEGylated polyplexes were investigated in the presence of serum, in terms of siRNA complexation (fluorescence correlation spectroscopy), size (dynamic light scattering and single-particle tracking), interaction with proteins (isothermal titration calorimetry) and cellular uptake. Surprisingly, both PEGylated and non-PEGylated formulations presented relatively good behavior in the presence of fetal bovine serum (FBS). Hemocompatibility tests showed no effect of these polyplexes on hemolysis and coagulation. In vivo biodistribution in mice was performed and showed a better siRNA accumulation at the tumor site for PEGylated polyplexes. However, cellular uptake in protein-rich conditions showed that PEGylated polyplex lost their ability to interact with biological membranes and enter into cells, showing the importance to perform in vitro investigations in physiological conditions closed to in vivo situation. In vitro, the efficiency of PEGylated nanoparticles decreases compared to non-PEGylated particles, leading to the loss of the antiproliferative effect on cancer cells. PMID- 28029255 TI - Engineering and Probing Topological Properties of Dirac Semimetal Films by Asymmetric Charge Transfer. AB - Dirac semimetals (DSMs) have topologically robust three-dimensional Dirac (doubled Weyl) nodes with Fermi-arc states. In heterostructures involving DSMs, charge transfer occurs at the interfaces, which can be used to probe and control their bulk and surface topological properties through surface-bulk connectivity. Here we demonstrate that despite a band gap in DSM films, asymmetric charge transfer at the surface enables one to accurately identify locations of the Dirac node projections from gapless band crossings and to examine and engineer properties of the topological Fermi-arc surface states connecting the projections, by simulating adatom-adsorbed DSM films using a first-principles method with an effective model. The positions of the Dirac-node projections are insensitive to charge transfer amount or slab thickness except for extremely thin films. By varying the amount of charge transfer, unique spin textures near the projections and a separation between the Fermi-arc states change, which can be observed by gating without adatoms. PMID- 28029256 TI - Conjugation to 10 kDa Linear PEG Extends Serum Half-Life and Preserves the Receptor-Binding Ability of mmTRAIL with Minimal Stimulation of PEG-Specific Antibodies. AB - The poor in vivo potencies of most therapeutic proteins might be attributed to their short serum half-lives. PEGylation is a well-established method and has been clinically proven to improve pharmacokinetics. mmTRAIL exhibited supercytotoxicity in a variety of tumor cells, but its serum half-life was less than 10 min in mice. Here, mmTRAIL-5K, mmTRAIL-10K, and mmTRAIL-20K were produced by N-terminus-specific PEGylation of mmTRAIL with 5, 10, or 20 kDa mPEG, respectively. The particle sizes of mmTRAIL-5K, mmTRAIL-10K, and mmTRAIL-20K were 9.09 +/- 2.76, 12.62 +/- 4.05, and 15.68 +/- 4.95 nm, which were higher than the threshold (~7 nm) of renal clearance. Accordingly, mmTRAIL-5K exhibited a serum half-life of 30 min only 3 times longer than that of mmTRAIL. However, both mmTRAIL-10K and mmTRAIL-20K exhibited similar serum half-lives ranging from 350 to 400 min, indicating that PEGylation with 10 or 20 kDa mPEG significantly improved the pharmacokinetics of mmTRAIL. However, death receptor binding of mmTRAIL-20K was reduced 5- to 8-fold, resulting in a 3-fold reduction of cytotoxicity. Additionally, repeated administration of mmTRAIL-20K elicited both mPEG-specific IgG and IgM antibody responses in rats. In contrast, the receptor binding and cytotoxicity of mmTRAIL-10K were similar to those of mmTRAIL. Repeated administration of mmTRAIL-10K did not obviously stimulate mPEG-specific antibody responses in rats and rhesus monkeys. Of the three PEGylated mmTRAIL analogues, mmTRAIL-10K exerted the greatest tumor suppression in mice bearing human tumor xenografts. These results demonstrated that conjugation of mmTRAIL to 10 kDa mPEG was better than that to 5 or 20 kDa mPEG for enhancing antitumor effects. PMID- 28029257 TI - Green Organocatalytic Synthesis of Isoxazolines via a One-Pot Oxidation of Allyloximes. AB - A green, sustainable, organocatalytic, and efficient synthesis of isoxazolines from allyloximes was developed. A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes, utilizing H2O2 as the green oxidant, was taken advantage of in order to introduce a cheap and environmentally friendly protocol for the synthesis of substituted isoxazolines. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in moderate to excellent yields. PMID- 28029258 TI - Liposomes for PET and MR Imaging and for Dual Targeting (Magnetic Field/Glucose Moiety): Synthesis, Properties, and in Vivo Studies. AB - We describe the potentiality of a new liposomal formulation enabling positron emission tomography (PET) and magnetic resonance MR() imaging. The bimodality is achieved by coupling a 68Ga-based radiotracer on the bilayer of magnetic liposomes. In order to enhance the targeting properties obtained under a permanent magnetic field, a sugar moiety was added in the lipid formulation. Two new phospholipids were synthesized, one with a specific chelator of 68Ga (DSPE PEG-NODAGA) and one with a glucose moiety (DSPE-PEG-glucose). The liposomes were produced according to a fast and safe process, with a high radiolabeling yield. MR and PET imaging were performed on mice bearing human glioblastoma tumors (U87MG) after iv injection. The accumulation of the liposomes in solid tumor is evidenced by MR imaging and the amount is evaluated in vivo and ex vivo according to PET imaging. An efficient magnetic targeting is achieved with these new magnetic liposomes. PMID- 28029260 TI - Cu(II) Ion-Responsive Self-Assembly Based on a Water-Soluble Pillar[5]arene and a Rhodamine B-Containing Amphiphile in Aqueous Media. AB - Cu(II) ion-responsive self-assembly in aqueous media was achieved based on a water-soluble pillar[5]arene host and a rhodamine B-containing amphiphile guest. The host-guest complex acted as a supra-amphiphile and self-assembled into vesicles. After addition of Cu(II), vesicles turned into solid nanoparticles, accompanied by the color change of the solution from colorless to red and a fluorescence "on" phenomenon. PMID- 28029259 TI - Contrasting Structural Reconstructions, Electronic Properties, and Magnetic Orderings along Different Edges of Zigzag Transition Metal Dichalcogenide Nanoribbons. AB - Two-dimensional transition metal dichalcogenides represent an emerging class of layered materials exhibiting various intriguing properties, and integration of such materials for potential device applications will necessarily invoke further reduction of their dimensionality. Using first-principles approaches, here we investigate the structural, electronic, and magnetic properties along the two different edges of zigzag MX2 (M = Mo, W; X = S, Se) nanoribbons. Along the M edges, we reveal a previously unrecognized but energetically strongly preferred (2 * 1) reconstruction pattern, which is universally operative for all the four systems (and possibly more), characterized by an elegant self-passivation mechanism through place exchanges of the outmost X and M edge atoms. In contrast, the X edges undergo a much milder (2 * 1) or (3 * 1) reconstruction for MoX2 or WX2, respectively. These contrasting structural preferences of the edges can be exploited for controlled fabrication of properly tailored transition metal dichalcogenide nanoribbons under nonequilibrium growth conditions. We further use the zigzag MoX2 nanoribbons to demonstrate that the Mo and X edges possess distinctly different electronic and magnetic properties, which are significant for catalytic and spintronic applications. PMID- 28029261 TI - Modeling the Effect of Monomer Conformational Change on the Early Stage of Protein Self-Assembly into Fibrils. AB - Filamentous self-assembly of proteins is an important process implicated in a plethora of human diseases and of interest for nanotechnology. Using rate equations, we analyze the early stage of the process in solutions that initially contain fibrillation-passive protein monomers and in which the nascent fibrils are practically insoluble. The analysis is based on a model accounting for the conformational and/or other changes the passive monomers experience to transform themselves into fibrillation-active monomers and thus become fibril nuclei. The model allows exact, comprehensive, and simple mathematical description of the early stage of fibrillation, which reveals the usually neglected role of the nucleation nonstationarity in this stage of fibrillation. We obtain exact and user-friendly expressions for experimentally accessible quantities such as the size distribution of fibrils, their number and mass concentrations, the rate and nonstationary period of fibril nucleation, and the delay time of fibril formation. Analyzing available experimental data, we find that the theory successfully describes the fibrillation time course of pathological and nonpathological ataxin-3, a protein involved in the neurodegenerative disorder spinocerebellar ataxia type-3. The analysis provides mechanistic insight into the reason for the higher fibril nucleation and elongation rates of the pathological ataxin-3. PMID- 28029262 TI - Photocurrent Switching of Monolayer MoS2 Using a Metal-Insulator Transition. AB - We achieve switching on/off the photocurrent of monolayer molybdenum disulfide (MoS2) by controlling the metal-insulator transition (MIT). N-type semiconducting MoS2 under a large negative gate bias generates a photocurrent attributed to the increase of excess carriers in the conduction band by optical excitation. However, under a large positive gate bias, a phase shift from semiconducting to metallic MoS2 is caused, and the photocurrent by excess carriers in the conduction band induced by the laser disappears due to enhanced electron-electron scattering. Thus, no photocurrent is detected in metallic MoS2. Our results indicate that the photocurrent of MoS2 can be switched on/off by appropriately controlling the MIT transition by means of gate bias. PMID- 28029263 TI - Commiphoranes A-D, Carbon Skeletal Terpenoids from Resina Commiphora. AB - Commiphoranes A-D (1-4), four novel aromatic terpenoids with unprecedented carbon skeletons, were isolated from Resina Commiphora. Their structures were identified by spectroscopic and crystallographic methods. Compounds 1 and 2 are dinorditerpenoids characteristic of a 6/6/6/6 ring system. In contrast, compounds 3 and 4 are sesquiterpenoids possessing a 5/6/7 backbone. Biological evaluation reveals that 3 could significantly attenuate overproduction of fibronectin, collagen I, and alpha-SMA in TGF-beta1-induced rat renal proximal tubular cells. PMID- 28029264 TI - Dahurelmusin A, a Hybrid Peptide-Polyketide from Elymus dahuricus Infected by the Epichloe bromicola Endophyte. AB - One novel hybrid peptide-polyketide, dahurelmusin A (1), was isolated from Elymus dahuricus infected by the Epichloe bromicola endophyte. Comprehensive spectroscopic analysis revealed that 1 is the first example of hybrid peptide polyketide possessing an unprecedented 5-hydroxy-2,2,4,6-tetramethyl-3 oxooctanoic acid moiety. The single-crystal X-ray diffraction analyses allowed the absolute configuration assignment of this compound. Compound 1 also exhibited significant insecticidal activities against Rhopalosiphum padi and Brevicoryne brassicae with LC50 values of 0.092 and 0.251 mM, respectively. PMID- 28029265 TI - Biomimetic Bubble-Repellent Tubes: Microdimple Arrays Enhance Repellency of Bubbles Inside of Tubes. AB - The adhesion of bubbles underwater remains the greatest cause of malfunctions in applications such as microfluidics, medical devices, and heat exchangers. Recently, the combination of oxidization and peeling the top layer of self organized honeycomb films with an adhesive tape resulted in the formation of an ultra-bubble-repellent and pillared polymer surface structure. However, the fabrication of honeycomb films on the inner surface of tubes and the formation of structured hydrophilic textures by peeling the top layer of honeycomb films still remain problematic. In this report, a simple fabrication technique for producing a honeycomb-patterned polymer film on the interior of a tube by dip-coating a polymer solution and blowing humid air in the tube is described. Furthermore, an ultra-bubble-repellent dimple-arrayed structure was fabricated by applying ultrasonication to the honeycomb structure formed on the interior surface of the tubes. PMID- 28029266 TI - Pain and discomfort during the first week of rapid maxillary expansion (RME) using two different RME appliances: A randomized controlled trial. AB - OBJECTIVES: To evaluate and compare perceived pain intensity, discomfort, and jaw function impairment during the first week with tooth-borne or tooth-bone-borne rapid maxillary expansion (RME) appliances. MATERIALS AND METHODS: Fifty-four patients (28 girls and 26 boys) with a mean age of 9.8 years (SD 1.28 years) were randomized into two groups. Group A received a conventional hyrax appliance and group B a hybrid hyrax appliance anchored on mini-implants in the anterior palate. Questionnaires were used to assess pain intensity, discomfort, analgesic consumption, and jaw function impairment on the first and fourth days after RME appliance insertion. RESULTS: Fifty patients answered both questionnaires. Overall median pain on the first day in treatment was 13.0 (range 0-82) and 3.5 (0-78) for groups A and B, respectively, with no significant differences in pain, discomfort, analgesic consumption, or functional jaw impairment between groups. Overall median pain on the fourth day was 9.0 (0-90) and 2.0 (0-71) for groups A and B, respectively, with no significant differences between groups. There were also no significant differences in pain levels within group A, while group B scored significantly lower concerning pain from molars and incisors and tensions from the jaw on day 4 than on the first day in treatment. There was a significant positive correlation between age and pain and discomfort on the fourth day in treatment. No correlations were found between sex and pain and discomfort, analgesic consumption, and jaw function impairment. CONCLUSIONS: Both tooth-borne and tooth-bone-borne RME were generally well tolerated by the patients during the first week of treatment. PMID- 28029267 TI - The pathological spectrum associated with the ultrastructural finding of thin glomerular basement membrane: A tertiary medical city experience and review of the literature. AB - BACKGROUND: Thin glomerular basement membrane (GBM) has been noted in several glomerular diseases including IgA nephropathy, focal segmental glomerulosclerosis (FSGS), Fabry's disease, and Alport's syndrome. We conducted this study to investigate the pathological ultrastructural spectrum of thin GBMs, to identify associated diseases, and to measure the GBM thickness in thin GBMs in our adult population. MATERIALS AND METHODS: All renal biopsies with thin GBM, diagnosed between 2010 and 2016, were retrieved and reviewed. RESULTS: Of 24 cases, 50.0% were diagnosed with FSGS, 12.5% with IgA nephropathy, 8.3% with tubulointerstitial nephritis, 4.2% with acute thrombotic microangiopathy, 4.2% with focal global sclerosis, 4.2% with lupus nephritis, and 16.7% with only thin GBM disease. Mean GBM thickness was 213.4 +/- 24.7 nm. Mean interstitial fibrosis/tubular atrophy percentage (IF/TA) was 27.9 +/- 22.2%. There was no significant correlation between GBM thickness and patients' age or IF/TA percentage. CONCLUSION: The association of thin GBM with FSGS and IgA nephropathy is high. Morphometric analysis of the GBM thickness should be made routine, noting that ethnic variations in the GBM thickness are reported. Cases of thin GBM should be reported to facilitate proper diagnosis and institute the most appropriate treatment. PMID- 28029268 TI - The second myocardial infarction: Higher risk factor burden and earlier second myocardial infarction in women compared with men. The Northern Sweden MONICA study. AB - BACKGROUND: Several studies have examined various parameters and experiences when patients suffer their first myocardial infarction (MI), but knowledge about when they suffer their second MI is limited. AIM: To compare risk factors for MI, that is, diabetes, hypertension and smoking, for the first and second MI events in men and women affected by two MIs and to analyse the time intervals between the first and second MIs. METHODS: A retrospective cohort study of 1017 patients aged 25-74 years with first and second MIs from 1990 through 2009 registered in the Northern Sweden MONICA registry. RESULTS: More women than men have diabetes and hypertension and are smokers at the first MI. Similar differences between the genders remain at the time of the second MI for diabetes and hypertension, although both risk factors have increased. Smoking decreased at the second MI without any remaining difference between genders. Women suffer their second MI within a shorter time interval than men do. Within 16 months of their first MI, 50% of women had a second MI. The corresponding time interval for men was 33 months. CONCLUSION: Patients affected by an MI should be made aware of their risk of recurrent MI and that the risk of recurrence is highest during the first few years after an MI. In patients affected by two MIs, women have a higher risk factor burden and suffer their second MI earlier than men do and thus may need more aggressive and more prompt secondary prevention. PMID- 28029269 TI - Vaginal birth after caesarean delivery in Chinese women and Western immigrants in Shanghai. AB - Recent studies show a steep rise in caesarean sections in China. Most couples are now eligible to apply for a second child. This retrospective cohort study compares the prevalence of trial of labour and vaginal birth after caesarean section among Chinese and foreign women in Shanghai. In total, 135 of 368 women underwent trial of labour (36.68%), and of those, 77 (57.04%) had a vaginal birth. After inclusion in a multivariate model, factors associated with trial of labour were maternal age <35 years with an adjusted odds ratio of 2.58 (1.49 4.46), absence of a history of >=3 abortions (2.22 (1.08-4.57)), and European citizenship (1.94 (1.05-3.59)). The prevalence of trial of labour and vaginal birth seems to mirror rates found in countries of origin, but despite a high rate of caesarean section, Chinese women had a higher rate of vaginal birth after caesarean section than North American and Australian women, in particular. Impact statement What is already known on this subject: Caesarean section (CS) rates are rising worldwide. Repeat CS contributes largely to these rates, although vaginal birth after CS (VBAC) rates varies widely between countries. What the results of this study add: North American and Australian women who deliver in Shanghai have low rates of attempted trial of labour after CS (TOLAC) and VBAC, with European women having the highest rate of TOLAC, followed by Chinese women. Implications for clinical practice and/or further research: These findings might reflect different levels of acceptance in line with respective national trends. Studies evaluating the influence of cultural norms on birth preferences after CS are needed. Further research is also needed to assess the overall acceptance of TOLAC in the context of the softening of the one-child policy in China. PMID- 28029270 TI - Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet? AB - Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing-remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS. PMID- 28029271 TI - Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients. AB - Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38-0.45) compared to controls (interquartile range = 0.29-0.38), similar to participants with SCA (interquartile range = 0.37-0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF. PMID- 28029272 TI - Therapeutic effect of mesenchymal stem cells on experimentally induced hypertensive cardiomyopathy in adult albino rats. AB - Hypertensive heart diseases affect millions of people worldwide. We aimed to investigate the hypertensive left ventricular histological changes and assess the effectiveness of bone marrow derived mesenchymal stem cells (MSCs) therapy in the treatment of hypertensive cardiomyopathy. Adult male albino rats were assigned into two groups: group I (control), group II (Experimental) subdivided into subgroup IIa (hypertensive) and subgroup IIb (stem cell therapy). Left ventricles (LVs) were processed for light and electron microscope. Mallory's trichrome and immunostaining for caspase-3 and desmin were carried out. Hypertension caused left ventricular histological and immunohistochemical changes that had been effectively improved by MSCs therapy. PMID- 28029274 TI - Prevalence of Victimization in Patients With Dual Diagnosis. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of victimization in patients with co-occurring mental health and substance use disorders (dual diagnosis) and compare them to the general population. METHODS: In this cross-sectional survey study conducted in the Netherlands, 9 different types of victimization (e.g., physical assault) were assessed with the Safety Monitor in patients with dual diagnosis (n = 243) and a sample of the general population (n = 10,865). Chi-square tests were used to compare patients with a weighted sample of the general population. RESULTS: Compared to the general population, patients with dual diagnosis were more likely to have been a victim of violence (60% vs. 11%), property crime (58% vs. 30%), and vandalism (21% vs. 14%) in the year preceding the assessment. Threats, sexual assault, physical assault, robbery, bicycle theft, other theft, and vandalism were more prevalent in patients with dual diagnosis compared to the general population. Car theft was more prevalent in the general population. The risk of burglary did not differ significantly between groups. CONCLUSIONS: Patients with dual diagnosis are highly prone to victimization. In patients with severe mental illness, victimization is associated with psychopathology, substance use, homelessness, and engagement in criminal activity. Future research is necessary to explore underlying mechanisms in patients with dual diagnosis and develop interventions to reduce their vulnerability for victimization. PMID- 28029273 TI - MRI-based mismatch detection in acute ischemic stroke: Optimal PWI maps and thresholds validated with PET. AB - Perfusion-weighted (PW) magnetic resonance imaging (MRI) is used to detect penumbral tissue in acute stroke, but the selection of optimal PW-maps and thresholds for tissue at risk detection remains a matter of debate. We validated the performance of PW-maps with 15O-water-positron emission tomography (PET) in a large comparative PET-MR cohort of acute stroke patients. In acute and subacute stroke patients with back-to-back MRI and PET imaging, PW-maps were validated with 15O-water-PET. We pooled two different cerebral blood flow (CBF) PET-maps to define the critical flow (CF) threshold, (i) quantitative (q)CBF-PET with the CF threshold <20 ml/100 g/min and (ii) normalized non-quantitative (nq)CBF-PET with a CF threshold of <70% (corresponding to <20 ml/100 g/min according to a previously published normogram). A receiver operating characteristic (ROC) curve analysis was performed to specify the accuracy and the optimal critical flow threshold of each PW-map as defined by PET. In 53 patients, (stroke to imaging: 9.8 h; PET to MRI: 52 min) PW-time-to-maximum (Tmax) with a threshold >6.1 s (AUC = 0.94) and non-deconvolved PW-time-to-peak (TTP) >4.8 s (AUC = 0.93) showed the best performance to detect the CF threshold as defined by PET. PW-Tmax with a threshold >6.1 s and TTP with a threshold >4.8 s are the most predictive in detecting the CF threshold for MR-based mismatch definition. PMID- 28029275 TI - Oligodendroglial cell proliferation arising in an ovarian mature cystic teratoma. Clinicopathological, inmunohistochemical, and ultrastructural study of a case that may represent an oligodendroglioma. AB - Ovarian mature cystic teratoma (OMCT) is an ovarian benign neoplasm with excellent prognosis presenting components of the three germinal layers. However, transformation into a malignant neoplasm is a rare event (so-called somatic transformation). In most of the cases, the malignant component expresses as epidermoid carcinoma, but occasionally central nervous system tumors occur. Some of the previously reported tumors are astrocytoma, glioblastoma, and ependymoma. Somatic transformation of OMCT into an oligodendroglioma is exceptional. We report a 19-year-old female with a left OMCT with an area of oligonedroglial cells proliferation characterized by immunohistochemical studies with positivity for GFAP and S100, with a low Ki67 index (5%). Additionally, electron microscopy revealed oligodendrocytes with parallel bundles of cytoplasmic intermediate filaments, confirming the oligodendroglial nature of the proliferation. The patient was treated only with left oophorectomy, and three and half years after surgery, there is no evidence of disease. PMID- 28029276 TI - Response to Miccio-Fonseca (2015) and Defeo (2015) Concerning Commentary About DSM-5 Sexual Disorders Section. AB - Responses by Miccio-Fonseca (2015) and DeFeo (2015) to a commentary by Ross on problems with the sexual disorders sections of DSM-5 are based on a misunderstanding of Ross's article (2015a). Miccio-Fonseca and DeFeo describe what they consider to be confusion and misunderstanding in Ross's opinions about gender, sexuality, and related topics. However, Ross offered no personal opinions in his commentary and was focused solely on inconsistencies and contradictions within DSM-III, DSM-IV, and DSM-5. PMID- 28029277 TI - Local context effects during emotional item directed forgetting in younger and older adults. AB - This paper explored the differential sensitivity young and older adults exhibit to the local context of items entering memory. We examined trial-to-trial performance during an item directed forgetting task for positive, negative, and neutral (or baseline) words each cued as either to-be-remembered (TBR) or to-be forgotten (TBF). This allowed us to focus on how variations in emotional valence (independent of arousal) and instruction (TBR vs. TBF) of the previous item (trial n-1) impacted memory for the current item (trial n) during encoding. Different from research showing impairing effects of emotional arousal, both age groups showed a memorial boost for stimuli when preceded by items high in positive or negative valence relative to those preceded by neutral items. This advantage was particularly prominent for neutral trial n items that followed emotional items suggesting that, regardless of age, neutral memories may be strengthened by a local context that is high in valence. A trending age difference also emerged with older adults showing greater sensitivity when encoding instructions changed between trial n-1 and n. Results are discussed in light of age-related theories of cognitive and emotional processing, highlighting the need to consider the dynamic, moment-to-moment fluctuations of these systems. PMID- 28029278 TI - A novel trimeric complex in plant cells that contributes to the lamina inclination of rice. AB - The architecture determining grain production in rice is mainly affected by factors such as lamina angle, tillering, plant height and panicle morphology. In particular, leaf angle, the degree of bending between the leaf blade and leaf sheath directly affects crop architecture and grain yields. Balancing activities between the 2 antagonistic groups of proteins, atypical helix-loop-helix (HLH) and basic HLH (bHLH) proteins have been regarded as one of the major molecular machineries regulating lamina angles through the control of cell elongation in the lamina joint of rice. Recently, formation of a complex consisting of atypical HLH protein, OsBUL1, a KxDL motif-containing protein, LO9-177 and a bHLH protein, OsBC1 has been reported to play a positive role in lamina inclination of rice unraveling a novel layer of cell elongation control in rice lamina joint. Here, we demonstrate a trimeric complex formation in rice cells by a combination of BiFC and FRET-FLIM assays. PMID- 28029279 TI - Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold. AB - Recent years have seen a proliferation of methods leading to successful organ decellularization. In this experiment we examine the feasibility of a decellularized liver construct to support growth of functional multilineage cells. Bio-chamber systems were used to perfuse adult rat livers with 0.1% SDS for 24 hours yielding decellularized liver scaffolds. Initially, we recellularized liver scaffolds using a human tumor cell line (HepG2, introduced via the bile duct). Subsequent studies were performed using either human tumor cells co-cultured with human umbilical vein endothelial cells (HUVECs, introduced via the portal vein) or rat neonatal cell slurry (introduced via the bile duct). Bio-chambers were used to circulate oxygenated growth medium via the portal vein at 37C for 5-7 days. Human HepG2 cells grew readily on the scaffold (n = 20). HepG2 cells co-cultured with HUVECs demonstrated viable human endothelial lining with concurrent hepatocyte growth (n = 10). In the series of neonatal cell slurry infusion (n = 10), distinct foci of neonatal hepatocytes were observed to repopulate the parenchyma of the scaffold. The presence of cholangiocytes was verified by CK-7 positivity. Quantitative albumin measurement from the grafts showed increasing albumin levels after seven days of perfusion. Graft albumin production was higher than that observed in traditional cell culture. This data shows that rat liver scaffolds support human cell ingrowth. The scaffold likewise supported the engraftment and survival of neonatal rat liver cell slurry. Recellularization of liver scaffolds thus presents a promising model for functional liver engineering. PMID- 28029280 TI - Biomechanics of an orthosis-managed cranial cruciate ligament-deficient canine stifle joint predicted by use of a computer model. AB - OBJECTIVE To evaluate effects of an orthosis on biomechanics of a cranial cruciate ligament (CrCL)-deficient canine stifle joint by use of a 3-D quasistatic rigid-body pelvic limb computer model simulating the stance phase of gait and to investigate influences of orthosis hinge stiffness (durometer). SAMPLE A previously developed computer simulation model for a healthy 33-kg 5 year-old neutered Golden Retriever. PROCEDURES A custom stifle joint orthosis was implemented in the CrCL-deficient pelvic limb computer simulation model. Ligament loads, relative tibial translation, and relative tibial rotation in the orthosis stabilized stifle joint (baseline scenario; high-durometer hinge]) were determined and compared with values for CrCL-intact and CrCL-deficient stifle joints. Sensitivity analysis was conducted to evaluate the influence of orthosis hinge stiffness on model outcome measures. RESULTS The orthosis decreased loads placed on the caudal cruciate and lateral collateral ligaments and increased load placed on the medial collateral ligament, compared with loads for the CrCL-intact stifle joint. Ligament loads were decreased in the orthosis-managed CrCL deficient stifle joint, compared with loads for the CrCL-deficient stifle joint. Relative tibial translation and rotation decreased but were not eliminated after orthosis management. Increased orthosis hinge stiffness reduced tibial translation and rotation, whereas decreased hinge stiffness increased internal tibial rotation, compared with values for the baseline scenario. CONCLUSIONS AND CLINICAL RELEVANCE Stifle joint biomechanics were improved following orthosis implementation, compared with biomechanics of the CrCL-deficient stifle joint. Orthosis hinge stiffness influenced stifle joint biomechanics. An orthosis may be a viable option to stabilize a CrCL-deficient canine stifle joint. PMID- 28029281 TI - Pharmacokinetics of intravenous continuous rate infusions of sodium benzylpenicillin and ceftiofur sodium in adult horses. AB - OBJECTIVE To determine plasma drug concentrations after IV administration of a bolus followed by continuous rate infusion (CRI) of sodium benzylpenicillin and ceftiofur sodium to healthy adult horses. ANIMALS 6 Thoroughbred mares (3 to 9 years old; mean +/- SD body weight, 544 +/- 55 kg) with no history of recent antimicrobial treatment. PROCEDURES Horses were used in 2 experiments conducted 14 days apart. For each experiment, horses were housed individually in stables, and catheters were placed bilaterally in both jugular veins for drug administration by CRI (left catheter) and for intermittent collection of blood samples (right catheter). Synovial fluid samples were obtained from carpal joints following ceftiofur administration to evaluate drug diffusion into articular spaces. RESULTS Plasma concentrations above accepted minimum inhibitory concentrations for common pathogens of horses were achieved within 1 minute after bolus administration and remained above the minimum inhibitory concentration for 48 (ceftiofur) or 12 (benzylpenicillin) hours (ie, the duration of the CRI). Mean synovial fluid ceftiofur free acid equivalent concentrations were approximately 46% (range, 25.4% to 59.8%) of plasma concentrations at the end of infusion. CONCLUSIONS AND CLINICAL RELEVANCE Compared with intermittent bolus administration, the loading dose and CRI used less drug but maintained high plasma concentrations for the duration of infusion. By use of pharmacological parameters derived in this study, a loading dose of 2.5 mg/kg and CRI of 200 MUg/kg/h should achieve plasma ceftiofur concentrations of 4 MUg/mL; a loading dose and CRI of 1.3 mg/kg and 2.5 MUg/kg/h, respectively, should achieve plasma benzylpenicillin concentrations of 2 MUg/mL. PMID- 28029282 TI - Assessment of eosinophil peroxidase as a potential diagnostic and prognostic marker in dogs with inflammatory bowel disease. AB - OBJECTIVE To evaluate a method for identifying intact and degranulated eosinophils in the small intestine of dogs with inflammatory bowel disease (IBD) by use of a monoclonal antibody (mAb) against eosinophil peroxidase (EPX). ANIMALS 11 untreated dogs with IBD, 5 dogs with IBD treated with prednisolone, and 8 control dogs with no clinical evidence of gastrointestinal tract disease and no immunosuppressive treatment. PROCEDURES 4-MUm-thick sections of paraffin embedded tissues from necropsy specimens were immunostained with EPX mAb. Stained intact and degranulated eosinophils in consecutive microscopic fields (400X magnification) of the upper (villus tips) and lower (between the muscularis mucosae and crypts) regions of the lamina propria of the jejunum were manually counted. RESULTS Compared with control and treated IBD dogs, untreated IBD dogs had a significantly higher number of degranulated eosinophils in the lower region of the lamina propria. However, no significant differences were detected in the number of intact eosinophils in this region among groups. In the upper region of the lamina propria, untreated IBD dogs had a significantly higher number of degranulated and intact eosinophils, compared with control and treated IBD dogs. Number of degranulated and intact eosinophils did not differ significantly between control and treated IBD dogs. CONCLUSIONS AND CLINICAL RELEVANCE Immunohistologic analysis with EPX mAb yielded prominent granule staining that allowed reliable morphological identification of degranulated and intact eosinophils, which may provide a strategy for quantitative and selective evaluation of eosinophils in gastrointestinal biopsy specimens and a potential method to diagnose IBD and evaluate treatment outcome. PMID- 28029285 TI - Effect of fentanyl and lidocaine on the end-tidal sevoflurane concentration preventing motor movement in dogs. AB - OBJECTIVE To determine effects of fentanyl, lidocaine, and a fentanyl-lidocaine combination on the minimum alveolar concentration of sevoflurane preventing motor movement (MACNM) in dogs. ANIMALS 6 adult Beagles. PROCEDURES Dogs were anesthetized with sevoflurane in oxygen 3 times (1-week intervals). Baseline MACNM (MACNM-B) was determined starting 45 minutes after induction of anesthesia. Dogs then received 1 of 3 treatments IV: fentanyl (loading dose, 15 MUg/kg; constant rate infusion [CRI], 6 MUg/kg/h), lidocaine (loading dose, 2 mg/kg; CRI, 6 mg/kg/h), and the fentanyl-lidocaine combination at the same doses. Determination of treatment MACNM (MACNM-T) was initiated 90 minutes after start of the CRI. Venous blood samples were collected at the time of each treatment MACNM measurement for determination of plasma concentrations of fentanyl and lidocaine. RESULTS Mean +/- SEM overall MACNM-B for the 3 treatments was 2.70 +/- 0.27 vol%. The MACNM decreased from MACNM-B to MACNM-T by 39%, 21%, and 55% for fentanyl, lidocaine, and the fentanyl-lidocaine combination, respectively. This decrease differed significantly among treatments. Plasma fentanyl concentration was 3.25 and 2.94 ng/mL for fentanyl and the fentanyl-lidocaine combination, respectively. Plasma lidocaine concentration was 2,570 and 2,417 ng/mL for lidocaine and the fentanyl-lidocaine combination, respectively. Plasma fentanyl and lidocaine concentrations did not differ significantly between fentanyl and the fentanyl-lidocaine combination or between lidocaine and the fentanyl lidocaine combination. CONCLUSIONS AND CLINICAL RELEVANCE CRIs of fentanyl, lidocaine, and the fentanyl-lidocaine combination at the doses used were associated with clinically important and significant decreases in the MACNM of sevoflurane in dogs. PMID- 28029283 TI - Evaluation of procoagulant tissue factor expression in canine hemangiosarcoma cell lines. AB - OBJECTIVE To evaluate expression of procoagulant tissue factor (TF) by canine hemangiosarcoma cells in vitro. SAMPLES 4 canine hemangiosarcoma cell lines (SB HSA [mouse-passaged cutaneous tumor], Emma [primary metastatic brain tumor], and Frog and Dal-1 [primary splenic tumors]) and 1 nonneoplastic canine endothelial cell line (CnAoEC). PROCEDURES TF mRNA and TF antigen expression were evaluated by quantitative real-time PCR assay and flow cytometry, respectively. Thrombin generation was measured in canine plasma and in coagulation factor-replete or specific coagulation factor-deficient human plasma by calibrated automated thrombography. Corn trypsin inhibitor and annexin V were used to examine contributions of contact activation and membrane-bound phosphatidylserine, respectively, to thrombin generation. RESULTS All cell lines expressed TF mRNA and antigen, with significantly greater expression of both products in SB-HSA and Emma cells than in CnAoEC. A greater percentage of SB-HSA cells expressed TF antigen, compared with other hemangiosarcoma cell lines. All hemangiosarcoma cell lines generated significantly more thrombin than did CnAoEC in canine or factor replete human plasma. Thrombin generation induced by SB-HSA cells was significantly lower in factor VII-deficient plasma than in factor-replete plasma and was abolished in factor X-deficient plasma; residual thrombin generation in factor VII-deficient plasma was abolished by incubation of cells with annexin V. Thrombin generation by SB-HSA cells was unaffected by the addition of corn trypsin inhibitor. CONCLUSIONS AND CLINICAL RELEVANCE Hemangiosarcoma cell lines expressed procoagulant TF in vitro. Further research is needed to determine whether TF can be used as a biomarker for hemostatic dysfunction in dogs with hemangiosarcoma. PMID- 28029286 TI - Survivability of Mycobacterium bovis on salt and salt-mineral blocks fed to cattle. AB - OBJECTIVE To determine the survivability of Mycobacterium bovis on salt and salt mineral blocks in typical weather conditions in Michigan over two 12-day periods at the height of summer and winter. SAMPLE 4 salt (NaCl) and 4 salt-mineral blocks inoculated with pure cultures of a strain of M bovis currently circulating in Michigan livestock and wildlife. PROCEDURES In the summer and again in the winter, inoculated blocks were placed in secured outdoor facilities where equal numbers of each block type (2/type/season) were exposed to shade or sunlight. Samples were collected from randomly selected areas on the surface of each block beginning within 1 hour after placement (day 0) twice a day for the first 4 days and once a day from days 7 through 11. Bacterial culture of samples was performed to detect viable M bovis. RESULTS Depending on the exposure conditions, salt blocks yielded viable M bovis for up to 2 days after inoculation and salt-mineral blocks yielded viable M bovis for > 3 days. Survival time was greatest on salt mineral blocks kept outdoors in the shade during the winter. The odds of recovering viable M bovis from salt-mineral block samples were 4.9 times as great during the winter (vs the summer) and 3.0 times as great with exposure to shade (vs sunlight). CONCLUSIONS AND CLINICAL RELEVANCE Results from this study indicated that salt and salt-mineral blocks should be considered potential sources of bovine tuberculosis when designing risk mitigation programs for cattle herds in areas with wildlife reservoirs of M bovis. PMID- 28029288 TI - Effects of prophylactic incisional gastropexy on markers of gastric motility in dogs as determined by use of a novel wireless motility device. AB - OBJECTIVE To evaluate effects of laparoscopic-assisted incisional gastropexy (LAIG) on gastric motility in dogs by use of a wireless motility device (WMD). ANIMALS 10 healthy client-owned large or giant-breed dogs. PROCEDURES 10 dogs owned by clients interested in prophylactic LAIG were enrolled. To determine effects of LAIG on gastrointestinal motility in dogs during the nonfed state, each dog was evaluated by use of a noninvasive WMD before and > 4 weeks after LAIG. All dogs underwent LAIG, with or without concurrent elective gonadectomy. Data obtained before and after LAIG were analyzed by use of proprietary software to determine the gastric emptying time, small bowel transit time, large bowel transit time, whole bowel transit time, and motility index. RESULTS No changes in variables were detected between measurements obtained before and after prophylactic LAIG. CONCLUSIONS AND CLINICAL RELEVANCE In this study, prophylactic LAIG did not have an effect on gastrointestinal motility. The WMD was tolerated well by all dogs and appeared to be a safe and effective method for evaluating gastrointestinal motility in this population of dogs. PMID- 28029289 TI - Effects of diurnal variation and anesthetic agents on intraocular pressure in Syrian hamsters (Mesocricetus auratus). AB - OBJECTIVE To determine effects of diurnal variation and anesthetic agents on intraocular pressure (IOP) in Syrian hamsters (Mesocricetus auratus). ANIMALS 90 healthy adult Syrian hamsters (45 males and 45 females). PROCEDURES IOP was measured with a rebound tonometer. In phase 1, IOP was measured in all hamsters 3 times during a 24-hour period (7 am, 3 pm, and 11 pm). In phase 2, hamsters were assigned to 5 groups (18 animals [9 males and 9 females]/group). Each group received an anesthetic agent or combination of anesthetic agents (ketamine hydrochloride, xylazine hydrochloride, diazepam, ketamine-diazepam [KD], or ketamine-xylazine [KX] groups) administered via the IP route. The IOP was measured before (time 0 [baseline]) and 10, 30, 60, 90, 120, and 150 minutes after administration of drugs. RESULTS Mean +/- SD IOP values were 2.58 +/- 0.87 mm Hg, 4.46 +/- 1.58 mm Hg, and 5.96 +/- 1.23 mm Hg at 7 am, 3 pm, and 11 pm, respectively. Mean baseline IOP was 6.25 +/- 0.28 mm Hg, 6.12 +/- 0.23 mm Hg, 5.75 +/- 0.64 mm Hg, 5.12 +/- 1.40 mm Hg, and 4.50 +/- 1.30 mm Hg for the ketamine, xylazine, diazepam, KD, and KX groups, respectively. A significant decrease in IOP, compared with baseline IOP, was detected in only the KX group at 30, 60, and 90 minutes after drug administration. CONCLUSIONS AND CLINICAL RELEVANCE Maximum IOP in Syrian hamsters was detected at night. The ketamine xylazine anesthetic combination significantly decreased IOP in Syrian hamsters. PMID- 28029290 TI - High-resolution melting analysis for detection of a single-nucleotide polymorphism and the genotype of the myostatin gene in warmblood horses. AB - OBJECTIVE To develop a high-resolution melting (HRM) assay to detect the g.66493737C>T polymorphism in the myostatin gene (MSTN) and determine the frequency of 3 previously defined g.66493737 genotypes (T/T, T/C, and C/C) in warmblood horses. SAMPLES Blood samples from 23 horses. PROCEDURES From each blood sample, DNA was extracted and analyzed by standard PCR methods and an HRM assay to determine the MSTN genotype. Three protocols (standard protocol, protocol in which a high-salt solution was added to the reaction mixture before the first melting cycle, and protocol in which an unlabeled probe was added to the reaction mixture before analysis) for the HRM assay were designed and compared. Genotype results determined by the HRM protocol that generated the most consistent melting curves were compared with those determined by sequencing. RESULTS The HRM protocol in which an unlabeled probe was added to the reaction mixture generated the most consistent melting curves. The genotypes of the g.66493737C>T polymorphism were determined for 22 horses (16 by HRM analysis and 20 by sequencing); 14, 7, and 1 had the T/T, T/C, and C/C genotypes, respectively. The genotype determined by HRM analysis agreed with that determined by sequencing for 14 of 16 horses. The frequency of alleles T and C was 79.5% and 20.5%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HRM analysis may be a faster and more economical alternative than PCR methods for genotyping. Genotyping results might be useful as predictors of athletic performance for horses. PMID- 28029291 TI - Evaluation of gastroscopy and biopsy of the proventriculus and ventriculus in pigeons (Columba livia). AB - OBJECTIVE To evaluate the efficacy and safety of gastroscopy and biopsy of the proventriculus and ventriculus in pigeons (Columba livia). ANIMALS 15 adult pigeons. PROCEDURES Each pigeon was anesthetized, and the upper gastrointestinal tract (from the cervical portion of the esophagus to the ventriculus) was endoscopically evaluated by use of a rigid endoscope inserted orally. Saline (0.9% NaCl) solution was orally infused to achieve lumen dilation and visibility. Two mucosal biopsy specimens were collected from each of the proventriculus and ventriculus, histologically evaluated, and graded for crush artifacts and depth. Pigeons were monitored for adverse effects for 3 to 6 days after the procedure, after which they were euthanized for necropsy. RESULTS Gastroscopy via the oral approach provided excellent visibility of the lumen and mucosal surfaces of the proventriculus and cranial portion of the ventriculus and was safe provided that appropriate precautions were taken. Two intraoperative deaths occurred at the beginning of the study; following procedure refinement, no additional deaths occurred. No major adverse effects of the procedure were detected in the remaining 13 pigeons during the postoperative monitoring period or at necropsy. Diagnostic quality of proventriculus specimens was adequate for 10 of 13 pigeons. Eight of 13 ventriculus specimens were of inadequate quality, and only 3 were of adequate quality. CONCLUSIONS AND CLINICAL RELEVANCE Gastroscopy was useful for evaluating the lumen and mucosal surface of the proventriculus and ventriculus in pigeons, and biopsy of those organs was safely performed with the appropriate technique. Further evaluation of these techniques is needed in birds with clinical disease and birds of other species. PMID- 28029292 TI - Ability of clinicopathologic variables and clinical examination findings to predict race elimination in endurance horses. AB - OBJECTIVE To compare results of point-of-care laboratory testing with standard veterinary clinical examination findings at a single time point during endurance competition to identify horses at risk for elimination. ANIMALS 101 endurance horses participating in the 2013 Western States 160-km (100-mile) endurance ride. PROCEDURES At the 58-km checkpoint, blood samples were collected from all horses. Samples were analyzed for pH, Pco2, base excess, anion gap, PCV, and whole blood concentrations of sodium, potassium, chloride, total carbon dioxide, BUN, glucose, and bicarbonate. Corrected electrolyte and PCV values were calculated on the basis of plasma total protein concentration. Immediately following the blood sample collection, each horse underwent a clinical examination. In addition to standard examination variables, an adjusted heart rate was calculated on the basis of the variable interval between entry into the checkpoint and heart rate recording. A combination of stepwise logistic regression, classification and regression tree analysis, and generalized additive models was used to identify variables that were associated with overall elimination or each of 3 other elimination categories (metabolic elimination, lameness elimination, and elimination for other reasons). RESULTS Corrected whole blood potassium concentration and adjusted heart rate were predictive for overall elimination. Breed, plasma total protein concentration, and attitude were predictive for elimination due to metabolic causes. Whole blood chloride concentration and corrected PCV were predictive for elimination due to lameness. Corrected PCV was predictive for elimination due to other causes. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that for horses in endurance competition, a combination of breed and clinical examination and laboratory variables provided the best prediction of overall elimination. PMID- 28029293 TI - Pharmacokinetics of terbinafine in little brown myotis (Myotis lucifugus) infected with Pseudogymnoascus destructans. AB - OBJECTIVE To determine the pharmacokinetics of terbinafine in little brown myotis (Myotis lucifugus) infected with Pseudogymnoascus destructans. ANIMALS 123 bats from a P destructans-infected hibernation site in Virginia. PROCEDURES 3 bats were euthanized and necropsied to confirm the presence of P destructans within the population. The remaining 120 bats were systematically assigned to 6 groups (20 bats/group). Bats in each of 3 groups received 6, 20, or 60 mg of terbinafine/kg, SC, once daily for 10 days. Bats in another group received 200 mg of terbinafine/kg, SC, once daily for 5 days. Bats in 1 group received the terbinafine vehicle solution (0.1 mL/kg, SC, once daily for 10 days). Bats in the remaining group did not receive any treatment. Following the treatment period (days 1 through 10), bats were housed in a hibernation chamber and monitored daily until euthanasia on day 42, 75, or 109. Tissue specimens were collected from all bats as soon as possible after death or euthanasia to determine terbinafine concentration. Within each group and tissue type, terbinafine concentration data were pooled, and pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS Adverse neurologic effects and a high mortality rate before day 10 were observed in bats that received the highest terbinafine dose (200 mg/kg) but not those that received lower doses. Presumed therapeutic terbinafine concentrations (>= 2 MUg/g) were maintained in skin and wing for at least 30 and 6 days in bats that received the 60 and 20 mg/kg doses, respectively, but were not achieved in most bats that received the 6 mg/kg dose. Tissue terminal half-life ranged from 14 to 22 days. Terbinafine concentration in hair was positively correlated with that in skin and wing. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated terbinafine doses > 6 but < 200 mg/kg should be further evaluated for the treatment of P destructans-infected bats. Collection of serial hair specimens may represent a noninvasive method for monitoring terbinafine concentration in treated bats. PMID- 28029294 TI - Corneal thickness of eyes of healthy goats, sheep, and alpacas manually measured by use of a portable spectral-domain optical coherence tomography device. AB - OBJECTIVE To determine corneal thickness of eyes of healthy goats, sheep, and alpacas by use of a portable spectral-domain optical coherence tomography (SD OCT) device and evaluate intraoperator reliability for measurements. ANIMALS 11 female goats, 10 female sheep, and 11 (4 males and 7 females) alpacas. PROCEDURES Each animal was sedated, and gentle manual restraint was used to ensure proper positioning of the head and globe. Corneal pachymetry was performed (in triplicate) with a portable SD-OCT device on both eyes of each animal. All corneal measurements were obtained manually by use of the integrated caliper function. Corneal epithelial thickness (CET), corneal stromal thickness (CST), Descemet membrane thickness (DMT), and total corneal thickness (TCT) were measured twice on each image, and a mean value was calculated. RESULTS Mean +/- SD values for CET, CST, DMT, and TCT were 96.1 +/- 5.0 MUm, 486.0 +/- 10.3 MUm, 36.8 +/- 4.8 MUm, and 616.9 +/- 7.1 MUm, respectively, for the goats; 111.6 +/- 5.7 MUm, 599.8 +/- 10.0 MUm, 31.0 +/- 4.5 MUm, and 741.1 +/- 9.9 MUm, respectively, for the sheep; and 147.4 +/- 5.7 MUm, 446.1 +/- 7.4 MUm, 44.5 +/- 5.0 MUm, and 634.8 +/- 6.2 MUm, respectively, for the alpacas. Intraclass correlations ranged from 0.49 to 0.83 for CET, CST, and TCT and from 0.13 to 0.36 for DMT. CONCLUSIONS AND CLINICAL RELEVANCE SD-OCT provided manual measurement of corneal thickness (CET, CST, and TCT) with clinically acceptable intraoperator reliability for eyes of healthy goats, sheep, and alpacas. PMID- 28029295 TI - Effectiveness of manual bladder expression in paraplegic dogs. AB - OBJECTIVE To determine the effectiveness of manual bladder expression in paraplegic dogs by comparing urine volumes measured by use of intermittent catheterization and ultrasonography. ANIMALS 36 paraplegic dogs. PROCEDURES 93 measurements of bladder volume were collected for the 36 dogs. Residual urine volume was determined by use of intermittent urethral catheterization and estimated by use of ultrasonography. RESULTS Manual bladder expression voided a mean of 49% of urine from the bladder in this population of dogs. There was no correlation (R2, 0.06) between the effectiveness of manual bladder expression and body weight. Ultrasonographic estimation of bladder volume had good correlation (R2, 0.62) with bladder volume determined by use of intermittent bladder catheterization, but clinically unacceptable variation for predicting actual bladder volume (mean difference, 22 mL; 95% confidence interval, -96 to 139 mL). CONCLUSIONS AND CLINICAL RELEVANCE Manual bladder expression was ineffective at completely emptying urine from the bladder of paraplegic dogs, but the effectiveness of the procedure was not affected by body weight. Manual bladder expression would likely be a useful procedure to prevent increases in pressure within the bladder. Ultrasonographic estimation of bladder volume could be a useful predictor of actual bladder volume, but it was susceptible to wide variations among dogs, and results should therefore be interpreted with caution. PMID- 28029296 TI - Characterization of Kewda volatile components by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. AB - Kewda (Pandanus fascicularis Lam.) is a well known medicinal and aromatic plant. The paper aims to precisely characterize volatile constituents present in Kewda flower oil using comprehensive two-dimensional gas chromatography coupled to time of flight mass spectrometry (GCxGC-TOFMS). A total of 159 components were identified due to enhanced chromatographic separation and mass spectral deconvolution of GCxGC-TOFMS. On the basis of its chemical structure, the identified compounds were grouped into hydrocarbons, alcohols, ethers, ketones, esters, nitrogen compounds, aldehydes, acids, lactones, halides and sulfur containing compounds. Ethers were the major components. The predominant compounds identified by GCxGC-TOFMS were kewda ether, ortho-cymene and terpinen-4-ol. A database containing retention indices of compounds was created for the bi dimensional column, thus proving to be a remarkable step for analysis of constituents using a GCxGC system. GCxGC-TOFMS separated a number of co-eluting components which were unresolved on a single GC column. PMID- 28029297 TI - Capturing High-Value Cancer Care in the Wild. PMID- 28029298 TI - Unintended Consequences in Cancer Care Delivery Created by the Medicare Part B Proposal: Is the Clinical Rationale for the Experiment Flawed? AB - PURPOSE: Medicare currently enrolls >= 45 million adults, and by 2030 this is projected to increase to >= 80 million beneficiaries. With this growth, the Centers for Medicare & Medicaid Services (CMS) issued a proposal, the Medicare Part B Drug Payment Model, to shrink drug expenditures, a major contributor to overall health care costs. For this to not adversely affect patient outcomes, lower-cost alternative medications with equivalent efficacy and no increased toxicity must be available. This is often not true in the treatment of cancer. Herein, we examine the flaws in the rationale of the CMS and the potential unintended consequences of this experiment. METHODS: We identified the top three oncology expenditures (rituximab, bevacizumab, and trastuzumab) and their vetted alternatives (per the National Comprehensive Cancer Network guidelines) to ascertain whether lower-cost equivalent alternatives are available. Drug cost was based on April 2016 average sale price. We explored both efficacy of the agents and, when applicable, toxicity to compare alternatives to these high-dollar medications. RESULTS: For the largest Medicare oncology drug expenditures, there is not a lower-cost option with equal efficacy for their primary indications. Without lower-cost alternatives, the unintended consequence of this CMS experiment may include curtailing access to care or an increase in patient/program costs. CONCLUSION: The CMS proposal, by simply lowering reimbursement for drugs, does not acknowledge the value of these agents and could unintentionally reduce quality of care. Alternative approaches to value-based care, such as the Oncology Care Model and similar frameworks, should be explored. PMID- 28029299 TI - Establishing a Core Set of Performance Measures to Improve Value in Cancer Care: ASCO Consensus Conference Recommendation Report. PMID- 28029300 TI - Hospice Utilization and Its Effect on Acute Care Needs at the End of Life in Medicare Beneficiaries With Hepatocellular Carcinoma. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is a poor-prognosis cancer with a high symptom burden. Multidisciplinary HCC care is complex and unique in cancer medicine. We sought to determine whether the distinct process affects hospice use and how hospice affects end-of-life acute care utilization. PATIENTS AND METHODS: Patients dying after HCC diagnosed from 2004 to 2011 were identified within SEER Medicare. Hospice use and associated factors were described using logistic regression. Coarse exact and propensity score matching created groups of hospice and nonhospice comparators balanced on clinical characteristics. Health care use from first hospice claim to death and the matched duration in the nonhospice group were compared. RESULTS: Of 7,992 decedent patients with HCC, 63% used hospice before death, with a median duration of 18 days (interquartile range, 5 51 days). Initial treatment with surgery and ablation (odds ratio [OR], 0.63; 95% CI, 0.53 to 0.74) or chemoembolization/radioembolization (OR, 0.71; 95% CI, 0.62 to 0.80) was associated with decreased odds of subsequent hospice use compared with untreated patients. Hospice use was more likely in those consulting hematology/oncology (OR, 1.33; 95% CI, 1.13 to 1.56) but not in those consulting gastroenterology (OR, 0.79; 95% CI, 0.65 to 0.95). Hospice patients had lower rates of hospitalization (7.9% v 47.8%; risk ratio [RR], 0.16; 95% CI, 0.14 to 0.19), intensive care unit stay (2.8% v 25.3%; RR, 0.11; 95% CI, 0.09 to 0.14), and in-hospital death (3.5% v 58.4%; RR, 0.06; 95% CI, 0.05 to 0.07). CONCLUSION: Processes of care influence which patients with HCC are referred to hospice. Hospice use has a marked effect on acute care use at the end of life in patients with HCC. Efforts to incorporate cancer-focused palliative care might improve the quality of end-of-life care in HCC. PMID- 28029302 TI - Neoadjuvant Chemotherapy or Primary Debulking Surgery for Stage IIIC Ovarian Cancer. PMID- 28029301 TI - Impact of Reflex EGFR/ ALK Testing on Time to Treatment of Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. AB - PURPOSE: Optimal first-line systemic therapy for patients with advanced nonsquamous (nonsq) non-small-cell lung cancer (NSCLC) requires confirmation of EGFR/ ALK status, which can delay treatment. We evaluated the impact of reflex testing, defined as pathologists initiating EGFR/ ALK testing at the time of diagnosis of nonsq NSCLC, on time to treatment (TTT). METHODS: We conducted a retrospective review of patients with nonsq NSCLC with medical oncology consultation at Sunnybrook Odette Cancer Centre between March 18, 2010 and April 30, 2014. Data were compared during routine and reflex testing. TTT was defined as the interval between the first medical oncology visit with advanced NSCLC and the initiation of systemic therapy. RESULTS: A total of 306 patients were included (n = 232 for routine testing, n = 74 for reflex testing). There was a trend to improvement in median TTT with reflex testing (36 days [interquartile range {IQR}, 16 to 71 days v 26 days [IQR, 8 to 41 days], P = .071). Omitting patients with intentional delays in systemic therapy for low-volume disease, poor performance status, comorbidity management, and/or radiation therapy, median TTT improved (34 days [IQR, 15 to 67 days] v 22 days [IQR, 8 to 42 days], P = .049). Time to optimal first-line systemic therapy according to published guidelines improved (median, 36 days [IQR, 16 to 91 days] v 24 days [IQR, 8 to 43 days], P = .036). There was no impact on receipt of any first-line systemic therapy (55% v 59%, P = .66). The quality of biomarker testing improved, with fewer unsuccessful tests ( EGFR, 14% v 4%, P = .039; and ALK, 17% v 3%, P = .037). CONCLUSION: Reflex testing of EGFR/ ALK improved the time to optimal systemic therapy and the quality of biomarker testing for patients with advanced nonsq NSCLC. PMID- 28029303 TI - E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group. AB - Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of <= 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2 year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and <= 10 pack-year smoking history who were treated with <= 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose <= 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status. PMID- 28029305 TI - Reply to J.K. Molitoris et al. PMID- 28029304 TI - Cognitive Complaints in Survivors of Breast Cancer After Chemotherapy Compared With Age-Matched Controls: An Analysis From a Nationwide, Multicenter, Prospective Longitudinal Study. AB - Purpose Cancer-related cognitive impairment is an important problem for patients with breast cancer, yet its trajectory is not fully understood. Some previous cancer-related cognitive impairment research is limited by heterogeneous populations, small samples, lack of prechemotherapy and longitudinal assessments, use of normative data, and lack of generalizability. We addressed these limitations in a large prospective, longitudinal, nationwide study. Patients and Methods Patients with breast cancer from community oncology clinics and age matched noncancer controls completed the Functional Assessment of Cancer Therapy Cognitive Function (FACT-Cog) at prechemotherapy and postchemotherapy and at a 6 month follow-up as an a priori exploratory aim. Longitudinal models compared FACT Cog scores between patients and controls at the three assessments and adjusted for age, education, race, menopausal status, and baseline reading ability, anxiety, and depressive symptoms. A minimal clinically important difference cutoff determined percentages of impairment over time. Results Of patients, 581 patients with breast cancer (mean age, 53 years; 48% anthracycline-based regimens) and 364 controls (mean age, 53 years) were assessed. Patients reported significantly greater cognitive difficulties on the FACT-Cog total score and four subscales from prechemotherapy to postchemotherapy compared with controls as well as from prechemotherapy to 6-month follow-up (all P < .001). Increased baseline anxiety, depression, and decreased cognitive reserve were significantly associated with lower FACT-Cog total scores. Treatment regimen, hormone, or radiation therapy was not significantly associated with FACT-Cog total scores in patients from postchemotherapy to 6-month follow-up. Patients were more likely to report a clinically significant decline in self-reported cognitive function than were controls from prechemotherapy to postchemotherapy (45.2% v 10.4%) and from prechemotherapy to 6-month follow-up (36.5% v 13.6%). Conclusion Patients with breast cancer who were treated in community oncology clinics report substantially more cognitive difficulties up to 6 months after treatment with chemotherapy than do age-matched noncancer controls. PMID- 28029306 TI - Improving Breast Cancer Risk Assessment Versus Implementing Breast Cancer Prevention. PMID- 28029307 TI - Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. AB - Purpose Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors. Methods In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 76 participants with WT GISTs, the median follow-up was 4.1 years. Overall EFS (+/- SE) was 72.6 +/- 5.4% at 1 year, 57.6 +/- 6.2% at 2 years, 23.7 +/- 6.0% at 5 years, and 16.3 +/- 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P = .04) and > 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS ( P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS ( P < .01). Five patients (6%) died after initial enrollment in 2008. Conclusion WT GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as obstruction or bleeding. PMID- 28029308 TI - Effects of Early Integrated Palliative Care in Patients With Lung and GI Cancer: A Randomized Clinical Trial. AB - Purpose We evaluated the impact of early integrated palliative care (PC) in patients with newly diagnosed lung and GI cancer. Patients and Methods We randomly assigned patients with newly diagnosed incurable lung or noncolorectal GI cancer to receive either early integrated PC and oncology care (n = 175) or usual care (n = 175) between May 2011 and July 2015. Patients who were assigned to the intervention met with a PC clinician at least once per month until death, whereas those who received usual care consulted a PC clinician upon request. The primary end point was change in quality of life (QOL) from baseline to week 12, per scoring by the Functional Assessment of Cancer Therapy-General scale. Secondary end points included change in QOL from baseline to week 24, change in depression per the Patient Health Questionnaire-9, and differences in end-of-life communication. Results Intervention patients ( v usual care) reported greater improvement in QOL from baseline to week 24 (1.59 v -3.40; P = .010) but not week 12 (0.39 v -1.13; P = .339). Intervention patients also reported lower depression at week 24, controlling for baseline scores (adjusted mean difference, -1.17; 95% CI, -2.33 to -0.01; P = .048). Intervention effects varied by cancer type, such that intervention patients with lung cancer reported improvements in QOL and depression at 12 and 24 weeks, whereas usual care patients with lung cancer reported deterioration. Patients with GI cancers in both study groups reported improvements in QOL and mood by week 12. Intervention patients versus usual care patients were more likely to discuss their wishes with their oncologist if they were dying (30.2% v 14.5%; P = .004). Conclusion For patients with newly diagnosed incurable cancers, early integrated PC improved QOL and other salient outcomes, with differential effects by cancer type. Early integrated PC may be most effective if targeted to the specific needs of each patient population. PMID- 28029309 TI - Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials. AB - Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula >= 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature. PMID- 28029310 TI - Reply to H.J.A. Adams et al and E. Laffon et al. PMID- 28029311 TI - Overestimated Value of Baseline Total Metabolic Tumor Volume at 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography in Follicular Lymphoma. PMID- 28029314 TI - On the Cutoff of Baseline Total Metabolic Tumor Volume in High-Tumor-Burden Follicular Lymphoma. PMID- 28029313 TI - Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study. AB - Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate consisting of a humanized anti-folate receptor alpha (FRalpha) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRalpha-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRalpha positivity by immunohistochemistry (>= 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (<= grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease. PMID- 28029312 TI - Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials. AB - Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model. Results SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio [IQ-OR], 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor-positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor-negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60). Conclusion A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment. PMID- 28029315 TI - Left Ventricular Dysfunction With Trastuzumab Therapy: Is Primary Prevention the Best Option? AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 51-year-old women with left sided, T2N1, grade 3, estrogen receptor- and progesterone receptor-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer was referred to a cardio-oncology clinic for pre-cancer treatment cardiovascular risk assessment. The planned cancer treatment was 3 cycles of FEC (fluorouracil, epirubicin [100 mg/m2 per dose], and cyclophosphamide), followed by 3 cycles of concurrent docetaxel and trastuzumab, followed by maintenance trastuzumab to complete a 1-year course. Other than a prior history of hysterectomy, there was no relevant medical history. Her cardiac history was notable for the absence of prior cardiovascular disease, hypertension, diabetes, or hypercholesterolemia. She was a nonsmoker. At initial clinic visit, her blood pressure was 138/84 with an unremarkable cardiovascular examination. Her echocardiography demonstrated normal sinus rhythm at 73 beats per minute. During cancer treatment, she was observed with echocardiography (baseline left ventricular ejection fraction [LVEF], 61%; global longitudinal strain, -21.5%), cardiac magnetic resonance imaging (CMR, as part of an ongoing study), high-sensitivity troponin I, and B type natriuretic peptide ( Table 1 ). Given that her baseline evaluations were negative at her initial visit, we discussed whether there were agents to prevent the rare, but serious, complication of congestive heart failure (HF) associated with anthracycline- and trastuzumab-based therapy. PMID- 28029316 TI - Is Induction Chemotherapy Needed to Select Patients for Deintensified Treatment of Human Papillomavirus-Associated Oropharyngeal Cancer? PMID- 28029317 TI - Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial. AB - Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS. PMID- 28029319 TI - The Tip of the Iceberg. PMID- 28029320 TI - Pulmonary Infiltrates in a Patient With Advanced Melanoma. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 60-year-old former smoker with metastatic melanoma presented with the chief complaint of pulmonary infiltrates. Five years ago, he was diagnosed with a left chest wall melanoma. He underwent surgery but received no additional therapy for an American Joint Committee on Cancer stage T3a N0 M0 tumor that was 2.7 mm in depth with no ulceration of the epidermal surface. Resection margins were free of tumor. Four years later, he underwent excision of a raised pigmented skin lesion on his left calf that proved to be melanoma with positive margins. He underwent re-excision of melanoma but 2 months later developed a new left hip soft tissue nodule. Positron emission tomography (PET) -computed tomography showed multiple hypermetabolic lesions involving subcutaneous tissue, muscle osseous structures, and bone marrow, consistent with advanced melanoma. He began systemic therapy with ipilimumab and nivolumab. After four cycles of immunotherapy, he developed a nonproductive cough and mild dyspnea on exertion (Modified Medical Research Council dyspnea scale score of 2 [ie, he had to stop for breath when walking at his own pace on level ground]). A chest x-ray showed bilateral hilar enlargement, thickening of the right paratracheal stripe, and scattered patchy increased interstitial markings bilaterally. PET and chest computed tomography images showed enlarged mediastinal adenopathy with increased [18F]fluorodeoxyglucose uptake on PET and scattered diffuse 1- to 2-mm pulmonary nodules with ground-glass opacities ( Fig 1 ). The patient was referred for pulmonary input. The patient had smoked one pack of cigarettes per day for 35 years; he quit 6 years ago. He had no history of pneumonia, childhood asthma, or tuberculosis. His mother had asthma, but there was no other family history of asthma or other lung disease. PMID- 28029318 TI - Impact of Examined Lymph Node Count on Precise Staging and Long-Term Survival of Resected Non-Small-Cell Lung Cancer: A Population Study of the US SEER Database and a Chinese Multi-Institutional Registry. AB - Purpose We investigated the correlation between the number of examined lymph nodes (ELNs) and correct staging and long-term survival in non-small-cell lung cancer (NSCLC) by using large databases and determined the minimal threshold for the ELN count. Methods Data from a Chinese multi-institutional registry and the US SEER database on stage I to IIIA resected NSCLC (2001 to 2008) were analyzed for the relationship between the ELN count and stage migration and overall survival (OS) by using multivariable models. The series of the mean positive LNs, odds ratios (ORs), and hazard ratios (HRs) were fitted with a LOWESS smoother, and the structural break points were determined by Chow test. The selected cut point was validated with the SEER 2009 cohort. Results Although the distribution of ELN count differed between the Chinese registry (n = 5,706) and the SEER database (n = 38,806; median, 15 versus seven, respectively), both cohorts exhibited significantly proportional increases from N0 to N1 and N2 disease (SEER OR, 1.038; China OR, 1.012; both P < .001) and serial improvements in OS (N0 disease: SEER HR, 0.986; China HR, 0.981; both P < .001; N1 and N2 disease: SEER HR, 0.989; China HR, 0.984; both P < .001) as the ELN count increased after controlling for confounders. Cut point analysis showed a threshold ELN count of 16 in patients with declared node-negative disease, which were examined in the derivation cohorts (SEER 2001 to 2008 HR, 0.830; China HR, 0.738) and validated in the SEER 2009 cohort (HR, 0.837). Conclusion A greater number of ELNs is associated with more-accurate node staging and better long-term survival of resected NSCLC. We recommend 16 ELNs as the cut point for evaluating the quality of LN examination or prognostic stratification postoperatively for patients with declared node-negative disease. PMID- 28029321 TI - Tissue Factor: Catch Me If You Can! PMID- 28029322 TI - Doctor, Now That My Chemotherapy Treatment Is Over, When Will My "Chemofog" Lift? PMID- 28029323 TI - Reply to D. Luvero et al. PMID- 28029324 TI - Whole-Brain Radiation in the Treatment of Brain Metastases in ALK-Positive Non Small-Cell Lung Cancer. PMID- 28029325 TI - Reply to M.S. Copur et al. PMID- 28029326 TI - Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. AB - Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD20+ DLBCL age >= 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m2 was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age >= 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for < 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio [HR], 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P = .35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P = .38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL. PMID- 28029327 TI - Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis. AB - Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio [OR], 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage. PMID- 28029328 TI - When, What, and Why of Perioperative Treatment of Potentially Curable Pancreatic Adenocarcinoma. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 64-year-old woman with a history of hypertension and type 2 diabetes had been in her usual state of health until she developed symptoms of diarrhea, abdominal bloating, and discomfort in the midepigastrium. Evaluation with a contrast-enhanced abdominopelvic computed tomography (CT) scan demonstrated a mass in the pancreatic body that was approximately 3.1 cm * 2 cm * 2.1 cm in size with abutment of the portal vein superior mesenteric vein confluence for less than 180 degrees . The confluence was narrowed but without thrombosis. No tumor-vessel interface was noted at the superior mesenteric artery, celiac artery, or common hepatic artery. Several peripancreatic lymph nodes were observed that measured up to 11 mm * 5 mm. No evidence for distant spread of disease was identified. An upper endoscopy with endoscopic ultrasound was performed and fine-needle aspirates of the pancreas mass were positive for malignant cells that were consistent with adenocarcinoma. Chest CT scan without intravenous contrast demonstrated no evidence of metastatic disease. The patient came to the clinic to discuss management of her newly diagnosed malignancy. PMID- 28029329 TI - Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial. AB - Purpose Circulating tissue factor (TF) has been studied as a biomarker for predicting initial, but not recurrent, venous thromboembolism (VTE) in cancer, a setting in which predictors are incompletely understood. We evaluated the association of TF, clinical risk factors, and other biomarkers measured at the time of initial VTE with recurrent VTE in a prespecified analysis of the CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trial. Methods CATCH was a randomized, multicenter trial that investigated tinzaparin 175 IU/kg once daily or dose-adjusted warfarin for 6 months in patients with cancer and acute, symptomatic VTE. TF ELISA, soluble P-selectin, d-dimer, FVIII, and C-reactive protein were assayed. Fisher's exact test was used to screen for association with VTE; competing risk regression analysis of time to recurrent VTE was conducted, accounting for multiple variables. Results The study population comprised 900 patients (recurrent VTE, n = 76; 8.4%). Of these patients, 805 had samples available for TF assay. Mean and median TF levels were 72.5 pg/mL and 50.3 pg/mL, respectively (range, 15.6 pg/mL to 4,798 pg/mL). Patients in the highest quartile of TF experienced the greatest VTE recurrence (> 64.6 pg/mL; 38 [19%] of 203 patients v 34 [6%] of 602 patients; relative risk, 3.3; 95% CI, 2.1 to 5.1; P < .001). In competing risk regression analysis of time to recurrent VTE, TF remained strongly associated with recurrent VTE (subdistribution hazard ratio [SHR], 3.3; 95% CI, 1.7 to 6.4). Other significant variables included venous compression from mass (SHR, 3.1; 95% CI, 1.4 to 6.5) and hepatobiliary cancer (SHR, 5.5; 95% CI, 2.3 to 13.6). Conclusion This is the first report, to our knowledge, to describe TF as a potential biomarker of recurrent VTE in patients with cancer who are on anticoagulation treatment. A risk-adapted strategy could help identify high-risk patients who may benefit from more intensive anticoagulation approaches. PMID- 28029330 TI - Preparation and Identification of Monoclonal Antibody Against C1q/TNF-Related Protein 4. AB - CTRP4 (C1q/TNF-related protein 4) is a secreted cytokine homologous to adiponectin, which plays an important role in immunity and metabolism. This study was designed to generate CTRP4 monoclonal antibodies (MAbs). Splenocytes extracted from mice immunized with prokaryotic protein were fused with myeloma cells Sp2/0 to generate hybridoma cells. Three hybridoma strains (16, 33, and 35) were chosen and their MAbs were purified. The specificity and affinity were identified by Western blot and enzyme-linked immunosorbent assay, whereas CTRP4 endogenous expression was identified by immunofluorescence staining. These MAbs could be useful tools for basic research and potential clinical application. PMID- 28029331 TI - Monoclonal Antibody Against Human GLRX3. PMID- 28029332 TI - MAM-6E7, MAM-3E7, MAM-6G7 (Antirecombinant Human Trypsin-2). PMID- 28029333 TI - Biochemical and organoleptic characteristics of muscle from early and late maturing bulls in different production systems. AB - In grass-based beef production systems (PS), early maturing (EM) breed types may be preferable to late maturing (LM) breed types in achieving adequate carcass fat cover. Biochemical and organoleptic characteristics of muscle from suckler bulls were investigated in EM and LM (n=28/breed) assigned to one of two PS (ad libitum concentrates and grass silage to slaughter (C) or ad libitum silage plus 2 kg concentrate daily during winter followed by 99 days at pasture and then an indoor finishing period on C (GSPC)) in a 2 breed type*2 PS factorial arrangement of treatments. Bulls were managed to have a common target carcass weight of 380 kg. Intramuscular fat (IMF) content was higher (P<0.05) for EM than LM, and for C than GSPC bulls. Collagen solubility was higher (P<0.05) for C than GSPC bulls. Lactate dehydrogenase (LDH) and phosphofructokinase activities were higher (P<0.05) for LM than EM. Isocitrate dehydrogenase activity and the Type I myosin heavy chain (MyHC) proportion were higher (P<0.05) for EM than LM. The LDH activity and the Type IIX MyHC proportion were higher (P<0.05) for C than GSPC bulls. Sensory ratings for tenderness and juiciness were higher (P<0.01) for beef from EM than LM while sensory ratings for tenderness, flavour liking and overall liking were higher (P<0.001) for C than for GSPC bulls. Differences in sensory quality were largely eliminated when adjusted for IMF. Overall, carcass fat scores, IMF and sensory scores were higher in EM than LM and in C than GSPC bulls but most differences in sensory quality could be attributed to differences in IMF. PMID- 28029334 TI - PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL. AB - OBJECTIVES: To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). METHODS: Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. RESULTS: Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. CONCLUSIONS: The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research. PMID- 28029335 TI - Enhanced susceptibility of CA3 hippocampus to prenatal nicotine exposure. AB - The brain is highly susceptible to adverse effects of drugs of abuse during early phases of life. Prenatal nicotine exposure (PNE), a preventable cause of gestational and infant mortality, can alter neuron wiring and induce sustained deficits in attention and learning. Here, a rat model of PNE (embryonic days 7 21) was used to examine the maturing hippocampus, which encodes new memories and processes emotional memory. Components of synaptic signaling were evaluated at postnatal day 14 (P14), a period of prolific synaptogenesis in rats, to determine if glutamatergic transmission-associated molecules are regulated in subregions of hippocampus as early as P14. PNE resulted in reduced expression of GluN2B, GluA2 and CaMKIIalpha, but elevated SNAP25 proteins specifically in the CA3 but not CA1. Only CaMKIIalpha was regulated in dentate gyrus at this age. These results suggest that glutamatergic and synaptic dysregulation of learning and memory may occur in hippocampus in a temporally and subregionally specific manner. PMID- 28029336 TI - Unit-Specific Rates of Hand Hygiene Opportunities in an Acute-Care Hospital. AB - OBJECTIVE To explore the frequency of hand hygiene opportunities (HHOs) in multiple units of an acute-care hospital. DESIGN Prospective observational study. SETTING The adult intensive care unit (ICU), medical and surgical step-down units, medical and surgical units, and the postpartum mother-baby unit (MBU) of an academic acute-care hospital during May-August 2013, May-July 2014, and June August 2015. PARTICIPANTS Healthcare workers (HCWs). METHODS HHOs were recorded using direct observation in 1-hour intervals following Public Health Ontario guidelines. The frequency and distribution of HHOs per patient hour were determined for each unit according to time of day, indication, and profession. RESULTS In total, 3,422 HHOs were identified during 586 hours of observation. The mean numbers of HHOs per patient hour in the ICU were similar to those in the medical and surgical step-down units during the day and night, which were higher than the rates observed in medical and surgical units and the MBU. The rate of HHOs during the night significantly decreased compared with day (P92% of HHOs on medical and surgical units, compared to 67% of HHOs on the MBU. CONCLUSIONS Assessment of hand hygiene compliance using product utilization data requires knowledge of the appropriate opportunities for hand hygiene. We have provided a detailed characterization of these estimates across a wide range of inpatient settings as well as an examination of temporal variations in HHOs. Infect Control Hosp Epidemiol 2017;38:411-416. PMID- 28029337 TI - Harbouring public good mutants within a pathogen population can increase both fitness and virulence. AB - Existing theory, empirical, clinical and field research all predict that reducing the virulence of individuals within a pathogen population will reduce the overall virulence, rendering disease less severe. Here, we show that this seemingly successful disease management strategy can fail with devastating consequences for infected hosts. We deploy cooperation theory and a novel synthetic system involving the rice blast fungus Magnaporthe oryzae. In vivo infections of rice demonstrate that M. oryzae virulence is enhanced, quite paradoxically, when a public good mutant is present in a population of high-virulence pathogens. We reason that during infection, the fungus engages in multiple cooperative acts to exploit host resources. We establish a multi-trait cooperation model which suggests that the observed failure of the virulence reduction strategy is caused by the interference between different social traits. Multi-trait cooperative interactions are widespread, so we caution against the indiscriminant application of anti-virulence therapy as a disease-management strategy. PMID- 28029339 TI - Long-term outcomes of single-ventricle palliation for unbalanced atrioventricular septal defects: Fontan survivors do better than previously thought. AB - BACKGROUND: Single-ventricle palliation (SVP) for children with unbalanced atrioventricular septal defect (uAVSD) is thought to carry a poor prognosis, but limited data have been reported. METHODS: We performed a retrospective review of children with uAVSD who underwent SVP at a single institution. Data were obtained from medical records and correspondence with general practitioners and cardiologists. RESULTS: Between 1976 and 2016, a total of 139 patients underwent SVP for uAVSD. A neonatal palliative procedure was performed in 83.5% of these patients (116 of 139), and early mortality occurred in 11.2% (13 of 116). Ninety four patients underwent stage II palliation, with an early mortality of 6.4% (6 of 94). Eighty patients (57.6%) underwent Fontan completion, with an early mortality of 3.8% (3 of 80). Interstage mortality was 11.7% (12 of 103) between stages I and II and 17.0% (15 of 88) between stage II and Fontan. Long-term survival was 66.5% (95% confidence interval [CI], 57.9%-73.9%) at 5 years, 64.4% (95% CI, 55.5%-72.0%) at 15 years, and 57.8% (95% CI, 47.5%-66.8%) at 25 years. Survival post-Fontan was 94.9% (95% CI, 86.9%-98.0%) at 5 years, 92.0% (95% CI, 80.6%-96.8%) at 15 years, and 82.4% (95% CI, 61.5%-92.6%) at 25 years. Risk factors associated with death or transplantation were aortic atresia (hazard ratio [HR], 5.3; P = .03) and hypoplastic aortic arch (HR, 2.5; P = .02). Atrioventricular valve operations were required in 31.7% of the patients (44 of 139), with 31.8% of them (14 of 44) requiring a further operation. CONCLUSIONS: Children undergoing SVP for uAVSD have substantial mortality, with <60% survival at 25 years. However, survival of children who achieve Fontan completion is better than has been reported previously. PMID- 28029340 TI - Horizontal gene transfer versus biostimulation: A strategy for bioremediation in Goa. AB - Bioaugmentation, Biostimulation and Horizontal gene transfer (HGT) of catabolic genes have been proven for their role in bioremediation of hydrocarbons. It also has been proved that selection of either biostimulation or bioremediation varies for every contaminated site. The reliability of HGT compared to biostimulation and bioremediation was not tested. The present study focuses on reliability of biostimulatiion, bioaugmentation and HGT during biodegradation of Diesel oil and Non aqueous phase liquids (NAPL). Pseudomonas aeruginosa (AEBBITS1) having alkB and NDO genes was used for bioaugmentation and the experiment was conducted using seawater as medium. Based on Gas chromatography results diesel was found to be degraded to 100% in both presence and absence of AEBBITS1. Denturing gradient gel electrophoresis result showed same pattern in presence and absence of AEBBITS1 indicating no HGT. NAPL degradation was found to be more by Biostimulated Bioaugmentation compared to biostimulation and bioaugmentation alone. This proves that biostimulated bioaugmentation is better strategy for oil contamination (tarabll) in Velsao beach, Goa. PMID- 28029341 TI - Theoretical Analysis of Drug Dissolution in Micellar Media. AB - A new theoretical approach combining convective diffusion and surface dissolution kinetics has been applied to micellar systems and tested on experimental data available for both rotating disk apparatus and particles. The micelles are shown to be in the state of dynamic equilibrium with solution for most systems but nanoparticles. For ionizable molecules, the variation of partition coefficient across diffusion boundary layer may affect the diffusivity. The intrinsic dissolution rate is generally a nonlinear function of the equilibrium concentration, c0, in which the diffusion kinetic coefficient, betaD, surface kinetic coefficient, beta0, and total kinetic coefficient of dissolution, beta, all typically decrease as functions of c0 (or increasing micellar concentration, Mc). The observed absolute values of beta0 are usually in the order of 10-3-10-2 cm/s and strongly dependent on the nature of surfactant and solute molecules. For dissolution of particles, the surface kinetics tend to become the rate-limiting step. PMID- 28029342 TI - Synthesis of Caffeine/Maleic Acid Co-crystal by Ultrasound-assisted Slurry Co crystallization. AB - A green approach has been used for co-crystallization of noncongruent co-crystal pair of caffeine/maleic acid using water. Ultrasound is known to affect crystallization; hence, the effect of high power ultrasound on the ternary phase diagram has been investigated in detail using a slurry co-crystallization approach. A systematic investigation was performed to understand how the accelerated conditions during ultrasound-assisted co-crystallization will affect different regions of the ternary phase diagram. Application of ultrasound showed considerable effect on the ternary phase diagram, principally on caffeine/maleic acid 2:1 (disappeared) and 1:1 co-crystal (narrowed) regions. Also, the stability regions for pure caffeine and maleic acid in water were narrowed in the presence of ultrasound, expanding the solution region. The observed effect of ultrasound on the phase diagram was correlated with solubility of caffeine and maleic acid and stability of co-crystal forms in water. PMID- 28029343 TI - Smoking in Movies and Adolescent Smoking Initiation: A Longitudinal Study among Argentinian Adolescents. AB - OBJECTIVE: To assess whether exposure to movie smoking is associated with cigarette smoking among Argentinian adolescents. STUDY DESIGN: A school-based longitudinal study involving 33 secondary schools in Argentina was performed. The sample included 2502 never smokers (average age at entry = 12.5 years), 1700 (67.9%) of whom completed follow-up surveys 17 months later. Exposure to the top 100 highest-grossing films for each year between 2009 and 2013 was assessed by content-coding films for tobacco and then by asking adolescents whether they had seen each of 50 titles, randomly selected from the larger pool, then parsing exposure into tertiles. Logistic regression models estimated aOR for the following transitions: nonsusceptible to susceptible never smoker, never smoker to ever smoker, and never smoker to current smoking (last 30 days). RESULTS: At follow-up, 34.4% of nonsusceptible never smokers became susceptible, 24.1% reported having tried smoking, and 9.4% were current smokers. Most exposure to movie smoking was from US-produced films (average 60.3 minutes compared with only 3.4 minutes from Argentine films). Greater exposure to smoking in movies was significantly associated with increased odds of becoming susceptible (aORfirst vs third tertile 1.77, 95% CI 1.30-2.41), of trying smoking (aORfirst vs third tertile 1.54, 1.14-2.08), and marginally associated with current smoking (AORfirst vs third tertile 1.54, 0.99-2.40). Exposure to smoking in US- or Argentine-produced films had similar associations. CONCLUSION: In Argentina, exposure to smoking in the movies predicted future smoking transitions among early adolescents, with most exposure coming from viewing US movies. PMID- 28029344 TI - Anticipatory Guidance on the Risks for Unfavorable Outcomes among Children with Medical Complexity. PMID- 28029345 TI - The Health Impact of Air Pollution and Outdoor Physical Activity on Children and Adolescents in Mainland China. PMID- 28029346 TI - Practice Patterns in Postoperative Echocardiographic Surveillance after Congenital Heart Surgery in Children: A Single Center Experience. AB - OBJECTIVES: To review current institutional practice and describe factors contributing to variation in inpatient postoperative imaging surveillance after congenital heart surgery. STUDY DESIGN: We reviewed records of all children who underwent congenital heart surgery from June to December 2014. Number and primary indications for postoperative transthoracic echocardiograms (TTEs), providers involved, cardiovascular intensive care unit (CVICU) and total hospital length of stay, and Risk-Adjustment for Congenital Heart Surgery-1 scores were recorded. RESULTS: A total of 253 children (age at surgery: 8 months [2 days-19 years]) received 556 postoperative TTEs (median 1 TTE/patient [1-14]), and 23% had >=3 TTEs. Fifteen of 556 TTEs (2.7%) revealed a new abnormal finding. The majority of TTEs (59%) were performed in the CVICU (1.5 +/- 1.1 TTEs/week/patient), with evaluation of function as the most common indication (44%). Attending physician practice >10 years was not associated with fewer TTEs (P = .12). Patients with >=3 TTEs had higher Risk-Adjustment for Congenital Heart Surgery-1 scores (P = .001), longer CVICU lengths of stay (22 vs 3 days; P < .0001), longer overall hospitalizations (28 vs 7 days; P < .0001), and a higher incidence of mechanical circulatory support (10% vs 0%; P < .0001) than those with <3 TTEs. Eight patients with >=3 TTEs did not survive, compared with 3 with <3 TTEs (P = .0004). CONCLUSIONS: There was wide intra-institutional variation in echocardiographic use among similar complexity surgeries. Frequency of postoperative echocardiographic surveillance was associated with degree of surgical complexity and severity of postoperative clinical condition. Few studies revealed new abnormal findings. These results may help establish evidence-based guidelines for inpatient echocardiographic surveillance after congenital heart surgery. PMID- 28029347 TI - Enhancing the Clinical Reasoning Skills of Postgraduate Students in Internal Medicine Through Medical Nonfiction and Nonmedical Fiction Extracurricular Books. AB - OBJECTIVE: To improve the clinical reasoning skills of postgraduate students in internal medicine through 2 kinds of extracurricular books: medical nonfiction and nonmedical fiction. METHODS: Clinical reasoning is difficult to define, understand, observe, teach, and measure. This is an educational innovation under an experimental framework based on a cognitive intervention grounded in constructivist and cognitivist theories. This study was conducted from June 1, 2014, through May 31, 2015. It was a pre-post, randomized, controlled, prospective, mixed-methods, small-group study. The intervention was through medical nonfiction and nonmedical fiction books. The process was structured to ensure that the students would read the material in phases and reflect on them. Clinical reasoning (pretests and posttests) was quantitatively assessed using the Diagnostic Thinking Inventory (DTI) and clinical reasoning exercises (CREs) and their assessment using a rubric. A qualitative design was used, and face-to-face semistructured interviews were conducted. RESULTS: Posttest total scores (DTI=188.92; CREs=53.92) were higher for the study group after the intervention compared with its own pretest scores (DTI=165.25; CREs=41.17) and with the pretest (DTI=159.27; CRE=40.73) and posttest (DTI=166.91; CREs=41.18) scores of the control group. Interviews with the study group confirmed that the intervention was acceptable and useful in daily practice. CONCLUSION: We introduced, evaluated, and proved an approach to teaching-learning clinical reasoning based on the assumption that the clinical reasoning skills of postgraduate students in internal medicine can be enhanced through 2 kinds of extracurricular books and that fun as well as interest will enhance learning. This study is not only about teaching-learning clinical reasoning but also about the humanities in medical education. PMID- 28029348 TI - Ethnic identity and paranoid thinking: Implicit out-group preference and language dominance predict paranoia in Emirati women. AB - BACKGROUND AND OBJECTIVES: Psychotic experiences including persecutory beliefs are elevated among immigrant and minority populations, especially when living in low ethnic density neighbourhoods (the ethnic density effect). Discrimination, victimization and experiencing a sense of 'not belonging' are hypothesized to play a role in this effect. Because a secure ethnic identity protects against poor self-esteem it may also protect against paranoia. This study explores the relationship between language proficiency (Arabic/English), in-group identity (implicit and explicit) and paranoia in female Emirati university students. METHODS: Female citizens of the United Arab Emirates (UAE), Emirati college women (N = 208), reported English/Arabic language proficiencies, and performed a computerized affective priming task engineered to implicitly assess in-group (Emirati) versus out-group (American) positivity. Participants also completed self-report measures of in-group identity (MIIS), and paranoia (PaDs). RESULTS: Arabic proficiency was negatively correlated with paranoia, as was implicit in group positivity. Furthermore, participants reporting English language dominance, and those demonstrating an implicit out-group preference, reported the highest levels of paranoia. LIMITATIONS: The study is limited by its use of an all female sample. CONCLUSIONS: Implicit in-group attitudes and linguistic competence protect against paranoia and may help to explain the ethnic density effect. PMID- 28029349 TI - Retrospective Observational Epidemiologic Study of Sensitization to Gold Sodium Thiosulfate in the Allergy Clinic of a Tertiary Hospital. PMID- 28029351 TI - The authors reply: in relation to the editorial: Sabate A, Koo M. Intravenous fluids: Concepts and rationality of use. Cir Esp. 2016;94:369-371. PMID- 28029350 TI - [Erratum to: "Breast cancer screening: On our way to the future" [Bull. Cancer 103 (2016) 753-763]]. PMID- 28029352 TI - [Mitral valve repair with the MitraClip following surgical mitral annuloplasty failure]. AB - Mitral repair using the MitraClip device is on ongoing expansion and has been evaluated in different patterns of mitral regurgitation. Nevertheless, surgical approaches to mitral regurgitation remain the standard of care, at least in absence of contraindication. We report the first Canadian experience of mitral valve repair with the MitraClip following surgical mitral annuloplasty failure. Therapeutic considerations and potential challenges are discussed. PMID- 28029353 TI - Intra-abdominal hypertension increases spatial QRS-T angle and elevates ST segment J-point in healthy women undergoing laparoscopic surgery. AB - BACKGROUND: Intra-abdominal hypertension (IAH) impairs cardiovascular function, however an effect of IAH on cardiac electrophysiology has been poorly documented. The aim of this study was to evaluate the effect of IAH following pneumoperitoneum on vectorcardiographic variables reflecting cardiac repolarisation and depolarisation. METHODS: Otherwise healthy women undergoing elective gynaecological laparoscopy were studied. Intra-abdominal pressure (IAP), spatial QRS-T angle and ST-segment J-point (STJ) were observed during surgery and the early postoperative period. RESULTS: Forty women, ages 22 to 43 were examined. Induction of IAH to 15mmHg significantly widened the spatial QRS-T angle, whereas the Trendelenburg position subsequently reduced this widening. IAH also increased STJ voltage in leads III, aVF, V2 and V3 during surgery, with increased STJ voltage persisting in several leads through the morning of postoperative day 1. CONCLUSION: Induction of IAH impacts the relationship between cardiac depolarisation and repolarisation and increases spatial QRS-T angle and STJ voltage. PMID- 28029354 TI - [IDEM-depression: Characteristics and evaluation of an open group that combines psychoeducation and cognitive-behavior therapy]. AB - INTRODUCTION: Depression is a highly prevalent mental illness that is associated with high rates of morbidity and functional impairment. At the psychiatric unit of the University Hospital of Strasbourg, France, we have developed an open group that combines psychoeducation and cognitive-behavior therapy (CBT), the information, discovery, exchange and mobilization for depression group (IDEM depression). IDEM-depression is composed of 17 thematic, structured, and independent sessions, which address different aspects of depression (i.e., rumination, pharmacological treatments). Because of its flexible format, patients with varying degrees of depression severity (from remission up to severe depressive symptoms) and whose depression might be bipolar or unipolar, are able to participate in the group. Thus, the group is well suited to a large number of patients with major depression. In the present study we aimed at describing the IDEM-depression group and presenting results regarding patients' overall satisfaction, assessed via two self-report questionnaires (the Client Satisfaction Questionnaire, the CSQ-8, and the IDEM ad hoc questionnaire), as well as its effect on mood following each session assessed via a visual analog scale (VAS) ranging from 0 up to 100. METHOD: Sixty-five patients participated in 50 sessions of the IDEM-depression group in two hospitals in Alsace. 61% of the patients had bipolar disorder, and 41% of them were inpatients. Sessions took place on a weekly basis, lasted 2hours and were proposed by a CBT-trained clinical psychologist. Patients were asked to fill-out the VAS at the beginning and at the end of each session. Moreover, they were asked to fill-out the CSQ-8 and the IDEM ad hoc questionnaire when they left the group. Other than one session ("yoga and mindfulness"), all the sessions (16 out of 17) were structured on a Powerpoint(c) presentation. During the first hour information was given regarding the topic (i.e., rumination), and a shared CBT conceptualization of the topic was formulated by the participants and the psychologist. For most sessions, the first hour was therefore communication and information-based, whereas during the second hour participants were asked to participate in in-session behavioral experiments and/or to evaluate specific aspects of their behavior (thoughts, emotions, activity, mindful behavior) during the last few days. The therapist manual and the slides for each session are available via e-mail to the first author. RESULTS: Regarding the results, self-reported mood on the VAS was compared between the onset (225 VAS) and the end (225 VAS) of each session. Overall, results suggest that self-reported mood is significantly improved following the participation in sessions (t=-5. 87, P<0.001). Moreover, mean results on the CSQ-8 suggest that patients are highly satisfied with the group (M=24.46, SD=6.42). Among them, 82% reported a moderate-high satisfaction with the group. On the IDEM ad hoc questionnaire, patients reported an overall high satisfaction level regarding (i) the content of sessions, (ii) the duration of sessions, (iii) the frequency of sessions, (iv) how much they felt they could express themselves during sessions. In the qualitative comments of this questionnaire, patients reported that the group helped them to gain an understanding of the mechanisms involved in depression; to feel less isolated and guilty; and to learn about specific psychotherapeutic tools (i.e., mindfulness) and to try to implement them. CONCLUSION: Our results suggest that an IDEM depression group is well suited to a wide-array of clinical pictures associated with depression (varying severity, bipolar or unipolar, inpatients and outpatients). This is probably due to its open-group format which is particularly well-adapted to the dynamic symptomatology associated with major depression, and may stimulate decentering in patients who have different levels of severity of symptoms but participate in the same session. Moreover, its impact on mood improvement, and the high satisfaction level reported by patients, seem to be related to its CBT and psychoeducation-based content on the one hand, which has shown its efficacy in depression. On the other hand, IDEM's structured open-group format might have also contributed to the improvement in mood and the overall good satisfaction reported by patients, through the social support provided by the group, improved feeling of self-efficiency, and its effect on stigmatization. Thus, IDEM-depression group is an efficacious, flexible, low-cost, and easy to implement (in different clinical settings) psychotherapeutic option for major depression. PMID- 28029355 TI - Medial temporal lobe reinstatement of content-specific details predicts source memory. AB - Leading theories propose that when remembering past events, medial temporal lobe (MTL) structures reinstate the neural patterns that were active when those events were initially encoded. Accurate reinstatement is hypothesized to support detailed recollection of memories, including their source. While several studies have linked cortical reinstatement to successful retrieval, indexing reinstatement within the MTL network and its relationship to memory performance has proved challenging. Here, we addressed this gap in knowledge by having participants perform an incidental encoding task, during which they visualized people, places, and objects in response to adjective cues. During a surprise memory test, participants saw studied and novel adjectives and indicated the imagery task they performed for each adjective. A multivariate pattern classifier was trained to discriminate the imagery tasks based on functional magnetic resonance imaging (fMRI) responses from hippocampus and MTL cortex at encoding. The classifier was then tested on MTL patterns during the source memory task. We found that MTL encoding patterns were reinstated during successful source retrieval. Moreover, when participants made source misattributions, errors were predicted by reinstatement of incorrect source content in MTL cortex. We further observed a gradient of content-specific reinstatement along the anterior posterior axis of hippocampus and MTL cortex. Within anterior hippocampus, we found that reinstatement of person content was related to source memory accuracy, whereas reinstatement of place information across the entire hippocampal axis predicted correct source judgments. Content-specific reinstatement was also graded across MTL cortex, with PRc patterns evincing reactivation of people and more posterior regions, including PHc, showing evidence for reinstatement of places and objects. Collectively, these findings provide key evidence that source recollection relies on reinstatement of past experience within the MTL network. PMID- 28029356 TI - Comparison of patient-reported outcomes after traumatic upper extremity amputation: Replantation versus prosthetic rehabilitation. AB - BACKGROUND: After major upper extremity traumatic amputation, replantation is attempted based upon the assumption that outcomes for a replanted limb exceed those for revision amputation with prosthetic rehabilitation. While some reports have examined functional differences between these patients, it is increasingly apparent that patient perceptions are also critical determinants of success. Currently, little patient-reported outcomes data exists to support surgical decision-making in the setting of major upper extremity traumatic amputation. Therefore, the purpose of this study is to directly compare patient-reported outcomes after replantation versus prosthetic rehabilitation. METHODS: At three tertiary care centers, patients with a history of traumatic unilateral upper extremity amputation at or between the radiocarpal and elbow joints were identified. Patients who underwent either successful replantation or revision amputation with prosthetic rehabilitation were contacted. Patient-reported health status was evaluated with both DASH and MHQ instruments. Intergroup comparisons were performed for aggregate DASH score, aggregate MHQ score on the injured side, and each MHQ domain. RESULTS: Nine patients with successful replantation and 22 amputees who underwent prosthetic rehabilitation were enrolled. Aggregate MHQ score for the affected extremity was significantly higher for the Replantation group compared to the Prosthetic Rehabilitation group (47.2 vs. 35.1, p<0.05). Among the MHQ domains, significant advantages to replantation were demonstrated with respect to overall function (41.1 vs. 19.7, p=0.03), ADLs (28.3 vs. 6.0, p=0.03), and patient satisfaction (46.0 vs. 24.4, p=0.03). Additionally, Replantation patients had a lower mean DASH score (24.6 vs. 39.8, p=0.08). CONCLUSIONS: Patients in this study who experienced major upper extremity traumatic amputation reported more favorable patient-reported outcomes after successful replantation compared to revision amputation with prosthetic rehabilitation. PMID- 28029357 TI - The Tragedy of the Commons - Drug Shortages and Our Patients' Health. PMID- 28029358 TI - Analysis of an early intervention distal femoral resurfacing implant for medial osteoarthritis. AB - A design concept was formulated for implants to treat medial osteoarthritis of the knee, using a metal plate resurfacing of the tibia plateau and a plastic bearing embedded in the distal end of the femur. A finite element analysis was carried out to determine whether a metal backing would be needed for the femoral component, and to what extent the stress and strain distribution in the trabecular bone surrounding the implant would match the normal intact condition. The CT scans from three knees scheduled for unicompartmental replacement were selected to generate computer models with variable bone densities in each element to cover a range of density patterns. Loading conditions were defined for a range of flexion angles, from loads at the center to the end of the component. A 2-peg fixation design was analyzed for both an all-plastic and a metal-backed construction. For the metal-backed, the interface von Mises stresses were close to intact values at the same level in the bone, although there was a 34 percent increase for loading at the end of the component. However, the all-plastic gave stresses elevated up to 109 percent. The maximum principal strain values for metal-backed in the trabecular bone below the implant were variable between specimens but close to intact under all conditions. In contrast the all-plastic showed strains up to 81 percent increased. The metal pegs showed load transfer, but the loads transmitted by the plastic pegs was small, as evidenced by the low interface stresses. The conclusion was that metal-backing was necessary to avoid excessive bone stresses and strains, while metal peg fixation was evidently an advantage. PMID- 28029359 TI - Computational modeling of the structure-function relationship in human placental terminal villi. AB - Placental oxygen transport takes place at the final branches of the villous tree and is dictated by the relative arrangement of the maternal and fetal circulations. Modeling techniques have failed to accurately assess the structure function relationship in the terminal villi due to the geometrical complexity. Three-dimensional blood flow and oxygen transport was modeled in four terminal villi reconstructed from confocal image stacks. The blood flow was analyzed along the center lines of capillary segments and the effect of the variability in capillary diameter, tortuosity and branching was investigated. Additionally, a validation study was performed to corroborate the simulation results. The results show how capillary variations impact motion of the fetal blood, and how their bends and dilatations can decelerate the flow by up to 80%. Vortical flow is also demonstrated not to develop in the fetal capillaries. The different geometries are shown to dictate the transport of gases with differences of over 100% in the oxygen flux between samples. Capillary variations are key for efficient oxygen uptake by the fetus; they allow the blood to decelerate where the villous membrane is thinnest allowing for a better oxygenation, but also by reducing the vessel diameter they carry the oxygenated blood away fast. The methodology employed herein could become a platform to simulate complicated in-vivo and in vitro scenarios of pregnancy complications. PMID- 28029360 TI - Deliberations on Diastolic Heart Failure. AB - Studies of left ventricular diastolic dysfunction and diastolic heart failure (DHF), published during the past 4 decades, include a prodigious number and wide variety of research efforts. This review report considers some of the historical literature and incorporates more recent information supporting the idea that patients with DHF constitute a subgroup of the heterogeneous population of patients with heart failure and a preserved ejection fraction. Clinical investigation, particularly therapeutic trials, should be directed at specific targets within the population of interest, not at the broad heart failure with preserved ejection fraction population. To accomplish this, it is important to stipulate criteria for the diagnosis of DHF and to limit our attention to specific subgroups or phenotypes. PMID- 28029361 TI - Comparison of Outcomes of Atrial Fibrillation in Patients With Reduced Versus Preserved Left Ventricular Ejection Fraction. AB - Patients with newly diagnosed atrial fibrillation (AF) and a rapid ventricular response may present with a reduced left ventricular ejection fraction (LVEF). We compared long-term outcomes of these patients with those with preserved LVEF. This retrospective cohort study included 385 consecutive adults with newly diagnosed AF with rapid ventricular response, presenting to a single medical center from January 2006 to August 2014. Patients with a history of coronary artery disease or known cardiomyopathy were excluded. Patients were divided into 2 groups: those with an LVEF <=55% (n = 147) (REF) and those with an LVEF >55% (n = 238) (PEF). Echocardiographic parameters, all-cause mortality, cardiovascular mortality, and stroke rates were compared between both groups at baseline and a minimum of 1-year follow-up. The mean age of patients was 68 +/- 1.1 in REF versus 60 +/- 7.4 in PEF (p = 0.39). There were no significant differences in baseline co-morbidities between both groups. The mean LVEF during the index admission was 47.7 +/- 0.8% in REF versus 65.5 +/- 0.3% in PEF. The average duration of follow-up was 2.8 years. Patients with REF had higher all-cause mortality (32.7% REF vs 20.6% PEF, odds ratio 2.17, p = 0.008). Patients with REF had higher rates of subsequent clinic or ER visits for AF with a rapid ventricular response (32% REF vs 22.7% PEF, p = 0.044). The incidence of stroke was similar between both groups (17% REF vs 18.9% PEF, p = 0.639). Of the patients with REF, 64% had subsequent EF recovery and had similar outcomes compared with patients with PEF. Baseline LV end-diastolic diameter predicted all cause mortality (odds ratio 1.14, p = 0.003) in the REF group. None of the echocardiographic parameters predicted EF recovery. In conclusion, in patients with new AF with rapid ventricular response, REF was associated with higher long term all-cause mortality. Those with subsequent LVEF recovery after medical therapy appear to have a similar prognosis compared with those with initial PEF. PMID- 28029362 TI - Impact of Multivessel Coronary Artery Disease With Versus Without Left Main Coronary Artery Disease on Long-Term Mortality After Coronary Bypass Grafting Versus Drug-Eluting Stent Implantation. AB - Limited data are available on the impact of concomitant left main coronary artery disease (CAD) on mortality after revascularization of multivessel coronary artery disease (MVD) alone or multivessel plus left main coronary artery disease (MVLMD). This study compared long-term mortality between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) with drug-eluting stents in 2,887 patients with MVD or MVLMD. Data were pooled from the BEST, PRECOMBAT, and SYNTAX trials. The primary outcome was death due to any cause. Of the 2,887 patients, 1,975 (68.4%) were classified as having MVD and 912 (31.6%) as having MVLMD. The median follow-up duration was 60.2 months. In the patients with MVD, primary outcome rate after CABG was significantly lower than after PCI (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.49 to 0.89; p = 0.007). In the patients with MVLMD, however, CABG and PCI showed similar primary outcome rates (HR 0.98; 95% CI 0.67 to 1.43; p = 0.896). Among those who underwent CABG, primary outcome rate was lower in the patients with MVD than in those with MVLMD (HR 0.66; 95% CI 0.46 to 0.95; p = 0.024). Kaplan-Meier analysis showed a clear separation between the patients with MVD and those with MVLMD 2.5 years after the index surgery. The risk of death due to any cause was significantly lower after CABG than after PCI with drug-eluting stents in patients with MVD but not in those with MVLMD. The advantage of CABG over PCI for multivessel CAD was significantly attenuated if concomitant left main CAD was present. PMID- 28029364 TI - Standard 12-Lead Electrocardiogram: A Plausible Patient Monitoring Tool for the Emerging Cardio-Oncology Programs. PMID- 28029363 TI - Comparison of the Edwards SAPIEN S3 Versus Medtronic Evolut-R Devices for Transcatheter Aortic Valve Implantation. AB - New generation of the most widely used devices for transcatheter aortic valve implantation have been recently introduced into practice. We compare the short term outcomes of transcatheter aortic valve implantation with the Edwards SAPIEN S3 and the Medtronic Evolut-R. We performed a retrospective analysis from a single high-volume tertiary center. Valve Academic Research Consortium-2 criteria were used to define composite end points of device success and safety at 30 days. Study population included 232 patients implanted with the SAPIEN S3 (n = 124) and Evolut-R (n = 108). Device success reached 91.9% and 95.4% in the SAPIEN S3 and Evolut-R groups, respectively (p = 0.289). Postprocedural echocardiography showed greater aortic valve gradients (22.8 +/- 7 vs 16 +/- 9 mm Hg, p <0.001) among SAPIEN S3 group. Paravalvular leak of >= moderate severity was observed in 2.4% and 0% in the SAPIEN S3 and Evolut-R groups, respectively (p = 0.251). Similar rates of in-hospital complications, including major bleedings, vascular complications, and pacemaker implantations were recorded in both groups. At 30 day follow-up, the combined safety end point was reached in 5.6% and in 6.5% of patients in the SAPIEN S3 and Evolut-R groups, respectively (p = 0.790). During follow-up of 237 +/- 138 days, all-cause mortality was higher in patients implanted with Evolut-R compared with SAPIEN S3 (7 vs 1 cases, respectively, p = 0.006), however, cardiovascular mortality was not significantly different between groups. In conclusions, in a single-center comparative analysis, comparable rate of device success as well as safety profile and long-term cardiovascular mortality were observed with the SAPIEN S3 and Evolut-R valves. PMID- 28029365 TI - Consider Cardiac, Neuromuscular, and Hereditary Aspects of Left Ventricular Hypertrabeculation or Noncompaction. PMID- 28029366 TI - Computational-aided design of magnetic ultra-thin dummy molecularly imprinted polymer for selective extraction and determination of morphine from urine by high performance liquid chromatography. AB - In this work, a novel magnetic ultra-thin dummy molecularly imprinted polymer (MMIP) for morphine (MO) was prepared. In order to obtain highly selective recognition cavities, the MMIP has been designed using semi-flexible docking to screen the optimal monomer and its ratio to morphine from six representative monomers. Furthermore, the dummy template was creatively screened by semi flexible docking method from opioid drugs. The system of dihydrocodeine (DI) as dummy template, methacrylamide (MAC) as founctional monomer, ethyleneglycol dimethacrylate (EGDMA) as crosslinker was chosen for MO imprinting. The morphological and magnetic properties of MMIP were characterized by FT-IR, TEM and VSM. The results suggested that molecularly imprinted polymer (MIP) was synthesized evenly on Fe3O4 surface. The adsorption experiments revealed that MMIP showed better extraction capacity and selectivity toward MO and its analogues than the non-imprinted polymer (NIP). The MMIP possessed adsorption capacity of 14.71mg/g for MO and the imprinting factor was 2.10 at separate adsorption and 1.87 at competitive adsorption. A magnetic molecularly imprinted solid phase extraction coupled with HPLC method (M-MISPE-HPLC) has been established for the analysis of MO in urine sample. The developed method was validated for its linearity (0.038-100mgL-1 R2=0.9937), precision (1.07%-3.72%) and accuracy (83.62%-100.37%). PMID- 28029367 TI - On the feasibility to conduct gradient liquid chromatography separations in narrow-bore columns at pressures up to 2000bar. AB - The limits in operating pressures are extended for narrow-bore columns in gradient elution up to 2000bar. As the required pumps for these pressures are incompatible with common chromatographic solvents and are not suitable to apply a mobile phase composition gradient, a mobile phase delivery and injection system is described and experimentally validated which allows to use any possible chromatographic solvent in isocratic and gradient elution. The mobile phase delivery and injection system also allows to perform multiple separations without the need to depressurize the column. This system consists out of 5 dual on/off valves and two large volume loops in which the gradient and equilibration volume of initial mobile phase are loaded by a commercial liquid chromatography pump. The loops are then flushed toward the column at extreme pressures. The mobile phase delivery and injection system is first evaluated in isocratic elution and shows a comparable performance to a state-of-the-art commercial flow-through needle injector but with twice the pressure rating. Distortion of the loaded gradient by dispersion in the gradient storage loop is studied. The effect of the most important parameters (such as flow rate, pressure and gradient steepness) is experimentally investigated. Different gradient steepnesses and volumes can be applied at different flow rates and operating pressures with a good repeatability. Due to the isobaric operation of the pumps, the gradient is monitored in real-time by a mass flow meter installed at the detector outlet. The chromatograms are then converted from time to volume-base. A separation of a 19 compound sample is performed on a 300*2.1mm column at 1000bar and on a 600*2.1mm column at 2000bar. The peak capacity was found to increase from 141 to 199 and thus scales with L as is predicted by theory. This allows to conclude that the inlet pressure for narrow-bore columns in gradient elution can be increased up to 2000bar without fundamental pressure-induced limitations. PMID- 28029368 TI - Coupling of metal-organic frameworks-containing monolithic capillary-based selective enrichment with matrix-assisted laser desorption ionization-time-of flight mass spectrometry for efficient analysis of protein phosphorylation. AB - Protein phosphorylation is a major post-translational modification, which plays a vital role in cellular signaling of numerous biological processes. Mass spectrometry (MS) has been an essential tool for the analysis of protein phosphorylation, for which it is a key step to selectively enrich phosphopeptides from complex biological samples. In this study, metal-organic frameworks (MOFs) based monolithic capillary has been successfully prepared as an effective sorbent for the selective enrichment of phosphopeptides and has been off-line coupled with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) for efficient analysis of phosphopeptides. Using s-casein as a representative phosphoprotein, efficient phosphorylation analysis by this off line platform was verified. Phosphorylation analysis of a nonfat milk sample was also demonstrated. Through introducing large surface areas and highly ordered pores of MOFs into monolithic column, the MOFs-based monolithic capillary exhibited several significant advantages, such as excellent selectivity toward phosphopeptides, superb tolerance to interference and simple operation procedure. Because of these highly desirable properties, the MOFs-based monolithic capillary could be a useful tool for protein phosphorylation analysis. PMID- 28029369 TI - Management and outcomes of scoliosis in children with congenital diaphragmatic hernia. AB - PURPOSE: The purpose of this study was to evaluate the management and outcomes of CDH patients with scoliosis. METHODS: From January 1996 to August 2015, 26 of 380 (7%) CDH patients were diagnosed with scoliosis. Six (23%) were prenatally diagnosed by ultrasound, and 9 (35%) were diagnosed postnatally. The remaining 11 (42%) developed scoliosis after discharge. Mean follow-up was 6.6years. RESULTS: Among the 15 patients with congenital scoliosis, there were 2 (13%) perinatal deaths. Five of the 13 (38%) survivors required orthopedic surgery, and 2 have required bracing. The mean age at initial surgery was 7years. These five children underwent an average of 2.8 (range 1-7) expansions or revisions. All surgical patients required supplemental oxygen at 28days of life, and 1 required a tracheostomy. None of the 11 patients who developed scoliosis later in life required surgery, but 3 have required bracing. Six of the 11 (55%) required a patch repair for CDH compared to 158 of 264 (60%) CDH patients without scoliosis (p=0.73). CONCLUSIONS: Early diagnosis of scoliosis in CDH patients is associated with a high rate of surgery. There was not a higher incidence of patch repair among patients who developed scoliosis. LEVEL OF EVIDENCE: Prognosis. Retrospective study, level II. PMID- 28029370 TI - Pneumoperitoneum and hemodynamic stability during pediatric laparoscopic appendectomy. AB - BACKGROUND: Conventional pneumoperitoneum (CP) and automatically maintained pneumoperitoneum using AirSeal Intelligent Flow System (AiFS) were compared during pediatric laparoscopic appendectomy (LA) using intraperitoneal pressure (IPP) and hemodynamic parameters. METHODS: A prospective review of 39 children aged 3-14years who had standard 3-trocar LA was performed. Pneumoperitoneum was either AiFS (n=18) or CP (n=21) according to the surgeon's preference. IPP during insertion of trocars in all subjects was initially 8-10mmHg, which was reduced to 5mmHg then maintained until LA was completed. Data were collected every 5min during pneumoperitoneum. RESULTS: Subject demographics were similar for both groups. During pneumoperitoneum, average IPP (AiFS: 7.9; CP: 9.0mmHg), average systolic blood pressure (AiFS: 100.4; CP: 106.9mmHg), and average end-tidal CO2 (EtCO2; AiFS: 35.7; CP: 38.5mmHg) were significantly different (p<.05, respectively), while pulse (AiFS: 92.1; CP: 96.4bpm), oxygen saturation (AiFS: 98.8; CP: 98.8%), body temperature (AiFS: 37.2; CP: 37.4), urine output (AiFS: 2.7; CP: 2.4mL/kg per hour), operative time (AiFS: 72.2; CP: 76.2mins), blood loss (AiFS: 3.6; CP: 3.5mL), recommencement of oral intake (AiFS: 1.3; CP: 1.4days), and postoperative hospitalization (AiFS: 4.3; CP: 3.8days) were not. CONCLUSION: Because IPP was significantly lower during LA with AiFS, EtCO2 and BP were significantly lower. LEVEL OF EVIDENCE: Treatment study; prospective comparative study - level II. PMID- 28029371 TI - The role of water-soluble meconium subfraction and lipid-soluble meconium subfraction on the superior mesenteric artery vasoconstriction in chick embryos. AB - OBJECTIVE: Intraamniotic meconium has been responsible for intestinal damage in gastroschisis and meconium-dependent intestinal ischemia has been proposed to induce additional intestinal damage in gastroschisis. This study is aimed to determine the effects of lipid and water-soluble meconium subfractions on the contractility of the superior mesenteric artery (SMA). MATERIALS AND METHODS: The study was conducted on 18-day fertilized chick embryos (Gallus Domesticus). Meconium is fractioned into water and lipid-soluble components. Only one SMA tissue was prepared from each embryo and suspended in the organ bath. Isometric contraction responses (ICR) were created in SMA tissues by one hour of incubation in Krebs-Henseleit solution for each group. Groups consisted of control, meconium, water-soluble meconium subfraction and lipid-soluble meconium subfraction. ICR of the SMA specimens were evaluated with a transducer-amplifier system on a computer. The data were expressed (mean+/-1SD) as milliNewton (mN). RESULTS: The ICR of the meconium, water-soluble meconium subfraction and lipid soluble meconium subfraction groups were significantly high when compared to the control group (p<0.01). The meconium and water-soluble meconium subfraction created more contraction response than the lipid-soluble meconium subfraction (p<0.01). The ICR of the meconium group was not different from the ICR of the water-soluble meconium subfraction group (p>0.05). CONCLUSION: Water-soluble meconium subfraction has a profound vasoconstrictor effect on the SMA compared to the lipid-soluble meconium subfraction. PMID- 28029372 TI - Cajal's unbearable cephalalgias: The consequences of a misdiagnosis. AB - Around the age of 66 Cajal consulted neurologist Nicolas Achucarro complaining of "unbearable cephalalgias". He had not ever suffered from headaches. The diagnosis of early arteriosclerosis that was considered at the time a physiological, irreversible ailment of ageing had a strong emotional impact on Cajal. Comorbid depression, insomnia and self-treatment with escalating doses of Veronal(r) (barbital), a short-acting barbiturate, presumably aggravated the situation. Exposure to warm environments and being involved in tense discussions were identified as triggering factors of the headaches. Achucarro and Cajal were probably assuming scientific concepts at the time, such as cerebral congestion, increased temperature at the cerebral cortex during mental activity and vasoconstriction and vasodilatation phenomena. Up to his death aged 82, no evidence was discovered of any organic nervous system disorder. Cajal remained anxious up to the end of his life fearing an impending cerebral haemorrhage. The diagnosis was followed by profound lifestyle changes such as social isolation, which forced him to leave his laboratory. Cajal's cephalalgias marked in some way the end of the Spanish school of neurohistology. PMID- 28029373 TI - Discharge decision-making after complex surgery: Surgeon behaviors compared to predictive modeling to reduce surgical readmissions. AB - BACKGROUND: Little is known about how information available at discharge affects decision-making and its effect on readmission. We sought to define the association between information used for discharge and patients' subsequent risk of readmission. METHODS: 2009-2014 patients from a tertiary academic medical center's surgical services were analyzed using a time-to-event model to identify criteria that statistically explained the timing of discharges. The data were subsequently used to develop a time-varying prediction model of unplanned hospital readmissions. These models were validated and statistically compared. RESULTS: The predictive discharge and readmission regression models were generated from a database of 20,970 patients totaling 115,976 patient-days with 1,565 readmissions (7.5%). 22 daily clinical measures were significant in both regression models. Both models demonstrated good discrimination (C statistic = 0.8 for all models). Comparison of discharge behaviors versus the predictive readmission model suggested important discordance with certain clinical measures (e.g., demographics, laboratory values) not being accounted for to optimize discharges. CONCLUSIONS: Decision-support tools for discharge may utilize variables that are not routinely considered by healthcare providers. How providers will then respond to these atypical findings may affect implementation. PMID- 28029374 TI - Selection bias: Examining the feasibility, utility, and participant receptivity to incorporating simulation into the general surgery residency selection process. AB - BACKGROUND: Opportunities exist to revise the current residency selection process to capture desirable candidate competencies. We examined the extent to which components of the American College of Surgeons/Association for Surgical Education simulation-based medical student curriculum combined with a teamwork activity could be used as potential screening method. METHODS: Students participated in a workshop consisting of training/evaluation of knot tying, suturing, airway management, gowning/gloving, and teamwork. Surveys were given to medical students (MS) and faculty/resident/staff (FRS) to examine their opinions about the residency screening process, the most critical competencies to assess, and the effectiveness of each station for candidate evaluation. RESULTS: Communication (FRS, 4.86 +/- .35; MS, 4.93 +/- .26), leadership (FRS, 4.41 +/- .80; MS, 4.5 +/- .76), judgment (FRS, 4.62 +/- .74; MS, 4.67 +/- .62), professionalism (FRS, 4.64 +/- .73; MS, 5.00 +/- .00), integrity (FRS, 4.71 +/- .78; MS, 4.87 +/- .35), and grit/resilience (FRS, 4.71 +/- .78; MS, 4.53 +/- .74) were considered most valuable for candidate screening. The simulation-based curriculum for evaluation of residency candidates was rated lowest by both groups. Open response comments indicated positive perceptions of this process. CONCLUSIONS: Employing simulation to assess candidates may be most beneficial for examining nontechnical attributes. Future work should continue to explore this area. PMID- 28029375 TI - Invited commentary on "outcomes and feasibility of nipple-sparing mastectomy for node-positive breast cancer patients" by Murphy et al. PMID- 28029377 TI - Introduced Species, Disease Ecology, and Biodiversity-Disease Relationships. AB - Species introductions are a dominant component of biodiversity change but are not explicitly included in most discussions of biodiversity-disease relationships. This is a major oversight given the multitude of effects that introduced species have on both parasitism and native hosts. Drawing on both animal and plant systems, we review the competing mechanistic pathways by which biological introductions influence parasite diversity and prevalence. While some mechanisms such as local changes in phylogenetic composition and global homogenization - have strong explanatory potential, the net effects of introduced species, especially at local scales, remain poorly understood. Integrative, community scale studies that explicitly incorporate introduced species are needed to make effective predictions about the effects of realistic biodiversity change and conservation action on disease. PMID- 28029378 TI - Urbanization and Disease Emergence: Dynamics at the Wildlife-Livestock-Human Interface. AB - Urbanization is characterized by rapid intensification of agriculture, socioeconomic change, and ecological fragmentation, which can have profound impacts on the epidemiology of infectious disease. Here, we review current scientific evidence for the drivers and epidemiology of emerging wildlife-borne zoonoses in urban landscapes, where anthropogenic pressures can create diverse wildlife-livestock-human interfaces. We argue that these interfaces represent a critical point for cross-species transmission and emergence of pathogens into new host populations, and thus understanding their form and function is necessary to identify suitable interventions to mitigate the risk of disease emergence. To achieve this, interfaces must be studied as complex, multihost communities whose structure and form are dictated by both ecological and anthropological factors. PMID- 28029379 TI - Characterization of nuclear foci-targeting of Luman/CREB3 recruitment factor (LRF/CREBRF) and its potential role in inhibition of herpes simplex virus-1 replication. AB - The recently identified Luman/CREB3-binding partner LRF (Luman/CREB3 recruitment factor) was shown to localize to discrete sub-nuclear foci. Luman is implicated in herpes simplex virus-1 (HSV-1) latency/reactivation and the unfolded protein response (UPR) pathway; therefore, we sought to characterize the formation of the LRF nuclear foci in the context of cellular signaling and HSV-1 replication. Here, we mapped the nuclear foci-targeting sequence to the central region containing the first leucine zipper (a.a.415-519), and found that the integrity of the whole region appears essential for LRF foci formation. LRF foci integrity was unaffected by inhibition of cellular DNA replication and translation, however, disruption of transcription resulted in altered LRF localization. When compared to other cellular and viral foci LRF co-localized with the nuclear receptor co-activator GRIP1, while the HSV-1 gene products ICP4, ICP27 and VP13/14 disrupted foci formation to varying degrees. Interestingly, cells over expressing LRF were resistant to productive HSV-1 infection and this resistance was dependent upon protein targeting and an N-terminal transactivation domain. When LRF knockdown cells were subjected to primary infection, HSV-1 gene expression and progeny virus yield were enhanced by ~3 fold compared to wildtype cells. Taken together, these results indicate that LRF is a key regulator that may act direct or indirectly as a repressor of essential genes required for productive viral infection. PMID- 28029380 TI - Do hospital factors impact readmissions and mortality after colorectal resections at minority-serving hospitals? AB - BACKGROUND: Minority-serving hospitals have greater readmission rates after operative procedures including colectomy; however, little is known about the contribution of hospital factors to readmission risk and mortality in this setting. This study evaluated the impact of hospital factors on readmissions and inpatient mortality after colorectal resections at minority-serving hospitals in the context of patient- and procedure-related factors. METHODS: More than 168,000 patients who underwent colorectal resections in 374 California hospitals (2004 2011) were analyzed using the State Inpatient Database and American Hospital Association Hospital Survey data. Sequential logistic regression analyses were performed to determine the associations between minority-serving hospital status and 30-day, 90-day, and repeated readmissions. RESULTS: Thirty-day, 90-day, and repeated readmission rates were 11.2%, 16.9%, and 2.9%, respectively. Odds for 30 day, 90-day, and repeated readmissions after colorectal resections were 19%, 20%, and 38% more likely at minority-serving hospitals versus non-minority-serving hospitals, respectively (P < .01), after controlling for age, sex, comorbidities, year, and procedure type. Patient factors accounted for up to 65% of the observed increase in odds for readmission at minority-serving hospitals while hospital level factors contributed roughly 40%. Inpatient mortality was significantly greater at minority-serving hospitals versus non-minority-serving hospitals (4.9% vs 3.8%; P < .001). Risk factors significantly associated with readmissions and inpatient mortality included Medicaid/Medicare primary insurance, emergent operation, and ostomy creation. Low procedure volume was significantly associated with increased odds for inpatient mortality. CONCLUSION: Patient-level factors seemed to dominate the increased readmission risk after colorectal resections at minority-serving hospitals while hospital factors were less contributory. These findings need to be further validated to shape quality improvement interventions to decrease readmissions. PMID- 28029381 TI - Chasing 60% of maternal deaths in the post-fact era: an issue of accountability. PMID- 28029382 TI - Letter to the Editor "Gender related aspects of bleeding with rivaroxaban in venous thromboembolism - Potential for pitfalls": A comment to "Impact of gender on safety and efficacy of rivaroxaban in adolescents & young adults with venous thromboembolism" by Manuela Krause et al. (Thrombosis Research 2016, published online). PMID- 28029383 TI - Pilot Results from a Randomized Trial in Men Comparing Alpha-Adrenergic Antagonist versus Behavior and Exercise for Nocturia and Sleep. AB - PURPOSE: Nocturia and sleep problems are common in older adults. We developed and tested a novel intervention, multicomponent behavioral treatment and exercise therapy (M-BET), that may reduce nocturia and improve sleep in men. We compared reductions in nocturia and improvement in sleep in men with M-BET versus an active drug comparator (alpha-blocker) used alone or in combination (M-BET + alpha-blocker) METHODS: This randomized, controlled trial was conducted in the ambulatory setting in 2 US Department of Veterans Affairs medical centers in men at least 40 years of age with nocturia (defined as >=2 nightly episodes). Participants were randomized to receive either M-BET, including pelvic floor muscle training, urge-suppression techniques, delayed voiding, fluid management, sleep hygiene, and peripheral edema management; an active comparator of known efficacy (the alpha-blocker tamsulosin, one 0.4-mg tablet nightly); or both therapies combined. Participants received interventions over 12 weeks. Outcomes were assessed via voiding diaries, wrist actigraphy, and validated questionnaires. The primary outcome was change in diary-recorded nocturia, assessed using ANCOVA for the between-group changes and paired t tests for within group changes. FINDINGS: A total of 72 men with a mean age of 65.8 years participated. At 12 weeks, mean diary-recorded nocturia changed with M-BET by 1.39 episodes/night (P < 0.001), with alpha-blocker therapy by -0.59 episodes/night (P < 0.01), and with combination therapy by -1.03 episodes/night (P < 0.01). Reductions were not statistically different across treatment groups (P = 0.41). M-BET also showed statistically significant improvements in sleep quality, bother from nocturia, and nocturia-specific quality of life. All treatment groups indicated global satisfaction with treatment. IMPLICATIONS: Behavioral therapy in men, alone or combined with alpha-blocker therapy, consistently showed large and statistically significant nocturia reductions and favorable effects on sleep and quality of life. Based on these findings, behavioral therapy, while not statistically superior to alpha-blocker therapy, may provide a meaningful treatment option for men with nocturia. Future research should include the development of behavioral treatment and exercise therapy interventions that could be more easily deployed. ClinicalTrials.gov identifier: NCT00824200. PMID- 28029384 TI - Fungal endophytes and their interactions with plants in phytoremediation: A review. AB - Endophytic microorganisms (including bacteria and fungi) are likely to interact closely with their hosts and are more protected from adverse changes in the environment. The microbiota contribute to plant growth, productivity, carbon sequestration, and phytoremediation. Elevated levels of contaminants (i.e. metals) are toxic to most plants, the plant's metabolism and growth were impaired and their potential for metal phytoextraction is highly restricted. Exploiting endophytic microorganisms to reduce metal toxicity to plants have been investigated to improve phytoremediation efficiencies. Fungi play an important role in organic and inorganic transformation, element cycling, rock and mineral transformations, bioweathering, mycogenic mineral formation, fungal-clay interactions, and metal-fungal interactions. Endophytic fungi also showed potentials to enhance phytoremediation. Compared to bacteria, most fungi exhibit a filamentous growth habit, which provides the ability to adopt both explorative or exploitative growth strategies and form linear organs of aggregated hyphae to protect fungal translocation. However, the information regarding the role of endophytic fungi in phytoremediation are incomplete, this review highlights the taxa, physiological properties, and interaction of endophytic fungi with plants in phytoremediation. PMID- 28029385 TI - A conserved gating element in TRPV6 channels. AB - The Ca2+-selective tetrameric Transient Receptor Potential Vanilloid 6 (TRPV6) channel is an inwardly rectifying ion channel. The constitutive current endures Ca2+-induced inactivation as a result of the activation of phospholipase C followed depletion of phosphatidylinositol 4,5-bisphosphate, and calmodulin binding. Replacing a glycine residue within the cytosolic S4-S5 linker of the human TRPV6 protein, glycine 516, which is conserved in all TRP channel proteins, by a serine residue forces the channels into an open conformation thereby enhancing constitutive Ca2+ entry and preventing inactivation. Introduction of a second mutation (T621A) into TRPV6G516S reduces constitutive activity and partially rescues the TRPV6 function. According to the recently revealed crystal structure of the rat TRPV6 the T621 is adjacent to the distal end of the transmembrane segment 6 (S6) within a short linker between S6 and the helix formed by the TRP domain. These results indicate that the S4-S5 linker and the S6 TRP-domain linker are critical constituents of TRPV6 channel gating and that disturbance of their sequences foster constitutive Ca2+ entry. PMID- 28029386 TI - Occurrence of organophosphorus flame retardants on skin wipes: Insight into human exposure from dermal absorption. AB - This study surveyed occurrences and influencing factors of organophosphorus flame retardants (PFRs) on skin surface. Skin wipe samples from palms, back-of-hands and forearms of 30 adults were collected by using gauze pads soaked in isopropyl alcohol in Beijing, China. Tris(chloropropyl) phosphate isomers (?TCPP), tris(2 chloroethyl) phosphate (TCEP) and triphenyl phosphate (TPHP) were the most abundant compounds with detection frequencies higher than 97%. ?TCPP showed the highest mean level (4.6MUg/m2), followed by TPHP (2.4MUg/m2) and TCEP (1.6MUg/m2). Levels on palms were slightly higher than on back-of-hands, and both were substantially higher than those on forearms. TCEP and ?TCPP levels were strong reliable in three repeated measurements from 4 participants over a three month period (intraclass correlation of coefficient of 0.91 and 0.95, respectively), while TPHP levels were not. Washing with soap and water removed a large fraction of PFRs on hands with median reduction of 76, 72 and 67% for TCEP, ?TCPP and TPHP, respectively. Paired dust samples, table surface wipe and hand wipe samples were collected from 17 offices (13 surface wipes and 22 hand wipes) in Beijing. Hand wipe TCEP, ?TCPP and TPHP were neither correlated with dust samples nor with table surface wipe samples. Two methods were used for dermal exposure assessments. The estimated lower median total exposure from palms, back of-hands and forearms by the relative absorption method were 0.6, 1.0, 0.3ng/kg BW-d for TCEP, ?TCPP and TPHP, respectively. These estimates were in the same range as those via dust ingestion for adults in Beijing, suggesting dermal absorption is likely a significant pathway of human PFR exposure. PMID- 28029387 TI - Structure and ultrastructure of spermatozoon in six species of Drosophilidae (Diptera). AB - The Drosophilidae family is formed by Brachycera Diptera distributed widely across different regions of the planet. It is composed of about 4000 species, 304 of which are found in Brazil. The objective of this work was to characterize morphologically the structure of the male internal reproductive apparatus and the ultrastructure of the spermatozoon in four Neotropical (Drosophila cardini, D. mercatorum, D. nebulosa and D. sturtevanti) and two invasive (D. simulans and Zaprionus indianus) species of drosophilids. The structural aspect of the internal reproductive apparatus corresponds with that described for other drosophilids; however, there are differences in the size and coloration of the structures, such as the testes, in each species analyzed. The spermatozoon of these species was seen to be long and fine, presenting morphological variation. The ultrastructure of the spermatozoon revealed that the morphological pattern is similar to that found in the majority of insects. The head region presents a nucleus with condensed chromatin and the acrosome positioned laterally to the nucleus. In the tail region, the axoneme presents the 9+9+2 pattern commonly described for other species of Diptera. The species presented differences regarding the shape and size of the mitochondrial derivatives. Cytochemical analysis using EPTA also revealed differences in terms of the location of the basic proteins in the mitochondrial derivates. The results obtained contribute to expanding the database for the Drosophilidae family, providing information that may contribute to intra- and inter-specific identification and supplying phylogenetic analyses. PMID- 28029388 TI - Emerging role of Cdc42-specific guanine nucleotide exchange factors as regulators of membrane trafficking in health and disease. AB - It is widely accepted that the Golgi complex operates as a main sorting station in the biosynthetic pathway. On the other hand, the Golgi complex harbors numerous signaling molecules that generate the platform for the coordination of the transduction of specific signals and of membrane transport events. A part of these processes, which require the complex integration of transport-, cytoskeleton- and polarity-associated mechanisms, is tightly regulated by molecular machineries comprising guanine nucleotide exchange factors (GEF) and their down-stream effectors, such as the small GTPase Cdc42. Dysfunction of several Cdc42-specific GEFs has been shown to cause a number of human diseases, which are associated with impaired intracellular trafficking at the level of the Golgi complex as well as in other compartments. Here we briefly overview how mutations in Cdc42-specific GEFs have an impact on the organization of intracellular trafficking fluxes and how such trafficking aberrations could be associated with a number of human disorders. PMID- 28029389 TI - Neonatology faculty development using simulation. AB - The goal of faculty development activities is to supply the public with knowledgeable, skilled, and competent physicians who are prepared for high performance in the dynamic and complex healthcare environment. Current faculty development programs lack evidence-based support and are not sufficient to meet the professional needs of practicing physicians. Simulation activities for faculty development offer an alternative to traditional, teacher-centric educational offerings. Grounded in adult learning theory, simulation is a learner centric, interactive, efficient, and effective method to train busy professionals. Many of the faculty development needs of clinical neonatologists can be met by participating in simulation-based activities that focus on technical skills, teamwork, leadership, communication, and patient safety. PMID- 28029390 TI - Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: A phase IIa, multicenter, randomized, vehicle-controlled study. AB - BACKGROUND: Olumacostat glasaretil (OG) inhibits acetyl-coenzyme A carboxylase, the enzyme responsible for the first, rate-limiting step in de novo fatty acid synthesis. OG inhibited in vitro human sebocyte lipid production and reduced in vivo sebaceous gland size in hamster ears. OBJECTIVES: Safety and efficacy of OG 7.5% gel were evaluated in patients with moderate to severe facial acne vulgaris. METHODS: Patients were randomized (1:1) to twice-daily application of OG or vehicle for 12 weeks. Efficacy was measured through changes in lesion counts and improvement in acne severity scores. RESULTS: A total of 108 patients received OG (n = 53) or vehicle (n = 55); these groups had mean baseline counts of 29.7 and 28.6 inflammatory and 40.9 and 38.8 noninflammatory lesions, respectively. At week 12, OG treatment showed greater reductions from baseline in inflammatory lesions (-63.9% vs -45.9%; P = .0006) and noninflammatory lesions (-48.1% vs 28.8%; P = .0025), and more patients with greater than or equal to 2-grade improvement in investigator global assessment score (24.5% vs 7.3%; P = .0070) than vehicle. Application-site adverse events (typically mild or moderate intensity) were more common with OG. LIMITATIONS: Larger trials are needed to optimize OG dosing and confirm the current results. CONCLUSION: OG was well tolerated and showed evidence of efficacy, suggesting further development is warranted. PMID- 28029391 TI - Off-Hour Surgery Among Orthopedic Subspecialties at an Urban, Quaternary-Care, Level 1 Trauma Center. AB - PURPOSE: We sought to determine and quantify which subspecialties of orthopedic surgeons are operating off hours in an urban, quaternary-care, level 1 trauma center. MATERIALS AND METHODS: We used our clinical registry to identify 43,211 orthopedic surgeries performed between January 2008 and December 2011. Our outcome measures were the number and proportion of off-hour surgeries performed as well as the number and proportion of off-hours per subspecialty. The denominators were the total number of surgeries and the total number of surgical hours worked per subspecialty. Subspecialties-based on the primary surgeon who performed the surgery-were arthroplasty, foot and ankle, hand, pediatrics, shoulder, spine, sports, orthopedic trauma, and orthopedic oncology. RESULTS: A total of 2,431 (5.6%) surgeries were off-hours; the overall ratio of off-hour to on-hour surgeries was 1 to 17. There was a difference in the proportion of off hour surgeries performed among orthopedic subspecialties: trauma (ratio, 1:5) and pediatric specialists (ratio, 1:5) had the lowest ratio, and shoulder (ratio, 1:152) and sports (ratio, 1:98) specialists the highest. The total number of surgical hours among all specialties was 59,026; of these hours, 3,833 (6.5%) were off-hour. The ratio of off-hour to on-hour surgical hours was 1 to 14. There was a difference in proportion of hours worked off-hour among orthopedic subspecialties; the ratios were greatest for trauma (1:5) and hand (1:5) specialists and the least for shoulder (1:157) and sports (1:92) specialists. Seven percent of hand surgery cases were off-hour, and 16% of the total surgical hours worked by hand surgeons were off-hour. CONCLUSIONS: In an urban, academic, level 1 trauma and microvascular replantation regional referral hospital, there is a large difference in off-hour surgical volume and duration among orthopedic subspecialties: trauma, pediatric, and hand surgeons performed more off-hour work than their colleagues, with hand and pediatric surgeons the most likely to be working at night. CLINICAL RELEVANCE: These data can inform how we organize, value, and incentivize off-hour care. PMID- 28029392 TI - Idiopathic Fenestrated Complex Syndactyly in a Unique Crisscross Fashion. AB - This case presents surgical treatment of a unique form of syndactyly: an isolated fenestrated, complex, crisscross syndactyly of the right middle and ring fingers. A 2-year-old boy presented with the ring finger lying dorsal and the middle finger lying volar, with the middle phalanges syndactylized. A surgical release was performed with a subsequent z-plasty, 2 years later, for scar elongation. At the age of 4, he has essentially full function of his hand with minimal limitations. This case demonstrates that 2 digits that were syndactylized in a coronal plane (ring finger dorsal and middle finger volar) can be successfully surgically separated. PMID- 28029394 TI - Non-Anion Gap Metabolic Acidosis: A Clinical Approach to Evaluation. AB - Acid-base disturbances can result from kidney or nonkidney disorders. We present a case of high-volume ileostomy output causing large bicarbonate losses and resulting in a non-anion gap metabolic acidosis. Non-anion gap metabolic acidosis can present as a form of either acute or chronic metabolic acidosis. A complete clinical history and physical examination are critical initial steps to begin the evaluation process, followed by measuring serum electrolytes with a focus on potassium level, blood gas, urine pH, and either direct or indirect urine ammonium concentration. The present case was selected to highlight the differential diagnosis of a non-anion gap metabolic acidosis and illustrate a systematic approach to this problem. PMID- 28029393 TI - Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study. AB - BACKGROUND: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 953 participants enrolled in the Cardiovascular Health Study. PREDICTOR: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples. OUTCOMES: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion. RESULTS: Median uromodulin level was 25.9 (IQR, 17.3-38.9) MUg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93MUg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (<=17.26MUg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58). LIMITATIONS: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations. CONCLUSIONS: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI. PMID- 28029395 TI - The current situation of infertility services provision in Europe. AB - Infertility is a global medical problem of the reproductive system which may affect the quality of a woman's life. Whether infertility provision varies between different European countries has not been investigated in the context of a comparative study. There are, however, differences in legislation between different countries, which encourage "infertility tourism". Women cross borders in order to get access to those treatment modalities that are not provided in their own country. Oocyte donation for example and the high cost of the services locally are common reasons for this mobility. Although treatment of infertility is still aetiology based, unexplained cause is most often the underlying reason. The invention of in vitro fertilisation (IVF) has changed the management of infertility globally. In most European countries, treatment is mainly provided by well-organised private IVF centres using highly effective methodologies. Different European scientific organisations, together with European Board and College of Obstetrics and Gynaecology (EBCOG), should provide recommendations to the European Union on the development of common legislation to streamline quality assured clinical care for infertile couples. This will hopefully help to eliminate possible inequalities, providing evidence based services according to patients' needs and also reduce the cross border healthcare demand in European countries. PMID- 28029396 TI - Standards of Care in infertility in Europe. AB - Evidence-based medicine is the principal approach to medical practice. There are several debatable issues in infertility, which require clarification. Over the past 20 years, reliable methodology has been developed for the management of infertile couples. This includes high quality diagnostic and therapeutic procedures, which are applied in highly specialised infertility centres. The European Board and College of Obstetrics and Gynaecology (EBCOG) has published Standards of Care for Women's Health in Europe, which should be the cornerstone for the clinicians and service providers in the European Union to establish common protocols within their centres. Each infertility treatment should result in the highest possible success rate and all appropriate measures for the patient's safety should be in place. The treatment protocols should minimise risk of complications, such as ovarian hyperstimulation syndrome (OHSS). The current use of GnRH agonists to trigger final follicle maturation has provided the means for avoiding this syndrome. Additionally, multiple pregnancy rates are still high in assisted reproductive technology (ART). These rates should be reduced by the adoption of single embryo transfer during IVF treatment and by the proper monitoring of ovulation induction protocols. EBCOG Standards of Care for infertility and assisted conception treatment derived from the best available evidence should underpin the provision of high quality infertility services in European countries. PMID- 28029397 TI - Matrin 3 variants are frequent in Italian ALS patients. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Recently, missense variants in MATR3 were identified in familial and sporadic ALS patients, but very few additional ALS patients have been reported so far. The p.S85C MATR3 variant was previously associated to a different phenotype, namely a distal myopathy associated with dysphagia and dysphonia. Here, we assessed the contribution of MATR3 variants in a cohort of 322 Italian ALS patients. We identified 5 different missense MATR3 variants (p.Q66K, p.G153C, p.E664A, p.S707L, and p.N787S) in 6 patients (1.9%). None of our patients showed signs of myopathy at electrophysiological examination. Muscle biopsy, performed in 2 patients, showed neurogenic changes and normal nuclear staining with anti-matrin 3 antibody. Our results confirm that MATR3 variants are associated with ALS and suggest that they are more frequent in Italian ALS patients. Further studies are needed to elucidate the pathogenic significance of identified variants in sporadic and familial ALS. PMID- 28029398 TI - Re: Marco Borghesi, Hashim Ahmed, Robert Nam, et al. Complications After Systematic, Random, and Image-guided Prostate Biopsy. Eur Urol 2017;71:353-65. PMID- 28029399 TI - Global Burden of Urologic Cancers, 1990-2013. AB - CONTEXT: Kidney, prostate, and bladder cancers increase with age and are influenced partly by modifiable risk factors. Urological cancer rates may increase substantially amid a growing, aging population. OBJECTIVE: To describe kidney, bladder, and prostate cancer incidence, mortality, and risk factor attributable bladder and kidney cancer deaths between 1990 and 2013, by age, sex, and development status. EVIDENCE ACQUISITION: Cancer mortality data were derived from global vital registries. Incidence data from cancer registries were transformed to mortality estimates using separately estimated mortality incidence ratios. These sources served as input data for an ensemble modeling approach to estimate bladder, prostate, and kidney cancer mortality. Cause-specific mortality estimates were transformed into incidence estimates using mortality incidence ratios. EVIDENCE SYNTHESIS: In 2013, 2.1 million kidney, bladder, and prostate cancers cases occurred worldwide, increasing 2.5-fold since 1990. Mortality increased 1.6-fold between 1990 and 2013. Eight-two percent of new cases in 2013 occurred in individuals aged 60 yr and older. Men from developed countries had the highest age-standardized death rates among all three cancers. Smoking attributable kidney cancer deaths decreased while obesity-related deaths rose, most prominently in women from developing countries. Smoking-related bladder cancer deaths increased among women from developed countries and decreased among men. CONCLUSIONS: Urologic cancer burden has increased globally amid population growth and aging. High income countries face the highest incidence and death rates; however, obesity-attributed kidney cancer deaths are increasing in developing countries. Efforts to expand the global oncologic workforce and reduce preventable factors may lessen cancer disparities in developing countries. PATIENT SUMMARY: We describe the impact of population growth, aging, and lifestyle factors such as smoking and obesity, on kidney, bladder, and prostate cancer rates worldwide. More new cancer cases and deaths occur in developed countries compared with developing countries. In addition to preventive efforts, healthcare systems must emphasize training of a urologic oncology workforce. PMID- 28029400 TI - Diagnostic testing methods for Clostridium difficile infection: A statewide survey of Ohio acute care hospitals. AB - We surveyed Ohio acute care hospitals on laboratory testing used for diagnosis of Clostridium difficile infection (CDI). Of 146 hospitals surveyed, 109 (84%) used nucleic acid amplification tests (NAATs) as stand-alone diagnostic assays. Only 53 (42.4%) hospitals using NAATs had a mechanism in place to prevent repeat CDI testing. PMID- 28029401 TI - "Equity-informative health technology assessment - A commentary on Ngalesoni, Ruhago, Mori, Robberstad & Norheim". PMID- 28029402 TI - Racial bias is associated with ingroup death rate for Blacks and Whites: Insights from Project Implicit. AB - RATIONALE: Research suggests that, among Whites, racial bias predicts negative ingroup health outcomes. However, little is known about whether racial bias predicts ingroup health outcomes among minority populations. OBJECTIVE: The aim of the current research was to understand whether racial bias predicts negative ingroup health outcomes for Blacks. METHOD: We compiled racial bias responses from 250,665 Blacks and 1,391,632 Whites to generate county-level estimates of Blacks' and Whites' implicit and explicit biases towards each other. We then examined the degree to which these biases predicted ingroup death rate from circulatory-related diseases. RESULTS: In counties where Blacks harbored more implicit bias towards Whites, Blacks died at a higher rate. Additionally, consistent with previous research, in counties where Whites harbored more explicit bias towards Blacks, Whites died at a higher rate. These links between racial bias and ingroup death rate were independent of county-level socio demographic characteristics, and racial biases from the outgroup in the same county. CONCLUSION: Findings indicate that racial bias is related to negative ingroup health outcomes for both Blacks and Whites, though this relationship is driven by implicit bias for Blacks, and explicit bias for Whites. PMID- 28029403 TI - Female political representation and child health: Evidence from a multilevel analysis. AB - This article explores the impact of female political representation in national parliaments on child health through a multilevel analysis. Using available Demographic and Health Surveys, we employ both cross-sectional data for 51 low- and middle-income countries and longitudinal data for 20 countries with multiple surveys. For both the cross-sectional and longitudinal analyses, female representation is negatively related to infant mortality and positively related to measles vaccination status. To explore potential mechanisms, we control for state spending on health and analyze whether the impact of female representation depends on a critical mass of female representatives. The analysis offers evidence that state spending accounts for some of the mediation effect and that the impact of female representation on infant death depends on a critical mass. PMID- 28029404 TI - A combined single high-dose rate brachytherapy boost with hypofractionated external beam radiotherapy results in a high rate of biochemical disease free survival in localised intermediate and high risk prostate cancer patients. AB - INTRODUCTION: Dose escalation has been shown to improve biochemical outcome in localised prostate cancer. An HDR brachytherapy boost is an effective strategy for dose escalation, since it exploits the low alpha/beta ratio in prostate cancer, allowing the delivery of a high biological dose to the tumour. We sought to evaluate the biochemical disease free survival in patients with intermediate and high risk localised prostate cancer treated with EBRT plus HDR brachytherapy as a boost, in our institution. PATIENTS AND METHODS: Biochemical outcome was collected prospectively in 95 patients treated from 2008 to 2010, with an HDR boost of 12.5Gy followed by EBRT delivered as 37.5Gy in 15 fractions over 3weeks. The ASTRO definition of biochemical failure (2MUg/L above PSA nadir) was used as the outcome measure. 61/95 (64%) were classified as high risk (stage>T2b or PSA>20MUg/L or Gleason score>7) while 34/95 (36%) were intermediate risk. 92/95 (97%) patients received neoadjuvant androgen deprivation therapy (ADT). Adjuvant hormone therapy was at the discretion of the treating clinician. RESULTS: The median follow-up for the cohort was 65months (range, 18-88) with a 5-year biochemical DFS of 80.5% (95% Confidence Interval [CI]: 72.8-89.0). The prognostic factors used in the analysis model were: clinical stage, presenting PSA, duration of ADT, Gleason score, risk category, prostate volume, D90 and V100. Only presenting PSA (HR 1.03; CI 1.00-1.05, p=0.03) predicted for a poorer biochemical DFS on multivariate analysis. CONCLUSION: These data confirm that EBRT plus a single-fraction HDR brachytherapy boost achieves good biochemical control in a cohort of predominantly high risk patients. PMID- 28029405 TI - Distributed learning: Developing a predictive model based on data from multiple hospitals without data leaving the hospital - A real life proof of concept. AB - PURPOSE: One of the major hurdles in enabling personalized medicine is obtaining sufficient patient data to feed into predictive models. Combining data originating from multiple hospitals is difficult because of ethical, legal, political, and administrative barriers associated with data sharing. In order to avoid these issues, a distributed learning approach can be used. Distributed learning is defined as learning from data without the data leaving the hospital. PATIENTS AND METHODS: Clinical data from 287 lung cancer patients, treated with curative intent with chemoradiation (CRT) or radiotherapy (RT) alone were collected from and stored in 5 different medical institutes (123 patients at MAASTRO (Netherlands, Dutch), 24 at Jessa (Belgium, Dutch), 34 at Liege (Belgium, Dutch and French), 48 at Aachen (Germany, German) and 58 at Eindhoven (Netherlands, Dutch)). A Bayesian network model is adapted for distributed learning (watch the animation: http://youtu.be/nQpqMIuHyOk). The model predicts dyspnea, which is a common side effect after radiotherapy treatment of lung cancer. RESULTS: We show that it is possible to use the distributed learning approach to train a Bayesian network model on patient data originating from multiple hospitals without these data leaving the individual hospital. The AUC of the model is 0.61 (95%CI, 0.51-0.70) on a 5-fold cross-validation and ranges from 0.59 to 0.71 on external validation sets. CONCLUSION: Distributed learning can allow the learning of predictive models on data originating from multiple hospitals while avoiding many of the data sharing barriers. Furthermore, the distributed learning approach can be used to extract and employ knowledge from routine patient data from multiple hospitals while being compliant to the various national and European privacy laws. PMID- 28029406 TI - The Withers archive: Online availability of rod Wither's data. AB - The contents of the lab notebooks of H.R. Withers have been digitized and stored as 23 excel files, a total of approximately 45 megabytes. A procedure is described whereby those interested may gain access to the data. PMID- 28029408 TI - Gut microbiota and allergy/asthma: From pathogenesis to new therapeutic strategies. AB - Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses worldwide. Emerging evidence relates atopy and asthma to the composition and function of gut microbiota composition. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. Although still a relatively nascent field of research, evidence to date suggests that the gut microbiome may represent fertile targets for prevention or management of allergic asthma and other diseases in which adaptive immune dysfunction is a prominent feature. The oral probiotics/prebiotic represents a possible therapeutic for improving asthma and allergic disease. Especially, recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review, we literaturely summarise the aggravation or improvement of metabolic diseases by role of gut microbiota, probiotics/prebiotic treatment. PMID- 28029407 TI - Management of chronic spontaneous urticaria in routine clinical practice: A Delphi-method questionnaire among specialists to test agreement with current European guidelines statements. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a frequent clinical entity that often presents a diagnostic and therapeutic challenge. OBJECTIVE: To explore the degree of agreement that exists among the experts caring for patients with CSU diagnosis, evaluation, and management. METHODS: An online survey was conducted to explore the opinions of experts in CSU, address controversial issues, and provide recommendations regarding its definition, natural history, diagnosis, and treatment. A modified Delphi method was used for the consensus. RESULTS: The questionnaire was answered by 68 experts (dermatologists, allergologists, and primary care physicians). A consensus was reached on 54 of the 65 items posed (96.4%). The experts concluded that CSU is a difficult-to control disease of unpredictable evolution. Diagnostic tests should be limited and based on clinical history and should not be indiscriminate. Autoinflammatory syndromes and urticarial vasculitis must be ruled out in the differential diagnosis. A cutaneous biopsy is only recommended when wheals last more than 24h, to rule out urticarial vasculitis. The use of specific scales to assess the severity of the disease and the quality of life is recommended. In patients with severe and resistant CSU, second-generation H1-antihistamines could be used at doses up to four times the standard dose before giving second-line treatments. Omalizumab is a safe and effective treatment for CSU that is refractory to H1 antihistamines treatment. In general, diagnosis and treatment recommendations given for adults could be extrapolated to children. CONCLUSIONS: This work offers consensus recommendations that may be useful in the management of CSU. PMID- 28029409 TI - Serum concentrations and gene expression of sirtuin 1 in healthy and slightly overweight subjects after caloric restriction or resveratrol supplementation: A randomized trial. AB - BACKGROUND: Sirtuin 1 (Sirt1) plays an important role in vascular biology, and influences aspects of age-dependent atherosclerosis. In animals, the sirtuin system is strongly influenced by resveratrol and caloric restriction, but its expression in humans is controversial. This study investigated the effects of resveratrol and caloric restriction on Sirt1 serum concentrations and vascular biomarkers in a healthy human population. METHODS AND RESULTS: Forty-eight healthy participants (24 women) aged 55-65years were randomized to either 30days of resveratrol administration (500mg/day) or caloric restriction (1000cal/day). Blood was collected at baseline and day 30. Laboratory data analyzed were triglycerides, total cholesterol, HDL, VLDL, LDL, apolipoprotein A1, apolipoprotein B, lipoprotein (a), non-esterified fatty acids (NEFA), glucose, insulin, oxidative stress, C-reactive protein, and Sirt1. Expression of the Sirt1 gene was analyzed using real-time PCR. Caloric restriction diminished the abdominal circumference and improved the lipid profile, but not resveratrol intervention. Resveratrol and caloric restriction increased serum concentrations of Sirt1, from 1.06+/-0.71 to 5.75+/-2.98ng/mL; p<0.0001, and from 1.65+/-1.81 to 5.80+/-2.23ng/mL; p<0.0001, respectively. Sirt1 increased in women and men in both interventions. On the other hand expression of Sirt1 mRNA was not different after caloric restriction and resveratrol treatment. CONCLUSIONS: Caloric restriction and resveratrol significantly increased plasma concentrations of Sirt1. The long-term impact of these interventions on atherosclerosis should be assessed. PMID- 28029410 TI - The effects of bile acid sequestrants on lipid profile and blood glucose concentrations: A systematic review and meta-analysis of randomized controlled trials. AB - AIM: To undertake a systematic review and meta-analysis of prospective clinical studies to determine the effect of bile acid sequestrants (BAS) on lipid profile and blood glucose concentrations. METHOD: PubMed-Medline, Web of Science, Cochrane Database and Google Scholar databases were searched (up until August 2016) to identify prospective studies evaluating the impact of BASs on the cardio metabolic profile. Random effects model meta-analysis was used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I2 index. Systematic review registration: CRD42016035973. RESULTS: From a total of 769 entries identified, 15 studies were included in the final analysis. The meta-analysis indicated a significant reduction in fasting serum triglyceride concentrations following treatment with BASs (weighted mean difference [WMD] 0.54mg/dL, 95% CI 0.43 to 0.65, heterogeneity p=0.021; I2 54.2%, n=11 studies). The WMDs for total serum cholesterol (TC) was -1.18mg/dL (95% CI -1.30 to -1.06, heterogeneity p=0012; I2 63.1%, n=11 studies), 0.126mg/dL (95% CI 0.02 to 0.22, heterogeneity p=0.231; I2 43.2%, n=11 studies) for HDL-cholesterol, and -0.24mg/dL (95% CI 0.35 to -0.14, heterogeneity p=0.562; I2 23.1%, n=10 studies) for LDL cholesterol, and -2.10mg/dL (95% CI -2.84 to -1.36, heterogeneity p=0.200; I2 42.6%, n=11 studies) fasting blood glucose (FBG) and -0.83% (95% CI -1.08 to 0.57, heterogeneity p=0.856; I2 20.9%, n=11 studies) for HbA1c. These findings were robust in sensitivity analyses. CONCLUSIONS: This meta-analysis suggests that therapy with BAS significantly improves HDL-C, LDL-C, and glycemic markers including fasting blood glucose, HbA1c levels, while deteriorating triglyceride levels. PMID- 28029411 TI - Atrial fibrillation and heart failure: Factors influencing the choice of oral anticoagulant. AB - Atrial fibrillation (AF) and heart failure (HF) frequently coexist. AF is identified in approximately one third of patients with HF and is linked to increased morbidity and mortality than from either condition alone. AF is relatively more common in HF with preserved ejection fraction (HFpEF) than with reduced ejection fraction (HFrEF). Nevertheless, the risk of stroke and systemic embolism (SSE) is significantly increased with both HF types and the absolute risk is heavily influenced by the presence and severity of associated additional stroke risk factors. The European Society of Cardiology has very recently introduced a third HF subtype entitled HF with mid-range ejection fraction (HFmrEF). At present oral anticoagulation is recommended for all patients with AF and HF, independent of HF type. In addition to warfarin there are currently four non-vitamin K oral anticoagulants (NOACs, previously called novel oral anticoagulants) that have been approved for the prevention of SSE. They consist of one direct thrombin inhibitor, dabigatran and three factor Xa inhibitors: rivaroxaban, apixaban and, most recently, edoxaban. In this review article we present an overview of the evidence to support the use of NOACs for the prevention of SSE in patients with AF and HF and review the influence of HF subtype and co-morbidities on the potential choice of oral anticoagulant. PMID- 28029412 TI - Is colchicine really harmful in viral myocarditis? PMID- 28029413 TI - Spontaneous coronary dissection: Unravelling the complex riddle of conservative or interventional treatment. PMID- 28029414 TI - Association between anthropometric indices and hyperuricemia in rural area of China: Methodological issues. PMID- 28029415 TI - Relating Health Technology Assessment recommendations and reimbursement decisions in Poland in years 2012-2014, a retrospective analysis. AB - OBJECTIVE: The aim of the study was to assess the influence of public advisory bodies (the Transparency Council and the President of AOTMiT, the Polish Agency for Health Technology Assessment and Tariff System) involved in the process on final reimbursement decisions performed by the Ministry of Health. METHODS: We have analysed all statements of the Transparency Council as well as the President of the AOTMiT recommendations and final reimbursement decisions in Poland for the period of three years: 2012 till 2014. For each recommendation we collected data on decisions as well as potential additional requirements regarding the reimbursement; data was presented for the whole analysed period and separately for each year, to assess the general tendencies in the reimbursement decision making in Poland. We collected all data accessible at February 2015. The kappa measurement of agreement was used to assess the compliance between statements, recommendations and reimbursement decisions. RESULTS: We collected data on 238 drugs evaluated by the Agency. The compliance between the Transparency Council and the President of the AOTMiT was 95% and remained constant in the analysed period. The agreement between the President of the AOTMiT recommendations and final reimbursement decisions was only fairly represented by a kappa coefficient of 0.23 and decreased in the subsequent years. We observed an increasing proportion of positive-conditional recommendations, with the introduction of a risk sharing scheme being the most common condition of a reimbursement recommendation. CONCLUSIONS: We observed that final reimbursement decisions did not reflect statements and recommendations issued by the advisory boards. Positive recommendations issued by the AOTMiT did not guarantee positive reimbursement status, and negative recommendations in some cases did not result in the lack of reimbursement. PMID- 28029416 TI - How to set challenging goals and conduct fair evaluation in regional public health systems. Insights from Valencia and Tuscany Regions. AB - The definition of "the right targets" and the way the evaluation of results is performed affect the willingness to commit to new challenges, which is a factor that influences the relationship between goal setting and performance results. Indeed, some authors claim that the choice of an inappropriate goal-setting procedure is a major cause of failure of management control systems. Goal setting theorists found that assigning a specific and challenging goal leads to higher performance than (a) an easy goal, (b) a general goal or (c) no goal setting. Despite this evidence, yet, few proposals concern the definition of what is "challenging". This paper focuses on two issues: (a) what is to be considered a challenging goal and (b) what is a "fair evaluation" in the health care sector. This work suggests that benchmarking is a valid support to solve the previous dilemmas. Relying on two Regional European advanced experiences - Valencia in Spain and Tuscany in Italy -, this paper aims to provide conceptual methods that can help managers define challenging goals and conduct fair evaluation about their achievement. Although these Regions adopted different governance models, both of them applied very similar techniques, which seem to be associated to an improvement of their performance and a reduction of unwarranted variation. PMID- 28029417 TI - Paying for volume: British Columbia's experiment with funding hospitals based on activity. AB - INTRODUCTION: For decades, Canadian hospitals have been funded using global budgets, a lump sum for providing care irrespective of the volume or mix of patients. In 2010, British Columbia (BC) introduced a controversial, but limited, form of activity-based funding (ABF) for hospitals. This study uses a quasi experimental design to evaluate the impact of the introduction of ABF funding in the province. METHODS: Our analysis used the population of patient-level acute hospitalization and day surgery discharge summaries from BC's acute hospitals from April 1, 2008 to March 31, 2013. Our outcome measures focused on both the intended and unintended impacts of ABF including the volume of cases, the efficiency of care, and the quality of care delivered. Our analysis used interrupted time series analysis. RESULTS: There was an increase in the volume of inpatient surgical activity associated with the implementation of ABF. The volume of medical cases dropped, and medical patients' lengths of stays increased. There were no changes in measures of quality. CONCLUSIONS: Hospitals' measurable responses to ABF policies on a number of key performance measures were mixed. Though BC's experiment with ABF was not associated with increases in hospital volumes for all types of care, the experience provides key lessons that small magnitude and short-term reforms are unlikely to change hospitals' behaviors quickly. PMID- 28029418 TI - Editorial Comment. PMID- 28029419 TI - Author Reply. PMID- 28029420 TI - Early dural metastasis from a case of glioblastoma with primitive neuroectodermal differentiation: A case report and literature review. AB - Glioblastoma with a primitive neuroectodermal (PNET) variant is a rare primary parenchymal tumor. Only a few cases of extraparenchymal metastasis are reported in world literature. Although the overall survival duration of glioblastoma multiforme (GBM) with primitive neuroectodermal tumor (PNET) variety may be prolonged in comparison to classical glioblastoma, the metastatic trend is completely different, and the prognosis is worse. We report an early dural metastasis of pure PNET component appearing in a case of primary glioblastoma with PNET variant. The lesson learned from this case is to look for early craniospinal metastasis in GBM patient with PNET component, even after completion of adjuvant radiochemotherapy. PMID- 28029421 TI - Risk factors for intervertebral instability assessed by temporal evaluation of the radiographs and reconstructed computed tomography images after L5-S1 single level transforaminal interbody fusion: A retrospective study. AB - Intervertebral instability risks following L5-S1 transforaminal lumbar interbody fusion (TLIF) and causes of bony bridge formation on computed tomography (CT) remain largely unknown. We evaluated the temporal changes on plain radiographs and reconstructed CT images from 178 patients who had undergone single-level L5 S1 TLIF between February 2011 and February 2015. We statistically analyzed temporal changes the L5-S1 angle on radiographs and intervertebral stability (IVS) at the last observation. Bony bridge formation between the L5-S1 vertebral bodies and the titanium cage subsidence were analyzed by using reconstructed CT. Preoperative L5-S1 angle in the non-IVS group was significantly greater than that in the IVS group. The cage subsidence was classified as follows: type A, both upper and lower endplates; type B, either endplate; or type C, no subsidence. Types B and C decreased over time, whereas type A increased after surgery. The bony bridges between vertebral bodies were found in 87.2% of patients, and 94.5% of all bony bridges were found only in the cage, not on the contralateral side. Our findings suggested that high preoperative L5-S1 angle increased the risk of intervertebral instability after TLIF. The L5-S1 angle decreased over time with increasing type A subsidence, and almost all bony bridges were found only in the cage. These results suggest that the vertebral bodies were stabilized because of cage subsidence, and final bony bridges were created. Methods to improve bony bridge creation are needed to obtain reliable L5-S1 intervertebral bone union. PMID- 28029423 TI - Prognostic factors in mandibular gingival squamous cell carcinoma: A 10-year retrospective study. AB - The mandibular gingiva is the second most common site of oral cavity squamous cell carcinoma. This retrospective study was designed to determine the clinicopathological features of squamous cell carcinoma of the mandibular gingiva (MGSCC) and to establish a new risk model to predict overall survival. The study included 207 patients with primary MGSCC from January 2000 to September 2009. The medical charts were reviewed and data related to clinical characteristics, treatment provided, histopathological analysis, and follow-up were recorded. All patients underwent surgery as the first-line therapy; follow-up ranged from 1 to 171 months (median 63 months). Clinical characteristics and pathological outcomes were analyzed with respect to the 5-year overall survival rate. A survival risk model was established, and patients were classified into low-, moderate-, and high-risk groups based on the prognostic index designed in this study. The 5-year overall survival rates for the low-, moderate-, and high-risk groups were 92.3%, 76.9%, and 34.2%, respectively. Pathological node metastasis, perineural invasion, and extracapsular spread were the most significant predictive factors for 5-year overall survival. MGSCC is not aggressive, and the survival outcomes of MGSCC are better than those of squamous cell carcinoma (SCC) at other sites. It is suggested that patients with T2-T4 tumours undergo elective neck dissection and those with T1 tumours be followed up without addressing the neck. PMID- 28029424 TI - The utility of a country-specific Bartonella henselae antigen in an IgM-indirect fluorescent antibody assay for the improved diagnosis of cat scratch disease. AB - Bartonella henselae strains genetically differ among nations. The utility of Japanese-specific YH-01 strain was investigated in developing indirect fluorescence antibody assay (IFA) for IgM in comparison with conventional IFA employing Houston-1 strain by testing 100 Japanese patients suspected of cat scratch disease. The country-specific IFA greatly improved the accuracy of diagnosis. PMID- 28029425 TI - Comparative study of millennials (age 20-34 years) grip and lateral pinch with the norms. PMID- 28029426 TI - Three-dimensional finite element analysis of a newly developed aliform internal fixation system for occipitocervical fusion. AB - For patients with occipital malformation, it is difficult to obtain reliable stability using three screws on the midline. A new aliform occipitocervical internal fixation system was designed. The occiput was fixed with 3, 7, or 11 screws, and a three-dimensional finite element model of the system was established. A compressive preload of 40N combined with a pure moment of 1.5Nm was applied to simulate normal flexion, extension, lateral bending, and axial rotation. The stress distribution across the screws on the occiput and the occipital displacement produced by the newly developed system were compared with those produced by the DePuy SUMMIT system. Compared with the SUMMIT system (control group), in the new system, the maximum stress on the occiputs fixed with 3 screws (group A) and 7 screws (group B) increased by 16.5% and 15.0%, respectively. In contrast, the maximum stress on the occiput fixed with 11 screws (group C) decreased by 15.6%. In addition, the maximum occipital displacements under extension decreased by 10.0%, 11.4%, and 11.8% in the A, B, and, C groups, respectively. Our results indicate that both group A and the control group exhibited sufficient strength and instant stability; however, group C exhibited the highest stability and the lowest maximum von Mises stress. PMID- 28029427 TI - Predicting tDCS treatment outcomes of patients with major depressive disorder using automated EEG classification. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising treatment for major depressive disorder (MDD). Standard tDCS treatment involves numerous sessions running over a few weeks. However, not all participants respond to this type of treatment. This study aims to investigate the feasibility of identifying MDD patients that respond to tDCS treatment based on resting-state electroencephalography (EEG) recorded prior to treatment commencing. METHODS: We used machine learning to predict improvement in mood and cognition during tDCS treatment from baseline EEG power spectra. Ten participants with a current diagnosis of MDD were included. Power spectral density was assessed in five frequency bands: delta (0.5-4Hz), theta (4-8Hz), alpha (8-12Hz), beta (13-30Hz) and gamma (30-100Hz). Improvements in mood and cognition were assessed using the Montgomery-Asberg Depression Rating Scale and Symbol Digit Modalities Test, respectively. We trained the classifiers using three algorithms (support vector machine, extreme learning machine and linear discriminant analysis) and a leave one-out cross-validation approach. RESULTS: Mood labels were accurately predicted in 8 out of 10 participants using EEG channels FC4-AF8 (accuracy=76%, p=0.034). Cognition labels were accurately predicted in 10 out of 10 participants using channels pair CPz-CP2 (accuracy=92%, p=0.004). LIMITATIONS: Due to the limited number of participants (n=10), the presented results mainly aim to serve as a proof of concept. CONCLUSIONS: These finding demonstrate the feasibility of using machine learning to identify patients that will respond to tDCS treatment. These promising results warrant a larger study to determine the clinical utility of this approach. PMID- 28029428 TI - The serotonin transporter gene 5-HTTLPR polymorphism is associated with affective psychoses but not with schizophrenia: A large-scale study in the Russian population. AB - BACKGROUND: Affective syndrome is thought to be a key feature that differentiates schizophrenia from schizoaffective disorder (SA) and bipolar disorder with psychotic features (BDP). However genetic underpinnings of these differences remain unresolved. OBJECTIVES: We compared clinical variables of affective psychoses (SA, BDP and schizophrenia with affective symptoms (AFF SCZ)) and schizophrenia without affective symptoms (non-AFF SCZ) and searched for a genetic variant that may differentiate affective psychosis from non-AFF SCZ. METHODS: A total of 2677 subjects, including 831 patients with affective psychosis, 785 patients with non-AFF SCZ and 1061 healthy controls, were used. Clinical symptoms were assessed with the PANSS. The sample was genotyped for 5-HTTLPR polymorphism of the serotonin transporter gene. RESULTS: The diagnostic groups differed significantly on demographic and clinical variables. The percentage of men was higher, the current age and age at illness onset were lower in non-AFF SCZ and SA compared to AFF SCZ and BDP. The severity of positive and negative symptoms decreased significantly from group to group in the following manner: non-AFF SCZ>AFF SCZ>SA>BDP. There was the association between 5-HTTLPR polymorphism and affective psychosis (p=0.01). The frequency of the SS genotype was higher in the affective psychosis group compared to non-AFF SCZ and controls. No differences in the genotype distribution were identified between the non-AFF SCZ group and controls. LIMITATIONS: Difficulties in the differentiation between non-AFF SCZ and AFF SCZ or SA and between AFF SCZ and SA due to uncertain diagnostic boundaries between these conditions. CONCLUSIONS: SA is intermediate between non AFF SCZ and BDP in the severity of positive and negative symptoms. The first episode patients, carriers of the SS genotype have a higher risk of developing affective psychosis than non-AFF SCZ. This finding carries implications for the prognosis of psychosis outcomes in the first-episode patients. PMID- 28029429 TI - High cognitive reserve in bipolar disorders as a moderator of neurocognitive impairment. AB - BACKGROUND: Cognitive reserve (CR) reflects the capacity of the brain to endure neuropathology, minimize clinical manifestations and successfully complete cognitive tasks. The present study aims to determine whether high CR may constitute a moderator of cognitive functioning in bipolar disorder (BD). METHODS: 102 patients with BD and 32 healthy controls were enrolled. All patients met DSM-IV criteria for I or II BD and were euthymic (YMRS<=6 and HDRS<=8) during a 6-month period. All participants were tested with a comprehensive neuropsychological battery, and a Cerebral Reserve Score (CRS) was estimated. Subjects with a CRS below the group median were classified as having low CR, whereas participants with a CRS above the median value were considered to have high CR. RESULTS: Participants with BD with high CR displayed a better performance in measures of attention (digits forward: F=4.554, p=0.039); phonemic and semantic verbal fluency (FAS: F=9.328, p=0.004; and Animal Naming: F=8.532, p=0.006); and verbal memory (short cued recall of California Verbal Learning Test: F=4.236, p=0.046), after multivariable adjustment for potential confounders, including number of admissions and prior psychotic symptoms. LIMITATIONS: The cross-sectional design of the study does not allow the establishment of causal inferences. Additionally, the small size of the sample may have limited some results. CONCLUSIONS: High cognitive reserve may therefore be a valuable construct to explore for predicting neurocognitive performance in patients with BD regarding premorbid status. PMID- 28029430 TI - Reduced human transitional B cell T1/T2 ratio is associated with subsequent deterioration in renal allograft function. AB - Human transitional B cells express relatively high IL-10 and low TNF-alpha levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2 fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-alpha than T2 cells or other B subsets. When analyzed in 45 kidney transplant recipients at the time of late for cause biopsy, the T1/T2 ratio was independently associated with allograft dysfunction over the next 5 years. Next, the T1/T2 ratio was examined in an independent set of 97 clinically stable kidney transplant recipients 2 years after transplant. Again, the T1/T2 ratio was strongly and independently associated with allograft dysfunction over the ensuing 5 years. In these clinically quiescent patients, a low T1/T2 ratio identified a 41-patient subgroup in which 35% developed allograft dysfunction, with 25% losing their allografts. However, none of the 56 patients with a high ratio developed graft dysfunction. In both the initial study and validation groups, the T1/T2 ratio was a much stronger predictor of graft dysfunction than donor-specific antibodies or the estimated glomerular filtration rate. Thus, the T1/T2 ratio, a relative measure of expressing an anti-inflammatory cytokine profile, is a novel prognostic marker that might inform individualized immunosuppression. PMID- 28029432 TI - Frequent overexpression of PDK1 in primary nasopharyngeal carcinoma is associated with poor prognosis. AB - OBJECTIVE: Pyruvate dehydrogenase kinase 1 (PDK1) is reported to be up-regulated and play multiple functions in several cancers. Herein, we investigated its roles in primary nasopharyngeal carcinoma. METHODS: Expression of PDK1 protein was examined by immunohistochemical staining in 102 samples of primary nasopharyngeal carcinoma (pNPC) and 31 samples of chronic nasopharyngitis. The relationships of PDK1 expression levels with clinical features and prognosis in NPC patients were analyzed. RESULTS: PDK1 protein expression was significantly greater in pNPC tissues than in the chronic nasopharyngitis tissues (P<0.01). In addition, overexpression of PDK1 was associated with advanced clinical stage (P<0.01), advanced N classification (P=0.024), and distant metastasis (P=0.048). Kaplan Meier survival analysis demonstrated that patients with higher PDK1 expression had significantly shorter overall survival (P=0.006), disease-free survival (P=0.015), loco-regional relapse-free survival (P=0.008), and distant metastasis free survival (P=0.017). Furthermore, multi-variate analysis showed that PDK1 expression was an independent prognostic factor in pNPC patients. CONCLUSION: PDK1 is frequently upregulated in pNPC and may serve as a prognostic marker. PMID- 28029433 TI - MMP-1 and MMP-8 expression in giant-cell fibroma and inflammatory fibrous hyperplasia. AB - The aim of this study is to compare the immunoexpression of metalloproteinases 1 and 8 in giant-cell fibroma, inflammatory fibrous hyperplasia and normal mucosa. Twenty-two cases of giant-cell fibroma, inflammatory fibrous hyperplasia and oral mucosa (control) each were subjected to immunohistochemistry using anti metalloproteinase-1 and anti-metalloproteinase-8 antibodies. Eight images of each case were captured and analysed through the a) application of a count grid to count the number of positive neutrophils, macrophages, lymphocytes, plasma cells, fibroblasts and blood vessels to obtain the percentage of staining and b) semi automated segmentation quantifying the stained area in square micrometres. Statistical tests included ANOVA Two-way, Kruskal Wallis and Games-Howell, with a significance level of 5%. An increased percentage of metalloproteinase-1 immunopositive blood vessels were observed in giant-cell fibroma (26.6+/-22.4; p=0.02) and inflammatory fibrous hyperplasia (34.3+/-31.5; p=0.01) compared with the control group (19.6+/-9.2). No significant differences in inflammatory cells, fibroblasts and total area of metalloproteinase-1 and -8 were noted among the three groups. Metalloproteinase-1 apparently acts within the pathogenesis of giant-cell fibroma and inflammatory fibrous hyperplasia. PMID- 28029434 TI - Healthy competition: A qualitative study investigating persuasive technologies and the gamification of cycling. AB - Changing socio-technical practices occurring within cycling are leading the pursuit, and its participants, to become ever more embedded into the networked digital world. GPS enabled mobile-technologies have introduced a new element of competition into recreational riding, whether on the road, competing over timed virtual segments, or online dissecting and comparing the data that has been logged and shared via dedicated ride-logging applications. In order to understand these technologies qualitative study using reflective diaries and semi-structured interviews has been conducted with experienced club cyclists who had fully experienced the effects of their arrival. These riders claim that the applications influence their route choice and motivate them to cycle more frequently, and at a greater intensity although the engagement changes over time. This paper explores how this increased motivation to exercise and compete is instigated, manifested and maintained in the everyday practices of cyclists, as well as the negative consequences of gamification. PMID- 28029431 TI - Urine biomarkers of tubular injury do not improve on the clinical model predicting chronic kidney disease progression. AB - Few investigations have evaluated the incremental usefulness of tubular injury biomarkers for improved prediction of chronic kidney disease (CKD) progression. As such, we measured urinary kidney injury molecule-1, neutrophil gelatinase associated lipocalin, N-acetyl-beta-D-glucosaminidase and liver fatty acid binding protein under highly standardized conditions among 2466 enrollees of the prospective Chronic Renal Insufficiency Cohort Study. During 9433 person-years of follow-up, there were 581 cases of CKD progression defined as incident end-stage renal disease or halving of the estimated glomerular filtration rate. Levels of the urine injury biomarkers, normalized for urine creatinine, were strongly associated with CKD progression in unadjusted Cox proportional hazard models with hazard ratios in the range of 7 to 15 comparing the highest with the lowest quintiles. However, after controlling for the serum creatinine-based estimated glomerular filtration rate and urinary albumin/creatinine ratio, none of the normalized biomarkers was independently associated with CKD progression. None of the biomarkers improved on the high (0.89) C-statistic for the base clinical model. Thus, among patients with CKD, risk prediction with a clinical model that includes the serum creatinine-based estimated glomerular filtration rate and the urinary albumin/creatinine ratio is not improved on with the addition of renal tubular injury biomarkers. PMID- 28029435 TI - Assessment of complex dissociative disorder patients and simulated dissociation in forensic contexts. AB - Few assessors receive training in assessing dissociation and complex dissociative disorders (DDs). Potential differential diagnoses include anxiety, mood, psychotic, substance use, and personality disorders, as well as exaggeration and malingering. Individuals with DDs typically elevate on many clinical and validity scales on psychological tests, yet research indicates that they can be distinguished from DD simulators. Becoming informed about the testing profiles of DD individuals and DD simulators can improve the accuracy of differential diagnoses in forensic settings. In this paper, we first review the testing profiles of individuals with complex DDs and contrast them with DD simulators on assessment measures used in forensic contexts, including the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), Personality Assessment Inventory (PAI), and the Structured Inventory of Reported Symptoms (SIRS), as well as dissociation-specific measures such as the Dissociative Experiences Scale (DES) and Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D-R). We then provide recommendations for assessing complex trauma and dissociation through the aforementioned assessments. PMID- 28029436 TI - Psychiatric/ psychological forensic report writing. AB - Approaches to forensic report writing in psychiatry, psychology, and related mental health disciplines have moved from an organization, content, and stylistic framework to considering ethical and other codes, evidentiary standards, and practice considerations. The first part of the article surveys different approaches to forensic report writing, including that of forensic mental health assessment and psychiatric ethics. The second part deals especially with psychological ethical approaches. The American Psychological Association's Ethical Principles and Code of Conduct (2002) provide one set of principles on which to base forensic report writing. The U.S. Federal Rules of Evidence (2014) and related state rules provide another basis. The American Psychological Association's Specialty Guidelines for Forensic Psychology (2013) provide a third source. Some work has expanded the principles in ethics codes; and, in the third part of this article, these additions are applied to forensic report writing. Other work that could help with the question of forensic report writing concerns the 4 Ds in psychological injury assessments (e.g., conduct oneself with Dignity, avoid the adversary Divide, get the needed reliable Data, Determine interpretations and conclusions judiciously). One overarching ethical principle that is especially applicable in forensic report writing is to be comprehensive, scientific, and impartial. As applied to forensic report writing, the overall principle that applies is that the work process and product should reflect integrity in its ethics, law, and science. Four principles that derive from this meta-principle concern: Competency and Communication; Procedure and Protection; Dignity and Distance; and Data Collection and Determination. The standards or rules associated with each of these principles are reviewed. PMID- 28029437 TI - The nature and extent of police use of force in encounters with people with behavioral health disorders. AB - Previous research studies have examined the treatment of people with mental illnesses by the police. Much available data support the adoption of the Crisis Intervention Team (CIT) model. A key issue in CIT development has been reduction in the use of force by CIT officers, and it is suggested that such adoption does accomplish such reduction. However, to date, scant research compares variation in police use of force by CIT officers across populations with mental illnesses, co occurring disorders, and substance abuse disorders, as compared to their non disordered peers. Using data from the Portland Police Bureau, a police agency in which all patrol officers have been trained in the CIT model, we analyze whether police use-of-force differs across these groups. Police use-of-force data were collected for 4211 incidents from the Portland Police Bureau from 2008 to 2011. Results indicate that people perceived as having comorbid behavioral health disorders were generally more likely to have force used against them, and more likely to be perceived as resistant, than people that were perceived as having only substance use disorder, only mental health disorders, or no apparent behavioral health disorders. People with co-occurring disorders are more likely to be perceived as violently resisting police officers and have force used against them. Further, people with no perceived disorders are more likely to have a firearm pointed at them in use-of-force encounters, but also the least likely to be perceived as resisting. PMID- 28029439 TI - Parental separation in childhood and self-reported psychological health: A population-based study. AB - The aim of the present study is to investigate associations between parental separation/divorce during childhood, and self-reported psychological health, adjusting for social capital, social support, civil status and economic stress in childhood. A cross-sectional public health survey was conducted in the autumn of 2012 in Scania, southern Sweden, with a postal questionnaire with 28,029 participants aged 18-80. Associations between parental separation/divorce during childhood and self-reported psychological health (GHQ12) were investigated using logistic regressions. A 16.1% proportion of all men 22.4% of all women reported poor psychological health. Among men, 20.4% had experienced parental separation during childhood until age 18 years, the corresponding prevalence among women was 22.3%. Parental separation/divorce in childhood was significantly associated with poor self-rated psychological health among men who had experienced parental separation/divorce at ages 0-4, and among women with this experience at ages 0-4, 10-14 and 15-18. These significant associations remained throughout the multiple analyses. The results support the notion that the experience of parental separation/divorce in childhood may influence psychological health in adulthood, particularly if it is experienced in the age interval 0-4 years. PMID- 28029440 TI - Impulsivity, alexithymia and dissociation among pathological gamblers in different therapeutic settings: A multisample comparison study. AB - Since many psychopathological traits seem to be related to Gambling Disorder (GD), impulsivity, alexithymia and dissociation could play a central role in gambling behaviors, particularly in pathological gambling. We test this hypothesis in four distinct samples of gamblers, three undergoing different types of treatments and a control group. The study sample consists of 204 subjects (males 87.3%, mean age=47.75 years, SD=12.08) divided into four groups: (1) 59 subjects belonging to an Outpatients Treatment Program in the National Health System (NHS); (2) 60 subjects of an Outpatients Self-Help Group Program; (3) 35 subjects belonging to a Residential Treatment Program (Inpatients Program); and (4) 50 subjects without gambling problems (Control Group). Results show a positive relationship between gambling behaviors, impulsivity and alexithymia, and a negligible link between gambling behaviors and dissociation. Findings also display the presence of higher levels of all these features in pathological gamblers with higher scores on the SOGS, and particularly, in participants attending a Residential Treatment Program (Inpatients Program). This study confirms the hypothesis of the presence of higher levels of impulsivity, alexithymia and dissociation in pathological gamblers with a greater severity and seems to indicate a significant importance of impulsivity and alexithymia in predicting gambling behaviors. PMID- 28029441 TI - Is history of suicidal behavior related to social support and quality of life in outpatients with bipolar I disorder? AB - Bipolar disorder (BD) affects the social functioning and quality of life (QoL) of its patients. This study aimed to investigate whether there is an association between social support (SS), and suicidal behavior in BD I patients compared to healthy controls; secondarily, we evaluated the influence of QoL on those variables. A total of 119 euthymic outpatients with BD I, 46 of whom had attempted suicide (SAs) and 73 who had not (non-SAs), were compared to 63 healthy controls, through the Medical Outcomes Study Social Support Scale and World Health Organization's Quality of Life Instrument. No differences were noted in SS and QoL between SAs and non-SAs. Compared to healthy controls, non-SAs showed lower values in the positive social interaction domain of SS, and the patients, as a whole, showed lower values in affectionate and positive social interaction domains of SS. Compared to healthy controls, SAs had lower values in the environmental domain of QoL, and the patients, as a whole, had lower values in the environmental, social, and psychological domains of QoL. There was positive correlation between SS and QoL. Although BD is a disabling disease, patients receive inadequate SS. Interventions that may alter the SS in these patients should be investigated. PMID- 28029442 TI - Intergenerational similarity in callous-unemotional traits: Contributions of hostile parenting and household chaos during adolescence. AB - Extant research has examined both genetic and environmental risk involved in the transmission of callous-unemotional traits in youth populations, yet no study has examined the intergenerational similarity of these traits between parents and their offspring. The current study examined whether the association between parent callous-unemotional traits and child callous-unemotional traits was mediated by parenting behavior and whether this association was moderated by household environment. Participants included 115 dyads of adolescents (48% female; Mean age=13.97) and their primary caregivers (87% female; Mean age=42.54). Measures of callous-unemotional traits, hostile parenting, and household chaos were collected from both adolescents and parents. A two group structural equation modeling revealed that hostile parenting serves as a mediating process in the association between parent and adolescent callous unemotional traits, but only in the context of high household chaos. Our findings suggest that hostile parenting practices are a mediating process that may explain intergenerational similarity in callous-unemotional traits. Additionally, household chaos may exacerbate the effects of hostile parenting on callous unemotional traits within adolescents, resulting in heightened vulnerability to intergenerational transmission of callous-unemotional traits. PMID- 28029443 TI - [Presence of Legionella spp. in household drinking water reservoirs in Resistencia, Chaco, Argentina. Preliminary report]. AB - Legionella spp. is an environmental bacterium that can survive in a wide range of physicochemical conditions and may colonize distribution systems of drinking water and storage tanks. Legionella pneumophila is the major waterborne pathogen that can cause 90% of Legionnaires' disease cases. The aim of this study was to detect the presence of Legionella spp. in household drinking water tanks in the city of Resistencia, Chaco. The detection of Legionella in water samples was performed by culture methods as set out in ISO 11731:1998. Thirty two water samples were analyzed and Legionella spp. was recovered in 12 (37.5%) of them. The monitoring of this microorganism in drinking water is the first step towards addressing the control of its spread to susceptible hosts. PMID- 28029444 TI - Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study. AB - PURPOSE: To study associations between early and late age-related macular degeneration (AMD) and neovascular AMD (nvAMD) with serum 25-hydroxy vitamin D (25(OH)D) and genetic variants in vitamin D pathway genes. DESIGN: Population based, cross-sectional study in a random sample aged 65 years or older from 7 European countries. PARTICIPANTS: Of 4753 participants, 4496 (2028 men and 2468 women), with a mean age of 73 years, provided a blood sample; 2137 had no signs of AMD, 2209 had early AMD, and 150 had late AMD, of whom 104 had nvAMD. METHODS: Participants were interviewed to determine smoking and alcohol use, sunlight exposure, and diet; underwent fundus photography. Fundus images were graded using the International Classification System for Age-Related Maculopathy. The 25(OH)D was measured by liquid chromatography-tandem mass spectrometry and categorized as deficient (<30 nmol/l), insufficient (30-50 nmol/l), or adequate (>=50 nmol/l). Genotyping was performed on a subsample of 1284 AMD cases and controls for 93 single nucleotide polymorphisms (SNPs) from 7 genes. Associations were investigated by linear or logistic regression adjusted for potential confounders. MAIN OUTCOME MEASURES: Adjusted odds ratio (OR) for 3 outcomes (early AMD, late AMD, nvAMD). RESULTS: No linear association was found with 25(OH)D and early or late AMD or nvAMD. There was no association between insufficient or deficient status with early or late AMD. Deficient status was associated with nvAMD (adjusted OR, 1.27; 95% confidence interval, 1.1-1.45; P < 0.0001). Significant (P < 0.05) associations with 25(OH)D were found for SNPs in genes GC, VDR, CYP2R1, and CYP27B1. Two SNPs (VDR) were associated with early AMD, 4 SNPs (RXRA) and 1 SNP (VDR) were associated with nvAMD, and 1 SNP (RXRA), 2 SNPs (VDR), and 1 SNP (CYP2R1) were associated with late AMD. After Bonferroni correction, no SNPs were associated with early AMD, late AMD, or nvAMD. CONCLUSIONS: Deficiency in 25(OH)D was associated with nvAMD, but the adjusted OR was small, and we cannot exclude residual confounding. The hypothesis of a causal association of vitamin D with AMD is not supported by clear evidence for an association of vitamin D SNPs with early AMD, late AMD, or nvAMD. PMID- 28029445 TI - Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled Trial. AB - PURPOSE: To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial. PARTICIPANTS: Four hundred forty-nine patients with treatment-naive nAMD. METHODS: Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks. MAIN OUTCOME MEASURES: The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks. RESULTS: No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (>=15 ETDRS letter gain, final VA >=20/40 or >=20/25) and visual loss (>=1 ETDRS line loss, >=2 ETDRS line loss, final VA <=20/125 or <=20/200) favored the E10030 1.5 mg combination group. CONCLUSIONS: In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial. PMID- 28029446 TI - Quality of information about maxillofacial trauma on the Internet. AB - Patients increasingly search the Internet for information about health and potential treatments, but the content and accuracy of some websites are questionable. To evaluate the quality of information on maxillofacial trauma, we searched for the terms "jaw fracture" and "cheekbone fracture" on Google, Yahoo, and Bing. We assessed the first 10 results of each search and excluded duplicates or those that were unrelated. We then used the DISCERN tool and the JAMA (Journal of the American Medical Association) benchmarks to assess those that remained. Of the original 60 found, 38 were excluded (29 duplicates, 9 unrelated). The mean (range) DISCERN score for each search was 38.5 (27-57) for jaw fracture and 41.9 (26-61) for cheekbone fracture. No website achieved an excellent score (more than 63), and over three-quarters were categorised as poor (27-38) or fair (39-50). None met all the JAMA benchmarks, but most adhered to at least two. The standard of online information on maxillofacial trauma varies, but is generally of poor quality. Patients should therefore be advised to be cautious of online sources and should be directed towards higher-quality websites. PMID- 28029448 TI - Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma. AB - OBJECTIVE: Present long-term outcomes in primary cervical cancer treated with external beam and high dose rate interstitial brachytherapy. METHODS: High dose rate (HDR) interstitial (IS) brachytherapy (BT) and external beam (EBRT) were administered from 1992 to 2009 to 315 patients who were unsuitable for intracavitary (IC) BT alone. Histology was 89% squamous cell, 8% adenocarcinoma, and 3% adenosquamous. FIGO stage was I-14%, II-47%, III-34%, and IVA-5%. Median tumor size was 6cm. Lymph node metastases were 26% pelvic and 9.5% para-aortic. Treatment planning was 49% 2D and 51% 3D-CT. The mean doses were central EBRT EQD210 37.3+/-4.3Gy (sidewall 49.2+/-3.6Gy) and HDR EQD210 42.3+/-5.3Gy (nominal 5.4Gy*6 fractions using a mean of 24 catheters and 1 tandem). Total EQD210 mean target dose was 79.5+/-5.4Gy. Standardized planned dose constraints were ICRU points or D0.1cc bladder 80%, rectum 75% and urethra 90% of the HDR dose per fraction. Morbidity assessment was CTCAEv3. Median and mean follow-up were 50 and 61months (3-234). RESULTS: The 10-year actuarial local control was 87%, regional control 84%, and loco-regional control 77%. Distant metastasis free survival was 66%, cause specific survival 56%, disease free survival 54%, and overall survival 40%. The rates of late grade GU and GI toxicities were 4.8% G3 and 5.4% G4. CONCLUSIONS: Template-guided interstitial can be safely performed to successfully deliver high radiation dose to locally advanced cervix cancer and avoid excessive dose and injury to adjacent vital pelvic organs. We achieved high tumor control with low morbidity in patients who were poor candidates for intracavitary brachytherapy. PMID- 28029447 TI - A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study. AB - BACKGROUND: The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. METHODS: Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. RESULTS: Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade>=3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. CONCLUSION: In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. PMID- 28029449 TI - Perioperative fluid status and surgical outcomes in patients undergoing cytoreductive surgery for advanced epithelial ovarian cancer. AB - OBJECTIVE: The objective of this study is to investigate the impact of fluid status on perioperative outcomes of patients undergoing cytoreductive surgery (CRS) for advanced epithelial ovarian cancer (EOC). METHODS: Patients undergoing CRS for stage III or IV EOC at a comprehensive cancer center from 12/2010 to 05/2015 were identified. Those who underwent upper abdominal procedures or colon resections were included. Demographic, perioperative, and 30-day complication data were collected. Perioperative weight change was utilized as a surrogate for fluid status. The time to diuresis (tD) was defined as the postoperative day the patient's weight began to downtrend. RESULTS: One hundred ten patients were included. Median age was 62years and median BMI 25.8kg/m2. The majority (74.5%) were stage IIIC. At least 1 bowel resection was performed in 60 cases (54.5%). A median of 5381mL of crystalloid (range 1000-17,550mL) and 500mL of colloids (range 0-2783mL) was given intraoperatively. The median perioperative weight change was +7.3kg (range-0.9kg to +35.7kg). The median tD was 3days (range 1 17days). On univariate analysis, net positive fluid status was associated with unscheduled reoperation, anastomotic leak, surgical site infections (SSI), and length of stay >5days. On multivariate analysis, fluid status was independently associated with SSI (p=0.01). CONCLUSIONS: Perioperative fluid excess is common in patients undergoing CRS for EOC and is independently associated with SSI. PMID- 28029450 TI - Droughts of the twentieth and early twenty-first centuries: Influences on the production of beef and forage in Kentucky, USA. AB - Drought affects societies world-wide in many different ways. It is a natural hazard that is complex and not well understood and as a result, its impacts are often poorly documented. The purpose of this research is to quantify (in dollars) the impacts of drought on Kentucky's beef and forage (hay) production. Observations suggest that the most important droughts in Kentucky occurred in 1930-31, 1940-42, 1952-55, 1987-88, 1999-2000 and 2007. The total state revenue for these commodities were analyzed during these severe drought years and non drought years. The research estimated revenue deficit from these severe droughts in Kentucky for these (beef and hay) agricultural commodities. This study is important to the general public as well as planners and policy makers. Proper documentation of drought impacts should help identify drought vulnerabilities and result in better risk management and mitigation. PMID- 28029451 TI - The interactive effects between high temperature and air pollution on mortality: A time-series analysis in Hefei, China. AB - Recent evidence suggests that there may be an interaction between air pollution and heat on mortality, which is pertinent in the context of global climate change. We sought to examine this interaction in Hefei, a hot and polluted Chinese city. We conducted time-series analyses using daily mortality, air pollutant concentration (including particulate matter with aerodynamic diameter <10MUm (PM10), sulphur dioxide (SO2) and nitrogen dioxide (NO2)), and temperature data from 2008 to 2014. We applied quasi-Poisson regression models with natural cubic splines and examined the interactive effects using temperature-stratified models. Subgroup analyses were conducted by age, gender, and educational levels. We observed consistently stronger associations between air pollutants and mortality at high temperatures than at medium temperatures. These differences were statistically significant for the associations between PM10 and non accidental mortality and between all pollutants studied and respiratory mortality. Mean percentage increases in non-accidental mortality per 10MUg/m3 at high temperatures were 2.40% (95% confidence interval: 0.64 to 4.20) for PM10, 7.77% (0.60 to 15.00) for SO2, and 6.83% (-1.37 to 15.08) for NO2. The estimates for PM10 were 3.40% (0.96 to 5.90) in females and 4.21% (1.44 to 7.05) in the illiterate, marking them as more vulnerable. No clear trend was identified by age. We observed an interaction between air pollutants and high temperature on mortality in Hefei, which was stronger in females and the illiterate. This may be due to differences in behaviours affecting personal exposure to high temperatures and has potential policy implications. PMID- 28029452 TI - Seasonal and spatial differences in source contributions to PM2.5 in Wuhan, China. AB - Fine particle (PM2.5) samples were collected in 2011 and 2012 simultaneously at three sites in Wuhan in an industrial area (ID), downtown Wuhan (DT), and the Wuhan botanical gardens (BG). The annual average concentration of PM2.5 was highest in the industrial area at 180MUgm-3 and lowest in the botanical gardens, with an average of 93MUgm-3. The average downtown PM2.5 concentration was 113MUgm 3. All sites had concentrations well above the World Health Organization (WHO) guidelines and the Chinese air quality standard. The concentration of major constituents of PM2.5 varied seasonally across all sites; specifically, sulfate, nitrate, and organic carbon varied most strongly during spring, followed by summer and fall. Organic carbon varied the most across sites for all seasons, which is attributable to large differences in local source emissions. The major primary sources contributing to OC were vehicle emissions (38.1+/-8.3%), coal combustion (7.0+/-6.2%), meat cooking (3.0+/-1.6%), and biomass burning (3.0+/ 1.0%). All these sources had large seasonal variations across the three sites. Biomass burning had the largest impact at BG, mobile sources had the largest impact at DT, and coal combustion had the largest impact at ID. Mineral dust was a major contributor to PM2.5 (average 16.8+/-9.6MUgm-3) and had very homogenous concentrations across the sites during springtime due to regional dust storms, but had much higher concentration at ID during the summer and fall. The results demonstrate the need for both regional and local air pollution control strategies to reduce air pollution in Wuhan. This research contributes to the field of particulate matter studies by providing information about seasonal and regional fluctuations in PM2.5 in large urban areas, which helps advance understanding of the sources responsible for urban haze. PMID- 28029453 TI - Evaluation of 11 polycyclic aromatic hydrocarbon metabolites in urine of Czech mothers and newborns. AB - Polycyclic aromatic hydrocarbons (PAHs) represent a large group of ubiquitous contaminants of the environment, including food chain where they are released as by-products of incomplete combustion of an organic matter. Epidemiological studies have shown that exposure to PAHs correlated with increased incidence of cancer. Carcinogenicity is associated mainly with metabolites that are formed during metabolic degradation of these substances in exposed organism. In this study monohydroxylated PAHs (OH-PAHs), the major metabolites excreted into urine, were determined in 531 urine samples collected from mothers and their newborns from two localities of the Czech Republic - heavily air polluted Karvina and control locality of Ceske Budejovice and in two sampling rounds - August-October 2013 (summer, less air polluted season) and January-April 2014 (winter, more air polluted season). From all targeted analytes, naphthalene-2-ol was the most abundant compound present in 100% of the samples and it represented also the analyte with the highest concentration. Median concentration of SigmaOH-PAHs in the urine of children was on average 1.6 times lower compared to the respective mother which correlates with higher intake of PAHs by mothers. SigmaOH-PAHs concentrations determined in mothers' urine collected in the summer were comparable in both localities. No significant increase occurred in Ceske Budejovice in winter, while in samples from the Karvina region a statistically significant difference (alpha=0.05) in the amount of SigmaOH-PAHs was observed. The median concentrations of SigmaOH-PAHs in mothers' urine samples in the winter were 1.5 times higher than in the summer in the same locality. The amounts of SigmaOH-PAHs in newborns' urine from Karvina in the winter season were 1.5 times higher than in the summer collected in the same locality and 3.3 times higher when compared with the less polluted locality of Ceske Budejovice. PMID- 28029454 TI - Impact of legacy soil phosphorus on losses in drainage and overland flow from grazed grassland soils. AB - Rates and quantities of legacy soil phosphorus (P) lost from agricultural soils, and the timescales for positive change to water quality, remain unclear. From 2000 to 2004 five 0.2ha grazed grassland plots located on a drumlin hillslope in Northern Ireland, received chemical fertiliser applications of 0, 10, 20, 40, 80kgPha-1yr-1 resulting in soil Olsen P concentrations of 19, 24, 28, 38 and 67mgPL-1, respectively, after which applications ceased. Soil Olsen P and losses to overland flow and drainage were monitored from 2005 to 2011 on an event and weekly flow proportional basis, respectively. Soluble reactive P and total P time series were synchronised with daily rainfall and modelled soil moisture deficits. From 2005 to 2011 soil Olsen P decline was proportional to soil P status with a 43% reduction in the plot at 67mgPL-1 in 2004 and a corresponding 12% reduction in the plot with lowest soil P. However, there was no significant difference in the flow-weighted mean concentration for overland flow among plots, all of which exceeded 0.035mgL-1 in >98% of events. Strong interannual and event variations in losses were observed with up to 65% of P being lost during a single rainfall event. P concentrations in drainage flow were independent of Olsen P and drain efficiency was potentially the primary control on concentrations, with the highest concentrations recorded in the plot at 38mgL-1 Olsen P in 2004 (up to 2.72mgL-1). Hydrological drivers, particularly antecedent soil moisture, had a strong influence on P loss in both overland and drainage flow, with higher concentrations recorded above a soil moisture deficit threshold of 7mm. This study demonstrates that on some soil types, legacy P poses a significant long term threat to water quality, even at agronomically optimum soil P levels. PMID- 28029455 TI - Management of Burn Injuries in the Wilderness: Lessons from Low-Resource Settings. AB - Burns are a common source of injuries worldwide, with a high burden of disease in low- and middle-income countries. Burns also account for 2%-8% of wilderness injuries. Although many are minor, the potential for serious morbidity and mortality exists, and standard treatments used in high-resource settings are not readily available in the backcountry. A literature review was performed to find evidence from low-resource settings that supports alternative or improvised therapies that may be adapted to care of burns in the wilderness. There is good evidence for use of oral rehydration to support volume status in burn patients. There is moderate evidence to support cold therapy as first aid and adjunct for pain control. Some evidence supports use of alternative dressings such as boiled potato peel, banana leaf, aloe vera, honey, sugar paste, and papaya when standard therapies are not available. PMID- 28029456 TI - Preface. PMID- 28029457 TI - New glutathione peroxidase mimetics-Insights into antioxidant and cytotoxic activity. AB - A series of N-alkyl benzisoselenazol-3(2H)-ones has been obtained and transformed to corresponding diselenides by the reduction with sodium borohydride. Additionally, efficient methodology for the oxidative Se-N bond formation by potassium iodate has been presented, new conversion of diselenide to benzisoselenazolone was observed. The GPx-like activity of all synthetized derivatives has been evaluated by NMR. N-Allyl diselenide was up to five times better antioxidant than ebselen. Anticancer capacity towards MCF7 and DU145 cancer cells has been also tested. The highest antiproliferative activity was obtained for N-cyclohexyl benzisoselenazolone. PMID- 28029458 TI - Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors. AB - All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 5-HT6 (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R. PMID- 28029459 TI - Real-time monitoring of cytotoxic effects of electroporation on breast and colon cancer cell lines. AB - PURPOSE: To study the effects of electroporation on different cell lines. MATERIAL: The effects of electroporation on human breast cancer (MDA-MB-231), human colon cancer (SW-480 and HCT-116), human fibroblast cell line (MRC-5), primary human aortic smooth muscle cells (hAoSMC) and human umbilical vein endothelial cells (HUVEC) were studied. Real-time technology was used for cell viability monitoring. Acridine orange/ethidium bromide assay was applied for cell death type determination. A numerical model of electroporation has been proposed. RESULTS: Electroporation induced inhibition of cell viability on dose (voltage) dependent way. The electroporation treatment 375-437.5Vcm-1 caused irreversible electroporation of cancer cells and reversible electroporation of healthy cells. The application of lower voltage rating (250Vcm-1) led to apoptosis as the predominant type of cell death, whereas the use of higher voltage (500Vcm-1) mainly caused necrosis. CONCLUSION: Electroporation represents a promising method in cancer treatment. Different cancer cell lines had different response to the identical electroporation treatment. Electroporation 375-437.5Vcm-1 selectively caused permanent damage of cancer cells (SW-480), while healthy cells (MRC-5, hAoSM and HUVEC) recovered after 72h. The type of cell death is dependent of electroporation conditions. The proposed numerical model is useful for the analysis of phenomena related to electroporation treatment. PMID- 28029460 TI - [Predictive tools of preterm birth in asymptomatic high-risk pregnancy]. AB - OBJECTIVE: Describe tools designed to predict preterm birth in asymptomatic high risk pregnancy and determine their predictive value. METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: Obstetric history particularly spontaneous preterm birth identifies a population at risk for preterm birth for the current pregnancy (LE3). This risk is related to the number of prior preterm birth and is even higher than the term of the prior event is more premature and that the event concerns the last pregnancy (LE3). The literature data are insufficient to recommend systematic cervical examination at each prenatal visit in asymptomatic high-risk pregnancy (multiple pregnancy, uterine malformations, history of spontaneous preterm birth, excisional cervical procedure or at least two voluntary first trimester abortion) (professional consensus). Regular recording of uterine activity and home visits for asymptomatic high-risk pregnancy did not predict nor reduce the risk of preterm birth (LE2) and are not recommended (grade B). In asymptomatic high-risk pregnancy, ultrasonographic measurement of cervical length estimates the risk of preterm birth (LE2). Shorter is the cervical length higher is the risk of preterm birth (LE3). In asymptomatic patient with prior preterm birth, ultrasonographic measurement of cervical length estimates the risk of preterm birth (LE2). The strategy of ultrasound indicated cerclage are discussed in dedicated chapter. The measurement of cervical length by transvaginal ultrasonography in asymptomatic pregnancy with uterine malformation, a history of cervical treatment, at least two voluntary abortions or having a multiple pregnancy would estimate the risk of preterm birth (LE3). A shortening of more than 10% of the cervical length at 3 week interval is associated with an increased risk of preterm birth (LE3). Systematic detection of fetal fibronectin is not recommended in asymptomatic high risk population (grade C). The combination of ultrasound measurement of cervical length and fetal fibronectin detection improves modestly the prediction of preterm birth (LE3). However, literature data are insufficient to recommend routine measurement of cervical length by transvaginal ultrasonography during surveillance ultrasounds and/or detection of fetal fibronectin because this policy has never demonstrated its interest in preventing preterm birth and in the reduction of neonatal morbidity and mortality (professional consensus). CONCLUSION: Several predictive tools are described to define the risk of preterm birth but there is no evidence to date of the effectiveness of systematic screening strategy on the prevention of prematurity in asymptomatic high-risk population, except the ultrasound measurement of the cervical length in the population of patients having had a prior preterm birth. PMID- 28029461 TI - [Prevention of preterm birth by uterine cervical cerclage]. AB - OBJECTIVE: To review the scientific literature on cervical insufficiency and indications of cervical cerclage cervix. MATERIALS AND METHODS: The PubMed database, the Cochrane Library and the recommendations from the French and international obstetrical societies between 1972 and June 2016 have been consulted. RESULTS: Cervical insufficiency is a pathophysiological concept and to date no consensual definition is available: the diagnosis is clinical and discussed retrospectively in case of patients with a history of late miscarriages and/or spontaneous preterm delivery, with asymptomatic dilatation of the cervix (professional consensus). The risk of preterm birth is higher in case of surgical cold-knife conisation as compared to loop electrosurgical excision (LE3) and laser vaporization has a negligible impact (LE3). In patients with a history of late pregnancy loss or preterm birth, investigations for the diagnosis of uterine malformation are recommended (grade C). No investigation is recommended for the diagnosis of a cervical insufficiency (professional consensus). A history indicated cerclage is not recommended in case of only past history of conisation (grade C), uterine malformation (professional consensus), isolated history of preterm delivery (grade B) or twin pregnancies in primary (grade B) or secondary (grade C) prevention of preterm birth. A history-indicated cerclage is recommended for single pregnancy with a history of at least three late miscarriages or preterm deliveries (grade A). In case of history of one or two late miscarriages or preterm deliveries, there are not sufficient arguments to recommend a history-indicated cerclage (professional consensus). Further studies are needed. The ultrasound-indicated cerclage is not recommended in case of short cervical length during the 2nd trimester of single pregnancy without past history of gynecologic or obstetrical event (grade B). In case of past history of a single pregnancy delivery before 34 weeks gestation (WG), ultrasound cervical length screening is recommended between 16 and 22 WG in order to propose a cerclage in case of length<25mm before 24 WG (grade C). Ultrasound-indicated cerclage is not recommended for multiple pregnancy with a short cervix (grade B). Emergency cerclage using the MacDonald technique is recommended during the second trimester of pregnancy in case of major changes of the cervix, with or without protrusion of the fetal membranes, but without premature rupture of membranes or chorioamnionitis (grade C). Tocolysis and antibiotics during cerclage should be considered individually (professional consensus). There is no reason to recommend a period of expectative before considering an emergency cerclage (professional consensus). A maximum gestational age to perform a cerclage cannot be recommended (professional consensus). A cervico-isthmic cerclage can be discussed in case of failure of MacDonald cerclage (professional consensus). Scientific data are insufficient to recommend or not a vaginal bacteriological analysis before performing a cerclage (professional consensus). The use of double cerclage does not improve perinatal outcome (NP3) and is not recommended (grade C). There is insufficient scientific argument to recommend a type of stitch over another (grade C). The available data are not in favor of a superiority of the Shirodkar cerclage in case of history- or ultrasound-indicated cerclage and the MacDonald cerclage is firstly recommended because technically easier and less risky (grade C). Overall, complications of cerclage are rare but potentially serious. The occurrence of complications is no different between the history-indicated and echo-indicated cerclage (LE4). There is no scientific evidence on the benefit of bed rest and adjuvant treatments (antibiotics or indomethacin) during history or ultrasound-indicated cerclage (professional consensus). CONCLUSION: Available data in the literature about cervical cerclage are generally of low level of evidence. PMID- 28029462 TI - [Prediction of preterm delivery in symptomatic women (preterm labor)]. AB - OBJECTIVES: To evaluate the predictors of spontaneous preterm birth in case of preterm labor. MATERIALS AND METHODS: Literature search in Medline and Cochrane databases and recommendations of international societies. Selection of studies in symptomatic women (with preterm labor). RESULTS: Preterm labor is defined as a clinical situation occurring between 22 and 36 weeks + 6 days, in which cervical changes are observed associated with uterine contractions, evolving spontaneously or not to preterm delivery (Professional consensus). Uterine contractions can be detected by the cardiotocometry and by the patient herself. Uterine contractions frequency does not reliably predict spontaneous preterm birth (NP3). Cervical modifications may be appreciated by ultrasonographic measurement of cervical length and vaginal examination (Bishop score). Cervical length is significantly correlated with the risk of spontaneous preterm birth (NP1). The 15 and 25mm thresholds are the most relevant to respectively predict and rule out spontaneous premature birth at 48hours and 7 days (professional consensus). In symptomatic patients, routine ultrasonographic measurement of cervical length at admission is not associated with a significant reduction of spontaneous preterm birth rate (NP3). Clinical evaluation of the cervix (Bishop score) by vaginal examination is an effective parameter for the prediction of preterm birth (NP2). The higher the Bishop score, the higher the risk of preterm birth (NP3). It is not possible to recommend the use of a tool more than another (cervix ultrasound versus vaginal examination) in women experiencing preterm labor (grade B). However, due to the excellent negative predictive value of cervical ultrasound measurement and the lower interobserver variability, we suggest to perform a cervical ultrasonographic measurement before an in utero transfer for preterm labor (professional consensus). Screening for fetal fibronectin in the genital tract of patients with preterm labor has an excellent negative predictive value for predicting the absence of spontaneous preterm birth at 48hours and 7 days (NP2). Nevertheless, its use in symptomatic women is not associated with a reduction of preterm birth rate (NP2) and is therefore not recommended (professional consensus). CONCLUSION: Predictors of preterm birth in women with preterm labor are effective but do not allow a reduction of the preterm birth rate. The high negative predictive value of these predictors (Bishop score, ultrasound measurement of the cervix, fetal fibronectin detection in the genital tract) is an asset in the choice of an appropriate management in women with preterm labor (in utero transfer or corticosteroids). PMID- 28029463 TI - [Tocolysis for preterm labor without premature preterm rupture of membranes]. AB - OBJECTIVES: To propose guidelines for clinical practice for tocolysis in preterm labor without premature preterm rupture of the membranes (PPROM). MATERIALS AND METHODS: Bibliographic searches were performed in the Medline and Cochrane databases and gynecologist and obstetricians' international society guidelines. It is important to note that most studies included women in preterm labour with and without PPROM. RESULTS: Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2). Compared with betamimetics, nifedipine is associated with a reduction in necrotizing enterocolitis, intraventricular hemorrhage and respiratory distress syndrome (LE2). There is no difference between nifedipine and atosiban regarding neonatal prognosis, except a modest reduction in NICU transfer with nifedipine (LE2). Betamimetics, atosiban and nifedipine are equivalent to prolong pregnancy for more than 48hours (LE2). Compared with betamimetics, nifedipine reduces delivery before 34 WG and is associated with a longer pregnancy (LE2). Atosiban and nifedipine are equivalent to prolong the pregnancy over 7 days (LE2), but in women with spontaneous preterm labour without PPROM, nifedipine reduces deliveries before 37 WG and pregnancy prolongation is longer, without improving neonatal prognosis (LE2). Maternal severe adverse effects may occur with all tocolytics (LE4). Betamimetics cardiovascular adverse effects are frequents (LE2) and may be serious (maternal death) (LE4). Nifedipine and atosiban reduce maternal adverse effect compared with placebo (LE2). Cardiovascular adverse effects are moderately increased with nifedipine compared with atosiban (LE2), without increasing treatment discontinuation (LE2). Regarding their benefits on pregnancy prolongation and good maternal tolerance, atosiban and nifedipine can be used for tocolysis in spontaneous preterm labour without PPROM (Grade B), for singleton and multiple pregnancies (Professional Consensus). Advantageously, nifedipine is orally taken and is inexpensive (Professional Consensus). Nicardipine should not be used for tocolysis (Professional Consensus) and betamimetics should not be prescribed anymore for tocolysis (Grade C). All tocolytic treatment should be prescribed for up to 48hours (Grade B). In case of initial tocolysis failure, another treatment may be proposed with the other class of tocolytic (Professional Consensus). Different class of tocolytics should not be combined (Grade C). Scientific data are lacking to propose guidelines regarding a rescue tocolysis, after a first previous successful tocolysis with complete antenatal corticosteroid therapy (Professional Consensus). There is no scientific evidence to propose a tocolysis in women with advanced dilatation (GradeC), nor prescribe a tocolysis after 34 WG (Professional Consensus). There is no evidence to define a gestational age lower limit for tocolysis (Professional Consensus). CONCLUSION: Nifedpine and atosiban can be used for tocolysis (Grade B), including for multiple pregnancies (Professional Consensus). Maintenance tocolysis is useless (Grade C) and potentially harmful (Grade C). Betamimetics should not be used for tocolysis (Professional Consensus). PMID- 28029464 TI - [Induced abortion: Guidelines for clinical practice - Introduction]. PMID- 28029465 TI - [Psychological aspects of abortion]. AB - OBJECTIVE: To propose recommendations for women's counseling in abortion request and the psychological experience of orthogenic teams. MATERIALS AND METHODS: Bibliographic search in the Medline database, PubMed, Cochrane Database Library, EM Premium bases, ENT Unistra and Cairn from 1990 to 2016. RESULTS: During the pre-abortion consultations, it is recommended to respect the choice of the woman on to see or not the ultrasound images (gradeC) and determine with her the time it needs to perform abortion (professional agreement). Women's satisfaction seems greater when they have the possibility to choose the abortion method (grade B). It is therefore important that both methods are available to all gestational ages (professional agreement). There is no relationship between an increase in psychiatric disorders and induced abortion (NP2). Meetings for professionals are useful and should, to the extent possible, be established (professional agreement). CONCLUSION: Improving psychological support for women involve listening them and respect their choice. This also involves thinking as a team. PMID- 28029466 TI - [Accreditation of Independent Ethics Committees]. AB - OBJECTIVE: According to Law 14/2007 and Royal Decree 1090/2015, biomedical research must be assessed by an Research Ethics Committee (REC), which must be accredited as an Research ethics committee for clinical trials involving medicinal products (RECm) if the opinion is issued for a clinical trial involving medicinal products or clinical research with medical devices. The aim of this study is to ascertain how IEC and IECm accreditation is regulated. METHODS: National and regional legislation governing biomedical research was analysed. RESULTS: No clearly-defined IEC or IECm accreditation procedures exist in the national or regional legislation. DISCUSSION: Independent Ethics Committees are vital for the development of basic or clinical biomedical research, and they must be accredited by an external body in order to safeguard their independence, multidisciplinary composition and review procedures. PMID- 28029467 TI - [Frail-VIG index: Design and evaluation of a new frailty index based on the Comprehensive Geriatric Assessment]. AB - INTRODUCTION: Frailty is closely linked to health results. Frailty indexes (FI) and the Comprehensive Geriatric Assessment (CGA) are multidimensional tools. FI serve to quantitatively measure frailty levels. They have shown to have an excellent correlation with mortality. However, they are infrequently used in clinical practice. Given the need for new, more concise, and pragmatic FI, a new FI is proposed based on a CGA (Frail-VIG Index). MATERIAL AND METHODS: A prospective, observational, longitudinal study was conducted, with cohort follow up at 12 months or death. Participants were patients admitted in the Geriatric Unit of the University Hospital of Vic (Barcelona, Spain) during 2014. Contrast of hypothesis log-rank for survival curves according to Frail-VIG index, and analysis of ROC curves were performed to assess prognostic capacity. RESULTS: A total of 590 patients were included (mean age=86.39). Mortality rate at 12 months was 46.4%. The comparative analysis showed statistically significant differences (P<.05) for almost all variables included in the Frail-VIG index. Survival curves also show significant differences (X2=445, P<.001) for the different Frail-VIG index scores. The area under the ROC curve at 12 months was 0.9 (0.88-0.92). An administration time of the Index is estimated at less than 10minutes. CONCLUSIONS: Results endorse the Frail-VIG index as a simple (as for contents), rapid (for administration time) tool, with discriminative (for situational diagnosis) and predictive capacity (high correlation with mortality). PMID- 28029468 TI - [Usefulness of the FEV1/FEV6 ratio to detect the prevalence of lung obstruction in hospitalised patients with multiple morbidities]. AB - BACKGROUND: The prevalence of lung obstruction increases with age and the presence of comorbidities. Although a complete spirometry is necessary to confirm the diagnosis, this may be impractical in elderly patients with cognitive impairment or functional dependence. Recently, the use of portable devices using the FEV1/FEV6 ratio have shown to be useful for assessing the presence of lung obstruction, with greater ease of use, but its usefulness has not been established in the elderly population with multiple morbidities. METHODS: A cross sectional study was conducted on patients hospitalised in the complex chronic patients Unit of the University Hospital Mutua de Terrassa. All of them completed a questionnaire that included -among other things- measurements of functional dependence and cognitive impairment. Three manoeuvres validated with the Piko-6 device were attempted before discharge, and considering an FEV1/FEV6<0.75 as criteria for obstruction. An analysis was performed on the characteristics of the population that was able to perform the tests, as well as the prevalence of pulmonary obstruction. RESULTS: A total of 54 patients were included in the study, of which 35 (64.81%) performed the manoeuvres correctly. Patients who were unable to complete the manoeuvres of the Piko-6 had more functional dependence (Barthel 19 vs. 72, P<.0001) and cognitive impairment (Pfeiffer 1 vs. 9, P<.0001; MEC 28/35 vs. 3/35, P<.010). The prevalence of obstruction was 71.43%, with an underdiagnosis of 72%. CONCLUSIONS: The FEV1/FEV6 ratio was not determined in 35.18% of the patients due to cognitive impairment or functional dependence. The prevalence of obstruction and underdiagnosis exceeded 70%. PMID- 28029469 TI - Lactobacillus casei subsp. rhamnosus septicaemia in three patients of the paediatric intensive care unit. PMID- 28029470 TI - Clostridium difficile-associated clinical burden from lack of diagnostic testing in a Chinese tertiary hospital. AB - Despite Clostridium difficile infection (CDI) being a common cause of diarrhoea in hospitals worldwide, diagnostic testing or management guidelines are not available in most hospitals in China. In this prospective two-year study, the incidence of CDI among 276 patients with watery diarrhoea was 23.1%. Lack of diagnostic testing for CDI was associated with improper management in 26.4% of patients, risk of nosocomial transmission from lack of isolation precautions, and risk of community transmission from discharging symptomatic toxigenic C. difficile carriers. Updating practice guidelines in line with the current evidence and implementing diagnostic testing for CDI are recommended in hospitals in China. PMID- 28029471 TI - Treatment of Clostridium difficile infection: a national survey of clinician recommendations and the use of faecal microbiota transplantation. AB - Adherence to Clostridium difficile infection treatment guidelines is associated with lower recurrence rates and mortality as well as cost savings. This survey of Irish clinicians indicates that patients are managed using a variety of approaches. Faecal microbiota transplantation is potentially underused despite its recommendation in national and European guidelines. PMID- 28029472 TI - The Role of Interventional Cardiology to Our Understanding of Basic Mechanisms Related to Coronary Atherosclerosis: "Thinking outside the box". AB - Interventional cardiology has contributed significantly to our understanding of coronary atherosclerosis. Interventional cardiology has allowed a correlation between the clinical picture of coronary atherosclerosis with the underlying pathology and has helped establish the evolution of atherosclerotic plaques in vivo. Better understanding of the basic mechanisms of coronary atherosclerosis, due to the contributions of interventional cardiology, will help cure and/or prevent coronary atherosclerosis in the next few decades. In this mini review, several of the remarkable contributions of interventional cardiology, which have allowed a better understanding of the pathophysiologic mechanisms related to coronary atherosclerosis, will be emphasized. In addition, certain projections for the future will be made based on current knowledge. PMID- 28029473 TI - Incidental migration of a right ventricular lead into the peritoneal cavity. PMID- 28029474 TI - Hypertension after injury among burned combat veterans: A retrospective cohort study. AB - BACKGROUND: The long-term health effects of burn are poorly understood. We sought to evaluate the relationship between burn and the subsequent development of hypertension. METHODS: Retrospective cohort study of patients admitted to our burn center from 2003 to 2010. Data collected included demographic variables, burn size, injury severity score, presence of inhalation injury, serum creatinine, need for renal replacement therapy, as well as days spent in the hospital, in the intensive care unit and on mechanical ventilation. Data for the subsequent diagnosis of hypertension was obtained from medical records. Cox proportional hazard regression models were performed to determine what factors were associated with hypertension. RESULTS: Of the 711 patients identified, 670 were included for analysis after exclusions. After adjustment, only age (HR 1.06 per one year increase, 95% confidence interval 1.03-1.08; p<0.001), percentage of total body surface area burned (HR 1.11 per 5% increase, 95% confidence interval 1.04-1.19; p=0.002) and acute kidney injury (HR 1.68, 95% confidence interval 1.05-2.69; p=0.03) were associated with hypertension. CONCLUSION: Burn size is independently associated with the subsequent risk of hypertension in combat casualties. Clinical support for primary prevention techniques to reduce the incidence of hypertension specific to burn patients may be warranted. PMID- 28029475 TI - TRALI following fresh frozen plasma resuscitation from burn shock. AB - INTRODUCTION: Resuscitation from burn shock using fresh frozen plasma (FFP) has been described. Critics of FFP resuscitation cite the development of transfusion related acute lung injury (TRALI) as a deterrent to its use. This study examines the occurrence of TRALI with FFP resuscitation of critically ill burned patients. METHODS: A retrospective chart review was conducted of severely burned patients who received FFP resuscitation. Data points included age, TBSA, TBSA full thickness, presence of alternate etiologies of acute lung injury, total FFP administered, and signs and symptoms of TRALI as defined per the Canadian Blood Services Consensus Conference. RESULTS: Eighty-three patients met the definition of severe burn and received FFP resuscitation. Of those, 65 met exclusion criteria. Eighteen patients were left for analysis with only one found to have signs and symptoms of TRALI. That patient suffered a 53.5% TBSA burn, received a total of 6228ml FFP, had no competing etiologies of ALI, and was diagnosed with TRALI within 6h of completing the FFP transfusion. CONCLUSION: The possible occurrence of TRALI in burn patients receiving FFP resuscitation should be weighed against the reported benefits of such a resuscitation strategy. PMID- 28029476 TI - A murine model of orthotopic periorbital subunit transplantation. AB - BACKGROUND: Conventional reconstructive methods fail to achieve satisfactory results in total eyelid defect cases. Vascularized composite tissue allotransplantation might provide both good appearance and function for these patients. We developed an orthotopic periorbital transplantation model in rats to facilitate further experimentation in this field. METHODS: In anatomical studies, the vascular distribution to and innervation of the periorbital unit were identified and recorded. Then, according to the anatomical studies, eight orthotopic transplantations and two transplantations with pedicle ligation were performed. The posterior facial vein and the external carotid artery were selected as the graft pedicles, while the temporal and upper zygomatic facial nerves were used for graft innervation. All transplanted eyelids were assessed daily. Micro-CT scanning and hematoxylin and eosin staining of the grafts were performed 60 days after the operation. RESULTS: In total, 90% of recipients tolerated the operation well. All grafts without pedicle ligation survived, and new hair growth was observed. The position of the eyelid was maintained, and eyelid function was partially restored. In the recipients with graft pedicle ligation, the grafts became necrotic and mummified within four to five days. Micro-CT of the surviving grafts showed a good blood supply, and histological staining revealed normal morphology. CONCLUSIONS: A periorbital subunit orthotopic transplantation model was established, which might facilitate future eyelid allotransplantation-related experimentation. PMID- 28029477 TI - Relating farmer's perceptions of climate change risk to adaptation behaviour in Hungary. AB - Understanding how farmers perceive climate change risks and how this affects their willingness to adopt adaptation practices is critical for developing effective climate change response strategies for the agricultural sector. This study examines (i) the perceptual relationships between farmers' awareness of climate change phenomena, beliefs in climate change risks and actual adaptation behaviour, and (ii) how these relationships may be modified by farm-level antecedents related to human, social, financial capitals and farm characteristics. An extensive household survey was designed to investigate the current pattern of adaptation strategies and collect data on these perceptual variables and their potential antecedents from private landowners in Veszprem and Tolna counties, Hungary. Path analysis was used to explore the causal connections between variables. We found that belief in the risk of climate change was heightened by an increased awareness of directly observable climate change phenomena (i.e. water shortages and extreme weather events). The awareness of extreme weather events was a significant driver of adaptation behaviour. Farmers' actual adaptation behaviour was primarily driven by financial motives and managerial considerations (i.e. the aim of improving profit and product sales; gaining farm ownership and the amount of land managed; and, the existence of a successor), and stimulated by an innovative personality and the availability of information from socio-agricultural networks. These results enrich the empirical evidence in support of improving understanding of farmer decision-making processes, which is critical in developing well-targeted adaptation policies. PMID- 28029478 TI - Development and evaluation of a comprehensive drought index. AB - Droughts are known as the world's costliest natural disasters impacting a variety of sectors. Despite their wide range of impacts, no universal drought definition has been defined. The goal of this study is to define a universal drought index that considers drought impacts on meteorological, agricultural, hydrological, and stream health categories. Additionally, predictive drought models are developed to capture both categorical (meteorological, hydrological, and agricultural) and overall impacts of drought. In order to achieve these goals, thirteen commonly used drought indices were aggregated to develop a universal drought index named MASH. The thirteen drought indices consist of four drought indices from each meteorological, hydrological, and agricultural categories, and one from the stream health category. Cluster analysis was performed to find the three closest indices in each category. Then the closest drought indices were averaged in each category to create the categorical drought score. Finally, the categorical drought scores were simply averaged to develop the MASH drought index. In order to develop predictive drought models for each category and MASH, the ReliefF algorithm was used to rank 90 variables and select the best variable set. Using the best variable set, the adaptive neuro-fuzzy inference system (ANFIS) was used to develop drought predictive models and their accuracy was examined using the 10 fold cross validation technique. The models' predictabilities ranged from R2 = 0.75 for MASH to R2 = 0.98 for the hydrological drought model. The results of this study can help managers to better position resources to cope with drought by reducing drought impacts on different sectors. PMID- 28029479 TI - To transfer or not to transfer? Evidence from validity and reliability tests for international transfers of non-market adaptation benefits in river basins. AB - The attempt to design cost-effective adaptation policies incorporating non-market values to inhibit climate change impacts on water resources may increase the interest in applying the Benefit Transfer method. Benefit Transfer is a practical way to consider non-market values using functions and estimates acquired through primary valuation methods from other sites. Among the primary methods, Choice Experiments appear to particularly accommodate Benefit Transfer. Nevertheless, validity and reliability of international value transfers obtained from Choice Experiments have not been adequately examined. To this end, two identical Choice Experiments were conducted in Greece and Italy in the context of river services adaptation, testing validity and reliability of Benefit Transfer. The application of validity and reliability tests for different types of transfers is supportive for the use of Benefit Transfer, at least for the value transfer types. In particular the reliability of value transfer was higher when income adjustments were taken into account. Overall, Benefit Transfer can be attentively considered to evaluate cost-effective adaptation policies across countries experiencing similar climate change trends. The latter gains more importance given that an international Benefit Transfer setting as regards the non-market benefits of adaptation to climate change for river services is absent in the relevant literature. PMID- 28029480 TI - Sediment source identification and load prediction in a mixed-use Piedmont watershed, South Carolina. AB - Many streams in the Piedmont region of the southeastern United States transport a disproportionately large amount of suspended sediment in response to moderately increased streamflows. Transport and deposition of excess sediment affect the stability of the channel and the health of the biological community; therefore, identifying the main source(s) of sediment and assessing the relationships between source, transport, and streamflow are critical to aquatic life and habitat management, dynamic equilibrium preservation, and development of feasible mitigation scenarios. The objectives of this study were to: (1) predict the annual suspended sediment yield and (2) identify significant contributing upland sources of sediment in the Lawsons Fork Creek basin, a 217 km2 mixed-use watershed in the South Carolina Piedmont. A regularly monitored cross-section located in the downstream reach was equipped with a passive sediment sampler, gage-height recorder, and sediment tiles. Streamflow and sediment concentration were measured over a 24-month period under variable hydrologic regimes. Results indicated that the average annual sediment yield (168 t/km2/yr) is significantly higher than yields documented in Piedmont watersheds of comparable size. To identify and prioritize sources of sediment contribution, stable isotopes of nitrogen (delta15N) and carbon (delta13C) were used as tracers. Source material was compared with suspended sediment near the watershed outlet (target material) and SIAR, a Bayesian Inference model, was used to estimate source apportionment. Results of this source study indicate that approximately 60% of the total sediment load in the water column during high flow events is derived from stream bank erosion. Findings are consistent with observed unstable stream bank conditions in the watershed. This study supports the use of a dual-isotopic fingerprinting approach in tandem with traditional sediment monitoring as a cost effective method to identify and target sediment sources in a mixed-use watershed. PMID- 28029481 TI - Industrial metal pollution in water and probabilistic assessment of human health risk. AB - Concentration of eight heavy metals in surface and groundwater around Dhaka Export Processing Zone (DEPZ) industrial area were investigated, and the health risk posed to local children and adult residents via ingestion and dermal contact was evaluated using deterministic and probabilistic approaches. Metal concentrations (except Cu, Mn, Ni, and Zn) in Bangshi River water were above the drinking water quality guidelines, while in groundwater were less than the recommended limits. Concentration of metals in surface water decreased as a function of distance. Estimations of non-carcinogenic health risk for surface water revealed that mean hazard index (HI) values of As, Cr, Cu, and Pb for combined pathways (i.e., ingestion and dermal contact) were >1.0 for both age groups. The estimated risk mainly came from the ingestion pathway. However, the HI values for all the examined metals in groundwater were <1.0, indicating no possible human health hazard. Deterministically estimated total cancer risk (TCR) via Bangshi River water exceeded the acceptable limit of 1 * 10-4 for adult and children. Although, probabilistically estimated 95th percentile values of TCR exceeded the benchmark, mean TCR values were less than 1 * 10-4. Simulated results showed that 20.13% and 5.43% values of TCR for surface water were >1 * 10 4 for adult and children, respectively. Deterministic and probabilistic estimations of cancer risk through exposure to groundwater were well below the safety limit. Overall, the population exposed to Bangshi River water remained at carcinogenic and non-carcinogenic health threat and the risk was higher for adults. Sensitivity analysis identified exposure duration (ED) and ingestion rate (IR) of water as the most relevant variables affecting the probabilistic risk estimation model outcome. PMID- 28029482 TI - A chronic toxicity study of diphenylarsinic acid in F344 rats in drinking water for 52 weeks. AB - Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. The purpose of the present study was to evaluate the potential toxicity of DPAA when administered to rats in their drinking water for 52 weeks. DPAA was administered to groups 1-4 at concentrations of 0, 5, 10, and 20ppm in their drinking water for 52 weeks. There were no significant differences in the final body weights between the control groups and the treatment groups in male or female rats. In serum biochemistry, in females 20ppm DPAA significantly increased alkaline phosphatase and gamma glitamyl transferase compared to controls, and 10 and 20ppm DPAA significantly increased total cholesterol compared to controls. Absolute and relative liver weights were significantly increased in females treated with 20ppm DPAA compared to the control group. Dilation of the common bile duct outside the papilla of Vater and stenosis of the papilla of Vater was observed in all male and female rats administered 20ppm DPAA. The incidence of intrahepatic bile duct hyperplasia was significantly increased in male and female rats treated with 20ppm DPAA compared to the control groups. These results suggest that DPAA is toxic to the bile duct epithelium in rats. The no-observed adverse effect levels of DPAA were estimated to be 10ppm (0.48mg/kg b.w./day) for males and 5ppm (0.35mg/kg b.w./day) for females under the conditions of this study. PMID- 28029483 TI - Key factors in disease spreading: Spatial heterogeneity, time dependence, and human behavior: Comment on "Pattern transitions in spatial epidemics: Mechanisms and emergent properties" by Gui-Quan Sun et al. PMID- 28029484 TI - Cities' influence on spatial epidemics: Comment on "Pattern transitions in spatial epidemics: Mechanisms and emergent properties" by Gui-Quan Sun et al. PMID- 28029485 TI - Shenfu injection for improving cellular immunity and clinical outcome in patients with sepsis or septic shock. AB - PURPOSE: To assess the efficacy of Shenfu injection (SFI) for enhancing cellular immunity and improving the clinical outcomes of patients with septic shock. METHODS: Patients with sepsis were randomly assigned to receive either SFI at a dose of 100mL every 24hours for 7 consecutive days or a placebo in addition to conventional therapy. The immunologic parameters were collected on days 1, 3, and 7 after the above treatments, and the clinical outcomes were updated for 28days. RESULTS: Of these160 patients, 3 were excluded from the analysis due to protocol violation and withdrawal of consent; thus, 157 completed the study (78 in the SFI group and 79 in the placebo group). We found that SFI increased both CD4+ and CD8+ T cells in peripheral blood and up-regulated HLA-DR expression in monocytes (P<.05). Furthermore, SFI was also found to restore ex vivo monocytic tumor necrosis factor alpha and interleukin 6 proinflammatory cytokine release in response to the endotoxin (P<.05). Importantly, the SFI group showed better clinical outcomes than did the placebo group in terms of the duration of vasopressor use (P=.008), Acute Physiology and Chronic Health Evaluation II score (P=.034), Marshall score (P=.01), and length of intensive care unit stay (10.5+/ 3.2 vs 12.2+/-2.8days; P=.012). However, the 28-day mortality rate was not significantly different between the SFI (20.5%; 16/78) and placebo groups (27.8%; -22/79; P=.28). CONCLUSION: These findings suggest that SFI can enhance the cellular immunity of patients with septic shock and could be a promising adjunctive treatment for patients with septic shock. PMID- 28029486 TI - Parenchymal lung injuries related to standard cardiopulmonary resuscitation. AB - OBJECTIVES: We analyzed chest computed tomographic scan to evaluate parenchymal lung injury and its clinical significance in patients who received standard cardiopulmonary resuscitation and were resuscitated from cardiac arrest. METHODS: We enrolled nontraumatic out-of-hospital cardiac arrest patients older than 19 years who had been admitted to the emergency department in cardiac arrest and successfully resuscitated after cardiopulmonary resuscitation. Chest computed tomography was obtained immediately after return of spontaneous circulation (ROSC). To allocate the area of lung contusion, we divided both hemithoraces into 3 regions longitudinally, and each part was subdivided into 4 segments except the lower part of the left lung. To stratify the severity of lung contusion, each segment was scored depending on the area of lung contusion. Oxygen index (OI) was measured at the time of ROSC, 24, 48, and 72 hours and 1 week after cardiac arrest. RESULTS: Lung contusion was developed in 37 (41%) patients and median lung contusion score (LCS) was 17 (12-26). Lung contusion was not associated with hospital mortality (P = .924) or length of intensive care unit stay (P = .446). The OI at the time of ROSC was lower in patients with LCS greater than 23 than that in patients with LCS less than or equal to 23 (126 [93-224] vs 278 [202 367]; P = .008); however, the OI at the other timelines was not different between patients with LCS greater than 23 and patients with LCS less than or equal to 23. CONCLUSION: Extensive lung contusion is associated with a lower oxygenation index at the time of ROSC, but did not affect the resuscitation outcome. PMID- 28029487 TI - Newly approved antibiotics and antibiotics reserved for resistant infections: Implications for emergency medicine. AB - Millions of patients are evaluated every year in the emergency department (ED) for bacterial infections. Emergency physicians often diagnose and prescribe initial antibiotic therapy for a variety of bacterial infections, ranging from simple urinary tract infections to severe sepsis. In life-threatening infections, inappropriate choice of initial antibiotic has been shown to increase morbidity and mortality. As such, initiation of appropriate antibiotic therapy on the part of the emergency physician is critical. Increasing rates of antibiotic resistance, drug allergies, and antibiotic shortages further complicates the choice of antibiotics. Patients may have a history of prior resistant infections or culture data indicating that common first-line antibiotics used in the ED may be ineffective. In recent years, there have been several new antibiotic approvals as well as renewed interest in second and third line antibiotics because of the aforementioned concerns. In addition, several newly approved antibiotics have the advantage of being administered once weekly or even as a single infusion, which has the potential to decrease hospitalizations and healthcare costs. This article reviews newly approved antibiotics and antibiotics used to treat resistant infections with a focus on implications for emergency medicine. PMID- 28029488 TI - Impact of language on prescription fill rates after discharge from a pediatric ED. PMID- 28029489 TI - Acute aortic occlusion with complications from delayed presentation. PMID- 28029490 TI - Factors influencing drainage setting and cost for cutaneous abscesses among pediatric patients. AB - OBJECTIVE: To evaluate the clinical and microbiological factors associated with skin and soft tissue infections drained in the emergency department (ED) vs operative drainage (OD) in a tertiary care children's hospital. METHODS: This was a cross-sectional study among children aged 2 months to 17 years who required incision and drainage (I&D). Demographic information, signs and symptoms, abscess size and location, and wound culture/susceptibility were recorded. Patient specific charges were collected from the billing database. Multivariate regression analysis was used to determine factors determining setting for I&D and the effect of abscess drainage location on cost. RESULTS: Of 335 abscesses, 241 (71.9%) were drained in the ED. OD for abscesses was favored in children with prior history of abscess (odds ratio [OR], 3.18; 95% confidence interval [CI], 1.36-7.44; P = .01) and labial location (OR, 37.81; 95% CI, 8.12-176.03; P < .001). For every 1-cm increase in size, there was approximately a 26% increase in the odds of having OD (OR, 1.26; 95% CI, 1.11-1.44, P < .001). Methicillin resistant Staphylococcus aureus was identified in 72% of the 300 abscesses cultured and 12.3% were clindamycin resistant. OD was more expensive than I&D in the ED. Per abscess that underwent I&D, OD is $3804.29 more expensive than I&D in the ED while controlling for length of stay. DISCUSSION: Clinical factors associated with OD rather than I&D in the ED included history of abscess, increased abscess length, and labial location. Microbiological factors did not differ based on I&D setting. For smaller, nonlabial abscesses, ED drainage may result in significant cost savings. PMID- 28029491 TI - Editorial: Overdoing in breast cancer: The risks of over-screening, over diagnosing and over-treating the disease. PMID- 28029492 TI - Overdiagnosis in breast imaging. AB - The main harm of overdiagnosis is overtreatment. However a form of overdiagnosis also occurs when foci of cancer are found by imaging in addition to the symptomatic lesion when this leads to additional treatment which does not benefit the patient. Even if overtreatment is avoided, knowledge of the diagnosis can still cause psychological harm. Overdiagnosis is an inevitable effect of mammographic screening as the benefit comes from diagnosing breast cancer prior to clinical detectability. Estimates of the rate of overdiagnosis at screening are around 10%. DCIS represents 20% of cancers detected by screening and is the main focus in the overdiagnosis debate. Detection and treatment of low grade DCIS and invasive tubular cancer would appear to represent overdiagnosis in most cases. Supplementary screening with tomosynthesis or US are both likely to increase overdiagnosis as both modalities detect predominantly low grade invasive cancers. MRI causes overdiagnosis because it is so sensitive that it detects real tumour foci which after radiotherapy and systemic therapy do not, in many cases go on and cause local recurrence if the women had had no MRI and undergone breast conservation and adjuvant therapy with these small foci left in situ. PMID- 28029493 TI - Reply to Tagliafico AS, Bignotti B, Rossi F, et al. PMID- 28029494 TI - Reply to Maxine Jochelson, Marc B.I. Lobbes, Blanca Bernard-Davila. PMID- 28029495 TI - An Algorithm of Image Heterogeneity with Contrast-Enhanced Ultrasound in Differential Diagnosis of Solid Thyroid Nodules. AB - Enhancement heterogeneity on contrast-enhanced ultrasonography (CEUS) is used to differentiate between benign and malignant thyroid nodules. In this study, we used an algorithm to quantify enhancement heterogeneity of solid thyroid nodules on CEUS. The heterogeneity value (HV) is calculated as standard deviation/mean intensity * 100 (using Adobe Photoshop). The heterogeneity ratio (HR) is calculated as the ratio of the HV of the nodule to that of the surrounding parenchyma. Three phases-ascending, peak and descending phases-were studied. HV values at ascending (HVa) and peak (HVp) phases were significantly higher in malignant nodules than in benign nodules (95.57 +/- 43.87 vs. 73.06 +/- 44.04, p = 0.009, and 32.53 +/- 10.73 vs. 26.44 +/- 8.25, p = 0.002, respectively). HRa, HRp and HRd were significantly higher in malignant nodules than in benign nodules (1.93 +/- 1.03 vs. 1.00 +/- 0.47, p = 0.000, 1.43 +/- 0.51 vs. 1.09 +/- 0.28, p = 0.000, and 1.33 +/- 0.40 vs. 1.08 +/- 0.33, p = 0.001, respectively). HRa achieved optimal diagnostic performance on receiver operating characteristic curve analysis. The algorithm used for assessment of image heterogeneity on CEUS examination may be a useful adjunct to conventional ultrasound for differential diagnosis of solid thyroid nodules. PMID- 28029496 TI - Accuracy of the estimation of dental age in comparison with chronological age in a Spanish sample of 2641 living subjects using the Demirjian and Nolla methods. AB - Age estimation is an important procedure in forensic medicine and is carried out for a number of reasons. For living persons, age estimation is performed in order to assess whether a child has attained the age of criminal responsibility, in scenarios involving rape, kidnapping or marriage, in premature births, adoption procedures, illegal immigration, pediatric endocrine diseases and orthodontic malocclusion, as well as in circumstances in which the birth certificate is not available or the records are suspect. According to data from the UNHCR (United Nations High Commissioner for Refugees), the number of people seeking refugee status continued to increase in the last years, driven by the wars in Syria and Iraq, as well as by conflict and instability in Afghanistan, Eritrea and elsewhere. The objective of this study is to compare the accuracy of estimating dental age versus chronological age using the Nolla and Demirjian methods in a Spanish population. A final sample of 2641 panoramic X-rays corresponding to Spanish patients (1322 males and 1319 females) between 7-21 years of age was analyzed. Dental age was assessed using the Nolla and Demirjian methods, establishing comparisons with mean chronological age based on the Student t-test for paired samples, followed by the generation of a linear regression model. Both methods showed slight discrepancy between dental and chronological age. On examining the reproducibility of the Nolla and Demirjian methods, technical errors of 0.84% and 0.62%, respectively, were observed. On average, the Nolla method was found to estimate an age 0.213years younger than the chronological age, while the Demirjian method estimated an age 0.853years older than the chronological age. Linear combination of the mean Nolla and Demirjian estimates increased the predictive capacity to 99.2%. In conclusion the Nolla and Demirjian methods were found to be accurate in estimating chronological age from dental age in a Spanish population. The error was found to be greater in males than in females, and involved an over-estimation of age with the Demirjian method and under-estimation of age with the Nolla method. Combination of the Nolla and Demirjian methods for estimating chronological age from dental age affords a predictive capacity of over 99%, and is fast and easy to perform, and inexpensive. PMID- 28029497 TI - Active numerical model of human body for reconstruction of falls from height. AB - Falls from height constitute the largest group of incidents out of approximately 90,000 occupational accidents occurring each year in Poland. Reconstruction of the exact course of a fall from height is generally difficult due to lack of sufficient information from the accident scene. This usually results in several contradictory versions of an incident and impedes, for example, determination of the liability in a judicial process. In similar situations, in many areas of human activity, researchers apply numerical simulation. They use it to model physical phenomena to reconstruct their real course over time; e.g. numerical human body models are frequently used for investigation and reconstruction of road accidents. However, they are validated in terms of specific road traffic accidents and are considerably limited when applied to the reconstruction of other types of accidents. The objective of the study was to develop an active numerical human body model to be used for reconstruction of accidents associated with falling from height. Development of the model involved extension and adaptation of the existing Pedestrian human body model (available in the MADYMO package database) for the purposes of reconstruction of falls from height by taking into account the human reaction to the loss of balance. The model was developed by using the results of experimental tests of the initial phase of the fall from height. The active numerical human body model covering 28 sets of initial conditions related to various human reactions to the loss of balance was developed. The application of the model was illustrated by using it to reconstruct a real fall from height. From among the 28 sets of initial conditions, those whose application made it possible to reconstruct the most probable version of the incident was selected. The selection was based on comparison of the results of the reconstruction with information contained in the accident report. Results in the form of estimated injuries overlap with the real injuries sustained by the casualty. PMID- 28029498 TI - Determination of VOC marker combinations for the classification of individuals by gender and race/ethnicity. AB - Human scent has been demonstrated to allow for the differentiation of individuals. The extent of this differentiation may allow scent to be used as a characteristic, capable of revealing information on an individual's traits. The ability to use scent as a biometric human feature has enabled the use of scent as forensic evidence. However, its reliability, value, and admissibility in courts of law have sometimes been challenged as a result of limited scientific validation. Full acceptance of human scent evidence has been hindered by the limited availability of peer reviewed information that provides greater understanding of how human scent originates and how it may be used. The objective of this study is to report new data that further enhances our understanding of the value of human scent evidence and its acceptance in courts of law. In order to fulfill this objective, volatile organic compound combinations were identified as markers for race/ethnicity and gender from hand odor samples from 105 individuals. The accuracy of human classification by race/ethnicity and gender, on the basis of these markers, was determined and validated. Overall accuracies of 80% and 72% were obtained for the classification of subjects by gender and race/ethnicity, respectively. The results obtained demonstrate that the identified VOC marker combinations represent a viable resource for the classification and/or differentiation of persons of interest and, as such, may be considered a valuable forensic tool for subject identification. PMID- 28029499 TI - Development of an enantioseparation method for novel psychoactive drugs by HPLC using a Lux(r) Cellulose-2 column in polar organic phase mode. AB - Since the last decade, the hype of the recreational use of novel psychoactive drugs is still on its top in entire Europe. Every year, new derivatives enter the drug market and enlarge the broad spectrum of misused drugs. Many of these compounds contain a stereogenic centre and therefore two enantiomers exist. It is obvious that the pharmacological potency of the isomers differ as it is already known from various pharmaceutical ingredients. Therefore, the development of analytical methods for the chiral separation of new psychoactive substances is of great medical and forensic interest. The aim of this study was to establish an enantioseparation method, which is applicable at equal conditions for different drug compound classes including cathinones, amphetamines, benzofurans, thiophenes, phenidine and phenidate derivatives. A commercially available Lux(r) Cellulose-2 column consisting of cellulose tris(3-chloro-4-methylphenylcarbamate) coated on silica gel was found to be appropriate for the chiral separation of the mentioned drug classes. Experiments were performed under isocratic conditions in polar organic phase mode using UV-detection. With a mobile phase consisting of acetonitrile:isopropanol:diethylamine:formic acid (100%) (95:5:0.1:0.1) 40 out of 43 psychoactive compounds were successfully baseline or partially separated. 3 Fluoroamphetamine, 4-fluoroamphetamine and 1-(benzofuran-6-yl)-N-ethylpropan-2 amine were not chirally separated. The established method enabled enantioseparation of a broad spectrum of different psychoactive compounds under equal conditions. Forty of forty-three compounds were separated in their enantiomers, thus this method has a wide applicability for the enantioseparation of novel psychoactive drugs. PMID- 28029500 TI - Attenuation of the Effect of Multimorbidity on Cardiovascular Mortality by Physical Activity in Older Adults. PMID- 28029501 TI - Declining mortality due to severe sepsis and septic shock in Spanish intensive care units: A two-cohort study in 2005 and 2011. AB - OBJECTIVE: To analyze the evolution of sepsis-related mortality in Spanish Intensive Care Units (ICUs) following introduction of the Surviving Sepsis Campaign (SSC) guidelines and the relationship with sepsis process-of-care. DESIGN: A prospective cohort study was carried out, with the inclusion of all consecutive patients presenting severe sepsis or septic shock admitted to 41 Spanish ICUs during two time periods: 2005 (Edusepsis study pre-intervention group) and 2011 (ABISS-Edusepsis study pre-intervention group). SCOPE: Patients with severe sepsis or septic shock admitted to Spanish ICUs. PATIENTS: All ICU admissions from the emergency department or wards and all ICU patients with a diagnosis of severe sepsis or septic shock. A total of 1348 patients were included: 630 in the 2005 group and 718 in the 2011 group. INTERVENTION: None. PRIMARY ENDPOINTS: ICU mortality, 28-day mortality and Hospital mortality, hospital length of stay, ICU length of stay and compliance with the resuscitation bundle. RESULTS: Compliance with the resuscitation bundle was significantly greater in the 2011 group (5.7% vs. 9.9%; p=0.005), and was associated to lower mortality (OR 0.602 [0.365-0.994]; p=0.048). The 2011 group had lower absolute in hospital mortality (44.0% vs. 32.6%; p=0.01), 28-day mortality (36.5% vs. 23.0%; p=0.01), and adjusted mortality (OR 0.64 [0.49-0.83], p=0.001). CONCLUSIONS: Mortality related to severe sepsis or septic shock in Spain decreased between two patient cohorts in 2005 and 2011, and was attributable to earliness and improvement in sepsis care. PMID- 28029502 TI - Ovarian cancer in pregnancy. AB - Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor. PMID- 28029503 TI - Iron deficiency and iron deficiency anaemia in women. AB - Iron deficiency (ID) is the most common micronutrient deficiency worldwide with >20% of women experiencing it during their reproductive lives. Hepcidin, a peptide hormone mostly produced by the liver, controls the absorption and regulation of iron. Understanding iron metabolism is pivotal in the successful management of ID and iron deficiency anaemia (IDA) using oral preparations, parenteral iron or blood transfusion. Oral preparations vary in their iron content and can result in gastrointestinal side effects. Parenteral iron is indicated when there are compliance/tolerance issues with oral iron, comorbidities which may affect absorption or ongoing iron losses that exceed absorptive capacity. It may also be the preferred option when rapid iron repletion is required to prevent physiological decompensation or given preoperatively for non-deferrable surgery. As gynaecologists, we focus on managing women's heavy menstrual bleeding (HMB) and assume that primary care clinicians are treating the associated ID/IDA. We now need to take the lead in diagnosing, managing and initiating treatment for ID/IDA and treating HMB simultaneously. This dual management will significantly improve their quality of life. In this chapter we will summarise the importance of iron in cellular functioning, describe how to diagnose ID/IDA and help clinicians choose between the available treatment options. PMID- 28029504 TI - The authors response to the letter by Weekes et al 'Are oral nutritional supplements more effective than dietary advice in malnourished care home residents?' PMID- 28029505 TI - Parenteral nutrition dysregulates bile salt homeostasis in a rat model of parenteral nutrition-associated liver disease. AB - BACKGROUND & AIMS: Parenteral nutrition (PN), a lifesaving therapy in patients with intestinal failure, has been associated with hepatobiliary complications including steatosis, cholestasis and fibrosis, collectively known as parenteral nutrition-associated liver disease (PNALD). To date, the pathogenesis of PNALD is poorly understood and therapeutic options are limited. Impaired bile salt homeostasis has been proposed to contribute PNALD. The objective of this study was to establish a PNALD model in rats and to evaluate the effects of continuous parenteral nutrition (PN) on bile salt homeostasis. METHODS: Rats received either PN via the jugular vein or received normal diet for 3, 7 or 14 days. Serum biochemistry, hepatic triglycerides, circulating bile salts and C4, IL-6 and TNF alpha, and lipogenic and bile salt homeostatic gene expression in liver and ileum were assessed. RESULTS: PN increased hepatic triglycerides already after 3 days of administration, and resulted in conjugated bilirubin elevation after 7 or more days. This indicates PN-induced steatosis and impaired canalicular secretion of bilirubin, the latter which is in line with reduced hepatic expression of Mrp2 mRNA. There was no histological evidence for liver inflammation after PN administration, and circulating levels of pro-inflammatory cytokines IL-6 and TNF alpha, were comparable in all groups. Hepatic expression of Fxr mRNA was decreased after 7 days of PN, without apparent effect on expression of Fxr targets Bsep and Shp. Nonetheless, Cyp7a1 expression was reduced after 7 days of PN, indicative for lowered bile salt synthesis. Circulating levels of C4 (marker of bile salt synthesis) were also decreased after 3, 7 and 14 days of PN. Levels of circulating bile salts were not affected by PN. CONCLUSIONS: This study showed that PN in rats caused early mild steatosis and cholestasis, while hepatic and systemic inflammation were not present. The onset of these abnormalities was associated with alterations in bile salt synthesis and transport. This animal model serves as an experimental model to further investigate the pathogenesis of PNALD inflicted by steatosis and cholestasis. PMID- 28029506 TI - The effect of coffee intake on lysophosphatidylcholines: A targeted metabolomic approach. AB - BACKGROUND & AIM: Lysophosphatidylcholines (lysoPC) are known to be a pathological component of oxidized-LDL, and several studies demonstrate its pro inflammatory properties in vitro. Nevertheless, bioactive compounds found in coffee, such as phenolic acids might inhibit LDL oxidation. The relationship between coffee consumption and lysoPC has not been described previously in humans. The aim of the present study was to assess the association between coffee intake and plasma lysoPC levels in adults. METHODS: Data was from the "Health Survey of Sao Paulo (ISA-Capital)", a cross-sectional population-based survey in Sao Paulo, among 169 individuals aged 20 years or older. This population was categorized into three groups: non-coffee consumers (0 mL/day-G1), low coffee consumers (<=100 mL/day-G2), and high coffee consumers (>100 mL/day-G3). Usual coffee intake was estimated by two 24HR and one FFQ, using Multiple Source Method. Quantification of the metabolites was performed by mass spectrometry (FIA MS/MS and HPLC-MS/MS) and 14 lysoPC species were identified. The association between coffee intake and lysoPC was analyzed by multiple linear regression adjusted for age, sex, household per capita income, smoking, physical activity, body mass index, total energy intake, use of drugs, vegetables and fruit consumption and caffeine intake. RESULTS: LysoPC levels were significantly lower in G3 than in G1, for the lysoPC a C16:1 (beta = -0.56; p = 0.014), lysoPC a C18:1 (beta = -2.57; p = 0.018), and lysoPC a C20:4 (beta = -1.14; p = 0.037). In opposition, the ratios of C16:0/C16:1 and C18:0/18:1 was higher in G3 (beta = 5.04; p = 0.025 and beta = 0.28; p = 0.003, respectively). CONCLUSION: LysoPC profile differed according to coffee intake, showing a possible beneficial health effect of this beverage on inflammatory and oxidative processes. PMID- 28029507 TI - Spectroscopic and molecular docking study on the interaction between salicylic acid and the induced disease-resistant protein OsAAA1 of rice. AB - The interaction between salicylic acid (SA) and the induced disease-resistant protein OsAAA1 in rice was studied using spectroscopy and molecular docking. Ultraviolet (UV) absorption spectroscopy demonstrated an interaction between OsAAA1 protein and SA. Spectroscopy showed that this interaction was a dynamic quenching process. Synchronous fluorescence spectroscopy (SFS) further revealed that this interaction caused changes in the microenvironment of tyrosine and tryptophan and that the interaction site was closer to the tryptophan residue. The structural model of protein OsAAA1 was determined by homology modeling method, and the molecular docking simulation diagram of OsAAA1 with SA was obtained. These models, in combination with a Ramachandran plot analysis, showed amino acid residues ranging from position 240 to position 420 as the possible site interacting with SA. Among them, Gly389, Lys257 and Glu425 might be three key amino acids that can form hydrogen bonds with SA. PMID- 28029508 TI - New bimetallic dicyanidoargentate(I)-based coordination compounds: Synthesis, characterization, biological activities and DNA-BSA binding affinities. AB - Four compounds -two (2 and 3) completely new- of composition [Ni(edbea)Ag3(CN)5] (1), [Cu(edbea)Ag2(CN)4].H2O (2), [Cd(edbea)Ag3(CN)5].H2O (3) and [Cd(edbea)2] [Ag(CN)2]2.H2O (4) {edbea; 2,2'-(ethylenedioxy)bis (ethylamine)}, were synthesized and characterized using elemental, FT-IR, X-Ray (4), thermal, variable temperature magnetic measurement (1 and 2) and biological techniques. The DNA/BSA binding affinities of 2 and 3 were evaluated by UV-Vis spectrophotometric titrations, ethidium bromide exchange experiments and electrophoretic mobility measurements. Compounds 1 and 4 have previously been characterized and shown to reduce the proliferation and migration of tumor cells. For the sake of clarity, 1 precise mechanism of action on microbial organisms and temperature magnetic measurement were determined. The crystallographic analyses showed that 4 was built up of [Cd(edbea)2]II cations and [Ag2(CN)4]II anions. Complexes demonstrated a remarkable antibacterial (1-4), antifungal (1-4) and antiproliferative activities (2 and 3) to ten human bacterial pathogens, four plant pathogenic fungi or three tumor cells (HeLa, HT29, and C6), respectively. Therefore, our results strongly confirm that cell proliferation, cell morphology, Bcl-2, P53 changes and apoptosis can be related to the pharmacological effects of the complexes as suitable candidate for clinical trials. PMID- 28029509 TI - Renal function and venous thromboembolic diseases. AB - Anticoagulant agents have been approved by international regulatory agencies to prevent and treat venous thromboembolism (VTE). However, chronic kidney disease (CKD) is: (1) highly frequent in VTE patients; (2) strongly linked to VTE; and (3) a risk factor for cardiovascular morbidity/mortality and fatal pulmonary embolism. Therefore, an increasing number of patients are presented with CKD and VTE and more and more physicians must face the questions of the management of these patients and that of the handling of anticoagulant agents in CKD patients because of the pharmacokinetic modifications of these drugs in this population. These modifications may lead to overdosage and dose-related side effects, such as bleeding. It is therefore necessary to screen VTE patients for CKD and to modify the doses of anticoagulants, if necessary. PMID- 28029510 TI - Prevention of Poststroke Mortality Using Problem-Solving Therapy or Escitalopram. AB - OBJECTIVE: This study re-examined patients from a 1-year randomized controlled double-blind trial of escitalopram, problem-solving therapy (PST), or placebo to prevent depression among patients less than 3 months after a stroke. The objective of the current study was to determine if preventive treatment would predict time to death over 8-10 years of follow-up. Based on the importance of depression in poststoke mortality and a previous study of this population at 18 months' follow-up showing that stopping escitalopram but not PST led to a significant increase in depression, the authors hypothesized that PST would be associated with the longest time to death. METHODS: Of 129 eligible patients, 122 were contacted and 7 were lost to follow-up. Families and surviving patients were interviewed to determine current health status or the date and cause of death. RESULTS: Using the Weibull model of log time (years) to death, controlled for age, severity of physical illness, gender, severity of stroke, and history of depression after study entry, there was a significant independent effect of treatment. PST significantly and independently increased the time to mortality, whereas older age and major depression significantly and independently decreased the time to death. CONCLUSION: To the authors' knowledge, this is the first time a psychological antidepressant treatment administered for 1 year has been associated with increased survival among patients who have suffered a stroke. PMID- 28029511 TI - Design and synthesis of the penta(acetoxymethyl) ester of dioctanoyl phosphatidylinositol-3,5-bisphosphate. AB - Extracellular administration of water-soluble and membrane-permeant analogs of phosphatidylinositol phosphates (PIPs) is a useful strategy for understanding the cellular roles of PIPs as well as the mode of action of drugs whose biological activity is associated with PIPs. We herein established the synthetic route to the dioctanoyl analogue of phosphatidylinositol 3,5-bisphosphate (di-C8 PI(3,5)P2) and its penta(acetoxymethyl) ester (di-C8-PI(3,5)P2/5AM). PMID- 28029512 TI - Design, synthesis, and biological activity of 4-(imidazo[1,2-b]pyridazin-3-yl)-1H pyrazol-1-yl-phenylbenzamide derivatives as BCR-ABL kinase inhibitors. AB - A series of 4-((pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-)phenyl-3 benzamide derivatives were designed, synthesized as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. These new compounds were screened for BCR-ABL1 kinase inhibitory activity, and most of them appeared good inhibitory activity against BCR-ABL1 kinase. One of the most potent compounds 16a strongly suppressed BCR ABL1 kinase with IC50 value of 8.5nM. The tested compounds 16a and 16i showed strong inhibitory activities against K562 with IC50 value of less than 2nM. Molecular docking studies indicated that these compounds fitted well with the active site of BCR-ABL1 protein. The results showed these inhibitors may serve as lead compounds for further developing new drugs targeted BCR-ABL kinase. PMID- 28029513 TI - Inflammatory myofibroblastic tumour. AB - While initially controversial, the proposal that a subset of inflammatory pseudotumours were myofibroblastic neoplasms is now acknowledged. Inflammatory myofibroblastic tumour is a spindle cell neoplasm of intermediate biological potential that may arise in a wide range of anatomic sites but has a particular propensity for the lung and abdominal soft tissues. Depending on its location, IMT may present with a variety of clinical symptoms and it may also express a variable pathologic phenotype, leading to a broad range of clinical and pathological differentials. Recent discoveries about the molecular signatures of IMT not only provide additional tools to assist in their diagnosis, they also point to possible therapeutic interventions that may transform the management algorithms for patients with this condition. PMID- 28029514 TI - Planning a Radiotherapy Department. AB - The master planning of new radiotherapy facilities requires the input and engagement of a range of highly specialised professionals, both in the construction and health sector. Although radiation protection and safety aspects of radiotherapy services are universal, low and middle income countries are often presented with unique challenges that also need to be considered, e.g. competing needs within the health sector, lack of financial and human resources, environmental factors like poor provision of transport or electrical power, inadequate regulatory infrastructure, etc. Efforts to establish, upgrade or expand radiotherapy services should therefore not only focus on the technology that is appropriate and sustainable, but also be mindful of the need for quality, safety and optimal utilisation of technology. The workflow in a radiotherapy department can be facilitated by strategic placement of the main functional areas into the concept design. PMID- 28029515 TI - The "polyenviromic risk score": Aggregating environmental risk factors predicts conversion to psychosis in familial high-risk subjects. AB - BACKGROUND: Young relatives of individuals with schizophrenia (i.e. youth at familial high-risk, FHR) are at increased risk of developing psychotic disorders, and show higher rates of psychiatric symptoms, cognitive and neurobiological abnormalities than non-relatives. It is not known whether overall exposure to environmental risk factors increases risk of conversion to psychosis in FHR subjects. METHODS: Subjects consisted of a pilot longitudinal sample of 83 young FHR subjects. As a proof of principle, we examined whether an aggregate score of exposure to environmental risk factors, which we term a 'polyenviromic risk score' (PERS), could predict conversion to psychosis. The PERS combines known environmental risk factors including cannabis use, urbanicity, season of birth, paternal age, obstetric and perinatal complications, and various types of childhood adversity, each weighted by its odds ratio for association with psychosis in the literature. RESULTS: A higher PERS was significantly associated with conversion to psychosis in young, familial high-risk subjects (OR=1.97, p=0.009). A model combining the PERS and clinical predictors had a sensitivity of 27% and specificity of 96%. CONCLUSION: An aggregate index of environmental risk may help predict conversion to psychosis in FHR subjects. PMID- 28029516 TI - Marriage and outcomes of people with schizophrenia in rural China: 14-year follow up study. AB - The influence of marriage on the long-term outcomes of schizophrenia is largely unknown. This study was to examine the impact of marriage on the 14-year outcomes and identify the correlates of marriage among persons with schizophrenia in rural community. All study participants with schizophrenia (n=510) were identified in 1994 in an epidemiological investigation of 123,572 people aged 15years and older and followed up in 2004 and 2008 in Xinjin County, Chengdu, China. The Patients Follow-up Schedule (PFS) was used in 2004 and 2008. The rate of follow-up in 2008 was 95.9%. Unmarried individuals in 1994 had higher rates of homelessness and suicide, and lower rate of survival in 2004 and 2008 than those married. In 14 year follow-up, unmarried individuals were more likely to be male, to have higher level of psychiatric symptoms and lower rate of full remission of illness, and to report lower level of work functioning, as well as with fewer family members and caregiver, and lower family economic status. The predictors of being married in 2008 included being married in 1994, shorter duration of illness, being female, and lower level of education. Being married is predictive of more favorable 14 year outcomes of persons with schizophrenia in the rural community. Given that marriage can be instrumental for enhancing family-based support and caregiving, as well as improving the community tenure of persons with schizophrenia, it is important to develop programs to enhance opportunity for persons with schizophrenia to get and stay married. PMID- 28029517 TI - Stroke 1-2-0: a rapid response programme for stroke in China. PMID- 28029519 TI - Adrenocorticotropic hormone levels before treatment predict recurrence of Cushing's disease. AB - BACKGROUND/PURPOSE: Cushing's disease (CD) is the most common cause of endogenous Cushing's syndrome. Transsphenoidal surgery (TSS) is the first choice of treatment. Predicting prognosis after treatment can benefit further strategies of management, but currently there is no convenient predictor. This study aims to investigate characteristic changes after treatment and to identify potential prognostic predictors. METHODS: We retrospectively studied the records of CD patients presenting to the National Taiwan University Hospital, Taipei, Taiwan between 1992 and 2011. They were categorized according to treatment response. Clinical features and examination findings were compared between groups. RESULTS: Forty-one patients with CD were included. The follow-up time was 0.26-19.3 years. The time interval between the onset of symptoms and diagnosis was 2.1-120.0 months. The initial remission rate of CD after the first treatment was 82.9%. Mean body mass index (BMI) was 27.4 kg/m2 before treatment and 26.0 kg/m2 3 months after treatment. The patients in remission had a greater decrease in BMI after treatment and lower dehydroepiandrosterone sulfate (DHEAS) levels before treatment, compared with the recurrent group (both p < 0.05). Adrenocorticotropic hormone (ACTH) levels before treatment showed a significant positive correlation with recurrent diseases (p < 0.05). CONCLUSION: A larger decrease in BMI after treatment and lower DHEAS levels before treatment were noted for the patients who stayed in CD remission. Higher ACTH levels before treatment predicted a recurrence of CD. These are potentially simple and practical predictors of prognosis. PMID- 28029518 TI - A New View into the Regulation of Purine Metabolism: The Purinosome. AB - Other than serving as building blocks for DNA and RNA, purine metabolites provide a cell with the necessary energy and cofactors to promote cell survival and proliferation. A renewed interest in how purine metabolism may fuel cancer progression has uncovered a new perspective into how a cell regulates purine need. Under cellular conditions of high purine demand, the de novo purine biosynthetic enzymes cluster near mitochondria and microtubules to form dynamic multienzyme complexes referred to as 'purinosomes'. In this review, we highlight the purinosome as a novel level of metabolic organization of enzymes in cells, its consequences for regulation of purine metabolism, and the extent that purine metabolism is being targeted for the treatment of cancers. PMID- 28029520 TI - Ultrasonic nanoemulsification of food grade trans-cinnamaldehyde: 1,8-Cineol and investigation of the mechanism of antibacterial activity. AB - Using ultrasonic technology, trans-cinnamaldehyde as a natural antibacterial compound was used to prepare nano size emulsions to increase its bioavailability and therefore bactericidal action. Nanoemulsions containing trans-cinnamaldehyde as an active agent and 1,8 cineol as co additive oil (Ostwald ripening inhibitor) were formulated using probe sonicator. Three different determining factors, namely time of sonication, surfactant to oil ratio and type of emulsifier (Tween 80 and Tween 20) were investigated to enhance the stability profile. In addition, the effect of changes in the particle size and emulsifier on the antibacterial activity against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were examined using agar dilution method. Then, the effect of optimized formulation on the membrane fluidity and cell constituent release, were investigated by analysis of membrane lipids using GC-MS and IR spectrometry, respectively. The data showed that a 15min sonication of the formulation containing Tween 80 as emulsifier with surfactant to oil ratio of 2:1 (w/w) resulted in a significant stability for 6months with considerably small particle size of 27.76+/-0.37nm. Furthermore, the nanoemulsion showed great antibacterial activity and could reduce the minimum inhibitory concentration (MIC) from 8 to 1mg/mL against E. coli and S. aureus, and from 16 to 2mg/mL against P. aeruginosa. Interestingly, E. coli's membrane fluidity increased dramatically after treatment with the optimum nanoemulsion (T804). This study revealed that nanoemulsion of trans-cinnamaldehyde and 1,8 cineol has substantial antibacterial activity against selected microorganisms. PMID- 28029521 TI - Comparison of macauba and soybean oils as substrates for the enzymatic biodiesel production in ultrasound-assisted system. AB - The objective of this study is to evaluate the batch enzymatic production of biodiesel in solvent-free system under ultrasound using as substrates ethanol, soybean oil and macauba fruit oil. For this purpose, a Plackett & Burman experimental design was carried out for soybean oil while a 24-1 design was conducted for macauba oil in order to maximize the biodiesel conversion for each system. Good conversions to fatty acid ethyl esters (FAEE), 88% for soybean oil and 75.2% for macauba oil, was obtained thus demonstrating the potential use of ultrasound for this reaction system. PMID- 28029522 TI - A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain. AB - INTRODUCTION AND OBJECTIVES: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). METHODS: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. RESULTS: A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. CONCLUSIONS: The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age. PMID- 28029523 TI - Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) in colorectal cancer: Evidence-based review of patient selection and treatment algorithms. AB - Cytoreduction and heated intraperitoneal chemotherapy (CS/HIPEC) is increasingly utilized as a treatment strategy for patients with peritoneal metastases from various primary tumor sites. For this heterogenous procedure, related to patient characteristics, patient selection, and the extent of surgical completeness of cytoreduction, high level evidence (ex: multiple randomized controlled trials) is not available to support efficacy. This review of the available literature supporting application of the procedure, focusing on colorectal cancer, provides a summary of current evidence for patient selection and treatment algorithms based on patient presentation. PMID- 28029524 TI - [External lumbar drainage with volumetric continuing infusion pump in patients with cerebrospinal fluid leak. A case series]. AB - OBJECTIVE: To describe the incidence and complications arising in a number of cases of patients with cerebrospinal fluid leak treated by external lumbar drainage with infusion pump (IP) volumetric continuous from 2001 to 2014. Quantify cerebrospinal fluid leak closed by lumbar drainage with IP. METHODS: Retrospective descriptive case series study. POPULATION: patients undergoing transsphenoidal pituitary surgery, Chiari surgery and laminectomy, that developed postoperative cerebrospinal fluid leak treated with continuous external lumbar drainage by IP. VARIABLES: age, sex, type of intervention, variables related to the practice of the pump and complications. Average and medians were calculated for quantitative variables, frequencies and percentages for qualitative. RESULTS: Sample: 11 subjects. Incidence in running IP: disconnection, occlusion and acoustic alarm activation. Most frequently complication is headache; a case of pneumocephalus. DISCUSSION: The small number of subjects and the heterogeneity of these do not allow for comparison or establishing associations between variables. The resolution of the cerebrospinal fluid leak with continuous IP is lower in this study than others, and may be influenced by the small number of subjects. It should be noted the frequent activation of the pump alarm for no apparent cause. IMPLICATIONS FOR PRACTICE: Protocol would be developed for preparing the IP team to reduce the acoustic alarm activation, and would make a prospective multicenter study. PMID- 28029525 TI - [Everything is valid in chronic pain: Interventions by older adults for pain relief]. AB - OBJECTIVE: To describe interventions used by older adults with benign chronic pain. METHODS: Qualitative study with 25 older adults with benign chronic pain, inhabitants of the cities of Medellin and Bogota. The technique used to collect information was in-depth interview. The analysis was made using the tools of the theory based on the guidelines of Strauss and Corbin. Using open, axial and selective coding, the constant comparison method allowed the identification of categories and subcategories and simultaneously memos and diagrams were made to reach theoretical saturation. RESULTS: A number of categories were found in this study, suggesting interventions used by the elderly to address chronic pain. They started looking at a number of options such as: taking medication, self prescribing, feeling fear of taking pills, identifying the damage caused by drugs, using hot water, staying still, taking right postures, walking and exercising, using attachments that help them and making home remedies; all of them become alternatives that can cause pain relief. CONCLUSIONS: The study allowed describing interventions that older adults use to mitigate their pain. This ranged from pharmacological to non-pharmacological interventions, as simple as posture, cold, heat, massage or distractions among others, which play an important role in pain relief. Knowing these interventions helps healthcare professionals consider care options different to medication intake, proposing strategies that are easily accessible and can operate at the time to address a patient with chronic pain. PMID- 28029526 TI - Measuring the transportation needs of people with developmental disabilities: A means to social inclusion. AB - BACKGROUND: One of the major causes of social exclusion for people with developmental disability (PDD) is the inability to access different activities due to inadequate transportation services. OBJECTIVE: This research paper identifies transportation needs, and reasons for unmet, but desired untaken trips of adults with developmental disabilities in Hennepin County, Minnesota. We hypothesize that PDD cannot make trips they want to make due to personal and neighborhood characteristics. METHODS: A survey measuring existing travel behavior and unmet transportation needs of PDD (N = 114) was conducted. The survey included both demographic and attitudinal questions as well as a travel diary to record both actual and desired but untaken trips. Logistic regression analyses were conducted to determine reasons associated with their inability to make desired, but untaken trips. RESULTS: Most respondents did not live independently. More than half of the surveyed population worked every day and recreation trips occurred at least once a week for about two-thirds of the population. About 46% were unable to make trips they needed to make. Public transit posed physical and intellectual difficulties, however the presence of public transit in neighborhoods decreased odds of not making trips. Concerns about Paratransit services were also reported. CONCLUSION: Findings from this study can be of value to transportation engineers and planners interested in shedding light on the needs of a marginalized group that is rarely studied and have special transport needs that should be met to ensure their social inclusion in society. PMID- 28029527 TI - [Improved lung function in cystic fibrosis using mechanical insufflation exsufflation]. PMID- 28029528 TI - Cutting out the roots of acute hepatitis C. PMID- 28029529 TI - Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open label, single-arm, phase 2 study. AB - BACKGROUND: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection. METHODS: In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (>=18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918. FINDINGS: Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4.04 log10 IU/mL (1.71-7.20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament. INTERPRETATION: Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations. FUNDING: Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF). PMID- 28029530 TI - Survival of Asian Females With Advanced Lung Cancer in the Era of Tyrosine Kinase Inhibitor Therapy. AB - INTRODUCTION: We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation-enriched patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: We used the Surveillance Epidemiology and End Results database to study patients with stage IV lung adenocarcinoma diagnosed from 1998 to 2012. We compared survival (lung cancer-specific survival [LCSS] and overall survival) between AFs and non-Asian males (NAMs), an EGFR mutation-enriched and EGFR mutation-unenriched population, respectively, with a diagnosis in the pre EGFR TKI (1998-2004) and EGFR TKI (2005-2012) eras. We used Cox proportional hazards models to examine the interaction of access to TKI treatment and EGFR enrichment status. RESULTS: Among 3029 AF and 35,352 NAM patients, we found that LCSS was best for AFs with a diagnosis in the TKI era (median, 14 months), followed by AFs with a diagnosis in the pre-TKI era (median, 8 months), NAMs with a diagnosis in the TKI era (median, 5 months), and NAMs with a diagnosis in the pre-TKI era (median, 4 months; log-rank P < .0001). In a multivariable model, the effect of a diagnosis in the TKI era on survival was greater for AFs than for NAMs (LCSS, P = .0020; overall survival, P = .0007). A lung cancer diagnosis in the TKI era was associated with an overall mortality decrease of 26% for AFs (hazard ratio, 0.740; 95% confidence interval, 0.682-0.80) and 15.9% for NAMs (hazard ratio, 0.841; 95% confidence interval, 0.822-0.860). CONCLUSIONS: We found increased survival for lung adenocarcinoma diagnoses made after widespread access to EGFR TKIs, with the greatest increase among AF patients enriched for EGFR mutations. The present analysis eliminated the effect of crossover, which has complicated assessments of the survival advantage in EGFR TKI randomized trials. PMID- 28029531 TI - A novel risk model including vascular access site for predicting 30-day mortality after primary PCI: The ALPHA score. AB - BACKGROUND: The mortality benefit of transradial primary PCI has been shown by several studies. Previous risk models have not considered access site as a candidate predictor and many of them were developed using low risk populations of randomized trials. We conducted a prospective cohort study to construct and validate an admission risk model including access site as candidate variable for predicting 30-day mortality after primary PCI. METHODS: We analyzed data of 1255 patients using variables readily available at presentation. Predictor selection was based on backward logistic regression combined with bootstrap resampling. The model has been validated internally and temporally externally. RESULTS: Thirty day mortality was independently associated with older age, faster heart rate, need for life support on or prior to admission, and femoral access while it was inversely related to systolic blood pressure. ROC curve analysis revealed high discriminatory power, which was preserved in the validation set (c-statistic: 0.88 and 0.87, respectively). For the new score the acronym ALPHA (Age, Life support, Pressure, Heart rate, Access site) has been coined. Compared with previous models, our score achieved the highest c-statistic (0.87) followed by the GRACE 2.0 (0.86), APEX-AMI (0.86), and CADILLAC (0.85) models, the other scoring systems (TIMI, Zwolle, and PAMI) performed less well. The ALPHA, GRACE 2.0, APEX-AMI, and CADILLAC models predicted 30-day mortality better than the PAMI score (p=0.005, 0.004, 0.01, and 0.02, respectively). CONCLUSIONS: Using this tool, mortality risk may be precisely assessed at admission and patients who may benefit most from transradial access may be identified. PMID- 28029532 TI - Role of Periarticular Liposomal Bupivacaine Infiltration in Patients Undergoing Total Knee Arthroplasty-A Meta-analysis of Comparative Trials. AB - BACKGROUND: Over last 2 years, many trials have evaluated newly approved liposomal bupivacaine for periarticular infiltration in total knee arthroplasty (TKA) with mixed results. Our meta-analysis attempts to consolidate the results and make evidence-based conclusions. METHODS: Trails comparing periarticular infiltration of liposomal bupivacaine to conventional analgesic regimens for total knee arthroplasty published till June 2016 were searched in medical database. Comparisons were made for length of stay (LOS), postoperative pain scores, range of motion, and opioid consumption. Meta-regression was performed for LOS to evaluate various analgesic control subgroups. RESULTS: Sixteen trials were included in the final analysis. Liposomal bupivacaine group showed a shorter LOS (reported in 13 subgroups) than control group by 0.17 +/- 0.04 days (random effects, P < .001, I2 = 84.66%). Meta-regression for various types of control showed a predictability (R2) of 73%, tau2 = 0.013 (random effects, P < .001, I2 = 45.16). Only femoral block subgroup attained statistically significant shorter LOS on splitting the control group. Numeric pain scores were lower for pooled control group and local anesthetic infiltration subgroup in immediate postoperative phase. Second postoperative day analgesia was statistically superior to overall clubbed controls and femoral block subgroup. Superiority and/or inferiority of liposomal bupivacaine could not be proven for opioid consumption and range of motion because of a small pooled sample size. Publication bias is likely for LOS (Egger test, X intercept = 2.42, P < .001). CONCLUSION: Liposomal bupivacaine infiltration has questionable clinical advantage, as it marginally shortens patient's hospital stay especially in comparison with patients receiving analgesic femoral nerve block. Compared with conventional regimens, it can provide slightly superior yet sustained (till second postoperative day) perioperative analgesia. High heterogeneity suggests need for standardization of infiltration techniques for better predictability of results. PMID- 28029533 TI - Unexplained Pain Post Total Knee Arthroplasty With an Oxford Knee Score >=20 at 6 Months Predicts Good 2-Year Outcome. AB - BACKGROUND: Total knee arthroplasty (TKA) is an effective procedure for end-stage osteoarthritis of the knee. Some patients experience persistent unexplained pain post-TKA despite normal investigations. The purpose of this study is to identify which of these patients are likely to improve without any surgical intervention. We hypothesize that patients with unexplained persistent pain and a poor 6-month Oxford knee score (OKS) post-TKA can improve at 2 years. METHODS: Prospectively collected data for all primary unilateral TKA performed from June 2004 to January 2012 were analyzed to identify which patients with unexplained pain at 6 months will improve at 2 years. Patients were included if they had persistent pain and an OKS <27 at 6 months; normal radiological and clinical investigations; no infection identified; surgery performed for primary osteoarthritis. Two hundred sixty patients with OKS <27 at 6 months were analyzed. These patients were subdivided into 2 groups (group 1: 6-month OKS 20-26, group 2: 6-month OKS less than 20). RESULTS: One hundred ninety-one out of 208 (92%) patients in group 1 experienced improvement in pain and outcome at 2 years. Most of the group 1 patients attained a minimal clinically important difference in OKS of at least 5 (P < .001) at 2 years. Group 1 patients also reported better Knee Society Functional Score and Short Form Survey 36 mean scores at 2 years. CONCLUSION: In patients with unexplained pain, an OKS of at least 20 at 6 months predicts good functional outcome at 2 years. PMID- 28029535 TI - Foods, nutrients, and health: when will our policies catch up with nutrition science? PMID- 28029534 TI - The influence of fellowship training on the practice of pancreatoduodenectomy. AB - BACKGROUND: There has been a proliferation of gastrointestinal surgical fellowships; however, little is known regarding their association with surgical volume and management approaches. METHODS: Surveys were distributed to members of GI surgical societies. Responses were evaluated to define relationships between fellowship training and surgical practice with pancreatoduodenectomy (PD). RESULTS: Surveys were completed by 889 surgeons, 84.1% of whom had completed fellowship training. Fellowship completion was associated with a primarily HPB or surgical oncology-focused practice (p < 0.001), and greater median annual PD volume (p = 0.030). Transplant and HPB fellowship-trained respondents were more likely to have high-volume (>=20) annual practice (p = 0.005 and 0.029, respectively). Regarding putative fistula mitigation strategies, HPB-trained surgeons were more likely to use stents, biologic sealants, and autologous tissue patches (p = 0.007, <0.001 and 0.001, respectively). Surgical oncology trainees reported greater autologous patch use (p = 0.003). HPB fellowship-trained surgeons were less likely to routinely use intraperitoneal drainage (p = 0.036) but more likely to utilize early (POD <= 3) drain amylase values to guide removal (p < 0.001). Finally, HPB fellowship-trained surgeons were more likely to use the Fistula Risk Score in their practice (29 vs. 21%, p = 0.008). CONCLUSION: Fellowship training correlated with significant differences in surgeon experience, operative approach, and use of available fistula mitigation strategies for PD. PMID- 28029536 TI - Levothyroxine overuse: time for an about face? PMID- 28029537 TI - [Congenital undescended testis: Should open processus vaginalis have any impact on the elected surgical approach?] AB - PURPOSE: Compare the position of the undescended testis at clinical examination and under general anesthesia with the patency of an open processus vaginalis. PATIENTS AND METHODS: We included children from 2 to 18 years of age operated for a unilateral or bilateral undescended testis between January 2006 and April 2014 at the Annecy Genevois hospital, France. The analysis was conducted considering that the individual was the testis. Testicular position before surgery, under general anesthesia and patency of open processus vaginalis as a surgical finding were prospectively recorded. RESULTS: Three hundred and six children were included. The analysis was conducted over 401 testes. The position at clinical examination was significantly linked to a persistent open processus vaginalis (P=0.0045). Over the 282 testes considered as candidate for Bianchi's procedure, as to say intra- or supra-scrotal under general anesthesia, 154 had a persistent processus vaginalis (55%). CONCLUSION: There is a link between a persistent processus vaginalis and the location of the undescended testis which should encourage us not to neglect the inguinal approach, and eventually to question the relevance of Bianchi's procedure. LEVEL OF EVIDENCE: 4. PMID- 28029538 TI - An Unusual Etiology of Hypokalemia in a Patient With an Eating Disorder. AB - Patients with eating disorders are at risk for electrolyte imbalances that can lead to life-threatening complications. Timely recognition and evaluation of electrolyte abnormalities, including hypokalemia, are essential. In this case report, we describe an uncommon etiology of hypokalemia in a patient with disordered eating. PMID- 28029539 TI - Disordered Weight Management Behaviors, Nonprescription Steroid Use, and Weight Perception in Transgender Youth. AB - PURPOSE: Disordered weight management behaviors are prevalent among youth; recent case reports suggested that these behaviors might also be common in transgender youth. We studied associations of gender identity with disordered weight management behaviors, nonprescription steroid use, and weight perception among transgender and cisgender (nontransgender) high-school students in Massachusetts. METHODS: Data were analyzed from the 2013 Massachusetts Youth Health Survey, an anonymous survey in a random sample of Massachusetts public high schools. Respondents were divided into three groups: transgender (n = 67), cisgender male (n = 1,117), and cisgender female (n = 1,289). Fisher's exact tests and multivariable logistic regression models were used to examine unhealthy weight management behaviors in the past 30 days: fasting >24 hours, vomiting, diet pill use, and laxative use; nonprescription steroid use; and self-perceived weight status. Analyses controlled for age, race/ethnicity, and body mass index. RESULTS: Compared with cisgender males, transgender adolescents had higher odds of fasting >24 hours (adjusted odds ratio [AOR] = 2.9, confidence interval [CI] = 1.1-7.8), using diet pills (AOR = 8.9, 95% CI = 2.3-35.2) and taking laxatives (AOR = 7.2, 95% CI = 1.4-38.4). Transgender youth had higher odds of lifetime use of steroids without a prescription than male cisgender respondents (AOR = 26.6, 95% CI = 3.5-200.1). Compared with cisgender females, transgender respondents had higher odds of perceiving themselves as healthy weight/underweight when they were overweight/obese (AOR = 2.4, 95% CI = 1.5-4.1). CONCLUSIONS: Transgender youth disproportionately self-reported unsafe weight management behaviors and nonprescription steroid use compared with cisgender youth. Clinicians should be aware of this increased risk among transgender youth. Research is needed to further understand these disparities and to inform future interventions. PMID- 28029540 TI - Use of a booster dose of capsular group C meningococcal glycoconjugate vaccine to demonstrate immunologic memory in children primed with one or two vaccine doses in infancy. AB - BACKGROUND: Use of a polysaccharide vaccine challenge to demonstrate immunologic memory after priming with capsular group C meningococcal conjugate vaccines (MenCC) risks induction of immunologic hyporesponsiveness. For this reason, MenCC vaccines are now used as probes of immunologic memory, however, no studies have demonstrated their ability to distinguish primed from unprimed children. METHODS: This study was part of a randomised controlled trial investigating the immunogenicity of a booster dose of the combined Haemophilus influenzae type b and MenC-tetanus toxoid vaccine (Hib-MenC-TT) in infants receiving reduced dose MenCC vaccine priming schedules (one MenC-CRM/MenC-TT or two MenC-CRM vaccine doses) compared with an unprimed group. Antibody kinetics were studied in a subset of 269 children by measuring changes in the MenC serum bactericidal antibody, using rabbit complement, (MenC rSBA) titres and MenC specific IgG memory B-cells before and at 6 and 28days following the 12month booster vaccination. RESULTS: At 6days after the 12monthMenCC vaccine, the rise in MenC rSBA titres and MenC specific IgG memory B-cells of the primed groups were significantly higher than the infant MenCC naive group. Participants primed with one MenC-TT dose had the highest increase in MenC rSBA titres compared with all other groups. The MenC rSBA titres at the 28th compared with the 6th day after boosting was significantly higher in those primed with a single MenC-TT/MenC-CRM vaccine in infancy compared with those who were not primed or who were primed with two doses of the MenC-CRM vaccine. CONCLUSION: Immunologic memory can be demonstrated by a MenCC booster vaccination but is affected by the type and number of MenCC doses used for infant priming. The MenC rSBA responses can be used to demonstrate successful immunologic priming. PMID- 28029541 TI - Funding gap for immunization across 94 low- and middle-income countries. AB - Novel vaccine development and production has given rise to a growing number of vaccines that can prevent disease and save lives. In order to realize these health benefits, it is essential to ensure adequate immunization financing to enable equitable access to vaccines for people in all communities. This analysis estimates the full immunization program costs, projected available financing, and resulting funding gap for 94 low- and middle-income countries over five years (2016-2020). Vaccine program financing by country governments, Gavi, and other development partners was forecasted for vaccine, supply chain, and service delivery, based on an analysis of comprehensive multi-year plans together with a series of scenario and sensitivity analyses. Findings indicate that delivery of full vaccination programs across 94 countries would result in a total funding gap of $7.6 billion (95% uncertainty range: $4.6-$11.8 billion) over 2016-2020, with the bulk (98%) of the resources required for routine immunization programs. More than half (65%) of the resources to meet this funding gap are required for service delivery at $5.0 billion ($2.7-$8.4 billion) with an additional $1.1 billion ($0.9-$2.7 billion) needed for vaccines and $1.5 billion ($1.1-$2.0 billion) for supply chain. When viewed as a percentage of total projected costs, the funding gap represents 66% of projected supply chain costs, 30% of service delivery costs, and 9% of vaccine costs. On average, this funding gap corresponds to 0.2% of general government expenditures and 2.3% of government health expenditures. These results suggest greater need for country and donor resource mobilization and funding allocation for immunizations. Both service delivery and supply chain are important areas for further resource mobilization. Further research on the impact of advances in service delivery technology and reductions in vaccine prices beyond this decade would be important for efficient investment decisions for immunization. PMID- 28029542 TI - Vector-based genetically modified vaccines: Exploiting Jenner's legacy. AB - The global vaccine market is diverse while facing a plethora of novel developments. Genetic modification (GM) techniques facilitate the design of 'smarter' vaccines. For many of the major infectious diseases of humans, like AIDS and malaria, but also for most human neoplastic disorders, still no vaccines are available. It may be speculated that novel GM technologies will significantly contribute to their development. While a promising number of studies is conducted on GM vaccines and GM vaccine technologies, the contribution of GM technology to newly introduced vaccines on the market is disappointingly limited. In this study, the field of vector-based GM vaccines is explored. Data on currently available, actually applied, and newly developed vectors is retrieved from various sources, synthesised and analysed, in order to provide an overview on the use of vector-based technology in the field of GM vaccine development. While still there are only two vector-based vaccines on the human vaccine market, there is ample activity in the fields of patenting, preclinical research, and different stages of clinical research. Results of this study revealed that vector-based vaccines comprise a significant part of all GM vaccines in the pipeline. This study further highlights that poxviruses and adenoviruses are among the most prominent vectors in GM vaccine development. After the approval of the first vectored human vaccine, based on a flavivirus vector, vaccine vector technology, especially based on poxviruses and adenoviruses, holds great promise for future vaccine development. It may lead to cheaper methods for the production of safe vaccines against diseases for which no or less perfect vaccines exist today, thus catering for an unmet medical need. After the introduction of Jenner's vaccinia virus as the first vaccine more than two centuries ago, which eventually led to the recent eradication of smallpox, this and other viruses may now be the basis for constructing vectors that may help us control other major scourges of mankind. PMID- 28029543 TI - Single organ cutaneous vasculitis: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 28029544 TI - LC-MS/MS method for quantitation of seven biomarkers in human plasma for the assessment of insulin resistance and impaired glucose tolerance. AB - Early detection of insulin resistance (IR) and/or impaired glucose tolerance (IGT) is crucial for delaying and preventing the progression toward type 2 diabetes. We recently developed and validated a straightforward metabolite-based test for the assessment of IR and IGT in a single LC-MS/MS method. Plasma samples were diluted with isotopically-labeled internal standards and extracted by simple protein precipitation. The extracts were analyzed by LC-MS/MS for the quantitation of 2-hydroxybutyric acid (0.500-40.0MUg/mL), 3-hydroxybutyric acid (1.00-80.0MUg/mL), 4-methyl-2-oxopentanoic acid (0.500-20.0MUg/mL), 1-linoleoyl-2 hydroxy-sn-glycero-3-phosphocholine (2.50-100MUg/mL), oleic acid (10.0 400MUg/mL), pantothenic acid (0.0100-0.800MUg/mL), and serine (2.50-100MUg/mL). Liquid chromatography was carried out on a reversed phase column with a run time of 3.1min and the mass spectrometer operated in negative MRM mode. Method validation was performed on three identical LC-MS/MS systems with five runs each. Sufficient linearity (R2>0.99) was observed for all the analytes over the ranges. The imprecision (CVs) was found to be less than 5.5% for intra-run and less than 5.8% for inter-run for the seven analytes. The analytical recovery was determined to be between 96.3 and 103% for the seven analytes. This fast and robust method has subsequently been used for patient sample analysis for the assessment of IR and IGT. PMID- 28029545 TI - Highly sensitive LC-MS/MS methods for urinary biological monitoring of occupational exposure to cyclophosphamide, ifosfamide, and methotrexate antineoplastic drugs and routine application. AB - Highly sensitive ESI-LC-MS/MS methods were developed for urinary biological monitoring of occupational exposure to cyclophosphamide (CP), ifosfamide (IF), and methotrexate (MTX), which are hazardous antineoplastic drugs frequently handled by healthcare professionals. Extraction methods consisted of liquid/liquid extraction for simultaneous urinary CP and IF assays, and of solid phase extraction for the urinary MTX assay. A good linearity (r2>0.997), precision (CV<14.6%), and accuracy (bias<9.9%) were achieved for all compounds. The limit of detection (LOD) was 10pg/ml and the lower limit of quantification (LOQ) was 20pg/ml for all three drugs. Applying these methods in routine, more than 116 healthcare professionals occupationally exposed to antineoplastic drugs were monitored and 635 urines were analysed. Eleven healthcare professionals (9.5%) were found to be contaminated to at least one of the three antineoplastic drugs. Among analysed urines, 22 samples were found positives. The measured concentrations ranged from 20.1 to 1850pg/ml and, for six samples, concentrations were at CP trace level, between the LOD and LOQ values (10-20pg/ml). Such efficient analytical tools combining high specificity with high sensitivity are essential for reliable detection and routine biological monitoring of healthcare professionals occupationally exposed to these widely used antineoplastic drugs. These methods allow to monitor the healthcare professionals exposure to antineoplastic drugs in the aim to assess the effectiveness of collective and individual protective measures. PMID- 28029546 TI - Determination of antipsychotic drugs in hospital and wastewater treatment plant samples by gas chromatography/tandem mass spectrometry. AB - The development and performance evaluation of a method for the simultaneous determination of six antipsychotic drugs in hospital effluents and wastewater treatment plants (WWTP) samples are herein presented. The method involves an off line mixed mode (reversed-phase and strong cation exchange) solid phase extraction (SPE) with gas chromatography (GC) coupled to tandem mass spectrometry (MS/MS). The present methodology was validated following internationally accepted criteria, and the studied parameters included selectivity, linearity, limits of detection (LOD) and quantitation (LLOQ), instrumental limits, precision and accuracy, stability and recovery. The procedure was linear for concentrations ranging from 0.1 to 10MUg/L (0.02 to 2MUg/L for haloperidol), with determination coefficients higher than 0.99 for all analytes. Intra- and inter-day precision was lower than 15% for all analytes at the studied concentrations, while accuracy remained between a +/-15% interval. Recoveries ranged from 31% to 83%. Low LODs were achieved, between 2 and 10ng/L, allowing a reliable identification of all analytes at trace levels, using only 50mL as sample volume. All studied parameters complied with the defined criteria and the method was successfully applied to gather preliminary results of the determination of antipsychotics on hospital effluents and on influent and effluent of WWTPs, opening perspectives for the study of their fate in the aquatic environment. PMID- 28029548 TI - Hybrid systems based on gold nanostructures and porphyrins as promising photosensitizers for photodynamic therapy. AB - Gold nanostructures of two different shapes (spheres and rods) were synthesized to form a colloidal hybrid system with 5,10,15,20-tetrakis(N-methylpyridinium-4 yl)porphyrin tosylate salt (H2TM4PyP(OTs)4) (POR) for applications in photodynamic therapy (PDT) using light in the visible spectral range. Electron paramagnetic resonance (EPR) experiments in combination with spin trapping were used for the detection of reactive oxygen species (ROS) and evaluation of the efficiency of these novel hybrid systems as photosensitizers. It is shown that the hybrid system consisting of gold nanorods (AuNR) and porphyrin (POR) is by far more efficient than its isolated components. This enhanced efficiency is explained by a synergetic effect between the AuNR and the porphyrin, wherein a rapid energy transfer from the former to the latter produces a large amount of singlet oxygen followed by its conversion into hydroxyl radicals. The mechanism was investigated using different spin traps and different ROS inhibitors. On the other hand, spherical gold nanoparticles (AuNP) do not show this synergetic effect. The synergetic effect for gold nanorods/POR hybrid is attributed to a larger field enhancement close to the gold nanorod surface in addition to the electrostatic attraction between the components of the hybrid system. PMID- 28029547 TI - Improving sensitivity and specificity of capturing and detecting targeted cancer cells with anti-biofouling polymer coated magnetic iron oxide nanoparticles. AB - Detecting circulating tumor cells (CTCs) with high sensitivity and specificity is critical to management of metastatic cancers. Although immuno-magnetic technology for in vitro detection of CTCs has shown promising potential for clinical applications, the biofouling effect, i.e., non-specific adhesion of biomolecules and non-cancerous cells in complex biological samples to the surface of a device/probe, can reduce the sensitivity and specificity of cell detection. Reported herein is the application of anti-biofouling polyethylene glycol-block allyl glycidyl ether copolymer (PEG-b-AGE) coated iron oxide nanoparticles (IONPs) to improve the separation of targeted tumor cells from aqueous phase in an external magnetic field. PEG-b-AGE coated IONPs conjugated with transferrin (Tf) exhibited significant anti-biofouling properties against non-specific protein adsorption and off-target cell uptake, thus substantially enhancing the ability to target and separate transferrin receptor (TfR) over-expressed D556 medulloblastoma cells. Tf conjugated PEG-b-AGE coated IONPs exhibited a high capture rate of targeted tumor cells (D556 medulloblastoma cell) in cell media (58.7+/-6.4%) when separating 100 targeted tumor cells from 1*105 non-targeted cells and 41 targeted tumor cells from 100 D556 medulloblastoma cells spiked into 1mL blood. It is demonstrated that developed nanoparticle has higher efficiency in capturing targeted cells than widely used micron-sized particles (i.e., Dynabeads(r)). PMID- 28029549 TI - Amine-functionalized PVA-co-PE nanofibrous membrane as affinity membrane with high adsorption capacity for bilirubin. AB - In this study, poly(vinyl alcohol-co-ethylene) (PVA-co-PE) nanofibrous membrane was activated by sodium hydroxide and cyanuric chloride, and then the activated membranes were functionalized by 1,3-propanediamine, hexamethylenediamine and diethylenetriamine to be affinity membranes for bilirubin removal, respectively. The chemical structures and morphologies of membranes were investigated by SEM, FTIR and XPS. And the adsorption ability of different amine-functionalized nanofibrous membranes for bilirubin was characterized. Furthermore, the effects of temperature, initial concentration of bilirubin, NaCl concentration and BSA concentration on the adsorption capacity for bilirubin of diethylenetriamine functionalized nanofibrous membrane were studied. Results indicated that the adsorption capacity for bilirubin of diethylenetriamine-functionalized nanofibrous membrane could reach 85mg/g membrane when the initial bilirubin concentration was 200mg/L while the adsorption capacity could be increased to 110mg/g membrane if the initial bilirubin concentration was more than 400mg/L. The dynamic adsorption of diethylenetriamine-functionalized nanofibrous membrane showed that the ligands of amine groups on the membrane surface could be used as far as possible by recirculating the plasma with certain flow rates. Therefore, the diethylenetriamine-functionalized PVA-co-PE nanofibrous membrane possessed high adsorption capacity for bilirubin and it can be candidate as affinity membrane for bilirubin removal. PMID- 28029550 TI - Multifunctional nanoplatform for enhanced photodynamic cancer therapy and magnetic resonance imaging. AB - Co-delivery of photosensitizers and synergistic agents by one single nanoplatform is interesting for enhancing photodynamic therapy (PDT) of cancer. Here, a multifunctional nanoplatform for enhanced photodynamic therapy and magnetic resonance imaging of cancer was constructed. The poly (lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with hematoporphyrin monomethyl ether (HMME) were coated with multifunctional manganese dioxide (MnO2) shells, which were designed as PLGA/HMME@MnO2 NPs. Once the NPs were effectively taken up by tumor cells, the intracellular H2O2 was catalysed by the MnO2 shells to generate O2. Meanwhile, the higher glutathione (GSH) promoted the degradation of MnO2 into Mn2+ ions with the ability of magnetic resonance (MR) imaging. After the degradation of outer layer, the release of photosensitizer was promoted. Under irradiation, the released HMME produced cytotoxic reactive oxygen species (ROS) to damage the tumor cells when the O2 was generated in the hypoxic tumor site. Furthermore, the decreased GSH level further inhibited the consumption of the produced ROS, which greatly enhanced the PDT efficacy. Therefore, this study suggested that this multifunctional system has the potential for enhanced photodynamic therapy and magnetic resonance imaging. PMID- 28029551 TI - Recommendations for the use of ultrasound and magnetic resonance in patients with rheumatoid arthritis. AB - OBJECTIVE: To develop evidence-based recommendations on the use of ultrasound (US) and magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA). METHODS: Recommendations were generated following a nominal group technique. A panel of experts, consisting of 15 rheumatologists and 3 radiologists, was established in the first panel meeting to define the scope and purpose of the consensus document, as well as chapters, potential recommendations and systematic literature reviews (we used and updated those from previous EULAR documents). A first draft of recommendations and text was generated. Then, an electronic Delphi process (2 rounds) was carried out. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70% of experts voted >=7. The level of evidence and grade or recommendation was assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence. The full text was circulated and reviewed by the panel. The consensus was coordinated by an expert methodologist. RESULTS: A total of 20 recommendations were proposed. They include the validity of US and MRI regarding inflammation and damage detection, diagnosis, prediction (structural damage progression, flare, treatment response, etc.), monitoring and the use of US guided injections/biopsies. CONCLUSIONS: These recommendations will help clinicians use US and MRI in RA patients. PMID- 28029552 TI - Epilepsia partialis continua: A review. AB - Epilepsia partialis contina (EPC) in a narrow definition is a variant of simple focal motor status epilepticus in which frequent repetitive muscle jerks, usually arrhythmic, continue over prolonged periods of time. In a broader definition (used in this review) it also includes non-motor manifestations otherwise known as aura continua. EPC may occur as a single episode, repetitive episodes, it may be chronic progressive or non-progressive. It appears as an unusual manifestation of epilepsy in which more typical paroxysmal events are partly or entirely replaced by the sustained repetition of seizure fragments in rapid succession. The minimum duration is defined as one hour but EPC may continue for up to many years. There are multiple possible etiologies which can be local or systemic, including two disease entities, Rasmussen encephalitis and Russian tick-borne spring-summer encephalitis. Among systemic brain disorders, mitochondrial diseases and non-ketotic hyperglycemia are particularly likely to cause EPC whereas stroke is a frequent cause of acute EPC. The symptoms of motor EPC have been interpreted as cortical reflex myocloni but the pathophysiology is probably not uniform for all cases. In pathophysiological terms, EPC seems to represent an oscillation of excitation and inhibition in a feedback loop whose mechanisms are still poorly understood. However, EPC only seems to occur rarely in an otherwise healthy brain. Treatment has to take account of the etiology but, in general, EPC tends to be drug-resistant. Epilepsy surgery is often indicated in Rasmussen encephalitis. PMID- 28029554 TI - Validation of the Italian version of the Non Motor Symptoms Scale for Parkinson's disease. AB - OBJECTIVE: To validate the adapted Italian version of the Non-Motor Symptoms Scale (NMSS), a tool to assess non-motor symptoms (NMS) in Parkinson's disease (PD). METHODS: A cross cultural adaptation of the NMSS into Italian and a psychometric analysis of the translated version of the NMSS was carried out in patients with PD from two university centres-affiliated hospitals. The quality of data and the acceptability, reliability and construct validity of NMSS were analyzed. The following standard scales were also applied: Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale (UPDRS) part III, Montreal Cognitive Assessment, Beck Depression Inventory, Neuropsychiatric Inventory, Epworth Sleepiness Scale, Autonomic Scale for Outcomes in Parkinson's disease Motor, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part I and Modified Cumulative Illness Rating Scale (CIRS). Levodopa equivalent daily dose (LEDD) was calculated. RESULTS: Seventy-one patients with PD were assessed (mean age years 69.8 +/- 9.6 SD; 31% women; mean length of disease 6.3 +/- 4.6 years; H&Y median: 2). Mean NMSS was 39.76 (SD 31.9; skewness 0.95). The total score of NMSS was free of floor or ceiling effects and showed a satisfactory reliability (Cronbach's alpha coefficient on total score was 0.72 [range for domains: 0.64-0.73], SEM value was 3.88 [1/2 SD = 31.90]). Significant positive correlations were found among total NMSS and other NMS standard tests, but no significant correlation appeared with UPDRS part III, CIRS and LEDD. CONCLUSIONS: The Italian NMSS is a comprehensive and helpful measure for NMS in native Italian patients with PD. PMID- 28029555 TI - Speech Adjustments for Room Acoustics and Their Effects on Vocal Effort. AB - OBJECTIVES: The aims of the present study are (1) to analyze the effects of the acoustical environment and the voice style on time dose (Dt_p) and fundamental frequency (mean f0 and standard deviation std_f0) while taking into account the effect of short-term vocal fatigue and (2) to predict the self-reported vocal effort from the voice acoustical parameters. METHODS: Ten male and ten female subjects were recorded while reading a text in normal and loud styles, in three rooms-anechoic, semi-reverberant, and reverberant-with and without acrylic glass panels 0.5 m from the mouth, which increased external auditory feedback. Subjects quantified how much effort was required to speak in each condition on a visual analogue scale after each task. RESULTS: (Aim1) In the loud style, Dt_p, f0, and std_f0 increased. The Dt_p was higher in the reverberant room compared to the other two rooms. Both genders tended to increase f0 in less reverberant environments, whereas a more monotonous speech was produced in rooms with greater reverberation. All three voice parameters increased with short-term vocal fatigue. (Aim2) A model of the vocal effort to acoustic vocal parameters is proposed. The sound pressure level contributed to 66% of the variance explained by the model, followed by the f0 (30%) and the modulation in amplitude (4%). CONCLUSIONS: The results provide insight into how voice acoustical parameters can predict vocal effort. In particular, it increased when SPL and f0 increased and when the amplitude voice modulation decreased. PMID- 28029556 TI - A Formant Range Profile for Singers. AB - Vowel selection is important in differentiating between singing styles. The timbre of the vocal instrument, which is related to its frequency spectrum, is governed by both the glottal sound source and the vowel choices made by singers. Consequently, the ability to modify the vowel space is a measure of how successfully a singer can maintain a desired timbre across a range of pitches. Formant range profiles were produced as a means of quantifying this ability. Seventy-seven subjects (including trained and untrained vocalists) participated, producing vowels with three intended mouth shapes: (1) neutral or speech-like, (2) megaphone-shaped (wide open mouth), and (3) inverted-megaphone-shaped (widened oropharynx with moderate mouth opening). The first and second formant frequencies (F1 and F2) were estimated with fry phonation for each shape and values were plotted in F1-F2 space. By taking four vowels of a quadrangle /i, ae, a, u/, the resulting area was quantified in kHz2 (kHz squared) as a measure of the subject's ability to modify their vocal tract for spectral differences. PMID- 28029557 TI - Period for Normalization of Voice Acoustic Parameters in Indian Pediatric Cochlear Implantees. AB - OBJECTIVE: The purpose of this study was to investigate the duration required by children with cochlear implants to approximate the norms of voice acoustic parameters. STUDY DESIGN: The study design is retrospective. METHODS: Thirty children with cochlear implants (chronological ages ranging between 4.1 and 6.7 years) were divided into three groups, based on the postimplantation duration. Ten normal-hearing children (chronological ages ranging between 4 and 7 years) were selected as the control group. All implanted children underwent an objective voice analysis using Dr. Speech software (Tiger DRS, Inc., Seattle, WA, USA) at 6 months and at 1 and 2 years of implant use. Voice analysis was done for the children in the control group and means were derived for all the parameters analyzed to obtain the normal values. Habitual fundamental frequency (HFF), jitter (frequency variation), and shimmer (amplitude variation) were the voice acoustic parameters analyzed for the vowels |a|, |i|, and |u|. The obtained values of these parameters were then compared with the norms. RESULTS: HFF for the children with implant use for 6 months and 1 year did significantly differ from the control group. However, there was no significant difference (P > 0.5) observed in the children with implant use for 2 years, thus matching the norms. Jitter and shimmer showed a significant difference (P < 0.5) even at 2 years of implant use when compared with the control group. CONCLUSIONS: The findings of the study divulge that children with cochlear implants approximate age-matched normal-hearing kids with respect to the voice acoustic parameter of HFF by 2 years of implant use. However, jitter and shimmer were not found to stabilize for the duration studied. PMID- 28029558 TI - Radiation Dose Levels of Retrospectively ECG-Gated Coronary CT Angiography Using 70-kVp Tube Voltage in Patients with High or Irregular Heart Rates. AB - RATIONALE AND OBJECTIVES: Despite ongoing technical refinements, coronary computed tomography angiography (cCTA) remains challenging in its diagnostic value by electrocardiographic (ECG) misregistration and motion artifacts, which commonly occur in patients with atrial fibrillation and high or irregular heart rates. The aim of this study was to evaluate the radiation dose and the number of inconclusive coronary segments at cCTA using retrospective ECG gating at 100 and 70 kV. MATERIALS AND METHODS: With institutional review board approval, 154 patients (median age 54 years, 98 men) with high or irregular heart rate prospectively underwent retrospectively ECG-gated cCTA without tube current modulation on a third-generation dual-source computed tomography (DSCT) system at 70 kV (n = 103) or on a second-generation DSCT system at 100 kV (n = 51). Images were reconstructed in best diastolic phase (BDP), best systolic phase (BSP), and in all phases (APs) at 10% intervals across the R-R cycle. Objective and subjective image qualities were evaluated as well as the presence of motion artifacts with the three different reconstruction approaches. RESULTS: The mean heart rate was 93 +/- 16 bpm. The mean effective radiation dose was 4.5 mSv for 70 kV compared to 8.4 mSv for 100 kV (P < 0.05). At BDP reconstruction, 71% (n = 110) of the patients showed motion artifacts in one or more coronary segments. At BSP reconstruction, the number of patients with motion artifacts decreased to 37% (n = 57). In contrast, if images were reconstructed with the AP approach, all vessels and coronary segments were evaluable with both cCTA protocols. CONCLUSIONS: Retrospectively ECG-gated cCTA at 70 kV results in 52% decreased radiation dose. Further using the AP algorithm allowed for diagnostic evaluation of all coronary segments for stenosis, in contrast to BDP or BSP phase alone. PMID- 28029559 TI - Radiology Clinical Internship: Perhaps Another Way? PMID- 28029560 TI - HIV and Helminths - Not All Worms Created Equal? PMID- 28029561 TI - Acute myelomonocytic leukemia and leukocytoclastic vasculitis. PMID- 28029562 TI - [Sleep disorders in idiopathic non-specific interstitial pneumonia]. PMID- 28029563 TI - [Use of non-vitamin K antagonist oral anticoagulants in Primary Care: ACTUA study]. AB - OBJECTIVES: Approximately 40% of patients with non-valvular auricular fibrillation (NVAF) who receive vitamin K antagonists (VKA) in Primary Care in Spain have poor anticoagulation control. The objective of the study Actuacion en antiCoagulacion, Tratamiento y Uso de anticoagulantes orales de accion directa (ACOD) en Atencion primaria (ACTUA) (Action in Coagulation, Treatment and Use of direct oral anticoagulants [DOACs]) in Primary Care) was to analyse the current situation regarding the use of VKA and non-vitamin K antagonist oral anticoagulants (NOACs) in patients with NVAF in Primary Care in Spain and the possible issues arising from it. PATIENTS AND METHODS: An online survey was created covering various aspects of the use of oral anticoagulants in NAFV. A two round modified Delphi approach was used. Results were compiled as a set of practical guidelines. RESULTS: Forty-four experts responded to the survey. Consensus was reached in 62% (37/60) of the items. Experts concluded that a considerable number of patients with NVAF who receive VKA do not have a well controlled INR and that a substantial group of patients who could benefit from being treated with NOACs do not receive them. The use of NOACs increases the probability of having good anticoagulation control and decreases the risk of severe and intracranial haemorrhage. Current limitations to the use of NOACs include administrative barriers, insufficient knowledge about the benefits and risks of NOACs, limited experience of doctors in using them, and their price. Renal insufficiency influences the choice of a particular anticoagulant. CONCLUSIONS: The ACTUA study highlights the existing controversies about the use of oral anticoagulants for the treatment of NVAF in Primary Care in Spain, and provides consensus recommendations that may help to improve the use of these medications. PMID- 28029564 TI - [Reflections on scombroid fish poisoning]. PMID- 28029565 TI - Altered renal functions in patients with occlusion of an accessory renal artery after endovascular stenting of an infrarenal aneurysm. AB - OBJECTIVE: Coverage of an accessory renal artery (ARA) during endovascular aneurysm repair (EVAR) may result in renal infarction (RI) or decline in renal function. Until now, it remains vague which patients are at risk to develop these complications. We therefore analyzed the effect of ARA sealing by EVAR with respect to the occurrence of RI and renal function. METHODS: A retrospective analysis of the medical records and computed tomographic scans of patients who underwent EVAR within a period of 5 years was performed. Particular attention was paid to the presence or absence of accessory renal arteries and renal function before EVAR. Thirty-four patients with ARA were matched 1:3 to 102 patients without ARA. The results after EVAR were analyzed in patients with and without ARA. In patients with ARA, we further examined the results after EVAR in patients with an estimated glomerular filtration rate (eGFR) >= 60 mL/min and eGFR < 60 mL/min before EVAR. RESULTS: Before EVAR, the median eGFR was 74 mL/min (25th/75th percentiles, 57/89) in patients with ARA and 72 mL/min (25th/75th percentiles, 63/87) in patients without ARA. Alterations in eGFR were significantly pronounced in patients with ARA when compared with patients without ARA 1 week after EVAR (ARA, -10.7 +/- 16.9 mL/min vs without ARA, 1.2 +/- 13.3 mL/min; P = .002) and after 6 months (ARA, -10.8 +/- 17.4 mL/min vs without ARA, 1.2 +/- 13.3 mL/min; P = .001). RI only occurred in patients with ARA. Within the group of patients with ARA, patients with normal renal function (NF) showed a more pronounced decline in eGFR preoperatively when compared with patients with impaired renal function (IF) 1 week after EVAR (NF, -14.3 +/- 18.0 mL/min vs IF, 1.3 +/- 10.8 mL/min; P = .02) and after 6 months (NF, -15.8 +/- 17.9 mL/min vs IF, 0.1 +/- 15.2 mL/min; P = .007). CONCLUSIONS: The decrease in renal function was more pronounced in patients with ARA after EVAR when compared with patients without ARA undergoing EVAR. In patients with ARA, the observed decline in renal function was significantly distinct in patients presenting NF preoperatively. Consequently, the risk of IF after EVAR seems to be increased in patients with ARA and normal preoperative renal function. PMID- 28029566 TI - Midterm results of the fenestrated Anaconda endograft for short-neck infrarenal and juxtarenal abdominal aortic aneurysm repair. AB - OBJECTIVE: The fenestrated Anaconda endograft (Vascutek, Renfrewshire, Scotland) was introduced in 2010 and showed promising short-term results with high technical success and low morbidity rates. The aim of this study was to present the midterm results, with a minimum of 12 months follow-up, for all patients treated with the fenestrated Anaconda endograft in The Netherlands. METHODS: Patients treated with the fenestrated Anaconda endograft between May 2011 and February 2015 were included. Follow-up consisted of computed tomography angiography at 1 month and 1 year, and duplex ultrasound yearly thereafter with additional computed tomography angiography if indicated using a standard protocol. RESULTS: A total of 60 patients were included; 48 patients (80.0%) were treated for juxtarenal aneurysms, and 12 (20.0%) were short-neck infrarenal aneurysms. Mean aneurysm size was 64 +/- 9 mm. A total of 140 fenestrations were incorporated. Median follow-up was 16.4 months (interquartile range, 11.9-27.4). The 30-day mortality was 3.4% (n = 2). Kaplan-Meier estimates for 1-year, 2-year, and 3-year survival were 91.4%, 89.5%, and 86.3%, respectively, without aneurysm related mortality during follow-up. Main body primary and secondary endograft patencies were 98.3% and 100%, respectively. Target vessel primary and secondary patencies were 95.0% and 98.6%, respectively. Early type IA endoleaks occurred in seven patients (11.7%) and spontaneously resolved in all patients. At 1-year follow-up 4 (6.7%) type II endoleaks persisted. One patient experienced aneurysm rupture because of a late type III endoleak attributable to a dislodged renal stent and subsequently underwent successful conversion to open surgery. CONCLUSIONS: The fenestrated Anaconda is a viable treatment option for complex abdominal aortic aneurysms. Acceptable mortality and morbidity and low reintervention rates contribute to good midterm results. Occurrence of early type I endoleak was relatively common, but these resolved spontaneously in all patients. PMID- 28029567 TI - Blood discard rate in a blood center in Curitiba - Brazil. Ten years of study. AB - INTRODUCTION: Development of technologies to reduce transfusion risks of infectious diseases is a major characteristic of hemotherapy. Thus, each donation undergoes clinical and serological screening tests to ensure the donated blood do not offer risks to the receiver. OBJECTIVE: Evaluate the prevalence of positive serology in blood donations rejected by Hemobanco (Curitiba - PR) in the period ranging from January 2003 to December 2012. METHODOLOGY: During the period studied, we observed the total number of donations and its division according to gender. We also analyzed the number of rejected donations due to seropositivity, considering the diseases investigated routinely in blood banks in Brazil, and the frequency of discards according to age groups. RESULTS: Within the period studied, 399,280 donations were performed. 62.0% donors were male. Comparing 2003 to 2012, we noticed a significant decrease of discards, from 10.2% to 5.0%, respectively. There was a reduction of seropositivity for HIV, HBsAg and anti-HBc and an increase for Chagas Disease, hepatitis C, syphilis and HTLV. The age group with the highest prevalence for discards changed: it used to be the 40-59 years old group in 2003, and became the 20-39 years old group in 2012. CONCLUSION: There was an increase in the number of donations in Hemobanco and a decrease in total discards due to seropositive donations. Most donors were male. The most prevalent cause of discards only amongst seropositive donation discards is seropositivity for anti-HBc. There was a significant increase of donors aged between 20 and 39 years old. PMID- 28029568 TI - Differences in levels of platelet-derived microparticles in platelet components prepared using the platelet rich plasma, buffy coat, and apheresis procedures. AB - BACKGROUND: There has been an increased interest in platelet-derived microparticles (PMPs) in transfusion medicine. Little is known about PMP status during the preparation of platelet concentrates for transfusion. AIM: The aim of this study is to compare the PMP levels in platelet components prepared using the buffy coat (BC), platelet-rich plasma platelet concentrate (PRP-PC), and apheresis (AP) processes. METHODS: Platelet components were prepared using the PRP-PC and BC processes. Apheresis platelets were prepared using the Trima Accel and Amicus instruments. The samples were incubated with annexin A5-FITC, CD41-PE, and CD62P-APC. At day 1 after processing, the PMPs and activated platelets were determined using flow cytometry. RESULTS: Both the percentage and number of PMPs were higher in platelet components prepared using the Amicus instrument (2.6+/ 1.8, 32802+/-19036 particles/MUL) than in platelet components prepared using the Trima Accel instrument (0.5+/-0.4, 7568+/-5298 particles/MUL), BC (1.2+/-0.6, 12,920+/-6426 particles/MUL), and PRP-PC (0.9+/-0.6, 10731+/-5514 particles/MUL). Both the percentage and number of activated platelets were higher in platelet components prepared using the Amicus instrument (33.2+/-13.9, 427553+/-196965 cells/MUL) than in platelet components prepared using the Trima Accel instrument (16.2+/-6.1, 211209+/-87706 cells/MUL), BC (12.9+/-3.2, 140624+/-41003 cells/MUL), and PRP-PC (21.1+/-6.3, 265210+/-86257 cells/MUL). CONCLUSIONS: The study suggests high variability of PMPs and activated platelets in platelet components prepared using different processes. This result may be important in validating the instruments involved in platelet blood collection and processing. PMID- 28029569 TI - Key elements of optimal treatment decision-making for surgeons and older patients with colorectal or pancreatic cancer: A qualitative study. AB - OBJECTIVE: To identify key elements of optimal treatment decision-making for surgeons and older patients with colorectal (CRC) or pancreatic cancer (PC). METHODS: Six focus groups with different participants were performed: three with older CRC/PC patients and relatives, and three with physicians. Supplementary in depth interviews were conducted in another seven patients. Framework analysis was used to identify key elements in decision-making. RESULTS: 23 physicians, 22 patients and 14 relatives participated. Three interacting components were revealed: preconditions, content and facilitators of decision-making. To provide optimal information about treatments' impact on an older patient's daily life, physicians should obtain an overall picture and take into account patients' frailty. Depending on patients' preferences and capacities, dividing decision making into more sessions will be helpful and simultaneously emphasize patients' own responsibility. GPs may have a valuable contribution because of their background knowledge and supportive role. CONCLUSION: Stakeholders identified several crucial elements in the complex surgical decision-making of older CRC/PC patients. Structured qualitative research may also be of great help in optimizing other treatment directed decision-making processes. PRACTICE IMPLICATIONS: Surgeons should be trained in examining preconditions and useful facilitators in decision-making in older CRC/PC patients to optimize its content and to improve the quality of shared care. PMID- 28029570 TI - Validation of the Norwegian version of MAPPIN'SDM, an observation-based instrument to measure shared decision-making in clinical encounters. AB - OBJECTIVE: To validate the Norwegian version of MAPPIN'SDM observer scales with regard to reliability, accuracy and the extent to which the scales include the essentials of the shared decision-making concept. METHODS: Three MAPPIN'SDM scales, focusing on the skills of doctor, patient and dyad, were applied to audiovisual records of 35 decision sequences. Inter-rater reliabilities were determined based on kappa coefficients. Sensitivities and specificities were calculated with regard to an expert reference standard. Convergent validities were calculated with the OPTION5 scale. MAPPIN'SDM was qualitatively compared to OPTION5 using Makoul & Clayman's Integrative Model structure. RESULTS: Inter rater reliabilities were high on average over 11 items in each of three observer scales (MAPPINdoctor=0.77, MAPPINpatient=0.82, MAPPINdyad=0.77). Patient involvement was detected accurately (MAPPINdyad: mean sensitivity/specificity 93/91%). Comparison with OPTION5 showed weak to moderate correlation (Spearman's rho/p-value: MAPPINdoctor:=0.44/0.009, MAPPINpatient: 0.38/0.024, MAPPINdyad 0.40/0.016) and little content overlap. CONCLUSION: MAPPIN'SDMnorge is capable of assessing SDM highly reliably and accurately. Divergence from OPTION5 reflects explicit disagreement regarding the concept's assumptions. PRACTICE IMPLICATIONS: MAPPIN'SDMnorge is ready for use in Norway. In-depth debate on the SDM concept's essentials is urgently needed. PMID- 28029571 TI - In search of success in health promotion and alcohol education. PMID- 28029572 TI - Using digital interventions for self-management of chronic physical health conditions: A meta-ethnography review of published studies. AB - OBJECTIVES: To understand the experiences of patients and healthcare professionals (HCPs) using self-management digital interventions (DIs) for chronic physical health conditions. METHODS: A systematic search was conducted in 6 electronic databases. Qualitative studies describing users' experiences of self management DIs were included, and authors' interpretations were synthesised using meta-ethnography. RESULTS: 30 papers met the inclusion criteria, covering a range of DIs and chronic conditions, including hypertension, asthma and heart disease. The review found that patients monitoring their health felt reassured by the insight this provided, and perceived they had more meaningful consultations with the HCP. These benefits were elicited by simple tele-monitoring systems as well as multifaceted DIs. Patients appeared to feel more reliant on HCPs if they received regular feedback from the HCP. HCPs focused mainly on their improved clinical control, and some also appreciated patients' increased understanding of their condition. CONCLUSIONS: Patients using self-management DIs tend to feel well cared for and perceive that they adopt a more active role in consultations, whilst HCPs focus on the clinical benefits provided by DIs. PRACTICE IMPLICATIONS: DIs can simultaneously support patient condition management, and HCPs' control of patient health. Tele-monitoring physiological data can promote complex behaviour change amongst patients. PMID- 28029573 TI - Mechanical circulatory support and heart transplantation in the Asia Pacific region. AB - Globalization has resulted in epidemiologic transition in developing countries from infectious disease and nutritional deficiencies to non-communicable diseases. Epidemiologic data on heart failure (HF), particularly advanced HF therapy, in Asia are increasingly becoming available, although they remain sparse. Heart transplantation for advanced stage HF remains very low in Asia approximately 0.075 heart transplants per 1 million population. North America, which comprises 7.5% of the world population, accounted for 55.8% of transplants recorded in the 2012 International Society for Heart and Lung Transplantation (ISHLT) Registry, whereas Asia, with 62.5% of the world population, accounted for 5.7% of transplants. There is also lack of reporting from heart transplant centers in Asia to the ISHLT Registry. Most transplant programs in Asia are in economically stable South East Asian countries, whereas in other parts of developing countries, the cost and health care infrastructures remain prohibitive for the development of these programs. Multi-cultural and racial factors, religious beliefs, and diverse traditions of many centuries have resulted in reluctance to organ donation. Mechanical circulatory support (MCS) is emerging as a viable alternative to transplantation, but despite technical capabilities, limitations in embracing MCS in Asia exist. Discrepant practices in the reimbursement of costly MCS therapy have led to differences in the availability of these devices to patients in the region. The HeartMate II (St. Jude Medical, Inc, St. Paul, MN) left ventricular assist device is currently the most widely used durable device in Asia, whereas the HeartWare HVAD (HeartWare, Inc, Framingham, MA) is used most often in Australia. By September 9, 2015, 341 HeartMate implants (293 as bridge to transplant and 48 as destination therapy) had been performed, of which 180 implants were in Japan. The overall 4-year survival is 88%. The longest duration of support is 6.5 years. By the end of 2015, 243 HeartWare HVADs had been implanted in Asia Pacific. There is a need for focused efforts at improving the reporting of data and intensifying health policy within the region to advocate organ transplantation. Individual governments need to take national responsibility to fulfill organ donation and transplantation needs of their populations. International collaboratives, coordinated by societies such as the ISHLT, will be essential in moving this field forward in Asia Pacific. PMID- 28029574 TI - The axial continuous-flow blood pump: Bench evaluation of changes in flow associated with changes of inflow cannula angle. AB - BACKGROUND: Changes in the geometry of the HeartMate II (HMII) inflow cannula have been implicated in device thrombosis post-implant. The purpose of this in vitro study was to evaluate what effects changing the angle of the cannula in relation to the pump may have on pump flow and arterial pressure, under simulated inflow conditions. METHODS: The HMII with an inflow cannula was mounted on a mock loop consisting of a pulsatile pneumatic ventricle to simulate the native ventricle. The angles of the HMII in relation to the inflow cannula were adjusted by separate fixed gooseneck holders. A custom-made miniature steerable camera was introduced into a flexible portion of the HMII inflow cannula. Endoscopic views of various types of inflow cannula constriction (bending, squeezing, stretching and twisting) were recorded, and pump flow and systemic arterial pressure (AoP) were assessed during each simulation. RESULTS: Baseline mean pump flow (3.5 liters/min) and mean AoP (91.5 mm Hg) were unchanged by bending maximally in 2 different directions, twisting up to 30 degrees , stretching (compression or extension), or occluding the inflow graft <90%. However, mean pump flow and mean AoP decreased substantially when the inflow graft became occluded by >=90% by sliding or squeezing. CONCLUSIONS: "Less-than-critical" obstruction (what we define here as <90%) of the HMII inflow cannula did not reveal substantial changes in pump flow or AoP. Data suggest that a major alteration to inflow cannula geometry is required to achieve clinically relevant hemodynamic changes. These data confirm that minor changes in angulation of the inflow cannula have no impact on flow through the device. PMID- 28029575 TI - Use of sirolimus in pediatric heart transplant patients: A multi-institutional study from the Pediatric Heart Transplant Study Group. AB - BACKGROUND: Proliferation signal inhibitors, such as sirolimus, are increasingly used in solid-organ transplantation. However, limited data exist on sirolimus treated pediatric patients. We aimed to describe sirolimus use in pediatric heart transplant patients and test the hypothesis that sirolimus use is associated with improved outcomes. METHODS: A retrospective review and propensity-matched analysis of the Pediatric Heart Transplant Study database was performed on patients undergoing primary heart transplantation from 2004 to 2013 with at least 1 year of follow-up comparing patients treated vs not treated with sirolimus at 1 year after transplant. The primary outcome of interest was patient survival, with secondary outcomes including cardiac allograft vasculopathy, rejection, malignancy, and renal insufficiency. RESULTS: Between 2004 and 2013, 2,531 patients underwent transplantation. At least 1 year of follow-up was available for 2,080 patients, of whom 144 (7%) were on sirolimus at 1 year post-transplant. Sirolimus-treated and non-treated patients had similar survival in the overall cohorts and in the propensity-matched analysis. The secondary outcomes measures were also similar, including a composite end point of all outcome measures. There was a trend toward increased time to cardiac allograft vasculopathy (p = 0.09) and decreased time to infection (p = 0.05) among sirolimus-treated patients in the overall cohort (p = 0.19) but not in the propensity-matched cohort (p = 0.17). CONCLUSIONS: Sirolimus was used in less than 10% of patients at 1 year post-transplant. Overall outcomes of sirolimus treated and non-treated patients were similar with respect to survival and major transplant adverse events. Further study of sirolimus in pediatric heart transplant patients is needed. PMID- 28029576 TI - Could enzyme replacement therapy promote immune tolerance in Gaucher disease type 1? AB - Among the lysosomal storage disorders, Gaucher disease (GD) features some of the most striking alterations in the immune system, including increased levels of cytokines and chemokines. Although studies have demonstrated the efficacy of enzyme replacement therapy (ERT) for GD, the ideal dosage remains controversial. In this study, we report differences in levels of cytokines (IL-6, TNF-a, and IFN y) and chemokines (IL-8, IP-10, and MCP-1) in patients with GD type 1 treated with different ERT dosages and treatment durations. Patients were recruited from two ERT centers in Brazil and divided into two groups according to treatment facility. Comparison between groups showed that patients in group 1 had received ERT for longer (p=0.0078) and at higher doses (p=0.0002) than those in group 2. Patients in group 1 exhibited decreased levels of IL-6 (p=0.0006), TNF-alpha (p<0.0001), IFN-gamma (p<0.0001), IL-8 (p=0.0083), IP-10 (p<0.0001), and MCP-1 (p<0.0001) when compared to patients in group 2. Otherwise, patients in both groups were clinically similar, with no differences in hemoglobin, platelet, or leukocyte counts. Our data suggest that in GD type 1 the dosage and duration of therapy may be associated with establishment of peripheral tolerance and, consequently, decreased serum levels of inflammatory cytokines and chemokines. PMID- 28029577 TI - Forced knee extension test is a manual test that correlates with the unstable feelings of patients with ACL injury before and after reconstruction. AB - BACKGROUND: To investigate fear in patients with anterior cruciate ligament (ACL) injury before and after reconstruction, a forced knee extension (FKE) test was performed. The correlation of the test results was evaluated with the subjective function, sports performance and objective parameters. METHODS: The study included 102 patients with unilateral ACL reconstruction using a semitendinosus tendon with full clinical evaluation. This study was retrospective and determined the longitudinal results of the FKE test and investigated the effects on the subjective and objective outcomes at 2years. RESULTS: Preoperatively, 47% of patients showed positive FKE tests. The number of positive FKE tests was 31% at six months and 15% at 24months after ACL reconstruction. At two years, there were statistically significant differences between the FKE test positives and negatives regarding both subjective knee recovery (P=0.0095) and sports performance (P=0.0006). CONCLUSIONS: A new manual test, called the forced knee extension test, for fear in patients with ACL injury before and after reconstruction was introduced. The apprehension remained positive in 15% of the patients two years after ACL reconstruction, which affected subjective recovery of knee function and sports performance. PMID- 28029578 TI - Stemmed tibial revision component alignment: Does an anatomic conflict exist? AB - INTRODUCTION: Obtaining satisfactory coronal plane alignment is important for success in revision total knee arthroplasty (TKA). The study objective was to determine tibial coronal plane alignment after TKA when a tibial stem was used and assess if there was an anatomic conflict in tibial stemmed component alignment. MATERIALS AND METHODS: A radiographic review of 88 revision TKA cases was performed. Full length leg radiographs were examined for varus/valgus alignment, defined as greater than or equal to three degrees from neutral 180 degrees, canal or non-canal filling tibial stems, and any native tibial bow. RESULTS: In tibias with a native valgus alignment of three or more degrees, a canal-filling stem allowed little flexibility to improve final positioning of the tibial stem and resulted in a valgus alignment of the tibial stem in 87.5% of cases, where a canal filling stem was utilized. A non-canal filling stem utilized in native valgus tibias allowed on average a two-degree improvement in tibial alignment and 64.7% of cases resulted in a neutral placement of the tibial stem. CONCLUSION: Implanting the tibial component in a desired position is limited by type of stem and the native angulation of the tibia. When anatomic conflict exists between tibial mechanical axis and the intramedullary canal, canal filling stems may compromise coronal alignment. PMID- 28029579 TI - Patellar inversion: 180 degree rotation of the patella around its vertical axis within the intercondylar notch. AB - BACKGROUND: Dislocation of the patella can occur around its vertical as well as horizontal axis. However, near 180 degree rotation of the patella around its vertical axis within the intercondylar notch without its complete dislocation has never been previously reported to the best of our knowledge. We report one such neglected case along with its management. METHODS: The patient underwent open reduction and de-rotation of patella with repair of the medial and lateral patellar retinacula. The orientation of the patellar tendon intra-operatively was used as a guide for the reduction manoeuvre required. RESULTS: The patient had a good functional result at more than one year of follow-up. CONCLUSIONS: A skyline view of the knee in symptomatic patients with normal AP and lateral radiographs of the knee can be useful in diagnosing a rare intra-articular dislocation of the patella around its vertical axis. Neglected cases of such injuries can be easily treated with open reduction with the orientation of the patellar tendon guiding the manoeuvre to de-rotate the patella. Careful repair of lateral and medial retinacula in such cases is important in preventing future patellar instability. PMID- 28029580 TI - A new split arc VMAT technique for lymph node positive breast cancer. AB - PURPOSE: To investigate different volumetric modulated arc therapy (VMAT) field designs for lymph node positive breast cancer patients when compared to conventional static fields and standard VMAT designs. METHODS: Nineteen breast cancer patients with lymph node involvement (eleven left and eight right sided) were retrospectively analyzed with different arc designs. Proposed split arc designs with total rotations of 2*190 degrees and 2*240 degrees were compared to conventional field in field (FinF) and previously published non-split arc techniques with the same amount of total rotations. RESULTS: All VMAT plans were superior in dose conformity, when compared to the FinF plans. Split arc design decreased significantly ipsilateral lung dose and heart V5Gy for both left and right sided cases, when compared to non-split VMAT designs. For left sided cases no significant differences were seen in contralateral lung mean dose or V5Gy between different VMAT designs. For right sided cases the contralateral lung dose V5Gy was significantly higher in split VMAT group, when compared to non-split VMAT designs. The contralateral breast dose V5Gy increased significantly for split VMAT plans for both sides, when compared to non-split VMAT designs or FinF plans. CONCLUSIONS: The proposed split VMAT technique was shown to be superior to previously published non-split VMAT and conventional FinF techniques significantly reducing dose to the ipsilateral lung and heart. However, this came with the expense of an increase in the dose to the contralateral breast and for right-sided cases to the contralateral lung. PMID- 28029581 TI - Right atrial appendage aneurysms in veal calves and beef cattle: anatomopathological investigations and aetiopathogenetic hypotheses. AB - OBJECTIVES: Right atrial aneurysms have been reported in bovine species, but a clear aetiopathogenesis has never been elucidated. ANIMALS: One thousand and seventy-nine veal calves (6-9 months old) and 313 beef cattle (10-24 months old) housed in intensive livestock farming systems and regularly slaughtered were included in the present study. METHODS: Hearts were externally examined and the identified right atrial aneurysms were submitted for gross and histopathological investigations. RESULTS: Right atrial aneurysms, which involved the right auricle, were detected in both veal calves (4.63%) and beef cattle (8.63%). Two types of aneurysms were observed: one type showing communications with the atrial lumen, the other one having no connections with it. Aneurysms communicating with the atrial lumen were characterized by endocardial fibrosis, whereas the other ones showed arterial characteristics (intimal fibromuscular hyperplasia and medial elastic fibre and fibrous tissue deposition). CONCLUSIONS: Considering the similarities with the right atrial aneurysms reported in people, the aneurysms communicating with the atrial lumen were considered to be caused by an inherent atrial weakness (so called 'loci minoris resistentiae' areas). On the contrary, the aneurysms with no communications with the atrial lumen, whose localization suggested an origin from the intramural coronary arteries of the pectinate muscles, may be subsequent to systemic hypertension due to intensive livestock farming conditions. PMID- 28029582 TI - Obstructive sleep apnoea is frequent in patients with type 1 diabetes. AB - AIM: Obstructive Sleep Apnoea (OSA) is frequent in patients with type 2 diabetes. The aim of this study is to evaluate prevalence of OSA in patients with type 1 diabetes. METHODS: In a cross-sectional design, all patients with type 1 diabetes attending the outpatient clinic were offered screening for OSA for one night with the ApneaLink+ home-monitoring device. OSA was classified by the Apnoea-Hypopnea index (AHI; apnoeas/hypopneas per hour sleep). Symptoms of OSA were scored using the Epworth Sleepiness Score. Presence of autonomic neuropathy was evaluated by the Vagus(r) device. RESULTS: A total of 200 of 518 eligible patients with type 1 diabetes (39%) participated (68% men; age 52+/-15years (mean+/-SD), diabetes duration 24+/-14years and BMI 25.3+/-3.3kg/m2). OSA was diagnosed in 92 patients (46% (95% CI: 40-53)). Five patients had known OSA, and OSA was newly diagnosed in 87 patients, predominantly mild OSA (60 patients (69%)). OSA was present in 32% of the patients with normal BMI, in 60% of overweight patients, and in 61% of obese patients. Patients with type 1 diabetes and OSA were largely asymptomatic and did not report more sleepiness than patients without OSA. At multivariate analysis, age, BMI and presence of nephropathy were positively associated with risk of OSA. CONCLUSIONS: The prevalence of asymptomatic OSA is high in a cohort of patients with type 1 diabetes. Older age, overweight, and presence of nephropathy are associated with OSA. PMID- 28029583 TI - ACR Appropriateness Criteria Assessment of Fetal Well-Being. AB - Although there is limited evidence that antepartum testing decreases the risk for fetal death in low-risk pregnancies, women with high-risk factors for stillbirth should undergo antenatal fetal surveillance. The strongest evidence supporting antepartum testing pertains to pregnancies complicated by intrauterine fetal growth restriction secondary to uteroplacental insufficiency. The main ultrasound based modalities to determine fetal health are the biophysical profile, modified biophysical profile, and duplex Doppler velocimetry. In patients at risk for cardiovascular compromise, fetal echocardiography may also be indicated to ensure fetal well-being. Although no single antenatal test has been shown to be superior, all have high negative predictive values. Weekly or twice-weekly fetal testing has become the standard practice in high-risk pregnancies. The timing for the initiation of assessments of fetal well-being should be tailored on the basis of the risk for stillbirth and the likelihood of survival with intervention. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. PMID- 28029584 TI - Developing an Interventional Radiology Online Quality Assurance Database. PMID- 28029587 TI - Allele frequencies of 15 autosomal STR loci in the Yi ethnic minority from Yunnan Province in the far southwest of China. PMID- 28029586 TI - Social determinants, multimorbidity, and patterns of end-of-life care in older adults dying from cancer. AB - OBJECTIVE: Most prior studies on aggressive end-of-life care in older patients with cancer have accounted for social determinants of health (e.g., race, income, and education), but rarely for multimoribidity (MM). In this study, we examine the association between end-of-life care and each of the social determinants of health and MM, hypothesizing that higher MM is associated with less aggressive care. METHODS: From the linked 1991-2008 Health and Retirement Study, Medicare data, and the National Death Index, we identified fee-for-service patients age >=66years who died from cancer (n=835). MM was defined as the occurrence or co occurrence of chronic conditions, functional limitations, and/or geriatric syndromes. Aggressive care was based on claims-derived measures of receipt of cancer-directed treatment in the last two weeks of life; admission to the hospital and/or emergency department (ED) within the last month; and in-hospital death. We also identified patients enrolled in hospice. In multivariable logistic regression models, we analyzed the associations of interest, adjusting for potential confounders. RESULTS: While 61.2% of the patients enrolled in hospice, 24.6% underwent cancer-directed treatment; 55.1% were admitted to the hospital and/or ED; and 21.7% died in the hospital. We observed a U-shaped distribution between income and in-hospital death. Chronic conditions and geriatric syndromes were associated with some outcomes, but not with others. CONCLUSIONS: To improve quality end-of-life care and curtail costs incurred by dying patients, relevant interventions need to account for social determinants of health and MM in a nuanced fashion. PMID- 28029588 TI - Validation studies on dinucleotide STRs for forensic identification of black rhinoceros Diceros bicornis. PMID- 28029590 TI - A new short daily brachytherapy schedule in postoperative endometrial carcinoma. Preliminary results. AB - PURPOSE: To evaluate the preliminary results of vaginal-cuff relapses (VCR) and complications of a short brachytherapy (BT) schedule in postoperative endometrial carcinoma. METHODS AND MATERIALS: From September 2011 to December 2014, 102 patients were treated with postoperative BT for endometrial carcinoma. Seventy four patients received a single 7 Gy dose after external beam irradiation (Group 1), and 28 intermediate-risk patients received three daily fractions of 6 Gy (Group 2). The dose was prescribed at 5 mm from the applicator surface. Toxicity was prospectively evaluated after the objective late effects of normal tissues subjective, objective, management, analytic scores for vagina and RTOG scores for rectum and bladder. STATISTICS: chi2 and Student's t tests. RESULTS: The mean followup was 28.85 months (9.6-58.5) in Group 1 and 31.19 months (7.7-62.3) in Group 2. No VCR was found during followup. Late toxicity: vagina toxicity was developed in 24.32% of the patients in Group 1 (G1-G2) and in 21.4% in Group 2 (G1-G2 but 1 G3). Rectal toxicity appeared in only 2.7% of patients in Group 1 (G1). Neither Group 1 nor Group 2 presented late bladder toxicity. No differences were found in late toxicity between Groups 1 and 2. CONCLUSIONS: The present short BT schedule was safe in relation to VCR and late toxicity for the followup period studied. These results are similar to those of two larger previous schedules performed in our center in relation to the same point of followup. PMID- 28029589 TI - Diversity of retrievable heterotrophic bacteria in Kongsfjorden, an Arctic fjord. AB - The diversity and abundance of retrievable pelagic heterotrophic bacteria in Kongsfjorden, an Arctic fjord, was studied during the summer of 2011 (June, August, and September). Retrievable bacterial load ranged from 103 to 107CFUL-1 in June, while it was 104-106CFUL-1 in August and September. Based on 16S rRNA gene sequence similarities, a higher number of phylotypes was observed during August (22 phylotypes) compared to that during June (6 phylotypes) and September (12 phylotypes). The groups were classified into four phyla: Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes. Bacteroidetes was represented only by a single member Leewenhoekiella aequorea during the three months and was dominant (40%) in June. However, this dominance changed in August to a well-known phytopathogenic species Rhodococcus fascians (32%), which could be a result of decrease in the phytoplankton biomass following the secondary bloom. It is the first report of Halomonas titanicae isolation from the Arctic waters. It showed an increase in its abundance with the intrusion of Atlantic water into Kongsfjorden. Increased abundance of Psychrobacter species in the late summer months coincided with the presence of cooler waters. Thus, the composition and function of heterotrophic bacterial community was fundamentally different in different months. This could be linked to the changes in the water masses and/or phytoplankton bloom dynamics occurring in Arctic summer. PMID- 28029591 TI - Cardiorespiratory Interactions in Paediatrics: 'It's (almost always) the circulation stupid!' AB - The interaction of the heart and lungs is probably the most important aspect of life and survival. Fortunately, it is not difficult to understand the fundamentals. The purpose of the lungs and their ventilation is to present oxygen to the circulation via the alveoli and to receive carbon dioxide from the circulation and then expel it. The relations of the heart and lungs and the matching of blood flow to the various organs with ventilation and lung perfusion may be disrupted by a variety of congenital or acquired heart malformations. They include those giving rise to an increased or reduced pulmonary blood flow, elevated pulmonary venous pressure or external physical pressure on the airways or lung parenchyma. Respiratory disorders which compromise cardiac function include states with reduced alveolar ventilation, those with a barrier to ventilation or perfusion, ventilation/perfusion mismatch and pulmonary vascular disease. There is also a fascinating group in which congenital disorders of the heart and lung co-exist to produce very particular modes of abnormal cardiopulmonary interaction. PMID- 28029592 TI - Semen quality and alcohol intake: a systematic review and meta-analysis. AB - Alcohol consumption is widespread in the Western world. Some studies have suggested a negative association between alcohol intake and semen quality although others have not confirmed this. MEDLINE and Embase were searched using 'alcohol intake' OR 'alcohol consumption' OR 'alcohol drinking' OR 'lifestyle' combined with 'semen quality' OR 'sperm quality' OR 'sperm volume' OR 'sperm concentration' OR 'sperm motility' for full-length observational articles, published in English. Reference lists of retrieved articles were searched for other pertinent studies. Main outcome measures were sperm parameters, if provided as means (standard deviation or standard error) or as medians (interquartile range). Fifteen cross-sectional studies were included, with 16,395 men enrolled. Main results showed that alcohol intake has a detrimental effect on semen volume (pooled estimate for no/low alcohol consumption 0.25 ml, 95% CI, 0.07 to 0.42) and normal morphology (1.87%, 95% CI, 0.86 to 2.88%). The difference was more marked when comparing occasional versus daily consumers, rather than never versus occasional, suggesting a moderate consumption did not adversely affect semen parameters. Hence, studies evaluating the effect of changes on semen parameters on the reproductive outcomes are needed in advance of providing recommendations regarding alcohol intake other than the advice to avoid heavy alcohol drinking. PMID- 28029593 TI - Pulse Width Affects Scalp Sensation of Transcranial Magnetic Stimulation. AB - BACKGROUND: Scalp sensation and pain comprise the most common side effect of transcranial magnetic stimulation (TMS), which can reduce tolerability and complicate experimental blinding. OBJECTIVE: We explored whether changing the width of single TMS pulses affects the quality and tolerability of the resultant somatic sensation. METHODS: Using a controllable pulse parameter TMS device with a figure-8 coil, single monophasic magnetic pulses inducing electric field with initial phase width of 30, 60, and 120 us were delivered in 23 healthy volunteers. Resting motor threshold of the right first dorsal interosseus was determined for each pulse width, as reported previously. Subsequently, pulses were delivered over the left dorsolateral prefrontal cortex at each of the three pulse widths at two amplitudes (100% and 120% of the pulse-width-specific motor threshold), with 20 repetitions per condition delivered in random order. After each pulse, subjects rated 0-to-10 visual analog scales for Discomfort, Sharpness, and Strength of the sensation. RESULTS: Briefer TMS pulses with amplitude normalized to the motor threshold were perceived as slightly more uncomfortable than longer pulses (with an average 0.89 point increase on the Discomfort scale for pulse width of 30 us compared to 120 us). The sensation of the briefer pulses was felt to be substantially sharper (2.95 points increase for 30 us compared to 120 us pulse width), but not stronger than longer pulses. As expected, higher amplitude pulses increased the perceived discomfort and strength, and, to a lesser degree the perceived sharpness. CONCLUSIONS: Our findings contradict a previously published hypothesis that briefer TMS pulses are more tolerable. We discovered that the opposite is true, which merits further study as a means of enhancing tolerability in the context of repetitive TMS. PMID- 28029594 TI - Priming Hand Motor Training with Repetitive Stimulation of the Fingertips; Performance Gain and Functional Imaging of Training Effects. AB - BACKGROUND: Application of repetitive electrical stimulation (rES) of the fingers has been shown to improve tactile perception and sensorimotor performance in healthy individuals. OBJECTIVE: To increase motor performance by priming the effects of active motor training (arm ability training; AAT) using rES. METHODS: We compared the performance gain for the training increase of the averaged AAT tasks of both hands in two groups of strongly right-handed healthy volunteers. Functional Magnetic Resonance Imaging (fMRI) before and after AAT was assessed using three tasks for each hand separately: finger sequence tapping, visually guided grip force modulation, and writing. Performance during fMRI was controlled for preciseness and frequency. A total of 30 participants underwent a two-week unilateral left hand AAT, 15 participants with 20 minutes of rES priming of all fingertips of the trained hand, and 15 participants without rES priming. RESULTS: rES-primed AAT improved the trained left-hand performance across all training tasks on average by 32.9%, non-primed AAT improved by 29.5%. This gain in AAT performance with rES priming was predominantly driven by an increased finger tapping velocity. Functional imaging showed comparable changes for both training groups over time. Across all participants, improved AAT performance was associated with a higher contralateral primary somatosensory cortex (S1) fMRI activation magnitude during the grip force modulation task. CONCLUSIONS: This study highlights the importance of S1 for hand motor training gain. In addition, it suggests the usage of rES of the fingertips for priming active hand motor training. PMID- 28029595 TI - Pulse Duration as Well as Current Direction Determines the Specificity of Transcranial Magnetic Stimulation of Motor Cortex during Contraction. AB - BACKGROUND: Previous research suggested that anterior-posterior (AP) directed currents induced by TMS in motor cortex (M1) activate interneuron circuits different from those activated by posterior-anterior currents (PA). The present experiments provide evidence that pulse duration also determines the activation of specific interneuron circuits. OBJECTIVE: To use single motor unit (SMU) recordings to confirm the difference in onset latencies of motor-evoked potentials (MEPs) evoked by different current directions and pulse durations: AP30, AP120, PA30 and PA120. To test whether the amplitude of the MEPs is differentially influenced by somatosensory inputs from the hand (short-latency afferent inhibition, SAI), and examine the sensitivity of SAI to changes in cerebellar excitability produced by direct current stimulation (tDCSCb). METHODS: Surface electromyograms and SMUs were recorded from the first dorsal interosseous muscle. SAI was tested with an electrical stimulus to median or digital nerves ~20-25 ms prior to TMS delivered over the M1 hand area via a controllable pulse parameter TMS (cTMS) device. SAI was also tested during the application of anodal or sham tDCSCb. Because TMS pulse specificity is greatest at low stimulus intensities, most experiments were conducted with weak voluntary contraction to reduce stimulus threshold. RESULTS: AP30 currents recruited the longest latency SMU and surface MEP responses. During contraction SAI was greater for AP30 responses versus all other pulses. Online anodal tDCSCb reduced SAI for the AP30 currents only. CONCLUSIONS: AP30 currents activate an interneuron circuit with functional properties different from those activated by other pulse types. Pulse duration and current direction determine what is activated in M1 with TMS. PMID- 28029596 TI - Comment on: "Hemopericardium after laparoscopic perihiatal procedures: high index of suspicion facilitates early diagnosis and successful nonoperative management". PMID- 28029597 TI - Influence of bariatric surgery on quality of life, body image, and general self efficacy within 6 and 24 months-a prospective cohort study. AB - BACKGROUND: It has been proven that bariatric surgery affects weight loss. Patients with morbid obesity have a significantly lower quality of life (QOL) and body image compared with the general population. OBJECTIVE: To evaluate QOL, body image, and general self-efficacy (GSE) in patients with morbid obesity undergoing bariatric surgery within clinical parameters. SETTINGS: Monocentric, prospective, longitudinal cohort study. METHODS: Patients completed the short form 36 (SF-36) for QOL, body image questionnaire, and GSE scale 3 times: before surgery and within 6 months and 24 months after surgery. Influence of gender, age, and type of procedure, either laparoscopic sleeve gastrectomy (SG) or laparoscopic Roux-en Y gastric bypass, were analyzed. RESULTS: Thirty patients completed the questionnaires before and within 6 and 24 months after surgery. SF-36 physical summary score improved significantly from 34.3+/-11.0 before surgery to 46.0+/ 10.4 within 6 months (P<.001) and to 49.8+/-8.2 within 24 months (P<.001) after surgery. SF-36 mental summary score improved significantly from 42.1+/-14.7 before surgery to 52.3+/-8.4 within 6 months (P<.001) and to 48.4+/-12.2 within 24 months (P<.001) after surgery. There were no significant differences between gender, age, and type of operation. Body image and GSE improved significantly after bariatric surgery (P<.001), and both correlated to the SF-36 mental summary score. CONCLUSION: QOL, body image, and GSE improved significantly within 6 months and remained stable within 24 months after bariatric surgery. Improvements were independent of gender, age, and type of operation. Mental QOL was influenced by body image and GSE. PMID- 28029598 TI - Perioperative outcome of laparoscopic sleeve gastrectomy for high-risk patients. AB - BACKGROUND: Morbidly obese patients with excessive concomitant disease carry a significantly increased perioperative risk. Although they may benefit most from a bariatric intervention, they are often denied surgery. Laparoscopic sleeve gastrectomy (LSG), as it is less complication-prone than other bariatric procedures, suits the needs of those patients. OBJECTIVE: To review the short term outcome of LSG for high-risk patients SETTING: University hospital, Switzerland. METHODS: A total of 110 patients with high perioperative risk undergoing LSG between January 2008 and December 2014 were prospectively recorded. Patients were defined as "high-risk" if they met 2 of the following criteria: American Society of Anesthesiologists physical status score (ASA)>III, Obesity Surgery Mortality Risk Score (OS-MRS)>=4, Revised Cardiac Risk Index (RCRI) class IV, Obstructive Sleep Apnea-Severity Index (OSA-SI)>=5, renal insufficiency chronic kidney disease >=3, liver cirrhosis, or history of life threatening perioperative events. RESULTS: Of the patients, 59 (54%) were male. Median age was 49 years (range: 18-69), and median BMI was 51.7 kg/m2 (38.7 89.2). Median operating time was 65 minutes (27-260). Eighty-six patients (78%) were classified as ASA IV, 65 (59%) as RCRI class IV, 51 (46%) as OS-MRS>=4 and 63 (57%) as OSA-SI>=5. Eighty-nine (81%) had type 2 diabetes, 70 (64%) were under antiplatelet and or anticoagulant therapy. Four patients (4%) were converted to open. Length of stay was 5 days (1-70). Major complications occurred in 12 patients (11%), including 1 mortality (1%). CONCLUSION: "High-risk"-patients identified using a combination of established obesity- and co-morbidity-related risk scores profit from LSG as part of a uniform treatment pathway. Given the severity of co-morbidities, LSG can be performed safely. (Surg Obes Relat Dis 2016;X:XXX-XXX.) (c) 2016 American Society for Metabolic and Bariatric Surgery. All rights reserved. PMID- 28029599 TI - Laparoscopic sleeve gastrectomy in patients with abdominoplasty: a case-control study. AB - BACKGROUND: Abdominoplasty is increasingly performed after weight loss surgery. However, performing a laparoscopic sleeve gastrectomy (LSG) after abdominoplasty poses technical challenges. OBJECTIVE: The present study aimed to compare operative events and postoperative outcomes between LSG patients with and without a history of prior abdominoplasty. SETTING: University hospital, Qatar. METHODS: A case-control study was conducted on 2 groups of patients with (n = 33) and without (n = 69) prior abdominoplasty who underwent LSG. Patient demographics, baseline characteristics, as well as operative and postoperative events were compared between the 2 groups. RESULTS: A total of 102 patients with an average age of 39.6+/-7.7 years and body mass index (BMI) of 42.8+/-5.9 kg/m2 were included. There were no significant differences between the 2 groups in terms of demographic characteristics, preoperative BMI, and co-morbidities. The number of ports required was significantly higher in the LSG patients with a history of prior abdominoplasty than in the nonabdominoplasty patients. The operation time was also significantly longer in the abdominoplasty patients than in the nonabdominoplasty patients (90.3+/-36.7 minutes versus 57.1+/-17.7 minutes; P<.0001). However, no significant differences were observed in terms of postoperative complications, length of hospital stay, and weight loss results. CONCLUSION: LSG after abdominoplasty is associated with longer operative times and the need for additional port placement to overcome the decreased working space. However, operative strategies should be considered to overcome the technical challenges during LSG in patients who underwent a prior abdominoplasty. PMID- 28029602 TI - Use of both antegrade and retrograde internal mammary vessels in the bipedicled deep inferior epigastric perforator flap for unilateral breast reconstruction. AB - BACKGROUND: Autologous abdominal tissue transfer is a well-established method of breast reconstruction. The deep inferior epigastric perforator (DIEP) flap has the additional benefit of minimal donor site morbidity as it spares the muscle and fascia. Conventional DIEP flaps may not provide adequate volume in cases where the patient is thin, has midline abdominal scars, and/or has a large volume of tissue to replace. One solution is to use a bipedicled DIEP flap, incorporating all the available abdominal tissue. Bipedicled DIEP flaps have been described in a number of different configurations. The literature appears to favor intra-flap anastomosis, with a minimal exposition of two recipient vessels. It has been demonstrated that both the antegrade internal mammary artery (aIMA) and retrograde internal mammary artery (rIMA) are adequate recipient vessels. Here, the authors present a single-center experience with bipedicled DIEP flaps to both the aIMA and rIMA, showing their feasibility and safety. METHODS: A retrospective review of patients who underwent unilateral breast reconstruction using bipedicled DIEP flaps was performed to assess outcomes. RESULTS: A total of 20 patients who underwent unilateral breast reconstruction using a bipedicled DIEP flap were selected for this study. All of them were previously diagnosed with cancer. There were zero flap failure and zero instance of abdominal hernia or issue with abdominal wall functionality following the surgeries. CONCLUSIONS: The series of surgeries described in this study resulted in successful breast reconstruction in 20 women using a bipedicled DIEP flap. The results show that this approach allows for reconstruction in places where a conventional DIEP does not provide adequate volume, achieved safely, and does not increase morbidity. The bipedicled DIEP flap is a viable option for large-volume autologous breast reconstruction, providing ample tissue for successful reconstruction while also allowing for shorter recovery and limited donor site morbidity. PMID- 28029603 TI - Isolated hypoganglionosis in young man with autism. PMID- 28029600 TI - Therapeutic Targeting of Autophagy. AB - Autophagy is a catabolic process that facilitates nutrient recycling via degradation of damaged organelles and proteins through lysosomal mediated degradation. Alterations in this complex, and tightly regulated process, lead to disease. Autophagy is widely accepted as cytoprotective against neurodegenerative diseases and a variety of clinical interventions are moving forward to increase autophagy as a therapeutic intervention. Autophagy has both positive and negative roles in cancer and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy. Nevertheless, cancer is the disease where most current activity in trying to manipulate autophagy for therapy is taking place and dozens of clinical trials are using autophagy inhibition with Chloroquine or Hydroxychloroquine in combination with other drugs for the treatment of multiple neoplasms. Here, we review recent literature implicating autophagy in neurodegenerative diseases and cancer and highlight some of the opportunities, controversies and potential pitfalls of therapeutically targeting autophagy. PMID- 28029604 TI - Hemorrhagic pseudotumors of iliac bones in Noonan syndrome: PET/CT imaging. PMID- 28029605 TI - How should radiation oncologists interpret the ASTRO evidence-based guideline and ASTRO Choosing Wisely campaign for the treatment of uncomplicated bone metastases? PMID- 28029606 TI - Lacunar Infarcts Rather than White Matter Hyperintensity as a Predictor of Future Higher Level Functional Decline: The Ohasama Study. AB - OBJECTIVE: We aimed to determine the associations between silent cerebrovascular lesions, characterized by lacunar infarcts and white matter hyperintensity, and future decline in higher level functional capacity in older community-dwelling adults. MATERIALS AND METHODS: For this observational study, we selected individuals from the general population of Ohasama, a rural Japanese community. Three hundred thirty-one participants who were free of functional decline at baseline and who were at least 60 years old underwent brain magnetic resonance imaging and answered a questionnaire on higher level functional capacity derived from the Tokyo Metropolitan Institute of Gerontology Index of Competence. Weassessed the relationship between silent cerebrovascular lesions with a decline in higher level functional capacity at 7 years using multiple logistic regression analysis adjusted for possible confounding factors. RESULTS: During the follow up, 22.1% reported declines in higher level functional capacity. After adjustment for putative confounding factors, the presence of silent cerebrovascular lesions (odds ratio [95% confidence interval], 2.10 [1.05-4.21]) and both lacunar infarcts (2.04 [1.05-3.95]) and white matter hyperintensity (2.02 [1.02-3.95]) was significantly associated with the risk of functional decline at 7-year follow up. In subscale analysis, specifically lacunar infarcts were strongly associated with the future risk of decline in intellectual activity (3.16 [1.27-7.84]). CONCLUSION: Silent cerebrovascular lesions are associated with future risk of decline in higher level functional capacity. Appropriate management of health risk factors to prevent silent cerebrovascular lesions may prevent higher level functional decline in the elderly population. PMID- 28029607 TI - Reported Prestroke Physical Activity Is Associated with Vascular Endothelial Growth Factor Expression and Good Outcomes after Stroke. AB - INTRODUCTION: Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. METHODS: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Prestroke PhA was evaluated with the International Physical Activity Questionnaire (metabolic equivalent of minutes/week). We studied several circulating angiogenic and neurogenic factors at different time points: vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), and brain-derived neurotrophic factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (modified Rankin scale <= 2) as primary end point, and final infarct volume as secondary outcome. RESULTS: We studied 83 patients with at least 2 time point serum determinations (mean age 69.6 years, median National Institutes of Health Stroke Scale 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum VEGF on the seventh day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of prestroke PhA nor with stroke outcomes. CONCLUSIONS: Although there are probably more molecular mechanisms by which PhA exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed. PMID- 28029608 TI - Higher Stroke Risk with Lower Blood Pressure in Hemodynamic Vertebrobasilar Disease: Analysis from the VERiTAS Study. AB - BACKGROUND: Despite concerns regarding hypoperfusion in patients with large artery occlusive disease, strict blood pressure (BP) control has become adopted as a safe strategy for risk reduction of stroke. We examined the relationship between BP control, blood flow, and risk of subsequent stroke in the prospective Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) study. METHODS: The VERiTAS study enrolled patients with recent vertebrobasilar (VB) transient ischemic attack or stroke and >=50% atherosclerotic stenosis or occlusion of vertebral or basilar arteries. Hemodynamic status was designated as low or normal based on quantitative magnetic resonance angiography. Patients underwent standard medical management and follow up for primary outcome event of VB territory stroke. Mean BP during follow-up (<140/90 versus >=140/90 mm Hg) and flow status were examined relative to subsequent stroke risk using Cox proportional hazards analysis. RESULTS: The 72 subjects had an average of 3.8 +/- 1.2 BP recordings over 20 +/- 8 months of follow-up; 39 (54%) had mean BP of<140/90 mm Hg. The BP groups were largely comparable for baseline demographics, risk factors, and stenosis severity. Comparing subgroups stratified by BP and hemodynamic status, we found that patients with both low flow and BP <140/90 mm Hg (n = 10) had the highest risk of subsequent stroke, with hazard ratio of 4.5 (confidence interval 1.3-16.0, P = .02), compared with the other subgroups combined. CONCLUSIONS: Among a subgroup of patients with VB disease and low flow, strict BP control (BP <140/90) may increase the risk of subsequent stroke. PMID- 28029609 TI - Seeking control in the midst of uncertainty: Women's experiences of choosing mode of birth after caesarean. AB - PROBLEM: Clinical practice guidelines indicate that over 80% of women with a previous caesarean should be offered a planned vaginal birth after caesarean (VBAC), however only one third of eligible women choose to plan a VBAC. To support informed choices for birth after caesarean, it is necessary to understand the factors that influence women's decision-making. AIM: The goal of this study was to explore attitudes towards and experiences with decision-making for mode of delivery after caesarean from the perspectives of Canadian women. METHODS: In depth, semi-structured interviews were conducted with 23 women eligible for VBAC in three rural and two urban communities in British Columbia, Canada, during summer 2015. Constructivist grounded theory informed iterative data collection and analysis. FINDINGS: Women's decision-making experiences were a process of "seeking control in the midst of uncertainty." Women formed early preferences for mode of delivery after their primary caesareans and engaged in careful deliberation during their inter-pregnancy interval, consisting of: reflecting on their birth, clarifying their values, becoming informed, considering the feasibility of options, deliberating with the care team, and making an actual choice. Women struggled to make trade-offs between having a healthy baby and social attributes of delivery, such as uninterrupted bonding with their newborn. CONCLUSIONS: Women begin decision-making for birth after caesarean earlier than previously reported and their choices are influenced by personal experience and psychosocial concerns. Future interventions to support choice of mode of delivery should begin early after the primary caesarean, to reflect when women begin to form preferences. PMID- 28029610 TI - Impact of local injection of brain-derived neurotrophic factor-expressing mesenchymal stromal cells (MSCs) combined with intravenous MSC delivery in a canine model of chronic spinal cord injury. AB - BACKGROUND AIMS: The microenvironment of the chronically injured spinal cord does not allow for axonal regeneration due to glial scarring. To ameliorate this, several therapeutic strategies have been used. We investigated whether combined transplantation of chondroitinase ABC (chABC) and mesenchymal stromal cells (MSCs) genetically modified to secrete brain-derived neurotrophic factor (BDNF) with intravenous (IV) administration of MSCs can promote recovery of hindlimb function after chronic spinal cord injury (SCI). METHODS: Canine BDNF-expressing MSCs were generated using a lentivirus packaging protocol. Twelve beagle dogs with experimentally induced chronic SCI were divided into chABC/MSC-green fluorescent protein (GFP), chABC/MSC-BDNF and chABC/MSC-BDNF/IV groups. The MSCs (1 * 107 cells) and chABC were transplanted 3 weeks after SCI in all groups, and IV injection of MSC-GFP (1 * 107 cells) was performed 1 and 2 weeks after MSC transplantation in the chABC/MSC-BDNF/IV group. Spinal cords were harvested 8 weeks after transplantation. RESULTS: The dogs in the chABC/MSC-BDNF included groups had significantly improved functional recovery 8 weeks after transplantation compared with those in the chABC/MSC-GFP group. The animals in the chABC/MSC-BDNF/IV group showed significant improvements in functional recovery at 6, 7 and 8 weeks compared with those in the chABC/MSC-BDNF group. Fibrotic changes were significantly decreased in the chABC/MSC-BDNF/IV group. We also observed significant decreases in the expression levels of tumor necrosis factor-alpha, interleukin-6, COX-2, glial fibrillary acidic protein and GalC and increased expression levels of BDNF, beta3-tubulin neurofilament medium, and nestin in the chABC/MSC-BDNF/IV group. CONCLUSIONS: We suggest that transplantation of combined chABC and BDNF-expressing MSCs, along with IV injection of MSCs, is the optimal therapy for chronic SCI. PMID- 28029611 TI - Vitamin-D deficiency in patients with chronic pancreatitis - Prevalence and pitfalls. PMID- 28029612 TI - What are the most common domains of the core competencies of disaster nursing? A scoping review. AB - AIM: Scoping review was conducted to identify the most common domains of the core competencies of disaster nursing. BACKGROUND: Nurses play an essential role in all phases of disaster management. For nurses to respond competently, they must be equipped with the skills to provide comprehensive and holistic care to the populations affected by or at risk of disasters. METHODS: A scoping review was conducted using the Joanna Briggs Institute methodology. The review used information from six databases: the Cumulative Index to Nursing and Allied Health Literature, Ovid MEDLINE, ScienceDirect, ProQuest, Scopus and the Education Resources Information Center. Keywords and inclusion and exclusion criteria were identified as strategies to use in this review. RESULTS: Twelve studies were eligible for result extraction, as they listed domains of the core competencies. These domains varied among studies. However, the most common domains were related to communication, planning, decontamination and safety, the Incident Command System and ethics. CONCLUSION: Knowledge of the domains of the core competencies, such as understanding the content and location of the disaster plan, communication during disaster and ethical issues is fundamental for nurses. Including these domains in the planning and provision of training for nurses, such as disaster drills, will strengthen their preparedness to respond competently to disaster cases. Nurses must be involved in future research in this area to explore and describe their fundamental competencies in each domain. PMID- 28029613 TI - A MEMS Condenser Microphone-Based Intracochlear Acoustic Receiver. AB - GOAL: Intracochlear sound pressure (ICSP) measurements are limited by the small dimensions of the human inner ear and the requirements imposed by the liquid medium. A robust intracochlear acoustic receiver (ICAR) for repeated use with a simple data acquisition system that provides the required high sensitivity and small dimensions does not yet exist. The work described in this report aims to fill this gap and presents a new microelectromechanical systems (MEMS) condenser microphone (CMIC)-based ICAR concept suitable for ICSP measurements in human temporal bones. METHODS: The ICAR head consisted of a passive protective diaphragm (PD) sealing the MEMS CMIC against the liquid medium, enabling insertion into the inner ear. The components of the MEMS CMIC-based ICAR were expressed by a lumped element model (LEM) and compared to the performance of successfully fabricated ICARs. RESULTS: Good agreement was achieved between the LEM and the measurements with different sizes of the PD. The ICSP measurements in a human cadaver temporal bone yielded data in agreement with the literature. CONCLUSION: Our results confirm that the presented MEMS CMIC-based ICAR is a promising technology for measuring ICSP in human temporal bones in the audible frequency range. SIGNIFICANCE: A sensor for evaluation of the biomechanical hearing process by quantification of ICSP is presented. The concept has potential as an acoustic receiver in totally implantable cochlear implants. PMID- 28029614 TI - Spiking Neural P Systems With White Hole Neurons. AB - Spiking neural P systems (SN P systems) are a class of parallel and distributed spiking neural network models, which are inspired from the way biological neurons spiking and communicating by means of spikes. White hole rules, abstracted from the biological observation of neural information rejection, were recently introduced into SN P systems, by which a neuron consumes its complete contents when it fires. In this work, SN P systems with white hole neurons are proposed, in which each neuron has only white hole rules. The computational power of general and bounded SN P systems with white hole neurons are obtained. Specifically, it is achieved in a constructive way that i) general SN P systems (having both bounded and unbounded) white hole neurons are Turing universal as number generators; ii) bounded SN P systems with white hole neurons can only characterize semi-linear sets of numbers. These results show that "information storage capacity" of certain key neurons provides some "programming capacity" useful for SN P systems achieving a desired computation power. PMID- 28029615 TI - On Chip Bioelectric Impedance Spectroscopy Reveals the Effect of P-Glycoprotein Efflux Pumps on the Paracellular Impedance of Tight Junctions at the Blood-Brain Barrier. AB - Bioelectric impedance spectroscopy was used to elucidate the influence of P-gp efflux pumps on the kinetics of tight junction down-regulation in confluent monolayers of Madine Darby Canine Kidney Epithelial Cells (MDCK) following administration of phenylarsine oxide (PAO), a molecule that inhibits protein tyrosine phosphatases (PTP) and induces matrix metalloproteinase activity. Matrix metalloproteinases (MMPs) and phosphatase inhibitors induce modification of occludin tight junction proteins critical for the proper function of the blood brain barrier. The addition of PAO to MDCKII cell lines resulted in a dramatic decrease in monolayer resistance. In contrast, MDCKII-MDR1 cells transfected with the MDR1 gene treated with PAO showed an initial decrease in monolayer resistance followed by a partial recovery and subsequent decrease. This resistance decay reversal was suppressed with the addition of the P-glycoprotein (P-gp) pump inhibitor elacridar, and is attributed to PAO efflux. These results illustrate impedance spectroscopy can be used to characterize the competing kinetics of efflux and down-regulation of tight junctions. In addition, the resistance decay reversal effect can be used to evaluate P-gp pump inhibitor efficacy. PMID- 28029616 TI - Temporal Control of Osteoblast Cell Growth and Behavior Dictated by Nanotopography and Shear Stress. AB - Biomaterial design involves assessment of cellular response to nanotopography parameters such as shape, dimension of nanotopography features. Here, the effect of nanotopography alongside the in vivo factor, shear stress, on osteoblast cell behavior, is reported. Tantalum oxide nanodots of 50 or 100 nm diameter were engineered using anodized aluminum oxide as a template. Bare tantalum nitride coated silicon substrates were taken as control (flat). MG63 (osteoblast) cells were seeded for 72 hours on flat, 50 or 100 nm nanodots and modulation in cell morphology, cell viability and expression of integrins was studied. Cells displayed a well-extended morphology on 50 nm nanodots in contrast to an elongated morphology on 100 nm nanodots, as observed by scanning electron microscopy and immunofluorescence staining, thereby confirming the cellular response to different nanotopographies. Based on quantitative real-time polymerase chain reaction data, a greater fold change in the expression of alpha1 , alpha2 , alpha3 , alpha8 , alpha9 , [Formula: see text], beta1 , beta4 , beta5 , beta7 and beta8 integrins was observed in cells cultured on 100 nm than on 50 nm nanodots. Moreover, in the presence of a shear stress of 2 dyne/cm2, a 52% increase in the cell viability after culturing the cells for 72 hours was observed on 100 nm nanodots as compared to 50 nm nanodots, thereby validating the effect of shear stress on cell behavior. Duration-of-culture experiments revealed 100 nm nanodots to be an ideal nanotopography choice to engineer optimized implant geometries for an ideal cell response. This study highlights the in vivo factors which need to be considered while designing nanotopographies for in vivo applications, for an ideal response as the cell-nanomaterial interface. Applications in the field of Biomedical, tissue engineering and cancer research are expected. PMID- 28029617 TI - Di-Block PLCL and Tri-Block PLCLG Matrix Polymeric Nanoparticles Enhanced the Anticancer Activity of Loaded 5-Fluorouracil. AB - In the current study, 5-FU-loaded nanoparticles (NPs) were prepared using polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL), di-block poly lactide co-caprolactone (PLCL) and tri-block poly L-lactide-co-caprolactone-co-glycolide (PLCLG). The influence of these polymers on the particle sizes, morphology, drug loading, and in vitro drug release was investigated. The anticancer activity was assessed utilizing MTT assay in three human cancer cell lines of different tissue origin; brain (Daoy), liver (HepG2), and colorectal (HT29) using suitable negative and positive controls. The prepared NPs showed a uniform spherical shape with an average size range of 193.5+/- 6.3 to 303.5+/- 3.3 nm with negative zeta potential. The entrapment efficiency achieved with F4-F6 (block copolymer NPs) was 78-79% and significantly higher compared with F1 PLGA (31%) and F2; PCL (37%). An initial rapid 5-FU release followed by a slow release ranging from 35% to 81% after 72 h was observed. All the prepared NPs formulations showed enhancement in the cytotoxicity of 5-FU towards all the three cancer cell lines. Generally, block copolymer NPs (F4-F6) showed higher % cell death over PLGA (F1) and PCL (F2) NPs after 48 and 72 h incubation in the case of HepG2 and HT-29. The incorporation of PEG with the tri-block (F6) caused a significant increase in the cytotoxicity of NPs in all of the three cancer cell lines. Block copolymer-based NPs can be considered as promising carriers for enhancing the efficacy of 5-FU in cancer therapy. PMID- 28029618 TI - Correction to "Scalable High-Performance Image Registration Framework by Unsupervised Deep Feature Representations Learning". PMID- 28029619 TI - Network Flow Integer Programming to Track Elliptical Cells in Time-Lapse Sequences. AB - We propose a novel approach to automatically tracking elliptical cell populations in time-lapse image sequences. Given an initial segmentation, we account for partial occlusions and overlaps by generating an over-complete set of competing detection hypotheses. To this end, we fit ellipses to portions of the initial regions and build a hierarchy of ellipses, which are then treated as cell candidates. We then select temporally consistent ones by solving to optimality an integer program with only one type of flow variables. This eliminates the need for heuristics to handle missed detections due to partial occlusions and complex morphology. We demonstrate the effectiveness of our approach on a range of challenging sequences consisting of clumped cells and show that it outperforms state-of-the-art techniques. PMID- 28029620 TI - A Tensor B-Spline Approach for Solving the Diffusion PDE With Application to Optical Diffusion Tomography. AB - Optical Diffusion Tomography (ODT) is a modern non-invasive medical imaging modality which requires mathematical modelling of near-infrared light propagation in tissue. Solving the ODT forward problem equation accurately and efficiently is crucial. Typically, the forward problem is represented by a Diffusion PDE and is solved using the Finite Element Method (FEM) on a mesh, which is often unstructured. Tensor B-spline signal processing has the attractive features of excellent interpolation and approximation properties, multiscale properties, fast algorithms and does not require meshing. This paper introduces Tensor B-spline methodology with arbitrary spline degree tailored to solve the ODT forward problem in an accurate and efficient manner. We show that our Tensor B-spline formulation induces efficient and highly parallelizable computational algorithms. Exploitation of B-spline properties for integration over irregular domains proved valuable. The Tensor B-spline solver was tested on standard problems and on synthetic medical data and compared to FEM, including state-of-the art ODT forward solvers. Results show that 1) a significantly higher accuracy can be achieved with the same number of nodes, 2) fewer nodes are required to achieve a prespecified accuracy, 3) the algorithm converges in significantly fewer iterations to a given error. These findings support the value of Tensor B-spline methodology for high-performance ODT implementations. This may translate into advances in ODT imaging for biomedical research and clinical application. PMID- 28029621 TI - Drifts and Environmental Disturbances in Atomic Clock Subsystems: Quantifying Local Oscillator, Control Loop, and Ion Resonance Interactions. AB - Linear ion trap frequency standards are among the most stable continuously operating frequency references and clocks. Depending on the application, they have been operated with a variety of local oscillators (LOs), including quartz ultrastable oscillators, hydrogen-masers, and cryogenic sapphire oscillators. The short-, intermediate-, and long-term stability of the frequency output is a complicated function of the fundamental performances, the time dependence of environmental disturbances, the atomic interrogation algorithm, the implemented control loop, and the environmental sensitivity of the LO and the atomic system components. For applications that require moving these references out of controlled lab spaces and into less stable environments, such as fieldwork or spaceflight, a deeper understanding is needed of how disturbances at different timescales impact the various subsystems of the clock and ultimately the output stability. In this paper, we analyze which perturbations have an impact and to what degree. We also report on a computational model of a control loop, which keeps the microwave source locked to the ion resonance. This model is shown to agree with laboratory measurements of how well the feedback removes various disturbances and also with a useful analytic approach we developed for predicting these impacts. PMID- 28029623 TI - A Simple Push-Pull Algorithm for Blue-Noise Sampling. AB - We describe a simple push-pull optimization (PPO) algorithm for blue-noise sampling by enforcing spatial constraints on given point sets. Constraints can be a minimum distance between samples, a maximum distance between an arbitrary point and the nearest sample, and a maximum deviation of a sample's capacity (area of Voronoi cell) from the mean capacity. All of these constraints are based on the topology emerging from Delaunay triangulation, and they can be combined for improved sampling quality and efficiency. In addition, our algorithm offers flexibility for trading-off between different targets, such as noise and aliasing. We present several applications of the proposed algorithm, including anti-aliasing, stippling, and non-obtuse remeshing. Our experimental results illustrate the efficiency and the robustness of the proposed approach. Moreover, we demonstrate that our remeshing quality is superior to the current state-of-the art approaches. PMID- 28029624 TI - Evaluating Cartogram Effectiveness. AB - Cartograms are maps in which areas of geographic regions, such as countries and states, appear in proportion to some variable of interest, such as population or income. Cartograms are popular visualizations for geo-referenced data that have been used for over a century to illustrate patterns and trends in the world around us. Despite the popularity of cartograms, and the large number of cartogram types, there are few studies evaluating the effectiveness of cartograms in conveying information. Based on a recent task taxonomy for cartograms, we evaluate four major types of cartograms: contiguous, non-contiguous, rectangular, and Dorling cartograms. We first evaluate the effectiveness of these cartogram types by quantitative performance analysis (time and error). Second, we collect qualitative data with an attitude study and by analyzing subjective preferences. Third, we compare the quantitative and qualitative results with the results of a metrics-based cartogram evaluation. Fourth, we analyze the results of our study in the context of cartography, geography, visual perception, and demography. Finally, we consider implications for design and possible improvements. PMID- 28029625 TI - Comparison of Classifier Architectures for Online Neural Spike Sorting. AB - High-density, intracranial recordings from micro-electrode arrays need to undergo Spike Sorting in order to associate the recorded neuronal spikes to particular neurons. This involves spike detection, feature extraction, and classification. To reduce the data transmission and power requirements, on-chip real-time processing is becoming very popular. However, high computational resources are required for classifiers in on-chip spike-sorters, making scalability a great challenge. In this review paper, we analyze several popular classifiers to propose five new hardware architectures using the off-chip training with on-chip classification approach. These include support vector classification, fuzzy C means classification, self-organizing maps classification, moving-centroid K means classification, and Cosine distance classification. The performance of these architectures is analyzed in terms of accuracy and resource requirement. We establish that the neural networks based Self-Organizing Maps classifier offers the most viable solution. A spike sorter based on the Self-Organizing Maps classifier, requires only 7.83% of computational resources of the best-reported spike sorter, hierarchical adaptive means, while offering a 3% better accuracy at 7 dB SNR. PMID- 28029626 TI - HEMEsPred: Structure-Based Ligand-Specific Heme Binding Residues Prediction by Using Fast-Adaptive Ensemble Learning Scheme. AB - Heme is an essential biomolecule that widely exists in numerous extant organisms. Accurately identifying heme binding residues (HEMEs) is of great importance in disease progression and drug development. In this study, a novel predictor named HEMEsPred was proposed for predicting HEMEs. First, several sequence- and structure-based features, including amino acid composition, motifs, surface preferences, and secondary structure, were collected to construct feature matrices. Second, a novel fast-adaptive ensemble learning scheme was designed to overcome the serious class-imbalance problem as well as to enhance the prediction performance. Third, we further developed ligand-specific models considering that different heme ligands varied significantly in their roles, sizes, and distributions. Statistical test proved the effectiveness of ligand-specific models. Experimental results on benchmark datasets demonstrated good robustness of our proposed method. Furthermore, our method also showed good generalization capability and outperformed many state-of-art predictors on two independent testing datasets. HEMEsPred web server was available at http://www.inforstation.com/HEMEsPred/ for free academic use. PMID- 28029627 TI - A Memetic Algorithm for 3-D Protein Structure Prediction Problem. AB - Memetic Algorithms are population-based metaheuristics intrinsically concerned with exploiting all available knowledge about the problem under study. The incorporation of problem domain knowledge is not an optional mechanism, but a fundamental feature of the Memetic Algorithms. In this paper, we present a Memetic Algorithm to tackle the three-dimensional protein structure prediction problem. The method uses a structured population and incorporates a Simulated Annealing algorithm as a local search strategy, as well as ad-hoc crossover and mutation operators to deal with the problem. It takes advantage of structural knowledge stored in the Protein Data Bank, by using an Angle Probability List that helps to reduce the search space and to guide the search strategy. The proposed algorithm was tested on nineteen protein sequences of amino acid residues, and the results show the ability of the algorithm to find native-like protein structures. Experimental results have revealed that the proposed algorithm can find good solutions regarding root-mean-square deviation and global distance total score test in comparison with the experimental protein structures. We also show that our results are comparable in terms of folding organization with state-of-the-art prediction methods, corroborating the effectiveness of our proposal. PMID- 28029628 TI - Evolutionary Graph Clustering for Protein Complex Identification. AB - This paper presents a graph clustering algorithm, called EGCPI, to discover protein complexes in protein-protein interaction (PPI) networks. In performing its task, EGCPI takes into consideration both network topologies and attributes of interacting proteins, both of which have been shown to be important for protein complex discovery. EGCPI formulates the problem as an optimization problem and tackles it with evolutionary clustering. Given a PPI network, EGCPI first annotates each protein with corresponding attributes that are provided in Gene Ontology database. It then adopts a similarity measure to evaluate how similar the connected proteins are taking into consideration the network topology. Given this measure, EGCPI then discovers a number of graph clusters within which proteins are densely connected, based on an evolutionary strategy. At last, EGCPI identifies protein complexes in each discovered cluster based on the homogeneity of attributes performed by pairwise proteins. EGCPI has been tested with several real data sets and the experimental results show EGCPI is very effective on protein complex discovery, and the evolutionary clustering is helpful to identify protein complexes in PPI networks. The software of EGCPI can be downloaded via: https://github.com/hetiantian1985/EGCPI. PMID- 28029629 TI - Discovering Perturbation of Modular Structure in HIV Progression by Integrating Multiple Data Sources Through Non-Negative Matrix Factorization. AB - Detecting perturbation in modular structure during HIV-1 disease progression is an important step to understand stage specific infection pattern of HIV-1 virus in human cell. In this article, we proposed a novel methodology on integration of multiple biological information to identify such disruption in human gene module during different stages of HIV-1 infection. We integrate three different biological information: gene expression information, protein-protein interaction information, and gene ontology information in single gene meta-module, through non negative matrix factorization (NMF). As the identified meta-modules inherit those information so, detecting perturbation of these, reflects the changes in expression pattern, in PPI structure and in functional similarity of genes during the infection progression. To integrate modules of different data sources into strong meta-modules, NMF based clustering is utilized here. Perturbation in meta modular structure is identified by investigating the topological and intramodular properties and putting rank to those meta-modules using a rank aggregation algorithm. We have also analyzed the preservation structure of significant GO terms in which the human proteins of the meta-modules participate. Moreover, we have performed an analysis to show the change of coregulation pattern of identified transcription factors (TFs) over the HIV progression stages. PMID- 28029630 TI - Design of a Closed-Loop, Bidirectional Brain Machine Interface System With Energy Efficient Neural Feature Extraction and PID Control. AB - This paper presents a bidirectional brain machine interface (BMI) microsystem designed for closed-loop neuroscience research, especially experiments in freely behaving animals. The system-on-chip (SoC) consists of 16-channel neural recording front-ends, neural feature extraction units, 16-channel programmable neural stimulator back-ends, in-channel programmable closed-loop controllers, global analog-digital converters (ADC), and peripheral circuits. The proposed neural feature extraction units includes 1) an ultra low-power neural energy extraction unit enabling a 64-step natural logarithmic domain frequency tuning, and 2) a current-mode action potential (AP) detection unit with time-amplitude window discriminator. A programmable proportional-integral-derivative (PID) controller has been integrated in each channel enabling a various of closed-loop operations. The implemented ADCs include a 10-bit voltage-mode successive approximation register (SAR) ADC for the digitization of the neural feature outputs and/or local field potential (LFP) outputs, and an 8-bit current-mode SAR ADC for the digitization of the action potential outputs. The multi-mode stimulator can be programmed to perform monopolar or bipolar, symmetrical or asymmetrical charge balanced stimulation with a maximum current of 4 mA in an arbitrary channel configuration. The chip has been fabricated in 0.18 MU m CMOS technology, occupying a silicon area of 3.7 mm 2. The chip dissipates 56 MUW/ch on average. General purpose low-power microcontroller with Bluetooth module are integrated in the system to provide wireless link and SoC configuration. Methods, circuit techniques and system topology proposed in this work can be used in a wide range of relevant neurophysiology research, especially closed-loop BMI experiments. PMID- 28029631 TI - Localized Multiple Kernel Learning With Dynamical Clustering and Matrix Regularization. AB - Localized multiple kernel learning (LMKL) is an attractive strategy for combining multiple heterogeneous features with regard to their discriminative power for each individual sample. However, the learning of numerous local solutions may not scale well even for a moderately sized training set, and the independently learned local models may suffer from overfitting. Hence, in existing local methods, the distributed samples are typically assumed to share the same weights, and various unsupervised clustering methods are applied as preprocessing. In this paper, to enable the learner to discover and benefit from the underlying local coherence and diversity of the samples, we incorporate the clustering procedure into the canonical support vector machine-based LMKL framework. Then, to explore the relatedness among different samples, which has been ignored in a vector -norm analysis, we organize the cluster-specific kernel weights into a matrix and introduce a matrix-based extension of the -norm for constraint enforcement. By casting the joint optimization problem as a problem of alternating optimization, we show how the cluster structure is gradually revealed and how the matrix regularized kernel weights are obtained. A theoretical analysis of such a regularizer is performed using a Rademacher complexity bound, and complementary empirical experiments on real-world data sets demonstrate the effectiveness of our technique. PMID- 28029632 TI - SmartBAN With Periodic Monitoring Traffic: A Performance Study on Low Delay and High Energy Efficiency. AB - The smart body area network (SmartBAN) is a recently proposed system for wireless body area networks (WBANs). Compared to conventional WBANs, it is designed to support lower system complexity and ultralow power consumption. In a SmartBAN, the sensors' access is scheduled upon receiving a beacon on the data channel at the beginning of each working cycle, termed as interbeacon interval (IBI). As network performance, including delay and energy consumption, is highly dependent on the length of IBI, we present, in this paper, an optimal IBI frame for SmartBAN. Our focus is on the delivery of uplink periodically-generated sensor data with low delay and high energy efficiency. As periodic traffic is a common traffic pattern widely generated in e-health applications, for which most previously proposed Markov models for WBANs are inapplicable, a closed-form analytical delay model for periodic SmartBAN transmission is derived. Exploiting this model, a time-optimized framework that minimizes average uplink delay is formulated. An adaptive IBI algorithm is then proposed to determine the optimal IBI during the network connection between hub and sensors. Finally, sleep mode in sensors and doze mode in the hub are introduced to reduce energy consumption under the proposed framework. With optimal IBI, the percentage of energy savings and channel efficiency is evaluated. Simulation and theoretical results show that by using the proposed time-optimized framework, both delay and energy consumption of periodic traffic are significantly reduced. Comparisons with the IEEE 802.15.6 WBAN show performance improvements in periodic uplink delay and energy consumption with our proposed time-optimized framework for SmartBANs. PMID- 28029633 TI - Pairwise Identity Verification via Linear Concentrative Metric Learning. AB - This paper presents a study of metric learning systems on pairwise identity verification, including pairwise face verification and pairwise speaker verification, respectively. These problems are challenging because the individuals in training and testing are mutually exclusive, and also due to the probable setting of limited training data. For such pairwise verification problems, we present a general framework of metric learning systems and employ the stochastic gradient descent algorithm as the optimization solution. We have studied both similarity metric learning and distance metric learning systems, of either a linear or shallow nonlinear model under both restricted and unrestricted training settings. Extensive experiments demonstrate that with limited training pairs, learning a linear system on similar pairs only is preferable due to its simplicity and superiority, i.e., it generally achieves competitive performance on both the labeled faces in the wild face dataset and the NIST speaker dataset. It is also found that a pretrained deep nonlinear model helps to improve the face verification results significantly. PMID- 28029634 TI - Heuristics-Based Trust Estimation in Multiagent Systems Using Temporal Difference Learning. AB - The application of multiagent system (MAS) is becoming increasing popular as it allows agents in a system to pool resources together to achieve a common objective. A vital part of the MAS is the teamwork cooperation through the sharing of information and resources among the agents to optimize their efforts in accomplishing given objectives. A critical part of the teamwork effort is the ability to trust each other when executing any task to ensure efficient and successful cooperation. This paper presents the development of a trust estimation model that could empirically evaluate the trust of an agent in MAS. The proposed model is developed using temporal difference learning by incorporating the concept of Markov games and heuristics to estimate trust. Simulation experiments are conducted to test and evaluate the performance of the developed model against some of the recently reported model in the literature. The simulation experiments indicate that the developed model performs better in terms of accuracy and efficiency in estimating trust. PMID- 28029635 TI - Ergodicity-Based Cooperative Multiagent Area Coverage via a Potential Field. AB - This paper considers a problem of area coverage where the objective is to achieve given coverage density by use of multiple mobile agents. We present an ergodicity based coverage algorithm which enables a centralized feedback control for multiagent system based on radial basis function (RBF) representation of the ergodicity problem and a solution of an appropriately designed stationary heat equation for the potential field. The heat equation uses a source term that depends on the difference between the given goal density distribution and the current coverage density (time average of RBFs along trajectories). The agent movement is directed using the gradient of that potential field. The heat equation driven area coverage has a built-in cooperative behavior of agents which includes collision avoidance and coverage coordination. The algorithm is robust, scalable, and computationally inexpensive. PMID- 28029636 TI - Group Decision Making Based on Heronian Aggregation Operators of Intuitionistic Fuzzy Numbers. AB - Archimedean t -conorm and t -norm provide the general operational rules for intuitionistic fuzzy numbers (IFNs). The aggregation operators based on them can generalize most of the existing aggregation operators. At the same time, the Heronian mean (HM) has a significant advantage of considering interrelationships between the attributes. Therefore, it is very necessary to extend the HM based on IFNs and to construct intuitionistic fuzzy HM operators based on the Archimedean t -conorm and t -norm. In this paper, we first discuss intuitionistic fuzzy operational rules based on the Archimedean t -conorm and t -norm. Then, we propose the intuitionistic fuzzy Archimedean Heronian aggregation (IFAHA) operator and the intuitionistic fuzzy weight Archimedean Heronian aggregation (IFWAHA) operator. We also further discuss some properties and some special cases of these new operators. Moreover, we also propose a new multiple attribute group decision making (MAGDM) method based on the proposed IFAHA operator and the proposed IFWAHA operator. Finally, we use an illustrative example to show the MAGDM processes and to illustrate the effectiveness of the developed method. PMID- 28029637 TI - Attribute Selection for Partially Labeled Categorical Data By Rough Set Approach. AB - Attribute selection is considered as the most characteristic result in rough set theory to distinguish itself to other theories. However, existing attribute selection approaches can not handle partially labeled data. So far, few studies on attribute selection in partially labeled data have been conducted. In this paper, the concept of discernibility pair based on rough set theory is raised to construct a uniform measure for the attributes in both supervised framework and unsupervised framework. Based on discernibility pair, two kinds of semisupervised attribute selection algorithm based on rough set theory are developed to handle partially labeled categorical data. Experiments demonstrate the effectiveness of the proposed attribute selection algorithms. PMID- 28029638 TI - Diagnostic accuracy and safety of CT-guided fine needle aspiration biopsy of pulmonary lesions with non-coaxial technique: a single center experience with 442 biopsies. AB - PURPOSE: We aimed to evaluate the diagnostic accuracy and safety of computed tomography (CT)-guided biopsy of pulmonary lesions with fine needle aspiration (FNA) using non-coaxial technique. METHODS: We analyzed 442 patients who underwent CT-guided lung biopsy with FNA and non-coaxial technique to determine the diagnostic outcomes, complication rates, and independent risk factors for diagnostic failure and pneumothorax. RESULTS: Diagnostic accuracy, sensitivity, and specificity were 97.6%, 97.3%, and 100%, respectively. Age and >35 mm lesion size were significant risk factors for diagnostic failure. The rates of pneumothorax and chest tube placement were 19% and 2.9%, respectively. Middle and lower lobe location, lesion to pleura distance >7.5 mm, and >45 degrees needle trajectory angle were significant risk factors for pneumothorax. CONCLUSION: CT guided FNA of pulmonary lesions with non-coaxial technique is a safe and reliable method with a relatively low pneumothorax rate and an acceptably high diagnostic accuracy. PMID- 28029639 TI - Sleep-Disordered Breathing Exacerbates Muscle Vasoconstriction and Sympathetic Neural Activation in Patients with Systolic Heart Failure. AB - BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with heart failure (HF), and hypoxia and hypercapnia episodes activate chemoreceptors stimulating autonomic reflex responses. We tested the hypothesis that muscle vasoconstriction and muscle sympathetic nerve activity (MSNA) in response to hypoxia and hypercapnia would be more pronounced in patients with HF and SDB than in patients with HF without SDB (NoSBD). METHODS AND RESULTS: Ninety consecutive patients with HF, New York Heart Association functional class II-III, and left ventricular ejection fraction <=40% were screened for the study. Forty-one patients were enrolled: NoSDB (n=13, 46 [39-53] years) and SDB (n=28, 57 [54-61] years). SDB was characterized by apnea-hypopnea index >=15 events per hour (polysomnography). Peripheral (10% O2 and 90% N2, with CO2 titrated) and central (7% CO2 and 93% O2) chemoreceptors were stimulated for 3 minutes. Forearm and calf blood flow were evaluated by venous occlusion plethysmography, MSNA by microneurography, and blood pressure by beat-to-beat noninvasive technique. Baseline forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance were similar between groups. MSNA was higher in the SDB group. During hypoxia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.01 to all comparisons). Similarly, during hypercapnia, the vascular responses (forearm blood flow, forearm vascular conductance, calf blood flow, and calf vascular conductance) were significantly lower in the SDB group compared with the NoSDB group (P<0.001 to all comparisons). MSNA were higher in response to hypoxia (P=0.024) and tended to be higher to hypercapnia (P=0.066) in the SDB group. CONCLUSIONS: Patients with HF and SDB have more severe muscle vasoconstriction during hypoxia and hypercapnia than HF patients without SDB, which seems to be associated with endothelial dysfunction and, in part, increased MSNA response. PMID- 28029640 TI - Reductions in N-Terminal Pro-Brain Natriuretic Peptide Levels Are Associated With Lower Mortality and Heart Failure Hospitalization Rates in Patients With Heart Failure With Mid-Range and Preserved Ejection Fraction. AB - BACKGROUND: In heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF), feasible surrogate end points are needed for phase II trials. The aim was to assess whether a reduction in N-terminal pro-B type natriuretic peptide (NT-proBNP) is associated with improved mortality/morbidity in an unselected population of HFmrEF and HFpEF patients. METHODS AND RESULTS: In the Swedish Heart Failure Registry, HFmrEF (EF=40%-49%) and HFpEF (EF>=50%) patients reporting at least 2 consecutive outpatient NT proBNP assessments were prospectively studied. Associations between reduction in NT-proBNP and overall mortality, HF hospitalization, and their composite were assessed by multivariable Cox regressions, with NT-proBNP changes modeled as binary (decrease/increase) or quantitative predictor by restricted cubic splines. In 650 patients, at a median of 7 months between the 2 measurements of NT-proBNP and over a median follow-up of 1.65 years, 361 patients (55%) showed a reduction and 289 patients (45%) an increase in NT-proBNP. Change in NT-proBNP was associated with risk of outcomes. Fifty-seven patients (16%) who decreased their NT-proBNP versus 78 patients (27%) who increased it died from any cause (adjusted hazard ratio=0.53; 95% confidence interval=0.36-0.77), 61 (17%) versus 86 (30%) were hospitalized for HF (hazard ratio=0.41; 95% confidence interval=0.29-0.60), and 96 (27%) versus 125 (43%) reported the composite outcome (hazard ratio=0.46; 95% confidence interval=0.34-0.62). These findings were replicated in HFmrEF and HFpEF separately. CONCLUSIONS: In HFmrEF and HFpEF during routine care, decreases in NT-proBNP were associated with improved mortality and morbidity. Studies to determine whether NT-proBNP changes in response to therapy predict drug efficacy are needed. PMID- 28029641 TI - Angiogenic Imbalance and Residual Myocardial Injury in Recovered Peripartum Cardiomyopathy Patients. AB - BACKGROUND: Recent studies suggest that angiogenic imbalance during pregnancy may lead to acute peripartum cardiomyopathy (PPCM). We propose that angiogenic imbalance and residual cardiac dysfunction may exist even after recovery from PPCM. METHODS AND RESULTS: Twenty-nine women at least 12 months after presentation with PPCM, who exhibited recovery of left ventricular (LV) ejection fraction (>=50%), were included in the study (mean age 35+/-6 years, LV ejection fraction 61.0+/-3.9%). The number of circulating endothelial progenitor cells (EPCs) and plasma levels of proangiogenic vascular endothelial growth factor and of soluble vascular endothelial growth factor receptor Flt1 (sFlt1) were measured. All patients underwent comprehensive cardiac function assessment, including tissue Doppler imaging and 2-dimensional (2D) strain echocardiography. All measurements were compared with healthy controls. Patients with a history of PPCM have significantly higher sFlt1 concentrations (median [25th-75th percentile]; 149.57, [63.14-177.89] versus 20.29, [15.00-53.89] pg/mL, P<0.001) and significantly decreased vascular endothelial growth factor/sFlt1 ratio (P=0.012) compared with controls, with a trend toward lower concentration of circulating CD34+/KDR+ levels. In addition, patients with PPCM had lower early velocities E' septal (9.9+/-2.1 versus 11.0+/-1.5 cm/s, P=0.02), with a significantly lower systolic velocity S' septal (7.6+/-1.2 versus 8.5+/-1.2 cm/s, P=0.003) by tissue Doppler imaging. Significantly lower LV global longitudinal ( 19.1+/-3.3 versus -22.7+/-2.2%, P<0.001) and apical circumferential 2D strain ( 16.6+/-4.9 versus -21.2+/-7.9, P=0.02) were present in patients with PPCM compared with controls. CONCLUSIONS: Higher concentration of sFlt1 with concomitant decreased circulating endothelial progenitor cell levels along with inappropriate attenuated vascular endothelial growth factor levels may imply an angiogenic imbalance that exists even after recovery and may thus predispose to PPCM. In addition, tissue Doppler imaging and 2D strain were able to identify residual myocardial injury in post-PPCM women with apparent recovery of LV systolic function. Both angiogenic imbalance and residual myocardial injury may play an important role in the recurrence of LV dysfunction during subsequent pregnancies. PMID- 28029642 TI - Residents' perspectives on the final year of medical school. AB - Objective: To characterize junior residents' perspectives on the purpose, value, and potential improvement of the final year of medical school. Methods: Eighteen interviews were conducted with junior residents who graduated from nine different medical schools and who were in internal medicine, surgery, and psychiatry programs at one institution in the United States. Interview transcripts were coded and analyzed inductively for themes. Results: Participants' descriptions of the purpose of their recently completed final year of medical school contained three primary themes: residency-related purposes, interest- or need-based purposes, and transitional purposes. Participants commented on the most valued aspects of the final year. Themes included opportunities to: prepare for residency; assume a higher level of responsibility in patient care; pursue experiences of interest that added breadth of knowledge, skills and perspective; develop and/or clarify career plans; and enjoy a period of respite. Suggestions for improvement included enhancing the learning value of clinical electives, augmenting specific curricular content, and making the final year more purposeful and better aligned with career goals. Conclusions: The final year of medical school is a critical part of medical education for most learners, but careful attention is needed to ensure that the year is developmentally robust. Medical educators can facilitate this by creating structures to help students define personal and professional goals, identify opportunities to work toward these goals, and monitor progress so that the value of the final year is optimized and not exclusively focused on residency preparation. PMID- 28029643 TI - Making sense of Cronbach's alpha. PMID- 28029644 TI - The cornucopia of meaningful leads: Applying deep adversarial autoencoders for new molecule development in oncology. AB - Recent advances in deep learning and specifically in generative adversarial networks have demonstrated surprising results in generating new images and videos upon request even using natural language as input. In this paper we present the first application of generative adversarial autoencoders (AAE) for generating novel molecular fingerprints with a defined set of parameters. We developed a 7 layer AAE architecture with the latent middle layer serving as a discriminator. As an input and output the AAE uses a vector of binary fingerprints and concentration of the molecule. In the latent layer we also introduced a neuron responsible for growth inhibition percentage, which when negative indicates the reduction in the number of tumor cells after the treatment. To train the AAE we used the NCI-60 cell line assay data for 6252 compounds profiled on MCF-7 cell line. The output of the AAE was used to screen 72 million compounds in PubChem and select candidate molecules with potential anti-cancer properties. This approach is a proof of concept of an artificially-intelligent drug discovery engine, where AAEs are used to generate new molecular fingerprints with the desired molecular properties. PMID- 28029645 TI - An ensemble approach for large-scale identification of protein- protein interactions using the alignments of multiple sequences. AB - Protein-Protein Interactions (PPI) is not only the critical component of various biological processes in cells, but also the key to understand the mechanisms leading to healthy and diseased states in organisms. However, it is time consuming and cost-intensive to identify the interactions among proteins using biological experiments. Hence, how to develop a more efficient computational method rapidly became an attractive topic in the post-genomic era. In this paper, we propose a novel method for inference of protein-protein interactions from protein amino acids sequences only. Specifically, protein amino acids sequence is firstly transformed into Position-Specific Scoring Matrix (PSSM) generated by multiple sequences alignments; then the Pseudo PSSM is used to extract feature descriptors. Finally, ensemble Rotation Forest (RF) learning system is trained to predict and recognize PPIs based solely on protein sequence feature. When performed the proposed method on the three benchmark data sets (Yeast, H. pylori, and independent dataset) for predicting PPIs, our method can achieve good average accuracies of 98.38%, 89.75%, and 96.25%, respectively. In order to further evaluate the prediction performance, we also compare the proposed method with other methods using same benchmark data sets. The experiment results demonstrate that the proposed method consistently outperforms other state-of-the-art method. Therefore, our method is effective and robust and can be taken as a useful tool in exploring and discovering new relationships between proteins. A web server is made publicly available at the URL http://202.119.201.126:8888/PsePSSM/ for academic use. PMID- 28029648 TI - Genomic differences between black and white patients implicate a distinct immune response to papillary renal cell carcinoma. AB - Significant disparities in survival, incidence and possibly response to current therapies exist between black and white patients with renal cell carcinoma (RCC). Recent genomic evidence to account for these disparities has been reported for clear cell RCC. However, racial disparities at the genomic level for papillary RCC (pRCC) which is a genetically distinct and less responsive histologic subtype of RCC have not been reported. Using The Cancer Genome Atlas (TCGA) data, the present study assessed gene-level expression, somatic mutation and pathway differences between 58 black and 58 white patients with pRCC propensity matched on age, gender and pathologic T stage. Distinct tumor biology with differential expression patterns were observed in black vs. white patients with pRCC. Specifically, significance analysis of microarrays was applied to TCGA gene expression data and identified 163 genes and 120 genes overexpressed in black and white patients, respectively (FDR q<0.05). Gene Set Enrichment Analysis identified 62 gene sets enriched (p<0.10) in blacks. Enrichment of immune immune system pathways were noted in black patients. These included the B cell receptor signaling pathway, the NOD-like receptor signaling pathway and genes involved in defensins. The VEGF pathway was also more significant in black patients. CRYBB2, a gene associated with the WNT pathway was overexpressed in Black patients. While our data requires validation, these findings suggest that race may have implications for distinct immune responses to cancer and that the use of immunotherapies, and VEGFR inhibitors to target these pathways may improve survival in black patients with advanced pRCC. PMID- 28029646 TI - The role of prostate tumor overexpressed 1 in cancer progression. AB - Prostate-Tumor-Overexpressed-1 (PTOV1) is a conserved adaptor protein discovered as overexpressed in prostate cancer. Since its discovery, the number of binding partners and associated cellular functions has increased and helped to identify PTOV1 as regulator of gene expression at transcription and translation levels. Its overexpression is associated with increased tumor grade and proliferation in prostate cancer and other neoplasms, including breast, ovarian, nasopharyngeal, squamous laryngeal, hepatocellular and urothelial carcinomas. An important contribution to higher levels of PTOV1 in prostate tumors is given by the frequent rate of gene amplifications, also found in other tumor types. The recent resolution of the structure by NMR of the PTOV domain in PTOV2, also identified as Arc92/ACID1/MED25, has helped to shed light on the functions of PTOV1 as a transcription factor. In parallel, by studying its interaction with RACK1, we have discovered PTOV1 action in promoting mRNAs translation. Here, we will focus on the role of PTOV1 in cancer, re-examine its pro-oncogenic effects and re evaluate the most relevant interactions and evidences of its cellular functions. The data are used to formulate a model for the mechanisms of action of PTOV1 in line with its recently described activities and cellular pathways modulated in cancer. PMID- 28029647 TI - Peptide-guided targeting of GPR55 for anti-cancer therapy. AB - Expression of the lysophosphatidylinositol receptor GPR55 correlates with invasive potential of metastatic cells and bone metastasis formation of different types of tumors. These findings suggest a role for GPR55 signaling in cancer progression, including in lymphoproliferative diseases. Here, we screened a M13 phage-displayed random library using the bait of HEK293 cells that heterologously expressed full-length HA-GPR55. We selected a set of phagotopes that carried 7 mer insert peptides flanked by a pair of cysteine residues, which resulted in cyclized peptides. Sequencing of selected phagotopes dictated the primary structure for the synthetic FITC-labeled peptide P1, which was analyzed for binding specificity to immunoprecipitated HA-GPR55, and to endogenously expressed GPR55, using cells interfered or not for GPR55, as well as for co-localization imaging with HA-GPR55 at the membrane level. The peptide P1 stimulated GPR55 endocytosis and inhibited GPR55-dependent proliferation of EHEB and DeFew cells, two human B-lymphoblastoid cell lines. Our data support the potential therapeutic application of peptide ligands of GPR55 for targeting and inhibiting growth of neoplastic cells, which overexpress GPR55 and are dependent on GPR55 signaling for their proliferation. PMID- 28029649 TI - MiR-200c is a cMyc-activated miRNA that promotes nasopharyngeal carcinoma by downregulating PTEN. AB - The c-Myc transcription factor regulates a complex transcriptional program that leads to cellular transformation by targeting a large number of protein-encoding genes and non-coding RNAs. In this study, we show that a microRNA, miR-200c, is a novel c-Myc target that promotes cellular transformation and metastasis in nasopharyngeal carcinoma. MiR-200c achieves this oncogenic effect, at least in part, by targeting and inhibiting the tumor suppressor gene PTEN (phosphatase and tensin homolog), which is a key inhibitor of the AKT kinase signaling that promotes tumorigenesis in nasopharyngeal carcinoma. Our study thus identifies cMyc-miR-200c-PTEN-AKT as a functional module that promotes cellular transformation in nasopharyngeal carcinoma. PMID- 28029650 TI - Tumor-infiltrating lymphocytes predict prognosis of breast cancer patients treated with anti-Her-2 therapy. AB - PURPOSE: Infiltration of tumor associated lymphocytes and count of its different phenotypes are potentially new independent predictor of prognosis in breast cancer. However, research related to it is less reported in breast cancer patients treated with anti-Her-2 therapy. Thus, we evaluated the relationship between survival and tumor infiltrating lymphocytes including its different phenotypes in tumors of such patients. METHODS: Between 1999 and 2010, 98 patients diagnosed with primary breast cancer and treated with anti-Her-2 therapy at Sun-Yat-Sen University Cancer Center were included in the study. Biopsy specimens were collected post-operation but before chemotherapy. Tumor infiltrating lymphocytes as well as its FOXP3+, CD68+, IL-17+ phenotypes in both intratumoral and stromal sites and expression of FOXP3 in cancer cells were assessed. RESULTS: Median follow-up time of 98 patients was 83.3 months (range 7.4-201 months). It suggested that patients with high stromal infiltration of TILs, lower count of FOXP3+ Tregs and CD68+ Mphi in stromal site, and high expression of FOXP3 in cancer cells had longer survival of OS. In multivariate Cox regression analysis, high count of intratumoral CD68+ Mphi [HR: 2.70 (1.00 7.31); p=0.050] and high expression of FOXP3 in cancer cells [HR: 0.29 (0.09 0.91); p=0.034] were independent prognostic factors for overall survival. CONCLUSIONS: Tumor infiltrating lymphocytes as well as its FOXP3+, CD68+ phenotypes in stromal site, and expression of FOXP3 in cancer cells were significantly associated with OS, suggesting that they can be used as important pathological factor predicting prognosis of breast cancer patients treated with anti-Her-2 therapy. PMID- 28029651 TI - The pseudogene DUXAP10 promotes an aggressive phenotype through binding with LSD1 and repressing LATS2 and RRAD in non small cell lung cancer. AB - Pseudogenes have been considered as non-functional transcriptional relics of human genomic for long time. However, recent studies revealed that they play a plethora of roles in diverse physiological and pathological processes, especially in cancer, and many pseudogenes are transcribed into long noncoding RNAs and emerging as a novel class of lncRNAs. However, the biological roles and underlying mechanism of pseudogenes in the pathogenesis of non small cell lung cancer are still incompletely elucidated. This study identifies a putative oncogenic pseudogene DUXAP10 in NSCLC, which is located in 14q11.2 and 2398 nt in length. Firstly, we found that DUXAP10 was significantly up-regulated in 93 human NSCLC tissues and cell lines, and increased DUXAP10 was associated with patients poorer prognosis and short survival time. Furthermore, the loss and gain of functional studies including growth curves, migration, invasion assays and in vivo studies verify the oncogenic roles of DUXAP10 in NSCLC. Finally, the mechanistic experiments indicate that DUXAP10 could interact with Histone demethylase Lysine specific demethylase1 (LSD1) and repress tumor suppressors Large tumor suppressor 2 (LATS2) and Ras-related associated with diabetes (RRAD) transcription in NSCLC cells. Taken together, these findings demonstrate DUXAP10 exerts the oncogenic roles through binding with LSD1 and epigenetic silencing LATS2 and RRAD expression. Our investigation reveals the novel roles of pseudogene in NSCLC, which may serve as new target for NSCLC diagnosis and therapy. PMID- 28029652 TI - Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-kappaB signaling in nasopharyngeal carcinoma. AB - A putative tumor suppressor BLU mapped on the chromosomal 3p21 region, is frequently lost in human tumors including nasopharyngeal carcinoma (NPC). To explore the underlying mechanism of tumor suppression by BLU, its potential to promote apoptosis induced by TRAIL, an effector molecule elaborated by natural killer-T (NKT) cells was investigated. BLU was re-expressed in NPC-derived HNE1 cells by recombinant adenoviral infection and the cells were challenged with recombinant TRAIL. The growth inhibition of BLU was assayed and apoptosis was examined by flow cytometry-based tetramethylrhodamine ethyl ester (TMRE) and annexin V staining, cleavage of pro-caspase-8 and poly ADP ribose polymerase (PARP). The modulation of NF-kappaB pathway by BLU was evaluated by the reporter activity and estimation of the level of the molecules involved such as IKKalpha, p65 NF-kappaB, as well as NF-kappaB induced anti-apoptotic factors cFLIPL and cIAP2. The expression of BLU exerted in vitro and in vivo growth inhibitory effect and promoted TRAIL-induced apoptosis. This phenomenon was validated by FACS-based assays of mitochondrial membrane potential (BLU vs. Vector 87.8% +/- 7.7% and 72.1%+/-6.7% at 6h exposure to TRAIL) and phosphatidylserine turnover (BLU vs. vector: 28.7%+/-2.9% and 22.6%+/-2.5%), as well as, enhanced caspapse-8 cleavage. Similar with the findings that BLU promotes chemotherapeutic agent induced apoptosis, it also augmented death receptor-induced pathway through NF kappaB pathway inhibition. In conclusion, BLU suppressed tumor formation by strengthening the antitumor immunity. PMID- 28029653 TI - Antitumor effect of an adeno-associated virus expressing apolipoprotein A-1 fused to interferon alpha in an interferon alpha-resistant murine tumor model. AB - Interferon alpha (IFNalpha) is a cytokine approved for the treatment of several types of cancer. However, the modest effect on overall survival and the high toxicity associated with the treatment has reduced the clinical use of this cytokine. In this study, we have developed a tumor model that reproduces this clinical setting. A high dose of an adeno-associated virus encoding IFNalpha (AAV IFNalpha) was able to eradicate a liver metastases model of colon cancer but induced lethal pancytopenia. On the other hand, a safe dose of AAV-IFNalpha was not able to eliminate the liver metastases of colon cancer. In this IFNalpha resistant tumor model, administration of an adeno-associated vector encoding apolipoprotein A-1 fused to IFNalpha was able to fully eradicate the tumor in 43% of mice without toxicity. This antitumor effect was limited by suboptimal long term CD8+ T cell activation and the expansion of T regulatory cells. In contrast, IFNalpha upregulated suppressor molecules such as PD-1 and interleukin 10 on CD8+ T lymphocytes. In conclusion, we show that apolipoprotein A-1 fused to IFNalpha is a novel antitumor drug that differs from IFNalpha in the modulation of suppressor mechanisms of the immune response. These differential properties pave the way for rational combinations with other immunomodulatory drugs. PMID- 28029654 TI - ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining. AB - ABCG2, member of ATP-binding cassette (ABC) transporter family, is known as crucial regulator related to multi-drug resistance in human tumors and has recently been putatively studied as human carcinoma cell biomarker. While, effects of ABCG2 on human gastric cancer (GC) has not been illustrated thoroughly. In this study, by applying biostatistics mining methods, we observed that ABCG2 is frequently aberrantly expressed in GC patients through exploring dataset of GSE19826 in NCBI GEO database. Contemporary, extreme up-regulation of ABCG2 was discovered in both GC specimens and cell lines of our center, from which we observed high level of ABCG2 associated with GC clinicopathologic features and poor outcomes. Depletion of ABCG2 in MKN-45 GC cells, the cell proliferation was significantly impacted along with cell cycle arrest, and cell apoptosis was induced. Interestingly, combined with data mining of NCBI database, CRKL, a pivotal GC promoter, presents a significant positive correlation with ABCG2. And the expression of CRKL in GC cells was obviously affected through ABCG2 depletion. Simultaneously, over-expression of CRKL in MKN-45 cells significantly rescued most of the phenotypes induced by ABCG2 depletion. Thus, we suggest that ABCG2 is a potential biomarker and target upstream CRKL, which could be further studied for GC diagnosis and therapeutic treatment. PMID- 28029655 TI - Identifying prognostic biomarkers based on aberrant DNA methylation in kidney renal clear cell carcinoma. AB - The outcome of kidney renal clear cell carcinoma (KIRC) differs even among individuals with similar clinical characteristics. DNA methylation is regarded as a regulator of gene expression in cancers, which may be a molecular marker of prognosis. In this study, we aimed to mine novel methylation markers of the prognosis of KIRC. We revealed a total of 2793 genes differentially methylated in their promoter regions (DMGs) and 2979 differentially expressed genes (DEGs) in KIRC tissues compared with normal tissues using The Cancer Genome Atlas datasets. Then, we detected 57 and 34 subpathways enriched among the DMGs and DEGs, respectively, using the R package iSubpathwayMiner. We retained 56 subpathways related to both aberrant methylation and expression based on a hypergeometric test for further analysis. An integrated gene regulatory network was constructed using the regulatory relationships between genes in the subpathways. Using the top 15% of the nodes from the network ranked by degree, survival analysis was performed. We validated four DNA methylation signatures (RAC2, PLCB2, VAV1, and PARVG) as being highly correlated with prognosis in KIRC. These findings suggest that DNA methylation might become a prognostic predictor in KIRC and could supplement histological prognostic prediction. PMID- 28029656 TI - Low lymphocyte-to-white blood cell ratio and high monocyte-to-white blood cell ratio predict poor prognosis in gastric cancer. AB - Previous results regarding the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in gastric cancer are conflicting, and full analysis of other blood test parameters are lacking. We therefore examined the associations between various blood test parameters and prognosis in 3243 gastric cancer patients randomly divided into training (n=1621) and validation (n=1622) sets. Optimal cut-off values of 0.663 for neutrophil-to white blood cell ratio (NWR), 0.288 for lymphocyte-to-white blood cell ratio (LWR), 0.072 for monocyte-to-white blood cell ratio (MWR), 2.604 for NLR, 0.194 for monocyte-to-lymphocyte ratio (MLR), and 130.675 for PLR were identified in the training set. Univariate and survival analyses revealed that high NWR, low LWR, high MWR, high NLR, high MLR, and high PLR are all associated with a poor prognosis in gastric cancer. However, multivariate analysis revealed that only LWR, and MWR are independent prognostic predictors, and prognostic value increased when LWR and MWR were considered in combination. These findings suggest that low LWR and high MWR are each predictive of a poor prognosis, and exhibit greater prognostic value when considered in combination. PMID- 28029657 TI - Prognostication of serial post-intensity-modulated radiation therapy undetectable plasma EBV DNA for nasopharyngeal carcinoma. AB - Plasma Epstein-Barr virus (EBV) DNA titers have been used to monitor treatment response and provide prognostic information on survival for nasopharyngeal carcinoma (NPC). However, the long-term prognostic role of pretreatment and posttreatment titers after radical contemporaneous radiation therapy remains uncertain. We recruited 260 evaluable patients with non-metastatic NPC treated with radical intensity-modulated radiation therapy (IMRT) with or without adjunct chemotherapy. Plasma EBV DNA titers at baseline and then 8 weeks and 6 months after IMRT were measured. Cox regression models were employed to identify interaction between post-IMRT 8th week and 6th month undetectable titers and 3 year survival endpoints. Concordance indices (Ct) from time-dependent receiver operating characteristics (TDROC) were compared between patients with post-IMRT undetectable and those with detectable titers. After a median follow-up duration of 3.4 years (range 1.4-4.6 years), patients with post-IMRT 8th week and 6th month undetectable plasma EBV DNA titers enjoyed longer 3-year survival endpoints than those who had detectable titers at the same time points. Post-IMRT 8th week, and more significantly, post-IMRT 6th month undetectable plasma EBV DNA were the only significant prognostic factors of 3-year survival endpoints. Ct values for all 3-year survival endpoints for both post-IMRT 8th week and 6th month undetectable plasma EBV DNA were significantly higher in those with stage IVA-IVB diseases compared to stage I-III counterparts. Early post-IMRT undetectable plasma EBV DNA titers were prognostic of 3-year survival endpoints in patients with non-metastatic NPC. Intensified treatment should be further explored for patients with persistently detectable titers after IMRT. PMID- 28029658 TI - The inhibition of 45A ncRNA expression reduces tumor formation, affecting tumor nodules compactness and metastatic potential in neuroblastoma cells. AB - We recently reported the in vitro over-expression of 45A, a RNA polymerase III transcribed non-coding (nc)RNA, that perturbs the intracellular content of FE65L1 affecting cell proliferation rate, short-term response to genotoxic stress, substrate adhesion capacity and, ultimately, increasing the tumorigenic potential of human neuroblastoma cells. In this work, to deeply explore the mechanism by which 45A ncRNA contributes to cancer development, we targeted in vitro and in vivo 45A levels by the stable overexpression of antisense 45A RNA.45A downregulation leads to deep modifications of cytoskeleton organization, adhesion and migration of neuroblastoma cells. These effects are correlated with alterations in the expression of several genes including GTSE1 (G2 and S phase expressed-1), a crucial regulator of tumor cell migration and metastatic potential. Interestingly, the downregulation of 45A ncRNA strongly affects the in vivo tumorigenic potential of SKNBE2 neuroblastoma cells, increasing tumor nodule compactness and reducing GTSE1 protein expression in a subcutaneous neuroblastoma mouse model. Moreover, intracardiac injection of neuroblastoma cells showed that downregulation of 45A ncRNA also influences tumor metastatic ability. In conclusion, our data highlight a key role of 45A ncRNA in cancer development and suggest that its modulation might represent a possible novel anticancer therapeutic approach. PMID- 28029660 TI - Phenotypic characterization of circulating tumor cells in triple negative breast cancer patients. AB - INTRODUCTION: Patients with triple negative breast cancer (TNBC), are considered as a poor prognosis group for whom no targeted therapies are currently available. The aim of the present study was to phenotypically characterize their CTCs in order to explore potential therapeutic targets. METHODS: PBMC's cytospins were prepared from 45 early (before and after adjuvant chemotherapy), 10 metastatic TNBC and 21 hormone receptor (HR) -positive patients. The expression of Cytokeratins (CK), ER, PR, EGFR and HER2 on CTCs was assessed using immunofluoresence staining and ARIOL analysis. RESULTS: In early stage TNBC, ER, PR, HER2 and EGFR expressing-CTCs were detected in 24.4%, 24.4%, 20% and 40% of patients before the initiation of adjuvant chemotherapy, and in 17.8%, 13.3% 6.7% and 51.1% respectively after the completion of adjuvant treatment. Triple staining experiments revealed distinct subpopulations of CTC expressed HR, and ErbB family receptors. In patients with metastatic disease, the frequency of HER2+ CTCs was significantly increased compared to adjuvant setting (60% vs 20%, p=0.014). The presence of CK+PR- CTCs, before adjuvant treatment was associated with reduced OS (p=0.032) and DFI (p=0.04). Furthermore, the frequency of ER-, PR and HER2+ CTCs was higher in HR(+) than in TNBC tumors (57.1%, p=0.006; 52.4%, p=0.021 and 52.38%, p=0.009, respectively). CONCLUSIONS: The CTCs in patients with early TNBC are phenotypically heterogeneous based on the expression of HR, EGFR and HER2 both before and after the completion of adjuvant chemotherapy whereas the presence of HER2+ CTCs prevails during disease evolution. These findings could be of clinical relevance in terms of CTC targeting. PMID- 28029659 TI - Knockdown of RNF2 induces cell cycle arrest and apoptosis in prostate cancer cells through the upregulation of TXNIP. AB - RNF2, also known as RING1b or RING2, is identified as the catalytic subunit of polycomb repressive complex 1 (PRC1), which mediates the mono-ubiquitination of histone H2A. RNF2 has been proved to have oncogenic function in many kinds of cancers, but the function of RNF2 in prostate cancer (PCa) has not been evaluated. Here we show that PCa tissues showed higher RNF2 expression than the benign prostatic hyperplasia (BPH) tissues. Knockdown of RNF2 in PCa cells resulted in cell cycle arrest, increased apoptosis and inhibited cell proliferation, and the growth of RNF2 knockdown PCa xenografts were obviously inhibited in nude mice. Gene microarray analysis was performed and tumor suppressor gene TXNIP was found to be significantly increased in RNF2 knockdown cells. Simultaneously knockdown of RNF2 and TXNIP can partially rescue the arrested cell cycle, increased apoptosis and inhibited cell proliferation in RNF2 single knockdown cells. Furthermore, ChIP assay result showed that RNF2 enriched at the TXNIP promoter, and the enrichment of RNF2 and ubiquitination of H2A in TXNIP promoter was obviously inhibited in RNF2 knockdown cells. In conclusion, our results demonstrate that RNF2 functions as an oncogene in PCa and RNF2 may regulate the progression of PCa through the inhibition of TXNIP. PMID- 28029661 TI - Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer. AB - Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity. Overall, basal cell lines expressed higher COX-2, higher MRP4, lower PGT, and lower 15 PGDH than luminal cell lines resulting in higher PGE2 in the extracellular environment. Genetic or pharmacologic suppression of MRP4 expression or activity in basal cell lines led to less extracellular PGE2. The key finding is that xenografts derived from a basal breast cancer cell line with stably suppressed MRP4 expression showed a marked decrease in spontaneous metastasis compared to cells with unaltered MRP4 expression. Growth properties of primary tumors were not altered by MRP4 manipulation. In addition to the well-established role of high COX-2 in promoting metastasis, these data identify an additional mechanism to achieve high PGE2 in the tumor microenvironment; high MRP4, low PGT, and low 15-PGDH. MRP4 should be examined further as a potential therapeutic target in basal breast cancer. PMID- 28029662 TI - Guidance to rational use of pharmaceuticals in gallbladder sarcomatoid carcinoma using patient-derived cancer cells and whole exome sequencing. AB - PURPOSE: Gallbladder sarcomatoid carcinoma is a rare cancer with no clinical standard treatment. With the rapid development of next generation sequencing, it has been able to provide reasonable treatment options for patients based on genetic variations. However, most cancer drugs are not approval for gallbladder sarcomatoid carcinoma indications. The correlation between drug response and a genetic variation needs to be further elucidated. EXPERIMENTAL DESIGN: Three patient-derived cells-JXQ-3D-001, JXQ-3D-002, and JXQ-3D-003, were derived from biopsy samples of one gallbladder sarcomatoid carcinoma patient with progression and have been characterized. In order to study the relationship between drug sensitivity and gene alteration, genetic mutations of three patient-derived cells were discovered by whole exome sequencing, and drug screening has been performed based on the gene alterations and related signaling pathways that are associated with drug targets. RESULTS: It has been found that there are differences in biological characteristics such as morphology, cell proliferation, cell migration and colony formation activity among these three patient-derived cells although they are derived from the same patient. Their sensitivities to the chemotherapy drugs-Fluorouracil, Doxorubicin, and Cisplatin are distinct. Moreover, none of common chemotherapy drugs could inhibit the proliferations of all three patient derived cells. Comprehensive analysis of their whole exome sequencing demonstrated that tumor-associated genes TP53, AKT2, FGFR3, FGF10, SDHA, and PI3KCA were mutated or amplified. Part of these alterations are actionable. By screening a set of compounds that are associated with the genetic alteration, it has been found that GDC-0941 and PF-04691502 for PI3K-AKT-mTOR pathway inhibitors could dramatically decrease the proliferation of three patient-derived cells. Importantly, expression of phosphorylated AKT and phosphorylated S6 were markedly decreased after treatments with PI3K-AKT-mTOR pathway inhibitors GDC-0941 (0.5 MUM) and PF-04691502 (0.1 MUM) in all three patient-derived cells. These data suggested that inhibition of the PI3K-AKT-mTOR pathway that was activated by PIK3CA amplification in all three patient-derived cells could reduce the cell proliferation. CONCLUSIONS: A patient-derived cell model combined with whole exome sequencing is a powerful tool to elucidate relationship between drug sensitivities and genetic alternations. In these gallbladder sarcomatoid carcinoma patient-derived cells, it is found that PIK3CA amplification could be used as a biomarker to indicate PI3K-AKT-mTOR pathway activation. Block of the pathway may benefit the gallbladder sarcomatoid carcinoma patient with this alternation in hypothesis. The real efficacy needs to be confirmed in vivo or in a clinical trial. PMID- 28029663 TI - Regional hyperthermia combined with radiotherapy for esophageal squamous cell carcinoma with supraclavicular lymph node metastasis. AB - To assess the efficacy and toxicity of Intensity-modulated radiotherapy (IMRT) and hyperthermia for upper and middle thoracic esophageal squamous cell carcinoma (UMT-ESCC) with supraclavicular lymph node metastasis. A total of 50 patients with UMT-ESCC with supraclavicular lymph node metastasis were evaluated in this retrospective study. All patients received IMRT. Hyperthermia was delivered simultaneously with irradiation, in 45 minutes twice a week for 5-6 weeks. Hyperthermia included supraclavicular lymph node metastasis. Forty-four patients (88.0%) received concurrent chemoradiotherapy based on cisplatin regimens. The most common types of hematological toxicities were anemia (62.0%) and leukopenia (60.0%). Most of these events were grade 1-2 and transient. The 3-year progression-free survival (PFS) rate and overall survival (OS) rate were 34.9% and 42.5%, respectively. Cox regression revealed that tumor length and number of supraclavicular lymph node metastasis were two independent predictors of OS (tumor length: HR=3.65, p=0.008; nodal stage: HR=8.07, p=0.019). The IMRT combined with supraclavicular regional hyperthermia has low toxicity and well tolerated with excellent local control in UMT-ESCC with supraclavicular lymph node metastasis. PMID- 28029665 TI - Inguinal Hernia Repair: Principles and Practice in the United Kingdom. PMID- 28029664 TI - Depressive Symptoms and Salivary Telomere Length in a Probability Sample of Middle-Aged and Older Adults. AB - OBJECTIVE: To examine the association between depressive symptoms and salivary telomere length in a probability sample of middle-aged and older adults, and to evaluate age and sex as potential moderators of this association and test whether this association was incremental to potential confounds. METHODS: Participants were 3,609 individuals from the 2008 wave of the Health and Retirement Study. Telomere length assays were performed using quantitative real-time polymerase chain reaction on DNA extracted from saliva samples. Depressive symptoms were assessed via interview, and health and lifestyle factors, traumatic life events, and neuroticism were assessed via self-report. Regression analyses were conducted to examine the associations between predictor variables and salivary telomere length. RESULTS: After adjusting for demographics, depressive symptoms were negatively associated with salivary telomere length (b = -.003; p = .014). Furthermore, this association was moderated by sex (b = .005; p = .011), such that depressive symptoms were significantly and negatively associated with salivary telomere length for men (b = - .006; p < .001) but not for women (b = - .001; p = .644). The negative association between depressive symptoms and salivary telomere length in men remained statistically significant after additionally adjusting for cigarette smoking, body mass index, chronic health conditions, childhood and lifetime exposure to traumatic life events, and neuroticism. CONCLUSIONS: Higher levels of depressive symptoms were associated with shorter salivary telomeres in men, and this association was incremental to several potential confounds. Shortened telomeres may help account for the association between depression and poor physical health and mortality. PMID- 28029666 TI - Comparison of Fissure Healing and The Incidence of Headache Among the Patients Treated with Endo- and Perianal Application of 0.2% Glyceryl Trinitrate for Chronic Anal Fissure. AB - INTRODUCTION: Chronic anal fissure is associated with significant morbidity and reduction in quality of life mostly in young healthy adults. Glyceryl Trinitrate, a most commonly used agent for treatment, is associated with incidence of headache causing discontinuation of treatment. There is belief that endoanal application instead of perianal is associated with lower incidence of headache. This study is to compare the incidence and severity of headache in between perianal and endoanal application of GTN ointment. METHODS: Thirty patients were taken in each perianal and endoanal group. They were given orientation to apply 375gm of ointment either endoanally or perianally and to record severity of headache according to visual analogue scale. This record was noted by independent observer in telephonic conversation. Patients were followed up at 6 weeks for evaluation fissure. RESULTS: The mean age, male female ratio and features of chronicity was similar in both the group however the duration of symptoms between the group was different. Regarding outcome, Overall incidence of headache was seen in two-third of patient with severe headache in approx. 10%. Severity of headache was slightly lower in endoanal group but the difference was not significant. Healing rate was comparable. Two patient in perianal and 3 in endoanal group were lost for follow up. CONCLUSIONS: Endoanal application of GTN ointment is associated with slight decrease in intensity of headache and is comparable with perianal application for fissure healing. PMID- 28029667 TI - Outcomes Bronchoscopic Evaluation in A University Hospital. AB - INTRODUCTION: Study of clinical profile of the patients and diagnostic yield of the selected bronchoscopic procedures gives us important information in clinical decision making and better patient care. There are hardly very few studies regarding these entities. Therefore, we decided to study clinical characteristics and outcomes of the patients who underwent bronchoscopic evaluation in our setting. METHODS: This was a cross-sectional study the consecutive patients who underwent bronchoscopy from 1st May 2013- 30th April 2015 in division of pulmonary, critical care and sleep medicine. The main procedure performed was bronchoalveolar lavage. RESULTS: The mean age was 54.71 years with 76 (76%) males. Recurrent hemoptysis in 58 (58%) patients were the commonest indication. Total 95 (95%) patients have chest X-ray abnormalities. The commonest bronchoscopic finding was bronchiectasis 23 (23%) of patients followed by chronic bronchitis in 18 (18%) and endobronchial tuberculosis in 16 (16%). Total 10 (71%) of the 14 bronchoscopically suspected lung cancer patients have intraluminal lesions. Bronchoalveolar lavage culture for tuberculosis showed growth in 46 (46%), positive for malignancy in 7 (7%) positive Ziehl Neelson stain for tuberculosis in 6 (6%). CONCLUSIONS: Bronchoscopic evaluation of patients with pulmonary diseases gives us a lot of information that may help us in better patient care and bronchoalveolar lavage has high diagnostic yield in diagnosing pulmonary tuberculosis. PMID- 28029668 TI - Titanium Elastic Nailing System (TENS) for Tibia Fractures in Children: Functional Outcomes and Complications. AB - INTRODUCTION: Closed reduction and cast application is still regarded as first line treatment for pediatric tibial fractures. Over the past few decades, management of pediatric tibial fractures has shifted more towards operative intervention because of quicker recovery, shorter rehabilitation period, less immobilization, lack of stiffness of adjoining joints, and less psychological impact to the children. Flexible intramedullary nails not only fulfill the above advantage but also maintain alignment and rotation. METHODS: This was a retrospective study of pediatric tibial fractures fixed with two titanium elastic nails through proximal ends of bones. Alignment of fracture, any infection, delayed union, non union, limb length discrepancy, motion of knee joint, and fracture union time were measured during follow-up examination. RESULTS: Forty five patients were enrolled into the study out of which 28 (62.2%) were male and 17 (37.8%) were female. Average age of patient was 9.48+/-2.17 years and average time taken to heal the fractures (both clinical and radiological) was 11.17+/ 2.81 weeks. There were 2 (4.4%) of malunion, 4 (8.8%) of delayed union, 3 (6.6%) of limb shortening, 2 (4.4%) of limb lengthening, 6 (13.6%) of nail prominence and skin irritation, 2 (4.4%) of superficial infection at nail entry site and one case of re-fracture. CONCLUSIONS: Titanium elastic nail fixation is a simple, easy, rapid, reliable and effective method for management of pediatric tibial fractures in patients with operative indications. There may be the chances of complication following the TENS in tibia but these are avoidable as well as manageable with careful precautions. PMID- 28029669 TI - Safety and Efficacy of Spinal Anaesthesia in Percutaneous Nephrolithotomy. AB - INTRODUCTION: Renal stone is one of the common entities occurring in our population. There are different treatment modalities of stones; out of those percutaneous nephrolithotomy is one of the most popular and effective for the renal and upper tract stones. This study is based to compare the safety and efficacy of spinal anaesthesia and general anaesthesia in PCNL. METHODS: In a randomized prospective study 60 patients were divided in two groups; group 1 (n=30) underwent PCNL in general anaesthesia and group 2 (n=30) underwent PCNL in spinal anaesthesia in prone position with the conventional technique. Demographic, operative data, post operative complications, patients' satisfaction rate and follow up complications were recorded and analyzed between two groups. RESULTS: Mean age in group 1 was 39.10+/-12.45years and 36.10+/-14.18 in group 2 (P=0.100). Mean stone size in group 1 was 3.75+/-1.27cm and 3.23+/-1.36cm in group 2 (P=0.129).Similarly the operative time was 89.10 +/- 49.38 min and 62.53+/-35.91 min in group 1 and group 2 respectively (P=0.042). There was no significant difference between the complications regarding the anaesthesia. Post operative nausea and vomiting were significantly higher in group 1 and headache in group 2 (p=<0.001). Overall patient satisfaction rate was higher in group 2 then in group 1 (p=0.01). Hospital stay in group 1 was 5.27+/-1.87 days and 4.53+/-1.88 days in group 2 (p = 0.07). Stone success rate was similar in each group (p =0.50). CONCLUSIONS: Spinal anaesthesia is a safe and effective method in performing PCNL. PMID- 28029670 TI - Evaluation of Distensibility and Stiffness of Ascending Aortic Aneurysm using Magnetic Resonance Imaging. AB - INTRODUCTION: Magnetic resonance imaging emerging as a new tool for the diagnosis and evaluation of ascending aortic aneurysm. The aim of our study is to evaluate in vivo distensibility and pulse wave velocity of the aortic wall using functional magnetic resonance imaging technique. METHODS: We enrolled 25 patients undergoing surgery for ascending aortic aneurysm and or aortic valve replacement for a period of 8 months. Preoperatively, all the patients underwent functional MRI study of the aorta. Aortic wall distensibility and pulse wave velocity of ascending aorta was evaluated. RESULTS: Mean age of the patient was 66 years (66.68 +/- 5.62 years) with 60% (15) male patients. More than fifty percentages of patients were smoker (52%), hypertensive (64%) and diabetic (56%). We have observed significant decrease of distensibilty in the patients with aortic diameter above 50 mm (p-0.0002). Furthermore, we have found a significant inverse correlation between aortic distensibility and pulse wave velocity (R= -0.650, R2= 0.42, p-0.0004). Similarly, we have found a significant inverse correlation between ascending aortic diameter and distensibility of the aorta (R= -0.785, R2= 0.61, p-0.00001). Statistically significant positive correlation was observed between aortic diameter and pulse wave velocity (R= 0.865, R2= 0.74, p-0.00001). CONCLUSIONS: MRI measurement of aortic diameters, distensibility, and flow wave velocity is an easy, reliable and reproducible technique. Distensibility and pulse wave velocity define the elasticity of the aorta. We have observed that elasticity of aortic wall is decreased in ascending aorta aneurysm patients. PMID- 28029671 TI - Prescribing Skills of First and Second Year MBBS Students of A Teaching Hospital. AB - INTRODUCTION: To ensure safe, effective and rational prescribing by tomorrow's doctors it is important to assess the prescribing skills of today's medical students. The aim of this study was to assess the prescribing skills of MBBS preclinical students of a Teaching Hospital. METHODS: First and second year medical students were given different sets of common clinical scenarios and asked to write a prescription for these. The physician and drug related components were analyzed following the WHO guidelines. The data were statistically analyzed using Chi-square test for 99% and 99.99% Confidence Intervals. P values < 0.01 and < 0.0001 were considered significant respectively. RESULTS: MBBS first year student scored 123 (82%) and 94 (62.66%) in physician and drug related component respectively. MBBS second year students scored 139 (92.66%) and 111 (73.33%) in physician and drug related components respectively. Results obtained from the element prescriber's address and telephone number, date of prescription and patient's address on the prescription of first year and second year medical students were highly significant (p<0.0001). CONCLUSIONS: Prescribing skill of first and second year MBBS students is not satisfactory. Prescribing deficiencies were found on both the physician and drug related components which emphasizes the need of adequate prescribing knowledge in order to minimize the prescription errors and irrational prescribing. Based on this study, we suggest all the undergraduate medical students should be regularly trained and evaluated to further help minimize the prescribing errors. PMID- 28029672 TI - Estimation of Stature from Nasal Length. AB - INTRODUCTION: Estimation of stature for the purpose of identification has a significant forensic importance. This technique is based on a principle that bones or human body parts correlate positively with the stature. Stature can be estimated from measurements of various body parts such as arm, leg, feet, finger, facial height, nasal height etc. The aim of study was to correlate Stature of Nepalese with Nasal height and estimate Stature from Nasal height. METHODS: A cross-sectional study of 214 healthy adults comprising 110 males and 104 females in the age group of 25 to 35 years were carried out. Study was carried out in central Nepal where people from various parts of Nepal are migrated. Total body height and Nasal height were recorded with stadiometer and sliding caliper respectively. RESULTS: The mean of total body height in the male and female was 160.4 (+/-6.80) cm and 151.8 (+/-4.88) cm respectively. The mean of nasal height in the male and female was 4.6 (+/-0.31) cm and 4.3 (+/-0.29) cm respectively. This study observed that in both male and female nasal height had positive partial correlation with stature; r = 0.18 for male and 0.19 for female. Stature in nepali population could be calculated as: Stature=148.22+3.02x nasal height in male where as Stature=133.01+3.12x nasal height in female. CONCLUSIONS: Both Nepali male and female nasal height had positive partial correlation with stature; r = 0.18 for male and 0.19 for female. Stature in Nepali population could be calculated as: Stature=148.22+3.02x nasal height in male where as Stature=133.01+3.12x nasal height in female. PMID- 28029673 TI - Histopathologic Analysis of Pancreaticoduodenectomy Specimen. AB - INTRODUCTION: Whipple's Pancreaticoduodenectomy has increasingly been used as an appropriate resectional procedure for tumors of the periampullary region which are pancreatic, periampullary, ampullary and biliary tumors. Our aim was to study the distribution and histopathologic features of these tumors and to examine local trends of periampullary neoplasms resected with a PD. METHODS: A descriptive study was conducted in the department of Pathology, Kathmandu Medical College Teaching Hospital from July 2013 to June 2016. RESULTS: Thirty five patients underwent Whipple's Pancreaticoduodenectomy procedure during a period of 36 months from July 2013 to June 2016. Malignant tumor was present in 31 (88.57%) cases where as four cases (11.43%) harboured benign lesions. Periampullary mixed carcinoma was the predominant tumor (34.28%) followed by periampullary duodenal (20%), ampullary (14.28%), pancreatic adenocarcinoma (11.42%) and distal cholangiocarcinoma (5.71%). There was no significant difference in tumor size among periampullary, ampullary, pancreatic and biliary carcinomas. Ampullary carcinomas were predominantly well differentiated (80%) where as the other tumors were mostly moderately differentiated. Lymphovascular and perineural invasion varied in different tumor types. Four pancreatic adenocarcinomas showed lymphovascular and perineural invasion. Adequate surgical margin clearance was achieved in most of the cases except in one case each of periampullary duodenal carcinoma and distal cholangiocarcinoma and two cases of pancreatic adenocarcinoma.. CONCLUSIONS: Pancreaticoduodenectomy specimen requires thorough histopathological evaluation. Pathologists should also be aware of possibility of a benign diagnosis in PD specimens which have been resected presuming malignancy based on clinical judgement and radiological data. PMID- 28029674 TI - Knowledge, Attitude and Practice on Hypertension Among Antihypertensive Medication Users. AB - INTRODUCTION: Hypertension is growing among the population of Nepal. We aimed to determine the current knowledge, attitude and practice of hypertension among hypertensive patients taking antihypertensive medication in the community of Central Nepal. METHODS: A cross-sectional study was conducted among the hypertensive patients in Bharatpur, Chitwan, Nepal from July 2015 to September 2015 using clustered sampling technique. Suitably designed and validated questionnaire of knowledge, attitude and practice on hypertension consisting of 27 questions were used to determine the KAP scores. The difference in the median KAP scores between sex, level of education and duration of hypertension were assessed using Mann-Whitney U test. RESULTS: A total of 200 patients met the inclusion criteria and majority of them were male (60%), had received primary education (36%) and had hypertension for >=5 years (46.5%). The blood pressure ranged from 100-180/60-110 mmHg. The median K, A and P scores were 8 (6), 5 (1) and 6 (3) respectively. K and A were statistically associated with sex both at p<0.001 and level of education (K at p<0.001 and A at p=0.016). CONCLUSIONS: The current knowledge, attitude and practice among hypertensive patients using antihypertensive medication can be improved. PMID- 28029675 TI - An Overview of Menopausal Symptoms in A District Hospital of Nepal. AB - INTRODUCTION: Menopause is a universal reproductive phenomenon which confirms the end of fertility of the women. The objectives of this study were to establish the age of natural menopause and to identify the prevalence of menopausal symptoms among the rural women attending district hospital of Nepal. METHODS: This present study is a hospital based, observational cross-sectional study conducted in Outpatient department of Lamjung District Hospital, Lamjung, Nepal. The study was carried out from January 2014 till June 2014. Fifty four menopausal women were included in the study. A structured questionnaire was used and the data were analyzed using statistical package for social sciences. RESULTS: There were 54 participants with menopausal symptoms included in the study. Age ranged from 45 to 60 years with mean 51.2 years. Approximately seventy percentages of women were in age group of above 50 years. About two-third of participants had menarche in at 11 to 13 years of age and 32 (59.5%) of females were married before 15 years of age. In the study total 22 different health problems were reported by menopausal women. The most common symptoms were backache, fatigue/tiredness, numbness and tingling of the extremities, mental exhaustion, depressive mood, bladder problems and sexual symptoms. CONCLUSIONS: The study suggests that rural middle-age and elderly women suffer from variety of health problems related to natural menopause. The health care workers should adopt a holistic approach towards management to improve the quality of life. PMID- 28029676 TI - A Carcinoid Tumor of the Esophagus Treated with Endoscopic Ablation Therapy. AB - Esophageal carcinoids are exceedingly rare and only a few limited cases have been reported. Because knowledge about esophageal carcinoid is based primarily on case reports, the treatment of choice has not been settled. We report here on a localized carcinoid tumor in the esophagogastric junction. As our initial biopsy was nearly equal for the excision, we only performed coagulation ablation therapy instead of a wide excision which is traditionally recommended. The patient is free of recurrence so far during 50-month follow-up. Our report suggests that esophageal carcinoids may be not particularly associated with a poor prognosis. PMID- 28029677 TI - An Interesting Case of Basal Cell Carcinoma with Raynaud's Phenomenon Following Chronic Arsenic Exposure. AB - Arsenic is commonly known to be associated with squamous cell carcinoma. Among the lesser known associations is basal cell carcinoma and even rarer is its effect on blood vessels causing peripheral vascular disease. Here we present a case of a 55 yr old man with ulceroproliferative lesions on scalp and forehead along with several hyperpigmented patches on trunk and extremities. He had symptoms suggestive of Raynaud's phenomenon that eventually led to digital gangrene. FNAC was done which was suggestive of basal cell carcinoma. On further enquiry, he was found to reside in an arsenic endemic zone and was investigated for blood arsenic level which was elevated. Punch biopsy from different lesions from body confirmed nodular basal cell carcinoma. Presently the patient has stopped drinking water from the local tubewell. On follow-up he shows improvement of Raynaud's phenomenon and skin lesions. PMID- 28029678 TI - Service Users' Involvement and Engagement in Interprofessional Care. AB - Interprofessional care is joint working between health care professionals by pooling their skills, knowledge and expertise, to make joint decisions and learn from each other for the benefits of service users and healthcare professionals. Service users involvement is considered as one of the important aspects of planning, management and decision making process in the delivery of health care to service users. Service users' involvement is not the same as public involvement and partnership arrangements in health care. The active involvement and engagement of service users in health care positively contributes to improve quality of care, to promote better health and to shape the future of health services. Service users are always at the centre of health care professionals' values, work ethics and roles. Moreover, service users centred interprofessional team collaboration is very important to deliver effective health services. PMID- 28029679 TI - USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice. AB - Stroke is associated with over-production of misfolded and aggregating proteins. However, it remains largely unclear whether enhanced removal of protein aggregates following ischemic stroke is neuroprotective. Deubiquitinating enzymes (DUBs) are a large group of proteases that regulate protein degradation. The ubiquitin-specific protease 14 (USP14) is a DUB that is associated with the proteasome and negatively regulates proteasome activity. In this study, we examined the effect of 1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2 pyrrolidin-1-ylethanone (IU1), a specific small molecule inhibitor of USP14, on mouse focal cerebral ischemic stroke-induced neuronal injury in mice. We found that IU1 treatment attenuated ischemic stroke-caused neuronal injury, which was reflected by increased survival rate, reduced infarct volume, as well as decreased neuronal loss in the IU1-treated mice compared to the control-treated mice. Additionally, IU1 treatment is associated with reduced protein aggregates and enhanced proteasome functionality. These data not only highlight the significance of protein homeostasis in cerebral ischemia/reperfusion-induced neuronal injury but also extend the therapeutic role of DUB inhibitors. PMID- 28029680 TI - The function of NOD-like receptors in central nervous system diseases. AB - NOD-like receptors (NLRs) are critical cytoplasmic pattern-recognition receptors (PRRs) that play an important role in the host innate immune response and immunity homeostasis. There is a growing body of evidence that NLRs are involved in a wide range of inflammatory diseases, including cancer, metabolic diseases, and autoimmune disorders. Recent studies have indicated that the proteins of the NLR family are linked with the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), and psychological diseases. In this review, we mainly focus on the role of NLRs and the underlying signaling pathways in central nervous system (CNS) diseases. (c) 2016 Wiley Periodicals, Inc. PMID- 28029681 TI - Recovery of pectoralis major and triceps brachii after bench press exercise. AB - INTRODUCTION: The present study evaluated and compared the recovery of pectoralis major (PM) and triceps brachii (TB) muscles of trained men after bench press exercise. METHODS: Eighteen volunteers performed eight sets of bench press exercise to momentary muscle failure and were evaluated for TB and PM peak torque and total work on an isokinetic dynamometer. RESULTS: PM peak torque and total work remained lower than baseline for 72 and 96 h, respectively. TB peak torque was only different from baseline immediately post training, while total work was significantly lower than baseline immediately and 48 h after training. Normalized peak torque values were only different between TB and PM at 48 h after training. CONCLUSIONS: Considering the small and nonsignificant difference between the recovery of TB and PM muscles, the results suggest that bench press exercise may promote a similar stress on these muscles. Muscle Nerve 56: 963-967, 2017. PMID- 28029682 TI - Isolated nerve plasmacytoma in a patient previously in systemic myeloma remission. PMID- 28029683 TI - Alopecia areata incognita in Cronkhite-Canada syndrome. AB - Cronkhite-Canada syndrome is an acquired inflammatory polyposis syndrome in which alopecia, onychomadesis and hyperpigmentation occur concurrently with gastrointestinal symptoms. The pathophysiology of alopecia in Cronkhite-Canada syndrome has not been definitively elucidated. We present evidence for alopecia areata incognita as a possible mechanism of hair loss. PMID- 28029684 TI - The effectiveness of interventions to enhance self-management support competencies in the nursing profession: a systematic review. AB - AIM: The aim of this study was to explore the effectiveness and effective components of training interventions to enhance nurses' competencies in self management support in chronic care. BACKGROUND: The growing burden of chronic diseases puts an increasing focus on nurses' self-management support of people living with a chronic illness. The most effective method to train nurses' competencies in self-management support remains unclear. DESIGN: Systematic literature review. DATA SOURCES: PubMed, CINAHL, Cochrane CENTRAL, EMBASE, Web of Science, ERIC and PsycARTICLES databases were searched up to August 2015. REVIEW METHOD: Eligible studies reported on training interventions to enhance chronic care self-management support competencies in nurses. Outcomes were defined as trainees' reactions to the training (level 1), changes in trainees' competencies (level 2) or changes in trainees' performance in practice (level 3) concerning self-management support. Risk of bias was assessed. Level 1 outcomes were synthesized narratively. Standardized mean differences were calculated per study for level 2 and 3 outcomes. RESULTS: In total, 25 studies were included. Twelve of these studies included level 1 outcomes, eight studies included level 2 outcomes and 10 studies included level 3 outcomes. Effect sizes in favour of training ranged from -0.36 - 1.56 (level 2) and from 0.06 - 5.56 (level 3). Theory-driven training interventions with time to practice, (video) feedback and follow-up generated the most training effects. Caution is needed due to the inconsistent study quality. CONCLUSION: To date, there is a knowledge gap concerning the most effective method to train nurses' competencies in self management support. More well-designed, longitudinal studies are needed. PMID- 28029685 TI - Immunoprofile of metaplastic carcinomas of the breast. AB - AIMS: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer; its diagnosis in routine practice can be challenging, and may require immunohistochemical (IHC) characterization if no conventional invasive or in-situ carcinoma is present. Previous IHC studies of MBC often had a small sample size and did not investigate the different histological subtypes. This study aimed to assess the immunoprofile of MBC subtypes in a large series. METHODS AND RESULTS: A total of 172 MBC diagnosed in routine and referral practice in Nottingham during 26 years were reviewed by three breast pathologists. In addition, data on the immunoprofile of 730 MBC in 61 published studies were analysed. The antibodies to a broad spectrum of cytokeratins (AE1/AE3 and MNF116) are most frequently positive in MBC (approximately 80%). Basal cytokeratins (34betaE12, CK5/6, CK14 and CK17) are positive in approximately 70%. Luminal cytokeratins (CK8/18, CK7 and CK19) are positive in approximately 30-60%. Myoepithelial markers are also frequently positive, particularly p63. Oestrogen receptor (ER), progestogen receptor (PR) and HER2 are usually all negative. CD34 (a marker often positive in phyllodes tumours) is consistently negative in MBC. CONCLUSION: This study provides data on the frequency of expression of a wide range of markers in MBC based on a large number of tumours. No consistent immunophenotype was identified and no individual marker was positive in all tumours, most probably reflecting the morphological and molecular heterogeneity of this tumour class and the practical need to use a panel of different antibodies when trying to establish the diagnosis of metaplastic breast carcinoma. PMID- 28029686 TI - Comparison of four different nerve conduction techniques of the superficial fibular sensory nerve. AB - INTRODUCTION: There are many different nerve conduction study (NCS) techniques to study the superficial fibular sensory nerve (SFSN). We present reference distal latency values and comparative data regarding 4 different NCS for the SFSN. METHODS: Four different NCS techniques, Spartan technique, Izzo techniques (medial and intermediate dorsal cutaneous branches), and Daube technique, were performed on (114) healthy volunteers. A total of 108 subjects with 164 legs were included. RESULTS: The mean latency of the Spartan technique was longest (3.9 +/- 0.3 ms) while the Daube technique was the shortest (3.6 +/- 0.7 ms). The mean amplitude of the Daube technique displayed the highest (15.2 +/- 8.2 MUV) with the Spartan technique having the lowest (8.7 +/- 4.2 MUV). Among the absent sensory nerve action potentials (SNAPs), the Spartan technique was absent only twice (1.2%) and the Izzo Medial technique was absent more than the other techniques (2.9%). CONCLUSIONS: All 4 techniques were reliable methods for obtaining the superficial fibular nerve SNAP, present in 95% of individuals. Muscle Nerve 56: 458-462, 2017. PMID- 28029687 TI - Age-related changes in mastication. AB - The paper reviews human mastication, focusing on its age-related changes. The first part describes mastication adaptation in young healthy individuals. Adaptation to obtain a food bolus ready to be swallowed relies on variations in number of cycles, muscle strength and volume of emitted saliva. As a result, the food bolus displays granulometric and rheological properties, the values of which are maintained within the adaptive range of deglutition. The second part concerns healthy ageing. Some mastication parameters are slightly modified by age, but ageing itself does not impair mastication, as the adaptation possibilities remain operant. The third part reports on very aged subjects, who display frequent systemic or local diseases. Local and/or general diseases such as tooth loss, salivary defect, or motor impairment are then indistinguishably superimposed on the effects of very old age. The resulting impaired function increases the risk of aspiration and choking. Lastly, the consequences for eating behaviour and nutrition are evoked. PMID- 28029688 TI - Combining Gait Speed and Recall Memory to Predict Survival in Late Life: Population-Based Study. AB - OBJECTIVES: To evaluate the relationship between gait speed, recall memory, and mortality. DESIGN: A cohort study (last follow-up December 2009). SETTING: Tuscany, Italy. PARTICIPANTS: Individual data from 1,014 community-dwelling older adults aged 60 years or older with baseline gait speed and recall memory measurements and follow-up for a median time of 9.10 (IQR 7.1;9.3) years. Participants were a mean (SD) age of 73.9 (7.3) years, and 55.8% women. Participants walking faster than 0.8 m/s were defined as fast walkers; good recall memory was defined as a score of 2 or 3 in the 3-word delayed recall section of the Mini-Mental State Examination. MEASUREMENTS: All-cause mortality. RESULTS: There were 302 deaths and the overall 100 person-year death rate was 3.77 (95% CI: 3.37-4.22). Both low gait speed and poor recall memory were associated with mortality when analysed separately (HR = 2.47; 95% CI: 1.87-3.27 and HR = 1.47; 95% CI: 1.16-1.87, respectively). When we grouped participants according to both recall and gait speed, death rates (100 person-years) progressively increased from those with both good gait speed and memory (2.0; 95% CI: 1.6-2.5), to those with fast walk but poor memory (3.4; 95% CI: 2.8-4.2), to those with slow walk and good memory (8.8; 95% CI: 6.4-12.1), to those with both slow walk and poor memory (13.0; 95% CI: 10.6-16.1). In multivariate analysis, poor memory significantly increases mortality risk among persons with fast gait speed (HR = 1.40; 95% CI: 1.04-1.89). CONCLUSION: In older persons, gait speed and recall memory are independent predictors of expected survival. Information on memory function might better stratify mortality risk among persons with fast gait speed. PMID- 28029689 TI - Identification of a stable complex between a [NiFe]-hydrogenase catalytic subunit and its maturation protease. AB - Salmonella enterica serovar Typhimurium has the ability to use molecular hydrogen as a respiratory electron donor. This is facilitated by three [NiFe]-hydrogenases termed Hyd-1, Hyd-2, and Hyd-5. Hyd-1 and Hyd-5 are homologous oxygen-tolerant [NiFe]-hydrogenases. A critical step in the biosynthesis of a [NiFe]-hydrogenase is the proteolytic processing of the catalytic subunit. In this work, the role of the maturation protease encoded within the Hyd-5 operon, HydD, was found to be partially complemented by the maturation protease encoded in the Hyd-1 operon, HyaD. In addition, both maturation proteases were shown to form stable complexes, in vivo and in vitro, with the catalytic subunit of Hyd-5. The protein-protein interactions were not detectable in a strain that could not make the enzyme metallocofactor. PMID- 28029690 TI - Myofibroblasts could be recruited in a chemokine (C-C motif) ligand 2-dependent manner in pathogenesis of oral submucous fibrosis. AB - BACKGROUND: Monocyte chemoattractant protein-1 (CCL2) is a major profibrotic mediator with a proven role in fibrosis of different organs of the body. Recently, increased fibrosis in oral submucous fibrosis (OSMF) is linked with betel quid-related chronic irritation and myofibroblast. Hence, this study is designed to investigate expression of CCL2 in OSMF and its correlation with myofibroblasts. MATERIALS AND METHODS: Paraffin-embedded specimens of 30 OSMF and 10 tissues of normal buccal mucosa were subjected to immunohistochemical analysis for CCL2 and alpha-smooth muscle actin (alpha-SMA) expression. RESULTS: CCL2 expression in basal cells (CCL2-B) and connective tissue (CCL2-CT), and alpha-SMA showed significantly increased expression in advanced OSMF as compared with early OSMF and controls. Significant differences were observed in the expression of CCL2-B between control vs. OSMF (P = 0.002), control vs. advanced OSMF (P = 0.005), and early vs. advanced OSMF (P = 0.0377). Similarly, differences in the CCL2-CT expression were statistically significant between control vs. OSMF (P = 0.00086), control vs. early OSMF (P = 0.02914), and control vs. advanced OSMF (P = 0.0006). For alpha-SMA expression, significant differences were observed between control vs. OSMF (P = 0.0003), control vs. early OSMF (P = 0.036), control vs. advanced OSMF (P = 0.00008), and early vs. advanced OSMF (P = 0.0009). In OSMF group, a significant correlation was observed between CCL2-B and CCL2-CT (P < 0.00001), CCL2-B and alpha-SMA (P < 0.00001), and CCL2-CT and alpha SMA (P < 0.00001). CONCLUSION: CCL2 could be responsible for pathogenesis of OSMF by recruiting myofibroblasts. PMID- 28029691 TI - Electrophysiological testing is correlated with myasthenia gravis severity. AB - INTRODUCTION: Electrophysiological studies play an important role in the diagnosis of myasthenia gravis (MG). The objectives of this study was to explore the correlation of jitter and decrement with various clinical symptoms and signs and disease severity. METHODS: We performed a retrospective chart review of 75 MG patients who attended the neuromuscular clinic from April 2013 to May 2014. We compared clinical characteristics between patients with high jitter (>100 us) and decrement (>10%), and patients with lower values to explore the correlations and optimal thresholds of jitter and decrement for different clinical features. RESULTS: High jitter and decrement values were associated with more severe disease, manifested by more frequent symptomatic bulbar and limb muscle weakness, more frequent ocular and limb muscle weakness on examination, higher quantitative MG score, and generalized disease. CONCLUSIONS: The yield of the electrophysiological assessment in MG extends beyond disease diagnosis and correlates with disease severity and the presence of generalized disease. Muscle Nerve 56: 445-448, 2017. PMID- 28029692 TI - Isoflavin-beta modifies muscle oxidative stress and prevents a thyrotoxicosis induced loss of muscle mass in rats. AB - INTRODUCTION: We sought to verify whether isoflavin-beta (Iso-beta), a mixture of isoflavones with antioxidant properties, could prevent thyrotoxicosis-induced loss of muscle mass and the participation of oxidative stress (OS) in the mechanisms of this prevention. METHODS: Two experimental periods of thyrotoxicosis induction were used in Wistar rats: 3 and 5 days to assess Iso beta effects before and after thyrotoxicosis-induced muscle wasting. After euthanasia, peritoneal fat and gastrocnemius muscle were collected, weighed, and muscle OS was assessed. RESULTS: Iso-beta prevented the loss of gastrocnemius mass in thyrotoxic rats through the prevention of muscle OS generation during thyrotoxicosis, increasing muscle total antioxidant capacity and decreasing mitochondrial cytochrome c oxidase activity, lipid peroxidation, and protein carbonyl content. CONCLUSION: Iso-beta decreased oxidative modification of proteins, which is known to exert a major role during proteolysis induction and is present in thyrotoxic myopathy, highlighting the potential action of Iso-beta in this complication of the disease. Muscle Nerve 56: 975-981, 2017. PMID- 28029693 TI - Reply to Cognitive Reserve: Predictor of Onset of Postoperative Delirium in Older Adults? PMID- 28029694 TI - Type-I interferons mediate the neuroinflammatory response and neurotoxicity induced by rotenone. AB - Evidence from post-mortem human brains, animal studies and cell culture models has implicated neuroinflammation in the aetiology of chronic neuropathologies including Alzheimer's and Parkinson's diseases. Although the neuroinflammatory response is considered detrimental in contributing to these pathologies, the underlying mechanisms are still not well understood. The type-I interferons (IFNs) have been well characterised in the periphery and are known to initiate/modulate the immune response. Recently, they have been implicated in ageing and we have also demonstrated increased type-I IFN expression in post mortem human Alzheimer's and Parkinson's disease brains. We hypothesise that the type-I IFNs are key drivers of the damaging, self-perpetuating pro-inflammatory response that contributes to these chronic neuropathologies. In support of this, we have recently confirmed in models of Alzheimer's and Parkinson's disease that mice lacking the type-I IFN receptor (IFNAR1), display an attenuated neuroinflammatory response with subsequent neuroprotection. To further investigate type-I IFN-mediated neuroinflammation and the specific CNS cell types involved, this study treated primary cultured wild-type and IFNAR1-/- neurons or mixed glia with the mitochondrial complex I inhibitor, rotenone. Wild-type neurons and glia treated with 3 nM and 25 nM rotenone, respectively, exhibited a pro-inflammatory response, including increased type-I IFN expression that was attenuated in cells lacking IFNAR1. Reduced type-I IFN signalling in IFNAR1-/- neurons also conferred protection against caspase-3-mediated rotenone-induced cell death. Further, this reduced pro-inflammatory response in the IFNAR1-/- glia subsequently diminished their neurotoxic effects to wild-type neurons. In support of this, we confirmed that therapeutically targeting the type-I IFN glial response to rotenone through a specific IFNAR1 blocking monoclonal antibody was neuroprotective. Our data has confirmed that both neurons and glia contribute to the pro-inflammatory response induced by rotenone with attenuation of this response beneficial in reducing neuronal cell death. Read the Editorial Comment for this article on page 9. PMID- 28029695 TI - Sense of Control in End-of-Life Decision-Making. AB - OBJECTIVES: To explore how older adults in the community with a limited life expectancy make healthcare decisions and the processes used when they are not in an acute crisis. DESIGN: Grounded theory. SETTING: Medical programs and geriatrics clinics at the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center. PARTICIPANTS: Community-dwelling adults aged 67 to 98 with a life expectancy of less than 1 year (N = 20). MEASUREMENTS: In-depth semistructured interviews in participants' homes. Constant comparative analysis was used to develop codes and identify themes. RESULTS: Participants generally delegated decisions to others, expressing their wishes by describing desired end-of-life outcomes and highlighting meaningful aspects of their lives. They did this in the belief that the delegate would make appropriate decisions on their behalf. In this way, participants were able to achieve a sense of control without being in control of decisions. Four themes emerged from the analysis that reflect the various approaches participants used to articulate their goals and maintain a sense of control: direct communication, third-party analogies, adaptive denial, and engaged avoidance. CONCLUSION: These findings challenge the prevailing view of personal autonomy. These older adults suggest a path to decision-making that focuses on priorities and goals, allowing them to take a more-passive approach to decision-making while still maintaining a sense of control. PMID- 28029696 TI - Vastus medialis and lateralis activity during voluntary and stimulated contractions. AB - INTRODUCTION: The purpose of this study was to investigate the relative activation of vastus medialis (VM) and vastus lateralis (VL) muscles during voluntary and stimulated isometric contractions at different joint angles. METHODS: Sixteen healthy men (mean age: 26 years) completed maximal voluntary and stimulated contractions of the knee extensor muscles at 30 degrees , 65 degrees , and 100 degrees of knee flexion. VM/VL ratios were calculated from voluntary electromyographic (EMG) and evoked torque recordings. RESULTS: Both EMG and VM/VL torque ratios were significantly lower at 30 degrees than at 100 degrees of knee flexion (P < 0.05). CONCLUSIONS: These results can be explained by the relatively small contribution of the VM muscle to knee extension torque at short muscle length. Such disadvantage of the VM muscle at extended knee positions does not seem to be compensated by an increased neural drive. Muscle Nerve 56: 968 974, 2017. PMID- 28029697 TI - Validation of the italian version of the 15-item Myasthenia Gravis Quality-of Life questionnaire. AB - INTRODUCTION: In this study we assess the Italian version of the 15-item Myasthenia Gravis Quality-of-Life questionnaire (MG-QOL15). METHODS: The validation protocol included the MG-QOL15, the 36-item Short Form (SF-36), the Besta Neurological Institute Rating Scale for Myasthenia Gravis, and the MG Composite. We used the Cronbach alpha to test reliability, the Spearman correlation to test short-term test-retest, the Kruskal-Wallis test to assess differences in MG-QOL15 between patients with different disease severity, and the Wilcoxon signed-rank test to assess sensitivity to change. RESULTS: Seventy-two patients were enrolled in the study. The mean MG-QOL15 score was 15.2 +/- 12.2, with alpha = 0.93 and test-retest correlation = 0.93. Compared with the SF-36, the MG-QOL15 was superior in differentiating patients with different MG types (P = 0.041) and severity (P = 0.004), showed higher sensitivity to change (P = 0.003 for improved and P = 0.024 for worsened patients), and had higher correlations with the MG-Composite (rho = 0.367 vs. -0.213 and -0.154). CONCLUSION: The Italian version of the MG-QOL15 is valid, reliable, stable, and sensitive to changes. Muscle Nerve 56: 716-720, 2017. PMID- 28029698 TI - Preventing Ectopic Pregnancy and its Complications - What Next? PMID- 28029699 TI - Early and Later Gestation Outcomes: Competing Risks Across the Pregnancy Continuum. PMID- 28029700 TI - Association between Caesarean Delivery and Childhood Asthma in India and Vietnam. AB - BACKGROUND: While there is evidence of an association between caesarean birth and increased asthma in children in high-income countries, it is unknown whether this association exists in low-to-middle-income countries (LMICs). We investigated whether children born through caesarean in India and Vietnam are at increased risk of caregiver-reported asthma by 8 years of age. METHODS: Data from an ongoing multi-national longitudinal cohort study (the Young Lives Study) in two LMICs (India n = 2026; Vietnam n = 2000) were used. Caregiver questionnaires captured information on caregiver-reported long-term respiratory problems such as asthma or wheeze at age 8 years, birth mode and a range of sociodemographic factors. Multivariable logistic regression models using propensity score adjustment were used to explore birth mode and asthma at age 8 years adjusted for a range of known confounders. RESULTS: Children delivered by caesarean in India (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3, 5.4) and Vietnam (OR 2.0, 95% CI 1.2, 3.3) had greater odds of asthma at age 8 years, after adjustment for other risk factors including wealth, liveborn parity, low birthweight, geographic location, cooking fuel used, livestock ownership, household size, housing quality and parental smoking. CONCLUSIONS: The study suggests that caesarean birth may be associated with an increased risk of childhood asthma in India and Vietnam. The underlying mechanisms of this finding need to be further elucidated. PMID- 28029701 TI - Paediatric and Perinatal Epidemiology: Where We Stand, and Where Are We Headed? PMID- 28029702 TI - Evaluation of a scoring system based on conformation factors to predict cranial cruciate ligament disease in Labrador Retrievers. AB - OBJECTIVE: To determine the association of a radiographic score derived from tibial plateau angle (TPA) and femoral anteversion (FAA) with an outcome of cranial cruciate ligament deficiency (CCLD) in large dogs. STUDY DESIGN: Cross sectional study. ANIMALS: 167 Labrador Retrievers. METHODS: Hind limbs of sound Labrador Retrievers over 6 years of age were considered at low risk for CCLD. Limbs were considered high risk for CCLD if they were affected or predisposed (sound contralateral limb in dogs with unilateral CCLD). The radiographic CCLD score was calculated for each limb. The TPA, FAA, and CCLD scores were compared between limbs of the same dog and between risk categories. A contingency table was used to evaluate the association of the CCLD score with the CCLD status of limbs. RESULTS: TPA, FAA, and CCLD scores were greater in limbs categorized as high risk for CCLD than in normal limbs. The sensitivity and specificity of the CCLD score was 87% and 79%, respectively. The positive predictive value was 69% and the negative predictive value was 92%. Scores were similar between paired right and left limbs, but did not agree for predicted status in 14/106 dogs. DISCUSSION: Our study supports an association between TPA, FAA, and CCLD in Labrador Retrievers. The negative predictive value of the CCLD score supports its application for screening dogs considered at low risk for CCLD. Positive CCLD scores should be interpreted with caution and the status of a dog may be undetermined if scores obtained on each limb disagree. PMID- 28029703 TI - The Sonographic Stenosis Index: A New Specific Quantitative Measure of Transplant Hepatic Arterial Stenosis. AB - OBJECTIVES: This study evaluates the sensitivity and specificity of stenosis index (SI), which accounts for the entire spectral Doppler waveform, to detect significant transplant hepatic arterial stenosis. MATERIALS AND METHODS: In this institutional review board-approved, HIPAA compliant study, we retrospectively analyzed 69 patients who had catheter angiography for suspected transplant hepatic arterial stenosis (THAS) between January 2006 and December 2010; all patients had Doppler ultrasound within 30 days before angiography. Patients with angiographic stenosis requiring intervention were considered positive for THAS. Stenosis index was calculated from each patient's spectral Doppler ultrasound images by obtaining the ratio of the area under the high-frequency signal to low frequency signal in the spectral Doppler. Resistive index (RI) and pulsatility index (PI) were also calculated. Receiver operator curve analysis was performed and the area under the curve (AUC) was compared among the three metrics. RESULTS: Forty-eight of 69 patients had THAS by angiography requiring intervention; 21patients had no angiographic evidence of THAS. SI was significantly different (P < .001) between patients with THAS (SI = 1.04 +/- 0.20) and those without THAS (SI = 1.39 +/- 0.30). Stenosis index had an AUC of 0.86 for detecting THAS, which was significantly higher than that from RI (AUC = 0.68, P = .038 for the comparison) and PI (AUC = 0.70, P = .029). For SI < 1.35, the sensitivity for THAS was 94% and specificity was 52%. For RI < 0.5, the sensitivity was 96% and the specificity was 29%. CONCLUSIONS: Stenosis index is more accurate than the resistive index and the pulsatility index for detecting transplant hepatic artery stenosis. PMID- 28029704 TI - Dynamic mislocalizations of nuclear pore complex proteins after focal cerebral ischemia in rat. AB - Nuclear pore complexes (NPCs) play an important role in coordinating the transport of proteins and nucleic acids between the nucleus and cytoplasm, and are therefore essential for maintaining normal cellular function and liability. In the present study, we investigated the temporal immunohistochemical distribution of five representative components of NPCs-Ran GTPase-activating protein 1 (RanGap1), glycoprotein-210 (Gp210), nucleoporin 205 (Nup205), nucleoporin 107 (Nup107), and nucleoporin 50 (Nup50)-after 90 min of transient middle cerebral artery occlusion (tMCAO) up to 28 days after the reperfusion in rat brains. Single immunohistochemical analyses showed ring-like stainings along the periphery of the nucleus in sham control brains. After tMCAO, Gp210 and Nup107 immunoreactivity continuously increased from 1 day, and RanGap1, Nup205, and Nup50 increased from 2 days until 28 days, which also displayed progressive precipitations within the nucleus in the peri-ischemic area, while the ischemic core showed scarce expression with collapsed structure. Double immunofluorescent analyses revealed nuclear retention and apparent colocalization of RanGap1 with Nup205, Gp210 with Nup205, and partial colocalization of Nup205 with Nup107; most of the ischemic changes above were similar to those observed in patients with C9orf72-genetic amyotrophic lateral sclerosis. Taken together, these observations suggest that the mislocalization of these nucleoporins may be a common pathogenesis of both ischemic and neurodegenerative disease. (c) 2016 Wiley Periodicals, Inc. PMID- 28029705 TI - Cardiometabolic health and risk of amyotrophic lateral sclerosis. AB - INTRODUCTION: Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. METHODS: The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. RESULTS: ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P < 0.05) and more men with a normal body mass index than in the general population (47.2%, P < 0.001). The percentage of individuals who had never smoked was greater for the ALS cohort (55.8%, P <= 0.001), and the prevalence of dyslipidemia was lower (38.7%) compared with the general population (74.4%, P < 0.001). CONCLUSION: ALS patients had good cardiometabolic health, with evidence of a reduced vascular risk profile. Muscle Nerve 56: 721-725, 2017. PMID- 28029707 TI - Cognitive Reserve: Predictor of Onset of Postoperative Delirium in Older Adults? PMID- 28029708 TI - Comparison of maximum force to failure of 4 thoracostomy tube connecting devices. AB - OBJECTIVE: To compare the maximum force and displacement to failure of 4 different types of thoracostomy tube connecting devices. STUDY DESIGN: Experimental in vitro study. STUDY POPULATION: Four types of thoracostomy tube connecting devices (n = 10 each). METHODS: Four different connecting device configurations (10 constructs each) were tested by maximum distraction to failure using a dynamometer: (1) CTTWW-a 3-way connector with a male luer slip attached to a thoracostomy tube by a Christmas tree adapter and secured to the tube with 21 gauge orthopedic wire; (2) CTTWRCW-a 3-way connector with a male luer lock with a rotating collar attached to a tube by a Christmas tree adapter and secured to the tube with 21 gauge orthopedic wire; (3) LVSBC-a Lopez valve attached to a tube with its short-barbed connector; and (4) LVLBC-a Lopez valve attached to a tube with its long-barbed connector. RESULTS: The maximum distraction force to failure was significantly greater for CTTWRCW (250.9 N; range 143.7-293.6) than CTTWW (132.9 N; range 84.2-224.1), LVLBC (90.8 N; range 74.0-123.4), and LVSBC (54.6 N; range 39.6-164.2). The median displacement to failure of CTTWRCW (150 mm; range 54-190) was significantly longer than that of CTTWW (34.5 mm; range 22 70), LVLBC (32.5 mm; range 24-57), and LVSBC (16 mm; range 11-69). CONCLUSION: The CTTWRCW group required greater force to create failure and had a longer displacement to failure, making it a more secure choice for connection to thoracostomy tubes. PMID- 28029706 TI - Morphological brain measures of cortico-limbic inhibition related to resilience. AB - Resilience is the ability to adequately adapt and respond to homeostatic perturbations. Although resilience has been associated with positive health outcomes, the neuro-biological basis of resilience is poorly understood. The aim of the study was to identify associations between regional brain morphology and trait resilience with a focus on resilience-related morphological differences in brain regions involved in cortico-limbic inhibition. The relationship between resilience and measures of affect were also investigated. Forty-eight healthy subjects completed structural MRI scans. Self-reported resilience was measured using the Connor and Davidson Resilience Scale. Segmentation and regional parcellation of images was performed to yield a total of 165 regions. Gray matter volume (GMV), cortical thickness, surface area, and mean curvature were calculated for each region. Regression models were used to identify associations between morphology of regions belonging to executive control and emotional arousal brain networks and trait resilience (total and subscales) while controlling for age, sex, and total GMV. Correlations were also conducted between resilience scores and affect scores. Significant associations were found between GM changes in hypothesized brain regions (subparietal sulcus, intraparietal sulcus, amygdala, anterior mid cingulate cortex, and subgenual cingulate cortex) and resilience scores. There were significant positive correlations between resilience and positive affect and negative correlations with negative affect. Resilience was associated with brain morphology of regions involved in cognitive and affective processes related to cortico-limbic inhibition. Brain signatures associated with resilience may be a biomarker of vulnerability to disease. (c) 2016 Wiley Periodicals, Inc. PMID- 28029709 TI - Increasing Role of Nurse Practitioners in House Call Programs. AB - OBJECTIVES: Residence-based primary care provides homebound frail patients with a care plan that is individually tailored to manage multiple chronic conditions and functional limitations using a variety of resources. We (1) examine the visit volume and Medicare payments for residence-based health care provided by nurse practitioners (NPs) in the Medicare fee-for-service environment; (2) compare NP's residential visits to those of internists and family physicians; and (3) compare the geographical service area of full-time house call NPs versus NPs who make nursing facility visits a major portion of their work. DESIGN: An observational study using secondary data. SETTING: Medicare Provider Utilization and Payment Data. PARTICIPANTS: Medicare beneficiaries. MEASUREMENTS: Medicare payments for home and domiciliary care visits, the number of residence-based medical visits, provider volume, geographical distribution of full-time house call providers. RESULTS: About 3,300 NPs performed over 1.1 million home and domiciliary care visits in 2013, accounting for 22% of all residential visits to Medicare fee-for service beneficiaries. A total of 310 NPs individually made more than 1,000 residential visits (defined as a full-time house call provider); among full-time house call providers, including physicians, NPs are now the most common provider type. There are substantial variations in the geographic distribution of full time house call NPs, internists, and family physicians. Full time NP's service area is about 30% larger than family physicians and internists. Nursing home residents are far more likely to receive NP visits than are homebound persons receiving home visits. CONCLUSION: NPs are now the largest type of provider delivering residence-based care and NPs provide care over the largest geographical service area. However, the vast majority of frail Americans are more likely to receive NP's care in a nursing facility versus at home. PMID- 28029710 TI - Facilitators' delivery of a psychosocial intervention in a controlled trial for men with prostate cancer and their partners: a process evaluation. AB - AIM: The aim of this paper was to report the process evaluation of facilitators' delivery of a psychosocial intervention (called CONNECT), in a randomized controlled trial, to men with prostate cancer and their partners. BACKGROUND: There is a lack of information on the process of implementing psychosocial interventions in controlled trials and, in particular, on the role and performance of facilitators who deliver them. Yet, this information is crucial in assessing whether these interventions are effective or not and why. DESIGN: Qualitative design. METHODS: Semi-structured qualitative interviews and diaries were used to collect data (January-October 2012) from four facilitators and a co facilitator. Data were analysed using the Miles et al. FRAMEWORK: RESULTS: Five themes were discernible. These were 'difficulties to keep to the structure of the intervention', 'selective coverage of topics', 'partner participation', 'overall impression of the group and telephone sessions' and 'perceived benefits to participants'. Issues such as not keeping to the aim of the intervention, deviating from the content and/or reluctance in discussing sensitive issues such as sexual health may mean that the psychosocial effects of the intervention may not have been fully realized. CONCLUSIONS: These findings will be useful for further development and evaluation of the intervention. A tentative conceptual framework of factors, related to facilitators, influencing the fidelity of interventions in the context of controlled trials, is offered. This model, which requires further development and testing, will be useful for researchers worldwide who are involved in developing interventions and training facilitators. PMID- 28029711 TI - The complex interplay between macronutrient intake, cuticular hydrocarbon expression and mating success in male decorated crickets. AB - The condition dependence of male sexual traits plays a central role in sexual selection theory. Relatively little, however, is known about the condition dependence of chemical signals used in mate choice and their subsequent effects on male mating success. Furthermore, few studies have isolated the specific nutrients responsible for condition-dependent variation in male sexual traits. Here, we used nutritional geometry to determine the effect of protein (P) and carbohydrate (C) intake on male cuticular hydrocarbon (CHC) expression and mating success in male decorated crickets (Gryllodes sigillatus). We show that both traits are maximized at a moderate-to-high intake of nutrients in a P:C ratio of 1 : 1.5. We also show that female precopulatory mate choice exerts a complex pattern of linear and quadratic sexual selection on this condition-dependent variation in male CHC expression. Structural equation modelling revealed that although the effect of nutrient intake on mating success is mediated through condition-dependent CHC expression, it is not exclusively so, suggesting that other traits must also play an important role. Collectively, our results suggest that the complex interplay between nutrient intake, CHC expression and mating success plays an important role in the operation of sexual selection in G. sigillatus. PMID- 28029712 TI - Caregiver, patient, and nurse visit communication patterns in cancer home hospice. AB - OBJECTIVE: Few studies have examined the triadic communication between patients, spouse caregivers, and nurses in the home hospice setting. Thus, little is known about the types of communication patterns that unfold. The goals of the study were to, first, identify common patterns of communication in nurse-patient caregiver home hospice visits and, second, to identify nurse, caregiver-patient dyad, and visit characteristics that predict visit communication patterns. METHOD: Nurses (N = 58) and hospice cancer patient and spouse caregiver dyads (N = 101; 202 individuals) were recruited from 10 hospice agencies. Nurses audio recorded visits to patient/caregiver homes from study enrollment until patient death. All patient, caregiver, and nurse utterances from the audio recordings were coded using an adapted Roter interaction analysis system. Using identified codes, cluster analysis was conducted to identify communication patterns within hospice visits. Logistic regression was used with demographic variables to predict visit communication patterns. RESULTS: Six visit communication patterns were identified and were defined largely by 2 dimensions: (1) either the patient, the caregiver, or the patient and caregiver dyad interacting with the nurse and (2) the relatively high or low expression of distress during the visit. Time until death significantly predicted several clusters. CONCLUSION: This study leads the way in outlining triadic communication patterns in cancer home hospice visits. Our findings have implications for nursing education, letting future nurses know what to expect, and lays the foundation for future research to determine effectiveness and interventions to improve health care communication. PMID- 28029713 TI - Population genomic analyses reveal a history of range expansion and trait evolution across the native and invaded range of yellow starthistle (Centaurea solstitialis). AB - Identifying sources of genetic variation and reconstructing invasion routes for non-native introduced species is central to understanding the circumstances under which they may evolve increased invasiveness. In this study, we used genome-wide single nucleotide polymorphisms to study the colonization history of Centaurea solstitialis in its native range in Eurasia and invasions into the Americas. We leveraged this information to pinpoint key evolutionary shifts in plant size, a focal trait associated with invasiveness in this species. Our analyses revealed clear population genomic structure of potential source populations in Eurasia, including deep differentiation of a lineage found in the southern Apennine and Balkan Peninsulas and divergence among populations in Asia, eastern Europe and western Europe. We found strongest support for an evolutionary scenario in which western European populations were derived from an ancient admixture event between populations from eastern Europe and Asia, and subsequently served as the main genetic 'bridgehead' for introductions to the Americas. Introductions to California appear to be from a single source region, and multiple, independent introductions of divergent genotypes likely occurred into the Pacific Northwest. Plant size has evolved significantly at three points during range expansion, including a large size increase in the lineage responsible for the aggressive invasion of the California interior. These results reveal a long history of colonization, admixture and trait evolution in C. solstitialis, and suggest routes for improving evidence-based management decisions for one of the most ecologically and economically damaging invasive species in the western United States. PMID- 28029714 TI - Enantioselective Catalysis by Using Short, Structurally Defined DNA Hairpins as Scaffold for Hybrid Catalysts. AB - A new type of DNA metal complex hybrid catalyst, which is based on single stranded DNA oligonucleotides, is described. It was shown that oligonucleotides as short as 14 nucleotides that fold into hairpin structures are suitable as nucleic acid components for DNA hybrid catalysts. With these catalysts, excellent enantioinduction in asymmetric Diels-Alder reactions with selectivity values as high as 96 % enantiomeric excess (ee) can be achieved. Molecular dynamics simulations indicate that a rather flexible loop combined with a rigid stem region provides DNA scaffolds with these high selectivity values. PMID- 28029715 TI - The association of antidepressant drug usage with cognitive impairment or dementia, including Alzheimer disease: A systematic review and meta-analysis. AB - OBJECTIVE: To determine if antidepressant drug usage is associated with cognitive impairment or dementia, including Alzheimer disease (AD). METHOD: We conducted a systematic search of Medline, PubMed, PsycINFO, Web of Science, Embase, CINAHL, and the Cochrane Library. An initial screen by abstracts and titles was performed, and relevant full articles were then reviewed and assessed for their methodologic quality. Crude effect estimates were extracted from the included articles and a pooled estimate was obtained using a random effects model. RESULTS: Five articles were selected from an initial pool of 4,123 articles. Use of antidepressant drugs was associated with a significant twofold increase in the odds of some form of cognitive impairment or dementia (OR = 2.17). Age was identified as a likely modifier of the association between antidepressant use and some form of cognitive impairment or AD/dementia. Studies that included participants with an average age equal to or greater than 65 years showed an increased odds of some form of cognitive impairment with antidepressant drug usage (OR = 1.65), whereas those with participants less than age 65 revealed an even stronger association (OR = 3.25). CONCLUSIONS: Antidepressant drug usage is associated with AD/dementia and this is particularly evident if usage begins before age 65. This association may arise due to confounding by depression or depression severity. However, biological mechanisms potentially linking antidepressant exposure to dementia have been described, so an etiological effect of antidepressants is possible. With this confirmation that an association exists, clarification of underlying etiologic pathways requires urgent attention. PMID- 28029716 TI - Inactivation of human coagulation factor X by a protease of the pathogen Capnocytophaga canimorsus. AB - : Essentials Capnocytophaga canimorsus causes severe dog bite related blood stream infections. We investigated if C. canimorsus contributes to bleeding abnormalities during infection. The C. canimorsus protease CcDPP7 causes factor X dysfunction by N-terminal cleavage. CcDPP7 inhibits coagulation in vivo, which could promote immune evasion and trigger hemorrhage. SUMMARY: Background Capnocytophaga canimorsus is a Gram-negative bacterium that is present in the oral flora of dogs and causes fulminant sepsis in humans who have been bitten, licked, or scratched. In patients, bleeding abnormalities, such as petechiae, purpura fulminans, or disseminated intravascular coagulation (DIC), occur frequently. Objective To investigate whether C. canimorsus could actively contribute to these bleeding abnormalities. Methods Calibrated automated thrombogram and clotting time assays were performed to assess the anticoagulant activity of C. canimorsus 5 (Cc5), a strain isolated from a fatal human infection. Clotting factor activities were measured with factor-deficient plasma. Factor X cleavage was monitored with the radiolabeled zymogen and western blotting. Mutagenesis of Cc5 genes encoding putative serine proteases was performed to identify the protease that cleaves FX. Protein purification was performed with affinity chromatography. Edman degradation allowed the detection of N-terminal cleavage of FX. Tail bleeding times were measured in mice. Results We found that Cc5 inhibited thrombin generation and increased the prothrombin time and the activated partial thromboplastin time of human plasma via FX cleavage. A mutant that was unable to synthesize a type 7 dipeptidyl peptidase (DPP7) of the S46 serine protease family failed to proteolyse FX. The purified protease (CcDPP7) cleaved FX heavy and light chains from the N-terminus, and was active in vivo after intravenous injection. Conclusions This is, to our knowledge, the first study demonstrating a detailed mechanism for FX inactivation by a bacterial protease, and it is the first functional study associating DPP7 proteases with a potentially pathogenic outcome. PMID- 28029717 TI - Time course of gamma-band oscillation associated with face processing in the inferior occipital gyrus and fusiform gyrus: A combined fMRI and MEG study. AB - Debate continues over whether the inferior occipital gyrus (IOG) or the fusiform gyrus (FG) represents the first stage of face processing and what role these brain regions play. We investigated this issue by combining functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in normal adults. Participants passively observed upright and inverted faces and houses. First, we identified the IOG and FG as face-specific regions using fMRI. We applied beamforming source reconstruction and time-frequency analysis to MEG source signals to reveal the time course of gamma-band activations in these regions. The results revealed that the right IOG showed higher gamma-band activation in response to upright faces than to upright houses at 100 ms from the stimulus onset. Subsequently, the right FG showed greater gamma-band response to upright faces versus upright houses at around 170 ms. The gamma-band activation in the right IOG and right FG was larger in response to inverted faces than to upright faces at the later time window. These results suggest that (1) the gamma-band activities occurs rapidly first in the IOG and next in the FG and (2) the gamma band activity in the right IOG at later time stages is involved in configuration processing for faces. Hum Brain Mapp 38:2067-2079, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28029718 TI - A SMART data analysis method for constructing adaptive treatment strategies for substance use disorders. AB - AIMS: To demonstrate how Q-learning, a novel data analysis method, can be used with data from a sequential, multiple assignment, randomized trial (SMART) to construct empirically an adaptive treatment strategy (ATS) that is more tailored than the ATSs already embedded in a SMART. METHOD: We use Q-learning with data from the Extending Treatment Effectiveness of Naltrexone (ExTENd) SMART (N = 250) to construct empirically an ATS employing naltrexone, behavioral intervention, and telephone disease management to reduce alcohol consumption over 24 weeks in alcohol dependent individuals. RESULTS: Q-learning helped to identify a subset of individuals who, despite showing early signs of response to naltrexone, require additional treatment to maintain progress. CONCLUSIONS: Q-learning can inform the development of more cost-effective, adaptive treatment strategies for treating substance use disorders. PMID- 28029719 TI - Intimate partner violence screening in emergency department: a rapid review of the literature. AB - AIMS AND OBJECTIVES: The aim of the review was to identify intimate partner violence screening interventions used in emergency departments and to explore factors affecting intimate partner violence screening in emergency departments. BACKGROUND: Intimate partner violence against women is now clearly recognised as a global health and societal issue. Nurses working in emergency and urgent care settings can play a crucial role in identification, prevention and management of intimate partner violence. Research exploring optimal methods of intimate partner violence screening and factors affecting intimate partner violence screening in emergency departments are relatively limited. DESIGN: Literature review: Rapid Evidence Synthesis. METHODS: Literature published between 2000-2015 was reviewed using the principles of rapid evidence assessment. Six electronic databases: CINAHL, MEDLINE, EMBASE, Psych Info, the Cochrane Library and Joanna Briggs Library. RESULTS: Twenty-nine empirical studies meeting the eligibility criteria were independently assessed by two authors using appropriate Critical Appraisal Skills Programme Checklists. Intimate partner violence screening in emergency departments is usually performed using electronic, face to face or pen- and paper based instruments. Routine or universal screening results in higher identification rates of intimate partner violence. Women who screen positive for intimate partner violence in emergency departments are more likely to experience abuse in subsequent months. Factors that facilitate partner violence screening can be classified as healthcare professionals related factors, organisational factors and patient-related factors. CONCLUSIONS: Emergency departments provide a unique opportunity for healthcare professionals to screen patients for intimate partner violence. Competence in assessing the needs of the patients appears to be a very significant factor that may affect rates of intimate partner violence disclosure. RELEVANCE TO CLINICAL PRACTICE: Knowledge of appropriate domestic violence screening methods and factors affecting intimate partner violence screening in emergency can help nurses, and other healthcare professionals provide patient-centred and effective care to victims of abuse attending emergency department. PMID- 28029720 TI - Genetic patterns across an invasion's history: a test of change versus stasis for the Eurasian round goby in North America. AB - Biological invasions comprise accidental evolutionary experiments, whose genetic compositions underlie relative success, spread and persistence in new habitats. However, little is known about whether, or how, their population genetic patterns change temporally and/or spatially across the invasion's history. Theory predicts that most would undergo founder effect, exhibit low genetic divergence across the new range and gain variation over time via new arriving propagules. To test these predictions, we analyse population genetic diversity and divergence patterns of the Eurasian round goby Neogobius melanostomus across the two decades of its North American invasion in the Laurentian Great Lakes, comparing results from 13 nuclear DNA microsatellite loci and mitochondrial DNA cytochrome b sequences. We test whether 'genetic stasis', 'genetic replacement' and/or 'genetic supplement' scenarios have occurred at the invasion's core and expansion sites, in comparison with its primary native source population in the Dnieper River, Black Sea. Results reveal pronounced genetic divergence across the exotic range, with population areas remaining genetically distinct and statistically consistent across two decades, supporting 'genetic stasis' and 'founder takes most'. The original genotypes continue to predominate, whose high population growth likely outpaced the relative success of later arrivals. The original invasion core has stayed the most similar to the native source. Secondary expansion sites indicate slight allelic composition convergence towards the core population over time, attributable to some early 'genetic supplementation'. The geographic and temporal coverage of this investigation offers a rare opportunity to discern population dynamics over time and space in context of invasion genetic theory vs. reality. PMID- 28029721 TI - Risk of depression following uterine cancer: A nationwide population-based study. AB - BACKGROUND: Depression happens commonly in cancer patients. However, there is limited literature on uterine cancer. In this study, we aimed to evaluate the association between uterine cancer and depression as well as the moderating effect of age and hormone replacement therapy (HRT). METHODS: This was a population-based study using Taiwan's National Health Insurance Research Database. We conducted a matched cohort study and identified 6526 patients with uterine cancer and 65 260 controls. We adopted the competing risk analysis model as the statistical method and adjusted for potential confounding factors. RESULTS: From 1997 to 2008, 71 786 patients were included (6526 patients with uterine cancer and 65 260 controls). In the study, uterine cancer was not linked to depression. However, when we stratified the different age groups, those cancer patients aged <40 and 40 to 49 years showed significant higher risk of developing depression (subdistribution hazard ratio 1.64 and 1.41, respectively). In addition, among uterine cancer patients, 4602 patients had never used HRT and 1921 patients were prescribed HRT. The analysis of time-dependent Cox model showed that, compared with no use of HRT, patients with cumulative doses >=168 DDD had significant lower risk of depression (hazard ratio 0.49, 95% confidence interval = 0.26-0.92). CONCLUSIONS: An increased risk of depression among younger uterine cancer patients was observed. Our preliminary finding suggests a possible protective factor for developing depression after HRT usage. PMID- 28029722 TI - Taste function assessed by electrogustometry in burning mouth syndrome: a case control study. AB - OBJECTIVE: Idiopathic burning mouth syndrome (iBMS) is characterized by oral persistent pain without any clinical or biological abnormality. The aim of this study was to evaluate taste function in iBMS subjects and healthy controls. MATERIAL AND METHODS: Electrogustometric thresholds (EGMt) were recorded in 21 iBMS patients and 21 paired-matched controls at nine loci of the tongue assessing fungiform and foliate gustatory papillae function. Comparison of EGMt was performed using the nonparametric Wilcoxon signed-rank test. A correlation between EGMt and self-perceived pain intensity assessed using a visual analogic scale (VAS) was analyzed with the Spearman coefficient. The level of significance was fixed at P < 0.05. RESULTS: Mean EGMt were significantly increased with iBMS for right side of the dorsum of the tongue and right lateral side of the tongue (P < 0.05). In the iBMS group, VAS scores were significantly correlated to EGMt at the tip of the tongue (r = -0.59; P < 0.05) and at the right and left lateral sides of the tongue (respectively, r = -0.49 and r = -0.47; P < 0.05). CONCLUSION: These data depicted impaired taste sensitivity in iBMS patients within fungiform and foliate taste bud fields and support potent gustatory/nociceptive interaction in iBMS. PMID- 28029723 TI - Sensory trait variation contributes to biased dispersal of threespine stickleback in flowing water. AB - Gene flow is widely thought to homogenize spatially separate populations, eroding effects of divergent selection. The resulting theory of 'migration-selection balance' is predicated on a common assumption that all genotypes are equally prone to dispersal. If instead certain genotypes are disproportionately likely to disperse, then migration can actually promote population divergence. For example, previous work has shown that threespine stickleback (Gasterosteus aculeatus) differ in their propensity to move up- or downstream ('rheotactic response'), which may facilitate genetic divergence between adjoining lake and stream populations of stickleback. Here, we demonstrate that intraspecific variation in a sensory system (superficial neuromast lines) contributes to this variation in swimming behaviour in stickleback. First, we show that intact neuromasts are necessary for a typical rheotactic response. Next, we showed that there is heritable variation in the number of neuromasts and that stickleback with more neuromasts are more likely to move downstream. Variation in pectoral fin shape contributes to additional variation in rheotactic response. These results illustrate how within-population quantitative variation in sensory and locomotor traits can influence dispersal behaviour, thereby biasing dispersal between habitats and favouring population divergence. PMID- 28029724 TI - The role of the breast care nurse in patient and family care. AB - AIMS AND OBJECTIVES: To describe the role of the breast care nurse in caring for patients and families. BACKGROUND: The breast care nurse is an expert clinical nurse who plays a significant role in the care of women/men and their families with breast cancer. The role of these nurses has expanded since the 1990s in Australia. DESIGN: Descriptive study. METHODS: An online survey was sent to breast care nurses using peak body databases (n = 100). The survey consisted of nineteen nurse roles and functions from a previous Delphi technique study. Nurses rated the importance and frequency of role elements using a five-point Likert scale and four open-ended questions relating to role. RESULTS: There were 89 respondents. Most of the sample were from remote (n = 37, 41%) and rural areas (n = 47, 52%). The majority of responses regarding importance and frequency of the BCN role had a mean score above 4, which corresponds to 'moderately important' and 'occasionally as needed'. There were significant differences between the level of importance and frequency on 10 items. Four role themes arose from the thematic analysis: Breast care nurses as patient advocates, patient educators, care coordinators and clinical experts. CONCLUSIONS: This study delineated the important nurses role in caring for patients and families during a critical time of their life. Further, it details the important nursing roles and functions undertaken by these nurses and compared this to the frequency with which these nurses perform these aspects of their role. RELEVANCE TO CLINICAL PRACTICE: This study further delineates the important role that the nurses play in caring for patients and families during a critical time of their life. It extends further the frequency and importance of the supportive care and the need to educate their nurses on their role in providing spiritual care and research. PMID- 28029726 TI - A novel strategy for diagnosing viral vs bacterial infection: implications for oral diseases. PMID- 28029727 TI - Building nurses' capacity to address health inequities: incorporating lesbian, gay, bisexual and transgender health content in a family nurse practitioner programme. AB - AIMS AND OBJECTIVES: To describe our experience in incorporating lesbian, gay, bisexual and transgender health content into the family nurse practitioner curriculum at a Midwestern college of nursing in the United States. BACKGROUND: Globally, lesbian, gay, bisexual and transgender people face disparities in the domains of physical health, behavioural risks, mental health and victimisation. There remains a paucity of nursing research on most aspects of lesbian, gay, bisexual and transgender health and access to care. To date, nursing leadership and curricular bodies have not provided clear guidance on the role of nurse educators in preparing nursing students to provide care to lesbian, gay, bisexual and transgender people. DESIGN: Discursive paper describing the development of a lesbian, gay, bisexual and transgender health learning module for inclusion in a family nurse practitioner programme. METHODS: We summarise health disparities experienced by lesbian, gay, bisexual and transgender people, describe the process of module development and outline the learning content included in the module. We also discuss challenges faced in incorporating lesbian, gay, bisexual and transgender content into nursing curricula. CONCLUSIONS: Despite the lack of formal direction from the nursing sector, nursing faculty should prepare nursing students to provide culturally sensitive and competent care to lesbian, gay, bisexual and transgender people. Our experience incorporating lesbian, gay, bisexual and transgender-specific content into the family nurse practitioner programme has proven to be positive for both students and faculty. RELEVANCE TO CLINICAL PRACTICE: Given their large numbers and presence across systems of care, nurses are uniquely positioned to address barriers to care faced by lesbian, gay, bisexual and transgender people. Modules such as the one described here can be used by nurse faculty to guide the inclusion of lesbian, gay, bisexual and transgender-specific content in family nurse practitioner or other nursing courses-as well as to guide the development of nursing competencies in the care of lesbian, gay, bisexual and transgender people. PMID- 28029725 TI - Epicenters of dynamic connectivity in the adaptation of the ventral visual system. AB - OBJECTIVES AND DESIGN: Neuronal responses adapt to familiar and repeated sensory stimuli. Enhanced synchrony across wide brain systems has been postulated as a potential mechanism for this adaptation phenomenon. Here, we used recently developed graph theory methods to investigate hidden connectivity features of dynamic synchrony changes during a visual repetition paradigm. Particularly, we focused on strength connectivity changes occurring at local and distant brain neighborhoods. PRINCIPAL OBSERVATIONS: We found that connectivity reorganization in visual modal cortex-such as local suppressed connectivity in primary visual areas and distant suppressed connectivity in fusiform areas-is accompanied by enhanced local and distant connectivity in higher cognitive processing areas in multimodal and association cortex. Moreover, we found a shift of the dynamic functional connections from primary-visual-fusiform to primary multimodal/association cortex. CONCLUSIONS: These findings suggest that repetition-suppression is made possible by reorganization of functional connectivity that enables communication between low- and high-order areas. Hum Brain Mapp 38:1965-1976, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28029728 TI - Tyramine Hydrochloride Based Label-Free System for Operating Various DNA Logic Gates and a DNA Caliper for Base Number Measurements. AB - DNA is believed to be a promising candidate for molecular logic computation, and the fluorogenic/colorimetric substrates of G-quadruplex DNAzyme (G4zyme) are broadly used as label-free output reporters of DNA logic circuits. Herein, for the first time, tyramine-HCl (a fluorogenic substrate of G4zyme) is applied to DNA logic computation and a series of label-free DNA-input logic gates, including elementary AND, OR, and INHIBIT logic gates, as well as a two to one encoder, are constructed. Furthermore, a DNA caliper that can measure the base number of target DNA as low as three bases is also fabricated. This DNA caliper can also perform concatenated AND-AND logic computation to fulfil the requirements of sophisticated logic computing. PMID- 28029729 TI - Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non diabetic rat model of steatohepatitis. AB - AIM: Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model. METHODS: To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12 weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH. RESULTS: Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-beta1 and alpha1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies. CONCLUSIONS: The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH. PMID- 28029730 TI - Historical foundations and future directions in macrosystems ecology. AB - Macrosystems ecology is an effort to understand ecological processes and interactions at the broadest spatial scales and has potential to help solve globally important social and ecological challenges. It is important to understand the intellectual legacies underpinning macrosystems ecology: How the subdiscipline fits within, builds upon, differs from and extends previous theories. We trace the rise of macrosystems ecology with respect to preceding theories and present a new hypothesis that integrates the multiple components of macrosystems theory. The spatio-temporal anthropogenic rescaling (STAR) hypothesis suggests that human activities are altering the scales of ecological processes, resulting in interactions at novel space-time scale combinations that are diverse and predictable. We articulate four predictions about how human actions are "expanding", "shrinking", "speeding up" and "slowing down" ecological processes and interactions, and thereby generating new scaling relationships for ecological patterns and processes. We provide examples of these rescaling processes and describe ecological consequences across terrestrial, freshwater and marine ecosystems. Rescaling depends in part on characteristics including connectivity, stability and heterogeneity. Our STAR hypothesis challenges traditional assumptions about how the spatial and temporal scales of processes and interactions operate in different types of ecosystems and provides a lens through which to understand macrosystem-scale environmental change. PMID- 28029731 TI - Reduced blood glucose through thyroid hormone degradation product. PMID- 28029732 TI - The efficacy of aloe vera in management of oral lichen planus: a systematic review and meta-analysis. AB - OBJECTIVES: The main objective of oral lichen planus management is to control symptomatic outbreaks via eliminating lesions and alleviating symptoms. Corticosteroids, calcineurin inhibitors, and most of the available modalities are associated with adverse effects, which may limit their use. The aim of this review was to assess the effect of aloe vera on pain alleviation and/or clinical improvement in patients with symptomatic oral lichen planus. METHODS: MEDLINE PubMed; CENTRAL, and LILACS were searched in May 2016 to identify all clinical trials evaluating aloe vera vs placebo or corticosteroids for treatment of oral lichen planus. The included studies were five clinical trials and two case reports. RESULTS: From the included studies, there is weak evidence that aloe vera is more efficient than placebo and has comparable effect to triamcinolone acetonide. The meta-analyses show heterogeneity and reveals that aloe vera is inferior to the control in general. CONCLUSION: Although corticosteroids are still the gold standard, aloe vera shows promising results especially with no adverse effects compared with various adverse effects of corticosteroids. We recommend conducting new randomized clinical trials with larger sample size, sufficiently long follow-up period as well as standardized aloe vera formulations and outcome measures. PMID- 28029733 TI - Transplantation Remains Daunting for Many Veterans. PMID- 28029734 TI - Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016. AB - November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing. PMID- 28029735 TI - Super-MANF to the Rescue: Immunomodulation Improves Retinal Repair and Regenerative Cell Therapy. PMID- 28029736 TI - Erratum. PMID- 28029737 TI - Arterial Thrombus in a Heart Transplant Recipient. PMID- 28029738 TI - DRO1 influences root system architecture in Arabidopsis and Prunus species. AB - Roots provide essential uptake of water and nutrients from the soil, as well as anchorage and stability for the whole plant. Root orientation, or angle, is an important component of the overall architecture and depth of the root system; however, little is known about the genetic control of this trait. Recent reports in Oryza sativa (rice) identified a role for DEEPER ROOTING 1 (DRO1) in influencing the orientation of the root system, leading to positive changes in grain yields under water-limited conditions. Here we found that DRO1 and DRO1 related genes are present across diverse plant phyla, and fall within the IGT gene family. The IGT family also includes TAC1 and LAZY1, which are known to affect the orientation of lateral shoots. Consistent with a potential role in root development, DRO1 homologs in Arabidopsis and peach showed root-specific expression. Promoter-reporter constructs revealed that AtDRO1 is predominantly expressed in both the root vasculature and root tips, in a distinct developmental pattern. Mutation of AtDRO1 led to more horizontal lateral root angles. Overexpression of AtDRO1 under a constitutive promoter resulted in steeper lateral root angles, as well as shoot phenotypes including upward leaf curling, shortened siliques and narrow lateral branch angles. A conserved C-terminal EAR like motif found in IGT genes was required for these ectopic phenotypes. Overexpression of PpeDRO1 in Prunus domestica (plum) led to deeper-rooting phenotypes. Collectively, these data indicate a potential application for DRO1 related genes to alter root architecture for drought avoidance and improved resource use. PMID- 28029739 TI - Drying techniques for the visualisation of agarose-based chromatography media by scanning electron microscopy. AB - The drying of chromatography resins prior to scanning electron microscopy is critical to image resolution and hence understanding of the bead structure at sub micron level. Achieving suitable drying conditions is especially important with agarose-based chromatography resins, as over-drying may cause artefact formation, bead damage and alterations to ultrastructural properties; and under-drying does not provide sufficient resolution for visualization under SEM. This paper compares and contrasts the effects of two drying techniques, critical point drying and freeze drying, on the morphology of two agarose based resins (MabSelectTM/dw ~85 um and CaptoTM Adhere/dw ~75 um) and provides a complete method for both. The results show that critical point drying provides better drying and subsequently clearer ultrastructural visualization of both resins under SEM. Under this protocol both the polymer fibers (thickness ~20 nm) and the pore sizes (diameter ~100 nm) are clearly visible. Freeze drying is shown to cause bead damage to both resins, but to different extents. MabSelect resin encounters extensive bead fragmentation, whilst Capto Adhere resin undergoes partial bead disintegration, corresponding with the greater extent of agarose crosslinking and strength of this resin. While freeze drying appears to be the less favorable option for ultrastructural visualization of chromatography resin, it should be noted that the extent of fracturing caused by the freeze drying process may provide some insight into the mechanical properties of agarose-based chromatography media. PMID- 28029740 TI - Fluence Threshold Behaviour on Ablation and Bubble Formation in Pulsed Laser Ablation in Liquids. AB - The ablation yield and bubble-formation process during nanosecond pulsed-laser ablation of silver in water are analysed by stroboscopic videography, time resolved X-ray radiography and in situ UV/Vis spectroscopy. This process is studied as function of lens-target distance and laser fluence. Both the ablation yield and the bubble-cavitation process exhibit threshold behaviour as a function of fluence, which is linked to the efficiency of coupling of energy at the water/target interface. Although ablation happens below this threshold, quantitative material emission is linked to bubble formation. Above the threshold, both bubble size and ablation show linear behaviour. PMID- 28029741 TI - Envisaging the use of evidence-based practice (EBP): how nurse academics facilitate EBP use in theory and practice across Australian undergraduate programmes. AB - AIMS AND OBJECTIVES: This paper is drawn from a grounded theory study that aimed to investigate processes undertaken by academics when integrating evidence-based practice into undergraduate curricula. This paper focuses on how nurse academics facilitated students to apply evidence-based practice in theory and practice. BACKGROUND: Facilitating undergraduate nursing students to develop skills within an evidence-based practice framework is vital to achieving evidence-based care. Studies on evidence-based practice conducted globally suggests that there is a need to investigate approaches used by nurse academics in facilitating students' understanding and use of evidence-based practice during their nurse education. METHODS: Employing constructivist grounded theory approach, 23 nurse academics across Australian universities were interviewed and nine observed during their teaching. Some study participants shared their unit guides to enrich analysis. Data analysis was performed by following Charmaz's approach of coding procedures; as a result, four categories were constructed. This paper focuses on the category conceptualised as Envisaging the use of evidence-based practice. RESULTS: Findings revealed that most academics-assisted students to use evidence in academic-related activities. Recognising the importance of evidence-based practice in practice, some also expected students to apply evidence-based practice during clinical experiences. However, the level of students' appreciation for evidence-based practice during clinical experiences was unknown to participants and was influenced by practice-related barriers. Acknowledging these challenges, academics were engaged in dialogue with students and suggested the need for academia-practice collaboration in combating the cited barriers. CONCLUSION: Ensuring academics are supported to emphasise clinical application of evidence-based practice requires strategies at school and practice levels. Faculty development, engagement of clinical nurses with evidence-based practice, supportive culture for nurses and students to apply evidence-based practice principles, and collaboration between academia and practice will make facilitation by academics practical and meaningful for students. RELEVANCE TO CLINICAL PRACTICE: Findings from this study point to a number of initiatives for clinical leadership to provide infrastructure and support for academics, practising nurses and undergraduate students to adopt evidence-based practice in practice settings, thereby influencing practice outcomes. PMID- 28029742 TI - Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA-B27 Activates the Unfolded Protein Response. AB - OBJECTIVE: The basic mechanisms underlying the pathogenesis of ankylosing spondylitis (AS) remain unresolved. We previously reported an association of the single-nucleotide polymorphism (SNP) rs2549782 in the endoplasmic reticulum aminopeptidase 2 gene (ERAP2) with AS. It is known that patients homozygous for the G allele (GG) of another ERAP2 SNP, rs2248374, lack expression of ERAP2 (ERAP2 null). The present study utilized this information to study the impact of ERAP2 deficiency on HLA-B27 expression in patients with AS, specifically focusing on the functional interaction of ERAP2 and HLA-B27 in peripheral blood mononuclear cells (PBMCs) from patients with AS and assessing the effects in vitro in specific cell lines. METHODS: Expression of intact peptide HLA-B27 (pB27) or the major histocompatibility complex class I free heavy chains (FHCs) was assessed in PBMCs isolated from HLA-B27-positive patients with AS. ERAP2 suppressed, stable B27-expressing C1R cells (C1R-B27) were tested for the expression levels of pB27 and FHCs, as well as for markers of the unfolded protein response (UPR). Distribution of the ERAP2 SNPs rs2549782 and rs2248374 in patients with AS and in patients with Crohn's disease was assessed. RESULTS: PBMCs from AS patients lacking ERAP2 expressed higher levels of FHCs than did PBMCs from patients positive for ERAP2. This finding was replicated in C1R-B27 cells after suppression of ERAP2. In addition, ERAP2 suppression led to increased levels of the UPR markers BiP, CCAAT/enhancer binding protein homologous protein 10, and X-box binding protein 1 [spliced] as compared to that in short hairpin RNA-treated control cells. There was strong linkage disequilibrium in the ERAP2 locus. All patients with the rs2549782 T allele (which reportedly increases the function of the ERAP-2 protein) were homozygous for the G allele of rs2248374, leading to absence of ERAP2. CONCLUSION: ERAP2 deficiency causes increased FHC expression and up-regulation of the UPR pathway. PMID- 28029743 TI - Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase. AB - BACKGROUND: Pulmonary hypertension (PH) is a devastating disorder, for which no therapy is curative. It has been reported that pulmonary vascular remodeling, associated with increasing mean pulmonary arterial pressure and upregulated expression of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), RhoA/RhoH-kinase results in the development of PH. Oxidative stress and the RhoA/Rho-kinase pathway are also thought to be involved in the pathophysiology of PH. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors) with pleiotropic effects and are potential agents for the treatment of PH. In this study, we investigated the beneficial effects of simvastatin on the development of PH secondary to left ventricular dysfunction. METHODS: A PH secondary to left ventricular dysfunction model was established in 6-week-old aortic-banded rats. The pulmonary expression of Rho kinase, ET-1, eNOS, p-eNOS, nitrite/nitrate (NOx), cGMP, p47Phox , and p67Phox were investigated in the early-treatment group, to which was administered simvastatin (30 mg/kg/day) from days 1 to 42 or the late-treatment group, to which was administered simvastatin (30 mg/kg/day) from days 29 to 42. RESULTS: Simvastatin attenuated the mean pulmonary artery pressure, pulmonary arteriolar remodeling, plasma brain natriuretic peptide, ET-1, reactive oxygen species, and the NADPH oxidase 2 regulatory subunits, p47Phox and p67Phox , and upregulated pulmonary p eNOS, NOx, and cGMP in both the early- and late-treated groups. CONCLUSIONS: Inhibiting HMG-CoA reductase may have therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction through the Rho kinase pathway and NADPH oxidase. A translational study in humans is needed to substantiate these findings. Pediatr Pulmonol. 2017;52:443-457. (c) 2016 Wiley Periodicals, Inc. PMID- 28029744 TI - High-Titer Rheumatoid Arthritis Antibodies Preferentially Bind Fibrinogen Citrullinated by Peptidylarginine Deiminase 4. AB - OBJECTIVE: Most patients with rheumatoid arthritis (RA) harbor antibodies to citrullinated autoantigens such as citrullinated fibrinogen. Two isoforms of peptidylarginine deiminase (PAD), PAD type 2 (PAD2) and PAD4, which catalyze citrullination with different substrate specificities, can be detected in the synovium of RA patients. This study was undertaken to determine whether RA antibodies preferentially bind PAD2- or PAD4-citrullinated fibrinogen. METHODS: RA patient and normal donor plasma specimens were tested for binding to PAD2- or PAD4-citrullinated fibrinogen, native fibrinogen, or citrullinated fibrinogen peptides in various dilutions by enzyme-linked immunosorbent assay (ELISA) and Western blotting. Bands corresponding to masses demonstrating RA antibody reactivity by Western blotting were excised and analyzed by mass spectrometry. RESULTS: At low antibody titers (1:40 and 1:100), there was no significant difference between RA antibody reactivity to PAD2- and PAD4-citrullinated fibrinogen. When plasma was further diluted to 1:250 and 1:1,000, RA patient plasma bound PAD4-citrullinated fibrinogen significantly more than PAD2 citrullinated fibrinogen, as measured by ELISA and Western blotting. An increased antibody titer was associated with increased avidity for both PAD2- and PAD4 citrullinated fibrinogen. Both enzymes hypercitrullinated fibrinogen, but PAD4 citrullinated arginines more intermittently, generating a mix of citrullinated and noncitrullinated arginines. Peptide ELISA and preadsorption assays confirmed that the region of intermittent citrullination accounts for the majority of RA antibody binding to the beta-chain of citrullinated fibrinogen. CONCLUSION: At high titers, RA antibodies preferentially bind fibrinogen modified by PAD4, because intermittent citrullination offers a more diverse assortment of citrullinated epitopes. PMID- 28029746 TI - Respiratory manifestations in 38 patients with Alstrom syndrome. AB - OBJECTIVES: Alstrom syndrome (AS) is a rare, multi-system condition characterized by retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, hypertriglyceridemia, cardiomyopathy, hepatorenal disease, and recurrent respiratory infections. It belongs to a group of genetic disorders known as primary ciliopathies, which includes autosomal dominant and recessive polycystic kidney diseases, as well as Joubert and Bardet-Biedl syndromes. Prior studies have suggested phenotypic overlap between primary ciliopathies affecting the non-motile, sensory cilia, and primary ciliary dyskinesia (PCD), a motile ciliopathy characterized by respiratory tract disease. METHODS: We describe the burden of oto-sino-pulmonary disease in 38 individuals with AS and examines the degree of clinical overlap between PCD and AS. Evaluation at the NIH Clinical Center included clinical examination, chest imaging, and clinical history surveys, as well as measurement of nasal nitric oxide (nNO) in nine patients. RESULTS: Recurrent otitis media was ubiquitous in the AS cohort (92%) with 50% requiring pressure equalization tube placement. A history of bronchitis/pneumonia and sinusitis was reported in 61% and 50% of individuals, respectively. PCD characterizing symptoms (laterality defects, unexplained neonatal respiratory distress, year-round nasal congestion, and wet cough) were far less prevalent in the AS cohort compared to PCD, and the average nNO production in the AS cohort was 232 +/- 57.1 nl/min compared to a cut-off of <77 nl/min for PCD. CONCLUSIONS: These data suggest that the oto-sino-respiratory complications in AS are prominent enough to warrant increased clinical attention, but significantly impaired respiratory cilia function as seen in PCD is unlikely in AS. (www.clinicaltrials.gov, trial NCT00068224) Pediatr Pulmonol. 2017;52:487-493. (c) 2016 Wiley Periodicals, Inc. PMID- 28029745 TI - Early Mortality in a Multinational Systemic Sclerosis Inception Cohort. AB - OBJECTIVE: To determine mortality and causes of death in a multinational inception cohort of subjects with systemic sclerosis (SSc). METHODS: We quantified mortality as standardized mortality ratio (SMR), years of life lost, and percentage mortality in the first decade of disease. The inception cohort comprised subjects recruited within 4 years of disease onset. For comparison, we used a prevalent cohort, which included all subjects irrespective of disease duration at recruitment. We determined a single primary cause of death (SSc related or non-SSc related) using a standardized case report form, and we evaluated predictors of mortality using multivariable Cox regression. RESULTS: In the inception cohort of 1,070 subjects, there were 140 deaths (13%) over a median follow-up of 3.0 years (interquartile range 1.0-5.1 years), with a pooled SMR of 4.06 (95% confidence interval [95% CI] 3.39-4.85), up to 22.4 years of life lost in women and up to 26.0 years of life lost in men, and mortality in the diffuse disease subtype of 24.2% at 8 years. In the prevalent cohort of 3,218 subjects, the pooled SMR was lower at 3.39 (95% CI 3.06-3.71). In the inception cohort, 62.1% of the primary causes of death were SSc related. Malignancy, sepsis, cerebrovascular disease, and ischemic heart disease were the most common non-SSc related causes of death. Predictors of early mortality included male sex, older age at disease onset, diffuse disease subtype, pulmonary arterial hypertension, and renal crisis. CONCLUSION: Early mortality in SSc is substantial, and prevalent cohorts underestimate mortality in SSc by failing to capture early deaths, particularly in men and those with diffuse disease. PMID- 28029747 TI - It is the Best of Treatments, It is the Worst of Treatments: The Continuing Love Hate Relationship With Glucocorticoids in Rheumatoid Arthritis. PMID- 28029749 TI - ACR Presidential Address: Delivering High-Value Rheumatology Care: Using the American College of Rheumatology RISETM Registry to Promote Quality and Efficiency. PMID- 28029748 TI - Physical Activity Minimum Threshold Predicting Improved Function in Adults With Lower-Extremity Symptoms. AB - OBJECTIVE: To identify an evidence-based minimum physical activity threshold to predict improved or sustained high function for adults with lower-extremity joint symptoms. METHODS: Prospective multisite data from 1,629 adults, age >=49 years with symptomatic lower-extremity joint pain/aching/stiffness, participating in the Osteoarthritis Initiative accelerometer monitoring substudy were clinically assessed 2 years apart. Improved/high function in 2-year gait speed and patient reported outcomes (PROs) were based on improving or remaining in the best (i.e., maintaining high) function quintile compared to baseline status. Optimal thresholds predicting improved/high function were investigated using classification trees for the legacy federal guideline metric requiring 150 minutes/week of moderate-vigorous (MV) activity in bouts lasting 10 minutes or more (MV-bout) and other metrics (total MV, sedentary, light intensity activity, nonsedentary minutes/week). RESULTS: Optimal thresholds based on total MV minutes/week predicted improved/high function outcomes more strongly than the legacy or other investigated metrics. Meeting the 45 total MV minutes/week threshold had increased relative risk (RR) for improved/high function (gait speed RR 1.8, 95% confidence interval [95% CI] 1.6, 2.1 and PRO physical function RR 1.4, 95% CI 1.3, 1.6) compared to less active adults. Thresholds were consistent across sex, body mass index, knee osteoarthritis status, and age. CONCLUSION: These results supported a physical activity minimum threshold of 45 total MV minutes/week to promote improved or sustained high function for adults with lower extremity joint symptoms. This evidence-based threshold is less rigorous than federal guidelines (>=150 MV-bout minutes/week) and provides an intermediate goal towards the federal guideline for adults with lower-extremity symptoms. PMID- 28029750 TI - "Official View" on Glucocorticoids in Rheumatoid Arthritis: A Systematic Review of International Guidelines and Consensus Statements. AB - OBJECTIVE: To describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects. METHODS: We conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids. RESULTS: All guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid specific recommendations but also guideline quality in general. CONCLUSION: Current recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly. PMID- 28029751 TI - Effect of Continuous B Cell Depletion With Rituximab on Pathogenic Autoantibodies and Total IgG Levels in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. AB - OBJECTIVE: To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with continuous B cell depletion. METHODS: We conducted a retrospective analysis of 239 patients with AAV treated with rituximab-induced continuous B cell depletion. Two treatment cohorts were analyzed: an induction group (n = 52) and a maintenance group (n = 237). Changes in ANCA titers and total Ig levels over time were evaluated using mixed-effects models. Risk factors for serious infections during maintenance treatment were evaluated using Poisson regression. RESULTS: During induction, IgG levels fell at a mean rate of 6% per month (95% confidence interval [95% CI] 4, 8%), while ANCA levels declined at a mean rate of 47% per month (95% CI 42, 52%) and 48% per month (95% CI 42, 54%) for patients with antimyeloperoxidase (anti-MPO) antibodies and those with anti-proteinase 3 (anti PR3) antibodies, respectively. During maintenance treatment, with a median duration of 2.4 years (interquartile range 1.5, 4.0 years), IgG levels declined a mean of 0.6% per year (95% CI -0.2, 1.4%). New significant hypogammaglobulinemia (IgG level of <400 mg/dl) during maintenance treatment occurred in 4.6% of the patients, all of whom were in the lowest baseline IgG quartile. Serious infections during maintenance therapy occurred at a rate of 0.85 per 10 patient years (95% CI 0.66, 1.1) and were independently associated with an IgG level of <400 mg/dl. CONCLUSION: B cell-targeted therapy causes a preferential decline in ANCA titers relative to total IgG levels. Despite prolonged maintenance therapy with rituximab, IgG levels remain essentially constant. Serious infections were rare. PMID- 28029752 TI - Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis. AB - OBJECTIVE: To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. METHODS: Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. RESULTS: Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses ( 16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. CONCLUSION: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes. PMID- 28029753 TI - Performance of the Patient-Reported Outcomes Measurement Information System 29 Item Profile in Rheumatoid Arthritis, Osteoarthritis, Fibromyalgia, and Systemic Lupus Erythematosus. AB - OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed to improve measurement of patient-reported outcomes. We examined performance of the 29-item PROMIS Profile (PROMIS-29) in persons with rheumatoid arthritis (RA), osteoarthritis (OA), fibromyalgia (FM), and systemic lupus erythematosus (SLE). METHODS: Participants in the National Data Bank for Rheumatic Diseases completed the PROMIS-29, which includes 4-item forms for 7 PROMIS domains. Scales were scored and converted to T scores. Distributions of scale scores were examined, convergent and known-groups validity was tested, and differences in scores from online versus paper questionnaires were examined. RESULTS: Sample sizes were 4,346 for RA, 727 for OA, 241 for FM, and 240 for SLE. Participants were predominantly female, with a mean disease duration >=20 years, and were ages ~60 years. Large ceiling effects occurred for some PROMIS-29 scales. Correlations of PROMIS-29 scores with scales measuring similar constructs ranged from high to moderate for RA, OA, and SLE; correlations for FM were markedly lower for some scales. Consistent patterns of worsening PROMIS-29 scores with increasing disease severity or declining health status were observed. Differences in scores obtained by online versus paper questionnaires ranged from 0.3 to 2.2 points. CONCLUSION: Results provide guarded support for using the PROMIS-29 in these conditions. The PROMIS-29 4-item static forms appear to identify differences among levels of health and to measure constructs similar to those measured by legacy questionnaires. However, large ceiling effects suggest that measurement may be more precise at the "bad" ends of the scales, which may limit responsiveness, and differences by mode of administration appear to exist. PMID- 28029754 TI - Pulmonary hemorrhage as a complication of Respiratory Syncyntial Virus (RSV) bronchiolitis. AB - Respiratory Syncytial Virus (RSV) is a common cause of bronchiolitis. Although there are a number of recognized complications, pulmonary hemorrhage has not been reported previously. A retrospective case notes review was performed through an electronic search of a Pediatric Intensive Care Unit's medical records. Seven patients with RSV infection and pulmonary hemorrhage were identified and included in this case series. Six of the seven patients were born prematurely (30-36 weeks gestation). All patients required blood transfusion. The pulmonary hemorrhage events all occurred after a period of mechanical ventilation and following extubation. All of the patients required reintubation with a mean of 5 further days of mechanical ventilation. Pulmonary hemorrhage is an uncommon complication of RSV infection, which has not been reported previously in the literature. Further studies are required to determine incidence, pathogenesis, and outcome. Pediatr Pulmonol. 2017;52:E32-E36. (c) 2016 Wiley Periodicals, Inc. PMID- 28029755 TI - A novel approach to the quantification of aortic root in vivo structural mechanics. AB - Understanding aortic root in vivo biomechanics can help in elucidating key mechanisms involved in aortic root pathologies and in the outcome of their surgical treatment. Numerical models can provide useful quantitative information. For this to be reliable, detailed aortic root anatomy should be captured. Also, since the aortic root is never unloaded throughout the cardiac cycle, the modeled geometry should be consistent with the in vivo loads acting on it. Achieving such consistency is still a challenge, which was tackled only by few numerical studies. Here we propose and describe in detail a new approach to the finite element modeling of aortic root in vivo structural mechanics. Our approach exploits the anatomical information yielded by magnetic resonance imaging by reconstructing the 3-dimensional end-diastolic geometry of the aortic root and makes the reconstructed geometry consistent with end-diastolic loading conditions through the estimation of the corresponding prestresses field. We implemented our approach through a semiautomated modeling pipeline, and we applied it to quantify aortic root biomechanics in 4 healthy participants. Computed results highlighted that including prestresses into the model allowed for pressurizing the aortic root to the end-diastolic pressure while matching the image-based ground truth data. Aortic root dynamics, tissues strains, and stresses computed at relevant time points through the cardiac cycle were consistent with a broad set of data from previous computational and in vivo studies, strongly suggesting the potential of the method. Also, results highlighted the major role played by the anatomy in driving aortic root biomechanics. PMID- 28029756 TI - When and why to treat the child who snores? AB - Obstructive sleep-disordered breathing (SDB) can result in cardiovascular and neurocognitive morbidity as well as adversely affect behavior, growth, quality of life, and nocturnal continence. This article summarizes the latest evidence regarding the morbidity related to obstructive SDB, commenting on the impact of severity of obstruction, that is, the difference in effects seen of moderate to severe obstructive sleep apnea syndrome (OSAS) compared to those of mild OSAS or primary snoring. The impact of therapy is discussed, focusing on which children are likely to benefit from treatment interventions; namely those with moderate or severe OSAS irrespective of the presence of morbidity, children with mild OSAS with associated morbidity or predictors of SDB persistence such as obesity, and children with complex conditions accompanied by upper airway obstruction like craniosynostosis and Prader-Willi syndrome. The co-existing conditions which may improve when treatment for obstructive SDB is offered are reviewed, while the clinical parameters associated with spontaneous improvement or resolution of obstructive SDB are discussed. The intention being to enable clinicians to make informed decisions on who should be treated, when and why. Pediatr Pulmonol. 2017;52:399-412. (c) 2016 Wiley Periodicals, Inc. PMID- 28029758 TI - Adoption and Foster Care Analysis and Reporting System. Final rule. AB - The Social Security Act (the Act) requires that ACF regulate a national data collection system that provides comprehensive demographic and case-specific information on children who are in foster care and adopted. This final rule replaces existing Adoption and Foster Care Analysis and Reporting System (AFCARS) regulations and the appendices to require title IV-E agencies to collect and report data to ACF on children in out-of-home care, and who exit out-of-home care to adoption or legal guardianship, children in out-of-home care who are covered by the Indian Child Welfare Act, and children who are covered by a title IV-E adoption or guardianship assistance agreement. PMID- 28029759 TI - Americans With Disabilities Act (ADA) Accessibility Guidelines for Transportation Vehicles. Final rule. AB - The Architectural and Transportation Barriers Compliance Board (Access Board or Board) is issuing a final rule that revises its existing accessibility guidelines for non-rail vehicles--namely, buses, over-the-road buses, and vans--acquired or remanufactured by entities covered by the Americans with Disabilities Act. The revised guidelines ensure that such vehicles are readily accessible to, and usable by, individuals with disabilities. The U.S. Department of Transportation (DOT) is required to revise its accessibility standards for transportation vehicles acquired or remanufactured by entities covered by the Americans with Disabilities Act (ADA) to be consistent with the final rule. PMID- 28029760 TI - Evidence of Sulfate-Dependent Anaerobic Methane Oxidation within an Area Impacted by Coalbed Methane-Related Gas Migration. AB - We evaluated water quality characteristics in the northern Raton Basin of Colorado and documented the response of the Poison Canyon aquifer system several years after upward migration of methane gas occurred from the deeper Vermejo Formation coalbed production zone. Results show persistent secondary water quality impacts related to the biodegradation of methane. We identify four distinct characteristics of groundwater-methane attenuation in the Poison Canyon aquifer: (i) consumption of methane and sulfate and production of sulfide and bicarbonate, (ii) methane loss coupled to production of higher molecular weight (C2+) gaseous hydrocarbons, (iii) patterns of 13C enrichment and depletion in methane and dissolved inorganic carbon, and (iv) a systematic shift in sulfur and oxygen isotope ratios of sulfate, indicative of microbial sulfate reduction. We also show that the biogeochemical response of the aquifer system has not mobilized naturally occurring trace metals, including arsenic, chromium, cobalt, nickel, and lead, likely due to the microbial production of hydrogen sulfide which favors stabilization of metals in aquifer solids. PMID- 28029757 TI - Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. AB - OBJECTIVE: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. RESULTS: Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3) reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. CONCLUSION: This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV. PMID- 28029761 TI - Switchable Photonic Crystals Using One-Dimensional Confined Liquid Crystals for Photonic Device Application. AB - Photonic crystals (PCs) have recently attracted considerable attention, with much effort devoted to photonic bandgap (PBG) control for varying the reflected color. Here, fabrication of a modulated one-dimensional (1D) anodic aluminum oxide (AAO) PC with a periodic porous structure is reported. The PBG of the fabricated PC can be reversibly changed by switching the ultraviolet (UV) light on/off. The AAO nanopores contain a mixture of photoresponsive liquid crystals (LCs) with irradiation-activated cis/trans photoisomerizable azobenzene. The resultant mixture of LCs in the porous AAO film exhibits a reversible PBG, depending on the cis/trans configuration of azobenzene molecules. The PBG switching is reliable over many cycles, suggesting that the fabricated device can be used in optical and photonic applications such as light modulators, smart windows, and sensors. PMID- 28029762 TI - Prevascularization of Decellularized Porcine Myocardial Slice for Cardiac Tissue Engineering. AB - Prevacularization strategies have been implemented in tissue engineering to generate microvasculature networks within a scaffold prior to implantation. Prevascularizing scaffolds will shorten the time of functional vascular perfusion with host upon implantation. In this study, we explored key variables affecting the interaction between decellularized porcine myocardium slices (dPMSs) and reseeded stem cells toward the fabrication of prevascularized cardiac tissue. Our results demonstrated that dPMS supports attachment of human mesenchymal stem cells (hMSCs) and rat adipose derived stem cells (rASCs) with high viability. We found that cell seeding efficiency and proliferation are dPMS thickness dependent. Compared to lateral cell seeding, bilateral cell seeding strategy significantly enhanced seeding efficiency, infiltration, and growth in 600 MUm dPMS. dPMS induced endothelial differentiation and maturation of hMSCs and rASCs after 1 and 5 days culture, respectively. These results indicate the potential of dPMS as a powerful platform to develop prevascularized scaffolds and fabricate functional cardiac patches. PMID- 28029763 TI - Improvement of Na Ion Electrode Activity of Metal Oxide via Composite Formation with Metal Sulfide. AB - The composite formation with a conductive metal sulfide domain can provide an effective methodology to improve the Na-ion electrode functionality of metal oxide. The heat treatment of TiO2(B) under CS2 flow yields an intimately coupled TiO2(B)-TiS2 nanocomposite with intervened TiS2 domain, since the reaction between metal oxide and CS2 leads to the formation of metal sulfide and CO2. The negligible change in lattice parameters and significant enhancement of visible light absorption upon the reaction with CS2 underscore the formation of conductive metal sulfide domains. The resulting TiO2(B)-TiS2 nanocomposites deliver greater discharge capacities with better rate characteristics for electrochemical sodiation-desodiation process than does the pristine TiO2(B). The 23Na magic angle spinning nuclear magnetic resonance analysis clearly demonstrates that the electrode activities of the present nanocomposites rely on the capacitive storage of Na+ ions, and the TiS2 domains in TiO2(B)-TiS2 nanocomposites play a role as mediators for Na+ ions to and from TiO2(B) domains. According to the electrochemical impedance spectroscopy, the reaction with CS2 leads to the significant enhancement of charge transfer kinetics, which is responsible for the accompanying improvement in electrode performance. The present study provides clear evidence for the usefulness in composite formation between the semiconducting metal oxide and metal sulfide in exploring new efficient NIB electrode materials. PMID- 28029764 TI - Green and Mild Oxidation: An Efficient Strategy toward Water-Dispersible Graphene. AB - Scalable fabrication of water-dispersible graphene (W-Gr) is highly desirable yet technically challenging for most practical applications of graphene. Herein, a green and mild oxidation strategy to prepare bulk W-Gr (dispersion, slurry, and powder) with high yield was proposed by fully exploiting structure defects of thermally reduced graphene oxide (TRGO) and oxidizing radicals generated from hydrogen peroxide (H2O2). Owing to the increased carboxyl group from the mild oxidation process, the obtained W-Gr can be redispersed in low-boiling solvents with a reasonable concentration. Benefiting from the modified surface chemistry, macroscopic samples processed from the W-Gr show good hydrophilicity (water contact angle of 55.7 degrees ) and excellent biocompatibility, which is expected to be an alternative biomaterial for bone, vessel, and skin regeneration. In addition, the green and mild oxidation strategy is also proven to be effective for dispersing other carbon nanomaterials in a water system. PMID- 28029765 TI - Strong Composition Effects in All-Polymer Phototransistors with Bulk Heterojunction Layers of p-type and n-type Conjugated Polymers. AB - We report the composition effect of polymeric sensing channel layers on the performance of all-polymer phototransistors featuring bulk heterojunction (BHJ) structure of electron-donating (p-type) and electron-accepting (n-type) polymers. As an n-type component, poly(3-hexylthiopehe-co-benzothiadiazole) end-capped with 4-hexylthiophene (THBT-4ht) was synthesized via two-step reactions. A well studied conjugated polymer, poly(3-hexylthiophene) (P3HT), was employed as a p type polymer. The composition of BHJ (P3HT:THBT-4ht) films was studied in detail by varying the THBT-4ht contents (0, 1, 3, 5, 10, 20, 30, 40, and 100 wt %). The best charge separation in the P3HT:THBT-4ht films was measured at 30 wt % by the photoluminescence (PL) study, while the charge transport characteristics of devices were improved at the low THBT-4ht contents (<10 wt %). The photosensing experiments revealed that the photosensivity of all-polymer phototransistors was higher than that of the phototransistors with the pristine P3HT layers and strongly dependent on the BHJ composition. The highest (corrected) responsivity (RC) was achieved at 20 wt %, which can be attributable to the balance between the best charge separation and transport states, as investigated for crystal nanostructures and surface morphology by employing synchrotron-radiation grazing incidence wide-angle X-ray scattering, high-resolution/scanning transmission electron microscopy, and atomic force microscopy. PMID- 28029766 TI - Neuroprotective Effects of a Structurally New Family of High Affinity Imidazoline I2 Receptor Ligands. AB - The imidazoline I2 receptors (I2-IRs) are widely distributed in the brain, and I2 IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I2-IR remains unknown, the discovery of selective I2-IR ligands devoid of alpha2-adrenoceptor (alpha2-AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2 imidazolin-4-yl)phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I2-IRs than idazoxan, and high I2/alpha2 selectivity. In vivo studies in mice showed that acute treatments with 1b and 2c significantly increased p-FADD/FADD ratio (an index of cell survival) in the hippocampus when compared with vehicle-treated controls. Additionally, acute and repeated treatments with 2c, but not with 1b, markedly reduced hippocampal p35 cleavage into neurotoxic p25. The present results indicate a neuroprotective potential of (2-imidazolin-4-yl)phosphonates acting at I2-IRs. PMID- 28029767 TI - Experimental and Theoretical Investigation of the Restructuring Process Induced by CO at Near Ambient Pressure: Pt Nanoclusters on Graphene/Ir(111). AB - The adsorption of CO on Pt nanoclusters grown in a regular array on a template provided by the graphene/Ir(111) Moire was investigated by means of infrared visible sum frequency generation vibronic spectroscopy, scanning tunneling microscopy, X-ray photoelectron spectroscopy from ultrahigh vacuum to near ambient pressure, and ab initio simulations. Both terminally and bridge bonded CO species populate nonequivalent sites of the clusters, spanning from first to second-layer terraces to borders and edges, depending on the particle size and morphology and on the adsorption conditions. By combining experimental information and the results of the simulations, we observe a significant restructuring of the clusters. Additionally, above room temperature and at 0.1 mbar, Pt clusters catalyze the spillover of CO to the underlying graphene/Ir(111) interface. PMID- 28029768 TI - To Extract, or not to Extract Uranium from Phosphate Rock, that is the Question. PMID- 28029769 TI - Light-Harvesting and Amplified Energy Transfer in Conjugated Polymer Nanoparticles. AB - Conjugated polymer nanoparticles are a class of nanoparticles with many useful and interesting properties, including very high fluorescence brightness, excellent photostability, and sensing capabilities. They also exhibit interesting and potentially useful phenomena, such as highly efficient energy transfer, anomalous single particle blinking, and twinkling phenomena associated with polaron motion. As little as one dye molecule per nanoparticle can efficiently quench the fluorescence of hundreds of polymer chromophore units. Similarly, loss of a single electron can result in quenching of hundreds of chromophores. These phenomena and properties are dictated by the nature of interactions between chromophores in this dense, nanoscale multichromophoric system, and are characterized as amplified energy transfer or multiple energy transfer. In this review, we summarize the key aspects of conjugated polymer nanoparticles optical properties and phenomena, and discuss the current understanding of exciton dynamics in these and related systems. In particular, our current understanding and theoretical models for amplified or multiple energy transfer based on exciton theory and Forster resonance energy transfer are explored. PMID- 28029770 TI - Ultrasensitive and Highly Selective Photodetections of UV-A Rays Based on Individual Bicrystalline GaN Nanowire. AB - The detection of UV-A rays (wavelength of 320-400 nm) using functional semiconductor nanostructures is of great importance in either fundamental research or technological applications. In this work, we report the catalytic synthesis of peculiar bicrystalline GaN nanowires and their utilization for building high-performance optoelectronic nanodevices. The as-prepared UV-A photodetector based on individual bicrystalline GaN nanowire demonstrates a fast photoresponse time (144 ms), a high wavelength selectivity (UV-A light response only), an ultrahigh photoresponsivity of 1.74 * 107 A/W and EQE of 6.08 * 109%, a sensitivity of 2 * 104%, and a very large on/off ratio of more than two orders, as well as robust photocurrent stability (photocurrent fluctuation of less than 7% among 4000 s), showing predominant advantages in comparison with other peer semiconductor photodetectors. The outstanding optoelectronic performance of the bicrystalline GaN nanowire UV-A photodetector is further analyzed based on a detailed high-resolution transmission electron microscope (HRTEM) study, and the two separated crystal domains within the GaN nanowires are believed to provide separated and rapid carrier transfer channels. This work paves a solid way toward the integration of high-performance optoelectronic nanodevices based on bicrystalline or horizontally aligned one-dimensional semiconductor nanostructures. PMID- 28029771 TI - Ionic Liquids as Lubricant Additives: A Review. AB - In pursuit of energy efficiency and durability throughout human history, advances in lubricants have always played important roles. Ionic liquids (ILs) are room temperature molten salts that possess unique physicochemical properties and have shown great potential in many applications with lubrication as one of the latest. While earlier work (2001-2011) primarily explored the feasibility of using ILs as neat or base lubricants, using ILs as lubricant additives has become the new focal research topic since the breakthrough in ILs' miscibility in nonpolar hydrocarbon oils in early 2012. This work reviews the recent advances in developing ILs as additives for lubrication with an attempt to correlate among the cationic and anionic structures, oil-solubility, and other relevant physicochemical properties, and lubricating behavior. Effects of the concentration of ILs in lubricants and the compatibility between ILs and other additives in the lubricant formulation on the tribological performance are described followed by a discussion of wear protection mechanism based on tribofilm characterization. Future research directions are suggested at the end. PMID- 28029772 TI - Oxidation of Iron under Physiologically Relevant Conditions in Biological Fluids from Healthy and Alzheimer's Disease Subjects. AB - Ferroxidase activity has been reported to be altered in various biological fluids in neurodegenerative disease, but the sources contributing to the altered activity are uncertain. Here we assay fractions of serum and cerebrospinal fluid with a newly validated triplex ferroxidase assay. Our data indicate that while ceruloplasmin, a multicopper ferroxidase, is the predominant source of serum activity, activity in CSF predominantly derives from a <10 kDa component, specifically from polyanions such as citrate and phosphate. We confirm that in human biological samples, ceruloplasmin activity in serum is decreased in Alzheimer's disease, but in CSF a reduction of activity in Alzheimer's disease originates from the polyanion component. PMID- 28029773 TI - Colorimetric Polydiacetylene-Aerogel Detector for Volatile Organic Compounds (VOCs). AB - A new hybrid system comprising polydiacetylene (PDA), a chromatic conjugated polymer, embedded within aerogel pores has been constructed. The PDA-aerogel powder underwent dramatic color changes in the presence of volatile organic compounds (VOCs), facilitated through infiltration of the gas molecules into the highly porous aerogel matrix and their interactions with the aerogel-embedded PDA units. The PDA-aerogel composite exhibited rapid color/fluorescence response and enhanced signals upon exposure to low VOC concentrations. Encapsulation of PDA derivatives displaying different headgroups within the aerogel produced distinct VOC-dependent color transformations, forming a PDA-aerogel "artificial nose". PMID- 28029774 TI - The Structure of Murine N1-Acetylspermine Oxidase Reveals Molecular Details of Vertebrate Polyamine Catabolism. AB - N1-Acetylspermine oxidase (APAO) catalyzes the conversion of N1-acetylspermine or N1-acetylspermidine to spermidine or putrescine, respectively, with concomitant formation of N-acetyl-3-aminopropanal and hydrogen peroxide. Here we present the structure of murine APAO in its oxidized holo form and in complex with substrate. The structures provide a basis for understanding molecular details of substrate interaction in vertebrate APAO, highlighting a key role for an asparagine residue in coordinating the N1-acetyl group of the substrate. We applied computational methods to the crystal structures to rationalize previous observations with regard to the substrate charge state. The analysis suggests that APAO features an active site ideally suited for binding of charged polyamines. We also reveal the structure of APAO in complex with the irreversible inhibitor MDL72527. In addition to the covalent adduct, a second MDL72527 molecule is bound in the active site. Binding of MDL72527 is accompanied by altered conformations in the APAO backbone. On the basis of structures of APAO, we discuss the potential for development of specific inhibitors. PMID- 28029776 TI - Surface Distribution and Biophysicochemical Properties of Polymeric Micelles Bearing Gemini Cationic and Hydrophilic Groups. AB - Polymeric micelles containing cationic gemini quaternary ammonium (GQA) groups have shown enhanced cellular uptake and efficient drug delivery, while the incorporation of poly(ethylene glycol) (PEG) corona can potentially reduce the absorption of cationic carriers by opsonic proteins and subsequent uptake by mononuclear phagocytic system (MPS). To understand the interactions of GQA and PEG groups and their effects on the biophysicochemical characteristics of nanocarriers, a series of polyurethane micelles containing GQA and different molecular weights of PEG were prepared and carefully characterized. It was found that the GQA and PEG groups are unevenly distributed on the micellar surface to form two kinds of hydrophilic domains. As a result, the particle surface with some defects cannot be completely shielded by the PEG corona. Despite this, the longer PEG chains with a brush conformation provide superior stabilization and steric repulsion against the absorption of proteins and, thus, can reduce the cytotoxicity, protein absorption, and MPS uptake of micelles to some extent. This study provides a new understanding on the interactions between PEG chains and cationic groups and a guideline for the design and fabrication of safe and effective drug delivery systems. PMID- 28029775 TI - Combining a Ru(II) "Building Block" and Rapid Screening Approach to Identify DNA Structure-Selective "Light Switch" Compounds. AB - A chemically reactive Ru(II) "building block", able to undergo condensation reactions with substituted diamines, was utilized to create a small library of luminescent "light switch" dipyrido-[3,2-a:2',3'-c] phenazine (dppz) complexes. The impact of substituent identity, position, and the number of substituents on the light switch effect was investigated. An unbiased, parallel screening approach was used to evaluate the selectivity of the compounds for a variety of different biomolecules, including protein, nucleosides, single stranded DNA, duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two approaches allowed for the identification of hit molecules that showed different selectivities for biologically relevant DNA structures, particularly triplex and quadruplex DNA. PMID- 28029778 TI - Aqueous Exfoliation of Transition Metal Dichalcogenides Assisted by DNA/RNA Nucleotides: Catalytically Active and Biocompatible Nanosheets Stabilized by Acid Base Interactions. AB - The exfoliation and colloidal stabilization of layered transition metal dichalcogenides (TMDs) in an aqueous medium using functional biomolecules as dispersing agents have a number of potential benefits toward the production and practical use of the corresponding two-dimensional materials, but such a strategy has so far remained underexplored. Here, we report that DNA and RNA nucleotides are highly efficient dispersants in the preparation of stable aqueous suspensions of MoS2 and other TMD nanosheets at significant concentrations (up to 5-10 mg mL 1). Unlike the case of common surfactants, for which adsorption on 2D materials is generally based on weak dispersive forces, the exceptional colloidal stability of the TMD flakes was shown to rely on the presence of relatively strong, specific interactions of Lewis acid-base type between the DNA/RNA nucleotide molecules and the flakes. Moreover, the nucleotide-stabilized MoS2 nanosheets were shown to be efficient catalysts in the reduction of nitroarenes (4 nitrophenol and 4-nitroaniline), thus constituting an attractive alternative to the use of expensive heterogeneous catalysts based on noble metals, and exhibited an electrocatalytic activity toward the hydrogen evolution reaction that was not impaired by the possible presence of nucleotide molecules adsorbed on their active sites. The biocompatibility of these materials was also demonstrated on the basis of cell proliferation and viability assays. Overall, the present work opens new vistas on the colloidal stabilization of 2D materials based on specific interactions that could be useful toward different practical applications. PMID- 28029779 TI - Hydrogel Droplet Microfluidics for High-Throughput Single Molecule/Cell Analysis. AB - Heterogeneity among individual molecules and cells has posed significant challenges to traditional bulk assays, due to the assumption of average behavior, which would lose important biological information in heterogeneity and result in a misleading interpretation. Single molecule/cell analysis has become an important and emerging field in biological and biomedical research for insights into heterogeneity between large populations at high resolution. Compared with the ensemble bulk method, single molecule/cell analysis explores the information on time trajectories, conformational states, and interactions of individual molecules/cells, all key factors in the study of chemical and biological reaction pathways. Various powerful techniques have been developed for single molecule/cell analysis, including flow cytometry, atomic force microscopy, optical and magnetic tweezers, single-molecule fluorescence spectroscopy, and so forth. However, some of them have the low-throughput issue that has to analyze single molecules/cells one by one. Flow cytometry is a widely used high throughput technique for single cell analysis but lacks the ability for intercellular interaction study and local environment control. Droplet microfluidics becomes attractive for single molecule/cell manipulation because single molecules/cells can be individually encased in monodisperse microdroplets, allowing high-throughput analysis and manipulation with precise control of the local environment. Moreover, hydrogels, cross-linked polymer networks that swell in the presence of water, have been introduced into droplet microfluidic systems as hydrogel droplet microfluidics. By replacing an aqueous phase with a monomer or polymer solution, hydrogel droplets can be generated on microfluidic chips for encapsulation of single molecules/cells according to the Poisson distribution. The sol-gel transition property endows the hydrogel droplets with new functionalities and diversified applications in single molecule/cell analysis. The hydrogel can act as a 3D cell culture matrix to mimic the extracellular environment for long-term single cell culture, which allows further heterogeneity study in proliferation, drug screening, and metastasis at the single-cell level. The sol-gel transition allows reactions in solution to be performed rapidly and efficiently with product storage in the gel for flexible downstream manipulation and analysis. More importantly, controllable sol-gel regulation provides a new way to maintain phenotype-genotype linkages in the hydrogel matrix for high throughput molecular evolution. In this Account, we will review the hydrogel droplet generation on microfluidics, single molecule/cell encapsulation in hydrogel droplets, as well as the progress made by our group and others in the application of hydrogel droplet microfluidics for single molecule/cell analysis, including single cell culture, single molecule/cell detection, single cell sequencing, and molecular evolution. PMID- 28029777 TI - Nanoscale Characterization of Interaction of APOBEC3G with RNA. AB - The human cytidine deaminase APOBEC3G (A3G) is a potent inhibitor of the HIV-1 virus in the absence of viral infectivity factor (Vif). The molecular mechanism of A3G antiviral activity is primarily attributed to deamination of single stranded DNA (ssDNA); however, the nondeamination mechanism also contributes to HIV-1 restriction. The interaction of A3G with ssDNA and RNA is required for its antiviral activity. Here we used atomic force microscopy to directly visualize A3G-RNA and A3G-ssDNA complexes and compare them to each other. Our results showed that A3G in A3G-RNA complexes exists primarily in monomeric-dimeric states, similar to its stoichiometry in complexes with ssDNA. New A3G-RNA complexes in which A3G binds to two RNA molecules were identified. These data suggest the existence of two separate RNA binding sites on A3G. Such complexes were not observed with ssDNA substrates. Time-lapse high-speed atomic force microscopy was applied to characterize the dynamics of the complexes. The data revealed that the two RNA binding sites have different affinities for A3G. On the basis of the obtained results, a model for the interaction of A3G with RNA is proposed. PMID- 28029780 TI - A Transition Metal-Binding, Trimeric betagamma-Crystallin from Methane-Producing Thermophilic Archaea, Methanosaeta thermophila. AB - betagamma-Crystallins are important constituents of the vertebrate eye lens, whereas in microbes, they are prevalent as Ca2+-binding proteins. In archaea, betagamma-crystallins are conspicuously confined to two methanogens, viz., Methanosaeta and Methanosarcina. One of these, i.e., M-crystallin from Methanosarcina acetivorans, has been shown to be a typical Ca2+-binding betagamma crystallin. Here, with the aid of a high-resolution crystal structure and isothermal titration calorimetry, we report that "Methallin", a betagamma crystallin from Methanosaeta thermophila, is a trimeric, transition metal-binding protein. It binds Fe, Ni, Co, or Zn ion with nanomolar affinity, which is consistent even at 55 degrees C, the optimal temperature for the methanogen's growth. At the center of the protein trimer, the metal ion is coordinated by six histidines, two from each protomer, leading to an octahedral geometry. Small angle X-ray scattering analysis confirms that the trimer seen in the crystal lattice is a biological assembly; this assembly dissociates to monomers upon removal of the metal ion. The introduction of two histidines (S17H/S19H) into a homologous betagamma-crystallin, Clostrillin, allows it to bind nickel at the introduced site, though with micromolar affinity. However, because of the lack of a compatible interface, nickel binding could not induce trimerization, affirming that Methallin is a naturally occurring trimer for high-affinity transition metal binding. While betagamma-crystallins are known to bind Ca2+ and form homodimers and oligomers, the transition metal-binding, trimeric Methallin is a new paradigm for betagamma-crystallins. The distinct features of Methallin, such as nickel or iron binding, are also possible imprints of biogeochemical changes during the period of its origin. PMID- 28029781 TI - Aryl Hydrocarbon Receptor Activation Contributes to Benzanthrone-Induced Hyperpigmentation via Modulation of Melanogenic Signaling Pathways. AB - Benzanthrone (BA), an oxidized polycyclic aromatic hydrocarbon (PAH), has been found to be a potential health threat to occupational workers involved in dye manufacturing factories. It has been observed that occupational workers become exposed to BA either during manufacturing, pulverization, or storage and developed various kinds of skin diseases like contact dermatitis, itching, erythema, roughness, and foremost, hyperpigmentation. It has been shown that some environmental organic pollutants (POPs) like dioxins, furans, and polychlorinated biphenyls (PCBs) may act as ligands for the aryl hydrocarbon receptor (AhR) and regulate hyperpigmentation. Here, we hypothesized that BA may also act as a ligand for AhR and possibly regulate the melanogenic pathway to induced hyperpigmentation. Our computation results indicate that BA has a high binding affinity toward AhR for the initiation of melanogenic signaling. Following the in silico predictions, we used primary mouse melanocytes (PMMs) and confirmed that exposure to BA (5, 10, and 25 MUM) resulted in an increase in AhR expression, tyrosinase activity, and melanin synthesis. Moreover, to study the physiological relevance of these findings, C57BL/6 mice were topically exposed to BA, and enhanced pigmentation and melanin synthesis were observed. Furthermore, the study was extended to assess the mechanistic aspects involved in BA-induced hyperpigmentation in PMMs as well as in mouse skin. Our results suggest that BA exposure initiates AhR signaling and increases tyrosinase enzyme activity and melanin synthesis. Moreover, the genes that regulate the melanin synthesis, such as TRP-1, TRP-2 and the transcription factor MITF, were also found to be increased. Thus, altogether, we suggest that BA-AhR interactions are critical for BA-induced hyperpigmentation. PMID- 28029782 TI - A Tph2GFP Reporter Stem Cell Line To Model in Vitro and in Vivo Serotonergic Neuron Development and Function. AB - Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2GFP, in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene. Tph2GFP mES cells selectively express GFP upon in vitro differentiation toward the serotonergic fate, they synthesize serotonin, possess excitable membranes, and show the typical morphological, morphometrical, and molecular features of in vivo serotonergic neurons. Thanks to the vital reporter GFP, we highlighted by time-lapse video microscopy several dynamic processes such as cell migration and axonal outgrowth in living cultures. Finally, we demonstrated that predifferentiated Tph2GFP cells are able to terminally differentiate, integrate, and innervate the host brain when grafted in vivo. On the whole, the present study introduces the Tph2GFP mES cell line as a useful tool allowing accurate developmental and dynamic studies and representing a reliable platform for the study of serotonergic neurons in health and disease. PMID- 28029783 TI - Platinum-Coated Gold Nanorods: Efficient Reactive Oxygen Scavengers That Prevent Oxidative Damage toward Healthy, Untreated Cells during Plasmonic Photothermal Therapy. AB - As a minimally invasive therapeutic strategy, gold nanorod (AuNR)-based plasmonic photothermal therapy (PPT) has shown significant promise for the selective ablation of cancer cells. However, the heat stress experienced by cells during the PPT treatment produces significant amounts of reactive oxygen species (ROS), which could harm healthy, untreated tissue near the point of care by inducing irreversible damage to DNA, lipids, and proteins, potentially causing cellular dysfunction or mutation. In this study, we utilized biocompatible Pt-coated AuNRs (PtAuNRs) with different platinum shell thicknesses as an alternative to AuNRs often used for the treatment. We show that the PtAuNRs maintain the efficacy of traditional AuNRs for inducing cell death while scavenging the ROS formed as a byproduct during PPT treatment, thereby protecting healthy, untreated cells from indirect death resulting from ROS formation. The synergistic effect of PtAuNRs in effectively killing cancer cells through hyperthermia with the simultaneous removal of heat stress induced ROS during PPT was validated in vitro using cell viability and fluorescence assays. Our results suggest that the high photothermal efficiency and ROS-scavenging activity of PtAuNRs makes them ideal candidates to improve the therapeutic efficacy of PPT treatment while reducing the risk of undesired side effects due to heat-stress-induced ROS formation. PMID- 28029786 TI - Wang-Landau Reaction Ensemble Method: Simulation of Weak Polyelectrolytes and General Acid-Base Reactions. AB - We present a novel method for the study of weak polyelectrolytes and general acid base reactions in molecular dynamics and Monte Carlo simulations. The approach combines the advantages of the reaction ensemble and the Wang-Landau sampling method. Deprotonation and protonation reactions are simulated explicitly with the help of the reaction ensemble method, while the accurate sampling of the corresponding phase space is achieved by the Wang-Landau approach. The combination of both techniques provides a sufficient statistical accuracy such that meaningful estimates for the density of states and the partition sum can be obtained. With regard to these estimates, several thermodynamic observables like the heat capacity or reaction free energies can be calculated. We demonstrate that the computation times for the calculation of titration curves with a high statistical accuracy can be significantly decreased when compared to the original reaction ensemble method. The applicability of our approach is validated by the study of weak polyelectrolytes and their thermodynamic properties. PMID- 28029784 TI - Vault Nanoparticles: Chemical Modifications for Imaging and Enhanced Delivery. AB - Vault nanoparticles represent promising vehicles for drug and probe delivery. Innately found within human cells, vaults are stable, biocompatible nanocapsules possessing an internal volume that can encapsulate hundreds to thousands of molecules. They can also be targeted. Unlike most nanoparticles, vaults are nonimmunogenic and monodispersed and can be rapidly produced in insect cells. Efforts to create vaults with modified properties have been, to date, almost entirely limited to recombinant bioengineering approaches. Here we report a systematic chemical study of covalent vault modifications, directed at tuning vault properties for research and clinical applications, such as imaging, targeted delivery, and enhanced cellular uptake. As supra-macromolecular structures, vaults contain thousands of derivatizable amino acid side chains. This study is focused on establishing the comparative selectivity and efficiency of chemically modifying vault lysine and cysteine residues, using Michael additions, nucleophilic substitutions, and disulfide exchange reactions. We also report a strategy that converts the more abundant vault lysine residues to readily functionalizable thiol terminated side chains through treatment with 2 iminothiolane (Traut's reagent). These studies provide a method to doubly modify vaults with cell penetrating peptides and imaging agents, allowing for in vitro studies on their enhanced uptake into cells. PMID- 28029785 TI - Molecular Dissection of the Forces Responsible for Viral Capsid Assembly and Stabilization by Decoration Proteins. AB - Complex double-stranded DNA viruses utilize a terminase enzyme to package their genomes into a preassembled procapsid shell. DNA packaging triggers a major conformational change in the proteins assembled into the shell and most often subsequent addition of a decoration protein that is required to stabilize the structure. In bacteriophage lambda, DNA packaging drives a procapsid expansion transition to afford a larger but fragile shell. The gpD decoration protein adds to the expanded shell as trimeric spikes at each of the 140 three-fold axes. The spikes provide mechanical strength to the shell such that it can withstand the tremendous internal forces generated by the packaged DNA in addition to environmental insults. Hydrophobic, electrostatic, and aromatic-proline noncovalent interactions have been proposed to mediate gpD trimer spike assembly at the expanded shell surface. Here, we directly examine each of these interactions and demonstrate that hydrophobic interactions play the dominant role. In the course of this study, we unexpectedly found that Trp308 in the lambda major capsid protein (gpE) plays a critical role in shell assembly. The gpE-W308A mutation affords a soluble, natively folded protein that does not further assemble into a procapsid shell, despite the fact that it retains binding interactions with the scaffolding protein, the shell assembly chaparone protein. The data support a model in which the lambda procapsid shell assembles via cooperative interaction of monomeric capsid proteins, as observed in the herpesviruses and phages such as P22. The significance of the results with respect to capsid assembly, maturation, and stability is discussed. PMID- 28029787 TI - Development of a Modified Bouveault-Blanc Reduction for the Selective Synthesis of alpha,alpha-Dideuterio Alcohols. AB - A modified Bouveault-Blanc reduction has been developed for the synthesis of alpha,alpha-dideuterio alcohols from carboxylic acid esters. Sodium dispersions are used as the electron donor in this electron transfer reaction, and ethanol-d1 is employed as the deuterium source. This reaction uses stable, cheap, and commercially available reagents, is operationally simple, and results in excellent deuterium incorporation across a broad range of aliphatic esters, which provides an attractive alternative to reactions mediated by expensive pyrophoric alkali metal deuterides. PMID- 28029789 TI - gem-Diprenylation of Acylphloroglucinols by a Fungal Prenyltransferase of the Dimethylallyltryptophan Synthase Superfamily. AB - Aspergillus terreus aromatic prenyltransferase (AtaPT) catalyzes predominantly C monoprenylation of acylphloroglucinols in the presence of different prenyl diphosphates. With dimethylallyl diphosphate (DMAPP) as prenyl donor, gem diprenylated products 1D3, 2D3, and 3D3 were also detected. High conversion of 1D1 to 1D3, 2D1 to 2D3, and 3D1 to 3D3 was demonstrated by incubation with AtaPT and DMAPP. The first example of gem-diprenylation by a member of the dimethylallyltryptophan synthase superfamily is provided. PMID- 28029790 TI - Cu(OAc)2-Catalyzed Aerobic Oxidative Dehydrogenation Coupling: Synthesis of Heptacyclic Quinolizino[3,4,5,6-kla]perimidines. AB - A Cu(OAc)2-catalyzed domino tricyclization between naphthalene-1,8-diamine and 2 (phenylethynyl)benzaldehyde is described, enabling aerobic oxidative dehydrogenation coupling to access heptacyclic quinolizino[3,4,5,6 kla]perimidines. In this reaction, the formation of three new rings and four new bonds was achieved in a functional-group-compatible fashion, allowing a facile method toward fused aza-heterocycles containing both quinolizine and perimidine moieties. PMID- 28029788 TI - Critical Aspects of Heme-Peroxo-Cu Complex Structure and Nature of Proton Source Dictate Metal-O(peroxo) Breakage versus Reductive O-O Cleavage Chemistry. AB - The 4H+/4e- reduction of O2 to water, a key fuel-cell reaction also carried out in biology by oxidase enzymes, includes the critical O-O bond reductive cleavage step. Mechanistic investigations on active-site model compounds, which are synthesized by rational design to incorporate systematic variations, can focus on and resolve answers to fundamental questions, including protonation and/or H bonding aspects, which accompany electron transfer. Here, we describe the nature and comparative reactivity of two low-spin heme-peroxo-Cu complexes, LS-4DCHIm, [(DCHIm)F8FeIII-(O22-)-CuII(DCHIm)4]+, and LS-3DCHIm, [(DCHIm)F8FeIII-(O22-) CuII(DCHIm)3]+ (F8 = tetrakis(2,6-difluorophenyl)-porphyrinate; DCHIm = 1,5 dicyclohexylimidazole), toward different proton (4-nitrophenol and [DMF.H+](CF3SO3-)) (DMF = dimethyl-formamide) or electron (decamethylferrocene (Fc*)) sources. Spectroscopic reactivity studies show that differences in structure and electronic properties of LS-3DCHIm and LS-4DCHIm lead to significant differences in behavior. LS-3DCHIm is resistant to reduction, is unreactive toward weakly acidic 4-NO2-phenol, and stronger acids cleave the metal O bonds, releasing H2O2. By contrast, LS-4DCHIm forms an adduct with 4-NO2 phenol, which includes an H-bond to the peroxo O-atom distal to Fe (resonance Raman (rR) spectroscopy and DFT). With addition of Fc* (2 equiv overall required), O-O reductive cleavage occurs, giving water, Fe(III), and Cu(II) products; however, a kinetic study reveals a one-electron rate-determining process, ket = 1.6 M-1 s-1 (-90 degrees C). The intermediacy of a high-valent [(DCHIm)F8FeIV?O] species is thus implied, and separate experiments show that one electron reduction-protonation of [(DCHIm)F8FeIV?O] occurs faster (ket2 = 5.0 M-1 s-1), consistent with the overall postulated mechanism. The importance of the H bonding interaction as a prerequisite for reductive cleavage is highlighted. PMID- 28029791 TI - Antisymmetric Couplings Enable Direct Observation of Chirality in Nuclear Magnetic Resonance Spectroscopy. AB - Here we demonstrate that a term in the nuclear spin Hamiltonian, the antisymmetric J-coupling, is fundamentally connected to molecular chirality. We propose and simulate a nuclear magnetic resonance (NMR) experiment to observe this interaction and differentiate between enantiomers without adding any additional chiral agent to the sample. The antisymmetric J-coupling may be observed in the presence of molecular orientation by an external electric field. The opposite parity of the antisymmetric coupling tensor and the molecular electric dipole moment yields a sign change of the observed coupling between enantiomers. We show how this sign change influences the phase of the NMR spectrum and may be used to discriminate between enantiomers. PMID- 28029792 TI - Mechanistic Investigation of Water Oxidation Catalyzed by Uniform, Assembled MnO Nanoparticles. AB - The development of active water oxidation catalysts is critical to achieve high efficiency in overall water splitting. Recently, sub-10 nm-sized monodispersed partially oxidized manganese oxide nanoparticles were shown to exhibit not only superior catalytic performance for oxygen evolution, but also unique electrokinetics, as compared to their bulk counterparts. In the present work, the water-oxidizing mechanism of partially oxidized MnO nanoparticles was investigated using integrated in situ spectroscopic and electrokinetic analyses. We successfully demonstrated that, in contrast to previously reported manganese (Mn)-based catalysts, Mn(III) species are stably generated on the surface of MnO nanoparticles via a proton-coupled electron transfer pathway. Furthermore, we confirmed as to MnO nanoparticles that the one-electron oxidation step from Mn(II) to Mn(III) is no longer the rate-determining step for water oxidation and that Mn(IV)?O species are generated as reaction intermediates during catalysis. PMID- 28029793 TI - Entangled Photon Excited Fluorescence in Organic Materials: An Ultrafast Coincidence Detector. AB - We report the fluorescence emission from organic systems selectively excited by entangled pairs of photons. We have demonstrated a linear dependence of this two photon excited fluorescence on the excitation intensity which is a unique nonclassical feature of two-photon interactions induced by entangled photons. The entangled photon (ETPA) excited fluorescence has been detected in several organic molecules possessing a high entangled photon absorption cross section. The ETPA fluorescence showed a nonmonotonic dependence on the delay between signal and idler beams. The fluorescence signal was detectable within the signal-idler relative delay time interval of ~100 fs. This time is comparable with the estimated entanglement time, TE, making the ETPA-excited fluorescence in organic materials an ideal ultrafast coincidence detector. These results have widespread impact in applications ranging from spectroscopy to chemical and biological sensing, imaging, and microscopy. PMID- 28029794 TI - A Monte Carlo Resampling Approach for the Calculation of Hybrid Classical and Quantum Free Energies. AB - Hybrid free energy methods allow estimation of free energy differences at the quantum mechanics (QM) level with high efficiency by performing sampling at the classical mechanics (MM) level. Various approaches to allow the calculation of QM corrections to classical free energies have been proposed. The single step free energy perturbation approach starts with a classically generated ensemble, a subset of structures of which are postprocessed to obtain QM energies for use with the Zwanzig equation. This gives an estimate of the free energy difference associated with the change from an MM to a QM Hamiltonian. Owing to the poor numerical properties of the Zwanzig equation, however, recent developments have produced alternative methods which aim to provide access to the properties of the true QM ensemble. Here we propose an approach based on the resampling of MM structural ensembles and application of a Monte Carlo acceptance test which in principle, can generate the exact QM ensemble or intermediate ensembles between the MM and QM states. We carry out a detailed comparison against the Zwanzig equation and recently proposed non-Boltzmann methods. As a test system we use a set of small molecule hydration free energies for which hybrid free energy calculations are performed at the semiempirical Density Functional Tight Binding level. Equivalent ensembles at this level of theory have also been generated allowing the reverse QM to MM perturbations to be performed along with a detailed analysis of the results. Additionally, a previously published nucleotide base pair data set simulated at the QM level using ab initio molecular dynamics is also considered. We provide a strong rationale for the use of the Monte Carlo Resampling and non-Boltzmann approaches by showing that configuration space overlaps can be estimated which provide useful diagnostic information regarding the accuracy of these hybrid approaches. PMID- 28029795 TI - Spoxazomicin D and Oxachelin C, Potent Neuroprotective Carboxamides from the Appalachian Coal Fire-Associated Isolate Streptomyces sp. RM-14-6. AB - The isolation and structure elucidation of six new bacterial metabolites [spoxazomicin D (2), oxachelins B and C (4, 5), and carboxamides 6-8] and 11 previously reported bacterial metabolites (1, 3, 9-12a, and 14-18) from Streptomyces sp. RM-14-6 is reported. Structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry data analysis, along with direct comparison to synthetic standards for 2, 11, and 12a,b. Complete 2D NMR assignments for the known metabolites lenoremycin (9) and lenoremycin sodium salt (10) were also provided for the first time. Comparative analysis also provided the basis for structural revision of several previously reported putative aziridine-containing compounds [exemplified by madurastatins A1, B1, C1 (also known as MBJ-0034), and MBJ-0035] as phenol-dihydrooxazoles. Bioactivity analysis [including antibacterial, antifungal, cancer cell line cytotoxicity, unfolded protein response (UPR) modulation, and EtOH damage neuroprotection] revealed 2 and 5 as potent neuroprotectives and lenoremycin (9) and its sodium salt (10) as potent UPR modulators, highlighting new functions for phenol oxazolines/salicylates and polyether pharmacophores. PMID- 28029797 TI - Sequence-Dependent Persistence Lengths of DNA. AB - A Monte Carlo code applied to the cgDNA coarse-grain rigid-base model of B-form double-stranded DNA is used to predict a sequence-averaged persistence length of lF = 53.5 nm in the sense of Flory, and of lp = 160 bp or 53.5 nm in the sense of apparent tangent-tangent correlation decay. These estimates are slightly higher than the consensus experimental values of 150 bp or 50 nm, but we believe the agreement to be good given that the cgDNA model is itself parametrized from molecular dynamics simulations of short fragments of length 10-20 bp, with no explicit fit to persistence length. Our Monte Carlo simulations further predict that there can be substantial dependence of persistence lengths on the specific sequence [Formula: see text] of a fragment. We propose, and confirm the numerical accuracy of, a simple factorization that separates the part of the apparent tangent-tangent correlation decay [Formula: see text] attributable to intrinsic shape, from a part [Formula: see text] attributable purely to stiffness, i.e., a sequence-dependent version of what has been called sequence-averaged dynamic persistence length ld (=58.8 nm within the cgDNA model). For ensembles of both random and lambda-phage fragments, the apparent persistence length [Formula: see text] has a standard deviation of 4 nm over sequence, whereas our dynamic persistence length [Formula: see text] has a standard deviation of only 1 nm. However, there are notable dynamic persistence length outliers, including poly(A) (exceptionally straight and stiff), poly(TA) (tightly coiled and exceptionally soft), and phased A-tract sequence motifs (exceptionally bent and stiff). The results of our numerical simulations agree reasonably well with both molecular dynamics simulation and diverse experimental data including minicircle cyclization rates and stereo cryo-electron microscopy images. PMID- 28029796 TI - Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning. AB - The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated Streptomyces sp. RM-14-6 is reported. Using the engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of 4, while glycosylation of the structurally related inactive spoxazomicin C (3) remarkably invoked neuroprotective activity. PMID- 28029798 TI - Should the Ipsilateral Hamstrings Be Used for Anterior Cruciate Ligament Reconstruction in the Case of Medial Collateral Ligament Insufficiency? Biomechanical Investigation Regarding Dynamic Stabilization of the Medial Compartment by the Hamstring Muscles. AB - BACKGROUND: Semitendinosus and gracilis muscles are frequently harvested for autologous tendon grafts for cruciate ligament reconstruction. This study investigated the joint-stabilizing effects of these hamstring muscles in cases of insufficiency of the medial collateral ligament (MCL). HYPOTHESES: First, both the semitendinosus and gracilis muscles can actively stabilize the joint against valgus moments in the MCL-deficient knee. Second, the stabilizing influence of these muscles decreases with an increasing knee flexion angle. STUDY DESIGN: Controlled laboratory study. METHODS: The kinematics was examined in 10 fresh frozen human cadaveric knees using a robotic/universal force moment sensor system and an optical tracking system. The knee kinematics under 5- and 10-N.m valgus moments were determined in the different flexion angles of the (1) MCL-intact and (2) MCL-deficient knee using the following simulated muscle loads: (1) 0-N (idle) load, (2) 200-N semitendinosus (ST) load, and (3) 280-N (200/80-N) combined semitendinosus/gracilis (STGT) load. RESULTS: Cutting the MCL increased the valgus angle under all tested conditions and angles compared with the MCL-intact knee by 4.3 degrees to 8.1 degrees for the 5-N.m valgus moment and 6.5 degrees to 11.9 degrees for the 10-N.m valgus moment ( P < .01). The applied 200-N simulated ST load reduced the valgus angle significantly at 0 degrees , 10 degrees , 20 degrees , and 30 degrees of flexion under 5- and 10-N.m valgus moments ( P < .05). At 0 degrees , 10 degrees , and 20 degrees of flexion, these values were close to those for the MCL-intact joint under the respective moments (both P > .05). The combined 280-N simulated STGT load significantly reduced the valgus angle in 0 degrees , 10 degrees , and 20 degrees of flexion under 5- and 10-N.m valgus moments ( P < .05) to values near those for the intact joint (5 N.m: 0 degrees , 10 degrees ; 10 N.m: 0 degrees , 10 degrees , 20 degrees ; P > .05). In 60 degrees and 90 degrees of flexion, ST and STGT loads did not decrease the resulting valgus angle of the MCL-deficient knee without hamstring loads ( P > .05 vs deficient; P = .0001 vs intact). CONCLUSION: In this human cadaveric study, semitendinosus and gracilis muscles successfully stabilize valgus moments applied to the MCL-insufficient knee when the knee is near extension. CLINICAL RELEVANCE: In the valgus-unstable knee, these data suggest that the hamstring muscles should be preserved in (multi-) ligament surgery when possible. PMID- 28029799 TI - On the Nature and Role of Peer Review in Mathematics. AB - For the past three decades, peer review practices have received much attention in the literature. But although this literature covers many research fields, only one previous systematic study has been devoted to the practice of peer review in mathematics, namely a study by Geist, Lowe, and Van Kerkhove from 2010. This lack of attention may be due to a view that peer review in mathematics is more reliable, and therefore less interesting as an object of study, than peer review in other fields. In fact, Geist, Lowe, and Van Kerkhove argue that peer review in mathematics is relatively reliable. At the same time, peer review in mathematics differs from peer review in most, if not all, other fields in that papers submitted to mathematical journals are usually only reviewed by a single referee. Furthermore, recent empirical studies indicate that the referees do not check the papers line by line. I argue that, in spite of this, mathematical practice in general and refereeing practices in particular are such that the common practice of mathematical journals of using just one referee is justified from the point of view of proof validity assessment. The argument is based on interviews I conducted with seven mathematicians. PMID- 28029800 TI - Patellofemoral Kinematics and Tibial Tuberosity-Trochlear Groove Distances in Female Adolescents With Patellofemoral Pain. AB - BACKGROUND: Patellofemoral pain (PFP) is a prevalent disorder among female adolescents. Overuse is frequently cited as the cause of pain for this population. What is currently unclear, however, is if the patella demonstrates abnormal tracking patterns relative to the femoral trochlear groove in female adolescents with PFP. PURPOSE: The aim of this case-control study was to determine if abnormal patellar tracking patterns are present in female adolescents with PFP. The secondary aim was to identify if an increased tibial tuberosity-trochlear groove (TT-TG) distance is associated with the observed kinematic patterns. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty female adolescent knees from 12 patients with PFP and 20 age-matched female knees from 13 healthy controls were recruited for this study. Patellofemoral kinematics (eg, lateral patellar displacement) during a repetitive knee extension-flexion maneuver was quantified by dynamic cine phase-contrast magnetic resonance imaging (MRI). Static MRI scans were used to determine the TT-TG distance. RESULTS: Relative to the control cohort, female adolescents with PFP demonstrated significantly greater lateral displacement at 10 degrees (3.2 mm; P < .001), 20 degrees (2.3 mm; P < .001), and 30 degrees (1.7 mm; P = .014) of knee flexion. A subgroup within this cohort (7 knees from 5 patients) demonstrated extreme lateral maltracking >2 SDs of the mean of the control cohort. This subgroup also demonstrated a greater TT-TG distance relative to the controls (Delta = 4.2 mm; P = .001). CONCLUSION: This study demonstrates abnormal lateral patellar displacement in the absence of patellar tilt in female adolescents with PFP. Because all adolescents from both cohorts participated in impact sports, it appears that rigorous athletic training alone is inadequate to produce symptoms in this population. Rather, PFP may derive from a combination of physical activity in the context of pathological kinematics. CLINICAL RELEVANCE: Abnormal patellar tracking patterns and abnormal static alignment have been shown to contribute to the etiology of patellofemoral pain in adults. This study demonstrates that pathologic patellar tracking patterns are present in adolescent females with patellofemoral pain. PMID- 28029802 TI - Should Medicare Value-Based Purchasing Take Social Risk into Account? PMID- 28029801 TI - Sinus Computed Tomographic Findings in Adult Smokers and Nonsmokers with Asthma. Analysis of Clinical Indices and Biomarkers. AB - RATIONALE: When they occur together, sinusitis and asthma are often thought to represent anatomically separate components of the same chronic inflammatory airway disease. Information about the effect of smoking on the interaction between sinusitis and asthma in patients who have both disorders is limited. OBJECTIVES: To evaluate the effect of cigarette smoking on the relationship between the presence and severity of sinusitis and selected asthma-related indices in adults who have asthma. METHODS: This study included 127 patients with severe asthma and 79 patients with mild to moderate asthma. Clinical data were obtained from all subjects during a 2-day stay at Hokkaido University Hospital (Sapporo, Japan). The Lund-Mackay scoring system was used to assess the anatomic extent and severity of sinusitis as revealed by sinus computed tomographic (CT) images obtained during hospitalization. We examined associations between Lund Mackay scores and a variety of asthma-related indices and levels of biomarkers in blood and sputum. To clarify the effect of smoking on these associations, we conducted separate analyses for nonsmoking (<10 pack-years; n = 130) and smoking subjects (>=10 pack-years; n = 76). MEASUREMENTS AND MAIN RESULTS: In our cohort of adults with asthma, we found significant positive relationships between the presence and severity of sinusitis as assessed by Lund-Mackay score and the severity of asthma as measured by percent predicted FEV1 or FEV1/FVC for nonsmoking subjects (<10 pack-years) but not for cigarette smokers (>10 pack years). Lund-Mackay scores correlated with blood and sputum eosinophil counts, serum IgE levels, and fractional exhaled nitric oxide, regardless of smoking status. Lund-Mackay scores also showed significant positive associations with serum periostin and chemokine C-C motif ligand 18 levels, regardless of smoking status, whereas a positive association with plasma osteopontin level was seen only for nonsmoking subjects. CONCLUSIONS: We found an association between the severity of sinusitis on CT imaging and the severity of concomitant asthma on spirometry for nonsmoking adults but not for smokers. In adults with asthma, CT imaging evidence of severe sinusitis indicates intense Th2-related inflammation, regardless of smoking status. PMID- 28029803 TI - Pathology's Stepchild. PMID- 28029805 TI - Therapeutic Laryngoscopy during Exercise for Treatment of Refractory Exercise induced Laryngeal Obstruction. A Personal Experience. PMID- 28029804 TI - Prospective Evaluation of Surgical Treatment of Humeral Avulsions of the Glenohumeral Ligament. AB - BACKGROUND: Humeral avulsion of the glenohumeral ligament (HAGL) is an infrequent but significant contributor to shoulder dysfunction, instability, and functional loss. PURPOSE: To prospectively identify patients with HAGL lesions and then conduct retrospective evaluation of the clinical history, examination findings, and surgical outcomes of these patients. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Over a 6-year period (2006-2011), patients with shoulder dysfunction and a HAGL lesion that was confirmed via magnetic resonance arthrogram (MRA) were prospectively evaluated with a minimum 2-year follow-up. Patient demographics, presentation, examination, and surgical findings were documented. Outcomes of return to activity as well as Western Ontario Shoulder Instability Index (WOSI) and Single Assessment Numeric Evaluation (SANE) scores were recorded at final follow-up. Anterior HAGL (aHAGL) lesions were repaired with a partial subscapularis tenotomy approach, while reverse (rHAGL) lesions were repaired arthroscopically. RESULTS: Of 28 patients, 27 (96%) completed the study requirements at a mean of 36.2 months (range, 24-68 months). The sample contained 12 females (44%) and 15 males (56%), who had a mean age of 24.9 years (range, 18-34 years). The chief complaint reported was pain in 23 patients (85%), while only 4 (15%) patients complained primarily of recurrent instability symptoms. Fourteen patients (52%) had aHAGL lesions, 10 patients (37%) had rHAGL lesions, and 3 patients (11%) had combined aHAGL and rHAGL lesions. Ten patients (37%) had concomitant HAGL lesions and labral tears, whereas 17 patients (63%) had isolated HAGL lesion without labral tear. The 17 patients (63%) with aHAGL lesions or combined lesions underwent a partial subscapularis tenotomy approach, while the remaining 10 patients (37%) with rHAGL lesions underwent arthroscopic surgical repair. After surgery, WOSI outcomes improved from 54% to 88% and SANE outcomes improved from 50% to 91% ( P < .01 for both), with no reports in recurrence of instability symptoms at final follow-up. CONCLUSION: This study demonstrated that patients with symptomatic HAGL lesions predominantly report shoulder pain and dysfunction, with few chief complaints of recurrent instability complaints. After surgery, patients showed predictable return to full activity, improvement in objective and patient-reported outcomes, and satisfaction with treatment outcome. PMID- 28029806 TI - Liberation from Mechanical Ventilation in Critically Ill Adults. An Official ATS/ACCP Clinical Practice Guideline. PMID- 28029807 TI - Physicians' Perspectives and Practice Patterns Toward Opportunistic Salpingectomy in High- and Low-Risk Women. AB - BACKGROUND: Opportunistic bilateral salpingectomy (OBS) has been proposed as an ovarian cancer risk-reducing strategy. METHODS: A survey was emailed to 300 members of the American College of Obstetricians and Gynecologists. RESULTS: 125 (42%) surveys were returned: 60% female, 88% generalists, 67% private practice. Only 36% correctly identified the lifetime risk of ovarian cancer, only 23% understood the risk-reducing benefit of bilateral salpingo-oophorectomy. 75% perform salpingectomy during hysterectomy, 26-53% use for sterilization depending on approach. Concerns were increased operative time and complications. For BRCA mutations, 64% recommend BSO, 12% recommend a two-step risk-reducing strategy, and 14% refer to gynecologic oncology. CONCLUSIONS: We identified broad support and factors limiting willingness to perform OBS. PMID- 28029904 TI - Statement of Retraction. PMID- 28029852 TI - Impact of a Mindfulness-Based Weight-Loss Intervention on Sleep Quality Among Adults with Obesity: Data from the SHINE Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVE: Sleep disturbance is a common problem among adults with obesity. Mindfulness interventions have been shown to improve sleep quality in various populations but have not been investigated in adults with obesity. The aim of this study was to compare the effects of a mindfulness-based weight-loss intervention with an active control on self-reported sleep quality among adults with obesity. METHOD: This study was a secondary analysis of a randomized controlled trial and included 194 adults with a body mass index in the range 30 45 kg/m2. The treatment intervention included mindfulness-based eating and stress management practices, and the active control intervention included training in progressive muscle relaxation (PMR). Both groups received identical diet and exercise guidelines in 17 group sessions conducted over 5.5 months that were matched for time, attention, and social support. The primary outcome of this analysis was between-group change in self-reported sleep quality, which was assessed using the Pittsburgh Sleep Quality Index (PSQI) global score at baseline and at 6, 12, and 18 months. RESULTS: Between-group differences in mean PSQI change scores in the mindfulness group (n = 100) compared to the control group (n = 94) were -0.27 (-0.68, 1.22; p = 0.58) at 6 months, -0.57 (-0.35, 1.50; p = 0.22) at 12 months, and -0.50 (-0.53, 1.53; p = 0.34) at 18 months, all in the direction of more sleep improvement in the mindfulness group but none reaching statistical significance. In the mindfulness group, average weekly minutes of meditation practice time was associated with improved sleep quality from baseline to 6 months. CONCLUSIONS: No statistically significant evidence was found that a weight-loss program that incorporates mindfulness improves self-reported sleep quality compared to a control diet/exercise intervention that included PMR. Within the mindfulness group, average weekly minutes of mindfulness practice was associated with improved sleep quality. PMID- 28029905 TI - The Cost of Synoptic Reporting. PMID- 28029906 TI - In Reply. PMID- 28029907 TI - CDH17 Is a More Sensitive Marker for Gastric Adenocarcinoma Than CK20 and CDX2. AB - CONTEXT: -CDH17, which is expressed in the intestinal epithelium, is a novel oncogene involved in tumor invasion and metastasis. A panel consisting of cytokeratin (CK) 7, CD20, and CDX2 antibodies is typically used to diagnose gastrointestinal adenocarcinomas. However, studies have shown that CDH17 is a highly specific marker for gastrointestinal adenocarcinoma and may be important in clinical diagnosis. OBJECTIVE: -To evaluate the sensitivity and specificity of CDH17, CK20, and CDX2 antibodies in neoplastic tissues, with emphasis on colon, stomach, and esophageal gastrointestinal lineage. DESIGN: -Immunohistochemistry was performed with CDH17, CK20, and CDX2 antibodies on formalin-fixed, paraffin embedded tissue microarrays from normal (n = 26) and neoplastic (n = 884) tissues. RESULTS: -CDH17 immunostaining was positive in 97.3% (145 of 149) of colon adenocarcinomas, whereas CK20 and CDX2 stained positively in 88.6% (132 of 149) and 93.3% (139 of 149), respectively. In metastatic colon cancers, CDH17, CK20, and CDX2 positive staining was observed in 90.6% (29 of 32), 59.4% (19 of 32), and 81.3% (26 of 32) of cases, respectively. In stomach adenocarcinomas, CDH17 positively stained 64.0% (112 of 175) of tissues, compared to CK20 and CDX2, where staining was observed in only 24.6% (43 of 175) and 46.9% (82 of 175), respectively. In esophageal adenocarcinomas, CDH17, CK20, and CDX2 stained 38.7% (12 of 31), 25.8% (8 of 31), and 29% (9 of 31) of specimens, respectively. Low or no expression was observed in other neoplastic tissues, except pancreatic cancers, where CDH17 displayed higher expression than CK20 and CDX2. CONCLUSIONS: -CDH17 is a specific and more sensitive marker in the gastrointestinal tract than CK20 and CDX2. CDH17 may be especially valuable when gastrointestinal tumors are suspected in cancers of unknown primary. PMID- 28029908 TI - Pathology of Ischemic Optic Neuropathy. AB - Ischemic optic neuropathy (ION) describes a state of hypoxic injury of the optic nerve. Clinically, ION is divided into anterior and posterior forms defined by the presence or absence of optic disc swelling, respectively. It is further classified as arteritic when secondary to vasculitis, and nonarteritic when not. The site of vascular occlusion for anterior ION from giant cell arteritis is the short posterior ciliary arteries, but mechanical vascular obstruction does not play a role in most nonarteritic cases. Histologically, ION is characterized by axon and glial necrosis, edema, and a sparse mononuclear response. Like other ischemic injuries, the morphologic alternations in the nerve are time dependent. A variant of ION called cavernous degeneration (of Schnabel) features large cystic spaces filled with mucin. Several conditions can histologically mimic cavernous degeneration of the optic nerve. The scarcity of cases of ION examined histologically has contributed to an incomplete understanding of its pathogenesis. PMID- 28029909 TI - Rhesus Immunoglobulin Dosage and Administration in Obese Individuals. PMID- 28029910 TI - The Health Effects of Electronic Cigarettes. PMID- 28029911 TI - Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease. PMID- 28029912 TI - Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease. PMID- 28029913 TI - Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease. PMID- 28029914 TI - Breathing Easier with Fish Oil - A New Approach to Preventing Asthma? PMID- 28029915 TI - Effectiveness of Fluticasone Furoate-Vilanterol in COPD. PMID- 28029916 TI - Effectiveness of Fluticasone Furoate-Vilanterol in COPD. PMID- 28029917 TI - Disseminated Cysticercosis. PMID- 28029919 TI - More on Treatment Outcomes in Multidrug-Resistant Tuberculosis. PMID- 28029918 TI - Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. AB - BACKGROUND: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of >=20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of >=20%) has not been observed to date. Anecdotal evidence of decreases in tumor related pain, disfigurement, and functional impairment was observed. CONCLUSIONS: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .). PMID- 28029920 TI - More on Treatment Outcomes in Multidrug-Resistant Tuberculosis. PMID- 28029921 TI - Case 40-2016. A 14-Month-Old Girl with Recurrent Vomiting. PMID- 28029922 TI - Supporting Family Caregivers of Older Americans. PMID- 28029923 TI - Safety of Nonsteroidal Antiinflammatory Drugs. PMID- 28029924 TI - Engineering Social Incentives for Health. PMID- 28029925 TI - Myasthenia Gravis. PMID- 28029926 TI - Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. AB - BACKGROUND: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS: We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS: A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS: Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .). PMID- 28029928 TI - Infected Urachal Cyst. PMID- 28029927 TI - Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. AB - A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Ralpha2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Ralpha2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .). PMID- 28030128 TI - Statement of retraction. PMID- 28029929 TI - Fish Oil Supplementation in Pregnancy. PMID- 28030282 TI - The Global Trachoma Mapping Project: A Catalyst for Progress Against Neglected Tropical Diseases. PMID- 28030331 TI - Morphological and molecular characterization of Cucullanus bourdini Petter et Le Bel, 1992 (Ascaridida: Cucullanidae) from the yellowback fusilier Caesio xanthonota Bleeker (Perciformes: Caesionidae). AB - The detailed morphology of Cucullanus bourdini Petter et Le Bel, 1992 was further studied using both light and scanning electron microscopy, based on specimens collected from the yellowback fusilier Caesio xanthonota Bleeker (Perciformes: Caesionidae) from off the Taiwan Strait. In addition, C. bourdini was characterized genetically for the first time using molecular approaches by sequencing and analysing ribosomal [small ribosomal subunit (18S rDNA) and internal transcribed spacer 2 (ITS-2)] and mitochondrial [cytochrome c oxidase subunit 1 (cox1)] target regions. The molecular analysis of C. bourdini displayed no nucleotide differences in the 18S sequences, but detected 0.20-2.82% and 0.52 1.04% nucleotide divergence in the ITS-2 and cox1 regions, respectively. The new morphological and genetic data obtained herein would enable us to identify this hitherto little known species more rapidly and accurately. PMID- 28030332 TI - Spermatological characteristics of the enigmatic monogenean Dictyocotyle coeliaca Nybelin, 1941 (Monopisthocotylea: Monocotylidae) reveal possible adaptation to endoparasitism. AB - Spermatological characters of Dictyocotyle coeliaca Nybelin, a unique endoparasitic monogenean from the body cavity of the ray Amblyraja radiata (Elasmobranchii: Rajidae), was investigated by means of scanning and transmission electron microscopy for the first time. The process of the spermatozoon formation begins with the appearance of the differentiation zone which contains two centrioles. Subsequently developed two free flagella rotate to lie parallel before their fusing. After fusion, both the mitochondrion and nucleus migrate alongside the axonemes. Spermatids are formed within parallel cytoplasmic canals. During late spermiogenesis, an electron-dense spiral end-piece is formed proximally to the centriolar region of some spermatids. At the end of spermiogenesis, this end-piece is separated by a plasma membrane from the late spermatid and remains in the residual cytoplasm when spermatozoa are released into the testis lumen. The mature spermatozoon of D. coeliaca contains two parallel axonemes with the 9 + "1" trepaxonematan pattern, mitochondrion, nucleus, parallel cortical microtubules, and electron-dense granules. Especially the presence of electron-dense granules, occurring frequenly in the spermatozoa of endoparasitic flatworms, may indicate an adaptation to endoparasitic lifestyle in D. coeliaca. The anterior extremity of the male gamete contains one centriolar derivative, a small component of the second centriolar derivative and anterior extremity of the mitochondrion. The posterior extremity of the mature spematozoon exhibits tubular elements of the disorganized axoneme. Variations of the spermatozoon ultrastructural characters within monocotylid monogeneans and possible evolutionary significance of glycogen in sperm to the endoparasitic habit are discussed. PMID- 28030333 TI - Serosurvey of anti-Toxoplasma gondii antibodies in sport horses from Paraiba state, Northeastern Brazil. AB - Although the infection by Toxoplasma gondii in horses is usually asymptomatic, it may be characterized by the presence of tissue cysts and maintenance of detectable antibody titers. The aim of this study was to detect anti-T.gondii antibodies and to determine risk factors associated in sport horses from Paraiba State, Northeastern Brazil. A total of 138 apparently healthy sport horses of different age and gender were sampled. Anti-Toxoplasma gondii antibodies were detected in 16/138 (11.6%; 95% CI: 6.77-18.14%) horses by indirect immunofluorescence antibody assay (IFA). A significant association was found between the water source and seropositivity to T. gondii (p<0.05). The present study highlights the importance of providing good quality water to the animals. PMID- 28030334 TI - Trichuris suis secrete products that reduce disease severity in a multiple sclerosis model. AB - Multiple sclerosis is a chronic inflammatory central nervous system (CNS) disease, which affects about 1 in 1000 individuals in the western world. It has been suggested that this relatively high prevalence is linked to a high level of hygiene, i.e. a reduced exposure to various microorganisms, including parasites. Parasites are known to employ different immunomodulatory and antiinflammatory strategies, which enable them to evade destruction by the immune system. We have investigated the immunomodulation by the swine whipworm, Trichuris suis, by measuring the impact of oral administration of T. suis ova as well as of intraperitoneal administration of T. suis excretory/secretory products on the development and progression of experimental autoimmune encephalomyelitis - an animal model that shares clinical and pathological characteristics with multiple sclerosis. Intraperitoneal administration of excretory/secretory products before disease onset, resulted in a significant decrease in disease severity as well as markedly reduced TH1 and TH17 T-cell responses, centrally in the spinal cord as well as in the periphery, i.e. the spleen. Thus, parenteral administration of T. suis-derived products results in a skewing of the immune response with a significant impact on disease severity in a CNS inflammatory disease model. PMID- 28030335 TI - Coccidiosis in European rabbit (Oryctolagus cuniculus algirus) populations in the Iberian Peninsula. PMID- 28030336 TI - Genetic diversity among Babesia rossi detected in naturally infected dogs in Abeokuta, Nigeria, based on 18S rRNA gene sequences. AB - Adequate knowledge of the genetic diversity among Babesia species infecting dogs is necessary for a better understanding of the epidemiology and control of canine babesiosis. Hence, this study determined the genetic diversity among the Babesia rossi detected in dogs presented for routine examination in Veterinary Hospitals in Abeokuta, Nigeria. Blood were randomly collected from 209 dogs. Field-stained thin smears were made and DNA extracted from the blood. Partial region of the 18S small subunit ribosomal RNA (rRNA) gene was amplified, sequenced and analysed. Babesia species was detected in 16 (7.7%) of the dogs by microscopy. Electrophoresed PCR products from 39 (18.66%) dogs revealed band size of 450 bp and 2 (0.95%) dogs had band size of 430 bp. The sequences obtained from 450 bp amplicon displayed homology of 99.74% (387/388) with partial sequences of 18S rRNA gene of Babesia rossi in the GeneBank. Of the two sequences that had 430 bp amplicon, one was identified as T. annulata and second as T. ovis. A significantly (p<0.05) higher prevalence of B. rossi was detected by PCR compared to microscopy. The mean PCV of Babesia infected dogs was significantly (p<0.05) lower than non-infected dogs. Phylogenetic analysis revealed minimal diversity among B. rossi with the exception of one sequence that was greatly divergent from the others. This study suggests that more than one genotype of B. rossi may be in circulation among the dog population in the study area and this may have potential implication on clinical outcome of canine babesiosis. PMID- 28030337 TI - Occurrence of Naegleria species in therapeutic geothermal water sources, Northern Iran. AB - Potentially pathogenic Free-Living Amoebae include members belonging to Naegleria genus. The species N. fowleri is known worldwide as the causative agent of the lethal Primary Amoebic Meningoencephalitis (PAM). Only one clinical case of N. fowleri has been reported in Iran. Several species of Naegleria have been reported to be natural carriers of other potentially pathogenic microbial agents. The thermotolerance properties of this genus facilitates their presence in geothermal water sources including hot springs and spas. In the current study water samples were collected from 22 therapeutic hot springs, Northern Iran and investigated for the presence of Naegleria spp. using morphological keys and PCR/DNA sequencing based methods. Incubation of collected samples were done at both 30 degrees C and 45 degrees C in order to detect Naegleria spp. and N. fowleri, respectively. Thermotolerance assay and flagellation tests were also performed. The obtained results revealed that 54% of the investigated water samples were positive for Naegleria spp. including N. australiensis, N. americana, N. dobsoni, N. pagei, N. polaris and N. fultoni. The pathogenic N. fowleri was not detected. The most detected Naegleria was belonged to N. australiensis. This is the first report on the Naegleria spp. occurrence in hot springs in Northern Iran showing that most of the surveyed hot spring sources were contaminated with non-pathogenic Naegleria spp. However, due to the recent report of PAM in the country, further studies to investigate the presence of pathogenic N. fowleri in the environment and clinical samples is needed in the region and worldwide. PMID- 28030338 TI - Lethal Angiostrongylus vasorum infection in a Hungarian dog. AB - During post-mortem examination of lungs and heart of a 7-month-old female French bulldog, 158 worms were collected from the lung vessels and they proved Angiostrongylus vasorum by their morphological and genetic identification by PCR. The histopathological investigation found a multifocal interstitial inflammation characterized by numerous lymphocytes and a smaller number of plasma cells and eosinophils whilst L1 stage larvae could be seen inside dilated alveoli. We suggested a lethal angiostrongylosis supposed to lead to a fatal effect. Our report attracts attention to the presence of the nematode A. vasorum as causative agent of canine cardiopulmonary disorder in the south-western region of Hungary. PMID- 28030339 TI - Intra and inter species genetic variability of transferrin receptor gene regions in Trypanosoma evansi isolates of different livestock and geographical regions of India. AB - Trypanosoma evansi, the aetiological agent of Surra affects a wide range of livestock and wild animals in India. In the present study, we studied intra- and inter species genetic variability in the transferrin receptor encoding gene regions (ESAG6/7 gene region) of T. evansi isolates by cloning, sequencing and phylogenetic study collected from camel, cattle, donkeys and ponies from North Western and Central India. The nucleotide sequence variation of ESAG6/7 gene region between Indian T. evansi isolates was up to 17.7% and amino acid sequence variation was up to 31%. Twenty nine clones from six T. evansi isolates from geographical regions of India were included into Clade 1, 5, 6, 7 and 9 consisting of ESAG6 variants reported among T. evansi isolates from South-east Asia and South America. The cladogram indicated a relation between the host species and the genetic variability in the hyper-variable region of ESAG6 gene. Analysis of the Indian ESAG6 variants and their respective Clade positions presented a host specific distribution indicating homogenous parasite population in their respective animal hosts. PMID- 28030340 TI - A new species of myocoptid mites Myocoptes (Comyocoptes) nesokia sp. nov. (Acariformes: Myocoptidae) parasitizing Nesokia indica (Rodentia: Muridae) in Pakistan. AB - A new species of parasitic mites, Myocoptes (Comyocoptes) nesokia sp. nov. (Acariformes: Myocoptidae) is described from Nesokia indica (Gray, 1830) (Rodentia: Muridae) from Pakistan. Females of this species differ from the morphologically similar species, Myocoptes (Comyocoptes) striatus Fain, 1970, by the presence of a verrucose pattern in the middle part of the hysteronotum, longer setae cp (120-140 MUm vs. 55-60 MUm), and by the absence of scales on the opisthosomal cuticle posterior to the level of setal bases ps3. PMID- 28030341 TI - The genetic structure of hypoderatid mites (Actinotrichida: Astigmata) parasitizing great cormorant (Phalacrocorax carbo) during host post-breeding dispersal in Milicz, SW Poland. AB - The astigmatid family Hypoderatidae includes over 80 mite species exhibiting peculiar life cycle. Deutonymphs are parasitic instars inhabiting subcutaneous or visceral tissues of birds and rodents, while all other instars are nidicolous forms. In this study we investigated genetic diversity of deutonymphs of two hypoderatid species, Neottialges evansi and Phalacrodectes gaudi, collected from 16 individuals of the great cormorant Phalacrocorax carbo in SW Poland during host post-breeding dispersal. The initial alternative hypotheses were: (1) populations of deutonymphs in both mite species found in tissues of particular bird individuals form genetically distinct populations, (2) mites are panmictic among hosts. The topologies of NJ phylogenetic trees and median-joining haplotype networks reconstructed for COI haplotypes revealed lack of hostdependent genetic structure in populations of N. evansi and P. gaudi. Furthermore, high haplotype diversity (Hd) and low nucleotide diversity (Pi) prove high genetic differentiation of both mite species. We concluded, that unlimited dispersal of mites among cormorant specimens could be explained by host specific breeding behavior: free mating between cormorants originating from different European populations and low contribution of reunited pairs in breeding colonies in subsequent breeding seasons, reuse of the same nest material by different members of the colony, and host behavior called prospecting. PMID- 28030342 TI - Molecular diagnosis of Entamoeba spp. versus microscopy in the Great Cairo. AB - Amoebiasis is a human disease produced by Entamoeba histolytica which causes widespread mortality and morbidity worldwide through diarrheal disease and abscess establishment in parenchymal tissues such as liver, lung, and brain. The true prevalence of infection is unknown for most areas of the world due to the difficulty to characterise Entamoeba histolytica versus other non-pathogenic amoebas with identical morphology, as Entamoeba dispar, and Entamoeba moshkovskii. To overcome microscopy misidentification issues, we tested a nested multiplex polymerase chain reaction (PCR) and a real-time PCR on 194 stool samples collected from incoming dysentery patients in Cairo hospitals diagnosed with E. histolytica by microscopy. Nested PCR showed only 20 (10.3%) samples positive to E. histolytica and 17 (8.7%) to E. dispar. The real-time PCR detected only 19 and 11 samples positive to E. histolytica and E. dispar respectively, showing less sensitivity than the nested PCR. The data show that prevalence of E. histolytica in Cairo is lower when specific diagnosis methods are used instead of traditional microscopy, allowing to differentiate between morphologically identical human amoebas species. PMID- 28030343 TI - Anti-Anisakis sp. antibodies in serum of healthy subjects. Relationship with alphabeta and gammadelta T cells. AB - Anisakiosis is nowadays one of the nematodoses more prevalent in Spain, with rates that oscillate between 0.43% in Galicia (N.W. Spain), and 15.7% and 22.1% in inland and southern regions, respectively. Likewise, it has been proved that Anisakis larvae have developed mechanisms to modulate the dichotomy of the host immune response for their own benefit. The experimental hypothesis of the present study was that Anisakis sp. larval products can be mediators of immune suppression and induce changes on the populations of alphabeta+ and gammadelta+ T cells. In the present study we determined the levels of anti-Anisakis antibodies in the serum of healthy people, and their relationship with the B and T cell subsets. Levels of anti-Anisakis antibodies (Ig's, IgG, IgM, IgA and IgE) were measured by ELISA, while B and T cell subsets were studied by flow cytometry. Cells were labelled with monoclonal antibodies against CD45, CD4, CD8, CD56, CD3, CD19, TCRalphabeta and TCRgammadelta. All the specific isotypes studied were negatively correlated with NKT cell rates with the exception of IgG. A previous contact with Anisakis was related to a decrease in CD56+alphabeta+ and all gammadelta+ T cell subsets. The CD3+gammadelta+ population was lower in the group of subjects that showed IgA anti-Anisakis. We observed an inverse correlation among alphabeta-gammadelta NKT cells and anti-Anisakis sp. antibodies. CD3+CD56+ cells showed a significant decrease in the group of anti-Anisakis positive subjects. This fact was especially significant with CD3+CD56+gammadelta+ cells in the case of the anti-Anisakis IgA positive group. PMID- 28030344 TI - Report of fatal mixed infection with Cryptosporidium parvum and Giardia intestinalis in neonatal calves. AB - In the production and management of beef and dairy cattle, controlling diarrhea is one of the important concerns. Pathogenic agents of the disease, protozoan parasites including Cryptosporidium spp., are difficult to control, making prevention, diagnoses, and treatment of diarrhea. In the present study, we investigated a farm with a history of calf deaths over a period of 10 years in order to determine the cause of disease and to clarify the detailed distribution of the pathogens. In four examined calves that were reared in calf pens, all were positive with Cryptosporidium and/or Giardia, while the other breeding stock and adult cattle were negative. Molecular analyses revealed that the isolates from calves were C. parvum subtype IIaA15G2R1 as a zoonotic and G. intestinalis assemblage E. Other pathogenic bacteria and diarrhea-causing viruses were not detected. After treating the calf pens with boiling water and milk of lime (Ca[OH]2), oocysts of C. parvum and cysts of G. intestinalis were not found and no additional calves died. This is the first report to describe the mixed infection of both parasites in Japan. PMID- 28030345 TI - Dictyocaulosis in dairy cows in Brazil: an epidemiological, clinical-pathological and therapeutic approach. AB - An outbreak of severe parasitic pneumonia caused by Dictyocaulus viviparus was diagnosed in adult dairy cows in the municipality of Arabuta, Southern Brazil. The total morbidity in the herd was 71.9%, and the morbidity amongst adult lactating cattle was 100%. The main clinical signs observed were dyspnea, tachypnea, nasal discharge, decreased milk production, and cough. A necropsy was conducted on one animal in order to establish the diagnosis. The herd had been treated previously with levamisole; however, clinical signs persisted and became worse. After treatment with eprinomectin the severity of clinical signs decreased, and the respiratory condition subsequently disappeared. It is believed that the high morbidity presented in this outbreak is related to epidemiological factors, such as increased rainfall in 2014 and 2015, associated with low immunity of the herd. This is the first report of dictyocaulosis in adult dairy cattle in Brazil. Furthermore, it describes an outbreak presenting very high morbidity. PMID- 28030346 TI - New records of host-parasite relationships between Coenagrion scitulum (Rambur, 1842) (Odonata) and water mite larvae (Hydrachnidia) in core and edge host populations. AB - The relationships between water mite larvae parasitizing Coenagrion scitulum in core and edge populations were described. A total of 636 larvae of 7 water mite species were found on 143 C. scitulum adults (82 females and 61 males). C. scitulum was recorded for the first time as a host species for Arrenurus cuspidator, A. bruzelii, A. bicuspidator, A. tricuspidator, A. claviger and Hydryphantes octoporus. The degree of infestation by particular parasite species was typical for these species. In contrast, the parasites' preferences for host body parts were not typical, as they preferred abdominal segments 2-4, which in earlier studies had been avoided by water mite larvae. No differences were found in degree of infestation of Coenagrion scitulum individuals between core and edge populations, with the exception of Hydryphantes octoporus, which parasitized damselflies only in core populations. PMID- 28030347 TI - Reduced [14C]-methionine uptake and fecundity in Schistosoma mansoni females treated with recombinant tumor necrosis factor alpha in vitro. AB - Recombinant human TNFalpha (rhTNFalpha) has previously been shown to reduce fecundity in Schistosoma mansoni adult females maintained in vitro without males, and adversely affect the uptake of [14C]-tyrosine, an amino acid required for schistosome vitellogenesis. Here we report on the effect of rhTNFalpha on [14C] methionine uptake in both separated and paired females, and the effect of three different preparations of rTNFalpha on schistosome oviposition in vitro. In the absence of rhTNFa, separated females incorporated only 30% of the [14C] methionine incorporated by paired females in a dose and time-dependent manner, suggesting low metabolic activity of females in the absence of males. Separated females and worm-pairs were treated with increasing doses of rhTNFalpha for 2 or 4 hr and then incubated in RPMI 1640 containing 10% fetal calf serum (FCS) and 5 uCi ml-1[14C]-methionine for 1 hr. Separated females treated with rhTNFa for 4 hr incorporated less methionine than those treated for 2 hr. In contrast, paired females treated with rhTNFa incorporated significantly smaller amounts of [14C] methionine in a TNFa dose-dependent but time-independent manner [2 hr (P = 0.001) or 4 hr (P = 0.027) One-Way ANOVA]. Worm-pairs maintained in RPMI 1640 containing 10% FCS and 100 ng ml-1 of any of the three rTNFa preparations laid significantly fewer eggs than the worms cultured without rTNFalpha(P = 0.001; Kruskal-Wallis Test). We also observed that among rTNFalpha-treated worm-pairs, females were sluggish and tended to separate from their male partners. These observations suggest that TNFa inhibits [14C]-methionine uptake and reduces fecundity in females paired with males. Since paired females incorporate substantially greater amounts of [14C]-methionine, the role of males in stimulating metabolic activity in females is affirmed. Reduced amino acid uptake, and possibly other nutrients, may contribute to the diminished fecundity observed in TNFa-treated females. PMID- 28030348 TI - Prochristianella clarkeae Beveridge, 1990 (Eutetrarhynchidae): a species complex or a species with intraspecific variation in the distribution of its tegumental microtriches? AB - The microthrix pattern of common forms of the trypanorhynch cestode Prochristianella clarkeae Beveridge, 1990 on which the microscopically visible microtriches almost extended to the posterior end of the scolex was described using SEM and compared to other forms for which this pattern was different. The proximal bothrial surface and the scolex peduncle of all the examined specimens were covered with palmate spinitriches and papilliform filitriches. Unlike the common specimens of P. clarkeae, on the surface of those specimens with unusual distributions of microtriches as well as those on which the microscopically visible microtriches were not observable, palmate spinitriches extended to the mid-pars vaginalis and not to the posterior end of the scolex. Statistical tests did not detect any significant difference in the measurements of the specimens possessing different microthrix patterns. Furthermore, the partial 28S rDNA confirmed that the different forms were conspecific and that P. clarkeae possesses an intraspecific variation in the distribution of palmate spinitriches. Pastinachus sephen as a new host record was also established for Prochristianella clarkeae reported for the first time from the Persian Gulf. PMID- 28030349 TI - Prevalence of three Oesophagostomum spp. from Tibetan Pigs analyzed by Genetic Markers of nad1, cox3 and ITS1. AB - Parasitic nematodes of Oesophagostomum spp., commonly known as 'nodular worms' are one of the most widely distributed and prevalent emerging zoonotic nematodes. However, little is known about the prevalence and gene characteristics of those parasites in Tibetan pigs. Therefore, a study was carried out to investigate the prevalence, isolation and identification of Oesophagostomum spp from Tibetan pigs by genetic markers of nad1,cox3 and ITS1 for the first time. The results revealed that the infection rate of O. dentatum and O. quadrispinulatum by genetic markers of nad1 was 81.13%; 35 (66.04%); the O. dentatum and O. quadrispinulatum by genetic markers cox3 was 66.04%, and O. dentatum and O. stephanostomum by genetic markers ITS1 was found to be 77.36%. Interestingly, the O. stephanostomum specie was identified and isolated from 90.48% stomach and 69.23% colon samples by genetic markers of ITS1. The present study, for the first time has described the presence and genetic characterization of Oesophagostomun spp of O. dentatum, O. quadrispinulatum and especially O. stephanostomum in Tibetan pigs from the high and remote Tibetan plateau. A public concern should be raised in terms of economical losses and severe public health problem. PMID- 28030350 TI - Prevalence and molecular characterization of Theileria equi and Babesia caballi in jereed horses in Erzurum, Turkey. AB - Equine piroplasmosis (EP) is a hemoprotozoan tick-borne disease with worldwide distribution that is caused by Theileria equi and Babesia caballi. There are studies reporting the presence of equine piroplasmosis in Turkey but the situation in Erzurum is unknown. The aim of the current study was to determine the situation of equine piroplasmosis in jeered horses in Erzurum. Between April and August 2015, a total of 125 Arabian horse were examined and blood samples were collected. At the time of sampling, animals were also examined for tick infestations and clinical signs. Besides microscopic examination of Giemsastained blood smears, multiplex PCR performed with species specific primers partially amplifying the 18S rRNA gene of B. caballi and T. equi. During the microscopic examination of blood smears, T. equi piroplasms were found in 6 (4.8%) samples. In total, 11 (8.8%) T. equi DNA were detected with multiplex PCR. B. caballi piroplasms or DNA were not obtained. BLAST analysis of the sequenced T. equi samples (GenBank: KU921661-KU921667) indicated 98.8-100% identity to each other, and 100% similarity to T. equi isolates in South Africa, Iran, China, Sudan, India, Mongolia, Trinidad, Kenya, Spain, Serbia, Bosnia and Herzegovina and Turkey (Bursa). The results of our study indicate that T. equi occurs more frequently than B. caballi in the study area. To the authors' knowledge, this is the first report of the molecular detection of equine piroplasmosis in jeered horses in Erzurum, Turkey. PMID- 28030351 TI - Occurrence of two novel actinospore types (Cnidaria: Myxosporea) in Brazilian fish farms, and the creation of a novel actinospore collective group, Seisactinomyxon. AB - The involvement of oligochaetes in the life cycles of fresh water myxozoan parasites in Brazil was investigated. Of 333 oligochaetes collected in a fish farm in the State of Sao Paulo, three (0.9%) released Aurantiactinomyxon type spores. From 86 worms collected in a fish farm in Mato Grosso do Sul State, 1 (0.9%) released actinospores with a novel morphology for which we propose the name Seisactinomyxon. Infected oligochaetes were identified by morphology: all belonged to family Naididae, with Pristina americana the host for Aurantiactinomyxon and Slavina evelinae the host of Seisactinomyxon. This is the first report of the involvement these two species of oligochaetes in the life cycle of myxozoans. Small subunit rDNA sequences of the Aurantiactinomyxon (1204 nt) and Seisactinomyxon (1877 nt) did not match any previously sequenced myxozoan. Phylogenetic analyses showed that both actinospore types fell in a clade formed by six Myxobolus spp. that parasitize Characiformes fishes. PMID- 28030352 TI - Characterization of immunoreactive proteins of Setaria cervi isolated by preparative polyacrylamide gel electrophoresis. AB - Filarial parasites are complex mixtures of antigenic proteins and characterization of these antigenic molecules is essential to identify the diagnostically important filaria-specific antigens. In the present study, we have fractionated the somatic extracts from adults of Setaria cervi (bovine filarial parasite) on preparative SDS-polyacrylamide gel electrophoresis and tested the immunoreactivity of the separated gel fractions with polyclonal antibodies against filarial excretory-secretory antigens as well as filarial patients sera. The SDS-PAGE analysis of gel eluted fractions revealed 1 protein band in F-1 fraction, 2 protein bands in F-2 fraction and 2-3 protein bands in all other fractions (F3- F11). Seven gel eluted fractions (F1, F2, F3, F4, F5, F6 and F11) showed high ELISA reactivity with the polyclonal antibody (against excretory secretory antigen) and four of these fractions (F-1, F-2, F3 and F6) exhibited high ELISA reactivity with antibodies present in filarial patient sera. The reactivities of the gel fractions (F1 and F2), recognized by filarial patients sera, were also tested with the monoclonal antibody (detecting the filarial circulating antigen). The F1 and F2 gel eluted fractions were found to have the target antigen of monoclonal antibody as evident by high reactivity with the monoclonal antibody in ELISA and immunoblotting. The S. cervi gel eluted F1 fraction (containing single antigen) could detect antibodies in filarial patients sera and not in non-filarial sera thereby suggesting its usefulness for specific serodiagnosis of human filariasis. PMID- 28030353 TI - The first successful report of the in vitro life cycle of Chinese Leishmania: the in vitro conversion of Leishmania amastigotes has been raised to 94% by testing 216 culture medium compound. AB - Chinese Leishmania isolate MHOM/CN/90/SC10H2 (L. H2), which was obtained from the spinal cords of patients from the Sichuan province of China, is an uncharacterized, pathogenic species closely related to Leishmania tarentolae. The in vitro transformation rate of L. H2 promastigotes into amastigotes has not been studied. This study is the first to successfully define the in vitro life cycle of L. H2 by investigating the percent conversion of L.H2 promastigotes to amastigotes in vitro under 216 different culture conditions. The highest proportion of L. H2 amastigotes observed (94%) was significantly higher than that previously reported. After conversion, the axenic amastigotes remained viable as verified by the levels of stage-specific genes (Gp46, A2 and beta-tubulin) detected by RT-PCR. Meanwhile, morphological and protein characterizations of these axenic amastigotes were carried out in order to confirm the successful conversion. Specific antibodies were only able to detect 46 kDa, 52 kDa and 75 kDa proteins in samples isolated from axenic amastigotes. Afterward, these converted axenic amastigotes were transformed into the promastigote form by altering the culture condition. These converted axenic promastigotes still have the ability to infect macrophages, and their morphology changed back to the amastigote form following infection. These findings will assist further investigations into the biological characteristics of the host-parasite relationship and the process of pathogenesis. PMID- 28030354 TI - Phylogenetic analysis of genetically distinct Enterocytozoon bieneusi infecting renal transplant recipients. AB - Enterocytozoon bieneusi (E. bieneusi), infecting renal transplant (RT) recipients may be transmitted anthroponotically or zoonotically. Accordingly, we aimed to, a) evaluate genotypes of E. bieneusi infecting RT recipients, and b) infer phylogenetic interpretation on transmission of different genotypes among infected hosts. Stool samples of 22 RT recipients infected with microsporidia (identified using modified trichrome staining) were subjected to species identification. All E. bieneusi positive samples were subjected to genotyping. The phylogenetic tree was constructed using Mega 5 software. Of 22 microsporidia infected RT recipients, 21 (95.5%) had E. bieneusi. ITS sequences of 21 E. bieneusi were classified into eight genotypes (Ind1 to Ind8). Among them, 4 (Ind5 to Ind8) were novel. Genotypes Ind2, Ind3, Ind4, Ind7 and Ind8 showed close sequence similarity to genotypes reported exclusively from humans. Phylogenetic analysis further supported their anthroponotic transmission. Genotypes Ind1, Ind5 and Ind6 showed close sequence similarity to genotypes reported from both animals and humans. Phylogenetic analysis further supported their zoonotic transmission. Anthroponotic transmission of E. bieneusi was more common among males (11, 100% vs. 7/10, 70%; P = 0.05), presenting with diarrhea (11, 100% vs. 6/10, 60%; P = 0.02) and watery stool (10/11, 91% vs. 5/10, 50%; P = 0.03). PMID- 28030355 TI - A new feather mite of the genus Neodectes Park and Atyeo 1971 (Acari: Proctophyllodidae) from New Zealand wrens (Passeriformes: Acanthisittidae). AB - A new feather mite species, Neodectes pilgrimi sp. n. (Proctophyllodidae: Pterodectinae), is described from three species of New Zealand wrens (Passeriformes: Acanthisittidae): Xenicus gilviventris Pelzeln, 1867 (type host), X. longipes (Gmelin, 1789) (extinct species), and Acanthisitta chloris (Sparrman, 1787). Based on known host associations of the genus Neodectes, it is hypothesized that Neodectes pilgrimi sp. n. has a secondary origin on New Zealand wrens and was probably transferred onto the ancestor of its hosts from honeyeaters (Passeriformes: Meliphagidae). PMID- 28030356 TI - Transcriptional immune response in mesenteric lymph nodes in pigs with different levels of resistance to Ascaris suum. AB - A single nucleotide polymorphism on chromosome 4 (SNP TXNIP) has been reported to be associated with roundworm (Ascaris suum) burden in pigs. The objective of the present study was to analyse the immune response to A. suum mounted by pigs with genotype AA (n = 24) and AB (n = 23) at the TXNIP locus. The pigs were repeatedly infected with A. suum from eight weeks of age until necropsy eight weeks later. An uninfected control group (AA; n = 5 and AB; n = 5) was also included. At post mortem, we collected mesenteric lymph nodes and measured the expression of 28 selected immune-related genes. Recordings of worm burdens confirmed our previous results that pigs of the AA genotype were more resistant to infection than AB pigs. We estimated the genotype difference in relative expression levels in infected and uninfected animals. No significant change in expression levels between the two genotypes due to infection was observed for any of the genes, although IL-13 approached significance (P = 0.08; Punadjusted = 0.003). Furthermore, statistical analysis testing for the effect of infection separately in each genotype showed significant up-regulation of IL-13 (P<0.05) and CCL17 (P<0.05) following A. suum infection in the 'resistant' AA genotype and not in the 'susceptible' AB genotype. Pigs of genotype AB had higher expression of the high-affinity IgG receptor (FCGR1A) than AA pigs in both infected and non infected animals (P = 1.85*10-11). PMID- 28030357 TI - Two new species of digeneans (Lecithasteridae and Haploporidae) of the intertidal blenny Scartichthys viridis (Valenciennes) from the central coast of Chile. AB - Two new digenean species are described from the intertidal blenny Scartichthys viridis (Valenciennes) (Blenniidae) collected off the coasts of Chile. The digenean Monorchimacradena viridis n. sp. (Lecithasteridae: Macradenininae) differs from the only known species described in the genus, M. acanthuri Nahhas and Cable 1964, in the presence of Drusenmagen in the caeca, the location of the seminal vesicle between the testis and ovary (anterior to the testis in M. viridis n. sp.), and the pre-ovarian vitellarium. Megasolena littoralis n. sp. (Haploporidae), which is also reported from Scartichthys gigas (Steindachner), differs from the five valid species of Megasolena in that the post-caecal region (from the posterior edge of the caeca to the end of the body) is larger in M. viridis n. sp., meaning that the caeca are shortest in this species. Also, M. littoralis n. sp. is distinguished, from the other congeneric species, in a combination of characteristics, e.g., body length, suckers, pharynx, testes, hermaphroditic sac and sucker-length ratio. Sequences of ITS2 rDNA were generated for specimens of both species from various localities, indicating that it was invariant within the species. This study describes species of Monorchimacradena and Megasolena in Chilean waters, here reported for the first time off the Pacific Coast of South America. PMID- 28030358 TI - A taxonomic review of hymenolepidids (Eucestoda, Hymenolepididae) from dormice (Rodentia, Gliridae), with descriptions of two new species. AB - In present study the systematic and taxonomic position of hymenolepidids parasitizing rodents of the family Gliridae from Europe and Central Asia is discussed. Hymenolepis myoxi is redescribed on the basis of the type material from the fat dormouse Glis glis deposited in the collection of the Museum fur Naturkunde, Berlin, Germany. Significant corrections of morphologically distinctive characters attributable to H. myoxi include: (1) recognition of a rudimentary rostellar apparatus; (2) absence of rostellar hooks and spination on the suckers; and (3) tissues of the scolex and neck filled with numerous "firm elements". Hymenolepis sulcata was recognised as a synonym of H. myoxi (sensu stricto). The generic allocation of true H. myoxi and validity of the genus Armadolepis is clarified. Specimens from Eliomys quercinus originally designated as H. myoxi by Baer (1932) are described as a new species, Armadolepis jeanbaeri n. sp. The taxonomy has potentially been confused as Spassky (1954) designated misidentified specimens of H. myoxi sensu Baer (1932) as the type species of the genus Armadolepis. In the current article, this error is corrected and A. jeanbaeri n. sp. is fixed as the type of the genus Armadolepis. An additional new species of Armadolepis, A. tenorai n. sp., is described from Dryomys nitedula from Almaty Province, Kazakhstan. The generic diagnosis of Armadolepis is amended. Armadolepis (sensu stricto) is subdivided into two subgenera; the nominotypical subgenus includes species having well developed rostellar apparatus armed by rostellar hooks and A. (Bremserilepis) n. subgen. includes species with rudimentary and unarmed rostellar apparatus. PMID- 28030359 TI - Exploring possibilities for an alternative approach in experimental schistosomiasis mansoni: the peritoneal cavity of mice. AB - The schistosome oviposition and granuloma constitution in the peritoneal cavity of AKR/J mice were evaluated. Groups of mice intraperitoneally infected with cercariae of Schistosoma mansoni were weekly euthanized during the acute (56 to 84 days post-infection (DPI)) and chronic (147 to 175 DPI) phase of infection. Schistosome developmental stages obtained via peritoneal lavage and perfusion of the portal system were inspected, counted and fixed, and peritoneal granulomata were then processed for histology. The morphological characterization and quantitative analysis of peritoneal schistosome eggs and granulomata were for the first time performed, such as the demonstration of the viability of miracidia obtained there from. Eutopic and ectopic mature schistosomes and normal pattern of worm oviposition were observed in all periods studied. However, the size of schistosome eggs from peritoneal cavity was smaller than observed for eggs laid by female worms from the portal system. The numbers of S. mansoni eggs and/or granulomata recovered from the peritoneal cavity was higher in chronic than acute infection, while the mean diameter of peritoneal chronic granulomata was smaller than for peritoneal acute granulomata. The constitution and evolution of these cellular reactions at histology were similar to that of hepatic granuloma, and peritoneal granulomata were subject to the host immunomodulation. In addition to the standardization of this experimental approach, which allows the obtaining of free schistosomal granulomata from peritoneal cavity of AKR/J mice, the potential use of these granulomata in ex vivo and in vivo studies is discussed. PMID- 28030360 TI - Effect of natural products on diabetes associated neurological disorders. AB - Diabetes mellitus, a metabolic disorder, is associated with neurological complications such as depression, anxiety, hypolocomotion, cognitive dysfunction, phobias, anorexia, stroke, pain, etc. Traditional system of medicine is long known for its efficient management of diabetes. The current review discusses the scope of some common medicinal herbs as well as secondary metabolites with a special focus on diabetes-mediated central nervous system complications. Literatures suggest that natural products reduce diabetes-mediated neurological complications partly by reducing oxidative stress and/or inflammation or apoptosis in certain brain regions. Natural products are known to modulate diabetes-mediated alterations in the level of acetylcholinesterase, choline acetyltransferase, monoamine oxidase, serotonin receptors, muscarinic receptors, insulin receptor, nerve growth factor, brain-derived neurotrophic factor, and neuropeptide in brain. Further, there are several natural products reported to manage diabetic complications with unknown mechanism. In conclusion, medicinal plants or their secondary metabolites have a wide scope and possess therapeutic potential to effectively manage neurological complications associated with chronic diabetes. PMID- 28030362 TI - The guilty brain: the utility of neuroimaging and neurostimulation studies in forensic field. AB - Several studies have aimed to address the natural inability of humankind to detect deception and accurately discriminate lying from truth in the legal context. To date, it has been well established that telling a lie is a complex mental activity. During deception, many functions of higher cognition are involved: the decision to lie, withholding the truth, fabricating the lie, monitoring whether the receiver believes the lie, and, if necessary, adjusting the fabricated story and maintaining a consistent lie. In the previous 15 years, increasing interest in the neuroscience of deception has resulted in new possibilities to investigate and interfere with the ability to lie directly from the brain. Cognitive psychology, as well as neuroimaging and neurostimulation studies, are increasing the possibility that neuroscience will be useful for lie detection. This paper discusses the scientific validity of the literature on neuroimaging and neurostimulation regarding lie detection to understand whether scientific findings in this field have a role in the forensic setting. We considered how lie detection technology may contribute to addressing the detection of deception in the courtroom and discussed the conditions and limits in which these techniques reliably distinguish whether an individual is lying. PMID- 28030361 TI - Redox-sensitive GFP to monitor oxidative stress in neurodegenerative diseases. AB - Redox processes are key events in the degenerative cascade of many adult-onset neurodegenerative diseases (NDs), but the biological relevance of a single redox change is often dependent on the redox couple involved and on its subcellular origin. The biosensors based on engineered fluorescent proteins (redox-sensitive GFP [roGFP]) offer a unique opportunity to monitor redox changes in both physiological and pathological contexts in living animals and plants. Here, we review the use of roGFPs to monitor oxidative stress in different three adult onset NDs: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Despite the many differences spanning from incidence to onset, the hypotheses on biological processes underlying both sporadic and familiar ND forms in humans outline a model in which noncompeting mechanisms are likely to converge in various unsuccessful patterns to mediate the selective degeneration of a specific neuronal population. roGFPs, targeted to different cell compartments, are successfully used as specific markers of cell toxicity, induced by expression of causative genes linked to a determined ND. We also report the use of roGFP to monitor oxidative stress induced by the expression of the ALS-causative gene SOD1. PMID- 28030363 TI - New dimensions of connectomics and network plasticity in the central nervous system. AB - Cellular network architecture plays a crucial role as the structural substrate for the brain functions. Therefore, it represents the main rationale for the emerging field of connectomics, defined as the comprehensive study of all aspects of central nervous system connectivity. Accordingly, in the present paper the main emphasis will be on the communication processes in the brain, namely wiring transmission (WT), i.e. the mapping of the communication channels made by cell components such as axons and synapses, and volume transmission (VT), i.e. the chemical signal diffusion along the interstitial brain fluid pathways. Considering both processes can further expand the connectomics concept, since both WT-connectomics and VT-connectomics contribute to the structure of the brain connectome. A consensus exists that such a structure follows a hierarchical or nested architecture, and macro-, meso- and microscales have been defined. In this respect, however, several lines of evidence indicate that a nanoscale (nano connectomics) should also be considered to capture direct protein-protein allosteric interactions such as those occurring, for example, in receptor receptor interactions at the plasma membrane level. In addition, emerging evidence points to novel mechanisms likely playing a significant role in the modulation of intercellular connectivity, increasing the plasticity of the system and adding complexity to its structure. In particular, the roamer type of VT (i.e. the intercellular transfer of RNA, proteins and receptors by extracellular vesicles) will be discussed since it allowed us to introduce a new concept of 'transient changes of cell phenotype', that is the transient acquisition of new signal release capabilities and/or new recognition/decoding apparatuses. PMID- 28030364 TI - Statistical models and computational algorithms for discovering relationships in microbiome data. AB - Microbiomes, populations of microscopic organisms, have been found to be related to human health and it is expected further investigations will lead to novel perspectives of disease. The data used to analyze microbiomes is one of the newest types (the result of high-throughput technology) and the means to analyze these data is still rapidly evolving. One of the distributions that have been introduced into the microbiome literature, the Dirichlet-Multinomial, has received considerable attention. We extend this distribution's use uncover compositional relationships between organisms at a taxonomic level. We apply our new method in two real microbiome data sets: one from human nasal passages and another from human stool samples. PMID- 28030365 TI - Individualized Developmental Care in the NICU: A Concept Analysis. AB - BACKGROUND: Individualized developmental care (IDC) is a collection of evidence based practices that include adapting care practices based on the infant's behavioral and developmental state, involving parents and families in the infant's care, and providing an environment that minimizes over stimulation of the infant. PURPOSE: To clarify the definition of IDC in the neonatal intensive care unit (NICU) and to provide guidelines for implementation of IDC for healthcare professionals through a concept analysis. METHOD/SEARCH STRATEGY: A literature review involving a search of multiple electronic databases from January 1982 to November 2016 was performed along with presentation of a model case and attributes of IDC. CONCLUSIONS: This concept analysis defines and provides guidelines for implementing an individualized developmentally sound environment for infants born premature and their families. IMPLICATIONS FOR PRACTICE: All NICUs need to strive to provide an environment that supports and promotes IDC. Education needs to be provided to healthcare providers and parents regarding IDC practices. IMPLICATIONS FOR RESEARCH: Further research into short- and long-term outcomes of IDC is needed. Research into whether IDC is being implemented by NICUs is also needed. PMID- 28030366 TI - NICU Nurses and Lactation-Based Support and Care. AB - BACKGROUND: The provision of human milk and breastfeeding is essential in the neonatal intensive care unit (NICU) population. However, recent national research has demonstrated very low percentages of NICU nurses providing lactation-based support and care to patients and families, and less than half of all NICUs have an International Board Certified Lactation Consultant (IBCLC) on staff. PURPOSE: The purpose of this study was to describe how NICU bedside nurses are providing lactation-based support and care during their shifts and the frequency of that support. The secondary aim was to gain an understanding of the NICU nurses' attitudes toward human milk and breastfeeding. METHODS: Through a prospective descriptive cohort design, the authors of this study created and disseminated a web-based survey (SurveyMonkey) of 21 questions including the Iowa Infant Feeding Attitude Scale (IIFAS) to a Northeastern urban hospital staff of bedside nurses. RESULTS: A total of 140 of the 389 eligible NICU bedside nurses responded to the survey. Between 50.7% and 72.9% of nurses reported to providing lactation-based support and care during the previous shift worked and during the previous week worked, respectively. The participants' responses to the IIFAS resulted in an overall score of 69.1, indicating an attitude of "positive to breastfeeding." IMPLICATIONS FOR PRACTICE: The study demonstrates that the majority provide lactation-based support and care on every shift and hold very positive attitudes toward the provision of human milk and breastfeeding. Hospitals should be encouraged to promote educational and training programs in their respective institutions. IMPLICATIONS FOR RESEARCH: Researchers should examine NICU nurses' attitudes and beliefs about human milk and breastfeeding on a national scale. PMID- 28030367 TI - Activation of PKCalpha and PI3K Kinases in Hypertrophic and Nodular Port Wine Stain Lesions. AB - Port wine stain (PWS) is a congenital, progressive vascular malformation. Many patients with PWS develop hypertrophy and discrete nodularity during their adult life, but the mechanism(s) remain incompletely understood. In this study, we attempted to investigate activation status of PKCalpha, PI3K, PDPK1 and PLC-gamma and protein levels of PP2A and DAG to explore their potential roles in the formation of hypertrophic and nodular PWS lesions. We found phosphorylated levels of PKCalpha, PI3K, PDPK1, and PLC-gamma and protein levels of PP2A and DAG showed moderate increases in the endothelial cells of hypertrophic PWS as compared to the adjacent normal skin. These increases extended throughout the entire stroma of blood vessels in PWS nodules. Many proliferating cells, such as fibroblasts, also showed strong activation of PKCalpha, PI3K, PDPK1 and PLC-gamma and upregulations of PP2A and DAG in nodular PWS lesions. Our data showed that there is aberrant activation of PKCalpha, PI3K, PDPK1 and PLC-gamma and upregulation of PP2A and DAG mainly in endothelial cells in hypertrophic PWS areas, but presenting in the entire vasculatures and surrounding fibroblasts in PWS nodules. Our data suggest that both PKCalpha and PI3K signaling pathways contribute to the development of hypertrophy and nodularity in adult PWS. PMID- 28030368 TI - Sphingolipids, ORMDL3 and asthma: what is the evidence? AB - PURPOSE OF REVIEW: Genome-wide association studies identified ORMDL3, a protein of the endoplasmic reticulum, as a significant asthma risk factor. ORMDL3 is one of three ORMDL proteins that integrate multiple signals to maintain sphingolipid homeostasis. Studies that investigated potential mechanisms for how increased ORMDL3 might affect asthma are summarized. RECENT FINDINGS: Investigations focused on decreased sphingolipid synthesis and on the unfolded protein response because ORMDL3 had been implicated in both.Airway reactivity is increased in a genetic model with decreased de-novo sphingolipid synthesis and in wild-type mice treated with myriocin, a sphingolipid synthesis inhibitor. Inflammation, mucus production and airway smooth muscle hypertrophy are absent. ORMDL3 was not evaluated directly but results suggest that decreased sphingolipid synthesis is sufficient to induce airway hyperreactivity (AHR).Direct effects of ORMDL3 were investigated in allergic asthma models. Sensitization with ovalbumin, house dust mites and Alternaria alternata increase ORMDL3 mRNA. Universal overexpression of ORMDL3 decreases serum sphingolipids, increases inflammatory markers, airway remodeling and AHR in response to allergic stimuli. Addition of myriocin during sensitization drastically exacerbates house dust mites-induced AHR.ORMDL3 knockout mice are protected from developing A. alternata-induced AHR. The effect is specific to Alternaria and limited to smooth muscle contraction, as inflammation persists. ORMDL3 might have a critical role for smooth muscle contraction.Little is known about how the different ORMDL3 single nucleotide polymorphisms affect human blood and tissue sphingolipid profiles. One group measured total sphingoid levels and found no association with ORMDL3 single nucleotide polymorphisms in a general population. Others evaluated sphingolipid profiles in 7-8-year old children with mild asthma and found significantly higher C18 and C20 ceramides in those with persistence of asthma symptoms 3 years later, suggesting that sphingolipid profiles might predict asthma persistence. SUMMARY: Possible mechanisms how ORMDL3 affects asthma include inhibition of sphingolipid synthesis, synergistic effects with known allergens and a combination of both. PMID- 28030369 TI - Intestinal microbiota in primary sclerosing cholangitis. AB - PURPOSE OF REVIEW: Alterations of the gut-liver axis have been linked to the pathogenesis of primary sclerosing cholangitis (PSC) since the disease was first described. The purpose of this review is to discuss multiple recent studies on the intestinal microbiota in human PSC and experimental models of this disease. RECENT FINDINGS: Data are available from eight cross-sectional studies of human PSC, which include a variable number of patients (n = 11-85), material (mucosal or fecal), and microbiota profiling methodology. Despite the heterogeneity of the studies, a pattern of differences is observed that could represent a theme or signature of the PSC gut microbiota, characterized by low diversity and with alterations in multiple bacterial taxa. In experimental models of PSC, re derivation of animals into germ-free facilities may either aggravate or attenuate the disease, depending on host genetics and putative disease mechanisms (e.g., fibrotic or immune-driven processes, respectively). SUMMARY: The present data provide a strong rationale to explore the functional consequences of the observed gut microbial alterations and their influence on the pathogenesis in PSC. Studies of gut microbiota as biomarker and treatment target may potentially also lead to early translation into clinical practice. PMID- 28030371 TI - Antibiotic dosing for multidrug-resistant pathogen pneumonia. AB - PURPOSE OF REVIEW: Nosocomial pneumonia caused by multidrug-resistant pathogens is increasing in the ICU, and these infections are negatively associated with patient outcomes. Optimization of antibiotic dosing has been suggested as a key intervention to improve clinical outcomes in patients with nosocomial pneumonia. This review describes the recent pharmacokinetic/pharmacodynamic data relevant to antibiotic dosing for nosocomial pneumonia caused by multidrug-resistant pathogens. RECENT FINDINGS: Optimal antibiotic treatment is challenging in critically ill patients with nosocomial pneumonia; most dosing guidelines do not consider the altered physiology and illness severity associated with severe lung infections. Antibiotic dosing can be guided by plasma drug concentrations, which do not reflect the concentrations at the site of infection. The application of aggressive dosing regimens, in accordance to the antibiotic's pharmacokinetic/pharmacodynamic characteristics, may be required to ensure rapid and effective drug exposure in infected lung tissues. SUMMARY: Conventional antibiotic dosing increases the likelihood of therapeutic failure in critically ill patients with nosocomial pneumonia. Alternative dosing strategies, which exploit the pharmacokinetic/pharmacodynamic properties of an antibiotic, should be strongly considered to ensure optimal antibiotic exposure and better therapeutic outcomes in these patients. PMID- 28030370 TI - The evolution of natural history of primary sclerosing cholangitis. AB - PURPOSE OF REVIEW: Primary sclerosing cholangitis (PSC) is a rare, idiopathic biliary disease often with an insidious onset, variable disease course, and premature death related to benign and malignant PSC-related sequelae. This review aims to discuss the epidemiology, clinical variants, and natural history of PSC, incorporating data from recent population-based studies. RECENT FINDINGS: PSC naturally leads to cirrhosis, cholangiocarcinoma, other hepatobiliary malignancies, dominant strictures, hepatic osteodystrophy, and bacterial cholangitis. The incidence of PSC appears to be increasing, the reasons for which are unclear. The time from diagnosis to liver transplant appears to be longer in more recent studies compared with earlier studies, suggesting a better overall prognosis than previously believed. In addition, with an increasing number of patients undergoing liver transplantation for PSC, the frequency of death because of liver failure has decreased, whereas cancer-related deaths have increased among patients with PSC. SUMMARY: PSC is a heterogeneous disease with a variety of clinical outcomes, both fatal and nonfatal. The progression of liver fibrosis in an individual patient is difficult to predict and may vary from a relatively benign, nonprogressive form to a rapidly progressive form with the need for liver transplantation. PMID- 28030372 TI - Does increased traffic flow around unconventional resource development activities represent the major respiratory hazard to neighboring communities?: knowns and unknowns. AB - PURPOSE OF REVIEW: The objective of this review is to demonstrate that the focus on air emissions causing respiratory effects and associated with gas development may be misplaced by attributing those exposures mainly to well pad activities. RECENT FINDINGS: The most recent publications on the health effects of hydraulic fracturing operations seem to parallel findings from studies of diesel particulate exposure near roadways and the health effects associated with those exposures. It seems at least possible that some, if not all, of the respiratory effects associated with unconventional resource development may be traffic related. Road traffic generated by hydraulic fracturing operations is one possible source of environmental impact whose significance has, until now, been largely neglected in the available literature with 4000 to 6000 vehicles visiting the well pad. SUMMARY: Exposures from well pads diminish rapidly with distances of only a few kilometers but there is evidence showing disease risk multiple kilometers from well pads. This leaves open the possibility that the several thousand vehicle trips per well pad create traffic emissions over wide areas away from the pad. This alternative source of exposure has not previously been well studied but is being more seriously considered. PMID- 28030373 TI - What are the most promising new agents in acute myeloid leukemia? AB - PURPOSE OF REVIEW: Although the treatment paradigm for acute myeloid leukemia (AML) had been largely unchanged for many years, in-depth molecular characterization has revolutionized our understanding of mutations that drive the disease, subsequently serving to guide current clinical investigation. Furthermore, recent advances in the field have highlighted the importance of optimizing known efficacious agents by improving drug delivery or bypassing resistance mechanisms. The current status of novel agents which are shaping the clinical management of AML patients are summarized in this review. RECENT FINDINGS: Practice changing findings over the past year include improved overall survival (OS) in a molecularly defined AML subgroup as well as in elderly patients with secondary AML (sAML). Specifically, synergistic combination of daunorubicin and cytarabine (i.e., CPX-351) was found to improve OS in sAML patients. Furthermore, although multiple mutation specific inhibitors have been developed, optimal combination with additional agents appears critical, as monotherapies have not resulted in durable remissions or improved outcomes. Improved OS via the addition of midostaurin to intensive chemotherapy in FLT3 mutant AML supports this concept. SUMMARY: For the first time in AML, personalized therapy has become possible through improved understanding of the molecular architecture and survival pathways of an individual's disease. The landscape of AML treatment is encouraging, with multiple novel agents likely to gain approval over the next 5 years. PMID- 28030374 TI - Patient-Centered Personal Health Record and Portal Implementation Toolkit for Ambulatory Clinics: A Feasibility Study. AB - Personal health records and patient portals have been shown to be effective in managing chronic illnesses. Despite recent nationwide implementation efforts, the personal health record and patient portal adoption rates among patients are low, and the lack of support for patients using the programs remains a critical gap in most implementation processes. In this study, we implemented the Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit in a large diabetes/endocrinology center and assessed its preliminary impact on personal health record and patient portal knowledge, self-efficacy, patient-provider communication, and adherence to treatment plans. Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit is composed of Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit-General, clinic level resources for clinicians, staff, and patients, and Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit Plus, an optional 4-week online resource program for patients ("MyHealthPortal"). First, Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit General was implemented, and all clinicians and staff were educated about the center's personal health record and patient portal. Then general patient education was initiated, while a randomized controlled trial was conducted to test the preliminary effects of "MyHealthPortal" using a small sample (n = 74) with three observations (baseline and 4 and 12 weeks). The intervention group showed significantly greater improvement than the control group in patient provider communication at 4 weeks (t56 = 3.00, P = .004). For other variables, the intervention group tended to show greater improvement; however, the differences were not significant. In this preliminary study, Patient-Centered Personal Health Record and Patient Portal Implementation Toolkit showed potential for filling the gap in the current personal health record and patient portal implementation process. Further studies are needed using larger samples in other settings to ascertain if these results are generalizable to other populations. PMID- 28030375 TI - Self-injurious behaviour in people with intellectual disability and autism spectrum disorder. AB - PURPOSE OF REVIEW: This review summarises the recent trends in research in the field of self-injurious behaviour in people with intellectual disability and autism spectrum disorder. RECENT FINDINGS: New data on incidence, persistence and severity add to studies of prevalence to indicate the large scale of the clinical need. A number of person characteristics have been repeatedly identified in prevalence and cohort studies that: can be considered as risk markers (e.g. stereotyped behaviour, autism spectrum disorder) and indicate possible causal mechanisms (e.g. sleep disorder, anxiety). Studies have started to integrate traditional operant learning paradigms with known person characteristics and reviews and meta-analyses of applied behaviour analytic procedures can now inform practice. SUMMARY: Despite these positive developments interventions and appropriate support falls far short of the required need. Expansions in applied research are warranted to develop and evaluate innovative service delivery models that can translate knowledge of risk markers and operant learning paradigms into widespread, low cost routine clinical practice. Alongside this, further pure research is needed to elucidate the direction of causality of implicated risk factors, in order to understand and intervene more effectively in self-injury. PMID- 28030378 TI - Does lifestyle contribute to disease severity in patients with inherited lipid disorders? AB - PURPOSE OF REVIEW: Patients with familial hypercholesterolemia, familial combined hyperlipidemia and hyperlipoprotein(a) are at high cardiovascular risk. Increasing evidence suggest that lifestyle-related risk factors such as physical inactivity, and poor diet quality could influence cardiovascular risk in these patients. Our objective is to review the evidence that supports the role of lifestyle-related factors in the prediction of cardiovascular risk in patients with inherited lipid disorders. RECENT FINDINGS: Recent studies have shown that smoking, a poor diet quality, physical inactivity, fitness levels, abdominal obesity, insulin resistance, and type 2 diabetes were associated with the presence of atherosclerosis and long-term cardiovascular outcomes in patients with familial hypercholesterolemia. Recent evidence also suggest that managing other cardiovascular risk factors such as cholesterol levels, obesity, glycemic control, blood pressure, smoking, physical inactivity, and diet quality could reduce long-term cardiovascular risk associated with hyperlipoprotein(a). Whether targeting these risk factors could ultimately decrease cardiovascular risk in these patients remains unknown. SUMMARY: Although reducing the number of atherogenic apolipoprotein-B containing particle with lipid-lowering therapy represents the cornerstone of treatment of patients with inherited lipid disorders, lifestyle-related risk factors such as physical inactivity and poor diet quality need to be targeted for the optimal management of these high-risk patients. PMID- 28030379 TI - Genotype-guided diagnosis in familial hypercholesterolemia: population burden and cascade screening. AB - PURPOSE OF REVIEW: In this review, how genetic testing has provided major new insights regarding the population burden of familial hypercholesterolemia (FH) are reviewed. In addition, the role of genetic testing in cascade screening for FH and an updated MEDPED (Make Early Diagnoses to Prevent Early Death in MEDical PEDigrees) algorithm for the clinical diagnosis of FH are presented. RECENT FINDINGS: For the first time, recent application of genetic testing for FH in large populations has provided firm estimates of the prevalence of FH (at least one in 220) in the USA. High associated risks of coronary artery disease make FH the most common genetic cause of premature coronary artery disease. SUMMARY: Genetic testing has yielded accurate, new estimates of the population burden of FH. The potential benefits of early diagnosis of FH on a population-wide level have not yet begun to be realized. PMID- 28030377 TI - Microbes, allergic sensitization, and the natural history of asthma. AB - PURPOSE OF REVIEW: Understanding factors that lead to asthma development in early life is essential to developing strategies aimed at primary or secondary prevention. RECENT FINDINGS: This article will review current evidence addressing the development of early life allergic sensitization in relation to microbes and the gut and airway microbiome. Wheezing illnesses, particularly viral, remain a significant risk factor for asthma inception; however, bacterial pathogens have recently emerged as an additional important contributor to asthma risk, either alone or as cofactors with viral infections. The combined influence and interaction of early life viral wheezing and aeroallergen sensitization is important, with allergic sensitization preceding the onset of viral wheeze. Lastly, we review recent data from longitudinal studies regarding the development of irreversible airway obstruction and its impact on the natural history of asthma. SUMMARY: The development of asthma remains complex and incompletely understood. There is interplay between genetic predisposition and environmental exposures, including allergens and microbes. Interventions aimed at these risk factors during the preschool years may prevent the longitudinal course of asthma progression to irreversible airway obstruction. PMID- 28030376 TI - The effect of obesity, weight gain, and weight loss on asthma inception and control. AB - PURPOSE OF REVIEW: There is ample and growing evidence that obesity increases the risk of asthma and morbidity from asthma. Here, we review recent clinical evidence supporting a causal link between obesity and asthma, and the mechanisms that may lead to 'obese asthma'. RECENT FINDINGS: Although in some children obesity and asthma simply co-occur, those with 'obese asthma' have increased asthma severity, lower quality of life, and reduced medication response. Underlying mechanistic pathways may include anatomical changes of the airways such as obstruction and dysanapsis, systemic inflammation, production of adipokines, impaired glucose-insulin metabolism, altered nutrient levels, genetic and epigenetic changes, and alterations in the airway and/or gut microbiome. A few small studies have shown that weight loss interventions may lead to improvements in asthma outcomes, but thus far research on therapeutic interventions for these children has been limited. SUMMARY: Obesity increases the risk of asthma - and worsens asthma severity or control - via multiple mechanisms. 'Obese asthma' is a complex, multifactorial phenotype in children. Obesity and its complications must be managed as part of the treatment of asthma in obese children. PMID- 28030380 TI - Potential anticancer role of colchicine-based derivatives: an overview. AB - Colchicine, the main alkaloid of the poisonous plant meadow saffron (Colchicum autumnale L.), is a classical drug used for the treatment of gout and familial Mediterranean fever. Although colchicine is not clinically used to treat cancer because of toxicity, it exerts antiproliferative effects through the inhibition of microtubule formation by blocking the cell cycle at the G2/M phase and triggering apoptosis. Colchicine can still be used as a lead compound for the generation of potential anticancer drugs. Thus, numerous analogues of colchicine have been synthesized in the hope of developing novel, useful drugs with more favourable pharmacological profiles. Several colchicine semisynthetics are less toxic than colchicine and research is being carried out on effective, less toxic colchicine semisynthetic formulations with potential drug-delivery strategies directly targeting multiple solid cancers. This review focuses on the anticancer role of some of colchicine-based derivatives and their therapeutic importance. PMID- 28030381 TI - 2016: An Unbelievable Year. AB - And not necessarily in a good way. PMID- 28030382 TI - Establishing a Voice at Home and Abroad. PMID- 28030383 TI - Progress in Policymaking. PMID- 28030384 TI - Importance of Forensic Nurses. PMID- 28030385 TI - Stop the Eye Rolling: Supporting Nursing Students in Learning. AB - Too often, they face an unwelcoming introduction to the profession. PMID- 28030386 TI - Top Health Stories of 2016: ACA, Opioids, Zika-Representation and Misrepresentation in a Post-Fact Era. AB - It's easier to discover a villain than to solve a complex public health problem. PMID- 28030387 TI - The Top Health Care Policy News Stories of 2016. PMID- 28030388 TI - The Top Nursing Stories of 2016. PMID- 28030391 TI - The Top Clinical News Stories of 2016. PMID- 28030393 TI - Stories to Watch in 2017. PMID- 28030394 TI - 2016 Win-Loss Scoreboard. AB - AJN takes a look back at some of the health care achievements (and disappointments) of 2016. PMID- 28030395 TI - Physical Activity in Schools Declines, Obesity Rates Climb: What Can Be Done? AB - Providing recess and physical education is ideal, but other approaches work, too. PMID- 28030398 TI - Teaching Patients How to Avoid Extortion Scams. PMID- 28030399 TI - FDA Offers Continuing Education Courses. PMID- 28030400 TI - Medication Errors Prompt Brand Name Change. PMID- 28030401 TI - First Drug Approved for Duchenne Muscular Dystrophy. PMID- 28030403 TI - CE: Triglycerides: Do They Matter? AB - : Since the introduction of HMG-CoA reductase inhibitors, also known as statins, as an adjunct to diet in the treatment of hyperlipidemia and the greater emphasis placed on reducing low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerosis and cardiovascular disease (CVD), there has been less focus on the value of lowering serum triglyceride levels. Many patients are aware of their "good" and "bad" cholesterol levels, but they may not be aware of their triglyceride level or of the association between high triglycerides and the development of CVD. In recent years, however, in light of the increasing incidences of obesity, insulin resistance, and type 2 diabetes, lowering triglyceride levels has gained renewed interest. In addition to the focus on lowering LDL cholesterol levels in CVD prevention, clinicians need to be aware of the role of triglycerides-their contribution to CVD, and the causes and treatment of hypertriglyceridemia. PMID- 28030405 TI - CE: Human Papillomavirus-Related Oral Cancers: The Nurse's Role in Mitigating Stigma and Dispelling Myths. AB - : The prevalence of human papillomavirus (HPV)-related oral cancers has been rising, the cancers occurring in adults at a younger age than HPV-negative oral cancers typically do and in men more often than women. Patients who are diagnosed often don't understand the disease's etiology. Because HPV is sexually transmitted, diagnosis with an HPV-related oral cancer may prompt feelings of shame, embarrassment, and guilt. There are currently three vaccines for HPV. It's essential for nurses to educate patients on HPV transmission and HPV-related oral cancer, thus helping to mitigate the stigma and dispel myths, and to promote vaccination in at-risk populations, including children and young adults. PMID- 28030407 TI - Book of the Year Awards 2016. AB - The most valuable texts of 2016, as chosen by AJN's panel of judges. PMID- 28030409 TI - Nurses Urged to Prepare for Sex Education. AB - Editors' note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but they also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times.This month we reprint a brief "Professional Practice" note from the June 1969 issue about what was described as the first family planning conference for nurse educators. Speakers emphasized the need to make this subject a routine part of nursing school curricula (despite debates over the nurse's role in family planning), "so that nurses can counsel out of wisdom and not from piety or ignorance." Speakers included James Lieberman, MD, who years later coauthored with his daughter a teen sex guide, and Alan Guttmacher, MD, then president of Planned Parenthood, whose Center for Family Planning Program Development within that organization was later renamed the Guttmacher Institute in his honor.Nurses today are deeply involved in sexual and reproductive health care. In this issue, public health specialist Diane Santa Maria and colleagues offer ways to advance sexual and reproductive health care for adolescents by devising more friendly, youth-oriented clinical settings. PMID- 28030408 TI - Nurses on the Front Lines: Improving Adolescent Sexual and Reproductive Health Across Health Care Settings. AB - : Nurses care for adolescents in a variety of settings, including communities, schools, and public health and acute care clinics, which affords them many opportunities to improve adolescents' sexual and reproductive health and reduce the rates of unplanned pregnancy and sexually transmitted infections. To ensure that adolescents have access to sexual and reproductive health care (which includes both preventive counseling and treatment) in all nursing practice sites, nurses need to gain the knowledge and hone the skills required to deliver evidence-based counseling and services to adolescents and parents. Collectively, nurses can use their unique combination of knowledge and skills to make a positive impact on adolescent sexual and reproductive outcomes. Nurses have the capacity and opportunity to disseminate information about sexual and reproductive health to adolescents and their parents in communities, schools, public health clinics, and acute care settings. This article discusses the Society for Adolescent Health and Medicine's goals and recommendations, which address adolescent sexual and reproductive health as both a health care and a human rights issue. PMID- 28030410 TI - Teaching Caregivers to Administer Eye Drops, Transdermal Patches, and Suppositories. AB - This article is the third in a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Public Policy Institute. Results of focus groups conducted as part of the AARP Public Policy Institute's No Longer Home Alone video project supported evidence that family caregivers aren't being given the information they need to manage the complex care regimens of their family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's medications. Each article explains the principles nurses should consider and reinforce with caregivers and is accompanied by a video for the caregiver to watch. The third video can be accessed at http://links.lww.com/AJN/A76. PMID- 28030411 TI - Electromagnetic-Guided Bedside Placement of Feeding Tubes by Nurses vs. Endoscopic Placement by Physicians. PMID- 28030412 TI - Omega-3 Fatty Acid Intake Lowers Risk of Diabetic Retinopathy. PMID- 28030413 TI - RN Assessments are Useful in Evaluating the Quality and Safety of Patient Care. PMID- 28030414 TI - Complementary Medicine Relieves Some Types of Chronic Pain. PMID- 28030415 TI - Teaching Students to Administer Medications Safely. AB - This article is one in a series on the roles of adjunct clinical faculty and preceptors, who teach nursing students and new graduates to apply knowledge in clinical settings. In this article, the authors discuss important methods in teaching nursing students to administer medications, and include best practices and strategies for student success, with a focus on safety. PMID- 28030416 TI - Public Health Nurse: Touching Death, Touching Life. AB - Negotiating the space between a patient's end and a child's impending birth. PMID- 28030417 TI - A "Resident-as-Teacher" Curriculum Using a Flipped Classroom Approach: Can a Model Designed for Efficiency Also Be Effective? AB - PROBLEM: The Accreditation Council for Graduate Medical Education requires training that enhances resident teaching skills. Despite this requirement, many residency training programs struggle to implement effective resident-as-teacher (RAT) curricula, particularly within the context of the 80-hour resident workweek. APPROACH: In 2013, the authors developed and evaluated an intensive one day RAT curriculum using a flipped classroom approach. Twenty-nine second-year residents participated in daylong RAT sessions. The curriculum included four 1 hour workshops focusing on adult learning principles, giving feedback, teaching a skill, and orienting a learner. Each workshop, preceded by independent reading, featured peer co-teaching, application, and feedback. The authors evaluated the curriculum using pre- and postworkshop objective structured teaching examinations (OSTEs) and attitudinal and self-efficacy teaching questionnaires. OUTCOMES: Residents demonstrated statistically significant improvements in performance between pre- and postworkshop OSTEs on each of three core skills: giving feedback (P = .005), orienting a learner (P < .001), and teaching a skill (P < .001). Residents expressed positive attitudes surrounding teaching on the retrospective pre-post attitudinal instrument (P < .001) and rated themselves as more effective teachers (P < .001) after the training. NEXT STEPS: The authors have demonstrated that the flipped classroom approach is an efficient and effective method for training residents to improve teaching skills, especially in an era of work hour restrictions. They have committed to the continuation of this curriculum and are planning to include assessment of its long-term effects on resident behavior change and educational outcomes. PMID- 28030418 TI - The Impact of a Junior Faculty Fellowship Award on Academic Advancement and Retention. AB - PURPOSE: Academic faculty experience barriers to career development and promotion. In 1996, Harvard Medical School (HMS) initiated an intramural junior faculty fellowship to address these obstacles. The authors sought to understand whether receiving a fellowship was associated with more rapid academic promotion and retention. METHOD: Junior faculty fellowship recipients and all other instructor and assistant professors at HMS between 1996 and 2011 were identified. Using propensity score modeling, the authors created a matched comparison group for the fellowship recipients based on educational background, training, academic rank, department, hospital affiliation, and demographics. Time to promotion and time to leaving were assessed by Kaplan-Meier curves. RESULTS: A total of 622 junior faculty received fellowships. Faculty who received fellowships while instructors (n = 480) had shorter times to promotion to assistant professor (P < .0001) and longer retention times (P < .0001) than matched controls. There were no significant differences in time to promotion for assistant professors who received fellowships (n = 142) compared with matched controls, but assistant professor fellowship recipients were significantly more likely to remain longer on the faculty (P = .0005). Women instructors advanced more quickly than matched controls, while male instructors' rates of promotions did not differ. CONCLUSIONS: Fellowships to support junior faculty were associated with shorter times to promotion for instructors and more sustained faculty retention for both instructors and assistant professors. This suggests that relatively small amounts of funding early in faculty careers can play a critical role in supporting academic advancement and retention. PMID- 28030419 TI - Healthy Exercise Habits Are Associated With Lower Risk of Burnout and Higher Quality of Life Among U.S. Medical Students. AB - PURPOSE: Although burnout and low quality of life (QOL) are common among medical students, little remains known about personal fitness habits of medical students that may promote well-being. METHOD: In 2012 the authors conducted a cross sectional study of U.S. medical students to explore relationships between burnout, QOL, and compliance with Centers for Disease Control and Prevention (CDC) exercise recommendations. Wilcoxon-Mann-Whitney tests, Fisher exact tests, and multivariate logistic regression were performed. RESULTS: Among approximately 12,500 medical students invited to participate, 4,402 (35.2%) completed surveys. Most (2,738/4,367; 62.7%) engaged in aerobic exercise in accordance with CDC recommendations, while fewer (1,685/4,376; 38.5%) adhered to muscle strengthening recommendations. Burnout prevalence was lower among students who exercised aerobically consistent with CDC recommendations compared with those who exercised less (53.1% vs. 60.8%, P < .0001). Similarly, rates of burnout were also lower among students who strength trained consistent with CDC recommendations (51.8% vs. 58.6%, P < .0001). Overall QOL scores were higher for medical students adhering to CDC recommendations for aerobic exercise (7.2 vs. 6.6, P < .0001), strength training (7.2 vs. 6.8, P < .0001), or both aerobic and strength training (8.0 vs. 7.0, P < .0001). Compliance with CDC exercise guidelines remained independently associated with lower risk of burnout and higher QOL on multivariate analysis controlling for age, sex, relationship status, children, and year in school. CONCLUSIONS: Students whose aerobic exercise and/or strength training habits are consistent with CDC guidelines appear less likely to experience burnout and to have higher QOL. PMID- 28030420 TI - Changes in Primary Care Graduate Medical Education Are Not Correlated With Indicators of Need: Are States Missing an Opportunity to Strengthen Their Primary Care Workforce? AB - PURPOSE: Federal and state graduate medical education (GME) funding exceeds $15 billion annually. It is critical to understand mechanisms to align undergraduate medical education (UME) and GME to meet workforce needs. This study aimed to determine whether states' primary care GME (PCGME) trainee growth correlates with indicators of need. METHOD: Data from the American Medical Association Physician Masterfile, the Association of American Medical Colleges, the American Association of the Colleges of Osteopathic Medicine, and the U.S. Census were analyzed to determine how changes between 2002 and 2012 in PCGME trainees-a net primary care physician (PCP) production estimate-correlated with state need using three indicators: (1) PCP-to-population ratio, (2) change in UME graduates, and (3) population growth. RESULTS: Nationally, PCGME trainees declined by 7.1% from the net loss of 679 trainees (combined loss of 54 postgraduate year 1 trainees in internal medicine, family medicine, and pediatrics and addition of 625 fellowship trainees in those specialties). The median state PCGME decline was 2.7%. There was no correlation between the percent change in states' PCGME trainees and PCP to-population ratio (r = -0.06) or change in UME graduates (r = 0.17). Once adjusted for population growth, PCGME trainees declined by 15.3% nationally; the median state decline was 9.7%. CONCLUSIONS: There is little relationship between PCGME trainee growth and state need indicators. States should capitalize on opportunities to create explicit linkages between UME, GME, and population need; strategically allocate Medicaid GME funds; and monitor the impact of workforce policies and training institution outputs. PMID- 28030421 TI - The Political Future of Social Medicine: Reflections on Physicians as Activists. AB - The academic discipline of social medicine has always had a political and policy advocacy component, in addition to its core functions of research and teaching. Its origins lie in the 18th and 19th centuries, in the work of Johann Peter Frank and Rudolph Virchow, among others. Virchow's dictum that "politics is nothing else but medicine on a large scale" highlights that most social determinants of health are politically determined and shape population health. Yet despite intense epidemiological and sociological research on the social determinants of health, less attention has been paid to this political and policy dimension.During the 1960s, the author and many other clinicians were directly involved in attempts to use health care institutions to foster structural change. However, the author argues that efforts to assist individual patients and more effectively manage their interactions with the health care system, as described in the articles in this issue's special collection on "structural competency," while worthy and useful, do not confront root causes. Going forward, efforts to effect structural change must take place outside the arena of the clinical encounter and involve interprofessional teams and collaborations with nongovernmental organizations. They should intervene directly on the structures that contribute to illness such as poor housing, income and wealth inequality, inferior education, racism and residential segregation, and toxic concentrations of extreme poverty in urban areas. Collectively, these efforts-within and outside the spheres of medicine-represent the real operative form of structural competency. PMID- 28030422 TI - Factors Influencing Mini-CEX Rater Judgments and Their Practical Implications: A Systematic Literature Review. AB - PURPOSE: At present, little is known about how mini-clinical evaluation exercise (mini-CEX) raters translate their observations into judgments and ratings. The authors of this systematic literature review aim both to identify the factors influencing mini-CEX rater judgments in the medical education setting and to translate these findings into practical implications for clinician assessors. METHOD: The authors searched for internal and external factors influencing mini CEX rater judgments in the medical education setting from 1980 to 2015 using the Ovid MEDLINE, PsycINFO, ERIC, PubMed, and Scopus databases. They extracted the following information from each study: country of origin, educational level, study design and setting, type of observation, occurrence of rater training, provision of feedback to the trainee, research question, and identified factors influencing rater judgments. The authors also conducted a quality assessment for each study. RESULTS: Seventeen articles met the inclusion criteria. The authors identified both internal and external factors that influence mini-CEX rater judgments. They subcategorized the internal factors into intrinsic rater factors, judgment-making factors (conceptualization, interpretation, attention, and impressions), and scoring factors (scoring integration and domain differentiation). CONCLUSIONS: The current theories of rater-based judgment have not helped clinicians resolve the issues of rater idiosyncrasy, bias, gestalt, and conflicting contextual factors; therefore, the authors believe the most important solution is to increase the justification of rater judgments through the use of specific narrative and contextual comments, which are more informative for trainees. Finally, more real-world research is required to bridge the gap between the theory and practice of rater cognition. PMID- 28030423 TI - Unique Educational Opportunities for PCPs and Specialists Arising From Electronic Consultation Services. AB - Health care reform should be driven by the goals of better patient experience, improved population health, lower per capita costs, and improved provider satisfaction. Electronic consultation (eConsult) services have been adopted by several jurisdictions in the United States, Canada, and Europe to improve access to specialists by primary care providers (PCPs) and are being heralded as a key component for delivery of coordinated care. The primary intent of an eConsult service is to provide PCPs with efficient, timely, direct access to specialist expertise to help guide the management of their patients, reduce the need for unnecessary face-to-face specialty consultations, and improve the quality of the initial face-to-face consultation when needed, through the preconsultative communication.In addition to improving access to care, eConsult services have been praised by PCPs and specialists for their educational value, in particular their ability to enrich practice-based learning. Less recognized, but equally important from the educational perspective, include the abilities of eConsult programs to promote reflection by PCPs and specialists, improve collegiality and professionalism between primary and specialist care, inform continuing professional development activities and maintenance of certification, and enhance training programs' teaching of effective communication and care coordination.As eConsult services become increasingly available, the medical community must leverage the educational opportunities inherent in eConsult programs to further improve the delivery of coordinated specialty care. The educational role of eConsults should be considered as a priority outcome in their evaluation and must be highlighted and optimized in next iterations of eConsult systems design. PMID- 28030424 TI - Situated Learning in Medical Education. PMID- 28030425 TI - Features of Hepatitis in Hepatitis-associated Aplastic Anemia: Clinical and Histopathologic Study. AB - OBJECTIVES: Hepatitis-associated aplastic anemia (HAA) is a rare variant of aplastic anemia in which patients present with severe pancytopenia after an episode of acute hepatitis. The marrow failure is often rapid, severe, and usually fatal if untreated. The preceding hepatitis is largely under-studied. METHODS: Retrospective study of the clinical and histopathologic features of hepatitis in pediatric patients who subsequently developed aplastic anemia and comparison with consecutive cases of acute liver failure and random cases of autoimmune hepatitis during the same time frame. RESULTS: All 7 patients of HAA had significant elevations in aminotransferases and conjugated hyperbilirubinemia at initial presentation. Echoing liver function indices, cholestatic hepatitis with sinusoidal obstruction-type endothelial injury was seen histomorphologically. Autoimmune hepatitis serology such as anti-F-actin, anti liver/kidney microsome, and hypergammaglobulinemia was negative in all patients. Five of 7 patients (71.4%) had, however, elevated antinuclear antibody, all with a speckled pattern. Hepatitis virus serology was negative in all patients. By immunohistochemical staining, the lobular CD8/CD4 lymphocyte ratio was markedly elevated in all of the initial samples with significant reduction in this ratio (P = 0.03) in 3 patients post treatment (ursodiol, antibiotics, and/or immunosuppressive therapy). CONCLUSIONS: Hepatitis preceding HAA is characterized by marked elevation of aminotransferases, conjugated hyperbilirubinemia, elevated antinuclear antibody with a speckled pattern, cholestatic hepatitis with sinusoidal obstruction morphology, and CD8 dominant lobular infiltrates. The present study suggests HAA may result from cytotoxic T-cell-mediated sinusoidal endothelial and hepatocytic injury. PMID- 28030426 TI - Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors. AB - OBJECTIVES: To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. METHODS: Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. RESULTS: A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P<5*10) in the meta analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), gamma aminobutyric acid receptor subunit gamma-2, sarcoma (Src) homology 2 (SH2) B adaptor protein 1 and membrane bound O-acyltransferase domain containing 1]. The strongest associated SNP was located in an intron of RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), which contains an RNA binding protein [rs2061538: minor allele frequency=0.16, odds ratio=1.52 (95% confidence interval: 1.32-1.76), P=6.2*10]. CONCLUSION: These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor induced adverse reactions. PMID- 28030428 TI - OUTER RETINAL LAYER CHANGES AFTER DEXAMETHASONE IMPLANT FOR CENTRAL RETINAL VEIN OCCLUSION. AB - PURPOSE: To analyze the outer retinal layer changes on spectral-domain optical coherence tomography after dexamethasone implant for the treatment of macular edema secondary to central retinal vein occlusions (CRVO). METHODS: Thirty patients affected by macular edema related to CRVO (8 patients less than 50 years of age with nonischemic CRVO [<50-niCRVO], 12 patients more than 50 years with niCRVO [>50-niCRVO], and 10 patients with ischemic CRVO [iCRVO]) were included in a prospective study. After a comprehensive ophthalmologic examination, including best-corrected visual acuity, fluorescein angiography, and spectral-domain optical coherence tomography, each patient received a first implant. Further retreatments were performed on the basis of macular edema detection from the fourth month. Main outcome measure was the change in outer retinal layers at the 12-month examination. RESULTS: The retinal layers of interest (external limiting membrane; ellipsoid zone; and retinal pigment epithelium) were classified as absent, disrupted, or present. The best baseline optical coherence tomography profile was found in <50-niCRVO group (absent external limiting membrane, ellipsoid zone, and retinal pigment epithelium layers in no patients; present and disrupted external limiting membrane in 25% and 75% of cases, respectively; disrupted ellipsoid zone and retinal pigment epithelium in 100% of cases), whereas the worst was detected in the iCRVO group (absent external limiting membrane, ellipsoid zone, and retinal pigment epithelium in 40%, 40%, and 10% of cases, respectively). A significant recovery of the retinal layers was observed in all CRVO subgroups; the greatest improvement was found in <50-niCRVO group. Median best-corrected visual acuity in the whole group improved from 0.85 to 0.45 (P = 0.0001). It is noteworthy that a significant best-corrected visual acuity gain was achieved only in eyes showing present or disrupted layers at baseline regardless of the CRVO subgroup examined, whereas eyes with absent layers at baseline were unable to attain any improvement. CONCLUSION: Dexamethasone implant can promote the resolution of macular edema in patients affected by any CRVO subform, but a beneficial functional outcome could be achieved by eyes showing no absence of outer retinal layers on spectral-domain optical coherence tomography at baseline. PMID- 28030429 TI - SUBFOVEAL NODULE IN COATS' DISEASE: Toward an Updated Classification Predicting Visual Prognosis. AB - PURPOSE: To determine the prevalence, clinical characteristics and nature of subfoveal nodules in Coats' disease and the associated impact on the long-term visual outcome. METHODS: Consecutive cases of Coats' disease with foveal exudation were retrospectively reviewed. The presence of a subfoveal nodule or macular fibrosis was recorded. Clinical characteristics, retinal imaging, and outcome were analyzed by comparative analysis. The histopathological description of an enucleated eye with subfoveal nodule was performed. RESULTS: Among 40 patients presenting unilateral Stage 2B or 3A1 Coats' disease, a subfoveal nodule was detected in 21 patients (52.5%). The median follow-up was 4.7 years. Nineteen patients (47.5%) did not present a subfoveal nodule. Three patients (15.8%) without subfoveal nodule and 21 patients (100%) with subfoveal nodule progressed to a macular fibrotic scar (P < 0.0001), and the mean time of macular fibrosis onset was 11.0 +/- 2.6 months. Final visual acuity was significantly worse in patients who presented a subfoveal nodule at diagnosis (P = 0.01). Of 18 cases with subfoveal nodule who underwent fluorescein angiography, retinal-retinal anastomosis and neovascularization were detected in 13 (72.2%) and 2 eyes (11.1%), respectively. Histopathological analysis of a subfoveal nodule revealed an aggregate of proteinaceous material including fibrin, spindle cells, macrophages, and pigmented cells. CONCLUSION: The presence of a subfoveal nodule at presentation is a predictive factor for macular fibrosis development and worse visual outcome in patients with Coats' disease. These observations suggest an updated classification introducing two subcategories within Stage 2B: without subfoveal nodule (Stage 2B1) and with subfoveal nodule (Stage 2B2). PMID- 28030430 TI - Prestroke treatment with beta-blockers for hypertension is not associated with severity and poor outcome in patients with ischemic stroke: data from a national stroke registry. AB - BACKGROUND: Beta-blockers are not recommended as the initial therapy for hypertension. Reports on associations between use of beta-blockers and stroke severity are inconclusive. We assessed associations between prestroke use of beta blockers and stroke severity, poststroke disability and death in a large group of hypertensive patients hospitalized with acute ischemic stroke. METHODS: All 3915 patients with ischemic stroke, treated prestroke for hypertension and registered in the National Acute Stroke ISraeli, were included. Treatment for hypertension was classified by medication type (beta-blockers, diuretics, calcium antagonists and renin-angiotensin system blockers). Odds ratios for stroke severity by the National Institutes of Health Stroke Scale score, disability or death at discharge (modified Rankin Score >=2) and 1-month mortality were calculated for patients treated vs. nontreated with beta-blockers, adjusted for admission SBP and additional risk factors. RESULTS: Use of beta-blockers was reported for 2043 (52%) participants. Mean (SD) admission SBP was lower in patients treated than nontreated with beta-blockers [156.7 (28.4) vs. 159.9 (27.8) mmHg; P = 0.0005]. Patients on combination therapy including beta-blockers used more antihypertensive medications than patients on combination therapy not including beta-blockers [mean (SD) = 2.63 (0.70) vs. mean (SD) = 2.17 (0.40); P < 0.0001]. Adjusted odds ratios (95% confidence intervals) for outcomes for beta-blocker users compared with nonusers were 1.09 (0.90-1.32) for severe stroke, 0.87 (0.73 1.03) for disability or death at discharge and 0.99 (0.74-1.31) for 1-month mortality. Findings were similar for patients on monotherapy. CONCLUSION: Prestroke use of beta-blockers in hypertensive patients with acute ischemic stroke was not associated with stroke severity, functional outcome or death. PMID- 28030431 TI - Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of sacubitril/valsartan (LCZ696, an angiotensin receptor and neprilysin inhibitor) add-on to amlodipine compared with amlodipine monotherapy in Asian patients with systolic hypertension uncontrolled with amlodipine. METHODS: Patients with mean clinic SBP at least 145 mmHg and less than 180 mmHg after a 4-week treatment with amlodipine 5 mg/day were randomized to receive LCZ696/amlodipine (200/5 mg/day) or amlodipine 5 mg/day for 8 weeks. The primary assessment was the superiority of LCZ696/amlodipine versus amlodipine in lowering 24-h ambulatory SBP from baseline to week 8. Secondary assessments included 24-h ambulatory DBP and pulse pressure (PP), daytime and night-time BP, clinic BP and PP, BP control/responder rate (<140/90 mmHg or a reduction >=20/10 mmHg from baseline), and safety. RESULTS: Of the 371 patients screened, 266 (71.7%) patients (mean age 55.4 years; 24-h SBP/DBP 139.0/86.1 mmHg at baseline) who did not respond to 4-week treatment with amlodipine 5 mg/day were randomized. At week 8, LCZ696/amlodipine provided greater reductions in 24-h SBP compared with amlodipine monotherapy from baseline (-13.9 versus -0.8 mmHg, P < 0.001). All the secondary efficacy assessments were significantly (P < 0.001) in favour of LCZ696/amlodipine, for instance, 24-h PP ( 5.8 versus -0.6 mmHg). Overall, the incidence of adverse events was 20.0% with LCZ696/amlodipine and 21.3% with amlodipine. CONCLUSION: LCZ696/amlodipine showed significantly greater 24-h ambulatory BP and PP reductions compared with amlodipine monotherapy. Both treatments were generally well tolerated. Therefore, LCZ696/amlodipine combination could be an effective treatment for patients with systolic hypertension uncontrolled with amlodipine. PMID- 28030432 TI - Outcomes and disparities in liver transplantation will be improved by redistricting-cons. AB - PURPOSE OF REVIEW: Over the last 2 years, the liver transplant community has been debating a proposal to redraw the maps of organ distribution. The basis for these proposed changes is reported disparities in severity of illness at transplantation across the USA - however, this is based on the allocation model for end-stage liver disease score. In this review, we provide a critical overview of the redistribution proposal, its flaws and how it may worsen outcomes and exacerbate disparities in liver transplantation. RECENT FINDINGS: The main findings we highlight are data questioning the disparity metric used to justify the redistribution. We also review data published in recent articles and presented at public forums questioning whether there truly are disparities in access to transplant care among the broader population with liver disease, and whether disparities even getting to the waitlist are important and not to be ignored. SUMMARY: This review article highlights major methodological and policy flaws with the current redistribution proposal. We demonstrate how the waitlist disparities that the proposal is intended to fix are not as they seem. Furthermore, if this proposal is passed, outcomes of liver transplantation nationally may worsen, and disparities for those with limited access to healthcare will worsen. PMID- 28030433 TI - The case against imminent death donation. AB - PURPOSE OF REVIEW: Imminent death donation (IDD) is a proposal to procure organs from patients prior to the withdrawal of life support, which is anticipated to lead to death. In this review, we outline substantial concerns that the transplant community should consider when deliberating the possibility of practicing IDD. RECENT FINDINGS: Although there are several compelling theoretical and intuitive reasons to support IDD, its application has been hindered because of inadequate definitions or protocols. A lack of published reports limits empirical data about the practice. Discussion on the topic has not adequately addressed potential harms to the donor, involvement of stakeholders, or the threat to public trust. SUMMARY: Although IDD has been proposed as a method to increase the number of organs or improve end-of-life care, the proposal currently poses more risk than benefit for patients and the transplant community. Until the major barriers to implementation of IDD are addressed, the transplant community should invest its efforts to increase the organ supply elsewhere. PMID- 28030434 TI - Exhaustive pathologic work-up in sentinel lymph node biopsy for melanoma: is it necessary? AB - The objective of this study is to determine whether a less exhaustive pathologic work-up to detect melanoma metastasis is clinically useful and does not affect patient prognosis. The success and evolution of the sentinel lymph node (SLN) depends on histological techniques. Several exhaustive protocols of SLN analysis have been published, but are time and cost consuming, with slight increases in the rates of metastasis detection. From 281 patients with SLN biopsy, each SLN was sectioned every 2 mm and from each paraffin block, 2-3 histological sections were evaluated. The patients were divided as follows: the first group (n=185) was subjected to extensive SLN examination (eSLNe) and the second group (n=96) was not subjected to an extensive SLN examination (wSLNe). The average SLN resected was 2 (range: 1-7), evaluating one in 50.9%. The SLN metastasis detection rate was 28.5%, whereas eSLNe increased by 3.2%. During follow-up, 4/26 (17.4%) cases in the wSLNe group showed recurrence in the SLN basin. Factors associated with decreased survival in univariant analysis were recurrence, Breslow thickness, advanced clinical stage, ulceration, and SLN metastasis. eSLNe did not affect disease-specific survival. Multivariate analysis showed recurrence (hazard ratio 23.475, 95% confidence interval: 1903-4559, P<0.001) and Breslow thickness of more than 3.5 mm (hazard ratio 15.222, 95% confidence interval: 1448-3059, P<0.001) as independent risk factors for decreased survival. Our routine for SLN examination enabled an adequate rate of SLN metastasis detection and the eSLNe increased the rate of detection in 3.2%, but did not affect the survival. We did not find any benefit from performing the eSLNe in patients with Breslow thickness less than 3.5 mm. PMID- 28030435 TI - Feasibility and Technique for Transvaginal Natural Orifice Transluminal Endoscopic Surgery Liver Resection: A Porcine Model. AB - INTRODUCTION: Natural orifice transluminal endoscopic surgery (NOTES) is a challenging minimally invasive procedure. Although laparoscopic techniques for liver resection are gaining acceptance worldwide, few studies have investigated NOTES liver resection. We used a porcine model to assess the feasibility and safety of transvaginal NOTES liver resection (TV NOTES LR). MATERIALS AND METHODS: Nine female pigs underwent TV NOTES LR. A nonsurvival acute porcine model with general anesthesia was used in all cases. Using hybrid NOTES technique, we placed only 1 umbilical 12-mm umbilical trocar in the abdominal wall, which was used to create pneumoperitoneum. A laparoscope was then advanced to obtain intra-abdominal visualization. A 15-mm vaginal trocar was inserted under direct laparoscopic vision, and a flexible endoscope was introduced through the vaginal trocar. A long, flexible grasper and endocavity retractor were used to stably retract the liver. The liver edge was partially transected using energy devices inserted through the umbilical trocar. To transect the left lateral lobe, a flexible linear stapler was inserted alongside the vaginal trocar. A specimen extraction bag was deployed and extracted transvaginally. Blood loss, bile leakage, operative time, and specimen size were evaluated. Necropsy studies were performed after the procedures. RESULTS: Eighteen transvaginal NOTES partial liver resections and 4 transvaginal NOTES left lateral lobectomies were successfully performed on 9 pigs. Mean operative time was 165.8 minutes, and mean estimated blood loss was 76.6 mL. All TV NOTES LRs were performed without complications or deaths. Necropsy showed no bile leakage from remnant liver. CONCLUSIONS: Our porcine model suggests that TV NOTES LR is technically feasible and safe and has the potential for clinical use as a minimally invasive alternative to conventional laparoscopic liver resection. PMID- 28030438 TI - The Use of the Alexander Technique in Nonburn Complex Wounds. PMID- 28030439 TI - Wound Management. PMID- 28030437 TI - Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease in South Korea. AB - Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P<0.001 for all), and between the ADD and OND groups (P<0.001 for all). The areas under the curve in differentiation of ADD from control subjects were 0.97 for Abeta42, 0.93 for total tau (tTau), 0.86 for pTau, and 0.99 for both tTau/Abeta42 and pTau/Abeta42 ratios. Our revised cutoff value for Abeta42 was higher than our previous one, whereas the values for the Tau proteins were similar. The tTau/Abeta42 ratio had the highest accuracy, 97%. Our findings highlight the usefulness of CSF AD biomarkers in South Korea, and the necessity of continually testing the reliability of cutoff values. PMID- 28030440 TI - Subclinical bioprosthetic aortic valve thrombosis: clinical and translational implications. AB - PURPOSE OF REVIEW: A recently published study has alerted the cardiovascular community to the existence of a significant and previously unrecognized risk of subclinical valve thrombosis following implantation of surgical and catheter based bioprosthetic valves. The purpose of this article is to review our current understanding of this new clinical entity and to identify unanswered questions and areas for future research. RECENT FINDINGS: Subclinical bioprosthetic valve thrombosis (BPVT) is a more common phenomenon than previously appreciated. It appears that the incidence of BPVT is higher following transcatheter aortic valve replacement compared with surgical aortic valve replacement. Four-dimensional computed tomography (CT) is the most sensitive imaging modality for detection of leaflet immobility and subclinical BPVT. Certain echocardiographic findings, such as increasing transaortic gradients, increased cusp thickness and abnormal cusp mobility, predict the presence of BPVT on four-dimensional CT. There is a growing body of evidence linking subclinical BPVT with premature valvular hemodynamic deterioration and structural valve degeneration. Furthermore, subclinical leaflet thrombosis may constitute a nidus for unrecognized subacute cerebral or other thromboembolic events. Oral anticoagulation seems effective in both the prevention and treatment of BPVT. SUMMARY: Subclinical valve thrombosis is an important and underappreciated cause of early bioprosthetic valve failure. Although several recent studies have improved our understanding of this newly recognized clinical entity, a number of questions remain unanswered. Further studies are warranted to elucidate the true incidence of subclinical BPVT, its clinical consequences, as well as the optimal antithrombotic regimen following bioprosthetic valve implantation. The subgroups of patients at highest risk of BPVT will need to be identified for risk stratification purposes. Several ongoing clinical trials will shed some light on these important issues. PMID- 28030441 TI - Does permissive hypoxaemia during extracorporeal membrane oxygenation cause long term neurological impairment?: A study in patients with H1N1-induced severe respiratory failure. AB - BACKGROUND: The Extracorporeal Life Support Organisation accepts permissive hypoxaemia in adult patients during extracorporeal membrane oxygenation (ECMO). The neurological long-term outcome of this approach has not yet been studied. OBJECTIVES: We investigated the prevalence of brain lesions and cognitive dysfunction in survivors from the Influenza A/H1N1 2009 pandemic treated with permissive hypoxaemia during ECMO for severe acute respiratory distress syndrome (ARDS). Our hypothesis was that this method is reasonable if tissue hypoxia is avoided. DESIGN: Long-term follow-up study after ECMO. SETTING: Karolinska University Hospital, Sweden, from October 2012 to July 2013. PATIENTS: Seven patients treated with ECMO for severe influenza A/H1N1-induced ARDS were studied 3.2 years after treatment. Blood lactate concentrations were used as a surrogate for tissue oxygenation. INTERVENTIONS: Neurocognitive outcome was studied with standardised cognitive tests and MRI of the brain. MAIN OUTCOME MEASURES: Cognitive functioning and hypoxic brain lesions after permissive hypoxaemia during ECMO. The observation period was the first 10 days of ECMO or the entire treatment period if shorter than 10 days. RESULTS: Eleven of 13 patients were still alive 3 years after ECMO. We were able to contact seven of these patients (mean age 31 years), who all agreed to participate in this study. Mean +/- SD peripherally measured arterial saturation during the observation period was 79 +/ 10%. Full-scale Intelligence Quotient was within one standard deviation or above from the mean of a healthy population in five patients, and was 1.5 SD below the mean in one patient. In one other patient, it could not be determined because of a lack of formal education. Memory functioning was normal in all patients. MRI showed no changes related to cerebral hypoxia. CONCLUSIONS: Permissive hypoxaemia during ECMO might not negatively affect long-term cognitive outcome if adequate organ perfusion is maintained. TRIAL REGISTRATION: at Clinicaltrials.gov NCT01763060. PMID- 28030443 TI - Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study. AB - BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 +/- 89 vs. 7 +/- 1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946. PMID- 28030444 TI - Impact of reversal strategies on the incidence of postoperative residual paralysis after rocuronium relaxation without neuromuscular monitoring: A partially randomised placebo controlled trial. AB - BACKGROUND: Electronic neuromuscular monitoring is not widely used to determine either the reversal requirements for neuromuscular block before extubation of the trachea, or to determine if there is any subsequent postoperative residual neuromuscular block (PORNB). OBJECTIVES: To investigate the incidence of PORNB using acceleromyography after spontaneous recovery of rocuronium-induced block and to compare this with the administration of sugammadex, neostigmine or a placebo. DESIGN: Partially randomised, partially randomised, placebo-controlled, double-blind, four-group parallel-arm study. SETTING: Single-centre study performed between October 2013 and December 2015 in a university hospital. PATIENTS: Of the 134 eligible patients, 128 gave their consent and 125 of these completed the study. INTERVENTIONS: Patients received general anaesthesia with propofol, sevoflurane, fentanyl and rocuronium. Neuromuscular transmission was measured by acceleromyography (TOF-Watch-SX; Organon Teknika B.V., Boxtel, the Netherlands) but the anaesthetist was blind to the results. If the anaesthetist deemed pharmacological reversal to be necessary before extubation of the trachea then patients were assigned randomly to receive either sugammadex (2.0 mg kg), neostigmine (0.05 mg kg) or a placebo. In the postanaesthesia care unit, an independent anaesthetist, unaware of the treatment given, assessed the neuromuscular function using acceleromyography. MAIN OUTCOME MEASURES: The incidence of a normalised train-of-four ratio less than 0.9 on arrival in the recovery room. RESULTS: In total, 125 patients were recruited. Neuromuscular block was allowed to recover spontaneously in 50 patients, whereas the remainder received either sugammadex (27), neostigmine (26) or placebo (22). The number of cases with PORNB were one (3.7%), four (15%), 13 (26%) and 10 (45%) after sugammadex, neostigmine, spontaneous recovery and placebo, respectively. Sugammadex and neostigmine were more effective than placebo [odds ratio (OR): 0.05, 95% confidence interval (CI): 0.005 to 0.403, P = 0.005; OR: 0.22, 95% CI: 0.056 to 0.85, P = 0.028, respectively]. Sugammadex performed better than spontaneous recovery (OR: 0.11, 95% CI: 0.014 to 0.89, P = 0.039) unlike neostigmine (OR: 0.52, 95% CI: 0.15 to 1.79, P = 0.297). Yet, antagonism (pooled data) was more effective than spontaneous recovery (OR: 0.3, 95% CI: 0.1 to 0.9, P = 0.03). CONCLUSION: Although pharmacological reversal based on clinical signs was superior to spontaneous recovery it did not prevent PORNB, irrespective of the reversal agent. TRIAL REGISTRATION: The study is registered under EUDRACT number 2013-001965-17. PMID- 28030445 TI - Mechanical Circulatory Support and Antithrombotic Therapy: Looking for the Holy Grail. PMID- 28030446 TI - Cancer-related cognitive impairment in older adults. AB - PURPOSE OF REVIEW: Cancer, aging, and cognition form a complicated interface that can challenge patients, caretakers, and healthcare professionals. Although the typical aging process allows for compensatory mechanisms to help maintain daily functioning, cancer and cancer treatments can remove the fail-safes and exacerbate cognitive decline. As a result, older cancer patients can experience increased morbidity and mortality. The goal of this article is to provide additional assessment strategies, diagnostic considerations, and treatment options for providers taking care of this growing population. RECENT FINDINGS: In this review, we will discuss current areas of research with regard to epidemiology and our current understanding of cancer-related cognitive impairment in the older patient, while reinforcing the importance of the Comprehensive Geriatric Assessment in assessment, prognosis, and treatment guidance. SUMMARY: Although cognitive impairment in the older cancer patient may be an increasing cause of concern with several gaps in research, there are opportunities to take a methodical treatment approach. PMID- 28030447 TI - Neurocognitive impact of cranial radiation in adults with cancer: an update of recent findings. AB - PURPOSE OF REVIEW: Radiation to the brain is associated with adverse effects on cognition in cancer patients. Advances in technology have improved treatment efficacy, while new or adjuvant approaches continue to be developed. The long term impact of both established and newer treatments on cognition is an active area of research. RECENT FINDINGS: The article reviews the 15 studies published between January 2015 and October 2016 that include data on neurocognitive functions following radiation to the brain in adults with brain metastases, primary brain tumors, or other cancers. These studies examine neurocognitive outcomes in relation to radiation treatment delivery, pharmacological interventions, and biomarkers of brain injury. SUMMARY: Advances in radiotherapy protocols have reduced neurotoxic side-effects. Implementation of standardized, validated neurocognitive measures and biomarkers of brain injury provide new insights into the impact of cranial radiation on cognitive functions. Several promising new lines of research will benefit from further study to address common challenges in the field, including high rates of attrition in longitudinal trials, absence of control groups, small sample sizes, and heterogeneous patient groups. PMID- 28030449 TI - Hemodynamic monitoring in thoracic surgical patients. AB - PURPOSE OF REVIEW: This article reviews the technology and clinical data describing hemodynamic monitoring devices available to anesthesiologists and intensivists caring for patients undergoing thoracic surgical procedures, so that they may better utilize available technology to improve outcomes in this high risk surgical population. RECENT FINDINGS: Noninvasive stroke volume monitors are based on several different technology platforms, all of which have distinct performance characteristics. Strong clinical outcomes data support the use of these devices in patients undergoing major surgical procedures although these studies generally do not target thoracic surgical procedures specifically. The predictive ability of respiratory variation (for measuring fluid responsiveness) is controversial in both one lung and low tidal volume ventilation. Extravascular lung water measurements are well validated, predict postoperative lung function, but require the use of transpulmonary thermodilution. SUMMARY: Technology that has been shown to improve clinical outcomes in major surgical procedures is likely applicable to patients undergoing thoracic surgical procedures; however, several unique features of these procedures limit or modify the way in which these devices can be used. Understanding the scientific basis of these devices is the key to using them effectively. PMID- 28030452 TI - Dietary patterns, Alzheimer's disease and cognitive decline: recent insights. PMID- 28030453 TI - Lipid metabolism: from genetic loci to functional understanding. PMID- 28030454 TI - 'Examine my kidneys and my heart': linking renal and cardiovascular disease. PMID- 28030455 TI - It is not just lipids: proatherogenic vs. antiatherogenic roles for amino acids in macrophage foam cell formation. PMID- 28030456 TI - The Heart Outcomes Prevention Evaluation (HOPE)-3 trial: where do we stand? PMID- 28030457 TI - RETINAL VASCULITIS ASSOCIATED WITH EPSTEIN-BARR VIRUS INFECTION, A CASE REPORT. AB - PURPOSE: To report a case of retinal vasculitis associated with Epstein-Barr virus infection. METHODS: Case report. RESULTS: A 26-year-old woman came with blurry vision. Funduscopy illustrated vasculitis with frosted branch-like appearance. The patient was treated with systemic acyclovir and topical steroid. Circulating polymerase chain reaction was positive for Epstein-Barr virus antibodies. Two months of treatment resolved the clinical manifestations. CONCLUSION: Epstein-Barr infection should be considered as the etiology of retinal vasculitis with similar clinical manifestations. PMID- 28030458 TI - Interorganizational Collaboration in Emergency Cardiovascular Care. AB - BACKGROUND: Interorganizational collaboration management theory contends that cooperation between distinct but related organizations can yield innovation and competitive advantage to the participating organization. Yet, it is unclear if a multi-institutional collaborative can improve quality outcomes across communities. METHODS: We developed a large regional collaborative network of 15 hospitals and 24 emergency medical service agencies surrounding Dallas, Texas, and collected patient-level data on treatment times for acute myocardial infarctions. Using a pre-/posttest research design, we applied median tests of differences to explore outcome changes between groups and over the 6-year period, using data extracted from participating hospital electronic health records. RESULTS: We analyzed temporal trends and changes in treatment times for 2302 patients with ST-elevation myocardial infarction between the pre- and posttest groups. We found a statistically significant 19-minute median reduction in the key outcome metric (total ischemic time, the time difference between the patient's first reported symptoms and the definitive opening of the artery). This represents a 10.8% community-wide improvement over time. CONCLUSIONS: Interorganizational collaboration focused on quality improvement can impact population health across a community. This study provides a basis for broader understanding and participation by health care organizations in multi institutional community change efforts. PMID- 28030459 TI - Implementation and Sequencing of Practice Transformation in Urban Practices with Underserved Patients. AB - BACKGROUND: Patient-centered medical home (PCMH) has gained momentum as a model for primary-care health services reform. METHODS: We conducted interviews at 14 primary care practices undergoing PCMH transformation in a large urban federally qualified health center in California and used grounded theory to identify common themes and patterns. RESULTS: We found clinics pursued a common sequence of changes in PCMH transformation: Clinics began with National Committee for Quality Assurance (NCQA) level 3 recognition, adding care coordination staff, reorganizing data flow among teams, and integrating with a centralized quality improvement and accountability infrastructure. Next, they realigned to support continuity of care. Then, clinics improved access by adding urgent care, patient portals, or extending hours. Most then improved planning and management of patient visits. Only a handful worked explicitly on improving access with same day slots, scheduling processes, and test result communication. The clinics' changes align with specific NCQA PCMH standards but also include adding physicians and services, culture changes, and improved communication with patients. CONCLUSIONS: NCQA PCMH level 3 recognition is only the beginning of a continuous improvement process to become patient centered. Full PCMH transformation took time and effort and relied on a sequential approach, with an early focus on foundational changes that included use of a robust quality improvement strategy before changes to delivery of and access to care. PMID- 28030460 TI - Health Care Professionals' Usage and Documentation of a Swedish Quality Registry Regarding Preventive Nutritional Care. AB - OBJECTIVES: To describe health care staff members' usage and documentation in a Swedish quality registry focusing on a preventive care process regarding the risk area of malnutrition among persons with dementia. The preventive care process includes risk assessment, analysis of underlying causes, planning and performing interventions, as well as evaluating effects. METHODS: Data were collected from 2 Swedish quality registries, Senior Alert and the Swedish Dementia Register (Svedem). In total, 1929 people with dementia were assessed and 1432 registered as being at risk of malnutrition or malnourished. RESULTS: Performed nutritional interventions were registered in approximately 65% of cases. In more than 80% of registrations, the analyses of underlying causes were missing. Those who had registered underlying causes had significantly more interventions and the evaluation of the performed intervention was registered. The time between assessment and evaluation depended on care setting and ranged from 0 to 702 days. CONCLUSIONS: Limitations in registration were noted; however, the register allows staff to focus on nutritional care and has resulted in many risk assessments. Rarely people were registered in all steps of the preventive care process. Large variances in when the performed interventions were evaluated makes it difficult to measure improvements. PMID- 28030461 TI - Does the Proportion of Same-Day and 24-Hour Appointments Impact Patient Satisfaction? AB - BACKGROUND: The relationship between open access and patient satisfaction is mixed. Our study is the first to assess the relationship between open access appointment scheduling and patient satisfaction in the Military Health System (MHS). It is also unique in that we examine both same-day and 24-hour access through a relationship with satisfaction. METHODS: We conducted a panel time series analysis with general estimating equations on the Army population of outpatient facilities (N = 32), with 32 364 957 total observations. Our primary independent variables were the proportion of a facility's appointments within 24 hours and same day from July 2013 to May 2015. RESULTS: We identified that a higher proportion of same-day appointments is associated with increased patient satisfaction with the ability to see their provider when needed. We did not find the same result when examining access within 24 hours. CONCLUSIONS: Open access appointment scheduling appears to have a greater impact on patient satisfaction with timeliness of care if that appointment is made the same day the patient presents to the facility. Facilities should consider opening more of their schedule to accommodate same-day appointments. This can result in less costly primary care instead of emergency department usage. PMID- 28030462 TI - Examining the Relationship Between Perceived Quality of Care and Actual Quality of Care as Measured by 30-Day Readmission Rates. AB - OBJECTIVE: To test the relationship between patient experience, as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS), and actual quality of care, as measured by 30-day readmission rates. DATA SOURCES: Both HCAHPS data and outcome data reported to the Centers of Medicare & Medicaid Services (CMS). STUDY DESIGN: This secondary, nationwide (N = 4060), hospital-level study focused only on acute care hospitals. HCAHPS question 22 "Would you recommend this hospital to your friends and family?" was used to determine level of overall satisfaction, and 30-day readmission rates, as reported to the CMS, was used as a proxy for actual quality of care. PRINCIPAL FINDINGS: A statistically significant relationship was found between patient experience and actual quality outcomes. CONCLUSION: The results of this study reinforce the inclusion of patient experience in Medicare's Value Based Purchasing program as a matter of good public policy. PMID- 28030463 TI - Promoting Continuous Quality Improvement in the Alabama Child Health Improvement Alliance Through Q-Sort Methodology and Learning Collaboratives. AB - OBJECTIVE: Q-sort methodology is an underutilized tool for differentiating among multiple priority measures. The authors describe steps to identify, delimit, and sort potential health measures and use selected priority measures to establish an overall agenda for continuous quality improvement (CQI) activities within learning collaboratives. METHODS: Through an iterative process, the authors vetted a list of potential child and adolescent health measures. Multiple stakeholders, including payers, direct care providers, and organizational representatives sorted and prioritized measures, using Q-methodology. RESULTS: Q methodology provided the Alabama Child Health Improvement Alliance (ACHIA) an objective and rigorous approach to system improvement. Selected priority measures were used to design learning collaboratives. An open dialogue among stakeholders about state health priorities spurred greater organizational buy-in for ACHIA and increased its credibility as a statewide provider of learning collaboratives. CONCLUSIONS: The integrated processes of Q-sort methodology, learning collaboratives, and CQI offer a practical yet innovative way to identify and prioritize state measures for child and adolescent health and establish a learning agenda for targeted quality improvement activities. PMID- 28030464 TI - Selecting Health Care Improvement Projects: A Methodology Integrating Cause-and Effect Diagram and Analytical Hierarchy Process. AB - OBJECTIVES: It is often vital to identify, prioritize, and select quality improvement projects in a hospital. Yet, a methodology, which utilizes experts' opinions with different points of view, is needed for better decision making. METHODS: The proposed methodology utilizes the cause-and-effect diagram to identify improvement projects and construct a project hierarchy for a problem. The right improvement projects are then prioritized and selected using a weighting scheme of analytical hierarchy process by aggregating experts' opinions. An approach for collecting data from experts and a graphical display for summarizing the obtained information are also provided. RESULTS: The methodology is implemented for improving a hospital appointment system. The top ranked 2 major project categories for improvements were identified to be system- and accessibility-related causes (45%) and capacity-related causes (28%), respectively. For each of the major project category, subprojects were then ranked for selecting the improvement needs. CONCLUSION: The methodology is useful in cases where an aggregate decision based on experts' opinions is expected. Some suggestions for practical implementations are provided. PMID- 28030465 TI - Mutual Mentorship: Patient-Partnered Care Starts at the Patient-CEO Level. PMID- 28030466 TI - From the Intermountain Institute for Health Care Delivery Research. PMID- 28030470 TI - Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial. AB - Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving >=50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS. PMID- 28030471 TI - Stress-related psychological symptoms contribute to axial pain persistence after motor vehicle collision: path analysis results from a prospective longitudinal study. AB - Posttraumatic stress disorder (PTSD) symptoms and pain after traumatic events such as motor vehicle collision (MVC) have been proposed to be mutually promoting. We performed a prospective multicenter study that enrolled 948 individuals who presented to the emergency department within 24 hours of MVC and were discharged home after evaluation. Follow-up evaluations were completed 6 weeks, 6 months, and 1 year after MVC. Path analysis results supported the hypothesis that axial pain after MVC consistently promotes the maintenance of hyperarousal and intrusive symptoms, from the early weeks after injury through 1 year. In addition, path analysis results supported the hypothesis that one or more PTSD symptom clusters had an influence on axial pain outcomes throughout the year after MVC, with hyperarousal symptoms most influencing axial pain persistence in the initial months after MVC. The influence of hyperarousal symptoms on pain persistence was only present among individuals with genetic vulnerability to stress-induced pain, suggesting specific mechanisms by which hyperarousal symptoms may lead to hyperalgesia and allodynia. Further studies are needed to better understand the specific mechanisms by which pain and PTSD symptoms enhance one another after trauma, and how such mechanisms vary among specific patient subgroups, to better inform the development of secondary preventive interventions. PMID- 28030472 TI - Epigenetic divergence in the TRPA1 promoter correlates with pressure pain thresholds in healthy individuals. AB - The expression pattern of important transduction molecules in nociceptive sensory neurons is likely to dictate pain sensitivity. While this notion is well established for increased pain sensitivities under conditions like inflammation and neuropathy, less is known as to which molecules are defining interindividual differences in pain sensitivity in healthy subjects. A genome-wide methylation analysis on monozygotic twins found that methylation of a CpG dinucleotide in the promoter of transient receptor potential ankyrin 1 (TRPA1) is inversely associated with the threshold for heat-induced pain. Several in vitro studies also suggest that TRPA1 mediates mechanical sensitivity of sensory afferents, thus potentially mediating pressure-evoked pain. In the present study, we therefore investigated the epigenetic predisposition for pressure pain by analyzing the methylation status of 47 CpG sites in the promoter region of TRPA1. Using DNA from whole-blood samples of 75 healthy volunteers, we found that the same CpG site previously found to affect the threshold for heat-evoked pain is hypermethylated in subjects with a low threshold for pressure pain. We also found gender differences, with females displaying higher methylation rates combined with higher pressure pain sensitivities as compared with males. In conclusion, our findings support the notion that epigenetic regulation of TRPA1 seems to regulate thermal and mechanical pain sensitivities. PMID- 28030473 TI - Intense pain influences the cortical processing of visual stimuli projected onto the sensitized skin. AB - Sensitization is a form of implicit learning produced by the exposure to a harmful stimulus. In humans and other mammals, sensitization after skin injury increases the responsiveness of peripheral nociceptors and enhances the synaptic transmission of nociceptive input in the central nervous system. Here, we show that sensitization-related changes in the central nervous system are not restricted to nociceptive pathways and, instead, also affect other sensory modalities, especially if that modality conveys information relevant for the sensitized body part. Specifically, we show that after sensitizing the forearm using high-frequency electrical stimulation (HFS) of the skin, visual stimuli projected onto the sensitized forearm elicit significantly enhanced brain responses. Whereas mechanical hyperalgesia was present both 20 and 45 minutes after HFS, the enhanced responsiveness to visual stimuli was present only 20 minutes after HFS. Taken together, our results indicate that sensitization involves both nociceptive-specific and multimodal mechanisms, having distinct time courses. PMID- 28030474 TI - Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury induced mechanical hypersensitivity and cognitive impairment in mice. AB - Despite considerable advances in understanding mechanisms involved in chronic pain, effective treatment remains elusive. Comorbid conditions including anxiety, depression, and cognitive impairment further impact quality of life. Chronic pain is associated with reversible changes in brain anatomy and function and with long term changes in gene expression. Epigenetic mechanisms, including DNA methylation, contribute to wide-spread and long-lasting reprogramming of gene expression. We previously reported decreases in global DNA methylation in the mouse frontal cortex 6 months after induction of neuropathic pain using the spared nerve injury (SNI) model. Here, we examined the therapeutic effect of increasing DNA methylation using the methyl donor S-adenosylmethionine (SAM). S adenosylmethionine is marketed as a nutritional supplement for a range of conditions including liver disease, depression, osteoarthritis, fibromyalgia, and dementia. Three months after SNI or sham surgery, animals were treated with SAM (20 mg/kg, 3*/week) or saline orally for 4 months, and the impact on sensory, motor, motivational, and cognitive indices was measured. S-adenosylmethionine attenuated SNI-induced mechanical hypersensitivity and reduced active avoidance of mechanical stimuli but had no effect on cold sensitivity or motor capacity. S adenosylmethionine completely blocked nerve injury-induced cognitive impairment and attenuated SNI-induced decreases in global DNA methylation in the frontal cortex. In summary, chronic oral administration of the methyl donor, SAM, attenuated sensory and cognitive symptoms associated with nerve injury in mice. These effects may be mediated, in part, through modulation of DNA methylation in the central nervous system by systemic administration of the methyl donor SAM. PMID- 28030475 TI - Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain. AB - Metabotropic glutamate receptor 5 (mGluR5) is an excitatory G-protein-coupled receptor (GPCR) present in the spinal cord dorsal horn (SCDH) where it has a well established role in pain. In addition to its traditional location on the cytoplasmic membrane, recent evidence shows that these receptors are present intracellularly on the nuclear membrane in the spinal cord dorsal horn and are implicated in neuropathic pain. Nuclear mGluR5 is a functional receptor that binds glutamate entering the cell through the neuronal glutamate transporter (GT) EAAT3 and activates transcription factor c-fos, whereas plasma membrane mGluR5 is responsible for c-jun activation. Here, we extend these findings to a model of inflammatory pain using complete Freund's adjuvant (CFA) and show that nuclear mGluR5 is also upregulated in the spinal cord dorsal horn following inflammation. We also show that pretreatment with an excitatory amino acid transporter (EAAT) inhibitor attenuates pain and decreases Fos, but not Jun, expression in complete Freund's adjuvant rats. In contrast, selective glial glutamate transporter inhibitors are pronociceptive and increase spinal glutamate concentrations. Additionally, we found that permeable mGluR5 antagonists are more effective at attenuating pain and Fos expression than nonpermeable group I mGluR antagonists. Taken together, these results suggest that under inflammatory conditions, intracellular mGluR5 is actively involved in the relay of nociceptive information in the spinal cord. PMID- 28030476 TI - Socioeconomic Disparities in Mortality Among Women With Incident Breast Cancer Before and After Implementation of Medicare Part D. AB - BACKGROUND: Breast cancer patients exhibit survival disparities based on socioeconomic status (SES). Disparities may be attributable to access to expensive oral endocrine agents. OBJECTIVES: Define recent socioeconomic disparities in breast cancer survival and determine whether these improved after implementation of the Medicare Part D program. DESIGN: Difference-in-difference natural experiment of women diagnosed and treated before or after implementation of Medicare Part D. SUBJECTS: Female Medicare beneficiaries with early-stage breast cancer: 54,772 diagnosed in 2001 and 46,371 in 2007. MEASURES: SES was based on Medicaid enrollment and zip code per capita income, all-cause mortality from Medicare, and cause of death from National Death Index. RESULTS: Among women diagnosed pre-Part D, 40.5% of poor beneficiaries had died within 5 years compared with 20.3% of high-income women (P<0.0001). Post-Part D, 33.6% of poor women and 18.4% of high-income women died by 5 years. After adjustment for potential confounders, improvement in all-cause mortality post-Part D was greater for poorer women compared with more affluent women (P=0.002). However, absolute improvement in breast cancer-specific mortality was 1.8%, 1.2%, and 0.8% (P=0.88 for difference in improvement by SES), respectively for poor, near-poor, and high income women, whereas analogous improvement in mortality from other causes was 5.1%, 3.8%, and 0.9% (P=0.067 for difference in improvement by SES). CONCLUSIONS: Large survival disparities by SES exist among breast cancer patients. The Part D program successfully ameliorated SES disparities in all-cause mortality. However, improvement was concentrated in causes of death other than breast cancer, suggesting remaining gaps in care. PMID- 28030477 TI - Fabulous at Forty! PMID- 28030478 TI - Looking Back, Looking Forward. PMID- 28030479 TI - Vascular Access Specialist Training, Experience, and Practice in the United States: Results From the National PICC1 Survey. AB - Vascular access specialists are increasingly responsible for insertion and care of peripherally inserted central catheters in the United States. Despite proliferation of the specialty, little is known about the training, practice patterns, and experiences of these clinicians. In partnership with a vascular access and an infusion nursing organization, a Web-based survey of 1698 clinicians was conducted. Substantial variation in practices related to insertion, use of technology, dressing and flushing, and management of complications was observed. Some reported practices were inconsistent with available evidence-based recommendations. Therefore, opportunities to improve patient care and further explore reasons driving such variation exist and should be explored. PMID- 28030480 TI - Development of an Evidence-Based List of Noncytotoxic Vesicant Medications and Solutions. AB - Infiltration of a vesicant medication, defined as extravasation, may result in significant patient injuries. The first step in preventing extravasation is the identification and recognition of vesicant medications and solutions. Because there is no list of noncytotoxic vesicants as established by a professional organization, the Infusion Nurses Society, as the global authority in infusion nursing, identified the need to address this gap. A task force was formed for the purpose of creating an evidence-based list of noncytotoxic vesicant medications and solutions. PMID- 28030481 TI - Thrombocytopenia: A Destruction of Platelets. AB - Platelets, or megakaryocytes, are irregular, disk-shaped cell fragments circulating in the blood. They are a primary component in maintaining hemostasis. Low platelet counts, or thrombocytopenia, leave patients at an increased risk of hemorrhage. This article discusses various etiologies of disorders of low platelets and current therapies for management. PMID- 28030482 TI - Pediatric Parenteral Nutrition-Associated Liver Disease. AB - Pediatric parenteral nutrition-associated liver disease (PNALD) is typically defined as a decrease in bile flow that is independent of a mechanical obstruction and of any other underlying liver disease. It is most often seen in pediatric patients receiving parenteral nutrition support. Up to 50% to 66% of children receiving long-term parenteral nutrition are reported to be diagnosed with PNALD. The goal of treatment for PNALD is advancement to full enteral nutrition and elimination of dependence on parenteral nutrition support. Achieving this goal is not always possible, especially in patients with short bowel syndrome. The following review article highlights some of the current treatment strategies focused on prevention or correction of PNALD as noted in current American Society for Parenteral and Enteral Nutrition guidelines. PMID- 28030483 TI - Antibiotic Classification and Indication Review for the Infusion Nurse. AB - Outpatient parenteral antimicrobial therapy (OPAT) has become an increasingly common practice for the treatment of infections. The infusion nurse plays a vital role in administering, monitoring, and educating patients about parenteral antibiotics, while bridging communication between the patient and OPAT team. It is important for the infusion nurse to know common indications, adverse effects, monitoring parameters, and the mechanism of action for antibiotics used in OPAT to provide optimal patient care. This review includes those antibiotics, which are frequently administered or recently approved with a high likelihood of being used in OPAT. PMID- 28030484 TI - Pharmacokinetics, Safety, and Efficacy of Recombinant Factor VIII Fc Fusion Protein: A Practical Review. AB - Prophylaxis for hemophilia A with conventional factor VIII (FVIII) products requires frequent intravenous dosing, which may reduce adherence. Recombinant factor VIII Fc fusion protein (rFVIIIFc) has a prolonged half-life compared with conventional rFVIII, and has demonstrated safety and efficacy for the prevention and treatment of bleeding episodes in phase 3 studies of patients with severe hemophilia A. Most subjects experienced reduced prophylactic dosing frequency with rFVIIIFc compared with prestudy FVIII; the median total weekly prophylactic consumption was comparable. No subjects developed inhibitors. These results suggest that prophylaxis with rFVIIIFc in patients with hemophilia A may allow less frequent prophylactic dosing while maintaining efficacy, with comparable prophylactic consumption. PMID- 28030485 TI - Combat amputees' health-related quality of life and psychological outcomes: A brief report from the wounded warrior recovery project. AB - BACKGROUND: This study extends what is known about long-term health-related quality of life (HrQoL) and other psychosocial outcomes (i.e., depression, posttraumatic stress disorder [PTSD]) among US military combat amputees serving in Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. METHODS: A total of 63 combat amputees were identified from the Wounded Warrior Recovery Project, a study assessing long-term self-reported HrQoL and psychological outcomes among those wounded during military service. Another 477 service members from the Wounded Warrior Recovery Project were identified as a comparison group (i.e., nonamputees with moderate to severe extremity injuries). RESULTS: After adjusting for age, time since injury, overall injury severity, and traumatic brain injury, amputees had poorer functional HrQoL than those in the nonamputee comparison group overall and in the specific area related to performance of usual activities, and, to some degree, chronic and acute symptoms, and mobility/self-care. On the other hand, depression and PTSD symptoms were not different for the two groups. CONCLUSION: Results suggest that when assessed over 5 years postinjury, on average, amputees have unique physical and functional limitations, yet do not report greater depression or PTSD symptoms than others seriously injured in combat. It may be that state-of-the-art integrated amputee care that includes support networks and emphasis on adjustment and psychological health may increase successful coping and adjustment, at least to a level that is on par with other types of serious combat injury. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. PMID- 28030488 TI - A novel method of optimizing patient- and family-centered care in the ICU. AB - BACKGROUND: Patient- and family-centered care permeates critical care where there are often multiple teams involved in management. A method of facilitating information sharing to support shared decision making is essential in appropriately rendering care.This study sought to determine whether incorporating family members on rounds in the intensive care unit (ICU) improves patient and family knowledge and whether doing so improves team time management and satisfaction with the process. METHODS: A nonrandomized comparative before-and after trial of incorporating family members on rounds (July to December 2009 vs January to July 2010) in a single quarternary center's surgical ICU assessed (1) family members' knowledge, (2) nurse's and physician's satisfaction with the intervention, (3) frequency and timing of family meetings, and (4) physician's workflow. RESULTS: Intensive care unit demographics and use were similar between time frames. Presurvey (n = 412 family members; 49 nurses) and postsurvey (n = 427 family members; 47 nurses) were coupled with presurvey (n = 5) and postsurvey (n = 6) physicians' informal feedback. Family knowledge of the clinical course and plans increased from 146 (35.4%) of 412 to 374 (87.6%) of 427 (p < 0.0001). Nurses were nearly uniformly satisfied with planned family interaction on rounds (presurvey: 9/49 [18.4%] vs postsurvey: 46/47 [97.9%]; p < 0.0001). Family meetings per week outside of rounds substantially decreased from a mean of 5.3 +/ 2.7 to 0.3 +/- 0.9; p < 0.001). Goals of therapy including end-of-life care became an element frequently discussed on rounds with families (presurvey: 9.4% +/- 4.7% vs postsurvey: 82.5% +/- 14.8%; p < 0.0001). One intensivist was dissatisfied with the process. CONCLUSION: Incorporating family members on rounds in the ICU improves communication and satisfaction and shifts the team's time away from family communication events outside of rounds, condensing most of those activities within the rounding structure. Critical care nurses and intensivists were principally satisfied with the process. LEVEL OF EVIDENCE: Therapeutic, level III. PMID- 28030489 TI - The mangled extremity score and amputation: Time for a revision. AB - BACKGROUND: The Mangled Extremity Severity Score (MESS) was developed 25 years ago in an attempt to use the extent of skeletal and soft tissue injury, limb ischemia, shock, and age to predict the need for amputation after extremity injury. Subsequently, there have been mixed reviews as to the use of this score. We hypothesized that the MESS, when applied to a data set collected prospectively in modern times, would not correlate with the need for amputation. METHODS: We applied the MESS to patient data collected in the American Association for the Surgery of Trauma PROspective Vascular Injury Treatment registry. This registry contains prospectively collected demographic, diagnostic, treatment, and outcome data. RESULTS: Between 2013 and 2015, 230 patients with lower extremity arterial injuries were entered into the PROspective Vascular Injury Treatment registry. Most were male with a mean age of 34 years (range, 4-92 years) and a blunt mechanism of injury at a rate of 47.4%. A MESS of 8 or greater was associated with a longer stay in the hospital (median, 22.5 (15, 29) vs 12 (6, 21); p = 0.006) and intensive care unit (median, 6 (2, 13) vs 3 (1, 6); p = 0.03). Of the patients' limbs, 81.3% were ultimately salvaged (median MESS, 4 (3, 5)), and 18.7% required primary or secondary amputation (median MESS, 6 (4, 8); p < 0.001). However, after controlling for confounding variables including mechanism of injury, degree of arterial injury, injury severity score, arterial location, and concomitant injuries, the MESS between salvaged and amputated limbs was no longer significantly different. Importantly, a MESS of 8 predicted in-hospital amputation in only 43.2% of patients. CONCLUSION: Therapeutic advances in the treatment of vascular, orthopedic, neurologic, and soft tissue injuries have reduced the diagnostic accuracy of the MESS in predicting the need for amputation. There remains a significant need to examine additional predictors of amputation following severe extremity injury. LEVEL OF EVIDENCE: Prospective, prognostic study, level III. PMID- 28030490 TI - Modeling Acinetobacter baumannii wound infections: The critical role of iron. AB - BACKGROUND: Acinetobacter baumannii has emerged as an increasingly important and successful opportunistic human pathogen due to its ability to withstand harsh environmental conditions, its characteristic virulence factors, and quick adaptability to stress. METHODS: We developed a clinically relevant murine model of A. baumannii traumatic wound infection to determine the effect of local wound environment on A. baumannii virulence. Mice underwent rectus muscle crush injury combined with ischemia created by epigastric vessel ligation, followed by A. baumannii inoculation. Reiterative experiments were performed using (1) a mutant deficient in the production of the siderophore acinetobactin, or (2) iron supplementation of the wound milieu. Mice were euthanized 7 days later, and rectus muscle analyzed for signs of clinical infection, HIF1alpha accumulation, bacterial abundance, and colony morphotype. To determine the effect of wound milieu on bacterial virulence, Galleria mellonella infection model was used. RESULTS: The combination of rectus muscle injury with ischemia and A. baumannii inoculation resulted in 100% incidence of clinical wound infection that was significantly higher compared with other groups (n = 15/group, p < 0.0001). The highest level of wound infection was accompanied by the highest level of A. baumannii colonization (p < 0.0001) and the highest degree of HIF1alpha accumulation (p < 0.05). A. baumannii strains isolated from injured/ischemic muscle with clinical infection displayed a rough morphotype and a higher degree of virulence as judged by G. mellonella killing assay as compared with smooth morphotype colonies isolated from injured muscle without clinical infection (100% vs. 60%, n = 30 Log-Rank test, p = 0.0422). Iron supplementation prevented wound infection (n = 30, p < 0.0001) and decreased HIF1alpha (p = 0.039643). Similar results of decrease in wound infection and HIF1alpha were obtained when A. baumannii wild type was replaced with its derivative mutant [INCREMENT]BasD deficient in acinetobactin production. CONCLUSION: The ability of A. baumannii to cause infections in traumatized wound relies on its ability to scavenge iron and can be prevented by iron supplementation to the wound milieu. PMID- 28030491 TI - Severe injuries associated with skiing and snowboarding: A national trauma data bank study. AB - BACKGROUND: Injuries after skiing and snowboarding accidents lead to an estimated 7,000 hospital admissions annually and present a significant burden to the health care system. The epidemiology, injury patterns, hospital resource utilization, and outcomes associated with these severe injuries need further characterization. METHODS: The National Trauma Data Bank was queried for the period 2007 to 2014 for admissions with Injury Severity Score > 15 and International Classification of Diseases Codes-9th Revision codes 885.3 (fall from skis, n = 1,353) and 885.4 (fall from snowboard, n = 1,216). Demographics, emergency department data, diagnosis and procedure codes, and outcomes were abstracted from the database. RESULTS: Severe (Injury Severity Score > 15) ski-associated and snowboard associated injuries differed with respect to age distribution (median age, 38; interquartile range, 19-59 for skiers and median age, 20; interquartile range, 16 25 for snowboarders; p < 0.001) and sex (78.9% and 86.4% males, respectively, p < 0.001). Traumatic brain injury was common for both sports (56.8% of skiers vs. 46.6% of snowboarders, p < 0.001). Injuries to the spine (28.9%), chest (37.6%), and abdomen (35.0%) were also common. Eighty percent of patients used emergency medical services (50% ambulance, 30% helicopter) with a median emergency medical services transport time of 84 minutes. 50.8% of patients required interhospital transport. 43.2% of injuries required surgical intervention (21.3% orthopedic, 12.5% neurosurgical, 10.5% thoracic, 7.8% abdominal). Median hospital length of stay was 5.0 days. 60.0% of patients required intensive care unit admission with median intensive care unit length of stay 3.0 days. Overall mortality was 4.0% for skiers and 1.9% for snowboarders. CONCLUSION: Severe injuries after ski and snowboard accidents are associated with significant morbidity and mortality. Differences in injury patterns, risk factors for severe injury, and resource utilization require further study. Increased resource allocation to alpine trauma systems is warranted. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level III. PMID- 28030492 TI - Stapled versus hand-sewn: A prospective emergency surgery study. An American Association for the Surgery of Trauma multi-institutional study. AB - BACKGROUND: Data from the trauma patient population suggests handsewn (HS) anastomoses are superior to stapled (ST). A recent retrospective study in emergency general surgery (EGS) patients had similar findings. The aim of the current study was to evaluate HS and ST anastomoses in EGS patients undergoing urgent/emergent operations. METHODS: The study was sponsored by the American Association for the Surgery of Trauma Multi-Institutional Studies Committee. Patients undergoing urgent/emergent bowel resection for EGS pathology were prospectively enrolled from July 22, 2013 to December 31, 2015. Patients were grouped by HS/ST anastomoses, and variables were collected. The primary outcome was anastomotic failure. Similar to other studies, anastomotic failure was evaluated at the anastomosis level. Multivariable logistic regression was performed controlling for age and risk factors for anastomotic failure. RESULTS: Fifteen institutions enrolled a total of 595 patients with 649 anastomoses (253 HS and 396 ST). Mean age was 61 years, 51% were men, 7% overall mortality. Age and sex were the same between groups. The overall anastomotic failure rate was 12.5%. The HS group had higher lactate, lower albumin, and were more likely to be on vasopressors. Hospital and intensive care unit days, as well as mortality, were greater in the HS group. Anastomotic failure rates and operative time were equivalent for HS and ST. On multivariate regression, the presence of contamination at initial resection (odds ratio, 1.965; 95% confidence interval, 1.183-3.264) and the patient being managed with open abdomen (odds ratio, 2.529; 95% confidence interval, 1.492-4.286) were independently associated with anastomotic failure, while the type of anastomosis was not. CONCLUSION: EGS patients requiring bowel resection and anastomosis are at high risk for anastomotic failure. The current study illustrates an apparent bias among acute care surgeons to perform HS techniques in higher-risk patients. Despite the individualized application of technique for differing patient populations, the risk of anastomotic failure was equivalent when comparing HS and ST anastomoses. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 28030493 TI - Enteral nutrition in traumatic brain injury. PMID- 28030495 TI - Resuscitative endovascular balloon occlusion of the aorta in trauma patients in youth. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has received increasing attention for critically uncontrolled hemorrhagic shock. However, the efficacy of REBOA in patients in youth is unknown. OBJECTIVES: The aim of this study was to evaluate the mortality and characteristics of patients of age <=18 years with severe traumatic injury who received REBOA. METHODS: We retrospectively analyzed observational cohort data from the Japan Trauma Data Bank (JTDB) from 2004 to 2015. All patients <=18 years old who underwent REBOA were included. Clinical characteristics and mortalities were analyzed and compared among patients <=15 years old (young children) and 16-18 years old (adolescents). RESULTS: Of the 236,698 patients in the JTDB (2004-2015), 22,907 patients were 18 years old or younger. A total of 3,440 patients without survival data were excluded. Of the remaining 19,467, 54 (0.3%) patients underwent REBOA, among which 15 (27.8%) were young children. Both young children and adolescents who underwent REBOA were seriously injured (median Injury Severity Score [ISS], 41 and 38, respectively). Also, 53.3% of young children and 38.5% of adolescents survived to discharge after undergoing REBOA. CONCLUSION: In a cohort of young trauma patients from the JTDB who underwent REBOA to control hemorrhage, we found that both young children and adolescents who underwent REBOA were seriously injured and had an equivalent survival rate compared to the reported survival rate from studies in adults. REBOA treatment may be a reasonable option in severely injured young patients in the appropriate clinical settings. Further prospective studies are needed to confirm our findings. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV. PMID- 28030496 TI - Temporary arterial shunts in damage control: Experience and outcomes. AB - BACKGROUND: Arterial shunting is a well-described method to control hemorrhage and rapidly reestablish flow, but optimal shunt dwell times remain controversial. We hypothesized that prolonged shunt dwell times of more than 6 hours are related to adverse outcomes after major arterial injury. METHODS: A review (2005-2013) of all patients with arterial shunts placed after traumatic injury at our urban Level I trauma center was undertaken. Patients who died prior to shunt removal (n = 7) were excluded. Shunt complications were defined as dislodgement, thrombosis, and distal ischemia. Patients were compared on the basis of shunt complications with respect to clinical parameters. RESULTS: The 42 patients who underwent arterial shunting after major vascular injury were primarily young (median, 26 years; interquartile range [IQR], 22-31 years) males (97.6%), severely injured (Injury Severity Score, 17.5 [IQR, 14-29]; shunted vessel Abbreviated Injury Scale score, 4 [IQR, 3-4]) by gunshot (85.7%) requiring neck/torso (33.3%) or upper-extremity (19.1%) or lower-extremity (47.6%) shunts. Thirty-five patients survived until shunt removal, and 5 (14.3%) of 35 developed shunt complications. Demographics and clinical characteristics were compared between those with shunt dwell times of less than 6 hours (n = 19) and more than 6 hours (n = 16). While patients appeared to have a greater injury burden overall in the group with dwell times of more than 6 hours, there were no statistical differences between groups with respect to age, gender, initial systolic blood pressure or hemodynamics during the shunt dwell period, use of vasopressors, Abbreviated Injury Scale score of the shunted vessel, Injury Severity Score, or outcomes including limb amputation or mortality. No patients (0/19) with shunt dwell times of less than 6 hours developed complications, whereas 5 (31.3%) of 16 patients with dwell times of more than 6 hours developed shunt complications (p = 0.05). CONCLUSIONS: In this civilian series, 14% of patients with arterial shunts developed shunt complications. Our data suggest that limiting shunt dwell times to less than 6 hours when clinically feasible may decrease adverse outcomes. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 28030498 TI - Re: Enteral nutrition in traumatic brain injury. PMID- 28030499 TI - The Coalition for National Trauma Research supports the call for a national trauma research action plan. PMID- 28030500 TI - Analysis of aeromedical retrieval coverage using elliptical isochrones: An evaluation of helicopter fleet size configurations in Scotland. AB - BACKGROUND: Trauma systems in remote and rural regions often rely on helicopter emergency medical services to facilitate access to definitive care. The siting of such resources is key, but often relies on simplistic modeling of coverage, using circular isochrones. Scotland is in the process of implementing a national trauma network, and there have been calls for an expansion of aeromedical retrieval capacity. The aim of this study was to analyze population and area coverage of the current retrieval service configuration, with three aircraft, and a configuration with an additional helicopter, in the North East of Scotland, using a novel methodology. Both overall coverage and coverage by physician-staffed aircraft, with enhanced clinical capability, were analyzed. METHODS: This was a geographical analysis based on calculation of elliptical isochrones, which consider the "open-jaw" configuration of many retrieval flights. Helicopters are not always based at hospitals. We modeled coverage based on different outbound and inbound flights. Areally referenced population data were obtained from the Scottish Government. RESULTS: The current helicopter network configuration provides 94.2% population coverage and 59.0% area coverage. The addition of a fourth helicopter would marginally increase population coverage to 94.4% and area coverage to 59.1%. However, when considering only physician-manned aircraft, the current configuration provides only 71.7% population coverage and 29.4% area coverage, which would be increased to 91.1% and 51.2%, respectively, with a second aircraft. CONCLUSIONS: Scotland's current helicopter network configuration provides good population coverage for retrievals to major trauma centers, which would only be increased minimally by the addition of a fourth aircraft in the North East. The coverage provided by the single physician-staffed aircraft is more limited, however, and would be increased considerably by a second physician staffed aircraft in the North East. Elliptical isochrones provide a useful means of modeling "open-jaw" retrieval missions and provide a more realistic estimate of coverage. LEVEL OF EVIDENCE: Epidemiological study, level IV; therapeutic study, level IV. PMID- 28030501 TI - Apocynin suppressed the nuclear factor-kappaB pathway and attenuated lung injury in a rat hemorrhagic shock model. AB - BACKGROUND: The aim of this study was to investigate whether a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) inhibitor, apocynin, reduces reactive oxygen species (ROS) production, suppresses the nuclear factor kappaB (NF-kappaB) pathway, attenuates lung injury, and improves survival in rat hemorrhagic shock (HS) model. METHODS: Blood was drawn from male Sprague-Dawley rats (290-340 g) to maintain a mean arterial pressure of 20-25 mm Hg for 40 minutes. The rats were resuscitated with the drawn blood, and a vehicle (HS), a low dose of apocynin (20 mg/kg, LD-Apo), or a high dose of apocynin (40 mg/kg, HD Apo) was administered intraperitoneally. The survival of the rats was observed for 72 hours. Then, a separated set of rats was euthanized at 6 hours post-HS induction. We measured gp91-phox (Nox2) expression, Nox activity, cytoplasmic phosphorylated inhibitor kappaB-alpha (p-IkappaB-alpha) expression, NF-kappaB p65 DNA-binding activity, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) gene expressions, malondialdehyde (MDA) level, myeloperoxidase (MPO) activity, and histological damage in the lung tissues. RESULTS: The survival rates of the sham, HS, HS + LD-Apo, and HS + HD-Apo groups were 100% (5/5), 30% (3/10), 40% (4/10), and 70% (7/10), respectively. A high dose of apocynin decreased gp91-phox expression, Nox activity, and MDA level in the lung tissues during HS and resuscitation. It also decreased p-IkappaB-alpha expression, NF kappaB p65 DNA-binding activity, TNF-alpha and IL-6 gene expressions, and MPO activity in the lung tissues and attenuated histological lung injuries. However, a low dose of apocynin failed to show these benefits. CONCLUSIONS: The administration of a high dose of apocynin inhibited Nox2 expression and Nox activity, reduced lipid peroxidation, suppressed the NF-kappaB pathway and subsequent pro-inflammatory cytokines transcription in the lung tissues, and attenuated lung injury during HS and resuscitation in rats. PMID- 28030502 TI - Operative fixation of rib fractures after blunt trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma. AB - BACKGROUND: Rib fractures are identified in 10% of all injury victims and are associated with significant morbidity (33%) and mortality (12%). Significant progress has been made in the management of rib fractures over the past few decades, including operative reduction and internal fixation (rib ORIF); however, the subset of patients that would benefit most from this procedure remains ill defined. The aim of this project was to develop evidence-based recommendations. METHODS: Population, intervention, comparison, and outcome (PICO) questions were formulated for patients with and without flail chest. Outcomes of interest included mortality, duration of mechanical ventilation (DMV), hospital and intensive care unit (ICU) length of stay (LOS), incidence of pneumonia, need for tracheostomy, and pain control. A systematic review and meta-analysis of currently available evidence was performed per the Grading of Recommendations Assessment, Development, and Evaluation methodology. RESULTS: Twenty-two studies were identified and analyzed. These included 986 patients with flail chest, of whom 334 underwent rib ORIF. Rib ORIF afforded lower mortality; shorter DMV, hospital LOS, and ICU LOS; and lower incidence of pneumonia and need for tracheostomy. The data quality was deemed very low, with only three prospective randomized trials available. Analyses for pain in patients with flail chest and all outcomes in patients with nonflail chest were not feasible due to inadequate data. CONCLUSION: In adult patients with flail chest, we conditionally recommend rib ORIF to decrease mortality; shorten DMV, hospital LOS, and ICU LOS; and decrease incidence of pneumonia and need for tracheostomy. We cannot offer a recommendation for pain control, or any of the outcomes in patients with nonflail chest with currently available data. LEVEL OF EVIDENCE: Systematic review/meta analysis, level III. PMID- 28030503 TI - Prophylaxis against venous thromboembolism in pediatric trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma and the Pediatric Trauma Society. AB - BACKGROUND: Despite the increasing incidence of venous thromboembolism (VTE) in hospitalized children, the risks and benefits of VTE prophylaxis, particularly for those hospitalized after trauma, are unclear. The Pediatric Trauma Society and the Eastern Association for the Surgery of Trauma convened a writing group to develop a practice management guideline on VTE prophylaxis for this cohort of children using the Grading of Recommendations Assessment, Development, and Evaluation framework. METHODS: A systematic review of MEDLINE using PubMed from January 1946 to July 2015 was performed. The search retrieved English-language articles on VTE prophylaxis in children 0 to 21 years old with trauma. Topics of investigation included pharmacologic and mechanical VTE prophylaxis, active radiologic surveillance for VTE, and risk factors for VTE. RESULTS: Forty-eight articles were identified and 14 were included in the development of the guideline. The quality of evidence was low to very low because of the observational study design and risks of bias. CONCLUSIONS: In children hospitalized after trauma who are at low risk of bleeding, we conditionally recommend pharmacologic prophylaxis be considered for children older than 15 years old and in younger postpubertal children with Injury Severity Score (ISS) greater than 25. For prepubertal children, even with ISS greater than 25, we conditionally recommend against routine pharmacologic prophylaxis. Second, in children hospitalized after trauma, we conditionally recommend mechanical prophylaxis be considered for children older than 15 years and in younger postpubertal children with ISS greater than 25 versus no prophylaxis or in addition to pharmacologic prophylaxis. Lastly, in children hospitalized after trauma, we conditionally recommend against active surveillance for VTE with ultrasound compared with routine daily physical examination alone for earlier detection of VTE. The limited pediatric data and paucity of high-quality evidence preclude providing more definitive recommendations and highlight the need for clinical trials of prophylaxis. LEVEL OF EVIDENCE: Systematic review/meta analysis, level III. PMID- 28030504 TI - Hospitals with higher volumes of emergency general surgery patients achieve lower mortality rates: A case for establishing designated centers for emergency general surgery. AB - BACKGROUND: Higher volume has been associated with lower mortality for several surgical diseases. It is not known if this relationship exists in the management of Emergency General Surgery (EGS). Our hypothesis was that EGS patients treated at hospitals with higher EGS volume experienced lower mortality rates than those treated at low-volume hospitals. METHODS: This was a retrospective analysis of 2010 National Inpatient Sample data, maintained by the Agency for Healthcare Quality and Research as a representative national sample of inpatients. Patients with EGS diseases were identified using American Association for the Surgery of Trauma definitions using ICD-9 codes (2,640,725 patients from 943 hospitals). Multivariable hierarchical logistic regression model was used to estimate the risk-standardized mortality rate (RSMR) for each hospital, adjusted for patient (age, sex, race, ethnicity, insurance type, socioeconomic status, comorbidities) and hospital (region, location, bed size, teaching status, ownership) characteristics. A cubic spline regression model with 4 knots was used to identify the volume associated with low mortality rates. RESULTS: The volume of EGS patients treated was inversely associated with hospital mortality rate. RSMR in hospitals in the highest quintile of volume (median, 7424 patients) was 1.62% (95% CI: 1.61-1.64%); at hospitals in the lowest quintile of volume (median, 68 patients), it was 6.1% (95% CI: 6.0-6.2%) (p < 0.0001). Mortality rate stabilized at an annual volume of 688 (95% CI: 554-753) patients. The mortality rate in hospitals that treated fewer than 688 patients was 5.0% (95% CI: 4.8-5.1%), compared to 1.99% (95% CI: 1.96-2.01%) at those that treated 688 or more patients (p < 0.0001). CONCLUSION: EGS patients treated at hospitals with a higher volume of EGS patients experienced lower mortality rates, with a possible threshold of 688 patients per year. A regionalized system of EGS care where complex patients are treated at large-volume centers may improve patient outcomes. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 28030505 TI - Ultrasound assessment of volume responsiveness in critically ill surgical patients: Two measurements are better than one. AB - BACKGROUND: The intended physiologic response to a fluid bolus is an increase in stroke volume (SV). Several ultrasound (US) measures have been shown to be predictive. The best measure(s) in critically ill surgical patients remains unclear. METHODS: This is a prospective observational study in critically ill surgical patients receiving a bolus of crystalloid, colloid or blood. A transthoracic echocardiogram was performed before (pre-transthoracic echocardiogram) and after. A positive volume response (+VR) was defined as a >=15% increase in SV. Predictive measures were: left ventricular velocity time integral (VTI), respiratory SV variation (rSVV), passive leg raise SVV (plr SVV), positional internal jugular (IJ) vein change (0-90 degrees) and respiratory variation in the IJ sitting upright (90 degrees IJ). For each measure the area under the receiver operating curve (AUROC) was assessed and the best measure(s) determined. RESULTS: Between November 2013 and November 2015, 199 patients completed the study. After the pilot analyses, plr SVV was abandoned because it could not be reliably assessed. VTI, rv 90 degrees IJ, 0 degree to 90 degrees IJ, were all significantly associated with VR (p < 0.05), rSVV and rv inferior vena cava were not. For VTI AUROC was 0.71 (95% confidence interval [CI], 0.64-0.77). For rv 90 degrees, it was 0.65 (95% CI, 0.57-0.71), and 0.61 (95% CI, 0.54-0.69) for 0 degrees to 90 degrees IJ. When VTI and rv 90 degrees were considered together, the AUROC rose to 0.76 (95% CI, 0.69-0.82) for the population as a whole and 0.78 (95% CI, 0.69-0.85) in mechanically ventilated patients. The positive predictive value for combined assessment was 80% and the negative 70%. CONCLUSION: In a clinically relevant heterogeneous population, US is moderately predictive of VR. Inferior vena cava diameter change is not predictive. IJ change and VTI are the best measures, especially when used together. Future work should focus on combination metrics and the IJ. LEVEL OF EVIDENCE: Diagnostic test, level II. PMID- 28030506 TI - Rib fracture fixation in the 65 years and older population: A paradigm shift in management strategy at a Level I trauma center. AB - BACKGROUND: Rib fractures after chest wall trauma are a common injury; however, they carry a significant morbidity and mortality risk. The impact of rib fractures in the 65-year and older patient population has been well documented as have the mortality and pneumonia rates. We hypothesize that patients 65 years and older receiving rib plating (RP) have decreased mortality, complication rates, and an accelerated return to normal functional states when compared with controls. METHODS: With institutional review board approval, a retrospective review analyzed patients 65 years and older with rib fractures admitted from 2009 to 2015 receiving RP (RP group) (n = 23) compared to nonoperative, injury-matched controls admitted from 2003 to 2008 (NO group) (n = 50). Patients were followed prospectively with regard to lifestyle and functional satisfaction. Independent variables analyzed included Injury Severity Score (ISS), number of rib fractures, mortalities, hospital days, intensive care unit days, pneumonia development, respiratory complications, readmission rates, need for and length of rehabilitation stay time. Comparisons were by chi tests/Fisher's exact tests, Student's t tests and Wilcoxon rank sum tests. RESULTS: From 2003 to 2008, 50 NO patients were admitted with ages ranging 65 to 97 years, average ISS of 18.47 (14.28-22.66) versus ages ranging from 63 to 89 years, average ISS of 20.71 (15.7 25.73) for the RP group (n = 23). Average hospital days were 16.76 (10.35-23.18) and 18.36 (13.61-23.11) in the NO and RP groups, respectively. Average intensive care unit days were 11.65 (6.45-16.85) and 8.29 (5.31-11.26) days in the NO and RP groups, respectively. Four respiratory readmissions, two deaths, seven pneumonias, seven pleural-effusions, and 19 recurrent pneumothoraces were encountered in the NO group versus 0 in the RP group (p < 0.001). An equal percentage of patients in both groups entered rehabilitation facilities with average stay time of 18.5 and 28.53 days for the RP and NO groups, respectively. CONCLUSION: RP in the 65-year and older trauma population demonstrates a measurable decrease in mortality and respiratory complications, improves respiratory mechanics, and permits an accelerated return to functioning state. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 28030507 TI - Defining multiple organ failure after major trauma: A comparison of the Denver, Sequential Organ Failure Assessment, and Marshall scoring systems. AB - BACKGROUND: Postinjury multiple organ failure (MOF) remains a significant cause of morbidity and mortality. A large number of scoring systems have been proposed to define MOF, with no criterion standard. The purpose of this study was to compare three commonly used scores: the Denver Postinjury Multiple Organ Failure Score, the Sequential Organ Failure Assessment (SOFA), and the Marshall Multiple Organ Dysfunction Score, by descriptive analysis of the populations described by each score, and their predictive ability for mortality. METHODS: An observational cohort study was performed at a UK trauma center on major trauma patients requiring intensive care unit admission from 2003 to 2011. A novel trauma database was created, merging national audit data with local electronic monitoring systems. Data were collected on demographics, laboratory results, pharmacy, interventions, and hourly physiological monitoring. The primary outcome measure was mortality within 100 days from injury. Sensitivity analyses and receiver operating characteristic curves were used to assess the predictive ability of MOF scores for mortality. RESULTS: In total, 491 patients were included in the trauma database. MOF incidence ranged from 22.8% (Denver) to 40.5% (Marshall) to 58.5% (SOFA). MOF definition did not affect timing of onset, but did alter duration and organ failure patterns. Overall mortality was 10.6%, with Denver MOF associated with the greatest increased risk of death (hazard ratio 3.87, 95% confidence interval, 2.24-6.66). No significant difference was observed in area under the receiver operating characteristic curve values between scores. Marked differences were seen in relative predictors, with Denver showing highest specificity (81%) and SOFA highest sensitivity (73%) for mortality. CONCLUSION: The choice of MOF scoring system affects incidence, duration, organ dysfunction patterns, and mortality prediction. We would recommend use of the Denver score since it is simplest to calculate, identifies a high-risk group of patients, and has the strongest association with early trauma mortality. LEVEL OF EVIDENCE: Epidemiological study, level III. PMID- 28030508 TI - Re: Preperitoneal pelvic packing reduces mortality in patients with life threatening hemorrhage due to unstable pelvic fractures. PMID- 28030509 TI - Impact of early operative pelvic fixation on long-term self-reported outcome following severe pelvic fracture. AB - BACKGROUND: Traumatic disruption of the pelvic ring is a significant cause of life-threatening hemorrhage. For those patients who survive the initial injury, these fractures are associated with long periods of immobilization and intense rehabilitation. There is little published information available regarding long term functional outcomes in these patients. This study evaluated the impact of severe pelvic fractures on those long-term outcomes. METHODS: All patients with severe pelvic fractures over an 18-year period were identified. Severe pelvic fractures were defined as those with vascular disruption, open-book component with symphysis diastasis, or sacroiliac disruption with vertical shear. Functional outcome was measured using the Boston University Activity Measure for Post-Acute Care to assess mobility (normal, >84) and daily activity (normal, >84). Multiple linear regression analysis was used to identify predictors of functional outcome after severe pelvic fracture. RESULTS: From January 1996 to September 2014, 401 patients were identified: 240 (60%) men and 161 (40%) women. Overall mortality was 29%. Of the 285 survivors, follow-up was obtained in 145 patients (51%). Mean follow-up was 8.3 years, with a maximum of 20 years. Mean age and Injury Severity Score were 53 years and 27, respectively. Mean Activity Measure for Post-Acute Care scores for mobility and daily activity were 55 and 63, respectively; both signifying significant impairment when compared with normal. Multiple linear regression analysis using age, traumatic brain injury, transfusions, Injury Severity Score, ventilator days, presence of associated lower-extremity fractures, and time to operative pelvic fixation identified time to pelvic fixation as the only predictor of decreased mobility (beta = -0.74, p = 0.04) and activity (beta = -0.21, p = 0.03) following severe pelvic fracture. CONCLUSIONS: Prolonged time to operative pelvic fixation led to worse long-term functional outcomes in patients with severe pelvic ring disruption. Early fixation of the pelvic ring is the only potentially modifiable risk factor for decreased functional outcomes in patients with severe pelvic fractures. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 28030510 TI - Clinical and Fecal Microbial Changes With Diet Therapy in Active Inflammatory Bowel Disease. AB - GOAL: To determine the effect of the specific carbohydrate diet (SCD) on active inflammatory bowel disease (IBD). BACKGROUND: IBD is a chronic idiopathic inflammatory intestinal disorder associated with fecal dysbiosis. Diet is a potential therapeutic option for IBD based on the hypothesis that changing the fecal dysbiosis could decrease intestinal inflammation. STUDY: Pediatric patients with mild to moderate IBD defined by pediatric Crohn's disease activity index (PCDAI 10-45) or pediatric ulcerative colitis activity index (PUCAI 10-65) were enrolled into a prospective study of the SCD. Patients started SCD with follow-up evaluations at 2, 4, 8, and 12 weeks. PCDAI/PUCAI, laboratory studies were assessed. RESULTS: Twelve patients, ages 10 to 17 years, were enrolled. Mean PCDAI decreased from 28.1+/-8.8 to 4.6+/-10.3 at 12 weeks. Mean PUCAI decreased from 28.3+/-23.1 to 6.7+/-11.6 at 12 weeks. Dietary therapy was ineffective for 2 patients while 2 individuals were unable to maintain the diet. Mean C-reactive protein decreased from 24.1+/-22.3 to 7.1+/-0.4 mg/L at 12 weeks in Seattle Cohort (nL<8.0 mg/L) and decreased from 20.7+/-10.9 to 4.8+/-4.5 mg/L at 12 weeks in Atlanta Cohort (nL<4.9 mg/L). Stool microbiome analysis showed a distinctive dysbiosis for each individual in most prediet microbiomes with significant changes in microbial composition after dietary change. CONCLUSIONS: SCD therapy in IBD is associated with clinical and laboratory improvements as well as concomitant changes in the fecal microbiome. Further prospective studies are required to fully assess the safety and efficacy of dietary therapy in patients with IBD. PMID- 28030511 TI - Ankle Distraction Arthroplasty: Indications, Technique, and Outcomes. AB - Ankle distraction is an alternative to ankle arthrodesis or total ankle arthroplasty in younger patients with arthritis. Ankle distraction involves the use of external fixation to mechanically unload the ankle joint, which allows for stable, congruent range of motion in the setting of decreased mechanical loading, potentially promoting cartilage repair. Adjunct surgical procedures are frequently done to address lower-extremity malalignment, ankle equinus contractures, and impinging tibiotalar osteophytes. Patients can bear full weight during the treatment course. The distraction frame frequently uses a hinge, and patients are encouraged to do daily range-of-motion exercises. Although the initial goal of the procedure is to delay arthrodesis, many patients achieve lasting clinical benefits, obviating the need for total ankle arthroplasty or fusion. Complications associated with external fixation are common, and patients should be counseled that clinical improvements occur slowly and often are not achieved until at least 1 year after frame removal. PMID- 28030512 TI - Short article: Risk of small intestinal bacterial overgrowth with chronic use of proton pump inhibitors in children. AB - BACKGROUND: Some theorize that prolonged use of proton pump inhibitors (PPIs) may increase the risk of small intestinal bacterial overgrowth (SIBO). Chronic acid suppression and resultant hypochlorhydria may lead to an altered intraluminal environment, which, in turn, may promote the growth of bacteria in the small intestine. A handful of studies measured the risk of SIBO in adults taking PPIs and obtained mixed results; however, this risk has not been exclusively measured in children. AIM: This study aimed to measure the risk of SIBO in children taking PPI versus those not taking PPI. PATIENTS AND METHODS: This was a prospective cohort study. Evaluation of SIBO was performed using the glucose hydrogen breath test. Patients younger than 18 years of age taking a PPI longer than 6 months were compared with healthy control participants. After ingestion of glucose substrate, breath samples were obtained every 15 min for 2 h. An increase in breath hydrogen or methane above 12 ppm was considered diagnostic of SIBO. RESULTS: Overall, 83 participants were tested, of whom 56 were taking PPIs. SIBO was detected in five (8.9%) of the 56 participants taking PPI versus one (3.7%) of the 27 participants in the control group (P=0.359), with a relative risk of 2.4 (95% confidence interval: 0.29-19.6). CONCLUSION: To our knowledge, this is the first study in the English literature measuring the risk of SIBO in children taking PPIs. Our results indicate a potential risk of SIBO in chronic PPI users; however, this is not statistically significant. This is an important finding as PPIs are readily prescribed for children and are often taken longer than 6 months' duration. PMID- 28030513 TI - Acute circulatory failure-chronic liver failure-sequential organ failure assessment score: a novel scoring model for mortality risk prediction in critically ill cirrhotic patients with acute circulatory failure. AB - BACKGROUND AND AIM: Acute circulatory failure (ACF) is associated with high mortality rates in critically ill cirrhotic patients. Only a few accurate scoring models exist specific to critically ill cirrhotic patients with acute circulatory failure (CICCF) for mortality risk assessment. The aim was to develop and evaluate a novel model specific to CICCF. PATIENTS AND METHODS: This study collected and analyzed the data on CICCF from the Multiparameter Intelligent Monitoring in Intensive Care-III database. The acute circulatory failure-chronic liver failure-sequential organ failure assessment (ACF-CLIF-SOFA) score was derived by Cox's proportional hazards regression. Performance analysis of ACF CLIF-SOFA against CLIF-SOFA and model for end-stage liver disease systems was completed using area under the receiver operating characteristic curve. RESULTS: ACF-CLIF-SOFA identified six independent factors: mean arterial pressure [hazard ratio (HR)=0.984, 95% confidence interval (CI): 0.978-0.990, P<0.001], vasopressin (HR=1.548, 95% CI: 1.273-1.883, P<0.001), temperature (HR=0.764, 95% CI: 0.694-0.840, P<0.001), bilirubin (HR=1.031, 95% CI: 1.022-1.041, P<0.001), lactate (HR=1.113, 95% CI: 1.084-1.142, P<0.001), and urine output (HR=0.854, 95% CI: 0.767-0.951, P=0.004). ACF-CLIF-SOFA showed a better predictive performance than CLIF-SOFA and model for end-stage liver disease in terms of predicting mortality (0.769 vs. 0.729 vs. 0.713 at 30 days, 0.757 vs. 0.707 vs. 0.698 at 90 days, 0.733 vs. 0.685 vs. 0.691 at 1 year, respectively, all P<0.05). CONCLUSION: ACF-CLIF-SOFA, as the first model specific to CICCF, enables a more accurate prediction at 30-day, 90-day, and 1-year follow-up periods than other existing scoring systems. PMID- 28030514 TI - The effect of vitamin D supplementation on pain, quality of life, and nerve conduction studies in women with chronic widespread pain. AB - The aim of this study was to investigate the effects of vitamin D supplementation on pain, quality of life, and nerve conduction studies (NCSs) in women with chronic widespread pain (CWP) diagnosed with Vitamin D insufficiency. Thirty three female participants with CWP and vitamin D insufficiency were included in this open-label trial. They were evaluated by routine NCSs in upper and lower limbs, pain scales, and the Nottingham Health Profile before and 8 weeks after starting vitamin D supplementation therapy. The P-value was adjusted to account for the number of comparisons performed in each assessment. After 8 weeks of treatment, participants reported significantly lower pain scores (P=0.000). The total Nottingham Health Profile score and subscores for pain, emotional reactions, and physical activity domains were significantly lower (0.000<=P<=0.008). However, no statistically significant changes in NCSs were detected, except trends toward increases in the amplitudes of left median and ulnar sensory nerve potentials and a decrease in the distal latency of the right median sensory potential (0.01<=P<=0.04). Vitamin D supplementation therapy decreased pain and increased quality of life without significantly affecting nerve conduction in patients with CWP. PMID- 28030515 TI - Employment outcomes following spinal cord injury in Taiwan. AB - It is important to maximize vocational achievement following spinal cord injury. Despite this recognition, unemployment remains a prevalent problem and continues to challenge rehabilitation professionals. This study aimed to examine the employment status and determinants of employability for individuals with spinal cord injury in Taiwan. A cross-sectional survey was conducted. A total of 353 participants aged 18-65 years were recruited from four branches of the Association of People with Spinal Cord Injury. The results showed that, of the participants, 107 were employed at the time of the survey, with an employment rate of 30.3%. Logistic regression analyses indicated that individuals with a college degree or higher [odds ratio (OR)=3.03; 95% confidence intervals (CI): 1.30-7.07], aged 26-40 years (OR=8.51; 95% CI: 3.14-23.02) and 41-55 years (OR=3.06; 95% CI: 1.31-7.18), sustaining injury longer than 10 years (OR=9.89; 95% CI: 2.61-37.46), experiencing less functional limitations (OR=0.90; 95% CI: 0.86-0.95), and perceiving greater social support (OR=1.04; 95% CI: 1.01-10.7) were associated with higher likelihood of employment. Vocational rehabilitation services can use the results to target efforts toward those at risk of unemployment. PMID- 28030516 TI - Scotoma Visibility and Reading Rate with Bilateral Central Scotomas. AB - PURPOSE: In this experiment, we tested whether perceptually delineating the scotoma location and border with a gaze contingent polygon overlay improves reading speed and reading eye movements in patients with bilateral central scotomas. METHODS: Eight patients with age-related macular degeneration and bilateral central scotomas read aloud MNRead style sentences with their preferred eye. Eye movement signals from an EyeLink II eyetracker were used to create a gaze contingent display in which a polygon overlay delineating the area of the patient's scotoma was superimposed on the text during 18 of the 42 trials. Blocks of six trials with the superimposed polygon were alternated with blocks of six trials without the polygon. Reading speed and reading eye movements were assessed before and after the subjects practiced reading with the polygon overlay. RESULTS: All of the subjects but one showed an increase in reading speed. A paired-samples t-test for the group as a whole revealed a statistically significant increase in reading speed of 0.075 +/- 0.060 (SD) log wpm after reading with the superimposed polygon. Individual subjects demonstrated significant changes in reading eye movements, with the greatest number of subjects demonstrating a shift in the average vertical fixation locus. Across subjects, there was no significant difference between the initial and final reading eye movements in terms of saccades per second, average fixation duration, average amplitude of saccades, or proportion of non-horizontal saccades. CONCLUSIONS: The improvement in reading speed (0.075 log wpm or 19%) over the short experimental session for the majority of subjects indicates that making the scotoma location more visible is potentially beneficial for improving reading speed in patients with bilateral central scotomas. Additional research to examine the efficacy of more extended training with this paradigm is warranted. PMID- 28030517 TI - Pain Assessment in Children Younger Than 8 Years in Out-of-Hospital Emergency Medicine: Reliability and Validity of EVENDOL Score. AB - OBJECTIVE: Pain in children is underestimated and undertreated in out-of-hospital emergency medicine. In this setting, caregivers need a reliable pain scale, but none has been validated. A single observational pain scale for all children younger than 8 years, EVENDOL, has been validated in emergency pediatric units. We study the feasibility of EVENDOL score in an out-of-hospital emergency setting. METHODS: This prospective multicenter study included all conscious children younger than 8 years transported by a mobile intensive care unit between October 2008 and May 2010. The emergency physician and nurse independently assessed the child's pain using first a numeric rating scale (score 0-10), then the 5-item EVENDOL scale (verbal/vocal expression, facial expression, movements, postures, and relationship with entourage) (score 0-3/item) at 3 time points (at rest, during examination, and after analgesia). We studied the scale's internal validity, interrater reliability, discriminant ability (influence of fever and anxiety), and face validity. RESULTS: Of the 422 included children, 82 and 62 (29%-39%) were in pain according to the emergency physician and nurses (numeric rating scale >3/10). All EVENDOL scale attributes were satisfied at all 3 time points, for all population subsets. Values for the first assessment (entire study population) were as follows: internal validity (0.78-0.89), interrater reliability (r = 0.63-0.76, weighted kappa = 0.49-0.65), construct validity, and discriminant ability (r = 0.6-0.7). Fever did not impact on EVENDOL score. Anxiety level and pain were correlated. Completion time was fast (mean, 2.3-3.4 minutes). Face validity was good. CONCLUSION: EVENDOL is a quick, easy-to-use, discriminant instrument to assess pain in young children in out-of-hospital emergency settings. PMID- 28030518 TI - Jet Pack Fun that Went Wrong: A Case of Serious Multivisceral Injuries From Water Sports. AB - The water jet pack is a relatively new and very exciting sporting activity for adventure seekers. However, there are some concerns raised in terms of safety, and some sporadic reports have appeared in newspapers about the injuries sustained from this sport. We are presenting an unfortunate case where a teenaged girl fell from a jet pack and sustained serious injuries including the loss of her kidney. This is the first reported serious injury from the Jet pack (Carbon Sports GmbH, Itzehoe, Germany). PMID- 28030519 TI - Incorporating a Computerized Cognitive Battery Into the Emergency Department Care of Pediatric Mild Traumatic Brain Injuries-Is It Feasible? AB - OBJECTIVES: The use of computers to test cognitive function acutely after a concussion is becoming increasingly popular, especially after sport-related concussion. Although commonly performed in the community, it is not yet performed routinely in the emergency department (ED), where most injured children present. The challenges of performing computerized cognitive testing (CCT) in a busy ED are considerable. The aim of this study was to evaluate the feasibility of CCT in the pediatric ED after concussion. METHODS: Children, aged 8 to 18 years with mild traumatic brain injury, presenting to the ED were eligible for this prospective study. Exclusion criteria included the use of drugs, alcohol, and/or physical injury, which could affect CCT performance. A 30- or 15-minute CCT battery was performed. Feasibility measures included environmental factors (space, noise, waiting time), testing factors (time, equipment reliability, personnel), and patient factors (age, injury characteristics). RESULTS: Forty nine children (28 boys; mean age, 12.6; SD, +/- 2.5) participated in the study. All children completed CCT. Mean testing times for the 30- and 15-minute battery were 29.7 and 15.2 minutes, respectively. Noise-cancelling headphones were well tolerated. A shorter CCT was more acceptable to families and was associated with fewer noise disturbances. There was sufficient time to perform testing after triage and before physician assessment in over 90% of children. CONCLUSIONS: Computerized cognitive testing is feasible in the ED. We highlight the unique challenges that should be considered before its implementation, including environmental and testing considerations, as well as personnel training. PMID- 28030520 TI - Parent Perceptions on Transfers to Pediatric Emergency Departments and the Role of Telemedicine. AB - OBJECTIVE: Real-time audiovisual consultation (telemedicine) has been proven feasible and is a promising alternative to interfacility transfer. We sought to describe caregiver perceptions of the decision to transfer his or her child to a pediatric emergency department and the potential use of telemedicine as an alternative to transfer. METHODS: Semistructured interviews of caregivers of patients transferred to a pediatric emergency department. Purposive sampling was used to recruit caregivers of patients who were transferred from varying distances and different times of the day. Interviews were conducted in person or on the phone by a trained interviewer. Interviews were recorded, transcribed, and analyzed using modified grounded theory. RESULTS: Twenty-three caregivers were interviewed. Sixteen (70%) were mothers; 57% of patients were transported from hospitals outside of the city limits. Most caregivers reported transfer for a specific resource need, such as a pediatric subspecialist. Generally, caregivers felt that the decision to transfer was made unilaterally by the treating physician, although most reported feeling comfortable with the decision. Almost no one had heard about telemedicine; after hearing a brief description, most were receptive to the idea. Caregivers surmised that telemedicine could reduce the risks and cost associated with transfer. However, many felt telemedicine would not be applicable to their particular situation. CONCLUSIONS: In this sample, caregivers were comfortable with the decision to transfer their child and identified potential benefits of telemedicine as either an adjunct to or replacement of transfer. As hospitals use advanced technology, providers should consider families' opinions about risks and out-of-pocket costs and tailoring explanations to address individual situations. PMID- 28030523 TI - Successful Introduction of Fine Needle Aspiration Biopsy for Diagnosis of Pediatric Lymphadenopathy. AB - Accurate and rapid diagnosis of extrapulmonary nodal tuberculosis in children is of paramount importance. This retrospective study performed at Tygerberg Hospital using data from the laboratory records between January 1, 2004 and June 30, 2014 demonstrates how since the introduction laboratory-run FNAB service; fine needle aspiration biopsy has become an acceptable and routine diagnostic procedure for triage of pediatric lymphadenopathy. PMID- 28030524 TI - Attitudes of Swiss Health Care Providers Toward Childhood Immunizations. AB - BACKGROUND: INFOVAC is a network providing information about immunization issues to health professionals. The aim of this study was to assess the attitude of INFOVAC subscribers toward the current Swiss immunization schedule, potential modifications, and current and hypothetical immunization practices regarding their own children. METHODS: In March 2015, a Web-based survey was sent to 4260 physicians and pharmacists subscribed to INFOVAC. Participation was anonymous and voluntary. The following information was obtained: (1) current immunization status of own children; (2) which immunizations would currently be accepted for a hypothetical own child and (3) attitudes toward potential modifications of the Swiss immunization schedule. Descriptive methods and multivariate models to correct for covariables were used for data analysis. RESULTS: Nine hundred and fifty-five valid questionnaires were received: 886/3704 (23.9%) from physicians and 69/556 (12.4%) from pharmacists. Current (>95%) and hypothetical (>99%) immunization rates were high for diphtheria, tetanus, pertussis, poliomyelitis and measles-mumps-rubella. Most pediatricians (61%) would support more vaccines for their children than currently recommended by the Swiss immunization advisory committee, whereas about 50% of other physicians and pharmacists would decline at least one of the recommended immunizations, most frequently varicella, pneumococcal or meningococcal C conjugate vaccines. Strong general support was expressed for the expansion of human papillomavirus immunization to males, acceleration of the measles-mumps-rubella schedule and a 2 + 1 instead of 3 + 1 diphtheria-tetanus-pertussis, acellular-inactivated poliomyelitis vaccine (DTPa IPV)/Haemophilus influenzae type b +/- hepatitis B virus (HBV) schedule. CONCLUSIONS: Survey participants generally demonstrated a positive attitude toward immunization, with pediatricians being the most progressive subgroup with the largest percentage of participants (63.1%) neither declining nor postponing any recommended immunization. PMID- 28030525 TI - Adherence to Antituberculosis Drugs in Children and Adolescents in A Low-Endemic Setting: A Retrospective Series. AB - Adherence to antituberculosis drug regimens is critical for the prevention and treatment of tuberculosis in pediatrics. In a large retrospective series of children and adolescents in Barcelona, Spain, completion of treatment was worse among patients treated for latent infection, compared with those treated for active tuberculosis or receiving primary chemoprophylaxis. Toxicity and cultural and language barriers were identified as predictors of nonadherence. PMID- 28030526 TI - Long-term Immunogenicity of a Single Dose of Japanese Encephalitis Chimeric Virus Vaccine in Toddlers and Booster Response 5 Years After Primary Immunization. AB - BACKGROUND: Japanese encephalitis (JE) is an important mosquito-borne viral disease that is endemic in Asia, Western Pacific countries and Northern Australia. Although there is no antiviral treatment, vaccination is effective in preventing this disease. METHODS: We followed a cohort of 596 children for 5 years after primary vaccination at 12-18 months of age with JE chimeric virus vaccine (JE-CV; IMOJEV) in a multicenter, phase III trial in Thailand and the Philippines to assess antibody persistence and safety. At the end of the 5 years, a subgroup of 85 participants, at 1 site in Thailand, was followed after administration of a JE-CV booster vaccination. JE antibody titers were measured annually after primary vaccination and 28 days after booster vaccination using a 50% plaque reduction neutralization test. Seroprotection was defined as a JE-CV neutralizing antibody titer >=10 (1/dil). Kaplan-Meier survival analysis was used to estimate the proportion of participants maintaining protective JE-CV neutralizing antibody titers. RESULTS: At 1, 2, 3, 4 and 5 years after vaccination with JE-CV, 88.5%, 82.9%, 78.2%, 74.0% and 68.6% of the participants followed remained seroprotected. Geometric mean titers in the subgroup assessed after receipt of a booster dose increased from 61.2 (95% confidence interval: 43.8-85.7) pre-booster to 4951 (95% confidence interval: 3928-6241) 28 days post booster, with all participants seroprotected. There were no safety concerns identified. CONCLUSIONS: Protective immune responses persisted for at least 5 years after a JE-CV primary immunization in the majority of participants. JE-CV booster induced a robust immune response even after a 5-year interval. PMID- 28030527 TI - Hepatitis B Surface Antigen Testing Among Pregnant Women, United States 2014. AB - BACKGROUND: Post-exposure prophylaxis administered to infants shortly after birth prevents approximately 90% of cases of perinatal hepatitis B virus (HBV) transmission. The Advisory Committee on Immunization Practices recommends that all pregnant women be tested for hepatitis B surface antigen (HBsAg) at an early prenatal visit during each pregnancy to detect active infection with HBV. This study sought to determine the proportion and characteristics of pregnant women tested?not tested according to Advisory Committee on Immunization Practices recommendations. METHODS: We analyzed MarketScan databases to assess prenatal HBsAg testing among women with commercial and Medicaid health care coverage according to demographic and clinical characteristics. Pregnant women 15-44 years of age continuously enrolled in a health plan in the MarketScan database during 2013 and 2014 and with a live birth in 2014 were included. RESULTS: Among commercially insured women, 239,955 (87.7%) received HBsAg testing and 59.6% were tested during their first trimester. Among Medicaid-enrolled women, 57,268 (83.6%) received HBsAg testing and 39.4% were tested during their first trimester. Among women with high risk pregnancies, HBsAg testing occurred in 87.3% of those with commercial insurance and 84.8% with Medicaid. Testing also varied by maternal age; among women with commercial insurance, testing was greatest among women 26-44 years of age, and among women with Medicaid, testing was greatest among younger women (15-25 years). Testing was lowest among women residing in the Northeast (commercial insurance only). CONCLUSIONS: Prenatal HBsAg testing identifies HBV-infected pregnant women so their infants can receive timely immunoprophylaxis. Efforts to optimize HBsAg testing among all pregnant women are needed to further prevent perinatal HBV transmission. PMID- 28030528 TI - Case Series Description and Genomic Characterization of Invasive Group A Streptococcal Infections in Pediatric Patients. AB - We report an unusual cluster of invasive group A Streptococcus infections in 6 pediatric patients and demonstrate that the strains were derived from diverse genetic backgrounds, confirming the occurrence of a community cluster rather than a clonal outbreak. Whole genome sequencing provided a rapid and comprehensive view of group A Streptococcus genotypes and helped guide our institutional response and public health maneuvers. PMID- 28030529 TI - Recurrent Lingual Abscess in a Child. AB - We report the case of a 14-month-old boy who developed a swelling of the tongue with fever, dyspnea during sleep and dysphagia. An anterior lingual abscess was identified by magnetic resonance imaging. He developed 4 recurrent lingual abscesses thereafter. Pediatricians should be aware of this problem because it can be a life-threatening condition. PMID- 28030530 TI - Hostage to History: The Duration of Antimicrobial Treatment for Acute Streptococcal Pharyngitis. AB - Oral antimicrobial treatment of acute streptococcal pharyngitis commonly is given for 10 days. An investigation was conducted of journal publications and textbooks from the dawn of the antimicrobial era to the present in order to discover the basis for this settled practice. Current treatment duration for acute streptococcal pharyngitis was established half a century ago under conditions significantly different from those currently encountered by the average clinician. The 10-day treatment standard evolved without scientific justification. There have been no therapeutic trials that have validated the necessity for 10 days of oral antimicrobial treatment. Yet, despite the lack of a scientific foundation, the rarity of acute rheumatic fever in developed countries, the high failure rate for streptococcal eradication and evidence that short-course therapy with a nonpenicillin antimicrobial yields equivalent eradication rates, the 10-day rule persists because of long clinical usage and the inherent power of the number 10. Efforts to change this clinical benchmark will likely meet with resistance from practicing physicians. PMID- 28030531 TI - Does Focus of Attention Improve Snatch Lift Kinematics? AB - Recent motor control literature has demonstrated that using verbal instructions to direct a performer's attention externally (i.e., toward the movement outcome) enhances motor skill performance. The purpose of this study was to investigate how an athlete's focus of attention impacts kinematic performance of the snatch. Using a counterbalanced within-participant design, 12 competitively trained athletes (8 male and 4 female athletes) performed 2 instructional blocks of 3 snatch repetitions at 80% of their most recent training 1 repetition maximum. Blocks of internal and external instructions were given to the athlete in a random fashion. Results showed that, when focusing internally, athletes significantly (p <= 0.05) increased elbow velocity relative to focusing externally, whereas the external instructions significantly increased horizontal barbell velocity, relative to internal instructions. Additionally, an internal focus resulted in significantly larger barbell-cervical-hip angles at maximum height of the barbell compared with an external focus, indicating that the athletes squatted under the barbell too soon. This information adds to the literature suggesting small changes in coaching instructions can impact performance significantly. It is recommended that coaches use instructions that direct an athlete's attention externally, toward the movement outcome, rather than the action itself. PMID- 28030532 TI - Application of a Simple Surveillance Method for Detecting the Prevalence and Impact of Overuse Injuries in Professional Men's Basketball. AB - The aim of this study was to use the Oslo Sports Trauma Research Center (OSTRC) Overuse Injury Questionnaire to record overuse injuries over a single season for a men's professional basketball team to (a) assess the prevalence and severity of overuse injuries and (b) determine the efficacy of this method in identifying overuse injuries in comparison with the team physiotherapist's detection of these injuries. Thirteen athletes from a men's professional basketball team participated in this study. The self-reported, OSTRC injury questionnaire was used to record overuse conditions of the ankle, knee, and lower back over an entire 24-week season. Standard time-loss injury registration methods were also used to record overuse conditions by the physiotherapist. Overuse injury rates per 1,000 hours of athlete exposure and average weekly prevalence of overuse injuries were calculated using the results of the questionnaire. A total of 183 overuse conditions were identified by the questionnaire, whereas only 28 overuse conditions were identified by the physiotherapist. The team's average weekly prevalence of all overuse conditions was 63% (95% confidence interval [CI]: 60 66), with the highest prevalence of injury affecting the lower back (25.9% [95% CI: 19.7-32.1]). The overuse injury rate per 1,000 hours of athlete exposure was 6.4. The OSTRC overuse injury questionnaire captures many more overuse injuries in basketball than standard time-loss methods. The prevalence of lower back injuries is higher than that previously reported in basketball. This additional method of overuse injury surveillance may more accurately quantify the overuse injury problem in basketball and aid earlier intervention and management of these conditions. PMID- 28030533 TI - Physical and Physiological Attributes of Wrestlers: An Update. AB - Chaabene, H, Negra, Y, Bouguezzi, R, Mkaouer, B, Franchini, E, Julio, U, and Hachana, Y. Physical and physiological profile of wrestler athletes: a short review. J Strength Cond Res 31(5): 1411-1442, 2017-Wrestling is one of the oldest combat sports, disputed since the ancient Greek Olympic Games. This combat sport discipline has caught the attention of scientists since 1943 which is the date that matches the appearance of the first scientific research dealing with wrestling. The current short review aimed to summarize and critically analyze the scientific literature related to wrestling's physical and physiological attributes and to provide practical recommendations for testing/training together with new perspective and areas of future scientific research. Regardless of sex and wrestling styles, an optimal level of cardiorespiratory fitness is important to help sustaining effort throughout the duration of the match and to stimulate the recovery process between periods. With regard to the anaerobic power and capacity, the available studies were in agreement about their critical importance toward reaching high-level wrestling success since these variables have discriminated well between successful and less-successful wrestlers regardless of age, weight classes, and wrestling styles. Physical fitness parameters such as maximal dynamic strength, isometric strength, explosive strength, and strength endurance are closely related to high-level wrestling performance. However, flexibility level seems not to be one of the key fitness variables that help to reach high-level wrestling success. Overall, to achieve high-level wrestling performance, training should be directed to develop anaerobic power and capacity, aerobic power, maximal dynamic and isometric strength, explosive strength, and strength endurance. PMID- 28030534 TI - Single-Nucleotide Polymorphism of CYP3A5 Impacts the Exposure to Tacrolimus in Pediatric Renal Transplant Recipients: A Pharmacogenetic Substudy of the TWIST Trial. AB - BACKGROUND: The pharmacokinetics of tacrolimus (TAC) and mycophenolic acid (MPA) are highly variable. An impact of single-nucleotide polymorphisms (SNPs) of the genes coding for enzymes and transporters involved in the pharmacokinetics of TAC and/or MPA is intuitively conceivable. Accordingly, we sought to analyze the influence of different SNPs on TAC and MPA exposure in pediatric renal transplant recipients. METHODS: A subpopulation of 37 patients (median age: 12.8 years, range 2.2-18.3 years) participating in the TWIST study was included in the analysis of SNPs of CYP3A5, ABCB1 (MDR1), ABCG2, SLCO1B3 (coding for OATP2), ABCC2 (coding for cMOAT), and UGT1/2. TAC trough concentrations and abbreviated area under the concentration-time curves (AUC) of MPA were measured on days 7, 28, 91, and 183 after transplant. Both of these were adjusted to the respective dose the patient received. RESULTS: The allele frequencies of analyzed SNP's were comparable to those reported previously for white populations. Dose-adjusted trough concentrations of TAC were approximately 60% lower in patients with the CYP3A5*1/*3 allele as compared with the CYP3A5*3/*3 allele (P = 0.004). Steroid free patients in CYP3A5*3/*3 and CYP3A5*1/*3 carrier subgroups had comparable dose-adjusted TAC concentrations to the subgroup on steroids (P = 0.13). Patients younger than 10 years had a significantly lower median dose-adjusted TAC C0 concentration than patients older than 10 years; this age effect was comparable in heterozygous and homozygous CYP3A5 carriers as well as in patients on and off steroid medication. As for MPA, the genetic variability of transporters or enzymes had no impact on dose-adjusted MPA-AUC due to the low allele frequencies. Patients off steroids had a higher dose-adjusted MPA-AUC (0.18 mg.h/L per mg/m, 0.012-0.27) compared with patients on steroids (0.12 mg.h.L.mg, 0.09-0.19; P = 0.04). CONCLUSIONS: Genetic variability of CYP3A5 has an impact on TAC metabolism in pediatric renal transplant recipients, contributing partly to the variability of TAC exposure. Therefore, adjusting initial TAC dosing to the genotype of CYP3A5 might be of clinical benefit. PMID- 28030535 TI - Development of a Limited Sampling Strategy for the Estimation of Exposure to High Dose Etoposide After Intravenous Infusion in Pediatric Patients. AB - BACKGROUND: Etoposide (VP-16), a podophyllotoxin derivative, is used in conditioning regimens before allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia. The aim of this study was to develop a limited sampling strategy (LSS) suitable for the prediction of exposure to VP-16 defined as area under time-concentration curve (AUC). METHODS: The study included 28 pediatric patients with acute lymphoblastic leukemia, who were administered a 4-hour infusion of 60 mg/kg VP-16. VP-16 concentrations were determined in samples collected 4-124 hours after the beginning of infusion. On obtaining the pharmacokinetic (PK) profiles, a population PK model was developed in NONMEM (ICON Development Solutions, Hanover, MD) with first-order conditional estimation with interaction algorithm. LSSs were chosen by means of a multivariate regression analysis and cross-validated with a leave-one-out approach. Predictive performance of LSSs was assessed by calculating relative prediction error (PE), mean PE, mean absolute PE, and root mean squared PE for model-predicted and observed AUC. RESULTS: VP-16 PKs was best described by a 2 compartment first-order model, and a large variability in the PK parameters was observed. A 3-sample strategy allowed the estimation of VP-16 with highest accuracy and precision (mean relative PE = 0.18%, 95% confidence interval, 1.73% 2.09%; mean absolute relative PE = 3.47%, 95% confidence interval, 2.28%-4.66%; root mean squared PE = 4.43%). The final equation was AUC = 6.85 * C6 h + 3.88 * C12 h + 46.11 * C28 h + 282.0 (adjusted R = 0.9540). CONCLUSIONS: In conclusion, developed LSS allows accurate and precise estimation of VP-16 AUC and might be useful for therapeutic drug monitoring. PMID- 28030536 TI - Effect of Refractive Correction Error on Retinal Nerve Fiber Layer Thickness: A Spectralis Optical Coherence Tomography Study. AB - BACKGROUND Identifying and assessing retinal nerve fiber layer defects are important for diagnosing and managing glaucoma. We aimed to investigate the effect of refractive correction error on retinal nerve fiber layer (RNFL) thickness measured with Spectralis spectral-domain optical coherence tomography (SD-OCT). MATERIAL AND METHODS We included 68 participants: 32 healthy (normal) and 36 glaucoma patients. RNFL thickness was measured using Spectralis SD-OCT circular scan. Measurements were made with a refractive correction of the spherical equivalent (SE), the SE+2.00D and the SE-2.00D. RESULTS Average RNFL thickness was significantly higher in the normal group (105.88+/-10.47 MUm) than in the glaucoma group (67.67+/-17.27 MUm, P<0.001). In the normal group, +2.00D of refractive correction error significantly affected measurements of average (P<0.001) and inferior quadrant (P=0.037) RNFL thickness. In the glaucoma group, +2.00D of refractive correction error significantly increased average (P<0.001) and individual quadrant (superior: P=0.016; temporal: P=0.004; inferior: P=0.008; nasal: P=0.003) RNFL measurements compared with those made with the proper refractive correction. However, -2.00D of refractive correction error did not significantly affect RNFL thickness measurements in either group. CONCLUSIONS Positive defocus error significantly affects RNFL thickness measurements made by the Spectralis SD-OCT. Negative defocus error did not affect RNFL measurement examined. Careful correction of refractive error is necessary to obtain accurate baseline and follow-up RNFL thickness measurements in healthy and glaucomatous eyes. PMID- 28030537 TI - Molecular Virologic and Clinical Characteristics of a Chikungunya Fever Outbreak in La Romana, Dominican Republic, 2014. AB - Since emerging in Saint Martin in 2013, chikungunya virus (CHIKV), an alphavirus transmitted by the Aedes aegypti mosquito, has infected approximately two million individuals in the Americas, with over 500,000 reported cases in the Dominican Republic (DR). CHIKV-infected patients typically present with a febrile syndrome including polyarthritis/polyarthralgia, and a macropapular rash, similar to those infected with dengue and Zika viruses, and malaria. Nevertheless, many Dominican cases are unconfirmed due to the unavailability and high cost of laboratory testing and the absence of specific treatment for CHIKV infection. To obtain a more accurate representation of chikungunya fever (CHIKF) clinical signs and symptoms, and confirm the viral lineage responsible for the DR CHIKV outbreak, we tested 194 serum samples for CHIKV RNA and IgM antibodies from patients seen in a hospital in La Romana, DR using quantitative RT-PCR and IgM capture ELISA, and performed retrospective chart reviews. RNA and antibodies were detected in 49% and 24.7% of participants, respectively. Sequencing revealed that the CHIKV strain responsible for the La Romana outbreak belonged to the Asian/American lineage and grouped phylogenetically with recent Mexican and Trinidadian isolates. Our study shows that, while CHIKV-infected individuals were infrequently diagnosed with CHIKF, uninfected patients were never falsely diagnosed with CHIKF. Participants testing positive for CHIKV RNA were more likely to present with arthralgia, although it was reported in just 20.0% of CHIKF+ individuals. High percentages of respiratory (19.6%) signs and symptoms, especially among children, were noted, though it was not possible to determine whether individuals infected with CHIKV were co-infected with other pathogens. These results suggest that CHIKV may have been underdiagnosed during this outbreak, and that CHIKF should be included in differential diagnoses of diverse undifferentiated febrile syndromes in the Americas. PMID- 28030538 TI - GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease. AB - The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non motor symptoms as well as treatment-related motor complications could be influenced by GBA variants. PMID- 28030539 TI - Local Cell Death Changes the Orientation of Cell Division in the Developing Drosophila Wing Imaginal Disc Without Using Fat or Dachsous as Orienting Signals. AB - Drosophila imaginal disc cells exhibit preferred cell division orientations according to location within the disc. These orientations are altered if cell death occurs within the epithelium, such as is caused by cell competition or by genotypes affecting cell survival. Both normal cell division orientations, and their orientations after cell death, depend on the Fat-Dachsous pathway of planar cell polarity (PCP). The hypothesis that cell death initiates a planar polarity signal was investigated. When clones homozygous for the pineapple eye (pie) mutation were made to initiate cell death, neither Dachsous nor Fat was required in pie cells for the re-orientation of nearby cells, indicating a distinct signal for this PCP pathway. Dpp and Wg were also not needed for pie clones to re-orient cell division. Cell shapes were evaluated in wild type and mosaic wing discs to assess mechanical consequences of cell loss. Although proximal wing disc cells and cells close to the dorso-ventral boundary were elongated in their preferred cell division axes in wild type discs, cell shapes in much of the wing pouch were symmetrical on average and did not predict their preferred division axis. Cells in pie mutant clones were slightly larger than their normal counterparts, consistent with mechanical stretching following cell loss, but no bias in cell shape was detected in the surrounding cells. These findings indicate that an unidentified signal influences PCP-dependent cell division orientation in imaginal discs. PMID- 28030540 TI - Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor. AB - Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4rmut mice) and the LDL receptor (Ldlr-/- mice). Mc4rmut mice develop obesity due to hyperphagia. Double-mutant mice (Mc4rmut;Ldlr-/-) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4rmut mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4rmut;Ldlr-/-. Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis. PMID- 28030541 TI - Tissue-Specificity of Gene Expression Diverges Slowly between Orthologs, and Rapidly between Paralogs. AB - The ortholog conjecture implies that functional similarity between orthologous genes is higher than between paralogs. It has been supported using levels of expression and Gene Ontology term analysis, although the evidence was rather weak and there were also conflicting reports. In this study on 12 species we provide strong evidence of high conservation in tissue-specificity between orthologs, in contrast to low conservation between within-species paralogs. This allows us to shed a new light on the evolution of gene expression patterns. While there have been several studies of the correlation of expression between species, little is known about the evolution of tissue-specificity itself. Ortholog tissue specificity is strongly conserved between all tetrapod species, with the lowest Pearson correlation between mouse and frog at r = 0.66. Tissue-specificity correlation decreases strongly with divergence time. Paralogs in human show much lower conservation, even for recent Primate-specific paralogs. When both paralogs from ancient whole genome duplication tissue-specific paralogs are tissue specific, it is often to different tissues, while other tissue-specific paralogs are mostly specific to the same tissue. The same patterns are observed using human or mouse as focal species, and are robust to choices of datasets and of thresholds. Our results support the following model of evolution: in the absence of duplication, tissue-specificity evolves slowly, and tissue-specific genes do not change their main tissue of expression; after small-scale duplication the less expressed paralog loses the ancestral specificity, leading to an immediate difference between paralogs; over time, both paralogs become more broadly expressed, but remain poorly correlated. Finally, there is a small number of paralog pairs which stay tissue-specific with the same main tissue of expression, for at least 300 million years. PMID- 28030542 TI - Acute Cognitively Engaging Exergame-Based Physical Activity Enhances Executive Functions in Adolescents. AB - The study aimed to elucidate the influence of cognitive engagement comprised in an acute bout of exergame-based physical activity on executive functions (inhibition, cognitive flexibility) in adolescents. Therefore, the level of cognitive engagement and the intensity of physical activity were systematically varied across three experimental conditions. Sixty-five healthy male adolescents (13-16 years) were randomly assigned to one of three conditions: (a) physical activity with high levels of cognitive engagement during active video gaming, (b) physical activity with low levels of cognitive engagement during active video gaming, (c) sedentary with low levels of cognitive engagement during passive video watching. Manipulation checks, including subjective and objective operationalizations of cognitive engagement, were applied. Executive functions were assessed before and after each condition using the D-KEFS design fluency test. Results showed that cognitive engagement, operationalized by subjects' ratings and heart rate variability, differed between conditions. The physical activity condition with a high level of cognitive engagement resulted in significantly better performance in cognitive flexibility compared to conditions with low levels of cognitive engagement. Regarding benefits for executive functions in male adolescents, the results indicate that acute physical activity with high cognitive engagement could be more efficient than physical activity of the same intensity with low cognitive engagement. Even though further evidence is needed, these results extend previous research and suggest a methodological approach for measuring cognitive engagement. PMID- 28030543 TI - Human Inferences about Sequences: A Minimal Transition Probability Model. AB - The brain constantly infers the causes of the inputs it receives and uses these inferences to generate statistical expectations about future observations. Experimental evidence for these expectations and their violations include explicit reports, sequential effects on reaction times, and mismatch or surprise signals recorded in electrophysiology and functional MRI. Here, we explore the hypothesis that the brain acts as a near-optimal inference device that constantly attempts to infer the time-varying matrix of transition probabilities between the stimuli it receives, even when those stimuli are in fact fully unpredictable. This parsimonious Bayesian model, with a single free parameter, accounts for a broad range of findings on surprise signals, sequential effects and the perception of randomness. Notably, it explains the pervasive asymmetry between repetitions and alternations encountered in those studies. Our analysis suggests that a neural machinery for inferring transition probabilities lies at the core of human sequence knowledge. PMID- 28030544 TI - Seeking Clearer Recommendations for Hand Hygiene in Communities Facing Ebola: A Randomized Trial Investigating the Impact of Six Handwashing Methods on Skin Irritation and Dermatitis. AB - : To prevent disease transmission, 0.05% chlorine solution is commonly recommended for handwashing in Ebola Treatment Units. In the 2014 West Africa outbreak this recommendation was widely extended to community settings, although many organizations recommend soap and hand sanitizer over chlorine. To evaluate skin irritation caused by frequent handwashing that may increase transmission risk in Ebola-affected communities, we conducted a randomized trial with 91 subjects who washed their hands 10 times a day for 28 days. Subjects used soap and water, sanitizer, or one of four chlorine solutions used by Ebola responders (calcium hypochlorite (HTH), sodium dichloroisocyanurate (NaDCC), and generated or pH-stabilized sodium hypochlorite (NaOCl)). Outcomes were self-reported hand feel, irritation as measured by the Hand Eczema Score Index (HECSI) (range 0 360), signs of transmission risk (e.g., cracking), and dermatitis diagnosis. All groups experienced statistically significant increases in HECSI score. Subjects using sanitizer had the smallest increases, followed by higher pH chlorine solutions (HTH and stabilized NaOCl), and soap and water. The greatest increases were among neutral pH chlorine solutions (NaDCC and generated NaOCl). Signs of irritation related to higher transmission risk were observed most frequently in subjects using soap and least frequently by those using sanitizer or HTH. Despite these irritation increases, all methods represented minor changes in HECSI score. Average HECSI score was only 9.10 at endline (range 1-33) and 4% (4/91) of subjects were diagnosed with dermatitis, one each in four groups. Each handwashing method has benefits and drawbacks: soap is widely available and inexpensive, but requires water and does not inactivate the virus; sanitizer is easy-to use and effective but expensive and unacceptable to many communities, and chlorine is easy-to-use but difficult to produce properly and distribute. Overall, we recommend Ebola responders and communities use whichever handwashing method(s) are most acceptable, available, and sustainable for community handwashing. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Registry ISRCTN89815514. PMID- 28030545 TI - Longitudinal Analysis of Serum Autoantibody-Reactivities in Patients with Primary Open Angle Glaucoma and Optic Disc Hemorrhage. AB - BACKGROUND: The aim of our current investigation was to analyze the autoantibody reactivities of primary open angle glaucoma patients with optic disc hemorrhage as possibly correlated to disease progression by means of a protein microarray approach. METHODS: Sera of patients with primary open angle glaucoma and optic disc hemorrhage (n = 16) were collected directly after study inclusion (0 weeks) and after 2 weeks, 4 weeks and 12 weeks. As a control group patients with primary open angle glaucoma (n = 18) were used (0 weeks and 12 weeks). Microarrays were incubated and occurring antibody-antigen-reactions were visualized with fluorescence labeled anti-human-IgG secondary antibodies. To detect changes in autoantibodies spot intensities were digitized and compared. RESULTS: With respect to the immunoreactivity at 0 weeks level increment of anti-adaptor protein 1 complex subunit mu-1 antibodies and anti-SPRY domain-containing SOCS box protein 3 antibodies in sera of primary open angle patients with optic disc hemorrhage was detected. Linear trend analysis revealed a positive correlation with r >= 0.8 between antibody-level and time course. Control group show no relevant changes in the same period. Significant changes were found in time point 4 comparison between patient groups in anti-adaptor protein 1 complex subunit mu 1-level (p = 0.01). No significant changes in visual acuity were found. CONCLUSION: With this approach we were able to detect autoimmune reactivities in sera of patients with primary open angle glaucoma and optic disc hemorrhage compared to patients without optic disc hemorrhage. These antibodies could give further insights into the pathogenesis and the autoimmune component of glaucomatous optic neuropathy. PMID- 28030546 TI - Early Improvement in Psychosocial Function Predicts Longer-Term Symptomatic Remission in Depressed Patients. AB - The goal of this study was to evaluate the relationship between early change in psychosocial function independent of depression severity and longer-term symptomatic remission. Participants of Combining Medications to Enhance Depression Outcomes trial were randomly selected for model selection (n = 334) and validation (n = 331). Changes in psychosocial function (Work and Social Adjustment Scale, WSAS) from baseline to week 6 were assessed and two data-driven sub-groups of WSAS change were identified in the randomly selected model selection half. Results of analyses to predict symptomatic remission at 3 and 7 months were validated for these sub-groups in the second half (validation sample). From baseline to week 6, psychosocial function improved significantly even after adjusting for depression severity at each visit and select baseline variables (age, gender, race, ethnicity, education, income, employment, depression onset before age 18, anxious features, and suicidal ideation), treatment-arm, and WSAS score. The WSAS change patterns identified two (early improvement and gradual change) subgroups. After adjusting for baseline variables and remission status at week 6, participants with early improvement in the second half (validation sample) had greater remission rates than those with gradual change at both 3 (3.3 times) and 7 months (2.3 times) following acute treatment initiation. In conclusion, early improvement in psychosocial function provides a clinically meaningful prediction of longer-term symptomatic remission, independent of depression symptom severity. PMID- 28030547 TI - Practice Doesn't Always Make Perfect: A Qualitative Study Explaining Why a Trial of an Educational Toolkit Did Not Improve Quality of Care. AB - BACKGROUND: Diabetes is a chronic disease commonly managed by family physicians, with the most prevalent complication being cardiovascular disease (CVD). Clinical practice guidelines have been developed to support clinicians in the care of diabetic patients. We conducted a pragmatic cluster randomized controlled trial (RCT) of a printed educational toolkit aimed at improving CVD management in diabetes in primary care, and found no effect, and indeed, the possibility of some harm. We conducted a qualitative evaluation to study the strategy for guideline implementation employed in this trial, and to understand its effects. This paper focuses solely on the qualitative findings, as the RCT's quantitative results have already been reported elsewhere. METHODS AND FINDINGS: All family practices in the province of Ontario had been randomized to receive the educational toolkit by mail, in either the summer of 2009 (intervention arm) or the spring of 2010 (control arm).A subset of 80 family physicians (representing approximately 10% of the practices randomized and approached, with records on 1,592 randomly selected patients with diabetes at high risk for CVD) then took part in a chart audit and reflective feedback exercise related to their own practice in comparison to the guideline recommendations. They were asked to complete two forms (one pre- and one post-audit) in order to understand their awareness of the guidelines pre-trial, their expectations regarding their individual performance pre-audit, and their reflections on their audit results. In addition, individual interviews with thirteen other family physicians were conducted. Textual data from interview transcripts and written commentary from the pre- and post-audit forms underwent qualitative descriptive analysis to identify common themes and patterns. Analysis revealed four main themes: impressions of the toolkit, awareness was not the issue, 'it's not me it's my patients', and chart audit as a more effective intervention than the toolkit. Participants saw neither the toolkit content nor its dissemination strategy to be effective, indicating they perceived themselves to be aware of the guidelines pre trial. However, their accounts also indicated that they may be struggling to prioritize CVD management in the midst of competing demands for their attention. Upon receiving their chart audit results, many participants expressed surprise that they had not performed better. They reported that the audit results would be an important motivator for behaviour change. CONCLUSIONS: The qualitative findings outlined in this paper offer important insights into why the intervention was not effective. They also demonstrate that physicians have unperceived needs relative to CVD management and that the chart audit served to identify shortcomings in their practice of which they had been hitherto unaware. The findings also indicate that new methods of intervention development and implementation should be explored. This is important given the high prevalence of diabetes worldwide; appropriate CVD management is critical to addressing the morbidity and mortality associated with the disease. PMID- 28030548 TI - Using LTI Dynamics to Identify the Influential Nodes in a Network. AB - Networks are used for modeling numerous technical, social or biological systems. In order to better understand the system dynamics, it is a matter of great interest to identify the most important nodes within the network. For a large set of problems, whether it is the optimal use of available resources, spreading information efficiently or even protection from malicious attacks, the most important node is the most influential spreader, the one that is capable of propagating information in the shortest time to a large portion of the network. Here we propose the Node Imposed Response (NiR), a measure which accurately evaluates node spreading power. It outperforms betweenness, degree, k-shell and h index centrality in many cases and shows the similar accuracy to dynamics sensitive centrality. We utilize the system-theoretic approach considering the network as a Linear Time-Invariant system. By observing the system response we can quantify the importance of each node. In addition, our study provides a robust tool set for various protective strategies. PMID- 28030549 TI - Prey Selection of Scandinavian Wolves: Single Large or Several Small? AB - Research on large predator-prey interactions are often limited to the predators' primary prey, with the potential for prey switching in systems with multiple ungulate species rarely investigated. We evaluated wolf (Canis lupus) prey selection at two different spatial scales, i.e., inter- and intra-territorial, using data from 409 ungulate wolf-kills in an expanding wolf population in Scandinavia. This expansion includes a change from a one-prey into a two-prey system with variable densities of one large-sized ungulate; moose (Alces alces) and one small-sized ungulate; roe deer (Capreolus capreolus). Among wolf territories, the proportion of roe deer in wolf kills was related to both pack size and roe deer density, but not to moose density. Pairs of wolves killed a higher proportion of roe deer than did packs, and wolves switched to kill more roe deer as their density increased above a 1:1 ratio in relation to the availability of the two species. At the intra-territorial level, wolves again responded to changes in roe deer density in their prey selection whereas we found no effect of snow depth, time during winter, or other predator-related factors on the wolves' choice to kill moose or roe deer. Moose population density was only weakly related to intra-territorial prey selection. Our results show that the functional response of wolves on moose, the species hitherto considered as the main prey, was strongly dependent on the density of a smaller, alternative, ungulate prey. The impact of wolf predation on the prey species community is therefore likely to change with the composition of the multi-prey species community along with the geographical expansion of the wolf population. PMID- 28030550 TI - Spatio-Temporal Pattern and Influencing Factors of Hemorrhagic Fever with Renal Syndrome (HFRS) in Hubei Province (China) between 2005 and 2014. AB - Hemorrhagic Fever with Renal Syndrome (HFRS) is considered as a globally distributed infectious disease, which results in many deaths annually in Hubei Province, China. The outbreak of HFRS is usually characterized with spatio temporal heterogeneity and is seasonally distributed. Further, it might also be impacted by the influencing factors such as socio-economic and geographical environment. To better understand and predict the outbreak of HFRS in the Hubei Province, the spatio-temporal pattern and influencing factors were investigated in this study. Moran's I Index value was adopted in spatial global autocorrelation analysis to identify the overall spatio-temporal pattern of HFRS outbreak. Kulldorff scan statistical analysis was performed to further identify the changing trends of the clustering patterns of HFRS outbreak. Spearman's rank correlation analysis was used to explore the possible influencing factors on HFRS epidemics such as climate and geographic. The results demonstrated that HFRS outbreak in Hubei Province decreased from 2005 to 2012 in general while increasing slightly from 2012 to 2014. The spatial and temporal scan statistical analysis indicated that HFRS epidemic was temporally clustered in summer and autumn from 2005 to 2014 except 2008 and 2011. The seasonal epidemic pattern of HFRS in Hubei Province was characterized by a bimodal pattern (March to May and September to November) while peaks often occurring in the spring time. SEOV-type HFRS was presumed to influence more on the total number of HFRS incidence than HTNV-type HFRS do. The average humidity and human population density were the main influencing factors during these years. HFRS outbreaks were more in plains than in other areas of Hubei Province. We did not find that whether the terrain of the wetland (water system) plays a significant role in the outbreak of HFRS incidence. With a better understanding of rodent infection rate, socio-economic status and ecological environment characteristics, this study may help to reduce the outbreak of HFRS disease. PMID- 28030551 TI - Dynamic Changes of Soil Surface Organic Carbon under Different Mulching Practices in Citrus Orchards on Sloping Land. AB - Mulching management has been used in many places all over the world to improve agricultural sustainability. However, the cycling of carbon in the soil under applications of mulch on sloping arable land is not yet fully understood. A four year field experiment was carried out in Xiaofuling watershed of Danjiangkou reservoir in China. The object was to evaluate the effects of the application of straw mulch (ST) and grass mulch (GT) on dynamic changes in soil organic carbon and its fractions. Results showed that mulch applied on the soil surface increased the contents of SOC and its active fractions in the soil. Compared to the control without cover (CK), ST and GT treatments increased the contents of SOC, LOC, DOC, POC and EOC by 14.73%, 16.5%, 22.5%, 41.5% and 21%, respectively, in the 0-40 cm soil layer, and by 17%, 14%, 19%, and 30%, respectively, in the 0 100 cm soil layer. The contents of organic carbon and its active fractions decreased with increasing soil depth in all of the treatments. SOC was accumulated in the period of December to the following March. The contents of soil DOC and LOC were high in January to March, while the contents of soil POC and EOC were high in June to September. The relative contents of soil organic carbon fractions were POC > EOC > LOC > DOC over the four years. Straw mulching had no significant effect on the changes in soil organic carbon active fractions during the different periods. Based on this long-term field experiment in Danjiangkou reservoir, we found that straw mulching had a significant effect on soil, increasing SOC content and stock in slopping arable land, and that live grass mulching was more effective than rice straw mulching. We discuss possible optimal periods for the implementation of mulching practices on sloping land. PMID- 28030552 TI - Cytochrome c Negatively Regulates NLRP3 Inflammasomes. AB - The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also interacts with NLRP3 recruiting NLRP3 to mitochondria and facilitating inflammasome assembly. In this study we investigated whether cytosolic cytochrome c impacts NLRP3 inflammasome activation in macrophages. We report that cytochrome c binds to the LRR domain of NLRP3 and that cytochrome c reduces the interactions between NLRP3 and cardiolipin and between NLRP3 and NEK7, a recently recognized component of the NLRP3 inflammasome needed for NLRP3 oligomerization. Protein transduction of cytochrome c impairs NLRP3 inflammasome activation, while partially silencing cytochrome c expression enhances it. The addition of cytochrome c to an in vitro inflammasome assay severely limited caspase-1 activation. We propose that there is a crosstalk between the NLRP3 inflammasome and apoptosome pathways mediated by cytochrome c, whose release during apoptosis acts to limit NLRP3 inflammasome activation. PMID- 28030553 TI - Crowd-Funding: A New Resource Cooperation Mode for Mobile Cloud Computing. AB - Mobile cloud computing, which integrates the cloud computing techniques into the mobile environment, is regarded as one of the enabler technologies for 5G mobile wireless networks. There are many sporadic spare resources distributed within various devices in the networks, which can be used to support mobile cloud applications. However, these devices, with only a few spare resources, cannot support some resource-intensive mobile applications alone. If some of them cooperate with each other and share their resources, then they can support many applications. In this paper, we propose a resource cooperative provision mode referred to as "Crowd-funding", which is designed to aggregate the distributed devices together as the resource provider of mobile applications. Moreover, to facilitate high-efficiency resource management via dynamic resource allocation, different resource providers should be selected to form a stable resource coalition for different requirements. Thus, considering different requirements, we propose two different resource aggregation models for coalition formation. Finally, we may allocate the revenues based on their attributions according to the concept of the "Shapley value" to enable a more impartial revenue share among the cooperators. It is shown that a dynamic and flexible resource-management method can be developed based on the proposed Crowd-funding model, relying on the spare resources in the network. PMID- 28030554 TI - Procedures and Frequencies of Embalming and Heart Extractions in Modern Period in Brittany. Contribution to the Evolution of Ritual Funerary in Europe. AB - The evolution of funeral practices from the Middle Ages through the Modern era in Europe is generally seen as a process of secularization. The study, through imaging and autopsy, of two mummies, five lead urns containing hearts, and more than six hundred skeletons of nobles and clergymen from a Renaissance convent in Brittany has led us to reject this view. In addition to exceptional embalming, we observed instances in which hearts alone had been extracted, a phenomenon that had never before been described, and brains alone as well, and instances in which each spouse's heart had been placed on the other's coffin. In some identified cases we were able to establish links between the religious attitudes of given individuals and either ancient Medieval practices or more modern ones generated by the Council of Trent. All of these practices, which were a function of social status, were rooted in religion. They offer no evidence of secularization whatsoever. PMID- 28030555 TI - TryCYCLE: A Prospective Study of the Safety and Feasibility of Early In-Bed Cycling in Mechanically Ventilated Patients. AB - INTRODUCTION: The objective of this study was to assess the safety and feasibility of in-bed cycling started within the first 4 days of mechanical ventilation (MV) to inform a future randomized clinical trial. METHODS: We conducted a 33-patient prospective cohort study in a 21-bed adult academic medical-surgical intensive care unit (ICU) in Hamilton, ON, Canada. We included adult patients (>= 18 years) receiving MV who walked independently pre-ICU. Our intervention was 30 minutes of in-bed supine cycling 6 days/week in the ICU. Our primary outcome was Safety (termination), measured as events prompting cycling termination; secondary Safety (disconnection or dislodgement) outcomes included catheter/tube dislodgements. Feasibility was measured as consent rate and fidelity to intervention. For our primary outcome, we calculated the binary proportion and 95% confidence interval (CI). RESULTS: From 10/2013-8/2014, we obtained consent from 34 of 37 patients approached (91.9%), 33 of whom received in-bed cycling. Of those who cycled, 16(48.4%) were female, the mean (SD) age was 65.8(12.2) years, and APACHE II score was 24.3(6.7); 29(87.9%) had medical admitting diagnoses. Cycling termination was infrequent (2.0%, 95% CI: 0.8%-4.9%) and no device dislodgements occurred. Cycling began a median [IQR] of 3 [2, 4] days after ICU admission; patients received 5 [3, 8] cycling sessions with a median duration of 30.7 [21.6, 30.8] minutes per session. During 205 total cycling sessions, patients were receiving invasive MV (150 [73.1%]), vasopressors (6 [2.9%]), sedative or analgesic infusions (77 [37.6%]) and dialysis (4 [2.0%]). CONCLUSIONS: Early cycling within the first 4 days of MV among hemodynamically stable patients is safe and feasible. Research to evaluate the effect of early cycling on patient function is warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01885442. PMID- 28030557 TI - Anthropometric Improvement among HIV Infected Pre-School Children Following Initiation of First Line Anti-Retroviral Therapy: Implications for Follow Up. AB - BACKGROUND: Antiretroviral therapy (ART) is a lifesaving intervention for HIV infected children. There is a scarcity of data on immunological recovery and its relation with growth indicators among HIV infected young children. The current study aims to assess the pattern of anthropometric Z-score improvement following initiation of first-line ART among under-five children and the relationship between anthropometric Z-score improvement and immunologic recovery. METHODS: We included under-five children who were on first-line ART at five major hospitals in Addis Ababa, Ethiopia. We measured anthropometry and collected clinical and laboratory data at follow up, and we retrieved clinical and anthropometric data at ART initiation from records. Z-scores for each of the anthropometric indices were calculated based on WHO growth standards using ENA for SMART 2011 software. Linear regression was used to assess the relationship between time on ART and anthropometric Z-score improvement; and the relationship between anthropometric Z score improvement and immunologic recovery. Multiple linear regression was used to assess the independent predictors of anthropometric Z-score change. RESULTS: The median age of the participants was 4.1 (Interquartile range (IQR): 3.3-4.9) years. More than half (52.48%) were female. The median duration of follow up was 1.69 (IQR: 1.08-2.63) years. There was a significant improvement in all anthropometric indices at any follow up after initiation of first-line ART (underweight; 39.5% vs16.5%, stunting; 71.3% vs 62.9% and wasting; 16.3% vs 1.0%; p-value< 0.0001). There was an inverse relationship between improvement in weight for age Z-score (WAZ) and duration of ART (R2 = 0.04; F (1, 158); p = 0.013). Height for age Z-score (HAZ) both at the time of ART initiation and follow up has a positive linear relationship with CD4 percentage at follow up (Coef. = 1.92; R2 = 0.05; p-value = 0.002). Duration on ART (Std. Err. = 0.206, t = -1.99, p-value = 0.049) and level of maternal education (Std. Err. = 0.290, t = 2.64, p-value = 0.009) were the only independent predictors of the change in WAZ and change in HAZ at any follow up visit respectively. CONCLUSION: There was a significant improvement in all anthropometric indices at any follow-up after initiation of first-line ART among under-five children. HAZ was linearly related with immunologic recovery following ART initiation. The findings indicate that anthropometric indices could be taken as proxy indicators of immunologic recovery for under-five children. PMID- 28030556 TI - Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing alpha subunit of hypoxia inducible factor-1 (HIF-1), a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis. METHODS: Wild-type mice and mice with hepatocyte-specific HIF-1alpha knockout (Hif1a-/-hep) were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2) or normoxia (16% O2) for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking. RESULTS: Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 MUg collagen/mg liver tissue, versus 1.23 MUg collagen/mg liver tissue, p = 0.03), which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia. CONCLUSIONS: Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver tissue hypoxia in hepatic steatosis. HIF-1 is necessary for collagen cross-linking in an in vitro model of fibrosis. PMID- 28030558 TI - Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas. AB - In humans suffering from pulmonary disease and a mouse model, transient receptor potential vanilloid 4 (TRPV4) channel activation contributes to fibrosis. As a corneal alkali burn induces the same response, we determined if such an effect is also attributable to TRPV4 activation in mice. Accordingly, we determined if the alkali burn wound healing responses in wild-type (WT) mice are different than those in their TRPV4-null (KO) counterpart. Stromal opacification due to fibrosis in KO (n = 128) mice was markedly reduced after 20 days relative to that in WT (n = 157) mice. Immunohistochemistry revealed that increases in polymorphonuclear leukocytes and macrophage infiltration declined in KO mice. Semi-quantitative real time RT-PCR of ocular KO fibroblast cultures identified increases in proinflammatory and monocyte chemoattractant protein-1 chemoattractant gene expression after injury. Biomarker gene expression of fibrosis, collagen1a1 and alpha-smooth muscle actin were attenuated along with macrophage release of interleukin-6 whereas transforming growth factor beta, release was unchanged. Tail vein reciprocal bone marrow transplantation between WT and KO chimera mouse models mice showed that reduced scarring and inflammation in KO mice are due to loss of TRPV4 expression on both corneal resident immune cells, fibroblasts and infiltrating polymorphonuclear leukocytes and macrophages. Intraperitoneal TRPV4 receptor antagonist injection of HC-067047 (10 mg/kg, daily) into WT mice reproduced the KO-phenotype. Taken together, alkali-induced TRPV4 activation contributes to inducing fibrosis and inflammation since corneal transparency recovery was markedly improved in KO mice. PMID- 28030559 TI - Breeding Dispersal by Birds in a Dynamic Urban Ecosystem. AB - Changes in land cover during urbanization profoundly affect the diversity of bird communities, but the demographic mechanisms affecting diversity are poorly known. We advance such understanding by documenting how urbanization influences breeding dispersal-the annual movement of territorial adults-of six songbird species in the Seattle, WA, USA metropolitan area. We color-banded adults and mapped the centers of their annual breeding activities from 2000-2010 to obtain 504 consecutive movements by 337 adults. By comparing movements, annual reproduction, and mate fidelity among 10 developed, 5 reserved, and 11 changing (areas cleared and developed during our study) landscapes, we determined that adaptive breeding dispersal of sensitive forest species (Swainson's Thrush and Pacific wren), which involves shifting territory and mate after reproductive failure, was constrained by development. In changing lands, sensitive forest specialists dispersed from active development to nearby forested areas, but in so doing suffered low annual reproduction. Species tolerant of suburban lands (song sparrow, spotted towhee, dark-eyed junco, and Bewick's wren) dispersed adaptively in changing landscapes. Site fidelity ranged from 0% (Pacific wren in changing landscape) to 83% (Bewick's wren in forest reserve). Mate fidelity ranged from 25% (dark-eyed junco) to 100% (Bewick's wren). Variation in fidelity to mate and territory was consistent with theories positing an influence of territory quality, asynchronous return from migration, prior productivity, and reproductive benefits of retaining a familiar territory. Costly breeding dispersal, as well as reduced reproductive success and lowered survival cause some birds to decline in the face of urbanization. In contrast, the ability of species that utilize edges and early successional habitats to breed successfully, disperse to improve reproductive success after failure, and survive throughout the urban ecosystem enables them to maintain or increase population size. PMID- 28030560 TI - The Effect of Significant International Sports Events on Qualified Detoxification Treatment Outcome - Do Drop-Out Rates Change during UEFA European Championship? AB - No previous studies have evaluated the influence of significant international sports events on qualified detoxification treatment outcome. This prospective study examines the impact of the 2012 UEFA European Football Championship on inpatient treatment outcome of alcohol dependent patients. Hospital admission and premature drop-out rates of consecutively admitted alcohol dependent patients were determined before, during and immediately after the UEFA Championship in the year 2012. The admission rate of male patients increased significantly after the European Football Championship had ended whereas for female patients, no change in admission rate was found. Daily average discharge rate was calculated. No statistically relevant differences between the treatment days before, during and after the UEFA Championship was found for the discharges. During the tournament, exclusively male patients dropped out. Our results are consistent with an interpretation of an association between European Football Championship and detoxification treatment outcome. Further research to replicate and extend our findings is necessary. PMID- 28030561 TI - Drosophila DDX3/Belle Exerts Its Function Outside of the Wnt/Wingless Signaling Pathway. AB - The helicases human DDX3 and Drosophila Belle (Bel) are part of a well-defined subfamily of the DEAD-box helicases. Individual subfamily-members perform a myriad of functions in nuclear and cytosolic RNA metabolism. It has also been reported that DDX3X is involved in cell signaling, including IFN-alpha and IFN beta inducing pathways upon viral infection as well as in Wnt signaling. Here we used a collection of EMS-induced bel alleles recovered from a Wingless (Wg) suppressor screen to analyze the role of the Drosophila homolog of DDX3 in Wg/Wnt signaling. These EMS alleles, as well as a P-element induced null allele and RNAi mediated knock down of bel, all suppressed the phenotype of ectopic Wg signaling in the eye. However, they did not affect the expression of known Wg target genes like senseless, Distalless or wingful/Notum. Ectopic Wg signaling in eye imaginal discs induces apoptosis by increasing grim expression. Mutations in bel revert grim expression to wild-type levels. Together, these results indicate that Bel does not function as a core component in the Drosophila Wg pathway, and that mutations affecting its helicase function suppress the effects of ectopic Wg signaling downstream of the canonical pathway. PMID- 28030562 TI - Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery. AB - Ex-vivo expanded mesenchymal stromal cells (MSCs) are increasingly used for paracrine support of hematopoietic stem cell (HSC) regeneration, but inconsistent outcomes have hindered ongoing clinical trials. Here, we show that significant heterogeneity in the niche activity of MSCs is created during their culture in various serum-supplemented media. The MSCs cultured under stimulatory or non stimulatory culture conditions exhibited differences in colony forming unit fibroblast contents, expression levels of cross-talk molecules (Jagged-1 and CXCL 12) and their support for HSC self-renewal. Accordingly, the enhancing effects of MSCs on hematopoietic engraftment were only visible when HSCs were co transplanted with MSCs under stimulatory conditions. Of note, these differences in MSCs and their effects on HSCs were readily reversed by switching the cultures, indicating that the difference in niche activity can be caused by distinct functional state, rather than by clonal heterogeneity. Supporting the findings, transcriptomic analysis showed distinct upstream signaling pathways such as inhibition of P53 and activation of ER-stress response gene ATF4 for MSCs under stimulatory conditions. Taken together, our study shows that the niche activity of MSCs can vary rapidly by the extrinsic cues during culture causing variable outcomes in hematopoietic recoveries, and point to the possibility that MSCs can be pre-screened for more predictable efficacy in various cell therapy trials. PMID- 28030563 TI - The Involvement of Pial Microvessels in Leukocyte Invasion after Mild Traumatic Brain Injury. AB - The pathophysiological mechanisms underlying mild traumatic brain injury (mTBI) are not well understood, but likely involve neuroinflammation. Here the controlled cortical impact model of mTBI in rats was used to test this hypothesis. Mild TBI caused a rapid (within 6 h post-mTBI) upregulation of synthesis of TNF-alpha and IL-1beta in the cerebral cortex and hippocampus, followed by an increase in production of neutrophil (CXCL1-3) and monocyte (CCL2) chemoattractants. While astrocytes were not a significant source of CXC chemokines, they highly expressed CCL2. An increase in production of CXC chemokines coincided with the influx of neutrophils into the injured brain. At 6 h post-mTBI, we observed a robust influx of CCL2-expressing neutrophils across pial microvessels into the subarachnoid space (SAS) near the injury site. Mild TBI was not accompanied by any significant influx of neutrophils into the brain parenchyma until 24 h after injury. This was associated with an early induction of expression of intercellular adhesion molecule 1 on the endothelium of the ipsilateral pial, but not intraparenchymal, microvessels. At 6 h post-mTBI, we also observed a robust influx of neutrophils into the ipsilateral cistern of velum interpositum (CVI), a slit-shaped cerebrospinal fluid space located above the 3rd ventricle with highly vascularized pia mater. From SAS and CVI, neutrophils appeared to move along the perivascular spaces to enter the brain parenchyma. The monocyte influx was not observed until 24 h post-mTBI, and these inflammatory cells predominantly entered the ipsilateral SAS and CVI, with a limited invasion of brain parenchyma. These observations indicate that the endothelium of pial microvessels responds to injury differently than that of intraparenchymal microvessels, which may be associated with the lack of astrocytic ensheathment of cerebrovascular endothelium in pial microvessels. These findings also suggest that neuroinflammation represents the potential therapeutic target in mTBI. PMID- 28030565 TI - Using Functional or Structural Magnetic Resonance Images and Personal Characteristic Data to Identify ADHD and Autism. AB - A clinical tool that can diagnose psychiatric illness using functional or structural magnetic resonance (MR) brain images has the potential to greatly assist physicians and improve treatment efficacy. Working toward the goal of automated diagnosis, we propose an approach for automated classification of ADHD and autism based on histogram of oriented gradients (HOG) features extracted from MR brain images, as well as personal characteristic data features. We describe a learning algorithm that can produce effective classifiers for ADHD and autism when run on two large public datasets. The algorithm is able to distinguish ADHD from control with hold-out accuracy of 69.6% (over baseline 55.0%) using personal characteristics and structural brain scan features when trained on the ADHD-200 dataset (769 participants in training set, 171 in test set). It is able to distinguish autism from control with hold-out accuracy of 65.0% (over baseline 51.6%) using functional images with personal characteristic data when trained on the Autism Brain Imaging Data Exchange (ABIDE) dataset (889 participants in training set, 222 in test set). These results outperform all previously presented methods on both datasets. To our knowledge, this is the first demonstration of a single automated learning process that can produce classifiers for distinguishing patients vs. controls from brain imaging data with above-chance accuracy on large datasets for two different psychiatric illnesses (ADHD and autism). Working toward clinical applications requires robustness against real-world conditions, including the substantial variability that often exists among data collected at different institutions. It is therefore important that our algorithm was successful with the large ADHD-200 and ABIDE datasets, which include data from hundreds of participants collected at multiple institutions. While the resulting classifiers are not yet clinically relevant, this work shows that there is a signal in the (f)MRI data that a learning algorithm is able to find. We anticipate this will lead to yet more accurate classifiers, over these and other psychiatric disorders, working toward the goal of a clinical tool for high accuracy differential diagnosis. PMID- 28030566 TI - Disentangling Phylogenetic Relationships in a Hotspot of Diversity: The Butterworts (Pinguicula L., Lentibulariaceae) Endemic to Italy. AB - The genus Pinguicula (Lentibulariaceae) consists of about 100 carnivorous species, also known as butterworts. Eleven taxa are endemic to Italy, which represents a biodiversity hotspot for butterworts in Europe. The aim of our study was to provide a phylogenetic framework for the Italian endemics, in order to: a) investigate the relationships between species in this group; b) evaluate their actual taxonomic value. To achieve this, we analysed all the taxa endemic to Italy, along with several other species, by means of ITS nrDNA analysis. Our results clarify the relationships between Italian endemics and other Pinguicula taxa identifying a basal polytomy defined by five clades. All of the Italian endemics (with the exception of P. lavalvae) fall within a single large clade, which includes P. vulgaris and allied species. Among them, P. poldinii represents the most isolated lineage. Other taxa show strong molecular similarities and form a single subclade, although their taxonomic ranks can be retained. Pinguicula lattanziae sp. nov., seemingly endemic to Liguria (NW Italy), is also described. PMID- 28030564 TI - Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas. AB - BACKGROUND: 5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). METHODS: Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival. RESULTS: 129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5 year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival. CONCLUSION: In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients. PMID- 28030567 TI - Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions. AB - The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise. PMID- 28030568 TI - Space Use and Movement of a Neotropical Top Predator: The Endangered Jaguar. AB - Accurately estimating home range and understanding movement behavior can provide important information on ecological processes. Advances in data collection and analysis have improved our ability to estimate home range and movement parameters, both of which have the potential to impact species conservation. Fitting continuous-time movement model to data and incorporating the autocorrelated kernel density estimator (AKDE), we investigated range residency of forty-four jaguars fit with GPS collars across five biomes in Brazil and Argentina. We assessed home range and movement parameters of range resident animals and compared AKDE estimates with kernel density estimates (KDE). We accounted for differential space use and movement among individuals, sex, region, and habitat quality. Thirty-three (80%) of collared jaguars were range resident. Home range estimates using AKDE were 1.02 to 4.80 times larger than KDE estimates that did not consider autocorrelation. Males exhibited larger home ranges, more directional movement paths, and a trend towards larger distances traveled per day. Jaguars with the largest home ranges occupied the Atlantic Forest, a biome with high levels of deforestation and high human population density. Our results fill a gap in the knowledge of the species' ecology with an aim towards better conservation of this endangered/critically endangered carnivore-the top predator in the Neotropics. PMID- 28030569 TI - Effect of an Education Programme for South Asians with Asthma and Their Clinicians: A Cluster Randomised Controlled Trial (OEDIPUS). AB - BACKGROUND: People with asthma from ethnic minority groups experience significant morbidity. Culturally-specific interventions to reduce asthma morbidity are rare. We tested the hypothesis that a culturally-specific education programme, adapted from promising theory-based interventions developed in the USA, would reduce unscheduled care for South Asians with asthma in the UK. METHODS: A cluster randomised controlled trial, set in two east London boroughs. 105 of 107 eligible general practices were randomised to usual care or the education programme. Participants were south Asians with asthma aged 3 years and older with recent unscheduled care. The programme had two components: the Physician Asthma Care Education (PACE) programme and the Chronic Disease Self Management Programme (CDSMP), targeted at clinicians and patients with asthma respectively. Both were culturally adapted for south Asians with asthma. Specialist nurses, and primary care teams from intervention practices were trained using the PACE programme. South Asian participants attended an outpatient appointment; those registered with intervention practices received self-management training from PACE-trained specialist nurses, a follow-up appointment with PACE-trained primary care practices, and an invitation to attend the CDSMP. Patients from control practices received usual care. Primary outcome was unscheduled care. FINDINGS: 375 south Asians with asthma from 84 general practices took part, 183 registered with intervention practices and 192 with control practices. Primary outcome data were available for 358/375 (95.5%) of participants. The intervention had no effect on time to first unscheduled attendance for asthma (Adjusted Hazard Ratio AHR = 1.19 95% CI 0.92 to 1.53). Time to first review in primary care was reduced (AHR = 2.22, (1.67 to 2.95). Asthma-related quality of life and self-efficacy were improved at 3 months (adjusted mean difference -2.56, (-3.89 to -1.24); 0.44, (0.05 to 0.82) respectively. CONCLUSIONS: A multi-component education programme adapted for south Asians with asthma did not reduce unscheduled care but did improve follow-up in primary care, self-efficacy and quality of life. More effective interventions are needed for south Asians with asthma. PMID- 28030570 TI - An Assessment of the Population of Cotton-Top Tamarins (Saguinus oedipus) and Their Habitat in Colombia. AB - Numerous animals have declining populations due to habitat loss, illegal wildlife trade, and climate change. The cotton-top tamarin (Saguinus oedipus) is a Critically Endangered primate species, endemic to northwest Colombia, threatened by deforestation and illegal trade. In order to assess the current state of this species, we analyzed changes in the population of cotton-top tamarins and its habitat from 2005 to 2012. We used a tailor-made "lure strip transect" method to survey 43 accessible forest parcels that represent 30% of the species' range. Estimated population size in the surveyed region was approximately 2,050 in 2005 and 1,900 in 2012, with a coefficient of variation of approximately 10%. The estimated population change between surveys was -7% (a decline of approximately 1.3% per year) suggesting a relatively stable population. If densities of inaccessible forest parcels are similar to those of surveyed samples, the estimated population of cotton-top tamarins in the wild in 2012 was 6,946 individuals. We also recorded little change in the amount of suitable habitat for cotton-top tamarins between sample periods: in 2005, 18% of surveyed forest was preferred habitat for cotton-top tamarins, while in 2012, 17% percent was preferred. We attribute the relatively stable population of this Critically Endangered species to increased conservation efforts of Proyecto Titi, conservation NGOs, and the Colombian government. Due to continued threats to cotton-top tamarins and their habitat such as agriculture and urban expansion, ongoing conservation efforts are needed to ensure the long-term survival of cotton-top tamarins in Colombia. PMID- 28030571 TI - Multidisciplinary Identification of the Controversial Freedom Fighter Jorg Jenatsch, Assassinated 1639 in Chur, Switzerland. AB - Jorg Jenatsch, a leading freedom fighter during the Thirty Year's War in Graubunden, Switzerland, was assassinated on carnival 1639. Jenatsch's controversial biography and the unclear circumstances of his death inspired the formation of various legends, novels and films. In 1959, a skeleton discovered in the cathedral of Chur with remains of wealthy baroque clothing was tentatively attributed to Jenatsch. Here, we reassess the skeleton based on a new exhumation. Our multidisciplinary analysis and the head injuries are consistent with reports of the eyewitnesses of the crime, demonstrating that Jenatsch was killed from behind with a semi-sharp implement, supposedly an axe, as well as by a blow with a broad-surfaced object. Moreover, our facial reconstruction closely matches an oil portrait of Jenatsch, and the HIrisPlex system applied to DNA-extracts from the femoral bone reveals brown eye and dark brown hair colour, which coincides well with the portrait, too. Finally, isotope analysis of the femoral bone and a molar support Jenatsch's high social status, luxury diet and a high mobility in the last decade of his life. This multidisciplinary approach thus reinforces personal identification and provides additional insight into the life of this important historic person beyond written resources. PMID- 28030572 TI - Decisions with Uncertain Consequences-A Total Ordering on Loss-Distributions. AB - Decisions are often based on imprecise, uncertain or vague information. Likewise, the consequences of an action are often equally unpredictable, thus putting the decision maker into a twofold jeopardy. Assuming that the effects of an action can be modeled by a random variable, then the decision problem boils down to comparing different effects (random variables) by comparing their distribution functions. Although the full space of probability distributions cannot be ordered, a properly restricted subset of distributions can be totally ordered in a practically meaningful way. We call these loss-distributions, since they provide a substitute for the concept of loss-functions in decision theory. This article introduces the theory behind the necessary restrictions and the hereby constructible total ordering on random loss variables, which enables decisions under uncertainty of consequences. Using data obtained from simulations, we demonstrate the practical applicability of our approach. PMID- 28030573 TI - Cation-Stress-Responsive Transcription Factors SltA and CrzA Regulate Morphogenetic Processes and Pathogenicity of Colletotrichum gloeosporioides. AB - Growth of Colletotrichum gloeosporioides in the presence of cation salts NaCl and KCl inhibited fungal growth and anthracnose symptom of colonization. Previous reports indicate that adaptation of Aspergillus nidulans to salt- and osmotic stress conditions revealed the role of zinc-finger transcription factors SltA and CrzA in cation homeostasis. Homologs of A. nidulans SltA and CrzA were identified in C. gloeosporioides. The C. gloeosporioides CrzA homolog is a 682-amino acid protein, which contains a C2H2 zinc finger DNA-binding domain that is highly conserved among CrzA proteins from yeast and filamentous fungi. The C. gloeosporioides SltA homolog encodes a 775-amino acid protein with strong similarity to A. nidulans SltA and Trichoderma reesei ACE1, and highest conservation in the three zinc-finger regions with almost no changes compared to ACE1 sequences. Knockout of C. gloeosporioides crzA (DeltacrzA) resulted in a phenotype with inhibited growth, sporulation, germination and appressorium formation, indicating the importance of this calciu006D-activated transcription factor in regulating these morphogenetic processes. In contrast, knockout of C. gloeosporioides sltA (DeltasltA) mainly inhibited appressorium formation. Both mutants had reduced pathogenicity on mango and avocado fruit. Inhibition of the different morphogenetic stages in the DeltacrzA mutant was accompanied by drastic inhibition of chitin synthase A and B and glucan synthase, which was partially restored with Ca2+ supplementation. Inhibition of appressorium formation in DeltasltA mutants was accompanied by downregulation of the MAP kinase pmk1 and carnitine acetyl transferase (cat1), genes involved in appressorium formation and colonization, which was restored by Ca2+ supplementation. Furthermore, exposure of C. gloeosporioides DeltacrzA or DeltasltA mutants to cations such as Na+, K+ and Li+ at concentrations that the wild type C. gloeosporioides is not affected had further adverse morphogenetic effects on C. gloeosporioides which were partially or fully restored by Ca2+. Overall results suggest that both genes modulating alkali cation homeostasis have significant morphogenetic effects that reduce C. gloeosporioides colonization. PMID- 28030574 TI - Endothelin Regulates Porphyromonas gingivalis-Induced Production of Inflammatory Cytokines. AB - Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21 amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1beta, TNFalpha, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment. PMID- 28030575 TI - Time Course of Leptin in Patients with Anorexia Nervosa during Inpatient Treatment: Longitudinal Relationships to BMI and Psychological Factors. AB - BACKGROUND: Leptin, a hormone secreted by adipose tissue, appears to play a major role in the homeostasis of body weight and psychobiological processes associated with anorexia nervosa (AN). However, there is scarce data on its exact influence on this disorder, in particular data over time. OBJECTIVE: The present study addresses whether leptin changes during inpatient treatment play a role for treatment outcome and psychological factors in underweight AN patients. METHODS: In order to understand whether leptin's role differs in relation to AN severity, data were assessed from 11 patients with a very low BMI and a higher chronicity (high severity group; HSS; mean BMI at the beginning of the study = 13.6; mean duration of illness = 5.1 years) vs. nine with less severe symptoms (LSS; mean BMI = 16.2; mean duration of illness = 3.7 years). During the course of treatment, serum leptin concentrations were assessed weekly while weight (BMI) was assessed twice per week. Concomitantly, psychological variables were obtained by means of electronic diaries. Unconditional linear growth models were calculated to evaluate the temporal course of leptin in relation to BMI. For HSS patients, two phases of treatment (BMI < 16 and BMI >= 16 kg/m2) were investigated. RESULTS: Leptin increased significantly with BMI in both groups of patients. For HSS patients, the increase of leptin in the first treatment phase did not predict later increases in BMI. Furthermore, the relationship of leptin and psychological factors was modulated by symptom severity. In HSS patients, higher leptin levels were associated with greater feelings of depression, anxiety, and stress whereas in LSS patients a higher leptin level showed the trend to be associated with lower psychological symptom burden. CONCLUSIONS: Our results suggest that leptin changes are differently associated with weight gain and psychological symptoms depending on the severity of starvation. PMID- 28030576 TI - Functional and Structural Analysis of a Highly-Expressed Yersinia pestis Small RNA following Infection of Cultured Macrophages. AB - Non-coding small RNAs (sRNAs) are found in practically all bacterial genomes and play important roles in regulating gene expression to impact bacterial metabolism, growth, and virulence. We performed transcriptomics analysis to identify sRNAs that are differentially expressed in Yersinia pestis that invaded the human macrophage cell line THP-1, compared to pathogens that remained extracellular in the presence of host. Using ultra high-throughput sequencing, we identified 37 novel and 143 previously known sRNAs in Y. pestis. In particular, the sRNA Ysr170 was highly expressed in intracellular Yersinia and exhibited a log2 fold change ~3.6 higher levels compared to extracellular bacteria. We found that knock-down of Ysr170 expression attenuated infection efficiency in cell culture and growth rate in response to different stressors. In addition, we applied selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis to determine the secondary structure of Ysr170 and observed structural changes resulting from interactions with the aminoglycoside antibiotic gentamycin and the RNA chaperone Hfq. Interestingly, gentamicin stabilized helix 4 of Ysr170, which structurally resembles the native gentamicin 16S ribosomal binding site. Finally, we modeled the tertiary structure of Ysr170 binding to gentamycin using RNA motif modeling. Integration of these experimental and structural methods can provide further insight into the design of small molecules that can inhibit function of sRNAs required for pathogen virulence. PMID- 28030577 TI - Resistance of Aerosolized Bacterial Viruses to Four Germicidal Products. AB - Viral diseases can spread through a variety of routes including aerosols. Yet, limited data are available on the efficacy of aerosolized chemicals to reduce viral loads in the air. Bacteriophages (phages) are often used as surrogates for hazardous viruses in aerosol studies because they are inexpensive, easy to handle, and safe for laboratory workers. Moreover, several of these bacterial viruses display physical characteristics similar to pathogenic human and animal viruses, like morphological size, type of nucleic acids, capsid morphology, and the presence of an envelope. In this study, the efficacy of four chemicals was evaluated on four airborne phages at two different relative humidity levels. Non tailed bacteriophages MS2 (single-stranded RNA), phi6 (double-stranded RNA, enveloped), PR772 (double-stranded DNA), and phiX174 (single-stranded DNA) were first aerosolized in a 55L rotative environmental chamber at 19 degrees C with 25% and 50% relative humidity. Then, hydrogen peroxide, Eugenol (phenylpropene used in commercial perfumes and flavorings), Mist(r) (automobile disinfectant containing Triethylene glycol), and Pledge(r) (multisurface disinfectant containing Isopropanol, n-Alkyl Dimethyl Benzyl Amonium Chlorides, and n-Alkyl Dimethyl Ethylbenzyl Ammonium Chloride) were nebulized with the phages using a separate nebulizer. Aerosols were maintained in suspension during 10 minutes, 1 hour, and 2 hours. Viral aerosols were sampled using an SKC BioSampler and samples were analyzed using qPCR and plaque assays. The resistance levels of the four phages varied depending on the relative humidity (RH) and germicidal products tested. Phage MS2 was the most stable airborne virus under the environmental conditions tested while phage PR772 was the least stable. Pledge(r) and Eugenol reduced the infectivity of all airborne phages tested. At 25% RH, Pledge(r) and Eugenol were more effective at reducing infectivity of RNA phages phi6 and MS2. At 50% RH, Pledge(r) was the most effective agent against phage MS2. These findings illustrate that various airborne viruses should be tested to demonstrate the effectiveness of germicidal treatments. This research also provides a set of parameters for testing germicidal products in large-scale settings to reduce the risk of virus transmission. PMID- 28030578 TI - Use of ECG and Other Simple Non-Invasive Tools to Assess Pulmonary Hypertension. AB - BACKGROUND: There is a broad consensus that pulmonary hypertension (PH) is to be diagnosed by right heart catheterization (RHC) and that the most important non invasive tool is echocardiography. However, the role of simple non-invasive tools in the work-up of PH is not clearly defined. We hypothesized that the use of simple non-invasive techniques may help to guide important decisions in the diagnostics of pulmonary hypertension. OBJECTIVES: We aimed to develop an algorithm with the use of simple, non-invasive tools in order to identify patients with very high or very low likelihood of PH. METHODS: We retrospectively analyzed all consecutive patients undergoing RHC between 2005 and 2010 in our center and performed logistic regression of simple non-invasive parameters regarding detection and exclusion of PH and derived a two-step algorithm. In a prospective study we evaluated this algorithm between 2011 and 2013. RESULTS: The retrospective cohort consisted of n = 394 patients of which 49% presented with PH. Right axis deviation in the ECG was present in 90/394 patients and had a positive predictive value (PPV) of 93% for PH. The combination of non-right axis deviation, N-terminal pro brain natriuretic peptide (NT-proBNP)<333pg/ml, arterial oxygen saturation (SO2)>=95.5% and WHO functional class I-II was present in 69/394 patients and excluded PH with a negative predictive value (NPV) of 96%. The prospective study confirmed these results in a cohort of n = 168 patients (PPV:92%, NPV:97%). Taken together, simple non-invasive tools allowed a prediction regarding the presence or absence of PH in 42% of patients with suspected PH. CONCLUSION: ECG, NT-proBNP, SO2 and WHO functional class may predict the presence or absence of PH in almost half of the patients with suspected PH, suggesting an important role for these variables in the work-up of patients at risk for PH. CLINICAL TRIAL REGISTRATION: NCT01607502. PMID- 28030580 TI - Historic Late Blight Outbreaks Caused by a Widespread Dominant Lineage of Phytophthora infestans (Mont.) de Bary. AB - Phytophthora infestans (Mont.) de Bary, the causal agent of potato late blight, was responsible for the Irish potato famine of the 1840s. Initial disease outbreaks occurred in the US in 1843, two years prior to European outbreaks. We examined the evolutionary relationships and source of the 19th-century outbreaks using herbarium specimens of P. infestans from historic (1846-1970) and more recent isolates (1992-2014) of the pathogen. The same unique SSR multilocus genotype, named here as FAM-1, caused widespread outbreaks in both US and Europe. The FAM-1 lineage shared allelic diversity and grouped with the oldest specimens collected in Colombia and Central America. The FAM-1 lineage of P. infestans formed a genetic group that was distinct from more recent aggressive lineages found in the US. The US-1 lineage formed a second, mid-20th century group. Recent modern US lineages and the oldest Mexican lineages formed a genetic group with recent Mexican lineages, suggesting a Mexican origin of recent US lineages. A survey of mitochondrial haplotypes in a larger set of global herbarium specimens documented the more frequent occurrence of the HERB-1 (type Ia) mitochondrial haplotype in archival collections from 1866-75 and 1906-1915 and the rise of the Ib mitochondrial lineage (US-1) between 1946-1955. The FAM-1 SSR lineage survived for almost 100 years in the US, was geographically widespread, and was displaced first in the mid-20th century by the US-1 lineage and then by distinct new aggressive lineages that migrated from Mexico. PMID- 28030579 TI - HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment. AB - : This study evaluated the interferon-free, oral combination of deleobuvir (non nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and 'other' (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%-83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%-76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53-61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT01830127. PMID- 28030581 TI - Oncoplastic Surgery for Upper/Upper Inner Quadrant Breast Cancer. AB - Tumors located in the upper/upper inner quadrant of the breast warrant more attention. A small lesion relative to the size of breast in this location may be resolved by performing a level I oncoplastic technique. However, a wide excision may significantly reduce the overall quality of the breast shape by distorting the visible breast line. From June 2012 to April 2015, 36 patients with breast cancer located in the upper/upper inner quadrant underwent breast-conservation surgery with matrix rotation mammoplasty. According to the size and location of the tumor relative to the nipple-areola complex, 11 patients underwent matrix rotation with periareolar de-epithelialization (donut group) and the other 25 underwent matrix rotation only (non-donut group). The cosmetic results were self assessed by questionnaires. The average weights of the excised breast lumps in the donut and non-donut groups were 104.1 and 84.5 g, respectively. During the 3 year follow-up period, local recurrence was observed in one case and was managed with nipple-sparing mastectomy followed by breast reconstruction with prosthetic implants. In total, 31 patients (88.6%) ranked their postoperative result as either acceptable or satisfactory. The treated breasts were also self-evaluated by 27 patients (77.1%) to be nearly identical to or just slightly different from the untreated side. Matrix rotation is an easy breast-preserving technique for treating breast cancer located in the upper/upper inner quadrant of the breast that requires a relatively wide excision. With this technique, a larger breast tumor could be removed without compromising the breast appearance. PMID- 28030582 TI - Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity. AB - Mitochondrial dysregulation is closely associated with excessive reactive oxygen species (ROS) production. Altered redox homeostasis has been implicated in the onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and proteins are particularly sensitive to ROS as they are in close proximity to the respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, selectively damages breast cancer cells possibly through damage induced via enhanced ROS production. However, the effects of MitoQ and other triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis remain unknown. The primary objective of this study was to determine the impact of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy number, as well as by measuring mitochondrial proteins essential to mtDNA stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial status was evaluated by measuring superoxide production, mitochondrial membrane depolarization, oxygen consumption, extracellular acidification and mRNA or protein levels of the RC complexes along with TCA cycle activity. In this study, we demonstrated that all investigated MTAs impair mitochondrial health and decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the degree of mitochondrial damage and mtDNA degradation suggest unique properties among each MTA that may be cell line, dose and time dependent. Collectively, our study indicates the potential for TPP+ conjugated molecules to impair breast and lung cancer cells by targeting mitochondrial homeostasis. PMID- 28030583 TI - Discounting and Augmentation in Causal Conditional Reasoning: Causal Models or Shallow Encoding? AB - Recent research comparing mental models theory and causal Bayes nets for their ability to account for discounting and augmentation inferences in causal conditional reasoning had some limitations. One of the experiments used an ordinal scale and multiple items and analysed the data by subjects and items. This procedure can create a variety of problems that can be resolved by using an appropriate cumulative link function mixed models approach in which items are treated as random effects. Experiment 1 replicated this earlier experiment and analysed the results using appropriate data analytic techniques. Although successfully replicating earlier research, the pattern of results could be explained by a much simpler "shallow encoding" hypothesis. Experiment 2 introduced a manipulation to critically test this hypothesis. The results favoured the causal Bayes nets predictions and not shallow encoding and were not consistent with mental models theory. Experiment 1 provided qualified support for the causal Bayes net approach using appropriate statistics because it also replicated the failure to observe one of the predicted main effects. Experiment 2 discounted one plausible explanation for this failure. While within the limited goals that were set for these experiments they were successful, more research is required to account for the pattern of findings using this paradigm. PMID- 28030584 TI - Neuroanatomical Abnormalities in Violent Individuals with and without a Diagnosis of Schizophrenia. AB - Several structural brain abnormalities have been associated with aggression in patients with schizophrenia. However, little is known about shared and distinct abnormalities underlying aggression in these subjects and non-psychotic violent individuals. We applied a region-of-interest volumetric analysis of the amygdala, hippocampus, and thalamus bilaterally, as well as whole brain and ventricular volumes to investigate violent (n = 37) and non-violent chronic patients (n = 26) with schizophrenia, non-psychotic violent (n = 24) as well as healthy control subjects (n = 24). Shared and distinct volumetric abnormalities were probed by analysis of variance with the factors violence (non-violent versus violent) and diagnosis (non-psychotic versus psychotic), adjusted for substance abuse, age, academic achievement and negative psychotic symptoms. Patients showed elevated vCSF volume, smaller left hippocampus and smaller left thalamus volumes. This was particularly the case for non-violent individuals diagnosed with schizophrenia. Furthermore, patients had reduction in right thalamus size. With regard to left amygdala, we found an interaction between violence and diagnosis. More specifically, we report a double dissociation with smaller amygdala size linked to violence in non-psychotic individuals, while for psychotic patients smaller size was linked to non-violence. Importantly, the double dissociation appeared to be mostly driven by substance abuse. Overall, we found widespread morphometric abnormalities in subcortical regions in schizophrenia. No evidence for shared volumetric abnormalities in individuals with a history of violence was found. Finally, left amygdala abnormalities in non-psychotic violent individuals were largely accounted for by substance abuse. This might be an indication that the association between amygdala reduction and violence is mediated by substance abuse. Our results indicate the importance of structural abnormalities in aggressive individuals. PMID- 28030585 TI - Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival? AB - Cochlear hair cells and the stria vascularis are critical for normal hearing. Hair cells transduce mechanical stimuli into electrical signals, whereas the stria is responsible for generating the endocochlear potential (EP), which is the driving force for hair cell mechanotransduction. We questioned whether hair cells and the stria interdepend for survival by using two mouse models. Atoh1 conditional knockout mice, which lose all hair cells within four weeks after birth, were used to determine whether the absence of hair cells would affect function and survival of stria. We showed that stria morphology and EP remained normal for long time despite a complete loss of all hair cells. We then used a mouse model that has an abnormal stria morphology and function due to mutation of the Mitf gene to determine whether hair cells are able to survive and transduce sound signals without a normal electrochemical environment in the endolymph. A strial defect, reflected by missing intermediate cells in the stria and by reduction of EP, led to systematic outer hair cell death from the base to the apex after postnatal day 18. However, an 18-mV EP was sufficient for outer hair cell survival. Surprisingly, inner hair cell survival was less vulnerable to reduction of the EP. Our studies show that normal function of the stria is essential for adult outer hair cell survival, while the survival and normal function of the stria vascularis do not depend on functional hair cells. PMID- 28030586 TI - Experiential Avoidance Mediates the Association between Emotion Regulation Abilities and Loneliness. AB - Experiential avoidance (EA) involves the unwillingness to remain in contact with aversive experiences such as painful feelings, thoughts, and emotions. EA is often associated with the development and maintenance of emotional problems. Since loneliness is characterized by negative emotions such as sadness and pessimism, which is often linked to emotional problems, this study aims to test the mediating effects of EA on the relationship between emotion regulation abilities (ERA) and loneliness in a sample of Chinese adults. Five hundred undergraduates completed questionnaires measuring EA (Acceptance and Action Questionnaire; AAQ-II), ERA (Failure-relate action orientation; Action Control Scale, ACS-90) and loneliness (UCLA Loneliness Scale). Structural equation modeling showed that EA fully-mediated the relationship between ERA and loneliness. The findings suggest EA is a key mechanism in explaining why people with high ERA are prone to feeling lower levels of loneliness. In particular, these findings have important implications for designing effective psychological interventions for loneliness. PMID- 28030587 TI - CD5-CK2 Signaling Modulates Erk Activation and Thymocyte Survival. AB - CD5 is well recognized for its importance in thymic selection. Although this property of CD5 has been attributed to its ITIM-domain dependent regulation of TCR-signal strength, the mechanism has not been established. A second major signaling domain within the cytoplasmic tail of CD5 is a CK2 binding/activation domain (CD5-CK2BD). Using a gene-targeted mouse in which the CD5-CK2BD is selectively ablated (CD5-DeltaCK2BD), we determined that loss of function of CD5 CK2 signaling in a MHC-II selecting TCR transgenic (OT-II) mouse resulted in decrease in double positive (DP) thymocytes, which correlated with enhanced apoptosis. Remarkably, DP cells expressing high levels of CD5 and CD69 and single positive (CD4+SP) thymocytes were increased in CD5-DeltaCK2BD mice indicating that CD5-CK2 signaling regulates positive selection and promotes survival. Consistent with this possibility, we determined that the activation and nuclear localization of ERK as well as apoptosis was greater in thymic populations from OTII CD5-DeltaCK2BD mice than OTII CD5-WT mice following injection of OVA323-339 peptide. The mobilization of Ca2+, an early event of TCR activation, was not altered by the loss of CD5-CK2 signaling. Collectively, these data demonstrate that the CD5-CK2 signaling axis regulates positive selection by modulating activation of ERK and promoting survival independent of proximal TCR signals. PMID- 28030588 TI - Bistable Mechanisms for Space Applications. AB - Compliant bistable mechanisms are monolithic devices with two stable equilibrium positions separated by an unstable equilibrium position. They show promise in space applications as nonexplosive release mechanisms in deployment systems, thereby eliminating friction and improving the reliability and precision of those mechanical devices. This paper presents both analytical and numerical models that are used to predict bistable behavior and can be used to create bistable mechanisms in materials not previously feasible for compliant mechanisms. Materials compatible with space applications are evaluated for use as bistable mechanisms and prototypes are fabricated in three different materials. Pin-puller and cutter release mechanisms are proposed as potential space applications. PMID- 28030589 TI - The Antibacterial Activity of Australian Leptospermum Honey Correlates with Methylglyoxal Levels. AB - Most commercially available therapeutic honey is derived from flowering Leptospermum scoparium (manuka) plants from New Zealand. Australia has more than 80 Leptospermum species, and limited research to date has found at least some produce honey with high non-peroxide antibacterial activity (NPA) similar to New Zealand manuka, suggesting Australia may have a ready supply of medical-grade honey. The activity of manuka honey is largely due to the presence of methylglyoxal (MGO), which is produced non-enzymatically from dihydroxyacetone (DHA) present in manuka nectar. The aims of the current study were to chemically quantify the compounds contributing to antibacterial activity in a collection of Australian Leptospermum honeys, to assess the relationship between MGO and NPA in these samples, and to determine whether NPA changes during honey storage. Eighty different Leptospermum honey samples were analysed, and therapeutically useful NPA was seen in samples derived from species including L. liversidgei and L. polygalifolium. Exceptionally high levels of up to 1100 mg/kg MGO were present in L. polygalifolium honey samples sourced from the Northern Rivers region in NSW and Byfield, QLD, with considerable diversity among samples. There was a strong positive relationship between NPA and MGO concentration, and DHA was present in all of the active honey samples, indicating a potential for ongoing conversion to MGO. NPA was stable, with most samples showing little change following seven years of storage in the dark at 4 degrees C. This study demonstrates the potential for Australian Leptospermum honey as a wound care product, and argues for an extension of this analysis to other Leptospermum species. PMID- 28030590 TI - Redox Balance in Lactobacillus reuteri DSM20016: Roles of Iron-Dependent Alcohol Dehydrogenases in Glucose/ Glycerol Metabolism. AB - Lactobacillus reuteri, a heterofermentative bacterium, metabolizes glycerol via a Pdu (propanediol-utilization) pathway involving dehydration to 3 hydroxypropionaldehyde (3-HPA) followed by reduction to 1,3-propandiol (1,3-PDO) with concomitant generation of an oxidized cofactor, NAD+ that is utilized to maintain cofactor balance required for glucose metabolism and even for oxidation of 3-HPA by a Pdu oxidative branch to 3-hydroxypropionic acid (3-HP). The Pdu pathway is operative inside Pdu microcompartment that encapsulates different enzymes and cofactors involved in metabolizing glycerol or 1,2-propanediol, and protects the cells from the toxic effect of the aldehyde intermediate. Since L. reuteri excretes high amounts of 3-HPA outside the microcompartment, the organism is likely to have alternative alcohol dehydrogenase(s) in the cytoplasm for transformation of the aldehyde. In this study, diversity of alcohol dehydrogenases in Lactobacillus species was investigated with a focus on L. reuteri. Nine ADH enzymes were found in L. reuteri DSM20016, out of which 3 (PduQ, ADH6 and ADH7) belong to the group of iron-dependent enzymes that are known to transform aldehydes/ketones to alcohols. L. reuteri mutants were generated in which the three ADHs were deleted individually. The lagging growth phenotype of these deletion mutants revealed that limited NAD+/NADH recycling could be restricting their growth in the absence of ADHs. Notably, it was demonstrated that PduQ is more active in generating NAD+ during glycerol metabolism within the microcompartment by resting cells, while ADH7 functions to balance NAD+/NADH by converting 3-HPA to 1,3-PDO outside the microcompartment in the growing cells. Moreover, evaluation of ADH6 deletion mutant showed strong decrease in ethanol level, supporting the role of this bifuctional alcohol/aldehyde dehydrogenase in ethanol production. To the best of our knowledge, this is the first report revealing both internal and external recycling for cofactor homeostasis during 3-HPA conversion in L. reuteri. PMID- 28030591 TI - Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron Like Cells and Localize to Lysosomes. AB - Parkinson's disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein. PMID- 28030592 TI - A Novel Missense Mutation 224G>T (R75M) in SRY Coding Region Interferes with Nuclear Import and Results in 46, XY Complete Gonadal Dysgenesis. AB - SRY-mutation-caused sex reversal is a rare disease and mostly associated with a de novo mutation since the patients with defective SRY is infertile. There are many reports about SRY-mutation associated 46, XY ovarian disorder of sex development (DSD), but few described their molecular mechanism. Here we report a de novo mutation 224G>T (R75M) in SRY associated with a phenotypic female, 46, XY karyotype and dysgerminoma. The wild and mutated SRY were cloned into recombinant plasmid and expressed in cells in vitro, the result showed the mutated SRY is greatly accumulated in cytoplasm while the wild type SRY is mostly localized in nucleus. To make sure no other genes were involved, we performed the trio-based whole exome sequencing using the DNA samples from the proband and the parents, and no mutations were identified especially in DHH, NR0B1, NR5A1, SOX9 and MAP3K1, indicating the de novo mutation in SRY is the single defect responsible for the female sex reversal. We also used bioinformatics simulation analysis to predict impact of the mutation on SRY function, and find the R75 in wild type SRY can form a hydrogen bond with serine at 91 (S91) that make the SRY protein well fit into the minor groove of target DNA, while the M75 in the mutated SRY can't. Finally, we reviewed SRY mutations based on the available references and analyzed the mutation distribution patterns according to density and continuity, which may be useful for further study of the SRY structure, function, and its relatedness with DSD. PMID- 28030593 TI - Identifying Children at Risk of High Myopia Using Population Centile Curves of Refraction. AB - PURPOSE: To construct reference centile curves of refraction based on population based data as an age-specific severity scale to evaluate their efficacy as a tool for identifying children at risk of developing high myopia in a longitudinal study. METHODS: Data of 4218 children aged 5-15 years from the Guangzhou Refractive Error Study in Children (RESC) study, and 354 first-born twins from the Guangzhou Twin Eye Study (GTES) with annual visit were included in the analysis. Reference centile curves for refraction were constructed using a quantile regression model based on the cycloplegic refraction data from the RESC. The risk of developing high myopia (spherical equivalent <= -6 diopters [D]) was evaluated as a diagnostic test using the twin follow-up data. RESULTS: The centile curves suggested that the 3rd, 5th, and 10th percentile decreased from 0.25 D, 0.00 D and 0.25 D in 5 year-olds to -6.00 D, -5.65D and -4.63 D in 15 year-olds in the population-based data from RESC. In the GTES cohort, the 5th centile showed the most effective diagnostic value with a sensitivity of 92.9%, a specificity of 97.9% and a positive predictive value (PPV) of 65.0% in predicting high myopia onset (<=-6.00D) before the age of 15 years. The PPV was highest (87.5%) in 3rd centile but with only 50.0% sensitivity. The Mathew's correlation coefficient of 5th centile in predicting myopia of -6.0D/-5.0D/-4.0D by age of 15 was 0.77/0.51/0.30 respectively. CONCLUSIONS: Reference centile curves provide an age-specific estimation on a severity scale of refractive error in school-aged children. Children located under lower percentiles at young age were more likely to have high myopia at 15 years or probably in adulthood. PMID- 28030594 TI - Understanding Misclassification between Neonatal Deaths and Stillbirths: Empirical Evidence from Malawi. AB - Improving the counting of stillbirths and neonatal deaths is important to tracking Sustainable Development Goal 3.2 and improving vital statistics in low- and middle-income countries (LMICs). However, the validity of self-reported stillbirths and neonatal deaths in surveys is often threatened by misclassification errors between the two birth outcomes. We assessed the extent and correlates of stillbirths being misclassified as neonatal deaths by comparing two recent and linked population surveys conducted in Malawi, one being a full birth history (FBH) survey, and the other a follow-up verbal/social autopsy (VASA) survey. We found that one-fifth of 365 neonatal deaths identified in the FBH survey were classified as stillbirths in the VASA survey. Neonatal deaths with signs of movements in the last few days before delivery reported were less likely to be misclassified stillbirths (OR = 0.08, p<0.05). Having signs of birth injury was found to be associated with higher odds of misclassification (OR = 6.17, p<0.05). We recommend replicating our study with larger sample size in other settings. Additionally, we recommend conducting validation studies to confirm accuracy and completeness of live births and neonatal deaths reported in household surveys with events reported in a full birth history and the extent of underestimation of neonatal mortality resulting from misclassifications. Questions on fetal movement, signs of life at delivery and improved probing among older mother may be useful to improve accuracy of reported events. PMID- 28030595 TI - Prognosis for Hospitalized Patients with Systemic Lupus Erythematosus in China: 5 Year Update of the Jiangsu Cohort. AB - OBJECTIVE: To identify early signs associated with poor prognosis in Chinese patients with systemic lupus erythematosus (SLE) through a large population-based follow-up study. METHODS: Medical records of > 2,500 SLE patients that first hospitalized between 1999-2009 were collected from 26 centers across Jiangsu province, China, and entered into a database. These patients were followed-up for 5 to 15 years, and those remained contact and had known survival status in 2015 were assessed for the association of factors presented at the initial hospitalization with mortality at two time points (<=1year and > 1year). The independency of mortality factors was evaluated using multivariate Cox regression analysis. RESULTS: Among 1,372 patients we assessed, 92.3% were women and 17.2% were deceased in 2015. The main causes of death were infection (30.1%), neuropsychiatric impairment (14.8%), renal failure (14.4%) and cardiopulmonary involvement (8.5%). Hazard ratios (HR) of independent predictors for mortality (<=1year and > 1year, respectively) included hospital presentation of neuropsychiatric involvement (2.03 and 1.91), cardiopulmonary involvement (1.94 and 1.61) and increased serum creatinine (2.52 and 2.58). Patients older than 45 years and with disease durations more than 2 years at admission had unfavorable short-term outcome (HR 1.76 and 1.79), while the presence of anti-dsDNA and anti Sm antibodies indicated diverse prognosis after 1 year (HR 1.60 and 0.45). Treatment with cyclophosphamide was beneficial for patient's first-year outcome (HR 0.50), and anti-malarial drugs significantly reduced the risk of mortality over different time points (HR 0.48 and 0.54). SLEDAI score, proteinuria or hypocomplementemia was not independently associated with the outcome in this cohort. CONCLUSION: SLE patients presented with vital organ damages rather than active disease at initial hospitalization are likely to have a poor outcome, especially for those with neuropsychiatric, cardiopulmonary involvements and renal insufficiency. Early and effective intervention with the use of anti malarial drugs may decrease mortality. PMID- 28030596 TI - Phase-Shift Dynamics of Sea Urchin Overgrazing on Nutrified Reefs. AB - Shifts from productive kelp beds to impoverished sea urchin barrens occur globally and represent a wholesale change to the ecology of sub-tidal temperate reefs. Although the theory of shifts between alternative stable states is well advanced, there are few field studies detailing the dynamics of these kinds of transitions. In this study, sea urchin herbivory (a 'top-down' driver of ecosystems) was manipulated over 12 months to estimate (1) the sea urchin density at which kelp beds collapse to sea urchin barrens, and (2) the minimum sea urchin density required to maintain urchin barrens on experimental reefs in the urbanised Port Phillip Bay, Australia. In parallel, the role of one of the 'bottom-up' drivers of ecosystem structure was examined by (3) manipulating local nutrient levels and thus attempting to alter primary production on the experimental reefs. It was found that densities of 8 or more urchins m-2 (>= 427 g m-2 biomass) lead to complete overgrazing of kelp beds while kelp bed recovery occurred when densities were reduced to <= 4 urchins m-2 (<= 213 g m-2 biomass). This experiment provided further insight into the dynamics of transition between urchin barrens and kelp beds by exploring possible tipping-points which in this system can be found between 4 and 8 urchins m-2 (213 and 427 g m-2 respectively). Local enhancement of nutrient loading did not change the urchin density required for overgrazing or kelp bed recovery, as algal growth was not affected by nutrient enhancement. PMID- 28030597 TI - ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase. AB - Inhibition of glycolysis is of great potential for the treatment of cancer. However, inhibitors of glycolytic enzymes with favorable pharmacological profiles have not been forthcoming. Due to the nature of their active sites, most high affinity transition-state analogue inhibitors of glycolysis enzymes are highly polar with poor cell permeability. A recent publication reported a novel, non active site inhibitor of the glycolytic enzyme Enolase, termed ENOblock (N-[2-[2 2-aminoethoxy)ethoxy]ethyl]4-4-cyclohexylmethyl)amino]6-4 fluorophenyl)methyl]amino]1,3,5-triazin-2-yl]amino]benzeneacetamide). This would present a major advance, as this is heterocyclic and fully cell permeable molecule. Here, we present evidence that ENOblock does not inhibit Enolase enzymatic activity in vitro as measured by three different assays, including a novel 31P NMR based method which avoids complications associated with optical interferences in the UV range. Indeed, we note that due to strong UV absorbance, ENOblock interferes with the direct spectrophotometric detection of the product of Enolase, phosphoenolpyruvate. Unlike established Enolase inhibitors, ENOblock does not show selective toxicity to ENO1-deleted glioma cells in culture. While our data do not dispute the biological effects previously attributed to ENOblock, they indicate that such effects must be caused by mechanisms other than direct inhibition of Enolase enzymatic activity. PMID- 28030598 TI - Instantaneous Metabolic Cost of Walking: Joint-Space Dynamic Model with Subject Specific Heat Rate. AB - A subject-specific model of instantaneous cost of transport (ICOT) is introduced from the joint-space formulation of metabolic energy expenditure using the laws of thermodynamics and the principles of multibody system dynamics. Work and heat are formulated in generalized coordinates as functions of joint kinematic and dynamic variables. Generalized heat rates mapped from muscle energetics are estimated from experimental walking metabolic data for the whole body, including upper-body and bilateral data synchronization. Identified subject-specific energetic parameters-mass, height, (estimated) maximum oxygen uptake, and (estimated) maximum joint torques-are incorporated into the heat rate, as opposed to the traditional in vitro and subject-invariant muscle parameters. The total model metabolic energy expenditure values are within 5.7 +/- 4.6% error of the measured values with strong (R2 > 0.90) inter- and intra-subject correlations. The model reliably predicts the characteristic convexity and magnitudes (0.326 0.348) of the experimental total COT (0.311-0.358) across different subjects and speeds. The ICOT as a function of time provides insights into gait energetic causes and effects (e.g., normalized comparison and sensitivity with respect to walking speed) and phase-specific COT, which are unavailable from conventional metabolic measurements or muscle models. Using the joint-space variables from commonly measured or simulated data, the models enable real-time and phase specific evaluations of transient or non-periodic general tasks that use a range of (aerobic) energy pathway similar to that of steady-state walking. PMID- 28030599 TI - Climate-Smart Livestock Systems: An Assessment of Carbon Stocks and GHG Emissions in Nicaragua. AB - Livestock systems in the tropics can contribute to mitigate climate change by reducing greenhouse gas (GHG) emissions and increasing carbon accumulation. We quantified C stocks and GHG emissions of 30 dual-purpose cattle farms in Nicaragua using farm inventories and lifecycle analysis. Trees in silvo-pastoral systems were the main C stock above-ground (16-24 Mg ha-1), compared with adjacent secondary forests (43 Mg C ha-1). We estimated that methane from enteric fermentation contributed 1.6 kg CO2-eq., and nitrous oxide from excreta 0.4 kg CO2-eq. per kg of milk produced. Seven farms that we classified as climate-smart agriculture (CSA) out of 16 farms had highest milk yields (6.2 kg cow-1day-1) and lowest emissions (1.7 kg CO2-eq. per kg milk produced). Livestock on these farms had higher-quality diets, especially during the dry season, and manure was managed better. Increasing the numbers of CSA farms and improving CSA technology will require better enabling policy and incentives such as payments for ecosystem services. PMID- 28030600 TI - Isoniazid Mono-Resistant Tuberculosis: Impact on Treatment Outcome and Survival of Pulmonary Tuberculosis Patients in Southern Mexico 1995-2010. AB - BACKGROUND: Isoniazid mono-resistance (IMR) is the most common form of mono resistance; its world prevalence is estimated to range between 0.0 to 9.5% globally. There is no consensus on how these patients should be treated. OBJECTIVE: To describe the impact of IMR tuberculosis (TB) on treatment outcome and survival among pulmonary TB patients treated under programmatic conditions in Orizaba, Veracruz, Mexico. MATERIALS AND METHODS: We conducted a prospective cohort study of pulmonary TB patients in Southern Mexico. From 1995 to 2010 patients with acid-fast bacilli or culture proven Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and microbiological evaluation. We included patients who harbored isoniazid mono-resistant (IMR) strains and patients with strains susceptible to isoniazid, rifampicin, ethambutol and streptomycin. All patients were treated following Mexican TB Program guidelines. We performed annual follow-up to ascertain treatment outcome, recurrence, relapse and mortality. RESULTS: Between 1995 and 2010 1,243 patients with pulmonary TB were recruited; 902/1,243 (72.57%) had drug susceptibility testing; 716 (79.38%) harbored pan-susceptible and 88 (9.75%) IMR strains. Having any contact with a person with TB (adjusted odds ratio (aOR)) 1.85, 95% Confidence interval (CI) 1.15-2.96) and homelessness (adjusted odds ratio (aOR) 2.76, 95% CI 1.08-6.99) were associated with IMR. IMR patients had a higher probability of failure (adjusted hazard ratio (HR) 12.35, 95% CI 3.38-45.15) and death due to TB among HIV negative patients (aHR 3.30. 95% CI 1.00-10.84). All the models were adjusted for socio-demographic and clinical variables. CONCLUSIONS: The results from our study provide evidence that the standardized treatment schedule with first line drugs in new and previously treated cases with pulmonary TB and IMR produces a high frequency of treatment failure and death due to tuberculosis. We recommend re-evaluating the optimal schedule for patients harboring IMR. It is necessary to strengthen scientific research for the evaluation of alternative treatment schedules in similar settings. PMID- 28030601 TI - Calcium Mass Balance during Citrate Hemodialysis: A Randomized Controlled Trial Comparing Normal and Low Ionized Calcium Target Ranges. AB - BACKGROUND: Regional citrate anticoagulation (RCA) during hemodialysis interferes with calcium homeostasis. Optimal ionized calcium (iCa) target range during RCA and consequent calcium balance are unknown. METHODS: In a randomized controlled trial (ACTRN12613001029785) 30 chronic hemodialysis patients were assigned to normal (1.1-1.2 mmol/) or low (0.95-1.05 mmol/l) iCa target range during a single hemodialysis with RCA. The primary outcome was calcium mass balance during the procedure, using a partial spent dialysate collection method; magnesium mass balance was also measured. Intact parathormone (iPTH), total calcium (tCa) and magnesium were measured before and after procedures. RESULTS: Mean iCa during procedures was significantly different in the two groups (1.12+/-0.06 in normal and 1.06+/-0.07 mmol/l in low iCa group, p <0.001), resulting in different tCa (2.18+/-0.22 vs. 1.95+/-0.17, p = 0.003) after the procedure. Mean delivered calcium during the procedure was 58.3+/-4.8 mmol in the normal and 51.5+/-8.2 mmol in the low iCa group (p = 0.010), which resulted in a significantly higher mean positive calcium mass balance of 14.6+/-8.3 mmol (584+/-333 mg) per procedure in normal as compared to 7.2+/-8.5 mmol (290+/-341 mg) in low iCa group (p = 0.024). Linear mixed effects model showed a significant interaction effect of time and iCa target range group on iPTH, i.e. a significant increase in iPTH in the low as compared to normal iCa target group (p = 0.008). Magnesium mass balance was mildly negative and comparable in both groups. CONCLUSIONS: Low iCa target range resulted in a significantly less positive calcium mass balance, but in a significant increase in iPTH. To achieve a more neutral calcium balance, we recommend allowing a mild hypocalcemia during hemodialysis with RCA, especially when it is used for prolonged periods. PMID- 28030602 TI - Structural and Biochemical Characterization of Chlamydia trachomatis DsbA Reveals a Cysteine-Rich and Weakly Oxidising Oxidoreductase. AB - The Gram negative bacteria Chlamydia trachomatis is an obligate intracellular human pathogen that can cause pelvic inflammatory disease, infertility and blinding trachoma. C. trachomatis encodes a homolog of the dithiol oxidoreductase DsbA. Bacterial DsbA proteins introduce disulfide bonds to folding proteins providing structural bracing for secreted virulence factors, consequently these proteins are potential targets for antimicrobial drugs. Despite sharing functional and structural characteristics, the DsbA enzymes studied to date vary widely in their redox character. In this study we show that the truncated soluble form of the predicted membrane anchored protein C. trachomatis DsbA (CtDsbA) has oxidase activity and redox properties broadly similar to other characterized DsbA proteins. However CtDsbA is distinguished from other DsbAs by having six cysteines, including a second disulfide bond, and an unusual dipeptide sequence in its catalytic motif (Cys-Ser-Ala-Cys). We report the 2.7 A crystal structure of CtDsbA revealing a typical DsbA fold, which is most similar to that of DsbA-II type proteins. Consistent with this, the catalytic surface of CtDsbA is negatively charged and lacks the hydrophobic groove found in EcDsbA and DsbAs from other enterobacteriaceae. Biochemical characterization of CtDsbA reveals it to be weakly oxidizing compared to other DsbAs and with only a mildly destabilizing active site disulfide bond. Analysis of the crystal structure suggests that this redox character is consistent with a lack of contributing factors to stabilize the active site nucleophilic thiolate relative to more oxidizing DsbA proteins. PMID- 28030603 TI - Reliable Refuge: Two Sky Island Scorpion Species Select Larger, Thermally Stable Retreat Sites. AB - Sky island scorpions shelter under rocks and other surface debris, but, as with other scorpions, it is unclear whether these species select retreat sites randomly. Furthermore, little is known about the thermal preferences of scorpions, and no research has been done to identify whether reproductive condition might influence retreat site selection. The objectives were to (1) identify physical or thermal characteristics for retreat sites occupied by two sky island scorpions (Vaejovis cashi Graham 2007 and V. electrum Hughes 2011) and those not occupied; (2) determine whether retreat site selection differs between the two study species; and (3) identify whether thermal selection differs between species and between gravid and non-gravid females of the same species. Within each scorpion's habitat, maximum dimensions of rocks along a transect line were measured and compared to occupied rocks to determine whether retreat site selection occurred randomly. Temperature loggers were placed under a subset of occupied and unoccupied rocks for 48 hours to compare the thermal characteristics of these rocks. Thermal gradient trials were conducted before parturition and after dispersal of young in order to identify whether gravidity influences thermal preference. Vaejovis cashi and V. electrum both selected larger retreat sites that had more stable thermal profiles. Neither species appeared to have thermal preferences influenced by reproductive condition. However, while thermal selection did not differ among non-gravid individuals, gravid V. electrum selected warmer temperatures than its gravid congener. Sky island scorpions appear to select large retreat sites to maintain thermal stability, although biotic factors (e.g., competition) could also be involved in this choice. Future studies should focus on identifying the various biotic or abiotic factors that could influence retreat site selection in scorpions, as well as determining whether reproductive condition affects thermal selection in other arachnids. PMID- 28030604 TI - Burden and Determinants of Smoking among Prisoners with Respiratory Tract Infection: A Cross-Sectional Study of Nine Major Prison Setups in Northern Ethiopia. AB - BACKGROUND: Morbidity, mortality and a wide range of associated risk factors are disproportionately clustered among prisoners compared to the general population. Smoking is one of the risk factors for the increased burden of unfavorable health outcomes particularly among prisoners. However, little is known about the level and determinants of smoking among the incarcerated population in Ethiopia. METHODS: We collected data from 738 prisoners in nine major prison setups in Tigray region by nurses and clinical officers. Data were entered in to Epi Data 3.1 and exported to stata 13.0 for cleaning and further analysis. Multivariable logistic regression model was fitted to identify determinants of smoking at p value of less than 5%. RESULT: The prevalence of smoking was 21 per cent (95%CI = 18.2%, 24.1). Urban residence (AOR = 2.15; 95%CI = 1.20, 3.84), previous history of incarceration (AOR = 1.91; 95%CI = 1.08, 3.40) and alcohol use before incarcerated (AOR = 4.20; 95%CI = 2.57, 6.87) were significantly associated with risk of smoking. In contrast, risk of smoking was significantly lower for farmers (AOR = 0.20; 95% CI = 0.08, 0.49), prisoners with family support (AOR = 0.52; 95% CI = 0.32, 0.87) and for those who were jailed in Shire prison site (AOR = 0.43; 95%CI = 0.20, 0.95). CONCLUSION: Our work clearly indicates that the observed smoking prevalence calls for the need of comprehensive and interdisciplinary interventions targeting prisoners. PMID- 28030605 TI - Correction: Longitudinal Metagenomic Analysis of Hospital Air Identifies Clinically Relevant Microbes. AB - [This corrects the article DOI: 10.1371/journal.pone.0160124.]. PMID- 28030606 TI - Body Condition Peaks at Intermediate Parasite Loads in the Common Bully Gobiomorphus cotidianus. AB - Most ecologists and conservationists perceive parasitic infections as deleterious for the hosts. Their effects, however, depend on many factors including host body condition, parasite load and the life cycle of the parasite. More research into how multiple parasite taxa affect host body condition is required and will help us to better understand host-parasite coevolution. We used body condition indices, based on mass-length relationships, to test the effects that abundances and biomasses of six parasite taxa (five trematodes, Apatemon sp., Tylodelphys sp., Stegodexamene anguillae, Telogaster opisthorchis, Coitocaecum parvum, and the nematode Eustrongylides sp.) with different modes of transmission have on the body condition of their intermediate or final fish host, the common bully Gobiomorphus cotidianus in New Zealand. We used two alternative body condition methods, the Scaled Mass Index (SMI) and Fulton's condition factor. General linear and hierarchical partitioning models consistently showed that fish body condition varied strongly across three lakes and seasons, and that most parasites did not have an effect on the two body condition indices. However, fish body condition showed a highly significant humpbacked relationship with the total abundance of all six parasite taxa, mostly driven by Apatemon sp. and S. anguillae, indicating that the effects of these parasites can range from positive to negative as abundance increases. Such a response was also evident in models including total parasite biomass. Our methodological comparison supports the SMI as the most robust mass-length method to examine the effects of parasitic infections on fish body condition, and suggests that linear, negative relationships between host condition and parasite load should not be assumed. PMID- 28030607 TI - Evolutionary Dynamics of Tumor-Stroma Interactions in Multiple Myeloma. AB - Cancer cells and stromal cells cooperate by exchanging diffusible factors that sustain tumor growth, a form of frequency-dependent selection that can be studied in the framework of evolutionary game theory. In the case of multiple myeloma, three types of cells (malignant plasma cells, osteoblasts and osteoclasts) exchange growth factors with different effects, and tumor-stroma interactions have been analysed using a model of cooperation with pairwise interactions. Here we show that a model in which growth factors have autocrine and paracrine effects on multiple cells, a more realistic assumption for tumor-stroma interactions, leads to different results, with implications for disease progression and treatment. In particular, the model reveals that reducing the number of malignant plasma cells below a critical threshold can lead to their extinction and thus to restore a healthy balance between osteoclast and osteoblast, a result in line with current therapies against multiple myeloma. PMID- 28030608 TI - Predicting Hospitalised Paediatric Pneumonia Mortality Risk: An External Validation of RISC and mRISC, and Local Tool Development (RISC-Malawi) from Malawi. AB - BACKGROUND: Pneumonia is the leading infectious cause of under-5 mortality in sub Saharan Africa. Clinical prediction tools may aide case classification, triage, and allocation of hospital resources. We performed an external validation of two published prediction tools and compared this to a locally developed tool to identify children admitted with pneumonia at increased risk for in-hospital mortality in Malawi. METHODS: We retrospectively analyzed the performance of the Respiratory Index of Severity in Children (RISC) and modified RISC (mRISC) scores in a child pneumonia dataset prospectively collected during routine care at seven hospitals in Malawi between 2011-2014. RISC has both an HIV-infected and HIV uninfected tool. A local score (RISC-Malawi) was developed using multivariable logistic regression with missing data multiply imputed using chained equations. Score performances were assessed using c-statistics, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood statistics. RESULTS: 16,475 in-patient pneumonia episodes were recorded (case-fatality rate (CFR): 3.2%), 9,533 with complete data (CFR: 2.0%). The c-statistic for the RISC (HIV-uninfected) score, used to assess its ability to differentiate between children who survived to discharge and those that died, was 0.72. The RISC-Malawi score, using mid-upper arm circumference as an indicator of malnutrition severity, had a c-statistic of 0.79. We were unable to perform a comprehensive external validation of RISC (HIV-infected) and mRISC as both scores include parameters that were not routinely documented variables in our dataset. CONCLUSION: In our population of Malawian children with WHO-defined pneumonia, the RISC (HIV-uninfected) score identified those at high risk for in-hospital mortality. However the refinement of parameters and resultant creation of RISC Malawi improved performance. Next steps include prospectively studying both scores to determine if incorporation into routine care delivery can have a meaningful impact on in-hospital CFRs of children with WHO-defined pneumonia. PMID- 28030609 TI - Impact of Exhaled Breath Acetone in the Prognosis of Patients with Heart Failure with Reduced Ejection Fraction (HFrEF). One Year of Clinical Follow-up. AB - BACKGROUND: The identification of new biomarkers of heart failure (HF) could help in its treatment. Previously, our group studied 89 patients with HF and showed that exhaled breath acetone (EBA) is a new noninvasive biomarker of HF diagnosis. However, there is no data about the relevance of EBA as a biomarker of prognosis. OBJECTIVES: To evaluate whether EBA could give prognostic information in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: After breath collection and analysis by gas chromatography-mass spectrometry and by spectrophotometry, the 89 patients referred before were followed by one year. Study physicians, blind to the results of cardiac biomarker testing, ascertained vital status of each study participant at 12 months. RESULTS: The composite endpoint death and heart transplantation (HT) were observed in 35 patients (39.3%): 29 patients (32.6%) died and 6 (6.7%) were submitted to HT within 12 months after study enrollment. High levels of EBA (>=3.7MUg/L, 50th percentile) were associated with a progressively worse prognosis in 12-month follow-up (log rank = 11.06, p = 0.001). Concentrations of EBA above 3.7MUg/L increased the risk of death or HT in 3.26 times (HR = 3.26, 95%CI = 1.56-6.80, p = 0.002) within 12 months. In a multivariable cox regression model, the independent predictors of all-cause mortality were systolic blood pressure, respiratory rate and EBA levels. CONCLUSIONS: High EBA levels could be associated to poor prognosis in HFrEF patients. PMID- 28030610 TI - Impact of Chronic Smoking on Meibomian Gland Dysfunction. AB - PURPOSE: The aim of this study was to explore the relationship between chronic cigarette smoking and meibomian gland dysfunction (MGD). METHODS: This study enrolled 322 smokers with MGD and 2067 non-smokers with MGD. All enrolled subjects were tested in the following sequence: Ocular Surface Disease Index (OSDI), tear film breakup time (TBUT), corneal fluorescein staining (CFS), Schirmer I test (SIT)and finally slit-lamp microscope examination of lid margin abnormalities, meibomian gland expression as well as meibum. RESULTS: Compared with the MGD patients without smoking, the MGD patients with smoking had significantly increased scores of lid margin abnormality and meibum (P<0.01 for each comparison). No significant difference was noted in OSDI, TBUT, CFS, SIT or the score of Meibomian gland expressibility between the smokers and non-smokers (P>0.05 for each comparison). In the smokers, the smoking index was significantly correlated with the scores of lid margin abnormality (Both sexes, R = 0.19, P<0.01; Male, R = 0.18, P<0.01) and meibum (Both sexes, R = 0.29, P<0.01; Male, R = 0.20, P<0.01), whereas it was not significantly correlated with OSDI, TBUT, CFS, SIT or score of Meibomian gland expressibility (P>0.05 for each comparison). CONCLUSION: The findings of this study suggest chronic smoking might be associated with MGD. PMID- 28030611 TI - Silibinin Inhibits Platelet-Derived Growth Factor-Driven Cell Proliferation via Downregulation of N-Glycosylation in Human Tenon's Fibroblasts in a Proteasome Dependent Manner. AB - The objective of this study was to evaluate the effects of silibinin on cell proliferation in platelet-derived growth factor (PDGF)-treated human Tenon's fibroblasts (HTFs). The effect of silibinin on cell proliferation in PDGF-treated HTFs was determined by examining the expression of proliferating cell nuclear antigen (PCNA) and performing WST-1 assays. Cell cycle progression was evaluated using flow cytometry. The related cyclins and cyclin-dependent kinases (CDKs) were also analyzed using western blot. A modified rat trabeculectomy model was established to evaluate the effect of silibinin on cell proliferation in vivo. Western blot analysis was carried out to determine the effect of silibinin on the expression of PDGF receptor and on the downstream signaling pathways regulated by PDGF receptor. PDGF elevated the expression of PCNA in HTFs, and this elevation was inhibited by silibinin. The inhibitory effect of silibinin on cell proliferation was also confirmed via WST-1 assay. PDGF-stimulated cell cycle in HTFs was delayed by silibinin, and the related cyclin D1 and CDK4 were also suppressed by silibinin. In the rat model of trabeculectomy, silibinin reduced the expression of PCNA at the site of blebs in vivo. The effects of silibinin on PDGF-stimulated HTFs were mediated via the downregulation of PDGF receptor regulated signaling pathways, such as ERKs and STATs, which may be partially caused by the downregulation of N-glycosylation of PDGF receptor beta (PDGFRbeta). The effect of silibinin on modulation of N-glycosylation of PDGFRbeta was mediated in a proteasome-dependent manner. Silibinin inhibited cell proliferation and delayed cell cycle progression in PDGF-treated HTFs in vitro. PDGF also modulated the process of N-glycosylation of the PDGFRbeta in a proteasome-dependent manner. Our findings suggest that silibinin has potential therapeutic applications in glaucoma filtering surgery. PMID- 28030613 TI - The Effects of Earphone Use and Environmental Lead Exposure on Hearing Loss in the Korean Population: Data Analysis of the Korea National Health and Nutrition Examination Survey (KNHANES), 2010-2013. AB - BACKGROUND: Although previous studies have reported that frequent earphone use and lead exposure are risk factors for hearing loss, most of these studies were limited to small populations or animal experiments. Several studies that presented the joint effect of combined exposure of noise and heavy metal on hearing loss were also mainly conducted on occupational workers exposed to high concentration. OBJECTIVES: We investigated both the individual and joint effects of earphone use and environmental lead exposure on hearing loss in the Korean general population. METHODS: We analyzed data from 7,596 Koreans provided by the Korea National Health and Nutrition Examination Survey (KNHANES) during the period 2010-2013. The pure-tone average (PTA) of hearing thresholds at 2, 3, and 4 kHz frequencies was computed, and hearing loss was defined as a PTA >= 25 dB in one or both ears. RESULTS: A dose-response relationship in hearing loss with earphone use time and blood lead level is observed after adjustment for confounding factors. With a 1-hour increase in earphone use time and 1 MUg/dL increase in blood lead concentration, the odds of hearing loss increased by 1.19 and 1.43 times, respectively. For hearing loss, the additive and multiplicative effect of earphone use and blood lead level were not statistically significant. CONCLUSIONS: Earphone use and environmental lead exposure have an individual effect on hearing loss in the general population. However, the estimated joint effect of earphone use and lead exposure was not statistically significant. PMID- 28030612 TI - Distinct and Shared Endophenotypes of Neural Substrates in Bipolar and Major Depressive Disorders. AB - Little is known about disorder-specific biomarkers of bipolar disorder (BD) and major depressive disorder (MDD). Our aim was to determine a neural substrate that could be used to distinguish BD from MDD. Our study included a BD group (10 patients with BD, 10 first-degree relatives (FDRs) of individuals with BD), MDD group (17 patients with MDD, 17 FDRs of individuals with MDD), and 27 healthy individuals. Structural and functional brain abnormalities were evaluated by voxel-based morphometry and a trail making test (TMT), respectively. The BD group showed a significant main effect of diagnosis in the gray matter (GM) volume of the anterior cingulate cortex (ACC; p = 0.01) and left insula (p < 0.01). FDRs of individuals with BD showed significantly smaller left ACC GM volume than healthy subjects (p < 0.01), and patients with BD showed significantly smaller ACC (p < 0.01) and left insular GM volume (p < 0.01) than healthy subjects. The MDD group showed a tendency toward a main effect of diagnosis in the right and left insular GM volume. The BD group showed a significantly inverse correlation between the left insular GM volume and TMT-A scores (p < 0.05). Our results suggest that the ACC volume could be a distinct endophenotype of BD, while the insular volume could be a shared BD and MDD endophenotype. Moreover, the insula could be associated with cognitive decline and poor outcome in BD. PMID- 28030614 TI - Identification and Cloning of Differentially Expressed SOUL and ELIP Genes in Saffron Stigmas Using a Subtractive Hybridization Approach. AB - Using a subtractive hybridization approach, differentially expressed genes involved in the light response in saffron stigmas were identified. Twenty-two differentially expressed transcript-derived fragments were cloned and sequenced. Two of them were highly induced by light and had sequence similarity to early inducible proteins (ELIP) and SOUL heme-binding proteins. Using these sequences, we searched for other family members expressed in saffron stigma. ELIP and SOUL are represented by small gene families in saffron, with four and five members, respectively. The expression of these genes was analyzed during the development of the stigma and in light and dark conditions. ELIP transcripts were detected in all the developmental stages showing much higher expression levels in the developed stigmas of saffron and all were up-regulated by light but at different levels. By contrast, only one SOUL gene was up-regulated by light and was highly expressed in the stigma at anthesis. Both the ELIP and SOUL genes induced by light in saffron stigmas might be associated with the structural changes affecting the chromoplast of the stigma, as a result of light exposure, which promotes the development and increases the number of plastoglobules, specialized in the recruitment of specific proteins, which enables them to act in metabolite synthesis and disposal under changing environmental conditions and developmental stages. PMID- 28030615 TI - Does Mental Health Status Influence Susceptibility to the Physiologic Effects of Air Pollution? A Population Based Study of Canadian Children. AB - BACKGROUND: Both air pollution exposure and the presence of mental illness are associated with an increased risk of physical illness. OBJECTIVE: To determine whether or not children with less favourable mental health are more susceptible to pulmonary and cardiovascular effects of ambient air pollution, compared to those who are mentally healthy. METHODS: We carried out a cross-sectional study of 1,883 children between the ages of 6 and 17 years of age who participated in the Canadian Health Measures population survey between 2007 and 2009. Subjects were assigned the air pollution values obtained from the National Air Pollution monitor closest to their neighborhood. Lung function, heart rate and blood pressure were stratified by indicators of mental health. The latter were ascertained by questions about feelings of happiness, a diagnosed mood disorder, and the emotional symptom subscale of the Strengths and Difficulties Questionnaire. RESULTS: Among those who reported a mood disorder, an interquartile increase in ozone was associated with increases in systolic and diastolic pressures of 3.8 mmHg (95% CI 1.6, 5.9) and 3.0mmHg (95%CI 0.9, 5.2) respectively, and a decreases in FVC of 7.6% (95% CI 2.9, 12.3). No significant changes in these variables were observed in those who did not report a mood disorder. Among those with unfavourable emotional symptoms, ozone was associated with a 6.4% (95% CI 1.7, 11.3) increase in heart rate, a 4.1% (95%CI 1.2, 7.1) increase in systolic blood pressure, and a 6.0% (95% CI 1.4, 10.6) decrease in FEVl. No significant effect was seen in these variables among those with no emotional symptoms. CONCLUSIONS: In the Canadian population, children who report mood disorders or unfavourable emotional symptoms appear to be more vulnerable to the adverse physiologic effects of air pollution. PMID- 28030616 TI - Rare CNVs in Suicide Attempt include Schizophrenia-Associated Loci and Neurodevelopmental Genes: A Pilot Genome-Wide and Family-Based Study. AB - Suicidal behavior (SB) has a complex etiology involving genes and environment. One of the genetic components in SB could be copy number variations (CNVs), as CNVs are implicated in neurodevelopmental disorders. However, a recently published genome-wide and case-control study did not observe any significant role of CNVs in SB. Here we complemented these initial observations by instead using a family-based trio-sample that is robust to control biases, having severe suicide attempt (SA) in offspring as main outcome (n = 660 trios). We first tested for CNV associations on the genome-wide Illumina 1M SNP-array by using FBAT-CNV methodology, which allows for evaluating CNVs without reliance on CNV calling algorithms, analogous to a common SNP-based GWAS. We observed association of certain T-cell receptor markers, but this likely reflected inter-individual variation in somatic rearrangements rather than association with SA outcome. Next, we used the PennCNV software to call 385 putative rare (<1%) and large (>100 kb) CNVs, observed in n = 225 SA offspring. Nine SA offspring had rare CNV calls in a set of previously schizophrenia-associated loci, indicating the importance of such CNVs in certain SA subjects. Several additional, very large (>1MB) sized CNV calls in 15 other SA offspring also spanned pathogenic regions or other neural genes of interest. Overall, 45 SA had CNVs enriched for 65 medically relevant genes previously shown to be affected by CNVs, which were characterized by a neurodevelopmental biology. A neurodevelopmental implication was partly congruent with our previous SNP-based GWAS, but follow-up analysis here indicated that carriers of rare CNVs had a decreased burden of common SNP risk-alleles compared to non-carriers. In conclusion, while CNVs did not show genome-wide association by the FBAT-CNV methodology, our preliminary observations indicate rare pathogenic CNVs affecting neurodevelopmental functions in a subset of SA, who were distinct from SA having increased SNP risk-allele burden. These observations may open up new avenues in the genetic etiology of SB. PMID- 28030617 TI - Sublethal Effects of Imidacloprid on Honey Bee Colony Growth and Activity at Three Sites in the U.S. AB - Imidacloprid is a neonicotinoid pesticide heavily used by the agricultural industry and shown to have negative impacts on honey bees above certain concentrations. We evaluated the effects of different imidacloprid concentrations in sugar syrup using cage and field studies, and across different environments. Honey bee colonies fed sublethal concentrations of imidicloprid (0, 5, 20 and 100 ppb) over 6 weeks in field trials at a desert site (Arizona), a site near intensive agriculture (Arkansas) and a site with little nearby agriculture but abundant natural forage (Mississippi) were monitored with respect to colony metrics, such as adult bee and brood population sizes, as well as pesticide residues. Hive weight and internal hive temperature were monitored continuously over two trials in Arizona. Colonies fed 100 ppb imidacloprid in Arizona had significantly lower adult bee populations, brood surface areas and average frame weights, and reduced temperature control, compared to colonies in one or more of the other treatment groups, and consumption rates of those colonies were lower compared to other colonies in Arizona and Arkansas, although no differences in capped brood or average frame weight were observed among treatments in Arkansas. At the Mississippi site, also rich in alternative forage, colonies fed 5 ppb imidacloprid had less capped brood than control colonies, but contamination of control colonies was detected. In contrast, significantly higher daily hive weight variability among colonies fed 5 ppb imidacloprid in Arizona suggested greater foraging activity during a nectar flow post treatment, than any other treatment group. Imidacloprid concentrations in stored honey corresponded well with the respective syrup concentrations fed to the colonies and remained stable within the hive for at least 7 months after the end of treatment. PMID- 28030618 TI - Whole-Genome Resequencing of Holstein Bulls for Indel Discovery and Identification of Genes Associated with Milk Composition Traits in Dairy Cattle. AB - The use of whole-genome resequencing to obtain more information on genetic variation could produce a range of benefits for the dairy cattle industry, especially with regard to increasing milk production and improving milk composition. In this study, we sequenced the genomes of eight Holstein bulls from four half- or full-sib families, with high and low estimated breeding values (EBVs) of milk protein percentage and fat percentage at an average effective depth of 10*, using Illumina sequencing. Over 0.9 million nonredundant short insertions and deletions (indels) [1-49 base pairs (bp)] were obtained. Among them, 3,625 indels that were polymorphic between the high and low groups of bulls were revealed and subjected to further analysis. The vast majority (76.67%) of these indels were novel. Follow-up validation assays confirmed that most (70%) of the randomly selected indels represented true variations. The indels that were polymorphic between the two groups were annotated based on the cattle genome sequence assembly (UMD3.1.69); as a result, nearly 1,137 of them were found to be located within 767 annotated genes, only 5 (0.138%) of which were located in exons. Then, by integrated analysis of the 767 genes with known quantitative trait loci (QTL); significant single-nucleotide polymorphisms (SNPs) previously identified by genome-wide association studies (GWASs) to be associated with bovine milk protein and fat traits; and the well-known pathways involved in protein, fat synthesis, and metabolism, we identified a total of 11 promising candidate genes potentially affecting milk composition traits. These were FCGR2B, CENPE, RETSAT, ACSBG2, NFKB2, TBC1D1, NLK, MAP3K1, SLC30A2, ANGPT1 and UGDH. Our findings provide a basis for further study and reveal key genes for milk composition traits in dairy cattle. PMID- 28030619 TI - Effects of Propidium Monoazide (PMA) Treatment on Mycobiome and Bacteriome Analysis of Cystic Fibrosis Airways during Exacerbation. AB - INTRODUCTION AND PURPOSE: Propidium monoazide (PMA)-pretreatment has increasingly been applied to remove the bias from dead or damaged cell artefacts, which could impact the microbiota analysis by high-throughput sequencing. Our study aimed to determine whether a PMA-pretreatment coupled with high-throughput sequencing analysis provides a different picture of the airway mycobiome and bacteriome. RESULTS AND DISCUSSION: We compared deep-sequencing data of mycobiota and microbiota of 15 sputum samples from 5 cystic fibrosis (CF) patients with and without prior PMA-treatment of the DNA-extracts. PMA-pretreatment had no significant effect on the entire and abundant bacterial community (genera expressed as operational taxonomic units (OTUs) with a relative abundance greater than or equal to 1%), but caused a significant difference in the intermediate community (less than 1%) when analyzing the alpha biodiversity Simpson index (p = 0.03). Regarding PMA impact on the airway mycobiota evaluated for the first time here; no significant differences in alpha diversity indexes between PMA-treated and untreated samples were observed. Regarding beta diversity analysis, the intermediate communities also differed more dramatically than the total and abundant ones when studying both mycobiome and bacteriome. Our results showed that only the intermediate (or low abundance) population diversity is impacted by PMA-treatment, and therefore that abundant taxa are mostly viable during acute exacerbation in CF. Given such a cumbersome protocol (PMA-pretreatment coupled with high-throughput sequencing), we discuss its potential interest within the follow-up of CF patients. Further studies using PMA-pretreatment are warranted to improve our "omic" knowledge of the CF airways. PMID- 28030620 TI - Simulating Heterogeneous Tumor Cell Populations. AB - Certain tumor phenomena, like metabolic heterogeneity and local stable regions of chronic hypoxia, signify a tumor's resistance to therapy. Although recent research has shed light on the intracellular mechanisms of cancer metabolic reprogramming, little is known about how tumors become metabolically heterogeneous or chronically hypoxic, namely the initial conditions and spatiotemporal dynamics that drive these cell population conditions. To study these aspects, we developed a minimal, spatially-resolved simulation framework for modeling tissue-scale mixed populations of cells based on diffusible particles the cells consume and release, the concentrations of which determine their behavior in arbitrarily complex ways, and on stochastic reproduction. We simulate cell populations that self-sort to facilitate metabolic symbiosis, that grow according to tumor-stroma signaling patterns, and that give rise to stable local regions of chronic hypoxia near blood vessels. We raise two novel questions in the context of these results: (1) How will two metabolically symbiotic cell subpopulations self-sort in the presence of glucose, oxygen, and lactate gradients? We observe a robust pattern of alternating striations. (2) What is the proper time scale to observe stable local regions of chronic hypoxia? We observe the stability is a function of the balance of three factors related to O2 diffusion rate, local vessel release rate, and viable and hypoxic tumor cell consumption rate. We anticipate our simulation framework will help researchers design better experiments and generate novel hypotheses to better understand dynamic, emergent whole-tumor behavior. PMID- 28030621 TI - HIV Clinical Pathway: A New Approach to Combine Guidelines and Sustainability of Anti-Retroviral Treatment in Italy. AB - The present article describes the case study of a "real world" HIV practice within the debate concerning the strategic role of Clinical Governance (CG) tools in the management of a National Healthcare System's sustainability. The study aimed at assessing the impact of a Clinical Pathway (CP) implementation, required by the Regional Healthcare Service, in terms of effectiveness (virological and immunological conditions) and efficiency (economic resources absorption), from the budget holder perspective. Data derived from a multi-centre cohort of patients treated in 6 Hospitals that provided care to approximately 42% of the total HIV+ patients, in Lombardy Region, Italy. Two phases were compared: Pre-CP (2009-2010) vs. Post-CP implementation (2011-2012). All HIV infected adults, observed in the participating hospitals during the study periods, were enrolled and stratified into the 3 categories defined by the Regional CP: first-line, switch for toxicity/other, and switch for failure. The study population was composed of 1,284 patients (Pre-CP phase) and 1,135 patients (Post-CP phase). The results showed that the same level of virological and immunological effectiveness was guaranteed to HIV+ patients: 81.2% of Pre-CP phase population and 83.2% of Post-CP phase population had undetectable HIV-RNA (defined as <50 copies/mL) at 12-month follow up. CD4+ cell counts increased by 28 +/- 4 cells/mm3 in Pre-CP Phase and 39 +/- 5 cells/mm3 in Post-CP Phase. From an economic point of view, the CP implementation led to a substantial advantage: the mean total costs related to the management of the HIV disease (ART, hospital admission and laboratory tests) decreased (-8.60%) in the Post-CP phase (p-value < 0.0001). Results confirmed that the CP provided appropriateness and quality of care, with a cost reduction for the budget holder. PMID- 28030622 TI - Effects of Menthol Supplementation in Feedlot Cattle Diets on the Fecal Prevalence of Antimicrobial-Resistant Escherichia coli. AB - The pool of antimicrobial resistance determinants in the environment and in the gut flora of cattle is a serious public health concern. In addition to being a source of human exposure, these bacteria can transfer antibiotic resistance determinants to pathogenic bacteria and endanger the future of antimicrobial therapy. The occurrence of antimicrobial resistance genes on mobile genetic elements, such as plasmids, facilitates spread of resistance. Recent work has shown in vitro anti-plasmid activity of menthol, a plant-based compound with the potential to be used as a feed additive to beneficially alter ruminal fermentation. The present study aimed to determine if menthol supplementation in diets of feedlot cattle decreases the prevalence of multidrug-resistant bacteria in feces. Menthol was included in diets of steers at 0.3% of diet dry matter. Fecal samples were collected weekly for 4 weeks and analyzed for total coliforms counts, antimicrobial susceptibilities, and the prevalence of tet genes in E. coli isolates. Results revealed no effect of menthol supplementation on total coliforms counts or prevalence of E. coli resistant to amoxicillin, ampicillin, azithromycin, cefoxitin, ceftiofur, ceftriaxone, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfisoxazole, and sulfamethoxazole; however, 30 days of menthol addition to steer diets increased the prevalence of tetracycline-resistant E. coli (P < 0.02). Although the mechanism by which menthol exerts its effects remains unclear, results of our study suggest that menthol may have an impact on antimicrobial resistance in gut bacteria. PMID- 28030623 TI - Genome-Wide Association Study for Muscle Fat Content and Abdominal Fat Traits in Common Carp (Cyprinus carpio). AB - Muscle fat content is an important phenotypic trait in fish, as it affects the nutritional, technical and sensory qualities of flesh. To identify loci and candidate genes associated with muscle fat content and abdominal fat traits, we performed a genome-wide association study (GWAS) using the common carp 250 K SNP assay in a common carp F2 resource population. A total of 18 loci surpassing the genome-wide suggestive significance level were detected for 4 traits: fat content in dorsal muscle (MFdo), fat content in abdominal muscle (MFab), abdominal fat weight (AbFW), and AbFW as a percentage of eviscerated weight (AbFP). Among them, one SNP (carp089419) affecting both AbFW and AbFP reached the genome-wide significance level. Ten of those loci were harbored in or near known genes. Furthermore, relative expressions of 5 genes related to MFdo were compared using dorsal muscle samples with high and low phenotypic values. The results showed that 4 genes were differentially expressed between the high and low phenotypic groups. These genes are, therefore, prospective candidate genes for muscle fat content: ankyrin repeat domain 10a (ankrd10a), tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 (tanc2), and four jointed box 1 (fjx1) and choline kinase alpha (chka). These results offer valuable insights into the complex genetic basis of fat metabolism and deposition. PMID- 28030624 TI - Pseudomonas aeruginosa Microcolonies in Coronary Thrombi from Patients with ST Segment Elevation Myocardial Infarction. AB - Chronic infection is associated with an increased risk of atherothrombotic disease and direct bacterial infection of arteries has been suggested to contribute to the development of unstable atherosclerotic plaques. In this study, we examined coronary thrombi obtained in vivo from patients with ST-segment elevation myocardial infarction (STEMI) for the presence of bacterial DNA and bacteria. Aspirated coronary thrombi from 22 patients with STEMI were collected during primary percutaneous coronary intervention and arterial blood control samples were drawn from radial or femoral artery sheaths. Analyses were performed using 16S polymerase chain reaction and with next-generation sequencing to determine bacterial taxonomic classification. In selected thrombi with the highest relative abundance of Pseudomonas aeruginosa DNA, peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) with universal and species specific probes was performed to visualize bacteria within thrombi. From the taxonomic analysis we identified a total of 55 different bacterial species. DNA from Pseudomonas aeruginosa represented the only species that was significantly associated with either thrombi or blood and was >30 times more abundant in thrombi than in arterial blood (p<0.0001). Whole and intact bacteria present as biofilm microcolonies were detected in selected thrombi using universal and P. aeruginosa-specific PNA-FISH probes. P. aeruginosa and vascular biofilm infection in culprit lesions may play a role in STEMI, but causal relationships remain to be determined. PMID- 28030625 TI - Use of the Method of Triads in the Validation of Sodium and Potassium Intake in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - INTRODUCTION: Biomarkers are a good choice to be used in the validation of food frequency questionnaire due to the independence of their random errors. OBJECTIVE: To assess the validity of the potassium and sodium intake estimated using the Food Frequency Questionnaire ELSA-Brasil. SUBJECTS/METHODS: A subsample of participants in the ELSA-Brasil cohort was included in this study in 2009. Sodium and potassium intake were estimated using three methods: Semi-quantitative food frequency questionnaire, 12-hour nocturnal urinary excretion and three 24 hour food records. Correlation coefficients were calculated between the methods, and the validity coefficient was calculated using the method of triads. The 95% confidence intervals for the validity coefficient were estimated using bootstrap sampling. Exact and adjacent agreement and disagreement of the estimated sodium and potassium intake quintiles were compared among three methods. RESULTS: The sample consisted of 246 participants, aged 53+/-8 years, 52% of women. Validity coefficient for sodium were considered weak (rfood frequency questionnaire actual intake = 0.37 and rbiomarker actual intake = 0.21) and moderate (rfood records actual intake 0.56). The validity coefficient were higher for potassium (rfood frequency questionnaire actual intake = 0.60; rbiomarker actual intake = 0.42; rfood records actual intake = 0.79). Conclusions: The Food Frequency Questionnaire ELSA-Brasil showed good validity in estimating potassium intake in epidemiological studies. For sodium validity was weak, likely due to the non quantification of the added salt to prepared food. PMID- 28030626 TI - Increased Incidence of Thyroid Disease in Patients with Celiac Disease: A Systematic Review and Meta-Analysis. AB - The prevalence of thyroid disease is likely increased among individuals with celiac disease (CD). In addition, exposure to gluten-free treatment may be associated with a risk of thyroid disease, but this association remains controversial. A systematic review was performed to evaluate the association between thyroid disease and CD. The articles were obtained from the PubMed, Web of Science, Embase, and Chinese WanFang bibliographical databases for the period up to May 2016. The results were analysed in a meta-analysis with odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). There were 13 articles in this meta-analysis, including 15629 CD cases and 79342 controls. Overall, the prevalence of thyroid disease in patients with CD was significantly increased compared with that in the control groups (OR 3.08, 95% CI 2.67-3.56, P<0.001). Moreover, there was no significant difference in the OR between the gluten-treated and untreated groups (OR 1.08, 95% CI 0.61-1.92, P = 0.786). The results of our meta-analysis support the hypothesis that the prevalence of thyroid disease in patients with CD is increased compared with that in controls, which suggests that CD patients should be screened for thyroid disease. The effect of gluten-free treatment on thyroid disease needs further investigation. PMID- 28030627 TI - The Effect of Random Error on Diagnostic Accuracy Illustrated with the Anthropometric Diagnosis of Malnutrition. AB - BACKGROUND: It is often thought that random measurement error has a minor effect upon the results of an epidemiological survey. Theoretically, errors of measurement should always increase the spread of a distribution. Defining an illness by having a measurement outside an established healthy range will lead to an inflated prevalence of that condition if there are measurement errors. METHODS AND RESULTS: A Monte Carlo simulation was conducted of anthropometric assessment of children with malnutrition. Random errors of increasing magnitude were imposed upon the populations and showed that there was an increase in the standard deviation with each of the errors that became exponentially greater with the magnitude of the error. The potential magnitude of the resulting error of reported prevalence of malnutrition were compared with published international data and found to be of sufficient magnitude to make a number of surveys and the numerous reports and analyses that used these data unreliable. CONCLUSIONS: The effect of random error in public health surveys and the data upon which diagnostic cut-off points are derived to define "health" has been underestimated. Even quite modest random errors can more than double the reported prevalence of conditions such as malnutrition. Increasing sample size does not address this problem, and may even result in less accurate estimates. More attention needs to be paid to the selection, calibration and maintenance of instruments, measurer selection, training & supervision, routine estimation of the likely magnitude of errors using standardization tests, use of statistical likelihood of error to exclude data from analysis and full reporting of these procedures in order to judge the reliability of survey reports. PMID- 28030628 TI - Estimation of the Heteroskedastic Canonical Contagion Model with Instrumental Variables. AB - Knowledge of contagion among economies is a relevant issue in economics. The canonical model of contagion is an alternative in this case. Given the existence of endogenous variables in the model, instrumental variables can be used to decrease the bias of the OLS estimator. In the presence of heteroskedastic disturbances this paper proposes the use of conditional volatilities as instruments. Simulation is used to show that the homoscedastic and heteroskedastic estimators which use them as instruments have small bias. These estimators are preferable in comparison with the OLS estimator and their asymptotic distribution can be used to construct confidence intervals. PMID- 28030629 TI - Co-Activation of Th17 and Antibody Responses Provides Efficient Protection against Mucosal Infection by Group A Streptococcus. AB - Conserved protein antigens among serotypes of group A Streptococcus pyogenes (GAS) have been focused for vaccine development because of the diversity of GAS serotypes and risks of autoimmunity post-GAS infection. Precise delineation of protective immune response to each of GAS antigens is critical for vaccine efficacy and safety. We recently reported that immunization with SrtA of GAS provides Th17-dependent clearance of heterologous serotypes of GAS in NALT. SCPA is a surface virulence molecule of GAS and known to induce antibody-mediated protection against GAS. We hypothesized that co-immunization with SrtA and SCPA would provide more efficient protection by eliciting combined Th17 and antibody responses. The present study showed that mice that were intranasally co-immunized with SrtA/SCPA cleared GAS more efficiently than the mice that were immunized with either SrtA or SCPA individually, and as efficient as the mice that experienced repeated GAS infections. The co-immunization induced Th17 and robust SCPA antibody responses, accompanied by a rapid influx of neutrophils and high myeloperoxidase activity in NALT, suggesting that simultaneous induction of mucosal Th17 and neutralizing antibody responses offers more effective GAS elimination through rapid infiltration and activation of neutrophils. Moreover, Th17 response was strongly induced in mice that experienced repeated GAS infection and maintained at a high level even after the bacteria were cleared; whereas, it was moderately induced and promptly returned to baseline following bacterial elimination in SrtA/SCPA co-immunized mice. Additional results showed that the survival rate of systemic challenge was significantly higher in infection experienced than in co-immunized mice, indicating that more immune elements are required for protection against systemic than mucosal GAS infection. PMID- 28030630 TI - System-Wide Adaptations of Desulfovibrio alaskensis G20 to Phosphate-Limited Conditions. AB - The prevalence of lipids devoid of phosphorus suggests that the availability of phosphorus limits microbial growth and activity in many anoxic, stratified environments. To better understand the response of anaerobic bacteria to phosphate limitation and starvation, this study combines microscopic and lipid analyses with the measurements of fitness of pooled barcoded transposon mutants of the model sulfate reducing bacterium Desulfovibrio alaskensis G20. Phosphate limited G20 has lower growth rates and replaces more than 90% of its membrane phospholipids by a mixture of monoglycosyl diacylglycerol (MGDG), glycuronic acid diacylglycerol (GADG) and ornithine lipids, lacks polyphosphate granules, and synthesizes other cellular inclusions. Analyses of pooled and individual mutants reveal the importance of the high-affinity phosphate transport system (the Pst system), PhoR, and glycolipid and ornithine lipid synthases during phosphate limitation. The phosphate-dependent synthesis of MGDG in G20 and the widespread occurrence of the MGDG/GADG synthase among sulfate reducing ?-Proteobacteria implicate these microbes in the production of abundant MGDG in anaerobic environments where the concentrations of phosphate are lower than 10 MUM. Numerous predicted changes in the composition of the cell envelope and systems involved in transport, maintenance of cytoplasmic redox potential, central metabolism and regulatory pathways also suggest an impact of phosphate limitation on the susceptibility of sulfate reducing bacteria to other anthropogenic or environmental stresses. PMID- 28030631 TI - Impact of Audio-Visual Asynchrony on Lip-Reading Effects -Neuromagnetic and Psychophysical Study. AB - The effects of asynchrony between audio and visual (A/V) stimuli on the N100m responses of magnetoencephalography in the left hemisphere were compared with those on the psychophysical responses in 11 participants. The latency and amplitude of N100m were significantly shortened and reduced in the left hemisphere by the presentation of visual speech as long as the temporal asynchrony between A/V stimuli was within 100 ms, but were not significantly affected with audio lags of -500 and +500 ms. However, some small effects were still preserved on average with audio lags of 500 ms, suggesting similar asymmetry of the temporal window to that observed in psychophysical measurements, which tended to be more robust (wider) for audio lags; i.e., the pattern of visual-speech effects as a function of A/V lag observed in the N100m in the left hemisphere grossly resembled that in psychophysical measurements on average, although the individual responses were somewhat varied. The present results suggest that the basic configuration of the temporal window of visual effects on auditory-speech perception could be observed from the early auditory processing stage. PMID- 28030633 TI - Correction: Sources and Dynamics of Inorganic Carbon within the Upper Reaches of the Xi River Basin, Southwest China. AB - [This corrects the article DOI: 10.1371/journal.pone.0160964.]. PMID- 28030632 TI - Contribution of 1p, 19q, 9p and 10q Automated Analysis by FISH to the Diagnosis and Prognosis of Oligodendroglial Tumors According to WHO 2016 Guidelines. AB - OBJECTIVE: To study the feasibility and the diagnostic and prognostic interest of automated analysis of 1p, 19q, 9p and 10q status by FISH technique in oligodendroglial tumors. METHODS: We analyzed a retrospective series of 33 consecutive gliomas with oligodendroglial histology (originally diagnosed as 24 oligodendrogliomas and 9 oligoastrocytomas). For all cases, automated FISH analysis of 1p, 19q, 9p and 10q status were performed and compared to clinical and histological data, ATRX, IDH1R132H and alpha-internexin status (studied by immunohistochemistry) and overall survival (OS). Manual analysis of 9p and 10q status were also performed and compared to automated analysis to verify the concordance of the two methods. RESULTS: The 33 gliomas were reclassified into 13 low-grade oligodendrogliomas (OII), 10 anaplastic oligodendrogliomas (OIII), 3 diffuse astrocytomas (AII), 3 anaplastic astrocytomas (AIII) and 4 glioblastomas (GBM) according to the WHO 2016 histological criteria. The 1p and/or 19q imbalanced status were restricted to astrocytomas with no correlation to their grade or their OS. Chromosome 9p deletion was restricted to OIII (70%) and GBM (100%) and was correlated with a shorter OS in the total cohort (p = 0.0007), the oligodendroglioma cohort (p = 0.03) and the astrocytoma cohort (p = 0.001). Concordance between 9p manual and automated analysis was satisfactory (81%, kappa = 0.69). Chromosome 10q deletion was restricted to GBMs (50%) and was correlated with a poor OS in both the total cohort (p = 0.003) and the astrocytoma (AS) cohort (p = 0.04). Concordance between manual and automated analysis was satisfactory (79%, kappa = 0.62). CONCLUSION: Automated analysis of 1p, 19q, 9p and 10q status by FISH is a reliable technique which allows for refined classification of oligodendroglial tumors. 1p and/or 19q imbalanced status is evidence of astrocytic differentiation. 9p deletion is found in high grade oligodendrogliomas and astrocytomas with a poor OS. 10q is related to GBM status and a poor OS. PMID- 28030634 TI - Evaluation of Direct Colorimetric MTT Assay for Rapid Detection of Rifampicin and Isoniazid Resistance in Mycobacterium tuberculosis. AB - With the spread of multidrug-resistant tuberculosis (MDR-TB) strains there is an increasing need for new accurate and cost-effective methods for a rapid diagnostic and drug susceptibility testing (DST), particularly in low-income countries where tuberculosis is hyperendemic. A colorimetric assay using 3-(4, 5 dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) has been suggested as a promising method for DST, especially to rifampicin. In this study, we standardized and evaluated the MTT assay for a rapid direct detection of rifampicin and isoniazid resistant Mycobacterium tuberculosis strains from sputum specimens using Lowenstein-Jensen (LJ) culture medium as a gold standard. The MTT assay sensitivity, specificity, positive and negative predictive values for rifampicin were 100%, 86%, 100%, 99%, respectively. For isoniazid, the MTT assay had a 100% sensitivity, specificity, positive and negative predictive values. Interestingly, the MTT assay gave interpretable results within two weeks for 94% of the samples compared to 7-14 weeks for LJ media. Overall, an excellent agreement was observed between MTT assay and LJ proportion method (Kappa, 0.91 for rifampicin and 1.00 for isoniazid). In conclusion, the direct colorimetric MTT assay simultaneously detects susceptible and resistant strains of M. tuberculosis within three weeks. It significantly shortens the time required to obtain a DST result and could be a reliable alternative method for rapid detection of drug-resistant TB strains in high-TB-burden resource-limited settings. PMID- 28030635 TI - Expression and Prognostic Value of Oct-4 in Astrocytic Brain Tumors. AB - BACKGROUND: Glioblastomas are the most frequent type of malignant primary brain tumor with a median overall survival less than 15 months. Therapy resistance of glioblastomas has been attributed to the presence of tumor initiating stem-like cells (TSCs). TSC-related markers have therefore been suggested to have promising potentials as prognostic markers in gliomas. METHODOLOGY/PRINCIPAL FINDINGS: The aim of the present study was to investigate the expression and prognostic impact of the TSC-related marker Oct-4 in astrocytic brain tumors of increasing grade. In total 114 grade II, III and IV astrocytic brain tumors were immunohistochemically stained for Oct-4, and the fraction and intensity of Oct-4 positive cells were determined by morphometric analysis of full tumor sections. Oct-4 was expressed in all tumors, and the Oct-4 positive cell fraction increased with tumor grade (p = 0.045). There was no association between survival and Oct-4 positive cell fraction, neither when combining all tumor grades nor in analysis of individual grades. Oct-4 intensity was not associated with grade, but taking IDH1 status into account we found a tendency for high Oct-4 intensity to be associated with poor prognosis in anaplastic astrocytomas. Double immunofluorescence stainings showed co-localization in the perivascular niches of Oct-4 and two other TSC markers CD133 and nestin in glioblastomas. In some areas Oct-4 was expressed independently of CD133 and nestin. CONCLUSIONS: In conclusion, high Oct-4 fraction was associated with tumor malignancy, but seemed to be without independent prognostic influence in glioblastomas. Identification of a potential prognostic value in anaplastic astrocytomas requires additional studies using larger patient cohorts. PMID- 28030636 TI - Natal Host Plants Can Alter Herbivore Competition. AB - Interspecific competition between herbivores is widely recognized as an important determinant of community structure. Although researchers have identified a number of factors capable of altering competitive interactions, few studies have addressed the influence of neighboring plant species. If adaptation to/ epigenetic effects of an herbivore's natal host plant alter its performance on other host plants, then interspecific herbivore interactions may play out differently in heterogeneous and homogenous plant communities. We tested wether the natal host plant of a whitefly population affected interactions between the Middle-east Asia Minor 1 (MEAM1) and Mediterranean (MED) cryptic species of the whitefly Bemisia tabaci by rearing the offspring of a cabbage-derived MEAM1 population and a poinsettia-derived MED population together on three different host plants: cotton, poinsettia, and cabbage. We found that MED dominated on poinsettia and that MEAM1 dominated on cabbage, results consistent with previous research. MED also dominated when reared with MEAM1 on cotton, however, a result at odds with multiple otherwise-similar studies that reared both species on the same natal plant. Our work provides evidence that natal plants affect competitive interactions on another plant species, and highlights the potential importance of neighboring plant species on herbivore community composition in agricultral systems. PMID- 28030637 TI - Quality Matters: Influences of Citrus Flush Physicochemical Characteristics on Population Dynamics of the Asian Citrus Psyllid (Hemiptera: Liviidae). AB - Studies were conducted to relate the influence of the physical characteristics, leaf nutrient content and phloem sap amino acid concentration of citrus flush shoots on the densities of various Diaphorina citri life stages. Adult D. citri preferentially selected young shoots for feeding and numbers of D. citri immatures were positively correlated with flush shoot softness. Young flush shoots had higher concentrations of macro and micro nutrients relative to mature ones and this was associated with higher densities of all D. citri life stages. All D. citri life stages were positively correlated with higher nitrogen-carbon (N:C), nitrogen:sulfur (N:S) and nitrogen:calcium (N:Ca) ratios in leaf tissue, while densities of adults were negatively related to calcium, manganese and boron levels. Concentrations of total and essential amino acids were highest in phloem sap of young expanding flush shoots in both grapefruit and lemon, but dramatically declined as flush shoots matured. The sulfur-containing amino acids cystine, methionine and taurine occurred only in younger flush shoots. In contrast, cystathionine was only present in phloem sap of mature shoots. These results clearly indicate that young citrus flush shoots are a nutritionally richer diet relative to mature shoots, thus explaining their preference by D. citri for feeding and reproduction. Conversely, tissue hardness and the lower nutritional quality of mature flush shoots may limit oviposition and immature development. The data suggest that both physical characteristics and nutritional composition of flush shoots and their phloem sap are important factors regulating host colonization and behavior of D. citri, and this interaction can impact the dynamics and spread of HLB in citrus groves. PMID- 28030638 TI - Effects of Intracranial Pressure Monitoring on Mortality in Patients with Severe Traumatic Brain Injury: A Meta-Analysis. AB - BACKGROUND: The Brain Trauma Foundation (BTF) guidelines published in 2007 suggest some indications for intracranial pressure (ICP) monitoring in severe traumatic brain injury (TBI). However, some studies had not shown clinical benefit in patients with severe TBI; several studies had even reported that ICP monitoring was associated with an increased mortality rate. The effect of ICP monitoring has remained controversial, regardless of the ICP monitoring guidelines. Here we performed a meta-analysis of published studies to assess the effects of ICP monitoring in patients with severe TBI. METHODS: We searched three comprehensive databases, the Cochrane Library, PUBMED, and EMBASE, for studies without limitations published up to September 2015. Mortality, ICU LOS, and hospital LOS were analyzed with Review Manager software according to data from the included studies. RESULTS: Eighteen eligible studies involving 25229 patients with severe TBI were included in our meta-analysis. The results indicated no significant reduction in the ICP monitored group in mortality (hospitalized before 2007), hospital mortality (hospitalized before 2007), mortality in randomized controlled trials. However, overall mortality, mortality (hospitalized after 2007), hospital mortality (hospitalized after 2007), mortality in observational studies (hospitalized after 2007), 2-week mortality, 6-month mortality, were reduced in ICP monitored group. Patients with an increased ICP were more likely to require ICP monitoring. CONCLUSION: Superior survival was observed in severe TBI patients with ICP monitoring since the third edition of "Guidelines for the Management of Severe Traumatic Brain Injury," which included "Indications for intracranial pressure monitoring," was published in 2007. PMID- 28030639 TI - Limits to Causal Inference with State-Space Reconstruction for Infectious Disease. AB - Infectious diseases are notorious for their complex dynamics, which make it difficult to fit models to test hypotheses. Methods based on state-space reconstruction have been proposed to infer causal interactions in noisy, nonlinear dynamical systems. These "model-free" methods are collectively known as convergent cross-mapping (CCM). Although CCM has theoretical support, natural systems routinely violate its assumptions. To identify the practical limits of causal inference under CCM, we simulated the dynamics of two pathogen strains with varying interaction strengths. The original method of CCM is extremely sensitive to periodic fluctuations, inferring interactions between independent strains that oscillate with similar frequencies. This sensitivity vanishes with alternative criteria for inferring causality. However, CCM remains sensitive to high levels of process noise and changes to the deterministic attractor. This sensitivity is problematic because it remains challenging to gauge noise and dynamical changes in natural systems, including the quality of reconstructed attractors that underlie cross-mapping. We illustrate these challenges by analyzing time series of reportable childhood infections in New York City and Chicago during the pre-vaccine era. We comment on the statistical and conceptual challenges that currently limit the use of state-space reconstruction in causal inference. PMID- 28030640 TI - Patterns of Bat Distribution and Foraging Activity in a Highly Urbanized Temperate Environment. AB - Understanding how to manage biodiversity in urban areas will become increasingly important as density of humans residing in urban centers increases and urban areas expand. While considerable research has documented the shifts in biodiversity along urbanization gradients, much less work has focused on how characteristics of dense urban centers, effectively novel environments, influence behavior and biodiversity. Urban bats in San Francisco provide an opportunity to document changes in behavior and biodiversity to very high-density development. We studied (1) the distribution and abundance of bat foraging activity in natural areas; and (2) characteristics of natural areas that influence the observed patterns of distribution and foraging activity. We conducted acoustic surveys of twenty-two parks during 2008-2009. We confirmed the presence of four species of bats (Tadarida brasiliensis, Myotis yumanensis, Lasiurus blossevillii, and M. lucifugus). T. brasiliensis were found in all parks, while M. yumanensis occurred in 36% of parks. Results indicate that proximity to water, park size, and amount of forest edge best explained overall foraging activity. Proximity to water best explained species richness. M. yumanensis activity was best explained by reduced proportion of native vegetation as well as proximity to water. Activity was year round but diminished in December. We show that although bats are present even in very densely populated urban centers, there is a large reduction in species richness compared to that of outlying areas, and that most habitat factors explaining their community composition and activity patterns are similar to those documented in less urbanized environments. PMID- 28030641 TI - Validation of Synthetic CRISPR Reagents as a Tool for Arrayed Functional Genomic Screening. AB - To date, lentiviral-based CRISPR-Cas9 screens have largely been conducted in pooled format. However, numerous assays are not amenable to pooled approaches, and lentiviral screening in arrayed format presents many challenges. We sought to examine synthetic CRISPR reagents in the context of arrayed screening. Experiments were performed using aberrant DNA replication as an assay. Using synthetic CRISPR RNAs targeting the known control gene GMNN in HCT-116 cells stably expressing Cas9, we observed statistically significant phenotype among the majority of transfected cells within 72 hours. Additional studies revealed near complete loss of GMNN protein and editing of GMNN DNA. We next conducted a screen of synthetic CRISPR RNAs directed against 640 ubiquitin-related genes. Screening identified known and novel DNA replication regulators that were also supported by siRNA gene knockdown. Notably, CRISPR screening identified more statistically significant hits than corresponding siRNA screens run in parallel. These results highlight the possibility of using synthetic CRISPR reagents as an arrayed screening tool. PMID- 28030642 TI - A High Level of Soluble CD40L Is Associated with P. aeruginosa Infection in Patients with Cystic Fibrosis. AB - OBJECTIVE: The aim of this study was to evaluate whether the concentration of sCD40L, a product of platelet activation, correlates with the presence of Pseudomonas aeruginosa in the airway of patients with cystic fibrosis (CF) and to determine its possible clinical association. METHODS: Sixty patients with CF, ranging in age from 2 months to 36 years, were studied. The demographics, cystic fibrosis transmembrane conductance regulator (CFTR) genotype, spirometry measurements, radiographic and tomographic scans, platelet count in peripheral blood, sCD40L, IL-6, TNF-alpha and ICAM1 data were collected. Infection colonization of the airway was evaluated using sputum and throat swab cultures; the levels of anti-Pseudomonas aeruginosa antibodies (Anti-PaAb) were evaluated. RESULTS: Patients with CF and chronic colonization had anti-PaAb values of 11.6 +/- 2.1 ELISA units (EU) and sCD40L in plasma of 1530.9 +/-1162.3 pg/mL; those with intermittent infection had 5.7 +/- 2.7 EU and 2243.6 +/- 1475.9 pg/mL; and those who were never infected had 3.46 +/- 1.8 EU (p<=0.001) and 1008.1 +/- 746.8 pg/mL (p<=0.01), respectively. The cutoff value of sCD40L of 1255 pg/mL was associated with an area under the ROC (receiver operating characteristic curve) of 0.84 (95% CI, 0.71 to 0.97), reflecting P. aeruginosa infection with a sensitivity of 73% and a specificity of 89%. Lung damage was determined using the Brasfield Score, the Bhalla Score, and spirometry (FVC%, FEV1%) and found to be significantly different among the groups (p<=0.001). CONCLUSION: Circulating sCD40L levels are increased in patients with cystic fibrosis and P. aeruginosa infection. Soluble CD40L appears to reflect infection and provides a tool for monitoring the evolution of lung deterioration. PMID- 28030643 TI - Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder. AB - FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10-4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior. PMID- 28030644 TI - Timing and Location of Medical Emergency Team Activation Is Associated with Seriousness of Outcome: An Observational Study in a Tertiary Care Hospital. AB - PURPOSE: The medical emergency team (MET) can be activated anytime and anywhere in a hospital. We hypothesized the timing and location of MET activation are associated with seriousness of outcome. MATERIALS AND METHODS: We tested for an association of clinical outcomes with timing and location using a university hospital cohort in Japan (n = 328). The primary outcome was short-term serious outcome (unplanned ICU admission after MET activation or death at scene). RESULTS: Patients for whom the MET was activated in the evening or night-time had significantly higher rates of short-term serious outcome than those for whom it was activated during the daytime (vs. evening: adjusted OR = 2. 53, 95% CI = 1.24 5.13, P = 0.010; night-time: adjusted OR = 2.45, 95% CI = 1.09-5.50, P = 0.030). Patients for whom the MET was activated in public space had decreased short-term serious outcome compared to medical spaces (public space: adjusted OR = 0.19, 95% CI = 0.07-0.54, P = 0.0017). Night-time (vs. daytime) and medical space (vs. public space) were significantly associated with higher risks of unexpected cardiac arrest and 28-day mortality. CONCLUSIONS: Patients for whom the MET was activated in the evening/night-time, or in medical space, had a higher rate of short-term serious outcomes. Taking measures against these risk factors may improve MET performance. PMID- 28030645 TI - Disruption of Lipid Raft Function Increases Expression and Secretion of Monocyte Chemoattractant Protein-1 in 3T3-L1 Adipocytes. AB - The adipocyte is unique in its capacity to store lipids. In addition to triglycerides, the adipocyte stores a significant amount of cholesterol. Moreover, obese adipocytes are characterized by a redistribution of cholesterol with depleted cholesterol in the plasma membrane, suggesting that cholesterol perturbation may play a role in adipocyte dysfunction. We used methyl-beta cyclodextrin (MbetaCD), a molecule with high affinity for cholesterol, to rapidly deplete cholesterol level in differentiated 3T3-L1 adipocytes. We tested whether this perturbation altered adipocyte secretion of monocyte chemoattractant protein 1 (MCP-1), a chemokine that is elevated in obesity and is linked to obesity associated chronic diseases. Depletion of cholesterol by MbetaCD increased MCP-1 secretion as well as the mRNA and protein levels, suggesting perturbation at biosynthesis and secretion. Pharmacological inhibition revealed that NF-kappaB, but not MEK, p38 and JNK, was involved in MbetaCD-stimulated MCP-1 biosynthesis and secretion in adipocytes. Finally, another cholesterol-binding drug, filipin, also induced MCP-1 secretion without altering membrane cholesterol level. Interestingly, both MbetaCD and filipin disturbed the integrity of lipid rafts, the membrane microdomains enriched in cholesterol. Thus, the depletion of membrane cholesterol in obese adipocytes may result in dysfunction of lipid rafts, leading to the elevation of proinflammatory signaling and MCP-1 secretion in adipocytes. PMID- 28030646 TI - Tree Circumference Dynamics in Four Forests Characterized Using Automated Dendrometer Bands. AB - Stem diameter is one of the most commonly measured attributes of trees, forming the foundation of forest censuses and monitoring. Changes in tree stem circumference include both irreversible woody stem growth and reversible circumference changes related to water status, yet these fine-scale dynamics are rarely leveraged to understand forest ecophysiology and typically ignored in plot or stand-scale estimates of tree growth and forest productivity. Here, we deployed automated dendrometer bands on 12-40 trees at four different forested sites-two temperate broadleaf deciduous, one temperate conifer, and one tropical broadleaf semi-deciduous-to understand how tree circumference varies on time scales of hours to months, how these dynamics relate to environmental conditions, and whether the structure of these variations might introduce substantive error into estimates of woody growth. Diurnal stem circumference dynamics measured over the bark commonly-but not consistently-exhibited daytime shrinkage attributable to transpiration-driven changes in stem water storage. The amplitude of this shrinkage was significantly correlated with climatic variables (daily temperature range, vapor pressure deficit, and radiation), sap flow and evapotranspiration. Diurnal variations were typically <0.5 mm circumference in amplitude and unlikely to be of concern to most studies of tree growth. Over time scales of multiple days, the bands captured circumference increases in response to rain events, likely driven by combinations of increased stem water storage and bark hydration. Particularly at the tropical site, these rain responses could be quite substantial, ranging up to 1.5 mm circumference expansion within 48 hours following a rain event. We conclude that over-bark measurements of stem circumference change sometimes correlate with but have limited potential for directly estimating daily transpiration, but that they can be valuable on time scales of days to weeks for characterizing changes in stem growth and hydration. PMID- 28030647 TI - Correction: When Is the Brain Dead? Living-Like Electrophysiological Responses and Photon Emissions from Applications of Neurotransmitters in Fixed Post-Mortem Human Brains. AB - [This corrects the article DOI: 10.1371/journal.pone.0167231.]. PMID- 28030648 TI - Root Fungal Endophytes Enhance Heavy-Metal Stress Tolerance of Clethra barbinervis Growing Naturally at Mining Sites via Growth Enhancement, Promotion of Nutrient Uptake and Decrease of Heavy-Metal Concentration. AB - Clethra barbinervis Sieb. et Zucc. is a tree species that grows naturally at several mine sites and seems to be tolerant of high concentrations of heavy metals, such as Cu, Zn, and Pb. The purpose of this study is to clarify the mechanism(s) underlying this species' ability to tolerate the sites' severe heavy metal pollution by considering C. barbinervis interaction with root fungal endophytes. We measured the heavy metal concentrations of root-zone soil, leaves, branches, and fine roots collected from mature C. barbinervis at Hitachi mine. We isolated fungal endophytes from surface-sterilized root segments, and we examined the growth, and heavy metal and nutrient absorption of C. barbinervis seedlings growing in sterilized mine soil with or without root fungal endophytes. Field analyses showed that C. barbinervis contained considerably high amounts of Cu, Zn, and Pb in fine roots and Zn in leaves. The fungi, Phialocephala fortinii, Rhizodermea veluwensis, and Rhizoscyphus sp. were frequently isolated as dominant fungal endophyte species. Inoculation of these root fungal endophytes to C. barbinervis seedlings growing in sterilized mine soil indicated that these fungi significantly enhanced the growth of C. barbinervis seedlings, increased K uptake in shoots and reduced the concentrations of Cu, Ni, Zn, Cd, and Pb in roots. Without root fungal endophytes, C. barbinervis could hardly grow under the heavy metal contaminated condition, showing chlorosis, a symptom of heavy-metal toxicity. Our results indicate that the tree C. barbinervis can tolerate high heavy-metal concentrations due to the support of root fungal endophytes including P. fortinii, R. veluwensis, and Rhizoscyphus sp. via growth enhancement, K uptake promotion and decrease of heavy metal concentrations. PMID- 28030649 TI - Whole Genome Sequence and Comparative Genomics of the Novel Lyme Borreliosis Causing Pathogen, Borrelia mayonii. AB - Borrelia mayonii, a Borrelia burgdorferi sensu lato (Bbsl) genospecies, was recently identified as a cause of Lyme borreliosis (LB) among patients from the upper midwestern United States. By microscopy and PCR, spirochete/genome loads in infected patients were estimated at 105 to 106 per milliliter of blood. Here, we present the full chromosome and plasmid sequences of two B. mayonii isolates, MN14-1420 and MN14-1539, cultured from blood of two of these patients. Whole genome sequencing and assembly was conducted using PacBio long read sequencing (Pacific Biosciences RSII instrument) followed by hierarchical genome-assembly process (HGAP). The B. mayonii genome is ~1.31 Mbp in size (26.9% average GC content) and is comprised of a linear chromosome, 8 linear and 7 circular plasmids. Consistent with its taxonomic designation as a new Bbsl genospecies, the B. mayonii linear chromosome shares only 93.83% average nucleotide identity with other genospecies. Both B. mayonii genomes contain plasmids similar to B. burgdorferi sensu stricto lp54, lp36, lp28-3, lp28-4, lp25, lp17, lp5, 5 cp32s, cp26, and cp9. The vls locus present on lp28-10 of B. mayonii MN14-1420 is remarkably long, being comprised of 24 silent vls cassettes. Genetic differences between the two B. mayonii genomes are limited and include 15 single nucleotide variations as well as 7 fewer silent vls cassettes and a lack of the lp5 plasmid in MN14-1539. Notably, 68 homologs to proteins present in B. burgdorferi sensu stricto appear to be lacking from the B. mayonii genomes. These include the complement inhibitor, CspZ (BB_H06), the fibronectin binding protein, BB_K32, as well as multiple lipoproteins and proteins of unknown function. This study shows the utility of long read sequencing for full genome assembly of Bbsl genomes, identifies putative genome regions of B. mayonii that may be linked to clinical manifestation or tissue tropism, and provides a valuable resource for pathogenicity, diagnostic and vaccine studies. PMID- 28030650 TI - Two Genotypes of Coxsackievirus A2 Associated with Hand, Foot, and Mouth Disease Circulating in China since 2008. AB - Coxsackievirus A2 (CV-A2) has been frequently detected and commonly associated with hand, foot, and mouth disease (HFMD) in China since 2008. However, limited sequences of CV-A2 are currently available. As a result, we have been focusing on the genetic characteristics of CV-A2 in the mainland of China during 2008-2015 based on national HFMD surveillance. In this study, 20 CV-A2 strains were isolated and phylogenetic analyses of the VP1 sequences were performed. Full length genome sequences of two representative CV-A2 isolates were acquired and similarity plot and bootscanning analyses were performed. The phylogenetic dendrogram indicated that all CV-A2 strains could be divided into four genotypes (Genotypes A-D). The CV-A2 prototype strain (Fleetwood) was the sole member of genotype A. From 2008 to 2015, the CV-A2 strains isolated in China dispersed into two different genotypes (B and D). And the genotype D became the dominant circulating strains in China. Strains isolated in Russia and India from 2005 to 2011 converged into genotype C. Intertypic recombination occurred between the Chinese CV-A2 strains and other enterovirus-A donor sequences. This result reconfirmed that recombination is a common phenomenon among enteroviruses. This study helps expand the numbers of whole virus genome sequence and entire VP1 sequence of CV-A2 in the GenBank database for further researcher. PMID- 28030651 TI - Retinal Lateral Inhibition Provides the Biological Basis of Long-Range Spatial Induction. AB - Retinal lateral inhibition is one of the conventional efficient coding mechanisms in the visual system that is produced by interneurons that pool signals over a neighborhood of presynaptic feedforward cells and send inhibitory signals back to them. Thus, the receptive-field (RF) of a retinal ganglion cell has a center surround receptive-field (RF) profile that is classically represented as a difference-of-Gaussian (DOG) adequate for efficient spatial contrast coding. The DOG RF profile has been attributed to produce the psychophysical phenomena of brightness induction, in which the perceived brightness of an object is affected by that of its vicinity, either shifting away from it (brightness contrast) or becoming more similar to it (brightness assimilation) depending on the size of the surfaces surrounding the object. While brightness contrast can be modeled using a DOG with a narrow surround, brightness assimilation requires a wide suppressive surround. Early retinal studies determined that the suppressive surround of a retinal ganglion cell is narrow (< 100-300 MUm; 'classic RF'), which led researchers to postulate that brightness assimilation must originate at some post-retinal, possibly cortical, stage where long-range interactions are feasible. However, more recent studies have reported that the retinal interneurons also exhibit a spatially wide component (> 500-1000 MUm). In the current study, we examine the effect of this wide interneuron RF component in two biophysical retinal models and show that for both of the retinal models it explains the long-range effect evidenced in simultaneous brightness induction phenomena and that the spatial extent of this long-range effect of the retinal model responses matches that of perceptual data. These results suggest that the retinal lateral inhibition mechanism alone can regulate local as well as long range spatial induction through the narrow and wide RF components of retinal interneurons, arguing against the existing view that spatial induction is operated by two separate local vs. long-range mechanisms. PMID- 28030652 TI - Demodectic Frost of the Ear. PMID- 28030653 TI - Ongoing Management of Patients With Supraventricular Tachycardia. PMID- 28030654 TI - Trends in Perioperative Cardiovascular Events: Mostly Sunny, With Showers. PMID- 28030655 TI - Percutaneous Coronary Intervention With Bioresorbable Scaffolds in a Young Child. AB - Importance: Although much less frequent than in adults, coronary artery disease requiring revascularization may develop in children because of homozygous familial hypercholesterolemia or other underlying conditions. Percutaneous coronary intervention (PCI) with a bioresorbable scaffold (BRS) may have advantages over metallic coronary stents in this population. Objective: To present a case of the successful treatment of unstable, multivessel coronary artery disease in a child with PCI with BRS implantation. This case highlights the limitations of conventional metal stents and the potential benefits of using BRSs in children. Design, Setting, and Participants: This is a case report from an academic tertiary care institution of a 3-year-old boy with homozygous familial hypercholesterolemia and unstable coronary artery disease requiring revascularization. We also briefly review the related literature. Interventions/Exposures: Intravascular imaging-guided PCI of the proximal right coronary artery and the left main and proximal left circumflex arteries was performed with BRSs. Main Outcomes and Measures: The primary outcomes were acute procedural success and survival to liver transplant (3 months after PCI). Results: Following BRS implantation, the patient recovered and remained free of cardiovascular symptoms 3 months after PCI. He subsequently underwent an orthotopic liver transplant for definitive treatment of homozygous familial hypercholesterolemia but died of noncardiac complications. A postmortem examination, including a histological assessment, revealed both BRSs to be patent with nonobstructive neointimal hyperplasia. Conclusions and Relevance: To our knowledge, this is the first report of PCI with BRSs in a child. This represents an application of a BRS with potentially important implications for the future treatment of coronary artery disease in children and warrants further study. PMID- 28030656 TI - Association Between Hospitalization for Infection and Suicide. PMID- 28030657 TI - Rethinking How We Select Dermatology Applicants-Turning the Tide. PMID- 28030658 TI - Troponin Assessment in Heart Failure With Preserved Ejection Fraction: Time to Get With the Guidelines. PMID- 28030659 TI - Rituximab Treatment for Recalcitrant Dermatitis Herpetiformis. AB - Importance: Dermatitis herpetiformis (DH) is an autoimmune blistering condition seen in the context of celiac disease. While typically managed by gluten-free diet and dapsone, treatment of DH refractory to standard treatments is not well defined. Observations: A man in his 80s with DH not controlled by gluten-free diet (with poor adherence), dapsone, and conventional immune-suppressing agents responded to treatment with rituximab according to the lymphoma protocol (4 weekly infusions of 375 mg/m2). Thirteen months after treatment, the patient had achieved complete resolution of pruritus and clinical manifestations of the disease, as well as normalization of antibodies against epidermal and tissue transglutaminases. He achieved complete clinical and serological remission and has remained symptom-free up to 18 months following treatment. Conclusions and Relevance: We present here the first case of a patient with DH treated with rituximab who achieved complete clinical and serological remission. We suggest rituximab as a viable treatment option for recalcitrant DH. PMID- 28030660 TI - Leveraging Statistical Methods to Improve Validity and Reproducibility of Research Findings. PMID- 28030661 TI - Varieties of Contemplative Practice. PMID- 28030662 TI - Mortality After Peritonitis in Sub-Saharan Africa: An Issue of Access to Care. PMID- 28030663 TI - Perioperative Major Adverse Cardiovascular and Cerebrovascular Events Associated With Noncardiac Surgery. AB - Importance: Major adverse cardiovascular and cerebrovascular events (MACCE) are a significant source of perioperative morbidity and mortality following noncardiac surgery. Objective: To evaluate national trends in perioperative cardiovascular outcomes and mortality after major noncardiac surgery and to identify surgical subtypes associated with cardiovascular events using a large administrative database of United States hospital admissions. Design, Setting, Participants: Patients who underwent major noncardiac surgery from January 2004 to December 2013 were identified using the National Inpatient Sample. Main Outcomes and Measures: Perioperative MACCE (primary outcome), defined as in-hospital, all cause death, acute myocardial infarction (AMI), or acute ischemic stroke, were evaluated over time. Results: Among 10 581 621 hospitalizations (mean [SD] patient age, 65.74 [12.32] years; 5 975 798 female patients 56.60%]) for major noncardiac surgery, perioperative MACCE occurred in 317 479 hospitalizations (3.0%), corresponding to an annual incidence of approximately 150 000 events after applying sample weights. Major adverse cardiovascular and cerebrovascular events occurred most frequently in patients undergoing vascular (7.7%), thoracic (6.5%), and transplant surgery (6.3%). Between 2004 and 2013, the frequency of MACCE declined from 3.1% to 2.6% (P for trend <.001; adjusted odds ratio [aOR], 0.95; 95% CI, 0.94-0.97) driven by a decline in frequency of perioperative death (aOR, 0.79; 95% CI, 0.77-0.81) and AMI (aOR, 0.87; 95% CI, 0.84-0.89) but an increase in perioperative ischemic stroke from 0.52% in 2004 to 0.77% in 2013 (P for trend <.001; aOR 1.79; CI 1.73-1.86). Conclusions and Relevance: Perioperative MACCE occurs in 1 of every 33 hospitalizations for noncardiac surgery. Despite reductions in the rate of death and AMI among patients undergoing major noncardiac surgery in the United States, perioperative ischemic stroke increased over time. Additional efforts are necessary to improve cardiovascular care in the perioperative period of patients undergoing noncardiac surgery. PMID- 28030664 TI - Minimally Invasive Pancreaticoduodenectomy for the Treatment of Pancreatic-Head and Periampullary Tumors. PMID- 28030666 TI - Web Exclusives. Annals Graphic Medicine - Breach of Confidentiality. PMID- 28030665 TI - Comparison of Regional and State Differences in Melanoma Rates in the United States: 2003 vs 2013. PMID- 28030667 TI - Public Reporting of Mortality Rates for Hospitalized Medicare Patients. PMID- 28030668 TI - Public Reporting of Mortality Rates for Hospitalized Medicare Patients. PMID- 28030669 TI - Comparing Use of Low-Value Health Care Services Among U.S. Advanced Practice Clinicians and Physicians. PMID- 28030670 TI - Comparing Use of Low-Value Health Care Services Among U.S. Advanced Practice Clinicians and Physicians. PMID- 28030671 TI - Comparing Use of Low-Value Health Care Services Among U.S. Advanced Practice Clinicians and Physicians. PMID- 28030672 TI - The Fight Against Multidrug-Resistant Bacteria. PMID- 28030673 TI - The Fight Against Multidrug-Resistant Bacteria. PMID- 28030675 TI - Ague Dawn. PMID- 28030674 TI - The Fight Against Multidrug-Resistant Bacteria. PMID- 28030676 TI - Aortic Stenosis. AB - This issue provides a clinical overview of aortic stenosis, focusing on screening, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID- 28030677 TI - Pure Genius, the TV Series: Is There an ICD-10 Code for Hyperbole? PMID- 28030679 TI - Missing Negative Symbol. PMID- 28030678 TI - Eyebrow and Eyelash Loss. PMID- 28030680 TI - Omission of Funding/Support and Role of the Sponsor Acknowledgments and Disclaimer. PMID- 28030681 TI - Health Care in the United States: A Right or a Privilege. PMID- 28030682 TI - New Tool to Study Zika Virus. PMID- 28030683 TI - Reducing Recurrent Strokes. PMID- 28030684 TI - Relief for Painful Intercourse. PMID- 28030685 TI - Delirium: An Important Postoperative Complication. PMID- 28030686 TI - Nonsurgical Management of Urinary Incontinence in Women. PMID- 28030689 TI - Long-Acting Oral Drug Device May Help Combat Malaria. PMID- 28030688 TI - Preventi-Thought. PMID- 28030690 TI - Implantable Device Reverses Leg Paralysis in Monkeys. PMID- 28030691 TI - Pancreatic Cancer Blocked From Invading Nearby Nerves. PMID- 28030692 TI - Funding and Publication of Research on Gun Violence and Other Leading Causes of Death. PMID- 28030693 TI - Updated Recommendations for Cost-effectiveness Studies. PMID- 28030694 TI - Updated Recommendations for Cost-effectiveness Studies. PMID- 28030695 TI - Allergenic Food Introduction and Childhood Risk of Allergic or Autoimmune Disease. PMID- 28030696 TI - Generalizability in Pragmatic Trials. PMID- 28030697 TI - Updated Recommendations for Cost-effectiveness Studies-Reply. PMID- 28030698 TI - Allergenic Food Introduction and Childhood Risk of Allergic or Autoimmune Disease Reply. PMID- 28030699 TI - Generalizability in Pragmatic Trials-Reply. PMID- 28030700 TI - 23andMe, Big Data, and the Genetics of Depression. PMID- 28030701 TI - Geographic Variations and Temporal Trends in Cesarean Delivery Rates in China, 2008-2014. AB - Importance: The increasing use of cesarean delivery is an emerging global health issue. Prior estimates of China's cesarean rate have been based on surveys with limited geographic coverage. Objective: To provide updated information about cesarean rates and geographic variation in cesarean use in China. Design, Setting, and Data Sources: Descriptive study, covering every county (n = 2865) in mainland China's 31 provinces, using county-level aggregated information on the number of live births, cesarean deliveries, maternal deaths, and perinatal deaths, collected by the Office for National Maternal & Child Health Statistics of China, from 2008 through 2014. Exposures: Live births. Main Outcomes and Measures: Annual rate of cesarean deliveries. Results: Over the study period, there were 100 873 051 live births, of which 32 947 229 (32.7%) were by cesarean delivery. In 2008, there were 13 160 634 live births, of which 3 788 029 (28.8%) were by cesarean delivery and in 2014 there were 15 123 276 live births, of which 5 280 124 (34.9%) were by cesarean delivery. Rates varied markedly by province, from 4.0% to 62.5% in 2014. Despite the overall increase, by 2014 rates of cesarean delieries in 14 of the nation's 17 "super cities" had declined by 4.1 to 17.5 percentage points from their earlier peak values (median, 11.4; interquartile range, 6.3-15.4). In 4 super cities with the largest decreases, there was no increase in maternal or perinatal mortality. Conclusions and Relevance: Between 2008 and 2014, the overall annual rate of cesarean deliveries increased in China, reaching 34.9%. There was major geographic variation in rates and trends over time, with rates declining in some of the largest urban areas. PMID- 28030703 TI - Respiratory Syncytial Virus. PMID- 28030705 TI - Little White Lies. PMID- 28030702 TI - Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. AB - Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. Main Outcomes and Measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Conclusions and Relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. Trial Registration: clinicaltrials.gov Identifier: NCT00869206. PMID- 28030707 TI - Social Determinants of Health: Caveats and Nuances. PMID- 28030708 TI - The Toll of Death and Disability From Traumatic Injury in the United States-The "Neglected Disease" of Modern Society, Still Neglected After 50 Years. PMID- 28030709 TI - Association Between Hospitalization for Infection and Suicide-Reply. PMID- 28030710 TI - Association of Radiologic Indicators of Frailty With 1-Year Mortality in Older Trauma Patients: Opportunistic Screening for Sarcopenia and Osteopenia. AB - Importance: Assessment of physical frailty in older trauma patients admitted to the intensive care unit is often not feasible using traditional frailty assessment instruments. The use of opportunistic computed tomography (CT) scans to assess sarcopenia and osteopenia as indicators of underlying frailty may provide complementary prognostic information on long-term outcomes. Objective: To determine whether sarcopenia and/or osteopenia are associated with 1-year mortality in an older trauma patient population. Design, Setting, and Participants: A retrospective cohort constructed from a state trauma registry was linked to the statewide death registry and Comprehensive Hospital Abstract Reporting System for readmission data analyses. Admission abdominopelvic CT scans from patients 65 years and older admitted to the intensive care unit of a single level I trauma center between January 2011 and May 2014 were analyzed to identify patients with sarcopenia and/or osteopenia. Patients with a head Injury Severity Score of 3 or greater, an out-of-state address, or inadequate CT imaging or who died within 24 hours of admission were excluded. Exposures: Sarcopenia and/or osteopenia, assessed via total cross-sectional muscle area and bone density at the L3 vertebral level, compared with a group with no sarcopenia or osteopenia. Main Outcomes and Measures: One-year all-cause mortality. Secondary outcomes included 30-day all-cause mortality, 30-day readmission, hospital length of stay, hospital cost, and discharge disposition. Results: Of the 450 patients included in the study, 269 (59.8%) were male and 394 (87.6%) were white. The cohort was split into 4 groups: 74 were retrospectively diagnosed with both sarcopenia and osteopenia, 167 with sarcopenia only, 48 with osteopenia only, and 161 with no radiologic indicators. Among the 408 who survived to discharge, sarcopenia and osteopenia were associated with higher risks of 1-year mortality alone and in combination. After adjustment, the hazard ratio was 9.4 (95% CI, 1.2-75.4; P = .03) for sarcopenia and osteopenia, 10.3 (95% CI, 1.3-78.8; P = .03) for sarcopenia, and 11.9 (95% CI, 1.3-107.4; P = .03) for osteopenia. Conclusions and Relevance: More than half of older trauma patients in this study had sarcopenia, osteopenia, or both. Each factor was independently associated with increased 1 year mortality. Given the prevalent use of abdominopelvic CT in trauma centers, opportunistic screening for radiologic indicators of frailty provides an additional tool for early identification of older trauma patients at high risk for poor outcomes, with the potential for targeted interventions. PMID- 28030713 TI - Defining a Hospital Volume Threshold for Minimally Invasive Pancreaticoduodenectomy in the United States. AB - Importance: There is increasing interest in expanding use of minimally invasive pancreaticoduodenectomy (MIPD). This procedure is complex, with data suggesting a significant association between hospital volume and outcomes. Objective: To determine whether there is an MIPD hospital volume threshold for which patient outcomes could be optimized. Design, Setting, and Participants: Adult patients undergoing MIPD were identified from the Healthcare Cost and Utilization Project National Inpatient Sample from 2000 to 2012. Multivariable models with restricted cubic splines were used to identify a hospital volume threshold by plotting annual hospital volume against the adjusted odds of postoperative complications. The current analysis was conducted on August 16, 2016. Main Outcomes and Measures: Incidence of any complication. Results: Of the 865 patients who underwent MIPD, 474 (55%) were male and the median patient age was 67 years (interquartile range, 59-74 years). Among the patients, 747 (86%) had cancer and 91 (11%) had benign conditions/pancreatitis. Overall, 410 patients (47%) had postoperative complications and 31 (4%) died in-hospital. After adjustment for demographic and clinical characteristics, increasing hospital volume was associated with reduced complications (overall association P < .001); the likelihood of experiencing a complication declined as hospital volume increased up to 22 cases per year (95% CI, 21-23). Median hospital volume was 6 cases per year (range, 1-60). Most patients (n = 717; 83%) underwent the procedure at low volume (<=22 cases per year) hospitals. After adjustment for patient mix, undergoing MIPD at low- vs high-volume hospitals was significantly associated with increased odds for postoperative complications (odds ratio, 1.74; 95% CI, 1.03-2.94; P = .04). Conclusions and Relevance: Hospital volume is significantly associated with improved outcomes from MIPD, with a threshold of 22 cases per year. Most patients undergo MIPD at low-volume hospitals. Protocols outlining minimum procedural volume thresholds should be considered to facilitate safer dissemination of MIPD. PMID- 28030714 TI - Indoor Tanning and Skin Cancer Risk Among Diverse US Youth: Results From a National Sample. PMID- 28030715 TI - Future Directions of Geriatric Trauma Care: Function and Quality of Life Beyond Survival. PMID- 28030717 TI - Pathologic Evaluation of Skin Tumors With Ex Vivo Dermoscopy With Derm Dotting. AB - Importance: Ex vivo dermoscopy (EVD) with derm dotting (DD) improves clinicopathologic correlation and the quality of diagnosis in skin tumors. Objective: To compare the diagnostic performance of the standard method of skin biopsy processing with the practice of EVD with DD. Design, Setting, and Participants: This retrospective study compares the diagnostic performance in 6526 skin biopsy specimens examined from 2008 to 2010 with a standard method of processing with 8584 biopsy specimens examined in 2015 with EVD and DD. Data were analyzed from January 1 to March 31, 2016. A total of 15 110 skin biopsy specimens were included. The biopsy specimens from 2008 to 2010 were processed in a hospital-based general pathology laboratory; the biopsy specimens from 2015 were processed in a private dermatopathology laboratory. Biopsy specimens from both periods were diagnosed by the same dermatopathologist. Main Outcomes and Measures: The primary outcome measures were clinicopathological characteristics, usefulness of EVD with DD, and turnaround times (TATs). Results: Use of EVD with DD increased the detection of positive section margins in nonmelanoma skin cancer from 8.4% to 12.8%. The most significant increase was seen in Bowen disease, invasive squamous cell carcinoma, and a superficial type of basal cell carcinoma (BCC). With EVD and DD, a specific clinicopathologic diagnosis was made in 27.7% of nevi compared with only 10.3% using the standard method. The incidence of moderately and severely dysplastic nevi increased from 1.0% to 7.2% and from 0.6% to 1.4%, respectively. The detection of ulceration in melanomas with thicker than 1 mm increased from 24.0% to 31.3%. The number of nevi-associated melanomas increased from 15.5% to 33.3%. The number of collision lesions from 0.07% to 1.07%. The TAT for nevi decreased from 2 days to 1 day, for melanomas from 5 days to 2 days, and for BCC from 2 days to 1 day. Conclusions and Relevance: Ex vivo dermoscopy and DD with adapted sectioning in a dermatopathology setting allows a more accurate and less time consuming histopathologic diagnosis of skin tumors. These findings suggest that pathologists involved in skin tumor evaluation should be encouraged to learn dermoscopy and replace random transverse cutting with lesion-specific and DD-guided cutting. PMID- 28030716 TI - Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin Treated Patients With Type 2 Diabetes. AB - Importance: Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. Objective: To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. Design, Setting, and Participants: Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). Interventions: Passive follow-up of study participants previously treated with fenofibrate or masked placebo. Main Outcomes and Measures: Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. Results: The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56 0.95). Conclusions and Relevance: Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. Trial Registration: clinicaltrials.gov Identifier: NCT00000620. PMID- 28030718 TI - Treatments for Retinoblastoma Then and Now. PMID- 28030719 TI - Acute Lymphoblastic Leukemia Relapse Presenting as Optic Nerve Infiltration. PMID- 28030720 TI - Bleb Morphology After Needling With Viscoelastic of an Ab Interno Microstent Assessed by Optical Coherence Tomography. PMID- 28030721 TI - Vitreous Herniation After a Blow to the Eye. PMID- 28030728 TI - Error in Byline Tagging. PMID- 28030724 TI - A Propensity Score-Matched Analysis of Robotic vs Open Pancreatoduodenectomy on Incidence of Pancreatic Fistula. AB - Importance: The adoption of robotic pancreatoduodenectomy (RPD) is gaining momentum; however, its impact on major outcomes, including pancreatic fistula, has yet to be adequately compared with open pancreatoduodenectomy (OPD). Objective: To demonstrate that use of RPD does not increase the incidence of clinically relevant pancreatic fistula (CR-POPF) compared with OPD. Design, Setting, and Participants: Data were accrued from 2846 patients who underwent pancreatoduodenectomies (OPDs, n = 2661; RPDs, n = 185), performed by 51 surgeons at 17 institutions worldwide (2003-2015). All RPDs were conducted at a high volume, academic, pancreatic surgery specialty center-in a standardized fashion by surgeons who had surpassed the RPD learning curve. Propensity score matching was used to minimize bias from nonrandomized treatment assignment. The RPD and OPD cohorts were matched by propensity scores accounting for factors significantly associated with either undergoing robotic surgery or CR-POPF occurrence on logistic regression analysis. These variables included pancreatic gland texture, pancreatic duct diameter, intraoperative blood loss, pathologic findings of disease, and intraoperative drain placement. Interventions: Use of RPD or OPD. Main Outcomes and Measures: The major outcome of interest was CR-POPF occurrence, which is the most common and morbid complication following pancreatoduodenectomy. Results: The overall cohort was 51.5% male, with a median age of 64 years (interquartile range, 56-72 years). The propensity score-matched cohort comprised 152 RPDs and 152 OPDs; all covariate imbalances were alleviated. After adjusting for potential confounders, undergoing RPD was associated with a reduced risk for CR-POPF incidence (OR, 0.4 [95% CI, 0.2-0.7]; P = .002) relative to OPD. Other predictors of risk-adjusted CR-POPF occurrence included soft pancreatic parenchyma (OR, 4.7 [95% CI, 3.4-6.6]; P < .001), pathologic findings of high-risk disease (OR, 1.4 [95% CI, 1.1-1.9]; P = .01), small pancreatic duct diameter (vs >=5 mm: 2 mm, OR, 2.1 [95% CI, 1.4-3.1]; P < .001; <=1 mm, OR, 1.8 [95% CI, 1.0-3.0]; P = .03), elevated intraoperative blood loss (vs <=400 mL: 401 700 mL, OR, 1.5 [95% CI, 1.1-2.0]; P = .01; >1000 mL, OR, 2.1 [95% CI, 1.4-2.9]; P < .001), omission of intraoperative drain(s) (OR, 0.5 [95% CI, 0.3-0.8]; P = .005), and octreotide prophylaxis (OR, 3.1 [95% CI, 2.3-4.0]; P < .001). Patients undergoing RPD demonstrated similar CR-POPF rates compared with patients in the OPD cohort (6.6% vs 11.2%; P = .23). This relationship held for both grade B (6.6% vs 9.2%; P = .52) and grade C (0% vs 2.0%; P = .25) POPFs. Robotic pancreatoduodenectomy was also noninferior to OPD in terms of the occurrence of any complication (73.7% vs 66.4%; P = .21), severe complications (Accordion grade >=3, 23.05% vs 23.7%; P > .99), hospital stay (median: 8 vs 8.5 days; P = .31), 30-day readmission (22.4% vs 21.7%; P > .99), and 90-day mortality (3.3% vs 1.3%; P = .38). Conclusions and Relevance: To our knowledge, this is the first propensity score-matched analysis of robotic vs open pancreatoduodenectomy to date, and it demonstrates that RPD is noninferior to OPD in terms of pancreatic fistula development and other major postoperative outcomes. PMID- 28030730 TI - Sex Bias-Beyond Pay Inequity. PMID- 28030731 TI - A Perspective on Out-of-Pocket Spending. PMID- 28030732 TI - Prioritization of Generic Drug Review. PMID- 28030733 TI - Procalcitonin-Guided Antimicrobial Therapy-All About the Algorithm. PMID- 28030734 TI - Colorectal Cancer Screening Comparative Effectiveness-Clinical Trials Are Not Always the Answer. PMID- 28030735 TI - A Perspective on Out-of-Pocket Spending-Reply. PMID- 28030736 TI - Prioritization of Generic Drug Review-Reply. PMID- 28030737 TI - Procalcitonin-Guided Antimicrobial Therapy-All About the Algorithm-Reply. PMID- 28030738 TI - Colorectal Cancer Screening Comparative Effectiveness-Clinical Trials Are Not Always The Answer-Reply. PMID- 28030740 TI - Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis. AB - Importance: Although several strategies of repetitive transcranial magnetic stimulation (rTMS) have been investigated as treatment of major depressive disorder (MDD), their comparative efficacy and acceptability is unknown. Objective: To establish the relative efficacy and acceptability of the different modalities of rTMS used for MDD by performing a network meta-analysis, obtaining a clinically meaningful treatment hierarchy. Data Sources: PubMed/MEDLINE, EMBASE, PsycInfo, and Web of Science were searched up until October 1, 2016. Study Selection: Randomized clinical trials that compared any rTMS intervention with sham or another rTMS intervention. Trials performing less than 10 sessions were excluded. Data Extraction and Synthesis: Two independent reviewers used standard forms for data extraction and quality assessment. Random-effects, standard pairwise, and network meta-analyses were performed to synthesize data. Main Outcomes and Measures: Response rates and acceptability (dropout rate). Remission was the secondary outcome. Effect sizes were reported as odds ratios (ORs) with 95% CIs. Results: Eighty-one studies (4233 patients, 59.1% women, mean age of 46 years) were included. The interventions more effective than sham were priming low-frequency (OR, 4.66; 95% CI, 1.70-12.77), bilateral (OR, 3.96; 95% CI, 2.37-6.60), high-frequency (OR, 3.07; 95% CI, 2.24-4.21), theta-burst stimulation (OR, 2.54; 95% CI, 1.07-6.05), and low-frequency (OR, 2.37; 95% CI, 1.52-3.68) rTMS. Novel rTMS interventions (accelerated, synchronized, and deep rTMS) were not more effective than sham. Except for theta-burst stimulation vs sham, similar results were obtained for remission. All interventions were at least as acceptable as sham. The estimated relative ranking of treatments suggested that priming low-frequency and bilateral rTMS might be the most efficacious and acceptable interventions among all rTMS strategies. However, results were imprecise and relatively few trials were available for interventions other than low-frequency, high-frequency, and bilateral rTMS. Conclusions and Relevance: Few differences were found in clinical efficacy and acceptability between the different rTMS modalities, favoring to some extent bilateral rTMS and priming low-frequency rTMS. These findings warrant the design of larger RCTs investigating the potential of these approaches in the short-term treatment of MDD. Current evidence cannot support novel rTMS interventions as a treatment for MDD. Trial Registration: clinicaltrials.gov Identifier: PROSPERO CRD42015019855. PMID- 28030741 TI - Effects of Contemplative Dyads on Engagement and Perceived Social Connectedness Over 9 Months of Mental Training: A Randomized Clinical Trial. AB - Importance: Loneliness is a risk factor for depression and other illnesses and may be caused and reinforced by maladaptive social cognition. Secularized classical meditation training programs address social cognition, but practice typically occurs alone. Little is known about the effectiveness of contemplative practice performed in dyads. Objective: To introduce and assess the effectiveness of contemplative dyadic practices relative to classical-solitary meditation with regard to engagement and perceived social connectedness. Design, Setting, and Participants: The ReSource Project was a 9-month open-label efficacy trial of three, 3-month secularized mental training modules. Replacement randomization was used to assign 362 healthy participants in Leipzig and Berlin, Germany. Eligible participants were recruited between November 11, 2012, and February 13, 2013, and between November 13, 2013, and April 30, 2014. Intention-to-treat analyses were conducted. Interventions: Breathing meditation and body scan (the presence module), loving-kindness meditation and affect dyad (the affect module), and observing-thoughts meditation and perspective dyad (the perspective module). Main Outcomes and Measures: Primary outcomes were self-disclosure and social closeness. Engagement measures included compliance (ie, the mean [95% margin of error] number of meditation sessions that a participant engaged in per week), liking, and motivation to practice. Results: Thirty participants dropped out after assignment to 3 experimental groups; 90 participants were assigned to a retest control that did not complete the main outcome measures; 16 participants provided no state-change data for the affect and perspective modules (226 remaining participants; mean age of 41.15 years; 59.3% female). Results are aggregated across training cohorts. Compliance was similar across the modules: loving-kindness meditation (3.78 [0.18] sessions), affect dyad (3.59 [0.14] sessions), observing-thoughts meditation (3.63 [0.20] sessions), and perspective dyad (3.24 [0.18] sessions). Motivation was higher for meditation (11.20 [0.40] sessions) than the dyads (9.26 [0.43] sessions) and was higher for the affect dyad (10.11 [0.46] sessions) than the perspective dyad (8.41 [0.46] sessions). Social closeness increased during a session for the affect dyad (1.49 [0.12] sessions) and the perspective dyad (1.06 [0.12] sessions) and increased over time for the affect dyad (slope of 0.016 [0.003]) and the perspective dyad (slope of 0.012 [0.003]). Self-disclosure increased over time for the affect dyad (slope of 0.023 [0.004]) and the perspective dyad (slope of 0.006 [0.005]), increasing more steeply for the affect dyad (P < .001). Conclusions and Relevance: Contemplative dyads elicited engagement similar to classical contemplative practices and increased perceived social connectedness. Contemplative dyads represent a new type of intervention targeting social connectedness and intersubjective capacities deficient in participants who experience loneliness and in many psychopathologies. Trial Registration: clinicaltrials.gov Identifier: NCT01833104. PMID- 28030742 TI - Development of a first-generation miniature multiple reference optical coherence tomography imaging device. AB - Multiple reference optical coherence tomography (MR-OCT) is a technology ideally suited to low-cost, compact OCT imaging. This modality is an extension of time domain OCT with the addition of a partial mirror in front of the reference mirror. This enables extended, simultaneous depth scanning with the relatively short scan range of a miniature voice coil motor on which the scanning mirror is mounted. This work details early stage development of the first iteration of a miniature MR-OCT device. This iteration utilizes a fiber-coupled input from an off-board superluminescent diode. The dimensions of the module are 40 * 57 ?? mm . Off-the-shelf miniature optical components, voice coil motors, and photodetectors are used, with the complexity of design depending on the specific application. The photonic module can be configured as either polarized or nonpolarized and can include balanced detection. The results shown in this work are from the nonpolarized device. The system was characterized through measurement of the input spectrum, axial resolution, and signal-to-noise ratio. Typical B-scans of static and in vivo samples are shown, which illustrate the potential applications for such a technology. PMID- 28030743 TI - Retrieving the axial position of fluorescent light emitting spots by shearing interferometry. AB - A method for the depth-resolved detection of fluorescent radiation based on imaging of an interference pattern of two intersecting beams and shearing interferometry is presented. The illumination setup provides the local addressing of the excitation of fluorescence and a coarse confinement of the excitation volume in axial and lateral directions. The reconstruction of the depth relies on the measurement of the phase of the fluorescent wave fronts. Their curvature is directly related to the distance of a source to the focus of the imaging system. Access to the phase information is enabled by a lateral shearing interferometer based on a Michelson setup. This allows the evaluation of interference signals even for spatially and temporally incoherent light such as emitted by fluorophors. An analytical signal model is presented and the relations for obtaining the depth information are derived. Measurements of reference samples with different concentrations and spatial distributions of fluorophors and scatterers prove the experimental feasibility of the method. In a setup optimized for flexibility and operating in the visible range, sufficiently large interference signals are recorded for scatterers placed in depths in the range of hundred micrometers below the surface in a material with scattering properties comparable to dental enamel. PMID- 28030744 TI - Association Between Hospitalization for Infection and Suicide. PMID- 28030745 TI - Comparing Outcomes for Robotic and Open Pancreatoduodenectomy: A Technological Advance? PMID- 28030747 TI - Factors Associated With and Prognostic Implications of Cardiac Troponin Elevation in Decompensated Heart Failure With Preserved Ejection Fraction: Findings From the American Heart Association Get With The Guidelines-Heart Failure Program. AB - Importance: Elevated levels of cardiac troponins are associated with adverse clinical outcomes among patients with heart failure (HF) and reduced ejection fraction. However, the clinical significance of troponin elevation in the setting of decompensated HF with preserved ejection fraction (HFpEF) is not well established. Objective: To determine the clinical predictors of troponin elevation and its association with in-hospital and long-term outcomes among patients with decompensated HFpEF. Design, Setting, and Participants: Observational analysis of Get With The Guidelines-HF registry participants who were admitted for decompensated HFpEF (ejection fraction >=50%) from January 2009 through December 2014 and who had quantitative or categorical (elevated vs normal based on institution's reference laboratory) measures of troponin level (troponin T or troponin I, as available). Main Outcomes and Measures: In-hospital outcomes (mortality, length of stay, and discharge destination) and postdischarge outcomes (30-day mortality, 30-day readmission rate, 1-year mortality). Results: We included 34 233 patients with HFpEF from 224 sites with measured troponin levels (33.4% men; median age, 79 years): 78.6% (n = 26 896) with troponin I and 21.4% (n = 7319) with troponin T measurements. Among these, 22.6% (n = 7732) had elevation in troponin levels. In adjusted analysis, higher serum creatinine level, black race, older age, and ischemic heart disease were associated with troponin elevation. Elevated troponin was associated with higher odds of in hospital mortality (odds ratio [OR], 2.19; 95% CI, 1.88-2.56), greater length of stay (length of stay >4 days OR, 1.38; 95% CI, 1.29-1.47), and lower likelihood of discharge to home (OR, 0.65; 95% CI, 0.61-0.71) independent of other clinical predictors and measured confounders. Presence of elevated troponin I levels was also significantly associated with increased risk of 30-day mortality (hazard ratio [HR], 1.59; 95% CI, 1.42-1.80), 30-day all-cause readmission (HR, 1.12; 95% CI, 1.01-1.25), and 1-year mortality HR, 1.35; 95% CI, 1.26-1.45). Conclusions and Relevance: Troponin elevation among patients with acutely decompensated HFpEF is associated with worse in-hospital and postdischarge outcomes, independent of other predictive variables. Future studies are needed to determine if measurement of troponin levels among patients with decompensated HFpEF may be useful for risk stratification. PMID- 28030746 TI - Association of Fluid Intelligence and Psychiatric Disorders in a Population Representative Sample of US Adolescents. AB - Importance: Despite long-standing interest in the association of psychiatric disorders with intelligence, few population-based studies of psychiatric disorders have assessed intelligence. Objective: To investigate the association of fluid intelligence with past-year and lifetime psychiatric disorders, disorder age at onset, and disorder severity in a nationally representative sample of US adolescents. Design, Setting, and Participants: National sample of adolescents ascertained from schools and households from the National Comorbidity Survey Replication-Adolescent Supplement, collected 2001 through 2004. Face-to-face household interviews with adolescents and questionnaires from parents were obtained. The data were analyzed from February to December 2016. DSM-IV mental disorders were assessed with the World Health Organization Composite International Diagnostic Interview, and included a broad range of fear, distress, behavior, substance use, and other disorders. Disorder severity was measured with the Sheehan Disability Scale. Main Outcomes and Measures: Fluid IQ measured with the Kaufman Brief Intelligence Test, normed within the sample by 6-month age groups. Results: The sample included 10 073 adolescents (mean [SD] age, 15.2 [1.50] years; 49.0% female) with valid data on fluid intelligence. Lower mean (SE) IQ was observed among adolescents with past-year bipolar disorder (94.2 [1.69]; P = .004), attention-deficit/hyperactivity disorder (96.3 [0.91]; P = .002), oppositional defiant disorder (97.3 [0.66]; P = .007), conduct disorder (97.1 [0.82]; P = .02), substance use disorders (alcohol abuse, 96.5 [0.67]; P < .001; drug abuse, 97.6 [0.64]; P = .02), and specific phobia (97.1 [0.39]; P = .001) after adjustment for a wide range of potential confounders. Intelligence was not associated with posttraumatic stress disorder, eating disorders, and anxiety disorders other than specific phobia, and was positively associated with past-year major depression (mean [SE], 100 [0.5]; P = .01). Associations of fluid intelligence with lifetime disorders that had remitted were attenuated compared with past-year disorders, with the exception of separation anxiety disorder. Multiple past-year disorders had a larger proportion of adolescents less than 1 SD below the mean IQ range than those without a disorder. Across disorders, higher disorder severity was associated with lower fluid intelligence. For example, among adolescents with specific phobia, those with severe disorder had a mean (SE) of 4.4 (0.72) points lower IQ than those without severe disorder (P < .001), and those with alcohol abuse had a mean (SE) of 5.6 (1.2) points lower IQ than those without severe disorder (P < .001). Conclusions and Relevance: Numerous psychiatric disorders were associated with reductions in fluid intelligence; associations were generally small in magnitude. Stronger associations of current than past disorders with intelligence suggest that active symptoms of psychiatric disorders interfere with cognitive functioning. Early identification and treatment of children with mental disorders in school settings is critical to promote academic achievement and long-term success. PMID- 28030748 TI - Guidelines for Children With Peanut Allergy. PMID- 28030749 TI - Rash and Arthralgias in a Teenager With Autism. PMID- 28030752 TI - What's Changed? A Comparison of Army Suicide Surveillance Data to Cases from 1975 to 1982. AB - US Army suicide rates increased significantly in the last decade and have remained high. To inform future research hypotheses, Army suicide surveillance data (2012-2014) were compared to similar Army data for suicides from 1975 to 1982. Preliminary data suggest that suicide rates increased across most demographic groups, but may have decreased among divorced soldiers. Mental health utilization increased over time. Legal problems and physical health problems were identified in a higher percentage of cases in the recent data relative to the 1975-1982 era. Potential implications for suicide prevention are discussed. PMID- 28030753 TI - Expression dynamics and physiologically relevant functional study of STEVOR in asexual stages of Plasmodium falciparum infection. AB - The extensive modification of Plasmodium falciparum-infected erythrocytes by variant surface antigens plays a major role in immune evasion and malaria-induced pathology. Here, using high-resolution microscopy, we visualize the spatio temporal expression dynamics of STEVOR, an important variant surface antigens family, in a stage-dependent manner. We demonstrate that it is exported to the cell surface where protein molecules cluster and preferentially localize in proximity to knobs. Quantitative evidence from our force measurements and microfluidic assays reveal that STEVOR can effectively mediate the formation of stable, robust rosettes under static and physiologically relevant flow conditions. Our results extend previously published studies in P. falciparum and emphasize the role of STEVOR in rosetting, an important contributor to disease pathology. PMID- 28030755 TI - Epidemiology of infections following haploidentical peripheral blood hematopoietic cell transplantation. AB - BACKGROUND: The use of T-cell replete haploidentical hematopoietic cell transplant (haplo-HCT) has increased substantially since the introduction of post transplant cyclophosphamide (PTCy) regimens. Limited data exist concerning infectious complications of haplo-HCT utilizing mobilized peripheral blood (PB) hematopoietic cells. METHODS: This retrospective cohort study included all adult patients at our institution undergoing PB haplo-HCT with PTCy between June 2009 and June 2015. Infections were microbiologically confirmed. Invasive fungal infections (IFI) classified as "proven" or "probable" by standard definitions were included. RESULTS: In total, 104 patients were identified. Median follow-up was 218 days (range: 6-1576). A total of 322 episodes of infection were recorded. Eighty-nine percent of patients experienced at least one infection. Median time to first infection was 22 days. Patients experiencing at least one bacterial, viral, and IFI were 62%, 72%, and 6%, respectively. The majority (69%) of bacterial infections were caused by enteric organisms. Seven cases of Staphylococcus aureus infection were recorded, with one bacteremia case. Cytomegalovirus (CMV) viremia occurred in 54/71 (76%) at-risk patients at a median time of 24 days. Sixteen (15%) patients developed CMV disease. Nineteen percent (20/104) of patients developed BK polyomavirus-associated cystitis. Six (6%) patients experienced a total of seven IFI. Infection was the primary cause of death for 12% (6/51) of patients and was a secondary cause for 41%. CONCLUSION: In PB haplo-HCT patients, a high incidence of CMV viremia and disease was observed. Infections with enteric bacteria were common. Fungal and staphylococcal infections were uncommon. Further studies are needed to compare infectious complications in haplo-HCT with other transplant modalities. PMID- 28030756 TI - Risk Factors of a Suicide Reattempt by Seasonality and the Method of a Previous Suicide Attempt: A Cohort Study in a Japanese Primary Care Hospital. AB - Suicide has a great impact on the individual whose life is lost and the bereaved family members. The risk of a suicide reattempt is particularly high during the first 12 months after a suicide attempt. In this cohort study, risk factors for a suicide reattempt were explored among 291 patients at suicide risk. Clinical and demographic data were collected from a Japanese primary care hospital. Past psychiatric history and multiple diagnoses were associated with suicide reattempts in both genders. Drug overdose, past psychiatric history, and the summer season were linked to suicide reattempts among males. Past psychiatric history and multiple diagnoses were linked to suicide reattempts among females. Appropriate assessment of past psychiatric history, season and method of suicide attempt, gender, and diagnosis may play a role in preventing suicide. PMID- 28030754 TI - Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP. AB - KEY POINTS: Following the genetically controlled formation of neuronal circuits, early firing activity guides the development of sensory maps in the auditory, visual and somatosensory system. However, it is not clear whether the activity of central auditory neurons is specifically regulated depending on the position within the sensory map. In the ventral cochlear nucleus, the first central station along the auditory pathway, we describe a mechanism through which paracrine ATP signalling enhances firing in a cell-specific and tonotopically determined manner. Developmental down-regulation of P2X2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPA receptor currents, suggesting a high-to-low frequency maturation pattern. Facilitated action potential (AP) generation, measured as higher firing rate, shorter EPSP-AP delay in vivo and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. The long lasting change in intrinsic neuronal excitability is mediated by the heteromeric P2X2/3 receptors. ABSTRACT: Synaptic refinement and strengthening are activity-dependent processes that establish orderly arranged cochleotopic maps throughout the central auditory system. The maturation of auditory brainstem circuits is guided by action potentials (APs) arising from the inner hair cells in the developing cochlea. The AP firing of developing central auditory neurons can be modulated by paracrine ATP signalling, as shown for the cochlear nucleus bushy cells and principal neurons in the medial nucleus of the trapezoid body. However, it is not clear whether neuronal activity may be specifically regulated with respect to the nuclear tonotopic position (i.e. sound frequency selectivity). Using slice recordings before hearing onset and in vivo recordings with iontophoretic drug applications after hearing onset, we show that cell-specific purinergic modulation follows a precise tonotopic pattern in the ventral cochlear nucleus of developing gerbils. In high-frequency regions, ATP responsiveness diminished before hearing onset. In low-to-mid frequency regions, ATP modulation persisted after hearing onset in a subset of low-frequency bushy cells (characteristic frequency< 10 kHz). Down-regulation of P2X2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPA receptor currents, thus suggesting a high-to-low frequency maturation pattern. Facilitated AP generation, measured as higher firing frequency, shorter EPSP-AP delay in vivo, and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. Finally, by combining recordings and pharmacology in vivo, in slices, and in human embryonic kidney 293 cells, it was shown that the long lasting change in intrinsic neuronal excitability is mediated by the P2X2/3R. PMID- 28030758 TI - World Trade Center Health Program; Amendments to Definitions, Appeals, and Other Requirements. Final rule. AB - In 2011 and 2012, the Secretary, Department of Health and Human Services (HHS), promulgated regulations designed to govern the World Trade Center (WTC) Health Program (Program), including the processes by which eligible responders and survivors may apply for enrollment in the Program, obtain health monitoring and treatment for WTC-related health conditions, and appeal enrollment and treatment decisions, as well as a process to add new conditions to the List of WTC-Related Health Conditions (List). After using the regulations for a number of years, the Administrator of the WTC Health Program identified potential improvements to certain existing provisions, including, but not limited to, appeals of enrollment, certification, and treatment decisions, as well as the procedures for the addition of health conditions for WTC Health Program coverage. He also identified the need to add new regulatory provisions, including, but not limited to, standards for the disenrollment of a WTC Health Program member and decertification of a certified WTC-related health condition. A notice of proposed rulemaking was published on August 17, 2016; this action addresses public comments received on that proposed rulemaking, as well as three interim final rules promulgated since 2011, and finalizes the proposed rule and three interim final rules. PMID- 28030757 TI - Altered resting state functional connectivity of fear and reward circuitry in comorbid PTSD and major depression. AB - BACKGROUND: Individuals with comorbid posttraumatic stress disorder and major depressive disorder (PTSD-MDD) often exhibit greater functional impairment and poorer treatment response than individuals with PTSD alone. Research has not determined whether PTSD-MDD is associated with different network connectivity abnormalities than PTSD alone. METHODS: We used functional magnetic resonance imaging (fMRI) to measure resting state functional connectivity (rs-FC) patterns of brain regions involved in fear and reward processing in three groups: patients with PTSD-alone (n = 27), PTSD-MDD (n = 21), and trauma-exposed healthy controls (TEHCs, n = 34). Based on previous research, seeds included basolateral amygdala (BLA), centromedial amygdala (CMA), and nucleus accumbens (NAcc). RESULTS: Regardless of MDD comorbidity, PTSD was associated with decreased connectivity of BLA-orbitalfrontal cortex (OFC) and CMA-thalamus pathways, key to fear processing, and fear expression, respectively. PTSD-MDD, compared to PTSD-alone and TEHC, was associated with decreased connectivity across multiple amygdala and striatal-subcortical pathways: BLA-OFC, NAcc-thalamus, and NAcc-hippocampus. Further, while both the BLA-OFC and the NAcc-thalamus pathways were correlated with MDD symptoms, PTSD symptoms correlated with the amygdala pathways (BLA-OFC; CMA-thalamus) only. CONCLUSIONS: Comorbid PTSD-MDD may be associated with multifaceted functional connectivity alterations in both fear and reward systems. Clinical implications are discussed. PMID- 28030759 TI - Macroscopic Electrical Wires from Vapor Deposited Poly(3,4 ethylenedioxythiophene). AB - Conducting polymers represent a field of materials innovation that bridges the properties of metals (electrical conduction) with those of traditional polymers (mechanical flexibility). Although electronic properties have been studied, minimal attention is given to their mechanical properties such as tensile strength. This study presents macroscopic wires made from the vapor phase polymerization of poly(3,4-ethylenedioxythiophene) using triblock copolymers as a molecular template. These macroscopic wires are conductive (up to 5 * 104 S/m), and possess tensile properties (Young's modulus ~1.1 GPa; tensile strength ~90 MPa) comparable to commercially available polymers (Nylon-6 and poly(methyl methacrylate)), without need for nonconductive mechanical fillers. PMID- 28030760 TI - A General Silica-Templating Synthesis of Alkaline Mesoporous Carbon Catalysts for Highly Efficient H2S Oxidation at Room Temperature. AB - A general synthesis of alkaline mesoporous carbons (AMCs) is developed based on a simplified silica-templating method for room-temperature catalytic oxidation of H2S. The key to the success relies on dissolving the silica templates to create the interconnected mesoporous structure as well as leaving parts of the alkaline products in the pores; both of them are prerequisites for H2S oxidation. By adjusting the alkaline etching degree and organic/inorganic ratio, the porosity and basicity of the AMC could be simultaneously tuned, allowing the AMCs direct use for H2S catalytic oxidation with an unprecedented removal capacities of 4.49 +/- 0.12 g/g. Such excellent catalytic performance should be attributed to the developed pore structure that stores the product sulfur and the strong basicity that promotes the dissociation of H2S into HS- ions. Moreover, this simplified silica-templating method could be easily extended to the preparation of various silica templated mesoporous carbon catalysts. All these AMCs demonstrate a successful combination of low cost with high performance, which may well be the answer for the technical development of industrial H2S removal. PMID- 28030761 TI - A Mild and Ligand-Free Ni-Catalyzed Silylation via C-OMe Cleavage. AB - Metal-catalyzed transformations that forge carbon-heteroatom bonds are of central importance in organic synthesis. Despite the formidable potential of aryl methyl ethers as coupling partners, the scarcity of metal-catalyzed C-heteroatom bond formations via C-OMe cleavage is striking, with isolated precedents requiring specialized, yet expensive, ligands, high temperatures, and pi-extended backbones. We report an unprecedented catalytic ipso-silylation of aryl methyl ethers under mild conditions and without recourse to external ligands. The method is distinguished by its wide scope, which includes the use of benzyl methyl ethers, vinyl methyl ethers, and unbiased anisole derivatives, thus representing a significant step forward for designing new C-heteroatom bond formations via C OMe scission. Applications of this transformation in orthogonal silylation techniques as well as in further derivatizations are also described. Preliminary mechanistic experiments suggest the intermediacy of Ni(0)-ate complexes, leaving some doubt that a canonical catalytic cycle consisting of an initial oxidative addition of the C-OMe bond to Ni(0) species comes into play. PMID- 28030762 TI - Placental Proteomics Provides Insights into Pathophysiology of Pre-Eclampsia and Predicts Possible Markers in Plasma. AB - Pre-eclampsia is a hypertensive disorder characterized by the new onset of hypertension >140/90 mmHg and proteinuria after the 20th week of gestation. The disorder is multifactorial and originates with abnormal placentation. Comparison of the placental proteome of normotensive (n = 25) and pre-eclamptic (n = 25) patients by gel-free proteomic techniques identified a total of 2145 proteins in the placenta of which 180 were differentially expressed (>1.3 fold, p < 0.05). Gene ontology enrichment analysis of biological process suggested that the differentially expressed proteins belonged to various physiological processes such as angiogenesis, apoptosis, oxidative stress, hypoxia, and placental development, which are implicated in the pathophysiology of pre-eclampsia. Some of the differentially expressed proteins were monitored in the plasma by multiple reaction monitoring analysis, which showed an increase in apolipoproteins A-I and A-II in gestational weeks 26-30 (2-fold, p < 0.01), while haptoglobin and hemopexin decreased in gestational weeks 26-30 and week 40/at delivery (1.8 fold, p < 0.01) in pre-eclamptic patients. This study provides a proteomic insight into the pathophysiology of pre-eclampsia. Identified candidate proteins can be evaluated further for the development of potential biomarkers associated with pre eclampsia pathogenesis. PMID- 28030763 TI - Insight into the Role of Size Modulation on Tuning the Band Gap and Photocatalytic Performance of Semiconducting Nitrogen-Doped Graphene. AB - Considerable attention has been focused on transforming graphene (GR) into semiconducting GR by diverse strategies, which can perform as one type of promising photocatalyst toward various photoredox reactions. Herein, we report a facile alkali-assisted hydrothermal method for simultaneous tailoring of the lateral size of GR and nitrogen (N) doping into the GR matrix, by which small sized N-doped GR (S-NGR) can be obtained. For comparison, large-sized N-doped GR (L-NGR) has also been achieved through the same hydrothermal treatment except for the addition of alkali. The photocatalytic activity test shows that S-NGR exhibits much higher activity than L-NGR toward the degradation of organic pollutants under visible-light irradiation. Structure-photoactivity correlation analysis and characterization suggest that the underlying origin for the significantly enhanced visible-light photoactivity of S-NGR in comparison with L NGR can be assigned to the lateral size decrease in the NGR sheet, which is able to tune the band gap of semiconducting NGR, to facilitate the separation and transfer of photogenerated charge carriers, and to improve the adsorption capacity of NGR toward the reactant. It is expected that this work will cast new light on the judicious utilization of semiconducting GR with controlled size modulation and heteroatom doping to tune its physicochemical properties, thereby advancing further developments in the rational design of more efficient semiconducting GR materials for diverse applications in photocatalysis. PMID- 28030764 TI - High Efficiency Inverted Planar Perovskite Solar Cells with Solution-Processed NiOx Hole Contact. AB - NiOx is a promising hole-transporting material for perovskite solar cells due to its high hole mobility, good stability, and easy processability. In this work, we employed a simple solution-processed NiOx film as the hole-transporting layer in perovskite solar cells. When the thickness of the perovskite layer increased from 270 to 380 nm, the light absorption and photogenerated carrier density were enhanced and the transporting distance of electron and hole would also increase at the same time, resulting in a large charge transfer resistance and a long hole extracted process in the device, characterized by the UV-vis, photoluminescence, and electrochemical impedance spectroscopy spectra. Combining both of these factors, an optimal thickness of 334.2 nm was prepared with the perovskite precursor concentration of 1.35 M. Moreover, the optimal device fabrication conditions were further achieved by optimizing the thickness of NiOx hole transporting layer and PCBM electron selective layer. As a result, the best power conversion efficiency of 15.71% was obtained with a Jsc of 20.51 mA.cm-2, a Voc of 988 mV, and a FF of 77.51% with almost no hysteresis. A stable efficiency of 15.10% was caught at the maximum power point. This work provides a promising route to achieve higher efficiency perovskite solar cells based on NiO or other inorganic hole-transporting materials. PMID- 28030765 TI - Nonionic Fluorinated Surfactant Removal from Mesoporous Film Using sc-CO2. AB - Surfactant templated silica thin films were self-assembled on solid substrates by dip-coating using a partially fluorinated surfactant R8F(EO)9 as the liquid crystal template. The aim was 2-fold: first we checked which composition in the phase diagram was corresponding to a 2D rectangular highly ordered crystalline phase and second we exposed the films to sc-CO2 to foster the removal of the surfactant. The films were characterized by in situ X-ray reflectivity (XRR) and grazing incidence small angle X-ray scattering (GISAXS) under CO2 pressure from 0 to 100 bar at 34 degrees C. GISAXS patterns reveal the formation of a 2-D rectangular structure at a molar ratio R8F(EO)9/Si equal to 0.1. R8F(EO)9 micelles have a cylindrical shape, which have a core/shell structure ordered in a hexagonal system. The core contains the R8F part and the shell is a mixture of (EO)9 embedded in the silica matrix. We further evidence that the extraction of the template using supercritical carbon dioxide can be successfully achieved. This can be attributed to both the low solubility parameter of the surfactants and the fluorine and ethylene oxide CO2-philic groups. The initial 2D rectangular structure was well preserved after depressurization of the cell and removal of the surfactant. We attribute the very high stability of the rinsed film to the large value of the wall thickness relatively to the small pore size. PMID- 28030766 TI - Boosted Sensor Performance by Surface Modification of Bifunctional rht-Type Metal Organic Framework with Nanosized Electrochemically Reduced Graphene Oxide. AB - The surface and interface could be designed to enhance properties of electrocatalysts, and they are regarded as the key characteristics. This report describes surface modification of a bifunctional rht-type metal-organic framework (MOF, Cu-TDPAT) with nanosized electrochemically reduced graphene oxide (n-ERGO). The hybrid strategy results in a Cu-TDPAT-n-ERGO sensor with sensitive and selective response toward hydrogen peroxide (H2O2). Compared with Cu-TDPAT, Cu TDPAT-n-ERGO exhibits significantly enhanced electrocatalytic activities, highlighting the importance of n-ERGO in boosting their electrocatalytic activity. The sensor shows a wide linear detection range (4-12 000 MUM), and the detection limit is 0.17 MUM (S/N = 3) which is even lower than horseradish peroxidase or recently published noble metal nanomaterial based biosensors. Moreover, the sensor displays decent stability, excellent anti-interference performance, and applicability in human serum and urine samples. Such good sensing performance can be explained by the synergetic effect of bifunctional Cu TDPAT (open metal sites and Lewis basic sites) and n-ERGO (excellent conductive property). It is expected that rht-type MOF-based composites can provide wider application potential for the construction of bioelectronics devices, biofuel cells, and biosensors. PMID- 28030767 TI - Nonfullerene-Acceptor All-Small-Molecule Organic Solar Cells Based on Highly Twisted Perylene Bisimide with an Efficiency of over 6. AB - Two twisted singly linked perylene bisimide (PBI) dimers with chalcogen bridges in the PBI cores, named C4,4-SdiPBI-S and C4,4-SdiPBI-Se, were synthesized as acceptors for nonfullerene all-small-molecule organic solar cells (NF all-SMSCs). A moderate-band-gap small-molecule DR3TBDTT used as the electron donor displayed complementary absorption with C4,4-SdiPBI-S and C4,4-SdiPBI-Se. It was found that solvent-vapor annealing (SVA) played a critical role in the photovoltaic performance in NF all-SMSCs, which improves the crystallinity of the donor and acceptors, promotes the proper phase segregation domain size, and therefore enhances charge transport. The power conversion efficiencies (PCEs) of NF all SMSC devices based on DR3TBDTT/C4,4-SdiPBI-S and DR3TBDTT/C4,4-SdiPBI-Se increased from 2.52% to 5.81% (JSC = 11.12 mA cm-2, VOC = 0.91 V, and FF = 57.32%) and from 2.65% to 6.22% (JSC = 11.55 mA cm-2, VOC = 0.92 V, and FF = 58.72%), respectively, after exposure to chloroform vapor. The best efficiency of 6.22% is one of the highest PCEs for NF all-SMSC-based PBI acceptors so far. The studies illustrate that highly efficient NF all-SMSCs can be achieved by using a PBI acceptor with a suitable SVA process. PMID- 28030768 TI - Lake Recovery Through Reduced Sulfate Deposition: A New Paradigm for Drinking Water Treatment. AB - This study examined sulfate deposition in Nova Scotia from 1999 to 2015, and its association with increased pH and organic matter in two protected surface water supplies (Pockwock Lake and Lake Major) located in Halifax, Nova Scotia. The study also examined the effect of lake water chemistry on drinking water treatment processes. Sulfate deposition in the region decreased by 68%, whereas pH increased by 0.1-0.4 units over the 16-year period. Average monthly color concentrations in Pockwock Lake and Lake Major increased by 1.7 and 3.8*, respectively. Accordingly, the coagulant demand increased by 1.5 and 3.8* for the water treatment plants supplied by Pockwock Lake and Lake Major. Not only was this coagulant increase costly for the utility, it also resulted in compromised filter performance, particularly for the direct-biofiltration plant supplied by Pockwock Lake that was found to already be operating at the upper limit of the recommended direct filtration thresholds for color, total organic carbon and coagulant dose. Additionally, in 2012-2013 geosmin occurred in Pockwock Lake, which could have been attributed to reduced sulfate deposition as increases in pH favor more diverse cyanobacteria populations. Overall, this study demonstrated the impact that ambient air quality can have on drinking water supplies. PMID- 28030769 TI - Polarizable Multipole-Based Force Field for Aromatic Molecules and Nucleobases. AB - Aromatic molecules with pi electrons are commonly involved in chemical and biological recognitions. For example, nucleobases play central roles in DNA/RNA structure and their interactions with proteins. The delocalization of the pi electrons is responsible for the high polarizability of aromatic molecules. In this work, the AMOEBA force field has been developed and applied to 5 regular nucleobases and 12 aromatic molecules. The permanent electrostatic energy is expressed as atomic multipole interactions between atom pairs, and many-body polarization is accounted for by mutually induced atomic dipoles. We have systematically investigated aromatic ring stacking and aromatic-water interactions for nucleobases and aromatic molecules, as well as base-base hydrogen-bonding pair interactions, all at various distances and orientations. van der Waals parameters were determined by comparison to the quantum mechanical interaction energy of these dimers and fine-tuned using condensed phase simulation. By comparing to quantum mechanical calculations, we show that the resulting classical potential is able to accurately describe molecular polarizability, molecular vibrational frequency, and dimer interaction energy of these aromatic systems. Condensed phase properties, including hydration free energy, liquid density, and heat of vaporization, are also in good overall agreement with experimental values. The structures of benzene liquid phase and benzene-water solution were also investigated by simulation and compared with experimental and PDB structure derived statistical results. PMID- 28030770 TI - {Fe(NO)(2)(9) Dinitrosyl Iron Complex Acting as a Vehicle for the NO Radical. AB - To carry and deliver nitric oxide with a controlled redox state and rate is crucial for its pharmaceutical/medicinal applications. In this study, the capability of cationic {Fe(NO)2}9 dinitrosyl iron complexes (DNICs) [(RDDB)Fe(NO)2]+ (R = Me, Et, Iso; RDDB = N,N'-bis(2,6-dialkylphenyl)-1,4-diaza 2,3-dimethyl-1,3-butadiene) carrying nearly unperturbed nitric oxide radical to form [(RDDB)Fe(NO)2(*NO)]+ was demonstrated and characterized by IR, UV-vis, EPR, NMR, and single-crystal X-ray diffractions. The unique triplet ground state of [(RDDB)Fe(NO)2(*NO)]+ results from the ferromagnetic coupling between two strictly orthogonal orbitals, one from Fe dz2 and the other a pi*op orbital of a unique bent axial NO ligand, which is responsible for the growth of a half-field transition (DeltaMS = 2) from 70 to 4 K in variable-temperature EPR measurements. Consistent with the NO radical character of coordinated axial NO ligand in complex [(MeDDB)Fe(NO)2(*NO)]+, the simple addition of MeCN/H2O into CH2Cl2 solution of complexes [(RDDB)Fe(NO)2(*NO)]+ at 25 degrees C released NO as a neutral radical, as demonstrated by the formation of [S5Fe(NO)2]- from [S5Fe(MU S)2FeS5]2-. PMID- 28030771 TI - Harmonically Assisted Methods for Computing the Free Energy of Classical Crystals by Molecular Simulation: A Comparative Study. AB - Four methods for calculation of the classical free energy of crystalline systems are compared with respect to their efficiency and accuracy. Two of the methods involve thermodynamic integration along an unphysical path (lambda integration, lambdaI), and two involve integration in temperature from the low-temperature harmonic limit (T integration, TI). Specifically, the methods considered are (1) Frenkel-Ladd integration from a noninteracting Einstein crystal reference (ECR lambdaI); (2) conventional integration in temperature (Conv-TI); (3) integration from an interacting quasi-harmonic reference (QHR-lambdaI); and (4) temperature integration using harmonically mapped averaging to evaluate the integrand (HMA TI). The latter two methods are "harmonically assisted", meaning that they exploit the harmonic nature of the crystal to greatly reduce fluctuations in the relevant averages. This feature allows them to deliver a result of much higher precision for a given computational effort, compared to ECR-lambdaI and Conv-TI, and with no less accuracy. Regarding the harmonically assisted methods, HMA-TI has several advantages over QHR-lambdaI with respect to the simplicity of the integration path (which promotes a more accurate result), ease of implementation, and usefulness of the data recorded along the integration path. PMID- 28030772 TI - Donor/Acceptor Properties of Aromatic Molecules in Complex Metal-Molecule Interfaces. AB - We present a comparative study, combining density functional theory with scanning tunneling microscopy/spectroscopy, of two aromatic molecules bonded with a variable number of Cu adatom(s) on a Cu(111) surface. The two molecules, 1,3,5 tris(pyridyl)benzene (TPyB) and 1,3,5-tris(4-radical-phenyl)benzene (TPB), possess the same aromatic backbone but bond weakly versus strongly to Cu with different terminal groups, respectively. We find that TPyB and TPB exhibit, respectively, small versus large charge transfers between the surface and the molecule; this contrast results in opposite shifts in the calculated density of states distributions and thus explains the opposite STS peak shifts observed in our experiments. The two molecules exhibit weak donor versus strong acceptor characters. This work provides a fundamental understanding, on a single-molecule level, of the principle that selecting specific functional groups can effectively and intentionally modify the molecular electronic properties in a wider class of molecule-metal interfaces. PMID- 28030773 TI - Mitochondrial Donation - Clearing the Final Regulatory Hurdle in the United Kingdom. PMID- 28030774 TI - Local and Global Gestalt Laws: A Neurally Based Spectral Approach. AB - This letter presents a mathematical model of figure-ground articulation that takes into account both local and global gestalt laws and is compatible with the functional architecture of the primary visual cortex (V1). The local gestalt law of good continuation is described by means of suitable connectivity kernels that are derived from Lie group theory and quantitatively compared with long-range connectivity in V1. Global gestalt constraints are then introduced in terms of spectral analysis of a connectivity matrix derived from these kernels. This analysis performs grouping of local features and individuates perceptual units with the highest salience. Numerical simulations are performed, and results are obtained by applying the technique to a number of stimuli. PMID- 28030775 TI - Multistability of Delayed Recurrent Neural Networks with Mexican Hat Activation Functions. AB - This letter studies the multistability analysis of delayed recurrent neural networks with Mexican hat activation function. Some sufficient conditions are obtained to ensure that an [Formula: see text]-dimensional recurrent neural network can have [Formula: see text] equilibrium points with [Formula: see text], and [Formula: see text] of them are locally exponentially stable. Furthermore, the attraction basins of these stable equilibrium points are estimated. We show that the attraction basins of these stable equilibrium points can be larger than their originally partitioned subsets. The results of this letter improve and extend the existing stability results in the literature. Finally, a numerical example containing different cases is given to illustrate the theoretical results. PMID- 28030776 TI - Block-Regularized m * 2 Cross-Validated Estimator of the Generalization Error. AB - A cross-validation method based on [Formula: see text] replications of two-fold cross validation is called an [Formula: see text] cross validation. An [Formula: see text] cross validation is used in estimating the generalization error and comparing of algorithms' performance in machine learning. However, the variance of the estimator of the generalization error in [Formula: see text] cross validation is easily affected by random partitions. Poor data partitioning may cause a large fluctuation in the number of overlapping samples between any two training (test) sets in [Formula: see text] cross validation. This fluctuation results in a large variance in the [Formula: see text] cross-validated estimator. The influence of the random partitions on variance becomes serious as [Formula: see text] increases. Thus, in this study, the partitions with a restricted number of overlapping samples between any two training (test) sets are defined as a block-regularized partition set. The corresponding cross validation is called block-regularized [Formula: see text] cross validation ([Formula: see text] BCV). It can effectively reduce the influence of random partitions. We prove that the variance of the [Formula: see text] BCV estimator of the generalization error is smaller than the variance of [Formula: see text] cross-validated estimator and reaches the minimum in a special situation. An analytical expression of the variance can also be derived in this special situation. This conclusion is validated through simulation experiments. Furthermore, a practical construction method of [Formula: see text] BCV by a two-level orthogonal array is provided. Finally, a conservative estimator is proposed for the variance of estimator of the generalization error. PMID- 28030777 TI - Learning the Structural Vocabulary of a Network. AB - Networks have become instrumental in deciphering how information is processed and transferred within systems in almost every scientific field today. Nearly all network analyses, however, have relied on humans to devise structural features of networks believed to be most discriminative for an application. We present a framework for comparing and classifying networks without human-crafted features using deep learning. After training, autoencoders contain hidden units that encode a robust structural vocabulary for succinctly describing graphs. We use this feature vocabulary to tackle several network mining problems and find improved predictive performance versus many popular features used today. These problems include uncovering growth mechanisms driving the evolution of networks, predicting protein network fragility, and identifying environmental niches for metabolic networks. Deep learning offers a principled approach for mining complex networks and tackling graph-theoretic problems. PMID- 28030778 TI - Controllability Analysis of the Neural Mass Model with Dynamic Parameters. AB - The development of control technology for the brain is of potential significance to the prevention and treatment of neuropsychiatric disorders and the improvement of humans' mental health. A controllability analysis of the brain is necessary to ensure the feasibility of the brain control. In this letter, we investigate the influences of dynamical parameters on the controllability in the neural mass model by using controllability indices as quantitative indicators. The indices are obtained by computing Lie brackets and condition numbers of the system model. We show how controllability changes with important parameters of our dynamical (neuronal) model. Our results suggest that the underlying dynamical parameters have certain ranges with better controllability. We hope it can play potential roles in therapy for brain nervous disorder disease. PMID- 28030779 TI - Nitric oxide improves S-assimilation and GSH production to prevent inhibitory effects of cadmium stress on photosynthesis in mustard (Brassica juncea L.). AB - Nitric oxide (NO) is an important gaseous signalling molecule that participates in many developmental and physiological processes, including defense responses against toxic metals in plants. The role of NO in cadmium (Cd)-induced toxic effects on photosynthesis was examined in mustard (Brassica juncea L.) plants. Exposure of plants to 50 MUM Cd significantly enhanced oxidative stress (H2O2 content and lipid peroxidation) and impaired plant growth and photosynthesis, chlorophyll fluorescence and reduced chlorophyll content and stomatal conductance. However, the exogenous application of 100 MUM sodium nitroprusside (SNP, a donor of NO) reversed the effects of Cd through its stimulation of ROS scavenging compounds (superoxide dismutase, ascorbate peroxidase, glutathione reductase and reduced glutathione). Exogenous SNP significantly increased plant growth, photosynthesis and chlorophyll content and diminished the accumulation of reactive oxygen species (H2O2) and TBARS content. It also reduced the effects of Cd on thylakoid membrane of the chloroplasts. Application of SNP together with 1.0 mM SO42- showed better responses than SNP alone. The protective effect of NO was achieved through enhanced production of reduced glutathione (GSH). GSH biosynthesis in plants treated with buthionine sulfoximine (BSO), a GSH biosynthetic inhibitor, was not completely inhibited in presence of NO and S, suggesting that NO stimulated S-assimilation and GSH production of Cd exposed plants. This study concludes that NO counteracts Cd toxicity in B. juncea strongly by regulating S-assimilation and GSH production. PMID- 28030780 TI - In vitro nitro-fatty acid release from Cys-NO2-fatty acid adducts under nitro oxidative conditions. AB - Stress situations are characterized by a rise in reactive oxygen (ROS) and nitrogen (RNS) species levels. Nitro-fatty acids (NO2-FAs), or nitroalkenes, are produced by the interaction of RNS and unsaturated fatty acids, stored in cells, mostly as part of protein-adducted NO2-FAs, and are esterified in complex lipids. These molecules, which have been shown to play a pivotal role as anti inflammatory and pro-survival players, have been widely characterized in animal systems. Recently, it has been reported that NO2-FAs play an important role in plant defense against several stress conditions. Furthermore, a significant increase in NO2-FA levels has been observed under various inflammatory and stressful conditions in both animal and plant systems. In this study, we describe the in vitro release of NO2-FAs from protein-adducts under nitro-oxidative stress conditions. The findings of this study highlight the ability of hydrogen peroxide and peroxynitrite, as representative ROS and RNS molecules induced under stress conditions, to oxidize cysteine-adducted NO2-FAs, which is followed by the release of free nitroalkenes. This release may be partly responsible for the increase in NO2-FA content observed under different stressful conditions in both animal and plant systems as well as the activation of antioxidant and anti inflammatory properties attributed to these molecules. PMID- 28030781 TI - Effects of solid-liquid separation and storage on monensin attenuation in dairy waste management systems. AB - Environmental release of veterinary pharmaceuticals has been of regulatory concern for more than a decade. Monensin is a feed additive antibiotic that is prevalent throughout the dairy industry and is excreted in dairy waste. This study investigates the potential of dairy waste management practices to alter the amount of monensin available for release into the environment. Analysis of wastewater and groundwater from two dairy farms in California consistently concluded that monensin is most present in lagoon water and groundwater downgradient of lagoons. Since the lagoons represent a direct source of monensin to groundwater, the effect of waste management, by mechanical screen separation and lagoon aeration, on aqueous monensin concentration was investigated through construction of lagoon microcosms. The results indicate that monensin attenuation is not improved by increased solid-liquid separation prior to storage in lagoons, as monensin is rapidly desorbed after dilution with water. Monensin is also shown to be easily degraded in lagoon microcosms receiving aeration, but is relatively stable and available for leaching under typical anaerobic lagoon conditions. PMID- 28030782 TI - A comprehensive review of group level model performance in the presence of heteroscedasticity: Can a single model control Type I errors in the presence of outliers? AB - Even after thorough preprocessing and a careful time series analysis of functional magnetic resonance imaging (fMRI) data, artifact and other issues can lead to violations of the assumption that the variance is constant across subjects in the group level model. This is especially concerning when modeling a continuous covariate at the group level, as the slope is easily biased by outliers. Various models have been proposed to deal with outliers including models that use the first level variance or that use the group level residual magnitude to differentially weight subjects. The most typically used robust regression, implementing a robust estimator of the regression slope, has been previously studied in the context of fMRI studies and was found to perform well in some scenarios, but a loss of Type I error control can occur for some outlier settings. A second type of robust regression using a heteroscedastic autocorrelation consistent (HAC) estimator, which produces robust slope and variance estimates has been shown to perform well, with better Type I error control, but with large sample sizes (500-1000 subjects). The Type I error control with smaller sample sizes has not been studied in this model and has not been compared to other modeling approaches that handle outliers such as FSL's Flame 1 and FSL's outlier de-weighting. Focusing on group level inference with a continuous covariate over a range of sample sizes and degree of heteroscedasticity, which can be driven either by the within- or between-subject variability, both styles of robust regression are compared to ordinary least squares (OLS), FSL's Flame 1, Flame 1 with outlier de-weighting algorithm and Kendall's Tau. Additionally, subject omission using the Cook's Distance measure with OLS and nonparametric inference with the OLS statistic are studied. Pros and cons of these models as well as general strategies for detecting outliers in data and taking precaution to avoid inflated Type I error rates are discussed. PMID- 28030783 TI - Total tumor load assessed by one-step nucleic acid amplification assay as an intraoperative predictor for non-sentinel lymph node metastasis in breast cancer. AB - BACKGROUND: This study aimed to determine the relationship between CK19 mRNA copy number in sentinel lymph nodes (SLN) assessed by one-step nucleic acid amplification (OSNA) technique, and non-sentinel lymph nodes (NSLN) metastization in invasive breast cancer. A model using total tumor load (TTL) obtained by OSNA technique was also constructed to evaluate its predictability. METHODS: We conducted an observational retrospective study including 598 patients with clinically T1-T3 and node negative invasive breast cancer. Of the 88 patients with positive SLN, 58 patients fulfill the inclusion criteria. RESULTS: In the analyzed group 25.86% had at least one positive NSLN in axillary lymph node dissection. Univariate analysis showed that tumor size, TTL and number of SLN macrometastases were predictive factors for NSLN metastases. In multivariate analysis just the TTL was predictive for positive NSLN (OR 2.67; 95% CI 1.06 6.70; P = 0.036). The ROC curve for the model using TTL alone was obtained and an AUC of 0.805 (95% CI 0.69-0.92) was achieved. For TTL >1.9 * 105 copies/MUL we got 73.3% sensitivity, 74.4% specificity and 88.9% negative predictive value to predict NSLN metastases. CONCLUSION: When using OSNA technique to evaluate SLN, NSLN metastases can be predicted intraoperatively. This prediction tool could help in decision for axillary lymph node dissection. PMID- 28030784 TI - Dutch Melanoma Treatment Registry: Quality assurance in the care of patients with metastatic melanoma in the Netherlands. AB - BACKGROUND: In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. METHODS: The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma. This includes tumour and patient characteristics, treatment patterns, clinical outcomes, quality of life, healthcare utilisation, informal care and productivity losses. These data are used for clinical auditing, increasing the transparency of melanoma care, providing insights into real-world cost-effectiveness and creating a platform for research. RESULTS: Within 1 year, all melanoma centres were participating in the DMTR. The quality performance indicators demonstrated that the BRAF inhibitors and ipilimumab have been safely introduced in the Netherlands with toxicity rates that were consistent with the phase III trials conducted. The median overall survival of patients treated with systemic therapy was 10.1 months (95% confidence interval [CI] 9.1-11.1) in the first registration year and 12.7 months (95% CI 11.6-13.7) in the second year. CONCLUSION: The DMTR is the first comprehensive multipurpose nationwide registry and its collaboration with all stakeholders involved in melanoma care reflects an integrative view of cancer management. In future, the DMTR will provide insights into challenging questions regarding the definition of possible subsets of patients who benefit most from the new drugs. PMID- 28030786 TI - Flow cytometric assay to assess short-term effects of personal care products on the marine microalga Tetraselmis suecica. AB - Large quantities of personal care products (PCPs) are used daily and many of their chemical ingredients are subsequently released into marine environments. Cultures of the marine microalga Tetraselmis suecica were exposed for 24 h to three emerging compounds included in the main classes of PCPs: the UV filter benzophenone-3 (BP-3), the disinfectant triclosan (TCS) and the fragrance tonalide (AHTN). Concentrations tested, expressed as cellular quota (pg cell-1), ranged from 5 to 40 for BP-3, from 2 to 16 for TCS and from 1.2 to 2.4 for AHTN. A small cytometric panel was carried out to evaluate key cytotoxicity biomarkers including inherent cell properties, growth and metabolic activity and cytoplasmic membrane properties. BP-3 caused a significant increase in growth rate, metabolic activity and chlorophyll a fluorescence from 10 pg cell-1. However, growth and esterase activity decreased in cells exposed to all TCS and AHTN concentrations, except the lowest ones. Also these two compounds provoked a significant swelling of cells, more pronounced in the case of TCS-exposed cells. Although all treated cells remained viable, changes in membrane potential were observed. BP-3 and AHTN caused a significant depolarization of cells from 10 to 1.6 pg cell-1, respectively; however all TCS concentrations assayed caused a noticeable hyperpolarization of cells. Metabolic activity and cytoplasmic membrane potential were the most sensitive parameters. It can be concluded that the toxicological model used and the toxicological parameters evaluated are suitable to assess the toxicity of these emerging contaminants. PMID- 28030785 TI - Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension. AB - The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1MUM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-kappaB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-kappaB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH. PMID- 28030787 TI - DNA demethylation mediated by down-regulated TETs in the testes of rare minnow Gobiocypris rarus under bisphenol A exposure. AB - Inevitable BPA exposure resulted in disturbance of DNA methylation status and our published study suspected that BPA has the potentiality to disturb DNA demethylation and GSH production in Gobiocypris rarus testes. To confirm this conjecture, several experiments were carried out in the present study. Adult male G. rarus was exposed to 1, 15 and 225 MUg L-1 (nominal concentration) BPA for two weeks. The levels of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), glutathione (GSH), and enzyme levels for DNA methylation and GSH synthesis in the testes were detected. Meanwhile, the contents of substrates for GSH synthesis were measured. Furthermore, the transcriptional changes of the studied genes were examined. Results indicated that 1-225 MUg L-1 BPA caused decrease of testicular ten-eleven translocation proteins (TETs) with more obvious effects at low concentrations. Moreover, all concentrations of BPA resulted in decrease of 5hmC levels while only 225 MUg L-1 BPA resulted in significant increase of 5mC. In addition, all treatments resulted in significant decrease of GSH and the replenishment of GSH might be mainly accomplished by circular synthesis. These results indicated that BPA exposure inhibited TETs-mediated DNA demethylation and the declined DNA demethylation mediated by TETs may result in DNA hypermethylation at 225 MUg L-1 BPA. In addition, the changes of DNA methylation status were irrelevant with GSH levels. PMID- 28030788 TI - Definitive screening design applied to electrochemical degradation of Chromotrope 2R with BDD anodes. AB - Here, a novel three-level definitive screening design (DSD) was initially employed to investigate the electrochemical degradation of Chromotrope 2R (C2R) with boron-doped diamond (BDD) anodes. Experiments were performed using a synthetic C2R solution containing five supporting electrolytes (Na2SO4, NaCl, Na3PO4, NaNO3 and Na2CO3). The effects of nine quantitative parameters on C2R removal rate: initial C2R concentration (50-100 mg L-1), applied current density (1.29-3.87 mA cm-2), Na2SO4 concentration (0-10 mM), NaCl concentration (0-10 mM), Na3PO4 concentration (0-10 mM), NaNO3 concentration (0-10 mM), Na2CO3 concentration (0-10 mM), flow rate (300-500 mL min-1) and temperature (10-50 degrees C), were investigated. The model obtained was validated and used to select three most significant variables for further investigation. Interestingly, the differing roles of electrolytes during the electrolysis revealed the ion selective nature of BDD anode system. A five-level central composite rotatable design (CCRD) was then employed to describe the C2R conversion as a function of applied current density, NaCl concentration and temperature. The results obtained confirmed the strong capability of DSD to separate and identify the significant variables in BDD technology. Moreover, the strategy (DSD plus CCRD) employed here enabled a significant reduction in the number of experiments (from over 500 to only 38) compared to traditional screening methods. The possible degradation mechanism of C2R in BDD anode cells was also proposed. PMID- 28030789 TI - The SSRI fluoxetine exhibits mild effects on the reproductive axis in the cichlid fish Cichlasoma dimerus (Teleostei, Cichliformes). AB - Among the wide variety of pharmaceuticals released into the environment, Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is one of the most prescribed for the treatment of major depression. It inhibits serotonin (5-HT) reuptake at the presinaptic membrane, increasing serotonergic activity. In vertebrates, including fish, the serotonergic system is closely related to the Hypothalamic Pituitary Gonadal (HPG) axis which regulates reproduction. As FLX can act as an endocrine disrupting compound (EDC) by affecting several reproductive parameters in fish, the aim of this study was to provide an integral assessment of the potential effect of FLX on the reproductive axis of the Neotropical freshwater fish Cichlasoma dimerus. Adult fish were intraperitoneally injected with 2 MUg g-1 FLX or saline every third day for 15 days. No significant differences were found on serotonergic turnover (5-HIAA/5-HT ratio). Pituitary betaLH content in FLX injected females was significantly higher than control females; no significant differences were seen for betaFSH content. Sex steroids remained unaltered, both in males and females fish, after FLX treatment. No plasma vitellogenin was induced in treated males. Some alterations were seen in testes of FLX injected males, such as the presence of foam cells and an acidophilic PAS positive, Alcian-Blue negative secretion in the lobular lumen. Although there is no clear consensus about the effect of this drug on reproductive physiology, these results indicate that FLX is acting as a mild EDC in adults of C. dimerus. PMID- 28030790 TI - Nutrient deprivation in neuroblastoma cells alters 4-hydroxynonenal-induced stress response. AB - 4-hydroxy-2-nonenal (HNE), a toxic lipid peroxidation product, is associated with oxidative damage in cells and involved in various diseases including the initiation and progression of cancer. Cancer cells have a high, adaptable metabolism with a shift from oxidative phosphorylation to glycolysis and rely on high levels of glucose and glutamine as essential nutrients for cell growth. Here we investigated whether the toxic effects of HNE on the mitochondrial membrane potential (MMP) of cancer cells depends on their metabolic state by deprivation of glucose and/or glutamine. The addition of 16 MUM HNE to N18TG2 neuroblastoma cells incubated in glucose medium led to a severe reduction of MMP, which was similar to the MMP of cells fed with both glucose and glutamine. In contrast, HNE addition to cells starved in glutamine medium increased their MMP slightly for a prolonged time period and this was accompanied by increased cellular survival. We found that beta-oxidation of HNE did not cause the increased MMP, since the aldehyde dehydrogenase was distinctly more active in cells with glucose medium. However, after blocking fatty acid beta-oxidation in cells starved in glutamine medium with etomoxir, which inhibits carnitine palmitoyltransferase 1, HNE addition induced a strong reduction of MMP similar to cells in glucose medium. Surprisingly, the effect of more toxic 4-oxo-2-nonenal was less pronounced. Our results suggest that in contrast to cells fed with glucose, glutamine-fed cancer cells are capable of beta-oxidizing fatty acids to maintain their MMP to combat the toxic effects of HNE. PMID- 28030791 TI - Dexamethasone induces docetaxel and cisplatin resistance partially through up regulating Kruppel-like factor 5 in triple-negative breast cancer. AB - PURPOSE: Dexamethasone (Dex), a glucocorticoid (GC), is used as a pretreatment drug in cancer patients undergoing chemotherapy. Dex functions by binding to the glucocorticoid receptor (GR) to prevent allergic reactions and severe chemotherapeutic side effects such as nausea and vomiting. However, the mechanisms by which Dex causes chemoresistance remain unknown. METHODS: We used docetaxel and cisplatin to treat triple-negative breast cancer (TNBC) cells with or without Dex and assessed cell proliferation using a sulforhodamine B colorimetric (SRB) assay. Additionally, Western blotting was employed to measure Kruppel-like factor 5 (KLF5), GR and several apoptosis-related proteins. To determine how the GR regulates KLF5, we used qRT-PCR, luciferase reporter assays and ChIP assays. Finally, we detected the involvement of Dex in TNBC chemotherapeutic resistance using HCC1806 xenograft model in vivo. RESULTS: In this study, we demonstrated that Dex induces docetaxel and cisplatin resistance in TNBC cells in vitro and in vivo. Dex up-regulates pro-survival transcription factor KLF5 expression at both mRNA and protein levels dependent on GR. Importantly, Dex failed to promote cancer cell survival and tumor growth when KLF5 induction was blocked. CONCLUSIONS: We conclude that KLF5 is a Dex-induced gene that contributes to Dex-mediated drug chemoresistance, providing a potential novel target for TNBC treatment. PMID- 28030792 TI - Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis. AB - The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology. PMID- 28030793 TI - Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent. AB - Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALK G1201E mutations were originally identified in anaplastic thyroid cancer (ATC) and characterized as constitutively activating mutations. In this study, we employed in vitro cell culture assays together with biochemical and in vivo Drosophila analyses to characterize their sensitivity to either activation by the FAM150A (AUG-beta) and FAM150B (AUG-alpha) ALK ligands or inhibition by ALK inhibitors. Here we report that neither ALK-L1198F nor ALK-G1201E mutations result in ligand independent gain-of-function (GOF) activity in either in vitro biochemical analysis or the various model systems employed. ALK-L1198F is activated by the FAM150 (AUG) ligands and its ligand-dependant activity is similar to the wild type full length ALK receptor. ALK-G1201E is only very weakly activated by the FAM150 (AUG) ligands, most likely due to impaired protein stability. We conclude that neither ALK-L1198F nor ALK-G1201E displays ligand independent kinase activity, with ALK-L1198F belonging to the class of ligand dependent ALK mutations which are not constitutively active but that responds to ligand activation, while the ALK-G1201E mutation generates an unstable receptor with very low levels of kinase activity. PMID- 28030794 TI - Circulating miRNAs as biomarkers for oral squamous cell carcinoma recurrence in operated patients. AB - MicroRNAs (miRNAs) are small regulatory non-coding RNAs for which altered expression in cancers can serve as potential biomarkers for diseases. We here investigated whether circulating miRNAs can serve as biomarkers for predicting post-operational recurrence of oral squamous cell carcinoma (OSCC) in patients. Plasma samples from 8 Danish OSCC patients were collected before, and one year after surgical operation, as well as from 3 Danish healthy controls and subjected to miRNA profiling by next generation sequencing. Disease recurrence did not occur in the 8 patients when the post-operative plasma samples were collected. Based on the sequencing data, three up-regulated miRNAs (miR-148a-3p, miR-26a-5p and miR-21-5p) and three down-regulated miRNAs (miR-375, miR-92b-3p and miR-486 5p) in the OSCC samples compared to healthy controls were selected for qRT-PCR validation in a Chinese cohort of 20 plasma samples collected before, and 9-12 months after surgical operation, and 18 healthy controls. Disease recurrence had occurred in 8 out of the 20 Chinese patients at the time their post-operative plasma samples were collected. The results of qRT-PCR showed that down-regulation of miR-486-5p, miR-375 and miR-92b-3p were highly associated with OSCC recurrence. This study indicates that the plasma miRNA profile is altered in OSCC during its progression and can be used to monitor the likelihood of OSCC recurrence in patients after surgery. PMID- 28030795 TI - AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis. AB - Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action. PMID- 28030796 TI - The distress thermometer as a predictor for survival in stage III lung cancer patients treated with chemotherapy. AB - BACKGROUND: Depression and Health Related Quality of Life have been associated with prognosis in lung cancer. As the Distress Thermometer measures emotional problems and may share similarities with aspects of Health Related Quality of Life, we aimed to retrospectively assess the prognostic value of the Distress Thermometer in lung cancer patients treated with chemotherapy. METHODS: Patients with stage III lung cancer who were treated at the day-care oncology unit with chemotherapy containing carboplatin from 2009 to 2014 and in whom a Distress Thermometer was performed at the time of the first cycle of chemotherapy were included in this study. RESULTS: In total, one hundred and thirteen patients were included in the analysis. In the simple Cox regression analysis, overall survival did not significantly differ according to Distress Thermometer score. No significant differences in Distress Thermometer score according to stage, histology, (intended) treatment, age, sex, and comorbidity were observed. Also in a multivariable model the Distress Thermometer was not prognostic for overall survival, whereas sex and (intended) treatment was. CONCLUSIONS: In this study no prognostic value of the Distress Thermometer could be established in patients with stage III lung cancer treated with carboplatin. Further research is warranted to address this issue. PMID- 28030798 TI - Combined inhibition of Wee1 and Chk1 gives synergistic DNA damage in S-phase due to distinct regulation of CDK activity and CDC45 loading. AB - Recent studies have shown synergistic cytotoxic effects of simultaneous Chk1- and Wee1-inhibition. However, the mechanisms behind this synergy are not known. Here, we present a flow cytometry-based screen for compounds that cause increased DNA damage in S-phase when combined with the Wee1-inhibitor MK1775. Strikingly, the Chk1-inhibitors AZD7762 and LY2603618 were among the top candidate hits of 1664 tested compounds, suggesting that the synergistic cytotoxic effects are due to increased S-phase DNA damage. Combined Wee1- and Chk1-inhibition caused a strong synergy in induction of S-phase DNA damage and reduction of clonogenic survival. To address the underlying mechanisms, we developed a novel assay measuring CDK dependent phosphorylations in single S-phase cells. Surprisingly, while Wee1 inhibition alone induced less DNA damage compared to Chk1-inhibition, Wee1 inhibition caused a bigger increase in S-phase CDK-activity. However, the loading of replication initiation factor CDC45 was more increased after Chk1- than Wee1 inhibition and further increased by the combined treatment, and thus correlated well with DNA damage. Therefore, when Wee1 alone is inhibited, Chk1 suppresses CDC45 loading and thereby limits the extent of unscheduled replication initiation and subsequent S-phase DNA damage, despite very high CDK-activity. These results can explain why combined treatment with Wee1- and Chk1-inhibitors gives synergistic anti-cancer effects. PMID- 28030799 TI - Resveratrol-induced antinociception is involved in calcium channels and calcium/caffeine-sensitive pools. AB - Resveratrol has been widely investigated for its potential health properties, although little is known about its mechanism in vivo. Previous studies have indicated that resveratrol produces antinociceptive effects in mice. Calcium channels and calcium/caffeine-sensitive pools are reported to be associated with analgesic effect. The present study was to explore the involvement of Ca2+ channel and calcium/caffeine-sensitive pools in the antinociceptive response of resveratrol. Tail-flick test was used to assess antinociception in mice treated with resveratrol or the combinations of resveratrol with MK 801, nimodipine, CaCl2, ryanodine and ethylene glycol tetraacetic acid (EGTA), respectively. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) levels in the spinal cord were also investigated when treated with the above drugs. The results showed that resveratrol increased the tail flick latency in the tail-flick test, in dose-dependent manner. N-methyl-D aspartate (NMDA) glutamate receptor antagonist MK 801 potentiated the antinociceptive effects of sub-threshold dose of resveratrol at 10 mg/kg. Ca2+ channel blocker, however, abolished the antinociceptive effects of resveratrol. In contrast to these results, EGTA or ryanodine treatment (i.c.v.) potentiated resveratrol-induced antinociception. There was a significant decrease in p-CaMKII and an increase in BDNF expression in the spinal cord when combined with MK 801, nimodipine, ryanodine and EGTA. While an increase in p-CaMKII level and a decrease in BDNF expression were observed when high dose of resveratrol combined with CaCl2. These findings suggest that resveratrol exhibits the antinociceptive effects by inhibition of calcium channels and calcium/caffeine-sensitive pools. PMID- 28030800 TI - The role of miR-17-92 in the miRegulatory landscape of Ewing sarcoma. AB - MicroRNAs serve to fine-tune gene expression and play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a tissue still poses a significant problem since the presence of a seed sequence in the 3'UTR of an mRNA and its expression modulation upon ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in Ewing sarcoma. MiR-17-92, one of the most potent oncogenic miRNAs, was recently reported to be among the top EWS-FLI1 activated miRNAs. Using a combination of AGO2 pull-down experiments by PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) and of RNAseq upon miRNA depletion by ectopic sponge expression, we aimed to identify the targetome of miR-17-92 in Ewing sarcoma. Intersecting both datasets we found an enrichment of PAR-CLIP hits for members of the miR-17-92 cluster in the 3'UTRs of genes up regulated in response to mir-17-92 specific sponge expression. Strikingly, approximately a quarter of these genes annotate to the TGFB/BMP pathway, the majority mapping downstream of SMAD signaling. Testing for SMAD phosphorylation, we identify quiet but activatable TGFB signaling and cell autonomous activity of the BMP pathway resulting in the activation of the stemness regulatory transcriptional repressors ID1 and ID3. Taken together, our findings shed light on the complex miRegulatory landscape of Ewing Sarcoma pointing miR-17-92 as a key node connected to TGFB/BMP pathway. PMID- 28030801 TI - The embryonic type of SPP1 transcriptional regulation is re-activated in glioblastoma. AB - Osteopontin (SPP1, a secreted phosphoprotein 1) is primarily involved in immune responses, tissue remodelling and biomineralization. However, it is also overexpressed in many cancers and regulates tumour progression by increasing migration, invasion and cancer stem cell self-renewal. Mechanisms of SPP1 overexpression in gliomas are poorly understood. We demonstrate overexpression of two out of five SPP1 isoforms in glioblastoma (GBM) and differential isoform expression in glioma cell lines. Up-regulated SPP1 expression is associated with binding of the GLI1 transcription factor to the promoter and OCT4 (octamer binding transcription factor 4) to the first SPP1 intron of the SPP1 gene in human glioma cells but not in non-transformed astrocytes. GLI1 knockdown reduced SPP1 mRNA and protein levels in glioma cells. GLI1 and OCT4 are known regulators of stem cell pluripotency. GBMs contain rare cells that express stem cell markers and display ability to self-renew. We reveal that SPP1 is overexpressed in glioma initiating cells defined by high rhodamine 123 efflux, sphere forming capacity and stemness marker expression. Forced differentiation of human glioma spheres reduced SPP1 expression. Knockdown of SPP1, GLI1 or CD44 with siRNAs diminished sphere formation. C6 glioma cells stably depleted of Spp1 displayed reduced sphere forming capacity and downregulated stemness marker expression. Overexpression of the wild type Spp1, but not Spp1 lacking a Cd44 binding domain, rescued cell ability to form spheres. Our findings show re-activation of the embryonic-type transcriptional regulation of SPP1 in malignant gliomas and point to the importance of SPP1-CD44 interactions in self-renewal and pluripotency glioma initiating cells. PMID- 28030803 TI - Redox unbalance modifies neurogenic potential. PMID- 28030802 TI - Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. AB - The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications. PMID- 28030804 TI - Tumor-suppressive microRNA-218 inhibits tumor angiogenesis via targeting the mTOR component RICTOR in prostate cancer. AB - MicroRNAs, a kind of small non-coding RNAs, can regulate gene expression by targeting mRNAs for translational repression or degradation. Much evidence has suggested that miR-218 was a tumor suppressor in many human cancers including prostate cancer. However, the underlying role of miR-218 in tumor angiogenesis and the mechanisms in PCa and other cancers remains to be unclear. Here in this present study, we demonstrated that miR-218 inhibited the tumor angiogenesis of PCa cells in vitro and in vivo. RICTOR, the mTOR component 2, was a direct target of miR-218 and miR218-RICTOR-VEGFA axis was the mechanism inhibiting the tumor angiogenesis of PCa cells. RICTOR knockdown phenocopied miR-218 overexpression in inhibiting prostate cancer angiogenesis. Altogether, our findings indicate that down-regulation of miR-218 contributes to tumor angiogenesis through RICTOR/VEGFA axis in PCa, providing new insights into the potential mechanisms of PCa oncogenesis and revealing the potential of miR-218 as a useful serum biomarker and a new therapeutic target for human PCa. PMID- 28030805 TI - TIMP-1 and CD82, a promising combined evaluation marker for PDAC. AB - Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1-tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP 1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential. PMID- 28030807 TI - High expression of the long non-coding RNA HEIRCC promotes Renal Cell Carcinoma metastasis by inducing epithelial-mesenchymal transition. AB - Increasing evidence indicates that long non-coding RNAs (lncRNAs) have been associated with cancer development. However, the contributions of lncRNAs to renal cell carcinoma (RCC) remain poorly characterized. Here, we identified a novel lncRNA, termed HEIRCC, which was up-regulated in RCC tissues through lncRNA microarray analysis and subsequent validation in 60 RCC clinical specimens and cell lines. The high expression of HEIRCC is associated closely with the clinical pathology features such as larger tumor size, poor differentiation, lymphatic metastasis. In vitro assays revealed that HEIRCC knockdown could inhibit cell proliferation, trigger late apoptosis, suppress cell migration and invasion. We further demonstrated that depletion of HEIRCC reduce the epithelial to mesenchymal transition (EMT) program by regulating expression levels of EMT associated markers in RCC cells. Thus, HEIRCC might be act as an important regulator of EMT in RCC progression and might be a novel therapeutic target for the advanced RCC therapy. PMID- 28030808 TI - Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. Most patients are not diagnosed until the cancer is at an advanced stage with poor prognosis. Notch1 signaling pathway plays an oncogenic role in EOC. There have been few studies on enzymatic activity of gamma-secretase and the mechanism of how gamma-secretase inhibitor works on cancer cell. Here, we show that Jagged1 and NICD were highly expressed in ovarian carcinoma. The expressions of Notch1, Jagged1 and NICD in Notch1 pathway did not correlate with outcome in ovarian cancer. The enzymatic activity of gamma-secretase in ovarian cancer cell lines SKOV3, CAOV3 and ES2 is significantly higher than in normal ovarian epithelial cell line T29. DAPT (a gamma-secretase inhibitor) reduced the enzymatic activity of gamma-secretase, inhibited the proliferation, and increased the apoptosis in ovarian cancer cell lines. Hence, gamma-secretase inhibitor may become a highly promising novel therapeutic strategy against ovarian cancer in the field of precision medicine. PMID- 28030809 TI - Genomic regulation of invasion by STAT3 in triple negative breast cancer. AB - Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as "triple negative breast cancer" (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 5 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis. PMID- 28030810 TI - The tumor microenvironment promotes cancer progression and cell migration. AB - The tumor microenvironment contributes to cancer progression, in part through interactions between tumor and normal stromal cells. This study analyzed morphological and molecular changes induced in co-cultured human fibroblasts (HFs) and the MG-63 osteosarcoma cell line. Co-cultured cell monolayers were morphologically analyzed using high resolution scanning electron microscopy (HR SEM), and trans-well assays were performed to assess cell migration and invasion. Proteins involved in inflammatory responses, cancer cell invasion, and angiogenesis were assessed using western blotting. HR-SEM showed progressive spatial orientation loss by fibroblasts in contact with MG-63s, while MG-63s proliferated rapidly and invaded HF space. Trans-well assays showed enhanced MG 63 migration in the presence of HFs. IL-6 expression was increased in co-cultured HFs, possibly stimulated by TNF-alpha. HFs do not normally express YKL-40 but did so in co-culture. Band densitometric analyses showed that increasing YKL-40 expression was followed by VEGF overexpression, especially in MG-63s. Finally, our results confirmed fibroblasts as the main matrix metalloproteinase source in this tumor microenvironment. Our study sheds new light on how tumor-stroma interactions promote tumor development and progression, and may support identification of novel anti-cancer therapeutics. PMID- 28030811 TI - Systematic review of resecting primary tumor in MNETs patients with unresectable liver metastases. AB - BACKGROUND: Treatment for midgut neuroendocrine tumor patients with unresectable liver metastasis has long been a controversial issue. This system review aims to summarize existing evidence concerning the value of primary tumor resection in this group of patients. RESULTS: 8 cohort studies were identified for qualitative analysis. None of them strictly met with the inclusion criteria and meta-analysis was impossible. There was a tendency towards better overall survival for the primary tumor resected group in all 8 studies, in which 6 demonstrated significant difference. Progression free survival to liver disease was prolonged and less patients died of liver failure in the resected group. METHODS: MEDLINE, EMBASE and CENTRAL were searched until 2016/7/4 for relevant studies, with primary outcome being overall survival, and secondary outcome being progression free survival, cause of death and symptom relief. CONCLUSIONS: Current evidence supports resection of primary tumor for midgut neuroendocrine tumor patients with liver metastases, but randomized controlled trials are required to reach a final conclusion. PMID- 28030812 TI - Aflatoxin B1 invokes apoptosis via death receptor pathway in hepatocytes. AB - The fungal metabolites produced by Aspergillus flavus and Aspergillus parasiticus cause detrimental health effects on humans and animals. Particularly aflatoxin B1 (AFB1) is the most studied and a well-known global carcinogen, producing hepatotoxic, genotoxic and immunotoxic effects in multiple species. AFB1 is shown to provoke liver dysfunctioning by causing hepatocytes apoptosis and disturbing cellular enzymatic activities. In liver, AFB1 causes apoptosis via extrinsic mechanism because of high expression of death receptor pathway. The detailed mechanism of AFB1 induced hepatocytes apoptosis, via death receptor pathway still remains elusive. So the present study was conducted to explore apoptotic mechanism initiated by death receptors and associated genes in aflatoxin B1 induced liver apoptosis in chickens fed with AFB1 for 3 weeks. Results from the present study displayed histopathological and ultrastructural changes in liver such as hydropic degeneration, fatty vacuolar degeneration and proliferation of bile duct in hepatocytes in AFB1 group, along with imbalance between reactive oxygen species (ROS) and antioxidant defense system upon AFB1 ingestion. Moreover, AFB1 intoxicated chickens showed upregulation of death receptors FAS, TNFR1 and associated genes and downregulation of inhibitory apoptotic proteins XIAP and BCL-2. The results obtained from this novel and comprehensive study including histopathological, ultrastructural, flow cytometrical and death receptor pathway gene expression profiles, will facilitate better understanding of mechanisms and involvement of death receptor pathway in hepatocytes apoptosis induced by AFB1 and ultimately may be helpful in bringing down the toxigenic potential of AFB1. PMID- 28030813 TI - Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3 phosphorylation. AB - Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs).We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs.Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3 phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs.In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma. PMID- 28030814 TI - Paeoniflorin ameliorates interferon-alpha-induced neuroinflammation and depressive-like behaviors in mice. AB - Long-term treatment with high-dose Interferon-alpha (IFN-alpha) has resulted in depression in 30-50% of the patients. Paeoniflorin may ameliorate the IFN-alpha induced depression; however, the underlying mechanism is less studied. Here, we investigated the prophylactic antidepressant and anti-neuroinflammatory effects of paeoniflorin on the behaviors and specific emotion-related regions of the brain in mice with IFN-alpha-induced depression. A series of behavior assessments were conducted to identify the depressive state after subcutaneously IFN-alpha injections and with or without intragastrically paeoniflorin administration in C57BL/6J mice. Levels of many inflammatory-related cytokines in serum, mPFC, vHi and amygdala were determined by cytokine array analysis. Furthermore, microglia and astrocyte activation in these three regions were evaluated by immunohistochemistry. We found that the mice which were subcutaneously injected IFN-alpha 15*106 IU/kg for 4 successive weeks to mimic an IFN-alpha-induced depression model had distinct inflammatory changes in the amygdala. Interestingly, 4-week 20 mg/kg or 40 mg/kg paeoniflorin pretreatments reversed the depressive-like behaviors and the abnormal inflammatory cytokine levels in the serum, mPFC, vHi and amygdala. These cytokines were not limited to the commonly reported IL-6, IL-1beta and TNF-alpha, but also IL-9, IL-10, IL-12, and MCP-1. Besides, the increased density of microglia in IFN-alpha-treated mice was reversed by paeoniflorin in these three brain areas. Taken together, our data suggest that paeoniflorin can reverse the long-term, high-dose IFN-alpha-induced depressive-like behaviors that were associated with local distinct neuroinflammation in the mPFC, vHi and particularly the amygdala. Paeoniflorin might have a preventive therapeutic potential in IFN-alpha-induced depression. PMID- 28030815 TI - A novel non-canonical Wnt signature for prostate cancer aggressiveness. AB - Activation of the Canonical Wnt pathway (CWP) has been linked to advanced and metastatic prostate cancer, whereas the Wnt5a-induced non-canonical Wnt pathway (NCWP) has been associated with both good and poor prognosis. A newly discovered NCWP, Wnt5/Fzd2, has been shown to induce epithelial-to-mesenchymal transition (EMT) in cancers, but has not been investigated in prostate cancer. The aim of this study was to investigate if the CWP and NCWP, in combination with EMT, are associated with metabolic alterations, aggressive disease and biochemical recurrence in prostate cancer. An initial analysis was performed using integrated transcriptomics, ex vivo and in vivo metabolomics, and histopathology of prostatectomy samples (n=129), combined with at least five-year follow-up. This analysis detected increased activation of NCWP through Wnt5a/ Fzd2 as the most common mode of Wnt activation in prostate cancer. This activation was associated with increased expression of EMT markers and higher Gleason score. The transcriptional association between NCWP and EMT was confirmed in five other publicly available patient cohorts (1519 samples in total). A novel gene expression signature of concordant activation of NCWP and EMT (NCWP-EMT) was developed, and this signature was significantly associated with metastasis and shown to be a significant predictor of biochemical recurrence. The NCWP-EMT signature was also associated with decreased concentrations of the metabolites citrate and spermine, which have previously been linked to aggressive prostate cancer. Our results demonstrate the importance of NCWP and EMT in prostate cancer aggressiveness, suggest a novel gene signature for improved risk stratification, and give new molecular insight. PMID- 28030816 TI - Down-regulation of 14q32-encoded miRNAs and tumor suppressor role for miR-654-3p in papillary thyroid cancer. AB - Papillary thyroid carcinoma (PTC) is the most prevalent malignant neoplasia of the thyroid gland. A fraction of PTC cases show loss of differentiation and aggressive behavior, with radioiodine therapy resistance and metastasis. Although microRNAs (miRNAs) emerged as promising molecular markers for PTC, their role in the loss of differentiation observed during PTC progression remains to be fully understood. We performed the large-scale analysis of miRNA expression during PTC progression in BRAFT1799A-transgenic animals (Tg-Braf) and thyroid cancer cell lines and identified the marked downregulation of several miRNAs from the region 14q32. Data from The Cancer Genome Atlas (TCGA) confirmed the global downregulation of miRNAs from the 14q32 region in human PTC. The regulatory network potentially suppressed by these miRNAs suggests that key cancer-related biological processes such as cell proliferation, adhesion, migration and angiogenesis. Among the downregulated miRNAs, we observed that miR-654-3p levels decrease with long-term PTC progression in Tg-Braf mice and inversely correlate with EMT. The in vitro restoration of miR-654-3p decreased cell proliferation and migration and induced reprogramming of metastasis-related genes, suggesting a tumor suppressor role for this miRNA. In conclusion, we show global downregulation of 14q32-encoded miRNAs in an in vivo model of PTC progression. The potential circuitry in which these miRNAs are involved suggests that these miRNAs could play a key role in the pathophysiology of PTC and therefore be relevant for the development of new therapeutic strategies. PMID- 28030817 TI - CD44v6 overexpression related to metastasis and poor prognosis of colorectal cancer: A meta-analysis. AB - CD44v6 has recently been reported as a biomarker for colorectal cancer. However, the clinical and prognostic significance of CD44v6 in colorectal cancer remains controversial. Therefore, we performed a meta-analysis to clarify this issue. A comprehensive literature search was performed using Medline, Embase and Web of Science, and the statistical analysis was conducted using Stata software. A total of twenty-one studies including 3918 colorectal cancer cases were included. The pooled analysis showed that CD44v6 overexpression in colorectal cancer was an independent prognostic marker correlating with lower 5-year overall survival rate (OR=0.78, 95%CI =0.67-0.91, p=0.001). CD44v6 overexpression was also associated with more lymph node invasion (OR=1.48, 95%CI= 1.02-2.15, p=0.04), and advanced Dukes stage (OR=2.47, 95%CI= 1.29-4.73, p=0.01). In addition, while excluding Zolbec's study, CD44v6 overexpression was associated with distance metastasis (OR=1.65, 95%CI =1.13-2.40, p=0.01). Taken together, this meta-analysis suggested that CD44v6 is an efficient prognostic factor in colorectal cancer. PMID- 28030818 TI - ASIC1 promotes differentiation of neuroblastoma by negatively regulating Notch signaling pathway. AB - In neurons, up-regulation of Notch activity either inhibits neurite extension or causes retraction of neurites. Conversely, inhibition of Notch1 facilitates neurite extension. Acid-sensing ion channels (ASICs) are a family of proton-gated cation channels, which play critical roles in synaptic plasticity, learning and memory and spine morphogenesis. Our pilot proteomics data from ASIC1a knock out mice implicated that ASIC1a may play a role in regulating Notch signaling, therefore, we explored whether or not ASIC1a regulates neurite growth during neuronal development through Notch signaling. In this study, we determined the effects of ASIC1a on neurite growth in a mouse neuroblastoma cell line, NS20Y cells, by modulating ASIC1a expression. We also determined the relationship between ASIC1a and Notch signaling on neuronal differentiation. Our results showed that down-regulation of ASIC1a in NS20Y cells inhibits CPT-cAMP induced neurite growth, while over expression of ASIC1a promotes its growth. In addition, down-regulation of ASIC1a increased the expression of Notch1 and its target gene Survivin while inhibitor of Notch significantly prevented the neurite extension induced by ASIC1a in NS20Y cells. These data indicate that Notch1 signaling may be required for ASIC1a-mediated neurite growth and neuronal differentiation. PMID- 28030819 TI - Hyperhomocysteinemia results from and promotes hepatocellular carcinoma via CYP450 metabolism by CYP2J2 DNA methylation. AB - Hyperhomocysteinemia (HHcy) can result from liver disease or dysfunction and further alters intracellular lipid metabolism. Cytochrome P450 (CYP) arachidonic acid epoxygenases are expressed in human cancers and promote cancer metastasis. This study explored the interaction of Hcy and CYP450 metabolism in hepatocellular carcinoma (HCC). The levels of 4-epoxyeicosatrienoic acid (EET) isomers and their generative enzyme CYP2J2 level as well as intracellular Hcy level were higher in 42 cases of HCC than in paired non-tumor tissue. Elevated Hcy-decreased DNA methylation on SP1/AP1 binding motifs and enhancement on the CYP2J2 promoter via ERK1/2 signaling was essential for CYP2J2 upregulation and EET metabolism. Increased Hcy level enhanced the neoplastic cellular phenotype, which was reversed by CYP2J2 knockdown in vitro. Furthermore, tumor growth and size as well as patterns of CYP2J2 expression and DNA demethylation were increased with HHcy in mice induced orthotopically by 2% (wt/wt) L-methionine with or without folate deficiency. Moreover, the effect was attenuated by shRNA knockdown of CYP2J2. Thus, HHcy results from but can also promote hepatocarcingenesis via CYP450-EET metabolism by crosstalk of DNA demethylation of CYP2J2 and ERK1/2 signaling. PMID- 28030820 TI - Unsupervised consensus cluster analysis of [18F]-fluoroethyl-L-tyrosine positron emission tomography identified textural features for the diagnosis of pseudoprogression in high-grade glioma. AB - RATIONALE: Timely detection of pseudoprogression (PSP) is crucial for the management of patients with high-grade glioma (HGG) but remains difficult. Textural features of O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) mirror tumor uptake heterogeneity; some of them may be associated with tumor progression. METHODS: Fourteen patients with HGG and suspected of PSP underwent FET-PET imaging. A set of 19 conventional and textural FET-PET features were evaluated and subjected to unsupervised consensus clustering. The final diagnosis of true progression vs. PSP was based on follow up MRI using RANO criteria. RESULTS: Three robust clusters have been identified based on 10 predominantly textural FET-PET features. None of the patients with PSP fell into cluster 2, which was associated with high values for textural FET PET markers of uptake heterogeneity. Three out of 4 patients with PSP were assigned to cluster 3 that was largely associated with low values of textural FET PET features. By comparison, tumor-to-normal brain ratio (TNRmax) at the optimal cutoff 2.1 was less predictive of PSP (negative predictive value 57% for detecting true progression, p=0.07 vs. 75% with cluster 3, p=0.04). PRINCIPAL CONCLUSIONS: Clustering based on textural O-(2-[18F]fluoroethyl)-L-tyrosine PET features may provide valuable information in assessing the elusive phenomenon of pseudoprogression. PMID- 28030822 TI - Mu opioid receptor: from pain to glucose metabolism. PMID- 28030821 TI - Vitamin D status among long-term survivors of testicular cancer. AB - A correlation between disturbances in hormone levels and the onset of metabolic disorders has been reported in long-term survivors of testicular cancer (TC).We evaluated serum vitamin D levels and other biological parameters in a consecutive series of 61 long-term (>=3 years) unilateral TC survivors with a median a follow up of 4 years and in a cohort of healthy males. Deficient vitamin D levels were observed in 10 (17%) of the 58 long-term unilateral TC survivors but were not reported in healthy males (p=.019, Fisher test). Median vitamin D levels were 18.6 ug/L in 58 assessable TC survivors and 23.6 ug/L in 40 healthy males (p=.031). In univariate logistic regression analysis, TC diagnosis was associated with inadequate levels of vitamin D (p=.047). Vitamin D levels were lower when follow-up was > 10 years, albeit this difference was not statistically significant (p=.074). Long-term (especially > 10 years) TC survivors may have difficulty maintaining optimal vitamin D levels. Larger studies are needed to better characterize vitamin D status and possible correlations with premature hormonal aging reported in long-term TC survivors. PMID- 28030823 TI - GDE2/GDPD5 in neuroblastoma. PMID- 28030824 TI - mTOR pathway in familial focal epilepsies. PMID- 28030825 TI - Fas-associated factor 1 inhibits tumor growth by suppressing Helicobacter pylori induced activation of NF-kappaB signaling in human gastric carcinoma. AB - Loss of Fas-associated factor 1 (FAF1) may act as a pro-survival signal in diseased cells, but whether this is true in gastric carcinoma remains unclear. Here we report that FAF1 was expressed at low levels in gastric carcinoma tissues and cell lines, and its expression correlated with larger tumors, higher histology grade, higher TNM stage, tumor infiltration, and lymph node metastasis. Univariate analysis and survival curve analysis identified low FAF1 expression as a predictor of poor prognosis. FAF1 overexpression in HGC-27 gastric cancer cells induced cell apoptosis and inhibited cell proliferation and growth. It also reduced colony formation in vitro and tumor growth in mice. We found that Helicobacter pylori, a risk factor for gastric cancer, down-regulated FAF1 expression via NF-kappaB signaling. Knock-down of IKKbeta or p65 expression in gastric cancer cells reversed H. pylori-induced down-regulation of FAF1 expression and partially blocked H. pylori-induced secretion of inflammatory cytokines TNF-alpha and IL-8. Our results suggest that loss of FAF1 contributes to human gastric carcinogenesis by allowing H. pylori to activate NF-kappaB signaling. PMID- 28030826 TI - Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion. AB - Recent studies indicate that the transient receptor potential canonical 6 (TRPC6) channel is highly expressed in several types of cancer cells. However, it remains unclear whether TRPC6 contributes to the malignancy of human non-small cell lung cancer (NSCLC). We used a human NSCLC A549 cell line as a model and found that pharmacological blockade or molecular knockdown of TRPC6 channel inhibited A549 cell proliferation by arresting cell cycle at the S-G2M phase and caused a significant portion of cells detached and rounded-up, but did not induce any types of cell death. Western blot and cell cycle analysis show that the detached round cells at the S-G2M phase expressed more TRPC6 than the still attached polygon cells at the G1 phase. Patch-clamp data also show that TRPC whole-cell currents in the detached cells were significantly higher than in the still attached cells. Inhibition of Ca2+-permeable TRPC6 channels significantly reduced intracellular Ca2+ in A549 cells. Interestingly, either blockade or knockdown of TRPC6 strongly reduced the invasion of this NSCLC cell line and decreased the expression of an adherent protein, fibronectin, and a tight junction protein, zonula occluden protein-1 (ZO-1). These data suggest that TRPC6-mediated elevation of intracellular Ca2+ stimulates NSCLC cell proliferation by promoting cell cycle progression and that inhibition of TRPC6 attenuates cell proliferation and invasion. Therefore, further in vivo studies may lead to a consideration of using a specific TRPC6 blocker as a complement to treat NSCLC. PMID- 28030827 TI - Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue. AB - Sirtuin 1 (Sirt1) promotes adaptive thermogenesis by controlling the acetylation status of enzymes and transcriptional factors in interscapular brown adipose tissue (iBAT). However, the effects of Sirt1 on endoplasmic reticulum (ER) stress and apoptosis of iBAT remain elusive. In this study, the mRNA levels of Sirt1 and thermogenesis genes were reduced but the genes related with ER stress were elevated in iBAT of high-fat diet (HFD)-induced obese mice. Moreover, ER stress further inhibited mRNA level of Sirt1 and triggered brown adipocyte apoptosis in vitro and in vivo. Further analysis revealed that Sirt1 overexpression alleviated ER stress-induced brown adipocyte apoptosis by inhibiting Smad3 and ATF4. In addition, Smad3 bound to ATF4 promoter region and positively transcriptional regulation of ATF4. Our data also confirmed that Sirt1 reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by directly interacting with ATF4. Furthermore, Sirt1 attenuated tunicamycin-induced cold intolerance and elevating thermogenesis by inhibiting ER stress and apoptosis in iBAT. In summary, our data collectively revealed Sirt1 reduced ER stress and apoptosis of brown adipocyte in vivo and in vitro by inhibiting Smad3/ATF4 signal. These data reveal a novel mechanism that links Sirt1 to brown adipocyte apoptosis. PMID- 28030828 TI - Methicillin-resistant staphylococcus aureus isolates in a hospital of shanghai. AB - Methicillin-resistant Staphylococcus aureus (MRSA) strains are now common both in the health care setting and in the community. Active surveillance is critical for MRSA control and prevention. Specimens of patients (200 patients with 1119 specimens) as well as medical staff and hospital setting (1000 specimens) were randomly sampled in a level 2 hospital in Shanghai from September 2011 to August 2012. Isolation, cultivation and identification of S. aureus were performed. Totally, 67 S. aureus strains were isolated. 32 S. aureus strains were isolated from patient samples; 13 (13/32, 40.6%) of the 32 S. aureus isolates were MRSA; sputum sample and patients in the department of general internal medicine were the most frequent specimen and patient group for S. aureus strains isolation. Remaining 35 S. aureus strains were isolated from the medical staff and hospital setting; 20 (20/35, 57.1%) of the 35 S. aureus isolates were MRSA; specimens sampled from doctors and nurses' hands and nose and hospital facilities were the most frequent samples to isolate S. aureus. Resistant and virulent genes detection showed that, all 33 MRSA strains were mecA positive which accounts for 49.3% of the 67 S. aureus strains; 38 isolates were Panton-Valentine leukocidin (PVL) gene positive which accounts for 56.7% of the 67 S. aureus strains; and 17 (17/67, 25.4%) isolates are mecA and PVL genes dual positive. Multidrug-resistant strains of MRSA and PVL positive S. aureus are common in patients, medical staff and hospital setting, the potential health threat is worthy of our attention. PMID- 28030829 TI - CBX7 suppresses cell proliferation, migration, and invasion through the inhibition of PTEN/Akt signaling in pancreatic cancer. AB - Chromobox protein homolog 7 (CBX7), one of the polycomb group (PcG) proteins, is a transcriptional repressor involved in the regulation of cell proliferation and senescence. In the present study, we showed that CBX7 negatively regulates the proliferation, viability, chemoresistance, and migration of pancreatic cancer cells. Overexpression of CBX7 significantly inhibited the proliferation of pancreatic cancer cells in vitro and in vivo. Depletion of CBX7 facilitated their growth. CBX7 also impaired the viability and chemoresistance of pancreatic cancer cells. Transwell assays showed that CBX7 reduces the migratory capacity of pancreatic cancer cells. Of note, CBX7 reduced PTEN/Akt signaling in pancreatic cancer cells by increasing PTEN transcription, suggesting involvement of PTEN/Akt pathway in the tumor suppressive activity of CBX7. In addition, immunohistochemical analysis the CBX7 and PTEN expression in 74 surgically resected pancreatic ductal adenocarcinoma (PDAC) specimens revealed that CBX7 expression is significantly downregulated in pancreatic ductal adenocarcinoma, compared to normal pancreatic tissues. Reduced expression of CBX7 and PTEN was associated with increased malignancy grade in pancreatic adenocarcinoma, whereas maintenance of CBX7 and PTEN expression showed a trend toward a longer survival. These findings suggest CBX7 is an important tumor suppressor that negatively modulates PTEN/Akt signaling during pancreatic tumorigenesis. PMID- 28030830 TI - Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia. AB - B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL. PMID- 28030831 TI - Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug. AB - Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5 year survival rate for patients with recurrent or metastatic osteosarcoma is 20 30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p<0.001 compared to untreated control). The osteosarcoma was only partially sensitive to the molecular-targeting drug sorafenib, which did not arrest its growth. S. typhimurium A1-R was significantly more effective than sorafenib (P <0.001). S. typhimurium grew in the treated tumors and caused extensive necrosis of the tumor tissue. These data show that S. typhimurium A1-R is powerful therapy for an osteosarcoma patient-derived xenograft model. PMID- 28030833 TI - Exploring ncRNAs in Alzheimer's disease by miRMaster. PMID- 28030832 TI - Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis. AB - Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, few studies have identified metastasis-related epigenetic drivers, in part because a framework for identifying driver epigenetic changes in metastasis has not been established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns in three cutaneous primary and metastatic melanoma cell line pairs to identify metastasis-related epigenetic drivers. Globally, metastatic melanoma cell lines were hypomethylated compared to the matched primary melanoma cell lines. Using whole genome RRBS we identified 75 shared (10 hyper- and 65 hypomethylated) differentially methylated fragments (DMFs), which were associated with 68 genes showing significant methylation differences. One gene, Early B Cell Factor 3 (EBF3), exhibited promoter hypermethylation in metastatic cell lines, and was validated with bisulfite sequencing and in two publicly available independent melanoma cohorts (n = 40 and 458 melanomas, respectively). We found that hypermethylation of the EBF3 promoter was associated with increased EBF3 mRNA levels in metastatic melanomas and subsequent inhibition of DNA methylation reduced EBF3 expression. RNAi-mediated knockdown of EBF3 mRNA levels decreased proliferation, migration and invasion in primary and metastatic melanoma cell lines. Overall, we have identified numerous epigenetic changes characterising metastatic melanoma cell lines, including EBF3-induced aggressive phenotypic behaviour with elevated EBF3 expression in metastatic melanoma, suggesting that EBF3 promoter hypermethylation may be a candidate epigenetic driver of metastasis. PMID- 28030834 TI - Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells. AB - Resistance to chemotherapy and a high relapse rate highlight the importance of finding new therapeutic options for the treatment of acute myeloid leukemia (AML). Histone deacetylase (HDAC) inhibitors (HDACIs) are a promising class of drugs for the treatment of AML. HDACIs have limited single-agent clinical activities, but when combined with conventional or investigational drugs they have demonstrated favorable outcomes. Previous studies have shown that decreasing expression of important DNA damage repair proteins enhances standard chemotherapy drugs. In our recent studies, the pan-HDACI panobinostat has been shown to enhance conventional chemotherapy drugs cytarabine and daunorubicin in AML cells by decreasing the expression of BRCA1, CHK1, and RAD51. In this study, we utilized class- and isoform-specific HDACIs and shRNA knockdown of individual HDACs to determine which HDACs are responsible for decreased expression of BRCA1, CHK1, and RAD51 following pan-HDACI treatment in AML cells. We found that inhibition of both HDAC1 and HDAC2 was necessary to decrease the expression of BRCA1, CHK1, and RAD51, enhance cytarabine- or daunorubicin-induced DNA damage and apoptosis, and abrogate cytarabine- or daunorubicin-induced cell cycle checkpoint activation in AML cells. These findings may aid in the development of rationally designed drug combinations for the treatment of AML. PMID- 28030835 TI - Co-targeting translation and proteasome rapidly kills colon cancer cells with mutant RAS/RAF via ER stress. AB - Colorectal cancers with mutant RAS/RAF are therapy refractory. Deregulated mRNA translation has become an emerging target in cancer treatment. We recently reported that mTOR inhibitors induce apoptosis via ER stress and the extrinsic pathway upon acute inhibition of the eIF4F complex in colon cancer cells and xenografts, while mutant BRAF600E leads to therapeutic resistance via ERK mediated Mcl-1 stabilization. In this study, we demonstrated that several other translation inhibitors also activate ER stress and the extrinsic apoptotic pathway. Co-targeting translation and proteasome using the combination of Episilvestrol and Bortezomib promoted strong ER stress and rapid killing of colon cancer cells with mutant RAS/RAF in culture and mice. This combination led to marked induction of ER stress and ATF4/CHOP, followed by DR5- and BAX-dependent apoptosis, but unexpectedly with maintained or even increased levels of prosurvival factors such as p-AKT, p-4E-BP1, Mcl-1, and eiF4E targets c-Myc and Bcl-xL. Our study supports that targeting deregulated proteostasis is a promising approach for treating advanced colon cancer via induction of destructive ER stress that overcomes multiple resistance mechanisms associated with translation inhibition. PMID- 28030836 TI - Expression and clinical relevance of epithelial and mesenchymal markers in circulating tumor cells from colorectal cancer. AB - Circulating tumor cells (CTCs) with phenotypic hallmarks of epithelial mesenchymal transition (EMT) reportedly contribute to tumor metastasis in different cancer types. We therefore evaluated the expression of EMT markers in CTCs obtained from a large cohort of Chinese patients with colorectal cancer (CRC) and investigated their clinical relevance. The CanPatrolTM CTC enrichment technique was used to isolate and classify CTCs. CTCs were detected in 1046 of 1203 patients (86.9%), and three phenotypes were identified based on the expression of epithelial and mesenchymal markers: epithelial CTCs, biophenotypic (epithelial/mesenchymal) CTCs, and mesenchymal CTCs. Total CTC numbers positively correlated with both clinical stage and lymph node metastasis and distant metastasis. Furthermore, both biophenotypic and mesenchymal, but not epithelial, CTCs, correlated with the above parameters, suggesting CTCs displaying a mesenchymal phenotype denote more aggressive disease and metastatic potential. This is the first study to demonstrate a significant correlation between CTCs displaying a mesenchymal phenotype and both clinical stage and metastasis in a large cohort of patients with CRC. Our findings suggest that assessment of not only epithelial, but also mesenchymal markers in CTC analyses may offer valuable assistance for tumor staging and metastasis evaluation in patients with CRC. PMID- 28030837 TI - Bafilomycin A1 triggers proliferative potential of senescent cancer cells in vitro and in NOD/SCID mice. AB - Anticancer therapies that induce DNA damage tend to trigger senescence in cancer cells, a process known as therapy-induced senescence (TIS). Such cells may undergo atypical divisions, thus contributing to tumor re-growth. Accumulation of senescent cancer cells reduces survival of patients after chemotherapy. As senescence interplays with autophagy, a dynamic recycling process, we sought to study whether inhibition of autophagy interferes with divisions of TIS cells. We exposed human colon cancer HCT116 cells to repeated cycles of a chemotherapeutic agent - doxorubicin (doxo) and demonstrated induction of hallmarks of TIS (e.g. growth arrest, hypertrophy, poliploidization and secretory phenotype) and certain properties of cancer stem cells (increased NANOG expression, percentages of CD24+ cells and side population). Colonies of small and highly proliferative progeny appeared shortly after drug removal. Treatment with bafilomycin A1 (BAF A1), an autophagy inhibitor, postponed short term in vitro cell re-population. It was associated with reduction in the number of diploid and increase in the number of poliploid cells. In a long term, a pulse of BAF A1 resulted in reactivation of autophagy in a subpopulation of HCT116 cells and increased proliferation. Accordingly, the senescent HCT116 cells treated with BAF A1 when injected into NOD/SCID mice formed tumors, in contrast to the controls.Our results suggest that senescent cancer cells that appear during therapy, can be considered as dormant cells that contribute to cancer re-growth, when chemotherapeutic treatment is stopped. These data unveil new mechanisms of TIS-related cancer maintenance and re-population, triggered by a single pulse of BAF A1 treatment. PMID- 28030838 TI - Livin/BIRC7 expression as malignancy marker in adrenocortical tumors. AB - Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI H295R.The mRNA expression of livin, its isoforms alpha and beta, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression.Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 +/- 0.116 vs 0.004 +/- 0.014 and 0.002 +/- 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform beta more expressed than alpha. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 +/- 0.66) than in ACA (0.80 +/- 0.35) and NAG (0.88 +/- 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability.In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy. PMID- 28030839 TI - Antagonizing functions of BARD1 and its alternatively spliced variant BARD1delta in telomere stability. AB - Previous reports have shown that expression of BARD1delta, a deletion-bearing isoform of BARD1, correlates with tumor aggressiveness and progression. We show that expression of BARD1delta induces cell cycle arrest in vitro and in vivo in non-malignant cells. We investigated the mechanism that leads to proliferation arrest and found that BARD1delta overexpression induced mitotic arrest with chromosome and telomere aberrations in cell cultures, in transgenic mice, and in cells from human breast and ovarian cancer patients with BARD1 mutations. BARD1delta binds more efficiently than BARD1 to telomere binding proteins and causes their depletion from telomeres, leading to telomere and chromosomal instability. While this induces cell cycle arrest, cancer cells lacking G2/M checkpoint controls might continue to proliferate despite the BARD1delta-induced chromosomal instability. These features of BARD1delta may make it a genome permutator and a driver of continuous uncontrolled proliferation of cancer cells. PMID- 28030840 TI - Prognostic value and clinicopathological features of PD-1/PD-L1 expression with mismatch repair status and desmoplastic stroma in Chinese patients with pancreatic cancer. AB - Pancreatic cancer (PC) is a highly lethal cancer. Thus, the immune molecular markers which help to select PC patients are especially important. In this study, we aimed at systematically analyzing the expression of MLH1, MSH2, PD-L1 and PD 1, investigate their clinical significance and prognostic value. We found that high expression of PD-L1 on cancer cell membranes correlated with lymph node metastasis (P = 0.033) and strongly correlated with poor-differentiation (P = 0.008); high expression of PD-1 on cell membranes of T-cells correlated with well differentiation (P = 0.018) and strongly correlated with advanced T stage (P = 0.004); high PD-1 expression was associated with a significantly superior OS and was an independent prognostic factor (P = 0.031). Then we found an inverse correlation between MSH2 expression and PD-L1 expression (Spearman correlation coefficient r = -0.295, P = 0.004). In subgroup analyses, we observed that PD-1 expression level was associated with OS only at low PD-L1 expression subgroup (P = 0.021). Finally, when we stratified the cases into four subgroups based on PD-1 expression and stroma density, we found that patients with high PD-1 expression and dense stroma had a better OS, while patients with low PD-1 expression and moderate stroma showed a worst outcome. Our result may provide more effective molecular markers for immunotherapeutic strategies of PC patients in clinical practice. PMID- 28030841 TI - Vamorolone, a dissociative steroidal compound, reduces pro-inflammatory cytokine expression in glioma cells and increases activity and survival in a murine model of cortical tumor. AB - Corticosteroids, such as dexamethasone, are routinely used as palliative care in neuro-oncology for their anti-inflammatory benefits, however many patients experience dose limiting side effects caused by glucocorticoid response element (GRE)-mediated transcription. The purpose of this study was to use a murine model to investigate a new steroid alternative, vamorolone, which promises to reduce side effects through dissociating GRE-mediated transcription and NF-kappaB mediated anti-inflammatory actions. To compare vamorolone to dexamethasone in reducing pro-inflammatory signals in vitro, murine glioma cells were treated with dexamethasone, vamorolone or vehicle control. Changes in mRNA expression were assessed using the nanostring inflammatory platform. Furthermore, drug efficacy, post-treatment behavioral activity and side effects were assessed by treating two cohorts of brain tumor bearing mice with dexamethasone, vamorolone, or vehicle control. Our investigation showed that treatment with vamorolone resulted in a reduction of pro-inflammatory signals in tumor cells in vitro similar to treatment with dexamethasone. Treatment with vamorolone resulted in a better safety profile in comparison to dexamethasone treatment. Vamorolone- treated mice showed similar or better activity and survival when compared to dexamethasone treated mice. Our data indicate vamorolone is a potential steroid-sparing alternative for treating patients with brain tumors. PMID- 28030843 TI - Targeted delivery of CRISPR/Cas9 to prostate cancer by modified gRNA using a flexible aptamer-cationic liposome. AB - The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical development of CRISPR/Cas9 therapeutics. In this study, a flexible aptamer-liposome-CRISPR/Cas9 chimera was designed to combine efficient delivery and increased flexibility. Our chimera incorporated an RNA aptamer that specifically binds prostate cancer cells expressing the prostate-specific membrane antigen as a ligand. Cationic liposomes were linked to aptamers by the post-insertion method and were used to deliver therapeutic CRISPR/Cas9 that target the survival gene, polo-like kinase 1, in tumor cells. We demonstrate that the aptamer-liposome-CRISPR/Cas9 chimeras had a significant cell-type binding specificity and a remarkable gene silencing effect in vitro. Furthermore, silencing promoted a conspicuous regression of prostate cancer in vivo. Importantly, the approach described here provides a universal means of cell type-specific CRISPR/Cas9 delivery, which is a critical goal for the widespread therapeutic applicability of CRISPR/Cas9 or other nucleic acid drugs. PMID- 28030842 TI - Loss of RUNX3 expression inhibits bone invasion of oral squamous cell carcinoma. AB - High recurrence and lower survival rates in patients with oral squamous cell carcinoma (OSCC) are associated with its bone invasion. We identified the oncogenic role of RUNX3 during bone invasion by OSCC. Tumor growth and the generation of osteolytic lesions were significantly inhibited in mice that were subcutaneously inoculated with RUNX3-knockdown human OSCC cells. RUNX3 knockdown enhanced TGF-beta-induced growth arrest and inhibited OSCC cell migration and invasion in the absence or presence of transforming growth factor-beta (TGF beta), a major growth factor abundant in the bone microenvironment. RUNX3 knockdown induced cell cycle arrest at the G1 and G2 phases and promoted G2 arrest by TGF-beta in Ca9.22 OSCC cells. RUNX3 knockdown also inhibited both the basal and TGF-beta-induced epithelial-to-mesenchymal transition by increasing E cadherin expression and suppressing the nuclear translocation of beta-catenin. In addition, the expression and TGF-beta-mediated induction of parathyroid hormone related protein (PTHrP), one of key osteolytic factors, was blocked in RUNX3 knockdown OSCC cells. Furthermore, treating human osteoblastic cells with conditioned medium derived from RUNX3-knockdown OSCC cells reduced the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin ratio compared with treatment with conditioned medium from RUNX3-expressing cells. These findings indicate that RUNX3 expression in OSCC cells contributes to their bone invasion and the resulting osteolysis by inducing their malignant behaviors and production of osteolytic factors. RUNX3 alone or in combination with TGF-beta and PTHrP may be a useful predictive biomarker and therapeutic target for bone invasion by oral cancer. PMID- 28030844 TI - SS31 ameliorates age-related activation of NF-kappaB signaling in senile mice model, SAMP8. AB - Aging has been attributed to oxidative stress and inflammatory response, in which NF-kappaB and Nrf2-ARE signaling pathways play significant roles. Senescence accelerated mouse prone 8 (SAMP8) is generally used an animal model for aging studies. Here, we investigated the NF-kappaB and Nrf2-ARE signaling pathways in SAMP8 brains at different ages and their responses to SS31 peptide treatment. Thirty six SAMP8 mice were separated into aging groups and SS31-treatment groups. The hippocampus from each mouse was dissected for RNA and protein extraction. Cytokines and ROS levels were measured using ELISA and standardised method. Gene expressions of NF-kappaB, Nrf2 and HO-1 were measured by RT-qPCR. Total protein amount of NF-kappaB and HO-1, as well as the concentrations of nuclear and cytoplasmic Nrf2 were measured using Western blots. Our data showed that aging could activate both NF-kappaB and Nrf2-ARE signaling pathways, which could be suppressed and activated by SS31 treatment respectively. Regression analysis revealed that NF-kappaB gene expression was the most important parameter predicting aging process and SS31 treatment effects in SAMP8. Our findings suggested that SS31 treatment may modulate the inflammatory and oxidative stress status of the aged brains and exert protective effects during brain aging. PMID- 28030846 TI - Hepatitis B virus-associated intrahepatic cholangiocarcinoma: a malignancy of distinctive characteristics between hepatocellular carcinoma and intrahepatic cholangiocarcinoma. AB - It has been a decade since hepatitis B virus infection was identified as an etiological factor for the development of intrahepatic cholangiocarcinoma (ICC). In recent years, several studies have elucidated the critical impact of hepatitis B virus in ICC that significantly influenced the clinicopathological characteristics of ICC patients with intrahepatic cholangiocarcinoma. Distinctive features of patients with hepatitis B virus-associated ICC included younger age, preponderance of male patients, frequent elevation of alpha-fetoprotein, and infrequent lymph node metastasis. Furthermore, several studies indicated that the presence of hepatitis B virus is a favorable prognostic factor in terms of overall survival and relapse-free survival. However, there are also a few studies demonstrating that hepatitis B virus negatively influenced or showed no significant association with survival outcomes of patients with ICC. At present, there are no consensus on diagnostic procedures and treatments for such population. Therefore, we elucidated current knowledge and recent identifications of HBV-associated ICC to clarify the impact of chronic HBV infection on patients with ICC and to precisely conduct diagnostic procedures and curative treatments for HBV-associated ICC. PMID- 28030847 TI - Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis. AB - Increasing evidence suggests that regular physical exercise suppresses chronic inflammation. However, the potential inhibitory effects of swimming on dextran sulfate sodium (DSS)-induced chronic colitis, and its underlying mechanisms, remain unclear. In this study, rats were orally administered DSS to induce chronic colitis, and subsequently treated with or without swimming exercise. A 7 week swimming program (1 or 1.5 hours per day, 5 days per week) ameliorated DSS caused colon shortening, colon barrier disruption, spleen enlargement, serum LDH release, and reduction of body weight gain. Swimming for 1.5 hours per day afforded greater protection than 1 hour per day. Swimming ameliorated DSS-induced decrease in crypt depth, and increases in myeloperoxidase activity, infiltration of Ly6G+ neutrophils and TNF-alpha- and IFN-gamma-expressing CD3+ T cells, as well as fecal calprotectin and lactoferrin. Swimming inhibited pro-inflammatory cytokine and chemokine production and decreased the protein expression of phosphorylated nuclear factor-kappaB p65 and cyclooxygenase 2, whereas it elevated interleukin-10 levels. Swimming impeded the generation of reactive oxygen species, malondialdehyde, and nitric oxide; however, it boosted glutathione levels, total antioxidant capacity, and superoxide dismutase and glutathione peroxidase activities. Additionally, swimming decreased caspase-3 activity and expression of apoptosis-inducing factor, cytochrome c, Bax, and cleaved-caspase-3, but increased Bcl-2 levels. Overall, these results suggest that swimming exerts beneficial effects on DSS-induced chronic colitis by modulating inflammation, oxidative stress, and apoptosis. PMID- 28030848 TI - A novel read-through transcript JMJD7-PLA2G4B regulates head and neck squamous cell carcinoma cell proliferation and survival. AB - Recent findings on the existence of oncogenic fusion genes in a wide array of solid tumors, including head and neck squamous cell carcinoma (HNSCC), suggests that fusion genes have become attractive targets for cancer diagnosis and treatment. In this study, we showed for the first time that a read-through fusion gene JMJD7-PLA2G4B is presented in HNSCC, splicing neighboring jumonji domain containing 7 (JMJD7) and phospholipase A2, group IVB (PLA2G4B) genes together. Ablation of JMJD7-PLA2G4B significantly inhibited proliferation of HNSCC cells by promoting G1 cell cycle arrest and increased starvation-induced cell death compared to JMJD7-only knockdown HNSCC cells. Mechanistically, we found that JMJD7-PLA2G4B modulates phosphorylation of Protein Kinase B (AKT) to promote HNSCC cell survival. Moreover, JMJD7-PLA2G4B also regulated an E3 ligase S-phase kinase-associated protein 2 (SKP2) to control the cell cycle progression from G1 phase to S phase by inhibiting Cyclin-dependent kinase inhibitor 1 (p21) and 1B (p27) expression. Our study provides novel insights into the oncogenic control of JMJD7-PLA2G4B in HNSCC cell proliferation and survival, and suggests that JMJD7 PLA2G4B may serve as an important therapeutic target and prognostic marker for HNSCC development and progression. PMID- 28030849 TI - Combined and individual tumor-specific expression of insulin-like growth factor-I receptor, insulin receptor and phospho-insulin-like growth factor-I receptor/insulin receptor in primary breast cancer: Implications for prognosis in different treatment groups. AB - Clinical trials examining insulin-like growth factor-I receptor (IGF1R)-targeting strategies have emphasized that better predictive biomarkers are required to improve patient selection.Immunohistochemical tumor-specific protein expression of IGF1R, insulin receptor (InsR), and phosphorylated IGF1R/InsR (pIGF1R/InsR) individually and combined in relation to breast cancer prognosis was evaluated in a population-based cohort of 1,026 primary invasive breast cancer patients without preoperative treatment diagnosed in Sweden. IGF1R (n = 923), InsR (n = 900), and pIGF1R/InsR (n = 904) combined cytoplasmic and membrane staining was dichotomized. IGF1Rstrong/InsRmod/strong/pIGF1R/InsRpos tumors were borderline associated with 2-fold risk for events, HRadj (2.00; 95%CI 0.96-4.18). Combined IGF1R and pIGF1R/InsR status only impacted prognosis in patients with InsRmod/strong expressing tumors (Pinteraction = 0.041). IGF1Rstrong expression impacted endocrine treatment response differently depending on patients' age and type of endocrine therapy. Phospho-IGF1R/InsRpos was associated with lower risk for events among non-endocrine-treated patients irrespective of ER status, HRadj (0.32; 95%CI 0.16-0.63), but not among endocrine-treated patients (Pinteraction = 0.024). In non-endocrine-treated patients, pIGF1R/InsRpos was associated with lower risk for events after radiotherapy, HRadj (0.31; 95%CI 0.12-0.80), and chemotherapy, HRadj (0.29; 95%CI 0.09-0.99). This study highlights the complexity of IGF hetero-and homodimer signaling network and its interplay with endocrine treatment, suggesting that combinations of involved factors may improve patient selection for IGF1R-targeted therapy. PMID- 28030851 TI - Naringenin: an analgesic and anti-inflammatory citrus flavanone. PMID- 28030850 TI - Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection. AB - Interleukin (IL)-22+CD4+T (Th22) cells play crucial roles in the pathogenesis of autoimmune diseases and infectious diseases, although the role of Th22 cells remains largely unclear in children with hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71). This study aims to explore the role of circulating IL-22+IL-17A-CD4+T (cTh22) cells in children with EV71-associated HFMD. We found that during the acute stage of illness, the frequencies of cTh22 and circulating IL-22+IL-17A+CD4+T (IL-22+cTh17) cells in CD4+T cells infrom affected patients, and especially in severely affected patients, were significantly higher than in healthy controls (HC). The major source of IL-22 production was cTh22 cells, partially from cTh17 cells. Moreover, the protein and mRNA levels of IL-22, IL-17A, IL-23, IL-6, and TNF-alpha were significantly different among the mild patients, severe patients and HC, as well as AHR and RORgammat mRNA levels. A positive correlation was found between plasma IL-22 levels and cTh22 cell frequencies, and cTh17 cell and IL-22+ cTh17 cell frequencies. Furthermore, the frequencies of cTh22 were significantly decreased in the convalescent patients. Our findings indicated that cTh22 cells could play critical roles in the pathogenesis of EV71 infection, and are potential therapeutic targets for patients with EV71-associated HFMD. PMID- 28030853 TI - mGluR5, CB1 and neuroprotection. PMID- 28030854 TI - The Chromosomes of Birds during Meiosis. AB - The cytological analysis of meiotic chromosomes is an exceptional tool to approach complex processes such as synapsis and recombination during the division. Chromosome studies of meiosis have been especially valuable in birds, where naturally occurring mutants or experimental knock-out animals are not available to fully investigate the basic mechanisms of major meiotic events. This review highlights the main contributions of synaptonemal complex and lampbrush chromosome research to the current knowledge of avian meiosis, with special emphasis on the organization of chromosomes during prophase I, the impact of chromosome rearrangements during meiosis, and distinctive features of the ZW pair. PMID- 28030852 TI - Drug-induced premature senescence model in human dental follicle stem cells. AB - Aging is identified by a progressive decline of physiological integrity leading to age-related degenerative diseases, but its causes is unclear. Human dental pulp stem cells (hDPSCs) has a remarkable rejuvenated capacity that relies on its resident stem cells. However, because of the lack of proper senescence models, exploration of the underlying molecular mechanisms has been hindered. Here, we established a cellular model utilizing a hydroxyurea (HU) treatment protocol and effectively induced Human dental pulp stem cells to undergo cellular senescence. Age-related phenotypic changes were identified by augmented senescence-associated beta-galactosidase (SA-beta-gal) staining, declined proliferation and differentiation capacity, elevated G0/G1 cell cycle arrest, increased apoptosis and reactive oxygen species levels. Furthermore, we tested the expression of key genes in various DNA repair pathways including nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathways. In addition, our results showed that Dental pulp stem cells from young donors are more resistant to apoptosis and exhibit increased non-homologous end joining activity compared to old donors. Further transcriptome analysis demonstrate that multiple pathways are involved in the HU-induced Dental pulp stem cells ageing, including genes associated with DNA damage and repair, mitochondrial dysfunction and increased reactive oxygen species levels. Taken together, the cellular model have important implications for understanding the molecular exploration of Dental pulp stem cells senescence and aging. PMID- 28030855 TI - A Rare de novo Interstitial Duplication at 4p15.2 in a Boy with Severe Congenital Heart Defects, Limb Anomalies, Hypogonadism, and Global Developmental Delay. AB - Proximal 4p deletion syndrome is a relatively rare genetic condition characterized by dysmorphic facial features, limb anomalies, minor congenital heart defects, hypogonadism, cafe-au-lait spots, developmental delay, tall and thin habitus, and intellectual disability. At present, over 20 cases of this syndrome have been published. However, duplication of the same region in proximal 4p has never been reported. Here, we describe a 2-year-5-month-old boy with severe congenital heart defects, limb anomalies, hypogonadism, distinctive facial features, pre- and postnatal developmental delay, and mild cognitive impairments. A de novo 4.5-Mb interstitial duplication at 4p15.2p15.1 was detected by chromosomal microarray analysis. Next-generation sequencing was employed and confirmed the duplication, but revealed no additional pathogenic variants. Several candidate genes in this interval responsible for the complex clinical phenotype were identified, such as RBPJ, STIM2, CCKAR, and LGI2. The results suggest a novel contiguous gene duplication syndrome. PMID- 28030856 TI - Criteria for Determining Malignancy in Pancreatic Intraductal Papillary Mucinous Neoplasm Based on Computed Tomography. AB - INTRODUCTION: Determining the dignity of intraductal papillary mucinous neoplasms (IPMNs) by imaging procedures is challenging. Various CT-based criteria were evaluated. PATIENTS AND METHODS: Preoperative CT scans from 47 patients with IPMN were analyzed. Predefined criteria of malignancy were compared between patients with benign (bIPMN; n = 28) and malignant (mIPMN; n = 19) tumors, and a summation score was determined. RESULTS: Preoperative carbohydrate-antigen 19-9 levels were higher in patients with mIPMN (p = 0.013). The diameter of the main pancreatic duct was greater in patients with mIPMN (p < 0.0001). More patients with mIPMN showed bile duct obstruction (p = 0.0076), solid tumor components (p = 0.0076), contrast enhancement in cystic walls (p = 0.0086), peripancreatic lymph nodes (p = 0.0076), and abrupt diameter changes of the main pancreatic duct (p = 0.0008). The CT density of the cysts was higher in mIPMN (p = 0.0063). The diagnostic accuracy of the summation score (sensitivity: 0.84, specificity: 0.96) was greater when compared to each individual CT parameter. CONCLUSIONS: The prevalence and extent of various CT-based abnormalities are greater in patients with mIPMN, but the wide overlap limits the diagnostic value of each individual parameter. A simple summation score largely enhances the diagnostic accuracy. PMID- 28030857 TI - New Description of Telocyte Sheaths in the Bovine Uterine Tube: An Immunohistochemical and Scanning Microscopic Study. AB - Telocytes are a special type of interstitial cells characterized by distinctive cellular extensions with alternating thin segments (podomers) and dilations (podoms). Telocytes establish contact with various cells and structures, but their role in the regulation of the function of many cell types is still obscure. The aim of the current study was to investigate the morphology, histochemistry, and immunohistochemistry of telocytes, and their distribution, organization, and morphometric measurements in different layers of the adult bovine uterine tube. Telocytes showed positive immunostaining for CD117, S-100 protein, vimentin, desmin, alpha-smooth muscle actin, tubulin, laminin, estrogen receptor-alpha, and progesterone receptor. They were organized in different types of sheaths: subepithelial, inner/outer perimuscular, and intramuscular sheaths. Telocytes were scattered in the lamina propria, in the muscular layer, and the serosa. According to their size, they were grouped into different types of telocytes: small, large, and giant telocytes. Small telocytes were the most common type and located in all layers; large telocytes were observed in the epithelium, lamina propria, and inner/outer perimuscular and intramuscular sheaths, and giant telocytes were found in the external layer of the outer perimuscular sheath. Telocytes were connected by thin and thick telopodes (fenestrated membranes). Fenestrated membranes enabled connections between telocytes along the entire muscular wall of the uterine tube. Telocytes established an extensive biological network of different types of cells and structures, including epithelial, muscular, and mast cells, blood vessels, glomus, and nerve fibers. We hypothesize that telocytes help to organize the functional coordination between different types of cells in the uterine tube. PMID- 28030858 TI - Reviewing Patients Following Mesh Repair; The Benefits. AB - BACKGROUND/AIMS: The use of synthetic mesh implants for vaginal prolapse surgery is still a subject of debate due to safety concerns. We aimed to explore long term complications of all women treated with mesh surgery for pelvic organ prolapse (POP) in our centre. METHODS: This is a cross-sectional study of 188 women who underwent vaginal mesh surgery in a Dutch University Hospital between 2007 and 2012. The prevalence of mesh exposure, pain symptoms and patient satisfaction has been documented. RESULTS: Vaginal mesh surgery was performed in 188 women - in 147 (78%) because of recurrent POP. After a median follow-up of 40 months (range 12-76 months), 11 women (6%) had a symptomatic exposure of whom 8 women underwent surgery. Nine women (5%) had de novo pain following mesh surgery and in 3 women, (2%) this symptom was persistent despite treatment. Eighty-six percent of the responders were satisfied about their treatment. CONCLUSION: With this study, we showed that performing a total mesh recall is feasible. The prevalence of persisting symptomatic exposure and persisting pain symptoms was low in our population. Most of the complications we found were treatable. This is also reflected in the high overall satisfaction rate. PMID- 28030859 TI - Clinical Efficacy of Afatinib Treatment for a Patient with Leptomeningeal Carcinomatosis. AB - Leptomeningeal metastases occur in 1% of patients with non-small-cell lung cancer. There have been several reports on the treatment of leptomeningeal metastases with afatinib. Our patient was a 41-year-old woman who had never smoked and was diagnosed with stage IV adenocarcinoma of the lung with an epidermal growth factor receptor (EGFR) mutation. She was treated with afatinib for the recurrence of leptomeningeal metastases. After the treatment with afatinib was initiated, the neurological symptoms dramatically regressed, and she achieved progression-free survival for 7 months. The concentration of afatinib in the cerebrospinal fluid (CSF) ranged from 0.05 to 0.14 ng/mL, and the penetration rate of afatinib from the plasma to the CSF ranged from 0.28 to 0.40%. This concentration might be sufficient to achieve a clinical effect for leptomeningeal carcinomatosis. Therefore, afatinib administered at the usual doses may be an effective treatment for leptomeningeal carcinomatosis of EGFR-mutated or EGFR tyrosine kinase inhibitor-sensitive lung adenocarcinoma. PMID- 28030860 TI - Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells. AB - The long noncoding RNA MSNP1AS (moesin pseudogene 1, antisense) is a functional element that was previously associated with autism spectrum disorder (ASD) with genome-wide significance. Expression of MSNP1AS was increased 12-fold in the cerebral cortex of individuals with ASD and 22-fold in individuals with a genome wide significantly associated ASD genetic marker on chromosome 5p14.1. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of moesin protein, which is involved in neuronal process stability. In this study, we hypothesize that MSNP1AS knockdown impacts global transcriptome levels. We transfected the human neural progenitor cell line SK- N-SH with constructs that caused a 50% suppression of MSNP1AS expression. After 24 h, cells were harvested for total RNA isolation. Strand-specific RNA sequencing analysis indicated altered expression of 1,352 genes, including altered expression of 318 genes following correction for multiple comparisons. Expression of the OAS2 gene was increased >150-fold, a result that was validated by quantitative PCR. Gene ontology analysis of the 318 genes with altered expression following correction for multiple comparisons indicated that upregulated genes were significantly enriched for genes involved in immune response, and downregulated genes were significantly enriched for genes involved in chromatin remodeling. These data indicate multiple transcriptional and translational functions of MSNP1AS that impact ASD-relevant biological processes. Chromatin remodeling and immune response are biological processes implicated by genes with rare mutations associated with ASD. Our data suggest that the functional elements implicated by association of common genetic variants impact the same biological processes, suggesting a possible shared common molecular pathway of ASD. PMID- 28030861 TI - The Use of Automated Electronic Alerts in Studying Short-Term Outcomes Associated with Community-Acquired Acute Kidney Injury. AB - BACKGROUND/AIMS: The use of electronic alerts (e-alerts) may increase the detection rate of acute kidney injury (AKI) since they are sensitive to small changes in serum creatinine. Our aim was to follow-up a cohort of patients presenting to hospital from the community with AKI (community-acquired AKI [c AKI]), detected through the use of e-alerts, and describe their short-term outcomes regardless of whether they were subsequently admitted to hospital. METHODS: Blood samples for all hospital attenders from the community either to the Accidents and Emergency department or one of the acute care areas of the hospital during a 6-month period (November 1, 2013-April 30, 2014) were screened for presence of c-AKI using a locally developed e-alerts system based on Kidney Disease: Improving Global Outcomes criteria. Follow-up data were obtained for a period of 3 months. RESULTS: A total of 1,277 c-AKI episodes were identified in 1,185 patients (incidence 579 per 100,000 persons). Episodes that lead to hospitalization (n = 1,096 [86%]) were associated with a median length of hospital stay of 6.6 days; a graded increase in duration of stay was noted with increasing severity of AKI. Acute dialysis was needed during 21 (1.6%) episodes. For mortality rates, only the first AKI episode was considered. There were 298 deaths within 30 days of diagnosis irrespective of admissions status (30-day mortality rate: 25%). CONCLUSIONS: Using e-alerts in acute care settings to detect c-AKI is novel and may be used to stage and follow-up AKI using existing diagnostic criteria. c-AKI is relatively common and leads to significant mortality. PMID- 28030862 TI - A Comparative Study of a New Class of Gastric Acid Suppressant Agent Named Vonoparazan versus Esomeprazole for the Eradication of Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori eradication rates have decreased worldwide. Gastric acid inhibition during treatment is important to eradicate these bacteria successfully. A new potassium-competitive acid blocker, vonoprazan (VPZ), has been shown to achieve high eradication rates in a previous randomized controlled trial. OBJECTIVE: To determine the efficacy of VPZ for H. pylori eradication. METHODS: A total of 874 patients were enrolled; 431 received esomeprazole (EPZ) and 443 received VPZ. First-line regimens contained clarithromycin (CAM) 200 mg b.i.d., amoxicillin 750 mg b.i.d., and either EPZ 20 mg b.i.d. or VPZ 20 mg b.i.d. for 7 days. Metronidazole 250 mg b.i.d. replaced CAM in the second-line regimens. The eradication of H. pylori was assessed by 13C-urea breath tests 4-8 weeks after each therapy. RESULTS: The overall first-line eradication rate was 79.9% (341/427) with EPZ vs. 86.3% (377/439) with VPZ (p = 0.019). The second line eradication rate was 83.3% (45/51) with EPZ vs. 91.1% (41/45) with VPZ (p = 0.900). CONCLUSION: VPZ was significantly more effective than EPZ for first-line treatment. However, for second-line treatment, there was no significant difference between EPZ and VPZ. PMID- 28030864 TI - CD68-Positive Cells in Hepatic Angiomyolipoma. AB - Four resected specimens of hepatic angiomyolipoma in which uptake of Sonazoid was observed in the postvascular phase of Sonazoid-enhanced ultrasonography were analyzed. Macrophage localization in the tumor was revealed pathologically by immunohistochemical staining for CD68. CD68-positive cells were observed in the tumor in all cases. The density of CD68-positive cells was 100/mm2, and the ratio of CD68-positive cell density in the tumor to that in the surrounding parenchyma was 32-171%. These results suggested that the uptake of the contrast agent Sonazoid was related to the density of CD68-positive cells. PMID- 28030863 TI - Real-World Clinical Practice of Intensified Chemotherapies for Metastatic Pancreatic Cancer: Results from a Pan-European Questionnaire Study. AB - INTRODUCTION: Recently, FOLFIRINOX and gemcitabine + nab-paclitaxel have been introduced as a novel intensified chemotherapy regimen for patients with metastasized pancreatic cancer. This study aims to analyze the real-world clinical practice with FOLFIRINOX and gemcitabine + nab-paclitaxel across Europe. METHODS: Invitations to participate in an anonymous web-based questionnaire were sent via e-mail to 5,420 doctors in 19 European countries through the network of national gastroenterological, oncological, surgical and pancreatic societies as well as the European Pancreatic Club. The questionnaire consisted of 20 questions, 14 regarding the use of intensified chemotherapy, 4 regarding demographics of the participants, and 1 to verify the active involvement in the management of metastatic pancreatic cancer. RESULTS: Two hundred and thirteen responses were received and 153 entries were valid for analysis. Of those, 63.4% came from an academic institution, 51% were oncologists, and 52% treated more than 25 cases per year. A majority of responses (71%) were from Italy (40%), Germany (23%), and Spain (8%). As first-line therapy, 11% used gemcitabine +/- erlotinib, 42% used FOLFIRINOX, and 47% used gemcitabine + nab-paclitaxel. Of the intensified regimens, both were applied to equal parts, but the likelihood of protocol deviation was higher when using FOLFIRINOX (p < 0.01). FOLFIRINOX was considered more toxic than gemcitabine + nab-paclitaxel (neutropenia 88 vs. 68%; polyneuropathy 42 vs. 41%; rapid deterioration 42 vs. 31%). FOLFIRINOX was rated to achieve longer survival with an acceptable quality of life (52 vs. 44%). Moreover, 57% of participants thought that gemcitabine + nab-paclitaxel should be the backbone for further clinical trials in pancreatic cancer. CONCLUSION: Intensified chemotherapy is widely used in pancreatic cancer patients in Europe following its recent clinical approval. Interestingly, nab-paclitaxel and FOLFIRINOX were used at comparable frequency although the latter had to be de escalated more often. PMID- 28030865 TI - Recent Advances in Decellularization and Recellularization for Tissue-Engineered Liver Grafts. AB - Liver transplantation from deceased or living human donors remains the only proven option for patients with end-stage liver disease. However, the shortage of donor organs is a significant clinical concern that has led to the pursuit of tissue-engineered liver grafts generated from decellularized liver extracellular matrix and functional cells. Investigative efforts on optimizing both liver decellularization and recellularization protocols have been made in recent decades. In the current review, we briefly summarize these advances, including the generation of high-quality liver extracellular matrix scaffolds, evaluation criteria for quality control, modification of matrix for enhanced properties, and reseeding strategies. These efforts to optimize the methods of decellularization and recellularization lay the groundwork towards generating a transplantable, human-sized liver graft for the treatment of patients with severe liver disease. PMID- 28030866 TI - Increase of Mast Cell-Nerve Association and Neuropeptide Receptor Expression on Mast Cells in Perennial Allergic Rhinitis. AB - OBJECTIVES: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR. METHODS: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR. RESULTS: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MCtc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MCtc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs. CONCLUSIONS: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR. PMID- 28030867 TI - Medications That Increase Osmolality and Compromise the Safety of Enteral Feeding in Preterm Infants. AB - BACKGROUND: Medications added to preterm milk feeds have the potential to raise osmolality, causing feed intolerance and necrotizing enterocolitis. OBJECTIVE: The aim of this study was to evaluate changes in the osmolality of milk feeds and water with 14 medications and the diluent amounts required to keep the osmolality below the safety threshold of <=450 mOsm/kg. Changes in the osmolality of milk with medications while on continuous infusion over 2 and 4 h were determined. METHODS: This study was designed to measure the osmolality of 14 commonly used medications in preterm infants both neat and when supplemented with expressed breast milk (EBM), EBM with fortifier (EBMF), preterm formula (PTF), and water. Dose-effect curves were plotted, and the volume of each diluent was calculated to keep the osmolality <=450 mOsm/kg. Time-effect curves were plotted at 2 and 4 h for each medication for both EBM and EBMF. RESULTS: Neat osmolality of all except 5 medications were above 2,000 mOsm/kg. The osmolality rose with decreasing proportions of diluents used, depicting an indirect curvilinear relationship between the increasing dilution and osmolality for all except 2 medications. As a diluent, EBM was required in lower dilutions than EBMF. Dilutions needed for additives with PTF were very similar to those of EBM. The change in osmolality over time with additives was statistically significant for EBMF. CONCLUSIONS: EBM and PTF were found to be safer diluents than EBMF for enteral additives. The practice of keeping milk feeds with medications for continuous feeding is safe for a period of 4 h in EBM. PMID- 28030868 TI - Implementation of an Automated Primary Care Acute Kidney Injury Warning System: A Quantitative and Qualitative Review of 2 Years of Experience. AB - BACKGROUND: Acute kidney injury (AKI) is often detected late, leading to worse clinical outcomes. In 2012, we pioneered an AKI-alerting system for primary care clinicians (PCCs). We retrospectively analysed the alerts and evaluated PCC satisfaction to assess the feasibility of the system. METHODS: The study used a 2 pronged approach. AKI alerts, generated by an algorithm designed by University College London Hospital biochemistry department between June 2012 and June 2014, were analysed to reveal the demographics and outcomes of each patient generating an alert. Second, a survey was sent to all PCCs assessing awareness and satisfaction with the service. Simple statistical methods were applied (mean, median, SD and interquartile range). RESULTS: One hundred forty-two alerts were generated, of which 101 were genuine. Generally, the patient demographics, AKI stratification and aetiology were in keeping with the inpatient AKI population. Forty-eight percent of cases were referred to the hospital with a median length of stay of 9.9 days. Three-month mortality was 12%. Among PCCs, there was good awareness of the system with most finding it valuable. The key complaints around the system were to do with lack of knowledge of its existence. CONCLUSIONS: Our evaluation has demonstrated that the implementation of AKI alerts in the community is technically feasible, does not result in excessive demand on hospital services, appears to influence PCC behaviour and was perceived overwhelmingly as a useful service by these clinicians. This experience should inform further developments including behavioural interventions (such as clinician alerts) to improve community AKI care. PMID- 28030869 TI - Voice-Related Patient-Reported Outcome Measures: A Systematic Review of Instrument Development and Validation. AB - Purpose: The purpose of this study was to perform a comprehensive systematic review of the literature on voice-related patient-reported outcome (PRO) measures in adults and to evaluate each instrument for the presence of important measurement properties. Method: MEDLINE, the Cumulative Index of Nursing and Allied Health Literature, and the Health and Psychosocial Instrument databases were searched using relevant vocabulary terms and key terms related to PRO measures and voice. Inclusion and exclusion criteria were developed in consultation with an expert panel. Three independent investigators assessed study methodology using criteria developed a priori. Measurement properties were examined and entered into evidence tables. Results: A total of 3,744 studies assessing voice-related constructs were identified. This list was narrowed to 32 PRO measures on the basis of predetermined inclusion and exclusion criteria. Questionnaire measurement properties varied widely. Important thematic deficiencies were apparent: (a) lack of patient involvement in the item development process, (b) lack of robust construct validity, and (c) lack of clear interpretability and scaling. Conclusions: PRO measures are a principal means of evaluating treatment effectiveness in voice-related conditions. Despite their prominence, available PRO measures have disparate methodological rigor. Care must be taken to understand the psychometric and measurement properties and the applicability of PRO measures before advocating for their use in clinical or research applications. PMID- 28030870 TI - Diffusion-Weighted Imaging of Periventricular Leukomalacia in Very Young Children: Assessment of Peritrigonal Stripe of Restricted Diffusion. AB - Purpose In periventricular leukomalacia (PVL), apparent diffusion coefficient (ADC) reduction, normally shown as dark stripe in the peritrigonal (PT) white matter, may be incomplete. We assessed the PT dark stripe to differentiate between PVL patients and control subjects. Patients and Methods We reviewed the magnetic resonance studies of 27 neonates and young children with PVL and 67 control subjects to assess the PT dark stripe on ADC maps. In PVL patients, the assessment was referred to the location of PVL lesion on fluid-attenuated inversion recovery (FLAIR) imaging. In the controls, the PT region or the location corresponding to FLAIR hyperintensity was evaluated for the dark stripe. We compared the prevalence of the dark stripe on ADC map and the PT FLAIR hyperintensity between the PVL and the control subjects. Results On ADC map, complete PT dark stripe was present in 67 (100%) of 67 controls but only in 4 (14.8%) of 27 PVL patients (p-value < 0.01), with sensitivity of 0.85, specificity of 1.0, and accuracy of 0.96. PT FLAIR hyperintensity was present in 44 (65.7%) of 67 controls and in 18 (66.7%) of 27 PVL patients (p = 0.920). Conclusion PVL patients can be differentiated from the control subjects with PT dark stripe on ADC map. PMID- 28030871 TI - Obesity and Neonatal Cord Blood Gas Results at Cesarean: Effect of Intraoperative Blood Pressure. AB - Objective Our aims were to evaluate whether there is an inverse association between body mass index (BMI) and umbilical artery pH and to investigate the contribution of intraoperative hypotension on the umbilical artery pH. Study Design We conducted a retrospective cohort study of all women with a nonanomalous singleton at 37 to 41 weeks who underwent a scheduled cesarean delivery under spinal anesthesia at our facility from January 2006 to March 2012. The primary outcome was the proportion of patients in each BMI category with arterial cord pH < 7.10. Intraoperative blood pressure data were compared across BMI categories. Results In total, 717 mother-infant pairs met enrollment criteria. Mean arterial pH was significantly lower in women with elevated BMI (p = 0.014), notably with BMI >= 40 kg/m2. Baseline blood pressure increased linearly with increasing BMI (p < 0.001), however, so did the maximum drop in all blood pressure parameters (p < 0.001). After adjusting for potential confounders, including blood pressure, there was no longer an association between cord pH and BMI (p = 0.72). Conclusion For women undergoing a scheduled cesarean delivery under spinal anesthesia, umbilical artery pH is lower in women with BMI >=40 kg/m2. Relative hypotension after spinal anesthesia is more pronounced with increasing BMI and may explain this effect. PMID- 28030872 TI - Ultrasonography for Verification of Endotracheal Tube Position in Neonates and Infants. AB - Objective Ultrasonography (US) has been shown to be effective for verifying endotracheal tube (ETT) position in adults and older children but has been less studied in the neonates and infants. The literature regarding US utility for ETT positioning in this population is reviewed. Study Design A literature search was conducted using the EMBASE, Google Scholar, MEDLINE, Ovid, and Scopus databases with search terms regarding US relating to ETT intubation and positioning in neonates and infants. Result Nine relevant studies were included for review. All studies report > 80% visualization of the ETT tip by US. US interpretation of the ETT position correlated with the radiography position in 73 to 100% of cases when the ETT tip was visible. There were variations in technique, sonographer, and sonographer training between studies. Conclusion US appears to be well tolerated by neonates and infants and may augment the determination of proper ETT position. Further studies are needed regarding optimal technique and sonographer training. PMID- 28030873 TI - [MR image findings in CLIPPERS]. PMID- 28030874 TI - Letter to the Editor. PMID- 28030876 TI - From Surgical Responsibility to Abstract Ideology. PMID- 28030875 TI - Altered Regional Myocardial Mechanics in Transplanted Hearts: Influence of Time and Transplantation. AB - Background Global longitudinal strain is reduced in heart transplant recipients, but little is known about regional contractility of the transplanted heart. Moreover, it is unclear if factors such as time after transplant and ischemic time have an influence on regional contractility. To test for regional changes in myocardial deformation, we assessed regional myocardial deformation using three dimensional speckle tracking echocardiography in heart transplant recipients and controls. Methods Global and regional longitudinal, circumferential, and radial strain was assessed in 51 heart transplant recipients and a control group of healthy individuals (n = 26). Moreover, we correlated regional contractility with clinical characteristics and compared subgroups of heart transplant recipients with normal (n = 32) and reduced left ventricular ejection fraction (n = 32). Results Global longitudinal and circumferential strain was significantly reduced in all heart transplant recipients, as well as in the transplant group with normal ejection fraction compared with the control group (p < 0.001). Global radial strain (GRS) was elevated in both transplant groups, but was significantly higher in transplant recipients with normal ejection fraction compared with the control group (p < 0.01). Both transplant groups revealed lower longitudinal and circumferential strain values in the mid- and apical regions (p < 0.001), whereas longitudinal and circumferential strain was higher in the basal region (p < 0.01). In both groups, transplanted hearts showed increased radial strain in the basal (p < 0.05, p < 0.01) and midregions (p = 0.22; p < 0.01) and did not differ in the apical regions. Cold ischemic time (150 +/- 12.6 minutes) was independently associated with reduction in circumferential strain. Time since transplantation ranging from 18 days to 21 years had no effect on myocardial deformation parameters. Conclusion Left ventricular mechanics in transplanted hearts display significantly different systolic deformation patterns than native hearts. Strain capability forms a regional gradient from the base toward the apex. The presence of a time-independent deformation pattern and the correlation with cold ischemic time suggest damage induced by the transplantation itself. These findings might be important for understanding pseudo-abnormal echocardiograms in heart transplant patients. PMID- 28030877 TI - An alternative clinical routine for subjective refraction based on power vectors with trial frames. AB - PURPOSE: Subjective refraction determines the final point of refractive error assessment in most clinical environments and its foundations have remained unchanged for decades. The purpose of this paper is to compare the results obtained when monocular subjective refraction is assessed in trial frames by a new clinical procedure based on a pure power vector interpretation with conventional clinical refraction procedures. METHODS: An alternative clinical routine is described that uses power vector interpretation with implementation in trial frames. Refractive error is determined in terms of: (i) the spherical equivalent (M component), and (ii) a pair of Jackson Crossed Cylinder lenses oriented at 0 degrees /90 degrees (J0 component) and 45 degrees /135 degrees (J45 component) for determination of astigmatism. This vector subjective refraction result (VR) is compared separately for right and left eyes of 25 subjects (mean age, 35 +/- 4 years) against conventional sphero-cylindrical subjective refraction (RX) using a phoropter. The VR procedure was applied with both conventional tumbling E optotypes (VR1) and modified optotypes with oblique orientation (VR2). RESULTS: Bland-Altman plots and intra-class correlation coefficient showed good agreement between VR, and RX (with coefficient values above 0.82) and anova showed no significant differences in any of the power vector components between RX and VR. VR1 and VR2 procedure results were similar (p >= 0.77). CONCLUSIONS: The proposed routine determines the three components of refractive error in power vector notation [M, J0 , J45 ], with a refraction time similar to the one used in conventional subjective procedures. The proposed routine could be helpful for inexperienced clinicians and for experienced clinicians in those cases where it is difficult to get a valid starting point for conventional RX (irregular corneas, media opacities, etc.) and for refractive situations/places with inadequate refractive facilities/equipment. PMID- 28030878 TI - Evidence for Scottish General Ophthalmic Services improving true-positive referral rate for Glaucoma. PMID- 28030879 TI - Authors' reply. PMID- 28030880 TI - Correcting presbyopia: the problem of pupil size. PMID- 28030881 TI - Intra- and inter- examiner repeatability of cycloplegic retinoscopy among young children. AB - PURPOSE: To evaluate the intra- and inter-examiner repeatability of cycloplegic retinoscopy in young children aged 4-5 years old. METHODS: Examiner 1 refracted all children in the first sample (n = 108); firstly with masked loose lenses, then using unmasked loose lenses (intra-examiner repeatability). Examiners 1 and 2 refracted all children in the second sample (n = 97) using unmasked loose lenses, blind to the child's refractive error, presence/magnitude of habitual spectacle correction and to each other's findings (inter-examiner repeatability). Refractions were performed on one eye chosen at random. Mean differences, 95% limits of agreement (LOAs) and confidence intervals were calculated for intra- and inter-examiner repeatability of sphere, cylinder and spherical equivalent refraction (SER). RESULTS: Participants had a wide range of refractive errors ( 1.50DS to +7.25DS; >=4.50DC). Mean differences (95% LOAs) were small for both intra- and inter-examiner repeatability [Intra: Sphere 0.00D (-0.85, +0.85D), Cylinder -0.03D (-0.68, +0.62D), SER -0.06D (-0.90, +0.78D); Inter: Sphere -0.08D (-0.92, +0.76D), Cylinder -0.08D (-0.75, +0.59D), SER -0.13D (-0.95, +0.69D). A statistically significant proportional bias was present for intra-examiner repeatability of cylinder (rho = 0.20, p = 0.04) and SER measurement (rho = 0.19, p = 0.049). Proportional bias was not present for any other measure (p > 0.12). Examiners agreed on cylinder axis within +/-20 degrees in 71% of refractions where astigmatism of -0.75D or higher was present. 80% of intra- and inter examiner measures fell within +/-0.50D for spherical and cylindrical components. CONCLUSIONS: Differences of +/-1.00D and +/-0.75D or more for spherical and cylindrical measures respectively can be considered significant when performing cycloplegic retinoscopy on young children. PMID- 28030882 TI - Ocular response to environmental variations in contact lens wearers. AB - PURPOSE: To assess the influence of different indoor environments simulated in an environmental chamber on soft contact lens (CL) wearers. METHODS: Fifty-four CL wearers were grouped based on their symptoms while wearing their CLs. Subjects were fitted with two different CL types, conventional hydrogel (Omafilcon A) and silicone hydrogel (comfilcon A), and exposed to two controlled indoor environmental conditions, standard [50% relative humidity (RH), 23 degrees C, 930 mb of atmospheric pressure] and adverse (in-flight air cabin environment: 5% RH, localised air flow, 23 degrees C, 750 mb atmospheric pressure), for 90 min in an environmental chamber, making a total of four visits. Symptoms, tear osmolarity, pre-lens tear breakup time (PLBUT), phenol red thread test, visual acuity, bulbar and limbal hyperaemia, corneal and limbal staining, and CL dehydration were assessed using repeated measures analysis of variance. A linear mixed model was used to analyse the effect of environment, CL type, discomfort-based grouping, and time on blink rate. RESULTS: Environment was found to significantly (p <= 0.018) affect limbal and bulbar hyperaemia, PLBUT, tear osmolarity, and CL dehydration. Likewise, CL type significantly (p <= 0.04) affected nasal and total corneal staining, limbal conjunctival staining, CL dehydration, comfort, and blurred vision. The environment, CL type, and time had significant effects (p <= 0.0001) on the blink rate. CONCLUSIONS: Ocular surface integrity and blink rate in CL wearers depend on the environment CL users are exposed to, as well as on the soft CL type that they are wearing. Tight control of environmental conditions can contribute to a better understanding of CL-related discomfort. PMID- 28030883 TI - Accommodation stimulus and response determinations with autorefractors. AB - PURPOSE: To develop equations for accommodation stimulus and accommodation response with autorefractors when the accommodation stimulus is produced by combinations of object distances and lenses placed in front of eyes, and to give worked examples using these equations. METHODS: Simple ray tracing was used to determine stimulus and response equations, taking into account the reference positions for targets, for refraction, and for autorefractor readings. RESULTS: Several examples applying equations are provided. Features of these examples include evaluating approximate calculations that have been used previously, demonstrating which equations should be used in different circumstances, how to substitute numbers into equations, how to deal with discrepancies between subjective and objective refraction, and how to deal with astigmatism. Problems associated with measuring accommodation response by placing lenses in front of the eye are discussed. CONCLUSIONS: Accurate equations for accommodation stimulus and accommodation response for a range of accommodation stimuli in different setups have been developed. PMID- 28030884 TI - Ensuring Program Uniformity at the Hearing and Appeals Council Levels of the Administrative Review Process. Final rule. AB - We are revising our rules so that more of our procedures at the hearing and Appeals Council levels of our administrative review process are consistent nationwide. We anticipate that these nationally consistent procedures will enable us to administer our disability programs more efficiently and better serve the public. PMID- 28030885 TI - Food Labeling: Health Claims; Dietary Saturated Fat and Cholesterol and Risk of Coronary Heart Disease. Interim final rule; request for comments. AB - The Food and Drug Administration (FDA or we) is amending the regulation authorizing a health claim on the relationship between dietary saturated fat and cholesterol and risk of coronary heart disease (CHD) to permit raw fruits and vegetables that fail to comply with the low fat definition and/or the minimum nutrient content requirement to be eligible to bear the claim. We are taking this action in response to a petition submitted by the American Heart Association (the petitioner). The amendment expands the use of this health claim to certain fruits and vegetables that are currently ineligible for the health claim. PMID- 28030886 TI - Banned Devices; Powdered Surgeon's Gloves, Powdered Patient Examination Gloves, and Absorbable Powder for Lubricating a Surgeon's Glove. Final rule. AB - The Food and Drug Administration (FDA or Agency) has determined that Powdered Surgeon's Gloves, Powdered Patient Examination Gloves, and Absorbable Powder for Lubricating a Surgeon's Glove present an unreasonable and substantial risk of illness or injury and that the risk cannot be corrected or eliminated by labeling or a change in labeling. Consequently, FDA is banning these devices. PMID- 28030887 TI - General Hospital and Personal Use Devices: Renaming of Pediatric Hospital Bed Classification and Designation of Special Controls for Pediatric Medical Crib; Classification of Medical Bassinet. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final rule to rename pediatric hospital beds as pediatric medical cribs and establish special controls for these devices. FDA is also establishing a separate classification regulation for medical bassinets, previously under the pediatric hospital bed classification regulation, as a class II (special controls) device. In addition, this rule continues to allow both devices to be exempt from premarket notification and use of the device in traditional health care settings and permits prescription use of pediatric medical cribs and bassinets outside of traditional health care settings. PMID- 28030888 TI - Clarification of Employer's Continuing Obligation To Make and Maintain an Accurate Record of Each Recordable Injury and Illness. Final rule. AB - OSHA is amending its recordkeeping regulations to clarify that the duty to make and maintain accurate records of work-related injuries and illnesses is an ongoing obligation. The duty to record an injury or illness continues for as long as the employer must keep records of the recordable injury or illness; the duty does not expire just because the employer fails to create the necessary records when first required to do so. The amendments consist of revisions to the titles of some existing sections and subparts and changes to the text of some existing provisions. The amendments add no new compliance obligations and do not require employers to make records of any injuries or illnesses for which records are not currently required to be made. The amendments in this rule are adopted in response to a decision of the United States Court of Appeals for the District of Columbia Circuit. In that case, a majority held that the Occupational Safety and Health Act does not permit OSHA to impose a continuing recordkeeping obligation on employers. One judge filed a concurring opinion disagreeing with this reading of the statute, but finding that the text of OSHA's recordkeeping regulations did not impose continuing recordkeeping duties. OSHA disagrees with the majority's reading of the law, but agrees that its recordkeeping regulations were not clear with respect to the continuing nature of employers' recordkeeping obligations. This final rule is designed to clarify the regulations in advance of possible future federal court litigation that could further develop the law on the statutory issues addressed in the D.C. Circuit's decision. PMID- 28030889 TI - Claims Procedure for Plans Providing Disability Benefits. Final rule. AB - This document contains a final regulation revising the claims procedure regulations under the Employee Retirement Income Security Act of 1974 (ERISA) for employee benefit plans providing disability benefits. The final rule revises and strengthens the current rules primarily by adopting certain procedural protections and safeguards for disability benefit claims that are currently applicable to claims for group health benefits pursuant to the Affordable Care Act. This rule affects plan administrators and participants and beneficiaries of plans providing disability benefits, and others who assist in the provision of these benefits, such as third-party benefits administrators and other service providers. PMID- 28030890 TI - Assistance to States for the Education of Children With Disabilities; Preschool Grants for Children With Disabilities. Final regulations. AB - The Secretary amends the regulations under Part B of the Individuals with Disabilities Education Act (IDEA) governing the Assistance to States for the Education of Children with Disabilities program and the Preschool Grants for Children with Disabilities program. With the goal of promoting equity under IDEA, the regulations will establish a standard methodology States must use to determine whether significant disproportionality based on race and ethnicity is occurring in the State and in its local educational agencies (LEAs); clarify that States must address significant disproportionality in the incidence, duration, and type of disciplinary actions, including suspensions and expulsions, using the same statutory remedies required to address significant disproportionality in the identification and placement of children with disabilities; clarify requirements for the review and revision of policies, practices, and procedures when significant disproportionality is found; and require that LEAs identify and address the factors contributing to significant disproportionality as part of comprehensive coordinated early intervening services (comprehensive CEIS) and allow these services for children from age 3 through grade 12, with and without disabilities. PMID- 28030891 TI - Impact of Slow Blood Filling via Collaterals on Infarct Growth: Comparison of Mismatch and Collateral Status. AB - BACKGROUND AND PURPOSE: Perfusion-diffusion mismatch has been evaluated to determine whether the presence of a target mismatch helps to identify patients who respond favorably to recanalization therapies. We compared the impact on infarct growth of collateral status and the presence of a penumbra, using magnetic resonance perfusion (MRP) techniques. METHODS: Consecutive patients who were candidates for recanalization therapy and underwent serial diffusion weighted imaging (DWI) and MRP were enrolled. A collateral flow map derived from MRP source data was generated by automatic post-processing. The impact of a target mismatch (Tmax>6 s/apparent diffusion coefficient (ADC) volume>=1.8, ADC volume<70 mL; and Tmax>10 s for ADC volume<100 mL) on infarct growth was compared with MR-based collateral grading on day 7 DWI, using multivariate linear regression analysis. RESULTS: Among 73 patients, 55 (75%) showed a target mismatch, whereas collaterals were poor in 14 (19.2%), intermediate in 36 (49.3%), and good in 23 (31.5%) patients. After adjusting for initial severity of stroke, early recanalization (P<0.001) and the MR-based collateral grading (P=0.001), but not the presence of a target mismatch, were independently associated with infarct growth. Even in patients with a target mismatch and successful recanalization, the degree of infarct growth depended on the collateral status. Perfusion status at later Tmax time points (beyond the arterial phase) was more closely correlated with collateral status. CONCLUSIONS: Patients with good collaterals show a favorable outcome in terms of infarct growth, regardless of the presence of a target mismatch pattern. The presence of slow blood filling predicts collateral status and infarct growth. PMID- 28030892 TI - Non-Vitamin K Oral Anticoagulants in Stroke Patients: Practical Issues. PMID- 28030893 TI - Recent Advances in Understanding Audiovestibular Loss of a Vascular Cause. AB - Acute audiovestibular loss is characterized by abrupt onset of prolonged (lasting days) vertigo and hearing loss. Acute ischemic stroke in the distribution of the anterior inferior cerebellar artery (AICA) is known to be the leading cause of acute audiovestibular loss. So far, eight subgroups of AICA territory infarction have been identified according to the patterns of audiovestibular dysfunctions, among which the most common pattern is the combined loss of auditory and vestibular functions. Unlike inner ear dysfunction of a viral cause, which can commonly present as an isolated vestibular (i.e., vestibular neuritis) or cochlear loss (i.e., sudden deafness), labyrinthine dysfunction of a vascular cause rarely results in isolated loss of vestibular or auditory function. As audiovestibular loss may precede the central symptoms or signs of an ischemic stroke in the posterior circulation, early diagnosis and proper management of audiovestiubular loss may provide a window to prevent the progression of infarction to larger areas of the posterior circulation. A clinician should consider the possibility that acute audiovestibular loss may herald impending AICA territory infarction, especially when patients have basilar artery occlusive disease close to the origin of the AICA on brain MRA. This review aims to highlight the recent advances in understanding audiovestibular loss of a vascular cause and to address its clinical significance. PMID- 28030894 TI - Hypercoagulability and Mortality of Patients with Stroke and Active Cancer: The OASIS-CANCER Study. AB - BACKGROUND AND PURPOSE: Patients with active cancer are at an increased risk for stroke. Hypercoagulability plays an important role in cancer-related stroke. We aimed to test whether 1) hypercoagulability is a predictor of survival, and 2) correction of the hypercoagulable state leads to better survival in patients with stroke and active cancer. METHODS: We recruited consecutive patients with acute ischemic stroke and active systemic cancer between January 2006 and July 2015. Hypercoagulability was assessed using plasma D-dimer levels before and after 7 days of anticoagulation treatment. The study outcomes included overall and 1-year survival. Plasma D-dimer levels before and after treatment were tested in univariate and multivariate Cox regression models. We controlled for systemic metastasis, stroke mechanism, age, stroke severity, primary cancer type, histology, and atrial fibrillation using the forward stepwise method. RESULTS: A total of 268 patients were included in the analysis. Patients with high (3rd-4th quartiles) pre-treatment plasma D-dimer levels showed decreased overall and 1 year survival (adjusted HR, 2.19 [95% CI, 1.46-3.31] and 2.70 [1.68-4.35], respectively). After anticoagulation treatment, post-treatment D-dimer level was significantly reduced and independently associated with poor 1-year survival (adjusted HR, 1.03 [95% CI, 1.01-1.05] per 1 MUg/mL increase, P=0.015). The successful correction of hypercoagulability was a protective factor for 1-year survival (adjusted HR 0.26 [CI 0.10-0.68], P=0.006). CONCLUSIONS: Hypercoagulability is associated with poor survival after stroke in patients with active cancer. Effective correction of hypercoagulability may play a protective role for survival in these patients. PMID- 28030895 TI - Imaging of Intracranial Hemorrhage. AB - Intracranial hemorrhage is common and is caused by diverse pathology, including trauma, hypertension, cerebral amyloid angiopathy, hemorrhagic conversion of ischemic infarction, cerebral aneurysms, cerebral arteriovenous malformations, dural arteriovenous fistula, vasculitis, and venous sinus thrombosis, among other causes. Neuroimaging is essential for the treating physician to identify the cause of hemorrhage and to understand the location and severity of hemorrhage, the risk of impending cerebral injury, and to guide often emergent patient treatment. We review CT and MRI evaluation of intracranial hemorrhage with the goal of providing a broad overview of the diverse causes and varied appearances of intracranial hemorrhage. PMID- 28030896 TI - Cancer Metabolism: Fueling More than Just Growth. AB - The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slower growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy. PMID- 28030898 TI - Early hypopharyngeal cancer treated with different therapeutic approaches: a single-institution cohort analysis. AB - PURPOSE: Early hypopharyngeal squamous cell carcinoma (HPSCC) is a rarely diagnosed disease, for which the optimal treatment has not been defined yet. We assessed patterns of failure and outcomes in early HPSCC treated with various therapeutic approaches to identify its optimal treatment. MATERIALS AND METHODS: Thirty-six patients with stage I (n = 10) and II (n = 26) treated between January 1992 and March 2014 were reviewed. Patients received definitive radiotherapy (RT) (R group, n = 10), surgery only (S group, n = 19), or postoperative RT (PORT group, n = 7). All patients in both the R and PORT groups received elective bilateral neck irradiation. In the S group, 7 patients had ipsilateral and 8 had bilateral dissection, while 4 patients had no elective dissection. RESULTS: At a median follow-up of 48 months, the 5-year locoregional control (LRC) rate was 65%. Six patients had local failure, 1 regional failure (RF), 3 combined locoregional failures, and 2 distant failures. There was no difference in 5-year LRC among the R, S, and PORT groups (p = 0.17). The presence with a pyriform sinus apex extension was a prognosticator related to LRC (p = 0.01) in the multivariate analysis. Patients with a bilaterally treated neck showed a trend toward a lower RF rate (p = 0.08). CONCLUSION: This study shows that patients with early stage HPSCC involving the pyriform sinus apex might need a tailored approach to improve LRC. Additionally, our study confirms elective neck treatment might have an efficacious role in regional control. PMID- 28030897 TI - Imaging Single-mRNA Localization and Translation in Live Neurons. AB - Local protein synthesis mediates precise spatio-temporal regulation of gene expression for neuronal functions such as long-term plasticity, axon guidance and regeneration. To reveal the underlying mechanisms of local translation, it is crucial to understand mRNA transport, localization and translation in live neurons. Among various techniques for mRNA analysis, fluorescence microscopy has been widely used as the most direct method to study localization of mRNA. Live cell imaging of single RNA molecules is particularly advantageous to dissect the highly heterogeneous and dynamic nature of messenger ribonucleoprotein (mRNP) complexes in neurons. Here, we review recent advances in the study of mRNA localization and translation in live neurons using novel techniques for single RNA imaging. PMID- 28030899 TI - Analysis of treatment outcomes for primary tonsillar lymphoma. AB - PURPOSE: Although each Waldeyer's ring sub-site is considered an independent prognostic factor, few studies have assessed the prognosis and treatment of tonsillar lymphoma. Treatment outcomes were analyzed in patients with primary tonsillar lymphoma who were treated with chemotherapy and radiotherapy (RT). MATERIALS AND METHODS: Nineteen patients with diffuse large B-cell lymphoma were evaluated, with a median follow-up of 53 months. Age, sex, and histology, amongst other factors, were reviewed. Progression-free survival (PFS) and overall survival (OS) rates were analyzed. RESULTS: Most patients had Ann Arbor stage I II (94.7%), IPI score of 0 (89.5%), and complete remission after chemotherapy (89.5%). The 5-year PFS and OS rates were 74.6% and 80%, respectively. In univariate analysis, the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen resulted in a better PFS than the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (88.9% vs. 50.0%; p = 0.053). RT dose was related to the survival outcome (p = 0.010 for PFS, p = 0.044 for OS). Patients were classified into the CHOP + RT (>40 Gy) group and R-CHOP + RT (<=40 Gy) group. The 5-year PFS rates were 50% in the CHOP + RT group, and 100 % in the R-CHOP + RT group (p = 0.018). The 5-year OS rates were 66.7% and 100%, respectively (p = 0.087). CONCLUSION: Primary tonsillar lymphoma patients typically have favorable outcomes. Chemotherapy (R-CHOP) combined with relatively lower dose consolidative RT may be safe and effective for primary tonsillar lymphoma. PMID- 28030900 TI - Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy. AB - Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of 'reoxygenation' phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because 'reoxygenation' is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn't it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy. PMID- 28030902 TI - Comment on: "Association Between the XRCC3 Thr241Met Polymorphism and Risk of Colorectal Cancer: A Meta-Analysis of 5,193 Cases and 6,645 Controls" PMID- 28030901 TI - Radiotherapy and immune checkpoint blockades: a snapshot in 2016. AB - Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data. PMID- 28030903 TI - Comparison between Computer Tomography and Magnetic Resonance Imaging in the Diagnosis of Small Hepatocellular Carcinoma AB - Background: Hepatocellular carcinomas (HCCs) less than 2 cm in diameter generally demonstrate a good outcomeafter curative therapy. However, the diagnosis of small HCC can be problematic and requires one or more dynamicimaging modalities. This study aimed to compare the sensitivity and agreement between CT and MRI for the diagnosis ofsmall HCCs. Methods: CT and/or MRI scans of HCCs (1-2 cm) diagnosed by histopathology or typical vascular patternaccording to the 2005 AASLD criteria were blindly reviewed by an abdominal radiologist. The reports were definedas conclusive/typical when arterial enhancement and washout during the portal/delayed phases were observed and asinconclusive when typical vascular patterns were not observed. The sensitivity and Cohen's kappa (k) for agreementwere calculated. Results: In 27 patients, 27 HCC nodules (1-2 cm) were included. Diagnosis with a single-imagingmodality (CT or MRI) was 81 % versus 48 % (p = 0.01). The CT sensitivity was significantly higher than MRI (78 %versus 52 %, p = 0.04). Among 27 nodules that underwent both CT and MRI, a discordance in typical enhancementpatterns was found (k = 0.319, p = 0.05). In cases with inconclusive CT results, MRI gave only an additional 3.7 %sensitivity to reach a diagnosis. In contrast, further CT imaging following inconclusive MRI results gave an additional29.6 % sensitivity. Conclusions: A single typical imaging modality is sufficient to diagnose small HCCs. Comparedwith MRI, multiphasic CT has a higher sensitivity. The limitations of MRI could be explained by the greater need forpatient cooperation and the types of MRI contrast agent. PMID- 28030904 TI - Knowledge, Attitude and Practice of Chewing Gutka, Areca Nut, Snuff and Tobacco Smoking Among the Young Population in the Northern India Population AB - Objective: The objective of the study was to determine the Knowledge, Attitude and Practice of chewing gutka,arecanut, snuff and tobacco smoking among the young population in the Northern India Population between the age of 15 to22 years. Methods: The study was approved by the ethical committee. A total of 10 school and colleges located in therural and urban areas was selected. A total of 1500 young individuals aged between 15 to 22 years were selected . Aself-administered questionnaire was designed comprised of 14 closed ended questions about Knowledge, Attitude andPractice towards consumption of areca nut , gutka and tobacco smoking that were filled by the participants. Descriptivestatistics were obtained and mean, standard deviation, frequency and percentages were calculated. Data was analyzedby using SPSS. Result: A total of 1050 out of 1500 students responded to the questionnaire. A total of 227 subjectsagreed that they are consuming the tobacco. Out of this, 196 (86.34%) were boys and 31 (13.65%) were girls whoagreed in consumption of tobacco product. Out of 196, 150 boys (76.5%) practices the habit of smoking 1 -5 times a dayand 46 (23.4% ) practice the habit of chewing areca nut and gutkha 1 - 5 times a day. Out of 31 girls, 25 girls (80.6%)practices the habit of smoking 1 -5 times a day and 6 (19.4%) practice the habit of chewing areca nut and gutkha 1 - 5times a day. Out of 740 subjects, 530 were boys and 210 girls have full knowledge of deleterious long term effects oftobacco consumption. Conclusion:The present study concluded that young population of North India lack Knowledge,Attitude and Practice regarding consumption of areca nut, gutka and tobacco smoking. Here is an urgent need to takeeffective steps, especially on launching community awareness programs for the school children and public to educatethem about the consequences of tobacco use, and on assessing their effectiveness in curbing the problem. PMID- 28030905 TI - Comparison of Conventional and Hypofractionated Radiotherapy in Breast Cancer Patients in Terms of 5-Year Survival, Locoregional Recurrence, Late Skin Complications and Cosmetic Results AB - Bckground: Adjuvant radiation therapy is commonly administered following breast conserving surgery for breastcancer patients. Hypofractionated radiotherapy can significantly reduce the waiting time for radiotherapy, workingload on machines, patient visits to radiotherapy departments and medical costs. Material/Methods: Fifty-two patientswith operable breast cancer (pT1-3pN0M0) who underwent breast conservation surgery in Tehran Cancer Instituteduring January 2011 to January 2012, were randomly assigned to undergo radiotherapy in two arms (hypofractionatedradiotherapy arm with 30 patients, dose 42.5 Gy in 16 fractions; and conventional radiotherapy arm with 22 patients,dose 50 Gy in 25 fractions). W compared these two groups in terms of overall survival, locoregional control, late skincomplications and cosmetic results. Results: At a median follow-up of 52.4 months (range: 0-64 months), the follow-uprate was 82.6%. Overall, after 60 months, there was no detectable significant differences between groups regardingcosmetic results (p = 0.857), locoregional control or survival. Conclusions: The results confirm that hypofractionatedradiotherapy with a subsequent boost is as effective as conventional radiotherapy, is well-tolerated and can be used asan alternative treatment method following breast conservation surgery. PMID- 28030906 TI - Awareness of Cervical Cancer and Pap Smear Testing Among Omani Women AB - Background: In developed countries, awareness of cervical cancer screening is well documented. In contrast, inOman as a developing country, public responses regarding cervical screening are unclear. This study aimed to assess thelevel of awareness about cervical cancer and Papanicolau (Pap) smear testing and to establish any correlations betweenknowledge and demographic factors among Omani women. Methods: In this cross-sectional survey, participants weredivided into three groups: patients who attended the Outpatient Gynecology Department in Sultan Qaboos UniversityHospital (SQUH), Oman, female staff from SQUH, College of Medicine and College of Nursing at Sultan QaboosUniversity (SQU) and graduating female students at SQU. Data collection was through interview-based and onlineself-administered questionnaires. Cumulative scoring was used for data analysis. Results: There were 204 outpatients,133 staff and 157 students. Outpatients (79.4%), staff (97.7%) and students (75.2%) had heard of cervical cancer.Nevertheless, their specific knowledge, regarding signs and symptoms, risk factors and Pap smear, was low at 38.7%,35.3% and 7.6% among outpatients, staff and students, respectively. Some 39.9% of the married outpatients had adequateoverall knowledge as compared to none of the single women. Educational level was found to be significantly associatedwith outpatient knowledge with the highest awareness levels among postgraduates and medical university graduates(61.5%). Conclusion: Specific knowledge of cervical cancer, its risk factors and cervical Pap smear is generally pooramong Omani women. This lack of knowledge may be one of the contributing factors for the high incidence of cervicalcancer in Oman relative to that in developed countries. PMID- 28030907 TI - Factors Associated with Suicide Risk in Advanced Cancer Patients: A Cross Sectional Study AB - The study aimed to find out to what degree suicidal thoughts and associated factors affect the suicide risk ofadvanced cancer patients. The frequency of suicidal thoughts among patients with cancer, especially in the advancedstages, is about 3 times greater than the adult average in South Korea. We recruited 457 participants with four typesof cancers (colon, breast, cervical, and lung) using stratified sampling. Data collection was carried out through oneon-one interviews by trained nurses using a structured questionnaire. Advanced cancer patients with high, vs. low,levels of anxiety and pain had a higher suicide risk. In contrast, having one's spouse as the primary care provider wasassociated with a low suicide risk. Overall, the three factors of anxiety, pain, and the primary caregiver being one'sspouse explained 17.2% of the variance in suicide risk. In conclusion, we derived influencing factors of suicide riskusing a sample of patients with various types of advanced cancer. The results provide systematic baseline data forpreparing nurse-led interventions to prevent suicidal thoughts and suicide attempts among advanced cancer patients. PMID- 28030908 TI - Improved Survival of Cervical Cancer Patients in a Screened Population in Rural India AB - Objectives: To describe the survival experience of cervix cancer patients in a screened rural population in India.Methods: Included 558 cervical cancer patients diagnosed in 2000-2013 in a cohort of 100,258 women invited forscreening during 2000-2003. The primary end point was death from cervical cancer. We used the Kaplan-Meier methodto estimate cumulative observed survival and Cox proportional hazards regression to assess the effect of patientcharacteristics on survival after diagnosis. Results: Of the 558 cases included, 143 (26%) and 114 (20%) were diagnosedin stages IA and IB respectively; 252 (45.2%) were dead, and 306 (54.8%) were alive at the last follow-up. The overall5-year observed survival was 60.5%. The 5-year survival of stage IA patients was 95.1% and 5.3% for stage IV patients.All surgically treated stage IA patients, 94.1% of stage IB patients receiving intracavitary radiotherapy, 62% of stageIIB, 49% of stage III and 25% of stage IV patients receiving radiotherapy survived for 5 years. Conclusion: Higher5-year survival in our study than elsewhere in India is due to the high proportion of early stage cancers detected byscreening combined with adequate treatment, resulting into a favourable prognosis. PMID- 28030909 TI - Effects of Sexual Rehabilitation Using the PLISSIT Model on Quality of Sexual Life and Sexual Functioning in Post-Mastectomy Breast Cancer Survivors AB - Background and Objectives: As one of the most common treatments for breast cancer, mastectomy has adverseeffects on the quality of sexual life and sexual functioning in the impacted women. Various strategies have thereforebeen proposed to resolve their sexual problems. The present study was conducted to determine the effect of sexualrehabilitation using the PLISSIT model in post-mastectomy breast cancer survivors. Materials and Methods: Thepresent quasi-experimental study was conducted on a population of post-mastectomy breast cancer survivors and theirhusbands. Sample size was calculated as 50 each for intervention and non intervention groups. The former receivedsexual counseling based on the PLISSIT model consisting of four levels of intervention: permission, limited information,specific suggestion and intensive therapy, presented in four 90 minute sessions. Data were collected using the SexualQuality of Life-Female (SQOL F) questionnaire and the Female Sexual Function Index (FSFI). Results: No significantdifferences were observed in the mean quality of sexual life scores between the intervention and control groups (P>0.05)before the intervention; however, a significant difference emerged between the groups after the intervention (P<0.01).Thus the mean score for sexual functioning in the intervention group was 26.3+/-3.76 before and30.0+/-4.38 after theintervention (P<0.0001). In the control group, however, the difference between the pre- and post-intervention meanscores was not statistically significant (P=0.713). Conclusion: The present study showed that nurses can use the PLISSITmodel in conjunction with chemotherapy and radiotherapy to teach coping and problem solving skills to women withbreast cancer and their husbands and to encourage their participation in group programs for expressing their feelings andattitudes about their current sex life and thus help enhance quality of sexual life and sexual functioning in this group. PMID- 28030910 TI - In Vitro and In Vivo Anticancer Activity of Gimatecan against Hepatocellular Carcinoma AB - Objective: Gimatecan is a new camptothecin (CPT) analogue that inhibits tumor growth by targeting DNAtopoisomerase I (TOP I) and introducing strong and persistent DNA cleavage. Anti-tumor activity has been demonstratedwith a wide range of solid tumors in previous preclinical and clinical studies. Here, we investigated for the first time theeffects of gimatecan on the proliferation of hepatocellular carcinoma (HCC) cells both in vitro and in vivo. Methods:Anticancer efficacy of gimatecan were evaluated in a panel of HCC cell lines and corresponding mouse xenograftmodels. Inhibition of cell proliferation was measured by CellTiter-Glo cell viability assay. In vivo, gimatecan andcontrol preparations were orally administered every four days, for a total of four times. Tumor volume and body weightsof the mice were measured twice weekly. Results: In vitro cytotoxicity evaluation showed that gimatecan inhibitedthe proliferation of a large panel of HCC cell lines in a dose dependent manner, with IC50 values ranging between12.1~1085.0 nM. In vivo evaluation in mouse xenograft models showed significant antitumor effects of gimatecan at0.8mg/kg and 0.4mg/kg as compared to the control group. Conclusion: This study suggested that gimatecan may havethe potential to be used as a chemotherapeutic agent for the treatment of HCC. PMID- 28030911 TI - Anti-Proliferative Effects of Dendrophthoe pentandra Methanol Extract on BCR/ABL Positive and Imatinib-Resistant Leukemia Cell Lines AB - Background: Imatinib mesylate, a tyrosine kinase inhibitor specifically targeting the BCR/ABL fusion protein,induces hematological remission in patients with chronic myeloid leukemia (CML). However, the majority of CMLpatients treated with imatinib develop resistance with prolonged therapy. Dendrophthoe pentandra (L.) Miq. is aMalaysian mistletoe species that has been used as a traditional treatment for several ailments such as smallpox, ulcers,and cancers. Methods: We developed a resistant cell line (designated as K562R) by long-term co-culture of a BCR/ABL positive CML cell line, K562, with imatinib mesylate. We then investigated the anti-proliferative effects of D.pentandra methanol extract on parental K562 and resistant K562R cells. Trypan blue exclusion assays were performedto determine the IC50 concentration; apoptosis and cell cycle analysis were conducted by flow cytometry. Results: D.pentandra extract had greater anti proliferative effects towards K562R (IC50= 192 MUg/mL) compared to K562 (500 MUg/mL) cells. Upon treatment with D. pentandra extract at the IC50. concentration: K562 but not K562R demonstratedincrease in apoptosis and cell cycle arrest in the G2/M phase. Conclusion: D. pentandra methanol extract exerts potentanti-proliferative effect on BCR/ABL positive K562 cells. PMID- 28030912 TI - Human Papilloma Virus Detection by INNOLiPA HPV in Prostate Tissue from Men of Northeast Mexico AB - Background: Prostatic adenocarcinoma by Prosate cancer (PCa) is the most prevalent cancer and the second cause ofcancer-related death among men in the Western world. Human papilloma virus (HPV) may be considered as a preventablerisk factor. In this study, we assessed the frequencies of HPV infection in prostatic adenocarcinoma and benign prostatichyperplasia (BPH) cases in Northeast Mexico. Materials and Methods: A total of 87 paraffin-embedded blocks (from25 and 62 patients with definite diagnoses of BPH and adenocarcinoma, respectively) were selected and subjected toINNOLiPA HPV Genotyping to detect 28 high- and low-risk HPV types. The rates of infection were compared in the twostudied groups. Results: INNOLiPA HPV demonstrated great sensitivity for HPV detection on paraffin-embedded tissue.Global prevalence was 14.9% (13/87). HPV infection was positive in 19.4% (12/62) of patients with adenocarcinomaand 4.0% (1/25) of patients with BPH. HPV-11, which is considered to be low risk, was more prevalent. Interestingly,one patient with BPH and six with prostate cancer showed examples considered to be high risk (HPV-18, -51, -52,and -66). Conclusion: A higher rate of HPV infection among Mexican patients with prostatic carcinoma than amongthose with BPH was observed. HPV infections may thus contribute to the risk of prostate cancer. Further studies arerequired to elucidate any roles of HPV infection in prostate disease in Mexico and the effect of prevention and treatmentof HPV infection on prostatic adenocarcinoma. PMID- 28030913 TI - Gleason's Grading of Prostatic Adenocarcinoma: Inter-Observer Variation Among Seven Pathologists at a Tertiary Care Center in Oman AB - Prostatic adenocarcinoma is the commonest solid malignancy seen in Omani elderly males 60-80 years of age.The Gleason grade is the most widely used grading system for prostatic carcinoma and is recommended by the WorldHealth Organization. A peer review was carried out at the Pathology Department of Sultan Qaboos University Hospital(SQUH), Oman, to assess the quality of reporting at the center. The aim of this study was to determine inter-observervariation among 7 pathologists working at a tertiary care center in Oman. A total of 47 consecutive prostatic biopsieswere interdependently reviewed by seven pathologists and the results obtained were compared with each other andthe original diagnosis. This peer review indicated a fair inter-observer agreement (0.482) among 7 pathologists in thedepartment, with fair to moderate agreement when the results were compared to the reported diagnosis, comparable tothe published literature. Dual and sub-specialty reporting are being instituted to improve the performance in this vitalaspect of pathology. PMID- 28030914 TI - Automatic Colorectal Polyp Detection in Colonoscopy Video Frames AB - Colonoscopy is currently the best technique available for the detection of colon cancer or colorectal polyps orother precursor lesions. Computer aided detection (CAD) is based on very complex pattern recognition. Local binarypatterns (LBPs) are strong illumination invariant texture primitives. Histograms of binary patterns computed acrossregions are used to describe textures. Every pixel is contrasted relative to gray levels of neighbourhood pixels. In thisstudy, colorectal polyp detection was performed with colonoscopy video frames, with classification via J48 and Fuzzy.Features such as color, discrete cosine transform (DCT) and LBP were used in confirming the superiority of the proposedmethod in colorectal polyp detection. The performance was better than with other current methods. PMID- 28030915 TI - Current Treatments for Breast Cancer-Related Lymphoedema: A Systematic Review AB - Background and objective: Breast cancer-related lymphoedema (BCRL) is a disabling complication with longterm impact on quality on life after breast cancer treatment. Its management remains a major challenge for patients andhealth care professionals; the goal of this overview was to summarize effects of different treatment strategies for patientswith BCRL. Methods: A thorough search was undertaken to allow a systematic review or meta-analysis of treatmentsfor BCRL. Two investigators independently selected studies and abstracted the data. Results: Combined physicaltherapy (CPT) with different combinations of surgery, oral pharmaceuticals, low-level laser therapy, weight reduction,mesenchymal stem cell therapy, kinesio tex taping, and acupuncture might be effective in reducing lymphoedema, butexercise demonstrated no obvious benefit. The results of direct comparisons showed CPT might be more effective thanstandard physiotherapy (ST). Manual lymphatic drainage (MLD) may not offer additional benefits to ST for swellingreduction, but could facilitate compression bandaging. MLD seemed to have similar effects with self-administeredsimple lymphatic drainage (SLD) or using an intermittent pneumatic compression pump (IPC). IPC might also not beassociated with additional effectiveness for CPT. Efficacy of stem cell therapy vs. compression sleeve or CPT, as wellas the effects of daflon and coumarin could not be established. Conclusion: Although many treatments for BCRL mightreduce lymphoedema volume, their effects were not well established. The quality of many of the original studies in theincluded reviews was not optimal, so that in future randomized control trials are a high priority. PMID- 28030916 TI - Endoscopic Treatment of Intussusception due to Intestinal Tuberculosis. AB - Traditionally, adult intussusception has required a bowel resection because of the malignancy risk. A patient with anorexia, weight loss, and abdominal pain visited our clinic. A physical exam and imaging study revealed no acute peritoneal signs. A colonoscopy for biopsy and bowel reduction was attempted. The tissue sample was consistent with intestinal tuberculosis. We report intestinal tuberculosis complicating intussusception which was treated without surgical intervention. PMID- 28030917 TI - Application of the BPCQ questionnaire to assess pain management in selected types of cancer. AB - INTRODUCTION: Pain is one of the most prevalent unpleasant sensation in people that may significantly lower the quality of life. More than a half of cancer patients suffer from various forms of pain, which becomes more frequent and intense as disease progresses. OBJECTIVE: The objective of the study was to assess the degree of pain control in patients diagnosed with breast, lung, colorectal and prostate cancer. The analysis also covered the effect of socio economic factors on pain management in patients with the above types of cancer. MATERIALS AND METHOD: The study included 902 patients treated at the Outpatient's Department of the Maria Sklodowska-Curie Memorial Cancer Center - Institute of Oncology in Warsaw in 2013. The patients consisted of those diagnosed with breast, lung, colorectal or prostate carcinoma. The Paper and Pencil Interview (PAPI) technique was applied. A questionnaire interview included demographic-type questions (socio-economic variables) and the Beliefs about Pain Control Questionnaire (BPCQ) test which measures the power of factors influencing pain control in patients. RESULTS: It was demonstrated that regarding beliefs in the source of pain control, patients attributed the highest importance to the power of doctors (mean value = 16.60) and the lowest to chance events (mean = 15.82). The internal factors are regarded as having the strongest influence by respondents diagnosed with colorectal or breast cancer. With regards to the locus of pain control, only the internal control of pain is diversified by the primary site. CONCLUSIONS: With regards to the source of pain management, only the internal control of pain is diversified by the primary site. The external factors were regarded as having the strongest influence by respondents diagnosed with colorectal or breast cancer. The major socio-economic variables differentiating the way in which pain control is perceived are education and net income-per household-member. The results of analyses of individual groups of patients revealled strong correlations between the beliefs in the doctors' influence, and the beliefs in chance events and socio-economic factors. PMID- 28030918 TI - To treat or not to treat drug-refractory epilepsy by the ketogenic diet? That is the question. AB - Epilepsy is a serious neurologic disorder worldwide which affects about 1% of the population (ca. 50 million people), the highest prevalence occurring in both children and elderly. Apart from idiopathic forms, etiology of the disease involves multiple brain risk factors - the most frequent being cerebrovascular diseases, tumours and traumatic injuries. Several treatment options exist, including, for instance, pharmacotherapy, vagal nerve stimulation or epilepsy surgery. In spite of treatment, about 30% of patients with epilepsy still have seizures and become drug-refractory. This is why other treatment options may be recommended, and ketogenic diet seems a last-chance method, especially in children and adolescents with epilepsy. The diet contains high amounts of fat and low carbohydrates with vitamin supplementation. The elevated concentrations of ketones induced by the diet may result in inhibition of the synaptic activity of glutamate, the mammalian target of the rapamycin pathway, and activation of adenosine triphosphate-sensitive potassium channels. One of the main ketones is acetone, shown to increase the seizure threshold and potentiate the anticonvulsant activity of some antiepileptic drugs. The clinical effectiveness of the ketogenic diet has been confirmed in a number of clinical trials carried out mainly on children. A wider use of the ketogenic diet may be limited by the number of early adverse effects (gastrointestinal distress, acidosis, hypoglycaemia, dehydration and lethargy), and late adverse effects (hyperuricaemia, hyperlipidaemia, kidney stones, easy bruising, and decreases in height and weight). Recently, data are available on the negative impact of the ketogenic diet on the qualitative characteristics of lipoprotein subfractions which points to the atherogenic fenotype as a new side-effect. In conclusion, future research directed to the proper identification of patients (in terms of age, epilepsy type and duration, recommended antiepileptic drugs) is necessary to answer the title question. PMID- 28030919 TI - Cardiovascular system diseases in patients with polycystic ovary syndrome - the role of inflammation process in this pathology and possibility of early diagnosis and prevention. AB - Polycystic ovary syndrome is a disorder which affects 5-10% of women in reproductive age. PCOS is a cause of hyperandrogenism, menstrual disorders and infertility. The most common clinical symptoms are hirsutism, acne and obesity. Patients often suffer from metabolic disorders: insulin resistance, hyperinsulinemia, dislipidemia, leading to atherosclerosis and others irregularities of the metabolic syndrome. Patients are in the high risk group for cardiovascular diseases (CVD) development because of the metabolic abnormalities. Obesity is observed in 35-60% of women with PCOS. Lean women with PCOS are also exposed to a greater risk of glucose intolerance development and abnormalities in lipid profile than women without PCOS with comparable BMI. Adipocytes are the source of many compounds of the paracrine and endocrine activity. Some of them are also markers and mediators of inflammation. Increased levels of proinflammatory cytokines in blood can promote atherosclerosis and cardiovascular disease. Markers: IL-18, TNF, IL-6 and hs-CRP are often elevated in patients with polycystic ovary syndrome. An increase in inflammatory markers may be an early indicator of the risk of developing insulin resistance and atherosclerosis, and may become a useful prognostic and therapeutic tool for monitoring patients with PCOS: lean and those with overweight and obesity. Assessment of the concentrations of inflammatory markers may become a very useful test in evaluating the risk of developing atherosclerosis and cardiovascular disease, long before their clinical manifestation. It will also allow for the appropriate prophylaxis. PMID- 28030920 TI - Sandpits as a reservoir of potentially pathogenic fungi for children. AB - INTRODUCTION AND OBJECTIVE: Fungi belonging to various physiological and morphological groups present in the environment are potential human pathogens. Some of them are considered as emerging pathogens. Therefore, their presence in children's playgrounds should be regarded as health risk factor. MATERIALS AND METHOD: Sixty-eight samples of sand collected from 17 sandpits of different localities in Lodz, Poland, in autumn 2010 and 2011, and in spring 2011 and 2012 were evaluated. The fungi were isolated with classical mycological methods and identified on the basis of morphological and biochemical features. RESULTS: The prevalence of fungi in spring was 94.1% of sandpits in both layers of sand (depth 0-3 cm and 10-15 cm) and in one kindergarten sandpit, but only in a deeper layer. In autumn, fungi occurred in both layers in all sandpits (100%). The fungal concentration (CFU/g of sand) varied considerably (range 0 - uncountable) in both layers. A total of 352 isolates belonging to 80 species were found. There were 69 yeasts and yeast-like fungi isolates from 12 species (9 species in each season), and 283 filamentous fungi from 68 species: 35 species in spring and 55 in autumn, with 4 keratinolytic species. There were important causes of allergies, among them Cladosporium herbarum and Alternaria alternata, as well as of opportunistic mycoses: Cryptococcus neoformans, Aspergillus fumigatus and new and 'emerging' fungal pathogens e.g., Trichosporon, Rhodotorula, Fusarium and Scedosporium species. CONCLUSIONS: Potentially pathogenic fungi are present in the sand taken from sandpits in Lodz. This fact poses a significant threat to child health and therefore proper maintenance and periodic checking of sandpits are of great importance. PMID- 28030921 TI - Place of residence as a factor differentiating physical activity in the life style of Ukrainian students. AB - Determining the state of physical activity of societies as an important component of a health promoting life style is a very up-to-date problem. Studies of physical activity among students, the future elites in their environments, become of increasing importance. An important problem is the recognition of factors differentiating this activity on the example of place of residence. For this purpose, the study covered 2,125 students (60.8% females and 39.2% males) from the National Institute in Lutsk, Ukraine, aged 17-22 (mean age: 20.4). The method of a diagnostic survey was applied which included the International Physical Activity Questionnaire (IPAQ). The following measures of physical activity according to the place of residence (rural area, small town with a population up to 100,000; medium-size town - 100,000-200,000 inhabitants; large city - over 200,000) were taken into consideration: level of physical activity, self-reported physical fitness, sports disciplines practiced by the respondents, and those which they would like to practice, and the BMI, and leisure time possessed. The study showed that the place of residence positively differentiated physical activity among students from medium-size towns and rural areas, compared to their contemporaries from small towns and large cities. Significant differences were also found with respect to the BMI, which was significantly less favourable among respondents from the rural environment. However, no differences were observed between the place of residence for leisure time, self-reported physical activity, and forms of physical activity practiced, and those which the respondents would like to practice. PMID- 28030922 TI - Prevention of cardiovascular disease in a rural general practice. AB - INTRODUCTION: Cardiovascular disease (CVD) prophylaxis in general practice, especially in rural areas, is a major organizational challenge. OBJECTIVE: The aim of this study was to determine the prevalence of CVD risk factors in the studied population, and to identify the effect of the number of planned prophylactic consultations on selected clinical parameters, risk factors, and total cardiovascular risk on the SCORE scale (Systemic Coronary Risk Evaluation). MATERIALS AND METHOD: The study included patients of a rural general practice, aged 35-55 years, with at least one modifiable CVD risk factor. Medical history was obtained, a physical examination performed, blood glucose levels, lipid profile, BMI, waist circumference and blood pressure measured and the SCORE cardiovascular risk at baseline and at the end of the study calculated. All participants were provided with targeted specific education. Analysis was performed in two groups of patients (1 and 2), where group 1 had one more prophylactic consultation than Group 2. RESULTS: The results at baseline and a year later were compared in pharmacologically untreated patients, 26 in Group 1 and 34 in Group 2. In Group 1, which had had more prophylactic consultations, a statistically significant decrease was found in the mean systolic blood pressure: 131.000-124.782 (p= 0.02721), mean diastolic blood pressure: 86.846-83.462 (p=0.01111), and a statistically significant decrease in total cardiovascular risk on the SCORE scale (p=0.0478). CONCLUSIONS: The higher number of preventive consultations had an impact on a statistically significant decrease in mean blood pressure and mean SCORE value. The year-long cardiovascular disease prophylaxis programme proved less effective than expected, and neither a decrease in body weight nor an improvement in lipid metabolism was achieved in any of the groups. PMID- 28030923 TI - Microbiological characterization of vegetables and their rhizosphere soil in Eastern Poland. AB - The aim of this study was to investigate the bacteriological quality of 5 kinds of vegetables (lettuce, dill, radish, beetroot, carrot) and their rhizosphere soil, originating from conventional farms located in the Lublin Province of Eastern Poland. A total number of 35 samples of fresh vegetables (FV) taken immediately from soil, 35 samples of soil from rhizosphere of these vegetables (SR) and 35 samples of vegetables sold at retail in the markets in Lublin (VR) were examined. The samples were analysed for the content of: aerobic mesophilic bacteria (AMB) grown at 30 degrees C and 37 degrees C, Gram-negative bacteria of Enterobacteriaceae family, faecal coliform (FC) bacteria, Salmonella spp., and Clostridium perfringens. Median AMB values determined at 30 degrees C for FV, SR and VR were 5.27, 5.00, and 5.00 log10 CFU g-1 , respectively, being significantly greater compared to those recorded at 37 degrees C. The exceeding of the threshold value of 6.0 log10 CFU g-1 proposed by Gelosa (1998) was noted only in 5 FV samples grown at 30 degrees C (14.3%), and in 3 FV samples grown at 37 degrees C (8.6%). The threshold value was never exceeded in SR and VR samples. Median concentrations of Enterobacteriaceae determined for FV, SR and VR were 4.03, 3.87, and 3.04 log10 CFU g-1, respectively. Eleven species of Enterobacteriaceae were identified in the FV, SR and VR samples. The percent of samples containing Escherichia coli was greatest for VR (22.9%), smaller for FV (17.1%) and smallest for SR (5.7%). The median concentrations of the faecal coliform bacteria (FC), determined by culture at 44 degrees C, were low, amounting to 1.000 log10 CFU g-1 for FV and SR and 0.00 for VR. All examined vegetable and soil samples tested negative for the presence of Salmonella. The median concentrations of Clostridium perfringens were low, amounting to 0.00 log10 CFU g-1 for all categories of samples. This bacterium was relatively common in soil samples with the prevalence of 40.0%, but very rare in vegetable samples (occurring in 5.7% of FV and in none of VR samples). In conclusion, the results of the present study generally indicate that the microbiological quality of Polish vegetables grown on conventional farms is satisfactory and safe for consumers. PMID- 28030924 TI - Identification of infectious microbiota from oral cavity environment of various population group patients as a preventive approach to human health risk factors. AB - INTRODUCTION AND OBJECTIVE: This study presents the results of comparative investigations aimed to determine microbiota that can occur in the oral environment in different human populations. The objective of the research was to identify pathogenic oral microbiota, the potential cause of health complications in patients of different population groups. MATERIALS AND METHOD: The study included 95 patients requiring dental or surgical treatment; their oral cavity environment microbiota as risk factors of local and general infections were assessed. RESULTS: In clinical assessment, differences occurred in oral cavity conditions between patients with malformations of the masticatory system, kidney allograft recipients and individuals without indications for surgical procedures. The presence of various pathogenic and opportunistic bacterial strains in oral cavities were revealed by direct microscopic and in vitro culture techniques. CONCLUSIONS: Colonization of oral cavities of patients requiring surgical treatment by the potentially pathogenic bacteria constitutes the threat of their spread, and development of general infections. Assessment of oral cavity infectious microbiota should be performed as a preventive measure against peri surgical complications. PMID- 28030925 TI - Comparison of the efficiency of two commercial kits - ELFA and Western blot in estimating the phase of Toxoplasma gondii infection in pregnant women. AB - Sera of 89 pregnant women were selected according to the results of ELFA IgM, IgG and avidity IgG, and tested with commercial tests IgM, IgG and avidity IgG Western Blot (WB) to compare the efficacy of both techniques in determining the phase of T. gondii infection. In total, 81 of 89 tested sera (91.0%) were classified as positive, both in the ELFA and WB tests for the presence of anti Toxoplasma antibodies of class IgG, indicating a past infection, while the prevalence of anti-Toxoplasma positive reactions associated with the antibodies of class IgM indicating a recent infection was much lower - 31.5% and 20.2%, respectively. Sera of 81 women were also tested in the ELFA and WB tests for avidity, e.g. ability of forming high-molecular IgG antibody complexes. Low or medium results in these tests (in this study all classified as low), indicating a recent infection, were detected by ELFA and WB in 22.2% and 45.7% of the total examined samples, respectively. The Spearman's rank test for correlation, performed for recognition of quantitative data of the ELFA and WB tests (index, units or points), revealed a highly significant correlation between the ELFA and WB tests for homologous classes of antibodies, both for IgM and IgG (p<0.00001). In contrast, the ELFA and WB tests for detection of anti-Toxoplasma IgM antibodies were not correlated with the ELFA and WB tests for detection of anti Toxoplasma IgG antibodies (p>0.05), except for the WB test for IgM antibodies, which showed a significant correlation with the ELFA test for IgG antibodies (p<0.01). A highly significant negative correlation between the ELFA and WB test for IgM antibodies and ELFA and WB tests for IgG avidity was demonstrated (p<0.01), except for a relationship between the WB test for IgM and WB for avidity, which was not significant. Such negative correlations are theoretically expected, as strong complexes with the participation of IgG antibodies are absent in the early phase of toxoplasmosis when early antibodies of IgM class are present. Summarizing, this study indicates the high usefulness of the commercial ELFA and WB tests in serodiagnostics of toxoplasmosis in pregnant women. Special attention should be paid to parallel detection of IgM antibodies and low values in the ELFA and WB tests for IgG avidity, which indicates a recent infection which may be associated with a clinical form of congenital toxoplasmosis and damage to the foetus. PMID- 28030926 TI - Prevalence of rotavirus, adenovirus, hepatitis A virus and enterovirus in water samples collected from different region of Peshawar, Pakistan. AB - Viral gastroenteritis and other water-borne diseases are the most neglected areas of research in Pakistan. To determine the quality of water, 4 enteric viruses were studied from different localities of Peshawar, Pakistan. The study validates the viral detection method for Rotavirus (RV), Human adenovirus (HAdV), Enterovirus (EV) and Hepatitis A virus (HAV), directly from water sources of rural areas of Peshawar, KPK, Pakistan. Overall, 95 five water samples were tested; among them, 9.47% were positive for RV, 38.94% for HAdV, 48.42% for EV and 12.63% for HAV. The presence of these viruses in water was directly correlated with meteorological data. High prevalence of EV and HAdV was detected frequently in the wet season from May - September, which can be the potential cause of spreading of gastroenteritis in the population. Environmental surveillance is an additional tool to evaluate the epidemiology of enteric viruses circulating in a given community. PMID- 28030927 TI - Fogging low concentrated organic acid in a fattening pig unit - Effect on animal health and microclimate. AB - INTRODUCTION AND OBJECTIVE: In intensive pig production aerial contaminates are potential hazards for the health of animals and humans. In this study, the effect of fogging a low concentrated tartaric acid solution on pigs' health, environmental and hygiene parameters were evaluated in an inhabited fattening unit. MATERIALS AND METHOD: Pigs were housed in separate units (control group n=109 and experimental group n=110). During the whole fattening period, twice a week at 48 hour intervals, a 0.1% tartaric acid solution was aerosolized by a cold-fogging system for 20 minutes in the experimental unit. Environmental parameters were spot-checked on days of fogging. Sedimentation dust and surfaces were analysed for bacterial and fungal load. Dust particle size distribution was assessed. Pigs were clinically examined weekly. Standard meat examination at an abattoir was extended by individual quantification of lung alterations. RESULTS: The fogging procedure had no influence on ammonia concentrations. A significant reduction of mould, but not of bacteria, was found in sedimentation dust, and bacterial and mould scores of surface samples were improved. A significant reduction of particle size classes 1.6-2.0 um, 4.0-5.0 um, 7.5-10 um, as well as 10-15 um was observed. The high sound level of the fogging machine (82-102 dB) led to higher activity and pen-mate directed behaviour. More skin alterations, conjunctivitis and sneezing were recorded in the experimental group. Gross pathological lung alterations did not differ between both groups. CONCLUSIONS: Although fogging of tartaric acid is limited to a concentration of 0.1% due to its irritating effect on the respiratory mucosa, reduction of microbial load can be achieved, but it would be enhanced by using more powerful fogging systems. PMID- 28030928 TI - Seroprevalence of Toxoplasma gondii and Neospora caninum in goats from north western Spain. AB - INTRODUCTION AND OBJECTIVE: Toxoplasma gondii and Neospora caninum are protozoans involved in reproductive failure especially in ruminant livestock. The objective was to estimate the seroprevalence of both parasites in goats from north-western Spain and to study the influence of some factors on seropositivity. MATERIALS AND METHOD: Blood samples from 638 goats were collected in 50 farms. Presence of T. gondii and N. caninum antibodies were detected by direct agglutination and competitiveELISA techniques, respectively. The risk factor analysis was performed using a mixed-effects logistic regression. RESULTS: Individual (48%) and herd level (74%) T. gondii seroprevalence values were high; the within-herd prevalence was 53%. In contrast, 6% of animals tested positive to N. caninum and 38% of the herds had at least one positive animal, with a true within-herd prevalence of 10%. Mixed infections were limited; 91% of N. caninum seropositive goats were also positive to T. gondii. The risk factor analysis showed that T. gondii seroprevalence is influenced by the presence of sheep in the farm (OR=4.9) and the seropositivity to N. caninum (OR=16.5); goats from the Central-coastal area, more humid and warm, had a 15.7-fold probability of being seropositive to T. gondii than those from the Mountainous area. Cross-breed goats (OR=4.5) and the seropositivity to T. gondii (OR= 9.5) were factors associated with N. caninum seropositivity. CONCLUSIONS: The high T. gondii seroprevalence in goats constitute a noticeable zoonotic risk. The consideration of the risk factors identified in designing T. gondii and N. caninum control programs in goat herds should allow the implementation of more efficient measures, avoiding the appearance of outbreaks of reproductive disorders by both protozoans in goats. PMID- 28030929 TI - Risk exposure to vibration and noise in the use of agricultural track-laying tractors. AB - Human exposure to mechanical vibration may represent a significant risk factor for exposed workers in the agricultural sector. Also, noise in agriculture is one of the risk factors to be taken into account in the evaluation of workers' health and safety. One of the major sources of discomfort for the workers operating a tractors is the noise to which they are exposed during work. The aim of this study was to evaluate the risk of exposure to whole-body vibration for the operator driving track-laying tractors in vineyard orchard and the noise level. The experimental tests were performed with six different track-laying tractors coupled with the same rototilling machine. The results showed that the vibration values of track-laying tractors coupled to rototilling machine, referred to the 8 hour working day, were always higher than 0.5 m s-2, the daily exposure action value established by Directive 2002/44/EC of the European Parliament. The daily noise exposure levels always exceeded the exposure limit value of 87 dB(A) established by Directive 2003/10/EC of the European Parliament. The ANOVA repeated measures model showed that the factor 'site', namely, the soil characteristics, did not influence the vibration level on the X and Y-axes of the tractors measured, regardless of their age. In the Z-axis, the vibration level was enhanced as the soil structure increased. As tractor age increased, the influence of soil characteristics was less important. In term of the age of the tractor and the number of hours worked, it was possible to identify three risk classes, which were up to 3,000 hours worked and offered a low risk; from 3,000 - 6,000 hours worked with a medium risk, and over 6,000 hours with a high risk level. PMID- 28030930 TI - Years of life lost of inhabitants of rural areas in Poland due to premature mortality caused by external reasons of death 1999-2012. AB - INTRODUCTION: External causes of death are the third most common causes of death, after cardiovascular diseases and malignant neoplasms, in inhabitants of Poland. External causes of death pose the greatest threat to people aged 5-44, which results in a great number of years of life lost. OBJECTIVE: The aim of the study is the analysis of years of life lost due to external causes of death among rural inhabitants in Poland, particularly due to traffic accidents and suicides. MATERIAL AND METHODS: The study material included a database created on the basis of 2,100,785 certificates of rural inhabitants in Poland in the period 1999-2012. The SEYLLp (Standard Expected Years of Life Lost per living person) and the SEYLLd (per death) indices were used to determine years of life lost due to external causes of death. Joinpoint models were used to analyze time trends. RESULTS: In the period 1999-2012, 151,037 rural inhabitants died due to external causes, including 27.2% due to traffic accidents and 25.2% due to suicides. In 2012, the SEYLLp was 1,817 per 100,000 males and 298 per 100,000 females. Among males, suicides (SEYLLp = 633 years per 100,000) and traffic accidents (SEYLLp = 473 years per 100,000) contributed to the largest number of years of life lost. Among females, SEYLLp values were: 109 years due to traffic accidents and 69 years due to suicides (per 100,000). Among males, SEYLLp values started to decrease in 2008 at the average annual rate of 3.2%. In the group of females in the period 1999-2012, SEYLLp values were decreasing by 2.4% per year. CONCLUSIONS: The decreasing trend of the number of lost years of life due to external causes among rural inhabitants does not apply to suicides among men. The SEYLLp due to this group of causes has been steadily increasing since 1999. Analysis of the years of life lost focuses on the social and economic aspects of premature mortality due to external causes. PMID- 28030931 TI - Farm work injuries among a cohort of children in Kentucky, USA. AB - Children residing on farms with livestock may be at an increased risk for work related injuries, compared to children who work on other commodity farms. This study characterizes children's work tasks on Kentucky farms and assesses whether children who work on beef cattle farms are at an increased risk for farm work injuries. The results of a cohort study of children aged 5-18 years (N=999 at baseline) working on family farms in Kentucky, followed for two consecutive years after an initial enumeration five years previously, found that 70% of the children were involved in animal-related chores. Across all age groups, children on beef cattle farms devoted a greater number of hours per week to farm work, compared to children living on other commodity farms, especially during the school year. For all children in the study, working more than 180 days per year, performing farm work independently, and working on a beef cattle farm (compared to other commodity farm), increased the risk of a farm work injury. However, none of these associations were statistically significant. For male children only, the performance of work tasks independently was significantly associated with a 2.4 fold increased risk (OR = 2.41; 95% CI: 1.15-5.06; P=0.02) for a farm work injury, after controlling for days of working, age, period of data collection, and commodity type of the farm. PMID- 28030932 TI - Usage of perioperative anxiety neuromarker for improving the quality of life of a patient operated on for critical stenosis of the internal carotid artery. AB - OBJECTIVE: The aim of the study was to find a neuromarker of perioperative anxiety in a patient with critical carotid stenosis through the use of neuromarkers in Quantitative EEG (QEEG) and Event Related Potentials (ERPs). The indirect purpose of the research was evaluation of improvement in the patient's quality of life. CASE STUDY: A 45-year-old woman was admitted to the Department of Vascular Surgery and Endovascular Interventions at the John Paul II Hospital in Krakow, with the diagnosis of critical internal carotid stenosis (over 80%), confirmed by Doppler Ultrasound and Angio-CT examinations. Before hospitalization, the patient had not presented any symptoms of brain ischemia. It was found that severe anxiety on the Hospital Anxiety and Depression Scale (HAD) was worse before the surgery. After the operation, a reduction anxiety in occurred as well as an improvement in the majority of the dimensions of health. Therefore, her quality of life improved. CONCLUSIONS: Significant changes were observed on the Hospital Anxiety and Depression Scale (HAD). Modern neurotechnologies measures are necessary to capture all the changes in the symptoms of anxiety before and after the operation for a carotid stenosis. ERPs might be used to select patients with neuromarker of perioperative anxiety, and subsequently to serve in proper psychological care and minimalize the perioperative risk of complications. PMID- 28030933 TI - Event-related potentials (ERP) and SGIP1 gene polymorphisms in alcoholics: relation to family history of alcoholism and drug usage. AB - OBJECTIVE: The electrophysiological characteristics may serve as valuable biomarkers for the genetic vulnerability underlying alcoholism. The purpose of this study was to evaluate the potential associations between single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and the theta ERP quantitative traits. METHOD: The theta band (4-7 Hz) visual ERP occurring in the P300 response in the resting EEG were examined to explore the electrophysiological effects of alcohol on the brain in five regions: frontal, central, parietal, temporal and occipital in patients with alcohol addiction. In addition, we tested the potential associations between single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and ERP quantitative traits. RESULTS: We found that the amplitude of the auditory P300 response differed considerably among groups of alcoholics in the frontal, central and temporal areas of the brain and it was lower in the studied brain regions in alcoholics in comparison to non-alcoholics. However, among subjects in the young adult group (GR-1) there was no statistical difference in amplitude of P300 response with control subjects in all studied brain regions in comparison with non-alcoholics. Moreover, we revealed that SNP rs10889635 had a significant effect on P300 amplitude in the central and temporal regions. The reduced P300 amplitude was in AA carriers in comparison to both carriers of GG and GA alleles. CONCLUSION: The present study demonstrated a possible association of target P300 evoked theta and of alcohol dependence with SNPs from the gene SGIP1 in the region of rs10889635, but further studies are required. PMID- 28030934 TI - The physiotherapeutic context of loss of dominant arm function due to occupational accidents. AB - INTRODUCTION: The study examines the problem of dominant arm function loss in rural adult patients due to work-related accidents. The types of risks involved in farmyard work include falling from a height, manually moving loads, overturning/accident whilst driving an agricultural tractor, noise and vibration, use of pesticides, and the risk of being cut or injured. The study focuses on adaptation of the non-dominant arm. OBJECTIVE: The main aim of the study was evaluation of visual-motor coordination on the basis of performance of the non dominant hand in patients after the loss of function of the dominant arm. MATERIALS AND METHOD: The research sample consisted of 52 patients with a permanent or temporary loss of function or severely limited function of the dominant arm. The subjects were patients with arm amputations due to various occupational injuries sustained while operating agricultural and construction machinery and forestry equipment, following traumas or complicated medical surgeries of the arm, or due to car accidents. The following tests were applied in the analysis: I) Dufour cross-shaped apparatus test for assessing visual motor coordination; II) paper-and-pencil tests and the Relay Baton motor fitness test; III) anthropometric measurements; IV) Edinburgh Handedness Inventory; and V) a questionnaire survey. RESULTS: The results of the apparatus and motor tests indicate the same tendency: reaction to stimuli measured on the basis of performance of the non-dominant arm is longer in shorter and older patients. CONCLUSIONS: Visual-motor coordination, as measured by the performance of the non dominant arm, is significantly affected by the subject's body height and arm length. PMID- 28030935 TI - Prevalence of metabolic syndrome in normal weight individuals. AB - INTRODUCTION AND OBJECTIVE: The prevalence of metabolic syndrome and overweight in individuals with normal body weight is connected with higher exposure to type 2 diabetes and cardiovascular diseases. The aim of the study was to evaluate the risk and frequency of occurrence of metabolic syndrome and each of its components among individuals with normal weight. MATERIALS AND METHOD: Data were obtained by structured interview, and by measurements of anthropometric factors and blood analyses among 13,172 individuals aged 37-66. The risk of occurrence of metabolic syndrome was analysed in tertiles within the normal range of BMI (18.5-24.9 kg/m2 ). RESULTS: Metabolic syndrome was diagnosed in 17.27% of individuals with normal weight. A significant increase in the risk of occurrence of metabolic syndrome in females was observed within the second (OR = 2.22; 95% CI: 1.63-3.05) and the third (OR = 3.97; 95% CI: 2.97-5.36) tertiles of normal BMI values. In males, a significantly higher risk of occurrence of metabolic syndrome was noted only in the highest BMI tertile (OR = 2.16; 95% CI: 1.26-3.83), compared to the reference level. CONCLUSIONS: A high frequency of occurrence of metabolic syndrome risk factors was observed among individuals with BMI close to the upper cut-off point of the normal range. In order to early diagnose metabolically obese individuals with normal weight it is necessary to check the waist circumference when BMI >= 22.5 kg/m2 in females, and BMI >= 23.8 kg/m2 in males, where abnormal values should be a signal that further examinations should be performed to determine other risk factors of metabolic syndrome. PMID- 28030936 TI - Association of anthropometric measures of obesity and chronic kidney disease in elderly women. AB - INTRODUCTION AND OBJECTIVE: Growing evidence suggests that obesity is an important contributor to the development of chronic kidney disease (CKD). The relationship between obesity and CKD is complex and not completely understood, and the best anthropometric index of obesity in predicting CKD is controversial. This study aimed to determine the best anthropometric index of obesity in predicting CKD in a population of elderly women. MATERIALS AND METHODS: Anthropometric indexes of obesity including body mass index (BMI), waist circumference (WC), waist-to-height ratio (WheiR) and waist-to-hip-ratio (WHR), were obtained in 730 selected females. Biochemical measurements including blood glucose, lipid profile, and 2-h postprandial blood glucose were performed. GFR was estimated by using CKD-EPI equation. RESULTS: The prevalence of CKD stage >= 3 was 12.2%. Overweight and obesity was found in 50% and 36% of participants, respectively. Increased central fat distribution, as defined by WheiR, WC and WHR, was found in 89.6%, 91.7% and 89.4% individuals, respectively. Univariate linear regression analysis showed positive correlations between CKD and age (p<0.001), BMI (p<0.001), WC (p<0.001), WHR (p=0.007), WheiR (p<0.001), diabetes (p=0.002), as well as triglicerydes (p=0.031), and negative correlation between CKD and HDL level (p=0.017). Multivariable analysis demonstrated that hypertension, diabetes, WC and WheiR were independent predictors of CKD. The area under the receiver operating characteristics curve was best for WheiR (0.647), followed by WC (0.620), BMI (0.616), and WHR (0.532). CONCLUSIONS: Abdominal obesity is an important predictor of CKD. Of commonly used anthropometric parameters of obesity WheiR >= 0.6 is particularly associated with CKD in elderly females. PMID- 28030937 TI - Predictors of the quality of life of women in peri-menopausal period. AB - INTRODUCTION: The peri-menopausal period is the time of many biological, psychological and social changes. The quality of life of women in this period may be conditioned by many factors, and analysis of these factors may indicate the optimum directions of prophylactic and educational actions. OBJECTIVE: Analysis of selected predictive factors of the quality of life of women in the peri menopausal period. MATERIALS AND METHOD: The study covered 268 peri-menopausal women. The qualification criteria were: age 45-55, lack of mental disorders and diseases requiring hospitalization during the period of study. The study was conducted using standardized instruments: Women's Health Questionnaire - WHQ, Beck Depression Inventory (BDI) and an author-constructed questionnaire. RESULTS: The presented study of the quality of life showed that the women examined felt physically unattractive, lacking the full joy of life, and frequently experienced somatic complaints. Nevertheless, the respondents enjoyed life, had no constant feeling of anxiety and concern. Multi-factor analysis showed that the quality of life in the group of women in the study was affected by the following factors: level of depression, self-reported state of health, occurrence of menopausal symptoms, education level, and marital status. CONCLUSIONS: The quality of life of the peri-menopausal women examined was the highest with respect to depressive mood (DEP) and anxiety/depressed mood (ANX), while it was the lowest with respect to the sense of attractiveness (ATT), and somatic symptoms (SOM). In addition, in the group of women in peri-menopausal period the quality of life was conditioned: level of depression, self-reported state of health, occurrence of menopausal symptoms, education level, and marital status. PMID- 28030938 TI - Matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinases (TIMP-1) and transforming growth factor-beta2 (TGF-beta2) expression in eutopic endometrium of women with peritoneal endometriosis. AB - INTRODUCTION: The prevalence of endometriosis among reproductive age women is 7 17%; however, these figures reach 20-50% in patients suffering from infertility. Matrix metalloproteinases (MMPs) activity is thought to be particularly essential in the early phases of endometriosis development. Any changes in the equilibrium between MMPs activity and their tissue inhibitors (TIMPs) could be potentially harmful, promoting endometriosis development. The aim of this study was to investigate whether the MMP-2, MMP-9, TIMP-1 or TGF-B2 expression in eutopic endometrium from women with early endometriosis differ when compared with healthy subjects. The results were referred to the serum progesterone levels. MATERIALS AND METHOD: Endometrial biopsy was taken from 42 patients (18 in the study group, 22 in thecontrol group) at the time of hysteroscopy for routine histology and for RT-PCR procedures. Comparison of the quantity of gene products was performed with a programme for densitometry and compared to GADPH product, which was a reference value. RESULTS: The obtained results did not reveal any statistical difference in endometrial expression of MMP-2, MMp-9, TIMP-1, and TGF-beta2 or serum progesterone level between women with endometriosis and without visible signs of this illness. CONCLUSION: Despite the lack of statistical differences, it was observed that both examined metalloproteinases expressed a tendency to higher gene expression in the eutopic endometrium of women with endometriosis. However, both TIMP-1 and TGF-beta2 expressions had the same tendency - higher values in endometriosis patients. PMID- 28030939 TI - Evaluation of VCAM-1 and ICAM-1 concentration and values of global tests concerning the coagulation system of patients suffering from subarachnoid haemorrage. AB - INTRODUCTION: The term 'subarachnoid haemorrhage' (SAH) stands for bleeding into the subarachnoid space, regardless of its source. It may be of primary character when the source of bleeding is situated within the subarachnoid space. Subarachnoid haemorrhage is often described as spontaneous bleeding, mainly in order to differentiate it from post-traumatic bleeding. OBJECTIVE: The aim of the study was to evaluate the concentration of ICAM-1 and VCAM-1 in the blood of patients in the early phase following subarachnoid haemorrhage in terms of searching for markers useful in subarachnoid bleeding diagnostics and monitoring a patient's clinical state. MATERIALS AND METHOD: The study comprised 85 patients (47 women, 38 men), aged 29-81 (average 53+/-12 years), suffering from subarachnoid haemorrhage. The control group comprised 45 healthy people selected according to gender and age corresponding with the experimental group. RESULTS: The study revealed that the concentration of ICAM-1 and VCAM-1 was significantly higher in patients suffering from subarachnoid haemorrhage. Additionally, the concentration of fibrinogen decreased, aPTT was shorter and the concentration of D-dimers increased. The studied parameters did not differ with respect to the age or gender of the patients. It was stated that according to the Hunt and Hess scale, the concentration of ICAM-1 was considerably higher in the group of patients in the most severe neurological state, compared to other patients. It was also observed that the concentration of fibrinogen was significantly higher, aPTT was shorter, and the concentration of D-dimers increased in the afore mentioned group. CONCLUSIONS: Evaluation of the concentration of adhesion molecules, as well as values of global tests concerning the coagulation system, may serve as a useful diagnostic tool for SAH. PMID- 28030940 TI - The dependence of dental caries on oral hygiene habits in preschool children from urban and rural areas in Poland. AB - INTRODUCTION: Dental caries is considered to be a modern civilization disease;however, the state of oral health negatively influences psychological and sociological relations in children which leads to feelings of discomfort from early age. OBJECTIVE: The aim of study was evaluation of the association between incidence of dental caries (d3ft index) in preschool children from urban and rural areas, and determining the relationship between dental caries intensity and hygienic habits. MATERIALS AND METHOD: 844 children aged 3-6 years from the city and the countryside were examined. The survey was conducted among parents/care givers regarding dental care of children. With parents' consent, the children had a dental examination. RESULTS: The incidence of caries was recorded at the level of 52.61%, with an average value of 4.31 on the d3ft index; however, for the children from the urban area this ratio amounted to 4.15, and in the countryside it reached the value of 4.7. A correlation was found between age and area of residence of the children and various components of hygienic behavior model. CONCLUSIONS: More than a half of the children had dental caries in combination with a high frequency of unsatisfactory hygiene needs. There is a relationship between oral hygiene habits and age of the children, depending on the place of residence. PMID- 28030941 TI - Diagnostics of intestinal parasites in light microscopy among the population of children in eastern Afghanistan. AB - OBJECTIVES: The Afghans, living in poor socioeconomic conditions, are estimated to be a community with a high rate of intestinal parasitic infections. The aim of the study was to estimate the prevalence and species of intestinal parasites among children's population in eastern Afghanistan and to present the methods of optimizing the techniques for identification of pathogens in light microscopy. The research was carried out as a part of humanitarian project Capacity building of health care system in Ghazni Province. MATERIALS AND METHOD: The study involved 500 children aged 7-18 attending the Share Kona and the Khuija Ali High Schools in Ghazni, eastern Afghanistan in the period November 2013-April 2014. Three stool samples were collected from each patient at 2-day intervals, the samples were fixed in 10% formalin, transported to the Military Institute of Medicine in Poland, where they were pooled and examined using five different diagnostic methods in light microscopy (direct smear in Lugol's solution, Fulleborne's flotation, decantation in distilled water, Kato-Miura thick smear, and DiaSys/PARASYS sedimentation system). RESULTS: Pathogenic intestinal parasites were detected in 217 patients (43.4%), with the most common Ascaris lumbricoides (35.3%), Giardia intestinalis (31.1%), and Hymenolepis nana (15.7%). The use of direct smear method allowed for the detection of intestinal parasites in 161 individuals. The application of four following testing methods has improved the detection rates of infected patients by 11.2%. CONCLUSIONS: The variety of detected intestinal pathogens in examined children's population has required the use of combination of multiple diagnostic methods in light microscopy, and finally improved the detection rates of intestinal parasites and helped eliminate infections with nematodes, cestodes, trematodes, and protozoa using appropriate treatment in the study population. PMID- 28030942 TI - The role of vitamin D in reproductive dysfunction in women - a systematic review. AB - Vitamin D is essential for the proper functioning of the human body. There is also evidence of its strong association with fertility problems in women. This review aims to evaluate the relationship between vitamin D and diseases affecting women's fertility (polycystic ovarian syndrome (PCOS), uterine leiomyomas and endometriosis), and in vitro fertilization (IVF) outcome. A systematic review of the literature was conducted in Scopus and PubMed for relevant English language publications since 1989. Vitamin D influences the functioning of the reproductive system in women and has been associated with PCOS, uterine leiomyomas, endometriosis and in vitro fertilization (IVF) outcome. However, further studies on larger groups of patients are needed to establish what role vitamin D plays in the treatment of female infertility. PMID- 28030943 TI - Is there a rationale for aggressive breast cancer liver metastases resections in Polish female patients? Analysis of overall survival following hepatic resection at a single centre in Poland. AB - INTRODUCTION: Breast cancer (BC) makes up nearly 26% of malignant tumours worldwide and is the leading cause of cancer-related deaths in European women. With approximately 18,000 new cases of BC diagnosed in Polish women annually, breast cancer liver metastasis (BCLM) is respectively an increasing issue. Recent data found in literature indicates improved survival following liver resection with systemic therapy. OBJECTIVE: The aim of study was to evaluate surgical treatment in patients with isolated BCLM. MATERIALS AND METHOD: During 2009-2013, a retrospective study was undertaken and 30 cases analysed. From nearly 2,000 liver resections performed, 11 female patients at the mean age of 59.18 years with BCLM were qualified for surgery. RESULTS: The median time between primary and secondary treatment was 3.5 years (1-7). One patient (9.1%) presented an extrahepatic lesion - bone metastasis. The left lobe, right lobe and both lobes of the liver were affected, respectively, in 3 (27.3%), 4 (36.4%) and 4 (36.4%) patients. 5 patients (45.5%) presented single hepatic lesion, in contrast to the maximum number of lesions which equalled 6 in the right lobe. Average hospitalisation period was 13.27 days and discharge on the 11.3 postoperative day. One-year survival was 72.7% (8 patients); therefore, three-year survival was 36.4% (4 patients). CONCLUSIONS: Oncological centres should assess BCLM patients more openly and qualify them for hepatic resection along with adjuvant systemic treatment in order to improve overall survival. This, however, needs to be studied in a multicentre randomized trial. PMID- 28030944 TI - Withdrawal from bariatric treatment - an analysis under various demographic conditions. AB - : Poland is high on a list of countries affected by epidemics of obesity, a problem that has especially suddenly increased in the post-transformation period. MATERIALS AND METHOD: Documentation of 115 subsequent patients diagnosed with grade 3 obesity, considered eligible for surgical treatment, was analysed since 2015. A subgroup of 68 patients was selected from this group and the included patients who decided to cancel their treatment at various stages. Their history since presentation at the obesity treatment centre, BMI with its history, age, education and place of residence were analysed, followed by a telephone survey. 42 patients were finally contacted. Special attention was placed on the analysis of patients taking into account their place of residence. Patients were divided into inhabitants of rural and urban areas. RESULTS: In the study group of 68 patients, 19 (27.9%) were inhabitants of rural areas and 49 (72.1%) of urban areas. Women accounted for 67.6%, and men for 32.4%. The mean age of patients when they presented for treatment was 43 years. On average, men presented 5 years later compared to women. The mean BMI on qualification for treatment of obesity was 47.6 kg/m2. The mean BMI max - 49.6 kg/m2. There were no differences regarding education in both populations. Despite the lack of differences regarding changes in the BMI since withdrawal from treatment, as many as 63% of patients from rural areas reached the BMI max in this time. CONCLUSIONS: There were demographic differences between the degree of obesity observed among patients receiving bariatric treatment, and inhabitants of urban areas were favoured. Patients from rural areas who withdrew from bariatric treatment and were left without medical care significantly more often achieved their maximum body weight, when compared to those living in urban areas. The active participation of physicians, both specialists and general practitioners, in the life of obese patients is imperative. PMID- 28030945 TI - Advantages of implantation of acellular porcine-derived mesh in the treatment of human rectocele - Case report. AB - INTRODUCTION: A rectocele is a hernation of the rectum into the vaginal lumen developing as a consequence of weakness of the rectovaginal septum. It affects about 18% of women after childbearing age. Symptoms associated with a rectocele include constipation, vaginal fullness or heaviness, feeling of a bulging mass within vagina, incomplete stool evacuation and dyspareunia. Current methods of surgical treatment of a rectocele often require implantation of a mesh graft. In most of cases, synthetic and non-absorbable meshes are used. Although implantation of a synthetic and non-absorbable mesh is effective in the treatment of rectocele, a high rate of mesh erosion has been reported. CASE REPORT: This study presents a surgical technique and case report for the treatment of a rectocele in a 46-year-old women by implantation of a porcine-derived absorbable collagen mesh (Pelvicol(r)) by transvaginal approach, with six year follow-up. A review of the literature concerning implantation of Pelvicol(r) for the treatment of rectocele was also undertaken. CONCLUSIONS: The clinical experience and review of the literature by the authors suggest that a porcine-derived acellular mesh is non-cytotoxic, pyrogenic or allergenic, and the application of a biomesh in the management of rectocele is effective and safe, and the risk of mesh erosion is very low. PMID- 28030946 TI - First record of Giardia assemblage D infection in farmed raccoon dogs (Nyctereutes procyonoides). AB - The presence of Giardia genotypes was investigated in 18 raccoon dogs (Nyctereutes procyonoides) and 80 red foxes (Vulpes vulpes) on one farm. To demonstrate Giardia cysts, fresh and trichrome stained smears were microscopically screened. Two molecular markers were used for Giardia genotyping: a fragment of the beta-giardin gene and a fragment of the glutamate dehydrogenase gene. All faecal samples obtained from red foxes were negative. Giardia cysts were identified only in 2 of the 18 raccoon dogs. The result of genotyping and phylogenetic analysis showed that the G. duodenalis from both raccoon dogs belonged to the D assemblage. This finding of a new animal reservoir of G. duodenalis canids-specific genotypes is important in order to eliminate the risk of infecting other animals bred for fur. Further molecular analyses of Giardia isolates in raccoon dogs are required. The present study represents the first contribution to knowledge of G. duodenalis genotypes in raccoon dogs. PMID- 28030947 TI - Seroprevalence of Toxoplasma gondii and Neospora caninum in red deer from Central Italy. AB - Neospora caninum and Toxoplasma gondii are cosmopolite protozoan parasites impacting on human and animal health. In particular, T. gondii commonly infects human beings and all warm-blooded animals, while N. caninum is responsible for bovine abortion and neuromuscular disease in dogs. The aim of the presented survey was to evaluate the occurrence and prevalence of these parasites in the most numerous Italian red deer population. The sera of 60 red deer (Cervus elaphus) inhabiting Central Italy (43 degrees 56'N 10 degrees 55'E) and killed by selective hunting were examined using an indirect fluorescent antibody test (IFAT) for both N. caninum and T. gondii antibodies. White blood cells (buffy coat) were also checked by PCR and T. gondii DNA was genotyped. Thirteen out of 60 sera (22%) scored positive for Toxoplasma, 17 samples (28%) were Neospora positive. Coinfection was recorded in 5 cases (8%). T. gondii (genotype II) and N. caninum DNA was detected in one and 3 samples of buffy coat, respectively. The presented study is the first to examine the occurrence of these parasites in the most numerous red deer Italian population, confirming this animal species as carrier of the investigated pathogens. These animals spread near human settlements, co-inhabiting with final hosts of T. gondii and N. caninum and could contribute to their transmission to domestic ruminants and humans. In particular, the seroprevalence value for N. caninum was the highest among European records. PMID- 28030948 TI - Faraday Rotation Due to Surface States in the Topological Insulator (Bi1 xSbx)2Te3. AB - Using magneto-infrared spectroscopy, we have explored the charge dynamics of (Bi,Sb)2Te3 thin films on InP substrates. From the magneto-transmission data we extracted three distinct cyclotron resonance (CR) energies that are all apparent in the broad band Faraday rotation (FR) spectra. This comprehensive FR-CR data set has allowed us to isolate the response of the bulk states from the intrinsic surface states associated with both the top and bottom surfaces of the film. The FR data uncovered that electron- and hole-type Dirac Fermions reside on opposite surfaces of our films, which paves the way for observing many exotic quantum phenomena in topological insulators. PMID- 28030949 TI - Human Neuronal Calcium Sensor-1 Protein Avoids Histidine Residues To Decrease pH Sensitivity. AB - pH is highly regulated in mammalian central nervous systems. Neuronal calcium sensor-1 (NCS-1) can interact with numerous target proteins. Compared to that in the NCS-1 protein of Caenorhabditis elegans, evolution has avoided the placement of histidine residues at positions 102 and 83 in the NCS-1 protein of humans and Xenopus laevis, possibly to decrease the conformational sensitivity to pH gradients in synaptic processes. We used all-atom molecular dynamics simulations to investigate the effects of amino acid substitutions between species on human NCS-1 by substituting Arg102 and Ser83 for histidine at neutral (R102H and S83H) and acidic pHs (R102Hp and S83Hp). Our cumulative 5 MUs simulations revealed that the R102H mutation slightly increases the structural flexibility of loop L2 and the R102Hp mutation decreases protein stability. Community network analysis illustrates that the R102H and S83H mutations weaken the interdomain and strengthen the intradomain communications. Secondary structure contents in the S83H and S83Hp mutants are similar to those in the wild type, whereas the global structural stabilities and salt-bridge probabilities decrease. This study highlights the conformational dynamics effects of the R102H and S83H mutations on the local structural flexibility and global stability of NCS-1, whereas protonated histidine decreases the stability of NCS-1. Thus, histidines at positions 102 and 83 may not be compatible with the function of NCS-1 whether in the neutral or protonated state. PMID- 28030950 TI - Mechanism of Unfolding of Human Prion Protein. AB - Misfolding and aggregation of prion proteins are associated with several neurodegenerative diseases. Therefore, understanding the mechanism of the misfolding process is of enormous interest in the scientific community. It has been speculated and widely discussed that the native cellular prion protein (PrPC) form needs to undergo substantial unfolding to a more stable PrPC* state, which may further oligomerize into the toxic scrapie (PrPSc) form. Here, we have studied the mechanism of the unfolding of the human prion protein (huPrP) using a set of extensive well-tempered metadynamics simulations. Through multiple microsecond-long metadynamics simulations, we find several possible unfolding pathways. We show that each pathway leads to an unfolded state of lower free energy than the native state. Thus, our study may point to the signature of a PrPC* form that corresponds to a global minimum on the conformational free-energy landscape. Moreover, we find that these global minima states do not involve an increased beta-sheet content, as was assumed to be a signature of PrPSc formation in previous simulation studies. We have further analyzed the origin of metastability of the PrPC form through free-energy surfaces of the chopped helical segments to show that the helices, particularly H2 and H3 of the prion protein, have the tendency to form either a random coil or a beta-structure. Therefore, the secondary structural elements of the prion protein are only weakly stabilized by tertiary contacts and solvation forces so that relatively weak perturbations induced by temperature, pressure, pH, and so forth can lead to substantial unfolding with characteristics of intrinsically disordered proteins. PMID- 28030951 TI - Wide-Scope Screening Method for Multiclass Veterinary Drug Residues in Fish, Shrimp, and Eel Using Liquid Chromatography-Quadrupole High-Resolution Mass Spectrometry. AB - A screening method for veterinary drug residues in fish, shrimp, and eel using LC with a high-resolution MS instrument has been developed and validated. The method was optimized for over 70 test compounds representing a variety of veterinary drug classes. Tissues were extracted by vortex mixing with acetonitrile acidified with 2% acetic acid and 0.2% p-toluenesulfonic acid. A centrifuged portion of the extract was passed through a novel solid phase extraction cartridge designed to remove interfering matrix components from tissue extracts. The eluent was then evaporated and reconstituted for analysis. Data were collected with a quadrupole Orbitrap high-resolution mass spectrometer using both nontargeted and targeted acquisition methods. Residues were detected on the basis of the exact mass of the precursor and a product ion along with isotope pattern and retention time matching. Semiquantitative data analysis compared MS1 signal to a one-point extracted matrix standard at a target testing level. The test compounds were detected and identified in salmon, tilapia, catfish, shrimp, and eel extracts fortified at the target testing levels. Fish dosed with selected analytes and aquaculture samples previously found to contain residues were also analyzed. The screening method can be expanded to monitor for an additional >260 veterinary drugs on the basis of exact mass measurements and retention times. PMID- 28030952 TI - Calcium Stearate as an Effective Alternative to Poly(vinyl alcohol) in Poly Lactic-co-Glycolic Acid Nanoparticles Synthesis. AB - Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are among the most studied systems for drug and gene targeting. So far, the synthesis of stable and uniform PLGA NPs has involved the use of a large excess of polyvinyl surfactants such as poly(vinyl alcohol) (PVA) and polyvinylpyrrolidone (PVP), whose removal requires multistep purification procedures of high ecological and economic impact. Hence the development of environment-friendly and cost-effective synthetic procedures for the synthesis of PLGA NPs would effectively boost their use in clinics. This work aims to address this issue by investigating more efficacious alternatives to the so far employed polyvinyl surfactants. More specifically, we developed an innovative synthetic process to achieve stable and uniformly distributed PLGA NPs that involves the use of calcium stearate (CSt), gaining benefits of its high biocompatibility and efficacy at low concentrations and avoiding consequently expensive purification steps. With the help of minimum quantities of polysorbate 60 and sorbitane monostearate, CSt-stabilized PLGA NPs with different sizes and structures were synthesized. The influence of CSt on the encapsulation efficiency of bioactive molecules has been also investigated. The effective encapsulation of both hydrophobic (curcumin) and hydrophilic (fibrinogen labeled with Alexa647) biomolecules into NPs was demonstrated by confocal microscopy, and their release quantified by spectrofluorimetric analyses. Finally, degradation and cytotoxicity studies showed that CSt stabilized NPs were stable under physiological conditions and with good biocompatibility, thus looking promising for further investigation as controlled release devices. PMID- 28030953 TI - Attochemistry of Ionized Halogen, Chalcogen, Pnicogen, and Tetrel Noncovalent Bonded Clusters. AB - In general, charge migration can occur via pure electron-electron correlation and relaxation or via coupling with nuclear motion. We must understand both aspects of charge migration through the non-hydrogen noncovalent bonds to harness full potential of the halogen-, chalcogen-, pnicogen- and tetrel-bonded photosensitive functional materials. This feature article, however, is focused on the pure relaxation- and correlation-driven charge migration, subsequent charge localization, and finally on charge-directed reactivity in the non-hydrogen noncovalent bonded clusters. Pure relaxation- and correlation-driven charge migration can occur on a several hundred attosecond (as) time scale, and this is why chemical dynamics associated with this pure electronic charge migration can be named "attochemistry". One of the efficient ways to elucidate the attochemistry is via the vertical ionization by monitoring a nonstationary electronic charge density that evolves in time while the nuclear configuration remains unchanged. So far, attochemistry of several halogen-, chalcogen-, pnicogen-, and tetrel-bonded clusters has been studied theoretically by our group. All the interesting predictions have been summarized in this Feature Article. The time scales of relaxation- and correlation-driven charge migration through the halogen, chalcogen, pnicogen, and tetrel noncovalent bonds are found to be quite similar (approximately in the range of 300-600 as) in different (1:1) AX:NH3 and AX:OH2 complexes (where A represents different substituents, such as NH2, CN, etc.). Basis sets do not exhibit any effect on the predicted charge migration time scale. A very long intermolecular distance (approximately more than 10 A), for which (physically) no noncovalent bonding interaction can be present, ceases the intermolecular charge migration. The strength of the electron electron correlation interaction influences the charge migration through these noncovalent bonds, making charge migration faster with a higher correlation interaction. The initial nuclear configuration affects the charge migration through the non-hydrogen noncovalent bonds. For large clusters, in which both hydrogen and non-hydrogen noncovalent bonds are formed, non-hydrogen noncovalent bonds are found to facilitate the charge migration preferentially over the hydrogen bonds. As a result of nuclear wavepacket delocalization, the attosecond charge oscillation in noncovalent bonded clusters decoheres. This renders charge localization. Subsequent charge-directed reactivity is discussed. This article is the first review on the attochemistry of non-hydrogen noncovalent bonded clusters. PMID- 28030954 TI - Dielectric Allostery of Protein: Response of Myosin to ATP Binding. AB - Protein uses allostery to execute biological function. The physical mechanism underlying the allostery has long been studied, with the focus on the mechanical response by ligand binding. Here, we highlight the electrostatic response, presenting an idea of "dielectric allostery". We conducted molecular dynamics simulations of myosin, a motor protein with allostery, and analyzed the response to ATP binding which is a crucial step in force-generating function, forcing myosin to unbind from the actin filament. We found that the net negative charge of ATP causes a large-scale, anisotropic dielectric response in myosin, altering the electrostatic potential in the distant actin-binding region and accordingly retracting a positively charged actin-binding loop. A large-scale rearrangement of electrostatic bond network was found to occur upon ATP binding. Since proteins are dielectric and ligands are charged/polar in general, the dielectric allostery might underlie a wide spectrum of functions by proteins. PMID- 28030955 TI - Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury. AB - AIMS: A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. RESULTS: Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. INNOVATION: This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. CONCLUSIONS: These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432. PMID- 28030956 TI - Effects of Long-Duration Administration of 1% Isoflurane on Resting Cerebral Blood Flow and Default Mode Network in Macaque Monkeys. AB - Isoflurane is an inhalational anesthetic that is widely used in medical procedures or biomedical research. The duration of anesthesia administration varies from minutes to hours. It is known that isoflurane has dose-dependent effects on brain functionality and physiology, and long-duration anesthesia administration could cause neurocognitive decline in animals and humans. However, the duration effect of isoflurane on the brain physiology and functionality still remains poorly understood. In the present study, cerebral blood flow (CBF) and functional connectivity of adult rhesus monkeys (maintained with 1% isoflurane for 4 h) were examined by using magnetic resonance imaging. The results demonstrate that long-duration isoflurane exposure could result in CBF reduction in most brain areas and functional connectivity decrease in the dominant default mode network. This study reveals the anesthetic duration effects in the central nervous system of anesthetized subjects and suggests that such duration effects should be considered in examining the brain function of anesthetized animals or humans with contemporary neuroimaging approaches. PMID- 28030958 TI - Psychometric properties of the NOMO 1.0 tested among adult powered-mobility users. AB - BACKGROUND: The Nordic Mobility Related Outcome Evaluation of Assistive Device Intervention (NOMO 1.0) instrument evaluates the effectiveness of mobility devices in assessing mobility-related participation, captured by three scales (Need for Assistance, Frequency, and Ease/Difficulty) and one index (Participation Repertoire). PURPOSE: This study aimed to investigate a range of psychometric properties of the NOMO 1.0 in a sample of adult powered mobility device (PMD) users. METHOD: Data collected from PMD users ( N = 248) in Denmark, Finland, and Norway as part of a larger study were analyzed using state-of-the art statistical methods. FINDINGS: The acceptability and applicability of the NOMO 1.0 items were generally within recommended values. Some floor/ceiling effects were found and the reliability was acceptable for only the Frequency scale. The factor analysis identified one component for the Need for Assistance scale and six components of the Frequency scale. IMPLICATIONS: The NOMO 1.0 should be used for research purposes and not for clinical practice. Better reliability should be established for the Need for Assistance and Ease/Difficulty scales prior to further psychometric testing to establish the validity of the NOMO 1.0. PMID- 28030959 TI - Physical activity and sedentary behavior of US immigrant versus non-immigrant adolescents: findings from the NEXT Generation Health Study data. AB - OBJECTIVE: This study examined associations of physical activity (PA) and sedentary behavior (SB) with adolescents' immigration status and language spoken at home and with friends. METHODS: Participants (N = 2475) were included from Wave 1 of the NEXT Generation Health Study, a nationally representative 10th grade cohort study starting in 2009. PA included recommended moderate-to-vigorous PA (MVPA) and vigorous PA (VPA); SB included screen viewing and social-media use. Linear and logistic regressions were conducted controlling for complex survey variables. RESULTS: Adolescents with non US-born compared with US-born parents were less likely to engage in VPA (odds ratio = 0.60, p <= .05, 95% CI = 0.38 0.96). Parent country of origin and language spoken were not significantly associated with recommended MVPA engagement. None of screen viewing and social media use was significantly associated with immigration status. CONCLUSIONS: Recent immigration status was negatively associated with adolescents' PA documenting an important health disparity. PMID- 28030962 TI - Reliability and validity of the Japanese version of the Alzheimer's Disease Knowledge Scale. AB - Concerned with the importance of prevailing knowledge about dementia in supporting those with dementia, large-scale educational programs have been implemented in some countries. Although Japan is one of those few countries, the experience from Japanese programs has been rarely shared because of the lack of a standardized measurement for assessing knowledge about dementia. This study aims to develop a Japanese version of the Alzheimer's Disease Knowledge Scale (JADKS) and to examine its reliability and validity. The JADKS was developed through a translation-back-translation process and was distributed to 837 people including university students, community-dwelling older people, health and welfare professionals, and family caregivers. Using data from the 566 participants who fully completed the questionnaire, test-retest reliability, internal consistency, and concurrent validity were evaluated. The results indicate that the JADKS has acceptable psychometric properties. The JADKS may be useful in assessing knowledge about dementia and could help compare effectiveness of educational programs. PMID- 28030960 TI - Why female sex workers participate in HIV research: the illusion of voluntariness. AB - The purpose of this study was to examine factors influencing the motivation for and perceived voluntariness of participation in non-intervention HIV research among female sex workers (FSW) in India. FSW (n = 30) who participated in non intervention HIV studies in the previous three years were recruited from a local community-based organization. Semi-structured qualitative interviews focused on women's personal and economic motivations for participation and their perceptions of the informed consent process. Interviews were audio-recorded, translated, transcribed, and reviewed for common themes. Content analysis indicated that while many women reported willing participation, reports of obligatory participation were also a common theme. Obligations included money-related pressures and coercion by other FSW, social pressures, not wanting to disappoint the researchers, and perceiving that they had a contractual agreement to complete participation as a result of signing the consent form. Findings suggest a need for additional efforts during and following informed consent to prevent obligatory participation in HIV research studies among FSW. Findings emphasize the importance of integrating ongoing participant feedback into research ethics practices to identify issues not well addressed via standard ethics protocols when conducting HIV research among vulnerable populations. PMID- 28030961 TI - Three new xanthones from Swertia bimaculata and their anti-5alpha-reductase activity. AB - Three new xanthones (1-3), together with five known ones (4-8), were isolated from whole herb of Swertia bimaculata. Their structures were established on the basis of detailed spectroscopic analysis (1D- and 2D-NMR, HRESIMS, UV, and IR) and comparison with data reported in the literature. New isolates were evaluated for their anti-5alpha-reductase activity. The results revealed that all new compounds showed weak activity with reductase inhibitions of 40.5 +/- 2.8, 38.6 +/- 2.5, and 48.9 +/- 3.0%, respectively. PMID- 28030963 TI - Obese Patients Have Fewer Wound Complications Following Fixation of Ankle Fractures. AB - : Outcomes following ankle fracture surgery have been well studied; however, factors associated with surgical wound healing specifically are less clear. We aimed to study the relationship between wound healing and body mass index, as well as other variables following surgical treatment of ankle fractures. There were 127 consecutive, isolated, closed, malleolar ankle fractures treated with open reduction and internal fixation at a level-1 trauma center from 2008 to 2012. Patient, injury, and treatment variables were recorded and clinical records were reviewed to identify wound complications. There were 6 major and 18 minor wound complications. The overall rate of wound complication of any type was significantly lower in obese patients at 11.7% (7/60) compared with 25.4% (17/67, P < .05) in nonobese patients. When controlling for other variables obesity was associated with a significantly lower risk of developing a wound complication (OR 0.267, 95% CI 0.087-0.822), as was low energy mechanism (OR 0.246, 95% CI 0.067 0.906). No other covariates tested were associated with an increased risk of a wound infection. Ankle anatomy may present a unique situation whereby obesity may be protective against wound complications. Further studies are needed to confirm this clinical observation, and to demonstrate the mechanism through which this may occur. LEVELS OF EVIDENCE: Therapeutic, Level IV: Retrospective. PMID- 28030965 TI - Is Histopathological Analysis of Interdigital Morton's Neuroma Necessary? AB - BACKGROUND: Interdigital neuroma (IN), otherwise known as Morton's neuroma, is a common cause of metatarsalgia presenting to the elective foot and ankle clinic. Surgical excision of the IN in patients who fail to respond to nonoperative measures is considered to be the gold standard of care in many centers. The Royal College of Pathologists UK recommend that all excised interdigital Morton's neuromas are sent for formal histopathological analysis. We present a study correlating clinical and radiological diagnosis with histopathologic appearances of IN following surgical excision, and question if routine histopathological analysis is warranted. METHODS: A retrospective study was carried out in a single center. Ninety-six operative records were reviewed to identify all the cases of IN surgically resected between January 2007 and July 2016. The histopathology result of the resected IN specimen, that had a clinical and radiological diagnosis of IN, was analyzed. RESULTS: A total of 85 patients met the inclusion criteria and were included in the final analysis. We found that 100% of patients with a clinical, radiographic, and intraoperative diagnosis of a Morton's neuroma had a histopathological report confirming a Morton's interdigital neuroma. CONCLUSION: In our single-surgeon series, histopathologic diagnosis is in complete agreement with clinical and radiological diagnosis. We therefore recommend that routine histopathological analysis of IN is not necessary, saving resources and providing a cost benefit. Histopathologic examination should be reserved only in cases where intraoperative findings do not concur with clinical and radiological features. LEVELS OF EVIDENCE: Level IV: Case series. PMID- 28030964 TI - Charcot Collapse: Does Collapse Pattern Dictate Osseous Metabolism? AB - : Charcot fracture pattern (FP) and Charcot dislocation pattern (DP) are 2 distinct collapse patterns identified in Charcot neuroarthropathy of the foot and ankle. These patterns are believed to demonstrate relative differences in central bone mineral density (BMD), which has been theoretically extrapolated to describe local BMD. To assess variation in local bone composition of FP and DP patients, 10 patients, 5 DP and 5 FP were recruited. The patient's age, body mass index (BMI), radiographs, central BMD, local BMD, sRANKL (soluble receptor activator nuclear factor kappa-beta ligand), sRAGE (soluble receptors of advanced glycated end-products), and osteocalcin were measured to determined bone metabolic status and density. Central BMD was determined using DEXA (dual-energy X-ray absorptiometry) scans of the hip. peripheral BMD was determined using scans at the level of the ankle mortise and Chopart's joint, depending on the location of collapse. These scans were then compared with controls. Central and peripheral DEXA scans were significantly reduced in the FP ( P = .002 and P < .0001) when compared with healthy controls. Additionally, FP patients demonstrated statistically significant elevations in sRANKL ( P = .05) and sRAGE ( P = .002) when compared with DP. No significant difference was seen in osteocalcin ( P = 0.22); however, elevated values compared with normal reference ranges suggest increase bone production. These elevations combined with an osteoporotic profile may indicate difficulty of FP patients in repairing micro fracture. Results from this study emphasize the increased risk of nonunion during FP reconstruction, and highlight the variation in bone composition in these 2 Charcot subtypes. LEVELS OF EVIDENCE: Level III. PMID- 28030966 TI - Systemic drugs that influence titanium implant osseointegration. AB - Titanium implants are widely used on an increasing number of patients in orthopedic and dental medicine. Despite the good survival rates of these implants, failures that lead to important socio-economic consequences still exist. Recently, research aimed at improving implant fixation, a process called osseointegration, has focused on a new, innovative field: systemic delivery of drugs. Following implant fixation, patients receive systemic drugs that could either impair or enhance osseointegration; these drugs include anabolic and anti catabolic bone-acting agents in addition to new treatments. Anabolic bone-acting agents include parathyroid hormone (PTH) peptides, simvastatin, prostaglandin EP4 receptor antagonist, vitamin D and strontium ranelate; anti-catabolic bone-acting agents include compounds like calcitonin, biphosphonates, RANK/RANKL/OPG system and selective estrogen receptor modulators (SERM). Examples of the new therapies include DKK1- and anti-sclerostin antibodies. All classes of treatments have proven to possess positive impacts such as an increase in bone mineral density and on osseointegration. In order to prevent complications from occurring after surgery, some post-operative systemic drugs are administered; these can show an impairment in the osseointegration process. These include nonsteroidal anti inflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors. The effects of aspirin, acetaminophen, opioids, adjuvants, anticoagulants and antibiotics in implant fixations are not fully understood, but studies are being carried out to investigate potential ramifications. It is currently accepted that systemic pharmacological agents can either enhance or impair implant osseointegration; therefore, proper drug selection is essential. This review aims to discuss the varying effects of three different classes of treatments on improving this process. PMID- 28030968 TI - Thromboelastogram as a Tool to Predict Hypercoagulability in Children With Cystic Fibrosis. AB - Increased thrombophilic tendency in patients with cystic fibrosis (CF) has recently been reported. The determinants of thrombosis in children with CF remain largely unknown. Our aim in this study was to evaluate the thromboelastography (TEG) profile of children with CF through ROTEM (whole blood rotation thromboelastometry). Nineteen patients with CF and 20 controls were included in the study. Whole blood count, prothrombin time, activated prothrombin time, fibrinogen, d-dimer levels, and ROTEM assays (INTEM, EXTEM) were performed. Clotting time, clot formation time (CFT), and maximum clot firmness (MCF) were determined by INTEM and EXTEM analysis. In INTEM assay, MCF ( P = .001) value was significantly increased and CFT ( P = .031) value was decreased in patients with CF compared with those of the control group. In the EXTEM assay, there was a similar significant increase in MCF ( P = .023) value in patients with CF compared with that of the control group. There was a significant positive correlation between fibrinogen levels and MCF in EXTEM ( r = .72) and INTEM ( r = .76) assays, whereas there was a negative correlation with CFT in EXTEM ( r = .61) and INTEM ( r = -.67). The results of our study indicated that TEG profiles in patients with CF were more hypercoagulable compared with those of the control group. PMID- 28030967 TI - Factor X Friuli Coagulation Disorder: Almost 50 Years Later. AB - The story of factor X (FX) Friuli. Factor X Friuli was discovered in 1969 to 1970. However, the story of that disease was an international event since patients with this defect were studied in France and in Italy, and different diagnoses were reached-FVII; FX; combined prothrombin complex; and combined FII, FVII, and FX deficiencies. The diagnostic difficulties were due to the peculiar clotting pattern presented by these patients, namely, prolonged partial thromboplastin time, prolonged prothrombin time but normal Russell viper venom clotting time. Only suitable anti-FX antisera clarified the pattern. Altogether 12 homozygotes and 102 heterozygotes have been followed during 4 decades. Six homozygotes died, 2 of them due to HIV infection and 1 due to hepatitis B liver cirrhosis. The other 3 died of nontransfusion-related morbidity. Bleeding tendency has been moderate in agreement with the extrinsic or intrinsic system assay results-FX level of 4% to 5% is considered normal. Heterozygotes may present occasional bleeding manifestations usually during surgery or delivery. Molecular analysis have shown that the mutation responsible for the defect is a Pro343Ser substitution in exon 8. Chimeric FX Friuli mice have been useful in studying the effect of FX levels on embryonic or natal mortality of these animals. No new homozygote but several heterozygotes have been recently seen. The study of FX Friuli has revolutionized the diagnostic approach to FX deficiencies. The FX should be assayed by all assay systems. The FX Friuli has never been described in any other country, and all patients studied come from the Friuli Meduna River Valley. PMID- 28030970 TI - Health Communication With Same-Sex and Other-Sex Friends in Emerging Adulthood. AB - Objective We examined health-related communication between same-sex and other-sex friends and how communication was related to health-related behavior. Participants Data from 243 emerging adults attending college ( Mage = 18.96, SD = 1.43; 55.6% male) were analyzed. Methods Participants completed measures assessing the frequency in which they talked about and made plans to engage in exercise and nutrition-related behaviors with friends, as well as how often they engaged in exercise and nutrition-related behaviors. Results In general, participants reported more health-related communication with same-sex friends. Health-related communication with same-sex friends was positively related to health behaviors for men and women. However, the pattern of results differed for men and women depending on the topic of communication and the behavior being examined. Conclusion Our study extends the literature by examining the role of sex of friends in health communication and planning and how interactions with friends relate to health-promoting behavior. PMID- 28030969 TI - The effects of trait and state affect on diurnal cortisol slope among children affected by parental HIV/AIDS in rural China. AB - Affect is believed to be one of the most prominent proximal psychological pathway through which more distal psychosocial factors influence physiology and ultimately health. The current study examines the relative contributions of trait affect and state affect to the hypothalamic-pituitary-adrenal axis activity, with particular focus on cortisol slope, in children affected by parental HIV/AIDS. A sample of 645 children (8-15 years old) affected by parental HIV/AIDS in rural China completed a multiple-day naturalistic salivary cortisol protocol. Trait and state affect, demographics, and psychosocial covariates were assessed via self report. Hierarchical linear modeling was used for estimating the effects of trait affect and state affect on cortisol slope. Confidence intervals for indirect effects were estimated using the Monte Carlo method. Our results indicated that both trait and state negative affect (NA) predicted flatter (less "healthy") diurnal cortisol slopes. Subsequent analyses revealed that children's state NA mediated the effect of their trait NA on diurnal cortisol slope. The same relationships did not emerge for trait and state positive affect. These findings provide a rationale for future interventions that target NA as a modifiable antecedent of compromised health-related endocrine processes among children affected by parental HIV/AIDS. PMID- 28030973 TI - Self-Crash Murder-Suicide. PMID- 28030971 TI - Suicidal ideation and behaviour among persons seeking HIV testing in peri-urban areas of Cape Town, South Africa: a lost opportunity for suicide prevention. AB - Suicidal ideation and behaviour (SIB) are among the psychiatric sequela of HIV/AIDS. Few studies have however examined the prevalence and correlates of SIB among persons seeking HIV testing. We set out to document the prevalence and correlates of SIB among people seeking HIV testing in peri-urban areas of Cape Town, South Africa (SA). A cross-sectional research design was used to recruit a sample (n = 500) of individuals seeking HIV testing. Self-report measures were used to assess two-week prevalence of SIB as well as life-time prevalence of suicide attempt. A structured clinical interview was used to assess common mental disorders (CMDs). Regression analysis was used to determine if CMD and socio demographic variables predicted suicidal ideation. The mean age of the sample was 36 years, 51.6% were female and 46.6% were unemployed. The two-week prevalence of suicidal ideation was 24.27% while the two-week prevalence of suicide attempt and suicide plans was 2.8%. Suicidal ideation was not associated with age, gender, employment status, family income or household food insecurity. CMDs were significantly associated with suicidal ideation; individuals with depressive disorders were approximately 5.5 times more likely to report suicidal ideation, while those with generalised anxiety disorder, trauma-related disorders and alcohol use disorder were approximately 7, 4.7 and 2.8 times more likely to report suicidal ideation, respectively. Results suggest that persons seeking HIV testing may be a well-delineated group of persons at risk of suicide in this region of SA. Contact with the health care system during HIV testing provides an opportunity for targeted suicide prevention interventions in what appears to be a high risk group. PMID- 28030975 TI - Retrospective: Pursuing melancholia - The Australian contribution. PMID- 28030976 TI - Good guidelines but should the emphasis be on implementation? PMID- 28030977 TI - Seizure, sclerosis or space-occupying lesions? PMID- 28030978 TI - ANZJP: The first fifty years MCMLXVII-MMXVII. PMID- 28030979 TI - An erudite encounter with: Sir David Goldberg. PMID- 28030980 TI - Fifty-Fifty. PMID- 28030981 TI - Evaluation of oxidative stress induction in rats following exposure to silver nanorods. AB - The study investigated the oxidative stress induction by the 10 and 25 nm silver nanorods (SNRs) following intra-tracheal instillation in rats after 1 day, 1 week, 1 month and 3 months post instillation periods at 1 and 5 mg/kg b.w. doses. The blood was withdrawn by retro orbital plexus method after exposure periods and different oxidative stress markers were estimated. The results showed that the both sizes of SNRs induced increased levels of malondialdehyde (MDA) and depleted glutathione (GSH) levels after 1 day and 1 week post exposure periods. The 10 and 25 nm SNRs at both doses displayed that significantly reduced levels of superoxide dismutase (SOD) and catalase following 1 day and 1 week post exposure periods. Also, the results have shown that decrease in total antioxidant capacity (TAC) of both sizes of SNRs significantly following 1 day and 1 week post exposure periods, indicating the oxidative stress induction by SNRs. In spite, there were no significant changes in oxidative stress markers following 1 month and 3 months post exposure periods may be due to recovery. The increased levels of MDA and decreased levels of GSH, SOD, catalase and TAC activity are strongly associated to ROS production and lipid peroxidation, suggesting the induction of oxidative stress in rats. The 10 nm SNRs at 5 mg/kg b.w. dose exposures in rats have shown greater changes in all oxidative stress parameters, indicating the greater induction of oxidative stress when compared with the 25 nm SNRs, representing the size-dose-dependent induction of oxidative stress of SNRs. PMID- 28030982 TI - A minimal ingroup advantage in emotion identification confidence. AB - Emotion expressions convey valuable information about others' internal states and likely behaviours. Accurately identifying expressions is critical for social interactions, but so is perceiver confidence when decoding expressions. Even if a perceiver correctly labels an expression, uncertainty may impair appropriate behavioural responses and create uncomfortable interactions. Past research has found that perceivers report greater confidence when identifying emotions displayed by cultural ingroup members, an effect attributed to greater perceptual skill and familiarity with own-culture than other-culture faces. However, the current research presents novel evidence for an ingroup advantage in emotion decoding confidence across arbitrary group boundaries that hold culture constant. In two experiments using different stimulus sets participants not only labeled minimal ingroup expressions more accurately, but did so with greater confidence. These results offer novel evidence that ingroup advantages in emotion decoding confidence stem partly from social-cognitive processes. PMID- 28030984 TI - Clinical and Neuropsychological Characteristics of ADHD According to DSM-5 Age-of Onset Criterion in Korean Children and Adolescents. AB - OBJECTIVE: The aim of this study was to compare the clinical features and neuropsychological profiles of children and adolescents with ADHD according to the age-of-onset defined in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5). METHOD: We compared the following three groups: early onset ADHD group (onset before age 7, n = 86), late-onset ADHD group (onset between ages 7 and 12, n = 58), and the control group ( n = 88). RESULTS: Both early-onset and late-onset ADHD groups had more symptoms and functional impairments than the control group. Also, both ADHD groups scored higher on ADHD Rating Scale, Parent General Behavior Inventory, majority of the subscales of Social Responsiveness Scale, Hyperactivity subscale of Korean Personality Rating Scale for Children, and Omission Errors of Visual Continuous Performance Test compared with the control group. CONCLUSION: Our results support the extension of age-of-onset criterion made in DSM-5. PMID- 28030983 TI - Psychometric Evaluation of Three Psychosocial Measures Associated With Physical Activity Among Adolescent Girls. AB - The purpose of this study was to evaluate the psychometric properties of a Perceived Benefits Scale, a Perceived Barriers Scale, and a Physical Activity Enjoyment Scale with data from a group randomized controlled trial (RCT) and a test-retest study with 1-week interval. In the group RCT at baseline and Week 17, 1,012 fifth- to eighth-grade girls completed an iPad-delivered survey and wore 7 day accelerometers measuring moderate-to-vigorous physical activity (MVPA). In the test-retest study, 91 fifth- to seventh-grade girls completed the iPad delivered survey at Times 1 and 2. Benefits, barriers, and enjoyment scales had Cronbach's alphas of .75, .86, and .78 and test-retest reliability of .83, .88, and .79, respectively. Benefits Scale had a two-factor structure (physical and psychosocial benefits), while the remaining two had a one-factor structure indicating construct validity. Barriers ( r = -.16) and enjoyment ( r = .17) were correlated with MVPA indicating concurrent validity. Baseline MVPA and psychosocial benefits positively, while physical benefits negatively, predicted MVPA at Week 17 indicating predictive validity. The measures demonstrated satisfactory psychometric properties. PMID- 28030985 TI - DNA damage and adduct formation in immune organs of developing chicks by polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs) are persistent pollutants and chemically a class of structurally similar chemical compounds characterized by the presence of fused aromatic rings. This research was undertaken to find out immunotoxic effects produced by pyrene, phenanthrene and fluoranthene. These chemicals were injected into developing chicks at three dose levels (0.2, 2 and 20 mg per kg) through allantioc route to rule out possible mechanisms involved in immunotoxicity. DNA adduct produced by PAHs in immune organs were analyzed by DNA adduct enzyme-linked immunosorbent assay (ELISA) kit and DNA damage was assessed by comet assay. A significant increase in the DNA adduct levels was found in thymus and bursa in 2 mg and 20 mg dose levels of pyrene, fluoranthene and phenanthrene treated groups, whereas those in spleen simulated the value of controls. Comet assay indicated that PAHs especially pyrene, fluoranthene and phenanthrene were capable of inducing increased level of comet parameters in thymus at all the dose levels. Bursa of Fabricius and spleen also showed a gradual rise in comet parameters corresponding to all dose levels, but the increase was more marked as in thymus. Thus, it can be concluded that DNA adducts produced by PAHs lead to single-strand breaks and reduced DNA repair, which ultimately begin a carcinogenic process. Hence, this experiment can be considered as a strong evidence of genotoxic potential of PAHs like pyrene, phenanthrene and fluoranthene in developing chicks. PMID- 28030986 TI - Teen Dating Violence Victimization, Perpetration, and Sexual Health Correlates Among Urban, Low-Income, Ethnic, and Racial Minority Youth. AB - This study explores the associations between teen dating violence (TDV) perpetration, victimization, sexual risk behaviors, and pregnancy among a sample of low-income, urban, and predominately African-American and Latino youth age 15 to 21 years ( N = 513). Findings suggest that youth who experienced TDV victimization were more likely to report inconsistent condom use in the past 12 months ( OR = 1.6) and pregnancy ( OR = 2.2) compared with nonvictimized youth. Youth who reported perpetrating dating violence were more likely to be female ( OR = 3.8) and to report multiple sex partners ( OR = 2.0), inconsistent condom use ( OR = 2.6), and prostitution in the past 12 months ( OR = 6.7). TDV perpetration and victimization were highly associated (chi2 = 127.00, p < .001); that is, 30% of the sample reported both victimization and perpetration in their previous or current romantic relationships. Findings from this study highlight the need to integrate culturally informed TDV prevention and intervention strategies into existing adolescent sexual and reproductive health education programs. PMID- 28030988 TI - Functional roles of magnesium binding to extracellular signal-regulated kinase 2 explored by molecular dynamics simulations and principal component analysis. AB - Molecular dynamics (MD) simulations coupled with principal component (PC) analysis were carried out to study functional roles of Mg2+ binding to extracellular signal-regulated kinase 2 (ERK2). The results suggest that Mg2+ binding heavily decreases eigenvalue of the first principal component and totally inhibits motion strength of ERK2, which favors stabilization of ERK2 structure. Binding free energy predictions indicate that Mg2+ binding produces an important effect on binding ability of adenosine triphosphate (ATP) to ERK2 and strengthens the ATP binding. The calculations of residue-based free energy decomposition show that lack of Mg2+ weakens interactions between the hydrophobic rings of ATP and five residues I29, V37, A50, L105, and L154. Hydrogen bond analyses also prove that Mg2+ binding increases occupancies of hydrogen bonds formed between ATP and residues K52, Q103, D104, and M106. We expect that this study can provide a significant theoretical hint for designs of anticancer drugs targeting ERK2. PMID- 28030987 TI - Using a Cultural Framework to Understand Factors Influencing HIV Testing in Nigeria. AB - With support from the U.S. President's Emergency Plan for AIDS Relief and the global fund for HIV, tuberculosis, and malaria, Nigeria offers free services for prevention of mother-to-child transmission of HIV. However, uptake of these services is low, and pediatric transmission of HIV remains a significant public health challenge. Using the PEN-3 cultural model as the theoretical framework, we examined social, cultural, and contextual factors that influenced uptake of HIV counseling and testing among pregnant women and their male partners. This was a qualitative study of participants in the Healthy Beginning Initiative (HBI), a congregation-based program to prevent mother-to-child transmission of HIV in Enugu, southeast Nigeria. We conducted eight focus group discussion sessions with 83 pregnant women and their male partners. Participants' perspectives on why they did or did not test for HIV were obtained. The most cited reasons for getting tested for HIV included the following: "the need to know one's status", "the role of prenatal testing" (positive perceptions); "the role of the church", "personal rapport with healthcare worker" (positive enablers); and the "influence of marriage" (positive nurturer). The most cited reason for not testing were: "fear of HIV test", "shame associated with HIV+ test results", "conspiratorial beliefs about HIV testing" (negative perceptions); "lack of confidentiality with HIV testing", (negative enabler); and "HIV-related stigma from family and community systems" (negative nurturer). Overall, numerous facilitators and barriers influence uptake of HIV testing in the study setting. Public health practitioners and policymakers need to consider how sociocultural and religious factors unique to specific local contexts may promote or hinder uptake of available HIV/AIDS prevention and care interventions. PMID- 28030989 TI - Measuring emotion perception following traumatic brain injury: The Complex Audio Visual Emotion Assessment Task (CAVEAT). AB - INTRODUCTION: While emotion recognition difficulties in moderate-severe TBI are well established, the standard measures of emotion recognition significantly limit the conclusions which can be drawn regarding real-life deficits. Two studies report on the development of CAVEAT, a new measure of emotion recognition that attempts to overcome these limitations. METHOD: These studies were designed to establish CAVEAT's psychometric properties by examining performance of a TBI group and matched controls in order to provide estimates of its reliability and validity (study 1), and to compare performance of the TBI and control groups on a subgroup of emotions from the CAVEAT that represented the six basic emotions used in conventional emotion research (study 2). Thirty-two participants with TBI and 32 matched controls (study 1) and 16 participants with TBI and 12 matched controls (study 2) participated in this study. RESULTS: CAVEAT demonstrated high construct validity and internal consistency. Performance on the subgroup of "basic" six emotions was largely similar to the rates reported in the literature. CONCLUSIONS: These findings provided some evidence for the psychometric properties of CAVEAT, indicating that it can be used as a clinical test for assessing emotion recognition in people with moderate-severe TBI. PMID- 28030990 TI - Housing Policies and Health Inequalities. AB - A large body of literature shows the link between inadequate housing conditions and poor physical and mental health. The aim of this paper is to summarize the research on the impact of local housing policies on health inequalities, focusing on the issues of access to housing and fuel poverty as studied in the SOPHIE project. Our case studies in Spain showed that people facing housing insecurity, experienced intense levels of mental distress. We found that access to secure and adequate housing can improve the health of these populations, therefore, public policies that address housing instability and their consequences are urgently needed. Housing conditions related to fuel poverty are associated with poorer health and are unevenly distributed across Europe. We found possible positive effects of facade insulation interventions on cold-related mortality in women living in social housing; but not in men. Policies on housing energy efficiency can reduce the health consequences of fuel poverty, but need to be free to users, target the most vulnerable groups and be adaptable to their needs. PMID- 28030991 TI - Galangin, a dietary flavonoid, improves antioxidant status and reduces hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats. AB - OBJECTIVE: To examine the effect of galangin on hyperglycemia-mediated oxidative stress in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced by intraperitoneal administration of low-dose STZ (40 mg/kg body weight (BW)) into male albino Wistar rats. Galangin (8 mg/kg BW) or glibenclamide (600 ug/kg BW) was given orally, once daily for 45 days to normal and STZ-induced diabetic rats. RESULTS: Diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes. The levels of insulin and non-enzymatic antioxidants (vitamin C, vitamin E, reduced glutathione) and the activity of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase (GST)) were decreased significantly in diabetic control rats. These altered plasma glucose, insulin, lipid peroxidation products, enzymatic and non-enzymatic antioxidants ions were reverted to near-normal level after the administration of galangin and glibenclamide. CONCLUSION: The present study shows that galangin decreased oxidative stress and increased antioxidant status in diabetic rats, which may be due to its antidiabetic and antioxidant potential. PMID- 28030992 TI - Macrolides: a promising pharmacologic therapy for chronic obstructive pulmonary disease. AB - Chronic inflammation plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, there are no effective anti inflammatory pharmacologic therapies available for COPD so far. Recent evidence suggests that an immunologic mechanism has a role in the pathogenesis of COPD. Macrolides possess anti-inflammatory and immune-modulating effects may be helpful in the treatment of COPD. Several clinical studies have shown that long-term use of macrolides reduces the frequency of COPD exacerbations. However, the subgroups that most effectively respond to long-term treatment of macrolides still need to be determined. The potential adverse events to individuals and the microbial resistance in community populations raises great concern on the long-term use of macrolides. Thus, novel macrolides have anti-inflammatory and immuno-modulating effects, but without antibiotic effects, and are promising as an anti inflammatory agent for the treatment of COPD. In addition, the combination of macrolides and other anti-inflammatory pharmacologic agents may be a new strategy for the treatment of COPD. PMID- 28030993 TI - Circadian rhythms and gene expression during mouse molar tooth development. AB - OBJECTIVES: Incremental markings in dental enamel suggest that the circadian clock may influence the molecular underpinnings orchestrating enamel formation. The aim of this study was to investigate whether the genes and microRNAs (miRNAs) oscillate in a circadian pattern during tooth and enamel development. MATERIAL AND METHODS: Comparative gene and miRNA expression profiling of the first mandibular molar tooth germ isolated at different time-points during the light and night period was performed using microarrays and validated using real-time RT PCR. Bioinformatic analysis was carried out using Ingenuity Pathway Analysis (IPA), and TargetScan software was used in order to identify computationally predicted miRNA-mRNA target relationships. RESULTS: In total, 439 genes and 32 miRNAs exhibited significantly different (p < 0.05) levels of expression in the light phase compared with the night phase tooth germs. Genes involved in enamel formation, i.e. Amelx, Ambn, Amtn, and Odam, oscillated in a circadian pattern. Furthermore, the circadian clock genes, in particular Clock and Bmal1, oscillated in mouse molar tooth germ during 24-h intervals. The expression of Clock and Bmal1 was inversely correlated with the expression of miR-182 and miR-141, respectively. CONCLUSIONS: MiRNAs, including miR-182 and miR-141, are involved in the control of peripheral circadian rhythms in the developing tooth by regulating the expression of genes coding for circadian transcription factors such as CLOCK and BMAL1. Regulation of circadian rhythms may be important for enamel phenotype, and the morphology of dental enamel may vary between individuals due to differences in circadian profiles. PMID- 28030994 TI - Characterization of Myocardial Dysfunction in Fluid- and Catecholamine-Refractory Pediatric Septic Shock and Its Clinical Significance. AB - PURPOSE: Myocardial dysfunction is a known complication in patients with pediatric septic shock (PSS); however, its clinical significance remains unclear. The purpose of this study was to characterize left ventricular (LV) and right ventricular (RV) dysfunction and their prevalence in patients with PSS using echocardiography (echo) and to investigate their associations with the severity of illness and clinical outcomes. METHODS: Retrospective chart review between 2010 and 2015 from 2 tertiary care pediatric intensive care units. Study included 78 patients (mean age 9.3 +/- 7 years) from birth up to 21 years who fulfilled criteria for fluid- and catecholamine-refractory septic shock. Echocardiographic parameters of systolic, diastolic, and global function were measured offline. They were correlated with admission Pediatric Risk of Mortality III (PRISM III) and Pediatric Logistic Organ Dysfunction scores, vasoactive-inotrope score (VIS), beta-type natriuretic peptide (BNP), lactate, type of shock, duration of mechanical ventilation (MV), intensive care unit and hospital length of stay, and mortality. RESULTS: Overall, 28-day mortality was 26%, and 88% patients required MV. Prevalence of LV dysfunction was 72% and RV dysfunction was 63%. LV systolic dysfunction (fractional shortening z score <-2) was significantly associated with PRISM III, VIS, and BNP. RV systolic dysfunction (tricuspid annular plane systolic excursion z score <-2) was significantly associated with cold shock. LV and RV diastolic dysfunction did not have any significant clinical associations. No echocardiographic measures were associated with mortality. CONCLUSION: Myocardial dysfunction is highly prevalent in PSS but is not associated with mortality. LV systolic dysfunction is associated with a higher severity of illness, use of vasoactives, and BNP, whereas RV systolic dysfunction is associated with cold shock. Further studies are needed to determine the utility of echo in the bedside management of patients with PSS. PMID- 28030995 TI - Out-of-Hospital ICU Transfers to an Oncological Referral Center. AB - OBJECTIVE: To determine resource utilization and outcomes of out-of-hospital transfer patients admitted to the intensive care unit (ICU) of a cancer referral center. DESIGN: Single-center cohort. SETTING: A tertiary oncological center. PATIENTS: Patients older than 18 years transferred to our ICU from an outside hospital between January 2013 and December 2015. MEASUREMENTS AND MAIN RESULTS: A total of 2127 (90.3%) were emergency department (ED) ICU admissions and 228 (9.7%) out-of-hospital transfers. The ICU length of stay (LOS) was longer in the out-of-hospital transfers when compared to all other ED ICU admissions ( P = .001); however, ICU and hospital mortality were similar between both groups. The majority of patients were transferred for a higher level of care (77.2%); there was no difference in the amount of interventions performed, ICU LOS, and ICU mortality between nonhigher level-of-care and higher level-of-care patients. Factors associated with an ICU LOS >=10days were a higher Sequential Organ Failure Assessment (SOFA) score, weekend admissions, presence of shock, need for mechanical ventilation, and acute kidney injury on admission or during ICU stay ( P < .008). The ICU mortality of transferred patients was 17.5% and associated risk factors were older age, higher SOFA score on admission, use of mechanical ventilation and vasopressors during ICU stay, and renal failure on admission ( P < .0001). Data related to the transfer such as LOS at the outside facility, time of transfer, delay in transfer, and longer distance traveled were not associated with increased LOS or mortality in our study. CONCLUSION: Organ failure severity on admission, and not transfer-related factors, continues to be the best predictor of outcomes of critically ill patients with cancer when transferred from other facilities to the ICU. Our data suggest that transferring critically ill patients with cancer to a specialized center does not lead to worse outcomes or increased resource utilization when compared to patients admitted from the ED. PMID- 28030996 TI - Not a Big Deal? Examining Help-Seeking Behaviors of Sexually Victimized Women on the College Campus. AB - The sexual assault and coercion of women on university campuses continues to be an ongoing problem. It is estimated that more than 15% of women attending college experience some type of sexual assault or coercion each year. As universities and other social institutions begin to acknowledge the prevalence of sexual victimization, an increased emphasis has been placed on helping victims of sexual crimes. The current study uses results from 378 surveys completed by females at a midwestern university to examine the help-seeking behaviors of those who have been victimized. This study specifically focuses on formal and informal reporting, identifying help agents, and reasons for not reporting. Results reveal that 1% of women who were victimized reported their experience to a formal entity, whereas 45% told an informal agent, such as a friend or roommate. Reasons for not reporting included not identifying the experience as rape, wanting to keep the experience private, and feeling ashamed. PMID- 28030997 TI - Mandibular position influence on pilots' postural balance analyzed under dynamic conditions. AB - OBJECTIVE: The aim of this study is to evaluate the influence of the mandibular position on the postural stability in a sample of civilian and military pilots. METHODS: Twenty military pilots (males, mean age 35.15 +/- 3.14 years) and 17 civilian pilots (males, mean 34.91 +/- 2.15 years) were enrolled in this study and underwent a Sensory Organization Test (SOT) using the EquiTest(r) (NeuroCom International Inc., Clackamas, OR, USA) computerized dynamic posturography. The composite parameter was recorded and analyzed. RESULTS: The equilibrium score (ES) recorded in centric occlusion is slightly higher than the ES recorded in mandibular rest position; civilian pilots showed ESs slightly higher than military pilots. The two-way ANOVA analysis shows these differences are not statistically significant. DISCUSSION: The findings of this study seem to suggest that the composite parameter of the SOT is not sensitive in analyzing the influence of the stomatognathic system on the postural balance of civilian and military pilots. PMID- 28030998 TI - The Role of Thalamus Versus Cortex in Epilepsy: Evidence from Human Ictal Centromedian Recordings in Patients Assessed for Deep Brain Stimulation. AB - BACKGROUND: The onset of generalized seizures is a long debated subject in epilepsy. The relative roles of cortex and thalamus in initiating and maintaining the different seizure types are unclear. OBJECTIVE: The purpose of the study is to estimate whether the cortex or the centromedian thalamic nucleus is leading in initiating and maintaining seizures in humans. METHODS: We report human ictal recordings with simultaneous thalamic and cortical electrodes from three patients without anesthesia being assessed for deep brain stimulation (DBS). Patients 1 and 2 had idiopathic generalized epilepsy whereas patient 3 had frontal lobe epilepsy. Visual inspection was combined with nonlinear correlation analysis. RESULTS: In patient 1, seizure onset was bilateral cortical and the belated onset of leading thalamic discharges was associated with an increase in rhythmicity of discharges, both in thalamus and cortex. In patient 2, we observed bilateral independent interictal discharges restricted to the thalamus. However, ictal onset was diffuse, with discharges larger in the cortex even though they were led by the thalamus. In patient 3, seizure onset was largely restricted to frontal structures, with belated lagging thalamic involvement. CONCLUSION: In human generalized seizures, the thalamus may become involved early or late in the seizure but, once it becomes involved, it leads the cortex. In contrast, in human frontal seizures the thalamus gets involved late in the seizure and, once it becomes involved, it lags behind the cortex. In addition, the centromedian nucleus of the thalamus is capable of autonomous epileptogenesis as suggested by the presence of independent focal unilateral epileptiform discharges restricted to thalamic structures. The thalamus may also be responsible for maintaining the rhythmicity of ictal discharges. PMID- 28030999 TI - Seizure Control in a Computational Model Using a Reinforcement Learning Stimulation Paradigm. AB - Neuromodulation technologies such as vagus nerve stimulation and deep brain stimulation, have shown some efficacy in controlling seizures in medically intractable patients. However, inherent patient-to-patient variability of seizure disorders leads to a wide range of therapeutic efficacy. A patient specific approach to determining stimulation parameters may lead to increased therapeutic efficacy while minimizing stimulation energy and side effects. This paper presents a reinforcement learning algorithm that optimizes stimulation frequency for controlling seizures with minimum stimulation energy. We apply our method to a computational model called the epileptor. The epileptor model simulates inter ictal and ictal local field potential data. In order to apply reinforcement learning to the Epileptor, we introduce a specialized reward function and state space discretization. With the reward function and discretization fixed, we test the effectiveness of the temporal difference reinforcement learning algorithm (TD(0)). For periodic pulsatile stimulation, we derive a relation that describes, for any stimulation frequency, the minimal pulse amplitude required to suppress seizures. The TD(0) algorithm is able to identify parameters that control seizures quickly. Additionally, our results show that the TD(0) algorithm refines the stimulation frequency to minimize stimulation energy thereby converging to optimal parameters reliably. An advantage of the TD(0) algorithm is that it is adaptive so that the parameters necessary to control the seizures can change over time. We show that the algorithm can converge on the optimal solution in simulation with slow and fast inter-seizure intervals. PMID- 28031000 TI - Modeling the Kinetics of Serum Glial Fibrillary Acidic Protein, Ubiquitin Carboxyl-Terminal Hydrolase-L1, and S100B Concentrations in Patients with Traumatic Brain Injury. AB - Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), and S100B have been shown to be predictive of patients with brain injury. Kinetics of these biomarkers in injured humans have not been extensively examined. This prospective multi-center study included patients with mild-to moderate traumatic brain injury. Blood samples obtained at enrollment and every 6 h up to 24 h post-injury were assayed for GFAP, UCH-L1, and S100B. Random effects models examined changes in the biomarkers' level over time. A total of 167 patients were enrolled; mean age was 46.0 +/- 17.8, 61.1% were male, 143 (85.6%) had a Glasgow Coma Scale score of 15, and 33 (19.8%) had a positive head computed tomography (CT) scan. Baseline median biomarker concentrations for all three were higher among CT-positive patients (p < 0.0001) but GFAP was the only biomarker that significantly increased over time among CT-positive patients relative to CT negative patients (log transformed values 0.037; 95% confidence interval 0.02, 0.05; p < 0.001), indicating a 3.7% per hour rise in GFAP concentration. There was no significant increase in either UCH-L1 or S100B in CT-positive patients (p = 0.15 and p = 0.47, respectively). GFAP concentrations increased 3.7% per hour among CT-positive patients whereas neither UCH-L1 nor S100B increased, compared with CT-negative patients. The kinetics and temporal profile of GFAP suggest it may be a more robust biomarker to detect patients with positive CT findings, particularly at later post-injury times. Further study is needed to determine if GFAP is a useful test to follow throughout a patient's clinical course. PMID- 28031001 TI - What Is Actually Attributable to Glutamine? PMID- 28031002 TI - Response to Letter From Hoffer and Bistrian. PMID- 28031003 TI - Regarding "Is the Guideline Already Out of Date?" PMID- 28031004 TI - Iodine Deficiency in Parenteral Nutrition. PMID- 28031005 TI - JPEN Journal Club 24. Study Premise. PMID- 28031006 TI - Catheter Salvage During Infections in Patients Receiving Home Parenteral Nutrition. PMID- 28031007 TI - Polymorphisms of the Costimulatory Genes CTLA-4, CD28, PD-1, and ICOS and Outcome of Kidney Transplants in Iranian Patients. AB - OBJECTIVES: Costimulatory molecules are important factors determining the outcome of transplant. The aim of the present study was to investigate the effect of CTLA 4, CD28, PD-1, and ICOS gene polymorphisms on the outcome of kidney transplant. MATERIALS AND METHODS: A total of 172 kidney transplant recipients were included in this study. There were 45 recipients (26%) who experienced acute rejection. The CTLA-4, PD-1, ICOS, and CD28 gene polymorphisms were evaluated by polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: There were no differences between kidney transplant recipients with or without acute rejection in the distribution of genotypes and alleles of studied costimulatory molecules. Significant associations were observed between the AA genotype and the A allele of CTLA-4 1661 (P = .04, P = .05) and also CT and TT genotypes of PD-1.9 in the male compared with female subgroup of patients, with low frequency in the acute rejection group (P = .03; P = .04). Significant associations were observed between the AA genotype and the A allele of CTLA-4 1661 (P = .02; P = .01) and also GA genotype of PD-1.3 (P = .03) in the male subgroup compared with female subgroup with low frequency of acute rejection. A significant association was observed between TC genotype of CD28 in the female compared with male subgroup of patients with high frequency of acute rejection (P = .05). CONCLUSIONS: The above results suggest that genetic polymorphisms of costimulatory molecules function as sex-dependent risk factors for development of acute rejection. Further studies are needed in different populations. PMID- 28031008 TI - Action and Function of Vitamin D in Digestive Tract Physiology and Pathology. AB - BACKGROUND: The body of biomedical literature on Vitamin D effector mechanisms in gastrointestinal biology and pathophysiology is rapidly expanding. Accordingly, new possibilities of vitamin D biology-based therapeutical intervention in gastroenterological disease are being identified. However, the literature lacks a concise review on these developments, hampering comprehension of the possibilities involved for many in the community. RESULTS: Genetic vitamin D receptor (VDR) polymorphisms and other VDR biology regulation are involved in predisposition to gastrointestinal cancers and might allow tailored strategies for managing those individuals especially at risk, e.g. through vitamin D supplementation. Likewise, modulation of Hedgehog signaling by vitamin D analogues may have promise in combating gastrointestinal cancers or improving barrier function in IBD, but shortage in vitamin D levels may also influence inflammatory conditions of the gut through direct interaction with the mucosal immune system. Evidence justifying population-wide monitoring for vitamin D status is accumulating. CONCLUSION: There is kaleidoscopic interaction of vitamin D biology with many aspects of gastrointestinal tract biology. Vitamin D appears an attractive target for personalized approaches like precision and P4 medicine. PMID- 28031009 TI - Pathobiology and Therapeutic Implications of Tumor Acidosis. AB - Drug resistance and therapeutic failure are important causes of disease relapse and progression and may be considered as major obstacles preventing cure of cancer patients. Tumors use a large number of molecular, biochemical and cellular mechanisms to evade chemotherapy and targeted therapy. Important determinants of drug efficacy are the intrinsic pharmacological characteristics of drugs which may be largely affected by the tumor physiology. One feature of solid tumors is the acidic extracellular pH, resulting from metabolic shift and increased metabolic rates combined with low tissue perfusion due to defective vasculature. Besides its role in tumor pathobiology promoting tumor growth and metastasis, the acidic tumor environment creates a chemical barrier for many anticancer drugs, thus limiting their activity. The content of this review will be focused on the pathobiology of tumor acidosis and on its role in therapeutic resistance. PMID- 28031010 TI - Nanoemulsions for Improved Efficacy of Phytotherapeutics- A Patent Perspective. AB - BACKGROUND: Phytoceuticals have been used extensively worldwide due to their reduced toxicity and therapeutic efficacy. The major drawback associated with their delivery which includes lack of sustained action and lipophilicity has been overcome by applications of scientific approach by scientists and researchers. Novel drug delivery systems aimed at enhancing bioavailability, reducing toxicity and in turn improving the patient compliance have been developed with success in recent times. Recent developments in the modern phytopharmaceutical research methods have also solved the major hurdles related to the extraction, identification of constituents in polyherbal systems, and standardisation thereby further facilitating the formulation of improved dosage forms like nanoemulsions with better efficacy of the herbal drugs. METHOD: We did extensive literature review, which included an in depth study and collection of both peer reviewed research and review manuscripts as well as patents related to phytonanoemulsions, which were included in the manuscript. RESULTS: In this article, an attempt has been made to compile the therapeutic and non therapeutic applications of herbal drugs formulated as nanoemulsions, patented phytonanoemulsions, with a discussion on the toxicity and future aspects of the nanoemulsion based delivery of phytotherapeutics. CONCLUSION: The findings of the review confirm that phytonanoemulsions are novel formulations which can be utilized both for therapeutic as well as nontherapeutic applications. PMID- 28031011 TI - DephosSitePred: A High Accuracy Predictor for Protein Dephosphorylation Sites. AB - AIM AND OBJECTIVE: Protein tyrosine phosphatases (PTPs) are responsible for protein phosphorylation. Because the level of protein phosphorylation is correlated with tumor transformation, PTPs have been considered as candidate transformation suppressors. In this study, we developed a novel PTP site prediction model, DephosSitePred, based on bi-profile sequence features. MATERIALS AND METHOD: A dataset which contains 63-, 50- and 51-positive samples, and 868-, 856-, and 731-negative samples with less than 70% sequence identity for the three phosphatases was constructed in this study. Based on the dataset, a predictor model DephosSitePred was constructed, by applying the sequence-based bi profile Bayes feature extraction technique to identify three phosphatases, PTP1B, SHP-1, and SHP-2. Concerning the imbalance of datasets used in our study, the weight parameters (W1 and W-1) of the support vector machine (SVM) were selected according to jackknife cross-validation. RESULTS: DephosSitePred yielded Matthews correlation coefficients of 0.686 for protein tyrosine phosphatase 1B (PTP1B), 0.668 for Src homology region 2 domain-containing phosphatase (SHP)-1, and 0.748 for SHP-2 substrate sites, which significantly outperformed other existing predictors. Moreover, 30 times of 5-fold cross-validations showed that DephosSitePred achieved average area under the curve values of 0.968, 0.968, and 0.982 for PTP1B, SHP-1 and SHP-2, respectively, which were 0.115, 0.105 and 0.105 higher than those of the second best model, MGPS-DEPHOS, respectively. CONCLUSION: DephosSitePred is indeed an effective auxiliary tool for in silico identification of dephosphorylation sites and may help to reveal the physiological and pathological role of dephosphorylation protein. PMID- 28031012 TI - Synthesis of Spiro Indole-2-Ones Using Three Component Reaction of N-Alkylisatins and Triphenylphosphonium Intermediates. AB - OBJECTIVE: A simple and efficient procedure is achieved for the synthesis of indole-2-one derivatives via three-component reaction of N-alkylisatin, activated acetylenic compounds and alkyl bromide in the presence of triphenylphosphine in water under two conditions; room temperature and microwave irradiation. MATERIALS AND METHODS: All chemicals used in this work were prepared from Fluka (Buchs, Switzerland) and were used without further purification. N-alkylisatin were synthesized in the laboratory in the procedure that is reported in the literature. Electrothermal 9100 apparatus is employed for measuring of melting points of products. Elemental analyses for C, H, and N were performed with Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 spectrometer operating at an ionization potential of 70 eV. Measurement of IR spectra was performed by Shimadzu IR-460 spectrometer. 1H, and 13C NMR spectra were evaluated with a BRUKER DRX- 500 AVANCE spectrometer at 500.1 and 125.8 MHz, respectively. RESULTS: The results were demonstrated that simple mixing of N alkylisatin, dialkyl acetylenedicarboxylate and alkyl bromides in the presence of triphenylphosphine by using of microwave condition is the efficient method for preparation of indole derivatives in good yields. In the optimized reaction conditions, water is solvent and temperature of the mixture of reaction is 80 oC. CONCLUSION: In this study, the reaction of activated acetylenic compounds with N alkylisatin and alkyl bromide in the presence of triphenylphosphine is investigated which is led to a facile synthesis of some functionalized indoles. PMID- 28031013 TI - Development of a Web-Enabled SVR-Based Machine Learning Platform and its Application on Modeling Transgene Expression Activity of Aminoglycoside-Derived Polycations. AB - OBJECTIVE: Support Vector Regression (SVR) has become increasingly popular in cheminformatics modeling. As a result, SVR-based machine learning algorithms, including Fuzzy-SVR and Least Square-SVR (LS-SVR) have been developed and applied in various research areas. However, at present, few downloadable packages or public-domain software are available for these algorithms. To address this need, we developed the Support vector regression-based Online Learning Equipment (SOLE) web tool (available at http://reccr.chem.rpi.edu/SOLE/index.html) as an online learning system to support predictive cheminformatics and materials informatics studies. RESULTS: In this work, we employed the SOLE system to model transgene expression efficacy of polymers obtained from aminoglycoside antibiotics, which allowed the results of several modeling approaches to be easily compared. All models had test set r2 of 0.96-0.98 and test set R2 of 0.79-0.84. Y-scrambling test showed the models were stable and not over-fitted. CONCLUSION: SOLE has a user-friendly interface and includes routine elements of performing QSAR/QSPR studies that can be applied in various research areas. It utilizes rational and sophisticated feature selection, model selection and model evaluation processes. PMID- 28031014 TI - CEBP Epigenetic Dysregulation as a Drug Target for the Treatment of Hematologic and Gynecologic Malignancies. AB - BACKGROUND: The CCAAT/enhancer binding proteins (C/EBPs) form a family of transcription factors regulating many genes' expression in a variety of cells/tissues/organs at different developmental stages. With their capability of binding to their cognate DNA elements and through protein-protein interactions, C/EBPs modulate diverse functions including cell differentiation, metabolism, and immune response, under both physiological and pathological conditions such as the establishment of hematological lineages, the maintenance of normal reproductive function, and the development of malignancies. OBJECTIVES: This review concentrates on the role(s) and epigenetic alterations of C/EBP genes in hematologic malignancies and gynecologic organs and disorders. New research findings on molecular pathways involved in C/EBP function and regulation are reviewed and analyzed. The potential therapeutic values of these findings are also discussed. CONCLUSION: Unlike in hematologic malignancies in which C/EBP mutations and their disruption of wild type C/EBP tumor suppressive activities have been well documented, mutation of C/EBP does not appear to be a common event in gynecologic cancers, raising some doubt if C/EBPs may have tumor suppressor activity in gynecologic cancers. However, this notion could not exclude the possibility that downregulation or DNA methylation-meditated epigenetic silencing of C/EBPs may contribute to the development of gynecologic malignancies. PMID- 28031016 TI - Androgen Deficiency in Aging Male Questionnaire for the Clinical Detection of Testosterone Deficiency in a Population of Black Sub-Saharan African Men with Type 2 Diabetes Mellitus: Is it a Reliable Tool? AB - BACKGROUND: Androgen Deficiency in Aging Male (ADAM) questionnaire is increasingly popular for the evaluation of testosterone deficiency (TD) in Sub Saharan African men with type 2 diabetes mellitus (T2DM). However, its reliability in this population is unknown. OBJECTIVE: To evaluate the reliability of the ADAM questionnaire for the clinical detection of testosterone deficiency in Sub-Saharan African men with T2DM. METHODS: Total testosterone < 8nmol/L was used as gold standard for diagnosis of TD in a crosssectional survey of 200 males with T2DM aged 30-69 years. Participants also completed the Saint Louis University ADAM questionnaire whereby TD was diagnosed by a "yes" answer to question 1 (reduced libido) or 7 (erectile dysfunction) or any other three questions. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy of the ADAM tool were computed. RESULTS: The mean age of the participants was 58.0 +/- 8.8 years. 142 subjects (71.0%) had TD based on the ADAM questionnaire. However, TD was biochemically confirmed in 59 subjects (29.5%). ADAM questionnaire rendered sensitivity of 88.1%, specificity of 44.7%, PPV of 50.0%, NPV of 85.7% and accuracy of 61.4%. Low libido alone had better specificity (75.5%) and accuracy (73.2%) than the entire questionnaire. CONCLUSION: Despite an impressive sensitivity, the low specificity and overall accuracy of the ADAM questionnaire makes it unreliable for the detection of AD in Sub-Saharan African men with type 2 DM. However, presence of a sustained low libido appears to be a reliable pointer to underlying testosterone deficiency requiring biochemical confirmation. PMID- 28031017 TI - Nitric oxide signaling and the cross talk with prostanoids pathways in vascular system. AB - BACKGROUND: This review provides an overview of the cellular signaling of nitric oxide (NO) and prostanoids in vascular cells and the possible cross talk between their pathways, mainly in hypertension, since the imbalance of these two systems has been attributed to development of some cardiovascular diseases. It also deals with the modulation of vasodilation induced by NO donors. NO is a well-known second messenger involved in many cellular functions. CONCLUSION: In the vascular system, the NO produced by endothelial NO-synthase (eNOS) or released by NO donors acts in vascular smooth muscle cells, the binding of NO to Fe2+-heme of soluble guanylyl-cyclase (sGC) activates sGC and the production of cyclic guanosine-3-5-monophosphate (cGMP). The second messenger (cGMP) activates protein kinase G and the signaling cascade, including K+ channels. Activation of K+ channels leads to cell membrane hyperpolarization and Ca2+ channels blockade, which induce vascular relaxation. Moreover, the enzyme cyclooxygenase (COX) is also an important regulator of the vascular function by prostanoids production such as thromboxane A2 (TXA2) and prostacyclin (PGI2), which classically induce contraction and relaxation, respectively. Additionaly, studies indicate that the activity of both enzymes can be modulated by their products and reactive oxygen species (ROS) in cardiovascular diseases such as hypertension. The interaction of NO with cellular molecules, particularly the reaction of NO with ROS, determines the biological mechanisms of action and short half-life of NO. We have been working on the vascular effects of ruthenium-derived complexes that release NO. Our research group has published works on the vasodilating effects of ruthenium derived NO donors and the mechanisms of vascular cells involved in the relaxation of the vascular smooth muscle in health and hypertensive rats. In our previous studies, we have compared the new NO donors synthesized by our group to SNP. It shows the cellular signaling of NO in the endothelial and vascular smooth muscle cells. OBJECTIVE: This work focuses on the cellular mechanisms involved in the vasodilation induced by NO and the role of prostanoids in contractile or relaxing vascular responses. Since the NO is produced by NO-synthase (NOS) or released from NO donors we also discussed the perspectives to cross talk between NO and COX pathways on the vascular tone control. PMID- 28031018 TI - Titanocenes as anticancer agents: recent insights. AB - BACKGROUND: Enormous success of antitumor agent cisplatin initiated interest in other organometallic complexes. A subclass of organometallic compounds termed metallocenes, characterized by a transition metal central atom (M) bound to cyclopentadienide (Cp-/[C5H5]-) ligands with the basic formula Cp2M, has gained increasing interest as promising anticancer agents. OBJECTIVES: This review is aimed at a progress in the development of organometallic titanium-based compounds focusing primarily on the evaluation of their cytotoxic activity and mechanism of action in relation to potential utilization as anticancer drugs. RESULTS: Metallocenes bearing titanium as central atom were sorted according to their structure and modifications and their anticancer activity is further discussed. CONCLUSION: Titanocenes represent family of promising compounds exerting cytostatic activity. We suggest that their application not only as separate agents, but also in combination with newly developed carriers, e.g. nanomaterials, may lead to improvement of their delivery into tumor cells and following utilization in cancer treatment. PMID- 28031019 TI - Naphthyridines with Antiviral Activity - A Review. AB - BACKGROUND: Naphthyridine scaffold is an important pharmacophore in compounds which have shown various biological activities like antiviral, antimicrobial, anticancer, antiinflammatory and analgesic. This scaffold is also reported to exhibit activity against HIV, HCMV, HSV, HPV and HCV. Antiviral activity displayed by many naphthyridine analogs is in nM range. Only few review articles are available in literature which describe about various biological activities of naphthyridines, but there is no comprehensive compilation particularly for antiviral activities. OBJECTIVES: The objective of this review is to compile the literature on anti-viral activities of naphthyridine analogs. METHODS: SciFinder, Google Scholar and PubMed database were searched with keyword "naphthyridine" and the references obtained were further sorted using keywords "antihiv", "antiviral" and "virus", separately. References obtained were considered to review the antiviral literature of naphthyridines. RESULTS: Literature search using SciFinder database with different keywords gave several references. Only references of antiviral activities of naphthyridine compounds were reviewed. References to in-silico studies alone or on formulation development or on patents were excluded. CONCLUSION: This review will be helpful for future researches to design and synthesize naphthyridine analogs with improved antiviral activities. PMID- 28031020 TI - Assessing key cost drivers associated with caring for chronic kidney disease patients. AB - BACKGROUND: To examine key factors influencing chronic kidney disease (CKD) patients' total expenditure and offer recommendations on how to reduce total cost of CKD care without compromising quality. METHODS: Using the 2002-2011 Medical Expenditure Panel Survey (MEPS) data, our cross-sectional study analyzed 197 patient records-79 patients with one record and 59 with two entries per patient (138 unique patients). We used three patient groups, based on international statistical classification of diseases version 9 code for condition (ICD9CODX) classification, to focus inference from the analysis: (a) non-dialysis dependent CKD, (b) dialysis and (c) transplant. Covariate information included region, demographic, co-morbid conditions and types of services. We used descriptive methods and multivariate generalized linear models to understand the impact of cost drivers. We compared actual and predicted CKD cost of care data using a hold out sample of nine, randomly selected patients to validate the models. RESULTS: Total costs were significantly affected by treatment type, with dialysis being significantly higher than non-dialysis and transplant groups. Costs were highest in the West region of the U.S. Average costs for patients with public insurance were significantly higher than patients with private insurance (p < .0743), and likewise, for patients with co-morbid conditions over those without co-morbid conditions (p < .001). CONCLUSIONS: Managing CKD patients both before and after the onset of dialysis treatment and managing co-morbid conditions in individuals with CKD are potential sources of substantial cost savings in the care of CKD patients. Comparing total costs pre and post the United States Affordable Care Act could provide invaluable insights into managing the cost-quality tradeoff in CKD care. PMID- 28031021 TI - The efficacy of treadmill training with and without projected visual context for improving walking ability and reducing fall incidence and fear of falling in older adults with fall-related hip fracture: a randomized controlled trial. AB - BACKGROUND: The ability to adjust walking to environmental context is often reduced in older adults and, partly as result of this, falls are common in this population. A treadmill with visual context projected on its belt (e.g., obstacles and targets) allows for practicing step adjustments relative to that context, while concurrently exploiting the great amount of walking practice associated with conventional treadmill training. The present study was conducted to compare the efficacy of adaptability treadmill training, conventional treadmill training and usual physical therapy in improving walking ability and reducing fear of falling and fall incidence in older adults during rehabilitation from a fall-related hip fracture. METHODS: In this parallel-group, open randomized controlled trial, seventy older adults with a recent fall-related hip fracture (83.3 +/- 6.7 years, mean +/- standard deviation) were recruited from inpatient rehabilitation care and block randomized to six weeks inpatient adaptability treadmill training (n = 24), conventional treadmill training (n = 23) or usual physical therapy (n = 23). Group allocation was only blind for assessors. Measures related to walking ability were assessed as the primary outcome before and after the intervention and at 4-week and 12-month follow-up. Secondary outcomes included general health, fear of falling, fall rate and proportion of fallers. RESULTS: Measures of general walking ability, general health and fear of falling improved significantly over time. Significant differences among the three intervention groups were only found for the Functional Ambulation Category and the dual-task effect on walking speed, which were in favor of respectively conventional treadmill training and adaptability treadmill training. CONCLUSIONS: Overall, adaptability treadmill training, conventional treadmill training and usual physical therapy resulted in similar effects on walking ability, fear of falling and fall incidence in older adults rehabilitating from a fall-related hip fracture. Additional post hoc subgroup analyses, with stratification for pre-fracture tolerated walking distance and executive function, revealed several intervention effects in favor of adaptability and conventional treadmill training, indicating superiority over usual physical therapy for certain subgroups. Future well-powered studies are necessary to univocally identify the characteristics of individuals who will benefit most from a particular intervention. TRIAL REGISTRATION: The Netherlands Trial Register ( NTR3222 , 3 January 2012). PMID- 28031022 TI - Analysis of molecular networks and targets mining of Chinese herbal medicines on anti-aging. AB - BACKGROUND: Many kidney-tonifying Chinese herbal medicines exert effects on anti aging by comprehensive interactions of multiple targets. However, the interactions of multi-targets targeted by effective ingredients of kidney tonifying Chinese herbal medicines are unknown. In this study, to explore the systems pharmacology mechanisms of kidney-tonifying Chinese medicines on anti aging, we establish the molecular networks with the interactions of multi targets, analyze bio-functions and pathways with IPA, and calculated the mutual interaction pairs of targets (target pairs) with data mining, respectively. METHODS: Kidney-tonifying Chinese medicines with anti-aging effects were screened from the Chinese Pharmacopoeia and the literatures. Target proteins of these herbal medicines were obtained from bioinformatics databases. Comparisons of molecular networks, bio-functions and pathways given by Ingenuity Pathway Analysis system showed the similarities and the differences between kidney Yin tonifying herbal medicines and kidney Yang-tonifying herbal medicines. Target pairs with high correlation related to anti-aging were also discovered by data mining algorithm. And regulatory networks of targets were built based on the target pairs. RESULTS: Twenty-eight kidney-tonifying herbal medicines with anti aging effects and 717 related target proteins were collected. The main bio functions that all targets enriched in were "Cell Death and Survival", "Free Radical Scavenging" and "Cellular Movement", etc. The results of comparison analysis showed that kidney Yin-tonifying herbal medicines focused more on "Cancer related signaling", "Apoptosis related signaling" and "Cardiovascular related signaling". And kidney Yang-tonifying herbal medicines focused more on "Cellular stress and injury related signaling" and "Cellular growth, proliferation and development related signaling". Moreover, the results of regulatory network showed that the anti-aging related target pairs with high correlated degrees of Kidney Yin-tonifying herbal medicines included TNF-PTGS2, TNF-CASP3, PTGS2-CASP3, CASP3-NOS2 and TNF-NOS2, and that of kidney Yang tonifying herbal medicines included REAL-TNF, REAL-NFKBIA, REAL-JUN, PTGS2-SOD1 and TNF-IL6. CONCLUSIONS: In this study, we achieved some important targets, target pairs and regulatory networks with bioinformatics and data mining, to discuss the systems pharmacology mechanisms of kidney-tonifying herbal medicines acting on anti-aging. Mutual target pairs related to anti-aging found in this study included TNF-PTGS2, TNF-CASP3, PTGS2-CASP3, CASP3-NOS2, TNF-NOS2, REAL-TNF, REAL-NFKBIA, REAL-JUN, PTGS2-SOD1 and TNF-IL6. Target pairs and regulatory networks of targets could reflect more potential interactions between targets and comprehensive effects on anti-aging. Compared with the existing researches, it was found that the kidney-tonifying herbal medicines may exert anti-aging effects in multiple pathways in this study. PMID- 28031023 TI - Can longitudinal generalized estimating equation models distinguish network influence and homophily? An agent-based modeling approach to measurement characteristics. AB - BACKGROUND: Connected individuals (or nodes) in a network are more likely to be similar than two randomly selected nodes due to homophily and/or network influence. Distinguishing between these two influences is an important goal in network analysis, and generalized estimating equation (GEE) analyses of longitudinal dyadic network data are an attractive approach. It is not known to what extent such regressions can accurately extract underlying data generating processes. Therefore our primary objective is to determine to what extent, and under what conditions, does the GEE-approach recreate the actual dynamics in an agent-based model. METHODS: We generated simulated cohorts with pre-specified network characteristics and attachments in both static and dynamic networks, and we varied the presence of homophily and network influence. We then used statistical regression and examined the GEE model performance in each cohort to determine whether the model was able to detect the presence of homophily and network influence. RESULTS: In cohorts with both static and dynamic networks, we find that the GEE models have excellent sensitivity and reasonable specificity for determining the presence or absence of network influence, but little ability to distinguish whether or not homophily is present. CONCLUSIONS: The GEE models are a valuable tool to examine for the presence of network influence in longitudinal data, but are quite limited with respect to homophily. PMID- 28031024 TI - Sex trafficking and sexual exploitation in settings affected by armed conflicts in Africa, Asia and the Middle East: systematic review. AB - BACKGROUND: Sex trafficking and sexual exploitation has been widely reported, especially in conflict-affected settings, which appear to increase women's and children's vulnerabilities to these extreme abuses. METHODS: We conducted a systematic search of ten databases and extensive grey literature to gather evidence of sex trafficking and sexual exploitation in conflict-affected settings. International definitions of "sexual exploitation" and "sex trafficking" set the indicator parameters. We focused on sexual exploitation in forms of early or forced marriage, forced combatant sexual exploitation and sexual slavery. We extracted prevalence measures, health outcomes and sexual exploitation terminology definitions. The review adhered to PRISMA guidelines and includes quality appraisal. RESULTS: The search identified 29 eligible papers with evidence of sex trafficking and sexual exploitation in armed conflict settings in twelve countries in Africa, Asia, and the Middle East. The evidence was limited and not generalizable, due to few prevalence estimates and inconsistent definitions of "sexual exploitation". The prevalence estimates available indicate that females were more likely than males to be victims of sexual exploitation in conflict settings. In some settings, as many as one in four forced marriages took place before the girls reached 18 years old. Findings suggest that the vast majority of former female combatants were sexually exploited during the conflict. These studies provided various indicators of sexual exploitation compatible to the United Nation's definition of sex trafficking, but only 2 studies identified the exploitation as trafficking. None of the studies solely aimed to measure the prevalence of sex trafficking or sexual exploitation. Similar descriptions of types of sexual exploitation and trafficking were found, but the inconsistent terminology or measurements inhibited a meta-analysis. CONCLUSIONS: Findings indicate there are various forms of human trafficking and sexual exploitation in conflict-affected settings, primarily occurring as early or forced marriage, forced combatant sexual exploitation, and sexual slavery. The studies highlight the extraordinary vulnerability of women and girls to these extreme abuses. Simultaneously, this review suggests the need to clarify terminology around sex trafficking in conflict to foster a more cohesive future evidence-base, and in particular, robust prevalence figures from conflict-affected and displaced populations. PMID- 28031025 TI - Estimation of prevalence of sarcopenia by using a new bioelectrical impedance analysis in Chinese community-dwelling elderly people. AB - BACKGROUND: The aim of the present study was to validate the usefulness of the new octapolar multifrequency bioelectrical impedance analysis (BIA) for assessment of appendicular skeletal muscle mass (ASM) by comparing it with that of dual-energy X-ray absorptiometry (DXA) and to investigate the prevalence of sarcopenia in Chinese community-dwelling elderly according to Asian Working Group for Sarcopenia (AWGS) definition. METHODS: A cross-sectional study was conducted in communities of Chengdu, China. A total of 944 community-dwelling elderly adults aged >=60 years were included. ASM was measured by using DXA as a criterion method to validate a standing eight-electrode multifrequency BIA (InBody 720), followed by a further estimation of the prevalence of sarcopenia according the AWGS definition. RESULTS: In the Bland-Altman analysis, no significant difference was found between DXA and BIA based on the ASM measurements. The prevalence of AWGS-defined sarcopenia was 12.5% in the elderly women and 8.2% in the elderly men. CONCLUSIONS: BIA is suitable for body composition monitoring (ASM) in elderly Chinese as a fast, noninvasive, and convenient method; therefore, it may be a better choice in large epidemiological studies in the Chinese population. The prevalence of AWGS-defined sarcopenia was approximately 10.4% and increased with age in the Chinese community-dwelling elderly in this study. PMID- 28031026 TI - Acute caffeine ingestion reduces insulin sensitivity in healthy subjects: a systematic review and meta-analysis. AB - BACKGROUND: According to previous meta-analyses, coffee consumption reduces the risk of type 2 diabetes mellitus. However, the underlying mechanism remains unknown. Whether caffeine, the key ingredient in coffee, has a beneficial effect on the glycemic homeostasis and the anti-diabetic effect is particularly controversial. The aim of this study was to summarize the effect of acute caffeine ingestion on insulin sensitivity in healthy men. METHODS: A comprehensive literature search for papers published before April 2016 was conducted in EMBASE, PubMed, and Cochrane Library databases. Randomized controlled trials (RCTs) that investigated the effect of caffeine on insulin sensitivity in healthy humans without diabetes were included. A random effects meta-analysis was conducted using Review Manager 5.3. RESULTS: The search yielded 7 RCTs in which caffeine intake was the single variant. Compared with placebo, caffeine intake significantly decreased the insulin sensitivity index, with a standardized mean difference of -2.06 (95% confidence interval -2.67 to -1.44, I2 = 49%, P for heterogeneity = 0.06). CONCLUSION: Acute caffeine ingestion reduces insulin sensitivity in healthy subjects. Thus, in the short term, caffeine might shift glycemic homeostasis toward hyperglycemia. Long-term trials investigating the role of caffeine in the anti-diabetic effect of coffee are needed. PMID- 28031027 TI - Prevalence of anelloviruses (TTV, TTMDV, and TTMV) in healthy blood donors and in patients infected with HBV or HCV in Qatar. AB - BACKGROUND: Anelloviruses (TTV, TTMV, and TTMDV) have been associated with non A G hepatitis. The goal of the current study was to estimate the prevalence of these anelloviruses in Qatar. METHODS: A total of 607 blood samples (500 healthy donors, and 53 HBV-and 54 HCV-positive patients) representing different nationalities were tested for the presence of TTV, TTMV, and TTMDV DNA by nested PCR. RESULTS: Prevalence rates for the three viruses were high in all studied groups, and exceeding 95% in the HBV group (for TTV and TTMDV). Infection with more than one type of viruses was common and significant in most of the positive patients (p < 0.05) and ranging from 55.4% for TTV/TTMV and TTMV/TTMDV co infections in the healthy group, to 96.3% for TTV/TTMV co-infections in the HBV group. Further, and as with most previous studies, no significant association was found between anelloviruses infections and age, nationality, or gender (p > 0.05) albeit the detection of higher infection rates among females and Qatari subjects. CONCLUSION: This was the first published study to look at prevalence of Anellowviruses in the Middle East. High prevalence rates of the three viruses in all studied groups was noted. Further studies are needed to explore and compare the different genotypes of these viruses in the region. PMID- 28031028 TI - Enablers and barriers to implementing collaborative care for anxiety and depression: a systematic qualitative review. AB - BACKGROUND: Collaborative care is an increasingly popular approach for improving quality of care for people with mental health problems through an intensified and structured collaboration between primary care providers and health professionals with specialized psychiatric expertise. Trials have shown significant positive effects for patients suffering from depression, but since collaborative care is a complex intervention, it is important to understand the factors which affect its implementation. We present a qualitative systematic review of the enablers and barriers to implementing collaborative care for patients with anxiety and depression. METHODS: We developed a comprehensive search strategy in cooperation with a research librarian and performed a search in five databases (EMBASE, PubMed, PsycINFO, ProQuest, and CINAHL). All authors independently screened titles and abstracts and reviewed full-text articles. Studies were included if they were published in English and based on the original qualitative data on the implementation of a collaborative care intervention targeted at depression or anxiety in an adult patient population in a high-income country. Our subsequent analysis employed the normalization process theory (NPT). RESULTS: We included 17 studies in our review of which 11 were conducted in the USA, five in the UK, and one in Canada. We identified several barriers and enablers within the four major analytical dimensions of NPT. Securing buy-in among primary care providers was found to be critical but sometimes difficult. Enablers included physician champions, reimbursement for extra work, and feedback on the effectiveness of collaborative care. The social and professional skills of the care managers seemed critical for integrating collaborative care in the primary health care clinic. Day-to-day implementation was also found to be facilitated by the care managers being located in the clinic since this supports regular face-to-face interactions between physicians and care managers. CONCLUSIONS: The following areas require special attention when planning collaborative care interventions: effective educational programs, especially for care managers; issues of reimbursement in relation to primary care providers; good systems for communication and monitoring; and promoting face-to-face interaction between care managers and physicians, preferably through co-location. There is a need for well sampled, in-depth qualitative studies on the implementation of collaborative care in settings outside the USA and the UK. PMID- 28031029 TI - Quantifying western blots: none more black. AB - BACKGROUND: Western blotting is among the most common techniques used in molecular biology and a simple way of assessing the presence or absence of a protein. It is also commonly used to compare protein levels in different conditions or in different tissues. This article illustrates some of the easy ways to arrive at a false conclusion when trying to quantify protein levels from western blots. PMID- 28031030 TI - Outcome after protected full weightbearing treatment in an orthopedic device in diabetic neuropathic arthropathy (Charcot arthropathy): a comparison of unilaterally and bilaterally affected patients. AB - BACKGROUND: Charcot neuropathic arthropathy (CN) is a chronic, progressive, destructive, non-infectious process that most frequently affects the bone architecture of the foot in patients with sensory neuropathy. We evaluated the outcome of protected weightbearing treatment of CN in unilaterally and bilaterally affected patients and secondarily compared outcomes in protected versus unprotected weightbearing treatment. METHODS: Patient records and radiographs from 2002 to 2012 were retrospectively analyzed. Patients with Type 1 or Type 2 diabetes with peripheral neuropathy were included. Exclusion criteria included immunosuppressive or osteoactive medication and the presence of bone tumors. Ninety patients (101 ft), mean age 60.7 +/- 10.6 years at first diagnosis of CN, were identified. Protected weightbearing treatment was achieved by total contact cast or custom-made orthosis. Ulcer, infection, CN recurrence, and amputation rates were recorded. Mean follow-up was 48 (range 1-208) months. RESULTS: Per the Eichenholtz classification, 9 ft were prodromal, 61 in stage 1 (development), 21 in stage 2 (coalescence) and 10 in stage 3 (reconstruction). Duration of protected weightbearing was 20 +/- 21 weeks and 22 +/- 29 weeks in patients with unilateral and bilateral CN, respectively. In bilaterally affected patients, new ulcers developed in 9/22 (41%) feet. In unilaterally affected patients, new ulcers developed in 5/66 (8%) protected weightbearing feet and 4/13 (31%) unprotected, full weightbearing feet (p = 0.036). The ulceration rate was significantly higher in bilaterally versus unilaterally affected patients with a protected weightbearing regimen (p = 0.004). Soft tissue infection occurred in 1/13 (8%) unprotected weightbearing feet and 1/66 (2%) protected weightbearing feet in unilaterally affected patients, and in 1/22 (4%) protected weightbearing feet of bilaterally affected patients. Recurrence and amputation rates were similar across treatment modalities. CONCLUSIONS: Bilateral CN results in significantly more ulcers than unilateral CN and leads to slightly higher soft tissue infections. Protected weightbearing in an orthopedic device can reduce the risk for complications in acute CN of the foot and ankle. PMID- 28031031 TI - Gene regulatory network inference using PLS-based methods. AB - BACKGROUND: Inferring the topology of gene regulatory networks (GRNs) from microarray gene expression data has many potential applications, such as identifying candidate drug targets and providing valuable insights into the biological processes. It remains a challenge due to the fact that the data is noisy and high dimensional, and there exists a large number of potential interactions. RESULTS: We introduce an ensemble gene regulatory network inference method PLSNET, which decomposes the GRN inference problem with p genes into p subproblems and solves each of the subproblems by using Partial least squares (PLS) based feature selection algorithm. Then, a statistical technique is used to refine the predictions in our method. The proposed method was evaluated on the DREAM4 and DREAM5 benchmark datasets and achieved higher accuracy than the winners of those competitions and other state-of-the-art GRN inference methods. CONCLUSIONS: Superior accuracy achieved on different benchmark datasets, including both in silico and in vivo networks, shows that PLSNET reaches state-of the-art performance. PMID- 28031032 TI - Metabolic model of central carbon and energy metabolisms of growing Arabidopsis thaliana in relation to sucrose translocation. AB - BACKGROUND: Sucrose translocation between plant tissues is crucial for growth, development and reproduction of plants. Systemic analysis of these metabolic and underlying regulatory processes allow a detailed understanding of carbon distribution within the plant and the formation of associated phenotypic traits. Sucrose translocation from 'source' tissues (e.g. mesophyll) to 'sink' tissues (e.g. root) is tightly bound to the proton gradient across the membranes. The plant sucrose transporters are grouped into efflux exporters (SWEET family) and proton-symport importers (SUC, STP families). To better understand regulation of sucrose export from source tissues and sucrose import into sink tissues, there is a need for a metabolic model that takes in account the tissue organisation of Arabidopsis thaliana with corresponding metabolic specificities of respective tissues in terms of sucrose and proton production/utilization. An ability of the model to operate under different light modes ('light' and 'dark') and correspondingly in different energy producing modes is particularly important in understanding regulatory modules. RESULTS: Here, we describe a multi compartmental model consisting of a mesophyll cell with plastid and mitochondrion, a phloem cell, as well as a root cell with mitochondrion. In this model, the phloem was considered as a non-growing transport compartment, the mesophyll compartment was considered as both autotrophic (growing on CO2 under light) and heterotrophic (growing on starch in darkness), and the root was always considered as heterotrophic tissue dependent on sucrose supply from the mesophyll compartment. In total, the model includes 413 balanced compounds interconnected by 400 transformers. The structured metabolic model accounts for central carbon metabolism, photosynthesis, photorespiration, carbohydrate metabolism, energy and redox metabolisms, proton metabolism, biomass growth, nutrients uptake, proton gradient generation and sucrose translocation between tissues. Biochemical processes in the model were associated with gene-products (742 ORFs). Flux Balance Analysis (FBA) of the model resulted in balanced carbon, nitrogen, proton, energy and redox states under both light and dark conditions. The main H+ fluxes were reconstructed and their directions matched with proton-dependent sucrose translocation from 'source' to 'sink' under any light condition. CONCLUSIONS: The model quantified the translocation of sucrose between plant tissues in association with an integral balance of protons, which in turn is defined by operational modes of the energy metabolism. PMID- 28031033 TI - The ACEII recombinant Trichoderma reesei QM9414 strains with enhanced xylanase production and its applications in production of xylitol from tree barks. AB - BACKGROUND: ACEII transcription factor plays a significant role in regulating the expression of cellulase and hemicellulase encoding genes. Apart from ACEII, transcription factors such as XYR1, CRE1, HAP2/3/5 complex and ACEI function in a coordinated pattern for regulating the gene expression of cellulases and hemicellulases. Studies have demonstrated that ACEII gene deletion results in decreased total cellulase and xylanase activities with reduced transcript levels of lignocellulolytic enzymes. RESULTS: In this study, we have successfully transformed the ACEII transcription factor encoding gene in Trichoderma reesei to significantly improve its degrading abilities. Transformation experiments on parental strain T. reesei QM9414 has resulted in five genetically engineered strains T/Ace2-2, T/Ace2-5, T/Ace2-8, T/Ace5-4 and T/Ace10-1. Among which, T/Ace2 2 has exhibited significant increase in enzyme activity by twofolds, when compared to parental strain. The T/Ace2-2 was cultured on growth substrates containing 2% bark supplemented with (a) sugar free + MA medium (b) glucose + MA medium and (c) xylose + MA medium. The bark degradation efficiency of genetically modified T/Ace2-2 strain was assessed by analyzing the xylitol production yield using HPAEC. By 6th day, about 10.52 g/l of xylitol was produced through enzymatic conversion of bark (2% bark + MA + xylose) by the T/Ace2-2 strain and by 7th day the conversion rate was found to be 0.21 g/g. Obtained results confirmed that bark growth medium supplemented with D-xylose has profoundly increased the conversion rate of bark by T/Ace2-2 strain when compared to sugar free and glucose supplemented growth media. Results obtained from scanning electron microscopy has endorsed our current results. Bark samples inoculated with T/Ace2-2 strain has showed large number of degraded cells with clearly visible cavities and fractures, by exposing the microfibrillar interwoven complex. CONCLUSION: We propose a cost effective and ecofriendly method for the degradation of lignocellulosic biomass such as bark to produce xylitol by using genetically modified T. reesei. Efficient conversion rate and production yield obtained in our current study provides a great scope for the xylitol industries, as our method bypasses the pretreatment of bark achieving clean and low-cost xylitol production. PMID- 28031034 TI - UQlust: combining profile hashing with linear-time ranking for efficient clustering and analysis of big macromolecular data. AB - BACKGROUND: Advances in computing have enabled current protein and RNA structure prediction and molecular simulation methods to dramatically increase their sampling of conformational spaces. The quickly growing number of experimentally resolved structures, and databases such as the Protein Data Bank, also implies large scale structural similarity analyses to retrieve and classify macromolecular data. Consequently, the computational cost of structure comparison and clustering for large sets of macromolecular structures has become a bottleneck that necessitates further algorithmic improvements and development of efficient software solutions. RESULTS: uQlust is a versatile and easy-to-use tool for ultrafast ranking and clustering of macromolecular structures. uQlust makes use of structural profiles of proteins and nucleic acids, while combining a linear-time algorithm for implicit comparison of all pairs of models with profile hashing to enable efficient clustering of large data sets with a low memory footprint. In addition to ranking and clustering of large sets of models of the same protein or RNA molecule, uQlust can also be used in conjunction with fragment-based profiles in order to cluster structures of arbitrary length. For example, hierarchical clustering of the entire PDB using profile hashing can be performed on a typical laptop, thus opening an avenue for structural explorations previously limited to dedicated resources. The uQlust package is freely available under the GNU General Public License at https://github.com/uQlust . CONCLUSION: uQlust represents a drastic reduction in the computational complexity and memory requirements with respect to existing clustering and model quality assessment methods for macromolecular structure analysis, while yielding results on par with traditional approaches for both proteins and RNAs. PMID- 28031035 TI - Assessing the fidelity of delivery of an intervention to increase attendance at the English Stop Smoking Services. AB - BACKGROUND: Implementation fidelity refers to the extent to which a proposed intervention is enacted as designed and is necessary to determine how much the intervention in question is the primary mechanism in any changes observed. Start2quit was a randomised controlled trial that aimed to improve attendance at the English Stop Smoking Service (SSS). The complex intervention combining computer-tailored personal risk letters and no-commitment ("taster") sessions aimed at encouraging attendance at the SSS doubled attendance at the SSS and significantly increased abstinence rates, although attendance and abstinence varied between participating SSSs. Assessment of the fidelity of the delivery of the taster sessions to the protocol was embedded into the trial and is the focus of this study. METHODS: Eighteen SSSs participated in the study. Taster sessions were delivered by SSS advisors in the area. Of the 131 sessions delivered, 93 (71 %) were recorded and 41 (31.3 %) were selected for transcription and analysis. The taster session protocol contained 73 specified behaviours, which were independently classified into component behaviour change techniques (BCTs) using an established taxonomy for smoking cessation. All transcripts were coded by two authors with 25 % additionally coded by a third. The fidelity of each taster session was expressed as the percentage of overall protocol-specified behaviours that were delivered. Adherence to each BCT was measured as the number of behaviours applied by the advisors within each BCT divided by the total number classified within each. RESULTS: Adherence of protocol-specified behaviours was relatively high (median 71.23 %), though there was considerable variation (28.76 to 95.89 %) in individual sessions. Median fidelity to specific BCTs across sessions also varied from 50 to 100 %. Shorter sessions, sessions run jointly by two advisors, by female advisors, or by advisors aged 45 to 54 were associated with higher levels of adherence. There was no association between adherence and subsequent attendance at the SSS. CONCLUSIONS: These results suggest that the delivery of the intervention of this study is not likely to have been impacted by issues of fidelity. As such, we can have greater confidence that variability in the main outcome is not due to variability in SSS advisor adherence to the protocol of the taster sessions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76561916. PMID- 28031036 TI - Kinematic and spatiotemporal assessment of habituation to treadmill walking in Labrador retrievers. AB - BACKGROUND: This study investigated differences in kinematic and spatiotemporal variables in Labrador retrievers during introduction to treadmill walking, with the aim to determine the time required for them to become habituated. Twenty-five healthy, treadmill-naive Labrador retrievers participated in the study. The total angular displacement of the carpus, elbow, tarsus and stifle, as well as stride time and stance duration were calculated from the 3-D tracking of skin mounted reflective markers recorded with 6 infrared light emitting video cameras at 240 Hz. The measurements were done at two walking speeds, 0.78 and 0.96 m/s, in six sessions on the treadmill during two consecutive days. RESULTS: With a 1-2 min acclimatization period following each treadmill speed change, mean values of the study variables were significantly different from the last training session mainly in the first session on the first day. However, between-stride variability was significantly larger for at least one variable even in the fourth session for the slower walking speed, and in the fifth session for the higher walking speed. CONCLUSIONS: The results show the importance of proper pre-training of dogs in locomotion studies at walk using a treadmill, and the need to consider not only variable mean values but also between-stride variability, in order to ensure that dogs are sufficiently accustomed to allow collection of reliable data. PMID- 28031037 TI - tESA: a distributional measure for calculating semantic relatedness. AB - BACKGROUND: Semantic relatedness is a measure that quantifies the strength of a semantic link between two concepts. Often, it can be efficiently approximated with methods that operate on words, which represent these concepts. Approximating semantic relatedness between texts and concepts represented by these texts is an important part of many text and knowledge processing tasks of crucial importance in the ever growing domain of biomedical informatics. The problem of most state of-the-art methods for calculating semantic relatedness is their dependence on highly specialized, structured knowledge resources, which makes these methods poorly adaptable for many usage scenarios. On the other hand, the domain knowledge in the Life Sciences has become more and more accessible, but mostly in its unstructured form - as texts in large document collections, which makes its use more challenging for automated processing. In this paper we present tESA, an extension to a well known Explicit Semantic Relatedness (ESA) method. RESULTS: In our extension we use two separate sets of vectors, corresponding to different sections of the articles from the underlying corpus of documents, as opposed to the original method, which only uses a single vector space. We present an evaluation of Life Sciences domain-focused applicability of both tESA and domain adapted Explicit Semantic Analysis. The methods are tested against a set of standard benchmarks established for the evaluation of biomedical semantic relatedness quality. Our experiments show that the propsed method achieves results comparable with or superior to the current state-of-the-art methods. Additionally, a comparative discussion of the results obtained with tESA and ESA is presented, together with a study of the adaptability of the methods to different corpora and their performance with different input parameters. CONCLUSIONS: Our findings suggest that combined use of the semantics from different sections (i.e. extending the original ESA methodology with the use of title vectors) of the documents of scientific corpora may be used to enhance the performance of a distributional semantic relatedness measures, which can be observed in the largest reference datasets. We also present the impact of the proposed extension on the size of distributional representations. PMID- 28031038 TI - Using a smartphone app to reduce cognitive vulnerability and mild depressive symptoms: Study protocol of an exploratory randomized controlled trial. AB - BACKGROUND: Depression is a major challenge worldwide, with significant increasing personal, economic, and societal costs. Although empirically supported treatments have been developed, they are not always available for patients in routine clinical care. Therefore, we need effective and widely accessible strategies to prevent the onset of the very first depressive symptoms. Mental health apps could prove a valuable solution for this desideratum. Although preliminary research has indicated that such apps can be useful in treating depression, no study has attempted to test their utility in preventing depressive symptoms. The aim of this exploratory study is to contrast the efficacy of a smartphone app in reducing cognitive vulnerability and mild depressive symptoms, as risk factors for the onset of depression, against a wait-list condition. More specifically, we aim to test an app designed to (1) decrease general cognitive vulnerability and (2) promote engagement in protective, adaptive activities, while (3) counteracting (through gamification and customization) the tendency of premature dropout from intervention. METHODS/DESIGN: Romanian-speaking adults (18 years and older) with access to a computer and the Internet and who own a smartphone are included in the study. Two parallel randomized clinical trials are conducted: in the first one, 50 participants free of depressive symptoms (i.e., who obtain scores <=4 on the Patient Health Questionnaire, PHQ-9) will be included, while in the second one 50 participants with minimal depressive symptoms (i.e., who obtain PHQ-9 scores between 5 and 9) will be included. Participants undergoing therapy, presenting with substance abuse problems, psychotic symptoms, and organic brain disorders, or serious legal or health issues that would prevent them from using the app, as well as participants reporting suicidal ideation are excluded. Participants randomized to the active intervention will autonomously use the smartphone app for 4 weeks, while the others will be given access to the app after 4 weeks from randomization. The primary outcomes are (1) cognitive vulnerability factors as defined within the cognitive behavioral therapy (CBT) paradigm (i.e., dysfunctional cognitions, irrational beliefs, and negative automatic thoughts) (for the first trial), and (2) level of depressive symptomatology (for the second trial). The app includes self-help materials and exercises based on CBT for depression, presented in a tailored manner and incorporating gamification elements aimed at boosting motivation to use the app. DISCUSSION: This study protocol is the first to capitalize on the ubiquity of smartphones to large-scale dissemination of CBT based strategies aimed at preventing depression in non-clinical populations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02783118 . Registered on 26 May 2016. PMID- 28031039 TI - Attention training for infants at familial risk of ADHD (INTERSTAARS): study protocol for a randomised controlled trial. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder that can negatively impact on an individual's quality of life. It is pathophysiologically complex and heterogeneous with different neuropsychological processes being impaired in different individuals. Executive function deficits, including those affecting attention, working memory and inhibitory control, are common. Cognitive training has been promoted as a treatment option, based on the notion that by strengthening the neurocognitive networks underlying these executive processes, ADHD symptoms will also be reduced. However, if implemented in childhood or later, when the full disorder has become well-established, cognitive training has only limited value. INTERSTAARS is a trial designed to test a novel approach to intervention, in which cognitive training is implemented early in development, before the emergence of the disorder. The aim of INTERSTAARS is to train early executive skills, thereby increasing resilience and reducing later ADHD symptoms and associated impairment. METHODS/DESIGN: Fifty 10-14-month-old infants at familial risk of ADHD will participate in INTERSTAARS. Infants will be randomised to an intervention or a control group. The intervention aims to train early attention skills by using novel eye-tracking technology and gaze-contingent training paradigms. Infants view animated games on a screen and different events take place contingent on where on the screen the infant is looking. Infants allocated to the intervention will receive nine weekly home-based attention training sessions. Control group infants will also receive nine weekly home visits, but instead of viewing the training games during these visits they will view non-gaze contingent age-appropriate videos. At baseline and post treatment, infant attention control will be assessed using a range of eye-tracking, observational, parent-report and neurophysiological measures. The primary outcome will be a composite of eye-tracking tasks used to assess infant attention skills. Follow-up data will be collected on emerging ADHD symptoms when the infants are 2 and 3 years old. DISCUSSION: This is the first randomised controlled trial to assess the potential efficacy of cognitive training as a prevention measure for infants at familial risk of ADHD. If successful, INTERSTAARS could offer a promising new approach for developing early interventions for ADHD. TRIAL REGISTRATION: International Standard Randomised Controlled Trial registry: ISRCTN37683928 . Registered on 22 June 2015. PMID- 28031040 TI - When a vehicle becomes a weapon: intentional vehicular assaults in Israel. AB - BACKGROUND: We have recently witnessed an epidemic of intentional vehicular assaults (IVA) aimed at pedestrians. We hypothesized that IVA are associated with a specific injury pattern and severity. METHODS: Retrospective analysis of prospectively acquired data of patients injured following IVA from October 2008 to May 2016 who were admitted to the Hadassah Level I trauma center in Jerusalem, Israel. Comparison of injury parameters and outcome caused by vehicular attacks to non-intentional pedestrian trauma (PT). Measured outcomes included ISS, AIS, injury pattern, ICU and blood requirements, participating teams, length of stay, and mortality. RESULTS: There were 26 patients in the IVA group. Mean age in the IVA group was significantly younger and there were more males compared to the PT group (24.7 +/- 13.3 years vs. 48.3 +/- 21.3, and 81% vs. 52%, respectively, p < 0.01). Lower extremity (77% of patients), followed by head (58%) and facial (54%) injuries were most commonly injured in the IVA group, and this was significantly different from the pattern of injury in the PT group (54, 35, and 28%, respectively, p < 0.05). Mean ISS and median head AIS were significantly higher in the IVA group compared with the PT group (23.2 +/- 12.8 vs. 15.4 +/- 13.8, p = 0.012, and 4.5 vs. 3, p = 0.003, respectively). ICU admission and blood requirement were significantly higher in the IVA group (69% vs. 38%, and 50% vs. 19%, p < 0.01). Mortality was significantly higher in the IVA group (4 patients, 15%, vs. 3 patients, 4%, respectively, p = 0.036) and was caused by severe head trauma in all cases. DISCUSSION: The severity of injury and mortality rate following IVA are higher compared with pedestrian injury. The pattern of injury following IVA is significantly different from non-intentional pedestrian trauma. CONCLUSIONS: IVA results in higher mortality than conventional pedestrian trauma secondary to more severe head injury. More hospital resources are required following IVA than following conventional road traffic accidents. PMID- 28031041 TI - Building health research systems: WHO is generating global perspectives, and who's celebrating national successes? AB - In 2016, England's National Institute for Health Research (NIHR) celebrated its tenth anniversary as an innovative national health research system with a focus on meeting patients' needs. This provides a good opportunity to reflect on how the creation of the NIHR has greatly enhanced important work, started in 1991, to develop a health research system in England that is embedded in the National Health Service.In 2004, WHO identified a range of functions that a national health research system should undertake to improve the health of populations. Health Research Policy and Systems (HRPS) has taken particular interest in the pioneering developments in the English health research system, where the comprehensive approach has covered most, if not all, of the functions identified by WHO. Furthermore, several significant recent developments in thinking about health research are relevant for the NIHR and have informed accounts of its achievements. These include recognition of the need to combat waste in health research, which had been identified as a global problem in successive papers in the Lancet, and an increasing emphasis on demonstrating impact. Here, pioneering evaluation of United Kingdom research, conducted through the impact case studies of the Research Excellence Framework, is particularly important. Analyses informed by these and other approaches identified many aspects of NIHR's progress in combating waste, building and sustaining research capacity, creating centres of research excellence linked to leading healthcare institutions, developing research networks, involving patients and others in identifying research needs, and producing and adopting research findings that are improving health outcomes.The NIHR's overall success, and an analysis of the remaining problems, might have lessons for other systems, notwithstanding important advances in many countries, as described in papers in HRPS and elsewhere. WHO's recently established Global Observatory for Health Research and Development provides an opportunity to promote some of these lessons. To inform its work, the Observatory is sponsoring a thematic series of papers in HRPS focusing on health research issues such as funding flows, priority setting, capacity building, utilisation and equity. While important papers on these have been published, this series is still open to new submissions. PMID- 28031042 TI - Transitional cell carcinoma with extension of the renal vein and IVC tumor thrombus: report of three cases and literature review. AB - BACKGROUND: Transitional cell carcinoma (TCC) originating from the renal pelvis with a venous tumor thrombus is a rare entity. However, clinicians should be aware of it because of its high malignancy and poor prognosis. CASE PRESENTATION: Here, we report three cases of pathologically confirmed TCC originating from the renal pelvis with extension into the renal vein or inferior vena cava (IVC). Of these patients, two are males and one is female (58~73 years old). Their main symptom is flank pain; besides, gross hematuria and weight loss is observed in one of the patients. Computed tomography (CT) scan of the first patient revealed multiple space-occupying lesions in the left renal pelvis and left medium and lower ureter with a tumor thrombus in the left renal vein. CT scan of the second patient revealed a right renal mass and extension into the IVC. Abdominal magnetic resonance imaging (MRI) of the third patient showed a soft tissue mass in the region of the left renal sinus, and the signal of the soft tissue was observed in the left renal vein. The preoperative diagnoses of the first and third patient were TCC, while the second patient was renal cell carcinoma (RCC). Two patients with the preoperative diagnosis of TCC underwent laparoscopic radical nephroureterectomy with thrombectomy, and the other patient underwent radical nephrectomy with thrombectomy. The surgeries were successful. Although two of our patients underwent chemotherapy and radiotherapy, they died 2 and 19 months after the surgery, respectively. The other patient refused any adjuvant therapy and died 3 months after the operation. CONCLUSIONS: Compared to the extension of RCC to the renal vein or IVC, extension of TCC to the renal vein or IVC is rare. TCC with a venous tumor thrombus is often misdiagnosed as RCC. However, a correct preoperative or intraoperative diagnosis is of great importance to decide surgical strategy. Laparoscopic radical nephroureterectomy with thrombectomy may be a safe and feasible operative method in treatment of TCC with a renal vein thrombus. The prognosis of such cases is poor even if chemotherapy and radiotherapy are scheduled. PMID- 28031043 TI - Small interfering RNA targeting NF-kappaB attenuates lipopolysaccharide-induced acute lung injury in rats. AB - BACKGROUND: To investigate the anti-inflammatory effects of specific small interfering RNA targeting NF-kappaB on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. METHOD: Acute lung injury was induced in Sprague Dawley rats by intraperitoneal injection with LPS (5 mg/kg), followed by immediate intratracheal instillation of siRNA targeting NF-kappaB p65 (40 MUg/ml). Animals in each group were sacrificed at 1 h or 8 h after the instillation. Pulmonary histological changes were evaluated by hematoxylin-eosin staining. The levels of NF-kappaB and TNF-alpha were measured by qRT-PCR. Expressions of NF-kappaB in lung cells and TNF-alpha in bronchoalveolar lavage fluid (BALF) were determined by western blot analysis and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: LPS administration reduced the rectal temperature and white blood cell counts at 1 h, increased lung wet/dry weight ratios, caused evident lung histopathological injury, and increased the detectable transcript and cytokine levels of TNF-alpha in lung tissue in BALF. siRNA targeting of NF-kappaB p65 effectively abrogated the expression of NF kappaB p65 in lung cells and, aside from rectal temperatures, ameliorated all changes induced by LPS. CONCLUSIONS: NF-kappaB knockdown exerts anti-inflammatory effects on LPS-induced ALI especially in the initial phase, which may be due in part to reduced levels of the proinflammatory cytokine TNF-alpha. NF-kappaB siRNA's rapidity and effectiveness to abrogate ALI development may provide an effective therapeutic method with future clinical applications. PMID- 28031044 TI - Coping with stress in medical students: results of a randomized controlled trial using a mindfulness-based stress prevention training (MediMind) in Germany. AB - BACKGROUND: High prevalence rates of psychological distress in medical training and later professional life indicate a need for prevention. Different types of intervention were shown to have good effects, but little is known about the relative efficacy of different types of stress management interventions, and methodological limitations have been reported. In order to overcome some of these limitations, the present study aimed at evaluating the effect of a specifically developed mindfulness-based stress prevention training for medical students (MediMind) on measures of distress, coping and psychological morbidity. METHODS: We report on a prospective randomized controlled trial with three study conditions: experimental treatment (MediMind), standard treatment (Autogenic Training) and a control group without treatment. The sample consisted of medical or dental students in the second or eighth semester. They completed self-report questionnaires at baseline, after the training and at one year follow-up. Distress (Trier Inventory for the Assessment of Chronic Stress, TICS) was assessed as the primary outcome and coping (Brief COPE) as a co-primary outcome. Effects on the psychological morbidity (Brief Symptom Inventory, BSI) as a secondary outcome were expected one year after the trainings. RESULTS: Initially, N = 183 students were randomly allocated to the study groups. At one year follow up N = 80 could be included into the per-protocol analysis: MediMind (n =31), Autogenic Training (n = 32) and control group (n = 17). A selective drop-out for students who suffered more often from psychological symptoms was detected (p = .020). MANCOVA's on TICS and Brief COPE revealed no significant interaction effects. On the BSI, a significant overall interaction effect became apparent (p = .002, eta2partial = .382), but post hoc analyses were not significant. Means of the Global Severity Index (BSI) indicated that MediMind may contribute to a decrease in psychological morbidity. CONCLUSION: Due to the high and selective dropout rates, the results cannot be generalized and further research is necessary. Since the participation rate of the trainings was high, a need for further prevention programs is indicated. The study gives important suggestions on further implementation and evaluation of stress prevention in medical schools. TRIAL REGISTRATION: This trial is recorded at German Clinical Trials Register under the number DRKS00005354 (08.11.2013). PMID- 28031045 TI - Expansion of the molecular and morphological diversity of Acanthamoebidae (Centramoebida, Amoebozoa) and identification of a novel life cycle type within the group. AB - BACKGROUND: Acanthamoebidae is a "family" level amoebozoan group composed of the genera Acanthamoeba, Protacanthamoeba, and very recently Luapeleamoeba. This clade of amoebozoans has received considerable attention from the broader scientific community as Acanthamoeba spp. represent both model organisms and human pathogens. While the classical composition of the group (Acanthamoeba + Protacanthamoeba) has been well accepted due to the morphological and ultrastructural similarities of its members, the Acanthamoebidae has never been highly statistically supported in single gene phylogenetic reconstructions of Amoebozoa either by maximum likelihood (ML) or Bayesian analyses. RESULTS: Here we show using a phylogenomic approach that the Acanthamoebidae is a fully supported monophyletic group within Amoebozoa with both ML and Bayesian analyses. We also expand the known range of morphological and life cycle diversity found in the Acanthamoebidae by demonstrating that the amoebozoans "Protostelium" arachisporum, Dracoamoeba jormungandri n. g. n. sp., and Vacuolamoeba acanthoformis n.g. n.sp., belong within the group. We also found that "Protostelium" pyriformis is clearly a species of Acanthamoeba making it the first reported sporocarpic member of the genus, that is, an amoeba that individually forms a walled, dormant propagule elevated by a non-cellular stalk. Our phylogenetic analyses recover a fully supported Acanthamoebidae composed of five genera. Two of these genera (Acanthamoeba and Luapeleameoba) have members that are sporocarpic. CONCLUSIONS: Our results provide high statistical support for an Acanthamoebidae that is composed of five distinct genera. This study increases the known morphological diversity of this group and shows that species of Acanthamoeba can include spore-bearing stages. This further illustrates the widespread nature of spore-bearing stages across the tree of Amoebozoa. REVIEWERS: This article was reviewed by Drs. Eugene Koonin, Purificacion Lopez Garcia and Sandra Baldauf. Sandra Baldauf was nominated by Purificacion Lopez Garcia, an Editorial Board member. PMID- 28031046 TI - What is the effectiveness of obesity related interventions at retail grocery stores and supermarkets? -a systematic review. AB - BACKGROUND: The Prevalence of obesity and overweight has been increasing in many countries. Many factors have been identified as contributing to obesity including the food environment, especially the access, availability and affordability of healthy foods in grocery stores and supermarkets. Several interventions have been carried out in retail grocery/supermarket settings as part of an effort to understand and influence consumption of healthful foods. The review's key outcome variable is sale/purchase of healthy foods as a result of the interventions. This systematic review sheds light on the effectiveness of food store interventions intended to promote the consumption of healthy foods and the methodological quality of studies reporting them. METHODS: Systematic literature search spanning from 2003 to 2015 (inclusive both years), and confined to papers in the English language was conducted. Studies fulfilling search criteria were identified and critically appraised. Studies included in this review report health interventions at physical food stores including supermarkets and corner stores, and with outcome variable of adopting healthier food purchasing/consumption behavior. The methodological quality of all included articles has been determined using a validated 16-item quality assessment tool (QATSDD). RESULTS: The literature search identified 1580 publications, of which 42 met the inclusion criteria. Most interventions used a combination of information (e.g. awareness raising through food labeling, promotions, campaigns, etc.) and increasing availability of healthy foods such as fruits and vegetables. Few used price interventions. The average quality score for all papers is 65.0%, or an overall medium methodological quality. Apart from few studies, most studies reported that store interventions were effective in promoting purchase of healthy foods. CONCLUSION: Given the diverse study settings and despite the challenges of methodological quality for some papers, we find efficacy of in-store healthy food interventions in terms of increased purchase of healthy foods. Researchers need to take risk of bias and methodological quality into account when designing future studies that should guide policy makers. Interventions which combine price, information and easy access to and availability of healthy foods with interactive and engaging nutrition information, if carefully designed can help customers of food stores to buy and consume more healthy foods. PMID- 28031047 TI - Pathological fractures in predicting clinical outcomes for patients with osteosarcoma. AB - BACKGROUND: Studies reported contradictory results for the prognostic significance of a pathological fracture in osteosarcoma patients. The aim of this study is to report the outcomes for a cohort of patients with osteosarcoma who presented with and without pathological fractures and to identify the prognostic importance of pathological fracture in predicting outcomes and influences on survival. METHODS: Data of patients with osteosarcoma were retrospectively reviewed. Between March 1992 and June 2014, a total of 268 patients with osteosarcoma were included in this analysis, of whom 34 (12.7%) with fractures at diagnosis or sustained after chemotherapy and 234 (87.3%) without fracture. All patients were treated with approaches that integrated chemotherapy and surgical resections to maximal extent of all sites whenever feasible. The association between potential prognostic factors and survival for these patients were analyzed and compared. RESULTS: No significant difference was observed in overall survival, progression free survival, and disease free survival between osteosarcoma patients with pathological fractures and without fracture. The patients without fracture had a 5-year survival of 50% and 10-year survival of 21%, in contrast to 37% (5-year) and 22% (10-year) in patients with fractures. Lung metastasis was the significant predictor for the presence of fractures. Advanced stage (III) of tumor, lung metastasis, poor response to chemotherapy, and local recurrence were associated increased risk for death in all osteosarcoma patients. CONCLUSION: Pathological fracture is not a predictor of worse survival in this study. Further studies with matched cases are needed to confirm our observations. PMID- 28031048 TI - China's community-based strategy of universal preconception care in rural areas at a population level using a novel risk classification system for stratifying couples' preconception health status. AB - BACKGROUND: Preconception care (PCC) is recommended for optimizing a woman's health prior to pregnancy to minimize the risk of adverse pregnancy and birth outcomes. We aimed to evaluate the impact of strategy and a novel risk classification model of China's "National Preconception Health Care Project" (NPHCP) in identifying risk factors and stratifying couples' preconception health status. METHODS: We performed a secondary analysis of data collected by NPHCP during April 2010 to December 2012 in 220 selected counties in China. All couples enrolled in the project accepted free preconception health examination, risk evaluation, health education and medical advice. Risk factors were categorized into five preconception risk classes based on their amenability to prevention and treatment: A-avoidable risk factors, B- benefiting from targeted medical intervention, C-controllable but requiring close monitoring and treatment during pregnancy, D-diagnosable prenatally but not modifiable preconceptionally, X pregnancy not advisable. Information on each couple's socio-demographic and health status was recorded and further analyzed. RESULTS: Among the 2,142,849 couples who were enrolled to this study, the majority (92.36%) were from rural areas with low education levels (89.2% women and 88.3% men had education below university level). A total of 1463266 (68.29%) couples had one or more preconception risk factors mainly of category A, B and C, among which 46.25% were women and 51.92% were men. Category A risk factors were more common among men compared with women (38.13% versus 11.24%; P = 0.000). CONCLUSIONS: This project provided new insights into preconception health of Chinese couples of reproductive age. More than half of the male partners planning to father a child, were exposed to risk factors during the preconception period, suggesting that an integrated approach to PCC including both women and men is justified. Stratification based on the new risk classification model demonstrated that a majority of the risk factors are avoidable, or preventable by medical intervention. Therefore, universal free PCC can be expected to improve pregnancy outcomes in rural China. PMID- 28031049 TI - Clinical and radiological features driving patient selection for antiangiogenic therapy in non-small cell lung cancer (NSCLC). AB - BACKGROUND: The use of antiangiogenic therapy in non-small cell lung cancer (NSCLC) requires thorough evaluation of patient characteristics in order to avoid potential safety issues, particularly pulmonary haemorrhage (PH). The aim of this consensus by a panel of experts was to identify important criteria for the selection of patients with NSCLC who would benefit from antiangiogenic therapy. METHODS: Radiologists and oncologists were selected for the expert panel. The nominal group technique (NGT) and the Delphi questionnaire were used for consensus generation. The NGT consisted of four steps, the result of which was used to set the Delphi questionnaire. A final report was generated based on the opinions of the experts from the panel. RESULTS: An extremely important prerequisite for the evaluation of an antiangiogenic therapeutic approach in patients with NSCLC was thorough clinical and radiological analysis of the relationships between tumour and vascular or anatomical structures (performed in close co-operation by oncologists and radiologists). The panel identified major parameters to be considered before the use of antiangiogenic treatment, collectively agreeing on the relevance of tumour cavitation, vascular infiltration, endobronchial growth and thromboembolism for chest tumour sites, and of the presence of aneurysms, extra-thoracic bleeding, brain metastases or thrombi for extra-thoracic sites. Moreover, a structured report containing information not only on the tumour but also on the general vascular status is essential to guide the treatment choice The experts agreed that tumour localization in the absence of vessel infiltration, cavitation, and the use of antiplatelet therapy are relevant parameters to be assessed, but their presence should not necessarily exclude a patient from receiving antiangiogenic therapy. CONCLUSION: Close co-operation between oncologists and radiologists in the diagnosis, treatment selection, and assessment of response is essential for ensuring therapeutic appropriateness in the NSCLC setting. It should be noted that neither the use of antiplatelet therapy nor tumour localisation are to be considered as contraindications to antiangiogenic treatment. PMID- 28031051 TI - The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma. AB - Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutant-enriched PCR Kits (FemtoPath(r)), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I). PMID- 28031050 TI - Prognostic factors and failure patterns in non-metastatic nasopharyngeal carcinoma after intensity-modulated radiotherapy. AB - BACKGROUND: The prognostic values of staging parameters require continual re assessment amid changes in diagnostic and therapeutic methods. This study aimed to identify the prognostic factors and failure patterns of non-metastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. METHODS: We reviewed the data from 749 patients with newly diagnosed, biopsy proven, non-metastatic NPC in our cancer center (South China, an NPC endemic area) between January 2003 and December 2007. All patients underwent magnetic resonance imaging (MRI) before receiving IMRT. The actuarial survival rates were estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Multivariate analyses with the Cox proportional hazards model were used to test for the independent prognostic factors by backward eliminating insignificant explanatory variables. RESULTS: The 5-year occurrence rates of local failure, regional failure, locoregional failure, and distant failure were 5.4, 3.0, 7.4, and 17.4%, respectively. The 5-year survival rates were as follows: local relapse-free survival, 94.6%; nodal relapse-free survival, 97.0%; distant metastasis-free survival, 82.6%; disease-free survival, 75.1%; and overall survival, 82.0%. Multivariate Cox regression analysis revealed that orbit involvement was the only significant prognostic factor for local failure (P = 0.011). Parapharyngeal tumor extension, retropharyngeal lymph node involvement, and the laterality, longest diameter, and Ho's location of the cervical lymph nodes were significant prognostic factors for both distant failure and disease failure (all P < 0.05). Intracranial extension had significant prognostic value for distant failure (P = 0.040). CONCLUSIONS: The key failure pattern for NPC was distant metastasis in the IMRT era. With changes in diagnostic and therapeutic technologies as well as treatment modalities, the significant prognostic parameters for local control have also been altered substantially. PMID- 28031052 TI - Defeating cancer: the 150 most important questions in cancer research and clinical oncology. PMID- 28031054 TI - Decreased lymphocyte dopamine transporter in romantic lovers. AB - OBJECTIVE: The role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship. METHODS: All subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us. RESULTS: The results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax). CONCLUSIONS: Taken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling. PMID- 28031053 TI - Serum biomarkers and changes in clinical/MRI evidence of golimumab-treated patients with ankylosing spondylitis: results of the randomized, placebo controlled GO-RAISE study. AB - BACKGROUND: In the present study, we evaluated relationships between serum biomarkers and clinical/magnetic resonance imaging (MRI) findings in golimumab treated patients with ankylosing spondylitis. METHODS: In the GO-RAISE study, 356 patients with ankylosing spondylitis randomly received either placebo (n = 78) or golimumab 50 mg or 100 mg (n = 278) injections every 4 weeks through week 24 (placebo-controlled); patients continuing GO-RAISE received golimumab through week 252. Up to 139/125 patients had sera collected for biomarkers/serial spine MRI scans (sagittal plane, 1.5-T scanner). Two blinded readers employed modified ankylosing spondylitis spine magnetic resonance imaging score for activity (ASspiMRI-a) and ankylosing spondylitis spine magnetic resonance imaging score for chronicity. Spearman correlations (r s) were assessed between serum biomarkers (n = 73) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive-protein (CRP)-based Ankylosing Spondylitis Disease Activity Score (ASDAS), modified Stokes Ankylosing Spondylitis Spine Score (mSASSS), and ASspiMRI scores. Serum biomarkers predicting postbaseline spinal fatty lesion development and inflammation were analyzed by logistic regression. RESULTS: Significant, moderately strong correlations were observed between baseline inflammatory markers interleukin (IL)-6, intracellular adhesion molecule-1, complement component 3 (C3), CRP, haptoglobin, and serum amyloid-P and baseline ASDAS (r s = 0.39-0.66, p <= 0.01). Only baseline leptin significantly correlated with ASDAS improvement at week 104 (r s = 0.55, p = 0.040), and only baseline IL 6 significantly predicted mSASSS week 104 change (beta = 0.236, SE = 0.073, p = 0.002, model R 2 = 0.093). By logistic regression, baseline leptin, C3, and tissue inhibitor of metalloproteinase (TIMP)-1 correlated with new fatty lesions per spinal MRI at week 14 and week 104 (both p < 0.01). Changes in serum C3 levels at week 4 (r s = 0.55, p = 0.001) and week 14 (r s = 0.49, p = 0.040) significantly correlated with BASDAI improvement at week 14. Baseline IL-6 and TIMP-1 (r s = -0.63, -0.67; p < 0.05) and reductions at week 4 in IL-6 (r s = 0.61, p < 0.05) and C3 (r s = 0.72; p < 0.05) significantly correlated with week 14 ASspiMRI-a improvement. CONCLUSIONS: Extensive serum biomarker multiparametric analyses in golimumab-treated patients with ankylosing spondylitis demonstrated few correlations with disease activity or MRI changes; IL-6 weakly correlated with radiographic progression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00265083 . Registered on 12 December 2005. PMID- 28031055 TI - THE RETURNS OF FAMILY PLANNING: MACRO-LEVEL ASSESSMENT OF THE EFFECT OF CONTRACEPTIVE USE ON WOMEN'S ANAEMIA AND CHILDHOOD UNDERNUTRITION. AB - This study investigated the effect of family planning on the levels of women's anaemia and child undernutrition at the aggregate level using the compiled databases of the World Bank, UNICEF and the Economist Intelligence Unit. Correlation scatter matrix plots and multivariate OLS regression models were employed to assess the effect of family planning on women's anaemia and child nutritional status across countries. At the aggregate level, the bivariate correlation estimates found that the Contraceptive Prevalence Rate (CPR) was negatively associated with women's anaemia (r=-0.62, p<0.01), child underweight (r=-0.57, p<0.01) and child stunting (r=-0.63, p<0.01). The results of the OLS regression showed that the independent effect of CPR on women's anaemia (beta= 0.35, p<0.01), child underweight (beta=-0.13, p<0.01) and child stunting (beta= 0.18, p<0.05) was negative, even after controlling for child marriage, female literacy, per capita GDP, poverty ratio, health expenditure and food security. The synthesis of these findings with the existing literature based on micro-data suggests pathways through which family planning influences the nutritional status of women and children. Family planning helps in avoiding shorter birth intervals, unintended pregnancy and unsafe abortion, which would otherwise result in nutrient depletion among mothers and further increase the risk of undernutrition in their children. PMID- 28031056 TI - Affective startle potentiation differentiates primary and secondary variants of juvenile psychopathy. AB - Individuals with psychopathic traits show an attenuated emotional response to aversive stimuli. However, recent evidence suggests heterogeneity in emotional reactivity among individuals with psychopathic or callous-unemotional (CU) traits in the identification of primary and secondary subtypes, or variants. We hypothesized that primary CU variants will respond with blunted affect to negatively valenced stimuli, whereas individuals with a history of childhood maltreatment, fitting with theoretical conceptualizations of secondary psychopathy, will display heightened emotional reactivity. To test this hypothesis, we examined fear-potentiated startle between CU variants while viewing aversive, pleasant, and neutral scenes. Two hundred thirty-eight incarcerated adolescent (M age = 16.8 years, SD = 1.11 years) boys completed a picture-startle paradigm and self-report questionnaires assessing CU traits, aggressive behavior, and maltreatment. Latent profile analysis of CU trait, aggression, and maltreatment scores identified four classes: primary psychopathy variants (high CU traits, high aggression, low maltreatment; n = 46), secondary psychopathy variants (high CU traits, high aggression, high maltreatment; n = 42), and two nonpsychopathic groups differentiated on maltreatment experience (n = 148). Primary CU variants displayed reduced startle potentiation to aversive images relative to control, maltreated, and also secondary variants that exhibited greater startle modulation. Findings add to a rapidly growing body of literature supporting the possibility of multiple developmental pathways to psychopathic traits (i.e., equifinality), and extend it by finding support for divergent potential biomarkers between primary and secondary CU variants. PMID- 28031057 TI - Examining bidirectional relationships between parenting and child maladjustment in youth with autism spectrum disorder: A 9-year longitudinal study. AB - Longitudinal bidirectional effects between parents and children are usually studied in samples of typically developing children, but remain understudied in families with a child with autism spectrum disorder. This three-wave longitudinal study examined how parents and children with autism spectrum disorder influence one another, relying on parent reports of parenting behaviors and children's problem behaviors across 9 years, in a sample of 139 youngsters (M age Time 1 = 10.2 years, 83% boys). Cross-lagged analyses indicated that children's externalizing problems at Time 1 predicted negative controlling parenting 6 years later (Time 2) that in turn predicted externalizing problems 3 years later (Time 3). Negative parental control at Time 1 also increased the risk for internalizing problems at Time 2. It was surprising that externalizing problems at Time 2 also predicted positive parental involvement at Time 3. Thus, although results indicate that externalizing problems generally elicit maladaptive reactions in parents, this study also suggests that parents adjust their way of reacting to externalizing child problems as their child reaches adolescence/emerging adulthood. Implications for future research on parenting dynamics in families with a child with autism spectrum disorder are discussed. PMID- 28031058 TI - ASSESSMENT OF KNOWLEDGE, ATTITUDE AND PRACTICE TOWARDS CONSANGUINEOUS MARRIAGES AMONG A COHORT OF MULTIETHNIC HEALTH CARE PROVIDERS IN SAUDI ARABIA. AB - This study aimed to assess knowledge, attitude and practice related to consanguinity among multiethnic health care providers in the Kingdom of Saudi Arabia. Using a cross-sectional study design, a validated, self-administered close-ended questionnaire was randomly distributed to health care providers in different health institutions in the country between 1st August 2012 and 31st July 2013. A total of 1235 health care providers completed the study questionnaire. Of the 892 married participants (72.23% of total), 11.43% were married to a first cousin, and were predominantly Arabs, younger than 40 years and male. Only 17.80% of the patients seen by the health care providers requested consanguinity related counselling. A knowledge barrier was expressed by 27.49% of the participants, and 85.67% indicated their willingness to have more training in basic genetic counselling. A language barrier was expressed as a limiting factor to counselling for consanguinity among non-Arabs. The health care providers had a major dearth of knowledge that was reflected in their attitude and practice towards consanguinity counselling. This finding indicates the need for more undergraduate and postgraduate medical and nursing education and training in the counselling of consanguineous couples. It is recommended that consanguinity counselling is included in the current premarital screening and counselling programmes in the Kingdom. PMID- 28031060 TI - Furthering food security surveillance in Australia. PMID- 28031059 TI - Suicide ideation among high-risk adolescent females: Examining the interplay between parasympathetic regulation and friendship support. AB - Poor physiological self-regulation has been proposed as a potential biological vulnerability for adolescent suicidality. This study tested this hypothesis by examining the effect of parasympathetic stress responses on future suicide ideation. In addition, drawing from multilevel developmental psychopathology theories, the interplay between parasympathetic regulation and friendship support, conceptualized as an external source of regulation, was examined. At baseline, 132 adolescent females (M age = 14.59, SD = 1.39) with a history of mental health concerns participated in an in vivo interpersonal stressor (a laboratory speech task) and completed self-report measures of depressive symptoms and perceived support within a close same-age female friendship. Respiratory sinus arrhythmia (RSA) was measured before and during the speech task. Suicide ideation was assessed at baseline and at 3, 6, and 9 months follow-up. The results revealed that females with greater relative RSA decreases to the laboratory stressor were at higher risk for reporting suicide ideation over the subsequent 9 months. Moreover, parasympathetic responses moderated the effect of friendship support on suicide ideation; among females with mild changes or higher relative increases in RSA, but not more pronounced RSA decreases, friendship support reduced risk for future suicide ideation. Findings highlight the crucial role of physiological and external regulation sources as protective factors for youth suicidality. PMID- 28031061 TI - Which Comorbid Conditions Should We Be Analyzing as Risk Factors for Healthcare Associated Infections? AB - OBJECTIVE To determine which comorbid conditions are considered causally related to central-line associated bloodstream infection (CLABSI) and surgical-site infection (SSI) based on expert consensus. DESIGN Using the Delphi method, we administered an iterative, 2-round survey to 9 infectious disease and infection control experts from the United States. METHODS Based on our selection of components from the Charlson and Elixhauser comorbidity indices, 35 different comorbid conditions were rated from 1 (not at all related) to 5 (strongly related) by each expert separately for CLABSI and SSI, based on perceived relatedness to the outcome. To assign expert consensus on causal relatedness for each comorbid condition, all 3 of the following criteria had to be met at the end of the second round: (1) a majority (>50%) of experts rating the condition at 3 (somewhat related) or higher, (2) interquartile range (IQR)<=1, and (3) standard deviation (SD)<=1. RESULTS From round 1 to round 2, the IQR and SD, respectively, decreased for ratings of 21 of 35 (60%) and 33 of 35 (94%) comorbid conditions for CLABSI, and for 17 of 35 (49%) and 32 of 35 (91%) comorbid conditions for SSI, suggesting improvement in consensus among this group of experts. At the end of round 2, 13 of 35 (37%) and 17 of 35 (49%) comorbid conditions were perceived as causally related to CLABSI and SSI, respectively. CONCLUSIONS Our results have produced a list of comorbid conditions that should be analyzed as risk factors for and further explored for risk adjustment of CLABSI and SSI. Infect Control Hosp Epidemiol 2017;38:449-454. PMID- 28031062 TI - Maximizing the benefits of ART and PrEP in resource-limited settings. AB - Antiretroviral therapy (ART) is increasingly being used as an HIV-prevention tool, administered to uninfected people with ongoing HIV exposure as pre-exposure prophylaxis (PrEP) and to infected people to reduce their infectiousness. We used a modelling approach to determine the optimal population-level combination of ART and PrEP allocations required in South Africa to maximize programme effectiveness for four outcome measures: new infections, infection-years, death and cost. We considered two different strategies for allocating treatment, one that selectively allocates drugs to sex workers and one that does not. We found that for low treatment availability, prevention through PrEP to the general population or PrEP and ART to sex workers is key to maximizing effectiveness, while for higher drug availability, ART to the general population is optimal. At South Africa's current level of treatment availability, using prevention is most effective at reducing new infections, infection-years, and cost, while using the treatment as ART to the general population best reduces deaths. At treatment levels that meet the UNAIDS's ambitious new 90-90-90 target, using all or almost all treatment as ART to the general population best reduces all four outcome measures considered. PMID- 28031063 TI - Risk factors for secondary post-tonsillectomy haemorrhage following tonsillectomy with bipolar scissors: four-year retrospective cohort study. AB - OBJECTIVE: To analyse risk factors associated with secondary post-operative bleeding when only one technique, namely bipolar scissors, is used. METHODS: The medical records of all consecutive patients aged six years or older who underwent tonsillectomy or adenotonsillectomy between 1 December 2010 and 30 November 2014 were retrospectively analysed. RESULTS: A total of 1734 patients were included in the study. A secondary haemorrhage occurred in 208 patients (12 per cent). Patients aged 15 years or older were 4.5 times (95 per cent confidence interval = 2.6-7.9; p < 0.001) more likely to experience secondary haemorrhage. In cases of acute quinsy, patients aged 15 years or older had an 8.1-fold (95 per cent confidence interval = 1.1-59.6; p = 0.02) increased likelihood of experiencing secondary haemorrhage. CONCLUSION: Patients aged 15 years or older have a higher risk for bleeding regardless of the primary indication for the tonsillectomy. The risk for secondary haemorrhage does not seem to depend on the primary indication itself. PMID- 28031064 TI - Impact of food supplementation on weight loss in randomised controlled dietary trials: a systematic review and meta-analysis - CORRIGENDUM. PMID- 28031065 TI - Phenotypic and genetic associations between reading and attention deficit/hyperactivity disorder dimensions in adolescence. AB - Multiple studies have shown that reading abilities and attention deficit/hyperactivity disorder symptoms, mainly inattention symptoms, are phenotypically and genetically associated during childhood. However, few studies have looked at these associations during adolescence to investigate possible developmental changes. The aim of the study is to examine the genetic and environmental etiology of the associations between inattention and hyperactivity reported by parents, and reading accuracy, reading speed, and word reading in a population-based twin sample (Quebec Newborn Twin Study). Participants were between 14 and 15 years of age at the time of testing (N = 668-837). Phenotypic results showed that when nonverbal and verbal abilities were controlled, inattention, but not hyperactivity/impulsivity, was a modest and significant predictor of reading accuracy, reading speed, and word reading. The associations between inattention and all reading abilities were partly explained by genetic and unique environmental factors. However, the genetic correlations were no longer significant after controlling for verbal abilities. In midadolescence, inattention is the attention-deficit/hyperactivity disorder dimension associated with reading abilities, but they could also share genetic factors with general verbal skills. PMID- 28031066 TI - Expression of maspin in invasive fungal rhinosinusitis. AB - OBJECTIVE: This study aimed to test the expression of maspin in invasive fungal rhinosinusitis and explore its value in diagnosing invasive fungal rhinosinusitis. METHODS: Forty-two fungal rhinosinusitis cases (12 invasive and 30 non-invasive) were selected as the experimental group, and 30 chronic rhinosinusitis cases comprised the control group. Maspin expression was assessed in nasal mucous membrane specimens by immunohistochemical staining. RESULTS: Compared with the control group, maspin expression was down-regulated in the fungal rhinosinusitis group (p < 0.05). Furthermore, the staining score for maspin was lowest in the invasive fungal rhinosinusitis group, as compared with both the non-invasive fungal rhinosinusitis group and the control group (p < 0.05). A maspin staining score of 5.70 was the critical value for diagnosis of invasive fungal rhinosinusitis, with sensitivity and specificity of 91.7 per cent and 88.3 per cent, respectively. CONCLUSION: The results of this study suggest that the maspin staining score may be a biomarker for effective and rapid diagnosis of invasive fungal rhinosinusitis. PMID- 28031068 TI - What defines mindfulness-based programs? The warp and the weft. AB - There has been an explosion of interest in mindfulness-based programs (MBPs) such as Mindfulness-Based Stress Reduction (MBSR) and Mindfulness-Based Cognitive Therapy. This is demonstrated in increased research, implementation of MBPs in healthcare, educational, criminal justice and workplace settings, and in mainstream interest. For the sustainable development of the field there is a need to articulate a definition of what an MBP is and what it is not. This paper provides a framework to define the essential characteristics of the family of MBPs originating from the parent program MBSR, and the processes which inform adaptations of MBPs for different populations or contexts. The framework addresses the essential characteristics of the program and of teacher. MBPs: are informed by theories and practices that draw from a confluence of contemplative traditions, science, and the major disciplines of medicine, psychology and education; underpinned by a model of human experience which addresses the causes of human distress and the pathways to relieving it; develop a new relationship with experience characterized by present moment focus, decentering and an approach orientation; catalyze the development of qualities such as joy, compassion, wisdom, equanimity and greater attentional, emotional and behavioral self-regulation, and engage participants in a sustained intensive training in mindfulness meditation practice, in an experiential inquiry-based learning process and in exercises to develop understanding. The paper's aim is to support clarity, which will in turn support the systematic development of MBP research, and the integrity of the field during the process of implementation in the mainstream. PMID- 28031067 TI - Effects of faba beans with different concentrations of vicine and convicine on egg production, egg quality and red blood cells in laying hens. AB - The faba bean (Vicia faba L.) is a potential source of proteins for poultry, mainly for laying hens whose protein requirements are lower than those of other birds such as growing broilers and turkeys. However, this feedstuff contains anti nutritional factors, that is, vicine (V) and convicine (C) that are already known to reduce laying hen performance. The aim of the experiment reported here was to evaluate the effects of a wide range of dietary V and C concentrations in laying hens. Two trials were performed with laying hens fed diets including 20% or 25% of faba bean genotypes highly contrasting in V+C content. In Trial 1, faba beans from two tannin-containing cultivars, but with high or low V+C content were dehulled in order to eliminate the tannin effect. In addition to the contrasting levels of V+C in the two cultivars, two intermediate levels of V+C were obtained by mixing the two cultivars (70/30 and 30/70). In Trial 2, two isogenic zero tannin faba bean genotypes with high or low V+C content were used. In both trials, a classical corn-soybean diet was also offered to control hens. Each experimental diet was given to 48 laying hens for 140 (Trial 1) or 89 (Trial 2) days. Laying performance and egg quality were measured. The redox sensitivity of red blood cells (RBCs) was assessed by measuring hemolysis and reduced glutathione (GSH) concentration in these cells. Egg weight was significantly reduced by the diets containing the highest concentrations of V+C (P<0.0001) in Trial 1 and slightly reduced (P<0.10) in Trial 2, but only weak linear relationships between egg weight and dietary V+C concentration were established. No negative effect of V+C level was observed for egg quality parameters. In contrast, certain parameters (i.e. Haugh units, yolk color) were improved by feeding low V+C diets (P<0.05). Hemolysis of RBCs was higher in hens fed high V+C diets. A decrease in GSH concentration in RBCs of hens fed the highest levels of V+C was observed. Faba bean genotypes with low concentrations of V+C can therefore be used in laying hen diets up to 25% without any detrimental effects on performance levels or egg characteristics, without any risk of hemolysis of RBCs. PMID- 28031070 TI - Mixed features in bipolar disorder. AB - Mixed affective states, defined as the coexistence of depressive and manic symptoms, are complex presentations of manic-depressive illness that represent a challenge for clinicians at the levels of diagnosis, classification, and pharmacological treatment. The evidence shows that patients with bipolar disorder who have manic/hypomanic or depressive episodes with mixed features tend to have a more severe form of bipolar disorder along with a worse course of illness and higher rates of comorbid conditions than those with non-mixed presentations. In the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM 5), the definition of "mixed episode" has been removed, and subthreshold nonoverlapping symptoms of the opposite pole are captured using a "with mixed features" specifier applied to manic, hypomanic, and major depressive episodes. However, the list of symptoms proposed in the DSM-5 specifier has been widely criticized, because it includes typical manic symptoms (such as elevated mood and grandiosity) that are rare among patients with mixed depression, while excluding symptoms (such as irritability, psychomotor agitation, and distractibility) that are frequently reported in these patients. With the new classification, mixed depressive episodes are three times more common in bipolar II compared with unipolar depression, which partly contributes to the increased risk of suicide observed in bipolar depression compared to unipolar depression. Therefore, a specific diagnostic category would imply an increased diagnostic sensitivity, would help to foster early identification of symptoms and ensure specific treatment, as well as play a role in suicide prevention in this population. PMID- 28031069 TI - Adolescent cannabis use, change in neurocognitive function, and high-school graduation: A longitudinal study from early adolescence to young adulthood. AB - The main objective of this prospective longitudinal study was to investigate bidirectional associations between adolescent cannabis use (CU) and neurocognitive performance in a community sample of 294 young men from ages 13 to 20 years. The results showed that in early adolescence, and prior to initiation to CU, poor short-term and working memory, but high verbal IQ, were associated with earlier age of onset of CU. In turn, age of CU onset and CU frequency across adolescence were associated with (a) specific neurocognitive decline in verbal IQ and executive function tasks tapping trial and error learning and reward processing by early adulthood and (b) lower rates of high-school graduation. The association between CU onset and change in neurocognitive function, however, was found to be accounted for by CU frequency. Whereas the link between CU frequency across adolescence and change in verbal IQ was explained (mediated) by high school graduation, the link between CU frequency and tasks tapping trial and error learning were independent from high school graduation, concurrent cannabis and other substance use, adolescent alcohol use, and externalizing behaviors. Findings support prevention efforts aimed at delaying onset and reducing frequency of CU. PMID- 28031071 TI - Emergence of an extended-spectrum beta-lactamase-producing serotype K1 Klebsiella pneumoniae ST23 strain from Asian countries. AB - Extended-spectrum beta-lactamase (ESBL) production has been very rare in serotype K1 Klebsiella pneumoniae ST23 strains, which are well-known invasive community strains. Among 92 ESBL-producing strains identified in 218 isolates from nine Asian countries, serotype K1 K. pneumoniae strains were screened. Two ESBL producing K. pneumoniae isolates from Singapore and Indonesia were determined to be serotype K1 and ST23. Their plasmids, which contain CTX-M-15 genes, are transferable rendering the effective transfer of ESBL resistance plasmids to other organisms. PMID- 28031072 TI - Preparedness in Long-Term Care: A Novel Approach to Address Gaps in Evacuation Tracking. AB - With an aging population, the number of elderly individuals residing in long-term care (LTC) facilities will continue to grow and pose unique challenges to disaster preparedness and response. With this rapidly growing vulnerable population, it becomes imperative to identify enhanced and novel preparedness strategies and measures. LTC residents not only have complicated medical needs, including the timing of dispensing multiple medications, but frequently have cognitive and mobility deficits as well. In nearly every major disaster, elderly populations have suffered disproportionate morbidity and mortality. This is often due to elderly evacuees getting overlooked in the chaos of an initial response. Instituting measures to rapidly recognize this population in a crowd during an evacuation will reduce their risk. This commentary reviews the LTC facility evacuation challenges of the 2013 explosion of the West Fertilizer Company plant in West, Texas, and offers a novel solution of mandating the wearing of pink vests by all nursing home residents in case of an evacuation. The pink vests quickly alert disaster rescue and response workers of LTC residents with special needs. (Disaster Med Public Health Preparedness. 2017;11:28-30). PMID- 28031073 TI - Evaluation of Real-Time Mortality Surveillance Based on Media Reports. AB - OBJECTIVE: We evaluated the usefulness and accuracy of media-reported data for active disaster-related mortality surveillance. METHODS: From October 29 through November 5, 2012, epidemiologists from the Centers for Disease Control and Prevention (CDC) tracked online media reports for Hurricane Sandy-related deaths by use of a keyword search. To evaluate the media-reported data, vital statistics records of Sandy-related deaths were compared to corresponding media-reported deaths and assessed for percentage match. Sensitivity, positive predictive value (PPV), and timeliness of the media reports for detecting Sandy-related deaths were calculated. RESULTS: Ninety-nine media-reported deaths were identified and compared with the 90 vital statistics death records sent to the CDC by New York City (NYC) and the 5 states that agreed to participate in this study. Seventy five (76%) of the media reports matched with vital statistics records. Only NYC was able to actively track Sandy-related deaths during the event. Moderate sensitivity (83%) and PPV (83%) were calculated for the matching media-reported deaths for NYC. CONCLUSIONS: During Hurricane Sandy, the media-reported information was moderately sensitive, and percentage match with vital statistics records was also moderate. The results indicate that online media-reported deaths can be useful as a supplemental source of information for situational awareness and immediate public health decision-making during the initial response stage of a disaster. (Disaster Med Public Health Preparedness. 2017;11:460-466). PMID- 28031074 TI - Improving the Culture of Culturing: Critical Asset to Antimicrobial Stewardship. PMID- 28031076 TI - Assessment of lifetime performance of small ruminants under different feeding systems. AB - Evaluation of lifetime productivity of individual animals in response to various interventions allows assessment of long-term investment opportunities for farmers. In order to gain a better understanding of promising feed interventions for improvement of small ruminant production in Southwestern Nigeria, a dynamic modelling approach was used to explore the effect of different feeding strategies on the lifetime productivity of West African Dwarf (WAD) goats. Modifications were made to the current version of Livestock Simulator developed for cattle production to simulate goat production systems particularly for WAD goats. Effects of changes in input parameters (quality of feed and potential adult weight) confirmed the sensitivity of the modelled weight development and reproductive performance. The values of simulated model outputs corresponded well with observed values for most of the variables, except for the pre-weaning mortality rate in the cut-and-carry system where a wide discrepancy between simulated (2.1%) and observed (23%) data was found. The scenario analysis showed that simulated goats in the free grazing system attained sexual maturity and kidded much later than those in the grazing with supplementation and the cut-and carry systems. The simulated results suggested that goats require supplementation with protein and energy sources, in order to promote lifetime productivity, early sexual maturity and higher birth weight. In terms of economic returns based on feed cost alone, the moderately intense system produced the most profit. We therefore conclude that grazing with adequate supplementation using farm generated feed resources offers an opportunity for improving smallholder goat production systems in West Africa. PMID- 28031075 TI - Prenatal phthalate exposure and 8-isoprostane among Mexican-American children with high prevalence of obesity. AB - Oxidative stress has been linked to many obesity-related conditions among children including cardiovascular disease, diabetes mellitus and hypertension. Exposure to environmental chemicals such as phthalates, ubiquitously found in humans, may also generate reactive oxygen species and subsequent oxidative stress. We examined longitudinal changes of 8-isoprostane urinary concentrations, a validated biomarker of oxidative stress, and associations with maternal prenatal urinary concentrations of phthalate metabolites for 258 children at 5, 9 and 14 years of age participating in a birth cohort residing in an agricultural area in California. Phthalates are endocrine disruptors, and in utero exposure has been also linked to altered lipid metabolism, as well as adverse birth and neurodevelopmental outcomes. We found that median creatinine-corrected 8 isoprostane concentrations remained constant across all age groups and did not differ by sex. Total cholesterol, systolic and diastolic blood pressure were positively associated with 8-isoprostane in 14-year-old children. No associations were observed between 8-isoprostane and body mass index (BMI), BMI Z-score or waist circumference at any age. Concentrations of three metabolites of high molecular weight phthalates measured at 13 weeks of gestation (monobenzyl, monocarboxyoctyl and monocarboxynonyl phthalates) were negatively associated with 8-isoprostane concentrations among 9-year olds. However, at 14 years of age, isoprostane concentrations were positively associated with two other metabolites (mono(2-ethylhexyl) and mono(2-ethyl-5-carboxypentyl) phthalates) measured in early pregnancy. Longitudinal data on 8-isoprostane in this pediatric population with a high prevalence of obesity provides new insight on certain potential cardiometabolic risks of prenatal exposure to phthalates. PMID- 28031077 TI - Deployment of Medical Relief Teams of the Indian Army in the Aftermath of the Nepal Earthquake: Lessons Learned. AB - In April 2015 a 7.8-magnitude earthquake hit Nepal. As part of relief operations named Operation Maitri, the Indian Armed Forces deployed 3 field hospitals in the disaster zone. Rapid deployment of mobile surgical teams to far-flung, inaccessible areas was done by helicopters. In an operational deployment spanning 1 month, a total of 7532 patients were treated and 105 surgeries were carried out on 83 patients. One-fifth of the patients were less than 18 years of age. One third of the patients had traumatic injuries directly attributable to the earthquake, whereas the remaining patients were treated for diseases of poor sanitation and hygiene as well as chronic illness that had been neglected owing to the collapse of the local health infrastructure. Cases of traumatic injuries directly related to the earthquake were seen maximally on the 5th day after the index event but tapered off rapidly by the 10th day. Nontraumatic illness required more attention thereafter and a need was felt for separate child health and reproductive health services later in the mission. Although immediate management of injuries and surgical intervention in selected cases was possible, ensuring long-term care and rehabilitation of cases proved problematic. This was especially so for spinal injury cases. Data capturing by a paper-based system was found to be inadequate. The lessons learned from this mission have led to a reimagining of the composition of future relief operations. Apart from mobile surgical teams, on which conventional field hospitals are generally centered, a separate section for preventive medicine and child and maternal services is needed. (Disaster Med Public Health Preparedness. 2017;11:394-398). PMID- 28031078 TI - Autism spectrum traits and visual processing in young adults with very low birth weight: the Helsinki Study of Very Low Birth Weight adults. AB - Visual processing problems may be one underlying factor for cognitive impairments related to autism spectrum disorders (ASDs). We examined associations between ASD traits (Autism-Spectrum Quotient) and visual processing performance (Rey Osterrieth Complex Figure Test; Block Design task of the Wechsler Adult Intelligence Scale-III) in young adults (mean age=25.0, s.d.=2.1 years) born preterm at very low birth weight (VLBW; <1500 g) (n=101) or at term (n=104). A higher level of ASD-traits was associated with slower global visual processing speed among the preterm VLBW, but not among the term-born group (P<0.04 for interaction). Our findings suggest that the associations between ASD-traits and visual processing may be restricted to individuals born preterm, and related specifically to global, not local visual processing. Our findings point to cumulative social and neurocognitive problems in those born preterm at VLBW. PMID- 28031079 TI - Oligopeptidase B and B2: comparative modelling and virtual screening as searching tools for new antileishmanial compounds. AB - Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis. PMID- 28031080 TI - The interaction between monoamine oxidase A and punitive discipline in the development of antisocial behavior: Mediation by maladaptive social information processing. AB - Previous studies demonstrate that boys' monoamine oxidase A (MAOA) genotype interacts with adverse rearing environments in early childhood, including punitive discipline, to predict later antisocial behavior. Yet the mechanisms by which MAOA and punitive parenting interact during childhood to amplify risk for antisocial behavior are not well understood. In the present study, hostile attributional bias and aggressive response generation during middle childhood, salient aspects of maladaptive social information processing, were tested as possible mediators of this relation in a sample of 187 low-income men followed prospectively from infancy into early adulthood. Given racial-ethnic variation in MAOA allele frequencies, analyses were conducted separately by race. In both African American and Caucasian men, those with the low-activity MAOA allele who experienced more punitive discipline at age 1.5 generated more aggressive responses to perceived threat at age 10 relative to men with the high-activity variant. In the African American subsample only, formal mediation analyses indicated a marginally significant indirect effect of maternal punitiveness on adult arrest records via aggressive response generation in middle childhood. The findings suggest that maladaptive social information processing may be an important mechanism underlying the association between MAOA * Parenting interactions and antisocial behavior in early adulthood. The present study extends previous work in the field by demonstrating that MAOA and harsh parenting assessed in early childhood interact to not only predict antisocial behavior in early adulthood, but also predict social information processing, a well established social-cognitive correlate of antisocial behavior. PMID- 28031081 TI - Restrictive Cardiomyopathy Resulting from a Troponin I Type 3 Mutation in a Chinese Family. AB - Objective To identify the pathogenic variant responsible for restrictive cardiomyopathy (RCM) in a Chinese family.Methods Next generation sequencing was used for detecting the mutation and Results verified by sequencing. We used restriction enzyme digestion to test the mutation in the family members and 200 unrelated normal subjects without any cardiac inherited diseases when the mutation was identified.Results Five individuals died from cardiac diseases, two of whom suffered from sudden cardiac death. Two individuals have suffered from chronic cardiac disorders. Mutation analysis revealed a novel missense mutation in exon 7 of troponin I type 3 (TNNI3), resulting in substitution of serine (S) with proline (P) at amino acid position 150, which cosegregated with the disease in the family, which is predicted to be probably damaging using PolyPhen-2. The mutation was not detected in the 200 unrelated subjects we tested.Conclusion Using next generation sequencing, which has very recently been shown to be successful in identifying novel causative mutations of rare Mendelian disorders, we found a novel mutation of TNNI3 in a Chinese family with RCM. PMID- 28031082 TI - Association Between Geranylgeranyl Pyrophosphate Synthase Gene Polymorphisms and Bone Phenotypes and Response to Alendronate Treatment in Chinese Osteoporotic Women. AB - Objective To investigate the relationship between geranylgeranyl pyrophosphate synthase (GGPPS) gene polymorphisms and bone response to alendronate in Chinese osteoporotic women.Methods A total of 639 postmenopausal women with osteoporosis or osteopenia were included and randomly received treatment of low dose (70 mg per two weeks) or standard dose (70 mg weekly) of alendronate for one year. The six tag single nucleotide polymorphisms of GGPPS gene were identified. Bone mineral density (BMD), serum cross-linked C-telopeptide of type I collagen (beta CTX), and total alkaline phosphatase (ALP) were measured before and after treatment. GGPPS gene polymorphisms and the changes of BMD and bone turnover markers after treatment were analyzed.Results rs10925503 polymorphism of GGPPS gene was correlated to serum beta-CTX levels at baseline, and patients with TT genotype had significantly higher serum beta-CTX level than those with TC or CC genotype (all P<0.05). No correlation was found between polymorphisms of GGPPS gene and serum total ALP levels, as well as BMD at baseline. After 12 months of treatment, lumbar spine and hip BMD increased and serum bone turnover markers decreased significantly (P<0.01), and without obvious differences between the low dose and standard dose groups (all P>0.05). However, GGPPS gene polymorphisms were uncorrelated to percentage changes of BMD, serum total ALP, and beta-CTX levels (all P>0.05).Conclusion GGPPS gene polymorphisms are correlated to osteoclasts activity, but all tag single nucleotide polymorphisms of GGPPS gene have no influence on the skeletal response to alendronate treatment. PMID- 28031083 TI - Positive Rate of Different Hepatitis B Virus Serological Markers in Peking Union Medical College Hospital, a General Tertiary Hospital in Beijing. AB - Objective s To investigate the positive rate of different hepatitis B virus (HBV) serological markers, and the demographic factors related to HBV infection.Methods We enrolled all patients tested for HBV serological markers, such as HBV surface antigen (HBsAg), HBV surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), HBV core antibody (HBcAb), and HBV-DNA from July 2008 to July 2009 in Peking Union Medical College Hospital. The positive rate of each HBV serological marker was calculated according to gender, age, and de- partment, respectively. The positive rates of HBV-DNA among patients with positive HBsAg were also analyzed.Results Among 27 409 samples included, 2681 (9.8%) were HBsAg positive. When patients were divided into 9 age groups, the age specific positive rate of HBsAg was 1.2%, 9.6%, 12.3%, 10.9%, 10.3%, 9.7%, 8.0%, 5.8%, and 4.3%, respectively. The positive rate of HBsAg in non-surgical department, surgical department, and health examination center was 16.2%,5.8%,and 4.7%, respectively. The positive rate of HBsAg of males (13.3%) was higher than that of females (7.3%, P=0.000). Among the 2681 HBsAg (+) patients, 1230 (45.9%) had HBV-DNA test, of whom 564 (45.9%) were positive. Patients with HBsAg (+), HBeAg (+), and HBcAg (+) result usually had high positive rate of HBV-DNA Results (71.8%, P=0.000).Conclusions Among this group of patients in our hospital, the positive rate of HBsAg was relatively high. Age group of 20-29, males, and patients in non-surgical departments were factors associated with high positive rate of HBsAg. PMID- 28031084 TI - Establish Albumin-creatinine Ratio Reference Valueof Adults in the Rural Area of Hebei Province. AB - Objective To establish albumin-creatinine ratio (ACR) reference value of the rural population in Hebei province.Methods This study enrolled 5154 participants. By excluding subjects with hypertension, diabetes, dyslipidemia, cardiovascular and cerebrovascular diseases, kidney diseases, and overweight condition, as well as those with an estimated glomerular filtration rate (eGFR)<60 ml/(min.1.73 m2), apparently healthy subjects (1168) were selected. Urine albumin was measured by using the immunoturbidimetic method, serum creatinine was measured by using Jaffe's kinetic method on a morning spot-urine sample, and ACR was calculated. The 95th percentile of ACR in the healthy subjects was used as the normal upper limit.Results The normal upper limit of ACR was 28.71 mg/g (3.25 mg/mmol) for males and 31.85 mg/g (3.60 mg/mmol) for females. Based on this ACR reference value, the age-gender standardized prevalence of albuminuria in the rural areas of Hebei province was 12.9%.Conclusion The ACR reference value in the rural of Hebei province is higher than that of the Western population. PMID- 28031085 TI - Percutaneous Removal of Benign Breast Lesions with an Ultrasound-guided Vacuum assisted System: Influence Factors in the Hematoma Formation. AB - Objective To explore the influence factors in hematoma formation after removing benign breast lesions with an ultrasound-guided vacuum-assisted system.Methods A total of 232 females with 312 benign breast masses received excisional biopsy with ultrasound- guided vacuum-assisted system. The pathology of patients, Results of hematoma development and outcome, influence factors for hematoma occurrence (nodule size, nodule location, number of nodule, breast shape, menstrual period, efficacy time of bandage, and application of hemostatic agents during the procedure) were recorded.Results Pathologic examination revealed fibroadenomas in 138 lesions, fibroadenosis in 127 lesions, intraductal papillomas in 39 lesions, inflammatory change in 4 lesions, retention cyst of the breast in 3 lesions, and benign phyllodes tumor in 1 lesion. Thirty hematomas were observed in patients (9.6%). Finally, 97.0% hematomas were absorbed completely within 6 months follow-up. The incidence rates of hematoma were increased by 24.7%, 10.0%, 63.2%, 13.9% in the nodule diameter larger or equal to 25 mm group, removal of larger or equal to two nodules once time from one patient group, menstrual period group, and larger and loose breast group, respectively (all P<0.05). However, the incidences were decreased by 60.6% in the bandage performed for 12-24 hours or beyond 24 hours group (P<0.05). The multiple logistic regression models revealed that nodule size (chi2=15.227, P<0.001), number of nodule (chi2=7.767, P=0.005), menstrual period (chi2=24.530, P<0.001), and breast shape (chi2=9.559, P=0.002) were independent risk factors associated with hematoma occurrence, but efficacy time of bandage was a protective factor associated with hematoma occurrence.Conclusion The occurrence of hematoma after the minimally invasive operation was associated with nodule size, number of nodule, menstrual period, breast shape, and efficacy time of bandage. PMID- 28031086 TI - Respiratory and Cardiac Characteristics of ICU Patients Aged 90 Years and Older: A Report of 12 Cases. AB - Objective To investigate the respiratory and cardiac characteristics of elderly Intensive Care Unit (ICU) patients.Methods Twelve senior ICU patients aged 90 years and older were enrolled in this study. We retrospectively collected all patients' clinical data through medical record review. The basic demographics, primary cause for admission, the condition of respiratory and circulatory support, as well as prognosis were recorded. Shock patients and pneumonia patients were specifically analyzed in terms of clinical manifestations, laboratory variables, echocardiography, and lung ultrasound Results.Results The mean age of the included patients was 95 years with a male predominance (8 to 4, 66.7%). Regarding the reasons for admission, 6 (50.0%) patients had respiratory failure, 1 (8.3%) patient had shock, while 5 (41.7%) patients had both respiratory failure and shock. Of the 6 patients who suffered from shock, only 1 was diagnosed with distributive shock, 5 with cardiogenic shock. Of the 5 cardiogenic shock patients, 1 was diagnosed with acute coronary syndrome. The rest 4 cardiogenic shock patients were diagnosed with Takotsubo cardiomyopathy. The patient with ST-segment elevation myocardial infarction died within 24 hours. Of the 4 Takotsubo patients, 1 died on day-6 and the other 3 patients were transferred to ward after heart function recovered in 1 to 2 weeks. Of the 10 pneumonia patients, 3 were diagnosed as community acquired pneumonia, and 7 as hospital acquired pneumonia. Only 3 patients were successfully weaned from ventilator. The others required long-term ventilation complicated with heart failure, mostly with diastolic heart failure. Lung ultrasound of 6 patients with diastolic dysfunction showed bilateral B-lines during spontaneous breathing trial.Conclusions Elderly patients in shock tend to develop Takotsubo cardiomyopathy. Diastolic heart dysfunction might be a major contributor to difficult weaning from ventilator in elderly patients. Bedside lung ultrasonography and echocardiography could help decide the actual cause of respiratory failure and shock more accurately and effectively. PMID- 28031087 TI - Life-threatening Spontaneous Retroperitoneal Haemorrhage: Role of Multidetector CT-angiography for the Emergency Management. AB - Objective To evaluate the role of multidetector computed tomography-angiography (MDCTA) for management of life-threatening spontaneous retroperitoneal haemorrhage (SRH).Methods A retrospective analysis of the medical records of all SRH patients admitted to our hospital from January 1, 2005 to November 31, 2014 was performed. SRH was defined as unrelated to invasive procedures, surgery, trauma, abdominal tumor or aortic aneurysm. Life-threatening SRH was defined as hemodynamic instability with hypotension. Sixteen cases met the inclusive criteria. Patients' characteristics, clinical presentation, imaging of MDCTA, treatment modalities, morbidity, and follow-up data were analyzed.Results The group of 16 patients included 11 men and 5 women, with a mean age of 51.5+/-16.4 years. All patients underwent MDCTA scan examinations, and active contrast media (CM) extravasation were found in 9 patients. Angiography was performed for 8 patients in the CM extravasation group. Bleeding vessels were found in 7 patients who underwent successful embolization. One patient in the CM extravasation group did not undergo angiography and died of bleeding. Seven patients without active CM extravasation underwent conservative management. Bleeding was controlled for all these 7 patients, and 1 patient died of multiple organ failure. Fourteen patients survived from SRH were successfully discharged. One patient died of heart failure during follow-up.Conclusion MDCTA was useful in the diagnosis of SRH and proved to be predictive for the outcome of conservative treatment and early intervention. PMID- 28031088 TI - Therapy and Prevention of Postoperative Urosepsis of Ureter Endoscopic Lithotripsy for Non-infection. AB - Objective To analyze the risk factors causing postoperative urosepsis in ureter endoscopic lithotripsy without infection preoperatively, in order to make a more effective and safer preventive and therapeutic strategy.Methods From January 2010 to January 2015, 5 ureteral calculus patients undergoing ureter endoscopic lithotripsy with holmium laser were retrospectively enrolled in this clinical study. These patients suffered urosepsis postoperatively confirmed by the clinical presentations and laboratory Results, while they had no infection in their blood and urine preoperatively. Without delay, 5 patients were treated by anti-inflammation and anti-shock.Results The vasopressor drug was stopped gradually after 12-36 hours. The body temperature was recovered to normal in 2 or 3 days, and the blood and urine test Results were not abnormal in 7 days. At last, 5 patients were all cured.Conclusions Stone and operation themselves are potential factors to cause urosepsis after ureter endoscopic lithotripsy. Especially for patients who had not presented infection preoperatively, careful preparation preoperatively, corrective manipulation, low pressure irrigation, drainage and controlling time during operation, and early diagnosis, appropriate treatment postoperatively are the key to cure and prevent urosepsis. PMID- 28031089 TI - Pathology Verified Concomitant Papillary Thyroid Carcinoma in the Sonographically Suspected Thyroid Lymphoma: A Case Report. PMID- 28031090 TI - Treatment of Breast Cancer Accompanied by POEMS Syndrome: A Case Report. PMID- 28031091 TI - Roles of Long-chain Acyl Coenzyme A Synthetase in Absorption and Transport of Fatty Acid. AB - Long-chain acyl coenzyme A synthetase (ACSL) is a member of the synthetase family encoded by a multigene family; it plays an important role in the absorption and transport of fatty acid. Here we review the roles of ACSL in the regulating absorption and transport of fatty acid, as well as the connection between ACSL and some metabolic diseases. PMID- 28031092 TI - Effect of Autophagy Over Liver Diseases. AB - In recent years, increasingly evidences show that autophagy plays an important role in the pathogenesis and development of liver diseases, and the relationship between them has increasingly become a focus of concern. Autophagy refers to the process through which the impaired organelles, misfolded protein, and intruding microorganisms is degraded by lysosomes to maintain stability inside cells. This article states the effect of autophagy on liver diseases (hepatic fibrosis, fatty liver, viral hepatitis, and liver cancer), which aims to provide a new direction for the treatment of liver diseases. PMID- 28031093 TI - Clinical Characteristics of 261 Cases of Hospitalized Patients with Type 1 Diabetes Mellitus. AB - Objective To retrospectively analyze the clinical characteristics of 261 cases of hospitalized patients with type 1 diabetes mellitus (T1DM) in Peking Union Medical College Hospital (PUMCH).Methods Clinical data of 261 cases of hospitalized patients diagnosed with T1DM in the Department of Endocrinology at PUMCH from January 2007 to December 2014 were analyzed retrospectively. All patients were divided into the T1DM antibodies positive group (n=180) and negative group (n=81) according to the results of immunohistochemistry, in which 123 newly diagnosed T1DM patients were divided into the adult onset group (>18 years, n=58) and non-adult onset group (<=18 years, n=65) according to the onset age of T1DM, respectively. The clinical characteristics from different groups were compared.Results In 261 patients, the average age was 26.6+/-15.4 years, the average disease duration was 49 (1-480) months, the positive rate of antibodies to glutamic acid decarboxylase antibody was 58.8% (153/260). The level of 2-hour postprandial C peptide and the positive rate of T1DM antibodies in the non-adult onset group were higher than those in the adult onset group (0.98 vs. 0.52 ng/ml, P=0.002 and 80.4% vs. 62.5%, P=0.048). The age of onset in the T1DM antibodies positive group was smaller than that in the T1DM antibodies negative group (19.7+/-11.4 vs. 24.7+/-15.6 years, P=0.04), while the incidence of ketosis in the T1DM antibodies positive group was higher than that in the T1DM antibodies negative group (48.3% vs. 34.2%, P=0.035). With the progress of the disease, the fasting C peptide level of the T1DM antibodies positive group decreased more rapidly. Compared with the single time hospitalized patients, multiple hospitalized patients had a lower incidence of diabetic retinopathy (8.2% vs. 22.4%, P=0.032), a lower hemoglobin A1c level (8.04%+/-2.10% vs. 9.56%+/-2.64%, P<0.001) and fasting blood glucose level (8.7+/-3.1 vs. 10.9+/-4.2 mmol/L, P<0.001).Conclusions Compared with the non-adult onset T1DM patients, the islet function of adult onset patients was even worse. In the T1DM antibodies positive patients, the islet beta cell function decreased more rapidly, so the antibodies could not only clarify the diagnosis of T1DM and also predict prognosis of the islet beta cell function. In the management of T1DM patients, regular hospital revisits contributed to get better glycemic control and reduced the occurrence of diabetic complications. PMID- 28031094 TI - Determinants of Detection of Stones and Calcifications in the Hepatobiliary System on Virtual Nonenhanced Dual-energy CT. AB - Objective To retrospectively determine the features of stones and calcifications in hepatobiliary system on virtual nonenhanced (VNE) dual-energy computed tomography (CT), and to evaluate the possibility of VNE images in diagnosis for those lesions.Methods A total of 128 gall stones and calcifications of the liver found in 110 patients were examined with triple phase abdominal CT scan from July 2007 to December 2011, in which true nonenhanced (TNE) phase and arterial phase were performed with single-energy CT (120 kVp) and portal venous phase was performed with dual-energy CT (100 kVp and 140 kVp). VNE images were generated from the portal venous phase dual-energy CT data sets by using commercially VNC software. The mean CT values for the stone, liver, bile and paraspinal muscle, mean lesion density and size in area dimension, contrast-to-noise ratio (CNR) of lesion to the liver or bile, and image noise were assessed and compared between VNE and TNE images. The effective dose and size-specific dose estimate (SSDE) were also calculated.Results The mean CT values of the lesions measured on VNE images declined significantly compared with those measured on TNE images (164.51+/-102.13 vs. 290.72+/-197.80 HU, P<0.001), so did the lesion-to-liver CNR (10.80+/-11.82 vs.18.81+/-17.06, P<0.001) and the lesion-to-bile CNR (17.24+/ 14.41 vs. 21.32+/-17.31, P<0.001). There was no significant difference in size of lesions area between VNE and TNE images (0.69+/-0.88 vs. 0.72+/-0.85 cm2, P=0.062). Compared to the 128 lesions found in TNE images, VNE images showed the same density in 30 (23.4%) lesions, lighter density in 88 (68.8%) lesions, while failed to show 10 (7.8%) lesions, and showed the same size in 61 (47.7%) lesions and smaller size in 57 (44.5%) lesions. The CT cutoff values of lesion and size were 229.21 HU and 0.15 cm2, respectively. The total effective dose for triple phase scan protocol with TNE images was 19.51+/-7.03 mSv, and the SSDE was 39.84+/-11.10 mGy. The effective dose for dual phase scan protocol with VNE images instead of TNE images was 13.29+/-4.89 mSv, and the SSDE was 27.83+/-9.99 mGy. Compared with TNE images, the effective dose and SSDE of VNE images were down by 32.05%+/-3.69 % and 30.63%+/-2.34 %, respectively.Conclusions Although the CT values and CNR of the lesions decreased in VNE images, the lesions of which attenuation greater than 229.21 HU and size larger than 0.15 cm2 could be detected with good reliability and obvious dose reduction. There was good consistency in the size of stones and calcifications in hepatobiliary system between VNE images and TNE images, which ensured the possibility of the clinical application of VNE images. PMID- 28031095 TI - Effect of Point-of-care Hemoglobin/Hematocrit Devices and Autologous Blood Salvage on Reduction of Perioperative Allogeneic Blood Transfusion. AB - Objective To evaluate the effect of point-of-care hemoglobin/hematocrit (POC HGB/HCT) devices and intraoperative blood salvage on the amount of perioperative allogeneic blood transfusion and blood conservation in clinical practice.Methods A total of 46 378 medical records of 22 selected hospitals were reviewed. The volume of allogeneic red blood cell and plasma, number of patients transfused, number of intraoperative autologous blood salvage, total volume of autologous blood transfusion, and amount of surgery in the year of 2011 and 2013 were tracked. Paired t-test was used in intra-group comparison, while t-test of two isolated samples carried out in inter-group comparison. P<0.05 was defined as statistically significant difference.Results In the hospitals where POC HGB/HCT device was used (n=9), the average allogeneic blood transfusion volume per 100 surgical cases in 2013 was significantly lower than that in 2011 (39.86+/-20.20 vs. 30.49+/-17.50 Units, t=3.522, P=0.008). In the hospitals without POC HGB/HCT meter, the index was not significantly different between 2013 and 2011. The average allogeneic blood transfusion volume was significantly reduced in 2013 than in 2011 in the hospitals where intraoperative autologous blood salvage ratio [autologous transfusion volume/(autologous transfusion volume+allogeneic transfusion volume)] was increased (n=12, t=2.290, P=0.042). No significant difference of the above index was found in the hospitals whose autologous transfusion ratio did not grow.Conclusion Intraoperative usage of POC HGB/HCT devices and increasing autologous transfusion ratio could reduce perioperative allogeneic blood transfusion. PMID- 28031096 TI - Impact of Intraoperative Blood Pressure Control and Temporary Parent Artery Blocking on Prognosis in Cerebral Aneurysms Surgery. AB - Objective In cerebral aneurysm clipping and embolization, blood pressure control and temporary parent artery blocking are common methods to prevent aneurysm rupture. Their influence on the prognosis is uncertain. In this study, we try to find out the association between methods above and prognostic indicators.Methods We held a retrospective analysis on patients' medical records of cerebral aneurysms surgical clipping and endovascular coiling , and recorded gender, age, diagnosis, Hunt-Hess grade, Glasgow coma scale score, treatment methods, a history of hypertension, preoperative systolic blood pressure, with or without controlled hypotension, systolic blood pressure difference before and after controlled hypotension, with or without temporary artery blocking, with or without hypertension after treated aneurysm, prognostic indicators including mortality after 1 month, intensive care unit (ICU) stay time of survivors, discharged Glasgow outcome scale (GOS) score. Prognostic indicators were regarded as dependent variable, all the factors were regarded as independent variable, and the strength analysis of influence factors on prognostic indicators was made by binary logistic regression.Results Total cases were 165, including 68 males and 97 females, with an average age of 56 (12-85) years. The mortality after 1 month was 10.9% (18 cases). The ICU stay time of survivors was 7.35 (0-67) days. GOS score at discharge was 1-3 in 40 (24.2%) patients and 4-5 in 125 (75.8%) patients. Systolic blood pressure difference before and after controlled hypotension was an independent factor influencing mortality (t=2.273, P=0.024), and the greater the difference was, the higher the mortality would be. Timely hypertension after aneurysm treated was an independent factor affecting ICU stay time of survivors and patients with hypertension had shorter ICU stay time (chi2=10.017, P=0.001). Blood pressure control (chi2=0.088, P=0.767) and temporary blocking (chi2=1.307, P=0.253) did not show significant influence on GOS score at discharge.Conclusions Timely controlled hypertension after aneurysm clipping and embolization can significantly shorten the stay time in ICU. The degree of controlled hypotension associates with postoperative mortality, the greater systolic blood pressure difference before and after antihypertensive treatment is, the higher the mortality will be. PMID- 28031097 TI - Effect of 4-week Whole Body Vibration on Distal Radius Density. AB - Objective To assess the effects of high-frequency loading using whole body vibration on distal radius density in adults.Methods The volunteers diagnosed with osteoporosis or osteopenia in the First Hospital of Jilin University from January 2011 to December 2014 were recruited. All the subjects performed foot based, whole body vibrations on the vibration platform (35 Hz, 0.25 g) once a day, for 15 minutes per session over a period of 4 weeks. The bone mineral density of distal radius (rBMD) was measured using dual-energy X-ray absorptiometry at before, 2-week, and 4-week after the vibration treatment. Blood pressures were measured at the end of the vibration treatment.Results A total of 114 volunteers were enrolled. The average rBMD before the treatment was 0.331+/ 0.014 g/cm2. It was reached 0.337+/-0.019 g/cm2 at the end of the fourth week, increased by 1.79% (P<0.05). Whole body vibration increased rBMD of men and women respectively (1.77% and 1.80%, P<0.05). Blood pressures did not change in any of the groups.Conclusion A 4-week whole body vibration was feasible and contributed to increase of rBMD. PMID- 28031098 TI - Mechanical Strain Regulates Osteoblast Proliferation Through Ca2+-CaMK-CREB Signal Pathway. AB - Objective To investigate the effects of mechanical strain on Ca2+-calmodulin dependent kinase (CaMK)-cAMP response element binding protein (CREB) signal pathway and proliferation of osteoblasts.Methods Using a four-point bending device, MC3T3-E1 cells were exposed to mechanical tensile strains of 2500 us and 5000 us at 0.5 Hz respectively. The intracellular free Ca2+ ([Ca2+]i) concentration and calmodulin activity were assayed by fluorospectrophotometry, CaMK II beta, CREB, and phosphorylated (activated) CREB (p-CREB) were assessed by Western blot, and cells proliferation was assayed with MTT. Pretreatment with verapamil was carried out to block Ca2+ channel, and inhibitor U73122 was used to inhibit phospholipase C (PLC).Results Mechanical strains of 2500 us and 5000 us for 1 to 10 minutes both increased [Ca2+]i level of the cells. The 2500 us strain, a periodicity of 1 h/d for 3 days, activated calmodulin, elevated protein levels of CaMK II beta and p-CREB, and promoted cells proliferation, which were attenuated by pretreatment of verapamil or U73122. The effects of 5000 us strain on calmodulin, CaMK II beta, p-CREB and proliferation were contrary to 2500 us strain.Conclusion The mechanical strain regulates osteoblasts proliferation through Ca2+-CaMK-CREB signal pathway via Ca2+ channel and PLC/IP3 transduction cascades. PMID- 28031099 TI - Low-dose Simvastatin Increases Skeletal Muscle Sensitivity to Caffeine and Halothane. AB - Objective To determine whether the myotoxic side effects of statin simvastatin affect skeletal muscle's sensitivity to caffeine and halothane.Methods Primary cultured neonate rat skeletal myotubes were treated with 0.01-5.0 MUmol/L simvastatin for 48 hours. MTT was used to evaluate cellular viability. The gross morphology and microstructure of the myotubes were observed with a light and electron microscope, respectively. The intracellular calcium concentrations ([Ca2+]i) at rest and in response to caffeine and halothane were investigated by fluorescence calcium imaging. Data were analyzed by analysis of variance (ANOVA) test.Results Simvastatin (0.01-5.0 MUmol/L) decreased myotube viability, changed their morphological features and microstructure, and increased the resting [Ca2+]i in a dose-dependent manner. Simvastatin did not change myotube's sensitivity to low doses of caffeine (0.625-2.5 mmol/L) or halothane (1.0-5.0 mmol/L). In response to high-dose caffeine (10.0 mmol/L, 20.0 mmol/L) and halothane (20.0 mmol/L, 40.0 mmol/L), myotubes treated with 0.01 MUmol/L simvastatin showed a significant increase in sensitivity, but those treated with 1.0 MUmol/L and 5.0 MUmol/L simvastatin showed a significant decrease. The sarcoplasmic reticulum Ca2+ storage peaked in the myotubes treated with 0.01 MUmol/L simvastatin, but it decreased when cells were treated with higher doses of simvastatin (0.1-5.0 MUmol/L).Conclusions The myotoxic side effect of simvastatin was found to change the sensitivity of myotubes in response to high dose caffeine and halothane. When dose was low, sensitivity increased mainly because of increased Ca2+ content in the sarcoplasmic reticulum, which might explain why some individuals with statin-induced myotoxic symptoms may show positive caffeine-halothane contracture test results. However, when the dose was high and the damage to the myotubes was severer, sensitivity was lower. It is here supposed that the damage itself might put individuals with statin-induced myotoxic symptoms at greater risks of presenting with rhabdomyolysis during surgery or while under anesthesia. PMID- 28031100 TI - Trends and Prospects of Stem Cell Research in China. AB - Great progresses have been made in fundamental and clinical stem cell research in China in recent years. The official policy on stem cells, which was announced in 2015, seems as the spring of stem cell therapy in China. However, the regulation, governance, and management of clinical expectations are still challenging. This review summarized the current stem cell research and development in the field, as well as its rapidly evolving commercial, regulatory and ethical environment in China. As expected, the prospects of stem cells in China look prospective. PMID- 28031101 TI - Relation Between Cellular Senescence and Liver Diseases. AB - Cellular senescence refers to a process that cellular proliferation and differentiation modulated by the multiple stimulating factors gradually decline. Aging cells present the irreversible stop of proliferation and differentiation and change in secretory function because the cell cycle of aging cells is steadily blocked at some point. It has have been shown that cellular senescence plays an important role in the occurrence and development of liver diseases. In this paper, we review the advances in relations between cellular senescence and liver diseases. PMID- 28031102 TI - 1.9 MUm Thulium Laser Treats Ureteral Carcinoma via Rigid-ureteroscopy. PMID- 28031103 TI - Cytomegalovirus and Helicobacter Pylori Co-infection in an Adult with Menetrier's Disease: A Case Report. PMID- 28031104 TI - Hepatocellular Carcinoma with Hypersplenic Thrombocytopenia and Situs Inversus Totalis: A Case Report. PMID- 28031105 TI - [Xinfeng Capsule improves pulmonary function of rats with adjuvant-induced arthritis via regulating the expressions of autophagy-related proteins]. AB - Objective To observe the effect of Xinfeng Capsule (XFC) on autophagy related gene (ATG), microtubule-associated protein 1 light chain 3II (LC3-II), beclin 1 in the rat model of adjuvant-induced arthritis (AA). Methods Rats were divided for four groups: normal control (NC) group, model control (MC) group, leflunomide (LEF) group, and XFC group, with 10 rats in each group. Complete Freund's adjuvant (CFA, 0.1 mL) was injected into the right foot plantar skin of all rats except for the NC group. To enhance the immune response, 0.05 mL CFA was injected into the tail root in the 10th day. XFC and LEF diluted in water were administrated via gavage, once a day from the 13th day to the 42th day after AA induction. The normal and model rats were orally administered the same volume of saline solution. Swelling degree (SD), arthritis index (AI) and pulmonary function were observed; B lymphocyte stimulating factor (BAFF), interleukin (IL) 1 beta, tumor necrosis factor alpha (TNF-alpha), IL-4, IL-10 were detected by ELISA; autophagosome of the synovium and lung were observed by transmission electron microscope; ATG5, ATG7, and ATG12 mRNAs were determined by reverse transcriptase PCR; LC3-II and beclin 1 were tested by Western blotting. Results Compared with the MC group, the parameters of pulmonary function, IL-4, IL-10, autophagosome, autophagolysosome, ATG12 mRNA, LC3-II, beclin 1 of the synovium and lung increased, while ATG7, ATG12 mRNA of the synovium, ATG5, ATG7 mRNA of the lung, serum IL-1beta and BAFF decreased in the XFC group. Conclusion XFC can regulate autophagy and improve the pulmonary function in AA rats. PMID- 28031106 TI - [Protective effect of human amnion epithelial cells through endotracheal instillation against lipopolysaccharide-induced acute lung injury in mice]. AB - Objective To investigate the therapeutic effect of human amnion epithelial cells (hAECs) through endotracheal instillation on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice and its underlying mechanism. Methods Male C57BL/6 mice were randomly divided into normal control group, hAECs control group, LPS-induced ALI group and hAECs treatment group (n=10 each group). In the latter two groups, mice were subjected to LPS (5 mg/kg) by oral insertion, and 1 hour later, PBS (50 MUL) and hAECs (1*107/mL, 50 MUL) were administered by oral insertion in the two groups, respectively. The normal control group and hAECs control group were injected with the same amount of PBS and hAECs by oral insertion, respectively. Twenty-four hours after LPS administration, the mice were sacrificed to collect blood and lung tissues. Cytoplasmic and nuclear proteins were extracted from the lung tissues, and other lung tissues were embedded in paraffin and cut into sections. The wet mass and dry mass of lung tissues were obtained to calculate the wet/dry mass ratios. Concentrations of interleukin (IL)-10, IL-6, IL-1beta and tumor necrosis factor (TNF)-alpha in sera were measured by ELISA. Pulmonary histological changes were evaluated by HE staining. The nuclear transcription factor-kappaBp65 (NF-kappaBp65) activation in lung tissues was detected by Western blotting. Results Compared with the control group, the lung wet/dry mass ratios and the serum concentrations of TNF-alpha, IL 1beta and IL-6 in the LPS-induced model group increased, while the level of IL-10 decreased. Under a light microscope, the lung tissues from LPS-induced model group showed serious pulmonary edema, haemorrhagia in stroma, alveolar wall thickness, alveolus collapse and obvious inflammatory cell infiltration. LPS administration also increased the activation of NF-kappaBp65 in lung tissues. hAECs administration significantly decreased LPS-induced lung histopathological changes, lung wet/dry mass ratios and the serum levels of IL-6, IL-1beta and TNF alpha, and inhibited the activation of NF-kappaBp65 in lung tissues. Conclusion hAECs can inhibit the activation of NF-kappaBp65 in lung tissues and significantly attenuat lipopolysaccharide-induced ALI. PMID- 28031107 TI - [Overexpression of NHE1 suppresses ABCA1 protein expression via increasing calpain activity in RAW264.7 cells]. AB - Objective To investigate the effect of over-expressed Na+/H+ exchanger 1 (NHE1) on the protein expression of adenosine three phosphate binding cassette transporter A1 (ABCA1) in RAW264.7 cells. Methods RAW264.7 cells were infected with the adenoviral vector encoding NHE1-EGFP (AdNHE1). The infected RAW264.7 cells were subjected to Western blot analysis for NHE1-EGFP fusion protein. The subcellular localization of NHE1-EGFP fusion protein was observed by confocal laser scanning microscopy. NHE1 activity was measured by the method of pH recovery in response to an acute acid pulse. Furthermore, Western blotting was performed to determine ABCA1 protein levels and calpain activity in NHE1 overexpressing RAW264.7 cells. The effect of calpain inhibitor N-acetyl-L-leucyl L-leucyl-L-norleucinal (ALLN) on ABCA1 protein levels in the presence of TO 901317 was examined by Western blotting. Results NHE1-EGFP fusion protein was highly expressed and localized in cytoplasm and cell membrane of RAW264.7 cells infected with AdNHE1. NHE1-EGFP fusion protein reduced ABCA1 protein expression and increased calpain activity. The calpain inhibitor ALLN blocked the decrease of ABCA1 protein expression. Conclusion Overexpressed NHE1 suppresses the expression of ABCA1 protein via increasing the calpain activity in RAW264.7 cells. PMID- 28031108 TI - [Outer membrane protein 31 of B. melitensis induces the formation of autophagosomes in BV-2 microglia cells]. AB - Objective To determine the influence of outer membrane protein 31 (Omp31) of B. melitensis on the formation of autophagosomes in BV-2 microglia cells. Methods BV 2 cells were treated for 6 hours with Omp31 at 0.17, 0.50, 1.50, 4.50, 13.50 MUg/mL. Real-time quantitative PCR was used to detect the expression of microtubule associated protein 1 light chain 3B (LC3B) mRNA; Western blotting was applied to detect the expressions of LC3B II and LC3B proteins; transmission electron microscopy was performed to observe cell autophagy in each group. The levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and IL-10 in the culture cell supernatant were determined with ELISA. Results Omp31 treatment resulted in an increase in the level of LC3B II protein, especially the most obvious increase in the ones treated by 0.5 MUg/mL Omp31. The concentration of Omp31, being no more than 0.5 MUg/mL, could promote the expression of LC3B mRNA, while more than 0.5 MUg/mL Omp31, it could inhibit the expression of LC3B mRNA; 0.5 MUg/mL Omp31 could induce the formation of more autophagosomes in BV-2 cells. Omp31 promoted the expressions of TNF-alpha and IL-6, and inhibited the expression of IL-10 in BV-2 cells. Conclusion Omp31 at the concentration of 0.5 MUg/mL can significantly induce autophagy in BV-2 cells. PMID- 28031109 TI - [Immature dendritic cells phagocytosing apoptotic human spleen cells treated with PUVA inhibits the maturation induced by LPS]. AB - Objective To investigate whether lipopolysaccharide (LPS) can induce the maturation of immature dendritic cells (imDCs) which phagocytose apoptotic spleen lymphocytes. Methods Human peripheral blood mononuclear cells (PBMCs) were induced to produce DCs by interleukin 4 (IL-4) and recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF). Human spleen cells (hSPs) were isolated and treated with psoralen combined with ultraviolet A(PUVA) to obtain apoptotic PUVA-hSPs. Co-culture of imDCs with PUVA-hSPs resulted in extracorporeal photochemotherapeutic dendritic cells (ecpDCs). The imDCs and ecpDCs were collected and stimulated by 10 ng/mL LPS for 1 day. The expressions of CD11c, CD83 and CD86 were detected by flow cytometry. The level of IL-10 in the supernatants of the above cells was detected by ELISA. Results There was no significant difference in the expressions of CD83 and CD86 between ImDCs and ecpDCs. However, the positive rates of CD83 and CD86 in the imDCs stimulated by LPS were significantly higher than those in the ecpDCs treated by LPS. The level of IL-10 in imDCs culture supernatant was lower than that in ecpDCs. The level of IL-10 in LPS-stimulated imDCs was lower than that in LPS-stimulated ecpDCs. Conclusion Both imDCs and ecpDCs showed immature phenotype, but ecpDCs can inhibit the maturation of DC induced by LPS. PMID- 28031110 TI - [Recombinant platanus pollen allergen 2 (rPla a2) up-regulates the expression of ORMDL3 mediated by GATA3 in NIH3T3 cells]. AB - Objective To identify the effect and mechanism of recombinant platanus pollen allergen 2 (rPla a2) on the transcription and expression of orosomucoid 1-like 3 (ORMDL3) gene in NIH3T3 cells. Methods Quantitative real-time PCR and Western blot analysis were used to detect the influence of rPla a2 on the mRNA and protein levels of ORMDL3 and GATA3. After transfection of GATA3 siRNA or pcDNA GATA3, the role of GATA3 was evaluated in rPla a2 regulating ORMDL3 expression. Dual-luciferase reporter assay was performed to measure the influence of rPla a2 and GATA3 on ORMDL3 promoter activity. Results The rPla a2 induced mRNA and protein expressions of ORMDL3 and GATA3. Knockdown of GATA3 inhibited the induction of rPla a2 upon ORMDL3. In addition, the induction effect was enhanced by over-expression of GATA3. ORMDL3 promoter activity was significantly promoted by rPla a2 and inhibited by knockdown of GATA3. Conclusion The rPla a2 up regulates the expression of ORMDL3 mRNA and protein, which is mediated by GATA3 through targeting promoter region of ORMDL3. PMID- 28031111 TI - [Cucurbitacin I (JSI-124)-induced apoptosis of HepG2 cells via p53 signaling pathway]. AB - Objective To study the mechanism underlying cucurbitacin I (JSI-124) inducing cell apoptosis in human hepatoma HepG2 cells. Methods HepG2 cells were exposed to 0.01, 0.10, 1.00 and 10.00 MUmol/L JSI-124 for 24, 48 and 72 hours. Cell proliferation was detected by CCK-8 assay; the nuclear morphological changes were observed by Hoechst 33258 staining; the formation of tumor cell colonies was visualized by violet staining; and cell apoptosis was detected by annexin V FITC/PI double staining combined with flow cytometry. Furthermore, the mRNA expression levels of p53 and its downstream Bax, Fas and MDM2 genes were measured by quantitative real-time PCR, and the protein levels of P53 and activated caspase-3 were evaluated by Western blotting. Results JSI-124 inhibited the proliferation and induced Hoechst 33258-stained chromatin condensation in HepG2 cells in a concentration- and time-dependent manner. Flow cytometry revealed that 1.00 MUmol/L JSI-124 treatment increased the apoptotic rate significantly in HepG2 cells compared with the control cells. Furthermore, JSI-124 significantly enhanced the mRNA expressions of p53 and its downstream apoptotic factors, including Bax and Fas, but did not change the gene expression of the p53 tumor suppressor, MDM2. The 48-hour treatment of JSI-124 in HepG2 cells significantly increased the levels of p53 and cleaved caspase-3 proteins. Conclusion JSI-124 induces the apoptosis of HepG2 cells through the activation of p53 and its downstream pro-apoptotic factors. PMID- 28031112 TI - [Overexpression of liver kinase B1 inhibits the proliferation of lung cancer cells]. AB - Objective To explore the effect of overexpressed liver kinase B1(LKB1) on the proliferation of lung cancer cell lines. Methods The expression levels of LKB1 and PTEN in A549, NCI-H23, NCI-H157, XWLC-05, NCI-H446 lung cancer cells were detected by immunocytochemistry (ICC) and Western blotting. Plasmid pcDNA3.1+ LKB1 and empty vector pcDNA3.1+-null were separately transfected into the above five cell lines, and then the expression of LKB1 mRNA and protein were determined by quantitative real-time PCR and Western blotting, respectively. Finally, CCK-8 assay was used to analyze the proliferation ability of the transfected cells. Results LKB1 and PTEN were positive in NCI-H23 cells; LKB1 was negative while PTEN was positive in A549 and NCI-H446 cells; both LKB1 and PTEN were negative in NCI-H157 and XWLC-05 cells. Quantitative real-time PCR and Western blotting showed that the expression level of LKB1 significantly increased in the above cell lines transfected with plasmid pcDNA3.1+-LKB1 compared with the ones with empty vector pcDNA3.1+-null. Besides, CCK-8 assay showed that the overexpression of LKB1 in the lung cancer cells transfected with pcDNA3.1+-LKB1 had an obvious inhibitory effect on cell proliferation. Conclusion The expression of LKB1 is down-regulated in most of the lung cell lines to different extent and the over expression of LKB1 can remarkably inhibit the proliferation ability of lung cancer cell lines. PMID- 28031113 TI - [GenomeLabTM GeXP analysis system to detect apoptosis-associated genes in A549 cells treated by recombinant human IL-24 combined with cisplatin]. AB - Objective To investigate the changes of apoptosis-associated genes in human lung adenocarcinoma cell line A549 after treated by the recombinant human interleukin 24 (rhIL-24) combined with cisplatin (DDP). Methods The mRNA levels of Bax, Bcl 2, survivin, caspase-3, retinoblastoma (Rb) gene, p53 were analyzed by GenomeLabTM GeXP genetic analysis system after A549 cells were treated with 160 ng/mL rhIL-24 or 3 MUg/mL DDP or 160 ng/mL rhIL-24 combined with 3 MUg/mL DDP. Results The rhIL-24 up-regulated the levels of Bax, Rb, caspase-3 mRNAs and down regulated Bcl-2, survivin mRNAs, but the change of p53 mRNA was not regular. The combination of rhIL-24 and DDP strengthened the above changes. Conclusion The rhIL-24 protein can induce the apoptosis of A549 cells by up-regulating Bax, caspase-3, Rb mRNAs and down-regulating Bcl-2, survivin mRNAs. PMID- 28031114 TI - [Overexpression of N-myc downstream regulated gene 2 (NDRG2) inhibits proliferation, migration and promotes apoptosis in SW480 rectal cancer cells]. AB - Objective To investigate the role of N-myc downstream regulated gene 2 (NDRG2) gene in the proliferation, migration and apoptosis of rectal cancer cells. Methods Human rectal cancer SW480 cells were cultured and transfected with pCDNA3.1-NDRG2 and empty vector (SW480-Ve). SW480 cells were set as a control group. Cell proliferation was detected in SW480 cells, SW480-Ve cells and SW480 NDRG2 cells by MTT assay; cell migration distance in the three groups at 24, 48, 72 hours was tested by wound healing assay; apoptosis rate was determined in the three groups at 48 hours by flow cytometry; the expressions of Bax, caspase-3, Bcl-2 proteins in the three groups were examined by Western blotting. Results After the cells were cultured for 7 days, cell survival rate in SW480-NDRG2 group was significantly lower than that in SW480 cells and SW480-Ve cells; the cell survival rate decreased gradually with the prolongation of the culture time; and it had no significant difference between SW480-Ve group and SW480 group. Cell migration distance in SW480-NDRG2 group was significantly lower than that in SW480-Ve cells and SW480 cells, and it had also no significant difference between SW480-Ve cells and SW480 cells. The apoptosis rate in SW480-NDRG2 group was significantly higher than that in SW480 group and SW480-Ve group, and SW480 cells and SW480-Ve cells had no significant difference in the rate. The expressions of Bax and caspase-3 proteins in SW480-NDRG2 group were significantly higher than those in SW480 cells and SW480-Ve cells; Bcl-2 protein expression was significantly lower in SW480-NDRG2 group than in SW480 cells and SW480-Ve cells; and the expressions of Bax, caspase-3 and Bcl-2 proteins were not significantly different between SW480 cells and SW480-Ve cells. Conclusion Overexpression of NDRG2 can inhibit the proliferation, reduce cell migration, and promote cell apoptosis by regulating the expressions of Bcl-2, Bax and caspase-3 proteins in SW480 cells. PMID- 28031115 TI - [Knockdown of Raf kinase inhibitor protein promotes the proliferation of LX-2 human hepatic stellate cells]. AB - Objective To investigate the role of Raf kinase inhibitor protein (RKIP) in the proliferation of LX-2 human hepatic stellate cells. Methods The recombinant plasmid siRNA-RKIP was transfected into LX-2 cells. Five days later, the stably transfected cells were screened and cultured. MTT assay was used to detect cell proliferation after RKIP was silenced. Cell apoptosis and cell cycle distribution were evaluated by flow cytometry. The expressions of alpha-smooth muscle actin (alpha-SMA) and collagen type 1 (Col1) mRNA were detected by quantitative real time PCR. The expressions of RKIP, alpha-SMA, Col1 and extracellular signal regulated kinases/mitogen-activated protein kinase (ERK/MAPK) signaling pathway related proteins were assessed by Western blot analysis. Results Compared with the control group, knockdown of RKIP significantly induced LX-2 cell proliferation, reduced cell apoptosis, raise cell number in G2, and increased the proteins and mRNA expressions of Col1 and alpha-SMA. Moreover, low-expression of RKIP significantly enhanced the phosphorylation of ERK/MAPK. Conclusion Knockdown of RKIP promotes LX-2 cell proliferation; its mechanism is related to the activation of ERK/MAPK signaling pathway. PMID- 28031116 TI - [Adipose-derived stem cell transplantation promotes the expression of netrin-1 in the rat cortex after focal cerebral ischemia]. AB - Objective To observe the effect of adipose-derived stem cells (ADSCs) transplantation on the expression of netrin-1 in rats after focal cerebral ischemia. Methods Male SD rats were randomly divided into control group, model group and ADSC group. ADSCs were harvested and purified. Focal cerebral ischemia models were established in rats by the suture method. ADSCs were injected into the lateral ventricle of ADSC group rats and the same does of PBS was given to model group rats. At day 4, 7 and 14 after reperfusion, six rats were sacrificed to remove the brain tissues at each time point. The expression of netrin-1 was detected by reverse-transcription PCR, Western blotting and immunohistochemistry. Results Compared with the control group, the expression of netrin-1 in the brain tissues of the model group increased after focal cerebral ischemia, reached the peak at 4 days, and the expression of netrin-1 was significantly higher than that of the control group at each time point. Compared with the model group, the expression of netrin-1 in the ADSC group increased further, reached the peak at 7 days, and the expression of netrin-1 in the ADSC group was significantly higher than that of the model group at each time point. Conclusion ADSC transplantation could up-regulate the expression of netrin-1, and promote axon regeneration and the recovery of neurological functions. PMID- 28031117 TI - [Knockdown of myeloid cell leukemia 1 gene inhibits the proliferation and promotes apoptosis of prostate cancer cells]. AB - Objective To detect the protein expression level of human myeloid cell leukemia 1 (MCL-1) gene in prostate cancer and its effect on the prognosis of prostate cancer. Methods MCL-1 protein expression was detected by immunohistochemistry in 517 cases of prostate cancer tissues and the corresponding adjacent tissues. The correlation was analyzed statistically between the expression level and the prognosis of prostate cancer patients. In addition, after the expression of human MCL-1 protein in prostate cancer cell line was interfered, MTT assay, clone formation assay and TUNEL assay were performed to test the ability of cell proliferation and apoptosis. Results The expression of MCL-1 in prostate cancer was significantly higher than that in adjacent tissues, and the prognosis of patients with MCL-1 high expression was poor. The proliferation and apoptotic resistance of prostate cancer cells significantly decreased after the expression of MCL-1 was knocked down in prostate cancer cells. Conclusion The expression of MCL-1 in prostate cancer tissues was much higher than that in normal prostate tissues, and knockdown of MCL-1 in prostate cancer cells inhibits the proliferation and promotes apoptotsis of prostate cancer cells. PMID- 28031118 TI - [Isolation, purification and primary culture of adult mouse cardiac fibroblasts]. AB - Objective To establish a method for primary culture of adult mouse cardiac fibroblasts. Methods Myocardial tissues from adult mice were digested with 1 g/L trypsin and 0.8 g/L collagenase IV by oscillating water bath for a short time repeatedly. Cardiac fibroblasts and myocardial cells were isolated with differential adhesion method. Immunofluorescence staining was used to assess the purity of cardiac fibroblasts. The cell morphology was observed under an inverted phase contrast microscope. The proliferation of cardiac fibroblasts was analyzed by growth curve and CCK-8 assay. The Smad2/3 phosphorylation induced by TGF-beta1 was detected by Western blotting. Results After 90 minutes of differential adhesion, adherent fibroblasts formed spherical cell mass and after 3 days, cells were spindle-shaped and proliferated rapidly. Cells were confluent after 5 days and the growth curve presented nearly "S" shape. The positive expression rate of vimentin was 95%. CCK-8 assay showed that the optimal cell proliferating activity was found from day 3 to day 5. The level of phosphorylated Smad2/3 obviously increased at the second passage induced by TGF-beta1. Conclusion This method is economical and stable to isolate cardiac fibroblasts with high activity and high purity from adult mice. PMID- 28031119 TI - [The expression of T-bet is negatively correlated with the expressions of IFN gamma and TNF-alpha in CD4+ T cells of patients with active pulmonary tuberculosis]. AB - Objective To investigate the relationship between T box expressed in T cells (T bet) and the production of interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and interleukin 2 (IL-2) in CD4+T cells of patients with active pulmonary tuberculosis. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood by density gradient centrifugation. Individuals with latent Mycobacterium tuberculosis (MTB) infection were screened by enzyme linked immunospot assay (ELISPOT). The expressions of T-bet, IFN-gamma, TNF-alpha and IL-2 in CD4+T cells were detected by flow cytometry. Results The expression of IFN-gamma significantly increased in PBMCs from the individuals with latent tuberculosis infection when stimulated with MTB H37Rv strain lysates. T-bet expression in CD4+IFN-gamma+ cells from the patients with active pulmonary tuberculosis was significantly higher than that from the individuals with latent tuberculosis infection when stimulated with MTB H37Rv strain lysates. The expressions of IFN-gamma and TNF-alpha in T-bet- MTB antigen-specific CD4+T cells were obviously higher than those in T-bet+ cells; however, the expression of IL-2 showed no significant difference between T-bet- cells and T-bet+ cells. Conclusion The expression of T-bet in MTB antigen-specific CD4+T cells from patients with active pulmonary tuberculosis is negatively correlated with IFN gamma and TNF-alpha. PMID- 28031120 TI - [Expression and clinical significance of ARID1A in gastric cancer and paired adjacent noncancerous tissues]. AB - Objective To investigate the expression pattern and clinical significance of chromatin remodeling AT-rich interactive domain 1A (ARID1A) protein in gastric cancer and paired adjacent noncancerous tissue samples. Methods The expression of ARID1A protein was examined in 90 gastric cancer tissue samples and 90 paired adjacent noncancerous tissue samples by immunohistochemistry. The relationship of ARID1A protein expression with clinical-pathological characteristics was evaluated by Mann-Whitney test and Spearman correlation analysis. The relationship with clinical prognosis was analyzed by Kaplan-Meier survival curve, Log-Rank test and Cox regression model. Results ARID1A was expressed in both cytoplasm and nucleus of adjacent noncancerous tissues and gastric cancer tissues. Both cytoplasmic and nuclear ARID1A expressions significantly decreased in gastric cancer tissues compared with adjacent noncancerous tissues. Cytoplasmic ARID1A expression in adjacent noncancerous tissues was negatively correlated with clinical TNM stage. Meanwhile, nuclear ARID1A expression in adjacent noncancerous tissues was positively correlated with patients' age and negatively correlated with tumor size. Survival analysis showed that cytoplasmic ARID1A expression in adjacent noncancerous tissues was related with overall survival but not significantly, and that both cytoplasmic and nuclear ARID1A expressions in gastric cancer tissues were not related with clinical-pathological characteristics and prognosis. Conclusion ARID1A may play an important role in the early events of gastric carcinogenesis, and it can serve as a potential biomarker for early diagnosis. PMID- 28031121 TI - [Increased expressions of peripheral PD-1+ lymphocytes and CD4+CD25+FOXP3+ T cells in gastric adenocarcinoma patients]. AB - Objective To detect the frequencies of peripheral programmed death-1+ (PD-1+) lymphocytes and CD4+CD25+FOXP3+ regulatory T cells in patients with gastric adenocarcinoma. Methods The study enrolled 29 patients with gastric adenocarcinoma and 29 age- and sex-matched healthy controls. Frequencies of PD-1+ lymphocytes and CD4+CD25+FOXP3+ regulatory T cells were detected using flow cytometry. Results The number of PD-1+ lymphocytes and CD4+CD25+FOXP3+ regulatory T cells in peripheral blood was higher in patients with gastric adenocarcinoma than that in the control group. Moreover, linear correlation analysis indicated a positive correlation between PD-1 expression and frequency of CD4+CD25+FOXP3+ regulatory T cells in peripheral blood of the patients. Conclusion Gastric adenocarcinoma patients present with increased PD-1+ lymphocytes and CD4+CD25+FOXP3+ regulatory T cells in the peripheral blood. PMID- 28031122 TI - [Increased eosinophils in nasal exudation after allergic rhinitis nasal provocation are positively correlated with serum level of specific IgE]. AB - Objective To study the relationship between specific nasal provocation test (SNPT) and serum specific IgE level in the patients with allergic rhinitis, and analyze the correlation between the eosinophil (EOS) percentage in nasal secretion and serum specific IgE level. Methods SNPT was performed in 80 cases of perennial allergic rhinitis due to dust mites. Specific IgE in the serum of those patients was detected by Unicap. EOS percentage in nasal secretions was recorded before and after SNPT. The correlation of EOS percentage and serum level of specific IgE was analyzed by Kendall's tau-b test. Results The positive result of SNPT had a concordance with serum specific IgE in recruited patients. And the increased EOS percentage in nasal secretions after SNPT had a positive correlation with the level of serum specific IgE. Conclusion Positive SNPT can be used as a diagnostic index of allergic rhinitis. And the increased percentage of EOS in nasal secretions after SNPT can also help evaluate the severity of allergic rhinitis. PMID- 28031123 TI - [Preparation of polyclonal antibody against recombinant sigma54 protein from Helicobacter pylori]. AB - Objective To express and purify recombinant sigma54 protein of Helicobacter pylori, and prepare polyclonal antibody against sigma54 protein. Methods Intact rpoN gene fragment was amplified from Helicobacter pylori (H. pylori) 26695 genome, and then cloned into prokaryotic expression vector pTriExTM-4 with 6His coding sequence. The recombinant plasmid was transformed into E.coli JM109DE. The recombinant protein with 6-His tag was expressed by IPTG induction and purified by His-Bind affinity columns. The purified protein supplemented with adjuvant was used to immunize rabbits to obtain the polyclonal antibody. Results Recombinant sigma54 protein was successfully expressed in E.coli JM109DE. SDS-PAGE that was used to detect the purified protein showed a single band which was consistent with the expected size of the recombinant protein. The polyclonal antibody exhibited a good recognition and specificity against sigma54 protein. Conclusion The study successfully expressed and purified sigma54 protein, and obtained its polyclonal antibody. PMID- 28031124 TI - [Preparation and application of melanoma-associated antigen D4 polyclonal antibody]. AB - Objective To prepare the rabbit polyclonal antibody recognizing human melanoma associated antigen D4 (MAGE-D4), and identify its immune characteristics for preliminary application. Methods MBP/MAGE-D4 fusion protein was expressed from pMAL-C2/MAGE-D4 recombinant plasmid constructed in the previous work. Then the purified MBP/MAGE-D4 protein was used to immunize the New Zealand white rabbits for generating polyclonal antibody. Subsequently, the anti-MAGE-D4 antibody was purified with protein A affinity chromatograph and identified by SDS-PAGE. The titer and specificity of the antibody were further detected by indirect ELISA and Western blotting, respectively. MAGE-D4 expression and localization of lung cancer tissues were analyzed by immunohistochemical staining. Results MAGE-D4 polyclonal antibody with high purity was obtained. Its titer was about 1:256 000. Western blot analysis demonstrated that the antibody could specifically react to the recombinant MAGE-D4 protein. Immunohistochemical staining showed that the antibody could recognize the endogenous MAGE-D4 protein in lung cancer tissues, and its positive rate was 69.6% (17/23). Conclusion The MAGE-D4 polyclonal antibody with high specificity and sensitivity has been successfully prepared. PMID- 28031125 TI - What Is Dry Skin? PMID- 28031126 TI - Can We Predict the Effectiveness of Intralesional Immunotherapy in Recalcitrant Warts? AB - Immunotherapy has been used for recalcitrant, large, and multiple warts, although it is difficult to predict which patient will respond. An open interventional cohort trial was conducted in 50 adult patients with recalcitrant multiple, nongenital warts in whom intralesional immunotherapy was given using the Mycobacterium welchii vaccine. The authors determined whether the wart resolution was dependent on the immune response. The response of various types of warts was also compared with the initial immune response. Complete cure was used as a treatment endpoint, which was defined as a lack of recurrence at follow-up of at least 6 months. The majority of patients had palmoplantar warts (54%). A total of 26 patients achieved a clinical cure. The high immune group achieved a higher complete cure rate (60%) as compared with the low immune group (20%) (P=.008; absolute risk reduction=.44; number needed to treat=3) with a fewer number of sessions (P=.004). This difference was most marked in palmoplantar warts (P=.04). Immunotherapy using M welchii is a useful modality in recalcitrant warts in patients who have a test site induration of >=10 mm, but this does not affect the recurrence rates. PMID- 28031127 TI - Wide Morphologic Variability of Chromoblastomycosis in the Western Hemisphere. AB - Chromomycosis is an uncommon fungal disease seen in tropical and subtropical regions of the world. The disorder is most likely the result of traumatic percutaneous inoculation of one of several etiologic dematiaceous fungi. Causative organisms have been associated with dead wood, soil, and plants. Chromomycosis may present clinically in a wide variety of manners. We illustrate the characteristic morphologic appearances of mycosis as it was encountered in both Panama and Texas, including verrucous papules and nodules, scaly plaques, exophytic or ulcerative tumor-like masses, and cicatricial plaques of both small and large dimension. As is typical of this disease, all lesions in this series were located on the extremities, and all patients had frequent and intimate exposure to vegetation in hot, humid environments. Chromomycosis characteristically runs an indolent course and is rarely fatal. The patients described herein had experienced cutaneous lesions for many months to several decades prior to diagnosis. This mycosis is often difficult to treat. Successful therapy may involve one or more oral antifungal drugs (such as itraconazole and terbinafine) and/or use of physically ablative modalities (such as laser, photodynamic therapy, and cryosurgery). PMID- 28031128 TI - Aging and Facial Changes-Documenting Clinical Signs, Part 2: Methods of Documentation of Facial Changes. AB - Skin metrology has emerged as a multidisciplinary approach for objectively documenting skin anatophysiologic aspects and transformations. Methods have been proposed to describe age-related changes of facial skin. Some of them capture information describing visible clinical signs of aging such as wrinkles, sagging, and pigmentation. These methods include but are not limited to digital imaging, 3 dimensional imaging, and colorimetry. Other methods focus more on structural or physiologic changes of underlying tissues, among these are reflectance confocal imaging, magnetic resonance imaging, and ultrasound imaging. Finally, a group of methods including corneometry and reviscometry are used to describe changes in skin properties. This contribution describes available methods for documenting age-related changes affecting the shape, texture, and color of the face. PMID- 28031130 TI - Eucerin: A Revolutionary Formulation Still Going Strong for Over a Century. AB - Eucerit, now more commonly known as Eucerin, was a revolutionary emulsion developed more than 100 years ago that is still popular and in common use today. The initial formulation is still the basis for a relevant global product line that holds significant market share today. The concept for Eucerin was originally developed in Germany by Dr Isaac Lifschutz, who helped develop Eucerin, meaning "beautiful wax," in 1898. The ointment was very smooth, allowing Eucerin to develop as a stable emulsion. Eucerin was revolutionary and outperformed all of its predecessors in emulsion stability, moisturizing ability, its ability to resist degradation, and its cost-effectiveness.1. PMID- 28031131 TI - Deadly Skin Tags! PMID- 28031132 TI - FINACEATM (Azelaic Acid) Foam, 15. PMID- 28031133 TI - Conceptual Confluence: The Marriage of IgG4-Related Disease and Adult-Onset Asthma With Periocular Xanthogranulomas. PMID- 28031134 TI - Psoriasis and Upper Respiratory Infection. PMID- 28031135 TI - Asymptomatic Swelling on the Inner Surface of the Lower Lip. PMID- 28031136 TI - Simultaneous Occurrence of Papulonecrotic Tuberculid and Erythema Induratum in an Asian Woman. AB - A 31-year-old Indonesian woman presented with a 2-month history of recurrent painful nodules on the legs. Review of systems did not reveal any respiratory, gastrointestinal, or abdominal findings. She had been to Singapore working as a domestic helper for close to a year. There was no contact history of tuberculosis. PMID- 28031137 TI - Voriconazole-Induced Subacute Cutaneous Lupus Erythematosus in an Adult With Aspergillosis. AB - A 59-year-old man was treated with voriconazole for chronic invasive aspergillosis and who subsequently developed subacute cutaneous lupus erythematosus (SCLE). The patient presented with a 6-week history of multiple erythematous papulosquamous lesions on his chest, upper and lower extremities, and back (Figure 1). They were nonpruritic and nonpainful. He was afebrile and otherwise well. He had no history of extensive sun exposure prior to the appearance of the eruption. He had been taking voriconazole for about 3 months prior to the onset of lesions. He denied any family history of connective tissue disease. PMID- 28031138 TI - A Yellow Papular Eruption on the Arms, Legs, and Neck: A Rare Masquerader. AB - A 54-year-old Caucasian woman with a medical history of mitral valve prolapse presented with a 5-year history asymptomatic papules. There was no family history of similar lesions. Physical examination revealed >100, 2- to 4-mm, firm, yellow, dermal papules located on the neck, antecubital and popliteal fossae, flexor surface of both forearms, and inner aspect of the thighs (Figure 1). There was no skin laxity. A 4-mm punch biopsy was obtained from the left thigh for histologic examination. Findings showed a focal increase in the concentration of elastic fibers highlighted by Verhoeff Van Gieson stain (Figure 2). There was no fragmentation, calcification, or phagocytosis of elastic fibers. There was also no evidence of actinic elastosis. A section stained with hematoxylin and eosin appeared relatively unremarkable. These findings were consistent with late-onset focal dermal elastosis. PMID- 28031139 TI - Multiple Familial Trichoepithelioma Successfully Treated With CO2 Laser and Imiquimod. AB - A 33-year-old woman presented with more than 100 flesh-colored papules and nodules centrally located on the face (Figure 1). Since their first appearance at the age of 7, the lesions had increased in number and spread laterally from the nasolabial folds. She underwent surgical removal at age 10 with recurrence afterward. Her mother, maternal grandmother, and maternal great aunt have similar lesions on the face. Histopathologic examination confirmed the diagnosis of trichoepitheliomas and multiple familial trichoepithelioma (MFT). PMID- 28031140 TI - Cutaneous Presentation of Angioimmunoblastic T-Cell Lymphoma: A Harbinger of Poor Prognosis? AB - A 62-year-old woman presented with a 2-year history of extensive, pruritic dermatosis over her face, trunk, and limbs. She was initially treated for psoriasis with methotrexate 5 mg twice weekly and topical clobetasol cream; however, her condition worsened, and she was admitted for generalized exfoliative dermatitis. Examination showed generalized erythema and scaling affecting her face (Figure 1A), chest (Figure 1B), back, and limbs. There were also cervical, axillary, and inguinal lymphadenopathy. Laboratory studies revealed a high white blood cell count of 125*109/L (reference range: 4-10*109/L), hemoglobin level of 11.9 g/dL (reference range: 12-16 g/dL), and normal platelet level of 396*109/L (reference range: 140-440*109/L). Results from direct Coombs test were negative and lactate dehydrogenase levels were normal. PMID- 28031141 TI - Inflamed Actinic Keratoses After Pemetrexed. AB - A 66-year-old man presented with a 1-day history of a mildly pruritic eruption on the face, chest, arms, and upper part of the back. The dermatitis began 3 weeks after receiving an initial infusion of pemetrexed (500 mg/m2) as induction chemotherapy for non-small cell lung cancer. Physical examination revealed numerous erythematous, scaly papules over the face, extensor surface of the arms, hands, and upper aspects of the chest and back, sparing sun-protected areas (Figure). He acknowledged that in the past he frequently went shirtless outdoors and rarely wore sunscreen or sun protective clothing during the many years he worked at construction sites. Results from a biopsy specimen from a typical lesion on the forearm revealed an inflamed actinic keratosis. Systemic chemotherapy was continued, and only emollients and mid-potency topical steroids were used to treat the skin eruption. At 2-week follow-up, the patient's eruption was greatly diminished with loss of significant erythema and scale, as well as absence of pruritus. PMID- 28031142 TI - Pilomatrix Carcinoma Mimicking a Pigmented Basal Cell Carcinoma. AB - A 76-year-old Caucasian man presented to the dermatology clinic for evaluation of a growing lesion in his right preauricular area. He first noticed the lesion several months prior to presentation but felt it had enlarged significantly in the past month. He denied any pain, pruritus, or bleeding. His medical history was significant for melanoma of the nose treated 47 years ago, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and chronic back pain. The patient reported having the melanoma treated but was unaware of any other details concerning the lesion. He denied any allergies and his medications included lisinopril, amlodipine, gabapentin, and budesonide. PMID- 28031143 TI - Neurofibromatosis Type 1 and Vitiligo, a Rare Association. PMID- 28031145 TI - A surgery trainee's guide to writing a manuscript. AB - Publishing clinical and research work for dissemination is a critical part of the academic process. Learning how to write an effective manuscript should be a goal for medical students and residents who hope to participate in publishing. While there are a number of existing texts that address how to write a manuscript, there are fewer guides that are specifically targeted towards surgery trainees. This review aims to direct and hopefully encourage surgery trainees to successfully navigate the process of converting ideas into a publication that ultimately helps understanding and improves the care of patients. PMID- 28031146 TI - Visual perspective during remembering: ERP evidence of familiarity-based source monitoring. AB - Autobiographical recollections are accompanied by visual perspectives that can be either a view through the person's own eyes (first-person) or a view that integrates visual characteristics of the rememberer into the reconstructed scene (third-person). Some have argued that a third-person perspective serves as a coping mechanism allowing the person to distance themselves from details of painful memories. The study reported here created first- and third-person memories in a novel experimental paradigm. Later, participants discriminated between these perspectives on a source memory test while event-related potentials (ERPs) were recorded. Experimental evidence from the current study suggests that memories from different perspectives can be effectively modeled in the lab. Directly comparing first-person and third-person memories revealed no strong source memory or ERP differences; however, more first-person memories were recognized. Surprisingly, the modeling of the behavioral data using ROC curves and Dual Process Signal Detection (DPSD) measures of recollection and familiarity suggest that familiarity contributed to source judgments of both first- and third person memories. The ERP data support this claim because the putative ERP correlate of familiarity (i.e., FN400) was observed during the source test. Because source monitoring tends to draw on recollection, evidence of familiarity based source monitoring has been elusive, and these results support a key prediction of the Source Monitoring Framework (SMF) - that source decisions can be based on familiarity in some contexts (Johnson, Hashtroudi, & Lindsay, 1993; Mitchell & Johnson, 2009). PMID- 28031147 TI - Review: Effects of maternal micronutrient supplementation on placental function. AB - Pregnancy is a physiological challenge that may require additional nutritional support. Suboptimal micronutrient intakes and micronutrient deficiencies during pregnancy are a global problem, often leading to poor maternal and child outcomes. Micronutrient supplementation is commonly recommended during pregnancy to support and enhance maternal metabolism. Recent studies suggest that the use of multiple micronutrient supplements may be of benefit during a normal pregnancy and may significantly reduce the risk of preeclampsia, preterm delivery, gestational diabetes, and improve pregnancy outcomes. Given the crucial role that the placenta plays in mediating pregnancy outcomes, it is important to consider the impact of micronutrient supplementation on the mechanisms associated with placental function, as well as maternal and fetal homeostasis. This review will consider the role of key micronutrients in supporting pregnancy and the possible mechanisms by which multiple micronutrients influence placental function and modulate placental oxidative stress and inflammation. PMID- 28031148 TI - Reliability and minimal detectable change of transcranial magnetic stimulation outcomes in healthy adults: A systematic review. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) is used worldwide for noninvasively testing human motor systems but its psychometric properties remain unclear. OBJECTIVE/HYPOTHESIS: This work systematically reviewed studies on the reliability of TMS outcome measures of primary motor cortex (M1) excitability in healthy humans, with an emphasis on retrieving minimal detectable changes (MDC). METHODS: The literature search was performed in three databases (Pubmed, CINAHL, Embase) up to June 2016 and additional studies were identified through hand searching. French and English-written studies had to report the reliability of at least one TMS outcome of M1 in healthy humans. Two independent raters assessed the eligibility of potential studies, and eligible articles were reviewed using a structured data extraction form and two critical appraisal scales. RESULTS: A total of 34 articles met the selection criteria, which tested the intra- and inter-rater reliability (relative and absolute subtypes) of several TMS outcomes. However, our critical appraisal of studies raised concerns on the applicability and generalization of results because of methodological and statistical pitfalls. Importantly, MDC were generally large and likely affected by various factors, especially time elapsed between sessions and number of stimuli delivered. CONCLUSIONS: This systematic review underlined that the evidence about the reliability of TMS outcomes is scarce and affected by several methodological and statistical problems. Data and knowledge of the review provided however relevant insights on the ability of TMS outcomes to track plastic changes within an individual or within a group, and recommendations were made to level up the quality of future work in the field. PMID- 28031149 TI - Diagnostic and prognostic value of a careful symptom evaluation and high sensitive troponin in patients with suspected stable angina pectoris without prior cardiovascular disease. AB - BACKGROUND AND AIMS: Typical angina pectoris (AP) and high-sensitive troponin I (hs-TnI) are independently associated with coronary artery disease (CAD) and future cardiovascular events (CVE). This study aimed to assess the individual and combined diagnostic and prognostic impact of symptoms and hs-TnI in stable chest pain patients without prior cardiovascular disease. METHODS: During a one-year period, 487 patients with suspected stable AP underwent invasive or CT-coronary angiography (significant stenosis >=50%). At study inclusion, a careful symptom evaluation was obtained, and patients were classified as having typical AP, atypical AP, or non-cardiac chest pain. Hs-TnI was measured in all patients and divided into tertiles for analysis. Follow-up was a median of 4.9 years with cardiovascular death, non-fatal myocardial infarction, unstable AP, ischemic stroke, coronary-artery-bypass-grafting, percutaneous coronary intervention, and peripheral vascular surgery as combined endpoint. RESULTS: Hs-TnI was detected in 486 patients (99.8%). By multivariate regression analysis, typical AP and hs-TnI elevation were associated with increased risk of having significant CAD (typical AP, OR: 3.46; 95% CI: 2.07-5.79; p < 0.0001, hs-TnI, OR: 1.50; 95% CI: 1.12-2.01; p = 0.007) and experiencing future CVE (typical AP, HR: 2.64; 95% CI: 1.74-3.99; p = 0.001, hs-TnI, HR: 1.26; 95% CI: 1.06-1.49; p = 0.008). Patients in the lowest hs-TnI tertile, without typical AP (n = 107) had a 1.9% absolute risk of significant CAD and a 3.7% absolute risk of long-term CVE. CONCLUSIONS: In clinical stable patients without known cardiovascular disease, a thorough chest pain history in combination with hs-TnI testing can identify a significant low risk group. The prognostic need for coronary angiography in these patients seems limited. PMID- 28031150 TI - Functional Dysconnection of the Inferior Frontal Gyrus in Young People With Bipolar Disorder or at Genetic High Risk. AB - BACKGROUND: Bipolar disorder (BD) is characterized by a dysregulation of affect and impaired integration of emotion with cognition. These traits are also expressed in probands at high genetic risk of BD. The inferior frontal gyrus (IFG) is a key cortical hub in the circuits of emotion and cognitive control, and it has been frequently associated with BD. Here, we studied resting-state functional connectivity of the left IFG in participants with BD and in those at increased genetic risk. METHODS: Using resting-state functional magnetic resonance imaging we compared 49 young BD participants, 71 individuals with at least one first-degree relative with BD (at-risk), and 80 control subjects. We performed between-group analyses of the functional connectivity of the left IFG and used graph theory to study its local functional network topology. We also used machine learning to study classification based solely on the functional connectivity of the IFG. RESULTS: In BD, the left IFG was functionally dysconnected from a network of regions, including bilateral insulae, ventrolateral prefrontal gyri, superior temporal gyri, and the putamen (p < .001). A small network incorporating neighboring insular regions and the anterior cingulate cortex showed weaker functional connectivity in at-risk than control participants (p < .006). These constellations of regions overlapped with frontolimbic regions that a machine learning classifier selected as predicting group membership with an accuracy significantly greater than chance. CONCLUSIONS: Functional dysconnectivity of the IFG from regions involved in emotional regulation may represent a trait abnormality for BD and could potentially aid clinical diagnosis. PMID- 28031151 TI - New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity. AB - Novel omega-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by NMR spectroscopy. Their antiprotozoal activities were examined in vitro against the sensitive NF54 strain as well as against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results were compared with the activities of clinically used drugs. Their antitrypanosomal activities were only moderate whereas their antiplasmodial activities looked very promising. Some were equal or slightly more active than chloroquine against the sensitive strain. However, in comparison to chloroquine, the activity of the new compounds was decreased much less in the resistant strain. Several possessed activity against both strains in low nanomolar concentration. PMID- 28031152 TI - Lycopene pretreatment improves hepatotoxicity induced by acetaminophen in C57BL/6 mice. AB - Acetaminophen (APAP) is an antipyretic and analgesic drug that, in high doses, leads to severe liver injury and potentially death. Oxidative stress is an important event in APAP overdose. Researchers are looking for natural antioxidants with the potential to mitigate the harmful effects of reactive oxygen species in different models. Lycopene has been widely studied for its antioxidant properties. The aim of this study was to evaluate the antioxidant potential of lycopene pretreatment in APAP-induced liver injury in C57BL/6 mice. C57BL/6 male mice were divided into the following groups: control (C); sunflower oil (CO); acetaminophen 500mg/kg (APAP); acetaminophen 500mg/kg+lycopene 10mg/kg (APAP+L10), and acetaminophen 500mg/kg+lycopene 100mg/kg (APAP+L100). Mice were pretreated with lycopene for 14 consecutive days prior to APAP overdose. Analyses of blood serum and livers were performed. Lycopene was able to improve redox imbalance, decrease thiobarbituric acid reactive species level, and increase CAT and GSH levels. In addition, it decreased the IL-1beta expression and the activity of MMP-2. This study revealed that preventive lycopene consumption in C57BL/6 mice can attenuate the effects of APAP-induced liver injury. Furthermore, by improving the redox state, and thus indicating its potential antioxidant effect, lycopene was also shown to have an influence on inflammatory events. PMID- 28031153 TI - Surgical Management and Hearing Outcome of Traumatic Ossicular Injuries. AB - OBJECTIVE: The purpose of this study was to investigate etiological, clinical, and pathological characteristics of traumatic injuries of the middle ear ossicular chain and to evaluate hearing outcome after surgery. MATERIAL AND METHODS: Thirty consecutive patients (31 ears) with traumatic ossicular injuries operated on between 2004 and 2015 in two tertiary referral otologic centers were retrospectively analyzed. Traumatic events, clinical features, ossicular lesions, treatment procedures, and audiometric results were evaluated. Air conduction (AC), bone conduction (BC), and air-bone gap (ABG) were analyzed preoperatively and postoperatively. Amsterdam Hearing Evaluation Plots (AHEPs) were used to visualize the individual hearing results. RESULTS: The mean age at the moment of trauma was 27.9+/-17.1 years (range, 2-75 years) and the mean age at surgery was 33.2+/-16.3 years (range, 5-75 years). In 10 cases (32.3%), the injury occurred by a fall on the head and in 9 (29.0%) by a traffic accident. Isolated luxation of the incus was observed in 8 cases (25.8%). Dislocation of the stapes footplate was seen in 4 cases (12.9%). The postoperative ABG closure to within 10 and 20 dB was 30% and 76.7%, respectively. CONCLUSION: Ossicular chain injury by direct or indirect trauma can provoke hearing loss, tinnitus, and vertigo. As injuries are heterogeneous, they require a tailored surgical approach. In this study, the overall hearing outcome after surgical repair was favorable. PMID- 28031154 TI - Single Administration of a Sustained-Release Formulation of KB-R7785 Inhibits Tympanic Membrane Regeneration in an Animal Model. AB - OBJECTIVE: A pressure equalization tube placed within the tympanic membrane is the only clinically available method for inhibiting tympanic membrane regeneration. Problems associated with this include associated otorrhea, biofilm formation, medial migration of the tube, tube retention, induction of granulation tissue, and a small but significant rate of cholesteatoma. We aimed to demonstrate that a single administration of a sustained-release polymer formulation of KB-R7785 maintains tympanic membrane perforation for at least 6 months. MATERIALS AND METHODS: Sustained-release KB-R7785 was delivered within a novel polymer hydrogel to 20 mice with bilateral acute tympanic membrane perforations (a total of 40 perforations). The perforations were monitored at 3 month intervals until 9 months. RESULTS: At 3 months, 90% of perforations were open (n=36/40). At 6 months, 75% of perforations were open (total n=30/40). At 9 months, 22.5% of perforations were open (total n=6/40). The majority of tympanic membrane perforations (75%) were open (not healed) beyond 6 months and close (fully healed) prior to 9 months (77.5%). Once healed, tympanic membranes resembled their normal histological appearance. CONCLUSION: This study demonstrates that a single administration of a sustained-release polymer formulation of KB-R7785 inhibits tympanic membrane regeneration for 6-9 months. PMID- 28031155 TI - An Implantable Hearing System As Rehabilitation for Hearing Loss Due to Bilateral Aural Atresia: Surgical Technique and Audiological Results. AB - OBJECTIVE: To demonstrate the surgical technique and audiological results of a middle ear implant for restoring hearing in patients with bilateral aural atresia and microtia with conductive or mixed hearing loss. MATERIALS AND METHODS: In this prospective study, 12 subjects aged 12 years and older presenting with hearing loss and bilateral congenital aural atresia underwent surgical insertion of a middle ear implant. The patients underwent tympanomastoidectomy with a wide opening of the attic and preservation of the roof of the atresic tympanic bone to expose the middle ear and position the floating mass transducer of the implant. RESULTS: There were no intraoperative or postoperative complications. The hearing threshold averages in a free field were 53.5 dB preoperatively and 25.6 dB postoperatively. Monosyllabic word recognition averaged 61% preoperatively and 91.3% postoperatively. The average speech perception in quiet conditions during the hearing in noise test improved from 67.11 dB to 45.99 dB, and the signal-to noise ratio improved from 5.64 to 1.31. CONCLUSION: The tested system is an excellent option for auditory rehabilitation of conductive hearing loss due to bilateral ear atresia. The surgery is well structured and safe and provides several alternatives to the surgeon, which is valuable in difficult cases. PMID- 28031156 TI - Endolymphatic Duct Blockage for Refractory Meniere's Disease: Assessment of Endolymphatic Sac Biopsy on Short-Term Surgical Outcomes. AB - OBJECTIVE: Endolymphatic sac decompression (ESD) for the treatment of Meniere's disease (MD) has had limited success and variable results in the literature. We have devised a novel technique that involves blocking the endolymphatic duct with surgical clips. In a separate effort to study the endolymphatic sac (ELS), we have sectioned the lateral part of the main body of the ELS as biopsies from a subset of patients. We aimed to evaluate the effect of the lateral part sectioning of the ELS on short-term surgical outcomes. MATERIALS AND METHODS: This was a single-physician, retrospective study in a tertiary medical center. MD patients underwent endolymphatic duct blockage (EDB) surgery with or without ELS biopsy. The assessed surgical outcomes were the occurrence of benign paroxysmal positional vertigo (BPPV), intraoperative CSF leaks, aural fullness, tinnitus, vertigo spells, and pure tone audiometry. Data were collected at the following visits: preoperatively 1st week, 1st month, and 6th months. RESULTS: A total of 63 patients were included. The outcomes of the biopsy group (EDB+B) (n=27) were compared to those of the EDB group (n=36) at each visit. There was no significant difference in the occurrence of postoperative BPPV, CSF leaks, aural fullness, tinnitus, or vertigo spells. The SDS, the PTA, and bone conduction were not significantly different at any visit, and PTA variations were similar in both groups. CONCLUSION: Our results suggest that aggressive decompression of the ELS by sectioning the sac does not benefit patients in the early postoperative period. The short-term success of EDB surgery is attributable to the effective obstruction of the endolymphatic duct regardless of pressure in the ELS. PMID- 28031157 TI - Evaluation of Cervical Vestibular-Evoked Myogenic Potential Findings in Benign Paroxysmal Positional Vertigo. AB - OBJECTIVE: Although there has been a wide consensus on the mechanism of nystagmus and clinical presentation of benign paroxysmal positional vertigo (BPPV), the neuroepithelial pathophysiology of BPPV still remains unclear. In this study, we aimed to clarify the pathophysiology of BPPV by evaluating the cervical vestibular-evoked myogenic potential (cVEMP) findings of patients. MATERIALS AND METHODS: Thirty-six BPPV patients and 20 healthy volunteers were included. Bilateral cVEMP tests were performed on all participants. The participants were divided into the following three groups: those with a BPPV-affected ear, those with a BPPV-unaffected ear, and the healthy control group. RESULTS: There were no significant differences regarding the latencies of the first positive (p1) and negative (n1) peaks among the three groups. The mean normalized amplitude asymmetry ratio also did not differ between the BPPV and control groups. However, the normalized amplitudes of the BPPV patients (with both affected and unaffected ears) were significantly lower than those of the healthy control group. CONCLUSION: We detected that the cVEMP data of the affected and unaffected ears of the BPPV patients was similar and that their normalized amplitudes significantly differed from those of the healthy controls. Eventually, we concluded that even if the symptoms of BPPV were unilateral, the findings suggest that the bilateral involvement of the macular neuroepithelium is important in understanding the pathophysiology of BPPV. This finding supports the conclusion that the pathophysiological process starts with neuroepithelial membrane degeneration and continues with otoconia separation. PMID- 28031158 TI - An Iatrogenic Cholesteatoma of the Squamous Part of the Temporal Bone. AB - A cholesteatoma is a relatively common condition within the middle ear cavity, whereas a cholesteatoma of the squamous part of the temporal bone is an exceptionally rare entity. A case of an iatrogenic cholesteatoma located in the squamous part of the temporal bone is presented, which was revealed by an intermittent purulent discharge from an opening above the right ear 20 years after retroauricular myringoplasty. The diagnosis of an iatrogenic cholesteatoma is often made after several years of evolution, sometimes even at the stage of complications. This set the importance of the otoscopic and radiological regular monitoring of patients who have undergone a surgery of the temporal bone. PMID- 28031161 TI - Leucotriene receptor antagonists for asthma can save millions, says NICE. PMID- 28031162 TI - Is Blood Pressure Independent Arterial Destiffening Possible? PMID- 28031160 TI - Myelo-erythroid commitment after burn injury is under beta-adrenergic control via MafB regulation. AB - Severely injured burn patients receive multiple blood transfusions for anemia of critical illness despite the adverse consequences. One limiting factor to consider alternate treatment strategies is the lack of a reliable test platform to study molecular mechanisms of impaired erythropoiesis. This study illustrates how conditions resulting in a high catecholamine microenvironment such as burns can instigate myelo-erythroid reprioritization influenced by beta-adrenergic stimulation leading to anemia. In a mouse model of scald burn injury, we observed, along with a threefold increase in bone marrow LSK cells (linneg Sca1+cKit+), that the myeloid shift is accompanied with a significant reduction in megakaryocyte erythrocyte progenitors (MEPs). beta-Blocker administration (propranolol) for 6 days after burn, not only reduced the number of LSKs and MafB+ cells in multipotent progenitors, but also influenced myelo-erythroid bifurcation by increasing the MEPs and reducing the granulocyte monocyte progenitors in the bone marrow of burn mice. Furthermore, similar results were observed in burn patients' peripheral blood mononuclear cell-derived ex vivo culture system, demonstrating that commitment stage of erythropoiesis is impaired in burn patients and intervention with propranolol (nonselective beta1,2 adrenergic blocker) increases MEPs. Also, MafB+ cells that were significantly increased following standard burn care could be mitigated when propranolol was administered to burn patients, establishing the mechanistic regulation of erythroid commitment by myeloid regulatory transcription factor MafB. Overall, results demonstrate that beta-adrenergic blockers following burn injury can redirect the hematopoietic commitment toward erythroid lineage by lowering MafB expression in multipotent progenitors and be of potential therapeutic value to increase erythropoietin responsiveness in burn patients. PMID- 28031159 TI - Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. AB - Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. (c)2017 AACR.See related commentary by Yang, p. 250This article is highlighted in the In This Issue feature, p. 235. PMID- 28031163 TI - GP surgeries will get 1500 more pharmacists after successful pilot. PMID- 28031164 TI - Improvement in 5-year mortality in incident rheumatoid arthritis compared with the general population-closing the mortality gap. AB - OBJECTIVE: Excess mortality in rheumatoid arthritis (RA) is expected to have improved over time, due to improved treatment. Our objective was to evaluate secular 5-year mortality trends in RA relative to general population controls in incident RA cohorts diagnosed in 1996-2000 vs 2001-2006. METHODS: We conducted a population-based cohort study, using administrative health data, of all incident RA cases in British Columbia who first met RA criteria between January 1996 and December 2006, with general population controls matched 1:1 on gender, birth and index years. Cohorts were divided into earlier (RA onset 1996-2000) and later (2001-2006) cohorts. Physician visits and vital statistics data were obtained until December 2010. Follow-up was censored at 5 years to ensure equal follow-up in both cohorts. Mortality rates, mortality rate ratios and HRs for mortality (RA vs controls) using proportional hazard models adjusting for age, were calculated. Differences in mortality in RA versus controls between earlier and later incident cohorts were tested via interaction between RA status (case/control) and cohort (earlier/later). RESULTS: 24 914 RA cases and controls experienced 2747 and 2332 deaths, respectively. Mortality risk in RA versus controls differed across incident cohorts for all-cause, cardiovascular diseases (CVD) and cancer mortality (interactions p<0.01). A significant increase in mortality in RA versus controls was observed in earlier, but not later, cohorts (all-cause mortality adjusted HR (95% CI): 1.40 (1.30 to 1.51) and 0.97 (0.89 to 1.05), respectively). CONCLUSIONS: In our population-based incident RA cohort, mortality compared with the general population improved over time. Increased mortality in the first 5 years was observed in people with RA onset before, but not after, 2000. PMID- 28031165 TI - Chasing crystals out of the body: will treat to serum urate target for gout help us get there? PMID- 28031166 TI - Very small relict populations suggest high extinction debt of gingers in primary forest fragments of a tropical city. AB - PREMISE OF THE STUDY: Tropical plant communities in fragmented forests are likely to experience an extinction debt, i.e., the habitat cannot support as many species as are present due to reduced habitat size and connectivity. There are few estimates of the number of species that represent extinction debt, and the number of extinctions over time has rarely been recorded. We recorded population sizes to assess threats and extinctions in gingers (sensu Zingiberales) in fragmented rainforest in Singapore, ca. 200 yr after fragmentation began. METHODS: We surveyed extant diversity and population sizes of gingers and used the results to estimate species survival. We critically assessed historic specimens to estimate initial extinctions and extinctions realized in present habitats. KEY RESULTS: We recorded 23 species, including five species previously presumed nationally extinct and four species omitted from the national checklist. The revised extinction rate is much lower than previously reported (12 vs. 37%). Most gingers have very small populations or miniscule ranges, implying that extinction debt has not been paid off. CONCLUSIONS: Ginger diversity remains high, but the number of species at immediate risk of extinction outnumber recorded extinctions. Although tropical forest fragments remain arks of plant diversity for a long time, extinction debt may be prevalent in all plant groups in Singapore. Slow relaxation of extinction debt should be explicitly identified as a conservation challenge and opportunity. For conserving plant diversity in tropical fragments, relaxation must be reversed through restoration of degraded landscapes and, where feasible, targeted ex situ conservation and planting. PMID- 28031167 TI - Pinus ponderosa: A checkered past obscured four species. AB - PREMISE OF THE STUDY: Molecular genetic evidence can help delineate taxa in species complexes that lack diagnostic morphological characters. Pinus ponderosa (Pinaceae; subsection Ponderosae) is recognized as a problematic taxon: plastid phylogenies of exemplars were paraphyletic, and mitochondrial phylogeography suggested at least four subdivisions of P. ponderosa. These patterns have not been examined in the context of other Ponderosae species. We hypothesized that putative intraspecific subdivisions might each represent a separate taxon. METHODS: We genotyped six highly variable plastid simple sequence repeats in 1903 individuals from 88 populations of P. ponderosa and related Ponderosae (P. arizonica, P. engelmannii, and P. jeffreyi). We used multilocus haplotype networks and discriminant analysis of principal components to test clustering of individuals into genetically and geographically meaningful taxonomic units. KEY RESULTS: There are at least four distinct plastid clusters within P. ponderosa that roughly correspond to the geographic distribution of mitochondrial haplotypes. Some geographic regions have intermixed plastid lineages, and some mitochondrial and plastid boundaries do not coincide. Based on relative distances to other species of Ponderosae, these clusters diagnose four distinct taxa. CONCLUSIONS: Newly revealed geographic boundaries of four distinct taxa (P. benthamiana, P. brachyptera, P. scopulorum, and a narrowed concept of P. ponderosa) do not correspond completely with taxonomies. Further research is needed to understand their morphological and nuclear genetic makeup, but we suggest that resurrecting originally published species names would more appropriately reflect the taxonomy of this checkered classification than their current treatment as varieties of P. ponderosa. PMID- 28031168 TI - Flowering phenology, growth forms, and pollination syndromes in tropical dry forest species: Influence of phylogeny and abiotic factors. AB - PREMISE OF THE STUDY: Analyses of the influence of temporal variation in abiotic factors on flowering phenology of tropical dry forest species have not considered the possible response of species with different growth forms and pollination syndromes, while controlling for phylogenetic relationships among species. Here, we investigated the relationship between flowering phenology, abiotic factors, and plant functional attributes, while controlling for phylogenetic relationship among species, in a dry forest community in Mexico. METHODS: We characterized flowering phenology (time and duration) and pollination syndromes of 55 tree species, 49 herbs, 24 shrubs, 15 lianas, and 11 vines. We tested the influence of pollination syndrome, growth form, and abiotic factors on flowering phenology using phylogenetic generalized least squares. KEY RESULTS: We found a relationship between flowering duration and time. Growth form was related to flowering time, and the pollination syndrome had a more significant relationship with flowering duration. Flowering time variation in the community was explained mainly by abiotic variables, without an important phylogenetic effect. Flowering time in lianas and trees was negatively and positively correlated with daylength, respectively. CONCLUSIONS: Functional attributes, environmental cues, and phylogeny interact with each other to shape the diversity of flowering patterns. Phenological differentiation among species groups revealed multiples strategies associated with growth form and pollination syndromes that can be important for understanding species coexistence in this highly diverse plant community. PMID- 28031169 TI - The hypoxanthine-xanthine oxidase axis is not involved in the initial phase of clinical transplantation-related ischemia-reperfusion injury. AB - The hypoxanthine-xanthine oxidase (XO) axis is considered to be a key driver of transplantation-related ischemia-reperfusion (I/R) injury. Whereas interference with this axis effectively quenches I/R injury in preclinical models, there is limited efficacy of XO inhibitors in clinical trials. In this context, we considered clinical evaluation of a role for the hypoxanthine-XO axis in human I/R to be relevant. Patients undergoing renal allograft transplantation were included (n = 40) and classified based on duration of ischemia (short, intermediate, and prolonged). Purine metabolites excreted by the reperfused kidney (arteriovenous differences) were analyzed by the ultra performance liquid chromatography-tandem mass spectrometer (UPLCMS/MS) method and tissue XO activity was assessed by in situ enzymography. We confirmed progressive hypoxanthine accumulation (P < 0.006) during ischemia, using kidney transplantation as a clinical model of I/R. Yet, arteriovenous concentration differences of uric acid and in situ enzymography of XO did not indicate significant XO activity in ischemic and reperfused kidney grafts. Furthermore, we tested a putative association between hypoxanthine accumulation and renal oxidative stress by assessing renal malondialdehyde and isoprostane levels and allantoin formation during the reperfusion period. Absent release of these markers is not consistent with an association between ischemic hypoxanthine accumulation and postreperfusion oxidative stress. On basis of these data for the human kidney we hypothesize that the role for the hypoxanthine-XO axis in clinical I/R injury is less than commonly thought, and as such the data provide an explanation for the apparent limited clinical efficacy of XO inhibitors. PMID- 28031171 TI - Whole body acid-base modeling revisited. AB - The textbook account of whole body acid-base balance in terms of endogenous acid production, renal net acid excretion, and gastrointestinal alkali absorption, which is the only comprehensive model around, has never been applied in clinical practice or been formally validated. To improve understanding of acid-base modeling, we managed to write up this conventional model as an expression solely on urine chemistry. Renal net acid excretion and endogenous acid production were already formulated in terms of urine chemistry, and we could from the literature also see gastrointestinal alkali absorption in terms of urine excretions. With a few assumptions it was possible to see that this expression of net acid balance was arithmetically identical to minus urine charge, whereby under the development of acidosis, urine was predicted to acquire a net negative charge. The literature already mentions unexplained negative urine charges so we scrutinized a series of seminal papers and confirmed empirically the theoretical prediction that observed urine charge did acquire negative charge as acidosis developed. Hence, we can conclude that the conventional model is problematic since it predicts what is physiologically impossible. Therefore, we need a new model for whole body acid base balance, which does not have impossible implications. Furthermore, new experimental studies are needed to account for charge imbalance in urine under development of acidosis. PMID- 28031170 TI - Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes. AB - The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration-an early hemodynamic abnormality associated with diabetic nephropathy-would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC (n = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [n = 36, T1D-N, glomerular filtration rate (GFR) 90-134 ml.min-1.1.73 m2] or hyperfiltration (n = 32, T1D-H, GFR >= 135 ml.min-1.1.73 m2) during euglycemic conditions (4-6 mmol/l). Gomez's equations were used to derive efferent (RE) and afferent (RA) arteriolar resistances, glomerular hydrostatic pressure (PGLO) from inulin (GFR) and paraaminohippurate [effective renal plasma flow (ERPF)] clearances, plasma protein and estimated ultrafiltration coefficients (KFG). Female patients with T1D with hyperfiltration (T1D-H) had higher RE (1,985 +/- 487 vs. 1,381 +/- 296 dyne.sec-1.cm-5, P < 0.001) and filtration fraction (FF, 0.20 +/- 0.047 vs. 0.16 +/- 0.03 P < 0.05) and lower ERPF (876 +/- 245 vs. 1,111 +/- 298 134 ml.min-1.1.73 m2P < 0.05) compared with male T1D-H patients. Overall, T1D-H patients had higher PGLO and lower RA vs. HC subjects, although there were no sex-based differences. In conclusion, female T1D-H patients had higher RE and FF and lower ERPF than their male counterparts with no associated sex differences in RA Prospective intervention studies should consider sex as a modifier of renal hemodynamic responses to renal protective therapies. PMID- 28031172 TI - Prorenin receptor controls renal branching morphogenesis via Wnt/beta-catenin signaling. AB - The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H+-ATPase. Renal branching morphogenesis, defined as growth and branching of the ureteric bud (UB), is essential for mammalian kidney development. Previously, we demonstrated that conditional ablation of the PRR in the UB in PRRUB-/- mice causes severe defects in UB branching, resulting in marked kidney hypoplasia at birth. Here, we investigated the UB transcriptome using whole genome-based analysis of gene expression in UB cells, FACS-isolated from PRRUB-/-, and control kidneys at birth (P0) to determine the primary role of the PRR in terminal differentiation and growth of UB-derived collecting ducts. Three genes with expression in UB cells that previously shown to regulate UB branching morphogenesis, including Wnt9b, beta-catenin, and Fgfr2, were upregulated, whereas the expression of Wnt11, Bmp7, Etv4, and Gfralpha1 was downregulated. We next demonstrated that infection of immortalized UB cells with shPRR in vitro or deletion of the UB PRR in double transgenic PRRUB-/-/BatGal+ mice, a reporter strain for beta-catenin transcriptional activity, in vivo increases beta-catenin activity in the UB epithelia. In addition to UB morphogenetic genes, the functional groups of differentially expressed genes within the downregulated gene set included genes involved in molecular transport, metabolic disease, amino acid metabolism, and energy production. Together, these data demonstrate that UB PRR performs essential functions during UB branching and collecting duct morphogenesis via control of a hierarchy of genes that control UB branching and terminal differentiation of the collecting duct cells. PMID- 28031174 TI - Clinical characteristics and prognostic factors of plasmablastic lymphoma patients: analysis of 135 patients from the LYSA group. AB - Background: Plasmablastic lymphoma (PBL), initially described in 1997 in the oral cavity of HIV positive patients, is now recognized as a distinct aggressive and rare entity of diffuse large B-cells lymphoma by the World Health Organization (WHO) classification. Since the original description, others cases have been reported. However, these are largely derived from case reports or small series limiting any definitive conclusions on clinical characteristics and outcome. Patients and methods: The clinical, biological, pathological features and outcome of a cohort including 135 patients with PBL, from LYSA centers in France and Belgium, were reported and analyzed. Results: The median age was 58 years, with a male predominance. The cohort was divided into 56 HIV-positive patients, 17 post transplant patients and 62 HIV-negative/non-transplanted patients. Within HIV negative/non-transplanted, a relative immunosuppression was found in most cases (systemic inflammatory disease, history of cancer, increased age associated with weakened immune system). We have also described a new subtype, PBL arising in a chronic localized inflammatory site, without any sign of immunosuppression. At presentation, 19% of patients showed oral involvement. Immunophenotype showed CD138 positivity in 88% of cases and CD20 negativity in 90% of cases. Chemotherapy was administered to 80% of patients, with a complete response (CR) rate of 55%. The median overall survival (OS) was 32 months. In univariate analysis, HIV positive status showed better OS when compared with HIV negative status. In multivariate analysis, International Prognostic Index score, chemotherapy and CR were associated with survival benefit. Conclusion(s): This cohort, the largest reported to date, increases the spectrum of knowledge on PBL, rarely described. However, specific guidelines to clarify treatment are lacking, and may improve the poor prognosis of this rare disease. PMID- 28031173 TI - Preference for subcutaneous or intravenous administration of rituximab among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, crossover study (PrefMab). AB - Background: The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients and methods: Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8. Results: At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected. Conclusion: Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration. Registered clinical trial number: NCT01724021 (ClinicalTrials.gov). PMID- 28031175 TI - Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients. AB - Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23. PMID- 28031176 TI - Evidence for an Optimal Algorithm Underlying Signal Combination in Human Visual Cortex. AB - How does the cortex combine information from multiple sources? We tested several computational models against data from steady-state electroencephalography (EEG) experiments in humans, using periodic visual stimuli combined across either retinal location or eye-of-presentation. A model in which signals are raised to an exponent before being summed in both the numerator and the denominator of a gain control nonlinearity gave the best account of the data. This model also predicted the pattern of responses in a range of additional conditions accurately and with no free parameters, as well as predicting responses at harmonic and intermodulation frequencies between 1 and 30 Hz. We speculate that this model implements the optimal algorithm for combining multiple noisy inputs, in which responses are proportional to the weighted sum of both inputs. This suggests a novel purpose for cortical gain control: implementing optimal signal combination via mutual inhibition, perhaps explaining its ubiquity as a neural computation. PMID- 28031177 TI - DMRT5 Together with DMRT3 Directly Controls Hippocampus Development and Neocortical Area Map Formation. AB - Mice that are constitutively null for the zinc finger doublesex and mab-3 related (Dmrt) gene, Dmrt5/Dmrta2, show a variety of patterning abnormalities in the cerebral cortex, including the loss of the cortical hem, a powerful cortical signaling center. In conditional Dmrt5 gain of function and loss of function mouse models, we generated bidirectional changes in the neocortical area map without affecting the hem. Analysis indicated that DMRT5, independent of the hem, directs the rostral-to-caudal pattern of the neocortical area map. Thus, DMRT5 joins a small number of transcription factors shown to control directly area size and position in the neocortex. Dmrt5 deletion after hem formation also reduced hippocampal size and shifted the position of the neocortical/paleocortical boundary. Dmrt3, like Dmrt5, is expressed in a gradient across the cortical primordium. Mice lacking Dmrt3 show cortical patterning defects akin to but milder than those in Dmrt5 mutants, perhaps in part because Dmrt5 expression increases in the absence of Dmrt3. DMRT5 upregulates Dmrt3 expression and negatively regulates its own expression, which may stabilize the level of DMRT5. Together, our findings indicate that finely tuned levels of DMRT5, together with DMRT3, regulate patterning of the cerebral cortex. PMID- 28031178 TI - Otitis-Prone Children Produce Functional Antibodies to Pneumolysin and Pneumococcal Polysaccharides. AB - The pneumococcus is a major otitis media (OM) pathogen, but data are conflicting regarding whether otitis-prone children have impaired humoral immunity to pneumococcal antigens. We and others have shown that otitis-prone and healthy children have similar antibody titers to pneumococcal proteins and polysaccharides (vaccine and nonvaccine types); however, the quality of antibodies from otitis-prone children has not been investigated. Antibody function, rather than titer, is considered to be a better correlate of protection from pneumococcal disease. Therefore, we compared the capacities of antibodies from otitis-prone (cases) and healthy (controls) children to neutralize pneumolysin, the pneumococcal toxin currently in development as a vaccine antigen, and to opsonize pneumococcal vaccine and nonvaccine serotypes. A pneumolysin neutralization assay was conducted on cholesterol-depleted complement inactivated sera from 165 cases and 61 controls. A multiplex opsonophagocytosis assay (MOPA) was conducted on sera from 20 cases and 20 controls. Neutralizing and opsonizing titers were calculated with antigen-specific IgG titers to determine antibody potency for pneumolysin, pneumococcal conjugate vaccine (PCV) polysaccharides, and non-PCV polysaccharides. There was no significant difference in antibody potencies between cases and controls for the antigens tested. Antipneumolysin neutralizing titers increased with the number of episodes of acute OM, but antibody potency did not. Pneumolysin antibody potency was lower in children colonized with pneumococci than in noncarriers, and this was significant for the otitis-prone group (P < 0.05). The production of functional antipneumococcal antibodies in otitis-prone children demonstrates that they respond to the current PCV and are likely to respond to pneumolysin-based vaccines as effectively as healthy children. PMID- 28031179 TI - PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. PMID- 28031180 TI - Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. AB - Over the past few years, substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel therapeutic targets with demonstrable clinical impact have been identified. Several of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored toward prognostic subgroups of patients have been developed. Emerging treatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells and will hopefully receive recognition by health authorities in the near future. This article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years. PMID- 28031182 TI - Does ruxolitinib prolong the survival of patients with myelofibrosis? PMID- 28031183 TI - dAPE: a web server to detect homorepeats and follow their evolution. AB - Summary: Homorepeats are low complexity regions consisting of repetitions of a single amino acid residue. There is no current consensus on the minimum number of residues needed to define a functional homorepeat, nor even if mismatches are allowed. Here we present dAPE, a web server that helps following the evolution of homorepeats based on orthology information, using a sensitive but tunable cutoff to help in the identification of emerging homorepeats. Availability and Implementation: dAPE can be accessed from http://cbdm-01.zdv.uni mainz.de/~munoz/polyx . Contact: munoz@uni-mainz.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28031181 TI - Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. AB - Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCbeta) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets. PMID- 28031184 TI - SVScore: an impact prediction tool for structural variation. AB - Summary: Here we present SVScore, a tool for in silico structural variation (SV) impact prediction. SVScore aggregates per-base single nucleotide polymorphism (SNP) pathogenicity scores across relevant genomic intervals for each SV in a manner that considers variant type, gene features and positional uncertainty. We show that the allele frequency spectrum of high-scoring SVs is strongly skewed toward lower frequencies, suggesting that they are under purifying selection, and that SVScore identifies deleterious variants more effectively than alternative methods. Notably, our results also suggest that duplications are under surprisingly strong selection relative to deletions, and that there are a similar number of strongly pathogenic SVs and SNPs in the human population. Availability and Implementation: SVScore is implemented in Perl and available freely at {{ http://www.github.com/lganel/SVScore }} for use under the MIT license. Contact: ihall@wustl.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28031185 TI - MetaDCN: meta-analysis framework for differential co-expression network detection with an application in breast cancer. AB - Motivation: Gene co-expression network analysis from transcriptomic studies can elucidate gene-gene interactions and regulatory mechanisms. Differential co expression analysis helps further detect alterations of regulatory activities in case/control comparison. Co-expression networks estimated from single transcriptomic study is often unstable and not generalizable due to cohort bias and limited sample size. With the rapid accumulation of publicly available transcriptomic studies, co-expression analysis combining multiple transcriptomic studies can provide more accurate and robust results. Results: In this paper, we propose a meta-analytic framework for detecting differentially co-expressed networks (MetaDCN). Differentially co-expressed seed modules are first detected by optimizing an energy function via simulated annealing. Basic modules sharing common pathways are merged into pathway-centric supermodules and a Cytoscape plug in (MetaDCNExplorer) is developed to visualize and explore the findings. We applied MetaDCN to two breast cancer applications: ER+/ER- comparison using five training and three testing studies, and ILC/IDC comparison with two training and two testing studies. We identified 20 and 4 supermodules for ER+/ER- and ILC/IDC comparisons, respectively. Ranking atop are 'immune response pathway' and 'complement cascades pathway' for ER comparison, and 'extracellular matrix pathway' for ILC/IDC comparison. Without the need for prior information, the results from MetaDCN confirm existing as well as discover novel disease mechanisms in a systems manner. Availability and Implementation: R package 'MetaDCN' and Cytoscape App 'MetaDCNExplorer' are available at http://tsenglab.biostat.pitt.edu/software.htm . Contact: ctseng@pitt.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28031186 TI - ACTG: novel peptide mapping onto gene models. AB - Summary: In many proteogenomic applications, mapping peptide sequences onto genome sequences can be very useful, because it allows us to understand origins of the gene products. Existing software tools either take the genomic position of a peptide start site as an input or assume that the peptide sequence exactly matches the coding sequence of a given gene model. In case of novel peptides resulting from genomic variations, especially structural variations such as alternative splicing, these existing tools cannot be directly applied unless users supply information about the variant, either its genomic position or its transcription model. Mapping potentially novel peptides to genome sequences, while allowing certain genomic variations, requires introducing novel gene models when aligning peptide sequences to gene structures. We have developed a new tool called ACTG (Amino aCids To Genome), which maps peptides to genome, assuming all possible single exon skipping, junction variation allowing three edit distances from the original splice sites, exon extension and frame shift. In addition, it can also consider SNVs (single nucleotide variations) during mapping phase if a user provides the VCF (variant call format) file as an input. Availability and Implementation: Available at http://prix.hanyang.ac.kr/ACTG/search.jsp . Contact: eunokpaek@hanyang.ac.kr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28031187 TI - PhosD: inferring kinase-substrate interactions based on protein domains. AB - Motivation: Identifying the kinase-substrate relationships is vital to understanding the phosphorylation events and various biological processes, especially signal transductions. Although large amount of phosphorylation sites have been detected, unfortunately, it is rarely known which kinases activate those sites. Despite distinct computational approaches have been proposed to predict the kinase-substrate interactions, the prediction accuracy still needs to be improved. Results: In this paper, we propose a novel probabilistic model named as PhosD to predict kinase-substrate relationships based on protein domains with the assumption that kinase-substrate interactions are accomplished with kinase domain interactions. By further taking into account protein-protein interactions, our PhosD outperforms other popular approaches on several benchmark datasets with higher precision. In addition, some of our predicted kinase-substrate relationships are validated by signaling pathways, indicating the predictive power of our approach. Furthermore, we notice that given a kinase, the more substrates are known for the kinase the more accurate its predicted substrates will be, and the domains involved in kinase-substrate interactions are found to be more conserved across proteins phosphorylated by multiple kinases. These findings can help develop more efficient computational approaches in the future. Availability and Implementation: The data and results are available at http://comp-sysbio.org/phosd. Contact: xm_zhao@tongji.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28031188 TI - MRI appearance does not change in the first 7 days after acute hamstring injury-a prospective study. AB - BACKGROUND: The optimal timing of MRI following acute hamstring injury is not known and is mainly based on expert opinions. AIMS: To describe the day-to-day changes in the extent of oedema and investigate the optimal timing for detection of fibre disruption on MRI following acute hamstring injuries. STUDY DESIGN: Prospective, descriptive study. METHODS: We performed standardised MRI (1.5T) <=1 day after injury in male athletes with acute hamstring injury. If initial MRI revealed positive signs of injury (increased signal intensity on fluid sensitive sequences), consecutive MRIs were obtained daily throughout the subsequent week (ie, 7 times). The MRI parameters (day 1-7) were scored by a single radiologist using a standardised scoring form. The day-to-day changes in the extent of oedema (distance from tuber, craniocaudal length, mediolateral width and anteroposterior depth) and the presence and extent of fibre disruption (tear) were assessed with descriptive statistics and repeated measures using analysis of variance of log transformed data. The overall main effect for time was reported with a significance level set at p<0.05. RESULTS: 13 out of 132 male athletes assessed for eligibility between January 2014 and December 2015 were included. 1 dropped out, while 12 (31 years, range 20-49) completed the study; 11 had 7 MRI scans each and one had 5 MRI scans performed. There were no significant day-to-day changes for any of the extent of oedema measures (p values ranging from 0.12 to 0.81). Fibre disruption (tear), present in 5 of the athletes, was detectable from day 1, with small and insignificant day-to-day changes (p values ranging from 0.45 to 0.95). CONCLUSIONS: We observed insignificant day-to-day changes in the extent of oedema throughout the first week following acute hamstring injury. Fibre disruption (tear) was detectable from the first day after injury. These findings indicate that MRI can be performed on any day during the first week following an acute (hamstring) muscle injury. PMID- 28031189 TI - Nine-year study of US high school soccer injuries: data from a national sports injury surveillance programme. AB - BACKGROUND: Research on high school soccer injury epidemiology is sparse. AIM: To describe high school soccer injury rates, trends and patterns by type of athlete exposure (AE), position and sex. METHODS: This descriptive epidemiological study used data from a large national high school sports injury surveillance programme to describe rates and patterns of soccer-related injuries including concussion sustained from 2005/2006 to 2013/2014. Injury rates are calculated per 1000 AEs. RESULTS: Overall, 6154 soccer injuries occurred during 2 985 991 AEs; injury rate=2.06 per 1000 AEs. Injury rates were higher during competition (4.42) than practice (1.05; rate ratio (RR)=4.19; 95% CI 3.98 to 4.41), and in girls (2.33) than boys (1.83; RR=1.27, 95% CI 1.21 to 1.34). Boys' non-concussion injury rates decreased significantly (p=0.001) during the study period while reported concussion rates increased significantly (p=0.002). Girls' non-concussion rates were relatively stable and reported concussion rates increased significantly (p=0.004). Player-player contact was the injury mechanism that led to the most competition injuries (injury proportion ratio (IPR)=2.87; 95% CI 2.57 to 3.21), while non-contact injuries were the most common mechanisms among practice injuries (IPR=2.10; 95% CI 1.86 to 2.38). Recovery from concussion was >7 days in a third of the cases. Injury patterns were similar between sexes with respect to position played and location on the field at the time of injury. CONCLUSIONS: High school soccer injury rates vary by sex and type of exposure, while injury patterns are more similar across sexes. Reported concussion rates increased significantly over the study period in male and female athletes. PMID- 28031190 TI - Risk factors for death in children during inpatient treatment of severe acute malnutrition: a prospective cohort study. AB - BACKGROUND: Children who receive in-hospital treatment of severe acute malnutrition often have high mortality rates, and the reasons are not well understood. OBJECTIVE: We assessed risk factors for death in children who were treated for malnutrition in a hospital. DESIGN: In a prospective observational study of 120 children who were receiving in-hospital treatment of severe acute malnutrition in Uganda with therapeutic formulas F-75 and F-100, we collected data on symptoms, clinical findings, plasma markers of refeeding syndrome (electrolytes and phosphate), and acute phase reactants, and recorded the nutritional therapy given in hospital. RESULTS: Seventeen children (14%) died. Clinical risk factors for death were the presence of oral thrush (HR: 5.0; 95% CI: 1.6, 15.2), a caretaker-reported severity of illness on a visual analog scale (HR: 1.7; 95% CI: 1.1, 2.6), impaired consciousness (HR: 16.7; 95% CI: 3.1, 90.4), and a capillary refill time >2 s (HR: 3.9; 95% CI: 1.4, 11.3). HIV infection was not associated with mortality (HR: 3.0; 95% CI: 0.7, 12.4), which was most likely due to low power. Biochemical risk factors were a plasma C reactive protein concentration >15 mg/L on admission and low plasma phosphate that was measured on day 2 (HR: 8.7; 95% CI: 2.5, 30.1), particularly in edematous children. The replacement of F-75 with unfortified rice porridge to ameliorate diarrhea was associated with a higher risk of death, particularly if given during the first 2 d (HR: 5.0; 95% CI: 1.9, 13.3), which was an association that remained after adjustment for potential confounders (HR: 69.5; 95% CI: 7.0, 694.6). CONCLUSIONS: Refeeding syndrome may occur in children who are treated for malnutrition, even with moderately low plasma phosphate, and, in particular, in children with edematous malnutrition. The replacement of F-75 with unfortified rice porridge is associated with increased risk of death, which is possibly mediated by lowering plasma phosphate. The identified clinical risk factors may potentially improve the triage of children with malnutrition. This trial was registered at www.isrctn.com as ISRCTN55092738. PMID- 28031191 TI - Dietary biomarker evaluation in a controlled feeding study in women from the Women's Health Initiative cohort. AB - BACKGROUND: Controlled human feeding studies are necessary for robust nutritional biomarker development and validation. Previous feeding studies have typically evaluated single nutrients and tested relatively few diets. OBJECTIVES: The objectives were 1) to simultaneously associate dietary intake with a range of potential nutritional biomarkers in postmenopausal women by using a controlled feeding study whereby each participant was provided a diet similar to her usual diet and 2) to evaluate serum concentrations of select nutrients as potential biomarkers with the use of established urinary recovery biomarkers of energy and protein as benchmarks for evaluation. DESIGN: Postmenopausal women from the Women's Health Initiative (n = 153) were provided with a 2-wk controlled diet in which each individual's menu approximated her habitual food intake as estimated from her 4-d food record and adjusted for estimated energy requirements. Serum biomarkers, including carotenoids, tocopherols, folate, vitamin B-12, and phospholipid fatty acids, were collected at the beginning and end of the feeding period. Doubly labeled water and urinary nitrogen biomarkers were used to derive estimates of energy and protein consumption, respectively. RESULTS: Linear regression of (ln-transformed) consumed nutrients on (ln-transformed) potential biomarkers and participant characteristics led to the following regression (R2) values for serum concentration biomarkers: folate, 0.49; vitamin B-12, 0.51; alpha-carotene, 0.53; beta-carotene, 0.39; lutein + zeaxanthin, 0.46; lycopene, 0.32; and alpha-tocopherol, 0.47. R2 values for percentage of energy from polyunsaturated fatty acids and urinary recovery biomarkers of energy and protein intakes were 0.27, 0.53, and 0.43, respectively. Phospholipid saturated fatty acids and monounsaturated fatty acids and serum gamma-tocopherol were weakly associated with intake (R2 < 0.25). CONCLUSIONS: Serum concentration biomarkers of several vitamins and carotenoids performed similarly to established energy and protein urinary recovery biomarkers in representing nutrient intake variation in a feeding study, and thus are likely suitable for application in this population of postmenopausal women. Further work is needed to identify objective measures of categories of fatty acid intake. This trial was registered at clinicaltrials.gov as NCT00000611. PMID- 28031193 TI - Associations of dietary, lifestyle, and sociodemographic factors with iron status in Chinese adults: a cross-sectional study in the China Health and Nutrition Survey. AB - BACKGROUND: Although a high prevalence of anemia and related disease burden have been documented in China, limited evidence is available on the current population level iron status and risk factors for iron imbalance. OBJECTIVE: We explored the associations of dietary, lifestyle, and sociodemographic factors with iron status in Chinese adults. DESIGN: Our study population consisted of 7672 adults aged 18 65 y from the 2009 China Health and Nutrition Survey. Diet was assessed with the use of 3 consecutive 24-h dietary recalls. Serum ferritin, serum transferrin receptor, and hemoglobin concentrations were measured. RESULTS: The geometric means +/- SDs for ferritin concentrations were 135.9 +/- 2.7 ng/mL in men and 42.7 +/- 3.1 ng/mL in women. After adjustment for potential risk factors, including high-sensitivity C-reactive protein concentration, the association between age and ferritin concentration was inverse in men (P-trend < 0.001) and positive in women (P-trend < 0.001). We observed a positive association between body mass index (in kg/m2) and ferritin concentration in both men and women (both P-trends < 0.001). Dietary phytate intake was inversely associated with ferritin concentration in men (P-trend = 0.002) but not in women. Red meat consumption was positively associated with ferritin concentration both in men (P-trend = 0.002) and in older women (P-trend = 0.009). Lower intakes of grains and higher intakes of pork and poultry were associated with higher ferritin concentrations (all P trends <= 0.05) in men but not in women. We observed variations in ferritin concentrations across different geographic regions (both P <= 0.01). CONCLUSIONS: Serum ferritin concentrations varied across different sociodemographic, lifestyle, and dietary factors in this Chinese population. A higher intake of red meat was associated with higher ferritin concentrations in men and older women. PMID- 28031192 TI - Identifying biomarkers of dietary patterns by using metabolomics. AB - BACKGROUND: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality. OBJECTIVE: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites. DESIGN: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985-1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses. RESULTS: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: -0.30 to 0.20; P = 6 * 10-15 to 8 * 10-6). Food based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e.g., percentages of protein and cholesterol). The lysolipid and food and plant xenobiotic pathways were most strongly associated with diet quality. CONCLUSIONS: Diet quality, measured by healthy diet indexes, is associated with serum metabolites, with the specific metabolite profile of each diet index related to the diet components used to score adherence. This trial was registered at clinicaltrials.gov as NCT00342992. PMID- 28031194 TI - Azithromycin-Ciprofloxacin-Impregnated Urinary Catheters Avert Bacterial Colonization, Biofilm Formation, and Inflammation in a Murine Model of Foreign Body-Associated Urinary Tract Infections Caused by Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a multifaceted pathogen causing a variety of biofilm mediated infections, including catheter-associated urinary tract infections (CAUTIs). The high prevalence of CAUTIs in hospitals, their clinical manifestations, such as urethritis, cystitis, pyelonephritis, meningitis, urosepsis, and death, and the associated economic challenges underscore the need for management of these infections. Biomaterial modification of urinary catheters with two drugs seems an interesting approach to combat CAUTIs by inhibiting biofilm. Previously, we demonstrated the in vitro efficacy of urinary catheters impregnated with azithromycin (AZM) and ciprofloxacin (CIP) against P. aeruginosa Here, we report how these coated catheters impact the course of CAUTI induced by P. aeruginosa in a murine model. CAUTI was established in female LACA mice with uncoated or AZM-CIP-coated silicone implants in the bladder, followed by transurethral inoculation of 108 CFU/ml of biofilm cells of P. aeruginosa PAO1. AZM-CIP-coated implants (i) prevented biofilm formation on the implant's surface (P <= 0.01), (ii) restricted bacterial colonization in the bladder and kidney (P < 0.0001), (iii) averted bacteriuria (P < 0.0001), and (iv) exhibited no major histopathological changes for 28 days in comparison to uncoated implants, which showed persistent CAUTI. Antibiotic implants also overcame implant-mediated inflammation, as characterized by trivial levels of inflammatory markers such as malondialdehyde (P < 0.001), myeloperoxidase (P < 0.05), reactive oxygen species (P <= 0.001), and reactive nitrogen intermediates (P < 0.01) in comparison to those in uncoated implants. Further, AZM-CIP-coated implants showed immunomodulation by manipulating the release of inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-10 to the benefit of the host. Overall, the study demonstrates long-term in vivo effectiveness of AZM-CIP-impregnated catheters, which may possibly be a key to success in preventing CAUTIs. PMID- 28031195 TI - attI1-Located Small Open Reading Frames ORF-17 and ORF-11 in a Class 1 Integron Affect Expression of a Gene Cassette Possessing a Canonical Shine-Dalgarno Sequence. AB - By searching the Integrall integron and GenBank databases, a novel open reading frame (ORF) of 51 nucleotides (nts) (ORF-17) overlapping the previously described ORF-11 was identified within the attI1 site in virtually all class 1 integrons. Using a set of isogenic plasmid constructs carrying a single gene cassette (blaGES-1) and possessing a canonical translation initiation region, we found that ORF-17 contributes to GES-1 expression. PMID- 28031196 TI - Nanotized Curcumin and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis. AB - Leishmaniasis chemotherapy remains very challenging due to high cost of the drug and its associated toxicity and drug resistance, which develops over a period of time. Combination therapies (CT) are now in use to treat many diseases, such as cancer and malaria, since it is more effective and affordable than monotherapy. CT are believed to represent a new explorable strategy for leishmaniasis, a neglected tropical disease caused by the obligate intracellular parasite Leishmania In the present study, we investigated the effect of a combination of a traditional Indian medicine (ayurveda), a natural product curcumin and miltefosine, the only oral drug for visceral leishmaniasis (VL) using a Leishmania donovani-hamster model. We developed an oral nanoparticle-based formulation of curcumin. Nanoformulation of curcumin alone exhibited significant leishmanicidal activity both in vitro and in vivo In combination with miltefosine, it exhibited a synergistic effect on both promastigotes and amastigotes under in vitro conditions. The combination of these two agents also demonstrated increased in vivo leishmanicidal activity accompanied by increased production of toxic reactive oxygen/nitrogen metabolites and enhanced phagocytic activity. The combination also exhibited increased lymphocyte proliferation. The present study thus establishes the possible use of nanocurcumin as an adjunct to antileishmanial chemotherapy. PMID- 28031197 TI - Ciprofloxacin-Mediated Mutagenesis Is Suppressed by Subinhibitory Concentrations of Amikacin in Pseudomonas aeruginosa. AB - Resistance to antibiotics is a global health problem. Activation of the SOS response, and the subsequent elevation in mutagenesis, contributes to the appearance of resistance mutations. Among currently used drugs, quinolones are the most potent inducers of the SOS response. In the present study, we show that amikacin inhibits ciprofloxacin-mediated SOS induction and mutagenesis in Pseudomonas aeruginosa. PMID- 28031198 TI - A Phage-Like IncY Plasmid Carrying the mcr-1 Gene in Escherichia coli from a Pig Farm in China. AB - We report here a new type of plasmid that carries the mcr-1 gene, the pMCR-1-P3 plasmid, harbored in an Escherichia coli strain isolated from a pig farm in China. pMCR-1-P3 belongs to the IncY incompatibility group and is a phage-like plasmid that contains a large portion of phage-related sequences. The backbone of this plasmid is different from that of other mcr-1-carrying plasmids reported previously. PMID- 28031199 TI - Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function. AB - A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 * CrCLCKD-EPI [creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC24/MIC ratio (>=95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) against Escherichia coli and Haemophilus influenzae, borderline against Staphylococcus aureus, and suboptimal against Pseudomonas aeruginosa The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of <=0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens. PMID- 28031200 TI - Low Frequency of Ceftazidime-Avibactam Resistance among Enterobacteriaceae Isolates Carrying blaKPC Collected in U.S. Hospitals from 2012 to 2015. AB - Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying blaKPC collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 MUg/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 MUg/ml; 98.9% susceptible at <=2 MUg/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (K. pneumoniae; MICs, >=16 MUg/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-beta-lactamase genes, blaNDM-1 or blaVIM-4, among other beta-lactam resistance mechanisms, and one displayed a premature stop codon in ompK35 and decreased expression of ompK36 Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carrying blaKPC-3 (n = 221) and blaKPC-2 (n = 145), respectively. Isolates carrying blaKPC were more commonly recovered from pneumonia (n = 155), urinary tract (n = 93), and skin/soft tissue (n = 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites. K. pneumoniae (83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidime avibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidime avibactam was active against this large collection of isolates carrying blaKPC and represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producing Enterobacteriaceae. PMID- 28031202 TI - Pilot Study of a Slow-Release Ivermectin Formulation for Malaria Control in a Pig Model. PMID- 28031201 TI - Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. AB - Ceftazidime-avibactam is a novel beta-lactam/beta-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne blaKPC-3, which were not present in baseline isolates. blaKPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs >=4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced >=4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of blaKPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to blaKPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring blaKPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates. PMID- 28031203 TI - PER-8, a Novel Extended-Spectrum beta-Lactamase PER Variant, from an Acinetobacter baumannii Clinical Isolate in Nepal. AB - A novel PER-type extended-spectrum beta-lactamase, PER-8, was identified in an Acinetobacter baumannii clinical isolate obtained in Nepal. The amino acid sequence of PER-8 has a substitution at position 39 (Gly to Glu) compared with that of PER-7. The kcat/Km ratio of PER-8 for aztreonam was lower than that of PER-7, while the kcat/Km ratio of PER-8 for imipenem was higher than that of PER 7. The genomic environment surrounding blaPER-8 was intI1 blaPSE-1qacEDI sulI ISCR1-blaPER-8gts sulI orfX on a 100-kb plasmid. PMID- 28031204 TI - Chromosomal Integration of the Klebsiella pneumoniae Carbapenemase Gene, blaKPC, in Klebsiella Species Is Elusive but Not Rare. AB - Carbapenemase genes in Enterobacteriaceae are mostly described as being plasmid associated. However, the genetic context of carbapenemase genes is not always confirmed in epidemiological surveys, and the frequency of their chromosomal integration therefore is unknown. A previously sequenced collection of blaKPC positive Enterobacteriaceae from a single U.S. institution (2007 to 2012; n = 281 isolates from 182 patients) was analyzed to identify chromosomal insertions of Tn4401, the transposon most frequently harboring blaKPC Using a combination of short- and long-read sequencing, we confirmed five independent chromosomal integration events from 6/182 (3%) patients, corresponding to 15/281 (5%) isolates. Three patients had isolates identified by perirectal screening, and three had infections which were all successfully treated. When a single copy of blaKPC was in the chromosome, one or both of the phenotypic carbapenemase tests were negative. All chromosomally integrated blaKPC genes were from Klebsiella spp., predominantly K. pneumoniae clonal group 258 (CG258), even though these represented only a small proportion of the isolates. Integration occurred via IS15-DeltaI-mediated transposition of a larger, composite region encompassing Tn4401 at one locus of chromosomal integration, seen in the same strain (K. pneumoniae ST340) in two patients. In summary, we identified five independent chromosomal integrations of blaKPC in a large outbreak, demonstrating that this is not a rare event. blaKPC was more frequently integrated into the chromosome of epidemic CG258 K. pneumoniae lineages (ST11, ST258, and ST340) and was more difficult to detect by routine phenotypic methods in this context. The presence of chromosomally integrated blaKPC within successful, globally disseminated K. pneumoniae strains therefore is likely underestimated. PMID- 28031205 TI - In Vitro Activity of Posaconazole against Talaromyces marneffei by Broth Microdilution and Etest Methods and Comparison to Itraconazole, Voriconazole, and Anidulafungin. AB - We determined the susceptibilities of 57 Talaromyces marneffei strains to anidulafungin, itraconazole, voriconazole, and posaconazole with MICs of 2 to 8, 0.002 to 0.004, 0.016 to 0.063, and 0.001 to 0.002 MUg/ml by broth microdilution and >32, <=0.002 to 0.008, <=0.002 to 0.008, and <=0.002 MUg/ml by Etest, respectively, at yeast phase; MICs at mycelial phase for anidulafungin and posaconazole were 1 to 2 and 0.004 to 0.063 MUg/ml, respectively. The results suggest promising activities of posaconazole. Etest can be used for testing of azoles against T. marneffei. PMID- 28031206 TI - Physiological Differences in Cryptococcus neoformans Strains In Vitro versus In Vivo and Their Effects on Antifungal Susceptibility. AB - Cryptococcus neoformans is an environmentally ubiquitous fungal pathogen that primarily causes disease in people with compromised immune systems, particularly those with advanced AIDS. There are estimated to be almost 1 million cases per year of cryptococcal meningitis in patients infected with human immunodeficiency virus, leading to over 600,000 annual deaths, with a particular burden in sub Saharan Africa. Amphotericin B (AMB) and fluconazole (FLC) are key components of cryptococcal meningitis treatment: AMB is used for induction, and FLC is for consolidation, maintenance and, for occasional individuals, prophylaxis. However, the results of standard antifungal susceptibility testing (AFST) for AMB and FLC do not correlate well with therapeutic outcomes and, consequently, no clinical breakpoints have been established. While a number of explanations for this absence of correlation have been proffered, one potential reason that has not been adequately explored is the possibility that the physiological differences between the in vivo infection environment and the in vitro AFST environment lead to disparate drug susceptibilities. These susceptibility-influencing factors include melanization, which does not occur during AFST, the size of the polysaccharide capsule, which is larger in infecting cells than in those grown under normal laboratory conditions, and the presence of large polyploid "titan cells," which rarely occur under laboratory conditions. Understanding whether and how C. neoformans differentially expresses mechanisms of resistance to AMB and FLC in the AFST environment compared to the in vivo environment could enhance our ability to interpret AFST results and possibly lead to the development of more applicable testing methods. PMID- 28031207 TI - Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model. AB - Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa However, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against three P. aeruginosa strains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (fAUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection (R2 = 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). The fAUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDR P. aeruginosa lung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy. PMID- 28031208 TI - Perception of first respiratory infection with Pseudomonas aeruginosa by people with cystic fibrosis and those close to them: an online qualitative study. AB - BACKGROUND: People with cystic fibrosis (CF) are susceptible to respiratory infection with Pseudomonas aeruginosa (PA), which may become chronic if initial eradication fails. Environmental acquisition and person-to-person transmission can occur. Respiratory PA infection is associated with increased mortality and more hospitalisations. This may cause patients and families anxiety and lead them to adopt preventive measures which may be ineffectual and intrusive. It is not possible to hold a conventional focus group to explore these issues because people with CF cannot meet together due to the risk of cross-infection. OBJECTIVE: To explore the perceptions of first respiratory infection with PA in people with CF and those close to them. DESIGN: We designed an online survey, to maximise accessibility and avoid the risk of cross-infection. This established the respondent's relationship with CF, asked 3 open questions about perceptions of PA and a final question about the prioritisation of research. Responses were analysed using a structured, iterative process. We identified keywords, analysed these incontext and derived key themes. SETTING: Promotion through social media allowed respondents from any country to participate. PARTICIPANTS: People with CF and those close to them. RESULTS: Responses were received from 393 people, including 266 parents and 97 people with CF. The key themes were the emotional burden of PA (fear in particular); the burden of treatment PA entails and the need for accurate knowledge about PA. CONCLUSIONS: Lack of knowledge and the health beliefs of individuals may promote fear of infection and inappropriate avoidance measures. Uncertainty about the implications of PA infection and the treatment required may cause anxiety. Healthcare professionals should provide clear information about how PA might be acquired and the treatment necessary, making clear the limitations of current understanding and acknowledging health beliefs. PMID- 28031209 TI - Factors associated with influenza vaccination coverage among the elderly in South Korea: the Fourth Korean National Health and Nutrition Examination Survey (KNHANES IV). AB - OBJECTIVE: The annual outbreak of influenza is one of the major causes of morbidity and mortality among the elderly population around the world. While there is an annual vaccine available to prevent or reduce the incidence of disease, not all older people in Korea choose to be vaccinated. There have been few previous studies to examine the factors influencing influenza vaccination in Korea. Thus, this study identifies nationwide factors that affect influenza vaccination rates in elderly Koreans. METHODS: We obtained data from the Fourth Korean National Health and Nutrition Examination Survey 2007-2009 (KNHANES IV), a nationwide health survey in Korea. To assess influenza vaccination status, we analysed answers to a single question from the survey. From the respondents, we selected 3567 elderly population aged 65 years or older, to analyse the effects of variables including sociodemographic, health behavioural risk, health status and psychological factors on vaccination coverage. We identified factors that affect vaccination status using a multiple logistic regression analysis. RESULTS: The rate of influenza vaccination in this elderly population was 75.8%. Overall, the most significant determinants for choosing influenza vaccination were a recent history of health screening (adjusted OR (aOR) 2.26, 95% CI 1.92 to 2.66) and smoking (aOR 0.78, 95% CI 0.62 to 0.98). Other contributing factors were age, household income, marital status, alcohol consumption, physical activity level, self-reported health status and a limitation in daily activities. In contrast, psychological factors, including self-perceived quality of life, stress and depressive mood, did not show close association with vaccination coverage. CONCLUSIONS: To boost influenza vaccination rates in the elderly, an influenza campaign should focus on under-represented groups, especially smokers. Additionally, promoting routine health screening for the elderly may be an efficient way to help achieve higher vaccination rates. Our results highlight the need for a new strategy for the vaccination campaign. PMID- 28031210 TI - Randomised feasibility study of a novel experience-based internet intervention to support self-management in chronic asthma. AB - OBJECTIVE: To determine the feasibility of a randomised controlled trial (RCT) assessing the effects of an experience-based website as a resource for the self management of chronic asthma. DESIGN AND SETTING: Feasibility, single-blind RCT in 2 regions of England. Randomisation used computer-generated random number sequence in a 1:1 ratio, after baseline data collection, to website access for 2 weeks. PARTICIPANTS: Adults (age >=18 years), with clinically diagnosed asthma as coded in their primary care electronic record, prescribed inhaled corticosteroids for at least 3 months in the previous year, were recruited from 9 general practices. INTERVENTION: The EXPERT asthma intervention is an interactive PC/laptop/tablet/smartphone compatible website designed with extensive input from adults with asthma. It provides experience-based information and aims to support subjective perception of self-efficacy, self-management and improve health status. OUTCOME MEASURES: Primary outcomes were consent/recruitment, website usage and completion of outcome measures. Secondary outcomes included Partners in Health (PIH) questionnaire, the Chronic Disease Self-Efficacy Scale, the SF36 and the E-Health Impact Questionnaire. Participant blinding postrandomisation was not possible. The analysis was blind to allocation. RESULTS: Recruitment target exceeded. 148 participants randomised (73 intervention group). Age range 19-84 years; 59% female. 121 of 148 (84%; 62 intervention group) followed up. The median number of logins was 2 (IQR 2-3, range 1-48). Minimal differences of change from baseline between groups; both showed improvement in health state or management of their condition with no significant differences between arms. No adverse events. CONCLUSIONS: Recruitment and retention confirmed feasibility. The trends towards improved outcomes suggest that further research on digital interventions based on exposure to others' personal experiences may be of value in the self-management of chronic asthma. TRIAL REGISTRATION NUMBER: ISRCTN29549695; Results. PMID- 28031212 TI - Correction. PMID- 28031211 TI - Model-based cost-effectiveness analysis of B-type natriuretic peptide-guided care in patients with heart failure. AB - OBJECTIVE: Monitoring B-type natriuretic peptide (BNP) to guide pharmacotherapy might improve survival in patients with heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). However, the cost effectiveness of BNP-guided care is uncertain and guidelines do not uniformly recommend it. We assessed the cost-effectiveness of BNP-guided care in patient subgroups defined by age and ejection fraction. METHODS: We used a Markov model with a 3-month cycle length to estimate the lifetime health service costs, quality-adjusted life years (QALYs) and incremental net monetary benefits (iNMBs) of BNP-guided versus clinically guided care in 3 patient subgroups: (1) HFrEF patients <75 years; (2) HFpEF patients <75 years; and (3) HFrEF patients >=75 years. There is no evidence of benefit in patients with HFpEF aged >=75 years. We used individual patient data meta-analyses and linked primary care, hospital and mortality data to inform the key model parameters. We performed probabilistic analysis to assess the uncertainty in model results. RESULTS: In younger patients (<75 years) with HFrEF, the mean QALYs (5.57 vs 5.02) and costs (L63 527 vs L58 139) were higher with BNP-guided care. At the willingness-to-pay threshold of L20 000 per QALY, the positive iNMB (L5424 (95% CI L987 to L9469)) indicates that BNP guided care is cost-effective in this subgroup. The evidence of cost effectiveness of BNP-guided care is less strong for younger patients with HFpEF (L3155 (-L10 307 to L11 613)) and older patients (>=75 years) with HFrEF (L2267 ( L1524 to L6074)). BNP-guided care remained cost-effective in the sensitivity analyses, albeit the results were sensitive to assumptions on its sustained effect. CONCLUSIONS: We found strong evidence that BNP-guided care is a cost effective alternative to clinically guided care in younger patients with HFrEF. It is potentially cost-effective in younger patients with HFpEF and older patients with HFrEF, but more evidence is required, particularly with respect to the frequency, duration and BNP target for monitoring. Cost-effectiveness results from trials in specialist settings cannot be generalised to primary care. PMID- 28031213 TI - Relationship Between Distance and Change in Surface ECG Morphology During Pacemapping as a Guide to Ablation of Ventricular Arrhythmias: Implications for the Spatial Resolution of Pacemapping. AB - BACKGROUND: Pacemapping is used to localize the exit site of ventricular arrhythmia. Although the relationship between distance and change in QRS morphology is its basis, this relationship has not been systematically quantified. METHODS AND RESULTS: Patients (n=68) undergoing ventricular arrhythmia ablation between March 2012 and July 2013 were recruited. Pacemapping was targeted to areas of voltage >0.5 mV. Linear mixed-effects models were constructed of distance against morphology difference measured by the root mean square error sum across all 12 ECG leads (E12). Forty of 68 (58%) patients had structural heart disease, and 21/40 (53%) patients were ischemic. Nine hundred thirty-five pacing points were collected, generating 6219 pacing site pair combinations (3087 [50%] ventricular bodies, 756 [12%] outflow tract, and 162 [3%] epicardial). In multivariable analysis, increase in E12 was predicted by increasing distance (0.07 per mm; 95% confidence interval 0.07-0.08; P<0.001). Compared with the left ventricle, E12 values were lower in the right ventricle (P=0.037) and left ventricular outflow tract (P<0.001) and higher in left ventricle-right ventricle pairs (P=0.021) and left ventricular epicardium (P=0.08). There was no difference in E12 in the right ventricular outflow tract compared with the right-left ventricular outflow tract (P=0.75) pairs. Structural heart disease or inadvertent pacing in scar was not associated with changes in E12; however, the presence of latency and split potentials were associated with higher and lower E12 values, respectively (P<0.001). CONCLUSIONS: A robust positive relationship exists between distance and QRS morphological change when restricting pacing points to areas of voltage >0.5 mV. Significant differences in the spatial resolution of pacemapping exist within the heart. PMID- 28031214 TI - Editorial. PMID- 28031215 TI - Mutations and mechanism: how PINK1 may contribute to risk of sporadic Parkinson's disease. PMID- 28031216 TI - Phase matters: cancelling pathological tremor by adaptive deep brain stimulation. PMID- 28031217 TI - Fleeting footprints: finding MRI biomarkers of transient ischaemic attack. PMID- 28031218 TI - Increased heart rate and energy expenditure in frontotemporal dementia. PMID- 28031220 TI - Pathological ponto-cerebello-thalamo-cortical activations in primary orthostatic tremor during lying and stance. AB - Primary orthostatic tremor is a rare neurological disease characterized mainly by a high frequency tremor of the legs while standing. The aim of this study was to identify the common core structures of the oscillatory circuit in orthostatic tremor and how it is modulated by changes of body position. Ten patients with orthostatic tremor and 10 healthy age-matched control subjects underwent a standardized neurological and neuro-ophthalmological examination including electromyographic and posturographic recordings. Task-dependent changes of cerebral glucose metabolism during lying and standing were measured in all subjects by sequential 18F-fluorodeoxyglucose-positron emission tomography on separate days. Results were compared between groups and conditions. All the orthostatic tremor patients, but no control subject, showed the characteristic 13 18 Hz tremor in coherent muscles during standing, which ceased in the supine position. While lying, patients had a significantly increased regional cerebral glucose metabolism in the pontine tegmentum, the posterior cerebellum (including the dentate nuclei), the ventral intermediate and ventral posterolateral nucleus of the thalamus, and the primary motor cortex bilaterally compared to controls. Similar glucose metabolism changes occurred with clinical manifestation of the tremor during standing. The glucose metabolism was relatively decreased in mesiofrontal cortical areas (i.e. the medial prefrontal cortex, supplementary motor area and anterior cingulate cortex) and the bilateral anterior insula in orthostatic tremor patients while lying and standing. The mesiofrontal hypometabolism correlated with increased body sway in posturography. This study confirms and further elucidates ponto-cerebello-thalamo-primary motor cortical activations underlying primary orthostatic tremor, which presented consistently in a group of patients. Compared to other tremor disorders one characteristic feature in orthostatic tremor seems to be the involvement of the pontine tegmentum in the pathophysiology of tremor generation. High frequency oscillatory properties of pontine tegmental neurons have been reported in pathological oscillatory eye movements. It is remarkable that the characteristic activation and deactivation pattern in orthostatic tremor is already present in the supine position without tremor presentation. Multilevel changes of neuronal excitability during upright stance may trigger activation of the orthostatic tremor network. Based on the functional imaging data described in this study, it is hypothesized that a mesiofrontal deactivation is another characteristic feature of orthostatic tremor and plays a pivotal role in development of postural unsteadiness during prolonged standing. PMID- 28031219 TI - Preoperative automated fibre quantification predicts postoperative seizure outcome in temporal lobe epilepsy. AB - Approximately one in every two patients with pharmacoresistant temporal lobe epilepsy will not be rendered completely seizure-free after temporal lobe surgery. The reasons for this are unknown and are likely to be multifactorial. Quantitative volumetric magnetic resonance imaging techniques have provided limited insight into the causes of persistent postoperative seizures in patients with temporal lobe epilepsy. The relationship between postoperative outcome and preoperative pathology of white matter tracts, which constitute crucial components of epileptogenic networks, is unknown. We investigated regional tissue characteristics of preoperative temporal lobe white matter tracts known to be important in the generation and propagation of temporal lobe seizures in temporal lobe epilepsy, using diffusion tensor imaging and automated fibre quantification. We studied 43 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis and 44 healthy controls. Patients underwent preoperative imaging, amygdalohippocampectomy and postoperative assessment using the International League Against Epilepsy seizure outcome scale. From preoperative imaging, the fimbria-fornix, parahippocampal white matter bundle and uncinate fasciculus were reconstructed, and scalar diffusion metrics were calculated along the length of each tract. Altogether, 51.2% of patients were rendered completely seizure-free and 48.8% continued to experience postoperative seizure symptoms. Relative to controls, both patient groups exhibited strong and significant diffusion abnormalities along the length of the uncinate bilaterally, the ipsilateral parahippocampal white matter bundle, and the ipsilateral fimbria fornix in regions located within the medial temporal lobe. However, only patients with persistent postoperative seizures showed evidence of significant pathology of tract sections located in the ipsilateral dorsal fornix and in the contralateral parahippocampal white matter bundle. Using receiver operating characteristic curves, diffusion characteristics of these regions could classify individual patients according to outcome with 84% sensitivity and 89% specificity. Pathological changes in the dorsal fornix were beyond the margins of resection, and contralateral parahippocampal changes may suggest a bitemporal disorder in some patients. Furthermore, diffusion characteristics of the ipsilateral uncinate could classify patients from controls with a sensitivity of 98%; importantly, by co-registering the preoperative fibre maps to postoperative surgical lacuna maps, we observed that the extent of uncinate resection was significantly greater in patients who were rendered seizure-free, suggesting that a smaller resection of the uncinate may represent insufficient disconnection of an anterior temporal epileptogenic network. These results may have the potential to be developed into imaging prognostic markers of postoperative outcome and provide new insights for why some patients with temporal lobe epilepsy continue to experience postoperative seizures. PMID- 28031221 TI - Molecular magnetic resonance imaging discloses endothelial activation after transient ischaemic attack. AB - SEE SUN ET AL DOI101093/AWW306 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: About 20% of patients with ischaemic stroke have a preceding transient ischaemic attack, which is clinically defined as focal neurological symptoms of ischaemic origin resolving spontaneously. Failure to diagnose transient ischaemic attack is a wasted opportunity to prevent recurrent disabling stroke. Unfortunately, diagnosis can be difficult, due to numerous mimics, and to the absence of a specific test. New diagnostic tools are thus needed, in particular for radiologically silent cases, which correspond to the recommended tissue-based definition of transient ischaemic attack. As endothelial activation is a hallmark of cerebrovascular events, we postulated that this may also be true for transient ischaemic attack, and that it would be clinically relevant to develop non invasive in vivo imaging to detect this endothelial activation. Using transcriptional and immunohistological analyses for adhesion molecules in a mouse model, we identified brain endothelial P-selectin as a potential biomarker for transient ischaemic attack. We thus developed ultra-sensitive molecular magnetic resonance imaging using antibody-based microparticles of iron oxide targeting P selectin. This highly sensitive imaging strategy unmasked activated endothelial cells after experimental transient ischaemic attack and allowed discriminating transient ischaemic attack from epilepsy and migraine, two important transient ischaemic attack mimics. We provide preclinical evidence that combining conventional magnetic resonance imaging with molecular magnetic resonance imaging targeting P-selectin might aid in the diagnosis of transient ischaemic attack. PMID- 28031222 TI - The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor. AB - Nerve growth factor is a therapeutic candidate for Alzheimer's disease. Due to its pain-inducing activity, in current clinical trials nerve growth factor is delivered locally into the brain by neurosurgery, but data on the efficacy of local nerve growth factor delivery in decreasing amyloid-beta deposition are not available. To reduce the nerve growth factor pain-inducing side effects, thus avoiding the need for local brain injection, we developed human painless nerve growth factor (hNGFp), inspired by the human genetic disease hereditary sensory and autonomic neuropathy type V. hNGFp has identical neurotrophic potency as wild type human nerve growth factor, but a 10-fold lower pain sensitizing activity. In this study we first mimicked, in the 5xFAD mouse model, the intraparenchymal delivery of hNGFp used in clinical trials and found it to be ineffective in decreasing amyloid-beta plaque load. On the contrary, the same dose of hNGFp delivered intranasally, which was widely biodistributed in the brain and did not induce pain, showed a potent anti-amyloidogenic action and rescued synaptic plasticity and memory deficits. We found that hNGFp acts on glial cells, modulating inflammatory proteins such as the soluble TNFalpha receptor II and the chemokine CXCL12. We further established that the rescuing effect by hNGFp is mediated by CXCL12, as pharmacological inhibition of CXCL12 receptor CXCR4 occludes most of hNGFp effects. These findings have significant therapeutic implications: (i) we established that a widespread exposure of the brain is required for nerve growth factor to fully exert its neuroprotective actions; and (ii) we have identified a new anti-neurodegenerative pathway as a broad target for new therapeutic opportunities for neurodegenerative diseases. PMID- 28031223 TI - Disrupted prediction errors index social deficits in autism spectrum disorder. AB - Social deficits are a core symptom of autism spectrum disorder; however, the perturbed neural mechanisms underpinning these deficits remain unclear. It has been suggested that social prediction errors-coding discrepancies between the predicted and actual outcome of another's decisions-might play a crucial role in processing social information. While the gyral surface of the anterior cingulate cortex signalled social prediction errors in typically developing individuals, this crucial social signal was altered in individuals with autism spectrum disorder. Importantly, the degree to which social prediction error signalling was aberrant correlated with diagnostic measures of social deficits. Effective connectivity analyses further revealed that, in typically developing individuals but not in autism spectrum disorder, the magnitude of social prediction errors was driven by input from the ventromedial prefrontal cortex. These data provide a novel insight into the neural substrates underlying autism spectrum disorder social symptom severity, and further research into the gyral surface of the anterior cingulate cortex and ventromedial prefrontal cortex could provide more targeted therapies to help ameliorate social deficits in autism spectrum disorder. PMID- 28031224 TI - Carl Gustav Jung and the psychobiology of schizophrenia. PMID- 28031226 TI - High impact research: investigating the effects of repetitive head injury. PMID- 28031225 TI - Reply: Pupil area and photopigment spectral sensitivity are relevant to study of migraine photophobia. PMID- 28031227 TI - Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism. AB - Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K allele), which is expressed in >40% of HNSCC cases. Patients expressing the K allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K521 was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521 that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K521 expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. Cancer Res; 77(5); 1188-99. (c)2016 AACR. PMID- 28031228 TI - Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4. AB - The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416-26. (c)2016 AACR. PMID- 28031230 TI - Rare association of endomyocardial fibrosis and Chagas heart disease. PMID- 28031229 TI - Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire. AB - While immune checkpoint blockade elicits efficacious responses in many patients with cancer, it also produces a diverse and unpredictable number of immune related adverse events (IRAE). Mechanisms driving IRAEs are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T-cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T-cell repertoire in IRAE patients compared with patients without IRAEs. Specifically, ipilimumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T-cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T-cell numbers relative to patients without IRAEs. Prostate-specific antigen responses to ipilimumab were also associated with increased T-cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for patients with cancer. Cancer Res; 77(6); 1322-30. (c)2016 AACR. PMID- 28031231 TI - A harmless 'Scimitar'. PMID- 28031232 TI - The absence of a left atrial appendage in a patient with paroxysmal atrial fibrillation with a persistent left superior vena cava. PMID- 28031233 TI - Quantitative intravascular biological fluorescence-ultrasound imaging of coronary and peripheral arteries in vivo. AB - Aims: (i) to evaluate a novel hybrid near-infrared fluorescence-intravascular ultrasound (NIRF-IVUS) system in coronary and peripheral swine arteries in vivo; (ii) to assess simultaneous quantitative biological and morphological aspects of arterial disease. Methods and results: Two 9F/15MHz peripheral and 4.5F/40MHz coronary near-infrared fluorescence (NIRF)-IVUS catheters were engineered to enable accurate co-registrtation of biological and morphological readings simultaneously in vivo. A correction algorithm utilizing IVUS information was developed to account for the distance-related fluorescence attenuation due to through-blood imaging. Corrected NIRF (cNIRF)-IVUS was applied for in vivo imaging of angioplasty-induced vascular injury in swine peripheral arteries and experimental fibrin deposition on coronary artery stents, and of atheroma in a rabbit aorta, revealing feasibility to intravascularly assay plaque structure and inflammation. The addition of ICG-enhanced NIRF assessment improved the detection of angioplasty-induced endothelial damage compared to standalone IVUS. In addition, NIRF detection of coronary stent fibrin by in vivo cNIRF-IVUS imaging illuminated stent pathobiology that was concealed on standalone IVUS. Fluorescence reflectance imaging and microscopy of resected tissues corroborated the in vivo findings. Conclusions: Integrated cNIRF-IVUS enables simultaneous co registered through-blood imaging of disease related morphological and biological alterations in coronary and peripheral arteries in vivo. Clinical translation of cNIRF-IVUS may significantly enhance knowledge of arterial pathobiology, leading to improvements in clinical diagnosis and prognosis, and helps to guide the development of new therapeutic approaches for arterial diseases. PMID- 28031234 TI - The Multiple Roles of Exosomes in Metastasis. AB - Exosomes are important contributors to cell-cell communication and their role as diagnostic markers for cancer and the pathogenesis for cancer is under intensive investigation. Here, we focus on their role in metastasis-related processes. We discuss their impact regarding promotion of invasion and migration of tumor cells, conditioning of lymph nodes, generation of premetastatic niches and organotropism of metastasis. Furthermore, we highlight interactions of exosomes with bone marrow and stromal components such as fibroblasts, endothelial cells, myeloid- and other immune-related cells in the context of metastases. For all processes as described above, we outline molecular and cellular components for therapeutic intervention with metastatic processes. PMID- 28031235 TI - HTP Nutraceutical Screening for Histone Deacetylase Inhibitors and Effects of HDACis on Tumor-suppressing miRNAs by Trichostatin A and Grapeseed (Vitis vinifera) in HeLa cells. AB - BACKGROUND/AIM: Aggressive tumor malignancies are a consequence of delayed diagnosis, epigenetic/phenotype changes and chemo-radiation resistance. Histone deacetylases (HDACs) are a major epigenetic regulator of transcriptional repression, which are highly overexpressed in advanced malignancy. While original chemotherapy drugs were modeled after phytochemicals elucidated by botanical screenings, HDAC inhibitors (HDACi) such as apicidin, trichostatin A (TSA) and butyrate were discovered as products of fungus and microbes, in particular, gut microbiota. Therefore, a persistent question remains as to the inherent existence of HDACis in raw undigested dietary plant material. In this study, we conduct a high-throughput (HTP) screening of ~1,600 non-fermented commonly used nutraceuticals (spices, herbs, teas, vegetables, fruits, seeds, rinds etc.) at (<600 MUg/ml) and food-based polyphenolics (<240 MUg/ml) for evidence of HDAC activity inhibition in nuclear HeLa cell lysates. MATERIALS AND METHODS: Human HDAC kinetic validation was performed using a standard fluorometric activity assay, followed by an enzymatic-linked immuno-captured ELISA. Both methods were verified using HDACi panel drugs: TSA, apicidin, suberohydroxamic acid, M344, CL 994, valproic acid and sodium phenylbutyrate. The HTP screening was then conducted, followed by a study comparing biological effects of HDACis in HeLa cells, including analysis of whole-transcriptome non-coding RNAs using Affymetrix miRNA 4.1-panel arrays. RESULTS: The HTP screening results confirmed 44/1600 as potential HDACis to which 31 were further eliminated as false-positives. Methodological challenges/concerns are addressed regarding plant product false positives that arise from the signal reduction of commercial lysine development reagents. Only 13 HDACis were found having an IC50 under <200 MUg/ml: Grapeseed extract (Vitis vinifera), Great burnet root (Sanguisorba Officinalis), Babul (Acacia arabica), Chinese gallnut (Melaphis chinensis), Konaberry extract (Coffea arabica), Uva Ursi (Arctostaphylos uva ursi), Green tea (Camellia sinensis), Meadowsweet (Filipendula ulmaria), Sassafras (Sassafras officinale), Turkey rhubarb (Rheum palmatum), epigallocatechin gallate (EGCG), gossypol and gallic acid. Next, we investigate the biological consequence of HDACi panel drugs in HeLa cells, where the data suggest predominant effects are anti-mitotic rather than cytotoxic. Lastly, differential effects of TSA vs. GSE at sub-lethal concentrations tested on HeLa cells show 6,631 miRNAs expressed in resting cells, 35 significantly up-regulated (TSA) and 81 up-regulated (GSE), with several miRNAs overlapping in the upward direction by both GSE and TSA (e.g. hsa-miR-23b 5p, hsa-miR-27b-5p, hsa-miR-1180-3p, hsa-miR-6880-5p and hsa-mir-943). Using DIANA miRNA online tools, it was determined that GSE and TSA simultaneously cause overexpression of similar miRNAs predicted to destroy the following influential oncogenes: NFkB, NRAS, KRAS, HRAS, MYC, TGFBR1, E2F1, E2F2, BCL21, CDKN1A, CDK6, HIF1a, and VEGFA. CONCLUSION: The data from this study show that plant- based HDACis are relatively rare, and can elicit a similar pattern to TSA in up regulating miRNAs involved with tumor suppression of HeLa cervical carcinoma. PMID- 28031236 TI - Proteomics Analysis of Ovarian Cancer Cell Lines and Tissues Reveals Drug Resistance-associated Proteins. AB - BACKGROUND: Carboplatin and paclitaxel form the cornerstone of chemotherapy for epithelial ovarian cancer, however, drug resistance to these agents continues to present challenges. Despite extensive research, the mechanisms underlying this resistance remain unclear. MATERIALS AND METHODS: A 2D-gel proteomics method was used to analyze protein expression levels of three human ovarian cancer cell lines and five biopsy samples. Representative proteins identified were validated via western immunoblotting. Ingenuity pathway analysis revealed metabolomic pathway changes. RESULTS: A total of 189 proteins were identified with restricted criteria. Combined treatment targeting the proteasome-ubiquitin pathway resulted in re-sensitisation of drug-resistant cells. In addition, examination of five surgical biopsies of ovarian tissues revealed alpha-enolase (ENOA), elongation factor Tu, mitochondrial (EFTU), glyceraldehyde-3-phosphate dehydrogenase (G3P), stress-70 protein, mitochondrial (GRP75), apolipoprotein A-1 (APOA1), peroxiredoxin (PRDX2) and annexin A (ANXA) as candidate biomarkers of drug resistant disease. CONCLUSION: Proteomics combined with pathway analysis provided information for an effective combined treatment approach overcoming drug resistance. Analysis of cell lines and tissues revealed potential prognostic biomarkers for ovarian cancer. PMID- 28031237 TI - Expression Profiling of a Human Thyroid Cell Line Stably Expressing the BRAFV600E Mutation. AB - BACKGROUND/AIM: The BRAFV600E mutation acts as an initiator of cancer development in papillary thyroid carcinoma (PTC). Gene expression changes caused by the BRAFV600E mutation may have an important role in thyroid cancer development. MATERIALS AND METHODS: To study genomic alterations caused by the BRAFV600E mutation, we made human thyroid cell lines that harbor the wild-type BRAF gene (Nthy/WT) and the V600E mutant-type BRAF gene (Nthy/V600E). RESULTS: Flow cytometry and western blotting showed stable transfection of the BRAF gene. In functional experiments, Nthy/V600E showed increased anchorage-independent growth and invasion through Matrigel, compared to Nthy/WT. Microarray analysis revealed that 2,441 genes were up-regulated in Nthy/V600E compared to Nthy/WT. Gene ontology analysis showed that the up-regulated genes were associated with cell adhesion, migration, and the ERK and MAPK cascade, and pathway analysis showed enrichment in cancer-related pathways. CONCLUSION: Our Nthy/WT and Nthy/V600E cell line pair could be a suitable model to study the molecular characteristics of BRAFV600E PTC. PMID- 28031238 TI - Customized Array Comparative Genomic Hybridization Analysis of 25 Phosphatase encoding Genes in Colorectal Cancer Tissues. AB - BACKGROUND/AIM: Molecular mechanisms of alterations in protein tyrosine phosphatases (PTPs) genes in cancer have been previously described and include chromosomal aberrations, gene mutations, and epigenetic silencing. However, little is known about small intragenic gains and losses that may lead to either changes in expression or enzyme activity and even loss of protein function. MATERIALS AND METHODS: The aim of this study was to investigate 25 phosphatase genes using customized array comparative genomic hybridization in 16 sporadic colorectal cancer tissues. RESULTS: The analysis revealed two unique small alterations: of 2 kb in PTPN14 intron 1 and of 1 kb in PTPRJ intron 1. We also found gains and losses of whole PTPs gene sequences covered by large chromosome aberrations. CONCLUSION: In our preliminary studies using high-resolution custom microarray we confirmed that PTPs are frequently subjected to whole-gene rearrangements in colorectal cancer, and we revealed that non-polymorphic intragenic changes are rare. PMID- 28031239 TI - MicroRNAs 142-3p, miR-155 and miR-203 Are Deregulated in Gastric MALT Lymphomas Compared to Chronic Gastritis. AB - BACKGROUND: Over the last years, our knowledge on pathogenesis of gastric MALT lymphoma has greatly improved, but its morphological diagnosis is still hampered by overlapping histological features with advanced chronic gastritis. MicroRNAs are deregulated in lymphomas, but their role and usefulness in gastric MALT lymphoma has not been extensively investigated. MATERIALS AND METHODS: We analyzed the expression of 384 miRNAs using TaqMan microRNA assay in a training series of 10 gastric MALT lymphomas, 3 chronic gastritis and 2 reactive lymph nodes. Then, significantly deregulated miRNAs were individually assessed by real time PCR in a validation series of 16 gastric MALT lymphomas and 12 chronic gastritis. RESULTS: Gastric MALT lymphoma is characterized by a specific miRNA expression profile. Among the differentially expressed miRNAs, a significant overexpression of miR-142-3p and miR-155 and down-regulation of miR-203 was observed in gastric MALT lymphoma when compared to chronic gastritis. CONCLUSION: miR-142-3p, miR-155 and miR-203 expression levels might be helpful biomarkers for the differential diagnosis between gastric MALT lymphomas and chronic gastritis. PMID- 28031240 TI - Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide resistant Glioblastoma Cell Line. AB - BACKGROUND: Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach to overcome resistance is needed. MATERIALS AND METHODS: The efficacy of a combination treatment of STAT3 inhibitor, STX-0119, with rapamycin was investigated against our established TMZ-resistant U87 cell line. RESULTS: The growth-inhibitory effect of the combination treatment was significant against the TMZ-R U87 cell line (IC50: 78 MUM for STX-0119, 30.5 MUM for rapamycin and 11.3 MUM for combination of the two). Western blotting analysis demonstrated that the inhibitory effect of STX-0119 on S6 and 4E-BP1 activation through regulation of YKL-40 expression occurred in addition to the inhibitory effect of rapamycin against the mTOR pathway. CONCLUSION: These results suggest that the STAT3 pathway is associated with the mTOR downstream pathway mediated by YKL-40 protein, and the combination therapy of the STAT3 inhibitor and rapamycin could be worth developing as a novel therapeutic approach against TMZ-resistant relapsed gliomas. PMID- 28031241 TI - A tragedy of modern cardiology: using ejection fraction to gauge left ventricular function in mitral regurgitation. PMID- 28031242 TI - Withdrawal of life-sustaining therapy: the case for delay. PMID- 28031243 TI - Caenorhabditis elegans Male Copulation Circuitry Incorporates Sex-Shared Defecation Components To Promote Intromission and Sperm Transfer. AB - Sexual dimorphism can be achieved using a variety of mechanisms, including sex specific circuits and sex-specific function of shared circuits, though how these work together to produce sexually dimorphic behaviors requires further investigation. Here, we explore how components of the sex-shared defecation circuitry are incorporated into the sex-specific male mating circuitry in Caenorhabditis elegans to produce successful copulation. Using behavioral studies, calcium imaging, and genetic manipulation, we show that aspects of the defecation system are coopted by the male copulatory circuitry to facilitate intromission and ejaculation. Similar to hermaphrodites, male defecation is initiated by an intestinal calcium wave, but circuit activity is coordinated differently during mating. In hermaphrodites, the tail neuron DVB promotes expulsion of gut contents through the release of the neurotransmitter GABA onto the anal depressor muscle. However, in the male, both neuron and muscle take on modified functions to promote successful copulation. Males require calcium dependent activator protein for secretion (CAPS)/unc-31, a dense core vesicle exocytosis activator protein, in the DVB to regulate copulatory spicule insertion, while the anal depressor is remodeled to promote release of sperm into the hermaphrodite. This work shows how sex-shared circuitry is modified in multiple ways to contribute to sex-specific mating. PMID- 28031244 TI - Fine Mapping of Ur-3, a Historically Important Rust Resistance Locus in Common Bean. AB - Bean rust, caused by Uromyces appendiculatus, is a devastating disease of common bean (Phaseolus vulgaris) in the Americas and Africa. The historically important Ur-3 gene confers resistance to many races of the highly variable bean rust pathogen that overcome other rust resistance genes. Existing molecular markers tagging Ur-3 for use in marker-assisted selection produce false results. Here, we describe the fine mapping of the Ur-3 locus for the development of highly accurate markers linked to Ur-3 An F2 population from the cross Pinto 114 (susceptible) * Aurora (resistant with Ur-3) was evaluated for its reaction to four different races of U. appendiculatus A bulked segregant analysis using the SNP chip BARCBEAN6K_3 placed the approximate location of Ur-3 in the lower arm of chromosome Pv11. Specific SSR and SNP markers and haplotype analysis of 18 sequenced bean varieties positioned Ur-3 in a 46.5 kb genomic region from 46.96 to 47.01 Mb on Pv11. We discovered in this region the SS68 KASP marker that was tightly linked to Ur-3 Validation of SS68 on a panel of 130 diverse common bean cultivars containing all known rust resistance genes revealed that SS68 was highly accurate and produced no false results. The SS68 marker will be of great value in pyramiding Ur-3 with other rust resistance genes. It will also significantly reduce time and labor associated with the current phenotypic detection of Ur-3 This is the first utilization of fine mapping to discover markers linked to rust resistance in common bean. PMID- 28031245 TI - Robotic-enhanced coronary surgery in octogenarians. AB - Objectives: Robotic-enhanced minimally invasive direct coronary artery bypass grafting surgery (RE-MIDCAB) is based on the use of a robotic console and instrumentation for the dissection of the left internal thoracic artery (LITA). The LITA to left anterior descending (LAD) artery anastomosis is subsequently constructed through a mini thoracotomy. The purpose of this study is to present our experience of RE-MIDCAB outcomes in elderly patients. Methods: From 2002 until 2015, 44 octogenarians (the mean age of 82.9 years) underwent RE-MIDCAB. The mean logistic EuroSCORE was 9.2. The majority of the patients were male with a medical history of hypertension, dyslipidaemia and previous coronary interventions. Of these patients 25% underwent RE-MIDCAB combined with percutaneous coronary intervention (PCI) for the treatment of multi-vessel disease (hybrid revascularization). Results: All RE-MIDCABs and combined 'hybrid' PCI procedures were successfully completed. The mean intensive care unit (ICU) and hospital stay were 1.6 days and 10.9 days, respectively. There was 1 in hospital mortality (2.3%). After an average follow-up period of 29.2 months, 5 patients required repeat revascularization procedures (9.1%). Mortality on follow up was estimated at 25.6%. Conclusions: Our report suggests that considering the age and frailty of the octogenarian population, RE-MIDCAB is a feasible and safe procedure which is associated with acceptable mid-term results. PMID- 28031246 TI - More than ever, scientists need to engage with the public: the stakes are high and they may be for keeps. PMID- 28031247 TI - Thioredoxin-dependent disulfide bond reduction is required for protamine eviction from sperm chromatin. AB - Cysteine oxidation in protamines leads to their oligomerization and contributes to sperm chromatin compaction. Here we identify the Drosophila thioredoxin Deadhead (DHD) as the factor responsible for the reduction of intermolecular disulfide bonds in protamines and their eviction from sperm during fertilization. Protamine chaperone TAP/p32 dissociates DNA-protamine complexes in vitro only when protamine oligomers are first converted to monomers by DHD. dhd-null embryos cannot decondense sperm chromatin and terminate development after the first pronuclear division. Therefore, the thioredoxin DHD plays a critical role in early development to facilitate the switch from protamine-based sperm chromatin structures to the somatic nucleosomal chromatin. PMID- 28031248 TI - Protein splicing of a recombinase intein induced by ssDNA and DNA damage. AB - Inteins (or protein introns) autocatalytically excise themselves through protein splicing. We challenge the long-considered notion that inteins are merely molecular parasites and posit that some inteins evolved to regulate host protein function. Here we show substrate-induced and DNA damage-induced splicing, in which an archaeal recombinase RadA intein splices dramatically faster and more accurately when provided with ssDNA. This unprecedented example of intein splicing stimulation by the substrate of the invaded host protein provides compelling support in favor of inteins acting as pause buttons to arrest protein function until needed; then, an immediate activity switch is triggered, representing a new form of post-translational control. PMID- 28031249 TI - Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response. AB - Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understand how this complex network regulates the metabolic response to fasting, we aimed at isolating the enhancers and TFs dictating it. Measuring chromatin accessibility revealed that fasting massively reorganizes liver chromatin, exposing numerous fasting-induced enhancers. By utilizing computational methods in combination with dissecting enhancer features and TF cistromes, we implicated four key TFs regulating the fasting response: glucocorticoid receptor (GR), cAMP responsive element binding protein 1 (CREB1), peroxisome proliferator activated receptor alpha (PPARA), and CCAAT/enhancer binding protein beta (CEBPB). These TFs regulate fuel production by two distinctly operating modules, each controlling a separate metabolic pathway. The gluconeogenic module operates through assisted loading, whereby GR doubles the number of sites occupied by CREB1 as well as enhances CREB1 binding intensity and increases accessibility of CREB1 binding sites. Importantly, this GR-assisted CREB1 binding was enhancer-selective and did not affect all CREB1-bound enhancers. Single-molecule tracking revealed that GR increases the number and DNA residence time of a portion of chromatin-bound CREB1 molecules. These events collectively result in rapid synergistic gene expression and higher hepatic glucose production. Conversely, the ketogenic module operates via a GR-induced TF cascade, whereby PPARA levels are increased following GR activation, facilitating gradual enhancer maturation next to PPARA target genes and delayed ketogenic gene expression. Our findings reveal a complex network of enhancers and TFs that dynamically cooperate to restore homeostasis upon fasting. PMID- 28031250 TI - A-to-I RNA editing promotes developmental stage-specific gene and lncRNA expression. AB - A-to-I RNA editing is a conserved widespread phenomenon in which adenosine (A) is converted to inosine (I) by adenosine deaminases (ADARs) in double-stranded RNA regions, mainly noncoding. Mutations in ADAR enzymes in Caenorhabditis elegans cause defects in normal development but are not lethal as in human and mouse. Previous studies in C. elegans indicated competition between RNA interference (RNAi) and RNA editing mechanisms, based on the observation that worms that lack both mechanisms do not exhibit defects, in contrast to the developmental defects observed when only RNA editing is absent. To study the effects of RNA editing on gene expression and function, we established a novel screen that enabled us to identify thousands of RNA editing sites in nonrepetitive regions in the genome. These include dozens of genes that are edited at their 3' UTR region. We found that these genes are mainly germline and neuronal genes, and that they are down regulated in the absence of ADAR enzymes. Moreover, we discovered that almost half of these genes are edited in a developmental-specific manner, indicating that RNA editing is a highly regulated process. We found that many pseudogenes and other lncRNAs are also extensively down-regulated in the absence of ADARs in the embryo but not in the fourth larval (L4) stage. This down-regulation is not observed upon additional knockout of RNAi. Furthermore, levels of siRNAs aligned to pseudogenes in ADAR mutants are enhanced. Taken together, our results suggest a role for RNA editing in normal growth and development by regulating silencing via RNAi. PMID- 28031251 TI - Expression and biochemical characterization and substrate specificity of the fucoidanase from Formosa algae. AB - A gene that encodes fucoidanase ffa2 in the marine bacterium Formosa algae strain KMM 3553T was cloned, and the protein (FFA2) was produced in Escherichia coli. Recombinant fucoidanase FFA2 was purified, and the biochemical properties of this enzyme were studied. The amino acid sequence of FFA2 showed 57% identity with known fucoidanase FcnA from Mariniflexile fucanivorans. The mass of the gene product FFA2 is 101.2 kDa (918 amino acid residues). Sequence analysis has revealed that fucoidanase FFA2 belongs to the GH107 (CAZy) family. Detailed substrate specificity was studied by using fucoidans from brown seaweeds as well as synthetic fucooligosaccharide with distinct structures. Fucoidanase FFA2 catalyzes the cleavage of (1->4)-alpha-glycosidic bonds in the fucoidan from Fucus evanescens within a structural fragment (->3)-alpha-l-Fucp2S-(1->4)-alpha-l Fucp2S-(1->)n but not in a fragment (->3)-alpha-l-Fucp2S,4S-(1->4)-alpha-l-Fucp2S (1->)n. Using synthetic di-, tetra- and octasaccharides built up of the alternative (1->4)- and (1->3)-linked alpha-l-Fucp2S units, the difference in substrate specificity and in the rate of enzymatic selectivity was investigated. Nonsulfated and persulfated synthetic oligosaccharides were not transformed by the enzyme. Therefore, FFA2 was specified as poly[(1->4)-alpha-l-fucoside-2 sulfate] glycanohydrolase. This enzyme could be used for the modification of natural fucoidans to obtain more regular and easier characterized derivatives useful for research and practical applications. PMID- 28031252 TI - Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non syndromic LHON-like optic neuropathy. AB - BACKGROUND: Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non consanguineous parents of French origin. METHODS: We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica. RESULTS: We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively. CONCLUSIONS: Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function. PMID- 28031253 TI - Global snapshots of bacterial RNA networks. PMID- 28031254 TI - FATAL FOETAL ABNORMALITY, IRISH CONSTITUTIONAL LAW, AND MELLET v IRELAND. AB - Under the Irish Constitution abortion is allowed only where the life of the pregnant woman is at risk. The provision in question, Article 40.3.3 (or the 8th Amendment) has long been criticised for failing to respect women's autonomy, and in Mellet v Ireland, the UN Human Rights Committee found that Amanda Jane Mellet, who travelled to Liverpool to access abortion following a finding that her foetus suffered a fatal abnormality, had suffered a violation of her rights under the International Covenant on Civil and Political Rights (ICCPR). In this commentary I demonstrate the value of Mellet when compared to the possible legal findings in such circumstances under both the Constitution and the European Convention on Human Rights, and argue that the findings are not restricted to cases of fatal foetal abnormality. Rather, the Committee's decision illustrates the suffering that all women in Ireland who travel to access abortion experience, arguably constituting a violation of their right to be free from cruel, inhuman, and degrading treatment. On that reading, Mellet signifies the need to implement a comprehensive rethink of Irish abortion law including, but going beyond, access to abortion in cases of fatal foetal abnormality. PMID- 28031256 TI - Organ donation after medical assistance in dying or cessation of life-sustaining treatment requested by conscious patients: the Canadian context. AB - In June 2016, following the decision of the Supreme Court of Canada to decriminalise assistance in dying, the Canadian government enacted Bill C-14, legalising medical assistance in dying (MAID). In 2014, the province of Quebec had passed end-of-life care legislation making MAID available as of December 2015. The availability of MAID has many implications, including the possibility of combining this practice with organ donation through the controlled donation after cardiac death (cDCD) protocol. cDCD most often occurs in cases where the patient has a severe neurological injury but does not meet all the criteria for brain death. The donation is subsequent to the decision to withdraw life sustaining treatment (LST). Cases where patients are conscious prior to the withdrawal of LST are unusual, and have raised doubts as to the acceptability of removing organs from individuals who are not neurologically impaired and who have voluntarily chosen to die. These cases can be compared with likely scenarios in which patients will request both MAID and organ donation. In both instances, patients will be conscious and competent. Organ donation in such contexts raises ethical issues regarding respect for autonomy, societal pressure, conscientious objections and the dead-donor rule. In this article, we look at relevant policies in other countries and examine the ethical issues associated with cDCD in conscious patients who choose to die. PMID- 28031255 TI - ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. AB - Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a KrasG12D/p53R172H mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three-dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK-induced genes that facilitate extracellular matrix remodeling, with greatest fold-changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13 MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three-dimensional contexts. Treatment of KrasG12D/p53R172H PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth. PMID- 28031258 TI - Christmas-New Year Influenza Lull: Not Too Late for Vaccination. PMID- 28031257 TI - Sexual pheromone modulates the frequency of cytosolic Ca2+ bursts in Saccharomyces cerevisiae. AB - Transient and highly regulated elevations of cytosolic Ca2+ control a variety of cellular processes. Bulk measurements using radioactive Ca2+ and the luminescent sensor aequorin have shown that in response to pheromone, budding yeast cells undergo a rise of cytosolic Ca2+ that is mediated by two import systems composed of the Mid1-Cch1-Ecm7 protein complex and the Fig1 protein. Although this response has been widely studied, there is no treatment of Ca2+ dynamics at the single-cell level. Here, using protein calcium indicators, we show that both vegetative and pheromone-treated yeast cells exhibit discrete and asynchronous Ca2+ bursts. Most bursts reach maximal amplitude in 1-10 s, range between 7 and 30 s, and decay in a way that fits a single-exponential model. In vegetative cells, bursts are scarce but preferentially occur when cells are transitioning G1 and S phases. On pheromone presence, Ca2+ burst occurrence increases dramatically, persisting during cell growth polarization. Pheromone concentration modulates burst frequency in a mechanism that depends on Mid1, Fig1, and a third, unidentified, import system. We also show that the calcineurin-responsive transcription factor Crz1 undergoes nuclear localization bursts during the pheromone response. PMID- 28031259 TI - Contact, Travel, and Transmission: The Impact of Winter Holidays on Influenza Dynamics in the United States. AB - Background: The seasonality of influenza is thought to vary according to environmental factors and human behavior. During winter holidays, potential disease-causing contact and travel deviate from typical patterns. We aim to understand these changes on age-specific and spatial influenza transmission. Methods: We characterized the changes to transmission and epidemic trajectories among children and adults in a spatial context before, during, and after the winter holidays among aggregated physician medical claims in the United States from 2001 to 2009 and among synthetic data simulated from a deterministic, age specific spatial metapopulation model. Results: Winter holidays reduced influenza transmission and delayed the trajectory of influenza season epidemics. The holiday period was marked by a shift in the relative risk of disease from children toward adults. Model results indicated that holidays delayed epidemic peaks and synchronized incidence across locations, and that contact reductions from school closures, rather than age-specific mixing and travel, produced these observed holiday influenza dynamics. Conclusions: Winter holidays delay seasonal influenza epidemic peaks and shift disease risk toward adults because of changes in contact patterns. These findings may inform targeted influenza information and vaccination campaigns during holiday periods. PMID- 28031260 TI - Immunization with Pneumocystis Cross-Reactive Antigen 1 (Pca1) Protects Mice against Pneumocystis Pneumonia and Generates Antibody to Pneumocystis jirovecii. AB - Pneumocystis pneumonia (PcP) is a life-threatening infection that affects immunocompromised individuals. Nearly half of all PcP cases occur in those prescribed effective chemoprophylaxis, suggesting that additional preventive methods are needed. To this end, we have identified a unique mouse Pneumocystis surface protein, designated Pneumocystis cross-reactive antigen 1 (Pca1), as a potential vaccine candidate. Mice were immunized with a recombinant fusion protein containing Pca1. Subsequently, CD4+ T cells were depleted, and the mice were exposed to Pneumocystis murina Pca1 immunization completely protected nearly all mice, similar to immunization with whole Pneumocystis organisms. In contrast, all immunized negative-control mice developed PcP. Unexpectedly, Pca1 immunization generated cross-reactive antibody that recognized Pneumocystis jirovecii and Pneumocystis carinii Potential orthologs of Pca1 have been identified in P. jirovecii Such cross-reactivity is rare, and our findings suggest that Pca1 is a conserved antigen and potential vaccine target. The evaluation of Pca1-elicited antibodies in the prevention of PcP in humans deserves further investigation. PMID- 28031261 TI - Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization. AB - Urinary tract infection (UTI) is a major global infectious disease affecting millions of people annually. Human urinary copper (Cu) content is elevated during UTI caused by uropathogenic Escherichia coli (UPEC). UPEC upregulates the expression of Cu efflux genes during clinical UTI in patients as an adaptive response to host-derived Cu. Whether Cu is mobilized to urine as a host response to UTI and its role in protection against UTI remain unresolved. To address these questions, we tested the hypothesis that Cu is a host effector mobilized to urine during UTI to limit bacterial growth. Our results reveal that Cu is mobilized to urine during UTI caused by the major uropathogens Proteus mirabilis and Klebsiella pneumoniae, in addition to UPEC, in humans. Ceruloplasmin, a Cu containing ferroxidase, is found at higher levels in UTI urine than in healthy control urine and serves as the molecular source of urinary Cu during UTI. Our results demonstrate that ceruloplasmin decreases the bioavailability of iron in urine by a transferrin-dependent mechanism. Experimental UTI with UPEC in nonhuman primates recapitulates the increased urinary Cu content observed during clinical UTI. Furthermore, Cu-deficient mice are highly colonized by UPEC, indicating that Cu is involved in the limiting of bacterial growth within the urinary tract. Collectively, our results indicate that Cu is a host effector that is involved in protection against pathogen colonization of the urinary tract. Because urinary Cu levels are amenable to modulation, augmentation of the Cu based host defense against UTI represents a novel approach to limiting bacterial colonization during UTI. PMID- 28031262 TI - Pseudomonas aeruginosa GroEL Stimulates Production of PTX3 by Activating the NF kappaB Pathway and Simultaneously Downregulating MicroRNA-9. AB - As one of the first lines of host defense, monocytes play important roles in clearing infected microbes. The defensive response is triggered by recognition of diverse microbial moieties, including released factors, which modulate host immune responses to establish a harsh environment for clinically important bacterial pathogens. In this study, we found that the expression of PTX3, a soluble form of pattern recognition receptor, was induced by infection with live Pseudomonas aeruginosa or treatment of cells with its supernatant. P. aeruginosa GroEL, a homolog of heat shock protein 60, was identified as one of the factors responsible for inducing the expression of PTX3 in host cells. GroEL induced PTX3 expression by activating the Toll-like receptor 4 (TLR4)-dependent pathway via nuclear factor-kappa B (NF-kappaB), while simultaneously inhibiting expression of microRNA-9, which targets the PTX3 transcript. Finally, by acting as an opsonin, GroEL-induced PTX3 promoted the association and phagocytosis of Staphylococcus aureus into macrophages. These data suggest that the host defensive environment is supported by the production of PTX3 in response to GroEL, which thus has therapeutic potential for clearance of bacterial infections. PMID- 28031263 TI - Interaction between SWP9 and Polar Tube Proteins of the Microsporidian Nosema bombycis and Function of SWP9 as a Scaffolding Protein Contribute to Polar Tube Tethering to the Spore Wall. AB - All microsporidia possess a unique, highly specialized invasion mechanism that involves the polar tube and spore wall. The interaction between spore wall proteins (SWPs) and polar tube proteins (PTPs) in the formation, arrangement, orderly orientation, and function of the polar tube and spore wall remains to be determined. This study was undertaken to examine the protein interactions of Nosema bombycis SWP7 (NbSWP7), NbSWP9, and PTPs. Coimmunoprecipitation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and yeast two-hybrid data demonstrated that NbSWP9, but not NbSWP7, interacts with NbPTP1 and NbPTP2. Furthermore, immunoelectron microscopy (IEM) showed that NbSWP9 was localized mainly in the developing polar tube of sporoblasts, while NbSWP7 was found randomly in the cytoplasm. However, both NbSWP9 and NbSWP7 were located in the polar tube and spore wall of N. bombycis mature spores. The reason why NbSWP7 was localized to the polar tube may be due to the interaction between NbSWP9 and NbSWP7. Interestingly, the majority of NbSWP9, but not NbSWP7, accumulated in the beginning part of the extruded polar tube and the ruptured spore wall called the anchoring disk (AD) when the mature spores germinated under weak-alkaline environmental stimulation. Additionally, anti-NbSWP9 antibody reduced spore germination in a dose-dependent manner. In conclusion, our study further confirmed that NbSWP9 is a scaffolding protein that not only anchors and holds the polar tube but also tethers the polar tube to the spore wall. PMID- 28031264 TI - Mycobacterium bovis Requires P27 (LprG) To Arrest Phagosome Maturation and Replicate within Bovine Macrophages. AB - Mycobacterium bovis causes tuberculosis in a wide variety of mammals, with strong tropism for cattle and eventually humans. P27, also called LprG, is among the proteins involved in the mechanisms of the virulence and persistence of M. bovis and Mycobacterium tuberculosis Here, we describe a novel function of P27 in the interaction of M. bovis with its natural host cell, the bovine macrophage. We found that a deletion in the p27-p55 operon impairs the replication of M. bovis in bovine macrophages. Importantly, we show for the first time that M. bovis arrests phagosome maturation in a process that depends on P27. This effect is P27 specific since complementation with wild-type p27 but not p55 fully restored the wild-type phenotype of the mutant strain; this indicates that P55 plays no important role during the early events of M. bovis infection. In addition, we also showed that the presence of P27 from M. smegmatis decreases the association of LAMP-3 with bead phagosomes, indicating that P27 itself blocks phagosome lysosome fusion by modulating the traffic machinery in the cell host. PMID- 28031265 TI - The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum. AB - Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen. PMID- 28031266 TI - Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis. AB - Exposure to blood-stage malaria infection is often persistent, leading to generation of CD4 effector and effector memory T cells that contribute to protection. We showed previously that chronic exposure to blood-stage Plasmodium chabaudi offers the best protection from parasitemia and pathology in reinfection cases, correlating with an increase in Th1 cells. Although much is known about the features of resting or exhausted memory T cells (Tmem), little is known about the functional capacities of chronically stimulated but protective T cells. To determine the functional capacity of CD4 T cells generated by chronic infection upon reexposure to parasite, we compared their responses to known features of classical Tmem. The numbers of cytokine-producing T cells increased following infection in the polyclonal populations, suggesting an increase in pathogen specific T cells. Malaria antigen-specific B5 T cell receptor (TCR) transgenic (Tg) T cells from chronic infection proliferated on reinfection and were highly sensitive to TCR stimulation without costimulation, as shown for Tmem in acute stimulations. However, B5 Tmem did not accumulate more than naive B5 T cells in vivo or in vitro and became apoptotic. Failure to accumulate was partly the result of chronic stimulation, since eliminating persistent parasites before reinfection slightly increased the accumulation of B5 Tg T cells upon reinfection. The levels of specific gamma interferon-positive, interleukin-10 positive T cells, which protect animals from pathology, increased after malaria infection. These data demonstrate that although chronic infection generates a protective T cell population with increased TCR sensitivity and cytokine production, they do not reexpand upon reexposure due to increased apoptosis. PMID- 28031267 TI - Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine. AB - Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei-P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced. PMID- 28031268 TI - Distinct Roles of Opioid and Dopamine Systems in Lateral Hypothalamic Intracranial Self-Stimulation. AB - Background: Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both u-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems. Methods: Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed. Results: Significant differences are observed between opioid and dopamine systems in reward function. u-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward. Conclusions: The absence of u-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in u-opioid receptor knockout mice are consistent with the suppressive involvement of u-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in u-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward. PMID- 28031270 TI - Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline. AB - Objectives: Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. Methods: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort. Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs. Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility. PMID- 28031271 TI - Voriconazole MICs are predictive for the outcome of experimental disseminated scedosporiosis. AB - Background: Scedosporiosis is associated with a mortality rate of up to 90% in patients suffering from disseminated infections. Recommended first-line treatment is voriconazole, but epidemiological cut-off values and clinical breakpoints have not been determined. Objectives: To correlate voriconazole treatment response in mice suffering from disseminated scedosporiosis with MIC values determined using CLSI broth microdilution, Etest (bioMerieux) and disc diffusion. Methods: Voriconazole MICs for 31 Scedosporium apiospermum strains were determined using CLSI broth microdilution, Etest and disc diffusion. Groups of mice were challenged intravenously with 1 out of 16 S. apiospermum strains (voriconazole CLSI broth microdilution MIC range: 0.125-8.0 mg/L) and treated with 40 mg/kg voriconazole orally by gavage once daily. Efficacy of voriconazole was evaluated by a statistically significant ( P < 0.05) reduction in fungal burden in brain. Results: A categorical agreement of 90.4% was reached for CLSI broth microdilution and disc diffusion and of 93.6% for CLSI broth microdilution and Etest. Correlation of CLSI MICs and in vivo outcome was good, as mice challenged with strains with an MIC <=2 mg/L responded to voriconazole therapy in 92.3% and those challenged with strains with an MIC >=4 mg/L responded to voriconazole therapy in 33.3%. Conclusions: CLSI broth microdilution and Etest deliver comparable results that enable a prediction of in vivo outcome. Our results suggest that voriconazole is able to reduce fungal burden in the brain of 92.3% of all mice challenged with strains with voriconazole CLSI MICs <=2 mg/L, while mice challenged with strains with CLSI MICs >=4 mg/L showed limited response to voriconazole treatment. PMID- 28031269 TI - Strategies for Utilizing Neuroimaging Biomarkers in CNS Drug Discovery and Development: CINP/JSNP Working Group Report. AB - Despite large unmet medical needs in the field for several decades, CNS drug discovery and development has been largely unsuccessful. Biomarkers, particularly those utilizing neuroimaging, have played important roles in aiding CNS drug development, including dosing determination of investigational new drugs (INDs). A recent working group was organized jointly by CINP and Japanese Society of Neuropsychopharmacology (JSNP) to discuss the utility of biomarkers as tools to overcome issues of CNS drug development.The consensus statement from the working group aimed at creating more nuanced criteria for employing biomarkers as tools to overcome issues surrounding CNS drug development. To accomplish this, a reverse engineering approach was adopted, in which criteria for the utilization of biomarkers were created in response to current challenges in the processes of drug discovery and development for CNS disorders. Based on this analysis, we propose a new paradigm containing 5 distinct tiers to further clarify the use of biomarkers and establish new strategies for decision-making in the context of CNS drug development. Specifically, we discuss more rational ways to incorporate biomarker data to determine optimal dosing for INDs with novel mechanisms and targets, and propose additional categorization criteria to further the use of biomarkers in patient stratification and clinical efficacy prediction. Finally, we propose validation and development of new neuroimaging biomarkers through public-private partnerships to further facilitate drug discovery and development for CNS disorders. PMID- 28031272 TI - Polyclonal emergence of vanA vancomycin-resistant Enterococcus faecium in Australia. AB - Objectives: To investigate the genetic context associated with the emergence of vanA VRE in Australia. Methods: The whole genomes of 18 randomly selected vanA positive Enterococcus faecium patient isolates, collected between 2011 and 2013 from hospitals in four Australian capitals, were sequenced and analysed. Results: In silico typing and transposon/plasmid assembly revealed that the sequenced isolates represented (in most cases) different hospital-adapted STs and were associated with a variety of different Tn 1546 variants and plasmid backbone structures. Conclusions: The recent emergence of vanA VRE in Australia was polyclonal and not associated with the dissemination of a single 'dominant' ST or vanA -encoding plasmid. Interestingly, the factors contributing to this epidemiological change are not known and future studies may need to consider investigation of potential community sources. PMID- 28031273 TI - Complete genome sequencing revealed novel genetic contexts of the mcr-1 gene in Escherichia coli strains. PMID- 28031274 TI - Escherichia coli carrying IncX4 plasmid-mediated mcr-1 and blaCTX-M genes in infected migratory Magellanic penguins (Spheniscus magellanicus). PMID- 28031275 TI - MCR-1 in ESBL-producing Escherichia coli responsible for human infections in New Caledonia. PMID- 28031276 TI - Patients upgraded to cardiac resynchronization therapy due to pacing-induced cardiomyopathy are at low risk of life-threatening ventricular arrhythmias: a long-term cause-of-death analysis. AB - Aims: Upgrade to cardiac resynchronization therapy (CRT) should be offered to patients who have developed pacing-induced cardiomyopathy with conventional right ventricular pacing. The extent to which these patients would also benefit from defibrillator back-up at the time of CRT upgrade is, however, unknown. Methods and results: Retrospective observational cohort study of 199 patients with pacing induced cardiomyopathy and no history of sustained ventricular arrhythmia, including 104 upgraded to CRT-Pacemaker (CRT-P) and 95 upgraded to CRT Defibrillator (CRT-D). The incidence of ventricular arrhythmias and the risk of sudden arrhythmic death obtained through a cause-of-death analysis based on clinical data and necropsy results were assessed and compared between the two groups. During a mean follow-up of 66 +/- 24 months, 40 (38.5%) CRT-P patients died: three from primary arrhythmic death, while the remaining died of different causes (especially progressive heart failure), giving an incidence of 6.2 sudden arrhythmic deaths per 1000 patient-years. No episode of sustained VT was observed in the study group. There were no sudden arrhythmic deaths in the CRT-D group during a shorter follow-up, but the small and non-significant difference in all cause mortality between CRT-Pacemaker (CRT-P) and CRT-D groups was mostly accounted for by an increase in non-sudden death. Women upgraded to CRT were at particularly low risk of all-cause mortality compared with men (HR 0.232, P = 0.048). Conclusion: Our findings suggest that patients who develop pacing-induced cardiomyopathy and are upgraded to CRT may not derive any significant benefit from the addition of the defibrillator in the absence of a history of ventricular arrhythmias. PMID- 28031277 TI - The increased risk of stroke/transient ischemic attack in women with a cardiac implantable electronic device is not associated with a higher atrial fibrillation burden. AB - Aims: To evaluate if the increased thromboembolic risk in female patients may be related to a higher burden of atrial fibrillation (AF). Methods and results: Data collected in a prospective observational research of patients implanted with a cardiac implantable electrical device (CIED) were analysed. We included 2398 patients: 489 (20.4%) were female and 1909 (79.6%) were male (oral anticoagulants treatment in 23.2%, independent of gender). During the follow-up (mean 42.8, median 37.7 months), 26 thromboembolic events occurred in 22 patients, with an incidence rate ratio of both stroke and stroke/transient ischemic attack (TIA) significantly higher in females compared with males [2.00, 95% confidence interval (CI) 1.53-2.61, P< 0.001 for stroke; 1.77 (95% C1.37-2.31, P< 0.001 for stroke/TIA]. An AF burden >=5 min was a common finding (44% of patients), with no difference between men and women. The maximum daily AF burden and the time to evolution in permanent AF did not differ according to gender. The results of multivariate Cox regression showed that female gender, as well as history of CABG, were significant independent predictors of stroke and female gender was also an independent predictor of stroke/TIA. Conclusions: Among patients implanted with a CIED, an AF burden of at least 5 min is a common finding, (44% of patients). Female patients have a risk of stroke and TIAs that is around two fold that of male patients, but this increased risk cannot be ascribed to a higher burden of AF or to differences in the evolution to permanent AF. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01007474. PMID- 28031278 TI - VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System. AB - In previous studies, we identified the fatty acid kinase virulence factor regulator B (VfrB) as a potent regulator of alpha-hemolysin and other virulence factors in Staphylococcus aureus In this study, we demonstrated that VfrB is a positive activator of the SaeRS two-component regulatory system. Analysis of vfrB, saeR, and saeS mutant strains revealed that VfrB functions in the same pathway as SaeRS. At the transcriptional level, the promoter activities of SaeRS class I (coa) and class II (hla) target genes were downregulated during the exponential growth phase in the vfrB mutant, compared to the wild-type strain. In addition, saePQRS expression was decreased in the vfrB mutant strain, demonstrating a need for this protein in the autoregulation of SaeRS. The requirement for VfrB-mediated activation was circumvented when SaeS was constitutively active due to an SaeS (L18P) substitution. Furthermore, activation of SaeS via human neutrophil peptide 1 (HNP-1) overcame the dependence on VfrB for transcription from class I Sae promoters. Consistent with the role of VfrB in fatty acid metabolism, hla expression was decreased in the vfrB mutant with the addition of exogenous myristic acid. Lastly, we determined that aspartic acid residues D38 and D40, which are predicted to be key to VfrB enzymatic activity, were required for VfrB-mediated alpha-hemolysin production. Collectively, this study implicates VfrB as a novel accessory protein needed for the activation of SaeRS in S. aureusIMPORTANCE The SaeRS two-component system is a key regulator of virulence determinant production in Staphylococcus aureus Although the regulon of this two-component system is well characterized, the activation mechanisms, including the specific signaling molecules, remain elusive. Elucidating the complex regulatory circuit of SaeRS regulation is important for understanding how the system contributes to disease causation by this pathogen. To this end, we have identified the fatty acid kinase VfrB as a positive regulatory modulator of SaeRS-mediated transcription of virulence factors in S. aureus In addition to describing a new regulatory aspect of SaeRS, this study establishes a link between fatty acid kinase activity and virulence factor regulation. PMID- 28031280 TI - Proteolytic Cleavage of the Immunodominant Outer Membrane Protein rOmpA in Rickettsia rickettsii. AB - Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, contains two immunodominant proteins, rOmpA and rOmpB, in the outer membrane. Both rOmpA and rOmpB are conserved throughout spotted fever group rickettsiae as members of a family of autotransporter proteins. Previously, it was demonstrated that rOmpB is proteolytically processed, with the cleavage site residing near the autotransporter domain at the carboxy-terminal end of the protein, cleaving the 168-kDa precursor into apparent 120-kDa and 32-kDa fragments. The 120- and 32-kDa fragments remain noncovalently associated on the surface of the bacterium, with implications that the 32-kDa fragment functions as the membrane anchor domain. Here we present evidence for a similar posttranslational processing of rOmpA. rOmpA is expressed as a predicted 224-kDa precursor yet is observed on SDS-PAGE as a 190-kDa protein. A small rOmpA fragment of ~32 kDa was discovered during surface proteome analysis and identified as the carboxy-terminal end of the protein. A rabbit polyclonal antibody was generated to the autotransporter region of rOmpA and confirmed a 32-kDa fragment corresponding to the calculated mass of a proteolytically cleaved rOmpA autotransporter region. N-terminal amino acid sequencing revealed a cleavage site on the carboxy-terminal side of Ser-1958 in rOmpA. An avirulent strain of R. rickettsii Iowa deficient in rOmpB processing was also defective in the processing of rOmpA. The similarities of the cleavage sites and the failure of R. rickettsii Iowa to process either rOmpA or rOmpB suggest that a single enzyme may be responsible for both processing events.IMPORTANCE Members of the spotted fever group of rickettsiae, including R. rickettsii, the etiologic agent of Rocky Mountain spotted fever, express at least four autotransporter proteins that are protective antigens or putative virulence determinants. One member of this class of proteins, rOmpB, is proteolytically processed to a passenger domain and an autotransporter domain that remain associated on the rickettsial outer membrane. The protease responsible for this posttranslation processing remains unknown. Here we show that another autotransporter, rOmpA, is similarly processed by R. rickettsii Similarities in sequence at the cleavage site and predicted secondary protein structure suggest that all four R. rickettsii autotransporters may be processed by the same outer membrane protease. PMID- 28031279 TI - Progress in Understanding the Molecular Basis Underlying Functional Diversification of Cyclic Dinucleotide Turnover Proteins. AB - Cyclic di-GMP was the first cyclic dinucleotide second messenger described, presaging the discovery of additional cyclic dinucleotide messengers in bacteria and eukaryotes. The GGDEF diguanylate cyclase (DGC) and EAL and HD-GYP phosphodiesterase (PDE) domains conduct the turnover of cyclic di-GMP. These three unrelated domains belong to superfamilies that exhibit significant variations in function, and they include both enzymatically active and inactive members, with a subset involved in synthesis and degradation of other cyclic dinucleotides. Here, we summarize current knowledge of sequence and structural variations that underpin the functional diversification of cyclic di-GMP turnover proteins. Moreover, we highlight that superfamily diversification is not restricted to cyclic di-GMP signaling domains, as particular DHH/DHHA1 domain and HD domain proteins have been shown to act as cyclic di-AMP phosphodiesterases. We conclude with a consideration of the current limitations that such diversity of action places on bioinformatic prediction of the roles of GGDEF, EAL, and HD-GYP domain proteins. PMID- 28031281 TI - Polynucleotide Phosphorylase, RNase E/G, and YbeY Are Involved in the Maturation of 4.5S RNA in Corynebacterium glutamicum. AB - Corynebacterium glutamicum has been applied for the industrial production of various metabolites, such as amino acids. To understand the biosynthesis of the membrane protein in this bacterium, we investigated the process of signal recognition particle (SRP) assembly. SRP is found in all three domains of life and plays an important role in the membrane insertion of proteins. SRP RNA is initially transcribed as precursor molecules; however, relatively little is known about its maturation. In C. glutamicum, SRP consists of the Ffh protein and 4.5S RNA lacking an Alu domain. In this study, we found that 3'-to-5' exoribonuclease, polynucleotide phosphorylase (PNPase), and two endo-type RNases, RNase E/G and YbeY, are involved in the 3' maturation of 4.5S RNA in C. glutamicum The mature form of 4.5S RNA was inefficiently formed in DeltarneG Deltapnp mutant cells, suggesting the existence of an alternative pathway for the 3' maturation of 4.5S RNA. Primer extension analysis also revealed that the 5' mature end of 4.5S RNA corresponds to that of the transcriptional start site. Immunoprecipitated Ffh protein contained immature 4.5S RNA in Deltapnp, DeltarneG, and DeltaybeY mutants, suggesting that 4.5S RNA precursors can interact with Ffh. These results imply that the maturation of 4.5S RNA can be performed in the 4.5S RNA-Ffh complex.IMPORTANCE Overproduction of a membrane protein, such as a transporter, is useful for engineering of strains of Corynebacterium glutamicum, which is a workhorse of amino acid production. To understand membrane protein biogenesis in this bacterium, we investigated the process of signal recognition particle (SRP) assembly. SRP contains the Ffh protein and SRP RNA and plays an important role in the membrane insertion of proteins. Although SRP RNA is highly conserved among the three domains of life, relatively little is known about its maturation. We show that PNPase, RNase E/G, and YbeY are involved in the 3' maturation of the SRP RNA (4.5S RNA) in this bacterium. This indicates that 3' end processing in this organism is different from that in other bacteria, such as Escherichia coli. PMID- 28031284 TI - Drug-drug interaction discovery and demystification using Semantic Web technologies. AB - Objective: To develop a novel pharmacovigilance inferential framework to infer mechanistic explanations for asserted drug-drug interactions (DDIs) and deduce potential DDIs. Materials and Methods: A mechanism-based DDI knowledge base was constructed by integrating knowledge from several existing sources at the pharmacokinetic, pharmacodynamic, pharmacogenetic, and multipathway interaction levels. A query-based framework was then created to utilize this integrated knowledge base in conjunction with 9 inference rules to infer mechanistic explanations for asserted DDIs and deduce potential DDIs. Results: The drug-drug interactions discovery and demystification (D3) system achieved an overall 85% recall rate in terms of inferring mechanistic explanations for the DDIs integrated into its knowledge base, while demonstrating a 61% precision rate in terms of the inference or lack of inference of mechanistic explanations for a balanced, randomly selected collection of interacting and noninteracting drug pairs. Discussion: The successful demonstration of the D3 system's ability to confirm interactions involving well-studied drugs enhances confidence in its ability to deduce interactions involving less-studied drugs. In its demonstration, the D3 system infers putative explanations for most of its integrated DDIs. Further enhancements to this work in the future might include ranking interaction mechanisms based on likelihood of applicability, determining the likelihood of deduced DDIs, and making the framework publicly available. Conclusion: The D3 system provides an early-warning framework for augmenting knowledge of known DDIs and deducing unknown DDIs. It shows promise in suggesting interaction pathways of research and evaluation interest and aiding clinicians in evaluating and adjusting courses of drug therapy. PMID- 28031283 TI - Diversification of the AlpB Outer Membrane Protein of Helicobacter pylori Affects Biofilm Formation and Cellular Adhesion. AB - Helicobacter pylori is one of the most common causes of bacterial infection in humans, and it forms biofilms on human gastric mucosal epithelium as well as on in vitro abiotic surfaces. Bacterial biofilm is critical not only for environmental survival but also for successful infection. We previously demonstrated that strain TK1402, which was isolated from a Japanese patient with duodenal and gastric ulcers, has high biofilm-forming ability in vitro relative to other strains. In addition, we showed that outer membrane vesicles (OMV) play an important role in biofilm formation. The aim of this study was to analyze which protein(s) in the OMV contributes to biofilm formation in TK1402. We obtained a spontaneous mutant strain derived from TK1402 lacking biofilm-forming ability. The protein profiles of the OMV were compared between this mutant strain and the wild type, and it was found that AlpB, an outer membrane protein in the OMV of the mutant strain, was markedly decreased compared to that of the wild type. Restoration of TK1402 alpB to the mutant strain fully recovered the ability to form biofilm. However, restoration with alpB from other strains demonstrated incomplete recovery of biofilm-forming ability. We therefore inferred that the variable region of AlpB (amino acid positions 121 to 146) was involved in TK1402 biofilm formation. In addition, diversification of the AlpB sequence was shown to affect the ability to adhere to AGS cells. These results demonstrate a new insight into the molecular mechanisms of host colonization by H. pyloriIMPORTANCE Bacterial biofilm is critical not only for environmental survival but also for successful infection. The mechanism of Helicobacter pylori adherence to host cells mediated by cell surface adhesins has been the focus of many studies, but little is known regarding factors involved in H. pylori biofilm formation. Our study demonstrated that AlpB plays an important role in biofilm formation and that this property depends upon the specific sequence of alpB This in turn was shown to be important in the ability to adhere to gastric cells. We anticipate that these results will provide new insight into the molecular mechanisms of H. pylori colonization. PMID- 28031282 TI - TonB-Dependent Heme/Hemoglobin Utilization by Caulobacter crescentus HutA. AB - Siderophore nutrition tests with Caulobacter crescentus strain NA1000 revealed that it utilized a variety of ferric hydroxamate siderophores, including asperchromes, ferrichromes, ferrichrome A, malonichrome, and ferric aerobactin, as well as hemin and hemoglobin. C. crescentus did not transport ferrioxamine B or ferric catecholates. Because it did not use ferric enterobactin, the catecholate aposiderophore was an effective agent for iron deprivation. We determined the kinetics and thermodynamics of [59Fe]apoferrichrome and 59Fe citrate binding and transport by NA1000. Its affinity and uptake rate for ferrichrome (equilibrium dissociation constant [Kd ], 1 nM; Michaelis-Menten constant [KM ], 0.1 nM; Vmax, 19 pMol/109 cells/min) were similar to those of Escherichia coli FhuA. Transport properties for 59Fe-citrate were similar to those of E. coli FecA (KM , 5.3 nM; Vmax, 29 pMol/109 cells/min). Bioinformatic analyses implicated Fur-regulated loci 00028, 00138, 02277, and 03023 as TonB dependent transporters (TBDT) that participate in iron acquisition. We resolved TBDT with elevated expression under high- or low-iron conditions by SDS-PAGE of sodium sarcosinate cell envelope extracts, excised bands of interest, and analyzed them by mass spectrometry. These data identified five TBDT: three were overexpressed during iron deficiency (00028, 02277, and 03023), and 2 were overexpressed during iron repletion (00210 and 01196). CLUSTALW analyses revealed homology of putative TBDT 02277 to Escherichia coli FepA and BtuB. A Delta02277 mutant did not transport hemin or hemoglobin in nutrition tests, leading us to designate the 02277 structural gene as hutA (for heme/hemoglobin utilization).IMPORTANCE The physiological roles of the 62 putative TBDT of C. crescentus are mostly unknown, as are their evolutionary relationships to TBDT of other bacteria. We biochemically studied the iron uptake systems of C. crescentus, identified potential iron transporters, and clarified the phylogenetic relationships among its numerous TBDT. Our findings identified the first outer membrane protein involved in iron acquisition by C. crescentus, its heme/hemoglobin transporter (HutA). PMID- 28031285 TI - The use of computerized clinical decision support systems in emergency care: a substantive review of the literature. AB - Objectives: : This paper provides a substantive review of international literature evaluating the impact of computerized clinical decision support systems (CCDSSs) on the care of emergency department (ED) patients. Material and Methods: : A literature search was conducted using Medline, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Embase electronic resources, and gray literature. Studies were selected if they compared the use of a CCDSS with usual care in a face-to-face clinical interaction in an ED. Results: : Of the 23 studies included, approximately half demonstrated a statistically significant positive impact on aspects of clinical care with the use of CCDSSs. The remaining studies showed small improvements, mainly around documentation. However, the methodological quality of the studies was poor, with few or no controls to mitigate against confounding variables. The risk of bias was high in all but 6 studies. Discussion: : The ED environment is complex and does not lend itself to robust quantitative designs such as randomized controlled trials. The quality of the research in ~75% of the studies was poor, and therefore conclusions cannot be drawn from these results. However, the studies with a more robust design show evidence of the positive impact of CCDSSs on ED patient care. Conclusion: This is the first review to consider the role of CCDSSs in emergency care and expose the research in this area. The role of CCDSSs in emergency care may provide some solutions to the current challenges in EDs, but further high-quality research is needed to better understand what technological solutions can offer clinicians and patients. PMID- 28031286 TI - Safety huddles to proactively identify and address electronic health record safety. AB - Objective: Methods to identify and study safety risks of electronic health records (EHRs) are underdeveloped and largely depend on limited end-user reports. "Safety huddles" have been found useful in creating a sense of collective situational awareness that increases an organization's capacity to respond to safety concerns. We explored the use of safety huddles for identifying and learning about EHR-related safety concerns. Design: Data were obtained from daily safety huddle briefing notes recorded at a single midsized tertiary-care hospital in the United States over 1 year. Huddles were attended by key administrative, clinical, and information technology staff. We conducted a content analysis of huddle notes to identify what EHR-related safety concerns were discussed. We expanded a previously developed EHR-related error taxonomy to categorize types of EHR-related safety concerns recorded in the notes. Results: On review of daily huddle notes spanning 249 days, we identified 245 EHR-related safety concerns. For our analysis, we defined EHR technology to include a specific EHR functionality, an entire clinical software application, or the hardware system. Most concerns (41.6%) involved " EHR technology working incorrectly, " followed by 25.7% involving " EHR technology not working at all. " Concerns related to "EHR technology missing or absent" accounted for 16.7%, whereas 15.9% were linked to " user errors ." Conclusions: Safety huddles promoted discussion of several technology-related issues at the organization level and can serve as a promising technique to identify and address EHR-related safety concerns. Based on our findings, we recommend that health care organizations consider huddles as a strategy to promote understanding and improvement of EHR safety. PMID- 28031287 TI - Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome. AB - Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 * 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 * 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans. PMID- 28031288 TI - A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. PMID- 28031290 TI - Retraction notice: the SMN structure reveals its crucial role in snRNP assembly. PMID- 28031291 TI - Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2. PMID- 28031289 TI - Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington's disease. AB - Circadian deficits in Huntington's disease (HD) are recapitulated in both fragment (R6/2) and full-length (Q175) mouse models of HD. Circadian rhythms are regulated by the suprachiasmatic nuclei (SCN) in the hypothalamus, which are primarily entrained by light detected by the retina. The SCN receives input from intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin, but also receive input from rods and cones. In turn, ipRGCs mediate a range of non-image forming responses to light including circadian entrainment and the pupillary light response (PLR). Retinal degeneration/dysfunction has been described previously in R6/2 mice. We investigated, therefore, whether or not circadian disruption in HD mice is due to abnormalities in retinal photoreception. We measured the expression of melanopsin, rhodopsin and cone opsin, as well as other retinal markers (tyrosine hydroxylase, calbindin, PKCalpha and Brna3), in R6/2 and Q175 mice at different stages of disease. We also measured the PLR as a 'readout' for ipRGC function and a marker of light reception by the retina. We found that the PLR was attenuated in both lines of HD mice. This was accompanied by a progressive downregulation of cone opsin and melanopsin expression. We suggest that disease-related changes in photoreception by the retina contribute to the progressive dysregulation of circadian rhythmicity and entrainment seen in HD mice. Colour vision is abnormal in HD patients. Therefore, if retinal deficits similar to those seen in HD mice are confirmed in patients, specifically designed light therapy may be an effective strategy to improve circadian dysfunction. PMID- 28031292 TI - Protein kinase CK2 modulates HSJ1 function through phosphorylation of the UIM2 domain. AB - HSJ1 (DNAJB2), a member of the DNAJ family of molecular chaperones, is a key player in neuronal proteostasis maintenance. It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation. Mutations in the DNAJB2 gene lead to inherited neuropathies such as Charcot-Marie-Tooth type-2, distal hereditary motor neuropathies, spinal muscular atrophy with parkinsonism and the later stages can resemble amyotrophic lateral sclerosis. HSJ1 overexpression can reduce aggregation of neurodegeneration-associated proteins in vitro and in vivo; however, the regulation of HSJ1 function is little understood. Here we show that CK2, a ubiquitous and constitutively active protein kinase, phosphorylates HSJ1 within its second UIM, at the dominant site Ser250 and the hierarchical site Ser247. A phospho-HSJ1 specific antibody confirmed phosphorylation of endogenous HSJ1a and HSJ1b. A tandem approach of phospho-site mutation and treatment with CK2 specific inhibitors demonstrated that phosphorylation at these sites is accompanied by a reduced ability of HSJ1 to bind ubiquitylated clients and to exert its chaperone activity. Our results disclose a novel interplay between ubiquitin- and phosphorylation-dependent signalling, and represent the first report of a regulatory mechanism for UIM-dependent function. They also suggest that CK2 inhibitors could release the full neuroprotective potential of HSJ1, and deserve future interest as therapeutic strategies for neurodegenerative disease. PMID- 28031294 TI - Glyco-Forum. PMID- 28031293 TI - The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells. AB - Usher syndrome (USH) is the most common cause of inherited deaf-blindness, manifested as USH1, USH2 and USH3 clinical types. The protein products of USH2 causative and modifier genes, USH2A, ADGRV1, WHRN and PDZD7, interact to assemble a multiprotein complex at the ankle link region of the mechanosensitive stereociliary bundle in hair cells. Defects in this complex cause stereociliary bundle disorganization and hearing loss. The four USH2 proteins also interact in vitro with USH1 proteins including myosin VIIa, USH1G (SANS), CIB2 and harmonin. However, it is unclear whether the interactions between USH1 and USH2 proteins occur in vivo and whether USH1 proteins play a role in USH2 complex assembly in hair cells. In this study, we identified a novel interaction between myosin VIIa and PDZD7 by FLAG pull-down assay. We further investigated the role of the above mentioned four USH1 proteins in the cochlear USH2 complex assembly using USH1 mutant mice. We showed that only myosin VIIa is indispensable for USH2 complex assembly at ankle links, indicating the potential transport and/or anchoring role of myosin VIIa for USH2 proteins in hair cells. However, myosin VIIa is not required for USH2 complex assembly in photoreceptors. We further showed that, while PDZ protein harmonin is not involved, its paralogous USH2 proteins, PDZD7 and whirlin, function synergistically in USH2 complex assembly in cochlear hair cells. In summary, our studies provide novel insight into the functional relationship between USH1 and USH2 proteins in the cochlea and the retina as well as the disease mechanisms underlying USH1 and USH2. PMID- 28031295 TI - Vasectomy: A Long, Slow Haul to Successful Takeoff. PMID- 28031296 TI - Improving the Safety and Security of Those Engaged in Global Health Traveling Abroad. PMID- 28031297 TI - Benefits and Limitations of a Community-Engaged Emergency Referral System in a Remote, Impoverished Setting of Northern Ghana. AB - Although Ghana has a well-organized primary health care system, it lacks policies and guidelines for developing or providing emergency referral services. In 2012, an emergency referral pilot-the Sustainable Emergency Referral Care (SERC) initiative-was launched by the Ghana Health Service in collaboration with community stakeholders and health workers in one subdistrict of the Upper East Region where approximately 20,000 people reside. The pilot program was scaled up in 2013 to a 3-district (12-subdistrict) plausibility trial that served a population of approximately 184,000 over 2 years from 2013 to 2015. The SERC initiative was fielded as a component of a 6-year health systems strengthening and capacity-building project known as the Ghana Essential Health Intervention Program. Implementation research using mixed methods, including quantitative analysis of key process and health indicators over time in the 12 intervention subdistricts compared with comparison districts, a survey of health workers, and qualitative systems appraisal with community members, provided data on effectiveness of the system as well as operational challenges and potential solutions. Monitoring data show that community exposure to SERC was associated with an increased volume of emergency referrals, diminished reliance on primary care facilities not staffed or equipped to provide surgical care, and increased caseloads at facilities capable of providing appropriate acute care (i.e., district hospitals). Community members strongly endorsed the program and expressed appreciation for the service. Low rates of adherence to some care protocols were noted: referring facilities often failed to alert receiving facilities of incoming patients, not all patients transported were accompanied by a health worker, and receiving facilities commonly failed to provide patient outcome feedback to the referring facility. Yet in areas where SERC worked to bypass substandard points of care, overall facility-based maternal mortality as well as accident-related deaths decreased relative to levels observed in facilities located in comparison areas. PMID- 28031298 TI - Strengthening Government Leadership in Family Planning Programming in Senegal: From Proof of Concept to Proof of Implementation in 2 Districts. AB - Given Senegal's limited resources, the country receives substantial support from externally funded partner organizations to provide family planning and maternal and child health services. These organizations often take a strong and sometimes independent role in implementing interventions with their own structures and personnel, thereby bypassing the government district health system. This article presents findings from the Initiative Senegalaise de Sante Urbaine (ISSU) (Senegal Urban Health Initiative) that assessed in 2 districts, Diamniadio and Rufisque, the extent to which it was feasible to create stronger government ownership and leadership in implementing a simplified package of family planning interventions from among those previously tested in other districts. The simplified package consisted of both supply- and demand-side interventions, introduced in October 2014 and concluding at the end of 2015. The interventions included ensuring adequate human resources and contraceptive supplies, contraceptive technology updates for providers, special free family planning service days to bring services closer to where people live, family planning integration into other routine services, household visits for family planning education, religious sermons to clarify Islam's position on family planning, and radio broadcasts. District leadership in Diamniadio and Rufisque were actively involved in guiding and implementing interventions, and they also contributed some of their own resources to the project. However, reliance on external funding continued because district budgets were extremely limited. Monitoring data on the number of contraceptive methods provided by district facilities supported by a sister project, the Informed Push Model project, indicate overall improvement in contraceptive provision during the intervention period. In Diamniadio, contraceptive provision increased by 43% between the 6-month period prior to the ISSU interventions (November 2013 through April 2014) and a 6-month intervention period (November 2014 through April 2015), from about 8,000 units to nearly 12,000 units. In Rufisque, contraceptive provision increased by 30%, from more than 17,000 units to more than 22,000 units. Couple-years of protection provided in Diamniadio increased by 82% and in Rufisque by 56%. The experience in these 2 districts in Senegal suggests that it is feasible for districts to play a leadership role in implementing family planning services and mobilizing some of their own resources and that international projects can facilitate capacity building and sustainability within public-sector systems. PMID- 28031299 TI - Key Role of Drug Shops and Pharmacies for Family Planning in Urban Nigeria and Kenya. AB - BACKGROUND: The Family Planning 2020 initiative aims to reach 120 million new family planning users by 2020. Drug shops and pharmacies are important private sector sources of contraception in many contexts but are less well understood than public-sector sources, especially in urban environments. This article explores the role that drug shops and pharmacies play in the provision of contraceptive methods in selected urban areas of Nigeria and Kenya as well as factors associated with women's choice of where to obtain these methods. METHODS: Using data collected in 2010/2011 from representative samples of women in selected urban areas of Nigeria and Kenya as well as a census of pharmacies and drug shops audited in 2011, we examine the role of drug shops and pharmacies in the provision of short-acting contraceptive methods and factors associated with a women's choice of family planning source. RESULTS: In urban Nigeria and Kenya, drug shops and pharmacies were the major source for the family planning methods of oral contraceptive pills, emergency contraceptives, and condoms. The majority of injectable users obtained their method from public facilities in both countries, but 14% of women in Nigeria and 6% in Kenya obtained injectables from drug shops or pharmacies. Harder-to-reach populations were the most likely to choose these outlets to obtain their short-acting methods. For example, among users of these methods in Nigeria, younger women (<25 years old) were significantly more likely to obtain their method from a drug shop or pharmacy than another type of facility. In both countries, family planning users who had never been married were significantly more likely than married users to obtain these methods from a drug shop or a pharmacy than from a public-sector health facility. Low levels of family planning-related training (57% of providers in Kenya and 41% in Nigeria had received training) and lack of family planning promotional activities in pharmacies and drug shops in both countries indicate the need for additional support from family planning programs to leverage this important access point. CONCLUSIONS: Drug shops and pharmacies offer an important and under-leveraged mechanism for expanding family planning access to women in urban Nigeria and Kenya, and potentially elsewhere. Vulnerable and harder-to reach groups such as younger, unmarried women and women who do not yet have children are the most likely to benefit from increased access to family planning at drug shops and pharmacies. PMID- 28031300 TI - Referral Systems to Integrate Health and Economic Strengthening Services for People with HIV: A Qualitative Assessment in Malawi. AB - BACKGROUND: Supporting the diverse needs of people living with HIV (PLHIV) can help reduce the individual and structural barriers they face in adhering to antiretroviral treatment (ART). The Livelihoods and Food Security Technical Assistance II (LIFT) project sought to improve adherence in Malawi by establishing 2 referral systems linking community-based economic strengthening and livelihoods services to clinical health facilities. One referral system in Balaka district, started in October 2013, connected clients to more than 20 types of services while the other simplified approach in Kasungu and Lilongwe districts, started in July 2014, connected PLHIV attending HIV and nutrition support facilities directly to community savings groups. METHODS: From June to July 2015, LIFT visited referral sites in Balaka, Kasungu, and Lilongwe districts to collect qualitative data on referral utility, the perceived association of referrals with client and household health and vulnerability, and the added value of the referral system as perceived by network member providers. We interviewed a random sample of 152 adult clients (60 from Balaka, 57 from Kasungu, and 35 from Lilongwe) who had completed their referral. We also conducted 2 focus group discussions per district with network providers. FINDINGS: Clients in all 3 districts indicated their ability to save money had improved after receiving a referral, although the percentage was higher among clients in the simplified Kasungu and Lilongwe model than the more complex Balaka model (85.6% vs. 56.0%, respectively). Nearly 70% of all clients interviewed had HIV infection; 72.7% of PLHIV in Balaka and 95.7% of PLHIV in Kasungu and Lilongwe credited referrals for helping them stay on their ART. After the referral, 76.0% of clients in Balaka and 92.3% of clients in Kasungu and Lilongwe indicated they would be willing to spend their savings on health costs. The more diverse referral network and use of an mHealth app to manage data in Balaka hindered provider uptake of the system, while the simpler system in Kasungu and Lilongwe, which included only 2 referral options and use of a paper-based referral tool, seemed simpler for the providers to manage. CONCLUSIONS: Participation in the referral systems was perceived positively by clients and providers in both models, but more so in Kasungu and Lilongwe where the referral process was simpler. Future referral networks should consider limiting the number of service options included in the network and simplify referral tools to the extent possible to facilitate uptake among network providers. PMID- 28031301 TI - Social Mobilization and Community Engagement Central to the Ebola Response in West Africa: Lessons for Future Public Health Emergencies. AB - Following the World Health Organization (WHO) declaration of a Public Health Emergency of International Concern regarding the Ebola outbreak in West Africa in July 2014, UNICEF was asked to co-lead, in coordination with WHO and the ministries of health of affected countries, the communication and social mobilization component-which UNICEF refers to as communication for development (C4D)-of the Ebola response. For the first time in an emergency setting, C4D was formally incorporated into each country's national response, alongside more typical components such as supplies and logistics, surveillance, and clinical care. This article describes the lessons learned about social mobilization and community engagement in the emergency response to the Ebola outbreak, with a particular focus on UNICEF's C4D work in Guinea, Liberia, and Sierra Leone. The lessons emerged through an assessment conducted by UNICEF using 4 methods: a literature review of key documents, meeting reports, and other articles; structured discussions conducted in June 2015 and October 2015 with UNICEF and civil society experts; an electronic survey, launched in October and November 2015, with staff from government, the UN, or any partner organization who worked on Ebola (N = 53); and key informant interviews (N = 5). After triangulating the findings from all data sources, we distilled lessons under 7 major domains: (1) strategy and decentralization: develop a comprehensive C4D strategy with communities at the center and decentralized programming to facilitate flexibility and adaptation to the local context; (2) coordination: establish C4D leadership with the necessary authority to coordinate between partners and enforce use of standard operating procedures as a central coordination and quality assurance tool; (3) entering and engaging communities: invest in key communication channels (such as radio) and trusted local community members; (4) messaging: adapt messages and strategies continually as patterns of the epidemic change over time; (5) partnerships: invest in strategic partnerships with community, religious leaders, journalists, radio stations, and partner organizations; (6) capacity building: support a network of local and international professionals with capacity for C4D who can be deployed rapidly; (7) data and performance monitoring: establish clear C4D process and impact indicators and strive for real time data analysis and rapid feedback to communities and authorities to inform decision making. Ultimately, communication, community engagement, and social mobilization need to be formally placed within the global humanitarian response architecture with proper funding to effectively support future public health emergencies, which are as much a social as a health phenomenon. PMID- 28031302 TI - A Review of 10 Years of Vasectomy Programming and Research in Low-Resource Settings. AB - Vasectomy is a highly effective and safe contraceptive method for couples who want to stop childbearing, but only 2.4% of men around the world use this method. We conducted an extensive review of the vasectomy research literature and programmatic reports, published between April 2005 and April 2015, to synthesize barriers and facilitators to vasectomy adoption. Of the more than 230 documents initially retrieved in our search, we ultimately included 75 documents in our review and synthesized the findings according to the Supply-Enabling Environment Demand (SEED) Programming Model. Regarding promoting demand for vasectomy services, we found there was a general lack of awareness about the method among both men and women, which often fueled erroneous assumptions about how vasectomy affects men. Several types of programmatic activities directly addressed knowledge gaps and negative misperceptions, including community-based and mass media communications, employer-based promotion, and group counseling. For supply of services, the lack of or inaccurate knowledge about vasectomy was also prevalent among providers, particularly among community-based health workers. Programmatic activities to improve service delivery included the use of evidence based vasectomy techniques such as no-scalpel vasectomy, whole-site trainings, task shifting, cascade training, and mobile outreach. Finally, programmatic approaches to building a more enabling environment included engagement of governments and other community and religious leaders as well as campaigns with gender transformative messaging that countered common myths and encouraged men's positive engagement in family planning and reproductive health. In summary, a successful vasectomy program is comprised of the mutually reinforcing components of continual demand for services and access to and supply of well-trained providers. In addition, there is an underlying need for enabling policies within the cultural and gender environments that extend beyond vasectomy and include men not just as default partners of female family planning clients but as equal beneficiaries of family planning and reproductive health programs in their own right. Accelerating progress toward meaningful integration of vasectomy into a comprehensive contraceptive method mix is only possible when political and financial will are aligned and support the logistical and promotional activities of a male reproductive health agenda. PMID- 28031303 TI - Mobile-Based Nutrition and Child Health Monitoring to Inform Program Development: An Experience From Liberia. AB - BACKGROUND: Implementing complex nutrition and other public health projects and tracking nutrition interventions, such as women's diet and supplementation and infant and young child feeding practices, requires reliable routine data to identify potential program gaps and to monitor trends in behaviors in real time. However, current monitoring and evaluation practices generally do not create an environment for this real-time tracking. This article describes the development and application of a mobile-based nutrition and health monitoring system, which collected monitoring data on project activities, women's nutrition, and infant and young child feeding practices in real time. PROGRAM DESCRIPTION: The Liberia Agricultural Upgrading Nutrition and Child Health (LAUNCH) project implemented a nutrition and health monitoring system between April 2012 and June 2014. The LAUNCH project analyzed project monitoring and outcome data from the system and shared selected behavioral and programmatic indicators with program managers through a short report, which later evolved into a visual data dashboard, during program-update meetings. The project designed protocols to ensure representativeness of program participants. FINDINGS: LAUNCH made programmatic adjustments in response to findings from the monitoring system; these changes were then reflected in subsequent quarterly trends, indicating that the availability of timely data allowed for the project to react quickly to issues and adapt the program appropriately. Such issues included lack of participation in community groups and insufficient numbers of food distribution points. Likewise, the system captured trends in key outcome indicators such as breastfeeding and complementary feeding practices, linking them to project activities and external factors including seasonal changes and national health campaigns. CONCLUSION: Digital data collection platforms can play a vital role in improving routine programmatic functions. Fixed gathering locations such as food distribution points represent an opportunity to easily access program participants and enable managers to identify strengths and weaknesses in project implementation. For programs that track individuals over time, a mobile tool combined with a strong database can greatly improve efficiency and data visibility and reduce resource leakages. PMID- 28031304 TI - Web-Based Quality Assurance Process Drives Improvements in Obstetric Ultrasound in 5 Low- and Middle-Income Countries. AB - High quality is important in medical imaging, yet in many geographic areas, highly skilled sonographers are in short supply. Advances in Internet capacity along with the development of reliable portable ultrasounds have created an opportunity to provide centralized remote quality assurance (QA) for ultrasound exams performed at rural sites worldwide. We sought to harness these advances by developing a web-based tool to facilitate QA activities for newly trained sonographers who were taking part in a cluster randomized trial investigating the role of limited obstetric ultrasound to improve pregnancy outcomes in 5 low- and middle-income countries. We were challenged by connectivity issues, by country specific needs for website usability, and by the overall need for a high throughput system. After systematically addressing these needs, the resulting QA website helped drive ultrasound quality improvement across all 5 countries. It now offers the potential for adoption by future ultrasound- or imaging-based global health initiatives. PMID- 28031305 TI - Qualitative Assessment of the Application of a Discrete Choice Experiment With Community Health Workers in Uganda: Aligning Incentives With Preferences. AB - BACKGROUND: Maximizing the benefits of community health worker (CHW) programs requires strategies for improving motivation, performance, and retention. Discrete choice experiments (DCE) are increasingly used to inform policy response to health workforce shortages in rural areas, and may be of value in the context of CHW programs. Participants are presented with pairs of hypothetical jobs that are described by job attributes with varying levels and are asked what their preferred job is within each pair. Responses are then analyzed quantitatively to obtain information on what attributes are important to participants. We conducted a qualitative assessment to examine the appropriateness and validity of applying a DCE to a new population of CHWs with lower literacy. METHODS: In 2011, we conducted a mixed-method study with CHWs in Uganda, consisting of 183 surveys and 43 in-depth interviews (IDIs). The DCE was administered to both survey and IDI participants. This article reports on the qualitative assessment of the implementation of the DCE. We compare DCE responses between survey and IDI participants to determine whether administering the DCE in a qualitative (IDI) context altered responses. We then present additional information collected on CHWs' decision-making processes and their experiences with the DCE in the IDIs. RESULTS: Choices made by IDI participants were consistent with the choices made by survey participants. In-depth exploration of CHWs' observations in answering the DCE suggest that, overall, CHWs comprehended the DCE exercise and made reasoned choices. However, the data revealed some level of cognitive difficulty and highlighted some design and implementation challenges that are important to consider, particularly when applying a DCE to populations with lower literacy. These include the need to keep the number of attributes small; to choose levels that are realistic yet show sufficient range; and to clearly define attributes and their levels. CONCLUSION: DCEs can be an appropriate approach with CHWs but require careful design and implementation. PMID- 28031306 TI - An Implementer's Perspective on Vouchers for Sexual and Reproductive Health Services. PMID- 28031307 TI - Zika Travel Policies May Reduce Women's Leadership in Global Health. PMID- 28031308 TI - Exposure to out-of-home care in childhood and adult all-cause mortality: a cohort study. AB - Background: Children placed in out-of-home care (OHC) have exceedingly high rates of health problems. Their poor health tends to persist across adolescence and into young adulthood, resulting in increased risks of mortality. Yet, very little is known about this group's mortality risks later in life. The aim of this study was to investigate whether OHC was associated with the risk of all-cause mortality across adulthood, and whether these risks varied across different placement characteristics. Moreover, the study addressed potential confounding by including two comparison groups with children who grew up under similarly adverse living conditions but did not experience placement. Methods: Data were derived from a 60-year follow-up of a Stockholm cohort born in 1953 ( n = 15 048), of whom around 9% have had experiences of OHC. The associations between OHC and subsequent all-cause mortality were analysed by means of Cox's proportional hazards regression models. Results: Individuals who were placed in OHC at any point during their formative years had increased mortality risks across ages 20 to 56 years. Elevated risk of mortality was particularly pronounced among those who were placed in adolescence and/or because of their own behaviours. Children who were exposed to OHC had increased risks of mortality also when compared with those who grew up under similar living conditions but did not experience placement. Conclusions: Children in OHC constitute a high-risk group for subsequent mortality. In order to narrow the mortality gap, interventions may need to monitor not only health aspects but also to target the cognitive and social development of these children. PMID- 28031309 TI - Assessment of causality between serum gamma-glutamyltransferase and type 2 diabetes mellitus using publicly available data: a Mendelian randomization study. AB - Background: In observational studies, high levels of gamma-glutamyltransferase (GGT) have been associated with a higher risk of type 2 diabetes mellitus (T2D). We aimed to assess whether this association is causal, using Mendelian randomization. Methods: A Mendelian randomization study was conducted using publicly available data from a genome-wide association study (GWAS) on T2D (12 171 cases of T2D and 56 862 controls), and additionally from GWAS on glycaemic traits ( N = 46 186) and HbA1c ( N = 46 368) in nondiabetic participants. Independent genetic variants (26 in total), identified in the largest GGT GWAS comprising studies of European ancestry, were used as genetic instruments. Inverse-variance weighted and MR-Egger regression analyses were used to estimate the effect of the combined genetic instrumental variables on T2D and glycaemic traits and HbA1c. Results: F-statistics of the 26 genetic instrumental variables, as a measure of instrumental strength, ranged from 23.4 ( ATP8B1 ) to 258.3 ( GGT1 ). Using inverse-variance analyses, we found no evidence of an association between the combined genetic instrumental variables for GGT and the risk of T2D, or glucose-, insulin- or HbA1c-levels. More specifically, a 10% higher genetically determined GGT was not associated with a higher risk of T2D (odds ratio: 0.99; 95% confidence interval: 0.95; 1.02). Results were similar for MR Egger regression analyses, which did not show evidence for directional pleiotropy. Conclusion: The previously observed association between high levels of serum GGT and T2D in observational studies might not be causal. Likely, results from the observational studies can be explained by reverse causality and/or residual confounding. PMID- 28031310 TI - The effects of New York City's coordinated public health programmes on mortality through 2011. AB - Background: In 2003, New York City (NYC) implemented a series of coordinated policies designed to reduce non-communicable disease. Methods: We used coarsened exact matching (CEM) of individuals living inside and outside NYC between the years of 1992-2000 and 2002-10 to estimate difference-in-difference survival time models, a quasi-experimental approach. We also fitted age-period-cohort (APC) models to explore mortality impacts by gender, race, age, borough and cause of death over this same time period. Results: Both CEM and APC models show that survival gains were large in the pre-2003 era of health policy reform relative to the rest of the USA, but small afterwards. There is no clear link between any policy and changes in mortality by age, gender, ethnicity, borough, or cause of death. Conclusions: NYC's gains in survival relative to the rest of the nation were not linked to the city's innovative and coordinated health policy efforts. PMID- 28031311 TI - Life course models: improving interpretation by consideration of total effects. AB - Life course epidemiology has used models of accumulation and critical or sensitive periods to examine the importance of exposure timing in disease aetiology. These models are usually used to describe the direct effects of exposures over the life course. In comparison with consideration of direct effects only, we show how consideration of total effects improves interpretation of these models, giving clearer notions of when it will be most effective to intervene. We show how life course variation in the total effects depends on the magnitude of the direct effects and the stability of the exposure. We discuss interpretation in terms of total, direct and indirect effects and highlight the causal assumptions required for conclusions as to the most effective timing of interventions. PMID- 28031312 TI - Physical assault in the previous year and total and cause-specific mortality in Russia: a case-control study of men aged 25-54 years. AB - Background: Violence has important health effects. The results of exposure to physical violence include, but may not be limited to, death from suicide and homicide. The connection between the experience of assault and risk of death from causes other than homicide and suicide has rarely been examined. Methods: We analysed data from the first Izhevsk Family Study (IFS-1), a population-based case-control study of premature mortality in Russian men. Structural equation models were used to obtain odds ratios (ORs) for the association between the proxy report of physical attack in the previous year and mortality. Results: The estimate of the all-cause mortality OR for assault, after adjusting for alcohol use and socio-demographic confounders, was 1.96 (95% confidence interval: 1.71, 3.31). Strong cause-specific associations were found for external causes, but associations were also found for deaths from cardiovascular and alcohol-related deaths. Conclusions: We found that, in our population of working-aged Russian men, there was a strong association between physical assault and mortality from a wide range of causes. Other than direct effects of physical assault on mortality, residual confounding is an important possibility. The association between assault and mortality, particularly from cardiovascular and alcohol-related causes requires replication and further investigation. PMID- 28031313 TI - Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. AB - Background: Existing observational studies provide conflicting evidence for the causal effect of metformin use on cancer risk in patients with type-2 diabetes, and there are concerns about bias affecting a number of studies. Methods: MEDLINE was used to identify observational studies investigating the association between metformin and overall or site-specific cancer in people with type-2 diabetes. A systematic data extraction and bias assessment was conducted, in which risk of eight bias domains (outcome, exposure, control selection, baseline confounding, time-dependent confounding, immortal time, missing data, censoring methods) were assessed against pre-defined criteria, and rated as unlikely, low, medium or high. Results: Of 46 studies identified, 21 assessed the effect of metformin on all cancer. Reported relative risks ranged from 0.23 to 1.22, with 12/21 reporting a statistically significant protective effect and none a harmful effect. The range of estimates was similar for site-specific cancers; 3/46 studies were rated as low or unlikely risk of bias in all domains. Two of these had results consistent with no effect of metformin; one observed a moderate protective effect overall, but presented further analyses that the authors concluded were inconsistent with causality. However, 28/46 studies were at risk from bias through exposure definition, 22 through insufficient baseline adjustment and 35 from possible time-dependent confounding. Conclusions: Observational studies on metformin and cancer varied in design, and the majority were at risk of a range of biases. The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk. PMID- 28031314 TI - Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. AB - Methods: We studied 1491 mothers and children enrolled in the Danish National Birth Cohort (DNBC; 1996-2002). Prenatal paracetamol use was prospectively recorded in three telephone interviews. Trained psychologists assessed child's attention function using the Test of Everyday Attention for Children at Five (TEACh-5). Parents and preschool teachers completed Behaviour Rating Inventory of Executive Function (BRIEF) to assess executive functions. We estimated the differences of composite mean outcome scores, and odds ratios (OR) for subnormal attention or executive function (defined as 1 standard deviation below the mean), adjusting for maternal IQ, maternal mental health, indications for paracetamol use and other potential confounders. Results: First trimester use of paracetamol was associated with poorer attention scores in childhood [mean difference -0.34, 95% confidence interval (CI) -0.63, -0.05 for overall attention, and -0.25, 95% CI -0.50, 0.01 for selective attention]. Children prenatally exposed to paracetamol were also at a higher risk for subnormal overall attention (OR = 1.5, 95% CI 1.0, 2.5), selective attention difficulties (OR = 1.5, 95% CI 1.0, 2.4), and parent-rated subnormal executive function (metacognition index, OR = 1.5, 95% CI 0.9, 2.3). The risks for subnormal overall attention or executive function were elevated with longer duration of paracetamol use in pregnancy. Conclusions: We found some evidence that maternal paracetamol use during pregnancy was associated with poorer attention and executive function in 5-year-olds. PMID- 28031316 TI - Implementing medical abortion with mifepristone and misoprostol in Norway 1998 2013. AB - Background: Medical abortion with mifepristone and misoprostol was introduced in Norway in 1998, and since then there has been an almost complete change from predominantly surgical to medical abortions. We aimed to describe the medical abortion implementation process, and to compare characteristics of women obtaining medical and surgical abortion. Methods: Information from all departments of obstetrics and gynaecology in Norway on the time of implementation of medical abortion and abortion procedures in use up to 12 weeks of gestation was assessed by surveys in 2008 and 2012. We also analysed data from the National Abortion Registry comprising 223 692 women requesting abortion up to 12 weeks of gestation during 1998-2013. Results: In 2012, all hospitals offered medical abortion, 84.4% offered medical abortion at 9-12 weeks of gestation and 92.1% offered home administration of misoprostol. The use of medical abortion increased from 5.9% of all abortions in 1998 to 82.1% in 2013. Compared with women having a surgical abortion, women obtaining medical abortion had higher odds for undergoing an abortion at 4-6 weeks (adjusted OR 2.33; 95% confidence interval 2.28-2.38). Waiting time between registered request for an abortion until termination was reduced from 11.3 days in 1998 to 7.3 days in 2013. Conclusions: Norwegian women have gained access to more treatment modalities and simplified protocols for medical abortion. At the same time they obtained abortions at an earlier gestational age and the waiting time has been reduced. PMID- 28031315 TI - Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies. AB - Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status. Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 * 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2*10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P value for homogeneity=3*10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident. Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking. PMID- 28031317 TI - Coffee intake, cardiovascular disease and all-cause mortality: observational and Mendelian randomization analyses in 95 000-223 000 individuals. AB - Background: Coffee has been associated with modestly lower risk of cardiovascular disease and all-cause mortality in meta-analyses; however, it is unclear whether these are causal associations. We tested first whether coffee intake is associated with cardiovascular disease and all-cause mortality observationally; second, whether genetic variations previously associated with caffeine intake are associated with coffee intake; and third, whether the genetic variations are associated with cardiovascular disease and all-cause mortality. Methods: First, we used multivariable adjusted Cox proportional hazard regression models evaluated with restricted cubic splines to examine observational associations in 95 366 White Danes. Second, we estimated mean coffee intake according to five genetic variations near the AHR (rs4410790; rs6968865) and CYP1A1/2 genes (rs2470893; rs2472297; rs2472299). Third, we used sex- and age adjusted Cox proportional hazard regression models to examine genetic associations with cardiovascular disease and all-cause mortality in 112 509 Danes. Finally, we used sex and age-adjusted logistic regression models to examine genetic associations with ischaemic heart disease including the Cardiogram and C4D consortia in a total of up to 223 414 individuals. We applied similar analyses to ApoE genotypes associated with plasma cholesterol levels, as a positive control. Results: In observational analyses, we observed U-shaped associations between coffee intake and cardiovascular disease and all-cause mortality; lowest risks were observed in individuals with medium coffee intake. Caffeine intake allele score (rs4410790 + rs2470893) was associated with a 42% higher coffee intake. Hazard ratios per caffeine intake allele were 1.02 (95% confidence interval: 1.00-1.03) for ischaemic heart disease, 1.02 (0.99-1.02) for ischaemic stroke, 1.02 (1.00-1.03) for ischaemic vascular disease, 1.02 (0.99-1.06) for cardiovascular mortality and 1.01 (0.99-1.03) for all-cause mortality. Including international consortia, odds ratios per caffeine intake allele for ischaemic heart disease were 1.00 (0.98 1.02) for rs4410790, 1.01 (0.99-1.03) for rs6968865, 1.02 (1.00-1.04) for rs2470893, 1.02 (1.00-1.04) for rs2472297 and 1.03 (0.99-1.06) for rs2472299. Conversely, 5% lower cholesterol level caused by ApoE genotype had a corresponding odds ratio for ischaemic heart disease of 0.93 (0.89-0.97). Conclusions: Observationally, coffee intake was associated with U-shaped lower risk of cardiovascular disease and all-cause mortality; however, genetically caffeine intake was not associated with risk of cardiovascular disease or all cause mortality. PMID- 28031318 TI - Effects of invitation to participate in health surveys on the incidence of cardiovascular disease: a randomized general population study. AB - Background: The effects of health checks on reducing cardiovascular disease morbidity and mortality in the general population have been questioned. There are few randomized studies with long-term follow-up. We used a cohort randomly selected from a general population as a randomized trial to study the effect of repeated general health checks on the 30-year incidence of ischaemic heart disease (IHD), stroke and all-cause mortality. Methods: The study included all persons ( n = 17 845) aged 30, 40, 50 and 60 years living in 11 municipalities in Copenhagen, the capital of Denmark. An age- and gender-stratified random sample ( n = 4789) was invited to up to three health checks, from 1982 to 1994 (intervention group). The remaining 12 994 persons were defined as the control group. Complete follow-up on mortality, emigration and fatal and non-fatal IHD and stroke until 31 December 2012 was obtained by linkage to registries. Results: There were 3209 and 2190 incident cases of IHD and stroke, respectively, and a total of 6432 deaths during follow-up (mean = 25.2 years). The hazard ratios (HRs) (95% confidence intervals, CIs) for persons in the intervention group versus persons in the control group were as follows: IHD (HR: 0.99, 95% CI: 0.92, 1.07), stroke (HR: 1.14, 95% CI: 1.04, 1.25) and all-cause mortality (HR: 1.03, 95% CI: 0.98, 1.09). Conclusions: Repeated general health checks offered to the general population had no beneficial effects on the development of IHD, stroke or all-cause mortality during 30 years of follow-up. An increased incidence of stroke was observed in the group offered health checks. PMID- 28031320 TI - Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules. AB - CD63 is a ubiquitously expressed member of the tetraspanin superfamily. Using a mating-based split-ubiquitin-yeast 2-hybrid system, pull-down experiments, total internal reflection fluorescence microscopy, Forster resonance energy transfer, and biotinylation assays, we found that CD63 interacts with human organic cation transporter 2 (hOCT2), which transports endogenous and exogenous substrates, such as neurotransmitters and drugs in several epithelial cells. CD63 overexpression affects cellular localization of hOCT2 expressed in human embryonic kidney (HEK)293 cells. Studies with CD63-knockout mice indicate that in renal proximal tubules, CD63 determines the insertion of the mouse ortholog of the transporter into the proper membrane domain and mediates transporter regulation by trafficking processes. In polarized Madin-Darby kidney canine kidney (MDCK) epithelial cells, CD63 and hOCT2 colocalize with the small GTPase Rab4, which controls the rapid recycling from sorting endosomes back to the cell surface. Suitable negative and positive control experiments were performed for each experimental approach. Empty vector transfected cells and wild-type mice were used as control. CD63 seems to play a role in the recycling of hOCT2 from endosomes to the basolateral membrane in polarized epithelia. These data indicate that CD63 has a previously uncharacterized function in regulating trafficking of specific membrane proteins in polarized cells.-Schulze, U., Brast, S., Grabner, A., Albiker, C., Snieder, B., Holle, S., Schlatter, E., Schroter, R., Pavenstadt, H., Herrmann, E., Lambert, C., Spoden, G. A., Florin, L., Saftig, P., Ciarimboli, G. Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules. PMID- 28031319 TI - Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden. AB - The apolipoprotein E4 (E4) allele is present worldwide, despite its associations with higher risk of cardiovascular morbidity, accelerated cognitive decline during aging, and Alzheimer's disease (AD). The E4 allele is especially prevalent in some tropical regions with a high parasite burden. Equatorial populations also face a potential dual burden of high E4 prevalence combined with parasitic infections that can also reduce cognitive performance. We examined the interactions of E4, parasite burden, and cognitive performance in a traditional, nonindustrialized population of Amazonian forager-horticulturalists (N = 372) to test whether E4 protects against cognitive decline in environments with a heavy pathogen burden. Contrary to observations in industrial populations, older adult E4 carriers with high parasite burdens either maintained or showed slight improvements in cognitive performance, whereas non-E4 carriers with a high parasite burden showed reduced cognitive performance. Being an E4 carrier is the strongest risk factor to date of AD and cognitive decline in industrial populations; it is associated with greater cognitive performance in individuals facing a high parasite and pathogen load, suggesting advantages to the E4 allele under certain environmental conditions. The current mismatch between postindustrial hygienic lifestyles and active parasite-rich environs may be critical for understanding genetic risk for cognitive aging.-Trumble, B. C., Stieglitz, J., Blackwell, A. D., Allayee, H., Beheim, B., Finch, C. E., Gurven, M., Kaplan, H. Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden. PMID- 28031321 TI - Inflammatory hypoxia induces syndecan-2 expression through IL-1beta-mediated FOXO3a activation in colonic epithelia. AB - Chronic inflammation is known to be a key causative factor in tumor progression, but we do not yet fully understand the molecular mechanism through which inflammation leads to cancer. Here, we report that the dextran sulfate sodium (DSS)-induced mouse model of chronic colitis is associated with increases in the serum level of IL-1beta and the colonic epithelial expression of the cell-surface heparan sulfate proteoglycan, syndecan-2. We further show that IL-1beta stimulated the transcription of syndecan-2 via NF-kappaB-dependent FOXO3a activation in CCD841CoN normal colonic epithelial cells and early-stage HT29 colon cancer cells. Inflammatory hypoxia was observed in the colonic epithelia of mice with chronic colitis, suggesting that hypoxic stress is involved in the regulation of syndecan-2 expression. Consistently, experimental inflammatory hypoxia induced hypoxia inducible factor-1alpha-dependent FOXO3a expression and the p38 MAPK-mediated nuclear localization of FOXO3a. FOXO3a directly mediated syndecan-2 expression in both cell lines and the colonic epithelia of mice with DSS-induced colitis. Moreover, syndecan-2 expression was detected in azoxymethane/DSS-induced colon tumors. Together, these data demonstrate that inflammatory hypoxia up-regulates syndecan-2 via the IL-1beta-NF-kappaB-FOXO3a pathway. These findings provide new mechanistic insights into inflammatory hypoxia-mediated syndecan-2 expression to connect chronic inflammation and the development of colon cancer.-Choi, S., Chung, H., Hong, H., Kim, S. Y., Kim, S. E., Seoh, J.-Y., Moon, C. M., Yang, E. G., Oh, E.-S. Inflammatory hypoxia induces syndecan-2 expression through IL-1beta-mediated FOXO3a activation in colonic epithelia. PMID- 28031322 TI - Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis. AB - In this review, we focus on the role played by the protein partners of ligand activated extranuclear androgen receptor (AR) in the final effects of hormone action, such as proliferation, migration, and neuritogenesis. The choice of AR partner, at least in part, depends on cell type. Androgen-activated receptor directly associates with cytoplasmic Src tyrosine kinase in epithelial cells, whereas in mesenchymal and neuronal cells, it prevalently interacts with filamin A. In the former, proliferation represents the final hormonal outcome, whereas in the latter, either migration or neuritogenesis, respectively, occurs. Furthermore, AR partner filamin A is replaced with Src when mesenchymal cells are stimulated with very low androgen concentrations. Consequently, the migratory effect is replaced by mitogenesis. Use of peptides that prevent receptor/partner assembly abolishes the effects that are dependent on their association and offers new therapeutic approaches to AR-related diseases. Perturbation of migration is often associated with metastatic spreading in cancer. In turn, cell cycle aberration causes tumors to grow faster, whereas toxic signaling triggers neurodegenerative events in the CNS. Here, we provide examples of new tools that interfere in rapid androgen effects, including migration, proliferation, and neuronal differentiation, together with their potential therapeutic applications in AR-dependent diseases-mainly prostate cancer and neurodegenerative disorders. Castoria, G., Auricchio, F., Migliaccio, A. Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis. PMID- 28031323 TI - Inter-observer and intra-observer agreement between embryologists during selection of a single Day 5 embryo for transfer: a multicenter study. AB - STUDY QUESTION: What is the inter-observer and intra-observer agreement between embryologists when selecting a single Day 5 embryo for transfer? SUMMARY ANSWER: The inter-observer and intra-observer agreement between embryologists when selecting a single Day 5 embryo for transfer was generally good, although not optimal, even among experienced embryologists. WHAT IS KNOWN ALREADY: Previous research on the morphological assessment of early stage (two pronuclei to Day 3) embryos has shown varying levels of inter-observer and intra-observer agreement. However, single blastocyst transfer is now becoming increasingly popular and there are no published data that assess inter-observer and intra-observer agreement when selecting a single embryo for Day 5 transfer. STUDY DESIGN, SIZE, DURATION: This was a prospective study involving 10 embryologists working at five different IVF clinics within a single organization between July 2013 and November 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: The top 10 embryologists were selected based on their yearly Quality Assurance Program scores for blastocyst grading and were asked to morphologically grade all Day 5 embryos and choose a single embryo for transfer in a survey of 100 cases using 2D images. A total of 1000 decisions were therefore assessed. For each case, Day 5 images were shown, followed by a Day 3 and Day 5 image of the same embryo. Subgroup analyses were also performed based on the following characteristics of embryologists: the level of clinical embryology experience in the laboratory; amount of research experience; number of days per week spent grading embryos. The agreement between these embryologists and the one that scored the embryos on the actual day of transfer was also evaluated. Inter-observer and intra-observer variability was assessed using the kappa coefficient to evaluate the extent of agreement. MAIN RESULTS AND THE ROLE OF CHANCE: This study showed that all 10 embryologists agreed on the embryo chosen for transfer in 50 out of 100 cases. In 93 out of 100 cases, at least 6 out of the 10 embryologists agreed. The inter-observer and intra-observer agreement among embryologists when selecting a single Day 5 embryo for transfer was generally good as assessed by the kappa scores (kappa = 0.734, 95% CI: 0.665-0.791 and 0.759, 95% CI: 0.622-0.833, respectively). The subgroup analyses did not substantially alter the inter-observer and intra-observer agreement among embryologists. The agreement when Day 3 images were included alongside Day 5 images of the same embryos resulted in a change of mind at least three times by each embryologist (on average for <10% of cases) and resulted in a small decrease in inter-observer and intra-observer agreement between embryologists (kappa = 0.676, 95% CI: 0.617-0.724 and 0.752, 95% CI: 0.656-808, respectively).The assessment of the inter-observer agreement with regard to morphological grading of Day 5 embryos showed only a fair-to-moderate agreement, which was observed across all subgroup analyses. The highest overall kappa coefficient was seen for the grading of the developmental stage of an embryo (0.513; 95% CI: 0.492-0.538). The findings were similar when the individual embryologists were compared with the embryologist who made the morphological assessments of the available embryos on the actual day of transfer. LIMITATIONS, REASONS FOR CAUTION: All embryologists had already completed their training and were working under one organization with similar policies between the five clinics. Therefore, the inter-observer agreement might not be as high between embryologists working in clinics with different policies or with different levels of training. WIDER IMPLICATIONS OF THE FINDINGS: The generally good, although not optimal uniformity between participating embryologists when selecting a Day 5 embryo for transfer, as well as, the surprisingly low agreement when morphologically grading Day 5 embryos could be improved, potentially resulting in increased pregnancy rates. Future studies need to be directed toward technologies that can help achieve this. STUDY FUNDING/COMPETING INTERESTS: None declared. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 28031324 TI - Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective, population-based cohort study. AB - STUDY QUESTION: What are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years? SUMMARY ANSWER: The risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM. WHAT IS KNOWN ALREADY: PCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear. STUDY DESIGN, SIZE, DURATION: In a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS per se significantly increased the risk of T2DM in overweight/obese (BMI >= 25.0 kg/m2) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28-4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was significantly greater in women with PCOS developing T2DM than in women with PCOS and normal glucose tolerance, with the most significant increase occurring in early adulthood (between 14 and 31 years: median with [25%; 75% quartiles]: 27.25 kg [20.43; 34.78] versus 13.80 kg [8.55; 20.20], P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The diagnosis of PCOS was based on self reporting, and the questionnaire at 46 years did not distinguish between polycystic ovaries only in ultrasonography and the syndrome. Ovarian ultrasonography was not available to aid the diagnosis of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: These results emphasize weight management already during adolescence and early adulthood to prevent the development of T2DM in women with PCOS, as the period between 14 and 31 years seems to be a crucial time window during which the women with PCOS who are destined to develop T2DM by 46 years of age experience a dramatic weight gain. Furthermore, our results support the view that, particularly in times of limited sources of healthcare systems, OGTT screening should be targeted to overweight/obese women with PCOS rather than to all women with PCOS. STUDY FUNDING/COMPETING INTERESTS: Finnish Medical Foundation; North Ostrobothnia Regional Fund; Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE); Sigrid Juselius Foundation; Biocenter Oulu; University Hospital Oulu and University of Oulu (75617); Medical Research Center Oulu; National Institute for Health Research (UK); National Heart, Lung, and Blood Institute (grant 5R01HL087679-02) through the STAMPEED program (1RL1MH083268-01); National Institute of Health/National Institute of Mental Health (5R01MH63706:02); ENGAGE project and grant agreement HEALTH-F4-2007 201413; EU FP7 EurHEALTHAgeing-277849 European Commission and Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and Medical Research Center, Centenary Early Career Award. The authors have no conflicts of interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 28031325 TI - Diethylstilbestrol activates CatSper and disturbs progesterone actions in human spermatozoa. AB - STUDY QUESTION: Is diethylstilbestrol (DES), a prototypical endocrine-disrupting chemical (EDC), able to induce physiological changes in human spermatozoa and affect progesterone actions? SUMMARY ANSWER: DES promoted Ca2+ flux into human spermatozoa by activating the cation channel of sperm (CatSper) and suppressed progesterone-induced Ca2+ signaling, tyrosine phosphorylation and sperm functions. WHAT IS KNOWN ALREADY: DES significantly impairs the male reproductive system both in fetal and postnatal exposure. Although various EDCs affect human spermatozoa in a non-genomic manner, the effect of DES on human spermatozoa remains unknown. STUDY DESIGN, SIZE, DURATION: Sperm samples from normozoospermic donors were exposed in vitro to a range of DES concentrations with or without progesterone at 37 degrees C in a 5% CO2 incubator to mimic the putative exposure to this toxicant in seminal plasma and the female reproductive tract fluids. The incubation time varied according to the experimental protocols. All experiments were repeated at least five times using different individual sperm samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human sperm intracellular calcium concentrations ([Ca2+]i) were monitored with a multimode plate reader following sperm loading with Ca2+ indicator Fluo-4 AM, and the whole-cell patch-clamp technique was performed to record CatSper and alkalinization-activated sperm K+ channel (KSper) currents. Sperm viability and motility parameters were assessed by an eosin-nigrosin staining kit and a computer-assisted semen analysis system, respectively. The ability of sperm to penetrate into viscous media was examined by penetration into 1% methylcellulose. The sperm acrosome reaction was measured using chlortetracycline staining. The level of tyrosine phosphorylation was determined by western blot assay. MAIN RESULTS AND THE ROLE OF CHANCE: DES exposure rapidly increased human sperm [Ca2+]i dose dependently and even at an environmentally relevant concentration (100 pM). The elevation of [Ca2+]i was derived from extracellular Ca2+ influx and mainly mediated by CatSper. Although DES did not affect sperm viability, motility, penetration into viscous media, tyrosine phosphorylation or the acrosome reaction, it suppressed progesterone stimulated Ca2+ signaling and tyrosine phosphorylation. Consequently, DES (1-100 MUM) significantly inhibited progesterone-induced human sperm penetration into viscous media and acrosome reaction. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Although DES has been shown to disturb progesterone actions on human spermatozoa, this study was performed in vitro, and caution must be taken when extrapolating the results in practical applications. WIDER IMPLICATIONS OF THE FINDINGS: The present study revealed that DES interfered with progesterone stimulated Ca2+ signaling and tyrosine phosphorylation, ultimately inhibited progesterone-induced human sperm functions and, thereby, might impair sperm fertility. The non-genomic manner in which DES disturbs progesterone actions may be a potential mechanism for some estrogenic endocrine disruptors to affect human sperm function. STUDY FUNDING/COMPETING INTERESTS: National Natural Science Foundation of China (No. 31400996); Natural Science Foundation of Jiangxi, China (No. 20161BAB204167 and No. 20142BAB215050); open project of National Population and Family Planning Key Laboratory of Contraceptives and Devices Research (No. 2016KF07) to T. Luo; National Natural Science Foundation of China (No. 81300539) to L.P. Zheng. The authors have no conflicts of interest to declare. PMID- 28031326 TI - Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy. AB - Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90 inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy. PMID- 28031327 TI - INPP5E Preserves Genomic Stability through Regulation of Mitosis. AB - The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of INPP5E in human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity. Consistent with a cell cycle regulatory role, we found that INPP5E expression is cell cycle dependent, peaking at mitotic entry. INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. Our findings identify the previously unknown, essential role of INPP5E in mitosis and prevention of aneuploidy, providing a new perspective on the function of this phosphoinositide phosphatase in health and development. PMID- 28031328 TI - Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage. AB - RAD6, an E2 ubiquitin-conjugating enzyme, is a key node for determining different DNA damage repair pathways, controlling both the error-prone and the error-free DNA damage repair pathways through differential regulation of the ubiquitination of the proliferating cell nuclear antigen (PCNA) protein. However, whether other pathways are involved in the RAD6-mediated regulation of DNA damage repair is still unclear. To deeply understand the molecular mechanisms of RAD6 in DNA damage repair, we performed a proteomic analysis and identified the changes of the protein-protein interaction (PPI) networks of RAD6 before and after X-ray irradiation. Furthermore, our study indicated that a proteasome-related event is likely involved in the DNA damage repair process. Moreover, we found that RAD6 promotes proteasome activity and nuclear translocation by enhancing the degradation of PSMF1 and the lamin B receptor (LBR). Therefore, we provide a novel pathway that is employed by RAD6 in response to DNA damage. PMID- 28031329 TI - HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation. AB - The mammalian intestinal mucosa exhibits a spectrum of responses after acute injury and repairs itself rapidly to restore the epithelial integrity. The RNA binding protein HuR regulates the stability and translation of target mRNAs and is involved in many aspects of gut epithelium homeostasis, but its exact role in the regulation of mucosal repair after injury remains unknown. We show here that HuR is essential for early intestinal epithelial restitution by increasing the expression of cell division control protein 42 (Cdc42) at the posttranscriptional level. HuR bound to the Cdc42 mRNA via its 3' untranslated region, and this association specifically enhanced Cdc42 translation without an effect on the Cdc42 mRNA level. Intestinal epithelium-specific HuR knockout not only decreased Cdc42 levels in mucosal tissues, but it also inhibited repair of damaged mucosa induced by mesenteric ischemia/reperfusion in the small intestine and by dextran sulfate sodium in the colon. Furthermore, Cdc42 silencing prevented HuR-mediated stimulation of cell migration over the wounded area by altering the subcellular distribution of F-actin. These results indicate that HuR promotes early intestinal mucosal repair after injury by increasing Cdc42 translation and demonstrate the importance of HuR deficiency in the pathogenesis of delayed mucosal healing in certain pathological conditions. PMID- 28031330 TI - SETD4 Regulates Cell Quiescence and Catalyzes the Trimethylation of H4K20 during Diapause Formation in Artemia. AB - As a prominent characteristic of cell life, the regulation of cell quiescence is important for proper development, regeneration, and stress resistance and may play a role in certain degenerative diseases. However, the mechanism underlying quiescence remains largely unknown. Encysted embryos of Artemia are useful for studying the regulation of this state because they remain quiescent for prolonged periods during diapause, a state of obligate dormancy. In the present study, SET domain-containing protein 4, a histone lysine methyltransferase from Artemia, was identified, characterized, and named Ar-SETD4. We found that Ar-SETD4 was expressed abundantly in Artemia diapause embryos, in which cells were in a quiescent state. Meanwhile, trimethylated histone H4K20 (H4K20me3) was enriched in diapause embryos. The knockdown of Ar-SETD4 reduced the level of H4K20me3 significantly and prevented the formation of diapause embryos in which neither the cell cycle nor embryogenesis ceased. The catalytic activity of Ar-SETD4 on H4K20me3 was confirmed by an in vitro histone methyltransferase (HMT) assay and overexpression in cell lines. This study provides insights into the function of SETD4 and the mechanism of cell quiescence regulation. PMID- 28031331 TI - Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element. AB - Cell-type-specific and inducible alternative splicing has a fundamental impact on regulating gene expression and cellular function in a variety of settings, including activation and differentiation. We have recently shown that activation induced skipping of TRAF3 exon 8 activates noncanonical NF-kappaB signaling upon T cell stimulation, but the regulatory basis for this splicing event remains unknown. Here we identify cis- and trans-regulatory elements rendering this splicing switch activation dependent and cell type specific. The cis-acting element is located 340 to 440 nucleotides upstream of the regulated exon and acts in a distance-dependent manner, since altering the location reduces its activity. A small interfering RNA screen, followed by cross-link immunoprecipitation and mutational analyses, identified CELF2 and hnRNP C as trans-acting factors that directly bind the regulatory sequence and together mediate increased exon skipping in activated T cells. CELF2 expression levels correlate with TRAF3 exon skipping in several model systems, suggesting that CELF2 is the decisive factor, with hnRNP C being necessary but not sufficient. These data suggest an interplay between CELF2 and hnRNP C as the mechanistic basis for activation-dependent alternative splicing of TRAF3 exon 8 and additional exons and uncover an intronic splicing silencer whose full activity depends on the precise location more than 300 nucleotides upstream of the regulated exon. PMID- 28031332 TI - Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity. AB - RGS10 has emerged as a key regulator of proinflammatory cytokine production in microglia, functioning as an important neuroprotective factor. Although RGS10 is normally expressed in microglia at high levels, expression is silenced in vitro following activation of TLR4 receptor. Given the ability of RGS10 to regulate inflammatory signaling, dynamic regulation of RGS10 levels in microglia may be an important mechanism to tune inflammatory responses. The goals of the current study were to confirm that RGS10 is suppressed in an in vivo inflammatory model of microglial activation and to determine the mechanism for activation-dependent silencing of Rgs10 expression in microglia. We demonstrate that endogenous RGS10 is present in spinal cord microglia, and RGS10 protein levels are suppressed in the spinal cord in a nerve injury-induced neuropathic pain mouse model. We show that the histone deacetylase (HDAC) enzyme inhibitor trichostatin A blocks the ability of lipopolysaccharide (LPS) to suppress Rgs10 transcription in BV-2 and primary microglia, demonstrating that HDAC enzymes are required for LPS silencing of Rgs10 Furthermore, we used chromatin immunoprecipitation to demonstrate that H3 histones at the Rgs10 proximal promoter are deacetylated in BV-2 microglia following LPS activation, and HDAC1 association at the Rgs10 promoter is enhanced following LPS stimulation. Finally, we have shown that sphingosine 1-phosphate, an endogenous microglial signaling mediator that inhibits HDAC activity, enhances basal Rgs10 expression in BV-2 microglia, suggesting that Rgs10 expression is dynamically regulated in microglia in response to multiple signals. PMID- 28031334 TI - Respiratory Influenza Virus Infection Induces Memory-like Liver NK Cells in Mice. AB - Although NK cells are classified as innate immune cells, recent studies have demonstrated the transformation of NK cells into long-lived memory cells that contribute to secondary immune responses in certain mouse models. However, whether NK cells mount an Ag-specific memory response to acute influenza virus infection has not yet been examined. Here, we show that, consistent with previous studies, lung NK cells play an important role in controlling viral proliferation after primary influenza virus infection. However, although lung NK cells display a memory phenotype at the late stage of infection, these cells do not protect mice against secondary influenza virus infection. Interestingly, liver NK cells from influenza virus-infected mice possess a memory phenotype and protect mice against secondary influenza virus infection. Memory-like liver NK cells display a CD49a+DX5- phenotype, and the adoptive transfer of purified liver CD49a+DX5- NK cells into naive mice followed by viral infection results in protective immunity and decreased viral titer. Moreover, we demonstrate that primary inactivated influenza virus induces memory NK cells residing in the liver of Rag1-/- mice. Collectively, these data suggest that liver CD49a+DX5- NK cells remember encountered Ag from influenza virus after primary infection and are more protective upon subsequent infection. PMID- 28031333 TI - T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System. AB - NK cells, which are highly enriched in the liver, are potent regulators of antiviral T cells and immunopathology in persistent viral infection. We investigated the role of the NKG2D axis in T cell/NK cell interactions in hepatitis B. Activated and hepatitis B virus (HBV)-specific T cells, particularly the CD4 fraction, expressed NKG2D ligands (NKG2DL), which were not found on T cells from healthy controls (p < 0.001). NKG2DL-expressing T cells were strikingly enriched within HBV-infected livers compared with the periphery or to healthy livers (p < 0.001). NKG2D+NK cells were also increased and preferentially activated in the HBV-infected liver (p < 0.001), in direct proportion to the percentage of MICA/B-expressing CD4 T cells colocated within freshly isolated liver tissue (p < 0.001). This suggests that NKG2DL induced on T cells within a diseased organ can calibrate NKG2D-dependent activation of local NK cells; furthermore, NKG2D blockade could rescue HBV-specific and MICA/B-expressing T cells from HBV-infected livers. To our knowledge, this is the first ex vivo demonstration that non-virally infected human T cells can express NKG2DL, with implications for stress surveillance by the large number of NKG2D-expressing NK cells sequestered in the liver. PMID- 28031335 TI - NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection. AB - CD4 T cells can differentiate into multiple effector subsets, including ThCTL that mediate MHC class II-restricted cytotoxicity. Although CD4 T cell-mediated cytotoxicity has been reported in multiple viral infections, their characteristics and the factors regulating their generation are unclear, in part due to a lack of a signature marker. We show in this article that, in mice, NKG2C/E identifies the ThCTL that develop in the lung during influenza A virus infection. ThCTL express the NKG2X/CD94 complex, in particular the NKG2C/E isoforms. NKG2C/E+ ThCTL are part of the lung CD4 effector population, and they mediate influenza A virus-specific cytotoxic activity. The phenotype of NKG2C/E+ ThCTL indicates they are highly activated effectors expressing high levels of binding to P-selectin, T-bet, and Blimp-1, and that more of them secrete IFN gamma and readily degranulate than non-ThCTL. ThCTL also express more cytotoxicity-associated genes including perforin and granzymes, and fewer genes associated with recirculation and memory. They are found only at the site of infection and not in other peripheral sites. These data suggest ThCTL are marked by the expression of NKG2C/E and represent a unique CD4 effector population specialized for cytotoxicity. PMID- 28031336 TI - Autophagy in Dendritic Cells and B Cells Is Critical for the Inflammatory State of TLR7-Mediated Autoimmunity. AB - Individuals suffering from autoimmune disorders possess a hyperactive cellular phenotype where tolerance to self-antigens is lost. Autophagy has been implicated in both the induction and prevention of autoimmunity, and modulators of this cellular recycling process hold high potential for the treatment of autoimmune diseases. In this study, we determine the effects of a loss of autophagy in dendritic cells (DCs), as well as both B cells and DCs, in a TLR7-mediated model of autoimmunity, similar to systemic lupus erythematosus, where both cell types are critical for disease. Although a loss of DC autophagy slowed disease, the combined loss of autophagy in both cell types resulted in a lethal sepsis-like environment, which included tissue inflammation and hyperproduction of inflammasome-associated cytokines. Ablation of B cell signaling reversed this phenotype, indicating that activation of these cells is an essential step in disease induction. Thus, autophagy plays a dichotomous role in this model of disease. PMID- 28031337 TI - Immune Modifications in Fetal Membranes Overlying the Cervix Precede Parturition in Humans. AB - In humans, parturition is currently viewed as an intrauterine outbreak of inflammation, accompanied by a massive release of proinflammatory cytokines at the maternal-fetal interface that comprises the maternal decidua, placenta, and fetal membranes. At term, fetal membranes overlying the cervix, the future site of rupture, show altered morphology and are termed the zone of altered morphology (ZAM). These alterations occur in normal fetal membranes during late pregnancy, in preparation for labor. In this study, transcriptome, flow cytometry, electron microscopy, and immunohistochemistry analyses collectively highlight a local shift in gene expression and lymphocyte activation in the ZAM. Just before labor, we show that highly polymorphic HLA-A, -B, and -C determinants of fetal origin are selectively exposed in the ZAM to the maternal immune system. A graft rejection-like program occurs in the ZAM, which involves 1) the activation of cytotoxic decidual NK cells, and 2) the decline of decidual immunotolerant M2 like macrophages. Comparison with a prior cohort of fetal membranes shows that acute inflammation only takes place after these first steps of immune modifications. Our results therefore strongly argue in favor of local immune remodeling at the onset of parturition. PMID- 28031338 TI - Deletion of Nlrp3 Augments Survival during Polymicrobial Sepsis by Decreasing Autophagy and Enhancing Phagocytosis. AB - NLRP3 inflammasome is a critical player in innate immunity. Neutrophil recruitment to tissues and effective neutrophil function are critical innate immune mechanisms for bacterial clearance. However, the role of NLRP3 in neutrophil-dependent bacterial clearance in polymicrobial sepsis is unclear. In this study, we evaluated the role of NLRP3 in polymicrobial sepsis induced by cecal ligation and puncture (CLP). Our results showed protection from death in NLRP3-deficient (Nlrp3-/-) and NLRP3 inhibitor-treated wild-type (C57BL/6) mice. Nlrp3-/- and NLRP3 inhibitor-treated mice displayed lower bacterial load but no impairment in neutrophil recruitment to peritoneum. However, neutrophil depletion abrogated protection from death in Nlrp3-/- mice in response to CLP. Intriguingly, following CLP, Nlrp3-/- peritoneal cells (primarily neutrophils) demonstrate decreased autophagy, augmented phagocytosis, and enhanced scavenger receptor (macrophage receptor with collagenous structure) and mannose-binding leptin expression. These findings enhance our understanding of the critical role of NLRP3 in modulating autophagy and phagocytosis in neutrophils and suggest that therapies should be targeted to modulate autophagy and phagocytosis in neutrophils to control bacterial burden in tissues during CLP-induced polymicrobial sepsis. PMID- 28031339 TI - Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells. AB - Infection with Staphylococcus aureus does not induce long-lived protective immunity for reasons that are not completely understood. Human and murine vaccine studies support a role for Abs in protecting against recurring infections, but S. aureus modulates the B cell response through expression of staphylococcus protein A (SpA), a surface protein that drives polyclonal B cell expansion and induces cell death in the absence of costimulation. In this murine study, we show that SpA altered the fate of plasmablasts and plasma cells (PCs) by enhancing the short-lived extrafollicular response and reducing the pool of bone marrow (BM) resident long-lived PCs. The absence of long-lived PCs was associated with a rapid decline in Ag-specific class-switched Ab. In contrast, when previously inoculated mice were challenged with an isogenic SpA-deficient S. aureus mutant, cells proliferated in the BM survival niches and sustained long-term Ab titers. The effects of SpA on PC fate were limited to the secondary response, because Ab levels and the formation of B cell memory occurred normally during the primary response in mice inoculated with wild-type or SpA-deficient S. aureus mutant. Thus, failure to establish long-term protective Ab titers against S. aureus was not a consequence of diminished formation of B cell memory; instead, SpA reduced the proliferative capacity of PCs that entered the BM, diminishing the number of cells in the long-lived pool. PMID- 28031340 TI - IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function. AB - Interleukin 15 is essential for the development and differentiation of NK and memory CD8+ (mCD8+) T cells. Our laboratory previously showed that NK and CD8+ T lymphocytes facilitate the pathobiology of septic shock. However, factors that regulate NK and CD8+ T lymphocyte functions during sepsis are not well characterized. We hypothesized that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8+ T cell integrity. To test our hypothesis, the pathogenesis of sepsis was assessed in IL-15-deficient (IL-15 knockout, KO) mice. IL-15 KO mice showed improved survival, attenuated hypothermia, and less proinflammatory cytokine production during septic shock caused by cecal ligation and puncture or endotoxin-induced shock. Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Ralpha complex) regenerated NK and mCD8+ T cells and re established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15-neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion if given 4 d prior to septic challenge and conferred protection. IL-15 SA treatment amplified endotoxin shock, which was prevented by NK cell or IFN-gamma depletion. IL-15 SA treatment also exacerbated septic shock caused by cecal ligation and puncture when given after the onset of sepsis. In conclusion, endogenous IL-15 does not directly augment the pathogenesis of sepsis but enables the development of septic shock by maintaining NK cell numbers and integrity. Exogenous IL-15 exacerbates the severity of sepsis by activating NK cells and facilitating IFN-gamma production. PMID- 28031341 TI - Differing Requirements for MALT1 Function in Peripheral B Cell Survival and Differentiation. AB - During a T cell-dependent immune response, formation of the germinal center (GC) is essential for the generation of high-affinity plasma cells and memory B cells. The canonical NF-kappaB pathway has been implicated in the initiation of GC reaction, and defects in this pathway have been linked to immune deficiencies. The paracaspase MALT1 plays an important role in regulating NF-kappaB activation upon triggering of Ag receptors. Although previous studies have reported that MALT1 deficiency abrogates the GC response, the relative contribution of B cells and T cells to the defective phenotype remains unclear. We used chimeric mouse models to demonstrate that MALT1 function is required in B cells for GC formation. This role is restricted to BCR signaling where MALT1 is critical for B cell proliferation and survival. Moreover, the proapoptotic signal transmitted in the absence of MALT1 is dominant to the prosurvival effects of T cell-derived stimuli. In addition to GC B cell differentiation, MALT1 is required for plasma cell differentiation, but not mitogenic responses. Lastly, we show that ectopic expression of Bcl-2 can partially rescue the GC phenotype in MALT1-deficient animals by prolonging the lifespan of BCR-activated B cells, but plasma cell differentiation and Ab production remain defective. Thus, our data uncover previously unappreciated aspects of MALT1 function in B cells and highlight its importance in humoral immunity. PMID- 28031343 TI - Screening for elevated albuminuria and subsequently hypertension identifies subjects in which treatment may be warranted to prevent renal function decline. AB - Background: We investigated whether initial population screening for elevated albuminuria with subsequent screening for hypertension in case albuminuria is elevated may be of help to identify subjects at risk for accelerated decline in kidney function. Methods: We included subjects who participate in the PREVEND observational, general population-based cohort study and had two or more glomerular filtration rate (eGFR) measurements available during follow-up. Elevated albuminuria was defined as an albumin concentration >=20 mg/L in a first morning urine sample confirmed by an albumin excretion >=30 mg/day in two 24-h urines. Hypertension was defined as systolic blood pressure >=140 mmHg, diastolic blood pressure >=90 mmHg or use of blood pressure-lowering drugs. eGFR was estimated with the CKD-EPI creatinine-cystatin C equation. Results: Overall, 6471 subjects were included with a median of 4 [95% confidence interval (CI) 2-5] eGFR measurements during a follow-up of 11.3 (95% CI 4.0-13.7) years. Decline in eGFR was greater in the subgroups with elevated albuminuria. This held true, not only in subjects with known hypertension (-1.84 +/- 2.27 versus -1.16 +/- 1.45 mL/min/1.73 m 2 per year, P < 0.05), but also in subjects with newly diagnosed hypertension (-1.59 +/- 1.55 versus -1.14 +/- 1.38 mL/min/1.73 m 2 per year, P < 0.05) and in subjects with normal blood pressure (-1.18 +/- 1.85 versus -0.81 +/- 1.02 mL/min/1.73 m 2 per year in subjects, P < 0.05). This effect was most pronounced in the population >=55 years of age and male subjects. In addition, subjects with elevated albuminuria had higher blood pressure than subjects with normoalbuminuria, and in subjects with elevated albuminuria as yet undiagnosed hypertension was twice as prevalent as diagnosed hypertension. Conclusions: Initial screening for elevated albuminuria followed by screening for hypertension may help to detect subjects with increased risk for a steeper decline in kidney function. PMID- 28031344 TI - Lifetime risk of renal replacement therapy in Europe: a population-based study using data from the ERA-EDTA Registry. AB - Background: Upcoming KDIGO guidelines for the evaluation of living kidney donors are expected to move towards a personal risk-based evaluation of potential donors. We present the age and sex-specific lifetime risk of renal replacement therapy (RRT) for end-stage renal disease in 10 European countries. Methods: We defined lifetime risk of RRT as the cumulative incidence of RRT up to age 90 years. We obtained RRT incidence rates per million population by 5-year age groups and sex using data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry, and used these to estimate the cumulative incidence of RRT, adjusting for competing mortality risk. Results: Lifetime risk of RRT varied from 0.44% to 2.05% at age 20 years and from 0.17% to 1.59% at age 70 years across countries, and was twice as high in men as in women. Lifetime RRT risk decreased with age, ranging from an average of 0.77% to 0.44% in 20- to- 70-year-old women, and from 1.45% to 0.96% in 20- to- 70-year-old men. The lifetime risk of RRT increased slightly over the past decade, more so in men than in women. However, it appears to have stabilized or even decreased slightly in more recent years. Conclusions: The lifetime risk of RRT decreased with age, was lower in women as compared with men of equal age and varied considerably throughout Europe. Given the substantial differences in lifetime risk of RRT between the USA and Europe, country-specific estimates should be used in the evaluation and communication of the risk of RRT for potential living kidney donors. PMID- 28031342 TI - Transcriptional Classification and Functional Characterization of Human Airway Macrophage and Dendritic Cell Subsets. AB - The respiratory system is a complex network of many cell types, including subsets of macrophages and dendritic cells that work together to maintain steady-state respiration. Owing to limitations in acquiring cells from healthy human lung, these subsets remain poorly characterized transcriptionally and phenotypically. We set out to systematically identify these subsets in human airways by developing a schema of isolating large numbers of cells by whole-lung bronchoalveolar lavage. Six subsets of phagocytic APC (HLA-DR+) were consistently observed. Aside from alveolar macrophages, subsets of Langerin+, BDCA1-CD14+, BDCA1+CD14+, BDCA1+CD14-, and BDCA1-CD14- cells were identified. These subsets varied in their ability to internalize Escherichia coli, Staphylococcus aureus, and Bacillus anthracis particles. All subsets were more efficient at internalizing S. aureus and B. anthracis compared with E. coli Alveolar macrophages and CD14+ cells were overall more efficient at particle internalization compared with the four other populations. Subsets were further separated into two groups based on their inherent capacities to upregulate surface CD83, CD86, and CCR7 expression levels. Whole-genome transcriptional profiling revealed a clade of "true dendritic cells" consisting of Langerin+, BDCA1+CD14+, and BDCA1+CD14- cells. The dendritic cell clade was distinct from a macrophage/monocyte clade, as supported by higher mRNA expression levels of several dendritic cell-associated genes, including CD1, FLT3, CX3CR1, and CCR6 Each clade, and each member of both clades, was discerned by specific upregulated genes, which can serve as markers for future studies in healthy and diseased states. PMID- 28031345 TI - Identifying subgroups of renal function trajectories. AB - Background: Renal function in patients with chronic kidney disease (CKD) may follow different trajectory profiles. The aim of this study was to evaluate and illustrate the ability of the latent class linear mixed model (LCMM) to identify clinically relevant subgroups of renal function trajectories within a multicenter hospital-based cohort of CKD patients. Methods: We analysed data from the NephroTest cohort including 1967 patients with all-stage CKD at baseline who had glomerular filtration rate (GFR) both measured by 51 Cr-EDTA renal clearance (mGFR) and estimated by the CKD-EPI equation (eGFR); 1103 patients had at least two measurements. The LCMM was used to identify subgroups of GFR trajectories, and patients' characteristics at baseline were compared between the subgroups identified. Results: Five classes of mGFR trajectories were identified. Three had a slow linear decline of mGFR over time at different levels. In the two others, patients had a high level of mGFR at baseline with either a strong nonlinear decline over time ( n = 11) or a nonlinear improvement ( n = 94) of mGFR. Higher levels of proteinuria and blood pressure at baseline were observed in classes with either severely decreased mGFR or strong mGFR decline over time. Using eGFR provided similar findings. Conclusion: The LCMM allowed us to identify in our cohort five clinically relevant subgroups of renal function trajectories. It could be used in other CKD cohorts to better characterize their different profiles of disease progression, as well as to investigate specific risk factors associated with each profile. PMID- 28031346 TI - Insecticidal Activity of Thymoquinone and Related Compounds Against Culex quinquefasciatus (Diptera: Culicidae). AB - Insecticides based on botanical sources have taken on increased attention due to differing modes of action from current insecticides in use and the view that they may be environmentally friendly. Thymoquinone, a component in the essential oil of incense cedar heartwood, has been shown to have insecticidal action against adult mosquitoes. This study evaluated relative toxicities of thymoquinone, selected derivatives of thymoquinone, hydroquinone, and arbutin to determine if any had similar or better activity. The intrinsic toxicities of hydroquinone and thymohydroquinone were not significantly different from thymoquinone, while libocedrol and arbutin were significantly less toxic. PMID- 28031347 TI - Impact of Autocidal Gravid Ovitraps on Chikungunya Virus Incidence in Aedes aegypti (Diptera: Culicidae) in Areas With and Without Traps. AB - Puerto Rico detected the first confirmed case of chikungunya virus (CHIKV) in May 2014 and the virus rapidly spread throughout the island. The invasion of CHIKV allowed us to observe Aedes aegypti (L.) densities, infection rates, and impact of vector control in urban areas using CDC autocidal gravid ovitraps (AGO traps) for mosquito control over several years. Because local mosquitoes can only get the virus from infectious residents, detecting the presence of virus in mosquitoes functions as a proxy for the presence of virus in people. We monitored the incidence of CHIKV in gravid females of Ae. aegypti in four neighborhoods-two with three AGO traps per home in most homes and two nearby neighborhoods without AGO mosquito control traps. Monitoring of mosquito density took place weekly using sentinel AGO traps from June to December 2014. In all, 1,334 pools of female Ae. aegypti (23,329 individuals) were processed by real-time reverse transcription PCR to identify CHIKV and DENV RNA. Density of Ae. aegypti females was 10.5 times lower (91%) in the two areas with AGO control traps during the study. Ten times (90.9%) more CHIKV-positive pools were identified in the nonintervention areas (50/55 pools) than in intervention areas (5/55). We found a significant linear relationship between the number of positive pools and both density of Ae. aegypti and vector index (average number of expected infected mosquitoes per trap per week). Temporal and spatial patterns of positive CHIKV pools suggested limited virus circulation in areas with AGO traps. PMID- 28031348 TI - Isolation of the Male-Specific Transformer Exon as a Method for Immature Specimen Sex Identification in Chrysomya megacephala (Diptera: Calliphoridae). AB - Being able to efficiently differentiate between male and female individuals in the immature forms of insects allows for investigations into sexually dimorphic patterns of growth rates and gene expression. For species lacking sex-specific morphological characteristics during these periods, alternative methods must be devised. Commonly, isolation of sex determination genes reveals sex-specific band patterns and allows for markers that can be used in insect control. For blow flies, a family that includes flies of medical and forensic importance, sex has previously been identified in some members using the male-specific exon in the transformer gene. This gene is relatively conserved between members of the genera Cochliomyia and Lucilia (Diptera: Calliphoridae), and we isolated a portion of this gene in an additional forensically and medically important blow fly genus using the widespread Chrysomya megacephala (F.). We found a relatively high level of conservation between exons 1 and 2 of transformer and were able to amplify a region containing the male-specific exon in C. megacephala. A sex-specific molecular diagnostic test based on the presence of sexually dimorphic PCR product bands showed the expected genotype for adults and intrapuparial period specimens of known sex. The same result could be obtained from single third-instar larval specimens, opening up the possibility to not only determine if development rates are sex dependent, but also to investigate the development of sexually dimorphic traits of interest in C. megacephala. PMID- 28031349 TI - Modeling the Response of Anopheles gambiae (Diptera: Culicidae) Populations in the Kenya Highlands to a Rise in Mean Annual Temperature. AB - A dynamical model of Anopheles gambiae larval and adult populations is constructed that matches temperature-dependent maturation times and mortality measured experimentally as well as larval instar and adult mosquito emergence data from field studies in the Kenya Highlands. Spectral classification of high resolution satellite imagery is used to estimate household density. Indoor resting densities collected over a period of one year combined with predictions of the dynamical model give estimates of both aquatic habitat and total adult mosquito densities. Temperature and precipitation patterns are derived from monthly records. Precipitation patterns are compared with average and extreme habitat estimates to estimate available aquatic habitat in an annual cycle. These estimates are coupled with the original model to produce estimates of adult and larval populations dependent on changing aquatic carrying capacity for larvae and changing maturation and mortality dependent on temperature. This paper offers a general method for estimating the total area of aquatic habitat in a given region, based on larval counts, emergence rates, indoor resting density data, and number of households.Altering the average daily temperature and the average daily rainfall simulates the effect of climate change on annual cycles of prevalence of An. gambiae adults. We show that small increases in average annual temperature have a large impact on adult mosquito density, whether measured at model equilibrium values for a single square meter of habitat or tracked over the course of a year of varying habitat availability and temperature. PMID- 28031350 TI - A Molecular Survey for Francisella tularensis and Rickettsia spp. in Haemaphysalis leporispalustris (Acari: Ixodidae) in Northern California. AB - Francisella tularensis and Rickettsia spp. have been cultured from Haemaphysalis leporispalustris Packard, but their prevalence in this tick has not been determined using modern molecular methods. We collected H. leporispalustris by flagging vegetation and leaf litter and from lagomorphs (Lepus californicus Gray and Sylvilagus bachmani (Waterhouse)) in northern California. Francisella tularensis DNA was not detected in any of 1,030 ticks tested by polymerase chain reaction (PCR), whereas 0.4% of larvae tested in pools, 0 of 117 individual nymphs, and 2.3% of 164 adult ticks were PCR-positive for Rickettsia spp. Positive sites were Laurel Canyon Trail in Tilden Regional Park in Alameda Contra Costa County, with a Rickettsia spp. prevalence of 0.6% in 2009, and Hopland Research and Extension Center in Mendocino County, with a prevalence of 4.2% in 1988. DNA sequencing revealed R. felis, the agent of cat-flea typhus, in two larval pools from shaded California bay and live oak leaf litter in Contra Costa County and one adult tick from a L. californicus in chaparral in Mendocino County. The R. felis in unfed, questing larvae demonstrates that H. leporispalustris can transmit this rickettsia transovarially. Although R. felis is increasingly found in diverse arthropods and geographical regions, prior literature suggests a typical epidemiological cycle involving mesocarnivores and the cat flea, Ctenocephalides felis. To our knowledge, this is the first report of R. felis in H. leporispalustris. Natural infection and transovarial transmission of this pathogen in the tick indicate the existence of a previously undocumented wild-lands transmission cycle that may intersect mesocarnivore reservoired cycles and collectively affect human health risk. PMID- 28031351 TI - Evaluation of Gulf Coast Ticks (Acari: Ixodidae) for Ehrlichia and Anaplasma Species. AB - Amblyomma maculatum Koch (the Gulf Coast tick) is an aggressive, human-biting ixodid tick distributed throughout much of the southeastern United States and is the primary vector for Rickettsia parkeri, an emerging human pathogen. Amblyomma maculatum has diverse host preferences that include white-tailed deer, a known reservoir for Ehrlichia and Anaplasma species, including the human pathogens E. ewingii and E. chaffeensis. To examine more closely the potential role of A. maculatum in the maintenance of various pathogenic Ehrlichia and Anaplasma species, we screened DNA samples from 493 questing adult A. maculatum collected from six U.S. states using broad-range Anaplasmataceae and Ehrlichia genus specific PCR assays. Of the samples tested, four (0.8%) were positive for DNA of Ehrlichia ewingii, one (0.2%) was positive for Anaplasma platys, and one (0.2%) was positive for a previously unreported Ehrlichia species closely related to Ehrlichia muris and an uncultivated Ehrlichia species from Haemaphysalis longicornis ticks in Japan. No ticks contained DNA of Ehrlichia chaffeensis, Ehrlichia canis, the Panola Mountain Ehrlichia, or Anaplasma phagocytophilum. This is the first identification of E. ewingii, A. platys, and the novel Ehrlichia in questing Gulf Coast ticks; nonetheless the low prevalence of these agents suggests that A. maculatum is not likely an important vector of these zoonotic pathogens. PMID- 28031353 TI - Model-guided combinatorial optimization of complex synthetic gene networks. AB - Constructing gene circuits that satisfy quantitative performance criteria has been a long-standing challenge in synthetic biology. Here, we show a strategy for optimizing a complex three-gene circuit, a novel proportional miRNA biosensor, using predictive modeling to initiate a search in the phase space of sensor genetic composition. We generate a library of sensor circuits using diverse genetic building blocks in order to access favorable parameter combinations and uncover specific genetic compositions with greatly improved dynamic range. The combination of high-throughput screening data and the data obtained from detailed mechanistic interrogation of a small number of sensors was used to validate the model. The validated model facilitated further experimentation, including biosensor reprogramming and biosensor integration into larger networks, enabling in principle arbitrary logic with miRNA inputs using normal form circuits. The study reveals how model-guided generation of genetic diversity followed by screening and model validation can be successfully applied to optimize performance of complex gene networks without extensive prior knowledge. PMID- 28031354 TI - Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke. AB - BACKGROUND: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy. OBJECTIVE: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization. METHODS: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we performed a dose-response (3.12, 6.25, 12.5, and 25 ug/uL) analysis. Next, we looked at blood perfusion (flow) through the middle cerebral artery using laser Doppler flowmetry. Functional outcomes, including forced motor movement rotor rod, were assessed in the 3.12, 6.25, and 12.5 ug/uL groups. Histological analysis was performed using cresyl violet for infarct volume, and glial fibrillary activating protein (GFAP) and NeuN immunohistochemistry for astrocyte activation and mature neuron survival, respectively. RESULTS: Overall, we found that acute post-stroke IA GTN had little effect on vessel dilatation after 15 min. Functional analysis showed a significant difference between GTN (3.12 and 6.25 ug/uL) and control at post-stroke day 1. Histological measures showed a significant reduction in infarct volume and GFAP immunoreactivity and a significant increase in NeuN. CONCLUSIONS: These results demonstrate that acute IA GTN is neuroprotective in experimental ischemic stroke and warrants further study as a potentially new stroke therapy. PMID- 28031355 TI - Evaluation of tumor burden after sequential molecular-targeted therapy in patients with metastatic renal cell carcinoma. AB - Background: To evaluate the effect of tumor burden on survival in patients with metastatic renal cell carcinoma who are administered sequential molecular targeted therapy. Methods: A total of 68 patients were recruited. Baseline tumor burden at the time of second-line therapy initiation was calculated according to the Response Evaluation Criteria in Solid Tumors v. 1.1. Patients were divided into two subgroups according to the median tumor burden: greater than the median as the high group, lower than the median as the low group. Progression-free survival and overall survival after second-line therapy were analyzed. The effect of tumor burden changes on survival during sequential targeted therapy were also evaluated. Results: Median second-line tumor burden was 57.7 cm. The patients with high tumor burden had significantly poorer progression-free survival and overall survival, compared to those with low tumor burden (median progression free survival = 4.36 vs. 8.19 months, P = 0.0119; overall survival = 9.6 vs. 23.5 months, P = 0.0107). For progression-free survival, multivariate analyses revealed that second-line objective response was an independent predictor (P < 0.0001), but second-line tumor burden was not (P = 0.0826). For overall survival, second-line tumor burden and objective response were independent predictors (P = 0.0300 and <0.0001, respectively). Moreover, there was a positive correlation between first- and second-line tumor burden (r2 = 0.460, P < 0.0001), although tumor burden changes between first- and second-line therapies did not affect survival (median progression-free survival, P = 0.812; overall survival, P = 0.415). Conclusions: Second-line tumor burden was an independent predictor of overall survival among patients with metastatic renal cell carcinoma after second line therapy. PMID- 28031356 TI - Elective nodal irradiation is not necessary in chemoradiotherapy for postoperative loco-regional recurrent esophageal cancer. AB - Purpose: The purposes of the present study were to evaluate prognostic factors for patients with postoperative loco-regional recurrent esophageal cancer treated with chemoradiotherapy by multivariate analysis and to determine which irradiation is better, involved field irradiation or elective nodal irradiation, by matched-pair analysis. Methods: We reviewed records for 80 patients with postoperative loco-regional recurrent esophageal cancer treated by chemoradiotherapy between 2000 and 2014. The median follow-up period was 62.0 months. Thirty-one cases were treated with elective nodal irradiation and were randomly matched by risk factors to 49 cases treated with involved field irradiation (1:1). Results: Fifty-one patients had disease recurrence again, and irradiated-field failure was observed in 26 patients. The 5-year overall survival rate was 30.5% with a median survival period of 26.5 months. Grade 3 or higher late toxicity was observed in only one patient. In multivariate analysis, short disease-free interval and anastomotic recurrence were statistically significant unfavorable prognostic factors for overall survival (hazard ratios: 2.1 and 2.5, respectively). Matched-pair analysis including disease-free interval, pattern of recurrence and number of recurrent regions revealed that overall survival rate and irradiated-field control rate in patients treated with involved field irradiation were significantly better than those in patients treated with elective nodal irradiation (P = 0.016 and P = 0.014, respectively). Conclusions: Short disease-free interval and anastomotic recurrence are unfavorable factors and elective nodal irradiation is not necessary in chemoradiotherapy for patients with postoperative loco-regional recurrent esophageal cancer. PMID- 28031357 TI - Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population. PMID- 28031352 TI - Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance. AB - Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP -> PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species. PMID- 28031358 TI - Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication. AB - Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication.IMPORTANCE HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification of infection. The recruitment of specific cellular protein complexes to these factories aids efficient and controlled viral replication. We have identified a novel HPV-host interaction that functions in the cellular response to DNA damage and cell cycle control. We show that the HPV E2 protein targets Rad50-interacting protein 1 (Rint1) to facilitate virus genome replication. These findings add to our understanding of how HPV replicates and the host cell pathways that are targeted by HPV to support virus replication. Understanding these pathways will allow further research into novel inhibitors of HPV genome replication. PMID- 28031359 TI - Zika Virus Methyltransferase: Structure and Functions for Drug Design Perspectives. AB - The Flavivirus Zika virus (ZIKV) is the causal agent of neurological disorders like microcephaly in newborns or Guillain-Barre syndrome. Its NS5 protein embeds a methyltransferase (MTase) domain involved in the formation of the viral mRNA cap. We investigated the structural and functional properties of the ZIKV MTase. We show that the ZIKV MTase can methylate RNA cap structures at the N-7 position of the cap, and at the 2'-O position on the ribose of the first nucleotide, yielding a cap-1 structure. In addition, the ZIKV MTase methylates the ribose 2' O position of internal adenosines of RNA substrates. The crystal structure of the ZIKV MTase determined at a 2.01-A resolution reveals a crystallographic homodimer. One chain is bound to the methyl donor (S-adenosyl-l-methionine [SAM]) and shows a high structural similarity to the dengue virus (DENV) MTase. The second chain lacks SAM and displays conformational changes in the alphaX alpha helix contributing to the SAM and RNA binding. These conformational modifications reveal a possible molecular mechanism of the enzymatic turnover involving a conserved Ser/Arg motif. In the second chain, the SAM binding site accommodates a sulfate close to a glycerol that could serve as a basis for structure-based drug design. In addition, compounds known to inhibit the DENV MTase show similar inhibition potency on the ZIKV MTase. Altogether these results contribute to a better understanding of the ZIKV MTase, a central player in viral replication and host innate immune response, and lay the basis for the development of potential antiviral drugs.IMPORTANCE The Zika virus (ZIKV) is associated with microcephaly in newborns, and other neurological disorders such as Guillain-Barre syndrome. It is urgent to develop antiviral strategies inhibiting the viral replication. The ZIKV NS5 embeds a methyltransferase involved in the viral mRNA capping process, which is essential for viral replication and control of virus detection by innate immune mechanisms. We demonstrate that the ZIKV methyltransferase methylates the mRNA cap and adenosines located in RNA sequences. The structure of ZIKV methyltransferase shows high structural similarities to the dengue virus methyltransferase, but conformational specificities highlight the role of a conserved Ser/Arg motif, which participates in RNA and SAM recognition during the reaction turnover. In addition, the SAM binding site accommodates a sulfate and a glycerol, offering structural information to initiate structure-based drug design. Altogether, these results contribute to a better understanding of the Flavivirus methyltransferases, which are central players in the virus replication. PMID- 28031360 TI - Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-kappaB Activation in DNA Sensing Signal Pathway. AB - The DNA sensing pathway triggers innate immune responses against DNA virus infection, and NF-kappaB signaling plays a critical role in establishing innate immunity. We report here that the herpes simplex virus 1 (HSV-1) ubiquitin specific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes NF kappaB activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of beta interferon (IFN-beta) and NF-kappaB induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). UL36USP restricted NF-kappaB activation mediated by overexpression of STING, TANK-binding kinase 1, IkappaB kinase alpha (IKKalpha), and IKKbeta, but not p65. UL36USP was also shown to inhibit IFN-stimulatory DNA-induced IFN beta and NF-kappaB activation under conditions of HSV-1 infection. Furthermore, UL36USP was demonstrated to deubiquitinate IkappaBalpha and restrict its degradation and, finally, abrogate NF-kappaB activation. More importantly, the recombinant HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed to cleave polyubiquitin chains on IkappaBalpha. For the first time, UL36USP was shown to dampen NF-kappaB activation in the DNA sensing signal pathway to evade host antiviral innate immunity.IMPORTANCE It has been reported that double-stranded-DNA-mediated NF-kappaB activation is critical for host antiviral responses. Viruses have established various strategies to evade the innate immune system. The N terminus of the HSV-1 UL36 gene-encoded protein contains the DUB domain and is conserved across all herpesviruses. This study demonstrates that UL36USP abrogates NF-kappaB activation by cleaving polyubiquitin chains from IkappaBalpha and therefore restricts proteasome dependent degradation of IkappaBalpha and that DUB activity is indispensable for this process. This study expands our understanding of the mechanisms utilized by HSV-1 to evade the host antiviral innate immune defense induced by NF-kappaB signaling. PMID- 28031361 TI - Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses. AB - Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMV seronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C+ NK cells, CD16+ Vdelta2(-) gammadelta T cells, and conventional HCMV-specific CD8+ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains. PMID- 28031362 TI - Interaction of the Small GTPase Cdc42 with Arginine Kinase Restricts White Spot Syndrome Virus in Shrimp. AB - Many types of small GTPases are widely expressed in eukaryotes and have different functions. As a crucial member of the Rho GTPase family, Cdc42 serves a number of functions, such as regulating cell growth, migration, and cell movement. Several RNA viruses employ Cdc42-hijacking tactics in their target cell entry processes. However, the function of Cdc42 in shrimp antiviral immunity is not clear. In this study, we identified a Cdc42 protein in the kuruma shrimp (Marsupenaeus japonicus) and named it MjCdc42. MjCdc42 was upregulated in shrimp challenged by white spot syndrome virus (WSSV). The knockdown of MjCdc42 and injection of Cdc42 inhibitors increased the proliferation of WSSV. Further experiments determined that MjCdc42 interacted with an arginine kinase (MjAK). By analyzing the binding activity and enzyme activity of MjAK and its mutant, DeltaMjAK, we found that MjAK could enhance the replication of WSSV in shrimp. MjAK interacted with the envelope protein VP26 of WSSV. An inhibitor of AK activity, quercetin, could impair the function of MjAK in WSSV replication. Further study demonstrated that the binding of MjCdc42 and MjAK depends on Cys271 of MjAK and suppresses the WSSV replication-promoting effect of MjAK. By interacting with the active site of MjAK and suppressing its enzyme activity, MjCdc42 inhibits WSSV replication in shrimp. Our results demonstrate a new function of Cdc42 in the cellular defense against viral infection in addition to the regulation of actin and phagocytosis, which has been reported in previous studies. IMPORTANCE The interaction of Cdc42 with arginine kinase plays a crucial role in the host defense against WSSV infection. This study identifies a new mechanism of Cdc42 in innate immunity and enriches the knowledge of the antiviral innate immunity of invertebrates. PMID- 28031363 TI - Unraveling the Armor of a Killer: Evasion of Host Defenses by African Swine Fever Virus. AB - African swine fever is an acute hemorrhagic disease of pigs. Extensive recent spread in the Russian Federation and Eastern Europe has increased the risk to global pig production. The virus is a large DNA virus and is the only member of the Asfarviridae family. In pigs, the virus replicates predominantly in macrophages. We review how the virus overcomes the barriers to replication in the macrophage and the virus mechanism to inhibit key host defense pathways. PMID- 28031364 TI - An Optimized Hepatitis C Virus E2 Glycoprotein Core Adopts a Functional Homodimer That Efficiently Blocks Virus Entry. AB - The hepatitis C virus (HCV) envelope glycoprotein E2 is the major target of broadly neutralizing antibodies in vivo and is the focus of efforts in the rational design of a universal B cell vaccine against HCV. The E2 glycoprotein exhibits a high degree of amino acid variability which localizes to three discrete regions: hypervariable region 1 (HVR1), hypervariable region 2 (HVR2), and the intergenotypic variable region (igVR). All three variable regions contribute to immune evasion and/or isolate-specific structural variations, both important considerations for vaccine design. A high-resolution structural definition of the intact HCV envelope glycoprotein complex containing E1 and E2 remains to be elucidated, while crystallographic structures of a recombinant E2 ectodomain failed to resolve HVR1, HVR2, and a major neutralization determinant adjacent to HVR1. To obtain further information on E2, we characterized the role of all three variable regions in E2 ectodomain folding and function in the context of a recombinant ectodomain fragment (rE2). We report that removal of the variable regions accelerates binding to the major host cell receptor CD81 and that simultaneous deletion of HVR2 and the igVR is required to maintain wild-type CD81-binding characteristics. The removal of the variable regions also rescued the ability of rE2 to form a functional homodimer. We propose that the rE2 core provides novel insights into the role of the variable motifs in the higher-order assembly of the E2 ectodomain and may have implications for E1E2 structure on the virion surface. IMPORTANCE Hepatitis C virus (HCV) infection affects ~2% of the population globally, and no vaccine is available. HCV is a highly variable virus, and understanding the presentation of key antigenic sites at the virion surface is important for the design of a universal vaccine. This study investigates the role of three surface-exposed variable regions in E2 glycoprotein folding and function in the context of a recombinant soluble ectodomain. Our data demonstrate the variable motifs modulate binding of the E2 ectodomain to the major host cell receptor CD81 and have an impact on the formation of an E2 homodimer with high affinity binding to CD81. PMID- 28031365 TI - Autographa californica Multiple Nucleopolyhedrovirus AC83 is a Per Os Infectivity Factor (PIF) Protein Required for Occlusion-Derived Virus (ODV) and Budded Virus Nucleocapsid Assembly as well as Assembly of the PIF Complex in ODV Envelopes. AB - Baculovirus occlusion-derived virus (ODV) initiates infection of lepidopteran larval hosts by binding to the midgut epithelia, which is mediated by per os infectivity factors (PIFs). Autographa californica multiple nucleopolyhedrovirus (AcMNPV) encodes seven PIF proteins, of which PIF1 to PIF4 form a core complex in ODV envelopes to which PIF0 and PIF6 loosely associate. Deletion of any pif gene results in ODV being unable to bind or enter midgut cells. AC83 also associates with the PIF complex, and this study further analyzed its role in oral infectivity to determine if it is a PIF protein. It had been proposed that AC83 possesses a chitin binding domain that enables transit through the peritrophic matrix; however, no chitin binding activity has ever been demonstrated. AC83 has been reported to be found only in the ODV envelopes, but in contrast, the Orgyia pseudotsugata MNPV AC83 homolog is associated with both ODV nucleocapsids and envelopes. In addition, unlike known pif genes, deletion of ac83 eliminates nucleocapsid formation. We propose a new model for AC83 function and show AC83 is associated with both ODV nucleocapsids and envelopes. We also further define the domain required for nucleocapsid assembly. The cysteine-rich region of AC83 is also shown not to be a chitin binding domain but a zinc finger domain required for the recruitment or assembly of the PIF complex to ODV envelopes. As such, AC83 has all the properties of a PIF protein and should be considered PIF8. In addition, pif7 (ac110) is reported as the 38th baculovirus core gene.IMPORTANCE ODV is essential for the per os infectivity of the baculovirus AcMNPV. To initiate infection, ODV binds to microvilli of lepidopteran midgut cells, a process which requires a group of seven virion envelope proteins called PIFs. In this study, we reexamined the function of AC83, a protein that copurifies with the ODV PIFs, to determine its role in the oral infection process. A zinc finger domain was identified and a new model for AC83 function was proposed. In contrast to previous studies, AC83 was found to be physically located in both the envelope and nucleocapsid of ODV. By deletion analysis, the AC83 domain required for nucleocapsid assembly was more finely delineated. We show that AC83 is required for PIF complex formation and conclude that it is a true per os infectivity factor and should be called PIF8. PMID- 28031366 TI - The Autographa californica Multiple Nucleopolyhedrovirus ac83 Gene Contains a cis Acting Element That Is Essential for Nucleocapsid Assembly. AB - Baculoviridae is a family of insect-specific viruses that have a circular double stranded DNA genome packaged within a rod-shaped capsid. The mechanism of baculovirus nucleocapsid assembly remains unclear. Previous studies have shown that deletion of the ac83 gene of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) blocks viral nucleocapsid assembly. Interestingly, the ac83-encoded protein Ac83 is not a component of the nucleocapsid, implying a particular role for ac83 in nucleocapsid assembly that may be independent of its protein product. To examine this possibility, Ac83 synthesis was disrupted by insertion of a chloramphenicol resistance gene into its coding sequence or by deleting its promoter and translation start codon. Both mutants produced progeny viruses normally, indicating that the Ac83 protein is not required for nucleocapsid assembly. Subsequently, complementation assays showed that the production of progeny viruses required the presence of ac83 in the AcMNPV genome instead of its presence in trans Therefore, we reasoned that ac83 is involved in nucleocapsid assembly via an internal cis-acting element, which we named the nucleocapsid assembly-essential element (NAE). The NAE was identified to lie within nucleotides 1651 to 1850 of ac83 and had 8 conserved A/T-rich regions. Sequences homologous to the NAE were found only in alphabaculoviruses and have a conserved positional relationship with another essential cis-acting element that was recently identified. The identification of the NAE may help to connect the data of viral cis-acting elements and related proteins in the baculovirus nucleocapsid assembly, which is important for elucidating DNA-protein interaction events during this process.IMPORTANCE Virus nucleocapsid assembly usually requires specific cis-acting elements in the viral genome for various processes, such as the selection of the viral genome from the cellular nucleic acids, the cleavage of concatemeric viral genome replication intermediates, and the encapsidation of the viral genome into procapsids. In linear DNA viruses, such elements generally locate at the ends of the viral genome; however, most of these elements remain unidentified in circular DNA viruses (including baculovirus) due to their circular genomic conformation. Here, we identified a nucleocapsid assembly-essential element in the AcMNPV (the archetype of baculovirus) genome. This finding provides an important reference for studies of nucleocapsid assembly related elements in baculoviruses and other circular DNA viruses. Moreover, as most of the previous studies of baculovirus nucleocapsid assembly have been focused on viral proteins, our study provides a novel entry point to investigate this mechanism via cis-acting elements in the viral genome. PMID- 28031367 TI - Barriers to Infection of Human Cells by Feline Leukemia Virus: Insights into Resistance to Zoonosis. AB - The human genome displays a rich fossil record of past gammaretrovirus infections, yet no current epidemic is evident, despite environmental exposure to viruses that infect human cells in vitro Feline leukemia viruses (FeLVs) rank high on this list, but neither domestic nor workplace exposure has been associated with detectable serological responses. Nonspecific inactivation of gammaretroviruses by serum factors appears insufficient to explain these observations. To investigate further, we explored the susceptibilities of primary and established human cell lines to FeLV-B, the most likely zoonotic variant. Fully permissive infection was common in cancer-derived cell lines but was also a feature of nontransformed keratinocytes and lung fibroblasts. Cells of hematopoietic origin were generally less permissive and formed discrete groups on the basis of high or low intracellular protein expression and virion release. Potent repression was observed in primary human blood mononuclear cells and a subset of leukemia cell lines. However, the early steps of reverse transcription and integration appear to be unimpaired in nonpermissive cells. FeLV-B was subject to G->A hypermutation with a predominant APOBEC3G signature in partially permissive cells but was not mutated in permissive cells or in nonpermissive cells that block secondary viral spread. Distinct cellular barriers that protect primary human blood cells are likely to be important in protection against zoonotic infection with FeLV.IMPORTANCE Domestic exposure to gammaretroviruses such as feline leukemia viruses (FeLVs) occurs worldwide, but the basis of human resistance to infection remains incompletely understood. The potential threat is evident from the human genome sequence, which reveals many past epidemics of gammaretrovirus infection, and from recent cross-species jumps of gammaretroviruses from rodents to primates and marsupials. This study examined resistance to infection at the cellular level with the most prevalent human cell tropic FeLV variant, FeLV-B. We found that blood cells are uniquely resistant to infection with FeLV-B due to the activity of cellular enzymes that mutate the viral genome. A second block, which appears to suppress viral gene expression after the viral genome has integrated into the host cell genome, was identified. Since cells derived from other normal human cell types are fully supportive of FeLV replication, innate resistance of blood cells could be critical in protecting against cross-species infection. PMID- 28031368 TI - The Structural Interface between HIV-1 Vif and Human APOBEC3H. AB - Human APOBEC3H (A3H) is a cytidine deaminase that inhibits HIV-1 replication. To evade this restriction, the HIV-1 Vif protein binds A3H and mediates its proteasomal degradation. To date, little information on the Vif-A3H interface has been available. To decipher how both proteins interact, we first mapped the Vif binding site on A3H by functionally testing a large set of A3H mutants in single cycle infectivity and replication assays. Our data show that the two A3H alpha helixes alpha3 and alpha4 represent the Vif-binding site of A3H. We next used viral adaptation and a set of Vif mutants to identify novel, reciprocal Vif variants that rescued viral infectivity in the presence of two Vif-resistant A3H mutants. These A3H-Vif interaction points were used to generate the first A3H-Vif structure model, which revealed that the A3H helixes alpha3 and alpha4 interact with the Vif beta-sheet (beta2-beta5). This model is in good agreement with previously reported Vif and A3H amino acids important for interaction. Based on the predicted A3H-Vif interface, we tested additional points of contact, which validated our model. Moreover, these experiments showed that the A3H and A3G binding sites on HIV-1 Vif are largely distinct, with both host proteins interacting with Vif beta-strand 2. Taken together, this virus-host interface model explains previously reported data and will help to identify novel drug targets to combat HIV-1 infection.IMPORTANCE HIV-1 needs to overcome several intracellular restriction factors in order to replicate efficiently. The human APOBEC3 locus encodes seven proteins, of which A3D, A3F, A3G, and A3H restrict HIV-1. HIV encodes the Vif protein, which binds to the APOBEC3 proteins and leads to their proteasomal degradation. No HIV-1 Vif-APOBEC3 costructure exists to date despite extensive research. We and others previously generated HIV-1 Vif costructure models with A3G and A3F by mapping specific contact points between both proteins. Here, we applied a similar approach to HIV-1 Vif and A3H and successfully generated a Vif-A3H interaction model. Importantly, we find that the HIV-1 Vif-A3H interface is distinct from the Vif-A3G and Vif-A3F interfaces, with a small Vif region being important for recognition of both A3G and A3H. Our Vif A3H structure model informs on how both proteins interact and could guide toward approaches to block the Vif-A3H interface to target HIV replication. PMID- 28031369 TI - Mapping the Human Memory B Cell and Serum Neutralizing Antibody Responses to Dengue Virus Serotype 4 Infection and Vaccination. AB - The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses responsible for dengue fever and dengue hemorrhagic fever. People exposed to DENV develop antibodies (Abs) that strongly neutralize the serotype responsible for infection. Historically, infection with DENV serotype 4 (DENV4) has been less common and less studied than infections with the other three serotypes. However, DENV4 has been responsible for recent large and sustained epidemics in Asia and Latin America. The neutralizing antibody responses and the epitopes targeted against DENV4 have not been characterized in human infection. In this study, we mapped and characterized epitopes on DENV4 recognized by neutralizing antibodies in people previously exposed to DENV4 infections or to a live attenuated DENV4 vaccine. To study the fine specificity of DENV4 neutralizing human antibodies, B cells from two people exposed to DENV4 were immortalized and screened to identify DENV-specific clones. Two human monoclonal antibodies (MAbs) that neutralized DENV4 were isolated, and their epitopes were finely mapped using recombinant viruses and alanine scan mutation array techniques. Both antibodies bound to quaternary structure epitopes near the hinge region between envelope protein domain I (EDI) and EDII. In parallel, to characterize the serum neutralizing antibody responses, convalescence-phase serum samples from people previously exposed to primary DENV4 natural infections or a monovalent DENV4 vaccine were analyzed. Natural infection and vaccination also induced serum-neutralizing antibodies that targeted similar epitope domains at the EDI/II hinge region. These studies defined a target of neutralizing antigenic site on DENV4 targeted by human antibodies following natural infection or vaccination.IMPORTANCE The four serotypes of dengue virus are the causative agents of dengue fever and dengue hemorrhagic fever. People exposed to primary DENV infections develop long term neutralizing antibody responses, but these principally recognize only the infecting serotype. An effective vaccine against dengue should elicit long lasting protective antibody responses to all four serotypes simultaneously. We and others have defined antigenic sites on the envelope (E) protein of viruses of dengue virus serotypes 1, 2, and 3 targeted by human neutralizing antibodies. The epitopes on DENV4 E protein targeted by the human neutralizing antibodies and the mechanisms of serotype 4 neutralization are poorly understood. Here, we report the properties of human antibodies that neutralize dengue virus serotype 4. People exposed to serotype 4 infections or a live attenuated serotype 4 vaccine developed neutralizing antibodies that bound to similar sites on the viral E protein. These studies have provided a foundation for developing and evaluating DENV4 vaccines. PMID- 28031370 TI - Binding of the Methyl Donor S-Adenosyl-l-Methionine to Middle East Respiratory Syndrome Coronavirus 2'-O-Methyltransferase nsp16 Promotes Recruitment of the Allosteric Activator nsp10. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) nonstructural protein 16 (nsp16) is an S-adenosyl-l-methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that is thought to methylate the ribose 2'-OH of the first transcribed nucleotide (N1) of viral RNA cap structures. This 2'-O-MTase activity is regulated by nsp10. The 2'-O methylation prevents virus detection by cell innate immunity mechanisms and viral translation inhibition by the interferon stimulated IFIT-1 protein. To unravel the regulation of nsp10/nsp16 2'-O-MTase activity, we used purified MERS-CoV nsp16 and nsp10. First, we showed that nsp16 recruited N7-methylated capped RNA and SAM. The SAM binding promotes the assembly of the enzymatically active nsp10/nsp16 complex that converted 7mGpppG (cap-0) into 7mGpppG2'Om (cap-1) RNA by 2'-OH methylation of N1 in a SAM-dependent manner. The subsequent release of SAH speeds up nsp10/nsp16 dissociation that stimulates the reaction turnover. Alanine mutagenesis and RNA binding assays allowed the identification of the nsp16 residues involved in RNA recognition forming the RNA binding groove (K46, K170, E203, D133, R38, Y47, and Y181) and the cap-0 binding site (Y30, Y132, and H174). Finally, we found that nsp10/nsp16 2'-O-MTase activity is sensitive to known MTase inhibitors, such as sinefungin and cap analogues. This characterization of the MERS-CoV 2'-O-MTase is a preliminary step toward the development of molecules to inhibit cap 2'-O methylation and to restore the host antiviral response. IMPORTANCE MERS-CoV codes for a cap 2'-O-methyltransferase that converts cap-0 into cap-1 structure in order to prevent virus detection by cell innate immunity mechanisms. We report the biochemical properties of MERS-CoV 2'O-methyltransferase, which is stimulated by nsp10 acting as an allosteric activator of the nsp16 2'-O-methyltransferase possibly through enhanced RNA binding affinity. In addition, we show that SAM promotes the formation of the active nsp10/nsp16 complex. Conversely, after cap methylation, the reaction turnover is speeded up by cap-1 RNA release and nsp10/nsp16 complex dissociation, at the low intracellular SAH concentration. These results suggest that SAM/SAH balance is a regulator of the 2'-O methyltransferase activity and raises the possibility that SAH hydrolase inhibitors might interfere with CoV replication cycle. The enzymatic and RNA binding assays developed in this work were also used to identify nsp16 residues involved in cap-0 RNA recognition and to understand the action mode of known methyltransferase inhibitors. PMID- 28031371 TI - Screening for Novel Small-Molecule Inhibitors Targeting the Assembly of Influenza Virus Polymerase Complex by a Bimolecular Luminescence Complementation-Based Reporter System. AB - Influenza virus RNA-dependent RNA polymerase consists of three viral protein subunits: PA, PB1, and PB2. Protein-protein interactions (PPIs) of these subunits play pivotal roles in assembling the functional polymerase complex, which is essential for the replication and transcription of influenza virus RNA. Here we developed a highly specific and robust bimolecular luminescence complementation (BiLC) reporter system to facilitate the investigation of influenza virus polymerase complex formation. Furthermore, by combining computational modeling and the BiLC reporter assay, we identified several novel small-molecule compounds that selectively inhibited PB1-PB2 interaction. Function of one such lead compound was confirmed by its activity in suppressing influenza virus replication. In addition, our studies also revealed that PA plays a critical role in enhancing interactions between PB1 and PB2, which could be important in targeting sites for anti-influenza intervention. Collectively, these findings not only aid the development of novel inhibitors targeting the formation of influenza virus polymerase complex but also present a new tool to investigate the exquisite mechanism of PPIs. IMPORTANCE Formation of the functional influenza virus polymerase involves complex protein-protein interactions (PPIs) of PA, PB1, and PB2 subunits. In this work, we developed a novel BiLC assay system which is sensitive and specific to quantify both strong and weak PPIs between influenza virus polymerase subunits. More importantly, by combining in silico modeling and our BiLC assay, we identified a small molecule that can suppress influenza virus replication by disrupting the polymerase assembly. Thus, we developed an innovative method to investigate PPIs of multisubunit complexes effectively and to identify new molecules inhibiting influenza virus polymerase assembly. PMID- 28031372 TI - High-throughput identification of C/D box snoRNA targets with CLIP and RiboMeth seq. AB - High-throughput sequencing has greatly facilitated the discovery of long and short non-coding RNAs (ncRNAs), which frequently guide ribonucleoprotein complexes to RNA targets, to modulate their metabolism and expression. However, for many ncRNAs, the targets remain to be discovered. In this study, we developed computational methods to map C/D box snoRNA target sites using data from core small nucleolar ribonucleoprotein crosslinking and immunoprecipitation and from transcriptome-wide mapping of 2?-O-ribose methylation sites. We thereby assigned the snoRNA guide to a known methylation site in the 18S rRNA, we uncovered a novel partially methylated site in the 28S ribosomal RNA, and we captured a site in the 28S rRNA in interaction with multiple snoRNAs. Although we also captured mRNAs in interaction with snoRNAs, we did not detect 2?-O-methylation of these targets. Our study provides an integrated approach to the comprehensive characterization of 2?-O-methylation targets of snoRNAs in species beyond those in which these interactions have been traditionally studied and contributes to the rapidly developing field of 'epitranscriptomics'. PMID- 28031373 TI - The replication initiator of the cholera pathogen's second chromosome shows structural similarity to plasmid initiators. AB - The conserved DnaA-oriC system is used to initiate replication of primary chromosomes throughout the bacterial kingdom; however, bacteria with multipartite genomes evolved distinct systems to initiate replication of secondary chromosomes. In the cholera pathogen, Vibrio cholerae, and in related species, secondary chromosome replication requires the RctB initiator protein. Here, we show that RctB consists of four domains. The structure of its central two domains resembles that of several plasmid replication initiators. RctB contains at least three DNA binding winged-helix-turn-helix motifs, and mutations within any of these severely compromise biological activity. In the structure, RctB adopts a head-to-head dimeric configuration that likely reflects the arrangement in solution. Therefore, major structural reorganization likely accompanies complex formation on the head-to-tail array of binding sites in oriCII. Our findings support the hypothesis that the second Vibrionaceae chromosome arose from an ancestral plasmid, and that RctB may have evolved additional regulatory features. PMID- 28031374 TI - Large-Scale Behavior-Change Initiative for Infant and Young Child Feeding Advanced Language and Motor Development in a Cluster-Randomized Program Evaluation in Bangladesh. AB - BACKGROUND: Promoting adequate nutrition through interventions to improve infant and young child feeding (IYCF) has the potential to contribute to child development. OBJECTIVE: We examined whether an intensive intervention package that was aimed at improving IYCF at scale through the Alive & Thrive initiative in Bangladesh also advanced language and gross motor development, and whether advancements in language and gross motor development were explained through improved complementary feeding. METHODS: A cluster-randomized design compared 2 intervention packages: intensive interpersonal counseling on IYCF, mass media campaign, and community mobilization (intensive) compared with usual nutrition counseling and mass media campaign (nonintensive). Twenty subdistricts were randomly assigned to receive either the intensive or the nonintensive intervention. Household surveys were conducted at baseline (2010) and at endline (2014) in the same communities (n = ~4000 children aged 0-47.9 mo for each round). Child development was measured by asking mothers if their child had reached each of multiple milestones, with some observed. Linear regression accounting for clustering was used to derive difference-in-differences (DID) impact estimates, and path analysis was used to examine developmental advancement through indicators of improved IYCF and other factors. RESULTS: The DID in language development between intensive and nonintensive groups was 1.05 milestones (P = 0.001) among children aged 6-23.9 mo and 0.76 milestones (P = 0.038) among children aged 24-47.9 mo. For gross motor development, the DID was 0.85 milestones (P = 0.035) among children aged 6-23.9 mo. The differences observed corresponded to age- and sex-adjusted effect sizes of 0.35 for language and 0.23 for gross motor development. Developmental advancement at 6-23.9 mo was partially explained through improved minimum dietary diversity and the consumption of iron-rich food. CONCLUSIONS: Intensive IYCF intervention differentially advanced language and gross motor development, which was partially explained through improved complementary feeding. Measuring a diverse set of child outcomes, including functional outcomes such as child development, is important when evaluating integrated nutrition programs. This trial was registered at clinicaltrials.gov as NCT01678716. PMID- 28031376 TI - Vitamin B-6 Status in Unsupplemented Pregnant Women Is Associated Positively with Serum Docosahexaenoic Acid and Inversely with the n-6-to-n-3 Fatty Acid Ratio. AB - BACKGROUND: Vitamin B-6-deficient diets decrease plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) concentrations in healthy adults. These fatty acids (FAs) are important for fetal neurodevelopment, but the relation between vitamin B-6 status and circulating polyunsaturated FAs (PUFAs) during pregnancy is unknown. OBJECTIVE: We sought to assess the relation between plasma pyridoxal 5' phosphate (PLP; the active form of vitamin B-6) and serum DHA, EPA, AA, linoleic acid, eicosadienoic, and alpha-linolenic acid concentrations during pregnancy. METHODS: A prospective cohort study in 186 healthy pregnant Brazilian women (aged 20-40 y) who were not using supplements was conducted in Rio de Janeiro, Brazil. Participants were enrolled in the first trimester of pregnancy (5-13 gestational weeks) and were followed up twice between 20-26 and 30-36 wk of gestation. Longitudinal linear mixed-effects regression models were used to evaluate the associations between 1) first trimester PLP and PUFA concentrations across pregnancy and 2) DeltaPLP (i.e., difference between third- and first-trimester plasma PLP concentrations) and PUFA concentrations across pregnancy. Models were adjusted for gestational week, first trimester body mass index, smoking habit, and dietary intakes of vitamin B-6, fish, total fat, and PUFAs. RESULTS: Plasma PLP concentrations (median, IQR) substantially declined during pregnancy from 35.8 nmol/L (28.6-44.3 nmol/L) in the first trimester to 21.0 nmol/L (15.8-26.3 nmol/L) in the second trimester, and 16.8 nmol/L (12.9-20.3 nmol/L) in the third trimester (both P < 0.0001). Changes in plasma PLP concentrations across trimesters were positively associated with serum DHA concentrations (beta = 0.252, P = 0.012) and inversely associated with serum n-6-to-n-3 (omega-6-to-omega-3) FA ratio (beta = -0.010; P = 0.015), after adjustments for confounders. CONCLUSIONS: Maternal vitamin B-6 status during pregnancy was positively associated with the circulating concentration of DHA and inversely associated with n-6:n-3 FAs in Brazilian women who were not taking vitamin supplements. Further study is required to determine the impact of poor vitamin B-6 status on fetal neurodevelopment. PMID- 28031375 TI - Urinary Phytoestrogen Concentrations Are Not Associated with Incident Endometriosis in Premenopausal Women. AB - BACKGROUND: Phytoestrogens have been associated with subtle hormonal changes, but their effects on endometriosis are largely unknown. OBJECTIVE: We assessed the association between urinary concentrations of phytoestrogens and incident endometriosis. METHODS: We included an operative sample of 495 premenopausal women aged 18-44 y undergoing laparoscopies and laparotomies at 14 clinical sites between 2007 and 2009 and a general population sample of 131 women from the same geographic area who were matched on age and menstruation status. Endometriosis in the surgical sample was assessed by surgical visualization (clinical gold standard), whereas disease in the general population sample was assessed with the use of a pelvic MRI. Urine concentrations of genistein, daidzen, O desmethylangolensin, equol, enterodiol, and enterolactone were measured at baseline. Poisson regression with robust error variance was used to estimate the risk of an endometriosis diagnosis for each sample after adjusting for age and body mass index (in kg/m2). Separate models were run for each phytoestrogen. RESULTS: Overall geometric mean urine concentrations of phytoestrogens were as follows: genistein [88 nmol/L (95% CI: 72, 108 nmol/L)], daidzein [194 nmol/L (95% CI: 160, 236 nmol/L)], O-desmethylangolensin [4 nmol/L (95% CI: 3, 6 nmol/L)], equol [4 nmol/L (95% CI: 4, 6 nmol/L)], enterodiol [29 nmol/L (95% CI: 22, 38 nmol/L)], and enterolactone [355 nmol/L (95% CI: 395, 544 nmol/L)]. Geometric mean concentrations of phytoestrogens did not significantly differ by endometriosis status in either sample. Adjusted RRs for endometriosis ranged from 0.87 to 1.09 for the 6 phytoestrogens measured, with all CIs including a value >=1. Phytoestrogens were not associated with the severity of endometriosis when restricting the analysis to women with moderate-to-severe disease per the revised American Society for Reproductive Medicine criteria. Furthermore, no associations were observed between self-reported high soy intake and endometriosis. CONCLUSIONS: Despite endometriosis being an estrogen-dependent disease, we found no evidence that urinary phytoestrogens were associated with a higher risk of an endometriosis diagnosis in either a sample of premenopausal women or in a surgical sample. PMID- 28031377 TI - Urine Cotinine Screening Detects Nearly Ubiquitous Tobacco Smoke Exposure in Urban Adolescents. AB - Introduction: Routine biochemical assessment of tobacco smoke exposure could lead to more effective interventions to reduce or prevent secondhand smoke (SHS) related disease in adolescents. Our aim was to determine using urine cotinine (major nicotine metabolite) measurement the prevalence of tobacco smoke exposure among adolescents receiving outpatient care at an urban public hospital. Methods: Surplus urine was collected in 466 adolescents attending pediatric or urgent care clinics at Zuckerberg San Francisco General Hospital, serving families with lower levels of income and education, in 2013-2014. The majority were Hispanic or African American. Urine cotinine cut points of 0.05 to 0.25 ng/ml, 0.25 to 30 ng/ml, and 30 ng/ml were used to classify subjects as light SHS or thirdhand smoke exposed, SHS or light/intermittent active users, and active tobacco users, respectively. Results: Among subjects 87% were exposed, including 12% active smoking, 46% SHS and 30% lightly exposed. The SHS exposed group adjusted geometric mean cotinine values were significantly higher in African Americans (1.48 ng/ml) compared to other groups (0.56-1.13 ng/ml). Conclusions: In a city with a low smoking prevalence (12%), a large majority (87%) of adolescents seen in a public hospital clinic are exposed to tobacco. This is much higher than reported in national epidemiological studies of adolescents, which used a plasma biomarker. Since SHS is associated with significant respiratory diseases and parents and adolescents underreport exposure to SHS, routine biochemical screening should be considered as a tool to reduce SHS exposure. The clinical significance of light exposure needs to be investigated. Implications: Urine biomarker screening found that a large majority (87%) of adolescents treated in an urban public hospital are exposed to tobacco. Since SHS is associated with significant respiratory diseases and parents and adolescents underreport exposure to SHS, routine biochemical screening should be considered as a tool to reduce SHS exposure. PMID- 28031379 TI - Message from the Editor-in-Chief. PMID- 28031378 TI - Cigarette Graphic Warning Labels Are Not Created Equal: They Can Increase or Decrease Smokers' Quit Intentions Relative to Text-Only Warnings. AB - Introduction: Cigarette graphic-warning labels elicit negative emotion. Research suggests negative emotion drives greater risk perceptions and quit intentions through multiple processes. The present research compares text-only warning effectiveness to that of graphic warnings eliciting more or less negative emotion. Methods: Nationally representative online panels of 736 adult smokers and 469 teen smokers/vulnerable smokers were randomly assigned to view one of three warning types (text-only, text with low-emotion images, or text with high emotion images) four times over 2 weeks. Participants recorded their emotional reaction to the warnings (measured as arousal), smoking risk perceptions, and quit intentions. Primary analyses used structural equation modeling. Results: Participants in the high-emotion condition reported greater emotional reaction than text-only participants (bAdult = 0.21; bTeen = 0.27, p's < .004); those in the low-emotion condition reported lower emotional reaction than text-only participants (bAdult = -0.18; bTeen = -0.22, p's < .018). Stronger emotional reaction was associated with increased risk perceptions in both samples (bAdult = 0.66; bTeen = 0.85, p's < .001) and greater quit intentions among adults (bAdult = 1.00, p < .001). Compared to text-only warnings, low-emotion warnings were associated with reduced risk perceptions and quit intentions whereas high-emotion warnings were associated with increased risk perceptions and quit intentions. Conclusion: Warning labels with images that elicit more negative emotional reaction are associated with increased risk perceptions and quit intentions in adults and teens relative to text-only warnings. However, graphic warnings containing images which evoke little emotional reaction can backfire and reduce risk perceptions and quit intentions versus text-only warnings. Implications: This research is the first to directly manipulate two emotion levels in sets of nine cigarette graphic warning images and compare them with text-only warnings. Among adult and teen smokers, high-emotion graphic warnings were associated with increased risk perceptions and quit intentions versus text-only warnings. Low emotion graphic warnings backfired and tended to reduce risk perceptions and quit intentions versus text-only warnings. Policy makers should be aware that merely placing images on cigarette packaging is insufficient to increase smokers' risk perceptions and quit intentions. Low-emotion graphic warnings will not necessarily produce desired population-level benefits relative to text-only or high-emotion warnings. PMID- 28031381 TI - Where size matters: imaging-based biomarkers for patient stratification. PMID- 28031383 TI - GlioVis data portal for visualization and analysis of brain tumor expression datasets. PMID- 28031391 TI - Understanding of the role of manganese in parkinsonism and Parkinson disease. PMID- 28031390 TI - Methylphenidate, cognition, and epilepsy: A double-blind, placebo-controlled, single-dose study. AB - OBJECTIVE: To evaluate the potential efficacy of immediate-release methylphenidate (MPH) for treating cognitive deficits in epilepsy. METHODS: This was a double-blind, randomized, single-dose, 3-period crossover study in patients with epilepsy and chronic cognitive complaints comparing the effects of placebo and MPH 10 and 20 mg given 1 week apart. Cognitive outcome was evaluated on the basis of an omnibus z score calculated from performance on the Conners Continuous Performance Test 3 (ability to discriminate between target and nontarget stimuli [d'] and hit reaction time standard deviation), Symbol-Digit Modalities Test, and Medical College of Georgia Paragraph Memory Test. Adverse events and seizure frequency were monitored. An open-label follow-up is reported elsewhere. RESULTS: Thirty-five adult patients with epilepsy participated, of whom 31 finished. Demographics included the following: mean age = 35.3 years (range 20-62 years), 13 men and 18 women, and baseline seizure frequency of 2.8 per month. Epilepsy types were focal (n = 24), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.5 years. A statistically significant performance benefit was present at both 10-mg (p = 0.030) and 20-mg (p = 0.034) MPH doses. No seizures were associated with either MPH dose. Adverse effects leading to withdrawal included cognitive "fogginess" (n = 1 on 20 mg), anxiety/agitation (n = 1 on 10 mg), and tachycardia (n = 1). One participant was lost to follow-up after one 20-mg dose without side effect. CONCLUSIONS: This single-dose study suggests that MPH may be effective in ameliorating some cognitive deficits in patients with epilepsy. Additional studies are required. CLINICALTRIALSGOV IDENTIFIER: NCT02178995. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that single doses of MPH improve cognitive performance on some measures of attention and processing speed in patients with epilepsy and cognitive complaints. PMID- 28031389 TI - Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma. AB - Brain metastases (BM) occur frequently in many cancers, particularly non-small cell lung cancer (NSCLC), breast cancer, and melanoma. The development of BM is associated with poor prognosis and has an adverse impact on survival and quality of life. Commonly used therapies for BM such as surgery or radiotherapy are associated with only modest benefits. However, recent advances in systemic therapy of many cancers have generated considerable interest in exploration of those therapies for treatment of intracranial metastases.This review discusses the epidemiology of BM from the aforementioned primary tumors and the challenges of using systemic therapies for metastatic disease located within the central nervous system. Cumulative data from several retrospective and small prospective studies suggest that molecularly targeted systemic therapies may be an effective option for the treatment of BM from NSCLC, breast cancer, and melanoma, either as monotherapy or in conjunction with other therapies. Larger prospective studies are warranted to further characterize the efficacy and safety profiles of these targeted agents for the treatment of BM. PMID- 28031392 TI - DCE-MRI blood-brain barrier assessment in acute ischemic stroke. AB - OBJECTIVE: To quantitatively evaluate blood-brain barrier changes in ischemic stroke patients using dynamic contrast-enhanced (DCE) MRI. METHODS: We examined 54 stroke patients (clinicaltrials.gov NCT00715533, NCT02077582) in a 3T MRI scanner within 48 hours after symptom onset. Twenty-eight patients had a follow up examination on day 5-7. DCE T1 mapping and Patlak analysis were employed to assess BBB permeability changes. RESULTS: Median stroke Ktrans values (0.7 * 10-3 min-1 [interquartile range (IQR) 0.4-1.8] * 10-3 min-1) were more than 3-fold higher compared to median mirror Ktrans values (0.2 * 10-3 min-1, IQR 0.1-0.7 * 10-3 min-1, p < 0.001) and further increased at follow-up (n = 28, 2.3 * 10-3 min 1, IQR 0.8-4.6 * 10-3 min-1, p < 0.001). By contrast, mirror Ktrans values decreased over time with a clear interaction of timepoint and stroke/mirror side (p < 0.001). Median stroke Ktrans values were 2.5 times lower than in hemorrhagic transformed regions (0.7 vs 1.8 * 10-3 min-1; p = 0.055). There was no association between stroke Ktrans values and the delay from symptom onset to baseline examination, age, and presence of hyperintense acute reperfusion marker. CONCLUSION: BBB in acute stroke patients can be successfully assessed quantitatively. The decrease of BBB permeability in unaffected regions at follow up may be an indicator of global BBB leakage even in vessel territories remote from the index infarct. PMID- 28031393 TI - A dysfunctional blood-brain barrier and cerebral small vessel disease. PMID- 28031394 TI - Dose-dependent progression of parkinsonism in manganese-exposed welders. AB - OBJECTIVE: To determine whether the parkinsonian phenotype prevalent in welders is progressive, and whether progression is related to degree of exposure to manganese (Mn)-containing welding fume. METHODS: This was a trade union-based longitudinal cohort study of 886 American welding-exposed workers with 1,492 examinations by a movement disorders specialist, including 398 workers with 606 follow-up examinations up to 9.9 years after baseline. We performed linear mixed model regression with cumulative Mn exposure as the independent variable and annual change in Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) as the primary outcome, and subcategories of the UPDRS3 as secondary outcomes. The primary exposure metric was cumulative Mn exposure in mg Mn/m3-year estimated from detailed work histories. RESULTS: Progression of parkinsonism increased with cumulative Mn exposure. Specifically, we observed an annual change in UPDRS3 of 0.24 (95% confidence interval 0.10-0.38) for each mg Mn/m3-year of exposure. Exposure was most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression. The association between welding exposure and progression appeared particularly marked in welders who did flux core arc welding in a confined space or workers whose baseline examination was within 5 years of first welding exposure. CONCLUSIONS: Exposure to Mn-containing welding fume may cause a dose dependent progression of parkinsonism, especially upper limb bradykinesia, limb rigidity, and impairment of speech and facial expression. PMID- 28031395 TI - Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease. AB - OBJECTIVE: As blood-brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)-MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex matched controls to discern cSVD-related BBB leakage from aging-related leakage. METHODS: We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter. RESULTS: Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions. CONCLUSION: We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD. PMID- 28031396 TI - Operant conditioning of neural activity in freely behaving monkeys with intracranial reinforcement. AB - Operant conditioning of neural activity has typically been performed under controlled behavioral conditions using food reinforcement. This has limited the duration and behavioral context for neural conditioning. To reward cell activity in unconstrained primates, we sought sites in nucleus accumbens (NAc) whose stimulation reinforced operant responding. In three monkeys, NAc stimulation sustained performance of a manual target-tracking task, with response rates that increased monotonically with increasing NAc stimulation. We recorded activity of single motor cortex neurons and documented their modulation with wrist force. We conditioned increased firing rates with the monkey seated in the training booth and during free behavior in the cage using an autonomous head-fixed recording and stimulating system. Spikes occurring above baseline rates triggered single or multiple electrical pulses to the reinforcement site. Such rate-contingent, unit triggered stimulation was made available for periods of 1-3 min separated by 3-10 min time-out periods. Feedback was presented as event-triggered clicks both in cage and in-booth, and visual cues were provided in many in-booth sessions. In booth conditioning produced increases in single neuron firing probability with intracranial reinforcement in 48 of 58 cells. Reinforced cell activity could rise more than five times that of non-reinforced activity. In-cage conditioning produced significant increases in 21 of 33 sessions. In-cage rate changes peaked later and lasted longer than in-booth changes, but were often comparatively smaller, between 13 and 18% above non-reinforced activity. Thus intracranial stimulation reinforced volitional increases in cortical firing rates during both free behavior and a controlled environment, although changes in the latter were more robust.NEW & NOTEWORTHY Closed-loop brain-computer interfaces (BCI) were used to operantly condition increases in muscle and neural activity in monkeys by delivering activity-dependent stimuli to an intracranial reinforcement site (nucleus accumbens). We conditioned increased firing rates with the monkeys seated in a training booth and also, for the first time, during free behavior in a cage using an autonomous head-fixed BCI. PMID- 28031397 TI - Electrical stimulation of superior colliculus affects strabismus angle in monkey models for strabismus. AB - Disruption of binocular vision during the critical period for development leads to eye misalignment in humans and in monkey models. We have previously suggested that disruption within a vergence circuit could be the neural basis for strabismus. Electrical stimulation in the rostral superior colliculus (rSC) leads to vergence eye movements in normal monkeys. Therefore, the purpose of this study was to investigate the effect of SC stimulation on eye misalignment in strabismic monkeys. Electrical stimulation was delivered to 51 sites in the intermediate and deep layers of the SC (400 Hz, 0.5-s duration, 10-40 MUA) in 3 adult optical prism-reared strabismic monkeys. Scleral search coils were used to measure movements of both eyes during a fixation task. Staircase saccades with horizontal and vertical components were elicited by stimulation as predicted from the SC topographic map. Electrical stimulation also resulted in significant changes in horizontal strabismus angle, i.e., a shift toward exotropia/esotropia depending on stimulation site. Electrically evoked saccade vector amplitude in the two eyes was not significantly different (P > 0.05; paired t-test) but saccade direction differed. However, saccade disconjugacy accounted for only ~50% of the change in horizontal misalignment while disconjugate postsaccadic movements accounted for the other ~50% of the change in misalignment due to electrical stimulation. In summary, our data suggest that electrical stimulation of the SC of strabismic monkeys produces a change in horizontal eye alignment that is due to a combination of disconjugate saccadic eye movements and disconjugate postsaccadic movements.NEW & NOTEWORTHY Electrical stimulation of the superior colliculus in strabismic monkeys results in a change in eye misalignment. These data support the notion of developmental disruption of vergence circuits leading to maintenance of eye misalignment in strabismus. PMID- 28031398 TI - Principles of auditory processing differ between sensory and premotor structures of the songbird forebrain. AB - Sensory and motor brain structures work in collaboration during perception. To evaluate their respective contributions, the present study recorded neural responses to auditory stimulation at multiple sites simultaneously in both the higher-order auditory area NCM and the premotor area HVC of the songbird brain in awake zebra finches (Taeniopygia guttata). Bird's own song (BOS) and various conspecific songs (CON) were presented in both blocked and shuffled sequences. Neural responses showed plasticity in the form of stimulus-specific adaptation, with markedly different dynamics between the two structures. In NCM, the response decrease with repetition of each stimulus was gradual and long-lasting and did not differ between the stimuli or the stimulus presentation sequences. In contrast, HVC responses to CON stimuli decreased much more rapidly in the blocked than in the shuffled sequence. Furthermore, this decrease was more transient in HVC than in NCM, as shown by differential dynamics in the shuffled sequence. Responses to BOS in HVC decreased more gradually than to CON stimuli. The quality of neural representations, computed as the mutual information between stimuli and neural activity, was higher in NCM than in HVC. Conversely, internal functional correlations, estimated as the coherence between recording sites, were greater in HVC than in NCM. The cross-coherence between the two structures was weak and limited to low frequencies. These findings suggest that auditory communication signals are processed according to very different but complementary principles in NCM and HVC, a contrast that may inform study of the auditory and motor pathways for human speech processing.NEW & NOTEWORTHY Neural responses to auditory stimulation in sensory area NCM and premotor area HVC of the songbird forebrain show plasticity in the form of stimulus-specific adaptation with markedly different dynamics. These two structures also differ in stimulus representations and internal functional correlations. Accordingly, NCM seems to process the individually specific complex vocalizations of others based on prior familiarity, while HVC responses appear to be modulated by transitions and/or timing in the ongoing sequence of sounds. PMID- 28031399 TI - Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip. AB - Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiology, potential neurotoxic effects of chemicals, and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell composition, protein expression, metabolism, and electrical activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and observed a reduction of overall firing activity, as well as altered amounts of astrocytes and specific neuronal cell types compared with separately cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas separately while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features.NEW & NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections. PMID- 28031400 TI - Spinal cord direct current stimulation differentially modulates neuronal activity in the dorsal and ventral spinal cord. AB - Spinal cord direct current stimulation (sDCS) has the potential for promoting motor function after injury through its modulatory actions on sensory processing, reflex functions, the motor cortex (M1) motor map, and motor output. Here we addressed systems-level mechanisms underlying sDCS neuromodulation of spinal circuits activated by M1 and peripheral forelimb electrical stimulation in anesthetized healthy rats. We determined the effects of cathodal and anodal sDCS (c- and a-sDCS) on local field potentials (LFP) and single-unit activity recorded at 32 sites simultaneously within the sixth cervical segment using a silicon multielectrode array. M1 stimulation produced distinctive dorsomedial and ventral LFP responses that showed polarity-dependent sDCS modulation. c-sDCS enhanced and a-sDCS depressed significantly ventral M1 responses; neither modulated dorsal responses significantly. Using evoked changes in beta- and gamma-oscillations to assay network function, c-sDCS enhanced and a-sDCS reduced oscillation power ventrally. c-sDCS increased and a-sDCS decreased background firing and firing synchrony of recorded pairs of single units. Peripheral stimulation produced a region-dependent response that showed polarity-dependent sDCS modulation. The dorsomedial LFP was unaffected by c-sDCS and weakly suppressed with a-sDCS. Peripheral-evoked unit responses showed limited polarity dependence. Our findings stress that ventral motor network behavior is enhanced by the neuromodulatory actions of c-sDCS. The combined actions of c-sDCS on M1-evoked neural responses and network behavior in the cervical spinal cord help explain the reported enhanced motor effects of this neuromodulation approach and inform the mechanisms of sDCS for promoting motor rehabilitation after spinal cord or brain injury.NEW & NOTEWORTHY Spinal cord direct current stimulation (sDCS) modulates spinal functions and shows potential for neural rehabilitation after motor systems injury. Using a multichannel electrode array, we found that cathodal DCS enhanced, and anodal depressed, M1-evoked local field potentials, network oscillations, neuronal activity, and neuronal synchrony, especially in the ventral horn. With this new understanding, it is hoped that sDCS can be developed into a tunable spinal neuromodulatory tool for promoting function after brain or spinal injury. PMID- 28031401 TI - Segmental specificity in belly dance mimics primal trunk locomotor patterns. AB - Belly dance was used to investigate control of rhythmic undulating trunk movements in humans. Activation patterns in lumbar erector spinae muscles were recorded using surface electromyography at four segmental levels spanning T10 to L4. Muscle activation patterns for movement tempos of 2 Hz, 3 Hz, and as fast as possible (up to 6 Hz) were compared to test the hypothesis that frequency modulates muscle timing, causing pattern changes analogous to gait transitions. Groups of trained and untrained female subjects were compared to test the hypothesis that experience modifies muscle coordination patterns and the capacity for selective motion of spinal segments. Three distinct coordination patterns were observed. An ipsilateral simultaneous pattern (S) and a diagonal synergy (D) dominated at lower frequencies. The S pattern was selected most often by novices and resembled the standing wave of activation underlying the alternating lateral trunk bending in salamander trotting. At 2 Hz, most trained subjects selected the D pattern, suggesting a greater capacity for segmental specificity compared with untrained subjects. At 3-4 Hz, there emerged an asynchronous pattern (A) analogous to the rostral-caudal traveling wave in salamander and lamprey swimming. The neural networks and mechanisms identified in primitive vertebrates, such as chains of coupled oscillators and segmental crossed inhibitory connections, could explain the patterns observed in this study in humans. Training allows modification of these patterns, possibly through improved capacity for selectively exciting or inhibiting segmental pattern generators.NEW & NOTEWORTHY Belly dance provides a novel approach for studying spinal cord neural circuits. New evidence suggests that primitive locomotor circuits may be conserved in humans. Erector spinae activation patterns during the hip shimmy at different tempos are similar to those observed in salamander walking and swimming. As movement frequency increases, a sequential pattern similar to lamprey swimming emerges, suggesting that primal involuntary control mechanisms dominate in fast lateral rhythmic spine undulations even in humans. PMID- 28031402 TI - Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb. AB - In the olfactory bulb, lateral inhibition mediated by local juxtaglomerular interneurons has been proposed as a gain control mechanism, important for decorrelating odorant responses. Among juxtaglomerular interneurons, short axon cells are unique as dual-transmitter neurons that release dopamine and GABA. To examine their intraglomerular function, we expressed channelrhodopsin under control of the DAT-cre promoter and activated olfactory afferents within individual glomeruli. Optical stimulation of labeled cells triggered endogenous dopamine release as measured by cyclic voltammetry and GABA release as measured by whole cell GABAA receptor currents. Activation of short axon cells reduced the afferent presynaptic release probability via D2 and GABAB receptor activation, resulting in reduced spiking in both mitral and external tufted cells. Our results suggest that short axon cells influence glomerular activity not only by direct inhibition of external tufted cells but also by inhibition of afferent inputs to external tufted and mitral cells.NEW & NOTEWORTHY Sensory systems, including the olfactory system, encode information across a large dynamic range, making synaptic mechanisms of gain control critical to proper function. Here we demonstrate that a dual-transmitter interneuron in the olfactory bulb controls the gain of intraglomerular afferent input via two distinct mechanisms, presynaptic inhibition as well as inhibition of a principal neuron subtype, and thereby potently controls the synaptic gain of afferent inputs. PMID- 28031403 TI - Cutaneous neurturin overexpression alters mechanical, thermal, and cold responsiveness in physiologically identified primary afferents. AB - Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFRalpha2 receptor, a receptor found primarily in isolectin B4-expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFRalpha2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal subpopulation of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties.NEW & NOTEWORTHY GDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show that overexpression of neurturin in basal keratinocytes regulates mechanical responsiveness in A-fiber primary sensory neurons while increasing the overall numbers of cold-sensing units. Results demonstrate a crucial role for cutaneous neurturin in modulating responsiveness to peripheral stimuli at the level of the primary afferent. PMID- 28031404 TI - Physiological processes influencing motor-evoked potential duration with voluntary contraction. AB - Voluntary contraction leads to facilitation of motor-evoked potentials (MEPs) producing greater amplitude, shorter onset latency, and prolonged duration of the electromyography potential. Whereas hyperexcitability of spinal motoneurons and changes in descending corticospinal volleys have been proposed as putative mechanisms for changes in MEP amplitude and onset latency, a contribution of propriospinal interneurons, exerting modulatory effects on alpha-motoneurons, has been proposed as a potential explanation for prolongation of MEP duration. The aim of the present study is to gain further insight into the physiological processes underlying changes in MEP duration. Transcranial magnetic stimulation (TMS) studies were undertaken on 30 healthy controls, using a 90-mm circular coil, with MEPs recorded at rest and during facilitation, produced by contraction of abductor pollicis brevis. In the same experiment, short interval-intracortical inhibition (SICI) was recorded at rest. Facilitation resulted in a significant prolongation of MEP duration, which increased with stimulus intensity and was accompanied by an increase in MEP amplitude. The main effect (TMS intensity * activation state) was correlated with MEP duration (F = 10.9, P < 0.001), whereas TMS intensity (F = 30.5, P < 0.001) and activation state (F = 125.8, P < 0.001) in isolation were correlated with MEP amplitude. There was a significant inverse relationship between SICI and MEP duration at rest (R2 = 0.141, P = 0.041) and during facilitation (R2 = 0.340, P = 0.001). The present findings suggest that similar physiological processes mediate changes in the facilitated MEP duration and amplitude and that both cortical and nonpropriospinal spinal mechanisms contribute to changes in MEP duration.NEW & NOTEWORTHY Muscle contraction is associated with a significant increase in motor-evoked potential (MEP) duration and amplitude. Whereas the increase in MEP duration was linear, the amplitude increase exhibited a ceiling effect. Importantly, the MEP duration increase strongly correlated with short interval-intracortical inhibition, a biomarker of motor cortical function. This suggests that whereas similar physiological processes contribute to changes in facilitated MEP duration and amplitude, cortical mechanisms appear to contribute to MEP duration changes. PMID- 28031405 TI - A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease. AB - CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP, delta-aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. The human peptide transporter 2 (PEPT2) expressed by proximal tubular cells mediates the reabsorption of ALA, and variants of PEPT2 have different affinities for ALA. We tested the hypothesis that PEPT2 genotypes affect the severity and prognosis of porphyria-associated kidney disease. We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped for PEPT2 At last follow-up, carriers of the PEPT2*1*1 genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variants PEPT2*1/*2 and PEPT2*2/*2 (mean+/-SD eGFR: 54.4+/-19.1, 66.6+/-23.8, and 78.1+/-19.9 ml/min per 1.73 m2, respectively). Change in eGFR (mean+/-SD) over the 10-year period was -11.0+/-3.3, -2.4+/-1.9, and 3.4+/-2.6 ml/min per 1.73 m2 for PEPT2*1/*1, PEPT2*1*2, and PEPT*2*2*2 carriers, respectively. At the end of follow-up, 68% of PEPT2*1*1 carriers had an eGFR<60 ml/min per 1.73 m2, compared with 37% of PEPT2*1*2 carriers and 15% of PEPT2*2*2 carriers. Multiple regression models including all confounders indicated that the PEPT2*1*1 genotype independently associated with an eGFR<60 ml/min per 1.73 m2 (odds ratio, 6.85; 95% confidence interval, 1.34 to 46.20) and an annual decrease in eGFR of >1 ml/min per 1.73 m2 (odds ratio, 3.64; 95% confidence interval, 1.37 to 9.91). Thus, a gene variant is predictive of the severity of a chronic complication of AIP. The therapeutic value of PEPT2 inhibitors in preventing porphyria-associated kidney disease warrants investigation. PMID- 28031406 TI - Complications of the Arteriovenous Fistula: A Systematic Review. AB - The implementation of patient-centered care requires an individualized approach to hemodialysis vascular access, on the basis of each patient's unique balance of risks and benefits. This systematic review aimed to summarize current literature on fistula risks, including rates of complications, to assist with patient centered decision making. We searched Medline from 2000 to 2014 for English language studies with prospectively captured data on >=100 fistulas. We assessed study quality and extracted data on study design, patient characteristics, and outcomes. After screening 2292 citations, 43 articles met our inclusion criteria (61 unique cohorts; n>11,374 fistulas). Median complication rates per 1000 patient days were as follows: 0.04 aneurysms (14 unique cohorts; n=1827 fistulas), 0.11 infections (16 cohorts; n>6439 fistulas), 0.05 steal events (15 cohorts; n>2543 fistulas), 0.24 thrombotic events (26 cohorts; n=4232 fistulas), and 0.03 venous hypertensive events (1 cohort; n=350 fistulas). Risk of bias was high in many studies and event rates were variable, thus we could not present pooled results. Studies generally did not report variables associated with fistula complications, patient comorbidities, vessel characteristics, surgeon experience, or nursing cannulation skill. Overall, we found marked variability in complication rates, partly due to poor quality studies, significant heterogeneity of study populations, and inconsistent definitions. There is an urgent need to standardize reporting of methods and definitions of vascular access complications in future clinical studies to better inform patient and provider decision making. PMID- 28031408 TI - Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC. AB - Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice. A comprehensive study including global transcriptomic analysis followed by biological validations confirmed that SPARC induces primary tumor growth by enhancing cell cycle and by promoting a COX-2-mediated expansion of myeloid derived suppressor cells (MDSC). The role of SPARC in metastasis involved a COX-2 independent enhancement of cell disengagement from the primary tumor and adherence to the lungs that fostered metastasis implantation. Interestingly, SPARC-driven gene expression signatures obtained from these murine models predicted the clinical outcome of patients with HER2-enriched breast cancer subtypes. In total, the results reveal that SPARC and its downstream effectors are attractive targets for antimetastatic therapies in breast cancer.Implications: These findings shed light on the prometastatic role of SPARC, a key protein expressed by breast cancer cells and surrounding stroma, with important consequences for disease outcome. Mol Cancer Res; 15(3); 304-16. (c)2016 AACR. PMID- 28031407 TI - Metabolic Acidosis and Long-Term Clinical Outcomes in Kidney Transplant Recipients. AB - Metabolic acidosis (MA), indicated by low serum total CO2 (TCO2) concentration, is a risk factor for mortality and progressive renal dysfunction in CKD. However, the long-term effects of MA on kidney transplant recipients (KTRs) are unclear. We conducted a multicenter retrospective cohort study of 2318 adult KTRs, from January 1, 1997 to March 31, 2015, to evaluate the prevalence of MA and the relationships between TCO2 concentration and clinical outcomes. The prevalence of low TCO2 concentration (<22 mmol/L) began to increase in KTRs with eGFR<60 ml/min per 1.73 m2 and ranged from approximately 30% to 70% in KTRs with eGFR<30 ml/min per 1.73 m2 Multivariable Cox proportional hazards models revealed that low TCO2 concentration 3 months after transplant associated with increased risk of graft loss (hazard ratio [HR], 1.74%; 95% confidence interval [95% CI], 1.26 to 2.42) and death-censored graft failure (DCGF) (HR, 1.66; 95% CI, 1.14 to 2.42). Cox regression models using time-varying TCO2 concentration additionally demonstrated significant associations between low TCO2 concentration and graft loss (HR, 3.48; 95% CI, 2.47 to 4.90), mortality (HR, 3.16; 95% CI, 1.77 to 5.62), and DCGF (HR, 3.17; 95% CI, 2.12 to 4.73). Marginal structural Cox models adjusted for time varying eGFR further verified significant hazards of low TCO2 concentration for graft loss, mortality, and DCGF. In conclusion, MA was frequent in KTRs despite relatively preserved renal function and may be a significant risk factor for graft failure and patient mortality, even after adjusting for eGFR. PMID- 28031409 TI - Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation. AB - Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently, we reported that mutant, but otherwise functional, p53v172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogues oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP) strongly stabilize and activate p53v172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2. This increase in MDM2 reduced MDM4 levels in cell lysates as well as the p53 immunocomplex and prevented reversion of p53 to the inactive p53-MDM2-MDM4-bound state. Phosphorylation of p53 at Ser15 was demonstrated by all three drugs in sensitive A2780 and corresponding resistant 2780CP/Cl-16 and 2780CP/Cl-24 cell lines. However, cisplatin induced Ser20 phosphorylation in A2780 cells only, but not in resistant cells; in contrast, both DAP and oxaliplatin induced this phosphorylation in all three cell lines. The inference that Ser20 phosphorylation is more important for p53 activation was confirmed by ectopic expression of a phosphomimetic (S20D) mutant p53 that displayed reduced binding, relative to wild-type p53, to both MDM2 and MDM4 in p53-knockout A2780 cells. In consonance, temporal studies demonstrated drug-induced Ser15 phosphorylation coincided with p53 stabilization, whereas Ser20 phosphorylation coincided with p53 transactivation.Implications: Cisplatin fails to activate the pathway involved in phosphorylating mutant p53v172F at Ser20 in resistant cells, but this phosphorylation is restored by oxaliplatin and DAP that reactivates p53 function and circumvents cisplatin resistance. Mol Cancer Res; 15(3); 328-39. (c)2016 AACR. PMID- 28031410 TI - Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma. AB - JAKs are non-receptor tyrosine kinases that are generally found in association with cytokine receptors. In the canonical pathway, roles of JAKs have well been established in activating STATs in response to cytokine stimulation to modulate gene transcription. In contrast, a noncanonical role of JAK2 has recently been discovered, in which JAK2 in the nucleus imparts the epigenetic regulation of gene transcription through phosphorylation of tyrosine 41 on the histone protein H3. Recent work further demonstrated that this noncanonical mechanism is conserved with JAK1, which is activated by the autocrine cytokines IL6 and IL10 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), a cancer type that is particularly difficult to treat and has poor prognosis. However, how JAK1 gains access to the nucleus to enable epigenetic regulation remains undefined. Here, we investigated this question and revealed that JAK1 has a classical nuclear localization signal toward the N-terminal region, which can be recognized by multiple importin alpha isoforms. Moreover, the nuclear import of JAK1 is independent of its kinase activity but is required for the optimal expansion of ABC DLBCL cells in vitroImplications: This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells, and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL. Mol Cancer Res; 15(3); 348-57. (c)2016 AACR. PMID- 28031411 TI - A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy. AB - Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested. Many genes essential for EOC spheroid viability are pertinent to the mammalian DREAM repressor complex. Mechanistically, the data demonstrate that DREAM is assembled upon the induction of spheroid formation, which is dependent upon Dyrk1A. Loss of Dyrk1A results in retention of the b-Myb MuvB complex, elevated expression of DREAM target genes, and increased DNA synthesis that is coincident with cell death. Inhibition of Dyrk1A activity using pharmacologic agents Harmine and INDY compromises viability of spheroids and blocks DREAM assembly. In addition, INDY treatment improves the response to carboplatin, suggesting this is a therapeutic target for EOC treatment.Implications: Loss of negative growth control mechanisms in cancer dormancy lead to cell death and not proliferation, suggesting they are an attractive therapeutic approach. Mol Cancer Res; 15(4); 371-81. (c)2016 AACR. PMID- 28031413 TI - Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors. AB - HER2+ breast tumors have been shown to express elevated levels of PARP1 protein. Yet, the mechanism by which PARP1 is upregulated in HER2+ breast cancer is unknown. Here, knockdown of HER2 (ERBB2) in HER2+ breast cancer cells resulted in a reduction in PARP1 protein. Conversely, ectopic overexpression of HER2 in a non HER2-overexpressing cell line resulted in increased PARP1 protein levels. Alterations in HER2 expression had no significant effect on PARP1 transcript levels. Instead, HER2 mRNA status was inversely correlated with let-7a miRNA levels in breast cancer cells. Ectopic expression of let-7a miRNA resulted in downregulation of PARP1 protein, whereas expression of the let-7a anti-miRNA increased PARP1 protein. Furthermore, luciferase assays demonstrate that let-7a regulates PARP1 via its 3'UTR. Importantly, let-7a was significantly lower in human HER2+ breast tumors compared with HER2- breast tumors and inversely correlated with PARP1 protein levels. Finally, HER2+ breast cancer cells exhibited similar cytotoxicity to ectopic let-7a expression as the PARP inhibitor veliparib (ABT-888). Collectively, these results reveal that increased PARP1 expression in HER2+ breast cancers is regulated by the let-7a miRNA, and that let 7a is a potential strategy to suppress PARP1 activity.Implications: This study reports the novel findings that HER2 increases PARP1 protein via suppression of the let-7a miRNA, which regulates the PARP1 3'-UTR. Moreover, HER2 status correlates with high PARP1 and low let-7a in breast cancer clinical specimens. Mol Cancer Res; 15(3); 340-7. (c)2016 AACR. PMID- 28031414 TI - Inhibition of the Human ABC Efflux Transporters P-gp and BCRP by the BDE-47 Hydroxylated Metabolite 6-OH-BDE-47: Considerations for Human Exposure. AB - High body burdens of polybrominated diphenyl ethers (PBDEs) in infants and young children have led to increased concern over their potential impact on human development. PBDE exposure can alter the expression of genes involved in thyroid homeostasis, including those of ATP-binding cassette (ABC) transporters, which mediate cellular xenobiotic efflux. However, little information exists on how PBDEs interact with ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The purpose of this study was to evaluate the interactions of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and its hydroxylated metabolite 6-OH-BDE-47 with P-gp and BCRP, using human MDR1- and BCRP-expressing membrane vesicles and stably transfected NIH-3T3-MDR1 and MDCK-BCRP cells. In P gp membranes, BDE-47 did not affect P-gp activity; however, 6-OH-BDE-47 inhibited P-gp activity at low uM concentrations (IC50 = 11.7 uM). In BCRP membranes, BDE 47 inhibited BCRP activity; however, 6-OH-BDE-47 was a stronger inhibitor [IC50 = 45.9 uM (BDE-47) vs. IC50 = 9.4 uM (6-OH-BDE-47)]. Intracellular concentrations of known P-gp and BCRP substrates [(3H)-paclitaxel and (3H)-prazosin, respectively] were significantly higher (indicating less efflux) in NIH-3T3-MDR1 and MDCK-BCRP cells in the presence of 6-OH-BDE-47, but not BDE-47. Collectively, our results indicate that the BDE-47 metabolite 6-OH-BDE-47 is an inhibitor of both P-gp and BCRP efflux activity. These findings suggest that some effects previously attributed to BDE-47 in biological systems may actually be due to 6-OH BDE-47. Considerations for human exposure are discussed. PMID- 28031415 TI - Evaluation of Batch Variations in Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes from 2 Major Suppliers. AB - Drug-induced proarrhythmia is a major safety issue in drug development. Developing sensitive in vitro assays that can predict drug-induced cardiotoxicity in humans has been a challenge of toxicology research for decades. Recently, induced pluripotent stem cell-derived human cardiomyocytes (iPSC-hCMs) have become a promising model because they largely replicate the electrophysiological behavior of human ventricular cardiomyocytes. Patient-specific iPSC-hCMs have been proposed for personalized cardiac drug selection and adverse drug response prediction; however, many procedures are involved in cardiomyocytes differentiation and purification process, which may result in large line-to-line and batch-to-batch variations. Here, we examined the purity, cardiac ion channel gene expression profile, and electrophysiological response of 3 batches of iPSC hCMs from each of 2 major cell suppliers. We found that iPSC-hCMs from both vendors had similar purities. Most of the cardiac ion channel genes were expressed uniformly among different batches of iCells, while larger variations were found in Cor.4U cells, particularly in the expression of CACNA1C, KCND2, and KCNA5 genes, which could underlie the differences in baseline beating rate (BR) and field potential duration (FPD) measurements. Although, in general, the electrophysiological responses of different batches of cells to Na+, Ca2+, Ikr, and Iks channel blockers were similar, with Ikr blocker-induced proarrhythmia, the sensitivities were depended on baseline BR and FPD values: cells that beat slower had longer FPD and greater sensitivity to drug-induced proarrhythmia. Careful evaluation of the performance of iPSC-hCMs and methods of data analysis is warranted for shaping regulatory standards in qualifying iPSC-hCMs for drug safety testing. PMID- 28031416 TI - Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials. AB - RATIONALE: Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery. OBJECTIVE: We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, -15.9 to -3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement. CONCLUSIONS: MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies. PMID- 28031418 TI - Peripheral Inflammatory Biomarkers for Myocardial Infarction Risk: A Prospective Community-Based Study. AB - BACKGROUND: Most previous studies regarding chronic inflammation and risk of myocardial infarction (MI) have lacked repeated measures of high-sensitivity C reactive protein (hs-CRP) and/or white blood cell (WBC) count over time. We examined whether cumulative average and longitudinal changes in these biomarkers were associated with subsequent MI risk. METHODS: In this prospective, community based study, we included 82544 Chinese participants [66796 men and 15748 women; mean (SD) age 55.1 (9.86) y] without prior cardiovascular diseases or cancer at baseline (2006-2007). hs-CRP, WBC and other clinical covariates were assessed at baseline and every 2 years during follow-up. RESULTS: During 6 years of follow-up (2006-2012), we documented 714 incident MI cases. Higher baseline and cumulative average concentrations of hs-CRP and/or WBC were consistently associated with increased risk of MI (Ptrend <0.001 for both). Longitudinal increase in hs-CRP (Ptrend <0.001), but not WBC, was also associated with a higher future risk of MI, after adjustment for their baseline values and other covariates. Each 1-mg/L increment per year in hs-CRP was associated with a 9.3% increase in risk for future MI [hazard ratio (HR) = 1.09, 95% CI, 1.03; 1.17]. Participants with high grade inflammatory status (hs-CRP >=10 mg/L and WBC >=10 * 109/L) had a higher risk of MI occurring <3 months after hs-CRP/WBC assessments vs those with hs-CRP <0.5 mg/L and WBC <5 * 109/L (HR = 6.64; 95% CI, 1.49-29.6), as compared with MI occurring >=4 years (HR = 2.95; 95% CI, 0.90, 9.65). CONCLUSIONS: Plasma hs-CRP concentration and WBC predicted MI risk. Longitudinal increase in hs-CRP was also associated with a higher risk of MI. PMID- 28031417 TI - Serious Illness Conversations in ESRD. AB - Dialysis-dependent ESRD is a serious illness with high disease burden, morbidity, and mortality. Mortality in the first year on dialysis for individuals over age 75 years old approaches 40%, and even those with better prognoses face multiple hospitalizations and declining functional status. In the last month of life, patients on dialysis over age 65 years old experience higher rates of hospitalization, intensive care unit admission, procedures, and death in hospital than patients with cancer or heart failure, while using hospice services less. This high intensity of care is often inconsistent with the wishes of patients on dialysis but persists due to failure to explore or discuss patient goals, values, and preferences in the context of their serious illness. Fewer than 10% of patients on dialysis report having had a conversation about goals, values, and preferences with their nephrologist, although nearly 90% report wanting this conversation. Many nephrologists shy away from these conversations, because they do not wish to upset their patients, feel that there is too much uncertainty in their ability to predict prognosis, are insecure in their skills at broaching the topic, or have difficulty incorporating the conversations into their clinical workflow. In multiple studies, timely discussions about serious illness care goals, however, have been associated with enhanced goal-consistent care, improved quality of life, and positive family outcomes without an increase in patient distress or anxiety. In this special feature article, we will (1) identify the barriers to serious illness conversations in the dialysis population, (2) review best practices in and specific approaches to conducting serious illness conversations, and (3) offer solutions to overcome barriers as well as practical advice, including specific language and tools, to implement serious illness conversations in the dialysis population. PMID- 28031419 TI - Serum Levels of Apolipoproteins and Incident Type 2 Diabetes: A Prospective Cohort Study. AB - OBJECTIVE: We aimed to investigate the role of serum levels of various apolipoproteins on the risk for type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We used data from 971 individuals from the prospective population-based Rotterdam Study. We studied the association of HDL cholesterol (HDL-C), apoA1, apoCIII, apoD, and apoE as well as the ratios of apolipoproteins with apoA1 with the risk of T2D. All apolipoproteins, ratios, and HDL-C levels were naturally log transformed to reach normal distribution. First, their cross-sectional associations with fasting glucose and insulin were investigated by using linear regression. Second, Cox proportional hazard models were used to examine whether apolipoproteins predict the risk for T2D among individuals free of diabetes at baseline. We also studied the apolipoproteins jointly by calculating the apolipoproteinic score from the first step and then performing Cox regression with it. RESULTS: During a median follow-up of 13.5 years, diabetes developed in 110 individuals. After adjustment for age, sex, BMI, parental history of diabetes, hypertension, alcohol use, smoking, prevalent cardiovascular disease, and serum lipid-reducing agents, HDL-C (per 1 SD naturally log-transformed hazard ratio 0.74 [95% CI 0.57, 0.97], apoCIII (1.65 [1.42, 1.91]), apoE (1.36 [1.18, 1.55]), apoCIII-to-apoA1 ratio (1.72 [1.51, 1.95]), apoE-to-apoA1 ratio (1.28 [1.13, 1.45]), and apolipoproteinic score (1.60 [1.39, 1.83]) remained significant. Only apoCIII (1.42 [1.03, 1.96]) and apoCIII-to-apoA1 ratio (1.56 [1.04, 2.36]) survived the adjustment for triglycerides in the last model. CONCLUSIONS: Serum apoCIII levels as well as apoCIII-to-apoA1 ratio are associated with incident T2D. They are associated independent of known risk factors and stronger than HDL-C levels. PMID- 28031420 TI - Novel Protein Glycan-Derived Markers of Systemic Inflammation and C-Reactive Protein in Relation to Glycemia, Insulin Resistance, and Insulin Secretion. AB - OBJECTIVE: N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB) moieties of glycosylated serum proteins are nonspecific measures of inflammation, but conclusive data on their relationship with insulin resistance or insulin secretion are missing. Therefore, we aimed to examine the relation of GlycA, GlycB, and C-reactive protein (CRP) to direct measures of insulin sensitivity (insulin sensitivity index [SI]) and insulin secretion (acute insulin response [AIR]). RESEARCH DESIGN AND METHODS: This study used cross-sectional analyses and included 1,225 participants with and without type 2 diabetes in the Insulin Resistance Atherosclerosis Study (IRAS). SI and AIR were measured using the frequently sampled intravenous glucose tolerance test, and GlycA and GlycB were measured using nuclear magnetic resonance spectroscopy. RESULTS: GlycA and GlycB had a strong correlation with CRP (r = 0.60 [P < 0.001] and r = 0.46 [P < 0.001], respectively). In a linear regression model with both GlycA and CRP as independent variables, GlycA (beta * 1 SD, -0.04 +/- 0.02; P < 0.01) and CRP ( 0.06 +/- 0.02; P < 0.001) were independently associated with SI even after adjusting for demographics, smoking, physical activity, plasma glucose, and BMI. However, neither CRP nor GlycA had an independent relationship with AIR. CONCLUSIONS: GlycA may complement CRP in evaluating the relationship between inflammation, glucose tolerance, and insulin resistance. PMID- 28031421 TI - The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat. AB - The large protocadherin Fat functions to promote Hippo pathway activity in restricting tissue growth. Loss of Fat leads to accumulation of the atypical myosin Dachs at the apical junctional region, which in turn promotes growth by inhibiting Warts. We previously identified Approximated (App), a DHHC domain palmitoyltransferase, as a negative regulator of Fat signaling in growth control. We show here that App promotes growth by palmitoylating the intracellular domain of Fat, and that palmitoylation negatively regulates Fat function. Independently, App also recruits Dachs to the apical junctional region through protein-protein association, thereby stimulating Dachs's activity in promoting growth. Further, we show that palmitoylation by App functions antagonistically to phosphorylation by Discs-overgrown, which activates Fat. Together, these findings suggest a model in which App promotes Dachs activity by simultaneously repressing Fat via posttranslational modification and recruiting Dachs to the apical junctional region, thereby promoting tissue growth. PMID- 28031422 TI - Organoids: A historical perspective of thinking in three dimensions. AB - In the last ten years, there has been a dramatic surge in the number of publications where single or groups of cells are grown in substrata that have elements of basement membrane leading to the formation of tissue-like structures referred to as organoids. However, this field of research began many decades ago, when the pioneers of cell culture began to ask questions we still ask today: How does organogenesis occur? How do signals integrate to make such vastly different tissues and organs given that the sequence of the genome in our trillions of cells is identical? Here, we summarize how work over the past century generated the conceptual framework that has allowed us to make progress in the understanding of tissue-specific morphogenetic programs. The development of cell culture systems that provide accurate and physiologically relevant models are proving to be key in establishing appropriate platforms for the development of new therapeutic strategies. PMID- 28031423 TI - Neurological Injury and Cerebral Blood Flow in Single Ventricles Throughout Staged Surgical Reconstruction. AB - BACKGROUND: Patients with a single ventricle experience a high rate of brain injury and adverse neurodevelopmental outcome; however, the incidence of brain abnormalities throughout surgical reconstruction and their relationship with cerebral blood flow, oxygen delivery, and carbon dioxide reactivity remain unknown. METHODS: Patients with a single ventricle were studied with magnetic resonance imaging scans immediately prior to bidirectional Glenn (pre-BDG), before Fontan (BDG), and then 3 to 9 months after Fontan reconstruction. RESULTS: One hundred sixty-eight consecutive subjects recruited into the project underwent 235 scans: 63 pre-BDG (mean age, 4.8+/-1.7 months), 118 BDG (2.9+/-1.4 years), and 54 after Fontan (2.4+/-1.0 years). Nonacute ischemic white matter changes on T2-weighted imaging, focal tissue loss, and ventriculomegaly were all more commonly detected in BDG and Fontan compared with pre-BDG patients (P<0.05). BDG patients had significantly higher cerebral blood flow than did Fontan patients. The odds of discovering brain injury with adjustment for surgical stage as well as >=2 coexisting lesions within a patient decreased (63%-75% and 44%, respectively) with increasing amount of cerebral blood flow (P<0.05). In general, there was no association of oxygen delivery (except for ventriculomegaly in the BDG group) or carbon dioxide reactivity with neurological injury. CONCLUSIONS: Significant brain abnormalities are commonly present in patients with a single ventricle, and detection of these lesions increases as children progress through staged surgical reconstruction, with multiple coexisting lesions more common earlier than later. In addition, this study demonstrated that BDG patients had greater cerebral blood flow than did Fontan patients and that an inverse association exists of various indexes of cerebral blood flow with these brain lesions. However, CO2 reactivity and oxygen delivery (with 1 exception) were not associated with brain lesion development. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02135081. PMID- 28031424 TI - The DART Study: Results from the Dose-Escalation and Expansion Cohorts Evaluating the Combination of Dalantercept plus Axitinib in Advanced Renal Cell Carcinoma. AB - Purpose: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and VEGF signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1-receptor fusion protein that acts as a ligand trap for bone morphogenetic proteins 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing.Experimental Design: Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance.Results: Twenty-nine patients were enrolled in the dose escalation (n = 15) and expansion (n = 14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects, such as fatigue and diarrhea, commonly seen treatment-related adverse events were peripheral edema, epistaxis, pericardial effusion, and telangiectasia. The objective response rate by RECIST v1.1 was 25% with responses seen at all dose levels. The overall median progression-free survival was 8.3 months.Conclusions: The combination of dalantercept plus axitinib is well tolerated and associated with clinical activity. On the basis of safety and efficacy results, the 0.9 mg/kg dose level was chosen for further study in a randomized phase II trial of dalantercept plus axitinib versus placebo plus axitinib. Clin Cancer Res; 23(14); 3557-65. (c)2016 AACR. PMID- 28031425 TI - Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors. AB - Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated.Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose limiting toxicities included rash and hypotension; the most frequent treatment related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520-8. (c)2016 AACR. PMID- 28031427 TI - Distribution, Predictors, and Impacts of Emerald Ash Borer (Agrilus planipennis) (Coleoptera: Buprestidae) Infestation of White Fringetree (Chionanthus virginicus). AB - Emerald ash borer, Agrilus planipennis (Fairmaire), is an invasive pest of ash trees (Fraxinus spp.) in North America that was recently found infesting white fringetree (Chionanthus virginicus L.). Initial reports of the infestation of white fringetree by emerald ash borer occurred in southwestern Ohio and Chicago, IL. We examined white fringetrees at additional sites in Illinois, Indiana, Ohio, and Pennsylvania in Summer and Fall 2015 and Winter 2016 for emerald ash borer infestation. Our aim was to examine white fringetrees at a limited number of sites with emerald ash borer infestation and to relate tree size, crown dieback, epicormic sprouting, tree sex, and adjacency to ash or white fringetrees with the likelihood of beetle infestation. A higher proportion of infested trees exhibited epicormic sprouting and the likelihood that a tree was infested increased with increasing crown dieback, variables that may be both predictors and responses to attack. The proportion of trees infested with emerald ash borer increased with increasing tree size. Signs consistent with emerald ash borer infestation were found in 26% of 178 white fringetrees, with at least one host infested at each site in all states. Infestation rates of white fringetrees increased with the density of white fringetrees at each site. The Chicago Botanic Garden site had a significantly lower infestation (3.7%) than other sites, which may be due to proactive management of ash. Overall, these data indicate white fringetree has been utilized by emerald ash borer throughout their overlapping ranges in the United States in ornamental settings likely due to ecological fitting. PMID- 28031426 TI - Molecular Profiling to Determine Clonality of Serial Magnetic Resonance Imaging/Ultrasound Fusion Biopsies from Men on Active Surveillance for Low-Risk Prostate Cancer. AB - Purpose: To determine whether MRI/ultrasound (MRI/US) fusion biopsy facilitates longitudinal resampling of the same clonal focus of prostate cancer and to determine whether high-grade cancers can evolve from low-grade clones.Experimental Design: All men on active surveillance who underwent tracking MRI/US fusion biopsy of Gleason 6 prostate cancer, on at least two distinct occasions, between 2012 and 2014 were enrolled. MRI/US fusion was used to track and resample specific cancer foci. IHC for ERG and targeted RNA/DNA next generation sequencing (NGS) were performed on formalin-fixed paraffin-embedded prostate biopsy specimens to assess clonality.Results: Thirty-one men with median age and PSA of 65 years and 4.6 ng/mL, respectively, were analyzed. The median sampling interval was 12 months (range, 5-35). Of the 26 evaluable men, ERG IHC concordance was found between initial and repeat biopsies in 25 (96%), indicating resampling of the same clonal focus over time. Targeted NGS supported ERG IHC results and identified unique and shared driving mutations, such as IDH1 and SPOP, in paired specimens. Of the nine men (34.6%) who were found to have Gleason >=7 on repeat biopsy, all displayed temporal ERG concordance. Prioritized genetic alterations were detected in 50% (13/26) of paired samples. Oncogenic mutations were detected in 22% (2/9) of Gleason 6 cancers prior to progression and 44% (4/9) of Gleason >=7 cancers when progression occurred.Conclusions: Precise tracking of prostate cancer foci via MRI/US fusion biopsy allowed subsequent resampling of the same clonal focus of cancer over time. Further research is needed to clarify the grade progression potential of Gleason 6 prostate cancer. Clin Cancer Res; 23(4); 985-91. (c)2016 AACR. PMID- 28031428 TI - Reaction of Leaf Weevil Phyllobius arborator (Coleoptera: Curculionidae) to Manganese Content in Diet. AB - Reaction of leaf weevil (Phyllobius arborator (Herbst)) to increased concentration of manganese in diet was investigated in laboratory rearing with controlled temperature, humidity, and light conditions. Food for leaf weevils in rearing (leaves of birch Betula pendula Roth) was contaminated by soaking the leaves in solutions of MnCl2.4H2O with graded concentration of manganese. Direct influence of food was characterized by the consumed amount of leaves, period of feeding, and weight of P. arborator adults. At the same time, the levels of manganese in unconsumed food, excrement, and bodies of adults were determined.Even very high content of manganese in food did not cause significantly different reaction of P. arborator adults in comparison to individuals in control treatment. No significant difference in the quantity of the consumed food, weight of adults, and duration of their feeding period was found between the treatments within the experiment. The content of manganese found in food, excrement, and adult beetles indicate that P. arborator avoided manganese intoxication through food by both-voiding manganese through the feces and sequestering it at relatively high concentrations in unspecified parts of their body. PMID- 28031429 TI - Effects of Temperature, Photoperiod, and Rainfall on Morphometric Variation of Diaphorina citri (Hemiptera: Liviidae). AB - Phenotypic plasticity provides a mechanism by which an organism can adapt to new or changing environments. Earlier studies have demonstrated the variability of Diaphorina citri Kuwayama (Asian citrus psyllid) population dynamics, but no analysis of morphological changes induced by seasonal or artificial laboratory induced conditions has yet been documented. Such morphometric variation has been found to correspond in dispersal capabilities in several insect taxa. In this study, the effects of temperature and photoperiod on morphometric variation of D. citri were examined through laboratory rearing of psyllids under controlled temperatures (20 degrees C, 28 degrees C, and 30 degrees C) and under a short photoperiod of 10.5:13.5 (L:D) h and a long photoperiod of 16:8 (L:D) h. Diaphorina citri were field-collected monthly from three citrus groves in Fort Pierce, Gainesville, and Immokalee, FL, to evaluate potential field-associated environmental effects. Both traditional and geometric morphometric data were used to analyze the correlation between environmental and morphometric variation. A strong correlation was found between temperature and shape change, with larger and broader wings at colder temperatures in the laboratory. Short day length resulted in shorter and narrower wings as well. From the field, temperature, rainfall, and photoperiod were moderately associated with shape parameters. Adult D. citri with blue/green abdomens collected in the laboratory and field studies were larger in size and shape than those with brown/gray abdomens. PMID- 28031430 TI - Metabolic Disposition of Luteolin Is Mediated by the Interplay of UDP Glucuronosyltransferases and Catechol-O-Methyltransferases in Rats. AB - Luteolin partially exerts its biologic effects via its metabolites catalyzed by UDP-glucuronosyltransferases (UGTs) and catechol-O-methyltransferases (COMTs). However, the interplay of UGTs and COMTs in mediating luteolin disposition has not been well clarified. In this study, we investigated the glucuronidation and methylation pathways of luteolin mediated by the interplay of UGTs and COMTs in vivo and in vitro. A total of nine luteolin metabolites was detected in rat plasma and bile by liquid chromatography-tandem mass spectrometry, namely, three glucuronides, two methylated metabolites, and four methylated glucuronides. Luteolin-3'-glucuronide (Lut-3'-G) exhibited the highest systemic exposure among these metabolites. Kinetics studies in rat liver S9 fractions suggested two pathways, as follows: 1) Luteolin was glucuronidated to luteolin-7-glucuronide, luteolin-4'-glucuronide, and Lut-3'-G by UGTs, and then Lut-7-G was methylated to chrysoeriol-7-glucuronide and diosmetin-7-glucuronide by COMTs. 2) Alternatively, luteolin was methylated to chrysoeriol and diosmetin by COMTs, and then chrysoeriol and diosmetin were glucuronidated by UGTs to their respective glucuronides. The methylation rate of luteolin was significantly increased by the absence of glucuronidation, whereas the glucuronidation rate was increased by the absence of methylation, but to a lesser extent. In conclusion, two pathways mediated by the interplay of UGTs and COMTs are probably involved in the metabolic disposition of luteolin. The glucuronidation and methylation of luteolin compensate for each other, although glucuronidation is the predominant pathway. PMID- 28031432 TI - Implementation of Rapid Molecular Infectious Disease Diagnostics: the Role of Diagnostic and Antimicrobial Stewardship. AB - New rapid molecular diagnostic technologies for infectious diseases enable expedited accurate microbiological diagnoses. However, diagnostic stewardship and antimicrobial stewardship are necessary to ensure that these technologies conserve, rather than consume, additional health care resources and optimally affect patient care. Diagnostic stewardship is needed to implement appropriate tests for the clinical setting and to direct testing toward appropriate patients. Antimicrobial stewardship is needed to ensure prompt appropriate clinical action to translate faster diagnostic test results in the laboratory into improved outcomes at the bedside. This minireview outlines the roles of diagnostic stewardship and antimicrobial stewardship in the implementation of rapid molecular infectious disease diagnostics. PMID- 28031433 TI - Comparison of Phenotypic Tests and an Immunochromatographic Assay and Development of a New Algorithm for Detection of OXA-48-like Carbapenemases. AB - OXA-48 is the most prevalent carbapenemase in Enterobacteriaceae in Europe and the Middle East, but it is frequently missed because many isolates display low MICs for carbapenems. Furthermore, in contrast to metallo-beta-lactamases or Klebsiella pneumoniae carbapenemases (KPC), no specific inhibitor is available for the phenotypic detection of OXA-48. Molecular detection of blaOXA-48 is the "gold standard" but is not available in many laboratories. A few phenotypic assays have been described but have not been independently evaluated. The aim of this study was the systematic comparison of phenotypic tests and an immunochromatographic assay (ICT) for the detection of OXA-48/OXA-48-like carbapenemases and the development of an algorithm for reliable phenotypic detection of OXA-48. Four phenotypic tests (temocillin disk test, faropenem disk test, OXA-48 disk test, and high-inoculum [HI] OXA-48 disk test) and a new ICT (OXA-48 K-SeT) were compared by using a set of 166 Enterobacteriaceae isolates, including isolates producing OXA-48/OXA-48-like carbapenemases (n = 84) or Ambler class A and B carbapenemases (n = 41) and carbapenemase-negative isolates (n = 41). The sensitivity and specificity for the different assays were 100% and 43.9% for temocillin, 57.1% and 98.8% for faropenem, 53.6% and 100% for the OXA-48 disk test, 98.8% and 97.6% for the HI OXA-48 disk test, and 100% and 100% for the ICT, respectively. The ICT displayed the highest sensitivity and specificity and was the most rapid assay, but it is more costly than phenotypic assays. Based on these results, a new algorithm incorporating temocillin, faropenem, and ICT which allows cost-effective detection of OXA-48 with 100% sensitivity and specificity was developed. PMID- 28031434 TI - Testing for Cytomegalovirus in Pregnancy. AB - Congenital cytomegalovirus (CMV) infection represents a relevant cause of deafness and neurological damage in newborns. Intrauterine CMV transmission might result after primary or nonprimary infections, though at different rates (30% versus 0.2%, respectively). At present, a prenatal diagnosis of CMV infection is based mainly on maternal serology, the detection of CMV-DNA in amniotic fluid and fetal blood, and ultrasound (US) and magnetic resonance imaging (MRI). Recent evidences suggest that congenital CMV infection may be an immune-mediated disease and that evaluation of humoral and especially T-cell immunities may improve the overall prenatal diagnosis. This review summarizes the most recent advancements in the diagnosis of maternal and prenatal CMV infections. PMID- 28031435 TI - Evaluation of a Commercial Multiplex Quantitative PCR (qPCR) Assay for Simultaneous Detection of Mycoplasma genitalium and Macrolide Resistance Associated Mutations in Clinical Specimens. PMID- 28031436 TI - Comparative Genome Analysis and Global Phylogeny of the Toxin Variant Clostridium difficile PCR Ribotype 017 Reveals the Evolution of Two Independent Sublineages. AB - The diarrheal pathogen Clostridium difficile consists of at least six distinct evolutionary lineages. The RT017 lineage is anomalous, as strains only express toxin B, compared to strains from other lineages that produce toxins A and B and, occasionally, binary toxin. Historically, RT017 initially was reported in Asia but now has been reported worldwide. We used whole-genome sequencing and phylogenetic analysis to investigate the patterns of global spread and population structure of 277 RT017 isolates from animal and human origins from six continents, isolated between 1990 and 2013. We reveal two distinct evenly split sublineages (SL1 and SL2) of C. difficile RT017 that contain multiple independent clonal expansions. All 24 animal isolates were contained within SL1 along with human isolates, suggesting potential transmission between animals and humans. Genetic analyses revealed an overrepresentation of antibiotic resistance genes. Phylogeographic analyses show a North American origin for RT017, as has been found for the recently emerged epidemic RT027 lineage. Despite having only one toxin, RT017 strains have evolved in parallel from at least two independent sources and can readily transmit between continents. PMID- 28031437 TI - Levels of Antibody against Glycopeptidolipid Core as a Marker for Monitoring Treatment Response in Mycobacterium avium Complex Pulmonary Disease: a Prospective Cohort Study. AB - The diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) is sometimes complicated and time-consuming. A serodiagnostic kit that measures the serum levels of IgA antibodies against the glycopeptidolipid (GPL) core is commercially available and has good diagnostic accuracy for MAC-PD. However, the significance of measurement of GPL core IgA antibody levels in monitoring for chemotherapy response in patients with MAC-PD was not well investigated. Thirty four treatment naive MAC-PD patients who were started on multidrug chemotherapy were enrolled. Their antibody levels were prospectively measured at regular intervals. The relationships between their antibody levels and the therapeutic outcomes were examined. The patients were classified into three groups (conversion, recurrence, and nonconversion) based on the bacteriological outcomes after chemotherapy. There were no significant differences in the antibody levels before treatment between the culture conversion (n = 19), recurrence (n = 7), and nonconversion (n = 8) groups (P = 0.9881). The levels decreased significantly after the chemotherapy (P < 0.0001). Recurrence and/or worsening of chest radiography findings were observed in cases whose antibody levels subsequently increased after cessation of the chemotherapy. No significant difference in the percent decrease in antibody levels by the chemotherapy was observed between the culture conversion and recurrence groups (P = 0.9338). The initial antibody levels are not a predictor of therapeutic outcomes, and also the percent decrease in antibody levels is not a sufficient indicator of the cessation of chemotherapy. However, serial measurements of antibody levels may allow objective monitoring of disease activity in individual MAC-PD patients. PMID- 28031438 TI - Integrating Advanced Molecular Technologies into Public Health. AB - Advances in laboratory and information technologies are transforming public health microbiology. High-throughput genome sequencing and bioinformatics are enhancing our ability to investigate and control outbreaks, detect emerging infectious diseases, develop vaccines, and combat antimicrobial resistance, all with increased accuracy, timeliness, and efficiency. The Advanced Molecular Detection (AMD) initiative has allowed the Centers for Disease Control and Prevention (CDC) to provide leadership and coordination in integrating new technologies into routine practice throughout the U.S. public health laboratory system. Collaboration and partnerships are the key to navigating this transition and to leveraging the next generation of methods and tools most effectively for public health. PMID- 28031439 TI - Successful treatment of renal tubular acidosis and recurrent secondary struvite kidney stones with rituximab in a patient with primary Sjogren's syndrome. PMID- 28031440 TI - Building a rheumatology team for East Africa: A call for action! PMID- 28031441 TI - Modular transcriptional repertoire analyses identify a blood neutrophil signature as a candidate biomarker for lupus nephritis. AB - Objective: LN is a severe complication of SLE. Non-invasive biomarkers are needed for identifying patients at risk of a renal flare, for differentiating proliferative from non-proliferative forms and for assessing prognoses for LN. Methods: We assessed the link between blood transcriptional signatures and LN using blood samples from patients with biopsy-proven LN, extra-renal SLE flares or quiescent SLE. Healthy controls, and control patients with glomerular diseases or bacterial sepsis were included. Modular repertoire analyses from microarray data were confirmed by PCR. Results: A modular neutrophil signature (upregulation of module M5.15) was present in 65% of SLE patients and was strongly associated with LN. M5.15 activity was stronger in LN than in extra-renal flares (88 vs 17%). M5.15 was neither correlated to IFN modules, nor to SLEDAI or anti-dsDNA antibodies, but moderately to CS dose. M5.15 activity was associated with severity of LN, was stronger when proliferative, and decreased in patients responding to treatment. M5.15 activation was not caused by higher CS dose because it correlated only moderately to neutrophil count and was also observed among quiescent patients. Among quiescent patients, those with a past history of LN had higher M5.15 activity (50 vs 8%). M5.15 activation was present in patients with bacterial sepsis or ANCA-associated vasculitis, but not in patients with other glomerular diseases. Overall, M5.15 activation was associated with past, present or future flares of LN. Conclusion: Modular neutrophil signature could be a biomarker for stratifying LN risk and for monitoring its response to treatment. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00920114. PMID- 28031442 TI - Decreased platelet size is associated with platelet activation and anti phospholipid syndrome in systemic lupus erythematosus. AB - Objectives: . SLE is an autoimmune disease with increased cardiovascular morbidity and platelet activation. In the general population, increased platelet size predicts platelet reactivity and cardiovascular disease. The aim of this study was to investigate whether platelet size related to platelet activation and cardiovascular disease in SLE. Methods: . Fresh blood samples from SLE patients ( n = 148), healthy volunteers ( n = 79) and disease controls ( n = 40) were analysed for platelet size and activation by flow cytometry, ELISA and cell count. Associations to manifest cardiovascular disease, venous thrombosis and APS were adjusted for traditional cardiovascular risk factors using logistic regression analysis. Results: . SLE patients had decreased platelet size as compared with healthy controls ( P = 0.003). In SLE, decreased platelet size was related to increased platelet activation, in particular microparticle formation ( P < 0.0001, r = -0.46) and release of serotonin from dense granules ( P < 0.001, r = 0.57). SLE patients with aCL had decreased platelet size ( P = 0.02) and aCL decreased platelet size in vitro ( P = 0.007). In contrast to the general population, increased platelet size was not associated with cardiovascular disease. Instead, decreased platelet size was associated with secondary APS, even after adjusting for traditional cardiovascular risk factors ( P = 0.01, odds ratio 3.58). Conclusion: . Platelet size is decreased in SLE patients and associated with microparticle formation and APS. Future studies are needed to determine the underlying mechanism(s) as well as the potential predictive value of small platelets for disease complications in SLE. PMID- 28031443 TI - Photo Quiz: A 44-Year-Old Kidney Transplant Patient with Pneumonia. PMID- 28031444 TI - The Brief Case: Bacteremia Caused by Helicobacter cinaedi. PMID- 28031445 TI - Universal PCR Primers Are Critical for Direct Sequencing-Based Enterovirus Genotyping. PMID- 28031446 TI - Reply to "Universal PCR Primers Are Critical for Direct Sequencing-Based Enterovirus Genotyping". PMID- 28031447 TI - Correction for Alhhazmi et al., Epidemiology of Invasive Group B Streptococcal Disease in Alberta, Canada, from 2003 to 2013. PMID- 28031448 TI - Correction for Shewmaker et al., Reevaluation of the Taxonomic Status of Recently Described Species of Enterococcus: Evidence that E. thailandicus Is a Senior Subjective Synonym of "E. sanguinicola" and Confirmation of E. caccae as a Species Distinct from E. silesiacus. PMID- 28031449 TI - Correction for Shewmaker et al., Evaluation of Methods for Identification and Determination of the Taxonomic Status of Strains Belonging to the Streptococcus porcinus-Streptococcus pseudoporcinus Complex Isolated from Animal, Human, and Dairy Sources. PMID- 28031450 TI - Correction for Shewmaker et al., Phenotypic, Genotypic, and Antimicrobial Characteristics of Streptococcus halichoeri Isolates from Humans, Proposal To Rename Streptococcus halichoeri as Streptococcus halichoeri subsp. halichoeri, and Description of Streptococcus halichoeri subsp. hominis subsp. nov., a Bacterium Associated with Human Clinical Infections. PMID- 28031451 TI - Closing the Brief Case: Bacteremia Caused by Helicobacter cinaedi. PMID- 28031452 TI - Answer to January 2017 Photo Quiz. PMID- 28031453 TI - Acute Liver Failure Meets SOPH Syndrome: A Case Report on an Intermediate Phenotype. AB - Acute liver failure (ALF) is a life-threatening condition in the absence of preexisting liver disease in children. The main clinical presentation comprises hepatic dysfunction, elevated liver biochemical values, and coagulopathy. The etiology of ALF remains unclear in most affected children; however, the recent identification of mutations in the neuroblastoma amplified sequence (NBAS) gene in autosomal recessively inherited ALF has shed light on the cause of a subgroup of fever-triggered pediatric ALF episodes. Previously, biallelic mutations in NBAS have been reported to be associated with a syndrome comprising short stature, optic atrophy, and Pelger-Huet anomaly (SOPH) specifically occurring in the Yakut population. No hepatic phenotype has been observed in individuals with this disorder who all carry the homozygous NBAS founder mutation c.5741G>A [p.(Arg1914His)]. We present the case of a 4-year-old girl with the cardinal features of SOPH syndrome: characteristic facial dysmorphism, postnatal growth retardation, delay of bone age, slender long bones, optic atrophy, and Pelger Huet anomaly. During the first 2 years of her life, a series of infections with episodes of fever were accompanied by elevated liver enzyme levels, but hyperammonemia, hypoglycemia, coagulopathy, or encephalopathy suggestive of acute and severe liver disease were never observed. Whole exome sequencing in the patient revealed compound heterozygosity of the 2 NBAS variants, p.(Arg1914His) and p.(Glu943*). This case highlights the variability of clinical presentation associated with NBAS deficiency. Absence of severe liver problems in this case and SOPH-affected Yakut subjects suggests that individuals carrying the NBAS missense mutation p.(Arg1914His) are less susceptible to developing ALF. PMID- 28031454 TI - RAD: Reactive Airways Disease or Really Asthma Disease? PMID- 28031455 TI - Independent effects of motivation and spatial attention in the human visual cortex. AB - Motivation and attention constitute major determinants of human perception and action. Nonetheless, it remains a matter of debate whether motivation effects on the visual cortex depend on the spatial attention system, or rely on independent pathways. This study investigated the impact of motivation and spatial attention on the activity of the human primary and extrastriate visual cortex by employing a factorial manipulation of the two factors in a cued pattern discrimination task. During stimulus presentation, we recorded event-related potentials and pupillary responses. Motivational relevance increased the amplitudes of the C1 component at ~70 ms after stimulus onset. This modulation occurred independently of spatial attention effects, which were evident at the P1 level. Furthermore, motivation and spatial attention had independent effects on preparatory activation as measured by the contingent negative variation; and pupil data showed increased activation in response to incentive targets. Taken together, these findings suggest independent pathways for the influence of motivation and spatial attention on the activity of the human visual cortex. PMID- 28031456 TI - A Novel Motif for S-Adenosyl-l-methionine Binding by the Ribosomal RNA Methyltransferase TlyA from Mycobacterium tuberculosis. AB - Capreomycin is a potent ribosome-targeting antibiotic that is an essential component of current antituberculosis treatments, particularly in the case of multidrug-resistant Mycobacterium tuberculosis (Mtb). Optimal capreomycin binding and Mtb ribosome inhibition requires ribosomal RNA methylation in both ribosome subunits by TlyA (Rv1694), an enzyme with dual 2'-O-methytransferase and putative hemolytic activities. Despite the important role of TlyA in capreomycin sensitivity and identification of inactivating mutations in the corresponding Mtb gene tlyA, which cause resistance to capreomycin, our current structural and mechanistic understanding of TlyA action remains limited. Here, we present structural and functional analyses of Mtb TlyA interaction with its obligatory co substrate for methyltransferase activity, S-adenosyl-l-methionine (SAM). Despite adopting a complete class I methyltransferase fold containing conserved SAM binding and catalytic motifs, the isolated TlyA carboxyl-terminal domain exhibits no detectable affinity for SAM. Further analyses identify a tetrapeptide motif (RXWV) in the TlyA interdomain linker as indispensable for co-substrate binding. Our results also suggest that structural plasticity of the RXWV motif could contribute to TlyA domain interactions, as well as specific recognition of its two structurally distinct ribosomal RNA targets. Our findings thus reveal a novel motif requirement for SAM binding by TlyA and set the stage for future mechanistic studies of TlyA substrate recognition and modification that underpin Mtb sensitivity to capreomycin. PMID- 28031457 TI - Force Spectroscopy of the Plasmodium falciparum Vaccine Candidate Circumsporozoite Protein Suggests a Mechanically Pliable Repeat Region. AB - The most effective vaccine candidate of malaria is based on the Plasmodium falciparum circumsporozoite protein (CSP), a major surface protein implicated in the structural strength, motility, and immune evasion properties of the infective sporozoites. It is suspected that reversible conformational changes of CSP are required for infection of the mammalian host, but the detailed structure and dynamic properties of CSP remain incompletely understood, limiting our understanding of its function in the infection. Here, we report the structural and mechanical properties of the CSP studied using single-molecule force spectroscopy on several constructs, one including the central region of CSP, which is rich in NANP amino acid repeats (CSPrep), and a second consisting of a near full-length sequence without the signal and anchor hydrophobic domains (CSPDeltaHP). Our results show that the CSPrep is heterogeneous, with 40% of molecules requiring virtually no mechanical force to unfold (<10 piconewtons (pN)), suggesting that these molecules are mechanically compliant and perhaps act as entropic springs, whereas the remaining 60% are partially structured with low mechanical resistance (~70 pN). CSPDeltaHP having multiple force peaks suggests specifically folded domains, with two major populations possibly indicating the open and collapsed forms. Our findings suggest that the overall low mechanical resistance of the repeat region, exposed on the outer surface of the sporozoites, combined with the flexible full-length conformations of CSP, may provide the sporozoites not only with immune evasion properties, but also with lubricating capacity required during its navigation through the mosquito and vertebrate host tissues. We anticipate that these findings would further assist in the design and development of future malarial vaccines. PMID- 28031458 TI - Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat. AB - Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 MUm in the plasma compartment of treated animals but were almost 100 fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1-/-) and missense (Npc1nmf164 ) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease. PMID- 28031459 TI - alpha4beta2 Nicotinic Acetylcholine Receptors: RELATIONSHIPS BETWEEN SUBUNIT STOICHIOMETRY AND FUNCTION AT THE SINGLE CHANNEL LEVEL. AB - Acetylcholine receptors comprising alpha4 and beta2 subunits are the most abundant class of nicotinic acetylcholine receptor in the brain. They contribute to cognition, reward, mood, and nociception and are implicated in a range of neurological disorders. Previous measurements of whole-cell macroscopic currents showed that alpha4 and beta2 subunits assemble in two predominant pentameric stoichiometries, which differ in their sensitivity to agonists, antagonists, and allosteric modulators. Here we compare agonist-elicited single channel currents from receptors assembled with an excess of either the alpha4 or beta2 subunit, forming receptor populations biased toward one or the other stoichiometry, with currents from receptors composed of five concatemeric subunits in which the subunit stoichiometry is predetermined. Our results associate each subunit stoichiometry with a unique single channel conductance, mean open channel lifetime, and sensitivity to the allosteric potentiator 3-[3-(3-pyridinyl)-1,2,4 oxadiazol-5-yl]benzonitrile (NS-9283). Receptors with the composition (alpha4beta2)2alpha4 exhibit high single channel conductance, brief mean open lifetime, and strong potentiation by NS-9283, whereas receptors with the composition (alpha4beta2)2beta2 exhibit low single channel conductance and long mean open lifetime and are not potentiated by NS-9283. Thus single channel current measurements reveal bases for the distinct functional and pharmacological properties endowed by different stoichiometries of alpha4 and beta2 subunits and establish pentameric concatemers as a means to delineate interactions between subunits that confer these properties. PMID- 28031460 TI - The Inhibitory Role of alpha2,6-Sialylation in Adipogenesis. AB - Adipose tissue plays critical roles in obesity and related diseases such as diabetes and cardiovascular diseases. Previous reports suggest that glycans, the most common posttranslational modifications, are involved in obesity-related diseases, but what type of glycan regulates adipogenesis during obesity remains unclear. In this study, we first quantified the mRNA levels of 167 genes (encoding 144 glycosyltransferases and 23 related enzymes) in visceral adipose tissues (VATs) from control mice and high-fat diet (HFD)-induced obese mice. We found that a gene encoding beta-galactoside alpha2,6-sialyltransferase-1 (St6gal1), a key enzyme responsible for the biosynthesis of alpha2,6-linked sialic acid in N-linked glycans, was most down-regulated in VATs from obese mice. We confirmed the reduction in alpha2,6-sialic acid in VATs from obese mice and differentiated adipocyte model 3T3-L1 cells. Using proteomic analysis, integrin beta1 was identified as one of the target alpha2,6-sialylated proteins in adipose tissues, and phosphorylation of its downstream molecule focal adhesion kinase was found to be decreased after HFD feeding. St6gal1 overexpression in differentiating 3T3-L1 cells inhibited adipogenesis with increased phosphorylation of focal adhesion kinase. Furthermore, St6gal1 knockout mice exhibited increased bodyweight and VAT weight after HFD feeding. The down regulation of St6gal1 during adipogenesis was canceled by treatment with a DNA methyltransferase inhibitor, suggesting an involvement of epigenetic DNA methylation in St6gal1 silencing. Our findings suggest that ST6GAL1 has an inhibitory role in adipogenesis through integrin-beta1 activation, providing new insights into the roles and regulation mechanisms of glycans in adipocytes during obesity. PMID- 28031461 TI - Heparan Sulfate Domains Required for Fibroblast Growth Factor 1 and 2 Signaling through Fibroblast Growth Factor Receptor 1c. AB - A small library of well defined heparan sulfate (HS) polysaccharides was chemoenzymatically synthesized and used for a detailed structure-activity study of fibroblast growth factor (FGF) 1 and FGF2 signaling through FGF receptor (FGFR) 1c. The HS polysaccharide tested contained both undersulfated (NA) domains and highly sulfated (NS) domains as well as very well defined non-reducing termini. This study examines differences in the HS selectivity of the positive canyons of the FGF12-FGFR1c2 and FGF22-FGFR1c2 HS binding sites of the symmetric FGF2-FGFR2-HS2 signal transduction complex. The results suggest that FGF12 FGFR1c2 binding site prefers a longer NS domain at the non-reducing terminus than FGF22-FGFR1c2 In addition, FGF22-FGFR1c2 can tolerate an HS chain having an N acetylglucosamine residue at its non-reducing end. These results clearly demonstrate the different specificity of FGF12-FGFR1c2 and FGF22-FGFR1c2 for well defined HS structures and suggest that it is now possible to chemoenzymatically synthesize precise HS polysaccharides that can selectively mediate growth factor signaling. These HS polysaccharides might be useful in both understanding and controlling the growth, proliferation, and differentiation of cells in stem cell therapies, wound healing, and the treatment of cancer. PMID- 28031462 TI - Phosphorylation at Ser8 as an Intrinsic Regulatory Switch to Regulate the Morphologies and Structures of Alzheimer's 40-residue beta-Amyloid (Abeta40) Fibrils. AB - Polymorphism of amyloid-beta (Abeta) fibrils, implying different fibril structures, may play important pathological roles in Alzheimer's disease (AD). Morphologies of Abeta fibrils were found to be sensitive to fibrillation conditions. Herein, the Ser8-phosphorylated Abeta (pAbeta), which is assumed to specially associate with symptomatic AD, is reported to modify the morphology, biophysical properties, cellular toxicity, and structures of Abeta fibrils. Under the same fibrillation conditions, pAbeta favors the formation of fibrils (Fpbeta), which are different from the wild-type Abeta fibrils (Fbeta). Both Fbeta and Fpbeta fibrils show single predominant morphologies. Compared with Fbeta, Fpbeta exhibits higher propagation efficiency and higher neuronal cell toxicity. The residue-specific structural differences between the Fbeta- and Fpbeta-seeded Abeta fibrils were identified using magic angle spin NMR. Our results suggest a potential regulatory mechanism of phosphorylation on Abeta fibril formation in AD and imply that the post-translationally modified Abeta, especially the phosphorylated Abeta, may be an important target for the diagnosis or treatment of AD at specific stages. PMID- 28031463 TI - New Insights into Structural Disorder in Human Respiratory Syncytial Virus Phosphoprotein and Implications for Binding of Protein Partners. AB - Phosphoprotein is the main cofactor of the viral RNA polymerase of Mononegavirales It is involved in multiple interactions that are essential for the polymerase function. Most prominently it positions the polymerase complex onto the nucleocapsid, but also acts as a chaperone for the nucleoprotein. Mononegavirales phosphoproteins lack sequence conservation, but contain all large disordered regions. We show here that N- and C-terminal intrinsically disordered regions account for 80% of the phosphoprotein of the respiratory syncytial virus. But these regions display marked dynamic heterogeneity. Whereas almost stable helices are formed C terminally to the oligomerization domain, extremely transient helices are present in the N-terminal region. They all mediate internal long-range contacts in this non-globular protein. Transient secondary elements together with fully disordered regions also provide protein binding sites recognized by the respiratory syncytial virus nucleoprotein and compatible with weak interactions required for the processivity of the polymerase. PMID- 28031464 TI - New Roles of Syntaxin-1A in Insulin Granule Exocytosis and Replenishment. AB - In type-2 diabetes (T2D), severely reduced islet syntaxin-1A (Syn-1A) levels contribute to insulin secretory deficiency. We generated beta-cell-specific Syn 1A-KO (Syn-1A-betaKO) mice to mimic beta-cell Syn-1A deficiency in T2D. Glucose tolerance tests showed that Syn-1A-betaKO mice exhibited blood glucose elevation corresponding to reduced blood insulin levels. Perifusion of Syn-1A-betaKO islets showed impaired first- and second-phase glucose-stimulated insulin secretion (GSIS) resulting from reduction in readily releasable pool and granule pool refilling. To unequivocally determine the beta-cell exocytotic defects caused by Syn-1A deletion, EM and total internal reflection fluorescence microscopy showed that Syn-1A-KO beta-cells had a severe reduction in the number of secretory granules (SGs) docked onto the plasma membrane (PM) at rest and reduced SG recruitment to the PM after glucose stimulation, the latter indicating defects in replenishment of releasable pools required to sustain second-phase GSIS. Whereas reduced predocked SG fusion accounted for reduced first-phase GSIS, selective reduction of exocytosis of short-dock (but not no-dock) newcomer SGs accounted for the reduced second-phase GSIS. These Syn-1A actions on newcomer SGs were partly mediated by Syn-1A interactions with newcomer SG VAMP8. PMID- 28031465 TI - Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate. AB - Intervention into amyloid deposition with anti-amyloid agents like the polyphenol epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and multiple myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL do they form amyloid deposits in vivo We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from the urine of AL and MM patients. We quantified their thermodynamic stabilities and monitored their aggregation under physiological conditions by thioflavin T fluorescence, light scattering, SDS stability, and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ~50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-beta and alpha-synuclein. PMID- 28031466 TI - Cell-based Fluorescence Complementation Reveals a Role for HIV-1 Nef Protein Dimerization in AP-2 Adaptor Recruitment and CD4 Co-receptor Down-regulation. AB - The HIV-1 Nef accessory factor enhances viral infectivity, immune evasion, and AIDS progression. Nef triggers rapid down-regulation of CD4 via the endocytic adaptor protein 2 (AP-2) complex, a process linked to enhanced viral infectivity and immune escape. Here, we describe a bimolecular fluorescence complementation (BiFC) assay to visualize the interaction of Nef with AP-2 and CD4 in living cells. Interacting protein pairs were fused to complementary non-fluorescent fragments of YFP and co-expressed in 293T cells. Nef interactions with both CD4 and AP-2 resulted in complementation of YFP and a bright fluorescent signal by confocal microcopy that localized to the cell periphery. Co-expression of the AP 2 alpha subunit enhanced the Nef.AP-2 sigma2 subunit BiFC signal and vice versa, suggesting that the AP-2 alpha-sigma2 hemicomplex interacts cooperatively with Nef. Mutagenesis of Nef amino acids Arg-134, Glu-174, and Asp-175, which stabilize Nef for AP-2 alpha-sigma2 binding in a recent co-crystal structure, substantially reduced AP-2 interaction without affecting CD4 binding. A dimerization-defective mutant of Nef failed to interact with either CD4 or AP-2 in the BiFC assay, indicating that Nef quaternary structure is required for CD4 and AP-2 recruitment as well as CD4 down-regulation. A small molecule previously shown to bind the Nef dimerization interface also reduced Nef interactions with AP-2 and CD4 and restored CD4 expression to the surface of HIV-infected cells. Our findings provide a mechanistic explanation for previous observations that dimerization-defective Nef mutants fail to down-regulate CD4 and validate the Nef dimerization interface as a target site for antiretroviral drug development. PMID- 28031467 TI - Maternal Sall4 Is Indispensable for Epigenetic Maturation of Mouse Oocytes. AB - Sall4 (Splat-like 4) plays important roles in maintaining pluripotency of embryonic stem cells and in various developmental processes. Here, we find that Sall4 is highly expressed in oocytes and early embryos. To investigate the roles of SALL4 in oogenesis, we generated Sall4 maternal specific knock-out mice by using CRISPR/Cas9 system, and we find that the maternal deletion of Sall4 causes developmental arrest of oocytes at germinal vesicle stage with non-surrounded nucleus, and the subsequent meiosis resumption is prohibited. We further discover that the loss of maternal Sall4 causes failure in establishment of DNA methylation in oocytes. Furthermore, we find that Sall4 modulates H3K4me3 and H3K27me3 modifications by regulating the expression of key histone demethylases coding genes Kdm5b, Kdm6a, and Kdm6b in oocytes. Moreover, we demonstrate that the aberrant H3K4me3 and H3K27me3 cause mis-expression of genes that are critical for oocytes maturation and meiosis resumption. Taken together, our study explores a pivotal role of Sall4 in regulating epigenetic maturation of mouse oocytes. PMID- 28031468 TI - PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch. AB - PRMT5 is the primary enzyme responsible for the deposition of the symmetric dimethylarginine in mammalian cells. In an effort to understand how PRMT5 is regulated, we identified a threonine phosphorylation site within a C-terminal tail motif, which is targeted by the Akt/serum- and glucocorticoid-inducible kinases. While investigating the function of this posttranslational modification, we serendipitously discovered that its free C-terminal tail binds PDZ domains (when unphosphorylated) and 14-3-3 proteins (when phosphorylated). In essence, a phosphorylation event within the last few residues of the C-terminal tail generates a posttranslational modification-dependent PDZ/14-3-3 interaction "switch." The C-terminal motif of PRMT5 is required for plasma membrane association, and loss of this switching capacity is not compatible with life. This signaling phenomenon was recently reported for the HPV E6 oncoprotein but has not yet been observed for mammalian proteins. To investigate the prevalence of PDZ/14-3-3 switching in signal transduction, we built a protein domain microarray that harbors PDZ domains and 14-3-3 proteins. We have used this microarray to interrogate the C-terminal tails of a small group of candidate proteins and identified ERBB4, PGHS2, and IRK1 (as well as E6 and PRMT5) as conforming to this signaling mode, suggesting that PDZ/14-3-3 switching may be a broad biological paradigm. PMID- 28031469 TI - Effects of Low-Oxygen Environments on the Radiation Tolerance of the Cabbage Looper Moth (Lepidoptera: Noctuidae). AB - Ionizing radiation is used as a phytosanitary treatment to mitigate risks from invasive species associated with trade of fresh fruits and vegetables. Commodity producers prefer to irradiate fresh product stored in modified atmosphere packaging that increases shelf life and delays ripening. However, irradiating insects in low oxygen may increase radiation tolerance, and regulatory agencies are concerned modified atmosphere packaging will decrease efficacy of radiation doses. Here, we examined how irradiation in a series of oxygen conditions (0.1 20.9 kPa O2) alters radiotolerance of larvae and pupae of a model lepidopteran Trichoplusia ni (Hubner) (Diptera: Noctuidae). Irradiating in severe hypoxia (0.1 kPa O2) increased radiation tolerance of insects compared with irradiating in atmospheric oxygen (20.9 kPa O2). Our data show irradiating pharate adult pupae at 600 Gy in moderately severe hypoxia (5 kPa O2) increased adult emergence compared with irradiation in atmospheric oxygen (20.9 kPa O2). Our data also show that in one of the three temporal replicates, irradiating T. ni larvae in moderately severe hypoxia (5 kPa O2) can also increase radiotolerance at an intermediate radiation dose of 100 Gy compared with irradiating in atmospheric oxygen conditions, but not at higher or lower doses. We discuss implications of our results in this model insect for the current generic doses for phytosanitary irradiation, including the recently proposed 250 Gy generic dose for lepidioptera larvae, and temporary restriction on irradiating commodities in modified atmosphere packaging that reduces the atmosphere to < 18 kPa O2. PMID- 28031470 TI - Effectiveness of Naturally Occurring Substances Added to Duck Litter in Reducing Emergence and Landing of Adult Musca domestica (Diptera: Muscidae). AB - Poultry barns provide an ideal breeding environment for Musca domestica L. (Diptera: Muscidae) owing to the controlled temperatures and litter (manure plus bedding material) accumulation. Management techniques that render the litter less suitable for immature stage development, such as the addition of naturally occurring insecticidal substances, could reduce fly infestations. The effectiveness of acetic, boric, and citric acids; diatomaceous earth; and hydrated lime at restricting female landing and growth of house flies in duck litter was evaluated. Litter treated with 1.9% and 4.7% by weight of acetic or boric acid had significantly lower adult emergence rates compared with the same concentrations of citric acid, diatomaceous earth, hydrated lime, or the untreated control litter. The pH of duck litter treated with acetic or citric acid was significantly reduced and remained significantly lower than the control litter (pH 8.7) for 10 d. Significantly more house flies landed on a house fly rearing substrate (wheat bran, powdered milk, bloodmeal, water, and yeast) than litter treated with any of the other test substances or the control. The LC50 for boric acid was estimated to be 0.01% by weight, which was lower than that of acetic acid (1.42%). Similarly, the LC90 of boric acid was estimated to be 0.12%, which was lower than that of acetic acid (10.03%). Acetic acid and boric acid have the potential to be incorporated into litter as a pest management tactic to reduce house fly populations in duck production facilities. PMID- 28031471 TI - Erratum. PMID- 28031472 TI - Seasonal Abundance and Phenology of Halyomorpha halys (Hemiptera: Pentatomidae) on Different Pepper Cultivars in the Mid-Atlantic (United States). AB - The brown marmorated stink bug, Halyomorpha halys (Stal), is an invasive stink bug (Hemiptera: Pentatomidae) introduced into the United States in the mid-1990s. Since its initial establishment, it has spread throughout the east coast as far south as Georgia, and as far north as New Hampshire. While information is available regarding H. halys behavior and life history in some crops, relatively little information is available for vegetables such as peppers. Key questions include understanding when H. halys enters pepper fields to feed and how best to predict infestations, what population levels create economic damage, and if peppers that vary in capsaicin levels also vary in susceptibility to attack. To answer these questions, replicated plots were set up across four mid-Atlantic states using three types of peppers: sweet bell, sweet banana, and hot chili. We found that there was no difference in the overall abundance of all life stages of H. halys on all pepper varieties tested. However, there were differences in bug density by site, but these differences did not translate to differences in the proportion of damaged fruit. The presence of adult H. halys is a better predictor of damage in banana peppers, whereas nymphs are a better predictor in bell pepper. In addition, across all sites, the presence of egg masses was low in pepper crops and densities of both adults and immatures tend to peak on pepper plants in early August. Altogether, this information can be used to help develop a pest management program in peppers that will reduce crop losses to this new devastating pest, while reducing the reliance on insecticides to manage this pest at the same time. PMID- 28031473 TI - Relative Efficacy of Two Clades of Aphelinus mali (Hymenoptera: Aphelinidae) for Control of Woolly Apple Aphid (Hemiptera: Aphididae) in China. AB - Aphelinus mali (Haldeman) is an effective natural enemy used in China to control woolly apple aphid. Previous studies have found that populations of A. mali in China fall into two distinct genetic clades. We found that one of these, the Shandong clade, is more effective as a biological control agent than the Liaoning clade. The control ability of the Shandong clade of A. mali (a/Th = 2.447) was found to be stronger than that of the Liaoning clade (a/Th = 1.278); the search parameter (Q) and the mutual interference parameter (m) of the Shandong clade (0.1166, 0.2567) were both significantly higher than that of the Liaoning clade (0.076, 0.185). The egg production and life (64.4 +/- 10.44 eggs and 16.26 +/- 1.04 (female), 13.54 +/- 0.75 (male) days, respectively) of the Shandong clade were both significantly higher than they were for the Liaoning clade (30.67 +/- 4.02 eggs and 9.34 +/- 0.67 (female), 7.64 +/- 0.48 (male) days, respectively), and the Shandong clade had a longer oviposition period for one oviposition (Shandong 86.6 s, Liaoning 61.4 s). We expect, in Shandong Province, the pest control ability of the Shandong clade of A. mali to be better than the Liaoning clade. PMID- 28031474 TI - Field Evaluation of Insecticides for Control of Cabbage Maggot (Diptera: Anthomyiidae) in Rutabaga in Canada. AB - At the time of this research, there were only two insecticides registered for control of cabbage maggot, Delia radicum L., in rutabaga in Canada, one of which (diazinon) will be deregistered by 2017, and resistance having been reported in some areas for the other (chlorpyrifos). To screen for chemistries to replace these organophosphates, and obtain efficacy data comparable between key vegetable brassica production areas in Canada, four small plot field studies were conducted concurrently in British Columbia, Saskatchewan, Ontario, and Quebec in 2009. These studies followed standardized protocols for seeding, application of insecticide drenches, sampling and damage assessment, and generally tested the same products. Of the insecticides evaluated, none provided maggot control comparable with the industry standard, chlorpyrifos. However, cyantraniliprole (Cyazypyr 200SC; registered in 2015 as Verimark) applied at 3 g AI (15.0 ml product)/100 m row of seeded rutabagas consistently provided the next highest reduction in % culls, suggesting the efficacy of this chemical may be improved if used at higher rates. The results of these studies are discussed in the context of current literature on D. radicum management in rutabaga. Future management strategies are also discussed, including a transplant plug treatment approach for increasing the dosage per plant and efficacy of chemistries such as Cyazypyr 200SC in the field. PMID- 28031476 TI - 5-hydroxytryptamine synthesized in the aorta-gonad-mesonephros regulates hematopoietic stem and progenitor cell survival. AB - The in vitro or ex vivo production of transplantable hematopoietic stem cells (HSCs) holds great promise for the treatment of hematological diseases in the clinic. However, HSCs have not been produced from either embryonic or induced pluripotent stem cells. In this study, we report that 5-hydroxytryptamine (5-HT; also called serotonin) can enhance the generation of hematopoietic stem and progenitor cells (HSPCs) in vitro and is essential for the survival of HSPCs in vivo during embryogenesis. In tryptophan hydroxylase 2-deficient embryos, a decrease in 5-HT synthesized in the aorta-gonad-mesonephros leads to apoptosis of nascent HSPCs. Mechanistically, 5-HT inhibits the AKT-Foxo1 signaling cascade to protect the earliest HSPCs in intraaortic hematopoietic clusters from excessive apoptosis. Collectively, our results reveal an unexpected role of 5-HT in HSPC development and suggest that 5-HT signaling may be a potential therapeutic target for promoting HSPC survival. PMID- 28031477 TI - Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation. AB - Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1beta or its receptor. However the role of lipin-2 during IL-1beta production remains elusive. We show here that lipin-2 controls excessive IL-1beta formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1beta during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K+ efflux, apoptosis associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1beta production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome. PMID- 28031475 TI - Physiological Characterization of a Plant Mitochondrial Calcium Uniporter in Vitro and in Vivo. AB - Over the recent years, several proteins that make up the mitochondrial calcium uniporter complex (MCUC) mediating Ca2+uptake into the mitochondrial matrix have been identified in mammals, including the channel-forming protein MCU. Although six MCU gene homologs are conserved in the model plant Arabidopsis (Arabidopsis thaliana) in which mitochondria can accumulate Ca2+, a functional characterization of plant MCU homologs has been lacking. Using electrophysiology, we show that one isoform, AtMCU1, gives rise to a Ca2+-permeable channel activity that can be observed even in the absence of accessory proteins implicated in the formation of the active mammalian channel. Furthermore, we provide direct evidence that AtMCU1 activity is sensitive to the mitochondrial calcium uniporter inhibitors Ruthenium Red and Gd3+, as well as to the Arabidopsis protein MICU, a regulatory MCUC component. AtMCU1 is prevalently expressed in roots, localizes to mitochondria, and its absence causes mild changes in Ca2+ dynamics as assessed by in vivo measurements in Arabidopsis root tips. Plants either lacking or overexpressing AtMCU1 display root mitochondria with altered ultrastructure and show shorter primary roots under restrictive growth conditions. In summary, our work adds evolutionary depth to the investigation of mitochondrial Ca2+ transport, indicates that AtMCU1, together with MICU as a regulator, represents a functional configuration of the plant mitochondrial Ca2+ uptake complex with differences to the mammalian MCUC, and identifies a new player of the intracellular Ca2+ regulation network in plants. PMID- 28031478 TI - TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity. AB - MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)-induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65-/- mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation. PMID- 28031479 TI - Peptidylarginine deiminase 4 promotes age-related organ fibrosis. AB - Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4-/- mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4-/- mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4-/- myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction. PMID- 28031480 TI - CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. AB - Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML. PMID- 28031482 TI - Involvement of fission yeast Pdc2 in RNA degradation and P-body function. AB - In this study we identified Pdc2, the fission yeast ortholog of human Pat1b protein, which forms a complex with Lsm1-7 and plays a role in coupling deadenylation and decapping. The involvement of Pdc2 in RNA degradation and P body function was also determined. We found that Pdc2 interacts with Dcp2 and is required for decapping in vivo. Although not absolutely essential for P-body assembly, overexpression of Pdc2 enhanced P-body formation even in the absence of Pdc1, the fission yeast functional homolog of human Edc4 protein, indicating that Pdc2 also plays a role in P-body formation. Intriguingly, in the absence of Pdc2, Lsm1 was found to accumulate in the nucleus, suggesting that Pdc2 shuttling between nucleus and cytoplasm plays a role in decreasing the nuclear concentration of Lsm1 to increase Lsm1 in the cytoplasm. Furthermore, unlike other components of P-bodies, the deadenylase Ccr4 did not accumulate in P-bodies in cells growing under favorable conditions and was only recruited to P-bodies after deprivation of glucose in a Pdc2-Lsm1-dependent manner, indicating a function of Pdc2 in cellular response to environmental stress. In supporting this idea, pdc2 mutants are defective in recovery from glucose starvation with a much longer time to re-enter the cell cycle. In keeping with the notion that Pat1 is a nucleocytoplasmic protein, functioning also in the nucleus, we found that Pdc2 physically and genetically interacts with the nuclear 5'-3' exonuclease Dhp1. A function of Pdc2-Lsm1, in concert with Dhp1, regulating RNA by promoting its decapping/destruction in the nucleus was suggested. PMID- 28031481 TI - Xenopus Piwi proteins interact with a broad proportion of the oocyte transcriptome. AB - Piwi proteins utilize small RNAs (piRNAs) to recognize target transcripts such as transposable elements (TE). However, extensive piRNA sequence diversity also suggests that Piwi/piRNA complexes interact with many transcripts beyond TEs. To determine Piwi target RNAs, we used ribonucleoprotein-immunoprecipitation (RIP) and cross-linking and immunoprecipitation (CLIP) to identify thousands of transcripts associated with the Piwi proteins XIWI and XILI (Piwi-protein associated transcripts, PATs) from early stage oocytes of X. laevis and X. tropicalis Most PATs associate with both XIWI and XILI and include transcripts of developmentally important proteins in oogenesis and embryogenesis. Only a minor fraction of PATs in both frog species displayed near perfect matches to piRNAs. Since predicting imperfect pairing between all piRNAs and target RNAs remains intractable, we instead determined that PAT read counts correlate well with the lengths and expression levels of transcripts, features that have also been observed for oocyte mRNAs associated with Drosophila Piwi proteins. We used an in vitro assay with exogenous RNA to confirm that XIWI associates with RNAs in a length- and concentration-dependent manner. In this assay, noncoding transcripts with many perfectly matched antisense piRNAs were unstable, whereas coding transcripts with matching piRNAs were stable, consistent with emerging evidence that Piwi proteins both promote the turnover of TEs and other RNAs, and may also regulate mRNA localization and translation. Our study suggests that Piwi proteins play multiple roles in germ cells and establishes a tractable vertebrate system to study the role of Piwi proteins in transcript regulation. PMID- 28031483 TI - Speedy A-Cdk2 binding mediates initial telomere-nuclear envelope attachment during meiotic prophase I independent of Cdk2 activation. AB - Telomere attachment to the nuclear envelope (NE) is a prerequisite for chromosome movement during meiotic prophase I that is required for pairing of homologous chromosomes, synapsis, and homologous recombination. Here we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is specifically localized to telomeres in prophase I male and female germ cells in mice, and plays an essential role in the telomere-NE attachment. Deletion of Spdya in mice disrupts telomere-NE attachment, and this impairs homologous pairing and synapsis and leads to zygotene arrest in male and female germ cells. In addition, we have identified a telomere localization domain on Speedy A covering the distal N terminus and the Cdk2-binding Ringo domain, and this domain is essential for the localization of Speedy A to telomeres. Furthermore, we found that the binding of Cdk2 to Speedy A is indispensable for Cdk2's localization on telomeres, suggesting that Speedy A and Cdk2 might be the initial components that are recruited to the NE for forming the meiotic telomere complex. However, Speedy A Cdk2-mediated telomere-NE attachment is independent of Cdk2 activation. Our results thus indicate that Speedy A and Cdk2 might mediate the initial telomere NE attachment for the efficient assembly of the telomere complex that is essential for meiotic prophase I progression. PMID- 28031484 TI - Identification of NAD+ capped mRNAs in Saccharomyces cerevisiae. AB - RNAs besides tRNA and rRNA contain chemical modifications, including the recently described 5' nicotinamide-adenine dinucleotide (NAD+) RNA in bacteria. Whether 5' NAD-RNA exists in eukaryotes remains unknown. We demonstrate that 5' NAD-RNA is found on subsets of nuclear and mitochondrial encoded mRNAs in Saccharomyces cerevisiae NAD-mRNA appears to be produced cotranscriptionally because NAD-RNA is also found on pre-mRNAs, and only on mitochondrial transcripts that are not 5' end processed. These results define an additional 5' RNA cap structure in eukaryotes and raise the possibility that this 5' NAD+ cap could modulate RNA stability and translation on specific subclasses of mRNAs. PMID- 28031485 TI - Human hunters and nonhuman predators: Fundamental differences. PMID- 28031486 TI - Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4. AB - Human cytochrome P450 3A4 (CYP3A4) is a major hepatic and intestinal enzyme that oxidizes more than 60% of administered therapeutics. Knowledge of how CYP3A4 adjusts and reshapes the active site to regioselectively oxidize chemically diverse compounds is critical for better understanding structure-function relations in this important enzyme, improving the outcomes for drug metabolism predictions, and developing pharmaceuticals that have a decreased ability to undergo metabolism and cause detrimental drug-drug interactions. However, there is very limited structural information on CYP3A4-substrate interactions available to date. Despite the vast variety of drugs undergoing metabolism, only the sedative midazolam (MDZ) serves as a marker substrate for the in vivo activity assessment because it is preferentially and regioselectively oxidized by CYP3A4. We solved the 2.7 A crystal structure of the CYP3A4-MDZ complex, where the drug is well defined and oriented suitably for hydroxylation of the C1 atom, the major site of metabolism. This binding mode requires H-bonding to Ser119 and a dramatic conformational switch in the F-G fragment, which transmits to the adjacent D, E, H, and I helices, resulting in a collapse of the active site cavity and MDZ immobilization. In addition to providing insights on the substrate-triggered active site reshaping (an induced fit), the crystal structure explains the accumulated experimental results, identifies possible effector binding sites, and suggests why MDZ is predominantly metabolized by the CYP3A enzyme subfamily. PMID- 28031487 TI - Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms. AB - Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance. PMID- 28031488 TI - CD74 is a novel transcription regulator. AB - CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor. Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which regulates cell survival. In the present study, we characterized the transcriptional activity of CD74-ICD in chronic lymphocytic B cells. We show that following CD74 activation, CD74-ICD interacts with the transcription factors RUNX (Runt related transcription factor) and NF-kappaB and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. This process leads to regulation of expression of these genes. Our results suggest that identifying targets of CD74 will help in understanding of essential pathways regulating B-cell survival in health and disease. PMID- 28031490 TI - Editorial: Giant Oaks from Little Acorns Grow. PMID- 28031491 TI - Correlation of femoral tunnel length with body height, limb length, and thigh length in Indian patients undergoing anterior cruciate ligament reconstruction. AB - PURPOSE: To measure the femoral tunnel length created through a far medial portal and determine its correlation with body height, limb length, and thigh length in 404 Indian patients undergoing anterior cruciate ligament (ACL) reconstruction. METHODS: 364 male and 40 female Indian patients aged 18 to 51 (mean, 26.8) years underwent ACL reconstruction by a single surgeon using the hamstrings tendon autograft. Their body height, limb length, and thigh length were measured by a single assessor, as was the femoral tunnel length. RESULTS: The mean femoral tunnel length was 34.5 mm. It was <30 mm in 28 patients and <25 mm in 2 patients. The correlation coefficients of the femoral tunnel length with body height, limb length, and thigh length were 0.485 (p<0.0001), 0.426 (p<0.0001), and 0.304 (p<0.0001). No patient had posterior wall blowout fracture. CONCLUSION: The femoral tunnel length positively correlated with body height, limb length, and thigh length in 404 Indian patients. PMID- 28031489 TI - Unrestrained AMPylation targets cytosolic chaperones and activates the heat shock response. AB - Protein AMPylation is a conserved posttranslational modification with emerging roles in endoplasmic reticulum homeostasis. However, the range of substrates and cell biological consequences of AMPylation remain poorly defined. We expressed human and Caenorhabditis elegans AMPylation enzymes-huntingtin yeast-interacting protein E (HYPE) and filamentation-induced by cyclic AMP (FIC)-1, respectively-in Saccharomyces cerevisiae, a eukaryote that lacks endogenous protein AMPylation. Expression of HYPE and FIC-1 in yeast induced a strong cytoplasmic Hsf1-mediated heat shock response, accompanied by attenuation of protein translation, massive protein aggregation, growth arrest, and lethality. Overexpression of Ssa2, a cytosolic heat shock protein (Hsp)70, was sufficient to partially rescue growth. In human cell lines, overexpression of active HYPE similarly induced protein aggregation and the HSF1-dependent heat shock response. Excessive AMPylation also abolished HSP70-dependent influenza virus replication. Our findings suggest a mode of Hsp70 inactivation by AMPylation and point toward a role for protein AMPylation in the regulation of cellular protein homeostasis beyond the endoplasmic reticulum. PMID- 28031492 TI - Tibial plateau slopes in Indian patients with or without anterior cruciate ligament injury: a magnetic resonance imaging study. AB - PURPOSE: To compare anterior cruciate ligament (ACL)-injured and ACL-intact patients as well as males and females in terms of tibial plateau slopes to determine their association with ACL injury. METHODS: Magnetic resonance images (MRI) of the knee of 310 male and 179 female skeletally mature Indian patients (mean age, 40 years) with (n=170+29) or without (n=140+150) ACL injury were reviewed. Their medial and lateral tibial plateau slopes (MTPS and LTPS), medial tibial plateau depth (MTPD), and lateral tibial plateau height (LTPH) were measured using MRI. RESULTS: The ACL-injured and ACL-intact groups were comparable in terms of MTPS (6.72o vs. 6.73o, p=0.07), LTPS (5.68o vs. 5.70o, p=0.09), MTD (1.74 vs. 1.73 mm, p=0.356), and LTH (2.21 vs. 2.22 mm, p=0.393). Males and females were also comparable in terms of MTPS and LTPS in both ACL injured and ACL-intact groups. CONCLUSION: ACL-injured and ACL-intact patients as well as males and females were comparable in terms of the tibial plateau slope parameters. PMID- 28031493 TI - Improvement in health-related quality of life after unilateral total knee arthroplasty in patients with bilateral knee osteoarthritis. AB - PURPOSE: To review the outcome of unilateral total knee arthroplasty (TKA) in patients with bilateral knee osteoarthritis (OA) to determine whether unilateral TKA can achieve good health-related quality of life (HRQoL). METHODS: Records of 68 women and 25 men with severe bilateral knee OA who underwent unilateral TKA on the more symptomatic knee by a single surgeon and did not return for the second TKA within 2 years were reviewed. Outcome at 6 months and 2 years was assessed using the mental and physical component summary (MCS and PCS) of the Short-Form 36 (SF-36) for HRQoL as well as the Oxford Knee Score (OKS) and Knee Society Score (KSS) for knee-specific outcome. RESULTS: The SF-36, OKS, and KSS improved significantly after unilateral TKA. Respectively for MCS and PCS of SF-36, OKS, and KSS knee and function scores, 65%, 89%, 98%, 98%, and 98% of patients reported absolute improvement at 2 years. Respectively for PCS, OKS, and KSS function score that a minimal clinically important difference (MCID) was established, 77%, 96%, and 80% of patients achieved MCID at 2 years. CONCLUSION: Unilateral TKA achieves good outcome in HRQoL at 2 years in patients with bilateral knee OA. PMID- 28031494 TI - Outcome in total knee arthroplasty with a medial-lateral balanced versus unbalanced gap. AB - PURPOSE: To evaluate the clinical outcome in 108 total knee arthroplasty (TKA) patients with a medial-lateral balanced versus unbalanced gap after a mean follow up of 34 months. METHODS: 64 women and 44 men (mean age, 69.5 years) underwent computer-assisted TKA for osteoarthritis using a cemented fixed-bearing cruciate retaining prosthesis. The medial-lateral gap difference (measured with the prosthesis in situ and the patella reduced) was balanced (<=2 mm) in 81 patients and unbalanced (>2 mm) in 27 patients. After a mean follow-up of 34 months, patients were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire for pain, stiffness, and physical function. Scores were normalised to 0% (worst) to 100% (best). RESULTS: The balanced and unbalanced gap groups were comparable in terms of age, severity of osteoarthritis, and proportion of pre- and post-operative mechanical alignment. Compared with the balanced gap group, the unbalanced gap group had a larger medial-lateral extension gap difference (0.75+/-0.57 vs. 2.02+/-1.15 mm, p=0.001) and medial-lateral flexion gap difference (0.79+/-0.63 vs. 2.98+/-2.13 mm, p=0.001) and lower normalised total WOMAC score (84.9+/-18 vs. 74.8+/-20.8, p=0.017). CONCLUSION: WOMAC score is better in TKAs with a medial-lateral balanced (<2 mm) gap. PMID- 28031495 TI - Risk factors for fear of falling in elderly patients with severe knee osteoarthritis before and one year after total knee arthroplasty. AB - PURPOSE: To evaluate the regression of fear of falling (FOF) and identify its risk factors in patients with severe knee osteoarthritis before and one year after total knee arthroplasty (TKA). METHODS: 11 men and 57 women with a mean age of 73 years and a mean body mass index of 30.36 kg/m2 who had severe (grade 3 or 4) knee osteoarthritis and knee pain of >=1 year were included. Two weeks before and one year after TKA, patients were asked about their FOF status and falls history. Patients were asked to complete the Physical Activity Scale for the Elderly, Short Form 36 (SF-36), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaires. Clinical performance was assessed using the Berg Balance Scale and Timed Up and Go (TUG) test. RESULTS: Of the 68 patients, 56 (82.4%) had FOF preoperatively and 30 (44.1%) had FOF one year after TKA (p<0.001). The strongest predictors for FOF preoperatively were fallers (odds ratio [OR]=9.83, p=0.028), mental component summary (MCS) score of SF-36 (OR=0.88, p=0.024), and TUG (OR=3.4, p=0.013). The strongest predictors for FOF one year postoperatively were fallers (OR=16.51, p=0.041), patients with >=2 chronic diseases (OR=17.33, p=0.011), physical function score of WOMAC (OR=1.015, p=0.005), and MCS score of SF-36 (OR=0.86, p=0.015). CONCLUSION: TKA positively affected FOF and gradually reduced the FOF rate over a year period after TKA in an elderly population. PMID- 28031496 TI - Arthroscopic transphyseal anterior cruciate ligament reconstruction in adolescent athletes. AB - PURPOSE: To evaluate the 5-year outcome of arthroscopic transphyseal anterior cruciate ligament (ACL) reconstruction in 19 adolescent athletes. METHODS: 14 male and 5 female adolescent athletes aged 12 to 16 (mean, 13.9) years with Tanner stage 2 or 3 open physes underwent arthroscopic transphyseal ACL reconstruction by a single surgeon and were followed up for 5 years. Patients were evaluated using the numerical rating score (NRS) for pain, knee osteoarthritis outcome score (KOOS), International Knee Documentation Committee (IKDC) score, Tegner Activity Scale, and Lysholm Score, as well as the leg length discrepancy, femorotibial alignment, varus or valgus deformities, active and passive knee range of motion. RESULTS: At 5-year follow-up, physes were closed in all patients. The mean NRS for pain improved from 7.2 to 1.6; the KOOS improved from 55.3 to 88; the mean IKDC score improved from 34.5 to 84; the mean Tegner Activity Scale improved from 2.7 to 8.2 and was comparable with that before injury (8.4); and the mean Lysholm score improved from 36.3 to 84.6. All except 2 patients returned to their pre-injury level of sports activity after a mean of 25 weeks. The 2 exceptions had a 2+ Jerk test and a 3+ Lachman test; one of them also had positive signs for a lateral meniscal lesion. Both had sustained a second trauma not long before the 5-year follow-up. Two patients had reduced sensitivity in the anteromedial aspect of the proximal third of the tibia. One patient had leg length discrepancy of +1.5 cm owing to overgrowth response of the physis. CONCLUSION: Transphyseal ACL reconstruction is a viable option for skeletally immature patients, with high reproducibility, a high rate of return to sport, and a low incidence of growth disturbance. Early surgery can prevent the onset of meniscal lesions and early osteoarthritis. PMID- 28031497 TI - The use of a 3-dimensional computed tomography bone database to evaluate the risk of distal contact between the rasp tip and the endosteal cortical bone. AB - PURPOSE: To use a 3-dimensional computed tomography (CT) bone database to evaluate the risk of distal contact between the rasp tip and the endosteal cortical bone. METHODS: Using a 3-dimensional CT bone database, the rasps for Exeter stems of 125 mm in length and body size 1, with a femoral offset of 37.5, 44, or 50 mm were compared with those for Exeter stems of 150 mm in length and same body size with the corresponding femoral offset. Rasp geometry was determined using an engineering drawing software. RESULTS: Of the 631 femurs in the database, 238 (187 Caucasian and 51 Asian) were of appropriate femoral offset and proximal body size to receive a stem with an offset of 37.5, 44, or 50 mm. Of these, 145 (115 Caucasian and 30 Asian) femurs were of champagne-flute type; the prevalence was comparable between the 2 populations (61% vs. 59%, p=0.729). When using the 150-mm rasp, 70 (55 Caucasian and 15 Asian) of the 238 femurs had distal contact between the rasp and femoral cortex; the prevalence was comparable between the 2 populations (29% vs. 29%, relative risk=1.0, p=1.0). Distal contact between the rasp and femoral cortex occurred more commonly in champagne-flute type femurs than other femurs in the anteroposterior plane (28% [41/145] vs. 2% [2/93], relative risk=13.1, p<0.001) and in the mediolateral plane (27% [39/145] vs. 14% [13/93], relative risk=1.92, p=0.019). When using the 125-mm rasp, only one femur (with a canal flare index of 4.52) had distal contact in the mediolateral plane with an offset of 37.5 mm. Distal contact between the rasp and femoral cortex occurred more often with the 150-mm rasp than the 125-mm rasp in both planes (p<0.001). CONCLUSION: The use of a shorter stem may enhance anatomic fit in patients with a narrow femoral canal and prevent distal contact between the rasp and femoral cortex. PMID- 28031498 TI - Distal femoral cortical hypertrophy after hip arthroplasty using a cementless doubletapered femoral stem. AB - PURPOSE: To review 437 hips in 404 patients who underwent total hip arthroplasty (THA) or hemiarthroplasty using the Accolade TMZF stem to determine the incidence and risk factors of distal femoral cortical hypertrophy (DFCH). METHODS: Records of 437 hips in 169 men and 235 women aged 26 to 100 (mean, 65.7) years who underwent THA (n=293) or hemiarthroplasty (n=144) using the Accolade TMZF femoral stem by 2 senior surgeons and were followed up for a mean of 54.7 months were reviewed. Clinical outcome was assessed using the modified Harris Hip Score and visual analogue score for pain. Proximal femoral geometry and canal flare index were assessed on preoperative radiographs, and DFCH, stem position, subsidence, loosening, and stress shielding were assessed on postoperative radiographs according to the Gruen zone. RESULTS: Of 437 hips, 27 (6.2%) developed DFCH and 410 did not. Hips with DFCH had a higher incidence of thigh pain (18.5% vs. 2.2%, p<0.001) and earlier onset of thigh pain (12.3 vs. 20.8 months, p=0.015), compared with those without. Nonetheless, all femoral stems were well-fixed, and no osteolysis or loosening was detected. The 2 groups achieved comparable clinical outcome in terms of Harris Hip Score and pain. The mean canal flare index was higher in hips with than without DFCH (3.706 vs. 3.294, p=0.002). The mean vertical subsidence of the femoral stem was lower in hips with than without DFCH (1.5 vs. 3.4 mmp<0.001). Subsidence negatively correlated with the canal flare index (correlation coefficient= -0.110, p=0.022). The incidence of the DFCH increased with each unit of increment in canal flare index (odds ratio [OR]=1.828, p=0.043) and each year younger in age (OR=0.968, p=0.015). CONCLUSION: The incidence of DFCH in hips withthe Accolade TMZF stem was 6.2%. Patients with a higher canal flare index and younger age had a higher incidence of DFCH. Nonetheless, DFCH did not affect clinical outcome or femoral stem stability. PMID- 28031499 TI - Mid-term outcome of total hip arthroplasty using a short stem. AB - PURPOSE: To review the outcome of total hip arthroplasty (THA) using a short femoral stem in 33 hips. METHODS: Records of 33 hips in 20 men and 10 women aged 25 to 40 (mean, 30) years who underwent cementless THA using a short femoral stem by a single senior surgeon were reviewed. The diagnosis included avascular necrosis (n=9), ankylosing spondylitis (n=12), rheumatoid arthritis (n=7), posttraumatic arthritis (n=4), and Hurler syndrome (n=1). Clinical outcome was assessed using the Harris Hip Score. Radiological outcome was assessed according to a modified Gruen zoning system. Stem positioning (neutral, varus, valgus) and bone contact wereevaluated, as were fixation and early host response as well as subsidence and changes in the calcar region (zone 5). Trabecular response (trabecular attachment), spot welds, cortical hypertrophy, and pedestal formation were determined. Heterotopic ossification was graded by the Brooker classification. RESULTS: The mean follow-up period was 6.5 years. The mean Harris Hip Score improved from 40 to 90. All hips achieved immediate postoperative stability. No patient had thigh pain. Four hips had varus placement (5o-7o) of the stem; all were asymptomatic and remained stable without any migration. Evidence of proximal load transfer (endosteal spot welds) between the endosteum and the stem in zones 2 and/or 4 was noted in 12 hips on both sides and in 8 hips on the lateral side only. At one year, all stems showed evidence of osseointegration. None had subsidence or progressive varus migration. There was no radiolucent line or osteolysis around the stem, pedestal formation or buttressing at the prosthesis tip, or cortical hypertrophy. One patient had grade I heterotopic ossification that was not clinically significant. One patient had a 1.5 cm leg lengthening. One patient had a discharging sinus, a loosened acetabular component, and intrapelvic migration at 2 years and underwent implant removal and debridement. One patient developed a crack in the proximal femur even with the smallest stem. The stem was fixed with cerclage wiring and remained stable with no migration. CONCLUSION: A short femoral stem design that transfers load proximally through a prominent lateral flare achieved good short-term outcome in younger patients. Nonetheless, the ease of removal and preservation of bone at the time of revision should guide the choice of the design of the short stem. PMID- 28031500 TI - Acetabular revision with bone grafting and cementation for aseptic loosening after primary Charnley low-friction hip arthroplasty with structural bulk autografts. AB - PURPOSE: To review the outcome of acetabular revision with bone grafting and cementation for aseptic loosening after primary Charnley low-friction hip arthroplasty with structural bulk autografts in 15 patients. METHODS: Records were reviewed for 3 men and 12 women aged 31 to 72 (mean, 53) years who underwent acetabular revision with bone grafting and cementation for aseptic loosening at a mean of 12.4 (range, 6.6-20.3) years after primary Charnley low-friction hip arthroplasty with superolateral structural bulk autografts from the femoral head for dysplastic hip (n=14) or bone loss secondary to acetabular fracture (n=1). RESULTS: After a mean follow-up of 6.7 (range, 1.1-14.5) years, the mean Merle d'Aubigne and Postel score improved from 8.55 to 16.5. Bridging trabeculae was noted in 10 hips and graft remodelling in 5 hips. Five hips had ectopic ossification of Brooker grade 1 to 2. The mean hip centre of rotation was 21.6 (range, 16.2-30.6) mm. Two women required re-revision for aseptic loosening of the acetabulum after 8.5 and 6.6 years. The first one underwent re-revision with solid allograft for superolateral deficiency of the acetabulum. The second one underwent re-revision with solid and morselised bone allografts for loosened acetabulum. One patient had superior migrationof the acetabulum for 9 mm at year 2, but it was asymptomatic. One patient had a dislocation that was reduced with manipulation under anaesthesia. Threepatients had trochanteric non-union and presented with lateral thigh pain and tenderness, but no further surgery was performed. CONCLUSION: The medium-term outcome of acetabular revision with bone grafting and cementation is satisfactory. Repeat bone grafting is required to restore the anatomic acetabular position and bone loss secondary to acetabular loosening. PMID- 28031501 TI - Frequent small distractions with a magnetically controlled growing rod for early onset scoliosis and avoidance of the law of diminishing returns. AB - PURPOSE: To assess the effect of frequent small distractions with a magnetically controlled growing rod (MCGR) on spinal length gain and achieved distraction length in children with early-onset scoliosis (EOS), and to determine whether the law of diminishing returns applies to this group of patients with MCGR. METHODS: A consecutive series of 3 males and 4 females with EOS who underwent MCGR implantation at a mean age of 10.2 years and were followed up for a mean of 3.8 years were reviewed. Distraction was aimed at 2 mm monthly. The coronal Cobb angle, T1-S1 length gain, and achieved distraction length were measured at 6 monthly intervals. RESULTS: The mean total number of distractions was 31. Four of the patients had problems that may have affected distractions. The mean coronal Cobb angle improved post-operatively and was maintained throughout the follow-up period. The mean T1-S1 length gain and achieved distraction length varied over the follow-up period and did not diminish with repeated lengthening. CONCLUSIONS: Frequent small distractions with the MCGR for EOS enable T1-S1 and achieved distraction length gain without significant reduction in gain after repeated lengthening. PMID- 28031502 TI - Four-level anterior cervical discectomy and fusion for cervical spondylotic myelopathy. AB - PURPOSE: To review the outcome of 32 consecutive patients who underwent 4-level anterior cervical discectomy and fusion (ACDF) with cages and plates and were followed up for at least 5 years. METHODS: Records of 19 men and 13 women aged 48 to 69 years who underwent 4-level ACDF with cages and plates for myelopathy (n=11) or myeloradiculopathy (n=21) at C3 to C7 by a single surgeon and were followed up for a minimum of 5 years were reviewed. Clinical outcome was assessed using the visual analogue scale (VAS), Neck Disability Index (NDI), and modified Japanese Orthopaedic Association (JOA) score for pain or myelopathic symptoms. Radiographic evaluation included fusion rate, range of motion, cervical lordosis (C2-to-C7 Cobb angle), and disc height. RESULTS: The mean follow-up was 66 months. All patients had good recovery of muscle strength and resolution of limb sensory disturbance, except for 4 who still had some numbness. The mean VAS for neck and arm pain improved from 14.2 to 6.84 (p=0.012); the mean NDI improved from 31.62 to 12.17 (p<0.01); and the mean JOA score improved from 10.1 to 13.9 (p=0.027). The mean percentage of recovery was 62.9. The mean Cobb angle improved from 10.24o to 1.28o (p=0.019); the mean disc height improved from 4.12 to 6.58 mm (p<0.01). 30 (94%) patients achieved solid fusion. CONCLUSION: Multilevel ACDF using PEEK cages and plates is safe and effective for multilevel cervical spondylotic myelopathy and achieves satisfactory mid-term outcome. PMID- 28031503 TI - Single-stage posterior instrumentation for progressive tubercular thoracic and thoracolumbar kyphosis. AB - PURPOSE: To review the outcome of single-stage posterior instrumentation for progressive tubercular thoracic and thoracolumbar kyphosis in 45 patients. METHODS: Records of 16 men and 29 women aged 20 to 59 (mean, 34.1) years who underwent single-stage posterior instrumentation for active thoracic (n=27) or thoracolumbar (n=18) tuberculosis by a single surgeon and were followed up for a minimum of 5 years were reviewed. Neurological status was evaluated using the Frankel grading system. Pain was assessed using the visual analogue score (VAS). Disability status was assessed using the Oswestry Disability Index (ODI). Outcome was graded according to the Kim and Lee criteria. Kyphosis at presentation, preoperation (after one month of conservative therapy), immediate postoperation, and 5-year follow-up was measured on radiographs to determine the kyphosis progression, correction of deformity, postoperative loss of correction, and residual deformity. RESULTS: Respectively for 27 and 18 patients with thoracic or thoracolumbar involvement, at 5 years the mean VAS score improved from 5.5 to 1.9 (p<0.001) and from 6.8 to 1.5 (p<0.001), whereas the mean ODI improved from 60.8 to 11.7 (p<0.001) and from 57.5 to 7.6 (p<0.001). The outcome was excellent in 17 and 11, good in 7 and 5, and fair in 3 and 2 patients, respectively. The mean kyphosis progression from presentation to preoperation was from 20.2o to 26.2o and from 10.3o to 14.1o, respectively, whereas the corresponding mean predicted kyphosis progression was from 15.5o to 48.1o and from 13.8o to 50.4o. The respective mean correction of deformity was -8.1o and -8.5o; the respective mean residual deformity was 4.1o and 6.8o; and the respective mean loss of correction at 5 years was 1.9 and 1.9. Two patients had a dural tear, and 3 patients had a transient root injury. Two diabetic patients had superficial wound infection. One patient had downward migration of one rod at 30 months but remained asymptomatic. CONCLUSION: Single-stage posterior instrumentation combined with continued chemotherapy for a minimum 12 months is a viable option for early progressive thoracic and thoracolumbar tubercular kyphosis. PMID- 28031504 TI - Comparison of early outcome of Weil osteotomy and distal metatarsal mini-invasive osteotomy for lesser toe metatarsalgia. AB - PURPOSE: To compare the 6-month outcome of Weil osteotomy with distal metatarsal mini-invasive osteotomy (DMMO) in 33 patients with lesser toe metatarsalgia. METHODS: Records of 33 patients who underwent Weil osteotomy (n=20, 41 toes) or DMMO (n=13, 22 toes) for lesser toe metatarsalgia by a single surgeon were reviewed. 25 of them had a concurrent procedure on the 1st toe. Outcome at 6 months was assessed using the visual analogue score (VAS) for pain, American Orthopaedic Foot and Ankle Society (AOFAS) lesser toe metatarsophalangeal interphalangeal (MTP-IP) score, and the RAND-36 score. RESULTS: The 2 groups were comparable in terms of age, gender, and preoperative MTP joint range of motion (ROM), VAS for pain, AOFAS lesser toe MTPIP score, and RAND-36 scores. At 6 months, the Weil osteotomy group had a higher RAND-36 (mental) score (92 vs. 78, p=0.026), and the DMMO group had a higher percentage of toes with greater MTP joint ROM (p=0.043). All patients achieved bone union within 6 months. Two patients in the DMMO group had prolonged oedema until 3 months post-surgery. CONCLUSION: DMMO is a safe and reliable alternative to Weil osteotomy for metatarsalgia and can preserve ROM of the MTP joints. PMID- 28031505 TI - Z-plasty of the flexor hallucis longus tendon at tarsal tunnel for checkrein deformity. AB - PURPOSES: To review the outcome of Z-plasty of the flexor hallucis longus (FHL) tendon at the tarsal tunnel for checkrein deformity in 8 patients. METHODS: Records of 6 males and 2 females aged 14 to 67 (mean, 39.5) years who underwent Z plasty (lengthening) of the FHL tendon at the tarsal tunnel for checkrein deformity in the first and second toes by a single surgeon were reviewed. All patients had undergone 3 months of conservative treatment. The mean time from injury to surgical treatment was 8.4 (range, 5-12) months. All patients had associated injuries including distal tibiofibular fracture (n=6), distal fibular fracture (n=1), and crush injury aroundthe ankle (n=1); they were treated with intramedullary nailing (n=6), long leg splinting (n=1), and short leg splinting (n=1). RESULTS: After a mean follow-up of 3.4 (range, 1-7) years, the FHL tendon was lengthened by a mean of 1.7 (range, 1.6-1.8) cm, and the mean American Orthopedic Foot and Ankle Society hallux score increased from 59 (range, 52-67) to 89 (range, 80-90). No patient had recurrence, nerve injury, or tarsal tunnel syndrome, although one patient had sensory disturbance of the posterior tibial nerve in the forefoot, which resolved spontaneously at week 2. CONCLUSION: Z plasty of the FHL tendon at the tarsal tunnel is a viable option for correction of checkrein deformity. PMID- 28031506 TI - Intramedullary and intra-osseous arthrodesis of the hallux metatarsophalangeal joint. AB - PURPOSE: To review the outcome of arthrodesis of the hallux metatarsophalangeal (MTP) joint in 23 patients. METHODS: Records of 9 men and 14 women aged 27 to 88 (mean, 57) years who underwent arthrodesis of the hallux MTP joint using an intramedullary device and an intra-osseous device were reviewed. Indications for surgery were severe hallux valgus (n=15), hallux rigidus (n=6) and rheumatoid arthritis (n=2). Outcome measures included visual analogue score (VAS) for pain, the American Orthopaedic Foot and Ankle Society (AOFAS) hallux score, bone union, hallux valgus angle (HVA), dorsiflexion angle (DA), complications, revision, and patient satisfaction. RESULTS: The mean follow-up was 19 (range, 6-38) months. The mean AOFAS score improved from 29 to 75.4 (p<0.0001) and the mean VAS for pain improved from 8.1 to 2.4 (p<0.0001). 20 (86%) of the patients were satisfied with the outcome. The mean HVA was 14o and the mean DA was 22o. 19 (83%) of the toes had a well-aligned hallux. 21 (91%) of the patients achieved arthrodesis of the hallux MTP joint. The remaining 2 patients underwent revision surgery for failed fusion or infected non-union; they continued to have transfer metatarsalgia despite bone union. CONCLUSION: The intramedullary and intra osseous devices for arthrodesis of the hallux MTP joint achieved good outcome in terms of AOFAS score, VAS for pain, HVA, DA, bone union, and patient satisfaction. PMID- 28031507 TI - Combined use of ibandronate and eldecalcitol in postmenopausal Japanese women with osteoporosis. AB - PURPOSE: To evaluate the effect of combined use of ibandronate and eldecalcitol for 6 to 12 months on bone mineral density (BMD) and bone strength of the proximal femur in postmenopausal Japanese women with osteoporosis. METHODS: BMD and bone strength of the proximal femur were evaluated in 78 postmenopausal women (mean age, 73.6 years) who underwent treatment for osteoporosis with combined use of ibandronate and eldecalcitol for at least 6 months. BMD was measured at the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry (DXA) at baseline and every 6 months thereafter. Hip structure analysis of the narrow neck and intertrochanter was performed by a radiologist using DXA images. RESULTS: Respectively for the lumbar spine, femoral neck, and total hip, BMD significantly increased (from baseline) by 4.54%, 2.31%, and 1.56% at 6 months and by 5.92%, 3.02%, and 2.70% at 12 months. In hip structure analysis, most parameters improved significantly. Respectively for the narrow neck and intertrochanter, BMD significantly increased (from baseline) by 2.37% and 2.71% at 6 months and by 3.46% and 3.52% at 12 months; cross-sectional area significantly increased by 1.83% and 3.39% at 6 months and by 2.91% and 3.46% at 12 months; section modulus significantly increased by 2.42% and 4.11% at 6 months and by 4.84% and 3.26% at 12 months; cortical thickness significantly increased by 2.49% and 3.33% at 6 months and by 3.73% and 3.37% at 12 months; and buckling ratio significantly decreased by 2.97% and 2.57% at 6 months and by 3.86% and 2.99% at 12 months. CONCLUSION: Combined use of ibandronate and eldecalcitol for 6 months significantly improved bone strength of the proximal femur in postmenopausal Japanese women with osteoporosis. PMID- 28031508 TI - Effect of cable cerclage on regional blood circulation in rabbits: a scintigraphic study. AB - PURPOSE: To evaluate changes in blood circulation of the femoral cortex in rabbits using scintigraphy before and after cable cerclage alone or combined with an intramedullary Kirschner wire. METHOD: Ten New Zealand rabbits were used. For the right femur, a 2-mm-thick cable was placed around the mid-diaphyseal region and squeezed with a 400-N force and locked with a clip. For the left femur, a 1.8 mm Kirschner wire was inserted retrogradely into the medullary canal, and a 2-mm thick cable was applied using the same technique. The blood perfusion ratio of the region of interest (ROI) before and after surgery was evaluated using scintigraphy. RESULTS: For the right femurs, the mean ROI perfusion ratio decreased by 45% from 2.51 to 1.37 after intervention (p=0.001). For the left femurs, the mean ROI perfusion ratio decreased by 56% from 2.12 to 0.92 after intervention (p<0.001). The mean ROI perfusion ratio post-intervention was higher in the right than left femurs (p=0.017). CONCLUSION: Cable cerclage around the femoral cortex significantly decreased blood circulation in the area. PMID- 28031509 TI - Cell morphology, viability, osteocalcin activity, and alkaline phosphatase activity in milled versus unmilled surface of the femoral head. AB - PURPOSE: To evaluate cellular activity in milled versus unmilled surface of the femoral head in 21 patients who underwent robot-assisted total hip arthroplasty(THA). METHODS: The femoral head of 21 consecutive patients who underwent robot-assisted THA for osteonecrosis was used. 10 cc of trabecular bone from the entire milled surface was obtained using a curette. The same amount of trabecular bone was obtained at least 1 cm away from the milled surface and served as a matched control. Cell morphology, viability, osteocalcin activity, and alkaline phosphatase activity in milled versus unmilled surface were assessed. RESULTS: Cell morphology of the milled or unmilled surface was comparable; cells were smaller in the milled surface. Cell viability was a mean of 40% higher in the milled surface (107.4% vs. 67.2%, p<0.001); cell viability at 5 time points was comparable in each group. Osteocalcin activity of cells was slightly higher in the milled surface (1.43 vs. 1.24 ng/ml, p=0.69). Alkaline phosphatase activity of cells was slightly higher in the unmilled surface (150 105 vs. 141 789 U/L, p=0.078). CONCLUSION: The milled and unmilled surfaces of the femoral head were comparable in terms of cell morphology, viability, osteocalcin activity, and alkaline phosphatase activity. PMID- 28031510 TI - Use of a magnetic bone nail for lengthening of the femur and tibia. AB - PURPOSE: To report our experience with the PRECICE nail for limb lengthening in 23 patients. METHODS: Records of 15 female and 8 male patients aged 14 to 38 (mean, 23.6) years who underwent lengthening of the tibia (n=6) or femur (n=21) using the PRECICE nail were reviewed. The reasons for lengthening included trauma (n=7), hemihypertrophy (n=2), focal femoral deficiency (n=2), Ellis-van Creveld syndrome (n=1), hip septic arthritis sequelae (n=1), hereditary multiple exostosis (n=1), club foot sequela (n=1), congenital tibial pseudoarthrosis (n=1), fibrous dysplasia (n=1), idiopathic limb length discrepancy (n=7), and cosmetic (n=1). RESULTS: The mean follow-up duration was 20.72 months. The mean lengthening was 48.20 mm, and the mean acute angular correction was 15.5o. The mean time to full weight-bearing was 5.15 months, and the mean consolidation index was 1.12 months/cm. The mean maturation index was 0.78 months/cm. One patient had nail breakage during the consolidation phase. The nail was replaced by an intramedullary nail until consolidation, after which another PRECICE nail was used to treat the residual shortening. Eight patients had over-lengthening and the nails were driven back to the desired length. No patient had infection. CONCLUSION: The PRECICE nail is a viable option for lengthening of the femur and tibia. PMID- 28031511 TI - Use of tranexamic acid in dynamic hip screw plate fixation for trochanteric fractures. AB - PURPOSE: To evaluate perioperative blood loss and blood transfusion requirement in patients who underwent dynamic hip screw plate fixation for a stable trochanteric fracture with or without preoperative intravenous tranexamic acid (TXA). METHODS: 49 men and 11 women (mean age, 56.5 years) who underwent open reduction and internal fixation with a dynamic hip screw plate for a stable trochanteric fracture by a single surgeon were equally randomised to receive either a single dose of intravenous TXA (15 mg/kg) 15 minutes prior to surgery or an equal volume of normal saline by slow infusion. Intra- and post-operative blood loss and the need for blood transfusion were assessed, as was any thromboembolic adverse event. RESULTS: The TXA and control groups were comparable in terms of age, gender, body mass index, blood pressure, pulse rate, time from injury to surgery, operating time, and preoperative haematological data. Blood loss was lower in the TXA than control group intraoperatively (320.3 vs. 403.33 ml, p<0.001), during 0 to 24 hours (61.67 vs. 186.67 ml, p<0.001), and during 24 to 48 hours (27 vs. 86.67 ml, p<0.001), as well as the total volume (408.97 vs. 676.67 ml, p<0.001). Respectively for the TXA and control groups, 27 and 30 required 28 and 41 units of blood intra-operatively (p<0.001), and 6 and 15 required 6 and 15 units of blood postoperatively (p=0.014). No patient had any thromboembolic adverse event. CONCLUSION: TXA is safe and effective in reducing blood loss in dynamic hip screw plate fixation for stable trochanteric fractures. PMID- 28031512 TI - Z-plasty for severe gluteal muscle contracture in children. AB - PURPOSE: To review the records of 363 patients with severe gluteal muscle contracture to determine its mechanism, underlying pathology, and treatment outcome. METHODS: Records of 136 males and 227 females aged 5 to 18 (mean, 12.2) years who underwent Z-plasty for bilateral (n=347) or unilateral (n=16) severe gluteal muscle contracture were reviewed. Severe gluteal muscle contracture was classified as typical (n=52) or special (n=311). The typical type is associated with symptoms of positive out-toe gait, Ober sign, back-extending test, cross-leg test, squatting with knee side-by-side test, and hip dysfunction. It is further subdivided into mild (n=0), moderate (n=40), or severe (n=12). The special type is associated with additional symptoms of pelvic tilt and leg length discrepancy (<2 cm in 181 hips, 2-4 cm in 82 hips, and >4 cm in 48 hips). 311 hips had pelvic tilt and 47 hips had lumbar compensatory scoliosis. Treatment outcome was assessed at 6 months. Hip functional score was assessed at the final follow-up. RESULTS: The mean hospitalisation period was 11 days. After a mean follow-up of 1.5 years, the mean hip functional score improved from 8.03 to 11.69; improvement was higher in children (age 5-13 years) than in adolescents (age 14-18 years) [3.7 vs. 2.9, p<0.001]. At 6 months, outcome was excellent in 280 hips, good in 80, fair in 3 hips, and poor in 0. The 3 hips with fair outcome had persistent slight pelvic tilt and swaying gait. Two of them had preoperative leg length discrepancy >4 cm, and intra-operatively the contracture band severely affected the joint capsule. The third patient did not comply with postoperative exercises. CONCLUSION: Surgical treatment for severe gluteal muscle contracture achieved good outcome. PMID- 28031513 TI - Double intertrochanteric osteotomy for trochanteric overgrowth and a short femoral neck in adolescents. AB - PURPOSE: To review the outcome of Wagner double intertrochanteric osteotomy for trochanteric overgrowth and a short femoral neck in 7 adolescents. METHODS: Records of one male and 6 females aged 15 to 20 years who underwent modified Wagner osteotomy for trochanteric overgrowth and a short femoral neck by a single senior surgeon were reviewed. The diagnoses were coxa vara (n=2), developmental dysplasia of the hip (n=3), Leg-Calve-Perthes (n=1), and proximal femoral focal deficiency (n=1). Radiological indication for double intertrochanteric osteotomy included a neck-shaft angle (NSA) <120o or a centre trochanter distance (CTD) <28 mm. Function was evaluated using the Children's Hospital Oakland Hip Evaluation Scale (CHOHES). The articulotrochanteric distance (ATD), CTD, NSA, and the distance between the centre of the femoral head and the centre of the acetabulum (MZ) were measured on radiographs. RESULTS: The mean follow-up duration was 61 (range, 28-86) months. The ATD improved from 16+/-11.5 mm to -6.3+/-10.2 mm (p=0.018), the CTD from 27.9+/-3.5 mm to 36.4+/-7.1 mm (p=0.018), the NSA from 112o+/-24.4o to 131o+/-16o (p=0.028), the MZ from 12.7+/-6.5 mm to 7.7+/-4.2 mm (p=0.028), and the CHOHES score from 62.1+/-8.7 to 84+/-9.6 (p=0.017). One patient had delayed union. Two patients had persistent Trendelenburg gait. Two patients declined second-stage surgery for acetabular dysplasia after solving the femoral side problems at the first stage. One of them developed hip arthrosis. CONCLUSION: Double intertrochanteric osteotomy is a viable treatment option for adolescents with trochanteric overgrowth and a short femoral neck. PMID- 28031514 TI - Long-term outcome of Rockwood capsular shift for recurrent shoulder dislocation. AB - PURPOSE: To review the long-term outcome of Rockwood capsular shift for recurrent shoulder dislocation secondary to trauma. METHODS: Records of 30 males and 4 females who underwent Rockwood capsular shift for recurrent (>=2 episodes) anterior shoulder dislocation were reviewed. An additional Bankart repair with different techniques was performed in 24 of the patients by 2 different surgeons. The outcome was assessed using the Western Ontario Shoulder Instability Index (WOSI) and the Western Ontario Osteoarthritis of the Shoulder (WOOS) index questionnaires, the modified Rowe score, and the Constant-Murley score. Shoulder range of motion (ROM) was measured. Degenerative joint changes were evaluated on radiographs. RESULTS: During a mean follow-up of 13 (range, 10-16) years, 6 (18%) patients had a mean of 1.2 recurrent dislocations. Four of the patients reported a traumatic event during recurrent dislocation. Of the 6 patients, 3 had undergone a Bankart lesion repair. Better Rowe and adjusted Constant scores were associated with lower age at first dislocation, at the index surgical procedure, and at follow-up. Four patients developed glenohumeral osteoarthritis: 2 were mild or moderate and 2 were severe and symptomatic. Glenohumeral osteoarthritis was associated with follow-up duration (p=0.03) and poorer Rowe score (p=0.012), adjusted Constant score (p=0.001), and WOOS score (p=0.006). CONCLUSION: Rockwood capsular shift can preserve shoulder ROM, with rates of recurrent dislocation and degenerative joint changes comparable with other techniques. PMID- 28031515 TI - Percutaneous radiofrequency ablation for osteoid osteoma under guidance of threedimensional fluoroscopy. AB - PURPOSE: To evaluate the outcome of percutaneous radiofrequency ablation under guidance of 3-dimensional fluoroscopy in 17 patients with osteoid osteoma. METHODS: Records of 11 male and 6 female consecutive patients aged 4 to 28 (mean, 13.8) years who underwent radiofrequency ablation under guidance of 3-dimensional fluoroscopy for osteoid osteoma and were followed up for a mean of 15.8 (range, 12-28) months were reviewed. All patients had been treated with analgesics but failed to achieve lasting pain relief. Visual analogue score (VAS) for pain was assessed pre- and post-operatively. Absence of pain was considered recovery. RESULTS: The mean operating time was 55 (range, 20-95) minutes, and the mean length of hospital stay was 2.8 (range, 2-7) days. The mean amount of radiation was 390.2 (range, 330.5-423.6) mGy/cm. Relief of pain occurred within the first 24 hours in 11 patients and by the end of the first week in 3 patients. Pain persisted in 3 patients at one month; they underwent revision surgery and achieved complete recovery. The mean VAS for pain was 7.2 (range, 6-9) in 17 patients preoperatively and decreased to 0.64 (range, 0-2) in the 14 patients with pain relief and 0.66 (range, 0-1) in the 3 patients after revision surgery. Two patients had severe discharge from the wound secondary to fat necrosis, which resolved within a week with antibiotics and local dressings. No patient had cellulitis, vasomotor instability, neurovascular injury, fracture, or deep infection. CONCLUSION: Percutaneous radiofrequency ablation under guidance of 3 dimensional fluoroscopy is a viable treatment option for osteoid osteoma. PMID- 28031516 TI - Review Article: Osteophytes. AB - An osteophyte is a fibrocartilage-capped bony outgrowth that is one of the features of osteoarthritis. This study reviewed the types, risk factors, pathophysiology, clinical presentations, and medical and surgical treatment of osteophytes. Extraspinal osteophytes are classified as marginal, central, periosteal, or capsular, whereas vertebral osteophytes are classified as traction or claw. Risk factors for development of osteophytes include age, body mass index, physical activity, and other genetic and environmental factors. Transforming growth factor beta plays a role in the pathophysiology of osteophyte formation. Osteophytes can cause pain, limit range of motion, affect quality of life, and cause multiple symptoms at the spine. Medical treatment involves the use of bisphosphonates and other non-steroidal anti-inflammatory agents. Surgical treatment in the form of cheilectomy for impingement syndromes during joint replacement is recommended. PMID- 28031517 TI - Review Article: Operative versus nonoperative treatment for displaced intraarticular calcaneal fracture: a meta-analysis of randomised controlled trials. AB - We reviewed 8 randomised controlled trials that compared operative and non operative treatment for displaced intra-articular calcaneal fractures. Patients with operative treatment were more likely to resume pre-injury work (relative risk [RR]=0.60, p=0.04), had fewer problems when wearing shoes (RR=0.42, p=0.0004), and had a higher physical component summary score of SF-36 (difference in means=6.75, p<0.0001) but a higher complication rate (RR=1.74, p=0.0005). PMID- 28031518 TI - Arthroscopic fixation with EndoButton for tibial eminence fractures visualised through a proximal superomedial portal: a surgical technique. AB - Most tibial eminence fractures are avulsion fractures of the anterior cruciate ligament (ACL) from its tibial insertion. This study describes a new arthroscopic technique using an additional proximal superomedial portal to visualise the tibial eminence fracture and to fix the fracture with the EndoButton to avoid the risk of fragment breakage. The proximal superomedial portal enables fracture reduction without damage to the intermeniscal ligament. Fixation with the EndoButton is strong enough to allow early rehabilitation with vigorous exercise. All 5 patients achieved bone union; no young patient had growth disturbance of the tibia; all knees were stable with excellent range of motion and negative Lachman and pivot shift tests and no flexion contracture. Arthroscopic fixation with the EndoButton visualised through the proximal superomedial portal is a safe, simple, and secure method for treating tibial eminence fractures, particularly in children with small fragments. PMID- 28031519 TI - Remarkable bone formation following gefitinib for extensive lytic bone metastasis: a report of two cases. AB - Gefitinib inhibits the epidermal growth factor receptor tyrosine kinase and improves survival in patients with non-small-cell lung cancer. We report 2 patients with extensive lytic bony metastasis in the spine and pelvis secondary to advanced pulmonary adenocarcinoma who were treated with gefitinib and had remarkable bone formation in the lytic bone lesions in the spine and pelvis. Surgery for stabilisation was avoided. PMID- 28031520 TI - Acute calcification of intervertebral disc and posterior longitudinal ligament in a 7-year-old girl: a case report. AB - A 7-year-old girl presented with a 2-day history of acute neck pain without any preceding injury. The pain was around the left posterior paraspinal muscle and was aggravated by neck movement. There was no neurological abnormality; white cell count and inflammatory markers were slightly elevated. Radiology of the cervical spine showed calcification of C3/4 and C4/5 discs as well as the posterior longitudinal ligament over C3/4. She was treated conservatively with a neck collar and Panadol syrup. No non-steroidal anti-inflammatory drug was prescribed. Two months later, calcification of the posterior longitudinal ligament had resolved and calcification at C3/4 and C4/5 discs and the C4 lower endplate had decreased. After one year, she was painfree with no tenderness over her neck and had full range of neck motion and complete resolution of the calcification. PMID- 28031521 TI - Letter to the Editor: Wide resection versus curettage with adjuvant therapy for giant cell tumour of bone. PMID- 28031522 TI - Letter to the Editor: Posterior spinal instrumented fusion for idiopathic scoliosis in patients with multisystemic neurodegenerative disorder: a report of two cases. PMID- 28031523 TI - Protective effects of resveratrol against mancozeb induced apoptosis damage in mouse oocytes. AB - Mancozeb, a mixture of ethylene-bis-dithiocarbamate manganese and zinc salts, is one of the most widely used fungicides in agriculture. Mancozeb could lead to mitochondria dysfunction, cellular anti-oxidation enzymes depletion and apoptotic pathways activation. Previous studies indicated the exposure of mancozeb through mother would lead to irregular estrous cycles, decreased progesterone levels, reduced litter sizes, and more frequent delivery of dead fetuses. In this study, we investigated mancozeb inducing reproductive toxicity, especially focusing on its apoptotic effect and epigenetic modifications. We also showed that resveratrol, a kind of phytoalexin found in peanuts and grapes, can alleviate mancozeb's adverse effects, such as declined fertility, decreased ovary weight and primary follicles. Besides, mancozeb treated oocytes displayed suboptimal developmental competence and this can also be improved by treatment of resveratrol. More detailed investigation of these processes revealed that mancozeb increased reactive oxygen species, causing cell apoptosis and abnormal epigenetic modifications, and resveratrol can block these cytotoxic changes. Collectively, our results showed that resveratrol can alleviate mancozeb induced infertility and this was mainly through the correction of apoptotic tendency and the abnormity of cellular epigenetic modification. PMID- 28031524 TI - Adenosine 5'-monophosphate blocks acetaminophen toxicity by increasing ubiquitination-mediated ASK1 degradation. AB - Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5'-monophsphate (5'-AMP). We demonstrated that co-administration of APAP and 5'-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function. The mechanism of protection by 5'-AMP was through inhibiting APAP-induced activation of JNK, and attenuating downstream c-jun and c-fos gene expression. This was triggered by attenuating apoptosis signal-regulated kinase 1(ASK1) methylation and increasing ubiquitination-mediated ASK1 protein degradation. Our findings indicate that replacing the current APAP with a safe and functional APAP/5'-AMP formulation could prevent APAP-induced hepatotoxicity. PMID- 28031525 TI - Filamin C promotes lymphatic invasion and lymphatic metastasis and increases cell motility by regulating Rho GTPase in esophageal squamous cell carcinoma. AB - To establish treatments to improve the prognosis of cancer patients, it is necessary to find new targets to control metastasis. We found that expression of FilaminC (FLNC), a member of the actin binding and cross-linking filamin protein family is correlated with lymphatic invasion and lymphatic metastasis in esophageal squamous cell carcinoma (ESCC) by increasing cell motility through activation of Rho GTPase.Immunohistochemistry analysis showed that FLNC expression in ESCC is associated with lymphatic invasion, metastasis, and prognosis. FLNC knockdown in esophageal cancer cell lines decreased cell migration in wound healing and transwell migration assays, and invasion in transwell migration assays. Furthermore, FLNC knockdown reduced the amount of activated Rac-1 (GTP-Rac1) and activated Cdc42 (GTP-Cdc42). Our results suggest that FLNC expression is a useful biomarker of ESCC metastatic tendency and that inhibiting FLNC function may be useful to control the metastasis of ESCC. PMID- 28031528 TI - Directly converted iNeuron as a screening model for pathogenic variants. PMID- 28031526 TI - Radiolabeled novel mAb 4G1 for immunoSPECT imaging of EGFRvIII expression in preclinical glioblastoma xenografts. AB - Epidermal growth factor receptor mutant III (EGFRvIII) is exclusively expressed in tumors, such as glioblastoma, breast cancer and hepatocellular carcinoma, but never in normal organs. Increasing evidence suggests that EGFRvIII has clinical significance in glioblastoma prognosis due to its enhanced tumorigenicity and chemo/radio resistance, thus the development of an imaging approach to early detect EGFRvIII expression with high specificity is urgently needed. To illustrate this point, we developed a novel anti-EGFRvIII monoclonal antibody 4G1 through mouse immunization, cell fusion and hybridoma screening and then confirmed its specificity and affinity by a serial of assays. Following biodistribution and small animal single-photon emission computed tomography (SPECT/CT) imaging of 125I-4G1 in EGFRvIII positive/negative tumor-bearing mice were performed and evaluated to verify the tumor accumulation of this radiotracer. The biodistribution indicated that 125I-4G1 showed prominent tumor accumulation at 24 h post-injection, which reached maximums of 11.20 +/- 0.75% ID/g and 13.98 +/- 0.57% ID/g in F98npEGFRvIII and U87vIII xenografts, respectively. In contrast, 125I-4G1 had lower tumor accumulation in F98npEGFR and U87MG xenografts. Small animal SPECT/CT imaging revealed that 125I-4G1 had a higher tumor uptake in EGFRvIII-positive tumors than that in EGFRvIII-negative tumors. This study demonstrates that radiolabeled 4G1 can serve as a valid probe for the imaging of EGFRvIII expression, and would be valuable into the clinical translation for the diagnosis, prognosis, guiding therapy, and therapeutic efficacy evaluation of tumors. PMID- 28031530 TI - A novel assay to detect calreticulin mutations in myeloproliferative neoplasms. AB - The myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive (Ph+), chronic myeloid leukemia, or negative: polycythemia vera (PV) essential thrombocythemia (ET), and primary myelofibrosis (PMF). Most Ph negative cases have an activating JAK2 or MPL mutation. Recently, somatic mutations in the calreticulin gene (CALR) were detected in 56-88% of JAK2/MPL negative patients affected by ET or PMF. The most frequent mutations in CARL gene are type-1 and 2. Currently, CALR mutations are evaluated by sanger sequencing. The evaluation of CARL mutations increases the diagnostic accuracy in patients without other molecular markers and could represent a new therapeutic target for molecular drugs.We developed a novel detection assay in order to identify type-1 and 2 CALR mutations by PNA directed PCR clamping. Seventy-five patients affected by myeloproliferative neoplasms and seven controls were examined by direct DNA sequencing and by PNA directed PCR clamping. The assay resulted to be more sensitive, specific and cheaper than sanger sequencing and it could be applied even in laboratory not equipped for more sophisticated analysis. Interestingly, we report here a case carrying both type 1 and type2 mutations in CALR gene. PMID- 28031527 TI - Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. AB - The importance of iron in the growth and progression of tumors has been widely documented. In this report, we show that tumor-initiating cells (TICs), represented by spheres derived from the MCF7 cell line, exhibit higher intracellular labile iron pool, mitochondrial iron accumulation and are more susceptible to iron chelation. TICs also show activation of the IRP/IRE system, leading to higher iron uptake and decrease in iron storage, suggesting that level of properly assembled cytosolic iron-sulfur clusters (FeS) is reduced. This finding is confirmed by lower enzymatic activity of aconitase and FeS cluster biogenesis enzymes, as well as lower levels of reduced glutathione, implying reduced FeS clusters synthesis/utilization in TICs. Importantly, we have identified specific gene signature related to iron metabolism consisting of genes regulating iron uptake, mitochondrial FeS cluster biogenesis and hypoxic response (ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 and TFRC). Principal component analysis based on this signature is able to distinguish TICs from cancer cells in vitro and also Leukemia-initiating cells (LICs) from non-LICs in the mouse model of acute promyelocytic leukemia (APL). Majority of the described changes were also recapitulated in an alternative model represented by MCF7 cells resistant to tamoxifen (TAMR) that exhibit features of TICs. Our findings point to the critical importance of redox balance and iron metabolism-related genes and proteins in the context of cancer and TICs that could be potentially used for cancer diagnostics or therapy. PMID- 28031531 TI - Overendocytosis of superparamagnetic iron oxide particles increases apoptosis and triggers autophagic cell death in human osteosarcoma cell under a spinning magnetic field. AB - The toxicity of superparamagnetic iron oxide nanoparticles (SPIONs) is still a vital topic of debate and the mechanisms remain unclear. In the present study, overdose SPIONs could induce osteosarcoma cell death and the effects were exaggerated when combined with spinning magnetic field (SMF). In the combination group, mitochondrial transmembrane potential decrease more obviously and reactive oxygen species (ROS) was found to generate much higher in line with that of the apoptosis ratio. Meantime, amount of autophagy was induced. Inhibiting the autophagy generation by 3-methyladenine (3-MA) increase cell viability but decrease the caspase 3/7 and caspase 8 activities in combination groups, and inhibiting apoptosis took the same effect. In the end, the SPIONs effects on xenograft mice was examed by intratumoral injection. The result showed that the combination group could greatly decrease the tumor volume and prolong the lifespan of mice. In sum, the result indicated that overdose SPIONs induced ROS generation, and excessive ROS induced by combination of SPIONs and SMF contribute to autophagy formation, which play a apoptosis-promoting role that formed as a platform to recruits initiate the caspase activities. PMID- 28031532 TI - Cell-free methylation markers with diagnostic and prognostic potential in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis and high mortality. There is a dearth of effective early diagnostic tools, so liver resection surgery and liver transplantation are the only effective medical treatments. The most commonly used marker for HCC detection is serum alpha fetoprotein (AFP), which has low sensitivity and specificity. Because aberrant DNA methylation of genes and miRNAs occurs early in most cancers, we explored whether circulating methylation markers could be promising clinical tools for HCC diagnosis. Using a whole-genome approach, we identified many hyper-methylated miRNAs in HCC. Furthermore, three abnormally methylated genes and one miRNA were combined to establish a methylation predictive model and tested for its diagnostic and prognostic potential in HCC. Using plasma samples, the predictive model exhibited high sensitivity and specificity (> 80%) for HBV-related HCC. Most importantly, nearly 75% of patients who could not be diagnosed with AFP at 20 ng/mL were detected by this model. Further, the predictive model exhibited an exceedingly high ability to predict 5-year overall survival in HCC patients. These data demonstrate the high diagnostic and prognostic potential of methylation markers in the plasma of HCC patients. PMID- 28031533 TI - Gene expression profiling of tumor-initiating stem cells from mouse Krebs-2 carcinoma using a novel marker of poorly differentiated cells. AB - Using the ability of poorly differentiated cells to natively internalize fragments of extracellular double-stranded DNA as a marker, we isolated a tumorigenic subpopulation present in Krebs-2 ascites that demonstrated the features of tumor-inducing cancer stem cells. Having combined TAMRA-labeled DNA probe and the power of RNA-seq technology, we identified a set of 168 genes specifically expressed in TAMRA-positive cells (tumor-initiating stem cells), these genes remaining silent in TAMRA-negative cancer cells. TAMRA+ cells displayed gene expression signatures characteristic of both stem cells and cancer cells. The observed expression differences between TAMRA+ and TAMRA- cells were validated by Real Time PCR. The results obtained corroborated the biological data that TAMRA+ murine Krebs-2 tumor cells are tumor-initiating stem cells. The approach developed can be applied to profile any poorly differentiated cell types that are capable of immanent internalization of double-stranded DNA. PMID- 28031534 TI - Autophagy inhibition enhances photocytotoxicity of Photosan-II in human colorectal cancer cells. AB - Photodynamic therapy (PDT) has emerged as an attractive therapeutic treatment for colorectal cancer because of its accessibility through endoscopy and its ability to selectively target tumors without destroying the anatomical integrity of the colon. We therefore investigated the therapeutic relevance of the interplay between autophagy and apoptosis in Photosan-II (PS-II)-mediated photodynamic therapy (PS-PDT) in in vitro and in vivo models for human colorectal cancer. We observed that PS-PDT-induced dose-dependently triggered apoptosis and autophagy in both SW620 and HCT116 cells. PS-PDT-treated SW620 cells exhibited nuclear condensation and increased levels of cleaved caspase-3, PARP and Bax, which is reminiscent of apoptosis. PS-PDT also induced autophagic vacuoles, double membrane autophagosome structures and the autophagy-related proteins P62, Bcl-2, ATG7 and LC3-II. In addition, the AKT-mTOR pathway was downregulated, while AMPK was upregulated in PS-PDT-treated cells. Inhibiting autophagy using chloroquine or by downregulating ATG7 using shRNA further upregulated apoptosis, suggesting autophagy was probably was protective to PS-PDT-treated tumor cells. In vivo relevance was demonstrated when a combination of chloroquine and PS-PDT significantly reduced the tumor size in a xenograft mice model. Our findings demonstrate that combination therapy using PS-PDT and autophagy inhibitors may be an effective approach to treating colorectal cancer patients. PMID- 28031535 TI - Resistance to glucose starvation as metabolic trait of platinum-resistant human epithelial ovarian cancer cells. AB - Deregulated glucose metabolism is observed in cancer but whether this metabolic trait influences response to or is modulated by cytotoxic drugs is unknown. We show here that tumor cells from epithelial ovarian cancer (EOC) patients can be categorized, according to their in vitro viability under glucose starvation, into glucose deprivation-sensitive (glucose-addicted, GA) and glucose deprivation resistant (glucose non-addicted, GNA). When EOC cells were cultured in the absence of glucose, all samples from platinum (PLT)-sensitive patients felt into the GA group; they disclosed higher expression of glucose metabolism enzymes, higher proliferation rates and in vitro sensitivity to PLT. Moreover, GA patients showed reduced multi-drug resistance pump expression and autophagy, compared to GNA samples. The close association between PLT sensitivity and glucose metabolic profile was confirmed in a xenograft model, where a stringent parallelism between PLT sensitivity/resistance and glucose metabolism was identified. Finally, in a cohort of naive EOC patients categorized as GA or GNA at diagnosis, Kaplan Meier curves showed that the GA phenotype was associated with significantly better progression-free survival, compared to GNA patients. PMID- 28031537 TI - Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells. AB - Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Increasing evidence indicates that the host DNA damage response (DDR) can influence and be influenced by EBV infection. Thus, we inoculated tonsillar B cells (TBCs) with EBV-B95.8 and investigated cell proliferation and the DDR during the first 96 hours thereafter. We identified for the first time that EBV infection of TBCs induces a period of hyperproliferation 48-96 hours post infection characterized by the activation of ataxia telangiectasia and Rad3 releated (ATR) and checkpoint kinase-1 (Chk1). Whereas inhibition of Chk1 did not affect B-cell transformation, the specific inhibition of ATR robustly decreased the transformation efficiency of EBV. Our results suggest that activation of ATR is key for EBV-induced B-cell transformation. Thus, targeting the interaction between ATR/Chk1 and EBV could offer new options for the treatment of EBV associated malignancies. PMID- 28031536 TI - Use of non-selective beta-blockers is associated with decreased tumor proliferative indices in early stage breast cancer. AB - Previous studies suggest beta-adrenergic receptor (beta-AR) antagonists (beta blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of beta1 AR and beta3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of beta-blocker usage on tumor proliferation. Our analysis revealed that non-selective beta blockers, but not selective beta-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of beta-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective beta-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3beta. In conclusion, use of non-selective beta-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation. PMID- 28031538 TI - Variants in microRNA genes in familial papillary thyroid carcinoma. AB - Papillary Thyroid Carcinoma (PTC) displays one of the highest familiality scores of all cancers as measured by case-control studies, yet only a handful of genes have been implicated until now. Variants in microRNAs have been associated with the risk of several cancers including PTC but the magnitude of this involvement is unclear. This study was designed to test to what extent genomic variants in microRNAs contribute to PTC risk. We used SOLiD technology to sequence 321 genomic regions encoding 427 miRNAs in one affected individual from each of 80 PTC families. After excluding variants with frequency >= 1% in 1000 Genomes Phase 1 (n = 1092) we detected 1978 variants. After further functional filtering steps 25 variants in pre-miRs remained. Co-segregation was observed for six out of 16 tested miRNA variants with PTC in the families, namely let-7e, miR-181b, miR 135a, miR-15b, miR-320, and miR-484. Expression of miR-135a and miR-181b was tested in normal thyroid and tumor tissue from patients that carry the variants and a decrease in expression was observed. In vitro assays were applied to measure the effect of the variants on microRNAs' maturation. Four out of six variants were tested. Only the let-7e and miR-181b variants showed an effect on processing leading to lower levels of mature miRNA. These two variants were not detected in 1170 sporadic PTC cases nor in 1404 controls. Taken together, our data show that high penetrance germline sequence variants of miRNAs potentially predispose to a fraction of all PTC but are not common. PMID- 28031540 TI - Cerebrospinal fluid in Alzheimer's: A precious tool. PMID- 28031539 TI - Recurrent genetic defects on chromosome 5q in myeloid neoplasms. AB - BACKGROUND: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. MATERIALS AND METHODS: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. FINDINGS: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. INTERPRETATION: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution. PMID- 28031541 TI - Ephrins in astrocytes: synaptic erasers on stage. PMID- 28031542 TI - Parvalbumin and autism: different causes, same effect? PMID- 28031543 TI - Molecular rescue of Tsc1-ablated cortical tuber mice. PMID- 28031544 TI - Myelinating cells can feel disturbances in the force. PMID- 28031545 TI - Intergenerational Change in Anthropometric Indices and Their Predictors Among Children in New Delhi Birth Cohort. AB - OBJECTIVE: To evaluate intergenerational change in anthropometric indices of children and their predictors. DESIGN: Prospective cohort. PARTICIPANTS: New Delhi Birth Cohort participants (F1), born between 1969 and 1972, were followed up for anthropometry at birth and 6-monthly intervals until 21 years. Their children (F2) below 10 years were evaluated anthropometrically. OUTCOME MEASURE: Intergenerational change (F2-F1) in height, weight and body mass index (BMI) of children in comparison to their parents at corresponding ages. RESULTS: 432 F2-F1 pairs were analyzed in age-groups of 0-5 (26.9%) and 5-10 (73.1%) years. Children were considerably taller (0-5 years 0.99 SD; 5-10 years 1.17 SD) and heavier (0-5 years 0.77 SD; 5-10 years 1.52 SD) while only those aged 5-10 years were broader (had a higher BMI; 1.03 SD), than their parents. These increases for 0-5 and 5-10 years, respectively corresponded to 3.9 and 6.4 cm for height, 1.3 and 5.4 kg for weight and 0.2 and 1.9 kg/m2 for BMI. Lower parents' anthropometric indices and poor water supply and sanitation facilities; higher age of parents at child birth and of children when measured (for height and weight); and more parental education (for weight and BMI), were associated with greater intergenerational gains in children. CONCLUSION: Over one generation in an urban middle-class population, whose general living conditions had improved, under-five children have become considerably taller and heavier, and 5-10 year old children have additionally become broader, than their parents at corresponding ages. Child populations probably 'grow up' before 'growing out'. PMID- 28031546 TI - Sunlight Exposure and Vitamin D Status in Breastfed Infants. AB - OBJECTIVE: To correlate the sunlight exposure in first 6 months to vitamin D status at 6 months of age in predominantly breastfed infants; and to quantify the sunlight exposure required to achieve serum 25(OH)D level >20 ng/mL, by 6 months of age. DESIGN: Design: Prospective cohort. SETTING: Tertiary-care hospital predominantly catering to urban poor population in Delhi. PARTICIPANTS: 132 healthy infants, delivered at term, and predominantly breastfed were enrolled at 6-8 weeks of age. Of these, 100 infants were available for final evaluation at 6 months of age (mean (SD) follow-up: 126 (17) days). METHODS: Baseline maternal vitamin D (serum 25(OH)D) levels were obtained at enrolment. The mothers were asked to maintain a daily record of duration of sunlight exposure, timing of exposure, and body surface area exposed, for the infant, on a pre-designed proforma, till the child was 6 months of age. Infant's serum 25(OH)D was measured at 6 months of age. MAIN OUTCOME MEASURES: Cumulative Sun Index was calculated as a composite measure of overall duration/time/body surface area exposed to sunlight; and correlated with the infant serum 25(OH)D after adjusting for baseline maternal serum 25(OH)D levels, season of exposure, and skin color of the infant. Sun index for exposure in morning (before 10 am) and afternoon (10 am-3 pm) were also correlated to vitamin D status. RESULTS: Of 100 mother-infant pairs completing the study, 90 mothers had vitamin D deficiency (serum 25(OH)D <12 ng/mL). The median duration of exposure of infants to sunlight was 17 min per week, on 6% of body surface area. Vitamin D levels of 67 (67%) infants at 6 months were less than 12 ng/mL and another 23% had insufficient levels (12-20 ng/mL). Cumulative sun index correlated positively to infant's serum 25(OH)D level at 6 months of age (r= 0.461, P<0.001). Increment in afternoon sun index by 1 unit increased the serum 25(OH)D level by 1.07 ng/mL (95% CI 0.37, 1.78; P= 0.003). A minimum 30 minute weekly afternoon sunlight exposure, between 10 am and 3 pm, over 40% body area (infant clothed in diapers, in prone position) for at least 16 weeks, was estimated requirement to achieve sufficient vitamin D levels (>20 ng/mL) by 6 months of age. CONCLUSION: There is a significant positive correlation between afternoon sunlight exposure and infant's vitamin D levels, independent of maternal vitamin D status. Randomized controlled trials are suggested to explore the effectiveness of this simple intervention to prevent or treat vitamin D deficiency in children. PMID- 28031547 TI - Behavioral Problems in Indian Children with Epilepsy. AB - OBJECTIVE: To assess prevalence of behavioral problems in children with epilepsy. METHODS: This was a cross-sectional study of children with epilepsy, and normal controls enrolled between July 2013 to June 2015. Child Behavior Checklist (CBCL) was used as a tool to assess the behavior based on parents reported observation. RESULTS: There were 60 children with epilepsy in 2-5 years and 80 in 6-14 years age groups, and 74 and 83 unaffected controls, respectively. Mean CBCL scores for most of the domains in children of both age groups were significantly higher than controls. Clinical range abnormalities were mainly detected in externalizing domain (23.3%) in 2-5 years, and in both internalizing (21.2%) and externalizing (45%) domains in children of 6-14 years. Younger age of onset, frequency of seizures and duration of disease had significant correlation with behavioral problems in both the age groups. Antiepileptic drug polytherapy was significantly associated with internalizing problems in older children. CONCLUSION: Age at onset, frequency of seizures and duration of disease were found to be significantly associated with occurrence of behavioral problems. PMID- 28031548 TI - Outcome of Antenatally Presenting Posterior Urethral Valves (PUV) in Children. AB - BACKGROUND: To analyze the outcome of children with posterior urethral valves who presented with antenatal hydronephrosis. METHODS: A 10-year retrospective review of records of 70 children with posterior urethral valves. RESULTS: The mean (SD) gestational age at diagnosis was 34 (4.48) weeks, and age at intervention was 130.5 (170.9) days. The nadir creatinine was significantly raised (<1.2 mg/dl) in children with oligohydramnios and diversion. CONCLUSION: All boys with antenatally detected hydronephrosis need postnatal evaluation to rule out posterior urethral valves. Short term outcome is improved with postnatal treatments, and longer follow-up is needed to ensure a favourable outcome. PMID- 28031549 TI - Clinicopathological Features and Prognosis of Hepatic Epithelioid Hemangioendothelioma After Liver Resection and Transplantation. AB - BACKGROUND Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor. We present a single-center study on hepatic EHE cases treated by hepatic resection (HR) or liver transplantation (LT). MATERIAL AND METHODS Six HR patients with hepatic EHE were identified during 5 years from 2010 to 2014; EHE represented 0.13% (6 of 4572) of all primary liver tumors. Two LT recipients were also identified during 12 years from 2003 to 2014, who represented 0.06% (2 of 3576) of all adult LT patients. RESULTS Mean age of the patients was 42.3+/-11.2 years and 7 were female. Preoperative diagnoses based on imaging studies were suspected liver metastasis or EHE; thus, all patients underwent liver biopsy. The extent of HR, which was determined by the location and size of tumors, consisted of right hepatectomy in two patients, right anterior sectionectomy in one, right posterior sectionectomy in one, central bisectionectomy plus partial hepatectomy in one, and right trisectionectomy plus partial hepatectomy in one. All patients recovered uneventfully from surgery. The disease-free survival rate was 83.3% at 1 year and 44.4% at 3 years in HR patients, but all patients are alive to date. Two patients underwent living-donor LT because they had multiple tumors scattered throughout the liver. Of these, one patient died from tumor recurrence at 9 months and the other is alive after 5 years without recurrence. CONCLUSIONS Hepatic EHE is often misdiagnosed as a metastatic tumor. This disease has malignant potential; thus, it requires aggressive treatment including HR, non surgical treatment, and LT. PMID- 28031550 TI - Bug Smash, Bug Splash: A Case Report of an Unusual Transmission of American Trypanosomiasis with a Brief Review of the Literature. AB - BACKGROUND Chagas disease is a chronic parasitosis transmitted by the inoculation of infected triatomine feces into wounds or conjunctival sac, transfusion, congenitally, organ transplantation, and ingestion of contaminated food. The disease is classified into an acute and chronic phase; the latter is a life-long infection that can be asymptomatic or progress to cardiac or digestive complications. CASE REPORT We report a case of acute-phase Chagas disease, transmitted by the splash of gut content from an infected triatomine into the conjunctival mucosa. CONCLUSIONS The diagnosis of Chagas disease is made by the direct visualization of the parasite in blood smears during the acute phase of the disease; during the chronic phase of the disease the diagnosis is made by the detection of IgG antibodies. Parasitological cure can be achieved in up to 80% of the cases in acute phase of the disease, in contrast with less than 30% during the chronic phase. PMID- 28031551 TI - A Two-Phase Case-Control Study of Autism Risk Among Children Born From the Late 1990s Through the Early 2000s in the United States. AB - BACKGROUND This study evaluated the hypothesis that the 1999 recommendation by the American Academy of Pediatrics (AAP) and US Public Health Service (PHS) to reduce exposure to mercury (Hg) from Thimerosal in US vaccines would be associated with a reduction in the long-term risk of being diagnosed with autism. MATERIAL AND METHODS A two-phase assessment utilizing a case (n=73) -control (n=11,783) study in the Vaccine Adverse Event Reporting System (VAERS) database (for hypothesis generating) and a more rigorous, independent matched case (n=40) control (n=40) study (hypothesis testing) was undertaken. RESULTS Analysis of the VAERS database using logistic regression revealed that the odds ratio (OR) for being an autism case in the VAERS database significantly decreased with a more recent year of vaccination in comparison to controls (OR=0.65) from 1998 to 2003. Sex-separated analyses revealed similar significant effects for males (OR=0.62) and females (OR=0.71). Analyses of the matched case-control data revealed, using the t-test statistic, that the mean date of birth among cases diagnosed with an autism spectrum disorder (ASD) (2000.5+/-1.2) was significantly more in the past than in controls (2001.1+/-1.3). Logistic regression also revealed that the OR for being diagnosed with ASD significantly decreased with a more recent date of birth in comparison to controls (OR=0.67) from 1998-2003. CONCLUSIONS This study reveals that the risk of autism during from the late1990s to early 2000s in the US significantly decreased with reductions in Hg exposure from Thimerosal containing childhood vaccines, but future studies should examine this phenomenon in other US populations. Vaccine programs have significantly reduced the morbidity and mortality associated with infectious disease, but Thimerosal should be removed from all vaccines. PMID- 28031552 TI - Autophagy-related IRGM genes confer susceptibility to ankylosing spondylitis in a Chinese female population: a case-control study. AB - It is known that ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) shared a common genetic component. The gist of current study is to assess the role of IBD-associated autophagy gene IRGM on AS susceptibility in a Chinese Han population. A total of 1270 unrelated subjects (643 AS and 627 controls) were enrolled. Two tag single-nucleotide polymorphisms (SNPs) (rs10065172 and rs4958846) were selected and were genotyped by iMLDR Assay technology. Genotypes and haplotype analysis were conducted by using SPSS 16.0 and haploview 4.2 software. Among two tag SNPs of IRGM, no correlation was observed between rs10065172 and AS susceptibility. For rs4958846, genotype and allelic frequencies were marginally discrepant between female cases and controls before, not after, Bonferroni correction (P=0.049; P=0.031). Logistic regression analysis revealed that carriers with CT+TT or CT genotype had a significantly decreased risk for developing AS among female subjects when compared with CC genotype (OR=0.514, 95% CI=0.301-0.876, P=0.014; OR=0.518, 95% CI=0.297-0.902, P=0.020, respectively). Additionally, a risk haplotype rs4958846C-rs10065172C (OR=2.093, 95% CI=1.301 3.368) and a protective haplotype rs4958846T-rs10065172C (OR=0.652, 95% CI=0.441 0.964) were also identified to be associated with female AS. IBD-associated IRGM gene is also associated with AS susceptibility in the Chinese female population, indicating that autophagy pathway may involve in AS genetic predisposition. PMID- 28031553 TI - Genetic origin of Behcet's disease population in Denizli, Turkey; population genetics data analysis; historical demography and geographical perspectives based on beta-globin gene cluster haplotype variation. AB - In our study, we aimed to investigate the possible genetic drift, relationships, expansion and historical origin based on haplotype frequencies of the beta-globin gene cluster of normal and Behcet's disease (BD) population in Denizli, Turkey. We examined blood DNA samples obtained from our DNA bank. The association of population genetic parameters such as haplotypes, diversity, differentiation, Hardy-Weinberg equilibrium and demographic analysis for two populations was performed by Arlequin ver. 3.5. Our results show that both populations have high similarity in genetic parameters in terms of development and expansion based on haplotype diversity through the history. We found that historical levels of gene flow were significantly higher between the two populations. According to historical population, growth parameter of tau values for normal and BD populations dated approximately 42 000 to 38 000 ybp, respectively. In conclusion, historically, two populations show similar genetic parameters and unimodal growth distribution. Our results are consistent with the view that the BD may have occurred in area, independent from Silk Road. PMID- 28031554 TI - Enhanced MAPK signaling is essential for CSF3R-induced leukemia. AB - Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone cannot induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL. PMID- 28031555 TI - Lung cancer: AURA3 magic reveals new standard. PMID- 28031557 TI - Immunotherapy: Benefit with anti-PD-L1. PMID- 28031558 TI - Lung cancer: ET - platinum therapy comes home. PMID- 28031559 TI - Urological cancer: Atezolizumab: an alternative to cisplatin? PMID- 28031556 TI - Advances in the molecular genetics of gliomas - implications for classification and therapy. AB - Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology. PMID- 28031561 TI - Bladder cancer: Atezolizumab: an alternative to cisplatin? PMID- 28031562 TI - Kidney cancer in 2016: RCC - advances in targeted therapeutics and genomics. PMID- 28031563 TI - Prostate cancer: Risk factors - you find what you are looking for. PMID- 28031564 TI - R&D returns continue to fall. PMID- 28031560 TI - The landscape of new drugs in lymphoma. AB - The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials. PMID- 28031565 TI - Diabetes: Turning down galectin 3 to combat insulin resistance. PMID- 28031566 TI - Anticancer drugs: Switching off immune suppression. PMID- 28031567 TI - Market watch: Upcoming market catalysts in Q1 2017. PMID- 28031568 TI - 3D cell technologies head to the R&D assembly line. PMID- 28031569 TI - Anticancer drugs: Cutting the antioxidant supply chain. PMID- 28031570 TI - Alzheimer amyloid hypothesis lives on. PMID- 28031571 TI - John Lechleiter. PMID- 28031572 TI - Alzheimer disease: BACE1 inhibitor reduces beta-amyloid production in humans. PMID- 28031573 TI - Antibacterials: Microcins limit intestinal infection. PMID- 28031574 TI - Cancer: Microtubule-straightening compound widens the therapeutic window. PMID- 28031575 TI - Cures Act shakes up the FDA and NIH. PMID- 28031577 TI - Computational chemistry: Novel virtual screening approach. PMID- 28031578 TI - Cardiovascular disease: Dietary supplement protects the heart. PMID- 28031579 TI - Drug delivery: Star-shaped pill sustains drug release. PMID- 28031576 TI - Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF; also known as CSF1), granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) can each play a part in the host response to injury and infection, and there is burgeoning interest in targeting these CSFs in inflammatory and autoimmune disorders, as well as in cancer. For success in clinical medicine, therapeutic targeting will need to be delineated from current strategies. The individual CSFs have unique biological roles, suggesting that they could be used to target specific conditions. This Review compares the CSFs, with a focus on how they could be targeted, discusses the relevant clinical trial data and summarizes the potential clinical applications of targeting each CSF. Importantly, we discuss the novelty of CSF biology and attempt to clarify some of the surrounding misconceptions and issues that can affect therapeutic decisions. PMID- 28031580 TI - Suicide Prevention: It's Time to Connect, Communicate, and Care. PMID- 28031581 TI - Suicide in India: Distinct Epidemiological Patterns and Implications. AB - Suicide is a societal crisis which also deeply impacts the personal and family realms. Indian suicidal data present distinctive epidemiological patterns when we compare it with the global suicide rates and trends. Higher proportions of young individuals are resorting to suicide compared to any other country in the world, and Indian suicide rates, especially South Indian rates, are one of the highest in the world. In this article, we present various historical aspects and theories of Indian suicide and review of available Indian research from various sources such as community, hospitals, schools and forensic settings. We discuss our findings which reveal the distinctiveness of Indian data when we compare these with global data and draw implications for practice and policy. PMID- 28031583 TI - Suicide and Suicidal Behavior among Transgender Persons. AB - BACKGROUND: Suicide rate and suicidal tendencies among transgender persons are considerably high compared to general population. Hence, this review is an attempt to understand the issues around the suicide and suicidal behavior among transgender persons. METHODOLOGY: The literature search conducted using three sources, i.e., electronic databases (PubMed, ProQuest, Google Scholar, PsycInfo), manual search (library catalog), and gray literature (consultation with experts). RESULTS: The suicide attempt rate among transgender persons ranges from 32% to 50% across the countries. Gender-based victimization, discrimination, bullying, violence, being rejected by the family, friends, and community; harassment by intimate partner, family members, police and public; discrimination and ill treatment at health-care system are the major risk factors that influence the suicidal behavior among transgender persons. CONCLUSION: In spite of facing a number of hardships in their day-to-day life, the transgender community holds a number of resiliency factors. Further, this community needs to be supported to strengthen their resiliency factors and draw culturally sensitive and transgender inclusive suicide prevention strategies and increase protective factors to tackle this high rate of suicidality. PMID- 28031582 TI - Brain-Derived Neurotrophic Factor and Suicide in Schizophrenia: Critical Role of Neuroprotective Mechanisms as an Emerging Hypothesis. AB - Suicide is a common occurrence in psychiatric disorders and is a cause of increased healthcare utilization worldwide. Schizophrenia is one of the most common psychiatric disorders worldwide and posited to be seen in 1% of the population worldwide. Suicide is a common occurrence in schizophrenia with 25% 30% patients with schizophrenia attempting suicide and 8%-10% completing it. There is a need for valid biological markers to help clinicians identify patients with schizophrenia that may be at a risk of suicide and thus help in them receiving better care and interventions at the earliest even before a suicide attempt occurring. There are clear neurobiological changes at a genetic, neuroimaging, and neurochemical level that occurs in patients with schizophrenia that attempt suicide. There is a new theory that postulates neuronal plasticity and neuroprotection to have a role in the biological changes that ensue when suicidal thoughts and feelings occur in patients with schizophrenia. Neurotrophic growth factors like brain-derived neurotrophic factor (BDNF) have been documented to play a role in the protection of neurons and in the prevention of neurobiological changes that may lead to suicide both in schizophrenia and depression. The present paper presents a commentary that looks at the role of BDNF as a protective factor and neurobiological marker for suicide in schizophrenia. PMID- 28031584 TI - Reducing Suicide Rates: Need for Public Health and Population Interventions. AB - Recent studies from India have challenged the fact that the majority of the people who die by suicide have severe mental illness; they have demonstrated its frequent links to environmental stress, social, cultural, economic, and political correlates. Suicide, a complex phenomenon, is a final common pathway for a variety of causal etiologies. Nevertheless, psychiatry continues to argue for curative solutions based on the reductionistic biomedical model, rather than support public health measures to manage the larger sociocultural, economic, and political context. While psychiatry and curative medicine help many people in distress, specific mental health interventions are unlikely to impact secular trends in the rates of suicide. The reduction of population rates of suicide requires a range of public health measures. PMID- 28031585 TI - Suicide Prevention: Beyond Mental Disorder. AB - Suicide is a conscious act of the will with personal and societal ramifications. Its conscious and volitional nature deepens its tragic impact. India has high suicide rates compared to the other countries and also has intriguing distinctiveness due to the reports of higher rates from areas with better health indices and gender opportunities. In this article, I present a broader paradigm, in contrast to the usual 'mental disorder paradigm', which puts forward practical points for a multi-level engagement of healthcare service, community and policy makers. PMID- 28031586 TI - Clinical Correlates of Suicide in Suicidal Patients with Schizophrenia Spectrum Disorders and Affective Disorders. AB - BACKGROUND: The most common psychiatric illnesses in the background of suicide are schizophrenia spectrum disorders (SSD) and affective disorders (AD). While depression and hopelessness are important factors for suicide in psychiatric patients, the role of psychotic symptoms is unclear. We examine the comparative differences in the clinical correlates of suicide in SSD and AD patients with suicidal risk. MATERIALS AND METHODS: One hundred and twenty suicidal psychiatric patients (aged between 17-60 years) were evaluated for depression severity, hopelessness, past attempts, and reasons for wanting to commit suicide at the emergency psychiatry centre. Of these 29% had SSD, 65% AD, and 6% other disorders. RESULTS: Lifetime history of suicide attempts and suicide attempts in previous month were higher in SSD patients. Mean Beck Depression scores, Hopelessness, and Suicide Intention scores were significantly lower in patients with SSD as compared to AD (P <= 0.05). More than 60% patients with SSD attributed psychotic symptoms as a reason for wanting to commit suicide, while more than 50% patients with AD attributed it to family and personal stressors (P <= 0.001). CONCLUSIONS: Factors associated with suicidal ideations were significantly different between SSD and AD patients. Hence, suicide prevention strategies should be based on the specific risk factors for each group, SSD and AD. PMID- 28031587 TI - Short-term Cost of Suicides in India. AB - BACKGROUND: India is experiencing increasing suicides that have much economic impact. OBJECTIVE: To calculate the short-term costs of suicide in India. MATERIALS AND METHODS: All the official data of suicides in India in 2014 formed the base of computation. Both direct and indirect costs were computed basing on market rates and official estimates. Perceived gains were deducted to arrive at the total cost. RESULTS: The contribution of middle age group in the loss was high. Each suicide costs 2.65 L and the total cost of suicide in 2014 amounts to 348842.65 L in the first year. CONCLUSION: Much suffering and burden on individuals, family, and society can be reduced if adequate treatment facilities for psychiatry patients are made available at affordable rates everywhere. This should be complemented by much needed public education. PMID- 28031588 TI - Assessment of Suicidal Intent. AB - BACKGROUND: Suicide and suicidal attempt are an important cause of mortality and denotes severe morbidity among the population. Successful suicide attempt is associated with previous suicide attempts. Identifying factors in suicide attempters will help in formulating a comprehensive response to these issues. OBJECTIVE: To identify the sub group who are more vulnerable and the factors associated with this group. SETTING AND DESIGN: A cross sectional observational study of this sub group was carried out. MATERIAL AND METHODS: study was conducted on patients who were referred to the Psychiatry department for attempted suicide. They were assessed to identify those with high suicidal intent and study the factors associated with high suicidal intent. STATISTICS: Epiinfo by CDC was used to analyze the results. RESULTS: High intent was associated with history of psychiatric illness, history of previous attempts and family history of suicidal attempts. CONCLUSIONS: A sub group was identified which had a high intent and possibly higher chance of repeating an attempt. PMID- 28031589 TI - Profile of Young Suicide Attempt Survivors in a Tertiary Care Hospital in Puducherry. AB - CONTEXT: Puducherry has the highest suicide prevalence rate in India by 2014, predominantly among the 14-30 years age group. AIMS: The aim of the present study is to study the characteristics of adolescent and youth suicide attempters in Puducherry and measure the suicide intent. SETTINGS AND DESIGN: An observational study of 6 months duration was conducted in the Department of Psychiatry, at Sri Manakula Vinayagar Medical College and Hospital, Puducherry, India. MATERIALS AND METHODS: Modified version of World Health Organizations SUicide PREvention Multisite Intervention Study on Suicidal questionnaire was used to collect sociodemographic data and Beck's suicide intent scale was used to measure the suicide intent scores. International Classification of Diseases-10 was used for diagnosis. STATISTICAL ANALYSIS: Statistical Package for the Social Sciences version 13 was used for descriptive analysis and correlation statistics. P value was set as <0.05. RESULTS: Of 56 eligible participants, 40 formed the sample, their mean age was 18. 13 (+/-2.50), more females (1.1:1), rural, literate, lower socioeconomic status (67.5%), mostly single (90%), living in nuclear (95%), and Hindu (87.5%). One hundred percent had psychosocial stressors before suicide attempt. Acute stress disorder/adjustment disorder was the most common diagnosis. Emotionally unstable and anankastic personality traits were seen in 12%. Pesticide ingestion (45%) was the most common suicide method. Sixty percent attempted suicide within <30 min of suicidal contemplation. Statistical associations were found between the alleged purpose, seriousness, attitude toward living/dying, conception about medical rescuability, and the overall suicide intent. CONCLUSIONS: Adolescent and youth suicide attempts occur due to psychosocial stressors rather than due to the past or on-going mental health disorders with above personality traits suggest poor coping skills and resilience taken to deal with stressful situations by younger people. PMID- 28031590 TI - Role of Demographic and Personality Factors in Mediating Vulnerability to Suicide Attempts under Intoxication with Alcohol: A Record-based Exploratory Study. AB - BACKGROUND: Identifying those who are likely to make suicide attempts under alcohol intoxication has important implications for management and prevention of further suicidal behavior. AIMS: To identify the frequency of suicide attempts made under the influence of alcohol and the percentage of impulsive suicide attempts among them. We also aimed to identify predictors of attempted suicide under intoxication with alcohol. SETTING AND DESIGN: Record-based study carried out at a tertiary care hospital. MATERIALS AND METHODS: The clinical charts of consecutive suicide attempters (n = 147) who presented to the crisis intervention clinic from July 2013 to June 2014 were reviewed, and relevant data were extracted. The participants were divided into three groups - nonusers of alcohol (n = 85), alcohol users who did not attempt under intoxication (n = 31) and alcohol users who attempted under intoxication (n = 31). These groups were compared on various sociodemographic and clinical variables. Logistic regression was done to identify predictors of suicide attempt under intoxication. STATISTICAL ANALYSIS USED: Chi-square (chi2) test, one-way ANOVA (F) test and backward stepwise logistic regression. RESULTS: About 21.08% of all suicide attempts occurred under alcohol intoxication. Such subjects were more likely to be older (F = 12.428, P < 0.001), male (chi2 = 87.367, P < 0.001), married (chi2 = 6.787, P = 0.034), employed (chi2 = 41.778, P < 0.001), and fewer years of formal schooling (F = 3.312, P = 0.039). Physical methods (hanging) were used more often in this group (chi2 = 19.510, P = 0.012). In regression analysis, only marital status and living condition emerged as predictors of attempt under intoxication (odds ratios 4.52 [confidence interval (CI) 1.34-15.24, P = 0.015] and 5.67 [CI 1.17-27.39, P = 0.031] respectively). CONCLUSION: Certain demographic features may help us in identifying those who are more likely to make attempts under intoxication. The role of personality factors as potential mediators of such behavior needs further exploration. PMID- 28031591 TI - Attitudes of General Hospital Staff Toward Patients Who Self-harm in South India: A Cross-Sectional Study. AB - BACKGROUND: There is growing global interest into the attitudes and clinical management of persons who deliberately self-harm. People who self-harm experience many problems and typically have many needs related to management of their psychological wellbeing. A positive attitude amongst general hospital staff should prevail with people who self-harm. The principal purpose was to determine student staff attitudes towards patients who self-harmed from a professional and cultural perspective, which might influence patient treatment following hospital admission. The focus concentrated upon staff knowledge, attitudes and beliefs regarding self-harm. METHODS: A cross sectional survey of the hospital staff using a validated questionnaire was carried out. This paper reports on interdisciplinary staff from two large general hospitals in Mysuru, South India (n=773). RESULTS: Findings suggest that within a general hospital setting there is wide variation in staff attitudes and knowledge levels related to self-harm. Whilst there is attitudinal evidence for staff attitudes, this study investigates interprofessional differences in an attempt to progress treatment approaches to a vulnerable societal group. Very few staff had any training in assessment of self harm survivors. CONCLUSION: There is an urgent need for training general hospital staff in self harm assessment and prevention in south India. The results allow a series of recommendations for educational and skills initiatives before progressing to patient assessment and treatment projects and opens potential for cross cultural comparison studies. In addition, interventions must focus on current resources and contexts to move the evidence base and approaches to patient care forward. PMID- 28031592 TI - Ideological Cause and Hero Worship Related Suicides: Indian Perspective and Changing Trends During 2001-2014: An Exploratory Study. AB - BACKGROUND: Of the various causes of suicides in India, very less number commit it for an ideological cause or due to hero worship (IHW). The prevalence and changing trends in IHW suicides are not much discussed. An attempt is made to draw attention to this subset of suicides during 2001-2014. MATERIALS AND METHODS: Accessible data from the National Crime Bureau Records in open domain was employed for this study. As only whole sum numbers associated with state, age groups, and genders and years were only available parameters, descriptive statistics of rate of suicides, linear trend with age groups, gender, and geographical divisions are presented. RESULTS: In 14 years period, 1,721,946 suicides with an average of 122,996 suicides per year were observed. In total, a sum of 2395 IHW related suicides was noted accounting an average 171 suicides per year was observed. The difference among genders and age group with respect to various parts of India is presented. Southern India and in particular, Tamil Nadu consistently had the highest IHW related suicides. DISCUSSION: The possible causes behind this unique phenomenon, cultural ethos, and implication are presented. In addition, the implication of changing trends in terms of geographical distribution, age group distribution, and gender dynamics are presented and discussed. PMID- 28031593 TI - Risk Factors for Farmers' Suicides in Central Rural India: Matched Case-control Psychological Autopsy Study. AB - BACKGROUND: Despite more than two decades since recognition of suicides by farmers in India, systematic studies comparing various risk factors are lacking. This is major hurdle for the formulation of strategies for farmers' suicide prevention. OBJECTIVE: To identify socioeconomic and psychological risk factors and their relative contribution in suicides by farmers. MATERIALS AND METHODS: A matched case-control psychological autopsy was done on 98 farmers' suicide victims and 98 controls in Central India. RESULTS: Economic problems, psychiatric illness, and stressful life events were found to be important contributors to farmers' suicides. Important economic risk factors were procurement of debt, especially from multiple sources and for nonagricultural reasons and leasing out farms. Psychiatric illness was present significantly in higher proportion among cases than controls. Crop failure, interpersonal problems, medical illness, and marriage of female family member were significant stressful life events. CONCLUSIONS: There are socioeconomic and psychological risk factors for suicide by farmers which can be targets of prevention policy. PMID- 28031594 TI - Suicide in Rural Central India: Profile of Attempters of Deliberate Self Harm Presenting to Padhar Hospital in Madhya Pradesh. AB - BACKGROUND: Suicide is a significant public health issue. India currently has the largest number of suicides in the world and has a disproportionate number of youth suicides including young women. The studies on patterns of suicide in rural central India are sparse, particularly among tribal communities. AIMS: The aim of this study is to describe the profile of suicide attempters presenting to a secondary-level hospital in rural central India and identify areas for potential future research toward preventive strategies. MATERIALS AND METHODS: A retrospective chart review was carried out of eighty patients who were admitted with presenting complaints of deliberate self-harm and survived until psychiatric consultation. Descriptive statistics was employed to generate the results. RESULTS AND CONCLUSIONS: 86% of the attempts were isolated impulsive attempts following triggers, the most common of which was interpersonal disputes (71%). Only 67% of patients had a mental health condition, the most common syndrome being alcohol use disorder, followed by depression, and personality disorders. Although 45% of attempters had background interpersonal conflicts, only 5% reported financial stressors as contributory. Psychosocial stressors, especially interpersonal conflicts within the family, appear to be at least as important factors as mental illnesses in contributing to suicide attempts in the area. PMID- 28031595 TI - Inpatient Suicide in a Psychiatric Hospital: A Nested Case-control Study. AB - OBJECTIVE: Risk factors for inpatient suicide are different from those in the general population. We examined sociodemographic and clinical variables of patients who committed suicide as an inpatient in a psychiatric hospital in India. METHODS: Matched retrospective nested case-control design was adopted. Ten patients who died by suicide as inpatients between 2000 and 2013 were included, along with fifty controls, matched with respect to age, sex, diagnosis, and period of admission. RESULTS: Suicide completers were mostly unskilled in occupation (P = 0.03), had a history of past suicide attempts (P < 0.001), shorter duration of hospital stay (P = 0.001), poorer improvement on psychopathology (P = 0.02), and were having more suicidal ideation (P = 0.02). Significantly more completers were receiving antidepressants (P = 0.04). CONCLUSION: This study adds to the existing sparse literature on inpatient suicides from Asia. Strength of the study was close matching between case and controls and blindedness. Limitations were retrospective design, and variations in prescription behavior and treatment decisions. PMID- 28031596 TI - Salami Slicing of Data Sets: What the Young Researcher Needs to Know. PMID- 28031597 TI - Revisiting and innovating pharmacology education. PMID- 28031598 TI - Pharmacology education in India: Challenges ahead. PMID- 28031599 TI - Competency-based medical education: An overview and application in pharmacology. AB - Competency-based medical education (CBME) is gaining momentum across the globe. The Medical Council of India has described the basic competencies required of an Indian Medical Graduate and designed a competency-based module on attitudes and communication. Widespread adoption of a competency-based approach would mean a paradigm shift in the current approach to medical education. CBME, hence, needs to be reviewed for its usefulness and limitations in the Indian context. This article describes the rationale of CBME and provides an overview of its components, i.e., competency, entrustable professional activity, and milestones. It elaborates how CBME could be implemented in an institute, in the context of basic sciences in general and pharmacology in particular. The promises and perils of CBME that need to be kept in mind to maximize its gains are described. PMID- 28031600 TI - Medical curriculum and pharmacology: An appraisal. AB - Pharmacology was introduced with Western Medical Education in India in 1900s. RN Chopra was the first Professor of Pharmacology along with patient care in School of Tropical Medicine Calcutta. Now Pharmacologists do not have clinical care nor give laboratory services to hospitals. Medical Education advanced in the West in 1960s with more emphasis on Integrated Teaching and Student Self-study and less on didactic lectures. System Based Learning and Problem Based Learning reduced importance of individual subjects. Medical Council of India (MCI) has mandatory regulations with no major changes in the last 5 decades. Universities and Medical institutions have no freedom in teaching programs. In Pharmacology didactic lectures dominate teaching. Practicals started with Dispensing Pharmacy were later replaced with Experimental Pharmacology. At present after restrictions on animals for study practicals are converted to Theoretical Exercises on Prescription writing and Incompatibilities. Students study mostly before examinations with little influence of yearlong teaching. Suggestions in line with Western Countries: Reduce the course of Pharmacology to 6 months. Examinations should be completely Internal with frequent tests by Internal Examiners. MD (Therapeutics) course may be introduced to teach Pharmacology in first semester. MCI rules to be only advisory and not mandatory. Teaching Institutions should form an independent Association and have freedom in teaching programs. A Nonofficial National Board of Medical Examination has to be formed to conduct an Entrance Test for admissions to Medical College and a National test for each graduate before registration. PMID- 28031601 TI - Undergraduate pharmacology curriculum at an international medical college in India. AB - Pharmacology is an important aspect of rational therapeutics. There has been a long-standing need for a change in the undergraduate medical curriculum of pharmacology. A review of literature throws up different approaches to improve the curriculum and to provide more importance to conceptualization and relevance to clinical practice. This article describes the undergraduate pharmacology curriculum which is revised to meet the needs of our unique status as an international medical college in India. We highlight how our curriculum prepares the students for future clinical practice by inculcating higher cognitive skills and soft skills. This article also provides a model for program evaluation and also challenges faced by our department while executing the planned curriculum. PMID- 28031602 TI - Opinion of stakeholders on existing curriculum for postgraduate (MD) course in Pharmacology: A survey. AB - OBJECTIVES: To survey the opinion about various curricular components of Doctor of Medicine (MD) pharmacology curriculum in India by stakeholders, including faculty and students. MATERIALS AND METHODS: An online survey was done to evaluate the various curricular components of MD pharmacology curriculum being used in India. A total of 393 respondents including faculty, MD students, and other stakeholders completed the survey. The survey was developed using SurveyMonkey platform and link to survey was E-mailed to stakeholders. The results were expressed as percentages. RESULTS: There was a balanced representation of respondents from various designations, teaching experience, regions, and age groups. Most of the respondents (83%) were aware of the MD pharmacology curriculum. However, they reported that it is more inclined to knowledge domain. About half of respondents (53%) said that animal experiments are being used. The most common teaching methods mentioned are seminars (98.5%), journal clubs (95%), and practical exercises by postgraduates (73%), but there is less use of newer methods (25%) in theory and less of clinical pharmacology exercise (39%) in practical classes. The log books are maintained but not assessed regularly. Internal assessment is sparingly used. CONCLUSION: The MD pharmacology curriculum needs to be made uniform at the national level and updated to include the newer methods in teaching-learning and assessment. There should be sharing of newer methods at a common platform implemented at the national level. PMID- 28031603 TI - Blended learning for reinforcing dental pharmacology in the clinical years: A qualitative analysis. AB - OBJECTIVES: Blended learning has become the method of choice in educational institutions because of its systematic integration of traditional classroom teaching and online components. This study aims to analyze student's reflection regarding blended learning in dental pharmacology. SUBJECTS AND METHODS: A cross sectional study was conducted in Faculty of Dentistry, Melaka-Manipal Medical College among 3rd and 4th year BDS students. A total of 145 dental students, who consented, participate in the study. Students were divided into 14 groups. Nine online sessions followed by nine face-to-face discussions were held. Each session addressed topics related to oral lesions and orofacial pain with pharmacological applications. After each week, students were asked to reflect on blended learning. On completion of 9 weeks, reflections were collected and analyzed. STATISTICAL ANALYSIS: Qualitative analysis was done using thematic analysis model suggested by Braun and Clarke. RESULTS: The four main themes were identified, namely, merits of blended learning, skill in writing prescription for oral diseases, dosages of drugs, and identification of strengths and weakness. In general, the participants had a positive feedback regarding blended learning. Students felt more confident in drug selection and prescription writing. They could recollect the doses better after the online and face-to-face sessions. Most interestingly, the students reflected that they are able to identify their strength and weakness after the blended learning sessions. CONCLUSIONS: Blended learning module was successfully implemented for reinforcing dental pharmacology. The results obtained in this study enable us to plan future comparative studies to know the effectiveness of blended learning in dental pharmacology. PMID- 28031604 TI - Assessment of knowledge and perceptions toward generic medicines among basic science undergraduate medical students at Aruba. AB - OBJECTIVE: Use of generic medicines is important to reduce rising health-care costs. Proper knowledge and perception of medical students and doctors toward generic medicines are important. Xavier University School of Medicine in Aruba admits students from the United States, Canada, and other countries to the undergraduate medical (MD) program. The present study was conducted to study the knowledge and perception about generic medicines among basic science MD students. MATERIALS AND METHODS: The cross-sectional study was conducted among first to fifth semester students during February 2015. A previously developed instrument was used. Basic demographic information was collected. Respondent's agreement with a set of statements was noted using a Likert-type scale. The calculated total score was compared among subgroups of respondents. One sample Kolmogorov Smirnov test was used to study the normality of distribution, Independent samples t-test to compare the total score for dichotomous variables, and analysis of variance for others were used for statistical analysis. RESULTS: Fifty-six of the 85 students (65.8%) participated. Around 55% of respondents were between 20 and 25 years of age and of American nationality. Only three respondents (5.3%) provided the correct value of the regulatory bioequivalence limits. The mean total score was 43.41 (maximum 60). There was no significant difference in scores among subgroups. CONCLUSIONS: There was a significant knowledge gap with regard to the regulatory bioequivalence limits for generic medicines. Respondents' level of knowledge about other aspects of generic medicines was good but could be improved. Studies among clinical students in the institution and in other Caribbean medical schools are required. Deficiencies were noted and we have strengthened learning about generic medicines during the basic science years. PMID- 28031605 TI - Role-play as an educational tool in medication communication skills: Students' perspectives. AB - OBJECTIVES: Medication communication skills are vital aspects of patient care that may influence treatment outcomes. However, traditional pharmacology curriculum deals with imparting factual information, with little emphasis on patient communication. The current study aims to explore students' perceptions of role-play as an educational tool in acquiring communication skills and to ascertain the need of role-play for their future clinical practice. MATERIALS AND METHODS: This questionnaire-based study was done in 2nd professional MBBS students. A consolidated concept of six training cases, focusing on major communication issues related to medication prescription in pharmacology, were developed for peer-role-play sessions for 2nd professional MBBS (n = 122) students. Structured scripts with specific emphasis on prescription medication communication and checklists for feedback were developed. Prevalidated questionnaires measured the quantitative aspects of role-plays in relation to their relevance as teaching-learning tool, perceived benefits of sessions, and their importance for future use. STATISTICAL ANALYSIS: Data analysis was performed using descriptive statistics. RESULTS: The role-play concept was well appreciated and considered an effective means for acquiring medication communication skills. The structured feedback by peers and faculty was well received by many. Over 90% of the students reported immense confidence in communicating therapy details, namely, drug name, purpose, mechanism, dosing details, and precautions. Majority reported a better retention of pharmacology concepts and preferred more such sessions. CONCLUSIONS: Most students consider peer-role-play as an indispensable tool to acquire effective communication skills regarding drug therapy. By virtue of providing experiential learning opportunities and its feasibility of implementation, role-play sessions justify inclusion in undergraduate medical curricula. PMID- 28031606 TI - Role of concept map in teaching general awareness and pharmacotherapy of HIV/AIDS among second professional medical students. AB - OBJECTIVE: Medical students as future doctors will play an important role in caring for HIV-infected patients. This study assessed and evaluated the existing level of knowledge of MBBS students about HIV/AIDS given through lecture delivery methods and by use of concept map (CM). MATERIALS AND METHODS: This study was carried out on 150 professional MBBS students of tertiary care hospital. A pretest was conducted by giving 10 multiple choice questions (MCQ) of general awareness and 15 questions regarding pharmacotherapy of HIV/AIDS. In between pre- and post-test, a session of 1-week integrated teaching module was organized. After completion of integrated teaching, 2 h session of CM on general awareness and pharmacotherapy of HIV/AIDS was taken. A posttest was conducted using MCQs and problem-based question (PBQ) to assess the effect of integrated teaching and CM on their knowledge about HIV/AIDS. Feedback was also taken from the students to regarding their views about CM. RESULTS: There was a significant increase in student's score in MCQ test after integrated teaching than pretest (P < 0.05). There was also significant improvement in PBQ score after CM than that of after integrated teaching (P < 0.05). Students' perception about the effectiveness of CM was positive. CONCLUSION: CM can make a significant improvement in the knowledge of medical students and were motivated and developed interest in the subject. PMID- 28031607 TI - Effectiveness of flipped classroom with Poll Everywhere as a teaching-learning method for pharmacy students. AB - OBJECTIVES: Flipped classroom (FC) is a pedagogical model to engage students in learning process by replacing the didactic lectures. Using technology, lectures are moved out of the classroom and delivered online as means to provide interaction and collaboration. Poll Everywhere is an audience response system (ARS) which can be used in an FC to make the activities more interesting, engaging, and interactive. This study aims to study the perception of undergraduate pharmacy students on FC activity using Poll Everywhere ARS and to study the effectiveness of FC activity as a teaching-learning tool for delivering complementary medicine module in the undergraduate pharmacy program. MATERIALS AND METHODS: In this nonrandomized trial on interrupted time series study, flipped class was conducted on group of 112 students of bachelor of pharmacy semester V. The topic selected was popular herbal remedies of the complementary medicine module. Flipped class was conducted with audio and video presentation in the form of a quiz using ten one-best-answer type of multiple-choice questions covering the learning objectives. Audience response was captured using web-based interaction with Poll Everywhere. Feedback was obtained from participants at the end of FC activity and debriefing was done. RESULTS: Randomly selected 112 complete responses were included in the final analysis. There were 47 (42%) male and 65 (58%) female respondents. The overall Cronbach's alpha of feedback questionnaire was 0.912. The central tendencies and dispersions of items in the questionnaire indicated the effectiveness of FC. The low or middle achievers of quiz session (pretest) during the FC activity were three times (95% confidence interval [CI] = 1.1-8.9) at the risk of providing neutral or negative feedback than high achievers (P = 0.040). Those who gave neutral or negative feedback on FC activity were 3.9 times (95% CI = 1.3-11.8) at the risk of becoming low or middle achievers during the end of semester examination (P = 0.013). The multivariate analysis of "Agree" or "Disagree" and "Agree" or "Strongly Agree" was statistically significant. CONCLUSION: This study provides insight on how the pharmacy students learn and develop their cognitive functions. The results revealed that the FC activity with Poll Everywhere is an effective teaching learning method. PMID- 28031608 TI - Introducing objective structured practical examination as a method of learning and evaluation for undergraduate pharmacology. AB - OBJECTIVE: Assessment method can influence student learning. Use of objective structured practical examination (OSPE) has been reported in various institutes with great benefits. We evaluated OSPE for the assessment of practical skills in pharmacology examination for undergraduate medical students and compared it with conventional practical examination (CPE). MATERIALS AND METHODS: After sensitizing the 2nd year MBBS students to OSPE, the students were divided into four batches with twenty students in each batch. Students were assessed by attending five OSPE stations, each for duration of 5 min. The effectiveness was assessed through a student's feedback questionnaire and was checked for its reliability by Cronbach's alpha. The result of OSPE was compared with that of CPE of the same batch. RESULTS: Cronbach's alpha of the feedback questionnaire was 0.71, with high internal consistency. The feedback given was categorized into three domains: cognitive, psychomotor, and affective, and an assessment was also done for its further use. In cognitive domain, 74% of the students felt that the questions asked and the syllabus taught were well correlated. In psychomotor domain, 81% agreed that it is excellent for assessing the applied part of the subject. Seventy percent of students opined that it was associated with lesser stress than CPE. On overall assessment, 76% rated this methodology as good/satisfactory and 23% as excellent in terms of better scoring. There was a significant difference in the mean score between the results of OSPE and CPE (P < 0.001, df = 158, confidence interval = 95%). CONCLUSION: OSPE is a feasible and skill enhancing tool for the assessment in pharmacology examinations for undergraduate students. PMID- 28031609 TI - Introducing structured viva voce examination in medical undergraduate pharmacology: A pilot study. AB - OBJECTIVE: Viva voce examination is an important tool of evaluation in medical examinations marred by high subjectivity. Gross subjectivity in viva voce assessment can be reduced by structuring it. MATERIALS AND METHODS: The marks obtained in theory and viva voce (traditional viva voce examination [TVVE]) of I sessional, II MBBS students were compared and a huge disparity was identified. A structured viva voce examination (SVVE) was then proposed and experimented as an objective and standardized alternative. Sets of equitable question cards for SVVE were prepared, each having eight questions with two parts each, arranged successively with increasing difficulty, domains of learning, and appropriate marks. The percentage variation in scoring in viva versus theory marks was calculated for both TVVE and SVVE, and students were grouped as Group I (+100 to +51%); Group II (+50 to -50%); Group III (-51 to -100%); Group IV (-101 to 150%); Group V (-151 to -200%); and Group VI (< -200%) variation, as? inappropriate, appropriate, inappropriate, erroneous, more erroneous and most erroneous respectively. Student's feedback on the SVVE was also obtained. RESULTS: In TVVE (n = 128), the students distributed were:none,17.2%, 23.4%, 22.7%, 11.7% and 25% in Group I, II, III, IV, V, and VI in contrast to SVVE (n = 107) as 7.5%, 57.9%, 19.6%, 6.5%, 5.6%, and 2.8%, respectively. Marked disparity of TVVE was annulled with SVVE. Student's feedback was quite encouraging with 83% overall acceptability and almost 66% preferred SVVE. CONCLUSION: SVVE was more realistic as compared to TVVE. Most of the students favored this approach. PMID- 28031610 TI - The need for a comprehensive medication safety module in medical education. AB - OBJECTIVE: A rising number of medicines and minimal emphasis on rational prescribing in the medical curriculum may compromise medication safety. There is no focused module in the curriculum dealing with factors affecting safety such as quality, medicines management, rational use, and approach to adverse effects. Creating awareness of these issues would hopefully plant a seed of safe prescribing and encourage pharmacovigilance. A study was therefore done to determine the need for such a module. METHOD: A quasi-experimental pre-post module study. Medical students (n = 88) completing pharmacology term were recruited after informed consent. A questionnaire containing 20 questions on various themes was administered and scored. Subsequently a module was developed and relevant safety themes taught to the students. After one month, the questionnaire was re-administered. RESULTS: The pre module score was 9.52/20. Knowledge about the various themes, adverse effects, medication management, quality issues and rational use were similar though poor knowledge was evident in specific areas such as clinical trials, look alike-sound alike medicines (LASA) and medicine storage. The post module score was 12.24/20. The improvement of score was statistically significant suggesting the effectiveness of the module. CONCLUSION: The relatively poor knowledge and improvement with a specific educational module emphasizes the need of such a module within the medical curriculum to encourage safe use of medicines by Indian Medical Graduates (IMG). It is hoped that the policy makers in medical education will introduce such a module within the medical curriculum. PMID- 28031611 TI - Poetry in teaching pharmacology: Exploring the possibilities. AB - OBJECTIVES: To explore poetry as a tool for active learning in linking knowledge and affective domains and to find if correlating learning with imagination can be used in "assessment for learning." MATERIALS AND METHODS: After taking a conventional lecture on Asthma, a creative writing assignment in the form of poetry writing was given to the students. Different triggers were given to the students to channelize their thought pattern in a given direction that was linked to specific areas of academic relevance. Students were asked to reflect on this learning experience and the faculty was asked to evaluate the student assignment on a 5-point Likert scale. RESULTS: Most student groups scored well in the "overall assessment" of creative assignments and were rated as good or fair by the faculty. Students reflections were very informative and revealed that more than 90% of the students liked the exercise and many were too exuberant and liberal with emotional reactions that breathed positive. Around 5% students found the exercise average and another 5% found it very childish. CONCLUSION: Poetry writing turned out to be like a simulation exercise that linked academic knowledge, creativity, and the affective domain in an assumed scenario, rehearsed in free locales of mind. The metaphorical transition embedded in its subtle creation helped assess deeper understanding of the subject and the logical sequence of thought pattern. PMID- 28031612 TI - Use of prelecture assignment to enhance learning in pharmacology lectures for the 2nd year medical students. AB - OBJECTIVES: Majority of teaching hours allotted by the Medical Council of India in pharmacology are utilized in the form of didactic lecture. Although these lectures are an excellent tool to deliver the information to a large group of students, it usually ends up as a one-sided teaching session with most students being the passive listeners. To make these lectures interesting and effective, we introduced the students to prelecture assignment (PLA) in the form of clinical case before the delivery of the lecture. METHODS: This prospective educational trial was conducted in the Department of Pharmacology with undergraduate medical students in their 2nd year of their professional course. They were divided into two groups of 75 each. Group A was provided the PLA before the lecture. Group B students directly attended the lecture, sans the PLA. Multiple-choice questions based test was conducted 2 days after the lecture. Students who failed to complete the assignment and were absent from the lecture and test were excluded from the study. Feedback from the students was obtained after the lecture. The scores in the test and responses were compiled and analyzed using Statistical Package for Social Sciences (SPSS) software version 21.0 (SPSS Inc., Chicago, IL, USA). Results were expressed in percentages and as mean +/- standard deviation as applicable. P < 0.05 was considered statistically significant. RESULTS: Fifty-six students from Group A and 42 from Group B appeared for the test. The students who were given PLA scored better. They felt more confident in answering and understood the topic better than the students of other group. CONCLUSION: PLA is a useful teaching-learning tool. The pharmacology lectures are interactive, interesting, and easy to understand with this tool. PMID- 28031613 TI - Implementation of a module to promote competency in adverse drug reaction reporting in undergraduate medical students. AB - OBJECTIVES: Underreporting and poor quality of adverse drug reaction (ADR) reports pose a challenge for the Pharmacovigilance Program of India. A module to impart knowledge and skills of ADR reporting to MBBS students was developed and evaluated. MATERIALS AND METHODS: The module consisted of (a) e-mailing an ADR narrative and online filling of the "suspected ADR reporting form" (SARF) and (b) a week later, practical on ADR reporting was conducted followed by online filling of SARF postpractical at 1 and 6 months. SARF was an 18-item form with a total score of 36. The module was implemented in the year 2012-2013. Feedback from students and faculty was taken using 15-item prevalidated feedback questionnaires. The module was modified based on the feedback and implemented for the subsequent batch in the year 2013-2014. The evaluation consisted of recording the number of students responding and the scores achieved. RESULTS: A total of 171 students in 2012-2013 batch and 179 in 2013-2014 batch participated. In the 2012-2013 batch, the number of students filling the SARF decreased from basal: 171; 1 month: 122; 6 months: 17. The average scores showed improvement from basal 16.2 (45%) to 26.4 (73%) at 1 month and to 27.3 (76%) at 6 months. For the 2013 2014 batch, the number (n = 179) remained constant throughout and the average score progressively increased from basal 10.5 (30%) to 27.8 (77%) at 1 month and 30.3 (84%) at 6 months. CONCLUSION: This module improved the accuracy of filling SARF by students and this subsequently will led to better ADR reporting. Hence, this module can be used to inculcate better ADR reporting practices in budding physicians. PMID- 28031614 TI - Temporal trends in pharmacology publications by pharmacy institutes: A deeper dig. AB - OBJECTIVE: Publications in Indian Journal of Pharmacology (IJP) are the face of contemporary pharmacology practices followed in health-care profession - a knowledge-based profession. It depicts trends in terms of quantity (proportions), quality, type (preclinical/clinical), thrust areas, etc., of pharmacology followed by biomedical community professions both nationally and internationally. This article aims to establish temporal trends in pharmacology research by pharmacy institutes in light of its publications to IJP from 2010 to 2015. METHODOLOGY: The website of IJP was searched for publications year and issue wise for contributing authors from pharmacy institutions and analyzed for types of publications, their source and the categories of research documented in these publications. RESULTS: A total of 1034 articles were published, of which 189 (18%) articles were published by pharmacy institutes, of which 90% (n = 170) were contributed from pharmacy institutes within India whereas 10% (n = 19) from international pharmacy institutes. 75% of these were research publication, the majority of which (65%) were related to preclinical screening of phytochemical constituents from plants. CONCLUSION: With multi and interdisciplinary collaborations in pharmacy profession the trend needs to improve toward molecular and cellular pharmacology and clinical studies. PMID- 28031615 TI - Effectiveness of student-led objective tutorials in pharmacology teaching to medical students. AB - OBJECTIVES: Current teaching in pharmacology is passive with less emphasis on clinical application. There is a need to incorporate newer instructional designs into pharmacology. Student-led objective tutorial (SLOT) is one of the novel designs to enhance interest among learners, provide opportunities for group learning, and facilitate self-directed learning. This study aims to assess the effectiveness of SLOTs over conventional tutorials (CTs) in pharmacology and to obtain feedback from the students regarding their perceptions about it. SUBJECTS AND METHODS: The regular batch of MBBS 2nd professional in pharmacology was randomly divided into two groups. Five topics from central nervous system (CNS) were selected. One group received SLOT as the instructional strategy, whereas the other group went through CTs. At the end of the module, a written test was conducted to assess the effectiveness of both strategies. The students provided feedback regarding their experience using a prevalidated questionnaire. STATISTICAL ANALYSIS: The mean scores of both the groups were analyzed using Mann Whitney U-test. RESULTS: There was no significant difference in the mean scores of the end of the module test. However, the overall passing percentage was significantly higher in the intervention group (P = 0.043). A total of 45.71% students favored it as a future tutorial method and expressed that SLOT enhanced their ability to learn independently. CONCLUSION: SLOT is an effective teaching learning method to teach pharmacology to medical undergraduates. It enhances interest among learners and increases the ability to learn independently. PMID- 28031616 TI - Student-led objective tutorials in Pharmacology: An interventional study. AB - OBJECTIVES: Students learn in a better way if they are involved in active learning. Hence, the study was designed to introduce student-led objective tutorials (SLOTs) as an alternative to conventional tutorials (CTs) in pharmacology and to compare SLOT and CT on outcomes such as improved score in tests, active involvement of students, and faculty requirement of each. MATERIALS AND METHODS: Didactic lectures taken on a topic in pharmacology were followed by a preintervention test for a batch of the 2nd year medical undergraduates. They were allotted either in SLOT or CT group. For a SLOT session, students of Group A (interventional group) were divided into teams and each team prepared five multiple choice questions on the given topic in PowerPoint format, which were presented to other teams and audience. The proceedings were facilitated by two lecturers. Group B undertook CT (controls). A postintervention test was then taken for both groups. Feedback was sought from students and teachers on SLOT. RESULTS: The total marks for the test were 20. The mean marks in Group A improved by 31% (from 5.1 to 11.2). In Group B, they improved by 11% (from 5 to 7.2). Academic performance following SLOT was better than CT. Students (63%) favored SLOT as it stimulated their interest in the topic, improved self-learning skills, and teamwork. The teachers also favored SLOT for similar reasons. CONCLUSION: SLOT leads to greater satisfaction and better performance in tests. SLOT is an effective alternative to CT to promote active learning among students through group work. It helps overcome the logistic difficulties due to faculty shortage. PMID- 28031617 TI - Knowledge, awareness and practice of ethics among doctors in tertiary care hospital. AB - INTRODUCTION: With the advancement of healthcare and medical research, doctors need to be aware of the basic ethical principles. This cross-sectional study is an attempt to assess the knowledge, awareness, and practice of health-care ethics among health-care professionals. MATERIALS AND METHODS: After taking written informed consent, a standard questionnaire was administered to 117 doctors. No personal information was recorded on the questionnaire so as to ensure the confidentiality and anonymity of participants. Data analysis was done using SPSS version 21 (IBM Corp., Armonk, NY, USA). RESULTS: Statistically significant difference observed between the opinions of consultant and senior resident (SRs) on issues like, adherence to confidentiality; paternalistic attitude of doctors (doctors should do their best for the patient irrespective of patient's opinion); doctor's decision should be final in case of disagreement and interest in learning ethics (P < 0.05). However, no difference reported among them with respect to patient wishes, informing patient regarding wrongdoing, informing close relatives, seeking consent for children and patients' consent for procedures. Furthermore, no significant difference observed between the two with respect to the practice of health-care ethics. Surprisingly, the response of clinical and nonclinical faculty did not differ as far as awareness and practice of ethics were concerned. CONCLUSION: The significant difference is observed in the knowledge, awareness, and practice of ethics among consultants and SRs. Conferences, symposium, and workshops, on health-care ethics, may act as a means of sensitizing doctors and thus will help to bridge this gap and protect the well being and confidentiality of the patients. Such an effort may bring about harmonious change in the doctor-patient relationship. PMID- 28031618 TI - Learning pharmacology by metaphors: A tale of aminoglycosides. PMID- 28031620 TI - Late Prof. P. C. Shastri: A Role Model and Teacher Par Excellence. PMID- 28031619 TI - Status of animal experiments in teaching pharmacology to undergraduate students. PMID- 28031621 TI - Preface: Positive Psychiatry, Neuroscience, End of Life, and Other Essays. PMID- 28031622 TI - Neuromodulation, Emotional Feelings and Affective Disorders. AB - Affective disorders such as anxiety, phobia and depression are a leading cause of disabilities worldwide. Monoamine neuromodulators are used to treat most of them, with variable degrees of efficacy. Here, we review and interpret experimental findings about the relation of neuromodulation and emotional feelings, in pursuit of two goals: (a) to improve the conceptualisation of affective/emotional states, and (b) to develop a descriptive model of basic emotional feelings related to the actions of neuromodulators. In this model, we hypothesize that specific neuromodulators are effective for basic emotions. The model can be helpful for mental health professionals to better understand the affective dynamics of persons and the actions of neuromodulators - and respective psychoactive drugs - on this dynamics. PMID- 28031623 TI - Neural Implications of Psychotherapy, Pharmacotherapy, and Combined Treatment in Major Depressive Disorder. AB - Numerous clinical trials have been conducted to determine the utility of antidepressant treatment (ADT), psychotherapy, and combined psycho-pharmaco psychotherapy (PPPT) in treating major depressive disorder (MDD). While all approaches have shown benefit over placebo to varying degrees, the parallel neurophysiological mechanisms that underlie their efficacy have received little attention. The authors will review and discuss a growing body of literature that relates the factors of treatment selection and response to the principles of neuromodulation, with emphasis regarding how neuroimaging and other experimental data reinforce the need for personalized MDD treatment. This manuscript and its theoretical approaches were supported by conducting relevant literature searches of MEDLINE and PubMed electronic databases, prioritizing systemic reviews, and randomized clinical trials using selected MeSH terms. The authors conclude that ADT, psychotherapy, and PPPT all create potentially observable neurofunctional changes and argue that additive and synergistic potentiation of these effects in PPPT may produce more sustained symptom relief than with monotherapy alone. PMID- 28031625 TI - Field of Psychiatry: Current Trends and Future Directions: An Indian Perspective. AB - Attempting to predict future is dangerous. This is particularly true in medical science where change is a result of chance discoveries. Currently, practicing psychiatrists are aware of deficiencies in psychiatric practice. However, we have a number of genuine reasons for optimism and excitement. Genetics, novel treatment approaches, new investigative techniques, large-scale treatment trials, and research in general medicine and neurology will give better insights in psychiatric disorders and its management. Psychiatric services in rural India can be reached by telemedicine. There are some threat perceptions which require solving and remedying. Subspecialties in psychiatry are the need of the hour. There is also a requirement for common practice guidelines. Mental Health Care Bill, 2013, requires suitable amendments before it is passed in the Indian Parliament. Research in psychiatry is yet to be developed as adequate resources are not available. PMID- 28031624 TI - Bioethical and Other Philosophical Considerations in Positive Psychiatry. AB - The paper begins by asserting the need for bioethical and related philosophical considerations in the emerging subspecialty Positive Psychiatry. Further discussion proceeds after offering operational definitions of the concepts fundamental to the field - Bioethics, Positive Psychology, Positive Psychiatry and Positive Mental Health - with their conceptual analysis to show their areas of connect and disconnect. It then studies the implications of positive and negative findings in the field, and presents the Positive Psychosocial Factors (PPSFs) like Resilience, Optimism, Personal Mastery, Wisdom, Religion/Spirituality, Social relationships and support, Engagement in pleasant events etc. It then evaluates them on the basis of the 4-principled bioethical model of Beneficence, Non-malfeasance, Autonomy and Justice (Beauchamp and Childress, 2009[5], 2013[6]), first offering a brief clarification of these principles and then their bioethical analysis based on the concepts of 'Common Morality', 'Specific Morality', 'Specification', 'Balancing' and 'Double Effects'. The paper then looks into the further development of the branch by studying the connectivity, synergy and possible antagonism of the various Positive Psychosocial Factors, and presents technical terms in place of common terms so that they carry least baggage. It also takes note of the salient points of caution and alarm that many incisive analysts have presented about further development in the related field of Positive Mental Health. Finally, the paper looks at where, and how, the field is headed, and why, if at all, it is proper it is headed there, based on Aristotle's concept of the four causes - Material, Efficient, Formal and Final. Suitable case vignettes are presented all through the write-up to clarify concepts. PMID- 28031626 TI - Task before Indian Psychiatry Today: Commentary. AB - In this commentary on the article, "The Task Before Psychiatry Today Redux: STSPIR," (Singh, 2014)[20], the author, while agreeing with most of the paper's findings, proposes a rather parallel judgment that intersects at the same paths ahead. There is a need for widespread and easily available essential mental health services in India. Health agenda must focus on spreading and scaling up psychiatric services. There is also a need to spread awareness of psychiatry and mental health and, as a psychiatrist, one must focus on making psychiatry available to a wider audience. Psychiatrists need to maintain a holistic view of psychiatric disorders while viewing them from both a neurobiological and psychosocial perspective. There is a need to revamp psychiatric training in departments with an increase in the thrust toward fostering translational research excellence in various spheres. Psychiatrists must continue to be trained in psychotherapy and practice it regularly. Psychiatric departments need to promote research excellence and focus on reducing brain drain. The practical applications of the tasks set out for psychiatry are more difficult than one can imagine, and a conscientious effort in that direction shall serve for its betterment. The future is bright and psychiatry must work toward making it brighter. PMID- 28031627 TI - Out of Flatland: The Role of the Notion of a Worldview in the Science of Well being. AB - This paper discusses the suggestion of the notion of a worldview as part of the Science of Well-Being. We present, at first, an allegoric comparison as to why the view of a ternary unity of being (i.e. a coherence of the three parts of the being, body, mind, and psyche to maximize well-being) is difficult to grasp. We also discuss that humans do have unique experiences and memories, but that we are also connected to both all living things and to our environment. Finally, we point to a ternary model of personality to increase our understanding of a person's well-being: Temperament, character, and identity. PMID- 28031628 TI - The Problem of Dualism in Modern Western Medicine. AB - Dualism is historically important in that it allowed the medical practice to be divorced from church oversight. The reductionist approaches of modern Western medicine facilitate a dispassionate and mechanistic approach to patient care, and dualist views promoted by complementary and alternative medicine are also problematic. Behavioural disorders are multifactorally realizable and emerge apparently chaotically from interactions between internal physiological systems and the patient's environment and experiential history. Conceptualizations of behavioural disorders that are based on dualism deny the primacy of individual physiology in the generation of pathology and distract from therapies that are most likely to produce positive outcomes. Behavioural health professionals should adopt holistic models of patient care, but these models must be based on methodologies that emphasize radical emergence over the artificial separation of the "physical" and "mental." This will allow for the humanistic practice of medicine while simultaneously maximizing the likelihood of treatment success. PMID- 28031630 TI - Lessons of Being a Patient--Personal Thoughts about Psycho-oncology in India. AB - Psycho-oncology is a well-established field in the developed countries and 'distress' is recognised as the sixth vital sign in the care of persons diagnosed with cancer. However, centres in India caring for cancer do not make psycho social aspects an essential part of their care programmes. The present narrative presents the personal journey of the author, reviews the situation of psycho oncology in India and presents a three-part agenda for action. PMID- 28031629 TI - End-of-Life Care and Psychiatry: Current Trends and Future Directions in India. AB - Although 80% of the deaths worldwide occur in middle- and low-income countries such as India, there is less awareness of end-of-life care (EOLC) for people with chronic, serious, progressive, or advanced life-limiting illnesses, including dementia. EOLC involves good communication, clinical decision-making, liaison with medical teams and families, comprehensive assessment of and specialized interventions for physical, psychological, spiritual, and social needs of patients and their caregivers. The psychiatrist can play a significant role in each of the above domains in EOLC. The current trends in India are examined, including ambiguities between EOLC and euthanasia. Future directions include formulating a national EOLC policy, providing appropriate services and training. The psychiatrist should get involved in this process, with major responsibilities in providing good quality EOLC for patients with both life-limiting physical illnesses and severe mental disorders, supporting their caregivers, and ensuring dignity in death. PMID- 28031631 TI - In Search of Rationality in Human Longevity and Immortality. AB - The human body is machine-like, but self-moving, self-regulating, and self adjusting, governed by willpower and intelligence. Aging of the body is basically a maintenance problem and so it could perhaps be postponed by thorough and frequent maintenance. Aging brings on a cascade of ills and health problems leading to deterioration of physical, mental, emotional, and social dimensions of life. This paper deals with solution of the problem philosophically in the light of Indian scriptures without entering into traditional bioethical issues. With a meaningful reason for existence, life can be extended. Examining the scientific perspectives on aging, some common manipulations for its extension are discussed. These are calorie restriction, vitamin and antioxidant treatment, exercise and hormonal interventions, etc. Finally, the question of longevity is explored through pursuance of eternal value-based activity and spirituality in the tradition of Indian heritage. PMID- 28031633 TI - Happy New Year. PMID- 28031632 TI - Why Me? PMID- 28031634 TI - Split Personality. PMID- 28031635 TI - My Trysts and Travails. PMID- 28031637 TI - Instructions to Contributors. PMID- 28031636 TI - What Music Means To Me. AB - The author talks about two defining influences in his musical career: his father, whom he addressed as 'Pitaji' and his guru, Shri Vinayak Kunte, fondly known as Kunte-guruji to his students. Pitaji taught him, by example and precept, what emotive singing meant and the nuances of poetry appreciation and Urdu pronunciation (talaffuz). Kunte-guruji acquainted him with the richness and profundity of Hindustani Classical Music and the perfection of musical notes or "sur". He also showed, by example, the need to lead a simple, uncomplicated lifestyle to experience the divinity inherent in music. Finally, the author also learned from Kunte-guruji the need to pass on one's learning to others and go out of one's way to do so. PMID- 28031638 TI - Template for MSM Submissions. PMID- 28031639 TI - Takayasu Arteritis with Multiple Coronary Artery Fistulas to Bronchial Arteries. AB - Takayasu arteritis (TA) is an inflammatory disease that commonly occurs in young females. Coronary involvement occurs rarely and mostly with stenosis. Here, we present a case of TA associated with fistulas between the coronary arteries and the bronchial arteries. PMID- 28031640 TI - Rheumatic Heart Disease Predisposing to Embolic Myocardial Infarction: A Multimodality Imaging Approach. AB - We report a clinical case of a 45-year-old male with a diagnosis of inferior myocardial infarction and previous history of rheumatic fever during his childhood. Coronary angiography demonstrated normal coronary arteries. Transthoracic echocardiogram showed hypokinetic left ventricular inferolateral wall and mitral stenosis; furthermore, speckle tracking analysis revealed reduction of global longitudinal strain involving the inferior wall. A three dimensional transesophaegeal echocardiography, performed to better characterize the anatomy of the valve and to find possible source of embolic infarct in an enlarged left atrium, showed rheumatic valvular involvement. Cardiac magnetic resonance confirmed the ischemic damage and also provided prognostic information. A multimodality imaging approach should be mandatory in patients with acute myocardial infarction and normal coronary angiography, to define possible sources of embolic infarction and to quantify myocardial damage. PMID- 28031641 TI - Ergotism: Case Report and Review of the Literature. AB - A case of ergotism is presented to illustrate the role of duplex ultrasonography in the diagnosis and management of this nonatherosclerotic cause of peripheral arterial disease. Historical aspects of ergotism are discussed together with reference to the relative vulnerability of different segments of the arterial circulation. Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early. PMID- 28031642 TI - Plausible Role of Acute HIV Infection Mediated Immune Activation in Causing Renal Allograft Rejection: A Case Report. AB - Current research states that AIDS pathogenesis has its roots in a chronic activation of immune system secondary to human immunodeficiency virus (HIV) induced proliferation of T cells, B cells, NK cells, and macrophages. Immune activation due to acute HIV infection can be highly detrimental to allograft survival in a renal transplant recipient. In this report, we describe a 32-year old African-American male patient who underwent a second live donor renal transplant, following which he developed acute allograft rejection coincident with newly acquired HIV seropositivity. PMID- 28031643 TI - Dynamic Systolic Compression of the Left Anterior Descending Coronary Artery by a Postinfarction Dyskinetic Left Ventricular Aneurysm. AB - Dynamic systolic compression of the coronary arteries is almost always due to the existence of myocardial bridging that is most commonly localized in the middle segment of the left anterior descending coronary artery. However, it has rarely been reported in patients with pericardial adhesions, tumor, foreign body, or pseudoaneurysms. Only rare case reports exist regarding dynamic coronary compression by a dyskinetic left ventricular aneurysm. We present a patient with a myocardial bridge-like systolic compression of the distal left anterior descending caused by postinfarction dyskinetic left ventricular aneurysm. PMID- 28031644 TI - Ineffective Treatment of Low-Molecular-Weight Heparin in Obese Subject with Traumatic Fractures of the Leg. AB - American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 9th edition, 2012, suggest no prophylaxis rather than pharmacological thromboprophylaxis in management of venous thromboembolism (VTE) risk of isolated lower leg injuries distal to knee requiring leg immobilization. Low-molecular weight heparin (LMWH) is a class of drugs commonly used as antithrombotics in surgery and in case of prolonged bed rest and hypomobility. A 35-year-old obese man with no history of health disease (height, 170 cm; weight, 95 kg; and body mass index, 32.9 kg/m2) was involved in a car accident, and as a result of the trauma he suffered the compound fracture of left tibia and fibula. Tibial intramedullary nailing was performed. The injury was near the knee, and the patient was advised long-term bed rest. For these reasons, he was treated with enoxaparin 40 mg once daily subcutaneously. On the 7th day of hospitalization, the leg became edematous and reddish. A Doppler ultrasonography evaluation was performed which showed a massive deep vein thrombosis of left leg and then a pulmonary angiotomography showed a massive pulmonary embolism. In this clinical case, there was a pharmacological treatment failure to prevent VTE after orthopedic surgery and related long-term rest using enoxaparin at prophylaxis dosage in a patient without history of health disease but at high risk of VTE for obesity, trauma, orthopedic surgery, and immobilization. Enoxaparin dosage to prevent VTE in patients with high risk should be reconsidered and especially in obese a weight-adjusted dosage can be better than a fixed dosage. PMID- 28031645 TI - Shining Pearls Sign: A New Identity for Venous Malformations on Computed Tomographic Imaging. AB - Vascular malformations, in particular venous malformations (VM), are common lesions involving the pediatric and adolescent population. VM occur at approximately 1:5,000 to 10,000; approximately 40% of them occur in the head and neck regions. Classical appearance of VM on imaging is a demonstration of near normal-sized or mildly dilated feeding arteries which subsequently lead to dilated venous structures of varying caliber, thus constituting the malformation. Phleboliths are the hallmark of VM. Plain radiography has been an established modality for demonstrating phleboliths. The emergence of computed tomographic (CT) as a preferred imaging modality for the evaluation of a complex vascular malformation necessitates familiarity with the spectrum of CT appearances of this lesion. This presentation illustrates an additional CT sign, "shining pearls sign," highlighting the striking display of phleboliths in the vascular malformations, prompting correct diagnosis. PMID- 28031646 TI - Angioplasty and Stenting of Distal Anastomotic Stenosis of Femoropopliteal Bypass Graft Using Helical Interwoven Nitinol Stents. AB - Minimally invasive endovascular options of angioplasty and stenting can be used to treat distal anastomotic stenoses in lower limb bypass grafts, but stents near the knee joint may fracture. The nitinol helical interwoven structure of the Supera stents (IDEV Technologies Inc., Houston, TX) has improved flexibility and kink resistance. We report a patient who received salvage angioplasty and Supera stenting of the distal anastomosis of femoropopliteal bypass grafts with good mid term results. Considering the high radial strength and fracture resistance, these Supera stents may be a good treatment option in salvaging failing bypass grafts. PMID- 28031647 TI - Are Congenital Arteriovenous Malformations of Proximal Upper Extremity, More on the Right: Case Report and Literature Review. AB - This is a case of a 9-year-old boy with a congenital arteriovenous malformation (AVM) of the right upper extremity arising from the right subclavian artery. He underwent open surgical excision of the vascular tumor. Upon reviewing the literature, a high incidence of right-sided congenital AVM of the proximal upper extremity was identified. It has been suggested that this high incidence may be related to the complexity of the embryologic development of the right subclavian artery. PMID- 28031648 TI - Successful Retrieval of the Detached Porous Metallic Tip of a Mechanical Aspiration Catheter during Thrombectomy in a Case with May-Thurner Syndrome: A Case Report. AB - Modern, minimally invasive techniques used to treat deep venous thrombosis, such as percutaneous mechanical thrombectomy (PMT) and catheter-directed thrombolysis, have gained worldwide acceptance. PMT has the advantage of speed and is also associated with improved outcomes, shortened hospital stays, and low complication rates. The main complications associated with PMT have been primarily due to iatrogenic vascular damage resulting in perforation, embolic occlusion, and arteriovenous fistula formation; to date, there has been no publication in the literature describing complications resulting from device failure. We present an unusual complication of PMT resulting from detachment of the catheter tip during thrombectomy and bailout technique employed. PMID- 28031649 TI - Non-ST Elevation Myocardial Infarction Triggered by Subclavian Steal Syndrome. AB - Coronary-subclavian artery (SCA) steal syndrome is an uncommon phenomenon in which coronary flow is diverted into the SCA through the patent left internal mammary artery (LIMA) conduit due to critical subclavian stenosis. The prevalence of significant left SCA (LSCA) stenosis in patients, referred for coronary bypass surgery, has been reported to be 0.2 to 6.8%. Most patients usually present with angina pectoris, and secondary myocardial infarction is rarely reported. Herein, we present a case of coronary bypass graft in which a left anterior descending artery-LIMA graft was applied to supply the left arm due to complete LSCA occlusion. The patient was hospitalized with a diagnosis of non-ST elevation myocardial infarction. PMID- 28031650 TI - Endovascular Repair of Bilateral Internal Mammary Artery Aneurysms in a Patient with Marfan Syndrome-A Case Report. AB - Marfan syndrome (MFS) is an autosomal dominant condition that is caused by abnormal synthesis of connective tissue. The syndrome classically affects the ocular, musculoskeletal, and cardiovascular systems. The most common cardiovascular manifestations include mitral valve prolapse/regurgitation and aortic aneurysms at high risk of rupture and dissection. However, internal mammary artery (IMA) true aneurysms are rarely reported. In this case report, we describe a 43-year-old male patient with MFS and three previous thoracotomies referred for endovascular repair of bilateral IMA true aneurysms. To the best of our knowledge, there are no cases of endovascular treatment of bilateral IMA true aneurysms reported in the literature. PMID- 28031651 TI - Spontaneous Retroperitoneal Hematoma Simulating Ruptured Infrarenal Aortic Aneurysm in a Patient with End-Stage Renal Disease. AB - We reported a case of spontaneous retroperitoneal hematoma (SRH) simulating a ruptured infrarenal aortic aneurysm. A 72-year-old man with a history of infrarenal aortic aneurysm and end-stage renal disease on hemodialysis presented with malaise and nonspecific central abdominal pain and left loin discomfort. An emergency computed tomography scan showed a large retroperitoneal hematoma and clinical suspicion of ruptured infrarenal aortic aneurysm. However, the hematoma was discontinuous with the aneurysm sac and raised the clinical suspicion on dual pathology. The SRH was treated conservatively with transfusion of blood products, and the aneurysm was treated with nonemergency endovascular repair electively. This case demonstrates the importance of recognizing different clinical and radiological characteristics and be aware of dual pathology. PMID- 28031652 TI - Anomalous the Left Main Coronary Artery Originating from the Right Coronary Artery. AB - The coronary anomalies are rarely seen in clinical practice. A 47-year-old female patient presented to hospital with chest pain on exertion. The coronary angiography and cardiac tomography showed the anomalous origin of the left main from the right coronary artery. PMID- 28031653 TI - Complications after a Bidirectional Cavopulmonary Anastomosis with Accessory Sources of Pulmonary Blood Flow. AB - Creating an accessory source of pulsatile pulmonary blood flow in a patient with a bidirectional cavopulmonary anastomosis may have advantages and disadvantages. In relation to the latter, we report the complications seen in a cyanotic congenital heart disease patient who developed a superior vena cava syndrome plus severe swelling of his right hand that evolved satisfactorily after percutaneous and medical treatment. PMID- 28031654 TI - Aortic Root Rupture during Transcatheter Aortic Valve Implantation in a Patient with Idiopathic Thrombocytopenic Purpura: Utility of Transesophageal Echocardiography in Early Detection and Description of a Semiconservative Surgical Management Approach. AB - An 87-year-old man with idiopathic thrombocytopenic purpura and platelet count of 56 * 109/L underwent transesophageal echocardiography (TEE)-guided transcatheter aortic valve implantation using a femoral approach. Post valve deployment, a new pericardial effusion was noted which was successfully drained. Despite this, the patient became hypotensive needing vasopressor support with reaccumulation of pericardial fluid. Emergent sternotomy was performed and a perforation of the right ventricular apex was noted which was sealed with a pledgeted suture. Continued bleeding prompted further exploration; the aorta was seen to be mottled in conjunction with clear aortic root hematoma on TEE and a diagnosis of root rupture was made. This was semiconservatively managed without conversion to a full aortic root repair or replacement procedure. Multiple sutures were applied to the periaortic space and the bleeding sealed with use of BioGlue (Cryolife Inc., Kennesaw, GA) and Surgicel (Ethicon Inc., Somerville, NJ). The postoperative course was stable and the patient remained well at 3-month follow up. PMID- 28031655 TI - Transperitoneal Intervascular Approach for Repair of the Lumbar Spine. AB - This report describes a novel anterior surgical approach to the midlumbar spine. A transperitoneal dissection separating the tissue planes between the infrarenal vena cava and abdominal aorta allows for ample exposure in the reconstruction of midlumbar vertebral body fractures. PMID- 28031656 TI - A Very Unusual Cause of Hemoptysis. AB - The use of Lucite balls or spheres played a role in the management of tuberculosis during the first decade of the 20th century. Several complications have been reported with the use of this surgical technique, but are rarely seen nowadays. The availability of effective oral regimens has forced to abandon this approach. Calcification of these spheres within the lung cavity produced a series of late complications result of the migration of these foreign bodies to adjacent structures, causing erosion of blood vessels and nerves. Herein, we present a case where the aforementioned complication caused significant bleeding with hemodynamic instability. The source of the profuse hemoptysis was identified and was resolved with the combined use of noninvasive approaches such as bronchoscopy and angiographic embolization. PMID- 28031657 TI - Risks Factors for Atrial Septal Defect Occlusion Device Migration. AB - Atrial septal defect (ASD) is one of the most common congenital heart defects requiring procedural intervention. In such cases, transcatheter closure of secundum ASDs has been demonstrated to be safe and effective in both children and adults, with similar success and complication rates to surgery. However, appropriate patient selection and an accurate device selection is mandatory to prevent serious complications such as ventricular arrhythmias, outflow tract obstruction of the left and right ventricle, or ischemic events secondary to the obstruction of blood flow due to device embolization. PMID- 28031658 TI - Reverse Movahed Maneuver: Maximal Expiration Maneuver during Saphenous Vein Graft Intervention for Facilitated Balloon and Stent Delivery in Tortuous Vein Grafts - A Novel Technique. AB - Percutaneous coronary intervention involving tortuous saphenous vein grafts can be difficult during balloon or stent advancement. There are many available techniques to facilitate stent delivery in tortuous vessel, such as using specialized catheter body wires, use of extra support wires or using extra back up guide catheters. All these techniques have limitations and can be costly and time-consuming. We previously published a maneuver that showed how to facilitate stent delivery in tortuous native coronary arteries by instructing the patient to take a deep breath leading to straightening of the coronary tree, thereby, substantially improving stent deliverability. However, this maneuver will cause worsening of tortuosity in a proximal segment of a vein graft during vein graft interventions as the aorta will be pulled downward during inspiration leading to increasing kink in the vein graft. Hereby, the so called reverse "Movahed Maneuver" during vein graft interventions is described. It is the exact opposite maneuver of deep inspiration previously described for native coronary interventions. By letting the patient perform complete expiration, the body of the intervening saphenous vein graft will be straightened as the aorta and aortic arch will be moved upward in the chest leading to facilitated stent deliverability. This maneuver has been performed successfully in many cases of difficult vein graft interventions due to tortuosity. This maneuver is easy to perform and can save substantial time as well as radiation in many challenging vein graft interventions and has not been described previously. PMID- 28031659 TI - Successful Percutaneous Coronary Intervention for Chronic Total Occlusion of Left Anterior Descending Coronary Artery in a Patient with Dextrocardia. AB - Dextrocardia is a rare cardiac anomaly in which the heart is located in the right chest along with the cardiac long axis directing to the right and inferiorly. Although, it is a rare clinical phenomenon, coronary artery disease with dextrocardia is presumed to be of similar frequency as in the general population. Percutaneous coronary intervention has some technical difficulties in these patients. We hereby report a male patient with dextrocardia who was previously treated with coronary artery bypass graft surgery. PMID- 28031661 TI - Percutaneous In situ Left Subclavian Artery Fenestration Using Reentry Catheter during Endovascular Thoracic Aortic Aneurysm Repair. AB - Left subclavian artery (LSA) revascularization is recommended during elective thoracic endovascular aortic aneurysm repair (TEVAR) when coverage is required for adequate proximal seal. Reported method for LSA revascularization includes open bypass, covered stent placement using chimney technique, and in situ laser fenestration. We reported a novel technique using percutaneous Outback reentry device for LSA revascularization in a 68-year-old male patient who underwent TEVAR for a 9-cm thoracic aortic aneurysm. This technique can be used as an alternative method for LSA in situ fenestration, and laser equipment is not required. PMID- 28031660 TI - A Rare Case of Gastric Mantle Cell Lymphoma causing Superior Mesenteric Artery Syndrome in an Adult. AB - Superior mesenteric artery (SMA) syndrome or Wilkie syndrome is a rare condition that arises when the distal third of the duodenum becomes trapped between the SMA and the abdominal aorta causing intestinal obstruction. It is most commonly described in adolescents and rarely in adult patients. We present an interesting case of an adult who developed SMA syndrome from an uncommon gastric mantle cell lymphoma that was recognized early and treated surgically. PMID- 28031662 TI - Hereditary Hemorrhagic Telangiectasia and Myocardial Infarction. AB - Hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disorder that leads to epistaxis, gastrointestinal bleeding, iron deficiency anemia, and arteriovenous malformations at the lungs, the liver, and the brain. However, due to its rarity and its unspecific findings on routine examinations, diagnosis is not easy unless suspected due to hypoxemia or paradoxical embolism. We present a case of a 46 year-old-woman with hereditary hemorrhagic telangiectasia and hypoxemia who presented a myocardial infarction secondary to paradoxical embolism through pulmonary arteriovenous malformations. PMID- 28031663 TI - Cardiovascular Involvement in Behcet Disease: Clinical Implications. AB - Behcet disease (BD) is a multisystem disorder, with vasculitis as its underlying pathological process, in contrast to the classic triad of recurrent oral and genital ulcerations, with uveitis. Vascular involvement in BD includes venous thrombosis, arterial occlusion, and pulmonary artery and aortic aneurysm formation. Cardiac involvement is rare and often obscure. It includes intracardiac thrombi formation, and is associated with a poor prognosis. Our objectives are to describe two cases with BD, complicated with vascular and cardiac involvement, and to raise awareness of these rare complications, the needed routine surveillance, and thus to prevent inappropriate interventions, serious outcomes, and mortality. We present two male patients from the Mediterranean Basin with BD. The first was diagnosed early as a BD patient. The second was diagnosed at the time of cardiovascular (CV) involvement. We recommend that patients who are diagnosed, or even suspected of suffering from BD, especially in endemic areas along the Silk Route pathway, should be followed up routinely for CV involvement, even if rare, obscure, or with a bizarre presentation. PMID- 28031664 TI - Using a Single Internal Mammary Artery as Retrograde and Antegrade Flow for Bilateral Deep Inferior Epigastric Artery Perforator Reconstruction: A Case Report. AB - Deep inferior epigastric artery perforator (DIEP) flaps have become an attractive option for autologous breast reconstruction. The internal mammary artery (IMA) is the usual artery of choice for reconstruction. Unfortunately, there are certain situations when the IMA may not be suitable for usage as in previous radiation or diminutive size. Several options have been documented, such as using the thoracodorsal vessels. In this case report, we report usage of the distal and proximal ends of a contralateral single mammary artery to supply antegrade and retrograde flow to bilateral DIEP flaps. With increasing complexity of patient populations, the use of alternate approaches to recipient vessel in DIEP reconstruction becomes essential for effective outcomes. PMID- 28031665 TI - Splenorenal Arterial Bypass: Description of Technique and Case Example in an Instance of Renal Revascularization during Adrenalectomy for Adrenocortical Carcinoma. AB - We present a patient with a 16 cm adrenocortical carcinoma that underwent a left adrenalectomy en bloc with resection of the involved segment of the left renal artery. A splenectomy and splenorenal bypass was performed to revascularize the left kidney. To our knowledge, this is the first instance in the literature of a splenorenal arterial bypass being reported for renal revascularization during an extirpative oncologic procedure. A 64-year-old male patient, with history significant for adrenocortical carcinoma, status post prior right adrenalectomy with partial right nephrectomy, presented for an elective left adrenalectomy. Preoperative work-up revealed an 11.4 * 13.2 * 16 cm left adrenal mass, most consistent with an adrenocortical carcinoma. At the time of surgery, the mass was found to be intimately adherent to the aorta at the takeoff of the left renal artery. Moreover, the left renal artery appeared to be coursing directly through the mass. The involved segment of the left renal artery was resected en bloc with the tumor. Because of concerns for a small and likely poorly functioning right renal remnant, a decision was made to attempt to salvage the left kidney. This was accomplished by performing a splenectomy and constructing a splenorenal bypass. Serial Duplex Doppler renal ultrasound studies were obtained over the first three postoperative days and demonstrated improved arterial waveforms. Serum creatinine reached a peak level of 3.76 mg/dL on postoperative day 3, and then began to slowly trend down to 3.37 mg/dL on the day of discharge (postoperative day7). PMID- 28031666 TI - Thrombus Resolution in Two Patients with Portal Vein Thrombosis without Anticoagulation: Do We Need to Anticoagulate Patients with Portal Vein Thrombosis? AB - Portal vein thrombosis (PVT) is a thrombosis that develops in the trunk of the portal vein which can extend to its branches. It results from a combination of local and systemic prothrombotic factors. Anticoagulation is generally considered in PVT patients as long as the risk of bleeding is low. Limited data have been published regarding spontaneous resolution of PVT. We describe two cases of asymptomatic PVT who were not given anticoagulation in view of several factors, who, on repeat scans, showed resolution of their thrombus. PMID- 28031667 TI - Progression of Thrombus in Portal Vein, Superior Mesenteric Vein, and Splenic Vein Even on Anticoagulation in a Patient with Ascending Colonic Malignancy with Liver Metastasis: Portal Vein Thrombosis versus Portal Vein Tumor Thrombosis. AB - Portal vein thrombosis (PVT) in a setting of liver metastasis is not easy to treat as it may be portal vein tumor thrombus (PVTT). A 77-year-old male patient was diagnosed as ascending colon carcinoma, underwent right hemicolectomy in 1991 with a recurrence in July 2009. In August 2009, he underwent computed tomography (CT) scan of the abdomen which showed evidence of superior mesenteric vein thrombosis with no liver metastasis. He was started with anticoagulation and decision was to treat long term. He was admitted with mesenteric artery ischemic symptoms in February 2012 on anticoagulation. CT scan abdomen and pelvis in February 2012 showed tumor thrombus involving the superior mesenteric vein, portal vein, and splenic vein with hepatic metastasis. His tumor marker chorioembryonic antigen was 34 ug/L. He was continued on anticoagulation. A repeat CT scan abdomen after 2 years (in January 2014) showed, increase in size of hepatic metastasis, extensive thrombus involving the superior mesenteric vein, portal vein, and splenic vein with collaterals. Mesentery was congested due to extensive superior mesenteric vein thrombus. He finally succumbed in June 2014. It is very important to differentiate PVT from PVTT as the prognosis is different. PVTT progresses despite of long-term anticoagulation with poor prognosis. PMID- 28031668 TI - Bilateral Superficial Femoral Artery Thrombosis in a 15-Year-Old Caucasian Male with Homozygous Prothrombin G20210A Genotype and Associated Antiphospholipid Syndrome. AB - Prothrombin mutation was usually associated with other well-established predisposing factors for venous thrombosis such as antiphospholipid antibodies. Recently, even isolated prothrombin gene mutation G20210A has been reported to present severe or unusual vein thrombosis. Less clear is the role of prothrombin mutation in the formation of arterial thrombosis. We present a case of a 15-year old healthy White male with acute bilateral femoral artery thrombosis. The patient presented with increasing left leg pain for about 1 week. He was a physically very active teenager with a new onset of leg pain aggravated by exercise. Physical examination revealed a pale and cold left foot with dorsal foot necrosis (2 * 2 cm) that started 2 days ago. In addition, he complained of moderate rest pain. No symptoms were noticed on the right lower extremity. The ankle brachial index was 0.3 on the left and 0.6 on the right. Duplex sonography showed bilateral superficial femoral artery thrombosis, which was confirmed by angiography. Subsequently, he undergoes left superficial femoral and popliteal artery lysis with rt-PA (Actilyse boehringer ingelheim, Ingelheim am Rhein, Germany) and full heparinization. Treatment was discontinued after 24 hours with no significant improvement of symptoms. Full anticoagulation with Coumadin (Bristol-Myers Squibb Company, New York, NY) and alprostadil (Prostavasin UCB, Brussels, Belgium) infusion for 2 weeks was initiated and eventually patient's symptoms improved. Laboratory testing revealed a homozygous prothrombin G20210A mutation and antiphospholipid syndrome. Homozygous prothrombin G20210A mutation in conjunction with antiphospholipid syndrome is a rare combination of coagulation disorder. Early intervention with full anticoagulation and subsequent lifelong anticoagulation should be considered in treatment strategy. PMID- 28031669 TI - Arteria Lusoria and Superdominant Right Coronary Artery: Two Rare Arterial Anomalies Diagnosed during Transradial Coronary Catheterization. AB - We present a case report of two rare arterial anomalies diagnosed during transradial coronary catheterization-arteria lusoria (aberrant right subclavian artery) and superdominant right coronary artery. Importantly, these anomalies may cause difficulty in performance or interpretation of catheterization procedure, especially in urgent situation and with wide acceptance of transradial approach. To the best of our knowledge, the combination of these anomalies has never been described in the literature. PMID- 28031670 TI - Femoropopliteal Bypass with Varicose Greater Saphenous Vein. AB - Surgical bypass for peripheral arterial occlusive disease can be performed using different graft materials. Autogenous greater saphenous vein (GSV) is the treatment of choice because of its superior long-term patency. We report a case of femoropopliteal bypass with varicose GSV in a 77-year-old man who was presented with limb ischemia and both varicose veins. We successfully performed bypass with varicose vein. He has been doing well for 15 months after the operation, and a computed tomography angiography of the lower leg, performed on the 15th postoperative month, demonstrated widely patent femoropopliteal bypass graft and no structural change. PMID- 28031671 TI - Endovascular Management of Type I Endoleak with Fenestrated Aortic "Cuff" and Afterwards Treatment of Endoleak Type III. AB - Endovascular aortic repair (EVAR) has become preferable treatment of abdominal aortic aneurysms because of proven mortality reduction as well as complications reduction compared with open surgery. Endoleak remains a primary complication of EVAR, however, and occurs in 20 to 25% of the patients. EVAR patients thus undergo lifelong surveillance for the presence of aneurysm expansion and endoleaks usually via computed tomographic angiography. We describe the endovascular management of an enlarged aneurysmal sac size 3 years after EVAR due to combined endoleak of types 1 and 3. We needed to use a fenestrated aortic cuff, a main body graft extension, and an aortouniiliac converter device to seal the leak. This case highlights the potential challenges in identifying and treating type III endoleaks. PMID- 28031672 TI - Laparoscopic Left Gastric Artery Aneurysm Resection. AB - Aneurysmal degeneration of the visceral branches of the abdominal aorta is a rare and potentially life-threatening disease entity. Visceral artery aneurysms (VAAs) are exceedingly rare and have a prevalence of 0.1 to 2%. The left gastric artery aneurysm (LGAA) is even more rare and accounts for less than 4% of all VAAs. There is scarce literature on treatment of LGAA by embolization; however, to date successful laparoscopic repair of an LGAA has not been described. We describe the successful treatment of an LGAA by laparoscopic ligation and resection in a 68 year-old male patient. PMID- 28031673 TI - Conservative Treatment of an Infected Aortic Graft with Antibiotic Irrigation. AB - Conservative management of an aortic graft infection is defined as "the nonresectional treatment of an aortic graft that has an established infection." Incidence of aortic graft infections is 0.5 to 5% and the estimated mortality rate from aortic graft infections ranges from 8 to 27%. We present the case of a 73-year-old male patient with an infected abdominal aortic graft following an emergency ruptured abdominal aortic aneurysm repair. Postemergency repair, he developed ischemic colitis with sigmoid colon perforation leading to fecal peritonitis and secondary sepsis. He developed a large infective collection within the aortic sac growing vancomycin-resistant enterococcus sensitive to linezolid. A percutaneous drain was placed in the aortic sac and this was irrigated with linezolid for a total of 28 days. The patient clinically improved. Overall, 7 months later, follow-up scan shows complete resolution of infection and the patient remains clinically stable. Conventional treatment of aortic graft infections involves an extra-anatomical bypass. Percutaneous drainage and antibiotic use may be used as bridging therapy for surgery or as definitive therapy when surgical treatment is impractical. Most aortic graft infections grow gram-positive cocci, the organisms form a biofilm which is protected from the external environment. Percutaneous drainage and antibiotic irrigation could possibly penetrate the biofilm and eradicate infection. Morris et al conducted a study on 10 patients having irrigation therapy and systemic antibiotic treatment and found a 1-year survival rate of 80%. In conclusion, conservative aortic graft treatment may be an effective alternative where surgical intervention is not suitable. PMID- 28031674 TI - Takotsubo Cardiomyopathy Associated with Primary Hyperthyroidism Secondary to Toxic Multinodular Goiter. AB - Takotsubo cardiomyopathy is increasingly recognized as a distinct clinical entity. An association with thyroid disease has been identified in several case reports, mostly in the context of Grave disease. We report the case of a 67-year old woman presenting with takotsubo cardiomyopathy and thyrotoxicosis secondary to toxic multinodular goiter. Previously unreported, this suggests that this association is related to the direct effects of thyroid hormone, rather than an autoimmune mechanism. Thyroid disease should be considered in patients presenting with takotsubo cardiomyopathy. PMID- 28031675 TI - Spontaneous Resolution of Catheter-Induced Iatrogenic Vein Graft Dissection: First Case Report and Review of Literature. AB - An 86-year-old female patient with a history of bypass surgery was admitted for recurrent dyspnea and chest pain on exertion. She underwent coronary angiography showing high-grade saphenous vein graft stenosis supplying the right coronary. During an attempt to perform percutaneous intervention, saphenous vein graft to the right coronary artery was injured by the guide catheter resulting in dissection with thrombus formation but with normal distal blood flow. The procedure was abandoned since she had normal distal flow and also due to a fear of causing extension of the dissection with further manipulation. The patient was hemodynamically stable and free of chest pain after 30 minutes of observation. The patient was later discharged home on medical treatment. After 1 month, a repeat angiography showed patent saphenous vein graft to the right coronary artery with healed dissection. This is the first case report of spontaneous recovery of iatrogenic saphenous vein graft dissection. This case is followed by the review of literature. PMID- 28031676 TI - New Chimney after Chimney EVAR for the Treatment of Type Ia Endoleak. AB - The chimney graft (CG) technique can be a useful alternative in treating aortic aneurysms with challenging anatomy, regarding the proximal sealing zone. We describe the case of a patient who developed a type Ia endoleak after chimney endovascular aneurysm repair for a juxtarenal AAA and underwent a proximal CG reconfiguration and implantation of an aortic cuff. The crossing configuration of the CGs should be avoided as it may compromise the circumferential apposition of the endograft and impede the thrombosis of the perigraft gutters. A proximal reconfiguration of the CGs, in case of type Ia endoleak is a useful option. The long-term efficacy of this option should be evaluated by meticulous follow-up. PMID- 28031677 TI - Durable Results with In Situ Graft Repair of Ruptured Salmonella Aneurysm in a Patient with Autoimmune Deficiency Syndrome. AB - We describe a case of a 42-year-old male patient with advanced autoimmune deficiency syndrome (AIDS) (CD4 count of 16 cells/mm3) found to have a ruptured infected infrarenal aortic aneurysm. Emergent in situ repair was performed with a Hemashield Dacron graft (Boston Scientific, Natick, MA). Aortic tissue cultures grew group D Salmonella. Patient was placed initially on intravenous ciprofloxacin followed by lifelong oral levofloxacin and trimethoprim. Over 2 years following repair, he remains asymptomatic, with repair intact and no recurrent infection. This case is the first reported successful long-term repair of a ruptured salmonella infected abdominal aortic aneurysm in the setting of advanced AIDS. PMID- 28031678 TI - A Case of Heparin-Induced Thrombocytopenia Type 2 after Repair of Juxtarenal Abdominal Aortic Aneurysm. AB - Heparin-induced thrombocytopenia (HIT) is still a relatively uncommon condition and it is not well known how to administer argatroban during continuous hemodiafiltration (CHDF). A 72-year-old man required CHDF with heparin because of the oliguria and hyperpotassemia directly after the open repair of a juxtarenal abdominal aortic aneurysm. As the postoperative blood platelet count dropped and there was a thrombus in the CHDF circuit, HIT was suspected and nafamostat mesilate, but not heparin, was immediately administered for CHDF. As heparin platelet factor 4 complex was positive, we diagnosed him with HIT and started argatroban while monitoring the activated clotting time (ACT), resulting in no further obstruction of the CHDF and an increase in the platelets. There was no disadvantage for administering nafamostat mesilate which we have commonly used instead of heparin, we should have used argatroban once we suspected HIT. It may be important to consider the history of heparin especially in administering heparin and it may be useful to monitor the ACT when initially starting argatroban for patients with HIT. PMID- 28031679 TI - Elevated Factor VIII Levels Associated with Acute Graft Occlusion and Arterial and Venous Thrombosis After Off Pump CABG. AB - Factor VIII is a common acute phase reactant and elevated levels confer an increased risk of thrombosis. Such thrombotic events have been documented in the literature, though to a limited extent. We present the case of a 54-year-old man presenting with a non-Q-wave myocardial infarction who was found to have triple vessel disease and subsequently underwent a 4-vessel coronary artery bypass grafting (CABG). Postoperatively, he was found to have multiple occluded vessels, deep vein thromboses, and a cerebrovascular accident (CVA). A hypercoagulability work-up revealed significantly elevated levels of factor VIII at 377% normal, which likely contributed to these thrombotic events. Further exploration is warranted to elucidate causal mechanisms of these thrombotic events, particularly of multiple graft occlusions, and to guide clinical decision making with regards to anticoagulation and stent management. PMID- 28031680 TI - Ultrasonographic, CTI and MRI of Aberrant Internal Carotid Artery: Infrequent but Important to Know. AB - This article describes the aberrant course of the internal carotid artery (ICA) through the middle ear as an extremely rare vascular anomaly. On the basis of a case report, the findings of magnetic resonance imaging, computed tomography imaging, and especially color-coded duplex sonography are presented. The diagnosis of an aberrant ICA is important to avoid severe surgical complications of a retrotympanic mass as well as unnecessary diagnostic or therapeutic approaches in expectation of a stroke. PMID- 28031681 TI - Spontaneous Round-Shaped Left Atrial Hematoma. AB - Spontaneously occurring left atrial hematomas are very rare and most of them followed acute clinical course due to hemodynamic deterioration. We presented a case of gradually developing hematoma protruding into the left atrial cavity as a round mass, which was completely encapsulated with intact endocardial wall. Emergency surgery was successfully performed. Histopathological study demonstrated subendocardial-aged hematoma with papillary endothelial hyperplasia. PMID- 28031682 TI - Diagnosing Left Coronary Ostial Atresia: Sometimes the Old Ways Are Best. AB - A 12-year-old boy with intermittent syncope associated with exercise. Exercise stress testing suggested myocardial ischemia and 2D echocardiography failed to confirm antegrade flow in the left main stem. Advanced imaging techniques including cardiac-gated computed tomography angiography and stress cardiac magnetic resonance imaging were falsely reassuring. Cardiac catheterization demonstrated left coronary artery ostial atresia with a good caliber left coronary system supplied by generous collaterals from the right coronary artery. The patient underwent successful coronary artery bypass grafting. PMID- 28031683 TI - Left Main Coronary Spasm: an Extremely Rare Entity with Possible Life-Threatening Complications. AB - Coronary artery spasm is a known cause of acute coronary syndrome. However, left main coronary spasm is an extremely rare entity and can present in different ways depending on the duration and severity of the spasm. We present a 44-year-old female patient who presented with transient ST elevation in the lead aVR and ST depression in the lateral and inferior leads. Coronary angiography showed mid left main and ostial right coronary artery spasm that significantly improved after intracoronary nitroglycerine administration. Intravascular ultrasound showed no significant left main coronary atherosclerosis. She was treated chronically with calcium channel blockers (CCB), nitrates, and arginine with significant improvement. In conclusion, left main coronary spasm is an extremely rare entity with wide spectrum of clinical manifestations. Definite etiology is still questionable, and special precaution is needed during coronary angiography in order not to be confused with significant fixed lesions. Intravascular ultrasound can be valuable in excluding underlying atherosclerosis. Medical management with nitrates acutely then CCB is the mainstay of chronic management with PCI preserved to refractory cases. PMID- 28031684 TI - Myectomy-Like Extended Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. AB - Currently, two therapeutic options are available for patients with drug-resistant obstructive hypertrophic cardiomyopathy. While there is a tendency in extended myectomy to perform a larger septal reduction to eliminate left ventricular outflow tract gradient more effectively, there has been a trend in recent years toward using lower dosages of alcohol during alcohol septal ablation (ASA) to reduce the risk of arrhythmic complications. We report a case of a symptomatic patient with severe septal hypertrophy who underwent an extended ASA of three septal branches. This led to a result similar to an extended myectomy with a favorable short-term follow-up. PMID- 28031685 TI - Staged Endovascular Repair of Isolated Bilateral Internal Iliac Artery Aneurysms: A Case Report. AB - This report aims to present an unusual case with isolated bilaterally located internal iliac artery aneurysms (IIAAs) that were incidentally detected. Owing to the high surgical risk of the patient and anatomical location of the aneurysms, an endovascular management was preferred. Initially, the patient underwent a percutaneous embolization of the right-sided aneurysm with coiling. A stent-graft deployment covering the orifice of the left-sided internal iliac artery and occluding the ipsilateral aneurysm followed 1 month later. The patient remains asymptomatic after 6 months. Endovascular management has been associated with lower morbidity and hospital stay compared with open repair for IIAAs, although both techniques show satisfying early and mid-term results. Especially for bilaterally located aneurysms, a staged strategy decreases the risk for ischemic complications. Finally, endovascular methods should be preferred when there are no compression symptoms or in cases of higher surgical risk. PMID- 28031686 TI - Successful Percutaneous Retrieval of a Guiding Catheter Tip that Had Unexpectedly Become Detached Using a Two-Wire Technique. AB - Device dislodgement during percutaneous coronary intervention (PCI) is a rare but potentially life-threatening complication. We herein report the successful retrieval of a guiding catheter tip that had unexpectedly become detached in the right coronary artery during PCI in a 68-year-old man. Interventional cardiologists must be familiar with a safer and more reliable retrieval technique. PMID- 28031687 TI - Congenital Aneurysm of the Left Sinus of Valsalva Involving the Left Main Coronary Artery. AB - Successful surgical management of a case of congenital aneurysm of the left sinus of Valsalva involving the left main coronary artery has been reported. To our knowledge, this is the first report describing an unusual case of congenital aneurysm of the left sinus of Valsalva, which involves the left main coronary artery. PMID- 28031688 TI - Premature Atherosclerosis and Drug Eluting Stent Restenosis in an Adult with Osteogenesis Imperfecta. AB - Mild form of osteogenesis imperfecta (OI) may have a normal life span. However, cardiovascular complications including aortic and valvular heart disease, and coronary artery disease may complicate the life period. We presented a patient with mild form of OI and premature coronary atherosclerosis. He had been performed primary percutaneous angioplasty and drug eluting stent implantation to left anterior descending coronary artery osteal lesion. Then he presented with unstable angina pectoris due to the diffuse in-stent restenosis and a highly critical lesion adjacent to previously stented segment. He was suggested coronary artery bypass grafting (CABG), but he preferred coronary angioplasty and was implanted everolimus eluting stent. Control angiography, performed at 9th month, revealed the everolimus eluting stent was satisfactorily patent and the patient was asymptomatic. Numerous genetic defects and histopathological abnormalities of collagen and bone formation that were reported in the etiology of OI may be accounted for premature atherosclerosis in OI. Patients with mild form of OI may present with premature atherosclerosis and acute myocardial infarction. Everolimus eluting stent implantation may be a better choice of drug eluting stent in patients with OI instead of other drug eluting stent or minimally invasive CABG. PMID- 28031689 TI - The Safety of Using Large Amount (30 cc) of Onyx (Ethylene-vinyl Alcohol Copolymer) for the Treatment of Large Type II Endoleak after Endovascular Repair of Abdominal Aortic Aneurysm. AB - Endovascular aneurysm repair (EVAR) is associated with late complications including the development of endoleaks as major complications. Type II endoleak is the consequence of collateral retrograde flow from the aortic branches; generally from the lumbar arteries, inferior mesenteric artery, or middle sacral artery. The method and the ideal timing for the treatment of endoleaks remain controversial. We are presenting a case of successful treatment of a large type II endoleak using embolization with large amount of Onyx copolymer via a percutaneous transfemoral route without any adverse outcome. A significant advantage of Onyx as opposed to glue is that it may be injected for a long period of time (20-60 minutes) with a lower risk for microcatheter entrapment. This case report suggests that much higher amount of Onyx can safely be used if needed to seal large endoleaks without adverse event. PMID- 28031690 TI - Reliability of Two Ankle-Brachial Index Methods to Predict Silent Lacunar Infarcts: A Population-Based Study in Stroke-Free Older Adults (the Atahualpa Project). AB - Individuals with an abnormal ankle-brachial index (ABI) are four times more likely to have a silent lacunar infarct (SLI), but reliability of ABI in predicting the presence of these lesions has not been estimated yet. We compared two methods of calculating ABI to assess their reliability in predicting SLIs. Stroke-free Atahualpa residents aged >= 60 years underwent MRI of the brain and ABI determinations. Persons with ABI >= 1.4 were excluded. Using receiver operator characteristic curve analysis, we calculated the reliability of the traditional as well as an alternative ABI method to identify individuals with SLI. The traditional ABI uses the higher systolic pressure of either the dorsalis pedis or the posterior tibial arteries as the numerator, whereas the alternative ABI uses the lower pressure. Of the 247 participants, 38 (15%) had traditional and 95 (38%) had alternative ABIs <= 0.9. Twenty-one individuals had SLI. Traditional and alternative ABIs <= 0.9 identified 9 and 13 individuals with SLI, respectively. The traditional ABI had sensitivity of 42.9% (22.6-65.6%) and specificity of 87.2% (81.9-91.1%). The alternative ABI had sensitivity of 61.9% (38.6-81%) and specificity of 63.7% (57-69.9%). The area under the curve for the predictive value of SLI was 0.65 (0.54-0.76) for the traditional and 0.63 (0.52 0.74) for the alternative ABI <= 0.9. The ABI is moderately reliable for identifying candidates for MRI screening in studies assessing the burden of SLI in older adults. The traditional ABI seems to be more suitable for this purpose. PMID- 28031691 TI - Cardiac Tamponade after Right Ventricular Perforation Caused by Screw-in Lead. AB - A 69-year-old man was admitted after syncope followed with chest pain and signs of cardiac tamponade. He had undergone permanent dual-chamber pacemaker implantation 3 weeks earlier. Transthoracic echocardiography (TTE) confirmed a pericardial effusion, and urgent pericardial drainage was performed. Right ventricular perforation caused by active-fixation (screw-in) lead was verified by multislice computed tomography. The lead was extracted under fluoroscopy and bedside TTE monitoring in the operating room with cardiothoracic surgery backup. In the same act, the new ventricular passive-fixation lead was implanted. PMID- 28031692 TI - A Case of True Brachial Artery Aneurysm with Severe Left Upper Limb Ischemia. AB - Brachial artery (BA) aneurysms are rare, and most are false aneurysms. Although true BA aneurysms have been reported, most have been reported without symptoms. A 65-year-old man was referred due to a left upper limb mass with rest pain and slight ulceration of the left second and third fingers. As enhanced computed tomography revealed the patency of only the left proximal and distal BA as well as the thrombosed mass, excision of the aneurysm and BA replacement were performed with a great saphenous vein graft. The postoperative course was uneventful, and the rest pain and ulceration were resolved. PMID- 28031695 TI - Mitigating Climate Change at the Carbon Water Nexus: A Call to Action for the Environmental Engineering Community. AB - Environmental engineers have played a critical role in improving human and ecosystem health over the past several decades. These contributions have focused on providing clean water and air as well as managing waste streams and remediating polluted sites. As environmental problems have become more global in scale and more deeply entrenched in sociotechnical systems, the discipline of environmental engineering must grow to be ready to respond to the challenges of the coming decades. Here we make the case that environmental engineers should play a leadership role in the development of climate change mitigation technologies at the carbon-water nexus (CWN). Climate change, driven largely by unfettered emissions of fossil carbon into the atmosphere, is a far-reaching and enormously complex environmental risk with the potential to negatively affect food security, human health, infrastructure, and other systems. Solving this problem will require a massive mobilization of existing and innovative new technology. The environmental engineering community is uniquely positioned to do pioneering work at the CWN using a skillset that has been honed, solving related problems. The focus of this special issue, on "The science and innovation of emerging subsurface energy technologies," provides one example domain within which environmental engineers and related disciplines are beginning to make important contributions at the CWN. In this article, we define the CWN and describe how environmental engineers can bring their considerable expertise to bear in this area. Then we review some of the topics that appear in this special issue, for example, mitigating the impacts of hydraulic fracturing and geologic carbon storage, and we provide perspective on emergent research directions, for example, enhanced geothermal energy, energy storage in sedimentary formations, and others. PMID- 28031694 TI - Embryonic markers of cone differentiation. AB - PURPOSE: Photoreceptor cells are born in two distinct phases of vertebrate retinogenesis. In the mouse retina, cones are born primarily during embryogenesis, while rod formation occurs later in embryogenesis and early postnatal ages. Despite this dichotomy in photoreceptor birthdates, the visual pigments and phototransduction machinery are not reactive to visual stimulus in either type of photoreceptor cell until the second postnatal week. Several markers of early cone formation have been identified, including Otx2, Crx, Blimp1, NeuroD, Trbeta2, Rorbeta, and Rxrgamma, and all are thought to be involved in cellular determination. However, little is known about the expression of proteins involved in cone visual transduction during early retinogenesis. Therefore, we sought to characterize visual transduction proteins that are expressed specifically in photoreceptors during mouse embryogenesis. METHODS: Eye tissue was collected from control and phosducin-null mice at embryonic and early postnatal ages. Immunohistochemistry and quantitative reverse transcriptase-PCR (qPCR) were used to measure the spatial and temporal expression patterns of phosducin (Pdc) and cone transducin gamma (Gngt2) proteins and transcripts in the embryonic and early postnatal mouse retina. RESULTS: We identified the embryonic expression of phosducin (Pdc) and cone transducin gamma (Gngt2) that coincides temporally and spatially with the earliest stages of cone histogenesis. Using immunohistochemistry, the phosducin protein was first detected in the retina at embryonic day (E)12.5, and cone transducin gamma was observed at E13.5. The phosducin and cone transducin gamma proteins were seen only in the outer neuroblastic layer, consistent with their expression in photoreceptors. At the embryonic ages, phosducin was coexpressed with Rxrgamma, a known cone marker, and with Otx2, a marker of photoreceptors. Pdc and Gngt2 mRNAs were detected as early as E10.5 with qPCR, although at low levels. CONCLUSIONS: Visual transduction proteins are expressed at the earliest stages in developing cones, well before the onset of opsin gene expression. Given the delay in opsin expression in rods and cones, we speculate on the embryonic function of these G-protein signaling components beyond their roles in the visual transduction cascade. PMID- 28031696 TI - Under-flap stromal bed CXL for early post-LASIK ectasia: a novel treatment technique. AB - PURPOSE: Collagen cross-linking (CXL) for post-laser-assisted in situ keratomileusis (LASIK) ectasia (PLE) is traditionally performed either epi-on or epi-off on the corneal surface. This study describes a novel technique in treating early PLE with under-flap CXL (ufCXL) to the stromal bed and reports on 6-month outcomes. PATIENTS AND METHODS: Case series of seven patients (eight eyes) with topography-diagnosed early PLE treated with ufCXL. Inclusion criteria were early, mild PLE defined as new-onset postoperative manifest refraction cylinder <=1.50 D, with new topographic inferior steepening consistent with ectasia, uncorrected distance visual acuity (UDVA) of 20/40 or better, and corrected distance visual acuity (CDVA) of 20/25 or better. Existing LASIK flap was lifted, riboflavin was applied directly to the stromal bed, flap was repositioned, and 18 mW/cm2 ultraviolet light was applied for 3 minutes to the corneal surface. Post-ufCXL manifest refraction, UDVA and CDVA, corneal cylinder, Kmax, and corneal irregularity index were compared with pre-ufCXL measurements. RESULTS: Patients had a pre-ufCXL sphere of 0.09+/-0.48 D and cylinder of -0.78+/ 0.49 D. At 6 months, post-ufCXL sphere (0.06+/-0.8 D; P=0.89) and cylinder ( 1.09+/-0.76 D, P=0.26) were unchanged. Cumulative post-ufCXL UDVA was unchanged, achieving 20/20, 20/30, and 20/40 in 25%, 88%, and 88%, respectively, compared with 13%, 63%, and 88% pre-ufCXL (P=0.68). Post-ufCXL CDVA was unchanged (P=0.93) with a gain of one line in two eyes, a loss of one line in one eye, and five eyes unchanged. The efficacy index (P=0.76), safety index (P=0.89), Kmax (P=0.94), and corneal irregularity index (P=0.73) were also unchanged. CONCLUSION: Preliminary results with ufCXL for early PLE are promising, demonstrating maintenance of visual accuracy, efficacy, safety, Kmax, and cylinder, with much quicker recovery times than surface CXL. PMID- 28031693 TI - Intake of dietary salt and drinking water: Implications for the development of age-related macular degeneration. AB - PURPOSE: Systemic hypertension is a risk factor of age-related retinal diseases such as diabetic retinopathy and age-related macular degeneration. High intake of dietary salt and low intake of water increase extracellular osmolality resulting in hypertension, in particular in salt-sensitive individuals. This review summarizes the present knowledge regarding the impact of salt and water intake on the regulation of blood pressure, retinal function, and the development of age related retinal diseases. METHODS: A literature search of the Medline database and a summary of recent studies that used human RPE cells. RESULTS: The salt sensitivity of the blood pressure and plasma osmolality increase with age, and body water deficits are common in older individuals. High plasma osmolality has adverse effects in the retina. In RPE cells, high osmolality induces expression and secretion of angiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor, and basic fibroblast growth factor, and expression of aquaporin-5, a water channel implicated in transepithelial water transport. The transcriptional activities of hypoxia-inducible factor-1 (HIF-1) and nuclear factor of activated T cell 5 (NFAT5) are critical for the production of VEGF in response to salt-induced osmotic stress. Salt-induced osmotic stress also induces priming of the NLRP3 inflammasome and activates inflammatory enzymes in RPE cells. CONCLUSIONS: Raised plasma osmolality may aggravate age-related retinal diseases by stimulation of local inflammation and angiogenic factor production in the RPE. Alterations in salt and water consumption, and of minerals that stimulate renal salt excretion, may offer nutritional approaches to prevent age-related retinal disorders, in particular in salt-sensitive individuals and individuals who show signs of body dehydration. PMID- 28031698 TI - Phototherapeutic keratectomy for epithelial basement membrane dystrophy. AB - PURPOSE: The purpose of this study was to evaluate the long-term efficacy of phototherapeutic keratectomy (PTK) in treating epithelial basement membrane dystrophy (EBMD). METHODS: Preoperative and postoperative records were reviewed for 58 eyes of 51 patients with >3 months follow-up (range 3-170 months) treated for EBMD with PTK after failure of conservative medical treatment at Byers Eye Institute of Stanford University. Symptoms, clinical findings, and corrected distance visual acuity (CDVA) were assessed. The primary outcome measure was symptomatic recurrence as measured by erosions or visual complaints >3 months after successful PTK. RESULTS: For eyes with visual disturbances (n=30), preoperative CDVA was20/32 (0.24 Log-MAR, SD 0.21) and postoperative CDVA was ~20/25 (0.07 LogMAR, SD 0.12; P<0.0001). Twenty-six eyes (86.7%) responded to treatment, with symptomatic recurrence in 6 eyes (23.1%) at an average of 37.7 months (SD 42.8). For eyes with painful erosions (n=29), preoperative CDVA was ~20/25 (0.12, SD 0.19) and postoperative CDVA was ~20/20 (0.05. SD 0.16; P=0.0785). Twenty-three eyes (79.3%) responded to treatment, with symptomatic recurrence in 3 eyes (13.0%) at an average of 9.7 months (SD 1.5). The probability of being recurrence free after a successful treatment for visual disturbances and erosions at 5 years postoperatively was estimated at 83.0% (95% confidence interval 68.7%-97.0%) and 88.0% (95% confidence interval 65.3%-96.6%), respectively. CONCLUSION: The majority of visual disturbances and painful erosions associated with EBMD respond to PTK. For those with a treatment response, symptomatic relief is maintained over long-term follow-up. PMID- 28031697 TI - Clinical and histological evaluation of large macular hole surgery using the inverted internal limiting membrane flap technique. AB - PURPOSE: The aims of this study were to analyze optical coherence tomography (OCT) imaging of large macular holes (MHs) treated with inverted internal limiting membrane (ILM) flap technique and to perform a histological examination of an ILM-like membrane tissue obtained during vitrectomy. PATIENTS AND METHODS: This is a retrospective observational case study. Nine patients, comprising of five males and four females, showing large and myopic MHs, underwent pars plana vitrectomy (PPV) with inverted ILM flap technique assisted by brilliant blue G (BBG) staining. Ophthalmological findings including visual acuity and OCT were investigated based on medical records. Formalin-fixed paraffin-embedded tissue section of an ILM-like membrane was submitted for immunohistochemistry with glial fibrillary acidic protein (GFAP). RESULTS: ILM was clearly stained with BBG in eight patients, whereas the ILM in one case revealed no staining with BBG during PPV. Visual acuities improved to >0.2 LogMAR in six patients. The complete closure of MH following PPV with inverted ILM technique was eventually achieved in all patients determined by OCT imaging (100%). Only one patient showed recovery of ellipsoid zone and interdigitation zone following the surgery. Elongation of outer nuclear layer was noted in three eyes. The ILM-like membrane not stained with BBG histologically revealed an amorphous structure admixed with GFAP-positive mononuclear cell infiltration. CONCLUSION: PPV with inverted ILM flap technique achieved 100% closure rates with favorable configuration at an initial surgery in large MHs. Our histopathological data also suggest that even BBG staining-negative membrane may be a useful material for autologous transplantation to the hole. PMID- 28031699 TI - Long-term follow-up of patients with choroidal neovascularization due to angioid streaks. AB - BACKGROUND: The following case series describes the long-term anatomical and functional outcome of a group of seven patients with choroidal neovascularization (CNV), secondary to angioid streaks (AS), who were treated with antiangiogenic drugs in a pro re nata (PRN) regimen. After the 4-year mark, visual acuity tends to return to pretreatment level. Treatment delays and lack of awareness and self referral by the patients are believed to be the cause of the PRN regimen failure. PURPOSE: To assess the long-term outcomes (>4 years) of patients with CNV due to AS treated with a PRN regimen of antiangiogenic. METHODS: This was a retrospective, case series, single-center study. We reviewed the electronic medical records from patients with CNV due to AS. From each record, we noted general demographic data and relevant medical history; clinical presentation, changes in best-corrected visual acuity (BCVA) over time, optical coherent tomography parameters, treatment and retreatment details, and systemic associations. Changes in BCVA and central macular thickness were assessed with a Wilcoxon two-sample test, with an alpha value of <=0.05 for statistical significance. RESULTS: The mean follow-up time was 53.8+/-26.8 months. BCVA at baseline was: 1.001+/-0.62 logMAR; at the end of follow-up: 0.996+/-0.56 logMAR (P=0.9). Central macular thickness at baseline was: 360.85+/-173.82 MUm; at the end of follow-up: 323.85+/-100.34 MUm (P=0.6). Mean number of intravitreal angiogenic drugs: 6+/-4.16 injections (range 4-15). Mean time between injections was 3.8+/-2.7 months (range 1.9-5.8 months). CONCLUSION: Despite initial anatomical and functional improvement, patients at the end of the follow-up had no visual improvement after a pro re nata regimen of antiangiogenic drugs. The amount of retreatments, number of recurrences, and time between intravitreal injections were similar to previous reports with shorter follow-up. PMID- 28031700 TI - Long-term results of combination therapy using anti-VEGF agents and dexamethasone intravitreal implant for retinal vein occlusion: an investigational case series. AB - BACKGROUND: One limitation of anti-VEGF therapy is the need for monthly retreatment to maintain efficacy. The purpose of this study was to determine the duration of effect in eyes with macular edema (ME) secondary to branch or central retinal vein occlusion (BRVO or CRVO) treated with anti-VEGF therapy plus sustained-release dexamethasone (DEX implant; Ozurdex). MATERIALS AND METHODS: This open-label, interventional case series included 62 eyes with ME due to RVO, central foveal thickness (CFT) >300 MUm, and best-corrected visual acuity (BCVA) of 20/40 or worse. Each treatment cycle included an anti-VEGF injection followed 2 weeks later with DEX implant. Patients were eligible for retreatment if CFT increased to >290 MUm or increased by >50 MUm from the lowest measurement, or if BCVA decreased by six or more Snellen letters. Efficacy and safety were evaluated 2 and 4-6 weeks after the beginning of each treatment cycle and every 4 weeks thereafter until retreatment criteria were met. The primary outcome measure was time to retreatment. Secondary outcome measures included BCVA, CFT, and safety parameters. RESULTS: The mean reinjection interval for all patients was 135.5+/ 36.4 days. There was no statistically significant difference in mean intertreatment interval for up to six cycles of treatment or between eyes with BRVO or CRVO (P>=0.058). Mean peak change in BCVA was 13.8 letters, and 47.6% of eyes gained three or more lines of BCVA. The mean peak decrease in CFT across all treatment cycles was 200.9 MUm for eyes with BRVO and 219.2 MUm for eyes with CRVO. The percentage of patients with CFT <=300 MUm at any time during a given treatment cycle ranged from 78% to 94% among eyes with BRVO and from 85% to 100% among eyes with CRVO. Intraocular pressure increased in 19 of 62 eyes, and 26 of 44 phakic eyes underwent cataract surgery. CONCLUSION: In eyes with ME due to RVO, treatment with an anti-VEGF agent plus DEX implant provided a predictable duration of effect, as well as significant improvements in BCVA and CFT. PMID- 28031701 TI - Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy. AB - This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax) at which the maximum concentration of metformin HCl in the blood (Cmax) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. Cmax and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region. PMID- 28031702 TI - Development of docetaxel nanocrystals surface modified with transferrin for tumor targeting. AB - The purpose of this study was to develop the surface modification of docetaxel nanocrystals (DTX-NCs) with apo-Transferrin human (Tf) for improving the cellular uptake and cytotoxicity of DTX. DTX-NCs were prepared by a nanoprecipitation method, and the surface modified with Tf by an adsorption method (Tf-DTX-NCs). The morphology and particle size of DTX-NCs and Tf-DTX-NCs were characterized using a field emission scanning electron microscope and zetasizer. An in vitro drug release study was performed in phosphate-buffered saline containing 0.5% (w/v) Tween 80 for 24 hours. Cellular uptake was studied at 0.5, 1, and 2 hours. A cytotoxicity study was performed using the A549 (human lung cancer) cell line after 24-, 48-, and 72-hour treatments. The mean sizes were 295+/-97 and 398+/ 102 nm for DTX-NCs and Tf-DTX-NCs, respectively. Tf-DTX-NCs and DTX-NCs exhibited rapid drug release, whereas DTX (pure) was slowly released. Tf-DTX-NCs showed higher cellular uptake than DTX-NCs in confocal microscopic and quantitative studies. Moreover, at DTX concentration of 100 ug/mL, Tf-DTX-NCs (82.6%+/-0.8%) showed higher cytotoxicity than DTX-NCs (77.4%+/-4.1%) and DTX (pure; 20.1%+/ 4.6%) for 72-hour treatment. In conclusion, Tf-DTX-NCs significantly improved the cellular uptake and cytotoxicity of DTX in the A549 cell line. PMID- 28031703 TI - Evaluation of individual quality of life among hemodialysis patients: nominated themes using SEIQoL-adapted. AB - BACKGROUND: Quality of life (QoL) has become an important issue for patients with chronic renal failure diseases who are permanently undergoing hemodialysis. In this study, an adapted schedule for the evaluation of individual quality of life (SEIQoL-adapted) was used to evaluate QoL among hemodialysis patients, to explore their views about the most important aspects of life satisfaction. METHODS AND RESULTS: A multiple approach design and convenience sampling were applied to recruit 53 patients from a hemodialysis unit in Iran. Data were collected through structured interviews and then analyzed using conventional content analysis. A total score for QoL was calculated using scale guideline. The most important aspects of life were health, family, financial status, living conditions, leisure activities, relationships and socializing, religious and spiritual issues, medical knowledge, and therapies or treatments. The calculated mean QoL score was 66.2, indicating a relatively high life satisfaction. Males had higher QoL scores than females in both married and single groups. Moreover, the relationships between the QoL scores and education, job and marital status were not statistically significant. CONCLUSION: The SEIQoL-adapted revealed reasonable lay definitions of QoL in a group of patients following chronic renal failure. The patients' views of the aspects of life could be used by health policy makers, clinicians, and caregivers as a reliable guide to the most important priorities for treatment and medical interventions. PMID- 28031704 TI - Is the acute care of frail elderly patients in a comprehensive geriatric assessment unit superior to conventional acute medical care? AB - OBJECTIVE: The aim of this study was to investigate whether the acute care of frail elderly patients in a comprehensive geriatric assessment (CGA) unit is superior to the care in a conventional acute medical care unit. DESIGN: This is a clinical, prospective, randomized, controlled, one-center intervention study. SETTING: This study was conducted in a large county hospital in western Sweden. PARTICIPANTS: The study included 408 frail elderly patients, aged >=75 years, in need of acute in-hospital treatment. The patients were allocated to the intervention group (n=206) or control group (n=202). Mean age of the patients was 85.7 years, and 56% were female. INTERVENTION: This organizational form of care is characterized by a structured, systematic interdisciplinary CGA-based care at an acute elderly care unit. MEASUREMENTS: The primary outcome was the change in health-related quality of life (HRQoL) 3 months after discharge from hospital, measured by the Health Utilities Index-3 (HUI-3). Secondary outcomes were all cause mortality, rehospitalizations, and hospital care costs. RESULTS: After adjustment by regression analysis, patients in the intervention group were less likely to present with decline in HRQoL after 3 months for the following dimensions: vision (odds ratio [OR] =0.33, 95% confidence interval [CI] =0.14 0.79), ambulation (OR =0.19, 95% CI =0.1-0.37), dexterity (OR =0.38, 95% CI =0.19 0.75), emotion (OR =0.43, 95% CI =0.22-0.84), cognition (OR = 0.076, 95% CI =0.033-0.18) and pain (OR =0.28, 95% CI =0.15-0.50). Treatment in a CGA unit was independently associated with lower 3-month mortality adjusted by Cox regression analysis (hazard ratio [HR] =0.55, 95% CI =0.32-0.96), and the two groups did not differ significantly in terms of hospital care costs (P>0.05). CONCLUSION: Patients in an acute CGA unit were less likely to present with decline in HRQoL after 3 months, and the care in a CGA unit was also independently associated with lower mortality, at no higher cost. PMID- 28031705 TI - Earlier nephrology consultation may not be associated with improved short-term survival of acute kidney injury in very elderly men. AB - OBJECTIVES: A delayed nephrology consultation (NC) may be associated with a poor prognosis in acute kidney injury (AKI) patients. The aims of this study were to compare the clinical and laboratory characteristics of elderly AKI patients evaluated and not evaluated by nephrologists and to generate a hypothesis regarding the relationship between the timing of the NC and 90-day outcomes. METHODS: From 2007 to 2015, this study explored associations among the presence and timing of NC with the non-intensive care unit stay and 90-day mortality in elderly AKI patients at the Geriatric Department of the Chinese People's Liberation Army General Hospital. Early NC and delayed NC were defined as NCs performed before and 2 days after the day of AKI diagnosis, respectively. Multivariable logistic regression was used to adjust for confounding and selection bias. RESULTS: In total, 623 patients were included for the final analysis, of whom 162 (26%) were evaluated by nephrologists. The 90-day mortality rate was 33.2%, and dialysis was required in 1.4% of patients (9/623). Multivariable analysis showed that a higher prevalence of preexisting chronic obstructive pulmonary disease, AKI diagnosis time, peak serum creatinine level, blood urea nitrogen level, AKI stage, and mortality was associated with the NC. The NC was delayed (>48 h) in 59 patients (36.4%) (median time to consultation, 4 days). The median AKI diagnosis time, presence of oliguria, uric acid level, and a more severe AKI stage were associated with delayed consultation. Moreover, delayed consultation presented a similar 90-day mortality rate to that of an early NC (50.8% vs 44.7%, respectively, P=0.448). CONCLUSION: In very elderly AKI patients, those evaluated by nephrologists have more severe AKI and a higher mortality rate than those not evaluated by nephrologists. An earlier NC may not be associated with improved 90-day survival. PMID- 28031706 TI - Domain-specific cognitive impairment in patients with COPD and control subjects. AB - Impaired cognitive function is increasingly recognized in COPD. Yet, the prevalence of cognitive impairment in specific cognitive domains in COPD has been poorly studied. The aim of this cross-sectional observational study was to compare the prevalence of domain-specific cognitive impairment between patients with COPD and non-COPD controls. A neuropsychological assessment was administered in 90 stable COPD patients and 90 non-COPD controls with comparable smoking status, age, and level of education. Six core tests from the Maastricht Aging Study were used to assess general cognitive impairment. By using Z-scores, compound scores were constructed for the following domains: psychomotor speed, planning, working memory, verbal memory, and cognitive flexibility. General cognitive impairment and domain-specific cognitive impairment were compared between COPD patients and controls after correction for comorbidities using multivariate linear and logistic regression models. General cognitive impairment was found in 56.7% of patients with COPD and in 13.3% of controls. Deficits in the following domains were more often present in patients with COPD after correction for comorbidities: psychomotor speed (17.8% vs 3.3%; P<0.001), planning (17.8% vs 1.1%; P<0.001), and cognitive flexibility (43.3% vs 12.2%; P<0.001). General cognitive impairment and impairments in the domains psychomotor speed, planning, and cognitive flexibility affect the COPD patients more than their matched controls. PMID- 28031707 TI - Early efficacy of budesonide/formoterol in patients with moderate-to-very-severe COPD. AB - BACKGROUND AND OBJECTIVE: Large clinical trials have confirmed the long-term efficacy of inhaled corticosteroid/long-acting beta2-agonist combinations in patients with chronic obstructive pulmonary disease (COPD). It was hypothesized that significant treatment effects would already be present within 3 months after the initiation of treatment across a range of clinical outcomes, irrespective of COPD severity. METHODS: Post hoc analysis of 3-month post-randomization outcomes, including exacerbation rates, dropouts, symptoms, reliever use, and lung function, from three studies with similar inclusion criteria of moderate-to-very severe COPD. Patients (n=1,571) were treated with budesonide/formoterol (B/F) 320/9 MUg or placebo, twice daily; in one study, tiotropium 18 MUg once daily was also given. RESULTS: Over the first 3 months of treatment, fewer patients randomized to B/F experienced exacerbations versus the placebo group (111 and 196 patients with >=1 exacerbation, respectively). This was true in each COPD severity group. Compared with placebo, B/F treatment led to significantly lower 3 month exacerbation rates in the moderate and severe COPD severity groups (46% and 57% reduction, respectively), with a nonsignificant reduction (29%) in very severe COPD. Fewer dropouts occurred among patients treated with B/F versus placebo, this effect being greater with increasing COPD severity. B/F was associated with improved forced expiratory volume in 1 s, morning peak expiratory flow rate, total reliever use, and total symptom score versus placebo. CONCLUSION: Treatment with B/F decreased exacerbations in patients with moderate to-very-severe COPD within 3 months of commencing treatment. This effect was paralleled by improved lung function, less reliever medication use, and fewer symptoms, irrespective of disease severity. PMID- 28031708 TI - Trend of cost and utilization of COPD medication in Korea. AB - BACKGROUND: There are only a few longitudinal studies regarding medical utilization and costs for patients with COPD. The purpose of this study was to analyze the trend of medical utilization and costs on a long-term basis. METHODS: Using the Korean Health Insurance Review and Assessment Service (HIRA) data from 2008 to 2013, COPD patients were identified. The trend of medical utilization and costs was also analyzed. RESULTS: The number of COPD patients increased by 13.9% from 2008 to 2013. During the same period, the cost of COPD medication increased by 78.2%. Methylxanthine and systemic beta agonists were most widely prescribed between 2008 and 2013. However, inhaled medications such as long-acting beta-2 agonist (LABA), long-acting muscarinic agonist, and inhaled corticosteroid plus LABA were dispensed to a relatively low proportion of patients with COPD. The number of patients who were prescribed inhaled medications increased gradually from 2008 to 2013, while the number of patients prescribed systemic beta agonist and methylxanthine has decreased since 2010. CONCLUSION: This study shows that there is a large gap between the COPD guidelines and clinical practice in Korea. Training programs for primary care physicians on diagnosis and guideline-based treatment are needed to improve the management of COPD. PMID- 28031709 TI - Magnetic and fluorescent Gd2O3:Yb3+/Ln3+ nanoparticles for simultaneous upconversion luminescence/MR dual modal imaging and NIR-induced photodynamic therapy. AB - The development of upconversion nanoparticles (UCNs) for theranostics application is a new strategy toward the accurate diagnosis and efficient treatment of cancer. Here, magnetic and fluorescent lanthanide-doped gadolinium oxide (Gd2O3) UCNs with bright upconversion luminescence (UCL) and high longitudinal relaxivity (r1) are used for simultaneous magnetic resonance imaging (MRI)/UCL dual-modal imaging and photodynamic therapy (PDT). In vitro and in vivo MRI studies show that these products can serve as good MRI contrast agents. The bright upconversion luminescence of the products allows their use as fluorescence nanoprobes for live cells imaging. We also utilized the luminescence-emission capability of the UCNs for the activation of a photosensitizer to achieve significant PDT results. To the best of our knowledge, this study is the first use of lanthanide-doped Gd2O3 UCNs in a theranostics application. This investigation provides a useful platform for the development of Gd2O3-based UCNs for clinical diagnosis, treatment, and imaging-guided therapy of cancer. PMID- 28031710 TI - A quality by design approach on polymeric nanocarrier delivery of gefitinib: formulation, in vitro, and in vivo characterization. AB - Gefitinib is an anticancer agent which acts by inhibiting epidermal growth factor receptor tyrosine kinase receptors. The aim of the present study was to prepare gefitinib nanosuspension. Gefitinib was encapsulated in Eudragit(r) RL100 and then dispersed in stabilizer solution, polyvinyl alcohol, and polyvinylpyrrolidone K30. Nanosuspension was prepared by using homogenization and ultrasonication techniques. The quality by design approach was also used in the study to understand the effect of critical material attributes (CMAs) and critical processing parameters (CPPs) on critical quality attributes and to improve the quality and safety of formulation. To study the effect of CMAs and CPPs, 23 full factorial design was applied. The particle size, polydispersity index, and zeta potential of the optimized solution were 248.20 nm, 0.391, and 5.62 mV, respectively. Drug content of the optimized nanoformulation was found to be 87.74%+/-1.19%. Atomic force microscopy studies of the optimized formulation confirmed that the prepared nanoparticles are smooth and spherical in nature. In vitro cytotoxicity studies of the nanosuspension on Vero cell line revealed that the formulation is nontoxic. The gefitinib nanosuspension released 60.03%+/-4.09% drug over a period of 84 h, whereas standard drug dispersion released only 10.39%+/-3.37% drug in the same duration. From the pharmacokinetic studies, half life, Cmax, and Tmax of the drug of an optimized nanosuspension were found to be 8.65+/-1.99 h, 46,211.04+/-5,805.97 ng/mL, and 6.67+/-1.77 h, respectively. A 1.812-fold increase in relative bioavailability of nanosuspension was found, which confirmed that the present formulation is suitable to enhance the oral bioavailability of gefitinib. PMID- 28031711 TI - Synergistic anti-glioma effect of a coloaded nano-drug delivery system. AB - The anti-glioma effect of temozolomide (Tem) is sometimes undermined by the emerging resistance. Recently, resveratrol (Res), herbal medicine extracted from grape seeds, has been demonstrated for its potential use in chemosensitization. In the current study, both these drugs were loaded simultaneously into nanoparticles with methoxy poly(ethylene glycol)-poly epsilon caprolactone (mPEG PCL) as drug carriers in order to achieve better antitumor efficiency. Tem/Res coloaded mPEG-PCL nanoparticles were constructed, characterized, and tested for antitumor effect on glioma cells by using in vitro and xenograft model system. The nanoparticle constructs were satisfactory with drug loading content (Res =~12.4%; Tem =~9.3%) and encapsulation capacity of >85% for both the drugs. In addition, the coencapsulation led to better in vitro stability of the nanoparticles than Tem-loaded nanoparticles. An in vitro uptake study demonstrated a high uptake efficiency of the nanoparticles by glioma cells. The synergistic antitumor effect against glioma cells was observed in the combinational treatment of Res and Tem. Tem/Res-coloaded nanoparticles induced higher apoptosis in U87 glioma cells as compared to cells treated by the combination of free drugs. Tem/Res-coloaded particles caused more effective inhibition of phosphor-Akt, leading to upregulation of the downstream apoptotic proteins. In addition, the in vivo study showed the superior tumor delaying effect of coloaded nanoparticles than that of free drug combination. These results suggest that Tem/Res-coloaded nanoparticles could be a potential useful chemotherapeutic formulation for glioma therapy. PMID- 28031712 TI - Minocycline and celecoxib as adjunctive treatments for bipolar depression: a study protocol for a multicenter factorial design randomized controlled trial. AB - BACKGROUND: Evidence suggests that the use of anti-inflammatory agents may improve depressive symptoms in patients with bipolar affective disorder. However, there are few well-designed clinical trials demonstrating the efficacy of these newer treatment strategies. PATIENTS AND METHODS: This is a multicenter, 3-month, randomized, placebo-controlled, double-blind, factorial design trial of minocycline and/or celecoxib added to TAU for the treatment of depressive symptoms in patients experiencing a DSM-5 bipolar I or II disorder and a current major depressive episode. A total of 240 participants will undergo screening and randomization followed by four assessment visits. The primary outcome measure will be mean change from baseline to week 12 on the Hamilton Depression Scale scores. Clinical assessments using the Clinical Global Impression scale, Patient Health Questionnaire-9, and the Generalized Anxiety Disorder 7-item scale will be carried out at every visit as secondary outcomes. Side-effect checklists will be used to monitor the adverse events at each visit. Complete blood count and plasma C-reactive protein will be measured at baseline and at the end of the treatment. Minocycline will be started at 100 mg once daily and increased to 200 mg at 2 weeks. Celecoxib will be started at 200 mg once daily and increased to 400 mg at 2 weeks. DISCUSSION: Anti-inflammatory agents have been shown to be potentially efficacious in the treatment of depressive symptoms. The aim of this study is to determine whether the addition of minocycline and/or celecoxib to TAU improves depressive symptoms in patients with bipolar affective disorder. PMID- 28031713 TI - Pioglitazone could induce remission in major depression: a meta-analysis. AB - BACKGROUND: Pioglitazone, a selective agonist of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), prescribed for the treatment of type 2 diabetes, could have antidepressant properties. However, its potential to induce remission of major depressive episodes, the optimal clinical target for an antidepressant drug, is a matter of concern. Indeed, only one out of four double-blind randomized controlled trials show higher remission rates with pioglitazone than with control treatments. Hence, the main aim of this study was to perform a meta-analysis of the efficacy of pioglitazone for the treatment of MDE, focusing on remission rates. METHODS: Four double-blind randomized controlled trials, comprising 161 patients with an MDE, were included in this meta-analysis. Pioglitazone was studied either alone (one study) or as add-on therapy to conventional treatments (antidepressant drugs or lithium salts). It was compared either to placebo (three studies) or to metformin (one study). Remission was defined by a Hamilton Depression Rating Scale score <8 after treatment. RESULTS: Pioglitazone could induce higher remission rates than control treatments (27% versus 10%, I2=17.3%, fixed-effect model: odds ratio [OR] =3.3, 95% confidence interval [95% CI; 1.4; 7.8], P=0.008). The OR was even higher in the subgroup of patients with major depressive disorder (n=80; 23% versus 8%, I2=0.0%; fixed-effect model: OR =5.9, 95% CI [1.6; 22.4], P=0.009) and in the subgroup of patients without metabolic comorbidities (n=84; 33% versus 10%, I2=0.0%; fixed-effect model: OR =5.1, 95% CI [1.5; 17.9], P=0.01). As compared to control treatments, results suggest six patients would need to be treated with pioglitazone in order to achieve the possibility of one more remission. CONCLUSION: Pioglitazone, either alone or as add-on therapy to conventional treatments, could induce remission of MDE, suggesting that drugs with PPAR-gamma agonist properties may be true and clinically relevant antidepressants, even in patients without metabolic comorbidities. PMID- 28031714 TI - Temperament, personality, and treatment outcome in major depression: a 6-month preliminary prospective study. AB - BACKGROUND: Despite available treatments, major depression is a highly heterogeneous disorder, which leads to problems in classification and treatment specificity. Previous studies have reported that personality traits predict and influence the course and treatment response of depression. The Temperament and Personality Questionnaire (T&P) assesses eight major constructs of personality traits observed in those who develop depression. The aim of this study was to investigate the influence of T&P's eight constructs on the treatment outcome of depressed patients. PATIENTS AND METHODS: A preliminary 6-month prospective study was conducted with a sample of 51 adult patients with a diagnosis of major depressive disorder (MDD) without remarkable psychomotor disturbance using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. All patients received comprehensive assessment including the T&P at baseline. We compared each T&P construct score between patients who achieved remission and those who did not achieve remission after 6 months of treatment for depression using both subjective and objective measures. All 51 (100%) patients received the 6-month follow-up assessment. RESULTS: This study demonstrated that higher scores on T&P personal reserve predicted poorer treatment outcome in patients with MDD. Higher levels of personal reserve, rejection sensitivity, and self-criticism correlated with higher levels of depression. Higher levels of rejection sensitivity and self-criticism were associated with non-remitters; however, when we controlled for baseline depression severity, this relationship did not show significance. CONCLUSION: Although the results are preliminary, this study suggests that high scores on T&P personal reserve predict poorer treatment outcome and T&P rejection sensitivity and self-criticism correlate with the severity of depression. Longer follow-up studies with large sample sizes are required to improve the understanding of these relationships. PMID- 28031715 TI - Urinary tract infections in Romanian patients with diabetes: prevalence, etiology, and risk factors. AB - AIM: Patients with diabetes mellitus (DM) have an increased risk of infections, especially urinary tract infections (UTIs). The aim of this study was to assess the prevalence and etiology of UTIs and identify the risk factors for their development in patients with DM. PATIENTS AND METHODS: In this retrospective, noninterventional study, the medical records of 2,465 adult patients with DM who were hospitalized in a Diabetes Clinic were reviewed. Data regarding the presence of UTI and possible associated risk factors were collected and their possible relation was analyzed. The study protocol and procedures were approved by the Ethics Committee of Timisoara Emergency Hospital. All data were collected and analyzed using SPSS v.17 statistical software. RESULTS: The prevalence of UTIs in patients with DM was 12.0% (297 cases), being higher in females than in males and higher in patients with type 2 DM compared with patients with type 1 DM. In univariate logistic regression analysis, risk factors associated with UTIs were female gender, age, type 2 DM, longer duration of DM, and the presence of chronic kidney disease and coronary artery disease. Multivariate analysis identified age, duration of DM, and metabolic control (hemoglobin A1c levels) as independent risk factors for UTIs. The gram-negative bacilli from the Enterobacteriaceae family were predominant, with Escherichia coli being the most frequent of them (70.4%). CONCLUSION: UTIs are a frequent condition associated with DM. It is necessary to improve the care and the screening of UTIs in patients with DM to prevent the occurrence of possible associated severe renal complications. PMID- 28031716 TI - Diagnostic accuracy of nodular gastritis for H. pylori infection. AB - BACKGROUND: The term nodular is not included in the Sydney classification and there is no widely accepted histopathological definition. It has been proposed that the presence of antral nodularity could predict Helicobacter pylori (H. pylori) infection. The aim of this study was to determine the diagnostic accuracy of nodular gastritis (NG) for H. pylori infection after a rigorous standardization process, and to describe the associated histopathological characteristics. MATERIALS AND METHODS: Endoscopic images of patients submitted to endoscopy with biopsy sampling were included. Endoscopic images were distributed among six endoscopists. The analysis was performed sequentially in three rounds: the first round assessed the interobserver variability, the second evaluated the intraobserver variability, and the third calculated the interobserver variability after training. A correlation analysis between endoscopic and histopathological findings was performed. RESULTS: A total of 917 studies were included. In the first analysis of interobserver variability, a poor kappa value (0.078) was obtained. The second evaluation yielded good intraobserver variability, with kappa values of 0.62-0.86. The evaluation of interobserver variability after training revealed an improvement in the kappa value of 0.42. A correlation was found between endoscopic images and histopathological reports. CONCLUSION: There was a strong correlation between NG and H. pylori, but only after rigorous evaluation. The use of the term NG requires extensive standardization before it can be used clinically. PMID- 28031717 TI - Association between TLR-9 polymorphisms and colon cancer susceptibility in Saudi Arabian female patients. AB - OBJECTIVE: The authors aimed to explore the relationship between the expression/polymorphisms of TLR-9 and susceptibility to colon cancer development in the Saudi Arabian population. METHODS: In total, blood samples from 115 patients with colon cancer and 102 participants without colon cancer were analyzed in this study. Three single-nucleotide polymorphisms (SNPs) were selected from the TLR-9 gene, including two sites within the TLR-9 gene's promoter region (rs352144 and rs187084) and one site in a TLR-9 intron region (rs5743839). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models after adjusting for age, gender, and tumor localization. To investigate the differential expression of TLR-9 in colon cancer, TLR-9 expression was evaluated using quantitative real-time reverse transcription polymerase chain reaction on 40 matched normal and colon tissues. RESULTS: The authors found that TLR-9 expression was decreased in colon cancer tissues as compared with that in normal tissues. Moreover, significant associations between the TLR-9 rs187084 SNP and colon cancer risk were observed in female patients only. In rs187084, the T allele had a significantly lower frequency (2.8 times) in female cancer patients than in controls (0.27 vs 0.41). The TLR-9 rs352139 and rs352144 SNPs were significantly associated with colon cancer development when the tumor was located in the rectal area. CONCLUSION: The findings support the hypothesis that TLR-9 has an anticancer role in colon cancer development. Furthermore, genetic variation may influence colon cancer development, and SNPs in TLR-9 could serve as biomarkers for decision making in the treatment of females with rectal cancer. PMID- 28031718 TI - J-pouch versus Roux-en-Y reconstruction after gastrectomy: functional assessment and quality of life (randomized trial). AB - PURPOSE: The aim of this study was to evaluate the quality of life and functional emptying of J-pouch versus Roux-en-Y reconstruction after total gastrectomy for malignancy. METHODS: This study was designed as a prospective, nonblinded, randomized, parallel clinical trial (Trial Number: MN Ostrava, 200604). With informed consent, patients undergoing gastrectomy for malignancy were randomized to J-pouch or Roux-en-Y reconstruction. The time taken for a test semisolid meal labeled with 99mTc-sulfur colloid to exit the reconstructed parts was measured by dynamic scintigraphy 1 year after resection. Quality of life was measured using the Eypasch questionnaire at the same time as functional emptying assessment. This trial was investigator-initiated. RESULTS: In all, 72 patients were included into the study. The time taken for the test meal to exit the postgastrectomy reconstruction was 16.5+/-10.0 minutes (mean +/- standard deviation) in the Roux en-Y group and 89.4+/-37.8 minutes in the "J-pouch" group; the difference was statistically significant (P<0.001). Emptying of the J-pouch appeared to be a linear decreasing function compared to the exponential pattern seen in the Roux en-Y group. The quality of life measurement showed scores of 106+/-18.8 points (mean +/- standard deviation) in the Roux-en-Y group compared to 122+/-22.5 points in the J-pouch group; the difference was statistically significant (P=0.0016). There were no important adverse events. CONCLUSION: After total gastrectomy, a J-pouch reconstruction empties more slowly and is associated with higher quality of life compared to Roux-en-Y reconstruction. Whether these two observations have a direct causative link remains unanswered. PMID- 28031719 TI - Potential role of immunotherapy in advanced non-small-cell lung cancer. AB - Immuno checkpoint inhibitors have ushered in a new era with respect to the treatment of advanced non-small-cell lung cancer. Many patients are not suitable for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (eg, gefitinib, erlotinib, and afatinib) or with anaplastic lymphoma kinase inhibitors (eg, crizotinib and ceritinib). As a result, anti-PD-1/PD-L1 and CTLA 4 inhibitors may play a novel role in the improvement of outcomes in a metastatic setting. The regulation of immune surveillance, immunoediting, and immunoescape mechanisms may play an interesting role in this regard either alone or in combination with current drugs. Here, we discuss advances in immunotherapy for the treatment of metastatic non-small-cell lung cancer as well as future perspectives within this framework. PMID- 28031720 TI - Atypical aleukemic presentation of large granular lymphocytic leukemia: a case report. AB - Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of transformed natural killer or T-cells attributed to chronic exposure to the proinflammatory cytokine IL-15. Diagnosis of the majority of T-cell LGLL is established by documenting clonal large granular lymphocytes (LGLs) in peripheral blood, by morphology and immunophenotype. The proteasome inhibitor bortezomib is known to target molecular pathways downstream of the IL-15 receptor signaling and has been proposed as a therapy in these patients. We report an uncommon presentation of LGLL with chronic neutropenia lacking typical blood LGLs, which failed to respond to bortezomib but obtained a very good partial remission with a classical methotrexate regimen. PMID- 28031721 TI - Long noncoding RNA MALAT1-regulated microRNA 506 modulates ovarian cancer growth by targeting iASPP. AB - MALAT1, an important cancer-associated long noncoding RNA (lncRNA), contributes to the development and progression of several cancers. Disordered expression of MALAT1 has been observed in several cancers, including cervical cancer, breast cancer, and ovarian cancer. However, the exact effects and molecular mechanisms of MALAT1 in ovarian cancer progression are still unknown. Here, we investigated the role of MALAT1 in human ovarian cancer cell lines and clinical tumor samples, in order to determine the function of this molecule. In our research, lncRNA MALAT1 was specifically upregulated in ovarian cancer cell lines and promoted ovarian cancer-cell growth through targeting microRNA (miR)-506. Knockdown of MALAT1 inhibited the proliferation and DNA synthesis of human ovarian cancer cell in vitro. In addition, miR-506-dependent iASPP regulation was required in MALAT1 induced ovarian cancer-cell growth. These findings indicated that MALAT1 might suppress tumor growth via miR-506-dependent iASPP regulation. Taken together, our data indicated that MALAT1 might be an oncogenic lncRNA that promotes proliferation of ovarian cancer and could be regarded as a therapeutic target in human ovarian cancer. PMID- 28031722 TI - Low PLCE1 levels are correlated with poor prognosis in hepatocellular carcinoma. AB - BACKGROUND: Previous reports show that phospholipase C epsilon-1 (PLCE1) expression is positively correlated with esophageal squamous cell carcinoma and gastric cardia adenocarcinomas; however, the expression of PLCE1 in hepatocellular carcinoma (HCC) and its correlation with clinical outcome still remain unclear. The aim of this study was to explore the expression of PLCE1 in HCC tissue and to determine whether PLCE1 was a prognostic factor for HCC patients. MATERIALS AND METHODS: PLCE1 levels in 20 paired HCC tissues and corresponding paracarcinomatous tissues was investigated by quantitative real time polymerase chain reaction and Western blot assays. In addition, protein levels of PLCE1 in one normal liver epithelial cell and four HCC cell lines were examined using Western blot assay. Moreover, immunohistochemistry was applied to determine the expression of PLCE1 in HCC and corresponding surrounding tissues from 90 patients. Statistical analyses were used to examine the association between PLCE1 levels and clinicopathological features. RESULTS: We found that the expression of PLCE1 in tumor tissues was significantly lower than those in paracarcinomatous tissues at both mRNA and protein levels (P<0.05). We also determined that PLCE1 protein expression levels were lower in HCC cell lines than normal liver epithelial cells (P<0.05). Notably, immunohistochemical assay showed that PLCE1 expression was significantly low in HCC tissues compared with the adjacent normal liver tissues (40% vs 18.9%; P<0.05). Besides, PLCE1 levels were negatively correlated with tumor capsulae, vascular invasion, Edmondson grade, alpha-fetoprotein, and tumor-node-metastasis stage (P<0.05). Univariate analysis revealed that lower level expression of PLCE1 was significantly associated with poorer overall survival (OS) rate (P<0.001) and disease-free survival rate (P<0.001). Multivariate analysis revealed that low PLCE1 level was an independent poor prognostic factor of OS and recurrence-free survival (P<0.001 and P=0.003, respectively). CONCLUSION: In brief, our results revealed that decreased PLCE1 expression was associated with tumor progression in HCC and may function as a promising biomarker for HCC prognosis. PMID- 28031723 TI - Economic report on the cost of dengue fever in Vietnam: case of a provincial hospital. AB - BACKGROUND: Dengue is a mosquito-borne viral illness with the world's fastest rate of infection. In 2014, Vietnam had recorded 43,000 cases in 53 provinces, with 28 deaths. MATERIALS AND METHODS: A 6-month cross-sectional study was conducted from September 2015 to March 2016 at Cu Chi General Hospital. Cost of illness in this study was estimated under the incidence-based approach from the societal perspective. RESULTS: The average cost per case was US$139.3+/-$61.7. The average cost per child was higher than per adult, but not significant ($151.0+/-$63.5 and $132.7+/-$59.9, respectively; P=0.068). Meanwhile, 50.2% of the total cost was contributed by the cost of hospital bed. According to the sensitivity analysis, if both the costs of the hospital bed and ultrasound were reduced by 10%, the total treatment cost of dengue fever would fall by 5% and 1.6%, respectively. CONCLUSION: This study is expected to be the basis for investment-plan formulation and fund allocation for the treatment and prevention of dengue. In an attempt to examine the entire socioeconomic encumbrance caused by the dengue virus, a larger scale study targeting both dengue and dengue hemorrhagic fever needs to be conducted in several hospitals. PMID- 28031724 TI - Erratum: Aloe sterol supplementation improves skin elasticity in Japanese men with sunlight-exposed skin: a 12-week double-blind, randomized controlled trial [Corrigendum]. AB - [This corrects the article on p. 435 in vol. 9.]. PMID- 28031725 TI - Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics. AB - Treatment of neuropathic pain using topical formulations is still in its infancy. Only few topical analgesic formulations have become available for clinical use, and among these, analgesic creams are still rare. This is unfortunate because analgesic creams offer a number of advantages over patches, such as convenience, ease of adapting the frequency of application, and dose, and "rubbing cream where it hurts" involves the patient much more in the therapeutic process compared to patches and other localized treatment modalities. Although the literature supporting the efficacy and safety of analgesic creams (mostly compounded) is growing since the last decade, most pain physicians have not yet noticed and appreciated the therapeutic potential and clinical value of these creams. This is most probably due to a prejudice that topical application should need to act transdermally, more or less as a slow-release formulation, such as in patches delivering opioids. We will discuss this prejudice and show that there are multiple important targets in the skin to be reached by topical analgesic or anti inflammatory compounds, and that the keratinocyte is one of those targets. By specifically targeting the keratinocyte, analgesia seems possible, effective, and safe, and thus topical analgesic creams may hold promise as a novel treatment modality for neuropathic pain. PMID- 28031726 TI - Complex regional pain syndrome: medical and legal ramifications of clinical variability and experience and perspective of a practicing clinician. AB - OBJECTIVE: The aim of this study was to demonstrate the ramifications of clinical variability of complex regional pain syndrome (CRPS) and how they can affect the various aspects of this condition, favorably or unfavorably, for both patients and participating medical and legal professionals. METHODS: Twelve patients diagnosed with CRPS at different times in the past 25 years were followed up, and their signs and symptoms were reviewed for variability. None had preexisting or ongoing medical disorders and prior injury to the peripheral nerves or musculoskeletal tissues. None had been involved in litigation. Physical traumas that triggered CRPS were job-related, vehicular accidents, and personal injuries. The presence of vasomotor symptoms (eg, swelling, skin discoloration, and temperature changes) and allodynia in the affected extremity was the basis for clinical diagnosis in all the patients. The need for imaging studies was precluded in some patients owing to the presence of vasomotor symptoms, which either fluctuated or were steady. Seven of the patients had type 1 CRPS, and five patients had type 2 CRPS. RESULTS: Most patients encountered delay in diagnosis and treatment and legal obstacles owing to the lack of "typical" objective signs of CRPS. The patients' symptoms fluctuated at different times of the day. Eight patients experienced spread of vasomotor symptoms and varying degree of allodynia in the opposite extremity. One patient, who developed signs and symptoms of rheumatoid arthritis, 2 months after the injury, continued to have CRPS symptoms in the injured hand. Treatment modalities administered in all the patients were essentially ineffective. All the patients, except one, were unable to return to their original line of work, and their symptoms persisted regardless of the outcome of their legal claims. CONCLUSION: It is likely that patients who continue to complain of pain and vasomotor symptoms followed by a physical injury have CRPS. The complex interaction between the peripheral, autonomic, and central nervous system in this condition makes it challenging to diagnose, treat, and prognosticate. PMID- 28031727 TI - Can consistent benchmarking within a standardized pain management concept decrease postoperative pain after total hip arthroplasty? A prospective cohort study including 367 patients. AB - BACKGROUND: The number of total hip replacement surgeries has steadily increased over recent years. Reduction in postoperative pain increases patient satisfaction and enables better mobilization. Thus, pain management needs to be continuously improved. Problems are often caused not only by medical issues but also by organization and hospital structure. The present study shows how the quality of pain management can be increased by implementing a standardized pain concept and simple, consistent, benchmarking. METHODS: All patients included in the study had undergone total hip arthroplasty (THA). Outcome parameters were analyzed 24 hours after surgery by means of the questionnaires from the German-wide project "Quality Improvement in Postoperative Pain Management" (QUIPS). A pain nurse interviewed patients and continuously assessed outcome quality parameters. A multidisciplinary team of anesthetists, orthopedic surgeons, and nurses implemented a regular procedure of data analysis and internal benchmarking. The health care team was informed of any results, and suggested improvements. Every staff member involved in pain management participated in educational lessons, and a special pain nurse was trained in each ward. RESULTS: From 2014 to 2015, 367 patients were included. The mean maximal pain score 24 hours after surgery was 4.0 (+/-3.0) on an 11-point numeric rating scale, and patient satisfaction was 9.0 (+/-1.2). Over time, the maximum pain score decreased (mean 3.0, +/-2.0), whereas patient satisfaction significantly increased (mean 9.8, +/-0.4; p<0.05). Among 49 anonymized hospitals, our clinic stayed on first rank in terms of lowest maximum pain and patient satisfaction over the period. CONCLUSION: Results were already acceptable at the beginning of benchmarking a standardized pain management concept. But regular benchmarking, implementation of feedback mechanisms, and staff education made the pain management concept even more successful. Multidisciplinary teamwork and flexibility in adapting processes seem to be highly important for successful pain management. PMID- 28031728 TI - The frequency of polycystic ovary syndrome in young reproductive females in Qatar. AB - This was a prospective cross-sectional study in which 126 female students between the ages of 18 and 30 years were evaluated for the frequency of polycystic ovary syndrome (PCOS) through clinical interview, questionnaire, and anthropometric measurements. The diagnostic criteria of the US National Institutes of Health criteria were used. Menstrual irregularities (MI) were identified, and clinical hyperandrogenism was evaluated by self-assessment of hirsutism using modified Ferriman-Gallwey score. Blood analysis was done for measurement of prolactin, thyroid-stimulating hormone, and the androgen hormones. Of all the students, 37 (30.8%) had MI, 38 (31.7%) had clinical hirsutism, 37 (30.8%) had acne, and 76 (63.3%) had a family history of type 2 diabetes. The estimated frequency of PCOS was 18.33% according to the US National Institutes of Health definition. Hormonal analysis demonstrated a significant increase in androgens (total testosterone, dehydroepiandrosterone sulfate, and free testosterone), and a significant decrease in sex hormone-binding globulin in our PCOS group, with a P-value <0.05. This study revealed a higher level of the androgen hormones among PCOS subjects with a frequency of PCOS (18.33%) similar to the global estimates of 10%-20%. PMID- 28031729 TI - Acanthosis nigricans in obese adolescents: prevalence, impact, and management challenges. AB - Obesity in adolescence is a public health priority because it usually tracks into adulthood, resulting in enormous medical and social costs. This underscores the importance of early identification and intervention. Acanthosis nigricans (AN) was once considered a rare paraneoplastic dermatosis, but is now frequently observed in obese adolescents. Current understanding suggests that it is associated with insulin resistance and has a unique role in secondary prevention. The purpose of this narrative review is to provide a comprehensive overview of AN in obese adolescents, covering its history, current knowledge on the condition, its clinical significance, management challenges, and the direction of future research. PMID- 28031730 TI - Improving quality of home-based postnatal care by microteaching of multipurpose workers in rural and urban slum areas of Chandigarh, India: a pilot study. AB - BACKGROUND: Microteaching is an efficient teaching tool to improve skills. Until now, its use is very limited in the health sector. A pilot study was carried out to improve the quality of home-based postnatal care by microteaching of health workers (HWs) and ascertain its feasibility for supportive supervision. METHODS: All (n=12) the HWs catering to a population of ~0.1 million were video recorded while performing home-based postnatal check up in Chandigarh from August 2013 to December 2014. After each round, HWs were shown their videos and trained in the facility and at home. Video recordings, assessments followed by training, continued until HWs acquired the intended skills. A pretested structured checklist based on the national home-based postnatal care guidelines was used for recording and assessing of postnatal skills. A score "0" given for no task, "1" for incorrectly done or partially done task, and "2" for correct task. The average score of each round was calculated and compared. RESULTS: The overall skill assessment score improved from 0.64 to 1.76, newborn examination skill from 0.52 to 1.63, maternal examination from 0.54 to 1.62, and counseling from 1.01 to 1.85 after three rounds of video recording. The proportion of HWs carrying a thermometer increased from 21% to 100%. Second and third rounds of video recording and microteaching were successfully carried out by the program supervisors. CONCLUSION: This was the first study to report on the effective use of microteaching in improving home-based postnatal care skills of the health care workers and its feasibility for supportive supervision. PMID- 28031731 TI - Erratum: Differences in Knowledge, Stress, Sensation Seeking, and Locus of Control Linked to Dietary Adherence in Hemodialysis Patients. AB - [This corrects the article on p. 1864 in vol. 7, PMID: 27965605.]. PMID- 28031732 TI - A spider derived peptide, PnPP-19, induces central antinociception mediated by opioid and cannabinoid systems. AB - BACKGROUND: Some peptides purified from the venom of the spider Phoneutria nigriventer have been identified as potential sources of drugs for pain treatment. In this study, we characterized the antinociceptive effect of the peptide PnPP-19 on the central nervous system and investigated the possible involvement of opioid and cannabinoid systems in its action mechanism. METHODS: Nociceptive threshold to thermal stimulation was measured according to the tail flick test in Swiss mice. All drugs were administered by the intracerebroventricular route. RESULTS: PnPP-19 induced central antinociception in mice in the doses of 0.5 and 1 MUg. The non-selective opioid receptor antagonist naloxone (2.5 and 5 MUg), MU-opioid receptor antagonist clocinnamox (2 and 4 MUg), delta-opioid receptor antagonist naltrindole (6 and 12 MUg) and CB1 receptor antagonist AM251 (2 and 4 MUg) partially inhibited the antinociceptive effect of PnPP-19 (1 MUg). Additionally, the anandamide amidase inhibitor MAFP (0.2 MUg), the anandamide uptake inhibitor VDM11 (4 MUg) and the aminopeptidase inhibitor bestatin (20 MUg) significantly enhanced the antinociception induced by a low dose of PnPP-19 (0.5 MUg). In contrast, the kappa-opioid receptor antagonist nor-binaltorphimine (10 MUg and 20 MUg) and the CB2 receptor antagonist AM630 (2 and 4 MUg) do not appear to be involved in this effect. CONCLUSIONS: PnPP-19-induced central antinociception involves the activation of CB1 cannabinoid, MU- and delta-opioid receptors. Mobilization of endogenous opioids and cannabinoids might be required for the activation of those receptors, since inhibitors of endogenous substances potentiate the effect of PnPP-19. Our results contribute to elucidating the action of the peptide PnPP-19 in the antinociceptive pathway. PMID- 28031733 TI - A review on the Scorpaena plumieri fish venom and its bioactive compounds. AB - The most poisonous fish species found along the Brazilian coast is the spotted scorpionfish Scorpaena plumieri. Though hardly ever life-threatening to humans, envenomation by S. plumieri can be quite hazardous, provoking extreme pain and imposing significant socioeconomic costs, as the victims may require days to weeks to recover from their injuries. In this review we will walk the reader through the biological features that distinguish this species as well as the current epidemiological knowledge related to the envenomation and its consequences. But above all, we will discuss the challenges involved in the biochemical characterization of the S. plumieri venom and its compounds, focusing then on the successful isolation and pharmacological analysis of some of the bioactive molecules responsible for the effects observed upon envenomation as well as on experimental models. Despite the achievement of considerable progress, much remains to be done, particularly in relation to the non-proteinaceous components of the venom. Therefore, further studies are necessary in order to provide a more complete picture of the venom's chemical composition and physiological effects. Given that fish venoms remain considerably less studied when compared to terrestrial venoms, the exploration of their full potential opens a myriad of possibilities for the development of new drug leads and tools for elucidating the complex physiological processes. PMID- 28031734 TI - Exploring the in vivo wound healing effects of a recombinant hemolin from the caterpillar Lonomia obliqua. AB - BACKGROUND: Hemolin proteins are cell adhesion molecules from lepidopterans involved in a wide range of cell interactions concerning their adhesion properties. However, hemolin's roles in cell proliferation and wound healing are not fully elucidated. It has been recently reported that rLosac, a recombinant hemolin from the caterpillar Lonomia obliqua, presents antiapoptotic activity and is capable of improving in vitro wound healing. Therefore, this study aimed to explore rLosac's in vivo effects using a skin wound healing model in rats. METHODS: Circular full-thickness wounds in the rat dorsum skin were treated either with rLosac, or with saline (control), allowing healing by keeping the wounds occluded and moist. During the wound healing, the following tissue regeneration parameters were evaluated: wound closure and collagen content. Furthermore, tissue sections were subjected to histological and immunohistochemical analyses. RESULTS: The rLosac treatment has demonstrated its capacity to improve wound healing, as reflected in findings of a larger number of activated fibroblasts, proliferation of epithelial cells, increase of collagen type 1, and decrease of inflammatory infiltrate. CONCLUSION: The findings have indicated the rLosac protein as a very promising molecule for the development of new wound-healing formulations. PMID- 28031735 TI - Endogenous phospholipase A2 inhibitors in snakes: a brief overview. AB - The blood plasma of numerous snake species naturally comprises endogenous phospholipase A2 inhibitors, which primarily neutralize toxic phospholipases A2 that may eventually reach their circulation. This inhibitor type is generally known as snake blood phospholipase A2 inhibitors (sbPLIs). Most, if not all sbPLIs are oligomeric glycosylated proteins, although the carbohydrate moiety may not be essential for PLA2 inhibition in every case. The presently known sbPLIs belong to one of three structural classes - namely sbalphaPLI, sbbetaPLI or sbgammaPLI - depending on the presence of characteristic C-type lectin-like domains, leucine-rich repeats or three-finger motifs, respectively. Currently, the most numerous inhibitors described in the literature are sbalphaPLIs and sbgammaPLIs, whereas sbbetaPLIs are rare. When the target PLA2 is a Lys49 homolog or an Asp49 myotoxin, the sbPLI is denominated a myotoxin inhibitor protein (MIP). In this brief overview, the most relevant data on sbPLIs will be presented. Representative examples of sbalphaPLIs and sbgammaPLIs from two Old World - Gloydius brevicaudus and Malayopython reticulatus - and two New World - Bothrops alternatus and Crotalus durissus terrificus - snake species will be emphasized. PMID- 28031736 TI - Dosimetric Improvements in Balloon Based Brachytherapy Using the Contura(r) Multi Lumen Balloon (MLB) Catheter to Deliver Accelerated Partial Breast Irradiation. AB - PURPOSE: Preliminary dosimetric findings in patients managed with the Contura(r) Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) on a multi-institutional phase IV registry trial were reviewed. MATERIAL AND METHODS: CT-based 3D planning with dose optimization was performed for all patients. For the study, new ideal dosimetric goals were developed: 1) >= 95% of the prescribed dose (PD) covering >= 90% of the target volume (TV), 2) a maximum skin dose <= 125% of the PD, 3) maximum rib dose <= 145% of the PD, and 4) the V150 <= 50 cc and V200 <= 10 cc. The frequency of concurrently achieving these dosimetric goals using the Contura(r) MLB was investigated. RESULTS: 194 cases were evaluable. Employing the MLB, all ideal dosimetric criteria were achieved in 76% of cases. Evaluating dosimetric criteria separately, 90% and 89% of cases met the new ideal skin and rib dose criteria, respectively. In 96%, ideal TV coverage goals were achieved and in 96%, dose homogeneity criteria (V150 and V200) were met. For skin spacing >= 5-7 mm, the median skin dose was 121% of the PD and when < 5 mm, the median skin dose was 124.4%. For rib distancees < 5 mm, the median rib dose was reduced to 136.4% of the PD. For skin spacing < 7 mm and distance to rib < 5 mm, the median skin and rib doses were concurrently limited to 121% and 142.8% of the PD, respectively. CONCLUSIONS: The Contura(r) MLB catheter provides potential improvements in dosimetric capabilities (i.e., reduced skin and rib doses and improved TV coverage) in many clinical scenarios. PMID- 28031737 TI - HDR and LDR Brachytherapy in the Treatment of Lip Cancer: the Experience of the Catalan Institute of Oncology. AB - PURPOSE: Lip cancer can be treated by surgery, external radiotherapy, and/or brachytherapy (BT). In recent years, BT has become increasingly favored for this type of cancer. The aim of the present study was to analyze local control and survival of patients treated at our institution between July 1989 and June 2008. MATERIAL AND METHODS: We performed a retrospective study of 121 patients (109 males and 12 females) who underwent lip cancer brachytherapy from July 1989 to June 2008. Median age was 67 years and median follow-up was 31.8 months (range 20 188 months). Out of 121 patients, 100 (82.6%) were treated with low dose rate (LDR) BT while the remaining 21 patients (17.4%) received high dose rate (HDR) BT. RESULTS: The most common cell type was squamous cell carcinoma (115 cases; 95%) and most tumors were located on the lower lip (107 patients; 88.4%). Most cases were either stage T1 (62 patients; 51.2%), or T2 (44 cases; 36.4%). After 15 years of follow-up, overall survival was 89.5%, cause-specific survival 97.8%, and disease-free survival 86.6%. Local, regional, and distant control at 15 years were 90%, 92%, and 98.8%, respectively. Grade 3 mucosal toxicity was observed in 23% of patients treated with LDR compared to 33% of HDR patients, and grade 4 mucosal toxicity in 9% versus 0% in the HDR group. CONCLUSIONS: Our findings confirm that brachytherapy is an effective treatment for lip cancer. The results from our series are in line with those published elsewhere. Based on our limited data, HDR appears to be equally as good as LDR, although this needs to be confirmed by further studies. PMID- 28031738 TI - Surgery combined with brachytherapy in patients with retroperitoneal sarcomas. AB - PURPOSE: The primary aim of this work was to analyze feasibility of combined treatment of retroperitoneal sarcomas (RS): surgery (S) and intraoperative brachytherapy (IOBRT). The secondary aim was to analyze results and complications after this treatment. MATERIAL AND METHODS: 84 patients with retroperitoneal sarcomas were qualified for combined treatment (S and IOBRT) between June 1998 and September 2006. 65 of the patients (77.4%) had local recurrences. Sarcomas with intermediate and high grade of histological malignancy (G2, G3 - 76.2%) were the most frequent within the all surgically treated patients. Resection ability (R0/R1) in analyzed group of patients was estimated as 85% (74 cases). After intraoperative evaluation, 57 (67.8%) patients were qualified for IOBRT. Since 2000, in 34 patients (60%) an adjuvant postoperative external beam radiation therapy (EBRT) in dose of 50 Gy was applied. Median follow-up of the surviving patients was 40 months. RESULTS: On the basis of the univariate analysis, relevant aspects negatively influencing overall survival rate within the RS group treated with IOBRT were as follows: surgery of sarcoma recurrence (p = 0.002), higher grade of histological malignancy (p = 0.05), histological type different than liposarcoma (p = 0.05) as well as no adjuvant EBRT (p = 0.05). On the basis of multivariate analysis one can ascertain that relevant factors negatively influencing LRFS in RS patients treated with IOBRT were: surgery due to recurrence of sarcoma (p = 0.008) and lack of EBRT (p = 0.01). CONCLUSIONS: Combined treatment (surgery and brachytherapy) was possible to be carried out on 68% of RS patients. The overall number of complications was quite high, however acceptable, taking into consideration the application of extensive, multi-organ treatments in case of sarcoma recurrences in this localization. The results suggest that the method of treatment will improve the final outcome when most of patients will be qualified for treatment of primary sarcomas in experienced centre. PMID- 28031739 TI - A study on the variation of bladder and rectal doses with respiration in intracavitary brachytherapy for cervix cancer. AB - PURPOSE: In cervical intracavitary brachytherapy, it is mandatory to evaluate if the doses to bladder and rectum are within tolerance limits. In this study, an effort has been made to evaluate the effect of respiration on the doses to bladder and rectum in patients undergoing brachytherapy. MATERIAL AND METHODS: Fifteen patients with cervix cancer treated with concurrent chemoradiation followed by intracavitary brachytherapy were included in this study. At the time of brachytherapy, all patients underwent 4D computed tomography (CT) imaging. Five out of fifteen patients were scanned with empty bladder while the rest had full bladder during sectional imaging. Four sets of pelvic CT image datasets with applicators in place were acquired at equal interval in a complete respiratory cycle. Treatment plans were generated for all the CT datasets on a PlatoTM Sunrise planning system. A dose of 7 Gy was prescribed to Point A. Doses to ICRU (Report No.38) bladder (IBRP) and rectal (IRRP) reference points were calculated in all the CT datasets. RESULTS: The mean of maximum dose to IBRP at four different respiratory phases for full and empty bladder were 53.38 +/- 19.20%, 55.75 +/- 16.71%, 56.13 +/- 17.70%, 57.50 +/- 17.48% and 60.93 +/- 15.18%, 60.29 +/- 16.28%, 60.86 +/- 15.90%, 60.82 +/- 15.42% of the prescribed dose respectively. Similarly, maximum dose to IRRP for full and empty bladder were 55.50 +/- 18.66%, 57.38 +/- 14.81%, 58.00 +/- 14.97%, 58.38 +/- 17.28% and 71.96 +/- 6.90%, 71.58 +/- 7.52%, 68.92 +/- 6.21%, 71.45 +/- 7.16% respectively. CONCLUSIONS: Our study shows that respiration affects the dose distribution to the bladder and rectum in intracavitary brachytherapy of cervix cancer. It is advisable to reduce the critical organ dose to account for the dose variation introduced by respiratory motion. PMID- 28031740 TI - Evaluation of interpolation methods for TG-43 dosimetric parameters based on comparison with Monte Carlo data for high-energy brachytherapy sources. AB - PURPOSE: The aim of this work was to determine dose distributions for high-energy brachytherapy sources at spatial locations not included in the radial dose function gL(r) and 2D anisotropy function F(r,theta) table entries for radial distance r and polar angle theta. The objectives of this study are as follows: 1) to evaluate interpolation methods in order to accurately derive gL(r) and F(r,theta) from the reported data; 2) to determine the minimum number of entries in gL(r) and F(r,theta) that allow reproduction of dose distributions with sufficient accuracy. MATERIAL AND METHODS: Four high-energy photon-emitting brachytherapy sources were studied: 60Co model Co0.A86, 137Cs model CSM-3, 192Ir model Ir2.A85-2, and 169Yb hypothetical model. The mesh used for r was: 0.25, 0.5, 0.75, 1, 1.5, 2-8 (integer steps) and 10 cm. Four different angular steps were evaluated for F(r,theta): 1 degrees , 2 degrees , 5 degrees and 10 degrees . Linear-linear and logarithmic-linear interpolation was evaluated for gL(r). Linear-linear interpolation was used to obtain F(r,theta) with resolution of 0.05 cm and 1 degrees . Results were compared with values obtained from the Monte Carlo (MC) calculations for the four sources with the same grid. RESULTS: Linear interpolation of gL(r) provided differences <= 0.5% compared to MC for all four sources. Bilinear interpolation of F(r,theta) using 1 degrees and 2 degrees angular steps resulted in agreement <= 0.5% with MC for 60Co, 192Ir, and 169Yb, while 137Cs agreement was <= 1.5% for theta < 15 degrees . CONCLUSIONS: The radial mesh studied was adequate for interpolating gL(r) for high-energy brachytherapy sources, and was similar to commonly found examples in the published literature. For F(r,theta) close to the source longitudinal-axis, polar angle step sizes of 1 degrees -2 degrees were sufficient to provide 2% accuracy for all sources. PMID- 28031741 TI - Modified Heyman packing performed with small number of Simon-Norman catheters. AB - PURPOSE: Modified Heyman packing method, performed usually with 6-11 flexible catheters is one out of many brachytherapy treatments. We described the insertion and dose planning method, with the use of 4-6 Simon-Norman catheters positioned to the fundus uteri, which is the most frequent source of the endometrial cancer. MATERIAL AND METHODS: We investigated the dose distribution of the main classes of regular catheter insertions with Simon-Norman applicators using dose profiles, obtained in lateral and axial direction at the fundus, and compared with the dose distribution of the Y-shaped catheter arrangements. RESULTS: The insertions with five and six Simon-Norman catheters produced higher dose at the fundus uteri, compared with the Y-shaped applicator. CONCLUSIONS: Insertions performed with small number of catheters permits to perform dosimetry optimisation for each treatment fraction. PMID- 28031742 TI - 2D to 3D Evaluation of Organs at Risk Doses in Intracavitary Brachytherapy for Cervical Cancer. AB - PURPOSE: To compare International Commission on Radiation Units and Measurements (ICRU) bladder and rectum reference points doses with volumetric doses in 3D intracavitary brachytherapy (ICBT) for cervical cancer. Also to compare bladder, rectum and sigmoid (organs at risk, OARs) volume doses with dose constraints recommended by the (GYN) GEC-ESTRO Working Group. MATERIAL AND METHODS: A retrospective study was carried out on 10 patients with a total of 55 fractions CT-based high dose rate (HDR) ICBT. ICRU bladder (bICRU) and rectum (rICRU) points were defined according to ICRU Report 38 on the CT images and prospectively kept to less than 80% of prescription dose to Point A during real treatment planning. Post-treatment, outer wall of OARs were contoured and minimum dose to 2cc (D2cc) of the most irradiated part of the OARs was obtained from the dose-volume histogram (DVH). Total dose (external beam radiotherapy plus ICBT) were computed with ICRU point dose and D2cc and compared. RESULTS: The mean ICRU point dose and D2cc volume dose were found to be significantly different for bladder (per fraction: p = 0.000; total dose: p = 0.004) but no differences were found for rectum (per fraction: p = 0.055; total dose: p = 0.090). bICRU point dose underestimated D2cc dose with an average ratio of 1.34 +/- 0.34. 3 out of 10 patients, 7 out of 10 patients, and 5 out of 10 patients exceeded the recommended dose constraint for bladder, rectum, and sigmoid, respectively. CONCLUSIONS: bICRU was not representative of bladder D2cc and resulted in different total dose. rICRU was found to be similar to D2cc dose and was reliable in total dose computation. Our current institutional practice of point-based planning in ICBT resulted in significant number of patients' OARs doses exceeded the volume constraint, because the total dose concept was not used propectively in planning. PMID- 28031743 TI - Sexual violence-related pregnancies in eastern Democratic Republic of Congo: a qualitative analysis of access to pregnancy termination services. AB - BACKGROUND: Sexual violence has been prevalent throughout the armed conflict in eastern Democratic Republic of Congo (DRC). Research on sexual violence-related pregnancies (SVRPs) and pregnancy termination in eastern DRC, a context with high prevalence of sexual violence, high maternal mortality, and restrictive abortion laws, is scant but crucial to improving the overall health of women in the DRC. Understanding women's perceptions and experiences related to an SVRP, and in particular to pregnancy termination in this context, is critical for developing effective, targeted programming. METHODS: Respondent-driven sampling (RDS) was used to recruit two subgroups of women reporting SVRPs, 1) women raising a child from an SVRP (parenting group) and 2) women who had terminated an SVRP (termination group), in Bukavu, DRC in 2012. Semi-structured qualitative interviews on pregnancy history and outcomes were conducted with a systematically selected sub-group of women recruited through RDS methodology. Interview responses were translated, transcribed and uploaded to the qualitative data analysis software Dedoose. Thematic content analysis, complemented by the constant comparative technique from grounded theory, was subsequently used as the analytic approach for data analysis. RESULTS: Fifty-five qualitative interviews (38 parenting group and 17 termination group) were completed. The majority of women in the termination group reported using traditional herbs to terminate the SVRP, which they often obtained on their own or through family, friends and traditional healers; whereas women in the parenting group reported ongoing pregnancies after attempting pregnancy termination with herbal medications. Three women in the termination group reported accessing services in a health center. Almost half of the women in the parenting group cited fear of death from termination as a reason for continuing the pregnancy. Other women in the parenting group contemplated pregnancy termination, but did not know where to access services. Potential legal ramifications and religious beliefs also influenced access to services. CONCLUSIONS: Women in this study had limited access to evidence-based safe abortion care and faced potential consequences from unsafe abortion, including increased morbidity and mortality. Increased access to reproductive health services, particularly safe, evidence-based abortion services, is paramount for women with SVRPs in eastern DRC and other conflict affected regions. PMID- 28031744 TI - Self-regulated 1-butanol production in Escherichia coli based on the endogenous fermentative control. AB - BACKGROUND: As a natural fermentation product secreted by Clostridium species, bio-based 1-butanol has attracted great attention for its potential as alternative fuel and chemical feedstock. Feasibility of microbial 1-butanol production has also been demonstrated in various recombinant hosts. RESULTS: In this work, we constructed a self-regulated 1-butanol production system in Escherichia coli by borrowing its endogenous fermentation regulatory elements (FRE) to automatically drive the 1-butanol biosynthetic genes in response to its natural fermentation need. Four different cassette of 5' upstream transcription and translation regulatory regions controlling the expression of the major fermentative genes ldhA, frdABCD, adhE, and ackA were cloned individually to drive the 1-butanol pathway genes distributed among three plasmids, resulting in 64 combinations that were tested for 1-butanol production efficiency. Fermentation of 1-butanol was triggered by anaerobicity in all cases. In the growth-decoupled production screening, only combinations with formate dehydrogenase (Fdh) overexpressed under FRE adhE demonstrated higher titer of 1 butanol anaerobically. In vitro assay revealed that 1-butanol productivity was directly correlated with Fdh activity under such condition. Switching cells to oxygen-limiting condition prior to significant accumulation of biomass appeared to be crucial for the induction of enzyme synthesis and the efficiency of 1 butanol fermentation. With the selection pressure of anaerobic NADH balance, the engineered strain demonstrated stable production of 1-butanol anaerobically without the addition of inducer or antibiotics, reaching a titer of 10 g/L in 24 h and a yield of 0.25 g/g glucose under high-density fermentation. CONCLUSIONS: Here, we successfully engineered a self-regulated 1-butanol fermentation system in E. coli based on the natural regulation of fermentation reactions. This work also demonstrated the effectiveness of selection pressure based on redox balance anaerobically. Results obtained from this study may help enhance the industrial relevance of 1-butanol synthesis using E. coli and solidifies the possibility of strain improvement by directed evolution. PMID- 28031745 TI - RNAi downregulation of three key lignin genes in sugarcane improves glucose release without reduction in sugar production. AB - BACKGROUND: Sugarcane is a subtropical crop that produces large amounts of biomass annually. It is a key agricultural crop in many countries for the production of sugar and other products. Residual bagasse following sucrose extraction is currently underutilized and it has potential as a carbohydrate source for the production of biofuels. As with all lignocellulosic crops, lignin acts as a barrier to accessing the polysaccharides, and as such, is the focus of transgenic efforts. In this study, we used RNAi to individually reduce the expression of three key genes in the lignin biosynthetic pathway in sugarcane. These genes, caffeoyl-CoA O-methyltransferase (CCoAOMT), ferulate 5-hydroxylase (F5H) and caffeic acid O-methyltransferase (COMT), impact lignin content and/or composition. RESULTS: For each RNAi construct, we selected three events for further analysis based on qRT-PCR results. For the CCoAOMT lines, there were no lines with a reduction in lignin content and only one line showed improved glucose release. For F5H, no lines had reduced lignin, but one line had a significant increase in glucose release. For COMT, one line had reduced lignin content, and this line and another released higher levels of glucose during enzymatic hydrolysis. Two of the lines with improved glucose release (F5H-2 and COMT-2) also had reduced S:G ratios. CONCLUSIONS: Along with improvements in bagasse quality for the production of lignocellulosic-based fuels, there was only one line with reduction in juice sucrose extraction, and three lines with significantly improved sucrose production, providing evidence that the alteration of sugarcane for improved lignocellulosic ethanol production can be achieved without negatively impacting sugar production and perhaps even enhancing it. PMID- 28031746 TI - A high complex karyotype involving eleven chromosomes including three novel chromosomal aberrations and monoallelic loss of TP53 in case of follicular lymphoma transformed into B-cell lymphoblastic leukemia. AB - BACKGROUND: Follicular lymphoma (FL) is one of the most common B-cell non Hodgkin's lymphoma (NHL). A subset of FL cases transform into more aggressive malignancies, most often to diffuse large B-cell lymphoma (DLBCL); in addition, lymphoblastic lymphoma and acute lymphoblastic leukemia (ALL) have also been rarely reported. The most common cytogenetic abnormalities associated with FL are translocation t(14;18)(q32;q21) with BCL2 rearrangements, present in 80-90% of all FL. However, that translocation alone is insufficient to cause FL and additional genomic events specifically leading to this kind of disease are still to be determined. The most frequently reported secondary changes are gains of chromosomes 7p or 7q, Xp, 12q and 18q, as well as losses on 6q and mutations within BCL2 and/or BCL6 genes. The presence of additional genomic aberrations, in particular 17p and 6q deletions is more frequent in grade 2 and 3 FL patients and correlated with shorter survival and a higher rate of transformation into DLBCL. CASE PRESENTATION: We describe here, an adult FL grade 2 patient that had transformed to B-ALL at diagnosis. Banding cytogenetics, refined by multi-color fluorescence in situ hybridization including array-proven multicolor banding revealed a unique complex karyotype involving eleven chromosomes, translocation t(X;20)(p21.3;q11.2), translocation t(3;20)(q26.2;q12), and a dicentric dic(17;18). Interestingly, the dicentric chromosome led to monosomy of the tumor suppressor gene TP53. The case had an immunophenotype consistent with follicular center cell lymphoma according to the World Health Organization (WHO) recommendations. CONCLUSIONS: To the best of our knowledge, a comparable adult FL grade 2 case that transformed to B-ALL associated with such a complex karyotype and loss of TP53 was not previously reported. Most of complex aberrations were found simultaneously in approximately 85% of studied malignant cells and the remained cells studied were non-clonal; mechanisms explaining this may be either multiple-step mechanisms or single step in sense of chromothripsis. TRIAL REGISTRATION: Identifying number: 3842. Registered 09 July 2012. PMID- 28031747 TI - The Interaction Network Ontology-supported modeling and mining of complex interactions represented with multiple keywords in biomedical literature. AB - BACKGROUND: The Interaction Network Ontology (INO) logically represents biological interactions, pathways, and networks. INO has been demonstrated to be valuable in providing a set of structured ontological terms and associated keywords to support literature mining of gene-gene interactions from biomedical literature. However, previous work using INO focused on single keyword matching, while many interactions are represented with two or more interaction keywords used in combination. METHODS: This paper reports our extension of INO to include combinatory patterns of two or more literature mining keywords co-existing in one sentence to represent specific INO interaction classes. Such keyword combinations and related INO interaction type information could be automatically obtained via SPARQL queries, formatted in Excel format, and used in an INO-supported SciMiner, an in-house literature mining program. We studied the gene interaction sentences from the commonly used benchmark Learning Logic in Language (LLL) dataset and one internally generated vaccine-related dataset to identify and analyze interaction types containing multiple keywords. Patterns obtained from the dependency parse trees of the sentences were used to identify the interaction keywords that are related to each other and collectively represent an interaction type. RESULTS: The INO ontology currently has 575 terms including 202 terms under the interaction branch. The relations between the INO interaction types and associated keywords are represented using the INO annotation relations: 'has literature mining keywords' and 'has keyword dependency pattern'. The keyword dependency patterns were generated via running the Stanford Parser to obtain dependency relation types. Out of the 107 interactions in the LLL dataset represented with two-keyword interaction types, 86 were identified by using the direct dependency relations. The LLL dataset contained 34 gene regulation interaction types, each of which associated with multiple keywords. A hierarchical display of these 34 interaction types and their ancestor terms in INO resulted in the identification of specific gene-gene interaction patterns from the LLL dataset. The phenomenon of having multi-keyword interaction types was also frequently observed in the vaccine dataset. CONCLUSIONS: By modeling and representing multiple textual keywords for interaction types, the extended INO enabled the identification of complex biological gene-gene interactions represented with multiple keywords. PMID- 28031748 TI - Impacts of resistant starch and wheat bran consumption on enteric inflammation in relation to colonic bacterial community structures and short-chain fatty acid concentrations in mice. AB - BACKGROUND: Identifying the connection among diet, the intestinal microbiome, and host health is currently an area of intensive research, but the potential of dietary fiber (DF) consumption to ameliorate intestinal inflammation has not been extensively studied. We examined the impacts of the DFs, wheat bran (WB) and resistant starch (RS) on host enteric health. A murine model of acute Th1/Th17 colitis (i.e. incited by Citrobacter rodentium) was used. RESULTS: Diets enriched with RS increased weight gain in mice inoculated with C. rodentium compared to mice consuming a conventional control (CN) diet. Short-chain fatty acid (SCFA) quantities in the cecum and distal colon were higher in mice consuming DFs, and these mice exhibited higher butyrate concentrations in the distal colon during inflammation. Histopathologic scores of inflammation in the proximal colon on day 14 post-inoculation (p.i.) (peak infection) and 21 p.i. (late infection) were lower in mice consuming DF-enriched diets compared to the CN diet. Consumption of WB reduced the expression of Th1/Th17 cytokines. As well, the expression of bacterial recognition and response genes such as Relmbeta, RegIIIgamma, and Tlr4 increased in mice consuming the RS-enriched diets. Furthermore, each diet generated a region-specific bacterial community, suggesting a link between selection for specific bacterial communities, SCFA concentrations, and inflammation in the murine colon. CONCLUSIONS: Collectively, data indicated that the consumption of DF-rich diets ameliorates the effects of C. rodentium-induced enteritis by modifying the host microbiota to increase SCFA production, and bacterial recognition and response mechanisms to promote host health. PMID- 28031749 TI - Impact of a 6-month treatment with intragastric balloon on body composition and psychopathological profile in obese individuals with metabolic syndrome. AB - BACKGROUND: The aim of this study was to investigate the effects of a 6-month treatment with intragastric balloon (IGB) on body composition and depressive/anxiety symptoms in obese individuals with metabolic syndrome (MS). METHODS: Fifty patients (aged 18-50 years) with obesity and MS were selected for treatment with IGB for 6 months. Body composition was verified with dual-energy X ray absorptiometry (DXA) at baseline and right after IGB removal. Anxiety/depressive symptoms were assessed with the Beck Depression Inventory (BDI) and the hospital anxiety and depression scale (HADS) at baseline and after 6 months of treatment. RESULTS: In total, 39 patients completed the study. After 6 months, there were significant decreases in weight (11.7 +/- 9.6 kg, p < 0.0001) and waist circumference (9.3 +/- 8.2 cm, p < 0.0001). Weight loss was also demonstrated by DXA and corresponded to decreases of 3.0 +/- 3.4% in body fat percentage, 7.53 +/- 7.62 kg in total body fat, and 3.70 +/- 4.89 kg in lean body mass (p < 0.001 for all comparisons). Depressive symptoms scores decreased by a mean of 4.57 +/- 10.6 points when assessed with the BDI (p = 0.002) and 1.82 +/- 5.16 points when assessed with the HADS-Depression (p = 0.0345). Anxiety symptoms scores decreased by a mean of 1.84 +/- 4.04 points when determined with the HADS-anxiety (p = 0.0066). The decrease in body fat percentage was the parameter that best correlated with improvements in depressive (p = 0.008) and anxiety symptoms (p = 0.014). CONCLUSIONS: In obese individuals with MS, fat mass reduction was associated with short-term improvements in depressive and anxiety symptoms. Trial Registration Registered at ClinicalTrials.gov, NCT01598233. PMID- 28031750 TI - Diabetes self-management education after pre-selection of patients: design of a randomised controlled trial. AB - BACKGROUND: Many self-management programs have been developed so far. Their effectiveness varies. The program 'Beyond Good Intentions' (BGI) is based on proactive coping and has proven to be (cost-) effective in achieving reductions in BMI and blood pressure in screen-detected type 2 diabetes patients up until nine months follow-up. However, its long-term effectiveness in people already known with diabetes is lacking. In addition, its (cost-) effectiveness might increase if people who are likely not to be benefit from the program are excluded in a valid way. Therefore it was aimed to investigate the long-term effects of the educational program BGI on cardiovascular risk, quality of life and diabetes self-management behaviour in a pre-selected group of patients known with type 2 diabetes up to 5 years. METHODS: Randomised controlled trial with 2.5 year follow up. Adults (<=75 years) with a type 2 diabetes duration between 3 months and 5 years will be included. With the use of a self-management screening tool (SeMaS) their potential barriers of self-management due to depression and/or anxiety will be determined. Based on the results of the SeMaS selection patients will be randomised (1:1) to the BGI-group (n = 53) or the control-group (n = 53). In addition to receiving usual care, patients in the BGI-group will follow the 12 week theory-based self-management program and a booster session a few months thereafter. The control-group will receive care as usual. The primary outcome is change in Body Mass Index after 2.5 years follow-up. Secondary outcomes are HbA1c, lipid profile and systolic blood pressure, (diabetes) quality of life, level of physical activity, dietary intake and medication adherence and proactive coping. Cost-effectiveness will be based on total use of health care resources during the entire study period. Difference between groups in change over time will be analysed according to intention-to-treat analysis. CONCLUSIONS: By differentiating between patients who will and those who are likely not to benefit from the educational program, a more (cost-) effective self-management program might be designed, also on the long-run. Trial registration NTR 5330. PMID- 28031752 TI - Postural Preparation to Stepping: Coupled Center of Pressure Shifts in the Anterior-Posterior and Medio-Lateral Directions. AB - We explored changes in the postural preparation to stepping introduced by modifications of the initial coordinates of the center of pressure (COP). We hypothesized that the postural adjustments in the anterior-posterior direction would persist across all initial COP manipulations while the adjustments in the medio-lateral direction would be highly sensitive to the initial COP coordinate. Healthy subjects stood on a force plate, shifted the body weight to one of the initial conditions that spanned the range of COP coordinates in both directions, and initiated a single step or started to walk. No major changes were observed between the stepping and walking conditions. Changes in the initial COP coordinate in the medio-lateral direction led to scaling of the magnitude of the COP shift in that direction prior to stepping accompanied by a nearly proportional change in the COP shift in the anterior-posterior direction. Changes in the initial COP coordinate in the anterior-posterior direction led to scaling of the magnitude of the COP shift in that direction prior to stepping without consistent changes in the COP shift in the medio-lateral direction. We interpret the results as reflecting a neural organization using a small set of referent body configurations for the postural adjustments. PMID- 28031751 TI - Tocotrienols induce endoplasmic reticulum stress and apoptosis in cervical cancer cells. AB - BACKGROUND: We have previously reported that gamma- and delta-tocotrienols (gamma and delta-T3) induce gene expression and apoptosis in human breast cancer cells (MDA-MB-231 and MCF-7). This effect is mediated, at least in part, by a specific binding and activation of the estrogen receptor-beta (ERbeta). Transcriptomic data obtained within our previous studies, interrogated by different bioinformatic tools, suggested the existence of an alternative pathway, activated by specific T3 forms and leading to apoptosis, also in tumor cells not expressing ER. In order to confirm this hypothesis, we conducted a study in HeLa cells, a line of human cervical cancer cells void of any canonical ER form. RESULTS: Cells were synchronized by starvation and treated either with a T3-rich fraction from palm oil (10-20 MUg/ml) or with purified alpha-, gamma-, and delta-T3 (5-20 MUg/ml). alpha-tocopherol (TOC) was utilized as a negative control. Apoptosis, accompanied by a significant expression of caspase 8, caspase 10, and caspase 12 was observed at 12 h from treatments. The interrogation of data obtained from transcriptomic platforms (NuGO Affymetrix Human Genechip NuGO_Hs1a520180), further confirmed by RT-PCR, suggested that the administration of gamma- and delta-T3 associates with Ca2+ release. Data interrogation were confirmed in living cells; in fact, Ca-dependent signals were observed followed by the expression and activation of IRE-1alpha and of other molecules involved in the unfolded protein response, the core pathway coping with endoplasmic reticulum stress in eukaryotic cells, finally leading to apoptosis. CONCLUSIONS: Our study demonstrates that gamma- and delta-T3 induce apoptosis also in tumor cells lacking of ERbeta by triggering signals originating from endoplasmic reticulum stress. Our observations suggest that tocotrienols could have a significant role in tumor cell physiology and a possible therapeutic potential. PMID- 28031753 TI - Accuracy of a 10 Hz GPS Unit in Measuring Shuttle Velocity Performed at Different Speeds and Distances (5 - 20 M). AB - The aim of this study was to validate the accuracy of a 10 Hz GPS device (STATSports, Ireland) by comparing the instantaneous values of velocity determined with this device with those determined by kinematic (video) analysis (25 Hz). Ten male soccer players were required to perform shuttle runs (with 180 degrees change of direction) at three velocities (slow: 2.2 m.s-1; moderate: 3.2 m.s-1; high: maximal) over four distances: 5, 10, 15 and 20 m. The experiments were video-recorded; the "point by point" values of speed recorded by the GPS device were manually downloaded and analysed in the same way as the "frame by frame" values of horizontal speed as obtained by video analysis. The obtained results indicated that shuttle distance was smaller in GPS than video analysis (p < 0.01). Shuttle velocity (shuttle distance/shuttle time) was thus smaller in GPS than in video analysis (p < 0.001); the percentage difference (bias, %) in shuttle velocity between methods was found to decrease with the distance covered (5 m: 9 +/- 6%; 20 m: 3 +/- 3%). The instantaneous values of speed were averaged; from these data and from data of shuttle time, the distance covered was recalculated; the error (criterion distance-recalculated distance) was negligible for video data (0.04 +/- 0.28 m) whereas GPS data underestimated criterion distance (0.31 +/- 0.55 m). In conclusion, the inaccuracy of this GPS unit in determining shuttle speed can be attributed to inaccuracy in determining the shuttle distance. PMID- 28031754 TI - Assessing Reactive Strength Measures in Jumping and Hopping Using the OptojumpTM System. AB - The aim of this study was to assess the concurrent validity of the OptojumpTM system (Microgate, Bolzano, Italy) versus a force platform in the estimation of temporal and reactive strength measures. In two separate investigations, twenty physically active males performed double-leg and single-leg drop jumps from a box height of 0.3 m and a 10 s vertical bilateral hopping test. Contact time, flight time and total time (the sum of contact and flight time) were concurrently assessed during single and double-leg drop jumps and during hopping. Jump height, the reactive strength index and the reactive strength ratio were also calculated from contact time and flight time. Despite intraclass correlation coefficients (ICCs) for all variables being close to 1 (ICC > 0.975), a significant overestimation was found in contact time (0.005 +/- 0.002 s) and underestimations in flight time (0.005 +/- 0.003 s), the reactive strength index (0.04 +/- 0.02 m.s-1) and the reactive strength ratio (0.07 +/- 0.04). Overestimations in contact time and underestimations in flight time were attributed to the physical design of the OptojumpTM system as the transmitter and receiver units were positioned 0.003 m above the floor level. The OptojumpTM demonstrated excellent overall temporal validity with no differences found between systems for total time. Coaches are advised to be consistent with the instrumentation used to assess athletes, however, in the case of comparison between reactive strength values collected with the OptojumpTM and values collected with a force platform, regression equations are provided. PMID- 28031755 TI - Performance Effects of Repetition Specific Gluteal Activation Protocols on Acceleration in Male Rugby Union Players. AB - Warm-up protocols have the potential to cause an acute enhancement of dynamic sprinting performance. The purpose of this study was to evaluate the effects of three repetition specific gluteal activation warm-up protocols on acceleration performance in male rugby union players. Forty male academy rugby union players were randomly assigned to one of 4 groups (control, 5, 10 or 15 repetition gluteal activation group) and performed 10 m sprints at baseline and 30 s, 2, 4, 6 and 8 min after their specific intervention protocol. Five and ten meter sprint times were the dependent variable and dual-beam timing gates were used to record all sprint times. Repeated measures analysis of variance found no significant improvement in 5 and 10 m sprint times between baseline and post warm-up scores (p >= 0.05) for all groups. There were no reported significant differences between groups at any of the rest interval time points (p >= 0.05). However, when individual responses to the warm-up protocols were analyzed, the 15 repetition gluteal activation group had faster 10 m times post-intervention and this improvement was significant (p = 0.021). These results would indicate that there is no specific rest interval for any of the gluteal interventions that results in a potentiation effect on acceleration performance. However, the individual response analysis would seem to indicate that a 15 repetition gluteal activation warm-up protocol has a potentiating effect on acceleration performance provided that the rest interval is adequately and individually determined. PMID- 28031756 TI - Does the MTHFR A1298C Polymorphism Modulate the Cardiorespiratory Response to Training? AB - The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphic variant is a candidate to explain the individual differences in trainability and response to exercise training. Therefore, the aim of the study was to verify whether the A1298C polymorphism influenced the aerobic and anaerobic performance as well as body and mass composition in young Polish women following low-high impact aerobic exercise training. Two hundred and one women aged 21 +/- 1 years (range 19-24) were included in the study. All of them completed a 12-week exercise training program and were measured for selected somatic features, aerobic capacity and cardiorespiratory fitness indices as well as peak anaerobic power and anaerobic capacity, before and after the intervention. A mixed 2 x 2 ANOVA for 20 dependent variables grouped in three categories was conducted. No significant interaction of the genotype with training for body mass and body composition variables was observed. Although, there were three significant genotype x training interactions for maximal oxygen uptake variables, regardless of body mass i.e.: for VO2max (p < 0.05), HRmax (p < 0.0001) and HRAT/HRmax (p < 0.0001). Significantly greater improvement in VO2max was gained by the CC+AC group compared to the AA genotype group. The present results support the hypothesis that individual differences in trainability are at least in part determined by the genetic component and MTHFR A1298C seems to be one of the many polymorphisms involved. PMID- 28031757 TI - Leukocyte Populations are Associated with Heart Rate Variability After a Triathlon. AB - The purpose of this study was to analyze cellular immune components and their association with heart rate variability in triathlon athletes. Twelve athletes were included (age 36.41 +/- 5.57 years, body mass 81.84 +/- 10.97 kg) and blood samples were taken one week before, immediately, at 2 and 48 hours, and one week after competition. Total lymphocytes and their subpopulations, neutrophils, basophils, eosinophils and monocytes were analyzed. At the same time, heart rate variability was recorded for 30 minutes using Polar Team2(r). A significant difference between lymphocyte subpopulations and heart rate variability was found in the different study periods. A positive correlation was found between total lymphocytes and rMSSD (r = .736, p <0.05), CD3+ and rMSSD (r = .785, p <0.05), and CD4+ and rMSSD (r = .795, p < 0.05) at the end of the competition. After one week of competition, a negative correlation was found between eosinophils and MRR, SDNN, pNN50, and rMSSD (p <0.01); and basophils and MRR, SDNN, pNN50, and rMSSD (p <0.01); while a positive correlation was found between CD19+ (B cells) and pNN50 (r = .678, p <0.05). Our results suggest that it is possible to predict the effect of training with regard to the athlete's performance. PMID- 28031758 TI - Somatic, Endurance Performance and Heart Rate Variability Profiles of Professional Soccer Players Grouped According to Age. AB - This cross-sectional study compared somatic, endurance performance determinants and heart rate variability (HRV) profiles of professional soccer players divided into different age groups: GI (17-19.9 years; n = 23), GII (20-24.9 years; n = 45), GIII (25-29.9 years; n = 30), and GIV (30-39 years; n = 26). Players underwent somatic and HRV assessment and maximal exercise testing. HRV was analyzed by spectral analysis of HRV, and high (HF) and low (LF) frequency power was transformed by a natural logarithm (Ln). Players in GIV (83 +/- 7 kg) were heavier (p < 0.05) compared to both GI (73 +/- 6 kg), and GII (78 +/- 6 kg). Significantly lower maximal oxygen uptake (VO2max, ml*kg-1*min-1) was observed for GIV (56.6 +/- 3.8) compared to GI (59.6 +/- 3.9), GII (59.4 +/- 4.2) and GIV (59.7 +/- 4.1). All agegroups, except for GII, demonstrated comparable relative maximal power output (Pmax). For supine HRV, significantly lower Ln HF (ms2) was identified in both GIII (7.1 +/- 0.8) and GIV (6.9 +/- 1.0) compared to GI (7.9 +/- 0.6) and GII (7.7 +/- 0.9). In conclusion, soccer players aged >25 years showed negligible differences in Pmax unlike the age group differences demonstrated in VO2max. A shift towards relative sympathetic dominance, particularly due to reduced vagal activity, was apparent after approximately 8 years of competing at the professional level. PMID- 28031759 TI - Evaluation of the Effects of Neuromuscular Electrical Stimulation of The Lower Limbs Combined with Pulmonary Rehabilitation on Exercise Tolerance in Patients with Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a systemic disease with multiple extrapulmonary manifestations including impeded skeletal muscle function, leading to decreased muscular strength and endurance in patients with COPD. Pulmonary rehabilitation eases the symptoms of the condition and produces increased muscular endurance. Neuromuscular electrical stimulation (NMES) may serve as a treatment alternative to traditional pulmonary rehabilitation. The aim of the study was to assess the effects of NMES combined with pulmonary rehabilitation on exercise tolerance in patients in comparison with pulmonary rehabilitation alone. The subjects included 30 patients with COPD randomly assigned to one of the two groups. The first group consisted of 15 patients who were treated with neuromuscular electrical stimulation at frequency of 35Hz and pulmonary rehabilitation (NMES+RP). The second group comprised 15 patients treated with pulmonary rehabilitation only (RP). Pre- and poststudy assessments were performed. The retrospective evaluation including an exercise tolerance test (i.e. six minute walk test (6MWT)), spirometry and blood gasometry was carried out after 3 weeks. Twenty-eight patients in total completed the study. In the NMES+RP group, an increase in exercise tolerance manifested by a longer distance walked in the 6MWT was observed in comparison to the pulmonary rehabilitation group. No effects of NMES combined with pulmonary rehabilitation on selected spirometric and gasometric parameters in patients with COPD were observed in comparison with traditional pulmonary rehabilitation. The acquired results suggest that NMES of the lower limbs may be applied as an additional form of pulmonary rehabilitation in patients with COPD. PMID- 28031760 TI - The Effect of Specific Sling Exercises on the Functional Movement Screen Score in Adolescent Volleyball Players: A Preliminary Study. AB - The existing data indicate that the result of the Functional Movement Screen (FMS) test influences the likelihood of subsequent injury in professional athletes. Therefore, exercises increasing test scores of the FMS may be useful at various stages of sports activity. This study evaluated the effects of the NEURAC sling exercises method on the FMS test score in teenage volleyball players. The study was conducted on 15 volleyball players aged 14 years. The FMS test was performed three times interspersed with a two-month interval. Between the first and the second assessment, neither additional treatment nor training was applied, while between the second and the third assessment, the participants performed stabilisation exercises based on the NEURAC method. Training was carried out twice a week, for eight weeks. The analysis showed that between the first and the second measurement, no significant differences occurred. The use of specific sling exercises caused a significant improvement in FMS results (p <= 0.01) between the first and the third, as well as the second and the third measurement. The applied stabilisation exercises based on the NEURAC method positively influenced the FMS test result in male subjects practicing volleyball. Performance of such exercises also resulted in more than 90% of the subjects having a total FMS test score >= 17, which may be important in the prevention of injuries. The preliminary results indicate that this type of exercise should be included in a teenage volleyball training routine. PMID- 28031761 TI - Physiological Responses During the Time Limit at 100% of the Peak Velocity in the Carminatti's Test in Futsal Players. AB - The aim of this study was to investigate the physiological responses during the time limit at the intensity of the peak velocity of the Carminatti's test (T CAR). Ten professional futsal players (age, 27.4 +/- 5.8 years, body mass, 78.8 +/- 8.5 kg, body height, 175.8 +/- 6.8 cm, body fat mass, 14.1 +/- 2.6%) took part in the study. The players performed three tests, with an interval of at least 48 hours, as follows: the T-CAR to determine the peak velocity and the maximal heart rate; an incremental treadmill protocol to determine the maximal physiological responses; and a time limit running test at the peak velocity reached in the T-CAR. During the last two tests, a portable gas analyzer was used for direct measurement of cardiorespiratory variables. It was shown that the peak velocity was not significantly different from the maximal aerobic speed achieved in the laboratory (p = 0.213). All athletes reached their maximum oxygen uptake during the time limit test. The maximum oxygen uptake achieved during the time limit test was not different from that observed in the laboratory condition (51.1 +/- 4.7 vs. 49.6 +/- 4.7 ml.kg-1.min-1, respectively, p = 0.100). In addition, Bland and Altman plots evidenced acceptable agreement between them. On average, athletes took ~140 s to achieve maximum oxygen uptake and maintained it for ~180 s. Therefore, the peak velocity intensity can be used as an indicator of maximal aerobic power of futsal athletes and the time limit can be used as a reference for training prescription. PMID- 28031763 TI - Evolution of Determinant Factors of Repeated Sprint Ability. AB - The aim of this study was to investigate the changes in the relationships between repeated sprint ability (RSA) and anthropometric measures as well as fitness qualities in soccer players. Twenty-one professional soccer players performed several anthropometric and physical tests including countermovement vertical jumps (CMJs), a straight-line 30 m sprint (T30), an RSA test (6 x 20 + 20 m with 20 s recovery), a progressive isoinertial loading test in a full squat, a Yo-Yo Intermittent Recovery Test Level-1 (YYIRT-1) and a 20 m shuttle run test (20mSRT). The mean (RSAmean), the fastest (RSAbest), each single sprint time, and the percentage in a sprint decrease (%Dec) in the RSA test were calculated. RSAbest correlated significantly with RSAmean (r = .82) and with all single sprints (p < 0.05), showing a downward trend as the number of sprints performed increased. No significant relationship was observed between the %Dec and RSA performance. CMJs and the T30 also showed a correlation with RSA performance, whereas lower limb strength did not show any relationship with RSA performance. RSAmean showed significant (p < 0.05) relationships with body mass (r = .44), adiposity (r = .59) and the YYIRT-1 (r = -.62), increasing as the number of repeated sprints increased. The 20mSRT showed minimal relationships with RSA performance. In conclusion, maximal sprint capacity seems to be relevant for the RSA performance, mainly in the first sprints. However, high intermittent endurance capacity and low adiposity might help enhance the RSA performance when increasing the number of repeated sprints. PMID- 28031762 TI - Effects of Fatigue on Throwing Performance in Experienced Team Handball Players. AB - The purpose of this study was to investigate the effect of central and peripheral physiological fatigue on throwing accuracy and ball release velocity in team handball. Twenty male subjects (age 24.7 +/- 3.9 yrs, body mass 88.5 +/- 5.0 kg, body height 1.86 +/- 0.05 m, training experience 12.7 +/- 3.8 yrs) from one handball team participated in this study. The participants completed four sets of eight laps of a circuit that consisted of specific team handball drills/exercises, with decreasing recovery times between the laps in each set in order to induce physiological fatigue. Duration of the recovery intervals determined the description of the effort made in each set: "light" (80 s recovery between laps), "moderate" (40 s), "hard" (20 s) and "very hard" (10 s). A heart rate, concentration of lactate in blood and the rate of perceived exertion (RPE) were recorded. Ball velocity and accuracy were measured after each set and they both decreased during a fatigue protocol. However, accuracy only decreased significantly in the end of the protocol, while ball release was already affected after the first round of the protocol. The results substantiate the initial hypothesis and confirm that both throwing accuracy and ball release velocity decrease significantly as physiological fatigue increases. These variables began to decrease when the fatigue quantification values were high or very high. The findings can be used by coaches to develop training programs to teach players how to identify fatigue thresholds and combat the effects of fatigue through decision making skills at critical game moments. PMID- 28031764 TI - The Effects of Modifying the Distance of the Penalty Shot in Water Polo. AB - The aim of this study was to determine the effects of changing the distance of the penalty shot in water polo from 4 to 5 m. While a shorter distance made the penalty shot more effective, it also reduced the use of this sanction. A total of 192 matches played in the 2003 and 2007 Water Polo World Championships were recorded. The sample included 278 penalty shots in both tournaments. Notational analysis using a longitudinal correlational and descriptive design was employed to determine whether a longer distance increased the number of sanctioned penalties (81 vs 197) and caused a non-significant decrease in scoring efficiency (7.4%) with significant differences in the relationship between the area and the type of a shot, with less centre and power shots (14.8% vs 7.1%) observed and predominance of bounce shots to the right of the goal posts. The rule change prompted more penalties, produced changes in shot direction as well as the type of a shot, and yielded a decrement of 7.4% in scoring efficiency. PMID- 28031765 TI - Physical Performance During Water-Polo Matches: The Effect of the Players' Competitive Level. AB - The purpose of the study was to compare playing intensity and performance changes within a water-polo match in players of different competitive levels. High-level (n = 7) and lower-level (n = 7) players performed a progressively increasing speed test of 5 x 200 m swimming and speed corresponding to lactate concentration of 4.0, 5.0 and 10.0 mmol*l-1 was calculated. Repeated sprint ability (8 x 20 m) was tested at pre-, the middle and post-match and a 400 m swimming test was completed at pre and post in five water-polo matches. A t-test and a two-way ANOVA were used for statistical analysis. High-level compared to lower-level players presented higher speed corresponding to lactate concentration of 4.0 and 5.0 mmol*l-1 (p < 0.05). Regardless of the sports level, the mean heart rate was reduced towards the end of the match. High-level players completed a shorter amount of match time with the heart rate lower than 85% of the peak heart rate (p < 0.05). However, when the speed corresponding to lactate concentration of 4.0 mmol*l-1 was used as a covariate, no differences were observed in the heart rate between groups. Both groups decreased repeated sprint and 400 m performance at post- compared to pre-match by 7 +/- 3% and 7 +/- 4%, respectively. High-level compared to lower-level players showed better performance in repeated sprints at the middle (p < 0.01) and in pre-, post-match 400 m tests (p < 0.01). It was concluded that high-level compared to lower-level players completed the match at a higher playing intensity and presented a lower performance decrement across the match as a result of their higher aerobic endurance. PMID- 28031766 TI - Performance Assessment in Water Polo Using Compositional Data Analysis. AB - The aim of the present study was to identify groups of offensive performance indicators which best discriminated between a match score (favourable, balanced or unfavourable) in water polo. The sample comprised 88 regular season games (2011-2014) from the Spanish Professional Water Polo League. The offensive performance indicators were clustered in five groups: Attacks in relation to the different playing situations; Shots in relation to the different playing situations; Attacks outcome; Origin of shots; Technical execution of shots. The variables of each group had a constant sum which equalled 100%. The data were compositional data, therefore the variables were changed by means of the additive log-ratio (alr) transformation. Multivariate discriminant analyses to compare the match scores were calculated using the transformed variables. With regard to the percentage of right classification, the results showed the group that discriminated the most between the match scores was "Attacks outcome" (60.4% for the original sample and 52.2% for cross-validation). The performance indicators that discriminated the most between the match scores in games with penalties were goals (structure coefficient (SC) = .761), counterattack shots (SC = .541) and counterattacks (SC = .481). In matches without penalties, goals were the primary discriminating factor (SC = .576). This approach provides a new tool to compare the importance of the offensive performance groups and their effect on the match score discrimination. PMID- 28031768 TI - Optimization of Game Formats in U-10 Soccer Using Logistic Regression Analysis. AB - Small-sided games provide young soccer players with better opportunities to develop their skills and progress as individual and team players. There is, however, little evidence on the effectiveness of different game formats in different age groups, and furthermore, these formats can vary between and even within countries. The Royal Spanish Soccer Association replaced the traditional grassroots 7-a-side format (F-7) with the 8-a-side format (F-8) in the 2011-12 season and the country's regional federations gradually followed suit. The aim of this observational methodology study was to investigate which of these formats best suited the learning needs of U-10 players transitioning from 5-aside futsal. We built a multiple logistic regression model to predict the success of offensive moves depending on the game format and the area of the pitch in which the move was initiated. Success was defined as a shot at the goal. We also built two simple logistic regression models to evaluate how the game format influenced the acquisition of technicaltactical skills. It was found that the probability of a shot at the goal was higher in F-7 than in F-8 for moves initiated in the Creation Sector-Own Half (0.08 vs 0.07) and the Creation Sector-Opponent's Half (0.18 vs 0.16). The probability was the same (0.04) in the Safety Sector. Children also had more opportunities to control the ball and pass or take a shot in the F-7 format (0.24 vs 0.20), and these were also more likely to be successful in this format (0.28 vs 0.19). PMID- 28031767 TI - Mechanical Differences between Barbell and Body Optimum Power Loads in the Jump Squat Exercise. AB - This study compared the values of bar-peak force (PFBar) and power (PPBar), body peak force (PFBody) and power (PPBody) and bar-mean propulsive power (MPPBar) in different jump-squat (JS) conditions: unloaded condition (UC); bar-loaded condition (BLC) and optimum bar-MPP condition (OBC). Twenty-five soccer players performed the JS using a bar with negligible mass (UC), using the Smith-machine bar (BLC) and using the load capable of maximizing the bar-MPP (OBC). The PFBody was significantly higher in the UC (2847.9 +/- 489.1 N) than in the OBC (2655.4 +/- 444.3 N). The UC presented greater PPBody (3775.9 +/- 631.5 W) than the BLC (3359.7 +/- 664.3 W) and OBC (3357.8 +/- 625.3 W). The OBC presented higher values of PFBar, PPBar and MPPBar (676.2 +/- 109.4 W) than the BLC (MPPBar = 425.8 +/- 53.7 W) (all p < 0.05). In the OBC (compared to the UC), the body peak power presented a reduction of ~ 11%, while generating bar-power output from ~ 59 to 73% higher than the BLC. While the fact that the body-peak power is maximized in the UC denotes a mechanical phenomenon, the bar-optimum load represents an intensity at which both components of the power equation (force and velocity) are optimized. This has important implications for sports training. PMID- 28031769 TI - Quality Perception of the 2012 World Indoor Athletics Championships. AB - The objective of this study was to compare the views of spectators concerning the quality perception of the World Indoor Athletics Championships. The study group consisted of 568 spectators who watched the events. A measurement scale of event quality in spectator sports (SEQSS) developed by Ko et al. (2011) was used as a data collection tool in the study. In order to determine the views of the spectators concerning the quality of the Indoor Athletics Championships, the dimensions constituting the scale were compared according to the demographic features of the sample group. As a consequence, important differences in most of the dimensions of the scale were revealed with respect to the demographic data of the subjects. The most relevant finding of the study is that the dimension of "physical environment quality", which is one of the dimensions constituting the event quality, differed significantly in all comparisons that were made according to demographic features. PMID- 28031770 TI - Soccer Players Cultural Capital and Its Impact on Migration. AB - The purpose of this study was to identify factors that constituted the cultural capital among soccer players. We assumed that in the increasingly globalized world of professional soccer, a player's success would often depend on migrating and adjusting to life in other countries. Willingness to migrate and successful adjustment are tied to player's previous attitudes and/or behaviours (habitus), significant support from others, including family members, and previous experiences and success in sports and education. Our hypothesised model of the cultural capital was based on the Pierre Bourdieu's theoretical framework. It consisted of 26 variables related to three sets of factors: soccer experiences, a family context and support, and educational achievements of the players and their parents. The model was tested using a sample of 79 current soccer coaches who also had been players at the elite level. A factor analysis was used to empirically verify the content of the hypothetical model of the soccer players' cultural capital. Nine latent factors were extracted and together, they accounted for 55.01% of the total model variance. Individual factors obtained showed a sufficient level of substantial connection. The Cronbach's alpha value of 0.77 confirmed the internal consistency of the operationalised variables in the hypothetical model. In addition, the impact of these aforementioned life dimensions on the migration of soccer players was studied. The results of the binary logistic regression analysis showed that the first factor of the hypothetical model (F1) had 2.2 times and the second factor (F8) had 3.9 times higher odds for migration abroad. Sociocultural findings using this new assessment approach could help create better "success conditions" in the talent development of young players.